PMID- 10330891
TI  - [Hygiene instruction--the basis of a healthy life style].

PMID- 10330892
TI  - [The management of medical care quality--the basis for reforming the treatment
      and diagnosis process].

PMID- 10330893
TI  - [The causes of death among the wounded during the conduct of combat operations in
      populated areas (on the 10th anniversary of the withdrawal of Soviet troops from
      Afghanistan)].

PMID- 10330894
TI  - [Complications during the treatment of victims with kidney wounds and injuries].
AB  - An analysis of treatment outcome in 141 patients with kidney traumas and 75
      kidney open wounds. Conclusions and recommendations on conservative and
      operational treatment.

PMID- 10330895
TI  - [The diagnosis and treatment of spontaneous pneumothorax].

PMID- 10330896
TI  - [Triderm in the treatment of atopic dermatitis].

PMID- 10330897
TI  - [Functional study of the visual system in the cosmonaut by color campimetry].
AB  - An investigation of series of experiments on the visual system dynamics carried
      out by cosmonaut-researcher Iurii Mikhailovich Baturin [correction of Yuri M.
      Batourin] in the piloted complex "Mir" in August 1998. The implementation of the
      method of the visual system investigation with the use of the luminance
      sensitivity thresholds to the stimuli of distinguished spectral components in
      different points of the visual field helps to clarify some negative dynamics of
      the visual system functional conditions reflected in the luminance sensitivity
      thresholds.

PMID- 10330898
TI  - [Specialized kits for delivering emergency medical care at chemical weapons
      disposal sites].

PMID- 10330899
TI  - [The hemodynamics and physical work capacity of divers after prolonged deep-water
      immersions].

PMID- 10330900
TI  - [Pavel Grigor'evich Stolypin (on the centenary of his birth)].

PMID- 10330901
TI  - Genetic screening with FENs.

PMID- 10330902
TI  - Sharp DNA bends as landmarks of protein-binding sites on straightened DNA.
AB  - We have developed a fluorescence-based method for mapping single or multiple
      protein-binding sites on straightened, large-size DNA molecules (> 5 kbp). In the
      described method, protein-DNA complexes were straightened and immobilized on a
      flat surface using surface tension. A fraction of the immobilized complexes
      displayed a sharp DNA bend with two DNA segments extending from the apex. The
      presence of DNA-binding proteins at the apex was verified by atomic force
      microscopy. The position of protein binding relative to the ends of the DNA
      molecule was determined by measuring the length of two DNA segments using
      fluorescence microscopy. We demonstrate the potential of the fluorescence-based
      method to localize protein-binding sites on the DNA template and to evaluate
      relative binding affinity. The proposed protein-binding-site mapping technique is
      simple and easy to perform. Practical applications include screening for DNA
      binding proteins and the localization of protein-binding sites on large segments
      of DNA.

PMID- 10330903
TI  - Separation of double- and single-stranded DNA restriction fragments: capillary
      electrophoresis with polymer solutions under alkaline conditions.
AB  - Capillary electrophoresis in buffers containing hydroxyethyl cellulose (HEC) was
      used to separate double- and single-stranded DNA restriction fragments under
      neutral and alkaline conditions in epoxy-coated capillaries. It was found that
      better resolution was achieved using highly entangled HEC solutions for a narrow
      range of DNA fragment sizes, while lower resolution was obtained over a wide
      separation range using diluted HEC solutions. Optimal resolution of these DNA
      fragments was obtained using buffers containing 0.5% HEC at pH 11 with plate
      numbers exceeding 3 x 10(6) plates/m. It was also found that the diffusion
      coefficients and electrophoretic mobilities of DNA fragments decreased with
      increasing pH. This may indicate a more extended DNA conformation and, therefore,
      enhancement of transient entanglement coupling between DNA and HEC polymers under
      alkaline condition. At pH 12, ss-DNA were well separated in entangled HEC
      solutions; however, the resolution of ss-DNA was significantly decreased in
      diluted polymer solution.

PMID- 10330904
TI  - Preservation of NADH voltammetry for enzyme-modified electrodes based on
      dehydrogenase.
AB  - Minimizing overpotential and generating high faradaic currents are critical
      issues for fast-scan voltammetry of beta-nicotinamide adenine dinucleotide (NADH)
      for the sensitivity of enzyme-modified electrodes based on dehydrogenases.
      Although NADH voltammetry exhibits high overpotential and poor voltammetric peak
      shape at solid electrode surfaces, modification of the electrode surface can
      improve the electrochemical response at carbon fibers. However, these
      improvements are severely degraded upon the covalent attachment of enzyme. The
      creation of improved electron-transfer properties and the retention of these
      properties throughout the enzyme attachment process is the focus of this study. A
      novel polishing and electrochemical pretreatment method was developed which
      generated a decreased overpotential and a high faradaic current at carbon-fiber
      electrodes for NADH. Factors that lead to a degradation of voltammetric response
      during the enzyme fabrication were investigated, and both the aging and the
      covalent modification of the pretreated surface contributed to this degradation.
      Attachment processes that minimized the preparation time, in turn, maximized the
      retention of the facile electron-transfer properties. These attachment processes
      included varying the surface attachment reactions for the enzyme. Preparation
      time reduction techniques included modeling existing techniques and then
      improving kinetic and mass transport issues where possible. Alternate covalent
      attachment methods included a direct electrochemical amine reaction and an
      electrochemically reductive hydrazide reaction. The surface attachment and
      retention of electron-transfer properties of these probes were confirmed by
      fluorescence and electrochemical studies.

PMID- 10330905
TI  - Use of evolutionary factor analysis in the spectroelectrochemistry of Escherichia
      coli sulfite reductase hemoprotein and a Mo/Fe/S cluster.
AB  - The deconvolution of spectroelectrochemical data is often quite difficult if the
      spectra of intermediates are not known. Factor analysis, however, has been shown
      to be a powerful technique which can make it possible to deconvolute overlapping
      spectra. In this work, evolving factor analysis will be used to determine the
      number of intermediates and the spectra of those species for two typical
      spectroelectrochemical experiments: linear scan voltammetry and
      chronoabsorptometry in a thin-layer cell. The first system was the reduction of
      E. coli sulfite reductase hemoprotein (SiR-HP). Principal factor analysis
      indicated that three species were present. By using evolving factor analysis, the
      potential regions where each of the species were present were identified, and
      their concentrations and spectra were determined by the use of the mass balance
      equation. The spectra of the one-electron (SiR-HP1-) and two-electron (SiR-HP2-)
      reduced product were compared with previous work. The second experiment was the
      chronoabsorptometry of Cl2FeS2MoS2FeCl2(2-) in methylene chloride. This
      experiment indicated that five species were present during the experiment. The
      entire set of 61 spectra were fit by assuming that there were 4 species present
      during the electrolysis. The rate constant for the appearance of subsequent
      species fit quite well with the rate constant for the disappearance of previous
      species. The spectra of the intermediates and final product were obtained using
      evolving factor analysis and a mass balance equation. Identification of the fifth
      species, which was probably the initial reduction product, Cl2FeS2MoS2FeCl2(3-),
      was difficult due to its low concentration and the fact that it was present in
      the same time region as the starting material.

PMID- 10330906
TI  - Electrochemical study of reversible hydrogenase reaction of Desulfovibrio
      vulgaris cells with methyl viologen as an electron carrier.
AB  - An electrode modified with immobilized whole cells of Desulfovibrio vulgaris
      (Hildenborough) produces an S-shaped voltammogram with both cathodic- and anodic
      catalytic-limiting currents in a methyl viologen-containing buffer saturated with
      H2. Methyl viologen penetrates into the bacterial cells to serve as an electron
      carrier in the reversible reaction of hydrogenase in the cells and functions as
      an electron-transfer mediator between the bacterial cells and the electrode, thus
      producing the catalytic currents for the evolution and consumption of H2. An
      equation for the catalytic current that takes into account the reversible
      hydrogenase reaction explains well the shape of the voltammogram. The potential
      at null current on the voltammogram agrees with the potential determined by
      potentiometry with the same electrode, which is equal to the redox potential of
      the H+/H2 couple in the solution--the standard potential of a hydrogen electrode
      at the pH of the solution. When D. vulgaris cells are suspended in an argon
      saturated buffer containing methyl viologen, the suspension produces a catalytic
      current at a bare glassy carbon electrode for the evolution of H2. Analysis of
      the current by a theory for a catalytic current for a unidirectional nonlinear
      enzyme catalysis allows us to determine the kinetic parameters of the reaction
      between methyl viologen and hydrogenase in intact D. vulgaris cells. Thus we
      obtain the apparent Michaelis constant for methyl viologen cation radical, K'MV.+
      = 0.16 mM, and the apparent catalytic constant (that is, the turnover number per
      D. vulgaris cell), zkcat,H+ = 1.2 x 10(7) s-1, for the H2 evolution reaction at
      pH 5.5 and at 25 degrees C, z being the number of hydrogenases contained in a D.
      vulgaris cell. The bimolecular reaction rate constant, kcat,H+/K'MV.+, of the
      reaction between methyl viologen cation radical and oxidized hydrogenase in
      intact D. vulgaris cells is estimated as 4.2 x 10(7) M-1 s-1. Similarly, the
      bimolecular reaction rate constant, kcat,H2/K'MV2+, of the reaction between
      methyl viologen and reduced hydrogenase is estimated to be 1.2 x 10(7) M-1 s-1 at
      pH 9.5 and 25 degrees C. Both rate constants are large enough for the reactions
      to be diffusion-limited processes.

PMID- 10330907
TI  - Ratiometric and fluorescence-lifetime-based biosensors incorporating cytochrome
      c' and the detection of extra- and intracellular macrophage nitric oxide.
AB  - Ratiometric and lifetime-based sensors have been designed for cellular detection
      of nitric oxide. These sensors incorporate cytochrome c', a hemoprotein known to
      bind nitric oxide selectively. The cytochrome c' is labeled with a fluorescent
      reporter dye, and changes in this dye's intensity or fluorescence lifetime are
      observed as the protein binds nitric oxide. The ratiometric sensors are composed
      of dye-labeled cytochrome c' attached to the optical fiber via colloidal gold,
      along with fluorescent microspheres as intensity standards. These ratiometric
      sensors exhibit linear response, have fast response times (< or = 0.25 s), and
      are completely reversible. The sensors are selective over numerous common
      interferents such as nitrite, nitrate, and oxygen species, and the limit of
      detection is 8 microM nitric oxide. The lifetime-based measurements are made
      using free, dye-labeled cytochrome c' in solution and have a limit of detection
      of 30 microM nitric oxide. The use of these two techniques has allowed
      measurement of intra- and extracellular macrophage nitric oxide. Employing the
      ratiometric fiber sensors gave a multicell culture average extracellular nitric
      oxide concentration of 210 +/- 90 microM for activated macrophages, while an
      average intracellular concentration of 160 +/- 10 microM was determined from the
      lifetime-based measurements of dye-labeled cytochrome c' in the macrophage
      cytosol. Microscopic adaptation of the lifetime-based methods described here
      would allow direct correlation of intracellular nitric oxide levels with specific
      cellular activities, such as phagocytosis.

PMID- 10330908
TI  - Use of a mixed-mode packing and voltage tuning for peptide mixture separation in
      pressurized capillary electrochromatography with an ion trap storage/reflectron
      time-of-flight mass spectrometer detector.
AB  - A mixed-mode (reversed-phase/anion-exchange) stationary phase has been used as
      the capillary column packing for investigation of the separation of peptide
      mixtures in pressurized capillary electrochromatography (pCEC). This stationary
      phase contains both octadecylsilanes and dialkylamines. The amine groups of the
      stationary phase determine the charge density on the surface of the packing and
      can produce a strong and constant electroosmotic flow (EOF) at low pH. A
      comparison was made in terms of the capability of separating tryptic digests
      between the mixed-mode phase and C18 reversed phase. In addition, the constant
      EOF enabled the tuning of the retention and the selectivity of the separation by
      adjusting the mobile phase pH from 2 to 5. Furthermore, the magnitude and the
      polarity of the electric voltage were demonstrated to greatly influence the
      elution profiles of the peptides in pCEC. An ion trap storage/reflectron time-of
      flight mass spectrometer was used as an on-line detector in these experiments due
      to its ability to provide rapid and accurate mass detection of the sample
      components eluting from the separation column.

PMID- 10330909
TI  - Direct identification of protein epitopes by mass spectrometry without
      immobilization of antibody and isolation of antibody-peptide complexes.
AB  - A rapid new approach is described that combines the selectivity and sensitivity
      of immunoaffinity and mass spectrometric based techniques for mapping protein
      epitopes. The approach alleviates the need to immobilize antibody, extract the
      antibody-peptide complex, and dissociate bound peptide, which are requirements of
      other methods. It avoids problems associated with limited proteolysis of an
      antigen-antibody complex particularly in the vicinity of the binding domain which
      can hinder identification of the epitope. Epitopic peptides are identified from a
      direct comparison of the matrix-assisted laser desorption ionization mass spectra
      of the antibody reaction mixture and an unreacted control. Samples are prepared
      for mass spectrometric analysis by heat-assisted and electrospray deposition to
      afford reproducible spectra that enable epitopic peptides to be identified in
      complex mixtures analyzed at the femtomole level. Indirect evidence is presented
      to suggest that the antibody-peptide complex is resilient to both sample
      deposition and the ionization event. The utility and sensitivity of the approach
      are illustrated for the lysozyme model. IgG-binding domains of human lysozyme are
      identified, and one epitope is refined to six residues that comprise part of an
      extended beta-loop region.

PMID- 10330910
TI  - Microfabricated porous membrane structure for sample concentration and
      electrophoretic analysis.
AB  - A microfabricated injection valve incorporating a porous membrane structure is
      reported that enables electrokinetic concentration of DNA samples using
      homogeneous buffer conditions followed by injection into a channel for
      electrophoretic analysis. The porous membrane was incorporated in the
      microchannel manifold by having two channels separated from each other by 3-12
      microns and connected by a thin porous silicate layer. This design allows the
      passage of current to establish an electrical connection between the separated
      channels but prevents large molecules, e.g., DNA, from traversing the membrane.
      Concentrated DNA can be injected into the separation channel and
      electrophoretically analyzed. Experiments exhibit a nonlinear increase in
      concentration with time, and DNA fragments can be concentrated up to 2 orders of
      magnitude as shown by comparison of peak intensities for analysis performed with
      and without concentration.

PMID- 10330911
TI  - Micronutrients Measurement Quality Assurance Program: helping participants use
      interlaboratory comparison exercise results to improve their long-term
      measurement performance.
AB  - Over the past decade, the Micronutrients Measurement Quality Assurance Program
      (M2QAP) at the National Institute of Standards and Technology (NIST) has
      administered nearly 40 interlaboratory comparison exercises devoted to fat
      soluble vitamin-related analytes in human serum. While M2QAP studies have been
      used to help certify reference materials and to document the performance of
      analytical systems, the primary focus of the M2QAP has been, and remains, the
      improvement of among-participant measurement comparability for target analytes.
      Recent analysis of historical measurement performance indicated the most
      efficient mechanism for further improving measurement comparability among
      participants is the improvement of long-term (months to years) comparability
      within each laboratory. The summary reports for the M2QAP studies are being
      redesigned to provide more chemist-friendly analyses of participant performance,
      dissecting systematic and random components of measurement incomparability as
      functions of analyte level and time. This report documents the semantic and
      graphical tools developed to help interlaboratory-comparison-exercise
      participants interpret their own measurement performance.

PMID- 10330912
TI  - Quantification and interpretation of total petroleum hydrocarbons in sediment
      samples by a GC/MS method and comparison with EPA 418.1 and a rapid field method.
AB  - Total petroleum hydrocarbons (TPH) as a lumped parameter can be easily and
      rapidly measured or monitored. Despite interpretational problems, it has become
      an accepted regulatory benchmark used widely to evaluate the extent of petroleum
      product contamination. Three currently used methods (GC/MS, conventional EPA
      418.1, and a rapid field method PetroFLAG) were performed to quantify the TPH
      content in samples collected from a site contaminated by transformer oil. To
      standardize the method and improve the comparability of TPH data, crucial GC
      based quantification issues were examined, e.g., quantification based on internal
      standards (ISTD) vs external standards (ESTD), single vs multiple ISTD, and
      various area integration approaches. The interpretation of hydrocarbon
      chromatographic results was examined in the context of field samples. The
      performance of the GC/MS method was compared with those of EPA 418.1 and
      PetroFLAG. As a result, it was observed that the ISTD quantification method was
      preferred to the ESTD method, multiple ISTD might be better than single ISTD, and
      three different area integration approaches did not have a significant effect on
      TPH results. Evaluation of the chromatograms between a reference sample and three
      unknown samples showed that the extent of contamination varied appreciably with
      sample depth. It was also found that there existed a good positive correlation
      between GC/MS and both EPA 418.1 and PetroFLAG, and that EPA 418.1 produced the
      higher overall estimate while GC/MS and PetroFLAG resulted in lower, more
      statistically comparable TPH values.

PMID- 10330913
TI  - Immunofiltration: a methodology for preconcentration and determination of organic
      pollutants.
AB  - A new concentration procedure using an immunofiltration-based method is
      described. The approach enables quantitative determination of organic pollutants
      by filtering large volumes of sample through a poly(vinylidene difluoride)
      membrane where antibodies have been immobilized by passive adsorption. The
      analysis is based on a sequential competitive enzyme immunoassay. A wide range of
      sample volumes have been tested (0.2-5.0 mL) for each type of antibody. The
      improvement on the assay sensitivity and specificity achieved by means of this
      concentration procedure is discussed. Using this technique and the insecticide
      carbaryl as a model analyte, a concentration factor of at least 13 and a limit of
      detection of 4.75 ng/L are accomplished. The suitability of this methodology is
      demonstrated by the quantification of the insecticide in several types of water
      samples (bottled, estuarine, and physiological-saline solutions) with recoveries
      ranging between 102 and 111%. This method has proved to concentrate carbaryl
      directly, in an accurate way, for residue analysis without using organic solvents
      or any extraction process. Furthermore, this procedure offers the advantages of
      carrying out in the same system both preconcentration and quantitative
      determination of the analyte.

PMID- 10330914
TI  - Subzero-temperature liquid-liquid extraction of benzodiazepines for high
      performance liquid chromatography.
AB  - On the basis of the phenomenon that hydrophilic acetonitrile is separated from
      the aqueous phase at -20 degrees C, we employed a novel extraction method,
      "subzero-temperature liquid-liquid extraction", to extract benzodiazepines
      (estazolam and triazolam) from serum or aqueous solution for liquid
      chromatography. A 1:1 mixture of acetonitrile and the specimen was cooled at -20
      degrees C for 20 min to separate the acetonitrile and aqueous phases. The
      acetonitrile phase was directly injected into a high-performance liquid
      chromatograph. Recovery rates of the drugs following the first subzero
      temperature liquid-liquid extraction were 50.3 +/- 0.6-54.0 +/- 0.9%, which were
      lower than those (73.9 +/- 3.3-80.6 +/- 0.6% and 81.6 +/- 4.7-96.1 +/- 2.6%) of
      the first conventional liquid-liquid extraction using diethyl ether and solid
      phase extraction using a Sep-Pak C18 column, respectively. However, three to four
      repeated subzero-temperature liquid-liquid extractions and conventional liquid
      liquid extractions resulted in recovery of almost 100% of the drugs. In the
      chromatogram of the benzodiazepines recovered from serum by the subzero
      temperature extraction, no coextracted component interfered with determination of
      the drugs. Detection limits of the drugs were 0.02-0.08 microgram/mL, and
      coefficients of variance were 1.14-2.17% suggesting high reproducibility.

PMID- 10330915
TI  - Women in Science and Engineering: Choices for Success. Proceedings of a
      conference. New York City, New York, USA. March 12-13, 1998.

PMID- 10330916
TI  - Adolescent urology.

PMID- 10330917
TI  - Hypertension in reflux nephropathy.

PMID- 10330918
TI  - Adolescent nephrourology: preventing progressive renal failure.

PMID- 10330919
TI  - The long-term complications of posterior urethral valves.

PMID- 10330920
TI  - Sexuality after hypospadias repair.

PMID- 10330921
TI  - The gynaecology of exstrophy.

PMID- 10330922
TI  - Long-term outcomes and changing attitudes to intersexuality.

PMID- 10330923
TI  - Survivors of cancer: organ preservation and reducing the morbidity of treatment
      in paediatric genitourinary oncology.

PMID- 10330924
TI  - Chronic lymphocytic leukaemia.

PMID- 10330925
TI  - Advances in the biology and treatment of myeloma.

PMID- 10330926
TI  - Cellular immunotherapy in haematological malignancies.

PMID- 10330927
TI  - Dyskeratosis congenita.

PMID- 10330928
TI  - Pathogenesis and management of haemochromatosis.

PMID- 10330929
TI  - Mechanisms and management of iron deficiency anaemia.

PMID- 10330930
TI  - 46th Annual meeting of the Society of Nuclear Medicine. Los Angeles, California,
      USA. June 6-10, 1999. Abstracts.

PMID- 10330931
TI  - XII National Congress of the Italian Polyspecialistic Society of the Young
      Surgeons (SPIGC). 20-22 May 1999. Abstracts.

PMID- 10330932
TI  - Role of the surgeon in managing hypercholesterolemia.

PMID- 10330933
TI  - Ethical considerations in human cloning.

PMID- 10330934
TI  - Management of penetrating colon trauma: a cost-utility analysis.
AB  - BACKGROUND: Management of penetrating colon injuries in the presence of multiple
      associated risk factors is controversial. Issues not considered in previous
      management strategies are patient perception of quality of life with a colostomy
      and the true cost of each therapeutic option, which includes colostomy supplies
      and costs of colostomy takedown. To evaluate these issues, we performed a cost
      utility analysis. METHODS: We constructed a decision tree with 3 options: primary
      repair, resection and anastomosis, and colostomy. Chance and decision nodes on
      each decision branch represent injury severity, complications, colostomy
      takedown, and death. Chance node frequencies and utility assignments were taken
      from published data. We obtained actual costs for all components of perioperative
      care. The outcomes reported are cost and quality of life. RESULTS: Colostomy has
      the least quality of life and the greatest cost. Primary repair and resection
      each dominate colostomy in the baseline analysis. No variable significantly
      altered these conclusions in sensitivity analyses. CONCLUSIONS: Simple suture or
      resection and anastomosis at the time of initial exploration is the dominant
      management method for penetrating colon trauma. It also demonstrates the trade
      off between cost and life expectancy of the 3 management options.

PMID- 10330935
TI  - Gastric symptoms and duodenogastric reflux in patients referred for
      gastroesophageal reflux symptoms and endoscopic esophagitis.
AB  - BACKGROUND: The role of excessive duodenogastric reflux (DRG) in the genesis of
      gastric symptoms in patients primarily referred for both gastroesophageal reflux
      (GER) symptoms and esophagitis is poorly understood. METHODS: The study is based
      on the clinical, endoscopic, histologic, and 24-hour gastric data from the
      Bilitec optoelectronic device (Prodotec, Florence, Italy, licensed by Synectics
      Medical, Stockholm, Sweden) from 49 patients having both typical GER symptoms and
      gastric symptoms suggestive of excessive DGR (i.e., epigastric pain, nausea, or
      bilious vomiting) in the absence of previous esophageal or gastric surgery (group
      1). Helicobacter pylori organisms were searched for on antral biopsy specimens
      with use of the Giemsa method. The percentages of total, upright, and supine time
      during which absorbance exceeded various thresholds through all the working range
      of the Bilitec device were calculated. Bilitec data from group 1 were compared
      with those from 16 patients with endoscopic esophagitis and GER symptoms only
      (group 2) and 25 healthy subjects (group 3). RESULTS: The prevalence of an
      abnormal Bilitec test result in group 1 increased from 27% (13/49) at the 0.25
      absorbance threshold to 36% (18/49) at thresholds ranging from 0.40 to 0.60 and
      to 41% (20/49) when multiple thresholds ranging from 0.25 to 0.60 were
      considered. In group 2 one patient had an abnormal Bilitec test result at the
      0.25 to 0.30 threshold, whereas the other 15 patients had a normal test result. H
      pylori antral infection was present in 14 group 1 patients. None of these had an
      abnormal Bilitec test result, whereas the test was positive in 40% of the H
      pylori-negative patients without endoscopic gastritis and in 70% of H pylori
      negative patients with endoscopic gastritis (P = .001). CONCLUSIONS: Twenty-four
      hour intragastric bile monitoring provides the clinician with unequivocal
      evidence of excessive DGR in 41% of patients with an intact stomach having
      endoscopic esophagitis, GER symptoms, and gastric symptoms suggestive of DGR. The
      most dependable data are obtained when absorbance thresholds higher than 0.40 are
      considered. H pylori antral infection and excessive DGR at 24-hour intragastric
      bile monitoring are mutually exclusive.

PMID- 10330936
TI  - The importance of the plasma amino acid molar ratio in patients with biliary
      atresia.
AB  - BACKGROUND: Plasma amino acid patterns and the therapeutic benefits of amino acid
      supplements are not examined well in postoperative patients with biliary atresia
      (BA). This study aimed to investigate profiles of the amino acid molar ratio, the
      Fischer molar ratio (FR, valine + leucine + isoleucine/phenylalanine + tyrosine),
      and relationships with other nutritional parameters and to assess the efficacy of
      enteral nutrient preparations for hepatic failure in patients with BA. METHODS:
      In study 1 profiles of FR were analyzed in 24 patients with BA (aged 3 to 12
      years) in the postoperative period and compared with liver function tests and
      anthropometric measures. In study 2 10 patients with BA with a FR < 2.0 were
      begun on a dietary regimen consisting of an ordinary diet supplemented with a
      branched-chain amino acid-enriched elemental diet. RESULTS: Study 1: In jaundiced
      patients with total bilirubin levels > 2.0 mg/dL the FR remained below 2.0
      throughout the period of observation, in contrast with nonjaundiced patients. The
      FR was closely related to the levels of serum albumin and plasma rapid turnover
      proteins and anthropometric measures as well as biochemical data reflecting
      intrinsic liver function. Study 2: A significant increase in rapid turnover
      proteins and improvement of general status were noted concurrently with an
      increase of the FR. CONCLUSIONS: The FR indicates a combination of nutritional
      status and intrinsic liver function in post-operative BA patients. The FR is a
      useful parameter in conducting nutritive therapy with a branched-chain amino acid
      enriched elemental diet in those patients.

PMID- 10330937
TI  - Are the motility abnormalities of achalasia reversible? An experimental outflow
      obstruction in the feline model.
AB  - BACKGROUND: Experimental and clinical evidence suggests that the loss of
      esophageal body function in achalasia may be a result of the outflow obstruction
      of a nonrelaxing, hypertensive lower esophageal sphincter. The reversibility of
      such abnormalities has implications to the timing of therapeutic interventions.
      This study was designed to evaluate the evolution and reversibility of motility
      abnormalities resulting from esophageal outflow obstruction in cats. METHODS:
      Twenty adult cats were divided into 2 groups. Group 1 consisted of 4 cats that
      underwent laparotomy as a sham procedure. Group 2 consisted of 16 cats that
      underwent surgical placement of a loose Gore-tex expanded polytetrafluoroethylene
      (W. L. Gore, Elkton, Md) band calibrated to 110% of the circumference of the
      gastroesophageal junction. The band was removed from 4 randomly selected cats
      each at 1, 2, 4, and 6 weeks after placement. Esophageal manometry was performed
      before placement of the band, at weekly intervals after placement of the band,
      and after removal of the band. The resting pressure and percent relaxation of the
      lower esophageal sphincter (LES), in addition to amplitude, duration, and
      propagation of esophageal body contractions, were measured at each interval. Data
      are expressed as median and interquartile range and compared with use of the Mann
      Whitney U test for independent samples. RESULTS: The LES resting pressure
      remained unchanged after placement of the band, but sphincter compliance was
      reduced, as manifested by a significant reduction in the percent of sphincter
      relaxation (98% prebanding, 65% postbanding, P < .05). The median amplitude of
      esophageal contraction decreased significantly after banding. By 6 weeks after
      banding the esophagus was markedly dilated and exhibited aperistaltic, low
      amplitude esophageal motility typical of that seen in clinical achalasia.
      Importantly, removal of the bands resulted in a prompt return of both peristalsis
      and amplitude of contraction. CONCLUSIONS: Loss of compliance of the lower
      esophageal sphincter produces outflow obstruction with the resultant loss of
      esophageal contraction amplitude and peristaltic waveform typical of achalasia in
      humans. These abnormalities were reversible after relief of obstruction in the
      feline model and may indicate that early relief of outflow obstruction in
      clinical achalasia may preserve esophageal function in patients.

PMID- 10330938
TI  - Parathyroid autotransplantation with total thyroidectomy for thyroid carcinoma:
      long-term follow-up of grafted parathyroid function.
AB  - BACKGROUND: Permanent hypoparathyroidism is a major complication of
      thyroidectomy. Autotransplantation of parathyroid glands has been attempted to
      prevent this complication. However, no direct data have been available to assess
      grafted parathyroid function after long-term follow-up in terms of the serum
      intact parathyroid hormone (PTH) concentration. METHODS: Eighty-four consecutive
      patients with differentiated thyroid carcinoma who underwent total thyroidectomy
      and bilateral modified neck dissection from 1992 to 1996 were enrolled. They
      concomitantly underwent total parathyroidectomy and autotransplantation of all
      parathyroid glands to the pectoralis major muscle. The serum intact PTH
      concentration was periodically measured as an index of grafted parathyroid
      function. RESULTS: The mean follow-up was 34 months. In all autotransplanted
      patients serum intact PTH concentrations fell below detectable limits immediately
      after surgery. They were restored to the normal range within 1 month
      postoperatively and were maintained during observation in 80 (95%) of 84
      patients. Seventy-eight of 80 patients with normal intact PTH values were
      normocalcemic without any treatment and the remainder were normocalcemic with 1
      microgram of 1 alpha-vitamin D3. Four hypoparathyroid patients were normocalcemic
      with 2 micrograms of 1 alpha-vitamin D3. The postoperative average serum intact
      PTH concentration of patients having more than 2 autotransplanted parathyroid
      glands was almost equal to that of patients with preservation of the parathyroid
      glands in situ. The incidence of permanent hypoparathyroidism was inversely
      correlated with the number of autotransplanted parathyroid glands. CONCLUSIONS:
      The recovery patterns of the intact PTH concentration indicate that the glands
      were grafted successfully and functioned for a long period. This feasible method
      of parathyroid autotransplantation bears comparison with the previous reports in
      terms of the incidence of permanent postoperative hypoparathyroidism, and it can
      be performed simply and is reproducible.

PMID- 10330939
TI  - Octreotide stimulates Ca++ secretion by the gallbladder: a risk factor for
      gallstones.
AB  - BACKGROUND: Gallstone formation during octreotide therapy has been linked to
      elevated levels of gallbladder bile Ca++, a well-known prolithogenic factor.
      Although the subcutaneous administration of octreotide raises gallbladder bile
      Ca++ in prairie dogs, the mechanism for this effect is unknown. Octreotide has
      been shown to increase gallbladder Na+ and water absorption in Ussing chamber
      studies. Given the known effects of octreotide on gallbladder ion transport, we
      hypothesized that octreotide may also promote gallstone formation by stimulating
      gallbladder Ca++ secretion, thereby raising the lumenal concentration of biliary
      Ca++. METHODS: After cholecystectomy, prairie dog gallbladders were mounted in
      Ussing chambers, and standard electrophysiologic parameters were recorded.
      Unidirectional fluxes of Ca++ and Na+ were measured before and after serosal
      exposure to 50 nmol/L octreotide. RESULTS: Under basal conditions normal prairie
      dog gallbladder absorbed mucosal Ca++. Serosal octreotide converted the
      gallbladder from a state of basal Ca++ absorption to one of net Ca++ secretion by
      stimulating serosa to mucosa Ca++ flux. As anticipated, octreotide increased net
      Na+ absorption by stimulating mucosa to serosa Na+ flux and decreased tissue
      conductance and short-circuit current significantly compared with baseline
      values. CONCLUSION: Fifty nanomoles per liter octreotide stimulated Ca++
      secretion by gallbladder epithelium, a possible mechanism for increased biliary
      Ca++ in prairie dogs receiving subcutaneous injections. Ca++ secretion linked to
      octreotide therapy may induce gallstones by raising biliary levels of Ca++, a
      known prolithogenic factor.

PMID- 10330940
TI  - Proximal bile duct stricture disguised as malignant neoplasm.
AB  - BACKGROUND: Discrimination of malignant proximal bile duct (PBD) stricture from a
      benign lesion is difficult with nonsurgical methods; indeed, 8% to 13% of PBD
      strictures prove to be benign after histologic examination of the surgically
      resected specimen. METHODS: In a 7-year period 178 patients with PBD stricture
      were admitted, and 99 of them underwent radical resection for presumably
      malignant lesions. In 14 of these patients the stenotic lesions were proved to be
      benign by postoperative histologic assessment. We reviewed these patients
      retrospectively by collecting data from their charts. RESULTS: Preoperative
      radiologic findings including cholangiography and angiography were compatible
      with malignancy in all 14 patients. Preoperative histologic studies suggested
      malignancy in 2 of 8 examined. Findings at laparotomy could not allow
      differentiation between malignant and benign lesions in any of the patients and
      strongly suggested malignancy in 3. Histologic examination of the resected
      specimens revealed extensive fibrosis with inflammatory cellular infiltration in
      all patients. There was 1 episode of significant morbidity postoperatively
      (transient cholangitis) but no mortality. CONCLUSION: Benign PBD strictures,
      although rare, are usually indistinguishable from malignant PBD strictures by
      preoperative or perioperative investigation. Given the minimal morbidity, all PBD
      strictures should be presumed malignant and managed accordingly, even at the risk
      of overtreating some benign cases.

PMID- 10330941
TI  - Reoperation as treatment of relapse after subtotal thyroidectomy in Graves'
      disease.
AB  - BACKGROUND AND METHODS: In Graves' disease radioiodine is the recommended
      treatment for relapses after subtotal thyroidectomy. If patients reject
      radioiodine, hyperthyroidism is managed with antithyroid drugs; surgery is
      generally not considered as an alternative. Here we retrospectively analyzed 30
      consecutive patients with Graves' disease who had recurrent hyperthyroidism after
      subtotal thyroidectomy. RESULTS: On relapse after the first operation, the
      patients were initially treated by medication; 25 opted for definitive treatment
      (19 for reoperation and 6 for radioiodine). Operations consisted of 10 unilateral
      and 8 bilateral resections (total or near-total with capsular remnants of < 1 g)
      and 1 transsternal approach (because of dystopic intrathoracic thyroid tissue).
      The decision between a unilateral and a bilateral reintervention was based on the
      ultrasonographic determination of remnant volumes. These size estimates were
      valid because they were significantly correlated to the weight of the resected
      remnants (r = 0.92, slope = 0.95). Eighteen of the 19 patients were adequately
      treated by this approach. Unilateral resection was performed in 1 patient with a
      remaining contralateral remnant of 5.4 mL; this patient had a second relapse. The
      complication rate was low (2 cases of transient recurrent nerve injury and 1 of
      transient hypocalcemia). CONCLUSION: Provided that no contraindication is
      present, reoperation is safe, effective, and expeditious in recurrent
      hyperthyroidism. Because the likelihood of a recurrence depends on the total
      remnant size, the goal is to keep it below 2 g. Preoperative ultrasonography can
      effectively guide the decision between a unilateral and a bilateral resection.

PMID- 10330942
TI  - Is prophylactic pelvic drainage useful after elective rectal or anal anastomosis?
      A multicenter controlled randomized trial. French Association for Surgical
      Research.
AB  - OBJECTIVE: We investigated the role of drainage in the prevention of
      complications after elective rectal or anal anastomosis in the pelvis.
      Anastomotic leakage after colorectal resection is more prevalent when the
      anastomosis is in the distal or infraperitoneal pelvis than in the abdomen. The
      benefit of pelvic drains versus their potential harm has been questioned. Drain
      related complications include (1) those possibly benefiting from drainage
      (leakage, intra-abdominal infection, bleeding) and (2) those possibly caused by
      drainage (wound infection or hernia, intestinal obstruction, fistula). METHODS:
      Between September 1990 and June 1995, 494 patients (249 men and 245 women), mean
      age 66 +/- 15 (range 15 to 101) years, with either carcinoma, benign tumor,
      colonic Crohn's disease, diverticular disease of the sigmoid colon, or another
      disorder located anywhere from the right colon to the midrectum undergoing
      resection followed by rectal or anal anastomosis were randomized to undergo
      either drainage (n = 248) with 2 multiperforated 14F suction drains or no
      drainage (n = 246). The primary end point was the number of patients with one or
      more postoperative drain-related complications. Secondary end points included
      severity of these complications as assessed by the rate of related repeat
      operations and associated deaths as well as extra-abdominally related morbidity
      and mortality. RESULTS: After withdrawal of 2 patients (1 in each group) both
      groups were comparable with regard to preoperative characteristics and
      intraoperative findings. The overall leakage rate was 6.3% with no significant
      difference between those with or without drainage. There were 18 deaths (3.6%), 8
      (3.2%) in those with drainage and 10 (4%) in those without drainage. Five
      patients with anastomotic leakage died (1%), 3 of whom had drainage. There were
      32 repeat operations (6.5%) for anastomotic leakage 11 in the group with drainage
      and 4 in the group with no drainage. The rate of these and the other intra
      abdominal and extra-abdominal complications did not differ significantly between
      the 2 groups. CONCLUSION: Prophylactic drainage of the pelvic space does not
      improve outcome or influence the severity of complications.

PMID- 10330943
TI  - Antiangiogenic therapy of human esophageal cancers with thalidomide in nude mice.
AB  - BACKGROUND: Thalidomide (alpha-N-phthalimidoglutarimide) is attracting new
      attention because of its antiangiogenic effect in corneal neovascularization
      models. However, the effect of this agent on esophageal carcinoma is yet to be
      established. METHODS: The human esophageal squamous cell carcinoma strains ES63
      and ES80 implanted subcutaneously in nude mice were used to evaluate the
      antiangiogenic effect of thalidomide (200 mg/kg/d) after daily gavage or
      intraperitoneal administration. Tumor size was measured, and assessment of
      microvessel density was performed histochemically with Griffonia simplicifolia
      lectin I. Characterizations of angiogenic growth factors, vascular endothelial
      growth factor, basic fibroblast growth factor, and thymidine phosphorylase in
      ES63 and ES80 tumors were done by immunohistochemical staining and reverse
      transcription-polymerase chain reaction. RESULTS: ES63 strongly expressed 3
      angiogenic factors, but ES80 showed moderate expression of thymidine
      phosphorylase and only weak or no expression of vascular endothelial grown factor
      and basic fibroblast growth factor at protein and messenger RNA levels. In ES63
      intraperitoneal injection of thalidomide produced significant (P < .05)
      inhibition of tumor growth, but there was no effect after gastric gavage. Also, a
      significantly (P < .0005) lower microvessel density was encountered in the
      intraperitoneal thalidomide group. However, in the ES80 tumor strain thalidomide
      had no antiangiogenic effect after either intraperitoneal or oral administration.
      CONCLUSIONS: These data indicate that thalidomide exerts an antiangiogenic effect
      on solid tumor after intraperitoneal administration. Thalidomide might be one of
      the hopeful antiangiogenic drugs for solid tumors.

PMID- 10330944
TI  - Factors influencing late survival after abdominal aortic aneurysm repair in
      Japanese patients.
AB  - BACKGROUND: To determine the factors influencing the prognosis of patients with
      abdominal aortic aneurysms (AAA), the clinical characteristics and long-term
      survival of 366 consecutive patients were examined and compared with those in
      previous Western studies. METHODS: During the period from January 1979 to
      December 1995, 376 patients with AAA were admitted to our hospital. Among these,
      332 consecutive patients underwent elective reconstruction of infrarenal AAAs.
      The remaining 44 patients were not surgically treated. With use of the data from
      the patients who underwent AAA resection, the relationship of various risk
      factors, such as cardiac dysfunction, hypertension, renal dysfunction, pulmonary
      dysfunction, and age, to survival rate was investigated by univariate and
      multivariate analysis. RESULTS: The operative mortality rate was 0.6%. The
      survival of the patients who underwent the operation at 5 years was 71.0% and at
      10 years 51.8%. The survival rate of the patients who were not surgically treated
      at 5 years was 26.0% and at 10 years 14.9%. There was a significant difference
      between the 2 groups. A univariate analysis was performed on each possible risk
      factor affecting survival rates. In relation to the survival rate of 5 and 10
      years, there was no statistical significant difference between patients with or
      without heart disease or hypertension. By contrast, factors influencing long-term
      survival were associated with renal dysfunction, pulmonary dysfunction, and age
      at time of surgery. Multivariate analysis of risk factors affecting survival
      rates demonstrated that renal dysfunction, pulmonary dysfunction, and age at the
      time of operation were found to be significant, respectively. The main cause of
      the death for the long-term survival patients with AAA repair was malignancy,
      whereas that in the patients without repair was rupture. CONCLUSIONS: Risk
      factors influencing survival after AAA repair were renal dysfunction, pulmonary
      dysfunction, and advanced age in Japanese patients. In addition, the main cause
      of death after aneurysmal resection was malignancy. These results were different
      from outcomes in Western patients. We need to carefully watch out for malignancy
      during the follow-up period after AAA resection.

PMID- 10330945
TI  - A model of port-site metastases of gallbladder cancer: the influence of
      peritoneal injury and its repair on abdominal wall metastases.
AB  - BACKGROUND: Recent surgical literature contains several reports of wound
      metastases of unexpected gallbladder cancer after laparoscopic cholecystectomy.
      We hypothesized that peritoneal injury caused by trocar insertion potentiates
      wound metastases. This study was designed to determine the effect of peritoneal
      injury on tumor implantation. METHODS: Cultured human gallbladder cancer cells
      were injected into the peritoneal cavity of mice immediately after surgical
      procedures. In a peritoneal injury group muscle and the peritoneum were
      perforated; in a peritoneal injury and repair group each muscle and peritoneal
      wound was sutured carefully; in a laparoscopic model group animals underwent
      peritoneal insufflation with carbon dioxide gas and tumor cell injection and then
      the abdominal wall was perforated. Some mice (controls) were not subjected to any
      surgical procedure. All mice (n = 178) were killed 2 weeks after tumor cell
      injection and were examined for tumor implantation. RESULTS: Although no control
      mice showed intraperitoneal tumor, all mice in the peritoneal injury group showed
      tumors at the injured sites. In the laparoscopic model group, 90% of injured
      sites had tumors. The traumatized site-specific implantation rate in the
      peritoneal injury and repair group was only 40%, whereas it was 100% in the
      peritoneal injury group (P < .001). CONCLUSIONS: Peritoneal injury enhances
      peritoneal implantation of carcinoma cells. Repair of injured peritoneum at
      trocar sites may reduce the frequency of wound metastases in laparoscopic surgery
      for unexpected gallbladder carcinoma.

PMID- 10330946
TI  - Surgical stress and the small intestine: role of oxygen free radicals.
AB  - BACKGROUND: Any surgical procedure can be associated with altered intestinal
      function. The mechanism involved in these changes at the cellular level during
      surgical stress has not been worked out. This study looked at the biochemical and
      functional alterations, along with ultrastructural changes, in the intestine
      during surgical stress in a simple rat model. METHODS: Surgical stress was
      induced by opening the abdominal wall and handling the intestine as during
      laparotomy. The effect of oxidative stress on the enterocyte and altered
      intestinal permeability as well as the ultrastructural changes to the mucosa were
      studied. RESULTS: Surgical stress results in oxidative stress on enterocytes, as
      evidenced by increased xanthine oxidase and decreased catalase activity along
      with altered thiol redox status. This was associated with increased intestinal
      permeability and widened intercellular spaces. These changes were prominent at 60
      minutes after laparotomy and returned to normal by 24 hours. CONCLUSIONS: Mild
      intestinal handling is capable of inducing oxidative stress in enterocytes; this
      could be one of the mechanisms by which intestinal mucosal alterations occur
      during surgical stress.

PMID- 10330947
TI  - Graft-versus-host disease after intraoperative blood transfusion: a rare and
      lethal condition.

PMID- 10330948
TI  - Generic immunosuppressant use in solid organ transplantation.
AB  - Although economics may be the driving force for generic development, these forces
      must be tempered by consumer safety and efficacy. Studies to date imply that we
      are gaining balance in attempts to reconcile these issues. With the development
      of more generic immunosuppressants imminent, the transplant community must
      continue to enforce their high standards of a research driven discipline where
      the transition from research to clinical practice is often seamless. Higher
      academic demands will continue to be expected for any generic developed for use
      in transplantation. Whether or not generic availability will subsequently impact
      other areas of transplantation such as legislative policies for reimbursement,
      compliance, and long-term graft survival has not been quantified and requires
      further study.

PMID- 10330949
TI  - Pharmacoeconomics of immunosuppressive agents in renal transplant recipients.

PMID- 10330950
TI  - Understanding bioequivalence testing.

PMID- 10330951
TI  - History and regulatory issues of generic drugs.
AB  - In the November 1987 edition of the Journal of the Society of Clinical
      Pharmacology and Therapeutics, Dr Richard Weinshilboum of the Department of
      Pharmacology at the Mayo Clinic made the following observation: "The past half
      century has been a golden age for pharmacologic therapy. Fifty years ago there
      were no antibiotics: there were no antihypertensives; there were no
      antineoplastics; there were no antipsychotics; there were no antidepressants; and
      the list could go on and on. With the exception of a few effective drugs, the
      pharmacopeia of that time was filled with placebos. Our generation has witnessed
      the transformation of medicine. A transformation due in part to the development
      of drugs capable of controlling or curing diseases that have plagued mankind
      throughout human history." There is plenty of room for both the innovator and
      generic manufacturer in this market, but both sides need protection. The
      regulations adopted by the FDA for providing a safe and effective route to drug
      approvals will foster both sides while maintaining its primary purpose, assurance
      to the public that the products they consume have been adequately studied and
      appropriately applied.

PMID- 10330952
TI  - Pediatric oncology and AIDS: therapeutic lessons of relevance to generic drug
      use.

PMID- 10330953
TI  - Generic drugs: the Canadian perspective.

PMID- 10330954
TI  - Generic immunosuppressants: the European perspective.

PMID- 10330955
TI  - A review of the safety of generic drugs.
AB  - Generic drugs have been around for many years. The Drug Price Competition and
      Patent Term Restoration Act 1984 makes the abbreviated new drug application
      process available to drugs approved after 1962. It does not lower any standards
      for generic drugs. FDA's comprehensive drug approval process evaluates
      information concerning (1) chemistry, manufacturing, and controls, (2) in vivo
      bioequivalence, (3) labeling, (4) in vitro dissolution data where applicable, and
      (5) inspection and auditing of all facilities. This stringent and comprehensive
      approval process ensures the quality of generic drug products marketed in the US
      and assures the health professionals and patients of the safety and efficacy of
      generic drug products.

PMID- 10330956
TI  - Cyclosporine: the case for expanding bioequivalence criteria to include measures
      of individual bioequivalence in relevant population subsets.

PMID- 10330957
TI  - The impact of generic drugs on the cost of transplantation medical care.

PMID- 10330958
TI  - The US multicenter double-blind, randomized, phase III trial of thymoglobulin
      versus atgam in the treatment of acute graft rejection episodes following renal
      transplantation: rationale for study design.
AB  - In this study intended to establish equivalence between two antibody therapies
      for acute rejection in kidney transplant recipients, it was important to develop
      a rigorous protocol. Assurance of the presence of acute rejection was imperative.
      Therefore, due to the lack of literature support for clinical assessment of renal
      dysfunction, histologic diagnosis of acute rejection was required for enrollment
      in the study. Likewise, supportive literature for a correlation between response
      to anti-rejection therapy and the severity of rejection lead to the decision that
      the study should be stratified by a measurement of rejection severity for which
      Banff criteria were used. Finally, quantification of the response to therapy was
      also measured against the available literature and a large, newly developed
      international database of kidney transplant rejection episodes (the Efficacy
      Endpoints database) where serum creatinine, expressed as a percentage of the
      baseline level at the time of rejection was shown to be the most effective,
      available clinical marker of rejection response. Therefore, the US Multicenter
      Phase III Trial for comparing Thymoglobulin to Atgam in the treatment of acute
      rejection exhibits a unique and detailed study design that could be implemented
      in future trials as well as in clinical practice to improve assessment of
      outcomes.

PMID- 10330959
TI  - Costs savings associated with thymoglobulin for treatment of acute renal
      transplant rejection in patient subsets.

PMID- 10330960
TI  - Effect of anti-lymphocyte antibody induction therapy on renal allograft survival.
AB  - Our two meta-analyses show that antilymphocyte antibody induction therapy extends
      allograft survival when compared to induction therapy with cyclosporine,
      azathioprine, and prednisone with the majority of the benefit seen during the
      first 2 years after transplant. The benefit of induction therapy with respect to
      allograft survival is particularly important among patients with pretransplant
      panel reactive antibodies greater than 20%. Although our understanding of the
      role of antilymphocyte antibody induction therapy continues to evolve, these two
      meta-analyses provide evidence for its use in clinical renal transplantation.

PMID- 10330961
TI  - Short- and long-term effects of polyclonal antibodies.

PMID- 10330962
TI  - Leukocyte response to thymoglobulin or atgam for induction immunosuppression in a
      randomized, double-blind clinical trial in renal transplant recipients.

PMID- 10330963
TI  - Ten-year cost effectiveness of alternative immunosuppression regimens in
      cadaveric renal transplantation.

PMID- 10330964
TI  - Immunosuppressive and antiproliferative effects of HMG-CoA reductase inhibitors.

PMID- 10330965
TI  - Donor cells that facilitate tolerance to rat heart allografts after
      posttransplant total lymphoid irradiation and rabbit anti-thymocyte globulin.

PMID- 10330966
TI  - Inducing unresponsiveness by the use of anti-CD3 immunotoxin, CTLA4-Ig, and anti
      CD40 ligand.

PMID- 10330967
TI  - Glances at the history of transplantation immunology.

PMID- 10330968
TI  - Felix Milgrom, immunologist and microbiologist par excellence.

PMID- 10330969
TI  - Milgrom symposium.

PMID- 10330970
TI  - Reflections on my mentor, Felix Milgrom.

PMID- 10330971
TI  - Reflections on tolerance, self-tolerance and Felix Milgrom.

PMID- 10330972
TI  - Immunomodulation: particular perspectives.

PMID- 10330973
TI  - Anterior chamber-associated immune deviation, ocular immune privilege, and
      orthotopic corneal allografts.

PMID- 10330974
TI  - Costimulation of human natural killer cells is required for interferon gamma
      production.

PMID- 10330975
TI  - Transplantation of cells and tissues expressing Fas ligand.

PMID- 10330976
TI  - Advances in cytokine signaling: the role of Jaks and STATs.

PMID- 10330979
TI  - My relations with five generations of immunologists.

PMID- 10330977
TI  - Genetic engineering for xenotransplantation.

PMID- 10330983
TI  - Molecular and biological properties of genes in the Grc and EC regions.

PMID- 10330984
TI  - Physical mapping and sequencing of class I genes in a 150-kb contig in the EC
      region.

PMID- 10330985
TI  - Sequence analysis of the genomic interval between the Rps18 and RT1-A genes in
      the RT1u haplotype.

PMID- 10330986
TI  - Gene order of the RT1.M region of the rat MHC exemplifies interspecies
      conservation with the mouse.

PMID- 10330987
TI  - Localization of immunogenic and tolerogenic epitopes in the RT1.A1 alloantigen.

PMID- 10330988
TI  - Interactions formed by truncated transporter associated with antigen-processing
      polypeptides.

PMID- 10330989
TI  - Characterization of RT1.B alleles from serologically identical and different
      RT1.B/D haplotypes.

PMID- 10330990
TI  - Nuclear transfer in the rat: potential access to the germline.

PMID- 10330991
TI  - Optimization of cryopreservation procedures for rat embryos.

PMID- 10330992
TI  - Endothelial expression of Fas ligand in transgenic rats under the temporal
      control of a tetracycline-inducible system.

PMID- 10330993
TI  - Rat genetic map and a rat/mouse/human comparative gene map.

PMID- 10330994
TI  - Gene-based anchoring of the rat genetic linkage and cytogenetic maps.

PMID- 10330995
TI  - Integrated linkage maps in the rat.

PMID- 10330996
TI  - An integrated rat genetic map: analysis of linkage conservation with the mouse
      and human maps.

PMID- 10330997
TI  - Congenic strains for genetic analysis of hypertension and dyslipidemia in the
      spontaneously hypertensive rat.

PMID- 10330998
TI  - Induction of tolerance by oral administration of a tolerogenic allochimeric
      donor/recipient class I MHC protein.

PMID- 10330999
TI  - Allopeptide-mediated expression of endothelial Fas-ligand (CD95L) in long-term
      tolerized heterotopic rat heart grafts.

PMID- 10331000
TI  - Immunization with Escherichia coli-produced soluble MHC class I proteins induces
      accelerated rejection or prolonged survival of rat cardiac allografts.

PMID- 10331001
TI  - Synergistic impact of "WOFIE" on the immunosuppressive potency of FK 506 in a
      heterotopic heart transplantation model in the rat.

PMID- 10331002
TI  - An alternative model to study intrathymic tolerance induction: the neonatal heart
      in-ear transplantation model in the rat.

PMID- 10331003
TI  - Orthotopic hindlimb transplantation in the rat: a technically challenging but
      useful animal model for solid organ engraftment.

PMID- 10331004
TI  - Graft-versus-host disease in the rat: a genetic analysis in recombinant inbred
      strains of SHR x BN. Lx and BN. Lx x SHR sets.

PMID- 10331005
TI  - Time course of chemokine expression in acutely rejecting rat kidneys.

PMID- 10331006
TI  - Interleukin 13 cloning from DA rats.

PMID- 10331007
TI  - Cloning and expression of interleukin-5 from rats.

PMID- 10331008
TI  - Identification of a rat invariant T-cell receptor; alpha chain similar to mouse V
      alpha 14-J alpha 281 and human V alpha 24-J alpha Q.

PMID- 10331009
TI  - T-cell development and susceptibility to cyclosporine A-induced autoimmunity in
      MHC-matched bone marrow/thymus chimeras.

PMID- 10331010
TI  - The anti-rat Thy-1.1 monoclonal antibody R2-12C5 recognizing rat, mouse, hamster,
      and Mongolian gerbil Thy-1 antigen had no effect on IL-2 induced rat thymocyte
      proliferation.

PMID- 10331011
TI  - Localization in rats of genetic loci regulating susceptibility to experimental
      erosive arthritis and related autoimmune diseases.

PMID- 10331012
TI  - MHC and non-MHC genes in the regulation of susceptibility to collagen-induced
      arthritis among DA, BB, and BN rats.

PMID- 10331013
TI  - Adjuvant arthritis in rats: susceptibility to arthritis induced by Mycobacterium
      butyricum and Mycobacterium tuberculosis.

PMID- 10331014
TI  - Rat congenic and recombinant inbred strains: a genetic model for the study of
      quantitative trait loci.

PMID- 10331015
TI  - Susceptibility of rats to homologous collagen-induced arthritis depends on MHC
      genes in the class II region.

PMID- 10331016
TI  - Susceptibility to oil-induced arthritis is linked to Oia2 on chromosome 4 in a
      DA(DA x PVG.1AV1) backcross.

PMID- 10331017
TI  - Integrins regulating the interaction of lymphocytes with vascular endothelium.

PMID- 10331018
TI  - Non-MHC determined resistance of Brown-Norway rats to develop experimental
      allergic encephalomyelitis is mediated by the endogenous production of
      transforming growth factor-beta.

PMID- 10331019
TI  - Polarization toward the T-helper(Th)1 type immune response is not required for
      rat experimental autoimmune myasthenia gravis.

PMID- 10331020
TI  - Promiscuous activation and cell cycle entry in T cells from autoimmune animals.

PMID- 10331022
TI  - Genetic map of the lymphopenia region on rat chromosome 4.

PMID- 10331021
TI  - Intravital dye-labeled diabetogenic rat T cells retain dye, home to the pancreas,
      and induce diabetes.

PMID- 10331023
TI  - Characterization of T-cell lymphomas in the Prague inbred Sprague-Dawley/cub rat
      strain: a model of spontaneous hematologic malignancy.

PMID- 10331024
TI  - Linkage mapping of rat hypodactyly locus to chromosome 10.

PMID- 10331025
TI  - Rapid induction of malignant tumors by chemical carcinogens in rats carrying the
      Grc.

PMID- 10331026
TI  - Contribution of the TNF alpha gene region of rat chromosome 20 to the body
      temperature response to endotoxin.

PMID- 10331027
TI  - Expression of the T-cell differentiation antigen RT6.2 in T-cell lines is
      correlated with hypomethylation of the RT6 promoter.

PMID- 10331028
TI  - Evidence that allelic variations in the main RT6 promoter modulate
      transcriptional activity.

PMID- 10331029
TI  - Mutation of a putative TATA motif does not affect transcription by the promoter
      of the rat T cell differentiation marker RT6.

PMID- 10331030
TI  - Recommendations concerning the introduction of generic formulations of
      cyclosporine.

PMID- 10331031
TI  - Considerations concerning generic formulations of immunosuppressive drugs.

PMID- 10331032
TI  - Relevance of pharmacokinetics in narrow therapeutic index drugs.

PMID- 10331033
TI  - Scientific and professional concerns regarding product interchange and subsequent
      monitoring of cyclosporine and other critical dose drugs.

PMID- 10331034
TI  - Bioequivalence criteria for cyclosporine.

PMID- 10331035
TI  - Relationship of pharmacokinetics to clinical outcomes.

PMID- 10331036
TI  - Lessons from the Neoral Global Database for renal transplantation.

PMID- 10331037
TI  - Long-term safety studies: insights into requirements for changing cyclosporine
      formulations.

PMID- 10331038
TI  - Influence of drug formulation on utilization and outcomes: Neoral and monitoring
      by sparse sample area under the curve.

PMID- 10331039
TI  - Overview of the clinical experience with Neoral in transplantation.
AB  - The microemulsion preparation of cyclosporine, Neoral, was introduced to improve
      the limited and sometimes unpredictable absorption of cyclosporine from the gut.
      Preclinical studies proved a superior bioavailability measured by the AUC and a
      definitively better predictability of the pharmacokinetic properties. Large-scale
      randomized and open-labeled studies have been carried out to prove and establish
      the safety, tolerability, and equal or superior efficacy of NEO if compared with
      SIM. There is broad evidence that NEO is safe and well tolerated in de novo and
      stable renal allografts. There are some arguments that NEO has favorable
      properties in poor absorbers, in patients in need for high dosage per kg body
      weight. Benefits for some populations such as children, African Americans, and
      diabetics have been detected. In combined kidney-pancreas transplantation a
      significant improvement of absorption has been proven. NEO has also been
      investigated in nonrenal transplants such as heart, lung, and liver
      transplantation. There are proven dose reduction in heart transplants;
      significant better absorption in lung transplants, in particular in patients with
      cystic fibrosis; and no further or even a diminished need for intravenously given
      CsA in liver transplantation. Studies are now reported for the use of NEO in
      differing indications of autoimmune disease. No characteristic profile of adverse
      events has been recognized, nor has an increase of nephrotoxicity if carefully
      monitoring in the first weeks after conversion was provided.

PMID- 10331040
TI  - Significance of chronic transplant nephropathy on early protocol biopsies for
      graft outcome in pediatric renal transplantation.

PMID- 10331041
TI  - Evolution and complications in the immediate postoperative period after pediatric
      liver transplantation: our experience with 176 transplantations.

PMID- 10331042
TI  - Histologic grading of acute renal allograft rejection.

PMID- 10331043
TI  - Estimating the potential effects of donor registries using a simple analytical
      model.

PMID- 10331044
TI  - Plasma endothelin in cyclosporine A-treated renal transplant patients.

PMID- 10331045
TI  - Effect of 15-deoxyspergualine on coronary arteriosclerosis and platelet-derived
      growth factor-A mRNA expression in the transplanted heart.

PMID- 10331046
TI  - Transarterial chemoembolization for hepatocellular carcinoma arising in a
      hepatitis C virus-seropositive renal allograft recipient.

PMID- 10331047
TI  - Brain death-induced myocardial dysfunction: a role for apoptosis?

PMID- 10331048
TI  - Percutaneous management of a high-output duodenal fistula after pancreas
      transplantation using occluding coiled embolus and fibrin sealant.

PMID- 10331049
TI  - Rheumatic complications following liver transplantation.

PMID- 10331050
TI  - Pleuropulmonary tuberculosis in patients with end-stage renal disease: findings
      on chest radiographs.

PMID- 10331051
TI  - Large-scale isolation of islets by tissue culture of adult mouse pancreas.

PMID- 10331052
TI  - Vitamin E suppresses cyclosporine A-induced increase in the urinary excretion of
      arachidonic acid metabolites including F2-isoprostanes in the rat model.

PMID- 10331053
TI  - Acute renal allograft rejection in the canine: evaluation with serial duplex
      Doppler ultrasonography.

PMID- 10331054
TI  - Persistently expressed interleukin-1 beta and tumor necrosis factor-alpha gene in
      accepted rat lung allografts.

PMID- 10331055
TI  - [Role of information system for the health care delivery in community].
AB  - Sophisticated information technologies have been applied in hospitals as well as
      in clinics. However, almost no information system has been developed which links
      hospitals and clinics. Medical care and welfare services are still separated
      activities and there are no information systems which exchange the data between
      the two sectors. Emergency medical information systems have been developed in the
      past, but they are usually used only for the exchange of bed occupancy
      information. Doctors started using the Internet, but there have been few medical
      books in Japanese in cyber space. Initiatives of medical personnel who are
      engaged in the daily health care delivery are necessary to solve the above stated
      problems. Some promising systems are emerging by the efforts of pioneers.
      Administrative agencies should assist the efforts of these initiatives to improve
      the community health care delivery. In the near future, the information systems
      will have some influence on the shape of medical care. Patient's medical data
      will be disclosed to patients. Specialty of hospitals will be also disclosed to
      the public. As a result, doctors will start to seek for more objective evidence
      for their medical care to patients. Clinical practice guidelines will be produced
      for common diseases in Japan as in Europe. Hospitals will cooperate with each
      other in the delivery of care, because it will be impossible for one hospital to
      give all types of care to patients. Hospitals in a community will function as if
      a virtually single hospital even though they are different in management.

PMID- 10331056
TI  - [Studies on the effects of constant exercise around the ventilatory threshold
      using spectral analysis of EMG and ECG-RR interval variability].
AB  - The effects constant exercise at three levels around the ventilatory threshold
      (VT) were investigated by spectral analysis of EMG and RR interval variability of
      ECG. The subjects were 11 healthy male students (ranging from 20 to 25 years
      old). Surface EMG from the knee extensor muscular (m. vastus medialis) and the RR
      interval of the ECG were recorded by bicycle ergometer during the three levels of
      exercise which were 20% less than the VT level (-20% VT), the VT level and 20%
      more than the VT level (+20 VT). Power spectral analysis of EMG was performed to
      obtain the power spectral density (PSD) of 4 bands (20-50Hz, 50-100Hz, 100-150Hz,
      150-200Hz) every 2 seconds by the maximum entropy method (MEM). Power spectral
      analysis of RR interval variability of ECG was performed every 1 minute by MEM to
      obtain the low-frequency band (LFB, 0.04 to 0.15 Hz), the high-frequency band
      (HFB, 0.15 to 0.4 Hz) and the ratio of LFB to HFB (L/H ratio). Changes in Total
      PSD from 20 Hz to 200 Hz on EMG showed a higher value at the +20 VT level than at
      the VT level or -20 VT level. The %PSD of EMG at the band of 100-150 Hz and 150
      200 Hz increased in the work load at the +20 VT level more than at the VT level
      or -20 VT level. Comparisons of the EMG parameters suggested a progressive
      recruitment of fast twitch fibers (type II b) with time. HF component of the RR
      interval variability showed a rapid decrease in proportion to load, whereas there
      was no such trend in the L/H ratio during the 3 levels of constant exercise
      levels. In each case, HF components of RR interval variability could be used as
      an indicator of parasympathetic nervous activities, but the L/H ratio did not
      clearly show sympathetic nervous activities during the constant exercise.

PMID- 10331057
TI  - [Usefulness of arterio-portal shunt in 40% hepatectomized and hepatic artery
      occluded model].
AB  - We performed an experimental study in dogs with 40% hepatectomy to prove the
      efficacy and safety of arterio-portal shunt (APS). Forty-two adult mongrel dogs
      were used for the experiments. After dearterialization of all the collateral
      arteries to the liver, the dogs were divided into 3 groups. In Group 1,
      dearterialization of the hepatic artery, 40% hepatectomy and APS were performed;
      in Group 2, only 40% hepatectomy was performed, and in Group 3, dearterialization
      of the hepatic artery and 40% hepatectomy were performed. APS was constructed by
      anastomosing the common hepatic artery with the portal vein. The hepatic
      hemodynamics, oxygen delivery and consumption were evaluated, and biochemical and
      histological studies were carried out in each group. The study consisted of a
      short-term (48-hour; Experiment 1) and a medium-term (4-weeks; Experiment 2)
      observations. In Experiment 2, liver regeneration was additionally examined. In
      Experiment 1, Group 1 and Group 2 showed almost the same findings in all the 4
      examination points. However, in Group 3, postoperative oxygen delivery and
      consumption significantly decreased, and biochemical and histological
      examinations evidenced the significant liver failure. These results show that APS
      is capable of preventing postoperative liver failure during the short-term
      observation period and can substitute for reconstruction of the hepatic artery.
      Experiment 2 was intended for a longer follow-up of Experiment 1. However, Group
      3 did not survive longer than 1 week and was thus excluded. In Group 1 and Group
      2, findings on the 4 examinations remained alike for p.o. 4 weeks. And, the two
      groups regained the preoperative liver weight, respectively, at p.o. 4 weeks. The
      number of PCNA (proliferating cell nuclear antigen)-positive hepatocytes
      significantly increased at p.o. 1 week in both groups. These findings revealed
      that regeneration of the liver in Group 1 with APS was equivalent to that in
      Group 2 with mere hepatectomy for p.o. 4 weeks at least. These results indicate
      that liver failure can be averted by constructing APS in hepatectomy cases where
      reconstruction of the hepatic artery is impossible.

PMID- 10331058
TI  - [Cu, Zn-superoxide dismutase release from cultured rat hepatocytes].
AB  - Oxygen free radicals have been reported to play an important role in some
      pathologic conditions. Some kinds of cells were reported to release superoxide
      anion (O2-) when they were exposed to anoxia followed by reoxygenation or some
      stimuli. As it is thought that hepatocytes are also attacked by exogenous O2-,
      cultured hepatocytes were subjected to this study. Firstly the reaction of rat
      cultured hepatocytes to exogenous O2- was investigated with the use of electron
      spin resonance (ESR) spectroscopy. The hepatocytes rapidly released a O2(-)
      scavenging factor and its activity was higher than that of fibroblasts. As the
      activity of the factor was inhibited by diethyldithiocarbamate (DDC), the factor
      was thought to be Cu, Zn-SOD. The release was not specifically to O2- and
      supposed to be caused by mechanical stress. Secondly the factor was analyzed by
      electrophoresis and Western blot analysis, and proved to be Cu, Zn-SOD. It was
      also confirmed by the inhibiting effects of DDC and potassium cyanide (KCN).
      Furthermore Cu, Zn-SOD release was observed for a period of 3 days, comparing
      with that of lactate dehydrogenase (LDH). The day-to-day release pattern of SOD
      was similar to that of LDH. But after replacement of medium on Day 1, Cu, Zn-SOD
      was released more rapidly than LDH. In conclusion the cultured rat hepatocytes
      released a substantial amount of Cu, Zn-SOD, capable of altering the levels of
      free radicals. Investigators should pay attention to this effect in an
      experimental study using cultured rat hepatocytes.

PMID- 10331059
TI  - [Effects of methamphetamine on responsiveness to conditioned fear stress].
AB  - The present study examined the effect of repeated methamphetamine (MA)
      pretreatment on conditioned fear stress in male Wistar-King rats. Rats received
      MA or the vehicle according to the repeated escalating dose schedule (1.25, 2.5,
      3.75, 5 mg/kg s.c x2/every other day for a week). After a 5 day drug abstinent
      period, the rats were exposed to conditioned fear stress (CFS; exposure to an
      environment paired previously with footshock). Repeated but not single MA
      pretreatment significantly increased conditioned freezing behavior, suggesting
      that rats previously exposed to chronic MA are hypersensitive to subsequent
      stress than control rats. Repeated MA treatment did not decrease basal dopamine
      concentrations in the brain. Furthermore, repeated co-administration of MK-801
      (non-competitive NMDA antagonist), amfonelic acid (dopamine reuptake inhibitor)
      or fluoxetine (serotonin reuptake inhibitor) with MA did not alter the enhanced
      freezing behavior. Taken together, it seems that MA-induced hypersensitivity to
      stress is not due to the neurotoxic effect of MA. While co-administration of
      SCH23390 (D1/5 antagonist) or raclopride (D2/3 antagonist) had no effect on the
      MA-induced increase in freezing, co-administration of nemonapride (D2/3/4
      antagonist) prevented this increase. These results suggest that MA-induced
      enhancement of anxiety might be mediated by D4 receptors. The homovanilic acid
      (HVA) levels in the striatum were elevated by footshock in MA-treated rats but
      not in saline-treated rats. Furthermore, MA-treated rats showed increased
      metabolism of dopamine (DA) in the medial prefrontal cortex (mPFC), even when
      placed in the shock chamber without shocks. The HVA levels in the striatum in MA
      treated rats were more elevated by CFS than these in saline-treated rats. These
      results suggest that the striatum DA system, as well as the mPFC DA system
      suggested previously, may be associated with emotional hypersensitivity to stress
      following repeated MA treatment.

PMID- 10331060
TI  - [A study on the role of the transmembrane V to VI regions of the human
      luteinizing hormone receptor in its constitutive activation].
AB  - Gonadotropin (luteinizing hormone: LH, and follicle stimulating hormone: FSH)
      receptors are members of the seven-transmembrane (TM) receptor family. Recently,
      point mutations have been identified in the LH receptor gene, leading to
      constitutive activation (ligand-independent activation) of the receptor in
      patients with familial male-limited precocious puberty. Most of such point
      mutations were found in the coding region consisting of TM V, VI and the
      intracellular loop 3 (i3). Because the primary structures of gonadotropin
      receptors are highly conserved, in vitro mutagenesis was performed to introduce
      the amino acid substitution in the i3 domain (Asp-->Gly) of FSH receptor,
      corresponding to the point mutation leading to constitutive activation in LH
      receptor. However, the FSH receptor mutant showed almost similar basal cAMP
      production to wild type counterpart. For investigation of this difference in
      constitutive activation between two receptors, the author designed chimeric
      LH/FSH receptors with or without an amino acid substitution in the i3 (Asp-->Gly)
      to identify the region in the LH receptor which is important for its constitutive
      activation. Introduction of the amino acid substitution into a chimeric receptor
      containing only TM V to VI from the LH receptor led to major increases in ligand
      independent cAMP production. Furthermore, the chimeric receptor with only TM V
      and VI derived from the LH receptor was constitutively activated by the amino
      acid substitution in the i3 from the FSH receptor. These results that
      interactions between TM V and VI of the FSH receptor are essential for
      maintaining the receptor conformation constrained, whereas interactions between
      these domains of the LH receptor are required for constitutive activation by the
      amino acid substitution in the i3.

PMID- 10331061
TI  - [Analysis of immunological mechanisms in the pathogenesis of generalized pustular
      psoriasis].
AB  - Generalized pustular psoriasis is one of life-threatening skin diseases which
      represents sudden onset of severe systemic symptoms such as high fever and chill
      as well as burning erythema and aseptic pustules over the entire skin. Although
      the precise mechanism of this rare disease is unknown, several lines of clinical
      and experimental observations have suggested that certain immunological
      mechanisms play important roles in the pathogenesis of this disease. In this
      study, in order to attain better understanding of the immunological events
      involved in generalized pustular psoriasis, several in vivo and in vitro
      immunological experiments have been performed. The results obtained are as
      follows: 1) sera from patients contained high amount of inflammatory cytokines,
      2) peripheral blood mononuclear cells(PBMC) showed high proliferative responses
      to bacteria-derived super antigens, 3) PBMC from patients produced a large amount
      of cytokines when stimulated by mitogens in vitro, 4) endothelial cells in the
      lesional skins of patients exhibited enhanced expression of adhesion molecules,
      and 5) the expressions of these adhesion molecules on human endothelial cells
      were differently regulated by several cytokines. These results suggest that the
      activation of peripheral blood mononuclear cells by bacteria-derived super
      antigens followed by cytokine production, and the induction of the adhesion
      molecules expressions on the endothelial cells are important immunological events
      in the forming the characteristic clinical symptoms of generalized pustular
      psoriasis.

PMID- 10331062
TI  - [A case report of diabetic scleredema in a patient with non-insulin-dependent
      diabetes mellitus].
AB  - A 70-year-old Japanese man with non-insulin-dependent diabetes mellitus showed
      scleredema diabeticorum. The patient complained of edematous feelings on his
      hands, both arms and face. The time of onset of these symptoms was not known. He
      had typical clinical and histopathological findings of diabetic scleredema. His
      diabetic control was poor and HbA1c level was 8.2% under insulin treatment. The
      patient had many complications such as diabetic retinopathy, diabetic nephropathy
      with benign nephrosclerosis, hyperlipidemia accompanied with a low level of high
      density lipoprotein cholesterol, hypertension and coronary heart disease. There
      were no abnormal laboratory findings except the diabetic controls and mild
      abnormal renal functions; however erythrocyte sedimentation rate was high.

PMID- 10331063
TI  - Cancer vaccines with emphasis on a viral oncolysate melanoma vaccine.
AB  - Biotherapy of malignant diseases has become the fourth treatment modality besides
      surgery, chemo- and radiotherapy. Whole cell melanoma vaccines with or without
      BCG and other adjuvants, purified ganglioside and shed antigens, recombinant
      viruses carrying tumor antigens, dendritic cells pulsed with antigenic peptides
      etc. are in clinical trials. Efficacious viral oncolysate vaccines induce the
      host to mount tumor-specific cytotoxic T-cell response and prevention of relapses
      is supported by clinical trials. The use of "polyvalent" whole cell vaccines vs.
      purified or genetically engineered single antigen vaccines is justified as i.
      only very few single tumor antigens are present in all tumors of a given
      histological type; and ii. antigen modulation occurs in tumors rendering them
      resistant to immune attack generated by vaccine against a single antigen. Thus
      polyvalent vaccines immunize against several antigens vs. against a selected
      antigen.

PMID- 10331064
TI  - Studies on influenza- and Newcastle disease virus at the University's Institute
      of Microbiology (Budapest) in 1948-50.

PMID- 10331065
TI  - Chromium-resistant soil actinomycetes: their tolerance to other metals and
      antibiotics.
AB  - Chromium occurs widely in most soils, but generally in trace amounts.
      Actinomycetes, one of the important components of the microbial population in
      soils interact with a variety of metals including chromium. This study was aimed
      to evaluate the tolerance of soil actinomycetes to Cr6+, other metals and
      antibiotics. Thirty-two actinomycete isolates were screened for their tolerance
      to Cr6+ on tryptone yeast extract agar medium supplemented with Cr6+ at
      concentrations ranging from 100 to 2000 micrograms ml-1. Thirteen Cr-tolerant
      isolates were selected on the basis of their growth at the highest concentration,
      but their performance was not satisfactory in Cr6+ containing liquid salts
      medium. Resistance of these isolates to other metals and antibiotics was assessed
      using agar-cup assay and disc diffusion technique, respectively. The sequence of
      metal toxicity for the actinomycete isolates was in the order Hg2+ > Ni2+ > Cu2+
      > Co2+ > Cd2+, but the Cr6+ resistance of the isolates could not be correlated
      with their antibiotic-resistance profile.

PMID- 10331066
TI  - Cryptosporidiosis in immunocompromised patients in a Turkish university hospital.
AB  - The prevalence of Cryptosporidiosis in 18 immunosuppressed diarrheic patients was
      evaluated by examination of fecal samples by direct staining (Modified Kinyoun
      and Giemsa), direct and indirect immunofluorescence methods. Forty patients (10
      nondiarrheic immunosuppressed, 10 nondiarrheic immunocompetent, and 20 diarrheic
      immunocompetent) were included in the study as the control group. 11 of 18
      samples were positive for cryptosporidial oocysts by at least one of the methods.
      Oocysts were detected in all (n = 7) of the AIDS patients. This high frequency
      was attributed to a probable nosocomial infection. None of the samples from
      control subjects were found positive for Cryptosporidium. Our results indicate
      that Cryptosporidial oocysts should be detected particularly in immunosuppressed
      patients with diarrhea. Modified Kinyoun staining method is practical and
      reliable for this purpose. Immunofluorescence staining methods can be applied for
      confirmation of the results.

PMID- 10331067
TI  - Basidiocarp and mycelium morphology of Ganoderma lucidum Karst. Strains isolated
      in Hungary.
AB  - Morphological, anatomical and cultural characteristics of 14 Ganoderma lucidum
      (Fr.) Karst strains isolated in Hungary have been investigated. Macroscopically
      the basidiocarps of the Hungarian strains are absolutely identical with those of
      described previously about the Ganoderma lucidum species-complex. Microscopic
      features of the fruitbodies and basidiospores showed some differences from the
      typical G. lucidum species. Pilocystidia, forming a homogeneous layer on the
      surface of the pileus, have smooth heads without protrusions and stalks not
      ramifying. Cell wall pillar density and width of the basidiospores also differ
      from that of regarded to be characteristic to G. lucidum. Although according to
      several authors chlamydospore formation is a characteristic feature of G. lucidum
      it has not been observed in mycelial cultures of the Hungarian strains.
      Antagonistic reactions between the Hungarian and Far Eastern G. lucidum isolates
      were mostly similar to the interspecific reactions between the two species G.
      lucidum and G. applanatum and corresponded only in a few cases to the
      interactions within one species. Our results suggest that the Hungarian strains
      significantly differ from the Far Eastern strains. To determine the taxonomic
      degree of this divergence genetical examinations should be carried out.

PMID- 10331068
TI  - Partial characterization of two lymphocyte-specific natural autoantibodies
      isolated from newborn mice.
AB  - The early antibody-repertoire is mainly composed of multi- and polyreactive IgM
      autoantibodies. Some of them (about 10%) also react with cell surface antigens.
      It is supposed that these latter antibodies promote--particularly under the
      maturation of the immune system--the expansion of different lymphocyte
      populations and subpopulations, namely the filling of the secondary lymphoid
      organs by immunocompetent cells. In order to verify this hypothesis we
      established hybridoma clones from newborn Balb/c mice. Almost all IgM antibodies
      produced by these hybridomas (94%) were found to be polyreactive, but only two-
      the 4/5 and the 8/8--react with cell surface structures. The 4/5 IgM recognizes a
      glicerin-phosphathydil-inositol (GPI)-anchored membrane component expressed on
      the early thymocytes. The 8/8 antibody reacts with resting splenic B lymphocytes
      as well as B and T cell blasts via an about 40 kD protein. They do not influence
      the spontaneous or the mitogen induced proliferation of the lymphocytes.
      Therefore we cannot confirm the hypothesis that increase of the expansion of
      peripheral lymphocytes would be the main function of these neonatal natural
      autoantibodies.

PMID- 10331069
TI  - Pancreatic neoplasms with abundant mucus production: emphasis on intraductal
      papillary-mucinous tumors and mucinous cystic tumors.
AB  - The clinicopathologic features and problems in classification and diagnosis of
      the pancreatic neoplasms with abundant mucus production are presented. In this
      article, the various reported concepts and terminology of these mucus-producing
      pancreatic tumors are summarized, and the differences between intraductal
      papillary-mucinous tumors and mucinous cystic tumors are specifically discussed.
      Intraductal papillary-mucinous tumors show diffuse or segmental dilatation of the
      pancreatic ducts with intraductal papillary growth. Mucinous cystic tumors are
      mucus-producing tumors showing cyst formation, which is often accompanied by
      intracystic papillary projections and "ovarian-type" stroma. Intraductal
      papillary-mucinous tumors occur most often in the pancreatic head of elderly men,
      whereas mucinous cystic tumors typically occur in the pancreatic tail or body of
      middle-aged women. Histologically, these tumors show a wide cytologic spectrum
      from benign to borderline to malignant. These tumors pursue an indolent clinical
      course compared with conventional ductal carcinoma of the pancreas. Mucinous
      cystadenocarcinomas have a higher malignant potential than intraductal papillary
      mucinous adenocarcinomas, yet these tumors recur infrequently if they are excised
      completely. Because of the differences in clinicopathologic features, these
      tumors should be clearly separated from conventional ductal carcinoma of the
      pancreas.

PMID- 10331070
TI  - Pathomorphology of thyroid gland lesions associated with radiation exposure: the
      Chernobyl experience and review of the literature.
AB  - The common sources of ionizing radiation exposure to the thyroid gland in humans
      are accidental environmental exposure and medical, therapeutic, or diagnostic
      irradiation. Radiation often induces notable histologic changes in the thyroid
      tissue and is a well-established risk factor for benign and malignant thyroid
      tumors. In this paper, we review the acute and chronic histologic changes in the
      thyroid gland subjected to irradiation, and characterize benign thyroid nodules
      and malignant tumors arising after exposure, with particular emphasis on thyroid
      lesions in the population exposed to ionizing radiation as a result of the
      Chernobyl nuclear accident.

PMID- 10331071
TI  - Sentinel lymph node biopsy: not the state of art in the management of breast
      cancer yet.

PMID- 10331072
TI  - Atypical teratoid/rhabdoid tumor--a stereogram unveiled.

PMID- 10331073
TI  - Testicular Sertoli cell tumors NOS, the final word?

PMID- 10331074
TI  - Cytochrome P-450 3A4: regulation and role in drug metabolism.
AB  - Cytochrome P-450 (P-450) 3A4 is the most abundant P-450 expressed in human liver
      and small intestine. P-450 3A4 contributes to the metabolism of approximately
      half the drugs in use today, and variations in its catalytic activity are
      important in issues of bioavailability and drug-drug interactions. The gene is
      known to be inducible by barbiturates, glucocorticoids, and rifampicin in humans
      and in isolated hepatocytes, although the mechanism remains unclear. The 5'
      untranslated region includes putative basal transcription element, hepatocyte
      nuclear factor, p53, AP-3, glucocorticoid regulatory element, pregnane X
      receptor, and estrogen receptor element sequences. Recently, the GRE element has
      been shown to act in a classic glucocorticoid response. Several issues remain to
      be resolved regarding the catalytic activity of the P-450 3A4 protein, including
      rate-limiting steps and the need for cytochrome b5, divalent cations, and acidic
      phospholipid systems for optimal activity. Another issue involves the basis of
      the homotropic and heterotropic cooperativity seen with the enzyme. The in vivo
      significance of these findings remains to be further established. In addition to
      more basic studies on P-450 3A4, several areas of practical interest to the
      pharmaceutical industry require development.

PMID- 10331075
TI  - Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine
      methyltransferase, and histamine N-methyltransferase.
AB  - Methyl conjugation is an important pathway in the biotransformation of many
      exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase
      enzymes have resulted in the identification and characterization of functionally
      important common genetic polymorphisms for catechol O-methyltransferase,
      thiopurine methyltransferase, and histamine N-methyltransferase. In recent years,
      characterization of these genetic polymorphisms has been extended to include the
      cloning of cDNAs and genes, as well as a determination of the molecular basis for
      the effects of inheritance on these methyltransferase enzymes. The thiopurine
      methyltransferase genetic polymorphism is responsible for clinically significant
      individual variations in the toxicity and therapeutic efficacy of thiopurine
      drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase
      genetic polymorphism represents one of the first examples in which testing for a
      pharmacogenetic variant has entered standard clinical practice. The full
      functional implications of pharmacogenetic variation in the activities of
      catechol O-methyltransferase and histamine N-methyltransferase remain to be
      determined. Finally, experimental strategies used to study methylation
      pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic,
      molecular, and genomic approaches that have been used to determine the role of
      inheritance in variation in drug metabolism, effect, and toxicity.

PMID- 10331076
TI  - The pineal gland and melatonin: molecular and pharmacologic regulation.
AB  - The pineal gland expresses a group of proteins essential for rhythmic melatonin
      production. This pineal-specific phenotype is the consequence of a temporally and
      specially controlled program of gene expression. Understanding of pineal
      circadian biology has been greatly facilitated in recent years by a number of
      molecular studies, including the cloning of N-acetyltransferase, the
      determination of the in vivo involvement of the cAMP-inducible early repressor in
      the regulation of N-acetyltransferase, and the identification of a pineal
      transcriptional regulatory element and its interaction with the cone-rod homeobox
      protein. Likewise, appreciation the physiological roles of melatonin has
      increased dramatically with the cloning and targeted knockout of melatonin
      receptors. With these molecular tools in hand, we can now address more specific
      questions about how and why melatonin is made in the pineal at night and about
      how it influences the rest of the body.

PMID- 10331077
TI  - Regulation of gene expression by reactive oxygen.
AB  - Reactive oxygen intermediates are produced in all aerobic organisms during
      respiration and exist in the cell in a balance with biochemical antioxidants.
      Excess reactive oxygen resulting from exposure to environmental oxidants,
      toxicants, and heavy metals perturbs cellular redox balance and disrupts normal
      biological functions. The resulting imbalance may be detrimental to the organism
      and contribute to the pathogenesis of disease and aging. To counteract the
      oxidant effects and to restore a state of redox balance, cells must reset
      critical homeostatic parameters. Changes associated with oxidative damage and
      with restoration of cellular homeostasis often lead to activation or silencing of
      genes encoding regulatory transcription factors, antioxidant defense enzymes, and
      structural proteins. In this review, we examine the sources and generation of
      free radicals and oxidative stress in biological systems and the mechanisms used
      by reactive oxygen to modulate signal transduction cascades and redirect gene
      expression.

PMID- 10331078
TI  - Induction of cytochrome P4501A1.
AB  - Cytochrome P4501A1 is a substrate-inducible microsomal enzyme that oxygenates
      polycyclic aromatic hydrocarbons, such as the carcinogen benzo(a)pyrene, as the
      initial step in their metabolic processing to water-soluble derivatives. Enzyme
      induction reflects increased transcription of the cognate CYP1A1 gene. The
      environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin is the most potent
      known cytochrome P4501A1 inducer. Two regulatory proteins, the aromatic (aryl)
      hydrocarbon receptor (AhR) and the AhR nuclear translocator (Arnt), mediate
      induction. AhR and Arnt are prototypical members of the basic helix-loop
      helix/Per-Arnt-Sim class of transcription factors. Mechanistic analyses of
      cytochrome P4501A1 induction provide insights into ligand-dependent mammalian
      gene expression, basic helix-loop-helix/Per-Arnt-Sim protein function, and dioxin
      action; such studies also impact public health issues concerned with molecular
      epidemiology, carcinogenesis, and risk assessment.

PMID- 10331079
TI  - Cytotoxicity of short-chain alcohols.
AB  - Ethanol and other short-chain alcohols elicit a number of cellular responses that
      are potentially cytotoxic and, to some extent, independent of cell type.
      Aberrations in phospholipid and fatty acid metabolism, changes in the cellular
      redox state, disruptions of the energy state, and increased production of
      reactive oxygen metabolites have been implicated in cellular damage resulting
      from acute or chronic exposure to short-chain alcohols. Resulting disruptions of
      intracellular signaling cascades through interference with the synthesis of
      phosphatidic acid, decreases in phosphorylation potential and lipid peroxidation
      are mechanisms by which solvent alcohols can affect the rate of cell
      proliferation and, consequently, cell number. Nonoxidative metabolism of short
      chain alcohols, including phospholipase D-mediated synthesis of alcohol
      phospholipids, and the synthesis of fatty acid alcohol esters are additional
      mechanisms by which alcohols can affect membrane structure and compromise cell
      function.

PMID- 10331080
TI  - Glial cells in neurotoxicity development.
AB  - Neuroglial cells of the central nervous system include the astrocytes,
      oligodendrocytes, and microglia. Their counterparts in the peripheral nervous
      system are the Schwann cells. The term neuroglia comes from an erroneous concept
      originally coined by Virchow (1850), in which he envisioned the neurons to be
      embedded in a layer of connective tissue. The term, or its shortened form--glia,
      has persisted as the preferred generic term for these cells. A reciprocal
      relationship exists between neurons and glia, and this association is vital for
      mutual differentiation, development, and functioning of these cell types.
      Therefore, perturbations in glial cell function, as well as glial metabolism of
      chemicals to active intermediates, can lead to neuronal dysfunction. The purpose
      of this review is to explore neuroglial sites of neurotoxicant actions, discuss
      potential mechanisms of glial-induced or glial-mediated central nervous system
      and peripheral nervous system damage, and review the role of glial cells in
      neurotoxicity development.

PMID- 10331081
TI  - Regulation and inhibition of phospholipase A2.
AB  - In recent years, there has been great interest in the study of phospholipid
      metabolism in intact cell systems. Such an interest arises mainly from the
      discovery that cellular membrane phospholipids serve not only in structural
      roles, but are also reservoirs of preformed second messenger molecules with key
      roles in cellular signaling. These second messenger molecules are generated by
      agonist-induced activation and secretion of intracellular and extracellular
      phospholipases, respectively, i.e. enzymes that cleave ester bonds within
      phospholipids. Prominent members of the large collection of signal-activated
      phospholipases are the phospholipase A2s. These enzymes hydrolyze the sn-2 ester
      bond of phospholipids, releasing a free fatty acid and a lysophospholipid, both
      of which may alter cell function. In addition to its role in cellular signaling,
      phospholipase A2 has recently been recognized to be involved in a wide number of
      pathophysiological situations, ranging from systemic and acute inflammatory
      conditions to cancer. A growing number of pharmacologic inhibitors will help
      define the role of particular phospholipase A2s in signaling cascades.

PMID- 10331082
TI  - Inhibition of nitric oxide synthase as a potential therapeutic target.
AB  - Nitric oxide (NO) regulates numerous physiological processes, including
      neurotransmission, smooth muscle contractility, platelet reactivity, and the
      cytotoxic activity of immune cells. Because of the ubiquitous nature of NO,
      inappropriate release of this mediator has been linked to the pathogenesis of a
      number of disease states. This provides the rationale for the design of therapies
      that modulate NO concentrations selectively. A well-characterized family of
      compounds are the inhibitors of NO synthase, the enzyme responsible for the
      generation of NO; such agents are potentially beneficial in the treatment of
      conditions associated with an overproduction of NO, including septic shock,
      neurodegenerative disorders, and inflammation. This article provides an overview
      of NO synthase inhibitors, focusing on agents that prevent binding of substrate L
      arginine.

PMID- 10331083
TI  - Genetic regulation of glutamate receptor ion channels.
AB  - Transcriptional and translational regulation of glutamate receptor expression
      determines one of the key phenotypic features of neurons in the brain--the
      properties of their excitatory synaptic receptors. Up- and down-regulation of
      various glutamate receptor subunits occur throughout development, following
      ischemia, seizures, repetitive activation of afferents, or chronic administration
      of a variety of drugs. The promoters of the genes that encode the NR1, NR2B,
      NR2C, GluR1, GluR2, and KA2 subunits share several characteristics that include
      multiple transcriptional start sites within a CpG island, lack of TATA and CAAT
      boxes, and neuronal-selective expression. In most cases, the promoter regions
      include overlapping Sp1 and GSG motifs near the major initiation sites, and a
      silencer element, to guide expression in neurons. Manipulating the levels of
      glutamate receptors in vivo by generating transgenic and knockout mice has
      enhanced understanding of the role of specific glutamate receptor subunits in
      long-term potentiation and depression, learning, seizures, neural pattern
      formation, and survival. Neuron-specific glutamate receptor promoter fragments
      may be employed in the design of novel gene-targeting constructs to deliver
      future experimental transgene and therapeutic agents to selected neurons in the
      brain.

PMID- 10331084
TI  - Redox regulation of c-Ha-ras and osteopontin signaling in vascular smooth muscle
      cells: implications in chemical atherogenesis.
AB  - Reduction/oxidation (redox) reactions play a central role in the regulation of
      vascular cell functions. Recent studies in this laboratory have identified c-Ha
      ras and osteopontin genes as critical molecular targets during oxidant-induced
      atherogenesis. This review focuses on the deregulation of gene transcription by
      redox-activated trans-acting factors after benzo(a)pyrene challenge and the
      modulation of extracellular matrix signaling in vascular smooth muscle cells by
      allylamine-induced oxidative injury. The induction of atherogenic vascular smooth
      muscle cell phenotypes by chemical injury exhibits remarkable parallels with
      those seen in other forms of atherogenesis.

PMID- 10331085
TI  - Metallothionein: an intracellular protein to protect against cadmium toxicity.
AB  - Metallothioneins (MT) are low-molecular-weight, cysteine-rich, metal-binding
      proteins. MT genes are readily induced by various physiologic and toxicologic
      stimuli. Because the cysteines in MT are absolutely conserved across species, it
      was suspected that the cysteines are necessary for function and MT is essential
      for life. In attempts to determine the function(s) of MT, studies have been
      performed using four different experimental paradigms: (a) animals injected with
      chemicals known to induce MT; (b) cells adapted to survive and grow in high
      concentrations of MT-inducing toxicants; (c) cells transfected with the MT gene;
      and (d) MT-transgenic and MT-null mice. Most often, results from studies using
      the first three approaches have indicated multiple functions of MT in cell
      biology: MT (a) is a "storehouse" for zinc, (b) is a free-radical scavenger, and
      (c) protects against cadmium (Cd) toxicity. However, studies using MT-transgenic
      and null mice have not strongly supported the first two proposed functions but
      strongly support its function in protecting against Cd toxicity. Repeated
      administration of Cd to MT-null mice results in nephrotoxicity at one tenth the
      dose that produces nephrotoxicity in control mice. Human studies indicate that 7%
      of the general population have renal dysfunction from Cd exposure. Therefore, if
      humans did not have MT, "normal" Cd exposure would be nephrotoxic to humans.
      Thus, it appears that during evolution, the ability of MT to protect against Cd
      toxicity might have taken a more pivotal role in the maintenance of life
      processes, as compared with its other proposed functions (i.e. storehouse for
      zinc and free radical scavenger).

PMID- 10331086
TI  - Cyclins and cell cycle checkpoints.
AB  - The eucaryotic cell cycle is regulated by the periodic synthesis and destruction
      of cyclins that associate with and activate cyclin-dependent kinases. Cyclin
      dependent kinase inhibitors, such as p21 and p16, also play important roles in
      cell cycle control by coordinating internal and external signals and impeding
      proliferation at several key checkpoints. Understanding how these proteins
      interact to regulate the cell cycle has become increasingly important to
      researchers and clinicians with the discovery that many of the genes that encode
      cell cycle regulatory activities are targets for alterations that underlie the
      development of cancer. Several therapeutic agents, such as DNA-damaging drugs,
      microtubule inhibitors, antimetabolites, and topoisomerase inhibitors, take
      advantage of this disruption in normal cell cycle regulation to target checkpoint
      controls and ultimately induce growth arrest or apoptosis of neoplastic cells.
      Other therapeutic drugs being developed, such as UCN-01, specifically inhibit
      cell cycle regulatory proteins.

PMID- 10331087
TI  - New insights into dopaminergic receptor function using antisense and genetically
      altered animals.
AB  - Dopaminergic receptors are widespread throughout the central and peripheral
      nervous systems, where they regulate a variety of physiological, behavioral, and
      endocrine functions. These receptors are also clinically important drug targets
      for the treatment of a number of disorders, such as Parkinson's disease,
      schizophrenia, and hyperprolactinemia. To date, five different dopamine receptor
      subtypes have been cloned and characterized. Many of these subtypes are
      pharmacologically similar, making it difficult to selectively stimulate or block
      a specific receptor subtype in vivo. Thus, the assignment of various
      physiological or behavioral functions to specific dopamine receptor subtypes
      using pharmacological tools is difficult. In view of this, a number of
      investigators have--in order to elucidate functional roles--begun to use highly
      selective genetic approaches to alter the expression of individual dopamine
      receptor subtypes in vivo. This review discusses recent studies involving the use
      of genetic approaches for the study of dopaminergic receptor function.

PMID- 10331088
TI  - Beta-adrenergic receptors and receptor signaling in heart failure.
AB  - Cardiac beta-adrenergic receptors, which respond to neuronally released and
      circulating catecholamines, are important regulators of cardiac function.
      Congestive heart failure, a common clinical condition, is associated with a
      number of alterations in the activation and deactivation of beta-adrenergic
      receptor pathways. Studies with failing hearts from humans and animals indicate
      that such alterations include changes in the expression or function of beta
      adrenergic receptors, G-proteins, adenylyl cyclases, and G-protein receptor
      kinases. The net effect of these alterations is the substantial blunting of beta
      adrenergic receptor-mediated cardiac response. An important unanswered question
      is whether the loss of cardiac beta-adrenergic receptor responsiveness is a
      contributing cause, or a result, of ventricular dysfunction. Even though this
      question remains unanswered, the concept of targeting the beta-adrenergic pathway
      in the failing heart is becoming increasing popular and several new therapeutic
      strategies are in development.

PMID- 10331089
TI  - Biochemical, cellular, and pharmacological aspects of the multidrug transporter.
AB  - Considerable evidence has accumulated indicating that the multidrug transporter
      or P-glycoprotein plays a role in the development of simultaneous resistance to
      multiple cytotoxic drugs in cancer cells. In recent years, various approaches
      such as mutational analyses and biochemical and pharmacological characterization
      have yielded significant information about the relationship of structure and
      function of P-glycoprotein. However, there is still considerable controversy
      about the mechanism of action of this efflux pump and its function in normal
      cells. This review summarizes current research on the structure-function analysis
      of P-glycoprotein, its mechanism of action, and facts and speculations about its
      normal physiological role.

PMID- 10331090
TI  - Teratology of retinoids.
AB  - Either an excess or a deficiency of vitamin A and related compounds (retinoids)
      causes abnormal morphological development (teratogenesis). Potential retinoid
      sources come from dietary intake, nutritional supplements, and some therapeutic
      drugs. Therefore, understanding the mechanisms of retinoid teratogenesis is
      important. This review first gives an overview of the principles of teratology as
      they apply to retinoid-induced malformations. It then describes relevant aspects
      of the biochemical pathway and signal transduction of retinoids. The teratogenic
      activity of various retinoid compounds, the role of the retinoid receptors, and
      important toxicokinetic parameters in teratogenesis are reviewed.

PMID- 10331091
TI  - Excitatory amino acid transporters: a family in flux.
AB  - As the most predominant excitatory neurotransmitter, glutamate has the potential
      to influence the function of most neuronal circuits in the central nervous
      system. To limit receptor activation during signaling and prevent the
      overstimulation of glutamate receptors that can trigger excitotoxic mechanisms
      and cell death, extracellular concentrations of excitatory amino acids are
      tightly controlled by transport systems on both neurons and glial cells. L
      Glutamate is a potent neurotoxin, and the inadequate clearance of excitatory
      amino acids may contribute to the neurodegeneration seen in a variety of
      conditions, including epilepsy, ischemia, and amyotrophic lateral sclerosis. To
      establish the contributions of carrier systems to the etiology of neurological
      disorders, and to consider their potential utility as therapeutic targets, a
      detailed understanding of transporter function and pharmacology is required. This
      review summarizes current knowledge of the structural and functional diversity of
      excitatory amino acid transporters and explores how they might serve as targets
      for drug design.

PMID- 10331092
TI  - Thrombophilia: disorders predisposing to venous thromboembolism.
AB  - Venous thromboembolism continues to present a challenge to clinicians. Over the
      years, a number of risk factors which predispose to venous thromboembolism have
      been identified, and these risk factors are taken into account in the formulation
      of recommendations for the prevention and treatment of these disorders. In more
      recent years, there have been major advances in our understanding of congenital
      or acquired defects that predispose to thrombosis leading to these so-called
      acquired or inherited forms of thrombophilia. The list of acquired forms of
      thrombophilia now includes anti-thrombin, protein C, protein S, activated protein
      C resistance, the prothrombin 20210A mutant, homocysteinemia and a number of rare
      defects which either enhance coagulation or interfere with fibrinolysis. In spite
      of these advances, there are numerous families with thrombophilia in whom none of
      the known defects can be demonstrated. The challenge for the future is to
      discover some of these as yet unknown factors and to determine the most
      appropriate methods for the prevention and treatment of venous thromboembolism in
      susceptible individuals with thrombophilia.

PMID- 10331093
TI  - Diagnostic management of venous thromboembolism.
AB  - The accuracy of diagnostic methods for the diagnosis of deep vein thrombosis and
      pulmonary embolism in symptomatic patients is critically reviewed. In addition,
      the safety of withholding anticoagulant therapy from patients with suspected deep
      vein thrombosis or pulmonary embolism in whom the qualified diagnostic strategy
      was normal is evaluated by determining the frequency of venous thromboembolic
      complications during 3 months of follow-up. It is shown that the currently used
      available diagnostic techniques for deep vein thrombosis are all able to identify
      the majority of patients who indeed have venous thrombosis. However, as result of
      its accuracy and practical advantages, compression ultrasound is the test of
      choice in the evaluation of symptomatic patients. Patients with a normal test
      outcome should be re-tested to detect the small proportion of patients with
      proximally extending calf vein thrombosis. In the strategy of repeated diagnostic
      testing, impedance plethysmography could be used as an alternative to
      ultrasonography. To obtain a reduction in repeat tests various diagnostic
      strategies have been evaluated and it was shown that these strategies, using non
      invasive tests, can be as accurate and safe as the invasive reference strategy.
      The safeties of the various strategies were very similar; however, important
      differences were observed with respect to the practical implementation of the
      various diagnostic strategies. Simplification of the repeated testing strategy by
      using a D-dimer assay and/or a clinical decision rule seems to be promising. The
      reference standard for the diagnosis of pulmonary embolism remains pulmonary
      angiography. Several strategies based on non-invasive diagnostic methods have
      been evaluated for their safety and complexability. Perfusion-ventilation lung
      scanning is the most thoroughly evaluated non-invasive technique so far. It seems
      safe to withhold anticoagulant therapy in patients suspected of pulmonary
      embolism with a normal perfusion lung scan result; however, further testing is
      needed in the case of a non-diagnostic perfusion-ventilation lung scan result. At
      this moment angiography is the method of choice in this category of patients. D
      dimer assays, clinical decision rules and ultrasound examinations of the legs
      seem to have a high potential to limit the need for angiography. Also, spiral
      computerized tomography and magnetic resonance imaging are promising techniques,
      but their role in the diagnostic management of pulmonary embolism is still
      uncertain.

PMID- 10331094
TI  - Laboratory diagnosis of venous thromboembolism.
AB  - Venous thromboembolism is a common medical condition in both out-patients and in
      patients. Despite the development of non-invasive tests, the diagnosis of deep
      vein thrombosis and pulmonary embolism remains a clinical challenge. In an effort
      to improve diagnostic accuracy and to reduce the necessity of serial testing,
      laboratory markers of thrombin generation and fibrinolysis have been investigated
      as first-line screening tests. Although the majority of markers are elevated in
      acute thrombosis, D-dimer, a specific derivative of cross-linked fibrin, appears
      to have the most potential clinical utility. Accuracy studies and preliminary
      management trials suggest that rapid D-dimer enzyme-linked immunosorbent assays
      and the whole blood agglutination assay, SimpliRED D-dimer (Agen Biomedical,
      Brisbane, Australia), have strong potential as exclusionary tests in patients
      with suspected venous thrombosis.

PMID- 10331095
TI  - Prevention of venous thromboembolism in general surgery.
AB  - Venous thromboembolism continues to be an important cause of death in
      hospitalized patients undergoing major elective surgery. A study of autopsy
      proven pulmonary embolism in hospital patients showed that venous thromboembolism
      accounted for 10% of deaths and that recognition of non-fatal thromboembolism
      continues to be a problem. The incidence of deep vein thrombosis increases with
      ageing, the annual rate per 1000 being one to three for those aged between 65 and
      69 years and from two to eight for those aged between 85 and 89 years. The
      introduction of low-molecular-weight heparins has resulted in important changes
      in the management and prophylaxis of venous thromboembolism. Low-molecular-weight
      heparin preparations reduce the overall incidence of deep vein thrombosis in
      general surgery by at least 70%. Furthermore, the effect of low-molecular-weight
      heparin against pulmonary embolism is at least as great as that of low-dose
      unfractionated heparin. The incidence of serious and minor haemorrhagic events
      with low-molecular-weight heparin is similar to that with low-dose unfractionated
      heparin. Prophylaxis is started pre-operatively, and the usual duration for the
      post-operative period has been 7 days, or until the patient is discharged from
      the hospital. In conclusion, low-molecular-weight heparin is highly effective in
      preventing post-operative venous thromboembolism.

PMID- 10331096
TI  - Heparin and low-molecular-weight heparin in the treatment of venous
      thromboembolism.
AB  - Venous thromboembolism (deep vein thrombosis and pulmonary embolism) continues to
      constitute a major clinical challenge. Effective and safe prophylactic measures
      against venous thromboembolism are now available for most high risk patients. In
      spite of this, pulmonary embolism is responsible for approximately 150,000 to
      200,000 deaths per year in the United States alone. Over the past 20 years, based
      on a number of high quality (Level I) clinical trials, patterns of practice with
      respect to the treatment of venous thromboembolism have changed dramatically. The
      standard treatment of venous thromboembolism has been the use of unfractionated
      heparin by continuous intravenous infusion, with laboratory monitoring using the
      activated partial thromboplastin time (APTT), with warfarin starting on day 1 or
      2 and continued for 3 months. Unfractionated heparin has withstood the test of
      time and has been shown to be safe and effective in preventing recurrent venous
      thromboembolism and death in numerous clinical trials. The response of individual
      patients to heparin is highly variable, requiring frequent laboratory monitoring.
      Heparin has a number of other troublesome side effects including bleeding,
      heparin-induced thrombocytopenia and osteoporosis. The low-molecular-weight
      heparins have a number of advantages over unfractionated heparin. In particular,
      their increased bio-availability and prolonged half-life permit once daily
      subcutaneous injections and their predictable antithrombotic response based on
      body weight permits treatment without laboratory monitoring. Low-molecular-weight
      heparin in therapeutic doses causes less bleeding than unfractionated heparin and
      evidence is accumulating that the incidence of heparin-induced thrombocytopenia
      and osteoporosis are decreased as well. In individual clinical trials and meta
      analyses, low-molecular-weight heparin treatment results in decreased recurrent
      thromboembolism, major bleeding and death when compared with unfractionated
      heparin in the treatment of deep vein thrombosis and pulmonary embolism. These
      agents have also been shown to be both effective and safe for the out-of-hospital
      treatment of venous thrombosis. Therefore, in many countries, low-molecular
      weight heparin has replaced unfractionated heparin for the treatment of venous
      thromboembolism.

PMID- 10331097
TI  - Oral anticoagulants for the treatment of venous thromboembolism.
AB  - Oral anticoagulation has been the mainstay of therapy for the long-term treatment
      of venous thromboembolism since the 1940s. The rationale for the use of oral
      anticoagulation is based on the results of both empirical clinical evidence and
      animal models of thrombosis in the 1950s and 1960s. Higher-quality studies
      emerged in the 1970s and 1980s demonstrating the benefit of initial
      heparinization for venous thromboembolism followed by long-term oral
      anticoagulation. Good clinical outcomes with oral anticoagulation are highly
      dependent on the quality of dose management. Excellent management is best
      achieved in a programme of focused and co-ordinated care, often referred to as an
      anticoagulation clinic. Such programmes achieve better outcomes at reduced costs
      because of fewer adverse events. New models of anticoagulation management are
      emerging with the development of point-of-care testing that enables patients to
      do their own prothrombin time monitoring and anticoagulation dose adjustment.
      These models have the potential to improve care further, to increase patient
      satisfaction and to reduce costs.

PMID- 10331098
TI  - Thrombolytic therapy for venous thrombosis and pulmonary embolism.
AB  - Streptokinase, urokinase, tissue plasminogen activator and similar drugs can all
      cause lysis of venous thrombi and pulmonary emboli, but there is small evidence
      that accelerated lysis achieves a significantly better clinical outcome, on
      average, in the shorter or longer term, than heparin alone. Thrombolytic therapy
      for deep leg vein thrombosis aims to restore flow and to preserve venous valves,
      and so to prevent chronic post-phlebitic disability, but no trial has
      convincingly demonstrated that the last can be achieved in more than a few
      patients. Only a small minority of people with extensive proximal thrombosis
      develop disabling post-phlebitic venous insufficiency, and there are no good
      clinical predictors of this outcome. As a result, any widespread use of
      thrombolytics would bring an immediate risk of major bleeding to many people who
      will never be destined to develop a clinically important problem. Thrombolytic
      therapy after venous thrombosis should be avoided except, perhaps, in a few
      carefully selected patients with severe obstruction. The case for using
      thrombolytics after recent pulmonary embolism is strongest in the limited number
      of patients with ongoing hypoxia, respiratory distress, pulmonary hypertension
      and right heart failure, because thrombolytic therapy often achieves an
      impressive and almost immediate clinical benefit in this clinical setting.
      Whether early relief from pulmonary artery obstruction translates into longer
      term advantage over heparin remains uncertain, however, because no comparative
      trial has ever shown these drugs to reduce mortality after pulmonary embolism. In
      all cases, both the physician and the patient must balance the certainty of an
      immediate bleeding risk against the uncertainty of a better than marginal real
      benefit.

PMID- 10331099
TI  - Venous thromboembolism and cancer.
AB  - The association of thrombosis with malignant disease has been recognized for well
      over 100 years. Evidence from experimental and clinical studies indicates that
      the haemostatic system is involved in the growth, invasion and metastasis of
      tumours. Laboratory parameters of haemostasis are frequently deranged in patients
      with cancer and overt thrombosis is common spontaneously where it may be the
      first sign of malignancy or secondary to therapy. The mechanisms by which
      coagulation activation facilitates the malignant process remain to be completely
      elucidated, but it is clear that cells and proteins of the coagulation and
      fibrinolytic systems are involved at many steps in the processes of tumour growth
      and dissemination. The low-molecular-weight heparins with their well-proven
      safety and efficacy profiles offer unique modalities for the prevention and
      treatment of cancer-associated thrombosis. They may also play a role in overall
      mortality reduction in patients with malignant disease.

PMID- 10331100
TI  - Cell atrophy and loss in major depression.

PMID- 10331101
TI  - Morphometric evidence for neuronal and glial prefrontal cell pathology in major
      depression.
AB  - BACKGROUND: This report provides histopathological evidence to support prior
      neuroimaging findings of decreased volume and altered metabolism in the frontal
      cortex in major depressive disorder. METHODS: Computer-assisted three-dimensional
      cell counting was used to reveal abnormal cytoarchitecture in left rostral and
      caudal orbitofrontal and dorsolateral prefrontal cortical regions in subjects
      with major depression as compared to psychiatrically normal controls. RESULTS:
      Depressed subjects had decreases in cortical thickness, neuronal sizes, and
      neuronal and glial densities in the upper (II-IV) cortical layers of the rostral
      orbitofrontal region. In the caudal orbitofrontal cortex in depressed subjects,
      there were prominent reductions in glial densities in the lower (V-VI) cortical
      layers that were accompanied by small but significant decreases in neuronal
      sizes. In the dorsolateral prefrontal cortex of depressed subjects marked
      reductions in the density and size of neurons and glial cells were found in both
      supra- and infragranular layers. CONCLUSIONS: These results reveal that major
      depression can be distinguished by specific histopathology of both neurons and
      glial cells in the prefrontal cortex. Our data will contribute to the
      interpretation of neuroimaging findings and identification of dysfunctional
      neuronal circuits in major depression.

PMID- 10331103
TI  - The size and fiber composition of the anterior commissure with respect to gender
      and schizophrenia.
AB  - BACKGROUND: In light of evidence for deviations in asymmetry and alterations in
      the anatomy of the corpus callosum in schizophrenia, this study examined the
      anterior commissure in post mortem brains (n = 14 female control patients, 15
      male control patients, 11 female schizophrenic patients, 15 male schizophrenic
      patients). METHODS: Measures were made of the cross-sectional area of the
      anterior commissure in the midsagittal plane. In addition, the fiber density and
      fiber number were measured in a subset of cases (n = 10 female control subjects,
      10 male control subjects, 8 female schizophrenic patients, 9 male schizophrenic
      patients), using the Palmgren silver stain and stereological methods. RESULTS: In
      control subjects, fiber numbers were greater (p = .024) in women than men. In
      schizophrenia, the cross-sectional area was unaffected, but for fiber density
      there was a significant gender x diagnosis interaction (p = .026), corresponding
      to a reduction in female, but not male patients with schizophrenia. CONCLUSIONS:
      The reduction in density of fibers in the anterior commissure is consistent with
      an alteration of interhemispheric connectivity in schizophrenia, but the
      restriction of the finding to women emphasizes the relevance of gender to
      understanding the nature of the hemispheric interaction.

PMID- 10331104
TI  - Schizophrenic subjects activate dorsolateral prefrontal cortex during a working
      memory task, as measured by fMRI.
AB  - BACKGROUND: Neuroimaging studies of schizophrenic subjects performing working
      memory (WM) tasks have demonstrated a relative hypoactivity of prefrontal cortex
      compared with normal subjects. METHODS: Using functional magnetic resonance
      imaging (fMRI), we compared dorsolateral prefrontal cortex (DLPFC) activation in
      12 schizophrenic and 10 normal subjects during rewarded performance of a WM task.
      Subjects performed a modified version of the Sternberg Item Recognition Paradigm
      (SIRP), a continuous performance, choice reaction time (RT) task that requires
      WM. We compared a high WM load condition with a nonWM choice RT condition and
      with a low WM load condition. RESULTS: Schizophrenic subjects performed the tasks
      better than chance but worse than normal subjects. They showed greater activation
      than normal subjects in the left DLPFC but did not differ in the right DLPFC or
      in the control region. In the schizophrenic group, left DLPFC activation was
      inversely correlated with task performance, as measured by errors. CONCLUSIONS:
      These findings contrast with previous studies that demonstrated task-related
      hypofrontality in schizophrenia. Task parameters that may contribute to this
      difference are discussed. We hypothesize that the performance and activation
      differences we observed are also manifestations of prefrontal dysfunction in
      schizophrenia. They reflect inefficient functioning of the neural circuitry
      involved in WM.

PMID- 10331102
TI  - MRI anatomy of schizophrenia.
AB  - Structural magnetic resonance imaging (MRI) data have provided much evidence in
      support of our current view that schizophrenia is a brain disorder with altered
      brain structure, and consequently involving more than a simple disturbance in
      neurotransmission. This review surveys 118 peer-reviewed studies with control
      group from 1987 to May 1998. Most studies (81%) do not find abnormalities of
      whole brain/intracranial contents, while lateral ventricle enlargement is
      reported in 77%, and third ventricle enlargement in 67%. The temporal lobe was
      the brain parenchymal region with the most consistently documented abnormalities.
      Volume decreases were found in 62% of 37 studies of whole temporal lobe, and in
      81% of 16 studies of the superior temporal gyrus (and in 100% with gray matter
      separately evaluated). Fully 77% of the 30 studies of the medial temporal lobe
      reported volume reduction in one or more of its constituent structures
      (hippocampus, amygdala, parahippocampal gyrus). Despite evidence for frontal lobe
      functional abnormalities, structural MRI investigations less consistently found
      abnormalities, with 55% describing volume reduction. It may be that frontal lobe
      volume changes are small, and near the threshold for MRI detection. The parietal
      and occipital lobes were much less studied; about half of the studies showed
      positive findings. Most studies of cortical gray matter (86%) found volume
      reductions were not diffuse, but more pronounced in certain areas. About two
      thirds of the studies of subcortical structures of thalamus, corpus callosum and
      basal ganglia (which tend to increase volume with typical neuroleptics), show
      positive findings, as do almost all (91%) studies of cavum septi pellucidi (CSP).
      Most data were consistent with a developmental model, but growing evidence was
      compatible also with progressive, neurodegenerative features, suggesting a "two
      hit" model of schizophrenia, for which a cellular hypothesis is discussed. The
      relationship of clinical symptoms to MRI findings is reviewed, as is the growing
      evidence suggesting structural abnormalities differ in affective (bipolar)
      psychosis and schizophrenia.

PMID- 10331105
TI  - Retinal function as a marker for cell membrane omega-3 fatty acid depletion in
      schizophrenia: a pilot study.
AB  - BACKGROUND: There is a growing body of evidence that abnormalities of the cell
      membrane, particularly depletion of n-3 essential fatty acids (EFA), are found in
      patients suffering from schizophrenia. These fatty acids particularly
      Docosohexaenoic acid (DHA) are found in particularly high concentrations in the
      photoreceptor cells of the retina and abnormalities of light sensitivity have
      been reported in patients with schizophrenia. Animal studies have demonstrated
      that reduced EFA levels are associated with changes in the electrophysiological
      response of the retina to light as measured by the electroretinogram (ERG).
      METHODS: We measured the ERG of 9 patients with schizophrenia and 9 age and sex
      matched control subjects. All but one of the patients was medicated. RESULTS:
      Schizophrenic subjects had significantly reduced a-wave amplitudes on the ERG
      when compared with control subjects and the a-wave amplitude was independent of
      the dose of antipsychotic agents being taken. The a-wave of the ERG is thought to
      reflect activity of the photoreceptor cells. CONCLUSIONS: These findings support
      the hypothesis that patients with schizophrenia have abnormalities of
      photoreceptor function, which may be a result of reduced levels of n-3 EFA in the
      cell membrane.

PMID- 10331106
TI  - Genetic antecedents of dopamine dysfunction in schizophrenia.
AB  - BACKGROUND: Relatives of schizophrenic probands frequently manifest attenuated
      features of this illness including the negative symptoms and the milder positive
      psychotic symptoms. These two symptom dimensions are hypothesized to be
      associated with decreased and increased brain dopamine (DA) functions,
      respectively, raising the possibility that DA abnormalities may be present in the
      relatives of schizophrenic probands. METHODS: Plasma homovanillic acid (HVA), the
      major DA metabolite and an indicator of brain DA activity, was measured in
      nonpsychotic, physically healthy first-degree relatives (n = 55) of schizophrenic
      probands and in normal subjects (n = 20) without a family history of
      schizophrenia. RESULTS: Plasma HVA inversely correlated with negative symptoms
      and positively correlated with attenuated positive symptoms. Also, relatives had
      decreased plasma HVA compared to normal subjects, consistent with the fact that
      these relatives are characterized by negative symptoms. These findings were not
      related to major peripheral factors that could affect plasma HVA suggesting that
      the findings may reflect changes in brain DA activity. CONCLUSIONS: Negative
      symptoms indicating a genetic diathesis to schizophrenia in relatives may have a
      biologic basis in reduced DA activity and the DA dysfunction of schizophrenia may
      have genetic antecedents. This opens an important new avenue for further study of
      DA in this illness.

PMID- 10331107
TI  - Serotonergic mediation of DRL 72s behavior: receptor subtype involvement in a
      behavioral screen for antidepressant drugs.
AB  - BACKGROUND: The functioning of the brain serotonin system has been implicated in
      the action of antidepressant drugs. The behavior of rats performing the
      Differential Reinforcement of Low Rate-72 sec (DRL 72s) has been used as a screen
      for drugs with antidepressant activity. Many antidepressant drugs alter
      serotonergic function. Hence, experiments were designed to investigate the role
      of the brain serotonin system in the performance of DRL 72s behavior. METHODS:
      Rats were trained to perform a DRL 72s, and then depleted (LESION) of brain
      serotonin (5-HT) using intracerebroventricular 5,7-dihydroxytryptamine (5,7-DHT).
      Control rats (SHAM) were injected with the 5,7-DHT vehicle. RESULTS: The 5,7-DHT
      treated rats showed a higher response rate, a decrease in the number of
      reinforcements, and a shift in the interresponse time (IRT) distribution toward
      shorter IRTs when compared to SHAM and prelesion performance. The behavioral
      deficit in the 5,7-DHT rats persisted for 17 weeks. Postmortem assays indicated
      extensive depletion of 5-HT in all the assayed brain regions of the LESION rats.
      The effects of the serotonergic agonists 8-hydroxy-2-di-N-propylaminotetralin (8
      OH-DPAT), 5-methoxy-dimethyltryptamine (5-MeODMT), buspirone, and 5
      hydroxytryptophan (5-HTP) were assessed. 5-MeODMT and 8-OH-DPAT resulted in
      greater improvement of DRL 72s performance in the LESION rats than in the SHAM
      rats. Buspirone failed to ameliorate the behavioral deficit in the LESION rats
      and produced a behavioral deficit in the SHAM rats. 5-HTP improved performance in
      the SHAM rats and in the LESION rats. CONCLUSIONS: These results support the
      contention that the brain 5-HT system is involved in the mediation of
      antidepressant drug effects.

PMID- 10331108
TI  - Modulation of the firing activity of rat serotonin and noradrenaline neurons by
      (+/-)pindolol.
AB  - BACKGROUND: (+/-)Pindolol is a beta-adrenergic/5-HT1A receptor antagonist used in
      combination with certain antidepressant drugs to accelerate the onset of the
      antidepressive response. METHODS: The aim of the present study was to assess,
      using an in vivo electrophysiologic paradigm, the effect of (+/-)pindolol on the
      spontaneous firing activity of rat dorsal raphe serotonin (5-HT) and locus
      coeruleus noradrenaline (NA) neurons. RESULTS: (+/-)Pindolol did not modify the
      firing activity of dorsal raphe 5-HT neurons at low doses (10 and 200
      micrograms/kg, i.v.), but it prevented the suppressant effect of the 5-HT
      autoreceptor agonist lysergic acid diethylamide (LSD, 10 micrograms/kg, i.v.) but
      not that of the 5-HT1A receptor 8-hydroxy-N,N-dipropyl-aminotetralin (8-OHDPAT, 5
      micrograms/kg, i.v.). At a higher dose (500 micrograms/kg, i.v.), (+/-)pindolol
      decreased 5-HT neuronal firing and this effect was reversed by the selective 5
      HT1A receptor antagonist WAY 100635 (100 micrograms/kg, i.v.), suggesting that it
      could act as a partial 5-HT1A autoreceptor agonist. In the locus coeruleus, the
      high dose of (+/-)pindolol decreased the firing activity of NA neurons and this
      effect was reversed by the 5-HT2A receptor antagonist MDL 100907 (200
      micrograms/kg, i.v.). Finally, both a lesion of NA neurons and the administration
      of MDL 100907 prevented the suppressant effect of (+/-)pindolol on the firing of
      5-HT neurons. CONCLUSIONS: It is suggested that, at low doses, (+/-)pindolol acts
      as a somatodendritic 5-HT1A autoreceptor antagonist whereas at a higher dose, it
      decreases the tonic excitatory input from NA neurons to 5-HT neurons.

PMID- 10331109
TI  - The use of pindolol with fluoxetine in the treatment of major depression: final
      results from a double-blind, placebo-controlled trial.
AB  - BACKGROUND: Preliminary reports have suggested that concomitant institution of
      pindolol and serotonin reuptake inhibitors robustly hastens clinical response;
      however, contradictory evidence from a randomized double-blind, controlled trial
      was recently reported by this group in a population of depressed patients who
      were prescribed fluoxetine and pindolol. Herein, we report final results from an
      extended sample size. METHODS: Drug-free outpatients with a major depressive
      episode were randomized in a double-blind manner to one of two treatment
      conditions: fluoxetine (20 mg daily) with pindolol (7.5 to 10 mg daily) or
      fluoxetine (20 mg daily) with placebo. After 6 weeks, patients were followed for
      3 more weeks in a single-blind manner, on fluoxetine and placebo pindolol.
      RESULTS: Eighty-six patients completed at least 1 or more weeks on protocol, with
      45 and 41 patients randomized to the pindolol and placebo groups respectively.
      After 2 weeks on protocol, partial remission (i.e., at least 50% decrease in
      depression rating scores from baseline) rates for pindolol (16%) and placebo
      (19%) groups were comparable. By the study's end, a partial remission was
      achieved, at least transiently, for 67% of the pindolol group and 80% of the
      placebo group. Pindolol treatment was associated with statistically significant
      reduction in blood pressure and pulse as compared to the control group. The two
      groups did not have overall differences in rates of attrition, time to response,
      and side effects. CONCLUSIONS: In accord with our previously published findings,
      these extended results do not support the efficacy of pindolol in hastening
      clinical response to fluoxetine in a patient population with predominantly
      chronic and recurrent depression.

PMID- 10331110
TI  - Family-based association studies support a sexually dimorphic effect of COMT and
      MAOA on genetic susceptibility to obsessive-compulsive disorder.
AB  - BACKGROUND: Obsessive-compulsive disorder (OCD) is a common and severe
      psychiatric illness that affects 1-3% of the population and presents a well
      established co-morbidity with major depressive disorder (MDD). Twin and family
      studies have suggested a genetic component in the etiology of OCD, although the
      mode of inheritance is unknown. Pharmacotherapy of the disease implicates both
      serotonergic and dopaminergic pathways. Previously, guided by the 22q11
      microdeletion-related psychiatric phenotype, we provided evidence for a sexually
      dimorphic association between OCD and the gene for catechol-O-methyltransferase
      (COMT). In this report, we use 110 nuclear OCD families to analyze the
      inheritance of variants of COMT and monoamine oxidase-A (MAOA), another gene
      modulating monoamine metabolism. METHODS: A sample of 110 nuclear OCD families
      was collected, and lifetime diagnoses were ascertained using the Diagnostic
      Interview for Genetic Studies (DIGS). DNA was genotyped for functional variants
      of the COMT and MAO genes, and allele inheritance was examined using the
      Transmission Disequilibrium Test (TDT) and Haplotype-based Haplotype Relative
      Risk (HHRR) test. RESULTS: We provide evidence supporting the previously reported
      sexually dimorphic association between low COMT enzymatic activity and OCD. We
      also provide evidence for a similar sexually dimorphic association between OCD
      and an allele of the MAOA gene, previously linked to high MAO-A enzymatic
      activity. In agreement with the well-established action of MAO-A inhibitors as
      antidepressants, this association is particularly marked among male OCD probands
      with co-morbid MDD, who represent more than 50% of our male OCD sample.
      CONCLUSIONS: Our analysis indicates that variants of two genes modulating
      monoamine metabolism contribute significantly to OCD susceptibility. Most
      importantly, an unexpected sexually dimorphic pattern of genetic susceptibility
      to OCD is revealed and suggests the possibility that profound gender differences
      in genetic predisposition may exist not only for other OCD susceptibility genes,
      but for an array of other psychiatric disorders as well.

PMID- 10331111
TI  - Regional cerebral blood flow in Down syndrome adults during the Wisconsin Card
      Sorting Test: exploring cognitive activation in the context of poor performance.
AB  - BACKGROUND: Prior studies have indicated abnormal frontal lobes in Down syndrome
      (DS). The Wisconsin Card Sorting Test (WCST) has been used during functional
      brain imaging studies to activate the prefrontal cortex. Whether this activation
      is dependent on successful performance remains unclear. To determine frontal lobe
      regional cerebral blood flow (rCBF) response in DS and to further understand the
      effect of performance on rCBF during the WCST, we studied DS adults who perform
      poorly on this task. METHODS: Initial slope (IS), an rCBF index, was measured
      with the 133Xe inhalation technique during a Numbers Matching Control Task and
      the WCST. Ten healthy DS subjects (mean age 28.3 years) and 20 sex-matched
      healthy volunteers (mean age 28.7 years) were examined. RESULTS: Performance of
      DS subjects was markedly impaired compared to controls. Both DS and control
      subjects significantly increased prefrontal IS indices compared to the control
      task during the WCST. CONCLUSIONS: Prefrontal activation in DS during the WCST
      was not related to performance of that task, but may reflect engagement of some
      components involved in the task, such as effort. Further, these results show that
      failure to activate prefrontal cortex during WCST in schizophrenia is unlikely to
      be due to poor performance alone.

PMID- 10331112
TI  - Effects of myo-inositol ingestion on human brain myo-inositol levels: a proton
      magnetic resonance spectroscopic imaging study.
AB  - BACKGROUND: Cerebrospinal fluid levels of myo-Inositol (m-Ino) are reported to be
      decreased in patients with affective disorder, and dietary supplements of m-Ino
      have been shown to reduce the symptoms of major depression. Myo-Inositol
      transport across the blood-brain barrier is mediated by a low capacity, saturable
      system. This study tests whether dietary m-Ino increases brain m-Ino or changes
      brain metabolism of m-Ino, possibly explaining the ability of this compound to
      alter mood. METHODS: Using proton magnetic resonance spectroscopic imaging, we
      measured m-Ino levels in occipital gray and parietal white matter of seventeen
      healthy subjects. Magnetic resonance spectroscopic imaging was performed twice at
      baseline as well as at day 4 and day 8 while subjects ingested 6 g of m-Ino twice
      a day. RESULTS: Following 4 days of m-Ino, m-Ino/Cr was 20% higher than baseline
      levels in occipital gray matter (p < 0.04) and 8% higher in parietal white matter
      (p = ns). By day 8, m-Ino/Cr ratios had returned to baseline values. CONCLUSIONS:
      Brain m-Ino levels initially increase during m-Ino administration and
      subsequently return to baseline levels. The time-limited increases observed for
      brain m-Ino may reflect homeostatic mechanisms, possibly associated with the role
      of m-Ino as a cerebral osmolyte, or with changes in brain phosphoinositide
      metabolism.

PMID- 10331113
TI  - Magnetic resonance imaging evidence of "silent" cerebrovascular toxicity in
      cocaine dependence.
AB  - BACKGROUND: Cocaine and its metabolites can produce vasospasm. Cocaine-dependent
      (CD) patients are at increased risk for stroke, and a high frequency of brain
      perfusion defects has been observed in clinically asymptomatic CD subjects. This
      is the first controlled magnetic resonance imaging (MRI) study of clinically
      asymptomatic CD subjects. METHODS: Two age-matched groups of male subjects (61 CD
      and 57 control) participated in the study. Subjects with a history of neurologic
      symptoms or major medical or neurologic illness, such as hypertension, diabetes,
      or significant head trauma, were excluded. The severity of hyperintense lesions
      observed on T2-weighted MRI images were rated on a 0-3-point scale by an
      experienced radiologist who was blind to all clinical data. Ratings of 3 were
      felt to be significant indicators of a possible disease process and were used in
      the data analysis. Three regions were separately rated: the cerebral white
      matter, subinsular white matter, and subcortical gray matter (basal ganglia and
      thalamus region). RESULTS: Despite the exclusion criteria minimizing risk factors
      for cerebrovascular events, 17 of the 61 (27.9%) CD subjects and 4 of 57 (7%) of
      the control subjects had severe hyperintense lesions suggestive of subclinical or
      "silent" anoxic vascular events. Significant group differences were observed in
      the two white matter regions but not in the subcortical gray matter region. The
      risk of severe white matter lesions in the CD group increased with age, reaching
      50% in the oldest age quartile (46-58 years), and this increase was not related
      to the number of years cocaine was used. CONCLUSIONS: The data suggest that
      asymptomatic CD patients are a heterogeneous population with a significantly
      increased age-related risk of white matter neurovascular toxicity. Premature
      neurovascular damage may impact treatment outcomes and, as the CD population
      ages, may manifest as an increased incidence of cognitive deficits.

PMID- 10331114
TI  - Cytokines in detoxified patients with chronic alcoholism without liver disease:
      increased monocytic cytokine production.
AB  - BACKGROUND: The aim of the present study was to examine the production of
      interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage
      colony stimulating factor (GM-CSF), interleukin-6 (IL-6), IL-10, IL-4, IL-5, IL-1
      receptor antagonist (IL-1RA), and prostaglandin E2 in relation to the number of
      leukocytes in the blood of detoxified, chronic alcoholic patients without
      apparent liver disease (AWLD). METHODS: Phytohemagglutinin + lipopolysaccharide
      induced production of the above variables as well as the number of white blood
      cells and differentials were determined in detoxified AWLD patients and normal
      volunteers. RESULTS: Detoxified AWLD patients have a significantly higher
      production of IL-6, IL-10, TNF-alpha, GM-CSF, and IL-1RA and significantly
      increased numbers of leukocytes and neutrophils compared to normal volunteers.
      CONCLUSIONS: Detoxified AWLD patients show an increased production of
      proinflammatory cytokines, i.e., IL-6, TNF-alpha, and GM-CSF, as well as negative
      immunoregulatory proteins, such as IL-10 and IL-1RA.

PMID- 10331115
TI  - Is amoxapine an atypical antipsychotic? Positron-emission tomography
      investigation of its dopamine2 and serotonin2 occupancy.
AB  - BACKGROUND: All currently available atypical antipsychotics have, at clinically
      relevant doses: i) high serotonin (5-HT)2 occupancy; ii) greater 5-HT2 than
      dopamine (D)2 occupancy; and iii) a higher incidence of extrapyramidal side
      effects when their D2 occupancy exceeds 80%. A review of pharmacologic and
      behavioral data suggested that amoxapine should also conform to this profile;
      therefore, we undertook a positron-emission tomography (PET) study of its 5-HT2
      and D2 occupancy. METHODS: Seven healthy volunteers received 50-250 mg/day of
      amoxapine for 5 days and then had [11C]-raclopride and [18F]-setoperone PET
      scans. RESULTS: 5-HT2 receptors showed near saturation at doses of 100 mg/day and
      above. The D2 receptor occupancies showed a dose-dependent increase, never
      exceeding 80%; at all doses 5-HT2 occupancy exceeded D2 occupancy. CONCLUSIONS:
      PET data show that amoxapine's profile is very similar to that of the established
      atypical antipsychotics. These data, together with amoxapine's in vitro
      pharmacologic profile, effectiveness in animal models, and efficacy in psychotic
      depression raise the possibility of amoxapine as an "atypical" antipsychotic
      agent in the treatment of schizophrenia.

PMID- 10331116
TI  - Increase of phosphodiesters during neuroleptic treatment of schizophrenics: a
      longitudinal 31P-magnetic resonance spectroscopic study.
AB  - BACKGROUND: Increased levels of phosphodiesters (PDE%) and reduced relative
      concentrations of phosphomonoesters (PME%) have been reported in unmedicated
      schizophrenics, whereas findings in brain of medicated patients were not
      consistent. METHODS: We determined in vivo the metabolism of phospholipids and
      high-energy phosphates in the left and right frontal lobes of 8 patients with
      schizophrenia using 31P-magnetic resonance spectroscopy (31P-MRS). Serial
      investigations were performed first after a neuroleptic-free period (mean 7.5 +/-
      1.9 days) and second, after neuroleptic treatment (mean 20.6 +/- 11.1 days).
      RESULTS: PDE% increased significantly in the left frontal lobe (32.0 +/- 5.9%
      versus 36.9 +/- 5.6%, p = .009) after medication. All other parameters showed no
      significant differences. CONCLUSIONS: Our study suggests that neuroleptics do not
      decrease phospholipase A2 activity in schizophrenia. Individual neuroleptics may
      have different effects on phospholipase A2 activity as indicated by animal
      studies. An influence of neuroleptics on high-energy phosphates cannot be
      confirmed by our data.

PMID- 10331117
TI  - A preliminary study of lamotrigine for the treatment of posttraumatic stress
      disorder.
AB  - BACKGROUND: The anticonvulsant, lamotrigine, may be useful for symptom management
      in PTSD. METHODS: Subjects enrolled in a 12-week double-blind evaluation of
      lamotrigine and placebo. Patients were randomized 2:1 to either lamotrigine or
      placebo. Lamotrigine was initiated at 25 mg/day and slowly titrated every 1 to 2
      weeks over 8 weeks to a maximum dosage of 500 mg/day if tolerated. RESULTS:
      Fifteen subjects entered treatment, fourteen of whom returned for subsequent
      visits. Of 10 patients who received lamotrigine, 5 (50%) responded according to
      the DGRP, compared to 1 of 4 (25%) who received placebo. Lamotrigine patients
      showed improvement on reexperiencing and avoidance/numbing symptoms compared to
      placebo patients. Treatments were generally well tolerated. CONCLUSIONS:
      Lamotrigine may be effective as a primary psychopharmacologic treatment in both
      combat and civilian PTSD and could also be considered as an adjunct to
      antidepressant therapy used in the treatment of PTSD. These promising results
      warrant further large sample double-blind, placebo-controlled trials.

PMID- 10331118
TI  - Serotonin transporter gene (HTTLPR) is not in linkage disequilibrium with
      prepubertal and early adolescent bipolarity.
AB  - BACKGROUND: As part of an ongoing, larger study, "Phenomenology and Course of
      Pediatric Bipolarity", a subset of prepubertal and early adolescent onset bipolar
      (PEA-BP) probands, on whom trio blood collection was complete, were used to study
      genetic transmission of the serotonin transporter linked promoter region (HTTLPR)
      short and long alleles using the transmission disequilibrium test(TDT). The
      HTTLPR alleles were selected based on postulated serotonergic mechanisms for PEA
      BP and on the burgeoning number of HTTLPR allele studies in bipolar (BP) adults.
      METHODS: There were 46 complete trios of PEA-BP probands and both biological
      parents. Probands had a mean age of 11.1 +/- 3.0 years and a mean age of onset of
      PEA-BP of 8.1 +/- 4.0 years. Comprehensive diagnostic assessments included a semi
      structured research interview, the WASH-U-KSADS, administered separately to
      mothers and to children by blind raters. Probands manifested severe impairment
      (CGAS 43.9 +/- 8.9), elated mood (84.8%), grandiosity (78.3%), rapid cycling
      (78.3%) and psychosis (63.0%). The HTTLPR length variant was genotyped using
      fluorescently labeled primers and automated capillary electrophoresis using laser
      induced fluorescence. RESULTS: The TDT was not significant (TDT chi square =
      .020, df = 1, p = .89). CONCLUSIONS: This negative result is consistent with the
      one negative TDT and two negative linkage studies of HTTLPR alleles in bipolar
      adults in the literature.

PMID- 10331119
TI  - Radiographic manifestations of rheumatic diseases affecting the foot and ankle.
AB  - Radiologic evaluation of the foot and ankle affected by rheumatic disease
      involves objective assessment of the radiologic changes that may be associated
      with a specific arthritis. Assessment of the severity of involvement and
      evaluation of progression or regression of the disease are important in the
      treatment regimen and ultimate clinical outcome of every patient.

PMID- 10331120
TI  - The pathomechanic effects of rheumatic diseases on the pedal joints.
AB  - Arthritis-affected foot joints can create function-related changes with regard to
      foot stability, shock attenuation, and normal foot function in gait.

PMID- 10331121
TI  - Pharmacologic management of the arthritic foot and ankle.
AB  - The arthritides discussed are presented with many drug therapies because of a not
      fully understood and accepted cause of the disease process. Similarly, the drug
      therapies offered are diverse and have mechanisms that are not always fully
      understood. Because of the destruction and disability the arthritides are capable
      of and the realization that destruction may be reversible early in the course of
      the disease, physicians are initiating earlier, aggressive treatment with DMARDs.
      Long-term outcome studies of the early institution of DMARDs, combination
      therapies, and newer medications need to be evaluated to produce the most
      efficient treatment regimens.

PMID- 10331122
TI  - Reconstruction of the rheumatoid forefoot.
AB  - The authors discuss the forefoot manifestations of RA and their effects on the
      biomechanics of the foot. Surgical intervention should be performed to alleviate
      the patient's pain and to restore and maintain stability of the forefoot. Each
      patient should be considered individually, and the best procedure for him or her
      should be selected as opposed to one procedure that is applied to all.
      Furthermore, each patient should be counseled about the progressive nature of his
      or her disease. Surgery should not be viewed as a cure. Reconstructive surgery
      can restore function and relieve pain, which is very rewarding for the surgeon
      and the patient.

PMID- 10331123
TI  - Evaluation and surgical management of the arthritic midfoot secondary to
      rheumatic disease.
AB  - RA is a common disorder that has significant destructive effects on the midfoot
      portion of the foot. When these degenerative joint changes occur, any motion at
      the involved joints causes severe pain and disability, and limits the patient in
      his or her attempt to perform daily activities. These changes have a significant
      social and economic impact, and cause unwanted lifestyle changes. Arthrodesis,
      when used judiciously, can offer pain relief and a restoration of normal activity
      for the patient with RA.

PMID- 10331124
TI  - Surgical correction of the rearfoot in rheumatoid arthritis.
AB  - With proper patient selection and perioperative planning, selective rearfoot
      arthrodesis in the patient with rheumatoid arthritis is effective in relieving
      pain and restoring ambulatory status. The overwhelming majority of current
      literature supports the early fusion of involved rearfoot joints in an effort to
      arrest the compensatory progression, which yields a rigidly deformed lower
      extremity. In keeping the patient with rheumatoid arthritis ambulatory, we can
      positively affect his or her quality of life and prevent the degradation into a
      sedentary disposition, and therefore heighten the long-term prognosis.

PMID- 10331125
TI  - Tibiotalar joint arthrodesis for the treatment of severe ankle joint degeneration
      secondary to rheumatoid arthritis.
AB  - The technical aspects of fusion of the rheumatoid ankle do not deviate from those
      in the post-traumatic or osteoarthritic ankle. Screw fixation can usually be
      achieved, and rarely is fixation failure a problem in rheumatoid ankle
      arthrodesis. If fixation is difficult because of deformity or bone quality,
      external fixation or locking intramedullary nails should be used. The placement
      of cannulated screws and adequacy of screw fixation has not been a problem (Fig.
      13). Screw fixation provides compression and prevents rotation. The surgeon,
      however, needs to be assured that no screws invade the subtalar joint and that
      all threads are beyond the arthrodesis site. A washer may be necessary for
      further stability if this screw is not inserted at too great an angle. The
      authors have found that troughing out of the cortical surface of the tibia with a
      power bur aids in screw insertion. Not only does the trough act as a countersink,
      but it also provides a path for screw insertion and prevents palpable screw
      irritation. Malalignment is unforgiving. The foot must be placed neutral to
      dorsiflexion and plantarflexion. Equinus positioning places added stress on the
      tibia and a back-knee gait occurs. Approximately 5 degrees of valgus is
      recommended, and varus positioning is unforgiving. Internal and external rotation
      is determined by the position of the contralateral extremity. Nonunion does not
      seem to be a problem with rigid internal fixation to any greater degree in
      patients with RA. Despite this, patients may continue to have pain despite solid
      fusion, which can be caused by incomplete correction of deformity, painful
      internal fixation, or adjacent joint pathology. Additionally, patients may
      experience supramalleolar pain above the fusion site consistent with tibial
      stress fracture, which is more common if the subtalar or midtarsal joint is rigid
      or if the patient is obese. A rocker sole shoe with impact-absorbing soles used
      after brief periods of guarded mobilization in a removable walking cast
      alleviates this stress on the tibia. Neurovascular insult can be avoided with
      careful dissection direct to bone, incisions placed in nerve-free zones, and
      avoidance of plunging deep posteriorly-medially and anteriorly when dissecting
      and resecting surfaces. Arthrodesis of the tibiotalar joint in the patient with
      RA should be performed to relieve severe pain caused by advanced arthrosis.
      Achieving a solid arthrodesis does not seem to be a problem and provides the
      patient with pain relief; however, marked improvement in patient function and
      level of activity remains limited by the nature of RA and adjacent joint
      involvement.

PMID- 10331126
TI  - Accidental hypothermia.
AB  - Individuals at extremes of age and those who have certain underlying medical
      conditions are at greatest risk for hypothermia. Hypothermia may occur during any
      season of the year and in any climate. Prompt recognition of hypothermia and
      early institution of the rewarming techniques are imperative for a successful
      outcome with minimal complications. Several rewarming techniques are available
      and the decision to use any of them depends on the degree of hypothermia, the
      condition of the patient, and the rewarming rate possible with the technique
      chosen.

PMID- 10331127
TI  - Heat-related illnesses.
AB  - The majority of clinicians will encounter patients with heat-related illness in
      one form or the other. Early recognition and management are important to prevent
      morbidity and mortality. In children and elderly, the clinical signs may be
      subtle and in such situations a sound knowledge of heat-related illnesses is
      crucial. Besides diagnosing and treating heat-related illnesses, it is equally
      important to know how to prevent them as they are easily preventable.

PMID- 10331128
TI  - Altitude-related pulmonary disorders.
AB  - The major physiologic stress encountered at high altitude is caused by the
      occurrence of hypobaric hypoxia. In this article, acute and chronic
      pulmonocardiac adaptation to altitude is reviewed, including possible genetic
      differences among highlanders from the Himalayan versus the Andean Mountains. The
      origin, symptoms, and treatment of acute mountain sickness and high altitude
      pulmonary edema are outlined. In addition, the prediction and prevention of
      pulmonary complications that may be encountered or exacerbated during commercial
      airflight are noticed.

PMID- 10331129
TI  - Near drowning.
AB  - Submersion accidents continue to be a significant cause of morbidity and
      mortality in children and adults. The key to successful management is prevention
      of these accidents. Proactive efforts to minimize submersion accidents in the
      community should be made by medical and legislative groups. Anticipatory guidance
      by primary care physicians, particularly for families and individuals at
      increased risk, should be performed. Outcomes of individuals who have become
      victims of submersion accidents can be optimized by the development of a rapid
      response system, because successful initial resuscitation efforts clearly improve
      outcomes. For individuals who have nearly drowned and who have arrived in the
      emergency department, a systematic and aggressive approach needs to be followed
      with particular emphasis on cardiorespiratory support to optimize neurologic
      outcome. Despite many studies aimed at developing predictors of outcomes, there
      is limited information that can be used in a prospective manner to guide the
      emergency-room physician in limiting the level of interventions. Thus, all
      aggressive supportive care and resuscitation should be performed at this stage,
      except in clearly futile situations. Once patients arrive in the ICU, meticulous
      care, including monitoring of cardiorespiratory and neurologic status and
      attention to electrolytes and acid-base status, needs to be continued. Besides
      providing basic supportive measures, the ICU physician should investigate for
      other associated trauma and medical conditions that may need to be addressed once
      the patient is stabilized. Patients who have nearly drowned are likely to have
      long ICU stays, predisposing them to nosocomial infections. Despite efforts at
      minimizing barotrauma and volutrauma, many patients who have nearly drowned and
      who need ventilatory support may develop ARDS. The management of these patients
      is similar to other patients who have ARDS. However, strategies like permissive
      hypercapnia that are used commonly in patients who have ARDS may not be suitable
      in patients who have CNS injury. Despite aggressive care, neurologic injury with
      long-term sequelae secondary to hypoxic ischemic injury remains a major problem
      in the management of victims of submersion accidents. It is important for the
      clinician to keep the pathophysiologic and cellular mechanisms of CNS injury in
      mind, because future interventions are likely to be based on these pathways.
      Besides providing care for the patient, it is important for the ICU physician to
      be sensitive to the needs of the family and to support them through this
      catastrophe that is likely to place a tremendous financial and emotional burden
      on most of them.

PMID- 10331130
TI  - Carbon monoxide poisoning.
AB  - Carbon monoxide (CO) poisoning is common and frequently unrecognized since the
      signs and symptoms are relatively nonspecific. CO poisoning causes tissue
      hypoxia. Additionally, various animal studies have demonstrated that CO
      interferes with myoglobin, P450, and other enzyme function; causes lipid
      peroxidation through neutrophil activation; produces oxidative stress manifested
      by peroxynitrate deposition in endothelium; binds to cytochrome aa3, disrupting
      intracellular oxygen utilization; can cause neuroexcitotoxicity; and contributes
      to hippocampal cellular death through apoptosis. Emergency treatment for CO
      poisoning is 100% oxygen. Hyperbaric oxygen therapy (HBO2) is accepted in CO
      poisoning, although data from randomized clinical trials regarding the efficacy
      of HBO2 in CO poisoning is conflicting. CO poisoning, even when treated with
      supplemental oxygen can leave the patient with permanent neurocognitive or
      affective problems. Unfortunately, there appears to be no marker or constellation
      of signs or symptoms at presentation that predicts long-term outcome following CO
      poisoning. Given the neurocognitive sequelae following CO poisoning, increased
      awareness and prevention of CO poisoning is imperative.

PMID- 10331131
TI  - Electrical and lightning injuries.
AB  - Electricity and lightning can cause injury in a variety of ways, some of which
      may remain hidden from the unsuspecting physician until it is too late. Prompt
      and, if necessary, prolonged resuscitation are of proven benefit. Particular
      attention must be paid to the patient who suffers high-voltage injury, and deep
      electrothermal burns on damage to vital organs should be excluded. Uncommonly
      late sequelae are seen, and such patients require appropriate care.

PMID- 10331132
TI  - Thermal injury.
AB  - Intensive care management of severely burned patients demands expertise in
      several areas. These include airway management, fluid resuscitation, support of
      the hypermetabolic response, infection control, and treatment of smoke inhalation
      injury. Surgical management of the burn wound, plastic reconstruction, and long
      term rehabilitation are also essential aspects of modern burn care.

PMID- 10331133
TI  - Envenomations.
AB  - Envenomations are uncommon, challenging causes of critical care admissions. This
      article describes the diagnosis and treatment of envenomations that cause the
      most critical care admissions in the United States. Most are caused by the
      following animals: rattlesnakes, copperheads, cottonmouths, coral snakes, brown
      recluse spiders, and bark scorpions.

PMID- 10331134
TI  - Serious waterborne and wilderness infections.
AB  - Serious waterborne and wilderness infections are common and usually treatable if
      diagnosed early. The differential diagnosis for these infections requires a
      careful and thorough history and physical examination. Common clinical
      presentations include acute febrile illnesses, altered mental status, diarrhea,
      or pneumonia. Pathogens causing serious infections include bacteria, fungi,
      viruses, and protozoa. Epidemiologic help can be obtained from local or state
      health departments as well as the Centers for Disease Control.

PMID- 10331135
TI  - Rhabdomyolysis.
AB  - Dissolution of the skeletal muscle, resulting in extravasation of the
      intracellular toxic metabolites into the circulatory system, and the accompanying
      manifestations, constitutes the clinical syndrome of rhabdomyolysis. The most
      frequent complication of this syndrome is acute renal failure, and its most life
      threatening side effects are hyperkalemia and metabolic acidosis. Intracellular
      release of free iron from hemeprotein and the oxidant stress is the principle
      mechanism by which the proximal tubular cytotoxicity is produced. The potential
      pathogenic mechanisms and the strategies to prevent rhabdomyolysis induced acute
      renal failure are discussed in this article.

PMID- 10331136
TI  - Treatment of diving emergencies.
AB  - Recognition of condition attributable to the environmental changes experienced by
      divers will facilitate appropriate treatment. The diagnosis of these conditions
      rarely requires sophisticated imaging or electrophysiologic testing. Divers who
      have suspected DCI, in addition to general supportive measures, should be
      administered fluids and oxygen and transported to a recompression chamber. For
      diving-related conditions, on-line consultation is available from the Divers
      Alert Network, Durham, NC (919-684-8111).

PMID- 10331137
TI  - Radiation injuries.

PMID- 10331138
TI  - Erythropoietin in the neonate.

PMID- 10331140
TI  - Preanesthetic evaluation.
AB  - A thorough preanesthetic evaluation is the most important function an
      anesthesiologist can perform to prevent anesthetic morbidity and mortality and
      ensure a smooth course of anesthetic administration. This evaluation is best
      accomplished by a thoughtful review of the patient's history, examination of the
      patient's airway, and anticipation of the effect of anesthesia on the patient.

PMID- 10331139
TI  - Office-based anesthesia in dentistry. Past, present, and future trends.
AB  - The history of office-based anesthesia dates back to the discovery of nitrous
      oxide and ether in the 1840s. In recent years, advances in intravenous anesthetic
      techniques and the rising costs of hospital-based services have combined to
      promote the practice of ambulatory anesthesia. Dental patients who may benefit
      from office-based anesthesia include patients undergoing stressful procedures,
      fearful patients, medically or behaviorally challenged patients, young children,
      and patients with a history of gagging or local anesthesia problems. The future
      of office-based anesthesia in dentistry appears bright. Its development, however,
      will be influenced by organized dentistry, medical anesthesia, and other groups
      interested in pain and anxiety control, and state legislatures reacting to public
      demands for both safe and cost-effective anesthesia care.

PMID- 10331141
TI  - Anesthesia for pediatric dentistry.
AB  - The administration of anesthesia to young patients creates a unique series of
      problems for the anesthesiologist. This article details these various problems
      and tackles the primary challenge facing clinicians in this environment:
      providing an environment that allows technically complex dental treatment to be
      delivered without inflicting any adverse psychological impact on the child or
      physical harm to the child or others.

PMID- 10331142
TI  - Anesthesia for endodontic practice.
AB  - The ability to provide excellent, high-quality pain control in endodontic
      practice is based on a practical knowledge of the indications and limits of
      intraoral local anesthesia. This article reviews clinically relevant aspects of
      anatomy, physiology, and pharmacology that contribute to the effective use of
      local anesthesia.

PMID- 10331143
TI  - Anesthesia for periodontal surgery.
AB  - This article provides an informational overview of clinical anesthesia for
      periodontal procedures. Patient health status, physical evaluation, preoperative
      preparation issues, and anesthetic approaches are discussed. The unique technical
      challenges offered by periodontal procedures requires both the anesthetist and
      surgeon to fully consider their surgical goals and patient's needs. Selecting and
      providing the optimum anesthetic approach is at once both an art and science. In
      the final analysis, successful patient care is a function of thoughtful planning
      and operator skill.

PMID- 10331144
TI  - Anesthesia for restorative dentistry.
AB  - The use of parenteral conscious sedation and general anesthesia for restorative
      dentistry has increased markedly over the past 20 years. Yet even this increased
      availability for patients to receive selected dental services under sedation and
      general anesthesia has not kept pace with the well-documented public demand. This
      article details the use of anesthesia in restorative dentistry, with particular
      focus on airway management.

PMID- 10331145
TI  - Anesthesia for the elderly and special needs patient.
AB  - This article focuses on the elderly patient and developmentally disabled children
      and adults. Although many individuals in these groups can receive dental care
      with only the use of local anesthetic, this article focuses on those that require
      sedation or general anesthesia. Areas in which the management of these patients
      significantly differs from routine anesthesia are emphasized.

PMID- 10331146
TI  - Management of the postoperative anesthetic period.
AB  - While anesthetic methods and drugs have undergone many changes in the last 100
      years, the incidence of complications during the postanesthesia recovery period
      remains constant. Prompt recognition and treatment of the complications observed
      during the postoperative period decreases unexpected hospital admissions and the
      undesirable mortality or morbidity associated with surgery and anesthesia.

PMID- 10331147
TI  - Oral and inhalation conscious sedation.
AB  - Many patients can benefit by having dental procedures carried out with conscious
      sedation administered by the oral or inhalation routes. Dentists who employ these
      techniques must be familiar with the pharmacology of the agents selected,
      cognizant of the risks and benefits of the technique employed, and able to manage
      adverse events that may arise with its use. Careful patient selection and prudent
      administration of one of the drugs described here is the basis for successful use
      of these techniques.

PMID- 10331148
TI  - Medicolegal considerations for office-based anesthesia in dentistry.
AB  - Over the past decade, there has been a virtual explosion in the demand and
      utilization of office-based ambulatory anesthesia services in dentistry. Not
      surprisingly, with this increased demand has come an increased exposure to
      medicolegal risks and concerns for the unwary or unprepared dental practitioner.
      This article provides the practitioner with a brief overview of the potential
      medicolegal risks and recent trends in litigation that may arise in today's
      office-based anesthesia practice.

PMID- 10331149
TI  - Lateral biases and fluctuations in infants' spontaneous arm movements and
      reaching.
AB  - The development of hand preference in infant reaching is marked by several
      lateral fluctuations. This study investigated whether similar lateral
      fluctuations were present in infants' spontaneous, nonreaching, and freely
      performed movements. We collected reaching and nonreaching movements kinematics
      in 4 infants that we followed longitudinally during their 1st year. In their 4th
      year, we assessed the direction of their hand preference. We found that lateral
      biases in spontaneous, nonreaching movements in the 1st year showed several
      shifts that were similar to those observed in reaching. Despite these shifts, all
      4 infants traversed a short period of right-handedness. This right-handedness
      matched the direction of their hand preference at 3 years of age. We propose that
      shifts in the development of hand preference in the 1st year are linked to
      successive reorganizations of the motor system. These reorganizations take place
      as infants learn to sit, crawl, and walk.

PMID- 10331150
TI  - Temporal organization of fetal behavior from 24-weeks gestation onwards in normal
      and complicated pregnancies.
AB  - Developmental aspects of behavioral organization were investigated in 29 healthy
      fetuses from 24-weeks gestation onwards: (a) short-term association between body
      (GM) and eye (EM) movements; (b) linkage of pairs of the three state variables
      [fetal heart rate pattern (FHRP), GM, and EM]; and (c) sequence of change of
      state variables during transitions. Linkage and sequence were also studied in
      complicated pregnancies. Short-term association between GM and EM was well
      established after 28 weeks. Linkage of state variables improved considerably
      after 32-34 weeks. FHRP was the first variable to change during synchronized
      transitions from 1F to 2F between 28-39 weeks, and the last variable during 2F to
      1F transitions between 32-39 weeks. Although clear developmental patterns could
      be recognized, the interfetal variability was such that identification of the
      abnormal fetus is still difficult. Only transitions were significantly different
      in growth-restricted fetuses, as they showed no specific sequence of change.
      Assessing the temporal organization of fetal behavior seems, therefore, until
      now, not of great clinical value.

PMID- 10331151
TI  - Maternally directed orienting behaviors of newborn rats.
AB  - We observed an organized repertoire of behaviors performed by newborns of the
      laboratory rat when placed under suspended artificial surfaces simulating various
      properties of the awake dam's ventrum. Pups traveled and wriggled, turned on
      their sides and upside down, ventroflexed and probed into the surface while on
      side or upside down, and audibly barked, all in a state of heightened behavioral
      arousal. Within 48 to 72 hr after birth, these behaviors generally increased with
      the addition to the simulation of more maternal features, including the texture
      of the dam's ventral fur and odor, separately and in combination. In addition,
      the behaviors were intensified by 18 hours of maternal deprivation. The possible
      functional relations among the components of this repertoire, which we refer to
      as "maternally directed orienting and proximity-seeking behaviors," and between
      these behaviors and nipple attachment and suckling, are discussed.

PMID- 10331152
TI  - A further investigation of the developmental emergence of fear-potentiated
      startle in rats.
AB  - This series of experiments was designed to reexamine the ontogenetic emergence of
      the fear-potentiated startle response in rats. Previous results (Hunt,
      Richardson, & Campbell, 1994) indicated that potentiated startle to a light
      conditioned stimulus (CS) paired with an acoustic unconditioned stimulus (US) was
      not observed until 30 days of age. In the present experiments, subjects were
      given pairings of a light CS with a brief footshock unconditioned stimulus (US)
      and were tested for fear-potentiated startle 24 hr later. Subjects 23 and 30 days
      of age exhibited significant potentiated responding in the presence of the light,
      while 17-and 20-day-olds did not. Subjects 17 days of age did reliably express
      conditioned decreases in heart rate to the light at the 24-hr test. The failure
      to observe fear-potentiated startle at the youngest age was shown not to be due
      to a general disruption of conditioned fear responding by either (a) pretest
      startle stimulus presentations or (b) contextual characteristics of the startle
      testing apparatus. The capacity to express fear through a potentiated startle
      response develops later than the capacity for other defensive responses in the
      rat.

PMID- 10331153
TI  - Ontogeny of calcium preference in the parathyroidectomized rat.
AB  - The ontogeny of calcium ingestion and preference was examined in
      parathyroidectomized (PTX) rats. Sucklings were tested by means of oral infusion.
      Four-day-old neonatal rats increased ingestion of CaCl2 after PTX but the effect
      was not specific to calcium because intake of MgCl2 was also increased. After 6
      days of age the increase was more specific to calcium. The response increased in
      potency until 20 days of age. Weanlings were tested by measuring intakes from two
      burets, one with CaCl2 and one with MgCl2. Twenty-six-day-old weanlings showed a
      mild preference for CaCl2, but by 30 days of age the preference for calcium was
      similar to that reported for adult rats.

PMID- 10331154
TI  - Audiogenic seizures in the developmentally primed Long-Evans rat.
AB  - The Long-Evans rat is a hybrid rodent strain with little innate susceptibility to
      audiogenic seizures (AGS). The present study examines parameters of acoustic
      priming (induced susceptibility) and testing for AGS during postnatal development
      subsequent to auditory function, and identifies the effects of stimulus
      intensity, repeated testing, and gender upon AGS activity. Rats were exposed to
      125-dB SPL 10-kHz tone bursts at 14-36 days of age and tested with white noise at
      14 or 19 days following sound exposure. All priming/testing combinations yielded
      AGS susceptibility; animals primed at 18 days showed the highest incidence of
      clonic seizures when tested 14 days later. All subjects displayed clonus at
      testing intensities of 120 dB, although some seizure behaviors could be elicited
      at 100 dB. Repeated testing at 120 dB increased latency to clonus and clonus
      duration, and total wild running activity. Gender differences for AGS expression
      were minimal. These results demonstrate the viability of the seizure-resistant
      Long-Evans rat for study of AGS.

PMID- 10331155
TI  - Delta (0.5-1.5 Hz) and sigma (11.5-15.5 Hz) EEG power dynamics throughout quiet
      sleep in malnourished infants.
AB  - The present study aimed to quantify, through power spectral analysis, the
      dynamics (temporal pattern and temporal interrelationship) of the EEG power in
      the low-delta (delta) and in the sigma-spindle (sigma) frequency band during
      quiet sleep (QS) in 5 malnourished infants (MI), 5.5 to 13.5 months old, and in 5
      age-matched, healthy control infants (CI). Malnutrition results in modification
      of the temporal pattern of delta and sigma band power during QS. The delta band
      power increases faster in MI than in CI, leading to higher power levels in MI at
      the same time segment. However, the overall trend of the delta band power
      throughout QS is similar in MI and CI. The premature ending of QS phases
      (uninterrupted QS periods), and the reduced total amount of QS which have been
      reported in MI could result in an increased slow wave sleep (SWS) "pressure".
      This SWS pressure could account for both the higher level and the faster increase
      of the delta band power during the QS phase which are found in MI when compared
      to CI.

PMID- 10331156
TI  - Nomenclature for factors of the HLA system, 1998.

PMID- 10331157
TI  - Negative association between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is
      attenuated with age at onset. Swedish Childhood Diabetes Study Group.
AB  - HLA-associated relative risks of type 1 (insulin-dependent) diabetes mellitus
      were analysed in population-based Swedish patients and controls aged 0-34 years.
      The age dependence of HLA-associated relative risks was assessed by likelihood
      ratio tests of regression parameters in separate logistic regression models for
      each HLA category. The analyses demonstrated an attenuation with increasing age
      at onset in the relative risk for the positively associated DQB1*0201
      A1*0502/B1*0302-A1*0301 (DQ2/8) genotype (P = 0.02) and the negatively associated
      DQB1*0602-A1*0102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive
      individuals had an estimated relative risk of 0.03, but this increased to 1.1 at
      age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ
      genotype 2/2 or 2/X, where X is any DQ haplotype other than 2, 8 or 6.2, were not
      significantly age-dependent. An exploratory analysis of DQ haplotypes other than
      2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for
      DQB1*0604-A1*0102 (DQ6.4) and that the peak risk for the negatively associated
      DQB1*0301-A1*0501 haplotype is at age 18 years. There was also weak evidence that
      the risk for DQB1*0303-A1*0301 (DQ9), which has a positive association in the
      Japanese population, may decrease with age. We speculate that HLA-DQ alleles have
      a significant effect on the rate of beta cell destruction, which is accelerated
      in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2
      positive individuals.

PMID- 10331158
TI  - Distributions of HLA-DRB1/DQB1 alleles and haplotypes in the north-eastern Thai
      population: indicative of a distinct Thai population with Chinese admixtures in
      the central Thais.
AB  - The phenotype and gene frequencies of HLA class II alleles were studied in the
      North-eastern Thai population. Blood samples were collected from 100 unrelated
      healthy North-eastern Thais. The HLA-DRB1 and DQB1 genes were typed using the
      polymerase chain reaction--sequence specific primer (PCR-SSP) and polymerase
      chain reaction--sequence specific oligonucleotide probe (PCR-SSO) techniques.
      Twenty-six HLA-DRB1 and 11 DQB1 alleles were found in this population. DRB1*1202,
      1502, 0405 and DQB1*0502/0504, 0301/0304 alleles were commonly found. Linkage
      disequilibrium analysis suggested the existence of 13 DR-DQ haplotypes. The
      DRB1*1502-DQB1*0501 haplotype was the most common. The DRB1*1106-DQB1*0301/0304
      haplotype was found only in North-eastern Thais and not in other Thai
      populations. Comparative analysis of the HLA-DR/DQ alleles revealed differences
      in the distributions of these alleles amongst different ethnic groups.
      Interestingly, the distributions of HLA class II alleles in Central Thai, North
      eastern Thai and Southern Chinese populations are similar. However, it appears
      that the distribution in the Central Thais is a mixture of those in Southern
      Chinese and North-eastern Thais, suggesting the existence of Thai-Chinese
      admixtures in the Central Thai population. This study provides basic information
      for further studies of the MHC in anthropology, organ transplantation and disease
      susceptibility in the North-eastern Thai population.

PMID- 10331159
TI  - Human cytokine gene nucleotide sequence alignments: supplement 1.

PMID- 10331160
TI  - Definition of new alleles of MIC-A using sequencing-based typing.
AB  - We have sequenced exons 2, 3 and 4 of MIC-A in 23 homozygous cell lines, 22
      families and 54 unrelated individuals. This has led to the definition of seven
      polymorphic positions in exon 2, 13 in exon 3 and 12 in exon 4, yielding a total
      of 33 different MIC-A allelic specificities, of which 16 have not been described
      before. The newly defined sequences and those of the alleles defined before were
      entered into a database of the SCORE program (Helmberg et al., 1998, Tissue
      Antigens, 51, 587) for comprehensive genotyping analysis. In the tested sample,
      only one genotype present in two individuals gave rise to an ambiguous genotype.
      If all possible combinations of the 33 alleles are considered, 10 of 636
      combinations are ambiguous. The MIC-A exon 2, 3 and 4 polymorphism is
      characterized by diallelic single base exchanges and by a considerable degree of
      exon shuffling. The majority of heterozygote positions identified are non
      synonymous, i.e. five of seven in exon 2, 13 of 13 in exon 3 and eight of 12 in
      exon 4, suggesting an important function for the MIC-A polymorphism.

PMID- 10331161
TI  - Phylogenetic analysis of primate MIC (PERB11) sequences suggests that the
      representation of the gene family differs in different primates: comparison of
      MIC (PERB11) and C4.
AB  - Duplication of segments within the MHC has led to numerous multicopy families
      such as class I, class II, C4 and MIC (PERB11). Different copy numbers between
      haplotypes and species may be explained by the extent of duplication and
      subsequent deletion. There are at least five copies of MIC (PERB11) in humans,
      but MICA (PERB11.1) appears to have been deleted from the chimpanzee. By
      comparing the sequences of primates (chimpanzee, gorilla, gibbon, orang-utan,
      pygmy chimpanzee, Patas monkey, Aethiops and baboon) we conclude that the gorilla
      has a copy of PERB11.1, whereas the baboon and Patas possess MICD (PERB11.4)
      and/or MICE (PERB11.5) rather than MICA (PERB11.1). These findings indicate that
      the primate MHC is more plastic than has been appreciated.

PMID- 10331162
TI  - MIC genes in non-human primates.
AB  - MIC molecules belong to the immunoglobulin superfamily, are encoded within the
      MHC region and are recognized by gamma/delta T-cell receptors. In humans, at
      least two functional genes (MIC-A* and MIC-B*) and two pseudogenes (MIC-C* and
      MIC-D*) exist. Functional MIC gene copies are characterized by a high degree of
      polymorphism, while pseudogenes bear several debilitating mutations either in the
      putative extracellular region or in the transmembrane region of the molecule. In
      this study we sequenced these segments of MIC genes in seven non-human primates
      in order to determine whether debilitating mutations were present. All the MIC
      primate genes studied were highly homologous to their human counterparts, and
      cystein residues involved in the maintenance of the immunoglobulin-like structure
      were highly conserved. Furthermore, none of the MIC genes studied contained stop
      codons in the extracellular or transmembrane segments of the molecule, which
      suggests that at least one functional gene copy exists in non-human primates. A
      distinct family of MHC immunoglobulin-like genes was recently identified within
      the MHC class I region in humans (Bahram et al., 1994; Leelayuwat et al., 1994).
      Members of this MIC (MHC class I chain related) gene family belong to the
      immunoglobulin superfamily. Similar to classical class I MHC genes, they are
      characterized by three distinct extracellular domains (alpha 1-3), a
      transmembrane (TM) segment and a cytoplasmic segment, each encoded by a separate
      exon (Bahram et al., 1994; Bahram et al., 1996). Other similarities between MIC
      genes and classical MHC genes include a high degree of polymorphism (Fodil et
      al., 1996; Pellet et al., 1997) and recognition by T-cell receptors (Groh et al.,
      1998). These findings suggest that the putative MIC-A* chain has evolved for a
      function that is related to, but quite distinct from, that of typical MHC class I
      chains.

PMID- 10331163
TI  - Nomenclature for factors of the HLA system, update October 1998.

PMID- 10331164
TI  - Nomenclature for factors of the HLA system, update November 1998.

PMID- 10331165
TI  - Nomenclature for factors of the HLA system, update December 1998.

PMID- 10331166
TI  - [Depressive disorders undermine body and soul. Seldom diagnosed--and even then
      treated like a stepchild].

PMID- 10331167
TI  - [Prevalence of upper urinary tract stones in Tajima, north Hyogo, Japan].
AB  - Toyooka Hospital is a central hospital in Tajima, a rural area in the northern
      part of Hyogo Prefecture. Because we possess the sole lithotripter in this area,
      almost all urolithiasis patients requiring treatment have been referred to our
      department. Based on the number of urolithiasis patients treated in our
      institution, we estimated the annual prevalence and incidence of upper urinary
      tract stones in the Tajima area. The mean annual prevalence of urolithiasis and
      incidence during the 1991-1993 period were 141 and 93 per 100,000, respectively.
      The male to female ratio was 2.0 to 1 in prevalence and 2.2 to 1.0 in incidence.
      Prevalence was highest in the sixties (245) and fifties (235), followed by the
      forties (205), seventies (162) and thirties (160). The incidence was highest in
      the fifties (169), followed by the forties (147), sixties (145) and thirties
      (118). In consideration of sex, the incidence was highest in males in the fifties
      and the forties. Of the patients with upper urinary calculi, 23.1% were treated
      by extracorporeal shock wave lithotripsy, while in 23.8% stones passed
      spontaneously and 50.9% were followed up without treatment. On stone analysis,
      calcium oxalate and/or calcium phosphate was present in 75.6%, uric acid in
      16.4%, struvite and/or carbonate apatite in 5.6% and cystine in 1.4%. In summary,
      the prevalence and incidence of upper urinary tract calculi in the Tajima area
      were considerably higher than those in the nationwide survey on urolithiasis in
      Japan conducted in 1985.

PMID- 10331169
TI  - [Comparison of Tandem-R PSA and Markit-M PA in the diagnosis of prostate cancer].
AB  - The Tandem-R PSA (TR) assay was compared with the Markit-M PA (MM) assay in the
      diagnosis of the prostate cancer. In patients with a serum prostate specific
      antigen (PSA) level higher than the cut-off values measured by either the TR
      assay or the MM assay (4.1 ng/ml and 3.7 ng/ml, respectively), or a suspicious
      digital rectal examination, sextant biopsy of the prostate was performed. Among
      227 patients undergoing biopsy, 64 patients were diagnosed as having prostate
      cancer. There was a significant difference of serum PSA values between patients
      with and without prostate cancer in either assay. There was no significant
      difference between the assays with respect to diagnosing according to prostate
      cancer using receiver operating characteristic analysis. The correlation between
      TR and MM in 150 men with a serum Tandem-R PSA below 10 ng/ml was Y = 1.12X +
      3.745 (R = 0.68, p < 0.001). The correlation coefficient for the relationship
      between TR and MM was only 0.68, indicating a poor correlation. Four of the 15
      patients with MM values below 4.0 ng/ml calculated by transformation from MM to
      TR values had prostate cancer. This suggested that conversion of MM values to TR
      values in the low PSA range presents problems.

PMID- 10331168
TI  - [Relationship between plasma hormones and ventricular premature contractions in
      extracorporeal shock wave lithotripsy--significance of human atrial natriuretic
      peptide (hANP)].
AB  - Extracorporeal shock wave lithotripsy (ESWL) is a safe and effective treatment
      for upper urinary tract stones. However, the mechanism by which this treatment
      may be involved in causing ventricular premature contractions (VPC) is unknown.
      We evaluated the relationship between VPC and plasma hormones in patients treated
      by ESWL. Holter monitoring was performed on 61 outpatients undergoing ESWL with
      electrocardiographic synchronization for upper urinary tract stones. The levels
      of cathecolamine, plasma renin activity (PRA), plasma aldosterone concentration
      (PAC), and human atrial natriuretic peptide (hANP) were measured before,
      immediately after, and 7 days after ESWL. Systolic blood pressure increased
      significantly immediately after, and decreased 7 days after ESWL. VPC occurred
      during 23 treatments (37.7%) but during ESWL no significant relationship was
      observed with the treatment side or location. Epinephrine increased significantly
      immediately after ESWL. hANP increased significantly immediately after ESWL, and
      decreased 7 days later. VPC occurred in all patients who had an hANP value above
      40 pg/ml before ESWL. These results suggest that VPC is related to hemodynamic
      changes, and that hANP can predict VPC during ESWL.

PMID- 10331170
TI  - [Chromophobe cell renal carcinoma: a case report].
AB  - A 61-year-old man was admitted to our hospital because of the left renal mass
      lesion. We performed left radical nephrectomy under the diagnosis of renal cell
      carcinoma. The tumor showed a dark red color. The pathological diagnosis was
      chromophobe cell renal carcinoma. We could not make the diagnosis before the
      operation by echography, computed tomography or magnetic resonance imaging. It is
      still controversial whether this diagnosis can be made preoperatively.

PMID- 10331171
TI  - [Nutcracker phenomenon treated with left renal vein transposition: a case
      report].
AB  - Herein is reported a case of the nutcracker phenomenon with severe gross
      hematuria which was surgically treated. A 14-year-old boy had been suffering from
      left flank pain and recurrent gross hematuria causing urinary retention with
      blood clots. Radiological images including three-dimensional computed tomography
      (CT) and angiography disclosed the nutcracker phenomenon with left renal venous
      hypertension. Since the aforementioned symptoms could not be managed
      conservatively, he underwent transposition of the left renal vein at 5.5 cm
      caudal from the original position. Postoperative course was uneventful and the
      patient has had no further hematuria after the surgery.

PMID- 10331172
TI  - [A case of paraganglioma of the urinary bladder].
AB  - A 50-year-old male was referred to our department because of dysuria. On
      cystoscopy, a submucosal bladder tumor was seen at the posterior wall of the
      urinary bladder. Transurethral resection was performed with no intraoperative
      complications. Histopathological diagnosis of paraganglioma was confirmed by
      immunohistochemical staining.

PMID- 10331173
TI  - [Two cases of giant testicular tumor with widespread extension to the spermatic
      cord: usefulness of upfront chemotherapy].
AB  - The first case was a 55-year-old man with biopsy-proven seminoma of the left
      inguinal undescended testis. The tumor, 10 x 9 x 9 cm in size, with a calculated
      weight of 520 g invaded the left spermatic cord up to the level of the renal
      hilum and metastasized to the retroperitoneal lymph nodes (13 x 10 cm). The serum
      level of lactate dehydrogenase (LDH) and beta human chorionic gonadotropin (beta
      hCG) was 3,669 U/l and 1.3 ng/ml, respectively. The second case was a 38-year-old
      man with non-seminoma of the left testis. The testicular tumor, 32 x 28 x 28 cm
      in size, with a calculated weight of 7,000 g invaded the left spermatic cord up
      to the level of the aortic-bifurcation and metastasized to the retroperitoneal
      and the left supraclavicular lymph nodes. The serum level of LDH,
      alphafetoprotein (AFP) and beta-hCG was 2,040 U/l, 240 ng/ml and 5.6 ng/ml,
      respectively. Both patients were initially treated with VIP chemotherapy
      (etoposide, ifomide and cis-platinum), 4 cycles for the 1st case and 3 for the
      2nd, and followed by high orchiectomy and retroperitoneal lymph node dissection.
      Histologic section of all resected specimens revealed only necrosis and fibrosis.
      The patients have been free of recurrence for 15 and 13 months, respectively,
      after the operation. In the Japanese literature, 42 cases of giant testicular
      tumor (> 400 g) including these two cases have been reported. To our knowledge,
      our second case is the largest among the non-seminomatous tumors. For giant
      testicular tumor with extensive invasion to the spermatic cord, initial
      chemotherapy followed by surgical resection appears to be a better management.

PMID- 10331174
TI  - [Hypogonadotropic hypogonadism treated with HCG monotherapy: report of 3 cases].
AB  - We report 3 cases of hypogonadotropic hypogonadism and the effects of human
      chorionic gonadotropin (HCG) monotherapy on plasma testosterone levels, which
      were related to clinical results. The patients were males 29, 21 and 14 years
      old. Each received 5,000 units of HCG subcutaneously or intramuscularly twice or
      three times a week for 16 to 40 months. Genital effects, including an increase in
      testicular volume were seen in all patients after 2 or 3 months. The increase in
      plasma testosterone level after HCG therapy was significantly correlated with the
      genital effects similarly to other treatments. Moreover, spermatozoa appeared in
      one case.

PMID- 10331175
TI  - [Treatment of azoospermic patient with genitourinary tuberculosis: a case
      report].
AB  - A case of azoospermia due to genitourinary tuberculosis is reported with
      discussion on the treatment of infertility in such a case. A 38-year-old man
      visited us complaining of 4-year sterility. We suspected obstructive azoospermia
      due to previous genitourinary tuberculosis because of his treatment history,
      calcifications in the seminal vesicles and nodules in the right epididymis. After
      microsurgical epididymal sperm aspiration (MESA) was performed twice without
      success, we extracted sperm from his testis (testicular sperm extraction, TESE)
      and fertilized his wife's egg by intracytoplasmic sperm injection.

PMID- 10331176
TI  - [Two cases of testicular infarction: the usefulness of enhanced MRI for
      preoperative diagnosis].
AB  - The differential diagnosis in acute scrotum, particularly torsion of spermatic
      cord and epididymitis, is sometimes difficult. An erroneous diagnosis may result
      in unnecessary and improper treatment. We report two cases of testicular
      infarction including torsion of spermatic cord, preoperatively diagnosed by
      enhanced magnetic resonance imaging (MRI). Case 1: A 16-year-old boy presented
      with a 3-day history of left scrotal swelling and left lower abdominal pain. He
      had fever and leukocytosis. Antibiotics for 2 days failed to relieve the
      symptoms. Enhanced MRI showed absence of blood flow in the left testis. Scrotal
      exploration revealed hemorrhage and necrosis in the left testis. Left orchiectomy
      and right orchiopexy were performed. Case 2: A 12-year-old boy visited with
      scrotal swelling and fever 30 hours after an acute onset of left scrotal pain.
      Enhanced MRI showed absence of blood flow in the left testis. Exploration
      revealed left necrotic testis with torsion of spermatic cord. Left orchiectomy
      and right orchiopexy were performed. Our two cases suggested that enhanced MRI,
      by which the intratesticular blood flow can be evaluated, may be useful for the
      diagnosis of testicular infarction.

PMID- 10331177
TI  - [Leiomyoma of the scrotum: a case report].
AB  - A case of intrascrotal leiomyoma is reported. A 62-year-old male was admitted to
      our hospital with the chief complaint of a painless intrascrotal mass, which had
      been gradually increasing in size during the past 25 years. Physical examination
      revealed impervious to light and elastic firm mass of 5 cm in diameter in the
      left scrotum. Although the serum level of some tumor markers such as alpha
      fetoprotein and human chorionic gonadotropin-beta were normal, since the border
      on the left testis was unclear on the ultrasonogram of the scrotum, a testicular
      tumor was suspected, and radical orchiectomy was performed. The tumor was 6 x 4 x
      4 cm, 55 g, and well-defined with testis, epididymis and tunica dartos. It was
      histopathologically diagnosed as leiomyoma arising from the tunica vaginalis. The
      post operative course has been uneventful for 9 months after the surgery, and no
      recurrence has been recognized. An intrascrotal tumor is relatively rare, and is
      generally defined as one arising between tunica dartos and tunica vaginalis
      testis, which is independent of testis, epididymis, and funiculus spermaticus.
      This is the 25th case of intrascrotal leiomyoma reported in the literature in
      Japan.

PMID- 10331178
TI  - [Sclerosing lipogranuloma of the scrotum: a case report].
AB  - We present a case of sclerosing lipogranuloma of the scrotum. A 42-year-old man
      who had complained of a painless intrascrotal mass of one week's duration visited
      our clinic. Physical examination revealed a symmetrical Y-shaped hard mass around
      the penile base in the scrotum. Laboratory examination showed no abnormal
      findings except for a 14.0% eosinophilia. Magnetic resonance imaging (MRI) with a
      surface coil showed an atypical mass at the penile base. Percutaneous needle
      biopsy under ultrasound guidance was performed and histopathological findings
      revealed lipogranuloma accompanied by infiltrating multinuclear giant cells,
      eosinocytes and lymphocytes. The tumor gradually disappeared during a 4-week
      administration of antibiotics and antiphlogistics. We have also reviewed 95 cases
      of sclerosing lipogranuloma of the scrotum in the Japanese literature.

PMID- 10331179
TI  - [Rhabdomyolysis following radical prostatectomy: a case report].
AB  - A case of postoperative rhabdomyolysis following radical prostatectomy for
      prostate cancer is reported. A 60-year-old man was referred to our hospital
      because of an elevation of prostate specific antigen detected by the health
      checkup system. Sextant biopsy for the prostate revealed moderately
      differentiated adenocarcinoma. Radical prostatectomy was performed after hormonal
      therapy for 10 months. Two to three days after surgery, the patient complained of
      a feeling of listlessness. Serum levels of creatine phosphokinase were elevated
      to 6,584 IU/ml and creatinine slightly elevated to 1.6 mg/dl. Symptoms and
      laboratory findings improved after sufficient fluid infusion and injection of
      furosemide. To our knowledge, this is only the third case report in the world
      literature of postoperative rhabdomyolysis after urological surgery.

PMID- 10331180
TI  - [Rhabdomyolysis following nephrectomy for pyonephrosis: a case report].
AB  - A 33-year-old man with chronic alcoholism presented with left flank pain and a
      low-grade fever. He had a previous history of left renal calculi treated by
      extracorporeal shockwave lithotripsy 3 months previously at a local hospital.
      Since a stone was impacted at the ureteropelvic junction resulting in septic
      hydronephrosis, a D-J catheter was introduced to relieve the condition. He
      underwent fluid therapy with antibiotics. Elective pyelolithotomy was scheduled
      on day 10. However, persistent pyonephrosis necessitated the removal of the
      infected kidney. Hyperthermia over 40 degrees C continued after surgery and dark
      urine developed on postoperative day 2. Rhabdomyolysis was suspected because of
      myoglobulinemia with a high creatine phosphokinase level. Systemic cooling and
      treatment with fluid and diuretics saved his renal function. He survived episodic
      malignant hyperthermia and was discharged from intensive care unit on
      postoperative day 5.

PMID- 10331181
TI  - Improved fusion partners transfected with DNA fragment encoding IL-11 on
      generation of human B lymphocyte hybridomas.
AB  - IL-11, a less identified cytokine, possesses some overlapping functions with IL-6
      that are able to facilitate the growth and antibody secretion of B lymphocyte
      hybridomas. In this report, a DNA fragment encoding human IL-11 was transduced
      into fusion partners (mouse myelomas Ag8.653 and SP2/0, and human lymphoblastoid
      cell line HF2) mediated by lipofection. The transfected cells selected with G418
      secreted IL-11 constitutively over the range of 32.4 +/- 10.5 units/ml to 76.6 +/
      18.4 units/ml, which could be inhibited by an IL-11 neutralizing MAb up to 80%.
      The fusion frequency of PBMC doubled, while that of LCLs displayed a 2.4- or 3.3
      fold increase, when fused with the transfected fusion partners, respectively. The
      derived hybridomas from IL-11 secreting fusion partner secreted 3 or 4 times as
      many immunoglobulins as that from its ancestor. Our data indicate that IL-11 gene
      transfected fusion partners are improved cell lines for generation of human B
      lymphocyte hybridomas, and IL-11 may contribute to the increased fusion frequency
      and antibody secretion of B lymphocyte hybridomas.

PMID- 10331182
TI  - Co-expression of tumor antigens and their modulation by pleiotrophic modifiers
      enhance targeting of human monoclonal antibodies to pancreatic carcinoma.
AB  - Cocktails of human monoclonal antibodies (HuMAbs) have been used to increase the
      likelihood of identifying heterogeneous cancer cells. We utilized 3 HuMAbs termed
      SK-1, GM4, and GMA1, which recognized a 42-46 kDa two chain structure, a 57 kDa
      antigen, and the ganglioside GD3, respectively. An estimated two dozen cell lines
      were tested for the coexpression of these antigens and this was found to be
      present only on pancreatic carcinoma cell line, PANC-1; A 24 hr treatment of PANC
      1 cells with interferon gamma (IFN gamma; 100 units), interferon beta (IFN beta;
      1000 units), as well as interferon alpha (IFN alpha; 1000 units) resulted in
      roughly a four fold increase in the co-expression of the 42-46 kDa/GD3 antigens
      as well as the 42-46 kDa/57 kDa antigens. After a 4 day incubation the co
      expression of these antigens progressed and IFN alpha treatment had the most
      pronounced effect, which was 8 fold higher than background for the 42-46 kDa/57
      kDa antigens, whereas IFN beta resulted in a five fold antigen upregulation. The
      pronounced effect of vinblastine on the co-expression of the 42-46 kDa/GD3
      antigens (4 fold on day 1 and, 10 fold on day 4) and 42-46 kDa/57 kDa antigens on
      PANC-1 (5 fold on day 1 and 7 fold over background on day 4) cells can be seen at
      concentrations as low as 10(-7)M. Colchicine and vincristine dramatically
      enhanced co-expression of these tumor antigens on day 4 but not on day 1 PANC-1
      cells. The expression of these antigens was also found to be cell cycle
      dependent.

PMID- 10331183
TI  - Targeting cytokines to tumors to induce active antitumor immune responses by
      recombinant fusion proteins.
AB  - Cytokines such as interleukin-2(IL-2), gamma interferon (IFN-gamma) and alpha
      tumor necrosis factor (TNF-alpha) are important mediators in immune responses
      against tumors. However, their therapeutic efficacy and clinical utilities in
      treatment of human malignancies are in large part limited due to the low
      concentrations of cytokine in tumors and the severe toxic side-effects derived
      from high-dose administration of cytokines. One critical issue to improve
      therapeutic efficacy is how to increase the local concentration of cytokine in
      tumors without causing severe side-effects. A series of recent reports
      demonstrated that the introduction of cytokine genes into tumor cells and
      subsequent local secretion can circumvent the limitations associated with the
      systemic cytokine administration. An alternative means of cytokine delivery is to
      target cytokines to tumor cells with tumor specific antibodies. Thereby,
      effective local cytokine concentrations can be achieved at the tumor sites
      without resorting to patient-specific therapy. With the advance in biotechnology,
      two structurally disparate domains of immunoglobulin and cytokine can be brought
      together into one fusion protein molecule by protein engineering These engineered
      antibody-cytokine fusion proteins combine the unique targeting ability of tumor
      specific antibodies with the multifunctional activity of cytokines. In general,
      there are two commonly engineered fusion proteins, the F(ab')2/cytokine expressed
      in mammalian cells and the single-chain FV/cytokine expressed in Escherichia
      coli. Both the tumor-binding reactivity and the functional cytokine activity are
      maintained in most of fusion proteins. Therefore, these fusion proteins may be
      useful in targeting cytokine to tumors to stimulate immune destruction of tumors,
      while limiting severe toxic side-effects by the high dose of cytokine
      administration. Recent preclinical studies have shown that these fusion proteins
      are able to target cytokines to tumors expressing the tumor-associated antigen in
      vivo, and to inhibit both the primary and metastatic tumors in an immune
      competent animal model. Therefore, these recombinant fusion proteins may
      represent a new generation of novel immunotherapeutic reagents for the treatment
      of human malignant diseases.

PMID- 10331184
TI  - Human monoclonal IgM DJ binds to ssDNA and human commensal bacteria.
AB  - In this study we tried to elucidate further the crossreactivity pattern and
      binding characteristics of human monoclonal IgM DJ which is an anti-DNA antibody
      and possesses Y7 natural idiotope. Isolated IgM DJ and its enzymatically obtained
      fragments Fab' and (Fab')2 were tested for binding to more than 26 antigens and
      nine bacteria in indirect ELISA. Inhibition of binding studies and examination of
      the stability of antigen-antibody complexes were also done in ELISA assay. IgM DJ
      bound to single stranded DNA and human lactic acid bacteria, such as L.
      acidophyllus, B. bifidum and L. plantarum. This binding was shown to be mediated
      through IgM DJ Fab' fragment. High avidity and low affinity of interactions was
      estimated from the binding curves of Fab', (Fab')2 fragments and whole IgM. The
      common epitopic motif on both antigens were negatively charged phosphodiester
      moieties. Complexes formed with ssDNA and B. bifidum were resistant to washing
      with high salt. This suggested that electrostatic attraction was not a strong
      component of the binding. A novel pattern of natural autoantibody reactivity in a
      human system related to cross-reactivity with DNA and LAB is described. Possible
      involvement of LAB in induction of natural anti-DNA antibodies is discussed.

PMID- 10331185
TI  - Development of a trispecific antibody conjugate that directs two distinct tumor
      associated antigens to CD64 on myeloid effector cells.
AB  - A trispecific F(ab')3 antibody conjugate (TAC) with specificities for the Fc
      gamma receptor I (Fc gamma RI/CD64), the epidermal growth factor receptor (EGFR)
      and the HER2/neu antigen has been developed to redirect effector cell-mediated
      cytotoxicity against cancer cells expressing both or either of the tumor
      associated antigens. The TAC was constructed in two steps using the sulfhydryl
      specific cross-linker o-phenylenedimaleimide (o-PDM). In step one, a bispecific
      antibody was prepared by linking the Fab' fragments of mAb m22 (a murine IgG1
      specific for Fc gamma RI) and mAb H425 (a humanized IgG1 antibody recognizing
      EGFR). The conjugation efficiency was about 60%. In the second step, the Fab'
      fragment of mAb 520C9, a murine IgG1 specific for HER2/neu, was coupled to the
      bispecific antibody made in step one. About 40% of the bispecific conjugate was
      derivatized to form the trispecific antibody. The purity of the TAC was more than
      90% after gel filtration purification. The TAC was characterized in vitro for its
      ability to bind specifically to all the three antigens and to kill target cells
      expressing the tumor antigens. In contrast to bispecific conjugates that can only
      target cells expressing either of the tumor antigens, the TAC was able to bind
      both the antigens more efficiently in cell-binding assays and to kill tumor cells
      expressing EGFR and HER2/neu antigens.

PMID- 10331186
TI  - Induction of neutralizing autoantibodies to interferon-gamma in patients with
      polyneuropathy.
AB  - We previously demonstrated the induction of IFN-gamma in polyneuropathy patients
      associated with monoclonal gammopathy, but not in patients with presumably non
      immunological types of neuropathy. We herein examined mechanism involving release
      of neutralizing autoantibodies (Aabs) to IFN-gamma in sera from those patients.
      In contrast to polyneuropathy patients with monoclonal gammopathy, patients with
      polyneuropathy of presumably non-immunological types showed increased production
      of neutralizing Aabs specific for IFN-gamma. These results demonstrate a role for
      autoimmunity in cytokine regulation. However, their association to the clinical
      manifestations of the disease requires further investigations, which are
      necessary for future consideration in therapeutic strategies.

PMID- 10331187
TI  - Immunohistochemically detecting target antigens in patient biopsies for tailoring
      monoclonal antibody based cancer therapy.
AB  - Immunohistochemical analysis of biopsies, cytology specimens or surgical
      resection specimens using antibodies directed towards tumor-associated antigens,
      lineage or differentiation antigens is a technique often used by surgical
      pathologists to aid in establishing the correct histologic classification of
      malignant tumors. With the proliferation of experimental approaches to cancer
      treatment using monoclonal antibodies as targeting agents, it is anticipated that
      surgical pathologists will increasingly be receiving requests from clinicians to
      define the antigen profile in biopsy specimens, even when not necessary to render
      the correct tumor classification. Clinicians may use the immunohistochemically
      delineated antigen profiles provided by surgical pathologists to plan tailored
      treatment regimens utilizing monoclonal antibodies to the antigens expressed in
      the tumor biopsy to target anticancer therapeutic agents. Some of the potential
      problems in such a process might include the differing sensitivities, and perhaps
      specificities, of the antibodies used for analyzing the surgical pathology biopsy
      specimens compared to the monoclonal antibodies actually used in vivo. Our
      approach to this dilemma is to develop murine monoclonal antibodies to tumor
      associated antigens that can reliably be used to detect antigens in routinely
      processed surgical pathology specimens as a starting point for further
      therapeutic monoclonal antibody development.

PMID- 10331188
TI  - Human single-chain Fv fragments from a combinatorial library using the loxP-Cre
      recombination system.
AB  - A human scFv display library has been constructed from peripheral blood
      lymphocytes of a patient suffering from Hashimoto's thyroiditis. Upon induction
      of Cre recombinase, the amplified VH and VL genes were recombined via two loxP
      sites inserted in amplification primers to construct in vitro scFv genes. Either
      soluble scFvs or scFvs displayed on phage were screened for binding to human
      thyroglobulin after two pannings with this antigen. Three scFvs were obtained
      which showed very similar nucleotidic sequences. The VH genes expressed display
      96.4% nucleotide sequence homology with the germline VH251 gene, one of the two
      functional members of the small VH5 family and are mutated in sites already
      described as "selectively neutral" mutations and the VL genes are close to the
      germline DPL8 gene. These scFvs bind not only to human thyroglobulin but also to
      other self and exogenous antigens.

PMID- 10331189
TI  - Molecular cloning of cDNA for equine follistatin and its gene expression in the
      reproductive tissues of the mare.
AB  - A cDNA clone encoding equine follistatin was isolated from an equine ovarian cDNA
      library. Out of 1.2 x 10(5) independent clones screened, one positive clone was
      isolated and its cDNA sequence determined. The isolated clone, named EQ-FS-1,
      contained a complete open reading frame encoding 344 amino acid residues. The
      similarity of its deduced amino acid sequence to these of other mammalian species
      was greater than 95%. Although its expression level varied among the tissues
      examined, follistatin mRNA was detected in the equine uteroplacental tissues,
      follicles and corpora lutea by Northern blot analysis. In situ hybridization
      revealed that the expression of follistatin mRNA in the equine follicle was
      restricted exclusively to granulosa cells. When the expression pattern of
      follistatin mRNA in the equine uteroplacental tissues from mid- to late-pregnancy
      was examined, it was shown that its expression level tended to decrease after mid
      pregnancy. These results suggest that follistatin acts in the reproductive
      tissues of the mare in maintaining pregnancy.

PMID- 10331190
TI  - Transferability of cephalothin to the alveolar cavity in thoroughbreds.
AB  - Five Thoroughbreds were classified into 4 groups according to the administration
      method used for saline solution (saline), ambroxol, and cephalothin sodium
      (cephalothin). In group A, cephalothin was injected intravenously after oral
      administration of ambroxol. In group B, cephalothin was injected intravenously
      after oral administration of saline. Groups C and D were used as control groups.
      The dose of cephalothin or ambroxol was clinically administrated. Venous blood
      and bronchoalveolar lavage fluid (BALF) were sampled from each group. In groups A
      and B, cephalothin concentrations in plasma reached their maximum level 5 min
      after cephalothin administration and then declined over time. In plasma obtained
      from groups A and B, there were no significant differences in pharmacokinetic
      parameters (T1/2, Kel, Vd). By contrast, cephalothin concentrations in BALF
      reached their peak at 180 min after cephalothin administration in both groups A
      and B and maintained a relatively high level even after 300 min. These findings
      indicate that cephalothin requires a relatively long period of time to move from
      the blood stream to the alveolar cavity, but once transferred to the alveolar
      cavity, it is preserved for a long time. In groups A and B, cephalothin
      concentrations in BALF were approximately at the same level. However, in group A,
      total protein in BALF was lower at 60, 180, and 300 min than the other groups.
      Then, cephalothin concentration was adjusted to total protein in BALF. After
      adjustment to total protein in BALF, group A showed a concentration level of
      cephalothin approximately 1.5-fold higher than that of group B. This suggests
      that the transferability of cephalothin to the alveolar cavity improves as a
      result of the oral administration of ambroxol.

PMID- 10331191
TI  - Cloning and studies of the mouse cDNA encoding Smad3.
AB  - Following stimulation by the transforming growth factor-beta (TGF-beta) family in
      the cytoplasm, the Smad family is phosphorylated and translocated to the nucleus
      and activates several gene transcriptions. In this study, the mouse Smad3 cDNA
      including the open reading frame (ORF) was cloned from the mouse brain using a
      RACE (rapid amplification of cDNA ends) technique, and its expression pattern was
      analyzed in mouse tissue using northern blot. The predicted amino acid (aa)
      sequences of mouse Smad3 showed a high homology with human Smad3 (99.3%) and
      mouse Smad2 (85.4%). It revealed that this protein may be highly conserved in
      different species of mammals. Northern blot analyses revealed that Smad3 was
      highly expressed in the brain and ovary, and that the size of major transcript
      was about 5.7 kb. In situ hybridization analyses revealed the high expression of
      Smad3 was detected in the pyramidal cells of the hippocampus, the granule cells
      of the dentate gyrus, the granular cells of the cerebral cortex and the granulosa
      cells of the ovary. Smad3 may be essential transducer of signals from TGF-beta
      and activin in these cells.

PMID- 10331192
TI  - Occlusion of the internal carotid artery by means of microcoils for preventing
      epistaxis caused by guttural pouch mycosis in horses.
AB  - Occlusion of the internal carotid artery by insertion of intravascular platinum
      microcoils for guttural pouch mycosis was experimentally evaluated in 9 healthy
      adult Thoroughbred horses. The internal carotid artery was ligated to its origin,
      and an arteriotomy was made distal to the ligature, which was then occluded by
      insertion of the microcoil approximately 13 cm distal to its origin. Cessation of
      blood flow was determined visually and by angiography at the arteriotomy site.
      Six horses were evaluated for complication clinically and by endoscopy after
      surgery. One horse was necropsied after 30 days of surgery for histological
      evaluation of artery thrombus formation. In the other 3 horses, the blood flow of
      the right internal carotid artery was monitored, before and after microcoil
      occlusion of the left internal carotid artery. One or 2 microcoils stopped blood
      flow within a few minutes. No other abnormal findings were observed clinically.
      Thrombus was observed in the occluded segment of 1 horse 30 days after insertion;
      but no abnormalities were detected. The blood flow in the right internal carotid
      artery increased by approximately 28-58% after occlusion of the left internal
      carotid artery. This microcoil vascular occlusion technique causes an effective
      thrombosis, and based on experimental studies and clinical application in 2
      horses with epistaxis due to guttural pouch mycosis, this technique would appear
      to be safe and efficacious.

PMID- 10331193
TI  - Immunohistological distributions of fibronectin, tenascin, type I, III and IV
      collagens, and laminin during tooth development and degeneration in fetuses of
      minke whale, Balaenoptera acutorostrata.
AB  - The immunohistological distributions of fibronectin, tenascin, type I, III and IV
      collagens, and laminin were observed in the tooth buds of fetuses of minke whale,
      Balaenoptera acutorostrata. Distributions of extracellular matrices (ECMs)
      examined in this study except for tenascin were generally similar to those of
      terrestrial mammalian species during development of the tooth bud. Tenascin in
      the fetuses of minke whale showed characteristic distributions in the dental
      lamina and the enamel organ in the early tooth developmental stage. In the
      physiological degeneration stage of tooth bud development, immunoreactivity of
      the ECMs were very weakly and limitedly detected in the dental papilla and the
      surrounding mesenchyme. Immunoreactivity of tenascin and type I and III collagens
      were positively detected in the developing baleen plate germ which was associated
      with the degenerating tooth bud. These findings suggested that expressions of the
      ECMs were related to the formation of the tooth bud and baleen plate germ, and
      that the lack of the ECMs was related to the degeneration of the tooth bud in the
      fetal minke whale.

PMID- 10331194
TI  - Immunohistochemical observations on the initial disorders of the epiphyseal
      growth plate in rats induced by high dose of vitamin A.
AB  - The initial disorders of the epiphyseal growth plate cartilage were
      immunohistochemically examined in the proximal tibia of rats administered a high
      dose of vitamin A. Male Wistar rats were given 100,000 IU/100 g body weight/day
      of vitamin A for administration periods of 1 to 5 days (Day 1 to 5) from 4 weeks
      after birth or were given deionized water and used as control. They were
      sacrificed after 5-bromo-2'-deoxyuridine (BrdU) injection on Day 1 to Day 5 to
      remove the tibiae. The tibiae were processed for immunohistochemical examinations
      using antibodies against type I, II, X collagens and BrdU. BrdU-incorporated
      chondrocytes and type X collagen-negative area were reduced since Day 2 and type
      X collagen-positive area was reduced since Day 4. The cartilage matrix partially
      lost type II collagen and deposited type I collagen in the epiphyseal growth
      plate near the periosteum on Day 5. These findings suggest that a high dose of
      vitamin A initially disturbed the differentiation from resting to proliferating
      chondrocytes, subsequently inhibited the differentiation from proliferating to
      hypertrophic chondrocytes, caused the chondrocytes to deviate from the process of
      normal differentiation, and finally resulted in the deformation of the epiphyseal
      growth plate.

PMID- 10331195
TI  - MR imaging of hepatic injury in the LEC rat under a high magnetic field (7.05 T).
AB  - Visualization of copper-induced hepatitis (CuH) in LEC rats was performed by
      using an MRI apparatus equipped with a magnet producing a high magnetic field of
      7.05 T. When three groups of LEC rats (6-16 [pre-hepatitis], 15-26 [acute
      hepatitis] and 40-77 [chronic hepatitis] weeks old) were examined by MRI under T2
      weighted imaging conditions which are suitable for the diagnosis of human
      hepatitis, hypointense MR images of the livers were, as a whole, obtained in all
      groups, suggesting that these conditions were not adequate for imaging of CuH of
      LEC rats. The shortening of the T1 and T2 relaxation times of livers due to an
      excess amount of paramagnetic irons under the high magnetic field was responsible
      for the lowering of MR signal intensities of the livers, especially those of 15
      to 26-week old rats showing acute hepatitis. However, theoretical calculation of
      the MR signal intensities using the T1 and T2 relaxation times of the livers
      indicated that their imaging might be possible under proton density-weighted
      conditions even with a high magnetic field. Experimental results showed that
      hepatic injury was visualized as hyperintense regions in the MR image of the
      liver in the acute-phase rat.

PMID- 10331196
TI  - Computerized digital image processing on radiographs of canine filariosis.
AB  - For objective evaluation in the lung arterial lesions, density histogram revealed
      by survey thoracic radiographies of fifteen canine filariosis and five normal
      canine were digitally analyzed, and preparation of pulmonary artery angiogram
      with inflated-fixed lung, the changes in the histogram and the pulmonary arterial
      lesion by a soft x-ray examination were compared. In the lung areas affected by
      filariosis, the density histogram increased the white level and decreased the
      black level in each part compared to a normal lung. In comparison with the normal
      parameters, those of the filariosis it were significantly increased in minimum
      grey level values (Min), maximum grey level values (Max), and the maximum
      frequency grey level values (Mode) and, it was significantly decreased in maximum
      frequency values (MaF). The pulmonary arterial lesion of the filariosis showed
      obvious morphological changes such as in distinction, pruning, angiectasis, and
      meandering. In the grade of pulmonary arterial lesion, the parameter Min, Max,
      Mode and MaF were changed significantly. From these results, it was clear that
      the methods for the lung arterial lesions analysis of x-ray images were confirmed
      to be highly beneficial in the lung arterial lesions for objective diagnosis.

PMID- 10331197
TI  - Expression of Recombinant bovine L-selectin in Escherichia coli and insect cells.
AB  - Bovine L-selectin was expressed in bacteria using pGEX vector and in insect cells
      infected with recombinant baculovirus in order to obtain recombinant protein for
      preparation of specific antiserum and its functional studies. In bacterial
      expression, L-selectin fusion protein with glutathione S-transferase was detected
      in the insoluble fraction with the expected molecular weight of 60 kDa by SDS
      PAGE and reacted with anti-bovine CD62L monoclonal antibody in immunoblot
      analysis. In insect cells infected with recombinant baculovirus, a band
      corresponding to L-selectin was not observed in SDS-PAGE with protein staining,
      but they apparently reacted with anti-bovine CD62L monoclonal antibody in
      immunoblot analysis. Furthermore, the indirect immunofluorescence test revealed
      that bovine L-selectin was efficiently expressed on the surface of Sf9 cells
      infected with recombinant baculovirus, and flow cytometric analysis showed that
      the percentage of CD62L positive cells in bovine PBMC was about 66% and that most
      Sf9 cells infected with recombinant baculovirus had specific immunofluorescence.

PMID- 10331198
TI  - Prevalence and persistence of Salmonella in broiler chicken flocks.
AB  - Cecal contents of 2,345 broiler chickens consisting of 28 flocks originated from
      12 farms were examined for the prevalence of Salmonella to know the actual status
      of infection with Salmonella in the chicken flocks. Salmonella was isolated from
      336 (14.3%) samples. From these isolates, eight serovars were identified. Of the
      336 Salmonella isolates, 242 (72.0%) were serotyped as S. Blockley, 60 (17.9%) S.
      Hadar, 15 (4.5%) S. Bredeney, nine (2.7%) S. Schwarzengrund, four (1.2%) S.
      Anatum, three (0.9%) S. Enteritidis, two (0.6%) S. Ohio, and one (0.3%) S.
      Livingstone. The same serovars of Salmonella were repeatedly found in the
      chickens from the same farms. S. Typhimurium and S. Enteritidis were detected in
      pooled broken eggshell samples collected from the hatchery. Analysis of plasmid
      profiles revealed 11 patterns of S. Blockley and seven patterns of S. Hadar.
      Strains of the same plasmid profiles of S. Blockley were isolated repeatedly from
      the same farm over one year after the first isolation.

PMID- 10331199
TI  - Distribution of cytokeratin polypeptides detected by monoclonal antibodies K8.13
      and K8.12 in the fetal bovine ruminal epithelium.
AB  - Temporal and spatial distributions of cytokeratin (CK) polypeptides were detected
      by monoclonal antibodies (mAbs) K8.13 and K8.12 during the development of the
      bovine ruminal epithelium. By the Western blotting analysis after the sodium
      dodecyl sulfate-polyacrilamide gel electrophoresis, mAb K8.13 confirmed 60.8 and
      63.0 kD CK polypeptides in the fetal ruminal epithelial extract, and mAb K8.12
      also 48.0 and 54.0 kD CK polypeptides. Immunohistochemical reactivities against
      both mAbs were detected only in the epithelial cells throughout the fetal
      periods. Distributions of CK polypeptides detected only by mAb K8.13 were
      observed on the basal side of the epitherial layer, but not by mAb K8.12 in the 7
      cm fetus in crown-rump length. MAb K8.13 reacted also intensely with columnar
      shaped cells in the basal layer in the fetuses of the later developmental
      periods. These results suggest that CK polypeptides detected by mAb K8.13 might
      be involved in the differentiation and/or the maintenance of the basal layer in
      the ruminal epithelial development.

PMID- 10331200
TI  - Calretinin immunoreactive nerve endings in the trachea and bronchi of the rat.
AB  - Nerve endings showing calretinin immunoreactivity were examined in the lower
      respiratory tract of the adult rat. Tree-like nerve endings were immunostained in
      the tracheal and bronchial smooth muscle layer. The endings that arose from thick
      nerve fibers and formed corpuscles composed of many arborized nerve terminals. A
      few of the nerve endings were also observed in the lamina propria of the tracheal
      mucosa, close to the epithelial layer. Immunoelectron microscopy revealed that
      the immunoreactive terminals were filled with mitochondria and scattered among
      the intermuscular collagen fibrils. Schwann cell sheath and collagen fibrils were
      intercalated between the smooth muscle cells and nerve endings. The calretinin
      immunoreactive nerve endings observed in the present study seem to be slowly
      adapting stretch receptors.

PMID- 10331201
TI  - Cloning of a cysteine proteinase gene of Theileria sergenti.
AB  - A cDNA encoding cysteine proteinase of Theileria sergenti was isolated from a
      piroplasm cDNA library and its nucleotide sequence was determined. The gene
      encodes a polypeptide of 402 amino acids with predicted molecular mass of 46.4
      kDa. Analysis of the predicted amino acid sequence revealed a number of features
      common to known cysteine proteinases. Southern blot analysis showed that the
      cysteine proteinase gene was likely to be a single copy per genome.

PMID- 10331202
TI  - Expression of a major piroplasm surface protein of Theileria sergenti in
      sporozoite stage.
AB  - A 32 kilodalton major piroplasm surface protein (MPSP) is expressed abundantly on
      the surface of intraerythrocytic piroplasms of Theileria sergenti and is
      considered to be a candidate antigen for vaccine development against
      piroplasmosis. In this study, transcripts of MPSP gene were detected in an
      expression cDNA library prepared from T. sergenti-infected tick salivary glands.
      Expression of MPSP in the sporozoite stage was also confirmed by immunoblot
      analysis. Its expression at the sporozoite and intraerythrocytic stages gives
      scope for possible induction of protective immunity being targeted at both stages
      by immunization with recombinant MPSP.

PMID- 10331203
TI  - Effects of in vitro atmospheric ammonia exposure on recovery rate and luminol
      dependent chemiluminescence of bovine neutrophils and bronchoalveolar
      macrophages.
AB  - The effects of atmospheric ammonia, a major pollutant in animal confinement
      facilities, on bovine neutrophils and bronchoalveolar macrophages were evaluated
      in vitro. Ammonia exposure at concentrations 50, 100 and 200 ppm for one hour
      impaired recovery rates of neutrophils dose-dependently but enhanced their
      chemiluminescence activity per cell at lower concentrations (50 and 100 ppm).
      Macrophages were resistant to the exposure. Their recovery rates and
      chemiluminescence remained unaffected even at 200 ppm exposure. The present
      results suggest that ammonia exposure is unfavorable for bovine neutrophils in
      vitro, and probably in vivo also, in light of causing cell damage and triggering
      wider inflammatory responses.

PMID- 10331204
TI  - Effects of four antigenic fractions of Pasteurella multocida serotype A on
      phagocytosis of chicken peripheral blood leukocytes.
AB  - The effects of four antigenic fractions of Pasteurella multocida serotype A
      isolated from a duck in the Philippines on the phagocytic activity of chicken
      peripheral blood leukocytes were studied by a flow cytometer. These fractions
      were the lipopolysaccharide-protein complex (LPS), crude capsular antigen (CCA),
      ribosomal fraction (RS) and outer cell layer (OCL). Among these four antigens,
      only CCA but not LPS RS and OCL, significantly increased the phagocytic
      activities of mononuclear cells (MNC) and polymorphonuclear cells (PMN). This
      result indicates that CCA has an immunological property enhancing the phagocytic
      activities of MNC and PMN.

PMID- 10331205
TI  - Chemical control of Haematobia irritans with 0.5% topical ivermectin solution in
      cattle.
AB  - A field trial was conducted to evaluate the efficacy of a topical formulation of
      ivermectin administered at the dose of 500 micrograms/kg against horn flies
      (Haematobia irritans) in cattle. Eighty-eight cattle in four herds naturally
      exposed to horn flies were used in the trial. Replicates were formed of two
      herds. Within replicates, one herd was randomly allocated to the untreated
      control and the other to the ivermectin treatment group. Horn fly counts were
      taken on the treatment day (Day 0) and on Days 7, 14, 21, 28, and 35 post
      treatment. There were no horn flies on any cattle in the treatment group, whereas
      all the control cattle were continuously infested by horn flies on each
      examination day.

PMID- 10331206
TI  - The cDNA sequences of equine antioxidative enzyme genes Cu/Zn-SOD and Mn-SOD, and
      these expressions in equine tissues.
AB  - The entire cDNA sequences were determined by reverse transcription-polymerase
      chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) techniques
      for equine copper/zinc superoxide dismutase (Cu/Zn-SOD) and manganese superoxide
      dismutase (Mn-SOD) through the use of total RNA extracted from the testis of an
      adult Thoroughbred. The results revealed a protein coding region for equine Cu/Zn
      SOD with bases totaling 465 bp, accompanied by an estimated 154 residues of amino
      acids. As for equine Mn-SOD, its coding region contained a total of 669 bp and an
      estimated 222 residues of amino acids. Further, the expression of Cu/Zn-SOD and
      Mn-SOD genes were confirmed in the equine tissues by RT-PCR and in situ
      hybridization.

PMID- 10331207
TI  - Some characteristics of bacteria found in a bioreactor to treat trichloroethylene
      contaminated groundwater.
AB  - A mixture of bacteria, having a methane-utilizing ability, was separated from a
      bioreactor supplied with air and methane gas. The bioreactor was operated to
      treat trichloroethylene (TCE)-contaminated groundwater. The mixture was composed
      of an obligate methane-utilizing bacterium and a heterotroph, identified as
      Methylomonas methanica and Pseudomonas sp., respectively. The mixed culture of
      these two strains removed TCE. In addition, it appeared that a cooperative
      metabolic interaction of these strains enabled Meth.methanica to maintain the TCE
      degradation ability.

PMID- 10331208
TI  - Neutralizing feature of commercially available feline calicivirus (FCV) vaccine
      immune sera against FCV field isolates.
AB  - Four types of commercially available feline calicivirus (FCV) vaccine were
      compared in terms of their efficacy on the basis of the ability of the sera of
      specific-pathogen-free cats immunized by two injections of each type of vaccine
      to neutralize FCV field isolates. Each vaccine immune serum neutralized
      relatively well strains F4, F9, and 255, which were FCV laboratory strains. As to
      36 strains of field isolates, however, vaccines A, B, C, and D immune sera did
      not neutralize 18-20 of the strains (50.0%-55.6%), 19-22 of the strains (52.8%
      61.1%), 22-25 of the strains (61.1%-69.4%), and 8-16 of the strains (22.2%
      44.4%), respectively. These results indicate that there is much difference in
      neutralizing antigenicity between the existing vaccine strains and the FCV
      strains that are prevalent in Japan, suggesting the need for improvement of FCV
      vaccines.

PMID- 10331209
TI  - Rumen ciliate protozoal fauna of native sheep, friesian cattle and dromedary
      camel in Libya.
AB  - Rumen ciliate species and composition were surveyed on the native sheep, Friesian
      cattle and dromedary (one-humped) camels kept in Libya. As a result of survey, 5
      genera including 14 species with 5 formae in native sheep, 9 genera including 27
      species with 6 formae in Friesian-cattle and 6 genera including 13 species and 7
      formae in dromedary camels were identified. All of the ciliate species and their
      percentage composition detected from the Libyan sheep and cattle in this
      examination were similar to those found from corresponding animals in the other
      countries. Libyan camels lacked some peculiar ciliate species found from camels
      in the other countries, but had many cosmopolitan species common with those in
      the domestic ruminants, suggesting that ciliate faunae of camel are easily
      affected by the other domestic ruminants kept together. The ciliate density was
      estimated as 105/ml in every host species.

PMID- 10331210
TI  - First isolation of Sarcocystis hominis from cattle in Japan.
AB  - Sarcocystis hominis was first isolated from slaughtered cattle raised in Japan.
      Cysts were 1,220-4,460 x 80-384 microns in size and their wall was 3 to 6 microns
      thick and appeared radially striated in the histopathological sections because of
      the presence of palisade-like villar protrusions on the surface. The protrusions
      were 3.1-4.3 x 0.7-1.1 microns in size and had many microtubules in the core. Two
      cynomolgus monkeys, Macaca fascicularis, fed with the Sarcocystis cysts began to
      pass sporocysts, which measured a size of 14.3-15 x 9.5-10 microns, in the feces
      10 days after ingestion.

PMID- 10331211
TI  - Effect of amaranth and oat bran on blood serum and liver lipids in rats depending
      on the kind of dietary fats.
AB  - The effect of amaranth and oat bran on the lipids of blood and liver in rats
      depending on the kind of fats in diet was the subject of our study. Sixty male
      Buffalo rats were fed for 28 days one of six diet containing 15% of fat (lard or
      sunflower oil), 20% of protein and 0.5% of cholesterol. Amaranth and oat bran
      added to diet provided 4-4.5% of dietary fiber, water soluble fraction of which
      amounted to 30%. Amaranth significantly decreased the level of total cholesterol
      in rats blood serum (by 10.7% in the case of diet with lard and by 14% with
      sunflower oil) and in liver (by 20% in the case of diet with lard and by 23% with
      sunflower oil). Similarly oat bran decreased the level of total cholesterol in
      the blood serum: by 19% in the case of diet with lard and by 22% with sunflower
      oil; and in liver by 22 and 27%, respectively. Amaranth and oat bran did not
      influence HDL-cholesterol in the blood of rats. The influence of amaranth and oat
      bran on the concentration of triglycerides in the blood serum depended on the
      kind of fats in a diet. The diets containing amaranth or oat bran with lard did
      not decrease the concentration of this lipids, however, the same diets but with
      sunflower oil decreased this concentration significantly (by 22%). In liver
      significant hypotriglyceridemic effect of amaranth and oat bran was observed for
      both of the diets: based on lard and sunflower. The decrease of triglycerides
      concentration under the influence of amaranth amounted to 10% (diet with lard)
      and 15% (diet with sunflower oil). Oat bran decreased the concentration of
      triglycerides in liver by 15% (diet with lard) and 20% (diet with sunflower oil).
      Sunflower oil added to the diets augmented the hypolipemic effect of amaranth and
      oat bran.

PMID- 10331212
TI  - Safety and quality of fresh water crayfish Procambarus clarkii in the river Nile.
AB  - Fresh water crayfish Procambarus clarkii which recently appeared in River Nile
      and its resources all over Egypt was microbiologically and chemically evaluated
      in order to determine its safety and quality as human food. The average aerobic
      plate and Enterobacteriaceae counts/g were 1.6 x 10(8) and 3.5 x 10(5), and the
      coliforms and E. coli were isolated from 100% and 40% of the examined samples
      respectively. However, Salmonellae could not be isolated from any of the examined
      samples. 20% of the samples were safe for human consumption, while 33.33% were
      marginally acceptable and 46.67% were unacceptable. The mean gross weight, yield
      of meat, moisture, fat, protein, ash and caloric values were 27.71 g, 12.37%,
      82.19%, 0.59%, 15.6%, 1.51% and 283.3 KJ (67.71 Kcal) respectively. Recommended
      rules for its safety were mentioned.

PMID- 10331213
TI  - Some selected analytical and sensory data of frozen stored yoghurt.

PMID- 10331214
TI  - Effect of altered gravity on the neurobiology of fish.
AB  - In vertebrates (including humans) altered gravitational environments such as
      weightlessness can induce malfunction of the inner ears due to a mismatch between
      canal and statolith afferents. This leads to an illusionary tilt because the
      inputs from the inner ear are not confirmed by the other sensory organs, which
      then results in intersensory conflict. Vertebrates in orbit therefore face severe
      orientation problems. In humans the intersensory conflict may additionally lead
      to a malaise commonly referred to as space motion sickness (SMS). After the
      initial days of weightlessness the orientation problems (and SMS) disappear as
      the brain develops a new interpretation of the available sensory data. The
      present contribution reviews the neurobiological responses, particularly those of
      fish, observed under altered gravitational states concerning behavior and
      neuroplastic reactivities. Investigations employing microgravity (spaceflight,
      parabolic aircraft flights, clinostat) and hypergravity (laboratory centrifuges
      as ground-based research tools) provide insights for understanding the basic
      phenomena, many of which remain only incompletely explained.

PMID- 10331215
TI  - Modification of glutamate receptor channels: molecular mechanisms and functional
      consequences.
AB  - Of the many possible mechanisms for modulating the efficiency of ion channels,
      the phosphorylation of receptor channel proteins may be the primary one. Changes
      in the set of molecular subunits of which the channels are composed are also
      important, especially for long-term regulation. In the central nervous system
      synaptic plasticity may be altered by modulating the ligand-activated neuronal
      ion channels involved in synaptic transmission; among them are channels gated
      directly by glutamate, the regulation of which we are only beginning to
      understand. This paper focuses on modulation of these channels [alpha-amino-3
      hydroxy-5-methyl-4-isoxazoleprionic acid (AMPA), kainate, and N-methyl-D
      aspartate (NMDA) types] by phosphorylation and changes in subunit composition.
      AMPA- and kainate-activated receptors are modulated by adenosine 3,5
      monophosphate (cAMP) dependent protein kinase A (PKA) coupled via D1 dopamine
      receptors. An increase in the intracellular concentration of cAMP and protein
      kinase A potentiates kainate-activated currents in alpha-motoneurons of the
      spinal cord by increasing the affinity of the ligand (glutamate) for the
      phosphorylated receptor protein (GluR6 and 7). The rapid desensitization of AMPA
      evoked currents normally observed in horizontal cells of the retina is completely
      blocked by increasing the intracellular concentration of cAMP. The effects of
      changes in subunit composition were examined in rat hippocampal neurons. The
      subunit composition of the NMDA receptor determines the kinetic properties of
      synaptic currents and can be regulated by the type of innervating neuron. Similar
      changes also occur during development. An important determinant here is the
      activity of the system. Dynamic regulation of excitatory receptors by both
      mechanisms may well be associated with some forms of learning and memory in the
      mammalian brain.

PMID- 10331216
TI  - [Treatment strategy for and clinical results in patients with recurrent
      esophageal cancer].
AB  - In the current study, we evaluate the frequency and pattern of recurrence in
      patients with esophageal cancer. Among 116 patients who had undergone curative
      resection for esophageal cancer, recurrence was found in 33 (28.4%). The most
      frequent pattern of recurrence was lymphatic (54.5%), followed by the mixed type
      (18.2%), hematogenic (12.1%), locoregional (12.1%), and anastomotic (3.0%)
      patterns. Recurrence was found within 1 year after surgery in 18 (54.5%), within
      2 years in 12 (36.4%), and within 3 years in 3 (9.1%). In patients with
      recurrence, lymph node metastasis and advanced stage were seen more frequently
      than in those without recurrence. The prognosis for patients with recurrent
      disease is poor. However, in some cases surgical resection, systemic
      chemotherapy, hepatic arterial infusion chemotherapy, and local radiation therapy
      have proven to be effective. The most appropriate therapy should be selected
      based on the region of extension and patient performance status to provide
      optimum treatment of recurrent disease.

PMID- 10331217
TI  - [Recurrence of hepatocellular carcinoma after liver resection].
AB  - Recurrence of hepatocellular carcinoma after liver resection is usually observed
      in the remnant liver, and includes metachronous multicentric occurrence and
      intrahepatic metastasis. In stage I and II, disease-free survival rates of
      clinical stage I patients are significantly better than those of clinical stage
      II patients, although there are no differences in the disease-free survival rates
      of patients with advanced disease. Disease-free survival rates in long-term
      survivors decreased at a constant rate due to metachronous multicentric
      recurrence. Therefore it is important to follow postoperative patients as long as
      possible. In the treatment of recurrent tumors, every effort should be made to
      resect the tumor in the liver. Then, other regional therapies, such as
      percutaneous ethanol injection therapy, microwave coagulation therapy, and
      transcatheter arterial chemoembolization, are indicated for patients for whom re
      resection is not indicated. To prevent recurrence of hepatocellular carcinoma, it
      is also important to suppress the hepatic necroinflammatory process due to viral
      hepatitis.

PMID- 10331218
TI  - [Treatment of recurrent cancer after surgery for biliary malignancies].
AB  - Our strategy for recurrent tumor after surgical resection for biliary
      malignancies, especially for hilar cholangiocarcinoma, is described. One hundred
      and thirty-three patients with hilar cholangiocarcinoma underwent curative
      resection in our department until November, 1998, and recurrent carcinomas have
      been pointed out in 73 patients (54.9%). The site of recurrence was peritoneum
      (21 cases), liver (16 cases), pre-caval and retro-duodenal space (15 cases),
      hepatic hilum (11 cases), lymph node (9 cases), bone (6 cases), sinus tract of
      percutaneous transhepatic biliary drainage (PTBD) (5 cases) and so on. Surgical
      resection was applied to recurrent carcinomas after careful evaluation, and 9
      patients underwent surgical resection of the recurrent tumor: sinus tract of PTBD
      in the abdominal and/or chest wall (4 cases), lymph node (2 cases), liver (1
      case), hepaticojejunostomy (1 case) and duodenum (1 case). There were three
      hospital death patients. Other six patients survived for 16 months on an average
      (11-20 months) after surgery for recurrent tumor. PTBD for recurrent cancer at
      the hepatic hilum and gastrojejunostomy for local recurrence around the duodenum
      improved quality of life of patients. Radiation therapy for bone metastasis or
      local recurrence at the hepatic hilum was sometimes very effective. Effect of
      systemic or transarterial chemotherapy is still unknown.

PMID- 10331219
TI  - [Therapeutic strategy for the recurrence of pancreatic cancer following
      pancreatectomy].
AB  - It is well-known that the patients with pancreatic cancer are vulnerable for
      recurrence such as local relapse and liver metastasis after surgical resection.
      We revealed that a patient with local relapse without liver metastasis showed
      better prognosis as compared with a patient having liver metastasis. We usually
      adapt further therapeutic intervention for local recurrence using external
      radiation therapy accompanied with 5FU infusion as a radiosensitizer, if the
      patient is not revealed with liver metastasis. On the other hand, there is no
      effective intervention for liver metastasis accompanying pancreatic cancer, as
      small lesions of multiple liver metastases progress rapidly. We insert the tip of
      catheter in proper hepatic artery in order to infuse MMC once a week at
      outpatient clinic. However, we were not yet able to evaluate the effect of
      arterial infusion therapy.

PMID- 10331220
TI  - [Treatment of post-operative recurrence of colorectal cancer].
AB  - The survival rate of patients with colorectal cancer is fairly good after
      curative surgery. Approximately 80 and 75% of patients suffering from colo-rectal
      cancer survive for 5 years after curative operation, respectively. However, 30%
      of patients experience recurrence (mainly liver, lung, and local lesions)
      postoperatively. Resection of the recurrence is carried out in an attempt to
      achieve prolonged survival. Thirty percent to 40% of patients survive after
      curative surgery for liver metastases and 35% to 45% after that for lung
      metastases. Total pelvic exenteration is performed in patients with local
      recurrence of rectal cancer and 30% to 40% survive for 5 years. However, for
      patients with unresectable recurrence, chemotherapy and radiation contribute to a
      better quality of life and prolonged survival. A 70% response rate is achieved in
      patients with liver metastases after continuous infusion chemotherapy into the
      hepatic artery. Currently, the most important factor in achieving prolonged
      survival after colorectal surgery is to follow patients carefully in order to
      detect recurrence as early as possible. In the treatment of recurrence, the
      possibility of curative surgery, a combined treatment strategy and the quality of
      life of patients must be considered.

PMID- 10331221
TI  - [Treatment of postoperative recurrence of digestive cancers: peritonitis
      carcinomatosa].
AB  - Carcinomatous peritonitis is the most frequent type of recurrence observed after
      surgery for cancer of the digestive tract. Most patients with carcinomatous
      peritonitis present with bowel obstruction and/or ascites. Surgical treatment
      including colostomy and intestinal anastomosis and chemotherapy have been
      attempted in patients with carcinomatous peritonitis, although the results have
      not been satisfactory. New drug delivery systems, such as mitomycin C-adsorbed
      charcoal, anticancer drugs entrapped in microspheres, and immunoconjugates
      composed of anticancer drugs and antibodies, will be powerful new tools for the
      treatment of metastatic cancer.

PMID- 10331222
TI  - [Surgical treatment of pulmonary metastases from digestive organs and management
      of malignant pleural effusions].
AB  - This article summarizes the indications for surgical treatment of pulmonary
      metastases from carcinomas of the digestive organs, mainly the colon and rectum.
      Survival rats after pulmonary metastasectomy from colorectal carcinomas range
      from 24% to 43% at 5 years, and from 20% to 34% at 10 years. However, the
      survival benefit after metastasectomy from other organs appears questionable.
      Survival analysis after metastasectomy from colorectal carcinomas shows that
      patients with fewer metastatic tumors with smaller diameters, complete resection
      of metastatic foci, no lymph node involvement, no history of extrapulmonary
      metastases, longer disease-free interval, and a lower serum CEA level at
      thoracotomy have a better prognosis. Prospective studies are needed to determine
      which factors are statistically significant for survival. Management of malignant
      pleural effusions commonly includes thoracenthesis and tube thoracostomy
      drainage, followed by the instillation of various anticancer drugs or sclerosing
      agents. The application of biological agents such as interleukin-2 and
      interferons is an experimental treatment under investigation. Thoracoscopy using
      video-assisted techniques is a new approach for the diagnosis and treatment of
      malignant pleural effusions.

PMID- 10331223
TI  - [Interventional radiology for recurrent cancer].
AB  - The indications for the reoperative treatment for postoperative recurrence of
      cancer in the field of gastroenterology are usually limited. Interventional
      radiology (IVR), which is less invasive and effectively enhances the quality of
      life, will play an important role in the treatment of patients with postoperative
      recurrent cancer. This paper evaluate IVR as a therapeutic strategy for
      postoperative recurrent cancer in gastroenterology based on our experience.
      Metallic stents have proven useful for stenosis of the alimentary tract due to
      recurrence after surgery for esophageal or gastric cancer and for jejuno-biliary
      anastomotic stenosis caused by postoperative recurrent bile duct cancer.
      Segmental Lipiodol TAE is more effective and result in better cumulative survival
      rates than conventional TAE in the treatment of postoperative recurrence of
      hepatoma.

PMID- 10331224
TI  - [A patient operated for occlusion of the superior mesenteric artery].
AB  - A 40-year-old woman presented with fever, dysarthria, and left hemiparesis.
      Diagnostic imaging detected an infarction in the right cerebrum; lupus
      anticoagulant was positive. A T4N3M0 adenocarcinoma coexisted in the left lung,
      which was irradiated once. Two days later, the superior mesenteric artery was
      occluded. The bowel was widely resected but she died of hepatic infarction. The
      lung cancer may have triggered catastrophic antiphospholipid syndrome.

PMID- 10331225
TI  - Food Standards Agency: call for further powers.

PMID- 10331226
TI  - Rabies, quarantine and the veterinary profession: the BVA's position.
AB  - The agriculture minister, Mr. Nick Brown, announced on March 26 that the
      government has decided to abandon quarantine for dogs and cats entering the UK
      from rabies-free islands and certain European countries and replace it with a
      system based on identification, certification, vaccination and blood testing. The
      BVA's current position on rabies and quarantine is given here.

PMID- 10331227
TI  - A blinded, placebo-controlled study of the efficacy of borage seed oil and fish
      oil in the management of canine atopy.
AB  - Twenty-one dogs with atopy were entered into a blinded, placebo-controlled study
      lasting eight weeks. They were randomly divided into three groups and were all
      given supplementary oils orally once daily. The dogs in groups A and B were given
      borage seed oil and fish oil in combination (Viacutan; Boehringer Ingelheim
      Vetmedica) to provide 176 mg/kg or 88 mg/kg borage seed oil respectively. The
      dogs in group C were given 204 mg/kg olive oil as a placebo. They were all re
      examined after four and eight weeks and scored for pruritus, erythema, oedema,
      alopecia and self-excoriation. After eight weeks the scores for erythema and self
      excoriation, and the total score for the dogs in group A, and the total score for
      the dogs in group B were significantly reduced (P < 0.05). The dogs in group C
      showed no significant improvement.

PMID- 10331228
TI  - Spinal cord injury in small animals. 1. Mechanisms of spontaneous recovery.
AB  - Spinal cord injury causes obvious clinical deficits early in the course of lesion
      evolution, but it is commonly observed that recovery can occur spontaneously
      during a period of days, weeks or even months afterwards. Spinal cord dysfunction
      arises after injury because of a combination of reversible alterations in the
      concentration of intra- and extracellular ionic constituents and irreversible
      tissue destruction. Recovery can therefore occur through re-establishment of the
      normal microenvironment of the spinal cord, which occurs soon after injury
      induction, and also by formation of new patterns of central nervous system
      circuitry. Alterations in circuitry, termed 'plasticity', can occur during the
      immediate period after injury but apparently continue for many weeks or months.
      There are differences in the extent and nature of recovery between complete and
      incomplete experimental spinal cord injuries that illustrate the roles played by
      reorganisation of intra- and suprasegmental circuitry. Information that is
      available on mechanisms of spontaneous recovery may aid development of novel
      therapies for clinical spinal cord injury.

PMID- 10331229
TI  - Reconstruction of the eyelids of a dog using grafts of oral mucosa.
AB  - A five-month-old English cocker spaniel with distichiasis had been treated four
      times surgically by a tarsomeibomian resection technique. As a result, three
      quarters of the margins of its upper eyelids had been eliminated and the lower
      eyelids had become considerably thinner. The dog had developed upper entropion
      and upper eyelid trichiasis, and keratoconjunctivitis sicca. It was treated
      medically and grafts of oral mucosa were used to reconstruct its upper eyelids. A
      year after surgery, the new palpebral margin was completely functional and
      cosmetically acceptable. The dog's eyes appear normal and only require treatment
      with artificial tears.

PMID- 10331230
TI  - Comparisons of different combinations of analogues of PGF2 alpha and dopamine
      agonists for the termination of pregnancy in dogs.
AB  - Groups of five pregnant bitches were treated to terminate the pregnancy with four
      combinations of drugs, starting 28 days after the estimated surge of luteinising
      hormone (LH), 22 to 28 days after the first mating. The treatments were:
      cabergoline administered orally for 10 days at a dose of 5 micrograms/kg and a
      single subcutaneous injection of 2.5 micrograms/kg cloprostenol at the start of
      the treatment; the same dose of cabergoline plus two doses of 1 microgram/kg
      cloprostenol administered on days 28 and 32 after the LH surge; bromocryptine
      administered orally at a dose of 30 micrograms/kg three times a day for 10 days
      plus a single dose of 2.5 micrograms/kg cloprostenol; the same dose of
      bromocryptine plus two doses of 1 microgram/kg cloprostenol; and a group of five
      pregnant bitches was left untreated. The pregnancies were terminated in all but
      one of the treated bitches, in each case by resorption of the fetuses. There were
      few side effects in the bitches treated with two doses of 1 microgram/kg
      cloprostenol, and were present but acceptable in those treated with one dose of
      2.5 micrograms/kg. Plasma progesterone concentrations decreased to less than 1
      ng/ml within 72 hours of the start of treatment and remained low except in the
      bitch in which pregnancy was not terminated. In the five untreated bitches,
      plasma progesterone remained high and they whelped normally. In the treated
      groups, the intervals between successive displays of oestrus were reduced by
      approximately 70 days in comparison with previous cycles or with the control
      group, but the fertility of the dogs was not affected adversely.

PMID- 10331231
TI  - Effect of ageing on resting energy expenditure in cats.

PMID- 10331232
TI  - Mammary neoplasia in a binturong (Arctictis binturong).

PMID- 10331233
TI  - Studies with an inactivated pheasant rotavirus vaccine.

PMID- 10331234
TI  - Veterinary fees.

PMID- 10331235
TI  - Findings in a fox rescued from hounds.

PMID- 10331236
TI  - Ecdysone 20-monooxygenase in eggs of the silkworm, Bombyx mori: enzymatic
      properties and developmental changes.
AB  - Ecdysone 20-monooxygenase in eggs of the silkworm Bombyx mori was characterized
      in relation to embryonic development. First, subcellular fractions were prepared
      by means of differential centrifugation, and analyzed using marker enzymes and
      antibodies against NADPH-cytochrome P450 reductase. It was demonstrated that most
      ecdysone 20-monooxygenase activity was associated with microsomes, and that there
      was little or no intrinsic mitochondrial ecdysone 20-monooxygenase. Next,
      conditions for the measurement of ecdysone 20-monooxygenase activity were
      established for the microsomal fraction, and changes in the enzyme activity were
      measured in diapause eggs and non-diapause eggs during early embryogenesis. It
      was demonstrated that enzyme activity in diapause eggs remained at a low level,
      while that in the non-diapause eggs increased from the gastrula stage. The
      increase in egg ecdysone 20-monooxygenase activity was prevented by actinomycin D
      and alpha-amanitin, suggesting that gene transcription is required for eliciting
      an increase in ecdysone 20-monooxygenase activity.

PMID- 10331237
TI  - Phytoecdysteroids in seeds and plants of Rhagodia baccata (Labill.) Moq.
      (Chenopodiaceae).
AB  - Seeds of Rhagodia baccata afforded, in addition to 20-hydroxy-ecdysone and
      polypodine B, a novel phytoecdysteroid, (20R)-22-deoxy-20,21-dihydroxyecdysone,
      the structure of which was elucidated unequivocally by UV, LSIMS and NMR
      techniques. This compound possessed agonistic activity in the Drosophila
      melanogaster BII cell bioassay, with an ED50 value of 2.0 x 10(-7)M (ED50 value
      for 20-hydroxyecdysone = 7.5 x 10(-9)M). The distribution of ecdysteroids in
      plants of R. baccata has been determined. Highest levels are associated with the
      youngest aerial tissues and with the roots. Ecdysteroid profiles are
      qualitatively very similar throughout the plant, with 20-hydroxyecdysone and
      polypodine B predominating in all plant parts tested.

PMID- 10331238
TI  - Organellar RNA polymerases of higher plants.
AB  - The nuclear genome of the model plant Arabidopsis thaliana contains a small gene
      family consisting of three genes encoding RNA polymerases of the single-subunit
      bacteriophage type. There is evidence that similar gene families also exist in
      other plants. Two of these RNA polymerases are putative mitochondrial enzymes,
      whereas the third one may represent the nuclear-encoded RNA polymerase (NEP)
      active in plastids. In addition, plastid genes are transcribed from another,
      entirely different multisubunit eubacterial-type RNA polymerase, the core
      subunits of which are encoded by plastid genes [plastid-encoded RNA polymerase
      (PEP)]. This core enzyme is complemented by one of several nuclear-encoded sigma
      like factors. The development of photosynthetically active chloroplasts requires
      both PEP and NEP. Most NEP promoters show certain similarities to mitochondrial
      promoters in that they include the sequence motif 5'-YRTA-3' near the
      transcription initiation site. PEP promoters are similar to bacterial promoters
      of the -10/-35 sigma 70 type.

PMID- 10331239
TI  - Eukaryotic transmembrane solute transport systems.
AB  - A comprehensive classification system for transmembrane molecular transporters
      has been proposed. This system is based on (i) mode of transport and energy
      coupling mechanism, (ii) protein phylogenetic family, (iii) phylogenetic cluster,
      and (iv) substrate specificity. The proposed "Transport Commission" (TC) system
      is superficially similar to that implemented decades ago by the Enzyme Commission
      for enzymes, but it differs from the latter system in that it uses phylogenetic
      and functional data for classification purposes. Very few families of
      transporters include members that do not function exclusively in transport.
      Analyses reported reveal that channels, primary carriers, secondary carriers (uni
      , sym-, and antiporters), and group translocators comprise distinct categories of
      transporters, and that transport mode and energy coupling are relatively
      immutable characteristics. By contrast, substrate specificity and polarity of
      transport are often readily mutable. Thus, with very few exceptions, a unified
      family of transporters includes members that function by a single transport mode
      and energy-coupling mechanism although a variety of substrates may be transported
      with either inwardly or outwardly directed polarity. The TC system allows cross
      referencing according to substrates transported and protein sequence database
      accession numbers. Thus, familial assignments of newly sequenced transport
      proteins are facilitated. In this article I examine families of transporters that
      are eukaryotic specific. These families include (i) channel proteins, mostly from
      animals; (ii) facilitators and secondary active transport carriers; (iii) a few
      ATP-dependent primary active transporters; and (iv) transporters of unknown mode
      of action or energy-coupling mechanism. None of the several ATP-independent
      primary active transport energy-coupling mechanisms found in prokaryotes is
      represented within the eukaryotic-specific families. The analyses reported
      provide insight into transporter families that may have arisen in eukaryotes
      after the separation of eukaryotes from archaea and bacteria. On the basis of the
      reported analyses, it is suggested that the horizontal transfer of genes encoding
      transport proteins between eukaryotes and members of the other two domains of
      life occurred very infrequently during evolutionary history.

PMID- 10331240
TI  - Mechanism of action of P-glycoprotein in relation to passive membrane permeation.
AB  - This review presents a survey of studies of the movement of chemotherapeutic
      drugs into cells, their extrusion from multidrug-resistant (MDR) cells
      overexpressing P-glycoprotein (Pgp), and the mode of sensitization of MDR cells
      to anticancer drugs by Pgp modulators. The consistent features of the kinetics
      from studies of the operation of Pgp in cells were combined in a computer model
      that enables the simulation of experimental scenarios. MDR-type drugs are
      hydrophobic and positively charged and as such bind readily to negatively charged
      phospholipid head groups of the membrane. Transmembrane movement of MDR-type
      drugs, such as doxorubicin, occurs by a flip-flop mechanism with a lifetime of
      about 1 min rather than by diffusion down a gradient present in the lipid core. A
      long residence time of a drug in the membrane leaflet increases the probability
      that P-glycoprotein will remove it from the cell. In a manner similar to ion
      transporting ATPases, such as Na+,K(+)-ATPase, Pgp transports close to one drug
      molecule per ATP molecule hydrolyzed. Computer simulation of cellular
      pharmacokinetics, based on partial reactions measured in vitro, show that the
      efficiency of Pgp, in conferring MDR on cells, depends on the pumping capacity of
      Pgp and its affinity toward the specific drug, the transmembrane movement rate of
      the drug, the affinity of the drug toward its pharmacological cellular target,
      and the affinity of the drug toward intracellular trapping sites. Pgp activities
      present in MDR cells allow for the efficient removal of drugs, whether directly
      from the cytoplasm or from the inner leaflet of the plasma membrane. A
      prerequisite for a successful modulator, capable of overcoming cellular Pgp, is
      the rapid passive transbilayer movement, allowing it to reenter the cell
      immediately and thus successfully occupy the Pgp active site(s).

PMID- 10331241
TI  - Studies on the interactions between human serum albumin and imidazolium [trans
      tetrachlorobis(imidazol)ruthenate(III)].
AB  - The interactions between imidazolium [trans-tetrachlorobis(imidazol)
      ruthenate(III)] (Ru-im) and human serum albumin (HSA) have been investigated
      through UV-Vis, CD, fluorescence spectroscopy and by the antibody precipitation
      test. Binding of Ru(III)-imidazole species to albumin has a strong impact on the
      protein structure and influences considerably the albumin binding of other
      molecules such as warfarin or heme. The metal complex-HSA interactions cause
      conformational changes with the loss of helical stability of the protein and
      local perturbation in the domain IIA binding pocket. The relative fluorescence
      intensity of the ruthenium-bound HSA decreased, suggesting that perturbation
      around the Trp 214 residue took place. This was confirmed by the destabilisation
      of the warfarin binding site which includes Trp 214, observed in the metal-bound
      HSA.

PMID- 10331242
TI  - Effects of fibronectin on hydroxyapatite formation.
AB  - There is increasing evidence that noncollagenous matrix proteins initiate bone
      mineralization in vivo. Fibronectin, which is present during the early phases of
      mineralization, may contribute to this process in bone tissues. In this context,
      the mineralization potential of fibronectin was tested in an agarose gel
      precipitation system and a metastable calcium phosphate solution. The protein
      inhibited the precipitation of calcium phosphate crystals in solution but had no
      apparent effect in gel. Conversely, fibronectin stimulated crystal formation when
      apatite powder was used to seed crystal growth in gel. Although these results in
      vitro do not clearly indicate that fibronectin is involved in the mineralization
      process, they are consistent with in vivo events. Free fibronectin (e.g. in
      biological fluids) could inhibit crystal growth but might also activate the
      mineralization process when absorbed on apatite powder in a bone environment and
      areas of ectopic mineralization.

PMID- 10331243
TI  - Copper(II) Schiff-base complexes and apoglobin stability.
AB  - N,N'-Propylene-bis-(N-salicylidene)copper(II) (Cu(Salprn)) explicitly stabilizes
      apomyoglobin. The optical spectrum of this copper(II) Schiff-base complex of
      apomyoglobin arises from the electronic excitations of pi *-O-Salprn-->dx2-y2 and
      N-Salprn-->dx2-y2. Shifts of these transitions with respect to those of the
      parent complex may be a consequence of hydrophobic solvatochromism or binding of
      an additional ligand. ESR parameters imply no change in the identity of the first
      coordination sphere around the copper, while hydrophobic solvatochromism cannot
      be excluded. Combination of copper(II) Schiff-base complex with apomyoglobin does
      not inhibit the ability of apomyoglobin to extract hemin from the main component
      of Glycera dibranchiata hemoglobin. Hemin replaces the copper complex, and the
      value of the apparent first-order rate constant varies with time. The mechanism
      involves dissociative and associative interchange pathways. Values of rate
      constants for transfer of hemin to copper(II) Schiff-base apomyoglobin complex,
      as well as the change of concentration with time are evaluated.

PMID- 10331244
TI  - Ethylenediamine-palladium(II) complexes with pyridine and its derivatives:
      synthesis, molecular structure and initial antitumor studies.
AB  - The synthesis of four mononuclear palladium complexes of general formula
      [Pd(en)Cl(L)]NO3 (en = ethylenediamine; L = pyridine (I), 4-methylpyridine (II),
      4-hydroxypyridine (III) or 4-aminopyridine (IV) has been achieved. The structure
      of these compounds was studied by elemental analysis, IR, far-IR and 1H NMR;
      complex I was analyzed by X-ray diffraction. The crystal of
      [Pd(en)(pyridine)Cl]NO3 is monoclinic, space group P21/c (a = 7.990(2), b =
      16.058(3), c = 9.846(2) A, beta = 103.81(3) degrees, Z = 4, R = 0.067, Rw =
      0.066). The Pd(II) atom exhibits an approximately square planar coordination with
      bond lengths in the range 2.017-2.042 A for Pd-N and 2.320 A for Pd-Cl. In order
      to determine the donor strength of the aromatic pyridine ligands, the stability
      constants of binary complex ML2+ (M = [Pd(en) (H2O)2]2+; L = pyridine, 4-Me
      pyridine, 4-OH-pyridine and 4-NH2-pyridine) were determined by potentiometric pH
      titration in aqueous solution (T = 25 degrees C, I = 0.1 mol l-1 NaNO3). The
      results show that the stability constants of the binary complexes systematically
      increase with increasing pKa of the pyridines. The above four palladium
      complexes, [Pt(en)(pyridine)Cl]NO3 and cis-diamminedichloroplatinum (II) (cis
      DDP) were assayed for cytotoxicity in vitro against the human leukemia cell line
      HL-60, and compounds I, II, III and cis-DDP show significant cytotoxic activity
      against HL-60.

PMID- 10331245
TI  - EPR and O2.- scavenger activity: Cu(II)-peptide complexes as superoxide dismutase
      models.
AB  - Several copper(II) complexes with aminoacids and peptides are known to show
      superoxide dismutase (SOD)-like activity. EPR spectroscopy has proved to be a
      useful tool for studying the complex equilibria of the copper(II) ion and various
      ligands of biological importance in solution. In the present work, a variety of
      copper(II) complexes with di-, tri- and tetra-peptides containing only glycine
      residues (GG, GGG and GGGG) and others containing a histidyl residue in different
      positions (HGG, GHG, GGH and GGHG) have been investigated. EPR parameters
      obtained by extensive use of computer simulation of spectra lead to reliable spin
      Hamiltonian EPR parameters at both room temperature and in frozen solution. The
      molecular orbital coefficients computed from the anisotropic EPR data and the d-d
      electronic energies are used to characterize different arrangements of the
      complexes. Estimation of the scavenger activity of the complexes due to the
      particular environment created by the ligands around copper is discussed in the
      frame of the structure-activity relationship.

PMID- 10331246
TI  - Potentiometric study of vitamin D3 complexes with manganese(II), iron(II),
      iron(III) and zinc(II) in water-ethanol medium.
AB  - Vitamin D3 (LH) complexes with manganese(II), iron(II), iron(III) and zinc(II)
      were identified in water-ethanol medium (30/70). Their stability constants were
      determined at 298 K and at a constant ionic strength of 0.100 M using
      potentiometric methods. The computerisation of the experimental data showed the
      presence of ML (M = metal, L = deprotonated vitamin D3) and ML2 species in all
      cases; in addition, the ML3 iron(III) complex was detected. The calculated
      overall stability constants beta for MnIIL, FeIIL, FeIIIL and ZnIIL are,
      respectively, in logarithms, 12.4, 16.5, 28.5 and 16.5. Under the experimental
      conditions, the only protonated species MLH detected was with iron(III).

PMID- 10331247
TI  - Synthesis, structures and antitumor activity of the first crown ester-linked
      bipyridyl platinum complexes.
AB  - Three new crown ester-linked bipyridine homologs with three, four or five
      ethylene glycol units, which are bulky and soluble in both hydrophilic and
      lipophilic media, were synthesized. The reaction of the appropriate macrocycles
      with K2PtCl4 in water gave yellow cisplatin analogs in good yield. These
      complexes were converted to carboplatin analogs by exchange of the leaving group.
      All the compounds were characterized by elemental analysis and various
      spectroscopic methods. Carboplatin analogs showed good solubility in both
      hydrophilic and lipophilic media. The crystal structure of 2c, the carboplatin
      analog with macrocycles containing five ethylene glycol units, was determined by
      X-ray diffraction: space group P1, a = 9.798(1), b = 12.580(3), c = 13.945(2) A,
      alpha = 108.61(2), beta = 94.59(1), gamma = 97.42(2) degrees, Z = 2, R = 0.0618.
      Some of platinum complexes showed a moderate cytotoxic effect on both murine
      leukemia L1210 and P388 even though they do not have any NH proton.

PMID- 10331248
TI  - Molecular evolution and mosaic structure of alpha, beta, and gamma intimins of
      pathogenic Escherichia coli.
AB  - Two types of pathogenic Escherichia coli, enteropathogenic E. coli (EPEC) and
      enterohemorrhagic E. coli (EHEC), cause diarrheal disease by disrupting the
      intestinal environment through the intimate attachment of the bacteria to the
      intestinal epithelium. This process is mediated by intimin, an outer membrane
      protein that is homologous to the invasins of pathogenic Yersinia. The intimin
      (eae) gene is part of a pathogenicity island, a 35-kb segment of DNA that has
      been acquired independently in different groups of pathogens. Nucleotide
      sequences of eae of three EPEC and four EHEC strains representing distinct clonal
      lineages revealed an exceptionally high level of divergence (15%) in the amino
      acid sequences of alpha, beta, and gamma intimin molecules, most of which is
      concentrated in the C-terminal region. The gamma intimin sequences from E. coli
      strains with serotypes O157:H7, O55:H7, and O157:H- are virtually identical,
      supporting the hypothesis that these bacteria belong to a single clonal lineage.
      Sequences of beta intimin of EPEC strains of serotypes O111:H2 and O128:H2 show
      substantial differences from alpha and gamma intimins, indicating that these
      strains have evolved independently. Strong nonrandom clustering of polymorphic
      sites indicates that the intimin genes are mosaics, suggesting that protein
      divergence has been accelerated by recombination and diversifying selection.

PMID- 10331249
TI  - Evolution of class I alcohol dehydrogenase genes in catarrhine primates: gene
      conversion, substitution rates, and gene regulation.
AB  - The three class I alcohol dehydrogenases (ADHs) in humans comprise homo- and
      heterodimers of three subunits (alpha, beta, and gamma) with greater than 90%
      sequence identity. These are encoded by distinct genes (ADH1, ADH2, and ADH3,
      respectively) and are all expressed in the liver. In baboons, only the beta ADH
      subunit is expressed in liver. A second class I ADH is expressed in the kidney;
      we isolated, cloned, and sequenced the cDNA corresponding to this ADH and
      conclude that it is of the gamma ADH lineage. We also amplified and sequenced the
      5' noncoding regions of all three class I baboon ADH genes and the rhesus monkey
      ADH1 gene and compared their nucleotide sequences with the corresponding human
      sequences. There is clear evidence that the evolution of these genes has been
      reticulate. At least three gene conversion events, affecting the coding and 3'
      noncoding regions of the genes, are inferred from compatibility and partition
      matrices and phylogenetic analysis of the sequences. Our estimation of the
      evolutionary history of these genes provides a framework for the investigation of
      relative substitution rates and functional variation among the sequences.
      Relative-rate tests, designed to account for the reticulate evolution of these
      genes, indicate no difference in substitution rate either between genes encoding
      different subunits or between human and Old World monkey lineages. The human and
      baboon gamma ADH sequences do not show clear differences at functionally
      important sites within the coding region, but they do differ at a number of sites
      in regions previously proposed to be regulatory sites for transcriptional
      control. This variation may explain the different patterns of gene expression in
      humans and baboons.

PMID- 10331250
TI  - Median-joining networks for inferring intraspecific phylogenies.
AB  - Reconstructing phylogenies from intraspecific data (such as human mitochondrial
      DNA variation) is often a challenging task because of large sample sizes and
      small genetic distances between individuals. The resulting multitude of plausible
      trees is best expressed by a network which displays alternative potential
      evolutionary paths in the form of cycles. We present a method ("median joining"
      [MJ]) for constructing networks from recombination-free population data that
      combines features of Kruskal's algorithm for finding minimum spanning trees by
      favoring short connections, and Farris's maximum-parsimony (MP) heuristic
      algorithm, which sequentially adds new vertices called "median vectors", except
      that our MJ method does not resolve ties. The MJ method is hence closely related
      to the earlier approach of Foulds, Hendy, and Penny for estimating MP trees but
      can be adjusted to the level of homoplasy by setting a parameter epsilon. Unlike
      our earlier reduced median (RM) network method, MJ is applicable to multistate
      characters (e.g., amino acid sequences). An additional feature is the speed of
      the implemented algorithm: a sample of 800 worldwide mtDNA hypervariable segment
      I sequences requires less than 3 h on a Pentium 120 PC. The MJ method is
      demonstrated on a Tibetan mitochondrial DNA RFLP data set.

PMID- 10331251
TI  - A simple method for estimating the intensity of purifying selection in protein
      coding genes.
AB  - We propose a method by which the intensity of purifying selection on a functional
      protein-coding gene is estimated by using three aligned homologous sequences: a
      processed pseudogene (psi), a functional paralog from the same species (g), and a
      functional ortholog from a different species (o). For each such trio, we
      calculate the numbers of nucleotide substitutions along the branches leading to
      psi and g, i.e., K psi and K(g). If we assume that the mutation rates are the
      same in the genes and the pseudogenes and that mutations occurring in a
      pseudogene do not affect the fitness of the organism, we can show that the
      fraction of mutations that are selectively neutral, fg, is equal to the ratio
      K(g)/K psi. Since advantageous mutations occur only very rarely, such that they
      do not contribute significantly to the rate of molecular evolution, the fraction
      of deleterious mutations that are subject to purifying selection is 1-fg.
      Therefore, the K(g)/K psi ratio can be used directly to estimate the intensity of
      purifying selection, thereby isolating its effects on the rate of evolution from
      those of mutation. We compared the selection intensities of 12 orthologous
      protein-coding pairs from humans and murids. As expected, the fraction of
      mutations that are subject to purifying selection is strongest in the second
      codon position and weakest in the third. Interestingly, the mean fractions of
      effectively neutral mutations in the third codon position were only 41% and 42%
      for murids and humans, respectively, indicating that many synonymous mutations
      are subject to selective constraint. In several orthologous genes, we found that
      the intensity of purifying selection is very different between murid and human
      orthologous genes. There was no statistically significant difference in overall
      intensity of purifying selection between humans and murids. Thus, purifying
      selection does not seem to be an important factor contributing to the observed
      differences in the rates of evolution between these two taxa.

PMID- 10331252
TI  - Mobilization of two retroelements, ZAM and Idefix, in a novel unstable line of
      Drosophila melanogaster.
AB  - We describe a novel transposition system in a line of Drosophila melanogaster
      called RevI in which two retroelements are mobilized. These elements are the
      retroelement ZAM, recently described in the literature, and a novel element
      designated Idefix. Like ZAM, Idefix displays the structural features of a
      vertebrate retrovirus. Its three open reading frames encode predicted products
      resembling the products of the gag, pol, and env genes of retroviruses. In situ
      hybridization and Southern analyses performed on the RevI genome revealed the
      presence of some 20 copies of ZAM and Idefix, whereas ZAM is absent and Idefix is
      present in only four copies on the chromosomal arms of the original parental
      line. From RevI, a series of mutations affecting eye coloration has been
      recovered. The genetic and molecular analyses of these mutations have shown that
      most of them affected the white locus through three rounds of mutational events.
      The first mutational event was previously shown to be caused by a ZAM insertion 3
      kb upstream of the transcription start site of white. It confers a red-brick
      phenotype to the orange eye coloration of the parental line. The second event
      results from the insertion of an Idefix copy 1.7 kb upstream of the transcription
      start site of the white gene, which modifies the red-brick phenotype to orange.
      This second mutational event was recovered as a recurrent specific mutation in 11
      independent individuals. The third event results from an additional Idefix
      located 1.7 kb upstream of white that is responsible for the full reversion of
      the orange phenotype to red-brick. The fact that such mutations due to recurrent
      appearances of both ZAM and Idefix at the white locus result in such a variety of
      phenotypes brings to light a new molecular system in which the interference of
      mobile elements with the correct expression of the host gene can be tested.

PMID- 10331253
TI  - Molecular systematics of cytochrome oxidase I and 16S from Neochlamisus leaf
      beetles and the importance of sampling.
AB  - If a gene tree is to be judiciously used for inferring the histories of closely
      related taxa, (1) its topology must be sufficiently resolved and robust that
      noteworthy phylogenetic patterns can be confidently documented, and (2) sampling
      of species, populations, and pertinent biological variation must be sufficiently
      broad that otherwise misleading sources of genetic variation can be detected.
      These principles are illustrated by the complex gene tree of Neochlamisus leaf
      beetles that I reconstructed using 90,000 bp of cytochrome oxidase I (COI) and
      16S mitochondrial DNA (mtDNA) sequences from over 100 specimens. Cytochrome
      oxidase I haplotypes varied up to 25.1% within Neochlamisus and up to 11.1%
      within the gibbosus species group, while exhibiting very low A + T bias for
      insect mtDNA (63%), low transition saturation, and conservative patterns of amino
      acid variation. 16S exhibited lower sequence divergences and greater A + T bias
      and transition saturation than COI, and substitutions were more constrained in
      stems than in loops. Comparisons with an earlier study of Ophraella leaf beetles
      highlighted conservative and labile elements of molecular evolution across genes
      and taxa. Cytochrome oxidase I parsimony and neighbor-joining analyses strongly
      supported a robust mtDNA genealogy that revealed the monophyly of Neochlamisus
      and of the gibbosus species group. Phylogeographic relationships suggested that
      the eastern U.S. gibbosus group derives from southwestern velutinus group
      ancestors. Haplotypes from individual velutinus group species clustered
      monophyletically, as expected. However, haplotypes from each of several gibbosus
      group taxa were polyphyletically distributed, appearing in divergent parts of the
      tree. 16S provided a less-resolved gibbosus group topology that was congruent
      with the COI tree and corroborated patterns of mitochondrial polyphyly. By
      subsampling haplotypes corresponding to particular species, populations, and
      ecological variants of gibbosus group taxa, I demonstrate that recovered
      topologies and genetic distances vary egregiously according to sampling regime.
      This study thus documents the potentially dire consequences of inadequate
      sampling when inferring the evolutionary history of closely related and
      mitochondrially polyphyletic taxa.

PMID- 10331254
TI  - Evidence for genetic drift in endosymbionts (Buchnera): analyses of protein
      coding genes.
AB  - Buchnera, the bacterial endosymbionts of aphids, undergo severe population
      bottlenecks during maternal transmission through their hosts. Previous studies
      suggest an increased effect of drift within these strictly asexual, small
      populations, resulting in an increased fixation of slightly deleterious
      mutations. This study further explores sequence evolution in Buchnera using three
      approaches. First, patterns of codon usage were compared across several
      homologous Escherichia coli and Buchnera loci, in order to test the prediction
      that selection for the use of optimal codons is less effective in small
      populations. A chi 2-based measure of codon bias was developed to adjust for the
      overall A + T richness of silent positions in the endosymbionts. In contrast to
      E. coli homologues, adaptive codon bias across Buchnera loci is markedly low, and
      patterns of codon usage lack a strong relationship with gene expression level.
      These data suggest that codon usage in Buchnera has been shaped largely by
      mutational pressure and drift rather than by selection for translational
      efficiency. One exception to the overall lack of bias is groEL, which is known to
      be constitutively overexpressed in Buchnera and other endosymbionts. Second,
      relative-rate tests show elevated rates of sequence evolution of numerous protein
      coding loci across Buchnera, compared to E. coli. Finally, consistently higher
      ratios of nonsynonymous to synonymous substitutions in Buchnera loci relative to
      the enteric bacteria strongly suggest the accumulation of nonsynonymous
      substitutions in endosymbiont lineages. Combined, these results suggest a
      decreased effectiveness of purifying selection in purging endosymbiont
      populations of slightly deleterious mutations, particularly those affecting codon
      usage and amino acid identity.

PMID- 10331255
TI  - Comparison of the evolutionary dynamics of symbiotic and housekeeping loci: a
      case for the genetic coherence of rhizobial lineages.
AB  - In prokaryotes, lateral gene transfer across chromosomal lineages may be mediated
      by plasmids, phages, transposable elements, and other accessory DNA elements.
      However, the importance of such transfer and the evolutionary forces that may
      restrict gene exchange remain largely unexplored in native settings. In this
      study, tests of phylogenetic congruence are employed to explore the range of
      horizontal transfer of symbiotic (sym) loci among distinct chromosomal lineages
      of native rhizobia, the nitrogen-fixing symbiont of legumes. Rhizobial strains
      isolated from nodules of several host plant genera were sequenced at three loci:
      symbiotic nodulation genes (nodB and nodC), the chromosomal housekeeping locus
      glutamine synthetase II (GSII), and a portion of the 16S rRNA gene. Molecular
      phylogenetic analysis shows that each locus generally subdivides strains into the
      same major groups, which correspond to the genera Rhizobium, Sinorhizobium, and
      Mesorhizobium. This broad phylogenetic congruence indicates a lack of lateral
      transfer across major chromosomal subdivisions, and it contrasts with previous
      studies of agricultural populations showing broad transfer of sym loci across
      divergent chromosomal lineages. A general correspondence of the three rhizobial
      genera with major legume groups suggests that host plant associations may be
      important in the differentiation of rhizobial nod and chromosomal loci and may
      restrict lateral transfer among strains. The second major result is a significant
      incongruence of nod and GSII phylogenies within rhizobial subdivisions, which
      strongly suggests horizontal transfer of nod genes among congenerics. This
      combined evidence for lateral gene transfer within, but not between, genetic
      subdivisions supports the view that rhizobial genera are "reproductively
      isolated" and diverge independently. Differences across rhizobial genera in the
      specificity of host associations imply that the evolutionary dynamics of the
      symbiosis vary considerably across lineages in native settings.

PMID- 10331256
TI  - Structural characteristics and possible horizontal transfer of group I introns
      between closely related plant pathogenic fungi.
AB  - We have characterized structural features and the distribution pattern of nuclear
      group I introns found in ribosomal DNA (rDNA) of closely related plant pathogenic
      fungi of the family Sclerotiniaceae. Sixteen introns, at two distinct positions
      in the small-subunit (SSU) and large-subunit (LSU) rDNA, were sequenced and
      analyzed among the 29 taxa included in the initial screening. Genera found to
      contain introns were Botrytis, Dumontinia, Encoelia, Grovesinia,
      Myriosclerotinia, and Sclerotinia. Secondary-structure analyses of the group I
      introns concluded that all belong to the common IC1 subclass. Interestingly, the
      SSU rDNA intron from Myriosclerotinia caricisampullacea contains an insertion
      like sequence extension which may be a relic of an open reading frame.
      Incongruent branching patterns of intron-based and rDNA-based (internal
      transcribed spacer) phylogenetic trees suggest that the fungal host genomes and
      the group I introns do not share a common evolutionary history. A model to
      explain how horizontal intron transfers may have occurred among the closely
      related fungal taxa is proposed.

PMID- 10331257
TI  - The diversification of plant cytosolic small heat shock proteins preceded the
      divergence of mosses.
AB  - A cDNA library was constructed with mRNA isolated from heat-stressed cell
      cultures of Funaria hygrometrica (Bryophyta, Musci, Funariaceae). cDNA clones
      encoding six cytosolic small heat shock proteins (sHSPs) were identified using
      differential screening. Phylogenetic analysis of these sHSP sequences with other
      known sHSPs identified them as members of the previously described higher plant
      cytosolic class I and II families. Four of the F. hygrometrica sHSPs are members
      of the cytosolic class I family, and the other two are members of the cytosolic
      class II family. The presence of members of the cytosolic I and II sHSP families
      in a bryophyte indicates that these gene families are ancient, and evolved at
      least 450 MYA. This result also indicates that the plant sHSP gene families
      duplicated much earlier than did the well-studied phytochrome gene family.
      Members of the cytosolic I and II sHSP families are developmentally regulated in
      seeds and flowers in higher plants. Our findings show that the two cytosolic sHSP
      families evolved before the appearance of these specialized structures. Previous
      analysis of angiosperm sHSPs had identified class- or family-specific amino acid
      consensus regions and determined that rate heterogeneity exists among the
      different sHSP families. The analysis of the F. hygrometrica sHSP sequences
      reveals patterns and rates of evolution distinct from those seen among angiosperm
      sHSPs. Some, but not all, of the amino acid consensus regions identified in seed
      plants are conserved in the F. hygrometrica sHSPs. Taken together, the results of
      this study illuminate the evolution of the sHSP gene families and illustrate the
      importance of including representatives of basal land plant lineages in plant
      molecular evolutionary studies.

PMID- 10331258
TI  - Elimination and rearrangement of parental rDNA in the allotetraploid Nicotiana
      tabacum.
AB  - Origin and rearrangement of ribosomal DNA repeats in natural allotetraploid
      Nicotiana tabacum are described. Comparative sequence analysis of the intergenic
      spacer (IGS) regions of Nicotiana tomentosiformis (the paternal diploid
      progenitor) and Nicotiana sylvestris (the maternal diploid progenitor) showed
      species-specific molecular features. These markers allowed us to trace the
      molecular evolution of parental rDNA in the allopolyploid genome of N. tabacum;
      at least the majority of tobacco rDNA repeats originated from N. tomentosiformis,
      which endured reconstruction of subrepeated regions in the IGS. We infer that
      after hybridization of the parental diploid species, rDNA with a longer IGS,
      donated by N. tomentosiformis, dominated over the rDNA with a shorter IGS from N.
      sylvestris; the latter was then eliminated from the allopolyploid genome. Thus,
      repeated sequences in allopolyploid genomes are targets for molecular
      rearrangement, demonstrating the dynamic nature of allopolyploid genomes.

PMID- 10331260
TI  - Evolutionary instability of operon structures disclosed by sequence comparisons
      of complete microbial genomes.
AB  - Gene orders have been shown to be generally unstable by comprehensive analyses in
      several complete genomes. In this study, we examined instability of genome
      structures within operons, where functionally related genes are clustered. We
      compared gene orders of known operons obtained from Escherichia coli and Bacillus
      subtilis with corresponding those of operons in 11 complete genome sequences. We
      found that in many cases, gene orders within operons could be shuffled frequently
      during evolution, although several operon structures, such as ribosomal protein
      operons, were well conserved. This suggests that shuffling of a genome structure
      is virtually neutral in long-term evolution. Moreover, degrees of instability of
      the operon structures depended on the genomes examined. Variation in degrees of
      instability of the genome structures was likely to be related to differences in
      amounts of insertion sequences. Effects on transcription regulation are also
      discussed in association with operon destruction.

PMID- 10331261
TI  - Partial sweeping of variation at the Fbp2 locus in a west African population of
      Drosophila melanogaster.
AB  - Departure of molecular variation from neutral equilibrium was studied in a highly
      recombining region of the Drosophila genome. A 2.2-kb region including the Fbp2
      locus was sequenced for 10 chromosomes from a D. melanogaster sample from West
      Africa and for the related species D. simulans. Of the 33 variable sites present
      in the 1.3-kb transcription unit, 32 made up a single haplotype present in half
      of the D. melanogaster sample. This pattern significantly departed from
      predictions of the neutral drift-mutation equilibrium model. The major haplotype
      presented a diagnostic restriction site which was investigated in 226 chromosomes
      from three distant European and African populations. It was found at a high
      frequency (31%) in the population from which the sequenced sample originated, but
      was nearly absent from the other two (below 4%), suggesting that the major
      haplotype frequency resulted from a local selective sweep event. Partial sweeping
      of variation in regions of high recombination rates has previously been found for
      American and European populations of D. melanogaster. Our study shows that this
      phenomenon also occurs in African populations, which are in the ancestral range
      of this species.

PMID- 10331262
TI  - Incongruence in the diploid B-genome species complex of Glycine (Leguminosae)
      revisited: histone H3-D alleles versus chloroplast haplotypes.
AB  - Variation at the single-copy nuclear locus histone H3-D was surveyed in the
      diploid B-genome group of Glycine subgenus Glycine (Leguminosae: Papilionoideae),
      which comprises three named Australian species and a number of distinct but as
      yet not formally recognized taxa. A total of 23 alleles was identified in the 44
      accessions surveyed. Only one individual was clearly heterozygous, which is not
      surprising given the largely autogamous breeding system of subgenus Glycine.
      Alleles differed by as many as 19 nucleotide substitutions, nearly all in the
      three introns; length variation was minimal. Phylogenetic analysis identified two
      shortest allele trees with very little homoplasy, suggesting that recombination
      has been rare. Both topological and data set incongruence were statistically
      significant between histone H3-D allele trees and trees inferred from chloroplast
      DNA haplotypes previously described from these same accessions. Whereas the
      distribution of H3-D alleles agrees well with morphologically based taxonomic
      groupings, chloroplast DNA haplotype polymorphisms transgress species boundaries,
      suggesting that the chloroplast genome is not tracking taxic relationships.
      Divergences among chloroplast DNA haplotypes involved in such transgressive
      patterns appear to be more recent than speciation events, suggesting
      hybridization rather than lineage sorting.

PMID- 10331263
TI  - Parallel evolution of drug resistance in HIV: failure of nonsynonymous/synonymous
      substitution rate ratio to detect selection.
AB  - Parallel or convergent evolution at the molecular level has been difficult to
      demonstrate especially when rigorous statistical criteria are applied. We present
      sequence data from the protease gene from eight patients infected with the human
      immunodeficiency virus (HIV-1). These patients have been on multiple drug
      therapies for at least 2 years. We present sequence data from two timepoints:
      time zero--the initiation of drug therapy--and a subsequent timepoint between 59
      and 104 weeks after the initiation of drug therapy. In addition to the sequence
      data, we present viral load data from both initial and final timepoints. Our
      phylogenetic analyses indicate significant evolution of virus from initial to
      final time points, even in three of eight patients who show low viral loads. Of
      the five patients who escaped drug therapy, identical amino acid replacements
      were seen in all five patients at two different codon positions, an indication of
      parallel evolution. We also measured genetic diversity for these patients and
      found no correlation between genetic diversity and viral load. Finally, we
      calculated the nonsynonymous and synonymous substitution rates and showed that
      the ratio of nonsynonymous to synonymous substitution compared to the value of
      one may be a poor indicator of natural selection.

PMID- 10331264
TI  - Phylogenetic analysis of the 5-aminolevulinate synthase gene.
AB  - The evolution of 5-aminolevulinate synthase (ALS) was studied by acquiring
      sequence data and generating phylogenetic trees. Gene sequences were already
      available for a variety of vertebrates (which have both a housekeeping and an
      erythroid form of the gene), fungi, alpha-proteobacteria, and one protist and one
      protostome. In order to generate representative trees, ALS sequence data were
      acquired from various deuterostomes and protostomes. The species and tissues
      selected for study were beluga whale liver, hagfish blood, sea urchin gonadal
      tissue, cuttlefish hepatopancreas, horseshoe crab hepatopancreas, and bloodworm
      blood. The new sequences and those previously published were examined for the
      presence of heme-regulatory motifs (HRMs) and iron-responsive elements (IREs).
      The HRMs are present in almost all eukaryotic species, which suggests their
      fundamental role in the regulation of ALS. The IREs are present in all vertebrate
      erythroid forms of ALS, which indicates that in those animals, expression of the
      erythroid form of the enzyme and, hence, hemoglobin production can be influenced
      by the intracellular content of iron. The new sequences were aligned with
      previously reported ALS sequences, and phylogenetic analyses were performed. The
      resulting trees provided evidence regarding the timing of the gene duplication
      event that led to the two forms of the ALS gene in vertebrates. It appears that
      the housekeeping and erythroid forms of ALS probably arose before the divergence
      of hagfish from the deuterostome line leading to the vertebrates. The data also
      add to the evidence indicating that alpha-proteobacteria are the nearest
      contemporary relatives of mitochondria.

PMID- 10331265
TI  - Multiplicity of glutamic acid decarboxylases (GAD) in vertebrates: molecular
      phylogeny and evidence for a new GAD paralog.
AB  - The evolution of chordate glutamic acid decarboxylase (GAD; EC 4.1.1.15), a key
      enzyme in the central nervous system synthesizing the neurotransmitter gamma
      amino-butyric acid (GABA) from glutamate, was studied. Prior to this study,
      molecular data of GAD had been restricted to mammals, which express two distinct
      forms, GAD65 and GAD67. These are the products of separate genes and probably are
      derived from a common ancestral GAD following gene duplication at some point
      during vertebrate evolution. To enable a comprehensive phylogenetic analysis,
      molecular information of GAD forms in other vertebrate classes was essential. By
      reverse transcriptase-polymerase chain reaction (RT-PCR), partial nucleotide
      sequences of GAD were cloned from brains of zebra finch (Taeniopygia guttata),
      turtle (Trachemys scripta), goldfish (Carassius auratus), zebrafish (Danio
      rerio), and armoured grenadier (Coryphaenoides (Nematonurus) armatus, a deep-sea
      fish), and from the cerebral ganglion plus neural gland of Ciona intestinalis, a
      protochordate. Whereas GAD65 and GAD67 homologs were expressed in birds,
      reptiles, and fish, only a single GAD cDNA with equal similarities to both
      vertebrate GAD forms was found in the protochordate. This indicates that the
      duplication of the vertebrate GAD gene occurred between 400 and 560 million years
      ago. For both GAD65 and GAD67, the generated phylogenetic tree followed the
      general tree topology for the major vertebrate classes. In turtle, an alternative
      spliced form of GAD65, putatively encoding a truncated, nonactive GAD, was found.
      Furthermore, a third GAD form, which is equally divergent from both GAD65 and
      GAD67, is expressed in C. (N.) armatus. This third form might have originated
      from an ancient genome duplication specific to modern ray-finned fishes.

PMID- 10331266
TI  - Phylogenetic evidence for recombination in dengue virus.
AB  - A split decomposition analysis of dengue (DEN) virus gene sequences revealed
      extensive networked evolution, indicative of recombination, among DEN-1 strains
      but not within serotypes DEN-2, DEN-3, or DEN-4. Within DEN-1, two viruses
      sampled from South America in the last 10 years were identified as recombinants.
      To map the breakpoints and test their statistical support, we developed a novel
      maximum likelihood method. In both recombinants, the breakpoints were found to be
      in similar positions, within the fusion peptide of the envelope protein,
      demonstrating that a single recombination event occurred prior to the divergence
      of these two strains. This is the first report of recombination in natural
      populations of dengue virus.

PMID- 10331267
TI  - Complete sequence, gene arrangement, and genetic code of mitochondrial DNA of the
      cephalochordate Branchiostoma floridae (Amphioxus)
AB  - We have determined the 15,083-nucleotide (nt) sequence of the mitochondrial DNA
      (mtDNA) of the lancelet Branchiostoma floridae (Chordata: Cephalochordata). As is
      typical in metazoans, the mtDNA encodes 13 protein, 2 rRNA, and 22 tRNA genes.
      The gene arrangement differs from the common vertebrate arrangement by only four
      tRNA gene positions. Three of these are unique to Branchiostoma, but the fourth
      is in a position that is primitive for chordates. It shares the genetic code
      variations found in vertebrate mtDNAs except that AGA = serine, a code variation
      found in many invertebrate phyla but not in vertebrates (the related codon AGG
      was not found). Branchiostoma mtDNA lacks a vertebrate-like control region; its
      largest noncoding region (129 nt) is unremarkable in sequence or base
      composition, and its location between ND5 and tRNAG differs from that usually
      found in vertebrates. It also lacks a potential hairpin DNA structure like those
      found in many (though not in all) vertebrates to serve as the second-strand
      (i.e., L-strand) origin of replication. Perhaps related to this, the sequence
      corresponding to the DHU arm of tRNAC cannot form a helical stem, a condition
      found in a few other vertebrate mtDNAs that also lack a canonical L-strand origin
      of replication. ATG and GTG codons appear to initiate translation in 11 and 2 of
      the protein-encoding genes, respectively. Protein genes end with complete (TAA or
      TAG) or incomplete (T or TA) stop codons; the latter are presumably converted to
      TAA by post-transcriptional polyadenylation.

PMID- 10331268
TI  - Phylogenetic perspective reveals abundant Ty1/Ty2 hybrid elements in the
      Saccharomyces cerevisiae genome.

PMID- 10331269
TI  - A new perspective on lower metazoan relationships from 18S rDNA sequences.

PMID- 10331270
TI  - Glyceraldehyde-3-phosphate dehydrogenase gene diversity in eubacteria and
      eukaryotes: evidence for intra- and inter-kingdom gene transfer.
AB  - Cyanobacteria contain up to three highly divergent glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH) genes: gap1, gap2, and gap3. Genes gap1 and gap2 are
      closely related at the sequence level to the nuclear genes encoding cytosolic and
      chloroplast GAPDH of higher plants and have recently been shown to play distinct
      key roles in catabolic and anabolic carbon flow, respectively, of the unicellular
      cyanobacterium Synechocystis sp. PCC6803. In the present study, sequences of 10
      GAPDH genes distributed across the cyanobacteria Prochloron didemni, Gloeobacter
      violaceus PCC7421, and Synechococcus PCC7942 and the alpha-proteobacterium
      Paracoccus denitrificans and the beta-proteobacterium Ralstonia solanacearum were
      determined. Prochloron didemni possesses homologs to the gap2 and gap3 genes from
      Anabaena, Gloeobacter harbors gap1 and gap2 homologs, and Synechococcus possesses
      gap1, gap2, and gap3. Paracoccus harbors two highly divergent gap genes that are
      related to gap3, and Ralstonia possesses a homolog of the gap1 gene. Phylogenetic
      analyses of these sequences in the context of other eubacterial and eukaryotic
      GAPDH genes reveal that divergence across eubacterial gap1, and gap2, and gap3
      genes is greater than that between eubacterial gap1 and eukaroytic glycolytic
      GapC or between eubacterial gap2 and eukaryotic Calvin cycle GapAB. These data
      strongly support previous analyses which suggested that eukaryotes acquired their
      nuclear genes for GapC and GapAB via endosymbiotic gene transfer from the
      antecedents of mitochondria and chloroplasts, and extend the known range of
      sequence diversity of the antecedent eubacterial genes. Analyses of available
      GAPDH sequences from other eubacterial sources indicate that the glycosomal gap
      gene from trypanosomes (cytosolic in Euglena) and the gap gene from the
      spirochete Treponema pallidum are each other's closest relatives. This specific
      relationship can therefore not reflect organismal evolution but must be the
      result of an interkingdom gene transfer, the direction of which cannot be
      determined with certainty at present. Contrary to this, the origin of the
      cytosolic Gap gene from trypanosomes can now be clearly defined as gamma
      proteobacterial, since the newly established Ralstonia sequence (beta
      proteobacteria) branches basally to the gamma-proteobacterial/trypanosomal
      assemblage.

PMID- 10331271
TI  - Evolution of the mitochondrial rps3 intron in perennial and annual angiosperms
      and homology to nad5 intron 1.
AB  - The plant mitochondrial rps3 intron was analyzed for substitution and indel rate
      variation among 15 monocot and dicot angiosperms from 10 genera, including
      perennial and annual taxa. Overall, the intron sequence was very conserved among
      angiosperms. Based on length polymorphism, 10 different alleles were identified
      among the 10 genera. These allelic differences were mainly attributable to large
      indels. An insertion of 133 nucleotides, observed in the Alnus intron was
      partially or completely absent in the other lineages of the family Betulaceae.
      This insertion was located within domain IV of the secondary-structure model of
      this group IIA intron. A mobile element of 47 nucleotides that showed homology to
      sequences located in rice rps3 intron and in intergenic plant mitochondrial
      genomes was found within this insertion. Both substitution and indel rates were
      low among the Betulaceae sequences, but substitution rates were increasingly
      larger than indel rates in comparisons involving more distantly related taxa.
      From a secondary-structure model, regions involved in helical structures were
      shown to be well preserved from indels as compared to substitutions, but
      compensatory changes were not observed among the angiosperm sequences analyzed.
      Using approximate divergence times based on the fossil record, substitution and
      indel rate heterogeneity was observed between different pairs of annual and
      perennial taxa. In particular, the annual petunia and primrose evolved more than
      15 and 10 times faster, for substitution and indel rates respectively, than the
      perennial birch and alder. This is the first demonstration of an evolutionary
      rate difference between perennial and annual forms in noncoding DNA, lending
      support to neutral causes such as the generation time, population size, and
      speciation rate effects to explain such rate heterogeneity. Surprisingly, the
      sequence from the rps3 intron had a high identity with the sequence of intron 1
      from the angiosperm mitochondrial nad5 gene, suggesting a common origin of these
      two group IIA introns.

PMID- 10331272
TI  - A new genetic distance with application to constrained variation at
      microsatellite loci.
AB  - Genetic variation at microsatellite loci is supposed to be constrained within
      some range in allele size. In this case, the average-square distance (delta mu)2
      between two diverged populations moves asymptotically around and underestimates
      the time since the populations had split. A distance based on the between-locus
      correlation in the mean repeat scores, DR, is introduced. Numerical simulations
      show that DR is a linear function of time if the constraints are approximated by
      a linear centripetal force, which might be due to mutation bias toward a definite
      range or be caused both by directional mutation bias toward larger allele size
      and by selection against the greater number of repeats.

PMID- 10331273
TI  - Selective constraints on P-element evolution.
AB  - P elements, like mariners, inhabit eukaryotic genomes and transpose via a DNA
      intermediate. Mutant and wild-type elements in the same genome should be
      transposed with equal probability by trans-acting transposase, and so no
      selection should counteract the accumulation of inactivating mutations in
      transposase genes. Thus, copies of mariner elements diverge within a host species
      under no selection (Robertson and Lampe 1995). It is unknown whether or not this
      pattern holds for P elements, which are unrelated to mariner elements but share
      the same life history. Publicly available P-element sequences were analyzed for
      evidence of conservative selection for the function of P-element-encoded
      proteins. Results were compared to predictions derived from several hypotheses
      that could explain selection, or the lack of it. P-element protein-coding
      sequences do evolve under conservative selection but apparently because of more
      than one selective force. Of the four exons in the P-element transposase, the
      first three (exons 0, 1, and 2) can be translated alone into a repressor of
      transposition, while the last (exon 3) is only expressed as part of the full
      length transposase and probably serves a transposition-specific role. As full
      length P-element copies diverge from each other within a host population,
      selection maintains exons 0-2 but apparently not exon 3. The selection acting on
      exons 0-2 may act at the host level for repression of transposition (since host
      level selection does act on orthologous truncated elements that contain only
      exons 0-2). Evidence of selection on exon 3 is only found in comparisons of more
      diverged elements from different species, suggesting that selection for
      transposition acts primarily at horizontal transfer events. Thus, horizontal
      transfer events may be the sole source of the selection that is crucial to the
      maintenance of autonomous P elements in the face of mutation (as suggested by
      Robertson and Lampe 1995). The predictions derived here suggest a strategy for
      collecting sequence data that could definitively answer these questions.

PMID- 10331274
TI  - Concerted evolution of two Mhc class II B loci in pheasants and domestic
      chickens.
AB  - The major histocompatibility complex (Mhc) of the ring-necked pheasant contains
      two polymorphic Mhc class II B genes. We show here, by screening of a cDNA
      library and RT-PCR from RNA, that both of these loci, Phco-DAB1 and Phco-DAB2,
      normally are transcribed in the spleen. They differ mainly in the 3' untranslated
      (UT) region, with the transcript lengths, not including the poly(A) tails, being
      1,100 nt for DAB1 and 955 nt for DAB2. These two loci are orthologous to the B
      LBI and B-LBII loci of the domestic chicken, respectively. DAB1 and DAB2
      therefore seem to have evolved from a duplication before the split of the
      evolutionary lineages leading to the pheasant and the domestic chicken ca. 20
      MYA. This is the first report of an orthologous relationship between avian Mhc
      genes. Yet, the third exons of DAB1 and DAB2 were identical in all available
      sequences and differed at 10 positions from the exon 3 sequences of B-LBI/B-LBII.
      The species-specific exon 3 suggests that DAB1 and DAB2 are subject to concerted
      evolution, i.e., interlocus genetic exchange. The exon 2 sequences show
      characteristic polymorphism, with hypervariable segments occurring in different
      combinations in different alleles. Given the divergence in the 3'UT region, the
      finding of the same exon 2 sequence at both the DAB1 and the DAB2 loci in one of
      the pheasant haplotypes also suggests that interlocus genetic exchange does
      occur. Accordingly, the exon 2 sequences tended to cluster irrespective of locus
      in the phylogenetic analyses. Genetic exchange simultaneously involving both exon
      2 and exon 3 may be facilitated by the short length of the intervening intron (<
      100 bp) in pheasants and domestic chickens compared with, e.g., humans (about 3
      kb).

PMID- 10331275
TI  - Low levels of nucleotide diversity at homoeologous Adh loci in allotetraploid
      cotton (Gossypium L.).
AB  - Levels of genetic diversity within and among populations and species are shaped
      by both external (population-level) and internal (genomic and genic) evolutionary
      forces. To address the effect of internal pressures, we estimated nucleotide
      diversity for a pair of homoeologous Adh loci in an allotetraploid species,
      Gossypium hirsutum. These data represent the first such estimates for a pair of
      homoeologous nuclear loci in plants. Estimates of nucleotide diversity for AdhA
      in Gossypium are lower than those for any plant nuclear gene yet described. This
      low diversity appears to reflect primarily a history of repeated, severe genetic
      bottlenecks associated with both speciation and recent domestication,
      supplemented by an unusually slow nucleotide substitution rate and an autogamous
      breeding system. While not statistically supportable, the sum of the observations
      also suggest differential evolutionary dynamics at each of the homoeologous loci.

PMID- 10331276
TI  - The domain structure and retrotransposition mechanism of R2 elements are
      conserved throughout arthropods.
AB  - R2 elements are non-LTR retrotransposons that insert in the 28S rRNA genes of
      arthropods. Partial sequence data from many species have previously suggested
      that these elements have been vertically inherited since the origin of this
      phylum. Here, we compare the complete sequences of nine R2 elements selected to
      represent the diversity of arthropods. All of the elements exhibited a uniform
      structure. Identification of their conserved sequence features, combined with our
      biochemical studies, allows us to make the following inferences concerning the
      retrotransposition mechanism of R2. While all R2 elements insert into the
      identical sequence of the 28S gene, it is only the location of the initial nick
      in the target DNA that is rigidly conserved across arthropods. Variation at the
      R2 5' junctions suggests that cleavage of the second strand of the target site is
      not conserved within or between species. The extreme 5' and 3' ends of the
      elements themselves are also poorly conserved, consistent with a target primed
      reverse transcription mechanism for attachment of the 3' end and a template
      switch model for the attachment of the 5' end. Comparison of the approximately
      1,000-aa R2 ORF reveals that it can be divided into three domains. The central
      450-aa domain can be folded by homology modeling into a tertiary structure
      resembling the fingers, palm, and thumb subdomains of retroviral reverse
      transcriptases. The carboxyl terminal end of the R2 protein appears to be the
      endonuclease domain, while the amino-terminal end contains zinc finger and c-myb
      like DNA-binding motifs.

PMID- 10331277
TI  - CRITICA: coding region identification tool invoking comparative analysis.
AB  - Gene recognition is essential to understanding existing and future DNA sequence
      data. CRITICA (Coding Region Identification Tool Invoking Comparative Analysis)
      is a suite of programs for identifying likely protein-coding sequences in DNA by
      combining comparative analysis of DNA sequences with more common noncomparative
      methods. In the comparative component of the analysis, regions of DNA are aligned
      with related sequences from the DNA databases; if the translation of the aligned
      sequences has greater amino acid identity than expected for the observed
      percentage nucleotide identity, this is interpreted as evidence for coding.
      CRITICA also incorporates noncomparative information derived from the relative
      frequencies of hexanucleotides in coding frames versus other contexts (i.e.,
      dicodon bias). The dicodon usage information is derived by iterative analysis of
      the data, such that CRITICA is not dependent on the existence or accuracy of
      coding sequence annotations in the databases. This independence makes the method
      particularly well suited for the analysis of novel genomes. CRITICA was tested by
      analyzing the available Salmonella typhimurium DNA sequences. Its predictions
      were compared with the DNA sequence annotations and with the predictions of
      GenMark. CRITICA proved to be more accurate than GenMark, and moreover, many of
      its predictions that would seem to be errors instead reflect problems in the
      sequence databases. The source code of CRITICA is freely available by anonymous
      FTP (rdp.life.uiuc.edu in/pub/critica) and on the World Wide Web
      (http:/(/)rdpwww.life.uiuc.edu).

PMID- 10331278
TI  - Assessing genetic structure with multiple classes of molecular markers: a case
      study involving the introduced fire ant Solenopsis invicta.
AB  - We used 30 genetic markers of 6 different classes to describe hierarchical
      genetic structure in introduced populations of the fire ant Solenopsis invicta.
      These included four classes of presumably neutral nuclear loci (allozymes,
      codominant random amplified polymorphic DNAs (RAPDs), microsatellites, and
      dominant RAPDs), a class comprising two linked protein-coding nuclear loci under
      selection, and a marker of the mitochondrial DNA (mtDNA). Patterns of structure
      revealed by F statistics and exact tests of differentiation were highly
      concordant among the four classes of neutral nuclear markers, although the
      microsatellites were the most effective markers for detecting structure. The
      results from the mtDNA complemented those from the neutral nuclear markers by
      revealing that strong limitations to female-mediated gene flow were the cause of
      the local structure registered by the nuclear markers. The pattern of structure
      inferred from the selected nuclear loci was markedly different from the patterns
      derived from the other sets of markers but was predictable on the basis of the
      presumed mode of selection acting on these loci. In general, the results for all
      six classes of markers can be explained by known features of the social and
      reproductive biology of fire ants. Thus, the results from these diverse sets of
      markers, combined with detailed natural history data, provide an unusually
      complete picture of how the fundamental evolutionary forces of gene flow, drift,
      and selection govern the distribution of genetic variation within and between
      fire ant populations.

PMID- 10331279
TI  - Characterization of homeodomain-leucine zipper genes in the fern Ceratopteris
      richardii and the evolution of the homeodomain-leucine zipper gene family in
      vascular plants.
AB  - The homeodomain-leucine zipper (HD-Zip) genes encode transcription factors that
      are characterized by the presence of both a homeodomain and a leucine zipper
      motif. They belong to the homeobox gene superfamily and have been reported only
      from flowering plants. This article is the first report on the ferm HD-Zip genes
      (named Crhb1-Crhb11) isolated from the homosporous ferm Ceratopteris richardii.
      Phylogenetic analyses of the II Crhb genes with previously reported angiosperm HD
      Zip genes show that the Crhb genes belong to three of the four different
      angiosperm HD-Zip subfamilies (HD-Zip I, II, and IV), indicating that these
      subfamilies of HD-Zip genes originated before the diversification of the ferm and
      seed plant lineages. The Crhb4-Crhb8 and Crhb11 genes belong to the HD-Zip I
      subfamily but differ from angiosperm HD-Zip I genes by the presence of a seven
      amino-acid indel in the leucine zipper motif. By the northern analyses, Crhb1 and
      Crhb3 were expressed only in gametophyte tissue. Expression of Crhb2 and Crhb11
      genes could not be detected in any tissue examined, while all other Crhb genes
      were expressed in most sporophytic and gametophytic tissues. Although the
      functions of the Crhb genes in Ceratopteris are unknown, their patterns of
      expression suggest that they regulate developmental or physiological processes
      common to both the gametophyte and the sporophyte generations of the fern.
      Differences in the expression of Crhb1 between male gametophytes and male
      hermaphrodite mixed populations of gametophytes suggests that the Crhb1 gene is
      involved in gametophytic sex determination.

PMID- 10331280
TI  - Phylogenetic relationships and evolution of the KNOTTED class of plant
      homeodomain proteins.
AB  - Knotted-like (KNOX) proteins constitute a group of homeodomain proteins involved
      in pattern formation in developing tissues of angiosperms and other green plants.
      We conducted phylogenetic analyses of nucleotide and amino acid sequences of all
      known KNOX proteins in order to examine their evolution. Our analyses reveal two
      groups of KNOX proteins, classes I and II. Dicot and monocot sequences occur in
      both classes, indicating that the protein classes arose prior to the origin of
      the monocots. A conifer (Picea) sequence is nested within class I, suggesting
      that there are likely to be other copies of KNOX genes in this and other
      conifers. The orthology of several grass genes (including Zea Kn1, ZMKN1) is
      strongly supported by phylogenetic and synteny analyses. However, no compelling
      evidence supports the hypothesis of orthology previously proposed for several
      dicot genes and ZMKN1. Analysis of expression patterns suggests that the
      ancestral KNOX gene was expressed in all plant parts and that the propensity to
      be downregulated in roots and leaves evolved in the class I genes.

PMID- 10331281
TI  - Topological bias and inconsistency of maximum likelihood using wrong models.

PMID- 10331282
TI  - The death of a microsatellite: a phylogenetic perspective on microsatellite
      interruptions.

PMID- 10331283
TI  - From gan-zi-gun-nu to anandamide and 2-arachidonoylglycerol: the ongoing story of
      cannabis.

PMID- 10331284
TI  - Enzymatic formation of C-terminal amides.

PMID- 10331285
TI  - Thiazole and oxazole peptides: biosynthesis and molecular machinery.

PMID- 10331286
TI  - Hybridizing Old and New World camelids: Camelus dromedarius x Lama guanicoe.
AB  - Thirty female dromedary camels were inseminated on a total of 50 occasions with 2
      4 ml of fresh guanaco semen diluted with an equal volume of commercially
      available camel semen extender. Similarly, nine female guanacos were inseminated
      on 34 occasions with 4-6 ml of fresh, diluted camel semen. Only two of the
      dromedary females conceived; one aborted a female foetus on day 260 of gestation
      and the other gave birth to a stillborn female calf on day 365. Six conceptions
      occurred in the female guanacos. Two of these conceptuses, diagnosed by
      ultrasound, were resorbed between days 25 and 40 of gestation, one female foetus
      was aborted on day 291, another female foetus was aborted on day 302, and one
      female calf was stillborn on day 365 of gestation. The sixth foetus, a male, was
      born prematurely but alive after a 328-day gestation. It had a phenotypic
      appearance intermediate between that of a camel and a guanaco and its hybrid
      parentage was confirmed by the DNA fingerprinting of eight llama microsatellites.
      To our knowledge, this is the first viable hybrid ever to be produced between Old
      World and New World camelids, which have been reproductively isolated from one
      another for at least 11 million years. The preponderance of female hybrids is in
      accordance with Haldane's law. Histological examination of their ovaries revealed
      a failure of meiosis, with only an occasional abnormal oocyte surrounded by
      follicle cells. Although the diploid chromosone number of camels and guanacos is
      the same (2n = 74), sufficient genetic change has taken place to make the pairing
      of homologous chromosomes no longer possible.

PMID- 10331287
TI  - Estimating population size by genotyping faeces.
AB  - Population size is a fundamental biological parameter that is difficult to
      estimate. By genotyping coyote (Canis latrans) faeces systematically collected in
      the Santa Monica Mountains near Los Angeles, California, we exemplify a general,
      non-invasive method to census large mammals. Four steps are involved in the
      estimation. First, presumed coyote faeces are collected along paths or roadways
      where coyotes, like most carnivores, often defaecate and mark territorial
      boundaries. Second, DNA is extracted from the faeces and species identity and sex
      is determined by mitochondrial DNA and Y-chromosome typing. Third, hypervariable
      microsatellite loci are typed from the faeces. Lastly, rarefaction analysis is
      used to estimate population size from faecal genotypes. This method readily
      provides a point count estimate of population size and sex ratio. Additionally,
      we show that home range use paternity and kinship can be inferred from the
      distribution and relatedness patterns of faecal genotypes.

PMID- 10331288
TI  - Molecular phylogenetic evidence for the evolution of specialization in
      anemonefishes.
AB  - Anemonefishes (genera: Amphiprion and Premnas; family Pomacentridae) are a group
      of 28 species of coral reef fishes that are found in obligate symbiosis with
      large tropical sea anemones. A phylogenetic hypothesis based on morphological
      analyses of this group suggests that the ancestral anemonefish was a generalist
      with similar morphology to other pomacentrids, and that it gave rise to other
      anemonefish species that were more specialized for living with particular species
      of host anemones. To test this hypothesis we constructed a molecular phylogeny
      for the anemonefishes by sequencing 1140 base pairs of the cytochrome b gene and
      522 base pairs of the 16S rRNA gene for six species of anemonefishes
      (representatives of all subgenera and species complexes) and two other
      pomacentrid species. Three methods of phylogenetic analysis all strongly
      supported the conclusion that anemonefishes are a monophyletic group. The
      molecular phylogeny differs from the tree based on morphological data in that the
      two species of specialized anemonefishes (Premnas biaculeatus and Amphiprion
      ocellaris) were assigned to a basal position within the clade, and the extreme
      host generalist (Amphiprion clarkii) to a more derived position. Thus, the
      initial anemonefish ancestors were probably host specialists and subsequent
      speciation events led to a combination of generalist and specialist groups.
      Further phylogenetic studies of additional anemonefish species are required to
      substantiate this hypothesis.

PMID- 10331289
TI  - How quickly do brains catch up with bodies? A comparative method for detecting
      evolutionary lag.
AB  - A trait may be at odds with theoretical expectation because it is still in the
      process of responding to a recent selective force. Such a situation can be termed
      evolutionary lag. Although many cases of evolutionary lag have been suggested,
      almost all of the arguments have focused on trait fitness. An alternative
      approach is to examine the prediction that trait expression is a function of the
      time over which the trait could evolve. Here we present a phylogenetic
      comparative method for using this 'time' approach and we apply the method to a
      long-standing lag hypothesis: evolutionary changes in brain size lag behind
      evolutionary changes in body size. We tested the prediction in primates that
      brain mass contrast residuals, calculated from a regression of pairwise brain
      mass contrasts on positive pairwise body mass contrasts, are correlated with the
      time since the paired species diverged. Contrary to the brain size lag
      hypothesis, time since divergence was not significantly correlated with brain
      mass contrast residuals. We found the same result when we accounted for
      socioecology, used alternative body mass estimates and used male rather than
      female values. These tests do not support the brain size lag hypothesis.
      Therefore, body mass need not be viewed as a suspect variable in comparative
      neuroanatomical studies and relative brain size should not be used to infer
      recent evolutionary changes in body size.

PMID- 10331294
TI  - [A useful index highly correlated with coronary risk factors for community based
      obesity screening].
AB  - Obesity is associated with an increased risk for all cause mortality especially
      coronary heart disease (CHD). An obesity index highly correlated with coronary
      risk factors (CRF) has not been well studied, especially in Japan. This study
      compared obesity indices: body mass index (BMI), percentage of body fat (%Fat),
      waist to hip ratio (WHR), waist to stature ratio (WSR) and subscapular to triceps
      subcutaneous fat ratio (Sub/Tri) with CRF, including systolic blood pressure
      (SBP), diastolic blood pressure (DBP), total cholesterol (TC), high density
      lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C),
      triglyceride (TG) and fasting blood sugar (FBS). The subjects were 4,551 Japanese
      males and females, aged 15-84 years who had a community based health examination
      between 1991-1997, and were initially free from CHD and other major chronic
      diseases. The strongest associations were revealed between WSR and waist
      circumference with all CRF in males and females, and also WHR with TC and FBS in
      males. After adjustment for age, the risk ratio of CRF rose significantly with
      increasing BMI, %Fat, WHR and WSR. Among these, WSR and waist circumference
      yielded the sharpest risk ratio gradient, although FBS was not significantly
      correlated. Moreover, for those who have at least one high value in a CRF,
      compared to the lowest category, the highest category of WSR and waist
      circumference had the highest age-adjusted risk ratio. The high correlation of
      WSR and waist circumference with these CRF suggests that WSR and waist
      circumference are potentially useful in community based obesity screening.

PMID- 10331293
TI  - Selection for high and low virulence in the malaria parasite Plasmodium chabaudi.
AB  - What stops parasites becoming ever more virulent? Conventional wisdom and most
      parasite-centred models of the evolution of virulence suppose that risk of host
      (and, hence, parasite) death imposes selection against more virulent strains.
      Here we selected for high and low virulence within each of two clones of the
      rodent malaria parasite Plasmodium chabaudi on the basis of between-host
      differences in a surrogate measure of virulence--loss of live weight post
      infection. Despite imposing strong selection for low virulence which mimicked 50
      75% host mortality, the low virulence lines increased in virulence as much as the
      high virulence lines. Thus, artificial selection on between-host differences in
      virulence was unable to counteract natural selection for increased virulence
      caused by within-host selection processes. The parasite's asexual replication
      rate and number of sexual transmission forms also increased in all lines,
      consistent with evolutionary models explaining high virulence. An upper bound to
      virulence, though not the asexual replication rate, was apparent, but this bound
      was not imposed by host mortality. Thus, we found evidence of the factors assumed
      to drive evolution of increased virulence, but not those thought to counter this
      selection.

PMID- 10331295
TI  - [Development of a "self efficacy for health promotion scale" in community
      dwelling elderly].
AB  - The purpose of this study is to develop a Japanese version of a self efficacy
      scale for health promotion activities by the elderly. In September to October
      1997, we asked all of 1758 persons aged 65 and over who were living in a village
      in Nagano Prefecture to answer a questionnaire. The questionnaire included 15
      self efficacy items for health promotion, Activities of Daily Living (ADL),
      general self efficacy, health behavior, and community activities. The present
      study examined reliability and validity of the scale by investigating the
      correlation to other factors. 1173 of the subjects completed the answer sheet by
      themselves. The mean age of the subjects was 72.9 +/- 6.1, and 54.7% were female,
      the education level of 52.2% was middle school, 54.0% worked as a laborers, and
      41 persons (3.5%) needed help in instrumental ADL. Almost half of the subjects
      participated in various community activities. When applied to the 1173 subjects,
      the first principal component accounted for 53.9% of variance. We considered a
      self efficacy scale for health promotion by using the sum of 15 items. Alpha
      coefficient of the scale was 0.93 and test-retest reliability was 0.68, showing
      the reliability of the scale. Criterion-related validity was demonstrated by the
      significant relationship between the self efficacy scale and general self
      efficacy (r = 0.42). The score of the 15-item version did not correlate with age
      and sex but ADL and health behavior (r = 0.29, 0.21, p < 0.001). High self
      efficacy was found among those who had high self rated health, and participated
      in health counseling, health screening, golden-age community center activity, and
      volunteer activities. This scale can be used to measure personal belief for
      health promotion as well as the effects of interventions to alter health
      behaviors. To standardize the scale, further study of urban dwelling elderly and
      the disabled elderly is necessary.

PMID- 10331296
TI  - [Prospective study on the relationship between physical fitness and all-cause
      mortality in Japanese men].
AB  - This study was conducted to examine the relationship between physical fitness and
      all-cause mortality in Japanese men. We evaluated the physical fitness and risk
      for all-cause mortality of 9,986 Japanese men who were given a submaximal
      exercise test and a medical examination between 1982 and 1984. Physical fitness
      was measured using a bicycle ergometer test, and maximal oxygen uptake was
      estimated. The average follow-up time was 14 years, for total of 139,836 person
      years of observation. There were 247 deaths during the observation period. The
      relative risk and 95% confidence intervals (95% CI) for all-cause mortality were
      obtained using the Cox proportional hazards model. Following age adjustment, and
      using the lowest physical fitness (quintile I) group as a reference, the hazard
      ratios for quintiles II through V were, 0.54 (0.39-0.77), 0.66 (0.47-0.94), 0.58
      (0.39-0.86), and 0.46 (0.27-0.78), respectively. After being adjusted for age,
      body mass index, hypertension, and urinary protein, the hazard ratios were, 0.52
      (0.37-0.73), 0.60 (0.42-0.87), 0.50 (0.33-0.75), and 0.39 (0.22-0.67),
      respectively. The results presented here support the hypothesis that a low level
      of physical fitness in an important risk factor for all-cause mortality in
      Japanese men.

PMID- 10331297
TI  - [Present situation of medical care for foreigners at medical facilities in Chiba
      City].
AB  - OBJECTIVE: The number of foreigners residing in Japan has increased during the
      past decade. The aim of this survey was to clarify the present situation and the
      disadvantages in the medical care for foreigners. METHODS: In October 1997, we
      mailed a questionnaire to all clinics and hospitals in Chiba City. The
      questionnaire included questions regarding the number of foreign patients who
      visited during the past three months, the proportion of patients who have any
      health insurance, procedures for handling foreign patients, and the disadvantages
      in medical care for them. RESULTS: Of the 210 respondents (183 clinics and 27
      hospitals), 133 facilities (63.3%) provided medical care for foreign patients
      during the past three months, and 187 (89.0%) during the past year. In 102
      facilities (76.7%), the number of foreign patients was fewer than 10 during the
      past three months. The mean number of foreign patients was 13.8 per facility
      (12.2 per clinic, and 23.5 per hospital). Of these foreign patients, 68.6% had
      any health insurance. In 172 facilities (81.9%), foreign patients were accepted
      in the same way as the Japanese. The main disadvantages in medical care for
      foreigners were difficulty in understanding because of communication problems,
      and default in payment of medical expenses for the foreigners with no health
      insurance. In 154 facilities (73.3%), no special preparation to communicate with
      foreign patients was provided, and few facilities could understand foreign
      languages except for English. In 20 facilities, fees for medical care had been
      left unpaid by foreign patients during the past year, and the total outstanding
      amount was about 23,800,000 yen. CONCLUSION: In Chiba City, many medical
      facilities provide medical care for foreign patients. This study suggests that
      support for communication with foreigners and compensation for default in medical
      expenses are necessary.

PMID- 10331298
TI  - [An Internet-based "distance" learning for health, environment and sustainable
      development "distance learning without a frontier"].
AB  - Quality of the environment is crucial for human health. Environmental hazards may
      lead to adverse health effects, while a sound environment can support of enable
      health. It has been clear that health and environment must be understood within
      the context of social and economic development, which was stressed especially in
      the Earth Summit held in Rio de Janeiro, Brazil, in 1992. Investing in
      improvement of people's health and their environment is a prerequisite for
      sustainable development. The telecommunication revolution enables distance
      learning without frontiers in a reansparent and interactive environment. Applying
      the Internet and other telecommunication into public health including
      environmental health holds the greatest promise for global health. A wide
      application and access would facilitate and expedite the reduction of inequity
      prevailing between the south and north in an unprecedented speed. This proposed
      course is thus designed to provide an overview on health and environment in
      sustainable development through the Internet.

PMID- 10331299
TI  - [Clinical significance of allergen analysis--food allergens].

PMID- 10331300
TI  - [Viral respiratory infection in bronchial asthma].

PMID- 10331301
TI  - [Allergic inflammation and cytokine network].

PMID- 10331302
TI  - [Dexamethasone-induced apoptosis in peripheral T lymphocytes from patients with
      asthma].
AB  - The corticosteroid is effective for treating allergic inflammation. However, the
      mechanisms of the effectiveness are still unclarified. In this study, we examined
      whether dexamethasone, one of corticosteroids, can induce apoptosis in peripheral
      T cells from patients with asthma. Dexamethasone induced significantly greater
      apoptosis in T cells from patients with asthma than from normal subjects at 10(
      4) M and 10(-5) M (p < 0.05). Apoptosis was assessed by flow cytometry, DNA
      fragmentation. By examining the function of T cell subsets, the augmentation of
      apoptosis was ascribed to CD4+HLADR+CD25+subsets. Elimination of
      HLADR+CD25+subsets from T cells caused a great reduction in IL-5 production and
      proliferation to mite on Day 3, suggesting that the subset might be primed by
      mite allergen. Dexamethasone may reduce allergen specific T cells through
      apoptosis, which is one of the mechanisms of effectiveness of dexamethasone in
      asthmatics.

PMID- 10331303
TI  - [Cough variant asthma improving with avoidance of pet rabbit].
AB  - The concept of cough variant asthma (CVA) has been defined recently, but little
      is known about the relation between CVA and antigen. A case of CVA due to per
      rabbit was presented here. A 49-year-old man who kept a pet rabbit indoors was
      admitted our hospital with nocturnal dry cough. Both serum total IgE level and
      eosinophil count were elevated (IgE 5580 IU/L. Eosinophil 1183/L). According to
      Sato's criteria, this case was diagnosed to be CVA. After the patient was kept
      out of contact with the rabbit, his coughing disappeared and never recurred and
      IgE (RAST) against rabbit decreased. The out come of this case clearly shows that
      CVA improved due to avoidance of the antigen. These facts suggest that the cause
      of CVA in this case in due to mainly an immunoglobulin E-mediated allergic
      reaction.

PMID- 10331304
TI  - [Annual change of the pet in allergic patients home for ten years].
AB  - There are only few paper in Japan which reports the prevalence of pet keepers in
      the allergic population and also of the type of pets they keep. We made
      investigation on these points in 1337 allergic patients employing a
      questionnaire. Among 1337 patients, allergic conjunctivitis patients were found
      in 67, eczema patients in 118, allergic rhinitis patients in 368 and bronchial
      asthmatic patients in 1043. These number contained those who overlapped in
      symptoms. Approximately 43% of allergy patients are currently keeping the pet at
      present while 11.2% of the patient had kept the pet in the past. There were two
      peaks in the age when they began to keep a pet, 6 to 12 and 30 to 40 years of
      age. Trend in the past decade showed that both the dog and cat bred in foreign
      countries were increasing. About 80% of patients who own the foreign bred dogs
      keep them indoor. This ratio is increasing gradually. Another conspicuous change
      is the sharp increase in those who keep hamsters which occupied 20% of all the
      pet keeper in 1997. Percentages of the patient who recognizes the aggravation of
      their symptoms in eye, nose, skin and also as asthma often pet keeping is a about
      10%. One out of 4 patients who keep the pet has a family member with rhinitis
      and/or asthma. We concluded that too many of the allergic patients keep the pet
      against their benefit and they must be informed that the pet could be the cause
      of allergy symptoms.

PMID- 10331305
TI  - [Antidiuretic hormone in severe cases of atopic dermatitis].
AB  - 32 out of 83 in patients with atopic dermatitis showed a decrease of urine
      excretion during acute exacerbation and elevated levels of antidiuretic hormone
      (ADH 23 of 29 cases), renin (18 of 32 cases), angiotensin (22 of 29 cases) and
      aldosterone (16 of 37 cases). Six cases with high ADH showed severe pitting edema
      of lower legs with hypoalbuminemia. ADH, volume of urine and edema were improved
      when their skin symptoms subsided. There was no statistically significant
      relationship between the dose of steroid ointment and ADH. Also there was no
      correlation between low 17-OHCS or 17-KS and high ADH or renin.

PMID- 10331306
TI  - [Usefulness of hypoallergenic rice (AFT-R 1) and analysis of the salt insoluble
      rice allergen molecule].
AB  - An involvement of rice allergy in development and exacerbation of recalcitrant
      atopic dermatitis (AD) has been suggested in some cases, and it has been also
      known that elimination diet of rice results in improvement of AD and reduction of
      the doses of steroid ointment and anti-allergic drugs used for the treatment. We
      prepared the hypoallergenic rice grain, AFT-R 1 (Allergen-free Technology Lab.
      Inc.-Rice 1), with alkali treatment from the rice material, Koshihikari, which is
      popular in Japan. Its usefulness was evaluated clinically and serologically. The
      serological study with IgE-ELISA showed that the major allergic protein were
      remarkably reduced to less than 1/6400 of them in the AFT-R 1. Then it was
      applied to the clinical trial, and evaluated as useful by the clinical effect in
      14 (93%) out of 15 patients, who were diagnosed to have rice allergy by the
      elimination (in 15 case) and ingestion (in 12 cases) of the regular rice. The
      serum taken from the patient, whom the AFT-R 1 was evaluated as unuseful in the
      clinical trial, was shown to have IgE antibodies reactive to the remaining
      protein in AFT-R 1 by IgE-ELISA, and the 60 kd protein band was detected as an
      IgE-binding component of AFT-R 1 by IgE-immunoblotting with the same serum. This
      60 kd rice protein was identified as ADP (UDP)-glucose-starch glycosyl
      transferase (EC: 2.4.1.21) by N-terminal amino acid analysis. These results
      indicated that AFT-R 1 is very useful as a substitute of rice in many AD patients
      with rice allergy, although IgE-binding component such as the 60 kd protein is
      remaining in one.

PMID- 10331307
TI  - [A case of eosinophilic gastroenteritis complicated with ileus and ascites
      collection].
AB  - A 30-year-old woman was admitted to our hospital because of ileus and ascites.
      Laboratory data on admission demonstrated marked eosinophilia (42.5% of WBC) but
      negative CRP-value. Abdominal CT showed marked ascites and diffuse thickening of
      intestinal walls. Ascites examination revealed eosinophilic ascites. The level of
      IL-5 both in the serum and in the ascites were also high. No evidence of
      eosinophilic infiltration was noted both gastric and colonic mucosal biopsy
      specimens. Oral prednisolone treatment (50 mg/day) was effective for her. We
      diagnosed her as a case of sub-serosal type eosinophilic gastroenteritis. It is
      essential to obtain eosinophilic ascites for correct diagnosis of the disease.
      And it is possible that serum and ascites IL-5 value would be reliable indicator
      of the activity of this disease.

PMID- 10331308
TI  - [Effectiveness of hypoallergenic rice-by cast analysis].
AB  - Rice is the main food taken every day in Japan. We introduced hypoallergenic rice
      (95% of albumin and globulin were taken off by hyperpressure method) for 4 weeks
      to 7 atopic dermatitis patients (m 3, f 4), 11 mo-4 y 8 m (mean 3 y 2 m) who
      showed the RAST score of rice 1 or more. Stimulation Index by CAST (cellular
      antigen stimulation test) were compared before and after taking the rice (50-100
      g). By albumin (0.1-100 micrograms/ml), maximum decreases of S.I. were 22.4-96.5%
      (mean 70.9) and by globulin maximum decreases of S.I. were (0.1-100
      micrograms/ml) 33.3-97.0% (mean 72.9). In all the patients the skin conditions
      were improved.

PMID- 10331309
TI  - Reasons for living and the paradox of suicide in old age.

PMID- 10331310
TI  - Letters across the Pacific.

PMID- 10331311
TI  - Use of the DSM at hotlines.

PMID- 10331312
TI  - Suicidal ideation in Sudanese women.
AB  - A literature review indicated that suicidal behavior in Sudan was very
      infrequent. However, an assessment of suicidal ideation in two Sudanese groups of
      women demonstrated high levels, particularly in women in a displaced-persons
      area. In addition, the recent establishment of a Befrienders International
      volunteer service allowed anecdotal evidence of substantial suicidal behavior to
      be collated. These findings highlight the need for further professional and
      volunteer assistance with continuing evaluation and research concerning programs
      for this vulnerable population.

PMID- 10331313
TI  - Suicide mortality in Slovenia: regional variation.
AB  - Different medical, social, and environmental regional characteristics were
      investigated as possible predictors of suicide rates in 60 self-governing
      communes in Slovenia. The distribution pattern of regional suicide rates for
      Slovenia shows some similarity to that of the rest of Europe, especially in terms
      of the substantial variation of suicide density within the country. On the basis
      of the multivariate analysis, prevalence of alcohol psychosis, percentage of
      Catholics, and low duration of sunshine appeared to be the most important
      predictors of regional suicide rates in Slovenia. The rate of murders was proven
      to be a highly useful clue of suicide potential among younger groups, whereas
      income per capita of population was associated with suicide risk in old age. The
      principal component analysis provided three suicide risk patterns: a socio
      economic risk pattern (Catholic religion in poor community), a behavioral one
      (antisocial features, including heavy drinking), and a depression-related risk
      pattern with a climatic component (lack of sunshine). Different approaches are
      necessary for the different risk patterns listed above. Psychiatry, especially
      clinical psychiatry, can only deal with components of two of the patterns,
      namely, depression and antisocial behavior.

PMID- 10331314
TI  - Suicide in Belarus.
AB  - Suicide rates have risen in Belarus since 1990, and suicide rates are higher in
      rural than in urban areas. The regional distribution of suicide rates suggests a
      North-South variation that may be a result of ethnic and cultural differences
      between the regions.

PMID- 10331315
TI  - Suicide and attempted suicide in Pakistan.
AB  - Suicide and attempted suicide are understudied subjects in Pakistan, an Islamic
      country where they are considered criminal offenses. National suicide statistics
      are not compiled nor are suicide mortality statistics reported to the World
      Health Organization (WHO). Although there are strong religious sanctions against
      suicide, there are no clear principles against attempted suicide in Islam.
      Despite this, Pakistan, like many other Islamic countries, has punitive laws
      against attempted suicide. This has led to both suicide and attempted suicide
      being underdiagnosed and underreported. Data on suicide and attempted suicide are
      also difficult to obtain. This article gives an overview of the current state of
      suicide and attempted suicide in Pakistan, in the context of existing religious
      and legal factors, high-lighting the main findings of the few studies carried out
      over the last 50 years. It is important that researchers in Islamic countries
      like Pakistan not be deterred by the apparent low rates of suicide in these
      countries, but conduct further research in this important yet neglected public
      health problem.

PMID- 10331316
TI  - Modified crisis intervention for personality disorder.
AB  - This study proposes that the goal of crisis intervention for persons with
      personality disorders should be to return them to their pre-crisis level of
      functioning, even though this is maladaptive. This is contrasted with standard
      crisis intervention, which aims to return normal or neurotic persons to their pre
      crisis normal or neurotic functioning, usually by means of few and short-term
      therapeutic encounters. The modification proposed costs more time and resources
      in persons with personality disorders in crisis and fits the intervention to the
      personality type. This is illustrated by the case of Eve, a patient in crisis,
      whose pre-crisis functioning was maladaptive because of a dependent personality
      disorder. The goal of (modified) crisis intervention in this case was to return
      the patient to her dependent lifestyle, by means of pharmacotherapy combined with
      intensive supportive psychotherapy during 3-4 months of partial (day)
      hospitalization. The special nature of crisis in personality disorders is
      discussed.

PMID- 10331317
TI  - Using rational suicide as an intervention to prevent irrational suicide.
AB  - This paper sets forth the idea that using the concept of, and criteria for,
      rational suicide can be a clinically useful intervention even with people who may
      be irrational in their suicidality. Case examples are used to illustrate ways in
      which reviewing the criteria may help move a person away from an impulsive
      decision to suicide.

PMID- 10331318
TI  - Recession and well-being.
AB  - In this paper we address two related questions: how much do economic recessions
      affect the aggregate well-being of a population, and by what means? Using data
      from the 1973-77 Quality of Employment Panel of full-time workers who experienced
      the 1974-75 recession (N = 830), we answer these questions by using an analytic
      procedure that allows us to determine the percentage of total aggregate (mean)
      change in well-being attributable to various changes in sociodemographic
      statuses, labor market positions, and job characteristics. Results from this
      procedure showed significant increases in the mean levels of distress and
      dissatisfaction for this sample and that the largest percentages of change were
      accounted for by changes in job characteristics: about 20 percent of the total
      change in distress and 47 percent of the total change for dissatisfaction. In
      particular, increased job demands and increasingly inadequate pay made
      substantial contributions, with the latter alone accounting for a quarter of the
      total change in dissatisfaction. Unemployment experiences also contributed
      substantial, but smaller, percentages to the change in distress (10 percent).

PMID- 10331319
TI  - Gender and the socioeconomic gradient in mortality.
AB  - Despite considerable evidence documenting a strong and persistent relationship
      between socioeconomic position and mortality, recent research suggests that this
      association may be weaker among women. In our examination of gender differences
      in the socioeconomic gradient in mortality, we argue that this inconsistency
      arises from the failure to consider the ways in which gender is a fundamental
      constituent of socioeconomic position. The data used are from the Panel Study of
      Income Dynamics. Respondents, including all household heads and their partners,
      aged 29 years and older in 1972 (N = 5,665; 56% female), were followed until
      1991, death, or attrition. Discrete time event history analysis was used to
      examine the predictors of death between 1972 and 1991. Of the key socioeconomic
      predictors, years of education was measured at baseline, while earned income was
      a time-varying covariate. We find no gender differences in the effect of
      respondents' own socioeconomic positions on their mortality risk. However,
      increasing spousal income raises men's odds of dying, while the opposite is true
      for women. Our results raise questions about the prevailing view that the
      socioeconomic gradient in mortality is weaker among women. Moreover, gender
      differences in the effects of spousal earnings on mortality risk suggest that
      their labor market rewards have fundamentally different meanings for women and
      men.

PMID- 10331320
TI  - Gender, household labor, and psychological distress: the impact of the amount and
      division of housework.
AB  - Using a national longitudinal survey of a representative sample of 1,256 adults,
      I assess the impact of the amount of household labor performed and its division
      within the household on men's and women's depression levels, adjusting for prior
      mental health status. I test two alternative explanations of the contributions of
      household labor and the division of household labor to gender differences in
      depression: differential exposure and differential vulnerability. The results
      indicate that men's lower contributions to household labor explain part of the
      gender difference in depression. Inequity in the division of household labor has
      a greater impact on distress than does the amount of household labor. Employment
      status moderates the effect of the division of labor on depression. Among those
      who describe themselves as keeping house, depression was lowest for those who
      performed 79.8 percent of housework. In contrast, for those employed full-time
      the minimum level of depression occurs at 45.8 percent of the household labor.
      Men report performing 42.3 percent of the housework in their homes compared to
      68.1 percent reported by women. Thus, on average women are performing household
      labor beyond the point of maximum psychological benefit, whereas men are not.
      Social support mediates the effects of the division of household labor. The only
      gender difference in effects occurred among those who are married, for whom
      social support was associated with lower levels of depression for women than men.

PMID- 10331321
TI  - Homeless mothers and depression: misdirected policy.
AB  - This paper is a critique of recent service-intensive shelter programs for
      homeless mothers and the policies that underlie these shelters. We first document
      the process by which mental health problems and family homelessness became so
      closely but mistakenly linked. We then demonstrate empirically that shelter
      programs for homeless families nonetheless presume that mental health problems
      are part of the causal nexus of family homelessness and indiscriminately deliver
      mental health services to homeless mothers. Simultaneously, shelter programs
      encourage the isolation of their residents from what they presume to be their
      "problematic" social networks. We show that, while mental health services had
      little impact on depression levels among homeless mothers, isolation from social
      networks did increase depression among homeless mothers. Our findings suggest
      that policy should put more emphasis on rapid reintegration into the community
      through providing housing, and it should put less emphasis on providing services.

PMID- 10331322
TI  - Social network characteristics associated with risky behaviors among runaway and
      homeless youth.
AB  - Runaway and homeless youth are at high risk for substance abuse and unsafe sexual
      behavior. Our study describes the personal social networks of these youth and
      examines network characteristics associated with risky behaviors. In 1995 and
      1996, we interviewed a purposive sample of youth aged 14 through 21 who were
      living in Washington, DC and were identified on the streets or through shelters
      or other service agencies (N = 327). Although we found that most youth reported
      current social relationships, a significant minority (26%) did not. Youth without
      a social network were significantly more likely to report current illicit drug
      use, multiple sex partners, and survival sex than youth with a network. For youth
      with a network, the networks were small, strong in affective and supportive
      qualities, comprised primarily of friends, typically included an alcohol or
      illicit drug user, and usually were not a source of pressure for risky behaviors.
      Our results indicate that networks had risk-enhancing and risk-decreasing
      properties in that network characteristics were associated in both positive and
      negative directions with risky behaviors.

PMID- 10331323
TI  - Psychiatric emergencies: the check effect revisited.
AB  - Federal income support to persons with alcohol and drug related disabilities was
      ended in 1997. The argument for ending the programs was that recipients were
      using their benefits to purchase drugs and alcohol. This supposedly led to the
      "check effect," an increase in psychiatric emergencies in American communities in
      the days following the receipt of disability benefits. We test two hypotheses
      implied by this argument. The first is that psychiatric emergencies are elevated
      in the fourth through eighth day of the month. The second is that the excess of
      emergencies in these days was significantly reduced when benefits were ended. The
      tests are based on 35,500 psychiatric emergencies in San Francisco, California
      occurring over 1,551 days. Results support the first hypothesis but not the
      second. The implications are that there is a general check effect and that it was
      not reduced by ending benefits to persons with drug and alcohol related
      disabilities.

PMID- 10331324
TI  - The influence of managed care on supply of certified nurse-midwives: an
      evaluation of the physician dominance thesis.
AB  - A key debate over the nature of professional power centers on the maintenance of
      physician dominance within the system of professions in health care. The changes
      in health care delivery and financing brought by managed care present a new
      context for evaluating the physician dominance thesis. I propose that increases
      in the supply of certified nurse-midwives, a "contending" health care
      professional group, are related to the expansion of managed care and may signal a
      decline in physician dominance. I analyze state-level data compiled from
      governmental, health professional, and industry sources to determine the
      influence of managed care market penetration, physician supply, state policy
      context, and demographic factors on the state-level supply of nurse-midwives.
      Results indicate that, despite high physician supply, nurse-midwife supply is
      higher in states with higher managed care penetration, as well as in those with
      more favorable state policy environments and a more educated demographic base.
      Outcomes from a series of hypothesis tests support my assertion that the
      expansion of managed care is altering the jurisdictional boundaries in the system
      of professions in health care, eroding the dominance of physicians while creating
      new openings for nurse-midwives.

PMID- 10331325
TI  - The role of the pediatric nurse practitioner in the comprehensive management of
      pediatric oncology patients in the inpatient setting.
AB  - The role of the pediatric nurse practitioner (PNP) in the comprehensive
      management of pediatric oncology patients in the inpatient setting was examined
      at a large tertiary teaching hospital. This article shows role responsibilities
      including new diagnosis teaching, procedures, routine chemotherapy, patients'
      comprehensive medical management, coordination of nursing care across settings,
      phone triage, and professional development. A PNP's typical day is highlighted to
      illustrate the innovative merging of traditional ambulatory care roles with that
      of the PNP as a comprehensive manager of pediatric oncology patients in the
      inpatient setting. This role provides a more seamless care experience and
      provides critical links in the delivery of health care to pediatric oncology
      patients.

PMID- 10331326
TI  - A program of acquired immune deficiency syndrome education for nurses in Romania.
AB  - After the fall of the communist government in Romania, many children were found
      to be human immunodeficiency virus (HIV) infected. The majority of these children
      were abandoned and currently live in orphanages. The children have been cared for
      on a day-to-day basis by nurses with little general nursing education and even
      less HIV education. The Romanian-American Pediatric AIDS Education and Clinical
      Research Program was established at Texas Children's Hospital and Baylor College
      of Medicine in May, 1996 to aid in the education of Romanian nurses. Syllabi
      developed by the U.S. nursing team were initially piloted in three pediatric HIV
      centers in Romania in July, 1997. Since that time, two annual nursing symposia
      have been held offering topics on general pediatrics and HIV-related content. The
      purpose of this article is to describe a program of HIV education for nurses in
      Romania.

PMID- 10331327
TI  - Palatability and cost comparison of five liquid corticosteroid formulations.
AB  - Difficulty administering oral corticosteroids to young children who are required
      to take these medications as part of their cancer treatment has been a concern
      among health care providers for many years. This problem is due in part to the
      bad taste associated with these preparations. Palatability is important to
      consider when prescribing a liquid corticosteroid. Seven members of a nursing
      research group in an academic pediatric setting evaluated palatability based on
      taste, aftertaste, texture, smell, and overall reaction to five different liquid
      corticosteroid formulations. These formulations included Pediapred (Medeva
      Pharmaceuticals, Rochester, NY), Prelone (Muro Pharmaceuticals, Tewksbury, MA),
      prednisone oral solution, prednisone intensol, and prednisone 10-mg tablet
      crushed in 10 mL of cherry syrup. The cost of each formulation was based on the
      cost to the participating institution. The results showed that the most palatable
      corticosteroid liquid formulation was also the most cost efficient. The results
      of this simple study have the potential to influence prescribing habits and
      provide caregivers with a palatable, cost-efficient corticosteroid liquid
      formulation.

PMID- 10331328
TI  - A review of the literature on resilience in the adolescent with cancer: Part II.
AB  - Adolescents with cancer experience multiple stressors that may stem from both the
      illness and from normal developmental tasks. Some adolescents remain or become
      resilient even when faced with multiple challenges. An understanding of what
      contributes to resilience in the adolescent cancer experience is important in
      caring for adolescents with cancer and childhood cancer survivors. The purpose of
      this article is to provide a synthesis of the literature related to resilience in
      the adolescent cancer experience. Research recommendations based on theoretical
      and methodological limitations noted in the review are presented.

PMID- 10331329
TI  - Y2K and the computer vestige.

PMID- 10331330
TI  - The preoperative period summary.

PMID- 10331331
TI  - The operation summary.

PMID- 10331332
TI  - The postoperative period summary.

PMID- 10331333
TI  - Special topics summary.

PMID- 10331334
TI  - Preoperative cardiac risk assessment.
AB  - Preoperative cardiac evaluation is aimed at evaluating the patient's current
      medical status, making recommendations concerning the risk of cardiac problems in
      the perioperative period, and providing a clinical risk profile that the patient,
      primary physician, consultants, anesthesiologist, and surgeon can use in making
      treatment decisions. Patients can be stratified on clinical grounds into low-,
      medium-, and high-risk categories. Use of these categories, along with
      consideration of the type and urgency of noncardiac surgery, allows for a
      reasonable approach to preoperative testing. In general, indications for cardiac
      testing and treatment are similar to the nonoperative setting, but their choice
      and timing is dependent on factors specific to the patient, the type of surgery,
      and the clinical situation. Use of invasive and noninvasive testing should be
      limited to situations in which the results of the tests will clearly affect
      patient management. Further research is necessary to define the most appropriate
      role of such testing, both in terms of efficacy and of cost-effectiveness.
      Cardiac intervention is rarely necessary to lower the risk of surgery, but
      noncardiac surgery often represents the first opportunity for a patient to
      receive an appropriate assessment of short- and long-term cardiac risk, and this
      should be taken into consideration in planning perioperative evaluation.

PMID- 10331335
TI  - Preoperative assessment of pulmonary risk.
AB  - STUDY OBJECTIVES: A summary of current modalities for and the utility of
      preoperative assessment of pulmonary risk. DESIGN: Review of recent literature
      published in the English language. SETTING: Not applicable. PATIENTS OR
      PARTICIPANTS: Patients who undergo elective cardiothoracic or abdominal
      operations. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS:
      Postoperative pulmonary complications occur after 25 to 50% of major surgical
      procedures. The accuracy of the preoperative assessment of the risk of such
      complications is only fair. The routine assessment for all preoperative patients
      includes age, general physiologic status, and the nature of the planned
      operation. Specific tests such as measurement of spirometric values and diffusing
      capacity are indicated routinely only for patients who are candidates for major
      lung resection or esophagectomy. CONCLUSIONS: Pulmonary complications are an
      important form of postoperative morbidity after major cardiothoracic and
      abdominal operations. The appropriate preoperative assessment of the risk of such
      complications is well defined for lung resection and esophagectomy operations,
      but it requires refinement for general surgical and cardiovascular operations.

PMID- 10331336
TI  - Preoperative issues in clinical nutrition.
AB  - Allowing a patient's nutritional state to deteriorate through the perioperative
      period adversely affects measureable outcome related to nosocomial infection,
      multiple organ dysfunction, wound healing, and functional recovery. Careful
      preoperative nutritional assessment should include a determination of the level
      of stress, an evaluation of the status of the GI tract, and the development of
      specific plans for securing enteral access. Patients already demonstrating
      compromise of nutritional status (defined by > 10% weight loss and serum albumin
      level < 2.5 g/dL) should be considered for a minimum of 7 to 10 days of
      nutritional repletion prior to surgery. Widespread use of total parenteral
      nutrition in unselected patients is unwarranted, may actually worsen outcome, and
      should be reserved for preoperative nutritional support only in severely
      malnourished patients in whom the GI tract is unavailable. Compared with the
      parenteral route, use of perioperative enteral feeding has been shown to provide
      more consistent and beneficial results, and can be expected to promote specific
      advantages in long-term morbidity and mortality.

PMID- 10331337
TI  - Variables affecting outcome in critically ill patients.
AB  - Critical care medicine has evolved as a field of science and clinical care.
      Despite important contributions to our understanding of the molecular basis of
      critical illness, we still remain troubled by our lack of insight into why some
      patients have favorable outcomes from critical illness and others do not. This
      article explores the hypothesis that at least five important variables may alter
      the outcome of patients suffering from a variety of critical illnesses. These
      variables include the premorbid immune or genetic status of the patient, the
      patient's gender, the circulating cholesterol concentration, the patient's age,
      and various iatrogenic and nosocomial events. Insights into the importance of
      these five variables may provide opportunities for physicians and scientists to
      improve outcome in patients suffering from critical illness. Clearly, altering
      iatrogenic and nosocomial events is already within the realm of opportunity.

PMID- 10331338
TI  - Assessing and modifying the risk of postoperative pulmonary complications.
AB  - Preoperative pulmonary evaluation and preparation involve first identifying
      patients at risk for complications and then attempting to modify that risk. For
      most patients without underlying lung disease, a thorough history and physical
      examination and preoperative instruction in the use of incentive spirometry is
      sufficient. In patients with known or suspected lung disease, preoperative
      pulmonary function tests, while unproven as prognostic tools, may reduce risk by
      aiding in medical management, and in the case of the lung resection candidate, by
      helping determine very directly his or her viability for the procedure.

PMID- 10331339
TI  - Preoperative cardiac preparation.
AB  - Preoperative preparation of the cardiac patient is based on matching the cardiac
      reserve to the blood flow demands imposed by surgical stress and the underlying
      disease state. Evaluation must include functional assessment of any coronary
      artery disease or other organic cardiac disease that may place myocardial tissue
      at risk of ischemia as demand for cardiac output increases. Monitoring should be
      individualized based on anticipated problems and the risk assessment of the
      patient. Preoperative therapy should include maneuvers that reduce congestive
      heart failure, optimize volume status, and provide adequate cardiac output to
      deliver oxygen sufficient to meet or exceed demand. Underlying electrical and
      metabolic abnormalities should be corrected and controlled in the perioperative
      period. Long-term therapy should be evaluated and modified in the context of the
      anesthetic and surgical plan. Preventive interventions such as fluid loading and
      low-dose dopamine should be considered prior to surgery.

PMID- 10331340
TI  - Cost-effective preoperative evaluation and testing.
AB  - Cost-effective preoperative evaluation can be approached from a variety of
      methods, educational strategies, and use of data to modify clinical practice.
      This article focuses on the proposed organizational and clinical changes in the
      process of preoperative evaluations, the cost-effective outcomes, and the
      relative merits these changes provide the physicians, operating room nurses, and
      center administrators.

PMID- 10331341
TI  - What intraoperative monitoring makes sense?
AB  - The routine practice of monitoring oxygenation, ventilation, circulation, and
      temperature during surgery is now the standard of care. However, with the
      possible exception of pulse oximetry and capnography, extensive physiologic
      monitoring has not been shown to reduce the incidence of adverse anesthetic
      related events. Monitors are useful adjuncts, but they alone cannot replace
      careful observation by a vigilant anesthesiologist.

PMID- 10331342
TI  - Intraoperative fluid management--what and how much?
AB  - An approach to intraoperative fluid management based on a monitored physiologic
      application of the Starling principles of cardiac function is recommended to
      individualize therapy to optimize hemodynamic function and tissue perfusion. The
      complexity of intraoperative fluid administration, beginning with preoperative
      cardiovascular function followed by innumerable intraoperative considerations,
      including anesthetic pharmacology, positive pressure ventilation, operative site,
      and surgical technique may lead to serious intraoperative and postoperative
      complications. Emphasis must be given to intraoperative fluid shifts resulting in
      hidden fluid loss and intravascular hypovolemia that must be replaced.
      Explanations for this fluid redistribution have included tissue trauma,
      endotoxemia, and proinflammatory cytokines with resultant increased capillary
      permeability.

PMID- 10331343
TI  - Perioperative blood transfusions: indications and options.
AB  - A reevaluation of the indications for and alternatives to transfusion of
      allogeneic blood was precipitated by transfusion-induced HIV. The transfusion
      trigger has shifted from an optimal hemoglobin level and hematocrit (10/30) to
      that level of hemoglobin necessary to meet the patient's tissue oxygen demands.
      This critical level can best be determined by physiologic measurements. A number
      of autologous blood options can reduce the patient's allogeneic blood needs.
      Pharmacologic measures to increase hemoglobin levels (erythropoietin) and to
      decrease blood loss at surgery are discussed as are the potential contributions
      of blood substitutes to transfusion support of the surgical patient.

PMID- 10331344
TI  - Choices in pain management following thoracotomy.
AB  - Effective analgesia and blockade of the perioperative stress response may improve
      outcome and accelerate recovery following thoracic surgery. Although different
      approaches can achieve the same goal, it seems that a multimodal pain management
      based on the use of synergistic drugs provides better analgesia. The route of
      administration of the postoperative analgesic drugs is important, and epidural
      analgesia plays a role in the reduction of pulmonary complications.

PMID- 10331345
TI  - Who goes to the ICU postoperatively?
AB  - OBJECTIVE: To describe changes in ICU postoperative management strategies
      utilized for patients undergoing cardiac surgery. The treatment of these patients
      serves as a useful illustration of the changing patterns of ICU utilization and
      care associated with contemporary surgery. DESIGN: Evidence-based review of the
      clinical literature following a MEDLINE search, direct observation of rapid
      recovery programs following surgery, and informal inquiry of others utilizing
      similar approaches to postoperative cardiac surgery care. SETTING AND PATIENTS:
      The reports reviewed are from a diverse set of hospitals providing cardiac
      surgery services in both Europe and the United States. Most reports focus efforts
      on patients undergoing coronary artery revascularization. MEASUREMENTS: Outcome
      measures used to gauge the effectiveness of postoperative ICU care typically
      include time to extubation, ICU and hospital length of stay, postoperative
      complications including reintubation and ICU readmission, patient satisfaction,
      and health resource savings. MAIN RESULTS: The literature regarding current
      practice for postoperative ICU management in cardiac surgery consists primarily
      of grade 2 and 3 literature. CONCLUSIONS: Despite the paucity of controlled data,
      rapid recovery, extubation, and discharge from the ICU following cardiac surgery
      is an approach to care that is growing in acceptance. The goals include reduction
      in the utilization of resources and costs associated with cardiac surgery and
      maintenance of quality of care and patient satisfaction. Assessment of outcomes
      requires a program to monitor outcomes. Success does not appear to be linked to
      preoperative risk for most patients but does relate directly to the anesthetic
      management delivered in the operating room. Few adverse consequences from this
      approach have been reported. Experience to date suggests that programs designed
      to truncate ICU admission following cardiac surgery can be implemented with the
      cooperation between the health delivery team including surgeon, anesthesiologist,
      intensivist where available, nursing, respiratory care, and patient and family.
      These programs can serve as useful models for reassessing the utilization and
      role of the ICU in the postoperative treatment of routine surgical patients.

PMID- 10331346
TI  - Postoperative ventilatory management.
AB  - Immediate postoperative evaluation of the patient remains a crucial role of the
      intensivist. Postoperative patients can be divided into the otherwise healthy,
      chronically ill, and acutely ill for strategizing about care. For chronically ill
      and acutely ill patients who require ongoing ventilation, ventilator management
      continues to evolve toward modes that are more interactive with patient needs.
      Newer modes of ventilation are also being explored to protect the lung against
      damage attributable to mechanical ventilation. Weaning indexes and associated
      protocols have become more sophisticated and now allow physicians greater
      certainty in evaluating patients' readiness for extubation. This article will
      discuss factors to be considered prior to extubation as well as the latest
      ventilatory and weaning strategies.

PMID- 10331347
TI  - Cardiac management in the ICU.
AB  - Coronary artery disease (CAD) is common in the surgical population, with up to
      50% of postoperative deaths due to cardiac events. Most of these events are
      ischemic, with some being exacerbations of underlying congestive heart failure
      (CHF). Recent data indicate that acute perioperative beta-adrenergic blockade can
      reduce ischemia and ischemic events. Postoperative monitoring should focus on
      myocardial ischemia, with preparation for rapid treatment using IV therapy. A few
      studies suggest that elderly patients with known CAD undergoing major procedures
      might benefit from perioperative treatment guided by information from a pulmonary
      artery catheter. Postoperative CHF, which is likely to present early after
      surgery, may need aggressive management with diuretics, vasodilators, and
      inotropic drugs. Mechanical ventilation should be considered. When the patient
      develops severe or refractory dysrhythmias, serum magnesium levels should be
      supplemented and consideration given to IV use of amiodarone. Postoperative
      hypertension is common and can precipitate ischemia, CHF, and arrhythmias as well
      as cause bleeding. Newer IV drugs are arterial specific and can lower BP in a
      smooth and predictable manner. All acute cardiac disorders can be precipitated or
      exacerbated by inadequate pain control, hypoxemia, and fluid or electrolyte
      disorders.

PMID- 10331348
TI  - Nutrition management in the ICU.
AB  - Nutrition support plays an important role in the management of nutritional
      deficiencies in properly selected critically ill patients. A full nutritional
      assessment allows the calculation of appropriate feeding goals. The route of
      feeding, enteral or parenteral, is determined by the presence or absence of a
      functioning intestine and hemodynamic status of the patient. The specific roles
      of carbohydrates, fats, and protein need to be considered in order to prevent
      overfeeding and other complications. The efficacy of certain disease-specific
      enteral formulas has been demonstrated in clinical trials, however, careful cost
      benefit analyses are required.

PMID- 10331349
TI  - Selective review of key perioperative renal-electrolyte disturbances in chronic
      renal failure patients.
AB  - The medical care of chronic renal failure patients is often complicated by the
      comorbid conditions of hypertension and coronary artery disease in the
      perioperative period. The limitations on solute and water excretion imposed by
      renal dysfunction increase the susceptibility of this population to both salt
      deficit and surfeit, as well as hyponatremia and hypernatremia perioperatively.
      Accurate assessment and successful treatment of these complications in renal
      failure patients require understanding of the concept of electrolyte-free water,
      proper utilization of diuretics, and calculated prescription of fluid therapy.
      The presence of hyperkalemia in the adapted renal failure patient generally
      indicates a severe reduction in glomerular filtration, such that nonrenal
      hypokalemic treatments are imperative. IV calcium-based therapy and infusion of
      insulin with glucose represent the mainstays of immediate therapy, and sodium
      bicarbonate therapy should be given only when severe acidemia is present.
      Perioperative aggravation of preexistent hypertension is common. Rebound
      hypertension attributable to injudicious adjustment of the medical regimen should
      be diligently searched for first, before any new therapies are recommended.
      Relief of pain or anxiety may be all that is necessary. Briefly acting calcium
      channel blocker therapy should not be employed in these cases, and smooth IV
      control by a variety of agents is preferable, the choice of the agent contingent
      on the clinical scenario.

PMID- 10331350
TI  - Special problems in the elderly.
AB  - With aging, the heart, kidneys, liver, lungs, and brain lose mass. While not
      inherently impaired, the reserve capacity of the older individual to compensate
      for stress, metabolic derangement, and drug metabolism is increasingly limited.
      Functional disability occurs faster and takes longer to remediate, necessitating
      early preventive interventions.

PMID- 10331351
TI  - Perioperative management of the patient with cancer.
AB  - There are a number of conditions that present commonly in patients with cancer
      that may have a significant effect on the preoperative, intraoperative, and
      postoperative treatment of these patients. These effects can be broadly
      categorized into anatomic and physiologic effects and may be examined as direct
      effects of the tumor or as effects of therapy administered for the tumors. Tumors
      that cause anatomic effects of importance to perioperative management include
      head and neck tumors with airway obstruction, mediastinal masses with respiratory
      compromise, pericardial effusion and cardiac tamponade, and superior vena cava
      syndrome. Some tumors that cause physiologic effects include pheochromocytomas
      and carcinoid tumors. Anatomic effects of tumor therapy are important after
      radiation therapy to the head and neck and after radiation therapy to the
      abdomen. Tumor therapy has important physiologic effects in such areas as the
      cardiopulmonary complications of chemotherapy, hematologic effects of
      chemotherapy, steroid administration, and wound healing. While the list of topics
      is not exhaustive, this is a useful framework for discussing the effects of
      tumors and their therapy on the cancer patient, especially in regard to
      perioperative management. Most importantly, these examples demonstrate the
      importance of close cooperation among surgeon, anesthesiologist, and referring
      physician to assure the conduct of surgical procedures on the patient with cancer
      with maximal safety.

PMID- 10331352
TI  - Are multifocal motor neuropathy and Lewis-Sumner syndrome distinct nosologic
      entities?

PMID- 10331353
TI  - Multifocal acquired demyelinating sensory and motor neuropathy: the Lewis-Sumner
      syndrome.
AB  - We report 11 patients with multifocal acquired demyelinating sensory and motor
      (MADSAM) neuropathy, defined clinically by a multifocal pattern of motor and
      sensory loss, with nerve conduction studies showing conduction block and other
      features of demyelination. The clinical, laboratory, and histological features of
      these patients were contrasted with those of 16 patients with multifocal motor
      neuropathy (MMN). Eighty-two percent of MADSAM neuropathy patients had elevated
      protein concentrations in the cerebrospinal fluid, compared with 9% of the MMN
      patients (P < 0.001). No MADSAM neuropathy patient had elevated anti-GM1 antibody
      titers, compared with 56% of MMN patients (P < 0.01). In contrast to the subtle
      abnormalities described for MMN, MADSAM neuropathy patients had prominent
      demyelination on sensory nerve biopsies. Response to intravenous immunoglobulin
      treatment was similar in both groups (P = 1.0). Multifocal motor neuropathy
      patients typically do not respond to prednisone, but 3 of 6 MADSAM neuropathy
      patients improved with prednisone. MADSAM neuropathy more closely resembles
      chronic inflammatory demyelinating polyneuropathy and probably represents an
      asymmetrical variant. Given their different clinical patterns and responses to
      treatment, it is important to distinguish between MADSAM neuropathy and MMN.

PMID- 10331354
TI  - Order effects in response times of parkinsonian patients and normal controls.
AB  - Response latencies were measured in 6 parkinsonian patients and 6 normal subjects
      in a choice reaction task requiring the discrimination of two different tones
      with different probabilities of occurrence (frequent and rare). Response latency
      was measured from stimulus onset to onset of electromyographic activity in the
      responding muscle. Rare-tone responses were separated on the basis of the number
      of frequent tones intervening between the rare tone of interest and the
      immediately preceding rare tone (defined as rare-tone position). Frequent-tone
      responses were separated by the number of consecutive frequent tones occurring
      either before or after a rare tone (defined as frequent-tone position). Rare- and
      frequent-tone position had a significant impact on response latency. Both
      patients and controls had the shortest response latencies to rare tones when four
      frequent tones (the median interval for these experiments) intervened. Similarly,
      the response latency to frequent tones increased at approximately this same
      median interval after a rare event for both patients and controls. These findings
      suggest that normal controls utilize probability information about both global
      probabilities and their immediate past experience in order to modify upcoming
      responses. Our findings also indicate that patients with Parkinson's disease do
      not differ from normal subjects in this regard, and thus that even subtle
      attributes of preprogramming are not affected in Parkinson's disease, despite
      suggestions by others to the contrary.

PMID- 10331355
TI  - The median nerve terminal latency index in carpal tunnel syndrome: a clinical
      case selection study.
AB  - The terminal latency index (TLI) adjusts the distal motor latency (DL) for the
      terminal distance and the proximal nerve conduction velocity. We prospectively
      studied 66 patients in order to assess the sensitivity of the median nerve TLI
      for the diagnosis of carpal tunnel syndrome (CTS). Clinical and
      electrophysiological evaluations were completed by separate, blinded examiners.
      Based on the clinical diagnosis, 54 patients were judged to have CTS (CTS group)
      and 12 were believed not to have CTS. Control data were obtained from 38 healthy
      hands. The mean TLI was 0.26 +/- 0.04 in the CTS group and 0.43 +/- 0.04 in the
      control group (P < 0.001). The sensitivity of the TLI was 81.5%. The TLI was
      statistically better than the median motor DL and sensory peak latency (PL) to
      the second digit. The TLI was always abnormal when the median mixed-nerve palmar
      latency was abnormal. In three cases from the CTS group, the TLI was the only
      abnormal electrophysiological parameter. The median TLI is a useful, sensitive
      electrodiagnostic parameter for CTS.

PMID- 10331356
TI  - Comparison of the muscle fiber diameter and satellite cell frequency in human
      muscle biopsies.
AB  - Satellite cells are responsible for the formation of postnatal muscle fibers. The
      number, mitotic activity, and differentiation potential of satellite cells and
      the muscle fiber diameter are tightly regulated events in normal muscle. The
      signal that induces satellite cells to stop proliferation once the determined
      muscle fiber size has been reached in normal growth is not known. The aim of the
      present study was to determine whether a correlation exists between satellite
      cell frequency and muscle fiber diameter in human muscle disease. Muscle biopsies
      from 7 cases of Duchenne muscular dystrophy (DMD), 8 other muscular dystrophies,
      23 cases of inflammatory myopathy, and 22 cases of neurogenic atrophy were
      examined. The satellite cell number was elevated in DMD and neurogenic atrophy
      but not in other muscular dystrophies or inflammatory myopathies. Nevertheless,
      in all the diseased muscles, but not in normal controls, there was a
      significantly higher relative frequency of satellite cells with increasing fiber
      diameter. It has been shown before that satellite cells show ultrastructural and
      autoradiographic signs of activation and proliferation in myopathic and
      neurogenic conditions. We assume that we are dealing with activated, not
      quiescent, satellite cells in diseased muscle and that under these conditions the
      fiber diameter does not represent a stop signal for satellite cells to
      proliferate. The data suggest that not only the number of satellite cells matters
      in diseased muscle, as has been shown before, but that it is their behavior that
      influences, at least in part, progress and severity of muscle diseases.

PMID- 10331357
TI  - The diagnostic power of motor unit potential analysis: an objective bayesian
      approach.
AB  - The notion of a "myopathic" or "neuropathic" electromyogram (EMG) is usually
      based on qualitative visual and acoustical impressions. Conventional
      quantification defines abnormality but not diagnosis, which requires
      interpretation of patterns of change. Discriminant analysis is a model for this
      multivariate decision. It tells how probable it is that a motor unit potential
      (MUP) comes from a normal, myopathic, or neuropathic muscle. Accumulation of
      single MUP information by a sequential Bayesian algorithm produced diagnostic
      probabilities above 0.95 in 91% of all muscles (223 biceps brachii muscles from
      80 patients with motoneuron disorders, 56 patients with neuropathies, 71 patients
      with myopathies, and 34 controls). Two muscles from patients with neurogenic
      disorders were misclassified as "myopathic." Misclassification was more frequent
      only in myositis (4 of 28 muscles) and in oculopharyngeal muscular dystrophy (2
      of 4 muscles). MUP discriminant classification was as sensitive as, and more
      specific than, conventional quantitative EMG, which discriminated between
      myopathic and neuropathic in only 22% of the muscles. This rate was 59% for
      discriminant analysis. As a knowledge-based expert system, MUP discriminant
      analysis successfully distinguishes between myopathic, neuropathic, and
      unclassifiable MUP samples. It discloses more information than conventional
      quantitative MUP analysis.

PMID- 10331358
TI  - Effective adenovirus-mediated gene expression in adult murine skeletal muscle.
AB  - We established an efficient method for obtaining expression of a foreign marker
      gene transferred in vitro into myoblasts and in vivo into adult mouse skeletal
      muscles using adenovirus vector. After infection of the C2 myoblasts with the
      adenovirus vector containing the beta-actin promoter with cytomegalovirus (CMV)
      enhancer (CAG promoter) AxCALacZ, significantly greater number of cells express
      beta-galactosidase when compared with the adenovirus vector expressing the lacZ
      gene under the control of the SR alpha viral terminal repeat promoter (AxSRLacZL)
      or the myosin heavy chain (MHC) IIB promoter (AxMHCLacZ). We also injected
      AxCALacZ into the skeletal muscles of 5- to 6-week-old C57BL/10 mice and
      determined that more than 60% of their muscle fibers expressed the lacZ gene 7
      days after injection. The CAG promoter may have application in the development of
      gene therapy for Duchenne muscular dystrophy (DMD) using adenovirus vector.

PMID- 10331359
TI  - Denervation and reinnervation in congenital brachial palsy.
AB  - Motor unit number estimation (MUNE) was shown to be useful in assessing the
      neurophysiological status of 18 subjects with congenital brachial palsy. This was
      especially so since conventional M-wave measurements may give misleading
      impressions as to the extent of motor axon regeneration. In most subjects the
      involvement of sensory nerve fibers indicated that the traumatic lesions included
      postganglionic segments of the fibers, with or without preganglionic damage. In a
      minority the lesions were purely preganglionic. Digital sensory nerve involvement
      was more in a mediolateral direction, consistent with greater damage to the
      uppermost elements in the brachial plexus. In 5 individuals, MUNE and sensory
      testing showed that there had been trauma to the supposedly unaffected arm.
      Discrepancies between sensory and motor results suggested that reinnervation of
      the biceps brachii muscle was greater than that of the intrinsic muscles of the
      hand. In one subject examined serially, reinnervation of the hand muscles was
      detected by 10 months and continued in the hypothenar muscles for the next 6
      years.

PMID- 10331360
TI  - Polyradiculopathy in sarcoidosis.
AB  - We present three new and 14 retrospective cases of polyradiculopathy in
      sarcoidosis. Of these, 71% had weakness and 59% areflexia of the lower
      extremities, and 35% had sphincter dysfunction. Cases often were associated with
      central nervous system sarcoidosis. All cases involved thoracolumbar or
      lumbosacral roots, except a single case of cervical polyradiculopathy. Of 14
      treated patients, nine improved with corticosteroids, laminectomy, or both.
      Polyradiculopathy complicating sarcoidosis: (1) is uncommon; (2) primarily
      involves thoracic and lumbar roots; (3) may arise from contiguous, hematogenous,
      or gravitational nerve root sleeve seeding; (4) may be asymptomatic; and (5) may
      improve with corticosteroids. Differential diagnosis of weakness in patients with
      sarcoidosis should include nerve root involvement from the primary process by
      direct sarcoid involvement.

PMID- 10331361
TI  - Reflex excitability of facial motoneurons at onset of muscle reinnervation after
      facial nerve palsy.
AB  - We studied 18 patients with complete unilateral denervation of the facial muscles
      after idiopathic facial nerve palsy to determine whether motoneuronal
      excitability is enhanced in the few motor units that are active at onset of
      muscle reinnervation. The study was carried out between 75 and 90 days after the
      facial nerve lesion. We used two needle electrodes to record simultaneously the
      spontaneous and voluntary activity of the orbicularis oris (OOris) and
      orbicularis oculi (OOculi) muscles, as well as the responses to ipsilateral and
      contralateral facial and supraorbital nerve stimuli. All patients showed
      involuntary firing of motor unit action potentials (MUAPs) in at least one of the
      muscles. Synkinetic activation of motor units in the OOris was induced by
      spontaneous blinking in all patients, and by inhalation and swallowing in some.
      Electrical stimulation of the ipsilateral facial nerve induced a direct M
      response in only 4 patients. In contrast, long-latency reflex responses were
      induced in both muscles by electrical stimulation of ipsilateral and
      contralateral facial and supraorbital nerves in all patients, at latencies
      ranging between 44 and 132 ms. The shape of such MUAP reflex responses was the
      same as that of the MUAPs seen to fire at rest. These findings provide evidence
      of enhanced excitability of facial motoneurons in our patients. Such
      hyperexcitability may be partly responsible for the postparalytic motor
      dysfunction syndrome that occurs after facial palsy with severe axonal damage.

PMID- 10331362
TI  - In vivo determination of altered hemoglobin saturation in dogs with M-type
      phosphofructokinase deficiency.
AB  - Muscle-type phosphofructokinase (M-PFK) deficiency causes an exertional myopathy
      and chronic hemolysis in affected humans and dogs, the only animal model
      available. Deficient individuals have impaired glycolytic metabolism, impaired
      oxidative metabolism, and increased hemoglobin-oxygen (HbO2) affinity as a result
      of low 2,3-diphosphoglycerate (2,3-DPG) levels. The purpose of this study was to
      determine if PFK-deficient muscle has abnormal oxygen saturation during exercise.
      Oxygen saturation of hemoglobin/myoglobin was measured noninvasively in skeletal
      muscle during progressive muscle activation using near-infrared spectroscopy
      (NIRS). Muscle metabolites were also measured using magnetic resonance
      spectroscopy (MRS). PFK-deficient and normal dogs were anesthetized and the
      cranial tibial muscles stimulated for 6 min at each of four different rates (1,
      2, 4, and 8 Hz). With increasing stimulation, muscles from normal dogs showed
      progressive decrease in hemoglobin saturation. In contrast, PFK-deficient dogs
      exhibited either an increase in hemoglobin saturation or an initial decrease with
      no further change. PFK-deficient muscles accumulated 11.1 +/- 3.5 mmol/L of sugar
      phosphate which was not seen in normal muscle and had higher calculated [ADP]
      levels at each stimulation level, indicating impaired oxidative metabolism. These
      findings are consistent with the hypothesis that these animals have impaired
      oxidative metabolism and impaired muscle O2 extraction from hemoglobin due to
      increased HbO2 affinity. NIRS appears to be a useful noninvasive method of
      monitoring tissue oxygen saturation in normal or disease conditions.

PMID- 10331363
TI  - Motor and somatosensory evoked potentials in asymptomatic spondylotic cord
      compression.
AB  - To assess whether electrophysiological tests are of use in differentiating
      between patients with asymptomatic cervical stenosis and patients with clinical
      evidence of myelopathy, we studied motor evoked potentials (MEPs) to magnetic
      brain stimulation and somatosensory evoked potentials (SEPs) in patients with
      asymptomatic cervical cord compression and compared the results to healthy age
      matched controls. The MEPs were normal in 23 of 25 patients and SEPs in 22 of 23
      patients. Thus, MEPs and SEPs are normal in most cases of asymptomatic cervical
      stenosis. As previous studies have shown MEPs, and to a lesser extent SEPs, to be
      sensitive in the detection of spondylotic myelopathy, our data indicate that MEP
      and SEP may be clinically useful for differentiating patients with cervical
      stenosis who have myelopathy from those who have not.

PMID- 10331364
TI  - Assessing muscle stiffness from quiet stance in Parkinson's disease.
AB  - In previous studies, we developed a postural stiffness measure that is extracted
      from foot center-of-pressure (COP) trajectories from quietly standing individuals
      and is based on an analytical mechanical model of posture control. Here we apply
      this measure to patients with Parkinson's disease (PD). We correlated the
      postural stiffness measure with different clinical rating scales, obtained from
      patients. Kendall's rank correlation was highly significant between the stiffness
      measure and rigidity, bradykinesia, posture impairment, gait, and leg agility,
      respectively, as rated by the Unified Parkinson's Disease Rating Scale. These
      results provide further evidence that a higher intrinsic muscle stiffness may
      contribute to the aforementioned clinically defined symptoms. From a clinical
      standpoint, this work indicates that the proposed postural stiffness measure may
      be useful as an assessment tool for the evaluation of PD patients subsequent to
      pharmacological and surgical treatment.

PMID- 10331366
TI  - Pustulosis palmaris et plantaris associated with peripheral neuropathy.

PMID- 10331365
TI  - Fisher syndrome with tetraparesis and antibody to GQ1b: evidence for motor nerve
      terminal block.
AB  - A Fisher syndrome (FS) patient with antibody to tetrasyaloganglioside GQ1b (GQ1b)
      developed late limb weakness. Serial motor conduction velocities (MCVs) showed a
      marked reduction of distal compound muscle action potential (CMAP) amplitudes,
      worse at 2-3 weeks, followed by a dramatic increase in week 5. Motor conduction
      velocities were always in the normal range, distal motor latencies changed only
      slightly, and conduction block in intermediate nerve segments was absent. These
      electrophysiological data might suggest an axonal neuropathy or a distal
      demyelinating conduction block. However, the dramatic increase of distal CMAP
      amplitudes over a short time without significant changes of distal motor
      latencies, CMAP duration, and morphology indicate that weakness in this FS
      patient might be due to a block of acetylcholine release from motor terminals,
      possibly mediated by anti-GQ1b antibodies.

PMID- 10331367
TI  - Nonsystemic vasculitic neuropathy presenting with truncal segmental sensory
      disturbance and hyperhidrosis.

PMID- 10331368
TI  - Musculocutaneous nerve lesion after strenuous physical activity.

PMID- 10331369
TI  - Mechanomyographic and electromyographic muscle responses are related to power.

PMID- 10331370
TI  - Proximal sensory neuropathy with preserved distal conduction and SEPs.

PMID- 10331371
TI  - Doxorubicin chemomyectomy as a treatment for cervical dystonia.

PMID- 10331372
TI  - UK failing to reap neuroscience rewards.

PMID- 10331373
TI  - Berkeley dispute festers over biotech deal.

PMID- 10331375
TI  - Africa moves to strengthen biotechnology.

PMID- 10331374
TI  - Embattled neuroscientist wins US support.

PMID- 10331376
TI  - GM advisory panel is slanted, say critics.

PMID- 10331377
TI  - Mixed response to NIH's web journal plan.

PMID- 10331378
TI  - EU warns on growth-hormone cancer risk.

PMID- 10331379
TI  - Automation 'could crack the big problems in science'.

PMID- 10331380
TI  - Editors' responsibility in defeating fraud.

PMID- 10331381
TI  - Cloning claims challenged.

PMID- 10331382
TI  - A calcium window to the gut.

PMID- 10331383
TI  - Neurobiology. A spine to remember.

PMID- 10331384
TI  - Palaeoanthropology. Stone legacy of skilled hands.

PMID- 10331385
TI  - David Phillips (1924-99)

PMID- 10331386
TI  - Cause and effect in evolution.

PMID- 10331387
TI  - Influence of a knot on the strength of a polymer strand.
AB  - Many experiments have been done to determine the relative strengths of different
      knots, and these show that the break in a knotted rope almost invariably occurs
      at the point just outside the 'entrance' to the knot. The influence of knots on
      the properties of polymers has become of great interest, in part because of their
      effect on mechanical properties. Knot theory applied to the topology of
      macromolecules indicates that the simple trefoil or 'overhand' knot is likely to
      be present in any long polymer strand. Fragments of DNA have been observed to
      contain such knots in experiments and computer simulations. Here we use ab initio
      computational methods to investigate the effect of a trefoil knot on the breaking
      strength of a polymer strand. We find that the knot weakens the strand
      significantly, and that, like a knotted rope, it breaks under tension at the
      entrance to the knot.

PMID- 10331388
TI  - Stress-induced recrystallization of a protein crystal by electron irradiation.
AB  - Ordering of a system of particles into its thermodynamically stable state usually
      proceeds by thermally activated mass transport of its constituents. Particularly
      at low temperature, the activation barrier often hinders equilibration--this is
      what prevents a glass from crystallizing and a pile of sand from flattening under
      gravity. But if the driving force for mass transport (that is, the excess energy
      of the system) is increased, the activation barrier can be overcome and
      structural changes are initiated. Here we report the reordering of radiation
      damaged protein crystals under conditions where transport is initiated by stress
      rather than by thermal activation. After accumulating a certain density of
      radiation-induced defects during observation by transmission electron microscopy,
      the distorted crystal recrystallizes. The reordering is induced by stress caused
      by the defects at temperatures that are low enough to suppress diffusive mass
      transport. We propose that this defect-induced reordering might be a general
      phenomenon.

PMID- 10331389
TI  - Early hominid stone tool production and technical skill 2.34 Myr ago in West
      Turkana, Kenya.
AB  - Well-documented Pliocene archaeological sites are exceptional. At present they
      are known only in East Africa, in the Hadar and Shungura formations of Ethiopia
      and in the Nachukui formation of Kenya. Intensive archeological survey and a
      series of test excavations conducted in the Nachukui formation since 1987 have
      led to the discovery of more than 25 archaeological sites whose ages range from
      2.34 to 0.7 million years before present (Myr), and to the extensive excavation
      of two 2.34-Myr sites, Lokalalei 1 in 1991 and Lokalalei 2C in 1997. Lokalalei 2C
      yielded nearly 3,000 archaeological finds from a context of such good
      preservation that it was possible to reconstitute more than 60 sets of
      complementary matching stone artefacts. These refits, predating the Koobi Fora
      refits by 500 Kyr, are the oldest ever studied. Here we describe a technological
      analysis of the core reduction sequences, based on these refits, which allows
      unprecedented accuracy in the understanding of flake production processes. We can
      thus demonstrate greater cognitive capacity and motor skill than previously
      assumed for early hominids, and highlight the diversity of Pliocene technical
      behaviour.

PMID- 10331390
TI  - Induction and organization of Ca2+ waves by enteric neural reflexes.
AB  - The motility of the gastrointestinal tract consists of local, non-propulsive
      mixing (pendular or segmental) and propulsive (peristaltic) movements. It is
      generally considered that mixing movements are produced by intrinsic pacemakers
      which generate rhythmic contractions, and peristalsis by intrinsic excitatory and
      inhibitory neural reflex pathways, but the relationship between mixing and
      peristalsis is poorly understood. Peristalsis is compromised in mice lacking
      interstitial cells of Cajal, suggesting that these pacemaker cells may also be
      involved in neural reflexes. Here we show that mixing movements within
      longitudinal muscle result from spontaneously generated waves of elevated
      internal calcium concentration which originate from discrete locations (pacing
      sites), spread with anisotropic conduction velocities in al directions, and
      terminate by colliding with each other or with adjacent neurally suppressed
      regions. Excitatory neural reflexes control the spread of excitability by
      inducing new pacing sites and enhancing the overall frequency of pacing, whereas
      inhibitory reflexes suppress the ability of calcium waves to propagate. We
      provide evidence that the enteric nervous system organizes mixing movements to
      generate peristalsis, linking the neural regulation of pacemakers to both types
      of gut motility.

PMID- 10331391
TI  - Dendritic spine changes associated with hippocampal long-term synaptic
      plasticity.
AB  - Long-term enhancement of synaptic efficacy in the hippocampus is an important
      model for studying the cellular mechanisms of neuronal plasticity, circuit
      reorganization, and even learning and memory. Although these long-lasting
      functional changes are easy to induce, it has been very difficult to demonstrate
      that they are accompanied or even caused by morphological changes on the
      subcellular level. Here we combined a local superfusion technique with two-photon
      imaging, which allowed us to scrutinize specific regions of the postsynaptic
      dendrite where we knew that the synaptic changes had to occur. We show that after
      induction of long-lasting (but not short-lasting) functional enhancement of
      synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in
      control regions on the same dendrite or in slices where long-term potentiation
      was blocked, no significant spine growth occurred.

PMID- 10331392
TI  - A family of mammalian Na+-dependent L-ascorbic acid transporters.
AB  - Vitamin C (L-ascorbic acid) is essential for many enzymatic reactions, in which
      it serves to maintain prosthetic metal ions in their reduced forms (for example,
      Fe2+, Cu+), and for scavenging free radicals in order to protect tissues from
      oxidative damage. The facilitative sugar transporters of the GLUT type can
      transport the oxidized form of the vitamin, dehydroascorbic acid, but these
      transporters are unlikely to allow significant physiological amounts of vitamin C
      to be taken up in the presence of normal glucose concentrations, because the
      vitamin is present in plasma essentially only in its reduced form. Here we
      describe the isolation of two L-ascorbic acid transporters, SVCT1 and SVCT2, from
      rat complementary DNA libraries, as the first step in investigating the
      importance of L-ascorbic acid transport in regulating the supply and metabolism
      of vitamin C. We find that SVCT1 and SVCT2 each mediate concentrative, high
      affinity L-ascorbic acid transport that is stereospecific and is driven by the
      Na+ electrochemical gradient. Despite their close sequence homology and similar
      functions, the two isoforms of the transporter are discretely distributed: SVCT1
      is mainly confined to epithelial systems (intestine, kidney, liver), whereas
      SVCT2 serves a host of metabolically active cells and specialized tissues in the
      brain, eye and other organs.

PMID- 10331393
TI  - Regulation of alternative splicing by RNA editing.
AB  - The enzyme ADAR2 is a double-stranded RNA-specific adenosine deaminase which is
      involved in the editing of mammalian messenger RNAs by the site-specific
      conversion of adenosine to inosine. Here we identify several rat ADAR2 mRNAs
      produced as a result of two distinct alternative splicing events. One such
      splicing event uses a proximal 3' acceptor site, adding 47 nucleotides to the
      ADAR2 coding region, changing the predicted reading frame of the mature ADAR2
      transcript. Nucleotide-sequence analysis of ADAR2 genomic DNA revealed the
      presence of adenosine-adenosine (AA) and adenosine-guanosine (AG) dinucleotides
      at these proximal and distal alternative 3' acceptor sites, respectively. Use of
      the proximal 3' acceptor depends upon the ability of ADAR2 to edit its own pre
      mRNA, converting the intronic AA to an adenosine-inosine (AI) dinucleotide which
      effectively mimics the highly conserved AG sequence normally found at 3' splice
      junctions. Our observations indicate that RNA editing can serve as a mechanism
      for regulating alternative splicing and they suggest a novel strategy by which
      ADAR2 can modulate its own expression.

PMID- 10331395
TI  - Hyperglycemia and cardiovascular disease in type 2 diabetes.
AB  - Cardiovascular disease (coronary heart disease, stroke, peripheral vascular
      disease) is the most important cause of mortality and morbidity among patients
      with type 2 diabetes. Conventional risk factors contribute similarly to
      macrovascular complications in patients with type 2 diabetes and nondiabetic
      subjects, and therefore, other explanations have been sought for enhanced
      atherothrombosis in type 2 diabetes. Among characteristics specific for type 2
      diabetes, hyperglycemia has recently been a focus of keen research. A recent meta
      analysis of 20 studies on nondiabetic subjects has demonstrated that in the
      nondiabetic range of glycemia (<6.1 mmol/l), increased glucose is already
      associated with an increased risk for cardiovascular disease. Similarly, 12
      recent prospective studies have convincingly indicated that hyperglycemia
      contributes to cardiovascular complications in patients with type 2 diabetes. The
      recently published U.K. Prospective Diabetes Study has shown that intensive
      glucose control reduces effectively microvascular complications among patients
      with type 2 diabetes, but that its effect on the prevention of cardiovascular
      complications was limited. Given the fact that in the U.K. Prospective Diabetes
      Study, none of the treatment modalities was particularly effective in reducing
      glucose, this underestimates the true potential of the correction of
      hyperglycemia in the prevention of cardiovascular disease in type 2 diabetes.
      However, in addition to intensive therapy of hyperglycemia, other conventional
      risk factors should also be normalized to prevent cardiovascular disease in
      patients with type 2 diabetes.

PMID- 10331394
TI  - Structural basis for initiation of transcription from an RNA polymerase-promoter
      complex.
AB  - Although the single-polypeptide-chain RNA polymerase from bacteriophage T7
      (T7RNAP), like other RNA polymerases, uses the same mechanism of polymerization
      as the DNA polymerases, it can also recognize a specific promoter sequence,
      initiate new RNA chains from a single nucleotide, abortively cycle the synthesis
      of short transcripts, be regulated by a transcription inhibitor, and terminate
      transcription. As T7RNAP is homologous to the Pol I family of DNA polymerases,
      the differences between the structure of T7RNAP complexed to substrates and that
      of the corresponding DNA polymerase complex provides a structural basis for
      understanding many of these functional differences. T7RNAP initiates RNA
      synthesis at promoter sequences that are conserved from positions -17 to +6
      relative to the start site of transcription. The crystal structure at 2.4 A
      resolution of T7RNAP complexed with a 17-base-pair promoter shows that the four
      base pairs closest to the catalytic active site have melted to form a
      transcription bubble. The T7 promoter sequence is recognized by interactions in
      the major groove between an antiparallel beta-loop and bases. The amino-terminal
      domain is involved in promoter recognition and DNA melting. We have also used
      homology modelling of the priming and incoming nucleoside triphosphates from the
      T7 DNA-polymerase ternary complex structure to explain the specificity of T7RNAP
      for ribonucleotides, its ability to initiate from a single nucleotide, and the
      abortive cycling at the initiation of transcription.

PMID- 10331396
TI  - Role of the human kidney in glucose counterregulation.
AB  - Animal experiments indicate that the kidney may play an important role in glucose
      counterregulation. Because the human kidney normally takes up and releases
      glucose, and since patients with end-stage renal disease are prone to
      hypoglycemia, we examined whether the kidney is also involved in human glucose
      counterregulation. Accordingly, we compared renal glucose release (RGR) and
      uptake (RGU) during 4-h hyperinsulinemic-hypoglycemic (approximately 3.2 mmol/l,
      n = 9) and -euglycemic (approximately 5 mmol/l, n = 10) control clamp experiments
      in normal postabsorptive subjects. A combination of renal balance and isotopic
      ([3H]glucose, [14C]glutamine) techniques was used, which permitted hepatic
      glucose release (HGR) and glutamine gluconeogenesis to be calculated as the
      difference between systemic (overall) and renal values. In both experiments,
      infusion of insulin increased plasma insulin comparably (approximately 210
      pmol/l). In euglycemic control experiments, RGR and HGR decreased more than 50%
      (both P<0.001) and RGU increased approximately 35% (P = 0.02). In hypoglycemic
      experiments, both HGR (P = 0.034) and RGR (P<0.001) increased to a comparable
      extent (1.69+/-0.47 and 1.67+/-0.15 pmol x kg-(-1) x min(-1), respectively, P =
      0.96) above rates observed in control experiments; hepatic and renal glutamine
      gluconeogenesis increased by 0.19+/-0.06 (P<0.008) and 0.30+/-0.07 pmol x kg(-1)
      x min(-1) (P< 0.001), respectively. RGU decreased by 65% compared with control
      experiments (P<0.001), so that renal glucose balance changed from a net uptake of
      80+/-19 micromol/min to a net release of 130+/-9 micromol/min, P< 0.001. These
      observations provide evidence that the kidney may play an important role in human
      glucose counterregulation.

PMID- 10331397
TI  - Insulin action on muscle protein kinetics and amino acid transport during
      recovery after resistance exercise.
AB  - We have determined the individual and combined effects of insulin and prior
      exercise on leg muscle protein synthesis and degradation, amino acid transport,
      glucose uptake, and alanine metabolism. Normal volunteers were studied in the
      postabsorptive state at rest and about 3 h after a heavy leg resistance exercise
      routine. The leg arteriovenous balance technique was used in combination with
      stable isotopic tracers of amino acids and biopsies of the vastus lateralis
      muscle. Insulin was infused into a femoral artery to increase the leg insulin
      concentrations to high physiologic levels without substantively affecting the
      whole-body level. Protein synthesis and degradation were determined as rates of
      intramuscular phenylalanine utilization and appearance, and muscle fractional
      synthetic rate (FSR) was also determined. Leg blood flow was greater after
      exercise than at rest (P<0.05). Insulin accelerated blood flow at rest but not
      after exercise (P<0.05). The rates of protein synthesis and degradation were
      greater during the postexercise recovery (65+/-10 and 74+/-10 nmol x min(-1) x
      100 ml(-1) leg volume, respectively) than at rest (30+/-7 and 46+/-8 nmol x min(
      1) x 100 ml(-1) leg volume, respectively; P<0.05). Insulin infusion increased
      protein synthesis at rest (51+/-4 nmol x min(-1) x 100 ml(-1) leg volume) but not
      during the postexercise recovery (64+/-9 nmol x min(-1) x 100 ml(-1) leg volume;
      P<0.05). Insulin infusion at rest did not change the rate of protein degradation
      (48+/-3 nmol x min(-1) 100 ml(-1) leg volume). In contrast, insulin infusion
      after exercise significantly decreased the rate of protein degradation (52+/-9
      nmol x min(-1) x 100 ml(-1) leg volume). The insulin stimulatory effects on
      inward alanine transport and glucose uptake were three times greater during the
      postexercise recovery than at rest (P<0.05). In contrast, the insulin effects on
      phenylalanine, leucine, and lysine transport were similar at rest and after
      exercise. In conclusion, the ability of insulin to stimulate glucose uptake and
      alanine transport and to suppress protein degradation in skeletal muscle is
      increased after resistance exercise. Decreased amino acid availability may limit
      the stimulatory effect of insulin on muscle protein synthesis after exercise.

PMID- 10331398
TI  - Splanchnic and leg substrate exchange after ingestion of a natural mixed meal in
      humans.
AB  - The disposal of a mixed meal was examined in 11 male subjects by multiple
      (splanchnic and femoral) catheterization combined with double-isotope technique
      (intravenous [2-3H]glucose plus oral U-[14C]starch). Glucose kinetics and organ
      substrate balance were measured basally and for 5 h after eating pizza (600 kcal)
      containing carbohydrates 75 g as starch, proteins 37 g, and lipids 17 g. The
      portal appearance of ingested carbohydrate was maximal (1.0 mmol/min) between 30
      and 60 min after the meal and gradually declined thereafter, but was still
      incomplete at 300 min (0.46+/-0.08 mmol/min). The total amount of glucose
      absorbed by the gut over the 5 h of the study was 247+/-26 mmol (45+/-6 g),
      corresponding to 60+/-6% of the ingested starch. Net splanchnic glucose balance (
      6.7+/-0.5 micromol x kg(-1) x min(-1), basal) rose by 250-300% between 30 and 60
      min and then returned to baseline. Hepatic glucose production (HGP) was
      suppressed slightly and only tardily in response to meal ingestion (approximately
      30% between 120 and 300 min). Splanchnic glucose uptake (3.7+/-0.6 micromol x kg(
      1) x min(-1), basal) peaked to 9.8+/-2.0 micromol x kg(-1) x min(-1) (P<0.001) at
      120 min and then returned slowly to baseline. Leg glucose uptake (34+/-5 micromol
      x leg(-1) x min(-1), basal) rose to 151+/-29 micromol x leg(-1) x min(-1) at 30
      min (P<0.001) and remained above baseline until the end of the study, despite no
      increase in leg blood flow. The total amount of glucose taken up by the
      splanchnic area and total muscle mass was 161+/-16 mmol (29+/-3 g) and 128 mmol
      (23 g), respectively, which represent 39 and 30% of the ingested starch. Arterial
      blood lactate increased by 30% after meal ingestion. Net splanchnic lactate
      balance switched from a basal net uptake (3.2+/-0.6 micromol kg(-1) x min(-1) to
      a net output between 60 and 120 min and tended to zero thereafter. Leg lactate
      release (25+/-11 micromol x leg(-1) x min(-1), basal) drastically decreased
      postprandially. Arterial concentration of both branched-chain amino acids (BCAA)
      and non-branched-chain amino acids (N-BCAA) increased significantly after meal
      ingestion (P<0.001). The splanchnic area switched from a basal net amino acid
      uptake (31+/-16 and 92+/-48 micromol/min for BCAA and N-BCAA, respectively) to a
      net amino acid release postprandially. The net splanchnic amino acid release over
      5 h was 11.3+/-4.2 mmol for BCAA and 37.8+/-9.7 mmol for N-BCAA. Basally, the net
      leg balance of BCAA was neutral (-3+/-5 micromol x leg(-1) x min(-1)), whereas
      that of N-BCAA indicated a net release (54+/-14 micromol x leg(-1) x min(-1)).
      After meal ingestion, there was a net leg uptake of BCAA (20+/-6 micromol x leg(
      1) x min(-1)), whereas leg release of N-BCAA decreased by 50%. It is concluded
      that in human subjects, 1) the absorption of a natural mixed meal is still
      incomplete at 5 h after ingestion; 2) HGP is only marginally and tardily
      inhibited; 3) splanchnic and peripheral tissues contribute to the disposal of
      meal carbohydrate to approximately the same extent; 4) the splanchnic area
      transfers >30% of the ingested proteins to the systemic circulation; and 5) after
      meal ingestion, skeletal muscle takes up BCAA to replenish muscle protein stores.

PMID- 10331399
TI  - NOD mice have a generalized defect in their response to transplantation tolerance
      induction.
AB  - A protocol consisting of a single donor-specific transfusion (DST) plus a brief
      course of anti-CD154 monoclonal antibody (anti-CD40 ligand mAb) induces permanent
      islet allograft survival in chemically diabetic mice, but its efficacy in mice
      with autoimmune diabetes is unknown. Confirming a previous report, we first
      observed that treatment of young female NOD mice with anti-CD154 mAb reduced the
      frequency of diabetes through 1 year of age to 43%, compared with 73% in
      untreated controls. We also confirmed that spontaneously diabetic NOD mice
      transplanted with syngeneic (NOD-Prkdc(scid)/Prkdc(scid)) or allogeneic (BALB/c)
      islets rapidly reject their grafts. Graft survival was not prolonged, however, by
      pretreatment with either anti-CD154 mAb alone or anti-CD154 mAb plus DST. In
      addition, allograft rejection in NOD mice was not restricted to islet grafts.
      Anti-CD154 mAb plus DST treatment failed to prolong skin allograft survival in
      nondiabetic male NOD mice. The inability to induce transplantation tolerance in
      NOD (H2g7) mice was associated with non-major histocompatibility complex (MHC)
      genes. Treatment with DST and anti-CD154 mAb prolonged skin allograft survival in
      both C57BL/6 (H2b) and C57BL/6.NOD-H2g7 mice, but it was ineffective in NOD,
      NOD.SWR-H2q, and NOR (H2g7) mice. Mitogen-stimulated interleukin-1beta production
      by antigen-presenting cells was greater in strains susceptible to tolerance
      induction than in the strains resistant to tolerance induction. The results
      suggest the existence of a general defect in tolerance mechanisms in NOD mice.
      This genetic defect involves defective antigen-presenting cell maturation, leads
      to spontaneous autoimmune diabetes in the presence of the H2g7 MHC, and precludes
      the induction of transplantation tolerance irrespective of MHC haplotype.
      Promising islet transplantation methods based on overcoming the alloimmune
      response by interference with costimulation may require modification or
      amplification for use in the setting of autoimmune diabetes.

PMID- 10331400
TI  - Islet cell membrane antigens activate diabetogenic CD4+ T-cells in the BB/Wor
      rat.
AB  - Type 1 diabetes is a major histocompatibility complex (MHC) class II-associated
      autoimmune disease mediated by beta-cell-specific T-cells and characterized by
      circulating autoantibodies to beta-cell molecules. In the BB/Wor diabetes-prone
      (DP) rat, type 1 diabetes develops spontaneously with an incidence of >90%. BB
      diabetes can be adoptively transferred to naive syngeneic or MHC class II
      compatible rats with islet cell-activated T-cell lines derived from diabetic
      BB/Wor rats. However, the target beta-cell autoantigen(s) in BB diabetes has not
      yet been defined. BB rat T-cell lines activated in vitro with antigen-presenting
      cells (APC) and BB islet cell crude membranes (CM), but not islet cell cytosol,
      adoptively transfer diabetes into young DP recipients. To determine if the target
      autoantigen is an integral or peripheral membrane protein, islet cell CM were
      treated with 0.5 mol/l KCl or 0.2 mol/l Na2CO3 (pH 11). Both treatments
      selectively extract peripheral proteins from the cell membrane without affecting
      the disposition of integral (transmembrane) proteins. T-cell lines activated in
      vitro with APC and 0.5 mol/l KCl, or pH 11 (0.2 mol/l Na2CO3)-treated islet cell
      CM, transferred diabetes into young DP rats. Conversely, T-cell lines activated
      in vitro with APC and the supernatant of 0.5 mol/l KCl-treated CM (containing
      extracted peripheral proteins), did not adoptively transfer diabetes. After
      activation in vitro with islet cell membrane antigens, the diabetes-inducing cell
      lines were comprised of both CD4+ CD8- T-cells and 10-30% B-cells. We conclude
      that a major CD4+ T-cell target autoantigen in BB diabetes is a membrane
      associated beta-cell molecule with the characteristics of an integral beta-cell
      membrane protein. The identification of this MHC class II-restricted beta-cell
      target molecule will allow the design of antigen-specific intervention protocols
      to prevent the onset of type 1 diabetes in genetically susceptible individuals.

PMID- 10331401
TI  - Cellular immune responses to human islet proteins in antibody-positive type 2
      diabetic patients.
AB  - Type 1 diabetes is a cell-mediated autoimmune disease characterized by
      autoantibody and peripheral blood mononuclear cell (PBMC) reactivity to islet
      cell proteins. Type 2 diabetes is not an autoimmune disease but rather results
      from both insulin resistance and a nonautoimmune insulin secretory defect. There
      is, however, a group of phenotypic type 2 diabetic patients who have islet
      autoantibodies that are similar to those of type 1 diabetic patients. In this
      study, we investigated, using cellular immunoblotting, whether type 2 diabetic
      patients positive for islet autoantibodies have PBMC responses to islet proteins.
      We observed that autoantibody negative (Ab-) type 2 diabetic patients (n = 9) and
      normal control subjects (n = 12) demonstrated PBMCs responsive to 0-3 molecular
      weight regions. In contrast, autoantibody positive (Ab+) type 2 diabetic patients
      (n = 11) demonstrated PBMC responses to 3-18 molecular weight regions, similar to
      that of type 1 diabetic patients (responsive to 4-18 molecular weight regions).
      PBMCs from over 90% of the Ab+ type 2 and type 1 diabetic patients were observed
      to proliferate to islet proteins in the vicinity of 97 kDa. In contrast, 65-90%
      of type 1 diabetic patients had responsive PBMCs for islet proteins in most of
      the molecular weight regions, whereas <60% of the Ab+ type 2 diabetic patients
      had PBMCs responsive to the same molecular weight proteins. Ab+ type 2 diabetic
      patients appear to be heterogeneous with respect to cellular reactivity to islet
      proteins. Some subjects demonstrate PBMC responses similar to those of "classic"
      type 1 diabetic patients, whereas others have PBMC responses potentially distinct
      from type 1 diabetic patients.

PMID- 10331402
TI  - Increased beta-cell proliferation and reduced mass before diabetes onset in the
      nonobese diabetic mouse.
AB  - To determine whether loss of beta-cell mass and function in the NOD mouse occurs
      gradually, beginning after the onset of insulitis, or abruptly, just before the
      onset of overt diabetes, beta-cell mass and rates of beta-cell proliferation and
      insulin secretory responses from the perfused pancreas were measured in NOD and
      control NOD/Scid mice at 8-9, 13, and 18 weeks of age. Of the NOD mice, 11 and
      70% had diabetes (fasting blood glucose >8.3 mmol/l) at 13 and 18 weeks of age,
      respectively. Beta-cell mass in 8-week-old NOD mice was 69% of control mice
      (P>0.05), but the rate of 5-bromo-2-deoxyuridine uptake was greater, suggesting a
      compensatory proliferative response to ongoing autoimmune beta-cell destruction.
      Despite an increase in the rate of beta-cell proliferation, beta-cell mass was
      significantly reduced by 42% in 13-week-old nondiabetic NOD mice and by 73% in 18
      week-old diabetic NOD mice. Insulin secretory responses to glucose and arginine
      demonstrated reductions of similar magnitude. In 18-week-old diabetic NOD mice,
      insulin secretion was reduced to a greater degree than beta-cell mass, suggesting
      the presence of beta-cell dysfunction in addition to reduced mass. These results
      suggest that in the NOD mouse, beta-cell destruction begins soon after the onset
      of insulitis. Despite a compensatory beta-cell proliferative response, beta-cell
      mass progressively falls and is significantly reduced by 13 weeks despite normal
      blood glucose concentrations. Diabetes may be present when residual beta-cell
      mass represents 30% of control levels.

PMID- 10331403
TI  - Beta-cell hypertrophy in fa/fa rats is associated with basal glucose
      hypersensitivity and reduced SNARE protein expression.
AB  - In normal isolated beta-cells, the response to glucose is heterogeneous and
      characterized by an increasing number of secretory cells as glucose concentration
      rises (Pipeleers DG, Kiekens R, Ling Z, Wilikens A, Schuit F: Physiologic
      relevance of heterogeneity in the pancreatic beta-cell population. Diabetologia
      37 (Suppl. 2):S57-S64, 1994). We hypothesized that fasting hyperinsulinemia in
      obesity might be explained by altered beta-cell heterogeneity of signal
      transduction mechanisms, possibly involving exocytotic proteins. Insulin
      secretion from individual beta-cells sorted according to the size of the islet
      donor (<125 microm, >250 microm, and intermediate diameter) was measured by
      reverse hemolytic plaque assay. Beta-cells from fa/fa rats were hypertrophied 25
      40%, independent of donor islet size. This was accompanied by an increased
      proportion of secretory cells (recruitment) at 5.5-11.0 mmol/l glucose, increased
      secretion per cell at 2.8 mmol/l glucose, and decreased insulin content after
      acute glucose exposure without an increase in secretion per cell. Decreased
      expression of exocytotic (soluble N-ethylmaleimide-sensitive fusion protein
      receptor [SNARE]) proteins, vesicle-associated membrane protein isoform 2 (VAMP
      2), synaptosomal protein of 25 kDa (SNAP-25), and syntaxin-1 and -2 in fa/fa beta
      cells may contribute to the failure to sustain excessive plaque size at higher
      glucose concentrations. Fasting hyperinsulinemia may be maintained by increased
      recruitment and an exaggerated secretory response in all fa-derived islet
      populations. Glucose regulates beta-cell responsiveness in the short term, and
      these effects may involve altered expression of SNARE proteins.

PMID- 10331405
TI  - Sustained proliferation of PDX-1+ cells derived from human islets.
AB  - Ex vivo expansion of human beta-cells is an important step toward the development
      of cell-based insulin delivery systems in type 1 diabetes. Here, we report that
      human pancreatic endocrine cells can be expanded through 15 cell doublings in
      vitro for an estimated total 30,000-fold increase in cell number. We believe that
      the cells resulting from these cultures are of beta-cell origin, since they
      uniformly express the transcription factor PDX-1 (STF-1, IDX-1, IPF-1), which is
      initially seen only in cells positive for insulin and negative for the ductal
      cell marker cytokeratin (CK)-19. To rule out the possibility that PDX-1
      expression might be induced by the culture conditions used here, cells from
      isolated human pancreatic ducts were cultured under the same conditions as the
      islet cells. Cells in these cultures expressed CK-19 but not PDX-1. Although the
      expanded beta-cells continued to express PDX-1, insulin expression was lost over
      time. Whether reexpression of islet-specific genes in vitro is essential for
      successful cell transplantation remains to be determined.

PMID- 10331404
TI  - cAMP enhances insulin secretion by an action on the ATP-sensitive K+ channel
      independent pathway of glucose signaling in rat pancreatic islets.
AB  - Cyclic AMP potentiates glucose-stimulated insulin release by actions
      predominantly at a site, or sites, distal to the elevation of the cytosolic free
      Ca2+ concentration ([Ca2+]i). Glucose also acts at a site, or sites, distal to
      the elevation of [Ca2+]i via the ATP-sensitive K+ channel (K+ATP channel)
      independent signaling pathway. Accordingly, using rat pancreatic islets, we
      studied the location of the action of cAMP and its interaction with the glucose
      pathway. Forskolin, an activator of adenylyl cyclase, raised intracellular cAMP
      levels and enhanced KCl-induced (Ca2+ -stimulated) insulin release in the
      presence, but not in the absence, of glucose. Thus, cAMP has no direct effect on
      Ca2+ -stimulated insulin release. The interaction between cAMP and glucose occurs
      at a step distal to the elevation of [Ca2+]i because forskolin enhancement of KCl
      induced insulin release, in the presence of glucose, was demonstrated in the
      islets treated with diazoxide, a K+ATP channel opener. The enhancement of insulin
      release was not associated with any increase in [Ca2+]i. Furthermore, the
      interaction between cAMP and glucose was unequivocally observed even under
      stringent Ca2+ -free conditions, indicating the Ca2+ -independent action of cAMP.
      This action of cAMP is physiologically relevant, because not only forskolin but
      also glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and
      pituitary adenylyl cyclase activating polypeptide exerted similar actions. In
      conclusion, the cAMP/protein kinase A pathway has no direct effect on Ca2+ 
      stimulated insulin exocytosis. Rather, it strongly potentiates insulin release by
      increasing the effectiveness of the K+ATP channel-independent action of glucose.

PMID- 10331406
TI  - Adenovirus-mediated overexpression of uncoupling protein-2 in pancreatic islets
      of Zucker diabetic rats increases oxidative activity and improves beta-cell
      function.
AB  - The discovery of uncoupling protein (UCP)-2, a ubiquitously expressed protein
      homologous to UCP-1, has raised the possibility that energy balance of cells
      might be regulated in tissues other than brown adipocytes. In normal pancreatic
      islets, UCP-2 is upregulated by leptin and is low in leptin-resistant islets of
      ZDF rats. To determine whether UCP-2 does, in fact, have uncoupling activity and,
      if so, whether such activity would favorably influence the abnormalities in
      leptin-unresponsive UCP-2-underexpressing islets of diabetic ZDF rats, we
      transferred the UCP-2 gene to the islets of diabetic ZDF rats and lean (+/+) ZDF
      control rats. Although ATP was reduced by 23% in both groups of islets, the
      ATP:ADP ratio increased by 42 and 141%, respectively. [3H]palmitate oxidation was
      increased by 50%, and [3H]glucose oxidation was 42-63% higher. Preproinsulin mRNA
      was 2.9-fold above control levels, and glucose-stimulated insulin secretion,
      which was negligible in control ZDF rat islets, was improved in UCP-2
      overexpressing islets. The high fat content of the islets was not reduced,
      however. We conclude that UCP-2 has uncoupling function when overexpressed in
      leptin-insensitive islets and that its overexpression corrects the
      underexpression of the insulin gene and ameliorates glucose-stimulated insulin
      secretion, possibly by increasing the ATP:ADP ratio.

PMID- 10331408
TI  - Overexpression of G11alpha and isoforms of phospholipase C in islet beta-cells
      reveals a lack of correlation between inositol phosphate accumulation and insulin
      secretion.
AB  - It has been suggested that insulin secretion from pancreatic islets may be
      mediated in part by activation of phospholipases C (PLCs) and phosphoinositide
      hydrolysis. The purpose of this study was to determine whether the relatively
      modest fuel-stimulated insulin secretion responses of rodent beta-cell lines
      might be explained by inadequate expression or activation of PLC isoforms. We
      have found that two insulinoma cell lines, INS-1 and betaG 40/110, completely
      lack PLC-delta1 expression but have levels of expression of PLC-beta1, -beta2, 
      beta3, -delta2, and -gamma1 that are similar to or slightly reduced from those
      found in fresh rat islets. Adenovirus-mediated overexpression of PLC-delta1, 
      beta1, or -beta3 in INS-1 or betaG 40/110 cells results in little or no
      enhancement in inositol phosphate (IP) accumulation and no improvement in insulin
      secretion when the cells are stimulated with glucose or carbachol, despite the
      fact that the overexpressed proteins are fully active in cell extracts.
      Overexpression of PLC-beta1 or -beta3 in normal rat islets elicits a larger
      increase in IP accumulation but, again, has no effect on insulin secretion.
      Because the effect of carbachol on insulin secretion is thought to be mediated
      through muscarinic receptors that link to the Gq/11 class of heterotrimeric G
      proteins, we also overexpressed G11alpha in INS-1 cells, either alone or in
      concert with overexpression of PLC-beta1 or -beta3. Overexpression of G11alpha
      enhances IP accumulation, an effect slightly potentiated by co-overexpression of
      PLC-beta1 or -beta3, but these maneuvers do not affect glucose or carbachol
      stimulated insulin secretion. In sum, our studies show a lack of correlation
      between IP accumulation and insulin secretion in INS-1 cells, betaG 40/110 cells,
      or cultured rat islets. We conclude that overexpression of PLC isoforms and/or
      G11alpha is not an effective means of enhancing fuel responsiveness in the
      insulinoma cell lines studied.

PMID- 10331407
TI  - Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese
      diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus
      monkeys (Macaca mulatta).
AB  - Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the
      Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon
      like peptide (GLP)-1. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering
      action in vivo. We compared the potency and duration of glucose-lowering effects
      of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions
      in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the
      same doses of exendin-4 resulted in a similar glucose-lowering effect that
      persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice
      (effective doses, 50% [ED50s] of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/
      0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of
      0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the
      percentage fall in plasma glucose at 1 h was used as the indicator response.
      Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus
      monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two
      experiments in which diabetic fatty Zucker rats were injected subcutaneously
      twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x
      day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline
      injected control rats. Exendin-4 treatment was also associated in each of these
      experiments with weight loss and improved insulin sensitivity, as demonstrated by
      increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR)
      in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase
      in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log,
      respectively. In conclusion, acute and chronic administration of exendin-4 has
      demonstrated an antidiabetic effect in several animal models of type 2 diabetes.

PMID- 10331410
TI  - Endogenous glucose production and glucose effectiveness in type 2 diabetic
      subjects derived from stable-labeled minimal model approach.
AB  - Insulin sensitivity, glucose effectiveness, and endogenous glucose production
      (EGP) during stable-labeled, frequently sampled insulin-modified intravenous
      glucose tolerance test (FSIGT) were evaluated by a single-and two-compartment
      minimal model combined with nonparametric deconvolution in eleven nonobese
      Japanese type 2 diabetic patients. Four patients were treated with sulfonylureas,
      and the remaining seven with diet therapy alone. None had diabetic retinopathy
      and microalbuminuria. Their fasting glucose level was 117+/-7 mg/dl (mean +/-
      SE), and HbA1c was 6.6+/-0.3%. Age-, sex-, and BMI-matched subjects with normal
      glucose tolerance served as control subjects. Plasma insulin response to the
      stimuli and insulin sensitivity indexes (S(I), S(I)*, and S(I)2* were derived
      from a minimal model and single- and two-compartment-labeled minimal models) were
      impaired in the type 2 diabetic patients. The combined ability of glucose, per
      se, to increase its own uptake and suppress EGP (glucose effectiveness [SG]),
      which was derived from kinetic analysis of plasma glucose by a minimal model, was
      significantly lower in the type 2 diabetic patients (0.0132+/-0.0015 vs. 0.0203+/
      0.0022; P<0.05). However, the ability of glucose, per se, to stimulate glucose
      uptake, assessed as S(G)* and S(G)2* from the kinetic analysis of labeled glucose
      by single- and two-compartment minimal model, was not impaired in those patients.
      EGP of the type 2 diabetic patients as a whole was suppressed to the level
      similar to that of the control subjects despite a higher plasma glucose level
      throughout FSIGT. When EGP in the diabetic subjects was analyzed, considering
      their recent glycemic control, the initial suppression was blunted in the
      patients with higher HbA1c levels. In conclusion, glucose mass action to
      stimulate glucose uptake remains near-normal in the lean Japanese type 2 diabetic
      patients of this study, whereas ability of glucose to suppress EGP is impaired in
      the patients with recent hyperglycemia. This blunted suppression of EGP might be
      one of the conspirators for decreased S(G) in subjects with type 2 diabetes.

PMID- 10331409
TI  - Glucagon-like peptide 1 increases insulin sensitivity in depancreatized dogs.
AB  - To determine whether glucagon-like peptide (GLP)-1 increases insulin sensitivity
      in addition to stimulating insulin secretion, we studied totally depancreatized
      dogs to eliminate GLP-1's incretin effect. Somatostatin was infused (0.8 microg x
      kg(-1) x min(-1)) to inhibit extrapancreatic glucagon in dogs, and basal glucagon
      was restored by intraportal infusion (0.65 ng x kg(-1) x min(-1)). To simulate
      the residual intraportal insulin secretion in type 2 diabetes, basal intraportal
      insulin infusion was given to obtain plasma glucose concentrations of
      approximately 10 mmol/l. Glucose was clamped at this level for the remainder of
      the experiment, which included peripheral insulin infusion (high dose, 5.4 pmol x
      kg(-1) x min(-1), or low dose, 0.75 pmol x kg(-1) x min(-1)) with or without GLP
      1(7-36) amide (1.5 pmol x kg(-1) x min(-1)). Glucose production and utilization
      were measured with 3-[3H]glucose, using radiolabeled glucose infusates. In 12
      paired experiments with six dogs at the high insulin dose, GLP-1 infusion
      resulted in higher glucose requirements than saline (60.9+/-11.0 vs. 43.6+/-8.3
      micromol x kg(-1) x min(-1), P< 0.001), because of greater glucose utilization
      (72.6+/-11.0 vs. 56.8+/-9.7 micromol x kg(-1) x min(-1), P<0.001), whereas the
      suppression of glucose production was not affected by GLP-1. Free fatty acids
      (FFAs) were significantly lower with GLP-1 than saline (375.3+/-103.0 vs. 524.4+/
      101.1 micromol/l, P<0.01), as was glycerol (77.9+/-17.5 vs. 125.6+/-51.8
      micromol/l, P<0.05). GLP-1 receptor gene expression was found using reverse
      transcriptase-polymerase chain reaction of poly(A)-selected RNA in muscle and
      adipose tissue, but not in liver. Low levels of GLP-1 receptor gene expression
      were also found in adipose tissue using Northern blotting. In 10 paired
      experiments with five dogs at the low insulin dose, GLP-1 infusion did not affect
      glucose utilization or FFA and glycerol suppression when compared with saline,
      suggesting that GLP-1's effect on insulin action was dependent on the insulin
      dose. In conclusion, in depancreatized dogs, GLP-1 potentiates insulin-stimulated
      glucose utilization, an effect that might be contributed in part by GLP-1
      potentiation of insulin's antilipolytic action.

PMID- 10331413
TI  - Hepatic insulin resistance and defects in substrate utilization in cystic
      fibrosis.
AB  - Patients with cystic fibrosis (CF)-related diabetes (CFRD) have clinical features
      of both type 1 and type 2 diabetes. Past studies have documented peripheral
      insulin resistance in CF, and some studies have noted high hepatic glucose
      production (HGP) in CF patients. We hypothesized that patients with CF, similar
      to patients with type 2 diabetes, have hepatic insulin resistance. Cystic
      fibrosis is a catabolic condition, yet the etiology of catabolism is poorly
      understood. De novo lipogenesis is energy wasteful and precludes ketogenesis.
      Patients with CFRD rarely develop ketogenesis, despite insulin deficiency. We
      speculated that CF patients have de novo lipogenesis, and therefore evaluated
      substrate utilization in CF. Using [6,6-2H2]glucose and a three-step
      hyperinsulinemic-euglycemic clamp, we measured HGP in 29 adult CF subjects and 18
      control volunteers. Using indirect calorimetry, we measured lipid oxidation,
      oxidative glucose metabolism, and resting energy expenditure at baseline and at
      high levels of insulin. All subjects were characterized by oral glucose tolerance
      testing (OGTT) and National Diabetes Data Group criteria. The CF subjects had
      increased HGP when compared with control subjects (CF, 3.5+/-0.6; control, 2.5+/
      0.5 mg x kg(-1) x h(-1); P = 0.002). Baseline HGP correlated with glucose levels
      obtained 2 h after a glucose load given for OGTT (r = 0.69, P = 0.001).
      Suppression of HGP by insulin was significantly less in all CF subgroups than in
      control subjects at peripheral insulin levels of 16 and 29 microU/ml. At
      peripheral insulin levels of 100 microU/ml and 198 microU/ml, there was no
      difference in insulin suppression of HGP between CF and control subjects. At
      baseline, there was no significant difference between control and CF subjects for
      glucose or lipid oxidation. During maximum insulin stimulation, there was a
      greater tendency for nonoxidative glucose metabolism in all CF subjects. The CF
      subjects with abnormal glucose tolerance also had de novo lipogenesis. Our
      results indicate that CF patients have several defects in substrate utilization,
      including de novo lipogenesis. Furthermore, these results suggest that high
      hepatic glucose production and hepatic insulin resistance contribute to the high
      incidence of abnormal glucose tolerance in CF.

PMID- 10331411
TI  - Effects of overexpression of human GLUT4 gene on maternal diabetes and fetal
      growth in spontaneous gestational diabetic C57BLKS/J Lepr(db/+) mice.
AB  - During gestation, heterozygous C57BLKS/J-Lepr(db/+) mice develop spontaneous
      gestational diabetes mellitus (GDM), and the newborn fetuses are macrosomic
      compared with offspring from wild-type (+/+) mothers. To investigate the effects
      of the leptin receptor mutation on maternal metabolism and fetal growth during
      pregnancy, we studied +/+, db/+, and db/+ transgenic mice that overexpress the
      human GLUT4 gene two- to three-fold (db/+TG6). During pregnancy, fasting plasma
      glucose and hepatic glucose production were twofold greater in db/+ than +/+
      mice, despite similar insulin levels. In skeletal muscle, insulin-stimulated
      tyrosine phosphorylation was decreased in pregnant +/+ mice, and even more so in
      db/+ mice: insulin receptor beta (IR-beta), +/+ 34%, db/+ 57% decrease, P<0.05;
      insulin receptor substrate 1 (IRS-1), +/+ 44%, db/+ 61% decrease, P<0.05; and
      phosphoinositol (PI) 3-kinase (p85alpha), +/+ 33%, db/+ 65% decrease, P<0.05.
      Overexpression of GLUT4 in db/+TG6 mice markedly improved glucose-stimulated
      insulin secretion, by 250%, and increased IRbeta, IRS-1, and p85alpha
      phosphorylation twofold, despite no change in concentration of these proteins.
      Plasma leptin concentration increased 40-fold during pregnancy, from 2.2+/-0.5 to
      92+/-11 ng/ml and 3.6+/-0.1 to 178+/-34 ng/ml in +/+ and db/+ mice, respectively
      (P<0.01), but was increased to only 23+/-3 ng/ml in pregnant db/+TG6 mice
      (P<0.001). Maternal fat mass and energy intake were greater in db/+ mice, and fat
      mass was reduced by GLUT4 overexpression, independent of food intake. Fetal body
      weight was increased by 8.1 and 7.9% in db/+ and db/+TG6 mothers, respectively
      (P<0.05), regardless of fetal genotype, whereas fetuses from db/+TG8 mothers
      (four- to fivefold overexpression) weighed significantly less compared with pups
      from +/+ or db/+ mothers (P<0.05). These results suggest that the single mutant
      db allele effects susceptibility to GDM through abnormalities in insulin receptor
      signaling, defective insulin secretion, and greater nutrient availability. GLUT4
      overexpression markedly improves insulin-signaling in GDM, resulting in increased
      insulin secretion and improved glycemic control. However, maternal hyperglycemia
      appears not to be the sole cause of fetal macrosomia. These data suggest that GDM
      is associated with defects in insulin receptor signaling in maternal skeletal
      muscle, and this may be an important factor provoking maternal and fetal
      perinatal complications.

PMID- 10331412
TI  - Plasma and interstitial glucose dynamics after intravenous glucose injection:
      evaluation of the single-compartment glucose distribution assumption in the
      minimal models.
AB  - Recent experimental evidence suggests that estimates of glucose effectiveness
      (S(G)) from the minimal model of unlabeled glucose disappearance (Cold-MM) are in
      error. The single-compartment glucose distribution assumption embedded in the
      model has been indicated as a possible source of error. In this study, to
      directly examine the single-compartment assumption, we measured plasma and
      interstitial glucose concentrations after intravenous glucose injection.
      Additionally, we compared the accuracy of the estimates of glucose effectiveness
      from the Cold-MM and the single-compartment tracer minimal model (Hot-MM). Paired
      labeled intravenous glucose tolerance tests (IVGTTs) were performed in each of
      six C-peptide-negative type 1 diabetic subjects. Two different insulin infusion
      protocols were used: an infusion at constant basal rates and an infusion at
      variable rates to mimic a normal insulin response. During the labeled IVGTT with
      basal insulin infusion, the microperfusion technique was employed to sample
      adipose tissue interstitial fluid. Marked differences between the plasma and
      interstitial dynamics of (cold) glucose were observed during the first 22 min
      after glucose injection. These results suggest that the requirements for a single
      compartment representation of glucose kinetics are not satisfied during at least
      the first 22 min of an IVGTT. Data from the labeled IVGTT with normal insulin
      response were used to identify the minimal-model parameters. The measure of S(G)
      derived using the Cold-MM was 3.44-fold higher than the direct measure obtained
      from the labeled IVGTT with basal insulin infusion (0.0179+/-0.0027 vs. 0.0052+/
      0.0010 min(-1), P<0.01). The measure of glucose effectiveness (S(G)*) derived by
      the Hot-MM was 1.36-fold higher than the direct measure available from the
      labeled IVGTT with basal insulin infusion (0.0079+/-0.0013 vs. 0.0058+/-0.0004
      min(-1), P>0.26). These results suggest that the Hot-MM is more appropriate for
      the evaluation of glucose effectiveness than the Cold-MM.

PMID- 10331414
TI  - Isolated low HDL cholesterol: an insulin-resistant state only in the presence of
      fasting hypertriglyceridemia.
AB  - Individuals with isolated low HDL cholesterol are at increased risk of coronary
      artery disease. It has been reported previously that this is an insulin-resistant
      state. We analyzed data from the 1992 Singapore National Health Survey with the
      objective of defining the clinical and metabolic parameters associated with
      isolated low HDL cholesterol. A total of 3,568 individuals were selected by
      stratified random sampling. Subjects with low HDL cholesterol (<0.9 mmol/l) and
      "ideal" total cholesterol (<5.2 mmol/l) were identified. Data on anthropometry,
      blood pressure (BP), insulin resistance, glucose tolerance, sex, smoking habit,
      and ethnic group were examined. We found that this group was heterogeneous. Those
      with fasting triglyceride (TG) >1.7 mmol/l (low HDL/high TG) displayed features
      of the insulin resistance syndrome characterized by obesity, higher diastolic BP,
      greater insulin resistance, and a greater tendency to have diabetes or impaired
      glucose tolerance (IGT). If fasting TG was <1.7 mmol/l (isolated low HDL
      cholesterol), individuals were similar to the general population in terms of
      insulin resistance and obesity. Both groups were more commonly men and Asian
      Indian. The ethnic difference in prevalence could not be explained by differences
      in diet, exercise, alcohol ingestion, or smoking. Our data support the view that
      Asian Indians are genetically predisposed to isolated low HDL cholesterol as well
      as the insulin resistance syndrome. The higher prevalence of isolated low HDL
      cholesterol, the young age at which individuals exhibit this phenotype (mean age
      32.5 years), along with the greater propensity for Asian Indians to develop
      insulin resistance and IGT contribute to the threefold increased incidence of
      myocardial infarction in those <65 years of age in this ethnic group.

PMID- 10331415
TI  - Metabolic and hemodynamic effects of moxonidine in the Zucker diabetic fatty rat
      model of type 2 diabetes.
AB  - We studied the effect of moxonidine, an imidazoline ligand, on metabolic and
      hemodynamic parameters in Zucker diabetic fatty rats, a model of type 2 diabetes.
      In one group (metabolic group), 8-week-old rats were started on a diet containing
      either moxonidine (3 or 10 mg x kg(-1) x day(-1)) or vehicle for 4 weeks. Body
      weight and food intake were monitored daily, plasma insulin and glucose were
      monitored weekly, and an oral glucose tolerance test (OGTT) was performed at
      study's end. In another group of rats (hemodynamic group), radio frequency
      transmitters were implanted 1 week before starting the diet, and mean blood
      pressure, heart rate, and motor activity were continuously monitored at baseline
      and for 4 weeks after beginning drug exposure. Moxonidine (10 mg x kg(-1) x day(
      1)) significantly decreased elevated glucose levels and prevented the decrease in
      plasma insulin noted in vehicle-treated or pair-fed groups. Moxonidine also
      decreased fasting glucose (3 and 10 mg x kg(-1) x day(-1)) and prevented the
      decrease in fasting insulin (10 mg x kg(-1) x day(-1)) compared with vehicle.
      Fasting glucose at 10 mg x kg(-1) x day(-1) was equivalent to lean littermates.
      Both doses significantly increased glucose disposal and the insulin secretory
      response during the OGTT. Moxonidine lowered daily mean arterial pressure
      compared with both baseline values and vehicle and decreased daily heart rates.
      Motor activity was unaffected, except for an increase in the 10 mg x kg(-1) x
      day(-1) group during low activity periods. Moxonidine did not significantly
      affect body weight, fluid intake, or urine volume, but the 10 mg x kg(-1) x day(
      1) dose reduced urinary protein excretion compared with vehicle-treated animals.
      These results demonstrate that, in an animal model of type 2 diabetes, the
      antihypertensive agent moxonidine induces a beneficial effect on abnormal glucose
      metabolism and renal protein excretion at doses that are effective in lowering
      arterial blood pressures and heart rate.

PMID- 10331416
TI  - Allosteric regulation of glycogen synthase and hexokinase by glucosamine-6
      phosphate during glucosamine-induced insulin resistance in skeletal muscle and
      heart.
AB  - Glucosamine infusion induces insulin resistance in vivo, but the effect of
      glucosamine on intracellular metabolites of the hexosamine pathway, especially
      glucosamine-6-phosphate (GlcN6P) is unknown. Because of the structural similarity
      of glucose-6-phosphate (G-6-P) and GlcN6P, we hypothesized that accumulation of
      this metabolite might alter the activities of enzymes such as glycogen synthase
      and hexokinase. We infused glucosamine (30 micromol x kg(-1) x min(-1)) to induce
      insulin resistance in rats during a euglycemic-hyperinsulinemic clamp.
      Glucosamine induced whole-body insulin resistance, which was apparent after 90
      min and continued progressively for 360 min. Despite inducing severe whole-body
      insulin resistance and decrease in glycogen synthase fractional activity in
      rectus abdominis muscle (69+/-3 vs. 83+/-1%, P<0.01) and heart (7+/-1 vs. 32+/
      4%, P<0.001), glucosamine did not change the glycogen content in rectus and even
      increased it in the heart (209+/-13 vs. 117+/-9 mmol/kg dry wt, P<0.001).
      Glucosamine increased tissue concentrations of UDP-GlcNAc 4.4- and 4.6-fold in
      rectus abdominis and heart, respectively. However, GlcN6P concentrations
      increased 500- and 700-fold in glucosamine-infused animals in rectus abdominis
      (590+/-80 vs. 1.2+/-0.1 micromol/kg wet wt, P<0.001) and heart (7,703+/-993 vs.
      11.2+/-2.3 micromol/kg wet wt, P<0.001). To assess the possible significance of
      GlcN6P accumulation, we measured the effect of GlcN6P on glycogen synthase and
      hexokinase activity in vitro. At the GlcN6P concentrations measured in rectus
      abdominis and heart in vivo, glycogen synthase was activated by 21 and 542%,
      while similar concentrations inhibited hexokinase activity by 5 and 46%,
      respectively. This study demonstrates that infusion of glucosamine during a
      euglycemic-hyperinsulinemic clamp results in marked accumulation of intracellular
      GlcN6P. The GlcN6P concentrations in the heart and rectus abdominis muscle reach
      levels sufficient to cause allosteric activation of glycogen synthase and
      inhibition of hexokinase.

PMID- 10331417
TI  - Tumor necrosis factor system activity is associated with insulin resistance and
      dyslipidemia in myotonic dystrophy.
AB  - Myotonic dystrophy (MyD) is a multisystem autosomal dominant disorder associated
      with progressive muscle wasting and weakness. The striking metabolic abnormality
      in MyD is insulin resistance. The mechanism by which target tissues are
      insensitive to insulin action remains uncertain. In a recent study, plasma
      soluble tumor necrosis factor receptor (sTNFR)2 levels were found to be
      associated with muscle tissue mass and insulin resistance. Given these
      associations, we speculated that disorders of the muscle cell membrane could lead
      simultaneously to insulin insensitivity and sTNFR2 leakage in MyD. To test this
      hypothesis, we measured the levels of circulating sTNFR1 and sTNFR2 and insulin
      resistance in MyD patients. We studied 22 MyD patients and 24 age-, BMI-, and fat
      mass-matched control subjects. Both MyD men and women showed higher plasma
      insulin levels in the presence of comparable glucose concentrations than did
      control subjects. sTNFR2, but not sTNFR1, levels were approximately 1.5-fold
      higher in MyD patients. In parallel with these findings, the fasting insulin
      resistance index (FIRI) was also higher in MyD patients. In fact, in the whole
      population, fasting insulin and FIRI strongly correlated with sTNFR2 in both men
      (r = 0.77 and r = 0.81, P<0.0001, respectively) and women (r = 0.67 and r = 0.64,
      P = 0.001, respectively). sTNFR2 levels were also associated with the insulin
      sensitivity index (S(I)), calculated from an oral glucose tolerance test (OGTT)
      according to the method by Cederholm and Wibell (r = -0.43, P = 0.006). We
      constructed a multiple linear regression to predict FIRI, with BMI, waist-to-hip
      ratio, and sTNFR2 as independent variables. In this model, both BMI (P = 0.0014)
      and sTNFR2 (P = 0.0048) levels contributed independently to 46% of the variance
      of FIRI. In another model, in which FIRI was substituted for S(I) from the OGTT,
      both BMI (P = 0.0001) and sTNFR2 (P = 0.04) levels contributed independently to
      48% of the variance of S(I) from the OGTT. Plasma cholesterol and triglyceride
      concentrations were significantly increased in MyD patients. sTNFR1 and sTNFR2
      levels were found to be strongly associated with plasma cholesterol, LDL
      cholesterol, and triglycerides. sTNFR1 and sTNFR2 also correlated with serum
      creatine kinase activity in MyD patients (r = 0.57, P = 0.006; r = 0.75,
      P<0.0001, respectively). In conclusion, here we describe, for the first time to
      our knowledge, a relationship between insulin action and plasma sTNFR2
      concentration in MyD patients. We have also found increased concentrations of
      plasma triglycerides and cholesterol levels in parallel with sTNFR1 and sTNFR2
      concentrations in MyD patients. We speculate that the latter associations are
      dependent on, and secondary to, increased tumor necrosis factor (TNF)-alpha
      action. Whether TNF action is implicated in the pathogenesis of MyD or is a
      simple marker of disease activity awaits further studies.

PMID- 10331418
TI  - Association of increased intramyocellular lipid content with insulin resistance
      in lean nondiabetic offspring of type 2 diabetic subjects.
AB  - Insulin resistance plays an important role in the pathogenesis of type 2
      diabetes; however, the multiple mechanisms causing insulin resistance are not yet
      fully understood. The aim of this study was to explore the possible contribution
      of intramyocellular lipid content in the pathogenesis of skeletal muscle insulin
      resistance. We compared insulin-resistant and insulin-sensitive subjects. To meet
      stringent matching criteria for other known confounders of insulin resistance,
      these individuals were selected from an extensively metabolically characterized
      group of 280 first-degree relatives of type 2 diabetic subjects. Some 13 lean
      insulin-resistant and 13 lean insulin-sensitive subjects were matched for sex,
      age, BMI, percent body fat, physical fitness, and waist-to-hip ratio. Insulin
      sensitivity was determined by the hyperinsulinemic-euglycemic clamp method (for
      insulin-resistant subjects, glucose metabolic clearance rate [MCR] was 5.77+/
      0.28 ml x kg(-1) x min(-1) [mean +/- SE]; for insulin-sensitive subjects, MCR was
      10.15+/-0.7 ml x kg(-1) x min(-1); P<0.002). Proton magnetic resonance
      spectroscopy (MRS) was used to measure intramyocellular lipid content (IMCL) in
      both groups. MRS studies demonstrated that in soleus muscle, IMCL was increased
      by 84% (11.8+/-1.6 vs. 6.4+/-0.59 arbitrary units; P = 0.008 ), and in tibialis
      anterior muscle, IMCL was increased by 57% (3.26+/-0.36 vs. 2.08+/-0.3 arbitrary
      units; P = 0.017) in the insulin-resistant offspring, whereas the
      extramyocellular lipid content and total muscle lipid content were not
      statistically different between the two groups. These data demonstrate that in
      these well-matched groups of lean subjects, IMCL is increased in insulin
      resistant offspring of type 2 diabetic subjects when compared with an insulin
      sensitive group matched for age, BMI, body fat distribution, percent body fat,
      and degree of physical fitness. These results indicate that increased IMCL
      represents an early abnormality in the pathogenesis of insulin resistance and
      suggest that increased IMCL may contribute to the defective glucose uptake in
      skeletal muscle in insulin-resistant subjects.

PMID- 10331420
TI  - Vascular endothelial growth factor activates nuclear factor-kappaB and induces
      monocyte chemoattractant protein-1 in bovine retinal endothelial cells.
AB  - Vascular endothelial growth factor (VEGF) has been suggested to play a role in
      the pathogenesis of diabetic vascular complications. In the present study, we
      investigated whether expression of monocyte chemoattractant protein-1 (MCP-1), a
      chemokine that has been proposed to recruit leukocytes to sites of inflammation,
      neovascularization, and vascular injury, can be modulated by VEGF in bovine
      retinal microvascular endothelial cells (BRECs). VEGF induced expression of MCP-1
      mRNA in BRECs in a concentration- and time-dependent manner. Secretion of MCP-1
      into the culture medium of BRECs treated with VEGF for 24 h was increased by 2.2
      fold compared with the control. Inhibitors of transcription factor NF-kappaB, N
      alpha-tosyl-L-lysine chloromethylketone (TLCK) and N-acetylcysteine (NAC), as
      well as an inhibitor of the extracellular signal-regulated kinase (ERK) pathway,
      PD 98059, attenuated VEGF-induced expression of MCP-1 mRNA. Using electrophoretic
      gel mobility shift assay, we observed that VEGF stimulated binding activity of NF
      kappaB. VEGF-induced NF-kappaB activation was inhibited by TLCK and NAC, but not
      by PD 98059. Binding activity of transcription factor AP-1, which is suggested to
      regulate induction of the MCP-1 gene together with NF-kappaB, was also stimulated
      by VEGF. PD 98059 inhibited the VEGF-induced activation of AP-1. These results
      indicate that VEGF induces MCP-1 expression in BRECs most likely by activating NF
      kappaB and AP-1 via ERK-independent and -dependent pathways. Activation of NF
      kappaB and induction of MCP-1 by VEGF in microvascular endothelial cells may
      contribute to the development of diabetic vascular complications.

PMID- 10331419
TI  - Endothelin-1 modulates insulin signaling through phosphatidylinositol 3-kinase
      pathway in vascular smooth muscle cells.
AB  - Diminished insulin action in the vasculature may contribute to the development of
      cardiovascular diseases in diabetes. We have studied insulin's effects on the
      phosphatidylinositol (PI) 3-kinase pathway in arterial smooth muscle cells (SMCs)
      and its inhibition by endothelin (ET)-1, a potent vasoactive hormone reported to
      be elevated in insulin resistance and other vascular diseases. ET-1 increased the
      level of serine phosphorylation of insulin receptor beta subunit but increased
      both tyrosine and serine phosphorylation of insulin receptor substrate (IRS)-2.
      Pretreatment of cells with ET-1 (10 nmol/l) inhibited insulin-stimulated PI 3
      kinase activity associated with IRS-2 by 50-60% and inhibited the association of
      p85 subunit of PI 3-kinase to IRS-2. The inhibition of insulin-stimulated PI 3
      kinase activity by ET-1 was prevented by BQ-123, a selective ET(A) receptor
      antagonist, but was not affected by pertussis toxin. Treatment of cells with
      phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), reduced
      both insulin-stimulated PI 3-kinase activity by 57% and the association of IRS-2
      to the p85 subunit of PI 3-kinase by 40%, whereas GF109203X, a specific inhibitor
      of PKC, partially prevented the inhibitory effect of ET-1 on insulin-induced PI 3
      kinase activity. These results suggested that ET-1 could interfere with insulin
      signaling in SMCs by both PKC-dependent and -independent pathways.

PMID- 10331421
TI  - Significance of glutathione-dependent antioxidant system in diabetes-induced
      embryonic malformations.
AB  - Hyperglycemia-induced embryonic malformations may be due to an increase in
      radical formation and depletion of intracellular glutathione (GSH) in embryonic
      tissues. In the past, we have investigated the role of the glutathione-dependent
      antioxidant system and GSH on diabetes-related embryonic malformations. Embryos
      from streptozotocin-induced diabetic rats on gestational day 11 showed a
      significantly higher frequency of embryonic malformations (neural lesions 21.5
      vs. 2.8%, P<0.001; nonneural lesions 47.4 vs. 6.4%, P<0.001) and growth
      retardation than those of normal mothers. The formation of intracellular reactive
      oxygen species (ROS), estimated by flow cytometry, was increased in isolated
      embryonic cells of diabetic rats on gestational day 11. The concentration of
      intracellular GSH in embryonic tissues of diabetic pregnant rats on day 11 was
      significantly lower than that of normal rats. The activity of y-glutamylcysteine
      synthetase (gamma-GCS), the rate-limiting GSH synthesizing enzyme, in embryos of
      diabetic rats was significantly low, associated with reduced expression of gamma
      GCS mRNA. Administration of buthionine sulfoxamine (BSO), a specific inhibitor of
      gamma-GCS, to diabetic rats during the period of maximal teratogenic
      susceptibility (days 6-11 of gestation) reduced GSH by 46.7% and increased the
      frequency of neural lesions (62.1 vs. 21.5%, P<0.01) and nonneural lesions (79.3
      vs. 47.4%, P<0.01). Administration of GSH ester to diabetic rats restored GSH
      concentration in the embryos and reduced the formation of ROS, leading to
      normalization of neural lesions (1.9 vs. 21.5%) and improvement in nonneural
      lesions (26.7 vs. 47.4%) and growth retardation. Administration of insulin in
      another group of pregnant rats during the same period resulted in complete
      normalization of neural lesions (4.3 vs. 21.5%), nonneural lesions (4.3 vs.
      47.4%), and growth retardation with the restoration of GSH contents. Our results
      indicate that GSH depletion and impaired responsiveness of GSH-synthesizing
      enzyme to oxidative stress during organogenesis may have important roles in the
      development of embryonic malformations in diabetes.

PMID- 10331422
TI  - Basic fibroblast growth factor induces expression of VEGF receptor KDR through a
      protein kinase C and p44/p42 mitogen-activated protein kinase-dependent pathway.
AB  - Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor
      (bFGF) are angiogenic molecules whose combined mitogenic activity is potently
      synergistic. However, the molecular mechanism underlying this synergy is
      incompletely understood. We examined whether VEGF and bFGF affect expression of
      each other or alter expression of the VEGF receptor KDR in retinal capillary
      endothelial cells. In addition, we investigated the intracellular signaling
      mechanisms involved in this response. VEGF-induced [3H]thymidine uptake was
      tightly correlated with KDR mRNA and protein concentrations, suggesting that
      increased KDR expression might account for VEGF's synergistic activity in the
      presence of bFGF. bFGF (10 ng/ml) induced KDR mRNA expression within 4 h and
      attained a 4.0-fold increase after 24 h. KDR protein expression was increased 7.5
      fold after 48 h. VEGF (= 50 ng/ml) did not alter bFGF, VEGF, or KDR mRNA
      expression under serum-deprived conditions. In contrast, VEGF increased KDR mRNA
      expression 87% under growth conditions and 2.9-fold under serum-deprived
      conditions in the presence of bFGF. The protein kinase C (PKC) agonist phorbol
      myristate acetate (PMA) induced KDR mRNA expression 5.1-fold at 100 nmol/l. bFGF
      increased p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation within
      5 min, reaching a maximum within 15 min and remaining significantly elevated for
      >6 h. bFGF-induced MAPK phosphorylation and KDR mRNA expression were almost
      completely inhibited by 5 micromol/l GFX, a non-isoform-selective PKC inhibitor.
      MAPK inhibitor PD98059 reduced KDR mRNA expression 72% at concentrations that
      inhibited bFGF-induced MAPK phosphorylation 100%, suggesting that pathways in
      addition to MAPK might also be involved. Inhibitors of the beta isoform of PKC
      (LY333531), protein kinase A (PKA) (H89), and phosphotidylinositol (PI) 3 kinase
      (wortmannin) had no significant effect. These data suggest that bFGF stimulates
      KDR expression through a PKC and p44/p42 MAPK-dependent pathway not primarily
      involving the beta isoform of PKC, PKA, or PI-3 kinase. Since bFGF induces VEGF
      expression and since increased KDR expression potentiates VEGF action, resulting
      in additional KDR expression and marked mitogenic activity, these data provide a
      novel mechanistic explanation for the angiogenic synergy between VEGF and bFGF.

PMID- 10331423
TI  - Activation of the tissue factor pathway of blood coagulation during prolonged
      hyperglycemia in young healthy men.
AB  - Patients with diabetes have an increased prevalence of premature atherosclerotic
      vascular disease, and alterations in plasma coagulation proteins have been
      incriminated as a possible cause. The roles of hyperglycemia and hyperinsulinemia
      in the pathogenesis of these changes are unknown. To examine the effects of
      prolonged hyperglycemia and of selective hyperinsulinemia on the tissue factor
      pathway of blood coagulation, nine healthy young men were infused with glucose to
      maintain levels at 11.1 mmol/l (approximately 200 mg/dl) for 18-72 h
      (hyperglycemia-hyperinsulinemia group). Five normal men were infused with regular
      insulin to maintain levels comparable to that in the previous group (900 pmol/l,
      approximately 150 microU/ml) and with glucose to maintain levels at 5.6 mmol/l
      (approximately 100 mg/dl) (euglycemia-hyperinsulinemia group). Measured were
      plasma activated factor VII activity (FVIIa), FVII coagulant (FVIIC) activity,
      FVIII coagulant (FVIIIC) activity, tissue factor pathway inhibitor (TFPI)
      antigen, and thrombin markers; and serum glucose, insulin, and electrolytes.
      Plasma FVIIa, FVIIC, FVIIIC, and TFPI rose during hyperglycemic-hyperinsulinemia
      but not during euglycemic-hyperinsulinemia. Markers of thrombin generation rose
      transiently and inconsistently during hyperglycemia-hyperinsulinemia. We
      concluded that in normal subjects, hyperglycemia-hyperinsulinemia induced
      activation of the tissue factor pathway, reflected by increases in plasma FVIIa,
      FVIIC, and TFPI. This activation was independent of hyperinsulinemia,
      hypertriglyceridemia, and hyperosmolality. The elevations in plasma coagulation
      factors during hyperglycemia-hyperinsulinemia, characteristic of type 2 diabetes,
      may constitute a potential for enhanced thrombin generation and thrombosis when
      triggered by exposure of tissue factor, such as during arterial plaque rupture.

PMID- 10331424
TI  - Functional study of the E276Q mutant hepatocyte nuclear factor-4alpha found in
      type 1 maturity-onset diabetes of the young: impaired synergy with chicken
      ovalbumin upstream promoter transcription factor II on the hepatocyte nuclear
      factor-1 promoter.
AB  - Seven mutations in the hepatocyte nuclear factor (HNF)-4alpha gene have been
      shown to correlate with type 1 maturity-onset diabetes of the young (MODY 1), a
      monogenic form of type 2 diabetes. Up to now, only the functional properties of
      two MODY 1 HNF-4alpha mutants, Q268X and V393I, have been investigated to address
      how the mutations in the HNF-4alpha gene, found by genetic studies, can give rise
      to impaired activities of mutated HNF-4alpha proteins and can cause this disease.
      The E276Q mutation results in a nonconservative substitution occurring in the HNF
      4alpha E domain, which is involved in dimerization and transactivation activities
      as well as in protein-protein interactions with other transcription factors or
      coactivators. Using the mutated human HNF-4alpha2, we have found that, in the
      absence of chicken ovalbumin upstream promoter transcription factor II (COUP
      TFII), the E276Q substitution does not significantly affect the dimerization and
      transactivating activities of HNF-4alpha, at least on the promoters studied
      herein. On the other hand, in the presence of COUP TFII, the substitution impairs
      the enhancement of HNF-4-mediated activation of HNF-1 promoter. The impaired
      synergy between COUP TFII and HNF-4 on the HNF-1 promoter results from an
      alteration of their interaction. HNF-1 expression plays a crucial role in
      transactivation of insulin promoter and of numerous genes coding for enzymes
      involved in glucose homeostasis. Therefore, its downregulation resulting from the
      E276Q mutation in HNF-4alpha gene most probably impairs the function of
      pancreatic beta-cells.

PMID- 10331425
TI  - Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex
      trait.
AB  - Type 2 diabetes is a complex trait with both genes and environmental factors
      contributing to susceptibility. Except for rare subtypes with monogenic
      inheritance, the genetic basis of type 2 diabetes is unknown because of the
      complex and heterogeneous nature of the disease. By using the NSY mouse, an
      inbred mouse model of type 2 diabetes, we genetically dissected late-onset type 2
      diabetes and demonstrated age-dependent changes in the genetic control of type 2
      diabetes as well as polygenic inheritance. Three major loci (Nidd1nsy, Nidd2nsy,
      Nidd3nsy) were mapped on mouse chromosomes (Chr) 11, 14, and 6, respectively. The
      existence of a fourth locus (Nidd4nsy) with an age-dependent effect was suggested
      by longitudinal, but not cross-sectional, analysis of linkage data. Nidd1nsy and
      Nidd4nsy appear to affect insulin secretion, whereas Nidd2nsy and Nidd3nsy appear
      to affect insulin sensitivity. A locus on Chr 6 was significantly linked to
      epididymal fat weight. A candidate disease gene (Tcf2) on Chr 11, encoding
      hepatic nuclear factor-1beta, was shown to have a rare sequence variant in the
      DNA binding domain in the model. The mouse model we used will serve as a useful
      model for future studies on the etiology of late-onset polygenic type 2 diabetes
      in humans.

PMID- 10331426
TI  - A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians.
AB  - Considerable evidence supports a major inherited component of type 2 diabetes. We
      initially conducted a genome-wide scan with 440 microsatellite markers at 10-cM
      intervals in 19 multigenerational families of Northern European ancestry with at
      least two diabetic siblings. Initial two-point analyses of these families
      directed marker typing of 23 additional families. Subsequently, all available
      marker data on the total of 42 families were analyzed using both parametric and
      nonparametric multipoint methods to test for linkage to type 2 diabetes. One
      locus on chromosome 1q21-1q23 met genome-wide criteria for significant linkage
      under a model of recessive inheritance with a common diabetes allele (logarithm
      of odds [LOD] = 4.295). Both pedigree-based nonparametric linkage (NPL) analysis
      and affected sib pair (MAPMAKER/SIBS) nonparametric methods also showed the
      highest genome-wide scores at this region, near markers CRP and APOA2, but failed
      to meet levels of genome-wide significance. The risk of type 2 diabetes to
      siblings of a diabetic person when compared with the population (lambdaS) was
      estimated from MAPMAKER/SIBS to be 2.8 in these 42 families. Simulation studies
      using study data confirmed a genome-wide significance level of P<0.05 (95% CI
      0.005-0.0466). However, analysis of 20 similarly ascertained but smaller families
      failed to confirm this linkage. The LOD score with 50% heterogeneity for all 62
      families considered together was only 2.25, with an estimated lambdaS of 1.87.
      Our data suggest a novel diabetes susceptibility locus near APOA2 on chromosome 1
      in a region with many transcribed genes.

PMID- 10331427
TI  - Genetic analysis of obese diabetes in the TSOD mouse.
AB  - The molecular pathogenesis of diabetes remains poorly understood because of the
      genetic complexity of the disease. One possibly effective approach to elucidate
      the pathogenesis is to study an animal model with a similar phenotype. The TSOD
      (Tsumura, Suzuki, Obese Diabetes) mouse, a newly developed animal model, exhibits
      both diabetes and obesity with marked hyperinsulinemia and hypertrophy of the
      pancreatic islets and might represent a common form of obese type 2 diabetes in
      humans. Phenotypic characterization revealed that the TSOD mouse had both insulin
      resistance and impaired glucose-stimulated insulin secretion. A comprehensive
      genetic dissection of diabetes and obesity has been performed using F1 and F2
      progeny between the TSOD and control BALB/cA strains. A genome-wide screen for
      loci linked to glucose homeostasis and body weight allowed us to map three
      quantitative trait loci (QTLs) involved in this disorder. The major genetic
      determinant of blood glucose levels was identified on chromosome 11. Furthermore,
      two independent QTLs involved in controlling body weight were found on
      chromosomes 1 and 2. The QTL on chromosome 2 also affected insulin levels
      significantly. Each QTL has distinct effects on different traits and a different
      mode of inheritance. Our study indicates that hyperglycemia and obesity are
      clearly controlled by distinct combinations of genetic loci in this mouse model
      and provides insights into the genetic basis of common forms of human type 2
      diabetes with obesity.

PMID- 10331428
TI  - Acute exercise induces GLUT4 translocation in skeletal muscle of normal human
      subjects and subjects with type 2 diabetes.
AB  - Total GLUT4 content in skeletal muscle from individuals with type 2 diabetes is
      normal; however, recent studies have demonstrated that translocation of GLUT4 to
      the plasma membrane is decreased in response to insulin stimulation. It is not
      known whether physical exercise stimulates GLUT4 translocation in skeletal muscle
      of individuals with type 2 diabetes. Five subjects (two men, three women) with
      type 2 diabetes and five normal control subjects (5 men), as determined by a
      standard 75-g oral glucose tolerance test, were recruited to determine whether an
      acute bout of cycle exercise activates the translocation of GLUT4 to the plasma
      membrane in skeletal muscle. Each subject had two open biopsies of vastus
      lateralis muscle; one at rest and one 3-6 weeks later from the opposite leg after
      45-60 min of cycle exercise at 60-70% of VO2max. Skeletal muscle plasma membranes
      were prepared by subcellular fractionation, and GLUT4 content was determined by
      Western blotting. Plasma membrane GLUT4 increased in each subject in response to
      exercise. The mean increase in plasma membrane GLUT4 for the subjects with type 2
      diabetes was 74 +/-20% above resting values, and for the normal subjects the
      increase was 71+/-18% above resting values. Although plasma membrane GLUT4
      content was approximately 32% lower at rest and after exercise in the muscle of
      the subjects with type 2 diabetes, the differences were not statistically
      significant. We conclude that in contrast to the previously reported defect in
      insulin-stimulated GLUT4 translocation in skeletal muscle of individuals with
      type 2 diabetes, a single bout of exercise results in the translocation of GLUT4
      to the plasma membrane in skeletal muscle of individuals with type 2 diabetes.
      These data provide the first direct evidence that GLUT4 translocation is an
      important cellular mechanism through which exercise enhances skeletal muscle
      glucose uptake in individuals with type 2 diabetes.

PMID- 10331429
TI  - Banting Lecture 1997. Control of glucose uptake and release by the liver in vivo.

PMID- 10331430
TI  - Developmental neuropathology and impact of perinatal brain damage. III: gray
      matter lesions of the neocortex.
AB  - The evolving neuropathology of primarily undamaged cortical regions adjacent to
      the injured site has been studied in 36 infants who survived a variety of
      perinatally acquired encephalopathies (microgyrias, ulegyrias, multicystic
      encephalopathies, porencephalies, and hydranencephalies) and later died of
      unrelated causes. Their survival times range from hours, days, weeks, or months,
      to several years. Ten of these children developed epilepsy, 2 developed cerebral
      palsy, and several were neurologically and mentally impaired. In all cases
      studied, the undamaged cortex adjacent to the injured site survives, retains its
      intrinsic vasculature, and is capable of continuing differentiation. However, its
      postinjury development is characterized by progressive alterations compatible
      with acquired cortical dysplasia that affects the structural and functional
      differentiation of its neurons, synaptic profiles, fiber distribution, glial
      elements, and vasculature. The synaptic profiles of many neurons are transformed
      by an increased number of intrinsic loci that replace extrinsic ones vacated by
      the destruction of afferent fibers. The intrinsic fibers of layer I and some
      Cajal-Retzius cells survive even in severe lesions and may be capable of
      interconnecting cortical regions that have lost other type of connections. Some
      intrinsic neurons undergo postinjury structural and functional hypertrophy,
      acquire new morphologic and functional features, and achieve a large size
      (meganeurons). Probably, these meganeurons acquire their structural and
      functional hypertrophy by partial endomitotic DNA and/or RNA reduplication
      (polyploidy). These postinjury alterations are not static but ongoing processes
      that continue to affect the structural and functional differentiation of the
      still developing cortex and may eventually influence the neurologic and cognitive
      maturation of affected children. This study proposes that, in acquired
      encephalopathies, the progressive postinjury reorganization of the undamaged
      cortex and its consequences (acquired cortical dysplasia), rather than the
      original lesion, represent the main underlying mechanism in the pathogenesis of
      ensuing neurological sequelae, such as, epilepsy, cerebral palsy, dyslexia,
      cognitive impairment, and/or poor school performance.

PMID- 10331432
TI  - Induction of apoptosis signal regulating kinase 1 (ASK1) after spinal cord injury
      in rats: possible involvement of ASK1-JNK and -p38 pathways in neuronal
      apoptosis.
AB  - The aims of this study were to clarify the mechanism of cell death by apoptosis
      in the spinal cord after traumatic injury, and to examine the role of the mitogen
      activated protein kinase (MAPK) pathways in the transmission of apoptosis
      signals. The rat spinal cord, experimentally injured by extradural static weight
      compression, was studied by hematoxylin and eosin staining, Nissl-staining,
      terminal deoxynucleotidyl transferase (TdT) mediated dUTP nick-end labeling
      (TUNEL) staining, and immunostaining using polyclonal antibodies against
      Apoptosis Signal-regulating Kinase 1 (ASK1), c-Jun N-terminal kinase (JNK), and
      p38 MAPK. TUNEL-positive cells were present at all stages studied until 7 days
      after injury, and percentage positivity for these cells was maximal at 3 days
      after injury. Electron microscopic analysis revealed the occurrence of apoptosis
      in both neuronal cells and glial cells. TUNEL-positive glial cells were stained
      by oligodendrocyte-specific maker. Expression of ASK1 was maximal at 24 h after
      injury in the gray matter and at 3 days after injury in the white matter.
      Following the expression of ASK1, activated forms of JNK and p38 were observed in
      apoptotic cells detected by the TUNEL method. Colocalization of ASK1 and
      activated JNK or activated p38 was observed in the same cell. These findings
      suggest the involvement of the stress-activated MAPK pathways including ASK1 in
      the transmission of apoptosis signals after spinal cord injury.

PMID- 10331431
TI  - Monoclonal antibody to human midkine reveals increased midkine expression in
      human brain tumors.
AB  - We produced a rat IgG2a monoclonal antibody against the carboxyl terminal region
      of human midkine (MK), a novel growth factor. This monoclonal antibody was used
      in immunohistochemical studies to compare the expression of MK, proliferating
      cell nuclear antigen (PCNA) and p53 protein in 133 primary brain tumors and 21
      carcinoma metastases to the central nervous system. Approximately half of the
      glioblastomas multiforme (GBMs) (19/32), medulloblastomas (8/14), primitive
      neuroectodermal tumors (PNETs) (5/11), breast carcinoma metastases (Br-Mts)
      (6/10) and lung carcinoma metastases (L-Mts) (5/11) as well as some astrocytomas
      (2/14) had tumor cells that expressed MK; however, oligodendrogliomas,
      ependymomas, schwannomas, meningiomas, and pituitary adenomas did not express MK.
      The values of the PCNA-labeling index were statistically higher in GBMs,
      medulloblastomas, PNETs, Br-Mts, and L-Mts that expressed MK than in those that
      did not (Wilcoxon rank-sum test, p < 0.05). There was no correlation between MK
      and p53 protein in all tumor types. Normal and non-neoplastic brain tissues were
      negative for MK, PCNA, and p53 protein. We conclude that primary and metastatic
      tumors of the brain express MK and that the MK expression in brain tumors may
      depend, in part, on the proliferating potential.

PMID- 10331433
TI  - 5'-Nucleotidase activity indicates sites of synaptic plasticity and reactive
      synaptogenesis in the human brain.
AB  - The localization and morphological assessment of plastic or newly formed synapses
      in the human brain remains difficult due to the lack of specific markers. The
      ectoenzyme 5'-nucleotidase may represent a useful marker of these structures,
      since in adult rodents synaptic 5'-nucleotidase activity is restricted to sites
      of spontaneous synaptic turnover and induced reactive synaptogenesis. However, it
      is unclear to what extent synaptic 5'-nucleotidase activity occurs in the normal
      human brain, and whether reactive synaptogenesis, as seen e.g. in temporal lobe
      epilepsy (TLE), is associated with this ectoenzyme. Therefore, we have
      investigated the histochemical distribution of 5'-nucleotidase in hippocampal
      control specimens (n = 3) and in the hippocampus of TLE patients (n = 13). In
      controls, 5'-nucleotidase activity was present in the dentate gyrus molecular
      layer (DG-ML) and the mossy fiber termination field within the CA4 and CA3
      subfields. Compared with controls, TLE specimens revealed markedly increased 5'
      nucleotidase labeling in the DG-ML, implying TLE-associated reactive
      synaptogenesis in this hippocampal region. In contrast to GAP-43, synaptophysin,
      and dynorphin A, synaptic 5'-nucleotidase activity may serve as a potential
      specific indicator of plastic synapses or newly formed terminals in the human
      brain and prove useful for the study of diseases involving aberrant sprouting or
      altered synaptic plasticity.

PMID- 10331434
TI  - Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible
      contribution of a programmed cell death mechanism.
AB  - The mechanisms for neurodegeneration in amyotrophic lateral sclerosis (ALS) are
      not understood. We found that motor neuron degeneration in ALS structurally
      resembles apoptosis. The progression of neuronal death is divisible into 3
      sequential stages: chromatolysis, somatodendritic attrition, and apoptosis. In
      ALS spinal cord anterior horn and motor cortex, DNA fragmentation is detectable
      in situ and in gels and is internucleosomal, occurring in the presence of DNA
      fragmentation factor-45/40 activation and increased caspase-3 activity. By
      immunoblotting, changes occur in the subcellular distribution of cell death
      proteins that would promote apoptosis. In selectively vulnerable CNS regions in
      ALS compared with controls, the proapoptotic proteins Bax and Bak are elevated in
      the mitochondrial-enriched membrane compartment, but are reduced or unchanged in
      the cytosol. In contrast, the antiapoptotic protein Bcl-2 is decreased in the
      mitochondrial-enriched membrane compartment of vulnerable regions in ALS, but is
      increased in the cytosol, whereas Bcl-xL levels are unchanged in both subcellular
      compartments. Coimmunoprecipitation experiments showed that Bax-Bax interactions
      are greater in the mitochondrial-enriched membrane compartment of ALS motor
      cortex compared with controls, whereas Bax-Bcl-2 interactions are lower in the
      membrane compartment of ALS motor cortex compared with controls. We conclude that
      a PCD mechanism, involving cytosol-to-membrane and membrane-to-cytosol
      redistribution of cell death proteins and caspase-3 activation, participates in
      the pathogenesis of ALS.

PMID- 10331435
TI  - Restoration of wild-type PTEN expression leads to apoptosis, induces
      differentiation, and reduces telomerase activity in human glioma cells.
AB  - PTEN is a candidate tumor suppressor gene identified on human chromosome 10q23.3
      that is frequently mutated or deleted in 30% to 44% of glioblastomas. Transient
      expression study of PTEN in glioma cells indicates that PTEN plays an important
      role in cellular proliferation, tumorigenicity, cell migration, and focal
      adhesions. In this study, we examined the biological consequences on U87MG glioma
      cells after stable gene transfer of wild-type PTEN. Cells stably expressing wild
      type PTEN protein were found to have suppressed proliferation, as determined by
      cell counting and Ki-67 staining, as well as inhibited anchorage-independent
      growth. The PTEN-expressing cells also showed higher expression of glial
      fibrillary acidic protein and changed morphologically from spindle-shaped to
      elongated cell bodies with multiple slender processes, suggesting that these
      cells have undergone differentiation. In addition, telomerase activity decreased
      more than 10-fold in PTEN-expressing cells when compared with control cells. More
      importantly, apoptosis was detected in about 5% of PTEN-expressing cells,
      representing a 17-fold (p < 0.01) increase over the control cells. Taken
      together, these results suggest that PTEN plays an important role in regulation
      of cell homeostasis by maintaining a balance between proliferation,
      differentiation, and apoptosis.

PMID- 10331436
TI  - CNS interleukin-3 (IL-3) expression and neurological syndrome in antisense-IL-3
      transgenic mice.
AB  - Interleukin-3 (IL-3) is an important mediator of physiological and
      pathophysiological processes affecting the central nervous system (CNS). It
      stimulates the proliferation and activation of microglia and can enhance
      differentiation of cholinergic and sensory neurons. To examine the role of IL-3
      in the CNS, we utilized transgenic mice expressing a murine antisense IL-3 (AS-IL
      3) RNA under the control of the T cell B19 promoter so that expression is limited
      to hematopoietic cells. The AS-IL-3 transgenic mice develop either a progressive
      neurologic dysfunction, which includes ataxia, bradykinesia, and paralysis, or a
      lymphoproliferative syndrome. Histopathology demonstrated accumulations of
      reactive astrocytes in the cerebellum, brain stem, and spinal cord, accompanied
      by activated microglia. Partial loss of cerebellar nuclei neurons as well as
      neurons in the cranial nerve nuclei and spinal cord motor neurons is seen.
      Despite depletion of IL-3 peripherally, expression of IL-3 mRNA and protein is
      turned on in the CNS of the transgenic mice. Astrocytes cultured from the AS-IL-3
      mice contain IL-3 mRNA and may thus be responsible for the activation of the
      microglia. This model should provide important insights into the role of
      cytokines in neurological disorders.

PMID- 10331437
TI  - Cell proliferation and nestin expression in the ependyma of the adult rat spinal
      cord after injury.
AB  - A population of precursor cells is known to exist in the subependyma of the
      lateral ventricles in adult rodents. However, the source of the precursor cells
      in the adult mammalian spinal cord has not been identified in vivo, although the
      adult spinal cord was recently reported to contain neural stem cells in vitro. In
      this study we found active cell proliferation and nestin expression in the adult
      ependyma of the central canal after spinal cord injury. The normal ependyma
      showed limited proliferative activity indicated by a low Ki-67 labeling index
      (1.5% at T1 level) and no immunoreactivity to nestin, a marker for neural
      precursor cells. In contrast, the spinal cord injured by clip compression
      demonstrated a dramatic increase in ependymal proliferation indicated by a high
      Ki-67 labeling index (maximum of 26% at 3 days [d] after injury) and concomitant
      strong nestin expression in the ependyma. These responses were downregulated by 7
      d after injury. The increased cell proliferation in the ependyma was observed
      only at sites immediately adjacent to the lesion. After injury, nestin positive,
      GFAP negative cell populations were found in areas surrounding the ependymal
      layer, which suggests migration of the ependymal cells. These results indicate
      the precursor cell qualities of the adult ependyma after injury. Thus, we propose
      the ependyma of the central canal, which is normally latent but activates locally
      and temporally in response to spinal cord injury, as the in vivo source for
      precursor cells in the adult mammalian spinal cord.

PMID- 10331438
TI  - Activation of the protease-activated thrombin receptor (PAR)-1 induces motoneuron
      degeneration in the developing avian embryo.
AB  - Several studies have shown that both neuronal and glial cells express functional
      thrombin receptors as well as prothrombin transcripts. Recently, we (and others)
      have shown that alpha-thrombin induces apoptotic cell death in different neuronal
      cell types, including motoneurons, in culture. Thrombin-induced effects on
      different cells are mediated through the cell surface protease-activated thrombin
      receptor, PAR-1. Furthermore, it has been shown that, in contrast to thrombin,
      which induces proteolysis of other proteins besides its receptor, the thrombin
      receptor agonist peptide, serine-phenylalanine-leucine-leucine-arginine
      asparagine-proline (SFLLRNP), is only known to activate this receptor. However,
      whether activation of the thrombin receptor in vivo affects the development of
      spinal cord motoneurons is not known. Here, we show that treatment with a
      synthetic SFLLRNP peptide induced a dose-dependent degeneration and death of
      spinal motoneurons both in highly enriched cultures and in the developing chick
      embryo in vivo. However, cotreatment with caspase inhibitors completely abolished
      SFLLRNP-induced motoneuron death both in vitro and in vivo. These results suggest
      that developing motoneurons express functionally active PAR-1 whose activation
      leads to cell death through stimulation of the caspase family of proteins. Our
      findings also suggest a novel and deleterious role for PAR-like receptors in the
      central nervous system, different from their previously known functions in the
      vascular and circulatory system.

PMID- 10331439
TI  - No association of HIV type 1 long terminal repeat sequence pattern with long-term
      nonprogression and in vivo viral replication levels in European subjects.
AB  - The HIV-1 long terminal repeat (LTR) promotes and modulates proviral
      transcription in the infected cell. It has been suggested that truncations and
      even point mutations in functional sites of the LTR are associated with low viral
      replication and attenuated pathogenesis in HIV-1-infected long-term
      nonprogressors (LTNPs). We performed a detailed analysis of LTR sequences from
      proviral DNA of 21 Italian and Swedish, well-characterized LTNPs and of 15
      progressor patients. No truncation was found and no correlation was identified
      between specific LTR mutations and disease progression. We also failed to find a
      significant correlation between phylogenetic distance and clinical status.
      Although HIV-1 LTR interpatient heterogeneity among LTNPs and subjects with HIV-1
      RNA levels <500 copies/ml tended to be lower, no sequence mutation was correlated
      with in vivo viral loads. Our results suggest that HIV-1 LTR defects are rare
      among Italian and Swedish LTNPs.

PMID- 10331441
TI  - Risk factors for cryptococcal meningitis in HIV-infected patients.
AB  - To identify the risk factors for cryptococcal meningitis in patients with HIV
      disease we conducted a nested case-control study of 37 incident cases of
      cryptococcal meningitis and 74 controls, identified from a cohort of more than
      2000 HIV-infected patients. Conditional logistic regression was used to study
      demographic and AIDS-related variables in addition to fluconazole and steroid
      use. No difference in demographic variables, HIV risk factors, or stage of AIDS
      was detected between cases and controls. Exposure to fluconazole for more than 90
      days reduced the risk of cryptococcal meningitis by 82% (OR=0.18; 95% CI=0.04
      0.85; p=0.03). We did not find a difference in steroid use between cases and
      controls for either the length or amount of steroid exposure (p=0.41). No
      difference in survival during follow-up in the clinic was observed by the log
      rank test (p=0.74). Among the cases, a cryptococcal antigen was positive in more
      than 97% of the CSF or blood samples. CSF and blood cultures were positive in 81
      and 44% of the samples, respectively. We conclude that demographic factors did
      not affect the risk of cryptococcal meningitis in an inner city United States
      population. While fluconazole use has a protective effect, steroid use was not
      associated with an increased risk of cryptococcal meningitis in HIV-infected
      patients.

PMID- 10331440
TI  - Immune restoration by combination of a cytostatic drug (hydroxyurea) and anti-HIV
      drugs (didanosine and indinavir).
AB  - Cell activation is essential for HIV infection. CD4+ T lymphocyte activation
      allows virus replication and CD8+ T lymphocyte activation may contribute to
      pathogenesis. We combined hydroxyurea, a cytostatic drug that inhibits cell
      activation and proliferation, with two drugs that inhibit HIV (didanosine and
      indinavir), to block the "cell activation-virus production-pathogenesis" cycle.
      HIV was strongly suppressed in treated patients, and the average CD4 count
      increased to 224/mm3. Compared with a matched group of patients who had declined
      antiretroviral treatment, treated patients had a significantly lower proportion
      of activated CD8+ T lymphocytes and a significantly higher number of naive CD8+
      and CD4+ T lymphocytes. The proliferative responses to allogeneic and influenza
      virus antigens were increased in treated patients, and a defect in CD3-zeta
      expression, the signaling chain of the T cell receptor complex, was reversed. The
      use of a cytostatic drug was not detrimental to the immune system; on the
      contrary, the combination of antiviral and cytostatic treatment improved all of
      the immune parameters tested.

PMID- 10331443
TI  - Phenotypic characteristics of human immunodeficiency virus type 1 subtype C
      isolates of Ethiopian AIDS patients.
AB  - It has been estimated that, to date, about 48% of all HIV-infected people in the
      world carry HIV-1 subtype C virus. Therefore, it is of great importance to gain
      better knowledge about the genetic and biological characteristics of this virus
      subtype. In the present study, the biological properties of HIV-1 isolates
      obtained from nine Ethiopian patients with AIDS were studied. DNA sequencing of
      the V3 loop of gp120 classified the isolates as subtype C. In primary isolation
      cultures, virus infection was accompanied by syncytium formation and cell lysis.
      Interestingly, when examining the growth in primary monocyte-macrophage cultures,
      initial low-level virus replication was followed by a nonproductive state, from
      which virus could be rescued by cocultivation with Jurkat(tat) cells.
      Furthermore, none of the isolates replicated in T cell lines (CEM, MT-2, HuT-78,
      and H9) or in the promonocytic cell line U937 clone 2. All isolates could use
      CCR5 as coreceptor, whereas no isolates could use CCR2b, CCR3, CCR5, CXCR4,
      Bonzo/STRL33, or BOB/GPR15. The genotype of the V3 region correlated with the MT
      2 negative/non-syncytium-inducing (NSI) phenotype. Comparative studies revealed
      that the scarcity of CXCR4 usage as well as other phenotypic characteristics of
      subtype C isolates distinguish this subtype. On the basis of these data, we
      suggest that in addition, factors other than viral phenotype may govern the
      pathogenic potential of subtype C isolates.

PMID- 10331442
TI  - Safety and immunogenicity of a live recombinant canarypox virus expressing HIV
      type 1 gp120 MN MN tm/gag/protease LAI (ALVAC-HIV, vCP205) followed by a p24E-V3
      MN synthetic peptide (CLTB-36) administered in healthy volunteers at low risk for
      HIV infection. AGIS Group and L'Agence Nationale de Recherches sur Le Sida.
AB  - A live recombinant canarypox vector expressing HIV-1 gpl20 MN tm/gag/protease LAI
      (ALVAC-HIV, vCP205) alone or boosted by a p24E-V3 MN synthetic peptide (CLTB-36)
      was tested in healthy volunteers at low risk for HIV infection for their safety
      and immunogenicity. Both antigens were well tolerated. ALVAC-HIV (vCP205) induced
      low levels of neutralizing antibodies against HIV-1 MN in 33% of the volunteers.
      None of them had detectable neutralizing antibodies against a nonsyncytium
      inducing HIV-1 clade B primary isolate (Bx08). After the fourth injection of
      vCP205, CTL activity was detected in 33% of the volunteers and was directed
      against Env, Gag, and Pol. This activity was mediated by both CD4+ and CD8+
      lymphocytes. On the other hand, the CLTB-36 peptide was poorly immunogenic and
      induced no neutralizing antibodies or CTLs. Although the ALVAC-HIV (vCP205) and
      CLTB-36 prime-boost regimen was not optimal, further studies with ALVAC-HIV
      (vCP205) are warranted because of its clear induction of a cellular immune
      response and utility as a priming agent for other subunit antigens such as
      envelope glycoproteins, pseudoparticles, or new peptides.

PMID- 10331444
TI  - Genetic heterogeneity of HIV type 1 subtypes in Kimpese, rural Democratic
      Republic of Congo.
AB  - A relatively low and stable seroprevalence of HIV-1 was previously reported among
      pregnant women attending for antenatal care between 1988 and 1993 in Kimpese, a
      rural town in the Democratic Republic of Congo (DRC, formerly Zaire). To
      characterize the HIV-1 subtypes circulating in this area, we have examined a 330
      bp fragment of the p17 region of the gag gene of HIV-1 strains obtained from 70
      patients (55 mothers, 15 children), of whom 61 were epidemiologically unlinked.
      Phylogenetic analyses revealed the existence of at least seven HIV-1 subtypes
      within the Kimpese region. Among the 61 epidemiologically unlinked patients,
      subtype A was predominant and found in 29 (47.5%) individuals. Other subtypes
      cocirculating in this rural part of DRC include subtypes C (1.6%), D (9.8%), F
      (3.2%), G (6.5%), H (21.3%), and J (4.9%). Sequences from four patients did not
      cluster with any of the currently documented HIV-1 subtypes, in analyses of
      fragments of both the gag (247 to 330 bp, 197 bp, and 310 bp) and env (340 bp)
      genes. Overall, comparisons of the gag(p17) gene regions revealed high pairwise
      divergences (mean, 19.9%; range, 1 to 46%). This level of gag(p17) gene variation
      in the DRC is considerably greater than previously appreciated. These results are
      relevant for the molecular epidemiology of HIV-1 in Africa and for the design of
      a future vaccine against HIV-1 in this region.

PMID- 10331445
TI  - CD8+ lymphocytes in pregnancy and HIV infection: characterization of CD8+
      subpopulations and CD8+ noncytotoxic antiviral activity.
AB  - The distribution and function of lymphocytes vary in different clinical states.
      The object of this study was to characterize the CD8+ lymphocyte subpopulations
      and CD8+ anti-HIV suppressor activity in HIV-infected and uninfected pregnant and
      nonpregnant women. The total percentage of CD8+ lymphocytes was not altered by
      pregnancy but the percentage of activated CD8+ T cells increased during pregnancy
      and decreased postpartum. HIV infection in pregnant women resulted in both an
      increased percentage of CD8+ lymphocytes and a marked increase in activated and
      memory CD8+ lymphocyte subsets, which did not change in the postpartum period.
      Most HIV-infected women had CD8+-mediated noncytotoxic antiviral activity.
      However, the activity was not correlated with alterations in CD8+ lymphocyte
      subsets. This study provides baseline information on changes in CD8 immunologic
      parameters during pregnancy and HIV infection for further studies that employ
      antiretroviral therapeutic regimens capable of impacting the immune response.

PMID- 10331446
TI  - Human immunodeficiency virus V3 peptide-reactive antibodies are present in normal
      HIV-negative sera.
AB  - A structural relation between consensus sequences of the portion of HIV-1 gp120
      involving the V3 loop (V3 peptide) and the variable domains of human
      immunoglobulin members of the VH-III gene family was proposed to trigger an
      imbalance of the idiotypic network during the course of HIV infection. Thus, the
      repertoires of immunoglobulins in healthy individuals should contain antigenic
      determinant(s) complementary to particular V3 loop epitope(s). In this study we
      investigated the specific binding to the V3 peptide of antibodies present in sera
      of HIV-positive and of clinically normal HIV-negative subjects. Two groups of HIV
      positive sera differing in antibody titers to V3 peptide, arbitrarily referred
      here as high- and low-reactive HIV-positive sera, were distinguished on the basis
      of an ELISA. Antibodies were affinity purified on V3 peptide and their titers in
      both HIV-negative and low-reactive HIV-positive sera were nearly superimposable
      and much lower than the titers of those from high-reactive HIV-positive sera.
      Also, the quality of the two groups of antibodies differed: much higher amounts
      of soluble V3 peptide were needed to partly compete the binding of antibodies
      from HIV-negative sera to insoluble V3 peptide as compared with those from HIV
      positive sera, suggesting that the latter had higher affinity for V3 peptide. All
      of the affinity-purified antibodies bound poorly to unrelated peptides, even to
      those sharing sequence similarity with the V3 peptide. The present observations
      suggest that in HIV infection antigen-driven affinity maturation of preimmune
      immunoglobulins with idiotypes complementary to V3 epitope(s) participating in
      physiological autoreactivity might be at work.

PMID- 10331447
TI  - HIV type 1 sequences with GGC substitution in injecting drug users in Greece.

PMID- 10331448
TI  - Characterization of V3 loop sequences from HIV type 1 subtype B in South Korea:
      predominance of the GPGS motif.

PMID- 10331449
TI  - HIV type 2 can bind to CD8 molecules but does not infect CD8+ T cells.

PMID- 10331450
TI  - Early embryonic expression of the growth hormone family protein genes in the
      developing rainbow trout, Oncorhynchus mykiss.
AB  - In fish, growth hormone (GH), prolactin (PRL) and somatolactin (SL) are three
      major peptide hormones produced in the pituitary gland. Using reverse
      transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis of
      the amplified products, the expression of GH, PRL, and SL genes were determined
      during the embryonic development in rainbow trout (Oncorhynchus mykiss). The mRNA
      for GH, PRL and SL were detected not only in embryos prior to or after
      organogenesis of the pituitary gland but also in mature oocytes as maternal
      messages. After hatching, all of these three mRNA species were detected at very
      high levels. Since the ontogenesis of the pituitary gland takes place on
      embryonic day (ED) 14, these observations suggest that the GH family protein
      genes are expressed in the developing embryos prior to the formation of the
      pituitary gland. Using the same RT-PCR assay, PRL mRNA was detected only in the
      head part of the fry whereas GH and SL mRNA were detected in both the head and
      trunk. In adult animals, though high levels of GH mRNA were primarily detected in
      the pituitary gland, brain, gill, and heart, low levels of GH mRNA were also
      detected in the kidney, liver, pyloric ceaca, and ovary. Results of the current
      study and those reported by Yang et al. (1997. Gen Comp Endocrinol 106:271-281)
      suggest that GH and SL genes are also expressed in extrapituitary tissues even
      after the organogenesis of the pituitary gland. Furthermore, these results
      suggest that these hormones may play important roles yet to be identified during
      embryonic development in fish.

PMID- 10331451
TI  - Molecular cloning and localization of caprine relaxin-like factor (RLF) mRNA
      within the goat testis.
AB  - The relaxin-like factor (RLF) is one of the insulin-like molecules, which also
      includes insulin, insulin-like growth factor I and II, placentin, and relaxin.
      Employing RT- and RACE-PCR on RNA isolated from goat testicular tissue, we report
      the cloning and nucleic acid sequence of goat RLF. The caprine RLF cDNA coding
      sequence consisted of 396 base pairs encoding a peptide of 131 amino acids.
      Caprine RLF showed the highest homology in nucleic acid and amino acid sequence
      with bovine and sheep RLF, suggesting conservation of the RLF gene among
      ruminants. Northern blot analysis revealed a single 0.9 kb RLF transcript
      expressed in the goat testis but not in the epididymis, liver, or muscle tissue.
      Only a single goat RLF gene is present in the goat genome as determined by
      Southern blot analysis. Employing nonradioactive in situ hybridization for goat
      RLF mRNA and immunohistochemistry for 3beta-hydroxysteroid dehydrogenase (3beta
      HSD) and 17alpha-hydroxylase, we identified the Leydig cells as the sole source
      of RLF mRNA in the goat testis.

PMID- 10331452
TI  - Computer assisted image analysis to assess colonization of recipient seminiferous
      tubules by spermatogonial stem cells from transgenic donor mice.
AB  - Transplantation of spermatogonial stem cells from fertile, transgenic donor mice
      to the testes of infertile recipients provides a unique system to study the
      biology of spermatogonial stem cells. To facilitate the investigation of
      treatment effects on colonization efficiency an analysis system was needed to
      quantify colonization of recipient mouse seminiferous tubules by donor stem cell
      derived spermatogenesis. In this study, a computer-assisted morphometry system
      was developed and validated to analyze large numbers of samples. Donor
      spermatogenesis in recipient testes is identified by blue staining of donor
      derived spermatogenic cells expressing the E. coli lacZ structural gene. Images
      of seminiferous tubules from recipient testes collected three months after
      spermatogonial transplantation are captured, and stained seminiferous tubules
      containing donor-derived spermatogenesis are selected for measurement based on
      their color by color thresholding. Colonization is measured as number, area, and
      length of stained tubules. Interactive, operator-controlled color selection and
      sample preparation accounted for less than 10% variability for all collected
      parameters. Using this system, the relationship between number of transplanted
      cells and colonization efficiency was investigated. Transplantation of 10(4)
      cells per testis only rarely resulted in colonization, whereas after
      transplantation of 10(5) and 10(6) cells per testis the extent of donor-derived
      spermatogenesis was directly related to the number of transplanted donor cells.
      It appears that about 10% of transplanted spermatogonial stem cells result in
      colony formation in the recipient testis. The present study establishes a rapid,
      repeatable, semi-interactive morphometry system to investigate treatment effects
      on colonization efficiency after spermatogonial transplantation in the mouse.

PMID- 10331453
TI  - Adenovirus-mediated introduction of DNA into pig sperm and offspring.
AB  - The ability of adenoviral vectors to transfer DNA into boar spermatozoa and to
      offspring was tested. Exposure of spermatozoa to adenovirus bearing the E. coli
      lacZ gene resulted in the transfer of the gene to the head of the spermatozoa.
      Treatment did not affect either viability or acrosomal integrity of boar sperm.
      Of the 2-to 8-cell embryos obtained after in vitro fertilization with adenovirus
      exposed sperm, 21.7% expressed the LacZ product. Four out of 56 piglets (about
      7%) obtained after artificial insemination with adenovirus-exposed spermatozoa
      were positive in PCR analyses, even though none of the piglets showed the LacZ
      gene after southern blot analysis. RT-PCR analysis performed in tissues from two
      positive stillborn piglets showed the presence of the LacZ mRNA in all of the
      tissues tested. The offspring obtained after mating two positive animals did not
      show LacZ gene presence. Our results indicate that adenovirus could be a feasible
      mechanism for the delivery of DNA into spermatozoa, even though the transfer of
      the transgene may be limited to the first generation.

PMID- 10331455
TI  - Embryo metabolism during the expansion of the bovine blastocyst.
AB  - Embryo metabolism was evaluated during re-expansion of in vitro produced bovine
      blastocysts collapsed with cytochalasin D (CCD) and incubated in the presence and
      absence of ouabain, a specific inhibitor of the Na+, K+ pump. Day 8 expanded
      blastocysts were treated for 2 to 4 hr with 20 microg/ml CCD. Four conditions
      were tested: untreated embryos and embryos collapsed with CCD and allowed to re
      expand for 4 hr in the presence of 0 M, 1 nM, or 1 microM ouabain. Incubation of
      collapsed embryos for 4 hr in the presence of 1 nM or 1 microM ouabain
      significantly inhibited blastocyst re-expansion. Glucose, pyruvate, and amino
      lactate uptake/release were not significantly affected by ouabain treatment and
      did not correlate with the degree of blastocyst re-expansion. Few variations in
      the uptake/release of amino acids by the embryos were observed. Ouabain treatment
      significantly decreased oxygen uptake which directly correlated with the degree
      of blastocyst re-expansion. For embryos allowed to re-expand in the presence or
      absence of ouabain, a direct correlation was observed between the uptake of
      oxygen and of glucose. One mM cyanide or 2,4 dinitrophenol inhibited blastocyst
      re-expansion although 0.01 and 0.1 mM were ineffective. This study indicates a
      role for oxidative metabolism in providing the energy necessary for blastocoel
      expansion in the bovine. Nevertheless, blastocyst expansion is relatively
      insensitive to inhibition of oxidative phosphorylation indicating the ability of
      the bovine blastocyst to adapt to hypoxic conditions.

PMID- 10331454
TI  - Offspring born from chimeras reconstructed from parthenogenetic and in vitro
      fertilized bovine embryos.
AB  - Chimeric embryos were produced by aggregation of parthenogenetic (Japanese Red
      breed) and in vitro fertilized (Holstein breed) bovine embryos at the Yamaguchi
      Research Station in Japan and by aggregation of parthenogenetic (Red Angus breed)
      and in vitro fertilized (Holstein breed) embryos at the St. Gabriel Research
      Station in Louisiana. After embryo reconstruction, live offspring were produced
      at each station from transplanting these embryos. The objective of this joint
      study was to evaluate the developmental capacity of reconstructed parthenogenetic
      and in vitro fertilized bovine embryos. In experiment I, chimeric embryos were
      constructed: by aggregation of four 8-cell (demi-embryo) parthenogenetic and four
      8-cell stage (demi-embryo) IVF-derived blastomeres (method 1) and by aggregation
      of a whole parthenogenetic embryo (8-cell stage) and a whole IVF-derived embryo
      (8-cell stage) (method 2). Similarly in experiment II, chimeric embryos were
      constructed by aggregating IVF-derived blastomeres with parthenogenetic
      blastomeres. In this experiment, three categories of chimeric embryos with
      different parthenogenetic IVF-derived blastomere ratios (2:6; 4:4, and 6:2) were
      constructed from 8-cell stage bovine embryos. In experiment III, chimeric embryos
      composed of four 8-cell parthenogenetic and two 4-cell IVF-derived blastomeres or
      eight 16-cell parthenogenetic and four 8-cell IVF-derived blastomeres were
      constructed. Parthenogenetic demi-embryos were aggregated with sexed (male) IVF
      demi-embryos to produce chimeric blastocysts (experiment IV). In the blastocyst
      stage, hatching and hatched embryos were karyotyped. In experiment V, chimeric
      embryos that developed to blastocysts (zona-free) were cryopreserved in ethylene
      glycol (EG) plus trehalose (T) with different concentrations of
      polyvinylpyrrolidone (PVP; 5%, 7.5%, and 10%). In experiment I, the aggregation
      rate of the reconstructed demi-embryos cultured in vitro without agar embedding
      was significantly lower than with agar embedding (53% for 0% agar, 93% for 1%
      agar, and 95% for 1.2% agar, respectively). The aggregation was also lower when
      the aggregation resulted from a whole parthenogenetic and IVF-derived embryos
      cultured without agar than when cultured with agar (70% for 0% agar, 94% for 1%
      agar, and 93% for 1.2% agar, respectively). The development rate to blastocysts,
      however, was not different among the treatments. In experiment II, the
      developmental rates to the morula and blastocyst stages were 81%, 89%, and 28%
      for the chimeric embryos with parthenogenetic:IVF blastomere ratios of 2:6, 4:4,
      and 6:2, respectively. In experiment III, the developmental rate to the morula
      and blastocyst stages was 60% and 65% for the two 4-cell and four 8-cell chimeric
      embryos compared with 10% for intact 8-cell parthenogenetic embryos and 15% for
      intact 16-cell parthenogenetic embryos. To verify participation of
      parthenogenetic and the cells derived from the male IVF embryos in blastocyst
      formation, 51 embryos (hatching and hatched) were karyotyped, resulting in 27
      embryos having both XX and XY chromosome plates in the same sample, 14 embryos
      with XY and 10 embryos with XX. The viability and the percentage of zona-free
      chimeric embryos at 24 hr following cryopreservation in EG plus T with 10% PVP
      were significantly greater than those cryopreserved without PVP (89% vs. 56%).
      Pregnancies were diagnosed in both stations after the transfer of chimeric
      blastocysts. Twin male (stillbirths) and single chimeric calves were delivered at
      the Yamaguchi station, with each having both XX and XY chromosomes detected.
      Three pregnancies resulted from the transferred 40 chimeric embryos at the
      Louisiana station. Two pregnancies were lost prior to 4 months and one
      phenotypically-chimeric viable male calf was born. We conclude that the IVF
      derived blastomeres were able to stimulate the development of bovine
      parthenogenetic blastomeres and that the chimeric parthenogenetic bovine embryos
      were developmentall

PMID- 10331456
TI  - Identification and initial characterization of calcyclin and phospholipase A2 in
      equine conceptuses.
AB  - For development to proceed normally, the appropriate genes must be expressed in
      the correct tissues and in the correct time frame. Knowledge of gene expression
      during development provides information about the changes taking place within the
      conceptus as well as possible reasons for pregnancy failure. However, little is
      known about gene expression during development in the equine conceptus. In this
      study, we examined differences in gene expression between day 12 and day 15
      equine conceptuses by suppression subtractive hybridization. This technique was
      used to isolate transcripts that are more abundantly expressed in day 15
      conceptuses compared to day 12 conceptuses. Between day 12 and 15 of pregnancy in
      horses, maternal recognition of pregnancy occurs, gastrulation is taking place,
      and mesoderm is beginning to form. Fifty cDNA clones were isolated, sequenced,
      and compared to known sequences in the GenBank database. Two cDNA clones
      identified that were of primary interest were calcyclin and phospholipase A2.
      Calcyclin is a calcium-binding protein of the S-100 protein family that has been
      found in mouse decidua and trophoblast. Calcyclin was found to be expressed in
      both day 12 and 15 equine conceptuses, with approximately a 30-fold increase in
      transcript abundance between days 12 and 15. Phospholipase A2 is an enzyme that
      cleaves phospholipids to release fatty acids and is involved in arachidonic acid
      release needed for prostaglandin, thromboxane, and leukotriene synthesis.
      Multiple forms of PLA2, that appear to be differentially regulated in day 12 and
      15 conceptuses, were detected by northern blotting.

PMID- 10331457
TI  - p53 independent, region-specific epithelial apoptosis is induced in the rat
      epididymis by deprivation of luminal factors.
AB  - Luminal testicular factors are known to be important for the regulation of the
      epididymal epithelium. The present study was undertaken to test the hypothesis
      that complete deprivation of luminal factors by efferent duct ligation (EDL)
      would induce apoptosis in the epididymal epithelium, as does removal of trophic
      factors from other cell types. Additionally, experiments were performed to
      determine whether the apoptosis detected was p53 dependent or independent.
      Apoptosis detection was by terminal deoxynucleotidyl-mediated deoxyuridine
      triphosphate-biotin nick-end labeling and by DNA fragmentation studies. EDL
      caused loss of testicular luminal contribution in zone 1A of the rat epididymis
      (proximal initial segment) within 6 hr and induced epithelial apoptosis within 12
      hr of the efferent duct obstruction. The wave of apoptosis in zone 1A was
      completed by three days after EDL and was followed by a much smaller wave in zone
      1B which peaked three days after EDL. Significant apoptosis was not detected in
      any epididymal region distal to the initial segment for periods as long as 15
      days after EDL. p53, a key apoptotic-pathway molecule in many tissues and
      conditions was tested by immunohistochemical and Western blot techniques and was
      not upregulated in the initial segment epithelium within the time cells were
      undergoing apoptosis and well before the wave of apoptosis was complete. It was
      concluded that epithelial apoptosis in the initial segment of the rat epididymis
      is induced by deprivation of luminal testicular factors, is localized to the
      proximal and middle initial segment, and is p53 independent.

PMID- 10331458
TI  - Homologous and heterologous ligands downregulate follicle-stimulating hormone
      receptor mRNA in porcine granulosa cells.
AB  - We investigated homologous and heterologous downregulation of FSH receptor mRNA
      in porcine granulosa cells from ovaries of immature pigs. Cultures were treated
      with 0, 40, or 200 ng/ml porcine FSH or medium and terminated at 24 hr intervals
      for Northern analysis of FSH receptor and cytochrome P450 side chain cleavage
      (P450scc) mRNA, and for radioimmunoassay of progesterone. Cells luteinized over
      96 hr, and control cultures displayed increases in P450scc (8-10 fold) and FSH
      receptor (2 fold) mRNA and progesterone (100 fold). FSH reduced FSH receptor mRNA
      by 50-90%, increased P450scc mRNA 8 fold within 48 hr, and elevated progesterone
      logarithmically over 96 hr. Luteinized cells, (after 96 hr) received FSH or LH (1
      200 ng/ml) or prostaglandin E2 (0.01-1.0 mg/ml) for 6 hr resulting in increased
      P450scc mRNA (2-8 fold), and progesterone (2-5 fold), and reduced FSH receptor
      mRNA. FSH (200 ng/ml) or the cAMP analog, dbcAMP (1 mM) for 0-24 hr reduced FSH
      receptor mRNA to 15% of control from 4-24 hr and elevated P450scc mRNA at 4 and 6
      hr, respectively, to maxima at 12-24 hr. Forskolin (1-10 mM) increased P450scc
      mRNA (2-3 fold) and downregulated FSH receptor mRNA, effects reversed by the
      inhibitor of cAMP, rpcAMPs. Both epidermal growth factor, and the activator of
      the protein kinase C pathway, phorbol 12-myristate, 13-acetate (PMA) at 10 nM
      reduced FSH receptor mRNA. We conclude that downregulation of FSH receptor mRNA
      in luteinized granulosa cells is mediated by both homologous and heterologous
      ligands which employ cAMP, and that growth factors that activate the PKC pathway
      reduce FSH receptor and P450scc mRNA abundance.

PMID- 10331460
TI  - Organelle-specific probe JC-1 identifies membrane potential differences in the
      mitochondrial function of bovine sperm.
AB  - The mitochondrial probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl
      carbocyan ine iodide (JC-1) not only identifies mitochondria exhibiting low
      membrane potentials by the emission of green fluorescence (range, 510-520 nm) but
      also differentiates these from mitochondria exhibiting relatively high membrane
      potentials. This discrimination occurs because JC-1 forms aggregates at high
      membrane potentials. These J-aggregates emit a bright red-orange fluorescence at
      590 nm. In this study, JC-1 was combined with the classical dead cell stain,
      propidium iodide (PI), to identify a spectrum of functional sperm along with
      degenerate sperm. Flow cytometric analysis of bull sperm showed that the
      aggregate:monomer ratio differed among bulls before cryopreservation (P < 0.001)
      but not afterwards (P > 0.05). The effects of stain equilibration time, sperm
      concentration, and live:dead ratios were examined. The addition of SYBR-14 to the
      JC-1 and PI combination enhanced the distinction between the red PI-stained and
      red-orange JC-1-stained populations. This discrimination between J-aggregates and
      the PI-stained sperm was affected by sperm concentration. These studies show that
      JC-1 can be useful in monitoring mitochondrial function in bovine sperm.

PMID- 10331461
TI  - Nucleotide content, oxidative phosphorylation, morphology, and fertilizing
      capacity of turbot (Psetta maxima) spermatozoa during the motility period.
AB  - The interdependence between motility, respiration, ATP production, and
      utilization was investigated in intact spermatozoa of turbot (Psetta maxima), a
      marine teleost. When spermatozoa were diluted in a hyperosmotic medium (>300
      mOsmol/kg), they immediately became motile, and the intracellular concentration
      of ATP as well as the adenylate energy charge ratio dropped concomitant with the
      straight-line velocity. The ADP and AMP levels increased from 1.4 to 8.0
      nmole/10(8) cells and from 0.6 to 6.0 nmole/10(8) cells, respectively. Moreover,
      31P-NMR spectra recorded prior to the swimming phase revealed the presence of
      phosphomonoesters (PMEs) and phosphodiesters (PDEs), intracellular inorganic
      phosphate (Pi), and phosphocreatine (PCr). At the end of the motility period,
      PCr, PDE, and PME decreased, while the Pi level increased markedly. Following
      initiation of motility, O2 consumption of spermatozoa increased from 34.9 to
      124.8 O2 nmole/10(9) spermatozoa/min. FCCP, an uncoupler of oxidative
      phosphorylation, did not significantly affect the respiratory rate of motile
      spermatozoa. Ouabain, a specific inhibitor of (Na+/K+)/ATPase, slightly decreased
      the respiration rate of motile spermatozoa, indicating that the major part of ATP
      catabolism was linked to dynein ATPase. Inhibitors of the respiratory chain (KCN,
      NaN3, NaHCO3-, oligomycin) reduced sperm respiration, percentage of motile cells,
      velocity, and adenylate contents. Following the reactivation of motility of
      demembranated spermatozoa, KCN, NaN3, NaHCO3- altered the flagellar beat
      frequency, demonstrating that these respiratory inhibitors possess action sites
      other than mitochondria. Mitochondrial oxidative phosphorylation is highly
      requested to produce energy required during motion. Nevertheless it is
      insufficient to maintain endogenous ATP stores. A second phase of motility was
      induced by a transfer of exhausted spermatozoa into an ionic medium of low
      osmolality (200 mOsmol/kg) for 30 min. Spermatozoa, once reactivated in AM,
      recovered 55% of initial motility and 31% of initial fertilization rate. In hypo
      osmotic medium, mitochondrial oxidative phosphorylation also induced ATP
      regeneration. Following activation of movement, several morphological changes
      were observed in the mitochondria and the midpiece.

PMID- 10331459
TI  - Uptake and metabolism of adenosine mediate a meiosis-arresting action on mouse
      oocytes.
AB  - This study was carried out to evaluate the possible role of adenosine uptake and
      metabolism in mediating the inhibitory actions of this nucleoside on spontaneous
      mouse oocyte maturation. Uridine blocked 3H-adenosine uptake by oocyte-cumulus
      cell complexes (OCCs) and cumulus cell-enclosed oocytes (CEOs) by 82-85%, whereas
      uptake by denuded oocytes (DOs) was suppressed by 97%. Uridine had no effect on
      germinal vesicle breakdown (GVB) in CEOs when meiotic arrest was maintained with
      hypoxanthine or hypoxanthine plus adenosine but reversed the combined inhibitory
      action of these purines in DOs. Five of six adenosine analogs that bind to
      purinoceptors demonstrated meiosis-arresting activity but not in relation to
      their relative affinities for inhibitory or stimulatory adenosine receptors and
      only at high concentrations. Moreover, in DOs, uridine reversed the inhibitory
      effect of 2-chloroadenosine and 5'-N-ethylcarboxamidoadenosine, two receptor
      agonists that are poor substrates for adenosine-metabolizing enzymes. Results of
      experiments with adenosine kinase inhibitors showed that methylmercaptopurine
      riboside (MMPR) and tubercidin, but not 5'-amino-5'-deoxyadenosine, reversed
      meiotic arrest maintained by hypoxanthine +/- adenosine, but this required an
      additional inhibitory action on de novo purine synthesis. Inhibition of de novo
      purine synthesis alone was not sufficient because azaserine failed to reverse
      meiotic arrest. MMPR was a very potent meiosis-inducing agent, completely
      reversing meiotic arrest in CEOs and DOs in the presence of a variety of meiotic
      inhibitors. The adenosine deaminase inhibitor deoxycoformycin had opposite
      effects on oocyte maturation depending on the presence or absence of adenosine:
      the inhibitory action of hypoxanthine alone was bolstered, but the meiosis
      arresting action of adenosine was reversed. These data therefore indicate that at
      low adenosine concentrations phosphorylation predominates, but at higher
      adenosine concentrations deaminated products contribute to the meiotic
      inhibition. This idea was borne out by the ability of inosine to mimic the
      synergistic interaction of adenosine with hypoxanthine. The action of adenosine
      is not due to deamination to inosine and conversion to nucleotides through the
      hypoxanthine salvage pathway because adenosine-mediated inhibition was not
      compromised in oocytes from mutant mice unable to salvage hypoxanthine.

PMID- 10331462
TI  - Stage-dependent effects of epidermal growth factor on Ca2+ efflux in mouse
      oocytes.
AB  - Epidermal growth factor (EGF) has received much attention recently for its
      positive effects on mammalian oocyte maturation and embryo development and its
      potential importance in cytoplasmic maturation of oocytes. Calcium (Ca2+)
      homeostasis in germinal vesicle stage oocytes has also been suggested to play a
      role in cytoplasmic maturation. This study examined the effects of EGF on Ca2+
      mobilization as measured by its efflux from mouse oocytes at three time periods
      throughout maturation (0-4 hr, 4-8 hr, and 12 hr). Immature cumulus oocyte
      complexes (COCs) removed from the ovary for less than 4 hr exhibit oscillations
      in Ca2+ efflux that initiated 5-30 min following EGF stimulation. This response
      was not observed in COCs matured for 4-8 hr or 12 hr or in unstimulated 0-4 hr
      COCs. Denuded oocytes and cumulus cells did not show the same response to EGF
      (8.2 nM and 16.4 nM). Immunohistochemistry for detection of the EGF receptor
      along with EGF internalization studies showed that receptors are present both on
      cumulus cells and the oocyte but EGF appears to be internalized mainly by the
      cumulus cells. These data demonstrate that EGF induces oscillations in Ca2+
      efflux in COCs 0-4 hr old and this response is mediated by the cumulus cells.

PMID- 10331463
TI  - Inherited long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and a fetal
      maternal interaction cause maternal liver disease and other pregnancy
      complications.
AB  - Fetal-maternal interactions are critical determinants of maternal health during
      pregnancy and perinatal outcome. This review explores the causative relationship
      of a fetal disorder of mitochondrial fatty acid oxidation, long-chain 3
      hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and the serious maternal liver
      diseases of pregnancy-preeclampsia, the HELLP syndrome (hemolysis, elevated liver
      enzymes, and low platelet counts), and acute fatty liver of pregnancy. Features
      of the metabolic adaptation necessitated during the fetal-neonatal transition;
      common phenotypes of pediatric fatty acid oxidation disorders, including neonatal
      hypoketotic, hypoglycemia and hepatic crisis; and clinical abnormalities of HELLP
      and acute fatty liver of pregnancy are presented. Evidence that a common mutation
      in the alpha-subunit (LCHAD) of trifunctional protein, E474Q, is always one of
      the mutant alleles in fetal isolated LCHAD deficiency associated with these
      disorders of pregnancy that cause high maternal, fetal, and newborn morbidity and
      mortality is reviewed. Recommendations for molecular testing for LCHAD deficiency
      in families with life-threatening maternal liver disease are given.

PMID- 10331464
TI  - Neonatal presentations of mitochondrial metabolic disorders.
AB  - Because of the high energy requirements of the growing neonate, disorders of
      mitochondrial metabolism caused by defects in fatty acid oxidation, pyruvate
      metabolism, and the respiratory chain may often present in the neonatal period.
      Common neonatal presentations are hypotonia, lethargy, feeding and respiratory
      difficulties, failure to thrive, psychomotor delay, seizures, and vomiting.
      Laboratory clues include alterations in the levels of lactate, pyruvate (and the
      lactate/pyruvate ratio), glucose, and ketone bodies. Diagnosis usually depends on
      specific enzyme assays or on molecular genetic analysis. Without treatment, most
      infants die in the first few days or months of life. In the last decade, there
      have been significant advances in the understanding of the molecular basis of
      these disorders. This review discusses the major subgroups of mitochondrial
      disorders, focusing on defects of pyruvate oxidation, the Krebs cycle, and the
      respiratory chain. Disorders caused by respiratory chain defects may involve
      nuclear DNA, mitochondrial DNA, or intergenomic signaling. Recognition and early
      diagnosis of these conditions are important in the genetic counseling of these
      families.

PMID- 10331465
TI  - Neonatal metabolic myopathies.
AB  - The primary presentations of neuromuscular disease in the newborn period are
      hypotonia and weakness. Although metabolic myopathies are inherited disorders
      that present from birth and may present with subtle to marked neonatal hypotonia,
      a number of these defects are diagnosed classically in childhood, adolescence, or
      adulthood. Disorders of glycogen, lipid, or mitochondrial metabolism may cause
      three main clinical syndromes in muscle, namely, (1) progressive weakness with
      hypotonia (e.g., acid maltase, debrancher enzyme, and brancher enzyme
      deficiencies among the glycogenoses; carnitine uptake and carnitine acylcarnitine
      translocase defects among the fatty acid oxidation (FAO) defects; and cytochrome
      oxidase deficiency among the mitochondrial disorders) or (2) acute, recurrent,
      reversible muscle dysfunction with exercise intolerance and acute muscle
      breakdown or myoglobinuria (with or without cramps), e.g., phosphorylase,
      phosphofructokinase, and phosphoglycerate kinase among the glycogenoses and
      carnitine palmitoyltransferase II deficiency among the disorders of FAO or (3)
      both (e.g., long-chain or very long-chain acyl coenzyme A (CoA) dehydrogenase,
      short-chain L-3-hydroxyacyl-CoA dehydrogenase, and trifunctional protein
      deficiencies among the FAO defects). Episodes of exercise-induced myoglobinuria
      tend to present in later childhood or adolescence; however, myoglobinuria in the
      first year of life may occur in FAO disorders during catabolic crises
      precipitated by fasting or infection. The following is a survey of genetic
      disorders of glycogen and lipid metabolism resulting in myopathy, focusing
      primarily on those defects, to date, that have presented in the neonatal or early
      infancy period. Disorders of mitochondrial metabolism are discussed in another
      chapter.

PMID- 10331466
TI  - Primary and secondary alterations of neonatal carnitine metabolism.
AB  - Carnitine plays an essential role in the transfer of long-chain fatty acids
      across the inner mitochondrial membrane, in the detoxification of acyl moieties,
      and in maintaining normal levels of free coenzyme A. Although carnitine can be
      synthesized in liver and kidney, normal adults obtain the majority of carnitine
      from the diet. Preterm newborns have a reduced capacity to synthesize carnitine.
      Total parenteral nutrition lacks carnitine and exposes very low birth weight
      infants to carnitine deficiency, with decreased production of ketones from long
      chain fatty acids. Supplementation with low doses of carnitine improves nitrogen
      balance and growth in these infants. Carnitine deficiency can be part of a number
      of inherited and acquired diseases. Primary carnitine deficiency is an autosomal
      recessive disorder characterized by increased losses of carnitine in the urine
      and decreased accumulation in the heart and skeletal muscle caused by defective
      carnitine transport. This condition is corrected by high-dose carnitine
      supplementation. Secondary carnitine deficiency can be caused by increased
      losses, pharmacological therapy, or a number of inherited metabolic disorders
      that must be correctly diagnosed before initiating carnitine supplementation.

PMID- 10331467
TI  - Clinical and biochemical approach to the neonate with a suspected inborn error of
      amino acid and organic acid metabolism.
AB  - Disorders of amino acid and organic acid metabolism collectively represent a
      group of over 70 inherited diseases that are most frequently encountered in the
      neonatal period. A neonate with clinical symptoms caused by one of these
      disorders is a real clinical emergency, a situation complicated by the
      similarities to the manifestations seen in sepsis or asphyxia. Delay of diagnosis
      and proper treatment often results in severe morbidity and high mortality. The
      vast majority of these patients are likely to be transferred to a neonatal
      intensive care unit, suggesting that amino acid and organic acid biochemical
      screenings should be performed in these newborns routinely at admission. The
      analysis of amino acids and acylcarnitines in blood spots by tandem mass
      spectrometry has the potential to significantly improve the morbidity and
      mortality rates of metabolic disorders with neonatal presentation. In the case of
      disorders lacking an effective treatment, an early diagnosis could lead to proper
      genetic counseling of the parents and to the option of reliable prenatal
      diagnosis of future pregnancies. This review offers an updated summary of the
      clinical, biochemical, and therapeutic features of the aminoacidopathies and
      organic acidurias most likely to be encountered in neonatal clinical practice.

PMID- 10331468
TI  - Temporary brittle bone disease: a true entity?
AB  - Temporary brittle bone disease is a recently described phenotype of increased
      fracture susceptibility in the first year of life in which there are multiple
      unexplained fractures without evidence of other internal or external injury. Most
      child abuse experts do not accept the existence of temporary brittle bone disease
      and presume these cases are child abuse. The author reviewed 26 cases of infants
      with multiple unexplained fractures that fit the criteria of temporary brittle
      bone disease and studied nine of them with either computed tomography or
      radiographic bone density measurements. The results show a striking association
      between temporary brittle bone disease and decreased fetal movement, usually from
      intrauterine confinement, and low bone density measurements in eight of the nine
      infants. The association with decreased fetal movement and intrauterine
      confinement is in keeping with the mechanostat-mechanical load theory of bone
      formation. The author feels that temporary brittle bone disease is a real entity
      and that historical information related to decreased fetal movement or
      intrauterine confinement and the use of bone density measurements can be helpful
      in making this diagnosis.

PMID- 10331469
TI  - Application of electrospray tandem mass spectrometry to neonatal screening.
AB  - For the past 30 years, neonatal screening programs have been performed largely by
      using the bacterial inhibition assays developed by Dr Robert Guthrie. These
      programs focused on a small number of diseases such as phenylketonuria and maple
      syrup urine disease and involved one test for each disease. During the same
      period many new diseases were discovered, such as organic acidemias and fatty
      acid oxidation defects, and they presented a diagnostic challenge to biochemical
      laboratories. Different mass spectrometric approaches have been the main tools
      for the diagnosis; however, each has its own limitation. Recently, electrospray
      tandem mass spectrometry (MS/MS) has provided an alternative automated high
      throughput, specific, and broad-spectrum approach to screening for a relatively
      large number of disorders, including those covered by bacterial inhibition assays
      tests. By using specific scan functions, a large number of amino acids and
      acylcarnitines in blood spots are quantified in 2 minutes analytical time. A new
      scan function is described here for quantification and screening for
      argininosuccinic acid in blood spots, which is a key metabolite in the diagnosis
      of argininosuccinase deficiency. We describe the results of a 3-year tandem MS/MS
      based neonatal study that was performed in our newborn population. We screened
      27,624 blood spots and identified 20 cases yielding a frequency of 1:1,381. No
      false-negative cases were identified, but several false-positive cases were
      eliminated by repeat analysis by MS/MS of blood or by other means. We also used
      MS/MS analysis of urine or blood either for confirmation of initial positive
      results or for follow-up of treatment, such as in glutaric acidemia,
      citrullinemia, argininosuccinase deficiency, and biopterin-dependent
      phenylketonuria.

PMID- 10331470
TI  - Presentation, diagnosis, and treatment of the disorders of monoamine
      neurotransmitter metabolism.
AB  - For many years, all of the described cases of monoamine neurotransmitter
      deficiency were associated with hyperphenylalaninemia that was generally detected
      at neonatal screening. It is now clear that inherited deficiency of monoamines
      often occurs in the absence of hyperphenylalaninemia and that the normal battery
      of screening tests used to investigate individuals with suspected metabolic
      disease will not detect these cases. Diagnosis in this situation must rely
      heavily on clinical suspicion. This article, therefore, describes the
      presentation and clinical symptoms that result from defective monoamine
      neurotransmission; outlines therapeutic approaches; and explains how
      cerebrospinal fluid profiles of monoamine metabolites, their precursors, and the
      cofactor required for monoamine synthesis can be used to pinpoint the exact site
      of the metabolic lesion.

PMID- 10331471
TI  - Sudden and unexpected neonatal death: a protocol for the postmortem diagnosis of
      fatty acid oxidation disorders.
AB  - Fatty acid oxidation (FAO) disorders are frequently reported as the cause of
      sudden and unexpected death, but their postmortem identification remains
      difficult. Over a period of 5 years, the authors have identified 44 cases
      representing five FAO disorders and 19 additional cases without a diagnosis of a
      specific defect. Among the two groups, 13 patients died in the neonatal period,
      10 in the FAO group, and three from the undetermined defect group. This outcome
      was consistently associated with exclusive breast feeding and presumably poor
      caloric intake. The diagnosis of FAO disorder in these cases was based on the
      analysis of postmortem liver and bile. In postmortem liver, informative findings
      are microvesicular steatosis, elevated fatty acid concentrations, glucose
      depletion, and low carnitine concentration. Bile carnitine analysis and
      acylcarnitine profiling have expanded significantly the effectiveness of the
      initial protocol and could lead, based on preliminary observations, to better
      identification of patients who may have been missed or left undetermined by the
      analysis of liver only. If an autopsy is not performed, informative findings can
      still be obtained by analysis of blood spots collected for newborn screenings and
      by biochemical testing of parents and asymptomatic siblings.

PMID- 10331472
TI  - Visual characteristics of clay target shooters.
AB  - A comprehensive battery of standardised visual tests was administered to 11
      skilled and 12 novice clay target shooters in an attempt to determine the
      distinctive visual characteristics of expert performers in this sport. The static
      and dynamic visual acuity, ocular muscle balance, ocular dominance, depth
      perception and colour vision of each of the subjects was measured in addition to
      their performance on simple and choice reaction time, peripheral response time,
      rapid tachistoscopic detection, coincidence timing and eye movement skills tasks.
      Expert superiority was observed on the simple reaction time measure only, and the
      novices actually outperformed the skilled subjects on a number of the other
      visual measures (viz., static acuity at near distance, dynamic acuity, vertical
      ocular muscle balance, choice reaction time and rapid target detection
      discriminability). Scores on all measures for both groups were within the
      expected normal range indicating that normal and not necessarily above-average
      basic visual functioning is sufficient to support skilled clay target shooting.
      An important implication of the finding that skilled shooters are not
      characterised by supranormal levels of basic visual functioning is the
      recognition that any attempt to improve shooting performance through training of
      general attributes of vision to supranormal levels is likely to be unproductive.

PMID- 10331473
TI  - Mouthguard use in Australian football.
AB  - A survey was performed of 961 Australian rules footballers of varying age and
      football ability in order to determine the prevalence of mouthguard use during
      training and match play. Emergency dental injury data was obtained to compare the
      frequency and timing of dental injury in a non-sporting community population. The
      prevalence of mouthguard use during match play varied between 60% for juniors and
      90% for elite footballers whereas the mouthguard use during training ranged
      between 2% for junior and 40% for elite players. One third of players used over
      the counter 'boil & bite' mouthguards, generally considered unsatisfactory for
      dental protection. Of the players who did not currently use mouthguards, most had
      tried them previously but found them uncomfortable to wear. The community dental
      injury data showed that the majority of emergency dental injuries were due to
      sport and followed the temporal pattern of sports participation on week days and
      weekends. The prevalence of mouthguard use in this population was not known. This
      study has implications for the provision of emergency dental treatment for sport
      participants and for improved dental injury prevention measures to avoid
      expensive and potentially disfiguring dental injuries in young athletes.

PMID- 10331474
TI  - Physical activity of adult Australians: epidemiological evidence and potential
      strategies for health gain.
AB  - Physical activity is now considered a major modifiable factor for preventing and
      reducing the mortality from cardiovascular disease, diabetes and some cancers, as
      well as improving musculoskeletal and mental health. Increasing epidemiological
      evidence confirms the health benefits of moderate regular physical activity. A
      dose response relationship remains, with greater benefits derived from increased
      intensity and duration of physical activity. Clinicians and exercise scientists
      should consider physical inactivity as important a risk factor as hypertension or
      elevated serum cholesterol levels. The broader public health objectives are to
      measure and monitor physical activity levels among all Australians, and to
      develop interventions to increase regular participation for the whole population.
      Population Campaigns and behaviour change programs are needed to increase the
      prevalence of participation in physical activity.

PMID- 10331476
TI  - Timing in the forward one and one half somersault with one twist 3m springboard
      dive.
AB  - The timing of actions to initiate and stop twist is critical to successful
      performance of the twisting and somersault rotations in 3m springboard dives. An
      important indicator of timing differences among subjects is the timing of hip
      flexion and extension. The purpose of this study was to quantify the timing and
      magnitude of hip flexions and extensions in the forward one and one half twisting
      dive with one twist. The timing and magnitude of hip flexion and extension of ten
      divers ranging in ability from New Zealand National to elite International
      standard were quantified using three-dimensional videography and analysis
      techniques. A Spearman (rho) correlation with p<.05 required for significance was
      conducted to determine the relationship between each of the variables and
      ability. The results indicated that skilled divers had more flight time than less
      skilled divers (rho=-.79), less hip flexion at takeoff (rho=.66), less pre-twist
      flexion (rho=.86), greater post-twist hip flexion, and had more time from the
      time of maximum post-twist flexion to entry than less skilled divers (rho=-.81).
      It was concluded that divers who currently initiate twist from a 'kick out'
      should learn to initiate twist without a 'kick out' and reduce hip flexion at
      takeoff to increase height and flight time.

PMID- 10331475
TI  - Injury surveillance during medical coverage of sporting events--development and
      testing of a standardised data collection form.
AB  - Medical coverage services have the potential to play a key role in sports injury
      surveillance activities. Provided that injury surveillance activities are fully
      coordinated and a standardised data collection procedure is implemented, valuable
      sports injury information can be obtained by medical coverage personnel. This
      paper describes the development of a standardised injury data collection form for
      use by medical coverage personnel during large sporting events. The form was
      trialed during two large sporting events in Melbourne, Australia in 1995. A range
      of sports medicine and sports first aid personnel was involved in the trial and
      injury details were collected on all persons receiving treatment from the
      coverage team, irrespective of injury severity. The final sports injury data
      collection form is easy to use, can be used by all types of medical coverage
      personnel and can provide valuable data in a timely manner. The form has since
      been adopted as the injury data collection standard at a number of major
      Australian sporting events. Recommendations for incorporating injury surveillance
      activities when organising sporting events and planning medical coverage services
      are given. Suggestions for maximising compliance with data collection procedures
      are also discussed.

PMID- 10331477
TI  - Eating attitudes, body shape perceptions and mood of elite rowers.
AB  - The study assessed the influence of age, gender and weight category upon eating
      attitudes, body shape perceptions, and mood. Elite rowers (N = 103) participating
      in the 1996 World Championships or Great Britain National Championships completed
      the Eating Attitude Test (EAT), the Body Shape Questionnaire (BSQ), and a short
      form of the Profile of Mood States (POMS-C). Participants were grouped as
      lightweight (Female: < 59 kg, n = 19; Male: < 72.5 kg, n = 31) or heavyweight
      (Female: n = 25; Male: n = 28) competitors. Results showed higher EAT scores
      among the lightweight group, 12.0% of whom reported scores above the threshold
      associated with eating disorders. Body shape concerns were higher for
      heavyweights than lightweights and for females than males. The interaction effect
      was not significant. BSQ scores were negatively correlated with age. Depression,
      Confusion and Tension scores collectively predicted 37% of the variance in BSQ
      scores while Depression scores predicted 9% of the variance in EAT scores. The
      results provide further evidence that the risk of eating disorders among elite
      rowers is moderated by age, gender and weight category. Further, they suggest
      that measures of mood may help identify athletes at risk from eating disorders.

PMID- 10331478
TI  - Preliminary assessment of force demands in laser racing.
AB  - The aim of this study was to measure forces acting on a laser sailor in order to
      obtain an indication of the physical demands in the major muscle groups used
      during dinghy racing. Force data were collected in the mainsheet and the hiking
      strap of a club level (body weight 94 kg) and an elite sailor (body weight 80 kg)
      in a range of wind conditions. The highest average and peak hiking strap forces
      were 647 N (59% of MVC) and 843 N (77% of MVC) respectively, recorded for the
      club level sailor. The highest average and peak mainsheet forces of 111 N (35% of
      MVC) and 289 N (90% of MVC) respectively were also recorded for the club sailor.
      The elite and the club sailors' results were similar in most cases. Differences
      were attributed to differing body weights and technique. The results provide a
      preliminary indication of the intensity of muscular forces required in a physical
      training programme for laser racing.

PMID- 10331479
TI  - Normative data of vertical ground reaction forces during landing from a jump.
AB  - This technical report provides normative data of vertical ground reaction forces
      (GRFs) associated with landing from a jump. Subjects were 234 adolescents (mean
      age: 16 years) who were categorised by gender, activity level and type of sport
      played. Subjects jumped from a box 0.3 metres high to land on a force plate.
      Results showed that there were no significant differences (p>0.05) across gender,
      activity levels, and type of sport played. Across all subjects, the mean peak
      vertical GRF was 4.5 bodyweights (SD: 1.7). In regard to gender, mean peak
      vertical GRFs were 4.6 (SD: 1.7) and 4.2 (SD: 1.4) for males and females
      respectively. The mean peak vertical GRF for subjects involved in recreational
      sport 1-3 times per week was 4.4 bodyweights (SD: 1.7), while the mean for those
      playing competitive sport 4-7 times per week was 4.5 bodyweights (SD: 1.7). The
      mean peak vertical GRF for subjects participating in sports involving jumping and
      landing activities was 4.6 bodyweights (SD: 1.8) as compared to 4.4 bodyweights
      (SD: 1.5) for subjects in sports that did not involve jumping activities.

PMID- 10331480
TI  - To die or not to die--the quest of the TRAIL receptors.
AB  - The last 18 months have witnessed the characterization of several new members of
      the tumor necrosis factor (TNF) receptor family. Among these are five receptors
      for the cytotoxic ligand TRAIL (TNF-related apoptosis-inducing ligand). Two of
      these receptors, TRAIL-R1 and TRAIL-R2, contain classical cytoplasmic death
      domains and are able to transduce an apoptotic signal. The others lack functional
      death domains and are not able to promote cell death. Indeed, one of the
      receptors for TRAIL, osteoprotegerin (OPG) is a soluble protein whose activities
      so far have been shown to be inhibition of osteoclastogenesis and increased bone
      density in vivo. The existence of multiple receptors for TRAIL suggests an
      unexpected complexity to TRAIL-mediated biological functions.

PMID- 10331481
TI  - The taming of IL-12: suppressing the production of proinflammatory cytokines.
AB  - Interleukin (IL)-12 is a cytokine that possesses both proinflammatory and
      immunoregulatory activity. IL-12, and the interferon-gamma (IFN-gamma) that is
      induced by IL-12, play central roles in the development of the Th1-type immune
      responses that are required for immunity to intracellular pathogens. Recently a
      number of these pathogens, including Leishmania, measles virus, and human
      immunodeficiency virus (HIV), have been shown to subvert the development of cell
      mediated immunity by actively inhibiting the production of IL-12. Similarly, the
      ligation of phagocytic receptors on macrophages has also been shown to suppress
      IL-12 production. The suppression of IL-12 production by receptor ligation occurs
      by at least two distinct mechanisms: one involves a direct inhibition of gene
      transcription and the other depends on the production of inhibitory cytokines. We
      review studies in which IL-12 has been experimentally manipulated, and we compare
      the mechanisms by which this regulation can occur. Because the IL-12 that is
      produced during acute inflammation and chronic autoimmune disorders can lead to
      exacerbated disease, the development of pharmacological means to suppress IL-12
      production is currently under investigation. This review focuses on the
      production of IL-12 by antigen-presenting cells and the methods by which the down
      regulation of IL-12 production can be exploited either by pathogens or for
      therapeutic ends.

PMID- 10331482
TI  - Chemokine immunobiology in HIV-1 pathogenesis.
AB  - The discovery of HIV-1-suppressive chemokines and the subsequent discovery of
      their cognate receptors as coreceptors for HIV-1 entry herald a paradigmatic
      shift in the study of HIV-1 pathogenesis. The presence of polymorphisms in
      chemokine receptor and chemokine genes associated with altered progression and
      susceptibility to the HIV-1 disease further underscores the potential importance
      that chemokines and their cognate receptors play in HIV-1 pathogenesis. It has
      become increasingly apparent that the immune system maintains a delicate balance
      between the positive and negative regulators that govern the chemokine and
      cytokine networks. Here we review the most recent developments in chemokine
      biology and relate how research into their structure, regulation, and the
      mechanism of their actions can shed light on the immnunopathogenesis of HIV-1
      disease.

PMID- 10331483
TI  - Dramatic decrease of circulating levels of monocyte chemoattractant protein-1 in
      Kawasaki disease after gamma globulin treatment.
AB  - Kawasaki disease (KD) is a systemic vasculitis preferentially affecting coronary
      arteries. Extensive monocytes/macrophages infiltrate in the vascular lesions,
      implying the involvement of a chemotactic cytokine in their recruitment. We
      investigated the role of monocyte chemoattractant protein-1 (MCP-1, also termed
      monocyte chemotactic and activating factor) in KD. In the immunohistochemical
      studies using the cardiac tissues of patients with fatal KD, MCP-1 but not
      interleukin (IL) -8 or macrophage inflammatory protein-1alpha was localized at
      the extracellular matrix associated with mononuclear cellular infiltration. The
      sites of MCP-1 expression correlated with the distribution of the acute
      inflammation, including early coronary vasculitis. In prospectively studied
      patients with KD, circulating levels of MCP-1, IL-8, tumor necrosis factor alpha
      (TNF-alpha), and IL-1alpha were elevated in 73, 77, 57, and 0% of samples before
      gamma globulin (GG) treatment (400 mg/kg x 5 days = total 2 g/kg), respectively,
      compared with respective control values. GG treatment correlated with a rapid
      decrease in the circulating levels of MCP-1 (P = 0.001) but not IL-8 (P = 0.19)
      or TNF-alpha (P = 0.33). In the sensitive Western blotting, MCP-1 bound to GG.
      Furthermore, GG inhibited the MCP-1-induced Ca2+ influx in a human monocytic cell
      line in vitro. These findings suggest a role of MCP-1 in KD, and indicate that GG
      treatment may block MCP-1 activity, thus alleviating KD vasculitis.

PMID- 10331484
TI  - Systemic suppression of human peripheral blood phagocytic leukocytes after whole
      body UVB irradiation.
AB  - We examined systemic effects of whole-body UVB irradiation on human peripheral
      blood phagocytes. We found that 24 h after a single erythemal dose of UVB
      radiation two phagocyte functions, adhesion and phagocytosis, were reduced by
      50%. This functional suppression was accompanied by a significant decrease in the
      expression of complement receptors (CR1 and CR3) and IgG Fc receptors (FcRII and
      FcRIII). The greatest reduction (47%) was observed in CR3, which is important for
      both adhesion and phagocytosis. A kinetic analysis showed that both CR1 and CR3
      levels started to decrease 15 min after the UVB exposure, reaching the lowest
      levels at 4.5- and 24-h time points, respectively. The down-modulation of CRs
      after whole-body UVB exposure was not due to a defective receptor synthesis or
      translocation from internal stores to plasma membrane because the maximal CR
      levels in stimulated cells were not affected by UVB. No change in the serum
      soluble ICAM-1 was detected after UVB, which rules out CD1 1b epitope masking by
      sICAM-1. UVB did not release low-receptor-density myeloid progenitor cells from
      storage pools into circulation. Interleukin 10, a mediator of UVB-induced
      immunosuppression, was unable to modulate CR expression in vitro. When seven
      suberythemal whole-body UVB exposures were given repeatedly within 2 weeks, a
      significant decrease in CR expression was seen, which was greatest after three
      irradiations. Our data suggest that an exposure to UVB has systemic effects in
      humans which, possibly due to the down-modulation of preexisting cell-surface
      receptors, suppress some important functions of circulating phagocytic cells.

PMID- 10331485
TI  - Modulation of cellular annexin I in human leukocytes infiltrating DTH skin
      reactions.
AB  - Based on our previous studies showing endogenous annexin I being depleted from
      migrated neutrophils (PMN) in vitro, we have tested whether the levels of this
      glucocorticoid-regulated protein in PMN and mononuclear cells (PBMC) were
      modified after adhesion to endothelial monolayers in vitro and extravasation into
      skin blisters in vivo. In vitro, annexin I levels were depleted more
      significantly (-70%) in post-adherent PMNs than in monocytes (-25%) and
      lymphocytes (-50%, only in the positive fraction). In vivo, a significant time
      dependent increase (approximately threefold, P < 0.05) in cell-associated annexin
      I was measured in PBMCs recovered from the blisters, whereas no significant
      changes were detected in extravasated PMNs. This was associated with annexin I
      release in the blister fluids (approximately 35 ng/mL), whereas no detectable
      protein was found in matched-paired plasmas. In conclusion, we report for the
      first time an activation of the annexin I pathway during an ongoing experimental
      inflammatory response in humans, which is differently regulated between PMNs and
      PBMCs.

PMID- 10331486
TI  - Morphine modulation of peritoneal inflammation in Atlantic salmon and CB6 mice.
AB  - Peritoneal inflammation is a convenient model for comparisons of modulatory
      effects of morphine in phylogenetically distant vertebrates. Both in salmon and
      mice morphine injected intraperitoneally together with an irritant
      (thioglycollate) significantly inhibits inflammation as estimated by the number
      of peritoneal leukocytes. The low number of exudate cells in morphine-treated
      animals seems to be compensated by their high activity, as evidenced by the
      enhanced phorbol myristate acetate-induced respiratory burst. The morphine
      inhibited influx of leukocytes into the irritated peritoneal cavity correlates
      with the morphine-lowered level of plasma chemotactic factors both in fish and
      mice. It implies that morphine impairs the level of plasma chemotactic factor
      either directly (affecting their release from the resident peritoneal cells) or
      indirectly (decreasing the number of inflammatory leukocytes by inhibition of
      their migration from hemopoietic sites). The inhibitory effects of morphine on
      both the cell number and chemoattractant level are completely reversed by the
      naltrexone pretreatment, which implicates the involvement of opioid receptors.

PMID- 10331487
TI  - Demonstration of iNOS-mRNA and iNOS in human monocytes stimulated with cancer
      cells in vitro.
AB  - Synthesis and localization of inducible nitric oxide synthase mRNA (iNOS-mRNA)
      and iNOS protein in the cultures of human monocytes (Mphi) and colon carcinoma
      cell line (DeTa) that resulted in nitric oxide (NO) synthesis has been studied.
      The iNOS-mRNA was observed around the sixth hour of culture and peaked at the
      twelfth hour. The iNOS-mRNA, as determined by the in situ hybridization and iNOS
      protein, as detected by staining with specific anti-iNOS monoclonal antibodies,
      were observed preferentially in the cytoplasm of some Mphi, but not in cancer
      cells. Mphi cultured alone did not show detectable iNOS-mRNA expression and iNOS
      protein. Mphi sorted out from tumor cells after 8 h of co-culture expressed iNOS
      protein and iNOS-mRNA, which were not detected in Mphi without previous contact
      with cancer cells. Prevention of NO synthesis by (L-N5-1-iminoethyl)-ornithine (L
      NIO) partly inhibited Mphi cytotoxic activity against DeTa (NO-inducing cancer
      cell line) but not against the human pancreatic cancer (HPC-4) cell line that
      does not induce NO production in Mphi. This suggests that Mphi cytotoxic
      activity, at least in some cases, may be NO dependent. These observations provide
      further evidence that Mphi can be directly stimulated by cancer cells for de novo
      production of NO and suggest that iNOS occurring in the tumor-infiltrating
      macrophages may arise as a result of their interactions with tumor cells.
      However, because only some tumor cells are able to induce NO production in a
      small proportion of Mphi, its role in the anti-tumor response of the host is
      probably limited.

PMID- 10331488
TI  - Interaction with vesicular stomatitis virus-infected BALB/c3T3 cells inhibits the
      synthesis of nitric oxide in activated murine bone marrow culture-derived
      macrophages.
AB  - Bone marrow-culture-derived macrophages activated with interferon-gamma and
      lipopolysaccharide produced less nitric oxide (NO) when cultured with vesicular
      stomatitis virus (VSV)-infected BALB/c3T3 (3T3-VSV) than macrophages activated in
      an identical manner and cultured alone, with uninfected BALB/c3T3 (3T3), or with
      P815. However, all four groups of macrophages produced nearly the same amount of
      interleukin-6 (IL-6). Addition of VSV to activated macrophages did not change the
      amount of NO produced. The amount of NO generated by two non-macrophage sources
      of NO was not affected by the presence of either P815 or 3T3-VSV. Reverse
      transcriptase-polymerase chain reaction showed a decrease in the amount of
      inducible nitric oxide synthase (iNOS) but not IL-6 mRNA from macrophages
      cocultured with 3T3-VSV compared with macrophages cocultured with P815. The
      reduction in iNOS mRNA was confirmed by ribonuclease protection assay. When RAW
      264.7 transfected with an iNOS regulatory construct were activated and incubated
      with 3T3-VSV there was a decrease in the expression of the reporter luciferase
      gene and NO production but not IL-6 production compared with cells incubated with
      either medium alone or with P815.

PMID- 10331489
TI  - Influenza A virus up-regulates neutrophil adhesion molecules and adhesion to
      biological surfaces.
AB  - Influenza A virus (IAV) binds to sialylated neutrophil surface components (e.g.,
      CD43 and sialyl Lewisx antigen) and induces both activation and functional
      depression of neutrophils. We report that IAV enhanced neutrophil adhesion to
      surfaces coated with serum or serum components, but not to uncoated plastic. IAV
      up-regulated expression of integrins (CD11b and CD11c) and carcinoembryonic
      related antigens on neutrophils, while reducing expression of CD43, L-selectin,
      and P-selectin glycoprotein ligand (PSGL). Although treatment of neutrophils with
      elastase or Osialoglycoprotease decreased surface CD43 and PSGL, they did not
      reduce binding of IAV to neutrophils, implying that IAV can bind to alternate
      binding sites in the absence of CD43. Pretreatment of neutrophils with elastase
      also did not prevent IAV from increasing expression of integrins and enhancing
      adhesion. Up-regulation of adhesion molecules and adhesion are important,
      previously unrecognized, features of neutrophil activation by IAV. Further
      studies will be needed to clarify the mechanism of these effects.

PMID- 10331490
TI  - Dendritic cell differentiation pathways of CD34+ cells from the peripheral blood
      of head and neck cancer patients.
AB  - Patients with head and neck squamous cell carcinoma (HNSCC) have increased levels
      of immune-suppressive peripheral blood CD34+ cells. This study showed that the
      peripheral blood CD34+ cells of HNSCC patients are capable of differentiating
      into dendritic cells. Because CD34+ cells can differentiate through several
      pathways into dendritic cell subpopulations, the intermediate cells through which
      the blood CD34+ cells of HNSCC patients differentiate were identified. After 6-7
      days of culturing the CD34+ cells of HNSCC patients with granulocyte-macrophage
      colony-stimulating factor, stem cell factor, and tumor necrosis factor at, there
      appeared CD14+CD1a+ and a lesser proportion of CD14(-)CD1a+ cells resembling the
      precursor cells of the bipotential and committed dendritic cell differentiation
      pathways that have been described for cord blood CD34+ cells. To functionally
      analyze whether these populations were in fact precursor cells, they were
      isolated and cultured for an additional 10-12 days. Each of these populations was
      shown to function as precursor cells because they were able to develop into cells
      that resembled dendritic cells, although a higher proportion developed from the
      CD14-CD1a+ cells. In contrast, expression of the dendritic activation/maturation
      marker CD83 was highest on the cells that developed from CD14+CD1a+ cells. Thus,
      the CD34+ cells whose levels are increased in HNSCC patients can develop into
      both committed and bipotential dendritic precursor cells, which can subsequently
      give rise to dendritic cells.

PMID- 10331491
TI  - NADPH oxidase is functionally assembled in specific granules during activation of
      human neutrophils.
AB  - In addition to the extracellular production of O2- by NADPH oxidase in
      neutrophils stimulated by soluble stimuli, the intracellular formation of oxygen
      reactive species has been described. Cytochrome b559, the redox component of the
      NADPH oxidase complex, is mainly associated with specific granule membrane in
      resting neutrophils. We examined whether these granules could be a site for
      intracellular production of O2-. Phorbol myristate acetate (PMA)-stimulated
      neutrophils were fractionated by differential centrifugation, and generation of
      O2- was detected in both the granule and the plasma membrane-enriched fractions,
      but more in the granules. Translocation of p47phox and p67phox, two cytosolic
      components of the NADPH oxidase, was also quantitatively more important in the
      granules than in the plasma membrane fraction. After separation of the specific
      from the azurophil granules, p47phox and p67phox were found to be present only in
      the specific granules of PMA-activated cells. As a control, the production of O2-
      was studied in retinoic acid-differentiated NB4 cells that lack specific
      granules. During stimulation of NB4 cells with PMA, only the plasma membrane
      enriched fraction was the site of O2- production. Together, these results
      indicate that NADPH oxidase can be functionally assembled in specific granules.

PMID- 10331492
TI  - Hyperglycemia in vitro attenuates insulin-stimulated chemokinesis in normal human
      neutrophils. Role of protein kinase C activation.
AB  - This study was performed to test whether the inhibitory effect of elevated D
      glucose concentrations on insulin-stimulated chemokinesis in normal human
      neutrophils is mediated by increase in protein kinase C (PKC) activity.
      Activation of PKC with phorbol 12-myristate 13-acetate (PMA) at 0-100 nM dose
      dependently inhibited neutrophil random locomotion in the absence of insulin. Sub
      optimal concentrations of PMA (0.1-0.5 nM) inhibited the chemokinetic effect of
      160 microU/mL insulin in a dose-dependent way. The specific PKC inhibitor
      bisindolylmaleimide (GF 109203x) did not affect the insulin-stimulated
      chemokinesis at 5 mM glucose but restored the chemokinetic effect of insulin at
      15 mM glucose. These results therefore suggest that glucose-induced PKC
      activation may mediate the inhibitory effects of high glucose levels on insulin
      stimulated chemokinesis in normal human neutrophils.

PMID- 10331493
TI  - Generation of CD28- cells from long-term-stimulated CD8+CD28+ T cells: a possible
      mechanism accounting for the increased number of CD8+CD28- T cells in HIV-1
      infected patients.
AB  - According to CD28 molecule expression, CD8+ T cells can be classed as CD28bright,
      CD28dim, and CD28-. The CD28dim T cells were found to derive from mitogenic
      stimulated CD28-T cells but also from CD28bright T cells through a mechanism of
      CD28 down-modulation. Moreover, after prolonged in vitro interleukin-2
      stimulation, clonal CD28bright, cells showed a CD28dim expression before further
      evolution to a stable CD28-phenotype. This loss was concomitant with the
      disappearance of CD28 mRNA. A study of the cytokine production pattern revealed
      that CD28dim and CD28- T cell clones produced similar levels of type 1 and type 2
      cytokines, which differed from those produced by the CD28bright T cell clones. A
      high percentage of CD28dim and CD28- cells, with similarities in their cytokine
      production pattern, were found in the blood samples of HIV-infected patients, as
      compared to healthy donors. The CD28 down-modulation may account for the
      increased number of CD8+CD28- T cells in HIV-infected patients.

PMID- 10331495
TI  - Increased neutrophil adherence and adhesion molecule mRNA expression in
      endothelial cells during selenium deficiency.
AB  - Leukocyte aggregation and activation on endothelial cells (EC) are important
      preliminary events in leukocyte migration into tissue and subsequent
      inflammation. Thus, an increase in leukocyte adherence has the potential to
      affect inflammatory disease outcome. Selenium (Se) is an integral part of the
      antioxidant enzyme glutathione peroxidase (GSH-Px) and plays an important role in
      the maintenance of the redox state of a cell. Se supplementation in the bovine
      has been shown to improve the outcome of acute mastitis caused by coliform
      bacteria, in part by enhancing the speed of neutrophil migration into the
      affected mammary gland. However, the mechanisms by which Se modulates neutrophil
      migration have not been elucidated. Therefore, an in vitro model of Se deficiency
      in primary bovine mammary artery EC was used to examine the impact of Se status
      on the adhesive properties of EC. The effect of Se on functional activities was
      examined by measuring neutrophil adherence to Se-deficient and Se-supplemented
      EC. Se-deficient EC showed significantly enhanced neutrophil adherence when
      stimulated with tumor necrosis factor alpha (TNF-alpha) for 4 or 24 h,
      interleukin-1 for 12 h, or H2O2 for 20 min (P < 0.05). To determine the
      mechanisms underlying these changes in neutrophil adherence, the expression of EC
      adhesion molecules, ICAM-1, E-selectin, and P-selectin were examined at the
      molecular level by a competitive reverse transcription-polymerase chain reaction.
      Results revealed higher mRNA expression for E-selectin and ICAM-1 in Se-deficient
      EC stimulated with TNF-alpha for 3 and 6 h, and greater expression of P-selectin
      mRNA in Se-supplemented EC with 3-h TNF-alpha stimulation. These studies provide
      new information to establish the role of Se nutrition in the initiation of
      leukocyte adherence to endothelium.

PMID- 10331494
TI  - Selective antibody blockade of lymphocyte migration to mucosal sites and mast
      cell adhesion.
AB  - The integrins alpha4beta7 and alpha4beta1 mediate adhesion to the mucosal
      addressin cell adhesion molecule-1 (MAdCAM-1) and the vascular cell adhesion
      molecule-1 (VCAM-1) and are important in T cell and allergic inflammatory
      reactions in the rat. The relative contributions of alpha4beta7 and alpha4beta1
      in these reactions is unknown. To examine the role of alpha4beta7 in the rat a
      new mAb, TA-6, was developed. TA-6 inhibited adhesion to MAdCAM-1 but not to VCAM
      1, a characteristic of alpha4beta7 adhesion, and immunofluorescence and
      immunoprecipitation studies were compatible with binding to alpha4beta7. TA-6
      blocked rat lymphocyte adhesion to mesenteric lymph nodes and T cell migration to
      mucosal lymphoid tissues and it bound to rat mucosal mast cells. TA-6 did not
      inhibit lymphocyte adhesion to peripheral lymph nodes and T cell migration to
      peripheral lymphoid tissues or cutaneous inflammatory sites, and was not
      expressed on connective tissue mast cells.

PMID- 10331496
TI  - Superantigens augment antigen-specific Th1 responses by inducing IL-12 production
      in macrophages.
AB  - Superantigens (SAg) are microbial proteins that mediate antigen-presenting cell
      (APC)-T cell interaction by cross-linking MHC class II molecules with subsets of
      TcRVbeta. SAgs are implicated in the pathogenesis of several infectious,
      inflammatory, and autoimmune diseases. In this study, we examined the influence
      of SEB on interleukin-12 (IL-12) production and the activation of antigen
      specific Th1 responses. Addition of SEB augmented the antigen-induced
      proliferation of HS-17, a murine MBPp91-103 peptide-specific TcRVbeta6+ CD4+ Th1
      clone. SEB augments HS-17 T cell proliferation through its interaction with IA(S)
      molecules on macrophages, but not with the TcRVbeta6 on HS-17 cells. On binding
      to IA(S), SEB induces IL-12 production in macrophages, which in turn augments
      antigen-induced proliferation of HS-17 T cells. Treatment with anti-IA(S) nmAb 10
      3.6 inhibited the antigen- and SEB-induced IL-12 production and T cell
      proliferation. These results suggest that SAgs augment antigen-specific T cell
      responses by inducing IL-12 production in macrophages.

PMID- 10331497
TI  - MCP-1 is selectively expressed in the late phase by cytokine-stimulated human
      neutrophils: TNF-alpha plays a role in maximal MCP-1 mRNA expression.
AB  - Culture supernatants of phytohemagglutinin (PHA)-stimulated human peripheral
      blood mononuclear cells (PHA-sup) induced monocyte chemoattractant protein-1 (MCP
      1) mRNA expression in human neutrophils. MCP-1 mRNA was first detected by
      Northern analysis at 8 h, and the peak level was detected at 16 h and sustained
      until 72 h. Cycloheximide and genistein, but not pertussis toxin, inhibited the
      expression of MCP-1 mRNA. Recombinant tumor necrosis factor alpha (TNF-alpha)
      induced a low level MCP-1 mRNA accumulation in neutrophils, and addition of anti
      TNF-alpha IgG blocked 30-70% of MCP-1 mRNA expression induced with PHA-sup. PHA
      sup-stimulated PMN synthesized and secreted 3.1+/-1.3 ng/5 x 10(6) PMN MCP-1
      within the first 24 h. Hybridization of 32P-labeled cDNA preparations to an array
      of human cytokine cDNAs further indicated that MCP-1 mRNA was selectively up
      regulated in the late phase after stimulation with the PHA-sup.

PMID- 10331498
TI  - TALL-1 is a novel member of the TNF family that is down-regulated by mitogens.
AB  - Members of the tumor necrosis factor (TNF) family play important roles in
      modulation of immune responses. We describe the identification and cloning of a
      novel TNF family member that has been designated as TALL-1. TALL-1 is a 285-amino
      acid type II transmembrane protein. Its carboxy terminus shares approximately 35%
      sequence identity with the recently identified APRIL and approximately 20-25%
      with TNF, FasL, TRAIL, and lymphotoxin-alpha, suggesting that TALL-1 and APRIL
      belong to a subfamily of the TNF family of ligands. Northern blot analysis
      suggests that TALL-1 is expressed abundantly in peripheral blood leukocytes and
      weakly in spleen but is barely detectable in all other tissues examined. Reverse
      transcriptase-polymerase chain reaction analysis indicates that TALL-1 is
      specifically expressed in monocytes and macrophages but is undetectable in T and
      B lymphocytes. Furthermore, TALL-1 expression is dramatically down-regulated by
      phorbol myristate acetate/ionomycin.

PMID- 10331499
TI  - Cloning of two chemokine receptor homologs (CXC-R4 and CC-R7) in rainbow trout
      Oncorhynchus mykiss.
AB  - Two rainbow trout chemokine receptors have been sequenced, with homology to CXC
      R4 and CC-R7 molecules. The CXC-R4 sequence consisted of 1681 nucleotides, which
      translated into a mature protein of 357 amino acids, with 80.7% similarity to
      human CXC-R4. The CC-R7 sequence consisted of 2287 nucleotides, which translated
      into a 368-amino acid mature protein with 64.5% similarity to human CC-R7. Both
      sequences contained seven hydrophobic regions, representing the seven
      transmembrane domains (TM) typical of G-protein-coupled receptors. Extracellular
      cysteines, transmembrane prolines, and the DRY motif immediately following TM3
      were conserved. Phylogenetic tree analysis revealed a tight clustering of trout
      CXC-R4 with CXC-R3-5 genes. Trout CC-R7 clustered with CC-R6-7 and CXC-R1-2.
      Reverse transcriptase-polymerase chain reaction analysis demonstrated a wide
      tissue distribution of CXC-R4 and CC-R7 message in trout, being present in head
      kidney leukocytes, blood, gill, brain, spleen, and liver.

PMID- 10331500
TI  - Assessment of chemokine receptor expression by human Th1 and Th2 cells in vitro
      and in vivo.
AB  - The preferential association of some chemokine receptors with human Th1 or Th2
      cells has recently been reported. In this study, the expression of CCR3, CCR5,
      CXCR3, and CXCR4 were analyzed by flow cytometry in three distinct in vitro
      models of Th1/Th2 polarization, activated naive and memory T cells, and T-cell
      clones, in which the intracellular synthesis of interferon-gamma (IFN-gamma) and
      interleukin-4 (IL-4) and the surface expression of CD30 and LAG-3 were also
      assessed. Moreover, by using immunohistochemistry the in vivo expression of CCR3,
      CCR5, CXCR3, and CXCR4 was examined in the gut of patients suffering from Crohn's
      disease, a Th1-dominated disorder, and in the skin of patients suffering from
      systemic sclerosis, a Th2-dominated disorder. CCR5 and LAG-3 exhibited the same
      pathway of Th1 association, whereas CXCR3 did not discriminate between Th1- and
      Th2-dominated responses. On the other hand, CCR3 was found only occasionally in a
      small proportion of allergen-specific memory T cells with Th2/ThO profile of
      cytokine production in vitro. However, it was neither seen in Th2-polarized
      activated naive T cells nor in established Th2 clones and could be detected in
      vivo only on non-T cells. Finally, whereas CXCR4 expression was not limited to
      Th2 cells in vivo, it was markedly up-regulated by IL-4 and down-regulated by IFN
      gamma in vitro. Thus, the results of this study confirm the existence of flexible
      programs of chemokine receptor expression during the development of Th1 and Th2
      cells. However, caution is advised in interpreting these receptors as surrogate
      markers of a given type of effector response.

PMID- 10331501
TI  - Involvement of JAK2, but not PI 3-kinase/Akt and MAP kinase pathways, in anti
      apoptotic signals of GM-CSF in human eosinophils.
AB  - Granulocyte-macrophage colony-stimulating factor (GM-CSF) transmits anti
      apoptotic signals in eosinophils and is involved in tissue eosinophilia at the
      site of allergic inflammation. We determined whether phosphatidylinositol 3
      kinase (PI 3-kinase) and mitogen-activated protein kinase (MAP kinase) are
      involved in anti-apoptotic signals of GM-CSF in eosinophils. GM-CSF
      phosphorylated Akt, a downstream component of PI 3-kinase, and MAP kinases (ERK1
      and ERK2) at 10 min after stimulation in eosinophils. GM-CSF prevented eosinophil
      apoptosis and sustained its survival during the 5-day culture. However, neither
      two PI-3 kinase inhibitors, wortmannin and LY294002, nor MEK inhibitor PD98059
      inhibited GM-CSF-induced survival of eosinophils, although wortmannin and PD98059
      inhibited GM-CSF-induced Akt phosphorylation and MAP kinase activation in
      eosinophils, respectively. In contrast, JAK2 inhibitor AG-490 inhibited both GM
      CSF-induced JAK2 phosphorylation and cell survival in eosinophils. These results
      indicate that activation of JAK2, but not activation of PI 3-kinase/Akt and MAP
      kinase pathways, is critical for anti-apoptotic signals of GM-CSF in human
      eosinophils. Our findings suggest that manipulation of JAK2 activation would be
      useful for the treatment of allergic disorders.

PMID- 10331502
TI  - Regulation of delta opioid receptor expression by anti-CD3-epsilon, PMA, and
      ionomycin in murine splenocytes and T cells.
AB  - Previous studies have shown that low levels of delta opioid receptor (DOR) mRNA
      were detectable by reverse transcription polymerase chain reaction (RT-PCR) in
      unstimulated splenocytes from BALB/c female mice. This study demonstrates that
      DOR transcripts can be detected in freshly obtained splenocytes froin CD 1 female
      mice as well. The results of studies using quantitative competitive RT-PCR showed
      that DOR transcripts in splenic T cells increased from < 1 copy/cell to 22 and 42
      copies/cell, respectively, after stimulation with anti-CD3-epsilon for 24 and 48
      h compared to the level in freshly obtained T cells. In the presence of
      actinomycin D, anti-CD3-epsilon did not affect the rate of degradation of DOR
      mRNA, suggesting that its stability is not altered by anti-CD3-epsilon. After
      incubation with phorbol myristate acetate (PMA) and ionomycin, the expression of
      DOR mRNA in splenocytes and T cells was significantly reduced compared with
      unstimulated cells in culture. In addition, the inhibitory effect of PMA
      prevented anti-CD3-epsilon-stimulated DOR expression. These data suggest that
      signaling through the T cell receptor complex by anti-CD3-epsilon regulates DOR
      expression differently than PMA and ionomycin.

PMID- 10331503
TI  - A novel 105 basepair deletion causing beta(0)-thalassemia in members of a Thai
      family.
AB  - We identified and characterized a novel beta(0)-thalassemia mutation due to
      partial deletion of the 5' end beta-globin gene including the mRNA cap site and a
      part of exon 1. The deletion was precisely 105 basepair (bp) in length extending
      from position -24 or -25 to +80 or +81 relative to the beta-globin gene mRNA cap
      site. This mutation was detected in three individuals from a family originating
      in the area of southern Thailand. The propositus was a 39-year-old female and
      noted to be heterozygous for beta-thalassemia with hemoglobin (Hb) level of 10.1
      g/dl, MCV 70 fl, MCH 23.1 pg, HbA2 6.3%, and HbF 2.4%. Her son was 9 years of age
      and was also heterozygous for the mutation, having Hb level of 10.8 g/dl, MCV 58
      fl, MCH 19.0 pg, HbA2 5.6%, and HbF 4.3%. Her 6-year-old daughter was affected,
      having a genotype of this mutation and a G-C transition at IVS 1 nt 5. Although
      the deletion does not include the beta-globin gene promoter sequences, the
      individuals heterozygous for this mutation have an elevated HbA2 level slightly
      higher than observed in most carriers of beta-thalassemia caused by point
      mutations.

PMID- 10331504
TI  - Telomere length shortening is associated with disease evolution in chronic
      myelogenous leukemia.
AB  - We studied telomere length in the peripheral blood leukocyte samples of a large
      group of patients with chronic myelogenous leukemia (CML) by Southern blot
      hybridization using the (TTAGGG)4 probe. The average telomere length expressed as
      the peak telomere repeat array (TRA) of the peripheral blood samples obtained
      from a group of 34 healthy age-matched controls ranged between 7.6 and 10.0 kb
      and the mean peak TRA was 8.7 kb. Forty-one patients in the chronic phase of CML
      were studied; 32/41 (78%) showed telomere reduction (<7.6 kb) relative to age
      matched controls and the mean peak TRA was 6.4 kb (range 4.0-10.6 kb). Serial
      samples were analysed from 12 patients at both chronic phase and during disease
      progression. The leukocyte DNA of all 12 patients in accelerated phase and/or
      blast crisis showed telomere reduction relative to age-matched controls and the
      mean peak TRA was 4.1 kb (range 3.0-5.4 kb). The peak TRA in the accelerated or
      blast phase was reduced compared with the corresponding paired sample in the
      chronic phase in all cases studied. These data show that a marked reduction in
      telomere length is associated with disease progression in CML.

PMID- 10331505
TI  - Population-based incidence and survival figures in essential thrombocythemia and
      agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995.
AB  - To provide basic information about occurrence and outcome of essential
      thrombocythemia (ET) and agnogenic myeloid metaplasia (AMM), we used the
      Rochester Epidemiology Project medical record linkage system for residents of
      Olmsted County, Minnesota. We identified all residents who were diagnosed with ET
      or AMM from 1976 to 1995. Community inpatient and outpatient medical records were
      reviewed to verify the diagnosis of ET or AMM, and patients were followed
      passively through their medical records to determine the outcome after diagnosis.
      We identified 39 cases of ET and 21 of AMM, with age- and sex-adjusted incidence
      rates of 2.53 and 1.46 cases/100,000 population annually, respectively. The
      respective median ages at diagnosis were 72 and 67 years. The female-to-male
      ratios were 1.8 and 1.6 for ET and AMM, respectively, and when adjusted for age,
      there was no difference in risk. The median follow-up period was 62.9 months for
      ET and 33.2 months for AMM. Five- and 10-year survivals were 74.4% and 61.3%,
      respectively, for ET and were significantly lower than expected for age-matched
      controls (P = 0.012). Prognosis was worse for AMM, with a median progression time
      of 7 months and a 3-year survival of 52.4%. This was significantly worse than for
      age-matched controls (P < 0.001). This study provides population-based incidence
      and comparative survival figures in ET and AMM.

PMID- 10331506
TI  - Chronic pure red cell aplasia caused by parvovirus B19 in AIDS: use of
      intravenous immunoglobulin--a report of eight patients.
AB  - The optimal management of chronic pure red cell aplasia caused by parvovirus B19
      (B19-PRCA) in patients with AIDS is unclear. Our purpose was to determine the
      effects of intravenous immunoglobulin (IVIg) in the treatment of B19-PRCA in
      patients with AIDS. The patients were eight adults with AIDS admitted during the
      period 1993-1997. A diagnosis of B19-PRCA was made if all the following criteria
      were met: 1. Bone marrow biopsy finding of pure red cell aplasia; 2. Detection of
      parvovirus B19 DNA in serum; and 3. No alternative explanation for PRCA. Initial
      (induction) therapy was with IVIg 1 g/kg daily for 1-2 days. Relapses were
      treated with IVIg 1 g/kg for 2 days. Maintenance therapy with IVIg 0.4-1.0 g/kg q
      4 weeks was given to those patients who developed a second or subsequent relapse.
      The patients were followed for a mean of 27 months (range 8-38 months). All
      patients responded to initial therapy with IVIg. Six patients with CD4 counts <
      80 cells/mm3 relapsed. The response was short lived in two patients with a CD4
      count < 80 cells/mm3 who were given a single infusion of IVIg 1 g/kg as initial
      therapy. Four patients were given regular maintenance IVIg therapy following a
      second or subsequent relapse and remain in remission. Two patients whose CD4
      counts were > 300 cells/mm3 remain in continuous unmaintained remission from B19
      PRCA for over 8 and 11 months, respectively, following induction therapy with
      IVIg. AIDS patients with B19-PRCA respond well to therapy with IVIg 2 g/kg given
      over 2 days. Most patients with CD4 counts of < or = 80 cells/mm3 suffer relapse
      within six months necessitating retreatment with IVIg; maintenance therapy with
      IVIg 0.4 g/kg q 4 weeks is effective in preventing relapse of B19-PRCA, and may
      be cost effective. Routine maintenance therapy is probably not indicated in
      patients with CD4 counts over 300 cells/mm3. Prospective studies are needed to
      confirm these findings.

PMID- 10331507
TI  - Plasma sFas and sFas ligand levels in patients with thrombotic thrombocytopenic
      purpura and in those with disseminated intravascular coagulation.
AB  - Fas, a member of the tumor necrosis receptor superfamily, is 36 kD surface
      protein containing a single transmembrane region and induces apoptosis by Fas-Fas
      ligand binding. Soluble Fas (sFas) is produced as the form lacking 21 amino acid
      residues containing the transmembrane domain by alternative splicing. We found
      that the plasma sFas levels of 33 patients with thrombotic thrombocytopenic
      purpura/hemolytic uremic syndrome (TTP/HUS), 19 patients with disseminated
      intravascular coagulation (DIC), and 10 non-DIC patients with multiple organ
      failure (MOF) were significantly higher than those of 21 non-DIC patients without
      organ failure and those of 25 healthy volunteers. The plasma sFas ligand levels
      of the TTP/HUS patients, the DIC patients, and the non-DIC patients with MOF were
      significantly higher than those of the non-DIC patients without organ failure and
      those of the healthy volunteers. The plasma sFas levels were significantly
      correlated with the plasma sFas ligand levels in all subjects. The plasma
      thrombomodulin (TM) levels were increased significantly in the TTP/HUS patients,
      the DIC patients, and the non-DIC patients with MOF compared with the levels of
      the non-DIC patients without organ failure and the healthy volunteers. The plasma
      sFas antigen levels were correlated significantly with the plasma TM levels in
      all subjects. These findings suggest that the increases of sFas and sFas ligand
      that cause apoptosis might be related to the vascular endothelial cell injuries
      in TTP and DIC with organ failure.

PMID- 10331508
TI  - Restricted diversification of T-cells in chronic active Epstein-Barr virus
      infection: potential inclination to T-lymphoproliferative disease.
AB  - To assess the abnormal T-cell expansion in chronic active Epstein-Barr virus
      infection (CAEBV), T-cell antigen receptor (TCR) repertoire was analyzed in four
      patients with the disease. All fulfilled the diagnostic criteria of CAEBV,
      presenting with fever, hepatosplenomegaly, cytopenia, abnormal high titers of
      anti EBV-antibodies, and positive EBV genome of unknown cause. Southern blotting
      probed with EBV-terminal repeats and TCR Cbeta gene indicated clonal expansion of
      the infected cells in 3 and 2 patients, respectively. The number of CD4+ HLA-DR+
      cells appreciably increased in patients 1 (59%) and 2 (24%), who had a coronary
      aneurysm and central nervous system involvement, respectively. TCR gene
      expression examined by the inverse polymerase chain reaction methods revealed
      that Vbeta gene usages were preferential in all patients (Vbeta7 and Vbeta12:
      patient 1, Vbeta4: patient 2, Vbeta13: patients 3 and 4), compared with those in
      healthy controls. Valpha18 gene expression was remarkably high in patients 1 and
      2. Moreover, Jbeta gene expression was skewing in the reigning Vbeta clones in
      all patients. Vbeta4-Jbeta1.5 and Vbeta13-Jbeta1.5 genes were clonally expressed
      in patients 2 and 4, respectively. These results suggest that CAEBV is associated
      with the restricted diversity of T-cells, which may stem from the sustained
      expansion of oligoclonal T-cells possibly driven by conventional viral antigens,
      but not, superantigens. Although the study is limited by the small number of
      patients, the unbalanced T-cell repertoire might contribute to the evolution of T
      lymphoproliferative disease, otherwise, imply the innate defective immunity to
      EBV in CAEBV patients.

PMID- 10331509
TI  - Activation of coagulation factor VII by tissue-type plasminogen activator.
AB  - To investigate the effect of tissue-type plasminogen activator (t-PA) on blood
      coagulation, we examined the effects of the addition of t-PA to normal pool
      plasma (NPP) on clotting times such as diluted prothrombin time (PT) and kaolin
      clotting time (KCT). The diluted PT but not the KCT was significantly shortened
      by the addition of t-PA to NPP compared with the normal controls, suggesting a t
      PA-induced activation of blood coagulation through factor VII (FVII) activation.
      The activated factor VII (FVIIa) concentration in the NPP was significantly
      increased by the addition of t-PA. Although the FVIIa formation was not observed
      following the incubation of purified FVII with only t-PA or plasminogen, an
      increase in the FVIIa level was observed after the incubation of purified FVII
      with t-PA together with plasminogen, or only plasmin. This plasmin-mediated FVIIa
      formation was also confirmed by Western blotting. These findings suggest that t
      PA enhances the activation of the coagulation system through FVII activation.

PMID- 10331510
TI  - Spontaneous erythroid colony formation in Brazilian patients with sickle cell
      disease.
AB  - The ability of circulating progenitor cells to develop erythroid colonies was
      studied in vitro in the presence or absence of growth factors (5637-CM and
      erythropoietin) in 63 patients with sickle cell disease (SCD) (36 homozygotes for
      hemoglobin [Hb] S, 13 double heterozygotes for Hb S and beta thalassemia, and 14
      SC patients) in Southeast Brazil. In the presence of growth factors, SCD patients
      (all genotypes) presented significantly higher numbers of circulating burst
      forming unit-erythroid (BFU-E/5 x 10(5) MNC), when compared with control
      subjects. However, when the progenitor cells were cultured in the absence of
      added stimulus, high numbers of BFU-E were observed only in the genotypes SS and
      S/beta thalassemia. SC patients presented a similar response to the control
      subjects. Moreover, there was an inverse correlation between spontaneous (without
      stimulus) BFU-E and Hb levels in SCD patients. These results suggest that the
      formation of spontaneous BFU-E observed in SCD may be due to an expanded
      erythropoiesis secondary to hemolysis.

PMID- 10331511
TI  - Expression of regeneration and tolerance factor on B cell chronic lymphocytic
      leukemias: a possible mechanism for escaping immune surveillance.
AB  - Regeneration and tolerance factor (RTF) is a protein expressed on developing
      tissue such as the thymus and the placenta. RTF has been reported to down
      regulate cell-mediated immune responses. To examine the potential role of tumor
      derived RTF to suppressing antitumor responses, we analyzed a panel of seven B
      cell tumor lines for the membrane RTF using a fluorescein isothiocyanate (FITC)
      conjugated monoclonal antibody, which reacts with membrane RTF. All the B cell
      tumor lines we examined express RTF on the cell surface. We also tested
      conditioned media from these B cell lines for their ability to suppress IL-2R
      expression on activated cells. Conditioned media from each B cell line suppressed
      IL-2R expression on activated Jurkat T cells and activated peripheral blood
      mononuclear cells. A monoclonal antibody to the biologically active portion of
      RTF reversed this suppressive activity. Finally, the tumor cell population from
      patients with chronic lymphocytic leukemia was found to express cell surface RTF.
      Thus, RTF expression could be a new mechanism used by tumor cells to escape
      immune surveillance.

PMID- 10331513
TI  - Sebastian syndrome: case report and review of the literature.
AB  - Macrothrombocytopenias (MTCP) are a heterogeneous group of disorders associated
      with thrombocytopenia and giant platelets, and may include other clinical or
      laboratory findings such as hereditary nephritis, sensorineural deafness,
      leukocyte inclusions, and cataracts. Patients with MTCP may have mild to moderate
      bleeding symptoms or be completely asymptomatic. The most recently described MTCP
      is the Sebastian syndrome (SS), which consists of thrombocytopenia with giant
      platelets and leukocyte inclusions. Only three previous reports about this
      syndrome have been published. Herein, we report the first African-American family
      with SS. The propositus is a 4-week-old male born to a mother carrying the
      diagnosis of chronic idiopathic thrombocytopenia purpura (ITP). His 4-year-old
      brother also has thrombocytopenia. There is no history of bleeding symptoms in
      any of the family members. The diagnosis was established by demonstrating
      thrombocytopenia with giant platelets and leukocyte inclusions on both peripheral
      smear and by electron microscopy. This report illustrates the importance of
      obtaining a family history when evaluating thrombocytopenia with special emphasis
      on a history of thrombocytopenia, renal disease, deafness, and cataracts. It is
      important to differentiate between MTCP and chronic ITP to avoid the unnecessary
      diagnostic studies, and, more critically, unneeded and potentially harmful
      therapy.

PMID- 10331512
TI  - Determination of heparin-induced thrombocytopenia: a rapid flow cytometric assay
      for direct demonstration of antibody-mediated platelet activation.
AB  - Heparin-induced thrombocytopenia (HIT) and thrombosis are serious complications
      of heparin therapy. Recently, we have reported a practical and rapid functional
      flow cytometric assay (FCA) for the diagnosis of HIT with high specificity and
      sensitivity compared with the radioactive serotonin-release assay (SRA). In the
      present study, we added an immune-neutralization assay to directly demonstrate
      the antibody-mediated process, and tested the immune compatibility of low
      molecular-weight heparin (LMWH) Lovenox and the heparinoid Orgaran (danaproid)
      using plasma from 18 patients with HIT confirmed by both FCA and SRA. The
      clinical utility of this modified method is demonstrated by a pediatric patient
      with a complex clinical presentation who developed thrombocytopenia with multiple
      thromboses while on heparin therapy. ELISA and SRA (performed in three
      independent laboratories) for diagnosis of HIT were both negative. In contrast,
      the FCA for detecting activated platelets expressing anionic phospholipids, was
      highly and reproducibly positive with both unfractionated and LMWH. Another FCA
      also demonstrated the surface expression of the alpha-granule membrane p-selectin
      (CD62p). Compatibility testing with the heparinoid Orgaran was also positive (and
      with plasma from 4 of the 18 patients with HIT). Heparin was discontinued, along
      with full recovery of the platelet count. The capacity of the patient's plasma to
      activate platelets in the presence of heparin gradually decreased over 4 weeks
      consistent with antibody clearance. The responsible mechanism was clarified using
      an immune-neutralization assay, which showed a dose response neutralization of
      the plasma activity by antibodies against human Immunoglobulin G (IgG) and IgM.
      This assay was also reproducible in the 18 patients with HIT. We conclude that
      the functional FCA with its modification is practical, sensitive, and specific
      for reliable diagnosis of HIT. It can simultaneously assess the compatibility of
      alternative therapies and directly confirm the antibody-mediated process.
      Further, it is particularly useful to clarify mechanisms of thrombocytopenia and
      thrombosis and to direct therapy in patients with a complex presentation and
      confounding laboratory results who often need prompt diagnosis and treatment.

PMID- 10331515
TI  - High prevalence of HTLV-I infection among the family members of a patient with
      adult T-cell leukemia/lymphoma from northeastern Japan.
AB  - Human T-cell lymphotropic virus type I (HTLV-I) is transmitted through infected
      lymphocytes mostly by breast feeding. In the present study, high prevalence of
      HTLV-I infection was disclosed in the family members of a patient with adult T
      cell leukemia/lymphoma (ATL), all of whom were residents of Iwate, northeastern
      Japan. Long-term follow-up is necessary for people with HTLV-I infection because
      of the risk of developing ATL after a certain period of latency. New inventive
      treatments for the acute and lymphomatous types of ATL are needed.

PMID- 10331516
TI  - Acute intravascular haemolytic transfusion reaction due to anti-c undetected by
      conventional pretransfusion cross-matching tests.

PMID- 10331514
TI  - Hyperfibrinolysis in a case of myelodysplastic syndrome with leukemic spread of
      mast cells.
AB  - Mast cells (MC) are multipotent hemopoietic effector cells producing diverse
      mediators like histamine, heparin, or tissue type plasminogen activator. We
      report a 75-year-old male patient with myelodysplastic syndrome (MDS) of recent
      onset (3 months' history) associated with a massive leukemic spread of immature
      tryptase+ MC (tentative term: myelomastocytic leukemia). The patient presented
      with pancytopenia, bleeding, hypofibrinogenemia, and an increased cellular
      tryptase level. Moreover, an excessive elevation of plasmin-antiplasmin complexes
      (9,200 ng/ml; normal range: 10-150), an elevated D-dimer, and an increase in
      thrombin-antithrombin III complexes were found. The identity of the circulating
      MC was confirmed by immunophenotyping (CD117/c-kit+, CD123/IL-3R alpha-,
      CD11b/C3biR-), biochemical analysis (cellular ratio [ng:ng] of tryptase to
      histamine >1), and electron microscopy. Bone marrow (bm) examination showed
      trilineage dysplasia (17% blasts), 30% diffusely scattered MC, and a complex
      karyotype. No dense, compact MC infiltrates (mastocytosis) were detectable in bm
      sections. Despite hyperfibrinolysis and mediator syndrome (flushing, headache),
      the patient received remission induction polychemotherapy (DAV) followed by two
      cycles of consolidation with intermediate dose ARA-C (2 x 1 g/m2/day on days 1,
      3, and 5). He entered complete remission after the first chemotherapy cycle
      without evidence of recurring MDS. Moreover, in response to chemotherapy, the
      hyperfibrinolysis and mediator syndrome resolved, and the circulating c-kit+ MC
      disappeared. We suggest consideration of polychemotherapy as a therapeutic option
      in patients with high-risk MDS of recent onset, even in the case of MC lineage
      involvement.

PMID- 10331517
TI  - Trisomy 10 in adult pre-B-cell leukemia.

PMID- 10331518
TI  - Thrombotic thrombocytopenic purpura and hypothyroidism.

PMID- 10331519
TI  - Utilization of developmental basic science principles in the evaluation of
      reproductive risks from pre- and postconception environmental radiation
      exposures.
AB  - The subject of the reproductive toxicity of various forms of radiation can be
      anxiety provoking to the public on two accounts, since reproductive failure
      engenders an unusual level of guilt and anger in the affected families, and
      radiation effects are misunderstood and feared by the public. Reproductive
      problems include an array of genetic and acquired diseases affecting parents and
      their offspring. Many of these problems are associated with the risk of being
      induced by preconception and/or postconception exposures to environmental agents.
      For the various forms of radiation, namely, ionizing radiation, ultrasound, low
      frequency electromagnetic fields (EMF), and microwaves, the potential for
      producing reproductive effects varies considerably with the form of "radiation"
      and, of course, the dose. Whether the exposure occurs preconceptionally or
      postconceptionally is another major consideration. In evaluating the actual
      reproductive risks, we rely on accurate dosimetry and information obtained in
      epidemiological studies and animal studies. Epidemiological studies must
      demonstrate consistency of the reproductive finding, and animal studies should be
      designed to add to the findings of the epidemiological studies. Most importantly,
      the conclusions must not contradict the basic principles of teratology, genetics,
      and reproductive biology, and they should be biologically plausible. But
      frequently important basic science principles are ignored in the evaluation
      process. Yet developmental basic science principles can be instrumental in
      refuting or supporting the concern about possible risks. Although there is some
      overlap with regard to the preconception and intrauterine effects of ionizing
      radiation, there are significant differences. Preconception effects are mainly
      stochastic effects, while intrauterine effects are mainly deterministic effects.
      The stochastic genetic risks are lower than the deterministic risks at equivalent
      exposures. Thus, it is frequently difficult to demonstrate the occurrence of
      stochastic effects in populations that have received low preconception exposures
      to ionizing radiation. The reproductive effects from preconception and
      intrauterine exposures to electromagnetic fields (low-frequency EMF, video
      display terminals, microwaves) and ultrasound represent much different problems,
      since the main effects of microwaves and ultrasound occur because of their
      hyperthermic effects at high exposures. Low-frequency EMF does not have the
      capacity to produce hyperthermia, and none of these forms of nonionizing
      radiation has the specificity to damage the DNA comparable to the specificity of
      ionizing radiation. Not only do they not have targeted mutagenic effects at the
      usual exposures that populations receive, they are not cytotoxic at these
      exposure levels as well. From the viewpoint of biological plausibility, these
      other forms of radiation are much less likely to have the potential for producing
      reproductive toxicity at the usual population exposures.

PMID- 10331520
TI  - Life cycle of the mammalian germ cell: implication for spontaneous mutation
      frequencies.
AB  - A brief history of the developmental life cycle of the mammalian germ cell, from
      fertilization to gametogenesis in the mature gonad, is presented. The differences
      between gametogenesis in the mature gonad of males and females are also described
      with regard to properties that may affect their susceptibilities to mutation. It
      is emphasized that any historical control background rate of necessity will
      include mutations that occur in germinal tissue at all stages of development and
      differentiation, although it is not always possible to determine at what stage of
      germline development a spontaneous mutation has occurred. Studies of induced
      mutations suggest that the impact on the molecular level and the distribution of
      mutations among the F1 and F2 progeny may be partly determined by the stage and
      sex of germ cells in which spontaneous mutations occur. In summary, historical
      control rates should only be considered the sum total of mutations that occur
      during the entire life of the individual and cannot represent the control values
      of any individual germ cell stage. Nonetheless, it is certainly important and
      valid to use historical control data for calculating human risk, because the
      primary use of the estimation of mutant frequencies is to access the potential
      impact of agents in increasing the genetic load in the human population.

PMID- 10331522
TI  - Changing perspectives on the genetic doubling dose of ionizing radiation for
      humans, mice, and Drosophila.

PMID- 10331521
TI  - Long-term genetic and reproductive effects of ionizing radiation and
      chemotherapeutic agents on cancer patients and their offspring.
AB  - The continuing search for a cure for cancer has lead to more aggressive therapies
      as new agents are developed with largely unknown late complications. Standard
      therapy for the majority of cancers today, following surgery, often consists of
      combinations of high doses of radiation and multi-drug therapy. Compared with
      exposures experienced by atomic bomb survivors, cancer survivors have been
      exposed to higher doses of partial body irradiation and combination chemotherapy
      over longer periods. Thus, cancer survivors provide a model system with which to
      evaluate the long-term effects on the human organism of high doses of agents
      known to damage DNA. Five-year survival after cancer diagnosis is now greater
      than 56%; more than 5 million Americans are considered cured of cancer. However,
      the late complications of cancer in long-term survivors has been poorly
      evaluated, especially in adults, and little is known of the most troubling
      possibility, that is, that the effects of cancer treatments could be passed on to
      the next generation. What little we know comes from studies of at most 5,000
      survivors of childhood cancer, treated decades ago. So far, results are
      reassuring that with the means now available, we cannot detect clinical evidence
      of heritable damage. However, reproductive effects, including infertility, are
      common consequences of cancer therapy and may represent germ cell damage. We are
      just in the infancy of studies of germ cell mutagenesis in cancer survivors. The
      relatively small numbers of survivors, and the few types of exposures studied so
      far, provide only limited grounds for reassurance. More comprehensive, properly
      designed, studies of modern new agents are urgently need.

PMID- 10331523
TI  - Cognitive function and prenatal exposure to ionizing radiation.
AB  - It is clear from the many studies of the prenatally exposed survivors of the
      atomic bombing of Hiroshima and Nagasaki that exposure to ionizing radiation
      during gestation has harmful effects on the developing human brain, particularly
      if that exposure occurs at critical stages in the development of the neocortex.
      Data on a variety of measures of cognitive function, including the occurrence of
      severe mental retardation as well as variation in the intelligence quotient (IQ)
      and school performance, show significant effects on those survivors exposed 8-15
      weeks and 16-25 weeks after ovulation. Studies of seizures, primarily those
      without known precipitating cause, also exhibit a radiation effect on those
      individuals exposed in the first 16 weeks after ovulation. The cellular and
      molecular events that subtend these abnormalities are still largely unknown
      although some progress toward an understanding has occurred. For example,
      magnetic resonance imaging of the brain of some of the mentally retarded
      survivors has revealed a large region of abnormally situated gray matter,
      suggesting an abnormality in neuronal migration, but cell killing could also
      contribute importantly to the effects on cognitive function that have been seen.
      The retardation of growth in stature observed in individuals exposed in the first
      and second trimesters of pregnancy suggests that the development of an atypically
      small head size, without conspicuously impaired cognitive function, may reflect a
      generalized retardation of growth.

PMID- 10331524
TI  - Childhood and adult cancer after intrauterine exposure to ionizing radiation.
AB  - Since the reports in 1956 and 1958 that in utero radiation was associated with an
      increased risk of leukemia and solid cancers during childhood, this issue has
      been debated. Many epidemiological studies have been performed. Evidence for a
      causal association derives almost entirely from case-control studies, whereas
      practically all cohort studies find no association, most notably the series of
      atomic bomb survivors exposed in utero. Although it is likely that in utero
      radiation presents a leukemogenic risk to the fetus, the magnitude of the risk
      remains uncertain. The causal nature of the risk of cancers other than leukemia
      is less convincing, and the similar relative risks (RR = 1.5) for virtually all
      forms of childhood cancer suggests an underlying bias. Few studies have addressed
      the potential risk of adult cancer after intrauterine exposure. Radiotherapy
      given to newborns, however, has been linked to cancers of the thyroid and breast
      later in life.

PMID- 10331525
TI  - Discussion: severe mental retardation and cancer among atomic bomb survivors
      exposed in utero.
AB  - When I was in medical school, Douglas Power Murphy, Professor of Obstetrics and
      Gynecology, told us of his inexpensive, simple study of "microcephaly" and mental
      retardation in newborn infants whose mothers had received therapeutic radiation
      early in pregnancy. His review of the literature and mail inquiry of other
      obstetrics centers in the United States revealed 14 published cases (Murphy, '28)
      and 16 unpublished (Goldstein and Murphy, '29). Here am I, 52 years later, still
      updating his findings.

PMID- 10331526
TI  - Administered radionuclides in pregnancy.
AB  - Radiopharmaceuticals are occasionally administered to pregnant patients either
      out of clinical necessity or by accident. In recognition of the latter, the
      Society of Nuclear Medicine recommends pregnancy testing before any procedure
      that will expose the fetus to >50 mGy. When pregnancy is known, the dose of
      radionuclide to be employed is kept as low as possible without sacrificing
      radiographic information. The commonly administered radiopharmaceuticals used for
      lung, gallbladder, kidney, bone, and bleeding scans are labeled with technetium
      99m: all deliver whole fetal doses of <5 mGy. These doses are lower than those
      known to produce deterministic effects, and are likely to be very conservative,
      since radionuclide exposure delivers protracted irradiation exposures to the
      embryo and fetus. The actual deterministic risks will decrease with the magnitude
      of the protraction as compared with the acute effects of irradiating the embryo
      and fetus. The probability of late effects is considered sufficiently low not to
      contraindicate the use of these radiopharmaceuticals when medically required or
      to raise undue concern when they are accidentally administered.

PMID- 10331527
TI  - Intrauterine effects of ultrasound: animal studies.
AB  - During the past several decades, the use of ultrasound technology in the clinical
      setting has greatly increased. Because nearly every pregnant woman receives at
      least one sonographic procedure today, there has been developing concern about
      the safety of such procedures. Since ultrasound exposure can result in
      hyperthermia and other physiological effects, the determination of a threshold or
      no-effect exposure has become a high-priority goal. Animal research has been
      important to the study of the effects of various exposures at all stages of
      pregnancy, since the clinical use of ultrasonography can occur during the
      preimplantation, organogenic, and fetal stages. Animal experiments using various
      mammalian species have been able to determine no-effect exposure levels for
      embryonic loss, congenital malformations and neurobehavioral effects. The
      preponderance of evidence from these studies indicates that, in the absence of a
      thermal effect, ultrasonography represents no measurable risk when used at
      recommended intensity levels.

PMID- 10331528
TI  - Intrauterine effects of ultrasound: human epidemiology.
AB  - Ultrasound imaging has been used clinically as an effective diagnostic tool over
      the past 30 years. In spite of literally millions of examinations, there is no
      verified documented evidence of adverse effects in patients caused by exposure to
      diagnostic ultrasound. A number of epidemiological studies of intrauterine
      ultrasound exposure have been conducted, including several case-control and
      prospective randomized control studies. In some studies, an association of one or
      another bioeffect was identified, such as low birth weight, delayed speech, or
      increased incidence of left-handedness. However, with the exception of low birth
      weight, these findings have never been duplicated, and the great majority of such
      studies have been completely negative.

PMID- 10331529
TI  - Reproductive and teratologic effects of low-frequency electromagnetic fields: a
      review of in vivo and in vitro studies using animal models.
AB  - In order to evaluate the reproductive risks of low-frequency electromagnetic
      fields (EMF), it is important to include epidemiological and animal studies in
      the evaluation, as well as the appropriate basic science information in
      developmental biology and teratology. This review presents a critical review of
      in vivo animal studies and in vitro tests, as well as the biological plausibility
      of the allegations of reproductive risks. In vitro or in vivo studies in nonhuman
      species can be used to study mechanisms and the effects that have been suggested
      by human investigations. Only well designed whole-animal teratology studies are
      appropriate when the epidemiologists and clinical teratologists are uncertain
      about the environmental risks. Even the inference of teratogenesis cannot be
      drawn from culture experiments, because the investigator is not in a position to
      know whether any of his observations will be manifested in living organisms at
      term. Other aspects of reproductive failure such as abortion, infertility,
      stillbirth, and prematurity, cannot be addressed by in vitro or culture
      experiments. In fact, they are very difficult to design and interpret in
      nonprimate in vivo models. The biological plausibility some of the basic
      mechanisms involved in reproductive pathology were evaluated, concentrating
      primarily on the mechanisms involved in the production of birth defects. The
      studies dealing with mutagenesis, cell death and cell proliferation using in
      vitro systems do not indicate that EMFs have the potential for deleteriously
      affecting proliferating and differentiating embryonic cells at the exposures to
      which populations are usually exposed. Of course, there is no environmental agent
      that has no effect, deleterious or not, at very high exposures. The animal and in
      vitro studies dealing with the reproductive effects of EMF exposure are
      extensive. There are >70 EMF research projects that deal with some aspect of
      reproduction and growth. Unfortunately, a large proportion of the embryology
      studies used the chick embryo and evaluated the presence or absence of
      teratogenesis after 48-52 h of development. This is not a stage of development at
      which an investigator could determine whether teratogenesis occurred. The
      presence of clinically relevant teratogenesis can only be determined at the end
      of the gestational period. The chick embryo studies are also of little assistance
      to the epidemiologist or clinician in determining whether EMF represents a hazard
      to the human embryo, and the results are, in any event, inconsistent. On the
      other hand, the studies involving nonhuman mammalian organisms dealing with fetal
      growth, congenital malformations, embryonic loss, and neurobehavioral development
      were predominantly negative and are therefore not supportive of the hypothesis
      that low-frequency EMF exposures result in reproductive toxicity.

PMID- 10331530
TI  - Intrauterine effects in animals exposed to radiofrequency and microwave fields.
AB  - The animal studies dealing with intrauterine exposure to radiofrequency (RF)
      fields have used only a few RF frequencies. More of the studies have used acute
      high exposures rather than low-level chronic exposures. Most studies have used
      considerably higher fields than are recommended for maximum permissible exposures
      for human occupational or environmental exposure. All studies in which effects
      have been observed have been above recommended maximum permissible exposure
      levels. Even at high levels, consistent morphological or organ abnormalities have
      not been reported. The most common observation at high exposures is a decrease in
      fetal mass which, by itself, may or may not have clinical importance. Research
      regarding teratogenic effects did not consistently produce effects that would
      lead investigators to suspect that RF exposure at or below the maximum
      permissible exposures to have embryopathic or teratogenic effects. Many other RF
      effects could be studied, but questions regarding teratogenic effects constitute
      one of the only areas in RF research that has been answered; namely, that RF
      exposure that have been studied present no teratogenic risk from exposures that
      do not exceed maximum permissible guidelines that are far below experimental
      teratogenic exposures to RF that have been reported.

PMID- 10331531
TI  - Intrauterine effects of electromagnetic fields--(low frequency, mid-frequency RF,
      and microwave): review of epidemiologic studies.
AB  - Electromagnetic radiations are named according to frequency or to wavelength
      (which is inversely proportional to frequency) and create electromagnetic fields
      (EMFs). Frequencies widely vary according to sources: high-voltage power lines,
      electrically heated beds, MRI, VDTs, microwave ovens, satellite, and radio/TV
      transmissions or cellular phone transmitters/receivers. Public concern has
      increased about the potential health effects of EMFs. There are arguments in
      favour of EMFs being biologically active, but no mechanism has been identified
      that explains the link between EMFs and bioeffects. Human data reviewed concern
      the potential reproductive effects (mainly spontaneous abortions, low birthweight
      and congenital malformations) of exposure to sources of EMFs: maternal residence,
      electrically heated beds, occupational exposure (mainly video display terminals),
      and medical exposures. The available epidemiologic studies all have limitations
      that prevent to draw clearcut conclusions on the effects of EMFs on human
      reproduction. EMFs are ubiquitous and unavoidable exposures. The matter of
      possible effects cannot be considered closed, but until our understanding of the
      biologic important parameters of EMFs exposures is stronger,design of new studies
      will be difficult and small epidemiologic studies are unlikely to provide
      definitive answers and should not be given high priority. No conclusion can be
      drawn for radiofrequencies and microwaves because of lack of data. There is no
      convincing evidence today that EMFs of the sort pregnant women or potential
      fathers meet in occupational or daily life exposures does any harm to the human
      reproductive process.

PMID- 10331532
TI  - CBS News: "60 Minutes," July 21, 1996: Who Poisoned Maryann?

PMID- 10331533
TI  - Radionuclide exposure during pregnancy: "60 Minutes" film.

PMID- 10331534
TI  - Two recent radiation-related genetic false alarms: leukemia in West Cumbria,
      England, and minisatellite mutations in Belarus.

PMID- 10331536
TI  - A personal story about pregnancy radiation risk counseling.

PMID- 10331535
TI  - Contribution of clinical teratologists and geneticists to the evaluation of the
      etiology of congenital malformations alleged to be caused by environmental
      agents: ionizing radiation, electromagnetic fields, microwaves, radionuclides,
      and ultrasound.
AB  - Analysis of these six clinical problems demonstrates the value of a complete
      clinical evaluation of a child with congenital malformations by an experienced
      and well-trained physician who is familiar with the fields of developmental
      biology, teratology , epidemiology, and genetics. Too often, the entire emphasis
      is placed on epidemiological data that may be meager or insufficient for a
      rational conclusion when clinical findings that are readily available can provide
      definitive answers with regard to the etiology of a child's malformations or the
      merits of an environmental etiology.

PMID- 10331537
TI  - Public perception of radiation: using the press to your advantage.

PMID- 10331538
TI  - In response to the editorial on pathogen status (1998, 48:557-558)

PMID- 10331540
TI  - Engaging mouse genes in motion.

PMID- 10331539
TI  - Corynebacterium bovis infection in waltzing mice.

PMID- 10331541
TI  - 2nd International Conference on Transgenic Animals (ICTA) in Beijing, China.

PMID- 10331542
TI  - Interpretation of phenotype in genetically engineered mice.
AB  - BACKGROUND AND PURPOSE: In mice, genetic engineering involves two general
      approaches-addition of an exogenous gene, resulting in transgenic mice, and use
      of knockout mice, which have a targeted mutation of an endogenous gene. The
      advantages of these approaches is that questions can be asked about the function
      of a particular gene in a living mammalian organism, taking into account
      interactions among cells, tissues, and organs under normal, disease, injury, and
      stress situations. METHODS: Review of the literature concentrating principally on
      knockout mice and questions of unexpected phenotypes, lack of phenotype,
      redundancy, and effect of genetic background on phenotype will be discussed.
      CONCLUSION: There is little gene redundancy in mammals; knockout phenotypes exist
      even if none are immediately apparent; and investigating phenotypes in colonies
      of mixed genetic background may reveal not only more phenotypes, but also may
      lead to better understanding of the molecular or cellular mechanism underlying
      the phenotype and to discovery of modifier gene(s).

PMID- 10331543
TI  - B-virus specific-pathogen-free breeding colonies of macaques (Macaca mulatta):
      retrospective study of seven years of testing.
AB  - BACKGROUND AND PURPOSE: National Institutes of Health's Division of Comparative
      Medicine has sponsored a multi-institutional program for the establishment of
      specific-pathogen-free (SPF) macaque colonies. B virus (Herpesvirus simiae,
      Cercopithecine herpesvirus type 1) has been targeted in this surveillance.
      Participating institutions have established individual timetables for frequency
      of testing and types of monitoring and husbandry techniques, all with the common
      goal of producing pathogen-free monkeys for research. The greatest biosecurity
      threat to the program comes from failure to detect seronegative latent
      infections, either in first-year macaques or macaques introduced in subsequent
      years, although these are supposed to operate as closed colonies. METHODS: From
      January 1990 through December 1996, we screened macaques for B virus, using
      enzyme-linked immunoabsorbant assay (ELISA) and Western blot analysis. RESULTS:
      During the first year, 1,097 macaques from six colonies were tested, and 88.4%
      tested negative for B virus. During the seventh year, 1,843 were tested, of which
      99.7% tested negative. Seropositive macaques were detected as late as the seventh
      year. CONCLUSIONS: An aggressive program to establish an SPF colony of captive
      breeding macaques can be effective in reducing the risk of B-virus exposure.

PMID- 10331544
TI  - Selection of the most efficacious of twenty-two inactivated Sendai virus nasal
      vaccines by determination of the protection index in mice.
AB  - BACKGROUND AND PURPOSE: Sendai virus nasal vaccines inactivated with various
      chemicals induce complete protection against contact-challenge exposure with the
      Nagoya strain. The study reported here was to reevaluate the efficacy of the
      inactivants by determining the protective index (PI) in mice, using the more
      virulent MN strain. METHODS: Mice were given each of 22 inactivated vaccines
      intranasally three times. After challenge exposure with 10(-2) to 10(6) MID50 of
      virus, infection of cells of the respiratory tract was determined by
      immunofluorescence. RESULTS: Twelve vaccines induced PI > or = 2.0 in the nasal
      mucosa and were classified as group 1. The first half of the preceding vaccines
      that induced PI > or = 3.2 in the larynx were classified subgroup a, and the rest
      were classified subgroup b. Of the other 10 vaccines, 6 that induced PI < or =
      2.0 in the larynx and 4 that induced intermediate PI in the nasal mucosa and
      larynx were ranked as groups 3 and 2, respectively; PI of the trachea decreased
      by numeric order of groups. Serum hemagglutination inhibition titer induced by
      intranasal vaccination was low in general. CONCLUSION: On the basis of PI values,
      6 of the 22 nasal vaccines provided the strongest defense in the respiratory
      tract.

PMID- 10331545
TI  - Cardiovascular pathology possibly associated with ketamine/xylazine anesthesia in
      Dutch belted rabbits.
AB  - BACKGROUND AND PURPOSE: After myocardial necrosis and fibrosis was observed in
      five rabbits which had been anesthetized a variable number of times, the
      potential relationship of these lesions and anesthesia was evaluated in 35 other
      rabbits. METHODS: Anesthesia was induced by intramuscular administration of
      ketamine and xylazine followed by infusion of lactated Ringer's solution also
      containing ketamine and xylazine. Group A rabbits (n = 9) were subjected to
      multiple anesthesias and were evaluated by echocardiography, thoracic
      radiography, electrocardiography, determination of serum coronavirus titer,
      vitamin E concentration, and complete necropsy. Prior to a single acute procedure
      followed by necropsy, group B rabbits (n = 11) were evaluated by echocardiography
      only. Group C rabbits (n = 10) had never been anesthetized and were necropsied
      after euthanasia. Group D rabbits (n = 5) had intermediate anesthesia exposure
      history and were evaluated by echocardiography only. Myocardial fibrosis was
      scored semi-quantitatively on a scale of 0 to 4. RESULTS: Canine coronavirus test
      results were negative; hypovitaminosis E was evident, and fibrosis scores were
      significantly increased in group A, compared with group B or group C, rabbits.
      CONCLUSION: Etiologic differentials included alpha2-agonist-mediated coronary
      vasoconstriction with associated myocardial hypoperfusion, hypovitaminosis E and
      free radical injury, and other anesthetic-induced physiologic trespass.

PMID- 10331546
TI  - Animal models of spinal cord contusion injuries.
AB  - BACKGROUND AND PURPOSE: Traumatic spinal cord injury causes initial mechanical
      disruption of tissue, leading to a complex secondary sequence of pathophysiologic
      changes and neurologic impairment. These sequelae depend on the impact force
      delivered to the spinal cord at the time of injury. Successful clinical
      evaluation of the efficacy of any therapeutic regimen depends on the reliability
      and reproducibility of an experimental animal model. We describe a trauma device
      and the biomechanical parameters required to induce severe or moderate spinal
      cord contusion injury in cats and rats. METHODS: Recovery after injury was
      determined by behavioral, electrophysiologic, and histologic evaluations.
      RESULTS: Behavioral and electrophysiologic tests after injury clearly identified
      the experimental groups. A stable severe paraplegic state (defined as 6 months
      for cats and 8 weeks for rats), without evidence of behavioral or
      electrophysiologic recovery, was induced by a 65-Newton (N) load for cats and a
      35-N load for rats. Moderate spinal cord contusion injury, from which cats and
      rats partially recovered after approximately 3 months and 4 weeks, respectively,
      was induced by a 45- and 25-N load, respectively. CONCLUSION: Use of these injury
      conditions provides reliable animal models for studies designed to evaluate
      potential therapeutic regimens for spinal cord injury.

PMID- 10331547
TI  - Auditory brainstem responses in Golden Syrian hamsters (Mesocricetus auratus)
      affected with the Wh gene.
AB  - BACKGROUND AND PURPOSE: The anophthalmic white (Wh) gene in Golden Syrian
      hamsters (Mesocricetus auratus) is autosomal semi-dominant and causes several
      developmental defects, including hearing loss. The Wh mutation is thought to be
      homologous to Waardenburg syndrome in humans, apparently affecting similar
      developmental processes. The purpose of this study was to assess the hearing of
      hamsters in the AN/As-Wh strain. METHODS: Using auditory brainstem responses,
      electrophysiologic activity was determined in 20 hamsters of the AN/As-Wh strain,
      with the aim of elucidating hearing status. Hamsters were classified into five
      genotypes and were evaluated by use of click stimuli. RESULTS AND CONCLUSION:
      Hamsters assigned to the genotypes differed in their hearing sensitivity and
      could be classified into categories of normal hearing, moderate hearing loss, and
      profound hearing loss.

PMID- 10331548
TI  - In vivo properties of three human HER2/neu-expressing murine cell lines in
      immunocompetent mice.
AB  - BACKGROUND AND PURPOSE: Expression of the HER2/neu proto-oncogene, a receptor
      like transmembrane protein expressed at low levels on some normal cells, is
      markedly increased in a subset of human breast, colon, lung, and ovarian cancers.
      A humanized HER2/neu antibody has been tested as a therapeutic agent in several
      clinical trials, with promising results. We have developed a family of anti
      HER2/neu fusion proteins. To evaluate the immunologic efficacy of these proteins,
      it is critical that tumors expressing the target antigen can grow in
      immunologically intact mice. METHOD: To produce murine tumors expressing human
      HER2/neu on the surface, CT26, MC38, and EL4 murine cell lines were transduced by
      use of a retroviral construct containing the cDNA encoding the human HER2/neu
      gene. RESULTS: Histologic features and kinetics of tumor growth in subcutaneous
      space of the human HER2/neu-expressing cells were similar to those of the
      respective parental cell lines. Intravenous inoculation with these cells induced
      disseminated malignant disease. Flow cytometric and immmunohistochemical analyses
      of freshly isolated tumors revealed in vivo expression of human HER2/neu.
      Secretion of antigen was not detected by use of an ELISA. CONCLUSION: Although an
      antibody response against the human HER2/neu antigen was observed, this response
      does not affect the growth rate of the HER2/neu-expressing cells. These murine
      models may be useful tools for evaluation of anti-cancer therapeutic approaches
      that target human HER2/neu.

PMID- 10331549
TI  - Rabbit intestinal xenograft model for human Encephalitozoon infections in mice.
AB  - BACKGROUND AND PURPOSE: The gastrointestinal tract is a common portal of entry
      for Encephalitozoon cuniculi, one of several microsporidial organisms emerging as
      opportunistic pathogens in immunocompromised humans. Although most human
      microsporidial pathogens can be propagated in vitro and in a variety of
      laboratory animals, an experimental animal system to specifically study
      intestinal uptake and systemic spread of these organisms does not exist. METHODS:
      Paired segments of near-term fetal rabbit small intestine were implanted
      subcutaneously into 25 athymic nude or 10 severe combined immune deficient mice.
      Five weeks after surgery, 65 xenografts were inoculated intraluminally with E.
      cuniculi (n = 14), E. intestinalis (n = 27), E. hellem (n = 20), or RK-13 cells
      (n = 2), or were left uninoculated (n = 2). RESULTS: Intestinal xenograft
      infection with E. cuniculi (n = 11), E. intestinalis (n = 17), and E. hellem (n =
      18) was determined by light microscopy; control xenografts remained uninfected.
      Extraintestinal infection with E. cuniculi developed in host mouse brain,
      respiratory tract, spleen, salivary glands, and gastrointestinal tract (3 of 3
      mice), and infection with E. intestinalis developed in the liver (8 of 15 mice).
      CONCLUSION: Intestinal xenografts provide a unique, sterile, and biologically
      relevant animal model system for studying host enterocyte/parasite interactions,
      mechanisms of microsporidial pathogenicity, antimicrosporidial chemotherapeutic
      agents, and immune effector mechanisms. This model provides evidence for
      persistent graft infection with three Encephalitozoon spp., and for intestinal
      spread of E. cuniculi and E. intestinalis from infected enterocytes in
      immunoincompetent mice.

PMID- 10331550
TI  - Rhesus monkey (Macaca mulatta) model of Helicobacter pylori: noninvasive
      detection and derivation of specific-pathogen-free monkeys.
AB  - BACKGROUND AND PURPOSE: Development of the rhesus monkey model of Helicobacter
      pylori has been hampered by problems with serodetection and by the difficulty of
      identifying specific-pathogen (Helicobacter)-free animals. Our purpose was to
      determine whether detection could be improved and to determine if pathogen-free
      monkeys could be derived by nursery rearing. METHODS: An enzyme-linked
      immunoabsorbent assay (ELISA) and a [14C]urea breath test were compared to
      endoscopy to determine H. pylori infection status in rhesus macaques; 18 animals
      were hand raised in the nursery to determine whether pathogen-free animals could
      be selected. RESULTS: Helicobacter pylori infection was common in colony-raised
      young rhesus monkeys and was nearly universal by adulthood. Serodetection, using
      antigen from rhesus-derived H. pylori strains, was 95% sensitive and 94%
      specific. The [14C]urea breath test was 96% sensitive and 88% specific for
      detection of chronic Helicobacter infection in rhesus monkeys. Segregation of
      newborn animals within the first 24 h of life was a reliable method to obtain
      pathogen-free rhesus monkeys. CONCLUSION: Isolation of specific-pathogen-free
      animals, together with better detection methods, may improve the value of the
      rhesus monkey model for the study of H. pylori pathogenesis, immune response, and
      vaccine development.

PMID- 10331552
TI  - Corynebacterium bovis infection in immunocompetent hirsute mice.

PMID- 10331551
TI  - Power spectral analysis of heart rate variability for assessment of diurnal
      variation of autonomic nervous activity in miniature swine.
AB  - BACKGROUND AND PURPOSES: The purpose of the study was to document diurnal
      variation of autonomic nervous functions by use of power spectral analysis of
      heart rate (HR) variability. METHODS: To clarify characteristics of power
      spectral analysis of HR variability, electrocardiogram (ECG), blood pressure
      (BP), and respiratory (Resp) waveform simultaneously were recorded. RESULTS: Two
      major spectral components were examined at low (LF)- and high (HF)-frequency
      bands for HR variability. Coherence between HR and Resp variabilities and HR and
      BP variabilities was maximal at approximately 0.14 and 0.03 Hz, respectively. On
      the basis of these data, two frequency bands of interest--LF (0.01 to 0.07 Hz)
      and HF (0.07 to 1.0 Hz)--were defined. Autonomic blockade studies indicated that
      the parasympathetic system mediated the HF and LF components, whereas the
      sympathetic system mediated only the LF component; HR had a diurnal pattern. The
      LF and HF bands in the dark phase tended to be higher than those in the light
      phase. The LF-to-HF ratio had a diurnal pattern similar to that of the HR.
      CONCLUSION: Parasympathetic nervous activity in miniature swine may be
      predominant in the dark phase. The characteristics of power spectra and diurnal
      variations of autonomic nervous functions are almost the same as those of humans.
      Therefore, miniature swine may be a useful animal model for future biobehavioral
      and pharmacotoxicologic studies.

PMID- 10331553
TI  - Influences of somatotropin on biomechanical properties of porcine skin.

PMID- 10331554
TI  - New technique for superselective arterial (chemo-) embolization of the rat liver.

PMID- 10331555
TI  - Idiopathic interstitial pneumonias: clinical findings, pathogenesis, pathology
      and radiologic findings.
AB  - Idiopathic interstitial pneumonias are currently classified into four categories:
      usual interstitial pneumonia, nonspecific interstitial pneumonia with fibrosis,
      acute interstitial pneumonia and desquamative interstitial pneumonia. The
      fibrotic process in interstitial pneumonias appears to result from a complex
      interaction between fibroblasts, other lung parenchymal cells and macrophages.
      The complex relationship between the local release of growth-promoting cytokines
      by alveolar macrophages and resident fibroblasts represents a necessary step for
      fibrosis or remodeling after lung injury. Injury to the epithelium and basement
      membranes is likely necessary for the fibrotic process to occur. Usual
      interstitial pneumonia, most frequent among interstitial pneumonias and has a
      poor prognosis, appears on high-resolution CT as patchy subpleural areas of
      ground-glass attenuation, irregular linear opacity, and honeycombing. Nonspecific
      interstitial pneumonia with fibrosis, the second most frequent and has a better
      prognosis than usual interstitial pneumonia, appears as subpleural patchy areas
      of ground-glass attenuation with associated areas of irregular linear opacity on
      CT. Acute interstitial pneumonia with high mortality rate presents as extensive
      bilateral airspace consolidation and patchy or diffuse bilateral areas of ground
      glass attenuation. Desquamative interstitial pneumonia with good prognosis
      presents as patchy subpleural areas of ground-glass attenuation in middle and
      lower lung zones.

PMID- 10331556
TI  - Clinical characteristics of children with mental retardation of unknown etiology
      in Korea.
AB  - The purpose of this study was to investigate the clinical characteristics of
      children with mental retardation (MR) of unknown etiology for early recognition
      and intervention. In this study, we defined children with MR of unknown etiology
      as those without clear etiologies for MR despite extensive evaluation and were
      not associated with pathological behavioral problems such as pervasive
      developmental disorders and attention-deficit/hyperactivity disorder. The
      clinical characteristics of children with MR of unknown etiology were as follows.
      1) MR of unknown etiology was 48.8% of all MR. 2) MR of unknown etiology was more
      common in males. 3) Delayed language development was a leading factor that made
      the parents of children with MR of unknown etiology seek help from physicians.
      However, most of the children with MR of unknown etiology showed a relatively
      uniform delay in several areas of development. 4) Most children with MR of
      unknown etiology were delayed walkers. 5) Most children with MR of unknown
      etiology were mild cases.

PMID- 10331557
TI  - Epinephrine-induced arrhythmias: effects of thoracic epidural anesthesia and
      vagotomy during enflurane anesthesia in rabbits.
AB  - For evaluating the effects of thoracic epidural anesthesia, with or without
      bilateral vagotomy, epinephrine-induced arrhythmias were studied in 31 rabbits
      anesthetized with 1 minimum alveolar concentration of enflurane. We divided the
      rabbits into 5 groups: Group I (epidural saline as control group; n=6), Group II
      (epidural lidocaine without vagotomy; n=6), Group III (intravenous lidocaine;
      n=7), Group IV (epidural saline with vagotomy; n=6), and Group V (epidural
      lidocaine with vagotomy; n=6). Using logdose protocol, epinephrine was infused at
      an initial rate of 0.67 microg/kg/min and increased by Exp[0.4] until arrhythmias
      occurred; if arrhythmias occurred at any of these doses, a smaller dose, divided
      by Exp[0.2], was tested. Arrhythmic dose of epinephrine was defined as the
      smallest infusion rate needed to produce four or more arrhythmias within 15 sec
      during epinephrine infusion. Arrhythmic dose of epinephrine and its plasma
      concentration in epidural lidocaine group were significantly higher than control
      (p<0.05). Similarity of results was also noted amongst the intravenous lidocaine
      group, vagotomy only group, and vagotomized epidural lidocaine group with respect
      to the control. These results suggest that thoracic epidural anesthesia raises
      the threshold for enflurane-epinephrine induced arrhythmias in rabbits and that
      this effect is eliminated by bilateral vagotomy.

PMID- 10331558
TI  - Cardiac laterality and ventricular looping in retinoic acid-treated rat embryos.
AB  - To determine the ventricular looping pattern in relation to cardiac laterality,
      we studied rat embryos treated with retinoic acid (RA). A total of 243 Wistar rat
      embryos from an in vivo treated group (a single dose of 20-40 mg/kg all-trans RA
      administered to pregnant rats on day 6.5 to 9.5) and 29 control embryos were
      examined on day 13 of gestation. Twenty-nine embryos from the in-vitro treated
      group (treated by all-trans RA at 2 x 10(-7) M for 6 hr on day 9.0 or 9.5 during
      the entire embryo culture for 72 hr) and seven control embryos were examined on
      day 12 of gestation. Abnormalities in cardiac laterality and ventricular looping
      were found in the in-vivo groups treated on day 8.5 and 8.75 and in the in-vitro
      group on day 9.0. Among 25 animals with abnormal laterality, right isomerism was
      the most common feature (22 cases), while the type of ventricular looping varied.
      Cases with normal laterality had a low incidence of abnormal looping (1.4%). In
      rat embryos treated with all-trans RA, normal cardiac looping was expected when
      cardiac laterality was normal. But in cases with abnormal laterality, the type of
      abnormal ventricular looping was unexpected.

PMID- 10331559
TI  - Video-assisted thoracoscopy versus open thoracotomy for spontaneous pneumothorax.
AB  - This retrospective study was designed to compare the contribution of the video
      assisted thoracoscopic surgery (VATS) and open thoracotomy in the management of
      spontaneous pneumothorax (SP). The medical records of 100 patients with recurring
      or persisting (SP) treated were reviewed. The patients were divided into two
      groups: group I treated by thoracotomy while in group II (VATS) was used. There
      were 96 men and 6 women aged from 16 to 75 years. Indications for operation and
      sex distribution were comparable. The mean age for group I was 35 years and for
      group II was 45 years. Hospital stay was identical in both groups. The amount of
      narcotic requirements was lesser in group II than in group I as well as the
      postoperative respiratory dysfunction. There have been no recurrence to date
      (mean follow-up 6 years for the group I and 3 years for the group II). VATS have
      been shown to produce results comparable to those obtained following open
      thoracotomy with reduction of postoperative pain, respiratory dysfunction,
      catabolic response to trauma and decrease in wound related complications. VATS is
      a valid alternative to open thoracotomy for primary (SP) but it should be used
      with caution for the management of secondary pneumothorax.

PMID- 10331560
TI  - Comparison of basophil histamine releasability between atopic and nonatopic
      asthmatics.
AB  - To compare the mediator releasability between atopic and nonatopic asthmatics, we
      measured basophil histamine releasability (BaHR) using a calcium-ionophore A23187
      and anti-IgE in 137 subjects who were treated at Seoul National University
      Hospital. Subjects were categorized into atopic (group AA, n=77) or nonatopic
      asthmatics (group NA, n=32), or normal controls (group NC, n=28). Serum total IgE
      levels were determined and correlation with BaHR was assessed. Anti-IgE-induced
      maximal BaHR in groups AA, NA, and NC was 41.0+/-3.2, 23.1+/-4.5, and 16.8+/-3.8,
      respectively (mean+/-SE, %). Anti-IgE-induced BaHR in group AA was significantly
      higher than that in groups NA and NC (p<0.05). Calcium ionophore A23187-induced
      maximal BaHR was 43.1+/-2.8, 40.8+/-4.4, and 50.5+/-5.2, respectively (mean+/-SE,
      %), and there was no significant difference among the groups. Serum total IgE
      level correlated significantly with anti-IgE-induced maximal BaHR (r=0.281,
      p<0.01) but not with that induced by calcium ionophore A23187. In conclusion, IgE
      receptor-related BaHR is higher in atopic asthmatics than in nonatopic
      asthmatics, and this increased BaHR in atopics is significantly associated with
      increased serum total IgE level.

PMID- 10331561
TI  - The clinical characteristics of pulmonary alveolar proteinosis: experience at
      Seoul National University Hospital, and review of the literature.
AB  - Pulmonary alveolar proteinosis is such an extremely rare disease in Korea, that
      only a few cases have been reported. Meanwhile five cases were experienced at
      Seoul National University Hospital over ten years since 1987. We summarized the
      clinical characteristics and courses of them. Seven cases reported in the
      literature were included to add data about clinical characteristics and courses
      although only a few case reports mentioned patient's course. Middle aged male
      patients were mainly affected. No association with particular environmental or
      occupational exposure was identified. Dyspnea on exertion was the main symptom.
      Bilateral crackles were consistent, and bilateral parahilar hazy infiltrations on
      plain chest radiograph and ground glass opacity on high-resolution CT were
      characteristic. Superimposed infection was not identified in any patient at the
      time of diagnosis. Decreased diffusing capacity and hypoxia were present in
      almost every case. Whole lung lavage proved to be an effective therapeutic
      measure. The response to treatment was good. Long-term course of the disease,
      e.g. recurrence rate, is not yet known.

PMID- 10331562
TI  - Monitoring antibody titers to recombinant Core-NS3 fusion polypeptide is useful
      for evaluating hepatitis C virus infection and responses to interferon-alpha
      therapy.
AB  - To evaluate the clinical feasibility of the antibody titer against a chimeric
      polypeptide (named Core 518), in which a domain of Core and NS3 of hepatitis C
      virus (HCV) was fused, ELISA was performed in a total of 76 serum samples. Each
      serum was serially diluted using two-fold dilution method with distilled water
      into 10 concentrations. They were all positive for second generation anti-HCV
      assay (HCV EIA II; Abbott Laboratories). Genotyping RT-PCR, quantitative
      competitive RT-PCR, and RIBA (Lucky Confirm; LG Biotech) were also assayed. Anti
      Core 518 antibody was detected in x 12800 or higher dilutions of sera from 35 of
      43 chronic hepatitis C (81.4%) and nine of 16 hepatocellular carcinoma sera
      (56.3%), one of four cirrhosis (25%), 0 of four acute hepatitis C, and one of
      nine healthy isolated anti-HCV-positive subjects (p=0.0000). The anti-Core 518
      antibody titers were well correlated with the presence of HCV RNA in serum
      (p=0.002). The anti-Core 518 antibody titers decreased significantly in nine of
      ten responders to IFN-alpha treatment. Monitoring anti-Core 518 titers may be
      helpful not only for differentiating the status of HCV infection among patients
      with various type C viral liver diseases, but also for predicting responses to
      IFN-alpha treatment.

PMID- 10331563
TI  - Correlation of changes in natural killer cell activity and glutathione S
      transferase placental form positive hepatocytes in diethylnitrosamine-induced rat
      hepatocarcinogenesis.
AB  - To evaluate the induction of preneoplastic hepatic foci in relation to natural
      killer cell (NK) activity, we sequentially analyzed glutathione S-transferase
      placental form positive (GST-P+) hepatocytes and NK activity during
      diethylnitrosamine (DEN) and phenobarbital (PB)-induced hepatocarcinogenesis in
      Sprague-Dawley rats. Previous studies have shown that NK activity can modulate
      the carcinogenic process induced by chemical carcinogens. Newborn females were
      initially given a single intraperitoneal injection of 15 mg DEN/kg and three
      weeks later, they were treated with 500 ppm phenobarbital (PB). From week 3, PB
      was administered in drinking water for 9 weeks. Interim and terminal sacrifices
      were performed at weeks 12, 15 and 30. GST-P+ hepatocytes increased with age in
      DEN-treated rats, especially in the population of more than two GST-P+
      hepatocytes. The NK activity of DEN-treated rats did not significantly differ
      from that of control rats until week 12, but it progressively decreased from week
      15 to 30. These results indicate that changes of NK activity inversely correlated
      with the induction of preneoplastic hepatic foci. This strong correlation of
      decreased NK activity with enhanced induction of GST-P+ foci suggests that NK
      activity is important in the early progression of hepatocarcinogenesis in rats.

PMID- 10331564
TI  - Expression of Th1 and Th2 type cytokines responding to HBsAg and HBxAg in chronic
      hepatitis B patients.
AB  - The cytokine pattern on viral antigen recognition is believed to exert a profound
      influence on the resolution of viral infections and viral clearance. This study
      was initiated to investigate whether a cytokine imbalance oriented toward Th2
      type response plays a role in chronic hepatitis B. Cytokine profiles of
      peripheral blood mononuclear cells associated with chronic hepatitis B were
      analysed by RT-PCR. Upon HBsAg stimulation, expression of IFN-gamma, IL-2, IL-4,
      and IL-10 was detected in 41%, 8%, 41%, and 50% of the patients, respectively.
      Among these cytokines, the expression of IFN-gamma was associated with high
      levels of serum AST/ALT. However, we could not prove that Th2 type cytokines had
      a protective effect on hepatocytes. Upon HBxAg stimulation, there was no
      recognizable association of cytokine patterns with AST/ALT levels. In conclusion,
      production of a Th1 cytokine, IFN-gamma, by HBsAg-reactive cells was associated
      with hepatocyte damage in chronic hepatitis B, while no counteracting effect of
      Th2 cytokines produced by those cells was observed.

PMID- 10331565
TI  - Detection of Helicobacter DNA in bile from bile duct diseases.
AB  - Several species of Helicobacter colonize the hepatobiliary tract of animals and
      cause hepatobiliary diseases. The aim of this study is to investigate
      Helicobacter found in the biliary tract diseases of humans. Thirty-two bile
      samples (15 from bile duct cancer, 6 from pancreatic head cancer, and 11 from
      intrahepatic duct stone) were obtained by percutaneous transhepatic biliary
      drainage. Polymerase chain reaction analysis using Helicobacter specific urease A
      gene and 16S rRNA primers, bile pH measurement, and Helicobacter culture were
      performed. Helicobacter DNA was detected in 37.5%, and 31.3% by PCR with ureA
      gene, and 16S rRNA, respectively. The bile pH was not related to the presence of
      Helicobacter. The cultures were not successful. In conclusion, Helicobacter can
      be detected in the bile of patients with bile duct diseases. The possibility of
      pathogenesis of biliary tract diseases in humans by these organisms will be
      further investigated.

PMID- 10331567
TI  - Homocyst(e)ine and atherosclerosis in patients on chronic hemodialysis.
AB  - Hyperhomocyst(e)inemia is an established risk factor for atherosclerosis. We
      performed this study to identify the correlating variables and risk factors for
      atherosclerosis, as measured by the atherosclerotic score (AS), and to determine
      the relative risk for cardiovascular disease in relation to plasma homocyst(e)ine
      levels in patients on chronic hemodialysis. We evaluated and measured 61 patients
      on chronic hemodialysis for clinical and biochemical parameters including
      atherosclerotic score (AS) and plasma homocyst(e)ine. We divided patients into
      high and low groups, first, by the mean AS, and second, by the median value of
      plasma total homocyst(e)ine levels. Then we compared the variables between the
      two groups. Out of the 61 patients, the median plasma total homocyst(e)ine level
      was 24.4 micromol/L (mean+/-SD, 27.7+/-17.4; range, 9.8-127.4 micromol/L), and
      the median AS was 5 (mean+/-SD, 6.2+/-2.8; range, 3-13) out of a possible 20
      points. AS was significantly correlated with plasma total homocyst(e)ine levels
      (r=0.37) and age (r=0.67). Through multivariate analysis, plasma total
      homocyst(e)ine level and age were determined as significant risk factors for the
      high-AS group (p<0.05). However, plasma total homocyst(e)ine level did not
      correlate with age (p>0.05). Eighteen of the 61 patients, presented with
      cardiovascular disease until the present study, had an AS>6. Cardiovascular
      disease was found more often in the high-homocyst(e)ine group (>24.4 micromol/L)
      than in the low-homocyst(e)ine group (odds ratio, 9.3; 95% confidence interval,
      2.3-37.4). Regardless of age, hyperhomocyst(e)inemia (especially homocyst(e)ine
      levels >24.4 micromol/L) is a risk factor that can be modified for the
      development of cardiovascular disease in patients on chronic hemodialysis.

PMID- 10331568
TI  - Role of p53 gene mutation in tumor aggressiveness of intracranial meningiomas.
AB  - The mutations that occur in the p53 tumor suppressor gene have been studied in
      various human malignant tumors. However, little is known about this gene in
      meningiomas. To investigate the relationship and frequency of p53 gene mutations,
      the p53 polymerase chain reaction-single stranded conformational polymorphism
      (PCR-SSCP) and immunohistochemical study were performed on the 41 intracranial
      meningiomas (21 benign, 11 atypical, and 9 malignant). The higher the p53 protein
      expression rate, the poorer the histologic grade (9.5%, 72.7%, and 88.9% in
      benign, atypical and malignant meningioma, respectively) (p=0.000). The p53
      protein expression rate was higher in recurrent meningioma (71.4%) than in
      nonrecurrent meningioma (10.5%) (p=0.002). PCR-SSCP method was performed in
      positive p53 protein immunoreactivity cases. p53 gene mutation rate was higher in
      the atypical (62.5%) and malignant (25%) meningiomas than in the benign
      meningioma (0%) (p=0.232). Also, the rate was higher in recurrent menigioma (20%)
      than in nonrecurrent meningioma (0%) (o=0.495). Among five to eight exons of the
      p53 gene, the mutation was observed on exon 7 more frequently. In conclusion, p53
      immunoreactivity and p53 gene mutation are closely correlated with histologic
      grade and histologic atypia of intracranial meningiomas. p53 gene mutation would
      be considered as a useful marker to detect the progression of intracranial
      meningiomas.

PMID- 10331566
TI  - DNA-mediated immunization of mice with plasmid encoding HBs antigen.
AB  - In order to develop an experimental DNA vaccine for the prevention and treatment
      of hepatitis B virus infection, hepatitis B virus surface antigen (HBsAg) DNA was
      subcloned into an E. coli-eukaryotic cell shuttle vector and was expressed in the
      Baculovirus expression system. Intramuscular, intradermal, and intraperitoneal
      injections of 30 microg of the plasmid DNA expressing HBsAg induced humoral and
      cellular immune responses in ICR mice. The first IgG antibodies were detected
      after ten days and specific IgG antibody titers peaked after two months of a
      single intramuscular DNA injection. Anti-HBs antibody titers gradually increased
      and peaked at four months following intradermal DNA injection, and in case of
      intraperitoneal injection they peaked at seven months. Generation of HBs-specific
      helper T lymphocytes was also investigated through the production of interleukin
      2 by T helper cells. Boosting effects of HBs DNA were investigated without much
      results. In general, DNA-mediated HBs immunization induced humoral and cellular
      immune responses in mice that appears to simulate immune responses in human
      during the course of HBV vaccination.

PMID- 10331569
TI  - The first imported case of pulmonary coccidioidomycosis in Korea.
AB  - Coccidioidomycosis is an endemic disease found in the southwestern part of North
      America. Travellers who visit the endemic area may carry the infection. We report
      a case of pulmonary coccidioidomycosis in a 74-year-old woman. She was healthy
      before visiting Arizona, U.S.A twice. After returning home, she began to complain
      of intermittent dry coughing. The symptom was mild, however, and she was treated
      symptomatically. Later a chest radiograph, which was taken 4 years after the
      onset of the symptom, showed a solitary pulmonary nodule in the right upper lobe.
      By percutaneous needle aspiration, a few clusters of atypical cells were noted in
      the necrotic background. A right upper and middle lobectomy was done. A 1.5 x 1.5
      x 1.2 cm sized tan nodule was present in otherwise normal lung parenchyma.
      Microscopically, the nodule consisted of aggregates of multiple solid granulomas
      inside of which was mostly necrotic. Neutrophils and nuclear debris were
      scattered along the periphery of the necrotic foci. Numerous multinucleated giant
      cells were associated with the granulomas. In the necrotic area, mature spherules
      of Coccidioides immitis, which were 30-100 microm in diameter, were present. They
      contained numerous endospores which ranged from 5 to 15 microm and were also
      noted in multinucleated giant cells. The diagnosis of coccidioidomycosis was
      made. She is doing well after the resection.

PMID- 10331570
TI  - Button battery impaction in nasal cavity.
AB  - A button battery inserted in the nose of children is an unusual foreign body
      which is capable of causing extensive tissue damage, resulting from electrical
      and chemical burns. We report a case of button battery in the nose of a 4-year
      old boy presenting with unilateral nasal discharge, and necrosis in the septum
      and turbinate of the right nasal cavity. Mercury level in concentrated urine was
      within normal limit. Microscopic examination disclosed extensive liquefaction
      necrosis with calcification and fibrosis. Numerous dark brown to black granules
      were noted in the elastic and collagen fibers and interstitium. Dark-field
      examination of the section revealed brilliantly refractile granules. Polarized
      microscopy failed to show the granules. Most brown pigments reacted to prussian
      blue. Tissue mercury analysis yielded a mercury content of 8.01 ppm. We report
      this case to emphasize the hazards of button battery impaction and to draw
      attention to the significance of the problem through histopathologic examination.

PMID- 10331571
TI  - Papillary adenocarcinoma of the stomach with psammoma bodies: report of two
      cases.
AB  - Calcification of gastric carcinoma is unusual and most of the reported cases were
      of the mucinous type. This report describes two cases of papillo-tubular
      adenocarcinoma of the stomach with psammomatous calcification confined only to
      the papillary portion. Calcification was so heavy that specimen X-ray was able to
      clearly delineate its distribution. Microscopically, the calcification was
      confined to the papillary carcinoma area and was not found in the area of the
      tubular adenocarcinoma. Polymorphic calcific bodies were found in the supportive
      stroma of papillae and extrapapillary spaces as concentrically laminated psammoma
      bodies. They were also found in tumor cells as minute corpuscles. The mechanism
      of neoplastic mineralization in these cases seemed different from ontogenic
      calcification of mucinous gastric carcinoma and we postulated the mechanism of
      psammomatous calcification which is referred as intracellular calcification.

PMID- 10331572
TI  - Clear cell carcinoma arising in a Cesarean section scar endometriosis: a case
      report.
AB  - Endometriosis of a surgical scar is rare and occurs mainly when a hysterectomy or
      Cesarean section was performed. We describe a 54-year-old woman with a large
      suprapubic mass as a definite case of a endomerioid carcinoma developing within
      the scar endometriosis following Cesarean section. Scar endometriosis, as well as
      endometriosis at other sites, can turn malignant. Endometrioid carcinoma is the
      most common histological pattern of malignant tumor arising in endometriosis. But
      clear cell carcinoma is very unusual. A case of primary clear cell carcinoma in
      endometriosis of a Cesarean section scar is described. To the best of our
      knowledge, this is the first documented case of endomerioid carcinoma developing
      within the scar endometriosis in Korea.

PMID- 10331573
TI  - Bilateral ovarian carcinoma metastatic from the ampulla of Vater: a rare
      Krukenberg tumor.
AB  - Carcinoma of the ampulla of Vater is a relatively rare neoplasm and its longterm
      survival rate is considerably high. However, because of differences in tumor
      pathologic features and local invasiveness, a 5-year survival rate differ widely.
      We present a case of metastatic carcinoma of the ampulla of Vater presenting as a
      Krukenberg tumor in a 59-year-old woman. Eight months earlier, she had been
      diagnosed as well-differentiated adenocarcinoma of the ampulla of Vater.
      Abdominal examination revealed a hard mass with mild tenderness in the RLQ area.
      The laboratory findings were unremarkable except for mild anemia. CT scan of the
      abdomen revealed enlargement of both ovaries. An exploratory laparotomy disclosed
      bilateral ovarian masses, 18 x 12 x 8 cm and 8 x 5.5 x 4 cm in size,
      respectively. Histologic findings of the both ovarian masses were consistent with
      metastatic adenocarcinoma from the ampulla of Vater.

PMID- 10331574
TI  - Extramammary Paget's disease with aggressive behavior: a report of two cases.
AB  - Extramammary Paget's disease (EMPD) is an intraepithelial neoplastic disorder
      which is included as a rare malignant condition. However, it sometimes shows
      aggressive behavior of local recurrence and coexisting malignancy. We had
      experienced nine cases of EMPD involving the scrotum for seven years. Two cases
      of them presented metastasis. The first case presented extensive inguinal lymph
      node metastasis with underlying adnexal adenocarcinoma one year after wide local
      excision. The second case initially presented multiple metastasis to the liver
      and in the lymph node. The latter, showing fulminant progression with liver
      metastasis, may be only the second case reported in English literature. EMPD is
      considered as a malignant neoplasm with aggressive behavior from initial
      presentation. Because wide local excision of the lesion alone may be occasionally
      insufficient, a careful follow-up must be done to detect recurrence or internal
      malignancy.

PMID- 10331575
TI  - Disseminated superficial actinic porokeratosis like drug eruption: a case report.
AB  - We report a 54-year-old male patient who developed an unusual form of generalized
      drug eruption. He had pain and breathlessness on the left chest wall. He had
      history of taking several drugs at private clinics under a diagnosis of herpes
      zoster. Two weeks later he had a generalized skin eruption. Examination showed
      multiple variable sized, mild pruritic, erythematous macules and papules on the
      face and upper extremities. Skin lesions take the form of a clinically consistent
      with disseminated superficial actinic porokeratosis (DSAP). Methylprednisolone 16
      mg, astemisole 10 mg, oxatomide 60 mg was prescribed. Topical corticosteroid
      cream was applied. Within two months, his eruption had cleared almost completely.
      The pathogenetic mechanisms of this case are unclear, but drug and UV light have
      been considered.

PMID- 10331576
TI  - Innervation of the esophagus in mice that lack MASH1.
AB  - The striated muscle of the esophagus differs from other striated muscle, because
      it develops by the transdifferentiation of smooth muscle, and the motor end
      plates receive a dual innervation from vagal (cholinergic) motor neurons and
      nitric oxide synthase (NOS)-containing enteric neurons. Mash1-/- mice have no
      enteric neurons in their esophagus and die within 48 hours of birth without milk
      in their stomachs (Guillemot et al. [1993] Cell 75:463-476). In this study, the
      innervation of the esophagus of newborn Mash1-/-, Mash1+/- and wild type mice was
      examined. There was no difference between Mash1-/-, Mash1+/-, and wild type mice
      in the transdifferentiation of the muscle and the development of nicotinic
      receptor clusters. However, there were significantly more cholinergic nerve
      terminals per motor end plate in Mash1-/- mice than Mash1+/- or wild type mice.
      Each of the Mash1-/- mice had fewer than 50 NOS neurons per esophagus, compared
      with approximately 3,000 in wild type mice. Newborn Mash1+/- mice also contained
      significantly fewer NOS neurons than wild type mice. In Mash1-/- mice, NOS nerve
      fibers were virtually absent from the external muscle but were present at the
      myenteric plexus. Unlike that of newborn wild type mice, the lower esophageal
      sphincter of Mash 1-/- mice lacked NOS nerve fibers; this may explain the absence
      of milk in the stomach. We conclude that 1) the transdifferentiation of the
      esophageal muscle and the development of the extrinsic innervation do not require
      enteric neurons or MASH1, 2) extrinsic NOS neurons only innervate the myenteric
      plexus.

PMID- 10331577
TI  - Parvalbumin-immunoreactive axon terminals in macaque monkey and human prefrontal
      cortex: laminar, regional, and target specificity of type I and type II synapses.
AB  - In sensory regions of primate neocortex, the calcium-binding protein parvalbumin
      (PV) is present in axon terminals that form both Gray's type I (asymmetric) and
      type II (symmetric) synapses. Those terminals forming type I synapses appear to
      arise from relay nuclei in the thalamus, whereas those forming type II synapses
      derive from cortical local circuit neurons. However, whether PV is present in
      both of these two types of terminals in the association regions of the primate
      prefrontal cortex (PFC) is not known. In the present study, PV-immunoreactive
      (IR) axon terminals in the superficial layers (layers 2-3a) of monkey PFC area 9
      were found to form exclusively type II synapses onto the dendritic spines (44%),
      shafts (39%), or somata/axon initial segments (17%) of pyramidal neurons. In
      contrast, in the middle layers (layers 3b-4), 52% of the PV-IR axon terminals
      formed type I synapses, and 79% of these terminals contacted dendritic spines.
      However, in the adjacent area 46, only 12% of the PV-IR terminals in the middle
      layers formed type I synapses. In addition, the PV-IR axon terminals forming type
      I synapses were 50% larger than those terminals forming type II synapses. Similar
      to the macaque monkey, in area 9 of the human PFC, PV-IR axon terminals forming
      type I synapses onto dendritic spines were found in the middle layers. These
      findings indicate that PV-IR axon terminals in macaque monkey and human PFC are
      likely to have both intrinsic and extrinsic sources. In addition, the laminar,
      regional, and target specificity of the labeled terminals forming type I synapses
      suggests that they arise from PV-IR neurons in the mediodorsal thalamic nucleus.

PMID- 10331578
TI  - Connections of the precommissural nucleus.
AB  - The connections of the precomissural nucleus (PRC) have been examined with
      anterograde and retrograde axonal tracing methods in the rat. Experiments with
      cholera toxin B subunit (CTb) indicate that the PRC shares a number of common
      afferent sources with the dorsolateral periaqueductal gray (PAG). Thus, we have
      shown that the nucleus receives substantial inputs from the prefrontal cortex,
      specific domains of the rostral part of the lateral septal nucleus, rostral zona
      incerta, perifornical region, anterior hypothalamic nucleus, ventromedial
      hypothalamic nucleus, dorsal premammillary nucleus, medial regions of the
      intermediate and deep layers of the superior colliculus, and cuneiform nucleus.
      Moreover, the PRC also receives inputs from several PAG regions and from neural
      sites involved in the control of attentive or motivational state, including the
      laterodorsal tegemental nucleus and the ventral tegmental area. The efferent
      projections of the PRC were analyzed by using the Phaseolus vulgaris
      leucoagglutinin (PHA-L) method. Notably, the PRC presents a projection pattern
      that resembles in many ways the pattern described previously for the rostral
      dorsolateral PAG in addition to projections to a number of targets that also are
      innervated by neighboring pretectal nuclei, including the rostrodorsomedial part
      of the lateral dorsal thalamic nucleus, the ventral part of the lateral
      geniculate complex, the medial pretectal nucleus, the nucleus of the posterior
      commissure, and the ventrolateral part of the subcuneiform reticular nucleus.
      Overall, the results suggest that the PRC might be viewed as a rostral component
      of the PAG, and the possible functional significance of the nucleus is discussed
      in terms of its connections.

PMID- 10331579
TI  - Development of sexually dimorphic vasotocinergic system in the bed nucleus of
      stria terminalis in chickens.
AB  - The bed nucleus of stria terminalis (BnST) of the domestic fowl contains two
      groups of parvicellular vasotocinergic neurons that are sexually dimorphic. In
      adult cockerels, arginine vasotocin (AVT) synthesis is well expressed in the
      dorsolateral and ventromedial portions of the BnST, whereas in corresponding
      brain areas of hens, AVT synthesis is completely lacking. In the present study,
      in situ hybridization and immunocytochemical methods were used to compare the
      ontogeny of sexually dimorphic AVT gene expression in the BnST of male and female
      chickens from day 12 of embryonic development (E12) until the onset of sexual
      maturation. By E12, both parvicellular groups of AVT-immunoreactive (AVT-ir)
      perikarya in the developing BnST can be distinguished in some males, whereas in
      females their presence is questionable. A quantitative analysis, beginning at
      E14, showed that the parvicellular dorsolateral portion of the BnST of male
      embryos had more AVT perikarya compared with females. In contrast, no evident sex
      difference in distribution pattern and number of AVT mRNA containing neurons in
      this BnST portion was observable by in situ hybridization at E15. At E18, as well
      as on the first and second days posthatch (D1 and D2), no differences in the
      number of AVT synthesizing cells and intensity of immunoreactive staining in male
      versus female chickens were found. Between D2 and D7, the number of AVT-ir cells
      in the BnST declined rapidly in both sexes until it disappeared completely in
      females before D35. In males, another increase in sexually dimorphic AVT-ir cells
      and innervation of the lateral septum was associated with the onset of puberty
      and fully matched a pattern observed in adult fowls. These results demonstrate
      that the sexually dimorphic part of the AVT system undergoes sexual
      differentiation during early stages of ontogeny.

PMID- 10331580
TI  - Immunocytochemical localization of glutamate and gamma-aminobutyric acid in the
      accessory olfactory bulb of the rat.
AB  - The synaptic organization of the accessory olfactory bulb (AOB) was studied in
      the rat with antibodies against the excitatory neurotransmitter glutamate (Glu)
      and the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). To a large
      extent, the immunoreactivity patterns produced by the two antibodies were
      complementary. Glu-like immunoreactivity (-LI) was observed in the glomerular
      neuropil, in the mitral cells, and in large neurons located in the periglomerular
      region. Immunogold electron microscopy revealed particularly high levels of Glu
      LI in the axon terminals of vomeronasal neurons. GABA-LI was present in granule
      and periglomerular cells and in their processes. The dendritic spines of granule
      cells, which were presynaptic to mitral cells, were strongly labelled by the
      antiserum against GABA. Labelling of serial semithin sections showed that the
      GABA-positive and Glu-positive neurons of the periglomerular region are generally
      distinct, and colocalization of Glu and GABA occurred only in a few cells. These
      results are consistent with electrophysiological studies indicating that the
      synaptic organization of the AOB is similar to that of the main olfactory bulb.
      In both systems, Glu is the neurotransmitter used by primary afferents and output
      neurons, whereas GABA is involved in the circuits underlying lateral and feed
      back inhibition.

PMID- 10331581
TI  - Anatomical and functional characterisation of a dopaminergic system in the
      suprachiasmatic nucleus of the neonatal Siberian hamster.
AB  - In altricial rodents, maternal influences entrain the developing circadian system
      in the perinatal period before the capacity to respond directly to photic cues
      develops. The aim of these studies was to investigate the potential role of
      dopamine in this process in the Siberian hamster. An initial study investigated
      the ontogeny of retinal innervation of the suprachiasmatic nuclei (SCN) by using
      cholera toxin B subunit as a tracer. This revealed that retinal fibres first
      innervate the SCN on postnatal day 3 (PD3), and ingrowth of fibres is extensive
      by PD6. In situ hybridisation studies revealed the presence of D1-dopamine
      receptor (D1-R) mRNA in the SCN on PD2, and levels of expression were similar in
      PD6 pups and adult hamsters. Immunocytochemical staining for tyrosine hydroxylase
      revealed abundant catecholaminergic fibres within the ventromedial zone of the
      SCN from the day of birth through PD20; however, in contrast, few fibres were
      present in adult SCN. Dopamine-beta-hydroxylase-immunoreactive fibres were absent
      from the neonatal and adult SCN, suggesting that the fibres in the SCN are
      dopaminergic. The function of this dopaminergic system was investigated by
      determining the effects of D1-R agonists on the expression of the immediate-early
      gene c-fos in the SCN. This was assessed in pups ages PD1- PD5 by in situ
      hybridisation and immunocytochemical localisation of its protein product. No
      induction was seen in the SCN, in marked contrast to studies in the developing
      rat. A final series of studies investigated dopaminergic function by determining
      whether a D1-agonist could induce phosphorylation of Ca2+/cyclic AMP response
      element-binding protein (CREB) on Ser133. Hypothalamic slices containing SCN
      taken from PD1 and PD2 hamsters were treated with D1-R agonists, and levels of
      phosphorylated CREB were assayed by Western blots. Phosphorylation of CREB was
      stimulated by D1-R agonists in both Syrian and Siberian hamster hypothalamus, but
      the response was far greater in Syrian hamster tissue (+138%+/-28%) than in
      Siberian hamster tissue (+43%+/-11%). Although the anatomical studies demonstrate
      the existence of a dopaminergic system in the SCN of the early postnatal Siberian
      hamster, the unresponsiveness of c-fos expression and the relative lack of
      phosphorylation of CREB after D1-R activation suggests a diminished role for
      dopamine in the regulation of circadian events during the postnatal period in
      this species.

PMID- 10331582
TI  - Costratification of a population of bipolar cells with the direction-selective
      circuitry of the rabbit retina.
AB  - We have stained a new population of bipolar cells in rabbit retina by using
      antibodies against the carbohydrate epitope, CD15. The CD15-positive bipolar
      cells comprise 6-8% of the total cone bipolar cells in peripheral retina. Their
      axonal and dendritic arbors are similar in size and range from 15 to 50 pm in
      diameter. The axonal arbors are narrowly stratified in sublamina b of the inner
      plexiform layer. Double label experiments using an antibody against the calcium
      binding protein, calbindin, or an antibody against protein kinase C, demonstrate
      that the CD15-positive bipolar cells are a separate population from the
      previously identified calbindin-positive cone bipolar cells and the rod bipolar
      cells. Labeling the processes of starburst amacrine cells with antibodies against
      choline acetyltransferase showed that the CD15-positive bipolar cells stratify
      within and slightly more distally to the processes of the ON-starburst amacrine
      cells. Confocal images of retinal wholemounts showed that the axons of the CD15
      positive bipolar cells follow the pattern of the ON-starburst cells' processes.
      Axonal varicosities of the CD15-positive bipolar cells penetrate the bundles
      formed by the processes of the ON-starburst cells. This finding suggests that the
      CD15-positive bipolar cell provides input to the ON-starburst amacrine cells
      and/or the ON-plexus of the ON-OFF direction-selective ganglion cells.

PMID- 10331583
TI  - Synaptic organization in the lamina of the superposition eye of a skipper
      butterfly, Parnara guttata.
AB  - The first optic neuropil of the compound eye, the lamina, of the skipper
      butterfly Parnara guttata, was examined by light microscopy after Golgi
      impregnation and by electron microscopy (EM) to clarify the cellular and synaptic
      organization. In the lamina, five different types of lamina neurons (L neurons)
      were characterized by using Golgi-impregnation. By EM, each cartridge was found
      to contain all nine receptor axons from an ommatidium, five L neurons, and a few
      putative centrifugal elements. Axons from photoreceptors (retinula cells) R2, R3,
      R4, R6, R7, and R8 terminate as short visual fibers (svfs) in the lamina
      cartridge. Those from R1, R5, and R9 penetrate the lamina and terminate in the
      medulla as long visual fibers (lvfs). In the cartridges, the synaptic contacts
      were formed from svfs onto L neurons, from the lvfs of R1 and/or R5 to the lvf of
      R9 and L neurons, and from the lvf of R9 to L neurons. The putative centrifugal
      fibers also make synapses to svfs and L neurons. At the most distal level of the
      cartridge, one of the centrifugal fibers containing dense-core vesicles makes
      presynaptic contacts to the putative long collaterals of the L neuron. A novel
      characteristic feature of this lamina is that svfs of R3 and R7 and the lvfs of
      R1 or R5 have long collaterals extending into neighboring cartridges. Presynaptic
      contacts were confirmed in such long collaterals from the svf. These results
      imply that receptor axons provide direct intercartridge connections as well as
      providing indirect connections to neighboring cartridges by way of their input
      upon L neurons.

PMID- 10331584
TI  - Desert toads discriminate salt taste with chemosensory function of the ventral
      skin.
AB  - Toads obtain water by absorption across their skin. When dehydrated, desert toads
      exhibit stereotyped hydration behavior in which they press their ventral skin
      onto a moist surface. However, dehydrated toads avoid surfaces moistened with
      hyperosmotic NaCl and KCl solutions (Hoff KvS, Hillyard SD. 1993. J. Exp. Biol.
      183:347-351). We have studied neural mechanisms for this avoidance with
      physiologic, behavioral, and morphologic approaches. Spinal nerves innervating
      the ventral skin could be stimulated by exposure to a hyperosmotic NaCl solution
      applied to the outer surface of the skin. This neural response occurred with much
      longer latency than to mechanical stimulation and could be reduced by amiloride,
      a blocker for Na+ channels known to be responsible for epithelial ion transport
      and salt taste transduction. In behavioral experiments, avoidance of a NaCl
      solution was also reduced by adding amiloride to the solution, suggesting
      involvement of amiloride-sensitive Na+ channels for detecting the hyperosmotic
      salt solution. Neural tracing with fluorescent dye revealed spinal nerve endings
      and connections to putative receptor cells, both located in the deeper layer of
      the epidermis. Either of these or both may be associated with the transduction of
      Na+ flowing into the skin. The ability of toads to detect hyperosmotic salt
      solutions in their environment reveals a previously unknown chemosensory function
      for spinal nerves in anuran amphibians.

PMID- 10331585
TI  - Representations of hindlimb digits in rat dorsal root ganglia.
AB  - The distribution in dorsal root ganglia of neurones that innervate the distal
      tips of the hindlimb digits in the rat were mapped after subcutaneous injections
      of the fluorescent tracers Fast Blue, Diamidino Yellow, and Fluoro-Gold into
      different digits. Three-dimensional reconstruction was used to describe the
      intraganglionic distribution of neurones labelled from different digits. Labelled
      neurones were found mainly in the L3-L5 ganglia. The distribution in ganglia and
      the number of neurones labelled from each digit varied considerably between
      cases, but mean numbers of labelled neurones were similar for the different
      digits. Neurones in L3 tended to innervate medial digits and neurones in L5
      tended to innervate lateral digits, but most neurones from any digit were found
      in L4. Although overlap was considerable, the three-dimensional reconstruction
      showed tendencies of neurones to be distributed in restricted territories within
      the dorsal root ganglia. This was especially clear in ganglion L5, where digit IV
      was found to be represented more rostrally than digit V. The results indicate
      that primary afferent neurones that innervate the hindlimb digits are represented
      by a crude rostrocaudal somatotopic organisation both among and within lumbar
      dorsal root ganglia.

PMID- 10331586
TI  - Trinucleotide CGG repeat in the FMR1 gene in Chinese mentally retarded patients.
AB  - The fragile X syndrome of mental retardation is related to the number of
      trinucleotide CGG repeats at the 5'-untranslated region of the FMR1 gene located
      on the X-chromosome. We have studied X-chromosomes from 649 unaffected Chinese
      subjects and 324 patients with mild mental retardation. All study subjects were
      unrelated. The CGG repeat number was analysed by electrophoresis of a polymerase
      chain reaction followed by gel transfer and hybridisation with a 32P-labeled
      (CCG)5 probe. The DNA samples having detectable CGG expansion were further
      analysed by Southern blot analysis with probe StB12.3 after restriction digestion
      by EcoR I and Eag I. For the unaffected Chinese subjects, a different
      distribution pattern of CGG allele size from Caucasians was observed. It was a
      bimodal pattern and the CGG repeat number ranged from 19 to 54. The most common
      CGG repeat allele was 29 compared with 30 in Caucasians. The second mode appeared
      at 36 repeats. There was mild statistical difference in the repeat patterns
      between the mentally retarded patients and unaffected subjects, although the
      essential features were similar. Among the mentally retarded patients, one male
      had an unmethylated full mutation and one female had a full mutation. The fragile
      X prevalence was 0.6%, which is lower than two previous studies in Chinese
      mentally retarded patients utilising cytogenetic analysis. Our results indicate
      that a large-scale screening program would be worthwhile to determine the
      prevalence of the fragile X syndrome in the Chinese population.

PMID- 10331587
TI  - Molecular screening of fragile X (FRAXA) and FRAXE mental retardation syndromes
      in the Hellenic population of Greece and Cyprus: incidence, genetic variation,
      and stability.
AB  - This study presents the first large, population-based molecular investigation of
      the fragile X (FRAXA) and FRAXE mental retardation syndromes in the Hellenic
      populations of Greece and Cyprus. The aims of this population screening were to
      determine the prevalence of FRAXA and FRAXE syndromes among idiopathic mentally
      retarded (IMR) individuals, to estimate the incidence in the general population,
      and to investigate the molecular mechanism of instability and expansion of the
      FMR1-repeat. Ten FRAXA patients were identified to have either the full mutation
      (eight) or premutation (two) from a Hellenic population of 866 unrelated IMR
      individuals (611 males and 255 females, age range 3-25 years). No FRAXE patients
      were identified among the 611 IMR males. The incidence of FRAXA in the Hellenic
      population of Cyprus is estimated at 1 in 4,246 males. The repeat sites from the
      FMR1 and FMR2 alleles were accurately determined and showed similar distribution
      and frequencies with other population studies. The analysis of AGG interspersion
      within the FMR1-repeat in normal males revealed long, pure CGG repeats within the
      "gray zone" as well as variation within the 3' end showing polarity of
      instability. This finding supports the hypothesis that the AGG interspersion and
      the length of the pure repeat are major factors in determining allele stability.
      Analysis of FRAXAC1, DXS548, and FRAXAC2 identified particular alleles and
      haplotypes to have a significant association with either gray zone alleles or
      alleles >15 pure CGG repeats. We hypothesize that this subgroup of alleles and
      haplotypes are associated with long pure CGGs (>15 CGG) or 35 repeats and, having
      shared an evolutionary past, would have the tendency to expand.

PMID- 10331588
TI  - Frequency of the fragile X syndrome in Chinese mentally retarded populations is
      similar to that in Caucasians.
AB  - Fragile X syndrome is recognized as the most common inherited cause of mental
      retardation in western countries. The prevalence of the fragile X syndrome in
      Asian populations is uncertain. We report a multi-institutional collaborative
      study of molecular screening for the fragile X syndrome from 1,127 Chinese
      mentally retarded (MR) individuals. We found that 2.8% of the Chinese MR
      population screened by DNA analysis had the fragile X full mutation. Our
      screening indicated that the fragile X syndrome prevalence was very close to that
      of Caucasian subjects. In addition, we found that 62.5% of fragile X chromosomes
      had a single haplotype for DXS548-FRAXAC1 (21-18 repeats) which was present in
      only 9.7% of controls. This unique distribution of microsatellite markers
      flanking the FMR1 CGG repeats suggests that the fragile X syndrome in Chinese
      populations, as in the Caucasian, may also be derived from founder chromosomes.

PMID- 10331589
TI  - Frequencies of "grey-zone" and premutation-size FMR1 CGG-repeat alleles in
      patients with developmental disability in Cyprus and Canada.

PMID- 10331590
TI  - Fully mutated and gray-zone FRAXA alleles in Brazilian mentally retarded boys.
AB  - We used a non-isotopic polymerase chain reaction (PCR) technique for fragile X
      syndrome diagnosis to screen 256 mentally retarded boys who were selected
      randomly from special schools. Patients identified as pre- or full-mutation
      carriers were further investigated by Southern blot analysis with the StB12.3
      probe. The PCR-based test identified five boys with the expanded allele and 17
      other patients as carriers of either premutated or gray-zone alleles. The full
      mutation was confirmed in four cases after Southern blotting and a fifth patient
      carried a normal allele. Of the 17 patients identified with a premutation allele
      by PCR, one individual was diagnosed as mosaic by Southern blotting, 12
      individuals displayed fragments of 2.90 kb or 2.85 kb, and the remaining four
      individuals showed apparently normal-sized fragments. However, sizing of these 16
      alleles by further PCR analysis showed them to be in the gray-zone range (40-60
      repeats). Therefore, the frequency of the full mutation in this cohort of
      mentally retarded boys was close to 2% (5/256). The prevalence of gray-zone
      alleles among those mentally impaired boys who did not carry the full mutation
      was 6.4% (16/251) and, although more than twice the prevalence of these alleles
      among a cohort of unaffected Brazilian males 2.8% (71251), the difference did not
      reach statistical significance.

PMID- 10331591
TI  - Frequency of fragile X syndrome among Turkish patients with mental retardation of
      unknown etiology.

PMID- 10331592
TI  - DXS548/FRAXAC1 haplotypes in fragile X chromosomes in the Brazilian population.
AB  - In order to investigate the origin of the fragile X mutation in the Brazilian
      population, we assessed the size of the microsatellite markers DXS548, FRAXAC1
      and FRAXAC2 in 72 X chromosomes from unrelated affected males and 64 control
      chromosomes. We found a significantly different distribution of alleles between
      fragile X and controls for loci DXS548 and FRAXAC1, but no apparent linkage
      disequilibrium was detected for the sequence FRAXAC2. The most frequent
      DXS548/FRAXAC1 haplotypes in affected males were haplotypes 204/158 bp (2-1) and
      196/152 bp (6-4). These findings are in accordance with the proposed two main
      mutational pathways for the generation of FMR-1 alleles that predispose to
      instability and hyperexpansion.

PMID- 10331593
TI  - FRAXAC1 and DXS548 polymorphisms in the Chinese population.
AB  - The fragile X syndrome is the most common inherited form of mental retardation.
      Haplotype studies using FRAXAC1 and DXS548 polymorphic markers flanking the
      fragile site have demonstrated linkage disequilibrium at the FMR1 locus. We
      investigated the association of the FRAXAC1, DXS548 and CGG alleles between
      normal subjects and mentally retarded (MR) patients of unspecified cause who do
      have fragile X syndrome. We have evaluated the FRAXAC1 site in 390 normal
      subjects and 321 MR patients and the DXS548 site in 146 normal and 319 MR
      subjects. Both FRAXAC1 and DXS548 alleles were determined by application of the
      polymerase chain reaction. When compared with Caucasians, the normal Chinese
      population has a different FRAXAC1 allele distribution. There are more AC18
      repeat alleles and fewer AC19 repeat alleles. The DXS548 allele distributions
      were similar between Chinese and Caucasians. The same distribution pattern of
      FRAXAC1 alleles was found in both normal subjects and MR patients, but there were
      significant differences in the distribution patterns of DXS548 alleles. The FMR1
      CGG-DXS548 and FRAXAC1-DXS548 haplotype distribution between normal subjects and
      MR patients also differed significantly. Our results suggest a possible
      association between DXS548 alleles and non-FRAXA mental retardation.

PMID- 10331594
TI  - Haplotype analysis of the fragile X syndrome gene FMR1 in the Czech Republic.
AB  - We report on the haplotype analysis with polymorphic repeat markers DXS548 and
      FRAXAC1 next to the FMR1 gene in 37 unrelated fragile X and 36 control
      chromosomes from Bohemia and Moravia. Our results suggest a significant linkage
      disequilibrium between fragile X mutations and certain DXS548-FRAXAC1 haplotypes.
      Allele frequencies obtained differ slightly from those of other European
      populations with allele 194 being less frequent in our control sample. Rare
      DXS548 alleles 6.5 (195) and 0 (208) were also present.

PMID- 10331595
TI  - Genetic variation and intergenerational FMR1 CGG-repeat stability in 100
      unrelated three-generation families from the normal population.
AB  - In order to identify genetic factors governing expansion of the CGG repeat in the
      FMR1 gene and to determine what predisposes or causes a normal stable allele to
      change to an unstable premutation allele, it is essential to study and understand
      the basis of normal variation. The aim of this study was to investigate genetic
      variation and intergenerational stability of the FMR1 CGG-repeat region in 100
      unrelated three-generation families from the general population (651 meioses).
      The number of CGG-repeats in the FMR1 gene was determined in all 750 individuals
      from the 100 families (a total of 1,132 X-chromosomes), and the allele
      frequencies and variability were analyzed. Thirty-six different alleles (12-60
      repeats) were seen with 30 (45.8%) as the most common allele; overall female
      heterozygosity was 73%. Most (>96%) of the normal array lengths were less than 40
      repeats. Fifteen families with at least one allele equal to or greater than 40
      repeats (40-60) were identified; in one of these families there was an increase
      of one triplet repeat during transmission from a mother to son. These findings,
      together with future molecular analyses, may provide data to test proposed models
      that attempt to explain the mutational process and the population dynamics of the
      triplet repeat region of the FMR1 gene, including the transition from normal to
      unstable alleles, or to test other putative cis-acting sequences that may be
      involved with instability in the FMR1 gene.

PMID- 10331596
TI  - Mosaicism for a full mutation and a normal size allele in two fragile X males.
AB  - Confirmation of the clinical diagnosis of fragile X syndrome by molecular tests
      is based on both the presence of a full mutation and methylation of the promotor
      region of the FMR1 gene. The mechanism leading to mosaic alleles of repeat number
      and the role of methylation in this process is still under discussion. We report
      two cases of males who show mosaic patterns for both number of CGG repeats and
      methylation status. In the first patient, a mosaic pattern of a normal allele of
      34+/-1 CGGs, a borderline premutation/full mutation, and a full mutation was
      observed. The mother exhibited alleles of 30+/-1 and approximately 100 CGGs. The
      second patient was mosaic for a normal allele of 47+/-1 CGGs and a full mutation.
      His mother carried alleles of 40+/-1 and approximately 100 CGGs. Chromosomal
      analysis in the patients showed normal male karyotypes with no evidence that they
      had inherited both maternal X chromosomes. Furthermore, haplotyping excluded
      disomy of the repeat flanking region in these patients. So far, it is not clear
      whether the normal alleles in the patients, leukocytes of 34 and 47 CGGs,
      respectively, may be caused by the contraction of the maternal premutations of
      100 CGGs or be caused by the deletion from the full mutation alleles.

PMID- 10331597
TI  - Mitotic behavior of expanded CGG repeats studied on cultured cells: further
      evidence for methylation-mediated triplet repeat stability in fragile X syndrome.

PMID- 10331598
TI  - Mosaicism in a fragile X male including a de novo deletion in the FMR1 gene.
AB  - In most cases the fragile X syndrome is caused by an amplification of the CGG
      trinucleotide repeat in the 5' untranslated region of the FMR1 gene, in
      combination with the hypermethylation of the proximal CpG island. Recently, also
      a few cases with deletions or a mosaic of a deletion and a full mutation in the
      FMR1 gene, leading to the same phenotype, have been described. Here we report the
      molecular analysis of a patient with typical fragile X phenotype and mosaicism of
      the FMR1 genomic region consisting of a premutation, a full mutation of the CGG
      repeats, and a 215 bp deletion, diagnosed by Southern blot hybridisation and
      polymerase chain reaction (PCR). Sequence analysis of the deletion demonstrated
      that the 5' breakpoint of the deletion is located within a putative hotspot
      region 75-53 bp proximal to the CGG repeat.

PMID- 10331599
TI  - Tissue heterogeneity of the FMR1 mutation in a high-functioning male with fragile
      X syndrome.
AB  - Few studies have been conducted comparing the FMR1 mutation in multiple tissues
      of individuals affected with fragile X syndrome. We report a postmortem study of
      the FMR1 mutation in multiple tissues from a high-functioning male with fragile X
      syndrome. This man was not mentally retarded and had only a few manifestations of
      the disorder such as learning disabilities and mild attention problems. Southern
      blot analysis of leukocytes demonstrated an unmethylated mutation with a wide
      span of sizes extending from the premutation to full mutation range. A similar
      pattern was seen in most regions of the brain. In contrast, a methylated full
      mutation of a single size was seen in the parietal lobe and in most non-brain
      tissues studied. Therefore, there were striking differences in both FMR1 mutation
      size and methylation status between tissues. Lack of mental retardation in this
      individual may have been due to sufficient expression of FMR1 protein (FMRP) in
      most areas of the brain. Immunocytochemistry showed FMRP expression in regions of
      the brain with the unmethylated mutation (superior temporal cortex, frontal
      cortex, and hippocampus) and no expression in the region with the methylated full
      mutation (parietal). Neuroanatomical studies showed no dendritic spine pathology
      in any regions of the brain analyzed.

PMID- 10331600
TI  - Strong similarities of the FMR1 mutation in multiple tissues: postmortem studies
      of a male with a full mutation and a male carrier of a premutation.
AB  - Studies of the FMR1 mutation in multiple tissues are important to further our
      understanding of CGG repeat expansion in development and of the frequency and
      possible clinical significance of inter-tissue heterogeneity in fragile X
      syndrome. With some exceptions, most cases reported have shown strong similarity
      of the mutation size and methylation status between tissues. However, there have
      been only a few studies of multiple tissues including regions of the brain. We
      report on two postmortem studies of multiple tissues, one of a male with a full
      mutation (fully methylated) and one of a male carrier of a premutation. The male
      with the full mutation (TH) had a typical presentation of fragile X syndrome,
      including mild mental retardation. He had a methylated full mutation of two
      predominant sizes in all 12 tissues analyzed, including three regions of the
      brain. The male carrier of a premutation (GC) was clinically unaffected, and the
      mutation was the same size in all 14 tissues examined including seven regions of
      the brain. Therefore, both cases demonstrated lack of inter-tissue heterogeneity,
      suggesting strong somatic stability after the period of expansion to the observed
      mutation size(s). Also, both cases showed consistency between clinical phenotype
      and mutation characteristics in the brain.

PMID- 10331601
TI  - Postmortem examination of two fragile X brothers with an FMR1 full mutation.
AB  - Large expansions of the CGG repeat in the 5' untranslated region of the FMR1 gene
      are found in patients with the fragile X syndrome. Amplified CGG repeats in FMR1
      are unstable and show intergenerational increase from mother to offspring. The
      exact timing of repeat amplification, however, is unknown. We have compared the
      extent of CGG expansion in various tissues of this deceased fragile X patient,
      and found only limited variation in repeat expansion. The repeat was fully
      methylated in all tissues examined. Therefore, no evidence for extensive mitotic
      expansion of the CGG repeat during fetal or postnatal life of a fragile X patient
      was found, in contrast to dynamic mutations caused by CAG/CTG repeat expansion.
      Extensive pathological examination of this patient and his affected brother
      revealed no evidence for specific abnormalities relevant to fragile X syndrome;
      cerebellar hypoplasia, which has been reported in this disorder, was not evident
      in either patient.

PMID- 10331602
TI  - FMRP expression as a potential prognostic indicator in fragile X syndrome.
AB  - Absence or deficit of FMR1 protein (FMRP) resulting from methylation of full
      mutation genes is the fundamental defect in fragile X syndrome. We used FMRP
      immunocytochemistry and detailed phenotypic assessment to investigate the
      relationship between degree of FMRP expression and the broad clinical spectrum of
      impairment in 80 individuals affected with fragile X syndrome. FMRP expression
      correlated with IQ in mosaic males (P=0.043), males with a partially methylated
      full mutation (P=0.0005), and females with a full mutation (P=0.046). In the
      females, FMRP expression also correlated with the number of fragile X physical
      features (P=0.0003). Even modest deficits in FMRP result in some manifestations
      of fragile X syndrome. In this initial study of 53 males, FMRP expression testing
      had a very high positive predictive value (100%, confidence interval of 29-100%)
      for a nonretarded IQ among males with expression of FMRP in > or = 50% of
      lymphocytes (3 males), suggesting that FMRP expression may have potential as a
      prognostic indicator in males with fragile X syndrome.

PMID- 10331603
TI  - Single-strand conformation polymorphism analysis in the FMR1 gene.
AB  - The fragile X syndrome is due to an expansion of the CGG trinucleotide repeat in
      the FMR1 gene and hypermethylation of its 5' upstream CpG island in about 95% of
      the cases. The remaining 5% of cases correspond to other molecular alterations in
      FMR1 gene such as partial or complete deletions, or point mutations within the
      coding sequence. We selected 31 patients with clinical manifestations of fragile
      X syndrome, scoring 16 or more in Hagerman's checklist, but without the CGG
      expansion. We performed single-strand conformation polymorphism analysis using a
      nonradioactive technique (silver staining) and we detected six anomalous
      migrations that, by sequence analysis, corresponded to six nucleotide changes. We
      screened two different populations (control and fragile X) for these changes, and
      concluded that they correspond to five new polymorphisms within the FMR1 gene and
      to one possible synonymous mutation.

PMID- 10331604
TI  - In vivo footprinting analysis of the FMR1 gene: proposals concerning gene
      regulation in high-functioning males.

PMID- 10331605
TI  - Reduced mRNA for G3BP in fragile X cells: evidence of FMR1 gene regulation.
AB  - Although fragile X syndrome is caused by the absence of fragile X gene
      expression, little is known about the pathogenic processes underlying the mental
      retardation. Recent findings that the fragile X protein, FMRP, contains RNA
      binding motifs and nuclear transport signals and associates with ribosomes
      suggest that FMRP may be involved in either mRNA processing, transport, or
      translation. To test the hypothesis that absence of FMRP may affect the
      processing of specific transcripts, we have used an RNA differential display
      assay (RDDA) to identify differentially expressed transcripts in lymphoblast
      lines derived from fragile X syndrome patients. A 0.9-kb cDNA fragment that
      showed reduced expression in a fragile X lymphoblast cell line was found to be
      identical to G3BP (Ras-GTPase-Activating protein SH3-domain-binding protein).
      Quantitative reverse transcriptase-polymerase chain reaction showed that the
      expressed levels of G3BP mRNA in fragile X lymphoblast cell lines were
      significantly less than controls. Our results indicate that G3BP mRNA may be
      regulated by FMRP and supports the hypothesis that FMRP may modulate the
      transcription of specific transcripts.

PMID- 10331606
TI  - KH domain-containing proteins of yeast: absence of a fragile X gene homologue.
AB  - The KH domain is a region defined by its homology to the RNA-binding domains of
      the heterogeneous nuclear ribonucleoprotein K (hnRNPK). There are two such
      domains in the FMR1 protein which is underexpressed in the fragile X syndrome. We
      developed a computer method to search the S. cerevisiae protein sequences as they
      became available for the KH domain of the FMR1 protein. Using our motif and
      FINDPATTERNS of the Wisconsin Package of GCG, nine proteins were identified in
      the completed yeast ORF database that contain KH domains. Five proteins have
      known or predicted functions; four await functional analysis. Using GeneWorks and
      GeneJockeyII alignments, we found that the yeast protein KH domain showing the
      most similarity to either FMR1P KH domain was a KH domain in HX/SCP160. Its
      sequence is 50% identical to the second KH domain of FMR1P. However, SCP160
      contains eight conserved and six degenerate KH domains. Further analysis showed
      that SCP160 is a better match overall to the vertebrate and C. elegans protein
      Vigilin, which also contains 14 KH domains. The next most similar yeast KH domain
      was found in YB83, a protein shorter than FMR1P and containing three KH domains,
      one of which shares 45% identity with the second KH domain in FMR1P. There is no
      significant overall sequence similarity between this yeast protein and FMR1P.
      Thus, while several proteins in yeast contain KH domains, no apparent yeast
      homologue exists for the FMR1 protein of the fragile X gene family.

PMID- 10331607
TI  - Learning and memory in the FMR1 knockout mouse.
AB  - The fragile X [fra(X)] syndrome is manifested phenotypically as a developmental
      disability comprised mainly of moderate-to-severe mental retardation (MR).
      Deficits are especially evident in auditory and visual short-term memory.
      Recently, an FMR1 knockout mouse developed by the Dutch-Belgian Fragile X
      Consortium demonstrated significantly lower visual-spatial abilities than
      littermate controls. We wondered if these results were associated with learning
      per se or to performance deficits only. Thus, we examined learning and memory in
      male FMR1 knockout mice crossbred from Fvb and E129 strains, and in male Fvb
      control mice, using operant conditioning techniques. In Experiment 1, we
      demonstrated that two aged male FMR1 knockouts could acquire the necessary bar
      press response to discriminate visual (L+) and auditory (N+) stimuli. In
      Experiment 2, we showed that three naive male knockouts and two naive male
      controls, all 12 weeks old, also learned to discriminate L+ and N+. A third
      component, a complex discrimination task, during which light and noise were
      presented concurrently without reinforcement (LN-) was added to each session. All
      knockouts acquired both L+ and N+ discriminative responses in fewer sessions and
      with higher discrimination ratios than either control. Moreover, all knockouts
      exhibited the typical response pattern associated with complex discrimination (LN
      ) tasks. However, neither control made the complex discrimination. Our findings
      were unexpected and raise issues concerning FMR1 mouse strains and their
      cognitive-behavioral testing.

PMID- 10331608
TI  - Search for a Caenorhabditis elegans FMR1 homologue: identification of a new
      putative RNA-binding protein (PRP-1) that hybridizes to the mouse FMR1 double K
      homology domain.
AB  - A mixed stage lambdagt10 Caenorhabditis elegans cDNA library was screened with a
      probe derived by polymerase chain reaction from the double K homology (KH) domain
      of mouse FMR1 cDNA, a region that is highly conserved in the human, mouse,
      chicken, and frog FMR1 proteins. Four positively hybridizing cDNAs were cloned
      and characterized by sequencing. The overlapping sequences map to cosmid R119
      from C. elegans linkage group (chromosome) I, and encode a novel proline-,
      polyglutamine-, and RGG box-rich putative RNA-binding protein. While the cDNA has
      two regions with similarity to the mouse double KH domain probe at the nucleotide
      level, there is no significant similarity of the amino acid sequence with human
      FMR1, FXR1 or FXR2, nor with KH amino acid motifs. The R119 protein, therefore,
      does not represent an FMR1 homologue.

PMID- 10331609
TI  - Possible founder effects for FRAXE alleles.
AB  - To determine if FRAXE alleles may have haplotype associations with nearby
      microsatellites, we analyzed 149 unrelated control Caucasian X chromosomes for
      FRAXE GCC alleles along with five nearby microsatellites. The microsatellites
      included three that are new; GT25, CA4, and CA5 located approximately 24,
      approximately 48, and approximately 50 kb proximal to the FRAXE GCC repeat, and
      two that were identified previously: DXS8091 and DXS1691, located approximately
      90 and approximately 5 kb distal. No significant correlations between haplotypes
      for the proximal microsatellites were found. Significant correlations of FRAXE
      GCC repeats and distal microsatellite allele sizes, DXS8091 (r = 0.24) and
      DXS1691 (r = -0.40), were found. One haplotype, 18-19 of DXS8091-DXS1691, was
      present on 57% of chromosomes with > or =22 FRAXE repeats but present on only 10%
      with <22 repeats. We conclude that this distal haplotype association likely
      reflects a FRAXE allele founder effect. The lack of association or founder
      effects seen for the three newly identified proximal markers, located within 50
      kb of FRAXE GCC, may reflect an unusually high rate of mutation for these
      microsatellites or a higher rate of recombination in the proximal region.

PMID- 10331610
TI  - Longitudinal changes in cognitive-behavioral levels in three children with FRAXE.

PMID- 10331611
TI  - Mapping of a gene (MRXS9) for X-linked mental retardation, microcephaly, and
      variably short stature to Xq12-q21.31.
AB  - Three boys from two families were identified as having a syndrome of X-linked
      mental retardation (XLMR) with microcephaly and short stature, clinically
      resembling Renpenning syndrome but with normal size of testicles in affected men.
      When the effort to map the gene for the above condition was initiated, it was
      realized that the two families were actually related to each other. Over 50
      polymorphic markers of known locations along the X chromosome were scored in this
      family in a study to map the disease gene. Nine affected and four unaffected
      males were genotyped to produce a maximum LOD score of 4.42 at zero recombination
      with markers in proximal Xq. The results indicate that the gene responsible for
      this disorder is located in the cytogenetic Xq12 to Xq21.31 interval of the X
      chromosome within a section of chromosome of about 17 cM between the AR and
      DXS1217 loci over some 25 mb. Since the gene for the X-linked mental retardation
      from the original Saskatchewan family described by Renpenning [Renpenning et al.,
      1962: Can Med Assoc J 87:954-956; Fox and Gerrard, 1980: Am J Med Genet 7:491
      495] was recently mapped to a different nonoverlapping region [Stevenson et al.,
      1998: Am J Hum Genet 62:1092-1101] this would appear to be a separate disorder.

PMID- 10331612
TI  - Premature ovarian failure (POF) and fragile X premutation females: from POF to to
      fragile X carrier identification, from fragile X carrier diagnosis to POF
      association data.
AB  - Early menopause in the fragile X carriers has been well documented in several
      reports. All surveys demonstrated that 13-25% of fragile X carriers experienced
      premature ovarian failure (POF), defined as menopause before the age of 40 years.
      In 1995 we started screening two groups of subjects as a part of a Fragile X
      Research Program: 1) women previously diagnosed as fragile X carriers from the
      register of our center and 2) women with POF and without a family history of
      fragile X or other forms of mental retardation. In this study we report the
      preliminary data collected from 75 fragile X families; in 30 of them, POF was
      present in one or several subjects, all of whom had a fragile X premutation. None
      of the women with a full mutation experienced POF in our series of patients. We
      also identified 89 families without a family history of fragile X or mental
      retardation, and there were 108 subjects who experienced POF, of which 6.5% had a
      fragile X premutation. This is 70-fold higher than the background prevalence of
      fragile X premutation in the Italian population and suggests an association with
      POF. These data confirm the results of other surveys.

PMID- 10331613
TI  - Improved amplification of the FMR2 GCC repeat from dried blood spots.

PMID- 10331614
TI  - Fragile X premutations and (TA)n estrogen receptor polymorphism in women with
      ovarian dysfunction.
AB  - We studied five groups of women with ovarian dysfunction for the CGG expansion in
      FMR1 and a (TA)n polymorphism in the estrogen receptor gene: a) poor responders
      to ovarian stimulation as part of in vitro fertilization (n = 13); b) women with
      familial premature ovarian failure (POF) (n = 7); c) sporadic cases with POF (n =
      16); d) FRAXA premutation carriers with POF (n = 7); and e) FRAXA premutation
      carriers without POF (n = 9). FRAXA premutation was found in one woman with
      familial POF. A significant association of familial POF and FRAXA premutation
      carriers with POF having low copy of the (TA)n polymorphism as compared to
      controls was observed. Our preliminary data suggest a potential role of the
      estrogen receptor in POF, and it may influence the variable age of menopause of
      the FRAXA premutation carriers.

PMID- 10331615
TI  - Distribution of apolipoprotein E genotypes in fragile X syndrome and Batten
      disease.

PMID- 10331617
TI  - Loudness scaling revisited.
AB  - The present work was undertaken in an attempt to evaluate whether it is
      reasonable to expect that categorical loudness scaling can provide useful
      information for nonlinear hearing aid fitting. Normative data from seven scaling
      procedures show that the individual procedures relate the perceptual categories
      differently to sound level and with a substantial between-subject variance.
      Hearing-impaired data from four studies demonstrate that the inverse slope of the
      loudness function varies linearly with hearing loss and with a constant variance.
      In relation to hearing aid fitting, the slope can, in most cases, be predicted
      from the hearing loss with an accuracy within the range of a normal finetuning.
      For the fitting of nonlinear hearing aids, the statistical properties of both
      normal and impaired loudness functions are equally important. The present
      analysis strongly suggests that categorical loudness scaling cannot, in general,
      provide significant information for the fitting process.

PMID- 10331616
TI  - One-year audiologic monitoring of individuals exposed to the 1995 Oklahoma City
      bombing.
AB  - This longitudinal study evaluated subjective, behavioral, and objective auditory
      function in 83 explosion survivors. Subjects were evaluated quarterly for 1 year
      with conventional pure-tone and extended high-frequencies audiometry, otoscopic
      inspections, immittance and speech audiometry, and questionnaires. There was no
      obvious relationship between subject location and symptoms or test results.
      Tinnitus, distorted hearing, loudness sensitivity, and otalgia were common
      symptoms. On average, 76 percent of subjects had predominantly sensorineural
      hearing loss at one or more frequencies. Twenty-four percent of subjects required
      amplification. Extended high frequencies showed evidence of acoustic trauma even
      when conventional frequencies fell within the normal range. Males had
      significantly poorer responses than females across frequencies. Auditory status
      of the group was significantly compromised and unchanged at the end of 1-year
      postblast.

PMID- 10331618
TI  - Pulsed versus continuous tones for evaluating the loudness of tinnitus.
AB  - Loudness balance techniques are commonly employed to match the loudness of
      tinnitus using either pulsed or continuous tones; however, it is not known
      whether the tone duration affects the observed loudness matches. In this study,
      hearing thresholds and tinnitus loudness matches were measured in 26 subjects
      with chronic tinnitus using both pulsed and continuous tones. Subjects'
      thresholds and loudness matches were determined at 11 frequencies between 0.5 and
      10 kHz. No significant differences were found between pulsed versus continuous
      measures, either for thresholds or for loudness matches. There were, however,
      nine subjects (34.5% of the group) who showed relatively large differences (> or
      =10 dB) at one or more test frequencies. These "outlier" values did not show
      systematic trends; some were positive, some negative. In conclusion, studies
      employing group data appear to be comparable if group sizes are sufficiently
      large (e.g., > or =25 subjects). Studies employing smaller numbers of subjects
      may, however, be vulnerable to potential positive or negative biases introduced
      by one or more outliers.

PMID- 10331619
TI  - Field trial evaluations of a switched directional/omnidirectional in-the-ear
      hearing instrument.
AB  - The use of directional microphones is one of the few methods available for
      hearing aids to increase the signal-to-noise ratio. The smaller microphones
      available with today's technology have increased the viability of their
      application for in-the-ear (ITE) hearing aids. This study evaluated an ITE
      hearing aid containing two nondirectional microphones that provides wearer
      selectable omnidirectional/directional operating modes. Ten sensorineural hearing
      impaired patients were fitted binaurally. During the first trial period, the low
      frequency gain decrease produced by the directional mode was not compensated for.
      The frequency responses were matched during the second trial period. For both
      trial periods, Hearing in Noise Test results using two uncorrelated noise sources
      indicated significant speech recognition improvements for the directional mode
      relative to the omnidirectional mode. Responses on Abbreviated Profile of Hearing
      Aid Benefit questionnaires, paired-comparison judgments, and interview data
      revealed that most subjects preferred the directional mode in noisier
      environments, but many also preferred the omnidirectional mode in quiet
      listening.

PMID- 10331620
TI  - It happened to us.

PMID- 10331621
TI  - In vitro motility evaluation of aggregated cancer cells by means of automatic
      image processing.
AB  - BACKGROUND: Set up of an automatic image processing based method that enables the
      motility of in vitro aggregated cells to be evaluated for a number of hours.
      METHODS: Our biological model included the PC-3 human prostate cancer cell line
      growing as a monolayer on the bottom of Falcon plastic dishes containing
      conventional culture media. Our equipment consisted of an incubator, an inverted
      phase contrast microscope, a Charge Coupled Device (CCD) video camera, and a
      computer equipped with an image processing software developed in our laboratory.
      This computer-assisted microscope analysis of aggregated cells enables global
      cluster motility to be evaluated. This analysis also enables the trajectory of
      each cell to be isolated and parametrized within a given cluster or, indeed, the
      trajectories of individual cells outside a cluster. RESULTS: The results show
      that motility inside a PC-3 cluster is not restricted to slight motion due to
      cluster expansion, but rather consists of a marked cell movement within the
      cluster. CONCLUSIONS: The proposed equipment enables in vitro aggregated cell
      motility to be studied. This method can, therefore, be used in pharmacological
      studies in order to select anti-motility related compounds. The compounds
      selected by the equipment described could then be tested in vivo as potential
      anti-metastatic.

PMID- 10331622
TI  - Standardisation of DNA quantitation by image analysis: quality control of
      instrumentation.
AB  - BACKGROUND: DNA image analysis is frequently performed in clinical practice as a
      prognostic tool and to improve diagnosis. The precision of prognosis and
      diagnosis depends on the accuracy of analysis and particularly on the quality of
      image analysis systems. It has been reported that image analysis systems used for
      DNA quantification differ widely in their characteristics (Thunissen et al.:
      Cytometry 27: 21-25, 1997). This induces inter-laboratory variations when the
      same sample is analysed in different laboratories. In microscopic image analysis,
      the principal instrumentation errors arise from the optical and electronic parts
      of systems. They bring about problems of instability, non-linearity, and shading
      and glare phenomena. METHODS: The aim of this study is to establish tools and
      standardised quality control procedures for microscopic image analysis systems.
      Specific reference standard slides have been developed to control instability,
      non-linearity, shading and glare phenomena and segmentation efficiency. RESULTS:
      Some systems have been controlled with these tools and these quality control
      procedures. Interpretation criteria and accuracy limits of these quality control
      procedures are proposed according to the conclusions of a European project called
      PRESS project (Prototype Reference Standard Slide). Beyond these limits, tested
      image analysis systems are not qualified to realise precise DNA analysis.
      CONCLUSIONS: The different procedures presented in this work determine if an
      image analysis system is qualified to deliver sufficiently precise DNA
      measurements for cancer case analysis. If the controlled systems are beyond the
      defined limits, some recommendations are given to find a solution to the problem.

PMID- 10331623
TI  - Artificial neural network-aided image analysis system for cell counting.
AB  - BACKGROUND: In histological preparations containing debris and synthetic
      materials, it is difficult to automate cell counting using standard image
      analysis tools, i.e., systems that rely on boundary contours, histogram
      thresholding, etc. In an attempt to mimic manual cell recognition, an automated
      cell counter was constructed using a combination of artificial intelligence and
      standard image analysis methods. METHODS: Artificial neural network (ANN) methods
      were applied on digitized microscopy fields without pre-ANN feature extraction. A
      three-layer feed-forward network with extensive weight sharing in the first
      hidden layer was employed and trained on 1,830 examples using the error back
      propagation algorithm on a Power Macintosh 7300/180 desktop computer. The optimal
      number of hidden neurons was determined and the trained system was validated by
      comparison with blinded human counts. System performance at 50x and lO0x
      magnification was evaluated. RESULTS: The correlation index at 100x magnification
      neared person-to-person variability, while 50x magnification was not useful. The
      system was approximately six times faster than an experienced human. CONCLUSIONS:
      ANN-based automated cell counting in noisy histological preparations is feasible.
      Consistent histology and computer power are crucial for system performance. The
      system provides several benefits, such as speed of analysis and consistency, and
      frees up personnel for other tasks.

PMID- 10331624
TI  - Surface antigen detection with non-fluorescent, antibody-coated microbeads: an
      alternative method compatible with conventional fluorochrome-based labeling.
AB  - BACKGROUND: Our goal was to devise a new labeling technique allowing the flow
      cytometric detection of an additional cell surface marker without the need for a
      supplementary fluorochrome. METHODS: Non-fluorescent polystyrene latex microbeads
      (0.1 or 0.5 microm in diameter) were coated with monoclonal antibodies (mAbs) by
      adsorption. Upon binding to their specific antigen on the surface of the cell,
      mAb-coated beads induced a dramatic shift in the side scatter channel (SSC),
      resulting in a well-defined cell population. RESULTS: We show that expression of
      CD4 on murine peripheral lymphocytes, labeled with anti-CD4 mAb-coated beads, can
      be readily detected through an amplification of the SSC signal. Simultaneous
      labeling of lymphocytes with phycoerythrin- (PE)-conjugated anti-CD4 mAb and anti
      CD4 mAb-coated beads, showed that all PE+ cells were SSChigh, thus establishing
      the specificity of the technique. Hence, we have demonstrated that staining with
      mAb-coated beads could be combined to conventional labeling methods with
      fluorochrome-conjugated mAbs. Using a standard 488 nm single laser cytometer, we
      have performed a five-parameter analysis, simultaneously detecting fluorescein
      isothiocyanate (FITC), PE, RED670 and RED613, in combination with SSC signal
      modulation induced by mAb-coated beads. Moreover, we have shown that beads coated
      with mAbs directed against various antigens (CD45R, Mac-1, and TCRbeta) can be
      used on various tissues, namely lymph nodes, spleen, or bone marrow. CONCLUSIONS:
      mAb-coated latex beads can therefore easily be used as an additional surface
      label, and provide a simple and reliable mean to upgrade the analysis
      capabilities of standard flow cytometry units.

PMID- 10331625
TI  - Nine color eleven parameter immunophenotyping using three laser flow cytometry.
AB  - BACKGROUND: This study describes a three laser flow cytometer, reagents, and
      software used to simultaneously evaluate nine distinct fluorescent parameters on
      one cell sample. We compare the quality of data obtained with (1) full software
      compensation and (2) the use of partial spectral compensation of selected pairs
      of parameters in analog hardware, in combination with final software
      compensation. An application characterizing low frequency murine B cell
      subpopulations is given. METHODS: The fluorochromes used are: fluorescein (FITC),
      phycoerythrin (PE), Cy5PE and Cy7PE, excited at 488 nm by an argon laser; Texas
      Red (TR), allophycocyanin (APC), and Cy7APC excited at 595 nm by a pumped dye
      laser; and cascade blue (CB) and cascade yellow (CY) excited at 407 nm by a
      violet-enhanced krypton laser. Custom additions to commercial electronics and an
      extended optical bench allow the measurement of these nine parameters plus
      forward and side scatter light signals. RESULTS: We find the use of partial
      analog compensation reduces the variation in the background staining levels
      introduced by the compensation process. Novel B cell populations with frequencies
      below 1% are characterized. CONCLUSIONS: Nine color flow cytometry is capable of
      providing measurements with high information content. The choice of reagent-dye
      combinations and the ability to compensate in multi-parameter measurement space
      are crucial to obtaining satisfactory results.

PMID- 10331626
TI  - Detection of anti-phosphatidylethanolamine antibodies using flow cytometry.
AB  - BACKGROUND: The finding that lupus anticoagulant (LA) is significantly associated
      with anti-phosphatidylethanolamine (PE) activity has led to great interest in its
      relation to the clinical features of the antiphospholipid syndrome (APS).
      Considerable variability has, however, been reported in the prevalence of anti-PE
      antibodies in APS patients using enzyme-linked immunosorbent assay (ELISA)
      methodology. The lack of standardization and differences in technique may in part
      explain these discrepancies. PE binds variably to different types of microtiter
      wells, reflected in the consequent detection, or lack of detection, of anti-PE
      antibodies. This study describes the use of flow cytometry as an alternative
      method for the detection of anti-PE antibodies. METHODS: Six LA-positive plasma
      samples were used in this original study. Polystyrene beads were coated with PE
      overnight. These were subsequently incubated with patient plasma. Both IgG and
      IgM binding were detected by flow cytometry using a cocktail of fluorescently
      labelled anti-human Ig isotypes. RESULTS: When these results were compared with
      those from ELISA, flow cytometric analysis provided an apparent enhanced
      detection of anti-PE antibodies. It was found that 6/6 were IgM anti-PE positive
      by flow cytometry, whereas 5/6 were IgM by ELISA; 2/6 negative for anti
      cardiolipin antibodies by ELISA were positive by flow cytometry; and 2/6 positive
      for antiphosphatidylcholine antibodies in cytometry were negative by ELISA.
      CONCLUSIONS: With appropriate quantification, this method may be more sensitive
      than ELISA in detecting anti-PE antibodies in plasma samples of patients with
      APS.

PMID- 10331627
TI  - Flow cytometric assessment of LDL receptor activity in peripheral blood
      mononuclear cells compared to gene mutation detection in diagnosis of
      heterozygous familial hypercholesterolemia.
AB  - BACKGROUND: Studies indicate that human peripheral blood mononuclear cells mirror
      low-density lipoprotein (LDL) receptor activity of other cells in the body. To
      measure LDL receptor activity in patients with heterozygous familial
      hypercholesterolemia (FH), we prepared peripheral blood mononuclear cells from
      individuals with molecularly verified LDL receptor defective (Trp66-Gly mutation,
      n = 18) or receptor negative (Trp23-stop mutation, n = 17) heterozygous FH and
      from healthy individuals (n = 24). METHODS: The cells were stimulated to express
      maximum LDL receptor by preincubation in lipoprotein-free medium. They were then
      incubated at 4 degrees or 37 degrees C with fluorescently conjugated LDL (DiI
      LDL). T-lymphocytes and monocytes were identified by fluorescently conjugated
      monoclonal antibodies. DiI-LDL bound (at 4 degrees C) or internalized (at 37
      degrees C) by the cells was measured using flow cytometry. Knowing the LDL
      receptor gene mutation of the FH patients allowed us to compare the diagnostic
      capability of our functional assay with the DNA diagnosis. RESULTS: The
      diagnostic accuracy did not allow our assay to be used for diagnosis of
      individual cases of heterozygous FH. CONCLUSIONS: We suggest that our two-color
      fluorescence flow cytometry assay can be used to characterize functionally gene
      mutations causing LDL receptor dysfunction in patients with heterozygous FH.

PMID- 10331628
TI  - Some theoretical and practical considerations for multivariate statistical cell
      classification useful in autologous stem cell transplantation and tumor cell
      purging.
AB  - BACKGROUND: As flow cytometric data becomes more complex, it becomes increasingly
      difficult to classify cells using conventional flow cytometry data techniques
      based on visual classification of the data by user-drawn regions. This paper
      shows some simple applications of multivariate statistical classification to
      classify flow cytometric data. METHODS: Discriminant Function Analysis (DFA) and
      Logistic Regression (LR) analysis techniques were evaluated with respect to their
      potential utility in the problem of detecting human breast cancer cells within
      normal bone marrow cells. Data sets having defined properties were employed to
      evaluate the potential utility of these statistical classification techniques
      whose performance was measured by ROC analysis. RESULTS: Two extreme but
      reasonable situations are presented: (1) data where the separation of cells was
      obvious by visual inspection and (2) data where major overlaps in the values of
      the individual FCM parameters made intuitive classification improbable. Both DFA
      and LR analysis were able to classify the cells of each type with acceptable
      accuracy and yield. CONCLUSIONS: The excellent empirical performance of both DFA
      and LR techniques, suggests that they offer promising approaches for classifying
      multiparameter FCM data using objective rules that may represent an improvement
      over commonly employed ad hoc approaches.

PMID- 10331629
TI  - Detection of residual aneuploid leukemic cells by "continuous gating".
AB  - BACKGROUND: A new method for the detection of residual aneuploid leukemic cells
      in bone marrow by flow cytometry is described. This method is based on the
      analysis of FCM derived list-mode-datasets with a new software called "Continuous
      Gating". The program is able to decrease the detection level of aneuploid tumor
      cells by analyzing groups of cells with comparable antigen density and scatter
      properties. METHODS: Aneuploid acute lymphocytic leukemia cells with a known CD34
      expression were diluted with diploid bone marrow cells to a concentration of 10,
      1, 0.1, 0.05, and 0.01%. Each sample was measured in a FACScan flow cytometer,
      after staining with CD34 Moab and propidium iodide. Listmode-data were analyzed
      with the new "Windows"-based "Continuous Gating" software. A gate was set in the
      DNA parameter, defining the channels in which the aneuploid G0/G1-peak of
      possible residual tumor-cells should be found. Ten thousand overlapping gates of
      size 200 x 200 channels (out of 1,023 x 1,023 channels) were set automatically by
      the program into the side-scatter (SSC)/CD34 dot-plot, calculating the percentage
      of aneuploid G0/G1-phase cells for every specific gate. RESULTS: The results are
      plotted in a contour-plot. In dot-plot gates with less than 20 cells, the
      calculation of the percentage of aneuploid cells was declared invalid and the
      area in the contour-plot was marked. Detection of residual aneuploid cells, based
      on a defined expression of CD34 and granularity (SSC), was possible down to a
      contamination of 0.1%. CONCLUSIONS: The new "Continuous Gating" software can be
      used for the automated detection of aneuploid leukemic cells, if the density of a
      certain surface-marker is slightly different from normal cells.

PMID- 10331630
TI  - High affinity binding of fluorescein isothiocyanate to eosinophils detected by
      laser scanning cytometry: a potential source of error in analysis of blood
      samples utilizing fluorescein-conjugated reagents in flow cytometry.
AB  - BACKGROUND: In samples of peripheral blood cells processed using the commercial
      kits for detection of apoptosis based on DNA strand break labeling, a
      subpopulation of cells characterized by high green fluorescence, similar in
      intensity to that of apoptotic cells but more uniform, was consistently observed
      by flow cytometry. The labeled cells had no other features of apoptosis. The
      labeling was observed regardless of the fixative used and was evident in control
      samples lacking terminal deoxynucleotidyltransferase. Common to all the kits that
      generated this labeling pattern was the presence of fluorescein (f) conjugated
      reagents, f-dUTP, f-avidin, or f-antibody. METHODS: Laser scanning cytometry was
      used to identify the labeled cells and study the mechanism of labeling. Because
      it was suspected that the traces of unconjugated f-isothiocyanate (FITC) that may
      contaminate the reagents were responsible for the labeling, FITC binding affinity
      to white blood cells was studied. Gel electrophoresis was used to detect the
      presence of unconjugated FITC in the reagents. RESULTS: After staining with
      Giemsa, the strongly fluorescent objects were identified as eosinophils with
      normal morphology and no evidence of apoptosis. The fluorescence was localized
      exclusively within the cytoplasmic granules. Labeling of eosinophils was observed
      at 2 nM concentration of FITC, which was over three orders of magnitude lower
      than that needed to label neutrophils, monocytes, or lymphocytes. Gel
      electrophoresis of the f-conjugated reagents revealed only minor contamination
      with FITC. CONCLUSIONS: (1) Trace amounts of unconjugated FITC contaminating the
      reagents are adequate to strongly label eosinophils thereby introducing
      experimental bias in analysis of apoptosis and in other studies on blood cells
      utilizing f-labeled antibodies, e.g., in detecting cytokines. (2) FITC at
      concentration 2-500 nM can be used as a marker of eosinophiles; (3) Because of
      high affinity to FITC, eosinophiles (or the protein from these cells) may serve
      as a means of removing traces of unconjugated FITC from the reagents during their
      manufacture or prior to use.

PMID- 10331631
TI  - Poly ADP-ribosylation: a DNA break signal mechanism.
AB  - Recent evidence obtained with transgenic knockout mice suggests that the enzyme
      poly(ADP-ribose)polymerase (PARP) does not play a direct role in DNA break
      processing. Nevertheless, inactivation of the catalytic or the DNA nick-binding
      functions of PARP affects cellular responses to genotoxins at the level of cell
      survival, sister chromatid exchanges and apoptosis. In the present report, we
      conceptualize the idea that PARP is part of a DNA break signal mechanism. In
      vitro screening studies revealed the existence of a protein family containing a
      polymer-binding motif of about 22 amino acids. This motif is present in p53
      protein as well as in MARCKS, a protein involved in the regulation of the actin
      cytoskeleton. Biochemical analyses showed that these sequences are directly
      targeted by PARP-associated polymers in vitro, and this alters several molecular
      functions of p53- and MARCKS protein. PARP-deficient knockout mice from
      transgenic mice were found to exhibit several phenotypic features compatible with
      altered DNA damage signaling, such as downregulation and lack of responsiveness
      of p53 protein to genotoxins, and morphological changes compatible with MARCKS
      related cytoskeletal dysfunction. The knockout phenotype could be rescued by
      stable expression of the PARP gene. We propose that PARP-associated polymers may
      recruit signal proteins to sites of DNA breakage and reprogram their functions.

PMID- 10331632
TI  - Measurement of poly(ADP-ribose) glycohydrolase activity by high resolution
      polyacrylamide gel electrophoresis: specific inhibition by histones and nuclear
      matrix proteins.
AB  - We have developed a novel enzyme assay that allows the simultaneous determination
      of noncovalent interactions of poly(ADP-ribose) with nuclear proteins as well as
      poly(ADP-ribose) glycohydrolase (PARG) activity by high resolution polyacrylamide
      gel electrophoresis. ADP-ribose chains between 2 and 70 residues in size were
      enzymatically synthesized with pure poly(ADP-ribose) polymerase (PARP) and were
      purified by affinity chromatography on a boronate resin following alkaline
      release from protein. This preparation of polymers of ADP-ribose was used as the
      enzyme substrate for purified PARG. We also obtained the nuclear matrix fraction
      from rat liver nuclei and measured the enzyme activity of purified PARG in the
      presence or absence of either histone proteins or nuclear matrix proteins. Both
      resulted in a marked inhibition of PARG activity as determined by the decrease in
      the formation of monomeric ADP-ribose. The inhibition of PARG was presumably due
      to the non-covalent interactions of these proteins with free ADP-ribose polymers.
      Thus, the presence of histone and nuclear matrix proteins should be taken into
      consideration when measuring PARG activity.

PMID- 10331633
TI  - Regulatory mechanisms of poly(ADP-ribose) polymerase.
AB  - Here, we describe the latest developments on the mechanistic characterization of
      poly(ADP-ribose) polymerase (PARP) [EC 2.4.2.30], a DNA-dependent enzyme that
      catalyzes the synthesis of protein-bound ADP-ribose polymers in eucaryotic
      chromatin. A detailed kinetic analysis of the automodification reaction of PARP
      in the presence of nicked dsDNA indicates that protein-poly(ADP-ribosyl)ation
      probably occurs via a sequential mechanism since enzyme-bound ADP-ribose chains
      are not reaction intermediates. The multiple enzymatic activities catalyzed by
      PARP (initiation, elongation, branching and self-modification) are the subject of
      a very complex regulatory mechanism that may involve allosterism. For instance,
      while the NAD+ concentration determines the average ADP-ribose polymer size
      (polymerization reaction), the frequency of DNA strand breaks determines the
      total number of ADP-ribose chains synthesized (initiation reaction). A general
      discussion of some of the mechanisms that regulate these multiple catalytic
      activities of PARP is presented below.

PMID- 10331634
TI  - Poly(ADP-ribose) polymerase: a guardian of the genome that facilitates DNA repair
      by protecting against DNA recombination.
AB  - We have studied the clonogenic survival response to X-rays and MNNG of V79
      Chinese hamster cells and two derivative cell lines, ADPRT54 and ADPRT351,
      deficient in poly(ADP-ribose) polymerase (PARP) activity. Under conditions of
      exponential growth, both PARP-deficient cell lines are hypersensitive to X-rays
      and MNNG compared to their parental V79 cells. In contrast, under growth
      arrested, confluent conditions, V79 and PARP-deficient cells become similarly
      sensitive to X-rays and MNNG suggesting that PARP may be involved in the repair
      of X-ray or MNNG-induced DNA damage in logarithmically growing cells but not in
      growth-arrested confluent cells. This suggestion, however, creates a dilemma as
      to how PARP can be involved in DNA repair in only selected growth phases while it
      is functionally active in all growth phases. To explain these paradoxical results
      and resolve this dilemma we propose a hypothesis based on the consistent
      observation that inhibition of PARP results in a significant increase in sister
      chromatid exchange (SCEs). Thus, we propose that PARP is a guardian of the genome
      that protects against DNA recombination. We have extended this theme to provide
      an explanation for our results and the studies done by many others.

PMID- 10331635
TI  - Trans-dominant inhibition of poly(ADP-ribosyl)ation potentiates alkylation
      induced shuttle-vector mutagenesis in Chinese hamster cells.
AB  - In most eukaryotic cells, the catalytic activation of poly(ADP-ribose) polymerase
      (PARP) represents one of the earliest cellular responses to the infliction of DNA
      damage. To study the biological function(s) of poly(ADP-ribosyl)ation, we have
      established stable transfectants (COM3 cells) of the SV40-transformed Chinese
      hamster cell line C060 which conditionally overexpress the PARP DNA-binding
      domain upon addition of dexamethasone. We could demonstrate that DNA-binding
      domain overexpression, which leads to trans-dominant inhibition of poly(ADP
      ribosyl)ation, potentiates the cytotoxicity of alkylation treatment and of gamma
      radiation. Likewise, carcinogen-induced gene amplification, viewed as a
      manifestation of genomic instability, was potentiated by the overexpression of
      the PARP DNA-binding domain. Recently, we studied the effect of trans-dominant
      PARP inhibition on mutagenesis by employing a shuttle-vector assay in which
      mutagen-exposed plasmid pYZ289 is electroporated into COM3 cells. We could show
      that dexamethasone-induced overexpression of the PARP DNA-binding domain in COM3
      cells potentiates the mutagenicity of the alkylating agent N-methyl-N
      nitrosourea, while no effect of dexamethasone treatment on mutation frequency was
      recorded in control cells lacking the PARP DNA-binding domain transgene. Taken
      together, our results further substantiate the role of poly(ADP-ribosyl)ation in
      the maintenance of genomic integrity and stability under conditions of genotoxic
      stress.

PMID- 10331636
TI  - Clostridial toxins: molecular probes of Rho-dependent signaling and apoptosis.
AB  - The Rho family small GTPases are members of the Ras superfamily of small GTPases.
      Rho proteins were first determined to act as key regulators of many types of
      actin cytoskeletal-dependent cellular functions. Recent work by several
      investigators indicates that Rho GTPases are also critical modulators of several
      important intracellular and nuclear signal transduction pathways. Certain
      clostridial toxins and exoenzymes covalently modify, and thereby inactivate,
      specific types of Rho family GTPases. As such, these microbial enzymes have
      proven invaluable in helping to identify structural and functional attributes of
      Rho GTPases.

PMID- 10331637
TI  - Role of brefeldin A-dependent ADP-ribosylation in the control of intracellular
      membrane transport.
AB  - The fungal toxin brefeldin A (BFA) dissociates coat proteins from Golgi
      membranes, causes the rapid disassembly of the Golgi complex and potently
      stimulates the ADP-ribosylation of two cytosolic proteins of 38 and 50 kDa. These
      proteins have been identified as the glycolytic enzyme glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH) and a novel guanine nucleotide binding protein (BARS-50),
      respectively. The role of ADP-ribosylation in mediating the effects of BFA on the
      structure and function of the Golgi complex was analyzed by several approaches
      including the use of selective pharmacological blockers of the reaction and the
      use of ADP-ribosylated cytosol and/or enriched preparations of the BFA-induced
      ADP-ribosylation substrates, GAPDH and BARS-50. A series of blockers of the BFA
      dependent ADP-ribosylation reaction identified in our laboratory inhibited the
      effects of BFA on Golgi morphology and, with similar potency, the ADP
      ribosylation of BARS-50 and GAPDH. In permeabilized RBL cells, the BFA-dependent
      disassembly of the Golgi complex required NAD+ and cytosol. Cytosol that had been
      previously ADP-ribosylated (namely, it contained ADP-ribosylated GAPDH and BARS
      50), was instead sufficient to sustain the Golgi disassembly induced by BFA.
      Taken together, these results indicate that an ADP-ribosylation reaction is part
      of the mechanism of action of BFA and it might intervene in the control of the
      structure and function of the Golgi complex.

PMID- 10331638
TI  - A dual approach in the study of poly (ADP-ribose) polymerase: in vitro random
      mutagenesis and generation of deficient mice.
AB  - A dual approach to the study of poly (ADP-ribose)polymerase (PARP) in terms of
      its structure and function has been developed in our laboratory. Random
      mutagenesis of the DNA binding domain and catalytic domain of the human PARP, has
      allowed us to identify residues that are crucial for its enzymatic activity. In
      parallel PARP knock-out mice were generated by inactivation of both alleles by
      gene targeting. We showed that: (i) they are exquisitely sensitive to gamma
      irradiation, (ii) they died rapidly from acute radiation toxicity to the small
      intestine, (iii) they displayed a high genomic instability to gamma-irradiation
      and MNU injection and, (iv) bone marrow cells rapidly underwent apoptosis
      following MNU treatment, demonstrating that PARP is a survival factor playing an
      essential and positive role during DNA damage recovery and survival.

PMID- 10331640
TI  - Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis.
AB  - Studies presented here show that cellular NAD, which we hypothesize to be the
      relevant biomarker of niacin status, is significantly lower in humans than in the
      commonly studied animal models of carcinogenesis. We show that nicotinamide and
      the resulting cellular NAD concentration modulate expression of the tumor
      suppressor protein, p53, in human breast, skin, and lung cells. Studies to
      determine the optimal NAD concentrations for responding to DNA damage in breast
      epithelial cells reveal that DNA damage appears to stimulate NAD biosynthesis and
      that recovery from DNA damage occurs several hours earlier in the presence of
      higher NAD or in cells undergoing active NAD biosynthesis. Finally, analyses of
      normal human skin tissue from individuals diagnosed with actinic keratoses or
      squamous cell carcinomas show that NAD content of the skin is inversely
      correlated with the malignant phenotype. Since NAD is important in modulating ADP
      ribose polymer metabolism, cyclic ADP-ribose synthesis, and stress response
      proteins, such as p53, following DNA damage, understanding how NAD metabolism is
      regulated in the human has important implications in developing both prevention
      and treatment strategies in carcinogenesis.

PMID- 10331641
TI  - Molecular heterogeneity and regulation of poly(ADP-ribose) glycohydrolase.
AB  - We have recently described the isolation and characterization of bovine cDNA
      encoding poly(ADP-ribose) glycohydrolase (PARG). We describe here the preparation
      and characterization of antibodies to PARG. These antibodies have been used to
      demonstrate the presence of multiple forms of PARG in tissue and cell extracts
      from bovine, rat, mouse, and insects. Our results indicate that multiple forms of
      PARG previously reported could result from a single gene. Analysis of PARG in
      cells in which poly(ADP-ribose) polymerase (PARP) has been genetically
      inactivated indicates that the cellular content of PARG is regulated
      independently of PARP.

PMID- 10331639
TI  - The RT6 (Art2) family of ADP-ribosyltransferases in rat and mouse.
AB  - Recent evidence suggests that a new member of the mono-ADP-ribosyltransferase/NAD
      glycohydrolase family, RT6, may be important in immune regulation. RT6 is
      expressed in two allelic forms and is present on post-thymic T cells in the rat.
      RT6-expressing T cells in the rat may have a regulatory role, a conclusion based
      on their ability to prevent autoimmune diabetes in the BB rat model of insulin
      dependent diabetes mellitus. This observation led to investigation of RT6 at a
      molecular and biochemical level resulting in the determination that RT6 protein
      exists as both glycosylated and non-glycosylated glycosylphosphatidylinositol
      (GPI)-linked cell surface molecules. RT6, like many GPI-linked proteins, can
      mediate cell signal transduction events associated with T cell activation, and is
      also present in a soluble form in the circulation. The discovery that RT6 is an
      NAD glycohydrolase and auto-ADP-ribosyltransferase led to the ongoing
      investigations into the role that enzymatic activity may have in the
      immunoregulatory function of rat RT6+ T cells. A homologue of rat RT6, termed
      Rt6, has been identified in the mouse. Rt6 is predominately an ADP
      ribosyltransferase enzyme as determined using simple guanidino compounds (e.g.
      arginine) as ribose acceptors. Abnormalities in mouse Rt6 mRNA are associated
      with the expression of autoimmunity. In the present manuscript, we review recent
      data on RT6/Rt6, and discuss the potential mechanisms by which RT6-expressing
      cells, and perhaps RT6 protein itself, may mediate immune regulation.

PMID- 10331642
TI  - Niacin deficiency increases the sensitivity of rats to the short and long term
      effects of ethylnitrosourea treatment.
AB  - Most chemotherapy agents function by causing damage to the DNA of rapidly
      dividing cells, such as those in the bone marrow, leading to anemia and
      leukopenia during chemotherapy and the development of secondary leukemias in the
      years following recovery from the original disease. We created an animal model of
      nitrosourea-based chemotherapy using ethylnitrosourea (ENU) to investigate the
      effect of niacin deficiency on the side effects of chemotherapy. Weanling Long
      Evans rats were fed diets containing various levels of niacin for a period of 4
      weeks. ENU treatment started after 1 week of feeding and consisted of 12 doses
      delivered by gavage, every other day. Cancer incidence was also monitored in the
      following months. ENU treatment caused many of the acute symptoms seen in human
      chemotherapy patients, including anemia and neutropenia. Niacin deficiency (ND)
      had several interesting effects, alone and in combination with ENU. Niacin
      deficiency alone caused a modest anemia, while in combination with ENU it induced
      a severe anemia. Niacin deficiency alone caused a 4-fold increase in circulating
      neutrophil numbers, and this population was drastically reduced by ENU-treatment.
      In the long term, macin deficiency caused an increased incidence of cancer,
      especially chronic granulocytic leukemias.

PMID- 10331644
TI  - Identification of the archaeal NMN adenylytransferase gene.
AB  - Increasing evidence on the importance of fluctuations in NAD+ levels in the
      living cell is accumulating. Therefore a deeper knowledge on the regulation of
      coenzyme synthesis and recycling is required. In this context the study of NMN
      adenylyltransferase (EC 2.7.7.1),. a key enzyme in the NAD+ biosynthetic pathway,
      assumes a remarkable relevance. We have previously purified to homogeneity and
      characterized the protein from the thermophilic archaeon Sulfolobus solfataricus.
      The determination of partial sequence of the S. solfataricus enzyme, together
      with the recent availability of the genome sequence of the archaeon Methanococcus
      jannaschii, allowed us, based on sequence similarity, to identify the M.
      jannaschii NMN adenylyltransferase gene. As far as we know from literature, this
      is the first report on the NMN adenylyltransferase gene.

PMID- 10331645
TI  - Functional analysis of poly(ADP-ribose) polymerase in Drosophila melanogaster.
AB  - Poly(ADP-ribose) polymerase (PARP) is conserved in eukaryotes. To analyze the
      function of PARP, we isolated and characterized the gene for PARP in Drosophila
      melanogaster. The PARP gene consisted of six translatable exons and spanned more
      than 50 kb. The DNA binding domain is encoded by exons 1-4. Although the
      consensus cleavage site of CED-3 like protease during apoptosis is conserved from
      human to Xenopus laevis PARPs, it is neither conserved in the corresponding
      region of Drosophila nor Sarcophaga peregrina. There are two cDNAs species in
      Drosophila. One cDNA could encode the full length PARP protein (PARP I), while
      the other is a truncated cDNA which could encode a partial-length PARP protein
      (PARP II), which lacks the automodification domain and is possibly produced by
      alternative splicing. The expression of these two forms of PARP in E. coli
      demonstrated that while PARP II has the catalytic NAD-binding domain and DNA
      binding domain it is enzymatically inactive. On the other hand PARP I is active.
      A deletion mutant of PARP gene could grow to the end of embryogenesis but did not
      grow to the adult fly. These results suggest that the PARP gene plays an
      important function during the development of Drosophila.

PMID- 10331643
TI  - Structures and activities of cyclic ADP-ribose, NAADP and their metabolic
      enzymes.
AB  - ADP-ribosyl cyclase and CD38 are multi-functional enzymes involved in calcium
      signaling. Both can cyclize NAD and its guanine analog, NGD, at two different
      sites of the purine ring, N1 and N7, respectively, to produce cyclic ADP-ribose
      (cADPR) and cyclic GDP-ribose, a fluorescent but inactive analog. Both enzymes
      can also catalyze the exchange of the nicotinamide group of NADP with nicotinic
      acid, producing yet another potent activator of Ca2+ mobilization, nicotinic acid
      adenine dinucleotide phosphate (NAADP). The Ca2+ release mechanism activated by
      NAADP is totally independent of cADPR and inositol trisphosphate indicating it is
      a novel and hitherto unknown Ca2+ signaling pathway. This article summarizes the
      current results on the structures and activities of cADPR, NAADP and the enzymes
      that catalyze their syntheses. A comprehensive model accounting for the novel
      multi-functionality of ADP-ribosyl cyclase and CD38 is presented.

PMID- 10331646
TI  - Characterization of NAD:arginine ADP-ribosyltransferases.
AB  - NAD:arginine mono-ADP-ribosyltransferases catalyze the transfer of ADP-ribose
      from NAD to the guanidino group of arginine on a target protein. Deduced amino
      acid sequences of one family (ART1) of mammalian ADP-ribosyltransferases, cloned
      from muscle and lymphocytes, show hydrophobic amino and carboxyl termini
      consistent with glycosylphosphatidylinositol (GPI)-anchored proteins. The
      proteins, overexpressed in mammalian cells transfected with the transferase
      cDNAs, are released from the cell surface with phosphatidylinositol-specific
      phospholipase C (PI-PLC), and display immunological and biochemical
      characteristics consistent with a cell surface, GPI-anchored protein. In
      contrast, the deduced amino acid sequence of a second family (ART5) of
      transferases, cloned from murine lymphoma cells and expressed in high abundance
      in testis, displays a hydrophobic amino terminus, consistent with a signal
      sequence, but lacks a hydrophobic signal sequence at its carboxyl terminus,
      suggesting that the protein is destined for export. Consistent with the surface
      localization of the GPI-linked transferases, multiple surface substrates have
      been identified in myotubes and activated lymphocytes, and, notably, include
      integrin alpha subunits. Similar to the bacterial toxin ADP-ribosyltransferases,
      the mammalian transferases contain the characteristic domains involved in NAD
      binding and ADP-ribose transfer, including a highly acidic region near the
      carboxy terminus, which, when disrupted by in vitro mutagenesis, results in a
      loss of enzymatic activity. The carboxyl half of the protein, synthesized as a
      fusion protein in E. coli, possessed NADase, but not ADP-ribosyltransferase
      activity. These findings are consistent with the existence at the carboxyl
      terminus of ART1 of a catalytically active domain, capable of hydrolyzing NAD,
      but not of transferring ADP-ribose to a guanidino acceptor.

PMID- 10331647
TI  - The CD38-cyclic ADP-ribose signaling system in insulin secretion.
AB  - Glucose induces an increase in the intracellular Ca2+ concentration in pancreatic
      beta-cells to secrete insulin. CD38 occurs in beta-cells and has both ADP-ribosyl
      cyclase, which catalyzes the formation of cyclic ADP-ribose (cADPR) from NAD+,
      and cADPR hydrolase, which converts cADPR to ADP-ribose. ATP, produced by glucose
      metabolism, competes with cADPR for the binding site, Lys-129, of CD38, resulting
      in the inhibition of the hydrolysis of cADPR and thereby causing cADPR
      accumulation in beta-cells. Cyclic ADP-ribose then binds to FK506-binding protein
      12.6 in the ryanodine receptor Ca2+ channel (RyR), dissociating the binding
      protein from RyR to induce the release of Ca2+ from the endoplasmic reticulum.
      Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) phosphorylates RyR to
      sensitize and activate the Ca2+ channel. Ca2+, released from the RyR, further
      activates CaM kinase II and amplifies the process. Thus, cADPR acts as a second
      messenger for Ca2+ mobilization to secrete insulin. The novel mechanism of
      insulin secretion described above is different from the conventional hypothesis
      in which Ca2+ influx from extracellular sources plays a role in insulin secretion
      by glucose.

PMID- 10331648
TI  - Newly discovered anti-inflammatory properties of the benzamides and
      nicotinamides.
AB  - Our laboratory has concentrated on the possible regulation the benzamides and
      nicotinamides may have on the processes of DNA repair and apoptosis. Recent
      reports have suggested that both apoptosis and inflammation are regulated by the
      transcription factor NF-kappaB. We have initiated studies regarding the
      hypothesis that the benzamides and nicotinamides could inhibit the production of
      tumor necrosis factor alpha (TNFalpha) and the inflammatory response as well as
      induce apoptosis via inhibition of NF-kappaB. Our data have shown that
      nicotinamide and two N-substituted benzamides, metoclopramide (MCA) and 3
      chloroprocainamide (3-CPA), gave dose dependent inhibition of lipopolysacharide
      induced TNFalpha in the mouse within the dose range of 10-500 mg/kg. Moreover,
      lung edema was prevented in the rat by 3 x 50 mg/kg doses of 3-CPA or MCA, and
      100-200 microM doses of MCA could also inhibit NF-kappaB in Hela cells. Taken
      together these data strongly support the notion that benzamides and nicotinamides
      have potent anti-inflammatory and antitumor properties, because their primary
      mechanism of action is regulated by inhibition at the gene transcription level of
      NF-kappaB, which in turn inhibits TNFalpha and induces apoptosis.

PMID- 10331649
TI  - Poly(ADP-ribose) turnover in quail myoblast cells: relation between the polymer
      level and its catabolism by glycohydrolase.
AB  - The concerted action of poly(ADP-ribose) polymerase (PARP) which synthesizes the
      poly(ADP-ribose) (pADPr) in response to DNA strand breaks and the catabolic
      enzyme poly(ADP-ribose) glycohydrolase (PARG) determine the level of polymer and
      the rate of its turnover. In the present study, we have shown that the quail
      myoblast cells have high levels of basal polymer as compared to the murine
      C3H10T1/2 fibroblasts. We have conducted this study to investigate how such
      differences influence polymer synthesis and its catabolism in the cells in
      response to DNA damage by alkylating agent. In quail myoblast cells, the presence
      of high MNNG concentration such as 200 microM for 30 min induced a marginal
      decrease of 15% in the NAD content. For C3H10T1/2 cell line, 64 microM MNNG
      provoked a depletion of NAD content by approximately 50%. The induction of the
      polymer synthesis in response to MNNG treatment was 6-fold higher in C3H10T1/2
      cells than in quail myoblast cells notwithstanding the fact that 3-fold higher
      MNNG concentration was used for quail cells. The polymer synthesis thus induced
      in quail myoblast cells had a 4-5 fold longer half life than those induced in
      C3H10T1/2 cells. To account for the slow turnover of the polymer in the quail
      myoblast cells, we compared the activities of the polymer catabolizing enzyme
      (PARG) in the two cell types. The quail myoblast cells had about 25% less
      activity of PARG than the murine cells. This difference in activity is not
      sufficient to explain the large difference of the rate of catabolism between the
      two cell types implicating other cellular mechanisms in the regulation of pADPr
      turnover.

PMID- 10331650
TI  - Involvement of PARP and poly(ADP-ribosyl)ation in the early stages of apoptosis
      and DNA replication.
AB  - We have focused on the roles of PARP and poly(ADP-ribosyl)ation early in
      apoptosis, as well as during the early stages of differentiation-linked DNA
      replication. In both nuclear processes, a transient burst of PAR synthesis and
      PARP expression occurs early, prior to internucleosomal DNA cleavage before
      commitment to apoptosis as well as at the round of DNA replication prior to the
      onset of terminal differentiation. In intact human osteosarcoma cells undergoing
      spontaneous apoptosis, both PARP and PAR decreased after this early peak,
      concomitant with the inactivation and cleavage of PARP by caspase-3 and the onset
      of substantial DNA and nuclear fragmentation. Whereas 3T3-L1, osteosarcoma cells,
      and immortalized PARP +/+ fibroblasts exhibited this early burst of PAR synthesis
      during Fas-mediated apoptosis, neither PARP-depleted 3T3-L1 PARP-antisense cells
      nor PARP -/- fibroblasts showed this response. Consequently, whereas control
      cells progressed into apoptosis, as indicated by induction of caspase-3-like PARP
      cleavage activity, PARP-antisense cells and PARP -/- fibroblasts did not,
      indicating a requirement for PARP and poly(ADP-ribosyl)ation of nuclear proteins
      at an early reversible stage of apoptosis. In parallel experiments, a transient
      increase in PARP expression and activity were also noted in 3T3-L1 preadipocytes
      24 h after induction of differentiation, a stage at which approximately 95% of
      the cells were in S-phase, but not in PARP-depleted antisense cells, which were
      consequently unable to complete the round of DNA replication required for
      differentiation. PARP, a component of the multiprotein DNA replication complex
      (MRC) that catalyzes viral DNA replication in vitro, poly(ADP-ribosyl)ates 15 of
      approximately 40 MRC proteins, including DNA pol alpha, DNA topo I, and PCNA.
      Depletion of endogenous PARP by antisense RNA expression in 3T3-L1 cells results
      in MRCs devoid of any DNA pol alpha and DNA pol delta activities. Surprisingly,
      there was no new expression of PCNA and DNA pol alpha, as well as the
      transcription factor E2F-1 in PARP-antisense cells during entry into S-phase,
      suggesting that PARP may play a role in the expression of these proteins, perhaps
      by interacting with a site in the promoters for these genes.

PMID- 10331651
TI  - Function of poly(ADP-ribose) polymerase in response to DNA damage: gene
      disruption study in mice.
AB  - To elucidate the biological functions of poly(ADP-ribose) polymerase (PARP, [EC
      2.4.2.30]) in DNA damage responses, genetic and biochemical approaches were
      undertaken. By disrupting exon 1 of the mouse PARP gene by a homologous
      recombination, PARP-deficient mouse embryonic stem (ES) cell lines and mice could
      be produced without demonstrating lethality. PARP-/- ES cells showed complete
      loss of PARP activity and increased sensitivity to gamma-irradiation and an
      alkylating agents, indicating a physiological role for PARP in the response to
      DNA damage. p53, a key molecule in cellular DNA damage response, was found to
      stimulate PARP activity and became poly(ADP-ribosyl)ated in the presence of
      damaged DNA. However, PARP-/- ES cells showed p21 and Mdm-2 mRNA induction
      following gamma-irradiation, indicating that PARP activity is not indispensable
      for p21 and Mdm-2 mRNA induction in the established p53-cascade. On the other
      hand, in a reconstituted reaction system, purified PARP from human placenta
      suppressed the pRB-phosphorylation activity in the presence of NAD and damaged
      DNA. Human PARP expressed in E. coli showed a similar effect on pRB
      phosphorylation activity of cdk2. These findings suggest a direct involvement of
      PARP in the regulation of cdk activity for cell-cycle arrest.

PMID- 10331652
TI  - Activation of toxin ADP-ribosyltransferases by eukaryotic ADP-ribosylation
      factors.
AB  - ADP-ribosylation factors (ARFs) are members of a multigene family of 20-kDa
      guanine nucleotide-binding proteins that are regulatory components in several
      pathways of intracellular vesicular trafficking. The relatively small
      (approximately 180-amino acids) ARF proteins interact with a variety of molecules
      (in addition to GTP/GDP, of course). Cholera toxin was the first to be
      recognized, hence the name. Later it was shown that ARF also activates
      phospholipase D. Different parts of the molecule are responsible for activation
      of the two enzymes. In vesicular trafficking, ARF must interact with coatomer to
      recruit it to a membrane and thereby initiate vesicle budding. ARF function
      requires that it alternate between GTP- and GDP-bound forms, which involves
      interaction with regulatory proteins. Inactivation of ARF-GTP depends on a GTPase
      activating protein or GAP. A guanine nucleotide-exchange protein or GEP
      accelerates release of bound GDP from inactive ARF-GDP to permit GTP binding.
      Inhibition of GEP by brefeldin A (BFA) blocks ARF activation and thereby
      vesicular transport. In cells, it causes apparent disintegration of Golgi
      structure. Both BFA-sensitive and insensitive GEPs are known. Sequences of
      peptides from a BFA-sensitive GEP purified in our laboratory revealed the
      presence of a Sec7 domain, a sequence of approximately 200 amino acids that
      resembles a region in the yeast Sec7 gene product, which is involved in Golgi
      vesicular transport. Other proteins of unknown function also contain Sec7
      domains, among them a lymphocyte protein called cytohesin-1. To determine whether
      it had GEP activity, recombinant cytohesin-1 was synthesized in E. coli. It
      preferentially activated class I ARFs 1 and 3 and was not inhibited by BFA but
      failed to activate ARF5 (class II). There are now five Sec7 domain proteins known
      to have GEP activity toward class I ARFs. It remains to be determined whether
      there are other Sec7 domain proteins that are GEPs for ARFs 4, 5, or 6.

PMID- 10331653
TI  - CD36 antisense expression in 3T3-F442A preadipocytes.
AB  - An adipocyte membrane glycoprotein, FAT, homologous to CD36, has been implicated
      in the binding/transport of long-chain fatty acids. FAT/CD36 was identified by
      reaction with reactive long chain fatty acids derivatives under conditions where
      they inhibited FA uptake. Expression of CD36 in fibroblasts lacking the protein
      led to induction of a saturable high affinity, phloretin-sensitive component of
      oleate uptake. In this report, we have examined the effects of FAT/CD36 antisense
      expression in 3T3-F442A preadipocyte cells, on FA uptake and cell
      differentiation. Cells were transfected with pSG5-TAF vector obtained by
      insertion of antisense coding sequence of FAT/CD36 into the BamH 1 site of pSG5.
      Four clones were selected based on expression of antisense CD36 mRNA. Levels of
      CD36 protein were determined by flow cytometry and correlated with rates of
      oleate uptake. Three clones, TAF13, TAF25, and TAF38 exhibited low CD36
      expression and one clone TAF 18 had expression comparable to that of F442A
      control cells. FA uptake rates in clones TAF13, TAF25 and TAF38 were lower than
      those observed in TAF18. At confluence, adipocyte differentiation could be
      promoted by addition of insulin and triiodothyronine only in TAF18 cells but not
      in TAF13, TAF25 or TAF38. Addition of fatty acids to clones TAF13, TAF25 and
      TAF38 lead to an induction of CD36 expression, an enhancement of FA uptake and
      better cell differentiation. The data support a role of CD36 in the membrane
      uptake of long chain FA. CD36 expression and FA uptake appear to be closely
      linked to preadipocyte differentiation.

PMID- 10331654
TI  - The liver fatty acid binding protein--comparison of cavity properties of
      intracellular lipid-binding proteins.
AB  - The crystal and solution structures of all of the intracellular lipid binding
      proteins (iLBPs) reveal a common beta-barrel framework with only small local
      perturbations. All existing evidence points to the binding cavity and a poorly
      delimited 'portal' region as defining the function of each family member. The
      importance of local structure within the cavity appears to be its influence on
      binding affinity and specificity for the lipid. The portal region appears to be
      involved in the regulation of ligand exchange. Within the iLBP family, liver
      fatty acid binding protein or LFABP, has the unique property of binding two fatty
      acids within its internalized binding cavity rather than the commonly observed
      stoichiometry of one. Furthermore, LFABP will bind hydrophobic molecules larger
      than the ligands which will associate with other iLBPs. The crystal structure of
      LFABP contains two bound oleate molecules and provides the explanation for its
      unusual stoichiometry. One of the bound fatty acids is completely internalized
      and has its carboxylate interacting with an arginine and two serines. The second
      oleate represents an entirely new binding mode with the carboxylate on the
      surface of LFABP. The two oleates also interact with each other. Because of this
      interaction and its inner location, it appears the first oleate must be present
      before the second more external molecule is bound.

PMID- 10331656
TI  - Biochemical and biophysical analysis of the intracellular lipid binding proteins
      of adipocytes.
AB  - Adipocytes express two lipid-binding proteins; the major one termed the adipocyte
      lipid-binding protein or aP2 (ALBP/aP2) and a minor one referred to as the
      keratinocyte lipid-binding protein (KLBP). In order to evaluate the potential
      physiological roles for these proteins, their biochemical and biophysical
      properties have been analyzed and compared. ALBP/aP2 and KLBP exhibit similar
      binding affinities for most long-chain fatty acids; however, ALBP/aP2 exhibits a
      two to three-fold increased affinity for myristic, palmitic, oleic and linoleic
      acids, the predominant fatty acids of adipocytes. As measured by guanidinium
      hydrochloride denaturation, the stability of ALBP/aP2 is nearly 3 kcal/mol
      greater than that of KLBP. While the pI of ALBP/aP2 was determined to be 9.0,
      that of KLBP is 6.5 suggesting differing net charges at physiological pH.
      Analysis of surface electrostatic properties of ALBP/aP2 and KLBP revealed
      similar charge polarity, although differences in the detailed charge distribution
      exist between the proteins. The distribution of hydrophobic patches was also
      different between the proteins,ALBP/aP2 has only scattered hydrophobic surfaces
      while KLBP has a large hydrophobic patch near the ligand portal into the binding
      cavity. In sum, these results point out that despite the striking similarity
      between ALBP/aP2 and KLBP in tertiary structure, significant differences in
      ligand binding and surface properties exist between the two proteins. Hence,
      while it is tempting to speculate that ALBP/aP2 and KLBP are metabolically
      interchangeable, careful analysis suggests that the two proteins are quite
      distinct and likely to play unique metabolic roles.

PMID- 10331655
TI  - Mechanisms of cellular uptake of long chain free fatty acids.
AB  - Cells take up long chain free fatty acids (FFA) in vivo from the non-protein
      bound ligand pools in extracellular fluid and plasma, which contain approximately
      100 and 600 microM albumin, respectively. The physiologic range of unbound FFA
      concentrations in such fluids has traditionally been calculated at <1 microM.
      Studies of [3H]-oleate uptake by hepatocytes, adipocytes, cardiac myocytes and
      other cell types demonstrate that FFA uptake within this range is saturable, and
      exhibits many other kinetic properties indicative of facilitated transport.
      Within this range, the uptake kinetics of the acidic (pKa = 0.5) FFA analog
      alpha2,beta2,omega3-heptafluorostearate are similar to those of stearate. Thus,
      uptake of physiologic concentrations of FFA involves facilitated transport of the
      FFA anion (FA). Over a much wider range of unbound FFA concentrations
      hepatocellular [3H]-oleate uptake exhibits both saturable and non-saturable
      components. Oleate binding to liver plasma membranes (LPM) also demonstrates such
      components. Comparing the two components of FFA uptake to the corresponding
      components of binding permits estimates of trans-membrane transport rates. T1/2
      for saturable uptake (approximately 1 sec) is less than for non-saturable uptake
      (approximately 14 sec). Others have determined the flip-flop rates of protonated
      FFA (FAH) across small and large unilamellar vesicles (SUV, LUV) and across
      cellular plasma membranes. These reported flip-flop rates, measured by the
      decrease in pH resulting from the accompanying proton flux, exhibit a highly
      significant inverse correlation with cell and vesicle diameter (r = 0.99).
      Although T1/2's in vesicles are in the msec range, those in cells are >10 sec,
      and thus comparable to the rates of non-saturable uptake we determined. Thus,
      under physiologic conditions, the predominant mechanism of cellular FFA uptake is
      facilitated transport of FA ; at much higher, non-physiologic FFA concentrations,
      passive flip-flop of FAH predominates. Several plasma membrane proteins have been
      identified as potential mediators of facilitated FFA transport. Studies in animal
      models of obesity and non-insulin dependent diabetes mellitus demonstrate that
      tissue-specific regulation of facilitated FFA transport has important
      pathophysiologic consequences.

PMID- 10331657
TI  - Long-chain fatty acid transport in bacteria and yeast. Paradigms for defining the
      mechanism underlying this protein-mediated process.
AB  - Protein-mediated transport of exogenous long-chain fatty acids across the
      membrane has been defined in a number of different systems. Central to
      understanding the mechanism underlying this process is the development of the
      appropriate experimental systems which can be manipulated using the tools of
      molecular genetics. Escherichia coli and Saccharomyces cerevisiae are ideally
      suited as model systems to study this process in that both [1] exhibit saturable
      long-chain fatty acid transport at low ligand concentration; [2] have specific
      membrane-bound and membrane-associated proteins that are components of the
      transport apparatus; and [3] can be easily manipulated using the tools of
      molecular genetics. In E. coli, this process requires the outer membrane-bound
      fatty acid transport protein FadL and the inner membrane associated fatty acyl
      CoA synthetase (FACS). FadL appears to represent a substrate specific channel for
      long-chain fatty acids while FACS activates these compounds to CoA thioesters
      thereby rendering this process unidirectional. This process requires both ATP
      generated from either substrate-level or oxidative phosphorylation and the proton
      electrochemical gradient across the inner membrane. In S. cerevisiae, the process
      of long-chain fatty acid transport requires at least the membrane-bound protein
      Fat1p. Exogenously supplied fatty acids are activated by the fatty acyl CoA
      synthetases Faa1p and Faa4p but unlike the case in E. coli, there is not a tight
      linkage between transport and activation. Studies evaluating the growth
      parameters in the presence of long-chain fatty acids and long-chain fatty acid
      transport profiles of a fat1delta strain support the hypothesis that Fatlp is
      required for optimal levels of long-chain fatty acid transport.

PMID- 10331658
TI  - Cytochrome P450, peroxisome proliferation, and cytoplasmic fatty acid-binding
      protein content in liver, heart and kidney of the diabetic rat.
AB  - Diabetes mellitus generally results in an increased systemic fatty acid
      mobilization which can be associated with an increase in mitochondrial and
      peroxisomal beta-oxidation of fatty acids in selected tissues. The latter is
      usually accompanied by a concomitant increase in the tissue content of
      cytoplasmic fatty acid-binding protein (FABP) which functions in the
      intracellular translocation of fatty acids. It was previously found that in liver
      clofibrate-induced proliferation of peroxisomes and increase in FABP expression
      each are dependent on the induction by cytochrome P4504A1 -mediated (CYP4A1)
      formation of dicarboxylic acids. We studied whether peroxisome proliferation and
      an increase of FABP contents in liver, heart and kidney of streptozotocin-induced
      diabetic rats are also accompanied by an increase of CYP4A1 activity, as this
      would indicate a possible regulatory role for dicarboxylic acids in peroxisome
      proliferation and FABP induction in diabetic organs other than liver. In livers
      of the diabetic rat, a concomitant increase was observed of the activities of
      CYP4A1 and the peroxisomal key enzyme fatty acyl-CoA oxidase (FACO) and of the
      FABP content. In the diabetic heart FACO activity and FABP content also
      increased, but there was no induction of CYP4A1 activity. Conversely, in diabetic
      kidney there was no increase in FACO activity nor FABP content in spite of a
      marked induction of CYP4A1 activity. It is concluded that streptozotocin-induced
      diabetes leads to increased peroxisome proliferation and increased levels of FABP
      in both liver and heart, which only in liver is accompanied by an induction of
      the cytochrome P450 system. Consequently, it is not likely that dicarboxylic
      acids are involved in the induction of peroxisome proliferation in the heart.

PMID- 10331659
TI  - Long chain fatty acids as modulators of gene transcription in preadipose cells.
AB  - During the last years, it has been clearly established that long-chain fatty
      acids act as modulators of gene expression in various tissues, such as adipose
      tissue, intestine and liver. This transcriptional action of fatty acids explains
      in part adaptation mechanisms of tissues to nutritional changes and especially to
      high-fat diets by increasing expression of proteins involved in lipid catabolism
      in liver and fatty acid uptake and utilization in other tissues. It is now
      clearly demonstrated that some of these transcriptional effects of fatty acids
      are mediated by activation of specific nuclear hormone receptors, called
      peroxisome proliferator-activated receptors (PPARs). These findings will be
      discussed with a special reference to control of gene expression in preadipocytes
      and adipose tissue development.

PMID- 10331660
TI  - Novel classes of fatty acid and retinol binding protein from nematodes.
AB  - Parasitic nematodes have recently been found to produce proteins which represent
      two new classes of fatty acid and retinoid binding protein. The first is the
      nematode polyprotein allergens/antigens (NPAs) which, as their name suggests, are
      synthesised as large polyproteins which are subsequently cleaved at regularly
      spaced sites to form multiple copies of a fatty acid binding protein of
      approximately 14.5 kDa. Binding studies using molecular environment-sensitive
      fluorescent ligands have shown that the binding site is highly unusual, producing
      blue-shifting in fluorescence to an unprecedented degree, suggesting a remarkably
      non-polar environment and isolation from solvent water. Computer-based structural
      predictions and biophysical observations have identified the NPAs as highly
      helical proteins which might form a four helix bundle, so constitute a new class
      of lipid binding protein from animals. The second class, like the NPAs, binds
      both fatty acids and retinol, but with a higher affinity for the latter. These
      are also highly helical but are structurally distinct from the NPAs. The
      biological function of these new classes of protein are discussed in the context
      of both the metabolic requirements of the parasites and the possible role of the
      proteins in control of the immune and inflammatory environment of the tissue
      sites parasitised.

PMID- 10331661
TI  - Fatty acid interactions with native and mutant fatty acid binding proteins.
AB  - The interactions of long chain fatty acids (FA) with wild type (WT) fatty acid
      binding proteins (FABP) and engineered FABP mutants have been monitored to
      determine the equilibrium binding constants as well as the rate constants for
      binding and dissociation. These measurements have been done using the fluorescent
      probes, ADIFAB and ADIFAB2, that allow the determination of the free fatty acid
      (FFA) concentration in the reaction of FA with proteins and membranes. The
      results of these studies indicate that forWT proteins from adipocyte, heart,
      intestine, and liver, Kd values are in the nM range and affinities decrease with
      increasing aqueous solubility of the FA. Binding affinities for heart and liver
      are generally greater than those for adipocyte and intestine. Moreover,
      measurements of the rate constants indicate that binding equilibrium at 37
      degrees C is achieved within seconds for all FA and FABPs. These results,
      together with the level of serum (unbound) FFA, suggests a buffering action of
      FABPs that helps to maintain the intracellular concentration of FFA so that the
      flux of FFA between serum and cells occurs down a concentration gradient.
      Measurements of the temperature dependence of binding reveal that the free energy
      is predominately enthalpic and that the enthalpy of the reaction results from FA
      FABP interactions within the binding cavity. The nature of these interactions
      were investigated by determining the thermodynamics of binding to engineered
      point mutants of the intestinal FABP. These measurements showed that binding
      affinities did not report accurately the changes in protein-FA interactions
      because changes in the binding entropy and enthalpy tend to compensate. For
      example, an alanine substitution for arginine 106 yields a 30 fold increase in
      binding affinity, because the loss in enthalpy due to the elimination of the
      favorable interaction between the FA carboxylate and Arg106, is more than
      compensated for by an increase in entropy. Thus understanding the effects of
      amino acid replacements on FA-FABP interactions requires measurements of enthalpy
      and entropy, in addition to affinity.

PMID- 10331662
TI  - The measurement of free fatty acid concentration with the fluorescent probe
      ADIFAB: a practical guide for the use of the ADIFAB probe.
AB  - The aqueous phase monomers of fatty acids (FFA) appear in many steps of fat
      metabolism. Understanding metabolism requires that accurate measurements of FFA
      levels be determined in enzyme-mediated as well as in membrane and protein
      binding reactions. Measuring long chain FFA levels with sufficient sensitivity
      and temporal resolution is now possible using fluorescent probes constructed by
      ligating fluorescent groups and fatty acid binding proteins. In this paper we
      provide a practical description of the use of ADIFAB, the acrylodan labeled
      intestinal fatty acid binding protein. We describe with specific examples how
      ADIFAB can be used to determine, (1) FFA concentrations in aqueous solutions, (2)
      binding affinities of fatty acid binding proteins, (3) membrane/water partition
      coefficients, (4) lipase activities, and (5) serum levels of FFA.

PMID- 10331664
TI  - Structure and function of cytoplasmic retinoid binding proteins.
AB  - We examined the ligand protein interactions of two highly homologous cellular
      retinol binding proteins, CRBP and CRBP-II, and two highly homologous cellular
      retinoic acid binding proteins, CRABP-I and CRABP-II. While the crystal
      structures of all four have been determined, nuclear magnetic resonance studies
      provide a means for observing dynamic aspects of ligand protein interactions of
      these proteins in solution. The cellular functions of these proteins are less
      well understood. We have modeled retinoid flux between cytoplasmic retinoid
      proteins and model membranes and with nuclear receptors. Based on our in vitro
      studies, we propose that certain retinoids may indirectly influence retinoid
      signaling by displacing endogenous retinoids from the cytoplasmic proteins to the
      nuclear receptors.

PMID- 10331663
TI  - Role of acylCoA binding protein in acylCoA transport, metabolism and cell
      signaling.
AB  - Long chain acylCoA esters (LCAs) act both as substrates and intermediates in
      intermediary metabolism and as regulators in various intracellular functions.
      AcylCoA binding protein (ACBP) binds LCAs with high affinity and is believed to
      play an important role in intracellular acylCoA transport and pool formation and
      therefore also for the function of LCAs as metabolites and regulators of cellular
      functions [1]. The major factors controlling the free concentration of cytosol
      long chain acylCoA ester (LCA) include ACBP [2], sterol carrier protein 2 (SCP2)
      [3] and fatty acid binding protein (FABP) [4]. Additional factors affecting the
      concentration of free LCA include feed back inhibition of the acylCoA synthetase
      [5], binding to acylCoA receptors (LCA-regulated molecules and enzymes), binding
      to membranes and the activity of acylCoA hydrolases [6].

PMID- 10331665
TI  - A comparative study of the backbone dynamics of two closely related lipid binding
      proteins: bovine heart fatty acid binding protein and porcine ileal lipid binding
      protein.
AB  - The backbone dynamics of bovine heart fatty acid binding protein (H-FABP) and
      porcine ileal lipid binding protein (ILBP) were studied by 15N NMR relaxation (T1
      and T2) and steady state heteronuclear 15N[1H] NOE measurements. The microdynamic
      parameters characterizing the backbone mobility were determined using the 'model
      free' approach. For H-FABP, the non-terminal backbone amide groups display a
      rather compact protein structure of low flexibility. In contrast, for ILBP an
      increased number of backbone amide groups display unusually high internal
      mobility. Furthermore, the data indicate a higher degree of conformational
      exchange processes in the microsec-msec time range for ILBP compared to H-FABP.
      These results suggest significant differences in the conformational stability for
      these two structurally highly homologous members of the fatty acid binding
      protein family.

PMID- 10331666
TI  - Probable interaction between S100A7 and E-FABP in the cytosol of human
      keratinocytes from psoriatic scales.
AB  - The overexpression of E-FABP and S100A7 in lesional psoriatic skin suggests a
      possible link with this hyperproliferative skin disease. In order to investigate
      a role for the proteins in this disease, the purifications for both proteins were
      re-analyzed. Moreover, a specific antiserum directed against purified human
      S100A7 was generated. By SDS-PAGE immunoblotting we show that E-FABP and S100A7
      are expressed in cultured human differentiating keratinocytes and confirm their
      overexpression in psoriatic scales. Gel filtration and non-denaturing PAGE
      revealed that S100A7 co-purified with E-FABP, indicating an association between
      the two proteins. Ion-exchange chromatography resulted in the dissociation of the
      complex. Finally, immunoprecipitations using antiserum against E-FABP revealed
      that S100A7 co-immunoprecipitated with E-FABP from protein extracts of psoriatic
      scales. These data indicate that E-FABP and S100A7 might form a complex in the
      cytosol of human keratinocytes.

PMID- 10331668
TI  - Structural and functional studies on different human FABP types.
AB  - Interaction of various ligands with recombinant proteins of 5 human FABP types
      was studied by radiochemical and fluorescence procedures. Liver, heart,
      intestinal and myelin FABP showed a higher affinity for oleic acid than adipocyte
      FABP. Intestinal and adipocyte FABP had a relatively high Kd value for
      arachidonic acid. Liver and intestinal FABP showed high affinity for DAUDA in
      contrast to the other FABP types. ANS was only well bound by liver and adipocyte
      FABP. Retinol was not bound by any FABP type, retinoic acid only by adipocyte
      FABP. Data indicate the importance of both electrostatic and hydrophobic
      interaction for the ligand-FABP binding. The immunological crossreactivity
      between six human FABP types including epidermal FABP and their respective
      antibodies raised in rabbit, chicken and mouse appeared to be low and may suggest
      heterogeneity of protein surface.

PMID- 10331667
TI  - CD36 mediates long-chain fatty acid transport in human myocardium: complete
      myocardial accumulation defect of radiolabeled long-chain fatty acid analog in
      subjects with CD36 deficiency.
AB  - Long-chain fatty acids (LCFA) are the major energy substrate for heart and their
      oxidation is important for achieving maximal cardiac work. However, the mechanism
      of uptake of LCFA by myocardium has not been clarified. We previously reported
      that bovine myocardial LCFA transporter has a sequence homology to human CD36.
      Clinically, total defect of myocardial uptake of radiolabeled long-chain fatty
      acid analog [123I-BMIPP: Iodine-123 15-(p-iodophenyl)-(R,S)-methylpentadecanoic
      acid] has been reported in some restricted cases, but the etiology has not been
      clarified. In the present study, we analyzed CD36 expression and CD36 gene in
      subjects who showed total lack of myocardial 123I-BMIPP accumulation, and, vice
      versa, evaluated myocardial 123I-BMIPP uptake in subjects with CD36 deficiency.
      Four unrelated subjects were evaluated, Two were found to have negative
      myocardial LCFA accumulation by 123I-BMIPP scintigraphy, after which the
      expression of CD36 on their platelets and monocytes was analyzed. Remaining two
      subjects were identified as CD36 deficiency by screening, then 123I-BMIPP
      scintigraphy was performed. Expression of CD36 on platelets and monocytes was
      measured by flow cytometric analysis. The molecular defects responsible for CD36
      deficiency was detected by allele-specific restriction enzyme analysis. CD36
      expression was totally deficient in all 4 subjects on both platelets and
      monocytes. Two subjects were homozygous for a 478C-->T mutation. One was
      heterozygous for the dinucleotide deletion of exon V and single nucleotide
      insertion of exon X, and remaining one was considered to be heterozygous for the
      dinucleotide deletion of exon V and an unknown gene abnormality. All cases
      demonstrated a completely negative accumulation of myocardial LCFA despite of
      normal myocardial perfusion, which was evaluated by thallium scintigraphy. In
      addition, all cases demonstrated apparently normal hepatic LCFA accumulation
      Thus, these findings suggested that CD36 acts as a major myocardial specific LCFA
      transporter in humans.

PMID- 10331669
TI  - The third leg: molecular dynamics simulations of lipid binding proteins.
AB  - Molecular dynamics computer simulations can provide a third leg which balances
      the contributions of both structural biology and binding studies performed on the
      lipid binding protein family. In this context, these calculations help to
      establish a dialogue between all three communities, by relating experimental
      observables with details of structure. Working towards this connection is
      important, since experience has shown the difficulty of inferring thermodynamic
      properties from a single static conformation. The challenge is exemplified by
      ongoing attempts to interpret the impact of mutagenesis on structure and function
      (i.e. binding). A detailed atomic-level understanding of this system could be
      achieved with the support of all three legs, paving the way towards rational
      design of proteins with novel specificities. This paper provides an outline of
      the connections possible between experiment and theory concerning lipid binding
      proteins.

PMID- 10331670
TI  - Lipid-transfer proteins from plants: structure and binding properties.
AB  - Plant cells contain lipid-transfer proteins (LTPs) able to transfer phospholipids
      between membranes in vitro. Plant LTPs share in common structural and functional
      features. Recent structural studies carried out by NMR and X-ray crystallography
      on an LTP isolated from maize seeds have showed that this protein involves four
      helices packed against a C-terminal region and stabilized by four disulfide
      bridges. A most striking feature of this structure is the existence of an
      internal hydrophobic cavity running through the whole molecule and able to
      accommodate acyl chains. It was thus of interest to study the ability of maize
      LTP to bind hydrophobic ligands such as acyl chains or lysophosphatidylcholine
      and to determine the effect of this binding on phospholipid transfer. The binding
      abilities of maize LTP, presented in this paper, are discussed and compared to
      those of lipid-binding proteins from animal tissues.

PMID- 10331671
TI  - Practicing neurology: a delicate balance.

PMID- 10331672
TI  - The search for diagnostic and progression markers in AD: so near but still too
      far?

PMID- 10331673
TI  - The Wada test: controversies, concerns, and insights.

PMID- 10331674
TI  - Is the devil we know the lesser of two evils? Vigabatrin and visual fields.

PMID- 10331675
TI  - Areas of consensus in withdrawing life-sustaining treatment in the neurointensive
      care unit.

PMID- 10331676
TI  - Practice advisory: The use of felbamate in the treatment of patients with
      intractable epilepsy: report of the Quality Standards Subcommittee of the
      American Academy of Neurology and the American Epilepsy Society.

PMID- 10331677
TI  - Assessment: Neurologic risk of immunization: report of the Therapeutics and
      Technology Assessment Subcommittee of the American Academy of Neurology.

PMID- 10331678
TI  - Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in
      CSF.
AB  - OBJECTIVE: To evaluate CSF levels of beta-amyloid(1-42) (Abeta42) alone and in
      combination with CSF tau for distinguishing AD from other conditions. METHODS: At
      10 centers in Europe and the United States, 150 CSF samples from AD patients were
      analyzed and compared with 100 CSF samples from healthy volunteers or patients
      with disorders not associated with pathologic conditions of the brain (CON), 84
      patients with other neurologic disorders (ND), and 79 patients with non-Alzheimer
      types of dementia (NAD). Sandwich ELISA techniques were used on site for
      measuring Abeta42 and tau. RESULTS: Median levels of Abeta42 in CSF were
      significantly lower in AD (487 pg/mL) than in CON (849 pg/mL; p = 0.001), ND (643
      pg/mL; p = 0.001), and NAD (603 pg/mL; p = 0.001). Discrimination of AD from CON
      and ND was significantly improved by the combined assessment of Abeta42 and tau.
      At 85% sensitivity, specificity of the combined test was 86% (95% CI: 81% to 91%)
      compared with 55% (95% CI: 47% to 62%) for Abeta42 alone and 65% (95% CI: 58% to
      72%) for tau. The combined test at 85% sensitivity was 58% (95% CI: 47% to 69%)
      specific for NAD. The APOE e4 gene load was negatively correlated with Abeta42
      levels not only in AD but also in NAD. CONCLUSIONS: The combined measure of CSF
      Abeta42 and tau meets the requirements for clinical use in discriminating AD from
      normal aging and specific neurologic disorders.

PMID- 10331680
TI  - Motor perseverative behavior on a line cancellation task.
AB  - OBJECTIVES: To study the behavioral and neuroanatomic characteristics of
      perseverative behavior encountered on a target cancellation task in patients with
      neglect. METHODS: Motor perseverative behavior during line cancellation task was
      evaluated retrospectively in 60 patients with left hemispatial neglect from right
      hemispheric stroke. RESULTS: More than 30% of the patients (21 of 60) showed
      perseveration, manifested as either repetitive cancellation of the same target
      (18/21) or cancelling extra lines created by the patients themselves (3/21).
      Neglect severity correlated positively with the frequency of perseverative
      errors. Perseveration was most prominent in the rightmost portion of the array.
      Anterior lesions or massive lesions involving anterior and posterior regions were
      more likely to be associated with motor perseveration than were lesions
      restricted to posterior areas. CONCLUSIONS: Although the mechanism of motor
      perseveration remains to be elucidated, our findings suggest that the combination
      of aberrant approach behaviors associated with frontal lobe injury and an
      attentional or intentional bias toward the rightsided targets might explain the
      behavior.

PMID- 10331679
TI  - High monounsaturated fatty acids intake protects against age-related cognitive
      decline.
AB  - OBJECTIVE: To study the relationships between dietary macronutrient intakes and
      age-related changes in cognitive functions. METHODS: We investigated these
      associations in the prevalence survey (1992 through 1993) of the Italian
      Longitudinal Study on Aging (ILSA). The population-based sample of 5,632 subjects
      of the ILSA, age 65 to 84 years, was identified from the electoral rolls of eight
      Italian municipalities. In this study, standardized test batteries assessing
      global cognitive functions (Mini-Mental State Examination [MMSE]), selective
      attention (Digit Cancellation Test [DCT]), and episodic memory (Babcock Story
      Recall Test), and a semi-quantitative food frequency questionnaire evaluating
      macronutrient energy intakes, were performed on 278 nondemented elderly subjects
      from the randomized cohort of Casamassima, Bari (n = 704). RESULTS: There was an
      inverse relationship between monounsaturated fatty acids (MUFAs) energy intake
      and cognitive decline (MMSE < 24). The effect of education on the odds of having
      a MMSE score <24 decreased exponentially with the increase of MUFA intakes (over
      2,400 kJ; odds ratio, 0.69). Moreover, a significant inverse association was
      observed between MUFA intakes and DCT score (odds ratio, 0.99). No association
      was found between nutritional variables and episodic memory. CONCLUSIONS: In an
      elderly population of Southern Italy with a typical Mediterranean diet, high MUFA
      intakes appeared to be protective against age-related cognitive decline.
      Prospective clinical trials are needed to evaluate the impact of specific dietary
      macronutrient intakes on the age-related changes of cognitive functions.

PMID- 10331681
TI  - Wada difference a day makes: interpretive cautions regarding same-day injections.
AB  - OBJECTIVE: To determine whether memory scores after second intracarotid
      amobarbital procedure (IAP) injections are affected by the time between the first
      and second injections. METHODS: Sixty-two patients received their second IAP
      injection on the day after the first injection. Forty-three other patients
      received the second injection on the same day as the first injection. Both groups
      underwent similar IAP protocols and memory assessments, except for the timing of
      the second injection. RESULTS: The second IAP memory scores in the two-day group
      were significantly higher (p < 0.05) than those in the one-day group. Timing of
      second injection was a significant correlate of second memory scores, but
      amobarbital dosage, first IAP memory score, and pre-IAP measures of memory and
      intelligence were not significant correlates. CONCLUSION: One-day and two-day IAP
      protocols do not result in similar memory scores after the second injection.
      Nineteen percent of a subset of patients in the one-day protocol were
      misclassified, in terms of IAP memory ratings, because of the deleterious effect
      of having both injections on the same day. It is recommended that correction
      scores be considered, for some patients who receive two IAP injections on one
      day, to approximate what the second IAP memory score would have been had the
      second injection occurred on a second day.

PMID- 10331682
TI  - Hemispheric asymmetries in arousal affect outcome of the intracarotid amobarbital
      test.
AB  - OBJECTIVE: To evaluate changes in arousal and their impact on memory performance
      during the intracarotid amobarbital test (IAT). METHODS: Along with memory
      measures, level of arousal was evaluated through clinical ratings and nonverbal
      self-ratings in epilepsy patients undergoing IAT before anterior temporal
      lobectomy. RESULTS: Irrespective of seizure focus, left-sided amobarbital
      injection resulted in decreased objective and subjective arousal more often than
      right-side injection. Impaired objective arousal was greater when the left
      hemisphere was injected second, because of the presumed additive effects of
      systemic amobarbital residual from the first injection. Decreased objective
      arousal was related to poorer performance on memory testing following left
      hemisphere injection. CONCLUSIONS: The IAT, as practiced in most centers, is
      biased, so patients with right temporal lobe seizure focus are more likely to
      "pass" the test, whereas patients with left seizure focus are more likely to
      "fail" the test. The significant impact of changes in arousal on memory testing
      needs to be considered when using IAT results to select patients for temporal
      lobectomy.

PMID- 10331683
TI  - Determination of language dominance: Wada test confirms functional transcranial
      Doppler sonography.
AB  - OBJECTIVE: To determine the efficacy of the invasive Wada test in determining
      language dominance, and to validate the functional transcranial Doppler
      sonography (fTCD) examination in patients. BACKGROUND: Previous work shows that
      simultaneous bilateral fTDC may identify cognitive hemispheric dominance in
      healthy individuals. METHOD: fTDC and the Wada test were performed prospectively
      in 14 patients with various diseases (tumors, cerebrovascular events, head
      injury, intractable epilepsy). fTDC hemispheric dominance was determined based on
      the hemispheric blood flow velocity shift for language and visuospatial tasks.
      RESULTS: fTDC was performed easily in patients. One patient could not be examined
      by fTDC because of absent temporal bone window for ultrasonic transmission. Two
      Wada tests were inconclusive due to patient somnolence. One of these patients
      suffered from right frontal tumor and had aphasia remitted under steroids when
      examined. fTDC indicated a bilateral language dominance. In the remaining 11
      patients the correlation between fTDC and Wada language lateralization indices
      was 0.75 (p = 0.008). If a post hoc cutoff score was taken for the fTDC language
      lateralization index, in eight patients, both fTDC and Wada testing determined
      the left hemisphere to be dominant for language; in the other three patients,
      language function was bilateral in both examinations. CONCLUSION: Although the
      current results are preliminary and require replication in a larger sample, fTDC
      seems to be able to assess hemispheric language dominance not only in healthy
      individuals, but also in patients. It might become an alternative noninvasive or
      complementary tool to the Wada test, particularly in patients in whom the Wada
      test is impractical or gives inconclusive results.

PMID- 10331684
TI  - Amobarbital effects on the posterior hippocampus during the intracarotid
      amobarbital test.
AB  - OBJECTIVE: To relate functional effects on the hippocampus during the
      intracarotid amobarbital test (IAT) to its direct perfusion with amobarbital.
      METHODS: In 17 patients with intractable temporal lobe epilepsy, 28 hemispheres
      were perfused with 2.3 mL of 10% solution of 200 mg amobarbital and 37 MBq 99mTc
      hexamethylpropylene amine oxime (HMPAO). For evaluation of amobarbital effects,
      data were combined from stereo-EEG (S-EEG) recordings from intrahippocampal depth
      electrodes and high-resolution SPECT after intracarotid injection of HMPAO.
      RESULTS: Perfusion of the entire hippocampus was observed only in hemispheres
      with a fetal origin of the posterior cerebral artery (PCA). In 10 hemispheres, S
      EEG recordings could not unequivocally be assigned to either the anterior or the
      posterior part of the hippocampus. In the remaining 18 hemispheres, only the two
      with a fetal type of PCA showed perfusion of the entire hippocampus. In both,
      hippocampal electrical activity changed under the influence of amobarbital but
      did not differ in anterior and posterior contacts. In 15 of 16 hemispheres in
      which SPECT demonstrated perfusion of the anterior hippocampus only, amobarbital
      injection resulted in significant S-EEG activity change in both the anterior and
      the posterior parts of the hippocampus. CONCLUSION: S-EEG effects on the
      posterior hippocampus during the IAT can occur without direct perfusion of those
      brain areas.

PMID- 10331685
TI  - Withdrawal of life support in the neurological intensive care unit.
AB  - OBJECTIVE: To describe the frequency and clinical course of terminal extubation
      in the neurological intensive care unit, to identify factors that influence the
      decision to withdraw life support, and to evaluate the experiences of surrogate
      decision-makers. BACKGROUND: The right of patients to refuse life-prolonging
      treatment is widely accepted. However, it is unknown how frequently critically
      ill neurologic patients are removed from life support, and practice guidelines
      for withdrawing mechanical ventilation remain poorly defined. METHODS: We
      reviewed the medical records of all patients cared for by the Columbia
      Presbyterian neurocritical care service over a 3-year period who died, and
      identified a subgroup of non-brain-dead patients who were terminally extubated.
      We retrospectively analyzed the clinical course of these patients and interviewed
      their surrogate decision-makers. RESULTS: Of 74 non-brain-dead patients, 32 (43%)
      were terminally extubated. Hispanic and white patients were more likely to be
      extubated than were African American patients (p = 0.02). The median duration of
      survival after extubation was 7.5 hours; 25% died within 1 hour, and 69% within
      24 hours. Depth of coma did not predict the duration of survival after
      extubation. The most frequent signs after extubation were agonal or labored
      breathing (59%) and tachypnea (34%). Morphine or fentanyl was given to relieve
      respiratory distress in 68% of cases; the average dose of morphine was 6.3
      mg/hour (range 2.5 to 20 mg/hour). In a structured interview of 24 surrogate
      decision-makers, 88% were satisfied or very satisfied with the overall process,
      and 75% felt the patient suffered minimally before death; all but one (96%) said
      that they would repeat the decision to withdraw life support. CONCLUSIONS: Forty
      three percent of our non-brain-dead patients who died were terminally extubated.
      The duration of survival after extubation exceeded 24 hours in one third, and was
      not predicted by level of consciousness. Two thirds of patients were treated with
      opioids for agonal respiratory distress. Most surrogate decision-makers were
      comfortable and satisfied with the process of withdrawing care.

PMID- 10331686
TI  - Neurobehavioral function and tibial and chelatable lead levels in 543 former
      organolead workers.
AB  - OBJECTIVE: To evaluate the associations between tibial lead, dimercaptosuccinic
      acid (DMSA)-chelatable lead, and neurobehavioral function in former organolead
      manufacturing workers with past exposure to organic and inorganic lead. METHODS:
      Data were collected from 543 subjects with a mean age of 58 years and an average
      of 17.8 years since last lead exposure. Years since last exposure to lead was
      used to estimate tibial lead levels in the year of last occupational lead
      exposure, termed "peak tibial lead." Current tibial lead levels, measured by x
      ray fluorescence, were extrapolated back using a clearance half-time of lead in
      tibia of 27 years, assuming first-order clearance from tibia. RESULTS: Peak
      tibial lead levels ranged from -2.2 to 105.9 microg Pb/g bone mineral, and DMSA
      chelatable lead levels were between 1.2 and 136 microg. After adjustment for
      confounding variables, peak tibial lead was a significant negative predictor of
      performance on the Wechsler Adult Intelligence Scale-Revised vocabulary subtest
      (p = 0.02), serial digit learning test (p = 0.04), Rey Auditory-Verbal Learning
      Test (immediate recall and recognition, p = 0.03 for each), Trail Making Test B
      (p = 0.03), finger tapping (dominant hand [p = 0.02] and nondominant hand [p <
      0.01]), Purdue pegboard (dominant hand, nondominant hand, both hands, and
      assembly, p < 0.01 for each), and Stroop Test (p < 0.01). Moreover, with one
      exception, average neurobehavioral test scores were poorer at higher peak tibial
      lead levels. DMSA-chelatable lead was only significantly associated with choice
      reaction time (p = 0.01). CONCLUSION: Peak tibial lead was consistently
      associated with poorer neurobehavioral test scores, particularly in the domains
      of manual dexterity, executive ability, verbal intelligence, and verbal memory.

PMID- 10331687
TI  - Racial differences in the incidence of intracerebral hemorrhage: effects of blood
      pressure and education.
AB  - OBJECTIVE: To determine the relative risk (RR) of intracerebral hemorrhage (ICH)
      among African Americans compared with that among whites. METHODS: Data from the
      First National Health and Nutrition Examination Survey Epidemiologic Follow-up
      Study were used to determine the incidence of ICH (n = 78) in 10,851 whites and
      1,802 African Americans during a 20-year follow-up period. Cox proportional
      hazards analyses were used to determine the RR of ICH among African Americans
      compared with that among whites. RESULTS: The estimated annual incidence of ICH
      was 50 per 100,000 among African Americans and 28 per 100,000 among whites. The
      age- and sex-adjusted RR for ICH among African Americans was 1.9 (95% confidence
      interval [CI], 1.1 to 3.2). With the addition of systolic blood pressure and
      educational attainment to the Cox proportional hazards model, the RR decreased to
      1.6 (95% CI, 0.9 to 2.7). The adjustment for additional cerebrovascular disease
      risk factors did not change this risk estimate appreciably. CONCLUSIONS: Compared
      with whites, African Americans have a twofold increased risk for ICH. Most of
      this risk may be explained by differences in educational attainment and systolic
      blood pressure. Unless additional efforts are undertaken to reduce racial
      differences in the prevalence of stroke risk factors, mainly systolic blood
      pressure and socioeconomic status, the African American-white disparities in the
      risk for ICH will likely continue.

PMID- 10331688
TI  - Potential source of cerebral embolism in migraine with aura: a transcranial
      Doppler study.
AB  - BACKGROUND: The recently found association between patent foramen ovale (PFO) and
      transient global amnesia (TGA) has suggested that paradoxical microembolization
      in the terminal vertebrobasilar territory might underlie at least some TGA cases.
      Migraine with visual aura is another paroxysmal disturbance in which a sudden
      dysfunction of cortical areas fed by the terminal branches of the basilar artery
      is believed to trigger the attack. Therefore we investigated the prevalence of
      PFO in a consecutive unselected cohort of migraine patients. OBJECTIVE: To
      investigate the prevalence of PFO in a consecutive unselected cohort of migraine
      patients to search for a possible mechanism for the reported association of
      migraine with stroke. METHODS AND RESULTS: A total of 113 patients, consecutively
      referred by the Headache Outpatient Clinic for migraine with aura (MA+, mean age
      34+/-12 years) were compared with 53 patients with migraine without aura (MA-,
      mean age 36+/-13 years) and with 25 age-matched nonmigraine subjects (mean age
      31+/-10 years) selected from the hospital staff. PFO was assessed with
      transcranial Doppler sonography with IV injection of agitated saline, a technique
      that is 90% sensitive and 100% specific. The prevalence of PFO was 48% (54/113)
      in MA+ patients, 23% (12/53) in MA- patients, and 20% (5/25) in control subjects.
      The difference between MA+ and MA- patients was significant (odds ratio [OR] =
      3.13, 95% confidence interval [CI] = 1.41 to 7.04, chi2 = 9.52,p = 0.002) as was
      the difference between MA+ patients and controls (OR = 3.66, 95% CI = 1.21 to
      13.25, chi2 = 6.46, p = 0.01), whereas MA- patients did not differ from controls
      (OR = 1.17, 95% CI = 0.32 to 4.45, chi2 = 0.07). MRI was negative in 22 MA+ and 8
      MA- patients. CONCLUSIONS: Patency of the foramen ovale is associated with
      migraine with aura but not with migraine without aura. The increased risk of
      stroke found in epidemiologic studies in patients with migraine with aura may be
      explained by an increased propensity to paradoxical cerebral embolism.

PMID- 10331689
TI  - Diffusion tensor imaging of lesions and normal-appearing white matter in multiple
      sclerosis.
AB  - OBJECTIVE: To determine whether diffusion tensor imaging (DTI) can detect
      structural changes in normal-appearing white matter, and to distinguish between
      plaques of different pathologic severity, in patients with MS. BACKGROUND:
      Conventional MRI detects lesions sensitively in MS but has limited pathologic
      specificity. The diffusion of water molecules in brain tissue, most fully
      expressed mathematically by a tensor quantity, reflects its intrinsic
      microstructure. It is now possible to estimate the diffusion tensor noninvasively
      in the human brain using MR DTI. This method is unique in providing precise and
      rotationally invariant measurements of the amount and directional bias
      (anisotropy) of diffusion in white matter tracts relating to tissue integrity and
      orientation. METHODS: DTI was performed in six patients with MS and in six age
      matched control subjects. Diffusion was characterized in normal-appearing white
      matter in both groups, and in lesions of different pathologic subtypes
      (inflammatory, noninflammatory, T1 hypointense, and T1 isointense). RESULTS: DTI
      identified significantly altered water diffusion properties in the normal
      appearing white matter of patients compared with control subjects (p < 0.001),
      and distinguished between lesion types. The highest diffusion was seen in
      destructive (T1 hypointense) lesions, whereas the greatest change in anisotropy
      was found in inflammatory (gadolinium-enhancing) lesions. CONCLUSIONS: DTI
      detects diffuse abnormalities in the normal-appearing white matter of MS
      patients, and the findings in lesions appear to relate to pathologic severity.
      Its use in serial studies and in larger clinical cohorts may increase our
      understanding of pathogenetic mechanisms of reversible and persistent disability.

PMID- 10331690
TI  - Familial factors influence disability in MS multiplex families. French Multiple
      Sclerosis Genetics Group.
AB  - BACKGROUND: Both genetic and environmental factors play a role in the
      pathophysiology of MS and may influence the clinical expression of the disease.
      OBJECTIVE: To determine the contribution of familial factors to the clinical
      expression of MS. METHODS: The French Multiple Sclerosis Genetics Group
      identified 87 sibling pairs. For each patient, sex, age at onset, duration of the
      disease, and disease course from onset were recorded. Disability was determined
      by the progression index (PI), defined as the ratio of the Expanded Disability
      Status Scale (EDSS) score disease duration when the latter exceeded 5 years.
      Statistical analyses were performed either with a group of patients (clinical
      features, relation between human leukocyte antigen and clinical features) or with
      a group of sibpairs (concordance for clinical features). RESULTS: The mean age at
      onset was 29.6 years, the ratio of women to men was 59:28, and the mean PI was
      0.27. There was no correlation for disease course and age at onset between sibs
      with MS. In contrast, we observed a weak but significant correlation of the PI in
      MS sibpairs (r = 0.234, p = 0.03). CONCLUSION: This study revealed a concordance
      in MS sibling pairs for the disease severity, supporting the hypothesis that the
      degree of disability might be partly influenced by familial factors
      (environmental or genetic).

PMID- 10331691
TI  - Emotional state of patients with relapsing-remitting MS treated with interferon
      beta-1b.
AB  - BACKGROUND: Depression has been cited as a possible side effect of interferon
      beta-1b (IFNbeta-1b) therapy in patients with MS. This association remains
      unproven because of a lack of longitudinal studies. OBJECTIVE: To determine the
      changes in emotional state in relapsing-remitting (RR) MS patients during the
      first 2 years of treatment with IFNbeta-1b. METHODS: Emotional state was
      evaluated in a sample of 90 patients at the onset of IFNbeta-1b treatment during
      an inclusion period of 2.5 years. Seventy-five patients were evaluated at their
      12th month of treatment and 56 patients at their 24th month. We assessed their
      emotional state with the following psychological tests: Hamilton Depression
      Rating Scale, Beck Depression Inventory, and State-Trait Anxiety Inventory.
      RESULTS: We found significant improvement in emotional state after the first and
      second years of treatment. CONCLUSIONS: Our findings show that IFNbeta-1b does
      not increase depression or anxiety in RR MS patients during the first and second
      years of IFNbeta-1b treatment. In fact, slight but significant improvement in
      depression and anxiety symptoms was observed during this period.

PMID- 10331692
TI  - Combination antiretroviral therapy improves psychomotor speed performance in HIV
      seropositive homosexual men. Multicenter AIDS Cohort Study (MACS).
AB  - BACKGROUND: Combination antiretroviral therapy including protease inhibitors
      (combo+PI) is effective in suppressing systemic viral load in HIV infection, but
      its impact on HIV-associated cognitive impairment is unclear. OBJECTIVE: To
      determine whether psychomotor speed, a sensitive measure of impairment in HIV
      dementia, improves with combo+PI compared with other antiretroviral treatments.
      METHODS: A total of 411 HIV-seropositive (HIV+) homosexual men (with longitudinal
      neuropsychological testing) in the Multicenter AIDS Cohort Study and, in a
      separate analysis, 282 HIV+ homosexual men with psychomotor slowing at baseline
      were classified by treatment into four groups: antiretroviral naive (no
      antiretroviral medication treatment), monotherapy, combination antiretroviral
      therapy without protease inhibitors (combo-noPI), and combo+PI. We compared
      longitudinal performance on three tests of psychomotor speed: the Grooved
      Pegboard (GP) (nondominant and dominant hands), Trail Making Test B, and the
      Symbol Digit Modalities Test (SDMT). RESULTS: Relative to antiretroviral-naive
      and monotherapy participants, on the GP nondominant hand test, combo+PI
      participants with abnormal baseline neuropsychological testing showed improved
      performance (difference = +0.63 standard deviation [SD], p = 0.02). For the SDMT,
      both combo+PI participants (difference = +0.26 SD, p = 0.03) and combo-noPI
      participants (difference = +0.29 SD, p = 0.01) with abnormal baseline
      neuropsychological testing improved compared with antiretroviral-naive and
      monotherapy groups. CONCLUSION: Combo+PI and combo-noPI are associated with
      improved psychomotor speed performance in HIV+ homosexual men with abnormal
      neuropsychological testing.

PMID- 10331693
TI  - Primary intracranial neoplasms in patients with HIV.
AB  - OBJECTIVE: To report a series of HIV-infected patients with intracranial tumors
      not known to be associated with immunodeficiency. BACKGROUND: The spectrum of HIV
      associated diseases is changing with improved treatments and prolonged patient
      survival. Although primary central nervous system lymphoma (PCNSL) and
      toxoplasmosis continue to be the most common intracranial lesions in HIV-infected
      patients, the recognition of other pathologic entities is increasingly important.
      METHODS: The clinical characteristics and outcome of eight HIV-infected patients
      with nine intracranial neoplasms other than PCNSL are reported. In addition, all
      available pathologic specimens were tested for evidence of either HIV or Epstein
      Barr virus (EBV) infection. An additional 28 patients reported in the literature
      are summarized. RESULTS: Five of eight patients had a glioblastoma multiforme;
      other tumors included an anaplastic ependymoma, a low-grade glioma, a
      subependymoma, and a leiomyosarcoma. More than half of the patients developed
      their tumor > or =6 years after the diagnosis of HIV infection. Patient prognosis
      and survival was best predicted by tumor histology. Treatment response and
      outcome did not appear to be influenced by HIV infection. Only the leiomyosarcoma
      demonstrated evidence of latent EBV infection. CONCLUSIONS: HIV-infected patients
      are at risk for intracranial neoplasms other than PCNSL, and benefit from
      aggressive tumor-specific therapy. It is possible that gliomas are occurring at a
      higher rate than in the general population. There was no evidence of HIV or EBV
      infection in any glial tumor.

PMID- 10331694
TI  - Sympathetic skin response differentiates hereditary sensory autonomic
      neuropathies III and IV.
AB  - OBJECTIVE: To evaluate whether sympathetic skin response (SSR) differs in
      patients with hereditary sensory autonomic neuropathy (HSAN) types III and IV.
      BACKGROUND: HSAN types III and IV are rare autosomal recessive disorders that
      cause many similar autonomic, sensory, and motor dysfunctions, but different
      sweating characteristics. HSAN III patients have preserved and at times,
      excessive sweating, whereas anhidrosis is characteristic of HSAN IV. SSR reflects
      the integrity of sympathetic sudomotor fibers and the activation of sweat glands
      through the change in skin resistance in response to an arousal stimulus.
      Therefore, SSR is a test method that might facilitate differential diagnosis of
      HSAN III and IV. METHODS: In 17 HSAN III patients (eight women, nine men; mean
      age, 20.65+/-5.45 years) and seven HSAN IV patients (five girls, two boys; mean
      age, 10.0+/-5.45 years) SSR was recorded from the palms and soles after repeated
      electrical, acoustic, and inspiratory gasp stimulations. In addition, all
      subjects underwent a neurologic examination; studies of median, peroneal motor,
      and sural nerve conduction velocities; and determination of vibratory and thermal
      perception thresholds. RESULTS: Although clinical differences were appreciated
      between the two types of HSANs, both HSANs had evidence of small-fiber
      involvement. Both HSANs had abnormal temperature and pain perception. In
      contrast, SSR was preserved in all HSAN III and absent in all HSAN IV patients.
      CONCLUSION: SSR provides another parameter to improve differentiation of HSAN III
      from HSAN IV, and also gives us additional information regarding sympathetic
      sudomotor fiber function in these developmental diseases.

PMID- 10331695
TI  - A 10-year study of mortality in a cohort of patients with myotonic dystrophy.
AB  - OBJECTIVE: To determine the age and causes of death as well as the predictors of
      survival in patients with myotonic dystrophy (DM). METHODS: In a longitudinal
      study, a cohort of 367 patients with definite DM was followed for 10 years.
      RESULTS: During the 10-year period, 75 of the 367 DM patients (20%) died. The
      mean age at death (53.2 years, range 24 to 81) was similar for men and women.
      Among these 75 patients, 32 (43%) died of a respiratory problem, 15 (20%) of
      cardiovascular disease, 8 (11%) of a neoplasia, and 8 (11%) died suddenly. The
      ratio of observed to expected deaths was significantly increased to 56.6 (95%
      confidence interval [CI] 38.7 to 78.0) for respiratory diseases, 4.9 (95% CI 2.7
      to 7.7) for cardiovascular diseases, and 2.5 (95% CI 1.1 to 4.6) for neoplasms.
      The mean age at death was 44.7 years for the childhood phenotype of DM, 47.8
      years for the early-adult, 55.4 years for the adult, and 63.5 years for the mild
      phenotype (F = 4.8, p = 0.005). The age-adjusted risk of dying was 3.9 (95% CI
      1.3 to 11.0) times greater for a patient with a distal weakness and 5.6 (95% CI
      2.2 to 14.4) times greater for a patient with proximal weakness as compared with
      a person without limb weakness. CONCLUSIONS: Life expectancy is greatly reduced
      in DM patients, particularly in those with early onset of the disease and
      proximal muscular involvement. The high mortality reflects an increase in death
      rates from respiratory diseases, cardiovascular diseases, neoplasms, and sudden
      deaths presumably from cardiac arrhythmias.

PMID- 10331696
TI  - Diffuse central neuronal involvement in Fabry disease: a proton MRS imaging
      study.
AB  - BACKGROUND: The in vivo determination of parenchymal involvement is important to
      evaluate disease burden. Proton MRS imaging (1H-MRSI) permits simultaneous
      measurement of N-acetylaspartate (NA), a putative neuron-specific molecule,
      choline-containing compounds, creatine-phosphocreatine, and lactate from four 15
      mm slices divided into 0.84-mL single-volume elements. OBJECTIVE: To assess the
      cortical and subcortical neuropathology in Fabry disease (FD). METHODS: Regions
      of interest (ROIs) were selected from several cortical and subcortical locations
      in nine FD patients. Mean ROI metabolite ratios were compared with control
      values. RESULTS: FD patients showed a widespread pattern of cortical and
      subcortical NA reduction. Seven patients showed discrete MRI abnormalities
      consisting of white matter hyperintensities or basal ganglia infarcts.
      CONCLUSION: We found diffuse neuronal involvement in FD extending beyond the
      areas of MRI-visible cerebrovascular abnormalities. 1H-MRSI may become useful in
      therapeutic trials.

PMID- 10331697
TI  - A new metabolite contributing to N-acetyl signal in 1H MRS of the brain in Salla
      disease.
AB  - OBJECTIVE: To determine whether N-acetylaspartate (NAA) is reduced in patients
      with Salla disease, a neurodegenerative disorder. BACKGROUND: 1H MRS allows the
      brain metabolism to be studied noninvasively in vivo. N-acetyl (NA) is composed
      primarily of NAA, which is regarded as a neuronal marker. The NA signal in 1H MRS
      is reduced in several neurodegenerative disorders. Increased NA signal has thus
      far only been found in Canavan's disease as a result of NAA accumulation in the
      brain tissue. In Salla disease, an autosomal recessive free sialic acid storage
      disorder, N-acetylneuraminic acid (NANA), accumulates in lysosomes of brain
      tissue. METHODS: The authors studied eight patients with Salla disease (age
      range, 6 to 44 years) and eight age-matched healthy volunteers using quantitative
      1H MRS. The spectra were obtained from two selected 8-cm3 volumes of interest
      localized in the basal ganglia and in the parietal white matter using
      conventional 1.5-T MRI equipment. The spectral resonance lines of NA groups,
      creatine and phosphocreatine (Cr), and choline-containing compounds (Cho) were
      analyzed quantitatively. All MR images were evaluated to verify the state of
      myelination. RESULTS: 1H MRS from parietal white matter revealed 34% higher NA
      and 47% higher Cr concentrations, and a 35% lower Cho concentration in the
      patients with Salla disease compared with the age-matched control subjects. The
      patients had a 22% higher water content in their parietal white matter, whereas
      in the basal ganglia the water concentrations did not differ significantly. In
      the patients' basal ganglia the Cr concentration was 53% higher. CONCLUSIONS: NAA
      is considered to be a neuronal marker that, except for Canavan's disease, has
      been found or assumed to be either stable or reduced. However, in Salla disease
      the high NA signal may have a contribution from accumulated lysosomal NANA, which
      offsets the possible loss of NAA. The high Cr is in line with the increased
      glucose uptake found in our earlier 2-fluoro-2-deoxy-D-glucose-PET study,
      reflecting increased energy demand. It is worth noting that in a conventional 1H
      MRS ratio-based analysis these underlying abnormalities would have remained
      undetected. Our study thus emphasizes the importance of a quantitative assessment
      of metabolite concentrations in 1H MRS for detecting altered brain metabolism.

PMID- 10331698
TI  - Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in
      MPTP-treated monkeys.
AB  - BACKGROUND: Chronic treatment with L-3,4-dihydroxyphenylalanine (L-dopa) is often
      associated with motor side effects in PD patients. The search for new therapeutic
      approaches has led to study the role of other neuromodulators including
      adenosine. Among the four adenosine receptors characterized so far, the A2A
      subtype is distinctively present on striatopallidal output neurons containing
      enkephalin and mainly bearing dopamine (DA) D2 receptors (indirect pathway).
      Studies in DA-denervated rats suggest that blockade of adenosine A2A receptors
      might be used in PD. OBJECTIVE: To evaluate the antiparkinsonian effect of a new
      selective adenosine A2A receptor antagonist, KW-6002, in 1-methyl-4-phenyl
      1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. METHODS: In the present study,
      we used six MPTP-exposed cynomolgus monkeys already primed and exhibiting L-dopa
      induced dyskinesias to evaluate both the antiparkinsonian and dyskinetic effect
      upon challenge with two oral doses (60 and 90 mg/kg) of KW-6002 administered
      alone or in combination with L-dopa/benserazide (50/12.5 mg). RESULTS: KW-6002
      administered alone produced a dose-dependent antiparkinsonian response that
      reached the level of efficacy of L-dopa/benserazide but was less likely to
      reproduce dyskinesias in these animals. When co-administered, KW-6002 potentiated
      the effects of L-dopa/benserazide on motor activity (up to 30%) without affecting
      the dyskinetic response. CONCLUSION: Adenosine A2A receptor antagonists have
      antiparkinsonian effects of their own with a reduced propensity to elicit
      dyskinesias. They might therefore be useful agents in the treatment of PD.

PMID- 10331699
TI  - Charcot and the myth of misogyny.
AB  - OBJECTIVE: To evaluate Jean-Martin Charcot's attitudes toward women and evaluate
      contemporary and modern accusations of misogyny. BACKGROUND: During the last
      quarter of the nineteenth century, issues of women's health and feminism became
      increasingly a medical and political priority. Early neurologists, and
      specifically Charcot, have been criticized for retarding the advancement of
      women, but the issue has never been studied in detail. METHODS: Review of
      original documents from the Bibliotheque Charcot, archives of the Sorrel-Dejerine
      and Leguay families, and materials from the Academie de Medecine, Paris. RESULTS:
      Several lines of evidence demonstrate that Charcot, although highly authoritarian
      and patronizing toward patients and colleagues in general, fostered the concepts
      of advancing women in the medical profession and eliminating former gender biases
      in neurologic disorders. The first woman extern in Paris, Blanche Edwards, worked
      directly under Charcot, and he later became her thesis advisor. When women
      lobbied for entrance rights to the intern competition, Charcot was one of the few
      professors to sign the original petition of support. Charcot worked extensively
      with hysteria and female patients, although he energetically rejected the idea
      that the disorder was restricted to women. He categorically deplored ovariectomy
      as a treatment for women with hysteria. His most important scientific
      contribution in the study of hysteria was his identification of the disorder in
      men. CONCLUSIONS: Although overtly apolitical throughout his life and certainly
      not a feminist in the modern definition of the term, Charcot worked to
      incorporate women professionally into neurology, advanced areas of women's health
      through his long-term commitment to work in a largely women's hospital (the
      Salpetriere), and dispelled the prejudice that hysteria was a woman's malady.

PMID- 10331700
TI  - Correlation between rates of brain atrophy and cognitive decline in AD.
AB  - Twenty-nine untreated patients diagnosed with probable AD and 15 control patients
      underwent two or more clinical and volumetric MRI assessments with intervals
      ranging from 5 months to 6 years. The change in global cerebral volume for an
      individual was calculated by a novel method of registration and subtraction of
      serial scans. Rate of global cerebral volume loss correlated strongly with rate
      of change in Mini-Mental State Examination scores (r = 0.80, p < 0.001), implying
      clinical relevance to this marker of progression.

PMID- 10331701
TI  - Assessment of cognition in advanced AD: the test for severe impairment.
AB  - The Test for Severe Impairment (TSI) was compared with the Mini-Mental State
      Examination (MMSE) and a modified MMSE (mMMSE) in a multisite, longitudinal study
      of AD. The TSI correlated highly with the MMSE (r = 0.83) and the mMMSE (r =
      0.82), but was not redundant. There was a wide range of scores on the TSI among
      those scoring in the severely impaired range on the MMSE and mMMSE. The slope of
      cognitive change over time detected by the TSI was greater than that revealed by
      the MMSE or the mMMSE. Performance on the TSI was a significant predictor of
      survival. The TSI is a valid measure that is sensitive to cognitive change over
      time in severely demented patients with AD.

PMID- 10331702
TI  - ACTH versus vigabatrin therapy in infantile spasms: a retrospective study.
AB  - ACTH is the standard treatment for infantile spasms (IS) in North America. Recent
      reports showed that vigabatrin is a valuable treatment for IS, but comparative
      studies with ACTH are limited. In this study, we compare the effectiveness of
      ACTH versus vigabatrin on IS. Our results support that vigabatrin is as effective
      as and better tolerated than ACTH. Because of their similar efficacy, we believe
      that vigabatrin should be the first intention drug for the treatment of IS.

PMID- 10331703
TI  - Pervasive developmental disorder and epilepsy due to maternally derived
      duplication of 15q11-q13.
AB  - Duplications of chromosome 15 have been reported in individuals with atypical
      autism, varying degrees of mental retardation, and epilepsy. The authors report
      the molecular analysis, neurophysiologic, and clinical evaluation of a 12-year
      old boy with atypical autism and epilepsy due to a maternally derived 15q11-q13
      duplication. Their findings suggest that this chromosomal region harbors genes
      for autism and possibly for partial epilepsy that may act in a dose-dependent
      manner.

PMID- 10331704
TI  - Acute deterioration from thrombosis and rerupture of a giant intracranial
      aneurysm.
AB  - The authors describe a patient with an unusual clinicopathologic picture of giant
      aneurysmal hemorrhage followed by sudden deterioration due to acute intra
      aneurysmal thrombosis and fatal rebleeding. This patient underscores the poor
      natural history associated with this devastating disease and serves to highlight
      the dangers inherent in the delayed treatment of these life-threatening lesions.

PMID- 10331705
TI  - Corneomandibular reflex in ALS.
AB  - To clarify the diagnostic value of corneomandibular reflex (CMR) in ALS, the
      authors examined the prevalence of CMR and other pathologic reflexes in 42
      patients with ALS and 110 patients with stroke. A total of 30 of 42 ALS patients
      had positive CMR. Compared with the patients with hemiparesis or pseudobulbar
      palsy after stroke, the ALS patients showed a significantly higher frequency of
      CMR but no other pathologic reflexes. CMR is a sensitive indicator of upper motor
      neuron involvement in ALS.

PMID- 10331706
TI  - IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using
      Rituximab.
AB  - Current treatments for anti-GM1 ganglioside or antimyelin-associated glycoprotein
      (anti-MAG) antibody-associated polyneuropathies are toxic or very costly. In this
      preliminary study the authors treated five patients with neuropathy and
      immunoglobulin M antibodies to GM1 ganglioside or MAG by depleting B cells using
      Rituximab--a monoclonal antibody directed against the B-cell surface membrane
      marker CD20. Within 3 to 6 months after treatment, all five patients had improved
      function, significantly increased quantitative strength measurements, and reduced
      titers of serum autoantibodies.

PMID- 10331707
TI  - Cochlear histopathology associated with mitochondrial transfer RNA(Leu(UUR)) gene
      mutation.
AB  - Using dot-blot hybridization and Southern blotting, the authors detected a point
      mutation at nucleotide pair (np) 3243 in mitochondrial DNA from temporal bone
      sections of a woman with diabetes and deafness. The mutation could not be
      detected with agarose gel electrophoresis, suggesting that the degree of
      heteroplasmy is low. Histologically, there was marked degeneration of the stria
      vascularis and outer hair cells throughout the cochlea, as well as a reduction of
      spiral ganglion cells in the base. These findings suggest that the mutation
      affects these inner ear structures preferentially and that deafness can occur
      even when the proportion of np 3243 mutation is low.

PMID- 10331708
TI  - Oral cyclosporine decreases severity of neurotoxicity in liver transplant
      recipients.
AB  - Neoral is a new formulation of cyclosporine that permits reliable absorption in
      patients with external biliary drainage. The authors reviewed 227 liver
      transplant patients receiving primary treatment with Neoral. Headache occurred in
      24 patients (11%), mild tremors in 12 patients, paresthesia in 5 patients, acute
      confusional state in 4 patients, and seizures in 2 patients. It is apparent that
      Neoral has profoundly reduced the severity of neurotoxicity in liver transplant
      recipients.

PMID- 10331709
TI  - Pain medicine education among American neurologists: a need for improvement.
AB  - To assess pain medicine education, surveys were mailed to practicing neurologists
      (PNs) and residency program directors (PDs). Thirty percent of PNs felt
      adequately trained to diagnose and 20% to treat pain disorders. PNs stated that
      more pain education is needed for resident training (89%) and for PNs (91%). PDs
      ranked the importance of a pain subspecialty seventh out of eight subspecialties;
      only 29% reported having a neurology pain specialist on the faculty. These data
      strongly suggest a need to improve the pain medicine education of neurologists.

PMID- 10331710
TI  - Visual field constriction in children treated with vigabatrin.

PMID- 10331711
TI  - Oculogyric crisis as an initial manifestation of Wilson's disease.

PMID- 10331712
TI  - Diaphragmatic paralysis with monoclonal gammopathy and antiganglioside GM1
      antibodies.

PMID- 10331713
TI  - Serial magnetization transfer imaging to characterize the early evolution of new
      MS lesions.

PMID- 10331714
TI  - Prevalence of dementia over age 100.

PMID- 10331715
TI  - Hippocampal malformation as a cause of familial febrile convulsions and
      subsequent hippocampal sclerosis.

PMID- 10331716
TI  - Hippocampal damage and the onset of epilepsy.

PMID- 10331717
TI  - Acute delirium after withdrawal of amantadine in Parkinson's disease.

PMID- 10331718
TI  - Postictal nose wiping: a lateralizing sign in temporal lobe complex partial
      seizures.

PMID- 10331719
TI  - Postictal nose wiping: a lateralizing sign in temporal lobe complex partial
      seizures.

PMID- 10331721
TI  - Health care workers and tuberculosis: the battle of a century.

PMID- 10331720
TI  - Neglect after right hemisphere stroke.

PMID- 10331722
TI  - Treatment failure and MDR-TB.

PMID- 10331723
TI  - Managerial successes, clinical failures.

PMID- 10331724
TI  - Current asthma and biochemical signs of inflammation in relation to building
      dampness in dwellings.
AB  - SETTING: Study of current asthma in adults in relation to the indoor environment.
      OBJECTIVES: To assess the effect of building dampness in dwellings on the
      occurrence of current asthma, and biochemical signs of inflammation. DESIGN: A
      nested case-control study with 98 prevalent cases of asthma and 357 controls,
      within a stratified random population sample (20-45 years) from the Uppsala,
      Sweden, part of the European Community Respiratory Health Survey (ECRHS). Current
      asthma was defined as a combination of bronchial hyperresponsiveness and at least
      one asthma symptom (wheeze or attacks of breathlessness). Statistical
      calculations were made by multiple linear or logistic regression, adjusting for
      age, sex and smoking. RESULTS: Building dampness was found in 27% of dwellings.
      Current asthma was more common among subjects living in damp dwellings (odds
      ratio [OR] 1.8; 95% confidence interval [CI] 1.1-3.0), particularly with dampness
      in the floor construction (OR = 4.6; 95% CI 2.0-10.5). The average forced
      expiratory flow in one second (FEV1) was lower and peak expiratory flow (PEF)
      variability was higher in subjects from dwellings with floor dampness, and blood
      eosinophil count was increased in damp dwellings. No relation was found between
      immediate type allergy to house dust mites and current asthma or building
      dampness. Immediate type allergy to moulds (Cladosporium or Alternaria) was more
      prevalent in damp dwellings (9.3% vs 3.9%), and was related to current asthma (OR
      = 3.4; 95% CI 1.4-8.5). CONCLUSIONS: Building dampness is common in dwellings in
      Sweden, and seems to be related to an increase in current asthma and biochemical
      signs of inflammation. Immediate type allergy to house dust mites does not seem
      to be the explanation, but immediate type allergy to moulds could explain some of
      the findings.

PMID- 10331725
TI  - Increased risk of Mycobacterium tuberculosis infection related to the
      occupational exposures of health care workers in Chiang Rai, Thailand.
AB  - SETTING: Chiang Rai, the northernmost province of Thailand. OBJECTIVE: To
      evaluate the occupational risk for tuberculous infection of health care workers
      (HCWs) and the utility of tuberculin skin test (TST) in a developing country
      setting. DESIGN: A cross-sectional TST survey, including a risk assessment
      questionnaire, of Chiang Rai Hospital HCWs. RESULTS: Of 911 HCWs tested, 623
      (68%) had indurations of > or = 10 mm and 322 (35%) indurations of > or = 15 mm.
      Factors most predictive for TST positivity, using either cut-off, were employment
      > 1 year, frequent direct patient contact, and male sex. Moreover, having a
      bacillus Calmette-Guerin (BCG) scar was predictive of a > or = 10 mm, but not a >
      or = 15 mm, reaction. CONCLUSIONS: Chiang Rai Hospital HCWs had an increased risk
      for Mycobacterium tuberculosis infection, which was significantly associated with
      occupational exposure. Where BCG coverage is high, a TST cut-off of > or = 15 mm
      may correlate better with M. tuberculosis infection than does a cut-off of > or =
      10 mm. Effective, affordable infection control measures are needed for health
      care facilities in developing countries such as Thailand, where HCWs may be at
      increased risk for M. tuberculosis infection from occupational exposures.

PMID- 10331726
TI  - The cost of tuberculosis: utilization and estimated charges for the diagnosis and
      treatment of tuberculosis in a public health system.
AB  - SETTING: An urban tuberculosis (TB) control program. OBJECTIVE: The use of
      medical services was analyzed from diagnosis through completion of treatment for
      TB patients in a public health system in order to estimate charges and service
      utilization. DESIGN: The in- and out-patient medical records, including long term
      care and jail health service records, were retrospectively reviewed for the first
      100 patients diagnosed with TB in 1993 at a public hospital. Because the hospital
      did not have a cost-accounting system, charges were estimated based on a variety
      of sources. RESULTS: Complete records were available for 92 patients; one outlier
      was excluded. The resulting 91 patients represented 11% of newly diagnosed
      patients in Chicago in 1993. Overall, almost 99% of the charges reflected in
      patient (acute and long term care) utilization. Total charges of $3,154,583
      represent the charges to complete therapy for only 46 patients, or $68,578 per
      completed case. CONCLUSIONS: This study attempts to overcome the limitations of
      aggregate data sets by looking at individual patients followed longitudinally
      through a complex public health system. Expensive in-patient care may be
      partially, but not completely, replaced by directly observed therapy. The
      findings may be used to predict resource utilization for diagnosis and treatment
      programs.

PMID- 10331727
TI  - Longer delays in tuberculosis diagnosis among women in Vietnam.
AB  - SETTING: Study conducted in 23 randomly selected districts in four provinces of
      Vietnam. OBJECTIVE: To describe and compare health seeking behaviour between men
      and women and to measure delays in tuberculosis (TB) diagnosis. DESIGN: All
      patients (n = 1027) aged 15-49 years with new smear-positive pulmonary TB
      detected in the selected districts during 1996 were interviewed using a
      structured questionnaire. RESULTS: Mean total delay to TB diagnosis was 13.3
      weeks (95% confidence interval [CI] 11.5, 15.1) for women and 11.4 weeks (95% CI
      10.6, 12.2) for men, including a patient's delay of 7.9 weeks (95% CI 6.5, 9.3)
      and 7.6 weeks (95% CI 6.9, 8.3) respectively. Doctor's delay was significantly
      longer among women (5.4 weeks, 95% CI 4.2, 6.6) than among men (3.8 weeks, 95% CI
      3.3, 4.3). Women did not start seeking care later than men, nor did they have a
      different health seeking pattern. Women visited more health care providers than
      men (1.7 and 1.5 providers, respectively, P = 0.02). CONCLUSION: Patient's delay
      is unacceptably long for both men and women. Women do not receive a diagnosis of
      TB by doctors or other health care providers as quickly as men once they seek
      health care. The reasons for this gender difference warrant further
      investigations.

PMID- 10331728
TI  - Tuberculosis control in the Caucasus: successes and constraints in DOTS
      implementation.
AB  - SETTING: The pilot projects for tuberculosis (TB) control, supported by the World
      Health Organization (WHO) and based on the WHO recommended control strategy,
      directly-observed treatment, short-course (DOTS) in the Caucasian countries
      (Armenia, Azerbaijan, Georgia). OBJECTIVE: To evaluate the results 2 years after
      the implementation of the pilot projects. METHODS: Analysis of data on case
      detection, sputum conversion and treatment outcome reported quarterly to the WHO
      from the Ministries of Health in each country. RESULTS: Since the establishment
      of the project, 1330, 764 and 4866 new cases and relapses, respectively, of TB
      have been detected in the pilot areas of Armenia, Azerbaijan and Georgia. In
      Armenia and Azerbaijan, respectively 46% and 57% of all cases were smear
      positive, whilst in Georgia, the corresponding figure was only 12%. After 3
      months' treatment, 93% of new smear-positive patients had become smear-negative.
      The sputum conversion rate for relapses and other retreatment cases (failure,
      treatment interrupted) was 85%. In Armenia, 78.1% of new smear-positive patients
      were treated successfully (cured or completed treatment). The corresponding
      percentages for Azerbaijan and Georgia were 87.9% and 59.6%. Treatment success
      rates among retreatment cases was generally low, at respectively 46%, 64%, and
      35%, in Armenia, Azerbaijan, and Georgia. CONCLUSION: The results of the
      implementation of the WHO TB control pilot projects in Armenia, Azerbaijan and
      Georgia suggest that the DOTS strategy is feasible in emergency situations in
      general, and in the Caucasus in particular.

PMID- 10331729
TI  - Efficacy of an unsupervised ambulatory treatment regimen for smear-negative
      pulmonary tuberculosis and tuberculous pleural effusion in Malawi.
AB  - SETTING: Queen Elizabeth Central Hospital, Blantyre, and Zomba Central Hospital,
      Zomba, Malawi. OBJECTIVE: To evaluate treatment outcome of unsupervised
      ambulatory treatment (2R3H3Z3/2TH[EH]/4H) in Blantyre and 'standard' treatment
      (1STH[SEH]/11TH[EH]) in Zomba in human immunodeficiency virus (HIV) seropositive
      and seronegative patients with smear-negative pulmonary tuberculosis (PTB) and
      pleural TB. DESIGN: All patients with smear-negative and pleural TB registered
      between 1 April and 31 December 1995 were assessed for enrolment in the study.
      Study patients were followed up and 12-month treatment outcomes were recorded.
      RESULTS: A total of 434 patients, 296 with smear-negative PTB and 138 with
      pleural TB, were enrolled: 366 (84%) of patients were HIV-positive; 220 (51%)
      completed treatment, and 144 (33%) died by 12 months. In patients from Blantyre
      and Zomba, baseline characteristics were similar, apart from older age in those
      from Zomba, and the proportion of patients who completed treatment and who died
      were similar. In both sites, significantly higher case fatality rates were found
      in older patients, HIV-positive patients and patients with pulmonary parenchymal
      lung disease. CONCLUSION: Unsupervised ambulatory treatment evaluated in this
      study had an efficacy similar to that of 'standard' treatment. For operational
      reasons, however, it will not be recommended for widespread use in Malawi's
      National Tuberculosis Control Programme.

PMID- 10331730
TI  - Epidemiology of tuberculosis in Sardinia: a comparison of two data-gathering
      methods.
AB  - SETTING: A complete surveillance system for tuberculosis should be able to
      guarantee constant updating of incidence and provide useful data on a variety of
      problems related to tuberculosis such as drug resistance, co-infection with the
      human immunodeficiency virus (HIV), the geographic origin of patients, and
      mycobacterial species. OBJECTIVE AND DESIGN: To assess the completeness of the
      surveillance system currently operating in Sardinia, cases seen by all medical
      centres between 1987 and 1995 were compared with those notified to Sardinian
      Public Health Services for the same period. RESULTS: Each year, on average 39% of
      cases seen in Sardinia are notified; 646 (40%) of the 1591 patients notified
      during the study period were never seen by regional medical centres. An analysis
      of the results shows that from 1992 the decline recorded in incidence rates in
      previous years ceased: 1992 (26/100,000), 1993 (25/100,000), 1994 (28/100,000),
      and 1995 (24/100,000). CONCLUSIONS: The current surveillance system in Sardinia
      is inadequate for performing an accurate epidemiological survey of the disease.
      Epidemiological analysis based solely on notification can provide neither
      reliable incidence rates nor useful information concerning many aspects of
      tuberculosis.

PMID- 10331731
TI  - Estimation of serial interval and incubation period of tuberculosis using DNA
      fingerprinting.
AB  - OBJECTIVE: To determine the frequency distributions of serial interval and
      incubation period of tuberculosis within 4 years of transmission, and to identify
      correlates of serial intervals and incubation periods. METHODS: DNA fingerprints
      were obtained for all isolates from all culture-positive patients notified in The
      Netherlands from 1993 to 1996. Patient information was obtained from the National
      Tuberculosis Register. Results from contact investigations were provided by
      public health services. Source cases and secondary cases of tuberculosis were
      identified, based on 1) identical DNA fingerprints, and 2) epidemiological
      confirmation of contact. Under-representation of long intervals were corrected
      for by weighting cases. RESULTS: A total of 69 source-secondary case couples were
      identified. The geometric mean serial interval was 29.5 weeks (95% confidence
      interval [CI] 22.8-38.2 weeks) and the geometric mean incubation period 20.8
      weeks (95% CI 15.5-27.8 weeks). Serial intervals and incubation periods tended to
      increase with age (P > 0.05). Three secondary cases with human immunodeficiency
      virus infection showed very short incubation periods (P > 0.05). CONCLUSION:
      Using a new methodology, the distribution of incubation periods of tuberculosis
      gave results consistent with earlier studies.

PMID- 10331732
TI  - Clinical utility of a commercial ligase chain reaction kit for the diagnosis of
      smear-negative pulmonary tuberculosis.
AB  - SETTING: In paucibacillary forms of smear-negative tuberculosis it is very
      difficult to establish a correct and rapid diagnosis, as several weeks are
      usually required to obtain positive results from culture. In the last few years
      new rapid techniques based on molecular biology for the detection of
      Mycobacterium tuberculosis have been introduced. OBJECTIVE: The aim of this study
      was to evaluate the utility of the ligase chain reaction method (LCx, Abbott) for
      the diagnosis of smear-negative pulmonary tuberculosis. DESIGN: Thirty smear
      negative patients with radiographic changes and clinical signs consistent with TB
      participated in the study. Sputum and bronchial aspirate were assessed according
      to traditional methods on Lowenstein-Jensen medium, and bronchoalveolar lavage
      (BAL) was assessed by the LCx test and the Bactec 460 system. Another 30 patients
      with non-tuberculous infections were included in the study as controls. RESULTS:
      Of the 30 patients suspected of tuberculosis, 19 had active disease on clinical,
      bacteriological and radiographic grounds, nine inactive tuberculosis and two had
      lung cancer. Bacteriological confirmation was obtained in 12 of the 19 (63.2%)
      patients with active tuberculosis. The sensitivity of sputum culture was 42.1%
      and bronchial aspirate culture 47.4%. BAL fluid revealed positive results in
      57.9% using both LCx and Bactec. The results of the LCx assay can be obtained in
      5 hours as opposed to several weeks using other methods. CONCLUSION: The LCx test
      may be useful in the diagnosis of smear-negative pulmonary tuberculosis and may
      be recommended in these clinical situations.

PMID- 10331734
TI  - Single and multiple dose pharmacokinetics of rifapentine in man: part II.
AB  - OBJECTIVE: To characterize the pharmacokinetics of rifapentine following single,
      multiple, and intermittent doses. DESIGN: Twenty-three healthy male volunteers
      were randomized in a two-period, incomplete block, crossover design to receive
      two of four possible treatments: single daily oral rifapentine doses of 150, 300,
      or 600 mg given on day 1 and again on days 4-10, or a single oral 600 mg dose
      given on days 1, 4, 7, and 10. RESULTS: Maximum rifapentine plasma concentrations
      were observed in 4-5 hours. Mean rifapentine t(1/2) ranged from 13.2-14.1 hours
      and was similar across the 150-600 mg dose range. The changes in rifapentine Cmax
      (R = 0.86) and AUC(0-->infinity) (R + 0.90) were dose linear. The active 25
      desacetyl metabolite appeared slowly in plasma, with mean Tmax of 14.4-17.8
      hours. Mean t(1/2) for 25-desacetyl-rifapentine ranged from 13.3-24.3 hours.
      Disproportionate, dose-dependent increases in rifapentine and 25-desacetyl
      rifapentine AUC were observed as single doses of rifapentine increased from 150
      to 600 mg. At steady state, however, the magnitude of dose dependency was much
      less. CONCLUSION: Maximum plasma rifapentine concentrations were well above
      minimum inhibitory concentrations for Mycobacterium tuberculosis and M. avium
      following single 600 mg doses. In addition, the extended t(1/2) of rifapentine
      and its active metabolite support clinical investigation of once or twice-weekly
      rifapentine dosage regimens of rifapentine for the management of tuberculosis.

PMID- 10331733
TI  - Enzyme induction observed in healthy volunteers after repeated administration of
      rifapentine and its lack of effect on steady-state rifapentine pharmacokinetics:
      part I.
AB  - OBJECTIVE: To determine the effects of rifapentine on hepatic mixed function
      oxidase activity and to assess the effect of enzyme induction on the steady-state
      pharmacokinetics of rifapentine. STUDY DESIGN: Twenty-three healthy males were
      randomized to receive two of the following treatments in a two-period, four
      treatment, incomplete block, crossover design: single daily oral rifapentine
      doses of 150 mg (group A), 300 mg (group B), or 600 mg (group C) on study days 1
      and 4-10, or single oral rifapentine 600 mg doses given every 3 days for a total
      of four doses (group D). Serial blood samples were collected after the first and
      last rifapentine dose and assayed for rifapentine and its active metabolite, 25
      desacetyl-rifapentine. Urine was collected for determination of cortisol and 6
      hydroxycortisol concentrations. RESULTS: The ratio of 6beta
      hydroxycortisol:cortisol increased during rifapentine administration (+229%,
      +317%, and +357% on day 10 for groups A, B, and C, respectively). Ratios returned
      to baseline 2 weeks after the last dose. The per cent increase in the ratio of
      6beta-hydroxycortisol:cortisol following daily doses (+357%) was much higher
      compared with every 72-hour dosing (+236%). Single-dose and steady-state
      comparisons of AUCss(0-24) and AUC(0-->infinity) for both rifapentine and 25
      desacetyl-rifapentine were similar (P = NS) at corresponding doses of
      rifapentine. Mean t(1/2) at steady-state was 84-98% of corresponding single-dose
      values. CONCLUSION: Rifapentine is a potent inducer of CYP3A activity. However,
      single-dose pharmacokinetics of rifapentine predict steady-state exposure,
      indicating no autoinduction of rifapentine metabolism with repeated
      administration. Enzyme activity returns to predose levels within 2 weeks of the
      last daily dose of rifapentine.

PMID- 10331735
TI  - Tuberculosis patient care decentralised to district clinics with community-based
      directly observed treatment in a rural district of South Africa.
AB  - SETTING: A rural district of the Northern Province, South Africa. OBJECTIVES: To
      measure the effect of decentralisation of a tuberculosis service in a rural area
      on treatment outcomes. DESIGN: An intervention study that measured treatment
      outcomes of patients attending district clinics for tuberculosis treatment and
      compared these with outcomes of patients attending the district hospital.
      RESULTS: Over the 4-year period 1992-1995, 928 patients were admitted to the
      tuberculosis unit of the district hospital. In the initial pre-intervention
      phase, the best estimate of completed treatment for all 503 cases was 61%, and
      for 206 new smear-positive patients it was 67%. The intervention process
      established a tuberculosis control programme with directly observed treatment for
      all patients, and training and supervision of clinic staff. Ninety per cent of
      all patients had community-based supporters. For most patients, cure was not
      proven, but assuming success from completion of and proven adherence to
      treatment, successful outcomes for new smear-positive cases rose to 82% for
      decentralised (clinic) treatment, and 88% for those patients who lived in the
      district but attended the hospital for treatment. CONCLUSIONS: These findings
      suggest that district clinics can achieve the same good results as the hospital.
      It is recommended that tuberculosis control needs a dedicated co-ordinator at
      district level to manage the necessary infrastructural and staff resources.

PMID- 10331737
TI  - Two excellent management tools for national tuberculosis programmes.

PMID- 10331736
TI  - Inadequacy of the current WHO re-treatment regimen in a central Siberian prison:
      treatment failure and MDR-TB.
AB  - Multidrug-resistant tuberculosis (MDR-TB) threatens the progress of global
      control efforts. Prisons represent a high risk setting for development and
      transmission of MDR-TB. In a Siberian TB referral prison (Kemerovo region), the
      treatment failure rate is 35% (June 1996-March 1997), despite implementation of a
      strict DOTS program and use of the World Health Organization Category 2 re
      treatment regimen for all new cases. Among 164 patients (December 1997-March
      1998), initial resistance to isoniazid and rifampin is 22.6%. Such a rate is a
      warning call to reconsider prison control strategies, and importantly, to address
      the treatment regimens necessary to combat an institutional epidemic of MDR-TB.

PMID- 10331738
TI  - Bilateral haemorrhagic tuberculous pleuritis in an 81-year-old female.

PMID- 10331739
TI  - A novel hypothesis for the mechanism of action of P-glycoprotein as a multidrug
      transporter.
AB  - For years, P-glycoprotein (P-gp) has been purported to be a membrane transporter
      capable of selectively transporting many (but not all) lipophilic anticancer
      drugs with diverse chemical structures. Because the alleged functions of P-gp
      provide a straightforward, near-perfect explanation for the molecular mechanism
      of multidrug resistance associated with P-gp overexpression. However, the exact
      molecular mechanism for P-gp's purported function has never been clearly
      understood since its initial discovery some 20 yr ago. In this paper, I develop a
      novel working hypothesis regarding the mechanism of P-gp's action and suggest
      that P-gp is an energy-dependent efflux pump only for certain conjugated
      metabolites (probably sulfates) of the lipophilic anticancer drugs but not for
      the parent compounds, as was always claimed. According to this hypothesis, P-gp
      overexpression in most cases is not the "culprit" but instead an "accomplice" in
      P-gp-associated multidrug resistance. The culprit is probably the enhanced
      function of the metabolizing enzymes for the lipophilic anticancer drugs. This
      hypothesis also predicts that one of the important physiological functions of P
      gp is to be part of an intracellular machinery (together with the phase I and II
      metabolizing enzymes) for the metabolism, detoxification, and disposition of
      lipophilic endogenous chemicals as well as xenobiotics, including cytotoxic
      anticancer drugs. There exists a considerable body of circumstantial evidence in
      the literature that lends strong support to this mechanistic hypothesis of P-gp's
      action as well as to the predicted physiological functions of P-gp. It will be of
      considerable interest to examine this novel hypothesis experimentally.

PMID- 10331740
TI  - Association of apoptosis with the inhibition of extracellular signal-regulated
      protein kinase activity in the tumor necrosis factor alpha-resistant ovarian
      carcinoma cell line UCI 101.
AB  - Tumor necrosis factor-alpha (TNF alpha) can function as both an autocrine and a
      paracrine growth factor and may therefore play a role in ovarian tumor
      progression. TNF alpha initiates multiple cellular responses, many of which are
      mediated through the mitogen-activated protein kinase pathways, which transduce
      signals from the TNF alpha receptors through the cytoplasm to the nucleus,
      resulting in regulation of gene expression. We examined the role of c-jun N
      terminal kinase 1 (JNK1) and extracellular signal-regulated protein kinase (ERK)
      1 and 2 in the cellular growth response to TNF alpha in the ovarian carcinoma
      cell line UCI 101. JNK1 activity was increased to a maximum level ninefold above
      the basal level after 10-20 min of treatment with 10 ng/mL TNF alpha. A maximum
      threefold induction of ERK1/2 activity was observed after 1 min of treatment. At
      concentrations up to 100 ng/mL, TNF alpha had neither a stimulatory nor an
      inhibitory effect on growth of UCI 101 cells. However, inhibition of TNF alpha
      induced ERK1/2 activity by the MAP/ERK kinase 1 inhibitor PD 98059 resulted in
      60% inhibition of cell growth in TNF alpha-treated UCI 101 cells. This decrease
      in cell growth was accompanied by apoptosis, as demonstrated by the presence of a
      180-bp DNA ladder. Thus, the inhibition of TNF alpha-induced ERK1/2 activity was
      associated with induction of apoptosis in the TNF alpha-resistant cell line UCI
      101. Inhibition of TNF alpha-induced ERK1/2 activity was accompanied by a
      subsequent transient increase in TNF alpha-induced JNK1 activity. The
      significance of this increase with respect to apoptosis induction remains to be
      determined. These findings demonstrated that ERK1/2 activity can modulate
      cellular sensitivity to TNF alpha and suggested that the balance between the
      levels of ERK1/2 and JNK1 activation may be critical in the cellular growth
      response to TNF alpha.

PMID- 10331741
TI  - Correlation of c-myc overexpression and amplification with progression of
      preneoplastic liver lesions to malignancy in the poorly susceptible Wistar rat
      strain.
AB  - Persistent liver nodules (PNs) and hepatocellular carcinomas (HCCs) induced in
      F344 rats by the resistant hepatocyte (RH) model exhibit c-myc overexpression and
      amplification. The role of these changes in progression of PN was investigated in
      nodules with different propensities to evolve to HCC in resistant Wistar rats
      and, for comparison, in susceptible F344 rats. Initiation of rats with
      diethylnitrosamine was followed by selection with 2-acetylaminofluorene (AAF)
      plus partial hepatectomy (RH groups). Two additional Wistar rat groups received a
      second AAF treatment without (RH+AAF) and with a necrogenic dose of CCl4
      (RH+AAF/CCl4) 15 d after selection. The number to liver ratio and volume of
      glutathione-s-transferase placental form-positive lesions were lower in the
      Wistar than the F344 RH groups 9 and 32 wk after initiation and increased after a
      second AAF cycle treatment with and without CCl4. DNA synthesis in glutathione-s
      transferase placental form-positive lesions was low in Wistar RH group at 9 wk
      and was stimulated by additional AAF treatments. HCCs developed at 57-60 wk in
      F344 RH, Wistar RH+AAF, and RH+AAF/CCl4 rats. Tumor incidence and multiplicity
      were lower in RH+AAF rats than in RH+AAF/CCl4 and F344 rats. At 32 wk, PN
      exhibited c-myc overexpression that increased from RH to RH+AAF rats and to
      RH+AAF/CCl4 Wistar rats. This was associated with c-myc amplification in Wistar
      RH+AAF/CCl4 rats. These results showed correlation of c-myc overexpression and
      amplification with nodule propensity to progress to HCC in poorly susceptible
      Wistar rats and suggested a possible genetic mechanism for susceptibility to
      hepatocarcinogenesis. The experimental system used in this work may be a valuable
      tool for studies on molecular mechanisms underlying liver growth and
      tumorigenesis supported by c-myc overexpression.

PMID- 10331742
TI  - Analysis of oncogene, tumor suppressor gene, and chromosomal alterations in HeLa
      x osteosarcoma somatic cell hybrids.
AB  - Using a series of tumorigenic and non-tumorigenic somatic cell hybrids that
      resulted from the fusion of the human osteosarcoma cell line OHS50-P16T (P16T)
      with the HeLa cell line D98OR, we investigated the role that genetic mutations,
      including alterations of oncogenes, tumor suppressor genes, and chromosomes, play
      in P16T tumorigenicity. Analysis of a previously identified oncogene mutation, c
      myc amplification, in the P16T cell line demonstrated that both the tumorigenic
      and non-tumorigenic hybrids contained the amplified c-myc gene. Analysis of
      previously identified P16T tumor suppressor gene alterations, p53 mutation, and
      loss of RB1 expression demonstrated that the mutated p53 gene was selectively
      maintained in both the non-tumorigenic and tumorigenic hybrids, whereas loss of
      RB1 expression was not maintained in either the non-tumorigenic or tumorigenic
      hybrids. Chromosomes 11, 13, 17, and 22 were analyzed for loss of heterozygosity
      (LOH) to characterize the status of these previously described chromosomal
      alterations in the tumorigenic and non-tumorigenic hybrids. Loss of HeLa D98OR
      chromosome 22, with maintenance of P16T chromosome 22, was observed in the
      tumorigenic hybrids, a result confirmed by LOH analysis, which demonstrated the
      specific loss of HeLa chromosome 22 genetic material in the tumorigenic
      segregants. Together, these results demonstrated that amplified c-myc, mutant
      p53, and RB1 genes seem to be important in osteosarcoma tumorigenicity and that
      an additional altered gene or genes on chromosome 22 may play a key role in
      osteosarcoma tumorigenicity.

PMID- 10331743
TI  - Rare mutations of p53, Ki-ras, and beta-catenin genes and absence of K-sam and c
      erbB-2 amplification in N-methyl-N'-nitro-N-nitrosoguanidine-induced rat stomach
      cancers.
AB  - Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) have
      been widely used as a model for human stomach cancers of the differentiated type.
      However, there has been little information regarding their molecular basis. In
      this study, we examined the genetic alterations reported in human stomach cancers
      in 10 rat stomach cancers that had been induced in male ACI/N rats by
      administering MNNG in the drinking water. One of the 10 cancers had a mutation of
      the p53 gene at the second position of codon 171 (Val --> Glu). However, none of
      the 10 cancers had mutations in codons 12, 13, or 61 of Ki-ras or in the N
      terminal phosphorylation sites of the beta-catenin gene. Southern blot analysis
      showed no amplification of K-sam or c-erbB-2 in the seven cancers examined.
      Finally, we searched for microsatellite alterations in 12 loci in nine cancers,
      but no alterations were observed. As these genetic alterations are observed in
      only a minor fraction of human stomach cancers, further analysis of genetic and
      epigenetic alterations in MNNG-induced rat stomach cancers is needed to disclose
      the major mechanisms of stomach carcinogenesis.

PMID- 10331745
TI  - Expression of aberrant functional and nonfunctional transcripts of the FHIT gene
      in Burkitt's lymphomas.
AB  - The 3p14.2 chromosome region, which contains the FHIT gene and the FRA3B fragile
      site, is frequently altered in carcinomas. We analyzed the expression of the FHIT
      gene in 21 Burkitt's lymphoma cell lines and normal lymphoid populations.
      Seventeen (80%) of these cell lines had a common aberrant FHIT transcript as well
      as the normal transcript. Exon 2 was often aberrantly spliced to several coding
      exons, skipping exons 3 and 4, which overlap FRA3B. Other aberrant transcripts
      lacked exons 4-7 or exons 5-8. Exon 5, which has the initiation codon, was the
      most commonly affected. In two cell lines, Raji and KK124, there were aberrant
      transcripts retaining only the coding exons, which were able to make a normal
      protein, as demonstrated by in vitro transcription-translation analysis. In these
      aberrant messages, the additional deletion of 11 nucleotides at the beginning of
      exon 10 resulted in loss of translation. The cell line Ramos did not have a
      normal transcript. Some transcripts had common insertions of unknown origin that
      replaced coding exons, mainly exons 6 and 7. None of these aberrant messages
      coded for a protein, whether normal or aberrant. Within an individual cell line,
      aberrant messages appeared to result from sequential splicing reactions of a
      transcriptional unit derived from one allele. There was no correlation between
      aberrant FHIT transcription and the type of Burkitt's lymphoma regarding
      chromosomal translocation or presence of Epstein-Barr virus. In normal tonsils,
      spleen, and peripheral blood lymphocytes, aberrant transcripts were not detected
      and might represent a very minor subpopulation if detectable.

PMID- 10331744
TI  - Factors influencing elevation of intracellular Ca2+ in the MCF-10A human mammary
      epithelial cell line by carcinogenic polycyclic aromatic hydrocarbons.
AB  - Carcinogenic polycyclic aromatic hydrocarbons and a halogenated aromatic
      hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), were evaluated for their
      effects on intracellular Ca2+ in the human mammary epithelial cell line MCF-10A.
      After two 18-h incubations with MCF-10A cells, benzo[a]pyrene (BaP; 1, 3, and 10
      microM) produced a dose-dependent increase in intracellular Ca2+. 7,12
      Dimethylbenz[a]anthracene increased Ca2+ at 10 microM, whereas 3
      methylcholanthrene and TCDD did not. The Ca2+-elevating effect of BaP appeared to
      be dependent on the influx of extracellular Ca2+, as addition of the Ca2+
      chelator EGTA to the extracellular medium prevented the increase in Ca2+. MCF-10A
      cells were found by polymerase chain reaction to express cytochrome P4501A and
      P4501B isozymes as well as the aryl hydrocarbon receptor and aryl hydrocarbon
      receptor nuclear translocator mRNAs associated with cytochrome P450 induction.
      Certain cytochrome P450-derived metabolites, including benzo[a]pyrene-7,8-diol
      (BP-diol) and benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), were more effective in
      increasing Ca2+ than was BaP. The Ca2+-elevating effect of BP-diol was prevented
      by alpha-naphthoflavone, a cytochrome P4501A and P4501B inhibitor, but not by the
      antioxidant N-acetylcysteine. These results suggest that cytochrome P450
      dependent formation of BPDE from BP-diol is a major mechanism required for
      elevation of Ca2+ in MCF-10A cells.

PMID- 10331746
TI  - Involvement of mutations in the DPC4 promoter in endometrial carcinoma
      development.
AB  - To define the target of chromosome 18q loss of heterozygosity, which is prevalent
      in endometrial carcinomas, we made a deletion map from 64 tumors. Loss of
      heterozygosity on 18q was found in 20 tumors. Among these, 14 tumors carried
      deletions at the 18q21.1 region, where the DPC4 gene is located. DPC4
      transcription was disturbed in all six of the tumors with deletions at 18q21.1
      examined, which sharply contrasted with the positive transcription in 12 tumors
      that retained heterozygosity at the 18q21.1 region. However, in the 14 tumors
      with the 18q21.1 deletions, the remaining allele had the wild-type sequence of
      the DPC4 coding region instead of somatic mutations in the DPC4 coding region. We
      found a one- and two-base substitutions in the DPC4 promoter in two of the six
      tumors that showed disturbed DPC4 transcription. Chloramphenicol
      acetyltransferase assays clearly demonstrated that the mutant promoters had the
      potential to suppress or silence DPC4 transcription, implicating the DPC4 gene in
      endometrial carcinoma.

PMID- 10331748
TI  - Looking for the Forrest.

PMID- 10331747
TI  - Alterations in focal adhesion kinase activity and associated proteins during
      malignant conversion of mouse keratinocytes.
AB  - Focal adhesion kinase (pp125FAK) has well-established functions in the attachment
      and growth of cells in culture and has been implicated as a marker of malignant
      progression in human tumors. To evaluate its role in the metastatic conversion of
      mouse skin tumors, pp125FAK activity and protein expression were examined in
      normal and transformed keratinocyte cell lines. Malignant mouse keratinocyte
      lines exhibited a reproducible increase in the specific activity of pp125FAK
      compared with that of nontransformed control cells. An increase in pp125FAK
      activity was not observed in papilloma-derived keratinocytes, indicating that
      this response correlated with malignant progression of cells and not cell
      transformation per se. Immune complex kinase assays and metabolic labeling with
      [32P]orthophosphate also revealed the specific loss of pp125FAK-associated
      proteins in the metastatic keratinocytes. Furthermore, immunocytochemical
      examination revealed an altered distribution of pp125FAK in the cells with
      malignant potential compared with normal and papilloma-inducing keratinocytes.
      The cells with malignant potential also exhibited reduced levels of paxillin and
      integrin beta1 as well as altered distribution of paxillin, reinforcing the
      notion that specific changes in the composition of focal adhesions contribute to
      the malignant conversion of mouse keratinocytes.

PMID- 10331749
TI  - Effects of side lying on lung function in older individuals.
AB  - BACKGROUND AND PURPOSE: Body positioning exerts a strong effect on pulmonary
      function, but its effect on other components of the oxygen transport pathway are
      less well understood, especially the effects of side-lying positions. This study
      investigated the interrelationships between side-lying positions and indexes of
      lung function such as spirometry, alveolar diffusing capacity, and inhomogeneity
      of ventilation in older individuals. SUBJECTS AND METHODS: Nineteen nonsmoking
      subjects (mean age=62.8 years, SD=6.8, range=50-74) with no history of cardiac or
      pulmonary disease were tested over 2 sessions. The test positions were sitting
      and left side lying in one session and sitting and right side lying in the other
      session. In each of the positions, forced vital capacity (FVC), forced expiratory
      volume in 1 second (FEV1), single-breath pulmonary diffusing capacity (DLCO/VA),
      and the slope of phase III (DN2%/L) of the single-breath nitrogen washout test to
      determine inhomogeneity of ventilation were measured. RESULTS: Compared with
      measurements obtained in the sitting position, FVC and FEV1 were decreased
      equally in the side-lying positions, but no change was observed in DLCO/VA or
      DN2%/L. CONCLUSION AND DISCUSSION: Side-lying positions resulted in decreases in
      FVC and FEV1, which is consistent with the well-documented effects of the supine
      position. These findings further support the need for prescriptive rather than
      routine body positioning of patients with risks of cardiopulmonary compromise and
      the need to use upright positions in which lung volumes and capacities are
      maximized.

PMID- 10331750
TI  - Effects of repetitive handgrip training on endurance, specificity, and cross
      education.
AB  - BACKGROUND AND PURPOSE: Exercise programs are more likely to be successful when
      they are based on research that predicts the outcomes of such training. This
      study determined the effect of submaximal rhythmic handgrip training on rhythmic
      handgrip endurance or work (RHW), isometric handgrip endurance time (IHE), and
      maximal voluntary isometric contraction for the handgrip force (MVIC) (in
      newtons). SUBJECTS: Twenty-four male subjects (mean age=26.2 years) with right
      hand dominance were randomly assigned to a regular training group (n=8), a low
      level training group (n=8), or a control group (n=8). METHODS: Rhythmic handgrip
      work, IHE, and MVIC were determined bilaterally before and after 6 weeks of a
      rhythmic right handgrip training program using 30% of MVIC. The low-level
      training group performed daily training with a near-zero load (<0.005% of MVIC).
      RESULTS: There was a 1,232% increase in RHW and an 8% decrease in IHE after the
      training program using 30% of MVIC for the right hand. The left hand showed a 43%
      increase in RHW after training, whereas the low-level training group showed a 35%
      increase in RHW. No differences were found between the change in the left-hand
      RHW of the regular training group and the change in the right-hand RHW of the low
      level training group, but both measurements were greater than the change in the
      control group (6.4%). CONCLUSION AND DISCUSSION: Submaximal handgrip endurance
      training at 30% of MVIC had a minimal effect on submaximal IHE and MVIC of the
      handgrip, but it had a large effect on RHW of the trained extremity. The regular
      training group and the low-level training group showed similar increases in cross
      education, suggesting that cross-education during endurance training is not
      intensity-dependent.

PMID- 10331751
TI  - Cardiopulmonary responses of middle-aged men without cardiopulmonary disease to
      steady-rate positive and negative work performed on a cycle ergometer.
AB  - BACKGROUND AND PURPOSE: Understanding physiological responses to negative work
      allows therapists to be more knowledgeable when they prescribe this form of
      exercise. The physiological responses of 12 men without cardiopulmonary disease,
      aged 39 to 65 years (X=49.7, SD=9.3), to negative work (eccentric muscle
      contractions) and to positive work (concentric muscle contractions) were
      compared. SUBJECTS AND METHODS: Subjects performed the 2 types of work on a
      motorized cycle ergometer at pedaling frequencies of 35, 55, and 75 rpm with a
      constant power output of 60 W. Steady-rate values of oxygen consumption (VO2),
      heart rate (HR), minute ventilation (VE), tidal volume (VT), and breathing
      frequency (fb) were obtained during 6 test conditions (positive and negative work
      at each of the 3 pedaling frequencies). RESULTS: Values for all measures were
      greater during positive work than during negative work, except for fb. During
      positive work, values for all variables were greatest at 75 rpm, except for fb.
      During negative work, VO2 and HR were greater at 75 and 35 rpm than at 55 rpm,
      and VE and VT were greater at 75 rpm than at 55 rpm. Breathing frequency was not
      different among pedaling frequencies. CONCLUSION AND DISCUSSION: The results
      confirmed that negative work performed on a cycle ergometer is associated with
      low metabolic cost in older men without cardiopulmonary disease. Although VE was
      determined primarily by changes in VT during negative work, a comparable
      disproportionate increase in fb was observed at the start of negative work. Such
      changes in breathing patterns have implications for the prescription of negative
      work for patients with lung disease.

PMID- 10331752
TI  - Multiple system atrophy.
AB  - Multiple system atrophy is a neurological disorder that has gone unrecognized for
      too long due to its involvement across multiple regions of the central nervous
      system. This disorder is finally being unveiled through increased reporting in
      the scientific literature. Further research will enhance our understanding of
      this disease and lead to more effective treatment regimens as well as an improved
      quality of life for patients with MSA.

PMID- 10331753
TI  - Health promotion for people with disabilities: the emerging paradigm shift from
      disability prevention to prevention of secondary conditions.
AB  - The premise of this article is that, until recently, health promotion for people
      with disabilities has been a neglected area of interest on the part of the
      general health community. Today, researchers, funding agencies, and health care
      providers and consumers are leading an effort to establish higher-quality health
      care for the millions of Americans with disabilities. The aims of a health
      promotion program for people with disabilities are to reduce secondary conditions
      (eg, obesity, hypertension, pressure sores), to maintain functional independence,
      to provide an opportunity for leisure and enjoyment, and to enhance the overall
      quality of life by reducing environmental barriers to good health. A greater
      emphasis must be placed on community-based health promotion initiatives for
      people with disabilities in order to achieve these objectives.

PMID- 10331754
TI  - Causes of injury from cervical manipulation.

PMID- 10331755
TI  - Global call to action on MR safety.

PMID- 10331757
TI  - Endoluminal MR imaging of anorectal diseases.
AB  - Endoluminal magnetic resonance imaging (MRI) has become an important technique in
      the diagnostic work-up of patients with anorectal diseases. The high spatial
      resolution of endoluminal MRI gives a detailed demonstration of the anal and
      rectal anatomy and pathology. This technique has been demonstrated to be superior
      to endoluminal sonography and body coil MRI. Endoanal MRI and phased-array coil
      MRI seem to have comparable results in perianal fistulas, but comparative data
      are lacking. Phased-array coil MRI is the imaging technique of choice for imaging
      rectal tumors, while endoluminal MRI is the alternative technique for imaging
      rectal tumors and the preferred technique for imaging anal tumors. Endoluminal
      MRI is superior to phased-array coil MRI in fecal incontinence, as phased-array
      coil MRI does not give the detailed spatial resolution required for evaluation of
      anal sphincter lesions.

PMID- 10331756
TI  - Comprehensive regulations concerning exposure of employees to electromagnetic
      fields.

PMID- 10331758
TI  - Solitary vertebral collapse: distinction between benign and malignant causes
      using MR patterns.
AB  - Differentiation of benign from malignant causes of vertebral compression fracture
      can be difficult at a single location. We studied 37 patients with solitary
      vertebral collapse (SVC) in the spine using magnetic resonance imaging (MRI).
      Sixteen of them were found to have a benign cause of SVC, while the remaining 21
      were found to have malignancy. The following four MRI characteristics were
      investigated: ill- or well-defined margin of the intravertebral lesion (P <
      0.005); pedicle involvement (P < 0.05); MR enhancement pattern (P < 0.005); and
      paravertebral soft tissue lesion (PSL) (P < 0.025). It was found that cases of
      malignant SVC tended to have an ill-defined margin, abnormal signal involvement
      of the pedicle, a marked and heterogenous MR enhancement pattern, and irregular
      nodular-type PSL. Pedicle change with expansile lesion totally excluded a benign
      cause. By using these criteria, we were able to differentiate benign or malignant
      causes of SVC accurately.

PMID- 10331759
TI  - Monitoring radiation-induced changes in bone marrow histopathology with ultra
      small superparamagnetic iron oxide (USPIO)-enhanced MRI.
AB  - The purpose of this study was to monitor radiation-induced alterations of the
      blood-bone marrow barrier (BMB) and the reticuloendothelial system (RES) with AMI
      227-enhanced magnetic resonance imaging (MRI). Twenty New Zealand white rabbits
      (n = 10 following total body irradiation and n = 10 controls) underwent AMI-227
      enhanced MRI. Pulse sequences included dynamic fast low-angle shot (FLASH; TR/TE
      50/4 msec, flip angle 60 degrees) MRI and static T1- and T2-weighted spin-echo
      (SE) and turbo-SE sequences of the lumbar spine and sacrum. Bone marrow
      enhancement was quantified as delta signal intensity (SI) (%) =|[(SIpost -
      SIpre)/SIpre] x 100%| and compared with histopathology, including iron stains and
      electron microscopy. Dynamic bone marrow deltaSI (%) data steadily increased up
      to 10-15 minutes after AMI-227 administration, while blood deltaSI (%) data
      stayed nearly constant, histologically corresponding to iron oxide leakage into
      the bone marrow interstitium. This bone marrow contrast enhancement increased
      significantly following irradiation, corresponding to alterations of the
      endothelial lining of the bone marrow sinusoids. Late postcontrast images
      exhibited a significant positive T1 enhancement and negative T2 enhancement of
      the normal bone marrow, which further increased with irradiation due to increased
      RES activity. Irradiation-induced changes in bone marrow physiology could be
      reliably assessed with AMI-227-enhanced MRI.

PMID- 10331760
TI  - A novel approach to observing articular cartilage deformation in vitro via
      magnetic resonance imaging.
AB  - The design of a pressure cell that compresses a cartilage specimen in one
      dimension within an imaging magnet is presented. One-dimensional projection
      images in a direction perpendicular to the articular surface of the cartilage
      specimen were used to generate a uniaxial confined deformation creep curve for
      normal and trypsin-degraded cartilage specimens during a continuous 0.690 MPa
      (100 psi) pressure application. The resulting curves are shown to fit a two time
      constant viscoelastic model well and also indicate that the elastic modulus of
      cartilage decreases and the deformation rate increases upon trypsin proteolysis.
      Furthermore, cartilage permeability is shown as a function of cartilage strain
      for both the normal and trypsin-degraded case. Several two-dimensional slice
      selective images were collected both before and after 80 minutes of continuous
      compression. These images were used to evaluate the relative changes in the spin
      lattice, T1, and spin-spin, T2, relaxation time constant maps for both normal and
      degraded cartilage specimens in response to compression. The results of this
      study demonstrate the utility of a novel, non-magnetic, cartilage compression
      device and also support the validity of a simple two-component rheological model
      of articular cartilage.

PMID- 10331761
TI  - Locally focused contrast-enhanced carotid MRA.
AB  - With conventional Fourier transform (FT) magnetic resonance imaging (MRI), it is
      difficult to perform contrast-enhanced three-dimensional (3D) MR angiography
      (MRA) with the temporal and spatial resolution necessary to depict the carotid
      arteries. However, locally focused (LF) MRI is a more efficient method that
      utilizes prior knowledge of the image content to reconstruct images from sparse k
      space samples. In this paper, we show how LF MRI can be used to perform high
      resolution gadolinium (Gd)-enhanced 3D carotid MRA in less than 10 seconds.
      First, the accuracy of the technique was demonstrated by comparing LF and
      conventional (FT) images of a vascular phantom. Then the method was used to
      perform Gd-enhanced 3D MRA of a patient's carotid arteries. Instead of using
      bolus timing, the arterial phase was retrospectively identified in a consecutive
      series of images, just as in X-ray angiography.

PMID- 10331762
TI  - Motion measurements from individual MR signals using volume localization.
AB  - A novel method is presented for measuring motion using individual magnetic
      resonance (MR) signals. This method uses a volume-localized excitation with
      reduced spatial encoding to measure displacement with a temporal resolution of
      several milliseconds. The trajectory of the excited volume is derived from the
      time-dependent frequency of the MR signal, which changes as the volume moves
      through a magnetic-field gradient. Phantom and in vivo experiments confirm that
      this method can monitor the trajectory of plug-like structures accurately, with
      T2* decay limiting the measurement period. The displacement of flowing blood in a
      human aorta has been measured for 65 msec from one MR signal, with a theoretical
      accuracy of 0.25 mm and an effective time resolution of 2 msec. The high temporal
      resolution of this method is useful for capturing rapid motions. An interesting
      property of this method is that it measures motion from the reference frame of
      the moving anatomy.

PMID- 10331763
TI  - Myocardial "low reflow" assessed by Dy-DTPA-BMA-enhanced first-pass MR imaging in
      a dog model.
AB  - The aim of this study was to determine whether the use of a magnetic resonance
      (MR) susceptibility contrast medium, dysprosium diethylenetriamine pentaacetic
      acid-bismethylamide (Dy DTPA-BMA; Sprodiamide), may characterize myocardial
      perfusion abnormalities in a dog model of 90 minutes of coronary occlusion
      followed by 24 hours of reperfusion (no-reflow phenomenon installed). First-pass
      MR imaging after an intravenous bolus administration of the contrast agent was
      performed at the end of reperfusion. Signal intensity analysis on MR imaging,
      planimetry of pathological data, and blood flow determination were obtained by
      reference methods for comparison. Dogs were separated into two groups according
      to the level of collateral blood flow level (group I, <22.5 % of the flow in the
      non-ischemic zone; group II, >22.5 % of the flow in the non-ischemic zone).
      Signal intensity-time curves in the ischemic and non-ischemic left ventricle
      walls were extracted. Mean collateral blood flow was lower during occlusion in
      group I (9.8 +/- 5.4%, n = 5) than in group II (38 +/- 12.5%, n = 7, P < 0.05).
      Mean infarct size (expressed as a percentage of the area at risk) was
      significantly larger in group I (low collateral blood flow; 25.3 +/- 14.6%) than
      in group II (high collateral blood flow; 5.8 +/- 1.1%, P < 0.05). After rapid
      injection, a transient decrease of signal intensity induced by Dy DTPA-BMA was
      observed in both remote and ischemic myocardium but more markedly in remote
      normally perfused myocardium. Hence, during the transit of a susceptibility-type
      contrast agent, ischemic myocardium after ischemia and reperfusion appeared as a
      relative high signal intensity area. First-pass MR imaging with susceptibility
      contrast agent demonstrated the no- or low-reflow phenomenon. However, the
      behavior of the myocardial signal intensity-time-related curves did not allow
      distinction between the two groups of dogs.

PMID- 10331765
TI  - MR imaging of focal lung lesions: elimination of flow and motion artifact by
      breath-hold ECG-gated and black-blood techniques on T2-weighted turbo SE and STIR
      sequences.
AB  - Respiratory and cardiac motion correction may result in better turbo spin-echo
      (SE) imaging of the lung. To compare breath-hold cardiac-gated black-blood T2
      weighted turbo SE and turbo short-inversion-time inversion-recovery (STIR)
      magnetic resonance (MR) imaging pulse sequences with conventional breath-hold
      turbo SE and half-Fourier acquisition single-shot turbo spin-echo (HASTE)
      sequences for lesion conspicuity of focal lung lesions, 42 patients with focal
      lung lesions were prospectively studied with MR imaging at 1.5 T. Helical
      computed tomography was used as a reference. In comparison with the conventional
      breath-hold turbo SE sequence, all black-blood sequences had fewer image
      artifacts arising from the heart and blood flow. The overall image quality for
      the black-blood turbo SE and turbo STIR sequences was superior to that for the
      breath-hold turbo SE and HASTE sequence (P < 0.01). Not only focal lung lesions
      but also surrounding inflammatory changes were clearly visualized with these two
      sequences. With the HASTE sequence, although several slices could be obtained in
      one breath-hold, both the tumor and vessels appeared blurred. We conclude that T2
      weighted turbo SE and turbo STIR imaging of the lung with effective suppression
      of flow and motion artifacts provide high-quality images in patients with focal
      lung lesions.

PMID- 10331764
TI  - Tumor blood volume assays using contrast-enhanced magnetic resonance imaging:
      regional heterogeneity and postmortem artifacts.
AB  - Tumor blood volume (BV), subject to both morphologic and physiologic influences,
      can be measured using contrast-enhanced magnetic resonance imaging (MRI). The
      aims of this study were to determine whether MRI enhanced with a macromolecular
      contrast medium (MMCM) could resolve differences in BV between different tumor
      types, between different regions within tumors, and within the same tumor in life
      and after death. Tumor BV estimates were based on the MRI signal intensity
      responses in the tumors and in reference venous blood following enhancement with
      a blood pool MMCM using two mammary adenocarcinoma models. Estimates of BV were
      made before and immediately following death. An in vitro measurement of tumor
      gadolinium concentration following death was correlated with MRI enhancement.
      Statistically significant differences (P < 0.05) were observed in MRI-estimated
      tumor BV between tumor subtypes, between in vivo and postmortem measurements, and
      between the tumor periphery and tumor centers. MRI assays enhanced with a
      macromolecular contrast agent can resolve blood volume differences between tumor
      types, between regions within the same tumor, and between vital and postmortem
      states.

PMID- 10331766
TI  - In vitro measurements of water content and T2 relaxation times in lung using a
      clinical MRI scanner.
AB  - The purpose of this study was to validate water content measurements and to
      determine the T2 distribution in lung on a 1.5 T clinical magnetic resonance
      imaging (MRI) scanner. A single-slice 16 echo pulse sequence with an echo spacing
      of 10 msec was employed to scan 19 healthy juvenile pig lungs. The in vitro water
      content of each lung was measured using MRI techniques and compared with
      gravimetric measurements. The mean difference between the gravimetric and MRI
      water contents was -4.1 +/- 7.6%, and an excellent linear correlation (R2 = 0.98)
      was observed between the two independent measurements. The dependence of the
      geometric mean T2 time upon lung water density exhibited two distinct regions
      (inflated and deflated) separated by a threshold density of about 0.4 g/mL.

PMID- 10331767
TI  - Delayed MR imaging of hepatocellular carcinoma enhanced by gadobenate dimeglumine
      (Gd-BOPTA).
AB  - The purpose of this study was to determine the efficacy of gadobenate dimeglumine
      (Gd-BOPTA)-enhanced magnetic resonance (MR) imaging for evaluation of
      hepatocellular carcinoma HCC. MR images were obtained in 14 patients with 31 HCC
      nodules as a part of a phase III clinical trial. T1- and T2-weighted images were
      obtained before and after iv administration of 0.1 mmol/kg of Gd-BOPTA. Two
      blinded readers evaluated pre- and delayed postcontrast images separately for
      detection of tumor nodules. Quantitative measurements of signal-to-noise (SNR)
      and tumor/liver contrast-to-noise (CNR) ratios were also performed. A
      signal/intensity ratio was calculated. Tumor enhancement was correlated with
      histologic findings. Consensus agreement of precontrast T1- and T2-weighted
      images revealed 23/31 HCC nodules in 14 patients; postcontrast T1-weighted images
      demonstrated 24/31 HCC nodules in the same number of patients. Combining both pre
      and postcontrast images, 27/31 lesions were detected. Four patients had four
      well-differentiated HCC nodules detected only on postcontrast images, while three
      well-differentiated lesions in two patients were only seen on precontrast images.
      Quantitative evaluation showed an SNR ratio increase in both liver parenchyma and
      HCC nodules, as well as a significant increase in the absolute CNR ratio on
      postcontrast T1-weighted gradient-recalled images (P < 0.05). Well-differentiated
      HCC lesions showed a greater enhancement than poorly differentiated HCC lesions.

PMID- 10331768
TI  - Aging of the adult human brain: in vivo quantitation of metabolite content with
      proton magnetic resonance spectroscopy.
AB  - The purpose of this study was to examine the effect of aging on brain metabolite
      concentrations, including N-acetyl aspartate (NAA), the major marker of neurones,
      using short echo proton spectroscopy. Single-voxel proton spectra (TE 30 msec, TR
      2 seconds) were obtained from white and gray matter using automated software
      (PROBE, G.E., Milwaukee, WI). Spectra were analyzed using the variable projection
      technique. Thirty healthy volunteers were studied within the age range 24-89
      years. No significant trend in change of concentrations of NAA, total creatine,
      total choline or myo-inositol were seen with age. The total creatine
      concentration of parietal white matter in the over 60 age group (6.5 +/- 0.3
      mmol/l) was significantly higher than the under 60 age group (6.0 +/- 0.4
      mmol/l:; P < 0.05). No other significant difference between the two age groups
      was seen. The tissue concentration of the major neuronal marker, NAA, does not
      decline with age. No age-related changes in the concentrations of choline and myo
      inositol and occipital gray matter total creatine were observed. These results
      provide a normal range of values for spectroscopically detectable metabolites
      within the regions studied, against which neurological diseases such as
      Alzheimer's disease can be compared in vivo.

PMID- 10331769
TI  - Partial wavelet encoding: a new approach for accelerating temporal resolution in
      contrast-enhanced MR imaging.
AB  - We propose a new approach using wavelet encoding to improve temporal resolution
      in contrast-enhanced magnetic resonance (MR) imaging. Exploiting the unique
      property of wavelets localized in space and frequency, we construct an efficient
      encoding scheme to capture signal changes due to contrast agent uptake, which in
      general is spatially localized with low- and mid-range frequency components. On
      the basis of space-frequency analysis, we describe mathematical formulations of
      our method and discuss its theoretical advantages over Fourier-based phase
      encoding methods (the keyhole and reduced-encoding imaging by generalized-series
      reconstruction [RIGR] techniques). The results obtained in computer simulations
      and a phantom study demonstrate the feasibility and practical advantages of our
      approach.

PMID- 10331770
TI  - Shielded biplanar gradient coil design.
AB  - An application of the target field method to the design of shielded biplanar
      gradient coils for magnetic resonance imaging electromagnets is presented. Some
      specific cases are studied, and optimized geometries are proposed for the axial
      and transverse gradient coils that eliminate the third- and minimize the fifth
      order terms in the magnetic field expansion.

PMID- 10331771
TI  - Lactate detection at 3T: compensating J coupling effects with BASING.
AB  - Detection of lactate by in vivo 1H magnetic resonance spectroscopy may provide a
      means of identifying regions of metabolic stress in brain and other human tissue,
      potentially identifying regional ischemia in stroke or necrosis in tumors. At
      higher field strengths (3 and 4 T), which have recently become available for
      whole-body human studies, the chemical shift difference between the doublet from
      the methyl protons and the quartet from the methine proton becomes comparable to
      the available radiofrequency (RF) pulse bandwidth. In this case "anomalous" J
      modulation occurs in PRESS and STEAM because the coupling partner of the observed
      resonance may or may not be refocused by the RF pulses depending on the position
      of the molecule within the voxel and the size of the chemical shift
      misregistration artifact. These anomalies lead to signal cancellation for echo
      times near odd multiples of 1/J (often used to highlight the inverted lactate
      doublet against nearby lipid peaks) in single voxel studies, and spatial
      variation of the doublet lineshape in chemical shift imaging studies, producing
      erroneous determination of relative lactate concentrations. While increasing the
      band-width of the RF pulses can reduce this effect by reducing the signal
      cancellation, some cancellation will always remain. A means of eliminating this
      effect using BASING/ MEGA (Mescher M et al. Solvent suppression using selective
      echo dephasing J Magn Reson A 1996;123:226-229; Star-Lack J et al. Improved water
      and lipid suppression for 3D PRESS CSI using RF band selective inversion with
      gradient dephasing (BASING). Magn Reson Med 1997;38: 311-321) water suppression
      pulses will be described, along with some of its limitations.

PMID- 10331772
TI  - Use of navigator-echo-gated MRI to diagnose a coronary shunt involving an
      anomalous origin of the right coronary artery from the pulmonary artery.
AB  - Origin of the right coronary artery from the main pulmonary artery is an anomaly
      that can cause formation of a left-to-right coronary shunt, leading to myocardial
      ischemia and early onset of congestive heart failure. We describe a case in which
      magnetic resonance imaging was able to show the anomalous origin of the right
      coronary artery, and magnetic resonance phase velocity mapping was able to
      demonstrate the presence of a left-to-right shunt through the coronary artery by
      showing retrograde flow in the right coronary artery.

PMID- 10331773
TI  - Improved diagnosis of contrast-enhancing brain lesions with multifunctional MRI
      assessment: a case report.

PMID- 10331774
TI  - Contrast optimization for assessment of the colonic wall and lumen in MR
      colonography.
AB  - This report focuses on the optimization of magnetic resonance colonography for
      combined virtual endoluminal and T2-weighted wall analysis of the colon and
      demonstrates the potential of the single-shot fast spin-echo (SSFSE) sequence for
      identifying colorectal pathologies. A 45 degrees flip angle in the three
      dimensional spoiled gradient-echo sequence and a TE of 60 msec in the SSFSE
      sequence in conjunction with a 10 mM gadolinium concentration in the enema
      results in maximal contrast for the delineation of the colonic lumen in T1
      weighted imaging and the colonic wall in T2-weighted imaging. The SSFSE sequence
      reveals hyperintense signal for inflammatory disease and most polyps exceeding 10
      mm in size. It supplements the virtual endoluminal assessment by aiding in the
      differentiation between mass lesions and fecal matter or residual air.

PMID- 10331775
TI  - Fast 3D cardiac cine MR imaging.
AB  - We describe a technique for three-dimensional cine MR imaging. By using short
      repetition times (TR) and interleaved slice encoding, volumetric cine data can be
      acquired throughout the cardiac cycle with a temporal resolution of approximately
      80 msec. A T1-shortening agent is used to produce contrast between blood and
      myocardium. A comparison between the acquisition times of this and several other
      two-dimensional techniques is presented.

PMID- 10331776
TI  - IPOs: is the party really over?

PMID- 10331777
TI  - Cloned genes, goats, and the future of the biopharm.

PMID- 10331778
TI  - Research & development. Basic science and pharmaceutical innovation.

PMID- 10331779
TI  - Genetic databases. Decoding developments in Iceland.

PMID- 10331780
TI  - Patent amplification.

PMID- 10331781
TI  - Patent amplification.

PMID- 10331782
TI  - Uncloaking RNases.

PMID- 10331783
TI  - EPA biotech rule reviewed yet again.

PMID- 10331784
TI  - Biotechs hedge against big pharma givebacks.

PMID- 10331785
TI  - Hercules and Kairos catalyze enzyme deal.

PMID- 10331786
TI  - European biotechnology governance seizes up.

PMID- 10331787
TI  - Biotech blooms in Europe's BioValley.

PMID- 10331789
TI  - Engineering a bioartificial kidney.

PMID- 10331788
TI  - "GM-free" food labels are value-free.

PMID- 10331790
TI  - Catalytic DNA: in training and seeking employment.

PMID- 10331791
TI  - Ciliates display promise for foreign gene expression.

PMID- 10331792
TI  - Spying on the hidden lives of proteins.

PMID- 10331793
TI  - Plant protein secretion on tap.

PMID- 10331795
TI  - Public biotech 98: the numbers.

PMID- 10331794
TI  - Transgenic phytoremediation blasts onto the scene.

PMID- 10331796
TI  - Developing biotechnology around the world.

PMID- 10331797
TI  - European biotechnology turns East.

PMID- 10331798
TI  - New blood for Taiwanese biotechnology.

PMID- 10331799
TI  - Sustaining the growth of UK biotechnology.

PMID- 10331800
TI  - Kick-starting biotechnology in Ontario.

PMID- 10331801
TI  - Promoting life science in Lyon.

PMID- 10331802
TI  - Biotechnology is booming in Washington State.

PMID- 10331803
TI  - Replacement of renal function in uremic animals with a tissue-engineered kidney.
AB  - Current renal substitution therapy with hemodialysis or hemofiltration has been
      the only successful long-term ex vivo organ substitution therapy to date.
      Although this approach is life sustaining, it is still unacceptably suboptimal
      with poor clinical outcomes of patients with either chronic end-stage renal
      disease or acute renal failure. This current therapy utilizes synthetic membranes
      to substitute for the small solute clearance function of the renal glomerulus but
      does not replace the transport, metabolic, and endocrinologic functions of the
      tubular cells. The addition of tubule cell replacement therapy in a tissue
      engineered bioartificial kidney comprising both biologic and synthetic components
      will likely optimize renal replacement to improve clinical outcomes. This report
      demonstrates that the combination of a synthetic hemofiltration device and a
      renal tubule cell therapy device containing porcine renal tubule cells in an
      extracorporeal perfusion circuit successfully replaces filtration, transport,
      metabolic, and endocrinologic functions of the kidney in acutely uremic dogs.

PMID- 10331804
TI  - Production of goats by somatic cell nuclear transfer.
AB  - In this study, we demonstrate the production of transgenic goats by nuclear
      transfer of fetal somatic cells. Donor karyoplasts were obtained from a primary
      fetal somatic cell line derived from a 40-day transgenic female fetus produced by
      artificial insemination of a nontransgenic adult female with semen from a
      transgenic male. Live offspring were produced with two nuclear transfer
      procedures. In one protocol, oocytes at the arrested metaphase II stage were
      enucleated, electrofused with donor somatic cells, and simultaneously activated.
      In the second protocol, activated in vivo oocytes were enucleated at the
      telophase II stage, electrofused with donor somatic cells, and simultaneously
      activated a second time to induce genome reactivation. Three healthy identical
      female offspring were born. Genotypic analyses confirmed that all cloned
      offspring were derived from the donor cell line. Analysis of the milk of one of
      the transgenic cloned animals showed high-level production of human antithrombin
      III, similar to the parental transgenic line.

PMID- 10331805
TI  - Surface display of a parasite antigen in the ciliate Tetrahymena thermophila.
AB  - The ciliated protozoan, Tetrahymena thermophila, offers an attractive medium for
      the expression of heterologous proteins and could prove particularly useful for
      the display of foreign proteins on the cell surface. Although progress has been
      made in transformation of Tetrahymena with heterologous DNA, methods that permit
      reliable expression of foreign genes have been lacking. Using a mutant strain of
      T. thermophila carrying a negatively selectable allele of a beta-tubulin gene, we
      have been able to direct foreign genes to this locus by homologous recombination.
      Transformed cell lines producing foreign proteins were readily identified and, in
      at least one case, targeting of proteins to the plasma membrane was accomplished.

PMID- 10331806
TI  - Production of recombinant proteins in plant root exudates.
AB  - The large-scale production of recombinant proteins in plants is limited by
      relatively low yields and difficulties in extraction and purification. These
      problems were addressed by engineering tobacco plants to continuously secrete
      recombinant proteins from their roots into a simple hydroponic medium. Three
      heterologous proteins of diverse origins (green fluorescent protein of jellyfish,
      human placental alkaline phosphatase [SEAP], and bacterial xylanase) were
      produced using the root secretion method (rhizosecretion). Protein secretion was
      dependent on the presence of the endoplasmic reticulum signal peptide fused to
      the recombinant protein sequence. All three secreted proteins retained their
      biological activity and, as shown for SEAP, accumulated in much higher amounts in
      the medium than in the root tissue.

PMID- 10331807
TI  - A system for the propagation of adenoviral vectors with genetically modified
      receptor specificities.
AB  - The development of genetically modified adenovirus (Ad) vectors with specificity
      for a single cell type will require both the introduction of novel tropism
      determinants and the ablation of endogenous tropism. Consequently, it will not be
      possible to exploit the native cellular entry pathway in the propagation of these
      targeted Ad vectors. Based on the concept that Ad enters cells by a two-step
      process in which a primary receptor serves as a high affinity binding site for
      the Ad fiber knob, with subsequent internalization mediated by alpha v integrins,
      we designed two artificial primary receptors. The extracellular domain of one of
      these synthetic receptors was derived from a single-chain antibody (sFv) with
      specificity for Ad5 knob, while the second receptor consisted of an icosapeptide
      identified by biopanning a phage display library against Ad5 knob. Expression of
      either of these artificial virus-binding receptors in fiber receptor-negative
      cells possessing alpha v integrins conferred susceptibility to Ad infection. We
      then created a novel mechanism for cell binding by genetically modifying both the
      vector and the target cell. In this approach, six histidine (His) residues were
      incorporated at the C-terminal of the Ad fiber protein. The resultant Ad vector
      was able to infect nonpermissive cells displaying the cognate artificial
      receptor, containing an anti-His sFv. This strategy, comprising a genetically
      engineered Ad virion and a modified cell line, should be useful in the
      propagation of targeted Ad vectors that lack the ability to bind the native fiber
      receptor.

PMID- 10331808
TI  - Reduction of fibronectin expression by intravitreal administration of antisense
      oligonucleotides.
AB  - We have investigated whether antisense oligonucleotides delivered intravitreally
      could reduce gene expression specifically in the retina. In this study,
      phosphorothioate antisense oligonucleotides targeted to fibronectin transcripts
      were coupled to a novel carrier and used to specifically reduce fibronectin (FN)
      expression in retinal vascular cells. Using confocal microscopy, fluorescence
      from fluorescein isothio-cyanate-labeled FN-oligonucleotides was detected in
      retinal vascular cells at 24 h postinjection and persisted until day 6 (the end
      point of this study). The fibronectin mRNA level was consistently decreased to
      86.7% +/- 7.9% of control (p<0.05) at day 2, and 46.7% +/- 4.9% of control
      (p<0.01) at day 6. In contrast, the beta-actin mRNA level, an internal control,
      was unaltered in rat retinas that received FN-oligonucleotides. Fibronectin
      protein level at day 6 was also significantly reduced to 61.4% +/- 16% of control
      (p<0.01). No toxic effect resulting from the carrier was detected histologically.
      Thus, intravitreal delivery of antisense oligonucleotides to modulate abnormal
      gene expression in retinal diseases may be an effective approach for ocular gene
      therapy.

PMID- 10331809
TI  - Target site selection for an RNA-cleaving catalytic DNA.
AB  - A small catalytic DNA, known as the 10-23 DNA enzyme or deoxyribozyme, has been
      shown to efficiently hydrolyze RNA at purine-pyrimidine (R-Y) junctions in vitro.
      Although these potentially cleavable junctions are ubiquitous, they are often
      protected from deoxyribozyme activity by RNA secondary structure. We have
      developed a multiplex cleavage assay for screening the entire length of a target
      RNA molecule for deoxyribozyme cleavage sites that are efficient, both in terms
      of kinetics and accessibility. This strategy allowed us to simultaneously compare
      the RNA cleaving activity of 80 deoxyribozymes for a model target gene (HPV16
      E6), and an additional 60 deoxyribozymes against the rat c-myc target. The human
      papilloma virus (HPV) target was used primarily to characterize the multiplex
      system and determine its validity. The c-myc target, coupled with a smooth muscle
      cell proliferation assay, allowed us to assess the relationship between in vitro
      cleavage efficiency and c-myc gene suppression in cell culture. The multiplex
      reaction approach streamlines the process of revealing effective deoxyribozymes
      in a functional assay and provides accessibility data that may also be applicable
      to site selection for other hybridization-based agents.

PMID- 10331810
TI  - A signal sequence trap based on a constitutively active cytokine receptor.
AB  - Targeting of secreted and cell-surface proteins to the cell membrane is mediated
      by a short hydrophobic stretch of amino acids, termed the signal sequence. We
      have developed a method that detects signal sequences in cDNA fragments based on
      their ability to redirect a constitutively active mutant of a cytokine receptor
      to the cell surface, thereby permitting interleukin-3 (IL-3)-independent growth
      of Ba/F3 cells. Retrovirus-mediated expression of the fusions in IL-3-dependent
      cells was followed by selection of clones for growth in the absence of IL-3.
      Infection of cells with 5x10(6) viral particles in a pilot experiment led to the
      isolation of 150 known and 48 novel cDNA clones, and all the known cDNA clones
      were found to encode secreted and cell-surface proteins. In addition, we isolated
      type II membrane proteins, which have not been detected by existing signal
      sequence trap strategies.

PMID- 10331812
TI  - A soybean cDNA encoding a chromatin-binding peptide inhibits mitosis of mammalian
      cells.
AB  - A soybean cDNA encoding the small subunit peptide of a cotyledon-specific 2S
      albumin (Gm2S-1) is thought to play a role in arresting mitosis during the DNA
      endoreduplication and cell expansion phase of seed development. The peptide
      (termed lunasin) contains the cell adhesion motif Arg-Gly-Asp (RGD) followed by
      eight aspartic acid residues at its C-terminal end. A chimeric gene encoding the
      lunasin peptide tagged with green fluorescent protein (GFP) arrested cell
      division, caused abnormal spindle fiber elongation, chromosomal fragmentation,
      and cell lysis when transiently transfected into murine embryo fibroblast, murine
      hepatoma, and human breast cancer cells. Deletion of the polyaspartyl end
      abolished the antimitotic effect. Subcellular localization of lunasin and
      immunobinding assay using synthetic peptides revealed the preferential adherence
      of lunasin to chromatin. Immunofluorescence showed that kinetochore proteins were
      displaced from the centromere in lunasin-transfected cells. These observations
      suggest that lunasin binds to the chromatin, leading to disruption of kinetochore
      formation and inhibition of mitosis.

PMID- 10331811
TI  - Biodegradation of explosives by transgenic plants expressing pentaerythritol
      tetranitrate reductase.
AB  - Plants offer many advantages over bacteria as agents for bioremediation; however,
      they typically lack the degradative capabilities of specially selected bacterial
      strains. Transgenic plants expressing microbial degradative enzymes could combine
      the advantages of both systems. To investigate this possibility in the context of
      bioremediation of explosive residues, we generated transgenic tobacco plants
      expressing pentaerythritol tetranitrate reductase, an enzyme derived from an
      explosive-degrading bacterium that enables degradation of nitrate ester and
      nitroaromatic explosives. Seeds from transgenic plants were able to germinate and
      grow in the presence of 1 mM glycerol trinitrate (GTN) or 0.05 mM
      trinitrotoluene, at concentrations that inhibited germination and growth of wild
      type seeds. Transgenic seedlings grown in liquid medium with 1 mM GTN showed more
      rapid and complete denitration of GTN than wild-type seedlings. This example
      suggests that transgenic plants expressing microbial degradative genes may
      provide a generally applicable strategy for bioremediation of organic pollutants
      in soil.

PMID- 10331813
TI  - Taxing biotechnology.

PMID- 10331814
TI  - Continuing education and networking in the workplace.

PMID- 10331815
TI  - Web cloning.

PMID- 10331816
TI  - Tissue engineering.

PMID- 10331817
TI  - Clinical pharmacy: just what the patient ordered.

PMID- 10331818
TI  - Clinical pharmacy services and hospital mortality rates.
AB  - We evaluated the associations between clinical pharmacy services and mortality
      rates in 1029 United States hospitals. A data base was constructed from Medicare
      mortality rates from the Health Care Financing Administration and the National
      Clinical Pharmacy Services data base. A multivariate regression analysis,
      controlling for severity of illness, was employed to determine the associations.
      Four clinical pharmacy services were associated with lower mortality rates:
      clinical research (p<0.0001), drug information (p=0.043), drug admission
      histories (p=0.005), and participation on a cardiopulmonary resuscitation (CPR)
      team (p=0.039). The actual number of deaths (lower) associated with the presence
      of these four services were clinical research 21,125 deaths in 108 hospitals,
      drug information 10,463 deaths in 237 hospitals, drug admission histories 3843
      deaths in 30 hospitals, and CPR team participation 5047 deaths in 282 hospitals.
      This is the first study to indicate that both centrally based and patient
      specific clinical pharmacy services are associated with reduced hospital
      mortality rates. This suggests that these services save a significant number of
      lives in our nation's hospitals.

PMID- 10331819
TI  - Gabapentin: a review of published experience in the treatment of bipolar disorder
      and other psychiatric conditions.
AB  - Successful therapy with valproate and carbamazepine in patients with psychiatric
      disorders led to investigation of other anticonvulsants for similar indications.
      Gabapentin is a relatively new anticonvulsant being investigated for potential
      use in the treatment of bipolar disorder (BD), anxiety disorders, behavioral
      dyscontrol, and substance use disorders. Its favorable side effect profile,
      absence of the need for therapeutic drug monitoring, and minimal drug
      interactions give gabapentin a potential role in these indications. Computer
      searches of the biomedical literature were undertaken to identify all pertinent
      case reports, case series, and studies of the drug as monotherapy or adjunctive
      therapy for BD; 10 reports were retrieved. In the treatment of various anxiety
      disorders, one study, one case report, and one case series were identified. At
      least one case series described gabapentin therapy for alcohol withdrawal and one
      case report of the drug for agitation associated with dementia. Published, well
      designed studies evaluating the agent's effectiveness as monotherapy for BD are
      lacking. Its benefit as an adjunctive treatment with other mood stabilizers is
      also unestablished. Data regarding its efficacy in the treatment of anxiety
      disorders or manifestations of substance abuse are limited. These areas may
      deserve further investigation.

PMID- 10331821
TI  - The role of dehydroepiandrosterone in diabetes mellitus.
AB  - Much has been written in the lay literature regarding potential benefits of
      dehydroepiandrosterone (DHEA). Although it was removed from the over-the-counter
      market in 1985, the Dietary Supplement Health Education Act of 1994 allowed the
      drug to be marketed as a food supplement. Because DHEA no longer falls under the
      scrutiny of the Food and Drug Administration, many unverified claims have been
      put forth in the press espousing its therapeutic value. This barrage of
      "infomercials" has left the average American consumer (and health care
      professional) curious about DHEA and its possible therapeutic utility. One focus
      of recent research is to define the role of DHEA in diabetes mellitus. Although
      it has been claimed that decreased levels of endogenous DHEA are associated with
      diabetes, impaired glucose tolerance, hyperglycemia, and insulin resistance, much
      of the information is based on cross-sectional studies. Other claims correlate
      decreased endogenous DHEA levels with adverse cardiovascular effects. Some
      information is contradictory and indicates high doses of exogenous DHEA may
      produce adverse cardiovascular effects, an undesirable outcome in patients with
      diabetes mellitus. At this time, its administration in patients with diabetes is
      not warranted. Long-term trials evaluating the role of exogenous DHEA and its
      effect on patients with diabetes should be conducted.

PMID- 10331820
TI  - The impact of first-line antihypertensive drugs on erectile dysfunction.
AB  - Erectile dysfunction, a problem estimated to affect up to 30 million American
      men, is associated with a number of systemic illnesses and drugs. Age is not
      thought to be an independent risk factor for the disorder, but accompanying
      illnesses and their treatments may contribute to its onset. Newer classes of
      antihypertensive agents are less frequently associated with sexual dysfunction
      than diuretics or beta-blockers. However, nearly every first-line
      antihypertensive drug has been reported to cause some degree of erectile
      dysfunction. Management options include lifestyle modification, dosage reduction,
      discontinuation of the offending agent, switching to an alternative drug, and
      pharmacologic therapy.

PMID- 10331822
TI  - Prophylactic antibiotics for severe acute pancreatitis: the beginning of an era.
AB  - Death from acute severe pancreatitis results from infection and multiple organ
      system failure occurring late in the course of illness. Patients with necrotizing
      pancreatitis involving at least one-third of the organ are at highest risk of
      secondary infection and death. We conducted a MEDLINE search to identify human
      trials of prophylactic antibiotics in acute pancreatitis. Results of early
      studies of prophylactic ampicillin to avoid secondary infection and death were
      negative, but the studies included patients with mild disease who are at low risk
      for infection. Antibiotics were beneficial in four recently completed studies:
      imipenem significantly reduced pancreatic and nonpancreatic sepsis (p< or =0.01);
      cefuroxime reduced all infectious complications (p<0.01) and deaths (p=0.0284); a
      regimen of ceftazidime, amikacin, and metronidazole reduced all infectious
      complications (p<0.03); and protocol use of imipenem significantly reduced
      pancreatic infection compared with nonprotocol antibiotics (p=0.04) and no
      antibiotics (p<0.001). Based on these results, we suggest early antibiotic
      prophylaxis in patients with necrotizing pancreatitis, but the best drug and
      duration of therapy are unknown.

PMID- 10331823
TI  - Itraconazole in cyclodextrin solution.
AB  - Itraconazole, a water-insoluble oral triazole antifungal, has been formulated in
      cyclodextrin as a solution. Cyclodextrin is a ring of glucose molecules that can
      accept a lipophilic guest molecule within the ring. This enables solubilization
      and delivery to the lipid interface of the gut lumen, resulting in absorption of
      the guest molecule without absorption of the ring. This new system enhances the
      absorption of itraconazole. Improved blood and tissue levels of itraconazole and
      topical effect in mucosal disease should result in greater efficacy for a variety
      of indications, particularly patients with gastroenteropathy in whom absorption
      of earlier preparations was sometimes problematic.

PMID- 10331824
TI  - Pharmacokinetics and protein binding of eprosartan in hemodialysis-dependent
      patients with end-stage renal disease.
AB  - STUDY OBJECTIVES: To compare eprosartan pharmacokinetics in hemodialysis patients
      and in volunteers with normal renal function, and to determine the effect of
      hemodialysis on these values. DESIGN: Open-label, parallel-group, single-dose
      study. SETTING: Outpatient hemodialysis treatment center and an industry
      affiliated clinical pharmacology unit. PATIENTS: Ten healthy volunteers and nine
      hemodialysis patients. INTERVENTION: A single oral dose of eprosartan 400 mg was
      administered to volunteers on 1 day and to patients on 2 days (a nondialysis and
      a dialysis day). Patients underwent high-flux hemodialysis. MEASUREMENTS AND MAIN
      RESULTS: Concentrations of eprosartan in plasma and dialysate were assayed by
      high-performance liquid chromatography; plasma protein binding was determined by
      ultrafiltration. Eprosartan pharmacokinetics showed greater variability in
      patients than in volunteers. However, six of nine patients had exposures that
      were within the range observed for volunteers. Mean total AUC(0-t) was increased
      approximately 60% (95% CI-22, 225) in patients. Total Cmax was similar between
      groups (PE = 1.01, 95% CI -40, 71). Mean percent fraction unbound (%f(u)) in
      patients (3.02%) was significantly greater than that in volunteers (1.74%).
      Unbound AUC(0-t) and unbound Cmax were, on average, approximately 172% (95% CI
      28, 479) and 73% (95% CI -1, 199) greater, respectively, in patients. After
      hemodialysis, the mean %f(u) decreased from 3.19-2.01%. Mean recovery of
      eprosartan in dialysate was 6.8 mg (range 0-23.1 mg) and hemodialytic clearance
      was approximately 11 ml/minute, which does not represent a significant portion of
      total clearance. CONCLUSIONS: Eprosartan was safe and well tolerated in both
      groups. Based on its known safety profile and because of its exaggerated
      pharmacokinetic variability in patients undergoing hemodialysis, treatment should
      be individualized based on tolerability and response. Supplemental doses of
      eprosartan after hemodialysis are unnecessary.

PMID- 10331825
TI  - A pilot study of the efficacy of constant-infusion ceftazidime in the treatment
      of endobronchial infections in adults with cystic fibrosis.
AB  - STUDY OBJECTIVE: To compare the efficacy of constant-infusion ceftazidime (CTZ)
      with that of traditional intermittent dosing in a pilot trial. DESIGN:
      Prospective, crossover trial. SUBJECTS: Five adults with cystic fibrosis
      requiring intravenous antibiotic therapy for pulmonary exacerbations of the
      disease. INTERVENTIONS: Patients were initially treated with standard CTZ 2 g 3
      times/day for 10 days. At the next hospitalization patients were crossed over and
      CTZ was administered as a constant infusion at a rate determined to achieve a
      serum concentration 6.6 times the minimum inhibitory concentration (MIC) of the
      least susceptible Pseudomonas aeruginosa isolate. MEASUREMENTS AND MAIN RESULTS:
      The pharmacokinetics of CTZ were determined, as were MICs for all P. aeruginosa
      isolates. Outcome parameters of interest were changes with therapy in white blood
      cell count, P aeruginosa density in sputum, and pulmonary function test results.
      Differences in these parameters for the two forms of administration were not
      significant. With the exception of one patient who received 6 g/day with both
      regimens, the average reduction in dosage with the constant infusion was 50%.
      CONCLUSION: These preliminary data suggest that constant-infusion CTZ may be as
      safe and efficacious as intermittent dosing.

PMID- 10331826
TI  - Antiischemic therapy in patients with coronary heart disease living in long-term
      care. Systematic Assessment of Geriatric Drug Use by Epidemiology (SAGE) Group.
AB  - We evaluated antiischemic therapy in elderly nursing home residents with a
      diagnosis of coronary heart disease (CHD) using a population-based data base with
      over 300,000 residents (1992-1995) of all Medicare/Medicaid-certified nursing
      homes of five states. We identified 72,263 patients age 65 years or older with a
      diagnosis of CHD. We examined data collected with the federally mandated Minimum
      Data Set, drug information, and Medicare hospital claims. Antiischemics were
      defined as beta-adrenergic blockers, long-term nitrates, and calcium channel
      blockers. We determined factors associated with use of the drugs by logistic
      regression. Antiischemic therapy was inversely related to age and cognitive and
      physical functioning, but positively associated with recent hospitalization and
      concomitant cardiovascular diseases. beta-Adrenergic blockers were least likely
      to be administered regardless of age, gender, or cognitive or physical function.
      We conclude that antiischemic therapy in nursing home residents may not be
      optimal.

PMID- 10331827
TI  - Prophylactic magnesium to decrease the arrhythmogenic potential of class III
      antiarrhythmic agents in a rabbit model.
AB  - We assessed the prophylactic effect of intravenous magnesium sulfate on the
      occurrence of torsades de pointes and early after-depolarizations, and on the QT
      interval (QTc) in an established rabbit model. Ten rabbits were given intravenous
      methoxamine to slow their heart rates. After 12 minutes five animals received a
      60-mg/kg bolus and continuous infusion of magnesium 0.6 mg/kg/minute, and five
      received equivolume normal saline concurrently with the class III antiarrhythmic
      agent clofilium 5 mg/kg over 30 minutes. Electrocardiogram lead II and the
      monophasic action potential were recorded continuously throughout the experiment.
      The magnesium group experienced significantly less torsades de pointes and early
      after-depolarizations than the normal saline group (1/5 and 5/5 both parameters,
      respectively, p=0.048). There were no differences between groups in QT or QTc
      interval at baseline or at maximum QT or QTc prolongation. Magnesium decreases
      the occurrence of torsades de pointes without affecting the QT or QTc interval
      but does decrease the occurrence of early after-depolarizations. These findings
      must be validated in human studies.

PMID- 10331828
TI  - Experience with ceftazidime parenteral-to-parenteral dosage stepdown in the
      empiric treatment of febrile neutropenia.
AB  - We assessed the clinical and economic impact of a new parenteral-toparenteral
      stepdown program involving ceftazidime for the treatment of febrile neutropenia.
      This was a two-phase (before and after), 12-month, single-center, prospective
      study with a historical control. Ninety-eight ceftazidime treatment courses (47
      preintervention, 51 postintervention) were administered for management of febrile
      neutropenia in 85 adults with hematologic malignancies. Multidisciplinary
      creation and promotion of parenteral-to-parenteral ceftazidime stepdown criteria
      were applied at the discretion of the health care team. Patient demographics
      between phases were similar. Only 2 (4%) treatment courses before the
      intervention involved parenteral-to-parenteral dosage stepdown, compared with 34
      (67%) after the intervention (p<0.00001). Mean number of total ceftazidime
      doses/treatment course and mean duration of therapy did not change between
      phases. Clinical cure or improvement was identified in 74% and 80% of treatment
      courses before and after the intervention, respectively. The two main reasons for
      discontinuing the drug before the intervention were recovery of neutrophil count
      (60%) and adverse reactions (19%). Neutrophil count recovery (59%) and hospital
      discharge (14%) were the two most common reasons for discontinuation after the
      intervention. Of 34 stepdown treatment courses after the intervention, 3 (9%)
      failed to meet established stepdown criteria, and 2 of these required stepdown
      reversal. Ancillary antibacterial drugs and treatment course outcomes were
      similar between phases. Total ceftazidime acquisition cost for 704 treatment days
      in the preintervention phase was $52,473 CAN compared with $54,778 CAN for 907
      days of therapy in the postintervention phase. The mean acquisition
      cost/ceftazidime treatment course was $1100 CAN and did not differ between
      phases. The mean daily cost of ceftazidime therapy was lower after the
      intervention ($60.39 vs $74.54 CAN) as a result of a greater frequency of
      stepdown (p<0.001). Assuming an equivalent number of treatment days, the
      projected annual acquisition cost avoidance associated with this stepdown program
      was $19,900 CAN.

PMID- 10331829
TI  - Economic evaluation of three methods of treating urogenital chlamydial infections
      in the emergency department.
AB  - We attempted to determine the economic impact of three alternatives for the
      treatment of chlamydial infections in the emergency department: a written
      prescription for 7 days of doxycycline therapy (D-RX); a prepacked 7-day supply
      of doxycycline (D-ED); or a single 1-g dose of azithromycin (AZI). Data inputs
      for the model were obtained from both patient experience and literature sources.
      Primary health outcomes of the model were number of infection relapses. Economic
      outcomes were costs for initial treatment, treatment of relapses, and treatment
      of complications of relapse. For every 1000 patients, D-ED and AZI resulted in
      21.6 (-10 to -41) and 36.2 (-25 to -63) fewer relapses than D-RX, respectively;
      AZI resulted in 14.6 (-35 to -4) fewer relapses than D-ED. Total costs were
      decreased for D-ED and AZI versus D-RX by $18,879 (-$39,000 to -$8000) and
      $24,039 (-$59,000 to -$10,000), respectively, and AZI resulted in a total cost
      decrease of $5160 (-$35,000 to +$6000) versus D-ED. Both D-ER and AZI decreased
      infection relapses and overall health care costs compared with D-RX. Also, AZI
      resulted in additional decreases in relapses versus D-ED, although the
      incremental impact on cost was inconclusive.

PMID- 10331830
TI  - Patterns of prescribing ACE inhibitors after myocardial infarction.
AB  - We attempted to determine physician prescribing patterns of angiotensin
      converting enzyme (ACE) inhibitors in patients who experienced a myocardial
      infarction, stratified by left ventricular function. We retrospectively reviewed
      drug therapy at discharge in 534 patients to assess prescription of ACE inhibitor
      therapy, including dosage. Thirty-four percent of patients were discharged taking
      an ACE inhibitor, of whom only 11% received recommended dosages. The drugs were
      prescribed more often for patients who had an ejection fraction below 40% than
      for those with an ejection fraction of 40% or above (54% vs 28%, p<0.05). We
      conclude that ACE inhibitors are underprescribed for patients who experienced a
      myocardial infarction, illustrating the gap between clinical research and
      clinical practice, and the need for programs to ensure optimal medical
      management.

PMID- 10331831
TI  - Mycobacterium fortuitum meningitis associated with an epidural catheter: case
      report and a review of the literature.
AB  - Mycobacterium fortuitum is a rapidly growing organism that has rarely been
      associated with meningitis. A patient developed M. fortuitum meningitis as the
      result of a permanent indwelling, contaminated, epidural catheter. Diagnosis and
      treatment of the disease are difficult in that clinical features may be indolent,
      and many antimicrobials with activity against M. fortuitum have minimal
      cerebrospinal fluid penetration. This patient was cured with an antibiotic
      regimen that consisted of doxycycline, ciprofloxacin, imipenem, and
      clarithromycin, and removal of the epidural catheter.

PMID- 10331832
TI  - Carbamazepine-induced hepatorenal failure in a child.
AB  - Carbamazepine is used to manage generalized tonic-clonic, partial, and mixed
      partial and generalized seizure disorders in children. It is frequently
      associated with neurologic adverse events, Stevens-Johnson syndrome, and
      hematologic side effects. Hepatic and renal adverse effects are less common but
      can cause death. A 6-year-old boy receiving carbamazepine for partial seizure
      disorder developed hepatorenal failure. With discontinuation of the drug, his
      liver and kidney function returned to normal within 2 weeks.

PMID- 10331833
TI  - Critical pathways or treatment algorithms in infectious diseases: do they really
      work?

PMID- 10331834
TI  - Adolescents' diaries.

PMID- 10331835
TI  - Patterns of sexual partnerships among adolescent females.
AB  - OBJECTIVE: To develop a multidimensional classification of sexual partnerships.
      METHODS: Eighty-two female subjects (ages 15-20 years; 77% African American) used
      coital logs to record dates of 1265 coital events, partner initials, and condom
      use. Logs were collected at 1-, 3-, 9-, 15-, and 21-month return visits. Three
      adolescent health professionals independently classified partnership patterns of
      each subject; classification schemes were revised until complete consensus for
      each subject was obtained. RESULTS: Complete agreement in partnership
      classification was reached after 3 rounds. The consensus partnership
      classification had three dimensions: number (1, > or = 2 partners), pattern (1
      partner, serially exclusive, concurrent), and duration (any partnership < or = 21
      days, all partnerships >21 days). A total of 34 of 82 (34%) of subjects had > or
      = 2 partners; 11 of 34 (32%) had concurrent partnerships. Twenty of 82 (24%) had
      only partnerships lasting >21 days. Condom use was less common for subjects in
      only longer-term (>21 days) partnerships, but did not significantly vary by
      number or pattern. CONCLUSION: Multiple dimensions of adolescent sexual
      partnerships may be identified. Detailed research and clinical assessments along
      these dimensions may improve understanding of protective behaviors such as condom
      use.

PMID- 10331836
TI  - Sociodemographic correlates of virginity in seventh-grade black and Latino
      students.
AB  - PURPOSE: To examine rates of virginity in seventh-grade black and Latino students
      and assess the extent to which various sociodemographic factors are correlated
      with virginity. METHODS: A total of 523 seventh-grade students from five junior
      high schools and one middle school in the District of Columbia completed an
      anonymous self-administered questionnaire. Students responded to questions about
      age at first intercourse, demographics, grades, educational expectations, and
      risk behaviors. Multivariate analysis was used to determine the independent
      strength of the association of these variables with virginity. RESULTS: Eighty
      one percent of girls and 44% of boys reported never having had sexual
      intercourse, i.e., being virgins. Black and Latino students were equally as
      likely to report being virgins. Younger age and absence of other risk behaviors,
      including smoking and alcohol use, were associated with virginity for males and
      females. For boys, reporting high academic achievement and living with both
      parents was significantly correlated with virginity and appeared to be
      protective. CONCLUSIONS: Although prevalent particularly in seventh-grade black
      and Latino boys, sexual activity was clearly associated with other risk behaviors
      in both boys and girls. Sociodemographic correlates of virginity were gender
      specific. School-based efforts to delay the onset of initiation of sexual
      activity in high-risk populations should be targeted at boys 12 years and younger
      with interventions which are gender-specific. This study underscores a need to
      examine correlates of virginity to generate practical approaches to prevention of
      early sexual activity.

PMID- 10331837
TI  - Adolescents' pregnancy intentions: relations to life situations and caretaking
      behaviors prenatally and 2 years postpartum.
AB  - PURPOSE: This study explores if and how adolescents' pregnancy intentions relate
      to life situations and health-related behaviors prenatally and up to 2 years
      postpartum. METHODS: Adolescent girls who reported that they had "wanted a baby"
      (n = 75) as their reason for pregnancy were compared with those who reported that
      the pregnancy "just happened" (n = 79) at four separate time periods: prenatally,
      at 6 and 24 months postpartum, and at 18 months postpartum for teens who became
      pregnant again subsequent to the study pregnancy. RESULTS: Those who stated that
      they wanted a baby were more likely to be Hispanic, married, and out of school
      before becoming pregnant. They were less likely to receive welfare as their
      primary means of support and to have run away from home in the past than teens
      who stated that their pregnancy just happened. Self-reported reason for pregnancy
      was unrelated to repeat pregnancy by 18 months postpartum, but those who had
      wanted the study baby were less likely to undergo elective termination of a
      subsequent pregnancy and less likely to become pregnant by a different partner.
      The groups diverged at 24 months postpartum when those who wanted a baby were
      more likely to be married to the father of the baby, be financially supported by
      him, receive child care assistance from him, and have attempted or succeeded at
      breastfeeding the study child. CONCLUSION: Self-reported reason for pregnancy
      reveals many important characteristics of pregnant adolescents both at the time
      of presentation and up to 2 years postpartum. Young women in this study who
      reported intentional pregnancy seem to fare better with regard to their financial
      status and their relationship with the father of the baby.

PMID- 10331838
TI  - Smoking patterns of Asian-American youth in California and their relationship
      with acculturation.
AB  - PURPOSE: To examine patterns of smoking behavior among subgroups of Asian
      American youth in California and their relationship with acculturation status.
      METHODS: Data were from the 1990-1996 California Tobacco Survey and the
      California Youth Tobacco Survey, which assessed smoking-related attitudes and
      behaviors among California youth in grades 7-12. Among the 20,482 respondents,
      1,810 were Asian-Americans. Variables assessed included lifetime smoking
      prevalence, 30-day smoking prevalence, and age of smoking onset. Acculturation
      status was assessed with measures of English usage, language spoken at home, and
      age at immigration to the United States. RESULTS: Of the 1,810 Asian-Americans
      (52% male), 19% were Chinese, 33% Filipino, 8% Japanese, 13% Korean, and 26%
      other Asian-Americans. Lifetime smoking prevalence was 16.1% for Asians and 26.1%
      for non-Asians. The 30-day smoking rate was 6.9% for Asians and 14.2% for non
      Asians. Subgroup-specific analyses revealed differences in lifetime smoking
      prevalence (18.9% for Filipinos, 17.3% for Japanese, 16.3 % for Koreans, 11.0%
      for Chinese, and 13.7% for other Asian-Americans) and 30-day smoking rate (8.6%
      for Filipinos, 8.3% for Koreans, 7.4% for Japanese, 2.8% for Chinese, and 7.2%
      for other Asian-Americans). Gender differences in lifetime smoking prevalence
      varied by Asian subgroup; smoking prevalence was higher among males than among
      females for Chinese and Koreans, but smoking prevalence was higher among females
      than among males for Japanese and other Asians. The average age of smoking onset
      was 12.9 years for Asians and 12.8 years for non-Asians. Age of smoking onset
      differed among Asian-American subgroups but did not differ by gender. In
      addition, smoking behaviors of the Asian respondents were significantly
      associated with their acculturation status. CONCLUSIONS: Asian-American youth
      have relatively lower smoking rates and later age of smoking onset than non-Asian
      youth in California. In addition, subgroups of Asian-American youth vary widely
      in their smoking behavior. High levels of acculturation among Asian-American
      youth are associated with higher smoking prevalence rates and earlier age of
      smoking onset.

PMID- 10331839
TI  - Anti-tobacco socialization in homes of African-American and white parents, and
      smoking and nonsmoking parents.
AB  - PURPOSE: To examine parental perceptions and behaviors with regard to teen
      smoking, comparing African-American and white parents, and those who did and did
      not smoke. METHODS: Focus groups consisting of African-American and white parents
      who smoked provided initial in-depth information. A computer-assisted telephone
      survey of a biracial sample of 311 parents of children ages 8 to 17 years
      provided more generalizable information regarding parental beliefs and behaviors.
      RESULTS: Nearly 50% of households either allowed teen smoking, had no ground
      rules, or had set restrictive rules but never communicated them to the children.
      Compared to white parents, African-American parents felt more empowered to affect
      their children's behaviors and were more likely to actively participate in anti
      tobacco socialization within the home (all p values < 0.01). Among the African
      American parents, 98% reported 18 years or older to be an appropriate age for
      teens to make up their own minds about using tobacco, whereas 26% of white
      parents thought 16 years to be an appropriate age (p < 0.001). Parents who smoked
      reported more frequent rule-making than those who did not smoke (p = 0.02), but
      were more likely to believe that childhood tobacco use is inevitable (p = 0.01).
      CONCLUSIONS: Many parents are not engaged in antitobacco socialization in the
      home. Differences in the degree of parental participation may contribute to the
      variance in smoking prevalence between African-American and white children.

PMID- 10331840
TI  - Students who carry weapons to high school: comparison with other weapon-carriers.
AB  - PURPOSE: To determine if those who have recently carried a weapon on school
      grounds differ from those who carry weapons elsewhere. We hypothesized that
      involvement in other problem behaviors and exposure to school crime and violence
      would be associated with risk for weapon carrying on school grounds. METHODS: The
      data for this study were from the 1995 Youth Risk Behavior Survey of 10,904 high
      school students. Logistic regression analysis was used to examine risk for weapon
      carrying on school grounds. RESULTS: Among the students who carried a weapon, 48%
      carried a weapon on school grounds. Female gender, lower parental education
      levels, substance use on school grounds, involvement in physical fights, exposure
      to school crime and violence, frequency of weapon-carrying, and gun carrying
      distinguished students who carried weapons on school grounds from those who
      carried weapons off school grounds. CONCLUSIONS: The results suggest that weapon
      carrying on school grounds is associated with individual and school-related
      characteristics. Efforts to reduce weapon-carrying on school grounds might focus
      on reduction of students' actual and perceived vulnerability to victimization, as
      well as by helping students understand that other problem behaviors increase
      their risk for violence.

PMID- 10331841
TI  - Hospitalization for mental illness in adolescents: risk groups and impact on the
      health care system.
AB  - PURPOSE: To determine the extent and cost of hospitalizations for mental illness
      among adolescents and to identify differences in acute care hospital use by
      gender and between racial/ethnic groups. METHODS: Analysis of discharge data for
      adolescents, 10 to 19 years of age (n = 27,595), with a principal diagnosis of
      mental illness from acute care hospitals in California in 1994. Relative risks
      (RRs) were calculated by race/ethnicity and gender and stratified by
      race/ethnicity and payment source. RESULTS: Mental illness accounted for 14.8% of
      hospitalizations in this age group; the mean length of stay was 10.9 days. Total
      charges exceeded $300 million. Overall, adolescent boys had a slightly lower risk
      of hospitalization for mental illness than did adolescent girls (RR = 0.90, 95%
      confidence interval [CI] = 0.87, 0.92) but a higher risk for certain diagnoses.
      Overall, nonwhite adolescents had a lower risk of hospitalization for mental
      illness than did white adolescents: African-Americans (RR = 0.77, 95% CI = 0.74,
      0.81), Latinos (RR = 0.32, 95% CI = 0.31, 0.33), and Asians/others (RR = 0.27,
      95% CI = 0.26, 0.29). These differences remained significant after stratification
      by payment source. CONCLUSIONS: The risk of hospitalization for mental illness
      among adolescents varies by specific mental illness and by race/ethnicity. In
      light of the significant human and financial costs associated with
      hospitalization for mental illness, further research into the determinants of
      illness and the options for care is warranted.

PMID- 10331843
TI  - Bibliography of journal articles (January to June 1997).

PMID- 10331844
TI  - DNA damage and repair in individual cells: applications of the comet assay in
      radiobiology.
AB  - The comet assay is a single-cell gel electrophoresis method that can measure a
      variety of types of DNA damage, and repair of damage, in individual cells. It is
      now in widespread use in genetic toxicology and oncology. This review describes
      the history of the development of this method and its applications in radiation
      biology, with particular emphasis on the use of the comet assay to measure
      heterogeneity in DNA damage in cells exposed to ionizing radiation.

PMID- 10331842
TI  - Partner condom use among adolescent girls with sexually transmitted diseases.
AB  - PURPOSE: To explore associations of self-reported condom use with sexual risk
      knowledge and behaviors, perceptions of peer condom use, and communication with
      sexual partners about condom use among adolescent girls with sexually transmitted
      diseases (STDs). METHODS: Adolescent girls with cervicitis or pelvic inflammatory
      disease (PID) completed a 62-item self-administered questionnaire on sexual risk
      knowledge and behaviors, condom use, perceptions of peer condom use, and condom
      use negotiation with partners. Associations with frequency of condom use and
      condom use at last sexual intercourse were analyzed. RESULTS: A total of 24 girls
      were enrolled: 13 with cervicitis and 11 with PID; 22 had complete data for
      analysis. Compared with girls who reported low frequency of condom use, girls who
      reported condom use all or most of the time were younger (16.7 vs. 19.5 years; p
      = .008), were less likely to have a prior history of STD (67% vs. 0%; p = .03),
      and were more likely to think that all or most of their friends use condoms (72%
      vs. 0%; p = .02). Compared with girls who had not used a condom with last sexual
      intercourse, girls who had used a condom were younger (16.2 vs. 17.9 years; p =
      .04), had fewer lifetime partners (2.7 vs. 8.4; p = .03) and had higher mean
      scores in condom use negotiation (29.1 vs. 24.4; p = .02), and were more likely
      to think that all or most of their friends used condoms (100% vs. 31%; p = .001).
      Knowledge about condoms and STD prevention was high (mean 14.3 +/- 2.3 of 16) but
      was not associated with condom use. CONCLUSIONS: STD interventions for partner
      condom use among high-risk adolescent girls must recognize the decrease in condom
      use with increasing age and focus on maintaining safer sex behaviors, building
      condom use negotiation skills, and promoting the perception of condom use by
      friends.

PMID- 10331845
TI  - Multicolour FISH painting for the analysis of chromosomal aberrations induced by
      220 kV X-rays and fission neutrons.
AB  - PURPOSE: The quantification of radiation-induced chromosome aberrations
      identified by multicoloured FISH painting and classified according to different
      nomenclature systems (PAINT, S&S and a conventional method). MATERIAL AND
      METHODS: Blood samples were irradiated with five different doses of 220 kV X-rays
      or fission neutrons respectively. Cell cycle-controlled, multicoloured FISH
      painting was performed with a cocktail of chromosomes 1, 4, 12 and a
      pancentromeric probe. RESULTS: Ten aberration parameters or categories were
      selected according to the three nomenclature systems and dose-response curves
      were constructed for the observed yields. Fitted coefficients of the linear
      quadratic dose-response function show the relative importance of the quadratic
      term for aberration parameters of the low-LET radiation (X-rays) data set and of
      the linear term for those of the high-LET radiation (fission neutrons) data set.
      The relative proportion of complex aberrations observed was larger for the
      densely ionizing fission neutrons than for sparsely ionizing X-rays. CONCLUSION:
      Compared with single-colour FISH painting, a multicolour approach provides
      extended information for a mechanistic and quantitative interpretation of
      radiation-induced chromosome aberrations. The choice of a nomenclature system and
      the selection of an appropriate aberration parameter or category depend on these
      specific aspects. Practical application requires a rapid and reproducible
      description of the observed painting patterns and should also throw light on the
      origin of aberrations.

PMID- 10331846
TI  - Heterogeneity of Chinese hamster X chromosomes in X-ray-induced chromosomal
      aberrations.
AB  - PURPOSE: To study the frequencies and distribution of X-ray-induced chromosomal
      aberrations in different arms as well as different regions of the long arms of
      Chinese hamster X chromosomes by fluorescence in situ hybridization (FISH).
      MATERIAL AND METHODS: Female embryonic primary cells of Chinese hamster were
      exposed to 1 and 4 Gy X-rays during the G1 stage and metaphases were collected 20
      h later with colcemid-blocking. Induced aberrations involving different arms as
      well as different regions of the long arm of the X chromosomes were analysed by
      three-colour FISH using arm-specific painting probes. Distributions of
      aberrations in the arms were statistically analysed by chi2-test, with the
      hypothesis that aberrations are proportionally distributed on the basis of their
      relative lengths of the arms. RESULTS: The long arms of the X chromosomes were
      frequently involved in breaks than was the short arm. The result of the chi2-test
      indicates a non-proportional distribution of breaks between the arms, while
      exchanges (dicentrics and translocations) involving the arms were proportionally
      distributed. Differential involvement of regions of the long arm, i.e. Xq1 and
      Xq2, in breaks was also observed. Xq21, a known common fragile site in the X
      chromosome, was often involved in terminal deletions. CONCLUSION: Arm-specific
      probes of Chinese hamster chromosomes are useful for the detailed study of X-ray
      induced aberrations in the X chromosome. The heterogeneity of the Chinese hamster
      X chromosome in response to X-ray-induced aberrations exists not only between the
      short (euchromatin) and the long (heterochromatin) arms, but also between
      different heterochromatic regions of the long arm of the X chromosome.

PMID- 10331847
TI  - Manned missions to Mars and chromosome damage.
AB  - PURPOSE: To estimate the frequencies of dicentric chromosomes in peripheral
      lymphocytes of astronauts on missions to Mars. MATERIALS AND METHODS:
      Calculations of expected frequencies of dicentrics are based on dose estimations
      and lymphocyte biology. RESULTS: Frequencies of dicentrics are predicted to be 10
      40 times higher than the background level. CONCLUSIONS: Stressing the importance
      of careful mission planning and optimized shielding of transfer vehicle to Mars.

PMID- 10331848
TI  - Alpha coefficient of dose-response for chromosome translocations measured by FISH
      in human lymphocytes exposed to chronic 60Co gamma rays at body temperature.
AB  - PURPOSE: To measure the alpha coefficient, the initial slope of the translocation
      dose-response curve, for 60Co gamma-rays in human lymphocytes. MATERIALS AND
      METHODS: Human lymphocytes were exposed to 0, 0.32, 0.62 and 0.92 Gy of chronic
      60Co gamma-rays under conditions that reduce the metabolic stress to the cells.
      Chromosome translocation frequencies were measured using fluorescence in situ
      hybridization with a whole-chromosome probe cocktail specific for chromosomes 1,
      2, 4 (orange) and 3, 5, 6 (green). RESULTS: A total of 72,383 metaphases were
      analysed (33,429 in exposed cells) in two individuals. The shape of the dose
      response curves for translocations was linear, and alpha coefficient was measured
      as 0.024 +/- 0.002 translocations per cell per Gy for the combined data for two
      24 year old male donors. CONCLUSION: The alpha coefficients measured after
      chronic exposure were in good agreement with that reported in the literature for
      acute, low-dose exposure of human lymphocytes to 60Co gamma-rays.

PMID- 10331849
TI  - Easy biodosimetry for high-dose radiation exposures using drug-induced,
      prematurely condensed chromosomes.
AB  - PURPOSE: To propose a practical method of biodosimetry for high-dose estimation.
      MATERIALS AND METHODS: Okadaic acid in the range 100 nM to 500 nM was given for 1
      6 h to cultured lymphocytes that had been exposed in the range of 0 Gy to 40 Gy.
      The frequency of the cells with prematurely condensed chromosomes (PCC) was
      compared with that of metaphases accumulated by 0.05 microg/ml colcemid. The dose
      response relationship of the yield of prematurely condensed ring chromosomes (PCC
      rings) in the irradiated lymphocytes was examined. RESULTS: The 0.05 microg/ml
      colcemid collected few metaphases when lymphocytes were irradiated to over 10 Gy.
      However, 500 nM okadaic acid produced a substantial number of analysable PCC in
      lymphocytes that had been exposed in the range of 0 Gy to 40 Gy. After 1 h of
      treatment, the 500 nM okadaic acid gave the most suitable chromosome morphology
      for the analysis. PCC rings were narrow, which facilitated their detection in
      Giemsa-stained preparations. The yield of PCC rings increased dose-dependently up
      to 20 Gy. CONCLUSION: PCC rings are a more suitable indicator than dicentrics at
      high doses over 10 Gy. This technique requires no particular equipment or
      exceptional skill. After a serious radiation accident, it can be easily performed
      in a short time in most medical facilities to obtain dose information to assist
      physicians.

PMID- 10331850
TI  - Effect of a 915-MHz simulated mobile phone signal on cognitive function in man.
AB  - PURPOSE: To examine whether a simulated mobile telephone transmission at 915 MHz
      has an effect on cognitive function in man. MATERIALS AND METHODS: Thirty-six
      subjects in two groups were each given two training sessions and then three test
      sessions in a randomized three-way cross-over design. About 1 W mean power at 915
      MHz from a quarter-wave antenna mounted on a physical copy of an analogue phone,
      as a sine wave, or modulated at 217 Hz with 12.5% duty cycle, or no power, was
      applied to the left squamous temple region of the subjects while they undertook a
      series of cognitive function tests lasting approximately 25-30 min. The second
      group was investigated for sleep, consumption of alcohol and beverages, and any
      other substances that might affect performance. RESULTS: In both groups, the only
      test affected was the choice reaction time and this showed as an increase in
      speed (a decrease in reaction time). There were no changes in word, number or
      picture recall, or in spatial memory. While an effect of visit-order was evident
      suggesting a learning effect of repeat tests, the design of the study allowed for
      this. Additionally, there was no systematic error introduced as a result of
      consumption of substances or sleep time. CONCLUSIONS: There was evidence of an
      increase in responsiveness, strongly in the analogue and less in the digital
      simulation, in choice reaction time. This could be associated with an effect on
      the angular gyrus that acts as an interface between the visual and speech centres
      and which lies directly under and on the same side as the antenna. Such an effect
      could be consistent with mild localized heating, or possibly a non-thermal
      response, which is nevertheless power-dependent.

PMID- 10331851
TI  - Static magnetic fields generated by a 0.5 T MRI unit affects in vitro expression
      of activation markers and interleukin release in human peripheral blood
      mononuclear cells (PBMC).
AB  - PURPOSE: To investigate the effects of the static magnetic field (SMF) generated
      by a 0.5 T superconducting MRI unit on in vitro activation marker expression and
      interleukin release in human peripheral blood mononuclear cell (PBMC) samples
      from healthy volunteers. MATERIALS AND METHODS: PBMC samples were split into two
      groups: exposed and sham-exposed under isothermal conditions. PBMC were exposed
      for 2 h at 24 degrees C to the SMF of a 0.5 T superconducting MRI unit.
      Immediately after exposure, both samples were cultured for 24 h at 37 degrees C
      with or without mitogenic stimulation by phytohaemagglutinin (PHA). PBMC were
      examined for expression of CD25, CD69 and CD71 by immunofluorescence analysis and
      supernatants were assayed to quantify IFN-gamma, TNF-alpha and IL-4 by ELISA.
      RESULTS: The 0.5 T SMF produced, after 24 h of culture, a reduced expression of
      CD69 from PBMC in vitro, that was enhanced after PHA stimulation. An increased
      release of IFN-gamma and IL-4 was also found, which was reduced after PHA
      stimulation. The release of TNF-alpha, IL-6 and IL-10 was not modified.
      CONCLUSIONS: The SMF generated by a 0.5 T superconducting MRI unit modified in
      vitro activation marker expression and interleukin release from human PBMC.

PMID- 10331852
TI  - Late ophthalmological complications after total body irradiation in non-human
      primates.
AB  - PURPOSE: To investigate the long-term effects of total body irradiation (TBI) on
      the incidence and time course of ocular complications. MATERIALS AND METHODS:
      Rhesus monkeys treated with TBI photon doses up to 8.5 Gy and proton doses up to
      7.5 Gy were studied at intervals up to 25 years post-irradiation. They were
      compared with control groups with a similar age distribution. Cataract formation
      and ocular fundus lesions were scored according to a standardized protocol.
      Fluorescein angiography and histopathology was performed in selected animals.
      RESULTS: Cataract formation occurred after a latent period of 3-5 years.
      Significant cataract induction was observed for photon-doses of 8 and 8.5 Gy and
      beyond 20 years after proton irradiation. The severity of the lesions represents
      significant impairment of vision and would require cataract surgery if similar
      results occurred in human bone marrow transplant patients. Fluorescein
      angiography demonstrated a normal pattern of retinal vessels in 13 out of 14
      animals (93%) from the irradiated group and in eight out of nine animals (89%)
      from the control group. No additional lesions apart from age-related degenerative
      changes could be demonstrated. Histological evaluation revealed no radiation
      associated vasculopathy. CONCLUSIONS: Radiation alone for doses up to 8.5 Gy of
      photons does not carry a potential risk for fundus pathology, whereas clinically
      important cataract induction should be anticipated within 5 years after photon
      doses of 8.0 and 8.5 Gy and proton doses in excess of 2.5 Gy.

PMID- 10331853
TI  - TGF-beta 1 production in radiation nephropathy: role of angiotensin II.
AB  - PURPOSE: Angiotensin II receptor antagonists are effective in the prophylaxis of
      radiation nephropathy. Studies were designed to determine whether TGF-beta 1, a
      fibrogenic cytokine, plays a role in mediating the protective effect of AII
      antagonism. These studies explored the time-course of glomerular TGF-beta 1
      production in the irradiated kidney, and whether AII mediates TGF-beta 1
      production in glomeruli isolated from irradiated rats. MATERIALS AND METHODS:
      Rats received 20 Gy of bilateral renal irradiation in five fractions and were
      randomized to receive an AII type 1 receptor antagonist (L-158,809) at 20mg/l in
      their drinking water, or no treatment. Drug therapy began 9 days prior to
      irradiation and continued for the duration of the study. RESULTS: Analysis of
      renal function showed a significant increase in urinary proteinuria and blood
      urea nitrogen by 37 days and 63 days after irradiation, respectively. Estimation
      of glomerular TGF-beta1 levels by quantitative sandwich enzyme immunoassay
      technique revealed a significant increase in latent but not active TGF-beta 1
      levels at 50 days and 63 days after irradiation. In animals treated with the AT1
      receptor antagonist, there was a complete elimination in the rise of TGF-beta 1.
      CONCLUSIONS: These studies demonstrate that glomerular TGF-beta 1 production is
      elevated in the course of radiation nephropathy, and that AII mediates this
      induction of TGF-beta 1.

PMID- 10331854
TI  - Caffeine-increased radiosensitivity is not dependent on a loss of G2/M arrest or
      apoptosis in bladder cancer cell lines.
AB  - PURPOSE: Bladder cancer cell lines UCRU-BL-13, UCRU-BL-17/2 and UCRU-BL-28, with
      differing p53 status and molecular responses to irradiation, were used to
      investigate possible mechanisms for caffeine-induced radiosensitization.
      MATERIALS AND METHODS: After treatment with caffeine and exposure to X-radiation,
      radiosensitivity was determined by clonogenic assay. Cell-cycle arrest and
      apoptosis were measured by flow cytometry. RESULTS: Both BL-13 and BL-28 cells
      (each expressing p53 with a wild-type sequence) fail to arrest at the G2
      checkpoint after radiation, but nevertheless caffeine did induce
      radiosensitization. In contrast, in BL-17/2 cells (expressing p53 with a point
      mutation in codon 280), caffeine treatment abrogated the radiation-induced G2
      arrest but was not accompanied by radiosensitization. No effects on
      radiosensitivity were seen in RT112 cells (expressing a functionally defective
      p53) at low caffeine doses (2 mM), but at higher doses (4 mM and 10 mM) caffeine
      caused both abrogation of radiation-induced G2 arrest and radiosensitization. In
      none of the cell lines examined did caffeine treatment and/or irradiation result
      in apoptosis. CONCLUSIONS: In contrast with previous studies, the data suggest
      that radiosensitization induced by caffeine is not dependent on abrogation of G2
      arrest or the induction of apoptosis, and is not selective for cells expressing
      p53 proteins with mutations.

PMID- 10331855
TI  - Mitochondrial and intracellular free-calcium regulation of radiation-induced
      apoptosis in human leukemic cells.
AB  - PURPOSE: To investigate the mechanisms and pathways of X-ray apoptosis in Molt-4
      cells, focusing on mitochondrial and cytosolic Ca2+ ([Ca2+]i) regulation.
      MATERIALS AND METHODS: X-irradiated Molt-4 cells and cell extract (CE) were used
      to analyse: (1) induced apoptosis (Giemsa stain), (2) p53, Bcl-2 and Bax
      expressions (immunoblot), (3) mitochondrial potential deltapsi(m) and (4) [Ca2+]i
      (flow cytometry), (5) caspase-3 activity, and (6) roles of [Ca2+]- and caspase-3
      mediated pathways by inhibiting either or both pathways for induced apoptosis.
      RESULTS: Molt-4 cells were sensitive to apoptosis since 5 Gy induced 57 and 94%
      apoptosis at 6 and 24 h. After 5Gy, p53 was accumulated that upregulated Bax but
      which repressed Bcl-2 with time, resulting in a 7-fold increase in Bax/Bxl-2 at 6
      h. Predominant Bax reduced deltapsi(m), and low-deltapsi(m) cells increased 45
      min earlier than apoptosis after 5 Gy. Caspase-3 was activated in apoptotic CE.
      The caspase-3 inhibitor Ac-DEVD-CHO inhibited apoptosis and DNA-ladder formation
      by approximately 50%, suggesting a approximately 50% role of caspase-3-activated
      DNase (CAD). [Ca2+]i was increased after 5 Gy. [Ca2+]i-chelating BAPTA-AM (5
      microM) and/or DNase gamma-inhibiting Zn2+ (0.5 mM) inhibited approximately 50%
      of induced apoptosis and DNA-laddering, indicating a 50% participation of
      Ca2+/Mg2+-dependent DNase gamma. CONCLUSIONS: The p53-Bax-mitochondria-caspase-3
      CAD pathway and the [Ca+2]i-mediated DNase gamma pathway were involved in the
      regulation of X-ray apoptosis in sensitive Molt-4 cells.

PMID- 10331856
TI  - Accelerated reoxygenation of a murine fibrosarcoma after carbon-ion radiation.
AB  - PURPOSE: Reoxygenation of a murine tumour after irradiation with carbon ions was
      investigated and compared to that after gamma-rays. MATERIALS AND METHODS: NFSa
      fibrosarcoma cells were transplanted into the right hind legs of syngeneic C3H
      male mice. Conditioning irradiation with either 290 MeV/u carbon ions or 137-Cs
      gamma-rays was delivered to the tumours at 8 mm diameter. At given times after
      irradiation the leg tumours, either clamped or not, received test doses of
      photons. Differences in tumour growth delay between the clamped and non-clamped
      tumours were interpreted in terms of reoxygenation. A lung-colony assay was used
      to obtain cell-survival curves. RESULTS: The oxygen enhancement ratio in the NFSa
      tumour for 74 keV microm(-1) carbon ions was 1.6 while that for gamma-rays was
      3.4. The NFSa tumours reoxygenated 4 days after 30 Gy of gamma-ray irradiation,
      but reoxygenated as early as 1 day after 16 Gy of carbon ions. Reoxygenation
      after gamma-rays shortened to 1 day when the tumours were initially clamped for
      the conditioning irradiation. CONCLUSIONS: The fraction of surviving oxic cells
      in the NFSa tumours is larger after irradiation with carbon ions than with gamma
      rays, resulting in accelerated reoxygenation.

PMID- 10331858
TI  - Would you use an e-print server?

PMID- 10331857
TI  - Variability in the radiosensitivity of normal cells and tissues. Report from a
      workshop organised by the European Society for Therapeutic Radiology and Oncology
      in Edinburgh, UK, 19 September 1998.

PMID- 10331859
TI  - How the regulatory and catalytic domains get together.

PMID- 10331860
TI  - The name is bond--H bond.

PMID- 10331862
TI  - A new type of PDZ domain recognition.

PMID- 10331861
TI  - Trapped in the act of catalysis.

PMID- 10331863
TI  - Picture story. Predicting channel structures with genetics.

PMID- 10331864
TI  - Early crystals.

PMID- 10331865
TI  - Penicillin V acylase crystal structure reveals new Ntn-hydrolase family members.

PMID- 10331866
TI  - Solution structure of the extended neuronal nitric oxide synthase PDZ domain
      complexed with an associated peptide.
AB  - The PDZ domain of neuronal nitric oxide synthase (nNOS) functions as a scaffold
      for organizing the signal transduction complex of the enzyme. The NMR structure
      of a complex composed of the nNOS PDZ domain and an associated peptide suggests
      that a two-stranded beta-sheet C-terminal to the canonical PDZ domain may mediate
      its interaction with the PDZ domains of postsynaptic density-95 and alpha
      syntrophin. The structure also provides the molecular basis of recognition of Asp
      X-Val-COOH peptides by the nNOS PDZ domain. The role of the C-terminal extension
      in Asp-X-Val-COOH peptide binding is investigated. Additionally, NMR studies
      further show that the Asp-X-Val-COOH peptide and a C-terminal peptide from a
      novel cytosolic protein named CAPON bind to the same pocket of the nNOS PDZ
      domain.

PMID- 10331867
TI  - Structure and mechanism of glutamate racemase from Aquifex pyrophilus.
AB  - Glutamate racemase (MurI) is responsible for the synthesis of D-glutamate, an
      essential building block of the peptidoglycan layer in bacterial cell walls. The
      crystal structure of glutamate racemase from Aquifex pyrophilus, determined at
      2.3 A resolution, reveals that the enzyme forms a dimer and each monomer consists
      of two alpha/beta fold domains, a unique structure that has not been observed in
      other racemases or members of an enolase superfamily. A substrate analog, D
      glutamine, binds to the deep pocket formed by conserved residues from two
      monomers. The structural and mutational analyses allow us to propose a mechanism
      of metal cofactor-independent glutamate racemase in which two cysteine residues
      are involved in catalysis.

PMID- 10331868
TI  - Structure of the arginine repressor from Bacillus stearothermophilus.
AB  - The arginine repressor (ArgR) is a hexameric DNA-binding protein that plays a
      multifunctional role in the bacterial cell. Here, we present the 2.5 A structure
      of apo-ArgR from Bacillus stearothermophilus and the 2.2 A structure of the
      hexameric ArgR oligomerization domain with bound arginine. This first view of
      intact ArgR reveals an approximately 32-symmetric hexamer of identical subunits,
      with six DNA-binding domains surrounding a central oligomeric core. The
      difference in quaternary organization of subunits in the arginine-bound and apo
      forms provides a possible explanation for poor operator binding by apo-ArgR and
      for high affinity binding in the presence of arginine.

PMID- 10331869
TI  - X-ray structures along the reaction pathway of cyclodextrin glycosyltransferase
      elucidate catalysis in the alpha-amylase family.
AB  - Cyclodextrin glycosyltransferase (CGTase) is an enzyme of the alpha-amylase
      family, which uses a double displacement mechanism to process alpha-linked
      glucose polymers. We have determined two X-ray structures of CGTase complexes,
      one with an intact substrate at 2.1 A resolution, and the other with a covalently
      bound reaction intermediate at 1.8 A resolution. These structures give evidence
      for substrate distortion and the covalent character of the intermediate and for
      the first time show, in atomic detail, how catalysis in the alpha-amylase family
      proceeds by the concerted action of all active site residues.

PMID- 10331870
TI  - Crystal structure of the human leukocyte Fc receptor, Fc gammaRIIa.
AB  - Fc gamma receptors bind IgG to initiate cellular responses against pathogens and
      soluble antigens. We have determined the three-dimensional structure of the
      extracellular portion of human Fc gammaRIIa to 2.0 A resolution providing a
      structural basis for the unique functions of the leukocyte FcR family. The
      receptor is composed of two immunoglobulin domains and arranged to expose the
      ligand-binding site at one end of domain 2. Using alanine mutants we find that
      the binding sites for IgG1 and 2 are similar but the relative importance of
      specific regions on the receptor varies. In crystals, Fc gammaRIIa molecules
      associate to resemble V(L)V(H) dimers, suggesting that two Fc gammaRIIa molecules
      could cooperate to bind IgG in an asymmetric manner.

PMID- 10331871
TI  - Structural basis of autoregulation of phenylalanine hydroxylase.
AB  - Phenylalanine hydroxylase converts phenylalanine to tyrosine, a rate-limiting
      step in phenylalanine catabolism and protein and neurotransmitter biosynthesis.
      It is tightly regulated by the substrates phenylalanine and tetrahydrobiopterin
      and by phosphorylation. We present the crystal structures of dephosphorylated and
      phosphorylated forms of a dimeric enzyme with catalytic and regulatory properties
      of the wild-type protein. The structures reveal a catalytic domain flexibly
      linked to a regulatory domain. The latter consists of an N-terminal
      autoregulatory sequence (containing Ser 16, which is the site of phosphorylation)
      that extends over the active site pocket, and an alpha-beta sandwich core that
      is, unexpectedly, structurally related to both pterin dehydratase and the
      regulatory domains of metabolic enzymes. Phosphorylation has no major structural
      effects in the absence of phenylalanine, suggesting that phenylalanine and
      phosphorylation act in concert to activate the enzyme through a combination of
      intrasteric and possibly allosteric mechanisms.

PMID- 10331872
TI  - X-ray structure of the Escherichia coli periplasmic 5'-nucleotidase containing a
      dimetal catalytic site.
AB  - The crystal structure of 5'-nucleotidase (5'-NT) from E. coli, also known as UDP
      sugar hydrolase, has been determined at 1.7 A resolution. Two zinc ions are
      present in the active site, which is located in a cleft between two domains. The
      dimetal center and a catalytic Asp-His dyad are the main players in the catalytic
      mechanism. Structure-based sequence comparisons show that the structure also
      provides a model for animal 5'-NTs, which together with other ectonucleotidases
      terminate the action of nucleotides as extracellular signaling substances in the
      nervous system.

PMID- 10331873
TI  - Sequence dependent conformational variations of collagen triple-helical
      structure.
AB  - The 2 A crystal structure reported here of the collagen-like model peptide, T3
      785, provides the first visualization of how the sequence of collagen defines
      distinctive local conformational variations in triple-helical structure.

PMID- 10331874
TI  - Automated protein model building combined with iterative structure refinement.
AB  - In protein crystallography, much time and effort are often required to trace an
      initial model from an interpretable electron density map and to refine it until
      it best agrees with the crystallographic data. Here, we present a method to build
      and refine a protein model automatically and without user intervention, starting
      from diffraction data extending to resolution higher than 2.3 A and reasonable
      estimates of crystallographic phases. The method is based on an iterative
      procedure that describes the electron density map as a set of unconnected atoms
      and then searches for protein-like patterns. Automatic pattern recognition (model
      building) combined with refinement, allows a structural model to be obtained
      reliably within a few CPU hours. We demonstrate the power of the method with
      examples of a few recently solved structures.

PMID- 10331875
TI  - A new use for the 'wing' of the 'winged' helix-turn-helix motif in the HSF-DNA
      cocrystal.
AB  - The 1.75 A crystal structure of the Kluyveromyces lactis heat shock transcription
      factor (HSF) DNA-binding domain (DBD) complexed with DNA reveals a protein-DNA
      interface with few direct major groove contacts and a number of phosphate
      backbone contacts that are primarily water-mediated interactions. The DBD, a
      'winged' helix-turn-helix protein, displays a novel mode of binding in that the
      'wing' does not contact DNA like all others of that class. Instead, the monomeric
      DBD, which crystallized as a symmetric dimer to a pair of nGAAn inverted repeats,
      uses the 'wing' to form part of the protein-protein contacts. This dimer
      interface is likely important for increasing the DNA-binding specificity and
      affinity of the trimeric form of HSF, as well as for increasing cooperativity
      between adjacent trimers.

PMID- 10331876
TI  - DNA-binding mechanism of the monomeric orphan nuclear receptor NGFI-B.
AB  - The 2.7 A X-ray crystal structure of the DNA-binding domain (DBD) of the orphan
      nuclear receptor, nerve growth factor-induced-B (NGFI-B), complexed to its high
      affinity DNA target, represents the first structure analysis of a nuclear
      receptor DBD bound as a monomer to DNA. The structure of the core DBD and its
      interactions with the major groove of the DNA are similar to previously
      crystallographically solved DBD-DNA complexes in this superfamily; however,
      residues C-terminal to this core form a separate and unique substructure that
      interacts extensively and in a sequence-specific way with the minor groove of its
      DNA target, in particular with the characteristic 3 A-T base-pair identity
      element that extends 5' to the usual nuclear receptor half-site (AGGTCA).

PMID- 10331877
TI  - A folding transition and novel zinc finger accessory domain in the transcription
      factor ADR1.
AB  - The region responsible for sequence-specific DNA binding by the transcription
      factor ADR1 contains two Cys2-His2 zinc fingers and an additional N-terminal
      proximal accessory region (PAR). The N-terminal (non-finger) PAR is unstructured
      in the absence of DNA and undergoes a folding transition on binding the DNA
      transcription target site. We have used a set of HN-HN NOEs derived from a
      perdeuterated protein-DNA complex to describe the fold of ADR1 bound to the UAS1
      binding site. The PAR forms a compact domain consisting of three antiparallel
      strands that contact A-T base pairs in the major groove. The three-strand domain
      is a novel fold among all known DNA-binding proteins. The PAR shares sequence
      homology with the N-terminal regions of other zinc finger proteins, suggesting
      that it represents a new DNA-binding module that extends the binding repertoire
      of zinc finger proteins.

PMID- 10331878
TI  - Structure and interactions of NCAM modules 1 and 2, basic elements in neural cell
      adhesion.
AB  - The structure in solution of the second Ig-module fragment of residues 117-208 of
      NCAM has been determined. Like the first Ig-module of residues 20-116, it belongs
      to the I set of the immunogloblin superfamily. Module 1 and module 2 interact
      weakly, and the binding sites of this interaction have been identified. The two
      module fragment NCAM(20-208) is a stable dimer. Removal of the charged residues
      in these sites in NCAM(20-208) abolishes the dimerization. Modeling the dimer of
      NCAM(20-208) to fit the interactions of these charges produces one coherent
      binding site for the formation of two antiparallel strands of the first two NCAM
      modules. This mode of binding could be a major element in trans-cellular
      interactions in neural cell adhesion.

PMID- 10331879
TI  - Validation of the PASE in older adults with knee pain and physical disability.
AB  - PURPOSE: To examine the validity of the Physical Activity Scale for the Elderly
      (PASE) among individuals with disability. METHODS: A sample of 471 participants
      (mean age = 71.36) in an epidemiological study of chronic knee pain completed the
      PASE and self-report measures of knee pain, perceived physical function,
      satisfaction with physical function, and importance of physical function. A 6-min
      walk test and an isokinetic assessment of knee strength were also administered.
      RESULTS: PASE scores were significantly correlated in expected directions with
      performance on the 6-min walk, knee strength, frequency of knee pain during
      transfer, and perceived difficulty with physical functioning. Gender and age were
      identified as significant moderators of PASE scores and the scale's construct
      validity was supported by testing a conceptually driven hypothesis regarding
      patterns of physical activity. CONCLUSIONS: These results support the PASE's
      validity for the assessment of physical activity among older adults with pain and
      disability.

PMID- 10331880
TI  - The effect of Tai Chi on cardiorespiratory function in patients with coronary
      artery bypass surgery.
AB  - PURPOSE: This study prospectively evaluated the training effect of a 1-yr Tai Chi
      Chuan (TCC) program for low-risk patients with coronary artery bypass surgery
      (CABS) after a postoperative outpatient (phase II) cardiac rehabilitation
      program. METHODS: Twenty patients with mean age of 56.5+/-7.4 yr completed this
      study. The TCC group included nine men who practiced classical Yang TCC with an
      exercise intensity of 48-57% heart rate range (HRR). The control group included
      11 men whom were recommended to do a home-based self-adjusted exercise program
      with similar intensity of phase II cardiac rehabilitation. Graded exercise tests
      were performed before and after 1 yr of training for all subjects. RESULTS: Mean
      attendance of the TCC group was 3.8+/-1.5 times weekly in contrast to 1.7+/-1.1
      times for the control group. During the follow-up examination, the TCC group
      increased 10.3% in VO2peak (from 26.2+/-4.4 to 28.9+/-5.0 mL x kg(-1) min(-1),
      P<0.01) and increased 11.9% in peak work rate (from 135+/-26 W to 151+/-28 W,
      P<0.01). However, the control group showed slight decrease in VO2peak from 26.0+/
      3.9 to 25.6+/-4.6 mL x kg(-1) x min(-1) and in peak work rate from 131+/-23 W to
      128+/-32 W. At the ventilatory threshold, the TCC group also showed significant
      increase in VO2 and work rate (P<0.05). The control group did not significantly
      change in these variables. CONCLUSIONS: The study demonstrated that a 1-yr TCC
      program for low-risk patients with CABS could favorably enhance cardiorespiratory
      function.

PMID- 10331881
TI  - Effects of erythropoietin administration in training athletes and possible
      indirect detection in doping control.
AB  - PURPOSE: This study investigated the effects of repeated subcutaneous injection
      of rHuEpo (50 IU x kg(-1)) in athletes and proposes a method based on the
      measurement in blood samples of the sTfR/serum protein ratio to determine if the
      observed values of this marker are related to rHuEpo abuse. METHODS: Serum
      erythropoietin concentrations, and hematological and biochemical parameters were
      evaluated, during treatment and for 25 d posttreatment in nine training athletes.
      Moreover, the effect of rHuEpo administrations on the maximum oxygen uptake
      (VO2max) and ventilatory threshold (VT) of these athletes was also studied.
      Threshold values for sTfr and the sTfr/serum protein ratio were determined from
      233 subjects (185 athletes, 15 athletes training at moderately high altitude, and
      33 subjects living at >3000 m). RESULTS: Significant changes in reticulocytes,
      hemoglobin (Hb) concentration, hematocrit (Hct), sTfr, and sTfr/serum proteins
      were observed during and after rHuEpo treatment. The maximal heart rate of 177
      beats x min(-1) at the beginning of the study was significantly higher than the
      value of 168 beats x min(-1) after 26 d of rHuEpo administration. Compared with
      the values measured at baseline, the VT measured after rHuEpo administration
      occurred at a statistically significant high level of oxygen uptake. CONCLUSIONS:
      When oxygen uptake measured at the VT was expressed as a percentage of V02 max,
      the values obtained were also significantly higher. The increased values of Tfr
      and sTfr/serum proteins, respectively, above 10 microg x mL(-1) and 153,
      indicated the probable intake of rHuEpo.

PMID- 10331882
TI  - Changes in bone mineral content with decreased training in competitive young
      adult tennis players and controls: a prospective 4-yr follow-up.
AB  - PURPOSE: The purpose of this 4-yr prospective follow-up study of male tennis
      players was to determine the changes in the playing-to-nonplaying arm differences
      in bone mineral content (BMC) and answer two questions: 1) Are training induced
      bone gains lost with decreased training? and 2) Are the possible bone changes
      related to the changes in training? METHODS: Subjects were 13 former competitive
      male tennis players and their 13 controls. The players had started their playing
      career at the mean age of 11 yr. The initial comparisons between the playing and
      contralateral arms' BMC were done in 1992 (mean age 26 yr), and follow-up was
      performed 4 yr later. The players were competing at the national top level in the
      beginning of the study, and all had retired from the top tennis (mean) 2.3+/-0.6
      yr before follow-up. Accordingly, they had reduced the average training frequency
      from 5.2 times a week to 2.6 times a week and the mean hours of training per week
      from 7.6 to 3.3. RESULTS: The 1996 measurements revealed that on average the
      players' exercise-induced bone gain in the playing arm had not disappeared with
      time despite decreased average playing activity and that observed bone changes
      were not related to changes in training. The side-to-side BMC differences were
      largest in the humeral shaft (25% in 1992 and 26% 4 yr later) and the proximal
      humerus (19% and 18%). The radial shaft difference was 14% and the distal radius
      difference 13% in both 1992 and 1996. In controls, the side-to-side BMC
      differences were small, less than 5%, and they did not change by time.
      CONCLUSIONS: In conclusion, this study suggests that bone gain obtained by
      regular tennis training does not disappear by time despite decreased playing
      activity. Regular exercise can be valuable for maximizing peak bone mass and thus
      contributing to prevention of osteoporosis and related fractures later in life.

PMID- 10331883
TI  - Ulnar variance and skeletal maturity of radius and ulna in female gymnasts.
AB  - It is has been suggested that repetitive loading on the distal end of the radius
      in elite gymnasts may lead to epiphyseal changes, a premature closure (union) of
      the radius growth plate, and ulnar overgrowth. PURPOSE: It is hypothesized that
      ulnar overgrowth in female gymnasts is associated with advanced maturity status
      and early onset of epiphyseal closure of the radius, and later maturity status
      and later onset of epiphyseal closure of the ulnar. METHODS: Posterior-anterior
      radiographs of 201 female gymnasts, participants of the 1987 World Championships
      Artistic Gymnastics, were used to measure ulnar overgrowth, to determine skeletal
      maturation of the hand and wrist with the Tanner-Whitehouse technique, and to
      determine the maturity status of the radius and ulna separately, particularly
      with regard to the onset of epiphyseal closure. To test the hypothesis, extreme
      quintiles for ulnar overgrowth were contrasted for skeletal maturation of the
      hand and wrist and for maturity stages of the radius and ulna as defined by the
      Tanner-Whitehouse criteria. RESULTS: Female gymnasts who demonstrate ulnar
      overgrowth are skeletally more advanced in maturity status of the entire hand
      wrist compared with gymnasts who did not show ulnar overgrowth. There were,
      however, no differences between gymnasts in the extreme quintiles of ulnar
      overgrowth in the maturation of the radius, although gymnasts with ulnar
      overgrowth show more advanced maturity status of the ulna. CONCLUSIONS: Ulnar
      overgrowth is thus not apparently associated with advanced maturity of the distal
      radial epiphysis as defined in protocols for assessing skeletal maturity and does
      not apparently lead to premature epiphyseal closure of the distal radius.

PMID- 10331884
TI  - Degree of arterial desaturation in normoxia influences VO2max decline in mild
      hypoxia.
AB  - PURPOSE: Elite endurance athletes display varying degrees of pulmonary gas
      exchange limitations during maximal normoxic exercise and many demonstrate
      reduced arterial O2 saturations (SaO2) at VO2max--a condition referred to as
      exercise induced arterial hypoxemia (EIH). We asked whether mild hypoxia would
      cause significant declines in SaO2 and VO2max in EIH athletes while non-EIH
      athletes would be unaffected. METHODS: Nineteen highly trained males were divided
      into EIH (N = 8) or Non-EIH (N = 6) groups based on SaO2 at VO2max (EIH <90%, Non
      EIH >92%). Athletes with intermediate SaO2 values (N = 5) were only included in
      correlational analyses. Two randomized incremental treadmill tests to exhaustion
      were completed--one in normoxia, one in mild hypoxia (FIO2 = 0.187; approximately
      1,000 m). RESULTS: EIH subjects demonstrated a significant decline in VO2max from
      normoxia to mild hypoxia (71.1+/-5.3 vs. 68.1+/-5.0 mL x kg(-1) min(-1), P<0.01),
      whereas the non-EIH group did not show a significant deltaVO2max (67.2+/-7.6 vs.
      66.2+/-8.4 mL x kg(-1) x min(-1)). For all 19 athletes, SaO2 during maximal
      exercise in normoxia correlated with the change in VO2max from normoxia to mild
      hypoxia (r = -0.54, P<0.05). However, the change in SaO2 and arterial O2 content
      from normoxia to mild hypoxia was equal for both EIH and Non-EIH (deltaSaO2 =
      5.2% for both groups), bringing into question the mechanism by which changes in
      SaO2 affect VO2max in mild hypoxia. CONCLUSIONS: We conclude that athletes who
      display reduced measures of SaO2 during maximal exercise in normoxia are more
      susceptible to declines in VO2max in mild hypoxia compared with normoxemic
      athletes.

PMID- 10331885
TI  - Temporal effects of testosterone propionate injections on serum lipoprotein
      concentrations in rats.
AB  - The chronic abuse of androgenic anabolic steroids, a group of synthetic
      derivatives of testosterone, to improve athletic performance have demonstrated
      compromised serum lipoprotein concentrations reflecting an elevated risk for
      cardiovascular disease. While the detrimental alterations in the lipoprotein
      profile have been reported consistently for orally administered androgenic
      anabolic steroids, the reports examining the effects of parenteral administration
      of testosterone upon the lipid profile remain equivocal. PURPOSE: The purpose of
      this study was to determine whether compromised serum lipoprotein concentrations
      would be manifest in rats receiving testosterone injections (twice per week) over
      the time course of 7 wk. METHODS: Male rats were randomly assigned to either an
      experimental group (dose per injection, 3 mg x kg(-1) testosterone propionate
      solubilized in 1 mL of safflower oil) or a control group (injected with an
      isovolumic amount of safflower oil alone). The effects of the steroid regimen on
      the serum lipoprotein profiles were followed after 1, 3, 5, and 7 wk of
      injections. To assess the relative effects of testosterone propionate, testicular
      mass was determined at the time of sacrifice. RESULTS: Testicular mass (mean +/-
      SE) was significantly lower (P<0.01) in the experimental group, 3.08+/-0.03 g,
      compared with that in controls, 3.82+/-0.05 g, by week 3 and continued to decline
      for the remainder of the steroid regimen, reaching a nadir of 2.70+/-0.01 g at
      week 5. No significant differences were observed between groups for total serum
      cholesterol, serum triacylglycerols, or serum low density lipoprotein (LDL)-C at
      any time point. However, at week 7, serum high density lipoprotein (HDL)-C (mean
      +/- SE) was significantly lower (P<0.02) in the testosterone treated animals,
      32+/-2 mg x dL(-1), compared with that in controls, 47+/-2 mg x dL(-1). As a
      result, the ratio of total cholesterol to HDL-C (mean +/- SE) significantly
      increased (P<0.02) by the seventh week in the testosterone treated group, 3.5+/
      0.2, versus controls, 2.5+/-0.2. CONCLUSIONS: The results suggest that while
      testosterone propionate injections elicit a reduction in testicular mass within 3
      wk, the lipoprotein profile is not altered until week 7. Further, the only
      compromised parameter under the conditions of this study is the decrease in serum
      HDL-C.

PMID- 10331886
TI  - Plasma lactate decline during passive recovery from high-intensity exercise.
AB  - PURPOSE: An athlete's ability to repeatedly perform at high intensities during
      intermittent exercise could be related to an accelerated plasma lactate removal
      ability during recovery periods. METHODS: We determined the decline in plasma
      lactate levels during passive recovery after an incremental exercise test to
      exhaustion on a bicycle ergometer in five trained and five untrained male
      subjects. Venous blood samples were taken during exercise and recovery for the
      analysis of plasma lactate concentration. The endurance fitness of the subjects
      was characterized using a variable known as the maximum turn point power output
      (MTP), measured in W x kg(-1). MTP describes the workload at which lactate levels
      rise significantly above resting concentrations. RESULTS: The decline in plasma
      lactate levels during recovery was determined at selected intervals from the
      exponential recovery curve plotted as a percentage of peak plasma lactate versus
      time. No significant relationships were found between the recovery parameters
      measured from the curve and the MTP values of these subjects (Spearman's rank
      order correlation; r(s) values from -0.042 to -0.31). CONCLUSIONS: Therefore, we
      can conclude that training confers no advantage to the decline in plasma lactate
      while recovering passively from exercise at equivalent relative maximal work
      intensities.

PMID- 10331887
TI  - Intermittent running: muscle metabolism in the heat and effect of hypohydration.
AB  - PURPOSE: This study reports two studies that investigated the reason for a poorer
      intermittent supramaximal running performance previously found in the heat
      (Maxwell et al., The effect of climatic heat stress on intermittent supramaximal
      running performance in humans. Exp. Physiol. 81:833-845, 1996). The first study
      tested the hypothesis that it was due to different rates of substrate metabolism.
      The second study tested whether a greater level of hypohydration led to an
      earlier exhaustion time. METHODS: A maximal anaerobic running test (MART) was the
      exercise model used. This involved repeated 20-s runs, each at increasing
      intensities, with 100 s of passive recovery between runs. RESULTS: In study 1,
      eight male subjects performed the MART on two occasions at either 32.8+/-0.3
      degrees C, 80.5+/-1.6% relative humidity (RH), or 21.3+/-0.4 degrees C, 48.8+/
      2.2% RH. Needle biopsy samples were taken from the vastus lateralis muscle before
      and immediately after the MART. In study 2, 11 male subjects performed the MART
      in a moderately hypohydrated (HYPO) and euhydrated (EUH) state while in a cool
      environment. In study 1, performance was significantly worse in the hot compared
      with the cool environment (138+/-7 vs. 150+/-6 s, respectively, P<0.05). No
      differences were observed in the change in muscle glycogen (100.3+/-15.1 vs.
      107.0+/-15.6 mmol glucosyl units x kg dry muscle(-1)) or muscle lactate (102.9+/
      18.2 vs. 100.5+/-16.6 mmol x kg dry muscle(-1)) between the hot and cool
      environments, respectively. In study 2, performance was worse in the HYPO (148+/
      9 s) compared with the EUH (154+/-9 s) trial (P<0.05). CONCLUSIONS: These results
      indicate that a reduced intermittent supramaximal running performance in the heat
      is not caused by greater muscle glycogenolysis or lactate accumulation. Further,
      a poorer intermittent sprinting performance is experienced in a hypohydrated
      compared with a euhydrated state.

PMID- 10331888
TI  - Exercise cardiac function in young through elderly endurance trained women.
AB  - PURPOSE: To clarify the physiological reasons for the decline in aerobic power of
      endurance trained (ET) women with aging. METHODS: Blood volume, VO2max, and
      exercise cardiac function were examined in 23 ET women; six age 20-29 yr, six age
      40-45 yr, six age 49-54 yr, and five age 58-63 yr. RESULTS: Blood volume was
      unchanged with aging. VO2max declined progressively at a rate of 0.51 mL x kg(-1)
      x min(-1) x yr(-1). During maximal exercise, there was an increase in total
      peripheral resistance (TPR) and a decrease in heart rate, stroke volume, and
      cardiac output with increasing age. At all ages, cardiac filling (diastole) was
      significantly faster than cardiac emptying (systole). Stroke volume did not
      plateau at a submaximal work rate but increased progressively to maximum.
      CONCLUSIONS: The decline in VO2max with age in ET women is due to decreases in
      maximal heart rate, stroke volume and cardiac output, and the primary advantage
      in the exercise cardiac performance of ET women of all ages is diastolic rather
      than systolic function.

PMID- 10331889
TI  - Apolipoprotein E polymorphism and the relationships of physical fitness to plasma
      lipoprotein-lipid levels in men and women.
AB  - PURPOSE: A high level of cardiovascular fitness is generally associated with a
      plasma lipoprotein-lipid profile predictive of a low cardiovascular disease risk.
      We have investigated whether apolipoprotein (apo) E polymorphism could alter the
      relationships of physical fitness to plasma lipoprotein-lipid levels in a sample
      of healthy untrained subjects (64 premenopausal women and 65 men). METHODS:
      Subjects were grouped according to gender and apo E phenotype determined by
      isoelectric focusing electrophoresis. RESULTS: In both genders, VO2max expressed
      in mL x kg(-1) x min(-1) was negatively correlated with plasma triglyceride
      levels in apo E2 carriers and apo E3 homozygotes (-0.55< or =r< or =0.31;
      P<0.05), whereas these associations were not found in apo E4 groups. Plasma low
      density lipoprotein (LDL)-C levels were negatively associated with VO2max (r = 
      0.39; P<0.05) only in women homozygotes for apo E3 whereas VO2max was positively
      correlated with plasma high-density lipoprotein (HDL)2-C levels only in men (r =
      0.51; P<0.001) and women (r = 0.65; P<0.001) who were apo E3 homozygotes. A
      control for concomitant association with body fat mass and glucose intolerance
      performed by partial correlation analyses revealed that, with the exception of
      the plasma HDL2-C levels in the apo E3 homozygotes, most of the significant
      associations between VO2max (mL x kg(-1) x min(-1)) and plasma lipoprotein-lipid
      levels were mediated by concomitant variation in body fatness and glucose
      tolerance. CONCLUSIONS: These results suggest that the magnitude of the
      relationships between VO2max and plasma lipoprotein-lipid levels is influenced by
      the apo E polymorphism. Thus, apo E2 carriers may be particularly responsive to
      improved fitness, thereby preventing the development of hypertriglyceridemia and
      type III dyslipoproteinemia.

PMID- 10331891
TI  - Prophylactic ankle stabilizers affect ankle joint kinematics during drop
      landings.
AB  - PURPOSE: Ankle joint dorsiflexion contributes to energy absorption during
      landing, but wearing ankle stabilizers is known to restrict passive measures of
      dorsiflexion. This study compared the effects of various ankle stabilizers on
      ankle joint kinematics during soft and stiff landings. METHODS: Subjects (N = 14)
      performed two-legged landings off a 0.59-m platform. Kinematics of the right
      ankle were calculated from a sagittal plane video recording (120 Hz). Five soft
      and five stiff landings were performed in five ankle stabilizer conditions (no
      stabilizer, taping, Swede-O, AirCast, and Active Ankle), a total of 50 trials per
      subject. Style and stabilizer conditions were randomized across subjects. Each
      subject's five-trial mean value of selected kinematic variables for each landing
      style/stabilizer condition was entered into a two-way repeated MANOVA (alpha =
      0.05). RESULTS: Differences between soft and stiff landing conditions were
      similar to those reported in the literature. Compared with the No stabilizer
      condition, most stabilizer conditions significantly reduced ankle dorsiflexion
      ROM and angular velocity during landing. CONCLUSIONS: The results indicate that
      some ankle stabilizers adversely affect ankle joint kinematics during landing.

PMID- 10331890
TI  - Linkage between a muscle-specific CK gene marker and VO2max in the HERITAGE
      Family Study.
AB  - PURPOSE: We have reported a significant association between VO2max in the
      sedentary state and its response (delta VO2max) to an endurance training program
      with a muscle-specific creatine kinase (CKMM) gene polymorphism. The purpose of
      this study was to test the hypothesis of genetic linkage between the same CKMM
      marker and VO2max in the sedentary state as well as delta VO2max. METHODS: Sib
      pair linkage analysis was performed on 277 full sib-pairs from 98 Caucasian
      nuclear families of the HERITAGE Family Study. VO2max was measured during cycle
      ergometry tests before and after 20 wk of endurance training. The CKMM
      polymorphism was detected by the polymerase chain reaction and digestion with the
      Ncol restriction enzyme. RESULTS: Frequencies for the rare (1170 base pairs) and
      common (985 + 185 base pairs) alleles were 0.32 and 0.68, respectively. No
      significant linkage (t = -0.02, P = 0.49) was detected between the CKMM marker
      and the age and sex adjusted VO2max (mL x kg(-1) x min(-1)) in the sedentary
      state. However, after adjustment of delta VO2max for the effects of age, sex,
      initial VO2max, and body mass, evidence for linkage between the CKMM locus and
      delta VO2max was suggestive (P = 0.04). CONCLUSION: The present results provide
      further support for the notion that the CKMM gene, or some gene in close linkage
      disequilibrium with it, may contribute to individual differences in the VO2max
      response to endurance training.

PMID- 10331892
TI  - Foot placement modifies kinematics and kinetics during drop jumping.
AB  - PURPOSE: Sprinting, bouncing, and spontaneous landings are associated with a
      forefoot contact whereas walking, running, and jumping are associated with heel
      toe foot placement. Because such foot placement strategies influence landing
      mechanics or the ensuing performance, the purpose of this work was to compare
      lower extremity kinematics and kinetics and muscle activation patterns between
      drop vertical jumps performed with heel-toe (HTL) and forefoot (FFL) landings.
      METHODS: Ten healthy male university students performed two types of drop jump
      from a 0.4-m high box placed 1.0-m from the center of the force plate. They were
      instructed to either land first on the ball of the feet without the heels
      touching the ground during the subsequent vertical jump, i.e., forefoot landing
      jump (FFL), or to land on the heels followed by depression of the metatarsals,
      i.e., heel-toe landing jump (HTL). Three successfully performed trials per jump
      type were included in the analysis. The criteria for selection of the correct
      jumps was proper foot position at contact as judged from video records and the
      shape of force-time curve. RESULTS: The first peak and second peak determined
      from the vertical force-time curves were 3.4 times greater and 1.4 times lower
      for HTL compared with those with FFL (P<0.05). In the flexion phase of HTL, the
      hip and knee joints contributed 40% and 45% to the total torque, whereas during
      FFL the greatest torque contributions were 37% for both the knee and ankle
      joints. During the extension phase, the greatest torque contributions to the
      total torque were 41% and 45% by the knee and ankle joints during HTL and 34% and
      55% during FFL. During the flexion phase, power production was 20% greater
      (P<0.05) in HTL than in FFL, whereas during the extension phase power production
      was 40% greater in FFL than in HTL. In the flexion phase of HTL the hip and knee
      joints produced the greatest power, and during the extension phase the knee and
      ankle joints produced the greatest power. In contrast, during both the flexion
      and extension phases of FFL, the knee and ankle joints produced the greatest
      power. The EMG activity of gluteus, vastus lateralis, and plantar flexor muscles
      was similar between HTL and FFL in most cases except for the greater vastus
      lateralis EMG activity during precontact phase in HTL than in FFL and the greater
      gastrocnemius activity in FFL than in HTL. CONCLUSION: Foot placement strategy
      modifies the individual joint contributions to the total power during drop
      jumping.

PMID- 10331893
TI  - Biofeedback and relaxation techniques improves running economy in sub-elite long
      distance runners.
AB  - PURPOSE: The purpose of this investigation was to determine whether a
      psychophysiological intervention of biofeedback and relaxation could decrease the
      submaximal oxygen consumption (VO2submax) during treadmill running and improve
      running economy for a group of trained long distance runners. METHODS: Before and
      after a 6-wk control phase, seven long distance runners were tested for running
      economy, peak oxygen consumption (VO2peak), peak running velocity, and stretch
      shortening cycle efficiency. These runners then participated in a 6-wk training
      program in which they learned and practiced relaxation techniques and ran on the
      treadmill at a velocity eliciting 70% of peak running velocity for 10 min while
      biofeedback of heart rate (HR), ventilation (VE), and VO2 was presented to them.
      RESULTS: Data indicated that participants were able to lower their VO2, HR, and
      VE at lactate threshold by 7.3%, 2.5%, and 9.2%, respectively, using relaxation
      techniques (P<0.05). Post-tests of lactate threshold, VO2peak, peak running
      velocity, and stretch-shortening cycle efficiency showed that these changes did
      not occur as a result of a training effect. CONCLUSION: It was concluded that the
      improvements in running economy occurred as a result of the psychophysiological
      intervention.

PMID- 10331894
TI  - Marathons in altitude.
AB  - PURPOSE: We examined the effect of altitude up to 5200 m on marathon (42,195 m)
      performances. METHODS: Eight elite and four good runners participated in a
      marathon at 4300-m altitude (A1), and five elite runners participated both in A1
      and in a marathon at 5200-m altitude (A2). The maximal aerobic power (VO2max) was
      determined indirectly in altitude during A1 and A2 expeditions from the scores of
      a 12-min running test. The fractions of VO2max utilized during both races were
      calculated from the linear relationship between running speed and VO2 described
      by Costill and Fox (1969). RESULTS: VO2max significantly decreases with altitude
      (P<0.001). We found a linear relationship (R2 = 0.73, P<0.001) between the speed
      of each participant in the sea level marathon and the speed of A1. The mean
      difference between the sea level and the A1 speed was 35+/-9% (P<0.001). In A1,
      elite runners utilized 63+/-8% whereas good runners utilized 52+/-8% of VO2max
      (P<0.001). The five elite runners utilized 74+/-6%; 67+/-1% (P< 0.01), and 71+/
      3% (P<0.01) of their VO2max at sea level, A1, and A2, respectively. In Al, the
      mean heart rate (HR) was higher in elite than in good runners (P<0.001), whereas
      the percentage of maximum theoretical HR was 83+/-3% and 81+/-5%, respectively
      (P>0.05). CONCLUSIONS: Marathon performance in altitude is mainly affected by the
      lower VO2max. The better performance of elite marathoners in altitude compared
      with good runners was related to the higher % of VO2max maintained during every
      marathon. The differences between the expected and the observed performances at
      high altitude depend on the uneven running path and on a poorer economy of
      running that is related to the higher mechanical work of breathing. The
      fractional utilization of VO2max seems lowered by acute exposure to altitude and
      slightly increases with acclimatization.

PMID- 10331895
TI  - Effect of hand paddles on anaerobic energy release during supramaximal swimming.
AB  - PURPOSE: Swimmers swim faster using hand paddles. In this study the effect of
      maximal performance using hand paddles on aerobic and anaerobic energy release
      during supramaximal swimming was examined by comparing the maximal accumulated O2
      deficit, and the aerobic and anaerobic energy release during exhaustive swimming
      with paddles (P) to swimming without paddles (hands only, H). METHODS: The
      subjects were six trained college male swimmers. Experiments were carried out in
      a swimming flume. The water flow rate was set before each exercise bout such that
      exhaustion occurred in 30 s, 1 min, or 2-3 min. Accumulated O2 deficit during
      exercise was determined by the accumulated oxygen demand minus the accumulated O2
      uptake. RESULTS: Water flow rates at which maximal accumulated O2 deficit was
      obtained were significantly higher in P than that in H. However, mean values of
      maximal accumulated O2 deficit during H and P were 2.40+/-0.42 L and 2.32+/-0.37
      L, respectively, and there was no significant difference between these two
      values. Furthermore, during the supramaximal swimming to exhaustion in 30 s, 1
      min, or 2-3 min, both accumulated O2 uptake and accumulated O2 deficit did not
      significantly differ between these conditions, although mean water flow rates of
      these supramaximal swimming bouts were significantly higher in P than those in H
      again. CONCLUSIONS: These results suggest that the faster swimming speed
      accomplished with hand paddles does not affect metabolic responses and that it
      may be realized by recruitment of roughly the same muscle mass. Therefore, the
      ability to swim faster with hand paddles might mainly be attributed to other than
      metabolic factors, i.e., a higher propelling efficiency.

PMID- 10331896
TI  - Effects of different interval-training programs on cycling time-trial
      performance.
AB  - PURPOSE: We have investigated the effect of varying the intensity of interval
      training on 40-km time-trial performance in 20 male endurance cyclists (peak
      oxygen uptake 4.8+/-0.6 L x min(-1), mean +/- SD). METHODS: Cyclists performed a
      25-kJ sprint test, an incremental test to determine peak aerobic power (PP) and a
      simulated 40-km time-trial on a Kingcycle ergometer. They were then randomly
      assigned to one of five types of interval-training session: 12x30 s at 175% PP,
      12x60 s at 100% PP, 12x2 min at 90% PP, 8x4 min at 85% PP, or 4x8 min at 80% PP.
      Cyclists completed 6 sessions over 3 wk, in addition to their usual aerobic base
      training. All laboratory tests were then repeated. RESULTS: Performances in the
      time trial were highly reliable when controlled for training effects (coefficient
      of variation = 1.1%). The percent improvement in the time trial was modeled as a
      polynomial function of the rank order of the intensity of the training intervals,
      a procedure validated by simulation. The cubic trend was strong and statistically
      significant (overall correlation = 0.70, P = 0.005) and predicted greatest
      enhancement for the intervals performed at 85% PP (2.8%, 95% CI = 4.3-1.3%) and
      at 175% PP (2.4%, 95% CI = 4.0-0.7%). Intervals performed at 100% PP and 80% PP
      did not produce statistically significant enhancements of performance. Quadratic
      and linear trends were weak or insubstantial. CONCLUSIONS: Interval training with
      work bouts close to race-pace enhance 1-h endurance performance; work bouts at
      much higher intensity also appear to improve performance, possibly by a different
      mechanism.

PMID- 10331897
TI  - Noninvasive estimation of the maximal lactate steady state in trained cyclists.
AB  - PURPOSE: The purposes of this study were to estimate noninvasively the maximal
      lactate steady state (MLSS) in trained cyclists on a windload simulator with a
      velocity based technique and to determine whether the HR at MLSS (HR(MLSS))
      elicited a similar blood lactate concentration (BLC) during field testing.
      METHODS: To determine and verify MLSS, 10 male cyclists performed five to seven
      laboratory trials on separate days, including a VO2max test; a 5-km time trial
      (TT); and two or more 30-min trials at specific percentages of each subject's
      average 5-km TT speed (AVS5km). Mean+/-SD for the following variables were
      obtained at MLSS: velocity was 90.3+/-2.7% of the AVS5km, BLC was 5.4+/-1.6 mM,
      RPE was 15+/-2.1, VO2 was 80+/-6.3% of VO2max, and HR was 167+/-9.5 beats x min(
      1), which was 88+/-3.8% of the mean maximum HR. Field tests included three laps
      of an 8-km road circuit at HR(MLSS) +/-3 beats x min(-1) and one lap at maximum
      sustainable velocity (a road TT). RESULTS: There were no significant differences
      in BLC, HR, and RPE between the three steady-state road laps and the lab MLSS
      trial. There was also good agreement between the road and lab MLSS velocity/TT
      velocity ratios. CONCLUSIONS: Our data suggest that 5-km TT cycling velocity, as
      measured on a windload simulator, may be used to estimate MLSS and the HR at MLSS
      for training purposes.

PMID- 10331898
TI  - The accuracy of the TriTrac-R3D accelerometer to estimate energy expenditure.
AB  - PURPOSE: This study examined the reliability and validity of the TriTrac-R3D
      triaxial accelerometer to estimate energy expenditure during various modes of
      exercise. METHODS: Twenty subjects (age = 21.5+/-3.4 yr; body mass index = 23.3+/
      3.6 kg x m(-2)) performed five exercises (treadmill walking, treadmill running,
      stepping, stationary cycling, and slideboard), with each lasting 20-30 min and
      workload increased at 10-min intervals. To test the inter-TriTrac reliability,
      two TriTrac-R3D accelerometers were worn during each exercise period, and to
      examine validity, a simultaneous measurement of energy expenditure was made using
      indirect calorimetry (SensorMedics 2900 Metabolic Cart). RESULTS: Results showed
      a significant correlation between the two TriTrac-R3D accelerometers during all
      exercises. The difference in estimated energy expenditure between the two
      accelerometers during the walking, stepping, and slideboard exercises was less
      than 1 kcal x min(-1) but statistically significant (P<0.05). There was also a
      significant correlation between energy expenditure estimated by each of the
      TriTrac-R3D accelerometers and indirect calorimetry during walking, running,
      stepping, and slideboard exercise (P<0.05). The interaction of Method x Workload
      was significant (P<0.05) for each exercise, indicating that the TriTrac-R3D
      underestimates energy expenditure and that the magnitude of this underestimation
      increases as workload increases. CONCLUSIONS: Therefore, energy expenditure
      estimated via triaxial accelerometry does not increase with increasing workloads.
      These results suggest that there are limitations to using triaxial accelerometry
      to quantify energy expenditure.

PMID- 10331899
TI  - Sport performance enhancement: design and analysis of research.

PMID- 10331900
TI  - Biomechanical and structural characteristics of canine femoral and tibial
      cartilage.
AB  - To analyze the interrelationships between the structure, composition, and
      mechanical properties of articular cartilage, canine knee (n = 10) femoral and
      tibial cartilages were used as experimental tissues. The biomechanical
      properties, instant shear modulus (IM), and equilibrium shear modulus (EM) of
      articular cartilage were investigated using an in situ indentation creep
      technique. The local variations in the concentration of glycosaminoglycans (GAGs)
      in the cartilage were measured with a microspectrophotometer after safranin-O
      staining of histological sections. Using a computer-based quantitative polarized
      light microscopy method, area-specific measurements of the optical path
      difference were performed to quantitate collagen-related optical retardation
      (gamma) of cartilage zones. The IM and EM were 131.3 and 51.2% higher (p < 0.001)
      in the femoral cartilage than in the tibial cartilage, respectively. The mean
      thickness of the superficial zone and the relative proportion of the superficial
      zone from the total uncalcified cartilage was 107.1 and 155.3% higher (p < 0.001)
      at the femoral test points than in the tibial ones, respectively. The mean
      thickness of the tibial uncalcified cartilage was 21.1% higher (p < 0.001) than
      the thickness of the femoral cartilage. The GAG concentration of the tibial
      cartilage was higher (14.8%, p < 0.001) than that of the femoral cartilage,
      especially in the superficial zone (50.0%, p < 0.05), whereas the gamma of the
      collagen network in the superficial zone of the femoral cartilage was 64.7%
      higher (p < 0.001) than in the tibial cartilage. The percent relative thickness
      and retardation gamma of the superficial zone correlated positively with the
      indentation stiffness of the canine knee articular cartilage. These observations
      indicate that cartilage is structurally inhomogenous and layered tissue and the
      local organization of collagen and GAG concentration of the articular cartilage
      regulate the biomechanical properties of the tissue. The structure and
      composition of the superficial articular cartilage significantly affects the
      indentation response of the canine knee articular cartilage.

PMID- 10331901
TI  - Cell culture test of TCP/CPLA composite.
AB  - Thermoplastic polymers filled with a ceramic powder (here described as a
      "composite") of beta-tricalcium phosphate (TCP) and copoly-L-lactide (CPLA) was
      prepared by a heat-kneading method. The TCP/CPLA composite obtained had a three
      point bending strength of 51.26 +/- 634 MPa, a Young's modulus of 5.18 +/- 1.11
      GPa, and a fracture strength of 52.64 +/- 2.975 MPa, which is sufficient for
      usage as an artificial bone implant material. According to cell culture tests
      using MC3T3-E1 cells, the TCP/CPLA composite showed no cytotoxicity and the cells
      were in close contact with the surfaces of the composite without any observable
      morphological change. These results suggest that a composite consisting of
      osteoconductive TCP and biodegradable CPLA is suitable as a bioactive artificial
      bone material.

PMID- 10331902
TI  - Effects of dry heat and saturated steam on the physical properties of chitosan.
AB  - Heat may be employed to facilitate the processing of chitosan and to confer
      sterility on chitosan-based medical products. In this study, changes were
      analyzed of the physical properties of purified chitosan heated at 60 to 160
      degrees C under specified conditions for periods ranging from 0.5 to 4 h. Two
      forms of heat were used for processing: dry heat generated by a convection oven
      and saturated steam generated by an autoclave. Dry heat at < or = 80 degrees C
      resulted in less rigid chains with lower glass transition temperature, improved
      aqueous solubility, and slightly higher [eta]. At higher temperatures, dry heat
      produced chromophores, which may be related to interchain crosslink formation
      involving the NH2 groups. The [eta] and aqueous solubility of the samples
      decreased with temperatures > or = 120 degrees C. The coloration of the samples
      intensified from yellow to brown with increasing temperatures and duration of
      heat exposure. Chitosan heated at 160 degrees C for > or = 2 h was insoluble in
      the 0.2 M acetic acid/0.1 M sodium acetate solvent. The rate and extent of the
      thermal reactions were increased in the presence of saturated steam; the
      autoclaved samples became insoluble after 2 h of heating at 115 degrees C and
      after 1 h at > or = 120 degrees C. On the other hand, the physical changes
      induced by dry heat at < or = 120 degrees C were not affected significantly by
      heating the chitosan samples under anoxic conditions.

PMID- 10331903
TI  - Coating of hydroxyapatite on porous alumina substrate through a thermal
      decomposition method.
AB  - A thin film of hydroxyapatite (HA) was uniformly coated onto a highly porous
      substrate of alumina through the thermal decomposition method. Calcium 2-ethyl
      hexanoate and bis(2-ethyhexyl) phosphite were used as starting materials.
      Scanning electron microscopy, X-ray diffraction, and infrared spectroscopy were
      used to characterize the chemical and structural evolution of the coating. In
      vitro tests were conducted to evaluate the reactivity of the synthetic HA. It was
      found that the sintering process greatly influenced the in vitro behavior of HA.
      High temperature sintering may reduce the reactivity of HA, suggesting that the
      reactivity is structure dependent.

PMID- 10331904
TI  - Effect of porosity and environment on the mechanical behavior of acrylic bone
      cement modified with acrylonitrile-butadiene-styrene particles: I. Fracture
      toughness.
AB  - The elastomeric copolymer acrylonitrile-butadiene-styrene (ABS) was added to a
      conventional acrylic bone cement matrix. The results obtained show that although
      strength and stiffness decreased with an increasing second phase volume fraction,
      ductility and toughness both increased. The crack propagation became stable for
      specimens containing over a 5% volume fraction of the second phase. The fracture
      toughness increased up to 60% when the amount of ABS reached 20% (v/v). For
      larger amounts linear elastic fracture mechanics techniques could not be used
      properly. The effects of porosity and environmental conditions on the mechanical
      behavior were also studied. The mechanisms that control the fracture process were
      investigated by means of scanning electron microscopy.

PMID- 10331905
TI  - Effect of porosity and environment on the mechanical behavior of acrylic bone
      cement modified with acrylonitrile-butadiene-styrene particles: part II. Fatigue
      crack propagation.
AB  - The aim of this study was to investigate the effect of adding an elastomeric
      second phase, acrylonitrile-butadiene-styrene, on the fatigue crack propagation
      behavior of poly(methyl methacrylate) bone cement. Moreover, the influence of
      porosity and environmental conditions was studied. When comparing the plain
      cement to the modified cement, a decrease in the crack propagation rate was
      observed at between 1 and 2 orders of magnitude. The storage in a physiological
      environment (saline solution at 37 degrees C) also caused a decrease in the crack
      propagation rate of about 2 orders of magnitude for the plain and modified cement
      prepared in air or under a vacuum. Porosity did not have any noticeable effect on
      the fatigue crack propagation behavior of the cement.

PMID- 10331906
TI  - Improvement of fatigue properties of poly(methyl methacrylate) bone cement by
      means of plasma surface treatment of fillers.
AB  - The fatigue properties of poly(methyl methacrylate) (PMMA) bone cement were
      significantly improved through 13.56-MHz radio frequency plasma treatments on the
      X-ray opaque powder and on the reinforcing fibers. For the plasma treatments of
      particle surfaces, a specially designed plasma reactor was used to modify the
      surfaces of the ZrO2 powder (X-ray opaque filler) and milled carbon fibers
      (reinforcing filler). The reactor chamber was designed to be rotated continuously
      to mix the particles during the plasma treatments to obtain uniformly treated
      particle surfaces. The surface peroxides resulting from the plasma treatments
      seemed to have a significant effect on the improvement of fatigue properties. The
      peroxides on the particles may yield free radicals by the reaction with the
      reducing agent (N,N-dimethyl-p-toluidine) in the bone cement mixture, which can
      initiate methyl methacrylate (MMA) polymerization. Through this graft
      polymerization process, the interfacial bond strength between the filler
      particles and the MMA matrix may be enhanced, resulting in efficient stress
      transfer from the matrix to the fillers. The best results of the fatigue tests
      were seen in the reinforced bone cement, which contained surface modified
      fillers, with hexamethyldisiloxane plasma, and with O2 plasma posttreatment.

PMID- 10331907
TI  - Effect of mixing method and storage temperature of cement constituents on the
      fatigue and porosity of acrylic bone cement.
AB  - The influence of the storage temperature of the cement constituents prior to
      mixing (21 vs. 4 degrees C) and the mixing method (hand mixing vs. vacuum mixing)
      on the uniaxial tension-compression fatigue performance and porosity of Palacos R
      acrylic bone cement was studied. The fatigue results were analyzed using the
      three-parameter Weibull equation. The fatigue performance was expressed as an
      index I, which was defined as the product of the Weibull characteristic fatigue
      life and the square root of the Weibull slope. Statistical analyses of these
      results show that although the mixing method (for a given storage temperature)
      exerts a significant influence on the fatigue performance and areal porosity, the
      effect of storage temperature (for a given mixing method) on either of these
      parameters is not significant.

PMID- 10331908
TI  - Polymethylmethacrylate-based bone cement modified with hydroxyapatite.
AB  - A commercial acrylic bone cement was modified by the incorporation of different
      weight fractions of polycrystalline hydroxyapatite (HA), and the modified
      formulation was investigated. The influence of the filler proportion on the flow
      characteristics and the mechanical behavior of the resultant composite was
      evaluated. The residual monomer present in the cured materials was measured by
      gas chromatography. The comparison of the residual monomer present in the cements
      with and without reinforcement demonstrated that the degree of polymerization was
      not affected by the addition of HA. Porosity morphology was analyzed by optical
      and scanning electron microscopy. Image examination revealed that the porosity
      and the pore size of the hardened cement increased with an increasing amount of
      particulate filler. Flexural, compressive, and fracture properties of the cement
      with varying amounts of HA reinforcement were measured. It was found that up to
      15 wt% HA could be added for increases in flexural modulus and fracture
      toughness. HA acts as a rigid filler that enhances fracture resistance and
      flexural modulus. Our results show that the workability of the modified
      formulation limited the incorporation of the ceramic filler to a maximum value of
      15 wt%.

PMID- 10331909
TI  - Analysis of ultrahigh molecular weight polyethylene failure in artificial knee
      joints: thermal effect on long-term performance.
AB  - The mechanism resulting in damage to and failure of ultrahigh molecular weight
      polyethylene (UHMWPE) tibial inserts was investigated on clinically retrieved
      components. The severity of the subsurface damage increased with the length of
      time that the component had been implanted. A theoretical analysis was developed
      to account for the generation of subsurface damage based on a heat transfer
      model. Friction generates surface heat during articulation of total knee systems.
      Due to the cooling effect of body fluid on the surface, the rise in temperature
      on the UHMWPE surface is lower than that below the surface. The peak temperature
      was estimated to occur on a plane positioned about 1 to 2 mm below the surface.
      This result was similar to the bulk temperature variation observed during in vivo
      and in vitro studies by other investigators. Although the difference in
      temperature on and below the surface is only a few degrees, the thermal effect
      becomes apparent after a long time and may be explained by the viscoelastic
      behavior of polymers: the temperature-time equivalence. It is therefore suggested
      that this thermal effect is another contributory factor to material damage, in
      addition to high stress and oxidative degradation (in appropriate cases).
      Therefore, any technological efforts aimed at improving the performance of
      artificial joint prostheses should minimize the thermal effects at the subsurface
      of the articular components.

PMID- 10331911
TI  - Vascular graft healing: I. FTIR analysis of an implant model for studying the
      healing of a vascular graft.
AB  - FTIR analysis of sequential biopsy samples of the primary and replacement
      segments obtained from 70 to 80-cm long carotid-femoral bypass grafts implanted
      bilaterally in the dog indicate that the healing pattern is similar over the
      entire length of these grafts. Preliminary analysis of the spectra also indicates
      that the major developments in the formation of the biological layer appear to
      occur during the first 4 weeks after implantation. Collagen IV could be detected
      by both FTIR and antibody staining in the 8-week samples. Thus, this study
      supports the application of FTIR attenuated total reflectance to determine the
      components of the biological tissue that forms on an implanted vascular graft
      surface.

PMID- 10331910
TI  - Preliminary investigation of the effects of surface treatments on biological
      response to shape memory NiTi stents.
AB  - Nickel-titanium (NiTi) offers many advantages for the fabrication of coronary
      stents: shape memory, superelasticity, and radiopacity. However, many authors
      highlighted the selective dissolution of Ni from the alloy during the corrosion
      process that could lead to potential toxicity. The improvement of the NiTi
      stent's corrosion resistance by different surface treatments (electropolishing,
      heat treatment, and nitric acid passivation) was reported in a previous article.
      In the present study a comparative biocompatibility evaluation of such stents was
      performed through in vitro and in vivo assays. A cell proliferation test was
      completed to evaluate the cytotoxicity of surface treated NiTi using human
      fibroblasts. Then a stent implantation was performed in rabbit paramuscular
      muscle to study the inflammatory response generated by the same implants. Cell
      proliferation tests generally indicated an in vitro biocompatibility of our
      samples similar to the control group. An in vivo implantation study demonstrated
      the gradual overall reduction with time of the fibrocellular capsule thickness
      surrounding the implants. After a 12-week implantation period, the fibrous
      capsules surrounding the different implants tended toward the same value of 0.07
      mm, which suggested that all surface treatments produced a similar biological
      response. This low value of the fibrocellular capsule indicated that our NiTi
      surface treated implants were relatively inert.

PMID- 10331912
TI  - Mechanical properties of medical grade expanded polytetrafluoroethylene: the
      effects of internodal distance, density, and displacement rate.
AB  - Expanded polytetrafluoroethylene (e-PTFE) is used successfully in a multitude of
      biomedical and clinical applications. The success of this biomaterial is due to
      its microporous structure that allows biointegration for fixation, as well as
      overall mechanical integrity. The mechanical properties and degree of tissue
      ingrowth depend on the microstructure of the expanded polymer foam, yet little is
      known about the correlation of the internodal distance and other microstructural
      features with the monotonic tensile properties. Complete structure-property
      correlation can be used to provide invaluable knowledge for the design of
      biomedical devices. The purpose of this study was to investigate the monotonic
      tensile properties of e-PTFE over a range of medically relevant microstructural
      features and manufacturing parameters. The microstructural and manufacturing
      parameters considered were internodal distance, linear density, volumetric
      density, and reduction ratio. Additionally, the effect of displacement rate on
      mechanical properties was studied. We found that the ultimate stress and strain
      increased linearly with linear density (R2 = 0.88 and 0.67, respectively).
      Surprisingly, elastic modulus did not correlate with any parameter measured and
      only weak correlations were found between all properties and internodal distance.
      The yield and ultimate stresses increased with increasing displacement rate (R2 =
      0.88 and 0.57, respectively). The findings from this study indicate that linear
      density is a better predictor of mechanical properties than internodal distance
      and may be the preferred parameter to control when specifying a material for
      implantation in load bearing situations.

PMID- 10331913
TI  - Biomechanical performance of orthopedic gloves.
AB  - The purpose of this study was to compare the biomechanical performance of
      commercially available orthopedic gloves to that of a single surgical glove, as
      well as a double glove system. The orthopedic gloves were found to be thicker
      than the single surgical glove. This increased thickness of the orthopedic glove
      was associated with a greater resistance to glove puncture. The thickest
      orthopedic gloves also had reduced tactile sensitivity when compared to the
      single surgical glove. In addition, the glove donning forces and glove hydration
      rates varied considerably. These latter biomechanical performance parameters were
      not significantly related to glove thickness. The double glove systems tested in
      this study had similar performance characteristics in regard to many of the
      orthopedic gloves. The glove donning forces for the double glove systems were the
      lowest of the gloves tested. In addition, the double glove systems displayed the
      greatest resistance to glove hydration of the gloves tested. Their performance in
      the glove hydration tests and the force required to don the double glove systems
      were much more desirable than any of the orthopedic gloves. The results of this
      study indicate that the double glove systems may provide a desirable alternative
      to the use of the single orthopedic gloves.

PMID- 10331914
TI  - Failure of a new double glove hole detection system in the Emergency Department.
AB  - The purpose of this study was to evaluate the performance of a new double glove
      hole detection system in the Emergency Department. First, the frequency of holes
      in both gloves of the double glove hole detection system was determined using a
      watertight test method. Second, the frequency of glove puncture was determined
      first by searching for the optical color change that occurs with the ingress of
      fluid in the double glove hole detection system. These same gloves were then
      removed and also checked for holes by the watertight test method. After removal
      from the package, no holes were detected in the two gloves of the system using
      the watertight test method. In 50 consecutive patients, there was no color change
      in the inner glove indicating glove puncture. When these same gloves were then
      tested with the watertight test method, 14 of the 50 double glove hole detection
      systems failed; all 14 outer gloves were punctured, and three of the inner gloves
      had holes without demonstrable injury to the skin. This double glove hole
      detection system is not a reliable system to detect holes in relatively dry
      clinical settings because the ingress of fluid by capillary action between the
      gloves is necessary to cause a color change in the inner glove that signals the
      presence of a hole.

PMID- 10331915
TI  - Timing and classifying brief acoustic stimuli by songbirds and humans.
AB  - The durations of animals' brief vocalizations provide conspecifics with important
      recognition cues. In the present experiments, zebra finches and humans (trained
      musicians) were rewarded for responding after S+ (standard) auditory signals from
      56 to 663 ms and not for responding after shorter or longer S- (comparison)
      durations from 10 to 3684 ms. With either a single standard (Experiment 1) or
      multiple standards (Experiment 2), both zebra finches and humans timed brief
      signals to about the same level of accuracy. The results were in qualitative
      agreement with predictions from scalar timing theory and its connectionist
      implementation in both experiments. The connectionist model provides a good
      quantitative account of temporal gradients with a single standard (Experiment 1)
      but not with multiple standards (Experiment 2).

PMID- 10331916
TI  - Incentive downshifts evoke search repertoires in rats.
AB  - Negative incentive contrast effects (NCEs) have typically been attributed to
      frustration or the decremental generalization of learned associations. The
      purpose of these experiments was to clarify the relation of NCEs to the
      repertoires of functional search behaviors evoked by incentive downshifts. Rats
      shifted from 32% to 4% sucrose-solution decreased consummatory responses but
      increased nose-down locomotion, orientation, location entries, and sampling of
      alternatives relative to unshifted controls. These changes in behavior were
      terminated or failed to occur under incentive upshifts. Furthermore, reward
      downshifts did not produce avoidance of the location of the shifted incentive.
      Increased search occurred whether or not alternative reward locations were
      available. Together the evidence suggests that NCEs are related to evoked search
      modes supporting a repertoire of functional behaviors related to finding food.

PMID- 10331917
TI  - Can memory requirements account for species' differences in invisible
      displacement tasks?
AB  - We tested the hypothesis that poor performance on the Piagetian invisible
      displacement task is related to increased memory requirements. Rhesus monkeys and
      orangutans received 3 types of problems (invisible, visible, and no transfer
      problems) each containing a number of steps equivalent to that of standard
      invisible displacements. If failure to solve invisible displacements was due to
      increased memory requirements, then the primates should perform at chance level
      on all 3 problems. However, rhesus monkeys solved visible and no transfer
      problems, but not invisible transfer problems. Half of the orangutans solved all
      3 transfer problems, although their performance on invisible transfer problems
      was lower than that on the other problems. A subsequent cuing phase led to
      improved performance, and a few monkeys solved invisible transfer problems.

PMID- 10331918
TI  - Theoretical mechanisms underlying the trial-spacing effect in Pavlovian fear
      conditioning.
AB  - Contemporary explanations of the trial-spacing effect (TSE) were evaluated.
      Experiment 1 revealed, in rats given tone-footshock trials with 15-, 60-, or 900
      s intertrial intervals (ITIs), a direct relationship between freezing to the tone
      and ITI (the TSE) but an inverted U-shaped relationship between freezing to the
      training context and ITI. In Experiment 2, footshock preexposure eliminated the
      TSE that otherwise occurs across 15- to 60-s ITIs but had no effect on the TSE
      that occurs across 60- to 900-s ITIs. In Experiments 3 and 4, neither (a)
      increasing posttraining exposure to the training context in rats trained with 60
      s ITIs nor (b) reducing between-trial exposure to this context in rats trained
      with 900-s ITIs influenced freezing to the tone. These findings suggest that the
      TSE obtained in this research is due to more than 1 mechanism: 1 responsible for
      the TSE that occurs with ITIs less than approximately 60 s and another
      responsible for the TSE that occurs with ITIs greater than this. Although the
      perceptual-defensive-recuperative model may correctly describe the former
      mechanism, none of the theories tested seems to correctly describe the latter.

PMID- 10331919
TI  - Dynamic object perception by pigeons.
AB  - Three experiments examined pigeon discrimination of computer-generated three
      dimensional (3-D) projections of cube and pyramid objects. Four pigeons were
      tested using a go/no-go procedure involving static and dynamically rotating
      presentations of these stimuli. Transfer tests with different types of rotational
      and featural transformations suggested the pigeons may have used a 3-D
      representation of the objects as their primary means of performing the
      discrimination. The comparative implications for object and motion perception in
      animals are considered.

PMID- 10331920
TI  - Reevaluating evaluative conditioning: a nonassociative explanation of
      conditioning effects in the visual evaluative conditioning paradigm.
AB  - In 2 studies, the authors investigated whether evaluative conditioning (EC) is an
      associative phenomenon. Experiment 1 compared a standard EC paradigm with
      nonpaired and no-treatment control conditions. EC effects were obtained only when
      the conditioned stimulus (CS) and unconditioned stimulus (UCS) were rated as
      perceptually similar. However, similar EC effects were obtained in both control
      groups. An earlier failure to obtain EC effects was reanalyzed in Experiment 2.
      Conditioning-like effects were found when comparing a CS with the most
      perceptually similar UCSs used in the procedure but not when analyzing a CS
      rating with respect to the UCS with which it was paired during conditioning. The
      implications are that EC effects found in many studies are not due to associative
      learning and that the special characteristics of EC (conditioning without
      awareness and resistance to extinction) are probably nonassociative artifacts of
      the EC paradigm.

PMID- 10331921
TI  - Blocking in the Morris swimming pool.
AB  - Four experiments demonstrate that spatial blocking is governed by the same
      principles that govern blocking in Pavlovian conditioning. In the 2nd stage of
      each experiment, rats escaped from a Morris swimming pool by swimming to a
      submerged platform with a beacon attached to it. Test trials were then conducted
      in the absence of the platform and the beacon to assess the extent to which
      subjects had learned about the position of the platform with reference to the
      room cues. For the 1st stage of their training, rats either swam to the platform
      and beacon in the presence of curtains that prevented the room cues from being
      seen (Experiments 1 & 2), or they swam to the platform and beacon that were moved
      from trial to trial (Experiments 3 & 4). In each experiment, learning about the
      room cues in the 2nd stage of the experiment was blocked by the presence of the
      beacon. This blocking effect was disrupted by changing the appearance of the
      beacon for the 2nd stage of training or by restricting the amount of exposure to
      the beacon during the 1st phase of training.

PMID- 10331922
TI  - The benzodiazepine midazolam does not impair Pavlovian fear conditioning but
      regulates when and where fear is expressed.
AB  - Rats were injected with a benzodiazepine (midazolam) and shocked after
      presentation of an auditory conditioned stimulus (CS). They were then tested for
      fear reactions (freezing) to the CS in either the original context or a 2nd
      context after either a short (1-day) or long (21-day) retention interval. Rats
      tested in the original context froze less after 1 day than rats tested after that
      interval in the 2nd context or rats tested after 21 days. Moreover, rats tested
      after the long interval in the original context froze less than rats tested after
      that interval in the 2nd context. Therefore, midazolam does not impair the
      acquisition of conditioned fear but regulates when and where that fear is
      expressed. These effects of midazolam were interpreted as a contextually
      controlled deficit in the expression of conditioned fear that is similar to that
      associated with latent inhibition and extinction (M. E. Bouton, 1993).

PMID- 10331923
TI  - Associative changes in elements and compounds when the other is reinforced.
AB  - Four experiments investigated the symmetry of associative changes in stimulus
      compounds and elements in a Pavlovian conditioned magazine-approach situation
      with rats. Experiment 1 used multiple groups to examine the associative changes
      in a conditioned element (A) as a result of its subsequent reinforcement in
      compound with a neutral X. These were compared with the changes in an AX compound
      when one of its elements (A) was subsequently reinforced alone. Although
      reinforcing A enhanced responding to the AX compound, compared with a control
      compound, reinforcing AX failed to enhance responding to A, compared with a
      control element. Experiments 2 and 3 made similar comparisons in a fully within
      subject design, finding greater changes in a previously trained AX compound when
      A was subsequently conditioned than in a B element when BY was subsequently
      conditioned. Experiment 4 found associative decrements in A when it was
      reinforced in the presence of a moderately conditioned X. The results observed in
      each of these experiments are more consistent with an elemental model of
      conditioning than with a recently proposed configural model.

PMID- 10331924
TI  - Does the context of reinforcement affect resistance to change?
AB  - Eight pigeons were trained on multiple schedules of reinforcement where pairs of
      components alternated in blocks on different keys to define 2 local contexts. On
      1 key, components arranged 160 and 40 reinforcers/hr; on the other, components
      arranged 40 and 10 reinforcers/hr. Response rates in the 40/hr component were
      higher in the latter pair. Within pairs, resistance to prefeeding and resistance
      to extinction were generally greater in the richer component. The two 40/hr
      components did not differ in resistance to prefeeding, but the 40/hr component
      that alternated with 10/hr was more resistant to extinction. This discrepancy was
      interpreted by an algebraic model relating response strength to component
      reinforcer rate, including generalization decrement. According to this model,
      strength is independent of context, consistent with research on schedule
      preference.

PMID- 10331925
TI  - Crystal structure of the hydrogenase maturating endopeptidase HYBD from
      Escherichia coli.
AB  - The maturation of [NiFe] hydrogenases includes formation of the nickel
      metallocenter, proteolytic processing of the metal center carrying large subunit,
      and its assembling with other hydrogenase subunits. The hydrogenase maturating
      enzyme HYBD from Escherichia coli, a protease of molecular mass 17.5 kDa,
      specifically cleaves off a 15 amino acid peptide from the C terminus of the
      precursor of the large subunit of hydrogenase 2 in a nickel-dependent manner.
      Here we report the crystal structure of HYBD at 2.2 A resolution. It consists of
      a twisted five-stranded beta-sheet surrounded by four and three helices,
      respectively, on each side. A cadmium ion from the crystallization buffer binds
      to the proposed nickel-binding site and is penta-coordinated by Glu16, Asp62,
      His93, and a water molecule in a pseudo-tetragonal arrangement. HYBD is
      topologically related to members of the metzincins superfamily of zinc
      endoproteinases, sharing the central beta-sheet and three helices. In contrast to
      the metzincins, the metal-binding site of HYBD is localized at the C-terminal end
      of the beta-sheet. Three helical insertions unique to HYBD pack against one side
      of the sheet, build up the active site cleft, and provide His93 as ligand to the
      metal. From this structure, we derive molecular clues into how the protease HYBD
      is involved in the hydrogenase maturation process.

PMID- 10331926
TI  - Growth of the Canadian Association of Gastroenterology: controlled, effective and
      impressive.

PMID- 10331927
TI  - Pregnancy in inflammatory bowel disease.

PMID- 10331928
TI  - Antidiarrheal therapy.

PMID- 10331929
TI  - Gene therapy for lactose intolerance.

PMID- 10331930
TI  - Pathobiology of Helicobacter pylori infection.

PMID- 10331932
TI  - Helicobacter pylori and its genome: lessons from the treasure map.
AB  - The availability of the complete genome sequence of Helicobacter pylori 26695 has
      opened new avenues for research in the molecular biology of this gastric
      pathogen. The present review gives a general overview of H pylori obtained from
      the complete genome sequence and compares this with data previously obtained from
      cloning and functional studies of H pylori. The cagA pathogenicity island of 40
      kilobases, which encodes a type IV secretion system, is discussed. The diversity
      of H pylori genomes is well known, yet new data indicate that some aspects of the
      genome, particularly outer membrane protein genes, are conserved. Genes encoding
      proteins involved in molecular mimicry between bacterium and gastric epithelial
      tissue, specifically those encoding Lewis X and Lewis Y antigens, are discussed.
      The large number of DNA restriction and modification genes and their role in H
      pylori infection are considered. Finally, gene transfer is discussed. The
      availability of the complete genome sequence of H pylori 26695 and the soon to be
      available sequence of J99 will speed up and assist in the analysis of H pylori
      genes and their encoded proteins. The genomes of both strains will be useful as
      references with which other H pylori genomes can be compared.

PMID- 10331931
TI  - Canadian Helicobacter pylori Consensus Conference update: infections in adults.
      Canadian Helicobacter Study Group.
AB  - The first Canadian Helicobacter pylori Consensus Conference took place in April
      1997. The initial recommendations of the conference were published in early 1998.
      An update meeting was held in June 1998, and the present paper updates and
      complements the earlier recommendations. Key changes included the following: the
      recommendation for testing and treating H pylori infection in patients with known
      peptic ulcer disease was extended to testing and treating patients with ulcer
      like dyspepsia; it was decided that the urea breath test (not serology) should be
      used for routine diagnosis of H pylori infection unless endoscopy is indicated
      for another reason; and recommended therapies were a twice daily, seven-day
      regimen of a proton pump inhibitor (omeprazole 20 mg, lansoprazole 30 mg,
      pantoprazole 40 mg) or ranitidine bismuth citrate 400 mg, plus clarithromycin 500
      mg and amoxicillin 1000 mg, or plus clarithromycin 500 or 250 mg and
      metronidazole 500 mg. The need was reiterated to have funding for readily
      accessible, accurate testing for H pylori infection with the urea breath test. It
      was strongly recommended that regional centres be established to monitor the
      prevalence of antibiotic-resistant H pylori infections. The initial consensus
      document referred to pediatric issues that were not addressed in this update but
      were the subject of a subsequent Canadian Helicobacter Study Group meeting, and
      will be published later in 1999.

PMID- 10331933
TI  - Role of Helicobacter pylori in the pathogenesis of gastric carcinoma and
      progression of lymphoid nodules to lymphoma.
AB  - The pathology of gastritis associated with Helicobacter pylori infection is
      summarized. The literature is reviewed regarding the role of H pylori in the
      pathogenesis of gastric carcinoma and mucosa-associated lymphoid tissue (MALT)
      lymphoma. The potential mechanisms of gastric carcinogenesis include
      transformation of the gastric mucosa by metabolic products of H pylori,
      transformation of the host cell by incorporation of H pylori DNA and genotoxic
      effects of the inflammatory response to the organism. A model for gastric
      carcinogenesis is proposed in which H pylori causes cell proliferation, and the
      risk of DNA damage is increased, leading to inadequate repair and malignant
      transformation. Investigation of early gastric carcinomas concluded that two main
      pathways operated in gastric carcinogenesis, both starting from H pylori
      gastritis and leading to phenotypically variable gastric or intestinal tumour
      growth. The histological features and molecular genetics of MALT lymphoma are
      briefly reviewed. There is evidence that tumour cells of low grade B cell MALT
      lymphoma proliferate specifically in response to H pylori. This response is
      dependent on T cell activation by H pylori. A proposed model for the pathogenesis
      of MALT lymphoma postulates that B lymphocytes with a genetic change acquire a
      growth advantage resulting in a monoclonal proliferation in response to H pylori
      activated T cells. Further genetic changes may result in escape from T cell
      dependency.

PMID- 10331934
TI  - Understanding disease outcome following acquisition of Helicobacter pylori
      infection during childhood.
AB  - Helicobacter pylori causes chronic active (type B) gastritis in the overwhelming
      majority of infected individuals. The relative contribution of virulence factors
      in the bacterium and host responses to the microbial infection in determining
      which subjects will go on to develop complications - such as peptic ulceration,
      gastric cancers and gastric lymphomas - is the subject of current investigative
      activities.

PMID- 10331935
TI  - Immunomodulation of helicobacter infection.
AB  - Helicobacter pylori leads to a chronic infection in humans that is associated
      with gastric inflammation and a vigorous immune response. Despite the humoral and
      cellular responses that can be detected in both human and animal models of
      helicobacter infection, the immune response fails to eliminate the organism.
      Eradication failure may be due to the niche in which H pylori confines itself,
      well away from direct contact with elements of the immune system. Alternatively,
      the general tendency of the intestinal immune response to down- regulate
      reactivity to noninvasive luminal bacteria also may contribute to the failure to
      eliminate helicobacter infection. Results of vaccine studies in mouse models
      indicate that modulating the helper T cell response from a T helper cell type 1
      to a T helper cell type 2 response likely is required for the prevention and
      elimination of helicobacter infection. Understanding the mechanisms by which the
      immune response controls bacterial infections will allow for the design of novel
      strategies of immune modulation and the development of vaccines for both the
      treatment and prevention of H pylori.

PMID- 10331936
TI  - Antibiotic resistance mechanisms of Helicobacter pylori.
AB  - Infection with Helicobacter pylori is most frequently associated with gastritis
      and peptic ulcer disease. Antimicrobial intervention, together with proton pump
      inhibitors, has become the standard therapy for treating this disease. Resistance
      to clarithromycin and metronidazole, two of the most commonly used antimicrobials
      for treatment of H pylori infections, is often associated with treatment failures
      and relapse of infection. Clarithromycin resistance arises through mutations
      leading to base changes in 23S ribosomal RNA subunits, while resistance to
      metronidazole is due to mutations in the rdxA gene, which encodes a novel
      nitroreductase that is responsible for reductive activation of the drug. Products
      of metronidazole activation are mutagenic and can be demonstrated to increase
      both the mutation frequency and the frequency at which antibiotic resistance
      arises in H pylori.

PMID- 10331937
TI  - Determinants of ethnic or geographical differences in infectivity and
      transmissibility of Helicobacter pylori.
AB  - The prevalence of Helicobacter pylori infection is variable in different
      countries. There are two distinct patterns of H pylori prevalence with respect to
      age depending on the geographical region studied. The first pattern is widespread
      infection early in childhood with elevated prevalence rates of close to 80%
      throughout adulthood, and the second is increasing prevalence with age. This
      variability in pattern suggests a difference in infectivity or transmissibility
      of H pylori infection. Potential determinants of these differences are reviewed
      including environmental, bacterial and host factors. The most important
      determinant is likely socioeconomic class, which affects living conditions and
      sanitation, thus altering exposure to the bacterium. Host factors also play a
      role, perhaps via host receptors for H pylori. Bacterial factors may also
      contribute, although compelling evidence is lacking.

PMID- 10331938
TI  - Liver transplantation: past accomplishments and future challenges.
AB  - Liver transplantation has evolved from a rare and risky operation of questionable
      therapeutic value to the preferred treatment for an extensive list of end-stage
      liver diseases. Superior immunosuppression (cyclosporine), and improvements in
      surgery and anesthesia brought liver grafting to its current level of success.
      Nearly 60,000 liver transplants have been performed, and survival rates are very
      good; however liver grafting faces serious immediate and long term challenges,
      mainly due to the widening gap between donor supply and recipient demand.
      Increasing numbers of sick candidates, recurrent disease (especially hepatitis C)
      and recidivism rates after transplantation for alcoholic cirrhosis will force
      increasingly difficult decisions on candidate selection and priority listing of
      potential recipients. Although xenotransplantation may be the ultimate solution,
      it has its own specific set of biological and societal challenges - the full
      extent of which should be revealed in the next several years.

PMID- 10331939
TI  - Serological testing in screening for adult celiac disease.
AB  - Assays for celiac-related antibodies are becoming widely available, and the
      present review aims to clarify the use of these investigations in the diagnosis
      of, management of and screening for adult celiac disease. The sensitivities and
      specificities of various antibody tests are discussed, along with their clinical
      use as an adjunct to small bowel biopsy, and as a first-line investigation for
      patients with atypical symptoms of celiac disease or patients at high risk of
      developing sprue.

PMID- 10331940
TI  - Construction and characterization of an eightfold redundant dog genomic bacterial
      artificial chromosome library.
AB  - A large insert canine genomic bacterial artificial chromosome (BAC) library was
      built from a Doberman pinscher. Approximately 166,000 clones were gridded on nine
      high-density hybridization filters. Insert analysis of randomly selected clones
      indicated a mean insert size of 155 kb and predicted 8.1 coverage of the canine
      genome. Two percent of the clones were nonrecombinant. Chromosomal fluorescence
      in situ hybridization studies of 60 BAC clones indicated no chimerism. The
      library was hybridized with dog PCR products representing eight genes (ADA, TNFA,
      GCA, MYB, HOXA, GUSB, THY1, and TOP1). The resulting positive clones were
      characterized and shown to be compatible with an eightfold redundant library.

PMID- 10331941
TI  - Acquisition of the H19 methylation imprint occurs differentially on the parental
      alleles during spermatogenesis.
AB  - The imprinted mouse H19 gene is hypomethylated on the expressed maternal allele
      and hypermethylated on the silent paternal allele. A 2-kb region of differential
      methylation located from -2 to -4 kb relative to the H19 transcriptional start
      site has been proposed to act as the imprinting mark since hypermethylation in
      this region is inherited from sperm and retained on the paternal allele
      throughout development. Here, we describe a temporal analysis of the methylation
      patterns at the H19 locus during postnatal male germ cell development. The 2-kb
      region is methylated on the paternal allele throughout spermatogenesis,
      suggesting that methylation is acquired in this region prior to the resumption of
      mitosis in postnatal male mice. Likewise, more than half of the maternal alleles
      are hypermethylated prior to the resumption of mitosis. However, the remaining
      maternal alleles are not hypermethylated until the completion of meiosis I,
      indicating that de novo methylation in this region is a continuous process.
      Sequences proximal to the H19 promoter, which are methylated in spermatozoa and
      on the paternal allele in somatic cells, are differentially methylated in
      diploid, mitotic spermatogonia. The maternal allele becomes hypermethylated in
      this region during meiotic prophase. Thus, the parental H19 alleles acquire
      methylation differentially in the male germline.

PMID- 10331942
TI  - Localization of retina/pineal-expressed sequences: identification of novel
      candidate genes for inherited retinal disorders.
AB  - More than 100 genes causing inherited retinal diseases have been mapped to
      chromosomal locations, but less than half of these genes have been cloned.
      Mutations in many retina/pineal-specific genes are known to cause inherited
      retinal diseases. Examples include mutations in arrestin, rhodopsin kinase, and
      the cone-rod homeobox gene, CRX. To identify additional candidate genes for
      inherited retinal disorders, novel retina/pineal-expressed EST clusters were
      identified from the TIGR Human Gene Index database and mapped to specific
      chromosomal sites. After known human gene sequences were excluded, and repeat
      sequences were masked, 26 novel retina and pineal gland cDNA clusters were
      identified. The retinal expression of each novel EST cluster was confirmed by PCR
      assay of a retinal cDNA library, and each cluster was localized in the genome
      using the GeneBridge 4.0 radiation hybrid panel. In silico expression data from
      the TIGR database suggest that these EST clusters are retina/pineal-specific or
      predominantly expressed in these tissues. This combination of database analysis
      and laboratory investigation has localized several EST clusters that are
      potential candidates for genes causing inherited retinopathy.

PMID- 10331944
TI  - Tissue-specific alternative splicing of the CSE1L/CAS (cellular apoptosis
      susceptibility) gene.
AB  - CSE1L/CAS (CAS) is a nuclear transport factor that plays a role in proliferation
      and apoptosis. The CAS gene consists of 25 exons. mRNA homologous over its entire
      length to the yeast homologue CSE1 is the predominant transcript in proliferating
      tissues. Additional mRNAs are generated by alternative splicing in a tissue
      specific manner. An extended 3'-end is found in fetal and adult brain. A mRNA
      containing the 5'-end of CAS up to position 690 and an alternative 3'-end is
      expressed in trachea and encodes a truncated Ran-binding domain. Fetal liver
      expresses a mRNA with deletions of a central portion of CAS and additional
      sequences encoded by the last intron. SW480 colon cancer cells express another
      approximately 1500-base mRNA. Western blot analyses of various human tissues and
      immunohistology of mouse embryos show a correlation of CAS transcripts and CAS
      protein in different tissues. CAS isoforms may control nuclear transport of
      tissue-specific proteins.

PMID- 10331943
TI  - Linkage analysis narrows the critical region for oculodentodigital dysplasia to
      chromosome 6q22-q23.
AB  - Oculodentodigital dysplasia (ODDD) is an autosomal dominant condition with high
      penetrance and variable expressivity. The anomalies of the craniofacial region,
      eyes, teeth, and limbs indicate abnormal morphogenesis during early fetal
      development. Neurologic abnormalities occur later in life and appear to be
      secondary to white matter degeneration and basal ganglia changes. In familial
      cases, the dysmorphic and/or neurodegenerative components of the phenotype can be
      more severe and/or present at a younger age in subsequent generations, suggesting
      genetic anticipation. These clinical features suggest that the ODDD gene is
      pleiotropic with important functions throughout pre- and postnatal development.
      We have performed two-point linkage analysis with seven ODDD families and 19
      microsatellite markers on chromosome 6q spanning a genetic distance of
      approximately 11 cM in males and 20 cM in females. We have refined the location
      of the ODDD gene between DNA markers D6S266/D6S261 (centromeric) and D6S1639
      (telomeric), an interval of 1.01 (male) to 2.87 (female) cM. The strongest
      linkage was to DNA marker D6S433 (Zmax = 8.96, thetamax = 0.001). Families show
      significant linkage to chromosome 6q22-q23 and no evidence for genetic
      heterogeneity.

PMID- 10331945
TI  - Guinea pig p53 mRNA: identification of new elements in coding and untranslated
      regions and their functional and evolutionary implications.
AB  - We report the sequence of the guinea pig p53 cDNA. The comparative analysis of
      the coding and noncoding regions of p53 cDNAs of all available complete
      vertebrate sequences has allowed us to single out new conserved signals possibly
      involved in p53 functional activity. We have focused our attention on the most
      variable region of the protein, the proline (P)-rich domain, suggested to play a
      fundamental role in antiproliferative pathways. In this domain we have identified
      the PXXXXP repeated motif and singled out a common consensus sequence that can be
      considered a signature for mammalian p53: PXXXXPX{0,4}PX{0,9}PA(T,P,I,)(S,P)WPL.
      We have demonstrated the significance of the PXXXXP motif in SH3-binding protein
      and suggested its structure to be a loop. Also, the 5' and 3' untranslated
      regions (UTRs) of the guinea pig were sequenced, and this study represents the
      first detailed structural analysis of the UTRs of the p53 mRNAs available in
      literature. The 5' UTR of guinea pig (233 nt) can be folded into a stable
      secondary structure resembling that predicted in mouse. The 3' UTR of guinea pig
      is 771 nt long and shows higher similarity with human than with rodent sequences,
      having a region of about 350 nt that is deleted in rat and mouse. In the 3' UTR
      we have identified the presence of a mammalian-wide interspersed repeat sequence
      and of a cytoplasmic polyadenylation element, which could be involved in
      translational activation by promoting polyadenylation of mRNA, providing
      information about a possible mechanism of regulation of p53 expression mediated
      by the 3' UTR of the mRNA. The observations presented here could open new avenues
      to targeted mutations and experimental approaches useful in investigating new
      regulation mechanisms of p53 translation, activity, and stability.

PMID- 10331947
TI  - Cloning of a novel member of the reticulon gene family (RTN3): gene structure and
      chromosomal localization to 11q13.
AB  - A novel member of the neuron-specific protein (NSP) or newly named reticulon
      (RTN) gene family was isolated during a subtraction cloning between macula and
      peripheral retina. The mRNA for this NSP/RTN-like gene is approximately threefold
      more abundant in macula than in peripheral retina. The cDNA is 2527 bp long and
      contains an open reading frame of 236 amino acids. The deduced peptide shows a
      strong similarity to the NSP/RTN and tropomyosin-like gene families but it is
      clearly a novel member. The gene contains seven exons and spans more than 15 kb.
      The gene was localized to chromosome 11q13 between markers D11S4535 and D11S4627
      using somatic cell hybrid panels. Southern blot analysis identified the presence
      of a pseudogene(s) that was subsequently localized to chromosome 4. Multitissue
      Northern blot analysis found this gene to be widely expressed in human tissues
      with the highest expression in the brain. We are calling this gene RTN3 to
      reflect the newly proposed nomenclature.

PMID- 10331946
TI  - Identification of SCML2, a second human gene homologous to the Drosophila sex
      comb on midleg (Scm): A new gene cluster on Xp22.
AB  - We have identified a novel gene with homologies to the Drosophila Sex comb on
      midleg (Scm) gene from the short arm of the X chromosome. Scm is a member of the
      Polycomb group (PcG) genes, which encode transcriptional repressors essential for
      appropriate development in the fly and in mammals. The newly identified
      transcript named SCML2 (sex comb on midleg like-2, HGMW-approved symbol) is
      ubiquitously expressed and encodes a protein of 700 amino acids. SCML2 maps very
      close to the recently identified SCML1, revealing the presence of a new gene
      cluster in Xp22. The homology and map location identify SCML2 as a candidate gene
      for Xp22-linked developmental disorders, including the oral-facial-digital type I
      (OFDI) syndrome. A study of the SCML1-SCML2 cluster in primates indicates that
      the two genes are localized to the same region in Old World monkeys, New World
      monkeys, and prosimians, suggesting that the duplication event leading to the
      formation of the SCML cluster on Xp22 occurred before primate divergence.

PMID- 10331948
TI  - Structure and chromosomal localization of the human and murine genes for the
      macrophage MARCO receptor.
AB  - The structures of the human and mouse genes for the macrophage receptor with
      collagenous structure were determined. Both genes have 17 exons, of which exons 4
      15 encode the collagenous domain. The transcription initiation sites in the mouse
      gene were identified using primer extension, SI nuclease mapping, and 5'
      capturing rapid amplification of cDNA ends assays. All three methods revealed two
      major initiation sites, one starting 27 bp downstream of a TATA box and another
      at positions -63 and -66 downstream of an AT-rich region. Several potential
      binding sites for transcription factors were identified in the promoter region,
      neither gene has a CAAT box or GC boxes. The human and mouse genes were localized
      to syntenic regions on chromosomes 2 and 1, respectively, using fluorescence in
      situ hybridization.

PMID- 10331949
TI  - Genomic organization and chromosomal location of the mouse vasoactive intestinal
      polypeptide 1 (VPAC1) receptor.
AB  - The gene encoding the mouse vasoactive intestinal polypeptide type 1 (VPAC1)
      receptor was cloned, and its structural organization was determined. The gene
      (Vipr1) is more than 16 kb in length and is divided into 13 exons. The 5'
      flanking region is highly GC-rich and lacks an apparent TATA box, but contains a
      CCAAT box, three potential Sp1-binding sites, and two potential AP-2-binding
      sites. Promoter analysis of the 5'-flanking region of Vipr1 using a luciferase
      gene reporter system revealed that the isolated 5'-flanking region has functional
      promoter activity. The mouse Vipr1 gene is encoded by a single gene, which was
      mapped to the distal region of mouse chromosome 9. This region is syntenic with
      human chromosome 3p, where the human VPAC1 receptor gene has been mapped.

PMID- 10331950
TI  - Cloning and characterization of RNF6, a novel RING finger gene mapping to 13q12.
AB  - Myeloproliferative disorders frequently show deletions or rearrangements of the
      long arm of chromosome 13. We report here the cloning of RNF6, a new gene that
      maps close to the chromosome 13 breakpoint in a case of myelofibrosis with a
      t(4;13)(q26;q12). RNF6 is predicted to encode a 685-amino-acid protein with a
      coiled-coil domain and a RING-H2 finger at the amino and carboxy terminis,
      respectively. In addition, we have identified a novel motif, Lys-X-X-Leu/Ile-X-X
      Leu/Ile (KIL motif), that is located shortly upstream of a subset of RING-H2
      proteins, including RNF6. Drosophila g1, rat Neurodap1, and mouse Praja1. FISH
      and physical mapping indicated that RNF6 is located at 13q12.2 close to marker
      D13S1121, and it is oriented from telomere to centromere. RNF6 is not disrupted
      by the t(4;13).

PMID- 10331953
TI  - The BTRC gene, encoding a human F-box/WD40-repeat protein, maps to chromosome
      10q24-q25.

PMID- 10331952
TI  - Mapping homologs of Drosophila odd Oz (odz): Doc4/Odz4 to mouse chromosome 7,
      Odz1 to mouse chromosome 11; and ODZ3 to human chromosome Xq25.

PMID- 10331951
TI  - Bestrophin gene mutations in patients with Best vitelliform macular dystrophy.
AB  - Best vitelliform macular dystrophy (VMD2) is an autosomal dominant dystrophy with
      a juvenile age of onset. Mutations in the Bestrophin gene were shown in patients
      affected with VMD2. In a mutation study, we made three new and interesting
      observations. First, we identified possible mutation hotspots within the gene,
      suggesting that particular regions of the protein have greater functional
      significance than others. Second, we described a 2-bp deletion in a part of the
      gene where mutations have not previously been reported; this mutation causes a
      frameshift and subsequent premature termination of the protein. Finally, we have
      evidence that some mutations are associated with variable expression of the
      disease, suggesting the involvement of other factors or genes in the disease
      phenotype.

PMID- 10331955
TI  - Volume 52, number 1 (1998), in article no. GE985365 "Analysis of distribution in
      the human, pig, and rat genomes points toward a general subtelomeric origin of
      minisatellite Structures," by Valerie amarger, dominique gauguier, martine yerle,
      Francoise apiou, philippe pinton, fabienne giraudeau, sylvaine monfouilloux, mark
      lathrop, bernard dutrillaux, Jerome buard, and gilles vergnaud, pages 62-71 

PMID- 10331954
TI  - Regional localization of the human epithelial membrane protein genes 1, 2, and 3
      (EMP1, EMP2, EMP3) to 12p12.3, 16p13.2, and 19q13.3.

PMID- 10331956
TI  - Volume 52, number 2 (1998), in article no. GE985408 "Strategy to sequence the 89
      exons of the human LRP1 gene coding for the lipoprotein receptor related protein:
      identification of one expressed mutation among 48 Polymorphisms," by F. Van
      leuven, L. Stas, E. Thiry, B. Nelissen, and Y. Miyake, pages 138-144 

PMID- 10331957
TI  - Investigative pathology for the millennium.

PMID- 10331958
TI  - Stealth adaptation of an African green monkey simian cytomegalovirus.
AB  - DNA extracted from cultures of a cytopathic virus isolated from a patient with
      chronic fatigue syndrome was cloned into pBluescript plasmid. The nucleotide
      sequences of the plasmid inserts were analyzed using the BlastN and BlastX
      programs of the National Center for Biotechnology Information. In confirmation of
      earlier studies, many of the sequences show partial homology to various regions
      within the genome of human cytomegalovirus (HCMV). The matching regions were
      unevenly distributed throughout the HCMV genome. No matches were seen with either
      the UL55 or the UL83 genes, which provide the major antigenic targets for anti
      HCMV cytotoxic T-cell-mediated immunity. This finding is consistent with the
      notion that certain viruses can avoid immune elimination by deleting genes
      required for effective antigenic recognition by the cellular immune system. The
      term "stealth" has been applied to such viruses. Comparisons were also made
      between the sequences of the stealth virus and the limited sequence data
      available on cytomegaloviruses from rhesus monkeys and from African green
      monkeys. These comparisons unequivocally establish that the virus was derived
      from an African green monkey simian cytomegalovirus.

PMID- 10331959
TI  - Bacteria-related sequences in a simian cytomegalovirus-derived stealth virus
      culture.
AB  - Extensive sequencing of cloned DNA isolated from the culture of an African green
      monkey simian cytomegalovirus-derived stealth virus has identified multiple
      regions of highly significant homology to various bacterial genes. The apparent
      acquisition of bacterial sequences extends the potential role of stealth viruses
      as natural vectors in the transfer of genetic information. The findings highlight
      the dynamic interface between viral and bacterial genomes and the potential of
      this interaction in the emergence and spread of novel pathogens. The term viteria
      is proposed for microorganisms that contain both eukaryotic-viral and prokaryotic
      bacterial genetic sequences.

PMID- 10331960
TI  - Melanoma growth stimulatory activity (MGSA/GRO-alpha) chemokine genes
      incorporated into an African green monkey simian cytomegalovirus-derived stealth
      virus.
AB  - DNA isolated from the culture of an African green monkey simian cytomegalovirus
      (SCMV)-derived stealth virus has been cloned. A region of the virus that contains
      genes coding proteins homologous to the UL141, UL144, and UL145 proteins of human
      cytomegalovirus has recombined with cellular sequences encoding several distinct
      copies of the melanoma growth stimulatory activity (MGSA/GRO-alpha) chemokine
      gene. This finding illustrates the capacity of stealth viruses to capture,
      amplify, and mutate genes with potential oncogenic activity. The lack of introns
      in the assimilated cellular genes indicates a role for reverse transcription in
      the assembly of stealth viruses.

PMID- 10331961
TI  - Stealth virus epidemic in the Mohave Valley: severe vacuolating encephalopathy in
      a child presenting with a behavioral disorder.
AB  - An infectious illness, attributed to atypically structured cytopathic "stealth"
      viruses, occurred in 1996 in the Mohave Valley region of the United States. A
      stealth virus-infected child from this region has developed a severe
      noninflammatory, vacuolating (spongiform) en cephalopathy. The illness initially
      presented as a behavioral problem without overt neurological signs. Extensive
      investigations, including repeated magnetic resonance imaging, two brain
      biopsies, and stealth virus cultures, have helped define the disease process
      occurring in this child. Significant clinical benefit with apparent retardation
      of disease progression occurred during a 6-week course of ganciclovir therapy.
      The potential contributing role of stealth virus infections in children
      presenting with behavioral problems needs to be addressed.

PMID- 10331962
TI  - Comparative effects of virulent and avirulent poxviruses on cell cycle
      progression.
AB  - We studied the impact of tumorigenic poxviral infection on key regulators of cell
      cycle progression. Malignant fibroma virus (MV) is a virulent poxvirus that
      causes severe immunological impairment in vivo and in vitro. It also directs
      expression of important cellular regulatory proteins, such as p53. Its avirulent
      relative, Shope fibroma virus (SFV), has little effect on the immune system or
      p53. Accordingly we examined the effects of MV and SFV on the cell cycle in RK-13
      rabbit kidney fibroblasts. MV caused an accumulation of cells in G2/M phase and
      decreased the percentage of cells in G0/G1. Prolongation of G2/M phase was
      associated with increased levels of cyclin B protein, decreases in cyclin A and
      cdc2 proteins, and diminished cdc2 activity. In contrast SFV did not affect
      cellular cycling detectably. SFV infection was accompanied by large increases in
      cyclin A and cdc2 proteins and increased cdc2 activity. Thus alterations in cell
      cycle transit during virus infection may reflect active direction in which virus
      induces changes in cell cycle regulators. Such changes may be important in the
      differences in virulence between MV and SFV.

PMID- 10331963
TI  - Overexpression of p21Waf-1 in vascular smooth muscle cells: regulation of
      proliferation, differentiation, and cell size.
AB  - Cyclin-dependent kinase inhibitor p21Waf-1 is recognized as a negative regulator
      of cell cycle progression, and it possibly mediates cell differentiation and
      apoptosis. To understand the role of p21Waf-1 in phenotypic modulation of
      vascular smooth muscle cells (SMC), we induced the overexpression of p21Waf-1 in
      cultured rat SMC. The recombinant adenovirus vector encoding p21Waf-1 (AdvCMVp21)
      was constructed by homologous recombination and the vector encoding beta
      galactosidase (AdvCMVLacZ) was used as an experimental control. Administration of
      AdvCMVp21 suppressed serum-induced proliferation and cell cycle progression;
      however, the number of quiescent cells and the population of TUNEL-positive cells
      were not altered. Overexpression of p21Waf-1 did not affect the expression of
      contractile proteins and the availability of an endogenous growth factor signal
      p21Waf-1 may regulate cell cycle progression in SMC without affecting the
      apoptotic process and cell differentiation. Furthermore, the longitudinal
      diameter of AdvCMVp21 infected cells was increased compared with that of
      AdvCMVLacZ infected cells. Total protein content was also increased in AdvCMVp21
      infected cells. Responses to the serum stimulation, proliferation and total
      protein synthesis may be independently regulated. Thus, the suppression of cell
      cycle progression by p21Waf-1 resulted in cellular hypertrophy of SMC.

PMID- 10331964
TI  - Increased insulin-like growth factor-1 protein in human left ventricular
      hypertrophy.
AB  - Animal models of cardiac hypertrophy demonstrated increased expression of insulin
      like-growth factor-1 (IGF-1) in the heart. To study protein expression of insulin
      like-growth factor 1 in left ventricular hypertrophy (LVH) in humans 11 hearts of
      autopsy cases with LVH were compared to 11 controls using immunohistochemical
      staining with anti-human IGF-1. LVH was defined as thickening of the left
      ventricular wall which ranged from 1.6 to 2.5 cm with hearts weights from 400 to
      900 g. Immunohistochemical staining for IGF-1 was increased in the presence of
      LVH. In cases of LVH 37.9 +/- 3.5% of the cross-sectional myocardial area stained
      positively for IGF-1 compared to 6.8 +/- 2.9% in controls (P < 0.001). The
      findings support the hypothesis that IGF-1 has a role in the pathogenesis of LVH
      in humans. The increase of IGF-1 protein with LVH suggests reactivation of the
      cardiac IGF-1 genes in the hypertrophied adult cardiomyocyte.

PMID- 10331965
TI  - Regional distribution in human of a novel aortic collagen-associated
      microfibrillar protein.
AB  - We have reported two hypothetical proteins of human aorta, based on sequences
      cloned from a cDNA library constructed from mRNAs purified from the adventitia.
      These sequences have immunoglobulin-kappa (IgK)-like domains, and we have shown
      that microfibrils of the aortic adventia are immunoreactive with antibodies
      against IgK. The present study was performed to characterize more specifically
      the regional distribution in human of one of these proteins in particular and the
      distribution of matrix proteins with IgK-like motifs in general. An antibody was
      raised in rabbit against a synthetic peptide based on a unique sequence in one of
      the hypothetical proteins (NPSNRVTPQKNFP), which has not been reported in the
      sequence of any other known protein. This antibody and a rabbit anti-human IgK
      antibody were used as first antibodies in the staining reactions. A monoclonal
      mouse anti-smooth muscle cell alpha-actin antibody was also used.
      Immunoreactivity with the sequence-specific antibody was limited to the aorta and
      large vessels. Adventitial microfibrillar staining was more conspicuous in the
      abdominal aorta than in the thoracic aorta and in the internal iliac than in the
      external iliac artery. The immunoreactive protein was associated with fibroblasts
      and not smooth muscle cells. Immunoreactivity coated the collagen fibers
      diffusely, while elastin fibers were not stained. Further studies using
      antibodies against IgK demonstrated immunoreactivity of collagen and fibroblasts
      in a variety of tissues: spleen, ovary, testicle, cervix, prostate, skin, and
      breast (but not brain). Immunoglobulin motifs may be a feature of matrix proteins
      produced by fibroblasts in many tissues, but the first motif that we identified
      from a cDNA library of aortic adventitia appears to be specific to aorta and
      large vessels.

PMID- 10331966
TI  - Effects of quercetin and sunphenon on responses of cancer cells to heat shock
      damage.
AB  - Quercetin is a flavonoid well known to inhibit growth and heat shock protein
      (HSP) synthesis of cancer cells. However, sunphenon has been scarcely reported
      concerning effects on cancer cells. We compared the effects of sunphenon with
      those of quercetin on the human cholangio-cellular carcinoma cell line (HuCC-T1).
      Both flavonoids inhibited HuCC-T1 growth in a concentration-dependent manner
      without reduction of HSP70 and HSP90 expression before heat shock damage. The
      heat shock reduced the cell viability of the quercetin-treated HuCC-T1, but not
      that of the sunphenon-treated cells. This inhibitory effect of quercetin on
      tolerance to heat shock is thought to be due to marked suppression of HSP72.
      Sunphenon conversely increased HSP72 expression after heat shock. Although
      neither flavonoid altered HSP90 protein levels before and after heat shock,
      quercetin delayed the reorganization of filamentous actin (F-actin) during the
      recovery period after heat shock. Since HSP90 could preserve F-actin structure
      during stresses, quercetin might affect the interaction between HSP90 and F-actin
      without influencing HSP90 expression. In conclusion, quercetin would be more
      useful than sunphenon in combined therapy with hyperthermia for cancer.

PMID- 10331967
TI  - Trisomy 8 in stage I and stage III ovarian cancer detected by fluorescence in
      situ hybridization.
AB  - Ovarian cancer is the leading cause of death from gynecologic maligancy among
      women in the United States. In 1997, there were nearly 27,000 ovarian cancer
      cases with over 14,000 deaths. Recent attempts at early detection of ovarian
      cancer have been aimed at the identification of biomarkers that would indicate an
      underlining malignant process or reflect the biological behavior of the tumor.
      Our previous studies revealed that chromosome 8 copy number abnormality,
      especially trisomy, is common in several cancers. Archival tissues from 24 cases
      of papillary serous ovarian carcinoma (10 stage I and 14 stage III) were analyzed
      by fluorescence in situ hybridization (FISH) with a chromosome 8-specific alpha
      satellite probe (Oncor, Gaithersburg, MD). The analysis was done according to
      standard protocols of the Lifespan Academic Medical Center Cytogenetics
      Laboratory at Rhode Island Hospital. Twenty-one of 24 cases (87.5%) were found to
      be trisomic for chromosome 8, if a cutoff point of >/=15% cells with three
      signals is adopted. Overall, 80% of stage I and 93% of stage III tumors had
      trisomy 8. This study confirms the presence of a high frequency of trisomy 8 in
      both early and late stages of the disease and suggests that trisomy 8 may be an
      early event in the multistep process leading to ovarian cancer. It is of interest
      to note that a higher frequency of trisomy 8 was found in a higher stage of
      disease, consistent with our previous results on breast cancer. Thus, additional
      FISH studies of ovarian tumors for chromosome 8 copy number assessment may be
      warranted.

PMID- 10331968
TI  - Apoptotic cells as immunogen and antigen in the antiphospholipid syndrome.
AB  - Apoptotic cell antigens have been increasingly recognized as the targets of
      autoantibodies across a broad spectrum of autoimmune diseases, including systemic
      lupus erythematosus (SLE) and the antiphospholipid (aPL) syndrome. In this
      review, we will focus on one set of apoptotic antigens, namely, those targeted in
      the aPL syndrome. Here we discuss the biology of aPL autoantibodies and recent
      work from our and other laboratories demonstrating that apoptotic cells express
      unique antigen(s) that serve(s) as both immunogen and antigen for aPL
      autoantibodies. Specific features or events occurring at the surface of apoptotic
      cells, which may influence immunogenicity and/or antigenicity, will also be
      discussed. Finally, we will speculate on the broader implications of these
      findings for the development of systemic autoimmunity as seen in SLE.

PMID- 10331969
TI  - CD44 modulates Hs578T human breast cancer cell adhesion, migration, and
      invasiveness.
AB  - CD44 is an adhesion molecule that has been implicated in tumor progression of
      epithelial and nonepithelial tumors. One of its variants, CD44v6, is involved in
      the production of experimental metastasis. Previous reports have indicated that
      in human breast cancer the overexpression of CD44, and moreover the presence of
      CD44v6, correlated with poor prognosis. This study focuses on the role of these
      molecules in in vitro invasion of breast cancer cells. The effect of antibodies
      against all CD44 isoforms and CD44v6 was evaluated in different in vitro
      experimental assays that are closely related to tumor cell invasion in vivo:
      adhesion to hyaluronan and purified extracellular matrix components; cell
      motility; haptotaxis; and invasion of purified extracellular matrix components.
      The highly metastatic human breast cancer cell line Hs578T was used in all
      assays. Our results show that both antibodies have a blocking effect on cell
      migration, on haptotatic migration, on in vitro invasion, and on adhesion to
      hyaluronan and purified extracellular matrix components. In conclusion, our data
      show that, in addition to its participation in adhesion to components of the
      extracellular matrix, CD44v6 is involved in the motility and in invasion of
      tumoral cells.

PMID- 10331970
TI  - Wnt-7a in feather morphogenesis: involvement of anterior-posterior asymmetry and
      proximal-distal elongation demonstrated with an in vitro reconstitution model.
AB  - How do vertebrate epithelial appendages form from the flat epithelia? Following
      the formation of feather placodes, the previously radially symmetrical primordia
      become anterior-posterior (A-P) asymmetrical and develop a proximo-distal (P-D)
      axis. Analysis of the molecular heterogeneity revealed a surprising parallel of
      molecular profiles in the A-P feather buds and the ventral-dorsal (V-D)
      Drosophila appendage imaginal discs. The functional significance was tested with
      an in vitro feather reconstitution model. Wnt-7a expression initiated all over
      the feather tract epithelium, intensifying as it became restricted first to the
      primordia domain, then to an accentuated ring pattern within the primordia
      border, and finally to the posterior bud. In contrast, sonic hedgehog expression
      was induced later as a dot within the primordia. RCAS was used to overexpress Wnt
      7a in reconstituted feather explants derived from stage 29 dorsal skin to further
      test its function in feather formation. Control skin formed normal elongated,
      slender buds with A-P orientation, but Wnt-7a overexpression led to plateau-like
      skin appendages lacking an A-P axis. Feathers in the Wnt-7a overexpressing skin
      also had inhibited elongation of the P-D axes. This was not due to a lack of cell
      proliferation, which actually was increased although randomly distributed. While
      morphogenesis was perturbed, differentiation proceeded as indicated by the
      formation of barb ridges. Wnt-7a buds have reduced expression of anterior
      (Tenascin) bud markers. Middle (Notch-1) and posterior bud markers including
      Delta-1 and Serrate-1 were diffusely expressed. The results showed that ectopic
      Wnt-7a expression enhanced properties characteristic of the middle and posterior
      feather buds and suggest that P-D elongation of vertebrate skin appendages
      requires balanced interactions between the anterior and posterior buds.

PMID- 10331971
TI  - Retinoic acid is required in the mouse embryo for left-right asymmetry
      determination and heart morphogenesis.
AB  - Determination of the left-right position (situs) of visceral organs involves
      lefty, nodal and Pitx2 genes that are specifically expressed on the left side of
      the embryo. We demonstrate that the expression of these genes is prevented by the
      addition of a retinoic acid receptor pan-antagonist to cultured headfold stage
      mouse embryos, whereas addition of excess retinoic acid leads to their
      symmetrical expression. Interestingly, both treatments lead to randomization of
      heart looping and to defects in heart anteroposterior patterning. A time course
      analysis indicates that only the newly formed mesoderm at the headfold-presomite
      stage is competent for these retinoid effects. We conclude that retinoic acid,
      the active derivative of vitamin A, is essential for heart situs determination
      and morphogenesis.

PMID- 10331972
TI  - A rapid and dynamic regulation of GDNF-family ligands and receptors correlate
      with the developmental dependency of cutaneous sensory innervation.
AB  - Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are
      members of the transforming growth factor-beta family and have been shown to
      elicit neurotrophic effects upon several classes of neurons including
      dopaminergic neurons, motoneurons, parasympathetic, sympathetic as well as
      primary sensory neurons. However, there is little information available on their
      roles in cutaneous innervation. Herein, we have studied the regulation of gdnf,
      ntn and the GDNF family receptors and examined their role in the development of
      facial cutaneous innervation in GDNF mutant mice. A dynamic spatial and temporal
      regulation of gdnf, ntn and their ligand binding receptors within the follicle
      sinus complex correlate with development of distinct subclasses of sensory nerve
      endings. Furthermore, development of NGF-dependent myelinated mechanoreceptors,
      i.e. reticular and transverse lanceolate endings also require GDNF during ending
      formation and maintenance. In addition, ligand and receptor association seems to
      be intricately linked to a local Schwann cell-axon interaction essential for
      sensory terminal formation. Our results suggests that functionally specified
      nerve endings depend on different GDNF family members and that in contrast to
      neurotrophins, this family of neurotrophic factors may be acting at local sites
      of terminal Schwann cell-axon growth cone interactions and that they collaborate
      with neurotrophins by supporting the same populations of neurons but at different
      times in development.

PMID- 10331973
TI  - Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of
      the hair follicle.
AB  - Skin appendages, such as hair, develop as a result of complex reciprocal
      signaling between epithelial and mesenchymal cells. These interactions are not
      well understood at the molecular level. Platelet-derived growth factor-A (PDGF-A)
      is expressed in the developing epidermis and hair follicle epithelium, and its
      receptor PDGF-Ralpha is expressed in associated mesenchymal structures. Here we
      have characterized the skin and hair phenotypes of mice carrying a null mutation
      in the PDGF-A gene. Postnatal PDGF-A-/- mice developed thinner dermis, misshapen
      hair follicles, smaller dermal papillae, abnormal dermal sheaths and thinner
      hair, compared with wild-type siblings. BrdU labeling showed reduced cell
      proliferation in the dermis and in the dermal sheaths of PDGF-A-/- skin. PDGF-A-/
      skin transplantation to nude mice led to abnormal hair formation, reproducing
      some of the features of the skin phenotype of PDGF-A-/- mice. Taken together,
      expression patterns and mutant phenotypes suggest that epidermal PDGF-A has a
      role in stimulating the proliferation of dermal mesenchymal cells that may
      contribute to the formation of dermal papillae, mesenchymal sheaths and dermal
      fibroblasts. Finally, we show that sonic hedgehog (shh)-/- mouse embryos have
      disrupted formation of dermal papillae. Such embryos fail to form pre-papilla
      aggregates of postmitotic PDGF-Ralpha-positive cells, suggesting that shh has a
      critical role in the assembly of the dermal papilla.

PMID- 10331974
TI  - Hedgehog activates the EGF receptor pathway during Drosophila head development.
AB  - The Hedgehog (Hh) and Epidermal growth factor receptor (EGFR) signaling pathways
      play critical roles in pattern formation and cell proliferation in invertebrates
      and vertebrates. In this study, we demonstrate a direct link between these two
      pathways in Drosophila melanogaster. Hh and EGFR signaling are each required for
      the formation of a specific region of the head of the adult fruitfly. We show
      that hh and vein (vn), which encodes a ligand of the Drosophila EGFR (Schnepp,
      B., Grumbling, G., Donaldson, T. and Simcox, A. (1996) Genes Dev. 10, 2302-13),
      are expressed in adjacent domains within the imaginal primordium of this region.
      Using loss- and gain-of-function approaches, we demonstrate that Hh activates vn
      expression. We also show that Hh activation of vn is mediated through the gene
      cubitus interruptus (ci) and that this activation requires the C-terminal region
      of the Ci protein. Finally, we demonstrate that wingless (wg) represses vn
      expression, thereby limiting the domain of EGFR signaling.

PMID- 10331975
TI  - The mammalian Tolloid-like 1 gene, Tll1, is necessary for normal septation and
      positioning of the heart.
AB  - Mammalian Tolloid-like 1 (mTLL-1) is an astacin-like metalloprotease, highly
      similar in domain structure to the morphogenetically important proteases bone
      morphogenetic protein-1 (BMP-1) and Drosophila Tolloid. To investigate possible
      roles for mTLL-1 in mammalian development, we have used gene targeting in ES
      cells to produce mice with a disrupted allele for the corresponding gene, Tll1.
      Homozygous mutants were embryonic lethal, with death at mid-gestation from
      cardiac failure and a unique constellation of developmental defects that were
      apparently confined solely to the heart. Constant features were incomplete
      formation of the muscular interventricular septum and an abnormal and novel
      positioning of the heart and aorta. Consistent with roles in cardiac development,
      Tll1 expression was specific to precardiac tissue and endocardium in 7.5 and 8.5
      days p.c. embryos, respectively. Tll1 expression was also high in the developing
      interventricular septum, where expression of the BMP-1 gene, Bmp1, was not
      observed. Cardiac structures that were not affected in Tll1-/- embryos either
      showed no Tll1 expression (atrio-ventricular cushions) or showed overlapping
      expression of Tll1 and Bmp1 (aortico-pulmonary septum), suggesting that products
      of the Bmp1 gene may be capable of functionally substituting for mTLL-1 at sites
      in which they are co-expressed. Together, the various data show that mTLL-1 plays
      multiple roles in formation of the mammalian heart and is essential for formation
      of the interventricular septum.

PMID- 10331976
TI  - Cell-autonomous and non-autonomous requirements for the zebrafish gene cloche in
      hematopoiesis.
AB  - Vertebrate embryonic hematopoiesis is a complex process that involves a number of
      cellular interactions, notably those occurring between endothelial and blood
      cells. The zebrafish cloche mutation affects both the hematopoietic and
      endothelial lineages from an early stage (Stainier, D. Y. R., Weinstein, B. M.,
      Detrich, H. W. R., Zon, L. I. and Fishman, M. C. (1995) Development 121, 3141
      3150). cloche mutants lack endocardium, as well as head and trunk endothelium,
      and nearly all blood cells. Cell transplantation studies have revealed that the
      endocardial defect in cloche is cell-autonomous: wild-type cells can form
      endocardium in mutant hosts, but mutant cells never contribute to the endocardium
      in wild-type or mutant hosts. In this paper, we analyze the cell-autonomy of the
      blood defect in cloche. The blood cell deficiency in cloche mutants could be an
      indirect effect of the endothelial defects. Alternatively, cloche could be
      required cell-autonomously in the blood cells themselves. To distinguish between
      these possibilities, we cotransplanted wild-type and mutant cells into a single
      wild-type host in order to compare their respective hematopoietic capacity. We
      found that transplanted wild-type cells were much more likely than mutant cells
      to contribute to circulating blood in a wild-type host. Furthermore, in the few
      cases where both wild-type and mutant donors contributed to blood in a wild-type
      host, the number of blood cells derived from the wild-type donor was always much
      greater than the number of blood cells derived from the mutant donor. These data
      indicate that cloche is required cell-autonomously in blood cells for their
      differentiation and/or proliferation. When we assessed early expression of the
      erythropoietic gene gata-1 in transplant recipients, we found that mutant
      blastomeres were as likely as wild-type blastomeres to give rise to gata-1
      expressing cells in a wild-type host. Together, these two sets of data argue that
      cloche is not required cell-autonomously for the differentiation of red blood
      cells, as assayed by gata-1 expression, but rather for their proliferation and/or
      survival, as assayed by their contribution to circulating blood. In addition, we
      found that transplanted wild-type cells were less likely to express gata-1 in a
      mutant environment than in a wild-type one, suggesting that cloche also acts non
      autonomously in red blood cell differentiation. This non-autonomous function of
      cloche in red blood cell differentiation may reflect its cell-autonomous
      requirement in the endothelial lineage. Thus, cloche appears to be required in
      erythropoiesis cell non-autonomously at a step prior to gata-1 expression, and
      cell-autonomously subsequently.

PMID- 10331977
TI  - Regulation of the spalt/spalt-related gene complex and its function during
      sensory organ development in the Drosophila thorax.
AB  - The nuclear proteins Spalt and Spalt-related belong to a conserved family of
      transcriptional regulators characterised by the presence of double zinc-finger
      domains. In the wing, they are regulated by the secreted protein Decapentaplegic
      and participate in the positioning of the wing veins. Here, we identify
      regulatory regions in the spalt/spalt-related gene complex that direct expression
      in the wing disc. The regulatory sequences are organised in independent modules,
      each of them responsible for expression in particular domains of the wing
      imaginal disc. In the thorax, spalt and spalt-related are expressed in a
      restricted domain that includes most proneural clusters of the developing sensory
      organs in the notum, and are regulated by the signalling molecules Wingless,
      Decapentaplegic and Hedgehog. We find that spalt/spalt-related participate in the
      development of sensory organs in the thorax, mainly in the positioning of
      specific proneural clusters. Later, the expression of at least spalt is
      eliminated from the sensory organ precursor cells and this is a requisite for the
      differentiation of these cells. We postulate that spalt and spalt-related belong
      to a category of transcriptional regulators that subdivide the thorax into
      expression domains (prepattern) required for the localised activation of
      proneural genes.

PMID- 10331978
TI  - rhomboid and Star interact synergistically to promote EGFR/MAPK signaling during
      Drosophila wing vein development.
AB  - Genes of the ventrolateral group in Drosophila are dedicated to developmental
      regulation of Egfr signaling in multiple processes including wing vein
      development. Among these genes, Egfr encodes the Drosophila EGF-Receptor, spitz
      (spi) and vein (vn) encode EGF-related ligands, and rhomboid (rho) and Star (S)
      encode membrane proteins. In this study, we show that rho-mediated
      hyperactivation of the EGFR/MAPK pathway is required for vein formation
      throughout late larval and early pupal development. Consistent with this
      observation, rho activity is necessary and sufficient to activate MAPK in vein
      primordium during late larval and early pupal stages. Epistasis studies using a
      dominant negative version of Egfr and a ligand-independent activated form of Egfr
      suggest that rho acts upstream of the receptor. We show that rho and S function
      in a common aspect of vein development since loss-of-function clones of rho or S
      result in nearly identical non-autonomous loss-of-vein phenotypes. Furthermore,
      mis-expression of rho and S in wild-type and mutant backgrounds reveals that
      these genes function in a synergistic and co-dependent manner. In contrast, spi
      does not play an essential role in the wing. These data indicate that rho and S
      act in concert, but independently of spi, to promote vein development through the
      EGFR/MAPK signaling pathway.

PMID- 10331979
TI  - A retinoic acid-inducible transgenic marker of sino-atrial development in the
      mouse heart.
AB  - To study the specification of inflow structures in the heart we generated
      transgenic animals harboring the human alkaline phosphatase (HAP) gene driven by
      the proximal 840 bp of a quail SMyHC3 promoter. In transgenic mice, the SMyHC3
      HAP reporter was expressed in posterior heart precursors at 8.25 dpc, in sinus
      venosa and in the atrium at 8.5 and 9.0 dpc, and in the atria from 10.5 dpc
      onwards. SMyHC3-HAP transgene expression overlapped synthesis and endogenous
      response to retinoic acid (RA) in the heart, as determined by antibodies directed
      against a key RA synthetic enzyme and by staining of RAREhsplacZ transgenic
      animals. A single pulse of all-trans RA administered to pregnant mice at 7.5, but
      not after 8.5, dpc induced cardiac dismorphology, ranging from complete absence
      of outflow tract and ventricles to hearts with reduced ventricles expressing both
      SMyHC3-HAP and ventricular markers. Blockade of RA synthesis with disulfiram
      inhibited RA-induced transcription and produced hearts lacking the atrial
      chamber. This study defines a novel marker for atrial-restricted transcription in
      the developing mouse heart. It also suggests that atrial-specific gene expression
      is controlled by localized synthesis of RA, and that exclusion of RA from
      ventricular precursors is essential for correct specification of the ventricles.

PMID- 10331980
TI  - The homeobox gene Msx1 is expressed in a subset of somites, and in muscle
      progenitor cells migrating into the forelimb.
AB  - In myoblast cell cultures, the Msx1 protein is able to repress myogenesis and
      maintain cells in an undifferentiated and proliferative state. However, there has
      been no evidence that Msx1 is expressed in muscle or its precursors in vivo.
      Using mice with the nlacZ gene integrated into the Msx1 locus, we show that the
      reporter gene is expressed in the lateral dermomyotome of brachial and thoracic
      somites. Cells from this region will subsequently contribute to forelimb and
      intercostal muscles. Using Pax3 gene transcripts as a marker of limb muscle
      progenitor cells as they migrate from the somites, we have defined precisely the
      somitic origin and timing of cell migration from somites to limb buds in the
      mouse. Differences in the timing of migration between chick and mouse are
      discussed. Somites that label for Msx1(nlacZ )transgene expression in the
      forelimb region partially overlap with those that contribute Pax3-expressing
      cells to the forelimb. In order to see whether Msx1 is expressed in this
      migrating population, we have grafted somites from the forelimb level of
      Msx1(nlacZ )mouse embryos into a chick host embryo. We show that most cells
      migrating into the wing field express the Msx1(nlacZ )transgene, together with
      Pax3. In these experiments, Msx1 expression in the somite depends on the axial
      position of the graft. Wing mesenchyme is capable of inducing Msx1 transcription
      in somites that normally would not express the gene; chick hindlimb mesenchyme,
      while permissive for this expression, does not induce it. In the mouse limb bud,
      the Msx1(nlacZ )transgene is downregulated prior to the activation of the Myf5
      gene, an early marker of myogenic differentiation. These observations are
      consistent with the proposal that Msx1 is involved in the repression of muscle
      differentiation in the lateral half of the somite and in limb muscle progenitor
      cells during their migration.

PMID- 10331981
TI  - Zebrafish tbx-c functions during formation of midline structures.
AB  - Several genes containing the conserved T-box region in invertebrates and
      vertebrates have been reported recently. Here, we describe three novel members of
      the T-box gene family in zebrafish. One of these genes, tbx-c, is studied in
      detail. It is expressed in the axial mesoderm, notably, in the notochordal
      precursor cells immediately before formation of the notochord and in the
      chordoneural hinge of the tail bud, after the notochord is formed. In addition,
      its expression is detected in the ventral forebrain, sensory neurons, fin buds
      and excretory system. The expression pattern of tbx-c differs from that of the
      other two related genes, tbx-a and tbx-b. The developmental role of tbx-c has
      been analysed by overexpression of the full-length tbx-c mRNA and a truncated
      form of tbx-c mRNA, which encodes the dominant-negative Tbx-c. Overexpression of
      tbx-c causes expansion of the midline mesoderm and formation of ectopic midline
      structures at the expense of lateral mesodermal cells. In dominant-negative
      experiments, the midline mesoderm is reduced with the expansion of lateral
      mesoderm to the midline. These results suggest that tbx-c plays a role in
      formation of the midline mesoderm, particularly, the notochord. Moreover,
      modulation of tbx-c activity alters the development of primary motor neurons.
      Results of in vitro analysis in zebrafish animal caps suggest that tbx-c acts
      downstream of early mesodermal inducers (activin and ntl) and reveal an
      autoregulatory feedback loop between ntl and tbx-c. These data and analysis of
      midline (ntl-/- and flh-/-) and lateral mesoderm (spt-/-) mutants suggest that
      tbx-c may function during formation of the notochord.

PMID- 10331982
TI  - The Arabidopsis FILAMENTOUS FLOWER gene is required for flower formation.
AB  - A screen for mutations affecting flower formation was carried out and several
      filamentous flower (fil) alleles were identified. In fil mutants, floral
      primordia occasionally give rise to pedicels lacking flowers at their ends. This
      defect is dramatically enhanced in fil rev double mutants, in which every floral
      primordium produces a flowerless pedicel. These data suggest that the FIL and REV
      genes are required for an early step of flower formation, possibly for the
      establishment of a flower-forming domain within the floral primordium. The FIL
      gene is also required for establishment of floral meristem identity and for
      flower development. During flower development, the FIL gene is required for
      floral organ formation in terms of the correct numbers and positions; correct
      spatial activity of the AGAMOUS, APETALA3, PISTILLATA and SUPERMAN genes; and
      floral organ development.

PMID- 10331983
TI  - The zebrafish detour gene is essential for cranial but not spinal motor neuron
      induction.
AB  - The zebrafish detour (dtr) mutation generates a novel neuronal phenotype. In dtr
      mutants, most cranial motor neurons, especially the branchiomotor, are missing.
      However, spinal motor neurons are generated normally. The loss of cranial motor
      neurons is not due to aberrant hindbrain patterning, failure of neurogenesis,
      increased cell death or absence of hh expression. Furthermore, activation of the
      Hh pathway, which normally induces branchiomotor neurons, fails to induce motor
      neurons in the dtr hindbrain. Despite this, not all Hh-mediated regulation of
      hindbrain development is abolished since the regulation of a neural gene by Hh is
      intact in the dtr hindbrain. Finally, dtr can function cell autonomously to
      induce branchiomotor neurons. These results suggest that detour encodes a
      component of the Hh signaling pathway that is essential for the induction of
      motor neurons in the hindbrain but not in the spinal cord and that dtr function
      is required for the induction of only a subset of Hh-mediated events in the
      hindbrain.

PMID- 10331984
TI  - Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles
      for EGF receptor ligands in mouse mammary gland development.
AB  - Targeted mice lacking functional EGF or amphiregulin (AR) were derived and bred
      to the TGFalpha-knockout to generate mice lacking various combinations of the
      three ligands. In contrast to EGF receptor (EGFR) knockout mice, triple null mice
      lacking half of the EGFR ligand family were healthy and fertile, indicative of
      overlapping or compensatory functions among EGF family members. Nevertheless,
      pups born to triple null dams frequently died or were runted, suggesting a
      mammary gland defect. Comparison of individual and combinatorial knockouts
      established that specific loss of AR severely stunted ductal outgrowth during
      puberty, consistent with dramatic expression of AR transcripts in normal
      developing ducts. Surprisingly, loss of all three ligands did not significantly
      affect cellular proliferation, apoptosis, or ERK activation within terminal end
      buds. Following pregnancy, most AR single null females, but few triple null
      females could nurse their young, revealing collaborative roles for EGF and
      TGFalpha in mammopoiesis and lactogenesis. In triple null glands, alveoli were
      poorly organized and differentiated, and milk protein gene expression was
      decreased. Additionally, Stat5a activation was frequently reduced in AR single
      and combinatorial nulls in association with impaired lactation. Collectively, our
      results provide genetic confirmation of a requirement for EGFR signaling
      throughout the development of the mouse mammary gland, and reveal stage-dependent
      activities for different EGFR ligands. Finally, the additional loss of growth
      factors from pups nursed by triple null dams further worsened their survival and
      growth, establishing functions for both maternal- and neonatal-derived growth
      factors.

PMID- 10331985
TI  - Specification of distinct motor neuron identities by the singular activities of
      individual Hox genes.
AB  - Hox genes have been implicated in specifying positional values along the
      anteroposterior axis of the caudal central nervous system, but their nested and
      overlapping expression has complicated the understanding of how they confer
      specific neural identity. We have employed a direct gain-of-function approach
      using retroviral vectors to misexpress Hoxa2 and Hoxb1 outside of the normal Hox
      expression domains, thereby avoiding complications resulting from possible
      interactions with endogenous Hox genes. Misexpression of either Hoxa2 or Hoxb1 in
      the anteriormost hindbrain (rhombomere1, r1) leads to the generation of motor
      neurons in this territory, even though it is normally devoid of this cell type.
      These ectopic neurons have the specific identity of branchiomotor neurons and, in
      the case of Hoxb1-induced cells, their axons leave the hindbrain either by
      fasciculating with the resident cranial motor axons at isthmic (trochlear) or r2
      (trigeminal) levels of the axis or via novel ectopic exit points in r1. Next, we
      have attempted to identify the precise branchiomotor subtypes that are generated
      after misexpression and our results suggest that the ectopic motor neurons
      generated following Hoxa2 misexpression are trigeminal-like, while those
      generated following Hoxb1 misexpression are facial-like. Our data demonstrate,
      therefore, that at least to a certain extent and for certain cell types, the
      singular activities of individual Hox genes (compared to a combinatorial mode of
      action, for example) are sufficient to impose on neuronal precursor cells the
      competence to generate distinctly specified cell types. Moreover, as these
      particular motor neuron subtypes are normally generated in the most anterior
      domains of Hoxa2 and Hoxb1 expression, respectively, our data support the idea
      that the main site of individual Hox gene action is in the anteriormost subdomain
      of their expression, consistent with the phenomenon of posterior dominance.

PMID- 10331986
TI  - Cell division genes promote asymmetric interaction between Numb and Notch in the
      Drosophila CNS.
AB  - Cell intrinsic and cell extrinsic factors mediate asymmetric cell divisions
      during neurogenesis in the Drosophila embryo. In the NB4-2->GMC-1->RP2/sib
      lineage, one of the well-studied neuronal lineages in the ventral nerve cord, the
      Notch (N) signaling interacts with the asymmetrically localized Numb (Nb) to
      specify sibling neuronal fates to daughter cells of GMC-1. In this current study,
      we have investigated asymmetric cell fate specifications by N and Nb in the
      context of cell cycle. We have used loss-of-function mutations in N and nb, cell
      division mutants cyclinA (cycA), regulator of cyclin A1 (rca1) and string/cdc25
      phosphatase (stg), and the microtubule destabilizing agent, nocodazole, to
      investigate this issue. We report that the loss of cycA, rca1 or stg leads to a
      block in the division of GMC-1, however, this GMC-1 exclusively adopts an RP2
      identity. While the loss of N leads to the specification of RP2 fates to both
      progeny of GMC-1 and loss of nb results in the specification of sib fates to
      these daughter cells, the GMC-1 in the double mutant between nb and cycA assumes
      a sib fate. These epistasis results indicate that both N and nb function
      downstream of cell division genes and that progression through cell cycle is
      required for the asymmetric localization of Nb. In the absence of entry to
      metaphase, the Nb protein prevents the N signaling from specifying sib fate to
      the RP2/sib precursor. These results are also consistent with our finding that
      the sib cell is specified as RP2 in N; nb double mutants. Finally, our results
      show that nocodazole-arrested GMC-1 in wild-type embryos randomly assumes either
      an RP2 fate or a sib fate. This suggests that microtubules are involved in
      mediating the antagonistic interaction between Nb and N during RP2 and sib fate
      specification.

PMID- 10331987
TI  - Distinct signaling molecules control Hoxa-11 and Hoxa-13 expression in the muscle
      precursor and mesenchyme of the chick limb bud.
AB  - The limb muscles, originating from the ventrolateral portion of the somites,
      exhibit position-specific morphological development through successive splitting
      and growth/differentiation of the muscle masses in a region-specific manner by
      interacting with the limb mesenchyme and the cartilage elements. The molecular
      mechanisms that provide positional cues to the muscle precursors are still
      unknown. We have shown that the expression patterns of Hoxa-11 and Hoxa-13 are
      correlated with muscle patterning of the limb bud (Yamamoto et al., 1998) and
      demonstrated that muscular Hox genes are activated by signals from the limb
      mesenchyme. We dissected the regulatory mechanisms directing the unique
      expression patterns of Hoxa-11 and Hoxa-13 during limb muscle development. HOXA
      11 protein was detected in both the myogenic cells and the zeugopodal mesenchymal
      cells of the limb bud. The earlier expression of HOXA-11 in both the myogenic
      precursor cells and the mesenchyme was dependent on the apical ectodermal ridge
      (AER), but later expression was independent of the AER. HOXA-11 expression in
      both myogenic precursor cells and mesenchyme was induced by fibroblast growth
      factor (FGF) signal, whereas hepatocyte growth factor/scatter factor (HGF/SF)
      maintained HOXA-11 expression in the myogenic precursor cells, but not in the
      mesenchyme. The distribution of HOXA-13 protein expression in the muscle masses
      was restricted to the posterior region. We found that HOXA-13 expression in the
      autopodal mesenchyme was dependent on the AER but not on the polarizing region,
      whereas expression of HOXA-13 in the posterior muscle masses was dependent on the
      polarizing region but not on the AER. Administration of BMP-2 at the anterior
      margin of the limb bud induced ectopic HOXA-13 expression in the anterior region
      of the muscle masses followed by ectopic muscle formation close to the source of
      exogenous BMP-2. In addition, NOGGIN/CHORDIN, antagonists of BMP-2 and BMP-4,
      downregulated the expression of HOXA-13 in the posterior region of the muscle
      masses and inhibited posterior muscle development. These results suggested that
      HOXA-13 expression in the posterior muscle masses is activated by the
      posteriorizing signal from the posterior mesenchyme via BMP-2. On the contrary,
      the expression of HOXA-13 in the autopodal mesenchyme was affected by neither BMP
      2 nor NOGGIN/CHORDIN. Thus, mesenchymal HOXA-13 expression was independent of BMP
      2 from polarizing region, but was under the control of as yet unidentified
      signals from the AER. These results showed that expression of Hox genes is
      regulated differently in the limb muscle precursor and mesenchymal cells.

PMID- 10331988
TI  - Signalling by the RET receptor tyrosine kinase and its role in the development of
      the mammalian enteric nervous system.
AB  - RET is a member of the receptor tyrosine kinase (RTK) superfamily, which can
      transduce signalling by glial cell line-derived neurotrophic factor (GDNF) and
      neurturin (NTN) in cultured cells. In order to determine whether in addition to
      being sufficient, RET is also necessary for signalling by these growth factors,
      we studied the response to GDNF and NTN of primary neuronal cultures (peripheral
      sensory and central dopaminergic neurons) derived from wild-type and RET
      deficient mice. Our experiments show that absence of a functional RET receptor
      abrogates the biological responses of neuronal cells to both GDNF and NTN.
      Despite the established role of the RET signal transduction pathway in the
      development of the mammalian enteric nervous system (ENS), very little is known
      regarding its cellular mechanism(s) of action. Here, we have studied the effects
      of GDNF and NTN on cultures of neural crest (NC)-derived cells isolated from the
      gut of rat embryos. Our findings suggest that GDNF and NTN promote the survival
      of enteric neurons as well as the survival, proliferation and differentiation of
      multipotential ENS progenitors present in the gut of E12.5-13.5 rat embryos.
      However, the effects of these growth factors are stage-specific, since similar
      ENS cultures established from later stage embryos (E14. 5-15.5), show markedly
      diminished response to GDNF and NTN. To examine whether the in vitro effects of
      RET activation reflect the in vivo function(s) of this receptor, the extent of
      programmed cell death was examined in the gut of wild-type and RET-deficient
      mouse embryos by TUNEL histochemistry. Our experiments show that a subpopulation
      of enteric NC undergoes apoptotic cell death specifically in the foregut of
      embryos lacking the RET receptor. We suggest that normal function of the RET RTK
      is required in vivo during early stages of ENS histogenesis for the survival of
      undifferentiated enteric NC and their derivatives.

PMID- 10331989
TI  - Different sequence requirements for expression in erythroid and megakaryocytic
      cells within a regulatory element upstream of the GATA-1 gene.
AB  - The lineage-restricted transcription factor GATA-1 is required for
      differentiation of erythroid and megakaryocytic cells. We have localized a 317
      base pair cis-acting regulatory element, HS I, associated with a hematopoietic
      specific DNase I hypersensitive site, which lies approx. 3.7 kilobases upstream
      of the murine hematopoietic-specific GATA-1 IE promoter. HS I directs high-level
      expression of reporter GATA-1/lacZ genes to primitive and definitive erythroid
      cells and megakaryocytes in transgenic mice. Comparative sequence analysis of HS
      I between human and mouse shows approx. 63% nucleotide identity with a more
      conserved core of 169 base pairs (86% identity). This core contains a GATA site
      separated by 10 base pairs from an E-box motif. The composite motif binds a multi
      protein hematopoietic-specific transcription factor complex which includes GATA
      1, SCL/tal-1, E2A, Lmo2 and Ldb-1. Point mutations of the GATA site abolishes HS
      I function, whereas mutation of the E-box motif still allows reporter gene
      expression in both lineages. Strict dependence of HS I activity on a GATA site
      implies that assembly of a protein complex containing a GATA-factor, presumably
      GATA-1 or GATA-2, is critical to activating or maintaining its function. Further
      dissection of the 317 base pair region demonstrates that, whereas all 317 base
      pairs are required for expression in megakaryocytes, only the 5' 62 base pairs
      are needed for erythroid-specific reporter expression. These findings demonstrate
      differential lineage requirements for expression within the HS I element.

PMID- 10331990
TI  - A myb-related protein required for culmination in Dictyostelium.
AB  - The avian retroviral v-myb gene and its cellular homologues throughout the animal
      and plant kingdoms contain a conserved DNA binding domain. We have isolated an
      insertional mutant of Dictyostelium unable to switch from slug migration to
      fruiting body formation i.e. unable to culminate. The gene that is disrupted,
      mybC, codes for a protein with a myb-like domain that is recognized by an
      antibody against the v-myb repeat domain. During development of myb+ cells, mybC
      is expressed only in prestalk cells. When developed together with wild-type cells
      mybC- cells are able to form both spores and stalk cells very efficiently. Their
      developmental defect is also bypassed by overexpressing cAMP-dependent protein
      kinase. However even when their defect is bypassed, mybC null slugs and
      culminates produce little if any of the intercellular signalling peptides SDF-1
      and SDF-2 that are believed to be released by prestalk cells at culmination. We
      propose that the mybC gene product is required for an intercellular signaling
      process controlling maturation of stalk cells and spores and that SDF-1 and/or
      SDF-2 may be implicated in this process.

PMID- 10331991
TI  - Gene therapy for the treatment of AIDS: animal models and human clinical
      experience.
AB  - Although antiretroviral drug therapy has had a significant impact on the natural
      history of HIV infection, complete virus eradication still remains an
      unattainable goal. Drug-mediated virological control only occurs transiently, in
      part as a result of the development of drug resistance. Gene therapy for the
      treatment of AIDS is a promising area of research that has as its goal the
      replacement of the HIV-infected cellular pool with cells engineered to resist
      virus replication. A variety of anti-HIV genes have been designed and tested in
      laboratory systems, and available results from pilot clinical trials demonstrate
      the safety and feasibility of this approach. Obstacles to effective application
      of this technology include partial protection of HIV resistance genes, lack of
      effective vectoring systems, and unregulated gene expression. Herein, we review
      recent advances in transduction methods, data from in vivo preclinical studies in
      relevant animal models, and emerging results derived from pilot clinical gene
      therapy studies.

PMID- 10331992
TI  - Direct and indirect antigen recognition: the pathways to allograft immune
      rejection.
AB  - The immune rejection of allografts is mediated by T cells via two distinct
      pathways: the direct and the indirect pathways. Direct alloresponse to intact
      donor MHC molecules is ensured by T cells which are polyclonal and directed
      toward a variety of antigens. This response is highly sensitive to treatment by
      immunosuppressive drugs including Cyclosporin A. Indirect alloresponse is
      oligoclonal and involves a few dominant antigen peptides on donor MHC. In
      contrast to its direct counterpart, indirect allorecognition is thought to be
      poorly sensitive to blockade by cyclosporin A. It is likely that indirect and
      direct types of alloresponses play different roles in the physiology of the
      rejection process. T cell responses occurring via direct allorecognition play a
      critical role during the early phase of acute graft rejection by sensitizing the
      host to graft antigens. Alternatively, once such sensitization has taken place,
      indirect type of alloresponse may become predominant and presumably represent the
      driving force in the actual destruction of transplanted tissues. In addition, we
      and others have provided strong circumstantial evidence indicating that secondary
      T cell responses via indirect allorecognition spread to new determinants on donor
      MHC and tissue-specific antigens. This phenomenon is likely to play an important
      role in late and chronic rejection, a major obstacle to long-term graft
      acceptance in clinical transplantation. Finally, a series of studies have
      demonstrated that early, pre-transplant treatment with tolerogenic donor-derived
      MHC peptides can protect the graft from rejection in rodents. Although the
      mechanisms involved in MHC-peptide-induced tolerance are ill defined, this
      strategy represents a promising approach for ensuring long-lasting graft
      acceptance in the absence of widespread immunosuppression. It is now crucial to
      further explore the mechanims involved in immunogenicity and tolerogenicity of
      MHC peptides and to initiate clinical studies to evaluate the efficacy of
      blocking indirect alloresponses in transplanted patients.

PMID- 10331993
TI  - Inhibitor resistant class A beta-lactamases.
AB  - Beta-lactamase inhibitors (clavulanic acid, tazobactam, and sulbactam) greatly
      enhance the therapeutic efficacy of their partner antibiotics (amoxacillin,
      ampicillin, piperacillin, and ticarcillin) against common enteric and non-enteric
      organisms possessing class A beta-lactamases. Unfortunately, the number of class
      A enzymes being discovered that are resistant to these combinations is
      increasingly rapidly. The TEM and SHV class A beta-lactamases resistant to
      inhibitors have point mutations in critical amino acids important for catalysis.
      Compared to the wild type beta-lactamase, inhibitor resistant enzymes are
      inefficient at hydrolyzing benzylpenicillin, aminopenicillins, and
      cephalosporins. Nevertheless, hyper-production of these enzymes resulting from
      mutations in the promoter region can confer substantial levels of resistance.
      Understanding the microbiologic and kinetic properties of these inhibitor
      resistant class A beta-lactamases can lead to the design of more potent beta
      lactam compounds as well as more effective inhibitors.

PMID- 10331994
TI  - Study of the electric activity of the cirrhotic liver with identification of an
      electrohepatogram.
AB  - In a recent study we could characterize an electrohepatogram (EHG) for the normal
      liver which consisted of regular monophasic, positively deflected slow waves or
      pacesetter potentials (PPs). We proposed that the EHG might act as an
      investigative tool in the diagnosis of liver diseases. In this communication, we
      studied the electric activity of the liver in hepatic cirrhosis. 42 patients with
      liver cirrhosis (30 men, 12 women, mean age 41.2+/-14.3 years) and 20 healthy
      volunteers (14 men, 6 women, mean age 42.2+/-13.1), who acted as controls, were
      enrolled in the study. Three silver-silver chloride electrodes were applied, 3-4
      cm apart, to the abdominal skin parallel to and 1.5-2 cm below the right costal
      margin. Two 20-minute recording sessions were performed for each subject. In
      contrast to the regular reproducible PPs recorded in the healthy volunteers, the
      PPs of the cirrhotic patients had irregular rhythm, frequency and amplitude with
      occasional silent (no PPs) areas. The registered waves were identical from the 3
      electrodes in the same subject in the healthy controls, while differed from one
      electrode to the other in the cirrhotic patients. The "hepatoarrhythmic" pattern
      encountered in the cirrhotic liver was consistent and reproducible. An EHG could
      be identified for the cirrhotic liver. It exhibited a "hepatoarrhythmic pattern"
      due probably to loss of the lobular architecture of the liver and its replacement
      with regeneration nodules and fibrosis.

PMID- 10331995
TI  - Telemedicine in paediatric cardiology.

PMID- 10331996
TI  - A randomised controlled trial of specialist health visitor intervention for
      failure to thrive.
AB  - AIMS: To determine whether home intervention by a specialist health visitor
      affects the outcome of children with failure to thrive. METHODS: Children
      referred for failure to thrive were randomised to receive conventional care, or
      conventional care and additional specialist home visiting for 12 months. Outcomes
      measured were growth, diet, use of health care resources, and Bayley, HAD
      (hospital anxiety and depression), and behavioural scales. RESULTS: Eighty three
      children, aged 4-30 months, were enrolled, 42 received specialist health visitor
      intervention. Children in both groups showed good weight gain (mean (SD) increase
      in weight SD score for the specialist health visitor intervention group 0.59
      (0.63) v 0.42 (0.62) for the control group). Children < 12 months in the
      intervention group showed a higher mean (SD) increase in weight SD score than the
      control group (0.82 (0.86) v 0.42 (0.79)). Both groups improved in developmental
      score and energy intake. No significant differences were found for the primary
      outcome measures, but controls had significantly more dietary referrals, social
      service involvement, and hospital admissions, and were less compliant with
      appointments. CONCLUSIONS: The study failed to show that specialist health
      visitor intervention conferred additional benefits for the child. However, the
      specialist health visitor did provide a more coordinated approach, with
      significant savings in terms of health service use. Problems inherent to health
      service research are discussed.

PMID- 10331997
TI  - A controlled trial of parent initiated and conventional preschool health
      surveillance using personal child health records.
AB  - OBJECTIVES: A comparison of parent initiated preschool surveillance, using
      personal child health records, with the then current system of child health
      surveillance using child health records. DESIGN: Prospective, controlled trial
      with randomisation of five general practices into two groups. SETTING: Five
      general practices, a well baby clinic, and an orthoptic clinic at Yeovil District
      Hospital. SUBJECTS: 538 babies born between 1 April 1992 and 1 November 1994,
      from within the five general practices. MAIN OUTCOME MEASURES: The number of
      screenable abnormalities in the two groups that were missed in the first 3 years
      of a baby's life. RESULTS: 163 babies from the parent initiated preschool
      surveillance group and 107 from the conventional group completed the study.
      Although all the mothers from the parent initiated preschool surveillance group
      understood the concept of parent initiated surveillance, 117 stated their health
      visitor had made their appointments. Only 45 mothers made their own appointments.
      The abnormality rates were: 12 of 163 and eight of 107 at 1 year and nine of 163
      and six of 107 at 3 years. No medically important conditions were missed. Most
      mothers did not want to make their own appointments because it was inconvenient.
      The system was unpopular with health visitors. CONCLUSION: Parent initiated
      preschool surveillance is as safe as the current system. Implementing the idea
      involved a small change in work practice and a large change conceptually for some
      of the primary health care team. It was not adopted in east Somerset.

PMID- 10331998
TI  - Controlled study of preschool development after surgery for congenital heart
      disease.
AB  - AIM: Research into intellectual impairment among children with congenital heart
      disease has focused mainly on older children. This study was designed to
      determine whether previous findings are applicable to preschool children.
      METHODS: Three groups of children under 31/2 years old were assessed immediately
      before treatment and 12 months later: a group with congenital heart disease
      awaiting surgery, another awaiting bone marrow transplantation, and a healthy
      comparison group. RESULTS: Although the means of the three groups were within the
      normal range, preoperatively the cardiac and transplant groups showed deficits
      compared with the healthy controls. Postoperatively, continuing developmental
      deficits were significant only in the children with cyanotic lesions.
      CONCLUSIONS: Conclusions about intellectual development in older children with
      congenital heart disease do not apply to preschool children. Before corrective
      surgery, chronic illness itself appears to be the predominant influence on
      development. Postoperatively, cyanotic and acyanotic lesions are associated with
      different short term outcomes.

PMID- 10331999
TI  - Metabolic effects of discontinuing growth hormone treatment.
AB  - AIMS: To evaluate the effects of discontinuing growth hormone (GH) treatment on
      energy expenditure and body composition, which might help predict those most
      likely to benefit from early reintroduction of GH treatment in young adult life.
      METHODS: Body composition was calculated from skinfold thicknesses and dual
      energy x ray absorptometry (DXA). Resting metabolic rate (RMR) and whole body
      bone mineral content (BMC) were also measured. Measurements were made before
      stopping treatment, at discontinuation of GH treatment, and two weeks, six
      months, and one year later in 11 adolescents with growth hormone deficiency (GHD)
      and five adolescents without GHD who were treated with GH. Measurements were
      compared with 10 healthy controls, in whom measurements were repeated one year
      later. RESULTS: During the nine months before discontinuation of GH there were no
      changes in body composition, RMR, or BMC of patients with GHD, nor differences
      when compared with controls. RMR was reduced by 11.3 kJ/kg fat free mass two
      weeks after stopping GH in GHD patients and remained suppressed thereafter
      compared with controls. Percentage body fat increased by 4.3%/year in patients
      with GHD after discontinuing GH, whereas no changes were noted in control or non
      GHD patients at one year. The patients experiencing the greatest reductions in
      RMR/kg fat free mass at six months showed the largest increases in body fat at
      one year. No change in BMC was noted in patients one year after stopping
      treatment. CONCLUSION: Important metabolic changes occur early after
      discontinuing GH treatment. In patients whose growth is complete, these changes
      might be used to predict those most likely to benefit from continuation of GH
      treatment into adult life.

PMID- 10332000
TI  - Anthropometry of patients with osteogenesis imperfecta.
AB  - Standing height, sitting height, armspan, subischial leg length, head
      circumference, and growth hormone-insulin-like growth factor I (IGF-I) axis were
      determined in 86 patients with osteogenesis imperfecta. The aim of this study was
      to determine standing height and body proportions and their variability among
      osteogenesis imperfecta types and collagen defects. Mean standing height was
      reduced in all groups of patients, to the greatest extent and variability in
      osteogenesis imperfecta type III/IV and in those with qualitative collagen
      defects. The mean standing height of patients with osteogenesis imperfecta was
      lower than that of their unaffected first degree family members. Truncal height
      of patients with osteogenesis imperfecta was reduced; head size was increased,
      and this was more pronounced in patients with osteogenesis imperfecta type III/IV
      and qualitative collagen defects than in patients with osteogenesis imperfecta
      type I and quantitative collagen defects. Mean concentrations of IGF-I and IGF
      binding protein 3 (IGFBP-3) were low, but most values were within age specific
      reference values. The reduction of standing height appears to correlate with
      osteogenesis imperfecta type and the type of collagen defect. A relatively short
      trunk is typical and head circumference and body length are disproportionate.

PMID- 10332001
TI  - Ambulatory blood pressure in schoolchildren.
AB  - OBJECTIVE: To define the range and variability of ambulatory blood pressure in
      normal schoolchildren. DESIGN: Prospective study. METHODS: Resting blood pressure
      of 1121 schoolchildren from Newcastle upon Tyne was recorded. An ambulatory blood
      pressure device, which uses both auscultatory (Korotkoff) and oscillometric
      methods of blood pressure measurement, was then put in place for 24 hours.
      RESULTS: The day was divided into three time periods: school, home, and night
      time. Normal centiles for blood pressure for each of these time periods were
      obtained and many daytime readings were outside reported normal resting levels.
      The normal variation of blood pressure was quantified by comparing each of these
      time periods with the resting readings. Resting systolic blood pressure did not
      predict 24 hour mean systolic blood pressure. CONCLUSIONS: The availability of
      normal ambulatory blood pressure data on the level and variation of blood
      pressure in children may facilitate the early identification of hypertension in
      this age group.

PMID- 10332002
TI  - Injury surveillance in an accident and emergency department: a year in the life
      of CHIRPP.
AB  - BACKGROUND: The design of childhood injury prevention programmes is hindered by a
      dearth of valid and reliable information on injury frequency, cause, and outcome.
      A number of local injury surveillance systems have been developed to address this
      issue. One example is CHIRPP (Canadian Hospitals Injury Reporting and Prevention
      Program), which has been imported into the accident and emergency department at
      the Royal Hospital for Sick Children, Glasgow. This paper examines a year of
      CHIRPP data. METHODS: A CHIRPP questionnaire was completed for 7940 children
      presenting in 1996 to the accident and emergency department with an injury or
      poisoning. The first part of the questionnaire was completed by the parent or
      accompanying adult, the second part by the clinician. These data were
      computerised and analysed using SPSSPC for Windows. RESULTS: Injuries commonly
      occurred in the child's own home, particularly in children aged 0-4 years. These
      children commonly presented with bruising, ingestions, and foreign bodies. With
      increasing age, higher proportions of children presented with injuries occurring
      outside the home. These were most commonly fractures, sprains, strains, and
      inflammation/oedema. Seasonal variations were evident, with presentations peaking
      in the summer. CONCLUSIONS: There are several limitations to the current CHIRPP
      system in Glasgow: it is not population based, only injuries presented to the
      accident and emergency department are included, and injury severity is not
      recorded. Nevertheless, CHIRPP is a valuable source of information on patterns of
      childhood injury. It offers local professionals a comprehensive dataset that may
      be used to develop, implement, and evaluate child injury prevention activities.

PMID- 10332003
TI  - Recurrent infections in homozygous sickle cell disease.
AB  - The characteristics of 214 episodes of invasive bacterial infection among 176
      patients with homozygous sickle cell (SS) disease were examined. Streptococcus
      pneumoniae occurred in 81 episodes, Salmonella spp in 70, Haemophilus influenzae
      type b in 30, Escherichia coli in 24, and Klebsiella spp in nine. The cumulative
      incidence showed that S pneumoniae and H influenzae occurred predominantly before
      5 years of age and were uncommon thereafter, Salmonella spp increased almost
      linearly with age, and Klebsiella spp and E coli predominated in patients over 10
      years of age. Escherichia coli had a different epidemiology-it was found in older
      children, almost entirely girls. Excluding this organism from an analysis of
      recurrent bacterial infections, the standardised incidence rates for second and
      third infections were 4.8 and 15.8 times greater, respectively, than the SS
      population average. This implies that the susceptibility to infection is
      characteristic of a subgroup of patients with SS disease and that sick patients
      with previous bacteraemia should be investigated early and aggressively for
      further infection.

PMID- 10332004
TI  - Feeding problems in merosin deficient congenital muscular dystrophy.
AB  - Feeding difficulties were assessed in 14 children (age range 2-14 years) with
      merosin deficient congenital muscular dystrophy, a disease characterised by
      severe muscle weakness and inability to achieve independent ambulation. Twelve of
      the 14 children were below the 3rd centile for weight. On questioning, all
      parents thought their child had difficulty chewing, 12 families modified the
      diet, and 13 children took at least 30 minutes to complete a meal. On examination
      the mouth architecture was abnormal in 13 children. On videofluoroscopy only the
      youngest child (2 years old), had a normal study. The others all had an abnormal
      oral phase (breakdown and manipulation of food and transfer to oropharynx). Nine
      had an abnormal pharyngeal phase, with a delayed swallow reflex. Three of these
      also showed pooling of food in the larynx and three showed frank aspiration.
      These six cases all had a history of recurrent chest infections. Six of eight
      children who had pH monitoring also had gastro-oesophageal reflux. As a result of
      the study five children had a gastrostomy, which stopped the chest infections and
      improved weight gain. This study shows that children with merosin deficient
      congenital muscular dystrophy have difficulties at all stages of feeding that
      progress with age. Appropriate intervention can improve weight gain and reduce
      chest infections. The severity of the problem has not been previously appreciated
      in this disease, and the study shows the importance of considering the
      nutritional status in any child with a primary muscle disorder.

PMID- 10332005
TI  - Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and
      amiloride.
AB  - Nephrogenic diabetes insipidus (NDI) is characterised by the inability of the
      kidney to concentrate urine in response to arginine vasopressin. The consequences
      are severe polyuria and polydipsia, often associated with hypertonic dehydration.
      Intracerebral calcification, seizures, psychosomatic retardation, hydronephrosis,
      and hydroureters are its sequelae. In this study, four children with NDI were
      treated with 3 mg/kg/day hydrochlorothiazide and 0.3 mg/kg/day amiloride orally
      three times a day for up to five years. While undergoing treatment, none of the
      patients had signs of dehydration or electrolyte imbalance, all showed normal
      body growth, and there was no evidence of cerebral calcification or seizures. All
      but one had normal psychomotor development and normal sonography of the urinary
      tract. However, normal fluid balance was not attainable (fluid intake, 3.8-7.7
      l/m2/day; urine output, 2.2-7.4 l/m2/day). The treatment was well tolerated and
      no side effects could be detected. Prolonged treatment with
      hydrochlorothiazide/amiloride appears to be more effective and better tolerated
      than just hydrochlorothiazide. Its efficacy appears to be similar to that of
      hydrochlorothiazide/indomethacin but without their severe side effects.

PMID- 10332006
TI  - Paediatric oncology and intensive care treatments: changing trends.
AB  - OBJECTIVES: To review the outcome of patients with childhood malignancy requiring
      intensive care treatment and to assess whether there is any secular trend for
      improved outcome. DESIGN: Retrospective chart reviews of 74 consecutive
      admissions to a paediatric intensive care unit from a regional paediatric
      oncology centre between 1990 and 1997. During the same period there were 6419
      admissions to the oncology unit, 814 of whom were new cases. RESULTS: The overall
      survival at discharge from the intensive care unit was 49 of 74. Patients with
      either systemic or respiratory infection requiring ventilation had the poorest
      survival (13 of 31) whereas postoperative patients had the best survival (15 of
      15). However, patients with respiratory or systemic infection who required
      inotropic support with more than three agents all died compared with about one
      quarter of those needing no inotrope. All patients with systemic or respiratory
      infective illness were neutropenic and positive microbiological identification
      was possible in 13 of 21 and five of 18, respectively. Non-survivors had a higher
      mean acute physiology and chronic health evaluation system (APACHE-II) score than
      survivors (24.2 v 15.94, respectively) but no patient with a score of > 27
      survived. CONCLUSION: Compared with previous series, there has been a great
      improvement in survival of oncology patients admitted to the intensive care unit
      especially those with either systemic or respiratory infection needing
      ventilation. Full intensive care treatment should be provided for these patients.

PMID- 10332007
TI  - Mercury intoxication presenting with hypertension and tachycardia.
AB  - An 11 year old girl presented with hypertension and tachycardia. Excess urinary
      catecholamine excretion suggested phaeochromocytoma but imaging studies failed to
      demonstrate a tumour. Other symptoms included insomnia and weight loss, and she
      was found to have a raised concentration of mercury in blood and urine. Mercury
      intoxication should be considered in the differential diagnosis of hypertension
      with tachycardia even in patients presenting without the skin lesions typical of
      mercury intoxication and without a history of exposure.

PMID- 10332010
TI  - How to organise a paediatric MRCP (UK) part II training course.

PMID- 10332008
TI  - Clinical management of brain stem glioma.

PMID- 10332009
TI  - Oculocutaneous albinism.

PMID- 10332011
TI  - Can paediatric medical students devise a satisfactory standard of examination for
      their colleagues?
AB  - OBJECTIVES: To determine what standard paediatric medical students would set for
      examining their peers and how that would compare with the university standard.
      DESIGN: Single blinded computer marked examination with questionnaire. SETTING:
      University medical school. SUBJECTS: Medical students during their final
      paediatric attachment. INTERVENTIONS: Medical students asked to derive 10, five
      branch negatively marked multiple choice questions (MCQs) to a standard that
      would fail those without sufficient knowledge. Each 10 were then assessed by
      another student as to the degree of difficulty and the relevance to paediatrics.
      One year later student peers sat a mock MCQ examination derived from a random 40
      questions (unaware that the mock MCQs had been derived by peers). MAIN OUTCOME
      MEASURES: Comparison of marks obtained in mock and final MCQ examinations;
      student perception of the standard in the two examinations assessed by
      questionnaire. RESULTS: 44 students derived 439 questions, of which 83% were
      considered an appropriate standard by a classmate. One year later 62 students sat
      the mock examination. Distribution of marks was better in the mock MCQ
      examination than the final MCQ examination. Students considered the mock
      questions to be a more appropriate standard (72% v 31%) and the topics more
      relevant (88% v 64%) to paediatric medical students. Questions were of a similar
      clarity in both examinations (73% v 78%). CONCLUSIONS: Students in this study
      were able to derive an examination of a satisfactory standard for their peers.
      Involvement of students in deriving examination standards may give them a better
      appreciation of how standards should be set and maintained.

PMID- 10332012
TI  - The Acheson report: challenges for the College.

PMID- 10332013
TI  - Quinolone-resistant Campylobacter jejuni infections in Minnesota, 1992-1998.
      Investigation Team.
AB  - BACKGROUND: Increasing resistance to quinolones among campylobacter isolates from
      humans has been reported in Europe and Asia, but not in the United States. We
      evaluated resistance to quinolones among campylobacter isolates from Minnesota
      residents during the period from 1992 through 1998. METHODS: All 4953
      campylobacter isolates from humans received by the Minnesota Department of Health
      were tested for resistance to nalidixic acid. Resistant isolates and selected
      sensitive isolates were tested for resistance to ciprofloxacin. We conducted a
      case-comparison study of patients with ciprofloxacin-resistant Campylobacter
      jejuni isolated during 1996 and 1997. Domestic chicken was evaluated as a
      potential source of quinolone-resistant campylobacter. RESULTS: The proportion of
      quinolone-resistant C. jejuni isolates from humans increased from 1.3 percent in
      1992 to 10.2 percent in 1998 (P<0.001). During 1996 and 1997, infection with
      quinolone-resistant C. jejuni was associated with foreign travel and with the use
      of a quinolone before the collection of stool specimens. However, quinolone use
      could account for no more than 15 percent of the cases from 1996 through 1998.
      The number of quinolone-resistant infections that were acquired domestically also
      increased during the period from 1996 through 1998. Ciprofloxacin-resistant C.
      jejuni was isolated from 14 percent of 91 domestic chicken products obtained from
      retail markets in 1997. Molecular subtyping showed an association between
      resistant C. jejuni strains from chicken products and domestically acquired
      infections in Minnesota residents. CONCLUSIONS: The increase in quinolone
      resistant C. jejuni infections in Minnesota is largely due to infections acquired
      during foreign travel. However, the number of quinolone-resistant infections
      acquired domestically has also increased, largely because of the acquisition of
      resistant strains from poultry. The use of fluoroquinolones in poultry, which
      began in the United States in 1995, has created a reservoir of resistant C.
      jejuni.

PMID- 10332014
TI  - Ultrasound therapy for calcific tendinitis of the shoulder.
AB  - BACKGROUND AND METHODS: Although ultrasound therapy is used to treat calcific
      tendinitis of the shoulder, its efficacy has not been rigorously evaluated. We
      conducted a randomized, double-blind comparison of ultrasonography and sham
      insonation in patients with symptomatic calcific tendinitis verified by
      radiography. Patients were assigned to receive 24 15-minute sessions of either
      pulsed ultrasound (frequency, 0.89 MHz; intensity, 2.5 W per square centimeter;
      pulsed mode, 1:4) or an indistinguishable sham treatment to the area over the
      calcification. The first 15 treatments were given daily (five times per week),
      and the remainder were given three times a week for three weeks. Randomization
      was conducted according to shoulders rather than patients, so a patient with
      bilateral tendinitis might receive either or both therapies. RESULTS: We enrolled
      63 consecutive patients (70 shoulders). Fifty-four patients (61 shoulders)
      completed the study. There were 32 shoulders in the ultrasound-treatment group
      and 29 in the sham-treatment group. After six weeks of treatment, calcium
      deposits had resolved in six shoulders (19 percent) in the ultrasound-treatment
      group and decreased by at least 50 percent in nine shoulders (28 percent), as
      compared with respective values of zero and three (10 percent) in the sham
      treatment group (P=0.003). At the nine-month follow-up visit, calcium deposits
      had resolved in 13 shoulders (42 percent) in the ultrasound-treatment group and
      improved in 7 shoulders (23 percent), as compared with respective values of 2 (8
      percent) and 3 (12 percent) in the sham-treatment group (P=0.002). At the end of
      treatment, patients who had received ultrasound treatment had greater decreases
      in pain and greater improvements in the quality of life than those who had
      received sham treatment; at nine months, the differences between the groups were
      no longer significant. CONCLUSIONS: In patients with symptomatic calcific
      tendinitis of the shoulder, ultrasound treatment helps resolve calcifications and
      is associated with short-term clinical improvement.

PMID- 10332015
TI  - Nonsurgical reconstruction of thoracic aortic dissection by stent-graft
      placement.
AB  - BACKGROUND: The treatment of thoracic aortic dissection is guided by prognostic
      and anatomical information. Proximal dissection requires surgery, but the
      appropriate treatment of distal thoracic aortic dissection has not been
      determined, because surgery has failed to improve the prognosis. METHODS: We
      prospectively evaluated the safety and efficacy of elective transluminal
      endovascular stent-graft insertion in 12 consecutive patients with descending
      (type B) aortic dissection and compared the results with surgery in 12 matched
      controls. In all 24 patients, aortic dissection was diagnosed by magnetic
      resonance angiography. In each group, the dissection involved the aortic arch in
      3 patients and the descending thoracic aorta in all 12 patients. With the patient
      under general anesthesia, either surgical resection was undertaken or a custom
      designed endovascular stent-graft was placed by unilateral arteriotomy. RESULTS:
      Stent-graft placement resulted in no morbidity or mortality, whereas surgery for
      type B dissection was associated with four deaths (33 percent, P=0.09) and five
      serious adverse events (42 percent, P=0.04) within 12 months. Transluminal
      placement of the stent-graft prosthesis was successful in all patients, with no
      leakage; full expansion of the stents was ensured by balloon inflation at 2 to 3
      atm. Sealing of the entry tear was monitored during the procedure by
      transesophageal ultrasonography and angiography, and thrombosis of the false
      lumen was confirmed in all 12 patients after a mean of three months by magnetic
      resonance imaging. There were no deaths or instances of paraplegia, stroke,
      embolization, side-branch occlusion, or infection in the stent-graft group; nine
      patients had postimplantation syndrome, with transient elevation of C-reactive
      protein levels and body temperature plus mild leukocytosis. All the patients who
      received stent-grafts recovered, as did seven patients who underwent surgery for
      type B dissection (58 percent) (P=0.04). CONCLUSIONS: These preliminary
      observations suggest that elective, nonsurgical insertion of an endovascular
      stent-graft is safe and efficacious in selected patients who have thoracic aortic
      dissection and for whom surgery is indicated. Endoluminal repair may be useful
      for interventional reconstruction of thoracic aortic dissection.

PMID- 10332016
TI  - Endovascular stent-graft placement for the treatment of acute aortic dissection.
AB  - BACKGROUND: The standard treatment for acute aortic dissection is either surgical
      or medical therapy, depending on the morphologic features of the lesion and any
      associated complications. Irrespective of the form of treatment, the associated
      mortality and morbidity are considerable. METHODS: We studied the placement of
      endovascular stent-grafts across the primary entry tear for the management of
      acute aortic dissection originating in the descending thoracic aorta. We
      evaluated the feasibility, safety, and effectiveness of transluminal stent-graft
      placement over the entry tear in 4 patients with acute type A aortic dissections
      (which involve the ascending aorta) and 15 patients with acute type B aortic
      dissections (which are confined to the descending aorta). Dissections involved
      aortic branches in 14 of the 19 patients (74 percent), and symptomatic compromise
      of multiple branch vessels was observed in 7 patients (37 percent). The stent
      grafts were made of self-expanding stainless-steel covered with woven polyester
      or polytetrafluoroethylene material. RESULTS: Placement of endovascular stent
      grafts across the primary entry tears was technically successful in all 19
      patients. Complete thrombosis of the thoracic aortic false lumen was achieved in
      15 patients (79 percent), and partial thrombosis was achieved in 4 (21 percent).
      Revascularization of ischemic branch vessels, with subsequent relief of
      corresponding symptoms, occurred in 76 percent of the obstructed branches. Three
      of the 19 patients died within 30 days, for an early mortality rate of 16 percent
      (95 percent confidence interval, 0 to 32 percent). There were no deaths and no
      instances of aneurysm or aortic rupture during the subsequent average follow-up
      period of 13 months. CONCLUSIONS: These initial results suggest that stent-graft
      coverage of the primary entry tear may be a promising new treatment for selected
      patients with acute aortic dissection. This technique requires further
      evaluation, however, to assess its therapeutic potential fully.

PMID- 10332017
TI  - Images in clinical medicine. Circumferential dissection of the aorta.

PMID- 10332018
TI  - Images in clinical medicine. Argyria.

PMID- 10332019
TI  - Vascular-bed--specific hemostasis and hypercoagulable states.

PMID- 10332020
TI  - Patients with refractory seizures.

PMID- 10332021
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 15-1999. A 77-year-old man with hemoptysis and cardiovascular
      disease.

PMID- 10332022
TI  - The consequences for food safety of the use of fluoroquinolones in food animals.

PMID- 10332023
TI  - Calcific tendinitis of the shoulder.

PMID- 10332024
TI  - Catheter-based treatment of aortic dissection.

PMID- 10332025
TI  - The loneliness of the long-term care giver.

PMID- 10332026
TI  - Dentatorubral-pallidoluysian atrophy protein interacts through a proline-rich
      region near polyglutamine with the SH3 domain of an insulin receptor tyrosine
      kinase substrate.
AB  - Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neuro
      degrees enerative disorder associated with CAG/glutamine repeat expansion. While
      the DRPLA gene is ubiquitously expressed, neuron death occurs in specific
      anatomical areas of the brain. This predicts that the DRPLA protein interacts
      with other proteins and that these interactions may play a role in pathogenesis.
      Here, we describe a protein that binds to the DRPLA product. One of the clones
      isolated with a yeast two-hybrid system was identified as a human homolog of the
      insulin receptor tyrosine kinase substrate protein of 53 kDa (IRSp53). The gene
      produced two mRNA forms by differential splicing and encoded 552 and 521 amino
      acids, respectively. The longer form was mainly expressed in the brain and the
      shorter one in other tissues. The products were phosphorylated upon stimulation
      of cultured cells with insulin or insulin-like growth factor 1. Binding of the
      DRPLA protein to IRSp53 was ascertained by co-immunoprecipitation with antibodies
      and also by co-localization in perinuclear oval dots in cells expressing
      engineered constructs. A proline-rich region near the polyglutamine tract of the
      DRPLA protein and the SH3 domain of IRSp53 were involved in the binding. An
      extended polyglutamine tract significantly reduced binding ability in yeast
      cells, but not in in vitro binding assays. The identification of IRSp53 and other
      proteins detected by the yeast hybrid system predicts that DRPLA functions in a
      signal transduction pathway coupled with insulin/IGF-1.

PMID- 10332027
TI  - T-STAR/ETOILE: a novel relative of SAM68 that interacts with an RNA-binding
      protein implicated in spermatogenesis.
AB  - RBM is an RNA-binding protein encoded on the Y chromosome in mammals and is
      expressed only in the nuclei of male germ cells. Genetic evidence from infertile
      men implicates it in spermatogenesis, but its function is unknown. Of a number of
      potential partners for RBM identified by a yeast two-hybrid screen with testis
      cDNA, the most frequent isolates encoded a novel RNA-binding protein, termed T
      STAR, that is closely related to SAM68, an Src-associated protein of unknown
      function. The mouse homologue was also cloned and designated etoile. It mapped to
      chromosome 15, while T-STAR mapped to the syntenic region on human chromosome 8.
      T-STAR/etoile is expressed primarily in the testis; in rat germ cells, the
      expression of both T-STAR/etoile and SAM68 is regulated during meiosis.
      Transfection of T-STAR/etoile fused with green fluorescent protein into HeLa
      cells caused an accumulation of protein in a novel compartment of the nucleus,
      adjacent to the nucleolus but distinct from the peri-nucleolar compartment. RBM
      and other hnRNP G family members are candidate downstream targets for regulation
      by T-STAR/ETOILE and SAM68.

PMID- 10332028
TI  - N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin
      disease striate palmoplantar keratoderma.
AB  - The N-terminal extracellular domain of the cadherins, calcium-dependent cell
      adhesion molecules, has been shown by X-ray crystallography to be involved in two
      types of interaction: lateral strand dimers and adhesive dimers. Here we describe
      the first human mutation in a cadherin present in desmosome cell junctions that
      removes a portion of this highly conserved first extracellular domain. The
      mutation, in the DSG1 gene coding for a desmoglein (Dsg1), results in the
      deletion of the first and much of the second beta-strand of the first cadherin
      repeat and part of the first Ca2+-binding site, and would be expected to
      compromise strand dimer formation. It causes a dominantly inherited skin disease,
      striate palmoplantar keratoderma (SPPK), mapping to chromosome 18q12.1, in which
      affected individuals have marked hyperkeratotic bands on the palms and soles. In
      a three generation Dutch family with SPPK, we have found a G-->A transition in
      the 3" splice acceptor site of intron 2 of the DSG1 gene which segregated with
      the disease phenotype. This causes aberrant splicing of exon 2 to exon 4, which
      are in-frame, with the consequent removal of exon 3 encoding part of the
      prosequence, the mature protein cleavage site and part of the first extracellular
      domain. This mutation emphasizes the importance of this part of the molecule for
      cadherin function, and of the Dsg1 protein and hence desmosomes in epidermal
      function.

PMID- 10332029
TI  - PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription
      activation by Brn-2 and affects cell survival.
AB  - A novel gene, designated PQBP-1, which encodes a 265 residue protein that binds
      to the polyglutamine tract of the brain-specific transcription factor Brn-2, was
      identified. PQBP-1, which also interacts with the polyglutamine tract of triplet
      repeat disease gene products, binds with a higher affinity to an expanded
      polyglutamine tract. PQBP-1 has several functional domains, including hepta- and
      di-amino acid repeat sequences rich in polar residues essential for its
      interaction with the polyglutamine tract, a WWP/WW domain which binds to proline
      rich motifs in other proteins, a putative nuclear localization signal sequence
      and a C2domain implicated in Ca2+-dependent phospholipid signaling. PQBP-1 is
      located in the nucleus and inhibits transcriptional activation by Brn-2.
      Overexpression of PQBP-1 in P19 embryonic carcinoma cells suppresses their growth
      rate and enhances their susceptibility to various stresses including serum
      deprivation, retinoic acid treatment and UV irradiation. Northern blot and in
      situ hybridization analyses revealed that PQBP-1 is a ubiquitous protein and is
      expressed primarily in neurons throughout the brain, with abundant levels in
      hippocampus, cerebellar cortex and olfactory bulb. These results suggest that
      PQBP-1 mediates important cellular functions under physiological and pathological
      conditions via its interaction with polyglutamine tracts.

PMID- 10332031
TI  - Adenovirus-mediated expression of mutant DRPLA proteins with expanded
      polyglutamine stretches in neuronally differentiated PC12 cells. Preferential
      intranuclear aggregate formation and apoptosis.
AB  - To investigate the molecular mechanisms of neurodegeneration caused by expanded
      CAG repeats in dentatorubral-pallidoluysian atrophy (DRPLA), an autosomal
      dominant neuro degrees enerative disorder caused by unstable expansion of a CAG
      trinucleotide repeat in the DRPLA gene on 12p13.31, we established an efficient
      expression system for truncated and full-length DRPLA proteins with normal or
      expanded polyglutamine stretches in neuronally differentiated PC12 cells and
      fibroblasts using an adenovirus expression system. Although aggregate body
      formation was observed both in neuronally differentiated PC12 cells and in
      fibroblasts expressing truncated DRPLA proteins with Q82, >97% ( n = 3) of
      neuronally differentiated PC12 cells showed intra-nuclear inclusions, while only
      31 21% ( n = 3) of fibro-blasts had intranuclear inclusions at 3 days after
      infection. The percentage of apoptotic cells was significantly higher in
      neuronally differentiated PC12 cells expressing the truncated DRPLA protein with
      Q82 than in fibroblasts, suggesting the possibility that intranuclear aggregate
      bodies are formed preferentially in neuronally differentiated PC12 cells and that
      these cells are more vulnerable than fibroblasts to the toxic effects of expanded
      polyglutamine stretches in the DRPLA protein. When the full-length DRPLA protein
      with Q82 was expressed, aggregate bodies were found exclusively in the nuclei of
      the neuronally differentiated PC12 cells, while they were found in the cytoplasm
      of fibroblasts. Despite the presence of aggregate bodies, apoptosis was not
      induced by expression of the full-length DRPLA protein with Q82 in either
      neuronally differentiated PC12 cells or fibroblasts, suggesting that the presence
      of intranuclear aggregate bodies is in itself not necessarily toxic to cells.

PMID- 10332030
TI  - A region of human chromosome 9p required for testis development contains two
      genes related to known sexual regulators.
AB  - Deletion of the distal short arm of chromosome 9 (9p) has been reported in a
      number of cases to be associated with gonadal dysgenesis and XY sex reversal,
      suggesting that this region contains one or more genes required in two copies for
      normal testis development. Recent studies have greatly narrowed the interval
      containing this putative autosomal testis-determining gene(s) to the distal
      portion of 9p24.3. We previously identified DMRT1, a human gene with sequence
      similarity to genes that regulate the sexual development of nematodes and
      insects. These genes contain a novel DNA-binding domain, which we named the DM
      domain. DMRT1 maps to 9p24. 3 and in adults is expressed specifically in the
      testis. We have investigated the possible role of DM domain genes in 9p sex
      reversal. We identified a second DM domain gene, DMRT2, which also maps to
      9p24.3. We found that point mutations in the coding region of DMRT1 and the DM
      domain of DMRT2 are not frequent in XY females. We showed by fluorescence in situ
      hybridization analysis that both genes are deleted in the smallest reported sex
      reversing 9p deletion, suggesting that gonadal dysgenesis in 9p-deleted
      individuals might be due to combined hemizygosity of DMRT1 and DMRT2.

PMID- 10332032
TI  - Characterization of regions functional in the nuclear localization of the Fanconi
      anemia group A protein.
AB  - Fanconi anemia (FA) is an autosomal recessive disease characterized by a variety
      of congenital abnormalities. Cells from FA patients show chromosomal instability
      and are hypersensitive to DNA cross-linking agents, though the basic cellular
      defect in FA is not known. The FANCA gene encodes a protein with an Mr of 162 kDa
      and with unknown function. The cellular localization of the FANCA protein has
      been controversial, and has been shown in different reports to be exclusively
      cytoplasmic and predominantly nuclear. In the present study, we further confirm
      that FANCA localizes primarily to the nucleus. Fusions of FANCA with the green
      fluorescent protein (GFP) showed a strong nuclear signal and a weak cytoplasmic
      signal in several cell types. Confocal laser microscopy confirmed that FANCA is
      evenly distributed throughout the nucleus. We also examined regions in FANCA that
      participate in its nuclear import. FANCA contains two bipartite nuclear
      localization signal (NLS) motifs at the extreme N-terminus. Deletion of amino
      acids N-terminal to the NLS motifs had no effect on the nuclear localization of
      FANCA or on its ability to correct mitomycin C sensitivity in an FA-A cell line,
      while deletion of both motifs impeded but did not prevent nuclear import.
      Deletions of 75, 90 and 150 residues from the N-terminus yielded a mixture of
      cells with only a cytoplasmic signal, and with both a nuclear and cytoplasmic
      signal. Deletion of the N-terminal 250 amino acids was required to block nuclear
      localization completely. Fusion of GFP to the N-terminal 250 amino acids showed a
      localization pattern similar to FANCA. Mutant forms of FANCA with deletions of
      the C-terminal 70 or 260 residues localized to the cytoplasm, although the C
      terminal 260 amino acids alone lacked NLS activity. The results show that nuclear
      localization of FANCA involves several functional regions.

PMID- 10332033
TI  - Myotonic dystrophy: tissue-specific effect of somatic CTG expansions on allele
      specific DMAHP/SIX5 expression.
AB  - Myotonic dystrophy (DM), the most common inherited muscle disorder, is caused by
      a CTG expansion in the 3"-untranslated region of a protein kinase gene ( DMPK ).
      The complex and variable phenotype is most likely caused by a complex molecular
      pathogenesis, including deficiency of the DMPK protein, a trans -dominant
      misregulation of RNA homeostasis and haploinsufficiency of a neighboring homeobox
      gene [DM locus-associated homeodomain protein (DMAHP )]. Here, we study the
      allele-specific transcriptional activity of the DMAHP/SIX5 gene in DM patient
      tissues. Using a quantitative fluorescent RT-PCR assay, we tested allele-specific
      accumulation of DMAHP/SIX5 transcripts in both total and poly(A)+pools. In muscle
      biopsies, we found that transcript reductions of DMAHP/SIX5 alleles in cis with
      CTG expansions correlated with the extent of expansion. A patient with
      approximately 90 CTG repeats in muscle DNA (normal n < 37) showed a 20% reduction
      of allele-specific transcript levels, while four other DM patients with larger
      expansions showed 80% reductions. The effects of the CTG expansions on DMAHP
      transcription were tissue specific: autopsy tissues from a patient with 1500
      repeats showed 80% reductions in muscle and liver; however, RNA from other
      tissues (lung, aorta, heart conduction tissue, cerebellum) showed 0-20%
      reductions. Our results suggest that the effect of the CTG repeat on the
      DMAHP/SIX5 promoter is variable and tissue-specific. Our data are consistent with
      abnormalities of DMAHP/SIX5 probably having a more prominent role in disease
      pathogenesis in muscle, liver and brain, but being less important in other
      tissues.

PMID- 10332034
TI  - Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman
      syndrome chromosome region (15q11-q13).
AB  - The most common etiology for Prader-Willi syndrome and Angelman syndrome is de
      novo interstitial deletion of chromosome 15q11-q13. Deletions and other recurrent
      rearrangements of this region involve four common 'hotspots' for breakage, termed
      breakpoints 1-4 (BP1-BP4). Construction of an approximately 4 Mb YAC contig of
      this region identified multiple sequence tagged sites (STSs) present at both BP2
      and BP3, suggestive of a genomic duplication event. Interphase FISH studies
      demonstrated three to five copies on 15q11-q13, one copy on 16p11.1-p11.2 and one
      copy on 15q24 in normal controls, while analysis on two Class I deletion patients
      showed loss of approximately three signals at 15q11-q13 on one homolog. Multiple
      FISH signals were also observed at regions orthologous to both human chromosomes
      15 and 16 in non-human primates, including Old World monkeys, suggesting that
      duplication of this region may have occurred approximately 20 million years ago.
      A BAC/PAC contig for the duplicated genomic segment (duplicon) demonstrated a
      size of approximately 400 kb. Surprisingly, the duplicon was found to contain at
      least seven different expressed sequence tags representing multiple
      genes/pseudogenes. Sequence comparison of STSs amplified from YAC clones uniquely
      mapped to BP2 or BP3 showed two different copies of the duplicon within BP3,
      while BP2 comprised a single copy. The orientation of BP2 and BP3 are inverted
      relative to each other, whereas the two copies within BP3 are in tandem. The
      presence of large duplicated segments on chromosome 15q11-q13 provides a
      mechanism for homologous unequal recombination events that may mediate the
      frequent rearrangements observed for this chromosome.

PMID- 10332035
TI  - Correlations of genotype and phenotype in hypophosphatasia.
AB  - Hypophosphatasia, a rare inherited disorder characterized by defective bone
      mineralization, is highly variable in its clinical expression. The disease is due
      to various mutations in the tissue-non-specific alkaline phosphatase ( TNSALP )
      gene. We report here the use of clinical data, site-directed mutagenesis and
      computer-assisted modelling to propose a classification of 32 TNSALP gene
      mutations found in 23 European patients, 17 affected with lethal hypophosphatasia
      and six with non-lethal hypophosphatasia. Transfection studies of the missense
      mutations found in non-lethal hypophosphatasia showed that six of them allowed
      significant residual in vitro enzymatic activity, suggesting that these mutations
      corresponded to moderate alleles. Each of the six patients with non-lethal
      hypophosphatasia carried at least one of these alleles. The three-dimensional
      model study showed that moderate mutations were not found in the active site, and
      that most of the severe missense mutations were localized in crucial domains such
      as the active site, the vicinity of the active site and homodimer interface. Some
      mutations appeared to be organized in clusters on the surface of the molecule
      that may represent possible candidates for regions interacting with the C
      terminal end involved in glycosylphosphatidylinositol (GPI) attachment or with
      other dimers to form tetramers. Finally, our results show a good correlation
      between clinical forms of the disease, mutagenesis experiments and the three
      dimensional structure study, and allowed us to clearly distinguish moderate
      alleles from severe alleles. They also confirm that the extremely high phenotypic
      heterogeneity observed in patients with hypophosphatasia was due mainly to
      variable residual enzymatic activities allowed by missense mutations found in the
      human TNSALP gene.

PMID- 10332036
TI  - Gene shifting: a novel therapy for mitochondrial myopathy.
AB  - Mutations in mitochondrial DNA (mtDNA) are the most frequent causes of
      mitochondrial myopathy in adults. In the majority of cases mutant and wild-type
      mtDNAs coexist, a condition referred to as mtDNA heteroplasmy; however, the
      relative frequency of each species varies widely in different cells and tissues.
      Nearly complete segregation of mutant and wild-type mtDNAs has been observed in
      the skeletal muscle of many patients. In such patients mutant mtDNAs pre-dominate
      in mature myofibers but are rare or undetectable in skeletal muscle satellite
      cells cultured in vitro. This pattern is thought to result from positive
      selection for the mutant mtDNA in post-mitotic myofibers and loss of the mutant
      by genetic drift in satellite cells. Satellite cells are dormant myoblasts that
      can be stimulated to re-enter the cell cycle and fuse with existing myofibers in
      response to signals for muscle growth or repair. We tested whether we could
      normalize the mtDNA genotype in mature myofibers in a patient with mitochondrial
      myopathy by enhancing the incorporation of satellite cells through regeneration
      following injury or muscle hypertrophy, induced by either eccentric or concentric
      resistance exercise training. We show a remarkable increase in the ratio of wild
      type to mutant mtDNAs, in the proportion of muscle fibers with normal respiratory
      chain activity and in muscle fiber cross-sectional area after a short period of
      concentric exercise training. These data show that it is possible to reverse the
      molecular events that led to expression of metabolic myopathy and demonstrate the
      effectiveness of this form of 'gene shifting' therapy.

PMID- 10332038
TI  - Cis-acting modifiers of expanded CAG/CTG triplet repeat expandability:
      associations with flanking GC content and proximity to CpG islands.
AB  - An increasing number of human genetic disorders are associated with the expansion
      of trinucleotide repeats. The majority of these diseases are associated with
      CAG/CTG expansions, including Huntington's disease, myotonic dystrophy and many
      of the spinocerebellar ataxias. Recently, two new expanded CAG/CTG repeats have
      been identified that are not associated with a phenotype. Expanded alleles at all
      of these loci are unstable, with frequent length changes during intergenerational
      transmission. However, variation in the relative levels of instability, and the
      size and direction of the length change mutations observed, between the CAG/CTG
      loci is apparent. We have quantified these differences, taking into account
      effects of progenitor allele length, by calculating the relative expandability of
      each repeat. Since the repeat motifs are the same, these differences must be a
      result of flanking sequence modifiers. We present data that indicate a strong
      correlation between the relative expandability of these repeats and the flanking
      GC content. Moreover, we demonstrate that the most expandable loci are all
      located within CpG islands. These data provide the first insights into the
      molecular bases of cis -acting flanking sequences modifying the relative
      mutability of dispersed expanded human triplet repeats.

PMID- 10332037
TI  - Simultaneous analysis of expression of the three myotonic dystrophy locus genes
      in adult skeletal muscle samples: the CTG expansion correlates inversely with
      DMPK and 59 expression levels, but not DMAHP levels.
AB  - The causative mutation in the majority of cases of myotonic dystrophy has been
      shown to be the expansion of a CTG trinucleotide repeat, but the mechanism(s) by
      which this repeat leads to the very complex symptomatology in this disorder
      remains controversial. We have developed a highly sensitive and quantifiable
      assay, based on competitive RT-PCR, to test the hypothesis that the expansion
      disrupts the expression of the genes in its immediate vicinity, DMPK, 59 and
      DMAHP. In order to avoid cell culture-induced artifacts we performed these
      experiments using adult skeletal muscle biopsy samples and analysed total
      cytoplasmic poly(A)+mRNA levels for each gene simultaneously, as this is more
      physiologically relevant than allele-specific levels. There was considerable
      overlap between the expression levels of the three genes in myotonic dystrophy
      patient samples and samples from control individuals. However, in the myotonic
      dystrophy samples we detected a strong inverse correlation between the repeat
      size and the levels of expression of DMPK and 59. This is the first report of a
      possible effect of the CTG expansion on gene 59. Our results indicate that whilst
      a simple dosage model of gene expression in the presence of the mutation is
      unlikely to be sufficient in itself to explain the complex molecular pathology in
      this disease, the repeat expansion may be a significant modifier of the
      expression of these two genes.

PMID- 10332039
TI  - Intracellular localization and loss of copper responsiveness of Mnk, the murine
      homologue of the Menkes protein, in cells from blotchy (Mo blo) and brindled (Mo
      br) mouse mutants.
AB  - Menkes disease is an X-linked copper deficiency disorder that results from
      mutations in the ATP7A ( MNK ) gene. A wide range of disease-causing mutations
      within ATP7A have been described, which lead to a diversity of phenotypes
      exhibited by Menkes patients. The mottled locus ( Mo, Atp7a, Mnk ) represents the
      murine homologue of the ATP7A gene, and the mottled mutants exhibit a diversity
      of phenotypes similar to that observed among Menkes patients. Therefore, these
      mutants are valuable models for studying Menkes disease. Two of the mottled
      mutants are brindled and blotchy and their phenotypes resemble classical Menkes
      disease and occipital horn syndrome (OHS) in humans, respectively. That is, the
      brindled mutant and patients with classical Menkes disease are severely copper
      deficient and have profound neurological problems, while OHS patients and the
      blotchy mouse have a much milder phenotype with predominantly connective tissue
      defects. In this study, in an attempt to understand the basis for the brindled
      and blotchy phenotypes, the copper transport characteristics and intracellular
      distribution of the Mnk protein were assessed in cultured cells from these
      mutants. The results demonstrated that the abnormal copper metabolism of brindled
      and blotchy cells may be related to a number of factors, which include the amount
      of Mnk protein, the intracellular location of the protein and the ability of Mnk
      to redistribute in elevated copper. The data also provide evidence for a
      relationship between the copper transport function and copper-dependent
      trafficking of Mnk.

PMID- 10332040
TI  - Nonsense and temperature-sensitive mutations in PEX13 are the cause of
      complementation group H of peroxisome biogenesis disorders.
AB  - Peroxisome biogenesis disorders, including Zellweger syndrome (ZS), neonatal
      adrenoleukodystrophy (NALD) and infantile Refsum disease, are lethal hereditary
      diseases caused by abnormalities in peroxisomal assembly. To date, 12 genotypes
      have been identified. We now have evidence that the complete human cDNA encoding
      Pex13p, an SH3 protein of a docking factor for the peroxisome targeting signal 1
      receptor (Pex5p), rescues peroxisomal matrix protein import and its assembly in
      fibroblasts from PBD patients of complementation group H. In addition, we
      detected mutations on the human PEX13 cDNA in two patients of group H. A severe
      phenotype of a ZS patient (H-02) was homozygous for a nonsense mutation, W234ter,
      which results in the loss of not only the SH3 domain but also the putative
      transmembrane domain of Pex13p. A more mildly affected NALD patient (H-01), whose
      fibroblasts showed the temperature-sensitive (TS) phenotype, was homozygous for a
      missense mutation in the SH3 domain of Pex13p, I326T. This mutant PEX13 cDNA
      expression in a PEX13-defective CHO mutant showed I326T to be a TS mutation and
      thus suggested that Pex13p with the I326T mutation in the SH3 domain is stable at
      30 degrees C but is somewhat unstable at 37 degrees C.

PMID- 10332041
TI  - The timing of XIST replication: dominance of the domain.
AB  - Contiguous replicons are coordinately replicated and may be organized in temporal
      spatial domains with early replication domains containing expressed genes and
      late ones carrying silent genes. XIST is silent on the active, early replicating
      X chromosome and expressed from the inactive, late replicating homolog. These
      circumstances potentially deviate from the aforementioned generalization and make
      studies of replication timing for XIST of special interest. Although earlier
      investigations of XIST replication in fibroblasts based on analysis of extracted
      DNA from cells at different stages of the cell cycle suggested that the silent
      gene does replicate before the expressed allele, studies using FISH technology
      produced the opposite results. Because the FISH replication studies could not
      directly distinguish between the active and inactive X chromosomes in the same
      cell, we undertook a re-investigation of this question utilizing FISH analysis
      under conditions that allowed us to make that distinction using cells sorted into
      different cell cycle stages by flow cytometry. The findings reported here
      indicate that the silent XIST gene on the active X chromosome does replicate
      before the expressed allele on the inactive X, supporting the view that the time
      of a gene's replication is determined by the large, multi-replicon domain in
      which it is located and not necessarily its expression state.

PMID- 10332042
TI  - Defective intracellular transport of CLN3 is the molecular basis of Batten
      disease (JNCL)
AB  - Batten disease [juvenile-onset neuronal ceroid lipofuscinosis (JNCL)], the most
      common progressive encephalopathy of childhood, is caused by mutations in a novel
      lysosomal membrane protein (CLN3) with unknown function. In this study, we have
      confirmed the lysosomal localization of the CLN3 protein by immunoelectron
      microscopy by co-localizing it with soluble and membrane-associated lysosomal
      proteins. We have analysed the intracellular processing and localization of two
      mutants, 461-677del, which is present in 85% of CLN3 alleles and causes the
      classical JNCL, and E295K [corrected], which is a rare missense mutation
      associated with an atypical form of JNCL. Pulse-chase labelling and
      immunoprecipitation of the two mutant proteins in COS-1-cells indicated that 461
      677del is synthesized as an approximately 24 kDa truncated polypeptide, whereas
      the maturation of E295K [corrected] resembles that of the wild-type CLN3
      polypeptide. Transient expression of the two mutants in BHK cells showed that 461
      677del is retained in the endoplasmic reticulum, whereas E295K [corrected] was
      capable of reaching the lysosomal compartment. The CLN3 polypeptides were
      expressed further in mouse primary neurons where the wild-type CLN3 protein was
      localized both in the cell soma and in neuronal extensions, whereas the 461
      677del mutant was arrested in the cell soma. Interestingly, co-localization of
      the wild-type CLN3 and E295K [corrected] proteins with a synaptic vesicle marker
      indicates that the CLN3 protein might participate in synaptic vesicle
      transport/transmission. The data presented here provide clear evidence for a
      cellular distinction between classical and atypical forms of Batten disease both
      in neural and non-neural cells.

PMID- 10332043
TI  - Mitochondrial intermediate peptidase and the yeast frataxin homolog together
      maintain mitochondrial iron homeostasis in Saccharomyces cerevisiae.
AB  - Friedreich's ataxia (FRDA) is a neurodegenerative disease typically caused by a
      deficiency of frataxin, a mitochondrial protein of unknown function. In
      Saccharomyces cerevisiae, lack of the yeast frataxin homolog ( YFH1 gene, Yfh1p
      polypeptide) results in mitochondrial iron accumulation, suggesting that frataxin
      is required for mitochondrial iron homeostasis and that FRDA results from
      oxidative damage secondary to mitochondrial iron overload. This hypothesis
      implies that the effects of frataxin deficiency could be influenced by other
      proteins involved in mitochondrial iron usage. We show that Yfh1p interacts
      functionally with yeast mitochondrial intermediate peptidase ( OCT1 gene, YMIP
      polypeptide), a metalloprotease required for maturation of ferrochelatase and
      other iron-utilizing proteins. YMIP is activated by ferrous iron in vitro and
      loss of YMIP activity leads to mitochondrial iron depletion, suggesting that YMIP
      is part of a feedback loop in which iron stimulates maturation of YMIP substrates
      and this in turn promotes mitochondrial iron uptake. Accordingly, YMIP is active
      and promotes mitochondrial iron accumulation in a mutant lacking Yfh1p ( yfh1
      [Delta]), while genetic inactivation of YMIP in this mutant ( yfh1 [Delta] oct1
      [Delta]) leads to a 2-fold reduction in mitochondrial iron levels. Moreover,
      overexpression of Yfh1p restores mitochondrial iron homeostasis and YMIP activity
      in a conditional oct1 ts mutant, but does not affect iron levels in a mutant
      completely lacking YMIP ( oct1 [Delta]). Thus, we propose that Yfh1p maintains
      mitochondrial iron homeostasis both directly, by promoting iron export, and
      indirectly, by regulating iron levels and therefore YMIP activity, which promotes
      mitochondrial iron uptake. This suggests that human MIP may contribute to the
      functional effects of frataxin deficiency and the clinical manifestations of
      FRDA.

PMID- 10332044
TI  - Sialidase-mediated depletion of GM2 ganglioside in Tay-Sachs neuroglia cells.
AB  - Tay-Sachs disease is a severe, inherited disease of the nervous system caused by
      accumulation of the brain lipid GM2 ganglioside. Mouse models of Tay-Sachs
      disease have revealed a metabolic bypass of the genetic defect based on the more
      potent activity of the enzyme sialidase towards GM2. To determine whether
      increasing the level of sialidase would produce a similar effect in human Tay
      Sachs cells, we introduced a human sialidase cDNA into neuroglia cells derived
      from a Tay-Sachs fetus and demonstrated a dramatic reduction in the accumulated
      GM2. This outcome confirmed the reversibility of GM2 accumulation and opens the
      way to pharmacological induction or activation of sialidase for the treatment of
      human Tay-Sachs disease.

PMID- 10332045
TI  - Suppression of a mitochondrial tRNA gene mutation phenotype associated with
      changes in the nuclear background.
AB  - We previously have characterized a pathogenic mtDNA mutation in the tRNAAsn gene.
      This mutation (G5703A) was associated with a severe mitochondrial protein
      synthesis defect and a reduction in steady-state levels of tRNAAsn. We now show
      that, although transmitochondrial cybrids harboring homoplasmic levels of the
      mutation do not survive in galactose medium, several galactose-resistant clones
      could be obtained. These cell lines had restored oxidative phosphorylation
      function and 2-fold higher steady-state levels of tRNAAsn when compared with the
      parental mutant cell line. The revertant lines contained apparently homoplasmic
      levels of the mutation and no other detectable alteration in the tRNAAsn gene. To
      investigate the origin of the suppression, we transferred mtDNA from the
      revertants (143B/206 TK-) to a different nuclear background (143B/207 TK-, 8AGr).
      These new transmitochondrial cybrids became defective once again in oxidative
      phosphorylation and regained galactose sensitivity. However, galactose-resistant
      clones could also be obtained by growing the 8AGr transmitochondrial cybrids
      under selection. Because the original rate of reversion was higher than that
      expected by a classic second site nuclear mutation, and because of the aneuploid
      features of these cell lines, we searched for the presence of chromosomal
      alterations that could be associated with the revertant phenotype. These studies,
      however, did not reveal any gross changes. Our results suggest that modulation of
      the dosage or expression of unknown nuclear-coded factor(s) can compensate for a
      pathogenic mitochondrial tRNA gene mutation, suggesting new strategies for
      therapeutic intervention.

PMID- 10332047
TI  - Novel genetic association between the corneodesmosin (MHC S) gene and
      susceptibility to psoriasis.
AB  - Psoriasis is an inflammatory skin disease of unknown origin, but with a clear
      genetic component. The strongest genetic association has been found with the
      major histocompatibility complex (MHC) region, and specifically between
      susceptibility to familial early onset psoriasis and human leukocyte antigen
      (HLA)-Cw6. The basis of this association of the HLA-C locus with disease
      pathogenesis is, however, not clear, and it is possible that other genes, or a
      combination of genes, in the HLA region are of functional importance. The MHC S
      gene is expressed specifically in keratinocyte differentiation and, being located
      160 kb telomeric of HLA-C, is a plausible candidate gene. We analysed the allelic
      distribution of two polymorphisms in the MHC S gene (at +619 and +1243) in a case
      control association study. We could confirm a significant association between
      psoriasis and HLA-Cw6 [odds ratio (OR) = 7.75]. No association was found between
      disease (or any subtypes) and the MHC S gene polymorphism at position +619,
      despite its close proximity to HLA-C and the strong linkage disequilibrium
      between the loci. However, a significant trend with the rarer allele at MHC S
      (+1243) and psoriasis was detected in the overall data set (OR = 2. 66; P = 2
      [times] 10(-)9). This effect was most pronounced in the type 1a (early onset)
      psoriatics (OR = 3.43). Furthermore, homozygosity for the associated allele at
      MHC S (+1243) increased the risk of disease over that for carriage of HLA-Cw6
      alone (OR = 9. 38), suggesting that allele 2 of MHC S (+1243) provides an
      additional risk in psoriasis susceptibility. The strong association found here,
      coupled with the biological involvement of the MHC S gene product corneodesmosin
      in skin physiology, implicates this locus (or a haplotype across HLA-C and MHC S
      ) in the impaired desquamation characteristic of psoriasis.

PMID- 10332046
TI  - The relative expression of mutated XPB genes results in xeroderma
      pigmentosum/Cockayne's syndrome or trichothiodystrophy cellular phenotypes.
AB  - The human XPB DNA helicase is a subunit of the DNA repair/basal transcription
      factor TFIIH, involved in early steps of the nucleotide excision repair pathway.
      Two distinct clinical phenotypes, xeroderma pigmentosum associated with
      Cockayne's syndrome (XP/CS) and trichothiodystrophy (TTD), can be due to
      mutations in the XPB gene. In the present work, we studied cellular DNA repair
      properties of skin fibro-blasts from two patients mutated in the XPB gene: an
      XP/CS patient cell (XPCS2BA) with a T296C (F99S) transition and a TTD patient
      cell (TTD6VI) exhibiting an A355C (T119P) transversion. Both cells are clearly
      associated with different levels of alterations in their response to UV light. To
      establish the relationship between the relative expression level of these two
      alleles and DNA repair properties, we transfected SV40-transformed XPCS2BA
      (XPCS2BASV) cells with a plasmid (pTTD6VI) carrying the XPB-A355C cDNA and
      examined DNA repair properties after UV irradiation (cell survival, unscheduled
      DNA synthesis and kinetics of photoproduct removal) in stable transfectants. We
      isolated three clones, which express the XPB-A355C gene (Cl-5) or the XPB-T296C
      gene (Cl-14) or both genes (Cl-19). This con-stitutes a model system allowing us
      to correlate the relative expression levels of the XPB-A355C (TTD) and XPB-T296C
      (XP/CS) genes with various DNA repair properties. Overexpression of the XPB-A355C
      (TTD) gene in an XP/CS cell gives rise to a cellular phenotype of increased
      repair similar to that of TTD6VI cells, while equal expression of the two mutated
      genes leads to an intermediate cellular phenotype between XP/CS and TTD.

PMID- 10332048
TI  - Quantitative analysis of polyvinyl alcohol on the surface of poly(D, L-lactide-co
      glycolide) microparticles prepared by solvent evaporation method: effect of
      particle size and PVA concentration.
AB  - Polyvinyl alcohol (PVA) is an emulsion stabilizer that is used in the solvent
      evaporation method for poly(D,L-lactide-co-glycolide) (PLG) microparticles
      preparation. In this study, the surface binding of PVA on PLG microparticles was
      quantitatively examined by employing gel permeation chromatography. The PVA
      binding can affect hydrophobicity and digestibility of the microparticle surface.
      GPC analysis detected the presence of PVA bound on the microparticle surfaces in
      an irreversible manner. The PVA content per weight of microparticle increased
      with the specific surface area as the particle size decreased. The surface PVA
      density, which is the PVA content per unit surface area of microparticle, changed
      with particle size in a biphasic manner. In the size range larger than 1 microm,
      the surface PVA density increased from 0.8 mg/m2 to 2.2 mg/m2 as the particle
      size decreased. But below 1 microm, the surface PVA density remained unchanged at
      about 1.8 mg/m2. The surface PVA density of PLG microparticles prepared in
      different PVA concentrations (0.1, 1, 5, 10% w/v) showed similar values and size
      dependency, indicating that the PVA concentration of the continuous phase did not
      affect the surface PVA density of PLG microparticles. These data suggest that the
      influence of the surface PVA layer would be larger in the smaller particles, but
      be independent of the PVA concentration of the continuous phase in the
      manufacturing process.

PMID- 10332050
TI  - Chemical enhancement of percutaneous absorption in relation to stratum corneum
      structural alterations.
AB  - The outermost layer of the skin, stratum corneum (SC), provides an outstanding
      barrier against the external environment and is also responsible for skin
      impermeability toward most solutes. The barrier function is related to the unique
      composition of the SC lipids and their complex structural arrangement. The
      lipoidal matrix of the SC, therefore, is a target of penetration enhancer action.
      The literature on the skin barrier structure and function and on the mechanisms
      of action of some well established permeation promoters, with a focus on their
      impact on SC structural alterations, is reviewed. Data obtained from infrared,
      thermal, and fluorescence spectroscopic examinations of the SC and its components
      imply enhancer improved permeation of solutes through the SC is associated with
      alterations involving the hydrocarbon chains of the SC lipid components. Data
      obtained from electron microscopy and X-ray diffraction reveals that the
      disordering of the lamellar packing is also an important mechanism for increased
      permeation of drugs induced by penetration enhancers.

PMID- 10332049
TI  - Chronic exposure to HPMA copolymer-bound adriamycin does not induce multidrug
      resistance in a human ovarian carcinoma cell line.
AB  - The influence of free and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer
      bound adriamycin (ADR) on the induction of multidrug resistance in the A2780
      human ovarian carcinoma cell line was studied in vitro. It was found that chronic
      exposure to free ADR led to an increase in resistance to ADR and Taxol and
      overexpression of the MDR1 gene. No significant changes in the expression of the
      MRP gene were found during adaptation to free ADR. In addition to MDR1 gene
      encoded multidrug resistance, a significant increase in the resistance against
      ADR was found before the overexpression of the MDR1 gene was measurable. This non
      P-glycoprotein resistance does not appear to be connected with MRP gene-encoded
      resistance. During adaptation to free ADR, changes in cellular metabolism such as
      increased rate of glucose uptake, oxidation and glycolysis were detected. Adapted
      sensitive A2780 cells expressed the MDR1 gene and possessed almost the same
      decreased sensitivity toward ADR as the ADR-resistant human ovarian carcinoma
      A2780/AD cells. However, they significantly differed in proliferation rate,
      cellular metabolism and MRP gene expression. On the contrary, multidrug
      resistance was not induced after repeated exposure of sensitive A2780 cells to
      HPMA copolymer-bound adriamycin. The cells did not express the MDR1 gene, the
      expression of the MRP gene was partially inhibited, and the resistance against
      Taxol was decreased. Differences were also observed in metabolic changes. In
      summary, the data indicate that, contrary to free ADR, HPMA copolymer-bound ADR
      does not induce multidrug resistance in A2780 cell culture after repeated
      exposure.

PMID- 10332051
TI  - Increased bioavailability of propranolol in rats by retaining thermally gelling
      liquid suppositories in the rectum.
AB  - Mucoadhesive liquid suppositories were prepared by adding mucoadhesive polymers
      (0.6%) to a formulation of thermally gelling suppositories that contained
      poloxamer 407 (15%), poloxamer 188 (15%) and propranolol HCl (2%).
      Hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carbopol, polycarbophil
      and sodium alginate were examined as mucoadhesive polymers. The characteristics
      of the suppositories differed depending on the choice of mucoadhesive polymer.
      For example, the gelation temperature was between 30 and 36 degrees C, the
      mucoadhesive force was between 430 and 5800 dyne/cm2, the apparent first-order
      release rate constant in phosphate buffer, pH 6.8, was between 0.399 and 0.271 h
      1, the migration distance of the suppository in the rectum 4 h after
      administration was between 1 and 5 cm, and the bioavailability of propranolol was
      between 60.9 and 84.7%. Rectal bioavailability increased as the mucoadhesive
      force increased (r=0.984, p<0.0005), and the migration distance decreased (r=
      0.951, p<0.005). No relationship was found between the bioavailability and the
      gelation temperature, drug release or irritation of the rectal mucosal membrane
      by the suppository. Therefore, retaining propranolol at the dosed site in the
      rectum by the addition of appropriate mucoadhesives to the formulation of liquid
      suppositories appears to be a very important factor in avoiding first-pass
      hepatic elimination and thereby increasing the bioavailability of the drug. Among
      the mucoadhesive polymers examined, sodium alginate and polycarbophil exhibited
      the largest mucoadhesive force and the smallest intrarectal migration resulting
      in the largest bioavailability of propranolol (84.7 and 82.3%, respectively). In
      contrast to other polymers, sodium alginate alone caused no irritation of the
      rectal mucosal membrane. Thus, poloxamer liquid suppositories containing sodium
      alginate appears to be a preferred formulation for drugs that are sensitive to
      extensive first-pass metabolism.

PMID- 10332052
TI  - Determining the absolute surface hydrophobicity of microparticulates using thin
      layer wicking.
AB  - Surface hydrophobicity is an important factor in the transport of
      microparticulates (MPs) across biological barriers. We have previously shown in
      our laboratory that the surface properties of polystyrene MPs influence the
      diffusion and transport through gastrointestinal (GI) mucus and mucin.
      Unfortunately, most currently used methods for evaluating the surface
      hydrophobicity of MPs involve a relative measurement resulting in a rank order
      rather than an absolute hydrophobicity value. Obtaining an absolute assessment of
      hydrophobicity is necessary in order to obtain meaningful comparisons and
      correlations across laboratories, polymers, methods of fabrication, and so on. A
      modified thin layer wicking (TLW) technique was developed and validated to allow
      for the determination of absolute surface hydrophobicity of intact MPs. The TLW
      method was validated by constructing a standard curve and comparing the rate of
      solvent rise through MPs dried on microscope slides to the known contact angle of
      PLGA polymers. MPs with surface contact angles ranging between 67.04 degrees and
      90.18 degrees were evaluated using the TLW technique. The modified TLW technique
      was also successfully validated using surface-modified polystyrene and OVA MPs.
      Based on the results of the current study, the modified TLW technique appears to
      be a reliable and quantitative method for assessing the surface hydrophobicity of
      intact MPs.

PMID- 10332053
TI  - Targeting of tumor necrosis factor to tumor by use of dextran and metal
      coordination.
AB  - Tumor targeting of recombinant human tumor necrosis factor alpha (TNF) and
      consequently an enhanced anti-tumor effect were achieved through conjugation with
      dextran having metal chelating, diethylenetriaminepentaacetic acid (DTPA)
      residues based on metal coordination. A simple mixing with the DTPA-dextran in an
      aqueous solution containing Cu2+ enabled TNF to coordinately conjugate to
      dextran. Following intravenous (i.v.) injection into tumor-bearing mice, the TNF
      DTPA-dextran conjugate caused a significantly higher tumor accumulation of TNF
      and the longer retention period than free TNF or its mixture with the DTPA
      dextran. Intravenous injection of the TNF-DTPA-dextran conjugate suppressed tumor
      growth to a significantly greater extent than that of free TNF at a lower
      injection dose. It is concluded that dextran conjugation based on Cu2+
      coordination is a promising way to enhance the anti-tumor effect of TNF as a
      result of its passive tumor targeting.

PMID- 10332054
TI  - Nonparametric analysis of the absorption profile of octreotide in rabbits from
      long-acting release formulation OncoLAR.
AB  - Octreotide (octreotide-acetate, Sandostatin(R)) is a somatostatin analogue, used
      in long-term treatment of acromegaly. The present study describes the absorption
      profile in rabbits of octreotide after release from the long-acting formulation
      OncoLAR (denoted as octreotide-LAR). In a first experiment, the disposition
      kinetics of octreotide was studied for 24 h in six rabbits after intravenous (i.
      v.) injection of 0.025 mg of a solution of octreotide. In a second experiment,
      release kinetics was studied in eight rabbits for 49 days after an i.m. injection
      of 5 mg/kg of octreotide-LAR. Concentrations were determined by radioimmunoassay.
      After i.v. injection of octreotide, one- and two-compartment models were compared
      for each rabbit. A typical disposition profile was computed using the mean
      parameters. After i.m. injection of octreotide-LAR, deconvolution was performed
      using the point-area method. Individual absorption profiles were characterised
      using natural splines. The number of breakpoints was selected using the
      generalised cross-validation criterion. The two compartment model was selected
      based on the i.v. study. After i.m. administration, octreotide exhibited a
      triphasic absorption profile, with large interindividual variability. A transient
      peak followed the initial burst phase. The third phase covered 85% of total drug
      released. The approach allows a model-independent description of the in vivo
      absorption profile of octreotide-LAR.

PMID- 10332055
TI  - Antibiotic release from biodegradable PHBV microparticles.
AB  - For the treatment of periodontal diseases, design of a controlled release system
      seemed very appropriate for an effective, long term result. In this study a
      novel, biodegradable microbial polyester, poly(3-hydroxybutyrate-co-3
      hydroxyvalerate), PHBV of various valerate contents containing a well established
      antibiotic, tetracycline, known to be effective against many of the periodontal
      disease related microorganisms, was used in the construction of a controlled
      release system. Tetracycline was loaded in the PHBV microspheres and
      microcapsules both in its acidic (TC) and in neutral form (TCN). Microcapsules of
      PHBV were prepared under different conditions using w/o/w double emulsion and
      their properties such as encapsulation efficiency, loading, release
      characteristics, and morphological properties were investigated. It was found
      that concentration of emulsifiers polyvinyl alcohol (PVA) and gelatin (varied
      between 0-4%) influenced the encapsulation efficiency appreciably. In order to
      increase encapsulation efficiency (from the obtained range of 18.1-30.1%) and
      slow down the release of the highly soluble tetracycline.HCl, it was neutralized
      with NaOH. Encapsulation efficiency of neutralized tetracycline was much higher
      (51.9-65.3%) due to the insoluble form of the drug used during encapsulation. The
      release behaviour of neither of the drugs was found to be of zero order. Rather
      the trends fitted reasonably well to Higuchi's approach for release from
      spherical micropheres. Biodegradability was not an appreciable parameter in the
      release from microcapsules because release was complete before any signs of
      degradation were observed.

PMID- 10332056
TI  - Controlled release of a model protein from enzymatically degrading dextran
      microspheres.
AB  - Protein-loaded dextran microspheres were prepared by a water-in-water emulsion
      technique. With this technique, an aqueous solution of methacrylated dextran (dex
      MA) is emulsified in an aqueous solution of poly(ethylene glycol) (PEG).
      Subsequently, the dispersed dex-MA phase is crosslinked by radical polymerization
      of the dextran-bound methacryloyl groups. This method renders microspheres with a
      hydrogel character of which the crosslink density can be controlled by the water
      content and the degree of substitution of the dex-MA (DS, the number of
      methacrylates per 100 glucopyranose residues). If an IgG solution was added to
      the dex-MA/PEG aqueous system prior to the polymerization reaction, the protein
      could be encapsulated in the dextran microspheres with a high yield (88-98%). The
      release of IgG was studied as a function of the water content, the DS and the
      degradation rate of the microspheres. The microspheres were rendered degradable
      by co-encapsulation of an endo-dextranase. Non-degrading microspheres mainly
      showed a burst release, which decreased with increasing crosslink density. By
      either a low water content (50%, w/w, or lower) or a high DS (DS 13), it was
      possible to reduce the burst release to about 10%, meaning that almost complete
      entrapment of the protein could be achieved. The release of IgG from degrading
      microspheres was predominantly dependent on the DS and the amount of encapsulated
      dextranase. No differences in release of IgG from microspheres with and without
      dextranase were observed at high DS (DS 13). This was ascribed to the inability
      of the enzyme to degrade these microspheres. On the other hand, the entrapped
      protein was completely released from enzymatically degrading microspheres with a
      DS 4. Moreover, the release rate of IgG was proportional to the degradation rate
      of these microspheres (depending on the amount of co-encapsulated dextranase).
      Interestingly, an almost zero-order release was observed from these microspheres
      for periods up to 30 days.

PMID- 10332058
TI  - In vitro release modulation from crosslinked pellets for site-specific drug
      delivery to the gastrointestinal tract. II. Physicochemical characterization of
      calcium-alginate, calcium-pectinate and calcium-alginate-pectinate pellets.
AB  - Pellets of calcium-alginate, calcium-pectinate and calcium-alginate-pectinate
      were produced via crosslinking in an aqueous medium for site-specific drug
      delivery in the gastrointestinal tract. A comparative study of their
      physicochemical characteristics by means of texture analysis, modulated
      temperature differential scanning calorimetry (MTDSC), scanning electron
      microscopy and swelling dynamics under different pH conditions was undertaken. It
      was found that the incorporation of low methoxylated pectin (i.e., degree of
      methoxylation approximately 35%) together with alginate appears to influence the
      degree of crosslinking and subsequently the physical, mechanical and resilience
      behavior. In general, texture analysis of various pellets indicated that both
      strength and resilience profiles were in the order of calcium-alginate>/=calcium
      alginate-pectinate>calcium-pectinate. Calcium-alginate pellets were found to be
      viscoelastic, while calcium-pectinate was highly brittle. Through the application
      of MTDSC, depolymerization transitions, reversing and non-reversing heat flow
      were determined and interpreted for each formulation. Scanning electron
      microscopy and micro-thermal analysis revealed distinct morphological differences
      in each case. The influence of and nature of crosslinking, and textural
      properties of such pellets on drug release rate modulation is discussed.

PMID- 10332057
TI  - In vitro release modulation from crosslinked pellets for site-specific drug
      delivery to the gastrointestinal tract. I. Comparison of pH-responsive drug
      release and associated kinetics.
AB  - Multiple unit dosage forms for oral delivery of bioactive agents offer many
      advantages over single unit products (e.g., site-specific delivery, predictable
      gastrointestinal transit time and less localized adverse effects). In view of
      such benefits, this paper investigates the crosslinking of sodium alginate, low
      methoxylated pectin and their novel binary mixture with calcium ions through
      ionotropic gelation to pelletize the model drug, diclofenac sodium, using
      "environmentally benign" solvents and processing techniques. Crosslinked pellets
      of the above polymers in 2% (w/v) aqueous calcium chloride solution were prepared
      and evaluated for their structural and release behavior. The average size of the
      different pellets was 1.3 mm and drug entrapment capacity was optimized by
      reducing the calcium chloride solution pH to 1.6. Three types of pellet
      formulations were subjected to dissolution studies using the USP 23 Apparatus 2
      and 3 over a pH range simulating the human gastrointestinal tract. Negligible
      drug release occurred in pH 1-4. However, rate of drug release in pH 6.6 ranged
      from rapid to slow (i. e., 100% drug release in 4 to 10 h, respectively) but
      always in a controlled manner. Weight change/erosion studies and swelling
      measurements were used to provide experimental correlation of kinetic model
      analysis for each of the three pellet systems. From model fitting studies and
      statistical treatment, the modified Hopfenberg equation {Mt/M infinity =1-[1-k1(t
      tL,min)]n} best described the release kinetics for calcium-pectinate pellets. The
      model assumes heterogeneous erosion with kinetic constant k1=k0/C0r0, in which k0
      is the erosion rate constant, C0 is the uniform initial concentration of drug in
      the matrix, r0 is the initial radius and tL, min is the lag time. The n values of
      1, 2 and 3 apply to a slab, cylinder and sphere, respectively. In addition, the
      exponential models, namely the Power Law (Mt/M infinity =k1tn) and its derivative
      containing the lag time [Mt/M infinity =k1(t-tL,min)n], employed in the
      statistical treatment of data provided n values of approximately 0.8-1 in the
      case of the calcium-alginate and calcium-alginate-pectinate release kinetics. It
      is concluded that the proper selection of rate-controlling polymers and their
      interactive potential for crosslinking is important, and will determine the
      overall size and shape of pellets, the duration and pattern of dissolution
      profiles, pH sensitivity, drug loading capacity and mechanism of drug release.

PMID- 10332059
TI  - Detection and determination of surface levels of poloxamer and PVA surfactant on
      biodegradable nanospheres using SSIMS and XPS.
AB  - The surface chemical characterisation of sub-200 nm poly(DL-lactide co-glycolide)
      nanospheres has been carried out using the complementary analytical techniques of
      static secondary ion mass spectrometry (SSIMS) and X-ray photoelectron
      spectroscopy (XPS). The nanospheres, which are of interest for site-specific drug
      delivery, were prepared using an emulsification-solvent evaporation technique
      with poly(vinyl alcohol), Poloxamer 407 and Poloxamine 908 respectively as
      stabilisers. The presence of surfactant molecules on the surface of cleaned
      biodegradable colloids was confirmed and identified on a qualitative molecular
      level (SSIMS) and from a quantitative elemental and functional group analysis
      (XPS) perspective. SSIMS and XPS data were also used in combination with electron
      microscopy to monitor the effectiveness of cleaning procedures in removing poorly
      bound surfactant molecules from the surface of nanospheres. The findings are
      discussed with respect to the development of nanoparticle delivery systems,
      particularly the composition of the surface for extending blood circulation times
      and achieving site-specific deposition.

PMID- 10332060
TI  - Microporous membrane drug delivery system for indomethacin.
AB  - Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) used in the
      treatment of rheumatoid arthritis for more than a decade. The high incidence and
      severity of side effects, which are dose-related and associated with long-term
      administration, have limited its use. This has led to the search for new delivery
      systems which can overcome the side effects by controlling the drug release. In
      this study, Indomethacin Extended Release Formulation was developed by
      pelletization using the method of extrusion/spheronization. The drug containing
      pellets were further coated to achieve the required release profile as per USP.
      Coating systems developed on the principle of microporous membrane drug delivery
      using soluble salt gave the best results.

PMID- 10332061
TI  - Modulating insulin-release profile from pH/thermosensitive polymeric beads
      through polymer molecular weight.
AB  - Stimuli-sensitive statistical terpolymers of N-isopropylacrylamide (NIPAAm)
      (temperature-sensitive), butyl methacrylate (BMA) and acrylic acid (AA) (pH
      sensitive) of various molecular weight (MW) with NIPAAm/BMA/AA feed mol ratio of
      85/5/10 were used to modulate release of insulin, a model protein drug, from
      pH/thermosensitive polymeric beads. Protein drug loading from an aqueous medium
      into the beads was achieved by preparing a 7 or 10% (w/v) polymer solution with
      0.2% (w/v) insulin at low pH and below the lower critical solution temperature
      (LCST) of the polymer (pH 2.0 and 4 degrees C), and then dropping the solution
      into an oil bath above the LCST of the solution (35 degrees C). This loading
      procedure maintained protein stability while achieving high loading efficiency,
      between 90 and 95% in the beads. Insulin-release studies from beads prepared from
      terpolymers of the same composition but increasing MW were performed at pH 2.0
      and 7.4, at 37 degrees C. It was observed that there was negligible loss of
      insulin at pH 2.0 from the beads, indicating no burst effect. At pH 7.4, insulin
      release was seen from all the beads and the release rate was a function of the MW
      of the polymer. The low MW polymeric beads eroded, dissolved and released most of
      the insulin within 2 h at pH 7.4 and 37 degrees C, the intermediate MW polymeric
      beads swelled slightly, dissolved and released most of the insulin within 4 h,
      whereas the high MW polymeric beads swelled slowly and gradually released the
      loaded insulin over a period of 8 h. Thus, the release of protein from the low MW
      polymeric beads is controlled by the rate of dissolution of the polymer, whereas
      the release from the high MW polymeric beads is controlled by swelling of the
      beads and drug diffusion. Studies using fluorescein-labeled insulin revealed that
      insulin was uniformly distributed in the beads regardless of polymer MW. The
      loaded and released insulin were fully bioactive. Based on the described results,
      the low MW polymeric beads may be used for immediate delivery of protein drugs in
      the duodenum, the intermediate MW polymeric beads may be used for lower small
      intestine targeting, while the high MW polymeric beads may be used to target
      protein drugs predominantly to the colon.

PMID- 10332062
TI  - Body distribution in mice of intravenously injected camptothecin solid lipid
      nanoparticles and targeting effect on brain.
AB  - The objective of the present study was to investigate the specific drug targeting
      of anticarcinogenic drugs, such as camptothecin (CA), after intravenous (i.v.)
      injection by incorporation into solid lipid nanoparticles (SLN). A CA loaded SLN
      suspension consisted of 0.1% (w/w) camptothecin, 2.0% (w/w) stearic acid, 1.5%
      (w/w) soybean lecithin and 0.5% (w/w) polyoxyethylene-polyoxypropylene copolymer
      (Poloxamer 188) was prepared by high pressure homogenization. In vitro drug
      release was investigated in pH 7.4 phosphate-buffered saline at 37 degrees C. The
      concentrations of camptothecin in various organs were determined using reversed
      phase high-performance liquid chromatography with a fluorescence detector after
      i.v. administration of CA-SLN and a camptothecin control solution (CA-Sol). The
      results showed that the CA-SLN had an average diameter 196.8 nm with a Zeta
      potential of -69.3 mV and in vitro drug release was achieved for up to a week. In
      tested organs, the AUC/dose and the mean residence times (MRT) of CA-SLN were
      much higher than those of CA-Sol, especially in brain, heart and
      reticuloendothelial cells containing organs. The brain AUC ratio of CA-SLN to CA
      Sol was the highest among the tested organs. These results indicate that SLN are
      a promising sustained release and drug targeting system for lipophilic antitumour
      drugs, and may also allow a reduction in dosage and a decrease in systemic
      toxicity.

PMID- 10332063
TI  - Biodegradable recombinant human erythropoietin loaded microspheres prepared from
      linear and star-branched block copolymers: influence of encapsulation technique
      and polymer composition on particle characteristics.
AB  - Recombinant human erythropoietin (EPO) and fluorescein isothiocyanate labeled
      dextran (FITC-dextran) loaded microspheres were prepared by a modified W/O/W
      double-emulsion technique. Biodegradable linear ABA block copolymers consisting
      of poly(L-lactide-co-glycolide) A blocks attached to central poly(ethyleneoxide)
      (PEO) B blocks and star-branched AB block copolymers containing A blocks of
      poly(L-lactide) or poly(L-lactide-co-glycolide) and star-branched
      poly(ethyleneoxide) B blocks were investigated for their potential as sustained
      release drug delivery systems. Microsphere characteristics were strongly
      influenced by the polymer composition. In the case of the linear block
      copolymers, a reduced lactic acid content in a linear block copolymer yielded
      smaller particles, a lower encapsulation efficiency, and a higher initial drug
      release both in the case of EPO and FITC-dextran. The investigation of the
      effects of several manufacturing parameters on microsphere formation showed that
      the process temperature plays an important role. Microsphere formation in a +1
      degrees C environment resulted in higher drug loadings without increasing the
      amount of residual dichloromethane inside the particles. Other parameters such as
      the homogenization of the primary W/O emulsion and of the W/O/W double-emulsion
      have less impact on microsphere characteristics. Branched block copolymers
      containing star-shaped PEO also showed potential for the preparation of drug
      loaded microspheres. A certain amount of glycolic acid in the copolymer was
      necessary for the successful preparation of non-aggregating microspheres at room
      temperature. Again, the processing temperature strongly affected particle
      characteristics. Microsphere preparation at +1 degrees C allows the formation of
      microspheres from a polymer not containing glycolic acid, a result which could
      not be achieved at room temperature. Moreover, compared to microsphere formation
      at room temperature, the effective FITC-dextran loading was increased. Concerning
      the EPO loaded microspheres, the amount of EPO aggregated was comparable to that
      using the linear ABA polymers. A continuous release of the protein from these
      star-shaped polymers could not be achieved. In conclusion, apart from microsphere
      preparation in a +1 degrees C environment the choice of the polymer represents
      the main factor for a successful entrapment of proteins into biodegradable
      microspheres.

PMID- 10332065
TI  - Mathematical modelling of drug permeation through a swollen membrane.
AB  - This work proposes two different mathematical models (linear and numerical) able
      to simulate the drug permeation through a swollen membrane sandwiched by two
      external layers (trilaminate system). Moreover, a solid drug dissolution
      phenomenon in the donor compartment may be accounted for. Indeed, this is a
      situation that may often occur in permeation experiments. An insufficient
      stirring of the donor and of the receiver volume may give rise to two sandwiching
      layers and the target of a constant drug concentration in the donor compartment
      may be accomplished by putting a solid drug amount in the saturated donor
      solution. The linear model shows the advantage of having an analytical expression
      which extremely simplifies the calculation of the drug diffusion coefficient D
      inside the membrane. Its main drawback lies in the fact that it works only for
      thin trilaminate systems. The numerical model is more general than the linear
      one, as it works for all kind of trilaminate thickness and it may account for a
      solid powder dissolution in the donor compartment. Of course, it does not have an
      analytical solution and, thus, the D determination is less easy to perform as the
      numerical model is more time consuming than the linear one. These two models are
      then compared with the classical approach developed by Flynn and Barrie in order
      to better define its validity limits.

PMID- 10332064
TI  - Identification of critical formulation and processing variables for metoprolol
      tartrate extended-release (ER) matrix tablets.
AB  - The objective of this study, was to examine the influence of critical formulation
      and processing variables as described in the AAPS/FDA Workshop II report on scale
      up of oral extended-release dosage forms, using a hydrophilic polymer
      hydroxypropyl methylcellulose (Methocel K100LV). A face-centered central
      composite design (26 runs+3 center points) was selected and the variables studied
      were: filler ratio (lactose:dicalcium phosphate (50:50)), polymer level
      (15/32.5/50%), magnesium stearate level (1/1.5/2%), lubricant blend time (2/6/10
      min) and compression force (400/600/800 kg). Granulations (1.5 kg, 3000 units)
      were manufactured using a fluid-bed process, lubricated and tablets (100 mg
      metoprolol tartrate) were compressed on an instrumented Manesty D3B rotary tablet
      press. Dissolution tests were performed using USP apparatus 2, at 50 rpm in 900
      ml phosphate buffer (pH 6.8). Responses studied included percent drug released at
      Q1 (1 h), Q4, Q6, Q12. Analysis of variance indicated that change in polymer
      level was the most significant factor affecting drug release. Increase in
      dicalcium phosphate level and compression force were found to affect the percent
      released at the later dissolution time points. Some interaction effects between
      the variables studied were also found to be statistically significant. The drug
      release mechanism was predominantly found to be Fickian diffusion controlled
      (n=0.46-0.59). Response surface plots and regression models were developed which
      adequately described the experimental space. Three formulations having slow-,
      medium- and fast-releasing dissolution profiles were identified for a future
      bioavailability/bioequivalency study. The results of this study provided the
      framework for further work involving both in vivo studies and scale-up.

PMID- 10332066
TI  - Evaluation of colonic absorbability of drugs in dogs using a novel colon-targeted
      delivery capsule (CTDC).
AB  - A series of dog studies were performed to examine the in vitro/in vivo
      relationship of drug release behavior of the newly developed colon-targeted
      delivery capsule (CTDC). The four kinds of CTDCs containing theophylline, each of
      which has a different in vitro dissolution lag time, were orally administered to
      four beagle dogs under fasted condition, and the onset times of drug absorption
      were compared. The CTDC with longer in vitro lag time had a later onset of drug
      absorption. It was also found that the time difference between the gastric
      emptying and the onset of drug absorption was almost equal to the in vitro
      dissolution lag time of the capsule, suggesting a similar performance of CTDC in
      the gastrointestinal tract. From the comparison to the absorption behavior of the
      colon arrival marker, i.e. sulfasalazine, it was proved that the CTDC with the
      lag time of 3 h can deliver the drug directly to the colon. This result implied
      that the CTDC can be used as a non-invasive means for assessing the regional
      absorbability of drugs in the gastrointestinal tract. To evaluate the
      absorbability of drugs in the colon, three model drugs, theophylline (THEO),
      acetaminophen (ACET), and phenylpropanolamine hydrochloride (PPA) were directly
      delivered to the colons of beagle dogs using the CTDC with the lag time of about
      3 h. The obtained relative bioavailabilities to the solution form were as high as
      94.2%, 71.0%, and 91.5% for THEO, ACET and PPA, respectively, suggesting that the
      colonic absorbability of those drugs is essentially good.

PMID- 10332067
TI  - Encapsulation of rotavirus into poly(lactide-co-glycolide) microspheres.
AB  - Two small-scale double emulsion techniques for incorporation of formaldehyde
      inactivated rotavirus particles (FRRV) into poly(lactide-co-glycolide) (PLG)
      microspheres were developed and optimised. The effects of high-speed
      homogenisation versus vortex mixing on the double emulsion stability, microsphere
      size, entrapment efficiency and in vitro release of FRRV in the second
      emulsification step were studied. A stable double emulsion was verified only when
      using vortex mixing in this step. Slow removal of the organic phase allowed
      measurement of the size of the emulsion droplets and subsequent prediction of the
      size of the resulting microspheres. Microspheres in the size range of 1-10 microm
      were prepared using both techniques. The homogenisation technique was sensitive
      to changes in the operating time, the emulsification energy and the volume of the
      outer aqueous phase, while the vortex technique was more robust. Rotavirus was
      released in vitro in a triphasic manner with both techniques. The more robust
      vortex technique was selected for preparation of PLG microspheres containing
      rotavirus for in vivo studies. After immunisation of mice with a single
      intramuscular injection, the PLG-FRRV microspheres elicited an IgG antibody
      response in serum detected by ELISA equally high as that elicited with FRRV
      alone. These results indicate that the antigenicity of FFRV was retained after
      incorporation into PLG microspheres using the vortex technique.

PMID- 10332068
TI  - How interactions between drugs and agarose-carrageenan hydrogels influence the
      simultaneous transport of drugs.
AB  - The diffusional transport of a series of small drug molecules (<400 Da) in
      agarose gel with and without kappa-carrageenan (a negatively charged
      polysaccharide) is studied. The drug molecules have amphiphile character, the
      hydrophilic part being a tertiary amine which is the same in all six drugs. The
      difference in structure resides in the hydrophobic part which give these
      molecules different properties such as a difference in CMC-values (critical
      micelle concentration). The transport studies show that the apparent diffusion
      coefficients (Dapp) of all the drugs in 1% (w/w) agarose gel are almost identical
      and with a value similar to that in water. These results were anticipated because
      of the small size of the drugs, the low concentration of agarose, and the lack of
      interaction between the diffusant and the polymer. In agarose gels also
      containing 0.02% (w/w) kappa-carrageenan, however, the Dapp-values are
      significantly decreased for all drugs, except for lidocaine. This lowering of the
      Dapp is ascribed to the interaction between the drug molecules and kappa
      carrageenan. The Dapp-values of the drugs in the gel system containing kappa
      carrageenan correlate well with the adsorption isotherms of the same drugs in the
      drug/kappa-carrageenan/water system obtained previously [1] and the Dapp-values
      follow the order: chlorpromazine<clomipramine<amitriptyline<imipramine<doxepin.
      Chlorpromazine has the lowest Dapp, with the highest degree of adsorption, and
      doxepin with the lowest degree of adsorption has the highest Dapp. Furthermore,
      results from the simultaneous transport of two drugs, chlorpromazine and
      amitriptyline, in the agarose gel containing kappa-carrageenan are also presented
      and clearly indicate a transport competition with good correlation to the
      adsorption isotherms.

PMID- 10332069
TI  - Intranasal absorption of melatonin in vivo bioavailability study.
AB  - The bioavailability of melatonin in rabbits after nasal administration of two
      formulations has been studied. In each case, a total amount of 1.5 mg melatonin
      in 50 microl was administered and compared with 1.5 mg i.v. The test solutions
      were formulated with 40% polyethylene glycol 300 (PEG 300), one with 1% sodium
      glycocholate (+GC) and one without (-GC). The bioavailability for +GC was 94%
      (S.D.+/-29%, n=4), whereas the bioavailability for -GC was 55% (S.D.+/-17%, n=6).
      These results indicate that GC has an enhancer effect (P<0.05). However, the
      relatively high bioavailability without GC shows that it might not be necessary
      to use an enhancer for a clinical relevant formulation. The pharmacokinetics of
      melatonin could be described by a one-compartment model, and the serum half-life
      was about 13 min. The absorption rate for both formulations was very fast (tmax=5
      min) and Cmax mean was 493+/-290 ng/ml (n=4) and 249+/-125 ng/ml (n=6) for +GC
      and -GC, respectively.

PMID- 10332070
TI  - Pharmaceutical grade phyllosilicate dispersions: the influence of shear history
      on floc structure.
AB  - The effect of mixing conditions on the flow curves of some clay-water dispersions
      was studied. Two Spanish fibrous phyllosilicates (sepiolite from Vicalvaro and
      palygorskite from Turon) and a commercial bentonite (Bentopharm Copyright, UK)
      were selected as model clays. The disperse systems were made up using a rotor
      stator mixer working at two different mixing rates (1000 and 8000 rpm), for
      periods of 1 and 10 min. Rheological measurements were taken and the
      corresponding flow curves obtained immediately after interposition and then after
      a period of 24 h under low shear caused by a roller apparatus. Aqueous sepiolite
      dispersions showed the highest viscosity and were easily interposed, whereas
      palygorskite dispersions were more difficult to obtain, resulting in low to
      medium viscosity gels. Bentonite dispersions provided medium viscosity systems,
      which greatly increased their viscosity after the low shear treatment (as a
      result of swelling), whereas the viscosity of the fibrous clays stayed at
      approximately the same values or even decreased. A linear relation was found
      between mixing energy and apparent viscosity in the bentonite systems, while
      apparent viscosity in the sepiolite samples was related to mixing power, with
      minor influence of mixing times. All the systems studied had thixotropic
      behaviour, changing from clearly positive to even negative thixotropy in some
      palygorskite systems. Finally, we studied the effect of drastic pH changes on the
      system structure. Results showed that rheological properties were highly
      sensitive to pH in the fibrous dispersions, but less sensitive behaviour was
      found in the laminar clay systems.

PMID- 10332071
TI  - Effect of chitosan on epithelial permeability and structure.
AB  - Numerous studies have shown that chitosan, a mucoadhesive polymer, is a potential
      enhancer for transmucosal drug delivery. To further understand the mechanisms
      involved in chitosan action on the mucosal barrier, the activity of chitosan on
      the function and structure of monolayers of intestinal epithelial cells was
      investigated. In Caco-2 cells, chitosan caused a reversible, time and dose
      dependent decrease in transepithelial electrical resistance. The effect of
      chitosan on tight junctions was confirmed by an increased permeability
      coefficient for mannitol transport when cells were treated with 0.1-0.5% w/v
      chitosan solution for 60 min compared to control cells. Involvement of tight
      junctions was visualized by confocal scanning microscopy using occludin and ZO-1,
      tight junctional proteins. Following an incubation with 0.01 or 0.1% w/v
      chitosan, labeling of both proteins varied in localization and decreased in
      fluorescent intensity at the cell periphery. In addition, a focal condensation of
      actin was observed preferentially at areas of cell-to-cell contacts. However,
      after 24-h recovery, the cell structure resembled untreated control cells.
      Simultaneous addition of cycloheximide, a protein synthesis inhibitor, prevented
      full recovery. This implied that protein synthesis was required for the cells to
      return to baseline levels. Chitosan treatment appeared to slightly perturb the
      plasma membrane as assessed by an increased release of lactate dehydrogenase.
      However, addition of 0.5% chitosan for 60 min did not affect cell viability as
      shown by Trypan blue dye exclusion. These data suggest that chitosan increases
      cell permeability by affecting paracellular and intracellular pathways of
      epithelial cells, in a reversible manner.

PMID- 10332072
TI  - Micronization of drugs using supercritical carbon dioxide.
AB  - Particles from gas saturated solutions, a novel method for high pressure material
      processing, has been used for micronization of practically insoluble calcium
      channel blockers nifedipine and felodipine and the hypolipidemic agent
      fenofibrate with the aim of increasing their dissolution rate and hence their
      bioavailability. Dependent on the pre-expansion conditions, a mean particle size
      of between 15 and 30 microm was achieved for micronized nifedipine and 42 microm
      for micronized felodipine. The particle size of processed fenofibrate, on the
      other hand, increased due to agglomeration. The highest dissolution rate was
      achieved by preparation of drug coprecipitates with PEG 4000.

PMID- 10332073
TI  - Topical delivery of caffeine from some commercial formulations.
AB  - Permeation of caffeine through human skin and artificial membranes (mounted in
      modified Franz type diffusion cells) was evaluated, either from saturated
      solutions or from commercially available topical formulations (all containing 3%
      caffeine). Data interpretation of the caffeine diffusion through human skin does
      not implicate transfer through pores despite caffeine being a relatively polar
      molecule. No correlation was found between transfer though the synthetic
      membranes (cellulose acetate impregnated with isopropyl myristate and silicone
      rubber soaked in isopropyl myristate) and that observed through skin. The
      synthetic membranes can be used for assessing product performance in quality
      assurance but will give little indication of its performance in vivo. The study
      investigated the percutaneous permeation of caffeine through human skin in order
      to obtain a mechanistic interpretation of its route of permeation. Synthetic
      membranes were also examined to determine if they could be used as models for
      human skin. Different commercial formulations investigated to determine the
      significance of enhancement strategies.

PMID- 10332074
TI  - Cellular delivery of hammerhead ribozymes conjugated to a transferrin receptor
      antibody.
AB  - Chemically-modified hammerhead ribozymes are sequence-specific RNA enzymes that
      can cleave target mRNA. These molecules have potential application as biological
      tools to understand gene expression and as therapeutic agents for the selective
      down-regulation of genes implicated in disease. However, as a result of their
      polyanionic character and relatively large molecular weights, ribozyme delivery
      to target cells is relatively inefficient. Using nuclease resistant 2'-O-methyl
      modified ribozymes targeting the c-erbB1 oncogene, we have evaluated the
      potential use of human monoclonal transferrin-receptor antibody (TRA)-ribozyme
      conjugates for the improved delivery of ribozymes to A431 tumour cells. A 37-mer
      ribozyme derivatized with a free thiol-group at the 5'-end and bearing an
      internal [32P]-radiolabel was conjugated to either TRA or a non-specific IgG
      antibody using the heterobifunctional crosslinker, succinimidyl 4-(maleimido
      methyl)cyclohexane-1-carboxylate (SMCC). Up to six molecules of the ribozyme
      could be conjugated to one molecule of antibody. Cellular uptake studies in
      cultured human epidermoid A431 carcinoma cells showed that approximately a three
      fold increase in cellular association could be obtained with the TRA-ribozyme
      conjugate compared to the free ribozyme. Cellular association of the conjugate
      was temperature-dependent and was inhibited by competition with excess free
      transferrin receptor antibody implying that conjugate uptake was consistent with
      the transferrin receptor-mediated endocytosis pathway. Treatment of cells with
      monensin further enhanced TRA-ribozyme conjugate cell association indicating that
      ribozyme delivery of conjugates may be further improved by strategies that
      modulate vesicular trafficking in cells.

PMID- 10332076
TI  - Water movement evaluation during extrusion of wet powder masses by collecting
      extrudate fractions.
AB  - Water is normally the liquid of choice in extrusion/spheronisation systems. Its
      behaviour during the process is crucial to its success. In most extrusion
      formulations water moves under the pressures involved. It is important to
      understand how to control and limit water movement, and to understand its
      consequences. Five drug models were mixed with microcrystalline cellulose and
      with three different ratios of water and extruded at two different speeds using a
      ram extruder. Whilst extruding, the extrudates were collected to small fractions
      and dried to constant weight. Different parameters were calculated to quantify
      the extent of water movement that occurred. The same formulations were also
      extruded and than spheronised to pellets, for which size and shape factor were
      measured. The correlation between water level and extrusion force at the same
      given time was calculated. It was found that at the faster speed and in the
      wettest formulation there was less water movement. A significant correlation was
      found between extrusion force and water going through the die. The
      extrusion/spheronisation technique was found to be tolerant to some extent of
      water movement during the extrusion process. Nevertheless, excessive water
      movement is not appropriate.

PMID- 10332075
TI  - Solid lipid nanoparticles as carriers of hydrocortisone and progesterone
      complexes with beta-cyclodextrins.
AB  - Inclusion complexes of hydrocortisone and progesterone were formed with beta
      cyclodextrin or 2-hydroxypropyl-beta-cyclodextrin. The formation of the complexes
      was confirmed by differential scanning calorimetry (DSC). The inclusion complexes
      were incorporated in two types of solid lipid nanoparticles (SLN). In the
      presence of the complexes the sizes of SLN remained below 100 nm. DSC analysis
      showed that hydrocortisone and progesterone are dispersed in SLN in an amorphous
      state. Using the beta-cyclodextrin complexes the incorporation of the more
      hydrophilic drug, hydrocortisone, was higher than that of progesterone. Release
      of hydrocortisone and progesterone from SLN was lower when they were incorporated
      as inclusion complexes than as free molecules.

PMID- 10332077
TI  - The in vitro evaluation of polyethylene glycol esters of hydrocortisone 21
      succinate as ocular prodrugs.
AB  - The rate of hydrolysis of polyethylene glycol esters of hydrocortisone 21
      succinate (H-PEGs) rate by a commercial esterase and by enzymes from ovine cornea
      was studied. Both the commercial esterase and the corneal enzymes rapidly
      hydrolysed the H-PEGs. Both lipophilicity and the PEG chain length had an
      influence on the rate of enzymatic hydrolysis, a significant decrease in
      enzymatic hydrolysis rate being associated with an increase in the polymer chain
      length. The in vitro penetration of H-PEGs across ovine cornea and sclera was
      assessed. In corneal penetration studies no prodrug was detected in the receiver
      phase while in the sclera penetration study both drug and prodrug were detected.
      Results from in vitro corneal and scleral absorption studies showed that the use
      of H-PEG400 increased the rate at which hydrocortisone diffused through excised
      ovine cornea compared to the use of hydrocortisone itself, particularly when the
      donor phase was removed after 15 min in order to mimic the situation in vivo. In
      addition, H-PEG200, H-PEG400, H-PEG600, H-PEG900 and H-PEG2000 gave a significant
      increase in the rate of diffusion of hydrocortisone+H-PEG through the sclera
      compared to hydrocortisone itself. Our results on ovine eye show that the rate of
      diffusion of hydrocortisone across the sclera is about six times higher than that
      in cornea and for the H-PEGs the scleral diffusion was 10-100 times higher than
      that observed in the cornea.

PMID- 10332078
TI  - A method using biodegradable polylactides/polyethylene glycol for drug release
      with reduced initial burst.
AB  - Post-coating of biodegradable polylactides (PLA)/polyethylene glycol (PEG)
      microspheres with a gelatin film produced by dipping the microspheres into a
      gelatin solution to reduce the initial drug release burst was investigated.
      Biodegradable block PLA/PEG microspheres, prepared by w/o emulsion/solvent
      evaporation, showed that the hydrophilic segment PEG protruded to the sphere
      surface. However, these microspheres also showed a large burst release in the
      initial period. Post-coating of the PLA/PEG microspheres with a gelatin film by
      dipping the microspheres into a dilute gelatin solution effectively inhibited the
      initial burst release rate in the drug release tests. Post-coating of gelatin
      reduced 98% of the burst release. With thicker coatings, there were slower
      releasing rates, and the release rate can be simply related to the coating
      thickness.

PMID- 10332079
TI  - A high sensitivity differential scanning calorimetry study of the interaction
      between poloxamers and dimyristoylphosphatidylcholine and
      dipalmitoylphosphatidylcholine liposomes.
AB  - High sensitivity differential scanning calorimetry (HSDSC) has been used to
      measure the thermal behaviour of dimyristoylphosphatidylcholine (DMPC) and
      dipalmitoylphosphatidylcholine (DPPC) liposomes to which poloxamer surfactants
      P338 or P407 had been added during or after preparation. The phospholipid pre
      transition was more sensitive than the main transition to the association of
      poloxamers with liposomal bilayers. Poloxamers reduced the enthalpy of the pre
      transition of liquid-crystalline state DMPC and DPPC MLVs but not that of gel
      state DPPC MLVs. Freezing and thawing DMPC and DPPC liposomes in the presence of
      poloxamers was shown to increase their interaction with the liposomal bilayers.

PMID- 10332080
TI  - Drug interactions with diosmectite: a study using the artificial stomach-duodenum
      model.
AB  - Drug interactions with diosmectite, a gastric-protective drug, were studied in
      vitro using an artificial stomach-duodenum model. The behavior of neutral and
      ionisable drugs with pKa values ranging between 2 and 8 was monitored to
      determine the physicochemical characteristics of the interactions. The main
      neutral (digoxin) and acid (valproic acid) drug substances were moderately fixed
      by clay (<27%), in a pH-independent manner. Basic compounds with a pKa<7
      (dapsone, metronidazole, cimetidine) were strongly fixed in acid medium (?62%),
      and fully released under neutral conditions. Amphoteric (fluoroquinolones) and
      basic compounds with a pKa>/=7 (ranitidine, pyrimethamine) were adsorbed by more
      than 81% by diosmectite in gastric and duodenal compartments. In the part of the
      model representing the distal duodenum, the potential site for drug absorption,
      only the active substances which remained positively charged (amphoteric and
      basic compounds) showed a large reduction (>/=80%) in their available free
      fraction. Ionisation of drug substances administered per os concomitantly with
      diosmectite plays a crucial role in these interactions.

PMID- 10332081
TI  - Formulation and in vivo evaluation of ocular insert containing phenylephrine and
      tropicamide.
AB  - A Gelfoam based ocular device containing 1.7 mg of phenylephrine and 0.6 mg of
      tropicamide was formulated and evaluated for pupillary dilation in rabbits. The
      manufacturing procedure is fairly simple and the required excipients are
      inexpensive. The in vivo results show that the mydriatic response produced by the
      proposed device is larger and longer lasting than that produced by eyedrops with
      an equivalent amount of phenylephrine and tropicamide. The results reported in
      this study, along with those of previous studies, imply that Gelfoam(R) is a
      versatile drug carrier for either local or systemic drug delivery via the
      ophthalmic route.

PMID- 10332082
TI  - The glow of the colonic pH microclimate kindled by short-chain fatty acids,
      chloride and bicarbonate.

PMID- 10332083
TI  - Autonomic integration: the physiological basis of cardiovascular variability.

PMID- 10332084
TI  - Aquaporin water channels in gastrointestinal physiology.
AB  - Fluid transport is a major function of the gastrointestinal (GI) tract with more
      than 9 litres of fluid being absorbed or secreted across epithelia in human
      salivary gland, stomach, the hepatobiliary tract, pancreas, small intestine and
      colon. This review evaluates the evidence that aquaporin-type water channels are
      involved in GI fluid transport. The aquaporins are a family of small (
      approximately 30 kDa) integral membrane proteins that function as water channels.
      At least seven aquaporins are expressed in various tissues in the GI tract: AQP1
      in intrahepatic cholangiocytes, AQP4 in gastric parietal cells, AQP3 and AQP4 in
      colonic surface epithelium, AQP5 in salivary gland, AQP7 in small intestine, AQP8
      in liver, pancreas and colon, and AQP9 in liver. There are functional data
      suggesting that some GI cell types expressing aquaporins have high or regulated
      water permeability; however, there has been no direct evidence for a role of
      aquaporins in GI physiology. Recently, transgenic mice have been generated with
      selective deletions of various aquaporins. Preliminary evaluation of GI function
      suggests a role for AQP1 in dietary fat processing and AQP4 in colonic fluid
      absorption. Further study of aquaporin function in the GI tract should provide
      new insights into normal GI physiology and disease mechanisms, and may yield
      novel therapies to regulate fluid movement in GI diseases.

PMID- 10332085
TI  - Protein kinase C activators induce membrane retrieval of type II Na+-phosphate
      cotransporters expressed in Xenopus oocytes.
AB  - 1. The rate of inorganic phosphate (Pi) reabsorption in the mammalian kidney is
      determined by the amount of type II sodium-coupled inorganic phosphate (Na+-Pi)
      cotransport protein present in the brush border membrane. Under physiological
      conditions, parathyroid hormone (PTH) leads to an inhibition of Na+-Pi
      cotransport activity, most probably mediated by the protein kinase A (PKA) and/or
      C (PKC) pathways. 2. In this study, PKC-induced inhibition of type II Na+-Pi
      cotransport activity was characterized in Xenopus laevis oocytes using
      electrophysiological and immunodetection techniques. Transport function was
      quantified in terms of Pi-activated current. 3. Oocytes expressing the type IIa
      rat renal, type IIb flounder renal or type IIb mouse intestinal Na+-Pi
      cotransporters lost > 50 % of Pi-activated transport function when exposed to the
      PKC activators DOG (1,2-dioctanoyl-sn-glycerol) or PMA (phorbol 12-myristate 13
      acetate). DOG-induced inhibition was partially reduced with the PKC inhibitors
      staurosporine and bisindolylmaleimide I. Oocytes exposed to the inactive phorbol
      ester 4alpha-PDD (4alpha-phorbol 12,13-didecanoate) showed no significant loss of
      cotransporter function. 4. Oocytes expressing the rat renal Na+-SO42-
      cotransporter alone, or coexpressing this with the type IIa rat renal Na+-Pi
      cotransporter, showed no downregulation of SO42--activated cotransport activity
      by DOG. 5. Steady-state and presteady-state voltage-dependent kinetics of type II
      Na+-Pi cotransporter function were unaffected by DOG. 6. DOG induced a decrease
      in membrane capacitance which indicated a reduction in membrane area, thereby
      providing evidence for PKC-mediated endocytosis. 7. Immunocytochemical studies
      showed a redistribution of type II Na+-Pi cotransporters from the oolemma to the
      submembrane region after DOG treatment. Surface biotinylation confirmed a DOG
      induced internalization of the transport protein. 8. These findings document a
      specific retrieval of exogenous type II Na+-Pi cotransporters induced by
      activation of a PKC pathway in the Xenopus oocyte.

PMID- 10332086
TI  - New roles for RGS2, 5 and 8 on the ratio-dependent modulation of recombinant GIRK
      channels expressed in Xenopus oocytes.
AB  - 1. The activation of G protein-regulated inward rectifying potassium (GIRK)
      channels is modulated by G protein-coupled receptors (GPCRs) via the G protein
      betagamma subunits and is accelerated by regulators of G protein signalling
      (RGS). In the present study we investigated the ratio dependence of receptor
      mediated activation and deactivation and the influence of new members of the RGS
      protein family on GIRK currents by coexpressing the recombinant protein subunits
      in Xenopus oocytes and further analysis of the whole cell currents. 2. The
      activation of GIRK channels by the muscarinic acetylcholine receptor M2 (M2
      mAChR) is strongly dependent on the ratio of receptor to channel in Xenopus
      oocytes. The increase and on-rate of the amplified current is affected by this
      ratio. An excess of receptor over channel is necessary for current amplification,
      while the reverse excess of channel over receptor abolishes the effect. 3. The
      speed of receptor-mediated activation of GIRK currents is accelerated for a high
      ratio of receptor to channel, while the time of deactivation is independent of
      this ratio. 4. Coexpression of RGS2, 5 and 8 accelerates the speed for ACh
      mediated activation and deactivation of GIRK1/2 and GIRK1/4 currents. Thereby the
      receptor/channel/RGS ratio determines the amount of current amplification. 5.
      Bordetella pertussis toxin completely abolished ACh-mediated current
      amplification of GIRK channels coexpressed with or without RGS2. 6. Two single
      point mutations in the RGS2 protein (RGS2(N109S) and RGS2(L180F)) reduced the
      acceleration of current amplification after ACh application on GIRK1/4 channels
      compared with RGS2 wild-type protein.

PMID- 10332087
TI  - Current modulation and membrane targeting of the calcium channel alpha1C subunit
      are independent functions of the beta subunit.
AB  - 1. The beta subunits of voltage-sensitive calcium channels facilitate the
      incorporation of channels into the plasma membrane and modulate calcium currents.
      In order to determine whether these two effects of the beta subunit are
      interdependent or independent of each other we studied plasma membrane
      incorporation of the channel subunits with green fluorescent protein and
      immunofluorescence labelling, and current modulation with whole-cell and single
      channel patch-clamp recordings in transiently transfected human embryonic kidney
      tsA201 cells. 2. Coexpression of rabbit cardiac muscle alpha1C with rabbit
      skeletal muscle beta1a, rabbit heart/brain beta2a or rat brain beta3 subunits
      resulted in the colocalization of alpha1C with beta and in a marked translocation
      of the channel complexes into the plasma membrane. In parallel, the whole-cell
      current density and single-channel open probability were increased. Furthermore,
      the beta2a isoform specifically altered the voltage dependence of current
      activation and the inactivation kinetics. 3. A single amino acid substitution in
      the beta subunit interaction domain of alpha1C (alpha1CY467S) disrupted the
      colocalization and plasma membrane targeting of both subunits without affecting
      the beta subunit-induced modulation of whole-cell currents and single-channel
      properties. 4. These results show that the modulation of calcium currents by beta
      subunits can be explained by beta subunit-induced changes of single-channel
      properties, but the formation of stable alpha1C-beta complexes and their
      increased incorporation into the plasma membrane appear not to be necessary for
      functional modulation.

PMID- 10332088
TI  - Comparison of glycine and GABA actions on the zebrafish homomeric glycine
      receptor.
AB  - 1. Glycine and GABA can be co-released from the same presynaptic terminals and in
      lower vertebrates they can activate the same glycine receptors (GlyRs). Thus we
      examined the effects of these two inhibitory transmitters on the homomeric GlyRs
      formed by the alphaZ1 subunit, of the zebrafish using two expression systems:
      Xenopus oocytes and the human BOSC 23 cell line. 2. The apparent affinity (EC50)
      of alphaZ1 for these neurotransmitters was highly variable. In Xenopus oocytes
      the EC50 ranged from 37 to 360 microM (mean +/- s. d. EC50 116 +/- 75 microM, n =
      83) for glycine and from 8 to 120 mM (mean EC50 40 +/- 30 mM, n = 37) for GABA.
      3. In BOSC cells the EC50 varied from 9 to 92 microM (mean EC50 33 +/- 17 microM,
      n = 19) and from 0.7 to 19.1 mM (mean EC50 4.9 +/- 4.7 mM, n = 29) for glycine
      and GABA, respectively. 4. GABA activated alphaZ1 GlyRs either as a weak or full
      agonist: its efficacy (defined as Imax,GABA/Imax,Gly) was related to EC50 by an
      exponential relationship. A linear relationship was observed between EC50 values
      for GABA and glycine. 5. In outside-out patches, GABA and glycine activated
      alphaZ1 with identical single-channel conductances (85-100 pS), but with
      different kinetics and marked effect of concentration on burst duration for
      glycine only. 6. In outside-out patches deactivation time constants were
      concentration dependent for glycine, but not for GABA. 7. Our data demonstrate
      that the kinetics of glycine and GABA interactions with alphaZ1 are different and
      that they determine the properties of these neurotransmitter actions on the GlyR.

PMID- 10332089
TI  - G protein-activated inwardly rectifying K+ (GIRK) currents in dendrites of rat
      neocortical pyramidal cells.
AB  - 1. We performed patch-clamp recordings on acutely isolated dendritic segments and
      cell somata of rat neocortical pyramidal neurons to determine and compare the
      relative density of G protein-activated K+ (GIRK) currents in the two cellular
      compartments. 2. Hyperpolarizing voltage ramps and elevation of extracellular K+
      concentration to 40 mM served to identify inwardly rectifying K+ currents. Near
      saturating concentrations of adenosine (100 microM), baclofen (20 microM) and
      serotonin (20 microM) all produced robust GIRK currents in cell somata as well as
      in dendritic segments that were completely abolished by Ba2+ (200 microM). In
      addition to agonist-activated GIRK currents, both somata and dendrites displayed
      a constitutive Ba2+-sensitive inward rectification. 3. In order to compare the
      relative strengths of GIRK current responses in the two compartments, GIRK
      conductance was normalized to surface area. In contrast to intrinsic, G protein
      independent inward rectification, which was comparable in size in the two
      compartments, all three agonists evoked significantly larger GIRK conductances in
      dendrites than in somata. 4. Our data suggest that several neurotransmitters
      might employ GIRK currents as a tool to directly modulate the electrical
      properties of dendrites. In concert with voltage-dependent K+ currents and the
      hyperpolarization-activated cation current (Ih) of the dendrite, GIRK currents
      should dampen dendritic excitability and thus influence various aspects of
      dendritic signal integration.

PMID- 10332090
TI  - K+ channel modulation in rodent neurohypophysial nerve terminals by sigma
      receptors and not by dopamine receptors.
AB  - 1. Sigma receptors bind a diverse group of chemically unrelated ligands,
      including pentazocine, apomorphine (a dopamine receptor agonist) and haloperidol
      (a dopamine receptor antagonist). Although sigma binding sites are widely
      distributed, their physiological roles are poorly understood. Here, the whole
      terminal patch-clamp technique was used to demonstrate that sigma receptors
      modulate K+ channels in rodent neurohypophysis. 2. Previous work suggested that
      dopamine type 4 (D4) receptors modulate neurohypophysial K+ current, so this
      study initially tested the role of dopamine receptors. Experiments using
      transgenic mice lacking D2, D3 or D4 receptors indicated that the reduction of K+
      current by PPHT and U101958 (ligands thought to be selective for dopamine
      receptors) is not mediated by dopamine receptors. The sensitivity of the response
      to U101958 (a drug that binds to D4 receptors) was the same in both wild-type and
      D4 receptor-deficient mice. 3. Experiments with other ligands revealed a
      pharmacological signature inconsistent with any known dopamine receptor.
      Furthermore, dopamine itself (at 100 microM) had no effect. Thus, despite the
      activity of a number of putative dopamine receptor ligands, dopamine receptors
      play no role in the modulation of neurohypophysial K+ channels. 4. Because of the
      negative results regarding dopamine receptors, and because some of the dopamine
      receptors ligands used here are known to bind also to sigma receptors,
      experiments were conducted to test for the involvement of sigma receptors. In rat
      neurohypophysis the sigma receptor ligands SKF10047, pentazocine, and
      ditolylguanidine all reversibly inhibited K+ current in a concentration-dependent
      fashion, as did haloperidol and apomorphine (ligands that bind to both dopamine
      and sigma receptors). The activity of these and other ligands tested here matches
      the reported binding specificity for sigma receptors. 5. Fifteen candidate
      endogenous sigma receptor ligands, including biogenic amines (e.g dopamine and
      serotonin), steroids (e.g. progesterone), and peptides (e.g. neuropeptide Y),
      were screened for activity at the sigma receptor. All were without effect. 6.
      Haloperidol reduced K+ current proportionally at all voltages without shifting
      the voltage dependence of activation and inactivation. Sigma receptor ligands
      inhibited current through two distinct K+ channels, the A-channel and the Ca2+
      dependent K+ channel. In rat, all drugs reduced current through both channels
      proportionally, suggesting that both channels are modulated by a single
      population of sigma receptors. In contrast, mouse peptidergic nerve terminals
      either have two receptors which are sensitive to these drugs, or a single
      receptor that is differentially coupled to ion channel function. 7. The
      inhibition of voltage-activated K+ current by sigma receptors would be expected
      to enhance the secretion of oxytocin and vasopressin from the neurohypophysis.

PMID- 10332091
TI  - Molecular correlates of the calcium-independent, depolarization-activated K+
      currents in rat atrial myocytes.
AB  - 1. In adult rat atrial myocytes, three kinetically distinct Ca2+-independent
      depolarization-activated outward K+ currents, IK, fast, IK,slow and Iss, have
      been separated and characterized. 2. To test directly the hypothesis that
      different voltage-dependent K+ channel (Kv channel) alpha subunits underlie rat
      atrial IK,fast, IK, slow and Iss, the effects of antisense oligodeoxynucleotides
      (AsODNs) targeted against the translation start sites of the Kv alpha subunits
      Kv1.2, Kv1.5, Kv4.2, Kv4.3, Kv2.1 and KvLQT1 were examined. 3. Control
      experiments on heterologously expressed Kv alpha subunits revealed that each
      AsODN is selective for the subunit against which it was targeted. 4. Peak outward
      K+ currents were attenuated significantly in rat atrial myocytes exposed to
      AsODNs targeted against Kv4.2, Kv1.2 and Kv1.5, whereas AsODNs targeted against
      Kv2.1, Kv4.3 and KvLQT1 were without effects. 5. No measurable effects on
      inwardly rectifying K+ currents (IK1) were observed in atrial cells exposed to
      any of the Kv alpha subunit AsODNs. 6. Kinetic analysis of the currents evoked
      during long (10 s) depolarizing voltage steps revealed that AsODNs targeted
      against Kv4.2, Kv1.2 and Kv1.5 selectively attenuate rat atrial IK,fast, IK, slow
      and Iss, respectively, thus demonstrating that the molecular correlates of rat
      atrial IK,fast, IK,slow and Iss are distinct. 7. The lack of effect of the Kv4.3
      AsODNs on peak outward K+ currents reveals that Kv4.2 and Kv4.3 do not
      heteromultimerize in rat atria in vivo. In addition, the finding that Kv1.2 and
      Kv1.5 contribute to distinct K+ currents in rat atrial myocytes demonstrates that
      Kv1.2 and Kv1.5 also do not associate in rat atria in vivo.

PMID- 10332092
TI  - Regulation of Na+-K+-2Cl- cotransport in turkey red cells: the role of oxygen
      tension and protein phosphorylation.
AB  - 1. Na+-K+-2Cl- cotransport (NKCC) was studied in turkey red cells using Na+
      dependence or bumetanide sensitivity of 86Rb+ influx to monitor activity of the
      transporter. 2. Deoxygenation was the major physiological stimulus for NKCC
      activity: oxygen tensions (PO2) over the physiological range modulated the
      transporter, with a PO2 for half-maximal activation of about 41 mmHg (n = 3). In
      air, activity of NKCC was also stimulated by shrinkage and isoproteronol
      (isoprenaline, 5 microgr;M). By contrast, in deoxygenated cells, although the
      transporter activity was markedly elevated, it was no longer sensitive to volume
      or beta-adrenergic stimulation. 3. Calyculin A, a protein phosphatase inhibitor,
      stimulated cotransport with a lag of about 5 min. N-Ethylmaleimide (NEM)
      inhibited cotransport and also blocked the stimulatory effect of calyculin A if
      administered before calyculin A. Stimulation by calyculin A and deoxygenation
      were not additive. Staurosporine (2 microM) inhibited deoxygenated-stimulated K+
      influxes, but not those stimulated by calyculin A. NEM added during calyculin A
      stimulation, i.e. during the 5 min lag, caused transport activity to be clamped
      at levels intermediate between maximal (calyculin A alone) and control. Cells
      treated with calyculin A alone or with calyculin A followed by NEM were no longer
      sensitive to volume, isoproteronol or PO2. 4. The results have characterized the
      interaction between deoxygenation and other stimuli of NKCC activity. They have
      also shown that it is possible to manipulate the transporter in a reciprocal way
      to that shown previously for K+-Cl- cotransport.

PMID- 10332093
TI  - Pre- and postsynaptic actions of opioid and orphan opioid agonists in the rat
      arcuate nucleus and ventromedial hypothalamus in vitro.
AB  - 1. Using whole-cell patch clamp recording from neurones in an in vitro slice
      preparation, we have examined opioid- and orphanin FQ (OFQ)-mediated modulation
      of synaptic transmission in the rat arcuate nucleus and ventromedial hypothalamus
      (VMH). 2. Application of OFQ activated a Ba2+-sensitive and inwardly rectifying
      K+ conductance in approximately 50 % of arcuate nucleus neurones and
      approximately 95 % of VMH neurones. The OFQ-activated current was blocked by the
      nociceptin antagonist [Phe1Psi(CH2NH)Gly2]-nociceptin(1-13) NH2 (NCA), a peptide
      that on its own exhibited only weak agonist activity at high concentrations (> 1
      microM). Similar current activation was observed with the mu agonist DAMGO but
      not delta (DPDPE) or kappa (U69593) agonists. 3. In arcuate nucleus neurones,
      DAMGO (1 microM), U69593 (1 microM) and OFQ (100 nM to 1 microM) but not DPDPE (1
      microM) were found to depress the amplitude of electrically evoked glutamatergic
      postsynaptic currents (EPSCs) and decrease the magnitude of paired-pulse
      depression, indicating that opioid receptors were located presynaptically. 4. In
      VMH neurones, DAMGO strongly depressed the EPSC amplitude in all cells examined.
      DAMGO decreased the magnitude of paired-pulse depression, indicating that mu
      receptors were located presynaptically. U69593 weakly depressed the EPSC while
      OFQ and DPDPE had no effect. 5. In VMH neurones, DAMGO depressed the frequency of
      miniature EPSCs (-58 %) in the presence of tetrodotoxin and Cd2+ (100 microM),
      suggesting that the actions of mu receptors could be mediated by an inhibition of
      the synaptic vesicle release process downstream of Ca2+ entry. 6. The data
      presented show that presynaptic modulation of excitatory neurotransmission in the
      arcuate nucleus occurs through mu, kappa and the orphan opioid ORL-1 receptors
      while in the VMH presynaptic modulation only occurs through mu opioid receptors.
      Additionally, postsynaptic mu and ORL-1 receptors in both the arcuate nucleus and
      VMH modulate neuronal excitability through activation of a K+ conductance.

PMID- 10332094
TI  - Effects of creatine phosphate on Ca2+ regulation by the sarcoplasmic reticulum in
      mechanically skinned rat skeletal muscle fibres.
AB  - 1. The effect of creatine phosphate (PCr) on sarcoplasmic reticulum (SR) Ca2+
      regulation was studied in mechanically skinned skeletal muscle fibres from rat
      extensor digitorium longus (EDL). Preparations were perfused with solutions
      mimicking the intracellular milieu and the [Ca2+] within the muscle was monitored
      continuously using fura-2. 2. Brief application of 40 mM caffeine caused a
      transient increase in [Ca2+] due to SR Ca2+ release, and an associated tension
      response. Withdrawal of PCr resulted in (i) a slow transient release of Ca2+ from
      the SR (ii) a marked prolongation of the descending phase of the caffeine-induced
      fluorescence ratio transient and (iii) a decrease in the Ca2+ transient amplitude
      to 69.2 +/- 2.7 % (n = 16) of control responses. 3. Prolongation of the caffeine
      induced Ca2+ transient also occurred following application of the SR Ca2+ pump
      inhibitor cyclopiazonic acid (CPA). This suggests that (i) the descending phase
      of the caffeine-induced Ca2+ transient is dependent on the rate of Ca2+ uptake by
      the SR and (ii) prolongation associated with PCr withdrawal may also reflect a
      decrease in the net Ca2+ uptake rate. 4. The effects of PCr withdrawal were
      mimicked by addition of the creatine kinase (CK) inhibitor 2,4-dinitro-1
      fluorobenzene (DNFB). Hence, reducing the [PCr] may influence SR Ca2+ regulation
      by limiting local ATP regeneration by endogenous CK. After treatment with DNFB,
      PCr withdrawal had no effect on the Ca2+ transient, confirming that PCr does not
      have an additional direct effect on the SR. 5. The Ca2+ efflux associated with
      PCr withdrawal was insensitive to ryanodine or Ruthenium Red, but was effectively
      abolished by pretreatment with the SR Ca2+ pump inhibitor cyclopiazonic acid
      (CPA). This suggests that the Ca2+ efflux associated with PCr withdrawal is
      independent of the SR Ca2+ channel, but may involve reversal or inhibition of the
      Ca2+ ATPase. 6. These data suggest that Ca2+ regulation by the SR is strongly
      dependent on the supply of ATP via endogenous CK. Depletion of PCr may contribute
      to impaired SR Ca2+ regulation known to occur in intact skeletal muscle under
      conditions of fatigue.

PMID- 10332095
TI  - Generation of rhythmic patterns of activity by ventral interneurones in rat
      organotypic spinal slice culture.
AB  - 1. In the presence of certain excitatory substances the rat isolated spinal cord
      generates rhythmic oscillations believed to be an in-built locomotor programme
      (fictive locomotion). However, it is unknown whether a long-term culture of the
      same tissue can express rhythmic activity. Such a simplified model system would
      provide useful data on the minimal circuitry involved and the cellular mechanisms
      mediating this phenomenon. For this purpose we performed patch clamp recording
      (under whole-cell voltage or current clamp conditions) from visually identified
      ventral horn interneurones of an organotypic slice culture of the rat spinal
      cord. 2. Ventral horn interneurones expressed rhythmic bursting when the
      extracellular [K+] was raised from 4 to 6-7 mM. Under voltage clamp this activity
      consisted of composite synaptic currents grouped into bursts lasting 0.9 +/- 0.5
      s (2.8 +/- 1.5 s period) and was generated at network level as it was blocked by
      tetrodotoxin or low-Ca2+-high-Mg2+ solution and its periodicity was unchanged at
      different potential levels. 3. In current clamp mode bursting was usually
      observed as episodes comprising early depolarizing potentials followed by
      hyperpolarizing events with tight temporal patterning. Bursting was fully
      suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and reduced in
      amplitude and duration by N-methyl-D-aspartate (NMDA) receptor antagonism without
      change in periodicity. Extracellular field recording showed bursting activity
      over a wide area of the ventral horn. 4. Regular, rhythmic activity similar to
      that induced by K+ also appeared spontaneously in Mg2+-free solution. The much
      slower rhythmic pattern induced by strychnine and bicuculline was also
      accelerated by high-K+ solution. 5. The fast and regular rhythmic activity of
      interneurones in the spinal organotypic culture is a novel observation which
      suggests that the oversimplified circuit present in this culture is a useful
      model for investigating spinal rhythmic activity.

PMID- 10332096
TI  - Properties of C1 and other ventrolateral medullary neurones with hypothalamic
      projections in the rat.
AB  - 1. This study compared (i) the properties of C1 cells with those of neighbouring
      non-C1 neurones that project to the hypothalamus and (ii) the properties of C1
      cells that project to the hypothalamus with those of their medullospinal
      counterparts. 2. Extracellular recordings were made at three rostrocaudal levels
      of the ventrolateral medulla (VLM) in alpha-chloralose-anaesthetized,
      artificially ventilated, paralysed rats. Recorded cells were filled with
      biotinamide. 3. Level I (0-300 microm behind facial nucleus) contained
      spontaneously active neurones that were silenced by baro- and cardiopulmonary
      receptor activation and virtually unaffected by nociceptive stimulation (firing
      rate altered by < 20 %). These projected either to the cord (type I; 36/39), or
      to the hypothalamus (type II; 2/39) but rarely to both (1/39). 4. Level II (600
      800 microm behind facial nucleus) contained (i) type I neurones (n = 3) (ii) type
      II neurones (n = 11), (iii) neurones that projected to the hypothalamus and were
      silenced by baro- and cardiopulmonary receptor activation but activated by strong
      nociceptive stimulation (type III, n = 2), (iv) non-barosensitive cells activated
      by weak nociceptive stimulation which projected only to the hypothalamus (type
      IV, n = 9), (v) cells that projected to the hypothalamus and responded to none of
      the applied stimuli (type V, n = 7) and (vi) neurones activated by elevating
      blood pressure which projected neither to the cord nor to the hypothalamus (type
      VI, n = 4). 5. Level III (1400-1600 microm behind facial motor nucleus) contained
      all the cell types found at level II except type I. 6. Most of type I and II
      (17/26) and half of type III cells (4/8) were C1 neurones. Type IV-V were rarely
      adrenergic (2/12) and type VI were never adrenergic (0/3). 7. All VLM
      baroinhibited cells project either to the cord or the hypothalamus and virtually
      all (21/23) C1 cells receive inhibitory inputs from arterial and cardiopulmonary
      receptors.

PMID- 10332097
TI  - Modulation of gastrin processing by vesicular monoamine transporter type 1
      (VMAT1) in rat gastrin cells.
AB  - 1. Gastrointestinal endocrine cells produce biogenic amines which are transported
      into secretory vesicles by one of two proton-amine exchangers, vesicular
      monoamine transporters type 1 and 2 (VMAT1 and 2). We report here the presence of
      VMAT1 in rat gastrin (G) cells and the relevance of VMAT1 function for the
      modulation of progastrin processing by biogenic and dietary amines. 2. In
      immunocytochemical studies VMAT1, but not VMAT2, was localized to subpopulations
      of G cells and enterochromaffin (EC) cells; neither was found in antral D cells.
      The expression of VMAT1 in antral mucosa was confirmed by Northern blot analysis,
      which revealed an mRNA band of approximately 3.2 kb, and by Western blot
      analysis, which revealed a major protein of 55 kDa. 3. In pulse-chase labelling
      experiments, the conversion of the amidated gastrin G34 to G17 was inhibited by
      biogenic amine precursors (L-DOPA and 5-hydroxytryptophan). This inhibition was
      stereospecific and sensitive to reserpine (50 nM), which blocks VMAT1 and VMAT2,
      but resistant to tetrabenazine, which is a selective inhibitor of VMAT2. 4.
      Dietary amines such as tyramine and tryptamine also inhibited G34 cleavage. This
      effect was associated with a loss of the electron-dense core of G cell secretory
      vesicles. It was not stereospecific or reserpine sensitive, but was correlated
      with hydrophobicity. 5. Thus rat antral G cells can express VMAT1; transport of
      biogenic amines into secretory vesicles by VMAT1 is associated with inhibition of
      G34 cleavage, perhaps by raising intravesicular pH. Dietary amines also modulate
      cleavage of progastrin-derived peptides, but do so by a VMAT1-independent
      mechanism; they may act as weak bases that passively permeate secretory vesicle
      membranes and raise intravesicular pH.

PMID- 10332098
TI  - Maintenance and regulation of the pH microclimate at the luminal surface of the
      distal colon of guinea-pig.
AB  - 1. The fluorescent dye 5-N-hexadecanoyl-aminofluorescein (HAF) was used to study
      the mechanisms involved in maintaining a relatively constant luminal surface pH
      (pHs) in the distal colon of the guinea-pig. The fatty acyl chain of the HAF
      molecule inserts into the apical membrane of epithelial cells. This allows a
      continuous measurement of the surface pH for several hours. 2. The localization
      of HAF was confirmed by confocal laser-scanning microscopy and by using
      monoclonal antibodies against fluorescein. The insertion of HAF into the apical
      membrane of the colonocytes did not change the transepithelial conductance or the
      short-circuit current of the epithelium. 3. With the HAF method a pH microclimate
      was confirmed at the colonic surface. Although the pH of the bulk luminal
      solution was decreased in bicarbonate-containing solution from 7.4 to 6.4 the pHs
      changed only in the range 7.54-6.98. 4. In the absence of bicarbonate pHs almost
      followed changes of bulk luminal pH. In the presence of bicarbonate there was a
      decrease in pHs after removal of chloride from the luminal side and an increase
      in pHs after addition of butyrate to the luminal solution. This suggests the
      involvement of a bicarbonate-anion exchange in bicarbonate secretion: a Cl--HCO3-
      as well as a short-chain fatty acid--HCO3- exchange. 5. The apical K+-H+-ATPase
      in the distal colon of guinea-pig has little influence on pHs in the presence of
      physiological buffer concentrations. 6. Our findings indicate that bicarbonate
      plays a major role in maintaining the pH microclimate at the colonic surface.

PMID- 10332099
TI  - Electrophysiological and morphological heterogeneity of rat dorsal vagal neurones
      which project to specific areas of the gastrointestinal tract.
AB  - 1. The electrophysiological properties of rat dorsal motor nucleus of the vagus
      (DMV) neurones (n = 162) were examined using whole cell patch clamp recordings
      from brainstem slices. Recordings were made from DMV neurones whose projections
      to the gastrointestinal tract had been identified by previously applying
      fluorescent retrograde tracers to the gastric fundus, corpus or antrum/pylorus,
      or to the duodenum or caecum. 2. The neuronal groups were markedly heterogeneous
      with respect to several electrophysiological properties. For example, neurones
      which projected to the fundus had a higher input resistance (400 +/- 25 Momega),
      a smaller and shorter after-hyperpolarization (16.7 +/- 0.49 mV and 63.5 +/- 3.9
      ms) and a higher frequency of action potential firing (19.3 +/- 1.4 action
      potentials s-1) following injection of depolarizing current (270 pA) when
      compared with caecum-projecting neurones (302 +/- 22 Momega; 23. 5 +/- 0.87 mV
      and 81.1 +/- 5.3 ms; 9.7 +/- 1.1 action potentials s-1; P < 0.05 for each
      parameter). Differences between neuronal groups were also apparent with respect
      to the distribution of several voltage-dependent potassium currents. Inward
      rectification was present only in caecum-projecting neurones, for example. 3.
      Neurones (n = 82) were filled with the intracellular stain Neurobiotin allowing
      post-fixation morphological reconstruction. Neurones projecting to the caecum had
      the largest cell volume (5238 +/- 535 microm3), soma area (489 +/- 46 microm2)
      and soma diameter (24.6 +/- 1.24 microm) as well as the largest number of
      dendritic branch segments (23 +/- 2). 4. In summary, these results suggest that
      DMV neurones are heterogeneous with respect to some electrophysiological as well
      as some morphological properties and can be divided into subgroups according to
      their gastrointestinal projections.

PMID- 10332100
TI  - Characteristics of mucosally projecting myenteric neurones in the guinea-pig
      proximal colon.
AB  - 1. Using retrograde tracing with 1,1'-didodecyl-3,3,3', 3'
      tetramethylindocarbocyanine perchlorate (DiI) in combination with
      electrophysiological and immunohistochemical techniques we determined the
      properties of the putative intrinsic primary afferent myenteric neurones with
      mucosal projections in the guinea-pig proximal colon. 2. Eighty-four out of
      eighty-five DiI-labelled myenteric neurones were AH neurones with a late after
      hyperpolarization. Thirty-three per cent of them exhibited atropine- and
      tetrodotoxin-resistant spontaneously occurring hyperpolarizing potentials (SHPs)
      during which the membrane resistance and excitability decreased. 3. DiI-labelled
      AH neurones had multipolar Dogiel type II morphology, primarily of the dendritic
      type. Sixty-one per cent of the neurones were immunoreactive for choline
      acetyltransferase (ChAT) and calbindin (Calb) and 23 % were ChAT positive but
      Calb negative. 4. DiI-labelled neurones did not receive fast excitatory
      postsynaptic potentials but 94 % (34/36) received slow excitatory postsynaptic
      potentials (sEPSPs). The neurokinin-3 (NK-3) agonist (MePhe7)-NKB but not the NK
      1 agonist [(SAR9,Met(O2)11]-SP mimicked this response. The NK-3 receptor
      antagonist SR 142801 (1 microM) significantly decreased the amplitude and
      duration of the sEPSPs; the NK-1 receptor antagonist CP-99,994 (1 microM) was
      ineffective. Atropine (0.5 microM) increased the duration but not the amplitude
      of the sEPSPs. 5. Microejection of 100 mM sodium butyrate onto the neurones
      induced in 90 % of the DiI-labelled neurones a transient depolarization
      associated with an increased excitability. In neurones with SHPs sodium butyrate
      evoked, additionally, a late onset hyperpolarization. Perfusion of 0.1-10 mM
      sodium butyrate induced a dose-dependent increase in neuronal excitability.
      Sodium butyrate was ineffective when applied directly onto the mucosa. 6.
      Mucosally projecting myenteric neurones of the colon are multipolar AH neurones
      with NK-3-mediated slow EPSPs and somal butyrate sensitivity.

PMID- 10332101
TI  - Contractile activity in intestinal muscle evokes action potential discharge in
      guinea-pig myenteric neurons.
AB  - 1. The process by which stretch of the external muscle of the intestine leads to
      excitation of myenteric neurons was investigated by intracellular recording from
      neurons in isolated longitudinal muscle-myenteric plexus preparations from the
      guinea-pig. 2. Intestinal muscle that was stretched by 40 % beyond its resting
      size in either the longitudinal or circular direction contracted irregularly.
      Both multipolar, Dogiel type II, neurons and uniaxonal neurons generated action
      potentials in stretched tissue. Action potentials persisted when the membrane
      potential was hyperpolarized by passing current through the recording electrode
      for 10 of 14 Dogiel type II neurons and 1 of 18 uniaxonal neurons, indicating
      that the action potentials originated in the processes of these neurons. For the
      remaining four Dogiel type II and 17 uniaxonal neurons, the action potentials
      were abolished, suggesting that they were the result of synaptic activation of
      the cell bodies. 3. Neurons did not fire action potentials when the muscle was
      paralysed by nicardipine (3 microM), even when the preparations were
      simultaneously stretched by 50 % beyond resting length in longitudinal and
      circular directions. Spontaneous action potentials were not recorded in
      unstretched (slack) tissue, but when the L-type calcium channel agonist (-)-Bay K
      8644 (1 microM) was added, the muscle contracted and action potentials were
      observed in Dogiel type II neurons and uniaxonal neurons. 4. The proteolytic
      enzyme dispase (1 mg ml-1) added to preparations that were stretched 40 % beyond
      slack width caused the myenteric plexus to lift away from the muscle, but did not
      prevent muscle contraction. In the presence of dispase, the neurons ceased firing
      action potentials spontaneously, although action potentials could still be evoked
      by intracellular current pulses. After the action of dispase, (-)-Bay K 8644 (1
      microM) contracted the muscle but did not cause neurons to fire action
      potentials. 5. Gadolinium ions (1 microM), which block some stretch activated ion
      channels, stopped muscle contraction and prevented action potential firing in
      tissue stretched by 40 %. However, when (-)-Bay K 8644 (1 microM) was added in
      the presence of gadolinium, the muscle again contracted and action potentials
      were recorded from myenteric neurons. 6. Stretching the tissue 40 % beyond its
      slack width caused action potential firing in preparations that had been
      extrinsically denervated and in which time had been allowed for the cut axons to
      degenerate. 7. The present results lead to the following hypotheses. The neural
      response to stretching depends on the opening of stretch activated channels in
      the muscle, muscle contraction in response to this opening, and mechanical
      communication from the contracting muscle to myenteric neurons. Distortion of
      sensitive sites in the processes of the neurons opens channels to initiate action
      potentials that are propagated to the soma, where they are recorded. Neurons are
      also excited indirectly by slow synaptic transmission from neurons that respond
      directly to distortion.

PMID- 10332102
TI  - Regenerative potentials evoked in circular smooth muscle of the antral region of
      guinea-pig stomach.
AB  - 1. Slow waves recorded from the circular smooth muscle layer of guinea-pig antrum
      consisted of two components, an initial component and a secondary regenerative
      component. Whereas both components persisted in the presence of nifedipine, the
      secondary component was abolished by a low concentration of caffeine. 2. Short
      segments of single bundles of circular muscle were isolated and impaled with two
      microelectrodes. Depolarizing currents initiated regenerative responses which
      resembled those initiated during normal slow waves. These responses had partial
      refractory periods of 20-30 s and were initiated about 1 s after the onset of
      membrane depolarization. 3. The regenerative responses persisted in the presence
      of either nifedipine or cobalt ions but were abolished by caffeine, BAPTA or
      cyclopiazonic acid. 4. The observations suggest that depolarizing membrane
      potential changes trigger the release of Ca2+ from intracellular stores and this
      causes a depolarization by activating sets of unidentified ion channels in the
      membranes of smooth muscle cells of the circular layer of guinea-pig antrum.

PMID- 10332103
TI  - Quantitative analysis of peristalsis in the guinea-pig small intestine using
      spatio-temporal maps.
AB  - 1. Peristalsis was evoked in guinea-pig small intestine by slow fluid infusion
      and recorded onto video and digitized. Spatio-temporal maps of diameter and
      longitudinal movement were constructed and parameters of motion were calculated.
      2. During the filling of the isolated segments of intestine, rhythmic local
      longitudinal movements were observed at several points along the preparation.
      These phasic longitudinal muscle contractions were associated with small but
      significant local increases in diameter and probably reflect a passive mechanical
      coupling by connective tissue in the gut wall. In addition, occasional
      synchronized longitudinal muscle contractions caused net shortening of the
      preparation and always preceded the onset of peristaltic emptying. 3. Peristaltic
      emptying was characterized by a contraction of the circular muscle which usually
      started at the oral end of the preparation, that propagated aborally, propelling
      the contents. However, in 19 % of trials, the first circular muscle contraction
      occurred in the aboral half of the preparation. 4. The propagation of peristalsis
      consisted of separate sequential circular muscle contractions several centimetres
      long, particularly in the oral half of the preparation, giving a 'step-like'
      appearance to the spatio-temporal map. The gut was transiently distended aboral
      to the propagating circular muscle contraction due to the propulsion of contents.
      5. At each point in the preparation, the longitudinal muscle remained contracted
      during the propulsive part of the circular muscle contraction. Only when the
      circular muscle contraction became lumen occlusive did lengthening of the
      longitudinal muscle take place. 6. Spatio-temporal maps are a powerful tool to
      visualize and analyse the complexity of gastrointestinal motility patterns.

PMID- 10332105
TI  - Prolonged enhancement of the micturition reflex in the cat by repetitive
      stimulation of bladder afferents.
AB  - 1. Prolonged modulation of the parasympathetic micturition reflex was studied in
      cats anaesthetized by alpha-chloralose. Reflex discharges were recorded from a
      thin pelvic nerve filament to the bladder and evoked by stimulation of the
      remaining ipsilateral bladder pelvic nerves or urethral branches of the pudendal
      nerve. 2. Stimulation of bladder or urethral afferents at Adelta intensity evoked
      micturition reflexes with a latency of 90-120 ms. Such reflexes were much
      enhanced following repetitive conditioning stimulation of the same afferents at
      20 Hz for 5 min. 3. The reflex enhancement lasted more than 1 h after the
      conditioning stimulation. The effect was not prevented by a preceding complete
      transection of the sympathetic supply to the bladder. A prolonged suppression of
      the reflex was obtained after conditioning stimulation of afferents in the dorsal
      clitoris nerves. 4. It is proposed that the prolonged modulations of the
      micturition reflex represent physiological adaptive processes, which preserve a
      flawless function of the bladder during life. The observations provide a
      theoretical explanation for the beneficial effect of electric nerve stimulation
      in patients with voiding disorders.

PMID- 10332104
TI  - Differential effects on motorcortical inhibition induced by blockade of GABA
      uptake in humans.
AB  - 1. Blockade of uptake carriers of gamma-aminobutyric acid (GABA) has been shown
      to modulate inhibition in cortical slices of experimental animals, although
      little is known about this mechanism in vivo and, in particular, in humans. 2.
      The effects of blockade of GABA uptake were studied using transcranial magnetic
      stimulation (TMS) in humans. In eight healthy volunteers several measures of
      cortical excitation and inhibition were obtained before and approximately 2 h
      after ingestion of 5-15 mg of tiagabine (TGB). 3. After TGB ingestion, the
      duration of the TMS-induced silent period observable in the electromyogram of the
      voluntarily contracted target muscle was prolonged. Similarly, paired-pulse
      inhibition of the motor-evoked potential (MEP), as tested by delivering two
      magnetic shocks of equal suprathreshold intensities at 160 ms interstimulus
      interval (ISI), was more pronounced. In apparent contradistinction, paired-pulse
      inhibition of the MEPs produced by a subthreshold conditioning stimulus delivered
      3 ms prior to a suprathreshold stimulus was reduced. Paired-pulse facilitation
      elicited by the same double-shock protocol at an ISI of 10 ms was increased. 4.
      The prolongation of the GABAB receptor-mediated component of the inhibitory
      postsynaptic potential observed with TGB in in vitro studies probably underlies
      the increase in cortical silent period duration. The reduction of the paired
      pulse inhibition at 3 ms, in turn, probably reflects inhibition of GABAA receptor
      mediated inhibition via presynaptic GABAB receptors. 5. These data provide in
      vivo evidence of differential modulation of cortical inhibition by blockade of
      GABA uptake. Presynaptic GABA autoreceptors may be involved in modulating
      cortical inhibition in the human motor cortex.

PMID- 10332106
TI  - Cholesterol-independent endothelial dysfunction in virgin and pregnant rats fed a
      diet high in saturated fat.
AB  - 1. Western diets high in saturated fat are associated with an increased incidence
      of cardiovascular diseases. In this study we have evaluated vascular endothelial
      function and oxidative stress in virgin rats fed a normal (VC) or high in
      saturated fat diet (VHF) (20 % lard and corn oil w/w) from weaning until
      adulthood, and throughout subsequent pregnancy (PC and PHF, respectively). 2. The
      saturated fat diet was associated with enhanced noradrenaline sensitivity in
      small mesenteric arteries from VHF rats (VHF vs. VC, P < 0.05) and blunted
      endothelium-dependent relaxation in VHF and PHF rats (VHF vs. VC, P < 0.001; PHF
      vs. PC, P < 0.05). Endothelial dysfunction was attributable to a reduced nitric
      oxide component of relaxation in VHF rats, and blunted prostacyclin and
      endothelium-derived hyperpolarizing factor components in PHF rats. 3. Other than
      plasma cholesterol, which was reduced in VHF and PHF rats, plasma lipids were
      normal. Fasting plasma insulin and glucose concentrations were raised in VHF rats
      (P < 0.05) and the plasma marker of oxidative stress, 8-iso PGF2alpha, was
      increased in PHF animals (P < 0.01). 4. These findings suggest that endothelial
      dysfunction induced by a saturated fat diet is cholesterol independent and likely
      to be of different mechanistic origin in virgin and pregnant rats.

PMID- 10332109
TI  - Myocardial perfusion and right ventricular function.
AB  - OBJECTIVE: Maximal right ventricular (RV) performance is influenced by left heart
      hemodynamics and hence coronary perfusion. We examined the role of myocardial
      perfusion of the right ventricle as potential determinant of maximal RV function.
      MATERIALS AND METHODS: In 6 canine isovolumic right heart preparations,
      incremental volumes were introduced into a high compliance RV balloon until RV
      failure occurred. Maximal RV developed pressure (RVDP) and maximal positive RV
      dP/dt were determined at a constant controlled left ventricular (LV) output of 2
      l/min and at controlled mean arterial pressures of 50, 80 and 120 mmHg. Right
      coronary artery (RCA) flow was measured. RESULTS: Maximal RVDP increased
      significantly with increasing mean arterial pressures (44.8+/-11.2 vs 57.2+/-15.5
      vs 75.4+/-2.5 mmHg for systemic pressures of 50, 80 and 120 mmHg respectively, p
      < 0. 05). With increasing mean arterial pressures RCA flow increased
      significantly (33.1+/-11.0 vs 46.1+/-20.4 vs 79.6+/-35.3 ml/min). At the onset of
      RV failure, RCA blood flow significantly decreased in all preparations compared
      to the maximal flow in the RCA (1.9+/-1.0 vs 33.1+/-11.0 ml/min at 50 mmHg;
      13.6+/-10.2 vs 46.1+/-20.4 ml at 80 mmHg and 18.7+/-8.0 vs 79.6+/-35.3 ml/min at
      120 mmHg; p < 0.05). CONCLUSIONS: These results suggest that coronary perfusion
      is a major determinant of maximal RV function. The coronary artery driving
      pressure must be sufficient to avoid the onset of RV failure. Maintaining
      systemic pressure and hence RV myocardial blood flow may thus extend RV function.

PMID- 10332108
TI  - An availability of video-assisted thoracic surgery for the resection of pulmonary
      metastases.
AB  - We report the use of video-assisted thoracic surgery (VATS) as a treatment for
      pulmonary metastases. Eight patients with metastatic lung cancer were treated
      with VATS techniques. These patients included 5 males and 3 females whose ages
      ranged from 34 to 61 years (average: 47.4). Their primary diseases were seminoma
      (n = 3), renal cell carcinoma (n = 2), colon carcinoma (n = 1), mammary carcinoma
      (n = 1) and choriocarcinoma (n = 1). Computed tomography (CT) scans with current
      generation scanners were performed preoperatively and revealed one metastatic
      lesion in each of five cases and two lesions in each of the other three cases. In
      one case, one lesion was located in each of the lungs. Tumor size ranged from 5
      to 30 mm in diameter, and all lesions were in the peripheral field of the lung.
      VATS was carried out with three surgical ports for three cases, two surgical
      ports for one case, and only one port for two cases. For all cases, an endo
      stapler was utilized. In two cases, the preoperative point-marking technique for
      tumors was employed under the guidance of CT imaging. All patients were
      discharged from the hospital with no complications, and were followed up with no
      evidence of lung recurrence. Our criteria in selecting patients for the VATS
      removal of metastatic lung tumors are as follows: 1) tumors are less than 30 mm
      in diameter in the peripheral lung, 2) the number of tumors detected by CT scan,
      etc., is one or two. We conclude that VATS is a good candidate for the resection
      of lung metastases in the selected cases. Long term outcome remains to be solved
      in the future.

PMID- 10332107
TI  - Human responses to upright tilt: a window on central autonomic integration.
AB  - 1. We examined interactions between haemodynamic and autonomic neural
      oscillations during passive upright tilt, to gain better insight into human
      autonomic regulatory mechanisms. 2. We recorded the electrocardiogram, finger
      photoplethysmographic arterial pressure, respiration and peroneal nerve muscle
      sympathetic activity in nine healthy young adults. Subjects breathed in time with
      a metronome at 12 breaths min-1 (0.2 Hz) for 5 min each, in supine, and 20, 40,
      60, 70 and 80 deg head-up positions. We performed fast Fourier transform (and
      autoregressive) power spectral analyses and integrated low-frequency (0.05-0.15
      Hz) and respiratory-frequency (0. 15-0.5 Hz) spectral powers. 3. Integrated areas
      of muscle sympathetic bursts and their low- and respiratory-frequency spectral
      powers increased directly and significantly with the tilt angle. The centre
      frequency of low-frequency sympathetic oscillations was constant before and
      during tilt. Sympathetic bursts occurred more commonly during expiration than
      inspiration at low tilt angles, but occurred equally in expiration and
      inspiration at high tilt angles. 4. Systolic and diastolic pressures and their
      low- and respiratory-frequency spectral powers increased, and R-R intervals and
      their respiratory-frequency spectral power decreased progressively with the tilt
      angle. Low-frequency R-R interval spectral power did not change. 5. The cross
      spectral phase angle between systolic pressures and R-R intervals remained
      constant and consistently negative at the low frequency, but shifted
      progressively from positive to negative at the respiratory frequency during tilt.
      The arterial baroreflex modulus, calculated from low-frequency cross-spectra,
      decreased at high tilt angles. 6. Our results document changes of baroreflex
      responses during upright tilt, which may reflect leftward movement of subjects on
      their arterial pressure sympathetic and vagal response relations. The intensity,
      but not the centre frequency of low-frequency cardiovascular rhythms, is
      modulated by the level of arterial baroreceptor input. Tilt reduces respiratory
      gating of sympathetic and vagal motoneurone responsiveness to stimulatory inputs
      for different reasons; during tilt, sympathetic stimulation increases to a level
      that overwhelms the respiratory gate, and vagal stimulation decreases to a level
      below that necessary for maximal respiratory gating to occur.

PMID- 10332111
TI  - An experimental study of surgical treatment for lymphedema in rats: A modified
      Kinmonth procedure and autologous lymph node capsule-venous anastomosis with
      lymph node transfer.
AB  - This study was carried out in order to determine the effect of various surgical
      procedures on lymphedema in a rat model. In 26 adult male Sprague-Dawley rats,
      randomly divided into four groups, surgical lymphedema was created in the left
      hind limbs.: The control group had no drainage, Group 1 had a conventional
      Kinmonth operation, Group 2 had a modified Kinmonth operation using the greater
      omentum and Group 3 had autologous lymph node capsule-venous anastomosis with
      lymph node transfer. Circumference measurement was performed to calculate percent
      difference and circumferential reduction rate. In Groups 2 and 3, patent blue
      violet was injected to identify lymphatics. In all groups, hematoxylin-eosin (H
      E) and 5'-nucleotidase stainning were done to evaluate lymphatics
      histopathologically. The percent difference and the circumferential reduction
      rate respectively showed the smallest and largest values in Group 2. A
      significant difference was found between the control group and Group 2 (p <
      0.05). Lymphatic vessels were shown by patent blue violet injection in Groups 2
      and 3. H-E and 5'-nucleotidase staining revealed patency of lymphatics. A
      modified Kinmonth procedure using the greater omentum was the most effective
      procedure for early lymphedema in a rat model and autologous lymph node capsule
      venous anastomosis with lymph node transfer was effective for lymph draining in
      certain conditions, so it may assist in elucidating surgical treatment of
      lymphedema.

PMID- 10332110
TI  - Can cardioplegia management influence cytokine responses during clinical
      cardiopulmonary bypass?
AB  - BACKGROUND: Cytokines play an important role in the inflammatory response
      associated with cardiopulmonary bypass (CPB) and may contribute to postoperative
      complications. Although it has been shown that the production of tumor necrosis
      factor a (TNF-a) and interleukin (IL)-6 were higher following normothermic CPB
      than hypothermic CPB, whether different cardioplegic management could influence
      the release of cytokines remains unknown. METHODS: We compared the blood
      concentrations of four cytokines (TNF-a, IL-6, IL-8, and IL-10) in two groups of
      patients undergoing complete revascularization with CPB in the same study period.
      Seventeen patients received cold crystalloid cardioplegia at a Belgian center
      (group-CC), while 21 patients received warm blood cardioplegia at a center in
      Hong Kong (group-WB). Blood samples were collected before and after surgery in
      each patient. RESULTS: There were no differences between the 2 groups in terms of
      age, sex ratio, number of grafts, duration of CPB and aortic crossclamping. All
      patients survived their hospital stay. The levels of TNF-a, IL-6 and IL-8 after
      surgery were higher in group-CC than in group-WB. However, IL-10 levels were
      significantly lower at the end of surgery in group-CC than in group-WB.
      CONCLUSIONS: Our data suggest that the use of warm blood cardioplegia, rather
      than cold crystalloid cardioplegia, may reduce the inflammatory response to CPB.
      This observation warrants future randomized investigation to determine its
      clinical relevance.

PMID- 10332112
TI  - Extended use of hemofiltration and high perfusion flow rate in cardiopulmonary
      bypass improves perioperative fluid balance in neonates and infants.
AB  - We evaluated the efficacy of the extended use of hemofiltration (EHF) and high
      perfusion flow rate in cardiopulmonary bypass (CPB) in pediatric open-heart
      surgery retrospectively. In the EHF method, hemofiltration was used for hemic
      prime before initiation of the bypass and ultrafiltration was used throughout the
      bypass. Thirty-four children, with transposition of great arteries who were
      undergoing arterial switch operation with the use of hemic prime, were subjects
      of this study. They were divided into 2 groups, a control group (n = 16) and a
      group (n = 18) that underwent EHF. There were no significant differences between
      groups in demographics, but the maximum perfusion index and lowest rectal
      temperature were higher in the EHF group. This study compared urination during
      bypass, arterial oxygen pressure at the end of bypass and operation, the duration
      of the ventilation, and postoperative soft tissue index (STI) expressing the
      severity of edema. In the EHF group, urination during bypass was significantly
      higher, and there was a tendency to higher arterial oxygen pressure. The patients
      in the EHF group were weaned from the ventilator significantly earlier.
      Postoperative STI was significantly higher, so edema was more severe in the
      control group. We consider that the use of EHF and a high perfusion flow rate in
      CPB are an ideal method to improve the perioperative fluid balance in pediatric
      open-heart surgery. We suspect that these good clinical effects result from
      maintaining the inflammatory mediators at a low level throughout the bypass,
      reducing the following release of the mediators and attenuating the interaction
      of the mediators.

PMID- 10332113
TI  - Long term follow-up of atrioventricular valve function after repair of
      atrioventricular septal defect.
AB  - To elucidate the factors which are associated with early and late operative
      results of atrioventricular septal defects, 102 consecutive patients who
      underwent reparative operation of atrioventricular septal defects (AVSD) in our
      institution since 1968 were studied. Our operative technique was basically the
      same through this period. That is the two patch method in its complete form (the
      so-called Shirotani's method) and preferential use of cleft closure supplemented
      with Kay-Reed-Wooler type annuloplasty. Early mortality (< 30 days) rate was
      18.6%. More than 80% of the early deaths were not related to atrioventricular
      valve malfunction. Non-complete closure of the cleft, high preoperative pulmonary
      vascular resistance, deficient atrioventricular valve, and complete form showed
      independent correlations with early mortality in multiple logistic regression
      analysis. For operative survivors, event-free survival curves, for
      atrioventricular valve related reoperations were drawn for various factors. Two
      late deaths and 3 late atrioventricular-valve-related reoperations occurred. The
      event-free actuarial survival for operative survivors at 5, 10, and 20 years were
      97.0%, 89.4%, and 89.4%, respectively. The survival analysis revealed that
      preoperative high pulmonary vascular resistance, preoperative severe
      atrioventricular regurgitation, and preoperative large cardiothoracic ratio in
      chest radiogram were related with late event occurrence. Higher early mortality
      in our series may be attributable to relatively advanced pulmonary vascular
      occlusive disease rather than post repair atrioventricular valve malfunction. On
      the other hand, our late results were rather good. We concluded that the
      Shirotani's method and preferential use of cleft closure supplemented with Kay
      Reed-Wooler type annuloplasty was effective for most of atrioventricular valves
      in atrioventricular septal defects. Early surgical intervention before pulmonary
      vascular disease progression or atrioventricular valve regurgitation development
      is also important.

PMID- 10332114
TI  - Mitral valve replacement through dilated aortic annulus in Marfan's syndrome.
AB  - A 30-year-old man presented with severe aortic regurgitation due to an ascending
      aortic aneurysm and mitral valve insufficiency in conjunction with active
      endocarditis. He underwent combined aortic root replacement by a composite graft
      and mechanical mitral valve replacement. After excision of the aortic valve cusps
      the mitral valve was approached through the extremely dilated aortic annulus.
      This technique is seldom used. Mitral valve replacement through the aortic root
      can be advantageous in selected patients to minimize trauma and reduce myocardial
      ischemic time.

PMID- 10332115
TI  - Surgical management of blunt traumatic rupture of the descending thoracic aorta.
AB  - Acute rupture of the descending thoracic aorta following blunt trauma is a life
      threatening injury that requires emergent operative intervention. From February
      1989 to January 1997, 4 patients with multiple injuries including traumatic
      rupture in the region of the aortic isthmus were surgically treated at our
      institution. Diagnosis was confirmed in all patients by aortogram prior to aortic
      repair. One patient had preoperative paraplegia secondary to an unstable spinal
      fracture. All patients underwent repair under cardiopulmonary bypass (3 partial,
      1 total with hypothermic arrest). The site of rupture was resected and replaced
      with an interposition artificial graft. There was no perioperative mortality and
      no additional occurrence of paraplegia. Our experience and a review of the
      literature indicate that for survivors of traumatic aortic rupture, excellent
      outcomes can be achieved only if the diagnosis is made early and the surgical
      treatment is prompt.

PMID- 10332116
TI  - A case of thoracoscopic bilateral lung volume reduction surgery in a supine
      position.
AB  - We present a case of thoracoscopic bilateral lung volume reduction surgery
      performed with the patient in a supine position. By rotating the operative table,
      bilateral apical resection could be performed without difficulty. The duration of
      the operation was 160 minutes and the patient's forced expiratory volume in 1
      second improved from 0.81 l to 2.49 l.

PMID- 10332117
TI  - Possibility of focal activation around the left upper pulmonary vein during
      chronic atrial fibrillation with mitral valve disease.
AB  - Focal regular activations were sometimes observed during chronic atrial
      fibrillation (AF) associated with mitral valve disease. We present a 58 year-old
      male diagnosed with mitral valvular stenosis and regurgitation with chronic
      atrial fibrillation. Intraoperative mapping of both atria was performed during
      mitral valvular surgery. Regular and repetitive activations around the left
      superior pulmonary vein were observed, in contrast to irregular and chaotic
      activations of the right atrium. This regular activation was supposed to be the
      focus of chronic AF. Surgical ablation of the posterior left atrium was
      successfully performed and eliminated the chronic AF, concomitant with mitral
      valve replacement.

PMID- 10332118
TI  - Ischemic heart attacks following cessation of aspirin before coronary artery
      bypass surgery: A report of two cases.
AB  - We present herein two patients who suffered life-threatening ischemic heart
      attacks following the preoperative discontinuation of aspirin. Since their
      cardiac conditions were stable in the long-term while under medication, the
      cessation of aspirin was highly suspected to have caused or at least to have
      contributed to their ischemic events. We thus discuss the appropriate timing for
      discontinuation of aspirin before surgery in patients with ischemic heart
      disease.

PMID- 10332119
TI  - Blunt traumatic rupture of the heart: case report and selected review.
AB  - Cardiac rupture is a common complication following blunt thoracic trauma. Blunt
      traumatic rupture of the heart is a frequent cause of death. Cardiac injuries are
      rarely diagnosed early in the preoperative period. Most of them die at the scene
      of the accident and only a few survive to make it to the hospital alive. Rapid
      evaluation and expeditious management may increase the number of survivors. We
      present here an illustrative case report and selected review of literature
      regarding clinical presentation, mechanism of injury, investigation and
      treatment.

PMID- 10332120
TI  - Descending branch of lateral femoral circumflex artery as a new alternative free
      graft in re-do CABG.
AB  - To re-do coronary artery bypass grafting (CABG), we employed the descending
      branch of the lateral femoral circumflex artery (LFCA) as a free arterial graft.
      Early postoperative angiography demonstrated that the graft was patent with a
      sufficient flow. The descending branch of the LFCA can be recommended as a
      possible arterial graft for re-do CABG.

PMID- 10332121
TI  - Two-stage operation for multiple aneurysms of the thoracic aorta, abdominal
      aorta, and left common iliac artery in an octogenarian.
AB  - Multiple aortic aneurysms are well described in the surgical literature. However,
      there are many problems related to surgical treatment of elderly patients with
      such aneurysms. This report presents the case, an octogenarian with multiple
      aortic aneurysms that were successfully treated by graft replacement. An 82-year
      old man with a descending aortic aneurysm was referred to our institution for
      surgery. In addition to the previously diagnosed aneurysm, computed tomography
      and aortography showed an abdominal aortic aneurysm and a left common iliac
      aneurysm. Since the patient was an elderly man with chronic obstructive pulmonary
      disease, a two-stage operation was performed. The abdominal aortic aneurysm and
      left common iliac aneurysm were resected first due to the risk of thromboembolism
      from the abdominal aortic aneurysm during surgery involving replacement of the
      descending aorta under femoro-femoral (F-F) bypass. Fifty-two days after the
      first operation, a second operation was performed to repair the descending aortic
      aneurysm. The postoperative course was uneventful. Angiography after the
      operation showed satisfactory replacement of the multiple aortic aneurysms. The
      patient was discharged 25 days after the second operation.

PMID- 10332122
TI  - Foxes in the henhouse.

PMID- 10332123
TI  - A tale of the well-intentioned.

PMID- 10332124
TI  - Early detection.

PMID- 10332125
TI  - Periodontal disease increases risk of diabetes and chronic lung disease.

PMID- 10332126
TI  - U.S. government provides Y2K help.

PMID- 10332127
TI  - Hydrogen peroxide is not carcinogenic.

PMID- 10332128
TI  - Risk and prevention of hepatitis C virus infection. Implications for dentistry.
AB  - BACKGROUND: The occupational risk of hepatitis C virus, or HCV, infection in
      dentistry is very low. Nonetheless, the lack of an effective vaccine, the high
      rates of chronic infection and the limited effectiveness of treatment may cause
      concern for dental workers who come into contact with blood in their daily
      practices. DESCRIPTION OF THE DISORDER: The authors discuss the natural history,
      diagnosis and treatment, and patterns of transmission of HCV infection, including
      the Centers for Disease Control and Prevention's recommendations for management
      and follow-up of health care workers after occupational exposure to HCV. CLINICAL
      IMPLICATIONS: In the absence of an effective vaccine or postexposure prophylaxis,
      prevention of occupational transmission of HCV in dental settings continues to
      rely on the use of universal precautions, including barrier precautions and the
      safe handling of sharp instruments.

PMID- 10332129
TI  - Cardiovascular effects of intraosseous injections of 2 percent lidocaine with
      1:100,000 epinephrine and 3 percent mepivacaine.
AB  - BACKGROUND: Because a number of patients have reported an increase in heart rate
      with the intraosseous, or i.o., injection, it is important to evaluate changes in
      the cardiovascular system with this injection technique. The purpose of this
      study was to determine the cardiovascular effects of an i.o. injection of 2
      percent lidocaine with 1:100,000 epinephrine and 3 percent mepivacaine. METHODS:
      With the use of a repeated-measures design, the authors randomly assigned 42
      subjects to receive i.o. injections of 1.8 milliliters of 2 percent lidocaine
      with 1:100,000 epinephrine or 1.8 mL of 3 percent mepivacaine in a double-blinded
      manner at two appointments. At each appointment the authors monitored
      electrocardiographic findings, cardiac rate, systolic and diastolic blood
      pressure, and mean arterial pressure before, during and after administration of
      anesthetic solutions. RESULTS: With the 2 percent lidocaine with 1:100,000
      epinephrine solution, 28 (67 percent) of 42 subjects experienced an increase in
      heart rate that might be attributed to the effect of the epinephrine. In 22 (79
      percent) of these subjects, the heart rate returned to within 5 beats of baseline
      values within four minutes after solution deposition. The authors found no
      significant increase in heart rate in subjects receiving the 3 percent
      mepivacaine. No significant differences (P > .05) were found in mean diastolic,
      mean systolic or mean arterial blood pressure values between the subjects
      receiving 2 percent lidocaine with 1:100,000 epinephrine and those receiving 3
      percent mepivacaine. CONCLUSIONS: The majority of subjects receiving the i.o.
      injection of the 2 percent lidocaine-epinephrine solution experienced a transient
      increase in heart rate. No significant increase in heart rate was seen with the
      i.o. injection of 3 percent mepivacaine. CLINICAL IMPLICATIONS: While patients
      would likely notice the heart rate increase with the lidocaine-epinephrine
      solution, it would not be clinically significant in most healthy patients. In
      patients whose medical condition, drug therapies or epinephrine sensitivity
      suggests caution, 3 percent mepivacaine is a good alternative for i.o.
      injections.

PMID- 10332130
TI  - A comparison of dental care expenditures and office-based medical care
      expenditures, 1987.
AB  - BACKGROUND: This article compares national estimates of utilization of and
      expenditures for dental care and office-based medical care. The comparison
      includes respondents in several socioeconomic and demographic categories.
      METHODS: The focus of the analyses is on dental care and office-based medical
      care utilization during 1987. Specifically, the authors provide national
      estimates for numbers of dental and office-based medical visits made,
      expenditures for and sources of payment for each of several socioeconomic and
      demographic categories using household survey data from the 1987 National Medical
      Expenditure Survey, or NMES. RESULTS: Data show that out-of-pocket expenditures
      are greater for dental care than for office-based medical care; that few Medicaid
      dollars are spent on dental care; that insurance is an important component of
      dental and office-based medical care; and that dentists provide greater amounts
      of unreimbursed care than do their office-based physician counterparts.
      CONCLUSIONS: NMES data show that dental care expenditures are considerable,
      almost as large as expenditures for office-based medical care, and are a
      significant component of all nonhospital health care expenditures for
      noninstitutionalized Americans. PRACTICE IMPLICATIONS: U.S. dentists provide a
      significant amount of care. By understanding these analyses, practitioners will
      be better positioned to provide care and to better meet the dental needs of all
      Americans.

PMID- 10332131
TI  - Early diagnosis of nevoid basal cell carcinoma syndrome.
AB  - BACKGROUND: Nevoid basal cell carcinoma syndrome, or NBCCS, is a hereditary
      condition characterized by basal cell carcinomas, or BCCs; odontogenic
      keratocysts, or OKCs; and skeletal abnormalities. The authors conducted this
      study to determine the early signs of NBCCS. METHODS: The authors reviewed files
      from two Italian dental schools from January 1980 to January 1995 to determine
      the early signs of NBCCS and the age at which patients were first examined. They
      re-examined all of the patients, using the diagnostic criteria for NBCCS.
      RESULTS: The authors found 14 patients who fulfilled the criteria for diagnosis
      of NBCCS in five families. All of the patients were 16 years of age or younger.
      In 11 cases (78 percent), the first sign of NBCCS in the patients was an OKC. The
      OKCs diagnosed in patients older than 13 years of age were large and
      characterized by widespread bone resorption. One 11-year-old patient had six
      large OKCs. The authors also found a case of multiple OKCs in an 8-year-old
      patient. Only one patient showed BCCs. CONCLUSIONS: OKCs are often the first
      signs of NBCCS and can be detected in patients younger than 10 years of age. Our
      data suggest that OKCs arise earlier in patients who have NBCCS than in patients
      who do not have NBCCS. The patients' young ages explain the low incidence of BCCs
      in this study. CLINICAL IMPLICATIONS: The presence of multiple OKCs in a child or
      onset of BCC in a patient younger than 20 years of age should alert dentists to
      the possibility of the patient's having NBCCS.

PMID- 10332132
TI  - A screw lock for single-tooth implant superstructures.
AB  - BACKGROUND: The most common complication in a single-tooth implant restoration is
      abutment screw loosening. Instability of the prosthetic superstructure is
      expressed by difficulty in chewing and functioning, as well as soft-tissue
      soreness and/or swelling that could lead to screw fracture. Manufacturers of oral
      implants have attempted to refine the connecting parts of the prosthesis to
      achieve a more predictable tightening method for the screws. METHODS: To maintain
      the abutment screw tightly in its correct position, the authors developed a
      technique in which an elongated hexagonal titanium bar is inserted into the hexed
      fixed screw head. The screw is locked, and the bar is then fixed with a light
      cured composite resin material that serves to seal the retaining screw access
      hole. The occlusal hexagonal bar thus serves as a secure screw lock that can be
      easily removed if needed. RESULTS: The authors have used the hexagonal bar for
      almost three years on 120 single-tooth screw-retained prostheses in 100 patients
      (65 in the first and second premolar region, 40 in the incisor region and 15 in
      the posterior molar region). All of these prostheses functioned successfully,
      including those with wider occlusal planes and increasing occlusal forces. No
      screw loosening or fractures were noted in any of the fixtures. CLINICAL
      IMPLICATIONS: This technique secures and stabilizes the single-tooth prosthesis,
      reduces chair time on follow-up procedures and reduces unnecessary frustration in
      patients and dental team members.

PMID- 10332133
TI  - Retrieval of a broken needle in the pterygomandibular space.
AB  - BACKGROUND: Dental needle breakage can be a devastating experience for both
      practitioners and patients. The authors describe the surgical management for
      localizing a broken dental needle in the pterygomandibular space and how to
      prevent needle breakage. CASE DESCRIPTION: The authors present the case of a 35
      year-old man who had a chief complaint of pain and the ability to feel a broken
      needle during mandibular movements after receiving an inferior alveolar nerve
      block from his general dentist before dental treatment. Surgical management
      involved localizing the broken needle using radiographs and removing the broken
      needle under general anesthesia. CLINICAL IMPLICATIONS: Preventing needle
      breakage is important, as it can be a traumatic experience for the patient.
      Practitioners should establish the patient's cooperation by explaining to him or
      her what to expect before injection. Practitioners also should routinely inspect
      dental needles before administering injections and minimize the number of
      repeated injections using the same needle.

PMID- 10332134
TI  - Rheumatoid arthritis: a review and suggested dental care considerations.
AB  - BACKGROUND: Rheumatoid arthritis, or RA, is a chronic multisystem disease of
      presumed autoimmune etiology. It is estimated that arthritis and other rheumatic
      conditions affect 42.7 million Americans. Medical complications due to RA and its
      treatment may affect the provision of oral health care. METHODS: The authors
      undertook an extensive review of the English literature relating to RA and dental
      care. They used primarily MEDLINE searches, which included such key words as
      "rheumatoid arthritis" and "dental care" and subsequent appropriate subheadings.
      While the MEDLINE search spanned the years from 1975 to the present, the most
      recent literature was prioritized. Appropriate medical and dental textbooks were
      also used. The authors extrapolated information from selected texts based on its
      relevance to dentistry, oral health and the role of the dental provider in the
      overall treatment of RA patients. RESULTS: The authors reviewed nearly 200
      articles and seven textbooks. Their determination of the texts' relevance to oral
      health care was based on content, significance, quality, journal in which
      articles were published and year of publication. Major features of RA--including
      its diagnosis, pathophysiology, clinical features and medical treatment--were
      identified, as well as complications due to treatment modalities and various
      related oral manifestations and conditions. CONCLUSIONS: Medical complications
      due to RA and its treatment can affect oral health care. Oral health care
      providers need to recognize and identify modifications of dental care based on
      the medical status of patients with RA. Furthermore, oral health care providers
      play an important role in the overall care of these patients as it release to
      early recognition, as well as control of the disease. CLINICAL IMPLICATIONS: In
      most patients with RA, the condition will necessitate few or no changes in
      routine dental care. However, considerations include the patient's ability to
      maintain adequate oral hygiene, xerostomia and its related complications, the
      patient's susceptibility to infections, impaired hemostasis, and untoward drug
      actions and interactions. Patients with RA may require antibiotic prophylaxis
      owing to joint replacement and/or immune suppression, glucocorticosteroid
      replacement therapy and modifications in oral hygiene procedures. Intra- and
      extraoral conditions such as ulcerations, gingival overgrowth, disease-associated
      periodontitis and temporomandibular pathology also need to be recognized.

PMID- 10332135
TI  - Adverse drug interactions in dental practice: interactions associated with
      vasoconstrictors. Part V of a series.
AB  - BACKGROUND: Adrenergic vasoconstrictors are commonly used by dentists to enhance
      the pain-relieving action of local anesthetics and to control local bleeding.
      Although normally considered safe for these applications, vasoconstrictors can
      participate in drug interactions that potentially are harmful to patients.
      METHODS: The faculty of a March 1998 symposium entitled "Adverse Drug
      Interactions in Dentistry: Separating the Myths From the Facts" extensively
      reviewed the literature on drug interactions. They then established a
      significance rating of alleged adverse drug interactions pertaining to dentistry,
      based on the quality of documentation and severity of effect. The author of this
      article focused on the adrenergic vasoconstrictors epinephrine and levonordefrin.
      RESULTS: Vasoconstrictor drug interactions involving tricyclic antidepressants,
      nonselective beta-adrenergic blocking drugs, certain general anesthetics and
      cocaine are well-documented in both humans and animals as having the potential
      for causing serious morbidity or death. Evidence for adverse interactions
      involving adrenergic neuronal blocking drugs, drugs with alpha-adrenergic
      blocking activity, local anesthetics and thyroid hormones is much less
      compelling, suggesting for the most part that clinically significant reactions
      may occur only when both the vasoconstrictor and the interacting drug are used in
      excessive doses. In the case of monoamine oxidase inhibitors, there is no
      credible evidence of a significant interaction with epinephrine or levonordefrin.
      CONCLUSIONS: Potentially serious adverse drug interactions involving adrenergic
      vasoconstrictors can occur in dental practice. In most circumstances, careful
      administration of small doses of vasoconstrictors and avoidance of gingival
      retraction cord containing epinephrine, coupled with monitoring of vita signs,
      will permit these drugs to be used with no risk or only minimally increased risk.
      Only in the case of cocaine intoxication must adrenergic vasoconstrictors be
      avoided completely. CLINICAL IMPLICATIONS: For optimal patient safety, dentists
      must recognize potential drug interactions involving adrenergic vasoconstrictors
      and modify their use of these agents accordingly.

PMID- 10332136
TI  - Ask the expert. What kind of accounting services do I need?

PMID- 10332137
TI  - Determining dental checkup frequency.
AB  - BACKGROUND: The authors assessed the dental checkup frequency of adults living in
      the Detroit tricounty area and identified demographic, access and subjective
      factors associated with visits to a dentist made not because of a dental problem.
      METHODS: Data are from a 1994 probability-based sample of adults who were
      interviewed and received an in-home oral examination. The authors used the
      variables of age, sex, education level, income level, dental insurance status,
      usual place for care, objective measures of oral health, and subjective
      assessments of health, pain and dental anxiety to predict the frequency of dental
      checkups. RESULTS: The authors found that differences in dental checkup behavior
      were related to demographics, access to dental care, subjective ratings of oral
      and general health and other self-assessments, and clinical parameters of oral
      health. In multiple logistic regression analysis considering all variables
      simultaneously, sex, income, having a usual place for care and level of dental
      care anxiety were found to be associated with having dental checkups. The authors
      determined the statistical significance level at P < .05. CONCLUSIONS: A total of
      69.7 percent of the study population reported having had a dental checkup at
      least once a year in the past five years. The authors found that four factors
      associated with infrequent dental checkups: being male, having lower income
      levels, not having a usual place for care and being anxious about receiving
      dental care. PRACTICE IMPLICATIONS: Dental health professionals should consider
      the correlates of dental checkup frequency identified in this study and the
      usefulness of proposed strategies to increase and sustain regular preventive
      visitation patterns in their own patient populations.

PMID- 10332138
TI  - Informing patients about treatment alternatives.

PMID- 10332139
TI  - Changing patterns of disease and mucosal immunity.

PMID- 10332140
TI  - Supreme Court eyes ERISA pre-emption. Employment Retirement Income Security Act.

PMID- 10332141
TI  - Using orthodontic wax to create a diagnostic cast.

PMID- 10332142
TI  - [Sensory receptors on oral thickness sensation].
AB  - The purpose of this study was to evaluate the role of the receptors connected
      with oral thickness perception. Twenty dentate volunteers participated in this
      study. The right second premolars were selected as test teeth. The thickness
      perception test was performed using aluminum foil. The experimental conditions
      were: 1) two types of occlusal contact positions; intercuspal position and teeth
      contact position of a single pair, 2) two types of closing velocities: "slow
      closure" and "fast closure" which were synchronized with 50 and 150/min
      metronome, and 3) application of local anesthesia to test teeth. The number of
      incorrect assessments for all trials and the proportion of correct assessments
      for actual trials were used for analysis. There were significant increases of
      incorrect assessments below 200 microns in "slow closure" at teeth contact
      position of a single pair. The minimum thickness of 80% of correct assessment was
      100 microns both with and without anesthesia in "fast closure" at teeth contact
      position of a single pair. There were significantly fewer incorrect assessments
      in "fast closure" than in "slow closure" with anesthesia at teeth contact
      position of a single pair. These findings suggest that the closing velocity may
      influence oral thickness perception.

PMID- 10332143
TI  - [Influence of wearing complete dentures on body balance in edentulous elderly].
AB  - The influence of wearing complete dentures on body balance of edentulous elderly
      was examined in this study. Eight edentulous volunteers (5 females and 3 males)
      who were satisfied with their new dentures participated in the study. Static and
      dynamic balance were compared between subjects with and without dentures. To
      evaluate static balance, path length of spontaneous postural sway with eyes
      closed was measured for 60 seconds using a stabilometer. To evaluate dynamic
      balance, gait cycle, gait velocity, and stride length during 15 meters of free
      gait were measured using a newly-developed gait-cycle-analyzing device and gait
      speedometer. The data analysis showed that path lengths of subjects when wearing
      complete dentures significantly decreased compared to subjects without dentures
      (p < 0.05). Subjects when wearing complete dentures performed significantly
      faster and more stable gait compared to subjects without dentures (p < 0.05).
      Significant increases were concurrently observed in frequency of gait cycle and
      stride length (p < 0.05). The results suggested that the presence of an
      established occlusal vertical dimension had an influence not only on static
      balance but also on dynamic balance of the subjects. It was concluded that for
      edentulous elderly, wearing complete dentures may enhance body balance rather
      than not wearing a complete denture.

PMID- 10332144
TI  - [Clinical retrospective study on outpatients at clinic for oral implant].
AB  - A retrospective study was made on 1,000 outpatients visiting the Clinic for Oral
      Implant, University Hospital, Faculty of Dentistry, Tokyo Medical and Dental
      University between April 1995 and June 1998. The following findings were obtained
      according to sex, age group, reason for visit, classification of edentulous area,
      indication and contraindication for implant therapy, and pre-implant surgical
      treatment. Forty percent of the outpatients were male and 60% were female. The
      largest number was in the 50-59-year-old group. The reason for visit of 822
      patients was request for implant therapy. 123 patients with uncomfortable
      implants done at other clinics, 12 patients undergoing maintenance of implants at
      other clinics and 43 other patients. There were 505 upper jaw cases and 529 lower
      jaw cases. Most anterior edentulous cases were in the upper jaw group. Most of
      the posterior edentulous cases were unilateral cases and many of them were free
      end saddle cases. Indication patients were 447 of the 822 outpatients. The main
      contraindication was insufficient volume of bone. Two hundred twenty-one of the
      477 indication patients did not need the pretreatment which consisted of
      extraction, bone graft, free gingival graft, provisional prosthetics, sinus lift,
      and so on.

PMID- 10332145
TI  - [Influence of tooth contacts during mandibular retrusion on terminal jaw
      relations and EMG activity during habitual opening and closing movements].
AB  - The purpose of this study was to clarify the influence of tooth contacts during
      mandibular retrusion on terminal jaw relations (TJR) and the surface EMG activity
      during habitual opening and closing movements. The age of five healthy subjects
      were 25 to 28 years. The maxillary stabilization splints with steep retrusive
      contacts (S-SP) and with flat retrusive contacts (F-SP) were prepared for each
      subject who was instructed to wear S-SP for one week and then to wear F-SP for
      one week after an interval of two weeks without S-SP. The EMG activity of the
      masseter and temporal muscles and the TJR during habitual opening and closing
      movements using a device for recording jaw movements in 6 degrees of freedom were
      simultaneously measured by an intraoral central bearing device. The results were
      as follows: 1. The TJR recorded after wearing F-SP shifted more posteriorly than
      that of wearing S-SP. 2. The posterior temporal muscle activity after wearing F
      SP, compared with that of wearing S-SP, resulted in a significant increase. In
      conclusion, the elimination of the retrusive guidance caused the predominance of
      posterior temporal muscle activity, and posterior displacement of the mandible.

PMID- 10332146
TI  - [Molecular cloning, expression of rat Msx-1 and Msx-2 during early embryo genesis
      and roles for mandibular chondrogenesis].
AB  - Quail-chick chimera experiments have shown a contribution of carnial neural crest
      cells to the craniofacial skeletal elements. Moreover, tissue interactions
      between epithelial-mesenchymal interaction during early facial process
      development are required for both skeletal differentiation and morphogenesis. In
      this study, it was observed that Msx homeobox containing genes expressed in the
      facial process were important molecules of cartilage morphogenesis. Rat cDNAs
      were isolated and encoded by Msx-1 and -2, and then the expression patterns using
      in situ hybridization were investigated during early rat face development. These
      genes were correlatively expressed in the cranial neural crest forming area (E
      9.5 dpc) and the facial process (E 12.5 dpc). Antisence inhibition of Msx genes
      in the E 12.5 mandibular process exhibited the alteration of their gene
      expression and cartilage patterns. Antisence inhibition of Msx-1 induced lack of
      the medial portion of cartilage, and antisence inhibition of Msx-2 enhanced
      chondrogenesis of mandibular process under the organ culture condition. Thus it
      was concluded that expression of Msx genes during mandibular process development
      comprises important signals of chondrogenesis.

PMID- 10332147
TI  - [A study on diagnosis of oral squamous cell carcinoma (oral SCC) by glutathione S
      transferase-pi (GST-pi)].
AB  - The purpose of this study was to estimate the usefulness of plasma GST-pi in
      diagnosis of oral SCC and to confirm the expression and localization of GST-pi in
      human oral SCC. Plasma GST-pi levels of 109 untreated oral SCC cases, 47
      recurrent oral SCC cases and 36 healthy controls were measured by the sandwich
      enzyme-immunoassay (EIA) system. Human oral SCC and human oral SCC cell lines
      (HSC-3, HSC-4) were examined immunohistochemically and by the immunoelectron
      microscopic technique. The results were as follows: 1. The cut off level was 30.0
      ng/ml (mean+2 S.D.). There was a statistically significant difference between the
      mean plasma GST-pi levels in oral SCC (both untreated and recurrent cases) and
      controls (p < 0.001). 2. The positive rate of GST-pi was 63.3% in untreated cases
      and 68.1% in recurrent cases. 3. There was no significant correlation between
      plasma GST-pi levels and each clinical factor. 4. The positive rates of plasma
      GST-pi were compared with those of serum SCC antigen in oral SCC. Plasma GST-pi
      was 62.9%, while serum SCC antigen 22.2%. 5. From immunohistochemical
      observation, GST-pi positive staining was evident in the cytoplasm and nucleus of
      oral SCC. 6. By immunoelectron microscopy, GST-pi was confirmed to be in the
      mitochondria and the inter-chromatinic regions of the nucleus.

PMID- 10332148
TI  - [Functional mobility measurement of removable partial dentures using newly
      developed analyzing system in six degrees of freedom--effect of cusp inclination
      of molar artificial teeth on denture displacement in function].
AB  - A measuring system to record three-dimensional displacement of removable partial
      dentures (RPDs) in six degrees of freedom has been developed. The system employed
      three pairs of photodiode and LED that were set up in a triangle. This system was
      capable of recording the in vivo RPD displacement with a recording sensitivity of
      0.1 mm. In vivo displacement of upper RPDs with unilateral distal extension
      saddle was investigated using this measuring system to determine the effect of
      artificial cusp inclination of molar teeth on denture mobility. Two groups of
      different artificial dentition were switched to be attached to each of three
      experimental RPDs. The artificial teeth with cusp inclinations were calibrated to
      contact with opposing natural dentition during lateral grinding of the mandible,
      while the other artificial teeth were prepared to disclude with the mandibular
      teeth (flat-cusp group). Displacement range and average position of a reference
      point at the first molar of the RPDs during mastication were measured and
      analyzed as a function of the cusp inclination and the test food. As a result,
      the average displacement of the RPDs toward the edentulous ridge was smaller in
      the cusp group than that in the flat-cusp group, while the range of horizontal
      displacement in the buccal-palatal direction was greater in the former group than
      the latter. The denture wearers demonstrated typical grinding strokes at the end
      of the closing phase of the mandiblar movements when they chewed a peanut, which
      was attributed to a wide range of horizontal displacement of the dentures.

PMID- 10332149
TI  - [Influence of interocclusal distance of mandibular unilateral distal extension
      removable partial denture on masticatory function].
AB  - The purpose of this study was to elucidate the influence on masticatory function
      when the mandibular unilateral distal extension removable partial denture changed
      the interocclusal distance. The experiments, crushability, the sense of
      mastication, and the masticatory strokes until swallowing, were conducted, on
      four subjects, using the denture with the apparatus that enabled to change the
      interocclusal distance. The results were as follows: The particle size
      distribution showed that the ratio of small particle (diameter 2.5-4.5 mm)
      decreased, while that of large particle (more than 5.0 mm) increased, on three of
      four subjects, and the value of crushability diminished. A reduction of the value
      of crushability when the interocclusal distance was extended more than 800
      microns was found. As for the other subject, no change was recognized on the
      particle size distribution under experimental condition, and the value of
      crushability showed no significant change.

PMID- 10332150
TI  - [Influence of bruxism during sleep on stomatognathic system].
AB  - Nocturnal tooth contact such as bruxism has been considered to be one of the
      major factors of temporo-mandibular disorders (TMD). However, little information
      has been reported regarding mandibular movements during bruxing, because of the
      limitation of the measuring method. The purpose of this study was to investigate
      the influence of bruxism on the stomatognathic system. A new device for measuring
      nocturnal mandibular movements was developed using a PIN photodiode sensor, which
      was integrated with the polysomnography including both masseter and anterior
      temporal EMG. The maximum error of the system was revealed to be less than 0.2
      mm. One episode was defined depending upon EMG activities above 5% MVC, and
      mandibular movement for each episode was classified into 3 patterns (Clenching,
      Grinding, and Mixed). Nine subjects were selected for the study. Two of them
      reported bruxing habits and one subject had some symptoms of TMD. Mandibular
      movement was analyzed only for these three subjects. Frequency and duration of
      the episode were 3.8-10.9 and 47.8-174.9 sec per hour, respectively. The values
      of two bruxism patients was high, comparing to the other seven subjects.
      Clenching pattern during "Mixed movement" was most frequently observed for all
      three subjects, and EMG activities during clenching were stronger than those
      during grinding. These findings suggested that tooth clenching during sleep may
      be harmful to the stomatognathic system, rather than other mandibular movements.

PMID- 10332151
TI  - [Brainstem segmental arrangement of sucking rhythm generators for trigeminal,
      facial and hypoglossal motoneurons].
AB  - Rhythmical sucking like activity (RSA) is known to be induced in the hypoglossal
      nerve (XII n) in an isolated brainstem-spinal cord preparation from newborn rats
      with bath application of N-methyl-D-aspartate (NMDA). Since natural sucking
      consists of well-coordinated rhythmical activities of the tongue, face, and jaw
      muscles, it is assumed that the trigeminal (V) and facial (VII) motoneurons would
      show rhythmical activities during the RSA. The purpose of this study was (1) to
      induce rhythmical activities in the V and VII ns in addition to XII n during bath
      application of NMDA, and (2) if they are induced, to locate the structures
      essential for generation of NMDA-induced rhythmical V, VII, and XII n activities
      using sectioning techniques. Experiments were performed on brainstem-spinal cord
      preparations isolated from newborn mice with or without the orofacial structure.
      Neural activities were recorded from the V, VII, and XII ns with suction
      electrodes. Movements of the tongue and jaw were recorded with a CCD camera
      system. It was found that (1) bath application of NMDA (5-20 microM) induced RSA
      in the V, VII, and XII ns, (2) it also induced rhythmical sucking-like movements
      of the jaw and tongue, and (3) after complete transections of the brainstem
      between the V and VII ns as well as at the pontomedullary junction, NMDA still
      induced the RSA in the V, VII, and XII ns. These results demonstrate that
      separate rhythm generators for rhythmical NMDA-induced activities in the V, VII,
      and XII motoneurons are located at the respective levels in the brainstem.

PMID- 10332152
TI  - [Ultrasonographic diagnosis of tongue cancer using intraoral high frequency
      probe].
AB  - Recent progress in ultrasonography has enabled to provide high-resolution images
      of superfical regions. In this study, the usefulness of ultrasonography using a
      high frequency probe for squamous cell carcinoma of the tongue was evaluated.
      Thirty normal adult subjects were examined to study ultrasonographic findings of
      normal tongue. The pattern of the normal tongue showed clearly three different
      zones, corresponding to three layers; mucosal epithelium, proper lamina and
      tongue muscle. The mean and standard deviation of epithelium thickness was 2.1 +/
      0.6 mm. The ultrasonographic findings for tongue carcinoma in 104 patients were
      evaluated. The ultrasonographic pattern of tongue carcinoma showed a hypoechoic
      structure as compared with surrounding tongue muscle. Depth of invasion defined
      as the distance between normal mucosal surface and the deepest point in 59
      patients was measured. The mean and standard deviation of depth of invasion
      measured by ultrasonography was 8.1 +/- 4.0 mm. The depth of invasion increased
      with T-stage. The difference of tumor depth between T1 and T2, or T1 and T3 was
      statistically significant (p < 0.001). A significant correlation (p < 0.001) was
      obtained between depth of invasion measured by ultrasonography and that measured
      by histological sections. In the group of patients with the tumor depth exceeding
      8 mm (mean depth), the lymph node metastasis rate was 75.0% (15/20). In the group
      of patients with the depth of less than 8 mm, the incidence of metastasis was
      29.8% (14/47). The difference between the two groups was statistically
      significant (p < 0.001). The 5-year survival rate calculated by the Kaplan-Meier
      method was 45.7% in patients with the depth exceeding 8 mm and was 87.5% in
      patients with the depth of less than 8 mm. The difference was statistically
      significant (p < 0.001). In conclusion, ultrasonography using a high-resolution
      probe was very useful for evaluation of squamous cell carcinoma of the tongue,
      and depth of invasion measured by ultrasonography could be a predictive factor
      for cervical lymph node metastasis and patient survival rate.

PMID- 10332153
TI  - [Studies on generation of cytotoxic T lymphocytes against oral squamous carcinoma
      by gene-transduction of a co-stimulatory molecule, CD80].
AB  - The effect of gene-transduction of a co-stimulatory molecule, CD80, on generation
      of cytotoxic T lymphocytes (CTL) against oral squamous cell carcinoma (SCC) was
      investigated. Long-term or primarily-established short-term cultured oral SCC
      cell lines were transfected with the human CD80 gene using a replication
      deficient recombinant adenovirus (Ad). High levels of CD80 expression were
      obtained in most tumor cell lines examined. Allogeneic peripheral blood
      mononuclear cells (PBMC) co-cultured with CD80-transduced tumor cells for 7 days
      elicited high cytotoxicity against melanoma (526 mel) and neuroblastoma (IMR32)
      cells, but not against oral SCCs (HSC3 and Ca9-22). Addition of either IL-2 or IL
      12 failed to induce specific cytotoxicity against oral SCC cell lines. The
      combined effect of CD80-transduced tumor cells and cytokines, IL-2 and IL-12, on
      generation of CTL in allogeneic and autologous system was investigated. PBMC from
      three SCC patients elicited MHC-restricted and TCR-dependent cytotoxicity against
      autologous SCC, although the level of induced cytotoxicity varied. In contrast,
      allogeneic PBMC obtained from healthy donors exhibited non-specific cytotoxicity
      alone. These results suggested that CD80-transduction may be effective in oral
      SCC for generating tumor specific CTL in an autologous system.

PMID- 10332154
TI  - [Biological effects of basic fibroblast growth factor (bFGF) and osteogenic
      protein-1 (OP-1/BMP-7) on bone marrow cells and development of cell-hybrid
      artificial bone].
AB  - In this study, the effects of bFGF and OP-1 on rat bone marrow cells and bone
      formation by the cultured bone marrow cells in porous hydroxyapatite (HA) in
      subcutaneous sites of syngeneic rats were investigated. The effects of bFGF and
      OP-1 on the proliferation and the differentiation of rat bone marrow cells were
      investigated by means of measurement of [3H] thymidine incorporation into DNA,
      ALP activity and bone nodule formation. This in vitro study showed that both bFGF
      and OP-1 increased [3H] thymidine incorporation, especially bFGF which stimulated
      it 3.5-fold at a dose of 30ng/ml. OP-1 stimulated ALP activity and bone nodule
      formation, whereas bFGF suppressed them. These data suggested that bFGF
      stimulates proliferation of rat bone marrow cells and OP-1 accelerates their
      differentiation. These growth factors were used to fabricate cell hybrid
      artificial bone, which consisted of the bone marrow cells. The ectopic bone
      formation was induced by the bone marrow cells cultured in HA, regardless of the
      treatment of these growth factors. However, the histological analysis revealed
      that the treatment with bFGF and/or OP-1 increased the area of new bone formation
      and accelerated the maturation of bone compared with the controls. The results
      suggested that the bone marrow cells cultured in HA three-dimensionally could be
      used clinically as a biomaterial. Furthermore, the use of bFGF and OP-1 to
      produce this cell-hybrid artificial bone increases its bone forming activity.

PMID- 10332155
TI  - The (un)workability of the disclosure provisions of the Criminal Procedure and
      Investigations Act 1996--disaster in the criminal law?

PMID- 10332156
TI  - The influence of drugs upon testimony.
AB  - A wide range of drugs (medicines) are used currently, many of which are designed
      to affect brain function. Others do so as a side-effect. The effects depend on
      how the body deals with the drug (pharmacokinetics) and how the drug affects the
      body, including the brain (pharmacodynamics). An extensive range of effects on
      the brain and psychological functioning can ensue, including effects on
      intellectual functioning, dexterity, memory, learning and subjective effects.
      Individual factors are important and can profoundly influence both the type and
      extent of drug effects. Relevant drugs can be divided into: 1. Those prescribed
      primarily to treat psychiatric disorders. These include sleeping tablets,
      tranquillizers, antidepressants and antipsychotics. 2. Those used to treat
      neurological disorders that have psychological side-effects. Examples are
      anticonvulsants and anti-parkinsonian drugs. 3. Those used to treat non-nervous
      disorders that may have psychological side-effects. 4. Illicit drugs used in the
      non-medical context by drug addicts. Drug-induced states that can influence
      testimony are mainly sedation, disinhibition, paradoxical reactions and
      alterations in memory. A list of pointers was given in this paper with respect to
      practical considerations in assessing the possible effects of drugs on testimony.

PMID- 10332157
TI  - Physiological illnesses and their potential for influencing testimony.

PMID- 10332158
TI  - False complaints of sexual assault: recovered memories of childhood sexual abuse.
AB  - False complaints are easily made and carry serious consequences for the accused.
      Many of those who make false claims sincerely believe the truth of what they
      report. Some are opportunistic and are consciously lying for personal gain. A
      special type of false allegation, the false memory syndrome, arises typically
      within therapy. People report the 'recovery' of memories of previously unknown
      childhood sexual abuse. The influence of practitioners' beliefs and practices in
      the eliciting of false 'memories' and of false complaints cannot be overlooked.
      The problems of diagnosis, issues of confidentiality and the role of the expert
      witness as court educator are discussed.

PMID- 10332159
TI  - Earwitness testimony.

PMID- 10332160
TI  - Obtaining witness statements: the psychology, best practice and proposals for
      innovation.

PMID- 10332161
TI  - 'Non-barking dogs and other odd species': identifying anomaly in witness
      testimony.

PMID- 10332163
TI  - The management of opiate addicts in police custody.
AB  - Many suspects detained at police stations for questioning are under the influence
      of illicit drugs. This presents a problem, as the reliability of confessions made
      under the influence of drugs or whilst experiencing withdrawal symptoms may be
      adversely affected. This paper reviews the current management of opiate addicts
      in police custody and relevant legislation in the UK to highlight some of the
      difficulties that arise. It concentrates in particular on the specific problem of
      defining and assessing fitness for interview in this group and reviews the
      current evidence of the effect of opiates and opiate withdrawal symptoms on the
      reliability of testimony. It concludes that any framework for the assessment of
      fitness for interview must address the question of reliability. More needs to be
      known about the effects of opiates and opiate withdrawal symptoms on the
      reliability of testimony in the police interview situation.

PMID- 10332162
TI  - Attempted child-stealing: post-ictal psychosis and psychological distress.
AB  - Baby-stealing is probably one of the more taboo crimes in our society. Its
      connection with psychological distress, while generally acknowledged, is not
      always well understood. In this paper we present an unusual and complex case of a
      woman who attempted to steal young babies while in a state of extreme
      psychological distress following epileptic seizures. While the post-epileptic
      state was characterized as 'psychotic' there were clear psychological antecedents
      to explain the form in which the postical psychosis was expressed. Treatment
      strategies included modification of medication regime and use of cognitive
      therapy to ameliorate the impact of postictal confusion.

PMID- 10332164
TI  - Crowding and violent behavior: the influence of patient density on violent and
      self-harming behaviour at a medium secure unit.
AB  - This study examines the influence of patient density (crowding) and number of
      potential perpetrators on the number of incidents of violence and self-harm at a
      medium secure unit. Of 2,053 incidents examined over a period of 974 days, 73%
      were perpetrated by 20% of the patients, the majority by patients identified as
      potential perpetrators. Increased patient density was not associated with
      increased risk of violence or self-harm. There was no evidence to suggest that
      the presence of those identified as potentially violent or self-harming increased
      the risk of others engaging in such behaviour.

PMID- 10332165
TI  - Psychological consequences of road traffic accidents.
AB  - Although accident-induced psychopathology was formerly considered as being
      associated with secondary gain, subsequent reports have refuted this contention.
      More recent studies have shown that road traffic accident-induced psychopathology
      can be a persistent and chronic disability, irrespective of whether the victim
      seeks compensation. This study describes the psychological assessment of 50
      potential road traffic accident litigants referred by solicitors. They were all
      assessed within a hospital setting approximately three weeks after the receipt of
      the request for a psychological report. All participants completed measures of
      depression, anxiety, post-traumatic stress and subjective distress, and
      information was obtained about injuries sustained. The results suggest that the
      potential litigants who sustained an injury presented with significantly higher
      post-traumatic distress intrusion and avoidance scores, and that these scores are
      also influenced by the delay between the accident and the assessment.
      Furthermore, the sample showed intrusion, avoidance and perceived stress scores
      above normal population data. Reducing the delay between the accident and
      assessment has important clinical implications. However, it appears that
      solicitors rather than general practitioners initiate these referrals. Some
      implications for assessment prior to treatment are discussed.

PMID- 10332166
TI  - Violent mortality patterns in immigrants in Israel (1990-95).
AB  - Since 1989, a large number of immigrants, mostly from the former Soviet Union,
      have arrived in Israel, increasing the local population (c. 5 million) by
      700,000. The morbidity and mortality of this immigrant population have been the
      concern of many investigations. In the present study we examine the mortality
      pattern of a sample of 1,000 immigrants, whose deaths occurred during the years
      1990-95 and were examined at the L. Greenberg (National) Institute of Forensic
      Medicine. The sample was divided into two subgroups, natural and unnatural,
      according to manner of death. Seventy-five per cent of the victims in the violent
      death subgroup were males with a mean age of 44.6 (SD 17.3) years, while the
      females of the same category were 52.7 years old on average (SD 19.9). The age
      distribution of the whole sample showed peaks in the 25-34-year-old group for
      males and the 35-44-year-old group for females. The most frequent causes of death
      were accident (44.1%), suicide (12.6%) and homicide (7%). In 5% of cases the
      cause of death could not be determined. The pattern of mortality from violent
      causes in the immigrant population differed from that of the country of origin in
      all parameters. The incidence of unnatural death in immigrants resembled the
      local pattern in Israel, and was significantly lower than that of their homeland.

PMID- 10332167
TI  - Hypertensive cardiomyopathy relieved by pacing?

PMID- 10332168
TI  - Working together: international medical readiness.

PMID- 10332169
TI  - Casualty management: scud missile attack, Dhahran, Saudi Arabia.
AB  - On the evening of February 25, 1991, an Iraqi scud missile plunged into a
      "barracks/warehouse" used to house U.S. Army soldiers assigned to the 475th
      Quartermaster Group in Dhahran, Saudi Arabia. As a consequence of this scud
      attack, 28 soldiers died, 110 were hospitalized, and 150 experienced minor
      physical injuries and/or subsequent mental health problems. This one scud's
      impact accounted for more than one-third of all U.S. soldiers killed during the
      war. Fortunately, there were very few "models" of mass casualty experiences
      during the Persian Gulf War to evaluate the critical clinical outcomes to the
      soldiers. An analysis of this event has important implications for future
      military operations that feature a multinational medical force structure. This
      article summarizes the medical preparations before the war, the key,
      chronological events, and the medical outcomes of the mass casualty event.
      Lessons learned in casualty management for future Army contingency medical
      planners are identified.

PMID- 10332170
TI  - The health status of Gulf War veterans: lessons learned from the Department of
      Veterans Affairs Health Registry.
AB  - OBJECTIVE: To describe the demographic characteristics and postwar health status
      of U.S. Gulf War veterans who participated in the Department of Veterans Affairs
      health examination registry program. DESIGN: Case records of 52,835 veterans who
      participated in a standardized health examination program were reviewed. SETTING:
      Participants volunteered for physical examinations at a Department of Veterans
      Affairs medical treatment facility from August 1992 to September 1996. SUBJECTS:
      U.S. Gulf War veterans deployed to southwest Asia between August 1990 and 1996.
      MAIN OUTCOME MEASURE: Demographic, military, symptom, and International
      Classification of Diseases, Ninth Revision, Clinical Modification, diagnostic
      categories. RESULTS: A wide variety of symptoms and diagnoses were reported
      without apparent internal variation by military characteristics (branch and
      service component). The frequency of symptoms (fatigue, skin rash, headache,
      muscle and joint pain, and memory loss) reported increased over time, whereas the
      proportion of individuals with physician-diagnosed illnesses remained fairly
      constant. No single category of disease increased or decreased substantially over
      time. CONCLUSIONS: Veterans have experienced a wide variety of health problems
      since their Gulf War service. These problems, in aggregate, are different from
      what has been seen in other armed conflicts. The Department of Veterans Affairs
      registry is a very large case series and has failed to identify a single, unique
      syndrome or new illness after Gulf War service. An epidemiologic study would
      better define the prevalence of specific symptoms and medical conditions among
      Gulf War veterans and to what extent any of the conditions identified are
      associated with Gulf War military service. The knowledge provided by such studies
      would be important to development of preventive measures and future deployment
      medical surveillance planning.

PMID- 10332171
TI  - Mass casualty triage knowledge of military medical personnel.
AB  - During battlefield and mass casualty incidents, triage has been traditionally
      performed by many different personnel, including medics, nurses, dentists, and
      physicians. The objective of this study was to determine which military medical
      providers are most knowledgeable in mass casualty triage. The design was a
      prospective, written, timed, case-based examination of triage knowledge.
      Participants were volunteers from the active duty medical (physician), dental,
      nursing, and enlisted corps of the three military services. Subjects completed a
      16-minute written examination consisting of seven cases in each of three
      simulated mass casualty scenarios: combat; nuclear, biological, and chemical; and
      humanitarian. Tests were taken anonymously, although demographic data on medical
      specialty, training, and experience were collected. Participants were instructed
      to classify the cases using the NATO categories of immediate, delayed, minimal,
      or expectant. Scores were tabulated according to two grading scales: an absolute
      scale of number correct, and a weighted scale amplifying gross
      misclassifications. Median scores between groups were tested pairwise using the
      Kruskal-Wallis one-way analysis of variance with p < or = 0.05. Statistically
      significant differences were noted between the highest and lowest scoring groups
      in each scenario. Our conclusion is that among the subject groups tested,
      physicians were best at mass casualty triage. Dentists, nurses, and medics scored
      progressively less well on our examination.

PMID- 10332172
TI  - Changes in the care of the battle casualty: lessons learned from the Falklands
      campaign.
AB  - In the Falklands War, advanced surgical centers were set up and 241 patients
      underwent surgery. There were three deaths. The patterns of wounding, method of
      casualty management, and lessons learned are discussed.

PMID- 10332173
TI  - Biomedical research: its mission within the French Military Medical Service.
AB  - The French Military Medical Service is organized as a distinct corps to support
      Army, Navy, and Air Force operations. This complex mission is accomplished
      through five operational components: (1) direct medical support of the force
      units; (2) hospital nursing and expertise; (3) biomedical research; (4)
      biomedical training; and (5) medical supply. Additionally, the French Military
      Medical Service is committed to humanitarian and civil medical support. Advanced
      biomedical research, particularly on infectious diseases and treatment of
      injuries, is actively pursued. Fundamental and applied research is needed to
      anticipate potential threats and improve medical support and care of French
      forces. The importance of biomedical research was recognized as necessary to
      develop technological improvements in rescue operations and to provide the
      military command with scientifically based advice. Biomedical military research
      has often been the engine of progress in medicine and surgery. Chief among those
      developments has been a special emphasis on infectious diseases and wound
      treatment.

PMID- 10332174
TI  - German military medicine: missions and innovations.
AB  - The German military medical service's foremost task in peacetime is to train and
      prepare medical personnel for their tasks in wartime. To this end, six medical
      subservices have been formed. They provide inpatient and outpatient care for the
      assigned military formations. Medical support for the reaction forces follows the
      principles of "operational medicine," which is provided in three qualitatively
      coordinated medical support levels. These support levels from the "lifesaving
      chain" for Bundeswehr soldiers deployed abroad, who are entitled to receive
      medical care that corresponds to the medical standard in Germany.

PMID- 10332176
TI  - Arthroplasty after war injuries to major joints.
AB  - From 1992 to 1995, replacement of the joint with an endoprosthesis after serious
      wounding and major destruction of joint elements was performed in 10 soldiers.
      Arthroplasty was performed on five knees, three hips, and two shoulders. The age
      range of the wounded soldiers was 22 to 55 years (mean, 37.7 years). Six soldiers
      suffered explosive injuries, and 4 were injured by gunfire. Time elapsed from the
      moment of wounding to the time of total joint replacement was 9 to 42 months. We
      decided on arthroplasty as the preferred treatment because of the presence of
      strong contractures and very painful movement. In 8 patients, the results of the
      treatment, based on a follow-up time of 36 to 48 months, were good. In 2
      patients, early septic arthritis developed after arthroplasty of the knee with
      concomitant loosening of the endoprosthesis. Staphylococcus aureus was detected
      in both patients. In those 2 patients, therefore, arthrodesis of the knee with
      external fixation was performed.

PMID- 10332175
TI  - Peripheral nerve war injuries.
AB  - OBJECTIVE: The purpose of this study is to evaluate peripheral nerve war injuries
      sustained during the war in southern Croatia and Bosnia and Herzegovina. PATIENTS
      AND METHODS: During the war in Croatia, 713 patients (99% male and 1% female)
      with wounds inflicted by firearms were examined at the Laboratory of
      Neurophysiology, University Hospital, Split. The patients, soldiers and civilians
      alike, ranged in age from 6 to 73 years (average, 28 years). All patients with
      firearm nerve war injuries underwent detection by electromyography and
      plurisegmental examination of the damaged peripheral nerve (neurography). The
      patients were examined and controlled on three occasions: within 2 months after
      wounding; up to 6 months after wounding; and more than 6 months after wounding.
      RESULTS: Single peripheral nerve lesions were present in 80% of the patients, and
      multiple peripheral nerve or plexus lesions were present in 20% of the patients.
      Peroneal and ulnar nerves were most often involved (20.9% and 19.8%,
      respectively). Associated massive injuries to the muscles, large blood vessels,
      or vital organs were present in 45% of the patients. Wounds were inflicted by
      shell fragments in 80% of the patients and by projectiles in 20% of the patients.
      CONCLUSION: According to our results, better recovery was achieved with
      conservative treatment and when physical therapy was initiated early with maximal
      patient cooperation. Electromyoneurographic findings were the most valid in the
      prognostic classification of war-inflicted peripheral nerve injuries.

PMID- 10332177
TI  - External fixator for war purposes: the CMC fixator.
AB  - More than 75% of all injuries in modern wars are localized on the extremities,
      and more than one-third of these injuries are accompanied by bone fracture.
      Application of an external fixator is one of the basic procedures in the
      treatment of war fractures. In this article, we present an external fixator for
      war purposes of our own construction called the CMC (Croatian Medical Corps)
      fixator. Although designed as a transport fixator, because of good biomechanical
      properties it has been widely used for definitive osteosynthesis of war injuries.
      The CMC fixator is manufactured as a sterile set, ready to use, with all
      necessary parts for application. On the battlefields of Croatia and Bosnia and
      Herzegovina during the war from 1991 to 1995, more than 2,500 CMC fixators were
      applied. The fixator has satisfied all required conditions and considerably
      contributed to diminishing the consequences of war fractures.

PMID- 10332178
TI  - One year's trauma mortality experience at Brooke Army Medical Center: is
      aeromedical transportation of trauma patients necessary?
AB  - The purpose of this study was to review whether air ambulance transportation of
      trauma patients to the Brooke Army Medical Center (BAMC) level I trauma center
      contributed to maintaining national mortality standards in the trauma care of
      these patients. Aeromedical transportation is considered a standard-of-care
      component of regional trauma systems throughout the United States. Pooled trauma
      database information from 792 consecutive ambulance-transported trauma patients
      received at BAMC during the fiscal year from October 1, 1995, to September 30,
      1996, were reviewed. The 792 trauma patients were composed of 687 patients
      transported by ground ambulance and 105 patients who received helicopter
      aeromedical evacuation. Aeromedical evacuation was associated with increased
      levels of prehospital medical care and faster transportation than ground
      ambulance service. The mortality rates (immediate, early, and late deaths) of
      both ambulance groups were compared with national mortality standards using the
      internationally recognized Trauma and Injury Severity Score methodology, based on
      the Major Trauma Outcome Study in 1986 and validated in 1992. The Z test for
      independent populations demonstrated no statistically significant difference
      between BAMC trauma mortality rates for either ambulance group compared with
      national trauma mortality rates. The results suggest that aeromedical evacuation
      of the more severely injured patients farthest from the BAMC trauma center
      resulted in mortality rates that met national standards.

PMID- 10332179
TI  - Rescue and salvage of casualties suffering from the crush syndrome after mass
      disasters.
AB  - Extensive muscle crush injury culminating in the crush syndrome (CS) is often
      lethal unless promptly and vigorously treated. The causes of death in the CS are
      extreme hypovolemic shock, hyperkalemia, hypocalcemia, metabolic acidosis, acute
      myoglobinuric renal failure, and the compartment syndrome. Treatment consists of
      early massive volume replacement, preferably administered in the field, followed
      by forced alkaline solute (mannitol) diuresis. With this regimen, it is possible
      to increase substantially the survival of lives and limbs and to prevent acute
      myoglobinuric renal failure in patients suffering from the CS. Preliminary
      experience suggests that intravenous hypertonic mannitol is protective also to
      the injured muscle and can be used as a noninvasive adjunct in the management of
      compartment syndrome in humans. Moreover, by preserving muscular integrity,
      mannitol can conceivably reduce sarcolemmal leakage of the nephrotoxic myoglobin
      urate and phosphate and thus further defend kidney function. Furthermore,
      mannitol reduces the plasma pool of these nephrotoxic metabolites by increasing
      urinary elimination.

PMID- 10332180
TI  - Prevention of pelvic stress fractures in female army recruits.
AB  - In 1991-1992, a pelvic stress fracture incidence of 11.2% was recorded in a
      cohort of 143 female Australian Army recruits. An incidence of 0.1% was recorded
      in a cohort of male recruits trained in the 1992-1993 year using a nearly
      identical program. A number of preventive strategies were instituted in an
      attempt to reduce the high incidence of injury in female recruits. Route march
      speed was reduced from 7.5 to 5 km/h, running occurred on softer surfaces,
      individual step length was promoted instead of marching in step, march and run
      formations were more widely spaced, and interval-running training replaced
      traditional middle-distance runs. Pelvic stress fracture incidence decreased
      significantly to 0.6% in an immediately subsequent cohort of 161 female recruits
      (chi 2 = 15.12 for 1 df; p < 0.001). It is likely that the preventive strategies
      reduced bone strain by reducing the frequency and forces of impact during the
      training period.

PMID- 10332181
TI  - Prosthetic rehabilitation of a warfare facial trauma.
AB  - This case report presents the prosthetic treatment of a warfare facial trauma
      patient with the aim of providing satisfactory function, esthetics, and
      alleviation of deformities. Veneer crowns with rests, root coping, and metal-base
      partial prostheses were used for the patient therapy and treatment.

PMID- 10332182
TI  - Contact urticaria to the MCU-2A/P gas mask.
AB  - A case of contact urticaria to the silicone rubber in the MCU-2A/P gas mask is
      presented. Contact urticaria is a type I hypersensitivity reaction mediated by
      immunoglobulin E that usually manifests as localized erythema, edema, pruritus,
      and urticarial plaques. It can also cause systemic reactions, including
      anaphylaxis. Allergic reactions to silicone rubber have been increasingly
      reported and are of importance in medical and military personnel. The implication
      of such a diagnosis in an active duty military member is significant because the
      individual cannot be worldwide-qualified. The correct diagnosis of allergic skin
      reactions to personal protective gear is critical to maintaining a strong
      fighting force and protecting military personnel from potentially life
      threatening allergic reactions.

PMID- 10332183
TI  - [Immunohistochemical studies on neuronal changes in brain stem nucleus of
      forensic autopsied cases. I. Various cases of asphyxia and respiratory disorder].
AB  - Several nuclei in brain stem are well known to play an important role in
      supporting human life. However, the connection between neural changes of brain
      stem and the cause of death is not yet fully understood. To investigate the
      correlation of brain stem damage with various cause of respiratory disorders,
      neural changes of the arcuate nucleus (ARC), the hypoglossal nucleus (HN) and the
      inferior olivary nucleus (IO) were examined using immunohistochemical technique.
      Based on the cause of death, the forensic autopsy cases were divided into 5
      groups as follows. Group I: hanging, ligature strangulation and manual
      strangulation, Group II: smothering and choking, Group III: drowning, Group IV:
      respiratory failure, control group: heat stroke and sun stroke. Brain was fixed
      with phosphate-buffer formalin, and the brain stem was horizontally dissected at
      the level of apex, then embedded in paraffin. The sections were stained with the
      antibodies against microtubule-associated protein 2 (MAP2), muscalinic
      acetylcholine receptor (mAChR), c-fos gene product (c-Fos) and 72 kD heat-shock
      protein (HSP70). Three nuclei showed no obvious morphological changes in all
      examined groups. However, in case of asphyxia (Group I to III), neurons in HN
      were positively stained with both HSP70 and c-Fos antibodies. This may indicate
      that the occlusion of upper airway results in the neuronal damage of HN without
      their morphological changes. Positive staining of HSP70 and c-Fos in IO was more
      frequently observed in Group III than other 4 groups. Since IO is involved in
      maintaining body balance which is often disturbed by drowning, it seems possible
      that neuronal damage in IO observed in drowning may be related to the disturbance
      of body balance. These observations indicate that immunohistochemical study on
      the damage to neurons in brain stem nuclei can provide useful information for
      determining the cause of death.

PMID- 10332184
TI  - [Immunohistochemical studies on neuronal changes in brain stem nucleus of
      forensic autopsied cases. II. Sudden infant death syndrome].
AB  - Several nuclei in brain stem are well known to play an important role in
      supporting human life. However, the connection between neural changes of brain
      stem and the cause of death is not yet fully understood. Previously, in sudden
      infant death syndrome (SIDS) it has been suggested that impaired
      cardioventilatory control might contribute to cause of death. So, to investigate
      the brain stem damage in SIDS, neural changes of the arcuate nucleus (ARC), the
      hypoglossal nucleus (HN) and the inferior olivary nucleus (IO) was examined using
      immunohistochemical technique. Brain was fixed with phosphate-buffer formalin,
      and the brain stem was horizontally dissected at the level of apex, then embedded
      in paraffin. The sections were stained with the antibodies against microtubule
      associated protein 2 (MAP2), muscalinic acetylcholine receptor (mAChR), c-fos
      gene product (c-Fos) and 72 kD heat-shock protein (HSP70). Morphological changes
      of neurons in three nuclei were not evident. Moreover, because MAP2 degeneration
      and expression of HSP70 and c-Fos were not observed, neuronal damage in those
      nuclei was not suspected. However, although there was no abnormality of mAChR
      immunostaining in HN and IO, the rate of mAChR-immunopositive neurons in ARC was
      less than that in control. These observations indicate that immunohistochemical
      study on the neuronal changes in ARC can provide useful information for
      diagnosing SIDS.

PMID- 10332185
TI  - [An autopsy case of sudden death caused by untreated sepsis after complete
      remission of acute promyelocytic leukemia].
AB  - The patient was 63 year-old man. He had been diagnosed as acute promyelocytic
      leukemia (APL) and treated until 4 month before his death with complete
      remission. The patient suddenly died 9 days after he complained of occipital
      headache. Autopsy and histopathologic findings were as follows: the left pleura
      was thick and calcificated with abscess, compatible with the findings of old
      tuberculosis complicated with bacterial infection. Furthermore, polynuclear
      leukocytes and gram-positive micro-organisms were accumulated in the lungs, and
      pyogenic meningitis, pyonephritis, splenitis were also found. Bacteologically,
      Streptococcus pneumoniae was detected from cadaver's blood and cerebrospinal
      fluid. Therefore, we concluded that the patient was died of septic shock caused
      by systemic infection of Streptococcus pneumoniae. The mortality of septic shock
      is high and in some patients, causative organisms may not be isolated. In the
      present case, although the original inflammation was left pleuritis due to
      Streptococcus pneumoniae, correct clinical diagnosis was not made before death as
      the patient had lacked any complaints except for occipital headache. This case
      revealed that the cause of sudden death was sepsis induced by Streptococcus
      pneumoniae instead of a relapse of APL. This case also illustrated the importance
      of reviewing the previous history of a patient and doing postmortem bacteologic
      examination in a case of suspected sepsis.

PMID- 10332186
TI  - [A case of identification of two persons from heavily burned teeth by age
      estimation].
AB  - A man murdered his two daughters, one five years and two months old and one seven
      months old. He placed them into a 750 degrees C aluminum liquefying furnace.
      Teeth and many fragments of the severely burned bones were recovered. However, at
      first, the bone fragments did not offer proof that two children were put into the
      furnace. The age estimation of the teeth burned in liquefied aluminum was carried
      out based on the maturity of the teeth and the degree of absorption of deciduous
      teeth roots. As a result from the admixture of permanent teeth and deciduous
      teeth, we presumed them to be derived from more than one person.

PMID- 10332187
TI  - [Mental health in the aged society].

PMID- 10332188
TI  - [Biological fluctuations and neuronal dynamics].

PMID- 10332189
TI  - [Cardiovascular disease in the elderly: the Hisayama Study].

PMID- 10332190
TI  - [Matured society in 21st century on the basis of the bio-defense].

PMID- 10332191
TI  - [Hyperlipidemia in elderly].

PMID- 10332192
TI  - [A study of the degree of burden and subjective sense of well being in care
      givers involved in home care].
AB  - We investigated the degree of burden on care-givers and their subjective sense of
      well being, and studied the factors affecting them. Twenty people who were
      responsible for at least a year for constant care of elderly or bed-ridden
      patients under visitation care and nursing supervision of this hospital were
      registered. Regarding the care-givers, we investigated age, sex, duration of
      care, the relations between the care-givers and the cared-for, assistant care
      givers, profession and hobbies, if any, of the care-givers, the depression
      scores; the social support, the degree of burden imposed by care, and the
      subjective sense of well being. As for the cared-for, we investigated their age,
      disease and degree of ADL. The burden felt by the care-giver became greater if
      the care-giver was a woman (p < 0.05), if the relationship with the cared or the
      health status of the care-giver was poor (p < 0.05, respectively), and if the
      scores for functional and emotional support networks were poor (p < 0.005 and p <
      0.05, respectively). As for the cared-for, the burden was greater if they were
      older (p < 0.05) and if it was difficult for them to leave bed (p < 0.05). The
      sense of subjective well being of the care-giver was greater if there was an
      assistant care-giver (p < 0.005); if the scores for the functional and the
      emotional support networks were higher (p < 0.05, respectively): and if
      understanding of information in terms of ADL was not adequate (p < 0.05). The
      present study suggested the importance of improving the emotional and functional
      support networks for the care-giver in helping them continue care by alleviating
      the burden and not suffering a loss in the subjective sense of well being.

PMID- 10332193
TI  - [Compliance in use of external protectors for hip fractures among the community
      elderly in Japan].
AB  - To protect femoral neck fractures which are the most serious complication of
      osteoporosis and are increasing in frequency in Japan, an external hip protector
      (EHP) fixed in special underwear has been proven to absorb a direct impact to the
      greater trochanter during a fall from standing height. In this study, we
      investigated compliance concerning the use of EHPs, for six months using two
      types of EHP, i.e., hard pad type (Hip Protector, Sahvatex) from Denmark (Fig. 1)
      and soft pad type (Safety Pants, Rounomo Oy) from Finland. The subjects were 20
      elderly women aged 70 years or more who had at least one experience of falling
      within the year preceding the baseline survey in September of 1997. The
      compliance rate is shown in Fig. 2. Though the soft type EHP had relatively
      better compliance than the hard type EHP, there was no significant difference
      between them. The main reason for early dropout (one or two weeks after base
      line) was "difficulty to remove especially with regard to using the toilet". The
      main reason for later dropout was "too tight to wear in winter". There were no
      significant differences with regard to anthropometric measurements, physical
      activity, ADL, and rate of falls between compliers and dropouts except age (73.6
      vs 78.5 yrs). Sufficient explanation at baseline and generatively good motivation
      for wearing the EHP will maintain a high compliance which may result in the
      effective prevention of hip fractures among the community elderly.

PMID- 10332194
TI  - [Elderly outpatients' attitudes toward care in terminal stage disease].
AB  - Responses to a questionnaire regarding 1) dying at home, 2) being told of a
      diagnosis of cancer, and 3) hydration and nutrition, uses of narcotics for pain
      and dyspnea, oxygen treatment, antibiotics, transfusion and surgery in a near
      vegetative state was obtained from 562 outpatients (73.4 +/- 8.6 years:mean +/-
      SD, men:women = 1.0:1.7). Dying at home was preferred by 64% and hospital death
      by 24%. Sixty and 65% of patients chose to be told of the diagnosis either in the
      last 3 months or at the early curable stage of the disease respectively, while
      only 53% wanted to be told precisely about their remaining estimated survival. If
      their spouse had terminal stage disease, 42% chose to inform the spouse of the
      diagnosis. Eighty percent chose palliative care, while 9.3% wished for intensive
      life-sustaining treatment. In a near vegetative state, tube feeding was desired
      by 8.7% and intravenous drip infusion by 39%; narcotics for pain or dyspnea were
      desired by 40 and 52%; oxygen or tracheostomy plus a respirator for dyspnea was
      chosen in 56 and 11% respectively; antibiotics for treatment of infection was
      desired by 38%; surgery for intestinal obstruction by 36 percent; transfusion for
      bleeding by 29%; and no treatment in any situation by 21%. Commonly expressed
      wishes were for a natural death, dying at home, and being told of the status of
      their disease, while details of palliative care were not well recognized.

PMID- 10332195
TI  - [Analysis of elderly patients, aged 60 years old or over, with acute
      lymphoblastic leukemia].
AB  - In order to obtain the realistic background information on clinical features, and
      the present status of treatment and outcome in elderly patients with acute
      lymphoblastic leukemia (ALL), we carried out random survey of patients with ALL
      aged 60 or over who had been admitted to 13 general hospitals in the Nagoya
      region from January 1990 through December 1995. Among the 20 cases collected,
      ages ranged from 60 to 88 (median age 68), and the male to female ratio was 11:9.
      Nineteen cases were L2 subtype in FAB classification. Among 17 patients, 13 had B
      cell series surface phenotypes (76%), 2 had T cell series (12%), one had stem
      cell type (6%) and one had an undetermined phenotype (6%). Ph chromosomes were
      detected in 4 cases among 15 analyzed (27%), whereas 5 were found to have no
      chromosomal abnormality. Half of the patients had some concurrent disease at
      diagnosis, including two with treatment-limiting complications. Common induction
      regimens were the combination of adriamycin (ADM) + vincristine (VCR) +
      cyclophosphamide (CPM) + mitoxdn trone + L-asparaginase [4 patients]. ADM + VCR +
      PSL [4 patients]. VCR + PSL [4 patients] and others [8 patients]. The overall
      remission rate was 55.0% (11/20) without any significant difference according to
      age. The median survival time (MST) for all cases was 205 days. (1-year survival
      rate:17.9%, 2-year survival rate:10.8%). There was no significant difference in
      survival times among patients with the Ph chromosome, those with other
      chromosomal abnormalities and those without them. All the patients aged 75 or
      over were treated with attenuated induction therapy, and they had a shorter
      survival than those aged less than 75, but with no statistical significance
      [MST:121 days versus 276 days, p = 0.307 (generalized Wilcoxon test)].

PMID- 10332197
TI  - [Recent advances in diagnostic imagings for the evaluation of pancreatic
      diseases].

PMID- 10332196
TI  - [An autopsy case of elderly idiopathic enlargement of the right atrium].
AB  - We report an autopsy case of an 88-year-old man with idiopathic enlargement of
      the right atrium which is considered to be the oldest case reported. The patient
      was given a diagnosis of atrial fibrillation at the age of 75 years, when he
      developed congestive heart failure. Bradycardia associated with partial atrial
      standstill was detected and, the patient underwent implantation of a pacemaker at
      age 77. An echocardiogram revealed marked enlargement of the right atrium and
      moderate enlargement of the left atrium. Thus, idiopathic enlargement of the
      right atrium was diagnosed. He had recurrent congestive heart failure before
      admission to our hospital because of malnutrition and anemia. Although he was
      treated with high calorie intravenous infusion and blood transfusion, he died of
      pneumonia and heart failure. Postmortem examination revealed that the heart
      weighed 430 g, and there was marked dilatation of the right atrium which had an
      extremely thin wall. The annular circumference of the tricuspid valve was
      markedly dilated, 170 mm, resulting in tricuspid regurgitation. The left atrium
      was moderately dilated and the right and left ventricles were slightly dilated.
      Histologically, the free wall of the right atrium was totally replaced by fibrous
      tissue and atrioventricular valves did not reveal any rheumatic changes. These
      pathological findings were compatible with idiopathic enlargement of the right
      atrium. There has been no previous case report of idiopathic enlargement of the
      right atrium in a patient aged 80 years of age or over.

PMID- 10332198
TI  - [New histological classification of chronic hepatitis].

PMID- 10332199
TI  - [Study of transforming growth factor-alpha expression in duodenal ulcer].
AB  - Various growth factors were also reported to promote healing of peptic ulcer. We
      have used a monoclonal antibody in conjunction with a standard
      immunohistochemical technique to characterize the expression of transforming
      growth factor-alpha (TGF-alpha) in duodenal ulcer. TGF-alpha immunoreactivity is
      found in Brunner's gland, also in immature gland and in duodenal epitheliums, but
      not in gastric metaplasia of the duodenum. TGF-alpha expression of healing and
      scar stage was higher than that of active stage. The presence or absence of
      Helicobacter pylori infection did not affect the expression of TGF-alpha in
      duodenal ulcer.

PMID- 10332200
TI  - [A study of hypertriglyceridemia occurring in patients with chronic hepatitis C
      during administration of interferon beta].
AB  - The prevalence and risk factors of hypertriglyceridemia during the administration
      of interferon (IFN) were examined in 78 patients with chronic hepatitis C who
      were treated with 6 MU of IFN-beta once or 3 MU of IFN-beta twice a day for 6
      weeks. Hypertriglyceridemia (serum triglyceride (TG) above 150 mg/dl) was found
      before the start of IFN treatment in 9% of the patients. During the
      administration of IFN, elevation of serum TG above 150 mg/dl was found in 82% of
      patients. In addition, serum TG level exceeded 500 mg/dl at least once during the
      administration of IFN in 13% of patients. On stepwise multiple regression
      analysis, three risk factors, high serum TG value before the administration of
      IFN, high ALT value before the administration of IFN, and divided administration
      of IFN-beta twice daily were found to be associated with hypertriglyceridemia
      during IFN administration.

PMID- 10332201
TI  - [A case of nutcracker esophagus complicated with angina pectoris].

PMID- 10332202
TI  - [A case of recurrent cancer in sigmoid colon with submucosal spread and hepatic
      metastasis 4 years and 6 months after polypectomy].

PMID- 10332204
TI  - [A case of elderly man with systemic lupus erythematosus (SLE) associated with
      paralytic ileus and fistula formation].

PMID- 10332203
TI  - [A case of mucinous cystadenocarcinoma which developed from the edge after
      appendectomy].

PMID- 10332205
TI  - [An autopsy case of primary non-Hodgkin lymphoma of the extrahepatic bile duct].

PMID- 10332207
TI  - [A case of severe alcoholic hepatitis with iliopsoas abscess].

PMID- 10332206
TI  - [A case of acute hepatitis infected with hepatitis B virus during pregnancy and
      complicated by Gianotti-Crosti syndrome].

PMID- 10332208
TI  - [A case of idiopathic portal hypertension complicated with multiple focal nodular
      hyperplasia (FNH) like lesions].

PMID- 10332209
TI  - [A case of Cruveilhier-Baumgarten syndrome].

PMID- 10332210
TI  - [Serum amyloid A (SAA) 1, SAA 2 and apolipoprotein E isotype frequencies in
      rheumatoid arthritis patients with AA amyloidosis].
AB  - OBJECTIVES: To examine the relationship between polymorphism of serum amyloid A
      (SAA) 1, SAA 2 and Apolipoprotein E (Apo E) and susceptibility to AA amyloidosis
      (AA) in rheumatoid arthritis (RA). METHODS: We compared the frequencies of SAA 1
      alleles (alpha, beta, gamma), SAA 2 alleles (alpha, beta) and apo E alleles
      (epsilon 2, epsilon 3, epsilon 4) in AA-positive RA with those in AA-negative RA.
      Each isotype was analyzed by the following method: SAA 1 and SAA 2 by PCR-RFLP
      and Apo E by Western blotting method. Blood samples were obtained from 50 AA
      positive RA patients with SAA 1 isotype, 50 AA-negative RA patients with SAA 1
      isotype, 27 AA-positive RA patients with SAA 2 isotype, and 26 AA-negative RA
      patients with SAA 2 isotype, respectively. Likewise, Apo E isotype was determined
      by withdrawing blood samples from 61 AA-positive RA cases and 51 AA-negative RA
      cases. RESULTS: In AA-positive RA, each frequency of three different alleles of
      SAA 1, i.e., alpha, beta and gamma was 15%, 32% and 53%, while it was 32%, 28%
      and 40% in AA-negative RA. The allelic distribution between AA-positive RA group
      and AA-negative RA group was significantly different (P = 0.00163) with a lower
      frequency of alpha allele and a higher gamma allele frequency observed in AA
      positive RA group. The frequency of each SAA 2 alleles (alpha & beta) was almost
      identical: 88.9% and 11.1% in AA-positive RA versus 90.4% and 9.6% in AA-negative
      RA with p value of 0.8007. Each frequency of three different Apo E alleles
      (epsilon 2, epsilon 3 & epsilon 4) was 4.9%, 85.2% and 9.8% in AA-positive RA,
      while in AA-negative RA it was 7.8%, 86.3% and 5.9%, respectively. The AA
      positive RA group showed a slightly higher prevalence of epsilon 4 allele than
      the AA-negative RA group, yet the difference did not reach statistical
      significance (P = 0.3969). CONCLUSIONS: These results suggest the possibilities
      that SAA 1 alpha may be working protectively against and SAA 1 gamma
      provocatively for the development of AA amyloidosis in RA. However, there was no
      significant association between SAA 2 isotype patterns and the development of AA
      amyloidosis in RA. Furthermore, there was no discernible association between AA
      amyloidosis in RA and Apo E 4 isotype.

PMID- 10332211
TI  - [Chlamydia-induced reactive arthritis--HLA-B 27 negative two patients].
AB  - Two cases with HLA-B 27 negative, Chlamydia-induced reactive arthritis (ReA) were
      described. Case 1: A 30 y.o. male developed balanitis, urethritis, arthritis of
      both knees, elbows, shoulders and hip joints on May in 1997. Laboratory findings
      revealed CRP 2.7 mg/dl (normal range < 0.3), ESR 33 mm/h and negative rheumatoid
      factor (RF) test. Anti-Chlamydia trachomatis antibodies, IgG 2.22, IgA 3.33 were
      positive. HLA-typing revealed A 2, A 24 (9), B 39 (16), B 52 (5). He was
      diagnosed as ReA and arthritis subsided with treatment of minocycline and
      nonsteroidal antiinflammatory drugs (NSAIDs). Case 2: A 40 y.o. Iranian American
      male developed balanitis, urethritis, lumbago, arthritis of both elbows, knees
      and foot joints, iridocyclitis on August in 1995. Chlamydia trachomatis was
      detected in the urethral swab culture. He was diagnosed as ReA and treated with
      minocycline and NSAIDs. He was referred to our hospital on June in 1996.
      Arthritis at both knees and feet was detected. Laboratory findings revealed CRP
      0.8 mg/dl, negative RF test was revealed. Antibodies to Chlamydia were positive
      (IgG 1.49, IgA 1.53) positive. HLA typing revealed A 1, A 2, B 37, B 55 (22). He
      was again treated with minocycline and NSAIDs and ReA ameliorated. Since HLA-B
      22, B 37 and B 39 have been reported to cross-react or to have homology with B
      27, B 22, B 37 and B 39 are likely to related to inducing ReA.

PMID- 10332212
TI  - [A case of seronegative spondylarthropathy with iritis and retroperitoneal
      fibrosis].
AB  - In 1985 a 41-year old male visited a local hospital because of congestion in the
      bulbar conjunctiva, which was diagnosed as iritis. In August 1990, right coxalgia
      and arthralgia of metatarsophalangeal joints appeared, with recurrence of iritis.
      In October, stiffness in the hands and arthralgia of proximal interphalangeal
      joints also started. In July 1991, the right coxalgia worsened, resulting in
      walking difficulty. He was admitted to the Kitasato University Hospital. He
      presented with bilateral iritis, polyarthritis with limited ranges of motion and
      sacroilitis. The Schober's test was positive at 3 cm. Serological tests for
      rheumatoid factor and HLA-B 27 were negative. Abdominal computer tomographic scan
      revealed low density lesion around the aorta. PSL 10 mg was initiated, and iritis
      and arthritis remitted. Progression of the periaortic lesion was not observed
      during the subsequent 5 years. In this case, iritis preceded limited ranges of
      motion in the vertebrae and sacroilitis. From these findings, seronegative
      spondylarthropathy with peripheral arthritis was diagnosed. The periaortic lesion
      seen in this case probably corresponds to chronic periaortitis recently reported
      as a subset of idiopathic retroperitoneal fibrosis. The two lesions observed in
      the present case may be interpreted as caused by inflammation of the connective
      tissue initially either at the vertebrae or around the aorta, which had advanced
      to involve the other lesion.

PMID- 10332213
TI  - [A case report of systemic lupus erythematosus patient with severe lupus
      retinopathy and antiphospholipid antibody].
AB  - An eleven-year-old boy with systemic lupus erythematosus (SLE) developed severe
      bilateral lupus retinopathy when he was in active stage of SLE. The patient, who
      had suffered from SLE for 3 years, was admitted to our hospital because of high
      grade fever, systemic lymphadenopathy, leukopenia, elevation of erythrocyte
      sedimentation rate and hypocomplementemia. The dose of prednisolone was increased
      considering he was exacerbated of SLE, however, the convulsion as CNS lupus
      occurred to him. After the event he noted loss of vision in his bilateral eyes.
      The ophthalmologic examination revealed the lesions of cotton-wool spots, retinal
      vessel dilatations and diffuse occlusions of the retinal arterioles and venules
      which were compatible with lupus retinopathy. Although the coagulation time was
      normal, antiphospholipid antibodies were positive at the time of ocular
      involvement. Careful attention should be paid to the occurrence of lupus
      retinopathy when the patients with SLE developed in the active stage or CNS
      lupus, especially they have antiphospholipid antibodies.

PMID- 10332214
TI  - [A case of secondary systemic amyloidosis associated with rheumatoid arthritis
      after 3-year disease duration].
AB  - A 63-year-old woman who started to have polyarthralgia in December 1993 has been
      diagnosed as rheumatoid arthritis (RA) and treated with muscular injection of
      gold sodium thiomalate. She began to have nausea, vomiting, anorexia and watery
      diarrhea in October 1995. A year later, she had to receive intravenous infusion
      on admission since more frequent watery diarrhea occurred more than ten times
      within a day. On admission in our hospital in December 1996, she had proteinuria
      in addition to gastrointestinal symptoms. The biopsy specimen from stomach,
      duodenum and kidney proved systemic amyloidosis associated with RA. In spite of
      steroid-pulse, dimethyl sulfoxide (DMSO) and colchicine therapy, profound
      proteinuria in nephrotic syndrome was continued in association with
      hypoproteinemia, anasarca and renal failure. She was treated on hemodialysis and
      intravenous hyperalimentation (IVH) until November 1997 when A-V shunt operation
      on left forearm was performed. However, the shunt was not available for HD and
      she suffered from septicemia and died on December 1997. This patient was a rare
      case of secondary systemic amyloidosis associated with RA in early clinical
      course.

PMID- 10332216
TI  - [Pathogenesis of rheumatoid arthritis].

PMID- 10332215
TI  - [A case of rheumatoid arthritis with bucillamine-induced myasthenia gravis
      treated by immunoadsorption therapy].
AB  - We report a case of 48-year old female with rheumatoid arthritis (RA) complicated
      with myasthenia gravis. In 1988, she was diagnosed of having RA, and several
      therapeutic drugs were administered, but her disease activity was in poor
      control. In July 1993, bucillamine (BU) was started at a dose of 100 mg/day, and
      her arthritis subsided. However, in October 1996, she was admitted with a rapidly
      progressive ptosis and double vision in the left eye, which became prominent in
      the evening. Because serum concentration of the antibody to acetylcholine
      receptors (AchR Ab) was elevated at 12.6 nmol/l, and the ptosis was reversed
      immediately after a tensilon test, ocular type myasthenia gravis (MG) was
      diagnosed and it was thought to have been induced by BU. Immunoadsorption therapy
      was started after discontinuation of this drug, and was continued for 6 months,
      resulting in improvement of neurological symptoms and decrease in AchR Ab level.
      MG has not recurred since. Although several cases of D-penicillamine (DP) induced
      MG are reported, only two cases are reported which were induced by BU, sulfhydryl
      compound which has a structure similar to DP. Since BU has been widely used as
      one of the disease modifying anti-rheumatic drugs in Japan, MG induced by this
      drug should be paid attention as one of the adverse effects.

PMID- 10332217
TI  - [Development of new anti-rheumatic drugs in Japan: present and future].

PMID- 10332218
TI  - [Collagen and arthritis: collagen-induced arthritis in monkey].

PMID- 10332219
TI  - [Structure and function of the yeast 26S proteasome].

PMID- 10332220
TI  - [Chemistry of conotoxins from cone snails].

PMID- 10332221
TI  - [Phosphatidylinositol 5-kinases].

PMID- 10332222
TI  - [Photo-activatable caged peptides and proteins].

PMID- 10332223
TI  - [Direct promotion of polypeptide folding by asnglycans].

PMID- 10332224
TI  - [Ribosomal abnormalities and human diseases].

PMID- 10332225
TI  - [Regulation of prostate gland-specific gene expression].

PMID- 10332226
TI  - [How does DNA recognize homologous sites and exchange strands? Molecular
      structure of DNA in homology search and strand exchange].

PMID- 10332227
TI  - [Structure of cytochrome bc1 complex from bovine heart mitochondria].

PMID- 10332228
TI  - [Regulation of B cell receptor signaling through tyrosine kinases and
      phosphatases].

PMID- 10332229
TI  - [Regulated nuclear localization of transcription factors: nuclear export of yAP-1
      is sensitive to oxidative stress].

PMID- 10332230
TI  - [Mechanism of COPI and COPII vesicle formation: coat assembly direct formation of
      coated vesicles].

PMID- 10332231
TI  - [Why a single molecule?].

PMID- 10332232
TI  - [Techniques for automatic recording of the oxygen equilibrium curve: precision
      determination of gaseous ligand binding (1)].

PMID- 10332233
TI  - [Capillary electrophoresis (3): how to utilize the capillary].

PMID- 10332234
TI  - Electronic length measurement using small and large files in enlarged canals.
AB  - Electronic apex locators are frequently used attached to a small size endodontic
      file; however, the effect on the measurement of the relative diameters of the
      file and the root canal has not been clarified. In this study, the length of
      enlarged canals was measured using small size files and files matching the canal
      diameter to observe a possible discrepancy. The accuracy of electronic length
      control during canal preparation with rotary files was also assessed. The root
      canals in 21 extracted, single rooted teeth were accessed, and their actual
      length (AL) established by passing a size 10 file just through the minor apical
      foramen. The teeth were then embedded in an alginate mold. The initial canal
      length (IL) was measured with the Root ZX apex locator by negotiating a size 10
      file to the apical constriction. The canal was enlarged to size 60 with rotary
      files while the length was continuously controlled with the apex locator. Then,
      the final length measurements were obtained with a size 10 file and a size 60
      file (FL-10 and FL-60, respectively). The average values of IL, FL-10 and FL-60
      were calculated and compared using Repeated Measures Analysis of Variance
      followed by Tukey's Studentized Range test (P < 0.05). Using composite resin, the
      size 60 files were secured at the FL-60 length, the teeth were removed from the
      alginate mold, stained with Picroformal DI Buoin stain and the position of the
      file tip was observed histomorphometrically after the apical 4 mm of the canal
      was exposed by grinding the buccal aspect of the root. The IL was 0.45 mm shorter
      than AL (P < 0.05). The differences between FL-10, FL-60 and IL were not
      statistically significant. Histomorphometrically, the apical constriction was
      absent in all the teeth, but the file tips were confined within the root. This
      study concluded that the Root ZX indicated the location of an apical constriction
      even when the anatomic constriction was eliminated. In the enlarged canals,
      length measurements obtained with small and large size files were comparable.

PMID- 10332235
TI  - The maxillary second molar: variations in the number of roots and canals.
AB  - A retrospective study was undertaken of 520 completed endodontic treatments of
      maxillary second molar teeth which were selected from a specialty endodontic
      practice. Radiographs were reviewed and studied, a classification of antomical
      root and canal variations was devised, and the frequency with which each variant
      occurred was recorded. There were six variants which occurred frequently enough
      to be considered as separate anatomic categories and their frequency of
      occurrence is illustrated. The six variants found in the study and their
      frequency of occurrence are as follows: (1) three separate roots and three
      separate canals (56.9%); (2) three separate roots and four canals (two in the
      mesiobuccal root) (22.7%); (3) three roots and canals whose mesiobuccal and
      distobuccal canals combine to form a common buccal with a separate palatal (9%);
      (4) two separate roots with a single canal in each (6.9%); (5) one main root and
      canal (3.1%); and (6) four separate roots and four separate canals including two
      palatal (1.4%). Clinical examples of these deviant variations are also presented.

PMID- 10332236
TI  - A comparison of stainless steel and nickel-titanium K-files in curved root
      canals.
AB  - The purpose of this study was to determine the effects of hand instrumentation
      using traditional stainless steel K-files and nickel-titanium K-files on the
      final shape of curved root canals. A total of 24 moderately curved canals in the
      mesial roots in extracted human mandibular first molars were randomly divided
      into two groups. These were instrumented manually using either stainless steel or
      nickel-titanium, K-files with the stepdown technique. The cross-sectional shape
      of each canal at three different horizontal levels were captured, before and
      after instrumentation, into a computer for comparison using image analyser
      software. Three parameters at each level were evaluated: (i) amount of dentine
      removed; (ii) least remaining dentine thicknesses on mesial and furcal aspects;
      and (iii) the amount and direction of canal transportation. The results showed
      that the two file types removed similar amounts of dentine at all three levels
      examined. The nickel-titanium files left a thicker layer of dentine on both the
      mesial and furcal aspects than stainless steel files. However, the difference was
      not significant (pooled T-test, P > 0.05). Both types of files transported the
      centre of the canals but the nickel-titanium instrument seemed to be safer
      because of the reduced amount of transportation towards the danger areas.

PMID- 10332237
TI  - A scanning electron and confocal laser microscope investigation of tetracycline
      affected human dentine.
AB  - Because of the well reported dental side-effects of tetracycline administration,
      the drug should not be administered to children. However, it and its derivatives
      are often administered over a prolonged period for treatment of acne in young
      adults. Dental side effects are also noticed in these patients. The aim of this
      study was to examine with scanning electron microscopy (SEM) and confocal laser
      scanning microscopy (CLSM) the root dentine of a tooth from a young adult
      affected by tetracycline therapy. The palatal root of an upper third molar,
      demonstrating distinct areas of tetracycline staining, was removed from the crown
      and sectioned longitudinally to produce two samples. The pulp tissue was peeled
      off the dentine and any remaining non-mineralized tissues were removed with
      sodium hypochlorite. One sample was prepared for SEM and the other as a ground
      section which was examined with a CLSM. It was demonstrated by SEM that the
      mineralizing front of unaffected dentine was of a normal calcospherite
      appearance; in contrast, the mineralizing front of the tetracycline-affected
      dentine was devoid of calcospherite formation and many surface defects were
      apparent. In addition, the number of dentinal tubules associated with the defects
      was reduced. It was shown by CLSM that tetracycline bands were made up of
      numerous smaller bands and that peritubular dentine not associated with
      fluorescent bands had incorporated tetracycline. The CLSM examination of the
      mineralization front of the affected dentine revealed that fluorescence of
      dentine was restricted to the peritubular dentine. The results confirm that
      dentine mineralization is affected by systemic tetracycline therapy and that
      tetracycline can be incorporated into peritubular dentine after mineralization of
      the primary dentine matrix.

PMID- 10332238
TI  - Effectiveness of the Canal Finder and hand instrumentation in removal of gutta
      percha root fillings during root canal retreatment.
AB  - The purpose of this study was to quantify the amount of remaining gutta
      percha/sealer on the canal walls when the Canal Finder system, hand
      instrumentation and a combination of both (hybrid technique) were used to remove
      these materials. The amount of apically-extruded debris and the time required for
      removal were also recorded. Sixty extracted maxillary anterior teeth were
      prepared using a stepback technique and obturated with gutta-percha.
      Reinstrumentation of all groups was done in conjunction with a solvent,
      chloroform. The teeth were split longitudinally and photographed, and the total
      area of the root canal and the area of the debris were traced and quantified
      using a computerized image analysis system. The ratio of remaining obturation
      material to root canal surface was derived and analysed statistically. Hand
      instrumentation resulted in less debris remaining than did the other two
      techniques (P < 0.05). The differences in the amount of apically extruded debris
      were not significant among the techniques (P > 0.05). The hybrid technique
      required significantly less time for filling material removal. The Canal Finder
      system alone was not superior to hand instrumentation.

PMID- 10332239
TI  - An assessment of microbial coronal leakage in teeth root filled with gutta-percha
      and three different sealers.
AB  - The aim of this in vitro study was to determine the effect of three different
      root canal sealers on the bacterial penetration of obturated root canals. Eighty
      extracted human teeth with straight, single root canals were prepared using the
      modified double-flared technique with balanced force under copious irrigation
      until the master apical file was size 40. The teeth were divided randomly into
      experimental groups (60 teeth) and control groups (20 teeth). Twenty experimental
      teeth each were obturated by lateral condensation of cold gutta-percha with AH26,
      Apexit or Tubliseal EWT sealer. In the control groups, 10 teeth were obturated
      using the same technique with AH26, Apexit or Tubliseal EWT sealer. These teeth
      were completely sealed to serve as negative controls. The remaining 10 teeth were
      not obturated and served as positive controls. The root surface of each tooth,
      except the apical 2 mm, was sealed with nail varnish. The coronal part of each
      root canal was sealed with the cut end of a polypropylene tube and placed in a
      glass bottle containing sterile Todd-Hewitt Broth (THB). Aliquots of 0.5 ml of
      THB were injected into the polypropylene tube and the model system was
      centrifuged at 168 g. An innoculum of Streptococcus sanguis in THB was added to
      the tube at 5-day intervals and daily observations were made for bacterial growth
      in the apical reservoir for 90 days. All positive control teeth showed bacterial
      penetration within 24 h and negative control teeth remained uncontaminated
      throughout the test period. Leakage through the experimental teeth varied from 7
      to 86 days. There was no statistically significant difference (P > 0.05) in
      leakage of the obturated canals between AH26, Apexit and Tubliseal EWT sealers.

PMID- 10332241
TI  - Dens invaginatus: aetiology, classification, prevalence, diagnosis, and treatment
      considerations.
AB  - Dens invaginatus is a malformation of teeth probably resulting from an infolding
      of the dental papilla during tooth development. Affected teeth show a deep
      infolding of enamel and dentine starting from the foramen coecum or even the tip
      of the cusps, and which may extend deep into the root. Teeth most affected are
      maxillary lateral incisors and bilateral occurrence is not uncommon. The
      malformation shows a broad spectrum of morphologic variations and frequently
      results in early pulp necrosis. Root canal therapy may present severe problems
      because of the complex anatomy of the teeth. Aetiology, prevalence,
      classification, and therapeutic considerations including root canal therapy,
      apical surgery and prevention of pulpal involvement are reviewed.

PMID- 10332240
TI  - Root canal treatment of a root-fractured incisor tooth with internal resorption:
      a case report.
AB  - A case is described in which root canal treatment with calcium hydroxide was used
      successfully to repair a fracture site with internal resorption of the tooth.

PMID- 10332242
TI  - Microbiological findings and clinical treatment procedures in endodontic cases
      selected for microbiological investigation.
AB  - The relationship between bacteriological findings and clinical treatment
      procedures was investigated in root canal treatment cases that were selected for
      bacteriological investigation by general dental practitioners in Finland. The
      cultures were sent to the Oral Microbiological Service Laboratory at the
      Institute of Dentistry in Helsinki. Two groups of teeth were selected based on
      the type of infection present in the root canal system. The 'enteric bacteria'
      group consisted of 40 sequential cases where Enterococcus faecalis and/or other
      facultative enteric bacteria or Pseudomonas sp. were found in the samples in pure
      culture (35%) or together with other types of bacteria. The group 'non-enteric
      bacteria' consisted of 40 sequential cases where only non-enteric bacteria were
      found. The dentists who had sent the bacteriological samples received a
      questionnaire where they were asked about the treatment protocol and procedures.
      A total of 70 out of 80 questionnaires were returned. If the root canals had been
      unsealed at some point during the treatment, enteric bacteria were found more
      frequently than in canals with an adequate seal between the appointments. Of
      cases with enteric bacteria 55% had been open during the treatment, while in the
      group where only non-enteric bacteria were found 30% had been open. Enteric
      bacteria were also more frequently isolated in cases with a high number of
      appointments before sampling. In the enteric bacteria group 35% of the samples
      were taken at the 10th visit or later, while the corresponding percentage in the
      non-enteric group was 3%. In addition, the number of retreatment cases was
      significantly higher, 12 out of 34, in the enteric bacteria group than in non
      enteric bacteria group, which was five out of 36. Other clinical parameters
      showed no differences between the two groups. The results emphasize the
      importance of controlled asepsis throughout the root canal treatment.

PMID- 10332243
TI  - Fungi in therapy-resistant apical periodontitis.
AB  - The occurrence of yeasts in 967 microbiological endodontic samples taken from
      root canals in persistent endodontic infections was studied. The sampling was
      done by general practitioners in various parts of Finland from root canal
      infections which did not respond favourably to standard conservative therapy. The
      samples were cultivated aerobically on a non-selective enriched horse blood agar
      medium, on TSBV agar medium in 5% CO2 and anaerobically on horse blood agar
      medium. Micro-organisms were found in 692 of the samples while 275 showed no
      growth. Forty-eight fungi were isolated from 47 samples which is 7% of the
      culture-positive samples. Twenty yeast strains were identified further by their
      colony morphology, growth and cellular characteristics and patterns of
      carbohydrate assimilation. All isolates except one belonged to the genus Candida.
      Candida albicans was the most common species. C. glabrata was found together with
      C. albicans in one sample. C. guilliermondii, C. inconspicua and Geotrichum
      candidum were each isolated once. Yeasts were found in pure culture in six
      samples and together with bacteria in 41 samples. In all the samples except two,
      the accompanying facultative bacteria were Gram positive. The most frequent of
      them were alpha- and non-haemolytic Streptococcus species which were found in 31
      samples. Anaerobic bacteria were isolated together with yeasts from 12 root
      canals. They included both Gram positive species such as Peptostreptococcus
      micros and Gram negative species such as Fusobacterium nucleatum. The regular
      isolation of yeasts, also in pure culture, indicates that yeasts may have an
      important role in cases of apical periodontitis persisting after conventional
      treatment.

PMID- 10332245
TI  - Periapical radiolucencies as evaluated by bisecting-angle and paralleling
      radiographic techniques.
AB  - Two groups of patients were included in the study. The first group consisted of
      patients who received root canal treatment of single-rooted teeth (n = 63). The
      completed roof fillings were exposed to two different radiographic techniques,
      the paralleling and the bisecting-angle technique. The second group consisted of
      1-year review radiographs of patients who had received apicectomies of single
      rooted teeth (n = 105). Three observers examined the radiographic images. First,
      they were asked to identify teeth with a normal apical condition and those with
      an apical radiolucency. Thereafter pairs of radiographs were compared; cases
      judged as normal by all observers were excluded. The observers were now asked to
      ascertain whether the apical radiolucency was largest in the first image, the
      apical radiolucency was largest in the second picture or both radiolucencies were
      the same size. Both intraobserver and interobserver agreement, calculated as
      Cohen's kappa, was high with respect to the presence of lesions within both
      samples and it was at the same level for both radiographic techniques. The
      evaluation of the size of the lesions proved to be more inconsistent. Kappa
      values were in the range 0.38-0.71 for intraobserver comparisons and in the range
      0.25-0.48 for interobserver comparisons. No significant difference was found
      between the size of lesions as recorded by the two techniques (P > 0.05). It is
      concluded that, when correctly adjusted the bisecting-angle technique and the
      paralleling technique provide similar diagnostic results.

PMID- 10332244
TI  - Tissue response to potential root-end filling materials in infected root canals.
AB  - The tissue responses to two potential root-end filling materials, a light-cured
      glass ionomer cement (Vitrebond) and a reinforced zinc oxide-eugenol cement
      (Kalzinol) were compared with that to amalgam. In 27 premolar teeth of beagle
      dogs (54 roots), a collection of endodontic pathogenic bacteria was first
      inoculated into the root canals to induce periapical lesions. On each root, an
      apicectomy was performed and root-end cavities prepared to receive fillings of
      each material. The teeth and surrounding jaw were removed after 8 weeks (24
      roots) and 4 weeks (30 roots); and they were prepared for histological
      examination. The tissue response to amalgam fillings after 4 and 8 weeks was
      marked by moderate or severe inflammation on all roots, and extended > 0.5 mm in
      10 out of 18 roots. In contrast, after 8 weeks, the majority of roots filled with
      Kalzinol showed little or moderate inflammation while the tissue response to
      Vitrebond was the best of the three materials, and was also less extensive. After
      4 weeks, the overall best tissue response was with Kalzinol, followed closely by
      Vitrebond. The differences between materials for both time periods with either
      none or few inflammatory cells when compared with that with either moderate or
      severe inflammation were statistically significant (P < 0.01). Similarly, the
      differences between materials for both time periods with no inflammation or
      inflammation extending < 0.2 mm when compared with that with inflammation
      extending > 0.2 mm (< or = 0.5 mm or > 0.5 mm) were statistically significant (P
      < 0.01). Both Vitrebond and Kalzinol have potential as root-end filling materials
      as the tissue response was considerably more favourable than that to amalgam.

PMID- 10332246
TI  - A comparative study of seven instruments in shaping the root canal in vitro.
AB  - The objective of this study was to evaluate the shaping characteristics of
      various root canal instruments using human teeth. A total of 420 extracted human
      roots were embedded in resin blocks. The embedded roots were divided into three
      groups, i.e. roots with (i) straight, (ii) apically curved, and (iii) whole
      length curved canals according to the Schneider's angle and the length of the
      radius of arc fitting the curvature of root canals. Each of the three groups
      containing 140 roots were randomly divided into seven subgroups prior to
      preparation. The canals were prepared manually with traditional and flexible
      instruments, engine driven Racer-type, Giro-type, randomly vibrating instruments
      and with sonic and ultrasonic instruments. The shortcomings of the seven
      preparation methods were assessed by the superimposition of projected radiographs
      taken in bucco-lingual and mesio-distal views before and after the preparation.
      The prepared straight canals showed a high percentage (75.7%) of apical
      asymmetry. Coronal transposition of the apical stop was graded with higher scores
      in all canal forms prepared with Racer-type and Giro-type instruments, which
      could have occurred through packing of debris towards the apical constriction.
      The majority of the prepared curved canals were asymmetrical in shape. The
      location of the aberrations depended on the original shape of the canal but the
      method of shaping also had a decisive effect on the post-operative form of the
      canal. Large differences were found between the incidence of elbow (11.7-40.0%)
      and zip (75.7-80.0%). K-Flex files produced minor canal aberrations and
      significantly less asymmetry (P < 0.05) than the conventional hand instruments.
      The MM 1400 handpiece and ultrasonic instruments were associated with less
      aberration and significantly less asymmetry than the other instruments tested.
      The Excalibur appeared to be superior to the conventional hand instruments in
      straight canals, but its shaping characteristics were similar to conventional
      instruments in curved canals. Under the conditions of this study, canal shaping
      with Cavi Endo, MM 1400 and K-Flex files appeared to be superior to that achieved
      with conventional hand instruments Excalibur, Intra Lux Endo Kopf 3LDSY, and 3LD
      instruments.

PMID- 10332247
TI  - The effect of root canal morphology on canal shape following instrumentation
      using different techniques.
AB  - The objective of this study was to evaluate the shaping characteristics of
      different root canal instruments in teeth with different root canal forms. A
      total of 420 extracted human roots were embedded in resin blocks. The embedded
      roots were divided into three groups, i.e., roots with (i) straight (I form),
      (ii) apically curved (J form), and (iii) entirely curved canals (C form) with
      reference to the Schneider's angle and the length of the radius of arc of the
      curvature of the root canals. Each of the three groups containing 140 roots were
      randomly divided into seven subgroups prior to preparation. The canals were
      enlarged manually with traditional and flexible hand instruments, three different
      engine driven instruments and sonically and ultrasonically powered instruments.
      The shortcomings of the seven preparation methods were assessed by
      superimposition of projected radiographs taken in bucco-lingual and mesio-distal
      views before and after preparation. Results showed that observation of
      perforation, incidence of elbow and of asymmetrical preparation of the root
      canals depended on root canal configuration. It was striking that the coronal
      transposition of the apical stop, uneven wall contour, ledge formation and
      incidence of zip were independent of root canal morphology. Evaluation of data of
      asymmetry of preparation (canal transposition) revealed significant differences
      (p < 0.05). Asymmetry of preparation was the most frequent aberration of the
      prepared root canals and it was possible to study it with precision. It was
      concluded that this measurement should be a priority for future instrument
      testing. The shaping characteristics of hand and engine driven instruments was
      modified by root canal morphology, but that of sonic and ultrasonic instruments
      was less dependent on the original anatomical form of root canals.

PMID- 10332248
TI  - Multilayer and monolayer cell cultures in a cytotoxicity assay of root canal
      sealers.
AB  - The aim of this study was to evaluate the response of a multilayer compared with
      a monolayer cell culture using six root canal sealers. Both monolayer and
      multilayer of MU-mu-1 (Mahidol University mouse cell line 1) were cultured in
      separate 96-well plates. Following incubation at 37 degrees C in 5% CO2 for 4 h
      in the presence of each sealer, cells were stained with 0.4% Sulphorhodamine-B,
      viable dye staining and the absorbance at 540 nm determined and calculated as
      cell viability. There was no statistical difference in the percentage viability
      for each sealer in both the multilayer and the monolayer cell culture (P > 0.01).
      Apexit and AH-26 were less toxic (P < 0.01) than MU (Mahidol University) sealer,
      ROCANAL 3, ROCANAL 2, and Endomethasone which demonstrated the same toxicity (P >
      0.01).

PMID- 10332249
TI  - Surgical treatment of a periradicular lesion on an invaginated maxillary lateral
      incisor (dens in dente).
AB  - The complex anatomy of invaginated teeth make their root canal treatment
      difficult. Moreover, this treatment may compromise the future of the tooth if it
      is destined to support a post-retained coronal restoration. This case reports the
      successful surgical root canal treatment of an invaginated tooth using a
      retrograde filling with gutta-percha. After surgical exposure of the root-end and
      cleaning of the root canal, the gutta-percha was compacted in the root canal
      which had been coated previously with a zinc oxide-eugenol cement. The gutta
      percha was then cold-burnished. Periapical radiographic examination after 1, 2,
      3, 6 and 12 months showed periapical healing with osseous formation. This
      procedure, resulting in minimal loss of hard tissues, permitted subsequent
      restoration of the tooth.

PMID- 10332250
TI  - A feasibility study evaluating rhBMP-2/absorbable collagen sponge for maxillary
      sinus floor augmentation.
AB  - This 16-week open-label study assessed the safety and technical feasibility of
      implanting human recombinant bone morphogenetic protein-2 delivered on an
      absorbable collagen sponge (rhBMP-2/ACS) for two-stage maxillary floor sinus
      augmentation. This first use of rhBMP-2/ACS in human clinical maxillary sinus
      floor augmentation included 12 patients with inadequate bone height in the
      posterior maxilla. The total delivered dose of rhBMP-2 implanted varied from 1.77
      to 3.40 mg per patient. The rhBMP-2/ACS device was easily handled. Significant
      bone growth was documented by computerized tomographic scans in all evaluable
      patients (11/12). The overall mean height response for the maxillary sinus floor
      augmentation was 8.51 mm (95% confidence interval 6.07 to 10.95). There were no
      serious or unexpected immunologic or adverse effects and no clinically
      significant changes in complete blood counts, blood chemistries, or urinalysis
      results. The most frequent adverse effects were facial edema, oral erythema,
      pain, and rhinitis. Eleven patients have received dental implants and follow-up
      examinations are still being conducted. Histologic examinations of core bone
      biopsies obtained at the time of dental implant placement confirmed the quality
      of the bone induced by rhBMP-2/ACS. These results tend to indicate that rhBMP
      2/ACS may provide an acceptable alternative to traditional bone grafts and bone
      substitutes for maxillary sinus floor augmentation procedures in humans.

PMID- 10332251
TI  - Autologous bone graft to augment the maxillary sinus in conjunction with
      immediate endosseous implants: a retrospective study up to 5 years.
AB  - This study reports the successful use of osseointegrated implants to replace
      posterior teeth combined with the autogenous bone graft technique in the sinus.
      Preliminary data (1 to 6 years experience) of this one-stage procedure are
      presented. A total of 33 patients were treated--44 sinus grafts were augmented
      with bone from the anterior iliac crest. Reconstruction was completed with
      ceramic fixed partial dentures, and there was a follow-up of 3 to 80 months (mean
      40.2 months) after loading. None of the 44 sinus grafts was lost. Of the 121
      implants placed, eight failed, resulting in a failure rate of 6.6% and a
      cumulative failure rate of 6.8%. Of the 44 prostheses placed in the 44 sinuses,
      one failed, resulting in a prosthesis stability of 97.7%. Complications were
      encountered in three patients (three sinuses, eight implants); treatments were
      administered, symptoms subsided, and the implants integrated in two patients (two
      sinuses, six implants). One patient lost the two implants and the prosthesis, but
      the graft integrated. No other complications have since occurred. The results
      compare favorably with previous reports in terms of implant survival and
      stability. The implant survival rate approached that of implants placed in
      uncompromised maxillary bone.

PMID- 10332253
TI  - Spacemaking metal structures for nonresorbable membranes in guided bone
      regeneration around implants. Two case reports.
AB  - This article presents a surgical technique to promote bone regeneration and
      enlargement of localized alveolar ridge defects in the mandible. The purpose of
      this study was to investigate the use of spacemaking gold frames used in
      combination with expanded polytetrafluoroethylene Gore-Tex augmentation membranes
      (WL Gore) on two patients to create and maintain adequate space for the
      regeneration of bone. The membrane was sutured under the frame and the assembly
      was bent and adapted over the residual bony defect to create a dome and prevent
      the expanded polytetrafluoroethylene barrier membranes from collapsing into the
      defects. The framed membranes have also been positioned over dehisced implants.
      After a healing period of 12 months, a second-stage surgery procedure was
      performed to remove the gold frames and expanded polytetrafluoroethylene
      membranes and to connect the healing abutments. The gain of bone dimension was
      assessed by standardized measurements. On both patients the spaces created by the
      framed membranes were completely filled with newly regenerated bone. Biopsies
      from the treated sites revealed new bone formation.

PMID- 10332252
TI  - Clinical results with exposed polyglactin 910 resorbable membranes for guided
      tissue regeneration.
AB  - Three cases are presented where early exposure of a resorbable membrane occurred
      during guided tissue regeneration therapy. An antimicrobial regimen was selected
      to determine whether infection of exposed membranes could be controlled to the
      point of achieving acceptable clinical results without membrane removal. The
      results suggest that with the use of the antimicrobial regimen: (1) exposure is
      compatible with successful clinical results, and (2) removal is not necessary.

PMID- 10332254
TI  - Periodontal and peri-implant bone regeneration: clinical and histologic
      observations.
AB  - The principle of guided tissue regeneration by barrier membranes to restore lost
      periodontal tissue around natural teeth has also been used around osseointegrated
      implants in an attempt to restore alveolar ridge defects. While most periodontal
      procedures in the literature describe root coverage by mucogingival surgery,
      which achieves healing through soft tissue attachment, regeneration of denuded
      root surfaces is performed by guided tissue regeneration using expanded
      polytetrafluoroethylene barrier membranes and demineralized freeze-dried bone
      allografts as inductive/conductive materials. In this study the technique is
      applied in two partially exposed cylindrical hydroxyapatite-coated implants in
      extraction sites in one patient. Surgical reentry in both sites is presented,
      with histologic examination revealing new bone formation on the exposed root
      surface and the hydroxyapatite-coated implants.

PMID- 10332255
TI  - Resin-ionomer and hybrid-ionomer cements: part II, human clinical and histologic
      wound healing responses in specific periodontal lesions.
AB  - Twenty-five subjects with a total of 50 subgingival restorations participated in
      this study. At the beginning of the investigation, nine teeth that were
      considered hopeless because of the extent of their pathology were selected for
      extraction to evaluate histologically the restorations and their effect on the
      adjacent tissues. The purpose of this article is to demonstrate the responses to
      the clinical applications as well as to the placement of resin-ionomers in
      subgingival lesions. Clinical and histologic evidence of epithelial and
      connective tissue adherence to resin-ionomer restorative materials was observed
      during the healing process.

PMID- 10332256
TI  - Removable partial denture design considerations where periodontally compromised
      teeth exist.
AB  - Restoration of a periodontally compromised dental arch with a removable partial
      denture may require one or more design modifications. Multiple rests ensure that
      adequate vertical support remains in the event primary abutment teeth are lost.
      An open or closed base can be strategically placed in the maxillary major
      connector to facilitate the replacement of subsequently lost teeth. The location
      of finish lines can be modified to provide a smoother resin-to-metal transition
      when posterior teeth are lost. Wire direct retainers that provide more
      physiologically acceptable clasping of compromised teeth and that are easily
      adjusted and added to the prosthesis should be considered.

PMID- 10332257
TI  - Mandibular distraction osteogenesis: types, applications, and indications.

PMID- 10332258
TI  - Rare craniofacial clefts.
AB  - I present a review of the pattern of rare craniofacial clefting in patients
      presenting to a tertiary referral craniofacial unit. Patients with an isolated
      rare cleft were uncommon; most had multiple axes of disruption. Midline and
      paramedian facial clefts, although occasionally occurring alone, often overlap
      with adjacent facial clefts and extend along an upward cranial axis. The
      corresponding midline and paramedian facial clefts were never seen in isolation
      but were almost always seen with their axial downward cleft. Lateral nasal, oro
      ocular, and lateral forehead clefts showed diffuse and often poorly defined
      regions of disruption, resulting in a multiplicity in clefts. The small subgroup
      of patients with features of the amniotic band sequence had more and differently
      distributed clefts compared with the larger nonamniotic band group.

PMID- 10332259
TI  - Surgical model to assess the effects and optimal timing of craniofacial fixation.
AB  - An in utero swine model of craniofacial deformity was developed as a potential
      alternative to neonatal models currently used for evaluating the optimal timing
      and long-term effects of rigid fixation techniques on a growing cranium. At 75%
      gestation, seven fetal piglets were randomly selected to undergo periosteal
      stripping of frontal and parietal bone segments with and without extensive
      coronal suture fusion procedures with cyanoacrylate adhesive. Fetal swine were
      killed postpartum at 4 and 11 weeks after fusion to assess craniofacial
      deformity. Piglets undergoing coronal fusion had slight deviation of the nose
      snout toward the side of fusion and taller cranial vaults. The vertical cranial
      index of the experimental fusion group was 0.34 in comparison to a vertical index
      of 0.27 for the controls, suggesting abnormal vertical height expansion. There
      was no difference in the horizontal cranial index of either control or
      experimental fusion groups. Neither sows nor piglets were lost to anesthetic
      complications, uterine sepsis, or preterm labor during the initial laparotomy or
      subsequent cesarean delivery.

PMID- 10332260
TI  - Promotion of the osteogenetic activity of recombinant human bone morphogenetic
      protein by basic fibroblast growth factor.
AB  - In this study, we investigated the promotive effect of basic fibroblast growth
      factor (bFGF) on the osteogenetic activity of bone morphogenetic protein (BMP)
      used in conjunction with porous hydroxyapatite ceramic pellets. Results showed
      that there was extensive bone formation as early as 3 weeks after insertion in
      the group that received pellets treated with a relatively large amount of
      recombinant human (rh) BMP alone as well as in the group in which pellets were
      treated with a small amount of rhBMP combined with rhbFGF. Subsequently,
      osteogenesis within the pores of the pellets of the two groups slowly progressed
      over time; by 9 weeks after insertion, most of the pellet pores were filled with
      newly generated bone. In contrast, the group that received pellets treated with
      rhbFGF alone showed little osteogenesis, as was the case with the control group.
      The group that received the pellets treated with the small amount of rhBMP as
      well as the rhbFGF group exhibited significantly greater bone induction than the
      group that received the pellets treated with the small amount of rhBMP alone.
      These results indicated that a very small amount of rhbFGF has a strong promotive
      effect on the osteogenetic activity of rhBMP.

PMID- 10332261
TI  - Abnormalities of the cranial base in synostotic frontal plagiocephaly.
AB  - Skeletal abnormalities of the cranial base in various craniosynostoses are well
      known. Cranial base angulation has been documented in synostotic frontal
      plagiocephaly--"unilateral coronal synostoses." We analyzed four infants with
      synostotic frontal plagiocephaly, focusing on computed tomographic images through
      the cranial base. The scans were performed on a GE advantage spiral with 1.5-mm
      images. The anatomical structures examined were length of the foramina ovale,
      length of the eustachian tubes, and sphenotemporal angles. Ratios for these
      measures were calculated comparing the normal and synostotic sides. The foramen
      ovale was 21% longer on the synostotic side; the eustachian canal was 11% shorter
      on the synostotic side. The average sphenotemporal angle on the synotic side was
      121 degrees compared with 149 degrees on the nonsynostotic side. Deformities of
      the cranial base (i.e., elongation of structures anterior to the synostosis and
      shortening of the structures posterior to the synostosis) can be documented
      before surgical correction of synostotic frontal plagiocephaly. Follow-up
      computed tomographic studies will permit study of the effect of fronto-orbital
      advancement and modeling on these basilar abnormalities.

PMID- 10332262
TI  - Evaluation of the anatomical position of the lateral canthal ligament: clinical
      implications and guidelines.
AB  - Controversy exists in the literature as to the precise anatomical location of the
      lateral canthal ligament. The ligament is a 3 mm-wide, two-tailed band; its
      average length is approximately 13 mm, while the width of the rima palpebralis is
      about 26 mm. The authors evaluated three different groups to pinpoint the
      anatomical position of the ligament's attachment to the lateral orbital wall, and
      to establish guidelines for placement of the ligament during surgery. In 90% of
      the cases, the ligament was attached to Whitnall's tubercle, which is located
      approximately 4 mm posterior to the lateral orbital rim, and 17 mm above the
      intersection of the lateral and inferior margins; this area is 9 mm below the
      zygomaticofrontal suture. Based on these anatomical criteria, a standardized
      procedure is suggested.

PMID- 10332263
TI  - Orbitometer-ophthalmometer: new surgical and clinical device.
AB  - On the basis of analysis of the orbital bony architecture and the locations of
      the medial and lateral canthi, as well as the pupillary position, a new
      orthomorphic linear scale was devised for orbital surgery. The measuring device
      was designed to facilitate hard- and soft-tissue repositioning during mono
      orbital and biorbital surgery. The device is useful for craniofacial,
      reconstructive, and periorbital trauma surgery and, to the best of our knowledge,
      is the first one described.

PMID- 10332264
TI  - Maxillary growth in children after early facial bipartition.
AB  - Facial osteotomies performed in young children are frequently associated with
      growth deficiencies, especially at the middle third of the face. This problem may
      be more severe when the initial deformity is associated with alveolar and palatal
      clefts. Orbital hypertelorism is a major congenital malformation requiring early
      correction. The resection of the ethmoid tissues located between the orbit and
      the medialization of the orbital skeleton through the intracranial approach
      modifies the exaggerated interorbital distance but does not correct the vertical
      shortness at the midline of the face. Also this procedure interferes with the
      sagittal growth of the maxilla possibly resulting from the horizontal osteotomy
      across the maxillae. The medial rotation of the two halves of the face performed
      by the intracranial approach or the subcranial approach simultaneously corrects
      the orbital hypertelorism and elongates the nose and the central segment of the
      face. Our experience with this procedure in infants and young children is
      analyzed. A series of nine patients with orbital hypertelorism associated with
      median and paramedian clefts underwent correction by hemifacial rotation. All
      patients were monitored from 6 to 10 years (mean, 7 years) and demonstrated
      normal sagittal growth of the maxillae.

PMID- 10332265
TI  - Less common orbital fracture patterns: the role of computed tomography in the
      management of depression of the inferior oblique origin and lateral rectus
      involvement in blow-in fractures.
AB  - During the past decade, advances in radiographic imaging have made it possible
      for the surgeon managing orbital fractures to adopt a rational therapeutic
      strategy based on a knowledge of alterations in surgical anatomy secondary to
      traumatic injury. To illustrate the value of computed tomography in the surgeon's
      armamentarium for management of orbital fractures, cases are presented in which
      imaging proved decisive in planning a course of therapy. Two patients presented
      with two types of isolated lateral blow-in fracture, an uncommon fracture
      pattern. The other cases underscore the value of defining involvement of the
      inferior oblique origin and lateral rectus muscles in imaging complex orbital
      fractures, issues not emphasized in earlier literature. Although diplopia alone
      does not always warrant surgical intervention, diplopia in the context of
      computed tomography-defined muscle entrapment or muscle origin displacement
      justifies operative therapy. These cases demonstrate the value of computed
      tomography in directing surgical therapy with resolution of diplopia and
      prevention and correction of enophthalmos.

PMID- 10332266
TI  - Heavy metal: beware.
AB  - A 19-year-old Crouzon's syndrome patient with a history of multiple craniofacial
      procedures presented with severe bilateral temporal and frontal depressions and
      metal implants protruding through the scalp in multiple locations. Preoperative
      analysis revealed an extensive cranial defect that had been reconstructed with
      multiple large metallic mesh implants. The mesh required complete removal with an
      autograft cranial reconstruction. We present this case to urge that caution and
      forethought be exercised when contemplating the use of metallic alloplasts for
      major craniofacial reconstructions.

PMID- 10332267
TI  - A mathematical model for mandibular distraction osteogenesis.
AB  - In this paper, we look at the mechanobiological processes involved in mandibular
      distraction and, as a first approximation, propose an elastoplastic uniaxial
      model.

PMID- 10332268
TI  - Simultaneous distraction osteogenesis and microsurgical reconstruction for facial
      asymmetry.
AB  - Restoring facial balance in patients with severe facial asymmetry is a
      challenging problem for the craniofacial team. Attention to bony reconstruction
      as well as soft-tissue contouring is required for patients with moderate to
      severe deformities. Traditionally, facial skeletal reconstruction was performed
      with osteotomies and bone grafting. More recently, distraction osteogenesis has
      proven to be successful in achieving bone lengthening. For select cases,
      distraction osteogenesis has lessened the need for major skeletal procedures and
      has allowed earlier surgical intervention. The reconstruction of the soft tissues
      in facial asymmetry has generally been performed as a second-stage procedure
      after skeletal reconstruction. The disadvantage of these traditional approaches
      is that it requires two separate major operative procedures, with the
      accompanying increased morbidity, hospital stay, and cost. We present a patient
      with hemifacial microsomia and a grade III mandibular deformity, in whom both the
      hard- and soft-tissue deficiencies were corrected in one surgical procedure with
      mandibular distraction osteogenesis and soft-tissue augmentation with a
      vascularized parascapular osteocutaneous flap. The technique and results at 1
      year follow-up are presented.

PMID- 10332269
TI  - Symposium "Implantable Materials in Facial Aesthetic and Reconstructive Surgery:
      Biocompatibility and Clinical Applications". American Society of Maxillofacial
      Surgeons. Montreal, Quebec, October 6, 1995.
AB  - On October 6, 1995, the American Society of Maxillofacial Surgeons sponsored a 1
      day symposium entitled "Implantable Materials in Facial Aesthetic and
      Reconstructive Surgery: Biocompatibility and Clinical Applications." The
      symposium examined issues relating to the biocompatibility and clinical role of
      alloplastic materials commonly used for facial bone and soft-tissue replacement
      and augmentation. It provided a forum for the interaction of basic scientists,
      clinicians, and manufacturers. Clinical and laboratory data concerning a variety
      of implantable materials were presented and discussed. The program consisted of
      three parts. The first session was designed to provide historical and scientific
      background as well as perspective on legal issues surrounding the use of
      implantable biomaterials. The second session involved the presentation of
      clinical data on bone and bone substitutes for augmentation of the facial
      skeleton. The third session was devoted to clinical reports of bone and bone
      substitutes used for the reconstruction of cranial vault and cranial base skull
      defects.

PMID- 10332270
TI  - A specialist's view of the new technology: the absorbable plating system.

PMID- 10332271
TI  - Resorbable biotechnology for craniomaxillofacial surgery.

PMID- 10332272
TI  - Bioabsorbable polymer science for the practicing surgeon.
AB  - The structure and function relationships of polymers have long been the purview
      of engineers and polymer chemists. As bioabsorbable polymer implants continue to
      make inroads in the medical implant armamentarium, surgeons, long familiar with
      the properties and handling characteristics of metal implants, may find it
      advantageous to become aware of some of the unique characteristics of these types
      of materials so that an informed decision can be made regarding their usage. In
      this article, we present, in relatively nontechnical terms, the salient features
      of polymers in general and absorbable polymers in particular.

PMID- 10332273
TI  - Bioabsorbable fixation devices: status for the craniomaxillofacial surgeon.
AB  - With time, more and more types of medical devices become available to assist the
      surgeon in managing patients. Bioabsorbable fixation devices, which have been
      directed toward the orthopedic surgeon over the past 10 years, are but one
      example. One aim of this article is to present the current status of
      bioabsorbable devices in medical practice to the craniomaxillofacial surgeon who
      may not be aware of the inroads this technology has made. A bioabsorbable
      fixation system has become available for use by the craniomaxillofacial surgeon,
      which is described. A further aim of this article is to present concisely the
      testing rigor required of such devices before their introduction to the U.S.
      market. This has the added benefit of explaining the important role of the
      surgeon in developing and helping reduce to standard clinical practice the use of
      new technologies.

PMID- 10332274
TI  - Bioabsorbable plates and screws in pediatric craniofacial surgery: a review of 22
      cases.
AB  - The purpose of this study was to evaluate the application of bioabsorbable
      fixation devices in reconstructive craniofacial procedures in the pediatric
      population. We reviewed 22 cases in which bioabsorbable plates and screws were
      used in craniofacial surgery for reconstruction. The procedures were performed in
      a 7-month period. The patients ranged in age from 5 to 228 months at the time of
      surgery (mean, 76.7 months). The postoperative clinical follow-up ranged from 2
      to 16 weeks. The fixation devices were evaluated with regards to satisfactory
      fixation at the time of procedure. The postoperative follow-up evaluated clinical
      wound healing, signs of infection or local inflammation, and visibility or
      palpability of plates through the skin. All patients except one showed
      satisfactory wound healing with no sign of infection or local inflammation. The
      plates provided satisfactory fixation and were not visible through the skin. Two
      patients had plates that were palpable at the 4-month follow-up period. One
      patient with repair of a blow-out fracture of the orbit with resorbable mesh had
      redness and swelling over the wound site 2 weeks postoperatively with resolution
      4 weeks postoperatively. Our early experience suggests reabsorbable fixation is
      an attractive option in pediatric plastic and craniofacial surgery. With further
      experience, this technology may represent the standard of care in reconstruction
      of the infant calvarium.

PMID- 10332275
TI  - Bioabsorbables: their use in pediatric craniofacial surgery.
AB  - The need to provide rigid bony fixation in the surgical treatment of craniofacial
      disorders has inspired an evolution of operative techniques and fixation devices
      over the past two decades, with the recent development of an absorbable miniplate
      fixation system. We present features of the LactoSorb absorbable system (Biomet,
      Inc., Warsaw, IN) and our initial experience in 35 pediatric craniofacial
      patients over a 10-month period.

PMID- 10332276
TI  - Nonmetallic fixation in traumatic midfacial fractures.
AB  - The possibility of resorbable plate and screw fixation devices that provide
      adequate strength to allow facial fracture healing and are completely degraded
      thereafter has long had significant appeal. Favorable clinical experiences,
      however, have been very limited, and their use in the traumatized facial skeleton
      has yet to be proven a useful technology in the actual patient. In this regard,
      we review our experience in the management of orbital, zygomatic, and maxillary
      skeletal injuries with resorbable fixation.

PMID- 10332277
TI  - Early experience with biodegradable fixation for congenital pediatric
      craniofacial surgery.
AB  - We describe early experience using a polymeric bioresorbable bone fixation system
      in a consecutive series of eight pediatric patients for the correction of
      craniofacial malformations. Indications for surgical treatment included
      craniosynostosis (7) and encephalocele (1). All patients underwent bifrontal
      craniotomies with cranial vault or orbital reconstruction or both. Segments were
      then stabilized using bioresorbable fixation systems. Patients were evaluated pre
      and postoperatively clinically and with radiographs and photographs. Mean follow
      up was 4.5 months, with a minimum follow-up of 3 months. In seven of eight
      patients, there was no incidence of infection, extrusion, exposure, erythema,
      instability of the advanced segments, relapse, hematoma, seroma formation, or
      adverse inflammatory reaction. One patient experienced difficulty with respect to
      system imperfections (i.e., drill holes after tapping were too large for screws).
      This study demonstrated the efficacy of bioresorbable plates and screws for the
      growing pediatric craniofacial patient; excellent short-term results were
      achieved. Prospective studies and longer longitudinal follow-up of larger numbers
      of patients are desirable to confirm these findings.

PMID- 10332278
TI  - Degradation characteristics of PLLA-PGA bone fixation devices.
AB  - Parietal craniotomies of the mature rabbit skull were repositioned and fixed with
      resorbable plate and screws made of LactoSorb (Walter Lorenz Surgical,
      Jacksonville, FL) poly L-lactic acid (PLLA) and polyglycolic acid (PGA) in 20
      mature rabbits. Changes in the resorbable devices as well as at the tissue
      implant interface were evaluated at 2, 6, 9, and 12 months postoperatively. At 2
      months, no change in the size of the implants was seen with a noninflammatory
      layer of surrounding fibrous tissue and intense birefringence of the screws. At 6
      months, substantial loss of implant size had occurred, accompanied by
      fibrovascular and a macrophage cellular infiltrate. At 9 months, more than 95% of
      the implant was resorbed, with a small amount remaining in the screw hole. Other
      than macrophages within the remaining material, very few giant cells were seen.
      By 1 year, no evidence of birefringent macromolecular polymer debris could be
      found. No contraindications for the clinical use of this specific PLLA-PGA
      copolyer could be found when implanted on craniofacial bone surface.

PMID- 10332279
TI  - Absorbable, invisible, and flexible plating system for the craniofacial skeleton.
AB  - This report demonstrates further experience in the use of the absorbable plating
      system since our preliminary report in 1996. We found more indications for the
      application of the absorbable plating system in the craniofacial skeleton in
      children and in covering cranial bone graft donor sites. The system is unique,
      the applications are widespread over the horizon, and the only limitations are
      those of the operating surgeon. The advantage is that in 1 year the system
      absorbs completely by hydrolysis, giving minimal inflammatory reaction at the
      site.

PMID- 10332281
TI  - Role of resorbable plates and screws in craniofacial surgery.
AB  - Twenty patients underwent craniomaxillofacial fixation procedures with the use of
      the LactoSorb (Walter Lorenz Surgical, Jacksonville, FL) resorbable plating
      system. The patients ranged in age from 4 months to 67 years. No significant
      problems from the use of this plating system were noted. The resorbable plating
      system offers several distinct advantages over traditional metallic systems.

PMID- 10332280
TI  - Potential for guided bone regeneration and bone graft fixation with resorbable
      membranes in pediatric craniofacial surgery.
AB  - Resorbable devices offer a significant technological advance for craniofacial
      surgery; however, the potential for their use may extend beyond that of bone
      fixation. Applications to assist bone regeneration and to secure bone grafts in
      cranial defects in the pediatric patient are presented.

PMID- 10332283
TI  - Reconstruction of a cranial bone defect with hydroxyapatite and free flap
      transfer.
AB  - The authors report a successful reconstruction of an extensive frontotemporal
      bone defect after craniotomy, which was complicated with infection and
      necessitated removal of frontal and temporal bones. The large frontotemporal bone
      defect was reconstructed using prefabricated hydroxyapatite blocks in combination
      with the free vastus lateralis muscle flap. The patient's functional and cosmetic
      restoration has been maintained for 10 months' follow-up.

PMID- 10332282
TI  - Maxillofacial fixation with absorbable miniplates: computed tomographic follow
      up.
AB  - Rigid internal fixation has become a mainstay of treatment for maxillofacial
      trauma. Refinement in materials and manufacturing have led to unobtrusive
      titanium miniplates and microplates. However, concerns remain regarding the
      presence of plates and screws after fracture healing has occurred. Absorbable
      rigid fixation systems ideally would provide sufficient strength and fixation to
      allow osseous healing and then be absorbed without sequelae. Plates and screws
      made from polylactic acid-polyglycolic acid copolymer approach this ideal. Four
      maxillofacial trauma patients underwent open reduction and internal fixation
      using absorbable plates and screws. Direct coronal computed tomographic (CT)
      scans were obtained before and after repair of the fractures. CT scan 6 months
      after repair shows adequate reduction of fractures and osseous healing. Clinical
      follow-up shows no significant sequelae.

PMID- 10332284
TI  - Aplasia of the vertex without scalp defect.
AB  - We report a case of an extremely rare craniofacial condition, which, to our
      knowledge, has previously been reported once only. A male infant presented with a
      giant congenital bone defect of the skull, in the vertex region (10 x 20 cm) and
      without scalp deficiency. Minimal turricephaly and moderate orbital hypertelorism
      were associated with slight limb abnormalities, but psychometrical assessments
      appeared normal. Nonsurgical treatment was initially decided upon, but
      spontaneous reossification was so moderate that skull reconstruction was carried
      out at 28 months of age because of the risk of trauma. A full-size resin cephalic
      skeletal reconstruction was obtained according to three-dimensional computed
      tomography using stereolithographic techniques. A titanium plate was customized
      on the resin model for ideal adaptation to the convex skull defect (8 x 16 cm).
      Surgery was simply performed, consisting of a preliminary undermining between the
      dura mater and the scalp and screwing of the custom titanium plate. The initial
      follow-up was uneventful.

PMID- 10332286
TI  - Re: Bone regeneration study.

PMID- 10332285
TI  - A preventable complication of LactoSorb craniomaxillofacial fixation.
AB  - The use of resorbable craniomaxillofacial fixation has recently garnered support,
      especially in the pediatric population. Its advantages are well summated in other
      articles within this journal. The aim of this article is to present a unique but
      preventable complication of the LactoSorb resorbable craniomaxillofacial fixation
      system (Lorenz/Biomet, Inc., Warsaw, IN): retention of the hex head of a
      LactoSorb screw. This article addresses the complication and its future
      avoidance.

PMID- 10332287
TI  - More on crooked heads.

PMID- 10332288
TI  - Abnormal cranial shape in infants.

PMID- 10332289
TI  - Controversies regarding the management of skull abnormalities.

PMID- 10332290
TI  - Microsurgical anatomy of the facial nerve.
AB  - Microsurgical dissection of cadaver facial nerves revealed quantifiable
      complexities not presented in standard description. Total branches, intraparotid
      connections between divisions, and extraparotid connections between divisions are
      more common than generally noted, and 33% of the dissections demonstrated an
      extraplanar buccal branch originating within the parotid gland, and innervating
      the perioral muscles. These details of facial nerve anatomy suggest surgical
      procedures such as tumor resection, facial nerve reconstruction, facial
      reanimation, and facelifting.

PMID- 10332291
TI  - Clinical features of Crouzon's syndrome patients with and without a positive
      family history of Crouzon's syndrome.
AB  - Crouzon's syndrome occurs in 1 in 25,000 live births and follows an autosomal
      dominant mode of transmission. However, 30 to 60% of cases are sporadic and
      represent fresh mutations. Previous reports involving large series of Crouzon's
      syndrome patients mixed sporadic and familial cases. In this article, the
      clinical features of 17 familial cases of Crouzon's syndrome were compared with
      another 27 sporadic cases. Furthermore, familial cases were studied to document
      (1) expressivity in members of the same family; (2) the skull base angle in
      unoperated members of the same family, and (3) the presence of germinal
      mosaicism. In familial cases of Crouzon's syndrome, craniosynostosis and
      proptosis were seen in 76% and 88% of patients, respectively. On the other hand,
      these two features were observed in 100% of sporadic cases. Variability of
      expression in members of the same family was a common finding. The cranial base
      angle was also variable in the affected members of the same family. In the
      series, germinal mosaicism was suspected in one family. Possible explanations for
      our findings are discussed as well as the implications of genetic mapping in
      Crouzon's syndrome.

PMID- 10332292
TI  - Holmium YAG laser-assisted osteotomies in plastic and reconstructive surgery: a
      preliminary report.
AB  - An Omnipulse holmium-yttrium aluminum garnet (YAG) laser was used to assist in
      the harvesting of outer table or split calvarial bone grafts in cadaver skulls.
      Two- or 4-mm depth and 0.55-mm width holes in the outer cortex of cadaveric
      calvarium were formed without apparent gross periosteal or bony injury.
      Osteotomes were then used to shave or split calvarial grafts by connecting the 2-
      and 4-mm depth holes, respectively. The procedure was efficient as well as
      precise. We believe that this method of bone graft harvesting may have the added
      benefit of safety by decreasing the incidence of inadvertent dural penetration.
      This study will lead to further analysis of the potential use for additional bony
      work with the Omnipulse holmium-YAG laser.

PMID- 10332293
TI  - Early and late surgical treatment of orbital dystopia in craniofacial
      malformation.
AB  - Orbital dystopia is one of the most frequent clinical signs of craniofacial
      malformation. The term dystopia indicates the mono- and bilateral asymmetry of
      the orbits at least in one of the three-dimensional planes. The diagnosis is
      based on the clinical test of the patient with the support of diagnostic
      instruments such as teleradiography in both standard projections, axial computed
      tomographic (CT) scans at a rate of 1:1 through the neuro-orbital plan, and the
      three-dimensional CT. Good results of the surgical treatment depend on the
      patient's age and on adequate programming, which should consider the anomalies in
      the three spatial planes. The VTO is obtained through a protocol of analysis on
      cephalometric graphics of the teleradiographics on the CT at a rate of 1:1. The
      surgical treatment of orbital dystopia is different depending on the age of the
      patient and the cause of the orbital anomaly. In the case of growing patients, it
      is preferable to use the fronto-orbital bandeau technique so as not to damage the
      dental buds, whereas in grown patients Tessier's orbital quadrant technique is
      used. Even the fixation is quite different between patients who are growing and
      those who are already grown. In still-growing patients, rigid internal fixation
      is used only in some cases to avoid the interference with the growth mechanisms.

PMID- 10332294
TI  - Intramuscular temporalis fascia: a guide to procurement of temporalis myofascial
      flaps.
AB  - The purpose of this study is to demonstrate an intramuscular fascial layer within
      the temporalis muscle. This can be used as an inferior plane when developing a
      temporalis myofascial flap for temporomandibular joint reconstruction. The
      advantages of using this plane include relatively bloodless zone, adequate
      thickness of flap for reconstructive purposes, and residual temporalis muscle to
      prevent the temporal concavity deformity. Cadaveric and clinical examples are
      presented.

PMID- 10332295
TI  - Late results of hypertelorism correction.
AB  - The late results of patients who were operated on for the correction of
      hypertelorism were evaluated. Follow-up ranged between 1 and 11 years (mean, 4.3
      years). The mean interorbital distance was 32.9 mm preoperatively and 26.7 mm
      postoperatively. The significant decrease in the interorbital distance and the
      absence of serious postoperative complications revealed that craniofacial surgery
      for the correction of hypertelorism was an effective and reliable procedure.

PMID- 10332296
TI  - Progressive unilateral mandibular swelling in adolescence: a diagnostic dilemma.
AB  - Asymmetrical swelling of the mandible in adolescence may pose a significant
      diagnostic dilemma. The differential diagnosis ranges from traumatic, infectious,
      and metabolic processes to benign and malignant tumors. Among them, fibrous
      dysplasia, osteomyelitis, and malignancy may present with similar clinical and
      radiological features, making an accurate diagnosis quite difficult. This is an
      illustrative case involving a 14-year-old girl who initially presented with
      diffuse fibrous dysplasia of the mandible and in whom a superimposed
      osteomyelitis of the left side subsequently developed. Multiple investigations
      and several biopsies were required to arrive at a diagnosis. Similarities in
      clinical and radiographic findings of fibrous dysplasia, osteomyelitis, and
      malignancy are presented, and implications for treatment are discussed.

PMID- 10332297
TI  - Management of the ventricular shunt in posterior deformities of the skull in
      craniosynostosis.
AB  - The existence of an occipitoparietal cerebrospinal fluid shunt complicates the
      attempt to remodel posterior skull deformities in craniosynostosis. A composite
      method to reposition the shunt hardware is described and discussed.

PMID- 10332298
TI  - Split-thickness calvarial grafts in young children.
AB  - Sixteen patients (mean age, 1.9 years) underwent split-thickness calvarial bone
      grafting using a full-thickness craniotomy, high-speed drill, and osteotomes for
      bone harvesting. The minimal calvarial bone thickness for a successful graft was
      found to be 7 mm. All patients were diagnostically studied preoperatively with
      computed tomographic scans and skull films. The mean follow-up was 2.9 years
      (range, 0.75-7.9 years). All patients had successful graft take. There were no
      infections or mortalities. Continued graft growth was seen in all patients. There
      was one dural tear during harvesting with no cerebrospinal fluid leak or
      postoperative sequelae. This analysis indicates that split-thickness calvarial
      grafts can be safely and adequately performed in children as young as 13 months
      of age.

PMID- 10332299
TI  - Reconstruction of the mandibular condyle using transport distraction
      osteogenesis.
AB  - Transport distraction osteogenesis was used to reconstruct the articulation of
      the temporomandibular joint in two patients. Patient 1 underwent a gap
      arthroplasty for release of a bony ankylosis. Patient 2 had degenerative joint
      disease after tumor resection. Both patients had painful, limited mouth opening
      and facial asymmetry as a result of condylar shortening. A reverse-L osteotomy
      was performed from the sigmoid notch to the posterior border of the mandible. An
      external transport distraction device was applied, and the segment was advanced
      superiorly, 1.0 mm per day, until contact was made with the glenoid fossa. After
      distraction, the bone was found to have remodeled, inducing a new cortical layer
      on the articular surface. Additionally, a pseudodisk was generated as a result of
      the transport distraction. The two patients tolerated the procedure well,
      returning to pain-free normal mouth opening and being able to masticate regular
      diets.

PMID- 10332300
TI  - Tessier type VI-VII cleft combination associated with congenital bimaxillary
      fusion and anophthalmia.
AB  - Congenital intermaxillary fusion is a rare anomaly. Combination of the anomaly
      with any type of facial cleft is extremely rare. Death in a majority of these
      patients as a result of feeding and aspiration problems in early life may have
      caused the reports to be limited. In this article a 5-year-old patient, probably
      the first in the literature having Tessier type VI-VII facial cleft combination
      associated with bimaxillary fusion and anophthalmia on the right side, is
      presented. The patient has survived on fluid meal through a very small opening
      for 5 years. The features of the case are presented, and the time and method of
      the management of such a rare anomaly are discussed with a review of the
      literature.

PMID- 10332301
TI  - Three different techniques for mandibular reconstruction after
      hemimandibulectomy.
AB  - Mandibular reconstruction is a condition in which both bone defect and function
      must be restored. A wide range of approaches--from grafts to distant bone flaps-
      have been used for correcting bony defects. However, adequate mastication has
      been restored in only a few cases. In this article the results of three different
      techniques for mandibular reconstruction after hemimandibulectomy were studied.
      Sixteen patients underwent a second mandibular reconstruction after
      hemimandibulectomy and were monitored at least 1 year. Three different techniques
      were used: (1) full-thickness galeoparietal bone flap (eight patients), (2) free
      iliac crest graft (three patients), and (3) free fibular grafts (five patients).
      Occlusion on the nonoperated side and the possibility and function of
      osseointegrated denture in the vascularized bone transfer were evaluated. The
      full-thickness galeoparietal flap and free iliac crest bone flap appeared to be
      good options. However, only acceptable or poor occlusion could be achieved on the
      normal side. The fibular free flap demonstrated good results and good occlusion.
      Nonetheless, dental implantation was difficult because a prosthesis for reaching
      the normal height of the mandible was necessary.

PMID- 10332302
TI  - Primary maxillary reconstruction after radical maxillectomy using a combined free
      flap and secondary dynamic suspension.
AB  - We report a case of maxillary reconstruction aimed at optimizing facial contour,
      oral function, and facial animation after radical maxillectomy. In the first
      stage, using combined latissimus dorsi serratus anterior flaps attached with
      ribs, we performed a three-dimensional restoration for midface defects. In the
      second stage, we performed dynamic reconstruction of the nasolabial fold and
      upper lip using a temporal muscle transposition. As a result, the upper lip was
      able to be elevated as much as 10 mm when the patient clenched his teeth, and the
      outcome was judged to be both aesthetically and functionally satisfactory.

PMID- 10332303
TI  - Cloverleaf skull anomaly with extreme orbitostenosis.
AB  - A neonate presented with cloverleaf skull anomaly and severe proptosis requiring
      urgent cranioplasty to attain eyelid closure. Despite this, she experienced
      exposure keratitis and corneal perforations. A ventriculoperitoneal shunt was
      performed subsequently to relieve hydrocephalus, but respiratory problems
      eventually led to her death at 6 months. This case highlights the complexity of
      the problems encountered in the cloverleaf skull anomaly, and a brief review
      discussing its management is included. Despite improvements in treatment of this
      condition, the overall prognosis remains poor.

PMID- 10332304
TI  - Localized vitiligo and frontoethmoidal meningoencephalocele.
AB  - A child with frontoethmoidal meningoencephalocele in whom localized facial
      vitiligo developed after surgical correction of the encephalocele is presented.
      The potential role of the ocular disease accompanying the encephalocele in the
      development of the hypopigmentation is discussed.

PMID- 10332306
TI  - The incidence and nature of fibrous continuity between the sphenomandibular
      ligament and the anterior malleolar ligament of the middle ear.
AB  - The purpose of this study was to determine the structural interrelationship
      between the temporomandibular joint (TMJ) and the middle ear, in terms of fibrous
      continuity between the sphenomandibular ligament (SML) of the mandible and the
      anterior malleolar ligament (AML) of the middle ear. Thirty-seven specimens of
      the TMJ and middle ear were obtained from adult human cadavers. The temporal
      bone, petrotympanic fissure, mandibular fossa, and middle ear were dissected en
      bloc, fixed, sectioned, stained, and observed microscopically. Of the 37
      specimens, 67.6% had a continuity of the SML through the fissure passing near the
      malleus of the middle ear. The AML was present at the fissure in 64.9% of the
      specimens, with 58.3% passing through and not stopping at the fissure. Results
      indicated a fibrous continuity between the SML and the AML. Structural
      differences between the two ligaments were also noted. The SML contained randomly
      arranged fibrous connective tissue with numerous interposed blood vessels. The
      AML had a smooth arrangement of fibers within the connective tissue, and few
      blood vessels were apparent. The clear anatomic relationship observed strongly
      supports the contention of a functional interrelationship between the TMJ and the
      middle ear.

PMID- 10332305
TI  - Re: Open transnasal approach to the midline skull base.

PMID- 10332307
TI  - Do bruxism and temporomandibular disorders have a cause-and-effect relationship?
AB  - Controversy continues to exist over the putative role of bruxism in the etiology
      of temporomandibular disorders. A commonly held concept is that bruxism leads to
      signs and symptoms characteristic of one or more of the subdiagnoses of
      temporomandibular disorders, while another hypothesis suggests that bruxism is a
      temporomandibular disorder itself that sometimes coexists with other forms of
      temporomandibular disorders. Following a thorough review of the literature in
      this article, it is concluded that the relationship between bruxism and
      temporomandibular disorders is still unclear. Future research should examine
      longitudinal epidemiologic and clinical/experimental data to establish or refute
      a cause-and-effect relationship. In doing so, the existence of various sub-groups
      of temporomandibular disorders should be taken into account, and sleep-related
      bruxism should be discriminated from its daytime variant.

PMID- 10332309
TI  - The prevalence of disc displacement in symptomatic and asymptomatic volunteers
      aged 6 to 25 years.
AB  - The purpose of this investigation was to determine a possible association between
      disc displacement and temporomandibular disorders (TMD). Fifty-six Brazilian
      asymptomatic volunteers (25 males and 31 females) and 181 symptomatic TMD
      patients (112 females and 69 males) participated. Volunteers did not have
      temporomandibular joint pain, limited jaw opening, joint sounds, or previous TMD
      treatment. Bilateral temporomandibular joint magnetic resonance imaging scans
      were obtained from all subjects. Joints were classified as normal or having disc
      displacement. Asymptomatic volunteers had 28 (25%) joints with disc displacement;
      10 (18%) had unilateral and 9 (16%) had bilateral disc displacement. Of the TMD
      patients, 25 (13.8%) had bilateral symptomatic but normal joints. Fifty-one
      (28.2%) had unilateral and 105 (58%) had bilateral disc displacement. Odds ratios
      (12.2 [95% confidence interval = 6.1 to 24.4, P = .001]) suggest a strong
      association between disc displacement and TMD. This study suggests that disc
      displacement is relatively common (34%) in asymptomatic volunteers and is highly
      associated with patients (86%) with TMD.

PMID- 10332310
TI  - Sexual and physical abuse history in subjects with temporomandibular disorders:
      relationship to clinical variables, pain sensitivity, and psychologic factors.
AB  - Recent evidence suggests that a past history of physical and/or sexual abuse is
      more frequently reported among chronic pain populations; however, the prevalence
      of reported abuse has not been examined in patients with chronic orofacial pain
      caused by temporomandibular disorders (TMD). This study compares reported
      physical/sexual abuse among female TMD subjects recruited from the general
      population with that of age-matched female control subjects. The association of
      reported abuse with clinical pain, experimental pain responses, and psychologic
      variables was examined in the TMD group. Results indicated that a slightly but
      not statistically greater percentage of TMD subjects (44.8%) reported a history
      of sexual or physical abuse compared to control subjects (33.3%). Reported abuse
      among TMD subjects was not related to clinical pain or psychologic variables.
      Regarding experimental pain responses, TMD subjects reporting a history of abuse
      exhibited longer ischemic pain tolerances compared to those not reporting abuse;
      however, the groups did not differ on other experimental pain measures. Results
      indicate that the reported prevalence of physical/sexual abuse is similar among
      TMD subjects compared to other chronic pain populations; however, the
      relationship of abuse to clinical and psychosocial variables remains unclear.

PMID- 10332308
TI  - Muscle activity and jaw movements as predictors of chewing performance.
AB  - Chewing performance can be defined in terms of the reduction in food particle
      size after 15 chewing strokes. In this study, the relationship between chewing
      performance and electromyographic activity was investigated to develop optimal
      values of electromyographic variables, based on their ability to predict chewing
      performance. Electrognathographic and electromyographic recordings from surface
      electrodes over the digastric (abductor), masseter, and temporalis (adductors)
      muscles were made from 24 subjects while they chewed a hard fruit gum. A moderate
      negative correlation was found between the food particle size and the root mean
      square calculation for masseter activity (-.48; P < .01). Weaker positive
      correlations were found between particle size and the asynchrony of ipsilateral
      and contralateral anterior temporalis muscles (.36; P < .05). A multiple
      regression model of electromyographic and electrognathographic variables was able
      to predict chewing performance with an R2 value of .66. If chewing performance is
      used as an output measure of masticatory function, it may be possible to
      determine optimal ranges for electromyographic variables and jaw movements.

PMID- 10332311
TI  - Temporomandibular disorders. Part I: A comparison of symptom profiles in
      Australian and Finnish patients.
AB  - Variability in the assessment methods of patients seeking treatment for
      musculoskeletal disorders of the masticatory system confounds comparative
      assessment of different studies. In this study, presenting symptom profiles were
      assessed in 40 Australian and 42 Finnish patients with temporomandibular
      disorders. The symptom parameters of these patients were compared with those of
      40 Australians reporting acute dental pain and were assessed with reference to
      response to conservative management. A self-administered anamnestic questionnaire
      was used in a standard, systematic, and comparative way to assess demographic
      data, general health status, and symptom parameters according to type, frequency,
      severity, duration, location, impact on the patients' lives, urgency for need of
      treatment, and possible initiating factors. It was found that the two
      nationalities studied had similar presentations of cardinal symptom profiles.
      Statistically significant differences in major presenting symptoms were found
      between patients with temporomandibular disorders and those with acute dental
      pain, but not between patients who responded rapidly as opposed to slowly to
      conservative therapy. It was concluded that the presenting symptom profiles were
      similar for the two nationalities and were not related to treatment outcome.

PMID- 10332312
TI  - The effect of occlusal appliances and clenching on the temporomandibular joint
      space.
AB  - It has been suggested that stabilization appliances and mandibular anterior
      repositioning appliances work by decompressing the temporomandibular joint. To
      indirectly test this assumption, tomograms of right temporomandibular joints of
      seven subjects were taken during comfortable closure and maximum clenching in
      maximum intercuspation and on the two types of occlusal appliances. Outlines of
      the condyle and the temporal fossa were automatically determined by an edge
      detection protocol. Upon comfortable closure, the anterior joint space dimension
      was reduced with stabilization appliances and mandibular anterior repositioning
      appliances. Upon maximum clenching, the minimum joint space dimension on
      stabilization appliances was equivalent to that seen in maximum intercuspation,
      while that on mandibular anterior repositioning appliances was substantially less
      (P < .05). Findings do not indicate that these appliances induce an increase in
      joint space during clenching.

PMID- 10332313
TI  - The scope of TMD/orofacial pain (head and neck pain management) in contemporary
      dental practice. Dental Practice Act Committee of the American Academy of
      Orofacial Pain.
AB  - The Dental Practice Act Committee of the American Academy of Orofacial Pain was
      convened in 1995 for the purpose of studying the scope of temporomandibular
      disorders (TMD)/orofacial pain and dental practice acts. The committee concluded
      that the scope of clinical practice of TMD/orofacial pain is expanding beyond the
      teeth and oral cavity to include the diagnosis and treatment of disorders
      affecting the entire head and neck. The expansion of clinical practice is
      consistent with historical precedent in dentistry and within the scope of current
      dental practice acts. The present report represents the position of the American
      Academy of Orofacial Pain.

PMID- 10332314
TI  - Evidence-based TMD guidelines.

PMID- 10332315
TI  - The structure of the human temporomandibular joint disc: a scanning electron
      microscopy study.
AB  - The articular disc of the temporomandibular joint was studied in fetuses (16 to
      39 weeks of intrauterine life), infants (up to 4 months of age), dentulous adults
      (aged 30 to 39 years), and completely edentulous adults (aged 60 to 69 years) by
      scanning electron microscopy. The constituents bundles of collagen fibers were
      stratified and were oriented anteroposteriorly, laterolaterally, and obliquely in
      the middle portion of the disc. A ring of laterolateral bundles constituted the
      main feature of the thick posterior portion. In the anterior portion of the disc,
      the fibers were anteroposteriorly and obliquely oriented. On the superior and
      inferior surfaces of the disc, a thin layer of perpendicularly arranged collagen
      fibers covered the underlying, thick, laterolateral oriented collagen fibers.

PMID- 10332317
TI  - Effects of stretch-based progressive relaxation training on the secretion of
      salivary immunoglobulin A in orofacial pain patients.
AB  - There is a growing body of evidence that psychologic stressors can affect
      physical health and proneness to disease through depletion of the body's immune
      system. Relatively little research, however, has investigated the potential
      immunoenhancing effect of stress-relieving strategies such as progressive muscle
      relaxation. This study explored the relationship between immune functioning and
      relaxation training with persons experiencing persistent facial pain. In a single
      experimental session, 21 subjects either received relaxation training or rested
      for an equivalent time period. Salivary immunoglobulin A, mood, pain, and tension
      levels were measured before and after relaxation and rest periods. Results
      indicated that a greater proportion of those receiving relaxation training had
      increases in secretion of salivary immunoglobulin A. These findings suggest that
      immunoenhancement may be another potential benefit of progressive relaxation
      training for persons with chronic pain conditions.

PMID- 10332316
TI  - Jaw movement tremor as a predictor of chewing performance.
AB  - The purpose of this study was to investigate normal physiologic tremor in jaw
      movement as a factor that may influence chewing performance more directly than
      either muscle activity or jaw displacement. Chewing performance was defined in
      terms of the reduction in food particle size after 15 chewing strokes. Data on
      chewing particle size and electromyographic activity were available for 24
      asymptomatic adults from an earlier study. Jaw movements during chewing were
      recorded using electrognathography, and velocity and acceleration in three planes
      were determined. Power spectrum for acceleration was calculated during opening
      and closing phases of the chewing cycle. The frequency of the peak amplitude in
      the power spectrum represented physiologic tremor of the jaw. Tremor frequencies
      during both opening and closing phases of the chewing cycle were strong
      predictors of chewing performance. A multivariate model composed of variables
      derived from acceleration, together with electromyographic and jaw movement
      variables, produced a multivariate model that was able to predict chewing
      performance with an adjusted R2 value of .78.

PMID- 10332318
TI  - Electromyographic data from TMD patients with myofascial pain and from matched
      control subjects: evidence for statistical, not clinical, significance.
AB  - This study tested the hypotheses that electromyographic (EMG) activity at rest
      would be significantly greater for temporomandibular disorder (TMD) patients with
      myofascial pain than for nonpain control subjects, and that a cutoff score based
      on EMG values could be established to accurately separate the two groups. Fifty
      four TMD patients diagnosed with myofascial pain and 54 nonpain control subjects
      who were matched for age and gender were examined. Both groups participated in an
      EMG scanning procedure in which the left and right frontalis, temporalis, and
      masseter muscles were examined. Results showed that the TMD group had
      significantly higher EMG activity at rest for three of the six sites examined.
      The application of a cutoff value that produced the smallest classification error
      nonetheless resulted in misclassification of about one third of the TMD and
      nonpain individuals. These data provide little support for the use of resting EMG
      data obtained via a scanning procedure in accurately distinguishing facial pain
      patients from nonpain control subjects.

PMID- 10332320
TI  - A controlled evaluation of ibuprofen and diazepam for chronic orofacial muscle
      pain.
AB  - The clinical efficacy, side effect liability, and hormonal effects of two
      prototypic pharmacologic agents were evaluated for the management of chronic
      myogenous facial pain in a double-blind, randomized, controlled clinical trial.
      Thirty-nine subjects (35 women,. 4 men) with daily or near-daily orofacial pain
      of at least 3 months' duration and tenderness to palpation of masticatory muscles
      participated. Patients were randomly allocated to one of four treatments:
      placebo, diazepam, ibuprofen, or the combination of diazepam and ibuprofen. Pain,
      mood, muscle tenderness, maximal interincisal opening, and plasma levels of beta
      endorphin were measured following 2-week baseline and 4-week treatment periods.
      Pain, as measured by a visual analog scale, was significantly decreased in the
      diazepam and diazepam plus ibuprofen groups but not for the ibuprofen or placebo
      groups. Analysis of variance showed a significant drug effect for diazepam but
      not for ibuprofen, indicating that pain relief was attributable to diazepam. No
      significant changes were noted in muscle tenderness, interincisal opening, or
      plasma beta-endorphin level. This study supports the efficacy of diazepam in the
      short-term management of chronic orofacial muscle pain. The lack of effect
      following administration of an anti-inflammatory analgesic suggests that
      inflammation is not the basis for chronic muscle pain in the orofacial region,
      and that the analgesic effect of such medications is not sufficient for pain
      relief in this condition.

PMID- 10332319
TI  - Practical implications of noncompliance in randomized clinical trials for
      temporomandibular disorders.
AB  - Randomized clinical trials are recognized as providing the most rigorous evidence
      of treatment efficacy. For temporomandibular disorders, randomized clinical
      trials have been used to evaluate the efficacy of low-cost occlusal appliances or
      the adjunct use of cognitive behavioral interventions. However, noncompliance
      with treatment regimens and losses to follow up are common randomized clinical
      trial protocol violations that compromise the desired rigor of the trial. At
      times it is not clear to the investigator how to deal with these issues during
      the trial and at the data analysis phase. Often treatment efficacy is based on
      the compliant subjects, subjects who may no longer represent randomized groups or
      yield the desired "fair" estimate of treatment efficacy. This study focuses on
      management of compliance issues, the description and collection of data needed to
      obtain a more accurate assessment of treatment efficacy, and results particularly
      relevant to actual clinical practice and patient care decisions. These are
      applied to a randomized clinical trial evaluating the efficacy of a cognitive
      behavioral intervention for temporomandibular disorders.

PMID- 10332321
TI  - Temporomandibular disorders: Part II. A comparison of psychologic profiles in
      Australian and Finnish patients.
AB  - Recent recommendations regard musculoskeletal disorders of the masticatory system
      as dual-axis disorders, but little comparative data of psychologic factors across
      different pain populations are available. In this study, presenting psychologic
      profiles were assessed in 40 Australian and 42 Finnish patients diagnosed with
      temporomandibular disorders. Findings were compared with those of a group of
      Australian patients reporting acute dental pain and with reference to response to
      conservative management. The psychologic testing instrument incorporated
      cognitive, motivational/affective, and illness behavior variables, and it was
      based on validated general pain questionnaires (Coping Strategies Questionnaire
      and Illness Behavior Questionnaire). This instrument was found internally
      reliable in the majority of its subscales in the group studies and provided
      comparable data to other pain populations. Significant differences in the
      presenting psychologic profiles were found according to nationality, type of pain
      suffered, and treatment outcome. Affective disturbance, hypochondriasis, lack of
      cognitive control, and feeling ill with symptoms were identified in discriminant
      function analysis as potential predictors of treatment outcome, and they
      correctly classified 79% of the Australian and 87% of the Finnish patients with
      temporomandibular disorders. It was concluded that psychologic profiles differed
      in the two nationalities and were related to treatment outcome. The concept of
      multiaxial assessment was supported.

PMID- 10332322
TI  - Occipital neuralgias: clinical recognition of a complicated headache. A case
      series and literature review.
AB  - The objective of this study was to assist clinicians in the diagnosis of the
      occipital neuralgia syndrome by describing its clinical characteristics.
      Bibliographies and clinical descriptions of occipital neuralgia syndrome were
      identified through a review of literature published between 1966 and 1993. A
      prospective case series was performed by the authors in a university emergency
      department during a 1-year period. Patients with unilateral aching pain of the
      head, coupled with pain in the distribution of the occipital nerve, Tinel's sign,
      and relief of pain after local anesthetic injection, were included. Patients
      rated pain relief on a 10-point scale. Twelve patients met the criteria for
      occipital neuralgia and were included in the study. All patients reported at
      least 80% decrease of pain after injection, and 42% had complete relief. Clinical
      features, other than headache, that were common in patients included tinnitus in
      33%; scalp paresthesia, 33%; nausea, 42%; dizziness, 50%; and visual
      disturbances, 67%. Occipital neuralgia is a benign extracranial cause of
      headache, and it may be confused with other more serious headache syndromes.
      Recognition depends on an understanding of the symptoms along with a careful
      history and physical examination. Local anesthetic injections produce significant
      relief of the headaches and can aid in the diagnosis of the syndrome.

PMID- 10332323
TI  - American Academy of Orofacial Pain. 22nd Meeting on Orofacial Pain and
      Temporomandibular Disorders. San Diego, California, February 14-16, 1997.
      Abstracts.

PMID- 10332324
TI  - MGDS log diary case report.
AB  - This log diary describes the treatment provided to Mrs ED, a 55-year-old female
      who presented with a 'broken front cap'. She also requested a complete course of
      treatment. This case report includes details of the treatment provided:
      Emergency/immediate treatment. Full history and examination and special
      investigations. Diagnosis and treatment planning. Provision of periodontal and
      restorative treatment. Crown lengthening and extractions. Provision of milled
      crowns and a post core and crown. Provision of upper and lower partial cobalt
      chrome dentures.

PMID- 10332325
TI  - Single-unit resin-bonded bridges using the natural tooth or a denture tooth.
AB  - Resin-bonded bridges were first described by Rochette in 1973. In the following
      year the author had occasion, for the first time, to experiment with a single
      unit resin-bonded bridge (RBB) which employed the exfoliated natural tooth as a
      pontic. That 'temporary' measure gave good service for 17 years and was the
      precursor of a number of successful RBBs which utilized natural or denture teeth.
      The very simple method described offers the means of preserving the patient's
      natural appearance, thereby maintaining the psychological well-being of the
      patient. It is particularly applicable in patients who present with gross loss of
      periodontal support and where a conventional RBB or fixed bridge may be contra
      indicated for personal or clinical reasons. It is not time consuming or
      clinically demanding. It has a high degree of patient acceptance and
      satisfaction. The contiguous teeth, involved as abutments, appear to be
      beneficially affected.

PMID- 10332326
TI  - A simple technique for data management in general dental practice audit.
AB  - General practice audit is essential in the process of developing an evidence
      based approach to dental care. The CHAID (CHi-Squared Automatic Interaction
      Detector) statistical software package is both practical and user-friendly for
      many simple applications. The types of questions asked in general practice audit
      projects will frequently be suitable for analysis using this technique. This may
      include the identification of patients who are likely to fail appointments and
      place an additional financial burden on the practice. This paper illustrates the
      potential value of CHAID to general dental practitioners (GDPs) by using examples
      of commonly cited dental audit topics. This paper aims to illustrate how a simple
      statistical package (SPSS CHAID) may be of use for both audit and practice
      management activities.

PMID- 10332327
TI  - An audit of antibiotic prescribing in general dental practice.
AB  - Clinical audit is widely recognised as the systematic and critical analysis of
      the quality of clinical care, including treatment regimes, the associated use of
      resources, and the resulting outcome and quality of life for the patient. The
      prescribing of antibiotics in general dental practice is an area 'wide open' for
      audit analysis since the profession must clearly accept its responsibility to use
      antibiotics sensibly; however, the definition of 'sensibly' is likely to vary
      from practitioner to practitioner. This audit reviews the need for antibiotic
      prescribing in general dental practice over two consecutive four-month periods. A
      consensus was achieved on the rationale for antibiotic prescribing and the number
      of prescriptions fell by 50% as a result.

PMID- 10332328
TI  - Panoramic radiographic screening: a risk-benefit analysis.
AB  - PURPOSE OF STUDY: To determine the amount of clinically relevant pathology found
      by panoramic radiographic screening in a young adult population and to assess
      whether such screening is justified. POPULATION STUDIED: The records of 1101 RAF
      recruits enlisted in 1988-89, average age 19 years (range 16-26). METHOD: The
      routine dental panoramic tomograph screening films of the sample population were
      inspected by the author on a masked-out screen under 2X magnification. Where
      instances of dubious pathology were found these films were shown to a consultant
      oral surgeon for a second opinion. The literature on the risks associated with
      radiographic screening and the prevalence of intra-osseous pathology was
      reviewed. FINDINGS: There was a considerable number of findings reported,
      including three large isolated radiolucent areas, 75 periradicular radiolucent
      areas, four probable cysts and 1187 unerupted mandibular third molars. However,
      when the clinical significance of these 'lesions' was assessed only those related
      to dental causes appeared to have significant clinical implications and the
      literature indicated that these could have been detected by selective radiology.
      CONCLUSION: The quantity of clinically relevant pathology did not justify routine
      panoramic radiographic screening in young adults.

PMID- 10332329
TI  - Endodontic disease: development and treatment.
AB  - Endodontic disease requires the involvement of micro-organisms. Microbial
      contamination of the pulp-dentine complex occurs in a number of different ways.
      The loss of integrity of teeth and the penetration of the pulp-dentine complex by
      a mixed microbial flora characterises the disease processes which can lead to
      pulpal and periradicular inflammation and infection. Endodontology is that part
      of dental science which deals with the biology of the pulp-dentine complex in
      health and disease, an understanding of which is a prerequisite to the provision
      of sound conservative care. The principles of endodontic treatment require the
      control of micro-organisms and potential nutrients by the microbial
      decontamination of teeth, the denaturing of protein and the sealing of dentine to
      prevent recolonisation.

PMID- 10332330
TI  - Assessment of a patient with orofacial pain.
AB  - Pain is the commonest complaint that brings a patient to a dentist. Most pain is
      acute, rapidly diagnosed and managed. However, more chronic pain must be more
      carefully evaluated if it is to be managed successfully. This paper proposes a
      systematic approach to the taking of a pain history and gives a short
      differential diagnosis of facial pain of non-dental origin.

PMID- 10332331
TI  - A survey of dental airlines and an examination of tooth-drying techniques.
AB  - The aims of this study were: 1. To assess the prevalence and severity of water
      and oil contamination in 20 dental airlines in clinical use, using a commercial
      test kit, LP Aerotest. 2. To determine the effect, in vitro, of such
      contamination on the shear bond strengths to etched bovine enamel, of composite
      resin and a dedicated bonding agent. The enamel was dried using either an oil-and
      water-contaminated 3-in-1 syringe, a warm-air tooth-dryer, silica gel-dried air
      or blotting paper, prior to bonding. A total of 11 (5 mm diameter) composite
      discs were bonded in each group. The samples were shear tested 72 hours later at
      a cross-head speed of 50 mm/min. All airlines had > 100 mg/m3 water and traces of
      oil (< 0.5 mg/m3) were present in 50% of samples. The mean shear bond strengths
      (MPa) for the 3-in-1 syringe, tooth-dryer, dried air and blotting paper-dried
      teeth were 14.5 +/- 3.8, 19.0 +/- 2.6, 19.6 +/- 4.2 and 19.7 +/- 1.9
      respectively. The differences between the values for the tooth dryer, dry air and
      blotting paper were not significant (P > 0.01) but a significant difference (P <
      0.01) was observed between these and the 3-in-1 syringe.

PMID- 10332332
TI  - Clinical audit of emergency out-of-hours service in general practice in Sefton.
AB  - Management of out-of-hours emergency services varies throughout the United
      Kingdom. A clinical audit of out-of-hours services was carried out by a group of
      general practitioners over a three-month period and the results compared with
      criteria agreed at the inception of the new General Dental Services (GDS)
      contract in 1990. Results showed that the management of all cases was within the
      standards set, with one exception, and that the criteria required modification.

PMID- 10332333
TI  - Under-registration for dental care of children with heart defects in the north
      east of England: a comparative study.
AB  - The main aim of this study was to discover the number of children with heart
      defects registered for dental care under capitation in the north-east of England.
      Subsidiary aims were to compare percentage registrations of these children with
      those of a similar age in the general population and to investigate the
      involvement of the Hospital Dental Service (HDS) and Community Dental Service
      (CDS) in providing dental care for children with heart defects. A sample of all
      patients under the age of 18 years attending the northern regional cardiothoracic
      unit between 1st August 1990 and 31st July 1992 was obtained. Details were sent
      to the Dental Practice Board for analysis during September 1993. A separate
      analysis was undertaken to estimate the number of children receiving dental care
      at the dental hospital, Newcastle upon Tyne and within the CDS. A total of 930
      children were identified during the study period. Only 38% of children were
      currently registered for capitation. Of the 930 patients 56 (6%) were registered
      at the dental hospital while 9% were estimated to be regularly attending the CDS.
      It is concluded that in the north-east of England, children with heart defects
      are registered under capitation at an unacceptably low level. They are less
      likely to be registered than children without this medical condition and it
      cannot be demonstrated that other dental services are making good the shortfall.

PMID- 10332334
TI  - Research in general dental practice--what is involved? Part 1. General
      considerations.
AB  - This paper examines the problems encountered by general dental practitioners
      (GDPs) when they attempt to carry out research. It outlines the possible stages a
      GDP might use when planning to undertake research and possible areas of interest
      to investigate. Part 2 will appear in a subsequent issue of Primary Dental Care.

PMID- 10332335
TI  - Using clinical audit in practice: a pilot peer review project.
AB  - A well-established study group undertook a pilot peer review project testing the
      use of clinical audit in members' practices. Two peer review groups were formed
      involving a total of 16 practices. Practice visits were undertaken and a series
      of meetings were held to prepare and discuss the various projects. The progress
      of the groups was monitored by questionnaires. All practitioners reported
      benefits from the project (specifically, from the practice visits) and made
      changes in areas of their practice other than those specifically chosen for their
      project. The benefits of carrying out audit projects in a peer review setting are
      stressed as are the benefits of reciprocal practice visits. The importance of
      prior establishment of mutual trust and confidence in the peer review group is
      emphasised.

PMID- 10332336
TI  - MGDS log diary summaries.
AB  - The editor invited the most recent group of successful candidates for the Diploma
      of Membership in General Dental Surgery (MGDS) to submit for publication selected
      log diary cases. Roy Dookun submitted the following cases which illustrate in a
      graphic way the broad spectrum of diagnostic and treatment problems confronting
      GDPs every day. It is hoped that this will be the first in a continuing series
      which will be of profound interest to colleagues working in a primary dental care
      setting.

PMID- 10332337
TI  - New technology, primary care, choice and opportunity[ editorial].

PMID- 10332338
TI  - Practice-based research: importance, challenges and prospects. A personal view.
AB  - Observation from the 'real-world' environment of dental practice is increasingly
      recognised to be of importance in the interpretation of research data from
      academia and dental health services research. In fact, most forms of applied
      dental research may be undertaken in the dental practice environment. However, in
      order to contribute to existing knowledge and understanding, practice-based
      research must be both rigorous and meticulous in its design, and subjected to
      scrutiny through presentation and publication before being considered to have
      been successfully concluded.

PMID- 10332339
TI  - The dentine-bonding of a fractured non-vital anterior tooth.
AB  - This case illustrates an alternative management of a fractured non-vital incisor
      using adhesive techniques to avoid the disturbance of, and offer protection to,
      successful endodontic treatment. The rationale for the maintenance of sound tooth
      structure and the minimisation of coronal leakage, while adequately restoring
      aesthetics, is discussed.

PMID- 10332340
TI  - General dental practitioners' opinions on orthodontics in primary and secondary
      care.
AB  - A survey of 232 general dental practitioners was undertaken by the purchasing
      authorities in Hereford and Worcester, England, in 1993, to establish local
      practitioners' views on primary and secondary care orthodontics. The response
      rate was 90.1%. The dentists overestimated their orthodontic case-load: 66.6% of
      contract holders submitted no claims for upper removable appliances (URA)
      treatment, but 70.8% claimed they undertook removable appliance therapy. Dentists
      believed orthodontics should be a feature of the General Dental Services (GDS)
      but did not seem inclined to commit themselves to providing it. A majority of
      GDPs (54.9%) felt orthodontics was uneconomic under the GDS. There was support
      for the treatment planning role of hospitals, but although this was available
      locally it did not appear to have stimulated primary care provision. Consultant
      outreach clinics were not generally supported but there was a desire for more
      opportunities for hospital clinical attachments in orthodontics. The implications
      for the policies of National Health Service (NHS) purchasers are considered:
      purchasing health authorities need to carry out systematic assessment of the
      views of their general dental practitioners and take account of their desired
      patterns of specialist provision. Policies encouraging the shift of orthodontics
      into primary care are called into question by this study. If demand for
      orthodontics is to be met, policy should concentrate on the development of
      hospital services and specialist practitioners.

PMID- 10332341
TI  - Trigeminal neuralgia.
AB  - Trigeminal neuralgia is a sudden, severe, brief, recurrent, stabbing pain in the
      distribution of the trigeminal nerve. It is a rare condition whose etiology
      remains unknown. Diagnosis is by careful history and there are few investigations
      that are of value in the management of this condition. Management is initially
      medical with anticonvulsant drugs being the primary drugs. If the drugs are no
      longer effective or tolerated then surgical management needs to be considered.
      Surgery can be at a variety of different levels along the pathway of the
      trigeminal nerve. Each procedure has its advantages and disadvantage. It is
      crucial that throughout treatment the patient has been given fully informed
      choice.

PMID- 10332342
TI  - An in vitro investigation of the abrasive qualities of a selection of denture
      cleaning pastes on poly(methyl methacrylate) denture base material.
AB  - This study investigated the damage to poly(methyl methacrylate) (PMMA) denture
      base material caused by brushing with a range of denture-cleaning pastes using an
      electric, motor-driven, reciprocal-action toothbrushing machine. Plate specimens
      of PMMA were exposed to 5000, 10,000 and 20,000 brush strokes with four
      commercial and one recently developed denture-cleaning pastes. Products were
      applied as slurries in dilutions of 1:2, 1:3 and 1:5. Wear and roughness
      measurements were made using a surfometer. Results of a one-way analysis of
      variance showed that there was a statistically significant difference between
      each of the different denture-cleaning pastes at each given dilution for each
      number of wear cycles. For the denture-cleaning pastes, doubling the number of
      brush strokes in most cases, increased the depth of abrasion by a factor of two.
      A reduction in the Roughness Index and depth of wear was seen, again in most
      cases, with a dilution from 1:2, 1:3 and to 1:5. A recently developed paste
      (Blend-a-Dent Hygienic denture paste) bad a comparatively low wear and roughening
      effect on PMMA denture base material; however, further investigation of its stain
      removal properties are necessary before it can be recommended as a suitable
      denture-cleaning paste.

PMID- 10332343
TI  - Controversies in the aetiology of temporomandibular disorders. Part 1.
      Temporomandibular disorders: all in the mind?
AB  - The aetiology of temporomandibular disorders (TMDs) is now considered to be
      multifactorial but the relative importance of individual aetiological factors is
      still controversial. Psychosocial factors play an important role in the aetiology
      of TMDs, in adaptation to pain and eventual recovery. TMD patients exhibit a
      variety of psychological and behavioural characteristics including increased
      somatization, stress, anxiety and depression. Subcategorisation of TMD patients
      into joint-related and muscle-related groups reveals psychological differences.
      Myogenic patients have increased severity of pain and suffer enhanced
      psychological distress. Within this group of patients are a minority of
      refractory cases who show marked overlap with those suffering from chronic pain
      syndrome; such patients benefit from psychiatric assessment and treatment.
      However, no common TMD personality profile has emerged from the psychometric test
      research. Recent knowledge of the molecular pathways induced by stress and the
      evaluation of stress-response substances may, in the future, provide
      diagnostically valuable biochemical markers of disease susceptibility. The role
      of psychological factors in the development of TMDs in the general population is
      critically examined.

PMID- 10332344
TI  - The provision of primary dental care for patients with special needs.
AB  - The Community Dental Service (CDS) has increasingly become associated with
      providing primary dental care for those people who are unable to access care by
      the usual means. The work reported here examines the provision of primary dental
      care by using the notion of a dental service continuum to demonstrate that in the
      treatment of patients with special needs the CDS acts as a safety net service.
      One hundred and twenty-four General Dental Service (GDS) practices and 33 CDS
      practices took part in the survey. The results suggest that both services provide
      primary dental care for a wide range of patients with special needs. Dentists in
      the GDS and CDS treat and care for different populations of patients with special
      needs. It is proposed that a continuum of service provision exists.

PMID- 10332345
TI  - Drug-induced oral mucosal hyperpigmentation.
AB  - This paper reports on a patient who developed oral hyperpigmentation and the
      literature on drug-induced oral hyperpigmentation is reviewed.

PMID- 10332347
TI  - Clarification of a point.

PMID- 10332346
TI  - Research in general dental practice--what is involved? Part 2. Specific
      considerations.
AB  - In the previous paper (Part 1. General Considerations), the problems which GDPs
      are likely to encounter when they embark on research were explored and an outline
      of the structure a GDP might use when planning to undertake a research project
      outlined. This paper explains how a recent mouthrinse study, carried out by five
      GDPs in five different practices, was planned and executed and how the principles
      described in the first paper were applied.

PMID- 10332348
TI  - Retrospective survey of resin-retained cast-metal palatal veneers for the
      treatment of anterior palatal tooth wear.
AB  - Anterior palatal tooth wear is easily recognized, but its precise pathogenesis
      remains unknown. Treatment of this condition with cast-alloy palatal veneers used
      in combination with an adhesive cement is described. Forty-eight patients, aged
      11 to 71, were treated with a total of 210 cast metal veneers over a period of 56
      months. Twenty-three of the restorations failed, resulting in an overall success
      rate of 89%. All failures were confined to 13 patients. A glass polyalkenoate
      cement was less effective than a chemically active resin composite luting agent.
      Nickel-chromium veneers cemented with activated resin composite recorded a
      survival probability of 0.74 at 56 months. Adhesive cast-alloy veneers provided a
      useful method of restoring maxillary anterior teeth affected by acid erosion.

PMID- 10332349
TI  - Supraoccluding cobalt-chrome onlays in the management of amelogenesis imperfecta
      in children: a 2-year case report.
AB  - Children suffering from the inherited dental anomaly amelogenesis imperfecta
      frequently present with sensitive, discolored teeth and decreased lower facial
      height. The aim of treatment is to reduce sensitivity while maintaining the
      maximum amount of hard tissue possible until the patient reaches an age at which
      advanced restorative techniques can be used to rehabilitate the dentition. A case
      is presented in which amelogenesis imperfecta in the mixed dentition was managed
      by the placement of adhesive cast restorations. These restorations have been in
      place for 2 years.

PMID- 10332350
TI  - Panoramic radiographic examination of edentulous jaws.
AB  - Many dentists routinely make panoramic radiographs of edentulous patients who
      request replacement dentures. A study was conducted in patients who attended a
      Jordanian dental school seeking a new set of dentures. Patients who had at least
      one set of complete dentures and were treated elsewhere, were included in this
      study. Any patient whose clinical findings suggested a need for further
      radiographic study was excluded. Of 286 patients (572 edentulous arches), only
      three were found to have impacted molars that required extraction and altered the
      treatment plan. The use of radiography in dentistry generates a large expense and
      there are risks of radiation hazards. The routine use of radiographs for patients
      who wear complete dentures and need replacement dentures should be discouraged. A
      thorough history must be obtained and a careful clinical examination must be
      performed for the diagnosis and treatment planning.

PMID- 10332351
TI  - Monitoring the caries risk of orthodontic patients.
AB  - Several caries activity tests were used to investigate the caries risk of
      patients with fixed orthodontic appliances. Twenty young individuals, with a mean
      age of 11 years, participated in this study. Ten subjects were free of any
      orthodontic appliances and formed the control group. The other 10 individuals had
      been wearing fixed orthodontic appliances for at least 4 months. Stimulated
      saliva samples were obtained from all patients. Saliva samples were used to
      investigate the salivary flow rate, the salivary buffer capacity, and mutans
      streptococci and lactobacilli counts. The orthodontic patients exhibited a
      significant increase in salivary flow rate. Results of statistical analyses were
      nonsignificant in all other tests, suggesting that fixed orthodontic appliances
      are not the sole factor increasing the patient's caries risk during orthodontic
      treatment.

PMID- 10332353
TI  - Glass fiber reinforcement in repaired acrylic resin removable dentures:
      preliminary results of a clinical study.
AB  - The clinical usefulness of continuous E-glass partial fiber reinforcement of
      acrylic resin removable dentures was evaluated an average 13 months after the
      insertion of the fibers. Twelve removable complete dentures and ten removable
      partial dentures with a history of recurrent fracture were selected for this
      study. The partial fiber reinforcement was incorporated into the denture at the
      time of repair. One complete denture and one removable partial denture fractured
      in the region of reinforcement during the examination period. These fractures
      were most likely caused by faulty placement of the fiber reinforcement in the
      denture in the dental laboratory. In six dentures, new fractures occurred in
      regions without partial fiber reinforcement. The results revealed the importance
      of both the correct positioning of the partial fiber reinforcement in the denture
      and the use of accurate laboratory techniques.

PMID- 10332352
TI  - Subcutaneous, orbital, and mediastinal emphysema secondary to the use of an air
      abrasive device.
AB  - Subcutaneous emphysema can occur whenever compressed air is employed intraorally.
      A case is presented of subcutaneous, orbital, and mediastinal emphysema
      subsequent to the use of an air-abrasive device. The case is believed to be the
      first reported case of an air-abrasive-related emphysema and is presented as a
      cautionary report.

PMID- 10332354
TI  - Peripheral dentinogenic ghost-cell tumor: a case report.
AB  - The dentinogenic ghost-cell tumor is a rare solid variant of the calcifying
      odontogenic cyst. Few peripheral cases of this tumor with clinical and
      radiographic documentation have been reported. A case of peripheral dentinogenic
      ghost-cell tumor is presented and the literature is reviewed.

PMID- 10332355
TI  - Adhesive liner incorporation in dental amalgam restorations.
AB  - Previous studies have indicated that adhesive liners can affect the mechanical
      properties of set amalgam and, therefore, may become incorporated within the
      amalgam. The purpose of this in vitro study was to determine the distribution of
      two adhesive liners within standardized Class I amalgam restorations. Cavity
      preparations were restored with dental amalgam or with dental amalgam and either
      of two adhesive liners. Thin sections were cut from the restored teeth in various
      planes and examined radiographically and with a reflecting microscope.
      Radiographs were digitized and computer enhanced for improved observation.
      Amalgam restorations placed with adhesive liner had greater amounts of nonamalgam
      substance than did the nonadhesive liner restorations. Both Amalgambond Plus and
      Resinomer used with All-Bond II were capable of becoming incorporated within the
      body of a Class I restoration placed with a standard restorative amalgam bonding
      technique.

PMID- 10332356
TI  - Dentinal adhesion and histomorphology of two dentinal bonding agents under the
      influence of eugenol.
AB  - This study examined the influence of eugenol on the dentinal adhesion of an
      enamel-dentin bonding agent that removes the smear layer (total-etch technique)
      and a system that partially dissolves the smear layer (self-conditioning adhesive
      system). The tensile bond strength was measured on flat, dentinal surfaces after
      application and removal of pure eugenol for 15 minutes and a eugenol-containing
      temporary luting agent for 24 hours. In addition, the resin-dentin interface was
      evaluated with confocal laser scanning microscopy. Dentinal adhesion was found to
      be significantly reduced after the application of eugenol when a dentin bonding
      agent that dissolves the smear layer was used. Under confocal laser scanning
      microscopy, the resin-dentin interdiffusion zone of both adhesive was found to be
      changed, not only after application of eugenol but also after application of a
      eugenol-containing temporary luting agent.

PMID- 10332358
TI  - The gap.

PMID- 10332357
TI  - A study of glass-ionomer cement and its interface with enamel and dentin using a
      low-temperature, high-resolution scanning electron microscopic technique.
AB  - This report describes a method of immobilizing the water contained in glass
      ionomer cement and dental hard tissues and stabilizing the delicate organic
      component of dentin. With this method, the intact interface between glass-ionomer
      and dental hard tissues can be observed under scanning electron microscope with
      few of the artifacts that are caused by the desiccation associated with
      conventional scanning electron microscopic studies. There was a distinct zone of
      interaction between the glass-ionomer cement and enamel and dentin. Under severe
      thermal stress, glass-ionomer cement failed cohesively, leaving an intact
      interface with enamel and dentin. Machine-mixed glass-ionomer cements displayed a
      high level of porosity. Some glass particles were separated from the matrix, and
      there was evidence that some are dislodged from the matrix during specimen
      preparation.

PMID- 10332359
TI  - Esthetic posterior restorations utilizing the double-inlay technique: a novel
      approach in esthetic dentistry.
AB  - The employment of adhesively bonded porcelain or resin composite inlays is
      considered problematic in Class II cavities extending into the dentin and cannot
      be recommended as a routine procedure for current clinical practice. A two-part
      restoration in the form of a double inlay provides an alternative to the
      clinically established gold inlay restoration. The double inlay is composed of a
      conventionally cemented metal base and an adhesively bonded porcelain inlay.
      After the metal substructure is coated with silica or a microretentive opaque
      glaze is fired, the porcelain inlay can be luted to the metallic base with a
      bonding resin composite. This procedure incorporates the advantages of cast
      restorations at the critical cervicoproximal cavity margin and the esthetic and
      stabilizing properties of the adhesively bonded restoration technique in visible
      areas.

PMID- 10332360
TI  - Guided tissue regeneration procedure applied to the treatment of endodontic
      periodontal disease: analysis of a case.
AB  - The clinical condition of a patient with chronic adult-type periodontal disease,
      as well as gingival recession reaching the tooth apex on a mandibular lateral
      incisor, is discussed. Because the use of conventional techniques would have
      resulted in tooth loss, the guided tissue regeneration procedure was applied,
      with successful results.

PMID- 10332361
TI  - Nondiseased dentinal root surface following citric acid or tetracycline
      hydrochloride conditioning: a scanning electron microscopic study on the effects
      of ultrasonic irrigation before and after root conditioning.
AB  - The scanning electron microscope was used to evaluate the effects of ultrasonic
      irrigation before and after root conditioning. Six groups of five specimens each
      received saline irrigation; ultrasonic irrigation; saline irrigation followed by
      root conditioning with either citric acid or tetracycline hydrochloride; or
      ultrasonic irrigation followed by root conditioning with either citric acid or
      tetracycline hydrochloride. After immersion in citric acid or tetracycline
      hydrochloride solutions, root dentin was rinsed again with saline or irrigated
      ultrasonically. Control specimens exhibited an amorphous, irregular surface smear
      layer. Ultrasonic irrigation, citric acid, and tetracycline hydrochloride were
      effective in removing the smear layer. Use of ultrasonic irrigation before and
      after acid application improved the exposure of dentinal fibrils.

PMID- 10332362
TI  - Computerized tomosynthetic radiography in operative dentistry.
AB  - A study of 15 extracted teeth with carious lesions and artificially prepared
      defects adjacent to restorations compared the macroscopic morphology of the
      lesions and the extent of the defects with their appearance on conventional and
      computerized tomosynthetic radiography. Tuned Aperture Computerized Tomography
      offers advantages for the diagnosis of the extent of carious lesions and of
      defective restorations. The display of computer sections through teeth (slice
      images) allows a three-dimensional view to permit an assessment of the extent of
      carious lesions, restorations, and defects often masked in conventional
      radiography.

PMID- 10332363
TI  - A useful evacuation aid for intraoral air-abrasive devices.
AB  - Air-abrasive technology offers several advantages over conventional handpieces.
      Although modern high-speed evacuation systems result in limited powder
      accumulation, the microabrasive debris continues to be a major concern. This
      article highlights the need for rubber dam isolation and introduces a makeshift
      evacuation device fabricated from a plastic soft drink container.

PMID- 10332364
TI  - Bone regeneration around an osseointegrated implant. A simultaneous approach in a
      fenestrated defect: a case report.
AB  - The use of a barrier membrane, with or without osseous allograft, has been shown
      to establish regeneration of osseous tissue around dental implants. Following
      three episodes of persistent symptomatic failed apicoectomy and subsequent tooth
      extraction, an osseointegrated implant was placed in a wide fenestrated defect.
      Demineralized freeze-dried bone allograft was covered by an occlusive expanded
      polytetrafluorethylene membrane. The reentry procedure revealed complete bone
      fill that followed the texture of the augmentation material beyond the previous
      buccal bony envelope.

PMID- 10332365
TI  - Various designs of ceramometal crown for implant restorations.
AB  - The posterior design of the implant superstructure (the ceramometal crown) was
      classified into four categories: a ceramometal crown with an access hole on top;
      a cemented ceramometal crown; a ceramometal crown retained with a lingual screw;
      and a telescopic ceramometal crown. Cemented ceramometal crowns and telescopic
      ceramometal crowns are considered simpler, more esthetic, and more resistant to
      fracture among the four models.

PMID- 10332366
TI  - Converting a fixed partial denture to an interim complete denture: esthetic and
      functional considerations.
AB  - This article describes a practical and expeditious method of converting an
      existing fixed partial denture into an interim complete-denture prosthesis with
      minimal inconvenience to the patient. The esthetic, phonetic, and functional
      demands are maintained during the fabrication of the prosthesis.

PMID- 10332367
TI  - A practical system for evaluating casting results in fixed restorations.
AB  - A practical and economical system of casting testers, formed by simple
      constituents that can be found anywhere, has been developed. Pattern formation is
      a quick procedure, and because the testers are small and imitate forms familiar
      to dental technicians, they can incorporate them easily into their daily work
      routine. Results can be interpreted without the use of any apparatus, because
      they are based on the principle of "all or nothing." The proposed system was
      field tested in 13 commercial dental laboratories, and the percentage of
      successes obtained affirmed that the goals of the procedure are attainable and
      valid.

PMID- 10332368
TI  - Microleakage of four Class II resin composite insertion techniques at intraoral
      temperature.
AB  - Twenty recently extracted human molars had standardized Class II slot cavities
      prepared on the mesial and distal surfaces with the gingival floor located on
      dentin. The teeth were embedded in a stone template, warmed to 37 degrees C, and
      restored immediately using one of two incremental placement techniques with
      visible light-cured composite (VLC), or one of two directed shrinkage placement
      techniques using an autocure/VLC composite combination. Teeth were stored at 37
      degrees C for 2 weeks, thermocycled, stained, sectioned in the middle of the
      preparation, and evaluated for dye penetration. Reevaluation of the microleakage
      following removal of the resin composite from the preparation revealed greater
      microleakage at the gingival margin than did the initial sectioning technique.
      There were no differences among any of the groups. Enamel margins exhibited
      minimal leakage and no differences among the groups.

PMID- 10332369
TI  - The dentulous, aging patient: what should we do?

PMID- 10332370
TI  - Glass-ionomer cement restorations and secondary caries.

PMID- 10332371
TI  - Current restorative modalities for young patients with missing anterior teeth.
AB  - The early loss of permanent teeth following trauma or congenital aplasia may be
      corrected by orthodontic or prosthetic means, sometimes combined with implant
      therapy. The orthodontic solution results usually in different anatomic,
      functional, and esthetic problems. Prosthetic and implant procedures, on the
      other hand, are very demanding and require long-term maintenance. Considering
      these limitations, a comprehensive diagnostic and treatment plan is mandatory to
      achieve the most satisfactory clinical result. Modern restorative modalities,
      such as recontouring, bleaching, and resin composite bonding, may improve the
      final clinical result after orthodontic space closure. In more difficult
      situations, veneers and crowns may also be indicated.

PMID- 10332372
TI  - Orthodontic-prosthetic treatment to replace maxillary incisors exfoliated because
      of improper use of orthodontic elastics: a case report.
AB  - This article describes the iatrogenic exfoliation of maxillary central incisors
      following the improper use of orthodontic elastic bands. The unsecured rubber
      band had migrated apically and caused an almost "bloodless extraction" of both
      maxillary central incisors. A combined orthodontic-prosthetic solution was used
      to replace the lost incisors.

PMID- 10332373
TI  - Reasons for placement and replacement of restorations of direct restorative
      materials by a selected group of practitioners in the United Kingdom.
AB  - This article reports the findings of a study on reasons for the placement and
      replacement of direct restorations in general dental practice in the United
      Kingdom. Twenty-two selected practitioners recorded information pertaining to up
      to 250 consecutive direct restorations placed by themselves during a 6-week
      period. From data derived from 2,379 restorations, it was found that about 60% of
      restorative practice in the United Kingdom may be found to comprise the
      replacement of existing restorations. For restorations of amalgam and glass
      ionomer cement, the principal reason for replacement was secondary caries. For
      restorations of resin composite, secondary caries and poor appearance accounted
      for equal proportions of failures. Apart from the need for more extensive surveys
      of the type reported, the data emphasize the need to monitor treatment trends in
      contemporary clinical practice.

PMID- 10332374
TI  - Simultaneous team approach of a crown-lengthening procedure and an operative
      restoration: technique and long-term effect.
AB  - Traditionally, crown-lengthening procedures to expose subgingival caries for
      operative restorative work are carried out in a two-stage approach. A
      disadvantage of this procedure is that the gingival margin associated with the
      treated tooth moves apically; this may create an esthetic problem. Resin-modified
      glass-ionomer cement has been demonstrated to have good biocompatibility with
      dental hard and soft tissues. Surgical and restorative procedures were combined
      at the same appointment in an effort to achieve a restoration with minimal change
      in the gingival margin. Four patients have been treated with this one-stage team
      approach and followed for 8 to 13 months. The clinical results demonstrated this
      team approach procedure is excellent for the dentition when esthetics is a
      consideration.

PMID- 10332376
TI  - A hygienic multiple-pontic design.
AB  - Fixed partial dentures should be designed for function, esthetics, and easy
      maintenance. The gingivolingual embrasures between multiple adjacent pontics are
      unnecessary for function and esthetics and create crevices where food, plaque,
      and calculus can accumulate. These spaces make oral hygiene procedures more
      difficult for the patient and the dentist to accomplish. A hygienic design for
      multiple pontics is suggested that eliminates these unnecessary embrasures and
      still displays an anatomically realistic, cosmetically acceptable facade.

PMID- 10332375
TI  - Clinical evaluation of hybrid ionomer restoratives in Class V abrasion lesions:
      two-year results.
AB  - Eighty Class V abrasion cavities were selected, and 20 cavities were restored
      with one of three resin-modified glass-ionomer materials (Fuji II LC, Photac-Fil,
      and Vitremer) or a polyacid-modified resin composite (Dyract). The restorations
      were clinically evaluated after 1 and 2 years with the US Public Health Service
      criteria. The results revealed a statistically significant difference in the
      percentage of restorations rated Alfa for color match at 2 years. No
      statistically significant difference was found in the percentage of alfa rating
      for anatomic form. Restorations of all materials showed some marginal
      discrepancies that were not statistically significant.

PMID- 10332377
TI  - Disposable carrier constructed with a fluoride tray and a mixing pad: an
      endodontic aid.
AB  - An endodontic file carrier is fabricated from disposable foam fluoride trays
      glued to a mixing pad. The carrier allows convenient retention and transfer of
      root canal instruments and is particularly useful when the clinician is utilizing
      a rotary handpiece canal-shaping technique with hand files and reamers.

PMID- 10332378
TI  - Melkersson-Rosenthal syndrome: review of the literature and case report of a 10
      year misdiagnosis.
AB  - Melkersson-Rosenthal syndrome is classically described as a triad of orofacial
      swelling, facial palsy, and fissured tongue. More often this syndrome presents in
      its oligosymptomatic forms. Melkersson-Rosenthal syndrome may not be as rare as
      suspected but rather a syndrome that often goes undiagnosed. Presented is the
      case of a mentally challenged man who was eventually diagnosed with Melkersson
      Rosenthal syndrome only after being misdiagnosed and incorrectly treated for an
      odontogenic infection for more than a decade.

PMID- 10332379
TI  - Severe prosthetic valve-related endocarditis following dental scaling: a case
      report.
AB  - There is a well-known correlation between surgical dental procedures and the risk
      of bacterial endocarditis in patients with prosthetic cardiac valves. A 43-year
      old patient with prosthetic aortic and mitral valves, which already have been
      removed twice because of endocarditis, suffered from a prosthetic valve-related
      endocarditis following dental scaling, which was performed without any antibiotic
      prophylaxis. Invasive medical procedures in patients with prosthetic heart valves
      may lead to endocarditis. Antibiotic prophylaxis is recommended even for dental
      procedures considered to be "harmless," such as dental scaling.

PMID- 10332380
TI  - Gangrenous stomatitis (cancrum oris): clinical features, etiologic factors, and
      complications.
AB  - Gangrenous stomatitis (cancrum oris) is a lesion involving the orofacial
      structures that is primarily seen in areas where the socioeconomic standards are
      low and there is poor hygiene. The general clinical features, associated
      etiologic factors, and ensuing complications in eight consecutive cases diagnosed
      between 1991 and 1995 are presented and discussed.

PMID- 10332381
TI  - Marsupialization of a cyst lesion to allow tooth eruption: a case report.
AB  - Marsupialization of a dentigerous cyst allowed eruption of a tooth related to the
      cyst cavity.

PMID- 10332382
TI  - The move toward managed care is opening new doors for hygiene.

PMID- 10332383
TI  - Case 7. Inflammatory papillary hyperplasia.

PMID- 10332384
TI  - Addison's disease.

PMID- 10332385
TI  - Do's and don'ts of infection control before, during and after treatment.

PMID- 10332386
TI  - Choose your words wisely when discussing periodontal disease.

PMID- 10332387
TI  - Looking inside a child's world.

PMID- 10332388
TI  - Case 8. Verrucous carcinoma.

PMID- 10332389
TI  - Help patients before they hit rock bottom.

PMID- 10332390
TI  - Examine the origins of calculus to uncover its link with tartar.

PMID- 10332391
TI  - Eye to eye.

PMID- 10332392
TI  - The infection control program needs regular checkups, too.

PMID- 10332393
TI  - Mom, career or both: it's a matter of personal choice.

PMID- 10332395
TI  - Partners in periodontal therapy.

PMID- 10332394
TI  - Case 6. Lymphoepithelial cyst.

PMID- 10332396
TI  - . . . Insidious disease.

PMID- 10332397
TI  - Living with life's transitions.

PMID- 10332398
TI  - Effective mechanical instrumentation requires a light, controlled touch.

PMID- 10332399
TI  - Be sharp and learn to handle sharps carefully.

PMID- 10332400
TI  - Denmark and the U.S. share common goals in dental care.

PMID- 10332401
TI  - Tell your patients about a new alternative to flossing.

PMID- 10332402
TI  - Managed care. Don't let quality patient care slip away.

PMID- 10332403
TI  - Expand your mind.

PMID- 10332404
TI  - Case 9. Pemphigus vulgaris.

PMID- 10332405
TI  - Surfing the Internet.

PMID- 10332406
TI  - Review your infection control procedures to protect the staff.

PMID- 10332408
TI  - Let your voice be heard.

PMID- 10332407
TI  - Hygienist expands dental knowledge for Lithuanian dentists and patients.

PMID- 10332409
TI  - Look for the obvious ways to use skills and education.

PMID- 10332411
TI  - Navigating career change successfully.

PMID- 10332410
TI  - Case 5. Erosion.

PMID- 10332412
TI  - The new wave. Acoustic energy products shake up the oral healthcare industry.

PMID- 10332413
TI  - In a perfect dental world there wouldn't be any sharps injuries.

PMID- 10332414
TI  - The road to excellence. Part III.

PMID- 10332415
TI  - Anti-diabetic agents.

PMID- 10332416
TI  - Periodontist advocates therapy based on individual needs.

PMID- 10332418
TI  - Do not let the changes in dental hygiene pass you by.

PMID- 10332417
TI  - Break the ice.

PMID- 10332419
TI  - Case No. 3. Lymphangioma.

PMID- 10332420
TI  - Freedom from fear.

PMID- 10332421
TI  - Eliminating pockets no longer the goal of periodontal therapy.

PMID- 10332422
TI  - Delegating the responsibility.

PMID- 10332423
TI  - CDC addresses ways to prevent the transmission of tuberculosis.

PMID- 10332424
TI  - Anti-anxiety drugs.

PMID- 10332425
TI  - The road to excellence. Part II.

PMID- 10332426
TI  - American hygienists set practice standards at home and abroad.

PMID- 10332427
TI  - It's standard practice.

PMID- 10332428
TI  - Cyclophosphamide induced hemorrhagic cystitis.

PMID- 10332429
TI  - Chemoprevention of urological cancer.
AB  - PURPOSE: Cancer is a major cause of mortality and morbidity throughout the world,
      and ranks as the second leading cause of death in the United States. Most cancers
      have a latent period of 10 to 20 years, which provides ample time for preventive
      measures. Transitional cell carcinoma of the bladder and adenocarcinoma of the
      prostate have protracted courses and may be ideal for chemopreventive strategies.
      We review the biochemistry and epidemiology of chemopreventive agents, and the
      laboratory and clinical studies of their role in urological cancer. MATERIALS AND
      METHODS: We performed a computerized MEDLINE search and manual bibliographical
      review of relevant peer reviewed studies and reports from 1966 to 1998. These
      reports were analyzed and scrutinized, and the important findings are summarized.
      RESULTS: Neoplastic lesions of the bladder and prostate are uniquely suited to
      the development and evaluation of chemopreventive agents. Epidemiological reports
      provide the strongest evidence of a protective role for dietary agents in cancer
      of the bladder, prostate and kidney. Observational and recent experimental trials
      support these findings in cases of adenocarcinoma of the prostate and
      transitional cell carcinoma of the bladder. There is strong evidence for a
      protective effect of vitamin A in bladder cancer. Superior protection has been
      reported with a combination of high doses of vitamins A, B6, C and E plus zinc.
      For prostate cancer strong evidence exists for a preventive effect of reduced fat
      intake, vitamin E, selenium and soy proteins. A lesser benefit is also suggested
      with intake of vitamins D and C. Evidence of chemoprevention against renal cell
      cancer is supported mainly by epidemiological studies, and animal studies
      indicate possible benefit of vitamin D supplementation. CONCLUSIONS: Although
      there is no incontrovertible proof, numerous studies implicate dietary and
      nutritional factors in the onset and progression of cancer of the bladder,
      prostate and kidney. It is possible that the preventive effect of dietary
      constituents may be in part from consumption with other nutrients and bioactive
      compounds in whole foods. Further research is needed before vitamins and other
      nutritional supplements can be advocated as standard therapy but the
      preponderance of evidence supports increased intake of vitamins A, B6, C, D and
      E, reduction of animal fat, and increased consumption of fruits and vegetables.

PMID- 10332430
TI  - Orthotopic urinary diversion with preservation of erectile and ejaculatory
      function in men requiring radical cystectomy for nonurothelial malignancy: a new
      technique.
AB  - PURPOSE: Nerve sparing techniques to preserve sexual function in men undergoing
      cystoprostatectomy have been well documented. The patient who desires to remain
      fertile with ejaculatory function poses an additional challenge. We describe a
      new technique for radical cystectomy and orthotopic diversion with preservation
      of the vasa deferentia, seminal vesicles, posterior prostate and neurovascular
      bundles. MATERIALS AND METHODS: Four men with a median age of 26 years presented
      with bladder pathology necessitating cystectomy, including signet ring carcinoma
      of the bladder dome, leiomyosarcoma of the anterior bladder wall, leiomyosarcoma
      of the lateral bladder wall, and extensive polypoid cystitis glandularis of the
      trigone and posterior wall refractory to conservative and transurethral
      management. All patients wished to maintain fertility and ejaculatory function.
      We detail the surgical technique of extirpation of the bladder and anterior
      proximal prostate en bloc with preservation of the vasa deferentia, seminal
      vesicles, posterior prostate and neurovascular bundles as well as construction of
      an orthotopic reservoir. RESULTS: Followup ranges from 4 months to 5 years. All
      patients remain completely continent and void to completion without difficulty.
      Erectile function is normal in all cases. Of 3 patients who ejaculate antegrade 1
      has fathered a child. The remaining patient ejaculates retrograde. There has been
      no tumor recurrence. CONCLUSIONS: The technique of cystectomy with preservation
      of the vasa deferentia, seminal vesicles, posterior prostate and neurovascular
      bundles is an excellent option in men with nonurothelial malignancy or another
      pathological condition that necessitates cystectomy, and in whom preservation of
      fertility and potency is desirable. All of our patients are fully potent and
      achieve ejaculation. Even the patient with retrograde ejaculation remains
      fertile. In terms of practicality semen retrieval from urine is much simpler than
      epididymal sperm aspiration and in vitro fertilization.

PMID- 10332431
TI  - Indinavir urolithiasis: an emerging cause of renal colic in patients with human
      immunodeficiency virus.
AB  - PURPOSE: We evaluate the clinical, diagnostic and radiographic findings in
      patients on indinavir therapy who presented with renal colic, and propose
      appropriate treatment options for indinavir urolithiasis. MATERIALS AND METHODS:
      A total of 16 patients positive for human immunodeficiency virus on indinavir
      were evaluated for 18 episodes of severe renal colic requiring hospitalization.
      Laboratory evaluation was performed in all patients followed by an imaging study.
      Conservative treatment included intravenous hydration, narcotic analgesics and
      temporary cessation of indinavir. Intervention was elected only in patients with
      persistent fever or intractable pain. A month after hospital discharge an
      excretory urogram and metabolic stone evaluation were performed. Mean followup
      was 9.3 months and 2 patients had recurrent symptoms. RESULTS: All patients
      presented with nausea or vomiting and hematuria. Imaging studies confirmed
      obstruction in all patients with 13 radiolucent (indinavir) and 3 radiopaque
      (calcium oxalate) stones. Patients with radiolucent and radiopaque stones
      demonstrated significant differences in urinary pH (p = 0.002) and serum
      creatinine (p = 0.03). Conservative therapy was successful in 11 patients (68.8%)
      within 48 hours and 4 patients (25%) with radiolucent calculi required endoscopic
      stenting for persistent fever. Metabolic stone evaluation demonstrated
      significant hypocitruria (less than 50 mg./24 hours) in all patients with
      radiolucent calculi. CONCLUSIONS: The urologist should be familiar with this
      growing cause of renal colic in patients on indinavir therapy. Pure indinavir
      stones are radiolucent and have a soft, gelatinous endoscopic appearance.
      Conservative treatment is successful in most patients and if intervention is
      deemed medically necessary, endoscopic stent placement should be the procedure of
      choice.

PMID- 10332432
TI  - Use of spiral computerized tomography in lieu of angiography for preoperative
      assessment of living renal donors.
AB  - PURPOSE: We evaluate whether spiral computerized tomography (CT) can be used in
      lieu of renal angiography for preoperative assessment of living renal donors,
      with special attention to multiplicity of renal vasculature. MATERIALS AND
      METHODS: A total of 47 living renal donor candidates were evaluated with spiral
      CT and all but 2 underwent donor nephrectomy. Patients were divided into early
      and late groups because there was a learning curve with spiral CT. In the early
      group 18 donors underwent renal angiography as well as spiral CT and 10 underwent
      nephrectomy after spiral CT only. In the late group 5 had dual radiographic
      evaluation for ambiguities in spiral CT interpretation and 12 underwent
      nephrectomy after spiral CT only. Spiral CT was performed and interpreted blind
      to angiographic results, and vice versa. RESULTS: Spiral CT identified 50 of 52
      renal arteries (96%) found at surgery overall and 23 of 25 (92%) found at surgery
      after spiral CT only. Two accessory arteries were missed in the 10 early group
      donors evaluated with spiral CT only, yielding an early negative predictive value
      of 80%. Renal angiography identified another accessory artery missed by spiral CT
      in the early group. All 3 missed vessels were identified retrospectively. No
      arteries found at surgery were missed in the late group (negative predictive
      value 100%), although there were 2 false-positive results detected by spiral CT
      relative to renal angiography in 1 candidate renal unit. Overall accuracy to
      predict early renal artery division relative to surgical findings was 93% for
      spiral CT and 91% for renal angiography. However, early renal artery division was
      clinically significant for only 1 of 11 vessels found at surgery. Spiral CT
      demonstrated 4 anomalous venous returns and renal angiography identified none.
      However, spiral CT missed 2 accessory veins and identified only 1 of 2
      fibromuscular dysplasia cases. Total cost for spiral CT and renal angiography was
      $886 and $2,905, respectively. CONCLUSIONS: Spiral CT is a reasonably good
      alternative to renal angiography for living renal donor assessment but there is a
      profound learning curve for performance and interpretation. Renal angiography is
      still the gold standard with respect to the identification of arterial
      multiplicity and fibromuscular dysplasia, and it should be used adjunctively in
      cases with spiral CT ambiguity. Neither spiral CT nor renal angiography is ideal
      for the assessment of early renal artery division which is seldom an issue. The
      benefits of spiral CT over renal angiography are potentially lower morbidity,
      improved donor convenience and reduced cost.

PMID- 10332433
TI  - Retroperitoneal laparoscopic versus open radical nephrectomy.
AB  - PURPOSE: We analyze the retroperitoneal approach to laparoscopic radical
      nephrectomy in regard to feasibility, safety, morbidity and cancer control, and
      compare results and outcomes in patients who underwent retroperitoneal
      laparoscopic or open radical nephrectomy from 1995 to 1998. MATERIALS AND
      METHODS: The records of 58 consecutive patients with renal cancer who underwent
      radical nephrectomy from 1995 through 1998 were reviewed. Of the patients 29
      underwent open radical nephrectomy (group 1) and 29 underwent retroperitoneal
      laparoscopic radical nephrectomy (group 2). Various parameters were compared and
      statistical analyses were performed. RESULTS: The 2 groups were similar in regard
      to age, gender and side of the tumor. Operative time was slightly shorter in
      group 1 (mean 121.4 versus 145 minutes in group 2, p = 0.047). Mean tumor size
      plus or minus standard deviation was larger in group 1 (5.71 +/- 2.01 versus 4.02
      +/- 1.87 cm. in group 2). Group 2 patients had significantly less operative blood
      loss (mean 100.0 versus 284.5 ml. in group 1, p < 0.005) and used significantly
      less parenteral pain medication (p < 0.05). Postoperative hospital stay was
      significantly longer in group 1 (9.7 +/- 3.6 versus 4.8 +/- 2.0 days in group 2,
      p < 0.001), and the complication rate was higher (24 versus 8%, respectively).
      One group 1 patient died of renal cancer (pT2G2) after 14 months and local
      recurrence with hepatic metastasis occurred after 9 months in a group 2 patient
      with a pT3G2 tumor. CONCLUSIONS: Retroperitoneal laparoscopic nephrectomy for
      kidney cancer requires further assessment. It seems to have several advantages
      over open radical nephrectomy, and to be effective and safe for less than 50 cm.
      renal tumors but a risk of spillage cannot be ruled out for larger tumors.

PMID- 10332434
TI  - Proteinuria and renal function during and after acute urinary retention.
AB  - PURPOSE: Benign prostatic hyperplasia is the most common neoplasm as well as the
      main cause of bladder outlet obstruction in men. It may progress to involve a
      risk of urinary retention. We investigated the effects of acute urinary retention
      on renal function. MATERIALS AND METHODS: We evaluated renal function using
      biochemical markers in 25 men with a mean age of 69 years in whom an episode of
      acute urinary retention a mean of 31 hours in duration was due to bladder outlet
      obstruction. Patients were followed for 6 months after acute retention was
      relieved. Patients were not known to have had any renal disease previously.
      RESULTS: During acute urinary retention at presentation, and after 1 and 6 months
      we noted albuminuria in 100, 92 and 54% of patients, elevated alpha 1
      microglobulin excretion in 54, 39 and 58%, and elevated beta 2-microglobulin
      excretion in 17, 19 and 9%. Serum creatinine or creatinine clearance did not
      predict proteinuria. All parameters became normal at 6 months in only 2 cases.
      CONCLUSIONS: Acute urinary retention affects glomerular and tubular renal
      function. After acute urinary retention was relieved increased glomerular
      permeability and tubular damage persisted in the majority of patients. This
      condition may have been partially due to previous long-term bladder outlet
      obstruction. Our findings stress the importance of the rapid recognition and
      treatment of acute urinary retention.

PMID- 10332435
TI  - The urinary glycoprotein GP51 as a clinical marker for interstitial cystitis.
AB  - PURPOSE: GP51 is a urinary glycoprotein with a molecular weight of 51 kDa. This
      glycoprotein is produced and secreted by the transitional epithelium of the
      genitourinary tract, and has been isolated from human urine. Studies have
      demonstrated that GP51 levels are decreased in bladder biopsies of patients with
      interstitial cystitis. We evaluated urinary GP51 in a noninvasive manner as a
      clinical marker of interstitial cystitis. MATERIALS AND METHODS: Urinary GP51
      levels were measured using antigen inhibition enzyme-linked immunosorbent assay.
      In blinded fashion we analyzed for quantitative differences 24-hour urine samples
      of 36 patients with interstitial cystitis and 23 normal controls who were age
      matched within 5 years (mean age 47.3). We also evaluated GP51 in random urine
      specimens of 17 normal controls, 14 patients with interstitial cystitis and 11
      subjects who had undergone cystectomy to determine whether urinary GP51 is mainly
      produced by the bladder, which is the site of interstitial cystitis. To ascertain
      the specificity of urinary GP51 to interstitial cystitis urine samples of 34
      patients with other urological diseases were measured and compared with findings
      in the samples of 15 with interstitial cystitis. RESULTS: Low GP51 levels
      appeared to be unique to the interstitial cystitis state compared to normal (p =
      0.008). GP51 in patients with interstitial cystitis and in those who underwent
      cystectomy was lower (p < 0.001) than in normal controls. These findings suggest
      that the major source of urinary GP51 is the bladder. Also, we observed lower
      GP51 levels in interstitial cystitis than in other urinary tract diseases (p <
      0.0001). CONCLUSIONS: Our study substantiates the possibility of using GP51 as a
      clinical marker for diagnosing interstitial cystitis by a noninvasive urinary
      assay.

PMID- 10332436
TI  - Potassium leak test predicts outcome in interstitial cystitis.
AB  - PURPOSE: We tested whether the potassium leak test predicts the outcome of
      therapy with heparinoids and antidepressants in interstitial cystitis. MATERIALS
      AND METHODS: We retrospectively reviewed the records of 38 evaluable patients
      with interstitial cystitis who underwent a potassium leak test at the initial
      evaluation and who were treated intravesically with heparin or oral sodium
      pentosan polysulfate for a minimum of 6 months. All but 1 patient were also
      treated with tricyclic antidepressants. Changes in average pain score during
      voiding, urinary frequency and nocturia were evaluated. RESULTS: The potassium
      leak test was positive and negative in 23 and 15 patients, respectively. There
      was no significant difference in the 2 groups at baseline in regard to the male
      to-female ratio, patient age, years of symptoms, pain score, urinary frequency,
      nocturia or anesthetic capacity. After a minimum of 6 months of therapy patients
      in whom the potassium leak test was positive were more likely to have improvement
      than those in whom it was negative, as shown by a decrease of greater than 25% in
      pain score (78 versus 40%, p = 0.01), frequency (83 versus 47%, p = 0.02) and
      nocturia (83 versus 53%, p = 0.05). However, potassium leak test results showed
      no significant difference at the 50% decrease level in pain score, frequency or
      nocturia. CONCLUSIONS: The potassium leak test may predict outcome in patients
      with interstitial cystitis who are treated with combined heparinoid and tricyclic
      antidepressant medication.

PMID- 10332437
TI  - Interstitial cystitis--a light at the end of the tunnel?

PMID- 10332438
TI  - Micropapillary bladder carcinoma: a clinicopathological study of 20 cases.
AB  - PURPOSE: Micropapillary bladder carcinoma is rare, with only 18 cases reported to
      date. We report 20 additional cases with long-term followup. MATERIALS AND
      METHODS: A total of 680 patients with an initial diagnosis of bladder carcinoma
      in western Sweden in 1987 and 1989 were prospectively registered. The clinical
      records of all 816 patients with bladder cancer treated at Sahlgrenska University
      Hospital with external beam irradiation between 1962 and 1989 were reviewed. The
      histopathological material was reviewed and immuno-histochemical analyses were
      performed on 20 cases identified with micropapillary bladder carcinoma. RESULTS:
      The incidence of micropapillary bladder carcinoma was 0.7%. Mean patient age at
      diagnosis was 69 years (range 45 to 82) and the male-to-female ratio was 2.3:1.
      All but 5 patients had stage T3a disease or higher. There was no difference in
      stage or prognosis between the 5 prospectively identified patients and those
      treated with external beam irradiation. Only 2 patients had micropapillary
      bladder carcinoma as the only pattern, while 1 had 10% and the remainder had 20
      to 95% micropapillary bladder carcinoma. Transitional cell carcinoma was noted in
      17 patients and 5 had areas of gland forming adenocarcinoma. Carcinoma in situ
      was noted in 13 patients and 15 had lymphatic invasion. Only 5 patients survived
      5 years, 1 of whom died of bladder cancer after 7 years. Radiation and
      chemotherapy did not seem to be effective. CONCLUSIONS: The light microscopic
      appearance, which is strikingly similar to ovarian papillary serous carcinoma,
      and immunohistochemical staining pattern lend some support to the theory that
      micropapillary bladder carcinoma is a variant of adenocarcinoma. Since even the
      focal presence of micropapillary bladder carcinoma is associated with a poor
      prognosis, recognition of this entity is important. Due to its rarity, the
      optimal treatment of micropapillary bladder carcinoma needs to be determined in a
      multicenter study.

PMID- 10332439
TI  - Long-term outcome of incontinent ileovesicostomy management of severe lower
      urinary tract dysfunction.
AB  - PURPOSE: We evaluated the extended 5-year followup outcome of incontinent
      ileovesicostomy. MATERIALS AND METHODS: We reviewed the charts of 25 men and 13
      women with a mean age of 44.9 years who underwent incontinent ileovesicostomy,
      including the original 23 patients whom we reported on in 1993. Mean followup was
      52 months. We compared the incidence of complications before and after
      ileovesicostomy as well as long-term urinary tract status. RESULTS: Before
      ileovesicostomy the incidence of serious complications associated with an
      indwelling catheter was significant, including poor bladder compliance in 50% of
      cases, urosepsis in 45%, hydronephrosis in 21%, renal struvite calculi in 18%,
      urethrocutaneous fistula in 18%, autonomic dysreflexia in 13% and bladder calculi
      in 2%. After conversion to ileovesicostomy our data show that 83 to 91% of this
      high risk population maintained a normal upper urinary tract and normal bladder
      storage compliance. CONCLUSIONS: Compared with preoperative status the incidence
      of postoperative complications was relatively low and they were readily
      corrected. Ileovesicostomy is an excellent long-term management solution for
      severe lower urinary tract dysfunction in patients who are unable to perform
      intermittent self-catheterization.

PMID- 10332440
TI  - Changing concepts in orthotopic urinary diversion.

PMID- 10332441
TI  - Once daily controlled versus immediate release oxybutynin chloride for urge
      urinary incontinence. OROS Oxybutynin Study Group.
AB  - PURPOSE: We compared the efficacy and safety of once daily controlled and
      immediate release oxybutynin for incontinence. MATERIALS AND METHODS: This
      multicenter, randomized, double-blind, active control, parallel study was
      designed to evaluate urge urinary incontinence episodes using a 7-day diary.
      RESULTS: A total of 97 women and 8 men 34 to 76 years old with urge incontinence
      or mixed incontinence with a clinically significant urge component were enrolled
      in the study. The number of weekly urge incontinence episodes decreased from 27.4
      to 4.8 after controlled and from 23.4 to 3.1 after immediate release oxybutynin
      (p = 0.56), and total incontinence episodes decreased from 29.3 to 6 and from
      26.3 to 3.8, respectively (p = 0.6). Weekly urge incontinence episodes from
      baseline to end of study also decreased to 84% after controlled and 88% after
      immediate release oxybutynin (p = 0.7). Continence was achieved in 41% of the
      controlled and 40% of the immediate release group (p = 0.9). Dry mouth of any
      severity was reported by 68 and 87% of the controlled and immediate release
      groups, respectively (p = 0.04), and moderate or severe dry mouth occurred in 25
      and 46%, respectively (p = 0.03). CONCLUSIONS: Participants taking a single daily
      does of controlled release oxybutynin had similar reductions in urge incontinence
      and total incontinence episodes compared to those taking oxybutynin 1 to 4 times
      daily. A lower incidence of dry mouth was reported for controlled release
      oxybutynin.

PMID- 10332442
TI  - Antegrade continence enema for the treatment of fecal incontinence in adults: use
      of gastric tube for catheterizable access to the descending colon.
AB  - PURPOSE: We describe the use of a gastric segment in performing the antegrade
      continence enema procedure in patients with refractory fecal incontinence.
      MATERIALS AND METHODS: The antegrade continence enema procedure was performed in
      4 women and 3 men with refractory neurogenic fecal incontinence. Preoperative
      evaluation included defecography and anorectal manometry. Operative technique
      involves tunneling a 10 cm. segment of tubularized stomach isolated along the
      greater curve with preservation of the right gastroepiploic vessels through the
      anterior tenia of the colon just distal to the splenic flexure. After the stoma
      is mature the patient passes a catheter and runs 1 to 2 l. warm tap water through
      it while seated on the toilet. Digital stimulation may be required to initiate
      bowel emptying and irrigation is continued until clear. RESULTS: Creation of a
      nonrefluxing catheterizable gastric tube to the descending colon was successful
      in all 7 patients. At a mean postoperative followup of 22.4 months all patients
      are continent and use antegrade continence enema irrigation every other day on
      average. One patient required early revision because of stomal stenosis. Special
      measures include application of a generic antacid tablet to the stoma and use of
      a skin barrier. CONCLUSIONS: Catheterizable access to the descending colon for
      the antegrade continence enema procedure more closely approximates normal
      defecation patterns by emptying ("unloading") the left side of the colon. The
      stomach is a suitable option in close proximity for this purpose and is
      especially advantageous when the appendix is not available. The antegrade
      continence enema procedure using a gastric segment can be safely and effectively
      performed, and is well suited for use by reconstructive surgeons who are familiar
      with the Mitrofanoff principle.

PMID- 10332443
TI  - Cocaine associated priapism.
AB  - PURPOSE: Cocaine abuse is an ongoing epidemic in the United States. Priapism
      associated with cocaine use has been reported only twice in the urological
      literature. To our knowledge we report the first series of priapism associated
      with cocaine use and the first case associated with the use of this drug in its
      solid form, known as crack. MATERIALS AND METHODS: We retrospectively reviewed
      the presentation of 3 patients to our emergency department within the last year.
      Each patient presented with priapism and no identifiable predisposition other
      than the use of cocaine within 24 hours, as evident on positive urine toxicology.
      RESULTS: Each patient delayed seeking treatment, which added to the complexity of
      therapy. Intracavernosal aspiration and irrigations failed in all 3 cases.
      Cavernous spongiosal shunting failed in the first 2 cases. Cases 2 and 3 were
      complicated by the high flow variant of priapism. Case 1 ultimately required
      partial penectomy for infected, gangrenous, distal penile tissue. CONCLUSIONS: It
      appears that cocaine can be a cause of refractory priapism and treatment can be
      challenging. We suggest that urine toxicology screening be considered in such
      cases. The identification of underlying cocaine abuse is important in preventing
      priapism recurrence in these patients.

PMID- 10332444
TI  - Oral trazodone is not effective therapy for erectile dysfunction: a double-blind,
      placebo controlled trial.
AB  - PURPOSE: The unusual side effect of priapism associated with the antidepressant
      trazodone has led researchers to evaluate its use for the treatment of erectile
      dysfunction. Previous studies have shown nearly 70% efficacy in patients.
      Unfortunately, these studies have been anecdotal, retrospective or of combination
      therapy with yohimbine. A placebo controlled, fixed dose, double-blind crossover
      study was performed to evaluate the safety and efficacy of oral trazodone for the
      treatment of erectile dysfunction. MATERIALS AND METHODS: A total of 51 patients
      with at least 3 months of complete erectile dysfunction were randomized in a
      double-blind fashion to receive 50 mg. trazodone or placebo at bedtime.
      Evaluation consisted of a history, physical examination and laboratory studies,
      including hormonal evaluation, nocturnal penile tumescence evaluation, penile
      Doppler ultrasound and the Index of Sexual Satisfaction. Patients were followed
      at monthly intervals with an in clinic interview. After a 3-month treatment
      interval patients were reevaluated with index scores and crossed over after a 3
      week washout period. Study end points included patient diary evaluations and
      index scores at the beginning of the study interval and the end of the first
      treatment period. RESULTS: Of the 51 patients who enrolled in the study 48
      completed both phases. Mean patient age was 65 years (range 31 to 80). After the
      first 3-month treatment interval 19% of patients receiving trazodone had improved
      erections compared to 24% receiving placebo (p < 0.50). Of the trazodone group
      35% had improvement in sex drive compared to 20% of the placebo group (p < 0.36).
      Mean Index of Sexual Satisfaction scores changed after treatment from 31.7 to
      27.5 for the trazodone group (p < 0.50) and from 28.5 to 30.8 for the placebo
      group (p < 0.49). Side effects included drowsiness in 31% of the patients, dry
      mouth in 1% and fatigue in 19%. CONCLUSIONS: Trazodone is no more effective than
      placebo in improving erections and sexual function in patients with severe
      physiological erectile dysfunction.

PMID- 10332445
TI  - Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the
      penis: a Southwest Oncology Group study.
AB  - PURPOSE: We ascertained whether combined cisplatin, methotrexate and bleomycin
      have efficacy for treating locally advanced or metastatic carcinoma of the penis,
      and evaluate the toxicity resulting from this regimen. MATERIALS AND METHODS:
      Patients had biopsy proved locally advanced or metastatic epidermoid carcinoma of
      the penis. Chemotherapy consisted of 75 mg./m.2 cisplatin infused intravenously
      on day 1, 25 mg./m.2 intravenous bolus of methotrexate on days 1 and 8, and 10
      unit per m.2 intravenous bolus of bleomycin on days 1 and 8 with a cycle length
      of 21 days. Our study was performed as a standard phase II evaluation with 2
      stages of accrual. RESULTS: Enrolled in this study were 45 patients, including 40
      who were evaluable for a response. There were 5 complete and 8 partial responses
      for a 32.5% response rate. Five treatment related deaths occurred and 6 of the 36
      remaining patients evaluable for toxicity had 1 or more life threatening toxic
      episodes. CONCLUSIONS: A regimen of cisplatin, methotrexate and bleomycin appears
      to have promising results. However, toxicity was prodigious, and an emphasis of
      future research should be to decrease toxicity.

PMID- 10332446
TI  - Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2
      single-blind placebo controlled crossover studies.
AB  - PURPOSE: We evaluate the efficacy of paroxetine hydrochloride as needed for the
      treatment of premature ejaculation. MATERIALS AND METHOD: Study 1 comprised 26
      potent men with a mean age of 39.5 years with premature ejaculation who were
      randomized to receive 20 mg. oral paroxetine (group A) or placebo (group B) as
      needed 3 to 4 hours before planned intercourse in a controlled single-blind
      crossover trial. Study 2 comprised 42 potent men with a mean age of 40.5 years
      with premature ejaculation who were randomized to receive 10 mg. paroxetine daily
      for 3 weeks and then 20 mg. paroxetine as needed (group C) for 4 weeks or placebo
      daily for 3 weeks and then placebo as needed (group D) for 4 weeks. RESULTS: Mean
      pretreatment ejaculatory latency time was 0.3 minute for study 1. At 4 weeks mean
      ejaculatory latency time was 3.2 minutes in the paroxetine as needed and 0.45 in
      the placebo as needed phase for group A (p < 0.001), and 0.6 in the placebo as
      needed and 3.5 in the paroxetine as needed phase for group B (p < 0.001). There
      were no adverse effects with paroxetine or placebo in study 1. Mean pretreatment
      ejaculatory latency time was 0.5 minute for study 2. At 3 weeks mean ejaculatory
      latency time was 4.3 minutes in the paroxetine daily and 5.8 in the paroxetine as
      needed phase, and 0.9 in the placebo daily and 0.6 in the placebo as needed phase
      for group C (p < 0.001). At 3 weeks mean ejaculatory latency time was 0.8 minutes
      in the placebo daily and 1.1 in the placebo as needed phase, and 3.3 in the
      paroxetine daily and 6.1 in the paroxetine as needed phase for group D (p <
      0.001). Adverse effects in 7 of 42 men (17%) given paroxetine daily included an
      ejaculation in 3, anorexia in 1, gastrointestinal upset in 3 and reduced libido
      in 2. Mean ejaculatory latency time was greater in the paroxetine as needed phase
      of study 2 than that of study 1 (p < 0.05), suggesting that ejaculatory control
      achieved with paroxetine as needed is significantly better if patients are
      initially treated with the drug daily. CONCLUSIONS: Paroxetine appears to be
      superior to placebo in the pharmacological treatment of premature ejaculation
      when administered on a chronic or as needed basis.

PMID- 10332448
TI  - Patient characteristics associated with vasectomy reversal.
AB  - PURPOSE: More than 30 million couples throughout the world are using vasectomy as
      a method of birth control. It is estimated that up to 6% of men who undergo
      voluntary sterilization will eventually request reversal, despite the high cost
      and relatively low success rate of the procedure. We identified characteristics
      that predict which vasectomy patients may request reversal. We also examined the
      cost and effectiveness of pre-vasectomy sperm cryopreservation followed by
      intrauterine insemination as an alternative method of achieving pregnancy.
      MATERIALS AND METHODS: We reviewed medical charts of 365 patients who underwent
      vasectomy and 290 who underwent vasectomy reversal between 1990 and 1997. Data
      were collected on patient age at the time of vasectomy, religion, occupation,
      wife employment status, number of marriages, number of children, reason for
      reversal, and number of years between vasectomy and reversal. Based on previously
      reported values, pregnancy rates and cost per successful pregnancy were estimated
      for vasectomy reversal surgery, and compared with a calculated cost per pregnancy
      for sperm cryopreservation and intrauterine insemination. RESULTS: Patient
      factors significantly associated with increased vasectomy reversal included
      younger age at time of vasectomy (p < 0.001) and a wife who worked outside the
      home (p < 0.001). Vasectomy reversal occurred 12.5 times more often (95%
      confidence interval [CI] 7.6 to 20.7) in men who underwent vasectomy in their 20s
      than in men who were older. Men whose wives were not employed requested reversal
      0.48 times as often (95% CI 0.33 to 0.71) as those whose wives worked. Men who
      were younger at vasectomy tended to wait longer before reversal (median 10 years)
      than other patients (p < 0.001). At 10 years our calculated pregnancy rates and
      cost per pregnancy were 44% and $12,727 for vasectomy reversal, and 41% and
      $9,512 for intrauterine insemination with banked sperm (3 attempts). CONCLUSIONS:
      Patients who requested vasectomy reversal most often chose voluntary
      sterilization at a younger age. We believe that younger men should be given
      better pre-vasectomy counseling. However, the success rate and cost-effectiveness
      of sperm cryopreservation before vasectomy, with subsequent intrauterine
      insemination, may make this nonsurgical alternative desirable for younger couples
      who choose vasectomy even when properly informed about reversal rates.

PMID- 10332447
TI  - Varicocele is associated with elevated spermatozoal reactive oxygen species
      production and diminished seminal plasma antioxidant capacity.
AB  - PURPOSE: Because varicocele is seen often in infertile men and oxidative stress
      has been implicated in sperm dysfunction, we assessed spermatozoal reactive
      oxygen species and seminal total antioxidant capacity in men with and without
      varicocele. MATERIALS AND METHODS: Levels of reactive oxygen species and total
      antioxidant capacity were measured in the semen of 21 infertile men with
      varicocele, 15 men with incidential varicocele and 17 normal donors without
      varicocele (controls). Men with leukocytospermia (more than 1 x 10(6) white blood
      cells per ml.) were excluded from study. Reactive oxygen species were measured in
      washed spermatozoa with a luminol dependent chemiluminescence assay. Total
      seminal antioxidant capacity was measured with an enhanced chemiluminescence
      assay, and the results were expressed as trolox equivalents. Sperm
      characteristics were assessed with a computer assisted semen analyzer, and sperm
      morphology was assessed using World Health Organization and Kruger's strict
      criteria. RESULTS: Patients with varicocele had significantly higher reactive
      oxygen species levels than controls (p = 0.02). Reactive oxygen species levels
      did not differ significantly between infertile and men with incidental
      varicocele. Total antioxidant levels were significantly lower among men with
      varicocele (p = 0.02) and those with incidental varicocele compared to controls
      (p = 0.05). Reactive oxygen species and total antioxidant capacity levels did not
      correlate in any group. CONCLUSIONS: Our results suggest that elevated reactive
      oxygen species and depressed total antioxidant capacity levels are associated
      with varicocele. These changes may be related to functional sperm abnormalities
      and infertility seen commonly in these patients. These findings support a
      possible rationale for controlled clinical trials of antioxidant supplementation
      in infertile men with varicocele.

PMID- 10332449
TI  - Postmortem sperm procurement: a legal perspective.
AB  - PURPOSE: Postmortem sperm procurement with subsequent artificial insemination has
      become a technically feasible method for posthumous conception. A variety of
      legal questions exist involving the rights and relationships of the deceased, his
      family and his issue. We addressed these questions and designed a workable
      protocol for postmortem sperm procurement. MATERIALS AND METHODS: MEDLINE,
      WESTLAW and LEXIS medical literature, and case law searches were conducted.
      United States and international case law, United States (federal and state)
      statutes, Uniform Law Commissions Acts, and law review commentaries and articles
      were reviewed. RESULTS: While postmortem sperm procurement is being requested
      throughout the United States, no standard protocol or procedural guidelines have
      been established by federal or state statute. Furthermore, the courts have not
      yet addressed this specific scenario in reported case law. Statutes and case law
      do address related factual scenarios and issues, including property rights in
      human bodies, rules governing transplantation of human organs/body parts, rights
      of parties in in vivo sperm bank donations and responsibilities of parents to the
      conceptus of artificial insemination. CONCLUSIONS: A workable protocol can be
      established by analyzing case law and statutes addressing factually similar
      scenarios. Urologists must focus on the express intent of the decedent and limit
      any postmortem sperm retrieval to the specific requests made by the decedent.
      Decedent requests should be documented in writing. The decedent must be competent
      and of majority age. In the absence of decedent expressed affirmative directive
      calling for sperm retrieval, no other relative or guardian may authorize this
      retrieval. Issues regarding the legitimacy and inheritance rights of the
      conceptus will most consistently be addressed when explicitly provided for in the
      will of the decedent.

PMID- 10332450
TI  - Paratesticular sarcoma: failure patterns after definitive local therapy.
AB  - PURPOSE: We examine disease control and patterns of failure for patients with
      adult paratesticular sarcoma treated with wide repeat excision and postoperative
      radiation for close margins. MATERIALS AND METHODS: A retrospective analysis was
      performed on 14 patients with paratesticular sarcomas referred to 1 institution
      from 1988 to 1995. RESULTS: Median followup was 50 months (range 26 to 90).
      Pathology review revealed malignant fibrous histiocytoma in 5 cases and
      liposarcoma in 3. Tumor grade was high in 8 cases. Microscopic residual disease
      was identified after repeat excision in 3 of 11 completely excised cases (27%).
      Cause specific survival 5 years after diagnosis was 70%. Both patients with local
      failure after wide excision had undergone initial intralesional excision and 1
      had also received postoperative irradiation. In 5 patients metastases developed
      in the liver, lung, nodes or multiple sites 0 to 60 months after diagnosis.
      CONCLUSIONS: Simple excision is inadequate treatment for paratesticular sarcoma,
      since wide repeat excision revealed microscopic residual disease in 27% of
      completely excised cases. The 2 local failures occurred in patients with a
      history of inadvertent intralesional surgery, which may be a risk factor for
      local relapse after wide repeat excision. Adjuvant radiation should be considered
      for these patients as well as those with narrow repeat resection margins.
      Systemic failure was frequent in patients with high grade tumors, who will
      require effective systemic adjuvant therapy.

PMID- 10332452
TI  - Prostatic tumor relapse in patients with superficial bladder tumors: 15-year
      outcome.
AB  - PURPOSE: We assessed the outcome of patients with superficial bladder tumors with
      relapse in the prostate and defined prognostic variables of survival. MATERIALS
      AND METHODS: A cohort of 186 men with superficial bladder tumors was followed for
      15 years. Tumor relapse in the prostate was classified as noninvasive (prostatic
      urethra and ducts) or invasive (stroma) with intraurethral or direct prostatic
      invasion. Bladder tumor stage at the time of prostatic relapse was defined as
      confined or not confined to the bladder. The end point of the study was disease
      specific survival. The effects of covariates on survival were estimated on
      multivariate analysis. RESULTS: Of the 186 patients 72 (39%) had relapse in the
      prostate after a median followup of 28 months (range 3 to 216), including 45
      (62%) with noninvasive prostatic tumor and 27 (38%) with stromal invasion. The
      survival rate was 82% in patients with prostatic urethra or duct involvement
      compared to 48% with stromal invasion. Intraurethral stromal invasion was
      associated with a 75% 15-year survival rate versus 9% for extravesical prostatic
      stromal invasion. Bladder tumor stage and prostatic stromal invasion were
      independent prognostic variables of survival. CONCLUSIONS: The prostate is a
      frequent site of tumor relapse in patients with superficial bladder tumors
      followed for 15 years. Prostatic relapse may portend tumor invasion in the
      bladder and stromal invasion in the prostate, which significantly reduce
      survival.

PMID- 10332451
TI  - Vasectomy and prostate cancer.
AB  - PURPOSE: Vasectomy has been associated with an increased risk of prostate cancer
      in some previous studies but not in others. We evaluated the association in a
      population based, case control study in Massachusetts. MATERIALS AND METHODS:
      Included in our study were 1,216 patients younger than 70 years with newly
      diagnosed prostate cancer and 1,400 controls with no history of prostate cancer
      who were matched to patients by age and town of residence. Data on vasectomy and
      potential confounding factors were obtained by telephone interview, and
      confounding was controlled by conditional logistic regression analysis. RESULTS:
      Overall 16% of patients and 15% of controls had undergone vasectomy. Compared
      with no vasectomy the odds ratio for ever having undergone vasectomy was 1.0 (95%
      confidence interval [CI] 0.8 to 1.3), which did not vary significantly by age at
      or interval since vasectomy. In men who reported urological symptoms and those
      without symptoms the odds ratio was 0.9 (95% CI 0.7 to 1.2) and 1.4 (1.0 to 1.9),
      respectively. In men younger than 55 years and those 55 years old or older at
      diagnosis of prostate cancer the odds ratio was 1.9 (95% CI 1.2 to 3.2) and 1.0
      (0.8 to 1.3), respectively [corrected]. In the younger men with stages A or B and
      C or D disease the odds ratio was 2.3 (95% CI 1.2 to 4.3) and 1.3 (0.5 to 3.5),
      respectively. CONCLUSIONS: Our findings do not support the hypothesis that
      vasectomy increases the risk of prostate cancer in men older than 55 years.
      Further study is needed to determine whether the observed association between
      vasectomy and prostate cancer in men younger than 55 years is due to chance,
      detection bias or a causal effect.

PMID- 10332453
TI  - Effects of implementation of 18 clinical pathways on costs and quality of care
      among patients undergoing urological surgery.
AB  - PURPOSE: We evaluated the effects on the costs and quality of care of
      implementation of 18 clinical pathways for urological operations. MATERIALS AND
      METHODS: From April 1997 to March 1998 patients undergoing 1 of 18 urological
      operations were treated according to clinical pathways. The outcomes in terms of
      length of hospital stay and admission charges of these patients were compared
      with those of patients treated between April 1996 and March 1997 before clinical
      pathways were implemented. We also selected 7 clinically relevant quality
      indicators to assess the quality of care before and after clinical pathway
      implementation. RESULTS: Of the 1,784 patients undergoing urological surgery from
      April 1997 to March 1998, 1,382 (77.5%) were treated according to 1 of the 18
      clinical pathways. Before implementation 1,279 of 1,615 patients (79.2%)
      underwent these procedures. The length of hospital stay decreased from 5.5 to 4.9
      days (p < 0.01) and the average hospital admission charges decreased by 12.9% (p
      < 0.01) after implementation. Five of the quality indicators, including the rate
      of surgical complications, were significantly improved after pathway
      implementation. The hospitalization rate was not affected (1.3 before versus 0.8%
      after implementation, p = 0.18). Variations from the clinical pathways occurred
      in 543 cases (39.3%) and affected the length of hospital stay only (11.6%) or the
      admission charge only (12.9%) more often than both (7.8%, p < 0.01) or neither
      (7.0%, p < 0.01). The most common variances in these patients were patient
      related (30.8%). CONCLUSIONS: Implementation of multiple clinical pathways in a
      urology department can improve urological practice by decreasing the length of
      hospital stay, admission charges and rate of surgical complications, and by
      improving the quality of care.

PMID- 10332454
TI  - Barcelona retrograde urethrography: a new device and technique.
AB  - PURPOSE: We describe a new device and technique for retrograde urethrography
      without instrumentation of the male urethra. MATERIALS AND METHODS: We performed
      retrograde urethrography with a vacuum uterine cannula in 160 patients. Stricture
      of the distal tip of the urethra and iatrogenic damage to the urethra were
      evaluated. RESULTS: No patient sustained iatrogenic damage to the urethra and
      stricture of the distal tip of the urethra was visualized in 12 patients.
      CONCLUSIONS: We recommend the use of this technique of retrograde urethrography
      without instrumentation to determine urethral disease when manipulation of the
      urethra must be avoided or is impossible due to meatal stenosis.

PMID- 10332455
TI  - Bladder microvasculature in women with interstitial cystitis.
AB  - PURPOSE: A cardinal cystoscopic finding in women with interstitial cystitis is
      mucosal small vessel hemorrhage or glomerulations after hydrodistention. We
      quantified and compared microvascular density and endothelial proliferation in
      the bladder biopsies of women with interstitial cystitis and a control group of
      women who were undergoing incontinence or prolapse surgery. MATERIALS AND
      METHODS: We performed computer assisted image analysis and immunohistochemical
      studies to compare differences in the blood vessel count, and proportional area
      in the bladder suburothelium and deeper submucosa of bladder biopsies of 52
      women, including 26 with interstitial cystitis. Routine light microscopy features
      were examined and correlated with microvascular density. RESULTS: In the bladder
      biopsies of women with interstitial cystitis there was a lower blood vessel count
      (p = 0.01), and a lower proportion of the total image consisted of blood vessel
      wall (p = 0.03) in the suburothelium than in control biopsies. We noted no
      difference in the blood vessel count of the deeper submucosa or in the degree of
      endothelial cell proliferation. Suburothelial blood vessel differences correlated
      with the degree of histological change, such as edema, inflammatory infiltrate
      and vascular congestion. CONCLUSIONS: We found decreased microvascular density in
      the suburothelium but not in the deeper submucosa in bladder biopsies of women
      with interstitial cystitis.

PMID- 10332456
TI  - Do urinary symptoms correlate with urodynamic findings?
AB  - PURPOSE: We determined whether urinary symptomatology correlates with video
      urodynamic findings. MATERIALS AND METHODS: A total of 115 women with complaints
      of urinary incontinence completed a 27-item questionnaire. Pelvic examination and
      video urodynamic study were performed. Subjective findings were scored from 0 to
      5, with 5 representing the most severe symptomatology. Patients were divided into
      5 subgroups based on etiology of incontinence, and analyzed by Student's t test
      with p < 0.05 considered statistically significant. RESULTS: Among the 115
      patients 11% had normal studies, 38% proximal urethral hypermobility with stress
      urinary incontinence, 33% intrinsic sphincter deficiency, 11% significant pelvic
      prolapse and stress urinary incontinence, and 10% detrusor instability.
      Subjective complaints, such as incontinence during physical activity, were
      prominent in both stress urinary incontinence groups as well as the prolapse
      group with stress urinary incontinence. Questions about nocturia, frequency,
      urgency, urge incontinence, number of pads, number of vaginal deliveries and
      incomplete emptying were not statistically significant for any group.
      CONCLUSIONS: Subjective complaints were not helpful in differentiating the
      etiology of incontinence. Few questions were helpful in predicting which patients
      would have a normal video urodynamic study.

PMID- 10332457
TI  - Orthotopic bladder substitution in women: functional evaluation.
AB  - PURPOSE: Orthotopic bladder substitution following cystectomy in women has
      recently been introduced at some specialized centers. Studies of such a procedure
      should consider the oncological and functional outcomes. We analyzed only the
      functional results of orthotopic bladder substitution since followup is too short
      (about 2 years) for a valid oncological assessment. MATERIALS AND METHODS: From
      October 1994 to November 1997, 60 women with a mean age of 48.3 years underwent
      standard radical cystectomy and orthotopic diversion (ileal W-neobladder with
      subserous tunnel in 47 and hemi-Kock reservoir in 13). The oncological criterion
      was organ confined invasive bladder cancer. RESULTS: There was no perioperative
      mortality. Postoperative complications included fatal pulmonary embolism in 1
      woman, deep vein thrombosis in 2, prolonged ileus in 1 and fistula of the vaginal
      pouch in 3, which was repaired successfully. Cancer recurred in the pelvis in 2
      cases and as distant metastases in 5. Of the patients 43 had been followed for a
      mean of 20.2 months (range 6 to 36), and 32 were continent day and night, 1 was
      totally incontinent, 2 had daytime stress incontinence and 6 had nighttime
      incontinence. Six women had difficulty emptying the pouch spontaneously with
      concomitant residual urine due to acute angulation between the urethra and pouch.
      CONCLUSIONS: Orthotopic bladder substitution after standard radical cystectomy in
      select women provides a satisfactory functional outcome. Failure of complete
      emptying seems to be due to anatomical rather than functional reasons.

PMID- 10332458
TI  - Female urethral adenocarcinoma: immunohistochemical evidence of more than 1
      tissue of origin.
AB  - PURPOSE: Urethral adenocarcinoma is a rare malignancy whose origin remains
      controversial. The monoclonal antibody mAbDas1 (formerly 7E12H12) was developed
      against a unique colonic epithelial epitope and is reactive in areas of
      intestinal metaplasia. Recently the antibody was shown to react in cystitis
      glandularis as well as adenocarcinoma of the bladder, suggesting that cystitis
      glandularis may be the precursor of bladder adenocarcinoma. We examined urethral
      adenocarcinomas and benign urethral specimens using mAbDas1 to determine whether
      it could provide insight into their histogenesis. MATERIALS AND METHODS: Archival
      tissue from 12 cases of primary female urethral adenocarcinoma and urethral
      specimens of inflamed urethral mucosa, urethritis glandularis and transitional
      cell carcinoma was studied. Immunohistochemical analysis of formalin fixed,
      paraffin embedded archival tissue was done using the monoclonal antibody mAbDas1.
      Tumors were also evaluated with a prostate specific antigen (PSA) polyclonal
      antibody as previous studies have noted PSA reactivity in these tumors. RESULTS:
      Of the 12 cases 9 were columnar/mucinous adenocarcinoma, 2 clear cell
      adenocarcinoma and 1 a cribriform pattern resembling adenocarcinoma of the
      prostate. All columnar/mucinous adenocarcinomas reacted positively (6 strongly
      and 3 focally) with the mAbDas1 antibody but did not react with the PSA antibody.
      The tumor with a cribriform pattern reacted strongly with PSA but did not react
      with mAbDas1. The 2 clear cell adenocarcinomas did not react with either
      antibody. The benign urethral specimens demonstrated strong reactivity to the
      mAbDas1 antibody in areas of urethritis glandularis but normal and inflamed
      urethral mucosa and transitional cell carcinoma did not react. CONCLUSIONS:
      Primary adenocarcinoma of the female urethra arises from more than 1 tissue of
      origin. Columnar/mucinous adenocarcinomas of the female urethra and urethritis
      glandularis demonstrate consistent reactivity with the mAbDas1 antibody,
      suggesting that these tumors arise from glandular metaplasia analogous to the
      potential histogenesis previously demonstrated in the bladder. PSA reactivity
      occurred in 1 tumor with a cribriform pattern and likely represents origin from
      Skene's glands. Clear cell adenocarcinomas did not react with either antibody,
      suggesting a third possible pathway in the development of this rare subset of
      adenocarcinomas.

PMID- 10332459
TI  - Bladder function after surgery for lumbar intervertebral disk protrusion.
AB  - PURPOSE: Urodynamic changes following surgical treatment for lumbar
      intervertebral disk protrusion were prospectively studied. MATERIALS AND METHODS:
      We evaluated 98 patients with lumbar intervertebral disk protrusion. Urodynamic
      evaluation was performed in all patients before and after surgery, and included
      simultaneous measurement of intravesical and abdominal pressure during bladder
      filling and voiding, and uroflowmetry (pressure flow measurement). RESULTS: Of
      the 27 patients with detrusor areflexia preoperatively detrusor activity was
      normal in only 6 after surgical treatment. Of the 71 patients with normal
      urodynamic findings preoperatively the findings became abnormal after surgery in
      7. CONCLUSIONS: Bladder function frequently remains unchanged after surgery for
      lumbar intervertebral disk protrusion.

PMID- 10332460
TI  - Urodynamic features of the gastric pouch after radical cystectomy and the
      relationship to oral intake.
AB  - PURPOSE: We studied the motility of orthotopic bladder substitution with stomach
      (gastric pouch) in adults with bladder cancer and the effect of oral intake as
      measured on urodynamics. We also investigated the probable relationship between
      continence and sensitivity of the proximal urethra. Anticholinergic medication
      effects on pouch motility were tested. MATERIALS AND METHODS: Six patients with a
      gastric pouch were questioned about quality of life 6 to 43 months after surgery,
      and examined urodynamically before and after oral intake. During the examination
      the proximal urethra (directly under the anastomosis between the pouch and
      urethra) was electrically stimulated to determine sensitivity. We tried to
      inhibit the peristaltic contractions with 20 mg. butylscopolamine intravenously.
      RESULTS: The main difference before and after oral intake was the onset time of
      peristaltic contractions. After eating the contractions began at a lower filling
      volume, which was statistically significant. There were no or insignificant
      differences in capacity and urodynamic parameters. We were successful in
      inhibiting the peristaltic contractions with anticholinergic medication.
      CONCLUSIONS: The gastric pouch is a valuable bladder substitute with sufficient
      volume, antireflux characteristics, satisfactory continence rate and adequate
      voiding behavior. Oral intake causes motor activity of the gastric pouch at a
      lower fill volume than fasting during urodynamic investigation. Anticholinergic
      medication may be useful for inhibiting peristalsis in the gastric pouch.

PMID- 10332461
TI  - Sphincteric stent versus external sphincterotomy in spinal cord injured men:
      prospective randomized multicenter trial.
AB  - PURPOSE: In a prospective randomized multicenter trial we compared the treatment
      results of conventional external sphincterotomy with those of UroLume sphincteric
      stent prosthesis placement in men with spinal cord injury and external detrusor
      sphincter dyssynergia. MATERIALS AND METHODS: We randomized 57 men with spinal
      cord injury in whom urodynamics verified external detrusor-sphincter dyssynergia
      into 2 groups to undergo either sphincter defeating procedure. We compared the
      primary urodynamic parameter of maximum detrusor pressure, and secondary
      urodynamic parameters of bladder capacity and post-void residual urine volume in
      men who underwent sphincterotomy or sphincteric stent placement. Parameters were
      measured preoperatively, and 3, 6, 12 and 24 months postoperatively. Patients
      completed questionnaires regarding voiding sensation and quality of life issues
      at each followup visit. RESULTS: Demographic data of the 26 patients treated with
      sphincterotomy and the 31 treated with sphincteric stent placement were
      statistically similar. Preoperatively mean maximum detrusor pressure plus or
      minus standard deviation in sphincterotomy and stent cases was 98.3 +/- 27.6 and
      95.7 +/- 27.7 cm. water, respectively (p = 0.73). At 12 months mean maximum
      detrusor pressure decreased to 48.9 +/- 16.4 and 52.6 +/- 31.6 cm. water in the
      sphincterotomy and stent groups, respectively (p = 0). Preoperatively mean
      bladder capacity in sphincterotomy and stent cases was 245 +/- 158 and 251 +/-
      145 ml., respectively (p = 0.87). Bladder capacity did not change significantly
      in either treatment group throughout followup. Preoperatively mean post-void
      residual urine volume in the sphincterotomy and stent groups was 212 +/- 163 and
      168 +/- 114 ml., respectively (p = 0.33). Residual urine volume decreased in each
      group at some but not all followup evaluations. The duration of hospitalization
      was greater for sphincterotomy than stenting (p = 0.036). Six stents required
      explantation. CONCLUSIONS: The UroLume stent is as effective as conventional
      external sphincterotomy for treating external detrusor-sphincter dyssynergia.
      However, sphincteric stent placement is advantageous because it involves shorter
      hospitalization and is potentially reversible.

PMID- 10332462
TI  - Recurrent calcium oxalate urolithiasis in a man with familial periodic paralysis
      and hypokalemia.

PMID- 10332463
TI  - Malignant transformation of renal angiomyolipoma.

PMID- 10332465
TI  - Melanosis vesica urinaria: is it a premalignant lesion?

PMID- 10332464
TI  - Transverse colon pouch with total replacement of the ureter by reconfigured colon
      segment.

PMID- 10332466
TI  - Cutaneous mucormycosis presenting as a penile lesion in a patient with acute
      myeloblastic leukemia.

PMID- 10332467
TI  - Monoclonal antibody confirmation of a primary leiomyoma of the testis.

PMID- 10332468
TI  - Prostatic paraganglioma: 5-year followup.

PMID- 10332469
TI  - Subsequent urethral relapses with extension into the corpora cavernosa of
      embryonal rhabdomyosarcoma of the prostate.

PMID- 10332470
TI  - Re: Endopyelotomy for horseshoe and ectopic kidneys.

PMID- 10332471
TI  - Re: Recovery of spontaneous erectile function after nerve-sparing radical
      retropubic prostatectomy with and without early intracavernous injections of
      alprostadil: results of a prospective, randomized trial.

PMID- 10332472
TI  - Multicystic dysplastic kidney as cause of gastric outlet obstruction and
      respiratory compromise.

PMID- 10332473
TI  - Kidney transplantation in children: a single center experience.
AB  - PURPOSE: We reviewed our most recent 10-year experience with kidney
      transplantation in children to determine the morbidity and mortality of the
      procedure, and to identify factors that affected outcome. MATERIALS AND METHODS:
      A total of 107 renal transplants were done in 95 children 1 to 17 years old (mean
      age 10.9) during the 10-year period ending January 1, 1997. The 4 most common
      causes of end stage renal disease were renal dysplasia, reflux nephropathy,
      obstructive uropathy and systemic immunological diseases. Cyclosporine based
      immunosuppression was used in all but 2 recipients. After April 1991
      antilymphocyte antibody induction, coagulopathy screening, systemic
      anticoagulation and cytomegalovirus prophylaxis were incorporated into the
      protocols. The effects of kidney source, recipient gender, recipient age,
      preformed anti-HLA antibody level, preemptive renal transplantation,
      cytomegalovirus risk, antilymphocyte antibody induction therapy and date of renal
      transplantation on kidney graft survival were examined with the log rank test.
      RESULTS: The 1-year graft and patient survival rates were 91 and 99%,
      respectively. The most common causes of graft failure were rejection and
      recurrence of primary renal disease. The only factors that significantly (p <
      0.05) influenced graft survival were antilymphocyte antibody induction
      immunosuppression and kidney transplantation after April 1991. Three urological
      complications required surgical correction. Medical morbidity included
      hypertension in 48.6% of the cases, short stature in 46.6% and obesity in 58.9%.
      CONCLUSIONS: Pediatric renal transplantation can be done with acceptable
      morbidity, a low rate of technical complications and low mortality. Hypertension,
      chronic rejection and abnormal body habitus continue to be problematic.

PMID- 10332474
TI  - Pseudosarcomatous myofibroblastic tumor of the distal ureter.

PMID- 10332475
TI  - Comparison of urodynamic and free voiding pattern in infants with dilating
      reflux.
AB  - PURPOSE: We compared simultaneous investigations of free voiding pattern and
      urodynamic assessment in infants with dilating reflux to obtain further
      information on previously suspected bladder dysfunction based on abnormal
      urodynamic findings. MATERIAL AND METHODS: A total of 33 male and 8 female
      infants with dilating reflux were included in the study. Free voiding pattern was
      determined by 4-hour voiding observation compared to previously described voiding
      pattern studies of healthy infants. Simultaneous invasive urodynamic assessments
      were performed. RESULTS: The patients were grouped according to urodynamic
      bladder capacity. Half of the male patients had low bladder capacity with high
      voiding pressure levels (hypercontractile) and the other half had either normal
      or high capacity bladders. The low capacity group had frequent small voids and a
      high rate of interrupted voiding, the high capacity group had infrequent voids of
      high volumes with high residual urine, and the pattern of the normal capacity
      group differed only from that of healthy infants by an increase in residual
      urine. All female infants had the typical characteristics of high capacity
      bladder on free voiding and urodynamic assessments. CONCLUSIONS: Infants with
      abnormal invasive urodynamic investigations, including those with a small
      capacity hypercontractile bladder and those with a high capacity bladder, could
      be identified on free voiding studies, indicating that an abnormal urodynamic
      pattern represents bladder dysfunction.

PMID- 10332476
TI  - Strategies for reconstruction after unsuccessful or unsatisfactory primary
      treatment of patients with bladder exstrophy or incontinent epispadias.
AB  - PURPOSE: Following unsuccessful or unsatisfactory primary treatment in patients
      with the epispadias/exstrophy complex, the options for a surgical solution to
      preserve the upper urinary tract, to achieve complete continence, and to
      reconstruct the external and female internal genitalia are limited. We reviewed
      the records of the patients treated at our institution to determine a surgical
      compromise between ingenious operative constructions and patient desires, both of
      which are secondary to stabilization of renal function. MATERIALS AND METHODS:
      From 1967 to December 1997, 128 patients with bladder exstrophy/epispadias
      complex were treated, of 80 whom had received previous unsuccessful or
      unsatisfactory treatment. Of these patients 72 were followed for an average of
      22.4 years after the first surgical intervention. There were 40 patients referred
      to our institution after primary bladder closure and bladder neck reconstruction,
      10 after rectal bladder, 7 after ureterosigmoidostomy and 5 after incontinent
      diversion. RESULTS: At the latest followup 19 patients had a rectal reservoir, 38
      an ileocecal pouch, 12 a conduit diversion and 3 an augmented Young-Dees
      procedure. The upper urinary tract remained stable in 95% of the renal units with
      rectal reservoir, 95% with ileocecal pouch, 96% with a colonic conduit and 100%
      with an augmented Young-Dees procedure. Day and night continence was achieved in
      95% of the patients with a rectal reservoir and 97% of those with an ileocecal
      pouch were continent, whereas only 2 of the 3 patients with an augmented Young
      Dees procedure were continent. Of the women 16 were satisfied with the cosmetic
      results and 6 delivered 8 children by cesarean section. Only 1 man was
      dissatisfied with the final cosmetic result. All adults but 1 engaged in sexual
      intercourse. CONCLUSIONS: The first operative intervention in patients with
      bladder exstrophy/epispadias complex determines their fate. After failure of
      primary treatment, the upper urinary tract must be stabilized. In patients with
      severely impaired renal function the colonic conduit is our method of choice
      while in those with a normal or slightly dilated upper urinary tract and intact
      anal sphincter we performed a rectal reservoir. In the remaining patients an
      ileocecal pouch guarantees continence day and night. The results of genital
      reconstruction are satisfactory.

PMID- 10332477
TI  - A modification for bladder neck reconstruction in the treatment of patients with
      exstrophy and incontinence.
AB  - PURPOSE: We present a modification of bladder neck reconstruction which resulted
      in improved continence and voiding compared to other techniques of bladder neck
      repairs in patients with exstrophy and complete incontinence. MATERIALS AND
      METHODS: The series consisted of 10 patients with the exstrophy-epispadias
      complex and complete incontinence who previously had undergone multiple
      operations for bladder closure, bladder neck reconstruction and epispadias
      repair. This modification combines bladder neck lengthening and narrowing of the
      distal half of the urethra, and submucosal embedding of the proximal half of the
      neourethra in the trigonal area. All patients also underwent bladder augmentation
      with detubularized sigmoid colon concurrent with bladder neck reconstruction.
      Additionally the appendical Mitrofanoff principle was applied to 5 cases.
      RESULTS: Of the 10 patients who underwent bladder neck reconstruction with
      sigmoid cystoplasty 8 are voiding voluntarily without catheterization and are dry
      for longer than 4 hours day and night. Only 2 patients are partially dry with
      stress nocturia incontinence and in both we performed a Mitrofanoff procedure as
      an adjunct to catheterization and to ensure voiding and continence. CONCLUSIONS:
      Our modified bladder neck reconstruction provides better overall voiding and
      continence rates than the other bladder neck/urethral reconstruction procedures
      in patients with exstrophy and complete incontinence.

PMID- 10332478
TI  - The Young-Dees-Leadbetter bladder neck repair for neurogenic incontinence.
AB  - PURPOSE: We review our experience with the Young-Dees-Leadbetter bladder neck
      repair among patients with neurogenic incontinence. MATERIALS AND METHODS:
      Between 1978 and 1997, 25 girls and 13 boys with a mean age of 10.5 years (range
      5 to 25) underwent a standard Young-Dees-Leadbetter bladder neck repair for
      neurogenic incontinence. Of the 38 patients 26 had undergone prior urological
      surgery, including bladder neck surgery in 6 and bladder augmentation in 4. A
      primary Young-Dees-Leadbetter bladder neck repair was performed in 24 patients, a
      secondary Young-Dees-Leadbetter procedure in 6 and a primary Young-Dees
      Leadbetter procedure with periurethral silicone sheath placement in 8. RESULTS:
      Of the 38 patients 30 (79%) are dry, 7 (18%) are partially dry and 1 remains
      incontinent. Total or partial dryness was achieved after the initial repair in 26
      cases (68%), while 8 required an additional procedure and 3 required more than 2
      procedures to achieve continence. All patients who underwent silicone sheath
      placement were initially dry but incontinence developed subsequently in 5 due to
      sheath erosion. Of the 38 patients 35 (92%) ultimately required bladder
      augmentation. CONCLUSIONS: The management of neurogenic incontinence remains
      difficult. Success with the Young-Dees-Leadbetter procedure in our experience
      nearly always requires augmentation cystoplasty. The majority of patients will
      achieve continence after the initial procedure, and persistent incontinence can
      frequently be cured with further bladder neck surgery.

PMID- 10332479
TI  - Heterotopic bone formation in association with pelvic fracture and urethral
      disruption.
AB  - PURPOSE: The initial and secondary management of pelvic fracture associated with
      disruption of the membranous urethra is the subject of a wide literature
      containing varied and controversial viewpoints. We have noted the presence of
      heterotopic bone formation surrounding the area of urethral injury in patients
      undergoing delayed repair. We investigated the etiology, incidence and risk
      factors associated with such an injury, as well as potential means of
      prophylaxis. MATERIALS AND METHODS: We reviewed the current literature on
      heterotopic bone formation with similar traumatic injury. While instances of
      severe urethral disruption of this type are fortunately rare in children we
      describe prepubertal boys with such an injury complicated by heterotopic
      ossification. RESULTS: The incidence of heterotopic ossification reported in
      children and adolescents is 3 to 15%, which is less than 15 to 80% reported in
      adults. Risk factors associated with traumatic heterotopic ossification include
      prolonged operating time, hematoma formation, degree of bony debris, devitalized
      muscle and concomitant infection. Prophylaxis with single low dose radiation or
      nonsteroidal anti-inflammatory drugs has been shown to be effective in the
      prevention of heterotopic ossification and may be beneficial in this patient
      population. CONCLUSIONS: Heterotopic bone formation associated with severe
      traumatic injury in the presence of devitalized tissue resulting in the
      pathological formation of new bone is rare. This complication is only associated
      with the most severe pelvic fractures. Prophylaxis in these most severe cases
      with low dose radiation or nonsteroidal anti-inflammatory drugs can prevent the
      formation of heterotopic bone.

PMID- 10332480
TI  - In vitro fertilization is associated with an increased risk of hypospadias.
AB  - PURPOSE: The purpose of this study was to determine if there is an increased
      incidence of hypospadias in male offspring conceived by in vitro fertilization
      (IVF). MATERIALS AND METHODS: A retrospective institutional chart review from
      1988 to 1992 and data from the Maryland Birth Defects Registry were statistically
      analyzed to assess the risk of hypospadias with IVF. RESULTS: The data for the 5
      year period indicated a 5-fold increased risk of hypospadias after IVF, with an
      incidence of approximately 1.5% in the IVF group and 0.3% in the control group.
      The only recognized difference between the groups was maternal progesterone
      administration in the IVF group but the cause of the increased risk of
      hypospadias was unknown. The distribution of hypospadias severity was similar in
      both groups. CONCLUSIONS: Male newborns conceived by IVF have a 5-fold increased
      risk of hypospadias, which may be related to maternal progesterone
      administration, or other maternal or fetal endocrine abnormalities that may or
      may not be related to infertility. Health care providers should be aware of this
      risk so that they can properly counsel infertile couples seeking assisted
      reproduction by IVF technology.

PMID- 10332481
TI  - CD1a dendritic cells predominate in transitional cell carcinoma of bladder and
      kidney but are minimally activated.
AB  - PURPOSE: In this study, we employed similar techniques to detail dendritic cell
      subsets within bladder transitional cell carcinoma and kidney transitional cell
      carcinoma. MATERIALS AND METHODS: To identify both the CD1a+ and CD1a- antigen
      expressing dendritic cell populations we employed a double labeling technique to
      identify non-lineage-expressing leukocytes similar to that employed to isolate
      blood dendritic cells. RESULTS: Dendritic cells were found in significant numbers
      within both bladder and kidney derived transitional cell carcinoma. Almost all
      the dendritic cells among the tumor cells belonged to the CD1a+ subset of
      epithelial dendritic cells. Similar numbers of dendritic cells were observed in
      the lamina propria adjacent to the tumor. These dendritic cells belonged
      predominantly to the CD1a- subset. These differences appear to reflect the
      different dendritic cell phenotypes reported for the epidermis and dermis.
      CONCLUSIONS: The number of dendritic cells increased as the grade of the tumor
      increased, reflecting an overall higher leukocyte density in higher grade tumors.
      However, a possible trend for less dendritic cell activation in higher grade
      cancers was noted, raising the intriguing possibility that this might be a
      relevant prognostic factor, to be confirmed in a larger study.

PMID- 10332482
TI  - Co-localization of carbon monoxide and nitric oxide synthesizing enzymes in the
      human urethral sphincter.
AB  - PURPOSE: Ineffective relaxation of the urethral sphincter during micturition can
      result in obstructive voiding symptoms. Several studies suggest carbon monoxide
      (CO) acts alongside nitric oxide (NO) as an inhibitory neurotransmitter, and may
      regulate NO production. We have investigated the distribution of the constitutive
      CO producing enzyme, heme oxygenase-2 (HO-2) and the NO producing enzyme,
      neuronal nitric oxide synthase (nNOS), in the human urethra. MATERIALS AND
      METHODS: Transverse cryostat sections (12 microns.) were cut from three male
      membranous and six female urethrae. Double immunofluorescence was carried out for
      co-localization of HO-2 with nNOS using standard methodology. RESULTS: Nerve
      trunks showing both HO-2 and nNOS immunoreactivities were identified in the
      urethrae in both sexes. In the female urethrae, of 152 ganglionic cell bodies
      expressing HO-2 or nNOS immunoreactivity, 74.3% exhibited both HO-2 and nNOS
      immunoreactivities, 25% exhibited only HO-2 immunoreactivity and 0.7% exhibited
      only nNOS immunoreactivity. CONCLUSIONS: Immunoreactivity for HO-2 has been
      demonstrated in neuronal structures innervating the male and female urethral
      sphincters. The dual expression of HO-2 with nNOS immunoreactivity in cell bodies
      and nerves suggests that there is an interaction between the CO and NO generating
      systems. Abnormality in these systems may play a role in urethral dysfunction.

PMID- 10332483
TI  - Selective detection of inactivating mutations of the tumor suppressor gene p53 in
      bladder tumors.
AB  - OBJECTIVE: Mutations in the p53 gene are implicated in the pathogenesis of half
      of all human tumors. In bladder tumors they are usually detected by
      immunohistochemistry. The assumption underlying protein analysis is that high
      level p53 expression is a consequence of mutations, but numerous exceptions have
      been reported. We describe the detection of p53 mutations in bladder cancer using
      a functional assay in yeast. MATERIALS AND METHODS: The prospective study
      consisted of 60 consecutive patients with bladder tumors (7 pT0, 2 CIS, 23 pTa,
      24 pT1 and 4 pT2). High grade 3 was observed in primary carcinoma in situ, in 75%
      of pT1 tumors and in all pT2 tumors. The p53 mRNA extracted from endoscopic
      resection tissue was reverse transcribed and PCR-amplified. The transcriptional
      competence of the p53 cDNA was then tested in a yeast reporter strain. A simple
      functional assay was developed for p53 mutation in which human p53 is expressed
      in Saccharomyces cerevisiae which activates transcription of the ADE2 gene.
      Colonies containing wild type p53 are white and colonies containing mutant p53
      are red. RESULTS: As this assay evaluates the critical biological function of
      p53, it can distinguish inactivating mutations from functionally silent
      mutations. In pTo and pTa bladder tumors, no p53 mutations were detected. In
      contrast, the functional assay permitted us to detect p53 mutations in 66% of
      patients with stage T1 tumors (72% of case of high grade 3) and in all cases with
      primary carcinoma in situ and in 4 cases of stage T2 tumors. CONCLUSION: This
      preliminary study demonstrates that this functional assay method is a simple and
      efficient procedure to detect p53 mutations in bladder cancers and suggests that
      p53 mutations seem to be associated with invasive bladder tumors.

PMID- 10332484
TI  - The action mechanism of relaxation effect of atropine on the isolated rabbit
      corpus cavernosum.
AB  - PURPOSE: Atropine has been used to block cholinergic neurotransmission in basic
      research and has received recent interest clinically in the intracavernosal
      pharmacotherapy of erectile dysfunction. It has been suggested that at a low dose
      (10(-8) M), atropine blocks muscarinic receptors, and that at a large dose (10(
      3) M), it induces the release of EDRF. However, no report has supported this idea
      experimentally. We tried to confirm the action of atropine in cavernosal tissue
      and define its mechanism. MATERIALS AND METHODS: Strips of rabbit corpus
      cavernosum were mounted in organ chambers. On the precontracted muscle strips
      with phenylephrine (PHE; 5 x 10(-6) M), atropine was treated with increasing
      concentration from 10(-11) M. The relaxing activity of atropine was observed in
      deendothelialized tissue and preparation with treatment with methylene blue (10(
      4) M), pyrogallol (10(-4) M), NW-nitro-L-arginine (L-NNA; 3 x 10(-4) M) and
      indomethacin (10(-4) M). To evaluate the relationship of atropine to Ca++, the
      muscle strip was incubated in Ca++ free solution, and Ca++ induced contraction by
      addition of CaCl2 (10(-3) M) was recorded with atropine. Depolarization by KCl
      was observed with atropine to investigate the relationship of atropine relaxation
      to K+. RESULTS: On the precontracted muscle strip with PHE, atropine induced a
      dose-related contraction up to 10(-8) M and began to exert a relaxing effect at
      the concentration of 10(-7) M and reached the 93.6% relaxation effect at the
      concentration of 10(-4) M, causing dose-dependent relaxation. The relaxing effect
      of atropine was partially inhibited by endothelial disruption, and by
      pretreatment with methylene blue, pyrogallol, L-NNA, and indomethacin, although
      they were not statistically significant. At the basal state of muscle strips in
      Ca++ free solution, atropine decreased basal tension as well as inhibited the
      contraction induced by CaCl2 dose-dependently. However, atropine did not
      influence depolarization by KCl. CONCLUSIONS: Atropine has both a contraction
      effect at lower concentrations and a relaxation effect at higher concentrations
      on cavernosal smooth muscle. It is presumed that the relaxation at higher
      concentrations is mediated via increasing intracellular calcium sequestration,
      not by hyperpolarization or secretion of EDRF.

PMID- 10332485
TI  - The effects of colchicine on a Peyronie's-like condition in an animal model.
AB  - PURPOSE: We have developed an animal model of Peyronie's disease by injecting
      transforming growth factor beta (TGF-beta) into the rat penis. Our objective is
      to study the effects of colchicine on the Peyronie's condition in an animal
      model. MATERIALS AND METHODS: Thirty-six adult male Sprague-Dawley rats received
      TGF-beta injections into the tunica albuginea and were divided into two groups (n
      = 18 each). Rats in the first group were divided into three subgroups (n = 6
      each). Each rat in the three subgroups received the following: Subgroup 1
      received colchicine, subgroup 2 received ibuprofen, and subgroup 3 received
      regular water. The rats were euthanized after 6 weeks. Rats in the second group
      were also divided into three subgroups. These rats received the same treatments
      as the rats in the first group, but treatments began 6 weeks after TGF-beta
      injection. These rats were euthanized after 12 weeks. Tunical tissue samples were
      collected and examined using Hart and trichrome stains, electron microscopy (EM),
      and western blot analysis for TGF-beta detection. RESULTS: In the first group,
      the colchicine-treated rats exhibited less collagen deposition and less elastic
      fiber fragmentation than the untreated or ibuprofen-treated rats. EM confirmed
      the results and showed normal distribution and shape of both collagen and elastic
      fibers in the colchicine-treated group. In the second group, the colchicine
      treated rats exhibited less crowding of the collagen fibers. However, the elastic
      fibers remained fragmented and scarce. Western blot analysis showed significant
      down-regulation of TGF-beta expression (5/6) in the colchicine-treated group
      after 6 weeks. Down-regulation was observed in only 1/6 in both ibuprofen and non
      treated groups. After 12 weeks 2/6, 1/6, and 1/6 rats displayed down regulation
      in the colchicine treated, ibuprofen treated, and non-treated groups,
      respectively. CONCLUSION: Early colchicine treatment may suppress a Peyronie's
      like condition in the rat animal model.

PMID- 10332486
TI  - CD44 is an independent prognostic factor in conventional renal cell carcinomas.
AB  - PURPOSE: CD44 is a transmembrane glycoprotein involved in cell-cell and cell
      matrix interactions. De novo expression of CD44 and its variant isoforms has been
      associated with aggressive behavior in various tumors. Since few data are
      available concerning the role of CD44 in the biological behavior of locally
      confined renal tumors, we analyzed the expression of CD44 in a large set of
      conventional renal cell carcinomas to determine its prognostic value in
      association with other clinicopathologic variables. MATERIALS AND METHODS: Ninety
      one patients with locally confined conventional renal cell carcinomas were
      studied. CD44 standard form (CD44H) and v6 isoform expressions were
      semiquantitatively evaluated on paraffin-embedded tumor tissue by
      immunohistochemistry. The prognostic value of the usual clinicopathological
      variables and CD44 expression was tested using Kaplan-Meier plots by the log rank
      test and Cox multiple hazard regression analysis. RESULTS: No immunostaining was
      observed in normal renal tissue. Thirty-two of the 66 conventional renal cell
      carcinomas (48%) showed CD44H membranous staining of the tumor cells. Only 2
      cancers displayed CD44v6 immunostaining. Among the different clinicopathological
      variables analyzed, tumor stage (p = 0.001), nuclear grade (p = 0.01), size (p =
      0.02), vascular (p = 0.05) and perirenal adipose tissue invasion (p = 0.005), and
      CD44H expression (p = 0.01) were found to be significant prognostic parameters
      for survival using univariate analysis. Moreover, multivariate analysis indicated
      stage, nuclear grade and CD44 expression as independent prognostic factors both
      for overall and disease-free survival. CONCLUSION: CD44 can be considered as a
      useful prognostic parameter in conventional renal cell carcinoma and may be used
      in evaluation of the outcome of these tumors.

PMID- 10332487
TI  - Prevention of cyclophosphamide-induced hemorrhagic cystitis by glucose-mannose
      binding plant lectins.
AB  - PURPOSE: Neutrophils are implicated in the physiopathologic alterations of
      hemorrhagic cystitis (HC). Thus, we decided to test the antiinflammatory activity
      of glucose-mannose binding lectins extracted from D. violacea and D. guianensis
      seeds, which showed an inhibitory effect upon neutrophil migration in a model of
      rat peritonitis based on HC experimentally induced by cyclophosphamide (CYP).
      MATERIALS AND METHODS: Mice were treated with mesna (40 mg./kg., i.p.), lectins
      (1 and 10 mg./kg., i.v.) and 0.1 M of alpha-D-methyl-mannoside (alpha-CH3) or
      alpha-D-galactose (alpha-D-gal). The HC was induced by CYP (200 mg./kg., i.p.).
      The results were evaluated 12 hours after HC induction, based on the following
      parameters: vesical edema measurements, macroscopic and microscopic analysis of
      the bladders (Gray's analysis). The vesical edema was quantified either by the
      increase in bladder wet weight or by the determination of vesical vascular
      permeability (Evans' blue leakage). RESULTS: CYP-induced vesical edema was
      prevented by mesna and lectin treatment. The lectin effects were dose-dependent,
      and at the highest dose were similar to that achieved by mesna treatment. alpha
      CH3 selectively reversed the lectin inhibitory effect. Histopathological analysis
      corroborated these findings and showed an intense reduction of leukocyte
      infiltration and tissue damage by lectin treatment. The bladders from the mesna
      treated group showed a nearly normal histological pattern. However, differently
      from this group, none of the lectins abolished CYP-induced hemorrhage.
      CONCLUSIONS: The glucose-mannose binding lectins showed strong antiinflammatory
      activity in the mouse model of HC induced by CYP. As lectins mainly affected
      leukocyte vesical infiltration, we suggest a competitive blockage of glucosylated
      (mannose-glucose) selectin binding sites by lectins.

PMID- 10332488
TI  - An approach for high sensitivity detection of prostate cancer by analysis of
      changes in structuredness of the cytoplasmic matrix of lymphocytes specifically
      induced by PSA-ACT.
AB  - PURPOSE: An alternative procedure for detection of prostate cancer was examined
      based on the observation that cells reexposed in vitro to antigenic or mitogenic
      stimulation will change their intracellular structuredness as measured by
      polarization of fluorescent light emitted by labeled cells (SCM test). MATERIALS
      AND METHODS: Lymphocytes derived from patients bearing a nonmalignant prostate
      tumor and healthy individuals were exposed to PSA-ACT, PHA, and MUC-1. RESULTS:
      Of sixty-five patients with prostate carcinoma (CaP), sixty-two were correctly
      diagnosed by the test. Of the eighty males in the control group, five were
      incorrectly diagnosed as having the disease and seventy-five were correctly
      diagnosed as healthy subjects. The sensitivity of the test was 96.8%. The
      specificity was 91.1%. The BPH (Benign Prostatic Hyperplasia) control group
      exhibited a sensitivity of 9.38%, but the specificity was 91.1%. Similar
      percentages for specificity and sensitivity were observed in the NRT (Non
      Relevant Tumor) control group. CONCLUSIONS: The results shown here indicate the
      possibility of a different use of PSA-ACT for detection of prostate cancer with
      high specificity and sensitivity.

PMID- 10332489
TI  - Focal intratumoral heterogeneity for telomerase activity in human prostate
      cancer.
AB  - PURPOSE: The value of telomerase activity as a marker in clinical decision-making
      is closely related to how representative the analysis of a small tumor sample is
      for the whole tumor. We therefore evaluated the intratumoral distribution pattern
      of telomerase activity in prostatic carcinomas. MATERIALS AND METHODS: From 50
      prostate cancer patients treated with radical prostatectomy, telomerase activity
      was determined using the telomeric repeat amplification protocol (TRAP assay).
      Comparative analysis of at least two separate cancer areas from a single tumor
      was performed in 42 cases. RESULTS: Telomerase activation has been demonstrated
      in 90% of the prostatic carcinomas. Focal intratumoral heterogeneity was found in
      38.1% of the tumors with at least two different areas examined. Telomerase
      positivity of all samples from one given tumor was detected in 50%, telomerase
      negativity of all samples in 11.9%. A heterogeneous telomerase activity pattern
      was more frequently detected in tumors with a Gleason score < or = 7 than in
      those with a Gleason score > 7. Furthermore, there was an increase in the
      proportion of homogeneously telomerase-positive tumors with increase in severity
      of the Gleason score. The differences reached statistical significance.
      Telomerase activity was also detected in non-cancerous prostatic tissue samples.
      CONCLUSIONS: Telomerase activation is nearly ubiquitous in prostatic carcinomas,
      although a heterogeneous telomerase activity pattern within tumors might produce
      a false-negative result in the telomerase activity assay. This limits the value
      of telomerase activity assays for diagnostic means. There is evidence for a shift
      from telomerase-negative prostate cancer tissue toward telomerase positivity
      during the progression process of prostate cancer. The relatively high proportion
      of telomerase-positive nonmalignant prostatic tissue samples argues against
      cancer-specificity of telomerase activation.

PMID- 10332490
TI  - Alpha 1-adrenoceptor antagonists terazosin and doxazosin induce prostate
      apoptosis without affecting cell proliferation in patients with benign prostatic
      hyperplasia.
AB  - PURPOSE: Recent evidence indicated that an alpha 1 blocker, doxazosin, induces
      prostate apoptosis in patients with benign prostatic hyperplasia (BPH). In this
      study, to determine whether this apoptotic response was mediated by alpha 1
      adrenoceptor-dependent mechanism or was specific to doxazosin, we examined the
      effect of another alpha 1 blocker, terazosin, in addition to doxazosin, on the
      dynamics of prostate cell growth. MATERIALS AND METHODS: Cell proliferation and
      apoptosis were evaluated in BPH patients, an untreated (control) group (n = 31),
      and men treated with terazosin (n = 42) and doxazosin (n = 61) for the relief of
      the obstructive symptoms. Terazosin (1 to 10 mg./day) and doxazosin (2 to 8
      mg./day) treatment varied from 1 week to 3 years. Ki-67 immunostaining and the
      TUNEL assay were used to evaluate the proliferative and apoptotic indices,
      respectively, in both the epithelial and stromal components of prostate (biopsy
      and prostatectomy) specimens. The smooth muscle cell content of the prostatic
      stroma was identified on the basis of smooth muscle alpha-actin immunoreactivity.
      RESULTS: A significant induction of apoptosis was observed in both the prostatic
      epithelial and stromal cells within the first month of terazosin and doxazosin
      therapy, as compared with untreated controls (p < 0.05). Furthermore, the marked
      induction of prostatic stroma apoptosis in response to both alpha 1 adrenoceptor
      antagonists was paralleled by a significant decrease in the smooth muscle alpha
      actin expression. This loss of prostatic smooth muscle cells correlated with
      morphological stromal regression (as detected by trichrome staining) and BPH
      symptom improvement. Neither terazosin nor doxazosin therapy resulted in
      significant changes in prostate cell proliferation. CONCLUSIONS: These findings
      demonstrate that alpha-blockers as a class may regulate prostate growth by
      inducing apoptosis in both the epithelial and stromal cells, with little effect
      on cell proliferation. Apoptosis-mediated prostate stromal regression appears as
      a molecular mechanism underlying the therapeutic response to alpha 1 blockade in
      the treatment of BPH.

PMID- 10332491
TI  - Different molecular forms of uncomplexed prostate specific antigen (PSA) show
      similar immunoreactivities.
AB  - PSA exists in multiple molecular forms in serum, with the majority complexed to
      proteinase inhibitors such as alpha 1-antichymotrypsin and alpha 2-macroglobulin.
      The uncomplexed, or "free" forms of PSA represent a very heterogenous
      distribution of molecular isoforms. It has been suggested that these variations
      in uncomplexed PSA may cause differences in their immunologic characteristics
      which may lead to analytical differences between various PSA assays. We report
      that various isoforms of uncomplexed PSA purified from seminal fluid as
      previously described show no differences in relative immunoreactivity and
      demonstrate equimolar behavior as measured by the TOSOH AIA-600 assay, which is a
      PSA assay based upon monoclonal PSA and monoclonal detecting antibodies (mono
      mono). Furthermore, we show that carbohydrate side-chain modification does not
      change the equimolar immunoreactivity of these isoforms.

PMID- 10332492
TI  - Induction of penile erection by intracavernosal and transurethral administration
      of novel nitric oxide donors in the cat.
AB  - PURPOSE: The effects of novel nitric oxide (NO) donors administered
      intracavernosally and transurethrally on erectile function in the anesthetized
      cat were evaluated. MATERIALS AND METHODS: In pentobarbital-anesthetized cats,
      increases in intracavernosal pressure, penile length, and duration of erectile
      response were determined after intracavernosal and transurethral injections of
      novel NO donors (MAHMA/NO, PAPA/NO, DEA/NO, PIPERAZI/NO and PROLI/NO). All
      parameters were measured after administration of NO donors intracavernosally via
      a 30-gauge needle and urethrally via a Jelco i.v. catheter in a volume of 200
      microliters. Systemic arterial pressure was also assessed in these experiments.
      All NO donors were compared with a triple-drug control combination comprised of
      papaverine (1.65 mg.), prostaglandin E1 (0.5 microgram.), and phentolamine (25
      micrograms.). RESULTS: MAHMA/NO, PAPA/NO, DEA/NO, PIPERAZI/NO and PROLI/NO
      induced dose dependent increases in intracavernosal pressure and penile length (p
      < 0.05) when administered intracavernosally. The increases in cavernosal pressure
      and penile length were comparable to those observed with the triple-drug control
      combination. The maximum increase in cavernosal pressure in response to PROLI/NO
      and PAPA/NO was associated with no significant change in systemic arterial
      pressure. Transurethral administration of PROLI/NO and PIPERAZI/NO induced dose
      dependent increases in cavernosal pressure and penile length (p < 0.05). The
      response was similar to that of the triple-drug control combination, except that
      transurethral PROLI/NO and PIPERAZI/NO had no significant effect on systemic
      blood pressure. CONCLUSIONS: NO donors caused dose-dependent increases in
      cavernosal pressure when administered intracavernosally and transurethrally.
      These data suggest further exploration of the use of NO donors for the treatment
      of erectile dysfunction.

PMID- 10332494
TI  - American Society for Artificial Internal Organs 45th annual conference. San
      Diego, California, USA. June 2-5, 1999. Abstracts.

PMID- 10332493
TI  - Stroke and incontinence.

PMID- 10332495
TI  - 667th meeting. University of Leicester. Abstracts.

PMID- 10332496
TI  - American Burn Association 31st annual meeting. Lake Buena Vista, Florida, USA.
      March 24-27, 1999. Abstracts.

PMID- 10332497
TI  - SCVIR99. 24th annual meeting of the Society of Cardiovascular and Interventional
      Radiology. Orlando, Florida, USA. March 20-25, 1999. Proceedings and abstracts.

PMID- 10332499
TI  - German Society for Experimental and Clinical Pharmacology and Toxicology. 40th
      Spring meeting. Mainz, Germany, 9-11 March 1999. Abstracts.

PMID- 10332498
TI  - 50th annual meeting of the Society for Natural Immunity. 17th International
      Natural Killer Cell Workshop. Warrenton, Virginia, USA. October 17-21, 1998.
      Abstracts.

PMID- 10332500
TI  - Therapeutic strategies involving the multidrug resistance phenotype: the MDR1
      gene as target, chemoprotectant, and selectable marker in gene therapy.

PMID- 10332501
TI  - The diversity of calcium channels and their regulation in epithelial cells.

PMID- 10332502
TI  - Gene therapy and vascular disease.

PMID- 10332503
TI  - Heparin in inflammation: potential therapeutic applications beyond
      anticoagulation.
AB  - In this chapter we have described anti-inflammatory functions of heparin distinct
      from its traditional anticoagulant activity. We have presented in vivo data
      showing heparin's beneficial effects in various preclinical models of
      inflammatory disease as well as discussed some clinical studies showing that the
      anti-inflammatory activities of heparin may translate into therapeutic uses. In
      vivo models that use low-anticoagulant heparins indicate that the anticoagulant
      activity can be distinguished from heparin's anti-inflammatory properties. In
      certain cases such as hypovolemic shock, the efficacy of a low-anticoagulant
      heparin derivative (GM1892) exceeds heparin. Data also suggest that
      nonconventional delivery of heparin, specifically via inhalation, has therapeutic
      potential in improving drug pharmacokinetics (as determined by measuring blood
      coagulation parameters) and in reducing the persistent concerns of systemic
      hemorrhagic complications. Results from larger clinical trials with heparin and
      LMW heparins are eagerly anticipated and will allow us to assess our predictions
      on the effectiveness of this drug class to treat a variety of human inflammatory
      diseases.

PMID- 10332504
TI  - The regulation of epithelial cell cAMP- and calcium-dependent chloride channels.
AB  - This chapter has focused on two types of chloride conductance found in epithelial
      cells. The leap from the Ussing chamber to patch-clamp studies has identified yet
      other conductances present which have also been electrophysiologically
      characterized. In the case of the swelling activated wholecell chloride current,
      a physiological function is apparent and a single-channel basis found, but its
      genetic identity remains unknown (see reviews by Frizzell and Morris, 1994; and
      Strange et al., 1996). The outwardly rectified chloride channel has been the
      subject of considerable electrophysiological interest over the past 10 years and
      is well characterized at the single-channel level, but its physiological function
      remains controversial (reviewed by Frizzell and Morris, 1994; Devidas and
      Guggino, 1997). Yet other conductances related to the CLC gene family also appear
      to be present in epithelial cells of the kidney (reviewed by Jentsch, 1996;
      Jentsch and Gunter, 1997) where physiological functions for some isoforms are
      emerging. Clearly, there remain many unknowns. Chief among these is the molecular
      basis of GCa2+Cl and many of other the conductances. As sequences become
      available it is expected that the wealth of information gained by investigation
      into CFTR function will provide a conceptual blueprint for similar studies in
      these later channel clones.

PMID- 10332505
TI  - Calcium channel blockers: current controversies and basic mechanisms of action.

PMID- 10332506
TI  - Mechanisms of antithrombotic drugs.

PMID- 10332507
TI  - Assessment of the U.S. Environmental Protection Agency methods for identification
      of hazards to developing organisms, Part I: The reproduction and fertility
      testing guidelines.
AB  - BACKGROUND: Successful reproduction depends on the coordination of many
      processes, particularly the normal development and subsequent maturation of the
      sexual organs. The Food Quality Protection Act of 1996 mandates that the U.S.
      Environmental Protection Agency must protect infants and children from the
      effects of toxins, including those that affect the reproductive system.
      Therefore, the Agency finds itself at a critical juncture to make sure that the
      methods it requires for toxicity testing, the Health Effects Test Guidelines or
      Series 870 Guidelines, are adequate to determine possible toxicity to children.
      METHODS AND RESULTS: We found that two testing protocols included in the core
      guidelines assess toxicological effects on developing animals. This article aims
      to provide a detailed analysis of the protocols included in the Reproduction and
      Fertility Effects Test Guideline. An accompanying article assesses the
      Developmental Toxicity Testing Guideline. We conducted this analysis on the basis
      of whether the test would yield the information needed to adequately determine
      risk to infants and children. CONCLUSIONS: Our analysis concludes that given the
      limitations inherent in testing for reproduction and fertility effects during
      development, it is necessary to include a safety factor during risk assessment of
      chemicals. This action will fulfill the mandate expressed in the FQPA to protect
      infants and children from environmental hazards.

PMID- 10332508
TI  - Assessment of the U.S. Environmental Protection Agency methods for identification
      of hazards to developing organisms, Part II: The developmental toxicity testing
      guideline.
AB  - BACKGROUND: The effects of toxins on developing animals depend not only on the
      nature of the chemical but also on the timing of exposure and assessment of
      outcomes. This complicates the task of regulatory agencies such as the U.S.
      Environmental Protection Agency (EPA), which must comply with the 1996 Food
      Quality Protection Act to ensure that their standards and policies protect
      infants and children from environmental toxins. For this task, the Agency relies
      heavily on scientific data obtained by manufacturers of industrial chemicals and
      pesticides following protocols collected under EPA's Health Effects Test
      Guidelines. METHODS AND RESULTS: This article reviews the protocols included in
      the EPA guidelines to assess developmental toxicity, which are required for food
      use pesticides under the core testing battery. We reviewed these protocols on the
      basis of their adequacy for identifying hazards to infants and children. Our
      analysis found limitations in the protocols that hinder their potential for
      identifying developmental hazards. CONCLUSIONS: Methods that the EPA currently
      depends upon to identify developmental toxicity of chemicals have limitations
      that impede obtaining complete and reliable data on which to base regulatory
      decisions that protect children. Other methodological approaches need to be
      explored as alternatives or supplements to the current protocols. Until more
      accurate testing protocols become available, it may well be necessary under
      existing laws to employ safety factors that are more protective of the health of
      children at all stages of development.

PMID- 10332509
TI  - Design of a state-based workers' compensation information system.
AB  - BACKGROUND: California policy makers have long been hampered by a lack of
      credible information for use in making legislative or administrative changes to
      address serious problems in the workers' compensation system. In 1993, the
      legislature directed the California Division of Workers' Compensation to develop
      a Workers' Compensation Information System (WCIS). METHODS: An advisory committee
      developed key questions and identified data sources regarding injury/illness
      incidence, costs, promptness of benefit delivery, adequacy of benefits,
      satisfaction with services, and other outcomes. RESULTS: Key data elements were
      identified, mostly from existing mandated reporting forms for employers and
      physicians, and from standardized medical billings. Data collection will be
      carried out using: 1) rapid electronic data interchange (EDI) for a minimum
      number of data elements; 2) electronic collection of data on medical services for
      a sample of claims; and 3) surveys to address adequacy of benefits, satisfaction
      with services, return to work, and other outcomes. A state-based repository will
      analyze data and provide de-identified public use data files. CONCLUSIONS: The
      proposed WCIS will provide information to improve the performance and to increase
      the accountability of all the participants in California's Workers' Compensation
      system. More importantly, it will provide information which will allow improved
      quality in the provision of mandated benefits to injured workers.

PMID- 10332511
TI  - Exposures to wood dust in U.S. industries and occupations, 1979 to 1997.
AB  - BACKGROUND: We analyzed 1,632 measurements of airborne wood dust reported to
      OSHA's Integrated Management Information System in the period 1979 to 1997.
      METHODS: The relationships between wood dust concentrations and various factors
      documented in the OSHA database were examined in a multiple regression model.
      RESULTS: Exposures ranged from less than 0.03 to 604 mg/m3, with an arithmetic
      mean of 7.93 and a geometric mean of 1.86. Reported exposure levels decreased
      substantially over time (e.g., unadjusted geometric mean in 1979 = 4.59 mg/m3; in
      1997 = 0.14 mg/m3). High exposure jobs included sanders in the transportation
      equipment industry (unadjusted geometric mean = 17.5 mg/m3), press operators in
      the wood products industry (12.3 mg/m3), lathe operators in the furniture
      industry (7.46 mg/m3), and sanders in the wood cabinet industry (5.83 mg/m3).
      CONCLUSIONS: In the multiple regression model, year, state, job, and industry
      were found to be predictors of exposure. Year and state were likely surrogates
      for other factors which directly influence exposure, but which were not included
      in the IMIS database, such as the use of engineering control measures.

PMID- 10332510
TI  - Zinc exposure in Chinese foundry workers.
AB  - BACKGROUND: Inhalational exposure to zinc oxide fumes is associated with metal
      fume fever, a self-limited but very uncomfortable condition closely resembling
      influenza. Very little is known regarding the toxicokinetics of inhaled zinc,
      making the interpretation of zinc measurements in serum and urine problematic.
      METHODS: Twenty workers in a zinc foundry in Baiyin, Peoples' Republic of China,
      were investigated with serial examinations by a physician, chest radiographs, and
      spirometry. Exposure assessment consisted of the measurement of zinc in serum,
      urine, and personal air samples. RESULTS: No cases of metal fume fever were
      observed during the study period despite exposures to as high as 36.3 mg/m3 over
      less than 4 hr. In addition, no radiographic or functional changes were noted.
      Serum zinc levels of all workers were within the reference range and did not
      correlate with external exposure measurements. However, elevations were noted in
      urinary zinc levels, which showed a significant association (Spearman's
      correlation coefficient = 0.47, P = 0.04) between exposure to zinc and urine
      zinc. CONCLUSIONS: These results provide exposure measurements for zinc at which
      workers demonstrate tolerance to the development of metal fume fever.
      Furthermore, they suggest that urine may be the preferred biological medium for
      the assessment of zinc exposure.

PMID- 10332512
TI  - Lung function disturbances and chest X-ray abnormalities among marine engineers.
AB  - BACKGROUND: The purpose of the study was to investigate to what extent marine
      engineers who are exposed to mineral oil mist in the engine rooms of ships have
      lung function disturbances and chest X-ray abnormalities. METHODS: A previous
      study examined a cohort of 492 seamen from which we received 169 full-scale (40 x
      40 cm) chest radiographs. Among these films were 68 from marine engineers and 101
      from seamen who had never worked as engineers (controls). Spirometric data were
      obtained from 44 engineers and from 71 of the controls. The chest X-rays were
      classified independently by two certified B-readers, using the ILO
      classification. RESULTS: Only 7% of the seamen had parenchymal or pleural
      changes. The only statistically significant difference between the two groups for
      the chest X-ray findings was for all comments made by the ILO readers which were
      termed "any symbol" (9.3% for the engineers and 0.6% for the controls; RR = 14.6
      (95% CI 1.1-75.5)) and the FEV% (FEV1/FVC x 100) for the spirometric values (82.8
      (SD = 10.8) for the engineers and 86.6 (SD = 8.0) for the controls; P = 0.03).
      CONCLUSIONS: The results of the study indicate a slight lung function impairment
      and an increase in chest X-ray abnormalities, other than small opacities, among
      the marine engineers.

PMID- 10332513
TI  - Relationship of blood lead levels to personal hygiene habits in lead battery
      workers: Taiwan, 1991-1997.
AB  - BACKGROUND: The blood lead concentrations of workers in lead battery factories
      are more than 4 times higher than those of the general population in Taiwan.
      Therefore, efforts are needed to reduce lead exposure in this high-risk
      population. A health promotion program on personal habits that reduce lead
      exposure has been carried out in a lead battery factory since 1991. This study
      investigated the longitudinal relationship of workers' blood lead concentrations
      and personal hygiene habits from 1991 through 1997. METHODS: In each of the 7
      years of the study, occupational physicians questioned workers regarding nine
      personal hygiene items, personal information, and medical history before their
      annual health examination. The relationship between blood lead concentrations and
      personal hygiene habits was analyzed by longitudinal multiple regression in a
      mixed effect model with adjustment for potential confounders. In addition, the
      risk ratio of a blood lead concentration exceeding 40 micrograms/dL in men and 30
      micrograms/dL in women (the action levels set by the Department of Health,
      Taiwan) was estimated by generalized estimating equations. RESULTS: Blood lead
      levels decreased significantly in the first 5 years of the study. The personal
      habits most closely related to blood lead concentrations were smoking at work
      sites (estimated coefficient = 3.13, P < 0.001), and eating at work sites
      (estimated coefficient = 1.38, P = 0.069). The risk ratio for workers with both
      these habits exceeding the action level of blood lead was 2.93 (95% CI 1.27
      6.77). Difference in job titles, however, accounted for a major portion of the
      variance in blood lead. For example, working in "pasting" and "plate-cutting" was
      associated with blood lead elevations > 20 micrograms/dL in comparison to the
      "low- or no-exposure jobs." CONCLUSIONS: Health promotion programs can decrease
      exposure of lead workers; reducing the practices of smoking and eating at work
      sites should be the core of such programs. However, a major reduction in lead
      exposure for some jobs (e.g., "pasting" and "plate cutting") in lead battery
      factories in Taiwan is unlikely to occur without major engineering changes.

PMID- 10332515
TI  - Duration of work disability after low back injury: a comparison of administrative
      and self-reported outcomes.
AB  - BACKGROUND: Workers' compensation wage replacement data have recently been used
      to estimate time to return to work (RTW) and the number of work days lost after
      occupational injury. The degree to which indemnity-based measures reflect self
      reported work disability has until now not been studied. METHOD: Kaplan-Meier
      curves of administrative and self-reported measures of duration of work
      disability were compared within a sample of 433 low back injury claimants
      followed up for 1 to 3.7 years. RESULTS: Administrative measures consistently and
      significantly underestimated the duration of disability when compared to self
      reported measures of RTW. The difference between the estimated mean number of
      work days lost for comparable administrative and self-reported measures ranged
      from 142 to 334 days. CONCLUSIONS: Number of work days lost after low back injury
      is substantially underestimated by measures based on the duration of wage
      replacement benefits. This calls into question the adequacy of indemnity benefits
      and underscores the need for disability prevention programs.

PMID- 10332514
TI  - Alternative approaches for measuring duration of work disability after low back
      injury based on administrative workers' compensation data.
AB  - BACKGROUND: Studies of low back pain (LBP) disability remain largely incomparable
      because of different outcome definitions. To date, systematic comparisons of
      alternative outcome measures have not been made. METHODS: Duration of work
      disability was studied in a 3-year cohort of 850 workers' compensation LBP
      claimants. Eleven administrative outcome measures were compared using Kaplan
      Meier estimates of the proportion of claimants still on disability benefits
      during 3.5 years of follow-up. RESULTS: The estimated mean duration of work
      disability was 75 days for the first temporary disability (TD) episode, 108 days
      for cumulative time on TD, and 337 for total compensated days, which includes all
      types of wage replacement benefits during vocational rehabilitation, temporary
      and permanent disability. CONCLUSIONS: Commonly used administrative measures of
      lost workdays--time to first return to work and time on temporary disability-
      substantially underestimate the duration of work disability compared to measures
      based on all wage replacement benefits.

PMID- 10332516
TI  - Long-term exposure to wood-preserving chemicals containing pentachlorophenol and
      lindane is related to neurobehavioral performance in women.
AB  - BACKGROUND: The adverse neurobehavioral effects of long-term low exposure to wood
      preserving chemicals (WPC) containing solvents, pentachlorophenol (PCP) and gamma
      hexachlorocyclohexane (gamma-HCH; lindane), and other neurotoxicants were
      investigated in a neuropsychological group study. METHODS: Out of a population of
      2,000 women visiting the outpatient practice of a gynecological department, a
      sample of 15 women aged 31-56 (mean 43) with long-term exposure to WPC verified
      by self-report, biological monitoring, and environmental samples was
      investigated. Fifteen controls aged 42 (31-56) years were drawn from the same
      population and pair-wise matched with respect to sex, age, education, and
      estimated intelligence. RESULTS: For the exposed group, mean PCP serum level was
      43.6 micrograms/l and mean gamma-HCH blood level was 0.085 microgram/l. Mean
      duration of exposure was 10 (5-17) years. Intellectual functioning, attention,
      memory, and visuo-motor performance were examined, suggesting significant group
      differences in visual short-term memory (Benton Test; d = 1.5, P = .005), verbal
      memory (paired associate learning and Peterson paradigm; d = 4.3 and 1.6, P <
      .001), and an incidental learning task (d = 2.3; P = .001). Frequent subjective
      complaints as assessed by questionnaire were attenuated motivation (d = 1.7; P =
      .001), increased fatigue (d = 1.6; P = .001), distractibility (d = 1.0; P =
      .003), and depressed mood (d = 1.9; P = .004). PCP blood level was significantly
      associated with paired-associate learning, Benton Test, and reading/naming speed.
      CONCLUSIONS: Long-term low-dose exposure to WPC in the domestic environment could
      be related to subjective complaints (attention, mood, and motivation) and to
      subtle alterations of neurobehavioral performance (e.g., working memory) in
      women.

PMID- 10332517
TI  - Chromosome aberrations in operating room personnel.
AB  - BACKGROUND: Long-term occupational exposure to volatile anesthetic agents may
      result in various adverse health effects. Additionally, certain surgical
      procedures involve exposure to the other agents such as X rays. Identification of
      chromosome damages in peripheral blood lymphocytes serves as a useful indicator
      of exposure to mutagenic agents. METHODS: The frequency of chromosomal
      aberrations was assayed in peripheral lymphocytes obtained from 129 subjects
      working in operating theatres and 41 control subjects. RESULTS: The results show
      an increased rate of chromosome aberrations in the exposed subjects. The
      differences in frequency of chromosome aberrations between particular job tasks
      were not distinct. Acentric fragments in anesthesiologists and dicentrics in
      surgeons seem to stand out. CONCLUSIONS: As the findings do not differ
      significantly between the exposed groups, one can hardly distinguish radiation
      and anesthetics effects from one another.

PMID- 10332518
TI  - Effect of four computer keyboards in computer users with upper extremity
      musculoskeletal disorders.
AB  - Eighty computer users with musculoskeletal disorders participated in a 6-month,
      randomized, placebo-controlled trial evaluating the effects of four computer
      keyboards on clinical findings, pain severity, functional hand status, and
      comfort. The alternative geometry keyboards tested were: the Apple Adjustable
      Keyboard [kb1], Comfort Keyboard System [kb2], Microsoft Natural Keyboard [kb3],
      and placebo. Compared to placebo, kb3 and to a lesser extent kb1 groups
      demonstrated an improving trend in pain severity and hand function following 6
      months of keyboard use. However, there was no corresponding consistent
      improvement in clinical findings in the alternative geometry keyboard groups
      compared to the placebo group. Overall, there was a significant correlation
      between improvement of pain severity and greater satisfaction with the keyboards.
      These results provide evidence that keyboard users may experience a reduction in
      hand pain after several months of use of some alternative geometry keyboards.

PMID- 10332519
TI  - Interpreting the female excess among births to women with adverse chemical or
      occupational exposures.

PMID- 10332520
TI  - Ultrastructural analysis of folliculogenesis in the ovary of the yellow spotted
      stingray, Urolophus jamaicensis.
AB  - The ovary of the yellow spotted ray, Urolophus jamaicensis, is embedded in the
      epigonal gland, a lymphomyeloid organ. The covering of the ovary is composed of a
      germinal epithelium that is cuboidal and dome-shaped with microvilli. Adjacent
      cells have elaborate intercellular folds that create dilated intercellular
      spaces. In previtellogenic follicles, the follicle cells are simple cuboidal and
      contain modest amounts of synthetic or transport organelles. As vitellogenesis
      proceeds, the epithelium becomes multilaminar. Follicle cells are columnar as
      yolk precursors are transported from the maternal circulation, through the
      follicle cell cytoplasm, to the oocyte. Large, round cells occur in the follicle
      wall that contain lipid-like substances. These cells decrease in size and number
      as folliculogenesis proceeds and eventually disappear prior to ovulation.
      Columnar follicular cells and the oocyte have cellular extensions that impinge
      upon the zona pellucida. Transosomes are follicle cell extensions that indent the
      oocyte membrane. Tips of transosmes become enclosed by a layer of oocyte
      plasmalemma. The tips of transosomes pinch off and become resident in the
      ooplasm. Dense staining material occurs on the inner surface of the transosome
      membrane derived from the follicle cell. In Other animals, this material has been
      described as ribosome-like. This study is the first to document the presence of
      transosomes in a group other than Aves or reptiles. Follicle cells are supported
      by an extremely thick basal lamina. Subjacent to the lamina is the vascularized
      theca with fibroblasts embedded in a collagenous network. There is no
      differentiation into definitive theca interna and externa. In vitellogenic eggs,
      extensive inward folding of the follicular epithelium occur thereby generating
      more surface area for the transport of yolk precursors to the oocyte. Atretic
      follicles are common.

PMID- 10332521
TI  - Immunocytochemical study of parafollicular (C) cells of the thyroid in some wild
      rodents.
AB  - Studies were done on 3 wild species of rodents: field voles (Microtus agrestis,
      Linnaeus 1761), bank voles (Clethrionomys glareolus, Schreber 1780), and forest
      mice (Apodemus flavicollis, Melchior 1834). Immunocytochemical reactions were
      used to detect calcitonin (CT), calcitonin gene-related peptide (CGRP), neuron
      specific enolase (NSE), chromogranin A (CgA) in the thyroid parafollicular (C)
      cells in all species examined. Antisera to human CT, rat CGRP, bovine CgA, rat
      NSE and human NSE give probably a positive reaction in all C cells in the rodents
      examined. However, in the NSE determining reaction, much feebler positive C cells
      were observed. Individual variation in respect of shape and distribution of C
      cells was observed in all species. In forest mice the C cells resembled in shape
      the C cells previously described in mouse and rat. In field voles and bank voles
      the C cells were assembled into small groups more often than in forest mice.
      Antibodies (anti-human CT, anti-rat CGRP, anti-bovine CgA, anti-rat NSE and anti
      human NSE) used by us were good markers of C cells in the thyroids of the 3
      species of free-living rodents examined.

PMID- 10332522
TI  - [Preferential direction of collagen fibrils in the sub-chondral bone bone and the
      hip and shoulder joint].
AB  - We hypothesised that--due to bending and tension--there should exist a
      preferential direction of the collagen fibrils in the subchondral bone of the
      concave components of the hip and shoulder joint that results from bicentric or
      eccentric loading, but there should be no preferential direction in the convex
      joint partners. We therefore examined 25 human hip and 27 shoulder joints, these
      being decalcified after maceration. To analyse the preferential direction of the
      collagen fibrils, we used the split line method. The subchondral plate was
      pierced at regular intervals with needles that had been previously dipped in
      diluted ink. In the acetabulum, we found a predominantly transverse direction of
      the split lines in the ventral and dorsal horn of the lunatic surface, and these
      usually continued through the acetabular fossa. In the ventral part of the
      acetabular roof, arch-like orientations of the split lines were observed. In the
      glenoid cavity, a clearly preferential orientation was found in anterior
      posterior direction, usually in the middle third of the articular surface. In the
      femoral and humeral heads, no preferential direction of the split lines was
      observed in any of the specimens. We interpret the split-line patterns in the
      acetabulum as an expression of the tensile stress that is encountered during a
      "spreading open" of the socket upon bicentric (ventral-dorsal) loading in the
      physiologically incongruous joint. In the glenoid, the relatively weak bony
      support in the ventral and dorsal part of the articular surface may be
      responsible for bending and tensile stress, particularly in view of eccentric
      loading during dynamic activity, and this could explain the observed anterio
      posterior split line pattern. The results support the idea that the subchondral
      bone of concave joint partners encounters tension, leading to a preferential
      direction of the collagen fibrils. This can be considered as a functional
      adaptation of the subchondral bone on a microstructural level.

PMID- 10332523
TI  - [Sex-specific analysis of bone mass in normal and growth hormone transgenic mice
      using dual energy x-ray absorptiometry (DXA)].
AB  - The aim of the present study was the non-invasive, sex-specific measurement of
      bone mass in bovine growth hormone (bGH) transgenic mice and normal controls with
      dual energy X-ray absorptiometry (DXA). The transgenic mouse constitutes a
      suitable animal model to study the influence of growth hormone on the skeletal
      system. We analysed 28 animals, aged 12 weeks (14 transgenic, 14 controls, 7 male
      and 7 female, respectively), using a peripheral DXA scanner that had been adapted
      to the measurement of small animals. At a measurement time of 20 min, the
      precision (RMS average CV%) was 4.4% for bone mass (BMC), 2.5% for areal bone
      density (BMD), 0.86% for total body weight and 4.5% for the percentage BMC
      (relative to body weight). While the absolute bone mass was not significantly
      different between male and female animals, we found a higher percentage of the
      BMC relative to the total bone mass in females (+21% in controls, +31% in
      transgenics; p < 0.01). The absolute bone mass was higher in the transgenic
      animals (+71% in females and +62% in males; p < 0.01), but relative to the body
      weight the transgenic females yielded similar and the transgenic males lower
      values (-7.2%; p < 0.05). Using DXA it is possible to non-invasively determine
      the mass of mineralised tissue in the mouse with relatively high precision and to
      effectively discriminate between different groups. Although a strong influence of
      growth hormone on the absolute bone mass is observed, the results show that this
      increase is not higher than that of the total body mass.

PMID- 10332524
TI  - Distribution of sensory receptors in joints of the upper cervical column in the
      laboratory marsupial monodelphis domestica.
AB  - In order to investigate the sensory innervation, the upper cervical spine of a
      small laboratory marsupial (monodelphis domestica) was examined with serial
      section light microscopy and re-embedding of selected sections for electron
      microscopy. Large numbers of free nerve endings supplied by A delta- and C-fibres
      were found in the longitudinal ligaments and facet joint capsules. Electron
      microscopically, areas of direct contact between axon and collagen fibres of the
      surrounding connective tissue separated only by the basal lamina were observed.
      Such structural adaptations suggest mechanoreceptive or polymodal nociceptive
      functions. In addition, about 100 small lamellated corpuscles were found in the
      longitudinal ligaments mainly concentrated around the first intervertebral disk.
      Electron microscopy shows finger-like processes extending from the axon terminal
      into the inner core lamellae. These are the likely sites of the mechanoelectric
      transduction process. Smaller numbers of lamellated corpuscles were seen in the
      lower intervertebral disks and facet joint capsules. Lamellated corpuscles are
      known to function as rapidly adapting mechanoreceptors supplementing information
      supplied by muscle spindles to the CNS about position and movement of the
      cervical spine.

PMID- 10332525
TI  - The subarcuate canaliculus and its artery--a radioanatomical study.
AB  - The anatomy of the subarcuate canaliculus (SAC), subarcuate fossa (SAF) and
      subarcuate artery (SAA) was studied in 12 cadavers and 35 dry temporal bones.
      Each cadaver was scanned with high resolution CT (HRCT) prior to microdissection.
      The SAC was always found to be a single canal located between the two arcs of the
      anterior semicircular canal in both microdissections and HRCT scans and the
      internal acoustic meatus was observed to be located just inferior to the SAC. The
      SAC was on average of 9.2 mm in length and 1 mm in width. The SAF was situated at
      a distance of 4.2 mm from the internal acoustic meatus, 3.5 mm from the groove
      for the superior petrosal sinus, 6.7 mm from the opening of the vestibular
      canaliculus and 11.5 mm from the most superior part of the jugular foramen. The
      SAA was found to originate from the anterior inferior cerebellar artery in 9
      cadavers and from the internal auditory artery in 3 cadavers. The SAA always
      emerged from the main artery outside the internal acoustic meatus. It ran through
      the SAC as a single artery. This study investigated CT correlated anatomical
      aspects of the subarcuate canaliculus and its artery which is claimed to be
      responsible for the blood supply of the mastoid antrum, facial canal and bony
      labyrinth.

PMID- 10332526
TI  - Communication between the axillary and radial nerves in the human upper arm.
AB  - The communication between the axillary (Ax) and the radial (R) nerves, which was
      observed in eight upper arms from 602 arms of 301 Japanese cadavers, was studied
      to determine its origin and distribution. The brachial plexus and spinal segments
      contributing to the Ax and R in all cases where communication occurred had no
      distinct differences from those in cases having no communication. According to
      the direction, the communication is divided into two groups: the communication
      from the Ax to R (7 cases) and vice versa (2 cases). One specimen had both groups
      of communication. The origin of communicating branches in these groups extended
      into the overlapping area (C5 + 6) of the origin of the Ax with that of the R,
      mainly from the ventral layer of the posterior cord from C6. The distribution of
      the communicating branch varied in development according to specimens. The
      communication from the Ax to R has a tendency to invade, from proximally to
      distally, the distribution of the muscular branches of the R to the radial
      extensor muscles of the forearm including the supinator muscle. However, the
      development into the cutaneous branches has no distinct inclination. These
      findings in humans and some other comparative anatomical descriptions show that
      in phylogeny the radial extensor muscles of the forearm have a different origin
      from other extensor muscles of the forearm and have a close relationship with the
      Ax. Therefore, the communication between the Ax and R holds an important clue in
      clarifying the morphological significance of the extensor nerves and muscles of
      the forearm.

PMID- 10332527
TI  - Studies on the vasa vasorum of the human renal artery.
AB  - The transplantation of a donor kidney is currently the treatment of choice for
      terminal renal insufficiency. However, major postoperative problems may be caused
      by vascular complications. It was therefore decided to look for possible
      correlations between these vascular problems and the arterial wall supply. The
      following methods were used to elucidate the origin and distribution of nutrient
      vessels: 1. Injection of the abdominal aorta with resin in three fresh cadavers.
      2. The precise microscopic location of the branches originating from the renal
      arteries in eighteen autopsy subjects. 3. Abdominal angiography and selective
      angiography of the first left lumbar artery and left renal artery in one patient.
      It was found that the renal artery receives its blood supply from both internal
      and external nutrient vessels. The external vascular supply of the renal arterial
      wall originates from the aorta itself, from the inferior suprarenal artery (which
      sometimes has connections with the first and/or second lumbar artery) or from the
      diffuse vascular system of the retroperitoneal space. Because of the variety in
      number, course and origin of these nutritional vessels, an ideal point for the
      anastomosis of the renal artery cannot be indicated.

PMID- 10332528
TI  - Physician over-the-counter drug prescribing patterns: an analysis of the National
      Ambulatory Medical Care Survey.
AB  - OBJECTIVE: To describe the prevalence of physician over-the-counter (OTC) drug
      prescribing in relation to selected physician, patient, and drug characteristics.
      DATA SOURCE AND METHODS: Data from the 1990 National Ambulatory Medical Care
      Survey, a multistage probability clustered sample, were analyzed. Physician drug
      utilization was expressed in drug mentions defined as "the physician's entry of a
      pharmaceutical agent ordered or provided, by any route of administration, for
      prevention, diagnosis, or treatment." Sampling weights were used to obtain
      unbiased national estimates. Cross tabulations of the drug prescription status
      (OTC or prescription [Rx]) with independent variables were performed, overall and
      by therapeutic class. The overall OTC/Rx ratio (0.11) was used as the cutoff
      point for distinguishing high- from low-level OTC drug prescribing. RESULTS: In
      1990, 9.7% of physician drug mentions were of OTC drugs. Women between 16 and 34
      years, Asian/Pacific Islanders, white Hispanics, and African-Americans
      experienced high OTC drug mentions (OTC/Rx > or = 0.11). After stratification by
      drug therapeutic class, physicians in general practice, family practice, internal
      medicine, obstetrics/gynecology, and pediatrics highly mentioned OTC drugs.
      CONCLUSIONS: OTC drug prescribing by physicians is substantial, and primary care
      specialties, patient gender, age, and race should be considered by those
      interested in evaluating OTC drug utilization in the ambulatory care setting.

PMID- 10332530
TI  - Therapeutic failure of trimethoprim/sulfamethoxazole in the treatment of
      Pneumocystis carinii pneumonia.
AB  - OBJECTIVE: To report a case of failure of treatment of Pneumocystis carinii
      pneumonia (PCP) with trimethoprim/sulfamethoxazole (TMP/SMX) in a patient with
      HIV infection, despite an adequate serum SMX concentration. CASE SUMMARY: A 52
      year-old white man was treated with TMP/SMX for PCP. After discharge he returned
      to the hospital with worsening of the PCP despite a serum SMX concentration of 60
      micrograms/mL 18 hours after his last dose of TMP/SMX. DISCUSSION: PCP is one of
      the most common complications of HIV infection. TMP/SMX is the drug of choice for
      prophylaxis and treatment. The causes of therapeutic failure with this agent are
      not well documented. CONCLUSIONS: Alternative therapies to TMP/SMX should be
      seriously considered if the serum concentrations are therapeutic and the patient
      is not clinically improved.

PMID- 10332529
TI  - Estimating risk factors for patients with potential drug-related problems using
      electronic pharmacy data. IMPROVE investigators.
AB  - OBJECTIVE: To validate a computer-based program to identify patients at high risk
      for drug-related problems. DESIGN: Computerized analysis of pharmacy dispensing
      records and manual review of medical records. SETTING: Ambulatory clinics at a
      Veterans Affairs Medical Center. PATIENTS: 246 randomly selected patients who
      were receiving at least one outpatient medication in the previous 24 months. MAIN
      OUTCOME MEASURES: Presence of six previously established criteria regarding
      medication use. These criteria are five or more medications, > or = 12 doses per
      day, four or more changes to the medication regimen, three or more chronic
      diseases, history of noncompliance, and presence of a drug requiring therapeutic
      drug monitoring (TDM). RESULTS: Spearman rho rank order correlation coefficients
      ranged from 0.63 to 0.91 for criteria pertaining to the number of medications,
      daily doses, changes in the medication regimen, and number of chronic diseases
      (all significant, p = 0.0001). The computer program underestimated the number of
      chronic diseases and overestimated the number of daily doses. The level of
      agreement between the computer program and chart review for patient noncompliance
      was low (Kappa = 0.38), with the computer more likely to indicate a patient was
      noncompliant. A high level of agreement was seen between the computer program and
      chart review for the presence of a drug requiring TDM (Kappa = 0.83). For all six
      criteria, the computer program had a sensitivity of 65.7% and specificity of
      88.2%. CONCLUSIONS: When compared with medical records, the use of this program
      to evaluate electronic pharmacy data can be efficient to screen large numbers of
      patients who may be at high risk for drug-related problems. This method may be
      useful for clinical pharmacists in providing pharmaceutical services to patients
      who are most likely to benefit.

PMID- 10332531
TI  - The use of alteplase in a newborn receiving extracorporeal membrane oxygenation.
AB  - OBJECTIVE: To present a case of the use of alteplase for the successful
      resolution of an upper extremity occlusion in a newborn receiving extracorporeal
      membrane oxygenation (ECMO). CASE SUMMARY: A two-day-old full-term Hispanic girl
      receiving ECMO support developed a left upper extremity occlusion distal to the
      brachial artery. Alteplase therapy was initiated with a bolus dose of 0.48 mg/kg
      followed by a continuous infusion of 0.27 mg/kg/h for three hours. A repeat
      Doppler ultrasound revealed little improvement, resulting in continuation of
      alteplase therapy at an infusion rate of 0.27 mg/kg/h for an additional three
      hours. At the completion of the infusion, perfusion was greatly improved with
      palpable radial pulse present. While remaining on ECMO support, a brain
      ultrasound approximately 13 hours after alteplase therapy revealed a grade I
      right caudate head hemorrhage with normal ventricles. ECMO support was
      discontinued during the next 24 hours, with a repeat brain ultrasound three days
      later indicating no acute hemorrhage, normal ventricles, and almost complete
      resolution of the intraventricular hemorrhage. The neonate was discharged 19 days
      after discontinuing ECMO support. DISCUSSION: Patients receiving ECMO support are
      at risk of hematologic complications, including thrombi formation. Moreover,
      limited information is available regarding the most appropriate thrombolytic
      therapy for patients receiving ECMO support. Alteplase is an attractive
      thrombolytic agent given its antigenicity, clot specificity, and pharmacokinetic
      profile. However, both ECMO support and thrombolytic therapy are risk factors for
      the development of intraventricular hemorrhage, which our patient developed.
      Therefore, close monitoring of patients receiving ECMO support and alteplase
      therapy is essential given the potential for hematologic adverse effects.
      CONCLUSIONS: Alteplase is an effective thrombolytic agent in neonates receiving
      ECMO support. Additional experience with alteplase is necessary to determine the
      optimal dose and duration of therapy in this patient population.

PMID- 10332532
TI  - Phenobarbital dosing and pharmacokinetics in a neonate receiving extracorporeal
      membrane oxygenation.
AB  - OBJECTIVE: To describe the dosing and pharmacokinetics of phenobarbital in a
      neonate receiving extracorporeal membrane oxygenation (ECMO). CASE SUMMARY: The
      treatment of a 2.6 kg, 38-week gestational age boy with congenital diaphragmatic
      hernia who developed seizures while receiving ECMO support is described. A
      loading dose of 20 mg/kg resulted in concentrations of 16.4 and 12.9
      micrograms/mL at 3 and 24 hours, respectively. A maintenance dose of 5 mg/kg/d
      provided a peak concentration of 19.7 micrograms/mL and trough concentration of
      16.7 micrograms/mL after four doses. The calculated volume of distribution was
      1.2 L/kg and the estimated elimination half-life was 92 hours. Serum
      concentrations decreased after circuit changes unless the new circuit was
      redosed. DISCUSSION: The reported incidence of seizures in neonates while
      receiving ECMO support is 18%. Despite this frequency, there are no clinical
      reports describing anticonvulsant use in this population. This case demonstrates
      the use of standard phenobarbital doses to achieve low, but therapeutic, serum
      concentrations. Pharmacokinetic analysis revealed a volume of distribution
      slightly larger than expected in neonates and an elimination half-life similar to
      published values. Altering circulating blood volumes resulted in significant
      reductions in serum concentrations. CONCLUSIONS: Neonates on ECMO may have a
      larger volume of distribution than neonates not receiving ECMO and may require
      larger phenobarbital doses to achieve desired serum concentrations. This may
      result from the presence of large exogenous blood volumes for priming, as well as
      loss of drug during circuit changes, extraction by the circuit, or
      hemofiltration. Further work is needed to better define the pharmacokinetics and
      pharmacodynamics of phenobarbital in the neonatal ECMO population.

PMID- 10332533
TI  - Ototoxicity associated with vinblastine.
AB  - OBJECTIVE: To describe a patient with ototoxicity associated with vinblastine
      chemotherapy. CASE SUMMARY: A 29-year-old white man with recurrent Hodgkin's
      disease received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)
      chemotherapy once every two weeks for 12 cycles. He reported tinnitus after each
      treatment, with an onset of about six hours and a duration of seven to 10 days.
      This interfered with reading, watching television, and general concentration.
      Symptoms returned to baseline prior to the beginning of each subsequent cycle.
      Audiograms performed before and after several cycles showed mild sensorineural
      hearing loss in the high-decibel range, but no loss of speech recognition.
      DISCUSSION: No reported cases of ototoxicity or tinnitus from ABVD were found.
      All concomitant medications were eliminated as possible causes either due to lack
      of temporal association with the symptoms or no reports of ototoxicity in the
      literature. Vincristine, a more commonly used vinca alkaloid very similar to
      vinblastine, was noted to have caused several cases of sensorineural hearing
      loss. CONCLUSIONS: This case suggests that vinblastine may cause ototoxicity.

PMID- 10332534
TI  - Probable antagonism of warfarin by green tea.
AB  - OBJECTIVE: To report a case of the inhibition of the effect of warfarin by green
      tea. CASE SUMMARY: A 44-year-old white man was receiving warfarin for
      thromboembolic prophylaxis secondary to a St. Jude mechanical valve replacement
      in the aortic position. The patient had an international normalized ratio (INR)
      of 3.20 approximately one month prior to entering our clinic, and an INR of 3.79
      on entering our clinic. Twenty-two days later his INR was 1.37. One month later
      the patient's INR was 1.14. It was subsequently discovered that the patient began
      drinking one-half to one gallon of green tea per day about one week prior to the
      INR of 1.37. On discontinuation of the green tea, the patient's INR increased to
      2.55. DISCUSSION: Warfarin produces anticoagulation by inhibiting production of
      the vitamin K-dependent clotting factors (i.e., factors II, VII, IX, X). The
      exogenous administration of vitamin K inhibits the effect of warfarin and reduces
      a patient's degree of anticoagulation. Green tea can be a significant source of
      vitamin K and thus antagonize the effect of warfarin. CONCLUSIONS: Warfarin is a
      highly effective oral anticoagulant, but it requires close monitoring to prevent
      complications. Patients receiving warfarin need to be routinely questioned about
      their intake of vitamin K-containing foods and beverages.

PMID- 10332535
TI  - Domperidone: a peripherally acting dopamine2-receptor antagonist.
AB  - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of
      domperidone in the treatment of gastrointestinal motility disorders and emesis.
      DATA SOURCES: MEDLINE and Excerpta Medica online databases were searched to
      identify published reports. STUDY SELECTION: Domperidone has been marketed
      worldwide outside the US since 1978, and extensive clinical data for this drug
      are available. This review focuses on the clinical experience from controlled
      studies of domperidone in the treatment of motility disorders, particularly
      diabetic gastroparesis. Also, case reports are used in summarizing safety. The
      control comparator groups included placebo or other prokinetic drugs
      (metoclopramide and cisapride). Controlled clinical trials of domperidone's
      efficacy and safety as an antiemetic are also briefly examined. Although a
      variety of domperidone dosage forms have been marketed, data generated from
      trials using the 10-mg tablet are highlighted because this is the only dosage
      form available in Canada and is under investigation in the US. DATA EXTRACTION:
      Because symptoms do not correlate with objective measures of gastrointestinal
      motility and they are the primary reason that patients with motility disorders
      seek treatment, the primary outcome extracted from the clinical studies was
      symptomatic response to treatment. Safety and efficacy between domperidone and
      placebo, metoclopramide, or cisapride were compared. DATA SYNTHESIS: Domperidone,
      a peripheral dopamine2-receptor antagonist, regulates the motility of gastric and
      small intestinal smooth muscle and has been shown to have some effects on the
      motor function of the esophagus. It also has antiemetic activity as a result of
      blockade of dopamine receptors in the chemoreceptor trigger zone. In controlled
      clinical trials, domperidone provided better relief of symptoms (anorexia,
      nausea, vomiting, abdominal pain, early satiety, bloating, distension) than
      placebo in patients with symptoms of diabetic gastropathy; symptomatic
      improvement was similar with domperidone and metoclopramide or cisapride.
      Domperidone also provided short-term relief of symptoms in patients with
      dyspepsia or gastroesophageal reflux, prevented nausea and vomiting associated
      with emetogenic chemotherapy, and prevented the gastrointestinal and emetic
      adverse effects of antiparkinsonian drugs. Because very little domperidone
      crosses the blood-brain barrier, reports of central nervous system adverse
      effects, such as dystonic reactions, are rare. CONCLUSIONS: Domperidone is a
      unique gastrokinetic and antiemetic drug. Because of its favorable safety
      profile, domperidone appears to be an attractive alternative to metoclopramide.
      In the management of diabetic gastropathy, domperidone's antiemetic activity
      distinguishes it from cisapride.

PMID- 10332536
TI  - Cholinesterase inhibitors: a therapeutic strategy for Alzheimer disease.
AB  - OBJECTIVE: To provide a review of acetylcholinesterase inhibitors (AChEIs) tested
      as therapeutic agents for Alzheimer disease (AD). DATA SOURCES: MEDLINE searches
      (January 1986-July 1998) identified pertinent literature. Selected references
      from these articles, as well as abstracts from recent meetings and package insert
      literature from approved compounds, were also used as source material. DATA
      EXTRACTION: AChEIs were reviewed with regard to chemical structure, mechanism of
      inhibition, substrate specificity, pharmacokinetics/pharmacodynamics,
      safety/tolerability, and efficacy. DATA SYNTHESIS: Cholinergic deficits, leading
      to cognitive impairment, are a significant aspect of neurodegeneration in AD.
      AChEIs reduce the degradation of acetylcholine, thus enhancing cholinergic
      transmission. In addition to the two agents approved by the Food and Drug
      Administration, tacrine and donepezil, six other compounds of diverse chemical
      structure and mechanism of inhibition including physostigmine, metrifonate,
      rivastigmine, and galantamine are under investigation as potential therapy for
      AD. These compounds are structurally diverse, possess unique patterns of
      specificities for the various forms of cholinesterase enzymes, use distinct
      mechanisms of enzyme inhibition, present unique adverse event profiles, and offer
      relatively similar mean gains in cognitive abilities to patients with AD in
      controlled clinical trials. CONCLUSIONS: Relative to placebo, new AChEIs in
      development provide modest improvements in cognition for patients with mild to
      moderate AD, with improved tolerability profiles and more convenient dosing
      relative to tacrine. The availability of a wide array of AChEIs soon to be
      accessible to patients with AD will provide additional options to those who
      cannot tolerate or do not respond to drugs currently used for AD.

PMID- 10332537
TI  - Allergic-type reactions to corticosteroids.
AB  - OBJECTIVE: To review reported cases of suspected allergic reactions to various
      corticosteroids. DATA SOURCES: A MEDLINE search (January 1966-December 1997) was
      performed to obtain case reports and review articles on allergic-type reactions
      to corticosteroids. Further references were obtained from these publications.
      STUDY SELECTION: Reports involving allergic or allergic-type reactions to
      systemic administration of corticosteroids were chosen for this review. An
      allergic-type reaction was defined as any reaction after administration of the
      drug that involved the appearance of adverse symptoms that are characteristic of
      unwanted immune responses. These symptoms include rash, sneezing, dyspnea, edema,
      bronchospasm, or death. Articles were excluded from the evaluation if they
      described reactions to topical, intraarticular, or ophthalmic corticosteroid
      administration. DATA SYNTHESIS: Corticosteroids are medications that are often
      used to treat allergic reactions. However, it appears that patients can also have
      allergic-type reactions to these agents. The severity of the reaction can vary
      from a rash to anaphylaxis or death. Both immediate and delayed reactions can
      occur. Allergic-type reactions are reported to occur more frequently in asthmatic
      and renal transplant patients than other patient populations. However, it is
      questionable whether all of these are true allergic responses, as there is
      conflicting evidence regarding the mechanism of the reaction. The most commonly
      implicated corticosteroids are methylprednisolone and hydrocortisone, but
      reactions have also occurred with others. Intradermal skin testing can help
      determine cross-sensitivity, although its value has not been conclusively
      demonstrated. CONCLUSIONS: Clinicians should be aware that allergic reactions to
      corticosteroids are possible. Worsening of symptoms may not always mean treatment
      failure, but may indicate an allergic reaction. High doses of corticosteroids (>
      or = 500 mg) should be given over 30-60 minutes, and patients should be observed
      after administration for at least the same time period. Asthmatics, renal
      transplant patients, and hemodynamically unstable patients may be at higher risk
      for adverse events. If a patient is found to be allergic to one corticosteroid,
      intradermal skin testing may help identify another corticosteroid that can be
      tolerated.

PMID- 10332538
TI  - Significant interactions with new antiretrovirals and psychotropic drugs.
AB  - OBJECTIVE: To provide an update on relevant antiretroviral interactions and
      psychotropic medications for healthcare practitioners managing complex HIV
      related pharmacotherapy. DATA SOURCES: Information was retrieved via a MEDLINE
      search (January 1966-September 1998) using MeSH headings human immunodeficiency
      virus, drug interactions, psychiatry, psychotropics, psychiatric illness, and
      names of medications commonly prescribed for the management of HIV infection.
      Abstracts of international and national conferences (until February 1999), review
      articles, textbooks, and references of all articles also were searched. STUDY
      SELECTION AND DATA EXTRACTION: Literature on pharmacokinetic interactions was
      considered for inclusion. Pertinent information was selected and summarized for
      discussion. In the absence of specific data, pharmacokinetic and pharmacodynamic
      properties were considered in order to predict the likelihood of potential drug
      interactions. DATA SYNTHESIS: All protease inhibitors and nonnucleoside reverse
      transcriptase inhibitors are substrates of the cytochrome P450 system and possess
      enzyme-inhibiting and/or -inducing properties. Psychotropic medications also
      possess similar metabolic characteristics and may interact with antiretrovirals.
      Modifications in drug selection, dose, or dosing regimen may be needed to ensure
      adequate antiretroviral concentrations and thus minimize the risk of incomplete
      viral suppression and/or development of drug resistance. In the absence of
      specific data, consideration of metabolic characteristics may assist
      practitioners in predicting the likelihood of possible interactions. RESULTS: The
      incidence and implications of antiretroviral drug interactions are reviewed.
      Practical management strategies are also discussed. Comprehensive tables on
      clinically significant interactions with antiretroviral combinations and with
      psychiatric medications are provided. CONCLUSIONS: Given the increasing use of
      multiple-drug therapy, the potential for drug interactions is extremely high.
      Drug interactions may lead to undesirable outcomes including subtherapeutic drug
      concentrations and risk of antiretroviral resistance. Practitioners need to
      consider pharmacokinetic, pharmacologic, therapeutic, and adherence factors when
      managing interactions with complex antiretroviral therapy.

PMID- 10332539
TI  - Angiotensin-converting enzyme gene polymorphism: is there a link to nephropathy
      in patients with type 1 diabetes?
AB  - OBJECTIVE: To evaluate the association between the angiotensin-converting enzyme
      (ACE) gene polymorphism and diabetic nephropathy in patients with type 1
      diabetes. DATA SOURCES: Citations were selected using the MEDLINE database. Only
      those citations involving human subjects and available in English were selected.
      Key search words included angiotensin-converting enzyme (ACE), polymorphism,
      nephropathy, and type 1 diabetes. STUDY SELECTION: Selection criteria consisted
      of all MEDLINE-referenced clinical trials, review articles, and editorial
      comments assessing the potential link between the ACE gene polymorphism and
      diabetic nephropathy in insulin-dependent diabetes mellitus published between
      January 1990 and February 1998. DATA SYNTHESIS: Because diabetic nephropathy is a
      serious complication of type 1 diabetes, focus has been placed on the early
      identification of and intervention with patients genetically susceptible to this
      complication. Because the ACE gene polymorphism has an effect on plasma ACE
      concentration variations among individuals, it has been investigated as a
      potential genetic marker for diabetic nephropathy. The best studies to date are
      reviewed in order to assess the utility of the ACE polymorphisms as a genetic
      marker of diabetic nephropathy in patients with type 1 diabetes, and to determine
      what implications this holds for drug treatment. CONCLUSIONS: Although the ACE
      gene polymorphism's potential link to diabetic nephropathy in patients with type
      1 diabetes has been debated, the most definitive studies show that an association
      exists. Large epidemiologic studies must now be conducted to determine the
      implications this polymorphism holds for the best treatment strategies in the
      care of these patients.

PMID- 10332540
TI  - Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for
      schizophrenia: I. Adenosine agonists.
AB  - OBJECTIVE: To review preclinical and clinical information related to
      pharmacologic modulation of dopamine D2 receptors as potential novel
      antipsychotic therapy. Specifically, to summarize the data that suggest a
      modulatory action of adenosine A2A receptors on dopamine D2 receptors and,
      therefore, a possible rational role of adenosine A2A agonists as novel
      antipsychotic agents. DATA SOURCES: Primary and review articles were identified
      by MEDLINE search (from 1966 to May 1998) and through secondary sources. STUDY
      SELECTION AND DATA EXTRACTION: All of the articles identified from the data
      sources were evaluated and all information deemed relevant was included in this
      review. DATA SYNTHESIS: For all of the older and many of the newer antipsychotic
      agents, there is a strong correlation between clinical antipsychotic activity and
      affinity for dopamine D2 receptors. Unfortunately, dopamine D2 receptors are
      believed to also be involved in the adverse effect profile of these agents. The
      indirect modulation of dopamine D2 receptors, rather than direct block, might
      produce antipsychotic effects without the usual adverse reactions. Several lines
      of evidence from animal studies suggest that the use of selective A2A agonists
      might represent a novel approach to the treatment of psychoses. CONCLUSIONS:
      Dopamine receptor modulation might represent a novel antipsychotic approach or
      adjunct therapy. The data regarding adenosine agonists (particularly selective
      A2A receptor agonists) are inconclusive at the present time. Direct clinical
      demonstration of effectiveness is required.

PMID- 10332541
TI  - Ethics in Christianity and health care: can "character" be defined in this
      interdisciplinary course?
AB  - OBJECTIVE: To describe a unique interdisciplinary ethics course that incorporates
      elements of character into a decision-making model. METHODS: The Ethics in
      Christianity and Health Care course is divided into two sections: ethics in
      Christianity and ethics in health care. The first section comprises the initial
      30% of the course, and the second portion spans the latter 70%. Character traits
      of ethical persons are described in the second section of the course and are then
      used in an adapted decision-making model. A scenario from a nontraditional Doctor
      of Pharmacy student is included to illustrate this decision-making process.
      Texts, assignments, and assessments are also discussed briefly. SUMMARY: This
      course provides a framework within which ethical relationships are described and
      discussed. The character traits delineated in the article offer a logical
      approach when solving ethical dilemmas.

PMID- 10332542
TI  - Streptokinase and urokinase for the treatment of pleural effusions and empyemas.
AB  - It is evident from these studies that thrombolytics significantly increase the
      amount of drainage from pleural effusions or empyemas. The effect on other
      outcome measures, such as length of hospital stay, days before defervescence,
      days with chest tube, surgical procedures, and mortality is questionable. The
      lack of randomized, controlled trials comparing streptokinase and urokinase makes
      a true comparison rather difficult. Both agents are equally effective in
      increasing pleural drainage. Only one comparative trial demonstrated an increased
      incidence of fever with streptokinase, which was reversible on discontinuation.
      This reaction does not occur frequently based on the results of the published
      literature. Overall, the low incidence of adverse reactions associated with
      either agent may not justify the added expense of urokinase for this indication.
      A majority of the clinical trials can be criticized for their low numbers of
      patients along with lack of control groups. It is unknown whether statistical
      significance would have been obtained if adequate sample sizes were used.
      Inclusion criteria were not uniform, as characteristics of pleural fluid and
      presence of loculations may influence success. Volume of drainage is also less
      impressive when the amount used to instill the thrombolytic is subtracted from
      the amount of drainage. If this were considered, statistical significance could
      have been altered. Finally, therapeutic end points varied throughout the
      literature. Most studies used volume of drainage and X-ray findings as end
      points. However, such surrogate markers do not necessarily correlate with
      clinical improvement. The optimal dose of streptokinase is 250,000 units
      instilled through a chest tube (which is clamped for 2-4 h) on a daily basis
      until decreased drainage is obtained. The optimal dose of urokinase is not known
      and the administration methods vary throughout the literature, ranging from
      50,000 to 250,000 units. The AWP of streptokinase is $122 for 250,000 units
      compared with $433 for 250,000 units of urokinase. In the only comparative trial,
      the average number of instillations was the same, so the cost of therapy with
      urokinase is significantly higher. The study by Bouros et al. poses an
      interesting observation. They successfully treated patients with 50,000 units of
      urokinase, which would be approximately the same cost as streptokinase. Further
      studies are needed to truly evaluate the efficacy of low-dose urokinase as well
      as comparative trials with these two agents. In conclusion, urokinase offers no
      significant benefits over streptokinase. The incidence of fever was greater in
      one comparative trial with streptokinase than with urokinase. Based on cost
      considerations and lack of comparative studies, urokinase infusions should be
      reserved for patients who develop fever when receiving continued therapy with
      streptokinase.

PMID- 10332543
TI  - Calcitonin in phantom limb pain.
AB  - PLP is a challenging disorder that is often difficult to treat. Like all other
      types of pain, PLP is a tremendous source of morbidity and should be treated
      aggressively. Though evidence is very limited, one or two doses of intravenous
      salmon calcitonin 200 IU may be an effective treatment. The minor adverse effects
      reported in the literature would seem to indicate the relative safety of this
      regimen; however, clinicians should be aware of the rare but severe
      hypersensitivity reactions that can occur with salmon calcitonin. Intranasal
      calcitonin appears to be similar in efficacy to the parenteral formulation, at
      least in pain associated with vertebral crush fractures. Long-term studies using
      intranasal calcitonin for relief of PLP are warranted given the ease of
      administration of this dosage form.

PMID- 10332544
TI  - Potential metabolic interaction between St. John's wort and theophylline.

PMID- 10332545
TI  - Pentamidine-induced hemolytic anemia in an AIDS patient.

PMID- 10332546
TI  - Sublingual administration of all-trans-retinoic acid to a comatose patient with
      acute promyelocytic leukemia.

PMID- 10332549
TI  - Managing the new generation.
AB  - As the Silent Generation quickly approaches retirement, and the Baby Boomer
      generation moves into management and supervisory roles, a new generation is
      entering the workforce. Generation Xers were born between 1965 and 1975, at a
      time when the country experienced high prices, wage inflation, stagnant consumer
      demands, and increased unemployment. Perhaps as a result, newcomers to today's
      workforce often have different characteristics, behavioral traits, and belief
      systems from their predecessors. To effectively supervise and motivate
      individuals from this unique generation, health care managers must begin by
      understanding the evolutions that have shaped each generation and influenced the
      workforce. In doing so, managers can create a thriving multigenerational work
      environment and embrace supervisory concepts that attract and motivate the new
      generation.

PMID- 10332548
TI  - Potentiation of the acenocoumarol anticoagulant effect by acetaminophen.

PMID- 10332547
TI  - Unusual toxicity of deferoxamine.

PMID- 10332550
TI  - Life in the fast lane--helpful tips for OR charge nurses.
AB  - Today's ORs are fast-paced. Generally, charge nurses are given little training to
      be effective in their role and are expected to keep the OR running smoothly. This
      article examines ways in which charge nurses can satisfy the needs of surgeons
      and staff members and offers suggestions for dealing with delays and disgruntled
      surgeons, fostering good working relationships, demonstrating responsibility, and
      maintaining a financial perspective in decision making.

PMID- 10332551
TI  - Prion diseases--an evidence-based protocol for infection control.
AB  - Prion diseases are fatal, infectious, neurodegenerative disorders with special
      implications for infection control in the OR. The causative agent is highly
      resistant to disinfection and sterilization processes and has been transmitted
      during health care interactions. It is important to use evidence gained through
      research and case reports to minimize risk of infection. This article describes
      an infection control protocol developed for identifying high-risk patients,
      providing perioperative care, decontaminating the OR, and protecting health care
      personnel. This protocol provides multidisciplinary team members with a guideline
      for preventing transmission of these fatal diseases.

PMID- 10332552
TI  - Enhancing perioperative nursing effectiveness through informatics.
AB  - The science of nursing informatics is becoming increasingly important to
      delivering quality nursing care to all patient populations. Perioperative nursing
      informatics skills are practiced within the context of powerful and complex
      information systems that enhance nurses' ability to view and report clinical data
      in a manner that has never before been possible. This article explores how the
      analysis of several examples of two typical system indicators (i.e., the
      unplanned returns to surgery rate within the same admission event, surgical site
      infection rate) can result in improved patient outcomes. Nursing informatics is
      an invaluable tool for identifying trends and communicating them to perioperative
      nurses in a way that can positively influence the delivery of perioperative care
      and patient outcomes.

PMID- 10332553
TI  - Ethical perception and resulting action in perioperative nurses.
AB  - This study examined whether perioperative nurses (n = 40) were able to perceive
      and identify selected ethical issues occurring within their practice setting. The
      nurses described ethical conflicts and identified factors influential to their
      ethical decision making. The issues reported were organized into five categories:
      consent/advocacy, impaired provider/potential for unsafe practice,
      misrepresentation by care provider, disrespect for patient, and provider
      judgment/competency. The results of this study support that perioperative nurses
      both perceive and identify specific ethical issues in the surgical environment.
      Analysis of their reported actions revealed that the most common methods used for
      ethical conflict resolution were reporting to the immediate supervisor or
      personally confronting those directly involved.

PMID- 10332554
TI  - Clinical impact of preoperative respiratory syncytial virus testing.
AB  - The purpose of this study was to determine if preoperative assessment (i.e.,
      physical examination and history review) of pediatric patients can predict
      positive test results for respiratory syncytial virus (RSV) infection, surgery
      cancellations, and adverse anesthetic outcomes. Approximately 400 pediatric
      patients were identified for the study from infection control statistics and
      classified by RSV test result and surgery cancellation status into three groups
      for analyses. Researchers analyzed retrospective chart data of preoperative
      histories and physical findings using one way analysis of variance to compare age
      among the groups and Fisher's exact test to compare patient characteristics and
      signs and symptoms of illness. The results show that active RSV infection cannot
      be predicted by history and physical findings alone. In addition, patients who
      had a history of pulmonary disease and who were wheezing at the time of their
      examinations were more likely to have their surgeries cancelled, independent of
      positive test results for RSV infection.

PMID- 10332556
TI  - Hypothyroidism in elderly patients.
AB  - Hypothyroidism is an endocrine condition found in elderly patients that is often
      confused with normal changes associated with aging. Consequently, the disorder
      may be quite advanced before it is diagnosed and treated. Depressed T4 and
      elevated TSH levels confirm primary hypothyroidism. Patients are required to take
      levothyroxine for the rest of their lives. Myxedema coma, a life-threatening
      complication of hypothyroidism, occurs primarily in elderly women and requires
      immediate treatment to prevent death. Recovery and stabilization may take six to
      eight months.

PMID- 10332557
TI  - Patient rights still hot topic in Congress and the states.

PMID- 10332559
TI  - Androgen effects on body composition and muscle function: implications for the
      use of androgens as anabolic agents in sarcopenic states.
AB  - Testosterone-induced nitrogen retention in castrated male animals, eunuchoidal
      men, pre-pubertal boys and women, and the sex-related differences in the size of
      the muscles between male and female animals, have been cited as evidence that
      testosterone has anabolic effects. Recent studies have reported that replacement
      doses of testosterone in hypogonadal men and supraphysiological doses in
      eugonadal men increase fat-free mass, muscle size and strength. These effects
      have provided the rationale for exploring these anabolic applications in
      sarcopenic states. Although emerging data demonstrate modest gains in fat-free
      mass in HIV-infected men given replacement doses of testosterone, we do not know
      whether testosterone supplementation can produce clinically meaningful changes in
      muscle function and disease outcome in patients with wasting disorders.

PMID- 10332560
TI  - Androgen therapy in AIDS wasting.
AB  - Hypogonadism in HIV-infected men has been well described, having a prevalence of
      about 30%. Its aetiology is a combination of non-specific changes from chronic
      and acute illness, and specific effects due to HIV infection. A depressed serum
      testosterone level has been associated with viral or infectious invasion of the
      endocrine organs, and with medications commonly used in treating HIV infection.
      Recently, many have noted the association between decreased serum testosterone in
      men and women, and the wasting syndrome of HIV infection, particularly with a
      reduction in lean body mass. Our understanding of the risks and benefits of
      testosterone therapy in non-HIV infected men has grown significantly. Treatment
      in this population can improve sexual function, quality of life parameters and
      body composition. Based on this information, a few studies have been carried out,
      and more are being planned to test the hypothesis that therapy with testosterone
      or its analogues can benefit HIV-infected men and women with wasting and/or low
      circulating androgen concentrations. To date, the studies have been inconclusive.
      Not all studies have shown a statistical benefit of androgen therapy on weight,
      muscle mass or quality of life. Testosterone is now available in several forms
      for dosing, which has improved compliance and ease of administration. Its
      potential risk to the prostate or serum lipids should be monitored closely.
      Although the beneficial effects of androgenic steroids in HIV-infected men have
      not been demonstrated clearly, short-term studies suggest that testosterone
      supplementation may improve metabolic outcomes in HIV-infected men with androgen
      deficiency.

PMID- 10332561
TI  - The rationale for physiological testosterone replacement in women.
AB  - Androgens have an important physiological role in women. Not only are they the
      precursor hormones for oestrogen production in the ovaries and extragonadal
      tissues, but they also appear to act directly, via androgen receptors, throughout
      the body. Androgen levels decline with increasing age in women, who may
      experience a variety of physical symptoms secondary to androgen depletion, as
      well as physiological changes that affect their quality of life. In this chapter,
      the changes in androgens as women age are reviewed, and the rationale for
      physiological androgen, specifically testosterone replacement, in women is
      addressed.

PMID- 10332562
TI  - Rationale for anabolic therapy to facilitate rehabilitation in chronic
      obstructive pulmonary disease.
AB  - Chronic obstructive pulmonary disease (COPD) afflicts millions of people and is
      severely disabling. Exercise intolerance is usually the chief complaint. There
      are few effective therapies. Pulmonary rehabilitation seeks to return the patient
      to the highest possible level of function but cannot reverse the underlying
      pulmonary abnormalities. Several lines of evidence have recently pointed to
      abnormalities of the muscles of ambulation as a remediable source of exercise
      intolerance in COPD. Possible mechanisms of the muscle abnormalities include
      deconditioning, malnutrition, low levels of anabolic hormones and, perhaps, a
      specific myopathy. To date, most reports of attempts to reverse muscle
      dysfunction in COPD have focused on exercise training. However, abnormalities in
      the level of circulating anabolic hormones have recently been described,
      suggesting that anabolic hormone supplementation may be rational therapy for
      these patients. Accumulating evidence that anabolic steroids increase muscle mass
      and improve strength in older men is encouraging trials of anabolic steroids in
      men with COPD.

PMID- 10332563
TI  - Androgen replacement therapy to reverse and/or prevent age-associated sarcopenia
      in men.
AB  - Normal ageing is associated with a decline in lean body mass, muscle mass and
      strength. The functional consequences of these changes may be significant and
      include falls, fractures, loss of mobility and increasing dependency. The
      anabolic actions of testosterone on muscle have been known for over 60 years, and
      replacement studies in young hypogonadal men have shown that testosterone can
      improve muscle mass and strength. In addition, the supraphysiological replacement
      of testosterone in young eugonadal men has also been shown to increase muscle
      mass and improve strength. Although the data are limited, studies of testosterone
      replacement in healthy older men with relative testosterone deficiency have
      demonstrated some modest improvements in muscle mass and strength, although the
      clinical and functional relevance of the muscle changes have yet to be
      determined. More data and experience are needed before testosterone can be
      advocated for the prevention or reversal of sarcopenia in the ageing male.

PMID- 10332564
TI  - Androgen replacement in children with constitutional delay of puberty: the case
      for aggressive therapy.
AB  - Puberty describes the complex physiological transition between childhood and
      adulthood. Dramatic physical changes occur, most notably the development of
      secondary sexual characteristics and the pubertal growth spurt. During the
      adolescent growth spurt, growth velocity increases from pre-pubertal rates of 4-6
      cm per year to as much as 10-15 cm per year. Accompanying the increase in gonadal
      steroids is an increase in amplitude of growth hormone secretory bursts. Evidence
      suggests that adequate growth hormone and gonadal steroids are both necessary for
      the attainment of a normal pubertal growth velocity, and the complex interplay
      between these two hormonal axes is under intense investigation. Delayed onset of
      puberty, or constitutional delay of growth and adolescence, is a common
      phenomenon presenting particularly in boys. Physiologically, it represents an
      extension of the normal pre-pubertal hypogonadotropic hypogonadal state. Without
      intervention, these children will spontaneously undergo puberty and often reach
      their genetic height potential, but their delay compared with that of their peers
      is often of concern to the children and their families. Recent evidence suggest
      long-term physiological benefits of early androgen replacement therapy in these
      boys, including maximizing attained bone mineral density. Androgen replacement
      therapy in male adolescents with constitutional delay of growth and adolescence
      is beneficial psychologically as well as physiologically and should be initiated
      promptly.

PMID- 10332565
TI  - Androgens and abdominal obesity.
AB  - Central or visceral obesity is recognized as a main risk factor for
      cardiovascular disease and type 2 diabetes mellitus. The co-existence of visceral
      obesity, increased blood lipid levels, hypertension and impaired glucose
      tolerance defines the metabolic syndrome that today is widely recognized as one
      of the prime factors behind cardiovascular morbidity and mortality. Endocrine
      disorders such as insulinoma, hypothyroidism and hypercortisolism are known to
      cause obesity. However, it is only hypercortisolism that is associated with
      increased abdominal fat accumulation. Recently, new findings have shed light on
      subtle endocrinopathies that are prevalent in individuals presenting with the
      metabolic syndrome. Such derangements are of borderline character and often fall
      within the normal reference range. Intervention studies demonstrate that
      correction of relative hypogonadism in men with visceral obesity and other
      manifestations of the metabolic syndrome seem to decrease the abdominal fat mass
      and reverse the glucose intolerance, as well as lipoprotein abnormalities in the
      serum. Further analysis of the underlying mechanism has also disclosed a
      regulatory role for testosterone in counteracting visceral fat accumulation.
      Longitudinal epidemiological data demonstrates that relatively low testosterone
      levels are a risk factor for development of visceral obesity. The primary event
      that triggers the initial development of visceral obesity is not known, but it
      seems plausible that increased activity in the hypothalamus-pituitary-adrenal
      axis can be of major importance.

PMID- 10332566
TI  - Therapeutic role of androgens in the treatment of osteoporosis in men.
AB  - There has been much recent interest in the relationship between androgens and
      bone mineralization in men. Increases in serum androgens during puberty allow for
      skeletal maturation and the attainment of peak bone mass, and the persistence of
      normal testosterone secretion during adulthood is important for the maintenance
      of bone density. Testosterone deficiency is associated with heightened bone
      turnover and is a major risk factor for osteoporosis in men. The administration
      of testosterone to androgen-deficient men leads to an increase in bone mass,
      particularly in the trabecular bone compartment, and a reduction in levels of
      surrogate markers of bone turnover, suggesting that androgens have a dampening
      effect on bone remodelling. In addition, the administration of androgens to
      eugonadal men with idiopathic osteoporosis, with resulting supraphysiological
      testosterone concentrations, may lead to increases in bone mineral density. The
      risk of osteopenia due to androgen deficiency and the benefits of testosterone
      substitution therapy or supraphysiological administration on bone will be
      reviewed.

PMID- 10332568
TI  - Androgen therapy in chronic renal failure.
AB  - Chronic renal failure, dialysis and transplantation have major effects on male
      reproductive health because of the impairment of spermatogenesis, steroidogenesis
      and sexual function. Hypothalamo-pituitary testicular dysfunction in uraemia is
      manifest clinically as delayed growth and puberty, sexual dysfunction, androgen
      deficiency, impaired spermatogenesis and infertility. Apart from renal anaemia,
      there are at present no proven indications for androgen therapy in chronic renal
      failure. This chapter reviews the basis and scope for various clinical
      applications of gonadotropin and androgen therapy as an adjunct to the standard
      medical care of chronic renal failure. The therapeutic possibilities implied by
      experimental and clinical findings suggesting that uraemic hypogonadism may be a
      functional state of gonadotropin deficiency are emphasized.

PMID- 10332567
TI  - The use of testosterone as a male contraceptive.
AB  - Testosterone functions as a contraceptive by suppressing secretion of the
      pituitary gonadotropins luteinizing hormone and follicle stimulating hormone. Low
      levels of these hormones decrease endogenous testosterone secretion from the
      testis and deprive developing sperm of the signals required for normal
      maturation. Interference with sperm maturation causes a decline in sperm
      production and can lead to reversible infertility in men, raising the possibility
      that testosterone could be utilized in a commercially available contraceptive. To
      this end, testosterone has been studied alone and in combination with either
      gonadotropin releasing hormone analogues or progestins in efforts to improve its
      contraceptive efficacy. In this chapter, we will review efforts to use
      testosterone to create a safe, convenient, efficacious contraceptive method for
      men.

PMID- 10332569
TI  - Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen
      replacement therapeutic agent.
AB  - Testosterone therapy is commonly used to treat male hypogonadism, androgen
      deficiency of severe illness, androgen deficiency of ageing and microphallus in
      infancy. The effects of testosterone are mediated directly as testosterone or
      after conversion to either dihydrotestosterone (DHT) or oestradiol. DHT is a
      potent androgen and cannot be aromatized to oestrogens, therefore acting as a
      pure androgen. DHT has been proposed as an androgen replacement therapy, with
      possible advantages over testosterone in certain circumstances in the ageing
      population as well as in patients with gynaecomastia and microphallus. A
      potential advantage of DHT over testosterone as an androgen replacement therapy
      is the reported and seemingly paradoxically muted effects of DHT on prostate
      growth. The decreased effect of DHT compared with testosterone on the prostate
      gland of humans may be due to the decrease in intraprostatic oestradiol levels.
      The potential beneficial effect of less prostate growth after DHT requires
      substantiation and, if true, must be balanced against any negative effects that
      might occur on bone, lipids and sexuality when a pure androgen replaces treatment
      with an aromatizable androgen.

PMID- 10332570
TI  - Is there a case for DHEA replacement?
AB  - There are many hormonal changes that occur with ageing in humans, of which the
      most dramatic and intriguing change occurs for the adrenal androgenic steroid
      dehydroepiandosterone (DHEA). There are tantalizing epidemiological data
      demonstrating a significant association between the changes in circulating DHEA
      level and changes in the incidence of malignancy, atherosclerosis, Alzheimer's
      disease and other age-related changes. The pharmacological effects in animals
      such as rodents and rabbits have demonstrated many beneficial effects, for
      example increased immune function, the prevention of atherosclerosis, cancer,
      diabetes and obesity, and the improvement of memory. Clinical studies carried out
      in small groups of subjects have clearly demonstrated that the administration of
      DHEA to the elderly increases many hormone levels, including that of insulin-like
      growth factor-1, (free and total) testosterone, dihydrotestosterone, oestrone and
      oestradiol. It remains to be clearly defined whether these changes are clinically
      beneficial, and there is only insufficient information on the side-effects on
      long-term use. Results from short-term intervention studies in small groups of
      subjects have not demonstrated any convincing beneficial effects so far. A
      judgement on whether DHEA replacement has a place in preventing age-related
      disabilities could be determined only on the basis of results from studies of
      long-term DHEA replacement in elderly people.

PMID- 10332571
TI  - Potential adverse effects of long-term testosterone therapy.
AB  - Natural testosterone and its esters, even when applied in supraphysiological
      doses, rarely produce side-effects. Via a negative feedback mechanism, exogenous
      testosterone suppresses the production of lutenizing hormone and follicle
      stimulating hormone, and leads to reduced testicular sperm production and,
      consequently, reduced testicular volume. The main concerns for the potential
      adverse effects of testosterone treatment are the prostate and the cardiovascular
      system. Androgens play a permissive role in the development of prostate cancer
      and benign prostate hyperplasia; however, there are no data to indicate that
      testosterone administration can lead to the progression of pre-clinical or
      clinical prostate cancer. Whether the effects of testosterone treatment on lipid
      metabolism are clinically relevant is as yet undetermined. The effects of
      testosterone on behaviour, especially on aggression, have not been firmly
      established. Some androgen effects, such as virilization and coarsening of the
      voice, considered normal in adult men are inappropriate in women and children.

PMID- 10332572
TI  - Precursors to schizophrenia.

PMID- 10332573
TI  - Prenatal factors and adult mental and physical health.
AB  - OBJECTIVE: To review research on prenatal influences on adult mental and physical
      health and draw implications for future directions in psychiatric research.
      METHOD: Schizophrenia is selected as an example from mental health and
      cardiovascular disease as an example from physical health. For each of these
      disorders, empirical findings on prenatal influences are reviewed, and the
      methods used to demonstrate them are critiqued. RESULTS: Research on prenatal
      antecedents of these conditions has proceeded in parallel: intriguing findings
      have related fetal growth restriction or fetal insult to adult health; similar
      types of causal pathways have been proposed to explain the relationships; and
      research has been plagued by similar limitations, including lack of precise
      prenatal exposure data and difficulty of controlling confounding. The prevailing
      view of disease causation, which is not well-suited to investigation of prenatal
      antecedents, impedes research in both fields. Yet, there has been little
      interchange between researchers in the 2 fields. CONCLUSIONS: We propose a causal
      paradigm that could serve as a guide for future investigations on the prenatal
      antecedents of adult health and promote interchange between research on mental
      and physical health. The paradigm reflects current thinking in epidemiology by
      encompassing not only risk factors as traditionally conceived but also causal
      chains over time and causal influences at multiple levels of organization.
      Implications for the design of new research are illustrated with reference to an
      ongoing study.

PMID- 10332574
TI  - Precursors to schizophrenia: do biological markers have specificity?
AB  - This review addresses childhood antecedents and biological markers of
      schizophrenia within a neurodevelopmental framework. General-population birth
      cohort studies illustrate delays in developmental milestones, abnormalities in
      social functioning, and cognitive deficits throughout childhood, adolescence, and
      early adulthood. Abnormal neurology and motor dysfunction have been measured in
      children prior to the onset of schizophrenia, at first onset of disease, and in
      those with chronic schizophrenia. Minor physical anomalies, a static marker of
      developmental disturbance, are also increased in schizophrenia. None of these
      factors has high specificity for this disorder. This review examines the
      associations between these precursors and some etiological factors for
      schizophrenia, comments on their lack of complete specificity to this psychotic
      syndrome, and considers their usefulness as predictors of risk.

PMID- 10332575
TI  - Psychiatric aspects of sexual abuse involving persons with developmental
      disabilities.
AB  - OBJECTIVE: To consider psychiatric issues that relate to the prevention and
      management of sexual abuse involving persons with developmental disabilities as
      either abusers or victims. METHOD: Seven case descriptions illustrate the
      clinical challenges raised by allegations of sexual abuse. RESULTS: Mental
      disorders and communication problems often coexist with the cognitive impairment
      that is primary in developmental disabilities. Pedophilic behaviour prompts
      allegations of abuse, and posttraumatic stress disorder often follows abuse.
      Difficulties communicating with others may preclude the detection of abuse or
      normal legal proceedings once an allegation is made. CONCLUSIONS: Psychiatric
      expertise applied both directly and indirectly through others is relevant in the
      prevention of sexual abuse and the management of those with developmental
      disabilities who are abusers or abused.

PMID- 10332576
TI  - Measuring unfitness to stand trial: psychological analysis of a legal issue.
AB  - The structure of the legal concept of unfitness to stand trial and how it
      corresponds to psychometric concepts is examined. We conclude that psychometric
      attempts at quantification and measurement are logically flawed, because they
      inappropriately treat fitness/unfitness as an individual trait rather than as
      situation-specific conjunctive/disjunctive concepts. It is argued that, whereas
      psychometric approaches may be suitable for measuring single components of
      unfitness, an overall "fitness" score is meaningless and that the assessment
      should focus on elements of unfitness. The determination of unfitness requires
      the simultaneous consideration of several different individual capabilities in
      reference to the demands of a specific trial. The quantification of these
      specific capabilities by psychologists can assist psychiatrists and the court,
      but the evaluation of their influence on unfitness in the instant case must be
      left to the court.

PMID- 10332577
TI  - [Sex differences relating to psychiatric treatment].
AB  - OBJECTIVE: This paper reviews the literature discussing the influence of gender
      factors on the efficacy of the most frequently used psychiatric treatments. It
      recommends taking into account patient gender in order to optimize the treatment
      efficacy and tolerance. METHOD: Pharmaceutical and psychotherapeutic treatments
      as well as other types of therapy (psychosurgery, electroconvulsive therapy
      [ECT]) are discussed in the overview. Each section draws intermediate
      conclusions. RESULTS: Literature on the subject is scarce and uneven. From a
      pharmaceutical perspective, gender differences are marked; they affect substance
      absorption, distribution, metabolism, and elimination. As a result, differences
      in bioavailability affect efficacy and side effects of antidepressants,
      neuroleptics, and lithium as well as of hypnotics, sedatives, and anxiolytics.
      The menstrual cycle and birth-control pills also produce significant
      interactions. Few studies have discussed the influence of the gender-specific
      effect on the outcome of psychotherapy. However, some differences might exist,
      and serious further research is required before repeatable conclusions can be
      reached. Patient gender does not seem to affect certain physical kinds of
      treatment such as psychosurgery or ETC as much. CONCLUSIONS: Patient gender has a
      definite influence on the efficacy of the treatment administered. This influence,
      however, is often limited and should be considered for the optimization of
      treatment response and tolerance. Research in this field of psychiatry should be
      encouraged.

PMID- 10332579
TI  - A comparison of male and female adolescents referred to an eating disorder
      program.
AB  - OBJECTIVE: To compare gender-related psychopathology and psychiatric diagnoses in
      male and female adolescents referred to an adolescent eating disorder program.
      METHOD: All adolescents presenting at the Eating Disorder Program at our hospital
      completed the semistructured Diagnostic Interview for Children and Adolescents
      Revised (DICA-R) and self-report scales, including the Children's Depression
      Inventory (CDI), the Brief Symptom Inventory (BSI), the Eating Disorder Inventory
      (EDI-2), and the Family Assessment Measure (FAM-III), during their initial
      assessment. The 157 subjects (21 male, 136 female) were classified into
      Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) eating disorder
      (ED) subtypes and then recombined into male and female restricters (R) and ED
      related groups: showing eating-related concerns but not having a DSM-IV
      diagnosis. We compared the male and female restricter groups and ED-related group
      on 5 specific psychological dimensions to examine comorbid psychiatric diagnosis,
      ED-specific and nonspecific psychopathology, EDI clinical and provisional
      subscales, and family functioning using multivariate analyses of covariance
      (MANCOVAs). RESULTS: Males endorsed statistically significant lower drive for
      thinness and body dissatisfaction than did females. However, there are no
      representative norms for adolescent males on these variables. The ED-related
      group also endorsed statistically significant lower drive for thinness and body
      dissatisfaction (specific ED psychopathology) than did the ED-restricter groups.
      The males in both groups endorsed fewer EDI items than did their female
      counterparts, but the differences were not statistically significant. Comorbid
      psychiatric diagnoses of depression and anxiety in male and female restricters
      were common but did not distinguish the groups. CONCLUSIONS: Our results suggest
      that male and female adolescents with EDs are clinically similar to each other
      and therefore resemble adults for lack of gender-specific effects on self
      reported psychopathology, family functioning, and comorbid psychiatric disorders.

PMID- 10332578
TI  - Abnormal involuntary movements in neuroleptic-naive children and adolescents.
AB  - OBJECTIVE: To determine the prevalence of and identify risk factors for abnormal
      involuntary movements in a well-characterized community sample of neuroleptic
      naive children and adolescents. METHOD: The Abnormal Involuntary Movement Scale
      (AIMS) was administered to 390 subjects aged 3-17 years who were in foster care.
      Additional instruments were used to assess intellect and behaviour problems.
      RESULTS: A total 12.6% of subjects had at least 1 rating of "mild" movements on
      AIMS; these included 4.1% with at least 2 ratings of "mild" or 2 of "moderate"
      severity. Significant risk factors for movement disorder were younger age, lower
      IQ, and more severe behaviour problems. The abnormal movements were usually
      orofacial, and the affected subjects were generally unaware of these movements.
      CONCLUSION: The base prevalence of abnormal involuntary movements must be
      considered in children and adolescents assessed for medication in order to
      determine the true rate of motor side effects.

PMID- 10332580
TI  - Family-of-origin characteristics in bipolar disorder: a controlled study.
AB  - OBJECTIVE: To assess the family-of-origin characteristics of patients with
      bipolar disorder relative to those of control subjects. METHOD: Fifty-six
      euthymic patients meeting research diagnostic criteria for bipolar disorder and
      21 control subjects completed the Family Environment Scale (FES) for the family
      they grew up with. RESULTS: The 2 groups showed strikingly similar profiles on 10
      indices of family functioning or structure. CONCLUSIONS: The results do not
      support the hypothesis that specific family attributes contribute to the
      development of bipolar disorder.

PMID- 10332581
TI  - Re: Canadian clinical practice guidelines for the treatment of schizophrenia.

PMID- 10332582
TI  - Polyglandular autoimmune syndrome type II and paranoid schizophrenia with
      obsessive-compulsive disorder.

PMID- 10332583
TI  - Who will protect mentally ill individuals from themselves?

PMID- 10332584
TI  - Deafness mistaken for dementia.

PMID- 10332585
TI  - Re: Mental health legislation and the right to appropriate treatment.

PMID- 10332586
TI  - Lamotrogine and impulse behaviour.

PMID- 10332587
TI  - Pulmonary embolus possibly associated with clozapine treatment.

PMID- 10332588
TI  - Olanzapine in an intensive care unit.

PMID- 10332589
TI  - Arachnoiditis ossificans. Diagnosis with helical computed tomography.
AB  - Arachnoiditis ossificans (AO) is a rare entity in which ossification of the
      leptomeninges occurs. This report illustrates a patient with AO of the cervical
      and dorsal spine, diagnosed by helical computed tomography with multiplanar
      reconstruction. It demonstrates the value of computed tomography in diagnosing
      calcified plaques and the utility of multiplanar reconstruction in giving an
      exact anatomic reference to neurosurgeon.

PMID- 10332590
TI  - The use of intravenous contrast in postoperative MR imaging of pituitary
      macroadenomas.
AB  - In this study we reviewed 23 postoperative magnetic resonance (MR) imaging
      examinations of patients with pituitary macroadenomas to determine if intravenous
      contrast is of value in this setting. The addition of contrast enhanced images to
      noncontrast T1-weighted images changed the radiologist's assessment in 4/5 early
      postoperative examinations and in 0/18 late postoperative examinations.
      Intravenous contrast is of value in distinguishing residual tumor from packing
      material on early postoperative MR examinations but is less useful in later
      postoperative examinations.

PMID- 10332591
TI  - MRI findings of isolated beta-2 microglobulin amyloidosis presenting as a
      cervical spine mass. Case report and review of literature.
AB  - A patient without prior history of renal failure or hemodialysis presented with
      weakness of the extremities. On magnetic resonance imaging (MRI), a peri-odontoid
      soft-tissue mass hypointense to muscle on both T1- and T2-weighted images was
      noted without obvious bony destruction. Pathological examination revealed
      degenerated fibrocartilage which stained for amyloid. Further, peroxidase
      staining for beta-2 microglobulin was positive. We describe the first case of a
      beta-2 microglobulin peri-odontoid amyloidoma without preceding history of
      hemodialysis and a review of literature is performed.

PMID- 10332592
TI  - Anterior neopharyngeal pseudodiverticulum. A possible cause of dysphagia in
      laryngectomized patients.
AB  - Anterior neopharyngeal pseudodiverticula are out-pouchings of the neopharyngeal
      lumen in laryngectomized patients which can cause postoperative dysphagia. In
      this study 20 laryngectomized patients were examined endoscopically and with
      barium swallow to determine the frequency of pseudodiverticulum formation, the
      correlation with clinical symptoms, and to evaluate the best modality for
      diagnosis. In 12 patients an anterior neopharyngeal pseudodiverticulum was
      present. Of these patients eight complained of dysphagia. The barium swallow
      showed more clearly the pseudodiverticula than laryngoscopy and gave additional
      information on functional implications. All symptomatic patients were
      successfully operated on with endoscopic laser therapy.

PMID- 10332593
TI  - Ectopic thymic tissue: a cause of emphysema in infants.
AB  - Ectopic thymic tissue can present a diagnostic dilemma when it is located in the
      posterior mediastinum. The diagnosis can be made by awareness of it and by use of
      computed tomography (CT) and magnetic resonance imaging (MRI). Rarely, ectopic
      thymus are reported to cause airway obstruction. In infants ectopic thymic tissue
      should also be considered in the differential diagnosis of secondary pneumonias
      and emphysema especially located in the upper lung zones.

PMID- 10332594
TI  - Small bowel carcinoid presenting as a barolith.
AB  - Baroliths are rare complications of barium contrast roentgenography that occur
      almost exclusively in the colon. Baroliths are often asymptomatic, but may be
      associated with abdominal pain, appendicitis, bowel obstruction, or perforation.
      We present an unusual case of a barolith which developed within the lumen of the
      small bowel, and resulted in the detection of an otherwise occult carcinoid tumor
      of the ileum.

PMID- 10332595
TI  - T-1 weighted sequences for hepatic MRI: re-evaluation using a phased array coil.
AB  - The purpose of this study was to compare three T1-weighted sequences for hepatic
      magnetic resonance (MRI) imaging with the use of a body phased array coil. Three
      different T1-weighted MR sequences were compared: a conventional spin echo (CSE);
      half-Fourier spin echo (HFSE), and a gradient recalled echo (GRE). Three
      independent reviewers compared the sequences both quantitatively and
      qualitatively. The T1-weighted GRE sequence scored highest for overall image
      quality (p < 0.001), lesion conspicuity (p = 0.012), and yielded the highest
      contrast to noise (C/N) values. GRE T1-weighted images are the best for hepatic
      MRI.

PMID- 10332596
TI  - The role of power Doppler sonography in the prenatal evaluation of fetal renal
      vasculature.
AB  - This study was performed to determine whether power Doppler sonography is
      superior to color Doppler sonography in the depiction of the normal fetal
      intrarenal vasculature during pregnancy. Twenty-five fetal kidneys in 22 healthy
      fetuses between 22 and 40 weeks of gestation (mean 32.6 weeks) were studied with
      color and power Doppler sonography with a 3.75 MHz transducer. The efficacy of
      power and color Doppler sonography were compared in assessing fetal renal
      vasculature. Power Doppler sonography demonstrated diffuse "blush" in almost the
      entire cortex in 21 of 25 fetal kidneys, whereas it was demonstrated in half of
      the cortex in the other four kidneys. Color Doppler sonography failed to
      demonstrate a cortical blush in fetal kidneys. Power Doppler sonography has been
      shown to be superior to color Doppler sonography in the depiction of normal fetal
      intrarenal vasculature during pregnancy by demonstrating vascular blood flow
      better than color Doppler sonography.

PMID- 10332597
TI  - Urine leaks in renal transplant patients. Diagnostic usefulness of sonography and
      renography.
AB  - We evaluated the utility of sonography and nuclear medicine renography in the
      detection of urine leaks in 57 renal transplant patients. Sonography and
      renography were equally sensitive in detecting leaks. But renography was more
      specific and therefore accurate (p < 0.0001) in detecting leaks. Urine leaks
      should be considered on sonography, which is often the first imaging study
      ordered in evaluating renal transplants, with new or increasing peritransplant
      fluid collections. Leaks should be confirmed by renography before performing
      additional invasive radiologic or surgical procedures.

PMID- 10332598
TI  - MRI of cervical adenocarcinoma with cystic components.
AB  - We encountered two cases of endocervical well-differentiated adenocarcinoma with
      cystic components. Magnetic resonance findings of the first case showed cystic
      lesion with enhanced mural nodule in the uterine cervix. The second case showed
      multicystic lesion in the uterine cervix. The cystic walls were thickening in the
      postcontrast T1-weighted image. The cervical adenocarcinoma with cystic
      components should be added to one of differential diagnosis of the uterine
      cervical cystic lesion.

PMID- 10332600
TI  - Bilateral elastofibroma dorsi. Two case reports.
AB  - Elastofibroma dorsi is a benign fibroproliferative lesion of unknown
      pathogenesis. It is most commonly found in the periscapular region in elderly
      women. The majority of patients are asymptomatic. The lesions have a
      characteristic location and a specific magnetic resonance imaging (MRI)
      appearance allowing accurate prospective diagnosis. The importance of recognizing
      the benign nature of this lesion to avoid an unnecessary operation is apparent.
      We describe two cases of bilateral elastofibroma dorsi with characteristic
      findings on MRI and typical histological appearances.

PMID- 10332599
TI  - Subcapsular hemorrhage of adult Wilms' tumor.
AB  - Wilms' tumor is a rare malignancy of kidney in adults. It usually cannot be
      differentiated from other renal masses preoperatively. This is a presentation of
      a case of adult Wilms' tumor who developed spontaneous hemorrhage during
      radiological evaluation. As tumor rupture can change the stage of the tumor and
      alter the prognosis of the patient, urgent work-up and treatment is advised.

PMID- 10332601
TI  - CT appearances in abdominal tuberculosis. A pictorial essay.
AB  - Abdominal tuberculosis continues to be endemic in the developing world and has
      shown a resurgence in the West. Computed tomography (CT) evaluation is singularly
      informative as it demonstrates involvement of the bowel, peritoneum, lymph nodes,
      and solid organs in a single examination. A spectrum of CT findings in an
      immunocompetent population is presented, ranging from subtle to advanced and
      common to rare. Genitourinary tuberculosis and tuberculosis in AIDS are excluded
      as they merit separate discussions.

PMID- 10332602
TI  - Development of the leaf epidermis.
AB  - The leaf epidermis is essential to plant survival not only because of its
      protective role at the interface with the plant's environment but also because of
      crucial developmental functions. The protoderm is set aside early in
      embryogenesis, possibly in the zygote. Epidermal identity is determined by the
      interactions of a complex set of factors, including developmental phase of the
      plant, regional identity within the leaf, and axiality. For the most part, these
      characteristics appear to be specified by internal tissues. On the other hand,
      the epidermis has a key role in regulating organ growth and expansion; thus
      interactions between the epidermis and internal tissues regulate the overall leaf
      architecture. Overlying this is the specification of different cell types within
      the epidermis. Some aspects of this appear to involve interactions with internal
      tissues but the patterning of many epidermal cell types seems to occur within the
      two-dimensional field of the epidermis itself and to require both cell signaling
      and cell lineage dependent mechanisms. Genetic analyses have provided much of the
      insight into the underlying principles that regulate epidermal development and a
      number of molecules important for various aspects of the process have been
      identified. Yet, for the most part, our understanding of the molecular basis for
      each component of epidermal development is still rudimentary and we have not yet
      scratched the surface of understanding how these pieces are integrated. The
      emerging technologies of functional genomics will provide powerful tools for
      solving these problems and the near future is likely to produce rapid progress.

PMID- 10332603
TI  - Genes and their products in sea urchin development.

PMID- 10332604
TI  - The organizer of the gastrulating mouse embryo.

PMID- 10332605
TI  - Molecular genetics of gynoecium development in Arabidopsis.
AB  - Carpels are the ovule-bearing structural units in angiosperms. In Arabidopsis,
      the specification of carpel identity is achieved by at least two separate
      pathways: a pathway mediated by the C class gene AG and an AG-independent
      pathway. Both pathways are negatively regulated by A class genes. Two genes, SPT
      and CRC, can promote differentiation of carpel tissue independently of AG and are
      thus components of the AG-independent pathway. CRC and SPT appear to act in a
      redundant manner to promote the differentiation of subsets of carpel tissues. The
      carpel primordium is subdivided into regional domains, both medial versus lateral
      and abaxial versus adaxial. Based on morphological and gene expression analyses,
      it appears likely that these domains define developmental compartments. The
      medial domain appears fated to differentiate into the marginal tissue types of
      the carpel (septum with transmitting tract and placenta with ovules), whereas the
      lateral domain gives rise to the ovary walls. The expression of ETT defines the
      abaxial domain, and this gene is involved in the abaxial-adaxial and, possibly,
      the apical-basal patterning of tissues in the carpel. Once regional domains have
      been established, the differentiation of tissue and cell types occurs. The MADS
      box gene FUL and AGLI/5 are involved in the differentiation of specific tissue
      types in the valves and valve margins. Thus, the genes identified can be arranged
      in a functional hierarchy: specification of carpel identity, patterning of the
      carpel primordium and directing the differentiation of the specialized tissues of
      the carpel.

PMID- 10332606
TI  - Digging out roots: pattern formation, cell division, and morphogenesis in plants.
AB  - The analysis of plant development by genetic, molecular, and surgical approaches
      has accumulated a large body of data, and yet it remains a challenge to uncover
      the basic mechanisms that are operating. Early steps of development, when the
      zygote and its daughter cells organize the embryonic plant, are poorly understood
      despite considerable efforts toward the identification of relevant genes.
      Reported cases of genetic redundancy suggest that the difficulty in uncovering
      patterning genes may reflect overlapping gene activities. Our current knowledge
      on plant embryo development still leaves open whether mechanisms for axis
      formation and subsequent pattern formation are fundamentally different in animals
      and plants. Axis formation may follow the general principle of establishing a
      peripheral asymmetric cue and mobilizing the cytoskeleton toward this cue--in the
      case of plants possibly located in the cell wall--but the molecules involved may
      be entirely different. Embryonic pattern formation involves the establishment of
      different domains, but although there are candidates, it is not clear whether
      genes that define these domains are identified yet. Pattern formation continues
      postembryonically in the meristem, and the flexibility of this process may be
      explained by a feed-forward system of patterning cues originating from more
      mature cells. Control of cell division and differentiation, which is important in
      the meristems--regions of continuous development--has been studied intensively
      and appears to involve short-range signaling and transmembrane receptor kinase
      activation. Finally, although high importance of control of cell division rates
      and planes for plant morphogenesis have been often inferred, recent genetic
      studies as well as comparative morphological data point to a less decisive role
      of cell division and to global controls of as yet unknown nature.

PMID- 10332607
TI  - Job continuity among new mothers.
AB  - In the early 1990s, both state and federal governments enacted maternity-leave
      legislation. The key provision of that legislation is that after a leave of a
      limited duration, the recent mother is guaranteed the right to return to her
      preleave employer at the same or equivalent position. Using data from the
      National Longitudinal Survey of Youth, we correlate work status after childbirth
      with work status before pregnancy to estimate the prevalence, before the
      legislation, of returns to the preleave employer. Among women working full-time
      before the pregnancy, return to the prepregnancy employer was quite common. Sixty
      percent of women who worked full-time before the birth of a child continued to
      work for the same employer after the child was born. Furthermore, the labor
      market behavior of most of the remaining 40% suggests that maternity-leave
      legislation is unlikely to have a major effect on job continuity. Compared with
      all demographically similar women, however, new mothers have an excess
      probability of leaving their jobs.

PMID- 10332608
TI  - Is there competition between breast-feeding and maternal employment?
AB  - Theory suggests that the decision to return to employment after childbirth and
      the decision to breast-feed may be jointly determined. We estimate models of
      simultaneous equations for two different aspects of the relationship between
      maternal employment and breast-feeding using 1993-1994 data from the U.S. Food
      and Drug Administration's Infant Feeding Practices Study. We first explore the
      simultaneous duration of breast-feeding and work leave following childbirth. We
      find that the duration of leave from work significantly affects the duration of
      breast-feeding, but the effect of breast-feeding on work leave is insignificant.
      We also estimate models of the daily hours of work and breast-feedings at infant
      ages 3 months and 6 months postpartum. At both times, the intensity of work
      effort significantly affects the intensity of breast-feeding, but the reverse is
      generally not found. Competition clearly exists between work and breast-feeding
      for many women in our sample.

PMID- 10332609
TI  - The impact of wives' earnings on income inequality: issues and estimates.
AB  - We estimate the extent to which rising family income inequality can be explained
      by changes in the earnings of married women. We develop a decomposition equation
      that separates single persons from married couples (decomposition by population
      group) and, for married couples, distinguishes the impact of wives' earnings from
      other sources of income (decomposition by income source). Despite the rising
      correlation between husbands' and wives' earnings, changes in wives' earnings do
      not explain a substantial portion of the increase in family income inequality.
      Our results contradict those of some previous analyses. The inconsistency of
      recent estimates can be traced to the use of a variety of conceptually different
      approaches in the previous literature. We clarify these approaches by explicitly
      distinguishing the conceptual issues, analyzing the empirical components, and
      providing comprehensive estimates.

PMID- 10332610
TI  - The educational attainment of young women: role model effects of female high
      school faculty.
AB  - To test for the presence of role model effects of female high school faculty and
      professional staff on young women in high school, we estimate several models of
      educational attainment for young women using data from the National Longitudinal
      Survey of Youth. Exposure to female high school faculty and professional staff
      has a positive impact on the educational attainment of young women. This result,
      combined with our finding that female faculty and professional staff have no
      significant impact on the educational attainment of young men, supports a female
      role model hypothesis.

PMID- 10332611
TI  - The gender gap in the economic well-being of nonresident fathers and custodial
      mothers.
AB  - Using a unique sample of couples with children, we estimate the gender gap in
      economic well-being after marital separation, something that previous studies of
      individuals who divorce have not been able to do. The income-to-needs levels of
      formerly married mothers are only 56% those of their former husbands. The
      postseparation gender gap is reduced if the wife was employed full-time and was
      an above-average earner before marital disruption. The gap is also relatively
      small among the least economically independent wives, those who were not employed
      before separation. For the latter group, the husband's relatively low income
      tends to reduce the gender gap.

PMID- 10332612
TI  - Life course transitions of American children: parental cohabitation, marriage,
      and single motherhood.
AB  - We examine the life course transitions into and from families headed by unmarried
      cohabiting couples for a recent cohort of American children. Life table
      estimates, based on data from the National Longitudinal Survey of Youth mother
      child files, indicate about one in four children will live in a family headed by
      a cohabiting couple sometime during childhood. Economic uncertainty is an
      important factor determining whether children in single-parent families
      subsequently share a residence with a mother's unmarried partner. Moreover,
      virtually all children in cohabiting-couple families will experience rapid
      subsequent changes in family status. Our estimates provide a point of departure
      for future work on children's exposure to parental cohabitation and its social
      and economic implications.

PMID- 10332613
TI  - Time? Money? Both? The allocation of resources to older parents.
AB  - We provide estimates of a reduced-form model of the allocation of household time
      and money resources. We consider four demands for these resources: time spent
      working, time spent providing care for noncoresident elderly parents, time spent
      performing housework, and monetary transfers to noncoresident elderly parents. We
      focus on the effects of wage rates and parental characteristics on the allocation
      decisions of adult children and their households concerning these four demands.
      We find that households with individuals earning high wages rely relatively more
      on cash transfers and relatively less on time transfers than do lower-wage
      households. We also find evidence consistent with an unmeasured tendency of some
      families to provide multiple sources of support.

PMID- 10332614
TI  - The new labor market: immigrants and wages after IRCA.
AB  - We examine the effect of the Immigration Reform and Control Act (IRCA) on
      migrants' wages using data gathered in 39 Mexican communities and their U.S.
      destination areas. We examine changes in the determinants of wages before and
      after the passage of IRCA, as well as the effects of its massive legalization
      program. Migrants' wages deteriorated steadily between 1970 and 1995, but IRCA
      did not foment discrimination against Mexican workers per se. Rather, it appears
      to have encouraged greater discrimination against undocumented migrants, with
      employers passing the costs and risks of unauthorized hiring on to the workers.
      Although available data do not permit us to eliminate competing explanations
      entirely, limited controls suggest that the post-IRCA wage penalty against
      undocumented migrants did not stem from an expansion of the immigrant labor
      supply, an increase in the use of labor subcontracting, or a deterioration of the
      U.S. labor market.

PMID- 10332615
TI  - The impact of war, famine, and economic decline on marital fertility in Ethiopia.
AB  - We examine recent fertility trends in Ethiopia for evidence of short- and long
      term responses to famine, political events, and economic decline. We use
      retrospective data on children ever born from the 1990 National Family and
      Fertility Survey to estimate trends in annual marital conception probabilities,
      controlling for women's demographic and socioeconomic characteristics. The
      results of our analysis provide evidence of significant short-term declines in
      conception probabilities during years of famine and major political and economic
      upheaval. In the longer term, marital fertility in both urban and rural areas
      declined in the 1980s after increasing moderately in the 1970s.

PMID- 10332616
TI  - The effect of inbreeding on early childhood mortality: twelve generations of an
      Amish settlement.
AB  - An unresolved issue in research on child survival is the extent to which familial
      mortality risk in infancy is due to biological influences net of sociodemographic
      and economic factors. We examine the effect of consanguinity on early childhood
      mortality in an Old Order Amish settlement by using the inbreeding coefficient,
      an explicit measure of the degree of relatedness in one's ancestry. Inbreeding
      has a net positive effect on neonatal and postneonatal deaths. We find social,
      demographic, and population-based sociocultural explanations for this effect
      among the Amish population which is known to experience certain genetically
      transmitted defects associated with mortality.

PMID- 10332618
TI  - Viscous properties of human muscle during contraction.
AB  - The purpose of this study was to determine viscous properties of human muscle
      during plantarflexion efforts. Experiments were performed on 17 subjects with an
      ankle ergometer allowing sinusoidal oscillations during isometric contractions
      and isokinetic movements. Sinusoidal oscillations led to the expression of (i)
      Bode diagrams of the musculo-articular system allowing the determination of a
      damping coefficient (Bbode); and (ii) a viscous coefficient (Bsin) using an
      adaptation of Hill's equation to sinusoidal oscillations. Isokinetic movements
      led to torque-velocity relationships. They showed a fall in torque associated to
      an increase in angular velocity what was quantified by calculating a damping
      coefficient (Biso). Both experiments gave consistent results indicating that
      Bbode was the lowest viscous parameter. This difference is discussed in terms of
      (i) "analog" viscosity originating from muscle cross-bridges; and (ii) real
      mechanical damping of passive structures.

PMID- 10332617
TI  - Religious involvement and U.S. adult mortality.
AB  - We use recently released, nationally representative data from the National Health
      Interview Survey-Multiple Cause of Death linked file to model the association of
      religious attendance and sociodemographic, health, and behavioral correlates with
      overall and cause-specific mortality. Religious attendance is associated with
      U.S. adult mortality in a graded fashion: People who never attend exhibit 1.87
      times the risk of death in the follow-up period compared with people who attend
      more than once a week. This translates into a seven-year difference in life
      expectancy at age 20 between those who never attend and those who attend more
      than once a week. Health selectivity is responsible for a portion of the
      religious attendance effect: People who do not attend church or religious
      services are also more likely to be unhealthy and, consequently, to die. However,
      religious attendance also works through increased social ties and behavioral
      factors to decrease the risks of death. And although the magnitude of the
      association between religious attendance and mortality varies by cause of death,
      the direction of the association is consistent across causes.

PMID- 10332619
TI  - Modelling of location- and time-dependent deformation of chondrocytes during
      cartilage loading.
AB  - Experimental evidence suggests that the biosynthetic activity of chondrocytes is
      regulated primarily by the mechanical environment. In order to study the
      mechanisms underlying remodeling, adaptation, and degeneration of articular
      cartilage in a joint subjected to changing loads, it is important to know the
      time-dependent fluid pressure and stress-strain state in chondrocytes. The
      purpose of the present study was to develop a theoretical model to simulate the
      mechanical behaviour of articular cartilage and to describe the time-dependent
      stress-strain state and fluid pressure distribution in chondrocytes during
      cartilage deformation. It was assumed that the volume occupied by the
      chondrocytes is small and that cartilage can be treated as a macroscopically
      homogenized material with effective material properties which depend on the
      material properties of the cells and matrix and the volumetric fraction of the
      cells. Model predictions on the time-dependent distribution of fluid pressure and
      stress and on the time-dependent cell deformation during confined and unconfined
      compression tests agree with previous theoretical predictions and experimental
      observations. The proposed model supplies the tools to study the mechanisms of
      degeneration, adaptation and remodelling of cartilage associated with cell
      loading and deformation.

PMID- 10332620
TI  - Statistical characterization of piezoelectric coefficient d23 in cow bone.
AB  - In a newly developed, highly sensitive dilatometer we applied pulsatile electric
      fields to five dry bone samples cut from mid-tibial sections within a 90 degrees
      angle from the rear to front axis. Samples of five cows were studied. We measured
      the piezoelectric coefficient d23 establishing its mean and confidence interval
      for the first time. An analysis of variance detected a significant difference of
      the coefficient between animals (P < 0.01) but not between samples (P = 0.5).
      Between animals the coefficient ranged from 9.6 x 10(-14) to 27.1 x 10(-14) C/N.
      It can no longer be assumed that piezoelectricity is an inherent property of
      bone, constant between animals.

PMID- 10332621
TI  - A biomathematical model for pressure-dependent lamina cribrosa behavior.
AB  - Investigating the relationship between intraocular pressure and the behavior of
      the lamina cribrosa (the primary site of the optic nerve damage in glaucoma) is
      important to insight into the pathogenesis of glaucomatous optic neuropathy. In
      most previous studies, unsuitable approaches were used since the lamina cribrosa
      was not taken as the main target. In the present study, a linear model of elastic
      mechanics theory on the bending of thin circular plate was developed for this
      purpose. The structural features of the lamina cribrosa and the forces acting on
      the lamina cribrosa were analyzed, and the constitutive equation was formulated.
      The general solution on a class of Karman Equation and the analytic solution on
      fixed boundary conditions were obtained, and from them, the morphological changes
      and the mechanical properties such as retrodisplacement and force distributions
      of the lamina cribrosa under pressure were derived. Some of the clinical
      phenomena occurring in glaucoma damage were explained with the results.
      Theoretical values were compared with the experimental data obtained by other
      investigators. The effects of structural parameters on susceptibilities to
      glaucoma damage were discussed. The biomathematical model, serving as formalistic
      expressions of the well-known hypothesis of pressure-dependent optic nerve damage
      in glaucoma, should make it possible for us to further understand and manage this
      disease.

PMID- 10332622
TI  - A geometric model of the human ankle joint.
AB  - A two-dimensional four-bar linkage model of the ankle joint is formulated to
      describe dorsi/plantarflexion in unloaded conditions as observed in passive tests
      on ankle complex specimens. The experiments demonstrated that the human ankle
      joint complex behaves as a single-degree-of-freedom system during passive motion,
      with a moving axis of rotation. The bulk of the movement occurred at the level of
      the ankle. Fibres within the calcaneofibular and tibiocalcaneal ligaments
      remained approximately isometric. The experiments showed that passive kinematics
      of the ankle complex is governed only by the articular surfaces and the
      ligaments. It was deduced that the ankle is a single-degree-of-freedom mechanism
      where mobility is allowed by the sliding of the articular surfaces upon each
      other and the isometric rotation of two ligaments about their origins and
      insertions, without tissue deformation. The linkage model is formed by the
      tibia/fibula and talus/calcaneus bone segments and by the calcaneofibular and
      tibiocalcaneal ligament segments. The model predicts the path of calcaneus
      motion, ligament orientations, instantaneous axis of rotation, and conjugate
      talus surface profile as observed in the experiments. Many features of ankle
      kinematics such as rolling and multiaxial rotation are elucidated. The
      geometrical model is a necessary preliminary step to the study of ankle joint
      stability in response to applied loads and can be used to predict the effects of
      changes to the original geometry of the intact joint. Careful reconstruction of
      the original geometry of the ligaments is necessary after injury or during total
      ankle replacement.

PMID- 10332623
TI  - Finite strain elastodynamics of intracranial saccular aneurysms.
AB  - Various investigators suggest that intracranial saccular aneurysms are
      dynamically unstable, that they resonate in response to pulsatile blood flow.
      This hypothesis is based on linearized analyses or experiments on rubber
      "models", however, and there is a need for a more critical examination. Toward
      this end, we (a) derive a new nonlinear equation of motion for a pulsating
      spherical aneurysm that is surrounded by cerebral spinal fluid and whose behavior
      is described by a Fung-type pseudostrain-energy function that fits data on human
      lesions, and (b) use methods of nonlinear dynamics to examine the stability of
      such lesions against perturbations to both in vivo and in vitro conditions. The
      numerical results suggest that this sub-class of lesions is dynamically stable.
      Moreover, with the exception of transients associated with initial perturbations,
      inertial effects appear to be insignificant for fundamental forcing frequencies
      less than 10 Hz and hence for typical physiologic and laboratory conditions. We
      submit, therefore, that further study of the mechanics of saccular aneurysms
      should be focused on quasi-static stress analyses that investigate the roles of
      lesion geometry and material properties, including growth and remodeling.

PMID- 10332624
TI  - The influence of the non-Newtonian properties of blood on the flow in large
      arteries: steady flow in a carotid bifurcation model.
AB  - Laser Doppler anemometry experiments and finite element simulations of steady
      flow in a three dimensional model of the carotid bifurcation were performed to
      investigate the influence of non-Newtonian properties of blood on the velocity
      distribution. The axial velocity distribution was measured for two fluids: a non
      Newtonian blood analog fluid and a Newtonian reference fluid. Striking
      differences between the measured flow fields were found. The axial velocity field
      of the non-Newtonian fluid was flattened, had lower velocity gradients at the
      divider wall, and higher velocity gradients at the non-divider wall. The flow
      separation, as found with the Newtonian fluid, was absent. In the computations,
      the shear thinning behavior of the analog blood fluid was incorporated through
      the Carreau-Yasuda model. The viscoelastic properties of the fluid were not
      included. A comparison between the experimental and numerical results showed good
      agreement, both for the Newtonian and the non-Newtonian fluid. Since only shear
      thinning was included, this seems to be the dominant non-Newtonian property of
      the blood analog fluid under steady flow conditions.

PMID- 10332625
TI  - Validation protocol of models for centre of mass estimation.
AB  - The estimation of the body centre-of-mass (COM) position requires the modelling
      of the human body as a system of rigid segments and the measurement of the
      position of related external anatomical landmarks. Many models for COM position
      estimation have been proposed with different levels of complexity and, in some
      cases, specific protocols have been used for model accuracy evaluation. In this
      paper, we propose a general method for the quantitative assessment of any COM
      model in relation to a determined set of movements. It consists of an
      experimental protocol and of a set of comparative indices, which quantify the
      congruence among the estimated kinematic variables and their expected values. The
      general applicability of the method is specifically addressed to models'
      comparison, aiming to support the user in the process of choice and validation of
      the most suitable model for her/his purposes. In this frame, the results of the
      analytical comparison among two kinematic models with different levels of
      complexity are reported.

PMID- 10332626
TI  - A marker-based measurement procedure for unconstrained wrist and elbow motions.
AB  - A protocol is proposed to obtain the joint angles of wrist and elbow from tracked
      triads of surface markers on each limb segment. Cuffs placed on the limb support
      the rigidity of the triads. Additional markers are used to mark the approximate
      positions of joints. Corrections of surface marker data for skin motion are
      derived from a priori knowledge about plausible joint motions. In addition, ill
      conditioned states are trapped when the elbow is nearly fully extended. The
      protocol is applied to sample motions which demonstrate the use and the effect of
      the corrections. The results show that the model assumptions are reasonable and
      that accurate joint rotations can be obtained. The correction steps prove to be
      an essential part of upper-extremity movement analysis.

PMID- 10332627
TI  - Plantar soft tissue thickness during ground contact in walking.
AB  - A technique is introduced for the measurement of plantar soft tissue thickness
      during barefoot walking. Subjects stepped into an adjustable Plexiglas frame
      which ensured that the required bony landmarks were appropriately positioned
      relative to a linear ultrasound probe connected to a conventional 7.5 MHz
      ultrasound scanner. Clear images of the metatarsal condyles or other foot bones
      were obtained throughout ground contact. Subsequent analysis of the video taped
      images using a motion analysis system allowed the tissue displacement to be
      calculated as a function of time. The tissue underneath the second metatarsal
      head was shown to undergo an average maximum compression of 45.7% during the late
      stages of ground contact during first step gait in a group of five normal
      subjects with a mean unloaded tissue thickness of 15.2 mm. The technique has a
      number of applications, including use in the validation of deformation predicted
      by finite element models of the soft tissue of the foot, and the study of
      alterations in the cushioning properties of the heel by devices which constrain
      the displacement of the heel pad.

PMID- 10332629
TI  - Comments on 'Asymmetric low back loading in asymmetric lifting movements is not
      prevented by pelvic twist'.

PMID- 10332628
TI  - Calibration of the "Flock of Birds" electromagnetic tracking device and its
      application in shoulder motion studies.
AB  - In this paper the applicability in terms of measurement accuracy of the "Flock of
      Birds" six D.O.F. electromagnetic tracking device in shoulder research is
      investigated. Position measurements in a workspace of approximately 1 m3 were
      performed using a stylus. The andom error at the stylus tip appeared to be 1.86,
      1.98 and 2.54 mm for x-, y- and z-coordinate, respectively. The error caused by
      distortion of the magnetic field by metal in the concrete of especially the floor
      was 20.8, 22.2 and 20.4 mm for the x-, y- and z-coordinate, respectively.
      Calibration and leaving out the measurements closest to the floor lowered this
      error to 2.07, 2.38 and 2.35 mm. Orientation errors of the shoulder bones
      evolving from the measurement inaccuracy were estimated from repeated
      measurements of shoulder bony landmarks of ten subjects by means of the stylus.
      These errors were generally below 2 degrees. This is lower than found for the
      same measurements using a spatial linkage digitizer. It is concluded that the
      "Flock of Birds" is a useful tool for shoulder kinematic studies.

PMID- 10332630
TI  - Immunological cross reactivity between Candida albicans and human tissue.
AB  - An old concept to account for autoimmunity is the existence of immunologic cross
      reactions, or shared determinants between an exogenous agent and self antigen. To
      study molecular mimicry between the Candida antigen and an autoantigen, sera from
      clinical specimens were screened, based on seronegativity or positivity for
      thyroid, ovary and adrenal antibodies. Compared with tissue antibody negative
      sera and sera from healthy controls, samples from positive tissue antibody
      subjects exhibited significantly higher levels of Candida IgG (P < 0.001) IgM (P
      < 0.001) and IgA (P < 0.01) antibodies. While Candida antibodies were elevated in
      60% of tissue antibody positive samples, these antibodies were present in only
      7.5% of tissue antibody negative subjects and in 10% of healthy controls. Since
      PAGE electrophoresis showed similar bands mobility in Candida and different
      tissues, these positive antibodies and rabbit anti Candida antibodies were
      reacted in immunodiffusion and Western Blot Assay against Candida and tissue
      antigens, simultaneously. The results of immunodiffusion showed a clear
      precipitation line against tissue antigens when rabbit anti Candida or human
      positive Candida serum was used. Similarly, Western Blot Assays with rabbit or
      human anti Candida serum showed several positive bands with Candida and one or
      two positive bands with different tissues. The common antigens were located in
      the regions of 72 and 36 KD. The 72 KD was detected in capsule antigens,
      placenta, ovary, adrenal, thymus, liver, pancreas, spleen, brain and kidney, but
      not in sperm or epithelial cell antigen. The 36 KD antigen was positive in
      placenta, spleen adrenal, pancreas and capsule tissues. Absorbtion of sera
      containing high levels of Candida antibodies with tissue antigens caused 10-15%
      reduction in antibody titers. Moreover, treatment of thyroid antibody positive
      sera with C. Albicans caused a similar reduction in thyroid antibody levels.
      These reductions in antibody levels are an additional support for cross
      reactivity between C. Albicans and mammalian tissues. A demonstration of
      immunological cross reactivity between Candida and human tissues may be
      associated with the possible pathogenic role of Candida Albicans in the
      development of autoimmune diseases which warrants further investigation.

PMID- 10332631
TI  - Tumor necrosis factor production by rat Kupffer cells-regulation by
      lipopolysaccharide, macrophage activating factor and prostaglandin E2.
AB  - Tumor necrosis factor (TNF) is considered to be deeply involved in the hepatocyte
      damages in severe hepatitis. To delineate which mediators are involved in the
      production of TNF in vivo, we examined regulatory mechanisms of the production of
      TNF by rat Kupffer cells using a variety of mediators. Lipopolysaccharide (LPS)
      markedly induced TNF production by Kupffer cells. Kinetic studies revealed a
      rapid release of TNF within 3-4 hrs after the addition of LPS to the culture
      medium. Spleen cell derived-macrophage activating factor prepared from rat spleen
      cells did not by itself induce the production of TNF. However, the presence of a
      small amount of the factor during or before exposure to LPS induced higher levels
      of TNF, suggesting that macrophage activating factor had a priming effect.
      Recombinant human interferon-gamma and recombinant human granulocyte-macrophage
      colony stimulating factor, the natural types of which are components of the
      macrophage activating factor, displayed similar effects. Prostaglandin E2 (PGE2)
      and dexamethasone both inhibited LPS-induced TNF production in a dose dependent
      manner. Indomethacin, a cyclooxygenase inhibitor, increased LPS-induced TNF
      production. Interestingly, a combination of PGE2 and indomethacin inhibited TNF
      production more strongly than PGE2 alone, suggesting that the simultaneous
      treatment with PGE2 and indomethacin decreases liver damage in severe hepatitis
      rather than PGE2 alone. In addition, PGE2 pretreatment reduced the response to
      the newly added PGE2, suggesting the presence of a desensitization mechanism in
      the PGE2 receptor system. These findings suggest that spleen cell-derived
      macrophage activating factor and bowel-derived LPS take important parts in TNF
      production through the portal blood in the liver in vivo.

PMID- 10332632
TI  - Over-utilization of the J delta 3 gene-segment in Crohn's disease.
AB  - A majority of normal human intestinal intraepithelial lymphocytes (iIEL) are
      CD8+, express the alpha beta-T cell receptor (TCR) and are oligoclonal. The
      remainder of normal iIELs, which are also oligoclonal, express the gamma delta
      TCR and preferentially utilize variable regions (V delta 1 and V delta 3) which
      are different from adult peripheral blood lymphocytes (V delta 2). The junctional
      region usage of gamma delta-TCRs in intestinal diseases is largely unknown. The
      aim of this study was to examine gamma delta-T cell clonality and junctional
      region usage of V delta 1 and V delta 3 transcripts in Crohn's Disease (CD) in
      comparison to several other chronic inflammatory diseases of the colon by
      polymerase chain reaction amplification, cloning and sequencing. As previously
      observed in normal subjects, all inflammatory cases examined, including CD (n =
      3), ulcerative colitis (n = 1), diverticulitis (n = 1) and lymphocytic colitis (n
      = 1), the V delta 1 and V delta 3 transcripts contained reiterated sequences
      consistent with the expansion of gamma delta-T cells expressing these receptors.
      In 2/3 CD cases, but none of the non-CD inflammatory cases, transcripts
      containing J delta 3, a rarely used J delta, was observed among the V delta 1
      and/or V delta 3 transcripts. Thus, in a subset of CD, gamma delta-T cells
      expressing J delta 3 may be expanded implicating a role for unique ligands that
      drive the expansion of T cells expressing these receptors.

PMID- 10332633
TI  - Innovations in integrated dual diagnosis treatment in public managed care: the
      Choate dual diagnosis case rate program.
AB  - This article describes the implementation and preliminary evaluation of a dual
      diagnosis case rate program developed as a collaborative experiment between a
      public managed Medicaid organization (MHMA) and a specialized integrated dual
      diagnosis provider (Choate) with a vertically integrated, managed-care oriented
      system of care. The case rate program applied to dually-diagnosed inpatient
      referrals for a period of 65 days. On admission, 68% of the patients had little
      insight, motivation and compliance regarding addiction or psychiatric management.
      Nonetheless, 56% maintained sobriety for 65 days, and 49% of these were still
      sober at 95-day follow up.

PMID- 10332634
TI  - Assertive Community Treatment for patients with chronic and severe mental illness
      who abuse drugs.
AB  - The Assertive Community Treatment model of mental health service delivery has
      been extensively studied and has undergone various modifications over the past
      twenty years. This article describes a modified ACT Team approach to the
      treatment of individuals who suffer from severe comorbid mental illness and
      substance abuse. Demographics of patients who are chosen to receive these
      intensive services, service utilization patterns, and elements of team treatment
      are discussed. Comparisons with less severely ill dual diagnosis patients who
      receive more traditional case management services are reviewed.

PMID- 10332635
TI  - Treatment for MICAs: design and implementation of the modified TC.
AB  - This article describes the main features of an innovative therapeutic community
      (TC) model adapted for use with mentally ill chemical abusers (MICAs). It
      describes the rationale for use of the modified TC with MICAs, the treatment
      structure and environment created, the essential components of the modified TC
      program, staffing, and the process and goals of client change. Details are given
      regarding issues and strategies for the implementation of the new program in
      terms of program planning, staff training, and system initiation. Evaluation data
      from the authors' research is summarized to support the adoption of the modified
      TC model. The article makes clear the feasibility of a modified TC model of
      established effectiveness with a MICA population. This model has now been
      successfully introduced into mental health, drug treatment, shelter, and
      correctional settings.

PMID- 10332636
TI  - Level of burden among women diagnosed with severe mental illness and substance
      abuse.
AB  - Women diagnosed with severe mental illness and substance abuse may face a variety
      of associated difficulties that require intervention, including other health
      related problems, housing instability or homelessness, and a history of or
      current physical or sexual abuse. This article expands upon the concept of "level
      of burden" by specifically examining issues for women with multiple
      vulnerabilities in a sample of 577 women participating in a residential substance
      abuse treatment program. Two types of outcomes were examined for the women. In
      Study 1, the effects of severe mental illness as well as overall level of burden
      on retention in treatment were examined. Cox regression analyses revealed that
      severe mental illness was significantly related negatively to retention in
      treatment; those women diagnosed with severe mental illness tended to stay in
      treatment less time than those without such a diagnosis. In Study 2, staff
      ratings of the women's status at departure from residential treatment for a
      subsample of 311 women were examined with respect to overall retention in
      treatment and severe mental illness. Ratings of client status at program exit
      were significantly related to time in program but were not related to having a
      severe mental illness diagnosis. For a few indicators (e.g., leaving treatment
      against advice, having scattered or disorganized thoughts, and having no specific
      plans for life outside of treatment), there was an interaction between time in
      program and severe mental illness such that women with severe mental illness who
      were retained for less than 180 days were more likely to demonstrate negative
      outcomes. Implications for the treatment of multiply-diagnosed women are
      discussed.

PMID- 10332637
TI  - The Addiction Treatment Unit: a dual diagnosis program at the California Medical
      Facility--a descriptive report.
AB  - The Addiction Treatment Unit is a dual diagnosis program which exists in the
      California Department of Corrections. It is housed in the California Medical
      Facility in Vacaville, California. Program residents must meet the diagnostic
      criteria of having a major mental disorder substantiated by a DSM-IV Axis I
      diagnosis and also meet the criteria for a substance abuse/dependence disorder.
      All patients are housed in one wing of the facility, which is based on the format
      of a modified therapeutic community and focuses on the concept of recovery. A
      multidisciplinary treatment team comprised of a psychiatrist, a psychologist, a
      social worker and a psychiatric technician delivers clinical interventions,
      including individual and group therapy as well as medication management. The
      focus of the drug treatment aspect is an Alcoholics Anonymous/Narcotics Anonymous
      approach based on 12-Step philosophy. Research involving other therapeutic
      communities running in prisons is discussed as is the aspect of dual diagnosis
      programs. Logistical and environmental constraints which pose challenges to
      running the Addiction Treatment Unit are considered. A summary section reflects
      on aspects which have been successful, what has not worked or has been changed
      and upcoming program revisions.

PMID- 10332638
TI  - A dual diagnosis typology to improve diagnosis and treatment of dual disorder
      patients.
AB  - A dual diagnosis typology was developed with three subtypes. Type I is a primary
      psychiatric disorder with substance use only when psychiatrically symptomatic
      (self-medication). Type II is a primary substance use disorder with substance
      induced psychiatric symptoms. Type III is psychiatric and substance use disorders
      of long duration that are co-occurring or present at different times. Type III is
      considered the "true" dual disorder state. This typology was found to be reliable
      and have consensual validity. It was used with a standardized interview and
      clinical interview plus questions designed to determine the subtype with patients
      in psychiatric and substance abuse outpatient programs and with state hospital
      inpatient dual disorder patients. The dual disorder subtypes found in the
      psychiatric outpatient programs were: Type I, 21%; Type II, 9%; and Type III,
      70%. In the substance abuse programs were found: Type I, none; Type II, 37%; and
      Type III, 63%. The subtypes in the state psychiatric patients were: Type I, 14%;
      Type II, 47%; and Type III, 39%. This method was found to be relatively easy to
      apply; it also increased staff interest in the dual disorder population and
      improved differential diagnoses and targeted interventions.

PMID- 10332639
TI  - Awareness of substance abuse problems among dually-diagnosed psychiatric
      inpatients.
AB  - This study examines the ability to acknowledge the need for treatment of mental
      illness and substance abuse problems among dually-diagnosed inpatients before and
      after an inpatient substance abuse treatment program. A cohort of 264
      consecutively admitted patients diagnosed with a mental illness and substance use
      disorder were entered into a dual diagnosis treatment program. Perceptions of
      patients diagnosed with a substance-induced mental disorder were compared to
      those of patients with a primary mental illness regarding their problems and need
      for treatment before and after the dual diagnosis program. Most patients
      acknowledged a substance abuse or mental illness problem and need for treatment.
      Patients with substance-induced mental disorders were more likely to acknowledge
      a substance use problem and need for treatment (p < .001). After treatment,
      changes in perception of mental illness were greater for substance-induced mental
      disorder patients compared to patients with a primary mental illness (p < .001).
      Persons with more severe substance abuse were more likely to acknowledge a
      problem and need for treatment. The majority of dually-diagnosed patients
      admitted with a substance use disorder agreed that substance use was a problem,
      suggesting that inpatient hospitalization presents a prime opportunity to address
      addiction in dually-diagnosed patients. The type of mental illness and severity
      of substance use influenced perceptions of illnesses and treatment readiness and
      must be considered by the clinician.

PMID- 10332640
TI  - Psychotropic medication management in persons with co-occurring psychiatric and
      substance use disorders.
AB  - Persons presenting with concurrent psychiatric and substance problems present
      unique challenges for diagnosis and for effective and rational treatment
      planning. This is especially true for psychiatrists attempting to prescribe
      pharmacologic interventions which will promote recovery from both disorders and
      improve function. In order to be effective in this endeavor it is important to
      have a clear understanding of the dynamics of addiction as well as the particular
      issues and struggles related to mental illness which will affect an individual's
      attitude toward and use of medication. This article discusses some of the common
      problems related to diagnostic decision making and initiation of medication in
      persons with co-occurring disorders. An algorithm for guiding these decisions is
      presented. Common misconceptions held by these individuals regarding medication,
      as distinguished from "drugs," are considered. Unique psychodynamic issues that
      may lead these persons to actively seek medication as a solution to their
      problems, or which may, conversely, lead them to an outright rejection of
      medication as a part of their recovery, are discussed. Countertransferential
      issues influencing the physician's approach to prescribing for this population
      are also considered. The article concludes with recommendations for pharmacologic
      approaches to address specific psychiatric syndromes which may present in this
      population.

PMID- 10332641
TI  - Dissociative identity disorder and substance abuse: the forgotten relationship.
AB  - The treatment and research of dissociative disorders, particularly dissociative
      identity disorder (DID), are hampered by professional skepticism and diagnostic
      uncertainties. Almost always associated with severe and sustained childhood
      trauma, its chief manifestations are at least two distinct and separate
      identities which have an independent manner of existing in the world. It is also
      associated with a high degree of psychiatric comorbidity. Among the most frequent
      diagnoses found in patients with DID are substance use and dependence. For a
      variety of reasons there has been little dialogue among the disciplines that
      study patients with trauma and those that study and treat substance abuse.
      Clinicians dealing with a primarily substance-abusing population are likely to
      encounter but not recognize these patients. The authors present several
      representative cases illustrative of features of patients with DID. The
      epidemiology, phenomenology and presentation of DID, as well as its relation to
      posttraumatic stress disorder are discussed. Little systematic investigation
      exists on the treatment of DID in general, and substance abuse in DID in
      particular. The authors draw upon the existing literature, and their experience
      to discuss treatment strategies aimed at treating patients with both diagnoses.
      Ignoring either diagnosis is likely to be detrimental to patients; both disorders
      and their coexistence need to be addressed.

PMID- 10332642
TI  - Treatment outcome of an outpatient treatment program for dually-diagnosed
      veterans: the Cincinnati Veterans Affairs Medical Center.
AB  - The Dual Diagnosis Clinic at the Cincinnati VA Medical Center is an integrated
      treatment program for veterans who have an Axis I psychiatric illness in addition
      to a substance dependence problem. With a high staff-to-patient ratio and an
      individualized approach, the DDC treats many dual diagnosis patients effectively.
      To demonstrate the effectiveness of this approach, an outcome study was conducted
      looking at the psychiatric emergency room visits, hospitalization rates, and the
      average length of stay for 557 DDC patients. Patients were divided into two
      groups: those who completed the assessment period, and those who did not. Equal
      periods of time before and after this assessment period were studied. Those who
      completed were more likely to have had fewer psychiatric emergency room visits (p
      < 0.000001) after the assessment period than before when compared to dropouts.
      The engaged group had the same or more hospital admissions after the assessment
      period than before, while the dropout group had fewer. This suggests that there
      is a significant disorder of engagement for the dual diagnosis populations, and
      that the first impact of successful treatment is engagement.

PMID- 10332643
TI  - Reflections on two decades of research on teen sexual behavior and pregnancy.
AB  - During the past 20 years, both researchers and program developers made great
      progress in their efforts to reduce adolescent unprotected sex and prevent teen
      pregnancy. Research studies are now more likely to employ experimental designs
      with random assignments, to have large sample sizes with adequate statistical
      power, to measure actual sexual and contraceptive behaviors, to measure longer
      term effects, to employ proper statistical methods, and to report results in an
      unbiased manner. As a result of this body of research, large advances have
      occurred in our understanding of: 1) the incidence of teen pregnancy, and its
      consequences; 2) the effects of improving adolescent knowledge, increasing access
      to contraception, and improving parent/child communication; and 3) the
      characteristics of effective programs. The on-going evaluation of sex and HIV
      education programs coupled with creativity and perseverance on the part of
      program developers led to two groups of effective programs--sex and HIV education
      programs that reduce sexual risk-taking behavior, and youth development programs
      that reduce teen-age pregnancy and childbearing.

PMID- 10332644
TI  - Recruiting adolescents into qualitative tobacco research studies: experiences and
      lessons learned.
AB  - An increasing barrier to the development and implementation of effective youth
      smoking prevention and cessation programs involves recruiting adolescents into
      research studies. Even for non-intervention studies, issues of consent,
      confidentiality, and motivation to participate are important considerations. In
      1996, 11 Prevention Research Center sites across the country conducted
      qualitative research using focus groups to explore ethnic differences in smoking
      among adolescents. The diversity in strategies used to interest, motivate, and
      retain potential focus group subjects provided a rich data set for information
      about effective strategies and challenges to recruitment. This article presents
      an overview of recruitment methods used in a multi-site qualitative study on
      adolescent tobacco use, reports on successful and less successful strategies, and
      provides recommendations for future recruitment.

PMID- 10332645
TI  - Promoting sun protection in elementary schools and child care settings: the
      SunSafe Project.
AB  - Elementary schools and child care settings in rural New Hampshire participated in
      a sun protection program that reached more than 4,200 children. The program was
      part of a successful multifaceted community intervention targeting children ages
      2-9. Program components included curricular materials, training and support for
      school/child care staff, and parent outreach. Evaluation showed good uptake of
      the curriculum by teachers and child care providers, improvements in sun
      protection policy in participating schools and child care settings, and
      significant knowledge and attitude improvements in fourth grade children tested,
      as well as actual behavior change. The study highlighted the importance of
      flexible, developmentally appropriate curricular materials and active engagement
      of principals and directors in policy review. In addition, for parent outreach
      programs to be successful, children needed to participate.

PMID- 10332646
TI  - Parent expectations of the school health program in Nebraska.
AB  - This article presents findings from the first phase of a comprehensive evaluation
      plan for the school health program in Nebraska public schools. The evaluation
      utilized the Targeting Outcomes of Programs (TOP) framework to gather parents'
      perspectives about the benefits of the school health program, and a ranking of
      important health activities and role providers. A survey was distributed to 1,200
      parents randomly selected from 60 school districts. Of these, 450 (38%) were
      returned: 96% supported funding of health programs; 88% believed families
      benefited from school health; 92% viewed the health programs as "essential" to
      the educational mission; 64% preferred a ratio of 1 nurse/500 students; and 89%
      believed all students needed access to a professional school nurse. The nurse was
      the only clearly defined role in the health program and had activities rated as
      "extremely important." Results were reported to the Nebraska legislature for
      support of state funding for school health nursing.

PMID- 10332647
TI  - Reducing risks and building developmental assets: essential actions for promoting
      adolescent health.
AB  - Developmental assets provide the positive building blocks young people need for
      success. In this article, based on a keynote address to attendees at the 1998
      American School Health Association annual conference, research is discussed that
      suggests building specific developmental assets relates to lowered risk behavior
      patterns and increased patterns of thriving behavior among an aggregate sample of
      nearly 100,000, 6th-12th grade youth in 213 US communities. Issues related to the
      scientific foundations, reliability, and validity of the development assets
      framework are discussed. The contribution that building youth's developmental
      assets makes toward their well-being is presented as both a unique component of a
      healthy community and a necessary complement to risk reduction and treatment
      strategies.

PMID- 10332648
TI  - Calcium intake in adolescents: an issue revisited.

PMID- 10332649
TI  - Alien nation: a problem-solving activity for dealing with pertinent health
      issues.

PMID- 10332650
TI  - A nutrition relay race for preschool health education.

PMID- 10332651
TI  - Preventing disease with stress management in elementary schools.

PMID- 10332652
TI  - Evaluation of vocabularies for electronic laboratory reporting to public health
      agencies.
AB  - Clinical laboratories and clinicians transmit certain laboratory test results to
      public health agencies as required by state or local law. Most of these
      surveillance data are currently received by conventional mail or facsimile
      transmission. The Centers for Disease Control and Prevention (CDC), Council of
      State and Territorial Epidemiologists, and Association of Public Health
      Laboratories are preparing to implement surveillance systems that will use
      existing laboratory information systems to transmit electronic laboratory results
      to appropriate public health agencies. The authors anticipate that this will
      improve the reporting efficiency for these laboratories, reduce manual data
      entry, and greatly increase the timeliness and utility of the data. The
      vocabulary and messaging standards used should encourage participation in these
      new electronic reporting systems by minimizing the cost and inconvenience to
      laboratories while providing for accurate and complete communication of needed
      data. This article describes public health data requirements and the influence of
      vocabulary and messaging standards on implementation.

PMID- 10332653
TI  - Continuous speech recognition for clinicians.
AB  - The current generation of continuous speech recognition systems claims to offer
      high accuracy (greater than 95 percent) speech recognition at natural speech
      rates (150 words per minute) on low-cost (under $2000) platforms. This paper
      presents a state-of-the-technology summary, along with insights the authors have
      gained through testing one such product extensively and other products
      superficially. The authors have identified a number of issues that are important
      in managing accuracy and usability. First, for efficient recognition users must
      start with a dictionary containing the phonetic spellings of all words they
      anticipate using. The authors dictated 50 discharge summaries using one
      inexpensive internal medicine dictionary ($30) and found that they needed to add
      an additional 400 terms to get recognition rates of 98 percent. However, if they
      used either of two more expensive and extensive commercial medical vocabularies
      ($349 and $695), they did not need to add terms to get a 98 percent recognition
      rate. Second, users must speak clearly and continuously, distinctly pronouncing
      all syllables. Users must also correct errors as they occur, because accuracy
      improves with error correction by at least 5 percent over two weeks. Users may
      find it difficult to train the system to recognize certain terms, regardless of
      the amount of training, and appropriate substitutions must be created. For
      example, the authors had to substitute "twice a day" for "bid" when using the
      less expensive dictionary, but not when using the other two dictionaries. From
      trials they conducted in settings ranging from an emergency room to hospital
      wards and clinicians' offices, they learned that ambient noise has minimal
      effect. Finally, they found that a minimal "usable" hardware configuration (which
      keeps up with dictation) comprises a 300-MHz Pentium processor with 128 MB of RAM
      and a "speech quality" sound card (e.g., SoundBlaster, $99). Anything less
      powerful will result in the system lagging behind the speaking rate. The authors
      obtained 97 percent accuracy with just 30 minutes of training when using the
      latest edition of one of the speech recognition systems supplemented by a
      commercial medical dictionary. This technology has advanced considerably in
      recent years and is now a serious contender to replace some or all of the
      increasingly expensive alternative methods of dictation with human transcription.

PMID- 10332654
TI  - A semantic lexicon for medical language processing.
AB  - OBJECTIVE: Construction of a resource that provides semantic information about
      words and phrases to facilitate the computer processing of medical narrative.
      DESIGN: Lexemes (words and word phrases) in the Specialist Lexicon were matched
      against strings in the 1997 Metathesaurus of the Unified Medical Language System
      (UMLS) developed by the National Library of Medicine. This yielded a "semantic
      lexicon," in which each lexeme is associated with one or more syntactic types,
      each of which can have one or more semantic types. The semantic lexicon was then
      used to assign semantic types to lexemes occurring in a corpus of discharge
      summaries (603,306 sentences). Lexical items with multiple semantic types were
      examined to determine whether some of the types could be eliminated, on the basis
      of usage in discharge summaries. A concordance program was used to find
      contrasting contexts for each lexeme that would reflect different semantic
      senses. Based on this evidence, semantic preference rules were developed to
      reduce the number of lexemes with multiple semantic types. RESULTS: Matching the
      Specialist Lexicon against the Metathesaurus produced a semantic lexicon with
      75,711 lexical forms, 22,805 (30.1 percent) of which had two or more semantic
      types. Matching the Specialist Lexicon against one year's worth of discharge
      summaries identified 27,633 distinct lexical forms, 13,322 of which had at least
      one semantic type. This suggests that the Specialist Lexicon has about 79 percent
      coverage for syntactic information and 38 percent coverage for semantic
      information for discharge summaries. Of those lexemes in the corpus that had
      semantic types, 3,474 (12.6 percent) had two or more types. When semantic
      preference rules were applied to the semantic lexicon, the number of entries with
      multiple semantic types was reduced to 423 (1.5 percent). In the discharge
      summaries, occurrences of lexemes with multiple semantic types were reduced from
      9.41 to 1.46 percent. CONCLUSION: Automatic methods can be used to construct a
      semantic lexicon from existing UMLS sources. This semantic information can aid
      natural language processing programs that analyze medical narrative, provided
      that lexemes with multiple semantic types are kept to a minimum. Semantic
      preference rules can be used to select semantic types that are appropriate to
      clinical reports. Further work is needed to increase the coverage of the semantic
      lexicon and to exploit contextual information when selecting semantic senses.

PMID- 10332655
TI  - The determination of relevant goals and criteria used to select an automated
      patient care information system: a Delphi approach.
AB  - OBJECTIVES: To determine the relevant weighted goals and criteria for use in the
      selection of an automated patient care information system (PCIS) using a modified
      Delphi technique to achieve consensus. DESIGN: A three-phase, six-round modified
      Delphi process was implemented by a ten-member PCIS selection task force. The
      first phase consisted of an exploratory round. It was followed by the second
      phase, of two rounds, to determine the selection goals and finally the third
      phase, of three rounds, to finalize the selection criteria. RESULTS: Consensus on
      the goals and criteria for selecting a PCIS was measured during the Delphi
      process by reviewing the mean and standard deviation of the previous round's
      responses. After the study was completed, the results were analyzed using a
      limits-of-agreement indicator that showed strong agreement of each individual's
      responses between each of the goal determination rounds. Further analysis for
      variability in the group's response showed a significant movement to consensus
      after the first goal-determination iteration, with consensus reached on all goals
      by the end of the second iteration. CONCLUSION: The results indicated that the
      relevant weighted goals and criteria used to make the final decision for an
      automated PCIS were developed as a result of strong agreement among members of
      the PCIS selection task force. It is therefore recognized that the use of the
      Delphi process was beneficial in achieving consensus among clinical and
      nonclinical members in a relatively short time while avoiding a decision based on
      political biases and the "groupthink" of traditional committee meetings. The
      results suggest that improvements could be made in lessening the number of rounds
      by having information available through side conversations, by having other
      statistical indicators besides the mean and standard deviation available between
      rounds, and by having a content expert address questions between rounds.

PMID- 10332656
TI  - Contrasting views of physicians and nurses about an inpatient computer-based
      provider order-entry system.
AB  - OBJECTIVE: Many hospitals are investing in computer-based provider order-entry
      (POE) systems, and providers' evaluations have proved important for the success
      of the systems. The authors assessed how physicians and nurses viewed the effects
      of one modified commercial POE system on time spent patients, resource
      utilization, errors with orders, and overall quality of care. DESIGN: Survey.
      MEASUREMENTS: Opinions of 271 POE users on medicine wards of an urban teaching
      hospital: 96 medical house officers, 49 attending physicians, 19 clinical fellows
      with heavy inpatient loads, and 107 nurses. RESULTS: Responses were received from
      85 percent of the sample. Most physicians and nurses agreed that orders were
      executed faster under POE. About 30 percent of house officers and attendings or
      fellows, compared with 56 percent of nurses, reported improvement in overall
      quality of care with POE. Forty-four percent of house officers and 34 percent of
      attendings/fellows reported that their time with patients decreased, whereas 56
      percent of nurses indicated that their time with patients increased (P < 0.001).
      Sixty percent of house officers and 41 percent of attendings/fellows indicated
      that order errors increased, whereas 69 percent of nurses indicated a decrease or
      no change in errors. Although most nurses reported no change in the frequency of
      ordering tests and medications with POE, 61 percent of house officers reported an
      increased frequency. CONCLUSION: Physicians and nurses had markedly different
      views about effects of a POE system on patient care, highlighting the need to
      consider both perspectives when assessing the impact of POE. With this POE
      system, most nurses saw beneficial effects, whereas many physicians saw negative
      effects.

PMID- 10332657
TI  - Use of computer-based records, completeness of documentation, and appropriateness
      of documented clinical decisions.
AB  - OBJECTIVE: To investigate whether using a computer-based patient record (CPR)
      affects the completeness of documentation and appropriateness of documented
      clinical decisions. DESIGN: A blinded expert panel of four experienced internists
      evaluated 50 progress notes of patients who had chronic diseases and whose
      physicians used either a CPR or a traditional paper record. MEASUREMENTS:
      Completeness of problem and medication lists in progress notes, allergies noted
      in the entire record, consideration of relevant patient factors in the progress
      note's diagnostic and treatment plans, and appropriateness of documented clinical
      decisions. RESULTS: The expert reviewers rated the problem lists and medication
      lists in the CPR progress notes as more complete (1.79/2.00 vs 0.93/2.00, P <
      0.001, and 1.75/2.00 vs. 0.91/2.00, P < 0.001, respectively) than those in the
      paper record. The allergy lists in both records were similar. Providers using a
      CPR documented consideration of more relevant patient factors when making their
      decisions (1.53/2.00 vs. 1.07/2.00, P < 0.001), and documented more appropriate
      clinical decisions (3.63/5.00 vs. 2.50/5.00, P < 0.001), compared with providers
      who used traditional paper records. CONCLUSIONS: Physicians in our study who used
      a CPR produced more complete documentation and documented more appropriate
      clinical decisions, as judged by an expert review panel. Because the physicians
      who used the CPR in our study volunteered to do so, further study is warranted to
      test whether the same conclusions would apply to all CPR users and whether the
      improvement in documentation leads to better clinical outcomes.

PMID- 10332658
TI  - Great earthquakes and medical information systems, with special reference to
      telecommunications.
AB  - The Hanshin-Awaji earthquake in January 1995 caused the greatest number of deaths
      and injuries in Japan since World War II. Various weaknesses of modern
      information systems were exposed during and after the earthquake. The authors
      carried out a questionnaire survey to investigate the current state of hospital
      information and to examine the kinds of information needed immediately after an
      earthquake. The survey results show that information about the ability to admit
      new patients and the availability of medical supplies is necessary immediately
      after such a disaster. These results will be useful for planning countermeasures
      against this kind of disaster.

PMID- 10332659
TI  - The view from 30,000 feet.

PMID- 10332660
TI  - Presentation of the Morris F. Collen Award to Robert S. Ledley, DDS.

PMID- 10332661
TI  - Is glucose a continuous risk factor for cardiovascular mortality?

PMID- 10332662
TI  - What do internal medicine residents need to enhance their diabetes care?
AB  - OBJECTIVE: To identify areas that should be targeted for improvement in care, we
      examined internal medicine resident practice patterns and beliefs regarding
      diabetes in a large urban hospital outpatient clinic. RESEARCH DESIGN AND
      METHODS: Internal medicine residents were surveyed to assess the frequency at
      which they performed key diabetes quality of care indicators. Responses were
      compared with recorded performance derived from chart and laboratory database
      reviews. Resident attitudes about diabetes were determined using the Diabetes
      Attitude Survey for Practitioners. Finally, an eight-item scale was used to
      assess barriers to diabetes care. RESULTS: Both self-described and recorded
      performance of recommended diabetes services short of national recommendations.
      For yearly eye examinations and lipid screening, recorded performance levels were
      similar to trainees' reports. However, documented inquiries about patient self
      monitoring of blood glucose, performance of foot examinations, and urine protein
      screening were lower than trainees' reports. Some 49% of the residents selected a
      target HbA1c of 6.6-7.5% as an attainable goal, yet half of the patients using
      oral agents or insulin had HbA1c values > 8.0%. No differences in self-described
      or recorded performance were found by year of training. Most residents did not
      perceive themselves to need additional training related to diabetes care, and
      residents were generally neutral about patient autonomy. Patient nonadherence and
      time constraints within the clinic were most often cited as barriers to care.
      CONCLUSIONS: The study identifies several areas that require improvement in
      resident care of diabetes in the ambulatory setting. Because experience during
      training contributes to future practice patterns, developing a program that
      teaches trainees how to implement diabetes practice guidelines and methods to
      achieve optimal glycemic control may be key to future improvements in the quality
      of diabetes care.

PMID- 10332663
TI  - Effects of meal carbohydrate content on insulin requirements in type 1 diabetic
      patients treated intensively with the basal-bolus (ultralente-regular) insulin
      regimen.
AB  - OBJECTIVE: In this study, we evaluated the effects of high-(55%) and low-(40%)
      carbohydrate diets on insulin requirements in nine type 1 diabetic subjects
      treated intensively with ultralente as basal insulin and regular insulin as
      premeal insulin adjusted to the carbohydrate content of meals. RESEARCH DESIGN
      AND METHODS: Nine subjects were randomized in a crossover design to follow two
      diets consecutively for a period of 14 days each. A 3-day food diary was
      completed for each diet with the amount of carbohydrate in the mixed meals
      ranging from 21 to 188 g. Preprandial (5.9 vs. 6.1 mmol/l) and postprandial (8
      vs. 8.9 mmol/l) capillary glucose and fructosamine (310 vs. 316 mumol/l) were
      comparable on both the low- and high-carbohydrate diets. RESULTS: The assessment
      of meal carbohydrate content by the patients was excellent, with > 85% of cases
      falling within 15% of computer-assisted evaluation. When premeal regular insulin
      was prescribed in U/10 g of carbohydrate, the postprandial glycemic rise remained
      constant (2.4 +/- 2.8 mmol/l) over a wide range of carbohydrate ingested (21-188
      g) and was not affected by the glycemic index, fiber, and caloric and lipidic
      content of the meals. This tight control was maintained during the low- and high
      carbohydrate diet without any change in insulin requirements (breakfast, 1.5 vs.
      1.5 U/10 g of carbohydrate; lunch, 1.0 vs. 1.0; supper, 1.1 vs. 1.2) and in basal
      ultralente insulin requirements (22.5 vs. 21.4 U/day). CONCLUSIONS: These results
      indicate that in type 1 diabetic subjects 1) increasing the amount of
      carbohydrate intake does not influence glycemic control if premeal regular
      insulin is adjusted to the carbohydrate content of the meals; 2) algorithms based
      on U/10 g of carbohydrate are effective and safe, whatever the amount of
      carbohydrate in the meal; 3) the glycemic index, fiber, and lipidic and caloric
      content of the meals do not affect premeal regular insulin requirements; 4) wide
      variations in carbohydrate intake do not modify basal (ultralente) insulin
      requirements; and, finally 5) the ultralente-regular insulin regimen allows
      dissection between basal and prandial insulin requirements, so that each can be
      adjusted accurately and independently.

PMID- 10332664
TI  - Therapy of severe diabetic ketoacidosis. Zero-mortality under very-low-dose
      insulin application.
AB  - OBJECTIVE: Despite modern concepts in therapy by low-dose insulin application and
      better care in intensive care units (ICUs), there still is a mortality of 5-10%
      for severe diabetic ketoacidosis (DKA). The aim of this study was to develop a
      therapy concept to reduce complications and mortality in DKA. RESEARCH DESIGN AND
      METHODS: From 1986 to 1997, 114 consecutive patients (mean [range]; age 34 [11
      74] years) with type 1 diabetes suffering from severe DKA were treated on ICUs
      and investigated in a retrospective and prospective study. The following are the
      criteria for admission onto ICUs: < 7.20 pH level, > 300 mg/dl blood glucose,
      less than -12 mmol/l base excess, or < 300 mg/dl blood glucose plus severe
      symptoms (i.e., coma). We treated patients according to the following concepts:
      very-low-dose insulin application by a basal insulin infusion of 1 U/h (0.5-4.0
      U/h i.v.), maximal decrease of blood glucose level by 50 mg. dl-1. h-1, slow
      motion reequilibration by fluid substitution of 1,000 ml/h (Ringer-Lactate, NaCl
      0.9% or half-electrolyte fluids) in the first 4 h, potassium replacement and
      heparin (500-1,000 U/h i.v.). RESULTS: When patients were admitted to ICU, we
      found the following parameters: mean (range); 609.0 (86.0-1,428.0) mg/dl blood
      glucose level; 7.13 (6.53-7.36) pH level; and -19.7 (-41.2 to -7.0) mmol/l base
      excess. After 12 h of treatment, we reached the following parameters: mean
      values; 251 mg/dl blood glucose level, 7.31 pH level, and -9.37 mmol/l base
      excess level. All patients survived without any lasting deficiencies or fatal
      complications. CONCLUSIONS: Very-low-dose insulin application and slow-motion
      reequilibration plus monitored substitution of electrolytes are the basic
      strategies in the treatment of severe DKA. In our view, small doses of infused
      insulin are the main reason for the safe results of this therapy program.

PMID- 10332665
TI  - Amputation prevention by vascular surgery and podiatry collaboration in high-risk
      diabetic and nondiabetic patients. The Operation Desert Foot experience.
AB  - OBJECTIVE: To describe a unique multidisciplinary outpatient intervention for
      patients at high risk for lower-extremity amputation. RESEARCH DESIGN AND
      METHODS: Patients with foot ulcers and considered to be high risk for lower
      extremity amputation were referred to the High Risk Foot Clinic of Operation
      Desert Foot at the Carl T. Hayden Veterans Affairs' Medical Center in Phoenix,
      Arizona, where patients received simultaneous vascular surgery and podiatric
      triage and treatment. Some 124 patients, consisting of 90 diabetic patients and
      34 nondiabetic patients, were initially seen between 1 October 1991 and 30
      September 1992 and followed for subsequent rate of lower-extremity amputation.
      RESULTS: In a mean follow-up period of 55 months (range 3-77), only 18 of 124
      patients (15%) required amputation at the level of the thigh or leg. Of the 18
      amputees, 17 (94%) had type 2 diabetes. The rate of avoiding limb loss was 86.5%
      after 3 years and 83% after 5 years or more. Furthermore, of the 15 amputees
      surviving longer than 2 months, only one (7%) had to undergo amputation of the
      contralateral limb over the following 12-65 months (mean 35 months). Compared
      with nondiabetic patients, patients with diabetes had a 7.68 odds ratio for
      amputation (95% CI 5.63-9.74) (P < 0.01). CONCLUSIONS: A specialized clinic for
      prevention of lower-extremity amputation is described. Initial and contralateral
      amputation rates appear to be far lower in this population than in previously
      published reports for similar populations. Relative to patients without diabetes,
      patients with diabetes were more than seven times as likely to have a lower
      extremity amputation. These data suggest that aggressive collaboration of
      vascular surgery and podiatry can be effective in preventing lower-extremity
      amputation in the high-risk population.

PMID- 10332666
TI  - Effects of aerobic or resistance exercise and/or diet on glucose tolerance and
      plasma insulin levels in obese men.
AB  - OBJECTIVE: This study had two objectives. First, we examined whether the
      influence of diet combined with either aerobic (DA) (n = 10) or resistance (DR)
      (n = 10) exercise has effects on insulin and glucose levels that are different in
      obese men. Second, we tried to determine whether the combination of diet and
      exercise is associated with improvements in insulin and glucose levels that are
      greater than those associated with diet alone (DO) (n = 9). RESEARCH DESIGN AND
      METHODS: Insulin and glucose levels were measured after an overnight fast and a
      75-g oral glucose challenge (OGTT). Visceral adipose tissue (AT), subcutaneous
      AT, and skeletal muscle were measured by magnetic resonance imaging (MRI) before
      and after treatment (16 weeks). RESULTS: Reductions in weight (12.4 +/- 3.8 kg)
      and in visceral (37 +/- 15.1%) and subcutaneous AT (24.3 +/- 8.6%) were not
      different between treatments (P > 0.05). Skeletal muscle was maintained in the DA
      and DR groups but was reduced (7.3 +/- 2.8%) in the DO group (P < 0.05).
      Independent of treatment, fasting glucose and OGTT glucose did not change (P >
      0.05). However, fasting insulin, OGTT insulin, and the insulin-to-glucose ratio
      decreased within all treatments (P < 0.05). Reductions in the OGTT insulin area
      under the curve were greater (P < 0.05) within the DA (52 +/- 12%) and DR (42 +/-
      17%) treatments than in the DO (20 +/- 15%) treatment. Collapsed across group,
      reductions in visceral AT were related to reductions in fasting and OGTT glucose
      (P < 0.05), whereas reductions in abdominal subcutaneous AT correlated with
      reductions in fasting insulin (P < 0.05). CONCLUSIONS: Weight loss induced by
      diet and aerobic or resistance exercise has similar positive effects on lowering
      fasting and OGTT insulin values that are greater than those with diet alone.
      Because changes in glucose and insulin were related to reductions in visceral and
      abdominal subcutaneous AT, we conclude that reduction in abdominal obesity
      consequent to diet and exercise-induced weight loss is important for attaining
      improvements in plasma insulin levels, observations that strengthen the concept
      that abdominal obesity has an important role in mediating insulin resistance.

PMID- 10332667
TI  - Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta
      analysis.
AB  - OBJECTIVE: The aim of the study was to determine the percentage of individuals
      with neuropathic diabetic foot ulcers receiving good wound care who heal within a
      defined period of time. RESEARCH DESIGN AND METHODS: We conducted a systematic
      review of the control groups of clinical trials that evaluated a treatment for
      diabetic neuropathic foot ulcers. The meta-analytic techniques used include an
      estimation of the weighted mean percentage healed by end point, an evaluation of
      the homogeneity of trials, and an estimate of the 95% CI of the grouped data.
      Grouped-data univariate and multivariate logistic regression was conducted to
      assess the impact of mean age, ulcer size, and duration on the percentage of
      ulcers healed at end point. RESULTS: We found a total of 10 control groups
      meeting our criteria. Six control groups used 20 weeks as the end point for
      healing or nonhealing. For the six control arms with a 20-week end point, we
      found a weighted mean healing rate of 30.9% (95% CI 26.6-35.1). A similar
      analysis for the four 12-week arms found a mean healing rate of 24.2% (19.5
      28.8). We failed to detect any statistically significant heterogeneity for either
      the 20-week or the 12-week trials. CONCLUSIONS: After 20 weeks of good wound
      care, approximately 31% of diabetic neuropathic ulcers heal. Similarly, after 12
      weeks of good care, approximately 24% of neuropathic ulcers attain complete
      healing. Further patient-level analyses are necessary to definitively determine
      the associations of age, wound size, and wound duration with likelihood of
      healing.

PMID- 10332668
TI  - Is there a glycemic threshold for mortality risk?
AB  - OBJECTIVE: To determine whether there are thresholds for fasting and for 2-h
      glucose above which the risk of death from all causes and from coronary heart
      disease (CHD) increases. RESEARCH DESIGN AND METHODS: We studied 23-year
      mortality data from the Paris Prospective Study of the 7,018 men, aged 44-55
      years, who were not known as diabetic at the baseline examination. The effect of
      glucose concentrations on mortality was studied using the observed relative risks
      and an age-adjusted Cox proportional hazards model. RESULTS: For all causes of
      death, there were J-shaped relationships with both fasting and 2-h glucose
      concentrations, and the lowest observed death rates were in the intervals
      centered on 5.5 mmol/l for fasting glucose and 5.0 mmol/l for 2-h glucose. The
      death rates for CHD were low in this population: for fasting glucose, the hazards
      ratio was best modeled by a positive linear relationship; for 2-h glucose, it was
      modeled by a J-shaped curve and the lowest observed death rate was in the
      interval centered on 6.0 mmol/l. CONCLUSIONS: In the Paris Prospective Study,
      there were no clear thresholds for fasting or 2-h glucose concentrations above
      which mortality sharply increased; in the upper levels of the glucose
      distributions, the risk of death progressively increased with increasing fasting
      and 2-h glucose concentrations.

PMID- 10332670
TI  - Correlates of physical activity in a sample of older adults with type 2 diabetes.
AB  - OBJECTIVE: Physical activity is integral to the management of type 2 diabetes.
      Unfortunately, the majority of adults with type 2 diabetes do not regularly
      engage in physical activity. The purpose of this study was to assess physical
      activity behavior and its correlates (i.e., physical activity knowledge,
      barriers, and performance and outcome expectations) in older adults with type 2
      diabetes. RESEARCH DESIGN AND METHODS: A subgroup of 260 adults with type 2
      diabetes was identified from a larger stratified random sample of adults aged >
      or = 55 years. Participants completed an interviewer-administered survey designed
      from focus group findings and social learning theory. RESULTS: The majority of
      the respondents (54.6%) reported 0 min of weekly physical activity. This was
      especially true of older female respondents. Performance expectation scores were
      lower among respondents who were in the oldest age-group, namely, white women.
      Physical activity knowledge varied by age-group, and barriers to physical
      activity were prevalent in all groups. The following are significant correlates
      of reported weekly physical activity: younger age, more education, fewer
      motivational barriers, and greater perceived health and performance expectations.
      CONCLUSIONS: Given the importance of physical activity to diabetes management,
      the low prevalence of physical activity found in this and other studies should
      raise concerns among clinicians. Future research to identify predictors of
      physical activity is needed to guide clinicians in the promotion of physical
      activity.

PMID- 10332669
TI  - Risk for metabolic control problems in minority youth with diabetes.
AB  - OBJECTIVE: We examined and quantified the degree of risk for poor glycemic
      control and hospitalizations for diabetic ketoacidosis (DKA) among black,
      Hispanic, and white children and adolescents with diabetes. RESEARCH DESIGN AND
      METHODS: We examined ethnic differences in metabolic control among 68 black, 145
      Hispanic, and 44 white children and adolescents with type 1 diabetes (mean age
      12.9 [range 1-21] years), who were primarily of low socioeconomic status.
      Clinical and demographic data were obtained by medical chart review.
      Glycohemoglobins were standardized and compared across ethnic groups. Odds ratios
      among the ethnic groups for poor glycemic control and hospitalizations for DKA
      were also calculated. RESULTS: The ethnic groups were not different with respect
      to age, BMI, insulin dose, or hospitalizations for DKA, but black children were
      older at the time of diagnosis than Hispanics (P < 0.05) and were less likely to
      have private health insurance than white and Hispanic children (P < 0.001). Black
      youths had higher glycohemoglobin levels than white and Hispanic youths (P <
      0.001 after controlling for age at diagnosis). Black youths were also at greatest
      risk for poor glycemic control (OR = 3.9, relative to whites; OR = 2.5, relative
      to Hispanics). CONCLUSIONS: These results underscore and quantify the increased
      risk for glycemic control problems of lower-income, black children with diabetes.
      In the absence of effective intervention, these youths are likely to be
      overrepresented in the health care system as a result of increased health
      complications related to diabetes.

PMID- 10332671
TI  - An office-based intervention to maintain parent-adolescent teamwork in diabetes
      management. Impact on parent involvement, family conflict, and subsequent
      glycemic control.
AB  - OBJECTIVE: To design and evaluate an office-based intervention aimed at
      maintaining parent-adolescent teamwork in diabetes management tasks without
      increasing diabetes-related family conflict. RESEARCH DESIGN AND METHODS: There
      were 85 patients (aged 10-15 years, mean 12.6 years) with type 1 diabetes (mean
      duration 5.5 years; mean HbA1c 8.5%) who were randomly assigned to one of three
      study groups--teamwork, attention control, and standard care--and followed for 24
      months. At each visit, parent involvement in insulin administration and blood
      glucose monitoring was assessed. The teamwork and attention control interventions
      were integrated into routine ambulatory visits over the first 12 months (four
      medical visits). Measures of diabetes-related family conflict were collected at
      baseline and after 12 months. All patients were followed for an additional 12
      months with respect to glycemic control. RESULTS: In the teamwork group, there
      was no major deterioration (0%) in parent involvement in insulin administration,
      in contrast to 16% major deterioration in the combined comparison (attention
      control and standard care) group (P < 0.03). Similarly, no teamwork families
      showed major deterioration in parent involvement with blood glucose monitoring
      versus 11% in the comparison group (P < 0.07). On both the Diabetes Family
      Conflict Scale and the Diabetes Family Behavior Checklist, teamwork families
      reported significantly less conflict at 12 months. An analysis of HbA1c over the
      12- to 24-month follow-up period indicated that more adolescents in the teamwork
      group (68%) than in the comparison group (47%) improved their HbA1c (P < 0.07).
      CONCLUSIONS: The data demonstrate that parent involvement in diabetes management
      tasks can be strengthened through a low-intensity intervention integrated into
      routine follow-up diabetes care. Moreover, despite increased engagement between
      teen and parent centered around diabetes tasks, the teamwork families showed
      decreased diabetes-related family conflict. Within the context of a broader
      cultural recognition of the protective function of parent involvement in the
      lives of adolescents, the findings of this study reinforce the potential value of
      a parent-adolescent partnership in managing chronic disease.

PMID- 10332672
TI  - Latino beliefs about diabetes.
AB  - OBJECTIVE: To describe Latino beliefs about diabetes and assess heterogeneity in
      beliefs across different groups. RESEARCH DESIGN AND METHODS: This study
      comprised a survey of 161 representative Latino adults from four diverse
      communities: Hartford, Connecticut; Edinburg, Texas; Guadalajara, Mexico; and
      rural Guatemala. A 130-item questionnaire covered causes symptoms, and treatments
      for diabetes. Information on demographics and acquaintanceship with someone with
      diabetes was also collected. The cultural consensus model was used to analyze the
      variation in responses to determine whether the degree of consistency within and
      between samples was sufficient to warrant aggregation and description as a single
      set of beliefs. RESULTS: Homogeneous beliefs were present within each of the four
      samples. Although variability in responses increased significantly from
      Connecticut to Guatemala (P < 0.00005), there was significant agreement between
      samples on the answers (P < 0.0005). Answers tended to be concordant with the
      biomedical description of diabetes. Greater acculturation, higher educational
      attainment, and higher diabetes prevalence were associated with greater cultural
      knowledge about diabetes. In Connecticut, greater knowledge correlated with
      longer mainland U.S. residency (P < 0.05). In Mexico, those with average
      educational attainment knew more (P < 0.05). Finally, average knowledge levels
      were higher in communities with greater diabetes prevalence. CONCLUSIONS: The
      cultural consensus model facilitated assessment of cultural beliefs regarding
      diabetes and diabetes management. Overall, Latino cultural beliefs about diabetes
      were concordant with the biomedical model. Variation in responses tended to
      characterize less knowledge or experience with diabetes and not different
      beliefs.

PMID- 10332673
TI  - Impact of maternal nativity on the prevalence of diabetes during pregnancy among
      U.S. ethnic groups.
AB  - OBJECTIVE: This study examines the impact of maternal nativity (birthplace) on
      the overall prevalence of diabetes during pregnancy and among 15 racial and
      ethnic groups in the U.S. RESEARCH DESIGN AND METHODS: Birth certificate data for
      all resident single live births in the U.S. from 1994 to 1996 were used to
      calculate reported diabetes prevalence during pregnancy and to assess the impact
      of maternal birthplace outside of the 50 states and Washington, DC, on the risk
      of diabetes before and after adjustment for differences in maternal age, other
      sociodemographic characteristics, and late or no initiation of prenatal care
      overall and for each racial and ethnic group. RESULTS: Mothers born outside of
      the U.S. are significantly more likely to have diabetes during pregnancy. The
      impact of maternal nativity on diabetes prevalence is largely explained by the
      older childbearing age of immigrant mothers. However, adjusted diabetes risk
      remains elevated for Asian-Indian, non-Hispanic black, Filipino, Puerto Rican,
      and Central and South American mothers who were born outside the U.S. Conversely,
      birthplace outside the U.S. significantly reduces diabetes risk for Japanese,
      Mexican, and Native American women. CONCLUSIONS: Identification, treatment, and
      follow-up of immigrant mothers with diabetes during pregnancy may require special
      attention to language and sociocultural barriers to effective care. Systematic
      surveillance of the prevalence and impact of diabetes during pregnancy for
      immigrant and nonimmigrant women, particularly in racial and ethnic minority
      groups, and more detailed studies on the impact of acculturation on diabetes may
      increase understanding of the epidemiology of diabetes during pregnancy in our
      increasingly diverse society.

PMID- 10332674
TI  - Antidiabetic treatment trends in a cohort of elderly people with diabetes. The
      cardiovascular health study, 1989-1997.
AB  - OBJECTIVE: This study characterizes the pharmaceutical treatment of type 2
      diabetes from 1989-1990 to 1996-1997 in an elderly cohort. RESEARCH DESIGN AND
      METHODS: A total of 5,888 adults aged > or = 65 years were recruited and attended
      a baseline clinic visit in 1989-1990 (n = 5,201, original cohort) or 1992-1993 (n
      = 687. African-American [new] cohort) as participants of the Cardiovascular
      Health Study. Fasting serum glucose (FSG) was measured at baseline. Medication
      use was ascertained by drug inventory at all annual clinic visits. Diabetes was
      defined at baseline as insulin or oral hypoglycemic agent (OHA) use or as having
      an FSG > or = 7.0 mmol/l (126 mg/dl), the current consensus definition of
      diabetes. RESULTS: A total of 387 (7%) original (FSG = 9.8 mmol/l [177 mg/dl])
      and 115 (17%) new (FSG = 10.6 mmol/l [191 mg/dl]) cohort members had
      pharmacologically treated diabetes at baseline. Among those in the original and
      in the new cohorts who survived follow-up, respectively, OHA use decreased from
      80 to 48% (P < 0.001) and from 67 to 50% (P < 0.003) and insulin use increased
      from 20 to 33% (P = 0.001) and from 33 to 37% (P = 0.603). There were 396 (8%)
      original (FSG = 8.8 mmol/l [159 mg/dl]) and 45 (7%) new (FSG = 10.0 mmol/l [181
      mg/dl]) cohort members with diabetes untreated at baseline. Among them,
      respectively, OHA use reached 38 and 30% and insulin use reached 6 and 16% in
      1996-1997. CONCLUSIONS: Diabetes was common in this elderly cohort, and > 80% of
      treated patients with diabetes at baseline were not achieving fasting glucose
      goals of < or = 6.7 mmol/l (120 mg/dl). Many untreated at baseline remained
      untreated after 7 years of follow-up.

PMID- 10332675
TI  - The 10-year incidence of renal insufficiency in people with type 1 diabetes.
AB  - OBJECTIVE: To describe the 10-year decrease in estimated creatinine clearance and
      the incidence of renal insufficiency and end-stage renal disease in a cohort of
      people with type 1 diabetes. RESEARCH DESIGN AND METHODS: A population-based
      cohort of individuals with younger-onset diabetes (diagnosed at < 30 years old
      and taking insulin) participated in an examination during 1984-1986 (n = 891), a
      6-year follow-up examination during 1990-1992 (n = 765), and a 10-year follow-up
      examination during 1995-1996 (n = 634). Serum creatinine and risk factors were
      measured during standardized protocols at each examination. Estimated adjusted
      creatinine clearance was computed by a modification of the Cockroft-Gault
      formula. A clinically meaningful change was defined as a decrease in the
      estimated annual creatinine clearance of > or = 3 ml.min-1.1.73 m-2.year-1. Renal
      insufficiency was defined by the development of a serum creatinine of 2.0 mg/dl
      or greater after the 1984-1986 examination. RESULTS: The 10-year estimated
      incidence of an annual decrease in the creatinine clearance of > or = 3 ml.min
      1.1.73 m-2 for the cohort was 52.5%, and the cumulative 10-year incidence of
      renal insufficiency and end-stage renal failure was 14.4%. In univariate
      analyses, incidence of a decrease in the estimated creatinine clearance of > or =
      3 ml.min-1.1.73 m-2.year-1 and the incidence of renal insufficiency were both
      related to higher glycosylated hemoglobin; higher diastolic blood pressure; the
      presence of microalbuminuria and gross proteinuria; more severe retinopathy; and
      a history of loss of tactile sensation or temperature sensitivity at baseline. In
      logistic regression analysis, after adjusting for the presence of
      microalbuminuria and gross proteinuria at baseline, higher glycosylated
      hemoglobin and higher diastolic blood pressure were associated with decreasing
      estimated creatinine clearance. In logistic regression analyses, after adjusting
      for the presence of microalbuminuria and gross proteinuria at baseline, the
      incidence of renal insufficiency was independently associated with age,
      glycosylated hemoglobin, hypertension, and serum HDL cholesterol. CONCLUSIONS:
      These data suggest that a public health approach aimed at controlling glycemia,
      blood pressure, and serum lipids might result in reducing the rate of decline in
      renal function and development of renal insufficiency in people with type 1
      diabetes.

PMID- 10332676
TI  - Effect of multiple patient reminders in improving diabetic retinopathy screening.
      A randomized trial.
AB  - OBJECTIVE: To determine whether multiple mailed patient reminders can produce an
      increase in the rate of diabetic retinal examinations (DRE) over that seen with a
      single reminder. RESEARCH DESIGN AND METHODS: All diabetic members > or = 18
      years who were enrolled in a large network-based health maintenance organization
      (HMO) in California from August 1996 to July 1997 were identified using claims
      and pharmacy databases. Members who had no record of DRE in the HMO's claims
      database were then randomized into two groups. Both groups received mailed
      educational materials and a reminder to obtain the examination. Their physician
      groups also received a letter explaining the program, current guidelines for DRE,
      and a list of their diabetes patients with their DRE status. The single
      intervention group received no additional reminders. The multiple intervention
      group received additional reminders at 3, 6, and 9 months after baseline if they
      continued with no record of service, as determined from the claims database.
      RESULTS: The study cohort comprised 19,523 diabetic members, which were
      randomized into single (n = 9,614) and multiple (n = 9,909) intervention groups.
      There was an increase in monthly DRE rates after the intervention in August 1996
      for both intervention groups. After the second reminder was sent to the multiple
      intervention group, the percentage of diabetic members receiving DRE was higher
      than the single intervention group. Rates before and after the third intervention
      were not significantly different, nor were monthly differences found. There was a
      significant difference in overall annual DRE rates between the groups (P =
      0.023). CONCLUSIONS: Multiple patient reminders are more effective than single
      reminders in improving DRE rates in a managed care setting. However, the
      improvement noted was clinically small and appeared only after the second
      reminder; no incremental improvement was seen with additional reminders.
      Resources used for multiple reminders aimed at diabetic retinopathy might better
      be spent on other approaches to reducing complications of diabetes.

PMID- 10332677
TI  - Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study.
AB  - OBJECTIVE: This population-based study, carried out in the framework of the
      Verona Diabetes Study, investigated mortality from specific causes in known type
      2 diabetic patients. RESEARCH DESIGN AND METHODS: A cohort of 7,148 known type 2
      diabetic patients (3,366 men and 3,782 women) was identified on 31 December 1986
      and followed up for 5 years (1987-1991). Underlying causes of death were obtained
      from death certificates and were coded according to the International
      Classification of Diseases, Ninth Revision. Cause-specific death rates of
      diabetic subjects were compared with those of the inhabitants of Verona. By 31
      December 1991, 1,550 diabetic subjects (744 men and 806 women) had died. RESULTS:
      The standardized mortality ratio (SMR) for all causes of death was 1.42 (95% CI
      1.35-1.50). The highest SMRs were for the following specific causes: diabetes
      (SMR 4.47 [3.91-5.10]), gastrointestinal diseases (1.83 [1.50-2.21])-
      particularly liver cirrhosis (2.52 [1.96-3.20])--and cardiovascular diseases
      (1.34 [1.23-1.44]), particularly cerebrovascular (1.48 [1.25-1.73]) and ischemic
      heart diseases (1.41 [1.24-1.62]). A significantly higher than expected risk of
      mortality for cardiovascular causes was already present in the first 5 years
      after diagnosis and decreased with age. Type 2 diabetic patients treated with
      insulin had a higher risk of dying than those treated orally or by diet.
      CONCLUSIONS: The highest SMRs in the diabetic cohort were for diabetes and liver
      cirrhosis. The mortality risk for cardiovascular diseases, although significantly
      higher than expected, was much lower in Italian type 2 diabetic patients than
      that reported for American patients. The evidence of an early effect on mortality
      suggests that prevention, early diagnosis, and treatment should be improved.

PMID- 10332678
TI  - Impact of new diagnostic criteria for diabetes on different populations.
AB  - OBJECTIVE: For epidemiological purposes, it has now been recommended that a
      fasting plasma glucose value of 7.0 mmol/l can be used to diagnose diabetes,
      instead of a 2-h value of 11.1 mmol/l. This study assesses the impact of making
      this change on the prevalence of diabetes and on the phenotype of individuals
      identified. RESEARCH DESIGN AND METHODS: Data were collated from nine population
      based southern hemisphere studies in which a 75-g oral glucose tolerance test was
      performed. Comparisons were made between the prevalence derived from fasting
      values only and the prevalence derived from 2-h values only. Cardiovascular risk
      was assessed in all individuals. RESULTS: There were 20,624 subjects in the nine
      surveys of whom 1,036 had previously diagnosed diabetes and 1,714 had newly
      diagnosed diabetes, according to either fasting or 2-h glucose. The differences
      in prevalence within each population resulting from changing the diagnostic
      criteria ranged from +30 to -19% (relative difference) and +4.1 percentage points
      to -2.8 percentage points (absolute difference). BMI was the most important
      determinant of disagreement in classification. A total of 31% of those
      individuals who were diabetic on the fasting value were not diabetic on the 2-h
      value, and 32% of those with diabetes on the 2-h value were not diabetic on the
      fasting value. Apart from obesity, there were no differences in cardiovascular
      risk between those identified by the fasting and the 2-h values. CONCLUSIONS:
      Changing the diagnostic criteria is likely to have variable and sometimes quite
      large effects on the prevalence of diabetes in different populations.
      Furthermore, the fasting criterion identifies different people as being diabetic
      than those identified by the 2-h criterion.

PMID- 10332679
TI  - Factor VIII and other hemostasis variables are related to incident diabetes in
      adults. The Atherosclerosis Risk in Communities (ARIC) Study.
AB  - OBJECTIVE: Our objective was to evaluate whether selected hemostasis variables,
      some of which may reflect inflammation or endothelial dysfunction, are
      independently associated with the development of diabetes. RESEARCH DESIGN AND
      METHODS: We studied a biethnic cohort of 12,330 men and women, 45-64 years of
      age, of the Atherosclerosis Risk in Communities Study. New cases of diabetes were
      diagnosed by a reported physician diagnosis, hypoglycemic medication use, or a
      casual or fasting serum glucose level of > or = 11.1 or > or = 7 mmol/l,
      respectively. RESULTS: Over an average follow-up of 7 years, 1,335 new cases of
      diabetes were detected. The odds ratios (4th versus 1st quartile) of developing
      diabetes, adjusted by logistic regression for age, sex, race, study center,
      family history of diabetes, fasting glucose, physical activity, and smoking, were
      1.2 (95% CI 1.0-1.5) for fibrinogen and 1.4 (1.1-1.6) for factor VII.
      Associations for factor VIII, von Willebrand factor, and activated partial
      thromboplastin time were found to be 1.8 (1.3-2.3), 1.4 (1.1-1.8), and 0.63 (0.49
      0.82), respectively, in women. Although further adjustment for BMI and waist-to
      hip ratio diminished the relationships, a highly statistically significant
      association (P = 0.001) remained for factor VIII (1.6 [1.2-2.1]) in women.
      CONCLUSIONS: Factor VIII and other hemostasis variables are associated with the
      development of diabetes in middle-aged adults. These findings support a role for
      inflammation and, particularly in women, endothelial dysfunction in the
      pathogenesis of type 2 diabetes.

PMID- 10332680
TI  - Incidence, prevalence, and mortality of diabetes in a large population. A report
      from the Skaraborg Diabetes Registry.
AB  - OBJECTIVE: Our objective was to analyze the prevalence, incidence, and mortality
      of diabetes in a population of 280,539 inhabitants. RESEARCH DESIGN AND METHODS:
      The incidence, prevalence, and deaths from diabetes at all ages of a population
      have been prospectively followed in the county of Skaraborg, Sweden, since 1991.
      RESULTS: The annual incidence of diabetes per 100,000 inhabitants in 1991-1995
      was (mean +/- 95% CI) 14.7 +/- 3.2 for type 1 diabetes (diagnosed at 24.1 +/- 2.2
      years of age) and 265.6 +/- 16.1 for type 2 diabetes (diagnosed at 66.6 +/- 0.6
      years of age). The incidence of type 2 diabetes was significantly (P < 0.001)
      higher among men. There was no significant change in the age at diagnosis of
      diabetes. Although the incidence rate and the age at diagnosis were constant, the
      prevalence of diabetes increased by 6% each year. The relative mortality risk for
      diabetic patients was almost four times higher than expected. The median age at
      death, however, increased significantly, from 77.2 to 80.2 years (P < 0.05),
      during the study. CONCLUSIONS: The prevalence but not the incidence rate of
      diabetes increased during the years 1991-1995. Although diabetic patients showed
      a high relative mortality, increased survival apparently explains the increase in
      prevalence of diabetes in the country of Skaraborg.

PMID- 10332681
TI  - Black-white differences in risk of developing retinopathy among individuals with
      type 2 diabetes.
AB  - OBJECTIVE: To assess racial differences in risk of developing retinopathy among
      individuals with type 2 diabetes, after taking into account differences in the
      distribution of risk factors for retinopathy. RESEARCH DESIGN AND METHODS: The
      participants were 105 individuals with type 2 diabetes, aged 40-69 years, who had
      no evidence of retinopathy at the time of a diabetic eye disease screening
      project. After an average of 4 years of follow-up, the subjects were reevaluated
      using nonmydriatic funds photography. RESULTS: Retinopathy occurred more often
      among black than white participants (50 vs. 19%). This difference could not be
      explained by differences in risk factors for retinopathy or potential confounders
      (odds ratio [95% CI] 2.96 [1.00-8.78] after adjustment for level of glycosylated
      hemoglobin, systolic blood pressure, type of diabetes treatment, and sex).
      CONCLUSIONS: These results are consistent with the concept that racial
      differences in risk of developing retinopathy exist among individuals with type 2
      diabetes and that these differences may be caused by differential (genetic)
      susceptibility to the adverse effects of increased levels of blood glucose and/or
      blood pressure. Discovery of the etiology of this differential susceptibility
      would allows us to identify and target secondary prevention efforts to
      individuals with type 2 diabetes who are at increased risk of retinopathy.

PMID- 10332682
TI  - Use of insulin lispro in continuous subcutaneous insulin infusion treatment.
      Results of a multicenter trial. German Humalog-CSII Study Group.
AB  - OBJECTIVE: Insulin lispro is an analog of human insulin with a faster onset and a
      shorter duration of action than regular human insulin. Efficacy and tolerability
      of insulin lispro in continuous subcutaneous insulin infusion (CSII) treatment
      were assessed in an open randomized crossover trial comparing insulin lispro and
      regular human insulin, both applied with insulin pumps. RESEARCH DESIGN AND
      METHODS: A total of 113 type 1 patients (60 male, 53 female, age [mean +/- SD] 37
      +/- 12 years, duration of diabetes 19 +/- 9 years) participated in this open,
      randomized crossover study. Both insulins were applied for 4 months each with the
      appropriate intervals between the prandial insulin bolus and the meal (human
      insulin: 30 min; lispro: 0 min). Observation parameters were HbA1c, daily and
      postprandial blood glucose profiles, adverse events, rate of hypoglycemic and
      hyperglycemic events, number of catheter obstructions, and treatment satisfaction
      as assessed with an international validated questionnaire. RESULTS: The patients
      were well controlled with a mean HBA1c of 7.24 +/- 1.0% at baseline. HbA1c
      decreased in both treatment periods, but it was better during insulin lispro
      treatment (insulin lispro: 6.8 +/- 0.9%, regular human insulin: 6.9 +/- 1.0%,
      Friedman's rank-sum test: P < 0.02). In addition, the 1-h and 2-h postprandial
      rises in blood glucose were significantly lower (P < 0.001 for each meal) with
      insulin lispro, resulting in smoother daily glucose profiles as compared with
      regular human insulin. No significant differences were reported for the rate of
      hypoglycemia (mean +/- SD [median]: insulin lispro 12.4 +/- 13.9 [8], regular
      human insulin 11.0 +/- 11.2 [8]), for the rate of catheter obstructions (42
      events in each treatment arm), and for the number and type of adverse events. No
      severe case of ketoacidosis was seen during insulin lispro treatment, whereas one
      case was reported during therapy with regular human insulin. Treatment
      satisfaction was better when patients were treated with insulin lispro.
      CONCLUSIONS: Insulin lispro is a suitable and very convenient pump insulin that
      may result in an improvement of long-term glucose control during CSII treatment.
      Its safety profile does not differ from that of regular human insulin.

PMID- 10332683
TI  - A double-blind randomized comparison of meal-related glycemic control by
      repaglinide and glyburide in well-controlled type 2 diabetic patients.
AB  - OBJECTIVE: This study was designed to compare diurnal blood glucose excursions
      and the effects of accidental dietary noncompliance in type 2 diabetic patients
      who are well-controlled on either repaglinide or glyburide treatment. RESEARCH
      DESIGN AND METHODS: This single-center double-blind randomized study comprised
      type 2 diabetic patients whose mean fasting blood glucose value after
      repaglinide/glyburide titration and stabilization was in the range of 90-140
      mg/dl. The study consisted of an initial screening day, a titration period of 3
      weeks, a 1-week stabilization period, a study period, and an end-of-study day.
      During the 3-day study period, half the patients of each group received two meals
      on the first day and three meals on the next 2 days, and in the other half, this
      sequence was reversed. Repaglinide was administered preprandially with each meal,
      and glyburide was administered as recommended in current labeling, i.e., either
      one or two daily doses before breakfast and dinner, regardless of whether lunch
      had been omitted. The diurnal blood glucose excursions on a day in which three
      meals were eaten were compared between the two groups, and the minimum blood
      glucose concentration (BGmin) measurements were compared between lunch and dinner
      on days with three and two meals. RESULTS: Of the 83 randomized patients, 43
      entered into the 3-day study period and completed the trial. The results showed
      no significant differences between the repaglinide and glyburide groups in
      average blood glucose excursions from fasting blood glucose (P = 0.44). The
      influence on the mean BGmin of omitting a meal differed significantly between the
      repaglinide and glyburide groups (P = 0.014). In the latter group, BGmin
      decreased from 77 to 61 mg/dl as a result of omitting lunch, whereas in the
      repaglinide group, BGmin was unchanged for the two-meal day (78 mg/dl) and the
      three-meal day (76 mg/dl). All hypoglycemic events (n = 6) occurred in the
      glyburide group on the two-meal day, in connection with omitting lunch. No
      hypoglycemic events were recorded in the repaglinide group. CONCLUSIONS: These
      results suggest that treatment with repaglinide in well-controlled type 2
      diabetic patients who miss or delay a meal is superior to treatment with longer
      acting sulfonylurea drugs (such as glyburide) with respect to the risk of
      hypoglycemic episodes.

PMID- 10332684
TI  - Contribution of postprandial versus interprandial blood glucose to HbA1c in type
      1 diabetes on physiologic intensive therapy with lispro insulin at mealtime.
AB  - OBJECTIVE: To quantitate the contribution of postprandial blood glucose, which
      improves with the short-acting insulin analog lispro [Lys(B28),Pro(B29)] in type
      1 diabetes, to the overall 24-h blood glucose concentration and the long-term
      HbA1c concentration under conditions of different postabsorptive blood glucose.
      RESEARCH DESIGN AND METHODS: A total of 24 type 1 diabetic patients on long-term
      intensive therapy with premeal human regular insulin (Hum-R) and bedtime NPH were
      randomly assigned to a continuation of Hum-R (group 1, n = 8), lispro (group 2, n
      = 8), or lispro + NPH (in variable proportions) administered at mealtime (group
      3, n = 8) for 3 months, NPH administered at bedtime was continued in all three
      groups. Data from home blood glucose monitoring were collected, and a 24-h plasma
      glucose and insulin profile was obtained during a 2-day hospital visit to
      calculate areas under the postprandial glucose curve (3.5 h after breakfast, 3.5
      h after lunch, and 3.0 h after dinner for a total of 10.0 h) and the
      postabsorptive blood glucose curve (the remaining 14.0 h out of 24.0 h) (AUC).
      Eight nondiabetic subjects were also studied. RESULTS: The substitution of Hum-R
      with lispro (group 2) resulted in lower postprandial blood glucose, but greater
      postabsorptive blood glucose (P < 0.05 vs. group 1). The postprandial blood
      glucose AUC was lower (161 +/- 19 vs. 167 +/- 20 mg.100 ml-1.h-1), but the
      postabsorptive blood glucose AUC was greater (155 +/- 22 vs. 142 +/- 19 mg.100 ml
      1.h-1) (P < 0.05). Therefore, the 24-h blood glucose AUC was no different (NS).
      Consequently, HbA1c was no different (NS). This occurred because in group 2,
      mealtime lispro resulted in normal prandial plasma insulin, but also resulted in
      lower interprandial concentration (P < 0.05 vs. group 1). When NPH was added to
      lispro (30% at breakfast, 40% at lunch, 10% at dinner) in group 3, postabsorptive
      plasma insulin was similar to group 1 (NS), in group 3, the postprandial blood
      glucose AUC (153 +/- 17 mg.100 ml-1.h-1) was lower and the postabsorptive blood
      glucose AUC was no different, as compared with group 1 (NS). Therefore, the 24-h
      blood glucose AUC was lower (147 +/- 17 vs. 155 +/- 21 and 158 +/- 20 mg.100 ml
      1.h-1), and HbA1c was lower (6.41 +/- 0.12 vs. 6.84 +/- 0.2 and 6.96 +/- 0.2%
      (groups 3, 1, and 2 respectively, P < 0.05). Frequency of hypoglycemia was
      greater in group 2 (P < 0.05), but not in group 3 (NS) vs. group 1.

PMID- 10332685
TI  - Improved postprandial glycemic control with insulin aspart. A randomized double
      blind cross-over trial in type 1 diabetes.
AB  - OBJECTIVE: Insulin aspart is a novel rapid-acting insulin analog. This study was
      performed to compare the postprandial serum glucose control after administration
      of insulin aspart with that of unmodified human insulin. RESEARCH DESIGN AND
      METHODS: The trial was a double-blind double-dummy injection three-way cross-over
      study in 22 subjects with type 1 diabetes. Insulin aspart was injected
      subcutaneously immediately before the meal, and human insulin was injected
      subcutaneously 30 min before the meal or immediately before the meal. RESULTS:
      The postprandial glucose control as assessed by the excursion of serum glucose
      was superior with insulin aspart as compared with that with human insulin
      injected immediately before or 30 min before a meal (891 +/- 521 vs. 1,311 +/-
      512 vs. 1,106 +/- 571 mmol.l-1.min-1, P < 0.0001 and P < 0.02). This was
      accompanied by a significantly lower glucose maximum concentration [Cmax(SG)] for
      insulin aspart than for human insulin injected immediately before the meal (13.5
      +/- 3.5 vs. 16.4 +/- 3.4 mmol/l, P < 0.001). Insulin aspart was, on average,
      absorbed twice as fast as human insulin, with median time to insulin aspart
      Cmax(ins) on the order of 40 min, and the maximum concentration was approximately
      twice as high for insulin aspart. The relative bioavailability of the insulins
      indicated a similar extent of absorption. Insulin aspart was well tolerated.
      CONCLUSIONS: This study demonstrates the ability of insulin aspart to improve
      postprandial glucose control when compared with human insulin.

PMID- 10332686
TI  - Protein metabolism in insulin-treated gestational diabetes.
AB  - OBJECTIVE: To test the hypothesis that protein metabolism is not totally
      normalized in insulin treated gestational diabetes mellitus (GDM) patients
      compared with normal, pregnant control subjects. RESEARCH DESIGN AND METHODS:
      Protein metabolism in eight Hispanic women with insulin-treated GDM and eight
      healthy Hispanic control women was studied in late gestation and at 6 weeks
      postpartum. Nitrogen flux was assessed from the disposal rate of [15N]-labeled
      urea over 12 h after a dose of [15N]-labeled leucine. Plasma amino acid
      concentrations were determined in fasting and 2-h postprandial samples using an
      amino acid analyzer. RESULTS: Protein turnover was normalized in insulin-treated
      GDM; however, fasting and postprandial plasma amino acids were elevated
      antepartum and postpartum. Nitrogen flux was significantly lower during pregnancy
      (P = 0.04-0.001) and did not differ between groups. Fasting and postprandial
      plasma amino acids were elevated in GDM antepartum and postpartum, despite
      satisfactory glycemic control. Fasting levels of taurine, hydroxyproline,
      glutamic acid, glutamine, cystine, tyrosine, phenylalanine, tryptophan, and
      histidine were higher in GDM antepartum and postpartum (P < 0.05). Postprandial
      concentrations of taurine, hydroxyproline, valine, cystine, isoleucine, leucine,
      tyrosine, phenylalanine, tryptophan, ornithine, lysine, histidine, and arginine
      were higher in GDM antepartum and postpartum (P < 0.05). With few exceptions,
      plasma amino acid concentrations were lower antepartum than postpartum (P <
      0.05). CONCLUSIONS: Protein turnover was normalized in insulin-treated women with
      GDM; however, fasting and postprandial plasma concentrations of amino acids were
      elevated in the antepartum and postpartum periods, despite satisfactory maternal
      glycemic control.

PMID- 10332687
TI  - Apolipoprotein(B) identifies dyslipidemic phenotypes associated with
      cardiovascular risk in normocholesterolemic type 2 diabetic patients.
AB  - OBJECTIVE: Apolipoprotein(B) [apo(B)] reflects the total mass of atherogenic
      particles (VLDL, IDL, and LDL), and its increase is associated with
      cardiovascular disease independently of LDL cholesterol (LDLc) levels. Apo(B)
      determination has been recently standardized, but attention to regional reference
      limits is advisable. Our aim was to analyze the frequency of dyslipidemic
      phenotypes, including those dependent on increased apo(B) in normocholesterolemic
      type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 100
      consecutively seen type 2 diabetic patients (63 men, 37 women; aged 59 +/- 11
      years) were included, after excluding those on lipid-lowering therapy. Apo(B)
      cutoff (1.1 g/l) was obtained from a group of normolipidemic (47 men, 21 women)
      control subjects, and LDLc, triglycerides, and HDL cholesterol (HDLc) cutoff
      points were those from the National Cholesterol Education Program guidelines.
      LDLc levels were obtained by ultracentrifugation if triglyceride levels were >
      3.45 mmol/l; otherwise, they were calculated (Friedwald). Apo(B) levels were
      measured by immunoturbidimetry. RESULTS: Normocholesterolemia (LDLc < 4.13
      mmol/l) appeared in 75 of the 100 patients, of whom 55 were normo- and 20
      hypertriglyceridemic. Hyperapolipoprotein(B) [hyperapo(B)] was the most frequent
      lipid disorder, present in 34 (45%) of the normocholesterolemic patients (22
      normo- and 12 hypertriglyceridemic). Low HDLc levels were more prevalent (53%) in
      patients with hyperapo(B) than in the rest (24%). CONCLUSIONS: Hyperapo(B) was
      found in almost half of the normocholesterolemic type 2 diabetic patients and was
      frequently associated with low HDLc levels and hypertriglyceridemia. Thus, given
      its independent association with cardiovascular disease and that it identifies
      high-risk phenotypes in normocholesterolemic diabetic patients apo(B) should be
      used to evaluate the lipidic pattern of these patients.

PMID- 10332688
TI  - Homeostasis model assessment as a clinical index of insulin resistance in type 2
      diabetic patients treated with sulfonylureas.
AB  - OBJECTIVE: To investigate whether the insulin resistance index (IR) assessed by
      homeostasis model assessment (HOMA) is associated with the insulin resistance
      index assessed by euglycemic-hyperinsulinemic clamp (clamp IR) in type 2 diabetic
      patients who received sulfonylureas (SUs), as well as in those treated by diet
      alone. RESEARCH DESIGN AND METHODS: Retrospectively, the association between HOMA
      IR and clamp IR was analyzed in 80 type 2 diabetic subjects (53 subjects treated
      with SUs and 27 subjects treated with diet alone). The 80 subjects, selected
      because they had not received insulin therapy, were among 111 diabetic
      participants in a clamp study for evaluation of insulin resistance from May 1993
      to December 1997 in Osaka City University Hospital. RESULTS: The HOMA IR showed a
      hyperbolic relationship with clamp IR. The log-transformed HOMA IR (all subjects,
      r = -0.725, P < 0.0001; SU group, r = -0.727, P < 0.0001; diet group, r = -0.747,
      P < 0.0001) correlated more strongly with clamp IR than did HOMA IR per se (all
      subjects, r = -0.594, P < 0.0001; SU group, r = -0.640, P < 0.0001; diet group, r
      = -0.632, P = 0.0004). The univariate regression line between log-transformed
      HOMA IR and clamp IR in the SU group did not differ from that in the diet group
      (slope, -6.866 vs. -5.120, P > 0.05; intercept, 6.566 vs. 5.478, P > 0.05).
      Stepwise multiple regression analyses demonstrated that the log-transformed HOMA
      IR was the strongest independent contributor to clamp IR (R2 = 0.640, P <
      0.0001). CONCLUSIONS: The HOMA IR strongly correlated with the clamp IR in type 2
      diabetic patients treated with SUs as well as in those treated with diet alone.

PMID- 10332689
TI  - Abnormality in urinary protein excretion in Japanese men with impaired glucose
      tolerance.
AB  - OBJECTIVE: To examine whether subjects with impaired glucose tolerance (IGT) for
      more than 2 years have any abnormality in the kidney. RESEARCH DESIGN AND
      METHODS: We measured urinary excretion rate and clearance of various plasma
      proteins with different molecular radii and different isoelectric points in 22
      Japanese men with IGT (IGT group) and 37 age-matched healthy control subjects
      (control group). RESULTS: Clearance of ceruloplasmin (molecular radius
      approximately 45 A; isoelectric point 4.4), IgG4 (molecular radius 55 A;
      isoelectric point 5.4), and IgG (molecular radius 55 A; isoelectric point 7.4)
      was significantly higher in the IGT group than in the control group, whereas
      there were no significant differences in urinary excretion rate of albumin
      (molecular radius 36 A; isoelectric points 4.8-5.2) and clearance of alpha 2
      macroglobulin (molecular radius 88 A; isoelectric point 5.4) between the two
      groups. CONCLUSIONS: In the present study, we found that clearance of neutral
      charged IgG, negatively charged IgG4, and ceruloplasmin with molecular radii of
      approximately 45-55 A was selectively increased in IGT subjects. This finding
      does not seem to be explained by impairment of charge and pore-size selectivity
      in the glomerulus. Therefore, considering the present result together with our
      recent finding that enhanced glomerular filtration rate (GFR) after acute protein
      loading in healthy subjects induced a selective increase in clearance of IgG,
      IgG4, and ceruloplasmin, we suggest that increased intraglomerular hydraulic
      pressure, although enhanced GFR was not demonstrated, may be at work in these
      mildly hyperglycemic subjects.

PMID- 10332690
TI  - Impact of peripheral neuropathy on bone density in patients with type 1 diabetes.
AB  - OBJECTIVE: To investigate whether peripheral neuropathy (PN), as part of the
      microangiopathic complex, affects bone mineral density (BMD) of the peripheral or
      the axial skeleton in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS:
      Three study groups were examined. Group 1 comprised 21 males with type 1 diabetes
      and severe PN with a mean (range) duration of diabetes of 28 (9-59) years and an
      HbA1c of 8.2% (6.3-10.4). Group 2 comprised 21 male type 1 diabetic patients with
      absent or mild PN matched to patients of group 1 regarding age, weight, and
      duration of diabetes. Group 3 comprised 21 control subjects. BMD was measured by
      dual-energy x-ray absorptiometry (DEXA) and by quantitative ultrasound of the
      calcaneus. PN was determined by biothesiometry. Levels of physical activity were
      assessed through guided questionnaires. RESULTS: In group 1, BMD was
      significantly reduced at all measured sites, compared with an expected Z score of
      0 (spine, -1.01 +/- 0.34; femur, -0.94 +/- 0.25; forearm, -1.10 +/- 0.36). To a
      lesser extent, but still significantly, group 2 also showed reduced BMD values
      (spine, -0.60 +/- 0.26; femur, -0.55 +/- 0.25; forearm, -1.05 +/- 0.36), whereas
      group 3 had normal BMD values (-0.23 +/- 0.25, -0.10 +/- 0.21, -0.07 +/- 0.25,
      respectively). Group 1 had lower mean BMD levels than group 2 and group 3 at all
      measured sites, but a significant difference was found only between groups 1 and
      3 at the site of the femur (analysis of variance, P < 0.05). Broadband ultrasound
      attenuation (BUA) of the calcaneus was significantly reduced in group 1 compared
      with groups 2 and 3 (108 +/- 3 vs. 115 +/- 2 and 115 +/- 2). Significant
      correlations between all DEXA measurements and BUA were demonstrated in both
      groups 1 and 2 (r values between 0.54 and 0.75). No significant differences in
      physical activity levels or body composition were demonstrated between the two
      patient groups. CONCLUSIONS: The present results suggest that in patients with
      type 1 diabetes, PN may be an independent risk factor for reduced BMD in the
      affected limbs as well as in the skeleton in general.

PMID- 10332691
TI  - Behavioral science in diabetes. Contributions and opportunities.
AB  - OBJECTIVE: To summarize the current status of behavioral research and practice in
      diabetes and to identify promising future directions. RESEARCH DESIGN AND
      METHODS: We review behavioral science contributions to diabetes in self
      management and patient empowerment, interventions with children and adolescents,
      and special problems including blood glucose awareness training and complications
      such as depression. We also identify emerging areas in which behavioral science
      stands to make significant contributions, including quality of life, worksite and
      community programs, interventions using new information technologies, and
      translation research evaluating practical programs in representative settings. We
      then discuss the gap between the generally encouraging research on behavioral
      contributions to diabetes and the infrequent incorporation of such contributions
      in practice. Suggestions are made for how to close this gap, including ways to
      increase understanding of behavioral issues, opportunities for funding of key
      research and implementation questions, and how behavioral science principles can
      become more integrated into diabetes organizations and care. CONCLUSIONS: Changes
      are required on the part of behavioral scientists in how they organize and
      present their research and on the part of potential users of this knowledge,
      including other health professions, organizations, and funding agencies.
      Integrating behavioral science advances with other promising genetic, medical,
      nutritional, technology, health care, and policy opportunities promises not only
      to broaden our understanding of diabetes but also to improve patient care,
      quality of life, and public health for persons with diabetes.

PMID- 10332692
TI  - On the need for outcome trials in preventive pharmacology. Lessons from the
      recent experience with adverse drug reactions.

PMID- 10332693
TI  - Retinopathy risk: what is responsible? Hormones, hyperglycemia, or humalog?
      Response to Kitzmiller et al.

PMID- 10332694
TI  - Genes and the cell biology of insulin secretion and insulin resistance.

PMID- 10332695
TI  - Metformin added to insulin therapy in poorly controlled type 2 diabetes.

PMID- 10332697
TI  - Coronary heart disease in women with diabetes. Positive association with past
      hysterectomy and possible benefits of hormone replacement therapy.

PMID- 10332696
TI  - Reliability of blood glucose self-monitoring and its influence on glycemic
      control in highly motivated type 1 diabetic patients.

PMID- 10332698
TI  - Orthodeoxia-platypnea due to diabetic autonomic neuropathy.

PMID- 10332699
TI  - Metformin and lipoprotein(a) levels.

PMID- 10332700
TI  - Troglitazone's effect on lipoprotein(a) levels.

PMID- 10332701
TI  - An interaction between digoxin and acarbose.

PMID- 10332702
TI  - Hypoglycemic urticaria revisited.

PMID- 10332703
TI  - Increased nitric oxide levels in aqueous humor of diabetic patients with
      neovascular glaucoma.

PMID- 10332704
TI  - Hypoglycemia associated with maprotiline in a patient with type 1 diabetes.

PMID- 10332705
TI  - Renal tubular function affects glycosuria-related urinary excretion of 1,5
      anhydroglucitol.

PMID- 10332706
TI  - Plasma magnesium concentration and progression of retinopathy.

PMID- 10332707
TI  - Premixed formulations of insulin lispro. Activity profiles in type 1 diabetic
      patients.

PMID- 10332708
TI  - Durable reversal of hypoglycemia unawareness in type 1 diabetes.

PMID- 10332709
TI  - A case of hepatocyte nuclear factor-1 alpha diabetes/MODY3 masquerading as type 1
      diabetes in a Mexican-American adolescent and responsive to a low dose of
      sulfonylurea.

PMID- 10332710
TI  - Insulin response to intravenous glucose correlates with plasma levels of the
      tumor necrosis factor receptor-1.

PMID- 10332711
TI  - Oxidative stress and antioxidant supplementation in type I diabetes.

PMID- 10332712
TI  - Of gestational diabetes, finesse, and an antipodean snark.

PMID- 10332713
TI  - Insulin lispro and the development of proliferative diabetic retinopathy during
      pregnancy.

PMID- 10332714
TI  - Association between central adiposity and multimetabolic syndrome in a special
      cohort of women with prior gestational diabetes.

PMID- 10332715
TI  - Increased serum levels of pentosidine, but not carboxymethyl lysine, in type 2
      diabetes without obvious diabetic nephropathy.

PMID- 10332716
TI  - The Staphylococcus aureus transposon Tn551: complete nucleotide sequence and
      transcriptional analysis of the expression of the erythromycin resistance gene.
AB  - The complete nucleotide sequence of Staphylococcus aureus transposon Tn551 was
      determined. The 5,266-bp sequence encoded five putative proteins. Comparison of
      the nucleotide sequence of Tn551 with that of the enterococcal transposon Tn917
      showed that the two transposons were 99.8% identical and differed only at 11
      positions along the entire sequence. The genetic organization of Tn551 was also
      identical to that of Tn917. Northern analysis of RNA prepared from a
      staphylococcal strain bearing Tn551 displayed three erm-associated transcripts
      that were constitutively produced. Mapping of the 5' ends of the transcripts by
      primer extension suggested that the constitutive transcription of erm was
      initiated from a nucleotide located 5 bp downstream of ORF1. A second set of
      three erythromycin-inducible transcripts was also detected and these showed a
      pattern similar to that described for Tn917. A simple and rapid method is
      described for the use of the Tn551 sequence information in sequencing transposon
      inactivated staphylococcal genes.

PMID- 10332717
TI  - Mrp--a new auxiliary gene essential for optimal expression of methicillin
      resistance in Staphylococcus aureus.
AB  - Screening of a library of Tn551 insertional mutants selected for reduction in the
      methicillin resistance level of the parental Staphylococcus aureus strain COL
      resulted in the isolation of mutant RUSA266 in which the minimal inhibitory
      concentration (MIC) of the parent was reduced from 1,600 to 1.5 micrograms/mL.
      Cloning and sequencing of the vicinity of the insertion site omega 726 identified
      an open reading frame (orf1365) encoding a very large polypeptide of more than
      1,365 amino acids. A unique feature of the deduced amino acid sequence was the
      presence of multiple tandem repeats of 75 amino acids in the polypeptide,
      reminiscent of the structure of high-molecular-weight cell-surface proteins EF*
      and Emb identified in some streptococcal strains. Mutant RUSA266 with the
      inactivated gene, which we shall provisionally refer to as mrp (for multiple
      repeat polypeptide), produced a peptidoglycan with altered muropeptide
      composition, and both the reduced antibiotic resistance and the altered cell wall
      composition were co-transduced in back-crosses into the parental strain COL.
      Additional sequencing upstream of mrp has revealed that this gene was part of a
      five-gene cluster occupying a 9.2-kb region of the staphylococcal chromosome and
      was composed of glmM (directly upstream of mrp), two open reading frames orf310
      and orf269 coding for two hypothetical proteins, and the gene encoding the
      staphylococcal arginase (arg). Transcriptional analysis demonstrated that the
      five genes in the cluster were transcribed together.

PMID- 10332718
TI  - Carriage of respiratory tract pathogens and molecular epidemiology of
      Streptococcus pneumoniae colonization in healthy children attending day care
      centers in Lisbon, Portugal.
AB  - In an effort to establish the rate of carriage of antibiotic resistant
      respiratory pathogens in children attending urban day care centers (DCC) in
      Portugal, seven DCC in Lisbon were selected for determining the rate of
      nasopharyngeal colonization of children between the ages of 6 months to 6 years
      by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.
      Of the 586 children studied between January and March 1996, 47% carried S.
      pneumoniae, 72% H. influenzae, and 54% M. catarrhalis. Twenty-four percent of the
      pneumococci had reduced susceptibility to penicillin, and most of these belonged
      to serogroups 19, 23, 14, and 6. An additional 19% were fully susceptible to
      penicillin but showed decreased susceptibility to other antimicrobials. These
      isolates expressed serogroups 6, 11, 14, 18, 19, and 34. The majority (96%) of M.
      catarrhalis and 20% of H. influenzae were penicillin resistant due to the
      production of beta-lactamases. Recent antimicrobial use was associated with
      carriage of penicillin non-susceptible pneumococci and beta-lactamase producing
      H. influenzae (p < 0.05). Individual DCC differed substantially from one another
      in their rates of carriage of antibiotic resistant H. influenzae and S.
      pneumoniae. Characterization of antibiotic resistant S. pneumoniae isolates by
      molecular fingerprinting techniques showed that each DCC had a unique
      microbiological profile, suggesting little, if any, exchange of the resistant
      microbial flora among them. An exception to this was the presence of isolates
      belonging to two internationally spread epidemic clones: the multiresistant
      Spanish/USA clone expressing serotype 23F, and the penicillin and
      sulfamethoxazole-trimethoprim resistant French/Spanish clone (serotype 14) which
      were detected in four and three DCC, respectively.

PMID- 10332719
TI  - Penicillin-resistant pneumococci in southern Sweden, 1993-1997.
AB  - In Malmohus County, Southern Sweden, the frequency of penicillin-resistant
      pneumococci in nasopharyngeal specimens of outpatients with respiratory tract
      infections increased from 3.1% in 1993 to 7.6% in 1995, and was thereafter rather
      stable. Over the period, 82-85% of the patients with penicillin-resistant strains
      were children 0-6 years of age. Ten groups/types constituted 96-100% of the
      penicillin-resistant isolates. Grouping/typing of 200 consecutive isolates in
      October and November each year indicated that the distribution of groups/types
      amongst patients with respiratory tract infections was rather constant over the
      period. The frequency of penicillin-resistant pneumococci of groups/types 6, 14,
      and 19 roughly corresponded to the occurrence of these groups/types amongst the
      consecutive isolates. Other groups/types 9, 15, 21, and 23 either showed a
      pronounced increase or decrease, which could not be related to the prevalence of
      these groups/types among the consecutive isolates or degree of antibiotic
      resistance. Penicillin-resistant group 9, introduced in the area in 1993,
      consisted of one single clone, 9V. The stabilized level of penicillin resistance
      since 1995 may be related to the preventive measures implemented in the area,
      including day-care interventions, and measures to reduce the prescription rate of
      antibiotics to outpatients with respiratory tract infections.

PMID- 10332720
TI  - Several different clones present during the penetration phase of resistant
      Streptococcus pneumoniae in the city of Malmo, Sweden.
AB  - A rapid increase in the prevalence of Streptococcus pneumoniae with reduced
      sensitivity to penicillin (MIC > or = 0.12 microgram/mL) was noted among clinical
      isolates during a 15-month period in 1994-1995 in the city of Malmo, Sweden. All
      first-time clinical isolates (n = 178) were consecutively collected and
      investigated for genetic relatedness with BOX-A PCR and arbitrarily primed (AP)
      PCR. An improved method for chromosomal DNA extraction and the use of three
      reliable discriminatory primers for AP-PCR of S. pneumoniae are described. Using
      molecular fingerprinting, 30 different genotypes were discerned among the 178
      isolates. The majority (87%) of isolates belonged to serogroups 6, 9, 15, 19, and
      23. Resistance patterns and serogrouping indicated the presence of at least three
      major phenotypic clones. DNA fingerprinting in conjunction with minimum
      inhibitory concentration (MIC) values, resistance patterns, and epidemiological
      data confirmed the existence of two clones belonging to serogroups 6 and 9. Of
      the 178 isolates, 82% were from children of preschool age, most of whom attended
      day-care centers. We conclude that abundant S. pneumoniae strains with MICs > or
      = 0.12 microgram/mL for penicillin were present in the city of Malmo during the
      study period. At least two genetically discrete clones causing clinical illness
      were identified, and attendance at day-care centers may be a major factor in the
      spread of these strains.

PMID- 10332721
TI  - Decreased incidence of VanA-type vancomycin-resistant enterococci isolated from
      poultry meat and from fecal samples of humans in the community after
      discontinuation of avoparcin usage in animal husbandry.
AB  - The use of the glycopeptide antibiotic avoparcin (AVO) as a feed additive in
      animal husbandry of many European countries led in 1994-1995 to frequent
      isolation of VanA-type vancomycin-resistant enterococci (VRE) from commercially
      produced animal foodstuffs as well as from fecal samples of nonhospitalized
      persons in Germany (Saxony-Anhalt state). However, at the end of 1997, a
      decreasing number of such VRE was detected in frozen and fresh poultry meat
      (chickens and turkeys) from German producers. At this point in time, AVO had been
      discontinued in animal husbandry for more than 2 and one-half years in
      Denmark/Norway, nearly 2 years in Germany, and about 8-9 months in all countries
      of the European Community and Switzerland, respectively. VRE were then only
      detected in very low concentrations in one-quarter of the poultry meat samples
      (eight of 31, originating from 18 distinct German producers and bought in 12
      different supermarkets). A decline of VRE prevalence was also observed in the gut
      flora of healthy persons (VRE carriers) in the same region (Saxony-Anhalt state,
      Germany), having fallen from 12% (12/100) in 1994 when AVO was being used to 6%
      (6/100) in 1996 and 3% (13/400) in 1997 after it was discontinued. These results
      likely indicate the importance of antibiotic selective pressure by glycopeptides
      such as AVO for the presence of VRE in animal meat products from commercial
      animal husbandry. Additionally, it underlines the role of animal products for the
      spread of resistant bacteria and transferable resistance genes to humans in the
      community.

PMID- 10332723
TI  - Otitis media: the chinchilla model.
AB  - Streptococcus pneumoniae infection and disease have been modeled in several
      animal species including infant and adult mice, infant and adult rats, infant
      Rhesus monkeys, and adolescent and adult chinchillas. Most are models of sepsis
      arising from intravenous or intraperitoneal inoculation of bacteria, and a few
      were designed to study disease arising from intranasal infection. Chinchillas
      provide the only animal model of middle ear pneumococcal infection in which the
      disease can be produced by very small inocula injected into the middle ear (ME)
      or intranasally, and in which the disease remains localized to the ME in most
      cases. This model, developed at the University of Minnesota in 1975, has been
      used to study pneumococcal pathogenesis at a mucosal site, immunogenicity and
      efficacy of pneumococcal capsular polysaccharide (PS) vaccine antigens, and the
      kinetics and efficacy of antimicrobial drugs. Pathogenesis experiments in the
      chinchilla model have revealed variation in ME virulence among different
      pneumococcal serotypes, enhancement of ME infection during concurrent intranasal
      influenza A virus infections, and natural resolution of pneumococcal otitis media
      (OM) without intervention. Research has explored the relative contribution of
      pneumococcal and host products to ME inflammation. Pneumococcal cell wall
      components and pneumolysin have been studied in the model. Host inflammatory
      responses studied in the chinchilla ME include polymorphonuclear leukocyte
      oxidative products, hydrolytic enzymes, cytokine and eicosanoid metabolites, and
      ME epithelial cell adhesion and mucous glycoprotein production. Both clinical
      (tympanic membrane appearance) and histopathology (ME, Eustachian tube, inner
      ear) endpoints can be quantified. Immunologic and inflammatory studies have been
      facilitated by the production of affinity-purified antichinchilla immunoglobulin
      G (IgG), IgM, and secretory IgA polyclonal antibody reagents, and the
      identification of cross-reactivity between human and chinchilla cytokines, and
      between guinea pig and chinchilla C3. Alteration of ME mucosa by pneumococcal
      neuraminidase and alteration of ME epithelial cell (MEEC) surface carbohydrates
      during intranasal pneumococcal infection have been demonstrated. Pathogenesis
      studies have been aided by cultured chinchilla MEEC systems, in which the ability
      of platelet activating factor and interleukin (IL)-1 beta to stimulate epithelial
      mucous glycoprotein synthesis has recently been demonstrated. Because chronic OM
      with effusion is characterized by presence of large amounts of mucous
      glycoprotein in the ME, pneumococcus may have an important role in both acute and
      chronic ME disease. Both unconjugated PS and PS-protein-conjugated vaccines are
      immunogenic after intramuscular administration without adjuvant in chinchillas.
      Passive protection studies with human hyperimmune immunoglobulin demonstrated
      that anti-PS IgG alone is capable of protecting the chinchilla ME from direct ME
      challenge with pneumococci. Active PS immunization studies demonstrated
      protection following direct ME and intranasal pneumococcal challenge with and
      without concurrent influenza A virus infection. An attenuated influenza A virus
      vaccine also showed protection for pneumococcal OM. Antimicrobial treatment of
      acute OM has been based almost exclusively on empirical drug use and clinical
      trials without a foundation of ME pharmacokinetics. Studies in the chinchilla
      model have started to bring a rational basis to drug selection and dosing.
      Microassays have been developed using high-pressure liquid chromatography for
      many relevant drugs. Studies have explored the in vivo ME response in
      pneumococcal OM to antimicrobial drugs at supra- and sub-minimum inhibitory
      concentration (MIC), the effect of concurrent influenza A virus infection on ME
      drug penetration, and the effect of treatment on sensorineural hearing loss
      produced by pneumococcal OM.

PMID- 10332722
TI  - Glycopeptide resistance in Enterococcus faecium from broilers and pigs following
      discontinued use of avoparcin.
AB  - The use of the glycopeptide growth promoter avoparcin was discontinued in Denmark
      in 1995 following concerns that vancomycin-resistant Enterococcus faecium
      occurring as a result of its use could be transferred to humans via food. The
      present study is an analysis of results obtained by the continuous surveillance
      of an antimicrobial resistance in Denmark (DANMAP) with the aim of determining
      the effect of the ban on the occurrence of glycopeptide resistance among E.
      faecium isolated from broilers and pigs. Among isolates from broilers, the
      proportion that were resistant to glycopeptides has shown a statistically high
      significant decline between the end of 1995 and the first half of 1998, whereas
      in pigs the ban appears to have no such effect. One possible explanation is that
      the broiler industry generally uses all in-all out production compared with
      continuous production in pig herds. Alternatively, the results indicate that the
      different outcomes may result from different co-selection patterns in pigs and
      broilers. In pigs, the antimicrobials most commonly used favored co-selection of
      glycopeptide resistant strains of E. faecium while in broilers the antimicrobials
      most widely used selected for glycopeptide-susceptible strains. The results show
      that intervention to reduce antimicrobial resistance may not always be effective
      and preventing resistance problems therefore becomes essential.

PMID- 10332724
TI  - Immunization and protection in pneumococcal otitis media studied in a rat model.
AB  - The recent and growing problem of bacterial resistance to common antibiotics has
      generated great interest in different methods for prevention of infections. The
      treatment of the pathogens causing upper airway infections and especially acute
      otitis media (AOM) is especially interesting in this context because these
      infections are a common cause of prescription of antibiotics all over the world.
      Both in AOM and recurrent AOM, Streptococcus pneumoniae, the most frequently
      occurring bacterium is isolated in 30-50% of all AOM attacks. In the last decade,
      multiresistant S. pneumoniae have emerged as a major problem. Thus, it is
      important to explore possibilities that immunization may protect against
      pneumococcal OM. In a well-defined animal model using Sprague-Dawley rats, we
      have investigated the effects of different routes of immunization with different
      antigens and whole cells. Together with otomicroscopical evaluation of middle ear
      (ME) status, samples for bacterial cultivation as well as for studies of
      histopathological changes have been collected. Antibody titers have been followed
      during and after pneumococcal AOM by an enzyme-linked immunosorbent assay (ELISA)
      method.

PMID- 10332725
TI  - Localization of choline acetyltransferase-expressing neurons in Drosophila
      nervous system.
AB  - A variety of approaches have been developed to localize neurons and neural
      elements in nervous system tissues that make and use acetylcholine (ACh) as a
      neurotransmitter. Choline acetyltransferase (ChAT) is the enzyme catalyzing the
      biosynthesis of ACh and is considered to be an excellent phenotypic marker for
      cholinergic neurons. We have surveyed the distribution of choline
      acetyltransferase (ChAT)-expressing neurons in the Drosophila nervous system
      detected by three different but complementary techniques. Immunocytochemistry,
      using anti-ChAT monoclonal antibodies results in identification of neuronal
      processes and a few types of cell somata that contain ChAT protein. In situ
      hybridization using cRNA probes to ChAT messenger RNA results in identification
      of cell bodies transcribing the ChAT gene. X-gal staining and/or beta
      galactosidase immunocytochemistry of transformed animals carrying a fusion gene
      composed of the regulatory DNA from the ChAT gene controlling expression of a
      lacZ reporter has also been useful in identifying cholinergic neurons and neural
      elements. The combination of these three techniques has revealed that cholinergic
      neurons are widespread in both the peripheral and central nervous system of this
      model genetic organism at all but the earliest developmental stages. Expression
      of ChAT is detected in a variety of peripheral sensory neurons, and in the brain
      neurons associated with the visual and olfactory system, as well as in neurons
      with unknown functions in the cortices of brain and ganglia.

PMID- 10332726
TI  - FMRFamide neuropeptides and neuropeptide-associated enzymes in Drosophila.
AB  - To review the histochemistry of neuropeptide transmitters system in insects, this
      chapter focuses on the biology of FMRFamide-related neuropeptides in Drosophila.
      dFMRFamide expression is limited to a small number of neurons that present a
      complex spatial pattern and whose functions appear heterogeneous. The
      neuropeptide is first expressed by a few neurons in late stage embryos, then
      dynamically in as many as 44 neurons in the larval CNS. This review describes
      histochemical procedures to evaluate this neuronal phenotype and its regulation,
      including descriptions of promoter activity, and RNA and peptide distributions.
      To evaluate the use of peptidergic transmitters on a broad scale, I also review
      experiments in Drosophila studying enzymes necessary for neuropeptide
      biosynthesis, and in particular, histochemical studies of an enzyme responsible
      for peptide alpha-amidation.

PMID- 10332728
TI  - Biogenic amine systems in the fruit fly Drosophila melanogaster.
AB  - Biogenic amines are important neuroactive molecules of the central nervous system
      (CNS) of several insect species. Serotonin (5HT), dopamine (DA), histamine (HA),
      and octopamine (OA) are the amines which have been extensively studied in
      Drosophila melanogaster. Each one of the four aminergic neuronal systems exhibits
      a stereotypic pattern of a small number of neurons that are widely distributed in
      the fly CNS. In this review, histochemical and immunocytochemical data on the
      distribution of the amine neurons in the larval and adult nervous system, are
      summarized. The majority of DA and 5HT neurons are interneurons, most of which
      are found in bilateral clusters. 5HT innervation is found in the feeding
      apparatus as well as in the endocrine organ of the larva, the ring gland. The
      octopaminergic neuronal population consists of both interneurons and efferent
      neurons. In the larval CNS all OA immunoreactive somata are localized in the
      midline of the ventral ganglion while in the adult CNS both unpaired neurons and
      bilateral clusters of immunoreactive cells are observed. One target of OA
      innervation is the abdominal muscles of the larval body wall where OA
      immunoreactivity is associated with the type II boutons in the axonal terminals.
      Histamine is mainly found in all photoreceptor cells where it is considered to be
      the major neurotransmitter molecule, and in specific mechanosensory neurons of
      the peripheral nervous system. Similarities between specific aminergic neurons
      and innervation sites in Drosophila and in other insect species are discussed. In
      addition, studies on the development and differentiation of 5HT and DA neurons
      are reviewed and data on the localization of 5HT, DA, and OA receptors are
      included as well. Finally, an overview on the isolation of the genes and the
      mutations in the amine biosynthetic pathways is presented and the implications of
      the molecular genetic approach in Drosophila are discussed.

PMID- 10332727
TI  - Neurotransmitter regulation of circadian structural changes in the fly's visual
      system.
AB  - The visual system of the fly's compound eye undergoes a number of cyclical
      day/night changes that have a circadian basis. Such responses are seen in the
      synaptic terminals of the photoreceptors and in their large monopolar-cell
      interneurons in the first optic neuropile, or lamina. These changes include, in
      the photoreceptor terminals, rhythms in the numbers of synapses and the vertical
      migration of screening pigment; and, in the monopolar cells L1 and L2, a rhythm
      in the transients of the electroretinogram and in the cyclical swelling of L1 and
      L2 lamina axons, as well as of the epithelial glia that surround these. Some of
      these changes are seen in both the housefly and the fruit fly, but the time
      course of such changes differs between the two species. Many of the changes are
      influenced by the injection of various transmitter candidates, in a direction
      that can be reconciled with the possibility of normal endogenous release of two
      substances, 5HT from the neurites of 5HT-immunoreactive neurons, and pigment
      dispersing factor peptide from the neurites of PDH cells. Consistent with this
      interpretation, the immunoreactive varicosities of PDH cells exhibit size changes
      attributable to their cyclical release of peptide, or to its cyclical synthesis
      and/or transport from the PDH cell somata. Thus, neurotransmitter substances not
      only have rapid electrophysiological actions in the optic lobe, but also longer
      lasting, presumably indirect, neuromodulatory actions, which are manifest as
      structural changes among the lamina's neurons and synapses. These actions involve
      an interplay between aminergic and peptidergic systems, but the exact role and
      especially the site of action of each has still to be elucidated.

PMID- 10332729
TI  - Ultrastructure and lectin cytochemistry of the cloacal ventral glands in the male
      newt Triturus marmoratus marmoratus.
AB  - Ventral glands are found in the cloacal walls of male urodele amphibians except
      for sirenids. These glands are mucous, and secrete substances that will form part
      of the spermatophore used in transfer of sperm during fertilization. Ventral
      glands are formed by secretory and ductal portions; both possess epithelial and
      myoepithelial cells with different characteristics. Urodeles have cyclic
      reproduction, and cloacal ventral glands show seasonal differences with electron
      microscopy. The glycoproteins secreted by these glands have been studied by means
      of lectin histochemistry. The labeling was detected mainly in the nuclei, rough
      endoplasmic reticulum, Golgi complex, and cytosol. Secretory granules in these
      glands are composed by mucous glycoproteins that bind PNA lectin (which binds
      galactose) and SBA and HPA lectins (N-acetylgalactosamine), UEA-I (fucose), and
      LcA (glucose and/or mannose). These findings suggest that the mucins secreted by
      ventral glands contain both N- and O-linked oligosaccharides. Ventral glands
      secrete higher quantity and more diverse mucous substances in the reproductive
      period, as confirmed by lectin-histochemical reactions. Based on these results,
      the major similarity between ventral cloacal glands and accessory mammalian
      glands, can be established with bulbourethral glands.

PMID- 10332730
TI  - Three-dimensional optical behaviour of a confocal microscope with single
      illumination and detection pinhole through imaging of subresolution beads.

PMID- 10332731
TI  - Construction of a cooling and heating substrate holder for the preparation of
      thin films for electron microscopy.
AB  - The PVD preparation of thin, oriented films for electron microscopy of materials
      with high adatom mobilities on the substrates requires cooling of the substrate
      holder. The construction of such a holder for cooling the substrate to -50 and
      heating it to 500 degrees C is described.

PMID- 10332732
TI  - Structural basis for membrane fusion by enveloped viruses.
AB  - Enveloped viruses such as HIV-1, influenza virus, and Ebola virus express a
      surface glycoprotein that mediates both cell attachment and fusion of viral and
      cellular membranes. The membrane fusion process leads to the release of viral
      proteins and the RNA genome into the host cell, initiating an infectious cycle.
      This review focuses on the HIV-1 gp41 membrane fusion protein and discusses the
      structural similarities of viral membrane fusion proteins from diverse families
      such as Retroviridae (HIV-1), Orthomyxoviridae (influenza virus), and Filoviridae
      (Ebola virus). Their structural organization suggests that they have all evolved
      to use a similar strategy to promote fusion of viral and cellular membranes. This
      observation led to the proposal of a general model for viral membrane fusion,
      which will be discussed in detail.

PMID- 10332733
TI  - The paramyxovirus fusion protein forms an extremely stable core trimer:
      structural parallels to influenza virus haemagglutinin and HIV-1 gp41.
AB  - The paramyxovirus fusion (F) protein mediates membrane fusion. The biologically
      active F protein consists of a membrane distal subunit F2 and a membrane anchored
      subunit F1. A highly stable structure has been identified comprised of peptides
      derived from the simian virus 5 (SV5) F1 heptad repeat A, which abuts the
      hydrophobic fusion peptide (peptide N-1), and the SV5 F1 heptad repeat B, located
      270 residues downstream and adjacent to the transmembrane domain (peptides C-1
      and C-2). In isolation, peptide N-1 is 47% alpha-helical and peptide C-1 and C-2
      are unfolded. When mixed together, peptides N1 + C1 form a thermostable (Tm > 90
      degrees C), 82% alpha-helical, discrete trimer of heterodimers (mass 31,300 M(r))
      that is resistant to denaturation by 2% SDS at 40 degrees C. The authors suggest
      that this alpha-helical trimeric complex represents the core most stable form of
      the F protein that is either fusion competent or forms after fusion has occurred.
      Peptide C-1 is a potent inhibitor of both the lipid mixing and aqueous content
      mixing fusion activity of the SV5 F protein. In contrast, peptide N-1 inhibits
      cytoplasmic content mixing but not lipid mixing, leading to a stable hemifusion
      state. Thus, these peptides define functionally different steps in the fusion
      process. The parallels among both the fusion processes and the protein structures
      of paramyxovirus F proteins, HIV gp41 and influenza virus haemagglutinin are
      discussed, as the analogies are indicative of a conserved paradigm for fusion
      promotion among fusion proteins from widely disparate viruses.

PMID- 10332734
TI  - Rabies virus-induced membrane fusion.
AB  - Rabies virus is a member of the rhabdovirus family. It enters cells by a process
      of receptor mediated endocytosis. Following this step, the viral envelope fuses
      with the endosomal membrane to allow release of the viral nucleocapsid into the
      cytoplasm. Fusion is induced by the low pH of the endosomal compartment and is
      mediated by the single viral glycoprotein G, a homotrimeric integral membrane
      protein. Rabies virus fusion properties are related to different conformational
      states of G. By different biochemical and biophysical approaches, it has been
      demonstrated that G can assume at least three different states: the native (N)
      state detected at the viral surface above pH 7, the activated (A) hydrophobic
      state which interacts with the target membrane as a first step of the fusion
      process, and the fusion inactive (I) conformation. Differently from other
      fusogenic viruses for which low pH-induced conformational changes are
      irreversible, there is a pH dependent equilibrium between these states, the
      equilibrium being shifted toward the I-state at low pH. The objective of this
      review is to detail recent findings on rhabdovirus-induced membrane fusion and to
      underline the differences that exist between this viral family and influenza
      virus which is the best known fusogenic virus. These differences have to be taken
      into consideration if one wants to have a global understanding of virus-induced
      membrane fusion.

PMID- 10332735
TI  - Structural intermediates in influenza haemagglutinin-mediated fusion.
AB  - Fusion pore formation in the haemagglutinin (HA)-mediated fusion is a culmination
      of a multistep process, which involves low-pH triggered refolding of HA and
      rearrangement of membrane lipid bilayers. This rearrangement was arrested or
      slowed down by either altering lipid composition of the membranes, or lowering
      the density of HA, and/or temperature. The results suggest that fusion starts
      with the lateral assembly of activated HA into multimeric complexes surrounding
      future fusion sites. The next fusion stage involves hemifusion, i.e. merger of
      only contacting membrane monolayers. Lysophosphatidylcholine reversibly arrests
      fusion prior to this hemifusion stage. In the normal fusion pathway, hemifusion
      is transient and is not accompanied by any measurable transfer of lipid probes
      between the membranes. A temperature of 4 degrees C stabilizes this 'restricted
      hemifusion' intermediate. The restriction of lipid flow through the restricted
      hemifusion site is HA-dependent and can be released by partial cleaving of low pH
      forms of HA with mild proteinase K treatment. Lipid effects indicate that fusion
      proceeds through two different lipid-involving intermediates, which are
      characterized by two opposite curvatures of the lipid monolayer. Hemifusion
      involves formation of a stalk, a local bent connection between the outer membrane
      monolayers. Fusion pore formation apparently involves bending of the inner
      membrane monolayers, which come together in hemifusion. To couple low pH-induced
      refolding of HA with lipid rearrangements, it is proposed that the extension of
      the alpha-helical coiled coil of HA pulls fusion peptides inserted into the HA
      expressing membrane and locally bends the membrane into a saddle-like shape.
      Elastic energy drives self-assembly of these HA-containing membrane elements into
      a ring-like complex and causes the bulging of the host membrane into a dimple
      growing towards the target membrane. Bending stresses in the lipidic top of the
      dimple facilitate membrane fusion.

PMID- 10332736
TI  - The influenza haemagglutinin-induced fusion cascade: effects of target membrane
      permeability changes.
AB  - To define the stages in influenza haemagglutinin (HA)-mediated fusion the
      kinetics of fusion between cell pairs consisting of single influenza HA
      expressing cells and single erythrocytes (RBC) which had been labelled with both
      a fluorescent lipid (Dil) in the membrane and a fluorescent solute (calcein) in
      the aqueous space have been monitored. It is shown that release of solute from
      the target cell occurs, following the formation of the hemi-fusion diaphragm.
      These results are discussed in terms of a model in which fusion peptide insertion
      into the target membrane induces lipid stalks, which results in the formation of
      a hemifusion diaphragm and a fusion pore. Bilayer expansion due to overproduction
      of these stalks can give rise to collateral damage of target membranes.

PMID- 10332737
TI  - HIV coreceptors, cell tropism and inhibition by chemokine receptor ligands.
AB  - HIV is a persistent virus that survives and replicates despite an onslaught by
      the host's immune system. A strategy for cell entry, requiring the use of two
      receptors, has evolved that may help evade neutralizing antibodies. HIV and SIV
      usually require both CD4 and a seven transmembrane (7TM) coreceptor for
      infection. At least eleven different 7TM coreceptors have been identified that
      confer HIV and/or SIV entry. For HIV-1, the major coreceptors are CCR5 and CXCR4,
      while the role of other coreceptors for replication and cell tropism in vivo is
      currently unclear. Polymorphisms in the CCR5 gene that reduce CCR5 expression
      levels, protect against disease progression, suggesting that drugs targeted to
      CCR5 could be effective. Such therapies however will not work if HIV simply
      adapts to use alternative coreceptors. In the light of these themes, this review
      will discuss the following topics: (i) the coreceptors used by primary HIV-1 and
      HIV-2 viruses, (ii) the properties and coreceptors of HIV-2 strains that infect
      cells without CD4, (iii) the role of coreceptors in HIV cell tropism and
      particularly macrophage infection and (iv) the properties of chemokine receptor
      ligands that block HIV infection.

PMID- 10332738
TI  - HIV-1 envelope determinants for cell tropism and chemokine receptor use.
AB  - Isolates of human immunodeficiency virus type-1 (HIV-1) display marked
      differences in their ability to replicate in macrophages and transformed T-cell
      lines in vitro, a property that has important implications for disease
      pathogenesis. The restriction in replication between these two CD4-positive cell
      types is largely at the level of viral entry and is regulated by the viral
      envelope (env) gene. The envelope protein (Env) is responsible for fusion of the
      viral and host membranes, and a particular region of Env called the V3-loop has
      been implicated in regulating viral tropism. However, other regions of Env, such
      as the V1- and V2-loops, have been shown to modulate the effects of the V3-loop.
      The discovery that Env initially binds the CD4 molecule on the target cell
      surface and then makes subsequent interactions with one of several members of the
      chemokine receptor family has greatly enhanced the molecular understanding of HIV
      1 entry. The differential use of chemokine receptors by different viral isolates
      and their expression in different cell types largely explains viral tropism. The
      same regions in Env responsible for virus tropism have also been shown to play an
      important role in mediating chemokine receptor use. The recent crystallization of
      HIV-1 Env in complex with CD4 illuminates the architecture of the components
      involved in mediating fusion between the viral and host membranes. The spatial
      relationship between variable structures of Env previously implicated in tropism
      and chemokine receptor use and conserved Env structures potentially involved in
      chemokine receptor binding are discussed.

PMID- 10332739
TI  - The role of the chemokine receptor CXCR4 in infection with feline
      immunodeficiency virus.
AB  - Infection with feline immunodeficiency virus (FIV) leads to the development of a
      disease state similar to AIDS in man. Recent studies have identified the
      chemokine receptor CXCR4 as the major receptor for cell culture-adapted strains
      of FIV, suggesting that FIV and human immunodeficiency virus (HIV) share a common
      mechanism of infection involving an interaction between the virus and a member of
      the seven transmembrane domain superfamily of molecules. This article reviews the
      evidence for the involvement of chemokine receptors in FIV infection and
      contrasts these findings with similar studies on the primate lentiviruses HIV and
      SIV (simian immunodeficiency virus).

PMID- 10332740
TI  - Regulation of endosome fusion.
AB  - Homotypic fusion between early endosomes can be reconstituted in vitro. By using
      wortmannin and LY294002, inhibitors of phosphatidylinositol (Pl) 3-kinase, a
      requirement for this activity has been established in order for fusion to proceed
      efficiently. It has been shown that Pl 3-kinase activity is required downstream
      of rab5 activation, although a large excess of activated rab5 can overcome
      wortmannin inhibition. A series of experiments have also been performed which
      indicate a role for early endosomal autoantigen 1 (EEA1) in determining fusion
      efficiency. EEA1 dissociates from membranes following wortmannin treatment. It is
      proposed that the requirement of endosome fusion for Pl 3-kinase activity is to
      promote the association of EEA1 with endosomes.

PMID- 10332741
TI  - Regulation of membrane transport through the endocytic pathway by rabGTPases.
AB  - Small GTP binding proteins of the rab family are associated with the cytoplasmic
      surface of compartments of the central vacuolar system. Several of them,
      including rab5, rab4 and rab11, are localized to early endocytic organelles where
      they regulate distinct events in the transferrin receptor pathway. Whereas rab5
      is controlling transport to early endosomes, rab4 and rab11 are involved in the
      regulation of recycling back to the plasma membrane. How GTP-hydrolysis of rab
      bound GTP is related to the role of these proteins in endocytosis is not yet
      known, but quick progress is being made towards this goal through the
      identification of proteins regulating the activity of these rab proteins.

PMID- 10332742
TI  - Calcium-induced fusion of sea urchin egg secretory vesicles with planar
      phospholipid bilayer membranes.
AB  - The fusion of sea urchin egg secretory vesicles to planar phospholipid bilayer
      membranes was studied by differential interference contrast (DIC) and fluorescent
      microscopy, in combination with electrical recordings of membrane conductance. A
      strong binding of vesicles to protein-free planar membranes was observed in the
      absence of calcium. Calcium-induced fusion of vesicles was detected using two
      independent assays: loss of the contents of individual vesicles visible by DIC
      microscopy: and vesicle content discharge across the planar membrane detected by
      an increase in the fluorescence of a dye. In both cases, no increase in the
      membrane conductance was observed unless vesicles were incubated with either
      Amphotericin B or digitonin prior to applying them to the planar membrane, an
      indication that native vesicles are devoid of open channels. Pre-incubation of
      vesicles with n-ethylmaleimide (NEM) abolished calcium-induced fusion. Fusion was
      also detected when vesicles were osmotically swollen to the point of lysis. In
      contrast, no fusion of vesicles to planar bilayers was seen when vesicles on
      plasma membrane (native cortices) were applied to a phospholipid membrane,
      despite good binding of vesicles to the planar membrane and fusion of vesicles to
      plasma membrane. It is suggested that cortical vesicles (CVs) have sufficient
      calcium-sensitive proteins for fusion to lipid membranes, but in native cortices
      granular fusion sites are oriented toward the plasma membrane. Removal of
      vesicles from the plasma membrane may allow fusion sites on vesicles access to
      new membranes.

PMID- 10332743
TI  - Surface aggregation and membrane penetration by peptides: relation to pore
      formation and fusion.
AB  - The peptide GALA undergoes a conformational change to an amphipathic alpha-helix
      when the pH is reduced, inducing leakage of contents from vesicles. Leakage from
      neutral or negatively-charged vesicles at pH 5.0 was similar and could be
      adequately explained by a mathematical model which assumed that GALA becomes
      incorporated into the vesicle bilayer and irreversibly aggregates to form a pore
      consisting of M = 10 +/- 2 peptides. Increasing cholesterol content in the
      membranes resulted in reduced leakage, and increased reversibility of surface
      aggregation of the peptide. Employing fluorescently labelled peptides confirmed
      that the degree of reversibility of surface aggregation of GALA was significantly
      larger in cholesterol containing liposomes. Orientation of the peptide GALA in
      bilayers was determined by a bodipy-avidin/biotin binding assay. The peptide was
      labelled by biotin at the N- or C-terminus and bodipy-avidin molecules were added
      externally or were preencapsulated in the vesicles. The peptides are arranged in
      the pore perpendicularly to the membrane, such that 3/4 of the N-termini are on
      the internal side of the membrane. The pores are stable and persist for at least
      10 min. When the peptides form an aggregate of size smaller than M, the
      orientation of the peptide is mostly parallel to the surface and the biotinylated
      peptide does not translocate. When a critical size of the aggregate is attained,
      a rearrangement of the peptide occurs, which amounts to rapid penetration and
      formation of a pore structure. Induction of fusion by peptides may be
      antagonistic to pore formation, the outcome being dependent on vesicle
      aggregation.

PMID- 10332744
TI  - Gene delivery mediated by cationic liposomes: from biophysical aspects to
      enhancement of transfection.
AB  - Cationic liposomes complexed with DNA have been used extensively as non-viral
      vectors for the intracellular delivery of reporter or therapeutic genes in
      culture and in vivo. However, the relationship between the features of the lipid
      DNA complexes ('lipoplexes') and their mode of interaction with cells, the
      efficiency of gene transfer and gene expression remain to be clarified. To gain
      insights into these aspects, the size and zeta potential of cationic liposomes
      (composed of 1,2-dioleoyl-3- (trimethylammonium) propane (DOTAP) and its mixture
      with phosphatidylethanolamine (PE)), and their complexes with DNA at different
      (+/-) charge ratios were determined. A lipid mixing assay was used to assess the
      interaction of liposomes and lipoplexes with monocytic leukaemia cells. The use
      of inhibitors of endocytosis indicated that fusion of the cationic liposomes with
      cells occurred mainly at the plasma membrane level. However, very limited
      transfection of these cells was achieved using the above complexes. It is
      possible that the topology of the cationic liposome-DNA complexes does not allow
      the entry of DNA into cells through a fusion process at the plasma membrane. In
      an attempt to enhance transfection mediated by lipoplexes composed of DOTAP and
      its equimolar mixture with dioleoylphosphatidylethanolamine (DOPE) two different
      strategies were explored: (i) association of a targeting ligand (transferrin) to
      the complexes to promote their internalization, presumably by receptor-mediated
      endocytosis; and (ii) association of synthetic fusogenic peptides (GALA or the
      influenza haemagglutinin N-terminal peptide HA-2) to the complexes to promote
      endosomal destabilization and release of the genetic material into the cytoplasm.
      These strategies were effective in enhancing transfection in a large variety of
      cells, including epithelial and lymphoid cell lines, as well as human
      macrophages, especially with the use of optimized lipid/DNA (+/-) charge ratios.
      Besides leading to high levels of transfection, the ternary complexes of cationic
      liposomes, DNA, and protein or peptide, have the advantages of being active in
      the presence of serum and being non-toxic. Moreover, such ternary complexes
      present a net negative charge and, thus, are likely to alleviate the problems
      associated with the use of highly positively charged complexes in vivo, such as
      avid complexation with serum proteins. Overall, the results indicate that these
      complexes, and their future derivatives, may constitute viable alternatives to
      viral vectors for gene delivery in vivo.

PMID- 10332745
TI  - Liposome-mediated delivery of antiviral agents to human immunodeficiency virus
      infected cells.
AB  - Intracellular delivery of novel macromolecular drugs against human
      immunodeficiency virus type-1 (HIV-1), including antisense oligodeoxynucleotides,
      ribozymes and therapeutic genes, may be achieved by encapsulation in or
      association with certain types of liposomes. Liposomes may also protect these
      drugs against nucleases. Low-molecular-weight, charged antiviral drugs may also
      be delivered more efficiently via liposomes. Liposomes were targeted to HIV-1
      infected cells via covalently coupled soluble CD4. An HIV-1 protease inhibitor
      encapsulated in conventional negatively charged multilamellar liposomes was about
      10-fold more effective and had a lower EC90 than the free drug in inhibiting HIV
      1 production in human monocyte-derived macrophages. The drug encapsulated in
      sterically stabilized liposomes was as effective as the free drug. The EC50 of
      the reverse transcriptase inhibitor 9-(2-phosphonylmethoxyethyl)adenine (PMEA)
      was reduced by an order of magnitude when delivered to HIV-1-infected macrophages
      in pH-sensitive liposomes. A 15-mer antisense oligodeoxynucleotide against the
      Rev response element was ineffective in free form against HIV-1 replication in
      macrophages, while delivery of the oligonucleotide in pH-sensitive liposomes
      inhibited virus replication. The oligodeoxynucleotide encapsulated in sterically
      stabilized pH-sensitive liposomes with prolonged circulation in vivo, which were
      recently developed in the laboratories of the authors, was also highly effective.
      A ribozyme complementary to HIV-1 5'-LTR delivered in pH-sensitive liposomes
      inhibited virus production by 90%, while the free ribozyme caused only a slight
      inhibition. Cationic liposome-mediated co-transfection of the HIV-regulated
      diphtheria toxin A fragment gene and a proviral HIV clone into HeLa cells
      completely inhibited virus production, while the frame-shifted mutant gene was
      ineffective. Co-transfection of the proviral genome and a gene encoding a Rev
      binding aptamer into HeLa cells via transferrin-associated cationic liposomes
      inhibited virus production. These studies indicate that liposomes can be used to
      facilitate the intracellular delivery of certain anti-HIV agents and to enhance
      their therapeutic effects. These properties may be particularly advantageous in
      the development of novel macromolecular drugs, which may be necessary because of
      the emergence of virus strains resistant to the currently available drugs.

PMID- 10332746
TI  - Development of a novel fusogenic viral liposome system (HVJ-liposomes) and its
      applications to the treatment of acquired diseases.
AB  - Toward human gene therapy and gene analysis in vivo, a novel hybrid vector based
      on liposome has been developed for more efficient gene delivery and gene
      expression. The liposome was decorated with HVJ (Sendal virus) envelope fusion
      proteins to introduce DNA directly into the cytoplasm, and contained DNA and DNA
      binding nuclear protein to enhance expression of the gene. Recently, several
      types of HVJ-liposomes were developed by altering the lipid components of the
      liposomes. HVJ-cationic liposomes increased gene delivery 100-800 times more
      efficiently in vitro than the conventional HVJ-anionic liposomes. HVJ-cationic
      liposomes were also more useful for gene expression in restricted portions of
      organs and for gene therapy of disseminated cancers. It was further discovered
      that the use of anionic liposomes with a virus-mimicking lipid composition (HVJ
      AVE liposomes) increased transfection efficiency by several fold in vivo,
      especially in liver and muscle. By coupling the Epstein-Barr (EB) virus replicon
      apparatus to HVJ-liposomes, transgene expression was sustained in vitro and in
      vivo. Most animal organs were found to be suitable targets for the fusigenic
      viral liposome system, and numerous gene therapy strategies using this system
      were successful in animals.

PMID- 10332747
TI  - Gene delivery systems using the Sendai virus.
AB  - Fusogenic liposome (FL) is a delivery system that can transfer encapsulated
      materials into living cells directly through membrane fusion. FL is a promising
      approach for gene therapy because it can deliver various genetic materials much
      more efficiently than other non-viral vectors without damaging the cell. FL
      mediated gene transfer consists of two independent membrane fusion phenomena;
      generation of a FL by fusing a Sendai virus (SV) particle with a simple liposome
      encapsulating DNA, and successive fusion of the FL with cell membrane. The former
      requires viral F protein but no other special molecule on the liposomal membrane,
      whereas the latter may require the receptor (sialic acid) and unidentified
      assistant molecule(s) on the cell membrane. Further analysis suggests that these
      assistant molecule(s), not the receptor, may control the fusion and govern the
      cell specificity of FL-mediated delivery. This review has described a detailed
      analysis of these fusion phenomena and discussed possible applications of FL
      mediated gene delivery to human gene therapy.

PMID- 10332749
TI  - Homology. Introduction.

PMID- 10332748
TI  - Lipid-based systems for the intracellular delivery of genetic drugs.
AB  - Currently available delivery systems for genetic drugs have limited utility for
      systemic applications. Cationic liposome/plasmid DNA or oligonucleotide complexes
      are rapidly cleared from circulation, and the highest levels of activity are
      observed in 'first pass' organs, such as the lungs, spleen and liver. Engineered
      viruses can generate an immune response, which compromises transfection resulting
      from subsequent injections and lack target specificity. A carrier, which can
      accumulate at sites of diseases such as infections, inflammations and tumours,
      has to be a small, neutral and highly serum-stable particle, which is not readily
      recognized by the fixed and free macrophages of the reticuloendothelial system
      (RES). This review summarizes lipid-based technologies for the delivery of
      nucleic acid-based drugs and introduces a new class of carrier systems, which
      solve, at least in part, the conflicting demands of circulation longevity and
      intracellular delivery. Plasmid DNA and oligonucleotides are entrapped into lipid
      particles that contain small amounts of a positively charged lipid and are
      stabilized by the presence of a polythylene glycol (PEG) coating. These carriers
      protect nucleic acid-based drugs from degradation by nucleases, are on average 70
      nm in diameter, achieve long circulation lifetimes and are capable of
      transfecting cells.

PMID- 10332750
TI  - Homology--history of a concept.
AB  - The concept of homology is traceable to Aristotle, but Belon's comparison in 1555
      of a human skeleton with that of a bird expressed it overtly. Before the late
      18th century, the dominant view of the pattern of organisms was the scala naturae
      -even Linnaeus with his divergent hierarchical classification did not necessarily
      see the resulting taxonomic pattern as a natural phenomenon. The divergent
      hierarchy, rather than the acceptance of phylogeny, was the necessary spur to
      discussion of homology and the concept of analogy. Lamarck, despite his proposal
      of evolution, attributed homology to his escalator naturae and analogy to
      convergent acquired characters. Significantly, it was the concept of serial
      homology that emerged at the end of the 18th century, although comparison between
      organisms became popular soon after, and was boosted by the famous
      Cuvier/Geoffroy Saint-Hilaire debate of the 1830s. The concepts of homology and
      analogy were well understood by the pre- (or anti-) evolutionary comparative
      anatomists before the general acceptance of phylogeny, and they were defined by
      Owen in 1843. The acceptance of evolution led to the idea that homology should be
      defined by common ancestry, and to the confusion between definition and
      explanation. The term 'homoplasy', introduced by Lankester in 1870, also arose
      from a phylogenetic explanation of homology.

PMID- 10332751
TI  - Homoplasy, homology and the problem of 'sameness' in biology.
AB  - The reality of evolution requires some concept of 'sameness'. That which evolves
      changes its state to some degree, however minute or grand, although parts remain
      'the same'. Yet homology, our word for sameness, while universal in the sense of
      being necessarily true, can only ever be partial with respect to features that
      change. Determining what is equivalent to what among taxa, and from what
      something has evolved, remain real problems, but the word homology is not helpful
      in these problematic contexts. Henning saw this clearly when he coined new terms
      with technical meanings for phylogenetic studies. Analysis in phylogenetic
      systematics remains contentious and relatively subjective, especially as new
      information accumulates or as one changes one's mind about characters. This
      pragmatic decision making should not be called homology assessment. Homology as a
      concept anticipated evolution. Homology dates to pre-evolutionary times and
      represents late 18th and early 19th century idealism. Our attempts to recycle
      words in science leads to difficulty, and we should eschew giving precise modern
      definitions to terms that originally arose in entirely different contexts. Rather
      than continue to refine our homology concept we should focus on issues that have
      high relevance to modern evolutionary biology, in particular homoplasy--derived
      similarity--whose biological bases require elucidation.

PMID- 10332752
TI  - Homology among divergent Paleozoic tetrapod clades.
AB  - A stringent definition of homology is necessary to establish phylogenetic
      relationships among Paleozoic amphibians. Many derived characters exhibited by
      divergent clades of Carboniferous lepospondyls resemble those achieved
      convergently among Cenozoic squamates that have elongate bodies and reduced
      limbs, and by lineages of modern amphibians that have undergone miniaturization.
      Incongruent character distribution, poorly resolved cladograms and functionally
      improbable character transformations determined by phylogenetic analysis suggest
      that convergence was also common among Paleozoic amphibians with a skull length
      under 3 cm, including lepospondyls, early amniotes and the putative ancestors of
      modern amphibians. For this reason, it is injudicious to equate apparent
      synapomorphy (perceived common presence of a particular derived character in two
      putative sister-taxa) with strict homology of phylogenetic origin. Identification
      of homology by the similarity of structure, anatomical position and pattern of
      development is insufficient to establish the synapomorphy of bone and limb loss
      or precocial ossification of vertebral centra, which are common among small
      Paleozoic amphibians. The only way in which synapomorphies can be established
      definitively is through the discovery and recognition of the trait in question in
      basal members of each of the clades under study, and in their immediate common
      ancestors.

PMID- 10332753
TI  - Generation, integration, autonomy: three steps in the evolution of homology.
AB  - The homology concept harbours implicit assumptions about the evolution of
      morphological organization. Homologues are natural units in the construction of
      organismal body plans. Their origin and maintenance should represent a key
      element of a comprehensive theory of morphological evolution. Therefore, it is
      necessary to understand the causation of homology and to investigate the
      mechanisms underlying its origination. The study of this issue cannot be limited
      to the molecular level, because there appears to exist no strict correspondence
      between genetic and morphological evolution. It is argued that the establishment
      of homology follows three distinct (if overlapping) steps: (a) the generation of
      morphological building elements; (b) the integration of new elements into a body
      plan; and (c) the autonomization of integrated construction units as lineage
      specific homologues of phenotypic evolution. In contrast with traditional views,
      it is proposed that the mechanistic basis for steps (a) and (b) is largely
      epigenetic, i.e. a consequence of the inherent propensities of developmental
      system under changing conditions. Step (c) transcends the proximate mechanisms
      underlying the establishment of homologues and makes them independent attractors
      of morphological organization at the phenotypic level.

PMID- 10332754
TI  - On the homology of structures and Hox genes: the vertebral column.
AB  - Research on expression patterns of Hox genes has revealed a surprisingly high
      conservation among vertebrates. In agreement with this conservation, a
      correlation has been found between the anterior limits of expression areas of
      certain Hox genes and the borders between morphological regions of the vertebral
      axis. These similarities are striking and important, but also counterintuitive,
      unless there are strong selection pressures to protect this conservatism. It is
      important to identify the selective forces that maintain these conservative
      networks. These selective forces can be due to pleiotropy or to internal
      selection. Discussed are the selective factors that are involved in the
      evolutionary constraint on the number of cervical vertebral numbers in mammals.
      Factors involved are due to internal selection and involve susceptibility to
      cancer, stillbirths and neuronal problems. It is intriguing how similar genetic
      networks can lead to fundamentally different animals. Clearly the same genes are
      used for different purposes. It is therefore important to try to find these
      differences. The search, for homology between organisms, and the enthusiasm about
      similarities that come with it, at times impedes the discovery of such
      differences. I have searched the literature for differences within vertebrates in
      the functioning and expression patterns of Hox genes during the development of
      the vertebral axis. The ensuing implications for homology of structures and genes
      are discussed. The vertebral column is a promising model system for the
      evaluation of the relationship between homologous Hox genes and homologous
      structures because of the large conservation of Hox gene expression patterns
      along the anterior axis. However, extensive remodelling of the vertebrate column
      indicates that important changes in the genetic basis must have taken place. A
      survey of the literature indicates that the correlation between Hox gene
      expression areas and vertebral regions is not such that one can predict the
      borders between vertebral regions on the basis of Hox gene expression patterns.
      The involvement of Hox genes in the development of identity of vertebrae is
      complex and the problems regarding the value of gene expression patterns for the
      determination of anatomical homology are discussed.

PMID- 10332755
TI  - Developmental basis of limb homology in urodeles: heterochronic evidence from the
      primitive hynobiid family.
AB  - The vertebrate limb is a classic example of homology, long assumed to be
      underpinned by a developmental 'bauplan' of the type proposed in the
      Shubin/Alberch branching and segmenting model. In the anuran/amniote pattern
      skeletogenesis proceeds in a proximodistal direction with digits forming from the
      posterior to the anterior. But in free-living larvae of 'advanced' urodeles, the
      pattern of skeletogenesis is distinctly different with digits 1 and 2 and the
      basal commune developing early, in an anterior/distal position. This different
      pattern is cited as evidence for a diphyletic theory of tetrapod evolution.
      Reassessing this problem, we analysed the pattern of early skeletogenesis of
      three genera (Salamandrella, Ranodon, Onychodactylus) of the 'basal' family of
      hynobiids, using immunofluorescence to localize chondroitin-6-SO4 in
      Salamandrella. Here the developmental sequence was more proximodistal
      (intermedium preceding basal commune; early formation of the digital arch). This
      pattern, also found in direct developing urodeles such as Bolitoglossa
      subpalmata, resembled that in anurans/amniotes. Uniquely amongst tetrapods,
      urodeles use their developing limbs for locomotion. We attribute the unusual
      pattern in 'advanced' urodeles to adaptive modification of the developing limb.
      Differences in the pattern between 'basic' and 'advanced' urodeles and between
      urodeles and anuran/amniotes are interpreted as heterochronic within an overall
      single tetrapod developmental bauplan.

PMID- 10332756
TI  - Larval homologies and radical evolutionary changes in early development.
AB  - Larval forms are highly conserved in evolution, and phylogeneticists have used
      shared larval features to link disparate phyla. Despite long-term conservation,
      early development has in some cases evolved radically. Analysis of evolutionary
      change depends on identification of homologues, and this concept of descent with
      modification applies to embryo cells and territories as well. Difficulties arise
      because evolutionary changes in development can obscure homologies. Even more
      difficult, threshold effects can yield changes in process whereby apparently
      homologous features can arise from new precursors or pathways. We have observed
      phenomena of this type in closely related sea urchins that differ in
      developmental mode. A species developing via a complex feeding larva and its
      congener, which develops directly, have different embryonic cell lineages and
      divergent patterns of early development, but converge on the adult sea urchin
      body plan. Despite differences in embryonic developmental pathways, conserved
      gene expression territories are evident, as are territories whose homologies are
      in doubt. The highly derived development of the direct developer evidently arises
      from an interplay of novel organization of the egg, loss of expression of
      regulatory gene involved in production of feeding larval features, and changes in
      site and timing of expression of a number of genes.

PMID- 10332757
TI  - A research programme for testing the biological homology concept.
AB  - The classical homology concept has served as a heuristic principle for organizing
      the enormous wealth of information on comparative anatomical patterns across a
      wide range of organisms. However, the classical homology concept reaches its
      limit as knowledge of the evolutionary, genetic and developmental processes that
      underlie these anatomical patterns increases. The biological homology concept
      places the known anatomical patterns into a mechanistic context and asserts that
      character identity is based on common variational properties in this chapter a
      research programme for testing the biological homology concept that involves the
      following steps is outlined: (1) identifying of two or more putative homologues
      is a clade; (2) determining the phylogenetic distribution of the putative
      homologues; (3) describing the intra- and interspecific variation patterns of
      each putative homologue; (4) describing the development of each putative
      homologue, and determining if modes of development and distribution of homologues
      are phylogenetically congruent; and (5) providing and testing a model of how
      differences in modes of development between putative homologues effect
      differences in variational tendencies. The goal is to demonstrate a link between
      developmental and variational differences of two homologues.

PMID- 10332758
TI  - Homology and homoplasy: the retention of genetic programmes.
AB  - Homology describes the inevitable evolutionary phenomenon that the similarity of
      structures among different organisms is due to the commonality of their descent.
      This continuity of information is maintained in evolutionary lineages in terms of
      genes and developmental mechanisms and will retain 'sameness' and retard, funnel
      and direct evolutionary diversification. Analogous 'sameness' is said to be due
      to independent, convergent evolution, and also involves similarity of function;
      the latter is not a necessary condition for structures to be identified as
      homologous. Here, I suggest that the biological basis for these seemingly
      disparate kinds of 'sameness' in evolution may in some, or even most, instances
      not be all that different and may be based on the same principle-the long
      evolutionary retention of genes, gene interactions and developmental mechanisms.
      Evolution might recycle and re-recruit similar mechanisms repeatedly during its
      course, and it often makes do with what is already available to it rather than to
      newly evolve or reinvent many gene interactions and developmental mechanisms
      repeatedly. Apparently there is no, or only a negligible, 'genomic cost' or even
      a selective advantage to maintaining genes and developmental mechanisms for long
      evolutionary periods of time, even if they are not continuously used in all
      members along an evolutionary line. Therefore, the biological basis of both
      homologous traits (those that are evolutionarily always expressed) and
      homoplasious traits (those that are not always 'on', but are 're-awakened' during
      evolution) might not be so different, and the distinction between homology and
      some forms of homoplasy may be somewhat artificial.

PMID- 10332759
TI  - Homology in the nervous system: of characters, embryology and levels of analysis.
AB  - The establishment of homologies is critically dependent upon the process of
      character identification. Valid characters must reliably appear in many
      individuals and be delimitable from other characters. They are not defined by any
      essential attributes, but rather by the formation of distinct clusters in a
      multidimensional morphospace. Features in two or more species can be considered
      possible homologues only if they are identifiable as the same character, for it
      would be nonsensical to homologize them as different characters. In order to
      confirm that a character is indeed homologous between species, one must examine
      its phylogenetic distribution to determine that it is unlikely to have evolved
      several times independently in the taxa being compared. This method of homologue
      identification can be applied to embryonic as well as adult characters and to
      characters at various levels of organization, including cell types and cellular
      aggregates. Difficulties arise, however, when one attempts to link the homology
      of adult characters to that of their embryonic precursors, or the homology of
      cellular aggregates to that of their constituent cell types. These efforts are
      misguided because different characters cannot be homologized to each other (as
      different characters). This perspective suggests that many neural characters may
      lack homologues, and therefore be truly novel, in other taxa.

PMID- 10332760
TI  - Natural history and behavioural homology.
AB  - Although similarities and differences among animals have long inspired
      ethologists, three misconceptions haunt the literature on behavioural evolution:
      the absence of 'ethofossils' seriously hampers detection of behavioural homology;
      behaviour is more variable and subject to experiential modification than
      morphology; and behaviour is especially subject to convergence. As a backdrop to
      address these issues, I briefly survey parental care by amniotes and antipredator
      mechanisms is non-avian reptiles. Although those behaviours remain inadequately
      sampled taxonomically, they clearly vary at several cladistic levels; they are
      conservative across some major groups, innovative within subclades, and exhibit
      apparent homoplasy among and within groups. These behavioural examples also
      illustrate contextual influences on the expression of traits, as well as how
      behavioural context can shape other aspects of development. Enhanced
      understanding of behavioural evolution will follow from greater emphasis on how
      developmental context, including behaviour itself, shapes phenotypes; from
      integration of data for fossil and recent organisms; and from much denser
      ethological sampling among taxa. Phylogenetic analyses of behavioural similarity
      should in turn provide exciting insights into the evolutionary roles of
      behavioural shifts and constraints, as well as inform our aesthetic appreciation
      for the richness of nature.

PMID- 10332762
TI  - Establishing homology criteria for regulatory gene networks: prospects and
      challenges.
AB  - One of the most remarkable discoveries to emerge from the field of developmental
      genetics is the observation that many regulatory genes and segments of their
      interactive networks (pathways) appear to have been conserved in several metazoan
      phyla. Determining whether these conserved regulatory networks are homologous,
      i.e. derived from an equivalent network in the most recent common ancestor, is
      critical to understanding comparisons between model system studies, and the
      evolution of metazoan body plans. To this end, I outline some of the evolutionary
      properties of regulatory networks, and propose both similarity and phylogenetic
      criteria that can be used to test the hypothesis that two regulatory networks are
      homologous. Furthermore, I propose that genetic networks can be treated as a
      distinct level of biological organization, and can be analysed together with
      other hierarchical levels, such as genes, embryonic origins and morphological
      structures, in a comparative framework. Examples from the literature,
      particularly the genetic regulatory networks involved in patterning arthropod and
      vertebrate limbs, are examined using the proposed criteria and hierarchical
      approach.

PMID- 10332761
TI  - Evolutionary dissociations between homologous genes and homologous structures.
AB  - Phenotype is encoded in the genome in an indirect manner: each morphological
      structure is the product of many interacting genes, and most regulatory genes
      have several distinct developmental roles and phenotypic consequences. The lack
      of a simple and consistent relationship between homologous genes and structures
      has important implications for understanding correlations between evolutionary
      changes at different levels of biological organization. Data from a variety of
      organisms are beginning to provide intriguing glimpses of the complex
      evolutionary relationship between genotype and phenotype. Much attention has been
      devoted to remarkably conserved relationships between homologous genes and
      structures. However, there is increasing evidence that several kinds of
      evolutionary dissociations can evolve between genotype and phenotype, some of
      which are quite unexpected. The existence of these dissocations limits the degree
      to which it is possible make inferences about the homology of structures based
      solely on the expression of homologous genes.

PMID- 10332763
TI  - The effect of gene duplication on homology.
AB  - Genes related by gene duplication within an organism's evolutionary lineage are
      termed paralogues; genes related by speciation are orthologues. It is generally
      agreed that orthologous genes must be compared when using DNA sequences to
      reconstruct the evolutionary history of organisms. There is an important
      exception: information from paralogous genes can reveal the root position of a
      phylogenetic tree. The duplicated rDNA genes of arrow worms provide an example.
      Gene duplication is also relevant when comparing gene expression between taxa;
      for example, when trying to identify homologous roles of genes. When gene
      duplication occurred after lineage divergence, single orthologues no longer
      exist, and comparison is complicated. This is a particular problem when comparing
      roles of vertebrate and invertebrate genes. Amphioxus and ascidian genes can be
      useful in such situations, since they diverged before extensive gene duplication
      in the vertebrate lineage. Using Otx and Pax as examples, I show how examination
      of amphioxus or ascidian genes reveals patterns of gene divergence after
      duplication, assisting the identification of homologous gene functions. Given the
      problems of comparing duplicated genes between species, the time is ripe for the
      introduction of additional terminology to elaborate on the concepts of paralogy
      and orthology.

PMID- 10332764
TI  - [Insulin-like effect of vanadium compounds].

PMID- 10332765
TI  - [The mechanisms of Na+, K(+)-ATPase in renal tubular epithelium].

PMID- 10332766
TI  - [Phosphatidylserine in Prokaryota and Eukaryota. Decarboxylation, synthesis and
      transport].

PMID- 10332767
TI  - [Liposome gene delivery system].

PMID- 10332768
TI  - [Oligonucleotides with aptameric properties].

PMID- 10332769
TI  - [Plant resistance genes and their role during infection].

PMID- 10332770
TI  - [Cyanogenesis in plants].

PMID- 10332771
TI  - [A role of heat-shock proteases in removal of denatured proteins from E. coli
      cells].

PMID- 10332772
TI  - [IHF protein as a regulator of Escherichia coli metabolism].

PMID- 10332773
TI  - Laparoscopy for diagnosis and staging of malignancy.
AB  - The use of minimally invasive surgery for abdominal pathology, including
      malignancy, has increased significantly within the past decade. Despite the
      advances in radiographic imaging, the use of laparoscopy for diagnosing and
      staging abdominal malignancy has become an important tool in the overall care of
      these patients. A review of published series for a variety of abdominal
      malignancies is presented. With the growing experience in this technique, some
      preliminary conclusions and ongoing issues are discussed.

PMID- 10332774
TI  - Role of laparoscopy for Hodgkin's and non-Hodgkin's lymphoma.
AB  - An efficacious approach to the diagnosis and treatment of lymphoma requires the
      expertise of both physicians and surgeons. The surgeon frequently is required to
      provide an adequate tissue diagnosis, stage the disease, and treat complications
      of the disease such as splenomegaly. Often, abdominal and retroperitoneal
      operations are required which may be unnecessarily morbid. Minimally invasive
      surgical techniques may favorably impact on the work-up and treatment of
      lymphoma. Laparoscopy can expeditiously access retroperitoneal lymphadenopathy,
      sample abdominal lymph node groups, and perform splenectomy with low morbidity
      and rapid recovery. In Hodgkin's disease, laparoscopic staging with splenectomy
      may be the best modality for infradiaphragmatic staging to tailor initial
      treatment. Laparoscopic splenectomy is also effective in the treatment of the
      symptoms and hematologic derangements of splenomegaly or primary splenic
      lymphoma. The technique of laparoscopic splenectomy is emphasized.

PMID- 10332775
TI  - Laparoscopic adrenalectomy for cancer.
AB  - We will review the literature on the operative techniques and patient outcomes of
      laparoscopic adrenalectomy for cancer. Further, in our own study, an analysis of
      the preoperative assessment, operative, and hospital course, and postoperative
      follow-up was performed on all patients undergoing a laparoscopic adrenalectomy
      for cancer or metastasis from October 1996 through February 1998. Twelve
      laparoscopic resections were performed in 11 patients. There were six males and
      five females with an average age of 62 years (range, 40 to 79). The mean American
      Society of Anesthesiologists (ASA) score was 3.1 (range, 2 to 4). All of the
      tumors except one were due to metastatic cancer. The metastatic sources included
      renal cell cancer (four), lung cancer (two), colon cancer (two), adrenal cancer
      (one), and melanoma (one). Seven patients required a left adrenalectomy, three
      underwent a right adrenalectomy, and one was bilateral. The approach was
      transperitoneal in eight cases and retroperitoneal in four. The mean size of the
      tumors was 5.9 cm (range, 1.8 to 12 cm). Operative time averaged 181 minutes
      (range, 100 to 315 minutes), and blood loss was 138 cc (range, 20 to 1,300 cc).
      Average hospital stay was 2.3 days (range, < 1 to 6 days). One patient required
      conversion to an open approach due to local invasion of the tumor into the
      lateral wall of the vena cava, which was resected with the specimen. This
      procedure resulted in the largest blood loss of the series (1,300 cc). All
      specimens had negative surgical margins. There was one complication (9%), a
      laceration of the epigastric artery, which was controlled laparoscopically. At a
      mean follow-up of 8.3 months (range, 0.5 to 19 months), there have been no port
      site or local recurrences. One patient has developed a new hepatic nodule, which
      is being worked up for metastatic disease. Ten of the 11 patients (91%) are
      currently alive; one has died of expansive cerebral metastases from melanoma.

PMID- 10332776
TI  - Port site recurrences after laparoscopy for malignant disease.
AB  - Reports of recurrent malignant disease developing at laparoscopic port sites has
      created considerable controversy among surgeons. Many have implicated the
      technique of laparoscopy as a cause of metastases and this has led to
      condemnation of laparoscopy in malignant disease by many surgeons. A review of
      the case reports, as well as animal studies, reveals the problem to be
      considerably more complex. Based on experimental models, reported cases, and our
      experience at the University of Texas M. D. Anderson Cancer Center, we have
      arrived at some substantive conclusions regarding this phenomenon. Port site
      recurrences (PSRs) after laparoscopy for malignant disease can occur as the only
      site of recurrence, but this is an extremely rare event, and the incidence does
      not appear to be significantly different from the development of wound
      recurrences after open laparotomy for malignancy. It is likely that port site
      recurrences reflect the underlying biology of the malignant disease, rather than
      an effect of the technique of laparoscopy.

PMID- 10332777
TI  - Laparoscopic biliary and enteric bypass.
AB  - Very few patients with a periampullary neoplasm present with resectable disease.
      Consequently, various operative and non-operative techniques have been developed
      to palliate patients with unresectable periampullary disease. Laparoscopic
      biliary (cholecystojejunostomy) and enteric bypass (gastrojejunostomy) are
      reasonable options as compared to their open counterparts for operative
      palliation. However, only a limited number of carefully selected patients meet
      selection criteria for laparoscopic palliation.

PMID- 10332778
TI  - Role of laparoscopy in the management of stomach cancer.
AB  - The use of laparoscopy for staging and treatment of gastric cancer has evolved in
      the past decade along with other advanced laparoscopic procedures. Laparoscopic
      staging of gastric cancer, especially with the addition of laparoscopic
      ultrasonography, has been shown more reliable than radiologic modalities and it
      effectively decreases the incidence of unnecessary laparotomy. Although it is not
      commonly performed in Western countries, the use of laparoscopic curative
      resection for gastric cancer is growing, especially in Japan. Laparoscopic
      resection of early gastric cancer has been shown to be safe and effective in many
      retrospective series though no prospective randomized studies comparing it to
      open resection have been performed. Despite being more controversial,
      laparoscopic curative resection of advanced gastric cancer also has been
      performed at multiple institutions with encouraging early results. This review
      will present the current worldwide experience of laparoscopy for gastric cancer.

PMID- 10332779
TI  - Laparoscopic cholecystectomy and unsuspected gallbladder carcinoma.
AB  - Gallbladder cancer is a relatively uncommon malignancy in the United States. Its
      presentation is similar to that of lithic disease of the gallbladder.
      Laparoscopic cholecystectomy has become the method of choice for removing the
      gallbladder in most benign conditions. Occasionally, unsuspected gallbladder
      carcinoma is encountered in association with laparoscopic cholecystectomy.
      Overall, gallbladder cancer portends a poor prognosis. However, in select cases,
      a favorable outcome can be expected and the less favorable predicted expected
      outcome can be improved. Management of patients with gallbladder cancer in
      different situations is discussed: gallbladder cancer noted postoperatively on
      final pathology, gallbladder cancer noted after removal of the gallbladder and
      opening of the specimen at the time of surgery, difficulty encountered at the
      time of dissection and resultant suspicion of gallbladder cancer, and diagnosis
      of extensive disease at initial placement of the laparoscope. The technique of
      extended cholecystectomy is outlined.

PMID- 10332780
TI  - Laparoscopic surgery for colorectal cancer.
AB  - Despite the widespread use of laparoscopic techniques in many fields, in the
      realm of malignant diseases, a great concern has been raised regarding safety,
      efficacy, and long-term results. The authors report their experience of 163
      patients operated on for colorectal malignancies by minimally invasive access.
      The conversion rate (20.4%), morbidity (15.1%), and null mortality compare well
      with other studies published worldwide. The postoperative outcome was
      characterized by a prompt return to activity (1.3 days) and of bowel movements
      (2.9 days), while length of stay and an adequate oral resumption were comparable
      to those of open surgery. Peritoneal lavage did not show tumor cells disseminated
      during the operative maneuvers. The distance of tumor from resection margins and
      the number of lymph nodes harvested with the operative specimen did not vary from
      those obtained in open surgery. Two patients (1.2%) recurred at the mini
      laparotomy and port sites, but, in both cases, the traumatic manipulation of the
      cancer specimen was probably responsible for the event. After a mean follow-up of
      over 3 years, 34 patients died of neoplastic recurrence, and 17 are alive with
      disease relapse. The laparoscopic approach to colectomy has not yet gained an
      unquestioned place in the experience of the colorectal surgeon. However, if sound
      surgical method and judgement are used to minimize local recurrences, and if a
      better preservation of postoperative immune function proves to be of clinical
      significance in the long term, laparoscopic colectomy may prove to be a safe and
      less stressful approach to colon resection.

PMID- 10332781
TI  - Genetic analysis of ossification of the posterior longitudinal ligament.
AB  - STUDY DESIGN: The human leukocyte antigen (HLA) haplotypes in families of
      patients with known ossification of the posterior longitudinal ligament (OPLL)
      were reviewed. OBJECTIVE: To clarify how genetic factors relate to the
      development of OPLL. SUMMARY OF BACKGROUND DATA: The association between genetic
      factors and the development of OPLL is still unknown. MATERIALS AND METHODS: The
      association between HLA haplotypes and OPLL was studied in families of 24
      patients with OPLL. RESULTS: The prevalence of OPLL was higher in the siblings
      showing a higher share of identical HLA haplotypes: 10 (53%) of 19 with
      concurrence of two strands, and 5 (24%) of 21 with concurrence of one strand. Of
      21 subjects who had no HLA haplotype identical with that in OPLL patients, only
      one showed evidence of OPLL. CONCLUSION: Genetic factors predispose toward the
      development of OPLL.

PMID- 10332782
TI  - Effects of basic fibroblast growth factor on spontaneous resorption of herniated
      intervertebral discs. An experimental study in the rabbit.
AB  - STUDY DESIGN: Histologic examination was performed on the autologous
      intervertebral disc material that was removed from the intervertebral space at L1
      L2 and then relocated to the L4 posterior epidural space after the addition of
      basic fibroblast growth factor (bFGF) in a rabbit. OBJECTIVES: To evaluate
      whether basic fibroblast growth factor influences the resorption process of the
      herniated intervertebral disc through the promotion of angiogenesis and
      chemotaxis. SUMMARY OF BACKGROUND DATA: It has been reported that newly formed
      vessels, inflammatory cells, and their products may play an important role in the
      spontaneous resorption process of herniated intervertebral discs. In a rabbit
      model that mimics the sequestration type of intervertebral disc herniation, it
      has been reported that the autologous intervertebral disc material that relocated
      into the epidural space was penetrated by newly formed vessels originating from
      the epidural fat tissue. Therefore, it is possible that promotion of angiogenesis
      may influence the resorption of herniated intervertebral discs. Basic fibroblast
      growth factor is well known as an angiogenesis stimulation factor in vivo.
      METHODS: Thirty-six adult rabbits were divided into three groups. The L1-L2
      intervertebral disc was partially incised through a retroperitoneal approach in
      each rabbit. The harvested disc material, which contained nucleus pulposus and
      anulus fibrosus, was immersed in one of three kinds of solution before relocation
      into the posterior epidural space at L4. In the control group, the harvested
      intervertebral disc was immersed in physiologic saline for 2 hours before
      relocation. In the group receiving 5 micrograms bFGF, the disc was immersed in 5
      micrograms/mL bFGF for 2 hours before the relocation. In the group receiving 20
      micrograms bFGF, the disc was immersed in 20 micrograms/mL bFGF for 2 hours
      before the relocation. Rabbits of each group were killed for histologic
      examination 1, 2, 4, and 8 weeks after surgery. RESULTS: In the bFGF-treated
      groups, newly formed vessels were observed to be in more numerous than those in
      the control group, 1 and 2 weeks after surgery. The number of inflammatory cells,
      including macrophages, lymphocytes, and fibroblasts, also increased in the bFGF
      treated groups. The period from the surgery to the degradation of the
      intervertebral disc in the bFGF-treated groups was shorter than that in the
      control group, although the resorption process of the relocated discs was also
      observed in the control group. The size of relocated intervertebral discs in the
      bFGF-treated groups decreased at a higher rate than in the control group as time
      progressed. The rate of decrease in the size of discs in the group treated with
      20 micrograms bFGF was more than that in the group treated with 5 micrograms.
      CONCLUSIONS: Epidural injection of bFGF facilitated the resorption of the
      intervertebral disc relocated to the epidural space.

PMID- 10332783
TI  - Corrosion on an internal spinal fixator system.
AB  - STUDY DESIGN: Thirteen spinal fixators with 26 stabilization bridges and 52
      pedicle screws and a mean length of implantation of 10 months were prospectively
      examined for corrosion. OBJECTIVES: To determine the type of corrosion and the
      correlation between the construction of the spinal fixator and the type of
      corrosion. SUMMARY OF BACKGROUND DATA: Evidence of fretting and crevice corrosion
      is seen in many stainless steel implants in retrieval studies. Such reactions
      have not been described in the literature on spinal fixator systems. METHODS:
      Macroscopic and microscopic alterations in the adjacent tissue were examined, and
      the corrosive alterations were documented photographically using stereoscopic
      optical light microscopy. The chemical composition of the implants was determined
      spectrographically. Microradiography and x-ray fluorescence analysis of the soft
      tissue were performed. RESULTS: At surgery, tissue discoloration was found in
      four cases. Histologic examination showed extensive fibrosis, foreign body
      reaction and inflammation associated with a small number of metal particles,
      indicating metallosis in five cases. Corresponding particles were detected by
      microradiography. Corrosion was found on 13 telescopic rods and on two pedicle
      screws. The alterations on the telescopic rods could be interpreted as crevice
      corrosion and the alterations in the pedicle screws as fretting corrosion. The
      two monobloc fixator bridges did not show signs of corrosion. In these implants,
      the neighboring tissue was macroscopically inconspicuous, and histologic
      examination showed minimal fibrosis or presence of metal particles.
      Spectrographic examination of the spinal fixators showed no structural
      imperfection. CONCLUSIONS: The construction constraints of a spinal fixator make
      it prone to corrosion. New spinal implants should be examined not only in vitro
      but also in vivo to ascertain whether corrosion and adjacent tissue reaction
      occur. Corrosion is one reason to explant the internal fixation system after
      fusion of the spinal fracture.

PMID- 10332784
TI  - Improving the evaluation of benign low back pain.
AB  - STUDY DESIGN: A prospective, blind study was conducted to investigate the factors
      underlying the decisions of expert clinicians in diagnosis of acute, benign low
      back pain, compared with results obtained with an automated physical examination
      by machine. From the results, a strategy to significantly improve clinical
      diagnosis in cases of discordance was determined. OBJECTIVES: To identify factors
      in the clinical assessment of low back pain that indicate when independent
      diagnostic testing would be useful. SUMMARY OF BACKGROUND DATA: The clinical
      evaluation of low back pain is often dominated by subjective reports of pain.
      Published medical literature has underscored several inherent weaknesses of the
      clinical examination, and concerns have been raised about its effectiveness for
      assessing patients with low back pain. Thus, it has been proposed that objective
      measures to complement the clinician's examination would be beneficial in the
      formulation of dependable diagnoses. METHODS: Randomly designated subjects, who
      in describing their conditions were objective or role playing, were assessed by
      clinicians and a machine for diagnosis of low back pain assessment versus normal
      backs. Each subject's pain assessment was compared with a gold standard that was
      established by experts in low back pain. Components of the clinical examination
      were analyzed to assess which were the most informative in making a reliable
      diagnosis. The information content of the machine assessment was also analyzed
      and a strategy to complement the clinical diagnosis with the machine diagnosis
      determined. RESULTS: Discordance among the various components of the clinical
      examination was a strong indicator of when the efficacy of the clinical
      examination dropped below a random level of decision making. When there was
      discordance, incorporating the functional evaluation by machine into the clinical
      diagnosis improved the performance of the clinician. Notably, in nonobjective
      subjects, the accuracy of diagnosis was enhanced by as much as 69%. CONCLUSIONS:
      It is possible to improve the accuracy of clinical diagnosis by incorporating a
      functional evaluation by machine when there is discordance between physical
      examination findings and reported pain.

PMID- 10332785
TI  - Use of a subjective health measure on Chinese low back pain patients in Hong
      Kong.
AB  - STUDY DESIGN: A prospective observational study on the use of the Aberdeen Low
      Back Pain Disability Scale. OBJECTIVE: To evaluate the reliability, validity, and
      responsiveness of the Chinese adaptation of the Aberdeen Low Back Pain Scale in
      Chinese patients in Hong Kong who have back pain. SUMMARY OF BACKGROUND DATA:
      Frontline clinicians, researchers, and health care managers in Hong Kong are
      urgently in need of a Chinese adaptation of a low back pain outcome measure that
      has been subjected to a rigorous process of psychometric and clinical testing.
      METHODS: Four samples with 473 consecutive adult patients with low back pain from
      six physiotherapy outpatient departments in Hong Kong who completed the Aberdeen
      Low Back Pain Scale were observed and measured at time points including the
      beginning physiotherapy; 10 days, 3 weeks, and 6 weeks after physiotherapy; and
      when discharged from treatment. RESULTS: The test-retest reliability coefficient
      was 0.94 (0.94 in the original English version; figures from the English version
      are reported in parentheses). The Cronbach alpha coefficient was 0.85 (0.80). The
      Spearman correlation coefficient, when the Aberdeen score was correlated with
      that of a generic current 42-item questionnaire regarding the patient's perceived
      health to establish cross-sectional construct validity, was 0.59 (0.36-0.66, with
      the Short Form 36 scale). The effect sizes (responsiveness) at weeks 3 and 6
      after treatment began were 0.59 and 0.81, respectively (a high of 0.62 reported
      in the English version). CONCLUSIONS: The Chinese version of the Aberdeen Low
      Back Pain Disability Scale retained the high levels of reliability, validity, and
      responsiveness of the original English version when tested in Hong Kong in four
      samples of Chinese patients with low back pain.

PMID- 10332786
TI  - Minimum 5-year follow-up of anterior column structural allografts in the thoracic
      and lumbar spine.
AB  - STUDY DESIGN: An analysis of consecutive adult patients treated surgically with
      anterior column structural allografts for sagittal plane abnormalities.
      OBJECTIVES: To evaluate the effectiveness of anterior structural allografts in
      maintaining long-term sagittal plane correction when combined with posterior
      spinal fusion and posterior segmental spinal instrumentation and to assess
      anterior allograft incorporation into adjacent vertebral bodies a minimum of 5
      years after implantation. SUMMARY OF BACKGROUND DATA: There is no study in the
      literature in which incorporation and remodeling of anterior column structural
      allografts with minimum 5-year follow-up are assessed. Do they collapse or resorb
      or sustain stress fractures between a 2-year and 5-year follow-up? METHODS:
      Twenty-three consecutive adult patients (mean age, 45 years; range, 25-63 years)
      had a combination of anterior structural fresh-frozen allograft plus posterior
      autogenous grafting and posterior segmental spinal instrumentation performed from
      June 1988 through August 1992. All patients had sagittal plane abnormalities, and
      all surgeries were performed by the same surgeon. Twenty of the 23 patients
      returned for follow-up examinations for at least 5 years (average, 7 +/- 3 years;
      range, 5 +/- 4-10 +/- 3 years). Diagnoses included kyphoscoliosis (n = 8),
      spondylolisthesis (n = 3), degenerative disc disease (n = 3), and acute or
      chronic fracture (n = 6). The allografts spanned only disc spaces in 16 patients,
      and vertebral bodies and disc spaces in 4 patients. Forty disc spaces and four
      vertebral bodies were grafted, and 67 structural allografts were placed. Upright
      radiographs were analyzed before surgery, immediately after surgery, and at final
      follow-up examination to assess the degree of anterior allograft incorporation
      and maintenance of sagittal correction. A strict 4-point grading system was used.
      Two independent observers, not involved with surgical procedures, analyzed the
      radiographic results. RESULTS: Of the 67 structural allografts, 66 (98.5%) showed
      incorporation. Both observers concluded that none of the 67 structural allografts
      showed evidence of collapse. In all grafted levels and in any patient, there was
      no difference in sagittal plane measurements obtained immediately after surgery
      and those obtained at follow-up examinations 2 years and 5 or more years after
      surgery. CONCLUSIONS: Anterior fresh-frozen structural allograft works
      effectively in the long term to maintain correction of sagittal plane
      abnormalities if combined with posterior fusion and instrumentation. A minimum of
      5 years after surgery, there is a high rate of structural allograft incorporation
      into the adjacent vertebral bodies.

PMID- 10332787
TI  - Are anatomic landmarks reliable in determination of fusion level in
      posterolateral lumbar fusion?
AB  - STUDY DESIGN: Determination of the fusion level by direct observation and
      palpation of anatomic landmarks is compared with the finding obtained from a
      lateral intraoperative radiograph. OBJECTIVES: To assess the reliability of the
      use of intraoperative anatomic landmarks in determination of the fusion level.
      SUMMARY OF BACKGROUND DATA: Accurate determination of the level to be fused in
      noninstrumented posterolateral fusion is crucial. No studies are available in
      which the value of direct observation and palpation of the anatomic landmarks in
      determination of the fusion level has been assessed. METHODS: Eighty patients who
      underwent posterolateral fusion without instrumentation in the lumbosacral spine
      were included in this study. During surgery, first, the cephalad transverse
      process at the desired level to be fused was determined by direct observation and
      palpation of the anatomic landmarks; second, a metal mark was placed beneath the
      cephalad transverse process at the level determined by anatomic landmarks. This
      was followed by a lateral radiograph. The consistency and discrepancy between the
      use of the anatomic landmarks and lateral radiography in determining the desired
      fusion level were recorded. RESULTS: The fusion level determined by direct
      observation and palpation of the anatomic landmarks was accurate in 76 (95%)
      cases. In the remaining four cases, intraoperative x-rays determined that the
      selection of the cephalad transverse process for fusion was one level too high in
      three cases and one level too low in the other case. All errors in determination
      of the level to be fused occurred in patients who had extensive laminectomy at L4
      S1. CONCLUSIONS: Determination of fusion level by direct observation and
      palpation of the anatomic landmarks is not reliable in patients who have had or
      require decompressive procedures. A lateral radiograph should be routinely
      obtained for accurate identification of the level to be fused.

PMID- 10332788
TI  - Radiation dose for pedicle screw insertion. Fluoroscopic method versus computer
      assisted surgery.
AB  - STUDY DESIGN: Comparison of the radiation dose between the traditional
      fluoroscopic approach and computed tomography (CT)-based computer-assisted
      surgery for pedicle screw placement was determined. OBJECTIVES: To evaluate the
      radiation dose delivered by fluoroscopy-controlled pedicle screw placement versus
      insertion guided by computer. To define the CT computer-assisted protocol,
      involving lower radiation exposure for the patient, that still provides
      acceptable image quality. SUMMARY OF BACKGROUND DATA: There are no published data
      describing the dose delivered in CT-based image-guided surgery, and there are few
      studies in which the organ dose and the effective dose delivered during pedicle
      screw insertion that is performed traditionally with fluoroscopic control are
      described. METHODS: Dose measurements were performed on two types (REMAB and
      RANDO) of anthropomorphic phantoms. Thermoluminescent dosimeters were used to
      measure the organ dose. Both phantoms were exposed to the fluoroscopic x-ray
      beam. The representative intraoperative scenario was determined by observation of
      20 consecutive surgical interventions featuring pedicle screw implantation. For
      the CT dose measurement only, the REMAB phantom was used with two types of CT
      scanners. Three scanning protocols were evaluated: sequential, spiral optimized,
      and sequential optimized. Optimization of the scanning protocol included changes
      of anode current. The CT images were subsequently processed to achieve three
      dimensional reconstruction of the lumbar spine for the computer-assisted
      intervention. RESULTS: Organ and effective doses were higher in any of the CT
      examinations than in the fluoroscopic procedure. There was a slight difference
      between doses registered during optimized spiral scanning and doses in the
      calculated optimized sequential CT protocol. Optimized sequential scanning was
      associated with an effective dose 40% lower than that in nonoptimized sequential
      scanning. The small anatomic structures of the spine could be easily recognized
      on each of the three-dimensional reconstructions, and all of them were suitable
      for use in computer-assisted surgery. CONCLUSIONS: Percutaneous pedicle screw
      insertion in the lumbar region of the spine, performed using fluoroscopic
      control, requires a lower radiation dose than do CT scans necessary for computer
      assisted surgery. The CT radiation dose can be significantly decreased by
      optimization of the scanner settings for computer-assisted surgery. The
      advantages of computer-assisted surgery justify CT scans, when based on correctly
      chosen indications.

PMID- 10332789
TI  - Helical computed tomography and three-dimensional reconstruction of a bipedicular
      developmental anomaly of the C2 vertebra.
AB  - STUDY DESIGN: A case of bilateral failure of fusion of the C2 neural arch
      resembling a bipedicular fracture in a 9-year-old boy involved in a motor vehicle
      accident. OBJECTIVES: To describe the use of helical computed tomography and
      three-dimensional reconstruction images to identify the defect as congenital.
      SUMMARY OF BACKGROUND DATA: Congenital defects in the C2 neural arch are rare.
      Diagnostic difficulties arise when they are discovered during the assessment of
      patients after trauma, when they may resemble C2 arch fractures. METHODS: Lateral
      cervical spine radiograph, transverse section computed tomography, and three
      dimensional reconstruction images were used to delineate the anatomy of the
      defect. RESULTS: The three-dimensional reconstruction views showed that normal
      alignment of the vertebrae was maintained, despite the pedicle defects.
      CONCLUSIONS: Differentiation of a C2 fracture from a congenital defect may be
      difficult. Reconstruction in three dimensions from helical computed tomography is
      a useful adjunct to conventional computed tomography in the evaluation of such
      patients.

PMID- 10332790
TI  - Spinal manifestation of metastasizing leiomyosarcoma.
AB  - STUDY DESIGN: Case report. OBJECTIVE: To provide additional information on
      possible relations between uterine and spinal manifestations of leiomyosarcoma.
      SUMMARY OF BACKGROUND DATA: Spinal metastases and primary spinal manifestation of
      leiomyosarcoma and other malignant smooth muscle tumors are rarely observed.
      METHODS: Clinical and radiologic follow-up of a patient with a spinal tumor.
      RESULTS: A 46-year-old women had rapidly progressive paraplegia caused by an
      extramedullary lesion in the extradural space at T2-T3, with spinal cord
      compression. After surgical decompression, the resected tumor was histologically
      classified as a leiomyosarcoma. Diagnostic work-up failed to detect the primary
      tumor site. Previous medical history had been uneventful except for hysterectomy
      3 years earlier for a leiomyoma. Extended necroses and focal metaplasia were
      already described in the hysterectomy specimen indicating malignant disease;
      however, it was not definitely diagnosed. Multiple leiomyosarcoma metastases
      developed 22 months later. CONCLUSIONS: In retrospect, the origin of the
      leiomyosarcoma that manifested in the thoracic spine of the patient must be
      reconsidered. Rather than a primary dural leiomyosarcoma, this tumor represented
      the first evidence of recurrence of a missed diagnosis of early-stage uterine
      leiomyosarcoma.

PMID- 10332791
TI  - The lumbar spine in the 2000s.

PMID- 10332792
TI  - Compression-induced changes in intervertebral disc properties in a rat tail
      model.
AB  - STUDY DESIGN: An Ilizarov-type apparatus was applied to the tails of rats to
      assess the influence of immobilization, chronically applied compression, and sham
      intervention on intervertebral discs of mature rats. OBJECTIVES: To test the
      hypothesis that chronically applied compressive forces and immobilization cause
      changes in the biomechanical behavior and biochemical composition of rat tail
      intervertebral discs. SUMMARY OF BACKGROUND DATA: Mechanical factors are
      associated with degenerative disc disease and low back pain, yet there have been
      few controlled studies in which the effects of compressive forces on the
      structure and function of the disc have been isolated. METHODS: The tails of 16
      Sprague-Dawley rats were instrumented with an Ilizarov-type apparatus. Animals
      were separated into sham, immobilization, and compression groups based on the
      mechanical conditions imposed. In vivo biomechanical measurements of disc
      thickness, angular laxity, and axial and angular compliance were made at 14-day
      intervals during the course of the 56-day experiment, after which discs were
      harvested for measurement of water, proteoglycan, and collagen contents. RESULTS:
      Application of pins and rings alone (sham group) resulted in relatively small
      changes of in vivo biomechanical behavior. Immobilization resulted in decreased
      disc thickness, axial compliance, and angular laxity. Chronically applied
      compression had effects similar to those of immobilization alone but induced
      those changes earlier and in larger magnitudes. Application of external
      compressive forces also caused an increase in proteoglycan content of the
      intervertebral discs. CONCLUSIONS: The well-controlled loading environment
      applied to the discs in this model provides a means of isolating the influence of
      joint-loading conditions on the response of the intervertebral disc. Results
      indicate that chronically applied compressive forces, in the absence of any
      disease process, caused changes in mechanical properties and composition of tail
      discs. These changes have similarities and differences in comparison with human
      spinal disc degeneration.

PMID- 10332793
TI  - A follower load increases the load-carrying capacity of the lumbar spine in
      compression.
AB  - STUDY DESIGN: An experimental approach was used to test human cadaveric spine
      specimens. OBJECTIVE: To assess the response of the whole lumbar spine to a
      compressive follower load whose path approximates the tangent to the curve of the
      lumbar spine. SUMMARY OF BACKGROUND DATA: Compression on the lumbar spine is 1000
      N for standing and walking and is higher during lifting. Ex vivo experiments show
      it buckles at 80-100 N. Differences between maximum ex vivo and in vivo loads
      have not been satisfactorily explained. METHODS: A new experimental technique was
      developed for applying a compressive follower load of physiologic magnitudes up
      to 1200 N. The experimental technique applied loads that minimized the internal
      shear forces and bending moments, made the resultant internal force compressive,
      and caused the load path to approximate the tangent to the curve of the lumbar
      spine. RESULTS: A compressive vertical load applied in the neutral lordotic and
      forward-flexed postures caused large changes in lumbar lordosis at small load
      magnitudes. The specimen approached its extension or flexion limits at a vertical
      load of 100 N. In sharp contrast, the lumbar spine supported a load of up to 1200
      N without damage or instability when the load path was tangent to the spinal
      curve. CONCLUSIONS: Until this study, an experimental technique for applying
      compressive loads of in vivo magnitudes to the whole lumbar spine was
      unavailable. The load-carrying capacity of the lumbar spine sharply increased
      under a compressive follower load, as long as the load path remained within a
      small range around the centers of rotation of the lumbar segments. The follower
      load path provides an explanation of how the whole lumbar spine can be lordotic
      and yet resist large compressive loads. This study may have implications for
      determining the role of trunk muscles in stabilizing the lumbar spine.

PMID- 10332794
TI  - The degree of decompressive relief and its relation to clinical outcome in
      patients undergoing surgery for lumbar spinal stenosis.
AB  - STUDY DESIGN: A cross-sectional, clinical study to evaluate surgical
      decompression of the stenotic area monitored by computed tomographic scan and its
      relation to clinical variables in patients operated on for lumbar spinal
      stenosis. OBJECTIVE: To study in patients with lumbar spinal stenosis the
      influence of the degree of compressive relief on the patients' clinical outcome.
      SUMMARY OF BACKGROUND DATA: The goal of surgical treatment in lumbar spinal
      stenosis is to decompress the stenotic area. Although the decompression should be
      adequate, there are no clear guidelines to determine the extent of necessary
      decompression. In fact, there is clinical evidence that there is a discrepancy
      between the surgical outcome in the patient with lumbar spinal stenosis and
      postoperative radiologic findings. METHODS: In 92 patients with lumbar spinal
      stenosis who had had no prior back surgery, preoperative and postoperative
      computed tomographic scans were obtained to determine the degree of
      decompression. The postoperative scan findings were classified according to the
      degree of decompression into a no-stenosis group (n = 35), an adjacent-stenosis
      group (n = 27), and a residual-stenosis group (n = 30). The postoperative
      instability of the lumbar spine was investigated by functional radiography. The
      subjective disability of the patients was assessed using the Oswestry score and
      the severity of pain using the visual analog scale. Walking capacity was
      evaluated by a treadmill test. The patients' estimations of the results of
      surgery were classified into groups of satisfied patients and dissatisfied
      patients. RESULTS: The mean Oswestry score in all 92 patients was 27.1, and mean
      walking capacity was 630 m. In the satisfied patients, the Oswestry score was
      18.8 and in the dissatisfied patients, 34.9 (P < 0.0000). Walking capacity was
      690 m and 594 m, respectively. There were 30 patients with postoperative spinal
      instability, but it had no influence on surgical outcome. There were no
      differences in the Oswestry score, walking capacity, and patients' satisfaction
      among the postoperative CT groups. In the linear regression analysis, the
      satisfied patient corresponded significantly with the Oswestry score.
      CONCLUSIONS: The satisfaction of the patients with the results of surgery was
      more important in surgical outcome than the degree of decompression detected on
      computed tomographic scan.

PMID- 10332795
TI  - An in vivo magnetic resonance imaging study of changes in the volume (and fluid
      content) of the lumbar intervertebral discs during a simulated diurnal load
      cycle.
AB  - STUDY DESIGN: Magnetic resonance imaging was used to measure the changes in
      volume of the lumbar intervertebral disc in vivo during a load cycle. OBJECTIVES:
      To measure changes in volume of the lumbar intervertebral disc during a load
      cycle and relate these changes to changes in fluid content. SUMMARY OF BACKGROUND
      DATA: There have been very few experiments conducted to measure the volume and
      fluid changes in intervertebral discs in vivo. METHODS: Five healthy subjects
      were recruited (aged 27, 29, 31, 34, and 52 years) in a study using magnetic
      resonance imaging to measure the changes in volume of the lumbar intervertebral
      disc in vivo, during a load cycle. The experiment was designed to simulate a
      diurnal load cycle, but over less time. The load cycle consisted of bed rest,
      followed by walking with a 20-kg backpack for 3 hours, followed by bed rest for 3
      hours. Magnetic resonance imaging scans of the lumbar spine were obtained 10
      times during this load cycle. The disc volume was calculated by summing the disc
      area contained in each slice of the scan. The changes in volume of the discs (L2
      L3, L3-L4, and L4-L5) recorded at the 10 times were then related to the fluid
      changes. RESULTS: Load-induced changes in disc volume can be detected and
      measured using MR imaging. The average volume increase 3 hours after removing a
      highly compressive load was 5.4%. The water content of the nucleus and anulus in
      the disc of the young human is said to be approximately 80% and 70%,
      respectively. If the disc gained 5.4% of its initial total volume, and assuming
      that the initial fluid content was approximately 75%, then it gained
      approximately 7% (i.e., 5.4%/75% x 100% approximately 7%) of its fluid.
      CONCLUSIONS: Load-induced changes in disc volume can be detected and measured
      using magnetic resonance imaging.

PMID- 10332796
TI  - Serial changes in trunk muscle performance after posterior lumbar surgery.
AB  - STUDY DESIGN: Serial changes in trunk muscle performance were prospectively
      studied in 20 patients who underwent posterior lumbar surgery. OBJECTIVE: To
      evaluate the influence of back muscle injury on postoperative trunk muscle
      performance and low back pain, to clarify the significance of minimization of
      back muscle injury during surgery. SUMMARY OF BACKGROUND DATA: The current
      investigators have reported examination of iatrogenic back muscle injury in an
      animal model and in humans. However, definite impairment caused by such back
      muscle injury has not been clarified. METHODS: The patients were divided into a
      short-retraction-time group (< 80 minutes; n = 12) and a long-retraction-time
      group (> or = 80 minutes; n = 8). Before surgery and 3 and 6 months after
      surgery, the degree of back muscle injury was estimated by magnetic resonance
      imaging, and trunk muscle strength was measured. In addition, the incidence and
      severity of low back pain were serially analyzed. RESULTS: Back muscle injury was
      directly related to the muscle retraction time during surgery. The damage to the
      multifidus muscle was more severe, and the recovery of extensor muscle strength
      was delayed in the long-retraction-time group. In addition, the incidence of
      postoperative low back pain was significantly higher in the long-retraction-time
      group. CONCLUSIONS: Postoperative trunk muscle performance is dependent on the
      muscle retraction time. Thus, it is beneficial to shorten the retraction time to
      minimize back muscle injury and subsequent postoperative low back pain.

PMID- 10332797
TI  - Intraoperative somatosensory evoked potential findings in acute and chronic
      spinal canal compromise.
AB  - STUDY DESIGN: Early and long-term postoperative outcome were analyzed by
      retrospective record review and compared with results of intraoperative
      somatosensory evoked potential (SEP) findings in 70 patients with chronic lumbar
      stenosis. SUMMARY OF BACKGROUND DATA: Adverse SEP changes occur in up to 2% of
      patients during scoliosis surgery and may reverse with intraoperative
      intervention. Little is known about the short- or long-term results of
      intraoperative intervention based on adverse SEP changes in patients with chronic
      lumbar stenosis during lumbar decompression and fusion. OBJECTIVE: To compare
      intraoperative SEP changes with immediate and long-term neurologic outcome in
      patients undergoing lumbar decompression, instrumentation and fusion for chronic
      lumbar stenosis and to determine whether the early correlation between
      intraoperative SEP deterioration and clinical outcome persisted. METHODS:
      Monitoring SEPs using an alternating arm and leg stimulation paradigm allowed
      rapid identification of intraoperative changes. Retrospective record review was
      conducted without knowledge of intraoperative SEP findings. Clinical and SEP
      findings were then compared, to determine whether the strong association between
      intraoperative SEP results and early clinical outcome persisted. RESULTS: Nine of
      12 patients who had unilateral intraoperative SEP deterioration that resolved
      with intervention had no adverse sequelae; the remaining three had new
      ipsilateral weakness that persisted during a 9-24-month follow-up. Intraoperative
      SEPs deteriorated in 15% of patients with normal and abnormal baseline SEPs.
      Intraoperative SEP deterioration could not be predicted by preoperative radicular
      pain, focal symptomatology or baseline SEP findings. 80% of patients with normal
      SEPs but only 54% with abnormal SEPs had immediate and sustained pain relief. SEP
      deterioration that reversed with surgical intervention or high-dose steroids
      resulted in no adverse neurologic outcome. CONCLUSIONS: Acute, unilateral,
      unresolved intraoperative SEP deterioration was associated with long-term
      ipsilateral weakness not predicted by clinical or neurologic findings before
      surgery. Clinical improvement persisted in 92% of patients, 4% were unchanged,
      and 4% had persistent neurologic changes during an average 12-month follow-up
      period. The findings underscore the need for monitoring SEPs during surgery in
      all patients undergoing invasive lumbar surgery and for rapid identification and
      intervention should a unilateral SEP change persist.

PMID- 10332799
TI  - Surgical management of lumbar spinal stenosis.
AB  - Lumbar stenosis includes various forms of constriction of the spinal canal or the
      intervertebral foramen. Stenosis may be present in isolation, with or without a
      disc bulge or herniation, or can be associated with degenerative
      spondylolisthesis or degenerative scoliosis. This article analyzes the indication
      for surgery and the methods and outcomes of operative treatment in central,
      lateral, and foraminal stenosis either isolated or associated with other
      conditions. The factors that most affect outcome are correct indications for
      surgery and adequate technique. At present, 70-80% of patients have a
      satisfactory result from surgery, but the outcome tends to deteriorate in the
      long term.

PMID- 10332798
TI  - The efficacy of active rehabilitation in chronic low back pain. Effect on pain
      intensity, self-experienced disability, and lumbar fatigability.
AB  - STUDY DESIGN: A randomized study comparing the results of active rehabilitation
      and passive control treatment in patients with chronic low back pain with follow
      up at 6 months and 1 year. OBJECTIVES: To study the efficacy of active
      rehabilitation on pain, self-experienced disability, and lumbar fatigability.
      SUMMARY OF BACKGROUND DATA: Exercises in an outpatient setting are widely used
      for the treatment of chronic low back pain. The efficacy of the active
      rehabilitation approach has been documented in randomized control studies, but
      these studies have seldom been focused on lumbar fatigability, which is now
      recognized as a frequent problem among patients with chronic low back pain.
      METHODS: Fifty-nine middle-aged patients (37 men and 22 women) with nonspecific
      chronic low back pain were randomly assigned to 12 weeks' active rehabilitation
      or to a passive control treatment (massage, thermal therapy). Pain and disability
      index, low back pain intensity (visual analog scale, 100 mm), and the objectively
      assessed lumbar muscle fatigability (spectral electromyogram, mean power
      frequency slope [MPFSLOPE]) in a new 90-second submaximal isoinertial back
      endurance test were recorded before and after the interventions and at 6-month
      and 1-year follow-up visits. RESULTS: Results of repeated measures multivariate
      analysis of variance indicated that back pain intensity (visual analog scale) and
      functional disability (pain and disability index score) decreased, and lumbar
      endurance (MPFSLOPE) improved significantly more (P < 0.05) in the active
      rehabilitation group than in the passive control treatment group, when measured
      at a 1-year follow-up examination. The group difference in visual analog scale
      and pain and disability index changes became even more significant at the end of
      1 year. The change in lumbar endurance was significantly greater in the active
      rehabilitation group than in the passive control treatment group at the 6-month
      follow-up, but not at the 1-year follow-up. CONCLUSIONS: The active progressive
      treatment program was more successful in reducing pain and self-experienced
      disability and also in improving lumbar endurance than was the passive control
      treatment. However, the group difference in lumbar endurance tended to diminish
      at the 1-year follow-up.

PMID- 10332800
TI  - NMDA receptor blockade attenuates the haloperidol induction of Fos protein in the
      dorsal but not the ventral striatum.
AB  - Neuroleptic blockade of dopamine receptors is known to produce an increase in the
      expression of Fos. This increase may be related to elevations in glutamate
      transmission which in turn activates N-methyl-D-aspartate (NMDA) receptors. In
      the present study, we examine the role of these receptors in the haloperidol
      induced augmentation of Fos in the caudate-putamen and nucleus accumbens of
      Wistar rats. Animals were divided into four groups for each experiment and each
      was injected either with saline; a noncompetitive NMDA antagonist, dizocilpine
      maleate (MK801, 5 mg/kg); haloperidol (0.5 mg/kg); or MK801 followed by an
      injection of haloperidol. Fos-immunoreactive cells appear in large numbers in all
      parts of the striatum 3 h after the administration of haloperidol. Pretreatment
      with MK801 attenuates the haloperidol-induced increase in Fos in the caudate
      putamen. However, antagonism of the NMDA receptor does not significantly reduce
      the density of Fos-immunoreactive cells in any territory of nucleus accumbens,
      i.e., shell, core, or rostral pole. These data suggest that haloperidol acts in
      an NMDA-dependent manner in the caudate-putamen, but independently in parts of
      nucleus accumbens traditionally considered to be targets of antipsychotic drugs.

PMID- 10332801
TI  - In vivo CRF release in rat amygdala is increased during cocaine withdrawal in
      self-administering rats.
AB  - Previous studies have suggested a role for corticotropin-releasing factor (CRF)
      in the central nucleus of the amygdala (CeA) in the aversive and anxiogenic
      effects of withdrawal from opiates and ethanol. To test whether this role of CRF
      extends to cocaine withdrawal as well, the release of CRF in rat amygdala was
      monitored by intracranial microdialysis during a 12-hour session of intravenous
      cocaine self-administration and subsequent 12-hour cocaine withdrawal period.
      Cocaine self-administration tended to lower dialysate CRF concentrations to
      approximately 75% of CRF levels in controls. In contrast, subsequent cocaine
      withdrawal produced a profound increase in CRF release, which reached peak levels
      of approximately 400% of baseline between 11 and 12 hours post-cocaine. These
      results provide evidence that cocaine withdrawal activates CRF neurons in the
      amygdala, a site that has been implicated in emotional and anxiogenic effects of
      stress and drug withdrawal syndromes.

PMID- 10332803
TI  - Differences in uniquantal amplitude between sites reduce uniquantal variance when
      few release sites are active.
AB  - In many types of central neurons, the coefficient of variation (CV) of stimulus
      evoked uniquantal events inferred from quantal analysis is small, frequently less
      than 20%. In contrast, spontaneous putative uniquantal events (minis) from the
      same neurons are much more variable in amplitude, having a CV of roughly 50% or
      more. One explanation for this discrepancy is that, if the variance in mini
      amplitude were generated by differences between release sites, the small number
      of sites activated during stimulation would sometimes fortuitously have similar
      quantal amplitudes. Only in these fortuitous cases where uniquantal variance is
      small could quantal peaks be resolved, and therefore the uniquantal CV seen in
      the subset of cells where quantal analysis can be performed would systematically
      be much smaller than predicted by the mini distribution. We have explored this
      possibility by Monte Carlo simulation assuming all variance in mini amplitude to
      be due to intersite differences in uniquantal amplitude. We find that when a
      small number of release sites are activated under these conditions, there is a
      reduction in the expected uniquantal variance. However, the expected uniquantal
      CV is highly variable from one experiment to the next, and low uniquantal CVs are
      not expected to be seen often enough to account for the high frequency with which
      quantal peaks with a uniquantal CV < 20% are observed experimentally. We conclude
      that variance in mini amplitude between release sites cannot account for the
      small uniquantal CV seen in quantal analysis of many central synapses.

PMID- 10332802
TI  - Role of muscarinic receptors, G-proteins, and intracellular messengers in
      muscarinic modulation of NMDA receptor-mediated synaptic transmission.
AB  - Previously, we reported that activation of muscarinic receptors modulates N
      methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission in auditory
      neocortex [Aramakis et al. (1997a) Exp Brain Res 113:484-496]. Here, we describe
      the muscarinic subtypes responsible for these modulatory effects, and a role for
      G-proteins and intracellular messengers. The muscarinic agonist oxotremorine-M
      (oxo-M), at 25-100 microM, produced a long-lasting enhancement of NMDA-induced
      membrane depolarizations. We examined the postsynaptic G-protein dependence of
      the modulatory effects of oxo-M with the use of the G-protein activator GTP gamma
      S and the nonhydrolyzable GDP analog GDP beta S. Intracellular infusion of GTP
      gamma S mimicked the facilitating actions of oxo-M. After obtaining the whole
      cell recording configuration, there was a gradual, time-dependent increase of the
      NMDA receptor-mediated slow-EPSP, and of iontophoretic NMDA-induced membrane
      depolarizations. In contrast, intracellular infusion of either GDP beta S or the
      IP3 receptor antagonist heparin prevented oxo-M mediated enhancement of NMDA
      depolarizations. The muscarinic receptor involved in enhancement of NMDA
      iontophoretic responses is likely the M1 receptor, because the increase was
      prevented by pirenzepine, but not the M2 antagonists methoctramine or AF-DX 116.
      Oxo-M also reduced the amplitude of the pharmacologically isolated slow-EPSP, and
      this effect was blocked by M2 antagonists. Thus, muscarinic-mediated enhancement
      of NMDA responses involves activation of M1 receptors, leading to the engagement
      of a postsynaptic G-protein and subsequent IP3 receptor activity.

PMID- 10332804
TI  - Effects of medial prefrontal cortical injections of GABA receptor agonists and
      antagonists on the local and nucleus accumbens dopamine responses to stress.
AB  - Stress stimulates dopamine (DA) release in nucleus accumbens (NAcc) but will do
      so more strongly in medial prefrontal cortex (PFC). Evidence indicates, however,
      that the cortical DA response to stress acts to dampen the concurrent increase in
      NAcc DA release. In the present study, we used voltammetry to investigate the
      role of PFC GABA in regulating the NAcc DA response to stress. The results of
      Experiment 1 show that the NAcc stress response is inhibited following bilateral
      cortical microinjections of baclofen (GABAB receptor agonist). While phaclofen
      (GABAB receptor antagonist) blocked the effect of baclofen, it had no significant
      effect of its own. Intra-PFC injections of muscimol (GABAA receptor agonist) and
      bicuculline (GABAA receptor antagonist) had no effect on the DA stress response
      in NAcc. In Experiment 2, we explored the possibility that GABA influences the
      NAcc DA stress response indirectly by modulating stress-induced DA release in
      PFC. None of the drugs tested had an effect on the PFC stress response at a dose
      (1 nmol) that produced reliable effects on the NAcc stress response. At an order
      of magnitude higher dose, however, locally applied phaclofen and muscimol
      enhanced and attenuated, respectively, the DA stress response in PFC. These
      results were validated in Experiment 3 by showing that intra-PFC injections of
      GBR-12395 (DA uptake blocker) and quinpirole (D2/D3 receptor agonist) dose
      dependently enhanced and inhibited, respectively, the local DA stress response.
      Together, these findings indicate that increased GABA transmission in PFC exerts
      an inhibitory influence on the NAcc DA response to stress, and that this action
      is mediated primarily but not exclusively by GABAB receptors which may be located
      both on cortical output neurons and on DA terminals.

PMID- 10332805
TI  - Effects of antihistamines on fenfluramine-induced depletion of indoles in the
      brain of rats.
AB  - Various effects of chlorpheniramine (CPA), diphenhydramine (DIPH), tripelennamine
      (TRIP), and pyrilamine (PYRI) on fenfluramine (FEN)-induced depletion of
      serotonin in the brain of rats were observed to be dependent on body temperature.
      Levels of 5-HT and 5-HIAA in the frontal cortex, hippocampus, and striatum of
      rats treated with FEN (10 mg/kg, once or twice daily x 4 days) decreased to
      approximately 30% (P < 0.01) that of controls with no significant changes after
      CPA, DIPH, TRIP, and PYRI. Treatment with FEN plus CPA (5, 10, 20 mg/kg) and FEN
      plus DIPH (20 mg/kg), but not FEN plus TRIP (20 mg/kg) and FEN plus PYRI (20
      mg/kg), increased brain serotonin levels 2- to 3-fold more than those treated
      with FEN plus saline. Treatment with FEN plus CPA and FEN plus DIPH, but not FEN
      plus TRIP and FEN plus PYRI, decreased rectal temperature with no significant
      change after FEN. The antihistamines alone decreased temperature at a 1-hour
      period and enhanced FEN-induced reduction in body weight. Possible mechanisms of
      the different effects of antihistamines on FEN-induced depletion of serotonin are
      discussed.

PMID- 10332806
TI  - An investigation of male-mediated F1 effects in mice treated acutely and sub
      chronically with urethane.
AB  - In order to investigate the alleged potential of paternally administered urethane
      to cause foetal abnormalities and heritable tumours, male CD-1 mice were treated
      with urethane, either acutely by intraperitoneal injection at doses of 1.25 and
      1.75 g/kg bodyweight (bwt) or sub-chronically in the drinking water at 1.25 for
      10 weeks, and 3.75 mg/ml for 9 weeks or vehicle for the control groups. They were
      mated to untreated females 1 week later. Uterine contents of half the pregnant
      females were examined just before full term, while the remaining females were
      allowed to deliver their litters. The resulting F1 offspring were observed for
      approximately 18 months and 12 months for acute and sub-chronic exposures
      respectively and subjected to necropsy examination. Some of the mice treated
      acutely with 1.75 g/kg bwt exhibited partial infertility but none of those
      treated with 1.25 g/kg bwt had an adverse effect on their reproductive ability.
      There was no genetic effect of acute urethane treatment on male germ cells as
      indicated by dominant lethality. After birth, there was an increase (P < 0.05) in
      post-implantation deaths possibly due to perinatal mortality. There was an
      increased incidence and earlier onset of liver tumours induced in F1 male
      offspring from F0 males treated with 1.75 g/kg bwt, (20.7% vs. 10.1%, P = 0.026)
      but not in the female offspring. F1 males from both treatment groups had mean
      bodyweights significantly higher than controls (P < 0.01). Some males from each
      dose group of the acute study were examined using the restriction site mutation
      assay involving analysis of exon sequences. No mutations were identified in
      testes, liver or spleen of DNA isolated from the urethane-treated animals. No
      reproductive or genetic effects were seen with sub-chronic treatment at either
      1.25 or 3.75 mg/ml urethane nor was there any predisposition of F1 animals to
      tumours although observation times were shorter.

PMID- 10332808
TI  - Issues related to the experimental design and subsequent statistical analysis of
      in vivo and in vitro comet studies.
AB  - A wide range of experimental designs are used in investigations using the Comet
      assay. The statistical issues associated with this assay are however not
      particularly unusual or difficult. It is important however to recognize that the
      sample rather than the cell is the experimental unit. Statistical analyses based
      upon measures from the individual cells can lead to serious misinterpretation of
      results. Interpretation of the results of the assay should be related to
      identifying changes of biological importance rather than relying solely on the P
      values of specific statistical tests.

PMID- 10332807
TI  - Commentary: paternal legacies.

PMID- 10332809
TI  - Antimutagenic activity of chemical fractions isolated from a commercial soybean
      processing by-product.
AB  - Commercial products of agronomic crop plants may become a reliable and
      inexpensive source of phytonutrients, such as antimutagenic food supplements. We
      previously demonstrated that PCC, an ethanol extract of a commercial soybean
      processing by-product, was able to repress induced genomic DNA damage, whole cell
      clastogenicity, and point mutation in mammalian cells. In this paper we separated
      PCC into a series of chemically defined fractions and determined their ability to
      repress induced mutagenic damage in Chinese hamster lung cells, Chinese hamster
      ovary cells and human lymphocytes. Fraction PCC70 (PCC 70% methanol eluate)
      contained the flavonoids from PCC and daidzin and genistin repressed 2
      acetoxyacetylaminofluorene (2AAAF)-induced DNA damage measured with single cell
      gel electrophoresis. Genistein, however, enhanced the genotoxic impact of 2AAAF.
      Fraction PCC100 (PCC 100% methanol eluate) had the greatest level of
      antigenotoxic activity against 2AAAF in CHO cells and repressed the genotoxic
      capacity of the dietary carcinogen 2-amino-3-methylimidazo-(4,5-f)quinoline (IQ)
      in human lymphocytes. These data indicate that commercial soybean products and by
      products may be a source of chemoprotective food additives.

PMID- 10332810
TI  - The effect of potassium diazoacetate on human peripheral lymphocytes, human
      adenocarcinoma Colon caco-2 cells, and rat primary colon cells in the comet
      assay.
AB  - In previous studies, N-(N'-acetyl-L-propyl)-N-nitrosoglycine (APNG) has been
      shown to be a potent mutagen in a variety of genotoxicity assays and a carcinogen
      in a limited cancer study. APNG decomposes to a carboxymethyldiazonium ion, which
      can also be generated from potassium diazoacetate (KDA). KDA is particularly
      interesting because it is a stable nitrosated derivative of glycine, one of the
      most common dietary amino acids. KDA has been shown to produce more O6
      carboxymethyl- and O6 methyl-adducts than APNG, so it was anticipated that it
      might also be a potent genotoxic agent. Thus in the present study KDA has been
      investigated in the single cell gel electrophoresis (Comet) assay, which
      primarily measures DNA strand breakage. Since KDA has been shown to be formed in
      the gut, the genotoxic effects of KDA were investigated in vitro in human
      adenocarcinoma colon Caco-2 cells, and in rat primary colon cells and compared to
      responses from human peripheral lymphocytes. KDA induced DNA damage in the three
      cell types, confirming that KDA is genotoxic in a range of mammalian cells.

PMID- 10332811
TI  - Aflatoxin exposure and DNA damage in the comet assay in individuals from the
      Gambia, West Africa.
AB  - The single cell gel electrophoresis assay (Comet assay) was used to measure DNA
      damage in peripheral lymphocytes from a group of individuals from The Gambia in
      order to determine whether such damage could be associated with increased
      exposure to aflatoxin in this population. Responses obtained were correlated to
      responses previously obtained [1] in a cross-sectional study in the same
      individuals of various cytogenetic alterations [chromosomal aberrations,
      micronuclei (crest positive and negative staining), and sister chromatid
      exchanges], and aflatoxin-albumin adducts. Analysis of variance methods were used
      to assess the effects of smoking, GSTM1 genotype, sex, age, and smoking status. A
      comparison was also made between The Gambian individuals and a group of healthy,
      non-smoking volunteers in the United Kingdom where aflatoxin exposure would be
      expected to be low. From the earlier study [1], it was determined that the levels
      of the sister chromatid exchanges and micronuclei were higher in The Gambian
      group than in a European group where aflatoxin exposure was lower, but that there
      were no correlations between the adduct levels and the cytogenetic abnormalities
      at the individual level. In the present study, DNA damage as measured in the
      Comet assay was not significantly higher than in the healthy United Kingdom
      volunteers. In addition, there were no associations between cytogenetic damage,
      GSTM1 genotype, age, sex, lifestyle factors (smoking and aflatoxin exposure), and
      Comet response at the individual level. Comet response was higher in females than
      males in The Gambia if one outlier was excluded from analysis and not taking into
      account other sources of variability. It would appear that DNA damage as measured
      in the Comet assay in peripheral blood lymphocytes is not a sensitive genotoxic
      marker of aflatoxin exposure in this population.

PMID- 10332812
TI  - Dose-response relationships for hepatic aflatoxin B1-DNA adduct formation in the
      rat in vivo and in vitro: the use of immunoslot blotting for adduct quantitation.
AB  - An immunoslot blotting (ISB) method for quantitating aflatoxin B1-DNA adduct
      levels has been developed and used to examine the relationship between dose and
      hepatic aflatoxin B1-DNA adduct levels in rats fed aflatoxin B1 (AFB1) in the
      diet at dose levels of between 0.5 and 10 micrograms/kg/day. The method has also
      been used to examine the dose-response relationship for adduct formation in
      precision-cut rat liver slices incubated with AFB1 at concentrations between 0.01
      and 2 microM. For the feeding studies, groups of male Fisher F344 rats were given
      AFB1 in the diet for periods of 1 to 10 weeks and hepatic DNA adduct levels
      determined using ISB. The time for adduct levels to reach steady-state conditions
      was determined in animals given approximately 10 micrograms of AFB1/kg/day and
      steady-state levels at lower concentrations measured. The time course for the
      accumulation of AFB1-DNA adducts in rat liver slices incubated with AFB1 at 0.5
      microM has been investigated and the relationship between adduct formation and
      AFB1 concentration over a wide concentration range in liver slices has been
      determined.

PMID- 10332813
TI  - Fluid therapy and newer blood products.
AB  - A fluid therapy plan for a patient is developed prior to surgery and is designed
      to meet each patient's needs. The volume and type of fluid are dependent on the
      patient's physical status; the acid-base, fluid, and electrolyte status; the
      surgical procedure; and the expected losses occurring during the procedure. No
      one fluid regimen is ideal for all patients. All fluid regimens must be
      continually re-evaluated. A brief minor surgical procedure in a healthy surgical
      candidate requires little or no fluid administration. In cases of more extensive
      surgical procedures involving invasion of the abdomen or chest as well as in
      cases with trauma and major blood loss, much more volume and a specific balanced
      replacement fluid are required. Depending on the severity of the surgical case,
      administration rates of 5 to 15 mL/kg/h or greater of crystalloid may be required
      to maintain perfusion. These rates are merely guidelines, and resuscitation
      should continue until the desired end point is reached. Balanced replacement
      fluids may be used to replace blood loss at a ratio of 3:1 and are added to
      maintenance and replacement requirements. Blood loss of 20% to 25% of the
      calculated blood volume or hematocrit values less than 20% are indications for
      colloids or blood replacement at a ratio of 1:1. The optimal fluid therapy
      regimen for a patient may involve a combination of crystalloids as well as
      natural and synthetic colloids, using each type of fluid to obtain and maintain
      perfusion and oxygenation to the tissues.

PMID- 10332814
TI  - Drug interactions during anesthesia. General principles.
AB  - Anesthesia for most procedures in small animal practice involves administration
      of more than one drug. In addition, many patients concurrently receive a number
      of other drugs related to their surgical condition or disease. The probability of
      a drug interaction increases exponentially with the number of drugs a patient
      receives; therefore, the potential for drug interactions may be greater in
      anesthesia than for any other area of medicine. This article describes
      potentially harmful drug interactions that may occur in the anesthetic setting.

PMID- 10332815
TI  - Equipment for inhalant anesthesia.
AB  - When used properly, anesthesia machines, breathing systems, anesthesia
      ventilators, and ancillary equipment allow the safe and efficient use of the
      inhalant anesthetics. Several veterinary anesthesia machines and ventilators have
      been introduced over the last few years. This article includes a discussion of
      some of these new pieces of anesthesia equipment, with particular emphasis on
      changes and innovations in the design of the equipment. In addition, principles
      of use and care of various anesthetic equipment is included where appropriate.

PMID- 10332816
TI  - Newer diagnostic and surgical techniques and their impact on anesthesia.
AB  - There are several newer diagnostic and surgical techniques available to
      veterinarians today. Careful anesthetic management is essential when using these
      modalities both to avoid accidents and to enable their use. For example, total
      intravenous anesthetic techniques can be used if the airway is occupied by an
      endoscope or laser surgery is being performed in the airway. The anesthesiologist
      must also be aware of the physiological changes that may occur during procedures
      such as laparoscopy and act to minimize their impact on patients.

PMID- 10332817
TI  - Management of geriatric patients. A common occurrence.
AB  - The anesthetic and perioperative care of geriatric animals requires increased
      vigilance and support. The margin of acceptable physiological variation is
      probably more narrow than in younger patients. Underlying disease, which is often
      subclinical, influences metabolism and recovery from anesthetics and also
      predisposes the patients to adverse outcome. Limited respiratory and
      cardiovascular reserve diminishes the ability of many older patients to meet the
      challenges of anesthesia and surgery or other stressful medical procedures. The
      psychological, as well as physiological, stress of hospitalization is increased
      in many geriatric patients.

PMID- 10332818
TI  - Analgesics and pain.
AB  - There has been a substantial increase in the use of analgesics for pain
      management in the last 10 years. Traditionally, veterinarians have not been
      trained in the identification of or monitoring of patients that are in pain, even
      though an evaluation of pain is inherent in assessing improvement in many medical
      and surgical diseases. Until recently, the physiology and pharmacology of
      opioids, NSAIDs, local anesthetics, and alpha 2 agonists were taught, but the
      therapeutic role of these drugs was generally believed to be related to
      restraint, anesthesia, or control of inflammation rather than to pain management.

PMID- 10332819
TI  - Newer analgesics. Nonsteroid anti-inflammatory drugs, opioids, and combinations.
AB  - Analgesia is an intrinsic part of anesthesia, and the use of opioids for
      premedication, supplementation of anesthesia, and postoperative analgesia is not
      new. Development of new potent and less toxic NSAIDs has now resulted in this
      type of analgesic, also playing a major role in perioperative analgesia. Weak
      cyclo-oxygenase inhibitors, and NSAIDs with high COX2 activity, are proving
      successful in the provision of analgesia in dogs and cats. Some newer opioids
      developed for man have potential for use in dogs and cats, and buprenorphine, a
      partial agonist, deserves further evaluation. Some novel analgesics have
      potential for use in animals, but the specific analgesic role of old friends
      ketamine and the alpha 2 adrenoceptor agonists is worthy of closer scrutiny.

PMID- 10332820
TI  - Alpha 2 agonists and antagonists.
AB  - The alpha 2 agonists can produce reliable dose-dependent sedation and analgesia
      in most species. Nevertheless, they can also produce significant physiological
      adverse side effects depending on dose, rate, route of administration, and the
      concurrent use of other CNS depressants. For this reason, it may be best to use a
      low dose of an alpha 2 agonist as a preanesthetic agent. The alpha 2 agonists are
      best suited for young, healthy, exercise-tolerant patients. The combining of low
      doses of alpha 2, opioid, and benzodiazepine agonists results in a synergistic
      CNS depressant response while minimizing the undesirable side effects of these
      three classes of drugs. Each group of drugs has specific antagonists available
      for their reversal, thus allowing veterinarians to reverse one or more of the
      agonists depending on the desired response. This may represent a significant
      advantage to the use of low-dose alpha 2 agonists in combination with opioids and
      benzodiazepines.

PMID- 10332821
TI  - Propofol anesthesia.
AB  - Although questions may still remain regarding the use of this unique sedative
      hypnotic drug with anesthetic properties in high-risk patients, our studies have
      provided cardiopulmonary and neurological evidence of the efficacy and safety of
      propofol when used as an anesthetic under normal and selected impaired conditions
      in the dog. 1. Propofol can be safely and effectively used for the induction and
      maintenance of anesthesia in normal healthy dogs. Propofol is also a reliable and
      safe anesthetic agent when used during induced cardiovascular and pulmonary
      impaired conditions without surgery. The propofol requirements to induce the safe
      and prompt induction of anesthesia prior to inhalant anesthesia with and without
      surgery have been determined. 2. The favorable recovery profile associated with
      propofol offers advantages over traditional anesthetics in clinical situations in
      which rapid recovery is important. Also, propofol compatibility with a large
      variety of preanesthetics may increase its use as a safe and reliable i.v.
      anesthetic for the induction and maintenance of general anesthesia and sedation
      in small animal veterinary practice. Although propofol has proven to be a
      valuable adjuvant during short ambulatory procedures, its use for the maintenance
      of general anesthesia has been questioned for surgery lasting more than 1 hour
      because of increased cost and marginal differences in recovery times compared
      with those of standard inhalant or balanced anesthetic techniques. When propofol
      is used for the maintenance of anesthesia in combination with a
      sedative/analgesic, the quality of anesthesia is improved as well as the ease
      with which the practitioner can titrate propofol; therefore, practitioners are
      able to use i.v. anesthetic techniques more effectively in their clinical
      practices. 3. Propofol can induce significant depression of respiratory function,
      characterized by a reduction in the rate of respiration. Potent alpha 2
      sedative/analgesics (e.g., xylazine, medetomidine) or opioids (e.g., oxymorphone,
      butorphanol) increase the probability of respiratory depression during
      anesthesia. Appropriate consideration of dose reduction and speed of
      administration of propofol reduces the degree of depression. Cardiovascular
      changes induced by propofol administration consist of a slight decrease in
      arterial blood pressures (systolic, mean, diastolic) without a compensatory
      increase in heart rate. Selective premedicants markedly modify this
      characteristic response. 4. When coupled with subjective responses to painful
      stimuli, EEG responses during propofol anesthesia provide clear evidence that
      satisfactory anesthesia has been achieved in experimental dogs. When propofol is
      used as the only anesthetic agent, a higher dose is required to induce an
      equipotent level of CNS depression compared with the situation when dogs are
      premedicated. 5. The propofol induction dose requirement should be appropriately
      decreased by 20% to 80% when propofol is administered in combination with
      sedative or analgesic agents as part of a balanced technique as well as in
      elderly and debilitated patients. As a general recommendation, the dose of
      propofol should always be carefully titrated against the needs and responses of
      the individual patient, as there is considerable variability in anesthetic
      requirements among patients. Because propofol does not have marked analgesic
      effects and its metabolism is rapid, the use of local anesthetics, nonsteroidal
      anti-inflammatory agents, and opioids to provide postoperative analgesia improves
      the quality of recovery after propofol anesthesia. 6. The cardiovascular
      depressant effects of propofol are well tolerated in healthy animals, but these
      effects may be more problematic in high-risk patients with intrinsic cardiac
      disease as well as in those with systemic disease. In hypovolemic patients and
      those with limited cardiac reserve, even small induction doses of propofol (0.75
      1.5 mg/kg i.v.) can produce profound hypotens

PMID- 10332823
TI  - Desflurane and sevoflurane. New volatile anesthetic agents.
AB  - Desflurane and sevoflurane, recently licensed for use in humans, have kinetics
      that result in rapid induction and easy maintenance of a stable level of
      anesthesia. Recovery is also rapid. Cardiopulmonary effects are similar to those
      of isoflurane. In humans, desflurane can cause airway irritation and sympathetic
      stimulation, but these side effects have not caused problems in animal trials.
      Metabolites of sevoflurane and breakdown products from its reaction with carbon
      dioxide absorbents theoretically could result in hepatic and renal damage, but
      such toxicity has not occurred despite extensive medical use. Clinical trials in
      animals are now in progress.

PMID- 10332822
TI  - Etomidate and telazol.
AB  - These two drugs, etomidate and Telazol, have different pharmacological
      properties. The good properties of these drugs should be employed in specific
      patients and procedures to be performed (Table 3). There is no ideal injectable
      agent available yet for clinical practice. This in itself makes practice quite
      interesting because of the continuous process of rationalizing and determining
      the best drug for a specific condition and patient.

PMID- 10332824
TI  - Newer neuromuscular blockers. Is the practitioner ready for muscle relaxants?
AB  - Current research on the development of new neuromuscular blocking agents is
      directed towards producing agents that have a rapid onset of action and
      predictable duration of action and recovery times, with minimal hemodynamic
      effects. For the veterinary practitioner, these newer agents should be considered
      when muscle relaxation is required for certain surgical procedures. Care must be
      taken to monitor paralyzed patients appropriately to ensure adequate ventilation
      and anesthetic depth. Vigilant monitoring should exist during the recovery period
      for the development of muscle weakness from residual blockade and the ability to
      reverse the effects of neuromuscular blockade. The use of neuromuscular blocking
      agents in veterinary patients should continue to increase as newer drugs and
      better monitoring techniques are developed.

PMID- 10332825
TI  - New thoughts on cardiopulmonary resuscitation.
AB  - The results of cardiopulmonary resuscitation (CPR) have been distressingly poor
      when one considers the amount of research in this field since 1960. Accordingly,
      some improvements to present protocols have been suggested. Some of the
      suggestions can be applied by practicing veterinarians to increase the success
      rate for external chest massage. In addition, veterinarians are encouraged to
      switch to internal cardiac massage early in the resuscitation period.

PMID- 10332827
TI  - Experimental infection of pregnant cows with Bacillus licheniformis bacteria.
AB  - To study the abortifacient potential and fetoplacental tropism of Bacillus
      licheniformis bacteria, eight cows in the sixth to eighth month of gestation were
      inoculated intravenously either once (n = 4) or on four successive days (n = 4)
      with B. licheniformis at doses ranging from 10(9) to 10(12) colony-forming units.
      Cows were euthanatized and necropsied prior to abortion (n = 2), at the time of
      abortion (n = 2), or at calving (n = 4). Live-born calves (n = 5) were
      euthanatized immediately after delivery and necropsied. B. licheniformis was
      reisolated from placentomes/endometrium in six of eight (75%) cows and from one
      fetus aborted 43 days after inoculation. Lesions associated with B. licheniformis
      were restricted to the pregnant uterus, with the exception of one cow, which
      developed pneumonia. Necrosis in the fetal compartment of the placenta were
      present in three of four (75%) cows of both inoculation groups. Lesions were
      mainly restricted to fetal membranes and especially to the fetal side of the
      placentomes. Necrosis and diffuse neutrophil infiltrations of both villi and
      intervillous areas occurred in the fetal part of the placenta, and the
      placentomal interface was distended by bacteria, neutrophils, erythrocytes, and
      debris. Within trophoblasts, bacteria were located both free in the cytoplasm and
      in cytoplasmatic vesicles. Inflammation was present in three of eight (38%)
      calves. Placental and fetal lesions were similar to those found in cases of
      spontaneous abortions associated with B. licheniformis. The abortifacient
      potential of B. licheniformis and the tropism for the bovine placenta is
      demonstrated here for the first time.

PMID- 10332826
TI  - Coordinate expression of cytokeratins 7 and 20 in feline and canine carcinomas.
AB  - Forty-seven feline and 60 canine epithelial tumors were studied to test the
      coordinate expression of cytokeratin 7 (CK 7) and cytokeratin 20 (CK 20) using
      commercially available monoclonal antibodies and an avidin-biotin
      immunoperoxidase staining technique. Previously, the distribution of both
      cytokeratins was examined in normal tissues from 4 cats and 4 dogs. The pattern
      of distribution of CK 7 in normal tissues was similar, with minor differences, to
      that described in humans, whereas the reactivity pattern of CK 20 in cats and
      dogs was wider than that in humans. The subset of tumors strongly expressing CK 7
      and CK 20 included pancreatic adenocarcinomas (100%), transitional cell
      carcinomas (75%), and endometrial carcinomas (67%) in the cat. None of the canine
      tumors had this immunophenotype. Feline (50%) and canine (56%) mammary gland
      carcinomas and canine cholangiocarcinomas (67%) were the only tumors presenting
      the CK 7 +/CK 20- immunophenotype, whereas the CK 7-/CK 20+ immunophenotype
      included thyroid carcinomas (100%), intestinal adenocarcinomas (60%),
      bronchioloalveolar carcinomas (50%), and renal carcinomas (50%) in the cat and
      intestinal adenocarcinomas (56%), gastric adenocarcinomas (50%), and ovarian
      carcinomas (50%) in the dog. The CK 7-/CK 20- immunophenotype included the rest
      of the analyzed tumors. The immunohistochemical evaluation of coordinate
      expression of both CK 7 and CK 20 in feline and canine carcinomas using
      monoclonal antibodies provides important information that can help to
      discriminate among carcinomas from different primary sites and could be
      particularly helpful in the determination of the primary site of origin of
      carcinomas presenting as metastatic disease.

PMID- 10332828
TI  - Age-related changes in the brain of the dog.
AB  - Although many age-related changes have been described in the nervous system of
      different species, few authors have specifically studied the topic. Knowledge of
      such changes is essential to veterinary pathologists, who must distinguish the
      lesions of specific pathologic processes from those arising as a result of normal
      aging. The brains of 20 old dogs, ranging in age from 8 to 18 years, were
      compared with those of 10 young dogs using routine staining techniques
      (hematoxilin and eosin, periodic acid-Schiff), special staining techniques
      (periodic acid-methenamine silver stain), and immunohistochemical techniques to
      detect glial fibrillary acid protein, neurofilaments, ubiquitin, and beta
      amyloid. Changes affected meninges and choroid plexuses, meningeal and
      parenchymal vessels, neurons, and glial cells. Of special interest was the
      presence of polyglucosan bodies, cerebrovascular amyloid deposition, senile
      plaques, and ubiquitinated bodies. Some of the age-related changes found,
      particularly lipofuscin, polyglucosan bodies, and beta-amyloid protein
      deposition, may play a role in the pathogenesis of the canine cognitive
      dysfunction syndrome. The dog could be used as a natural animal model for the
      study of normal aging and human neurodegenerative diseases.

PMID- 10332829
TI  - Neurotoxicity of 1,3,5-trinitrobenzene (TNB): immunohistochemical study of
      cerebrovascular permeability.
AB  - 1,3,5-Trinitrobenzene (TNB) is a soil and water contaminant at certain military
      installations. Encephalopathy in rats given 10 daily oral doses of TNB has been
      reported. The lesion was bilaterally symmetric vacuolation and microcavitation in
      the cerebellar roof nuclei, vestibular nuclei, olivary nuclei, and inferior
      colliculi. The contribution of the blood-brain barrier (BBB) in the genesis of
      these lesions remains uncertain. One of the main goals of the present work was to
      evaluate the functional state of the BBB. Male Fischer 344 rats (five rats/group)
      were euthanatized after four, five, six, seven, eight, or 10 daily doses of TNB
      (71 mg/kg). A different set of rats (five rats/group) was allowed to recover for
      10 or 30 days after receiving 10 doses of TNB. Integrity of the BBB was assessed
      by immunohistochemical staining for extravasated plasma albumin on paraffin
      embedded sections. Rats euthanatized after four to eight doses had no lesions,
      and albumin extravasation in the susceptible regions of the brain was minimal.
      Rats receiving 10 daily doses of TNB had bilaterally symmetric vacuolation and
      microcavitation in the cerebellar nuclei, vestibular nuclei, and inferior
      colliculi in association with multifocal, often confluent foci of extravasated
      albumin in susceptible nuclei. Albumin was present in vascular walls,
      extracellular space, and neurons. Immunoreactivity in neurons was of two types:
      cytoplasmic staining representing pinocytic uptake and homogeneous staining of
      the entire neuron (nucleus and cytoplasm) due to uncontrolled albumin leakage
      through the damaged cell membrane. In rats allowed to recover for 10 days, the
      microcavitated foci were infiltrated by glial and gitter cells. Albumin
      immunoreactivity was present as extracellular granular debris, and neuronal
      staining (for albumin) was mild. In rats allowed to recover for 30 days,
      immunoreactivity to albumin was not seen. This study demonstrates that TNB
      mediated tissue damage is accompanied by breakdown of the BBB. The presence of
      vacuolation and associated extravasated serum proteins in TNB-treated rats is an
      indication of vasogenic brain edema, which appears to be a critical event in TNB
      toxicity. Additional studies are needed to determine the reason for selective
      regional vulnerability and brain microvascular susceptibility to TNB.

PMID- 10332830
TI  - Dilated cardiomyopathy of Doberman pinschers: retrospective histomorphologic
      evaluation of heart from 32 cases.
AB  - Dilated cardiomyopathy of Doberman Pinschers (DCDP) is a progressive disease
      often presenting with a history of episodic weakness and syncope, or with
      clinical signs of predominantly left-sided congestive heart failure. A systematic
      dissection and histomorphologic evaluation of the heart from 32 Doberman
      Pinschers with a clinical diagnosis of dilated cardiomyopathy revealed a highly
      specific location for the characteristic myocardial lesions. The lesions of DCDP
      were found only in the left ventricular free wall, and in 30 cases, the lesions
      were characterized by myofiber degeneration and atrophy, and replacement of
      myocardium by dense bundles of collagen and clusters of adipocytes. In the two
      remaining hearts, myofiber atrophy and degeneration were accompanied by collagen
      deposition, but not adipocytes. In stained longitudinal (base to apex) tissue
      sections of the left ventricle, the lesions of DCDP were usually apparent to the
      unaided eye; appearing as a central linear pale zone, aligned in the long axis of
      the ventricular free wall. The lesions did not contain inflammatory cell
      infiltrates and often involved > 50% of ventricular wall.

PMID- 10332831
TI  - Dysregulation of beta-catenin is common in canine sporadic colorectal tumors.
AB  - Human colorectal tumorigenesis is often initiated by APC (adenomatous polyposis
      coli) or beta-catenin (CTNNB1) mutations, which result in dysregulation of beta
      catenin expression, followed by alterations in E-cadherin and/or p53. We examined
      32 canine intestinal tumors for expression and intracellular distribution of beta
      catenin, E-cadherin, and p53 using immunohistochemistry. beta-Catenin in normal
      mucosal epithelial cells was restricted to lateral cell membranes, but 13/13
      (100%) colorectal adenomas had intense cytoplasmic and/or nuclear reactivity.
      Three of six (50%) colorectal carcinomas, 2/13 (15%) small intestinal carcinomas,
      and dysplastic cells in 1/2 focal hyperplastic lesions in the small intestine had
      a similar pattern of staining; remaining tumors had normal membranous beta
      catenin reactivity. There was a correlation (P = 0.007) between abnormal beta
      catenin and E-cadherin staining with 11/13 (85%) colorectal adenomas, 3/6 (50%)
      colorectal carcinomas, and 3/13 (23%) small intestinal carcinomas showing
      decreased membranous reactivity compared with normal mucosal epithelium. E
      cadherin staining was reduced more often in adenomas than in carcinomas (P =
      0.04). There were two patterns of nuclear p53 staining: > 60% of nuclei in 2/26
      (8%) carcinomas (one colorectal, one small intestinal) were strongly labeled,
      whereas three colorectal adenomas and one small intestinal carcinoma had fainter
      staining in 10-20% of cells. Dysregulation of beta-catenin appears to be as
      important in canine colorectal tumorigenesis as it is in the human disease and
      could be due to analogous mutations. Malignant progression in canine intestinal
      tumors does not appear to be dependent on loss of E-cadherin or beta-catenin
      expression or strongly associated with overexpression of nuclear CMI antibody
      reactivity p53.

PMID- 10332832
TI  - Helicobacter felis infection in dogs: effect on gastric structure and function.
AB  - The relationship of Helicobacter felis, an organism that is observed in the
      stomachs of dogs, to gastric disease in dogs is unclear. The objective of this
      study was to determine if Helicobacter felis infection alters gastric morphology
      and gastric secretory function in dogs. Five specific-pathogen-free (SPF),
      Helicobacter-free Beagle dogs were examined before and for 26 weeks after
      inoculation with H. felis (ATCC 49179). Three SPF uninfected dogs served as
      controls. All five dogs became colonized by H. felis as determined by urease
      activity, histopathology, polymerase chain reaction, and transmission electron
      microscopic examination of serial gastric biopsies. The degree of colonization
      ranged from < 1 organism/400 x field to > 10 organisms/400 x field. The fundus,
      body, and cardia were most heavily colonized. Evaluation of gastric biopsies
      showed mild gastric inflammation and lymphoid follicles in both infected and
      uninfected dogs. There was no correlation between the number of organisms
      observed and the degree of gastric inflammation or number of lymphoid follicles.
      The gastric secretory axis, assessed by fasting and meal-stimulated plasma
      gastrin, mucosal gastrin and somatostatin immunoreactivity, fasting gastric pH,
      and pentagastrin-stimulated gastric acid secretion, was similar in both infected
      and uninfected dogs. Fasting gastric pH was not a reliable indicator of gastric
      secretory function. These findings suggest that H. felis may not be a gastric
      pathogen in dogs. However, the density of colonization and limited duration of
      infection should be considered when interpreting these findings.

PMID- 10332834
TI  - Naturally occurring Tyzzer's disease in a calf.
AB  - Naturally occurring Clostridium piliforme infection (Tyzzer's disease) was found
      in a calf. Light microscopic examination revealed multifocal coagulative necrosis
      in the liver, catarrhal gastroenteritis, tracheitis and pneumonia, and thymic
      atrophy. Warthin-Starry staining clearly showed large filamentous bacilli in
      bundles or criss-cross patterns within the hepatocytes and epithelium and smooth
      muscle cells of the ileum and cecum. Immunohistochemistry using anti-C. piliforme
      RT and MSK strain antisera showed positive reaction against the bacilli. Electron
      microscopic examination revealed bacilli within the hepatocytes that demonstrated
      a characteristic vegetative form, with peritrichous flagella, and spores. The
      polymerase chain reaction (PCR) study using the paraffin-embedded liver sections,
      the 196-bp DNA fragment specific to 16S ribosomal RNA of C. piliforme was
      amplified. The characteristics of these bacilli are consistent with those of of
      C. piliforme. The PCR technique using paraffin-embedded sections should be useful
      for confirming C. piliforme infection in spontaneous cases.

PMID- 10332833
TI  - A case of intestinal Mycobacterium simiae infection in an SIV-infected
      immunosuppressed rhesus monkey.
AB  - Although Mycobacterium simiae was identified and classified more than three
      decades ago, only a few cases are mentioned in the current literature. After
      experimental simian immunodeficiency virus infection, a 9-year-old female rhesus
      monkey (Macaca mulatta) developed progressive immunosuppression and
      gastrointestinal disease very similar to the clinical and pathomorphologic
      features of Johne's disease, which is caused by M. paratuberculosis. Acid-fast
      positive bacteria reacted immunohistochemically with antibodies against M.
      paratuberculosis and M. bovis but were not useful for differentiation because of
      a high degree of cross-reactivity. In contrast to immunohistochemistry and
      histopathology, biochemical methods and cycle sequencing analysis of the 16S
      ribosomal RNA identified M. simiae as the disease-causing pathogen. This case
      demonstrates the importance of molecular biological methods for the diagnosis of
      M. simiae infection in monkeys.

PMID- 10332835
TI  - Multifocal cerebellar granular layer necrosis in traumatically head-injured
      lambs.
AB  - In a blunt, nonmissile, head impact model of traumatic brain injury in 4-5-week
      old Merino lambs, multiple foci of internal granular layer necrosis were found in
      all 10 impacted animals. This lesion has not previously been reported after human
      or animal head injury. Temporal lobe impact contusions, predominantly microscopic
      (8/10) and contralateral contusions (2/10), parenchymal (10/10) and subarachnoid
      (10/10) hemorrhage, and widely distributed axonal injury were also observed.
      Although the precise pathogenesis of this focal granule cell necrosis and often
      attendant red cell change in Purkinje cells was unclear, an ischemic etiology due
      to trauma-related vascular damage is postulated.

PMID- 10332836
TI  - Actinobacillus pleuropneumoniae osteomyelitis in pigs demonstrated by fluorescent
      in situ hybridization.
AB  - Necrotizing osteomyelitis and fibrinopurulent arthritis with isolation of
      Actinobacillus pleuropneumoniae serotype 2 is reported in two pigs from a herd
      with lameness and mild coughing problems among 8 to 12-week-old pigs. Application
      of fluorescent in situ hybridization targeting 16S ribosomal RNA of A.
      pleuropneumoniae in formalin-fixed tissue was performed to verify the association
      of A. pleuropneumoniae with the bone and joint lesions. By in situ hybridization
      A. pleuropneumoniae was demonstrated as multiple microcolonies or single cells
      dispersed in focal fibrinonecrotizing pleuropneumonia, in joints with arthritis,
      and in bone necroses including lysis of growth plate and suppurative inflammation
      in the adjacent trabecular metaphysis, thus demonstrating that well-known
      infections manifest new, unusual lesions.

PMID- 10332837
TI  - "The clinical scope of porcine reproductive and respiratory syndrome virus
      infection has expanded since 1987": an alternative perspective.

PMID- 10332839
TI  - In vivo 1H NMR spectroscopy of rat brain at 1 ms echo time.
AB  - Using optimized, asymmetric radiofrequency (RF) pulses for slice selection, the
      authors demonstrate that stimulated echo acquisition mode (STEAM) localization
      with ultra-short echo time (1 ms) is possible. Water suppression was designed to
      minimize sensitivity to B1 inhomogeneity using a combination of 7 variable power
      RF pulses with optimized relaxation delays (VAPOR). Residual water signal was
      well below the level of most observable metabolites. Contamination by the signals
      arising from outside the volume of interest was minimized by outer volume
      saturation using a series of hyperbolic secant RF pulses, resulting in a sharp
      volume definition. In conjunction with FASTMAP shimming (Gruetter Magn Reson Med
      1993;29: 804-811), the short echo time of 1 msec resulted in highly resolved in
      vivo 1H nuclear magnetic resonance spectra. In rat brain the water linewidths of
      11-13 Hz and metabolite singlet linewidths of 8-10 Hz were measured in 65 microl
      volumes. Very broad intense signals (delta v(1/2) > 1 kHz), as expected from
      membranes, for example, were not observed, suggesting that their proton T2 are
      well below 1 msec. The entire chemical shift range of 1H spectrum was observable,
      including resolved resonances from alanine, aspartate, choline group, creatine,
      GABA, glucose, glutamate, glutamine, myo-inositol, lactate, N-acetylaspartate, N
      acetylaspartylglutamate, phosphocreatine, and taurine. At 9.4 T, peaks close to
      the water were observed, including the H-1 of alpha-D-glucose at 5.23 ppm and a
      tentative H-1 resonance of glycogen at 5.35 ppm.

PMID- 10332838
TI  - A combined 1H perfusion/3He ventilation NMR study in rat lungs.
AB  - The assessment of both pulmonary perfusion and ventilation is of crucial
      importance for a proper diagnosis of some lung diseases such as pulmonary
      embolism. In this study, we demonstrate the feasibility of combined magnetic
      resonance imaging lung ventilation and perfusion performed serially in rat lungs.
      Lung ventilation function was assessed using hyperpolarized 3He, and lung
      perfusion proton imaging was demonstrated using contrast agent injection. Both
      imaging techniques have been implemented using projection-reconstruction
      sequences with free induction decay signal acquisitions. The study focused on
      fast three-dimensional (3D) data acquisition. The projection-reconstruction
      sequences used in this study allowed 3D data set acquisition in several minutes
      without high-performance gradients. 3D proton perfusion/helium ventilation
      imaging has been demonstrated on an experimental rat model of pulmonary embolism
      showing normal lung ventilation associated with lung perfusion defect. Assuming
      the possibility, still under investigation, of showing lung obstruction
      pathologies using 3He imaging, these combined perfusion/ventilation methods could
      play a significant clinical role in the future for diagnosis of several pulmonary
      diseases.

PMID- 10332840
TI  - Concentrations of human cardiac phosphorus metabolites determined by SLOOP 31P
      NMR spectroscopy.
AB  - Human cardiac 31P nuclear magnetic resonance (NMR) spectra are usually quantified
      in relative terms, i.e., the ratio of metabolite signals is calculated. If 31P
      NMR spectroscopy of the heart is to emerge as a clinically relevant diagnostic
      modality, reliable quantification of absolute concentrations of 31P metabolites
      is required. We applied spectral localization with optimal point spread function
      (SLOOP) 31P NMR spectroscopy to measure absolute concentrations of
      phosphocreatine (PCr) and adenosine triphosphate (ATP) in human myocardium. The
      accuracy of the quantification was first validated in a phantom study. Seven
      healthy volunteers (aged 19-29 years) were then examined at 1.5 T using a nominal
      spatial resolution of 25 mL. SLOOP allowed us to obtain localized spectra from
      compartments anatomically matched to the left ventricular wall. The a priori
      knowledge of the anatomical structure was obtained from 1H images. The spatially
      varying effects of saturation, off-resonance, and sensitivity were considered
      during the reconstruction process. Metabolites were quantified with reference to
      an external 31P standard. Concentrations of 9.0 +/- 1.2 and 5.3 +/- 1.2 mmol/kg
      wet wt (mean +/- SD, n = 9) were determined for PCr and ATP in normal heart,
      respectively. The influence of nuclear Overhauser enhancement on metabolite
      quantification is discussed.

PMID- 10332841
TI  - Optimal gradient waveform design for projection imaging and projection
      reconstruction echoplanar spectroscopic imaging.
AB  - The use of modulated B0 projection gradient waveforms is proposed for magnetic
      resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) to
      shape the k-space sampling density function to match the profile of an applied
      reconstruction window function. This allows for a time-efficient means of
      maximizing the signal-to-noise ratio when, for example, a low-pass spatial
      filter, designed to reduce k-space truncation artifacts and corresponding point
      spread function sidelobe energies, is implemented. Both the two-dimensional (2D)
      and 3D cases are investigated. To create the projection gradient waveforms, a
      design method is developed that uses nonlinear constrained optimization (NLCO) to
      minimize the variance of the reconstruction noise. The design is subject to both
      equality and inequality constraints, which include the maximum gradient magnitude
      and slew rate. It is shown that NLCO can also be applied to twisting the
      projection trajectories for purposes of reducing the data acquisition time while
      still maintaining the desired sampling density. Applications to 1H MRSI are
      investigated via simulations. Advantages and limitations of the new sampling
      schemes are discussed.

PMID- 10332842
TI  - In vivo observation of lactate methyl proton magnetization transfer in rat C6
      glioma.
AB  - Magnetic resonance spectroscopy (MRS) measurements of the lactate methyl proton
      in rat brain C6 glioma tissue acquired in the presence of an off-resonance
      irradiation field, analyzed using coupled Bloch equation formalism assuming two
      spin pools, demonstrated the occurrence of magnetization transfer. Quantitative
      analysis revealed that a very small fraction of lactate (f = 0.0012) is
      rotationally immobilized despite a large magnetization transfer effect. Off
      resonance rotating frame spin-lattice relaxation studies demonstrated that
      deuterated lactate binds to bovine serum albumin and the proteins present in
      human plasma, thereby providing a possible physical basis for the observed
      magnetization transfer effect. These results demonstrate that partial or complete
      saturation of the motionally restricted lactate pool (as well as other
      metabolites) by the application of an off-resonance irradiation field, such as
      that used for water presaturation, can lead to a substantial decrease in
      resonance intensity by way of magnetization transfer effects, resulting in
      quantitation errors.

PMID- 10332843
TI  - Changes in myocardial oxygenation and perfusion under pharmacological stress with
      dipyridamole: assessment using T*2 and T1 measurements.
AB  - The aim of this pilot-study was to evaluate changes in myocardial oxygenation and
      perfusion under pharmacological stress with dipyridamole (DIP) by means of MRI.
      Twenty healthy volunteers were examined using a multi-echo gradient-echo
      sequence. The differential myocardial signal response due to the blood oxygen
      level dependent (BOLD) effect was studied under variable conditions of myocardial
      oxygen supply caused by the vasodilator DIP. Unlike contrast agents (CA) methods,
      which require at least two injections of CA and DIP, the presented methods
      require only a single infusion of DIP. To assess changes in myocardial perfusion,
      a saturation recovery TurboFLASH (SRTFL) sequence with centric reordering for T1
      measurements was used with global and slice-selective spin-preparation (five
      volunteers). The signal response was measured at baseline conditions and when
      myocardial blood flow was increased during pharmacological stress with DIP.
      Administration of DIP induced a 17 +/- 9% increase in T2*. Enhanced perfusion
      resulted in a 15 +/- 5% decrease of T1 after slice-selective spin preparation and
      a calculated increase in absolute perfusion of about 5.1 ml/(g x min), which
      reflects coronary reserve. The study shows that DIP-induced alterations in the
      relationship between myocardial oxygen supply and demand are detectable in
      healthy volunteers using T2* and T1 measurements. A combination of T2* and T1
      examinations could become a useful diagnostic tool for the non-invasive
      assessment of myocardial oxygenation and perfusion in patients with coronary
      artery disease (CAD).

PMID- 10332844
TI  - T1 and magnetization transfer at 7 Tesla in acute ischemic infarct in the rat.
AB  - T1 and magnetization transfer at a field strength of 7 Tesla were used to
      discriminate between water accumulation and protein mobilization in tissue
      undergoing infarction. Twelve rats subjected to acute stroke via intralumenal
      suture occlusion of the middle cerebral artery, and 19 controls, were studied. In
      MRI studies to 6 hr post-ictus, serial data acquisition allowed the measurement
      of cerebral blood flow (CBF), apparent diffusion coefficient of water (ADCw),
      equilibrium magnetization (M0) and T1, and equilibrium magnetization and T1 under
      an off-resonance partial saturation of the macromolecular pool (Msat and T1sat).
      Using these parameters, the apparent forward transfer rate of magnetization
      between the free water proton pool and the macromolecular proton pool, k(fa), was
      calculated. Regions of interest (ROIs) were chosen using depressed areas in maps
      of the ADCw. T1 measurements in bovine serum albumin at 7T were not affected by
      the mobility of the macromolecular pool (P > 0.2), but magnetization transfer
      between free water and protein depended strongly on the mobility of the
      macromolecular pool (P < 0.001). For 6 hr after ictus, k(fa) uniformly and
      strongly decreased in the region of the infarct (P < 0.0001). Ratios
      (ischemic/non-ischemic) of parameters M0, Msat, T1, and T1sat all uniformly and
      strongly increased in the infarct. The ratio T1/T1sat in the region of infarction
      showed that a progressive accumulation of free water in the region of interest
      was the major (>80%) contribution to the decrease in k(fa). There also existed a
      small contribution due to changes at the water-macromolecular interface, possibly
      due to proteolysis (P = 0.005).

PMID- 10332845
TI  - The relationship between magnetic resonance diffusion imaging and
      autoradiographic markers of cerebral blood flow and hypoxia in an animal stroke
      model.
AB  - This study examined the relationship between magnetic resonance diffusion imaging
      and autoradiographic markers of cerebral blood flow (99mTc-hexamethylpropylene
      amine oxime) and cerebral hypoxia (125I-iodoazomycin arabinoside) in a rat model
      of stroke. Middle cerebral artery occlusion in the rat was performed using an
      intraluminal suture approach. Diffusion, hypoxia, and blood flow maps were
      acquired 2 hr following occlusion, and were compared with T2 images and histology
      at 7 hr. Two hours following middle cerebral artery occlusion the lesion
      distributions from the diffusion maps and hypoxic autoradiographs were similar.
      The blood flow threshold for increased uptake of the hypoxic marker was
      approximately 34 +/- 7% of the normal flow. The combination of diffusion or
      hypoxic images with perfusion maps allowed differentiation between four regions:
      1) normal tissue; 2) a region of decreased perfusion but normal diffusion and
      normal uptake of hypoxic marker; 3) a region of decreased perfusion, decreased
      diffusion and increased uptake of hypoxic marker; 4) a region of decreased
      perfusion, decreased diffusion and low uptake of hypoxic marker. The areas for
      increased uptake of hypoxic marker and decreased diffusion are equivalent,
      indicating similar blood flow thresholds. Regions of oligaemic misery perfusion,
      ischaemic misery perfusion and lesion core may be delineated with the combination
      of diffusion or hypoxic images and perfusion maps.

PMID- 10332846
TI  - Restoration of electrophysiological signals distorted by inductive effects of
      magnetic field gradients during MR sequences.
AB  - A generally applicable method for almost complete suppression of signal artifacts
      on electrophysiological signals caused by B0-gradient switching (gradient noise)
      is presented. The method is demonstrated for electrocardiograms (ECGs) but can
      also be used for other electrophysiological signals. It takes advantage of the
      fact that under certain conditions, the effect of switching the B0-field gradient
      upon an electrophysiological signal can be modeled as a linear time-invariant
      system and fully characterized by pulse response functions. It is shown how the
      system's pulse response functions of the X, Y, and Z gradients can be determined
      and how gradient noise can be eliminated efficiently. The elimination of gradient
      noise by the proposed method causes in the current arrangement a constant delay
      of 128 msec, which is acceptable for patient monitoring and magnetic resonance
      sequence triggering.

PMID- 10332847
TI  - Transesophageal magnetic resonance imaging.
AB  - The purpose of this study was to develop a non-invasive method of imaging the
      thoracic aorta that would provide both morphological detail within the aortic
      wall and information about regional aortic wall motion. An esophageal probe is
      described that allows transesophageal MR imaging (TEMRI) of the thoracic aorta
      and has several potential advantages over the competing non-vasculoinvasive
      techniques of transesophageal echocardiography (TEE) or standard MRI. The probe
      consists of a loopless antenna housed inside a modified Levin gastric tube, with
      external matching and tuning circuitry. Using this probe, the thoracic aorta has
      been imaged in longitudinal and cross-sectional views. Details of the aortic wall
      were readily seen. Tissue tagging for measurement of focal stress/strain
      relationships was demonstrated to be feasible. TEMRI avoids the risks inherent in
      intravascular MRI yet provides comparable image quality. Potential applications
      of the device are discussed.

PMID- 10332848
TI  - Diffuse axonal pathology detected with magnetization transfer imaging following
      brain injury in the pig.
AB  - This study was designed to evaluate with magnetization transfer imaging (MTI) and
      conventional magnetic resonance (MR) imaging the manifestation of diffuse axonal
      injury (DAI) in an animal model of injury via nonimpact coronal plane rotational
      acceleration. A second objective was to investigate the diagnostic use of
      quantitative MTR imaging based on statistical parameters in a single subject, as
      opposed to grouped analysis. Seven mini-swine were subjected to brain trauma
      known to produce isolated DAI and to MR imaging at two time points. Following
      sacrifice, the brains were harvested for histopathologic examination.
      Magnetization transfer ratio (MTR) maps were generated for double-blinded
      comparison of regions with abnormal MTR values and regions with documented DAI.
      Positive and negative predictive values for MTR detection of DAI were 67 and 56%,
      respectively, and in acute studies alone, 89 and 61%. Gains in sensitivity over
      conventional imaging for detection of DAI were demonstrated.

PMID- 10332849
TI  - A novel fast split-echo multi-shot diffusion-weighted MRI method using navigator
      echoes.
AB  - Difficulties in obtaining diffusion-weighted images of acceptable quality using
      conventional hardware and in a reasonable time have hindered the clinical
      application of diffusion-weighted magnetic resonance imaging (DWI). Diffusion
      weighted fast spin-echo (FSE) sequences offer the possibility of fast DWI on
      standard hardware without the susceptibility problems associated with echoplanar
      imaging. However, motion in the presence of diffusion-sensitizing gradients can
      prevent fulfilment of the Meiboom Gill phase condition, leading to destructive
      interference between echo components and consequent signal losses. A recently
      proposed single-shot FSE sequence employed split-echo acquisition to address this
      problem. However, in a segmented FSE sequence, phase errors differ between
      successive echo trains, causing "ghosting" in the diffusion-weighted images that
      are not eliminated by split-echo acquistion alone. A DWI technique is presented
      that combines split-echo acquisition with navigator echo phase correction in a
      segmented FSE sequence. It is shown to be suitable for diffusion measurements in
      vivo using standard hardware.

PMID- 10332850
TI  - In vivo imaging of extracellular pH using 1H MRSI.
AB  - Tumor pH is physiologically important since it influences a number of processes
      relevant to tumorigenesis and therapy. Hence, knowledge of localized pH within
      tumors would contribute to understanding these processes. The destructiveness,
      poor spatial resolution, and poor signal-to-noise ratio (SNR) of current
      technologies (e.g., microelectrodes, 31P magnetic resonance spectroscopy) have
      limited such studies. An extrinsic chemical extracellular pH (pHe) probe is
      described that is used in combination with 1H magnetic resonance spectroscopic
      imaging to yield pHe maps with a spatial resolution of 1 x 1 x 4 mm3. The
      principle of the technique is demonstrated on a phantom. Further data are shown
      to demonstrate its application in vivo, and results agree with previously
      reported pH values. The accuracy of the reported pH measurements is <0.1 pH
      units, as derived from a detailed analysis of the errors associated with the
      technique, the description of which is included.

PMID- 10332851
TI  - Single-loop coil concepts for intravascular magnetic resonance imaging.
AB  - Compared with other coil designs that have been investigated for intravascular
      use, the single-loop coil can be designed with a very small diameter for
      insertion into small vessels and with a longitudinal extent over several
      centimeters for multislice imaging. If it designed to be expandable inside the
      target vessel, then it combines these features with increased signal-to-noise
      ratio (SNR) and penetration depth. Expandable single-loop coils that are capable
      of meeting these requirements were developed and integrated into two different
      commercial catheter-based delivery systems: a self-expandable, single-loop made
      from NiTinol and a single-loop coil mounted on an inflatable balloon. The
      influence of a small-diameter coaxial cable for remote tuning and matching on the
      coil performance was investigated. Calculations showed the dependence of the
      signal on the separation between the conductors. The comparison of both catheter
      approaches in in vitro flow experiments and in an in vivo pig experiment revealed
      the influence of pulsatile flow on image quality during intravascular imaging
      with these designs.

PMID- 10332852
TI  - Functional magnetic resonance imaging using non-Fourier, spatially selective
      radiofrequency encoding.
AB  - A new method for functional magnetic resonance imaging (fMRI) employing non
      Fourier encoding using spatially selective radiofrequency (RF) excitation is
      presented. The method uses manipulation of spatially selective RF pulses to
      encode spins in the slice-select direction. The method has several advantages
      over standard multislice approaches. It provides a simple means for monitoring
      irregularly distributed sections throughout a volume without the need to encode
      the whole volume. It offers the potential for increased signal-to-noise ratio if
      an appropriate basis is used for encoding. With a unique design of excitation
      pulses, it also appears possible to significantly reduce in-flow effects. An
      interleaved echo-planar imaging (EPI) sequence was adapted for non-Fourier
      encoding in the slice-select direction and was implemented on a conventional 1.5
      Telsa system. The method was then used for functional mapping of the visual and
      motor areas where significant reduction of in-flow effect was demonstrated. This
      approach can be adapted to other imaging sequences that are used for fMRI, such
      as single-shot EPI.

PMID- 10332853
TI  - Non-ionic bulky Gd(III) DTPA-bisamide complexes as potential contrast agents for
      magnetic resonance imaging.
AB  - A series of new diethylene triamine pentaacetic acid (DTPA)-bisamide chelates
      containing bulky alkyl and aryl side chains have been prepared and characterized.
      Nuclear magnetic relaxation dispersion profiles were measured for the neutral
      gadolinium [Gd(III)] DTPA-bisamide complexes in water solution, and their
      chemical exchange times (tau(m)) were found to be in the range of 1.4 to 4.9
      micros. Significant enhancements of solvent proton relaxation rates were observed
      between 10 and 50 MHz for one of the complexes of the series [Gd(III)-DTPA-bis-2
      ethylhexylamide] in human serum albumin (HSA) solution, indicating the formation
      of a paramagnetic macromolecular adduct. The binding association constant K(A) of
      the complex and the albumin 5.7 x 10(3) M(-1) was obtained, and the relaxivity of
      the fully bound adduct was determined to be 13.8 mM(-1) s(-1) at 20 MHz and 25
      degrees C. The high value of K(A) makes the above derivative a good potential
      blood pool contrast agent at the physiological HSA concentration.

PMID- 10332854
TI  - Multiple region MRI.
AB  - Traditional Fourier MR imaging (FT MRI) utilizes the Whittaker-Kotel'nikov
      Shannon (WKS) sampling theorem. This theorem specifies the spatial frequency
      components which need to be measured to reconstruct an image with a known field
      of view (FOV). In this paper, we generalize this result in order to find the
      optimal k-space sampling for images that vanish except in multiple, possibly non
      adjacent regions within the FOV. This provides the basis for "multiple region
      MRI" (mrMRI), a method of producing such images from a traction of the k-space
      samples required by the WKS theorem. Image reconstruction does not suffer from
      noise amplification and can be performed rapidly with fast Fourier transforms,
      just as in conventional FT MRI. The mrMRI method can also be used to reconstruct
      images that have low spatial-frequency components throughout the entire FOV and
      high spatial frequencies (i.e. edges) confined to multiple small regions. The
      greater efficiency of mrMRI sampling can be parlayed into increased temporal or
      spatial resolution whenever the imaged objects have signal or "edge" intensity
      confined to multiple small portions of the FOV. Possible areas of application
      include MR angiography (MRA), interventional MRI, functional MRI, and
      spectroscopic MRI. The technique is demonstrated by using it to acquire Gd
      enhanced first-pass 3D MRA images of the carotid arteries without the use of
      bolus-timing techniques.

PMID- 10332855
TI  - Functional MR microscopy of the lung using hyperpolarized 3He.
AB  - A new strategy designed to provide functional magnetic resonance images of the
      lung in small animals at microscopic resolution using hyperpolarized 3He is
      described. The pulse sequence is based on a combination of radial acquisition
      (RA) and CINE techniques, referred to as RA-CINE, and is designed for use with
      hyperpolarized 3He to explore lung ventilation with high temporal and spatial
      resolution in small animal models. Ventilation of the live guinea pig is
      demonstrated with effective temporal resolution of 50 msec and in-plane spatial
      resolution of <100 microm using hyperpolarized 3He. The RA-CINE sequence allows
      one to follow gas inflow and outflow in the airways as well as in the distal part
      of the lungs. Regional analysis of signal intensity variations can be performed
      and can help assess functional lung parameters such as residual gas volume and
      lung compliance to gas inflow.

PMID- 10332856
TI  - Particle trace visualization of intracardiac flow using time-resolved 3D phase
      contrast MRI.
AB  - The flow patterns in the human heart are complex and difficult to visualize using
      conventional two-dimensional (2D) modalities, whether they depict a single
      velocity component (Doppler echocardiography) or all three components in a few
      slices (2D phase contrast MRI). To avoid these shortcomings, a temporally
      resolved 3D phase contrast technique was used to derive data describing the
      intracardiac velocity fields in normal volunteers. The MRI data were corrected
      for phase shifts caused by eddy currents and concomitant gradient fields, with
      improvement in the accuracy of subsequent flow visualizations. Pathlines
      describing the blood pathways through the heart were generated from the
      temporally resolved velocity data, starting from user-specified locations and
      time frames. Flow trajectories were displayed as 3D particle traces, with
      simultaneous demonstration of morphologic 2D slices. This type of visualization
      is intuitive and interactive and may extend our understanding of dynamic and
      previously unrecognized patterns of intracardiac flow.

PMID- 10332857
TI  - Sensitivity and resolution in 3D NMR microscopy of the lung with hyperpolarized
      noble gases.
AB  - Three-dimensional magnetic resonance images of the guinea pig lung were acquired
      in vivo using hyperpolarized (HP) noble gases and radial projection encoding
      (PE). Results obtained with 3He (voxel size 17 microl) demonstrated high image
      quality showing airway structure down to the 5th or 6th generations. Signal-to
      noise ratios (SNRs) of 129Xe images (voxel size 40 microl) were lower by about 1
      order of magnitude as a consequence of the smaller gyromagnetic ratio, a more
      rapid relaxation in the gas reservoir, and lower polarization and isotope
      abundance. Comparison between experimentally obtained SNRs and results from
      calculations based on a model that accounts for the three-dimensional PE
      acquisition scheme and the non-equilibrium situation in HP gas imaging yielded
      excellent agreement for small flip angles. A theoretical examination of the
      potential resolution in HP gas MR microscopy of the lungs suggests that in vivo
      visualization of alveolar clusters distal to respiratory bronchioles may be
      possible.

PMID- 10332858
TI  - A dual-tuned resonator for proton-decoupled phosphorus-31 chemical shift imaging
      of the brain.
AB  - A fully quadrature dome-shaped resonator is presented that has been dual-tuned
      for proton and phosphorus operation at 1.5 T. The resonator is 16.5 cm in length
      and 23 cm in diameter. Phantom studies were performed to demonstrate the utility
      of the resonator for proton imaging, shimming, and proton-decoupled phosphorus
      spectroscopy. In human subjects, proton-decoupled phosphorus chemical shift
      imaging spectra of the brain were acquired at 27 cm3 resolution in 34 min.
      Volunteer studies demonstrated improved resolution of phosphomonoesters,
      phosphodiesters, and nucleoside triphosphates due to proton decoupling. Sensitive
      coverage of the brain extended from the most superior cerebral cortex to the
      cerebellum. Acquisition of good quality 31P spectra over this volume is due to
      the dome structure as well as quadrature operation at both proton and phosphorus
      frequencies.

PMID- 10332859
TI  - Specific absorption rates and induced current densities for an anatomy-based
      model of the human for exposure to time-varying magnetic fields of MRI.
AB  - A 6-mm resolution, 30-tissue anatomy-based model of the human body is used to
      calculate specific absorption rate (SAR) and the induced current density
      distributions for radiofrequency and switched gradient magnetic fields used for
      MRI, respectively. For SAR distributions, the finite-difference time-domain
      (FDTD) method is used including modeling of 16-conductor birdcage coils and outer
      shields of dimensions that are typical of body and head coils and a new high
      frequency head coil proposed for the 300-400 MHz band. SARs at 64, 128, and 170
      MHz have been found to increase with frequency (f) as f(k) where k is on the
      order of 1.1-1.2. The tables of the calculated maximum 1 kg and 100 g SAR may be
      used to calculate the maximum RF currents and/or magnetic fields that may be used
      in order not to exceed the safety guidelines. Because of the low frequencies
      associated with switched gradient magnetic fields, a quasi-static impedance
      method is used for calculation of induced current densities that are compared
      with the safety guidelines.

PMID- 10332860
TI  - 2D multislice and 3D MRI sequences are often equally sensitive.
AB  - A simple theoretical model was developed to compare the sensitivities (i.e.,
      signal-to-noise ratios per unit imaging time) of two-dimensional (2D) multislice
      and 3D imaging sequences. The model shows that the sensitivities of 3D and 2D
      multislice MRI sequences are usually similar. Sensitivities are identical in T2
      weighted sequences when the T(R)s of the two sequences are the same. In T1
      weighted gradient-echo sequences, sensitivities are very similar when Ernst angle
      excitation is used and the T(R) of the 2D sequence is less than T1. The
      predictions of the model are confirmed in phantom and animal experiments.

PMID- 10332861
TI  - Implementation of quantitative FAIR perfusion imaging with a short repetition
      time in time-course studies.
AB  - Flow-sensitive alternating inversion recovery (FAIR) is a pulsed arterial spin
      labeling magnetic resonance imaging method for perfusion quantification. In its
      standard implementation for quantification with full longitudinal relaxation
      between acquisitions, its use in time-course investigations of rapidly changing
      flow values is limited. The time efficiency can be improved by decreasing the
      repetition time but quantification becomes problematic. This situation is further
      complicated if a whole-body radiofrequency transmit coil is not used since fresh
      blood spins will flow in from outside the coil. To alleviate these problems, the
      use of global pre-saturation is proposed. The resulting expression for the flow
      signal depends on the relationship between the imaging parameters and the coil
      inflow time and can be significantly simplified under certain combinations of
      these parameters. With this implementation of FAIR, quantitative flow maps of
      gerbil brains were obtained with a 3 minute time resolution in a study of the
      effects of reperfusion. The pre-occlusion flow measurements were in good
      agreement with values obtained by the standard FAIR implementation and by other
      techniques, but the low values following occlusion were underestimated due to the
      increased transit times.

PMID- 10332862
TI  - MR image segmentation and tissue metabolite contrast in 1H spectroscopic imaging
      of normal and aging brain.
AB  - The impact of image segmentation on 0.84-ml nominal voxel volume proton
      spectroscopic imaging in normal brain and in age-related cortical atrophy was
      investigated. Segmentation improved the gray matter-white matter (GM-WM) contrast
      for N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr in normal brain,
      and for NAA/Cho and NAA/Cr in atrophic brain. NAA(GM/WM) (approximately 0.7),
      Cho(GM/WM) (approximately 0.8), and Cr(GM/WM) (approximately 1.3) in normal brain
      obtained with segmentation agreed with values obtained with quantitative magnetic
      resonance spectroscopy. Age-related cortical atrophy led to decreased cortical GM
      NAA/Cho and NAA/Cr; no changes were evident in WM or in NAA(GM/WM), Cho(GM/WM),
      or Cr(GM/WM). GM/WM metabolite analysis may be of limited use in conditions in
      which parallel metabolite changes occur in WM and GM.

PMID- 10332863
TI  - Interactive three-point localization of double-oblique sections using MR
      fluoroscopy.
AB  - Magnetic resonance imaging allows significant freedom in selecting the
      orientation and position of a tomographic section. However, it can nonetheless be
      challenging to determine quickly and efficiently the correct parameters required
      to image a targeted anatomic structure that may lie at an oblique angle in the
      imaging volume. We describe a three-point tool in which a) the user interactively
      selects three points from an anatomic structure of interest during live MR
      fluoroscopy; b) adjustments to pulse sequence are calculated to image the
      tomographic section defined by the three points; and c) the section is then
      immediately imaged fluoroscopically. The tool allows quick localization of, for
      example, longitudinal images of specific arterial structures.

PMID- 10332864
TI  - Regional heterogeneity in the brain's response to hypoxia measured using BOLD MR
      imaging.
AB  - Blood oxygenation level-dependent (BOLD) magnetic resonance (MR) imaging is
      sensitive, in part, to the amount of paramagnetic deoxyhemoglobin in a voxel.
      This project was designed to determine whether there would be differences in the
      BOLD response between the hippocampus and other brain regions to acute hypoxia.
      R2* was quantified using a multi-echo gradient-echo sequence. The pyramidal CA1
      region of the hippocampus showed a reduced response to changes in arterial
      oxygenation relative to cortex and basal ganglia and white matter. This
      difference may relate to the relative hypoxia sensitivity of the hippocampus. It
      also supports the premise that in functional MR imaging, the magnitude of the MR
      response to a stimulus may vary with the region of the brain.

PMID- 10332865
TI  - Nondestructive imaging of human cartilage glycosaminoglycan concentration by MRI.
AB  - Despite the compelling need mandated by the prevalence and morbidity of
      degenerative cartilage diseases, it is extremely difficult to study disease
      progression and therapeutic efficacy, either in vitro or in vivo (clinically).
      This is partly because no techniques have been available for nondestructively
      visualizing the distribution of functionally important macromolecules in living
      cartilage. Here we describe and validate a technique to image the
      glycosaminoglycan concentration ([GAG]) of human cartilage nondestructively by
      magnetic resonance imaging (MRI). The technique is based on the premise that the
      negatively charged contrast agent gadolinium diethylene triamine pentaacetic acid
      (Gd(DTPA)2-) will distribute in cartilage in inverse relation to the negatively
      charged GAG concentration. Nuclear magnetic resonance spectroscopy studies of
      cartilage explants demonstrated that there was an approximately linear
      relationship between T1 (in the presence of Gd(DTPA)2-) and [GAG] over a large
      range of [GAG]. Furthermore, there was a strong agreement between the [GAG]
      calculated from [Gd(DTPA)2-] and the actual [GAG] determined from the validated
      methods of calculations from [Na+] and the biochemical DMMB assay. Spatial
      distributions of GAG were easily observed in T1-weighted and T1-calculated MRI
      studies of intact human joints, with good histological correlation. Furthermore,
      in vivo clinical images of T1 in the presence of Gd(DTPA)2- (i.e., GAG
      distribution) correlated well with the validated ex vivo results after total knee
      replacement surgery, showing that it is feasible to monitor GAG distribution in
      vivo. This approach gives us the opportunity to image directly the concentration
      of GAG, a major and critically important macromolecule in human cartilage.

PMID- 10332866
TI  - Improved visualization of the human lung in 1H MRI using multiple inversion
      recovery for simultaneous suppression of signal contributions from fat and
      muscle.
AB  - 1H magnetic resonance imaging of the lung is hampered by the low contrast between
      lung parenchyma, and muscle and fat in the thorax. We show that it is possible to
      improve contrast greatly and thereby enhance the visibility of the lung, by
      suppression of signal of surrounding muscle and fat based on differences in T1
      relaxation times using a double inversion recovery preparation pulses (TI1 800
      msec, and TI2 150 msec) and a half-Fourier acquisition single-shot turbo spin
      echo (HASTE) sequence. The measured T1 values for the right and left lungs at 1.5
      T were 1.37 +/- 0.18 and 1.41 +/- 0.21 sec, respectively.

PMID- 10332867
TI  - Functional MRI of the human brain with GRASE-based BOLD contrast.
AB  - The application of T2*-weighted gradient and spin-echo (GRASE) imaging was
      investigated as a method for blood oxygenation level-dependent (BOLD)-based
      functional magnetic resonance imaging (fMRI). The displaced-echo method was
      implemented to produce single-shot T2*-weighted GRASE images. This technique
      removes the requirement that the Carr-Purcell Meiboom-Gill (CPMG) condition be
      fulfilled. T2*-weighted GRASE images that are free from interference artifacts
      can thus be obtained, hence allowing the possibility of using single-shot GRASE
      for BOLD-based functional imaging. The method was demonstrated at 3 T and gave
      robust and reproducible activation-induced signal changes.

PMID- 10332868
TI  - Echoplanar chemical shift imaging.
AB  - A novel method of chemical shift imaging utilizing echoplanar imaging (EPI) has
      been developed for the purpose of improving the spatial resolution of metabolite
      images for the specific goal of high spatial resolution mapping of neuronal
      content. An EPI sequence was modified to allow temporal offsets of the 180 degree
      refocusing pulse that encode the chemical shift information into the phase of the
      signal. Implementation of this method on 1.5 and 3 T human imagers has resulted
      in images of N-acetyl aspartate in humans with spatial resolution of 360 microl
      and signal-to-noise ratio approximately 7:1 in less than 13 min.

PMID- 10332869
TI  - Magnetic resonance imaging-based compartmentation and its application to
      measuring metabolite concentrations in the frontal lobe.
AB  - Partial volume mixing of water compartments within a spectroscopy voxel (e.g.
      cerebrospinal fluid within a "brain" voxel) may, if not corrected for, lead to
      underestimation of brain metabolite concentrations. To correct for this source of
      bias, a new imaging-based method of compartmentation analysis is presented. Brain
      water, cerebrospinal fluid and solid matter content were obtained from proton
      density- and T2-weighted images of the brain and an external standard in 10
      healthy young males (21 to 30 years), and results compared with a previously
      described technique based on spectroscopy. Mean (SD) fractional water content
      (betaMR) of the 2 x 2 x 2 cm3 voxel in the frontal lobes was 0.79 (0.03) by
      imaging, slightly but significantly (p = 0.03) smaller than the value of 0.83
      (0.03) obtained by spectroscopy. From water-suppressed spectra recorded at five
      echo times, using betaMR determined by imaging, the T2-corrected concentrations
      of compounds containing N-acetylaspartate, creatine, choline and myo-inositol
      were 10.6 (1.0), 8.0 (0.9), 1.6 (0.3) and 3.7 (0.7) mmol.l(-1) of brain,
      respectively. Imaging-based compartmentation is a rapid and straightforward
      technique, and can be performed on standard MR systems.

PMID- 10332870
TI  - Localized 1H NMR measurements of 2-pyrrolidinone in human brain in vivo.
AB  - Localized 1H NMR homonuclear J editing spectroscopy was used to measure the
      concentration of 2-pyrrolidinone (PRDN) in the human occipital lobe of five
      normal and six epileptic subjects taking vigabatrin. PRDN is a lactam cyclization
      product of gamma-aminobutyric acid (GABA). From a localized volume of 13.5 cm3 in
      the occipital cortex, the concentration of PRDN ranged from 0.2 to 0.3 micromol/g
      in normal subjects, whereas in epileptic subjects on vigabatrin PRDN was elevated
      to 0.6 +/- 0.1 micromol/g. The elevated PRDN in patients on vigabatrin was in
      accord with raised GABA levels compared with normals. 1H NMR measurements of PRDN
      will be important in assessment of the role of this metabolite for improved
      seizure control.

PMID- 10332871
TI  - Nm23-transfected MDA-MB-435 human breast carcinoma cells form tumors with altered
      phospholipid metabolism and pH: a 31P nuclear magnetic resonance study in vivo
      and in vitro.
AB  - Nm23 genes are involved in the control of the metastatic potential of breast
      carcinoma cells. To understand the impact of nm23 genes on tumor physiology and
      metabolism, a 31P nuclear magnetic resonance (NMR) spectroscopic study was
      performed on tumors formed in the mammary fat pad of severe combined
      immunodeficiency mice by MDA-MB-435 human breast carcinoma cells transfected with
      cDNA encoding wild type nm23-H1 and nm23-H2 proteins. Tumors formed by MDA-MB-435
      cells transfected with vector alone were used as controls. All transgene tumors
      exhibited significantly higher levels of phosphodiester (PDE) compounds relative
      to phosphomonoester (PME) compounds in vivo compared with control tumors. Similar
      differences in PDE and PME also were observed for spectra obtained from cells
      growing in culture. Intracellular pH was significantly lower and extracellular pH
      was significantly higher for transgene tumors compared with control tumors.
      Histologic analysis of lung sections confirmed reductions in incidence, number,
      and size of metastatic nodules for animals bearing transgene tumors. These
      results suggest that nm23 genes may affect suppression of metastasis through
      phospholipid-mediated signaling and cellular pH regulation.

PMID- 10332872
TI  - Chemical shift artifact-free microscopy: spectroscopic microimaging of the human
      skin.
AB  - A spectroscopic imaging technique with high spatial resolution was used for the
      study of human skin in vivo. The measurements were performed using a whole-body
      magnetic resonance system (1.5 T) with standard gradients and a standard 8-cm
      diameter circular surface coil. A decisive gain in signal-to-noise ratio was
      achieved by reducing the receiver bandwidth of the imaging system to values less
      than +/-5 kHz. The chemical shift misregistration was eliminated by post
      detection data processing. The method was tested on different kinds of skin, on
      the foot sole and head. Water, fat, and chemical shift artifact-free images were
      obtained with resolution 0.107 x 0.143 mm in plane and slice thickness 1 mm. A
      major advantage of the spectroscopic imaging procedure is that the pulse sequence
      can be optimized for the maximum signal-to-noise ratio. There is no need for
      special modification of the sequence to circumvent the chemical shift artifacts
      (water, fat suppression, etc.).

PMID- 10332873
TI  - Heat-source orientation and geometry dependence in proton-resonance frequency
      shift magnetic resonance thermometry.
AB  - The proton-resonance frequency (PRF) shift method of thermometry has become a
      promising tool for magnetic resonance image-guided thermal therapies. Although
      the PRF thermal coefficient has recently been shown to be independent of tissue
      type when measured ex vivo, significant discrepancy remains on its value for
      tissues measured in vivo under a variety of experimental conditions. The authors
      identify a potential source of variation in the PRF thermal coefficient that
      arises from temperature-induced changes in the volume magnetic susceptibility of
      tissue and is dependent on the orientation and geometry of the heat-delivery
      device and its associated heat pattern. This study demonstrates that spatial
      variations in the apparent PRF thermal coefficient could lead to errors of up to
      +/-30% in the magnetic resonance estimated temperature change if this effect is
      ignored.

PMID- 10332874
TI  - Accuracy of MR phase mapping for temperature monitoring during interstitial laser
      coagulation (ILC) in the liver at rest and simulated respiration.
AB  - The chemical shift or proton-resonance frequency (phase mapping) can be used to
      measure temperature changes. As a subtraction technique, it requires scans at
      exactly the same location, making it prone to respiration-induced artifacts. The
      accuracy of magnetic resonance (MR) phase mapping for temperature monitoring of
      interstitial laser coagulation (ILC) was therefore investigated in two ex vivo
      models with simulated respiration. MR temperatures were calibrated to
      interstitially measured temperature. Gradual cooling of a homogenous medium (gel)
      was monitored for four starting temperatures (room temperature, 40 degrees C, 50
      degrees C, and 60 degrees C) during 30 min. Temperature increases were measured
      during ILC in ex vivo porcine liver with Nd:YAG for 6 min with 5 Watt.
      Experiments were performed at rest and with simulated respiratory motion (both n
      = 5). In liver, accuracy did not decrease with respiration simulation (P = 0.32),
      whereas a significant decline was found in the gel model (P = 0.002). In all
      experiments a small drift over time was observed between temperature determined
      with MR and thermoprobes. Correction for temperature-independent phase-shift at a
      reference location did not enhance agreement. Temperatures could be determined
      correctly by MR in the moving liver within a range of +/-3.5 degrees C after 6
      min of laser application (95% confidence interval), justifying further pre
      clinical studies.

PMID- 10332875
TI  - Fitting cytosolic ADP recovery after exercise with a step response function.
AB  - Phosphorus magnetic resonance (MR) spectroscopy was used to measure the recovery
      kinetics of calculated cytoplasmic metabolically active adenosine diphosphate
      (ADP) after exercise in normal subjects and patients with mitochondrial
      myopathies. These kinetics have previously been fitted with a single exponential
      function, despite a complex time-dependent undershoot in many subjects. By
      considering the transition from ischemic-exercise to perfused-recovery as a step
      function input, a second-order linear system was developed yielding a step
      response function to fit the ADP recovery. Using this method, an average
      improvement in fit of 23% resulted in a significant improvement in the
      characterization of ADP recovery for all normal subjects with substantial
      undershoot. The patient group had a comparable improvement in fit of 11%. Fitting
      the ADP recovery with a second-order step response function can provide
      significantly better characterization of muscle oxidative metabolism in vivo.

PMID- 10332877
TI  - Analysis of functional magnetic resonance imaging data using self-organizing
      mapping with spatial connectivity.
AB  - Commonly used methods in analyzing functional magnetic resonance imaging (fMRI)
      data, such as the Student's t-test and cross-correlation analysis, are model
      based approaches. Although these methods are easy to implement and are effective
      in analyzing data obtained with simple paradigms, they are not applicable in
      situations in which patterns of neuronal response are complicated and when fMRI
      response is unknown. In this work, Kohonen's self-organizing mapping (SOM), which
      is a model-free approach, is adapted for analyzing fMRI data. Because spatial
      connectivity is an important function in the identification of activation sites
      in functional brain imaging, it is incorporated into the SOM algorithm. Receiver
      operating characteristic analysis on simulated data shows that the new algorithm
      achieves measurable improvement over the standard algorithm. The applicability of
      the new algorithm is demonstrated on experimental data.

PMID- 10332876
TI  - Longitudinal relaxation times of 129Xe in rat tissue homogenates at 9.4 T.
AB  - Longitudinal relaxation times of 129Xe were measured in homogenates of rat brain,
      kidney, liver, and lung at varying oxygenation levels as a means to assess the
      feasibility of magnetic resonance (MR) imaging of tissue using laser-polarized
      (LP) 129Xe as the signal source. The measured relaxation times ranged from 4.4 +/
      0.4 sec in deoxygenated lung homogenate to 22 +/- 2 sec in deoxygenated brain
      homogenate. When the LP gas is introduced to the subject via inhalation, these
      relaxation times are long enough to allow accumulation and subsequent MR imaging
      of LP 129Xe in tissues. Imaging of dissolved LP 129Xe will yield an intrinsic
      signal-to-noise ratio (SNR) that is approximately 3% of the proton intrinsic SNR.
      This relatively low intrinsic SNR is expected to be adequate for some tracer
      applications. T1 of 129Xe was found to depend on the oxygenation level of the
      tissue, and the effect of oxygenation is likely dependent on the amount of
      hemoglobin in the tissue homogenate.

PMID- 10332878
TI  - In vivo micro-imaging using alternating navigator echoes with applications to
      cancellous bone structural analysis.
AB  - In micro-magnetic resonance imaging of cancellous bone architecture, involuntary
      subject motion even on a sub-millimeter scale is detrimental and generally
      precludes accurate quantification of architectural parameters. In this work a
      navigator-assisted three-dimensional spin-echo technique is described and
      evaluated for imaging at 137 microm resolution in humans. The method is based on
      gradient navigator echoes following the spin-echo readout for sensing
      translational displacements alternately in x- and y-directions with a spatial
      resolution of 273 microm and a temporal resolution of 0.2 sec. The technique is
      shown to improve micro-images of the distal forearm significantly and to enhance
      accuracy and reproducibility of bone volume fraction, transverse contiguity, and
      tubularity, parameters introduced in prior work to characterize the trabecular
      network. It is further shown that a fourfold reduction in navigator sampling
      time, along with zero-filling, improves the accuracy of the navigator correction
      while reducing the minimum pulse repetition time or gradient heating. The data
      indicate that navigator-assisted micro-imaging is capable of effectively
      correcting sub-millimeter displacements in micro-imaging.

PMID- 10332879
TI  - Motion compensated projection reconstruction.
AB  - Over recent years, MRI has shown the capability for real-time applications.
      Although the acquisition times of fast MRI methods have been reduced
      significantly, patient motion during a magnetic resonance imaging (MRI)
      examination still causes artifacts in the image. In this paper, the effects of
      motion in MRI using a radial acquisition scheme are examined. It is shown that
      motion can be estimated without the use of additional measurement, based on the
      acquired projections only. A new reconstruction technique is introduced that
      integrates a motion compensation algorithm into the MR-reconstruction process,
      resulting in a significant reduction of blurring artifacts in the reconstructed
      images. The proposed method is applied to different kinds of motion such as
      kinetic joint studies.

PMID- 10332880
TI  - Motion correction in fMRI via registration of individual slices into an
      anatomical volume.
AB  - An automated retrospective image registration based on mutual information is
      adapted to a multislice functional magnetic resonance imaging (fMRI) acquisition
      protocol to provide accurate motion correction. Motion correction is performed by
      mapping each slice to an anatomic volume data set acquired in the same fMRI
      session to accommodate inter-slice head motion. Accuracy of the registration
      parameters was assessed by registration of simulated MR data of the known truth.
      The widely used rigid body volume registration approach based on stacked slices
      from the time series data may hinder statistical accuracy by introducing
      inaccurate assumptions of no motion between slices for multislice fMRI data.
      Improved sensitivity and specificity of the fMRI signal from mapping-each-slice
      to-volume method is demonstrated in comparison with a stacked-slice correction
      method by examining functional data from two normal volunteers. The data
      presented in a standard anatomical coordinate system suggest the reliability of
      the mapping-each-slice-to-volume method to detect the activation signals
      consistent between the two subjects.

PMID- 10332881
TI  - Improving contrast and tracking of tags in cardiac magnetic resonance images.
AB  - Cardiac tagging permits non-invasive study of myocardial motion with high
      accuracy. Unfortunately, tagging contrast is impaired at later heart phases due
      to longitudinal relaxation. Histogram modification is presented as a method for
      improving contrast in later, faded images of a tagging series by altering these
      images such that their intensity histograms approximate the shape of the first,
      unfaded image of the series. This technique greatly improves the contrast and
      facilitates automatic detection of tags. Furthermore, a method is described for
      automatically tracking tag positions in short-axis images of the left ventricle
      modulated with a tagging grid. The method differs from previously reported
      methods in that, in one single filtering process in the Fourier domain, both the
      grid crossings as well as the grid centers are detected, and thus increased
      sampling resolution is obtained. The method was validated by applying a
      mathematical model of left ventricular motion to tagged images of the thigh
      muscle. The average discrepancy between theoretically predicted and automatically
      detected tag positions was 0.04 +/- 0.17 mm (mean +/- SD).

PMID- 10332882
TI  - 3D spiral cardiac/respiratory ordered fMRI data acquisition at 3 Tesla.
AB  - Three-dimensional (3D), multi-shot functional magnetic resonance imaging (fMRI)
      data acquisitions are desirable because of higher resolution and reduced
      susceptibility artifacts, due to shorter readouts and thinner slices. However, 3D
      multi-shot techniques are more susceptible to physiological noise, which can
      increase inter-image variance and lead to inaccurate assessment of activation.
      This work presents a 3D spiral fMRI data acquisition method at 3 T in which the
      acquisition of views was ordered to match the phase of either the respiratory or
      the cardiac cycle. For the acquisition timing parameters used in this work,
      cardiac ordering was found to reduce inter-image variance by 19%. Cardiac ordered
      data acquisitions showed the same reduction in variance as sequentially ordered
      data with cardiac contributions estimated and removed using an externally
      acquired reference prior to reconstruction. Respiratory ordering showed no
      reduction in fluctuation noise due to poor alignment of views to the respiratory
      phase.

PMID- 10332883
TI  - Diffusion tensor microscopy of the intervertebral disc anulus fibrosus.
AB  - Morphologically accurate biomechanical models of the intervertebral disc anulus
      fibrosus (AF) require precise knowledge of its lamellar architecture; however,
      available methods of assessment are limited by poor spatial resolution or the
      destructive nature of the technique. In a novel approach, diffusion tensor
      microscopy was used in this study to characterize the microstructure of excised
      porcine AF samples. Results show diffusion in the AF to be anisotropic. The
      orientations of anisotropy exhibit a layered morphology that agrees with light
      micrographs of the corresponding samples, and the behavior of the orientation
      angles is consistent with the known AF collagen fiber architecture. A static
      magnetic field-dependent relaxation anisotropy was observed in the AF, which has
      methodological implications for magnetic resonance (MR) imaging of ordered
      collagenous tissues. These findings present MR diffusion tensor microscopy as a
      potentially valuable tool to assess quantitatively and nondestructively water
      diffusion anisotropy and lamellar structure of the intervertebral disc AF.

PMID- 10332884
TI  - An echo-shifted gradient-echo MRI method for efficient diffusion weighting.
AB  - A segmented magnetic resonance imaging (MRI) method is introduced with time
      efficient diffusion weighting resulting in total imaging times similar to those
      of single-shot methods. The approach is based on the principles of echo shifting
      with a train of observations (PRESTO) MRI sequence. The time efficiency of the
      sequence is based on the use of diffusion gradient pulses that also serve to
      shift the echo train to the next TR period, resulting in TE > TR. Each diffusion
      gradient is therefore used twice, for dephasing one set of spins as well as
      rephasing a second set of spins. Diffusion weighting and acquisition are thus
      achieved simultaneously. The sequence is validated in vitro and in vivo on rat
      kidney.

PMID- 10332885
TI  - Signal-to-noise ratio and signal-to-noise efficiency in SMASH imaging.
AB  - A general theory of signal-to-noise ratio (SNR) in simultaneous acquisition of
      spatial harmonics (SMASH) imaging is presented, and the predictions of the theory
      are verified in imaging experiments and in numerical simulations. In a SMASH
      image, multiple lines of k-space are generated simultaneously through
      combinations of magnetic resonance signals in a radiofrequency coil array. Here,
      effects of noise correlations between array elements as well as new correlations
      introduced by the SMASH reconstruction procedure are assessed. SNR and SNR
      efficiency in SMASH images are compared with results using traditional array
      combination strategies. Under optimized conditions, SMASH achieves the same
      average SNR efficiency as ideal pixel-by-pixel array combinations, while allowing
      imaging to proceed at otherwise unattainable speeds. The k-space nature of SMASH
      reconstructions can lead to oscillatory spatial variations in noise standard
      deviation, which can produce local enhancements of SNR in particular regions.

PMID- 10332886
TI  - Flow distortion and signal loss in spiral imaging.
AB  - The effect of in-plane motion on the point spread function (velocity PSF) in
      spiral imaging is studied experimentally and derived mathematically and is shown
      to consist of a smoothed, trailing edge and fringes around the leading edge. The
      velocity PSF remains largely in phase with the static PSF, consistent with the
      absence of signal loss by motion-related phase shifts in central k space.
      However, single-shot spiral imaging gives no clear improvement in complex and
      turbulent flow signal uniformity compared with echo-planar imaging with early,
      central k-space acquisition, which requires explanation given the spiral's
      earlier coverage of central k space. Alternate leading-edge fringes of the
      spiral's velocity PSF are in antiphase to the source, and cancellation may occur
      when these overlap other in-phase signals. Phase variations toward peripheral k
      space in turbulent flow also cause distortion. It is concluded that spiral
      imaging may lose complex and turbulent flow signals because of complex PSF
      distortion.

PMID- 10332887
TI  - A high-temperature superconducting Helmholtz probe for microscopy at 9.4 T.
AB  - The design and operation of a high-temperature superconducting (HTS) probe for
      magnetic resonance microscopy (MRM) at 400 MHz are presented. The design of the
      probe includes a Helmholtz coil configuration and a stable open-cycle cooling
      mechanism. Characterization of coil operating parameters is presented to
      demonstrate the suitability of cryo-cooled coils for MRM. Specifically, the
      performance of the probe is evaluated by comparison of signal-to-noise (SNR)
      performance with that of a copper Helmholtz pair, analysis of B1 field
      homogeneity, and quantification of thermal stability. Images are presented to
      demonstrate the SNR advantage of the probe for typical MRM applications.

PMID- 10332888
TI  - Visual feedback to stabilize head position for fMRI.
AB  - Head motion is a common cause of technical failure in functional magnetic
      resonance imaging. A simple visual alignment system has been developed to provide
      visual feedback to the subject about his or her head position. The subject is
      able to readjust his or her head position accurately during a study, should
      motion occur. This sighting system is incorporated into a visor that fits onto
      the commercial head coil. The accuracy of correcting head motion and activation
      maps obtained with this device are demonstrated. The cognitive workload of using
      the alignment system does not significantly alter the activation pattern
      associated with eye movement paradigms.

PMID- 10332889
TI  - Human brain activation under controlled thermal stimulation and habituation to
      noxious heat: an fMRI study.
AB  - Brain activity was studied with functional magnetic resonance imaging (fMRI)
      following thermal stimulation. Two groups (n = 6/group) of human male volunteers
      were given up to four noxious (46 degrees C) and four non-noxious (41 degrees C)
      stimuli. In the 46 degrees C experiment, positive signal changes were found in
      the frontal gyri, anterior and posterior cingulate gyrus, thalamus, motor cortex,
      somatosensory cortex (SI and SII), supplementary motor area, insula, and
      cerebellum. Low-level negative signal changes appeared in the amygdala and
      hypothalamus. All regions activated by 46 degrees C were also activated by 41
      degrees C. However, except for SI and thalamus, significantly more activation was
      observed for the 46 degrees C stimulus. A significant attenuation of the signal
      change was observed by the third stimulus for the 46 degrees C, but not for 41
      degrees C experiment. Similar findings were replicated in the second group. These
      fMRI findings specify differences between somatosensory and pain sensation and
      suggest a number of rich avenues for future research.

PMID- 10332890
TI  - Magnetic resonance angiography with hyperpolarized 129Xe dissolved in a lipid
      emulsion.
AB  - Hyperpolarized (HP) 129Xe can be dissolved in biologically compatible lipid
      emulsions while maintaining sufficient polarization for in vivo vascular imaging.
      For xenon in Intralipid 30%, in vitro spectroscopy at 2 T yielded a chemical
      shift of 197 +/- 1 ppm with reference to xenon gas, a spin-lattice relaxation
      time T1 = 25.3 +/- 2.1 sec, and a T2* time constant of 37 +/- 5 msec. Angiograms
      of the abdominal and pelvic veins in the rat obtained with 129Xe MRI after
      intravenous injection of HP 129Xe/Intralipid 30% into the tail demonstrated
      signal-to-noise ratios between 8 and 29. An analysis of the inflow effect on time
      of-flight images of two segments of the inferior vena cava yielded additional
      information. The mean blood flow velocity was 34.7 +/- 1.0 mm/sec between the
      junction of the caudal veins and the kidneys and 13.3 +/- 0.8 mm/sec at the
      position of the diaphragm. The mean volume flow rates in these segments were 7.2
      +/- 3.4 ml/min and 11.0 +/- 2.8 ml/min, respectively. Intravenous delivery of HP
      129Xe dissolved in a carrier may lead to novel biomedical applications of laser
      polarized gases.

PMID- 10332891
TI  - Quantitative imaging of magnetization transfer using multiple selective pulses.
AB  - New spectroscopic and imaging methods have been developed for quantitatively
      measuring magnetization transfer (MT). These methods use trains of radiofrequency
      (rf) pulses with pulse separations much longer than 1/k(mf) and pulse durations
      much shorter than 1/k(mf), where k(mf) is the rate of MT from the immobile
      (macromolecular) protons to the mobile (free water) protons. Signal sensitivity
      to MT occurs when these pulses affect the mobile and immobile proton pools to
      different degrees. The signal from water may be quantitatively related to the
      macromolecular content of the sample using theory. The method has been used to
      make quantitative measurements of macromolecular content in cross-linked bovine
      serum albumin and employed in conjunction with echoplanar imaging to produce maps
      of the spatial distribution of the macromolecular content.

PMID- 10332892
TI  - Systematic noise compensation for simultaneous multislice acquisition using
      rosette trajectories (SMART).
AB  - Simultaneous multislice acquisition using rosette trajectories (SMART) is a
      recently introduced functional magnetic resonance imaging pulse sequence that
      offers high-speed data acquisition by simultaneously exciting several slices. A
      drawback to its benefit of rapid acquisition is the cumulative effect of the
      systematic noise present in the off-resonant slices. In this work, a systematic
      noise compensation method is implemented to gauge the performance of the
      multislice SMART method versus a single-slice rosette method in a motor
      activation study. The normalized standard deviation of the noise-compensated
      image timecourse is reduced by 25% (single-slice rosette) and 62% (SMART), and
      the normalized volume of motor activation is increased by 25% (single-slice
      rosette) and 44% (SMART). The noise-compensated SMART method has an average
      timecourse standard deviation only 9% higher than the noise-compensated single
      slice rosette method, while increasing the acquisition rate threefold.

PMID- 10332893
TI  - Homelessness and mental illness: a story of failure.

PMID- 10332894
TI  - A comparison of practice patterns and a model continuum of ambulatory behavioral
      health services.

PMID- 10332895
TI  - Optimal treatment for psychosis in an international multisite demonstration
      project. Optimal Treatment Project Collaborators.

PMID- 10332896
TI  - Web sites worth watching.

PMID- 10332897
TI  - Improving cost-effectiveness in a substance abuse treatment program.

PMID- 10332898
TI  - General medical care for psychiatric patients.

PMID- 10332899
TI  - Legal system involvement and costs for persons in treatment for severe mental
      illness and substance use disorders.
AB  - OBJECTIVE: Persons with co-occurring severe mental illness and substance use
      disorders were followed for three years to better understand how they are
      involved with the legal system and to identify factors associated with different
      kinds of involvement. METHODS: Data came from a three-year study of 203 persons
      enrolled in specialized treatment for dual disorders. Cost and utilization data
      were collected from multiple data sources, including police, sheriffs and
      deputies, officers of the court, public defenders, prosecutors, private
      attorneys, local and county jails, state prisons, and paid legal guardians.
      RESULTS: Over three years 169 participants (83 percent) had contact with the
      legal system, and 90 (44 percent) were arrested at least once. Participants were
      four times more likely to have encounters with the legal system that did not
      result in arrest than they were to be arrested. Costs associated with nonarrest
      encounters were significantly less than costs associated with arrests. Mean costs
      per person associated with an arrest were $2,295, and mean costs associated with
      a nonarrest encounter were $385. Combined three-year costs averaged $2,680 per
      person. Arrests and incarcerations declined over time. Continued substance use
      and unstable housing were associated with a greater likelihood of arrest. Poor
      treatment engagement was associated with multiple arrests. Men were more likely
      to be arrested, and women were more likely to be the victims of crime.
      CONCLUSIONS: Effective treatment of substance use among persons with mental
      illness appears to reduce arrests and incarcerations but not the frequency of
      nonarrest encounters. Stable housing may also reduce the likelihood and number of
      arrests.

PMID- 10332900
TI  - HIV and people with serious mental illness: the public sector's role in reducing
      HIV risk and improving care.
AB  - OBJECTIVE: The paper discusses issues related to the detection, prevention of
      transmission, and treatment of human immunodeficiency virus (HIV) infection among
      persons with serious mental illness and suggests ways public mental health
      systems can address these issues. METHODS: MEDLINE was searched from 1980 through
      1998, and all pertinent references were reviewed. RESULTS: Persons with severe
      mental illness are at greatly increased risk of HIV infection due to increased
      likelihood of high-risk sexual behaviors and injection drug use. The formidable
      barriers to detection and effective treatment of HIV that exist in this
      population can be attributed to the unique characteristics of this population,
      lack of knowledge and expertise among mental and physical health care providers,
      and fragmented mental and physical health care systems. CONCLUSIONS: In the last
      five years, treatments for HIV that are far more efficacious than earlier
      treatments have become available, making it more important for HIV infection be
      detected and treated among persons with serious mental illness. Public mental
      health systems need to implement active prevention policies and practices,
      educate both mental health and physical health care providers about key treatment
      issues, and develop effective linkages between mental and physical health care
      providers and systems.

PMID- 10332901
TI  - Principles for priority setting in mental health services and their implications
      for the least well off.
AB  - Funding for mental health services has declined in recent years, posing the
      difficult challenge of setting program and individual client service priorities
      with reduced resources. The author reviews seven principles for resource
      allocation and their potential impact on people with severe and persistent mental
      illness. These principles address issues of the autonomy of individual health
      care needs; the need for client, stakeholder, and provider input into goal
      setting; cost-effectiveness; equity and fairness; client responsibility for
      making effective use of services; the impact of private industry on the
      development and marketing of new treatments; and the importance of considering
      local skill availability and population needs in setting program priorities.
      Because none of these principles take precedence over the others, their joint
      application does not necessarily yield consistent program priorities. However,
      they provide a frame of reference for approaching the task of priority setting
      and for understanding why priorities may vary from different perspectives.

PMID- 10332902
TI  - The obligation of mental health services to the least well off.
AB  - Since the 1970s public mental health policy has given priority to the least well
      off-those with the most severe impairments and those who are most indigent.
      Reforms during this era have focused on the social welfare as well as the health
      and mental health needs of this population. The author briefly examines the key
      service demonstration programs and policy changes of the past 20 years in the
      light of society's obligation to the least well off. Despite a variety of policy
      threats to the priority accorded this population in the 1980s, the focus on the
      least well off has been sustained. The mental health field could do a much better
      job, however, in implementing the lessons learned from service demonstration
      programs. Recent changes in managed care and social welfare policy challenge the
      field's commitment to the least well off. However, the rise in consumerism and
      self-advocacy has sounded a more optimistic note from a population determined no
      longer to be least well off.

PMID- 10332903
TI  - Balancing efficiency and need in allocating resources to the care of persons with
      serious mental illness.
AB  - The care of patients with serious mental illness, for whom a cure is unlikely and
      costs are high, is difficult to justify using ordinary standards of efficient
      resource allocation. The author examines the difficulties of using conventional
      utilitarian, cost-benefit, moral, and political arguments to justify allocation
      of resources to the care of persons with serious mental illness and offers an
      alternative approach to this problem based on the goals of medicine. Although
      care for persons with serious mental illness may not meet the usual standards of
      efficient health care spending, their treatment is justified by central and long
      standing goals of medicine such as relief of pain and suffering and care of those
      who cannot be cured. This approach suggests that the idea of efficiency in health
      care spending should be adapted to the goals of medicine rather than making those
      goals adapt to the idea of efficiency.

PMID- 10332904
TI  - Prediction of homelessness within three months of discharge among inpatients with
      schizophrenia.
AB  - OBJECTIVE: The authors' goal was to identify factors that place inpatients with
      schizophrenia at risk of becoming homeless after hospital discharge. METHODS:
      Patients with schizophrenia or schizoaffective disorder (N=263) were assessed at
      discharge from general hospitals in New York City and reassessed three months
      later to evaluate whether they had become homeless. Sociodemographic and clinical
      characteristics associated with homelessness were identified using likelihood
      ratio chi square analysis and logistic regression. RESULTS: Twenty patients (7.6
      percent) reported an episode of homelessness during the follow-up period.
      Patients who had a drug use disorder at hospital discharge were significantly
      more likely to report becoming homeless than those without a drug use disorder.
      Patients with a total score above 40 on the Brief Psychiatric Rating Scale (BPRS)
      at hospital discharge were more likely to report becoming homeless than patients
      with lower scores, as were those with Global Assessment Scores less than 43.
      Twelve of 30 patients with a drug use disorder, a BPRS score above 40, and a GAS
      score less than 43 at hospital discharge reported becoming homeless. CONCLUSIONS:
      The combination of a drug use disorder, persistent psychiatric symptoms, and
      impaired global functioning at the time of hospital discharge poses a substantial
      short-term risk of homelessness among patients with schizophrenia. Patients who
      fit this profile may be candidates for community-based programs that are
      specifically aimed at preventing homelessness among patients with severe mental
      illness.

PMID- 10332905
TI  - Housing placement and subsequent days homeless among formerly homeless adults
      with mental illness.
AB  - OBJECTIVE: The study examined the influence of group or individual housing
      placement and consumer characteristics on the number of days subsequently
      homeless among formerly homeless mentally ill persons. METHODS: A total of 303
      homeless shelter residents with severe mental illness were screened for
      dangerousness, 118 were randomly assigned to either independent apartment or
      staffed group living sites, and 110 were followed for 18 months. Study
      participants' sociodemographic characteristics, diagnosis, and residential
      preferences and the residential recommendations made by clinicians were measured
      at baseline. RESULTS: Overall, 76 percent of the study participants were housed
      at the end of the 18-month follow-up period, although 27 percent had experienced
      at least one episode of homelessness during the period. The number of days
      homeless was greater for individuals assigned to independent apartments than for
      those placed in staffed group homes, but only for members of minority groups.
      Substance abuse was the strongest individual-level predictor of days homeless.
      Individuals whom clinicians identified as needing group living experienced more
      days homeless, irrespective of the type of housing they received. Consumers who
      stated a strong preference for independent living had more days homeless than
      those who were amenable to staffed group homes. CONCLUSIONS: Although consumers
      more frequently prefer independent living, placement in staffed group housing
      resulted in somewhat fewer days homeless for some groups of consumers. Further
      experience of homelessness by formerly homeless mentally ill individuals may be
      reduced by providing effective substance abuse treatment and by paying special
      attention to consumers identified by clinicians to be at particular risk for
      housing loss.

PMID- 10332906
TI  - Mental illness as a predictor of satisfaction with inpatient care at Veterans
      Affairs hospitals.
AB  - OBJECTIVE: Patient satisfaction ratings are increasingly being used as an
      indicator of quality of care. However, satisfaction scores do not account for
      differences in satisfaction among patients that may be attributable to
      sociodemographic characteristics or type of illness rather than to the quality of
      service delivery. This study examines the role of psychiatric diagnosis in
      satisfaction with inpatient care delivered at Department of Veterans Affairs (VA)
      hospitals. METHODS: Data were taken from a large national VA customer feedback
      survey of patients discharged from VA hospitals between June 1 and August 31,
      1995 (N=38,789). Analyses examined whether patients discharged with a psychiatric
      diagnosis were less satisfied with care than those discharged with a
      nonpsychiatric diagnosis. RESULTS: Patients with a psychiatric diagnosis were
      less satisfied with their care, regardless of whether they were treated in a
      psychiatric treatment program or a medical unit, and this relationship remained
      after the analysis adjusted for other determinants of satisfaction. The
      association between low satisfaction and psychiatric diagnosis was more
      pronounced among nonblack patients. CONCLUSIONS: The results suggest the need for
      caution in using patient satisfaction measures to compare mental health programs
      and other health care programs.

PMID- 10332908
TI  - Mental health consumers as peer interviewers.
AB  - Although consumers are increasingly hired as mental health workers, they
      typically fulfill demanding jobs such as case manager. This study examined the
      performance and job satisfaction of 18 consumers with serious mental illness who
      were hired for less demanding work--to conduct highly structured interviews with
      their peers. The consumers completed interviews with 243 peers. Only one
      interviewer was unable to perform the work. Ninety percent of the interviews were
      completed satisfactorily. Interviewers reported increased skills and knowledge,
      improved self-assurance, and feelings of pride. Results of the study suggest that
      a wide range of consumers can perform structured treatment tasks.

PMID- 10332907
TI  - Effects of group treatment for women with a history of childhood sexual abuse.
AB  - OBJECTIVE: Empirical support for the effectiveness of group therapies for women
      with a history of childhood sexual abuse is scant. This study examined the
      feasibility of conducting abuse-focused research and group treatment on a short
      term unit and evaluated the effectiveness of the Women's Safety in Recovery
      group. METHODS: Eighty-six women with a history of childhood sexual abuse
      participated in treatment as usual (N=38) or in the Women's Safety in Recovery
      group (N=48). The latter group met three times weekly for one hour, focusing on
      patients' current safety and self-care. Participants completed the Symptom
      Checklist-Revised at baseline, discharge, and six-month follow-up. Patients rated
      their experience in treatment at discharge and six-month follow-up, and
      therapists rated patients' treatment experiences at discharge. The feasibility of
      the treatment group was measured by enrollment rates, group attendance, and
      attrition. RESULTS: Eighty-two percent of eligible patients agreed to enroll in
      the study. Women's Safety in Recovery participants attended an average of ten
      group meetings. Seventy percent of enrollees completed discharge assessments, and
      of these, 82 percent completed the six-month follow-up. Compared with treatment
      as-usual patients, Women's Safety in Recovery participants reported greater
      symptom improvement and reported that their childhood sexual abuse issues had
      been more thoroughly addressed. These differences were present at discharge and
      at six-month follow-up. Therapists also perceived that abuse issues of these
      participants had been more thoroughly addressed. CONCLUSIONS: Women's Safety in
      Recovery participants reported significant reductions in distress compared with
      those receiving treatment as usual. The abuse-focused research program and the
      Women's Safety in Recovery group proved feasible, despite attrition.

PMID- 10332909
TI  - Setting benchmarks and determining psychiatric workloads in community mental
      health programs.
AB  - Administrators and clinicians must find ways to effectively and efficiently use
      psychiatric resources without compromising the quality of care. The author
      outlines a model for setting benchmarks for allocating psychiatrists' time in a
      community mental health service setting. After the percentage of time for direct
      care activities is agreed on (for example, 60 percent), the amounts of time
      necessary for three direct-care clinical activities-assessment of new patients,
      follow-up of stable patients, and follow-up of unstable patients and emergencies-
      are established. Time for documentation should be included in each task. At the
      end of six months, workloads are evaluated, and benchmarks are reset as
      appropriate.

PMID- 10332910
TI  - Evaluation of compulsory ambulatory treatment in Israel.
AB  - The effectiveness of Israel's compulsory ambulatory treatment order was evaluated
      based on a one-year follow-up of the 326 orders served during the first four
      years of implementation. Demographic, epidemiological, clinical, and legal data
      were obtained from patient records. Success was defined as continuous treatment
      for the entire six-month period of compulsory ambulatory treatment, or as
      voluntary hospitalization during or after the compulsory treatment period. The
      compulsory ambulatory treatment order was found to be efficacious in 43.3 percent
      of the cases; in 32.5 percent it did not succeed in preventing compulsory
      hospitalization, and in the remaining cases (22.1 percent), success was partial.

PMID- 10332911
TI  - Views about treatment among parents of adolescents who received electroconvulsive
      therapy.
AB  - The study assessed the experience, knowledge, and attitudes of parents of
      adolescents who had been treated with electroconvulsive therapy (ECT) about that
      treatment. Twenty-eight parents were interviewed. Overall, their opinions about
      ECT were favorable. Seventeen of 28 parents thought that ECT had been helpful. If
      ECT was recommended by a doctor, the vast majority of parents would support a
      decision for their child to have the treatment again and would advise others to
      consider it.

PMID- 10332912
TI  - The schizophrenia algorithm.

PMID- 10332913
TI  - The schizophrenia algorithm.

PMID- 10332914
TI  - Weight gain among patients on clozapine.

PMID- 10332915
TI  - ADHD in adult psychiatric outpatients.

PMID- 10332916
TI  - Legislation to regulate use of restraints and seclusion in mental health
      facilities introduced in Congress.

PMID- 10332917
TI  - Best-practice guidelines focus on collaboration between criminal justice and
      substance abuse treatment systems.

PMID- 10332918
TI  - Nontraditional treatments for localized prostate cancer: ten rules to know before
      talking to my patients.
AB  - There is accumulating evidence that nontraditional treatments used by the general
      population are experiencing a dramatic increase. The use of these treatments by
      prostate cancer patients seems to at least parallel or exceed that of recent
      surveys for other groups. Unfortunately, much of the attention of nontraditional
      treatments has focused on "what to take and not to take," rather then "how to
      approach" the use of these therapies. One of the most widely used nontraditional
      treatments is the use of supplements. Outlined here are 10 general rules that the
      clinician should know before consulting on these treatments. Recording supplement
      use as a part of the general medical history, knowing the general behavior of
      supplement users, instructing individuals on the proper time to use supplements,
      and focusing on more than prostate cancer for our example patient are just some
      of the rules that will enable the health professional to be better equipped for
      handling this unique area of medicine.

PMID- 10332919
TI  - Prostate cancer chemoprevention by green tea.
AB  - Prostate cancer (PCA) is one of the most invasive cancers and the second leading
      cause of cancer-related deaths among males in the United States. According to an
      estimate, 1 of every 11 American men will eventually develop PCA. One way to
      reduce the occurrence of cancer is through chemoprevention. PCA represents an
      excellent candidate disease for chemoprevention because it is typically diagnosed
      in men over 50 years of age, and therefore even a modest delay in neoplastic
      development achieved through pharmacological or nutritional intervention could
      result in a substantial reduction in the incidence of clinically detectable
      disease. The ideal agent(s) suitable for chemoprevention of PCA should be the
      one(s) that has proven efficacy in the laboratory experiments on one hand, and
      also possesses proven epidemiological basis on the other hand. This review
      attempts to address the issue of possible uses of tea, especially green tea, for
      the prevention of PCA. We are providing the experimental as well as the
      epidemiological basis for this possibility. Many laboratory experiments conducted
      in cell culture systems and in animal models have shown the usefulness of green
      tea, and the polyphenols present therein, against PCA. The epidemiological basis
      for this possibility is twofold. First, some epidemiological observations have
      suggested that people who consume tea regularly have a lower risk of PCA-related
      deaths. Second, the incidence of PCA in China, a population that consumes green
      tea on a regular basis, is lowest in the world.

PMID- 10332920
TI  - Vitamin D in the prevention and treatment of prostate cancer.
AB  - Current approaches to the management of prostate cancer include surgery,
      radiation therapy, or hormonal manipulation either individually or in
      combination. With an increase in understanding of the etiology and natural
      history of prostate cancer, the influence of dietary factors on the disease is
      becoming more evident. There have been a number of studies in this regard that
      have demonstrated a relationship between prostate cancer and numerous dietary
      constituents including vitamins. The fat-soluble vitamins A and D have both been
      found to affect the growth of prostate cancer in preclinical experiments. Of the
      two, vitamin D has been the focus of greater attention in recent years, and there
      are indications that it may be useful both in the prevention and treatment of
      prostate cancer. This article reviews the current literature in this area to
      determine if treatment with vitamin D would be a viable management alternative
      for the patient described in the case study.

PMID- 10332921
TI  - Vitamin E, alpha- and gamma-tocopherol, and prostate cancer.
AB  - Vitamin E is one of the most researched compounds in medicine. Vitamin E is
      actually a general name for potentially eight different compounds, so supplements
      can contain several forms and vitamin E in the diet also differs from the form
      found over the counter. There has been a strong interest in this supplement in
      the prostate cancer arena primarily because of a Finnish study that demonstrated
      a lower morbidity and mortality from this disease in men taking 50 mg of
      synthetic (alpha-tocopherol) vitamin E daily. In addition, observations from
      laboratory and clinical studies dealing with heart disease have found that gamma
      tocopherol may also play a significant role in prevention; therefore, we decided
      to test the ability of this compound (versus synthetic vitamin E) to control the
      growth of a human prostate cancer cell line. Gamma-tocopherol was found to be
      superior to alpha-tocopherol in terms of cell inhibition in vitro. Both forms of
      vitamin E (and others) should be thoroughly evaluated in the future to provide
      the most effective chemoprevention information to the patient.

PMID- 10332922
TI  - Selenium and prostate cancer prevention.
AB  - Prostate cancer is the second leading cause of cancer deaths in men, therefore it
      is increasingly important to understand its biology and epidemiology. New
      approaches for the primary and secondary prevention of prostate cancer are
      needed, including innovative uses of chemoprevention. This review provides an
      overview of the epidemiological data suggesting that higher intakes of selenium
      may reduce the risk of prostate cancer. In addition, a discussion of preclinical
      data is presented. Special emphasis is placed on the following areas: (1)
      chemical forms of selenium and antitumorigenic activity, (2) in vitro effects of
      selenite versus monomethylated selenium, and (3) current clinical intervention
      trials with selenium in prostate cancer. Chemoprevention, especially with dietary
      forms of selenium, is a promising new approach that presently is undergoing
      intensive investigation.

PMID- 10332923
TI  - Soy, disease prevention, and prostate cancer.
AB  - Population-based studies from around the world support the theory that soy
      products and their constituents, primarily the isoflavones or phytoestrogens, are
      partly responsible for the lower rates of certain chronic diseases in different
      areas of the world. Cardiovascular disease and hormonally induced cancers are
      just a few of the conditions lower in Asian countries that consume large
      quantities of soy per average person. Genistein, one of soy's individual
      phytoestrogens, has been found to inhibit numerous breast and prostate cancer
      cell lines. A limited amount of clinical evidence also points to a beneficial
      role of soy in reducing hormonal levels and exhibiting weak estrogen and
      antiestrogen-like qualities. Other phytoestrogens found in nature, such as
      lignans, may also have a future role in cancer. Collectively, these
      phytoestrogens, like genistein, have enough evidence to warrant their use in a
      number of clinical trials as a potential chemopreventive agent or adjunct to
      prostate cancer treatment.

PMID- 10332924
TI  - Traditional Chinese medicine, acupuncture, and other alternative medicines for
      prostate cancer: an introduction and the need for more research.
AB  - There are several other alternative medicines apart from vitamins and minerals
      that the clinician should be aware of because they have grown in popularity in
      other fields of medicine. In time, these therapies should impact the arena of
      urologic oncology. Traditional Chinese Medicine, which includes acupuncture, is
      an area that has received some attention. The theory behind it can be quite
      daunting because it is so different from the theory behind Western Medical
      Science. In addition, exactly how acupuncture can be applied to a patient and its
      potential use in prostate cancer need to be addressed. Other herbal therapies for
      the patient experiencing symptoms related to a localized cancer diagnosis also
      need to be evaluated. St John's Wort for depression and Kava for anxiety are two
      examples of herbal alternatives that some prostate patients are inquiring about.
      Finally, Ginkgo biloba has received a great deal of attention in the media for
      erectile dysfunction, but there is a dearth of evidence in this area and the
      information that already exists can be misleading until further studies are
      conducted. Also, it is imperative that additional studies be performed in all of
      the above subjects as they relate to prostate cancer, but a general survey on
      alternative medicine use in urologic diseases is needed first before an adequate
      review of the most popular therapies can be published.

PMID- 10332925
TI  - Meditation and prostate cancer: integrating a mind/body intervention with
      traditional therapies.
AB  - There is growing attention to the health benefits of mind/body interventions,
      particularly relaxation and meditation. Biomedical research has provided
      undeniable evidence of the interconnectedness of the mind and body. The field of
      psychoneuroimmunology has defined the role of stress in reducing effectiveness of
      the immune system in combating infection and growth of malignant tumors. This
      article explains the development of meditation practice and explores the
      indications that the practice of meditation is effective reducing the harmful
      effects of stress. In addition, there are encouraging reports of studies citing
      the influence of melatonin on breast and prostate tumors. A preliminary study
      finds an association between meditation practice and levels of melatonin produced
      by the pineal gland.

PMID- 10332927
TI  - The Emerging Importance of Genetics in Epidemiologic Research III. Bioinformatics
      and statistical genetic methods.
AB  - PURPOSE: To outline potential benefits of integrating recent developments in
      bioinformatics and statistical genetics with traditional epidemiologic studies to
      localize genes influencing complex phenotypes and examine genetic effects on
      disease susceptibility. METHODS: An overview of bioinformatic and statistical
      approaches for localizing disease-susceptibility genes as well as challenges
      associated with identifying functional DNA variants and context-dependent genetic
      effects concludes this three-part series on the importance of genetics in
      epidemiologic research. RESULTS: Rapidly evolving bioinformatic and statistical
      methods are providing invaluable information on newly-discovered genes and
      molecular variation influencing human diseases that is readily available to
      epidemiologic researchers. CONCLUSIONS: Integrating bioinformatics and molecular
      biotechnology with epidemiologic methods of assessing disease risk is rapidly
      expanding our ability to identify genetic influences on complex human diseases.
      These technological advances are likely to have a profound impact on current
      knowledge of complex disease etiology, and may reveal novel approaches to disease
      treatment and prevention.

PMID- 10332926
TI  - Emphasizing and promoting overall health and nontraditional treatments after a
      prostate cancer diagnosis.
AB  - Although prostate cancer is the number one diagnosed cancer in men, the
      importance of emphasizing and preventing other common diseases after diagnosis is
      essential. For example, heart disease still remains the number one cause of
      mortality in men, accounting for 50% of the deaths in Western countries.
      Therefore, promoting overall healthy behaviors also seems essential, especially
      in light of past and recent evidence that an individual can maintain proper
      health by following some simple guidelines. The increased consumption of healthy
      foods, greater intakes of B-vitamins and minerals such as potassium can
      significantly reduce the risk of heart disease, stroke, and possibly cancer in a
      patient with a prior or current malignancy. Overall dietary change as observed
      from the Mediterranean diet, light exercise, and improved mental health should
      also be stressed to the patient because of recent studies.

PMID- 10332928
TI  - Methods and prevalence of ADL limitations in Hispanic and non-Hispanic white
      subjects in rural Colorado: the San Luis Valley Health and Aging Study.
AB  - PURPOSE: The Hispanic population in the United States is the fastest growing
      minority group, yet there is little understanding of the disability patterns that
      occur as this population ages. We conducted a cross-sectional study to define the
      prevalence of limitations of activities of daily living (ADL) and measures of
      observed function. METHODS: We censussed two rural counties in southern Colorado
      and selected a stratified sample of both Hispanic and non-Hispanic white (NHW)
      residents; 81.6% completed the protocol. RESULTS: Among the 1250 subjects aged 65
      years and older, Hispanic elderly living in the community had greater ADL
      disability than NHW subjects, both for any difficulty (p = 0.006), and for
      needing assistance (p = 0.002). Hispanic persons were less likely to reside in
      nursing homes (3.4%) compared with NHW persons (9.3%). Hispanic elderly had
      excess prevalence of dependent ADL tasks (needs assistance or unable to do),
      (age, gender-adjusted odds ratio = 1.39, 95% CI = 1.01-1.92) in community
      dwelling and nursing home residents combined. There was no Hispanic excess of
      less severe difficulty compared with NHW persons, and there was a similar
      prevalence of limitation on observed functional tasks (timed walk, stooping,
      rising from a chair) in both groups. CONCLUSIONS: There was a modest Hispanic
      excess of reported dependent ADL limitation, and no excess of observed functional
      difficulties. Hispanics enter older age with much less income and education, yet
      they do not have a marked excess prevalence of limitations in activities of daily
      living when compared with NHW persons living in the same area.

PMID- 10332929
TI  - Cigarette smoking among native and foreign-born African Americans.
AB  - PURPOSE: To examine differences in current smoking status and the number of
      cigarettes consumed daily between foreign and native-born African Americans, and
      the impact of demographic and socioeconomic status (SES) factors on smoking
      behavior. METHODS: Data were obtained from combining the 1990-1994 National
      Health Interview Surveys and consisted of 16,738 U.S. born and foreign-born
      African Americans between 18 and 64 years of age. The statistical analysis
      included cross-tabulations and weighted multiple logistic regression (MLR) using
      the Statistical Packages for the Social Sciences (SPSS) and the Survey Data
      Analysis (SUDAAN) computer programs. RESULTS: Adjusted MLR analysis revealed that
      native-born African Americans were more likely (odds ratio (OR) = 2.7, p < 0.001)
      to be current smokers than foreign-born blacks. Within the native-born group,
      smoking prevalence decreased with increasing education and income, but these
      associations were not found for foreign-born blacks. Women in both groups were
      less likely than men to be current smokers. Statistically significant differences
      were not found between the two groups in the number of cigarettes smoked per day.
      CONCLUSIONS: This analysis of nativity and smoking behavior further demonstrates
      the social diversity among African Americans and suggests the differential impact
      of social and cultural factors on smoking behavior within racially classified
      social groups. In areas where there are substantial numbers of foreign-born
      blacks, researchers should consider differentiating smoking status by nativity.
      Though differences in smoking prevalence were apparent for native and foreign
      born American Americans, prevention and cessation programs are needed for both
      groups.

PMID- 10332930
TI  - Blood pressure and the T174M and M235T polymorphisms of the angiotensinogen gene.
AB  - PURPOSE: The angiotensinogen gene (AGT), which encodes the precursor of the
      vasoactive hormone angiotensin II, has been reported to be associated with
      hypertension in Caucasian and Japanese populations. We examined the relationship
      between two common molecular variants of AGT, T174M and M235T and blood pressure
      in two cohorts from the Anqing region of China. Cohort I (N = 794) consisted of
      families ascertained by either hypertensive or hypotensive siblings; and Cohort
      II (N = 761) represented a collection of randomly selected families. METHODS:
      Blood pressure was measured according to standard protocols, and information on
      age, sex, body mass index, alcohol consumption, and cigarette smoking was
      collected by trained interviewers using standardized questionnaires. The
      association of AGT genotypes and blood pressure was examined in multivariate
      linear regression models, with adjustment for potential intrafamilial
      correlations. The respective T and M allele frequencies for T174M were 0.93 and
      0.07, and 0.80 and 0.20 for M235T among the parents for randomly selected
      families. All the analyses were conducted after exclusion of individuals
      currently under antihypertensive medication. RESULTS: In the pooled analysis of
      the two cohorts, neither the T174M nor the M235T polymorphism was significantly
      associated with variations of blood pressure assuming a recessive (T174M: p =
      0.73 and 0.61; M235T: p = 0.99 and 0.24; for SBP and DBP), dominant (T174M: p =
      0.54 and 0.72; M235T: p = 0.79 and 0.12; for SBP and DBP), or additive (T174M: p
      = 0.52 and 0.67, M235T: p = 0.91 and 0.11; for SBP and DBP) model. Likewise, no
      statistically significant association was detected when the two cohorts were
      analyzed separately. The logistic regression analysis of hypertension also failed
      to reveal any association with these markers. CONCLUSIONS: In summary, our
      analyses suggest that the molecular variants of AGT may not be associated with
      variations of blood pressure in this rural Chinese population.

PMID- 10332931
TI  - Alcohol and prostate cancer in the NHANES I epidemiologic follow-up study. First
      National Health and Nutrition Examination Survey of the United States.
AB  - PURPOSE: We prospectively investigated the association between alcohol
      consumption and prostate cancer in the Epidemiologic Follow-up Study (NHEFS) of
      the first National Health and Nutrition Examination Survey (NHANES I). METHODS:
      There were two cohorts: 1) Cohort I, followed from baseline (1971-75) through
      1992, included 5766 men ages 25-74 years (median follow-up = 17 years); and 2)
      Cohort II, followed from the first follow-up round for Cohort I (1982-84) through
      1992, included the 3868 men in Cohort I free of prostate cancer in 1982-84
      (median follow-up = 9 years). Alcohol consumption was assessed at baseline as
      usual consumption, and at follow-up as usual consumption and as distant past
      consumption at the ages of 25, 35, 45, and 55. RESULTS: There were 252 incident
      cases of prostate cancer. Consistent with most previous studies, we found no
      significant associations between usual total alcohol consumption and prostate
      cancer in Cohorts I or II [p = non significant (NS)], except for a significant
      inverse association at the heaviest level of drinking in Cohort II [relative risk
      (RR) = 0.23, 95% confidence interval (CI) = 0.06-0.95]. Further study of heavy
      drinkers in Cohort II revealed significant inverse associations between distant
      past heavy drinking (defined as > 25 drinks/week) and prostate cancer at age 25
      (RR = 0.20, 95% CI = 0.06-0.63), age 35 (RR = 0.30, 95% CI = 0.12-0.77), and age
      45 (RR = 0.39, 95% CI = 0.17-0.93), but not at age 55 (RR = 0.43, 95% CI = 0.17
      1.10). CONCLUSIONS: These results suggest that it may be important to consider
      distant past alcohol consumption in etiologic studies of prostate cancer.
      However, our results were based on small numbers of cases who were heavy drinkers
      and require replication.

PMID- 10332933
TI  - A profile of the burdens of care of Alzheimer's disease patients.

PMID- 10332932
TI  - The effect of comorbidity on care seeking for back problems in the United States.
AB  - PURPOSE: We assess the effect of comorbidity on self-reported use of health care
      for back problems in the United States. METHODS: Data from the 1989 National
      Health Interview Survey (NHIS) were used to perform cross-sectional analyses of
      adults who reported a back-related condition. The presence of one or more nonback
      related conditions (and associated disability and health care) were the primary
      predictor variables. Weighted logistic regression modeling was performed to
      estimate odds ratios (ORs) adjusted for the effects of covariates. RESULTS: The
      1989 NHIS included 84,572 adults, of which 4790 (5.7%) reported at least one back
      related condition. Of these, 931 (19.6%) sought health care for their back
      condition during the 2-week reference period. Among all adults with reported back
      problems, those with disabling comorbidities and those who sought care for their
      comorbidities during the reference period were less likely to have sought back
      care than were those with no comorbidities. Subjects with back-related
      disabilities who reported nondisabling comorbidities without associated health
      care were much more likely to have sought back care than were similar subjects
      without any comorbidities. CONCLUSIONS: The decision to seek care for a back
      problem is a complex process that depends upon the presence and impact of other
      conditions and the use of care for these conditions. Comorbid back problem
      sufferers may not seek back care when afflicted with other disabling conditions
      or conditions that may be perceived to be more amenable to care.

PMID- 10332934
TI  - Realistic expectations for the management of Alzheimer's disease.
AB  - Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder
      characterized clinically by cognitive and functional deficits and behavioural
      disturbances. Over the past two decades, the devastating nature of AD has
      captured the attention of the general and medical communities alike. This is due
      partly to the increased prevalence of AD and the expansion of the aged
      population. Furthermore, and perhaps inappropriately, the media have encouraged
      speculation concerning a 'cure' for AD. Such treatment strategies are in the
      early stages of pre-clinical investigation and well-designed clinical trials are
      awaited. Nevertheless, other strategies, aimed at reducing the progression or
      effects through pharmacological symptomatic therapies and psychosocial
      interventions have demonstrated some clinical benefit and are now available and
      practicable. This paper critically evaluates the merits of both currently
      available and potential future therapeutic strategies according to primary,
      secondary and tertiary levels of preventative treatment.

PMID- 10332935
TI  - Reappraising neurotransmitter-based strategies.
AB  - A number of observations support the hypothesis that a central deficit in
      acetylcholine (ACh) may be responsible for the initiation of Alzheimer's disease
      (AD). For example, cholinergic innervation in AD is reduced in areas of the brain
      important for processing information. Further, reduced concentrations of choline
      acetyltransferase (ChAT), the enzyme responsible for the synthesis of ACh,
      correlate with the number of beta-amyloid senile plaques and cognitive
      dysfunction in AD patients. Consequently, several strategies to increase
      cholinergic neurotransmission have been developed, including ACh precursors, ACh
      release enhancers, cholinesterase (ChE) inhibitors and receptor agonists.
      Although ChE inhibitors appear to be the most promising, tacrine, the first ChE
      inhibitor to be registered and approved for the treatment of AD, has significant
      tolerability problems. Thus, ChE inhibitors with improved side-effect profiles
      have been developed and subsequently awarded marketing approval. However, in
      addition to the cholinergic system that is the most severely affected
      neurotransmitter system in AD, other neurotransmitter systems may be involved
      (e.g. serotonergic, noradrenergic and glutamatergic). Therefore, bifunctional
      compounds or combinations of drugs may provide additional therapeutic value.

PMID- 10332936
TI  - Rational design of anti-dementia therapy.
AB  - Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics
      of new drugs is essential. The application of this information facilitates the
      design of a rational clinical trial programme and optimizes the chances for rapid
      and successful clinical development. Upon completion of each development phase,
      the information obtained must be evaluated critically to maximize the design of
      subsequent studies. Phase I trials represent the first time the drug is
      administered in humans and their primary objective is to evaluate the drug's
      safety and tolerability in man. Phase II trials represent the first time that the
      drug is administered to the target patient population. The objectives of Phase II
      trials are to verify the safety and tolerability of the drug in patients, and
      also to evaluate for the first time the clinical efficacy of the drug. During
      these phases of development, the use of PK and PD measures is helpful for
      establishing the therapeutic dose range as well as the suitability of the chosen
      efficacy measures for use in the pivotal Phase III trials. Here, using several
      examples of PK and PD data obtained from the clinical development studies of
      donepezil HCl, the application of these measures on the development of a drug for
      the treatment of Alzheimer's disease is discussed.

PMID- 10332937
TI  - Clinical benefits of a new piperidine-class AChE inhibitor.
AB  - Alzheimer's disease (AD) is associated with a deficiency of acetylcholine (ACh)
      in the forebrain that correlates with brain pathology and cognitive dysfunction.
      The most promising approach to enhancing central ACh neurotransmission has been
      the utilization of agents that inhibit cholinesterases which block its
      catabolism. Initially, the success of this strategy was limited by subtherapeutic
      levels of acetylcholinesterase (AChE) inhibition, tolerability problems and
      toxicity of the first agents. Donepezil HCI represents a new chemical class of
      AChE inhibitors, the piperidines. In clinical trials, donepezil has been shown to
      improve significantly cognition and global function in patients with mild to
      moderately severe AD, and has demonstrated an excellent tolerability and safety
      profile. These benefits, as well as a simple, once-daily dosing regimen, make
      donepezil a viable therapeutic option for AD patients.

PMID- 10332938
TI  - A 25-year prospective study of visual acuity in the Japan Air Self Defense Force
      personnel.
AB  - BACKGROUND: In the Japan Air Self Defense Force (JASDF), new vision standards for
      student pilots allow lower uncorrected monocular acuity (from 1.0 to 0.8). In
      flight environments, where the use of corrective lenses may present problems, the
      risk of decreasing visual acuity in pilots who should wear corrective lenses must
      be defined. METHODS: We conducted a 25-yr prospective study of visual acuity with
      regard to distance vision in 752 JASDF nonaviation personnel followed from ages
      20 to 45. The test subjects were divided into four groups according to their
      right monocular visual acuity at entry: > or =1.0, between 0.9 and 0.7, between
      0.6 and 0.2, and <0.2. RESULTS: At entry, 94.1% of all subjects had visual acuity
      > or =0.7. The proportion of subjects who required corrective lenses for distance
      increased with age from 15.8% to 37.1%. After 25-yr, 30.2% of subjects with
      visual acuity > or =1.0 at entry and 62.7% of subjects with visual acuity between
      0.9 and 0.7 at entry required corrective lenses. CONCLUSIONS: Over 25 yr, the
      population with the best eyesight at age 20 had a lower increase in the need for
      corrective lenses than the population with visual acuity between 0.9 and 0.7 at
      age 20. These results suggest an increased risk of visual acuity loss in pilots
      over time as a result of the lower vision standards for student pilots in the
      JASDF.

PMID- 10332939
TI  - Degradation of visual pursuit during sustained +3 Gz acceleration.
AB  - BACKGROUND: During positive acceleration, there is a diminished flow of blood to
      all regions above the heart. This is manifested by the commonly described loss of
      peripheral vision, greyout and blackout, which have been investigated
      extensively. The ability to select appropriate scanning patterns and to
      efficiently process visual information is one of the important determinants of
      scan effectiveness. This study investigates the performance of the smooth pursuit
      system under sustained +3 Gz before any signs of loss of vision. METHODS: Eleven
      subjects with no known oculomotor and vestibular anomalies participated in the
      study. Horizontal and vertical pursuit at amplitudes of 10 and 20 degrees were
      investigated in each of the subjects over 4 separate days. During each test
      session, pursuit targets of a predictable sine wave, oscillating at 0.2, 0.4,
      0.8, 1.2 and 1.6 Hz were presented to the subjects in a random order. Horizontal
      and vertical eye movements were recorded using the El-Mar eye tracking system.
      The subjects were tested in 4 trials: 1) at 1 G before exposure to increased
      acceleration; 2) during sustained +3 Gz; 3) immediately after the +3 Gz exposure;
      and 4) 5 min after the +3 Gz exposure. RESULTS: Breakdown in smooth pursuit in
      response to horizontal and vertical sinusoidal stimuli during +3 Gz is indicated
      by a statistically significant decrease in gain and an increase in phase lag (p <
      0.01). This is most obvious when the stimulus frequency is greater than 0.4 Hz.
      Qualitatively, the pursuit response during acceleration was ataxic and
      disorganized in appearance. CONCLUSION: It is postulated that degradation of
      pursuit gain and phase could be due to central hypoxia, and that the increase of
      G loading on the vestibular system could affect the neural integration of the
      pursuit signal in the vestibular nuclei with its direct output to the oculomotor
      system.

PMID- 10332940
TI  - Electrical and contractile parameters of muscle in man: effects of 7-day "dry"
      water immersion.
AB  - HYPOTHESIS: The purpose of this experiment was to test the hypothesis that the
      changes in single muscle twitch tension (Pt) in a cosmonaut following exposure to
      long-duration microgravity may have been due to the sarcoplasmic reticulum, while
      the decrease in maximal voluntary contraction (MVC) relative to the electrically
      evoked maximal tetanic tension (Po) may reflect a reduction in control neural
      drive resulting from the voluntary muscle inactivity. METHODS: The effects of 7-d
      "dry" water immersion were investigated in six subjects. Changes of contraction
      properties were studied in the triceps surae muscle. RESULTS: After immersion,
      the MVC was reduced by 33.8% (p < 0.01), and the Po was reduced by 8.2% (p >
      0.05). The difference between Po and MVC expressed as a percentage of Po and
      referred to as force deficiency, has also been calculated. The force deficiency
      increased by a mean of 44.1% (p < 0.01) after immersion. The decrease in Po was
      associated with increased maximal rate of tension development (7.2%). The twitch
      time-to-peak was not significantly changed, and half-relaxation time was
      decreased by 5.3%. However, the Pt was not significantly changed and the Pt/Po
      ratio was decreased by 8.7% (p < 0.01) after immersion. The muscle surface action
      potential presented an increase of its duration (18.8%) and a decrease of the
      amplitude and the total area (14.6% and 2.8%; p < 0.05-0.01, respectively).
      CONCLUSION: The comparison of the electrical and mechanical alterations recorded
      during voluntary contractions, and in contractions evoked by electrical
      stimulation of the motor nerve, suggests that immersion not only modifies the
      peripheral processes associated with contraction, but also changes central and/or
      neural command of the contraction. At peripheral sites, it is proposed that the
      intracellular processes of contraction play the role in a contractile impairment
      recorded during immersion.

PMID- 10332941
TI  - Renal, endocrine, and cardiovascular responses during head-out water immersion in
      legless men.
AB  - BACKGROUND: The hydrostatic pressure gradient during head-out water immersion
      (HOI) causes a blood shift from the legs into the thoracic cavity to stretch the
      receptors in the cardiac atria and results in a diuresis in hydrated subjects.
      The present study was conducted to examine whether the HOI-induced diuresis and
      related circulatory and hormonal changes were attenuated in the subjects who had
      no legs (legless men). METHODS: Two legless men served as the subjects. They lost
      both legs 15 and 17 yr ago by accidents and were otherwise healthy. Six normal
      males participated as controls. The experimental protocol was consisted of a 1-h
      control, a 3-h HOI (water temperature, 34.5 degrees C) and a 1-h recovery.
      RESULTS: Average urine flow (0.6 ml x min(-1)), urinary excretion of sodium (90
      microeq x min(-1)), and osmolal clearance (1.4 ml x min(-1)) of the legless
      subjects increased in the first h of immersion to 0.7 ml x min(-1), 139 microeq x
      min(-1), and 1.8 ml x min(-1), respectively. These values remained elevated
      during HOI, however, the magnitude of the increase was smaller compared with the
      control subjects. Plasma arginine vasopressin was significantly (p < 0.05)
      decreased from 1.0+/-0.4 microU x 100 ml(-1) to 0.4+/-0.2 microU x 100 ml(-1)
      during HOI in the normal subjects, but was not in the legless subjects (from 0.5
      at control period to 0.4 microU x 100 ml(-1) during HOI). A concurrent reduction
      of aldosterone and plasma renin activity was observed with an increase in atrial
      natriuretic peptide during HOI in both subject groups, however, the magnitude of
      the changes was smaller in the legless subjects compared with the control
      subjects. Similarly, the average increase in cardiac output during HOI in the
      legless subjects (by 17%) was less compared with the control subjects (by 31%).
      CONCLUSION: The magnitude of renal, endocrine, and cardiovascular changes in
      response to HOI in the legless subjects were less than in control subjects, but
      the responses were qualitatively similar. Accordingly, we suggest that the
      cephalad blood expansion during immersion is not only due to translocation of
      blood from the legs but also the abdominal region.

PMID- 10332942
TI  - Cardiovascular effects of the breathhold used in determining pulmonary diffusing
      capacity.
AB  - BACKGROUND: The single-breath technique for determination of the diffusion
      capacity of the lung for CO (DlCO) requires a 10-s breathhold at total lung
      capacity. The assumption has been that this breathhold does not alter the
      components of DlCO, i.e., the diffusion capacity of the membrane (Dm) and the
      pulmonary capillary blood volume (Qc), and therefore measurement of these
      variables during breathhold represents these variables as they exist during
      normal breathing. The purpose of this study was to determine the effect of the 10
      s breathhold on cardiac output (Q) and Qc while supine and standing. The
      hypothesis was that the standing posture would have a greater influence on Q and
      Qc during the breathhold than would the supine posture. METHODS: Twelve male
      subjects participated. Q, stroke volume (SV), heart rate (HR), BP (MAP), and
      total peripheral resistance (TPR) were determined before and during the 10-s
      breathhold determination of DlCO, Qc, and Dm. RESULTS: Results while supine were
      compared with those while standing. DlCO was reduced on standing, due mainly to a
      reduction in Qc. SV and Q decreased significantly during the 10-s breathhold in
      both postures. Both SV and Q decreased more when standing (-53% and -49.5%,
      respectively) than when supine (-40.5% and -36.5%, respectively). Thus, the 10-s
      breathhold caused significant reductions in Q and therefore may alter the
      measurement of DlCO and Qc. CONCLUSIONS: The greater decline in Q during the
      measurement of DlCO when standing would suggest that the DlCO and Qc values while
      breathing might be underestimated in the upright posture.

PMID- 10332943
TI  - Improved high altitude hypoxic tolerance and amelioration of anorexia and
      hypophagia in rats on oral glutamate supplementation.
AB  - BACKGROUND: The objective of this study is to evaluate the efficacy of oral
      glutamic acid supplementation in promoting hypoxic tolerance. METHODS: The
      experiments were conducted in albino rats by exposing them to three levels of
      hypoxia in a simulated environment for varying periods of time. The parameters
      studied include: gasping time at 35,000 ft (10,668 m), food and water intake, and
      heart to body weight (b.w.) ratio at 25,000 ft (7620 m), tolerance to composite
      stress at 15,000 ft (4572 m) and biodistribution of glutamate (glu). RESULTS:
      Supplementation of Glu (27 mg x kg(-1) b.w.) as glutamic acid dissolved in normal
      saline resulted in 4.8 times enhanced hypoxic tolerance (time taken for
      appearance of first gasp), 23% body weight gain and 24% increase in food
      consumption over control during hypoxia. When animals were subjected to composite
      stress of cold, hypoxia and restraint (CHR), the Glu fed animals showed higher
      resistance to fall in rectal temperature than the control group. Hypoxia
      significantly enhanced heart to body weight ratio compared with control, and Glu
      supplementation reduced and brought it down to that of control. CONCLUSION: The
      study reveals that Glu in optimal doses may be a conditionally essential amino
      acid resulting in enhanced tolerance to hypoxia and cold.

PMID- 10332944
TI  - Wet bulb globe temperature (WBGT)--to what extent is GT essential?
AB  - BACKGROUND: Industrial and military safety personnel often require an easy, quick
      and accurate assessment of heat stress as a potential risk. The widely used WBGT
      index to evaluate heat stress is cumbersome and suited for a fixed site station
      rather than a mobile situation. Recently, a modified discomfort index (MDI)
      compiled from ambient temperature (Ta) and wet bulb temperature (Tw) was
      suggested to evaluate heat stress. HYPOTHESIS: Validation of the simple and easy
      to-operate MDI on an independent database can determine whether this index is
      able to serve as a reliable and valid alternative to WBGT. METHODS: Four separate
      database sets obtained from the Marine Corps Training Site on Parris Island, SC,
      served to validate this index. Hourly weather measurements were collected daily
      during 4 yr, representing a wide range of environmental conditions. RESULTS: The
      MDI validity was tested vs. the WBGT index. A highly significant correlation
      coefficient (r) greater than 0.95 (p < 0.001) was found in each of the four
      database sets. CONCLUSIONS: The simply constructed and user friendly MDI is
      easier to calculate and use than WBGT, and it has the potential to serve as an
      attractive alternative to the WBGT index in assessing heat stress.

PMID- 10332945
TI  - 5-HT3 receptor antagonists ameliorate emesis in the ferret evoked by neutron or
      proton radiation.
AB  - BACKGROUND: Nausea and vomiting produced by sub-lethal doses of X- or gamma-rays
      can be ameliorated by serotonin subtype-three (5-hydroxytryptamine; 5-HT3)
      receptor antagonists. The effectiveness of these anti-emetics on blocking the
      emetic responses induced by fission neutron or proton radiation exposure was
      evaluated in the ferret animal model. HYPOTHESIS: 5-HT3 receptor antagonists or
      bilateral vagotomy will ameliorate that emesis evoked by fission neutrons or
      protons. METHODS: Groups of ferrets were exposed to whole-body or head-shielded
      radiations of varying qualities: fission spectrum neutons, high-energy protons,
      or gamma-rays. Prior to that exposure, some groups were either vagotomized or
      received subcutaneous (s.c.) or oral (p.o.) treatment with various doses of the 5
      HT3 receptor antagonist antiemetics eusatron and ondansetron. RESULTS: We
      demonstrated that both eusatron and ondansetron effectively abolished the emesis
      normally induced by 2-Gy doses of either 60Co gamma or neutron:gamma, mixed-field
      irradiation, the latter with a neutron-to-total dose ratio (Dn/Dt) of 0.9+/-2%
      (%SD). Different routes of delivery of the anti-emetics yielded different degrees
      of inhibition of the emetic responses; p.o. treatment was less efficacious than
      s.c. treatment for the emesis to fission neutrons. Eusatron was significantly
      more effective than ondansetron on a mg x kg(-1) basis. Bilateral vagotomy also
      attenuated or abolished the emetic responses to the mixed-field neutron
      exposures. Furthermore, emesis induced by exposure to 2.5 Gy of 200-MeV protons
      was effectively abolished by ondansetron. CONCLUSION: These results are
      consistent with the concept that similar physiological and pharmacological
      mechanisms underlie the emetic responses to different qualities of radiation.

PMID- 10332946
TI  - Naps and modafinil as countermeasures for the effects of sleep deprivation on
      cognitive performance.
AB  - Disruptions in wake-sleep rhythms, particularly induced by sleep deprivation are
      limiting factors for military personnel in operations. The role of sleep and naps
      in the recovery of performance is generally accepted. Pharmacological aids, for
      example hypnotic or stimulant substances can also be effective countermeasures.
      Recently, a new stimulant compound, modafinil (MODIODAL) has also proven
      effective. Considering the excellent results obtained with napping and modafinil,
      we have studied the combined effect of these two countermeasures on psychomotor
      performance under conditions simulating an operational situation. Beneficial
      effects of a few hours' nap on performance were confirmed. Consequently naps
      should be encouraged, even if limited and diurnal. Modafinil, which combines
      wakening and stimulating properties without any known side effects, was useful
      for longer periods of sleep deprivation and when there was no real possibility of
      sleep recovery. Modafinil did not prevent sleep if sleep opportunities were
      available. The combination of naps and modafinil demonstrated the best cognitive
      performance during sleep deprivation.

PMID- 10332947
TI  - Influence of centrifugation and hindlimb suspension on testosterone and
      corticosterone excretion in rats.
AB  - BACKGROUND: Alterations in mass loading have been shown to stimulate the
      pituitary-gonadal and pituitary-adrenal axes resulting in changes in testosterone
      (T) and corticosterone (B) production which may account for the previously
      reported variations in muscle mass under these conditions. HYPOTHESIS:
      Centrifugation and hindlimb suspension will induce opposing effects on
      testosterone and corticosterone excretion. METHODS: Effects of mass loading
      (centrifugation at -2Gx) and unloading (hindlimb suspension, HLS) on excreted T
      and B levels, and testicular mass were examined in Sprague-Dawley rats. For 12 d,
      16 (8 controls and 8 centrifuged) rats and 20 (10 unsuspended controls and 10
      suspended) rats were studied during the centrifugation and suspension portions of
      the study, respectively. Following the completion of each study, testicular mass
      was measured. RESULTS: Absolute testicular mass was not different, following 12 d
      of centrifugation. Excreted T was elevated between days 1 and 6 of
      centrifugation. Excreted B levels were elevated for the first 4 d of
      centrifugation. Suspension reduced absolute and relative testicular mass.
      Excreted T levels were reduced from days 3-12 of suspension, while excreted B
      levels were only elevated on the first day of suspension. CONCLUSIONS:
      Centrifugation stimulated an increase in T excretion despite a lack of a change
      in absolute testicular mass. Conversely, suspension resulted in a reduction in T
      excretion which may have been associated with a decrease in absolute testicular
      mass. The centrifugation-induced increase in T excretion is consistent with
      previously reported increases in lean body mass following centrifugation, while
      the HLS-induced reduction in T excretion correlates with previously reported
      decreases in lean body mass following suspension.

PMID- 10332948
TI  - Particulates from PTFE degradation in terrestrial and microgravity.
AB  - It has recently been discovered that the ultrafine particles generated during
      polymer thermodegradation are a major health hazard, owing to their unique
      pathway of processing in the lung. This hazard in manned spacecraft is poorly
      understood because the particulate products of polymer thermodegradation are
      generated under low gravity conditions. Particulates generated from the
      degradation of polytetrafluoroethylene (PTFE), insulation coating for 20 AWG
      copper wire (representative of spacecraft application) under intense current
      overload, were studied in terrestrial gravity and microgravity. Microgravity
      tests were done in a 1.2-s drop tower at the Colorado School of Mines.
      Thermophoretic sampling was used for particulate collection. Transmission
      electron microscopy (TEM) was used to examine the smoke particulates. The
      pigmentation of PTFE insulation seems to have an overwhelming effect on size,
      shape and morphology of the particulate. Nanometer-sized particles were found in
      all cases, but their extent of aggregation and size distribution were dependent
      on both PTFE pigmentation and gravity; higher aggregation occurred in low
      gravity. Four different color insulations (viz. white, black, red and yellow)
      were studied.

PMID- 10332949
TI  - Myogenin, MyoD, and myosin heavy chain isoform expression following hindlimb
      suspension.
AB  - BACKGROUND: Myogenin expression is associated with a slow myofiber phenotype, and
      MyoD expression is associated with a fast myofiber phenotype. Hindlimb suspension
      (HS) will induce muscular atrophy, and a transition from a slow to fast myofiber
      phenotype in the rat soleus. HYPOTHESIS: Hindlimb suspension will induce myofiber
      atrophy, and a slow to fast myofiber type transition with corresponding changes
      in myogenin and MyoD expression. METHODS: Myofiber phenotype was evaluated by
      electrophoretically separating the myosin heavy chain isoforms. Myogenin
      expression was evaluated by Northern analysis, while MyoD expression was
      evaluated by Northern analysis and semiquantitative RT-PCR. RESULT: After 28 d of
      hindlimb suspension, there was significantly (p < 0.05) less myosin heavy chain
      Type IIA, and more (p < 0.05) myosin heavy chain Type IIX in the soleus muscles
      of hindlimb suspended rats compared with soleus muscles from weight-bearing (WB)
      rats. Although there was a shift to a faster myosin heavy chain phenotype in
      soleus muscles from hindlimb suspended rats, there was no change in myogenin
      expression, and MyoD expression was undetectable by Northern analysis. Semi
      quantitative RT-PCR revealed an up-regulation of MyoD expression following 14 d
      of hindlimb suspension. CONCLUSIONS: Myogenin expression levels do not change
      during the slow to fast myofiber phenotypic transition that occurs during
      hindlimb suspension; MyoD expression appears to increase at the same time as the
      phenotypic transition. Thus, MyoD expression or the Myogenin: MyoD mRNA ratio may
      be important in the phenotypic transition. Neither myogenin nor MyoD appear to
      play a critical role in the muscular atrophy that occurs during weightlessness.

PMID- 10332950
TI  - Outcome after treatment of neurological decompression illness is predicted by a
      published clinical scoring system.
AB  - BACKGROUND: After recompression therapy, some cases of neurological decompression
      illness (DCI) have a significant residual deficit. Boussuges et al. report a
      scoring system to predict sequelae using weighted historical and clinical indices
      at presentation which we applied to the British Hyperbaric Association (BHA)
      database of UK diving accidents, held at the Institute of Naval Medicine (INM).
      METHODS: A database search identified 234 cases of neurological DCI from the 2
      yr, 1995-6. Of these, 217 case records contained sufficient data to apply the
      scoring system. Outcome was classified as severe sequelae (i.e., causing a
      functionally important deficit) or as mild/no sequelae. RESULTS: The median score
      in UK cases with severe sequelae was 13 (95% C.I. 11.5 to 14.5) and in cases with
      mild/no sequelae, 6 (95% C.I. 5.5 to 6.5). Significantly more cases with scores >
      7 had severe sequelae than cases with scores < or = 7 (chi2, p < 0.0001). The
      sensitivity of a score > 7 (for severe sequelae) was 94% and the specificity was
      65%. The positive predictive value of a score > 7 (for severe sequelae) was 18%
      and the negative predictive value of a score < or = 7 was 99%. CONCLUSIONS: When
      applied to the INM/BHA database a score of > 7 by this scoring system has a
      higher sensitivity and lower specificity for severe sequelae than reported by
      Boussuges et al. It has a higher predictive accuracy for successful outcome of
      treatment (99% vs. 89%) but a much lower predictive value for severe sequelae
      (18% vs. 86%). Convergence between this and other published scoring systems may
      allow derivation of a generic scoring system that could then be evaluated
      prospectively in multiple centers.

PMID- 10332951
TI  - Self-generated lower body negative pressure exercise.
AB  - BACKGROUND: Exercise during spaceflight helps prevent musculoskeletal and
      cardiovascular deconditioning to Earth gravity. This report evaluates the aerobic
      and anaerobic exercise stimulus provided by self-generated lower body negative
      pressure. METHODS: A lower body negative pressure cylinder expands and collapses
      longitudinally, but not radially. As the legs push footward to expand the
      cylinder, the air pressure in the cylinder decreases, increasing the force
      required to continue expanding the cylinder. In addition, valves control air flow
      into and out of the cylinder, and thus workload. In seven supine subjects, knee
      bend exercise was performed at 19 cycles per minute for 6 min. Footward force was
      measured with load cells, cylinder pressure with a transducer, heart rate from
      ECG, and oxygen consumption with turbine volumetry and gas analysis. RESULTS:
      Maximum footward force at the peak of the exercise cycle averaged 1120+/-88 N
      (114+/-9 kg), and pressure within the cylinder concomitantly decreased 26+/-3
      mmHg below ambient. Heart rate and oxygen consumption increased 75+/-4 bpm and
      26.3+/-1.4 ml O2/kg x min(-1) from supine resting values, respectively.
      CONCLUSIONS: With the air inlet valve nearly closed, exercise with this device
      approximates a resistance-type leg press. With more inflow of air, more rapid,
      aerobic knee bends can be performed. This exercise device/concept provides
      simultaneous dynamic musculoskeletal and cardiovascular stresses without an
      external power source.

PMID- 10332952
TI  - A first episode of syncope in a veteran pilot: a case report.

PMID- 10332953
TI  - On-board defibrillators.

PMID- 10332954
TI  - Pregnancy and in-flight cosmic radiation.

PMID- 10332955
TI  - Back pain in helicopter pilots.

PMID- 10332956
TI  - Comparative genomic hybridization: FISH and chips in our future?

PMID- 10332957
TI  - Comments on an article by Roy et al. (Teratology 58:62-68, 1998)

PMID- 10332958
TI  - Screening of human placentas for chromosomal mosaicism using comparative genomic
      hybridization.
AB  - Detection of confined placental mosaicism (CPM) in term placental tissues is
      usually accomplished by conventional cytogenetic analysis of cultured chorionic
      stroma and direct preparations from trophoblast or, more recently, by
      fluorescence in situ hybridization (FISH) on interphase nuclei. In this study, we
      describe the use of comparative genomic hybridization (CGH) for detection of
      chromosomal aneuploidy in term placentas and evaluate the sensitivity of this
      novel approach for CPM diagnosis in multiple placental samples acquired from five
      pregnancies prenatally diagnosed with CPM7 and CPM16. Each sample of placental
      villi was separated enzymatically into trophoblast and chorionic stroma, and the
      level of aneuploidy (three signals/nuclei) in each tissue was determined by FISH
      analysis, using centromeric DNA probes specific for chromosome 7 (D7Z1/Z2) or 16
      (D16Z2). Aneuploidy levels ranged from 5.2-96.1% in the 11 tissues with CPM7 and
      9.8-93% in the 29 tissues with CPM16. Subsequently, CGH analysis of DNA from the
      trophoblast and chorionic stroma of the same tissue sites detected the trisomic
      clone in all placental tissues with aneuploidy (16%, as determined by FISH
      analysis). Our results demonstrate the sensitivity of CGH analysis for detection
      of chromosomal aneuploidy mosaicism and support our contention that the CGH
      technique is the most effective cytogenetic method for screening term placentas
      for the presence of CPM.

PMID- 10332960
TI  - Morning stiffness: sharpening an old saw?

PMID- 10332959
TI  - Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural
      tube defect population.
AB  - Neural tube defects (NTDs) are a common birth defect, seen in approximately
      1/1,000 births in the United States. NTDs are considered a complex trait where
      several genes, interacting with environmental factors, create the phenotype.
      Using a Midwestern NTD population consisting of probands, parents, and siblings
      from Iowa, Minnesota, and Nebraska, we analyzed a range of candidate genes,
      including 5,10-methylenetetrahydrofolate reductase (MTHFR), folate receptors
      alpha (FOLR1; hereafter abbreviated "FR-alpha") and -beta (FOLR2; hereafter, "FR
      beta"), methionine synthase (hereinafter, "MS"), T, the human homolog of the
      murine Brachyury gene, and the paired-box homeotic gene 3 (PAX3), for association
      with NTDs. We were unable to demonstrate an association using a previously
      described Ala-->Val mutation in MTHFR and the majority of our NTD populations.
      However, we discovered a silent polymorphism in exon 6 of MTHFR which conserved a
      serine residue and which showed significant association with NTDs in our Iowa
      population. Analysis of exon 7 of MTHFR then demonstrated an Ala-->Glu mutation
      which was significantly associated with our Iowa NTD population; however, we
      could not replicate this result either in a combined Minnesota/ Nebraska or in a
      California NTD population. Using polymorphic markers for MS, FR-beta, T, and
      PAX3, we were unable to demonstrate linkage disequilibrium with our NTD
      populations. A mutation search of FR-alpha revealed one proband with a de novo
      silent mutation of the stop codon. This work provides a new panel of genetic
      variants for studies of folate metabolism and supports, in some NTD populations,
      an association between MTHFR and NTDs.

PMID- 10332961
TI  - Epidemiology versus outcome. The silicone breast implant controversy.

PMID- 10332962
TI  - Silicone breast implants: the saga continues.

PMID- 10332963
TI  - Generic health instruments, visual analog scales, and the measurement of clinical
      phenomena.

PMID- 10332965
TI  - Ligation of CD40 induced tumor necrosis factor-alpha in rheumatoid arthritis: a
      novel mechanism of activation of synoviocytes.
AB  - OBJECTIVE: To determine the immunopathological significance of CD40/CD40 ligand
      (CD40L) interaction in rheumatoid arthritis (RA). METHODS: The expression of CD40
      ligand (CD40L) in synovial tissues (ST) from patients with RA was examined by
      immunohistochemistry. Tumor necrosis factor-alpha (TNF-alpha) was measured by
      ELISA. Expression of CD40 on ST cells was quantified by anti-CD40 monoclonal
      antibodies and 125I labelled anti-mouse IgG. RESULTS: Immunohistochemistry showed
      CD40L+ T cells in RA ST. Ligation of CD40 on RA ST cells significantly increased
      the production of TNF-alpha in a dose dependent fashion. Adherent, but not non
      adherent, fraction of ST cells responded to ligation of CD40 to produce TNF
      alpha. Interferon-gamma (IFN-gamma), interleukin 4 (IL-4), or IL-13 acted
      synergistically with CD40 ligation to enhance TNF-alpha production by ST cells.
      IL-10 exerted inhibitory effects on both CD40 ligation induced and CD40 ligation
      plus IFN-gamma induced TNF-alpha production by ST cells. CONCLUSION: These data
      indicate activated T cells participate in synovial inflammation of RA via CD40L
      to stimulate the production of TNF-alpha by ST cells. The effect of CD40 ligation
      is modulated by the presence of several cytokines, e.g., IFN-gamma, IL-4, IL-10,
      and IL-13.

PMID- 10332964
TI  - HLA-DRB1 genotype influences risk for and severity of rheumatoid arthritis.
AB  - OBJECTIVE: To examine how HLA-DRB1 genotypes influence rheumatoid arthritis (RA)
      risk and clinical severity. METHODS: We performed polymerase chain reaction based
      DRB1 and tumor necrosis factor (TNF) genotyping of 309 Caucasian RA and 283
      Caucasian control subjects. For risk analyses, we grouped the DRB1 alleles
      encoding each specific shared epitope: *0401 alone, *0404 with *0102, *0405 with
      *0408 and *0101, and *1001 alone. For estimates of RA outcome, we retrospectively
      obtained data regarding ARA classification criteria, age of disease onset and
      disease duration, number of slow acting antirheumatic drugs (SAARD) used, and
      rheumatoid factor (RF). RESULTS: Homozygous shared-epitope DRB1 genotypes,
      compound heterozygous genotypes, and simple heterozygous genotypes all conferred
      elevated relative risk (RR) for RA (RR 4.3, 11.7, and 3.5, respectively).
      However, compound heterozygous genotypes conferred more risk than either simple
      heterozygous genotype (RR 3.3, p = 0.004) or homozygous genotype (RR 2.8, p =
      0.036). There was a trend toward more compound heterozygous genotypes in the male
      RA group than in the female RA group (p < 0.1), and male sex was associated with
      higher frequency of rheumatoid nodules (56 vs 35% for female RA). RA outcome was
      estimated by number of SAARD used; mean SAARD used was higher in male than in
      female RA (p < 0.01) and higher in genotypes containing one or 2 shared epitope
      DRB1 alleles than in those negative for shared epitope DRB1 alleles (p < 0.05).
      Analyses also suggested that shared epitope DRB1 genotype significantly
      influenced the occurrence of seropositive RA. Seropositive RA fraction was
      related to either number of shared epitope alleles (0, 1, or 2) represented in
      the DRB1 genotype, or, alternatively, to the combination of sex with shared
      epitope DRB1 genotype. The presence of one or 2 shared epitope DRB alleles
      influenced the occurrence of high titer seropositive RA as defined by sheep cell
      agglutination test (p < 0.01). TNFab microsatellite markers and TNF promoter
      polymorphisms did not influence SAARD number, seropositive RA, or high titer
      seropositive RA. CONCLUSION: Not all shared epitope DRB1 genotypes conferred the
      same relative risk, and the male RA group tended to have more compound
      heterozygous genotypes and more severe RA as indicated by rheumatoid nodules and
      SAARD usage. DRB1 genotypes with one or 2 shared epitope DRB1 alleles influenced
      the RA outcome as estimated by numbers of SAARD used and RF.

PMID- 10332966
TI  - Arachidonate 15-lipoxygenase of reticulocyte-type in human rheumatoid arthritis
      type B synoviocytes and modulation of its activity by proinflammatory cytokines.
AB  - OBJECTIVE: Lipoxygenases (LOX) are lipid-peroxidating enzymes that are implicated
      in the pathogenesis of a variety of inflammatory disorders such as arthritis,
      psoriasis, and asthma. 15-LOX catalyzes the oxygenation of free arachidonic acid
      to 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid (15-HPETE), which is reduced to
      15-hydroxyeicosatetraenoic acid (15-HETE). The biological role of 15-HETE is less
      clear. We sought to determine if cultured human rheumatoid synovial cells were
      able to express 15-LOX mRNA, leading to the synthesis of 15-HETE, and to examine
      the effect of different cytokines on 15-LOX activity. METHODS: Adherent synovial
      cells were obtained by enzymatic digestion of rheumatoid synovium, isolated from
      patients with rheumatoid arthritis (RA) undergoing hip synovectomy. Between
      passages 4 and 8, reticulocyte-type 15-LOX expression in these cells was
      determined by reverse transcription-polymerase chain reaction (RT-PCR) in situ
      and confirmed by classical RT-PCR analysis followed by enzymatic digestion. The
      PCR fragment was purified, amplified, and sequenced. Cultured synovial cells were
      incubated with or without different cytokines and exogenous [1-(14)C] arachidonic
      acid metabolism of synoviocytes was analyzed by reverse phase high performance
      liquid chromatography (RP-HPLC). RESULTS: RT-PCR results showed that human RA
      type B synoviocytes expressed a reticulocyte-type 15-LOX. By sequence analysis,
      the PCR fragment (474 bp) was determined to be 100% identical to that of
      reticulocyte-type 15-LOX cDNA. Other results associated specific inflammatory
      cytokines with the activity of 15-LOX in these cells. RP-HPLC analysis showed
      that interleukin 4 (IL-4) increased 15-HETE production (2.4-fold); we also
      observed an increase in 15-HETE production (1.2-fold) after incubation of the
      cells with IL-1beta. CONCLUSION: Human RA type B synoviocytes are able to express
      15-LOX mRNA leading to the synthesis of 15-HETE, which is modulated by various
      cytokines that play a major role in the pathophysiology of RA, especially IL-4
      and IL-1.

PMID- 10332967
TI  - Defining morning stiffness in rheumatoid arthritis.
AB  - OBJECTIVE: Morning stiffness is a common and clinically important symptom in
      patients with rheumatoid arthritis (RA); however, it has not performed well as a
      classification criterion, perhaps due to poor definition. This qualitative study
      was carried out to identify the characteristics of morning stiffness through the
      self-reports of patients with RA in order to develop a new patient centered
      definition. METHODS: Personal interviews with 24 patients with RA were analyzed
      independently by 2 reviewers using a grounded theory approach. A mail-out
      questionnaire was used to validate the information summarized from the
      interviews. RESULTS: These findings resulted in the following definition of
      morning stiffness in RA: slowness or difficulty moving the joints when getting
      out of bed or after staying in one position too long, which involves both sides
      of the body and gets better with movement. CONCLUSION: This new patient centered
      definition of morning stiffness may allow more precise classification of patients
      with RA.

PMID- 10332968
TI  - Behavioral coping and physical functioning: the effect of adjusting the level of
      activity on observed dexterity.
AB  - OBJECTIVE: To assess the relationship between behavioral coping and dexterity in
      rheumatoid arthritis (RA) after controlling for disease activity, impairment of
      the hands, and pain. METHODS: A random sample of 109 patients with RA was
      assessed twice within one year. Dexterity, disease activity, and impairment of
      the hands were measured using observational methods. Pain and coping with RA were
      assessed using self-report instruments. RESULTS: Correlational findings showed
      that "decreasing activity" to cope with pain was negatively related to dexterity.
      "Pacing" as a way of coping with limitations was positively related to dexterity.
      Both relations were significant after controlling for duration of disease,
      impairment of hands, disease activity, and pain. "Decreasing activity" as a way
      of coping with pain was related to a decrease in dexterity in the subsequent
      year, after controlling for baseline measurements of dexterity, impairment, and
      disease activity as well as measurements of current disease activity and pain.
      "Pacing" as a way of coping with limitations was unrelated to subsequent changes
      in dexterity, after controlling for the above mentioned variables. CONCLUSION:
      Behaviorial coping is related to current and subsequent levels of dexterity.
      Therefore, it is concluded that more attention should be given to behaviorial
      coping in both research and clinical practice.

PMID- 10332969
TI  - Self-administered joint counts and standard joint counts in the assessment of
      rheumatoid arthritis. MIRA Trial Group. Minocycline in RA.
AB  - OBJECTIVE: To determine the comparability of a text to a mannequin format for the
      assessment of joint counts (JC) among patients with rheumatoid arthritis (RA)
      participating in a randomized clinical trial (RCT). METHODS: A subgroup of
      patients participating in the MIRA (Minocycline in RA) RCT completed self
      administered JC and joint scores (JS), which were compared to those of a trained
      assessor. RESULTS: JC and JS data were consistently higher for the patient than
      for the assessor. Higher correlations were obtained for JC than for JS.
      CONCLUSION: Our data suggest JC can be used in the context of clinical trials or
      in the clinical setting, but are not interchangeable with trained assessor JC.

PMID- 10332970
TI  - Predicting the short term direct medical costs incurred by patients with
      rheumatoid arthritis.
AB  - OBJECTIVE: With increasing interest in revising the mechanisms of health care
      funding, the ability to anticipate patients' medical expenditures as well as to
      identify potentially modifiable predictors would be informative for health care
      providers, payers, and policy makers. METHODS: Eight hundred fifty-eight patients
      with rheumatoid arthritis from 2 Canadian centers reported semi-annually on their
      health services utilization and health status for up to 12 years. Annual direct
      costs were calculated using 1994 Canadian prices. Regression models for the
      variation in total direct costs and the individual resource components (i.e.,
      physicians, tests, medications, acute and non-acute hospital care) were estimated
      using previous values of age, sex, disease duration, education, methotrexate
      availability, employment status, global well being, pain, duration of morning
      stiffness, and functional disability as predictor variables. The models were
      developed using all available data except the last 2 observations (i.e., data
      collected on the last 2 self-report questionnaires) from each patient, which were
      reserved for model validation. The predictive abilities of the models were
      assessed by comparing the most recent costs with those predicted by the model
      using values of the predictor variables from the previous time period. Further,
      to assess whether the models conferred any advantage over cost estimates based
      only on previous costs, most recent observed costs were also compared with costs
      observed in the preceding time period. RESULTS: Self-reported indices of either
      global well being, pain, or functional disability predicted total direct costs as
      well as the costs of the 5 individual resource components. Being younger, female,
      disabled from the work force, having shorter disease duration, and receiving more
      formal education also predicted higher costs in at least on health resource
      category. However, being older predicted higher acute and non-acute care hospital
      costs. Regression models incorporating longitudinal data did not perform better
      than average costs in the preceding time period in predicting future short term
      costs. CONCLUSION: Global well being, pain, functional disability, and previous
      costs are the most important predictors of short term direct medical costs.
      Although we have demonstrated that regression models do not perform better than
      previous costs in predicting future short term costs, previous costs are a much
      less informative predictor than health status variables. Variables such as
      functional disability and pain identify potentially modifiable disease features
      and suggest interventions that may improve patient well being and reduce costs.

PMID- 10332971
TI  - Longterm outcome of total joint arthroplasty in nonambulatory patients with
      rheumatoid arthritis.
AB  - OBJECTIVE: To assess the outcome of minimum 10 year followup of total joint
      arthroplasty (TJA) in nonambulatory patients with rheumatoid arthritis (RA).
      METHODS: TJA was performed in 40 nonambulatory patients with RA who satisfied the
      following criteria: (1) strong motivation; (2) good relationship with our medical
      staff; (3) no marked cervical cord lesion: (4) absence of severe systemic
      complications. These included 38 women and 2 men whose average age at the
      initiation of TJA was 58.8 years. The duration of time between loss of walking
      ability and surgery was 2 months to 5 years. Average hospitalization time was 4.5
      months. Followup after the last surgery was 10 to 18 years. RESULTS: One year
      after the last surgery, 28 of the 40 patients could walk outdoors again, 11
      indoors, and one was still unable to walk. By 5 years after surgery, 9 patients
      had died of diseases unrelated to surgery. Of the remaining 31 patients, 19 could
      walk outdoors, 10 indoors, and 2 could not walk. Deterioration of walking was
      observed in 13 patients (41.9%) compared with one year after surgery. By 10 years
      after surgery, 32 patients had died of diseases unrelated to surgery, 4 could
      walk outdoors, 4 indoors. Of these, 4 patients (50%) had worsened in walking
      ability compared with one or 5 years after surgery. Major complications of TJA
      were observed in 12 patients. These were femoral neck fractures in 3,
      supracondylar femoral fractures in 3, loosening of the acetabulum socket in 4,
      loosening of the femoral hip prosthesis in 2. CONCLUSION: TJA should be a useful
      treatment for restoration of walking in nonambulatory patients with RA. However,
      even after TJA, walking ability deteriorated in about half of the patients as the
      duration of followup observations exceeded 5 years.

PMID- 10332972
TI  - A platelet activating factor receptor antagonist prevents the development of
      chronic arthritis in mice.
AB  - OBJECTIVE: To examine the effect of treatment with the platelet activating factor
      (PAF) receptor antagonist BN 50730 on the clinical and morphological evolution of
      collagen induced arthritis in mice. METHODS: Mice with collagen induced arthritis
      were treated with BN 50730 (0.3, 1, 3 mg/kg) or vehicle (0.1% Tween-20 in saline)
      once a day, from 3 days before the induction of the arthritis to 70 days after.
      Disease evolution was followed daily by inspection of inflammatory signs and
      measurement of the knee joint diameter on Days 0, 40, and 70. At the end of the
      treatment period, the morphological evaluation of the synovial membrane, the
      immunodetection of fibronectin, and the content of cartilage proteoglycans were
      studied. RESULTS: On Day 40, mice receiving the highest dose of BN 50730 (3
      mg/kg) showed a reduction in the knee joint diameter in comparison with untreated
      (2.1 +/- 0.2 vs 2.8 +/- 0.4 mm, p < 0.01). On Day 70, animals receiving 1 and 3
      mg/kg had a normal knee diameter, while it remained enlarged in the untreated
      ones. In BN 50730 treated mice (3 mg/kg) we also observed a significant reduction
      of the inflammation score (0.1 +/- 0.1 vs 2.5 +/- 0.2 in the untreated) and
      deposition of fibronectin. Depletion of cartilage proteoglycans was also reversed
      with BN 50730. CONCLUSION: The beneficial effects in this model of joint injury
      after administration of the PAF antagonist BN 50730 suggest that PAF could be
      implicated in the pathogenesis of chronic arthritis.

PMID- 10332973
TI  - Anti-corpus luteum antibody: a novel serological marker for ovarian dysfunction
      in systemic lupus erythematosus?
AB  - OBJECTIVE: To investigate the presence of autoantibodies directed to corpus
      luteum (CoL) in systemic lupus erythematosus (SLE) sera and its correlation with
      menstrual disturbances. METHODS: We evaluated 87 female patients with SLE, < 40
      years old, and 23 women with normal menses as controls. Anti-corpus luteum
      antibody was detected by immunoblot technique. RESULTS: Reactivity to a bovine
      CoL antigen was found in 22% of SLE sera. Characterization of the target antigen
      revealed a 67 kDa glycoprotein highly enriched in corpus luteum, but nearly
      absent in total ovary extract. Similarly, target antigen was also weakly
      detectable in tissues that produce or metabolize steroids, such as testis,
      adrenal cortex, and liver, and it was absent in adrenal medulla or HEp-2 cells.
      Anti-CoL antibody was easily distinguished from other frequent reactivities of
      SLE sera, including anti-RNP, anti-Sm, anti-Ro/La, anti-dsDNA, or
      anticardiolipin. The observation of anti-67 kDa reactivity to human CoL suggests
      a possible pathogenic role in gonadal dysfunction. Indeed, we observed an inverse
      association of anti-CoL antibody with the duration of hypergonadotropic
      amenorrhea. Supporting this hypothesis, in patients with normal or irregular
      menses, the presence of this antibody was associated with elevated serum level of
      follicle stimulating hormone, an early and specific sign of ovarian lesion.
      CONCLUSION: Anti-CoL antibody seems to be associated with early stages of ovarian
      dysfunction in SLE. Moreover, since similar association of antiovarian antibodies
      has been observed in an experimental model of autoimmune oophoritis, our findings
      raise the possibility of autoimmune ovarian lesion in patients with SLE.

PMID- 10332974
TI  - Incidence of inflammatory myopathies in Victoria, Australia, and evidence of
      spatial clustering.
AB  - OBJECTIVE: To determine the incidence of idiopathic inflammatory myopathies (IIM)
      in Victoria, Australia, and look for evidence of space-time or spatial
      clustering. METHODS: Cases of IIM diagnosed between 1989 and 1991 were identified
      by muscle biopsy and hospital discharge diagnosis review. Diagnosis was verified
      by medical record review and included if Bohan and Peter criteria for definite or
      probable disease were met. The pair-wise Euclidean distances between cases'
      residences were computed using grid references, and temporal distances were
      calculated between biopsy dates. The Mantel test for space-time clustering was
      computed. Each patient was also characterized by statistical local area (SLA)
      according to place of residence. For each SLA, the expected annual incidence of
      IIM was calculated, based upon its population distribution, and these were
      compared to the observed annual incidence. Confidence intervals for the true rate
      ratio (RR) for each SLA were calculated assuming a Poisson distribution, and the
      level of heterogeneity in the data was examined by calculation of a chi-squared
      for homogeneity. RESULTS: Ninety-four cases met inclusion criteria for an annual
      incidence of 7.4 (95% CI 6.0-9.0) per million person-years. No space-time
      clustering was found (z = -0.434, p = 0.665), but there was evidence of spatial
      clustering. A total of 67 observed cases were distributed among 58 urban SLA.
      Four SLA had a greater than expected incidence of myositis (95% Poisson based CI
      excluded 1), accounting for 20 of the observed cases. CONCLUSION: The incidence
      of IIM in Australia is higher than most previous population based estimates. The
      finding of spatial clustering supports the hypothesis that environmental factors
      may be important in the pathogenesis of these diseases.

PMID- 10332975
TI  - T cell receptor repertoire in B cell lymphoproliferative lesions in primary
      Sjogren's syndrome.
AB  - OBJECTIVE: Studies have analyzed T cell receptor (TCR)-Vbeta in benign, minor
      salivary or lacrimal gland, or kidney lesions in Sjogren's syndrome (SS). We
      investigated SS related lymphoproliferative lesions. METHODS: By "family" reverse
      transcriptase polymerase chain reaction, we studied the expression of 20
      different TCR-Vbeta families in parotid lymphoproliferative lesions and
      peripheral blood lymphocytes (PBL) from 7 patients with primary SS, in PBL from 6
      primary SS patients with no associated lymphoproliferative disorder, and in
      activated PBL from 2 healthy controls. T cell clonal expansion was investigated
      in 10 Vbeta families (i.e., the most expanded ones and those previously
      implicated in SS pathogenesis) by single strand conformation polymorphism (SSCP)
      analysis. Frozen sections from parotid gland specimens were tested by
      immunohistochemistry for the expansion of selected Vbeta families. Viral
      infection within the parotid lesions and serum autoantibody response were also
      studied. RESULTS: An unrestricted Vbeta pattern was observed. The most widely
      expressed Vbeta family in parotid lesions was Vbeta2, and Vbeta
      immunohistochemistry results were concordant with Vbeta mRNA findings. A similar
      pattern was observed in PBL, although the Vbeta2 family was expressed at lower
      levels. The parotid/PBL ratio was occasionally > 1.8-2.0 (indicative of local
      Vbeta overexpression) in different Vbeta families. T cell expansion proved to be
      largely polyclonal by SSCP analysis, and scattered T cell clonotypes were
      detected within different Vbeta families, with a different pattern from patient
      to patient. CONCLUSION: Our observations in SS related lymphoproliferative
      lesions largely reflect previous evidence in fully benign lesions. The
      pathogenetic events involved in autoimmune benign lesions in SS may then persist
      and play a role in SS related lymphoproliferative disorders. The link between the
      observed TCR-Vbeta repertoire and specific local triggering (auto)antigens
      remains to be elucidated.

PMID- 10332976
TI  - The -308.1 polymorphism in the promoter region of the tumor necrosis factor gene
      is associated with ankylosing spondylitis independent of HLA-B27.
AB  - OBJECTIVE: To investigate the allele frequencies of 6 polymorphic sites spanning
      the region of the genome close to the tumor necrosis factor (TNF) gene in a group
      of HLA-B27 positive patients with ankylosing spondylitis (AS) in the West of
      Scotland. METHODS: One hundred sixty-seven patients with AS, 93 healthy controls,
      and 88 HLA-B27 positive healthy controls, all from the West of Scotland, were
      typed by polymerase chain reaction (PCR) for 3 restriction fragment length
      polymorphisms (RFLP) and 3 microsatellite polymorphic sites spanning the TNF gene
      cluster. The distribution of these alleles was correlated with the presence of
      extraspinal manifestations such as peripheral joint disease and uveitis. RESULTS:
      The frequency of the Nco-1.2 allele was significantly reduced in patients
      compared to the genetically unselected control population (p < 0.05), but was no
      different from the HLA-B27 positive controls. However, the -308.1 allele was
      significantly increased in the patients compared to the HLA-B27 positive controls
      (p < 0.03). CONCLUSION: This study confirms the importance of correct matching in
      genetic analysis in disease association studies, and provides further evidence
      supporting the involvement of genes other than the MHC class I locus in the
      pathogenesis and features of AS.

PMID- 10332977
TI  - Predominance of CD8+ T lymphocytes in psoriatic arthritis.
AB  - OBJECTIVE: To characterize the synovial fluid (SF) derived T cell populations in
      psoriatic arthritis (PsA) and compare with similar populations from rheumatoid
      arthritis (RA). METHODS: Paired peripheral blood (PB) and SF samples were
      analyzed by 3 color flow cytometry using monoclonal antibodies to CD3, CD4, CD8,
      HLA-DR, CD25, CD45RA, and CD45RO. RESULTS: There was a significantly increased
      CD8+ T cell population in PsA SF compared to RA: PsA mean 61% (range 35-93), RA
      mean 46% (range 6-72) (p < 0.005). This resulted in a reversal of the CD4:CD8
      ratio in PsA SF compared to RA SF (p < 0.001). Patients with oligoarticular PsA
      had the most pronounced differences in SF derived T cell populations compared to
      RA (p < 0.0005) but these results were not significantly different from PsA
      patients with a polyarticular disease pattern. PB PsA T cell populations were not
      different from controls, in contrast to RA, where the CD4+ T cell population was
      increased (p < 0.0026), giving an exaggerated PB CD4:CD8 ratio. The majority of
      PsA SF CD8+ T cells expressed CD45RO, mean 73% (range 58-95), and HLA-DR antigen:
      mean 72% (range 38-94). Low levels of CD25 were detectable in this population,
      indicating a nonclassical activation pattern: mean 2% (range 0.3-4.4).
      CONCLUSION: In PsA, activated (HLA-DR+) and mature (CD45RO+) CD8+ T cells
      predominate in SE Analysis of this population may uncover clues to pathogenesis
      in this HLA class I mediated disease.

PMID- 10332978
TI  - The "distal-dorsal difference" as a possible predictor of secondary Raynaud's
      phenomenon.
AB  - OBJECTIVE: To investigate the possibility that a hand distal-dorsal difference in
      temperature of greater than 1 degree C (fingers colder than the dorsum) at a room
      temperature of 30 degrees C is a good predictor of secondary Raynaud's phenomenon
      (RP). METHODS: We imaged the hands of patients with primary Raynaud's phenomenon
      (PRP) and systemic sclerosis (SSc) using a thermal camera at room temperatures of
      23 and 30 degrees C. From these images we measured the distal-dorsal difference
      in temperature for all fingers excluding the thumbs. At a room temperature of 23
      degrees C we also performed a cold challenge test using water at 15 degrees C for
      1 min and thermally imaged the rewarming process for 15 min. Several variables
      were derived from the rewarming curve. The procedure was repeated within 3 days
      to assess reproducibility. RESULTS: The best discriminator between PRP and SSc
      was found to be a distal-dorsal difference of > 1 degree C at 30 degrees C (p =
      0.005). There is reasonable reproducibility when considering groups of patients.
      However, the intra-subject standard deviations were large, indicating that
      measurements for the same patient on separate visits may vary considerably.
      CONCLUSION: Our results suggest that the finding of a distal-dorsal difference of
      > 1 degree C (cold fingers) at 30 degrees C in a patient with RP is specific for
      underlying connective tissue disease.

PMID- 10332979
TI  - Validity of American College of Rheumatology criteria for diagnosing hip
      osteoarthritis in primary care research.
AB  - OBJECTIVE: To study the validity of the American College of Rheumatology (ACR)
      criteria for hip osteoarthritis (OA) in patients receiving primary care. Three
      different sets of criteria are available, one with clinical symptoms only, and 2
      with clinical symptoms and radiological signs combined. It is claimed that all 3
      sets, separate from each other, can be used to diagnose hip OA for research
      purposes. METHODS: Consecutive patients (n = 227) aged 50 years or older, who had
      consulted a general practitioner for pain in the hip and had been referred for
      radiographic investigation of the hip, were recruited for a standardized history
      taking and physical investigation. The radiographs were evaluated according to a
      standardized protocol. The cross validity of the 3 different sets of ACR criteria
      was assessed by calculating the percentage agreement and the kappa between the
      separate sets. RESULTS: There was poor agreement between the set of clinical
      criteria and the 2 sets in which radiological signs were included (kappa 0.11 or
      lower). The 2 sets that included radiological signs showed high agreement (kappa
      0.81-0.94, depending on cut off points for joint space narrowing). These sets
      also showed the highest agreement with the radiological OA defined as a Kellgren
      score 2 or more (kappa 0.13-0.48). CONCLUSION: The clinical ACR criteria showed
      no cross validity with the 2 other ACR criteria sets.

PMID- 10332980
TI  - Treatment of non-life threatening Wegener's granulomatosis with methotrexate and
      daily prednisone as the initial therapy of choice.
AB  - OBJECTIVE: To examine our experience with methotrexate (MTX) and daily prednisone
      (PRED) as the initial treatment of Wegener's granulomatosis (WG). METHODS:
      Between November 1992 and November 1997, we treated 19 patients with non-life
      threatening WG with the combination of oral weekly MTX (starting at 7.5-10.0
      mg/week) and daily PRED (median starting dose 40 mg/day, range 20-60). The MTX
      dose was increased to 15 mg/week by the end of the first month, and then by 2.5
      mg/week until the disease was controlled. We attempted to taper PRED to 20 mg/day
      by the end of the second month, but did not use alternate day corticosteroids.
      Before treatment with this regimen, no patient had received previous treatment
      for WG. RESULTS: At presentation, the average number of organ systems involved
      was 3.6. Nine of the 19 patients (47%) had glomerulonephritis, but none had a
      serum creatinine > 1.2 mg/dl at presentation. Only 37% of the patients were
      hospitalized at presentation. Seventeen of 19 patients (89%) improved with
      treatment, and 14 (74%) achieved remission. However, half those who achieved
      remission suffered relapses, and no patient achieved a durable, complete
      remission (disease-free status free of all medications). Fifteen patients (79%)
      were able to taper PRED to < 10 mg/day. Seven of 8 disease relapses responded to
      increases of MTX and/or PRED. Only one patient developed glomerulonephritis while
      receiving treatment and required a change of therapy to cyclophosphamide. There
      were no deaths among patients in this series. Treatment with MTX and PRED was
      well tolerated: only 2 (11%) of the patients stopped treatment because of side
      effects (major liver function test abnormalities in both cases). No patient
      suffered permanent morbidity from MTX treatment. CONCLUSION: In selected patients
      with WG, the combination of MTX and daily PRED effectively controls the disease.
      However, chronic disease courses are the rule with this treatment regimen, and
      the likelihood of disease relapse is high. In our experience, the use of MTX and
      PRED in WG was safer than previously described, despite the use of daily
      corticosteroids.

PMID- 10332981
TI  - Arthroscopic evaluation of post-traumatic patellofemoral chondropathy.
AB  - OBJECTIVE: To evaluate clinically and arthroscopically post-traumatic
      patellofemoral chondropathy. METHODS: Fifty-nine patients with post-traumatic
      patellofemoral chondropathy were included in a cross sectional study and 46 of
      them completed a 6 month longitudinal study. Evaluation of the disease, performed
      once in the cross sectional study and twice (at entry and after 6 months) in the
      longitudinal study, included clinical and arthroscopic variables evaluating
      disease activity and severity. Arthroscopy was performed under local anesthesia
      in an outpatient procedure using a small arthroscope. Chondropathy was evaluated
      by the overall assessment of the investigator using a visual analog scale, and by
      the Societe Francaise d'Arthroscopie (SFA) scoring system (SFA score: 0-100).
      Synovitis was assessed by the "synovitis score," which represents a composite
      index taking into account intensity, extent and location of synovial
      abnormalities. RESULTS: In the cross sectional study, severity of chondropathy
      correlated with age, body mass index, disease duration, functional impairment
      (Lequesne's index and maximum number of steps descended), patellofemoral crepitus
      on active motion, limitation of flexion, and presence and amount of synovitis.
      Knee effusion correlated with the presence of synovitis, but no correlation was
      found between pain or functional impairment and presence or amount of synovitis.
      In the longitudinal study, no statistically significant change in chondropathy
      was observed after 6 months followup despite a statistically significant
      improvement in pain, function, and knee effusion after this period. However, a
      statistically significant correlation was found between the progression of
      patellofemoral chondropathy and the presence and amount of synovitis at baseline.
      Synovitis was present at baseline in 10 patients. Changes in SFA scores were 1.2
      +/- 1.6 and -0.1 +/- 1.0 in the groups of patients with and without synovitis,
      respectively (p = 0.0062). CONCLUSION: These data suggest that synovitis might
      have a deleterious effect on the evolution of post-traumatic patellofemoral
      chondropathy or might be a marker for active cartilage breakdown.

PMID- 10332982
TI  - A metaanalysis on the use of bisphosphonates in corticosteroid induced
      osteoporosis.
AB  - OBJECTIVE: To conduct a metaanalysis on the use of bisphosphonates in
      corticosteroid induced osteoporosis. METHODS: A Cochrane systematic review
      including electronic database searching (MEDLINE and EMBASE), and selected hand
      searching of reference lists and scientific abstracts was conducted. Metaanalysis
      using random and fixed effects modeling was used on the selected trials to
      calculate summary effect measures. All controlled clinical trials dealing with
      prevention or treatment of corticosteroid induced osteoporosis with
      bisphosphonates of any type and reporting the outcome of interest were assessed.
      Trials had to involve adults only, and subjects had to be taking a mean steroid
      dose of 7.5 mg/day or more. Outcomes of interest were change in bone mineral
      density (BMD) at the lumbar spine and femoral neck at 6 and 12 months. If
      present, data on number of new fractures and adverse effects were also extracted.
      The extraction was performed by 2 independent reviewers. RESULTS: Results are
      reported as a weighted mean difference in the percentage change in BMD between
      the treatment and placebo groups, with trials being weighted by the inverse of
      their variance. At the lumbar spine the weighted mean difference between the
      treatment and placebo groups was 4.0% (95% CI 2.5, 5.5). At the femoral neck the
      weighted mean difference was 2.1% (95% CI 0.2, 4.0). Although there was a 24%
      reduction in spinal fractures, this result did not reach statistical
      significance. CONCLUSION: Bisphosphonates are effective at preventing and
      treating corticosteroid induced bone loss at the lumbar spine. Efficacy regarding
      fracture prevention cannot be concluded from this analysis, although bone density
      changes are correlated with fracture risk. Bisphosphonates are less efficacious
      at preventing or treating corticosteroid induced osteoporosis at the femoral
      neck.

PMID- 10332983
TI  - Human immunodeficiency virus infection associated arthritis: clinical
      characteristics.
AB  - OBJECTIVE: To define the frequency and characteristics of human immunodeficiency
      virus (HIV) associated arthritis. METHODS: A total of 270 patients with HIV
      infection were prospectively evaluated for the presence of rheumatic complaints.
      Diagnosis of HIV infection was performed by ELISA and confirmed by Western blot,
      and all HIV patients were classified according to the US Centers for Disease
      Control criteria. RESULTS: Twenty-one (7.8%) patients presented with HIV
      associated arthritis. Other arthritides including HLA-B27 related, such as
      Reiter's syndrome, psoriatic arthritis, and rheumatoid arthritis, were excluded.
      Seventeen were men and 4 women, with a mean age of 34.8 years (SD 11.1). Fourteen
      (66%) were homosexuals, 4 (19%) intravenous drug users, and 3 (14%)
      heterosexuals. Twelve (57%) were in stage IV, 5 (23%) in stage III, and 4 (9%) in
      stage II. Ten (47%) patients had oligoarticular involvement, 8 (38%)
      monoarticular, 2 (9%) asymmetric polyarthritis, and one (4%) symmetric
      polyarthritis. Rheumatoid factor and HLA-B27 antigen were negative in all (15)
      patients studied. The mean duration of arthritis was 2 weeks (1-24). No
      differences in duration of arthritis were found among the different risk factors
      (p = 0.811), HIV stages (p = 0.205), and type of articular involvement (p =
      0.252). There was, however, a trend between the number of involved joints and
      stages of HIV infection (p = 0.13). CONCLUSION: The pattern of joint involvement
      of HIV associated arthritis is similar to that of other viral disorders: acute
      onset, short duration, no recurrences, and no erosive changes.

PMID- 10332984
TI  - Generic health instruments do not comprehensively capture patient perceived
      improvement in patients with carpal tunnel syndrome.
AB  - OBJECTIVE: To assess the sensitivity to change of general quality of life indices
      in patients with rheumatic diseases, we assessed the performance of 4 instruments
      in patients with carpal tunnel syndrome (CTS) treated with local injection of
      corticosteroid. METHODS: We administered visual analog scales (VAS) incorporating
      measures of overall well being, discomfort, frequency of symptoms, and physical
      activity; 2 generic instruments [the Nottingham Health Profile (NHP), the Medical
      Outcomes Study 36 Item Short Form (SF-36)]; and a rheumatoid arthritis-specific
      instrument, the modified Health Assessment Questionnaire, at baseline and one
      month after injection. We assessed 30 patients. RESULTS: VAS were significantly
      better at determining improvement than the generic instruments or the arthritis
      specific instrument. For the generic scales, only the pain scales of NHP and SF
      36 showed moderate or greater change using standardized response means.
      CONCLUSION: These results suggest that standard tools may not be sufficiently
      sensitive to show clinically significant change in this common rheumatological
      problem.

PMID- 10332985
TI  - Fibromyalgia in inflammatory bowel disease.
AB  - OBJECTIVE: Studies of the rheumatological complications of inflammatory bowel
      disease (IBD; Crohn's disease and ulcerative colitis) have focused on peripheral
      arthritis and spondylitis, and less is known about soft tissue rheumatism,
      specifically the fibromyalgia syndrome (FM). Our aim was to estimate the
      prevalence of FM and assess pain thresholds in patients with Crohn's disease (CD)
      and ulcerative colitis (UC). METHODS: Seventy-two patients with UC and 41 with CD
      attending consecutively at the Gastroenterology Outpatient Clinic were assessed
      for the presence of FM and tenderness thresholds. FM was diagnosed according to
      the American College of Rheumatology 1990 criteria. Tenderness was measured by
      manual palpation and with a dolorimeter. One hundred twenty healthy subjects
      served as controls. RESULTS: FM was documented in 30 of 113 patients with IBD
      (30%), specifically in 49% of patients with CD and 19% with UC (p = 0.001); in
      controls the rate was 0%. Subjects with CD exhibited more tenderness and reported
      more frequent and more severe FM associated symptoms than subjects with UC.
      Patients with CD had a higher tender point count, 11.3 (+/- 6.5), than those with
      UC, 6.4 (+/- 5.7) (p = 0.001); in healthy controls, the count was 0.1 (+/- 0.5).
      Tenderness thresholds (kg) were lower in CD 2.9 (+/- 1.7) than UC 3.9 (+/- 2.0)
      (p = 0.005) and controls 5.8 (+/- 0.9). CONCLUSION: FM is common in IBD,
      particularly Crohn's disease. The lower pain threshold in Crohn's disease may
      suggest a disease-specific effect. Recognizing FM in patients with IBD will
      prevent misdiagnosis and ensure correct treatment.

PMID- 10332986
TI  - "Silicone related symptoms" are common in patients with fibromyalgia: no evidence
      for a new disease.
AB  - OBJECTIVE: To ascertain if the symptom content and rate of symptoms in patients
      with fibromyalgia (FM) are similar to those in what has been called silicone
      implant associated syndrome (SIAS), and to determine if SIAS is indeed a new
      disease or whether it is largely recognizable as FM. METHODS: Mailed survey to
      901 patients in Wichita, KS, Portland, OR, Los Angeles, CA, Peoria, IL, Boston,
      MA, San Antonio, TX, and eastern Kansas who were participating in a longterm
      outcome study of FM. Laboratory data were available from Wichita patients.
      RESULTS: Content of symptoms was similar to that in SIAS, and rates were
      generally as high or higher in patients with FM than in SIAS. In patients with
      FM, 37.2% had all of the following 5 items: arthralgias, myalgias, sicca complex,
      atypical rash, and symptoms of a peripheral neuropathy; and 55.2% had 4 of the 5
      items. CONCLUSION: These data do not suggest that SIAS is an unrecognized new
      disease, but suggest the opposite, that such symptoms are well known and
      previously recognized, and are common among those with musculoskeletal complaints
      and those seen in rheumatology clinics.

PMID- 10332987
TI  - US consensus guidelines for the use of cyclosporin A in rheumatoid arthritis.
AB  - Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that often
      leads to irreversible joint damage and loss of function. Although there are
      numerous treatment options, it is difficult to manage the disease in most
      patients. Use of cyclosporin A (CsA) for RA was first reported in 1979, and since
      that time many trials have investigated CsA use for this disease. Based on
      clinical evidence, CsA is an efficacious second-line agent for patients with
      active RA who have not responded adequately to methotrexate (MTX). In addition,
      CsA has been shown to provide clinical benefit when used in combination with MTX
      in patients responding inadequately to MTX monotherapy. Side effects associated
      with CsA treatment are manageable if dosing, monitoring, and intervention
      guidelines are followed. The purpose of this review is to provide recommendations
      for the use of CsA in severe RA to physicians experienced in the management of
      systemic immunosuppressive therapy for RA. Where possible and appropriate,
      recommendations are based on evidence available in the literature.

PMID- 10332988
TI  - Seasonal variation in systemic onset juvenile rheumatoid arthritis in Israel.
AB  - OBJECTIVE: To determine whether there is a seasonal peak onset of systemic
      juvenile rheumatoid arthritis (SOJRA) suggestive of an infectious etiology. We
      examined the seasonal variability of SOJRA in Israel. METHODS: A multicenter
      retrospective chart review of 59 patients with SOJRA, enrolled from 10
      rheumatology units or pediatric departments in Israel. All patients met defined
      criteria of SOJRA. RESULTS: Fifty-nine patients (31 female, 28 male) were
      followed from 1982 to 1997. Their mean age was 7.1 +/- 4.3 years (range 0.9-16).
      Forty-six were Jewish and 13 were Arabs or of Bedouin origin. Eighteen patients
      (31%) had disease onset in the winter, 16 (27%) in the spring, 12 (20%) in the
      summer, and 13 (22%) in the fall. Twenty-eight patients had a monophasic disease
      subtype, while 31 had a chronic or cyclic subtype. The seasonal onset in the
      patients with the monophasic type versus the chronic or the cyclic type shows 7
      versus 11 in the winter, 7 versus 9 in spring, 8 versus 4 in summer, and 6 versus
      7 in fall, respectively. CONCLUSION: There is no seasonal pattern to SOJRA
      disease onset in Israel. However, the disease onset of patients having the
      chronic or the polycyclic subtype tends to be more common in winter and spring.
      Since patients with this type have more severe disease, it is possible that
      another specific infectious agent is one of the factors involved in the
      pathogenesis of the disease. Larger sampling and multicenter studies are required
      to clarify this point.

PMID- 10332989
TI  - Cognitive effects of Lyme disease in children: a 4 year followup study.
AB  - OBJECTIVE: To measure cognitive effects of Lyme disease (LD) in a pediatric
      population 4 years after disease onset. METHODS: Prospective, blinded,
      multivariable controlled study of cognitive skills in children who have been
      treated for LD. The setting was a children's hospital in an area endemic for LD.
      Twenty-five children with strictly defined LD were compared with 17 control
      children (6 disease-control and 11 sibling-control). OUTCOME MEASURES: An
      extensive set of neuropsychological measures was administered. These included
      assessment of the cognitive areas of IQ, information processing speed, fine-motor
      dexterity, novel problem solving and executive functioning, short term and
      intermediate memory, and acquisition of new learning. Parents' ratings were also
      obtained concerning disease impact upon everyday activities. RESULTS: Seventeen
      of the 18 neuropsychological test measures showed the LD and control groups
      similar at time of 4 year followup. There were no differences between the groups
      regarding parents' impressions of disease impact. CONCLUSION: In contrast to
      studies of adults with LD, the results of longterm followup of the pediatric
      population continue to strongly support the finding that children treated
      appropriately for LD have an excellent prognosis for normal cognitive
      functioning.

PMID- 10332990
TI  - Pulmonary edema during acute infusion of epoprostenol in a patient with pulmonary
      hypertension and limited scleroderma.
AB  - Epoprostenol (prostacyclin) is currently approved for treatment of primary
      pulmonary hypertension; however, it is being evaluated in other forms of
      pulmonary hypertension, particularly scleroderma. Side effects associated with
      this medication are usually minor; serious complications are most often due to
      the delivery system required for continuous infusion. We describe a life
      threatening side effect of acute epoprostenol infusion (pulmonary edema) in a
      patient with pulmonary hypertension associated with limited scleroderma and
      discuss its management and potential etiology. This is the first case where
      epoprostenol has been successfully reinstituted.

PMID- 10332991
TI  - Extensive cutaneous necrosis associated with anticardiolipin antibodies.
AB  - Extensive cutaneous necrosis (ECN) associated with antiphospholipid antibodies is
      a rare presentation. We describe 2 patients with ECN and high titers of
      anticardiolipin antibodies. The mechanism by which these antibodies act has not
      been established and there is still controversy regarding treatment of these
      patients without established guidelines. In the few documented cases the use of
      pulse steroid therapy, anticoagulants, fibrinolytic agents, plasmapheresis, or a
      combination of them has shown some benefit. Early recognition and treatment of
      the antiphospholipid syndrome may limit the extent of thrombotic complications
      that can result in tissue necrosis.

PMID- 10332993
TI  - Gastric carcinoma in association with remitting seronegative symmetrical
      synovitis with pitting edema.
AB  - We describe an elderly woman who developed remitting seronegative symmetrical
      synovitis with pitting edema (RS3PE). In addition to typical findings, she had
      increased alkaline phosphatase; and investigations revealed metastatic gastric
      carcinoma. The literature relating to RS3PE in association with neoplasia is
      reviewed.

PMID- 10332992
TI  - Polyarthralgia-arthritis syndrome induced by low doses of rifabutin.
AB  - We describe 2 cases of polyarthralgia-arthritis syndrome induced by rifabutin, an
      effective treatment for infections of Mycobacterium avium intracellulare complex.
      This syndrome has been reported with doses higher than 1 g per day when rifabutin
      is given in monotherapy. But our cases were treated with low doses, 300-450 mg
      per day, in combination with clarithromycin. The plasma concentration of
      rifabutin has been shown to be increased by clarithromycin, suggesting that co
      prescription of clarithromycin could lead to development of rifabutin induced
      polyarthralgia-arthritis syndrome.

PMID- 10332994
TI  - Whiplash injury.

PMID- 10332995
TI  - Whiplash injury.

PMID- 10332996
TI  - Whiplash injury.

PMID- 10332997
TI  - Whiplash injury.

PMID- 10332998
TI  - Factors associated with active SLE after endstage renal disease.

PMID- 10332999
TI  - Apparent medium vessel vasculitis associated with a spinal meningioma.

PMID- 10333000
TI  - Polyarteritis nodosa complicated by severe progressive scleritis.

PMID- 10333001
TI  - Prevalence of antikeratin antibodies in an elderly population.

PMID- 10333002
TI  - Dual effect of alcohol on pain in rheumatoid arthritis.

PMID- 10333003
TI  - A hierarchical foundation for models of sensorimotor control.
AB  - Successful performance of a sensorimotor task arises from the interaction of
      descending commands from the brain with the intrinsic properties of the lower
      levels of the sensorimotor system, including the dynamic mechanical properties of
      muscle, the natural coordinates of somatosensory receptors, the interneuronal
      circuitry of the spinal cord, and computational noise in these elements.
      Engineering models of biological motor control often oversimplify or even ignore
      these lower levels because they appear to complicate an already difficult
      problem. We modeled three highly simplified control systems that reflect the
      essential attributes of the lower levels in three tasks: acquiring a target in
      the face of random torque-pulse perturbations, optimizing fusimotor gain for the
      same perturbations, and minimizing postural error versus energy consumption
      during low- versus high-frequency perturbations. The emergent properties of the
      lower levels maintained stability in the face of feedback delays, resolved
      redundancy in over-complete systems, and helped to estimate loads and respond to
      perturbations. We suggest a general hierarchical approach to modeling
      sensorimotor systems, which better reflects the real control problem faced by the
      brain, as a first step toward identifying the actual neurocomputational steps and
      their anatomical partitioning in the brain.

PMID- 10333004
TI  - Reaching beyond reach.
AB  - The analysis of errors in two-joint reaching movements has provided clues about
      sensorimotor processing algorithms. The present study extends this focus to
      situations where the head, trunk, and legs join with the arm to help reach
      targets placed slightly beyond arm's length. Subjects reached accurately to touch
      "real targets" or reached to the remembered locations of "virtual targets" (i.e.,
      targets removed at the start of the reach). Subjects made large errors in the
      virtual-target condition and these errors were analyzed with the aim of revealing
      the implications for whole-body coordination. Subjects were found to rotate the
      head less in the virtual-target condition (when compared with accurate movements
      to real targets). This resulted in a more limited range of head postures, and the
      final head angles at the end of the movements were geometrically related to the
      incorrect hand locations, perhaps accounting for some portion of the errors. This
      suggests that head-eye-hand coordination plays an important role in the
      organization of these movements and leads to the hypothesis that a representation
      of current gaze direction may serve as a reference signal for arm motor control.

PMID- 10333005
TI  - Combined use of T1-weighted MRI and MRA for stereotaxic lesioning of the nonhuman
      primate brain: application to the rhinal cortex.
AB  - Stereotaxic brain lesioning is widely used to develop experimental models of
      human brain disease in the nonhuman primate. To avoid intraoperative vascular
      complications such as intracranial hemorrhage, we developed a methodology that is
      easy to implement. This method combines T1-weighted magnetic resonance imaging
      (MRI) and magnetic resonance angiography (MRA). This technique is applied to
      produce bilateral neurotoxic lesions of the rhinal cortex, a structure located
      medially in the temporal lobe, in eight baboons (including five sham-operated
      animals with needle descents but no ibotenic acid injection). Two other baboons
      were lesioned before the MRA technology was available. The MRA sequence (two
      dimensional time-of-flight, axial acquisition) was used to localize the blood
      vessels in the needle trajectories, i.e., the highly vascularized sylvian fissure
      and temporal gyri. The vessel coordinates were transposed onto the coronal MRI-TI
      images, onto which the injection sites were determined and the planned needle
      tracks drawn. In the eight baboons that had MRA, 26.8% of these needle tracks had
      to be slightly displaced because of the presence of blood vessels. The
      stereotaxic coordinates of the final target sites were then calculated with
      respect to six skull landmarks that also served as a reference during surgery. No
      intracranial hemorrhage occurred in any of the eight baboons in which MRA was
      performed, in contrast to one of the two baboons not studied with MRA. The
      histological analysis showed a good extent of the rhinal lesions in all lesioned
      animals, with minimal damage to areas other than those that were targeted. Thus,
      combined use of MRI-TI and MRA proved to be reliable in reducing vascular
      complications, affording new advances for stereotaxic surgery in nonhuman
      primates.

PMID- 10333006
TI  - Amplitude of human head movements associated with horizontal saccades.
AB  - Human saccades may or may not be associated with head movements. To date, little
      attention has been devoted to the mechanisms determining head movement
      recruitment and scaling. Normal human subjects made horizontal, centrifugal
      saccades along an encircling array of light-emitting diodes. Measurements of
      gaze, head, and eye-in-head angle were made at the conclusion of the head
      movement (or at the end of the eye movement in eye-only saccades). We found that
      head movement amplitude (deltaH) related in a simple fashion to the eye
      eccentricity that would have resulted if the gaze shift had been performed
      without a head movement. Plots of deltaH vs this predicted eye eccentricity
      (E(PRED)) had a central flat region in which gaze shifts were unaccompanied by
      head movements (the eye-only range) and two flanking lobes in which deltaH was a
      linear function of E(PRED) (the eye-head ranges). DeltaH correlated with EPRED
      better than with gaze shift amplitude, as would be expected if head movements
      were controlled so as to keep eye eccentricity within a particular range. Head
      movement tendencies were quantified by the width of the eye-only range, the slope
      of the eye-head range, and the width of the region within which the eye was
      likely to be found at the conclusion of the completed gaze-shifting behavior (the
      customary ocular motor range). The measures ranged widely in these normal
      subjects: 35.8+/-31.9 degrees for the eye-only range (mean+/-SD), 0.77+/-0.16 for
      the slope of the eye-head range, and 44.0+/-23.8 degrees for the customary ocular
      motor range. Yet for a given subject, the measurements were reproducible across
      experimental sessions, with the customary ocular motor range being the most
      consistent measure of the three. The form of the deltaH vs E(PRED) plots suggests
      that the neural circuitry underlying eye-head coordination carries out two
      distinct functions--gating the head movement and scaling the head movement. The
      reason for the large intersubject variability of head movement tendencies is
      unknown. It does not parallel intersubject differences in full-scale eye (in
      orbit) range or full-scale neck range.

PMID- 10333007
TI  - Recruitment and sequencing of different degrees of freedom during pointing
      movements involving the trunk in healthy and hemiparetic subjects.
AB  - Previous studies have shown that in neurologically normal subjects the addition
      of trunk motion during a reaching task does not affect the trajectory of the arm
      endpoint. Typically, the trunk begins to move before the onset and continues to
      move after the offset of the arm endpoint displacement. This observation shows
      that the potential contribution of the trunk to the motion of the arm endpoint
      toward a target is neutralized by appropriate compensatory movements of the
      shoulder and elbow. We tested the hypothesis that cortical and subcortical brain
      lesions may disrupt the timing of trunk and arm endpoint motion in hemiparetic
      subjects. Eight hemiparetic and six age-matched healthy subjects were seated on a
      stool with the right (dominant) arm in front of them on a table. The tip of the
      index finger (the arm endpoint) was initially at a distance of 20 cm from the
      midline of the chest. Wrist, elbow, and upper body positions as well as the
      coordinates of the arm endpoint were recorded with a three-dimensional motion
      analysis system (Optotrak) by infrared light-emitting diodes placed on the tip of
      the finger, the styloid process of the ulna, the lateral epicondyle of the
      humerus, the acromion processes bilaterally, and the sternal notch. In response
      to a preparatory signal, subjects lifted their arm 1-2 cm above the table and in
      response to a "go" signal moved their endpoint as fast as possible from a near to
      a far target located at a distance of 35 cm and at a 45 degrees angle to the
      right or left of the sagittal midline of the trunk. After a pause (200-500 ms)
      they moved the endpoint back to the near target. Pointing movements were made
      without trunk motion (control trials) or with a sagittal motion of the trunk
      produced by means of a hip flexion or extension (test trials). In one set of test
      trials, subjects were required to move the trunk forward while moving the arm to
      the target ("in-phase movements"). In the other set, subjects were required to
      move the trunk backward when the arm moved to the far target ("out-of-phase
      movements"). Compared with healthy subjects, movements in hemiparetic subjects
      were segmented, slower, and characterized by a greater variability and by
      deflection of the trajectory from a straight line. In addition, there was a
      moderate increase in the errors in movement direction and extent. These deficits
      were similar in magnitude whether or not the trunk was involved. Although
      hemiparetic subjects were able to compensate the influence of the trunk motion on
      the movement of the arm endpoint, they accomplished this by making more segmented
      movements than healthy subjects. In addition, they were unable to stabilize the
      sequence of trunk and arm endpoint movements in a set of trials. It is concluded
      that recruitment and sequencing of different degrees of freedom may be impaired
      in this population of patients. This inability may partly be responsible for
      other deficits observed in hemiparetic subjects, including an increase in
      movement segmentation and duration. The lack of stereotypic movement sequencing
      may imply that these subjects had deficits in learning associated with short-term
      memory.

PMID- 10333008
TI  - Terminals of paraventricular spinal neurones are closely associated with adrenal
      medullary sympathetic preganglionic neurones: immunocytochemical evidence for
      vasopressin as a possible neurotransmitter in this pathway.
AB  - A recent study using transsynaptically transported pseudorabies virus, injected
      into the adrenal gland, showed labelled neurones in the paraventricular nucleus
      (PVN) of the hypothalamus, indicating that these neurones send projections to
      sympathoadrenal preganglionic neurones (SPNs). However, this technique cannot
      conclusively demonstrate that the pathway is monosynaptic. In order to
      investigate the possibility of a direct projection from the PVN to SPNs, the
      present study used the anterograde tracer biotin dextran amine to label
      paraventricular spinal projections and the retrograde tracer cholera toxin B
      conjugated to horseradish peroxidase to label SPNs. In addition, because
      electrophysiological evidence suggests vasopressin to be a neurotransmitter
      candidate in this pathway, immunocytochemical identification of the peptide and
      retrograde labelling of SPNs to the adrenal medulla were used to investigate
      this. The results of these studies show spinally projecting paraventricular axons
      with terminal varicosities closely associated with SPNs. Therefore some of these
      associations may represent boutons forming synaptic contact on SPNs. Similarly,
      vasopressin fibres were found close to the dendrites and soma of SPNs. It is
      suggested that spinal axons originating from paraventricular neurones can provide
      a direct influence on adrenal medullary function, that vasopressin is a possible
      neurotransmitter involved in some of these connections and this is one means by
      which the paraventricular nucleus can generate a defence to stressful stimuli.

PMID- 10333009
TI  - Inactivation of interposed nuclei in the cat: classically conditioned withdrawal
      reflexes, voluntary limb movements and the action primitive hypothesis.
AB  - The cerebellar interposed nuclei are considered critical components of circuits
      controlling the classical conditioning of eyeblink responses in several mammalian
      species. The main purpose of the present experiments was to examine whether the
      interposed nuclei are also involved in the control of classically conditioned
      withdrawal responses in other skeletomuscular effector systems. To achieve this
      objective, a unique learning paradigm was developed to examine classically
      conditioned withdrawal responses in three effector systems (the eyelid, forelimb
      and hindlimb) in individual cats. Trained animals were injected with muscimol in
      the cerebellar interposed nuclei, and the effects on the three conditioned
      responses (CRs) were examined. Although the effects of muscimol were less
      dramatic than previously reported in the rabbit eyeblink preparation, the
      inactivation of the cerebellar nuclei affected the performance of CRs in all
      three effector systems. In additional experiments, animals were injected with
      muscimol at the sites affecting classically conditioned withdrawal responses to
      determine the effects of these injections on reaching and locomotion behaviors.
      These tests demonstrated that the same regions of the cerebellar interposed
      nuclei which control withdrawal reflexes are also involved in the control of limb
      flexion and precision placement of the paw during both locomotion and reaching
      tasks. The obtained data indicate that the interposed nuclei are involved in the
      control of ipsilateral action primitives and that inactivating the interposed
      nuclei affects several modes of action of these functional units.

PMID- 10333010
TI  - Coordination of spinal locomotor activity in the lamprey: long-distance coupling
      of spinal oscillators.
AB  - The extent and strength of long-distance coupling between locomotor networks in
      the rostral and caudal spinal cord of larval lamprey were examined with in vitro
      brain/spinal cord preparations, in which spinal locomotor activity was initiated
      by chemical microstimulation in the brain, as well as with computer modeling.
      When locomotor activity and short-distance coupling were blocked in the middle
      spinal cord for at least 40 segments, burst activity in the rostral and caudal
      spinal cord was still coupled 1:1, indicating that long-distance coupling is
      extensive. However, in the absence of short-distance coupling, intersegmental
      phase lags were not constant but decreased significantly with increasing cycle
      times, suggesting that long-distance coupling maintains a relatively constant
      delay rather than a constant phase lag between rostral and caudal bursts. In
      addition, under these conditions, intersegmental phase lags, measured between
      rostral and caudal burst activity, were significantly less than normal, and the
      decrease was greater for longer distances between rostral and caudal locomotor
      networks. The above result could be mimicked by a computer model consisting of
      pairs of oscillators in the rostral, middle, and caudal spinal cord that were
      connected by short- and long-distance coupling. With short-distance coupling
      blocked in the middle spinal cord, strychnine was applied to either the rostral
      or caudal spinal cord to convert the pattern locally from right-left alternation
      to synchronous burst activity. Synchronous burst activity in the rostral spinal
      cord resulted in a reduction in right-left phase values for burst activity in the
      caudal cord. These results also could be mimicked by the computer model.
      Strychnine-induced synchronous burst activity in the caudal spinal cord did not
      appear to alter the right-left phase values of rostral burst activity. Taken
      together, the experimental and modeling results suggest that the descending and
      ascending components of long-distance coupling, although producing qualitatively
      different effects, are comparatively weak. In particular, the descending
      component of long-distance coupling appears to become progressively weaker with
      increasing distance between two given regions of spinal cord. Therefore, short
      distance coupling probably contributes substantially to normal rostrocaudal phase
      lags for locomotor activity along the spinal cord. However, short-distance
      coupling may be more extensive than "nearest neighbor coupling."

PMID- 10333011
TI  - The effects of delay on the kinematics of grasping.
AB  - We examined the effect on manual prehension of introducing a 5-s delay between
      viewing a target object and initiating a grasping movement. Subjects were tested
      in four conditions: three involved grasping the object and a fourth involved
      estimating its size. In the main experimental condition (Open Loop Delay),
      subjects viewed a target object for 300 ms, but did not initiate a grasping
      movement until an auditory signal was presented 5 s later. In this condition,
      subjects had to rely on stored visual information for guiding their grasp after
      the delay. In another condition (Open Loop), subjects initiated their grasping
      movement as soon as the target appeared. In both of these open-loop conditions,
      subjects reached out and grasped the object without seeing their hand. In the
      third grasping condition (Closed Loop), the target object and the hand were
      visible throughout the reach. In the three grasping conditions, subjects were
      instructed to pick up the object across its width using their index finger and
      thumb. In a final condition (Perceptual Estimation), subjects gave a manual
      estimate of the object's width with their index finger and thumb after viewing
      the object for 300 ms. In all four conditions, subjects were presented with a
      target object in which the height, length and width were independently varied
      from trial to trial. The results of the experiment indicated that reaching and
      grasping movements made in the Open-Loop and Closed-Loop conditions did not
      differ in any kinematic measures. In contrast, when subjects performed in the
      Open-Loop Delay condition, their reaches took significantly longer and achieved
      peak velocity proportionately earlier. As well, their maximum grip aperture was
      significantly larger. In addition, reaching movements in all three grasping
      conditions were affected by both the object's width (the 'relevant' dimension)
      and height. The manual estimates in the Perceptual-Estimation condition, however,
      reflected only the object's width. These results, together with evidence from
      other studies, suggest that motor actions performed after a delay use different
      transformations than those used for 'real-time' grasping. We argue that the
      stored visual information used to drive delayed actions arises from a perceptual
      rather than a visuomotor analysis of the target object.

PMID- 10333012
TI  - Comparison of the depression of H-reflexes following previous activation in upper
      and lower limb muscles in human subjects.
AB  - When conditioning-testing (C-T) stimuli are applied to Ia afferents to elicit H
      reflexes, the test reflex is abolished immediately following the conditioning
      reflex. As the C-T interval is increased, the test response slowly begins to
      recover, taking several hundred milliseconds to attain control values. The time
      course of this recovery is known as the H-reflex recovery curve. H-reflex
      recovery curves were compared using surface EMG and single motor unit activities
      in lower limb soleus and upper limb flexor carpi radialis (FCR) muscles in seven
      healthy human subjects. Under rest conditions, the recovery of H-reflexes and
      single motor unit activity was slow for soleus; the recovery was not complete
      even in 1 s. In comparison, the recovery was very fast for FCR motor units,
      occurring in 200-300 ms. The effects of rate of stimulation (0.1-10.0 imp/s) were
      also examined on the magnitude of H-reflex responses. The reflex response
      declined with increasing rate of stimulation, the decline being slightly greater
      in soleus than in FCR. When these phenomena were examined with voluntary
      facilitation of the spinal cord, the time of recovery shortened and the effect of
      stimulus rate also diminished. Changes with background facilitation were greater
      in FCR than in soleus. The differences between the two muscles are attributed
      mainly to differences in presynaptic inhibition in the two spinal segments,
      and/or to the differences in dynamics of the transmitter release in terminals of
      Ia afferents synapsing with slow soleus motoneurons and those synapsing with the
      fast FCR motoneurons.

PMID- 10333013
TI  - On the relation between brain potentials and the awareness of voluntary
      movements.
AB  - We investigated the relation between neural events and the perceived time of
      voluntary actions or the perceived time of initiating those actions using the
      method of Libet. No differences were found in either movement-related potentials
      or perceived time of motor events between a fixed movement condition, where
      subjects made voluntary movements of a single finger in each block, and a free
      movement condition, in which subjects chose whether to respond with the left or
      the right index finger on each trial. We next calculated both the readiness
      potential (RP) and lateralised readiness potential (LRP) for trials with early
      and late times of awareness. The RP tended to occur later on trials with early
      awareness of movement initiation than on trials with late awareness, ruling out
      the RP as a cause of our awareness of movement initiation. However, the LRP
      occurred significantly earlier on trials with early awareness than on trials with
      late awareness, suggesting that the processes underlying the LRP may cause our
      awareness of movement initiation.

PMID- 10333014
TI  - Effects of geometric joint constraints on the selection of final arm posture
      during reaching: a simulation study.
AB  - Significant debate exists regarding the neural strategies underlying the
      positioning and orienting of the hand during voluntary reaching movements of the
      human upper extremity. Some authors have suggested that positioning and orienting
      are controlled independently, while others have argued that a strong
      interdependence exists. In an effort to address this uncertainty, our study
      employed computer simulations to examine the impact of physiological limitations
      of joint rotation on the proposed independence of hand position and orientation.
      Specifically, we analyzed the effects of geometric constraints on final arm
      postures using a 7 degree-of-freedom model of the human arm. For 20 different
      hand configurations within the attainable workspace, we computed sets of
      achievable joint angles by applying inverse kinematics. From each set, we then
      calculated the locus of possible elbow positions for the particular final hand
      posture. When the joints were allowed 360 degrees of rotation, the loci formed
      complete circles; however, when joint ranges were limited to physiological
      values, the extent of the loci decreased to an average arc angle of 54.6 degrees
      (+/-27.9 degrees). Imposition of joint limits also led to practically linear
      relationships between joint angles within a solution set. These theoretical
      results suggest a requirement for coordinated interaction between control of the
      joints associated with hand position and those involved with hand orientation in
      order to ensure attainable joint trajectories. Furthermore, it is conceivable
      that some of the correlations observed between joint angles in the course of
      natural reaching movements result from geometric constraints.

PMID- 10333015
TI  - The evolution of minimally invasive valve surgery--2 year experience.
AB  - OBJECTIVES: The aim of the study was to evaluate the evolution of Port-Access
      minimally invasive mitral valve surgery to a robot assisted video assisted solo
      surgery approach. METHODS: One hundred and twenty-nine patients with non-ischemic
      mitral valve disease underwent 3D-video assisted mitral valve surgery via a 4 cm
      right lateral minithoracotomy using femoro-femoral bypass and endoaortic
      clamping. Transcranial Doppler and continuous transesophageal echocardiography
      were used to monitor placement and positional stability of the endoclamp. After
      the initial series (group I, n = 62), a simplified solo surgical technique using
      voice controlled robotic assistance for videoscope guidance was used in the last
      67 patients (group II). RESULTS: After an initial learning curve and
      modifications of catheter design, the procedure could be steadily redefined and
      simplified. In the last 67 patients, the procedure was completed without the need
      for an additional assistant as 'solo surgery'. The mitral valve was repaired in
      72 and replaced in all other patients. Duration of bypass and clamp time steadily
      improved during our study and in the most recent 67 patients average 107 +/- 34
      and 48 +/- 16 min, respectively. The voice controlled robotic arm (AESOP 3000,
      Automated Endoscope System for Optimal Positioning) provided a stable and precise
      video image with excellent exposure of all valvular and subvalvular structures.
      Hospital mortality was high in the early series (mean survival 88.7% at 804 +/-
      35 days; 95% CI: 735-873) and partially procedure related (aortic dissection in
      two patients). In group II, hospital mortality has declined to 3.0% (mean
      survival 97.0% at 568 +/- 12 days; 95% CI: 553-600). CONCLUSION: Port-Access
      minimally invasive mitral valve surgery has evolved to be a reliable video
      assisted technique with reproducible results. Surgery can now be performed almost
      in the same time as with conventional techniques. Robotic assistance has enabled
      a solo surgery approach.

PMID- 10333016
TI  - Intraoperative flow measurements in gastroepiploic grafts using pulsed Doppler.
AB  - OBJECTIVE: The patency of a pedicled right gastroepiploic artery (RGEA) graft can
      be compromised by intraoperative twists, kinks or spasms. Therefore, a systematic
      flow assessment was made in RGEA grafts and was compared with similar
      measurements made in other types of bypass conduits. METHODS: Intraoperative
      pulsed Doppler flowmeter measurements obtained in a series of 556 consecutive
      patients undergoing at least one coronary bypass grafting onto the right coronary
      system were studied. Eighty-five RGEA grafts were compared with 1427 bypass
      grafts implanted in the same group of patients and consisted of the following
      conduits: 442 left internal mammary (LIMA), 149 right internal mammary (RIMA),
      831 greater saphenous vein (GSV) and five inferior epigastric (EPIG) grafts.
      Sequential grafts were excluded from the analysis. RESULTS: Flow measurements and
      Doppler waveforms were abnormal and required graft repositioning, and the
      addition of a distal graft or intragraft papaverine injection (only in GSVs) in
      29 cases (2.0% of all grafts). These graft corrections were necessary in 5.9%
      RGEAs, 3.4% LIMAs, 2.0% RIMAs, and 0.7% GSVs (P < 0.001). The relative risk for
      graft correction was eight times higher for RGEAs than for GSVs (P = 0.002). Flow
      increased from 8 +/- 2 to 54 +/- 5 ml/min (P < 0.0001). Flow data were
      significantly influenced by the type of run-off bed (P < 0.001), the measurements
      obtained in grafts implanted onto the right coronary artery and the left anterior
      descending artery being superior. Flows in RGEAs, however, were comparable with
      values obtained in other grafts implanted onto the same recipient coronary
      artery. CONCLUSIONS: A significantly higher incidence of graft malpositioning
      caused inadequate flows in RGEAs. However, normal flow values could be restored
      simply by assigning a better graft orientation under pulsed Doppler flowmeter
      control. Overall flow capacity of the RGEA did not differ from values obtained in
      other arterial and venous grafts implanted onto the same recipient arteries.

PMID- 10333017
TI  - Free flow capacity of skeletonized versus pedicled internal thoracic artery
      grafts in coronary artery bypass grafts.
AB  - OBJECTIVE: The internal thoracic artery (ITA) is the ideal conduit for coronary
      artery bypass grafting (CABG). The skeletonization technique of this arterial
      conduit has been proposed to reduce chest wall trauma, increase graft length and
      facilitate construction of sequential anastomoses. Nevertheless, some surgeons
      decline this technique because of potentially increased trauma to the ITA with
      impairment of flow. In this investigation we compared the free flow of
      skeletonized with that of pedicled ITA grafts. METHODS: Two surgeons operated on
      80 consecutive patients with coronary artery disease for elective CABG. In group
      I (n = 40), the left ITA was dissected using the skeletonization technique. In
      group II (n = 40), it was harvested as a pedicled graft. In 23 patients of group
      I both ITA's were dissected in skeletonized fashion for complete arterial
      revascularization. Diluted papaverine was instilled into the lumen of the ITA
      after distal transection of the vessel in both groups. Free flow of the ITA was
      registered before and 15 min after intraluminal application of diluted
      papaverine. Mean arterial pressure was maintained at 70 mmHg. RESULTS: Before the
      application of papaverine, free flow of skeletonized and pedicled ITA grafts was
      identical between the two groups. After treatment with papaverine maximum free
      flow was significantly higher in the skeletonized ITA's (group I 197.2 (+/-66.6)
      ml/min; group II 147.1 (+/-70.5) ml/min; P < 0.05). There was no significant
      difference between free flow after dilatation of the left and right ITA in group
      I (left 197.2 (+/-66.6) ml/min; right 198.9 (+/-61.8) ml/min). CONCLUSIONS:
      Preparation of the ITA with the skeletonization technique results in
      significantly, higher free flow capacity than in pedicled grafts. This may
      increase the safety of arterial revascularization by reducing the risk of ITA
      hypoperfusion syndrome.

PMID- 10333018
TI  - Do internal mammary artery side-branches have the potential for haemodynamically
      significant flow steal?
AB  - OBJECTIVE: To evaluate the potential for flow steal of the internal mammary
      artery (IMA) side-branches at rest and in case of dilatation of their vascular
      bed (as probably occurs during physical exercise). METHODS: Transthoracic echo
      Doppler evaluation of IMA flow was performed preoperatively in 40 patients
      undergoing myocardial revascularization. IMA flow was measured at rest and in
      condition of peripheral vasodilatation (obtained using forced ventilation for 2
      min, dypiridamole 0.84 mg/kg endovenous (e.v.), xantinole nicotinate 500 mg e.v.,
      nifedipine 20 mg sublingual (s.l.)). RESULTS: IMA mean peak systolic velocity
      increased 23% after forced ventilation (from 67 to 83 cm/s), 6% after
      dypiridamole (from 75 to 80 cm/s), 30% after xantinole infusion (from 62 to 81
      cm/s) and 23% after nifedipine administration (from 60 to 74 cm/s). IMA flow
      increased 17.7% after forced ventilation (from 39.5 to 46.5 ml/min), 4.8% after
      dypiridamole (from 39.2 to 41.1 ml/min), 20.2% after xantinole infusion (from
      41.4 to 49.8 ml/min) and 16.5% after nifedipine administration (from 41.6 to 48.5
      ml/min). CONCLUSIONS: The limited functional flow reserve of the in situ IMA,
      even after pure muscular vasodilatation, seems to minimize the possibility of
      significant flow steal from patent IMA graft collaterals.

PMID- 10333019
TI  - Intracoronary shunt prevents left ventricular function impairment during beating
      heart coronary revascularization.
AB  - OBJECTIVE: Beating heart coronary revascularization is becoming increasingly
      popular world-wide. Temporary occlusion of the coronary artery is often required
      in order to perform the anastomosis. An alternative method to maintain perfusion
      is to use an intracoronary shunt. In this study, we monitored global left
      ventricular function and regional wall motion in the presence or absence of a
      shunt using transesophageal echocardiography (TEE). METHOD: Left ventricular wall
      motion score index (WMSI), wall motion score (WMS) in the left anterior
      descending (LAD) coronary artery territory, and ejection fraction (EF%) were
      measured by multiplane TEE during construction of the left internal mammary
      artery (LIMA)-LAD coronary artery anastomosis in 40 patients undergoing
      revascularization with or without the use of a shunt. WMSI was assessed
      preoperatively, 1, 3 and 6 min during the construction of the anastomosis and
      after 5 min of reperfusion. WMS was assessed at 6 min during anastomosis and
      after 5 min of reperfusion. EF% was calculated preoperatively, 5 min into the
      construction of the anastomosis, and 5 min after reperfusion. RESULTS: During
      construction of the anastomosis, when the shunt was used, there were no changes
      in WMSI, WMS in the LAD territory or EF%. A significant decline in these
      parameters was seen in the group in which the shunt was not used, although on
      reperfusion all the values returned to baseline control. CONCLUSION: (i)
      occlusion of the LAD to perform the anastomosis results in temporary impairment
      in left ventricular function with complete recovery on reperfusion; (ii) the use
      of an intracoronary shunt presumably by maintaining myocardial perfusion prevents
      deterioration in ventricular function; (iii) from this data it seems therefore
      advisable to use an intracoronary shunt in patients with unstable angina, poor
      left ventricular function, or in cases in which a longer time to perform the
      anastomosis is anticipated.

PMID- 10333020
TI  - Quality of computer enhanced totally endoscopic coronary bypass graft anastomosis
      -comparison to conventional technique.
AB  - OBJECTIVE: Aims of the study were to develop an endoscopic technique to perform
      robot assisted coronary anastomoses, using a computer enhanced telemanipulator
      and to compare the quality of the anastomoses with those performed using a
      standard open technique. METHODS: A surgical telemanipulator with two instrument
      arms and a central videoscopic arm was used to perform remote endoscopic coronary
      artery bypass grafting on isolated porcine hearts. The end effectors and the
      videoscope were placed through three 10 mm port incisions. All anastomoses (Cx to
      LAD) were performed using a double armed 7-0 Prolene suture of 5 or 7 cm in
      length. All operations were performed remotely from the master console using ten
      times magnification, tremor filtering and 3:1 motion scaling. Initially 20
      anastomoses were performed to develop and train the technique. Then, 20 robot
      assisted anastomoses (group I) were compared with 20 anastomoses using a standard
      open parachute technique (group II). All anastomoses were checked for patency and
      leakage. Patency was confirmed by bench angiography. After fixation, all
      anastomoses were macroscopically evaluated for patency, intactness, alignment,
      intimal tears and dehiscence. Both angiographic and pathologic evaluations were
      performed with the examiners blinded to the technique of anastomosis. RESULTS: In
      the initial feasibility series, time for anastomosis was 18.2 +/- 9.1 min. All
      anastomoses were patent although minor stenoses were found in two and minor
      leakage was noted in five anastomoses. In the second series all anastomoses were
      patent, not leaking and showed a good run-off at angiography. Mean time for
      anastomosis in group I was 12.8 +/- 2.4 min as compared with 6.3 +/- 0.2 min in
      group II (P < 0.001), respectively. Macroscopic analysis demonstrated equal
      quality for both groups. There were no stenoses, no intimal tears and no
      dehiscences. All anastomoses had a normal alignment and intact suture lines.
      CONCLUSION: Using the Intuitive surgical telemanipulator, it is possible to
      remotely perform endoscopic coronary anastomoses with the same quality as with an
      open standard technique after a brief learning curve. This will enable true
      endoscopic coronary artery bypass grafting with a precision that has not been
      achieved with any other previously applied endoscopic technique.

PMID- 10333021
TI  - Intraoperative local fibrinolysis as emergency therapy after early coronary
      artery bypass thrombosis.
AB  - OBJECTIVE: Acute graft occlusion early postoperatively after coronary artery
      bypass grafting (CABG) is a rare but dramatic complication, frequently making
      resuscitation necessary. Emergency reoperation with reanastomosing of the
      concerning grafts is the normal procedure to restrict the otherwise unavoidable
      myocardial damage. Mortality in these cases is up to 50%. Due to this
      unsatisfying situation, we perform since 1995 in such cases an adjuvant
      intraoperative intracoronary installed fibrinolysis with recombinant tissue type
      plasminogen activator (rt-PA; alteplase). METHODS: Between 1/1994 and 8/1998,
      4231 patients underwent CABG. In 18 of these patients, emergency reoperation
      within the first 12 h after CABG due to clinical signs of acute myocardial
      infarction was necessary. In nine of the patients (group II) additionally
      intraoperative rt-PA lysis of the involved vessel/s has been performed. When the
      peripheral anastomosis was reopened and the thrombotic material was removed, we
      inserted for this a left atrial-catheter (LA-catheter) of 1.2 mm in diameter,
      into the coronary artery. Then we administered within 3-5 min, up to 100 mg rt-PA
      (t1/2: 5-9 min.) locally into the vessel. All patients were treated
      postoperatively with acetylsalicyl acid (ASA) and heparine. RESULTS: In group I
      (n = 9; seven males, two females) without thrombolytic therapy, 78% of the
      patients (n = 7) could not have been prevented from large myocardial infarction
      despite emergency reoperation. Three of these patients died during or early after
      reintervention. In group II with fibrinolytic therapy (n = 9) three of the
      patients developed Q-wave myocardial infarction following reoperation. None of
      the patients died. Creatinkinase maximum were in group I significantly higher
      than in group II (group I: CK = 1254 units/I, CK-MB = 197 units/l; group II: CK =
      502 units/l, CK-MB = 61 units/l; P < 0.01). Postoperative bleeding was
      considerable elevated in both groups. In group I, 832 ml/24 h (375-1420 ml), in
      group II 1164 ml/24 h (520-1560 ml). Lysis-associated complications were not
      observed. CONCLUSIONS: Reoperation of patients with acute thrombotic bypass
      occlusion after CABG is characterized by a high mortality and morbidity. If
      additionally fibrinolysis is performed, a sufficient myocardial perfusion seems
      to be restored. A short half-life in combination with the presented non-systemic
      application technique of rt-PA seem to prevent unpredictable bleeding. Rt-PA
      lysis apparently contributes very effectively to the restoration of the macro-
      and microcirculation within the infarct-related area. Thrombolytic therapy during
      cardiac surgery with rt-PA is feasible, its application easy and harmful
      complications are not seen.

PMID- 10333022
TI  - Myocardial protection in operations requiring more than 2 h of aortic cross
      clamping.
AB  - OBJECTIVE: Long periods of aortic cross-clamping time during cardiac surgery are
      associated with high rates of morbidity and mortality because of damage to the
      myocardium. Recently, we have used a method of myocardial protection based on the
      principles of hyperkalemic cardioplegic arrest. We use antegrade administration
      of warm, undiluted blood followed by continuous retrograde infusion of tepid,
      undiluted blood supplemented with potassium and magnesium. In this study, we have
      retrospectively reviewed our experience with this method of cardioprotection in
      operations requiring more than 2 h of cross-clamp time. METHODS: We
      retrospectively reviewed the medical records of 1280 patients who underwent
      myocardial revascularization, valve repair or replacement, or a combination of
      both operations between January 1, 1994 and December 31, 1997. Patients were
      divided into two groups: the short cross-clamp group (SXC) (n = 1144) had cross
      clamp times < 120 min (mean, 78 +/- 20 min; range, 35-119 min) and the long cross
      clamp group (LXC) (n = 136) had cross-clamp times > 120 min (mean, 154 +/- 31
      min; range, 120-277 min). We compared preoperative, operative, and postoperative
      variables between the two groups. RESULTS: Significantly more patients in the
      long cross-clamp group (43.4%) underwent the combined operation than in the short
      cross-clamp group (2.3%), and the rate of reoperation was significantly higher in
      the long cross-clamp group (12%) than in the short cross-clamp group (5%).
      Despite these differences in operative complexity, we found no difference in
      hospital mortality rates between the two groups. The only significant
      postoperative differences were that the long cross-clamp group had a greater need
      for inotropic agents (43 vs. 29%), higher serum levels of creatine kinase (880 +/
      583 vs. 613 +/- 418) and CK-MB (10.9 +/- 6.4 vs. 5.9 +/- 5.2), and a longer
      hospital stay (9.6 vs. 6.1 days). CONCLUSION: Long, complex operations requiring
      more than 2 h of cross-clamping can be performed safely with our method of
      cardioprotection based on continuous retrograde infusion of tepid, hyperkalemic,
      undiluted blood.

PMID- 10333023
TI  - Double switch for congenitally corrected transposition of the great arteries.
AB  - OBJECTIVE: To evaluate the early and medium term results of operations for
      congenitally corrected transposition of the great arteries (CCTGA) wherein the
      left ventricle becomes the systemic ventricle. METHODS: Fourteen patients with
      CCTGA who underwent anatomic repair from 1994 to 1998 were placed in one of two
      groups: those without pulmonic stenosis (PS) (N = 7) and those with PS (N = 7).
      Main associations in the group without PS were: severe left atrioventricular (AV)
      valve regurgitation (N = 4), ventricular septal defect (VSD) (N = 4), criss-cross
      AV connection (N = 1), and hypoplasia of the morphologic RV (N = 1). Main
      associations in the group with PS were: VSD (N = 7), anomalous pulmonary venous
      drainage (N = 2) and major aorto-pulmonary collaterals (N = 1). All patients in
      the group without PS underwent an arterial switch operation and all except one
      had a modified senning repair for atrial rerouting for anatomic correction. All
      seven patients with PS underwent a Rastelli repair and all except one needed a
      modified senning repair. RESULTS: Early survivorship in both groups was 6/7.
      Follow-up ranges from 1 month to 48 months. The mean left ventricular ejection
      fraction (LVEF) in the arterial switch and senning patients was 65% and in the
      Rastelli and atrial rerouting was 52%. None of the survivors except one have any
      significant mitral regurgitation (MR). The one exception resulted from iatrogenic
      damage to a chorda during VSD closure. All except two patients are class I
      symptomatic and all are in normal sinus rhythm. CONCLUSION: Satisfactory early
      and mid term results of anatomic repair support the double switch option as the
      procedure of choice for patients of CCTGA amenable to biventricular repair.

PMID- 10333024
TI  - Clinical results of arterial switch operation for double-outlet right ventricle
      with subpulmonary VSD.
AB  - OBJECTIVE: An arterial switch operation is considered a good alternative for the
      repair of double-outlet right ventricle (DORV) with atrioventricular concordance
      connection and subpulmonary ventricular septal defect (VSD) when intraventricular
      rerouting is not feasible. The clinical results of an arterial switch operation
      with ventricular septal defect closure for this anomaly were studied. METHODS:
      Between 1986 and 1997, 27 patients ranging from 10 days to 5 years of age (mean
      0.4 years) underwent an arterial switch operation with ventricular septal defect
      closure for the correction of double outlet right ventricle with subpulmonary
      VSD. The 50% rule was used to define double-outlet right ventricle. Arch
      anomalies were associated in nine cases, and were corrected either previously or
      simultaneously. A subarterial muscle resection was performed in 14 without any
      subsequent stenosis of the ventricular outflow tract. The relationship of the
      great arteries was mostly anteroposterior in 15 and mostly side by side in 12.
      The left coronary artery (main trunk or circumflex artery) courses behind the
      pulmonary artery in 15/27 (six/15 in the anteroposterior relation and ten/12 in
      the side by side relation). The Lecompte maneuver was used to reconstruct the
      pulmonary artery in all but five cases with a side by side relationship of the
      great arteries. RESULTS: There was one operative death (3.7%) and three late
      deaths. The actuarial survival rate was 83 +/- 8% at 9 years. Right ventricular
      outflow tract obstruction including peripheral pulmonary stenosis developed in
      seven cases operated on in the early era. The reoperation free rate was 46 +/-
      20% at 9 years. CONCLUSION: Although double-outlet right ventricle with
      subpulmonary VSD has complex features, including an aortic arch obstruction and
      coronary artery anomalies, an optimal definitive surgical repair using an
      arterial switch operation can be performed safely with a thorough understanding
      of this variable anomaly. The prevention of right ventricular outflow tract
      obstruction at the time of an arterial switch operation may thus help improve the
      rate of late morbidity.

PMID- 10333025
TI  - Use of expanded polytetrafluoroethylene sutures as artificial tendinous cords in
      children with congenital mitral regurgitation.
AB  - OBJECTIVE: To determine the efficacy in the intermediate term of artificial cords
      inserted in children with congenital mitral regurgitation. METHODS: We
      reconstructed the tendinous cords using expanded polytetrafluoroethylene (ePTFE)
      sutures in 11 children with severe mitral regurgitation. In these patients, the
      aortic (anterior) leaflet of the mitral valve had been markedly prolapsed, the
      tendinous cords being partially lacking in seven, and elongated in the remaining
      four. In addition, one of the papillary muscles was hypoplastic in five and
      absent in three. The number of artificial cords constructed varied from two to
      six. Conventional annuloplasty was performed in all to plicate the dilated
      annular attachment of the valve. Ventricular septal defect was present in four
      patients, and other associated malformations in another two. Age at operation
      ranged from 9 months to 9 years old, with a mean of 4.5 years. RESULTS: All
      patients survived the operation. No reoperation has been needed thus far. No
      complications were encountered related to the use of the prosthetic materials or
      anticoagulation. As judged by echocardiography, regurgitation became trivial or
      slight immediately after the repair. In two patients, however, regurgitation
      recurred within 1 year of the operation. Coaptation between the leaflets was
      maintained by a compensatory growth at the site of attachment of the artificial
      cords. Catheterization demonstrated significant improvements in the end-diastolic
      volume of the left ventricle. CONCLUSION: Expanded polytetrafluoroethylene
      sutures can be used as artificial cords when attempting to repair the malformed
      mitral valve in children, providing excellent results in the short- and the
      intermediate-term after the surgical procedure.

PMID- 10333026
TI  - The influence of size mismatch on the hemodynamic performance of the pulmonary
      autograft in vitro.
AB  - OBJECTIVES: We established an in vitro model to investigate the effect of size
      mismatch between the aortic and pulmonary root on the hydrodynamic performance
      and leaflet motion of the pulmonary autograft. METHODS: Ten fresh porcine
      pulmonary roots (annulus diameter: 19-25 mm) were tested in a pulsatile flow
      simulator. The autografts then were implanted in fresh porcine aortic roots
      (annulus diameter: 19-30 mm) and retested in the flow simulator. Three roots were
      oversized by 21-39%, three were undersized by 32-45% and there were four size for
      size implantations. The external diameter of the roots and autografts was
      measured at the sinotubular junction at hydrostatic pressures of 0 - 120 mmHg.
      The transvalvular gradient and regurgitation were also measured and the effective
      orifice area was calculated. The leaflet motion was recorded on video. RESULTS:
      The fresh pulmonary roots were more compliant than the fresh aortic roots (46 +/-
      8.4% vs. 35 +/- 7.8% dilatation from 0 to 120 mmHg). The group of matching size
      autografts dilated by 43 +/- 4.9% in the same pressure range. The external
      diameter of the undersized autografts was 10 +/- 2.1% bigger than before
      implantation at 0 pressure and then the dilatation was 40 +/- 5.3% at 120 mmHg.
      The oversized implantation made the autografts 11 +/- 9.4% smaller in their
      relaxed state, but then they dilated by 65 +/- 11% as the pressure increased to
      120 mmHg, resulting in a net dilatation of 54% over the original undilated state.
      The under or oversizing had little effect on the pressure gradient measured
      across the valves (5.6 +/- 2.57 mmHg before, 6.3 +/- 3.27 mmHg after
      implantation). Only the oversized valves showed significantly higher gradients
      than the native pulmonary valves. The effective orifice area of the undersized
      autografts was slightly bigger and the oversized autografts was slightly smaller
      after implantation, although the differences were not significant. The size
      mismatch did not cause regurgitation on the valves. The video images showed very
      low-open leaflet-bending deformation, both on the fresh pulmonary and the
      autograft valves. CONCLUSION: Under or oversizing the pulmonary autograft up to
      40% of the annulus diameter did not affect the hydrodynamic parameters
      significantly. The compliance of the autograft root was able to compensate for
      the size mismatch without adversely influencing the valve performance.

PMID- 10333027
TI  - Intermediate-term durability of bicuspid aortic valve repair for prolapsing
      leaflet.
AB  - OBJECTIVE: To determine the durability of repair of a bicuspid aortic valve with
      leaflet prolapse, and to identify factors associated with repair failure.
      METHODS: From November 1988 to January 1997, 94 patients with a bicuspid aortic
      valve and regurgitation from leaflet prolapse had aortic valve repair. In 66
      patients, the repair employed triangular resection of the prolapsing leaflet. The
      remainder underwent mid-leaflet plication of the prolapsing leaflet. Mean age was
      38 +/- 10 years and 93% were male. Median follow-up was 5.5 years (range 0.2-9
      years). Factors associated with aortic valve competence and durability were
      identified by multivariable logistic and hazard function analyses. RESULTS: Early
      valve competence was more difficult to achieve in patients with large, poor
      functioning ventricles (P = 0.02). Aortic valve reoperation was necessary in 12
      patients that included three re-repairs and nine aortic valve replacements.
      Freedom from reoperation was 95, 87 and 84% at 1, 5 and 7 years, respectively.
      The instantaneous risk of reoperation was highest immediately after operation,
      and fell rapidly to approximately 2% per year and less after 2 years. The only
      risk factor identified was the presence of residual aortic regurgitation (trace
      to mild in 35 cases) on immediate intraoperative post-repair transesophageal
      echocardiography. Late aortic regurgitation did not progress detectably across
      time (P = 0.3). There were no deaths, early or late. CONCLUSION: Bicuspid aortic
      valve repair for prolapsing leaflet is a safe procedure with good intermediate
      term outcome. However, any residual aortic regurgitation jeopardizes repair
      durability and initial repair achievement is more difficult in patients with
      dilated, poor functioning ventricles.

PMID- 10333028
TI  - Surgery for endomyocardial fibrosis revisited.
AB  - OBJECTIVE: To identify life expectancy after surgery for endomyocardial fibrosis
      (EMF) and the events that influence it. METHODS: Eighty-three patients with EMF
      underwent endocardial decortication and atrioventricular valve replacement or
      repair, between December 1977 and December 1997. There were 66 (79.6%) female and
      17 (20.4%) male patients, ranging in age from 4 to 59 years (mean, 31). Thirty
      seven (44.5%) had biventricular disease, 34 (41.0%) had disease of the right
      ventricle alone and 12 (14.5%) had EMF confined to the left ventricle. All were
      in functional class III or IV (New York Heart Association classification).
      RESULTS: Sixty-eight (81.9%) patients survived the operation and were followed up
      for periods ranging from 2 months to 17 years. The total follow-up time was 6290
      patient/months (mean, 92 months). There were 15 late deaths, but in six, the
      cause was not related to the underlying disease. Four (5.8%) patients presented
      recurrence of the fibrosis and were reoperated on and in six (8.8%), EMF appeared
      in the other ventricle. Five (7.3%) patients were reoperated on to replace either
      a valve prosthesis or a native valve which had been preserved during the first
      procedure. Only 24 (45%) of the 53 surviving patients are in functional class I
      or II. The actuarial probability of survival at 17 years, including operative
      mortality, was 55%. CONCLUSION: Surgical treatment of EMF should be considered a
      palliative procedure because surgery does not alter the progressive nature of the
      disease. However, surgical therapy is recommended for patients with EMF and heart
      failure as it is their only hope of survival.

PMID- 10333029
TI  - Perioperative mortality and major cardio-pulmonary complications after lung
      surgery for non-small cell carcinoma.
AB  - OBJECTIVES: A database of patients operated of lung cancer was analyzed to
      evaluate the predictive risk factors of operative deaths and life-threatening
      cardiopulmonary complications. METHODS: From 1990 to 1997, data were collected
      concerning 634 consecutive patients undergoing lung resection for non-small cell
      carcinoma in an academic medical centre and a regional hospital. Operations were
      managed by a team of experienced surgeons, anaesthesiologists and chest
      physicians. Operative mortality was defined as death within 30 days of operation
      and/or intra-hospital death. Respiratory failure, myocardial infarct, heart
      failure, pulmonary embolism and stroke were considered as major non-fatal
      complications. Preoperative risk factors, extent of surgery, pTNM staging,
      perioperative mortality and major cardiopulmonary complications were recorded and
      evaluated using chi-square statistics and multivariate logistic regression.
      RESULTS: Complete data were obtained in 621 cases. The overall operative
      mortality was 3.2% (n = 19). Cardiovascular complications (n = 10), haemorrhage
      (n = 4) and sepsis or acute lung injury (n = 5) were incriminated as the main
      causative factors. In addition, there were 13 life-threatening complications
      (2.1%) consisting in strokes (n = 4), myocardial infarcts (n = 5), pulmonary
      embolisms (n = 1), acute lung injury (n = 1) and respiratory failure (n = 2).
      Four independent predictors of operative death were identified: pneumonectomy,
      evidence of coronary artery disease (CAD), ASA class 3 or 4 and period 1990-93.
      In addition, the risk of major complications was increased in hypertensive
      patients and in those belonging to ASA class 3 or 4. A trend towards improved
      outcome was observed during the second period, from 1994 to 97. CONCLUSION: Our
      data demonstrate that perioperative mortality is mainly dependent on the extent
      of surgery, the presence of CAD and provision of adequate medical and nursing
      care. Preoperative testing and interventions to reduce the cardiovascular risk
      factors may help to further improve perioperative outcome.

PMID- 10333030
TI  - Comparison of long-term results of total fundoplication gastroplasty and Belsey
      Mark IV antireflux operations in relation to the severity of oesophagitis.
AB  - OBJECTIVE: Belsey Mark IV (BM IV) and total fundoplication gastroplasty (TFG)
      were the standard anti-reflux operations in two consecutive periods in Nottingham
      City Hospital Thoracic Surgery Unit. The aim of this study was to compare the
      long-term results obtained by these two procedures emphasizing their relation to
      the severity of the oesophageal mucosal damage. METHODS: Ninety patients (50
      females and 40 males with a mean age of 57 years) who had a BM IV operation
      between 1976 and 1983 and 86 patients (46 females and 40 males, with a mean age
      of 56.5 years) undergoing a TFG procedure between 1983 and 1986 were evaluated.
      All patients were assessed preoperatively by means of clinical history, barium
      meal and endoscopy. In addition, 72 of the patients having a TFG had prolonged pH
      monitoring and manometric studies. The unit policy is for life-long follow-up.
      The symptoms at review were assessed and graded according to the criteria
      published by Orringer et al. (Orringer MB, Skinner DB, Belsey RHR. Long-term
      results of the Mark IV operation for hiatal hernia and analyses of recurrences
      and their treatment. J Thorac Cardiovasc Surg 1972;63:25-33). RESULTS: In the BM
      IV group there was one post-operative death (1.1%). The median follow-up was 11
      years (range 3-18 years). Overall good results were achieved in 64 patients
      (71.9%). In patients without oesophagitis (n = 24) the success rate was 91.7%
      while for grades I (n = 17), II-III (n = 36) and IV (n = 12) oesophagitis this
      was 76.5, 66.7 and 41.7%, respectively (P = 0.01). The actuarial success rate at
      10 through to 18 years was 71.0%. In the TFG group there was no postoperative
      death. The median follow-up was 10 years (range 2-14 years). Overall good results
      were achieved in 78 patients (90.7%). In the absence of oesophagitis (n = 10) the
      success rate was 90.0% and for grades I (n = 12), II-III (n = 26) and IV (n = 38)
      oesophagitis this was 91.6, 92.3 and 89.4%, respectively. The actuarial success
      rate at 10 through to 14 years was 90.3%. The differences in the overall success
      rate (P = 0.002), the success rates forgrades II-III (P = 0.02) and IV (P =
      0.001) oesophagitis and the long-term actuarial success rates (P = 0.001) were
      significant. CONCLUSION: These data provide evidence on the superiority of the
      TFG against the BM IV in achieving long-term relief of reflux symptoms in the
      presence of severe oesophagitis. We believe that failure of BM IV in this setting
      is due to obvious or subtle oesophageal shortening.

PMID- 10333031
TI  - Functional and mechanical sequelae of colon interposition for benign oesophageal
      disease.
AB  - OBJECTIVE: In an attempt to estimate the incidence and severity of the functional
      and mechanical problems associated with colon interposition for benign
      oesophageal disease, a retrospective analysis of a single centre experience was
      undertaken. METHODS: Between 1961 and 1990, a total of 365 patients who survived
      the postoperative stay in hospital were followed up over 7-38 years and form the
      basis for this study. Upper gastro intestinal symptoms in these patients were
      investigated clinically, radiologically, endoscopically and in the oesophageal
      laboratory. Mechanical and functional abnormalities requiring surgical
      intervention for relief of symptoms were documented. RESULTS: There were two late
      presentations of colo bronchial fistulae, two instances of persistent colo
      cutaneous fistulae, three cases of diaphragmatic herniation and two
      adenocarcinomata of the colo gastric junction in the patients with short segment
      colon interposition. Amongst the long segment colon interposition patients there
      was one hiatal obstruction, two thoracic inlet delays associated with pseudo
      diverticulosis and one hiatal obstruction. One other patient presented with an
      adenocarcinoma of the intrathoracic colon. There were four patients requiring
      revision of the cervical oesophago colic anastomosis, two of them on recurrent
      occasions. The remaining sequelae were functional and were associated with
      increasing redundancy of the colonic segments at different levels. There were 17
      such patients, two of whom developed significant redundancy at two different
      levels. CONCLUSIONS: Although the patients with short segment colon interposition
      developed predominantly avoidable iatrogenic complications, those undergoing long
      segment colon interposition developed functional sequelae requiring re-operations
      in later life.

PMID- 10333032
TI  - Clamshell or sternotomy for double lung or heart-lung transplantation?
AB  - OBJECTIVE: To evaluate the influence of either incision on the lungs and chest
      wall. METHODS: Ninety-two double lung (DLT) or heart-lung (HLT) transplantations
      were done since January 1990. There were 22 (24%) hospital deaths, leaving 70
      patients with complete data for evaluation. We did 38 DLT and 32 HLT for end
      stage chronic respiratory failure (n = 22) and primary (n = 34) or secondary (n =
      14) pulmonary hypertension, using 37 fourth or fifth interspace clamshell
      incisions and 33 median sternotomies. RESULTS: The clamshell group included a
      higher percentage of DLTs (73 vs. 33%, P = 0.001) but recipient age, gender,
      preoperative diagnosis, bronchial anastomotic complications, number of
      cytomegalovirus infection, episode of acute rejection per patient-months and
      incidence of bronchiolitis obliterans were not statistically different between
      the two groups. At a follow-up time of 3.7 +/- 2 years, the overall 5-year
      survival of 57% was not influenced by the type of incision. The clamshell
      incision caused sternal over-riding in 12 (32%) patients, and eight surgical
      clamshell revision were necessary as compared with one median sternotomy (P =
      0.02). The clamshell incision was associated with a significantly higher
      incidence of postoperative chronic pain (27 vs. 6%, P = 0.02). Postoperative
      mechanical properties of the chest wall were significantly (P < 0.0001) worse in
      the clamshell-group patients while the intrinsic properties of the airways were
      not different. CONCLUSIONS: The clamshell incision results in more postoperative
      deformity, chronic pain, and impaired function as compared with median
      sternotomy. A bilateral anterolateral thoracotomy without division of the sternum
      is proposed for the sequential bilateral lung transplantation technique.

PMID- 10333033
TI  - The heart produces but the lungs consume proinflammatory cytokines following
      cardiopulmonary bypass.
AB  - OBJECTIVE: Proinflammatory cytokines, such as interleukin-6 (IL-6), and soluble
      adhesion molecules, such as E-selectin, may play an important role in patient
      response to cardiopulmonary bypass (CPB). We sought to define whether the heart
      and the lungs serve as important sources of these inflammatory mediators under
      clinical conditions of myocardial revascularization using CPB and cardioplegic
      arrest. METHODS: Plasma levels of IL-6 and E-selectin were measured in coronary
      sinus (CS), arterial, pulmonary arterial (PA) and left atrial (LA) blood samples
      taken from 12 consecutive patients (68.3 +/- 11 years; five females) undergoing
      coronary artery bypass grafting (CABG). Blood samples were collected
      preoperatively, after reperfusion, and 1, 6, 12 and 18 h following surgery. CS
      and LA blood was drawn using transcutaneous catheters. PA artery blood was
      obtained through a Swan-Ganz catheter. Cytokine levels were determined by
      standard enzyme linked immunosorbent assay (ELISA) technique. RESULTS: A mean of
      3.8 +/- 1 coronary anastomoses were performed. The CPB time and aortic X-clamp
      time were 91 +/- 15 and 45 +/- 10 min, respectively. IL-6 levels increased
      significantly after CPB and peaked 6 h postoperatively. There was also a
      significant increase of E-selectin levels with an onset at 1 h and a peak at 12 h
      postoperatively. At all time points the IL-6 and E-selectin concentrations were
      significantly higher in the CS than in arterial blood. In contrast, the levels of
      both mediators measured in the LA were significantly lower than those in the PA.
      CONCLUSION: The reperfusion of ischemic myocardium during CABG results in a
      significant increase in plasma levels of IL-6 and E-selectin. Our data indicate
      that the myocardium, but not the lungs, is a predominant source of IL-6 and E
      selectin release following CPB. The lungs may consume rather than release those
      mediators during reperfusion. Not the CPB per se, but the myocardial ischemia
      seems to be crucial in the pathogenesis of the inflammatory response observed
      following open heart surgery.

PMID- 10333034
TI  - Acute pulmonary hypertension after cardiopulmonary bypass in pig: the role of
      endogenous endothelin.
AB  - BACKGROUND: Acute pulmonary hypertension occurring after cardiopulmonary bypass
      can be a cause of post-operative morbidity and mortality. The purpose of this
      study was to investigate whether bosentan, a non-peptidic mixed endothelin
      antagonist affected the pulmonary hypertension induced by experimental
      cardiopulmonary bypass. METHODS: Pigs were anesthetized and instrumented to
      determine hemodynamic measurements. Pigs were randomized to receive either 3
      mg/kg bolus + 7 mg/kg per h bosentan (n = 8) or saline (n = 7). All pigs
      underwent 90 min of cardiopulmonary bypass and were further observed for a 120
      min period. RESULTS: In the control group, cardiopulmonary bypass induced a
      dramatic pulmonary hypertension (+78 +/- 13%, P < 0.005) and accompanied an
      increase of pulmonary vascular resistance (+228 +/- 50%, P < 0.005), whereas, in
      the treated group, bosentan completely prevented these deleterious effects of
      cardiopulmonary bypass with only a moderate decrease of systemic vascular
      resistance (-19 +/- 14.6%, P < 0.05). CONCLUSIONS: The present findings support
      the hypothesis that endogenous endothelin is a mediator of acute pulmonary
      hypertension occurring after cardiopulmonary bypass. Bosentan, a mixed endothelin
      antagonist completely prevented pulmonary hypertension after cardiopulmonary
      bypass and may, therefore, have therapeutic applications in the management of
      patients following cardiac surgery.

PMID- 10333035
TI  - Circuits with surface modifying additive alter the haemodynamic response to
      cardiopulmonary bypass.
AB  - OBJECTIVE: Blood contact with synthetic surfaces during cardiopulmonary bypass
      (CPB), inevitably results in the activation of a variety of interrelated pathways
      of inflammation and coagulation that may contribute to postoperative
      complications in cardiac surgery patients. The objective of this trial was to
      evaluate clinical events and complement activation related to the use of a novel
      biomaterial, into which a surface modifying additive had been incorporated into
      the polymer used to prepare the bypass circuit. METHODS: A prospective, double
      blind trial was carried out with 34 patients randomized to surgery, with either a
      standard circuit or a circuit treated ('tip to tip') with the surface modifying
      additive. Variables recorded included perioperative haemodynamics, volume
      replacement, alpha-agonist and inotrope use. Terminal complement complex (SC5b-9)
      was measured using an ELISA. RESULTS: Upon initiation of bypass, there was a
      decrease in mean arterial pressure (MAP) in the control group, not seen in the
      test group (P = 0.0005, ANOVA). There was a decrease in the total volume of
      replacement fluid given intraoperatively in the test group as compared with the
      control group (total plus prime; control 5.3 +/- 1.2 L, test 4.4 +/- 1.9 L, P =
      0.03, Mann-Whitney test). There was a trend to decreased need for inotrope
      infusion in the test group after CPB (test 1/17, control 6/17, Fisher exact test;
      P = 0.085). No difference was seen in the generation of terminal complement
      complex between the groups either during or after CPB. CONCLUSIONS: The decrease
      in blood pressure in the control group, upon the initiation of CPB, did not occur
      in patients undergoing CPB with the circuit prepared with the surface modifying
      additive. The decrease in blood pressure was likely associated with the increase
      in total administered fluids intraoperatively (approximately 1 l/patient) and
      perhaps the trend towards higher use of inotropes in the control patients as
      opposed to the test patients. These haemodynamic changes did not appear to be
      related to complement activation early in CPB.

PMID- 10333036
TI  - An in-vitro evaluation of aortic arch vessel perfusion characteristics comparing
      single versus multiple stream aortic cannulae.
AB  - OBJECTIVE: During extracorporeal circulation design and orientation of aortic
      cannulae tips mainly determine flow pattern in the aortic arch and arch vessels
      which is the objective of this in vitro study, comparing single versus multiple
      stream cannulae. METHODS: In an aortic arch glass model, jet streams of 21-24
      French aortic cannulae which were inserted in the ascending aorta were directed
      alternatively at the different arch vessels. Flows and pressures in the arch
      vessels were measured at pump flows of 3-6 l/min. RESULTS: With optimal
      orientation of the jet stream in the aortic arch, no preferential flow in the
      arch vessels was seen. In the single jet stream aortic cannulae group a
      significant parallel increase in flow and pressure in the jet streamed arch
      vessels compared to the non-jet streamed arch vessels occurred (P < 0.05). With
      the jet stream directed on vessel 2 (left carotid vessel) there was a significant
      pressure and flow difference comparing the two non-jet streamed vessels with each
      other (P < 0.03). In the single stream 24 French cannulae the highest vessel
      pressure of 168 mmHg and an increase in flow of 186 ml/min was measured in the
      jet streamed left carotid artery at 6 l/min pump flow. The multiple stream
      cannulae provoked the highest vessel pressure of 106 mmHg in the corresponding
      jet streamed vessel and an increase in flow of 20 ml/min. CONCLUSION: Tip design
      of aortic cannulae and the orientation of its jet stream are potential sources of
      remarkable imbalance of arch vessel perfusion especially with single jet stream
      cannulae. These effects are more pronounced with single jet stream cannulae.
      These results may have important clinical implications regarding perfusion of
      arch vessels during extracorporeal circulation.

PMID- 10333037
TI  - A biomechanical study of median sternotomy closure techniques.
AB  - OBJECTIVE: Sternal dehiscence is a complication of median sternotomy incisions
      with high mortality and morbidity. Different techniques of sternal closure have
      been described. Rigid fixation of the sternum results in earlier union. We
      measured the rigidity of sternotomy fixation using a mechanical model in order to
      differentiate different techniques of sternal closure using their biomechanical
      characteristics. METHODS: We measured the force-displacement curves of six
      different fixation techniques using a metal sternal model using a computerized
      materials-testing machine. We tested straight wires (the most commonly used
      surgical technique), figure-of-8 wires, 'repair' technique (used when a wire
      breaks), Ethibond, Sterna-band and a 'multitwist' closure described for the first
      time. RESULTS: At 20 kg force, twisted wires used for sternotomy closures start
      to untwist. The most rigid closure was a multitwist closure that displaced only
      0.37 mm at a force of 20 kg. Straight wires displaced 0.78 mm, figure-of-8 wires
      1.20 mm, Sterna-band 1.37 mm, repair wires 5.08 mm, Ethibond 9.37 mm. The single
      factor Anova test for the rigidity of the different closures had P-values
      <0.0001. CONCLUSIONS: We applied a mathematical model to calculate chest wall
      forces during coughing, in order to determine the force placed upon a sternotomy
      closure. We conclude that severe coughing may cause wires to untwist. We discuss
      potential applications of different wire closures based on their characteristics.

PMID- 10333038
TI  - Combination of extracorporeal membrane oxygenation (ECMO) and pulmonary lavage in
      a patient with pulmonary alveolar proteinosis.
AB  - We describe a rare case of pulmonary alveolar proteinosis in a young woman with
      dyspnea and progressive hypoxaemia due to the alveolar deposition of insoluble,
      surfactant-like material. Routine treatment includes whole-lung-lavage (WLL)
      using double-lumen-tubes for selective lavaging of each lung. We performed three
      whole-lung-lavages and used veno-venous extracorporeal membrane oxygenation (v
      vECMO) to support oxygenation during these procedures.

PMID- 10333039
TI  - Resection of a right atrial metastatic melanoma with unknown origin of primary
      tumor.
AB  - Cardiac involvement of malignant melanoma is generally part of a widespread tumor
      dissemination, which is mostly multifocal. Hence the disease is usually not
      amenable to surgical intervention. We report successful resection of a large
      intracavitary melanoma to the right atrium, the primary origin of which was
      unknown. The right atrium was reconstructed with an autologous pericardial patch.
      At 12-month follow-up the patient remains asymptomatic.

PMID- 10333040
TI  - Aortic valve replacement through a limited bilateral thoracotomy in a patient
      with a tracheostoma.

PMID- 10333041
TI  - Diabetes epidemiology as a tool to trigger diabetes research and care.

PMID- 10333042
TI  - The impact of a family history of Type II (non-insulin-dependent) diabetes
      mellitus on the risk of diabetic nephropathy in patients with Type I (insulin
      dependent) diabetes mellitus.
AB  - AIMS/HYPOTHESIS: There is substantial evidence for a role of genetic factors in
      the development of diabetic nephropathy. In Pima Indians, a link between
      susceptibility to diabetic nephropathy and Type II (non-insulin-dependent)
      diabetes mellitus has been proposed. In this study, our aim was to examine the
      association between a family history of Type II diabetes and diabetic nephropathy
      in patients with Type I (insulin-dependent) diabetes mellitus. METHODS: In a
      cross-sectional case-control study, we assessed the prevalence of Type II
      diabetes in the parents of 137 Type I diabetic patients with diabetic nephropathy
      (albuminuria > 300 microg/min in two of three overnight urine collections)
      compared with the parents of 54 Type I diabetic patients without nephropathy
      (albuminuria < 20 microg/min). RESULTS: Thirty-four (25 %) of the patients with
      nephropathy compared with five (9 %) of the patients without nephropathy had a
      parental history of Type II diabetes (p = 0.019). A parental history of Type II
      diabetes was associated with a three-fold risk [odds ratio 2.95 (95% confidence
      interval: 1.03 to 8.40), p = 0.043] of diabetic nephropathy after adjustment for
      sex, glycaemic control and family history of hypertension. Furthermore, there was
      an excess of risk factors for development of Type II diabetes (higher fasting
      plasma glucose concentrations, higher prevalence of hypertension, higher waist
      hip ratio and a tendency towards more glucose intolerance) among previously non
      diabetic parents of patients with nephropathy. CONCLUSION/INTERPRETATION: Genetic
      or environmental factors or both related to familial Type II diabetes increase
      susceptibility to diabetic nephropathy in patients with Type I diabetes.

PMID- 10333043
TI  - Effect of thiazolidinediones on expression of UCP2 and adipocyte markers in human
      PAZ6 adipocytes.
AB  - AIMS/HYPOTHESIS: Thiazolidinediones, a new class of insulin sensitizers, up
      regulate the expression of uncoupling protein 2 in rodent adipocytes. It is not
      known, however, whether thiazolidinediones influence uncoupling protein 2
      expression in human adipocytes. We therefore investigated the effect of these
      drugs on uncoupling protein 2 expression in the recently immortalized human PAZ6
      adipocyte cell line. METHODS: Immortalized human PAZ6 preadipocytes were
      differentiated into adipocytes in the presence or absence of thiazolidinediones.
      The effect of the drugs on uncoupling protein 2 expression and adipocyte
      differentiation was measured by reverse transcription-polymerase chain reaction
      of mRNA of uncoupling protein 2 and of five adipocyte differentiation markers.
      RESULTS: When cells were differentiated 15 days in the presence of
      thiazolidinediones, uncoupling protein 2 expression was 2.1-fold higher than in
      the absence of the drugs. The expression of five adipocyte differentiation
      markers was, however, also increased by thiazolidinediones. Short-term incubation
      for 4 and 24 h with thiazolidinediones increased uncoupling protein 2 expression
      1.35-fold and 2.3-fold, respectively. The expression of adipocyte markers studied
      in parallel was also augmented. CONCLUSION/INTERPRETATION: Thiazolidinediones
      rapidly increase the expression of uncoupling protein 2 in human PAZ6 adipocytes
      but the increase of uncoupling protein 2 expression is always associated with an
      augmentation of the expression of all adipocyte markers studied in parallel. This
      indicates that the effect of thiazolidinediones on uncoupling protein 2 mRNA
      reflects a general increase in adipocyte differentiation rather than a specific
      augmentation of uncoupling protein 2 gene expression.

PMID- 10333044
TI  - Exaggerated vasopressin secretion and attenuated osmoregulated thirst in human
      survivors of hyperosmolar coma.
AB  - AIMS/HYPOTHESIS: To test the hypothesis that subnormal thirst sensation could
      contribute to the development of the hypernatraemia characteristic of
      hyperosmolar coma, we studied osmoregulation in survivors of hyperosmolar coma.
      METHODS: Eight survivors of hyperosmolar coma, eight control subjects with Type
      II (non-insulin-dependent) diabetes mellitus and eight healthy control subjects
      underwent water deprivation during which measurements of thirst, plasma
      osmolality and vasopressin were taken. RESULTS: Water deprivation caused greater
      peak plasma osmolality in the hyperosmolar coma group (301.7 +/- 2.7 mmol/kg)
      than in Type II diabetic (294.3 +/- 3.2 mmol/kg, p < 0.01) or control group
      (296.9 +/- 3.0 mmol/kg, p < 0.01) and a greater increase in plasma vasopressin
      concentration (hyperosmolar coma, 5.8 +/- 1.3 pmol/l, Type II diabetes, 1.8 +/-
      1.3 pmol/l, p < 0.001, control subjects, 2.2 +/- 1.8 pmol/l, p < 0.001). Thirst
      ratings were lower following water deprivation in the hyperosmolar coma group
      (3.5 +/- 0.8 cm) than in Type II diabetes (7.7 +/- 1.6 cm, p < 0.001) or control
      subjects (7.4 +/- 1.3 cm, p <0.001), and the hyperosmolar group patients drank
      less in 30 min following water deprivation (401 +/- 105 ml) than Type II diabetic
      (856 +/- 218 ml, p < 0.001) or control subjects (789 +/- 213 ml, p < 0.001).
      CONCLUSION/INTERPRETATION: Survivors of hyperosmolar coma have subnormal
      osmoregulated thirst and fluid intake, which might contribute to the
      hypernatraemic dehydration typical of the condition.

PMID- 10333045
TI  - Evidence for iNOS-dependent peroxynitrite production in diabetic platelets.
AB  - AIMS/HYPOTHESIS: The aim of the present study was twofold. Firstly, to determine
      whether diabetic platelets produce more peroxynitrite than normal platelets and
      secondly to correlate the peroxynitrite production with the intraplatelet
      induction of the inducible isoform of nitric oxide-synthase. METHODS:
      Intraplatelet peroxynitrite production was monitored with dichlorofluorescin
      acetate with a combination of confocal microscopy and steady-state fluorescence.
      The platelets were probed for the induction of the inducible-nitric oxide
      synthase by western immunoblotting. RESULTS: In the presence of extracellular L
      arginine (100 micromol/l), platelets from subjects with Type I (insulin
      dependent) diabetes displayed about 5 times higher fluorescence than those from
      control subjects. To determine whether inducible-nitric oxide-synthase was the
      source of peroxynitrite, dichlorofluorescein production was quantified as a
      function of L-arginine as well as nitric oxide-synthase inhibitors, in platelets
      from control subjects, subjects with Type I diabetes and subjects with Type II
      (non-insulin-dependent) diabetes mellitus. Platelets from subjects with Type I
      yielded about sevenfold and those from Type II about threefold larger amounts of
      L-arginine/nitric oxide-synthase-dependent dichlorofluorescein fluorescence than
      those from control subjects. The platelets were then immunologically probed for
      inducible-nitric oxide-synthase, which has previously been implicated in
      peroxynitrite production and detected in megakaryocytes of subjects with coronary
      heart disease. Western immunoblots of intraplatelet proteins indicated that the
      inducible-nitric oxide-synthase was absent in control subjects. Platelets from
      both Type I and Type II diabetic subjects, however, contained inducible-nitric
      oxide-synthase. CONCLUSION/INTERPRETATION: Inducible-nitric oxide-synthase
      derived peroxynitrite is a source of platelet damage in diabetes.

PMID- 10333046
TI  - The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and
      decreases cardiovascular risk and cachexia in diabetic mice suffering from
      pancreatic beta-cell dysfunction.
AB  - AIMS/HYPOTHESIS: Although retinoid X receptor (RXR) and peroxisome proliferator
      activated receptor-gamma (PPARgamma) agonists have antidiabetic effects in
      hyperinsulinaemic animals, little information exists on their effects after
      pancreatic beta-cell failure. Thus, we examined if RXR and PPARgamma agonists
      alter distinct metabolic pathways in animals suffering from impaired insulin
      secretion. METHODS: Adverse side effects and antidiabetic responses were measured
      in db/db mice treated from 14-16 weeks of age with the RXR agonist, LG100268,
      and/or the PPARgamma agonists, BRL49653 or GW1929. RESULTS: In animals treated
      with LG100268 or BRL49653, serum glucose, glycohaemoglobin and the cardiovascular
      risk factor, fibrinogen, decreased to the same extent. Both of these agonists
      were equally effective at increasing insulin accumulation in beta cells, although
      neither agent had an effect on serum insulin concentrations. In contrast, the RXR
      agonist was less effective than the PPARgamma agonists at lowering serum
      triglycerides and non-esterified fatty acids and increasing interscapular brown
      fat and body weight. Further, LG100268 increased serum alkaline phosphatase and
      liver mass, hepatic fat accumulation, lauric acid hydroxylase activity, catalase
      immunostaining and peroxisomal number more than the PPARgamma agonists. Moreover,
      co-treatment with the RXR and PPARgamma agonists reduced glucose, triglycerides,
      non-esterified fatty acids and cholesterol more than either agent alone.
      CONCLUSION/INTERPRETATION: These data suggest 1) RXR and PPARgamma agonists
      decrease islet degeneration, cardiovascular risk and cachexia during later stages
      of diabetes, 2) RXR agonists are less effective than PPARgamma agonists at
      decreasing serum lipids and causing weight gain and 3) RXR agonists have a more
      pronounced effect on liver metabolism (e.g. peroxisome accumulation and
      hepatomegaly) than PPARgamma agonists.

PMID- 10333047
TI  - Glutamate decarboxylase (GAD65) and tyrosine phosphatase-like protein (IA-2)
      autoantibodies index in a regional population is related to glucose intolerance
      and body mass index.
AB  - AIMS/HYPOTHESIS: Our aims were to investigate the concentrations and prevalence
      of autoantibodies against the Mr 65.000 isoform of glutamate decarboxylase
      (GAD65) and the tyrosine phosphatase-like protein (IA-2) in adults and to test
      the hypothesis that GAD65 and IA-2 autoantibodies in a regional population are
      related to abnormal oral glucose tolerance. METHODS: We analysed serum from 2157
      Swedish subjects aged either 30, 40, 50 or 60 years old who, in 1988-1992,
      participated in the Vasterbotten County Health Project and were subjected to the
      World Health Organisation (WHO) standard oral glucose tolerance test at entry
      into the study. RESULTS: We found 23 of 2157 (1.1%) and 17 of 2152 (0.8%)
      subjects exceeded the 99th centile of GAD65 autoantibody index and IA-2
      autoantibody index, respectively. In 18 subjects with diabetic oral glucose
      tolerance test, GAD65 autoantibody concentrations were higher than in those with
      normal oral glucose tolerance test (p = 0.02). Subjects with IGT (n = 185)
      [corrected] and diabetes (n = 18), i.e. abnormal OGTT (n = 203) [corrected], had
      higher GAD65Ab [corrected] index compared with those with normal OGTT (p = 0.026)
      [corrected]. A stepwise multiple logistic regression test showed that the odds
      ratios for subjects in the highest BMI group to exceed the 95th or 99th GAD65
      autoantibody centile were 3.6 (CI 1.4-8.9) and 17.6 (CI 2.6-121.6), respectively.
      CONCLUSION/INTERPRETATION: GAD65 and IA-2 autoantibodies, are associated with
      impaired or diabetic glucose tolerance in an adult regional population. This
      observation together with the association between GAD65 autoantibody
      concentrations and body mass index indicate a possible relation between islet
      autoimmunity and beta-cell function abnormalities with obesity and insulin
      resistance.

PMID- 10333048
TI  - Spontaneous T-cell proliferation in the non-obese diabetic mouse to a peptide
      from the unique class II MHC molecule, I-Ag7, which is also protective against
      the development of autoimmune diabetes.
AB  - AIMS/HYPOTHESIS: Major histocompatibility complex class II molecules present
      antigenic peptides to T-cells and have an important role in T-cell thymic
      education. The mechanism by which major histocompatibility complex alleles confer
      a high genetic risk for autoimmune diabetes is not known. One hypothesis is that
      during positive thymic selection, the peripheral T-cell repertoire is modelled by
      major histocompatibility complex-restricted presentation of self major
      histocompatibility complex molecule-derived peptides, some of which mimic tissue
      autoantigens. The sequence similarity between a known T-cell epitope of glutamic
      acid decarboxylase-65, 509:VPPSLRTLED and the non-obese diabetic mouse class II
      major histocompatibility complex molecule I-Ag7 86:VPTSLRRLEQ is consistent with
      this. METHODS: We measured spontaneous proliferation of peripheral T-cells from
      non-obese diabetic mice and other, non-diabetes-prone strains, to the I-Ag7 86
      101 and glutamic acid decarboxylase-65(509-524) peptides, binding of these
      peptides to intact I-Ag7 and assessed the effect of tolerance induction on
      diabetes development, by injecting young non-obese diabetic mice with high doses
      of peptide. RESULTS: T-cells from non-obese diabetic, but not other mice strains,
      spontaneously proliferate to the I-Ag7 86-101 and glutamic acid decarboxylase
      65(509-524) peptides, but not control peptides. Both test peptides bind I-Ag7.
      Tolerance induction prolongs diabetes-free survival in non-obese diabetic mice
      when either the I-Ag7 86-101 or glutamic acid decarboxylase-65(509-524) peptide,
      but not control peptide, is used. CONCLUSION/INTERPRETATION: A peptide from the
      unique class II major histocompatibility complex, diabetes-susceptibility
      molecule, I-Ag7, presented by I-Ag7 is a target of T-cell responses in diabetes
      prone nonobese diabetic mice and tolerance induction against the peptide offers
      appreciable protection against the development of diabetes.

PMID- 10333049
TI  - Apoptosis and remodelling of beta cells by paracrine interferon-gamma without
      insulitis in transgenic mice.
AB  - AIMS/HYPOTHESIS: To examine whether interferon-gamma destroys islet beta cells
      directly or indirectly through lymphocyte activation, or whether direct action of
      interferon-gamma on beta cells by itself induces diabetes without insulitis.
      METHODS: To avoid possible nonspecific breakdown of beta cells by transgenic
      overexpression of interferon-gamma by the insulin promoter, we generated
      transgenic mice expressing interferon-gamma under the control of rat glucagon
      promoter (RGP-IFN-gamma-Tg mice). RESULTS: The absence of insulitis in RGP-IFN
      gamma-Tg mice enabled us to investigate the direct effects of paracrine
      interferon-gamma. In RGP-IFN-gamma-Tg mice, serum concentrations of interferon
      gamma and tumour necrosis factor-alpha (TNF-alpha) were 50 and 6 times higher
      than those in their littermates, respectively, and glucose-responsive insulin
      secretion decreased to one-half the level of that in the littermates. Transgenic
      interferon-gamma induced remodelling of beta cells where apoptosis of many beta
      cells was compensated by their vigorous regeneration and diabetes did not occur
      in most of the RGP-IFN-gamma-Tg mice. CONCLUSION/INTERPRETATION: Interferon-gamma
      alone is insufficient for the complete destruction of beta cells in vivo, and
      factors other than interferon-gamma including activated lymphocytes or other
      cytokines, are necessary in addition to interferon-gamma for the development of
      Type I (insulin-dependent) diabetes mellitus.

PMID- 10333050
TI  - Immunological abnormalities in islets at diagnosis paralleled further
      deterioration of glycaemic control in patients with recent-onset Type I (insulin
      dependent) diabetes mellitus.
AB  - AIMS/HYPOTHESIS: To determine whether the clinical heterogeneity observed in the
      development of Type I (insulin-dependent) diabetes mellitus correlates with
      immunohistochemical differences observed at diagnosis. METHODS: Patients (n = 17)
      with recent-onset diabetes clinically considered to be insulin dependent (Type
      I), underwent pancreatic biopsy for immunohistological analysis. These patients
      were divided into two groups based on the presence or absence of islet
      immunological abnormalities (insulitis or hyperexpression of MHC class I antigens
      or both). The patients were also HLA typed and tested for islet cell antibodies
      and antibodies to glutamic acid decarboxylase (GAD-Ab). All patients were
      followed monthly for 2 years and their fasting plasma glucose, haemoglobin A1c
      and daily insulin doses were recorded. The clinical course of patients with islet
      immunological abnormalities was compared with that of patients without those
      abnormalities. RESULTS: Patients with and without islet immunological
      abnormalities did not differ with regard to HLA type or islet cell antibodies.
      Antibodies to glutamic acid decarboxylase correlated with the presence of
      insulitis and MHC class I hyperexpression. These local immunological
      abnormalities were also associated with higher haemoglobin A1c values (p < 0.05)
      and a trend towards greater insulin requirements. Further, patients with the
      islet abnormalities had higher fasting plasma glucose concentrations 2 years
      after the biopsy than at the time of the biopsy (p < 0.05).
      CONCLUSION/INTERPRETATION: The heterogeneous clinical course observed following
      diagnosis in patients with Type I diabetes correlates with islet immunological
      abnormalities. Insulitis and hyperexpression of MHC class I correlate with
      deteriorating glycaemic control.

PMID- 10333051
TI  - Suppression of transforming growth factor beta and vascular endothelial growth
      factor in diabetic nephropathy in rats by a novel advanced glycation end product
      inhibitor, OPB-9195.
AB  - AIMS/HYPOTHESIS: Advanced glycation end products (AGEs) participate in the
      pathogenesis of diabetic nephropathy. We reported earlier that OPB-9195, a
      synthetic thiazolidine derivative and novel inhibitor of advanced glycation,
      prevented progression of diabetic glomerulosclerosis by lowering serum
      concentrations of advanced glycation end products and reducing their deposition
      in the glomeruli. Here, we examined their contribution and that of growth
      factors, such as transforming growth factor-beta (TGF-beta) and vascular
      endothelial growth factor (VEGF), to the progression of diabetic nephropathy. We
      also investigated the expression of type IV collagen in the kidneys of Otsuka
      Long-Evans-Tokushima-Fatty (OLETF) rats, a Type II (non-insulin-dependent)
      diabetes mellitus model, after treatment with OPB-9195. METHODS: Using northern
      blots and immunohistochemical techniques, we determined the renal expression of
      TGF-beta and type IV collagen mRNAs and proteins in OLETF rats. We also examined
      OPB-9195's effects on renal expression of VEGF mRNA and protein. RESULTS:
      Concomitant increases in TGF-beta and type IV collagen expression were observed
      at each point in time in OLETF rats not given OPB-9195. In contrast, OPB-9195
      treatment greatly suppressed the renal expression of TGF-beta, VEGF and type IV
      collagen mRNAs and proteins to that seen in non-diabetic rats.
      CONCLUSION/INTERPRETATION: Since OPB-9195, an AGE-inhibitor, prevented the
      progression of diabetic nephropathy by blocking type IV collagen production and
      suppressing overproduction of two growth factors, TGF-beta and VEGF, in diabetic
      rats, this compound warrants further investigation.

PMID- 10333052
TI  - Effect of angiotensin converting enzyme inhibitor or beta blocker on glomerular
      structural changes in young microalbuminuric patients with Type I (insulin
      dependent) diabetes mellitus.
AB  - AIMS/HYPOTHESIS: To investigate the influence of angiotensin converting enzyme
      inhibitors and beta blockers on the progression of early diabetic glomerulopathy.
      METHODS: Thirteen patients with Type I (insulin-dependent) diabetes mellitus
      (mean age 18.8 years) with microalbuminuria 31 (19-160) microg/min were
      randomised to treatment with enalapril (group 1, n = 7) or metoprolol (group 2, n
      = 6). Renal biopsies were taken before and after 38 (36-48) months of treatment.
      Albumin excretion rate, blood pressure and HbA1c were measured every third month.
      A reference group without antihypertensive treatment (group 3, n = 9), with
      similar age, diabetes duration and degree of microalbuminuria as group 1 and 2,
      had baseline and follow-up renal biopsies taken previously with an interval of 26
      34 months, analysed at the same laboratory. Glomerular structures were measured
      by stereological methods. RESULTS: Measurements of basement membrane thickness,
      mesangial and matrix volume fractions were similar among groups at baseline.
      Structural variables were only increased in group 3 at follow-up. Delta values in
      basement membrane thickness and diabetic glomerulopathy index per 24 months were
      lower in group 1 and 2 than in group 3 (p < 0.05). Microalbuminuria returned to
      normal in group 1 and 2 only. Decreased albumin excretion rate tended to
      inversely correlate with increased basement membrane thickness (p = 0.08) and
      diabetic glomerulopathy index (p = 0.05). Mean HbA1c was similar between groups.
      Mean diastolic blood pressure was lower in group 1 and 2 than in group 3 (p <
      0.01). Mean HbA1c and mean diastolic blood pressure correlated to changes in
      basement membrane thickness, mesangial volume fraction and diabetic
      glomerulopathy index (p < 0.05). CONCLUSION/INTERPRETATION: Contrary to findings
      in the group without antihypertensive treatment, no progression of glomerulopathy
      was seen in those treated with enalapril or metoprolol.

PMID- 10333053
TI  - Increased expression of endothelial antigen PAL-E in human diabetic retinopathy
      correlates with microvascular leakage.
AB  - AIMS/HYPOTHESIS: The Pathologische Anatomie Leiden-Endothelium (PAL-E) antigen is
      a marker for loss of the blood-brain barrier function in brain tumours. It is
      endothelium specific and is associated with the endothelial plasmalemmal vesicles
      (caveolae) involved in transcellular transport. To test whether blood-retinal
      barrier loss in diabetic retinopathy is associated with cellular changes in the
      endothelium, the expression of antigen PAL-E in relation to microvascular leakage
      in human diabetic retinopathy was investigated. METHODS: Immunohistochemical
      staining of frozen tissue sections of postmortem eyes obtained from 30 persons
      without and 41 persons with diabetes mellitus was carried out with monoclonal
      antibodies against PAL-E and CD31 and with antibodies against endogenous
      fibrinogen, albumin and IgG as indicators of vascular leakage. RESULTS: Patchy or
      uniform microvascular PAL-E staining was observed in the retina of 17 of the 41
      eyes of diabetic patients and in 2 of the 30 normal control eyes. In the diabetic
      eyes, PAL-E staining co-localized with microvascular staining for endogenous
      fibrinogen, albumin and IgG. Strong staining for PAL-E was observed in sites
      without blood-tissue barriers, like the choroid. CONCLUSIONS/INTERPRETATION: In
      microvessels with an intact blood-retina barrier the endothelial antigen PAL-E is
      absent. Its expression is increased in retinal vessels of patients with diabetic
      retinopathy and correlates with microvascular leakage of plasma proteins. This
      phenotypic shift involving an antigen associated with caveolae suggests that
      dysfunction of the endothelium forms the cellular basis for microvascular leakage
      in diabetic retinopathy, rather than passive endothelial damage.

PMID- 10333054
TI  - Diabetic retinopathy risk correlates with intracellular concentrations of the
      glycoxidation product Nepsilon-(carboxymethyl) lysine independently of
      glycohaemoglobin concentrations.
AB  - AIMS/HYPOTHESIS: We investigated whether either the amount of diabetes-induced
      intracellular oxidative stress or the concentration of hyperglycaemia-induced
      advanced glycation endproducts is associated with the risk of diabetic
      retinopathy. METHODS: We measured concentrations of the glycoxidation product
      Nepsilon-(carboxymethyl)lysine and two non-oxidation-dependent advanced glycation
      end-products (methylglyoxal-derived and 3-deoxyglucosone-derived) in CD45RA+ T
      cells from 21 Type I (insulin-dependent) diabetic patients with and without
      diabetic retinopathy and from age-matched nondiabetic control subjects. RESULTS:
      Intracellular concentrations of both oxidation-dependent Nepsilon
      (carboxymethyl)lysine and oxidation-independent advanced glycation endproducts
      were increased in memory T-cells from diabetic patients. Nepsilon
      (carboxymethyl)lysine: diabetic median-24176 arbitrary units/mg protein (95%
      confidence interval 18690-34099 arbitrary units/mg protein); nondiabetic-9088
      arbitrary units/mg protein (confidence interval 6994-10696 arbitrary units/mg
      protein; p < 0.0001). Methylglyoxal-derived advanced glycation end products:
      diabetic-5430 arbitrary units/ mg protein (confidence interval 3458-13610);
      nondiabetic-271 arbitrary units/mg protein (confidence interval 61-760 arbitrary
      units/mg protein; p< 0.0001). 3-Deoxyglucosone-derived advanced glycation end
      products: diabetic-8070 arbitrary units/mg protein (confidence interval 7049
      16551 arbitrary units/mg protein); nondiabetic-1479 arbitrary units/ mg protein
      (confidence interval 1169-3170; p< 0.0001). Only Nepsilon-(carboxymethyl)lysine
      concentrations, however, inversely correlated with the duration of retinopathy
      free diabetes (r = -0.51; p < 0.02). Diabetes-dependent Nepsilon
      (carboxymethyl)lysine accumulation did not correlate with age, diabetes duration,
      or averaged glycohaemoglobin concentrations. In vitro experiments wih menadione
      and lymphocytes confirmed that Nepsilon-(carboxymethyl)lysine concentrations
      reflect intracellular oxidative stress. CONCLUSION/INTERPRETATION: Monitoring
      intracellular concentrations of increased oxidative stress in long-lived CD45RA+
      lymphocytes by markers such as Nepsilon-(carboxymethyl)lysine possibly identifies
      a subgroup of patients at high risk for microvascular complications.

PMID- 10333055
TI  - Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is
      influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43). UK Prospective Diabetes
      Study (UKPDS) Group.
AB  - AIMS/HYPOTHESIS: Juvenile-onset, insulin-dependent diabetes is associated with
      islet cell antibodies and with specific "high-risk" HLA-DRB1 and HLA-DQB1
      genotypes. Patients with Type II (non-insulin-dependent) diabetes mellitus can
      have islet-related antibodies, but the genotypic associations at different ages
      of onset have not been evaluated. Our aim was to determine (i) the prevalence of
      DRB1 and DQB1 genotypes in patients at diagnosis of Type II diabetes at different
      ages from 25 to 65 years compared with the general population, and (ii) whether
      the presence of islet cell antibodies (ICA) or glutamic acid decarboxylase
      antibodies (GADA) or both by age is associated with different DRB1 and DQB1
      genotypes. METHODS: The antibodies to islet cells and those to glutamic acid
      decarboxylase were measured in 1712 white Caucasian diabetic subjects at
      diagnosis of diabetes and they were genotyped for HLA DRB1*03 and DRB1*04 and the
      high-risk DRB1*04-DQB1* 0302 haplotype. To assess over-representation of high
      risk alleles for Type I (insulin-dependent) diabetes mellitus, the prevalence of
      high-risk alleles in diabetic patients was expressed relative to the prevalence
      of low-risk alleles, non-DR3/non-DR4, that provided a reference denominator in
      both the diabetic patients and in 200 non-diabetic control subjects. The
      prevalence of ICA or GADA or both in patients with different HLA genotypes was
      assessed in those diagnosed in four age groups, 25-34 years, 35-44 years, 45-54
      years and 55-65 years. RESULTS: In Type II diabetic patients presenting at ages
      25-34, 35-44 and 45-54 years, there was an increased prevalence of DR3/DR4
      compared with the general population with approximately 6.5-fold, 2.9-fold, 2.1
      fold over-representation, respectively (p < 0.0001, < 0.01, < 0.05) but this was
      not found in those aged 55-65 years old. In the group aged 25-34 years, 32 % of
      patients with ICA or GADA or both had DRB1*03/DRB1*04-DQB1*0302 compared with 10%
      in those aged 55-65 years and expected 3% prevalence. Conversely, only 14% of
      those aged 25-34 years with antibodies had non-DR3/non-DR4, compared with 35 % in
      those aged 55-65 years. There was thus pronounced age heterogeneity in DRB1 and
      DQB1 predisposition to Type II diabetes. The antibodies displaced DRB1 or DQB1
      genotypes in the multivariate model for requiring insulin therapy by 6 years of
      follow-up. CONCLUSION/HYPOTHESIS: The age of presentation of Type I diabetes in
      adulthood was in part dependent on the DRB1/DQB1 genotype. Islet cell antibodies
      and glutamic acid decarboxylase antibodies were strongly associated with
      DRB1*03/DRB1*04-DQB1*0302 in early adulthood but showed little relation with
      specific HLA genotypes after the age of 55 years.

PMID- 10333056
TI  - Variants in the sulphonylurea receptor gene: association of the exon 16-3t
      variant with Type II diabetes mellitus in Dutch Caucasians.
AB  - AIMS/HYPOTHESIS: We have analysed to what extent two previously reported single
      nucleotide polymorphisms in the sulphonylurea receptor gene (SUR1) are associated
      with Type II (non-insulin-dependent) diabetes mellitus in The Netherlands.
      Furthermore, we estimated haplotype frequencies in control and diabetic
      populations, including data extracted from three other studies. METHODS: Subjects
      with Type II diabetes (n = 388) and normoglycaemic subjects (n = 336) were
      randomly selected from two population-based studies, the Hoorn and Rotterdam
      studies. DNA was typed for variants in exon 16 (-3c-->t variant in the splice
      acceptor site) and exon 18 (Thr759Thr, ACC-->ACT). RESULTS: The genotype
      frequencies in both populations were similar. We observed an association of the
      exon 16-3t variant with Type II diabetes (allele frequencies 0.41 % vs 0.48 % in
      NGT and Type II diabetes, respectively, p = 0.01). There was no association
      between Type II diabetes and the variant in exon 18 or the combination of both
      variants (p > 0.5). A strong linkage disequilibrium between the exon 16 and exon
      18 variants was observed in the diabetic groups but not, or less pronounced, in
      the control groups from the different studies. Haplotype estimation shows that
      several different risk haplotypes exist in different Caucasian populations.
      CONCLUSION/INTERPRETATION: The exon 16-3t allele of the SUR1 gene is associated
      with Type II diabetes in the Netherlands. Based on estimated haplotype
      frequencies in different Caucasian populations we conclude that multiple
      haplotypes on the SUR1 gene seem to confer a risk for developing Type II diabetes
      in Caucasians.

PMID- 10333057
TI  - Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese
      subjects with diabetes mellitus: clinical features and functional
      characterization.
AB  - AIMS/HYPOTHESIS: Mutations in the hepatocyte nuclear factor-1alpha gene are a
      common cause of the type 3 form of maturity-onset diabetes of the young. We
      examined the clinical features and molecular basis of hepatocyte nuclear factor
      1alpha (HNF-1alpha) diabetes. METHODS: Thirty-seven Japanese subjects with early
      onset Type II (non-insulin-dependent) diabetes mellitus and 45 with Type I
      (insulin-dependent) diabetes mellitus were screened for mutations in this gene.
      Functional properties of mutant HNF-1alpha were also investigated. RESULTS: Three
      new mutations [G415R, R272C and A site of the promoter (+ 102G-to-C)] were found.
      Insulin secretion was impaired in the three subjects. Insulin and glucagon
      secretory responses to arginine in the subject with the R272C mutation were also
      diminished. Molecular biological studies indicated that the G415R mutation
      generated a protein with about 50% of the activity of wild-type HNF-1alpha. The
      R272C mutation had no transactivating or DNA binding activity and acted in a
      dominant negative manner. The + 102 G-to-C mutation in the A site of the promoter
      activity was associated with an increase in promoter activity and it had 42-75%
      more activity than the wild-type sequence. CONCLUSION/INTERPRETATION: Mutations
      in the HNF-1alpha gene may affect the normal islet function by different
      molecular mechanisms.

PMID- 10333059
TI  - A common mutation of the methylenetetrahydrofolate reductase gene as a risk
      factor for diabetic nephropathy.

PMID- 10333058
TI  - Reflexions on a newly discovered diabetogenic gene, wolframin (WFS1).

PMID- 10333060
TI  - Is Trp64Arg polymorphism of beta3-adrenergic receptor a clinically useful marker
      for the predisposition to diabetic nephropathy in Type II diabetic patients?

PMID- 10333061
TI  - Reduction of plasma leptin during a short-term fast, an oral glucose tolerance or
      a meal test can be a misleading bias in clinical studies.

PMID- 10333062
TI  - Confidence intervals for frequencies of rare alleles.

PMID- 10333063
TI  - Is the newly suggested fasting plasma glucose cut-off point for the diagnosis of
      diabetes the right one?

PMID- 10333064
TI  - Standardization of T-cell assays in Type I diabetes. Immunology of Diabetes
      Society T-cell Committee.

PMID- 10333066
TI  - Induction of ovulation with gonadotropin-releasing hormone during proestrus in
      cattle: influence on subsequent follicular growth and luteal function.
AB  - Induction of ovulation by administration of gonadotropin-releasing hormone (GnRH)
      is commonly practiced in cattle to treat repeat breeders or cows exhibiting long
      estrous periods. This treatment may, however, disturb normal reproductive
      functions if timing is incorrect. The objective of the present study was to
      investigate the effect of exogenous GnRH on estradiol secretion of the ovulatory
      follicle, occurrence of ovulation, development and function of the corpus luteum
      (CL) and growth of a dominant follicle after ovulation in the bovine, when GnRH
      treatment was given before the expected physiological LH-surge. Luteolysis was
      induced by cloprostenol (PG) in three cows and six heifers. Every animal was
      assigned once to each of the following treatment or control manipulations,
      receiving either a single dose (0.1 mg) of GnRH (gonadorelin) at (1) 24 h (T1),
      (2) 48 h (T2), or (3) 72 h (T3) after PG, or (4) no gonadorelin (control
      manipulation, C). Ovaries were scanned by ultrasound and blood samples were
      collected for progesterone (P4) and estradiol-17beta (E-17beta) determination.
      Growth curves of dominant follicles between treatment I and the control differed
      significantly (P < 0.01). One day after ovulation, the diameter of the dominant
      follicle was almost 1 mm larger in T1. This difference remained almost unchanged
      during the entire follow-up period. The recruitment of a new follicular wave
      after ovulation seemed to occur earlier. Development of CL and levels and
      profiles of P4-production remained unaffected. When GnRH was given 1 day after PG
      injection, two animals showed significantly different development of CL (P <
      0.05) and of P4-production (both in concentrations [P < 0.05] and profile [P <
      0.01]). After normal ovulation and CL development, luteolysis took place on days
      5 or 6 after ovulation, and animals ovulated on days 9 and 10. It is suggested
      that early induction of ovulation with GnRH can cause shortened luteal function
      in cattle and, ultimately, reduced fertility.

PMID- 10333065
TI  - The effect of high concentrations of cryoprotectants on the passage of bovine
      viral diarrhea virus through the zona pellucida of in vitro fertilized embryos.
AB  - The effect of high concentrations of cryoprotectants on the passage of bovine
      viral diarrhea virus (BVDV) through the zona pellucida (ZP) of intact bovine
      embryos during the pre-freezing step of cryopreservation was investigated in a
      series of experiments. In vitro fertilized (IVF) embryos at the blastocyst stage
      were exposed to 10(6) TCID50 BVDV (non-cytopathic NY-1 strain) in a 30%
      suspension of either ethylene glycol, glycerol, DMSO, or 2 M sucrose in
      physiological saline for 10 min at 20 degrees C. Subsequently, the embryos were
      washed free of residual unbound viral particles, and the ZP of some embryos were
      removed by micromanipulation. Groups of ZP-intact embryos, ZP-free embryonic
      cells and their respective ZP were then tested separately for the presence of
      virus. The infectious virus was detected in association with 81% (17/21) of
      samples containing non-micromanipulated ZP-intact embryos which were exposed to
      the virus and cryoprotectants and then washed 10 times and in 83% (43/53) of the
      samples containing only ZP from micromanipulated embryos (P > 0.05). The virus
      was not found in the samples containing the corresponding embryonic cells of
      embryos exposed previously to the virus and cryoprotectants. It was concluded
      that the transfer of embryos from the isotonic PBS solution into a highly
      hypertonic cryoprotectant solution did not cause the passage of BVDV through ZP
      and its entry to embryonic cells.

PMID- 10333067
TI  - New cases of XXY constitution in cattle.
AB  - The present paper describes two cases of an XXY condition in Chianina cattle.
      Both young bulls were routinely investigated cytogenetically before entering
      progeny test stations. Every cell examined in the blood cell cultures showed an
      XXY constitution. The histological study of the gonads, performed on only one
      bull, showed degradation of the seminiferous tubules. Only Sertoli cells and
      hyperplastic interstitial cells were observed.

PMID- 10333068
TI  - Effects of adrenocorticotrophin (ACTH) and progesterone on luteinising hormone
      (LH) secretion in recently castrated rams.
AB  - The goal of the present study was to determine whether ACTH and progesterone have
      any effect on LH secretion and pulse frequency in recently castrated rams. Six 2
      year-old Corriedale rams were castrated in the winter. The day before castration,
      blood samples were taken in order to establish the precastration LH levels. The
      rams were divided into an untreated group (group U: n = 2) and a treated group
      (group T: n = 4). The first treatment consisted of the i.v. administration of 0.5
      mg of ACTH on day 20 post-castration, immediately after the first sample had been
      taken. During the second treatment, subcutaneous progesterone implants were given
      to group T for 5 days. Control samplings were performed one week before each
      treatment. Prior to castration, the testosterone levels were low, while after
      castration they were below the detection limit of the assay. Cortisol and
      progesterone concentrations were basal before castration in all of the animals
      and after castration in group U and also in the control samplings for group T.
      ACTH treatment caused a significant increase in both cortisol and progesterone
      levels for 3 h (P < 0.001). Progesterone implants raised progesterone levels in
      group T, but cortisol levels remained basal. Before castration, all animals had
      low LH levels and hardly any pulse activity was seen. After castration, both the
      number of LH pulses and the mean LH production increased significantly in all of
      the animals (P < 0.01). During the ACTH trial, LH pulse frequency was
      significantly reduced for the first 4 h following ACTH administration (P =
      0.013), however, no such differences occurred in the prior control period. No
      effect was seen on mean LH concentration during the ACTH treatment. Progesterone
      treatment did not have any effect on either the number of LH pulses nor on LH
      concentrations (P > 0.05).

PMID- 10333069
TI  - Reproductive performance of farmed red deer (Cervus elaphus) in New Zealand. I.
      Descriptive data.
AB  - A longitudinal observational study of 15 red deer (Cervus elaphus) farms was
      carried out in New Zealand for 2 years from Mar 1992. Management of hind mobs and
      their composition during mating, calving, and weaning were recorded. About 2700
      hinds were individually monitored for live weight, body condition score and
      reproductive success. All hinds were pregnancy tested in June by ultrasound and
      classified as having conceived before May 1, after May 1, or as being not
      pregnant. Calving dates and dam-offspring pairs were recorded on four farms. The
      lactational status of hinds and live weight of calves were recorded at weaning.
      Mean pre-mating live weights of yearling hinds were 81.3-82.8 kg and of adult
      hinds 98.0-98.7 kg, respectively, for each year of study. The percentage of
      yearling and adult hinds conceiving before May ranged from 8.3 to 95.0% and from
      77.6 to 98.4%, respectively, between farms. Overall, the proportion of yearling
      and adult hinds not pregnant was 15.3% and 3.2%, respectively. Pregnancy rates at
      scanning of adult hinds within mating mobs were generally over 90%, and 41.7% of
      mating mobs had 100% pregnancy rates. In contrast, the pregnancy rates of
      yearling hind mobs were more variable, with five mobs below 50%, and 34.1% of
      mating mobs achieving 100% pregnancy rate. Estimated in utero loss rates from
      pregnancy diagnosis to calving were 0.66 and 0.79% for yearling and adult hinds,
      respectively. From four farms, median calving dates of yearling and adult hinds
      were Dec 13 and Nov 30, respectively. Overall, calf survival rates to weaning of
      yearling and adult offspring were 84.1 and 91.6%, respectively, while the
      reproductive efficiencies (number of calves weaned per hind mated) were 70 and
      83.6%, respectively. Farm mean weaner live weights standardised on Apr 1 ranged
      from 42-59 kg and 39-51 kg for stags and hinds, respectively. These data are
      currently the best estimates of reproductive parameters of New Zealand red deer
      herds, and highlight a wide variability in reproductive indices between farms.

PMID- 10333070
TI  - Applications of the green fluorescent protein as a molecular marker in
      environmental microorganisms.
AB  - In this review, we examine numerous applications of the green fluorescent protein
      (GFP) marker gene in environmental microbiology research. The GFP and its
      variants are reviewed and applications in plant-microbe interactions, biofilms,
      biodegradation, bacterial-protozoan interactions, gene transfer, and biosensors
      are discussed. Methods for detecting GFP-marked cells are also examined. The GFP
      is a useful marker in environmental microorganisms, allowing new research that
      will increase our understanding of microorganisms in the environment.

PMID- 10333071
TI  - Antimicrobial activity of diterpene resin acid derivatives.
AB  - C-13 deisopropylated and/or C-7 oxidized resin acid derivatives were tested
      against various microorganisms to determine structural features responsible for
      biological activity and to determine the influence of the C-13 isopropyl group on
      antimicrobial activity. Test results show that methyl cis and trans 7-oxo-13
      deisopropyldehydroabietate and a mixture of both isomers exhibited activity
      against fungi and bacteria.

PMID- 10333072
TI  - A novel colorimetric yeast bioassay for detecting trichothecene mycotoxins.
AB  - A novel colorimetric microbial bioassay for toxicity has been developed; it shows
      particular sensitivity to trichothecene mycotoxins. The assay uses inhibition of
      expression of beta-galactosidase activity within the yeast Kluyveromyces
      marxianus as a sensitive toxicity indicator, cultures remaining yellow, rather
      than turning deep green-blue, in the presence of X-gal, a chromogenic substrate.
      The assay is conducted in standard microtitre plates, permitting small volumes
      (160 microl) and many replicates, and can be scored either automatically by a
      plate-reader, or by eye. Factors likely to affect the efficacy of the bioassay,
      including carbon source, solvents, inoculum cell density, and the use of membrane
      modulating agents (MMAs), were assessed. Polymyxin B nonapeptide was the most
      effective toxicity-enhancing MMA tested, enabling the trichothecene mycotoxin,
      verrucarin A, to be detected at a concentration of about 1 ng/ml. The assay's
      reproducibility was examined using polymyxin B sulfate, a cheaper MMA, and
      another trichothecene mycotoxin, T2 toxin: reproducibility and sensitivity were
      better for the beta-galactosidase X-gal endpoint than for an alternative
      chromogenic toxicity indicator, the respiratory substrate 3-(4,5-dimethylthiazol
      2-yl)-2,5-diphenyl tetrazolium bromide (MTT).

PMID- 10333073
TI  - Preparation of a high titre Salmonella abortusovis H-antigen and antiserum and
      improvement of the microagglutination test.
AB  - Serological diagnosis of small ruminant abortions due to Salmonella abortusovis
      (S.a.o) was improved by using modified procedures to produce high titre H
      antigens and anti-H serum. While the titres of the two standard antigens were 1:8
      and 1:20, both modified antigens had a titre of 1:50. Similarly, the use of
      adjuvanted and non adjuvanted antigens for the production of anti-H hyperimmune
      serum resulted in a titre of 1:160,000 as compared to 1:20,000 when standard
      procedures were used. In addition, the slow micro-agglutination test has been
      modified and results can now be read within the same day.

PMID- 10333074
TI  - Characterization of microbial communities using randomly amplified polymorphic
      DNA (RAPD).
AB  - Similarity among a number of aquatic microbial communities was examined using
      randomly amplified polymorphic DNA (RAPD), a common polymerase chain reaction
      (PCR)-based DNA fingerprinting technique. After amplification of whole-community
      DNA extracts, the PCR products were resolved by agarose gel electrophoresis and
      the band patterns compared to determine percent similarity. Twelve different
      primers were used to amplify approximately 100 fragments (total) from each DNA
      sample; the bands were scored as present or absent and the similarity between
      each sample was determined using Jaccard's coefficient. From this information.
      dendrograms were constructed and a bootstrapping procedure was used to assess how
      well supported the tree topologies were. Principal component analyses were also
      conducted as a means of visualizing the relationships among samples. Results
      obtained for two different experimental systems (a pair of tidal creeks and
      several wells in a shallow groundwater aquifer) correlated well with the temporal
      and spatial variations in environmental regime at the sites confirming that
      arbitrarily primed PCR-based DNA fingerprinting techniques such as RAPD are
      useful means of discriminating among microbial communities and estimating
      community relatedness. Moreover, this approach has several advantages over other
      DNA-based procedures for whole-community analysis; it is less laborious and uses
      smaller quantities of DNA, making it amenable to sample-intensive monitoring, and
      it does not depend on culturing or the use of selective PCR primers.

PMID- 10333075
TI  - Use of automated ribotyping of Austrian Listeria monocytogenes isolates to
      support epidemiological typing.
AB  - We used automated ribotyping on the RiboPrinter Microbial Characterization System
      to study the epidemiology of listeriosis in western Austria over the period 1988
      1996. Thirty-six isolates containing three serotypes were included in this
      collection. Each of the 16 ribotype groupings (RiboGroups) produced in this study
      contained a single serotype. Isolates collected from within a single food factory
      environment all grouped into unique RiboGroups. One factory contained isolates
      showing two unique RiboGroups, both of which were also seen in patient isolates.
      This same set of Listeria isolates has previously been studied by automated laser
      fluorescence analysis of randomly amplified polymorphic DNA (RAPD-Alfa). The data
      produced by the RiboPrinter system correlated well with the epidemiological
      information, better than the results achieved with RAPD-Alfa. The RiboPrinter
      system provides a rapid, easy, and useful method for the typing of Listeria
      monocytogenes.

PMID- 10333076
TI  - Detection of beta-1,6-glucanase isozymes from Trichoderma strains in sodium
      dodecyl sulphate-polyacrylamide gel electrophoresis and isoelectrofocusing gels.
AB  - The filamentous fungus Trichoderma produces, under specific growth conditions,
      several extracellular fungal cell wall degrading enzymes, amongst them beta-1,6
      glucanases. These enzymes seem to play an important role in the antagonistic
      action of Trichoderma against a wide range of fungal plant pathogens. In this
      report we describe two different methods for the specific detection of the
      activity of beta-1,6-glucanase isozymes in gels. After sodium dodecyl sulphate
      polyacrylamide gel electrophoresis, beta-1,6-glucanase activity can be assayed in
      the gel by renaturation of the enzyme, incubation with an overlay agarose gel
      containing solubilized pustulan (a commercially available beta-1,6-glucan),
      followed by the staining of the agarose gel with Congo Red. In native
      isoelectrofocusing gels, as little as 1 mU can be detected after incubation with
      solubilized pustulan followed by a detection reaction of the released reducing
      sugars with 2,3,5-triphenyltetrazolium chloride. The latter technique has been
      successfully applied to the screening of beta-1,6-glucanase isozymes from
      different Trichoderma strains under different growth conditions.

PMID- 10333077
TI  - A simple assay for measuring cellobiose dehydrogenase activity in the presence of
      laccase.
AB  - The commonly used assay for measuring cellobiose dehydrogenase (CDH) activity,
      based on the reduction of dichlorophenol-indophenol (DCIP), has been adapted to
      measure this enzyme activity in the presence of laccase, which is often formed
      concurrently with CDH by a number of fungi. Laccase interferes with the assay by
      rapidly reoxidizing the reduced form of DCIP and can mask CDH activity
      completely. It can be conveniently and completely inhibited by 4 mM fluoride in
      the assay, while CDH activity is only slightly affected by the addition of this
      inhibitor. The modified assay enables the detection of low CDH activities even in
      the presence of very high excesses of laccase. It should be useful for screening
      culture supernatants of wood-degrading fungi for CDH since the assay is rapid and
      uses inexpensive and nontoxic reagents. Furthermore, it might be used for the
      detection of other enzyme activities which are assayed by following the reduction
      of quinones or analogue compounds such as DCIP.

PMID- 10333078
TI  - Detection of Ob-receptor in human adrenal neoplasms and effect of leptin on
      adrenal cell proliferation.
AB  - Leptin, a hormone mainly secreted from adipose tissue, communicates a metabolic
      signal to the adrenal gland. Ob-Receptor (Ob-R) expression was reported in rat,
      mice and human adrenal glands. This study intended to investigate possible
      differences in the Ob-R expression and distribution of Ob-R protein in human
      adrenal tumors as compared to normal adrenal tissue. Proliferative effects of
      leptin were analyzed in the human adrenocortical carcinoma cell line (NCI-H295).
      The full length Ob-R mRNA and the isoforms B219.1 and B219.3 could be
      demonstrated by RT-PCR in all adrenal tumors (n=8), the tumor cell line (NCI
      H295) and normal tissue. In contrast the Ob-R isoform B219.2 was absent in the
      carcinoma cell line and in most of the adrenal tumors (n=5), whereas it was
      present in normal adrenals. The Ob-R protein could be demonstrated in benign and
      malignant adrenocortical tumors. Pheochromocytomas showed only a weak
      immunostaining with the human Ob-R antibody. Human leptin did not affect the
      proliferation or variability of adrenal tumor cells as demonstrated by [3H]
      thymidine assay and WST-1 test. In conclusion, although functional leptin
      receptors are expressed in human adrenal tumors, leptin does not regulate tumor
      cell proliferation.

PMID- 10333079
TI  - Effect of acute streptozotocin diabetes on fatty acid content and composition in
      different lipid fractions of rat skeletal muscle.
AB  - The aim of the present study was to examine the effect of acute streptozotocin
      diabetes on long chain fatty acid content and composition in different lipid
      classes of particular muscle types in the rat. Two days after streptozotocin
      administration, rats were anesthetised, and the white and red sections of the
      gastrocnemius, the soleus and the blood were taken. Lipids were extracted with
      chloroform/methanol and separated into different fractions (phospholipids, free
      fatty acids, di- and triacylglycerols) by means of thin layer chromatography.
      Fatty acids of each fraction were identified and quantified by means of gas
      liquid chromatography. The diabetes resulted in elevation of the concentration of
      blood glucose (over four-fold) and the plasma free fatty acid (over two-fold).
      Total free fatty acid content in the muscles of diabetic rats increased by 26% in
      the white, 24% in the red gastrocnemius and 21% in the soleus. There were also
      changes in the composition of that fraction in each muscle. Diacylglycerol fatty
      acid content was elevated in both parts of the gastrocnemius (the white part by
      15%, the red part by 44%) and remained stable in the soleus of the diabetic rats.
      The content of triacylglycerol fatty acids was elevated only in the red
      gastrocnemius in the diabetic group (by 112%), but changes in fatty acid
      composition in this fraction occurred in each muscle. The content of phospholipid
      fatty acids was elevated in the white gastrocnemius (by 13%) and remained stable
      in other muscles. There were only minor changes in phospholipid fatty acid
      composition in the diabetic rats. We concluded that acute insulin deficiency
      changes fatty acid content and composition in skeletal muscle lipids. The changes
      depend both on lipid fraction and muscle type.

PMID- 10333080
TI  - Lactate stimulates insulin secretion without blocking the K+ channels in HIT-T15
      insulinoma cells.
AB  - To clarify the mechanism by which lactate affects insulin secretion, we
      investigated the effect of lactate on insulin secretion, cytosolic free Ca2+
      ([Ca2+](i), the ATP sensitive K+ channel (K(ATP)) and the Ca2+-activated K+
      channel (K(Ca)) in HIT-T15 cells, and the results were compared with those of
      glucose and glibenclamide. All three agents caused insulin secretion and
      increased [Ca2+](i), but the effects on the K+ channels were different. In cell
      attached patch configurations, 10 mmol/l glucose blocked both the K(ATP) and KCa
      channels, while 100 nmol/l glibenclamide had no effect on KCa channels, but
      blocked K(ATP) channels. Lactate at a concentration of 10 mmol/l activated both
      the K(ATP) and KCa channels, not only in cell-attached, but also in inside-out
      patch configurations, indicating that the increase in [Ca2+](i) and secretion of
      insulin by lactate cannot be explained by the blocking of the K+ channels.
      Lactate, at concentrations of 10 mmol/l and 50 mmol/l decreased 45Ca2+ efflux,
      while glibenclamide increased the efflux. These results suggest that the lactate
      induced Ca2+ increase is not due to the closing of K+ channels, but at least in
      part, to the suppression of Ca2+ efflux from HIT cells.

PMID- 10333081
TI  - Inhibition of insulin, glucose-dependent insulinotropic polypeptide (GIP) and
      glucagon-like peptide-1 (GLP-1) secretion by octreotide has no effect on post
      heparin plasma lipoprotein lipase activity.
AB  - This study examines the immediate effect of modulating postprandial insulin and
      insulinotropic hormone (glucose-dependent insulinotropic polypeptide, GIP;
      glucagon-like peptide-1, GLP-1) secretion on the activation of lipoprotein lipase
      (LPL) in six lean and six obese age-matched women. Subjects were given, on two
      separate occasions, 340 kcal of carbohydrate alone or combined with an IV
      infusion of octreotide, (100 microg infusion from 30 min before the meal for 150
      min). Post-heparin LPL activity (10,000 U) was measured on each occasion 120
      minutes post-carbohydrate. Following oral carbohydrate postprandial plasma
      insulin levels were significantly higher in obese subjects than in lean (p <
      0.01). Glucose tolerance was slightly impaired in obese subjects. Insulin, GIP
      and GLP-1 secretion post-carbohydrate was markedly reduced by octreotide in lean
      and obese subjects. LPL activity was similar in the two groups after carbohydrate
      administration and was unaffected by octreotide. Inhibition of postprandial
      insulin, GIP and GLP-1 secretion acutely did not reduce post-heparin LPL activity
      either in lean or obese subjects.

PMID- 10333082
TI  - Elevated plasma proinsulin/insulin ratio is a marker of reduced insulin secretory
      capacity in healthy young men.
AB  - AIM: To examine whether reduced insulin secretory capacity or increased insulin
      secretory demand is associated with elevated ratio of plasma proinsulin to
      immunoreactive insulin (PI/IRI ratio) in non-diabetic subjects. SUBJECTS AND
      METHODS: We measured various indices of insulin secretory function and insulin
      sensitivity by frequently sampled intravenous glucose tolerance test (FSIGT) and
      hyerglycemic glucose clamp in 21 healthy young men. We then examined the
      relationships between these indices and PI, IRI, or PI/IRI ratio in the fasting
      state. RESULTS: Insulin sensitivity index (SI) measured by FSIGT correlated
      inversely with basal IRI (r=-0.53, P < 0.01) and PI levels (r=-0.57, P < 0.01),
      but there was no significant correlation between SI and PI/IRI ratio (r=0.26,
      NS). On the other hand, PI/IRI ratio correlated inversely with insulin secretory
      indices, such as acute insulin responses during FSIGT (r =-0.46, P < 0.01) and
      hyperglycemic glucose clamp (r=-0.54, P < 0.01) and submaximum insulin response
      during hyperglycemic glucose clamp (r=-0.59, P < 0.01). CONCLUSIONS: These
      results indicate that elevated PI/IRI ratio may serve as a marker of reduced
      insulin secretory function in non-diabetic subjects.

PMID- 10333083
TI  - Calcium homeostasis during oral glucose load in healthy women.
AB  - It has been demonstrated that in healthy subjects during oral glucose tolerance
      test, serum calcium declines, while urinary calcium excretion increases, even if
      there is not a general agreement in this regard. The study was carried out in
      order to evaluate the effects of glucose oral load on calcium homeostasis in
      eight healthy adult women, also considering ionized calcium, plasma insulin and
      parathyroid hormone changes. The results showed a decline of total and ionized
      serum calcium (p < 0.05 and p < 0.01, respectively; maximum of the decrease at
      time 120'), in parallel with the increase of urinary calcium/ creatinine ratio (p
      < 0.05). Serum glucose and insulin increase (p < 0.0001 and p < 0.0005
      respectively; maximum value at time 60'), while the parathyroid hormone level
      decreases (maximum decline at time 120', p < 0.01). No changes were observed in
      fasting control subjects for all parameters considered. The changes of these
      parameters with time suggest that the effects of glucose oral load on calcium
      metabolism in healthy adult women may be the consequence of parathyroid hormone
      suppression induced by acute hyperglycemia/hyperinsulinemia. The results confirm
      in vivo the PTH behaviour in vitro, on cultured bovine parathyroid cells, with
      high glucose concentration.

PMID- 10333084
TI  - Serum leptin levels, body fat deposition, and weight in females with anorexia or
      bulimia nervosa.
AB  - The objective of this retrospective study was to investigate the relation between
      serum leptin level and fat deposition in patients with eating disorders. 40
      female inpatients with anorexia (n=24) or bulimia nervosa (n=16) were assessed
      for leptin level, body mass index (BMI), and percentage body fat by dual-energy X
      ray absorbometry (DXA). The results show that percentage body fat is a better
      predictor for leptin level and clinical findings in eating disordered patients
      than BMI. We discuss the necessity for DXA measurements in anorectic patients for
      prognostic and research purposes.

PMID- 10333085
TI  - Enhanced potential for oxidative stress in hyperinsulinemic rats: imbalance
      between hepatic peroxisomal hydrogen peroxide production and decomposition due to
      hyperinsulinemia.
AB  - Oxidative stress is involved in aging and age-related diseases. Several metabolic
      alterations similar to those encountered with aging and age-related diseases have
      been observed in response to hyperinsulinemia. Surprisingly, this metabolic
      derangement diminished hepatic peroxisomal beta-oxidation which is a major source
      of H2O2 production in the liver, suggesting a protective effect against oxidative
      stress. However, the impact of hyperinsulinemia on the balance between H2O2
      production and elimination in the liver is not known. Consequently, this study
      was undertaken to evaluate the effect of sustained high serum insulin levels on
      the activity of hepatic catalase, a peroxisomal antioxidant enzyme involved in
      the decomposition of H2O2. Male Sprague-Dawley rats received intravenous infusion
      of either 30% glucose, 30% galactose or normal saline for seven days. Activity of
      hepatic peroxisomal beta-oxidation and catalase decreased 58% and 74%,
      respectively, in glucose-infused rats compared with galactose- or saline-infused
      animals. When infused simultaneously with glucose, diazoxide blocked glucose
      enhanced insulin secretion and prevented the decrease in peroxisomal enzyme
      activities, without altering blood glucose concentration. Neither diazoxide alone
      nor galactose, which did not alter serum insulin levels, had any effect on enzyme
      activities. These results suggest that hyperinsulinemia is responsible for the
      decreased enzyme activities observed in glucose-infused rats. Indeed, a strong
      negative correlation between serum insulin levels and hepatic peroxisomal enzyme
      activities was found. To investigate the mechanism by which insulin modulates
      catalase activity, we studied rates of synthesis and degradation of catalase in
      saline- and glucose-infused rats. Data show that insulin diminishes rates of
      catalase synthesis, while exhibiting no effect on its degradation. Upsetting the
      balance between the cellular capacity to produce and eliminate H2O2 may be a
      contributing factor to the known deleterious effects of hyperinsulinemia.

PMID- 10333086
TI  - Lysophosphatidylcholine molecular species in low density lipoprotein of type 2
      diabetes.
AB  - To reveal the importance of lysoposphatidylcholine (LPC) in patients with Type 2
      diabetes (DM), LPC in low density lipoprotein (LDL) was determined by high
      performance liquid chromatography in 38 patients with Type 2 DM and 31 age and
      sex-matched non-diabetic controls. Stearoyl LPC (SLPC) and palmitoyl LPC (PLPC)
      were detected in LDL. The contents of both LPCs per gram protein in LDL were
      increased in diabetic patients compared with the non-diabetics (1.99+/-0.94mg
      SLPC and 3.02+/-1.81 mg PLPC vs 1.47+/-0.57 mg SLPC and 2.30+/-0.83 mg PLPC, mean
      +/- SD, p < 0.01 and p < 0.05, respectively). PLPC showed a weak correlation with
      the levels of fasting plasma glucose (FPG) and HbA1c (r=0.27 and r=0.33, p < 0.05
      and p < 0.01, respectively). The diabetic patients with macroangiopathy showed
      higher levels of PLPC per gram protein compared to those without macroangiopathy
      (4.60+/-2.61 mg vs 2.53+/1.15 mg, respectively, p < 0.05). The LPC molecular
      species may participate in the atherogenicity of LDL in patients with Type 2
      diabetes.

PMID- 10333087
TI  - Missense variants in the human cholecystokinin type A receptor gene: no evidence
      for association with early-onset obesity.

PMID- 10333088
TI  - Insulin increases in vitro production of Th2 profile cytokines in peripheral
      blood cultures in subjects at high risk of diabetes type 1 and patients with
      newly diagnosed IDDM.

PMID- 10333090
TI  - Activation and disturbance of blood haemostasis following strenuous physical
      exercise.
AB  - Physical exercise activates blood coagulation and enhances fibrinolytic activity.
      To investigate whether these activations of blood coagulation and fibrinolysis
      are balanced post-exercise and during the period of recovery, 11 moderately
      active young men were examined immediately after a standardised cycle ergometer
      test and during the 24 h period of recovery. Blood samples were obtained at rest,
      immediately after exercise, and 2, 6 and 24 h after exercise. All post-exercise
      values were corrected for any change in plasma volume. Exercise induced a
      significant increase in factor VIII activity and this occurred with a significant
      shortening of activated partial thromboplastin time. A concomitant enhancement of
      tissue plasminogen activity resulted in significant increases in tissue
      plasminogen activity antigen and total fibrin/fibrinogen degradation products,
      and a significant decrease in tissue plasminogen activator inhibitor-1 activity.
      Increases in coagulation and fibrinolytic activity changed in parallel during
      exercise. However, during recovery, while the increase in factor VIII activity
      post-exercise persisted 2 and 6 h into recovery, fibrinolytic activity
      demonstrated a sharp fall. It is concluded that whereas the enhanced fibrinolytic
      activity during exercise appears to counterbalance the increase in blood
      coagulability, this haemostatic balance is not maintained during recovery. This
      perturbed blood haemostasis could constitute an enhanced risk for coronary artery
      thrombosis and may contribute to exercise-related cardiovascular events.

PMID- 10333089
TI  - Failure of sulfonylureas in type 2 diabetes.

PMID- 10333091
TI  - No effect of antioxidant supplementation in triathletes on maximal oxygen uptake,
      31P-NMRS detected muscle energy metabolism and muscle fatigue.
AB  - A double-blind placebo-controlled cross-over trial was undertaken to evaluate the
      effect of antioxidant supplementation on maximal oxygen uptake during bicycling,
      31-phosphorus nuclear magnetic response spectroscopy (31P-NMRS) detected muscle
      energy metabolism during plantar flexion and muscle fatigue evaluated by 1-s
      electrical stimulation at low (10 Hz) and high (50 Hz) frequency. Seven male
      triathletes received daily oral antioxidant supplementation in capsule form
      including 100 mg coenzyme Q10 (CoQ10), 600 mg ascorbic acid and 270 mg alpha
      tocopherol or placebo over a 6-week interval. Serum concentration of CoQ10 was
      significantly higher in the antioxidant phase (1.80+/-1 microg x ml(-1), mean +/-
      SD) than control (0.9+/-0.21 microg ml(-1)) or placebo phase (0.9+/-0.3 microg x
      ml(-1)) (P<0.01). Maximal oxygen uptake was 63.8+/-3.0 ml x min(-1) x kg(-1) in
      the control phase, and did not change significantly in the antioxidant (67.6+/
      10.8 ml x min(-1) x kg(-1)) or the placebo phase (61.9+/-4.5 ml x min(-1) x kg(
      1)). The combined 31P-NMRS/low frequency fatigue test (plantar flexion of the
      foot) did not show differences in the gastrocnemius muscle pH (6.77+/-0.14),
      phosphocreatine reduction at the end of exercise (23+/-14% of rest) and half-time
      for recovery of phosphocreatine (33+/-12 sec) between the placebo and the
      antioxidant trial. No difference in muscle fatigue at 10 Hz electrical
      stimulation was found between the three phases. In conclusion, the results
      demonstrate no effect of antioxidative vitamin supplementation on maximal oxygen
      uptake, muscle energy metabolism or muscle fatigue in triathletes.

PMID- 10333092
TI  - Neuroendocrine system and mental function in sedentary and endurance-trained
      elderly males.
AB  - Hypothalamic-pituitary-adrenal (HPAA) and -gonadal (HPGA) axis modification and
      cognitive impairments have been reported in elderly subjects and related to
      physical training status. The aim of this study was to investigate if HPAA and
      HPGA regulation are altered in elderly distance runners (RUN; n = 8; age: 68.9+/
      4.2 yrs; training: 65+/-20 km/wk over the last 20 yrs; means +/- SD) or are
      affected in elderly sedentary individuals (SED; n = 11; age: 69.1+/-2.6 yrs) by
      an aerobic training over 20 weeks (3 times/week, 30-60 min walking),
      respectively. The protocol included assessment of the hormone profile in basal
      non-suppressed state as well as evaluation of hormonal responses to dexamethasone
      (DEX, 1.5 mg) induced adrenal suppression, to post-DEX combined corticotrophin
      releasing hormone (CRH; 0.7 microg/kg) and luteinizing hormone releasing hormone
      (LHRH, 0.7 microg/kg) stimulation and to exercise challenge (30 min cycle
      ergometry at 65% VO2max). Mental functions influenced by HPAA and HPGA activity
      were also assessed in RUN and SED before (SED-PRE) and after (SED-POST) the
      training program. Basal and post-DEX plasma concentrations of adrenocorticotropic
      hormone (ACTH), cortisol (CSL), luteinizing hormone (LH), follicle stimulating
      hormone (FSH) and testosterone (T) did not differ between RUN and SED-PRE. Basal
      plasma free T concentration was significantly lower in RUN (RUN: 10.23+/-2.41 pg
      x ml(-1) vs. SED-PRE: 16.6+/-5.59 pg x ml(-1)). During releasing hormone
      challenge test after DEX administration (DEX/RH), no differences were found
      between RUN and SED-PRE in plasma ACTH, LH, FSH and T response. During this
      stimulation test, plasma CSL was significantly higher in RUN than in SED-PRE
      after 90 min (RUN: 5.86+/-3.65 microg x dl(-1) vs. SED-PRE: 2.74+/-2.09 microg x
      dl(-1)). Differences in plasma CSL concentrations between groups were not induced
      by 30-min exercise challenge. Basal hormone profile was not altered by training
      in SED. During DEX/RH only plasma ACTH concentration was significantly higher in
      SED-POST compared to SED-PRE. Long and short-term memory function did not differ
      between RUN, SED-PRE and SED-POST. Our data suggest that following post-DEX
      CRH/LHRH challenge elderly endurance athletes reveal-in the absence of altered
      peak values-a pattern of prolonged secretion of glucocorticoids. However, the
      high interindividual variability of plasma ACTH and CSL concentrations shows that
      reduced corticotropic sensitivity to negative feedback is not always induced by
      chronic exercise stress. Lower plasma free T concentrations in RUN compared to
      SED are not caused by modified LH synthesis-secretion capacity.

PMID- 10333093
TI  - Heart rate response to professional road cycling: the Tour de France.
AB  - The aim of the present investigation was to evaluate the heart rate response of 8
      professional cyclists (26+/-3 yr; 68.9+/-5.2 kg; V02max: 74.0+/-5.8 ml x kg(-1) x
      min(-1)) during the 3-week Tour de France as an indicator of exercise intensity.
      Subjects wore a heart rate telemeter during 22 competition stages and recorded
      data were analysed using computer software. Two reference heart rates
      (corresponding to the first and second ventilatory thresholds or VT1 and VT2)
      were used to establish three levels of exercise intensity defined as phases I
      (<VT1), II (VT1 -VT2) and III (<VT2). The average total time spent by each
      subject in each of the 3 phases respectively was approximately 71, 23 and 8 h.
      The relative contributions of each phase were 70, 23 and 7%. The percentage
      relative contribution of each phase was significantly different (p<0.01) in each
      of the competition stages (time trials, flat stages, "high-mountain" stages and
      "medium-mountain" stages). Exercise intensity was particularly high during the
      time trials and high mountain stages. It may be concluded that during an
      endurance event such as the Tour de France, although the overall contribution of
      moderate (VT1 to VT2) or high intensity exercise (>VT2) is substantially lower
      than that of light, aerobic exercise (<VT1), a clear distinction must be made
      between the different type of stages (i.e. easy, flat parcours vs mountain stages
      or time trials) and the role of each cyclist in the team must be also considered.

PMID- 10333094
TI  - Isokinetic muscle performance after surgery of the lateral ligaments of the
      ankle.
AB  - In this study, we assessed the isokinetic strength and power profile of 138
      patients with a surgically treated lateral ligament injury of an ankle. In
      addition, the outcome predicting factors were analyzed. The measurements were
      done 6.2+/-0.8 years after the surgery using the Cybex II isokinetic dynamometer.
      The general strength status of the patients was good, the isokinetic testing
      showing no or only moderate (always < or = 18%) average strength deficits in the
      peak torque values of dorsiflexor and plantar flexor muscles of the injured
      ankle. Of the outcome predicting variables, only the age of the patient in the
      group with surgery for chronic ankle instability correlated significantly with
      the isokinetic peak torque deficits: the older the subject, the greater the peak
      torque deficit in the injured ankle (r(s) = -0.388 with p = 0.015) in ankle
      dorsiflexion at the speed of 60 degrees/s. In conclusion, patients having surgery
      for ankle ligament insufficiency, either in acute or chronic phase of the injury,
      seem to recover well showing no remarkable deficiencies in the isokinetic ankle
      muscle strengths several years after the repair.

PMID- 10333095
TI  - Validation of simple tests of biathlon shooting ability.
AB  - The aim of this study was to validate three simple tests of biathlon shooting
      abilities. Twelve expert biathletes performed visual reaction time tests adapted
      for the rifle in the standing (RT-S) and prone positions (RT-P), and a tremometer
      test adapted for the rifle in the standing position (TT-S). Six consecutive days'
      measurements showed an acceptable reproducibility for these tests (coefficient of
      variation = 1.2% for RT-S, 1.1% for RT-P and 6.5% for TT-S). A significant
      difference was observed between TT-S at rest and after roller skiing 2.1 km at 90
      % of maximal heart rate. This finding demonstrates the sensitivity of TT-S to
      discriminate the effects of fatigue on postural control. Among 24 biathletes of
      regional to expert level, significant correlations were observed between resting
      RT-P and prone shooting performance after roller skiing (r2 = 0.23; p = 0.01) and
      between resting TT-S and shooting performance in the standing position after
      roller skiing (r2 = 0.68; p = 0.0001), demonstrating the specificity of these
      tests. From these results, we conclude that TT-S is a valid field test of
      biathlon shooting performance.

PMID- 10333096
TI  - Health-related fitness test battery for middle-aged adults: associations with
      physical activity patterns.
AB  - To evaluate the validity of a health-related fitness (HRFI) test battery with
      respect to physical activity (PA), we studied how PA patterns of adults are
      related to different components of HRFI with special interest in musculoskeletal
      and motor fitness. Subjects (n = 498) were middle-aged (37-57 years) men and
      women, evenly selected from five age cohorts of a representative population
      sample. PA was assessed with a questionnaire and classified into three PA groups.
      Fitness assessment included 9 simple field tests. The odds ratio of low fitness
      (least fit 40 %) of the measured dimension of HRFI for three PA groups with
      reference to inactive group were analysed. All PA groups were strongly related to
      Walk Test results in both genders, and to BMI in women. Muscular type exercise
      was associated with modified push-ups strength and static back extension
      endurance in both genders, and with one-leg standing balance in women. One-leg
      squat for leg strength, jump-and-reach for leg power, trunk side-bending
      flexibility and hamstring muscle extensibility tests were not associated with PA.
      Five of the nine fitness tests demonstrated plausible associations with PA
      patterns among adults suggesting activity-related validity. An exercise
      intervention study is needed to evaluate the sensitivity of the tests to fitness
      changes.

PMID- 10333097
TI  - Comparison of treadmill and cycle ergometer measurements of force-velocity
      relationships and power output.
AB  - Since body balance and weight-bearing factors present while running on the
      treadmill might cause additional muscle recruitment and thus could influence the
      force-velocity relationship and power, the present study was undertaken to find
      out whether the F-V and F-P relationships measured while running on the treadmill
      are different from the respective indices measured during cycling. On two
      separate occasions, 32 male subjects were tested using a series of 5 sec, all-out
      sprints against different braking forces on the Gymrol Sprint treadmill and on
      the Monark ergometer. The maximal peak power (PPmax) and maximal mean power
      (MPmax) were measured. The equation: EP = 0.5 maximal force (Fo) x0.5 maximal
      velocity (Vo) was used to calculate the estimated values of peak power (EPP) and
      mean power (EMP). The F-V relationship was linear in both cycle ergometer and
      treadmill measurements. PPmax, MPmax, EPP, and EMP values on the treadmill were
      lower than the respective values on the ergometer. EPP on the ergometer and on
      the treadmill, as well as EMP values on the ergometer, were slightly higher than
      the corresponding measured values of PPmax and MPmax. The levels of braking force
      at which PP, MP, PPmax, and MPmax were obtained were lower on the ergometer than
      on the treadmill. High correlation coefficients were found between PPmax, MPmax,
      EPP, and EMP measured on the ergometer and on the treadmill (r = 0.86, r = 0.84,
      r = 0.71, r = 0.78, respectively, P<0.01). In both tests, significant
      relationships between PPmax, MPmax, EPP, and EMP were observed. It is concluded
      that independent of the type of ergometry the force-velocity relationship is
      similar in the measured range of velocities which suggests that the number of
      muscle groups and joints engaged in movement are more important than body balance
      and weight-bearing factors present while running on a treadmill.

PMID- 10333098
TI  - Clinical sciences and orthopaedics: case report homozygous APC resistance in an
      elite athlete.
AB  - We report the case of a 31 year old female elite athlete. During a routine check
      up including a search for hereditary hemostatic risk factors for thrombosis,
      resistance to activated protein C was detected. Molecular analysis of the factor
      V gene revealed homozygosity for the factor V Leiden mutation. This is the first
      documented case of an elite athlete who is a homozygous carrier of factor V
      Leiden. Elite athletes may be exposed to several circumstantial thrombogenic risk
      factors and, therefore, special preventive measures in carriers of a congenital
      risk factor such as APC resistance are indicated. Essential measures are early
      anticoagulation during periods of immobilisation e.g. after sports-related
      injuries, a single dose of low-molecular-weight heparin specially for individuals
      with several thrombotic risk factors and/or leg muscle exercises for long
      distance (air) travels and avoiding haemoconcentration with a sufficient oral
      fluid intake.

PMID- 10333099
TI  - Incidence and symptoms of clinically manifest rotator cuff lesions.
AB  - A clinical study of 200 unselected elderly subjects with an average age of 78
      years living in retirement homes was performed to determine the prevalence of
      clinically manifest rotator cuff tears and the relevance of the tear for daily
      life. A comprehensive questionnaire was performed and the examination included
      the UCLA- and Constant-shoulder assessment scales and a multitude of special
      tests. The criteria for clinical diagnosis of a rotator cuff tear were a positive
      Jobe-test, diminished external rotation, a positive zero-degree-abduction test,
      the drop arm sign, pseudoparalysis and atrophy. By these criteria we found 28
      (7%) rotator cuff tears in 25 people. There were 15 women and 10 men and the mean
      age of symptom onset was 55 years. Eleven craftsmen, 7 office workers and 7
      housewives met our criteria for rotator cuff tears. Pain was present in 22
      shoulders. Moderate weakness was found in 2 people and severe weakness in 22. In
      20 people the range of motion was severely reduced and in 8 moderately reduced.
      Activities of daily living were impaired in all affected subjects. Eight people
      reported onset of symptoms after trauma. Patients with clinically diagnosed
      rotator cuff tears scored an average of 13 points in the UCLA-shoulder assessment
      scales and 40 points in the Constant-shoulder assessment scales. In conclusion
      rotator cuff may be symptomatic only in some people. Probably more anatomic than
      symptomatic rotator cuff tears exist, and it can be supposed that physical
      activities may be one possible reason for clinically relevant tears.

PMID- 10333100
TI  - A computer-based method to quantify the classic pattern of choroidal
      neovascularization in order to monitor photodynamic therapy.
AB  - BACKGROUND: Photodynamic therapy (PDT) is a new treatment modality which relies
      on a nonthermal light exposure of choroidal neovascularization (CNV) which has
      accumulated a photosensitizer, to produce a photochemical thrombosis. The aim of
      the present study was to develop a more quantitative outcome parameter that can
      be used to optimize a number of treatment parameters which in PDT are larger than
      many other modalities. METHODS: Nine patients underwent up to four standardized
      fluorescein angiography (FA) examinations on a Zeiss 30 degrees retinograph using
      Kodak Trimax film. The 35-mm pictures were digitized. The CNV size was evaluated
      using the NIH Image 1.60 software, comparing the CNV surface to the disk area.
      The fluorescence intensity was measured comparing the grayscale fluorescence
      levels of the CNV classic pattern with the mean grayscale level of control areas.
      A combination of the CNV size parameter with the fluorescence contrast parameter
      was called "integrated contrast" (IC). The IC amplitude was then used to describe
      and compare the fluorescence before and after PDT. RESULTS: FAs on three normal
      patients defined the normal range of the IC. IC measurements on two patients with
      a classic CNV who underwent FA examinations respectively 1 and 3 months apart
      demonstrated the robustness and the reproducibility of the method. IC
      measurements on three patients who underwent PDT with three different treatment
      parameters demonstrated the feasibility of using this IC measurement as a PDT
      outcome criteria. CONCLUSION: We have developed a method to transform a
      qualitative clinical evaluation of CNV leakage into a more quantitative grading.

PMID- 10333101
TI  - In vivo imaging of the human zonular apparatus with high-resolution ultrasound
      biomicroscopy.
AB  - BACKGROUND: To investigate the potential of high-resolution ultrasound
      biomicroscopy (UBM) for studying the zonular apparatus of human beings in vivo.
      METHODS: Using transducer frequencies of 34 MHz and 50 MHz, criteria were
      developed to identify transcorneal and transscleral sections that allowed
      reproducible identification of the different fiber groups of the zonular
      architecture. For that purpose, 10 volunteers between the ages of 14 and 41 years
      underwent high-resolution ultrasound biomicroscopy under conditions of consensual
      far- and near-accommodation. The online video recordings of the respective UBM
      investigations were afterwards analyzed image by image. Good visibility of
      zonular fibers was obtained when the ultrasound wave propagation comprised an
      angle close to 90 degrees with the fiber orientation and when the oscillations of
      the UBM scan had a strict radial orientation towards the limbus and avoided,
      simultaneously, the ciliary processes. RESULTS: In all the volunteers, high
      resolution ultrasound biomicroscopy imaged the zonular fiber groups known from
      histology. In addition, it detected fibers that do not follow the course of the
      inner ciliary body surface but take a direct route from the ora serrata to the
      lens. It also demonstrated that fibers that seem to change direction at crossings
      with other fibers. Under conditions of near-accommodation, the zonular fibers
      showed signs of relaxation. CONCLUSIONS: High-resolution ultrasound biomicroscopy
      seems well suited for in vivo investigations of the zonular apparatus and of
      accommodation in man. The results support the fundamental features of the
      Helmholtz theory on accommodation.

PMID- 10333102
TI  - Optic disc surface smoothness and visual field indices.
AB  - BACKGROUND: In order to ascertain whether the optic disc surface smoothness
      (ODSS) could be used to predict the amount of visual field damage in glaucomatous
      eyes, the correlations between ODSS and visual field indices were evaluated.
      METHODS: One eye was randomly chosen from each of 40 normals and 50 patients with
      glaucoma. The morphology of the optic disc surface was analyzed using the Topcon
      IMAGEnet X Rev-3.51b. In order to define the level of "smoothness" of the optic
      disc surface, the differences of the relative position of each surface point was
      studied by measuring the standard deviation (SD) from the average height of the
      points (number of points ranged from 623 to 1883 depending on the size of the
      disc area) that identify the optic disc surface. All the subjects were also
      examined with the Humphrey perimeter (Program 30-2) and the results were analyzed
      by Mann-Whitney U-test and Spearman rank correlation coefficient. RESULTS: The
      difference in ODSS between the glaucomatous and the normal eyes was statistically
      significant. No significant correlation was found between age and ODSS. A
      significant correlation was found between ODSS and mean deviation (MD) and
      between ODSS and corrected pattern standard deviation (CPSD). In the glaucoma
      group there were significant correlations between ODSS and the perimetric indices
      MD and CPSD; no correlations were found in the normal group. CONCLUSION: The
      ability of ODSS to reflect the level of visual field change in glaucomatous eyes
      appears to be rather limited, even if statistically significant. This fact does
      not limit the clinical usefulness of ODSS as a diagnostic parameter in
      consequence of its strong correlations with the other morphometric parameters and
      its high sensitivity and specificity in separating normal from glaucomatous eyes.

PMID- 10333103
TI  - Colour vision disturbances in chronic smokers.
AB  - PURPOSE: The aim of the present study was to test the influence of smoking on
      colour perception. SUBJECTS AND METHODS: At the University Eye Hospital Tubingen,
      76 generally healthy smokers with inconspicuous ophthalmological findings (visual
      acuity, refraction, intraocular pressure, morphology) were examined by the cap
      sorting test, Roth 28-hue desaturated. Group 1 was comprised of smokers (n = 20;
      M 9, F 11; mean age 28.1+/-10.3 years) with a smoking consumption of less than
      one packet of cigarettes per day (8.4+/-5.3 cigarettes/day) for 9.1+/-8.3 years.
      Group 2 consisted of smokers (n = 32; M 22, F 10; mean age 28.6+/-9.7 years) with
      a smoking consumption of one or more than one packet per day (30+/-8.4
      cigarettes/ day) for 9.5+/-8.3 years. Generally healthy and ophthalmologically
      normal non-smokers served as a control group (n = 76; M 41, F 35; mean age 30+/-9
      years). RESULTS: The average error score of the control group was (median +/-
      mean absolute deviation) 42+/-18. Group 1 showed no difference to the control
      group (51+/-27; P = 0.42). On the other hand, group 2 had a significantly higher
      error score than the control group (102+/-45; P<0.0001). CONCLUSION: Otherwise
      healthy smokers with a cigarette consumption of less than 20 cigarettes per day
      do not show any disturbances in colour vision. Smokers who consume more than 20
      cigarettes per day may suffer colour vision defects as a result.

PMID- 10333104
TI  - Quantitative comparison of Zeiss-Humphrey model 840 and Rion UX-02 systems of
      ultrasound biomicroscopy.
AB  - BACKGROUND: Our objective was to estimate the agreement between two different
      ultrasound biomicroscopes (UBMs) and to evaluate the clinical implications of the
      measurements obtained. METHODS: We measured the anterior chamber depth,
      trabecular-iris angle, angle opening distance at 250 and 500 microm from the
      scleral spur, iris thickness and scleral-iris angle using the Humphrey UBM model
      840 and Rion UBM UX-02 in 25 eyes of 25 normal volunteers. RESULTS: No
      significant difference was found in the mean values of any parameters measured by
      the Humphrey and Rion systems. Correlation coefficients of greater than 90% were
      observed for the parameters studied. Each system showed high reproducibility for
      all measured parameters. There were significant differences between the two
      systems in coefficients of variation for all parameters measured except the
      anterior chamber depth. CONCLUSIONS: The parameters measured with the Humphrey
      and Rion systems showed correlation coefficients of greater than 90%. The
      Humphrey system showed better reproducibility than the Rion system.

PMID- 10333105
TI  - Wagner vitreoretinal degeneration with genetic linkage refinement on chromosome
      5q13-q14.
AB  - BACKGROUND: It has been previously described that Wagner disease is linked to
      chromosome 5q13-q14. This study was carried out to describe the ophthalmological
      aspects and report the results of genetic linkage analysis in a large pedigree
      affected by Wagner disease. METHODS: Fourty members of one same family agreed to
      be examined. RESULTS: Twenty patients presented vitreoretinal degeneration in
      both eyes without any extra-ocular abnormalities. In young patients, visual
      acuity was usually normal after correction of frequent mild myopia. Presenile
      cataracts progressed by the third decade and required removal for visual
      rehabilitation. The primary disorder involved an abnormal vitreous. A few
      avascular vitreous bands were usually the only optical feature in the mostly
      empty vitreous cavity. A circumferential vitreous condensation formed in contact
      with the retina on many spots. Less common retinal findings included retinal
      detachment, abnormal retinal pigmentation, progressive atrophy of the RPE
      simulating choroideremia and lattice degeneration. Genetic analysis revealed a
      highly significant linkage (lod score >5.0) between the disease and 10 markers of
      the chromosome 5q13-q14 region. Two recombination events allowed us to refine the
      linked interval to 20 cM between the D5S650 and D5S618 markers. CONCLUSION:
      Ophthalmological aspects of Wagner's disease appear to progress with age. Regular
      ophthalmological examination is important for detecting retinal abnormalities.
      The gene involved in Wagner's disease lies in a 20 cM interval on chromosome 5q13
      q14.

PMID- 10333106
TI  - Dry Drops: a new preservative-free drug delivery system.
AB  - PURPOSE: We compared the tolerability and safety of a lyophilisate (Dry Drops)
      with conventional eye drops containing the same polymer and electrolytes. In Dry
      Drops the active ingredient is incorporated in a drop of hydrophilic polymer
      solution freeze-dried on the tip of a soft hydrophobic carrier strip. Upon
      contact with tear film and/or conjunctiva the lyophilisate immediately rehydrates
      and detaches from the carrier. METHODS: Dry Drops containing HPMC as active
      ingredient and a preservative-free tear film substitute were applied to 64 eyes
      of 32 healthy volunteers according to a 22 factorial design in an open-label,
      cross-over, randomised study. Tolerability and safety were quantified and
      qualified at 0.5, 2, 5 and 10 min after administration via slit-lamp
      biomicroscopy, questionnaire and visual analogue scales. RESULTS: The differences
      between Dry Drops and conventional eye drops were not statistically significant.
      The initial sensation of Dry Drops was slightly less uncomfortable than that of
      the conventional ophthalmic solution. None of the eyes showed any clinical
      findings with safety implications. CONCLUSION: The safety and tolerability of a
      new application form were demonstrated in this phase I study. The improved
      chemical stability, exact dosing, reduced risk of lesions to the eye surface and
      good tolerability suggest that the new application device has promise for
      treatment in ophthalmology as well as in other medical subspecialties.

PMID- 10333108
TI  - Inhibitory effects of FK506 on the development of experimental allergic/immune
      mediated blepharoconjunctivitis in Lewis rats by systemic but not by topical
      administration.
AB  - BACKGROUND: FK506 has been used for treatment of cell-mediated immune disorders
      such as graft rejection in transplantation or Behcet disease. To evaluate the
      effectiveness of FK506 in another ocular disease model, we injected FK506 in rats
      with experimental allergic/immune-mediated blepharo conjunctivitis (EAC) the
      induction mechanism of which depends on cell-mediated immunity. METHODS: Lewis
      rats were immunized with ovalbumin (OVA) in emulsion of complete Freund's
      adjuvant (CFA). We injected 2 (n = 6), 20 (n = 6) or 200 (n = 5) microg of FK506
      intramuscularly daily from the day of immunization (day 0) to day 6. Control rats
      were not treated with FK506 (n = 4). In addition, we injected 200 microg of FK506
      from day 7 to day 13 (n = 12) to compare the timing of FK506 administration (day
      0 to day 6, n = 12; control, n = 12). Twenty-one days after immunization, all
      rats were challenged with OVA by eye drops, and 24 h later they were killed after
      clinical evaluation and their eyes, blood and draining lymph nodes were harvested
      for histology, antibody titers and proliferation assay or flow cytometric
      analysis. In another set of experiments, rats that had received OVA-primed lymph
      node cells did (n = 9) or did not (n = 9) receive additional FK506 by injection
      daily for 4 days. Four days after transfer, these rats were challenged with OVA
      and evaluated as mentioned. To investigate possible suppression of disease by
      topical administration of FK506, both actively immunized and passively immunized
      rats received OVA together with 0.3% (weight/volume) of FK506 (n = 16) or vehicle
      (n = 10) by eye drops and 24 h after challenge, rats were evaluated as mentioned.
      RESULTS: Development of disease, induced by either active or passive
      immunization, was inhibited in the group treated with 200 microg of FK506,
      regardless of timing of administration. Cellular proliferative responses to OVA
      were inhibited only in this group. Flow cytometry demonstrated a decrease of
      about 20% in the proportion of all cells made up by CD4-positive T cells. Topical
      administration of FK506 inhibited the development of EAC, though not
      significantly. CONCLUSIONS: Systemic treatment with 200 microg of FK506 either in
      the induction or the effector phase inhibits the development of EAC in Lewis
      rats. Topical administration is not so effective as systemic administration.

PMID- 10333107
TI  - CD4+ T-cell type 1 and type 2 cytokines in the HSV-1 infected cornea.
AB  - PURPOSE: It has been previously shown that CD4+ T-lymphocytes are critical
      mediators in HSV-1 stromal keratitis (HSK). CD4+ T cell subpopulations (type 1,
      type 2) can be defined by their capabilities of producing different sets of
      cytokines. This study was performed to determine the role of type 1 and type 2
      cytokines in murine HSK. METHODS: BALB/c mice (n = 20) were inoculated with 10(5)
      PFU of HSV-1 (KOS strain) and were followed clinically. At various time points
      post-infection (p.i.), the conjunctival and corneal tissues were analyzed
      histologically (n = 2 each time point), and immunohistochemically (n = 5 each
      time point) for the presence of interleukin-1alpha (IL-1alpha), type 1 cytokines
      (IL-2, interferon-gamma) and a type 2 cytokine (IL-4). The expression of cytokine
      mRNA was tested in eye samples by reverse transcription-polymerase chain reaction
      (RT-PCR). RESULTS: Stromal keratitis clinically progressed after day 9. In 15% of
      the mice, disease regressed until day 14 p.i. Polymorphonuclear neutrophils,
      lymphocytes and other mononuclear cells infiltrated the conjunctiva by day 2 and
      rapidly expanded to the central cornea between days 7 and 14. IL-1alpha, IFN
      gamma and IL-2 mRNA were found in the eyes at days 1 and 2 p.i. IL-1alpha protein
      was detected in the conjunctiva, limbus and corneal epithelium at day 2. The IL
      1alpha staining intensities increased with disease progression. This was
      paralleled by IL-2 and IFN-gamma staining intensities. In contrast, IL-4 mRNA and
      protein were detected at days 7 through 14 after HSV-1 infection; compared to IL
      2 and IFN-gamma, IL-4 staining intensities were lower. CONCLUSIONS: The findings
      suggest that the lymphocytic infiltrate during the development of HSV-1 keratitis
      is predominantly composed of type 1 cells expressing IL-2 and IFN-gamma. Type 2
      cytokines participate in the late stage of inflammation and might be useful to
      improve the course of the disease.

PMID- 10333109
TI  - Detection of dexamethasone in the cornea and lens by NMR spectroscopy.
AB  - BACKGROUND: To study the penetration and metabolism of dexamethasone phosphate in
      the cornea and lens from rabbit following topical administration. METHODS: After
      topical administration of 0.1, 1 and 10% dexamethasone phosphate solutions,
      respectively, the cornea and lens were removed and extracted with either
      perchloric acid (PCA) or with chloroform/methanol to study the lipophilic and
      hydrophilic metabolites of the drug. The extracts were analyzed with 1H and 19F
      NMR spectroscopy. RESULTS: Using 19F NMR spectroscopy, both dexamethasone and
      dexamethasone phosphate were detected simultaneously in the extract of the cornea
      and lens obtained from the eyes denuded of the epithelium before the treatment.
      Using 10 and 1% drug solutions, the signals from dexamethasone were also
      detectable in the 1H NMR spectra among many endogenous metabolites. CONCLUSION:
      1H and 19F NMR spectroscopy was shown to be a useful method in the study of
      penetration and metabolism of dexamethasone in the eye, particularly because both
      the lipophilic and hydrophilic metabolites of the drug could be detected
      simultaneously.

PMID- 10333110
TI  - Tapioca melanomas of the iris: immunohistology and report on two cases.
AB  - BACKGROUND: Tapioca-like tumors are rare, and their benign or malignant nature is
      obscure without histological work-up. We report on the clinical and histological
      features of different types of tumors in two patients. CASE REPORT: Two patients
      aged 17 and 45 years presented with brownish iris masses increasing in size. Full
      thickness en bloc excision of melanocytic tumors (5.5 mm and 7.0 mm in diameter)
      was carried out. Histological work-up revealed a nevus cell nevus in the young
      patient and an epithelioid malignant melanoma in the middle-aged patient evolving
      from the ciliary body. Staining for HMB-45 was marked in both tumors, for S-100
      low in the nevus and marked in the melanoma, and for p53 negative in the nevus
      and positive in the melanoma. Ki67 stains were negative. CONCLUSION: We propose
      that excision of anteriorly located pigmented tumors that increase in size is
      indicated in order to determine whether they are benign or malignant. In these
      case reports, tapioca-like tumors include a benign and a malignant entity. To our
      knowledge, a nevus cell nevus presenting as a tapioca-like tumor has not
      previously been described. Curative surgery and histological and
      immunohistological evaluation are required to characterize the malignant
      potential of these tumors and the prognosis.

PMID- 10333111
TI  - Familial macular cone dystrophy: diagnostic value of multifocal ERG and two-color
      threshold perimetry.
AB  - BACKGROUND: It is difficult to detect receptor dysfunction in patients with
      marked bilateral visual loss but only mild morphological alterations of the
      fundus. METHODS: Two patients, father and son, with visual acuity loss to 20/100
      were examined. Using the multifocal ERG, 61 local cone ERGs from each eye were
      derived from the central visual field. The dark-adapted two-color threshold
      perimetry using stimuli of 500 nm and 656 nm for rod and cone function was
      investigated along the horizontal meridian of the visual field. RESULTS: In the
      multifocal ERG of both patients a macular response was absent. From eccentricity
      at and anterior to 5 degrees, good multifocal cone activity was recorded. Cone
      thresholds were markedly diminished in the macula. The rod thresholds were
      borderline in the father and normal in the son. CONCLUSIONS: Multifocal ERG is a
      novel technique, very well suited to reveal the topography of cone function.
      Using two-color threshold perimetry affords an opportunity to differentiate
      between rod and cone functional defects. Both together helped to establish the
      diagnosis of macular cone dystrophy in the present family.

PMID- 10333112
TI  - Serum tryptase: an indicator of anaphylaxis following fluorescein angiography.
AB  - BACKGROUND: Anaphylaxis is a potentially fatal complication of fluorescein
      angiography. It is diagnosed by clinical signs. Serum beta-tryptase serves as a
      specific indicator of mast cell activation and of anaphylactic shock that can be
      detected by radioimmunoassay. METHOD: This is a report on a 48-year-old woman who
      developed anaphylaxis during fluorescein angiography. This study investigates the
      role of beta-tryptase in anaphylactic shock resulting from intravenous
      fluorescein angiogram. RESULTS: A serum sample of beta-tryptase collected at the
      time of an adverse reaction to fluorescein angiography was determined by
      radioimmunassay to be elevated above 20 ng/ml (normal level <1 ng/ml). This
      indicates massive mast cell activation and anaphylactic shock. CONCLUSION: This
      case is the first in which elevated levels of beta-tryptase in serum indicated
      that the systemic adverse reaction to fluorescein was mast cell dependent.
      Additionally, beta-tryptase levels can be assayed to detect anaphylactic
      reactions several hours after a precipitating event.

PMID- 10333113
TI  - Treatment of HSV-1 stromal keratitis with topical cyclosporin A: a pilot study.
AB  - BACKGROUND: In stromal keratitis induced by herpes simplex virus (HSV) the host's
      immune response contributes to corneal scarring and neovascularization. The
      purpose of this study was to analyze the efficacy of topically applied
      cyclosporin A (CsA) in patients with HSV keratitis. METHODS: The authors
      performed a prospective pilot study in patients with HSV stromal keratitis (n =
      18). Eyes were treated with CsA eyedrops and acyclovir ointment. The drugs were
      tapered off gradually. Visual acuity, slit-lamp appearance, intraocular pressure
      and corneal sensitivity were evaluated monthly (follow-up 5.2+/-0.28 months, mean
      +/- SEM. RESULTS: Keratitis resolved with CsA treatment in 10 of 14 patients with
      non-necrotizing keratitis and in 2 of 4 with necrotizing keratitis. As CsA was
      used topically, the corticosteroids could be withdrawn in all patients with non
      necrotizing keratitis and in 1 of 3 with necrotizing keratitis. Under CsA
      therapy, persistent or progressive inflammation was noted in 6 of the 18
      patients. These 6 patients with keratitis improved only with combined
      CsA/corticosteroids. Corneal ulcers healed in 4 patients with topical CsA, and
      corneal neovascularization improved in a further 8. Except for toxic
      epitheliopathy, no further CsA complications were noted. CONCLUSIONS: The
      findings in this pilot study suggest that HSV stromal keratitis can be treated
      successfully with CsA eyedrops, especially in non-necrotizing disease. CsA may be
      particularly helpful in the presence of steroid glaucoma, herpetic corneal
      ulcers, and to taper off topical corticosteroids. Additional use of acyclovir may
      aid in suppressing the recurrence of epithelial HSV keratitis. A randomized study
      should be performed to evaluate the role of topical CsA in more detail.

PMID- 10333114
TI  - European Forum on Immunization: report of Second General Meeting, Munich, 2-3
      June 1997.

PMID- 10333115
TI  - Risk factors for type I diabetes mellitus in children in Austria.
AB  - The aim of this study was to investigate environmental risk factors in the
      development of type 1 diabetes mellitus in a population-based case-control study.
      Parents of all patients with manifestation of type 1 diabetes between 1989 and
      1994 in Vienna were asked to complete a questionnaire (n = 114). Control children
      (n = 495), matched for age and sex, were randomly recruited from all schools in
      Vienna. Fathers of diabetic children were significantly older at the time their
      children were born than fathers of control children (P = 0.015). Children with
      diabetes were more likely to be second- or third-born children (P<0.05) and fewer
      went to kindergarten than the control group children (P = 0.007). No significant
      difference in duration of gestation, percentage of delivery by caesarean section,
      birth weight or length was found. Neonatal jaundice was more often observed in
      the patient group (P = 0.038). Breast feeding was reported by 82.7% of mothers of
      diabetic children and by 81% of mothers of control children, and the duration of
      breast feeding was longer in patients than in controls (n.s.). CONCLUSION: In our
      study, the development of type 1 diabetes mellitus was associated with higher
      paternal age and neonatal jaundice. No correlation could be found with dietary
      intake of cow's milk products in early infancy, vaccination and other
      environmental factors.

PMID- 10333116
TI  - Cirrhosis in a child with hypothalamic syndrome and central precocious puberty
      treated with cyproterone acetate.
AB  - Before the advent of gonadotropin-releasing-hormone analogues, cyproterone
      acetate (CPA) had been widely prescribed for the treatment of precocious puberty.
      Although it is usually well tolerated, liver toxicity has been recognized as a
      complication of its long-term use. We report the occurrence of cirrhosis in a 10
      year-old boy with hypothalamic syndrome and precocious puberty who was treated
      with CPA for over 50 months. Despite discontinuation of the medication, the liver
      disease progressed. The patient died of sepsis and multiorgan failure at the age
      of 14 years. This is the first paediatric report of substantial liver damage and
      liver toxicity progressing to cirrhosis associated with CPA treatment.
      CONCLUSION: Prolonged cyproterone acetate treatment may induce cirrhosis.
      Monitoring of liver function both during treatment and for several months after
      discontinuation of therapy is recommended.

PMID- 10333117
TI  - Acid oro-pharyngeal secretions can predict gastro-oesophageal reflux in preterm
      infants.
AB  - Acid gastro-oesophageal reflux (GOR) is common in preterm infants but there is a
      lack of a non-invasive technique to establish the diagnosis. The aim of this
      study was to identify whether the presence of acid in oro-pharyngeal secretions
      (OPS) was a valid indicator of clinically significant acid GOR in preterm
      infants. A total of 23 infants with suspected GOR were studied with 24 h lower
      oesophageal pH monitoring and during this period the OPS were tested for acid
      with litmus paper at 6 hourly intervals. Median (range) gestation was 28 weeks
      (24-31), birth weight 1023 g (480-1750) and age at study 34 days (11-76).
      Significant GOR was defined as a reflux index >5%. Of the investigated infants,
      18 subjects (78%) had significant GOR. Of this group, 16 infants had acid in the
      OPS on at least one occasion. Five infants did not demonstrate significant GOR
      and in four of these acid was not detected in the OPS. Our data indicate that as
      a predictor for significant GOR, litmus-testing OPS for acid has a sensitivity of
      89%, specificity of 80%, positive predictive value of 94% and a negative
      predictive value of 67%. The difference in the incidence of acid OPS between the
      GOR and the No GOR group was significant (P<0.03). CONCLUSION: The presence of
      acid in the oropharyngeal secretions may help in the prediction of acid gastro
      oesophageal reflux in preterm infants. The method is simple, inexpensive cheap
      and involves minimal disturbance. We suggest that it could aid clinical diagnosis
      and indicate a need for further investigation of gastro-oesophageal reflux.

PMID- 10333118
TI  - Late manifestation of Indian childhood cirrhosis in a 3-year-old German girl.
AB  - We report on a 3.8-year-old German girl who presented with signs of subacute
      liver failure based on a 4-month history. Investigations done before admission
      excluded infectious, metabolic and immunological diseases. Laboratory findings
      were increased values of aminotransferases, hyperbilirubinaemia, hyperammonaemia
      and deteriorated plasmatic coagulation. Caeruloplasmin and serum copper
      concentrations were normal; however, urinary copper excretion was elevated (80
      microg/l). Liver biopsy showed a micronodular liver cirrhosis and an extremely
      high liver copper concentration (1400 microg/g dry weight). Epidemiological
      investigations revealed an elevated copper concentration (8645 microg/l, normal:
      <2000) and a low pH value (6.3) of the drinking water supplied by copper pipes.
      The girl had been exposed to copper-contaminated drinking water since the age of
      2 years. CONCLUSION: Laboratory, histopathological findings and a proven chronic
      copper intoxication lead to the diagnosis of Indian childhood cirrhosis in a
      German girl. Whereas this disease is mostly described in patients with increased
      copper intake in infancy, our patient developed toxic liver cirrhosis with
      relatively late copper exposure. Indian childhood cirrhosis should be considered
      in the differential diagnosis of early childhood liver cirrhosis.

PMID- 10333119
TI  - Anaemia, thrombocytopenia and coagulopathy due to occult diffuse infantile
      haemangiomatosis of spleen and pancreas.
AB  - Diffuse infantile haemangiomatosis of the spleen is a very rare lesion. Large
      haemangiomas may cause trapping of platelets and coagulation disorders known as
      Kasabach-Merrit syndrome. We here report the case of an infant with splenic and
      pancreatic haemangiomatosis presenting with life-threatening thrombocytopenia,
      anaemia and intravascular coagulation. Diagnosis was hampered by reactive
      erythroblastosis and non-conclusive radiological findings. While treatment with
      corticosteroids was ineffective, administration of antithrombin III improved
      coagulation parameters. After splenectomy the child recovered promptly and has
      remained free of disease for 3 years to date. CONCLUSION: Occult visceral
      haemangiomatosis without visible cutaneous haemangiomas should be included in the
      differential diagnosis of thrombocytopenia, anaemia and consumption coagulopathy.
      Antithrombin III treatment may be considered to overcome bleeding problems in
      patients with Kasabach-Merrit syndrome.

PMID- 10333120
TI  - Limp as unusual presentation of Langerhans' cell histiocytosis.
AB  - An isolated eosinophilic granuloma involving the posterior elements of a lumbar
      vertebra is reported in a 3-year-old boy presenting with progressive limp.
      Radiological investigations revealed osteolysis of the L5 right pedicle. MRI
      showed a well-defined homogeneous mass with nonspecific signal intensity. An
      unusual feature was the paravertebral muscular location of the largest part of
      the tumour indicating a possible soft tissue origin. Immunohistochemical studies
      were typical for Langerhans' cell histiocytosis. CONCLUSION: A limp can be due to
      lumbar and paravertebral muscular location of Langerhans' cell histiocytosis.

PMID- 10333121
TI  - Pro- and anti-inflammatory cytokine patterns during and after cardiac surgery in
      young children.
AB  - The systemic inflammatory response that occurs after cardiopulmonary bypass shows
      many changes similar to those seen in sepsis. The mechanisms for these changes
      have been attributed to cellular and humoral activation, such as increased
      secretion of cytokines and complement. The aim of our study was to investigate
      the cytokine pattern of pro- and anti-inflammatory cytokines in young children
      during and after bypass surgery. Nineteen children undergoing either septal
      defect correction (n = 12), or more complex surgery (n = 7), were prospectively
      included in this study. There were significant higher pre-operative levels of
      circulating cytokines in the latter group. Cardiopulmonary bypass surgery induced
      in both groups a rise in circulating cytokine levels and a sharp decline in the
      capacity of the leucocytes to secrete interleukines-6 and -8 in response to ex
      vivo stimulation with lipopolysaccharide. Ex vivo production of interleukine-1
      receptor antagonist was slightly attenuated by the procedure. CONCLUSIONS: The
      downregulation of ex vivo pro- and, to some extent, anti-inflammatory cytokine
      production may be a reflection of a cellular stress response, induced by
      anaesthesia, cardiopulmonary bypass and surgery.

PMID- 10333122
TI  - Immunological reconstitution by allogeneic bone marrow transplantation in a child
      with the X-linked hyper-IgM syndrome.
AB  - A successful transplantation of sibling marrow in a patient with the X-linked
      hyper-IgM syndrome is reported. Engraftment of HLA-identical marrow cells was
      obtained, although complicated by grade I acute graft-versus-host disease.
      Expression of the CD40 ligand (CD40L, CD154) by activated T-cells from the
      recipient remained at low levels until 10 months after the transplantation, but
      then normalized. The patient is now fully competent in immune function without
      any episodes of severe infection 24 months later. CONCLUSION: Allogeneic bone
      marrow transplantation is a reasonable therapeutic option for X-linked hyper-IgM
      syndrome if HLA-matched family donors are available. Whether dysregulation of
      CD40L expression causes post-transplant immunological abnormalities remains to be
      clarified.

PMID- 10333123
TI  - Does concomitant injection of a combined diphtheria-tetanus-acellular pertussis -
      hepatitis B virus - inactivated polio virus vaccine influence the reactogenicity
      and immunogenicity of commercial Haemophilus influenzae type b conjugate
      vaccines?
AB  - Does concomitant injection of a combined diphtheria-tetanus-acellular pertussis -
      hepatitis B virus - inactivated polio virus vaccine influence the reactogenicity
      and immunogenicity of commercial Haemophilus influenzae type b conjugate
      vaccines? The immunogenic responses and local reactions to four Haemophilus
      influenzae type b (Hib) conjugate vaccines licensed for primary immunisation
      (Hiberix, ActHib, Pedvax, HibTITER) when administered concomitantly but in the
      opposite thigh with a candidate diphtheria-tetanus-acellular pertussis-hepatitis
      B-inactivated poliovirus vaccine were studied in 549 healthy infants at 3, 4.5
      and 6 months of age. Local reactions were mild, but different between the four
      groups, a tetanus conjugate Hib vaccine showing the fewest reactions. All local
      reactions resolved without sequelae. There was no apparent general reaction. The
      immunogenic response was similar with all four vaccines, geometric mean
      concentrations ranging from 4.95 to 7.2 microg/ml. All but one subject had
      antipolyribosylribitol phosphate polysaccharide antibody titres > or =0.15
      microg/ml, and 88.0% to 96% achieved high titres (>1.0 microg/ml) generally
      associated with long-term protection against Hib disease. CONCLUSION: There does
      not appear to be any interference with the immune response when current
      commercial Haemophilus influenzae type b conjugate vaccines are concomitantly
      administered with a candidate diphtheria-tetanus-acellular pertussis-hepatitis B
      inactivated polio virus vaccine as separate injections.

PMID- 10333124
TI  - Cat-scratch disease simulating a malignant process of the chest wall.
AB  - Cat-scratch disease is a well-known cause of regional adenopathy in
      immunocompetent children. Rarely, patients may present with symptoms simulating a
      neoplastic disease. The case of a 12-year-old boy with fever, swelling of the
      chest wall and hepatosplenic nodules is reported. Histological analysis of biopsy
      specimen obtained from the chest wall lesion and the liver revealed granulomatous
      reaction without malignant cells. Serological investigations were positive for
      Bartonella species. The symptoms and the lesions disappeared after oral
      antibiotic therapy (ciprofloxacin) was started. The patient remained symptom-free
      12 months later. CONCLUSION: The present case emphasizes the wide spectrum of
      clinical manifestations associated with cat-scratch disease which should be
      investigated as differential diagnosis of manifestations suggesting a neoplastic
      disease in children.

PMID- 10333125
TI  - N-acetylaspartylglutamate in Canavan disease: an adverse effector?
AB  - We measured N-acetylaspartate and its precursor/product N-acetylaspartylglutamate
      (NAAG) in urine of patients with Canavan disease using capillary zone
      electrophoresis. Abnormal levels of NAAG were found in 32 of 43 patients
      examined. Elevated NAAG was also present in the CSF of one patient. Given that
      NAAG may interfere with N-methyl-D-aspartate receptor function, the occurrence of
      high levels of NAAG in patients' urine conceivably represents a participating
      factor in the pathogenesis of Canavan disease. CONCLUSION: The biochemical role
      of N-acetylaspartylglutamate and its relationship to glutamatergic function may
      be relevant to the pathogenesis of Canavan disease.

PMID- 10333126
TI  - Hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia.
AB  - Two cases of hyperinsulinaemic hypoglycaemia associated with persistent
      hyperammonaemia in unrelated infants of 7 days and 4 months of age are reported.
      Blood ammonia levels were 100-300 micromol/l (normal values <40 micromol/l). The
      hyperammonaemia was asymptomatic and not associated with any of the abnormalities
      of amino acids or organic acids observed in urea cycle enzyme defects. Orotic
      aciduria was normal. The hyperammonaemia was not influenced by the levels of
      blood glucose nor by subtotal pancreatectomy. On admission blood glucose was ca.
      1.2 mmol/l (21.6 mg/dl) corresponding to blood insulin levels of 35 and 22 mU/l
      respectively in both infants. Continuous intravenous glucose perfusion was
      necessary to prevent hypoglycaemia. Furthermore 2-oxoglutaric acid in urine was
      increased in the second infant to 3.15 mg/mg creatinine (normal 0.41+/-0.12).
      This may point to mutations in the glutamate dehydrogenase gene. CONCLUSION: 2
      Oxoglutaric aciduria may be an important clue to the diagnose in this syndrome.

PMID- 10333127
TI  - Comparison of albumin versus bicarbonate treatment for neonatal metabolic
      acidosis.
AB  - In this study the effectiveness of 4.5% human albumin was compared with 4.2%
      sodium bicarbonate for neonatal metabolic acidosis, using a randomised controlled
      trial. The change in median pH following bicarbonate was more than twice that in
      the albumin group. This was statistically significant. CONCLUSION: In
      normotensive infants, use of bicarbonate to correct metabolic acidosis may be
      more effective than use of albumin.

PMID- 10333128
TI  - The clinical outcome after inferior vena cava thrombosis in early infancy.
AB  - The clinical outcome after inferior vena cava thrombosis in early infancy is
      unknown. We report the clinical long-term follow-up of 12 patients presenting
      inferior vena cava thrombosis within their first months of life (gestational age:
      24-41 weeks; follow-up: 7+/-3 years). Accompanying renal venous thrombosis
      occurred in 9, and adrenal bleeding in 4 patients. A central venous catheter was
      related to the thrombosis in only four patients. Heterozygous factor V Leiden
      mutation was found in two of the eight infants without central venous catheter.
      Thrombolysis was performed in seven and effective in three infants; one infant
      required surgical thrombectomy. In three of eight infants with ineffective or
      with no therapy, spontaneous recanalization occurred during follow-up. No patient
      died of the thrombosis. Although no long-term anticoagulatory prophylaxis was
      performed, none of the children with persisting occlusion (n = 5) or stenosis (n
      = 1) of the inferior vena cava developed symptomatic thrombo-embolic
      complications. However, extensive internal collaterals (n = 6), visible varicosis
      (n = 5), pain in the legs (n = 3) and persisting renal disease (n = 3) with
      arterial hypertension (n = 2) were observed during follow-up. CONCLUSION:
      Inferior vena cava thrombosis of early infancy frequently persists and may cause
      considerable long-term morbidity. New strategies for early and long-term therapy
      are necessary.

PMID- 10333129
TI  - Safety of lidocaine-prilocaine cream application four times a day in premature
      neonates: a pilot study.
AB  - Although safety is established for lidocaine-prilocaine cream application to the
      heel once a day in neonates, it is often necessary to repeat heel lances several
      times a day in the clinical situation. A pilot safety study applying 0.5 g
      lidocaine-prilocaine cream to the heel covering an area of 5 cm2 with an
      occlusive dressing during 30 min four times a day was carried out. Twelve
      neonates (5 male, 7 female) with a gestational age of 30.1-36.3 weeks (mean 31.6
      weeks) and a birth weight of 1100-2910 g (mean 1665 g) were enclosed. To
      establish safety, methaemoglobin levels and plasma concentrations of lidocaine,
      prilocaine and o-toluidine were measured until 24 h after the final application.
      Methaemoglobin levels were no different from baseline measurements, ranging from
      0.2-1.1% and 0.1-0.7% respectively. Plasma concentrations of lidocaine and
      prilocaine were very low, maxima at 0.230 and 0.223 mg/l respectively. Plasma o
      toluidine concentrations remained below the detection limit (0.025 mg/l).
      CONCLUSION: Application of 0.5 g lidocaine-prilocaine cream to the heel under
      occlusion four times a day during 30 min is safe in preterm neonates.
      Establishing safety by measuring the methaemoglobin level by daily application is
      recommended.

PMID- 10333130
TI  - Pulmonary alveolar proteinosis in infants.
AB  - We investigated the histological and molecular characteristics of pulmonary
      alveolar proteinosis (PAP) in two siblings (a brother and sister) who did not
      exhibit respiratory distress at birth but who each developed symptoms during
      infancy. Histological analysis of lung specimens showed positive staining for
      surfactant proteins in both patients. The polymerase chain reaction revealed
      expression of messenger RNA for surfactant protein B (SP-B) in the lung
      specimens. No defect in SP-B which is characteristic of the congenital form of
      PAP was observed. The concentration of surfactant protein A (SP-A) in bronchial
      alveolar lavage (BAL) fluid was elevated in patient 1 suggesting the BAL
      concentration of SP-A may be a clue to the diagnosis of this form of PAP.
      CONCLUSION: The accumulation of surfactant protein A in two siblings with an
      infantile form of pulmonary alveolar proteinosis could be a clue to the
      diagnosis.

PMID- 10333131
TI  - A 13-year-old girl with hyperlipoproteinaemia type IIb and low plasma protein
      levels.

PMID- 10333132
TI  - Methicillin-resistant Staphylococcus aureus enteritis in an immunologically
      uncompromised infant.

PMID- 10333134
TI  - Extreme Poland anomaly associated with congenital diaphragmatic hernia.

PMID- 10333133
TI  - Hepatosplenic cat scratch disease diagnosed by serology.

PMID- 10333135
TI  - Anaphylaxis following diphtheria-tetanus-pertussis vaccination--a reminder.

PMID- 10333136
TI  - Tuberculous mastoiditis in a child.

PMID- 10333137
TI  - Lack of response to botulinum toxin A in patients with hypertrophic pyloric
      stenosis.

PMID- 10333138
TI  - New developments in the epidemiology, natural history and management of genital
      herpes.
AB  - The prevalence of genital herpes is increasing in several populations worldwide.
      Factors that may be contributing to this increase include greater numbers of
      sexual partners, the high frequency of asymptomatic infections, poor use of safe
      sexual practices, and possibly the decreased incidence of childhood oral herpes
      simplex virus infection. Transmission occurs via skin-to-skin or mucous membrane
      contact during periods of viral shedding when lesions are present but may also
      occur when the patient is unaware of the lesions or when lesions are not
      clinically apparent. This has important implications for strategies to prevent
      transmission of the disease. The introduction of the antiherpes agent, acyclovir,
      and more recently famciclovir and valacyclovir, facilitates the management of
      genital herpes. Treatment of first-episode genital herpes reduces the severity
      and duration of symptoms, time to lesion healing, and cessation of viral
      shedding. Episodic treatment of recurrences as they occur may be of benefit to
      some patients. Daily suppressive therapy significantly reduces the frequency of
      recurrences and asymptomatic viral shedding. Accordingly, patients who experience
      frequent or severe recurrences, those particularly troubled by their disease, and
      those who wish to reduce the frequency of asymptomatic infection generally prefer
      suppressive therapy. The possibility that suppressive therapy may have an impact
      on transmission of the disease is currently under investigation. Antiviral
      treatments have important implications for public health and may help reduce the
      psychological and psychosocial impact of genital herpes on individual patients.

PMID- 10333139
TI  - Resistance mutations selected in vivo under therapy with anti-HIV drug HBY 097
      differ from resistance pattern selected in vitro.
AB  - The quinoxaline derivative HBY 097, an orally active nonnucleoside inhibitor of
      HIV-1 reverse transcriptase (NNRTI), showed an efficient suppression of viral
      load in a dose-escalating phase I study with mean trough concentrations
      increasing from 137-1299 ug/l [Rubsamen-Waigmann et al., Lancet 349:1517]. Half
      maximal inhibitory concentrations (IC50) for viruses grown from the patients at
      entry of the study were 0.1-3 nM, except for one patient who had a virus with
      reduced susceptibility to HBY 097 at entry (IC50: 160 nM). During therapy, only
      two patients developed a virus with a moderately increased IC50 (2.2 and 15 nM).
      This reduced susceptibility was associated with the known NNRTI-resistance
      mutation K ==> N at position 103, in contrast to resistance selection in vitro,
      which had yielded predominant mutations at positions 179 and 190. The Tyr
      mutation at position 181, inducing high resistance for other NNRTIs, was never
      observed. The resistant virus at study entry (IC50 = 160 nM) had a mutation at
      position 103 as well, combined with an AZT resistance mutation (K ==> R) at
      position 70, suggesting that nucleoside-resistance mutations may help increasing
      resistance to HBY 097. This is in line with our in vitro selection studies, where
      resistance mutations at the 'nucleoside sites' 74 and 75 increased the resistance
      phenotype of NNRTI mutations. Our findings highlight the crucial importance of
      IC50 determinations from cultured virus for determination of phenotypic
      resistance development during therapy and demonstrate that in vivo resistance
      development cannot be predicted from in vitro selection.

PMID- 10333140
TI  - The effects of antirhino- and enteroviral vinylacetylene benzimidazoles on
      cytochrome P450 function and hepatic porphyrin levels in mice.
AB  - In an ongoing effort to identify an orally bioavailable compound for the
      treatment of rhino- and enteroviral infections, a series of vinylacetylene
      benzimidazoles was recently examined. Previous studies demonstrated the potential
      for these compounds to possess both good in vitro antiviral activity as well as
      acceptable oral plasma concentrations in mice. Optimization of these properties
      led to four compounds as candidates for further evaluation. In view of the
      recognized potential for certain acetylenic drugs both to inhibit cytochrome P450
      enzymes by mechanism-based inactivation and to possibly perturb heme metabolism,
      information regarding drug effects on cytochromes P450 and hepatic porphyrin
      levels was sought. In an initial single-dose pharmacokinetic study, the four
      selected compounds were given orally to mice, and both plasma concentrations and
      porphyrin levels were determined. Two of the compounds, 4 and 5, caused a
      pronounced increase in liver porphyrin levels whereas compounds 6 and 7 exhibited
      almost no effect on porphyrin levels. Analysis of plasma concentrations showed
      that only 4 and 5 gave significant exposure and that 6 and 7 produced negligible
      levels of drug in the plasma even at the highest dose tested (500 mg/kg). A
      multiple dose study was then initiated in which compounds 4 and 5 were given for
      1 week in daily oral doses to mice. Upon completion of dosing, liver was analyzed
      for cytochrome P450-dependent 7-ethoxyresorufin O-deethylase (EROD) and
      benzphetamine N-demethylase (BND) activities, total cytochrome P450 content, and
      porphyrin levels. Both vinylacetylenes showed dose dependent inhibitory and
      induction effects on EROD and BND activities. In addition, these compounds caused
      a marked increase in hepatic porphyrin levels. Therefore, while all four selected
      compounds displayed potent antiviral activity and two of the compounds exhibited
      acceptable pharmacokinetic properties, the hepatic effects of these latter two
      compounds suggest the potential for drug induced porphyria with multidose
      therapeutic use.

PMID- 10333141
TI  - Guanosine nucleotide analogs as inhibitors of alphavirus mRNA capping enzyme.
AB  - The two virus-specific reactions in the capping of alphavirus RNAs, catalyzed by
      the replicase protein nsP1, are promising targets for developing virus-specific
      inhibitors. In this report, we have studied the effect of over 50 cap analogs on
      the guanine-7-methyltransferase and guanylyltransferase activities of Semliki
      Forest virus nsP1. Recombinant nsP1 was expressed in Escherichia coli and
      partially purified by flotation in a discontinuous sucrose gradient. The
      methyltransferase activity had a pH optimum between pH 6.5 and 7.1, and the
      apparent Km values were 1.9 mM for GTP, 6.0 microM for S-adenosyl-L-methionine
      and 170 microM for Mg2+. NsP1 methyltransferase was able to methylate efficiently
      GTP (relative activity 100%), GDP (16%), GpppG (35%), GppppG (50%) and less
      efficiently GpppA (12%), m2GTP (9%), and m2,2GTP (25%), but not m7GppG. The most
      potent inhibitors for nsP1 methyltransferase were et2m7GMP (Ki value 42 microM),
      m2,7GMP, (64 microM), m2,7GpppG (82 microM), m2et7GMP (105 microM), m2(2
      phet)7GMP (194 microM) and m2GMP (386 microM). Of these compounds, m2GMP,
      m2et7GMP and m2(2-phet)7GMP showed competitive inhibition, whereas the others
      showed mixed type inhibition. All compounds that inhibited the methyltransferase
      activity inhibited also the guanylyltransferase activity of nsP1.

PMID- 10333142
TI  - Inhibition of influenza A virus reproduction by a ribozyme targeted against PB1
      mRNA.
AB  - A ribozyme gene directed at a specific cleavage of mRNA coding for PB1 protein, a
      component of RNA-dependent RNA-polymerase of influenza A virus, was constructed.
      The avian adenovirus CELO virus-associated RNA (VA RNA CELO) promoter and human
      cytomegalovirus (CMV) promoter were used for the permanent expression of the
      ribozyme in cell lines. The cells were infected with influenza A virus strains
      A/Singapore/1/57 and A/WSN/33, and the suppression of the virus reproduction and
      virus-specific protein synthesis was measured. The maximal level of the
      inhibition of virus reproduction as compared to the reproduction in non
      transformed cells was 93.5%. Defective recombinant adenoviruses were constructed
      carrying the genes of functional and non-functional ribozymes under the control
      of human cytomegalovirus (CMV) promoter. The reproduction of A/WSN/33 virus in CV
      1 cells preinfected with recombinant adenoviruses was shown to be suppressed.

PMID- 10333144
TI  - Antiviral treatment for human immunodeficiency virus patients co-infected with
      hepatitis B virus: combined effect for both infections, an obtainable goal?
AB  - A large percentage of human immunodeficiency virus (HIV) patients have
      serological evidence of a past or present hepatitis B virus infection (HBV). Long
      term survival is increasing for HIV patients because of highly active
      antiretroviral therapy. Therefore, the chronic hepatitis B infection may become
      an important determinant of disease outcome in these co-infected patients. We
      describe two HIV/HBV co-infected patients who were treated with extended
      antiviral therapy, initially indicated for the HIV infection. Lamivudine, a
      suppressor of viral replication in both infections, was one of these antiviral
      drugs. One patient showed a severe rebound of the HBV after withdrawal of
      lamivudine, the other patient developed a mutant hepatitis B virus after 18
      months of treatment. This mutation was exclusively induced by lamivudine. These
      patients show that, with improved HIV-related survival, the HBV infection should
      be monitored carefully, thereby enabling the physician to interfere with therapy
      when necessary.

PMID- 10333145
TI  - Animal ethics in basic scientific research.

PMID- 10333143
TI  - In vitro effect of amantadine and interferon alpha-2a on hepatitis C virus
      markers in cultured peripheral blood mononuclear cells from hepatitis C virus
      infected patients.
AB  - The effects of amantadine (1-5 microM) and interferon alpha (IFNalpha)-2a alone
      (1000 IU/ml) and combined, have been studied in cultured peripheral blood
      mononuclear cells (PBMC) from 15 chronic hepatitis C patients and ten healthy
      donors. Amantadine itself did not affect cell viability and had minor effects on
      the response to mitogens by PBMC. Four patients (27%), but no donors, had
      hepatitis C virus (HCV) core and NS3-specific proliferative responses. Amantadine
      suppressed these responses in all cases and its antiproliferative effect was
      greater than that of IFNalpha (Mann-Whitney's U-test: P < 0.05 in both cases).
      All PBMC cultures from patients, but none from donors, were HCV RNA positive.
      Amantadine alone or combined with IFNalpha dose-dependently reduced HCV RNA
      content in individual PBMC (Wilcoxon's signed rank test: 1 microM, P < 0.05; 2
      microM, P < 0.02; and 5 microM, P = 0.16) with respect to untreated cultures. In
      addition, 7, 13 and 20% of PBMC cultures became HCV RNA negative with 2 microM
      amantadine alone, IFNalpha alone and their combination, respectively. Finally, in
      contrast to IFNalpha, amantadine did not modify expression of 2',5'
      oligoadenylate synthetase activity or the spontaneous or mitogen-stimulated
      IFNgamma and interleukin 10 production. In conclusion, these effects in PBMC from
      HCV patients suggest that the amantadine/IFNalpha combination might be considered
      a therapeutic option for treating chronic hepatitis C patients.

PMID- 10333146
TI  - A new approach to scoliosis.
AB  - Despite the advantages that new derotation-based systems have brought to the
      treatment of scoliosis, the debate continues, especially regarding adolescent
      idiopathic scoliosis. Problems like decompensation, junctional kyphosis, and
      insufficient sagittal plane alignment are met with new proposals. We now are
      using a technique and system, the Ibn-I Sina Spinal System (IBS), that we think
      is able to overcome these problems. It makes use of sublaminar wires, hooks,
      screws, and rods for correction. The main innovation is that the major corrective
      force is a controlled translation force acting simultaneously on all segments of
      the curve. A retrospective assessment of 25 patients treated with this system
      showed that besides dealing well with decompensation and junctional kyphosis
      problems, the technique was superior in sagittal plane adjustments, mainly in
      that it carried the normal kyphosis to its physiologic location. IBS has proved
      easy and successful in scoliosis treatment, especially with lordotic rigid
      curves. We encountered no neurologic injury or instrument failure. In addition to
      these advantages, ease of preoperative planning and application, decreased
      operation time, easy removal or revision, and versatility and safety of the
      system has made the Ibn-I Sina Spinal System (IBS) a treatment of choice,
      especially for adolescent idiopathic scoliosis cases, in some centers in Turkey.

PMID- 10333147
TI  - Dorsal instrumentation for idiopathic adolescent thoracic scoliosis: rod rotation
      versus translation.
AB  - The radiographic and clinical outcomes and complications among two groups of
      adolescent patients treated for idiopathic thoracic scoliosis with dorsal
      instrumentation using a unified implantation system (Universal Spinal System)
      were compared retrospectively. A total of 69 patients were included in the study.
      In 30 patients an intraoperative correction of the scoliosis was performed by
      translation and segmental correction (translation group, Helsinki). In 39
      patients the correction was achieved according to the Cotrel-Dubousset rod
      rotation maneuver (rod rotation group, Berlin). The goal of the present study is
      to investigate whether one of the operative procedures leads to a better
      correction of idiopathic adolescent thoracic scoliosis than the other. The mean
      follow-up interval was 30 months, with a minimum of 12 months. There were no
      significant preoperative differences in age (15+/-2 years in both groups),
      gender, or type of scoliosis (King types 2, 3, and 4). The preoperative
      radiographic measurements showed no significant differences between the two
      groups. In both patient groups, the thoracic primary curve, the lumbar secondary
      curve and the thoracic apical rotation were improved by the operation. Lumbar
      apical rotation and the sagittal profile were unchanged in both groups. The
      thoracic primary curve was corrected from 50 degrees +/-6 degrees to 24 degrees
      +/-7 degrees in the translation group and from 54 degrees +/-11 degrees to 220
      degrees +/-11 degrees in the rod rotation group. The extent of the correction of
      the thoracic curve was significantly greater in the rod rotation group than in
      the translation group (59% vs. 52% correction). In contrast, the translation
      procedure seems to have a more beneficial effect on spinal balance than rod
      rotation. Neurological complications did not occur. In both patient groups an
      increase in the non-instrumented lumbar curve was noted, in two cases each. In
      three patients from the rod rotation group the instrumentation had to be removed
      due to a late infection with negative microbiological results.

PMID- 10333148
TI  - Activities and functional assessment 1 year after spinal fusion for paralytic
      scoliosis.
AB  - The results of spinal fusion in patients with paralytic deformities are usually
      presented as the correction of the deformity. When evaluating the surgical
      results in such patients, it is advantageous to classify the patients into
      subgroups because of the varying dysfunction and disabilities. The aim of this
      study was to evaluate the effect of spinal fusion in patients with paralytic
      scoliosis in relation to function in terms of Impairments, activities in terms of
      Disabilities, and dependence in terms of Handicaps 1 year postoperatively, with
      emphasis on subgroups. A total of 94 patients with paralytic scoliosis and 18
      different diagnoses were evaluated 1 year after surgery. The patients were
      classified according to whether or not they could understand verbal instructions.
      The patients were also grouped according to the Scoliosis Research Society
      classification of diagnoses. A set of instruments was used with the variables
      classified according to WHO's International Classification of Impairments,
      Disabilities, and Handicaps (ICIDH). This consists of the patient's/relative's
      motives for surgery, persistent skin discoloration, ambulating or use of
      wheelchair, use of a brace, sitting balance, weight distribution on a sitting
      surface, angle of scoliosis, reaching, pain estimation, activities of daily
      living (ADL) Klein and Bell, care given, time spent resting, and seating
      supports. The set of instrument also included a follow-up questionnaire
      comprising 12 different areas, where the patients/relatives assessed the results
      of surgery. The study showed that spinal fusion in paralytic scoliosis led to
      showed improvements in the whole group of patients at the Impairment level in the
      angle of scoliosis, sitting balance, weight distribution, and reduced number of
      patients with persistent skin discoloration, and at the Handicap level in reduced
      time for resting during the day, reduced number of seating supports in the
      wheelchair, and in the use of a brace. Most of the parameters were unchanged. The
      results in the subgroups were almost the same as in the whole group, although
      pain and reaching at the Impairment level, and ADL at the Disability level, could
      not be measured in the patients who were unable to understand verbal
      instructions. The subjectively assessed results showed that seating posture was
      ranked positively irrespective of the motive for surgery. The study showed that
      the patients with paralytic scoliosis maintained or improved their function and
      level of independence in terms of Impairment and Handicap 1 year postoperatively.
      The subjective results assessed by the patients/relatives also showed a positive
      outcome of surgery. Weight distribution on a seating surface was improved, but
      still uneven, and with respect to better sitting balance and increasing time
      sitting in a wheelchair, this can involve a risk for pressure sores and needs
      further investigation. When introducing outcomes including the Disability level,
      one must take the importance of homogeneity in the groups into consideration.

PMID- 10333149
TI  - Reducing the cervical flexion tear-drop fracture with a posterior approach and
      plating technique: an original method.
AB  - Flexion tear-drop fractures (FTDF) in the cervical spine constitute a highly
      unstable condition with a high incidence of neurological complications due to
      posterior displacement of the fractured vertebra in the spinal canal. The widely
      accepted surgical management for this condition includes complete excision and
      grafting of the vertebral body through an anterior approach. Thorough
      radiological and CT analysis of FTDF shows that the vertebral body is often
      separated into two parts by a sagittal plane fracture, but remains continuous
      through the pedicle and anterior arch of the vertebral foramen with the lateral
      mass and the articular processes. We therefore hypothesized that reduction would
      be possible by acting on the articular process through a posterior approach with
      a particular plating technique. Eight patients with FTDF were operated on with
      the technique we describe. Three had complete tetraplegia, four had incomplete
      tetraplegia and one was normal. A preoperative CT scan was made in all patients.
      Local kyphosis, posterior displacement of the vertebral body, and general
      lordosis in the cervical spine were recorded. In all cases, a satisfactory
      reduction was achieved on the postoperative radiographs and at the mean follow-up
      of 18.6+/-12.1 months, with residual posterior displacement being less than 1 mm.
      No complication occurred. Out of seven neurologically impaired patients, five
      showed some motor recovery at the latest follow-up. The posterior technique is
      described, and the rationale and pros and cons are discussed. The study showed
      that posterior reduction and fixation of flexion tear-drop fracture is not only
      possible, but permits an accurate restoration of the anatomy of the fractured
      cervical spine.

PMID- 10333150
TI  - Cervical electromyographic activity during low-speed rear impact.
AB  - Whiplash motion of the neck is characterized by having an extension-flexion
      motion of the neck. It has been previously assumed that muscles do not play a
      role in the injury. Eight healthy males were seated in a car seat mounted on a
      sled. The sled was accelerated by a spring mechanism. Muscle electromyographic
      (EMG) activity was measured by wire electrodes in semi-spinalis capitis, splenius
      capitis, and levator scapulae. Surface EMG activity was measured over trapezius
      and sternocleidomastoideus. Wavelet analysis was used to establish the onset of
      muscle activity with respect to sled movement. Shorter reaction times were found
      to be as low as 13.2 ms from head acceleration and 65.6 ms from sled
      acceleration. Thus the muscles could influence the injury pattern. It is of
      interest that clinical symptoms are often attributed to muscle tendon injuries.

PMID- 10333151
TI  - Relationship of pain drawings to invasive tests assessing intervertebral disc
      pathology.
AB  - It has been found that the pain patterns in pain drawings are related to the
      presence of herniated disc identified by myelography. The purpose of this study
      was to determine whether the pattern of pain in the drawings or the type of pain
      indicated (aching, burning, numbness, pins and needles, stabbing) was related to
      the presence of symptomatic disc pathology identified by CT/discography. In a
      subgroup of patients who underwent myelography, the relationship of the drawings
      to myelographic findings was also investigated. Pain drawings were completed by
      187 patients with low back and/or radicular pain who were undergoing
      CT/discography. The drawings were scored in two ways, first by the system
      described by Ransford and secondly by visual inspection. They were classified as
      being indicative, or not, of disc pathology. The CT/discograms were classified as
      disrupted, or not, and the pain responses were recorded upon injection of each
      disc, based on the similarity of the pain provoked to clinical symptoms. Among
      the 133 patients with discogenic pain confirmed by discography, 110 (82.7%) had
      pain drawings that were classified as indicative. Among the 45 patients without
      discogenic pain, 29 (64.4%) had pain drawings classified as non-indicative.
      Patients with discogenic pain used more symbols indicating burning pain and
      aching pain than did non-discogenic pain patients. Our results confirmed those
      reported earlier by Uden, who found a relationship between the pattern of pain in
      the drawings and myelographic findings. Pain drawings may be helpful in the
      diagnosis of symptomatic disc pathology.

PMID- 10333152
TI  - Prognostic criteria for work resumption after standard lumbar discectomy.
AB  - The purpose of this study was to determine prognostic criteria for return to work
      9-12 years after standard nucleotomy for herniated nucleus pulposus confirmed by
      CT. From 1985 until 1988, 182 patients (102 male, 80 female, mean age 45 years)
      with a single-level herniated nucleus pulposus were operated on for the first
      time. In summer 1997, an average of 10.2 years after the operation, 101 of 182
      patients (55.5%) returned a standardised questionnaire. Eighteen patients (9.8%)
      had died during the intervening years, while 63 patients (34.6%) were lost to
      follow-up because of moving to other cities. Two groups could then be
      distinguished: group I worked full time in their usual job; group II did not. The
      influence of the degree of the paresis, time elapsed since the occurrence,
      intraoperative findings, age, sex, weight, type of work and re-operations were
      analysed statistically. Group I consisted of 44 patients who still worked full
      time in their usual job. Group II contained 57 patients, of whom 18 worked only
      part of the time, 9 had changed to a lighter full-time job, 23 had taken early
      retirement, and 7 were receiving a pension. Patients in group I were
      significantly younger (38 vs. 51 years), had a smaller proportion of patients
      with more than 20% overweight (27% vs. 44%), had a smaller proportion of severe,
      grade 0 and 1, motor dysfunction (0% vs. 16.3%), had been operated sooner (within
      3 days: 52.3% vs. 19.3%), had undergone fewer re-operations for recurrence of the
      herniation (4.5% vs. 21.1%), and had worked less frequently in physically
      demanding jobs (6.7% vs. 22.8%). We concluded that when there is a relative
      indication for herniated nucleus pulposus surgery, it should be limited to
      patients aged below 40 years, with slight motor dysfunction, who work in
      physically undemanding jobs, so as to make a satisfactory long-term result more
      likely.

PMID- 10333153
TI  - Expanded polytetrafluoroethylene membrane for the prevention of peridural
      fibrosis after spinal surgery: an experimental study.
AB  - One of the most common complications of lumbar spine surgery is peridural
      fibrosis, a fibroblastic invasion of the nerve roots and the peridural sac
      exposed at operation. Peridural fibrosis may produce symptoms similar to those
      the patient experienced preoperatively and, if another spinal operation is
      necessary, may increase the risk of injury at reexposure. In a controlled study
      in dogs, we assessed the use of expanded polytetrafluoroethylene (ePTFE) as a
      barrier to postoperative invasion of fibrous tissue into the laminectomy defect.
      In 14 dogs, a two-level laminectomy was done, at L4-L5 and L6-L7. In 12 dogs, an
      ePTFE membrane was placed directly over the dorsal surface of the laminectomy
      defect at L4-L5 and within the defect (over the surface of the dura) at L6-L7. No
      material was implanted in two dogs (controls). Tissue for histologic studies was
      obtained from the controls and from ten dogs with the membrane 12 weeks
      postoperatively. Two dogs with the membrane underwent reoperation. The study
      found that there was no peridural fibrosis in seven of the ten specimens in which
      the ePTFE membrane had been placed directly on the dorsal surface of the
      laminectomy defect, some peridural fibrosis in all specimens in which the
      membrane had been placed within the defect, and extensive fibrosis in controls.
      The ePTFE membrane created an excellent plane of dissection for reoperation. No
      foreign-body reactions to the membrane or membrane-related infections occurred.
      We conclude that the ePTFE spinal membrane, when properly implanted, is an
      effective barrier to postsurgical fibrous invasion of the vertebral canal.
      Clinical studies of use of this material in spinal surgery are warranted.

PMID- 10333154
TI  - Expanded polytetrafluoroethylene membrane for the prevention of peridural
      fibrosis after spinal surgery: a clinical study.
AB  - Peridural fibrosis developing after laminectomy may cause pain that can
      necessitate reoperation. Many materials have been used as a barrier to invasion
      of fibrous tissue into the vertebral canal, but the ideal material has not been
      found. Various studies in animals have achieved favourable results with an
      expanded polytetrafluoroethylene (ePTFE) membrane. In a prospective, randomized
      study, we compared postoperative results in 33 patients who had an ePTFE membrane
      implanted to cover the defect caused by laminectomy during lumbar spine
      decompression with the results in 33 patients in whom no material was implanted.
      At operation, an ePTFE membrane was placed after the decompression procedure to
      cover the laminectomy defect completely. Systematic clinical and MRI follow-up
      evaluations of patients with and without the membrane were conducted 3, 6, 12,
      and 24 months postoperatively. The effect of ePTFE membrane implantation over
      laminectomy sites on postoperative peridural fibrosis, pain and neurological
      claudication was assessed. The ePTFE-membrane group had a significantly lower
      rate of epidural fibrosis on MRI (P<0.0001) and of clinical manifestations of
      radiculalgia (P = 0.002) compared with the no-material group. Epidural fibrosis
      that occurred in the ePTFE group was generally less extensive than that in the no
      material group. There was no significant difference in the rate of postoperative
      claudication in the two groups. Significantly more seromas occurred in the ePTFE
      group (P = 0.0002). There were no infections or other complications in either
      group. The results showed that placement of an ePTFE spinal membrane over the
      laminectomy defect produced by lumbar spine surgery provided a physical barrier
      to invasion of fibrous tissue into the vertebral canal, and patients with the
      membrane had less postoperative radicular pain.

PMID- 10333155
TI  - MR imaging for early complications of transpedicular screw fixation.
AB  - This series comprises ten patients treated with transpedicular screw fixation,
      who suffered early postoperative problems such as radicular pain or motor
      weakness. Besides plain radiographs, all patients were also evaluated with MR
      imaging. Three patients were reoperated for either repositioning or removal of
      the screws. MR images, especially T1-weighted ones, were very helpful for
      visualizing the problem and verifying the positions of the screws. In cases of
      wide areas of signal void around the screws, the neighboring axial MR images at
      either side, which have fewer artifacts, gave more information about the screws
      and the vertebrae.

PMID- 10333156
TI  - Unusual presentation of spinal cord compression related to misplaced pedicle
      screws in thoracic scoliosis.
AB  - Utilization of thoracic pedicle screws is controversial, especially in the
      treatment of scoliosis. We present a case of a 15-year-old girl seen 6 months
      after her initial surgery for scoliosis done elsewhere. She complained of
      persistent epigastric pain, tremor of the right foot at rest, and abnormal
      feelings in her legs. Clinical examination revealed mild weakness in the right
      lower extremity, a loss of thermoalgic discrimination, and a forward imbalance. A
      CT scan revealed at T8 and T10 that the right pedicle screws were misplaced by 4
      mm in the spinal canal. At the time of the revision surgery the somatosensory
      evoked potentials (SSEP) returned to normal after screw removal. The clinical
      symptoms resolved 1 month after the revision. The authors conclude that after
      pedicle instrumentation at the thoracic level a spinal cord compression should be
      looked for in case of subtle neurologic findings such as persistent abdominal
      pain, mild lower extremity weakness, tremor at rest, thermoalgic discrimination
      loss, or unexplained imbalance.

PMID- 10333157
TI  - Pathologic odontoid fracture and benign fibrous histiocytoma of bone.
AB  - We present the case of a 44-year-old female patient, who sustained an odontoid
      fracture after a minor trauma (uncomplicated fall). The radiologic evaluation
      revealed a skeletal tumor of the second cervical vertebra together with a
      fracture line at the base of the odontoid process of the axis. The patient
      underwent surgery, the tumor was resected and the odontoid was stabilised using
      an autologous cortico-cancellous bone graft and a halo fixator. Histologic
      examination revealed benign fibrous histiocytoma, which is reported to be a very
      rare skeletal tumor.

PMID- 10333158
TI  - Frequency change detection in human auditory cortex.
AB  - We offer a model of how human cortex detects changes in the auditory environment.
      Auditory change detection has recently been the object of intense investigation
      via the mismatch negativity (MMN). MMN is a preattentive response to sudden
      changes in stimulation, measured noninvasively in the electroencephalogram (EEG)
      and the magnetoencephalogram (MEG). It is elicited in the oddball paradigm, where
      infrequent deviant tones intersperse a series of repetitive standard tones.
      However, little apart from the participation of tonotopically organized auditory
      cortex is known about the neural mechanisms underlying change detection and the
      MMN. In the present study, we investigate how poststimulus inhibition might
      account for MMN and compare the effects of adaptation with those of lateral
      inhibition in a model describing tonotopically organized cortex. To test the
      predictions of our model, we performed MEG and EEG measurements on human subjects
      and used both small- (<1/3 octave) and large- (>5 octaves) frequency differences
      between the standard and deviant tones. The experimental results bear out the
      prediction that MMN is due to both adaptation and lateral inhibition. Finally, we
      suggest that MMN might serve as a probe of what stimulus features are mapped by
      human auditory cortex.

PMID- 10333159
TI  - A connectionist model of left-right sound discrimination by the Mauthner system.
AB  - Artificial neural networks were used to explore the auditory function of the
      Mauthner system, the brainstem circuit in teleost fishes that initiates fast
      start escape responses. The artificial neural networks were trained with
      backpropagation to assign connectivity and receptive fields in an architecture
      consistent with the known anatomy of the Mauthner system. Our first goal was to
      develop neurally specific hypotheses for how the Mauthner system discriminates
      right from left in the onset of a sound. Our model was consistent with the phase
      model for directional hearing underwater, the prevalent theory for sound source
      localization by fishes. Our second goal was to demonstrate how the neural
      mechanisms that permit sound localization according to the phase model can
      coexist with the mechanisms that permit the Mauthner system to discriminate
      between stimuli based on amplitude. Our results indicate possible computational
      roles for elements of the Mauthner system, which has provided us a theoretical
      context within which to consider past and future experiments on the cellular
      physiology. Thus, these findings demonstrate the potential significance of this
      approach in generating experimentally testable hypotheses for small systems of
      identified cells.

PMID- 10333160
TI  - An improved parameter estimation method for Hodgkin-Huxley models.
AB  - We consider whole-cell voltage-clamp data of isolated currents characterized by
      the Hodgkin-Huxley paradigm. We examine the errors associated with the typical
      parameter estimation method for these data and show them to be unsatisfactorally
      large especially if the time constants of activation and inactivation are not
      sufficiently separated. The size of these errors is due to the fact that the
      steady-state and kinetic properties of the current are estimated disjointly. We
      present an improved parameter estimation method that utilizes all of the
      information in the voltage-clamp conductance data to estimate steady-state and
      kinetic properties simultaneously and illustrate its success compared to the
      standard method using simulated data and data from P. interruptus shal channels
      expressed in oocytes.

PMID- 10333162
TI  - Possible use of amantadine in depression.
AB  - Amantadine, originally used in the treatment and prophylaxis of influenza
      infection, has also proved beneficial in drug-induced Parkinsonism, Parkinson's
      disease, traumatic head injury, dementia, multiple sclerosis and cocaine
      withdrawal. Amantadine appears to act through several pharmacological mechanisms,
      none of which has been identified as the one chief mode of action. It is a
      dopaminergic, noradrenergic and serotonergic substance, blocks monoaminoxidase A
      and NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels.
      However, it is still uncertain which of these actions are relevant in therapeutic
      doses. One new aspect is the antiviral effect of amantadine on Borna disease
      virus, which it is suspected may possibly play a role in affective disorders. All
      of these actions could constitute an antidepressant property, and it is suggested
      that amantadine might work as an antidepressant not through one, but through
      several mechanisms thought to be related to antidepressant activity. Effects of
      amantadine on symptoms of affective disorders have been demonstrated in several
      trials administering it for varying purposes. Additionally, animal studies as
      well as clinical trials in humans have hinted at an antidepressant activity of
      amantadine. We present here an overview of the current data. However, only a
      limited body of evidence is available, and further studies are needed to
      investigate the efficacy of amantadine as well as its modes of action in
      depression.

PMID- 10333161
TI  - Electrical interactions via the extracellular potential near cell bodies.
AB  - Ephaptic interactions between a neuron and axons or dendrites passing by its cell
      body can be, in principle, more significant than ephaptic interactions among
      axons in a fiber tract. Extracellular action potentials outside axons are small
      in amplitude and spatially spread out, while they are larger in amplitude and
      much more spatially confined near cell bodies. We estimated the extracellular
      potentials associated with an action potential in a cortical pyramidal cell using
      standard one-dimensional cable theory and volume conductor theory. Their spatial
      and temporal pattern reveal much about the location and timing of currents in the
      cell, especially in combination with a known morphology, and simple experiments
      could resolve questions about spike initiation. From the extracellular potential
      we compute the ephaptically induced polarization in a nearby passive cable. The
      magnitude of this induced voltage can be several mV, does not spread
      electrotonically, and depends only weakly on the passive properties of the cable.
      We discuss their possible functional relevance.

PMID- 10333163
TI  - Fluoxetine versus moclobemide: cross-comparison between the time courses of
      improvement.
AB  - Competitive statistical methods were used in a meta-analysis of the data of 440
      fluoxetine-treated and 437 moclobemide-treated patients in order to address the
      issue of the timing of recovery from depression, and to elucidate potential
      differences in the onset of action between the two different classes of
      antidepressants. In spite of large biochemical and pharmacological differences,
      fluoxetine and moclobemide turned out to be virtually identical with regard to
      the overall efficacy, proportions and time characteristics of premature
      withdrawal, and most notably, the time course of recovery. The onset of
      improvement occurred in the majority of cases within the first two weeks of
      treatment and was highly predictive for the outcome after six weeks. The analyses
      yielded no indication of a delayed onset of action of antidepressants. Given the
      apparent nonspecificity of antidepressants, together with their relatively modest
      response rates, future research will need consider whether mechanisms different
      from those related to the monoaminergic systems may be involved in the
      pathogenesis of depression.

PMID- 10333164
TI  - Undesirable blood pressure changes under naturalistic treatment with moclobemide,
      a reversible MAO-A inhibitor--results of the drug utilization observation
      studies.
AB  - Blood pressure decrease, associated with postural hypotension, as well as
      spontaneous hypertension are considered to be typical side-effects of
      conventional, irreversible and nonselective MAO (A+B) inhibitors. The new
      generation of reversible MAO-A inhibitors is, however, expected to have
      negligible cardiovascular effects and low propensity to induce either blood
      pressure increases or decreases. But, the true incidence of such changes is
      largely unknown since observation studies, specifically assessing the frequency
      of blood pressure changes, in unselected population of patients treated in the
      practice, are lacking.

PMID- 10333165
TI  - Efficacy and safety of the sigma receptor ligand EMD 57445 (panamesine) in
      patients with schizophrenia: an open clinical trial.
AB  - EMD 57455 (panamesine) is a new sigma receptor ligand alleged to have
      antipsychotic effects. Animal studies have demonstrated that EMD 57445 has a
      functional antidopaminergic activity without extrapyramidal side effects and a c
      fos expression pattern similar to that obtained with atypical neuroleptics.
      Therefore, the substance might be of interest for the treatment of schizophrenia.
      The present article describes the results of an exploratory open clinical trial
      that was aimed at determining the appropriate dose range for clinical efficacy
      and safety of EMD 57455 in patients with an acute episode of schizophrenia. In a
      treatment period of 4 weeks, 12 patients received EMD 57445 up to 60 mg/day for 4
      weeks. Seven patients completed the study: four were classified as responders (as
      defined by at least a 50% decrease in the BPRS total score), two improved
      slightly and one patient remained unimproved. The intent-to-treat analysis showed
      significant improvement in the psychometric variables assessed by the Brief
      Psychiatric Rating Scale, Clinical Global Impression and Positive and Negative
      Symptoms Scale. Major side effects were extrapyramidal symptoms in two patients
      and restlessness in one patient. With respect to efficacy and safety, our data
      agree with a previous study, except that in our study EMD 57455 was not totally
      free of extrapyramidal side effects.

PMID- 10333166
TI  - Diurnal variability of orofacial dyskinetic movements.
AB  - OBJECTIVE: Instrumental methods to measure tardive dyskinesia (TD) have been
      introduced in the last few years to try to eliminate the differences in inter
      rater reliability. After eliminating variations attributed to the use of
      different raters, it is clear that TD frequently shows fluctuations in severity
      contributing to a low test-retest reliability. In the present study the diurnal
      variability of dyskinetic movements was explored by a computerized technique
      using digital imaging processing to measure orofacial movements. METHOD: Ten
      patients with persistent tardive dyskinesia were assessed three times a day once
      a week for four consecutive weeks. RESULTS: Four patients had significant diurnal
      variations in the severity of dyskinetic movements and six did not have
      significant variations. The period of time between waking and the assessment, the
      severity of dyskinetic movements, and smoking were significantly different
      between these two groups. CONCLUSION: Diurnal variations, particularly in
      relation to sleeping and smoking patterns, may need to be taken into account
      during longitudinal studies of tardive dyskinesia.

PMID- 10333167
TI  - Coadministration of clozapine and fluvoxamine in psychotic patients--clinical
      experience.
AB  - Fluvoxamine (FLUVOX) is an inhibitor of the cytochrome P450 isoenzyme 1 A2 and
      thereby inhibits clozapine (CLOZ) metabolism. We performed an open clinical study
      to gather experience in necessary dosages, plasma levels, side effects and
      clinical efficiency of the coadministration of the two drugs. Eighteen psychotic
      patients were studied. 50 mg FLUVOX were given throughout the study period, while
      the CLOZ dosage was increased individually (week 5: 96.9+/-37.2 mg). After 5
      weeks the plasma concentrations were as follows: CLOZ 252+/-174 ng/ml, N
      desmethylclozapine (DM-CLOZ) 143+/-74 ng/ml and clozapine N-oxide (CLOZ N-OX)
      30+/-14 ng/ml. There were no differences in side effects, especially sedation,
      after 5 weeks compared to the pretreatment condition. Moreover, we found a
      significant improvement in measures of cognitive speed which might be regarded as
      a measure of vigilance. The BPRS scores dropped continuously until week 5
      (pretreatment: 53.3+/-13.4; week 5: 33.2+/-12.9) and 5 patients were considered
      treatment responders (BPRS reduction > 50%). Ten patients continued the
      combination treatment after the study period and 9 of these patients were in
      clinical remission when discharged. Given strict therapeutic drug monitoring,
      coadministration of FLUVOX and CLOZ seems to be a safe and efficient treatment
      strategy with a low occurrence of the side effects associated with CLOZ
      treatment. This might be due to additive effects of the two drugs and/or
      metabolic interaction.

PMID- 10333168
TI  - Asymptomatic pancreatitis associated with clozapine.
AB  - Besides the well-known adverse effects of clozapine, such as granulocytopenia,
      tiredness and hypersalivation, acute pancreatitis is known to be a very rare
      complication of the drug. In the literature a total of five case reports have
      been published so far. We report a case of asymptomatic pancreatitis subsequent
      to clozapine treatment at therapeutic doses in a 38-year-old male patient with
      chronic paranoid-hallucinatory schizophrenia. The patient was rehospitalized
      after an acute exacerbation of the psychosis subsequent to an attempt to change
      medication on an outpatient basis. Treatment with clozapine was initiated again.
      During phases of progressively increasing the clozapine dose, serum levels of
      amylase and lipase were increased; after maintaining daily doses of clozapine of
      300 mg and/or 600 mg the pancreatic enzymes normalized quickly within a few days.
      The patient did not report any pancreas-related complaints, nor did specific
      diagnostic studies produce any indicative result, only a minor thickening of the
      head and body of the pancreas in the ultrasound. It is assumed that the
      phenomenon of subclinical, asymptomatic pancreatitis during increasing dosage of
      clozapine occurs more often than previously supposed. The monitoring of serum
      amylase levels during slow increase in clozapine is recommended; if leukocytosis
      or eosinophilia is present, the possibility of even a subclinical and
      asymptomatic pancreatitis should be considered.

PMID- 10333169
TI  - Perphenazine-induced hiccups.
AB  - Hiccup is a spasmodic, involuntary contraction of the inspiratory muscles,
      associated with delayed and abrupt glottic closure causing a peculiar sound
      (Launois et al., 1993). A number of medical conditions are known to cause
      persistent and intractable hiccups. Among the drugs reported to induce hiccups,
      Thompson et al. stated that corticosteroids and benzodiazepines are the drug
      classes most frequently associated with the development of hiccups (Thompson and
      Landry, 1997). Antidopaminergic agents such as chlorpromazine and haloperidol are
      the preferred drugs used for the treatment of chronic hiccups (Launois et al.,
      1993). We report a case of severe hiccups occurring in association with the
      administration of perphenazine, which is a dopamine antagonist. To the best of
      our knowledge, this is the first report of hiccups occurring as a side effect of
      antidopaminergic drugs.

PMID- 10333171
TI  - Analysis of the dynamics of rhizomucor miehei lipase at different temperatures.
AB  - The dynamics of Rhizomucor miehei lipase has been studied by molecular dynamics
      simulations at temperatures ranging from 200-500K. Simulations carried out in
      periodic boundary conditions and using explicit water molecules were performed
      for 400 ps at each temperature. Our results indicate that conformational changes
      and internal motions in the protein are significantly influenced by the
      temperature increase. With increasing temperature, the number of internal
      hydrogen bonds decreases, while surface accessibility, radius of gyration and the
      number of residues in random coil conformation increase. In the temperature range
      studied, the motions can be described in a low dimensional subspace, whose
      dimensionality decreases with increasing temperature. Approximately 80% of the
      total motion is described by the first (i) 80 eigenvectors at T=200K, (ii) 30
      eigenvectors at T=300K and (iii) 10 eigenvectors at T=400K. At high temperature,
      the alpha-helix covering the active site in the native Rhizomucor miehei lipase,
      the helix at which end the active site is located, and in particular, the loop
      (Gly35-Lys50) show extensive flexibility.

PMID- 10333170
TI  - Intermolecular contacts between the lambda-Cro repressor and the operator DNA
      characterized by nuclear magnetic resonance spectroscopy.
AB  - The specific interaction between lambda phage Cro repressor and the DNA fragment
      bearing the consensus sequence of operators has been studied using nuclear
      magnetic resonance (NMR). Using both 15N- and 13C/15N- labeled lambda-Cro in
      complex with unlabeled DNA, chemical shift assignments of the lambda-Cro-DNA
      complex were obtained using heteronuclear NMR experiments. Inter-molecular
      contacts between the protein and DNA were identified using heteronuclear filtered
      NOESY experiments. The inter-molecular contacts were supplemented with intra
      protein and intra-DNA NOE constraints to dock lambda-Cro to the bent B-form DNA
      using restrained molecular dynamics. The structure of one of the subunits of
      lambda-Cro in the complex is essentially the same as that of the unbound form. In
      the complex, inter-molecular NOEs were observed between the "helix-turn-helix"
      region comprising the alpha2 and alpha3 helices of the lambda-Cro protein and the
      major groove of the DNA. The methyl group of Thr17 forms a hydrophobic contact
      with the methyl group of the thymine at base pair 1 in the DNA, and Val25 and
      Ala29 make hydrophobic contacts with the methyl group of the thymine at base pair
      5. The presence and the absence of these contacts can explain the difference in
      the affinity of lambda-Cro to several variants of the operator sequence.

PMID- 10333172
TI  - QM/MM study of the active site of free papain and of the NMA-papain complex.
AB  - Hybrid quantum mechanical/molecular mechanical (QM/MM) calculations using
      restricted and unrestricted Hartree-Fock and B3LYP ab initio (QM) and Amber force
      field (MM), respectively, have been applied to study the catalytic site of papain
      in both free and substrate bonded forms. Ab initio geometry optimizations have
      been performed for the active site of papain and the N-methyl-acetamide (NMA)
      papain complex within the molecular mechanical treatment of the protein
      environment. A covalent tetrahedral intermediate structure could be obtained only
      when the amide N atom of the substrate molecule was protonated through a proton
      transfer from the His-159 in the catalytic site. Our results support the previous
      assumption that a proton transfer from His-159 to the amide N atom of the
      substrate occurs prior to or concerted with the nucleophilic attack of the Cys-25
      sulfur atom to the carbonyl group of the substrate. The electron correlation
      effect will reduce the proton transfer barrier. Therefore, this proton transfer
      can be easily observed in the B3LYP/6-31G* calculations. The HF/6-31G* method
      overestimates the reaction barrier against this proton transfer. The sulfur atom
      of Cys-25 and the imidazole ring of His-159 are found to be coplanar in the free
      form of the enzyme. However, the rotation of the imidazole ring of His-159 was
      observed during the formation of the tetrahedral intermediate. Without the papain
      environment, the coplanar thiolate-imidazolium ion pair RS-...ImH+ is much less
      stable than the neutral form of RSH....Im. Within the protein environment,
      however, the thiolate-imidazolium ion pair becomes more stable than its neutral
      form by 4.1 and 0.4 kcal/mol in HF/6-31G* and B3LYP/6-31G* calculations,
      respectively. The barrier of proton transfer from S-H group of Cys-25 to the
      imidazole ring of His-159 was reduced from 22.0 kcal/mol to 15.2 kcal/mol by the
      protein environment in HF/6-31G* calculations. This barrier is found to be much
      smaller (2.5 kcal/mol) in B3LYP/6-31G* calculations.

PMID- 10333173
TI  - Folding of alpha(r)beta and epsilonbeta reverse turns; a nanosecond molecular
      dynamics simulation of the hexapeptide MSALNT and the octapeptide NMSALNTL in
      water.
AB  - Folding of the hexapeptide MSALNT and the octapeptide NMSALNTL were investigated
      using 2.8 ns molecular dynamics (MD) simulations in aqueous solution. In the
      simulation, the central sequence SALN of the hexapeptide folded rapidly within
      200 ps into an alpha(r)beta turn conformation (type VIII conformation) and
      remained in this conformation for the rest of the trajectory. The sequence SALN
      of the octapeptide needed 2 ns to fold via epsilonbeta conformations into a
      similar conformation. The results join the sequences into a growing group of
      sequences which have a tendency to form secondary structures and thereby to
      direct protein folding. The structures of the reverse turn conformations were in
      accordance with the experimental results (Hakalehto et al., Eur J. Biochem. 250,
      19-29 (1997)). The main driving force of folding seems to be the hydrophobic
      interaction between the side chains of Ala and Leu at the i+1 and i+2 positions
      of the beta-turn.

PMID- 10333174
TI  - Assessment of the bioactive conformation of the farnesyltransferase protein
      binding recognition motif by computational methods.
AB  - Ras farnesyltransferase catalyzes the carboxyl-terminal farnesylation of Ras as
      well as other proteins involved in signal transduction processes. Previous
      studies demonstrated that its inhibition suppresses the activity of Ras
      transformed phenotypes in cultured cells, causing tumor regression in animal
      models. This observation led to the consideration of farnesyltransferase as a
      target for cancer therapy. In the present work we report the results of a
      computational study aimed at assessing the bioactive conformation of the peptide
      Cys-Val-Phe-Met, known to be the minimum peptide sequence that inhibits
      farnesyltransferase. For this purpose the conformational preferences of four
      analogs of the peptide were assessed by means of thorough searches of their
      respective conformational spaces, using a simulated annealing protocol as
      sampling technique. Specifically, two active analogs: Cys-Val-Tic-Met and Cys-Val
      psi(CH2NH)Tic-Met and two inactive analogs: Cys-Val-Tic-psi(CH2NH)Met and Cys-Val
      Aic-Met were selected for the present study. Low energy conformations of the four
      analogs were classified according to their structural motifs. The putative
      bioactive conformation of the minimum farnesyltransferase recognition motif was
      assessed by cross-comparison of the different classes of conformations obtained
      for the two active and the two inactive analogs. The putative bioactive
      conformation is characterized by two structural motifs: i) a C14 pseudo-ring
      stabilized by a hydrogen bond between the amino group of Cys1 and the carboxylate
      group of Met4 and a C11 pseudo-ring involving the residues Cys1 and Tic3. In
      addition, the thiol group of Cys1 side chain of the bioactive conformation points
      to the carboxylate moiety of Met4.

PMID- 10333175
TI  - On the structural stability of a small bioactive peptide of potential use in
      biotechnology.
AB  - A tridecapeptide with the sequence CCEICCNPACFGC has been synthesized to
      reproduce the active moiety of a heat stable enterotoxin from Vibrio cholerae.
      The proton NMR analysis indicates, for the active synthetic fragment, a rigid
      secondary structure stabilised by three disulfide bridges. Such a rigid peptide,
      suitably detoxified and activated, could be a good candidate to be used as a
      carrier for linear bioactive peptides or other functional groups.

PMID- 10333176
TI  - Structural studies by 1H NMR and molecular modeling of peptide substrates of
      thermolysin in relation with its proteasic activity in water and glycerol.
AB  - In an attempt to explain the relationship between conformations of peptide
      substrates of thermolysin in natural form and the experimental enzymatic
      cleavages, five peptides of various length were studied in two solvents H2O and
      glycerol, which may mimic the catalytic environmental conditions. As NMR failed
      to define sufficiently rough constraints to ensure a convergence of a refinement
      process for such short and flexible peptides, the conformational space was first
      searched using the MCMM method. The generated structures were then clustered in
      families using a 0.3A rmsd criterion and the derived structural characteristics
      were compared to the experimental NMR parameters. In a first approach, the NMR
      consistent conformations were compared with the structure of a thermolysin bound
      peptidic inhibitor ZG(P)LL to characterize the free-ligand predisposition to be
      cleaved. Further molecular dynamic calculations were performed at 300 K on the
      conformations corresponding to families in agreement with the ZG(P)LL structure
      in order to obtain information on their stability and on the trajectories of the
      torsion angles involved in the active site recognition. In conclusion, for four
      studied peptides, some conformations were found to be in agreement with 5 of the
      8 cleavages experimentally observed.

PMID- 10333177
TI  - NMR structures of a nonapeptide from DNA binding domain of human polymerase-alpha
      determined by iterative complete-relaxation-matrix approach.
AB  - Nuclear magnetic resonance structures of a nonapeptide, ERFKCPCPT, selected from
      the DNA binding domain of human polymerase-alpha, were determined by complete
      relaxation matrix analysis of transverse NOE data. The structures exhibit a type
      III turn with residues KCPC, and the remaining residues exhibit non-ordered
      structures. The turn was confirmed by alpha, N (i,i+3) connectivity, a low
      temperature coefficient of NH chemical shift (-3.1 x 10(-3)) of the fourth
      residue, 3J(NHalpha) coupling constants, and characteristic CD peaks at 228 and
      200 nm. Furthermore, phi and psi dihedral angles for the i + 1, and i + 2
      residues of the turn are found to be -80 and -41 and -60 and -40 degrees. The
      first proline residue is trans- while the second exists in both cis- and trans-
      configurations, with trans- being more than 80% populated. The trans
      configuration was established from C5alpha-P6alpha correlation and phi and psi
      angles of the proline. The five-membered proline ring is in DOWN puckered (C-beta
      exo/C-gamma-endo) conformation. The structure of the peptide reveals that the two
      cysteine thiols are approximately 5 A(o) apart and appropriately positioned to
      covalently bind cis-diamminedichloroplatinum(II), a widely used anti-cancer drug.

PMID- 10333178
TI  - Differences in conformational behavior of ATA and TAT sequences in single strand
      DNA trimer.
AB  - The conformational behavior of single strand (ss) TAT and ATA trimers of DNA have
      been studied by computational chemistry tools including CICADA software
      interfaced with AMBER molecular mechanics and dynamics. The Single-Coordinate
      Driving (SCD) method has been used in conjunction with molecular dynamics
      simulated annealing. It has been revealed that the conformational flexibility of
      each sequence differs substantially from the other one. Four common
      conformational families have been found for both trimers. These are: helical,
      reverse-stacked (base 3), half-stacked (base 3), reverse-stacked (base 1).
      However, the energies of conformers representing the families are different for
      both the studied systems. An additional conformational family, bulged, has been
      found for ss(ATA), while ss(TAT) has been found also in half-stacked (base 1)
      conformation. In general, ss(TAT) exhibits a higher number of low energy
      conformations while ss(ATA) shows one interesting low energy conformational
      interconversion between reverse-stacked (A3) family and half-stacked (A3) family.
      The high conformational variability of the trimers has been confirmed by
      flexibility analysis and by molecular dynamics simulations, which have also shown
      the conformational stability of single conformational families. It has been
      concluded that the methodology used is able to provide a very detailed picture of
      the conformational space of these molecules.

PMID- 10333179
TI  - Effect of in vivo histone hyperacetylation on the state of chromatin fibers.
AB  - We evaluated the contribution of in vivo histone acetylation to the folding of
      chromatin into its higher-order structures. We have compared high-order folding
      patterns of hyperacetylated vs. unmodified chromatin in living green monkey
      kidney cells (CV1 line) using intercalator chloroquine diphospate to induce
      alterations in the twist of internucleosomal linker DNA. We have shown that
      histone hyperacetylation induced by antibiotic Trichostatin A significantly
      alters intercalator-mediated chromatin folding pattern.

PMID- 10333181
TI  - Public health information via the World Wide Web.

PMID- 10333180
TI  - A study of the hydration of deoxydinucleoside monophosphates containing thymine,
      uracil and its 5-halogen derivatives: Monte Carlo simulation.
AB  - An extensive Monte Carlo simulation of hydration of various conformations of the
      dinucleoside monophosphates (DNP), containing thymine, uracil and its 5-halogen
      derivatives has been performed. An anti-anti conformation is the most
      energetically stable one for each of the DNPs. In the majority of cases the
      energy preference is determined by water-water interaction. For other dimers
      conformational energy is the most important factor, or both the factors are of
      nearly equal importance. The introduction of the methyl group into the 5-position
      of uracil ring most noticeably influences the conformational energy and leads to
      the decrease of its stabilizing contribution to the total interaction energy. The
      introduction of halogen atoms increases the relative content of anti-syn and syn
      anti conformations of DNPs as compared to the parent ones due to the formation of
      an energetically more favorable water structure around these conformations. A
      correlation is observed between the Monte Carlo results for the halogenated DNPs
      and their experimental photoproduct distribution. The data obtained demonstrates
      a sequence dependence in the photochemistry of the halogenated dinucleoside
      monophosphates.

PMID- 10333182
TI  - What is low vision? A re-evaluation of definitions.
AB  - PURPOSE: To re-evaluate definitions of low vision, visual impairment, and
      disability. METHODS: We review current definitions of legal blindness and low
      vision and how these definitions are variably based on disability or impairment.
      We argue for a definite distinction being made between criteria for visual
      impairment and visual disability, low vision being defined as the presence of a
      visual impairment that results in a disability. Visual impairment is defined
      according to population norms and a statistical cut-off is used. Visual
      disability is defined by consideration of the level of visual measures which
      result in measurable or reportable disability. We consider the evidence that
      contrast sensitivity should be a criterion for visual disability in addition to
      visual acuity and visual field. CONCLUSIONS: According to the current
      information, we define visual impairment as best monocular or binocular visual
      acuity <(worse than) 6/7.5, total horizontal visual field <146 degrees (Goldmann
      III-4e) or <109 degrees (III-3e), and contrast sensitivity <1.5 (PelliRobson); we
      define visual disability as best monocular or binocular visual acuity <6/12 or
      contrast sensitivity <1.05.

PMID- 10333183
TI  - Development and sensitivity to visual impairment of the Low Vision Functional
      Status Evaluation (LVFSE).
AB  - BACKGROUND: Functional limitation because of visual impairment is one of the most
      important measures of low vision rehabilitation outcome because it represents the
      true impact of visual impairment upon the daily lives of individuals. The Low
      Vision Functional Status Evaluation (LVFSE) was designed to evaluate functional
      limitation because of visual impairment using both observed and self-reported
      performance on daily activities. METHODS: Performance on 27 daily activities was
      evaluated for 155 visually impaired subjects. Subjects also provided ratings of
      task difficulty. RESULTS: Correlations between observed performance and visual
      acuity, contrast sensitivity, and visual field loss severity were moderate, r = 
      0.60 to r = 0.34. Correlations between self-reported task performance difficulty
      and measures of visual clinical state were weaker, r = -0.44 to r = 0.21.
      CONCLUSIONS: The LVFSE shows promise as a sensitive measure of low vision-related
      functional status but more work is needed to refine the measure.

PMID- 10333184
TI  - Prospective comparison of convergence insufficiency and normal binocular children
      on CIRS symptom surveys. Convergence Insufficiency and Reading Study (CIRS)
      group.
AB  - PURPOSE: To test the validity-related evidence of a child and a parent symptom
      survey developed by the Convergence Insufficiency and Reading Study (CIRS) group.
      METHODS: A case comparison method was used to measure differences in symptoms
      between 14 school-aged children (ages 8 to 13 years) with Convergence
      Insufficiency (CI) and 14 children with normal binocular vision (NBV). RESULTS: A
      pooled t-test indicated that CI children and their parents scored higher than the
      NBV children and their parents on the child's survey (p<0.001) and parent's
      survey (p<0.001), respectively. CI children also scored significantly higher
      (p<0.03) on the Conners' Rating Scale for Parents. CONCLUSIONS: The results
      suggest that the CIRS symptom survey is a valid instrument for differentiating CI
      children from those with normal binocular vision. Additionally, children in this
      age group were able to respond to a broad range of symptom questions associated
      with CI.

PMID- 10333185
TI  - Relationship between anisometropia, amblyopia, and binocularity.
AB  - PURPOSE: To determine if higher degrees of anisometropia cause deeper amblyopia
      and poorer binocularity than lower degrees of anisometropia in children and
      adults. METHODS: The clinical records for 60 patients with untreated
      anisometropic amblyopia without strabismus, ranging in age from 3 to 39 years,
      were reviewed. The refractive error, the initial best corrected visual acuities
      in the amblyopic and nonamblyopic eyes, and the level of binocularity were
      recorded from each chart. The degree of anisometropia was determined by: (1)
      calculating the difference between spherical equivalents for each eye; (2)
      calculating the difference in the vertical meridians for each eye; (3)
      calculating the difference in the horizontal meridians for each eye; and (4)
      calculating the root mean square difference which also takes into account
      differences in astigmatic axis. The depth of amblyopia was determined by
      converting the visual acuity score to its logarithmic value, logarithm of the
      minimum angle of resolution (logMAR), and calculating the difference between the
      amblyopic and nonamblyopic eye. The level of binocularity was determined from
      stereopsis testing. RESULTS: For all patients, there was a significant
      relationship between the four measures of anisometropia, the depth of amblyopia,
      and the level of binocularity (median correlations 0.61 and 0.61, respectively).
      For the myopes (N = 10), there was no significant relationship between the 4
      measures of anisometropia, the depth of amblyopia, and the level of binocularity
      (median correlations 0.34 and 0.61, respectively). For the hyperopes (N = 50),
      the relationship was significant for all 4 measures of anisometropia (median
      correlations 0.72 and 0.62, respectively). CONCLUSION: As the degree of
      anisometropia increases, the depth of amblyopia becomes greater and the level of
      binocularity becomes poorer, at least for hyperopic patients.

PMID- 10333186
TI  - Does rate of stimulus presentation affect measured visual field extent in infants
      and toddlers?
AB  - PURPOSE: To evaluate the effect of stimulus presentation rate on the measurement
      of visual field extent in infants and toddlers. METHODS: Visual field extent was
      measured for 300 children (N = 60 at 3.5, 7, 11, 17, and 30 months) and 24 adults
      using hybrid static-kinetic perimetry. Flickering light-emitting diode (LED)
      stimuli were illuminated sequentially, peripherally to centrally at 10.2 degrees
      intervals, along 4 diagonal meridia at 2 stimulus presentation rates: 2
      s/stimulus (equivalent to 5 degrees/s) and 3 s/stimulus (equivalent to 3
      degrees/s). Rate of presentation was a between-subjects variable. RESULTS: No
      effect of stimulus presentation rate was found for adults. The faster rate of
      stimulus presentation yielded smaller measured visual field extent for children
      between the ages of 7 and 30 months. The apparent difference seen with 3.5-month
      olds did not reach significance. CONCLUSIONS: Faster rates of stimulus
      presentation may result in underestimation of visual field extent in children
      between the ages of 7 and 30 months.

PMID- 10333187
TI  - Size constancy and angular size matching in size perception of near objects.
AB  - Accurate judgment of the relative sizes of near objects at various distances is
      important for a variety of occupational visual tasks. This study involved
      matching the apparent size of each of a series of standard targets, placed at
      distances between 0.2 and 3 m and all subtending 2 degrees at the eye, with a
      comparison target of similar geometry, but at a fixed distance of 2 m. Natural
      binocular viewing of the targets demanded exercise of accommodation and
      convergence in an environment rich in cues to target size and distance. As the
      available cues were reduced, judgements of the lateral dimensions of the targets
      were found to change gradually from those predominantly based on size constancy
      to those mainly based on angular size matching. These results are qualitatively
      very similar to those observed in past studies with more distant objects and
      emphasize the need to maintain adequate cues if linear size is to be judged
      accurately.

PMID- 10333188
TI  - Short-term repeatability of hand-held keratometry measurements.
AB  - PURPOSE: The Collaborative Longitudinal Evaluation of Ethnicity and Refractive
      Error (CLEERE) Study is a multi-center, observational investigation of ocular
      component and refractive error development in schoolchildren. Anterior corneal
      curvature is one of several ocular components which influence refractive status
      of the eye, and the CLEERE Study uses the Alcon Auto-Keratometer to measure
      corneal curvature. This report assesses the repeatability of this hand-held
      instrument. Previous studies have demonstrated the validity of the Alcon Auto
      Keratometer; however, none have assessed its repeatability. METHODS: Sixty
      children were recruited from clinics affiliated with the Southern California
      College of Optometry and the University of Houston College of Optometry. Two sets
      of five hand-held keratometry measurements were obtained on the right eye of each
      child by one investigator at each site using the Alcon Auto-Keratometer. The two
      sets of measurements were performed at least 10 minutes apart. RESULTS: The mean
      differences between the two occasions were not significantly different from zero
      for either the flat or steep corneal curvature measurements regardless of the
      number of readings taken. The largest improvement in repeatability, primarily for
      the steep meridian, occurred when the first two readings were averaged. The
      addition of readings 3, 4, and 5 to the average did not substantially improve
      repeatability for either meridian. The 95% limits of agreement between the
      average of two readings on two occasions for the flat and steep meridians were +/
      0.28 and +/-0.39 D, respectively. The 95% limits of agreement after two readings
      were +/-0.28, +/-0.20, and +/-0.24 D for the M, J0, and J45 vectors,
      respectively. CONCLUSION: The Alcon hand-held keratometer provides a repeatable
      measure of corneal curvature as demonstrated by short-term repeat agreement
      within +/-0.50 D. This level of repeatability can be achieved only by manually
      averaging two consecutive measurements.

PMID- 10333189
TI  - A method to analyze cylinder axis error.

PMID- 10333190
TI  - Guidelines for the management of dyspepsia.
AB  - Dyspepsia is a common problem necessitating strategies for investigation and
      management because of the scarcity of available resources for investigation, i.e.
      endoscopy, and the need to focus on those at risk of serious disease. It is
      agreed that those in the older age group, with the presence of alarm symptoms or
      non-steroidal anti-inflammatory drug use require prompt endoscopy, but there
      remains a significant proportion of patients in whom the underlying diagnosis is
      unclear, presenting a management problem. Unfortunately, no universally
      applicable approach to investigation and management is available. Each major
      community needs to modify its guidelines for the management of dyspepsia based
      upon such factors as the local incidence of organic disease, prevalence of
      Helicobacter pylori infection and lifestyle. Endoscopy off acid suppressive
      therapy remains the only way of making a certain diagnosis. A diagnosis of
      gastrooesophageal reflux disease can now be made confidently by endoscopy, with
      selective use of 24 h pH study of the lower oesophagus. The same cannot be said
      for other groups with dyspepsia where symptoms alone are a poor guide to
      diagnosis. Evidence is beginning to emerge, however, that further stratification
      of dyspeptics on the basis of symptoms and other risk factors, e.g. H. pylori
      status, may help in management. In addition, there is a clinical need for
      accurate, inexpensive tests of foregut motility. Integrating clinical data with
      specific investigation in dyspepsia is required in order for the practising
      clinician to better define the dyspeptic so that patients can be managed
      effectively and simply.

PMID- 10333191
TI  - Postgastrectomy pancreatic malabsorption: is there a case for intervention?
AB  - More patients are surviving surgery for gastric carcinoma than ever before. The
      possible causes of malabsorption following total gastrectomy are multifactorial,
      and pancreatic insufficiency has been proposed as one mechanism. Other
      contributing factors include loss of gastric reservoir, rapid small bowel
      transit, small bowel bacterial overgrowth and the type of operation performed.
      Although pancreatic exocrine insufficiency has been demonstrated after
      gastrectomy, the key question remains whether pancreatic enzyme supplements offer
      any substantial clinical benefit to the patient. The evidence to date does not
      support the routine use of pancreatic enzyme supplementation after gastrectomy.

PMID- 10333192
TI  - Decision-making in dyspepsia: controversies in primary and secondary care.

PMID- 10333193
TI  - The effect of pancreatic enzyme supplementation in patients with steatorrhoea
      after total gastrectomy.
AB  - OBJECTIVE: To assess the influence of pancreatic enzyme supplementation on
      symptoms, energy intake, bowel habits, and fat malassimilation in patients after
      total gastrectomy. DESIGN: A prospective, double-blind, randomized, parallel,
      placebo-controlled, multi-centre trial. SETTING: Institutionalized patients in
      three gastroenterological rehabilitation clinics. PARTICIPANTS: 52
      institutionalized patients with a faecal fat output > or = 14 g/day, operated on
      for malignant gastric disease a median of 198 days (interquartile range (IQR) 47
      608) previously, and free from recurrence and/or metastasis. INTERVENTIONS: Nine
      sachets of pancreatic enzymes per day (each containing lipase 36,000, amylase
      27,000, protease 2400 FIP (Federation International Pharmaceutique)) or identical
      looking placebo were given for 14 days. MAIN OUTCOME MEASURES: Abdominal
      symptoms, energy intake, bowel habits and fat malassimilation. RESULTS: After
      treatment, patients on enzyme therapy felt better overall (P = 0.006), but no
      improvement of a specific symptom could be identified. During the intervention,
      the median kilojoule intake per kilogram body weight was 9% higher in the placebo
      group (170.8 (IQR 146.9-202.6)) than in the enzyme-treated group (157.0 (IQR
      134.8-170.4)) (P = 0.03). Enzyme treatment did not result in a significant
      difference between the placebo and the enzyme-treated group regarding bowel
      habits or fat malassimilation. CONCLUSIONS: The effect of high-dose pancreatic
      enzymes supplementation on symptoms and steatorrhoea after total gastrectomy is
      marginal and does not justify its routine use.

PMID- 10333194
TI  - Prevalence of Helicobacter pylori infection in medical professionals in Spain.
AB  - OBJECTIVE: The epidemiology of Helicobacter pylori infection is still under
      investigation, and the exact source of infection and its mode of transmission are
      still unknown. The purpose of this prospective study was to determine whether
      medical professionals in Spain, especially gastroenterologists and
      gastrointestinal endoscopists, have a higher prevalence of H. pylori infection.
      METHODS: Two hundred and twenty four medical professionals attending the annual
      gastroenterology meeting in Spain (176 men, 48 women; mean age, 41.8 +/- 11.4
      years; range, 25-73 years) and a control group of 189 persons of similar age were
      investigated for the prevalence of H. pylori infection by using the 13C-urea
      breath test. All medical professionals completed a questionnaire regarding
      medical specialty and regular performing of gastrointestinal endoscopy
      procedures. RESULTS: The overall prevalence of H. pylori infection in total
      medical professionals was 52.7%, compared with 51.9% in the control group (P >
      0.05). When specialty was considered, the prevalence of H. pylori infection among
      gastroenterologists was 53.3%, also not significantly higher than 50.0% among non
      gastroenterologists (P > 0.05). There were no statistical differences of H.
      pylori prevalence among endoscopists and non-endoscopists. CONCLUSIONS: Medical
      practice and, more specifically, gastroenterology and the regular performance of
      gastrointestinal endoscopy pose no additional risk for H. pylori infection in
      Spain.

PMID- 10333195
TI  - Intragastric balloons in adolescents with morbid obesity.
AB  - OBJECTIVES: Morbid obesity inducing medical pathologies such as hypertension,
      hypercholesterolaemia or orthopaedic abnormalities is an increasing problem in
      adolescents. Intragastric balloons have been used, with a varying degree of
      success, in adults. METHODS: An intragastric silicone balloon was filled with 500
      700 ml physiological serum in five adolescents (11-17 years old) with a morbid
      obesity (body mass index percentage (BMI %, calculated as a percentage of normal
      BMI for patient's sex and age, range 148-293%), and was left in place for six
      months. RESULTS: The balloons were well tolerated. A transient beneficial effect
      was noted, with a non-significant trend in decrease of the BMI % after 3 months
      (P = 0.07). However, 3 months later (6 months after the insertion), the BMI % in
      all five adolescents was significantly higher than before insertion of the
      balloon (P < 0.05). CONCLUSION: We observed a failure to lose weight with the
      help of an intragastric balloon in five selected adolescents. Since the
      beneficial effect of intragastric balloons in the five adolescents studied was
      only temporary, these balloons seem not to be indicated in adolescents with
      morbid obesity.

PMID- 10333196
TI  - Three-day antibiotic therapy with azithromycin and tinidazole plus lansoprazole
      or pantoprazole to cure Helicobacter pylori infection: a pilot study.
AB  - OBJECTIVE: The aim of the present study was to investigate and compare the
      effects of two proton-pump inhibitors, lansoprazole (Limpidex 30 mg, Sigmatau) vs
      pantoprazole (Peptazol 40 mg, Boehringer Mannheim), included in a three-day
      antibiotic therapy regimen with azithromycin (Zitromax 500 mg, Pfizer) and
      tinidazole (Fasigin 500 mg, Pfizer). DESIGN: Seventy consecutive, H. pylori
      positive patients were randomly pre-treated with lansoprazole 30 mg o.d. (once
      daily) or pantoprazole 40 mg o.d. for two days, and subsequently respectively
      assigned to one of the two following treatment regimens, given for only three
      days: regimen A (LAT) comprising lansoprazole 30 mg o.d. plus azithromycin 500 mg
      o.d. and tinidazole 500 mg b.i.d. (bis in die), or regimen B (PAT) comprising
      pantoprazole 40 mg o.d. plus azithromycin 500 mg o.d. and tinidazole 500 mg
      b.i.d. H. pylori status was evaluated by means of histology and rapid urease test
      at entry, and by 13C-urea breath test alone 8 weeks after treatment. MAIN OUTCOME
      MEASURES: Sixty-nine of the enrolled patients completed the study: 34 in the LAT
      group and 35 in the PAT group. One patient in the LAT group was lost to follow
      up. In the LAT group, after the end of treatment, 28/34 patients were H. pylori
      negative (per protocol: 82%; intention-to-treat: 80%). In the PAT group, after
      treatment, 29/35 patients were H. pylori-negative (per protocol and intention-to
      treat: 83%). Mild or slight side-effects occurred in only one patient in the LAT
      group and in one in the PAT group. CONCLUSIONS: From this study there is no
      evidence that either of the two proton-pump inhibitors used is preferable in a
      three-day antibiotic regimen with azithromycin and tinidazole. The excellent side
      effect and tolerability profiles, associated with acceptable eradication rates,
      make the two treatment regimens we tested particularly useful when patient
      compliance is difficult to achieve.

PMID- 10333197
TI  - Detection of Helicobacter pylori cagA gene by polymerase chain reaction in faecal
      samples.
AB  - OBJECTIVE: The polymerase chain reaction (PCR) has been extensively and
      successfully used to detect Helicobacter pylori in gastric juice and gastric
      biopsies. In contrast, the results obtained using faeces as biological samples
      for PCR are rather conflicting. This may be due to the presence of faecal
      inhibitory compounds (polysaccharides) which can inhibit the amplification
      reaction. The aim of this study was to characterize the H. pylori genotype in
      faecal samples by using specific primers for the cagA gene. To overcome the
      problem of contamination by polysaccharides, we used a filter-based extraction
      technique already applied in a previous study. METHODS: Antral and body biopsies
      were obtained from 30 symptomatic patients undergoing upper endoscopy. PCR was
      used to detect the presence of H. pylori organisms in faecal samples by using
      primers selected for the urease gene A. In addition, H. pylori organisms were
      characterized both in faecal samples and paraffin-embedded biopsies by PCR with
      specific primers for the cagA gene. RESULTS: All patients showed a positive CLO
      test (rapid urease test) and evidence of H. pylori by Warthin-Starry stain. PCR
      detected the urease A gene in the faecal samples of all patients. The cagA gene
      was detected in the faecal and biopsy samples of 18 subjects (60%). Duodenal
      ulcer and/or antral erosions were observed in 15 of the 18 cagA-positive patients
      (83.3%) and in five of the 12 cagA-negative patients (41.7%). Endoscopic features
      of normal mucosa or gastritis were observed in three cagA-positive patients
      (16.7%) and in seven cagA-negative patients (56.3%). cagA-positive status was
      found to be significantly related to the endoscopic features of duodenal
      ulceration and/or antral erosions. CONCLUSIONS: Our findings prove that faeces
      are suitable samples for the detection of cagA status. Moreover, they confirm the
      existence of a significant relationship between cagA-positive status and duodenal
      ulcer and/or antral erosions.

PMID- 10333198
TI  - Adrenergic modulation of small bowel haemodynamics in interdigestive motility
      state of man.
AB  - OBJECTIVE: We previously reported a new application of semi-invasive laser
      Doppler flowmetry (LDF) to record small intestinal haemodynamics in man under
      basal motor conditions, i.e. during phase I of the migrating motor complex (MMC).
      In the present study, we evaluated the complete MMC cycle and its haemodynamics
      in humans; specifically, adrenergic influence on blood flow in all three MMC
      phases was studied. DESIGN: Twenty-one fasting healthy male volunteers (21-44
      years) were studied during two complete MMC cycles: the first as control period,
      the second as experimental period with different adrenergic drugs or saline.
      METHODS: Recording of LDF of intestinal blood flow was performed by attaching two
      single-fibre microprobes to a small intestinal manometry tube, which
      simultaneously monitored luminal pressure changes. RESULTS: Clonidine and
      oxymetazoline, two alpha2-adrenoceptor agonists, significantly decreased blood
      flow during all phases of the MMC cycle. In contrast, the non-selective beta
      adrenoceptor agonist isoprenaline induced phase II-like activity with a
      significant increase in blood flow. Propranolol, a beta-adrenoceptor antagonist,
      did not alter motility but decreased blood flow throughout the MMC cycle.
      CONCLUSIONS: Both alpha- and beta-adrenergic mechanisms modifying small bowel
      haemodynamics are in operation throughout phases I, II and III of MMC. Our
      findings support the use of the semi-invasive LDF technique to measure drug
      induced haemodynamic changes in the fasting gut.

PMID- 10333199
TI  - Mucosal cytokine expression, cellular markers and adhesion molecules in
      inflammatory bowel disease.
AB  - OBJECTIVE: To relate proinflammatory cytokines to leukocyte surface markers and
      adhesion molecules in the same paraffin-embedded biopsy specimen in inflammatory
      bowel disease (IBD) of varying activity. METHODS: Biopsies of seven cases of
      Crohn's disease, seven patients with ulcerative colitis, one case of intestinal
      infection and six control subjects were studied. We performed in situ
      hybridization on sections of tissue using probes specific to interleukin-1beta
      (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF alpha).
      Leucocyte markers and adhesion molecules were investigated in subsequent slides
      of selected specimens by immunohistochemistry. RESULTS: Cytokine mRNA was found
      in large numbers of cells throughout the inflamed intestine but also in some
      macroscopically unaffected tissue specimens. Transcripts were predominantly
      located within the lamina propria where immunohistochemistry of parallel sections
      revealed numerous macrophages and the presence of endothelial adhesion molecules.
      The expression of the different cytokines was closely related to each other and
      to histological but not to macroscopic (endoscopic) activity. CONCLUSIONS: The
      synthesis of IL-1beta IL-6 and TNF alpha mRNA is coordinately regulated. Cytokine
      production is located mostly in the lamina propria at sites that are rich in
      macrophages and show abundant staining of vascular adhesion molecules. This
      cascade of immune events is related to inflammatory cell infiltration in both
      Crohn's disease and ulcerative colitis.

PMID- 10333200
TI  - Low-dose budesonide treatment for prevention of postoperative recurrence of
      Crohn's disease: a multicentre randomized placebo-controlled trial. German
      Budesonide Study Group.
AB  - OBJECTIVE: Endoscopic recurrence of Crohn's disease frequently occurs within
      weeks after 'curative' operation. Treatment with 3 x 1 mg oral pH-modified
      release budesonide was tried to prevent postoperative recurrence. DESIGN: A
      multicentre randomized double-blind placebo-controlled trial of 1 year duration
      was performed. SETTING: Departments of surgery, endoscopy and pathology of three
      university hospitals participated in the trial. PATIENTS: Patients with Crohn's
      disease who underwent ileal and/or colonic resection and whose anastomosis was
      accessible to colonoscopy were admitted to the study. Of the 88 randomized
      patients, 83 patients were included in the efficacy analysis (budesonide n = 43,
      placebo n = 40). Treatment was started within 2 weeks after surgery.
      INTERVENTIONS: Colonoscopy was performed 3 and 12 months postoperatively. The
      anastomosis and the adjacent bowel were evaluated by endoscopy and histology. For
      follow-up of the clinical course of the disease the Crohn's disease activity
      index (CDAI) was used. MAIN OUTCOME MEASURES: The primary outcome variable was
      recurrence of Crohn's disease based on endoscopic findings. Secondary efficacy
      variables were histology scores, CDAI, time-to-failure and global judgement of
      well-being of the patient. RESULTS: The recurrence rate after 1 year (endoscopic
      and/or clinical) was 57% (20/35) in the budesonide group and 70% (19/27) in the
      placebo group (n.s.). Mean time-to-failure was 196 days under budesonide and 154
      days under placebo (n.s.). Median CDAI (relapse 19% vs. 28%) and global patients'
      judgement at the end of treatment (bad 5% vs. 15%) was slightly in favour of
      budesonide. One patient in each group discontinued the trial because of adverse
      events. Potentially steroid-related side effects were reported more frequently in
      the placebo than in the budesonide group (32% vs. 17%) (n.s.). SUMMARY AND
      CONCLUSION: Although the effect of budesonide was altogether positive in almost
      all variables studied in this trial (e.g. endoscopic and histopathological score,
      time-to-failure, CDAI, patients' global judgement and rate of side effects), this
      increase in efficacy was small and the power for detecting differences versus
      placebo was too low to be statistically significant. According to these results,
      low-dose oral budesonide cannot be recommended to be used for the prevention of
      postoperative relapse in Crohn's disease.

PMID- 10333201
TI  - Prevalence and clinical importance of hypertransaminasaemia in coeliac disease.
AB  - OBJECTIVE: To assess the prevalence and potential pathogenetic factors of
      hypertransaminasaemia in patients with coeliac disease prior to initiation of a
      gluten-free diet (GFD) and to assess the course of transaminases on a GFD.
      PATIENTS: A retrospective study was made of 178 patients with coeliac disease
      (130 women, 48 men; median age 36 years; range 17-84 years) at the
      gastroenterological department of a university hospital. METHODS: Aspartate
      aminotransferase (AST) and alanine aminotransferase (ALT) were measured prior to
      initiation of a GFD and at 3, 6 and 12 months of GFD. Intestinal permeability, a
      test for functional integrity of the small bowel, was investigated before
      starting a GFD in 116 patients by an oral test using lactulose and mannitol.
      RESULTS: In 72 patients (40.4%) AST and/or ALT were increased prior to initiation
      of a GFD. Within 1 year on a GFD ALT and AST normalized except in eight cases
      (4.6%). The intestinal permeability index (% lactulose/% mannitol in 5 h urine)
      was higher in patients with elevated (median 0.34; range 0.03-1.43) than in
      patients with normal transaminases (0.11; 0.02-1.28) (P < 0.0001) and correlated
      with AST (tau = 0.34; P < 0.0001) and ALT (tau = 0.32; P < 0.0001). In five cases
      with hypertransaminasaemia a liver biopsy was performed prior to initiation of a
      GFD. Two patients had mild to moderate hepatitis with septal fibrosis. The other
      three had minimal lymphocytic infiltrates of the portal tracts. Inflammatory
      alterations of the bile ducts were not found. CONCLUSION: Hypertransaminasaemia
      before GFD is frequent in coeliac patients, correlates with intestinal
      permeability and normalizes on a GFD in most patients. In cases of persistently
      elevated liver function tests of unknown origin underlying coeliac disease should
      be considered.

PMID- 10333202
TI  - Referral for anorectal function evaluation: therapeutic implications and
      reassurance.
AB  - AIM: To determine the impact of anorectal function evaluation (AFE) on patients
      and referring specialists. PATIENTS AND METHODS: In one year, 135 patients were
      referred for AFE, which consisted of proctoscopy, anal manometry, rectal
      compliance, anal sensitivity measurement and anal endosonography. Questionnaires
      were sent to the patients and referring specialists. RESULTS: In 70% of the 135
      patients there was total agreement about the referring and final diagnosis. The
      response rate of the patients was 78% (n = 100) and that of the specialists was
      91% (n = 117). The experience with regard to pain and embarrassment during AFE
      was good. Of the women, 13% preferred a female investigator. Fifty-nine patients
      answered that they had received one or more treatments after referral: surgery (n
      = 32), medication (n = 16), diet (n = 5), physiotherapy (n = 1) or a combination
      of the above (n = 5). Of the 41 patients who did not receive another treatment,
      29 were reassured and 12 did not experience any benefit from the visit, thus
      bringing the total benefit of the referral to 88%. The anorectal complaints
      before AFE and at follow-up improved significantly in the treated group (P <
      0.0001). The advice given was followed by the referring specialist in 98 cases
      (84%). The quality of the advice given was considered good in 98 (84%). The
      opportunity of referral for AFE was considered useful in 108 cases (93%). In 71
      patients, information from both the specialist and the patient was obtained.
      Three patients had therapies that were not advised and 19 patients did not follow
      the advice (mainly dietary). In the 135 patients, AFE changed the management in
      34 patients (25%). In the other 101 patients, endosonography was of value in
      determining the size of sphincter defects or the fistula tracks. CONCLUSION: AFE
      was well tolerated and changed the management in 25% of patients. Additional
      advice and reassurance were given in many patients; only 12% of patients claimed
      to have no benefit from the referral. Anal endosonography seems the most valuable
      test.

PMID- 10333203
TI  - The spectrum of ischaemic colitis.
AB  - OBJECTIVE: Ischaemic colitis is generally considered a disease of the elderly
      with considerable cardiovascular morbidity. We aimed to determine the effect of
      age, co-morbidity and clinical presentation on type, severity and anatomy of
      involvement of ischaemic colitis. Thrombophilic tendencies have been poorly
      studied and coagulation status was performed in available patients. DESIGN:
      Retrospective case identification with prospective follow-up. SETTING: University
      teaching hospital. PARTICIPANTS: Twenty-four patients (16 female, mean age 64
      years) with ischaemic colitis. INTERVENTIONS: Blood analysis for clotting
      tendencies. MAIN OUTCOME MEASURES: Operation rates, death rates and frequency of
      clotting abnormalities. RESULTS: Five patients (21%) were below the age of 45,
      and seven of the 24 had died by the time of follow-up. Four had died of ischaemic
      colitis during the acute episode. The four patients that died of ischaemic
      colitis had a more extensive and more severe type of disease and presented with
      worse clinical features. The main predisposing factors were ischaemic heart
      disease in 12 (50%) and malignancy in five (21%). Six of the 24 cases (25%) had
      right-sided lesions and this conferred a good prognosis. Shock, peritonism,
      extensive disease and uncontrolled atrial fibrillation were all poor prognostic
      factors. Clotting factor abnormalities could be detected in three of nine
      patients despite a time lapse between assay and episode of ischaemic colitis.
      CONCLUSIONS: Ischaemic colitis appears to have two patterns of severity.
      Anatomical distribution is more variable than a developmental explanation of the
      vascular supply. Clotting abnormalities may be detected in a minority even on
      retrospective testing.

PMID- 10333204
TI  - Decrease in serum levels of vitamin A and zeaxanthin in patients with colorectal
      polyp.
AB  - OBJECTIVE: Several retrospective and prospective epidemiological investigations
      have demonstrated that a diet rich in carotenoids could prevent the development
      of pre-cancerous and neoplastic lesions of the digestive tract. The aim of this
      examination was to analyse the correlation between colorectal polyps with
      different histological classifications and serum carotenoid levels. DESIGN AND
      METHODS: A 10 ml blood sample was taken from all of the patients after the
      colonoscopic diagnosis. The serum levels of vitamin A, lutein, zeaxanthin, alpha-
      and beta-cryptoxanthin, alpha- and beta-carotene were measured in patients with
      adenomatous colorectal polyp (n = 59, 35 males, 24 females) by high-pressure
      liquid chromatography (HPLC) and compared with those in healthy subjects (n = 20,
      10 males, 10 females). The patients were separated into four groups depending on
      their histological findings. RESULTS: The serum levels of vitamin A and
      zeaxanthin were significantly lower in all patients with polyps (vitamin A: 0.913
      +/- 0.112 micromol/l, zeaxanthin: 0.071 +/- 0.012 micromol/l) than in the control
      healthy group (vitamin A: 2.036 +/- 0.354 micromol/l, zeaxanthin: 0.138 +/- 0.048
      micromol/l). The lowest levels were found in patients with focal adenocarcinoma
      in the polyp. There were no significant differences in the serum levels of other
      carotenoids. The serum levels of cholesterol, haemoglobin, total protein and
      albumin were normal in these patients. CONCLUSIONS: There are close and inverse
      correlations between the serum level of carotenoids and colorectal polyps with
      different histological grades. The low mean carotenoid levels in patients with
      adenocarcinoma in the polyp indicate that deficiency of carotenoids may be an
      important factor in the development of colorectal cancer.

PMID- 10333205
TI  - Effect of radiation therapy on the potential doubling time of tumours in
      colorectal cancers.
AB  - OBJECTIVE: The aim of the present study was to investigate the effects of
      standard fractionated radiation therapy on the kinetic parameters of colorectal
      adenocarcinomas. METHODS: The study of tumour kinetics involved in vivo injection
      of bromodeoxyuridine. Endoscopic biopsies were obtained from the tumour and
      analysed with flow cytometry. This procedure provides a rapid calculation of
      qualitative parameters such as ploidy and quantitative parameters such as the in
      vivo S-phase fraction labelling index which indicates the percentage of cells
      that have entered into the cycle, the duration of S-phase (Ts) and the potential
      tumour doubling time (Tpot). RESULTS: Thirty-eight colorectal carcinomas were
      studied without prior chemotherapy or radiation therapy (group 1) and ten rectal
      carcinomas were studied following radiation therapy (group 2). In diploid
      tumours, the labelling index was significantly lower in the post-radiotherapy
      group than in the pre-radiotherapy group (2.7 +/- 1.1% versus 6.4 +/- 4.2%,
      respectively; P= 0.01), and the Tpot was significantly longer after radiotherapy
      (group 2) (22.0 +/- 7.0 days versus 8.6 +/- 6.0 days, P = 0.002). Standard
      fractionated radiation therapy also appears to result in a longer Tpot in diploid
      adenocarcinomas of the colon and rectum. This effect was not observed in
      aneuploid tumours. CONCLUSIONS: The effectiveness of hyperfractionated schedules
      of radiation therapy for aneuploid rectal tumours with short Tpot warrants
      further investigation in a larger patient population.

PMID- 10333206
TI  - Supportive treatment, resection and transcatheter arterial chemoembolization in
      resectable hepatocellular carcinoma: an analysis of survival in 419 patients.
AB  - OBJECTIVE AND DESIGN: Both surgical resection and transcatheter arterial
      chemoembolization (TACE) are effective treatments for hepatocellular carcinoma
      (HCC). Few reports have compared the different treatment modalities for
      resectable HCC based on clinically matched groups. The aim of this study was to
      compare the survival rate after surgery, TACE or supportive treatment in
      resectable HCC patients, and also in elderly patients (> or = 70 y/o). METHODS:
      From 1984 to 1993, 419 consecutive patients with resectable HCC were included in
      this study. Of these, 311 (74%) underwent resection of tumours and 46 (11%)
      refused operation, opting instead for TACE. The remaining 62 (15%) who refused
      both methods of treatment were given supportive care. Univariate and multivariate
      analyses for prognostic factors and the 5-year survival rate among the groups
      were studied. RESULTS: Both surgical resection and TACE groups had a better 5
      year survival rate than the supportive treatment group (43% and 34% vs. 7%).
      There was no difference in survival between the surgery and TACE groups. However,
      the 5-year survival rate was 11% in TACE and 41% in the surgical group when the
      patients were > or = 70. In multivariate analysis, female sex (P = 0.0466),
      tumour size < or = 3 cm (P = 0.0001), alpha-fetoprotein (AFP) < 400 U/l (P =
      0.0036), single tumour (P = 0.0474), serum creatinine < or = 1.5 mg/dl (P =
      0.0006) and alkaline phosphatase (AP) < or = 100 U/l (P = 0.0007) are associated
      with good prognosis for resectable HCC. CONCLUSION: TACE is an alternative for
      resectable HCC. Tumour size, tumour number, AFP level, renal function, AP level
      and female sex are prognostic factors. In elderly people, TACE must be used
      prudently and has a worse prognosis.

PMID- 10333207
TI  - Non-invasive assessment of bone density in primary biliary cirrhosis.
AB  - BACKGROUND/AIMS: Low bone mass is an important complication of primary biliary
      cirrhosis (PBC), resulting in an increased risk of fractures and reduced
      mobility. In the present study, we sought to determine the frequency of low bone
      mass in PBC, and its relationship to disease severity and non-invasive markers of
      bone turnover. METHODS: In 36 women with PBC, bone mineral density of the lumbar
      spine and hip was assessed by dual emission X-ray absorptiometry. Serum and
      urinary markers of bone turnover were compared with those from age- and sex
      matched controls. RESULTS: Spinal osteopenia (T score, -1.5 to -2.5) was present
      in 15 of the 36 patients (42%), while six others (16%) had established
      osteoporosis (T < -2.5). Osteopenia of the femoral neck was found in 17 patients
      (47%), and osteoporosis in five (14%). The severity of liver disease, as
      determined by Mayo Clinic R score and histological stage, correlated negatively
      with both regional bone mineral density and total bone mineral content expressed
      as a ratio to lean body mass. There was a strong positive correlation between
      serum levels of the procollagen degradation peptides, PICP and PIIINP (r = 0.65,
      P < 0.001), and both peptides correlated significantly (P < 0.001) with
      histological stage and Mayo Clinic R score. Fasting urinary pyridinoline and
      deoxypyridinoline to creatinine ratios were also significantly raised.
      CONCLUSIONS: Low bone mass in PBC correlates positively with disease severity,
      and is associated with a net increase in bone resorption, as assessed by urinary
      collagen cross-link excretion. These markers of bone turnover may be of value in
      controlled clinical trials aimed at improving bone mass in PBC.

PMID- 10333208
TI  - Biliary pancreatic reflux-induced acute pancreatitis--myth or possibility?
AB  - OBJECTIVE: The mechanism whereby gallstone passage through the choledochoduodenal
      junction initiates acute pancreatitis is not known. We mimicked different
      patterns of stone impaction at the choledochoduodenal junction in a rabbit model
      and studied whether these result in biliary pancreatic reflux and the initiation
      of pancreatic inflammation. METHODS: In rabbits, catheters were introduced into
      the common bile duct (CBD) and the pancreatic duct. In five experiments,
      obstruction of these catheters at various time intervals mimicked different
      patterns of stone obstruction of both ducts prior to a stone impaction at the
      papilla of Vater: experiment I--no obstruction of the pancreatic duct and the
      CBD; experiment II--separate obstruction of the CBD and the pancreatic duct;
      experiment III--selective obstruction of the CBD; experiment IV--separate
      obstruction of the CBD and the pancreatic duct and subsequent decompression of
      the pancreatic duct; experiment V--obstruction pattern as in experiment IV
      associated with a bacterial infection of bile (10(8) E. coli/ml). Ductal
      pressures were recorded for 24 h. In order to study the effects of a subsequent
      impaction of the stone at the papilla of Vater, the catheters in the CBD and in
      the pancreatic duct were connected and mimicked a common channel behind a
      papillary stone. The flow direction of bile and pancreatic juice was directly
      observed. Pancreatic histology was analysed 24 h later. RESULTS: In experiments I
      III, neither biliary pancreatic reflux nor acute pancreatitis was observed. In
      experiments IV and V, obstruction of the CBD caused an increase in the biliary
      pressure to 17 +/- 3 cm H2O, whereas the pancreatic duct pressure dropped to
      subnormal levels following obstruction and selective decompression (2 +/- 0.5 cm
      H2O). After the creation of a 'common channel', biliary pancreatic reflux was
      observed for 118 +/- 21 min. Flow of sterile bile into the pancreas was not
      harmful to the gland. Infected biliary pancreatic reflux initiated acute
      pancreatitis. CONCLUSIONS: 1. Bile flow into the pancreas may occur. 2. Biliary
      pancreatic reflux may initiate acute pancreatitis. 3. Bile reflux-induced acute
      pancreatitis requires previous biliary hypertension, temporary pancreatic duct
      obstruction, and the bacterial infection of choledochal secretions.

PMID- 10333209
TI  - Elevated adenosine deaminase activity in patients with HIV and tuberculous
      peritonitis.
AB  - OBJECTIVE: To evaluate the diagnostic potential of the ADA(T), ADA isoenzymes
      (ADA1 and ADA2) and the interferon-gamma (IFN-gamma) test in HIV-seropositive
      patients with tuberculous peritonitis. METHODS: Ascitic ADA(T), ADA1, ADA2 and
      IFN-gamma were prospectively evaluated in HIV-seronegative patients with
      tuberculous peritonitis (n = 17), HIV-seropositive patients with tuberculous
      peritonitis (n = 6) and in patients with cirrhosis (n = 22) and malignancy (n =
      5). RESULTS: ADA(T) and ADA2 isoenzyme activities of HIV-seronegative (ADA(T) =
      109 U/l; ADA2 = 94 U/l) and HIV-seropositive (ADA(T) = 109.5 U/l; ADA2 = 95.5
      U/l) patients with tuberculous peritonitis, respectively, were significantly
      different (P < 0.001) from patients with cirrhosis (ADA(T) = 10.5 U/l; ADA2 = 8
      U/l) and malignancy (ADA(T) = 13 U/l; ADA2 = 11 U/l). There was no significant
      difference in ADA(T) and ADA2 activities between HIV-seropositive and
      seronegative patients with tuberculous peritonitis. There was no significant
      correlation between ADA, its isoenzymes and IFN-gamma. CONCLUSIONS: The diagnosis
      of tuberculous peritonitis can be made by a sensitive, relatively non-invasive
      procedure in both HIV-seronegative and seropositive patients with minimal risk to
      the patient and the investigator. The diagnostic value of ADA(T) is not enhanced
      by measuring ADA isoenzymes or IFN-gamma.

PMID- 10333210
TI  - Small mucosal carcinoma of the stomach with para-aortic lymph node metastasis: a
      case report and review of the literature.
AB  - A 38-year-old woman presented with a mucosal gastric carcinoma measuring 0.7 x
      0.5 cm and para-aortic lymph node metastasis. Radiographic and endoscopic studies
      showed a small depressed lesion on the anterior border of the gastric angle,
      which was classified as a type II c + III lesion. Histological examination of the
      biopsy specimen revealed a signet-ring cell carcinoma. Distal gastrectomy with
      wide lymph node excision was performed. Detailed study of the resected specimen
      revealed that the tumour was limited to the mucosa, but metastasized to both the
      perigastric and para-aortic lymph nodes. The patient received adjuvant
      immunochemotherapy postoperatively. However, multiple bone metastases developed
      at 3 years and she died 4 years after the operation.

PMID- 10333211
TI  - A case of intra-abdominal multiple lymphangiomas in an adult in whom the
      immunological evaluation supported the diagnosis.
AB  - A 60-year-old patient with intra-abdominal lymphangiomatosis is described. He
      presented with anaemia due to enteric haemorrhage, hypoproteinaemia with heavy
      hypogammaglobulinaemia and T-cell lymphopenia. Duodenal biopsy showed
      lymphangiectasia while a small bowel study revealed several filling defects in
      the terminal ileum. On exploratory laparotomy, numerous inoperable lymphangio
      haemangiomata were found, involving the small and large intestine, appendix,
      mesenterium, gallbladder and main biliary tract. The importance of T-cell
      lymphopenia and hypogammaglobulinaemia in the diagnosis of intra-abdominal
      lymphangiomatosis with lymphangiectasia is stressed.

PMID- 10333212
TI  - Hepatic sarcoidosis complicated by hepatocellular carcinoma.
AB  - A case of a 63-year-old man with a long-standing history of portal hypertension
      secondary to hepatic sarcoidosis who developed hepatocellular carcinoma is
      reported.

PMID- 10333213
TI  - Helicobacter pylori, pre-neoplastic changes, gastric cancer: a point of view.

PMID- 10333215
TI  - Wallace H. Clark, Jr., MD: a biography and annotated bibliography.

PMID- 10333217
TI  - Correlating architectural disorder and cytologic atypia in Clark (dysplastic)
      melanocytic nevi.
AB  - Histological architecture is very important in the pathological diagnosis of
      Clark (also known as atypical or dysplastic) melanocytic nevi. However, few
      studies have attempted to quantify architectural features or to correlate them
      directly with cytology. In 166 consecutive Clark nevi, the presence or absence of
      the following features in the intraepidermal or junctional component was
      recorded: (1) Architecture: circumscription, symmetry, cohesiveness of nests,
      suprabasal melanocytes, confluence, and single-cell proliferation; (2) Cytology
      of melanocytes: round/euchromatic nuclei, nuclear enlargement, cell enlargement,
      and prominent nucleoli. Each criterion was given a value of 0 or 1, and a
      summation score was obtained for both architecture and cytology in each case. The
      chi-square test was used to determine the significance of relationships among
      these parameters. The degrees of architectural disorder and of cytologic atypia
      were positively correlated (P = .026). Scores for both parameters were
      distributed over a wide range of values and were concentrated toward the low
      middle portion of the spectrum. Several particular architectural and cytologic
      variables showed significant interdependence. Clark nevi exhibit a broad spectrum
      of architectural disorder and cytologic atypia, which, according to our data,
      generally are closely related features. Because some cases displayed a relatively
      high score for one parameter but a low score for the other, quantification of
      both parameters permits a more complete histopathologic evaluation of these
      lesions and may provide additional information for their clinical management.

PMID- 10333218
TI  - Recognition and evaluation of cytological dysplasia in acquired melanocytic nevi.

PMID- 10333219
TI  - Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from
      melanoma, and prediction of outcome.
AB  - The biological nature of Spitz nevi/tumors and their diagnostic distinction from,
      or relationship to, melanoma remain unresolved issues. In this report, a series
      of 30 melanocytic lesions removed from 28 patients, including atypical Spitz
      nevi/tumors and metastasizing Spitzoid tumors/melanomas, were evaluated by a
      panel of dermatopathologists to evaluate interobserver diagnostic concordance and
      to assess the prognostic power of histological criteria. For inclusion in the
      study, each lesion had to display some criteria for the Spitz nevus, and in
      addition one of the following was required: (1) definitive clinical outcome such
      as metastasis or death of disease, or (2) long-term follow-up if the patient
      remained disease free. Each lesion was reviewed independently and blinded as to
      the clinical data by 10 pathologists, who categorized them as (1) typical Spitz
      nevus/tumor, (2) atypical Spitz nevus/tumor, (3) melanoma, (4) tumor with unknown
      biological potential, or (5) other melanocytic lesion. There was limited
      discussion of criteria before the review. Evaluation of 17 Spitzoid lesions
      yielded no clear consensus as to diagnosis; in only one case did six or more
      pathologists agree on a single category, regardless of clinical outcome. Notably,
      however, some lesions that proved fatal were categorized by most observers as
      either Spitz nevi or atypical Spitz tumors. Conversely, seven or more
      pathologists scored 13 lesions as melanoma. These results illustrate (1)
      substantial diagnostic difficulties posed by many Spitz tumors, especially those
      with atypical features, even among experts, and (2) the lack of objective
      criteria for their distinction from melanoma and for gauging their malignant
      potential. Nevertheless, our observations do suggest that a biological
      relationship exists between the Spitz nevus/tumor and melanoma.

PMID- 10333220
TI  - Dimensionalities: borderline and intermediate melanocytic neoplasia.
AB  - The concept of minimal deviation melanoma is presented in diagrammatic form. In
      this approach, the precursors of melanoma are presented as having two dimensions
      and melanomas as having three dimensions. In turn, the relativity between
      dimensionalities and recommendations for treatment (as indirect correlates of
      prognostications) provides guidelines for the structuring of two major boundaries
      along the axis of the diagram. Finally, the domains defined by the two boundaries
      include borderline lesions, intermediate lesions, and "real melanomas." The
      lesions in the borderline and intermediate categories qualify as melanocytic
      neoplasias of indeterminant malignant potential; in these two categories, the
      predictability of metastases hardly justifies the use of the designation,
      malignant melanoma.

PMID- 10333221
TI  - Dermal squamo-melanocytic tumor: a unique biphenotypic neoplasm of uncertain
      biological potential.
AB  - We report four cases of an unusual cutaneous squamo-melanocytic neoplasm with
      histological features of malignancy and uncertain biological potential. These
      tumors developed on the face of middle-aged and older adults. Clinically, a
      purple-black nodule ranged in size from 3 to 10 mm in maximum diameter. After
      complete excision, neither recurrence nor metastasis has been observed (mean
      follow-up time, 3.25 years). Histologically, a discrete dermal nodule surrounded
      by a fibroblastic stroma was composed of large islands of mitotically active
      atypical epithelioid cells. The nodule was not connected to the epidermis in
      three of four cases. Two types of cells were either diffusely admixed or
      clustered in small groups within the nodule. Small, atypical, epithelioid cells
      containing finely granular brown pigment, proven to be melanin, constituted the
      first cell type. The second type consisted of atypical squamoid cells, some with
      abundant pink cytoplasm, giving rise to squamous pearls. A lentigo maligna was
      present in one case. The remaining three cases had neither significant
      intraepidermal melanocytic nor keratinocytic atypia. Immunohistochemical studies
      indicated that the melanin-containing epithelioid cells expressed S-100 antigens,
      and the squamoid cells expressed cytokeratins. A small population of tumor cells
      did not label with either of the antibodies. These four tumors (along with a
      previously reported, apparently identical tumor arising in the setting of lentigo
      maligna) represent a unique biphasic dermal neoplasm with histological features
      of malignancy but, at this time, uncertain biological behavior. Although none
      have recurred or metastasized, the follow-up time is too short in our estimation
      to guarantee a benign course. These neoplasms are easily recognized by their
      characteristic features. Further follow-up evaluations should allow determination
      of their biologic potential.

PMID- 10333223
TI  - Lentigo maligna and malignant melanoma in situ, lentigo maligna type.
AB  - Some authors have considered lentigo maligna to be an atypical melanocytic
      proliferation, whereas others have considered it to be melanoma in situ. We
      reviewed 50 cases of lentigo maligna. We have identified two subsets of lesions.
      The first has atypical melanocytic hyperplasia, which we postulate to be
      correctly designated lentigo maligna. The second subset has the following
      features in addition to the melanocytic hyperplasia: individual and nests of
      cells at varying layers of the epidermis, confluence of the melanocytes replacing
      the basilar region, uniformity of the cytological atypia, and nesting of
      uniformly atypical melanocytes. These lesions we designate as malignant melanoma
      in situ, lentigo maligna type. We are proposing that the lesions that have been
      termed lentigo maligna represent a spectrum of atypia and that the application of
      some of the traditional features for the diagnosis melanoma may permit the
      segregation of more and less aggressive lesions.

PMID- 10333222
TI  - Squamous carcinoma in situ of the skin containing premelanosomes, with
      melanocytic colonization of the tumor.
AB  - Premelanosomes in nonmelanocytic epithelial neoplasms and "colonization" of
      nonmelanocytic tumors by melanocytes are two phenomena rarely documented in the
      literature. We report a squamous carcinoma-in-situ of skin displaying both
      phenomena. Light microscopy showed clusters of tumor cells in the epidermis, some
      of which contained melanin. Dendritic melanocytes were admixed with the tumor
      cells. No ulceration was present. Immunoperoxidase stains for keratin showed no
      staining of tumor cells. Some nondendritic cells stained for HMB-45, consistent
      with a melanocytic lesion. Electron microscopy showed two cell types, one with
      desmosomes, tonofilaments, and premelanosomes and a second dendritic type with
      only premelanosomes. Premelanosomes were also present free in the intercellular
      space. These findings suggest that premelanosomes may first be discharged by
      melanocytes into the intercellular space and are then phagocytosed by the
      neoplastic cells. Thus the presence of premelanosomes in a tumor cell is not
      pathognomonic for melanoma or other neural crest tumors.

PMID- 10333224
TI  - Desmoplastic malignant melanoma: diagnosis of early clinical lesions.
AB  - Desmoplastic malignant melanoma (DMM) is an uncommon but potentially devastating
      malignancy that can be cured with early recognition and surgery. DMM has clinical
      as well as histological features that may be subtle and overlooked, or
      misdiagnosed as other benign or malignant lesions that would require less
      aggressive therapy for cure. We have reviewed the preliminary clinical diagnoses
      and histological features of 18 cases of desmoplastic malignant melanoma, defined
      as either an inapparent lesion clinically, or a papule or small nodule less than
      0.7 cm, which proved histologically to be DMM. Nine of 18 cases (50%) were
      clinically pigmented. Histologically, early lesions were characterized by
      superficial tumor fascicles, and random diffuse hypercellularity in the upper
      dermis identified as elongated hyperchromatic pleomorphic spindle cells with
      stromal myxoid change. Neuroidal melanocytic structures, invasion of adventitial
      dermis, islands of inflammation, and epidermal lentiginous melanocytic
      hyperplasia were often present. The most reliable and characteristic features of
      an early lesion of DMM are aggregates of lymphocytes, tumor cell cytological
      atypia, stromal myxoid change, and poor circumscription of the dermal infiltrate.
      DMM is a disease best treated by complete excision at the time of initial
      surgery, but is also a lesion easily missed or misdiagnosed in the early stages.
      Features of early DMM are identified and illustrated to enable early diagnosis
      and cure of these lesions.

PMID- 10333225
TI  - Malignant melanoma with prominent pigment synthesis: "animal type" melanoma--a
      clinical and histological study of six cases with a consideration of other
      melanocytic neoplasms with prominent pigment synthesis.
AB  - Rare skin neoplasms in humans, comprising nodules of heavily melanized cells,
      mimic melanocytic neoplasms seen in horses and laboratory animals and thus are
      termed animal type melanomas. In part because of their rarity, behavior is
      unpredictable; many cases manifest a long indolent phase, and metastases are
      reportable. Over 6 years, the authors encountered nine skin and one lymph node
      biopsy specimens from six patients in whom light microscopy of formalin-fixed,
      paraffin-embedded tissue sections stained with hematoxylin and eosin showed
      melanocytic neoplasms with prominent pigment synthesis. Clinical follow-up was
      obtained by telephone contact with clinicians. There were three women, two men,
      and one boy, aged 9 to 85 years, whose lesions were described as blue-black
      nodules with irregular borders from 1.0 to 4.0 cm in size, located on the scalp,
      lower extremities, back, and sacrum. The dermatopathology comprised confluent
      dermal sheets of heavily melanized cells whose nuclei, where discernible, were
      large with irregularly thickened membranes, coarse chromatin, prominent, often
      spiculated nucleoli, and irregular parachromatinic clearing. Mitoses were
      infrequent. Four lesions had an epidermal component. One patient suffered
      metastases to regional lymph nodes, liver, and lungs with lethal effect, one
      experienced regional lymph node metastases but is still alive, one had local
      cutaneous metastases but was lost to follow-up, and one has a chest wall mass
      that has not yet been investigated. This rare dermal-based melanocytic neoplasm
      with prominent pigment synthesis, the animal type melanoma, has a biological
      behavior difficult to predict on morphological grounds. We advise complete
      excision with a 1.0- to 2.0-cm margin of normal skin and clinical investigation
      for regional or distant metastases.

PMID- 10333226
TI  - The morphological features of locally recurrent melanoma and cutaneous metastases
      of melanoma.
AB  - Local recurrence of melanoma at the primary excision site usually implies that
      the primary excision was incomplete or "inadequate" and that the recurrence was
      attributable to retained primary melanoma cells or occult melanoma metastases in
      the adjacent tissue. Pathologists frequently report these tumors in the scar as
      recurrent or residual melanoma, apparently without considering the possibility
      that they may be local metastases and manifestations of systemic disease. In this
      study of 72 cases, we have shown that the morphological features of locally
      recurrent melanoma, excluding persistent incompletely excised primary melanoma,
      and cutaneous metastases of melanoma were identical. Because the prevention of
      local recurrence is the main reason for wide excision of melanoma beyond complete
      excision of the primary tumor itself, it is essential that pathologists should
      classify these neoplasms precisely as either persistent incompletely excised
      primary melanoma or metastatic melanoma.

PMID- 10333227
TI  - Cytoplasmic accumulation of peanut agglutinin-binding glycoconjugates in the
      cells of primary melanoma correlates with clinical outcome.
AB  - In an experimental model, human melanoma cell lines enriched for cells that
      express the glycoconjugate B-D galactose N-acetyl-D-galactosamine, which reacts
      with the peanut agglutinin lectin (PNA), are associated with an increase in the
      frequency of metastases. We previously showed that this glycoconjugate is
      expressed on the cells of some primary melanomas in humans and that such cells
      are found selectively in melanomas with a high risk for developing metastases and
      causing death. Using fixed archival tissues from 99 primary melanomas and lectin
      histochemistry, we found 65 tumors that contained melanoma cells that were PNA
      positive. PNA-reactive cells were not identified in normal melanocytes or in the
      nevocytes of 24 nevi. PNA-reactive material accumulates adjacent to the nucleus
      in the area of the Golgi apparatus, initially as a tiny dot, but later in
      quantities sufficient to displace and indent the nucleus, producing a signet ring
      cell-like appearance. Tumor cells containing PNA-reactive material were
      associated with more evolved, deeper, and thicker tumors. Two melanomas up to
      Clark level II were PNA positive (20%), compared with 60% of level III, 76% of
      level IV, and 100% of level V. Five of 13 tumors less than 0.76 mm thick (39%)
      were positive, compared with 50% of tumors 0.76 to 1.49 mm thick, 64% of tumors
      1.5 to 2.99 mm thick, and 85% of tumors 3 mm thick or thicker. PNA-reactivity was
      negatively correlated with disease-free survival (PNA-negative, 49.2+/-23 months;
      PNA-positive grade 1, 41.6+/-26 months and PNA-positive grade 2, 24.4+/-23
      months), survival rate 5 years after initial treatment (PNA-negative, 84.8%; PNA
      positive grade 1, 63.8%; and PNA-positive grade 2, 31.3%) and disease-free
      survival at 5 years after initial treatment (PNA-negative, 69.7%; PNA-positive
      grade 1, 53.2%; and PNA-positive grade 2, 25%).

PMID- 10333228
TI  - Progression-related expression of beta3 integrin in melanomas and nevi.
AB  - The expression of the beta3 integrin subunit was investigated in 130 fixed,
      paraffin-embedded specimens of human melanomas and nevi using two different
      monoclonal antibodies. Expression was not observed in melanocytes and was absent
      or low in most nevi. In primary melanomas, expression was absent or low in the
      nontumorigenic radial growth phase, which includes the classes of in situ and
      microinvasive melanomas. In contrast, expression was high in the tumorigenic or
      vertical growth phase compartment of many primary melanomas and in most
      metastatic melanomas. Expression patterns were similar with the two antibodies,
      SSA6 and SAP, and was membrane-related as well as cytoplasmically expressed. In
      those nevi that reacted focally, the reactivity tended to occur in the dermal
      component of neurotized nevi, and in Spitz nevi, where the reactivity was
      stronger and more diffuse. A few dysplastic nevi showed focal reactivity of the
      junctional component. These results are consistent with tumor progression-related
      expression of the beta3 integrin, which is expressed in melanocytic tumors as the
      alphavbeta3 integrin, having affinity for matrix molecules, including vitronectin
      and fibronectin. In all melanomas, and in the subset of tumorigenic vertical
      growth phase melanomas, expression increased with thickness (P < .01). For this
      reason, and because ligation of this integrin has been shown in vitro to have
      several properties that may be related to the malignant phenotype, it is likely
      that expression of this marker may have prognostic value. However, because of its
      consistent and strong expression in Spitz nevi, the diagnostic utility of this
      marker will likely be limited.

PMID- 10333229
TI  - What students owe teachers.

PMID- 10333230
TI  - Kearns-Sayre syndrome with features of Pearson's marrow-pancreas syndrome and a
      novel 2905-base pair mitochondrial DNA deletion.
AB  - Kearns-Sayre syndrome (KSS) and Pearson's marrow-pancreas syndrome (PMPS) are
      rare disorders caused by the same molecular defect, one of several deletion
      mutations in mitochondrial DNA (mtDNA). KSS is an encephalomyopathy with
      ophthalmoplegia, retinal degeneration, ataxia, and endocrine abnormalities. PMPS
      is a disorder of childhood characterized by refractory anemia, vacuolization of
      bone marrow cells, and exocrine pancreas dysfunction. Children with PMPS that
      have a mild phenotype, or are supported through bone marrow failure, often
      develop the encephalomyopathic features of KSS. The subject of numerous reports
      in the neuromuscular, genetic, and pediatric literature in recent years, very few
      cases of either disorder have ever been studied at autopsy. We report the results
      of our studies of a patient with clinically documented KSS who presented with
      renal dysfunction and was found to have a novel mtDNA deletion and degenerative
      changes in the central nervous system, retina, skeletal muscle, and pancreas.

PMID- 10333231
TI  - Multiple lymphomatous polyposis of the gastrointestinal tract is a heterogenous
      group that includes mantle cell lymphoma and follicular lymphoma: analysis of
      somatic mutation of immunoglobulin heavy chain gene variable region.
AB  - Multiple lymphomatous polyposis (MLP) is characterized by multiple polyps
      involving long segments of the gastrointestinal (GI) tract. MLP is thought to
      represent mantle cell lymphoma (MCL) of the GI tract; however, some cases of
      follicular lymphoma (FL) of the GI tract are found with a multiple polypoid
      appearance. In the present study, to clarify the cellular origin of MLP, clonal
      immunoglobulin heavy chain (IgH) gene rearrangement of four cases with MLP was
      amplified by polymerase chain reaction (PCR) and analyzed for the presence of
      somatic mutation. The IgH variable (VH) region sequences of three cases (CD5+
      CD10- cyclin D1+) showed a little somatic mutation compared with the closest
      published germline. The other case (CD10+ CD5- cyclin D1-) was highly mutated and
      showed intraclonal heterogeneity (ongoing somatic hypermutation). These data
      indicate that three of the cases with MLP are derived from pregerminal center B
      cells (mantle zone B cells) and one case with MLP from germinal center B cells.
      Our study suggests that MLP is a heterogenous group that includes MCL and FL.

PMID- 10333232
TI  - HPV in situ hybridization with catalyzed signal amplification and polymerase
      chain reaction in establishing cerebellar metastasis of a cervical carcinoma.
AB  - We report an unusual case of cerebellar metastasis from a cervical adenosquamous
      carcinoma in which molecular techniques assisted in establishing the correct
      diagnosis. The patient was a 43-year-old woman with surgically unresectable
      cervical carcinoma diagnosed 2 years before presenting with neurological
      symptoms. A magnetic resonance imaging scan showed a large, enhancing cerebellar
      lesion with significant brain stem compression. The excised cerebellar tumor
      resembled a small cell carcinoma and was initially not thought to be a metastasis
      from the cervical adenosquamous carcinoma. In situ hybridization with catalyzed
      signal amplification and polymerase chain reactions with primers specific for
      human papilloma virus (HPV) types 16 and 18 were used to determine the
      relationship between the cervical and the cerebellar neoplasms. A positive signal
      was present in the nuclei of both neoplasms by in situ hybridization using
      HPV16/18 DNA probes. Polymerase chain reaction revealed the presence of HPV-18
      DNA sequences in the cervical and cerebellar neoplasms confirming that the
      cerebellar neoplasm was a metastasis from the cervical primary.

PMID- 10333233
TI  - Disseminated intravascular meconium in a newborn with meconium peritonitis.
AB  - A 3-day-old premature infant with meconium peritonitis, periventricular
      leukomalacia, and pulmonary hypertension died with respiratory insufficiency. An
      autopsy disclosed intravascular squamous cells in the lungs, brain, liver,
      pancreas, and kidneys. Numerous pulmonary capillaries and arterioles were
      occluded by squamous cells, accounting for pulmonary hypertension. Brain
      parenchyma surrounding occluded cerebral vessels showed infarct and gliosis. A
      mediastinal lymph node filled with squamous cells alluded to the mechanism by
      which these cells from the peritoneal cavity likely entered the bloodstream-
      namely, via diaphragmatic pores connecting with lymphatics. Thus, disseminated
      intravascular meconium rarely may complicate meconium peritonitis and have
      devastating consequences.

PMID- 10333234
TI  - Le lymphome imaginaire.

PMID- 10333235
TI  - High take-off of the coronary arteries: an ascending aortic origin!

PMID- 10333236
TI  - Is a mature teratoma a premalignant condition?

PMID- 10333237
TI  - Recombinant fusion protein and DNA vaccines against foot and mouth disease virus
      infection in guinea pig and swine.
AB  - In this study, we provide evidence that a recombinant fusion protein containing
      beta-galactosidase and a tandem repeat peptide of immunogenic dominant epitope of
      foot-and-mouth disease virus (FMDV) VP1 protein elicits high levels of
      neutralizing antibody and protects both guinea pigs and swine against infection.
      Vaccination with this fusion protein induced a FMDV-specific proliferative T-cell
      response and a neutralizing antibody response. The immunized guinea pigs and
      swine were protected against FMD type O virus infection. Two DNA plasmids
      expressing genes of foot-and-mouth disease were constructed. Both plasmids pBO1
      and pCO1 contain a signal sequence of the swine immunoglobulin G (IgG) gene and
      fusion protein gene of pXZ84. The signal sequence and fusion protein gene were
      under the control of a metallothionein promoter in the case of the pBO1 plasmid
      and under the control of a cytomegalovirus immediate early promoter in the case
      of pCO1 plasmid. When pBO1 and pCO1 were inoculated intramuscularly into guinea
      pigs, both plasmids elicited a neutralizing antibody response and spleen cell
      proliferation increased following stimulation with FMDV antigen, but animals were
      not protected from viral challenge.

PMID- 10333238
TI  - Antigen-specific in vitro activation of T-lymphocyte subsets of cattle immunized
      with a modified live bovine herpesvirus 1 vaccine.
AB  - Bovine peripheral blood mononuclear cells from cattle immunized with a modified
      live virus bovine herpesvirus 1 (BHV1) vaccine and from BHV1-negative cattle were
      incubated in vitro with inactivated BHV1 for 6 days. Activation of T-lymphocyte
      subsets was measured by two-color flow cytometric analysis of T-cell phenotype
      and surface expression of CD25, the alpha-subunit of the high-affinity
      interleukin-2 receptor. Vaccinated animals, but not unvaccinated animals, had
      CD3+, CD4+, and gamma-delta T cells that significantly (p < 0.05) increased
      expression of CD25 when incubated with BHV1. CD8+ T cells from vaccinated animals
      did not consistently increase CD25 expression when incubated with inactivated
      BHV1.

PMID- 10333239
TI  - Enhanced human immunodeficiency virus infection in macrophages by high-molecular
      weight dextran sulfate is associated with conformational changes of gp120 and
      expression of the CCR5 receptor.
AB  - High-molecular-weight dextran sulfate (HMDS) inhibits infection of CD4+
      lymphocytes by T-cell (T)-tropic human immunodeficiency virus (HIV) isolates, but
      augments replication of macrophage (M)-tropic isolates in primary human
      macrophages and phorbol myristate acetate (PMA)-differentiated THP-1 monocytic
      cells. To address the mechanism responsible for HMDS-mediated increases in HIV
      replication in macrophages, we analyzed the interaction between HMDS and
      functional domains of gp120 on the surface of PMA-differentiated THP-1 cells
      infected with M-tropic HIV isolates. Immunofluorescence staining of the infected
      cells revealed that HMDS inhibited the binding of monoclonal antibodies (mAbs)
      directed to the V3 and C4 domains of gp120, but augmented the binding of three
      neutralizing antibodies directed to the V2 region of gp120. The extent of HMDS
      mediated changes within the V2 loop of gp120 was associated with increased virus
      binding and replication in PMA-differentiated THP-1 cells and primary
      macrophages. The effect was dependent on expression of the CCR5 receptor and was
      inhibited by the beta-chemokine RANTES. Results of this study suggest that HMDS
      mediated increases in HIV infection in macrophages are associated with
      conformational changes within the V2 region of gp120 and enhanced interaction
      between gp120 and the CCR5 coreceptor on the target cell.

PMID- 10333240
TI  - Delayed administration of interleukin-12 is efficacious in promoting recovery
      from lethal viral encephalitis.
AB  - Vesicular stomatitis virus (VSV) applied intranasally to mice initially infects
      the olfactory receptor neurons, and then spreads quickly to the rest of the
      central nervous system (CNS). Previously, we have shown that the cytokine
      interleukin-12 (IL-12) has a significant survival and recovery promoting effect
      in mice infected with VSV when administered at the time of infection. The
      question of whether IL-12 is efficacious under the more clinically relevant
      condition of post-infection administration was explored. The data show that when
      IL-12 is administered post-infection, it is as effective as at the time of
      infection.

PMID- 10333241
TI  - A novel and effective intranasal immunization strategy for respiratory syncytial
      virus.
AB  - In designing subunit vaccination strategies for respiratory syncytial virus
      (RSV), immunization by mucosal routes may present a realistic alternative to
      parenteral administration for inducing protective immune responses. To this end,
      we have utilized the BALB/c mouse model and an adjuvant formulation containing
      caprylic/capric glycerides (CCG) and polyoxyethylene-20-sorbitan monolaurate
      (PS). The intranasal (i.n.) delivery of purified natural F protein (3 microg per
      vaccine) formulated with CCG-PS resulted in the generation of statistically
      heightened serum anti-F protein immunoglobulin G (IgG), IgG1, IgG2b, and IgA
      antibodies. In addition, the presence of locally produced anti-F protein IgA was
      demonstrated in both vaginal and nasal washes of vaccinated mice. That production
      of specific serum and mucosal immunoglobulins resulted in functional immune
      responses was shown in neutralizing antibody assays and protection of mouse lungs
      against subsequent live virus challenge. Consequently, we propose a novel vaccine
      formulation composed of purified natural RSV F protein in CCG-PS as a viable
      intranasal immunogen to stimulate anti-RSV immune responses in humans.

PMID- 10333242
TI  - Simian retrovirus receptor and neutralization mechanism by antibodies to the
      envelope glycoprotein.
AB  - Type D simian retroviruses (SRV) cause an acquired immunodeficiency syndrome
      (AIDS) in monkeys. Results of infection with SRV range from complete recovery
      with absence of viremia to a viremic state, which produces AIDS-like symptoms and
      culminates in death. These varied outcomes render the interaction of the host and
      SRV an attractive model for the study of immunosuppressive retrovirus resulting
      in different pathologic consequences. We describe here the isolation and
      determination of the molecular weight of the receptor for SRV. We demonstrate
      that a cell receptor with the same molecular weight is bound by the envelope
      protein of all five serotypes of SRV. We also show that the receptor recognizes a
      region containing amino acids 142-167 of the envelope protein of SRV serotype 1
      (SRV-1). In addition, we show that a different region of SRV serotype 2 (SRV-2)
      envelope protein containing amino acids 93-106, interacts with a cell receptor of
      identical molecular weight. Furthermore, polyclonal and monoclonal antibodies
      that are directed to envelope epitopes 142-167 of SRV-1 or to 93-106 of SRV-2,
      specifically neutralize only the respective viral serotype. Our results indicate
      that the neutralization of SRV infectivity by antibodies is achieved through
      blocking the interaction between the virus and its cell receptor.

PMID- 10333243
TI  - Epitope mapping of rat neutralizing monoclonal antibody against human
      immunodeficiency virus type-1 by a phage peptide library: comparison with ELISA
      using synthetic peptides.
AB  - We generated a rat monoclonal antibody (mAb W#10) with the ability to neutralize
      human immunodeficiency virus type 1IIIB (HIV-1IIIB) infection. The epitope
      recognized by mAb W#10 was defined as R-I-Q-R-G-P-G by enzyme-linked
      immunosorbent assay (ELISA) with the use of synthetic peptides. The filamentous
      phage clones displaying random 15-amino-acid peptides on the amino terminus of
      the pIII coat protein reacting with mAb W#10 were identified with affinity and
      immunological selection procedures. Thirteen out of 16 selected phage clones
      contained the G-X-G-R-X-F sequence in the coat protein region representing
      significant homology to a part of conserved G-P-G-R-A-F sequence in the V3 loop
      of various HIV-1 strains. In addition, the phage clones included the G-X-G
      sequence in the sequence detected by synthetic peptides as the recognition site.
      The selected phage clones were stained by mAb W#10 specifically and were able to
      compete with mAb binding to cells expressing viral antigens.

PMID- 10333244
TI  - Immunization of neonates with DNA encoding a bovine herpesvirus glycoprotein is
      effective in the presence of maternal antibodies.
AB  - Neonates generally display low immune responsiveness to conventional vaccines,
      which may be due to the immaturity of their immune system and interference by
      maternal antibodies. Because of the unique capacity of plasmid DNA for the
      production of low doses of antigen over extended periods of time, we used DNA
      immunization as an approach to induce immunity in neonates. Previously, we
      demonstrated that a plasmid encoding a truncated secreted version of bovine
      herpesvirus-1 gD (tgD) induces protective immunity in adult animals. For the
      present study, 3-day-old lambs were immunized intradermally with the tgD
      expressing plasmid. The lambs developed antibody as well as T-cell responses to
      the tgD glycoprotein, which clearly demonstrates the ability of the animals to
      respond to vaccination at this age. Furthermore, lambs born to tgD-hyperimmunized
      ewes, thus containing high levels of passively acquired serum antibodies,
      responded to the tgD DNA vaccine in a similar manner, which shows that the
      maternal antibodies did not inhibit the development of an immune response. These
      results indicate that DNA immunization might be a useful approach to vaccinate
      neonates that possess high levels of maternal antibodies.

PMID- 10333245
TI  - Characterization of neutralizing sites in the second variable and fourth variable
      region in gp125 and a conserved region in gp36 of human immunodeficiency virus
      type 2.
AB  - Several determinants of human immunodeficiency virus (HIV) have been suggested to
      harbor sites important for neutralization. The third variable region (V3) of the
      envelope glycoprotein (gp) is an important neutralizing determinant for both
      serotypes of HIV. The localization of additional neutralizing regions is an
      urgent task because the virus appears to mutate to phenotypes that escape
      neutralizing antibodies. Therefore, we have focused on the possibility of finding
      other immunodominant regions in the envelope glycoproteins of human
      immunodeficiency virus type 2 (HIV-2). By immunization of guinea pigs with
      peptides corresponding to different selected regions of gp125 and gp36, we have
      found three antigenic determinants located in the V2 and V4 regions of the
      envelope protein gp125, and one region in the glycoprotein gp36, which are
      important for human antibody binding and also as targets for neutralization. The
      peptide representing the V2 region had the most pronounced capacity to induce
      neutralizing anti-HIV-2 antibodies in guinea pigs. Neutralizing activity was also
      detected in an antipeptide guinea pig sera representing a linear site in gp36,
      amino acids 644-658. A substitution set of peptides representing the conserved
      antigenic site in the central part of gp36 was used to identify the role of
      individual amino acids important for human antibody binding.

PMID- 10333246
TI  - Tumor suppressor genes and breast cancer.
AB  - The genetic determinants for most breast cancer cases remain elusive. However, a
      mutation in a tumor suppressor gene, such as p53, BRCA1, BRCA2, or ATM, has been
      determined to be one mechanism of breast carcinogenesis. It has been established
      that inherited mutations in p53, BRCA1, and BRCA2 significantly contribute to
      breast cancer risk, although the importance of an inherited ATM mutation is
      controversial. Sporadic mutations in p53 are also common in breast cancer cells.
      The precise deficiencies that result from these genetic mutations have yet to be
      fully described. Although the functions of these genes are different, they are
      all involved in the maintenance of genomic stability after DNA damage. Mutations
      that impair the function of these four genes may adversely affect the manner in
      which DNA damage is processed. It is likely that the risk of breast cancer
      development is increased through this mechanism. In this article, we review the
      relevancy of p53, BRCA1, BRCA2, and ATM mutations to breast cancer development,
      and review the in vitro, in vivo, and clinical data exploring the mechanisms by
      which these mutations affect genomic integrity and DNA damage repair.

PMID- 10333247
TI  - Heterogeneity of in vitro radiosensitivity in human bladder cancer cells.
AB  - Human bladder cancer is often heterogeneous containing biologically different
      populations. Radiotherapy plus chemotherapy is the most common treatment for
      invasive disease. However few studies have investigated the role of heterogeneity
      in determining radiosensitivity. The radiation sensitivities of a parent human
      bladder cancer cell line (UCRU-BL-17CL) and nine cloned cell lines derived from
      it were determined. These cloned cell lines were previously shown to exhibit
      different biological characteristics when grown in nude mice. Radiation
      sensitivity was determined using both MTT and clonogenic assays. The
      radiobiological parameters, alpha,beta, and surviving fractions at 2 Gy and 8 Gy
      from the linear-quadratic model, were used to assess radiation sensitivity in the
      statistical analyses. The nine clones differed in radiosensitivity by both
      assays. By MTT, but not by the clonogenic assay, their radiation sensitivities
      were relatively consistent within each of the three biological groups (non
      tumorigenic, tumorigenic, invasive); invasive clones were more sensitive than
      those of the non-tumorigenic and the tumorigenic groups for all the three-test
      criteria. The heterogeneity exhibited by this cell line may explain some of the
      variations in the clinical responses seen in the radiation treatment of invasive
      bladder cancer.

PMID- 10333248
TI  - Comparison between the clonogenic, MTT, and SRB assays for determining
      radiosensitivity in a panel of human bladder cancer cell lines and a ureteral
      cell line.
AB  - Using a series of human bladder cancer cell lines and an immortalised normal
      ureteral cell line, radiosensitivities measured by three different methods after
      a single dose of X-radiation are compared. Clear differences between cell
      survival curves obtained using the clonogenic, microtetrazoline (MTT) and
      sulforhodamine B (SRB) assays are shown. The most sensitive of the assays
      investigated was the clonogenic assay. The MTT and SRB assays were found to be
      relatively insensitive especially at lower radiation levels, suggesting that
      these assays may not be suitable for predicting therapeutic dose schedules in
      vivo, but will be important for investigating radio-sensitivity in cell lines
      with very low plating efficiencies. Each assay discriminated between a range of
      sensitivities in the cell lines examined, and with some minor differences, the
      ordering of sensitivities using the three assays was similar. Possible
      explanations for the differences between results obtained with the three assays
      are discussed.

PMID- 10333249
TI  - Induction of nitric oxide production in infiltrating leukocytes following in vivo
      irradiation of tumor-bearing mice.
AB  - Nitric oxide (NO) has been implicated both in regression and progression of
      tumors due to its production by both tumor cells and infiltrating leukocytes.
      Ionizing radiation causes the regression of tumors, and can augment the
      production of NO by macrophages in vitro. We examined the cellular and systemic
      production of NO in mice in which radiation-resistant RIF-1 fibrosarcoma cells
      were implanted subcutaneously and were then either irradiated or sham-treated at
      the tumor site. Ten days following implantation of the tumors, CD45- tumor cells
      and CD45+ leukocytes were derived from resected tumors immediately after
      irradiation with 60 Gy, a dose previously reported to reduce tumor growth.
      Leukocytes from tumors of irradiated hosts produced spontaneously up to four-fold
      more NO than did either leukocytes from unirradiated mice or CD45- tumor cells
      from either unirradiated or irradiated mice. Between days 10-14 following tumor
      implantation, serum NO2-/NO3- increased in both irradiated and unirradiated mice
      to an equal extent, culminating in levels higher than those of non-tumor-bearing
      mice. Though NO production is elevated in macrophages treated with 1-10 Gy of
      radiation in vitro, higher doses may be required by tumor-infiltrating
      macrophages in vivo and thus may indicate that tumor-infiltrating macrophages are
      deactivated.

PMID- 10333250
TI  - Induction chemotherapy and radiation therapy for T4 oropharyngeal carcinoma.
AB  - Between 1964 and 1996, 123 patients were treated for T4 oropharyngeal carcinoma;
      93 were treated with radiation therapy alone; 30 were treated with induction
      chemotherapy and radiation therapy. Patients who received induction chemotherapy
      and radiation therapy were treated between 1985 and 1996; during this time 39
      patients were treated with radiation therapy alone. Five-year local control rates
      for patients undergoing chemotherapy and radiation therapy, radiation therapy
      alone (all patients), and radiation therapy alone (patients treated since
      September 1985) were 63%, 38%, and 48%, respectively. The five-year rates of
      freedom from distant metastasis were 87%, 73%, and 76%, respectively. The five
      year actuarial cause-specific survival rates were 58%, 27%, and 37%,
      respectively, while the five-year absolute survival rates were 42%, 17%, and 23%,
      respectively. Improvements in local control and freedom from distant metastasis
      in those receiving chemotherapy were not statistically significant, while the
      improvements in cause-specific survival and absolute survival were significant at
      the P < or = 0.05 level. Induction chemotherapy may improve the cure rate for
      patients with T4 oropharyngeal carcinoma. Although encouraging, these data are
      nonrandomized and should be interpreted with caution.

PMID- 10333251
TI  - Is there a subset of patients with PSA > or = 20 ng/ml who do well after
      conformal beam radiotherapy?
AB  - To determine if there is a subgroup of patients with pretreatment PSA > or = 20
      ng/ml with a favorable outcome after external beam radiation therapy. We analyzed
      retrospectively treatment outcomes of 129 patients with pretreatment PSA > or =
      20 ng/ml treated in our department from 2/88-8/94. Median patient age was 70
      years (range 51-89 years). Tumor stage was T1/T2ab in 68, T2c/T3 in 61 patients.
      Initial Gleason grade was < 7 in 82 and > or = 7 in 47 patients. Median PSA was
      35 ng/ml (mean 45 ng/ml, range 20-191 ng/ml). Ninety-seven patients received four
      field conformal external beam radiation therapy. No patient received surgery or
      hormonal therapy prior to treatment. Median central axis dose was 73 Gy (range 68
      79 Gy). Covariates considered in univariate and multivariate analyses included
      central axis dose, pretreatment PSA, presence of perineural invasion, Gleason
      score, palpable tumor stage and patient age. bNED failure was defined as a PSA >
      or = 1.5 and rising on two consecutive determinations. Median follow up was 50
      months (range 3-100 months). Overall bNED control for the entire patient
      population was 22% at five years. Of the covariates analyzed, dose (P < 0.01),
      stage (P < 0.01), Gleason Score (P < 0.01), and the presence of PNI (P = 0.01)
      were significant on multivariate analysis. Based on these results, patients could
      be stratified into two distinct groups. Group I consisted of 19 patients with
      favorable features including T1/T2ab disease, Gleason Score 2-6, no perineural
      invasion treated to a dose > 73 Gy to the central axis. Patients in Group II had
      at least one of the above poor prognostic features or were treated to central
      axis doses < 73 Gy. The bNED control was significantly higher for patients in
      Group I than those in Group II (58% vs. 23%, P = 0.0027). There appears to be a
      favorable subgroup of patients with PSA > or = 20 ng/ml where treating to doses
      over 73 Gy to the central axis is warranted (four-year bNED rate of 58%).
      However, because of the small patient numbers, these results will need to be
      validated with longer follow up.

PMID- 10333252
TI  - Extent of margin positivity as a predictor for local recurrence after breast
      conserving irradiation.
AB  - The extent of positivity of the final excision margin in relationship to other
      relevant factors was evaluated as a predictor for local recurrence after breast
      conservation therapy (BCT). As part of an institutional practice policy for BCT
      in 509 stage I/II breast carcinomas, 105 cases had a final excision margin, which
      was positive. The median age for this cohort was 58 years and the median follow
      up was 86 months. All positive margin patients received whole breast irradiation
      to 50 Gy-50.4 Gy followed by a boost to the tumor bed for an additional 20 Gy.
      The extent of positivity (EOP) of the excision margin was graded according to a
      four-point scale: focal, minimal, moderate, extensive. Cases were then analyzed
      for local failure according to EOP grade, histology, age, tumor size, total
      excision volume, re-excision, tamoxifen therapy, and chemotherapy. A focal or
      minimal EOP grade was found in 70% of specimens while an additional 26% were
      moderate or extensive. The incidence of invasive carcinoma with prominently
      associated DCIS was significantly greater in cases with an EOP grade of
      moderate/extensive. There were nine ipsilateral breast recurrences, eight of
      which could be evaluated for EOP grade. All recurrences were in or near the
      previous biopsy cavity. A Kaplan-Meier plot of freedom from local failure showed
      a significant (P = 0.008) difference between cases grouped by EOP grade of
      focal/minimal as compared to moderate/extensive. A Cox proportional hazards
      regression model found that the only variable significantly related at the P < or
      = 0.05 level to local failure was an EOP grade of moderate/extensive. For breast
      excision specimens with a positive final margin, an EOP grade of
      moderate/extensive is a predictor for local recurrence after BCT, which may be
      independent of other variables such as age or histology.

PMID- 10333253
TI  - Palliative radiotherapy of malignant melanoma with reactor fission neutron
      therapy (RENT): a prospective study.
AB  - To study the efficacy and safety of relatively low-dosed reactor fission neutron
      therapy (RENT) at the research reactor of the Technical University Munich, we
      treated 33 superficial lesions of 20 patients with advanced malignant melanoma by
      neutron beam alone (n = 22), mixed neutron/electron beam (n = 5), or by neutron
      beam after incomplete surgery (n = 6). Median tumor volume was 17.0 cm3. Median
      dose for neutron beam alone was 8.0 Gy and for mixed beam 3.0 Gy n + 45.3 Gy e-.
      Local tumor response, local control time, survival and treatment related toxicity
      were followed prospectively over a time period of 52 months. Overall response
      rate (CR;PR) after neutron beam alone and mixed beam therapy was 64% (CR: 36%)
      and 100% (CR: 60%), respectively. Observed differences between complete (CR) and
      incomplete (PR, NC) responding lesions were as follows: median tumor volume: 2.0
      vs. 51.5 cm3, local control time: 13.3 vs. 3.7 months, median survival: 19.8 vs.
      9.0 months. No severe acute or late sequelae could be observed. In conclusion,
      low-dosed RENT is an effective and well tolerated palliative treatment of
      superficial malignant melanoma utilizing the biologic advantage of diminished
      cellular repair capacity. Because melanoma lesions of small size (< or = 6 cm3)
      tend to respond completely, neutron beam should be performed at an early stage.

PMID- 10333254
TI  - The diagnosis of feline heartworm infection.

PMID- 10333255
TI  - Risk factors for odontoclastic resorptive lesions in cats.
AB  - A cross-sectional study evaluating potential risk factors for odontoclastic
      resorptive lesions (ORL) in feline teeth was conducted. Owners of 32 cats with
      ORL and 27 cats without ORL were interviewed regarding their respective cat's
      demographic characteristics, diet, and medical and dental histories. Four factors
      were identified as significantly associated with ORL using unconditional logistic
      regression. A history of dental disease (gingivitis, calculus, or periodontal
      disease; odds ratio [OR], 4.5); city residence (OR, 4.4); and being an
      exclusively indoor cat (OR, 4.5) were associated with an increased risk for ORL.
      Consumption of commercial treats (OR, 0.3) appeared protective for ORL.

PMID- 10333256
TI  - Ultrasonographic characteristics of both adrenal glands in 15 dogs with
      functional adrenocortical tumors.
AB  - Ultrasonographic examination of both adrenal glands was performed in 15 dogs with
      functional adrenocortical tumors (FAT). Bilateral adrenal tumors were diagnosed
      in three of 15 dogs, and unilateral tumors were diagnosed in 12 of 15 dogs.
      Adrenal tumors were characterized by adrenal gland enlargement with loss of the
      normal shape and parenchymal structure. The contralateral adrenal gland could be
      imaged in all dogs with unilateral tumors. Based on size, shape, and parenchymal
      structure, the contralateral adrenal gland was similar to adrenal glands of
      normal dogs. The results of this study show that: 1) both adrenal glands should
      be imaged routinely in dogs with hyperadrenocorticism; 2) bilateral
      adrenocortical tumors seem to be more frequent than previously assumed; 3) one
      normal adrenal gland does not exclude the existence of a contralateral FAT; and
      4) the functional atrophy of the contralateral adrenal gland in dogs with FAT may
      not be apparent ultrasonographically.

PMID- 10333257
TI  - Iatrogenic hyperadrenocorticism in 28 dogs.
AB  - Twenty-eight dogs with iatrogenic hyperadrenocorticism were studied. The most
      common clinical signs were cutaneous lesions (27/28), polydipsia (21/28),
      polyuria (19/28), and lethargy (16/28). The most predominant findings on
      biochemical profile were elevated alkaline phosphatase (ALP, 15/28) and alanine
      transferase (ALT, 14/28); hypercholesterolemia (14/28); elevated aspartate
      transferase (AST, 12/28); and elevated triglycerides (12/18). Baseline cortisol
      levels of all 28 dogs were at the lower end of the reference range and exhibited
      suppressed or no response to adrenocorticotropic hormone (ACTH) stimulation. The
      mean time for each dog to show initial improvement of clinical signs after
      corticosteroid withdrawal was six weeks, with another mean time of 12 weeks to
      demonstrate complete remission.

PMID- 10333258
TI  - Radiographic findings in dogs with naturally-occurring primary
      hypoadrenocorticism.
AB  - Survey radiographs often are obtained in dogs with primary hypoadrenocorticism in
      adrenal crisis as part of the routine evaluation of a critically ill dog. In this
      study, standardized methods of cardiac, pulmonary vasculature, and vena cava
      mensuration were used in 22 dogs with naturally-occurring primary
      hypoadrenocorticism, and the findings were compared with those in 22 breed
      matched, clinically normal dogs. Most (81.8%) untreated dogs with primary
      hypoadrenocorticism had one or more radiographic abnormalities, including small
      size of the heart (45.5%), cranial lobar pulmonary artery (36.4%), caudal vena
      cava (54.5%), or liver (36.4%). Megaesophagus was not found in any of the dogs
      with hypoadrenocorticism, and therefore, compared to the other common
      radiographic findings, should be considered a rare finding.

PMID- 10333259
TI  - Ultrasonographic evaluation of the adrenal glands in six dogs with
      hypoadrenocorticism.
AB  - The purpose of this study was to determine the value of ultrasonographic
      characterization of the adrenal glands in dogs with hypoadrenocorticism.
      Measurements of adrenal glands were obtained in six dogs with
      hypoadrenocorticism. The adrenal glands on both sides were shorter (range: left
      adrenal gland length, 10.0 to 19.7 mm; right adrenal gland length, 9.5 to 18.8
      mm) and thinner (range: left adrenal gland thickness, 2.2 to 3.0 mm; right
      adrenal gland thickness, 2.2 to 3.4 mm) than in normal dogs (range: left adrenal
      gland length, 13.2 to 26.3 mm; right adrenal gland length, 12.4 to 22.6 mm; left
      adrenal gland thickness, 3.0 to 5.2 mm; right adrenal gland thickness, 3.1 to 6.0
      mm). Statistical analysis revealed a significant reduction in size of the left
      adrenal gland (p less than 0.05) in dogs with hypoadrenocorticism compared to the
      left adrenal gland in normal dogs. The results of this study show that atrophy of
      the adrenal glands in dogs with hypoadrenocorticism seems to lead to an
      ultrasonographic-measurable reduction in size of the adrenal glands.

PMID- 10333260
TI  - Nonresponsive generalized bacterial infection associated with systemic lupus
      erythematosus in a Beauceron.
AB  - A case of concurrent canine systemic lupus erythematosus (SLE) and generalized
      bacterial infection in a six-year-old female Beauceron is reported. The dog
      presented with purulent nasal and ocular discharges, skin lesions (including
      seborrhea, hyperkeratotic areas, and papules as well as ecchymoses around the
      eyes, on both sides of the pinnae, and on the vulva), generalized lymph node
      enlargement, a mitral murmur, and lameness. Later, facial swelling, a retrobulbar
      abscess, and a cough also developed. Occurrence of a generalized bacterial
      infection was established by culture of group-C, beta-hemolytic Streptococcus
      from the throat, the mouth, a biopsy site (popliteal lymph node area), the
      retrobulbar abscess, and the lung. The diagnosis of SLE was based on the clinical
      signs and particularly on the occurrence of antinuclear antibody (ANA) and
      antidoublestranded-desoxyribonucleic acid (ds-DNA) antibody. Interestingly, the
      latter type of antibodies were also detected in two young female puppies whelped
      by this dog. Salient histological findings included an extreme cell depletion of
      the lymph nodes and spleen and severe pneumonitis and peribronchiolitis. The
      results of this case indicate that a definite diagnosis of canine SLE can, at
      times, be made on the basis of the presence of serum ANA and ds-DNA antibodies.

PMID- 10333261
TI  - Reflex sympathetic dystrophy in a dog.
AB  - Reflex sympathetic dystrophy is a well-recognized syndrome in human patients
      following injury to an extremity. The syndrome may include hyperesthesia and
      autonomic changes. The autonomic changes are initial vasodilatation followed by
      vasoconstriction (e.g., edema followed by cyanosis, and cool skin); hyper- or
      hypohydrosis; atrophic changes in the skin, subcutis, and muscles; and
      osteoporosis. Early treatment with a short course of steroids and infiltration of
      the painful site with lidocaine may alleviate symptoms. If that fails,
      sympathetic ganglionic block with lidocaine (and possibly steroids) or surgical
      sympathectomy may provide resolution. A case of reflex sympathetic dystrophy in a
      dog is presented, involving bilateral distal hind-limb edema and hyperesthesia.

PMID- 10333262
TI  - Sensory polyganglioradiculoneuritis in a dog.
AB  - Generalized reduction of nociception and conscious and unconscious proprioception
      were found in an approximately eight-year-old, male, Maltese mixed-breed dog
      presented for difficulty prehending food and experiencing ataxia of three months
      duration. Results of needle electromyogram, motor nerve conduction velocity, and
      cerebrospinal fluid analysis were normal. A diagnosis of sensory polyneuropathy
      was suspected. No underlying cause could be determined. Neurological signs
      progressed to quadriparesis over the following four months despite treatment
      attempts with prednisone and procarbazine. Necropsy confirmed a sensory
      polyganglioradiculoneuritis, but no inciting cause could be established.

PMID- 10333263
TI  - Mitoxantrone and cyclophosphamide combination chemotherapy for the treatment of
      various canine malignancies.
AB  - Thirteen dogs with histopathologically confirmed malignancies were treated with
      mitoxantrone and cyclophosphamide combination therapy. One to four doses were
      administered at 21-day intervals. Recombinant human granulocyte colony
      stimulating factor was administered to ameliorate myelosuppression in dogs with
      neutrophil nadirs less than 1,000/microl. While the protocol appears to be safe
      for use in tumor-bearing dogs, an advantage over mitoxantrone single-agent
      protocols in terms of tumor response was not demonstrated in this initial pilot
      study.

PMID- 10333264
TI  - Prolapse of the gland of the third eyelid in a cat: a case report and literature
      review.
AB  - A one-year-old, castrated male, domestic shorthair was presented with a prolapse
      of the gland of the third eyelid. Similar to the dog, this cat did not appear to
      suffer from this eye condition. The prolapse was unilateral on the left eye. The
      right eye was normal. No accompanying eye diseases were found. Treatment
      consisted of a surgical pocket technique similar to the technique used in dogs.

PMID- 10333265
TI  - Bone plate fixation of distal radius and ulna fractures in small- and miniature
      breed dogs.
AB  - Bone plate fixation was reviewed in 29 distal radial fractures of small- and
      miniature-breed dogs. Twenty-two fractures in 18 dogs were available for follow
      up. Number of complications and return to function were evaluated. Complications
      occurred in 54% of the fractures. Catastrophic complications occurred in 18% of
      fracture repairs with follow-up, while minor complications occurred in 36%.
      Sixteen (89%) of 18 dogs had a successful return to function. Bone plate fixation
      is a successful repair method for distal radius and ulna fractures in small-breed
      dogs, compared to previously reported methods.

PMID- 10333266
TI  - Surgical repair of nasopharyngeal stenosis in a cat using a stent.
AB  - An intraluminal stent was used to maintain patency of a recurrent nasopharyngeal
      stenosis (NPS) in a cat. The stenotic membrane within the nasopharynx was
      resected, and a 2-cm long, braided-wire endoprosthesis was placed as a stent. The
      patient was evaluated at one day, six weeks, 19 weeks, and 49 weeks following
      surgery. The cat tolerated the stent well. The 19-week recheck revealed
      granulation tissue partially obstructing the pharyngeal aspect of the stent which
      was subsequently surgically resected. Complications after excision of the
      granulation tissue included intermittent upper respiratory congestion and nasal
      discharge. The 49-week recheck showed no increased granulation tissue; however,
      upper respiratory congestion was still present. This particular stent, and its
      use as described in this paper, is recommended in cases of chronic recurrent NPS.

PMID- 10333268
TI  - Distribution of protein kinase C in the brain of Apteronotus leptorhynchus as
      revealed by phorbol ester binding.
AB  - An antibody to the mammalian protein kinase C alpha (PKCalpha) subunit and brain
      dissection was used for immunoblot analysis of this protein in various brain
      regions of Apteronotus leptorhynchus. Western blots revealed that the antibody
      labeled a band of the expected molecular mass (approximately 80 kDa) for this
      enzyme in mammalian cortex and electric fish brain, suggesting that this protein
      is also found in gymnotiform brain. The 80-kDa band was enriched in fish
      forebrain and cerebellum compared with hypothalamus and brainstem areas.
      [3H]Phorbol 12,13-dibutyrate ([3H]PDBu) binding was used as a marker for the
      distribution of protein kinase C (PKC). [3H]PDBu binding was nearly completely
      displaced by excess cold PDBu; specific [3H]PDBu binding sites were
      heterogenously distributed with high densities in some gray matter regions and
      negligible densities in fiber tracts. A very high density of [3H]PDBu binding
      sites were found in the dorsal forebrain with far lower densities in most ventral
      forebrain nuclei. Low binding densities were observed in preoptic and
      hypothalamic areas with the exception of the nucleus diffusus and nucleus tuberis
      anterior. The thalamus and midbrain also had only low levels of binding. The
      cerebellar molecular layer had dense binding, in contrast to the granule cell
      layer where binding was negligible. In the electrosensory lateral line lobe
      (ELL), there was moderate binding in the dorsal molecular layer, which contains
      cerebellar parallel fibers; the other layers of the ELL had far lower binding
      densities.

PMID- 10333269
TI  - Distribution of adenylate cyclase in the brain of Apteronotus leptorhynchus as
      revealed by forskolin binding.
AB  - An antibody directed against an isoform of the rat regulatory subunit of protein
      kinase A and brain dissection was used for immunoblot analysis of this protein in
      various brain regions of Apteronotus leptorhynchus. Western blots revealed that
      the antibody labeled a band of the expected molecular mass (approximately 53 kDa)
      for this enzyme in mammalian cortex and electric fish brain, suggesting that this
      protein is also found in fish brains. The 53-kDa band was enriched in fish
      forebrain. [3H]Forskolin binding was used as a marker for the distribution of
      adenylate cyclase. [3H]Forskolin binding was nearly completely displaced by
      excess cold forskolin; specific [3H]forskolin binding sites were heterogenously
      distributed with relatively high densities in some gray matter regions and low
      densities in fiber tracts. A high density of [3H]forskolin binding sites was
      found in the dorsal forebrain with lower densities in most ventral forebrain
      nuclei. Moderate binding densities were observed in the preoptic and hypothalamic
      areas with the exception of the nucleus tuberis anterior, which had high levels.
      The thalamus and midbrain had low levels of binding. The cerebellar molecular
      layer had dense binding, in contrast to the granule cell layer where binding was
      low. In the electrosensory lateral line lobe (ELL), there was moderate binding in
      the dorsal and ventral molecular layers, which contain feedback inputs; the
      cellular layers of the ELL had low binding densities.

PMID- 10333267
TI  - Pax-6 is required for thalamocortical pathway formation in fetal rats.
AB  - Pax-6, a transcription regulatory factor, has been demonstrated to play important
      roles in eye, nose, and brain development by analyzing mice, rats, and humans
      with a Pax-6 gene mutation. We examined the role of Pax-6 with special attention
      to the formation of efferent and afferent pathways of the cerebral cortex by
      using the rat Small eye (rSey2), which has a mutation in the Pax-6 gene. In
      rSey2/rSey2 fetuses, cortical efferent axons develop with normal trajectory, at
      least within the cortical anlage, when examined with immunohistochemistry of the
      neuronal cell adhesion molecule TAG-1 and 1,1'-dioctadecyl-3,3,3',3'
      tetramethylindocarbocyanine perchlorate (DiI) labeling from the cortical surface.
      A remarkable disorder was found in the trajectory of dorsal thalamic axons by
      immunostaining of the neurofilament and the neural cell adhesion molecule L1 and
      DiI labeling from the dorsal thalamus. In normal rat fetuses, dorsal thalamic
      axons curved laterally in the ventral thalamus without invading a Pax-6
      immunoreactive cell cluster in the ventral part of the ventral thalamus. These
      axons then coursed up to the cortical anlage, passing just dorsal to another Pax
      6-immunoreactive cell cluster in the amygdaloid region. In contrast, in
      rSey2/rSey2 fetuses, dorsal thalamic axons extended downward to converge in the
      ventrolateral corner of the ventral thalamus and fanned out in the amygdaloid
      region without reaching the cortical anlage. These results suggest that Pax-6
      expressing cell clusters along the thalamocortical pathway (ventral part of the
      ventral thalamus and amygdala) are responsible for the determination of the
      axonal pathfinding of the thalamocortical pathway.

PMID- 10333270
TI  - Distribution of calcium/calmodulin-dependent kinase 2 in the brain of Apteronotus
      leptorhynchus.
AB  - Antibodies directed against the mammalian alpha and beta subunits of
      calcium/calmodulin-dependent kinase 2 (CaMK2) and brain dissection were used for
      immunoblot analysis of these proteins in various brain regions of Apteronotus
      leptorhynchus. Western blots revealed that the CaMK2alpha antibody labeled a
      single band of the expected molecular mass (approximately 50 kDa) for this enzyme
      in rat cortex and electric fish brain. CaMK2alpha was enriched in fish forebrain
      and hypothalamus and also strongly expressed in midbrain sensory areas. Western
      blots revealed that CaMK2beta antibodies labeled bands in an appropriate
      molecular mass range (approximately 58-64 kDa) for this enzyme in mammalian
      cortex and electric fish brain. However, a higher molecular mass band
      (approximately 80 kDa) was also labeled; because all these bands were eliminated
      by preadsorbtion with the CaMK2-derived peptide antigen, they may all represent
      CaMK2beta-like isoforms. We mapped the brain distribution of CaMK2 isoforms with
      emphasis on the electrosensory system. CaMK2alpha was present at high density in
      dorsal forebrain, hypothalamic nuclei, torus semicircularis, and tectum. It was
      also enriched in discrete fiber tracts in forebrain, diencephalon, and
      rhombencephalon. CaMK2beta-like isoforms were enriched in ventral forebrain,
      hypothalamic nuclei, torus semicircularis and the reticular formation. Unlike
      CaMK2alpha, CaMK2beta -like isoforms were predominantly present in cell bodies
      and rarely found in fiber tracts or neuropil. In the electrosensory lateral line
      lobe, CaMK2alpha was restricted to specific feedback fibers, i.e., tractus
      stratum fibrosum and its terminal field in the ventral molecular layer. In
      contrast, CaMK2beta-like isoforms were enriched in somata and dendrites of
      pyramidal cells and granular interneurons.

PMID- 10333271
TI  - The Eta ganglion cell type of cat retina.
AB  - We define a morphologic type of ganglion cell in cat retina by using
      intracellular staining in vitro. The eta cell has a small soma, slender axon, and
      delicate, highly branched dendritic arbor. Dendritic fields are intermediate in
      size among cat ganglion cells, with diameters typically two to three times those
      of beta cells. Fields increase in size as a function of distance from the area
      centralis, ranging in diameter from 90 microm to 200 microm centrally to a
      maximum of 600 microm in the periphery. This increase is unusually radially
      symmetric. By contrast with other cat ganglion cell types, eta cells do not have
      markedly smaller dendritic fields within the visual streak than above or below it
      nor much smaller fields nasally than temporally. Dendrites ramify broadly
      throughout sublamina a (OFF sublayer) of the inner plexiform layer. They arborize
      most densely in S2, where they costratify with dendrites of OFF alpha cells.
      There is apparently no matching ON variety of eta cell. Experiments combining
      retrograde labeling with intracellular staining indicate that eta cells project
      to the superior colliculus and to two components of the dorsal lateral geniculate
      nucleus (the C laminae and medial interlaminar nucleus). Eta cells apparently
      project contralaterally from the nasal retina and ipsilaterally from the temporal
      retina. The morphology and projection patterns of the eta cell suggest that its
      physiologic counterpart is a type of sluggish or W-cell with an OFF center, an ON
      surround, and possibly a transient light response.

PMID- 10333272
TI  - Colocalization of androgen receptors and mating-induced FOS immunoreactivity in
      neurons that project to the central tegmental field in male rats.
AB  - Bilateral lesions of the central tegmental field (CTF) in male rats virtually
      eliminate mating behavior. This study examined if mating-induced Fos expression
      (a measure of neuronal activation) and androgen receptors (AR) are colocalized in
      brain and spinal cord neurons which project to the CTF. Animals received
      unilateral injections of the retrograde tracer Fluorogold (FG) in the lateral
      part of the CTF (CTFl), and 10 days later were killed after ejaculating with
      females. Brains and spinal cords were examined for FG transport, AR
      immunoreactivity (AR-ir), and Fos-immunoreactivity (Fos-ir). AR-ir and Fos-ir
      were visualized with fluorescence microscopy using cyanine-conjugated and
      fluorescein-conjugated secondary antibodies. The CTFl received projections from
      AR-containing neurons in forebrain structures (bed nucleus of stria terminalis,
      medial preoptic area, lateral and ventromedial hypothalamus), in the central
      amygdala and various mid- and hindbrain structures (dorsolateral tegmentum,
      superior and inferior colliculi, pedunculopontine nucleus), and in the
      lumbosacral spinal cord (lamina X). Some of the AR-containing neurons in bed
      nucleus of stria terminalis and in the dorsal part of the medial preoptic area
      with projections to the CTFl were activated by mating. Most AR-containing neurons
      in spinal lamina X with projections to the CTFl were also activated by mating.
      Information from spinal cord and pontine nuclei and from outputs descending from
      the forebrain may be relayed in the CTFl. Thus, as part of a network of hormone
      sensitive neurons linking brain and spinal cord mechanisms for mating, the CTFl
      could participate in the integration of visceral and somatic information relevant
      for sexual behavior.

PMID- 10333273
TI  - Distribution of GABAergic cells and fibers in the hippocampal formation of the
      macaque monkey: an immunohistochemical and in situ hybridization study.
AB  - The gamma-aminobutyric acid (GABAergic) system of the hippocampal formation of
      Macaca fascicularis monkeys was studied immunohistochemically with a monoclonal
      antibody to GABA and with nonisotopic in situ hybridization with cRNA probes for
      glutamic acid decarboxylase 65 (GAD65) and GAD67. The highest densities of
      labeled cells were observed in the presubiculum, parasubiculum, entorhinal
      cortex, and subiculum, whereas the CA3 field and the dentate gyrus had the lowest
      densities of positive neurons. Within the dentate gyrus, most of the GABAergic
      neurons were located in the polymorphic layer and in the deep portion of the
      granule cell layer. GABAergic terminals were densest in the outer two-thirds of
      the molecular layer. GABAergic neurons were seen throughout all layers of the
      hippocampus. Terminal labeling was highest in the stratum lacunosum-moleculare. A
      higher terminal labeling was observed in the subiculum than in CA1 and was
      particularly prominent in layer II of the presubiculum. A bundle of GABAergic
      fibers was visible deep to the cell layers of the presubiculum and subiculum.
      This bundle could be followed into the angular bundle ipsilaterally and was
      continuous with stained fibers in the dorsal hippocampal commissure. This pattern
      of labeling is reminiscent of the presubicular projections to the contralateral
      entorhinal cortex. GABAergic cells were observed in all layers of the entorhinal
      cortex although the density was higher in layers II and III than in layers V and
      VI. The in situ hybridization preparations largely confirmed the distribution of
      GABAergic neurons in all fields of the hippocampal formation.

PMID- 10333274
TI  - Visual system of the European hummingbird hawkmoth Macroglossum stellatarum
      (Sphingidae, Lepidoptera): motion-sensitive interneurons of the lobula plate.
AB  - The European hummingbird hawkmoth Macroglossum stellatarum is a member of the
      sphingid family, denoted by their ability to hover in place in front of flowers.
      The fast and acrobatic flight behavior is thought to be under the control of the
      optomotor system both during normal, forward flight and during stationary,
      hovering flight. Electrophysiologic and neuroanatomic studies presented here
      reveal large-field, motion-sensitive neurons in the lobula plate. Anatomic and
      physiologic features characterize these nerve cells as horizontal and vertical
      motion-sensitive neurons. Horizontal cells react best to horizontal movement of
      vertical gratings moving in either direction and show no response to vertically
      moving horizontal gratings. The dendritic arborizations of horizontal cells are
      found characteristically in the two outer layers of the lobula plate. In
      contrast, vertical cells react best to upward or downward motion of horizontal
      gratings. They are not sensitive to horizontal-moving gratings. The dendritic
      arborizations of the vertical cells are restricted to the two innermost lobula
      plate layers. These anatomic and physiologic features, as well as a number of
      other characteristics, such as tonic responses and cosine-shaped tuning curves,
      are most reminiscent of neurons that comprise the horizontal and vertical systems
      described from the fly, thus suggesting comparable roles in the control of
      optomotor behavior. The present study also identifies a small group of neurons
      that exhibit phasic responses and reactions to specific orientations of the
      pattern. These cells are discussed with regard to their possible roles in control
      tasks, such as edge-orientation detection or the detection of sudden
      displacements of the visual surround.

PMID- 10333275
TI  - Subpopulations of striatal interneurons can be distinguished on the basis of
      neurotrophic factor expression.
AB  - Substantial evidence supports a role for trophic activities in the function and
      survival of fully mature striatal neurons, but little is known regarding trophic
      factor expression in adult striatum. In situ hybridization was used to identify
      the distribution and the neurotransmitter phenotypes (i.e., cholinergic and gamma
      aminobutyric acid [GABA]-ergic) of cells expressing acidic fibroblast growth
      factor (aFGF), glial cell line-derived neurotrophic factor (GDNF), or nerve
      growth factor (NGF) mRNA in adult rat striatum. Each trophic factor mRNA was
      localized to large, sparsely scattered striatal cells that corresponded to
      interneurons. Double-labeling studies demonstrated that NGF mRNA was expressed by
      GABAergic and never by cholinergic cells, whereas aFGF and GDNF mRNAs were
      expressed by both cell types. Approximately 75% of aFGF+ and GDNF+ cells in
      dorsal striatum and 46% of aFGF+ and 61% of GDNF+ cells in ventral striatum were
      cholinergic. Conversely, about 32% of aFGF+ and 24% of GDNF+ cells in dorsal
      striatum and 55% of aFGF+ and 27% of GDNF+ cells in ventral striatum were
      GABAergic. A portion of aFGF+ and NGF+ cells was of the parvalbumin GABAergic
      subtype. The colocalization of trophic factor expression was also examined. Of
      aFGF+ cells, 20% and 41% were NGF+ and 67% and 83% were GDNF+ in dorsal and
      ventral striata, respectively. These findings demonstrate that aFGF, GDNF, and
      NGF are synthesized by discrete but overlapping populations of striatal
      interneurons. The expression of these survival factors may contribute to the
      resistance of striatal interneurons to various insults including excitotoxicity.

PMID- 10333276
TI  - Learning from success: global priorities for HIV prevention--Thomas Parran Award
      Lecture.

PMID- 10333277
TI  - Racial/ethnic group differences in the prevalence of sexually transmitted
      diseases in the United States: a network explanation.
AB  - BACKGROUND: Many studies have observed that African Americans have comparatively
      high rates of selected STDs, often 10 to 20 times higher than whites and other
      racial/ethnic groups, but without convincing explanation. GOAL: This study
      attempts to solve this puzzle using data from a nationally representative
      probability sample and a network approach. STUDY DESIGN: The National Health and
      Social Life Survey (NHSLS) is a nationally representative probability sample of
      1,511 men and 1,921 women in the United States. Logistic regression analysis of
      these data permit a multivariate analysis of the individual risk factors
      associated with STDs. Using loglinear analysis and a simulation, we also identify
      the effects of sexual network patterns within and between racial/ethnic groups.
      RESULTS: Logistic regression analysis of the NHSLS revealed, even after
      controlling for all the appropriate individual-level risk factors, that African
      Americans are almost five times more likely to be infected by bacterial diseases
      than the other racial/ethnic groups. CONCLUSIONS: African Americans' higher
      infection rate for bacterial diseases can be explained by the patterns of sexual
      networks within and between different racial/ethnic groups. First, infections are
      more widespread in the African American population at large because partner
      choice is more highly dissortative--meaning that "peripheral" African Americans
      (who have had only one partner in the past year) are five times more likely to
      choose "core' African Americans (who have had four or more partners in the past
      year) than "peripheral" whites are to choose "core" whites. Secondly, sexually
      transmitted infections stay within the African American population because their
      partner choices are more segregated (assortative mating) than other groups. The
      likelihood of African Americans having a sexually transmitted infection is 1.3
      times greater than it is for whites because of this factor alone.

PMID- 10333278
TI  - Sexual network patterns as determinants of STD rates: paradigm shift in the
      behavioral epidemiology of STDs made visible.

PMID- 10333279
TI  - Sexual activity, substance use, and HIV/STD knowledge among detained male
      adolescents with multiple versus first admissions.
AB  - BACKGROUND: Incarcerated and detained youth are at high risk for sexually
      transmitted diseases (STD), including human immunodeficiency virus (HIV). GOAL OF
      THE STUDY: To compare the level of sexual activity and substance use-related risk
      and knowledge regarding HIV/STD among male adolescents with multiple (YMA) versus
      first admissions (YFA) to a detention facility as a basis for the development of
      specific intervention strategies. STUDY DESIGN: Sexual and substance use
      histories, HIV/STD knowledge, and perceived risk were collected through
      structured interviews of a consecutive sample of detained youth. Human
      immunodeficiency virus antibody seroprevalence was determined using a blind study
      of discarded blood. RESULTS: Overall, these youth (N = 486) reported high levels
      of noninjection drug use, sexual risk activities, and knowledge regarding HIV/STD
      prevention. Furthermore, most of these youth reported that their risk for HIV
      infection was low (68%). Eighty-one percent of all youth reported recent (past 6
      months) vaginal sex, and 14% reported insertive anal sex. Controlling for age,
      YMA were more likely to initiate sex at age 13 or younger (OR 1.38; 95% CI, 1.11
      1.70), to report eight or more lifetime sex partners (OR 1.36; 95% CI, 1.13
      1.63), and to have ever exchanged drugs or money for sex (OR 1.54; 95% CI, 1.08
      2.19). However, these youth were less likely to report condom use with their last
      sex partner (OR 0.74; 95% CI, 0.60-0.93). More than one third (34%) of all youth
      felt that consistent use of condoms would not provide a high level of protection
      against HIV. CONCLUSION: Youth with multiple versus first admissions are at
      higher risk of HIV/STD infections through their lifetime and recent sexual
      activities. Interventions targeted to this population will need to address the
      barriers to and facilitators of condom use, strategies to promote positive
      attitudes toward condoms, and strategies to reduce the high level of alcohol and
      substance use.

PMID- 10333280
TI  - Measured versus self-reported compliance with doxycycline therapy for chlamydia
      associated syndromes: high therapeutic success rates despite poor compliance.
AB  - OBJECTIVE: To compare self-reported doxycycline compliance in men and women
      attending an STD clinic with indications for Chlamydia trachomatis treatment to
      compliance measured using microprocessor-containing medication vials to count
      each time and date medication vials were opened. A secondary objective was to
      correlate outcomes of therapy, as measured by symptom resolution and persistence
      of chlamydial nucleic acids, with measured doxycycline compliance. METHODS:
      Between September 1995 and July 1997, Medication Event Monitoring System (MEMS)
      caps were used to measure compliance with recommended doxycycline therapy (14
      doses over 7 days) in patients treated for presumed C. trachomatis infections.
      Polymerase chain reaction (PCR) assays for C. trachomatis were performed on urine
      specimens collected at the time of follow-up evaluation. RESULTS: Of 221
      evaluable participants, although 90% reported taking their medication as
      directed, only 33 (16%) managed this level of compliance according to data
      obtained from the MEMS cap. Although 144 (65%) patients took more than 11 of 14
      doses over 8 days, 147 (67%) participants had at least one interval of 24 hours
      or longer between doses in an 8-day period. Of 81 participants with positive C.
      trachomatis cultures at enrollment, follow-up urine PCR for C. trachomatis was
      positive in 5 (6%). Medication Event Monitoring System data for four of the five
      patients with positive PCR tests as follow-up showed each had two or more 24-hour
      intervals when their medication vials were not opened and three of four had
      opened their vials less than 11 times. CONCLUSIONS: This study suggests that few
      patients take medications as prescribed and that self-report substantially
      underestimates medication noncompliance. Despite poor compliance, there were few
      treatment failures.

PMID- 10333281
TI  - What is the minimally effective treatment for Chlamydia trachomatis infection?:
      The compliance paradox.

PMID- 10333282
TI  - Disclosure of HIV status to sexual partners: predictors and temporal patterns.
AB  - BACKGROUND AND OBJECTIVES: Failure to disclose human immunodeficiency virus (HIV)
      infection to sexual partners interferes with risk reduction. GOAL OF THIS STUDY:
      The purpose of this study was to identify factors associated with disclosure and
      failure to disclose HIV infection to sexual partners and to describe condom use
      with nondisclosure. STUDY DESIGN: A longitudinal survey study of HIV seropositive
      persons recruited at a public STD clinic. RESULTS: Approximately 76% of the study
      population (n = 147) reported disclosing their HIV status to their last sex
      partner at baseline. Predictors of disclosure included consistent condom use and
      being in a monogamous relationship. Twenty-two percent of those who disclosed at
      baseline reported nondisclosure during follow-up. Approximately 23% reported not
      using a condom with a person to whom their status was not disclosed. CONCLUSIONS:
      These results suggest that ongoing partner notification may be necessary to
      increase disclosure of HIV status to sex partners over time.

PMID- 10333283
TI  - Self-reported sexual activity and condom use among symptomatic clients attending
      STD clinics.
AB  - BACKGROUND AND OBJECTIVES: A cross-sectional survey of sexually transmitted
      disease (STD) patients assessed sexual activity and condom use during the time
      between STD symptom onset and clinic attendance. STUDY DESIGN: Patients were
      asked to report sexual activity and condom use while STD symptoms were present.
      Medical records were abstracted for diagnoses. RESULTS: The study population (n =
      3025) was predominately African American (75.3%) and male (63.5%), with a mean
      age of 28.1 years. Sexual activity while experiencing STD symptoms was reported
      by 39.7% of 2,508 symptomatic patients, 17.2% of whom reported always using a
      condom. Logistic regression models identified the significant independent
      determinants of sexual intercourse while symptomatic were duration of symptoms
      before clinic visit [0-7 days versus 8 or more days, OR = 5.9]; race [African
      American versus other races (primarily Hispanics), OR = 2.1]; and gender [men
      versus women, OR = 1.5]. Older age [> or = 30 years versus 18-29 years, OR = 1.5]
      and higher education attainment [> or = high school versus > high school, OR =
      1.5] were the significant factors associated with reporting always using a
      condom. CONCLUSION: These data suggest patient groups with behaviors likely to
      enhance STD transmission could be targeted for educational messages.

PMID- 10333284
TI  - HIV surveillance: a dynamic, not static, process to assure accurate local data.
AB  - BACKGROUND AND OBJECTIVES: Accurate human immunodeficiency virus (HIV)
      surveillance data is critical for the allocation of resources for care services
      and community prevention planning efforts. GOAL OF THIS STUDY: To validate HIV
      status of women and assess risk factor information on all persons reported with
      either heterosexual transmission or no identifiable risk factor. STUDY DESIGN:
      The surveillance database is updated continually as additional information is
      received on all cases allowing continual monitoring of pregnant and nonpregnant
      women. Repeated queries of various record systems were employed to validate or
      reclassify reported heterosexual or no identifiable risk factor information for
      both men and women. RESULTS: Four pregnant women (24%) and one nonpregnant woman
      (0.4%) initially meeting HIV surveillance criteria were demonstrated not to be
      infected. Risk factors were validated or reclassified for 77 (58%) patients
      initially reported with heterosexual transmission or no identifiable risk.
      CONCLUSION: HIV surveillance should be a dynamic process and continual updating
      of case reports provides the most accurate information on which to base service
      and prevention decisions.

PMID- 10333285
TI  - Assessment of a geographically targeted field intervention on gonorrhea incidence
      in two New York State counties.
AB  - BACKGROUND AND OBJECTIVES: Using study findings that demonstrated the importance
      of core group members in gonorrhea transmission, in 1984, one New York State
      county changed its approach toward gonorrhea control by targeting its field
      intervention activities toward infected persons from a geographic core area. In
      late 1988, New York State experienced an epidemic increase in the number of
      syphilis cases. In response, the New York State sexually transmitted disease
      (STD) control program enacted a Syphilis Initiative, which required the diversion
      of field staff from gonorrhea to syphilis control activities for a 3-year period.
      Each of these events held the possibility of impacting gonorrhea incidence in
      this county. GOAL OF THIS STUDY: To evaluate the impact of core interventions on
      reducing gonorrhea incidence as compared to traditional nontargeted field
      intervention methods and to determine the influence on gonorrhea incidence of
      diverting field activities from gonorrhea to syphilis case finding. STUDY DESIGN:
      A Poisson regression method was used to estimate gonorrhea incidence for a 22
      year period in two similar counties: one county that used core intervention and
      one that applied traditional case-finding methods. The impact of core
      intervention was estimated in terms of the reduction in the gonorrhea incidence
      rate from the preintervention incidence rates. RESULTS: After initiation of the
      core intervention, the relative risk of gonorrhea decreased by 61%. Between 30 %
      to 40% of the total reported cases were interviewed for contacts annually during
      the intervention period. In the control county, the relative risk was reduced by
      50% despite a significantly higher percentage of annual case interviews (60%
      70%). In addition, a small change in the definition of core (from census tracts
      encompassing 50% of gonorrhea cases to 30%-35%) during the Syphilis Initiative
      led to a significant increase (16%) in the relative risk of gonorrhea.
      CONCLUSION: Targeting partner notification activities toward a geographic core
      area population appears effective in reducing the risk of gonorrhea, and it was
      more efficient because the overall percentage of cases interviewed was smaller
      than in a county using a nontargeted approach. Diversion of staff during a
      syphilis epidemic, combined with a narrowing of the geographic scope of the core
      intervention, was associated with an increase in gonorrhea incidence.

PMID- 10333286
TI  - Detection of Chlamydia trachomatis and Neisseria gonorrhoeae in swab specimens by
      the Hybrid Capture II and PACE 2 nucleic acid probe tests.
AB  - BACKGROUND AND OBJECTIVES: The Digene Hybrid Capture II (HC II) CT/GC Test
      (Digene Corp., Beltsville, MD) is a new nucleic acid signal amplification-based
      test for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae in
      specimens from the genital tract. For optimal results, the HC II CT/GC Test
      employs a special conical shaped brush for cervical specimen collection from
      nonpregnant women and swabs from pregnant women. GOALS: To validate a protocol
      for HC II C. trachomatis and N. gonorrhoeae testing of specimens collected for
      the GenProbe PACE 2 System. STUDY DESIGN: Specimens were collected from 1,746
      patients with a swab and placed in GenProbe transport media according to the
      manufacturer's recommended procedure. The specimens were first tested at two
      clinical laboratories by the PACE 2 system, and then blindly tested by HC II
      CT/GC using an adjusted cutoff value. Discrepant specimens were adjudicated by
      polymerase chain reaction (PCR), and the result common to two of the three
      testing methods (HC II, PACE 2, and PCR) was defined as the consensus result.
      RESULTS: Combining the data from both sites, the relative sensitivity of the HC
      II Test compared with the consensus result for the detection of 1,761 specimens
      for C. trachomatis and 1,750 specimens for N. gonorrhoeae was 100% for both
      organisms. The relative specificities for C. trachomatis and N. gonorrhoeae
      detection were 99.8% and 99.7%, respectively. The relative sensitivities of the
      PACE 2 CT and GC Systems were 86.5% and 87.1%, respectively, with relative
      specificities of 99.9% and 100%. The difference in sensitivity between HC II and
      PACE 2 for C. trachomatis detection was significant (P < 0.016). CONCLUSION: The
      HC II CT/GC Test can be performed using specimens collected in GenProbe transport
      media and has a significantly greater sensitivity for C. trachomatis detection
      than the PACE 2 System.

PMID- 10333287
TI  - Fluorescence and phosphorescence study of Tet repressor-operator interaction.
AB  - Fluorescence and phosphorescence measurements have been carried out on single-p
      tryptophan (Trp 43 or Trp 75)-containing mutants of Tet repressor (Tet R). Tet R
      containing Trp 43, the residue localized in the DNA recognition helix of the
      repressor, has been used to observe the binding of Tet R to two 20-bp DNA
      sequences of tet O1 and tet O2 operators. Binding of Tet R to tet O1 operator
      leads to a 78% decrease of the repressor fluorescence intensity, with an
      accompanying 20-nm blue shift of its fluorescence emission maximum to 330 nm.
      Upon binding of Tet R to tet O2 operator, the Trp 43 fluorescence intensity is
      quenched by 60%, and a 10-nm shift of its emission maximum to 340 nm occurs.
      Solute fluorescence quenching studies, using acrylamide, performed at low ionic
      strength indicate that in both the complex of Tet R with the O1 and that with the
      O2 operator, Trp 43 is moderately buried, as indicated by a bimolecular rate
      quenching constant of about 1.8 x 10(9) M(-1) sec(-1). In contrast to the Tet R
      tet O2 complex, the Stern-Volmer acrylamide quenching constant Ksv of the complex
      with tet O1 operator changes from 7.5 M(-1) at 5 mM NaCl to 22 M(-1) at 200 mM
      NaCl, indicating different exposures of Trp 43 in the two complexes in solutions
      of higher ionic strength. Phosphorescence studies showed a 0-0 vibronic
      transition at 408 and 403 nm for Trp 43 and Trp 75, respectively. Upon binding of
      Tet R to the tet operators, we observed red shifts of 0-0 vibronic bands of Trp
      43 to 413 and 412 nm for tet O1 and tet O2 operator, respectively, and the
      phosphorescence triplet lifetime of Trp 43 at 75 K was quenched from 6.0-5.5 to
      3.5-3.3 sec. The thermal phosphorescence quenching profile ranged from -200
      degrees C to -20 degrees C, and differed drastically for the two complexes,
      suggesting different dynamics of the microenvironment of the Trp 43 residue. The
      luminescence data for Trp 43 of Tet R suggest that the recognition helix of Tet R
      interacts in different fashions with the tet O1 and tet O2 operators.

PMID- 10333288
TI  - Mg2+ induces conformational changes in the catalytic subunit of phosphorylase
      kinase, whether by itself or as part of the holoenzyme complex.
AB  - Phosphorylase kinase (PhK) from skeletal muscle is a structurally complex, highly
      regulated, hexadecameric enzyme of subunit composition (alpha beta gamma delta)4.
      Previous studies have revealed that the activity of its catalytic gamma subunit
      is controlled by alterations in quaternary structure initiated at allosteric and
      covalent modification sites on PhK's three regulatory subunits; however, changes
      in the conformation of the holoenzyme initiated by the catalytic subunit have
      been more difficult to document. In this study a monoclonal antibody (mAb
      gamma79) has been generated against isolated gamma subunit and used as a
      conformational probe of that subunit. The epitope recognized by this antibody is
      within the catalytic core of the gamma subunit, between residues 100 and 240, and
      monovalent fragments of the antibody inhibit the catalytic activity of the
      holoenzyme, the gamma-calmodulin binary complex, and the free gamma subunit.
      Activation of PhK by a variety of mechanisms known or thought to act through its
      regulatory subunits (phosphorylation, ADP binding, or alkaline pH) increased the
      binding of the holoenzyme to immobilized mAb gamma79, indicating that activation
      by any of these distinct mechanisms involves repositioning of the portion of the
      catalytic domain of the gamma subunit containing the epitope for mAb gamma79. The
      activating ligand Mg2+ also stimulated the binding of the PhK holoenzyme to
      immobilized mAb gamma79, as well as the binding of mAb gamma79 to immobilized
      gamma subunit. Thus, Mg2+ increases the accessibility of the mAb gamma79 epitope
      in both the isolated gamma subunit and in the holoenzyme. Our results suggest
      that previously reported influences of Mg2+ on the quaternary structure of the
      PhK holoenzyme are directly mediated by the gamma subunit.

PMID- 10333289
TI  - Kinetic studies on the interaction of ferricytochrome c with anionic surfactants.
AB  - The kinetics of absorbance and fluorescence changes of cytochrome c as induced by
      an aqueous solution of the anionic surfactant sodium dodecyl sulfate (SDS) or
      sodium bis(2-ethylhexyl)sulfosuccinate (AOT) are studied. The results are
      compared with far-UV circular dichroism (CD) spectra. Both surfactants cause
      similar alterations in the secondary structure of cytochrome c, while their
      influence on the heme environment of cytochrome c is different. In the presence
      of AOT below and above critical micellar concentration a conversion of the low
      spin native cytochrome c to a denatured low-spin protein not having methionine
      ligand takes place. In the presence of SDS micelles conversion of the native
      protein to a denatured mixed-spin form occurs. The changes in the heme group
      induced by both surfactants occur independently of the alterations in tertiary
      structure.

PMID- 10333290
TI  - Apolipoprotein H is not affected by in vitro glycosylation.
AB  - Increased nonenzymatic glycosylation of all major classes of apolipoproteins has
      been demonstrated in diabetes. In this work we deal with the in vitro
      nonenzymatic glycosylation of apolipoprotein H, whose role in lipid metabolism is
      still poorly understood and whose levels increase in diabetes. Apolipoprotein H
      was isolated from human plasma and purified through a combination of affinity
      chromatography and continuous elution electrophoresis. The in vitro glycosylation
      was performed by incubating purified apolipoprotein H with high concentration of
      glucose. Our results indicate that the in vitro nonenzymatic glycosylation has no
      effect on the physical properties of apolipoprotein H, despite the fact that this
      apolipoprotein contains a high number of lysine residues. Since the in vitro
      concentration of glucose was far higher than the levels normally found in
      diabetic subjects, it is unlikely for apolipoprotein H to become glycosylated in
      diabetes.

PMID- 10333291
TI  - Subunit interacting surfaces of human hemoglobin in solution: localization of the
      alpha-beta subunit interacting surfaces on the alpha-chain by a comprehensive
      synthetic strategy.
AB  - By using synthetic overlapping peptides encompassing the entire alpha-chain of
      adult human hemoglobin (HbA), we have mapped on the alpha-chain the regions
      responsible for its binding to the beta-chain in solution. These binding surfaces
      were, in general, in good agreement with those expected from the crystal
      structure (peptides alpha81-95, alpha101-115, alpha111-125, and alpha131-141).
      However, we observed some significant differences in the levels of binding found
      here in solution and those expected from the crystal structure. Peptide alpha31
      45, which in the crystal had the highest number of contact residues of all the
      alpha-chain peptides, did not bind the beta-chain in solution. Similarly, peptide
      alpha91-105, with seven contact residues in the crystal, showed low binding with
      the beta-chain in solution. On the other hand, peptides alpha41-55 and alpha121
      135 possessed much higher binding activity in solution than would be expected
      from their contribution to subunit association in the crystal. In fact, peptide
      alpha121-135 had the highest binding activity of the alpha-chain peptides. These
      studies and our previous findings, which localized on the beta-chain the regions
      that bind to the alpha-chain in solution, have shown that the regions of subunit
      association in solution are close to, but not identical with, those in the
      crystal. The approach should be quite useful for mapping subunit association in
      oligomeric proteins and could even be applied to proteins that are isolated only
      in traces or whose three-dimensional structure is not yet known.

PMID- 10333292
TI  - Biosynthesis and characterization of 4-fluorotryptophan-labeled Escherichia coli
      arginyl-tRNA synthetase.
AB  - Escherichia coli 4-fluorotryptophan-substituted arginyl-tRNA synthetase was
      biosynthetically prepared and purified from a tryptophan auxotroph which could
      overproduce this enzyme. A method was developed to separate 4-fluorotryptophan
      from tryptophan and to determine accurately their contents in the 4
      fluorotryptophan-containing proteins. It was confirmed that more than 95% of the
      tryptophan residues in the purified 4-fluorotryptophan-substituted arginyl-tRNA
      synthetase were replaced by 4-fluorotryptophan. Studies on the effect of the 4
      fluorotryptophan replacement on properties of the enzyme showed that, when
      compared with the native enzyme, both the specific activity and the first-order
      rate constant of the fluorinated enzyme decreased by approximately 20% with just
      slightly higher Km values. CD studies, however, did not reveal any difference
      between the secondary structure of the native and fluorinated enzymes. In
      addition, thermal unfolding studies showed that the 4-fluorotryptophan
      replacement did not significantly affect the thermal stability of the enzyme. We
      may conclude that the substitution of 4-fluorotryptophan in arginyl-tRNA
      synthetase had no substantial effect on the structure and function of the enzyme.
      Finally, a preliminary study of 19F nuclear magnetic resonance spectroscopy of
      the fluorinated enzyme has shown promising prospect for further investigation of
      its structure and function with NMR.

PMID- 10333294
TI  - Binding specificity of hydrolytic catalytic antibody: lessons from the diverse
      immune system.
AB  - The diverse immune system has the potential to provide numerous antibodies that
      catalyze a great variety of reactions and exhibit diversity in mechanism and
      substrate specificity. However, to find such an antibody is not practical, unless
      we understand the immune response precisely and utilize it. We applied an
      alternative screening methodology based on the binding specificity of antibodies
      for the structure of the transition-state analog p-nitrophenyl phosphonate in
      order to study the built-in diversity of the immune response. This study
      uncovered the unpredictable binding and substrate specificity of catalytic
      antibodies derived from the diverse immune response.

PMID- 10333293
TI  - Role of cysteine residues in human plasma phospholipid transfer protein.
AB  - Phospholipid transfer protein (PLTP) belongs to a family of human plasma lipid
      transfer proteins that bind to small amphophilic molecules. PLTP contains
      cysteines at residues 5, 129, 168, and 318. Bactericidal/permeability-increasing
      protein, which is a member of the same gene family, contains an essential
      disulfide bond between Cys135 and Cys175; these residues, which correspond to
      Cys129 and Cys168 in PLTP, are conserved among all known members of the gene
      family. To identify the importance of these and the remaining cysteine residues
      to PLTP secretion and activity, each was replaced by a glycine by site-directed
      mutagenesis. The mutant as well as wild-type PLTP cDNAs were cloned into the
      mammalian expression vector pSV.SPORT1, and the PLTP cDNAs were transfected to
      COS-6 cells for expression. PLTP Cys129 --> Gly and PLTP Cys168 --> Gly were
      secretion incompetent. Neither PLTP mass nor activity was detectable in cell
      lysates and culture medium. Relative to wild-type PLTP, PLTP Cys5 --> Gly and
      PLTP Cys318 --> Gly exhibited similar specific activities but partially impaired
      PLTP synthesis and secretion. Intracellular PLTP appeared as two bands of 75 and
      51 kDa corresponding to reported molecular masses for the glycosylated and
      nonglycosylated forms. The specific activities of PLTP Cys5 --> Gly and PLTP
      Cys318 --> Gly were similar in the cell lysates and medium, suggesting that
      glycosylation does not affect transfer activity.

PMID- 10333295
TI  - Butyrylcholinesterase is complexed with transferrin in chicken serum.
AB  - The function of the enzyme butyrylcholinesterase (BChE) both in serum and in
      brain is unclear. In serum, BChE has been found complexed with several
      biomedically relevant proteins, with which it could function in concert. Here,
      the existence of a similar complex formed between BChE and sero-transferrin from
      adult chicken serum was elucidated. In order to identify both proteins
      unequivocally, we improved methods to highly purify the 81-kDa BChE and the
      coisolated 75-kDa transferrin, which then allowed us to tryptically digest and
      sequence the resulting peptides. The sequences as revealed for BChE peptides were
      highly identical to mammalian BChEs. A tight complex formation between the two
      proteins could be established (a) since transferrin is coisolated along with BChE
      over three steps including procainamide affinity chromatography, while
      transferrin alone is not bound to this affinity column, and (b) since
      imunoprecipitation experiments of whole serum with a transferrin-specific
      antiserum allows us to detect BChE in the precipitate with the BChE-specific
      monoclonal antibody 7D11. The possible biomedical implications of a complex
      between transferrin and BChE which here has been shown to exist in chicken serum
      are briefly discussed.

PMID- 10333296
TI  - Structural and functional studies on the overproduced L11 protein from Thermus
      thermophilus.
AB  - The L11 ribosomal protein from Thermus thermophilus (TthL11) has been
      overproduced and purified to homogeneity using a two-step purification protocol.
      The overproduced protein carries a similar methylation pattern at Lys-3 as does
      its homolog from Escherichia coli. Chymotrypsin digested only a small part of the
      TthL11 protein and did not cleave TthL11 into two peptides, as in the case of
      EcoL11, but produced only a single N-terminal peptide. Tryptic digestion of
      TthL11 also produced an N-terminal peptide, in contrast to the C-terminal peptide
      obtained with L11 from Bacillus stearothermophilus. The recombinant protein forms
      a specific complex with a 55-nt 23S rRNA fragment known to interact with members
      of the L11 family from several organisms. Cooperative binding of TthL11 and
      thiostrepton to 23S rRNA leads to an increased protection of TthL11 from tryptic
      digestion. The similar structural and biochemical properties as well as the
      significant homology between L11 from E. coli and B. stearothermophilus with the
      corresponding protein from Thermus thermophilus indicate an evolutionarily
      conserved protein important for ribosome function.

PMID- 10333297
TI  - Preparative high-resolution two-dimensional electrophoresis enables the
      identification of RNA polymerase B transcription factor 3 as an apoptosis
      associated protein in the human BL60-2 Burkitt lymphoma cell line.
AB  - Apoptosis or programmed cell death is essential in the process of controlling
      lymphocyte growth and selection. We identified RNA polymerase B transcription
      factor 3 (BTF3), which is associated with anti-IgM antibody-mediated apoptosis,
      using a subclone of the human Burkitt lymphoma cell line BL60. To identify the
      transcription factor BTF3, which is expressed only in minor amounts, we used
      preparative high-resolution two-dimensional gel electrophoresis (2DE) employing
      carrier ampholytes for isoelectric focusing. Comparison of the 2DE protein
      patterns from apoptotic and nonapoptotic cells showed BTF3 as a predominantly
      altered protein spot. The characterization of the differentially expressed
      transcription factor and 13 marker proteins described in this study were
      performed by internal Edman microsequencing and/or by peptide mass fingerprinting
      using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS).
      The proteome analysis was significantly improved by performing the newly
      developed preparative high-resolution two-dimensional gels employing high protein
      concentrations.

PMID- 10333298
TI  - Interaction of synthetic peptides from fasciculin with acetylcholinesterase.
AB  - Fasciculins (Fas) are three-looped polypeptides isolated from mamba venom which
      exert their toxic action by inhibiting noncompetitively acetylcholinesterase
      (AChE). A peptide (Fas-D) encompassing the first loop sequence was synthesized
      and characterized chemically, structurally, and functionally. Fas-D possesses an
      intramolecular disulfide bridge, present in the native toxin. Circular dichroism
      (CD) indicated the existence of 21.8% beta-sheet content and 24.2% beta-turn in
      this peptide, compatible with crystallographic data of the native toxin. The
      peptide showed only low partial AChE inhibition at submillimolar concentrations,
      much lower than that observed with Fas and a peptide (Fas-B) encompassing the
      second loop sequence. The simultaneous presence of Fas-D and Fas-B produced an
      additive inhibitory effect on AChE activity; calculated Ki and alphaKi values
      (7.3 +/-2.4 microM and 10.0 +/- 1.8 microM, respectively) were not significantly
      different, thus indicating noncompetitive inhibition. These results are
      consistent with site-directed mutagenesis studies and analysis of the crystal
      structure of the Fas-AChE complex, which indicate that residues from loops I and
      II contribute to Fas binding to the enzyme.

PMID- 10333299
TI  - Stability of some Cactaceae proteins based on fluorescence, circular dichroism,
      and differential scanning calorimetry measurements.
AB  - Characterization of three cactus proteins (native and denatured) from
      Machaerocereus gummosus (Pitahaya agria), Lophocereu schottii (Garambullo), and
      Cholla opuntia (Cholla), was based on electrophoretic, fluorescence, CD (circular
      dichroism), DSC (differential scanning calorimetry), and FT-IR (Fourier transform
      infrared) measurements. The obtained results of intrinsic fluorescence, DSC, and
      CD were dissimilar for the three species of cactus, providing evidence of
      differences in secondary and tertiary structures. Cactus proteins may be situated
      in the following order corresponding to their relative stability: Machaerocereus
      gummosus (Pitahaya agria) > Cholla opuntia (Cholla) > Lophocereu schottii
      (Garambullo). Thermodynamic properties of proteins and their changes upon
      denaturation (temperature of denaturation, enthalphy, and the number of ruptured
      hydrogen bonds) were correlated with the secondary structure of proteins and
      disappearance of alpha-helix.

PMID- 10333300
TI  - Care for kids is care for future. Preventing childhood diseases by stopping
      children's exposure to tobacco smoke.

PMID- 10333301
TI  - From in utero and childhood exposure to parental smoking to childhood cancer: a
      possible link and the need for action.
AB  - The objective of the present work is to critically summarize published studies
      and reassess the state of knowledge on a highly controversial topic: the
      potential association between prenatal exposure to passive smoking as well as
      maternal active smoking and postnatal exposure to environmental tobacco smoke
      (ETS) and enhanced incidence of childhood cancer. Elements to be considered
      include the substantial proportion of pregnant women who remain smokers, the
      widespread nature of exposure to ETS during pregnancy as well as during
      childhood, the known toxicology of tobacco smoke, and in particular sidestream
      smoke, characterized by a rich carcinogen content, the specific metabolism of
      foetuses and new-borns and finally the amount of epidemiologic data already
      available. We conducted a thorough review of the literature to identify studies
      either exclusively dealing with the effects of passive smoking on the occurrence
      of childhood cancers or more generally etiologic studies of cancer, be it overall
      or site-specific. We identified close to 50 publications presenting pertinent
      results from epidemiological investigations and about 50 more on mechanisms and
      metabolism, smoking in pregnancy and exposure to ETS as well as selected reviews
      and commentaries. Collaborative epidemiological studies were conducted in the
      United Kingdom (UK), USA, Sweden, Netherlands and internationally (France,
      Italy). In addition, other studies were also available from the USA, UK, Canada,
      Australia, Sweden, Italy, Denmark and People's Republic of China. The vast
      majority were case-control studies dealing with all cancers, leukaemia and
      lymphomas, central nervous system (CNS) tumours, Wilms' tumour, retinoblastoma,
      neuroblastoma, hepatoblastoma, rhabdomyosarcoma, bone and soft tissues tumours,
      germ cell tumours, as well as specific histological types of leukaemias,
      lymphomas or CNS tumours. No strong association between maternal smoking in
      pregnancy and/or exposure to ETS and childhood cancer is found. Yet, several
      studies found slightly increased relative risks, generally smaller than 1.5, i.e.
      the order of magnitude associated with some recognized hazards of exposure to ETS
      (1.2 to 1.3 for adult lung cancer and cardiovascular diseases). Tumours most
      often found associated with maternal smoking in pregnancy or ETS exposure are
      childhood brain tumours and leukaemia-lymphoma, with risks up to two or greater
      in selected studies. In a few studies, risks associated with paternal smoking are
      higher than the maternal ones. This evidence from human studies coupled with
      demonstration of genotoxic effects on the foetus of exposure to metabolites of
      tobacco smoke, and demonstrable presence of adducts should lead to strong
      recommendations aiming at fully protecting foetuses, new-borns and infants from
      tobacco smoke.

PMID- 10333302
TI  - Passive smoking, sudden infant death syndrome (SIDS) and childhood infections.
AB  - 1. A number of cohort and case-control studies have shown clear, dose-related
      associations between maternal smoking and infant death. The strongest
      relationships were found when the mother smoked during pregnancy as well as
      postnatally. Maternal smoking during pregnancy increases the risk for SIDS in
      most studies, whereas it appears that maternal smoking only postnatally also
      leads to an increase in risk. In addition, smoking only by the father appears to
      increase the risk for SIDS, but this is not seen in all studies. 2. Exposure of
      children to environmental tobacco smoke (ETS) increases the risk of having night
      cough and respiratory infections (bronchitis, bronchiolitis, pneumonia),
      especially during the first 2 years of life. An increased risk is also seen in
      studies not distinguishing between upper and lower respiratory diagnoses. Long
      term breastfeeding may have a protective effect on ETS-increased risk of lower
      respiratory tract illness. One study of older children reports that ETS combined
      with allergy increased the risk of acute respiratory tract infections above that
      due to ETS alone. 3. The number of new episodes and duration of otitis media with
      effusion in young children is positively correlated with ETS exposure. Especially
      infants with lower birth weights had a high risk of recurrent otitis media during
      the first year of life when the mother was a heavy smoker. 4. Passive smoking has
      been reported as a risk factor in meningococcal disease and tuberculosis in young
      children.

PMID- 10333303
TI  - Perinatal sidestream cigarette smoke exposure and the developing pulmonary
      surfactant system in rats.
AB  - 1. Epidemiological studies have strongly implicated passive smoking with
      increased incidence of various respiratory diseases in children. Our earlier
      studies have shown that chronic exposure to tobacco smoke significantly changes
      the composition and the surface activity of the pulmonary surfactant in adult
      rats. The aim of the present study was to determine if perinatal exposure to
      sidestream cigarette smoke influences the composition and function of pulmonary
      surfactant system in developing rat pups. 2. Pregnant Sprague Dawley rats were
      exposed to sidestream cigarette smoke in a whole body exposure chamber for a
      total of 6 h each day and the pups born to these dams were further exposed to
      sidestream smoke for 2 h/day during postnatal period. Exposure of animals to
      smoke was ascertained by measuring their plasma cotinine. Surfactant analysis was
      performed on bronchoalveolar lavage fluids (BALF) collected from pups on
      postnatal day 1, 3, 7, 14, 21 and 35. The phospholipid (PL) content, percentage
      disaturated phosphatidylcholine (DSPC) and surfactant proteins (SP-A and SP-B) in
      BALF surfactant preparations from sham and smoke-exposed pups were compared. 3.
      Significant differences between the two groups were observed at two exposure
      points: a reduced level of SP-A on day 1, and, a higher level of SP-A and PLs on
      day 21, in smoke-exposed pups. Surface activity analysis of the surfactant films
      by pulsating bubble surfactometer did not show any significant differences
      between the sham and smoke-exposed groups at any exposure point. 4. The results
      indicate that perinatal exposure to sidestream smoke is capable of producing
      biochemical changes in the composition of pulmonary surfactant at different
      stages of development but these changes do not influence surface tension reducing
      properties of the surfactant.

PMID- 10333304
TI  - Passive smoke exposure in infants and children with respiratory tract diseases.
AB  - 1. The adverse effect of passive smoke exposure on the respiratory tract,
      particularly in infants and children, is not an issue of dispute. It was the
      objective of this study to analyse the extent and the intensity of passive smoke
      exposure in infants and children with respiratory tract diseases, and compare the
      information obtained with parents' subjective assessment. At the time of
      admission to the hospital, the parents of 295 infants and children (aged 1 month
      to 11 years) were questioned by the physician as to the smoking habits in the
      families' homes. An HPLC method was employed to determine simultaneously
      nicotine, cotinine and trans-3'-hydroxycotinine in the children's urine. 2. The
      sum of the nicotine metabolites turned out to be a sensitive marker in
      determining passive smoke exposure. Measurements revealed passive smoke exposure
      in 66% of the children, the frequency in younger children being significantly (P
      < 0.001) higher than in children over 5 years (84% vs 52%). The average
      concentration of nicotine metabolites in younger passive smokers was
      significantly (P < 0.001) higher when compared to the older ones (193 nmol/l vs
      86 nmol/l). Forty-nine per cent of the parents assessed that their children had
      experienced passive smoke exposure, and another 10% emphasised that they only
      smoked in the absence of their child. In children with cystic fibrosis and
      bronchial asthma, the number of passive smokers as assessed by their parents were
      lower by 65% and 29% respectively when compared to the findings obtained from
      measurements. In children without respiratory diseases, the difference was as
      little as 18%. 3. Parents when questioned in conjunction with an illness of their
      children, tended to understate, or even withhold the truth about, passive smoke
      exposure. Therefore, reliable information on passive smoke exposure of patients
      can only be obtained through objective measurements.

PMID- 10333305
TI  - Passive smoking and respiratory symptoms in primary school children in Hong Kong.
      Child Health and Activity Research Group (CHARG).
AB  - 1. We aimed to study whether passive smoking is associated with respiratory ill
      health in primary school children in Hong Kong. 2. In this cross-sectional study,
      a standardised structured questionnaire was used to obtain information on
      respiratory symptoms, smokers in the household and smoking habit of the children.
      A random sample of 30 primary schools was included. Four classes were randomly
      selected for each school, one class each from each school year of primary 3-6. A
      total of 3964 children aged 8 - 13 years completed the questionnaire during
      October 1995-May 1996. The response rate was over 94%. 3. In 3480 children who
      had never smoked, after adjusting for gender, age, place of birth and living
      district, the odds ratios (95% confidence interval) were: (a) throat problems,
      1.35 (1.08-1.68); (b) cough, 1.54 (1.28-1.84); (c) phlegm, 1.43 (1.21-1.70); (d)
      wheezing, 1.21 (0.89-1.41); (e) nose problems, 1.17 (1.02-1.35). The odds ratios
      increased with increasing number of smokers at home (P for trend < 0.001; except
      for wheezing, P=0.3). The odds ratios for having any of the above symptoms for
      one, two and three smokers at home were respectively 1.15 (0.99-1.34), 1.48 (1.16
      1.88) and 2.03 (1.47 - 2.81); P for trend < 0.001. 4. We conclude that the
      results provide further evidence that passive smoking is a cause of respiratory
      ill health in school children in Hong Kong.

PMID- 10333306
TI  - Passive smoking exposure of sick children in Hong Kong.
AB  - 1. This study aims to investigate the extent of passive smoking exposure of sick
      children in Hong Kong; their father's smoking behaviors and their mother's action
      to protect the child from environmental tobacco smoke (ETS). 2. This cross
      sectional survey was the first phase of a randomized controlled trial on a health
      education intervention provided by nurses in the general paediatric wards of four
      major hospitals in Hong Kong. The subjects are non-smoking mothers of sick
      children admitted to hospital and with a smoking husband living together in the
      same household with the child. Eligible subjects completed a self-administered
      baseline questionnaire before entering into the trial. 3. All the 848 children
      whose mothers completed the questionnaire during December 1997 to April 1998 had
      a smoking father. They constituted about 24% (95% CI: 22.6-24.9%) of all the sick
      children during the same period. More than half of the children's fathers (55%;
      51.6-58.3%) smoked 1-14 cigarettes per day and about 68% (64.7-71.0%) of them
      were daily smokers for over 10 years. Over half (53%; 49.4-56.2%) of the fathers
      smoked 1-14 cigarettes at home every day. About 21% of the fathers smoked near
      the child occasionally and 31% (27.4-33.6%) smoked 1-14 cigarettes near the child
      per day. About 16% of the children lived with more than one smoker (2-3). About
      86% (83.3-88.0%) of the children had 1-3 smokers who smoked at home and 61% (58.1
      - 64.7%) of them had 1-3 smokers who smoked near them every day. However, 70% of
      the children were reported by their mothers as exposed to ETS at home. This
      percentage (70%) was less than the percentage (86%) of smokers who smoked at home
      daily. About 31.1% of the mothers reported symptoms of coughing and running nose
      (20.6%) in their children when they were exposed to ETS. To protect the child
      from ETS exposure, 43% of the mothers requested the father not to smoke near the
      child, 33.1% requested the father to smoke less cigarettes and 31.5% advised the
      father to quit smoking. 4. In conclusion, sick children in Hong Kong are at risk
      of exposure to ETS, but not all mothers are aware of the health risks and their
      actions were inadequate. There is a critical need to promote awareness of ETS
      exposure and the health risks in the family in Hong Kong so as to reduce illness
      and hospital admission in children.

PMID- 10333307
TI  - Passive smoking among adolescents in Estonia.
AB  - 1. The objective of this study was to assess prevalence and patterns of passive
      smoking in Estonia and to describe how environmental tobacco smoke is likely to
      initiate the desire in adolescents to start active smoking. 2. A population
      sample of 2170 students within the age groups of 13-14, 15-16 and 17-18 of school
      grades 8, 10 and 12, respectively, at Tallinn High Schools participated in this
      study. The data were collected using questionnaires which mainly consisted of
      structured multiple-choice and a few open questions. 3. Every fourth adolescent
      in Tallinn was either an occasional or a habitual smoker. 4. Nearly half (48%) of
      the respondents had no daily exposure to cigarette smoke. Almost one third (31%)
      was exposed daily for less than 1 h, 15% for 1-5 h and 6% for over 5 h a day. 5.
      The number of adolescent smokers was higher than non-smokers among those daily
      inhaling tobacco sidestream smoke. 6. In conclusion, environment gives
      considerable impact to the development of smoking habits among adolescents.
      Passive smoking as an inducing factor is associated with higher prevalence of
      smoking among the adolescents studied.

PMID- 10333308
TI  - Mainstream and sidestream cigarette smoke condensates suppress macrophage
      responsiveness to interferon gamma.
AB  - Sidestream smoke evolves from the smoldering end of a cigarette while the smoker
      is not puffing, and contributes substantially to environmental tobacco smoke
      (ETS). In contrast, main stream smoke emerges from the butt end of the cigarette
      and is mainly inhaled by the smoker. This study was performed to compare the
      effects of short-term exposure to cigarette smoke condensates prepared from
      sidestream (CSC-SS) and mainstream cigarette smoke (CSC-MS) on macrophage basal
      metabolism and responsiveness to two different stimuli, bacterial
      lipopolysaccharide (LPS) and interferon gamma (IFNgamma). Despite their
      generation at different temperatures and their different chemical composition,
      CSC - SS and CSC - MS had similar effects on macrophages. Both enhanced
      macrophage basal metabolism and responsiveness to LPS. Macrophage responsiveness
      to IFNgamma, assessed by their expression of four functional capacities, was
      suppressed by both CSC-SS and CSC-MS. The four assessed IFNgamma-inducible
      functional capacities were: enhanced phagocytosis of immuoglobulin-opsonized
      sheep red blood cells, TPA-induced peroxide production, class II major
      histocompatibility complex expression, and nitric oxide synthesis with LPS co
      stimulation. The effects of CSC - SS and CSC - MS were similar qualitatively;
      they differ quantitatively in some cases, with CSC-MS generally effective at
      lower concentrations (expressed as cigarette-equivalents) than CSC-SS.
      Considering dilution of sidestream smoke in room air and loss during passage
      through the respiratory system, we expect to deliver the maximal dose to lung
      macrophages in situ only in rooms dense with smokers. However, only a fraction of
      the maximal dose can partially suppress induction of some functions, such as
      nitric oxide production and MHC expression. Macrophages play critical roles in
      tissue modeling during development. Of particular concern are neonates, whose
      organs are still undergoing growth and development, and are therefore susceptible
      to impaired development. If involuntary exposure to ETS hinders induction of
      macrophage functional capacities by cytokines, then development of the lungs and
      perhaps other organs would be impaired. In general, since macrophages are potent
      effectors and regulators of immunity, impairment of their responsiveness to
      cytokine must disrupt the proper functioning of the immune system.

PMID- 10333309
TI  - The association between pre- and postnatal tobacco smoke exposure and allergic
      sensitization during early childhood. Multicentre Allergy Study Group, Germany.
AB  - AIM: of our study was to investigate the effect of pre- and postnatal passive
      tobacco smoke exposure on the incidence of allergic sensitization. PATIENTS AND
      METHODS: Specific sensitization to food, outdoor and indoor allergens was
      determined in 342 children at the age of 1, 2 and 3 years. Parents were asked
      about their smoking habit at the birth of their children, at 18 months and 3
      years of age. RESULTS: Multivariate regression analysis indicated, that during
      the first 3 years of life, pre- and postnatally exposed children had a
      significantly higher risk for sensitization to food allergens compared to
      children never exposed to tobacco smoke (OR 2.2, 95% CI 1.1-4.2; P = 0.02). With
      respect to inhalant allergens no significant influence of tobacco smoke exposure
      on specific sensitization could be demonstrated. CONCLUSION: During early
      childhood both pre- and postnatal tobacco smoke exposure has an adjuvant effect
      on allergic sensitization to food allergens.

PMID- 10333310
TI  - The experimental investigations of the toxic influence of tobacco smoke affecting
      progeny during pregnancy.
AB  - 1. Tobacco smoke contains around 4000 substances, most of which are described as
      toxic, and they may have an influence on the development of progeny. 2. The
      present studies concentrate on the measurement and calculation of indices
      describing the new-born's survival, rearing of pups, weight of foetuses, young
      animals, placenta and females in relation to different doses of tobacco smoke
      (carbon monoxide levels). The morphological studies of placenta, foetal and
      newborn lungs were done as a supplement. Biochemical placenta study was also
      done. 3. The results of the experiment proved that some indices for animals in
      groups which were passively exposed to the highest concentrations of tobacco
      smoke were lower, others fluctuated (4 day, 12 day and total survival) and some
      did not reveal any changes (rearing). Direct correlation between maternal passive
      exposure to tobacco smoke and the presence of acute respiratory distress syndrome
      symptoms in new-borns was observed. A decrease of body weight of pregnant females
      passively exposed to tobacco smoke was also observed. An increase of placenta
      foetal factor was found. A decrease of rat weight was observed after passive
      exposure to tobacco smoke. 4. We concluded that there is correlation between
      passive exposition to tobacco smoke during pregnancy and delayed lung maturation
      in the offspring. Exposure of the pregnant rats to cigarette smoke increases the
      activity of isocitric and glucose-6-phosphate dehydrogenases in placenta.

PMID- 10333312
TI  - Maternal passive smoking during pregnancy and foetal developmental toxicity. Part
      2: histological changes.
AB  - 1. Evidence has been accumulating on the growth suppressing effects of maternal
      passive smoking on foetus. Reviewing all literature released during the last two
      decades and screening for all possible variables such as previous smoking
      history, maternal age and weight gain, parity and length of gestation, placental
      weight, and diet, we found no reason to doubt the role of passive smoking during
      pregnancy in the induction of growth retardation. However, no literature
      indicates whether these birthweight deficits might hint at other possible hidden
      abnormalities in tissues. To verify this question, we performed an experiment on
      rats. 2. We have already reported that pups born to rats with previous exposure
      to cigarette's sidestream smoke during pregnancy showed a significant and dose
      dependent growth retardation. Those pregnant rats were exposed each in a 150 dm3
      glass chamber to diluted sidestream smoke of either 1, 2, 3 or 4 commercial blond
      filter brand cigarettes during either first, second or third week of pregnancy.
      We have selected a part of each group of pups at random and examined for possible
      histological changes of lung, liver, stomach, kidney and intestinal tissues. 3.
      Compared to controls, lung tissues of newborns of smoke exposed mothers showed an
      enhanced incidence of apoptosis, mesenchymal changes, and hyperplasia of
      bronchial muscles. Pronounced abnormal changes in haematopoiesis and
      proliferation of bile duct cells were the most variations from norm observed in
      liver tissues of exposed pups. Immature glomeruli of kidney, epithelhypoplasia of
      stomach, and hypoplasia of intestinal villi were common among newborns of exposed
      mothers than among controls. 4. These results indicate that passive smoking upon
      pregnancy causes abnormal morphological changes in internal tissues of newborns.
      At present, we can draw no conclusion as to whether these histological changes
      will result in functional malformations or possibly late effects, although they
      should be expected.

PMID- 10333311
TI  - Maternal passive smoking during pregnancy and fetal developmental toxicity. Part
      1: gross morphological effects.
AB  - 1. Prenatal exposure of human fetus to tobacco smoke through maternal passive
      smoking has been epidemiologically linked to reduced birth weight, enhanced
      susceptibility to respiratory diseases and changes in immune system. However, no
      data exists indicating teratogenicity of involuntary smoking. Since sidestream
      smoke of cigarettes makes the most constituent of whole smoke inhaled by
      nonsmokers, we performed experiments to determine whether passive inhalation of
      sidestream smoke by rats causes malformations in newborns. 2. Pregnant 230 - 300
      g Wistar rats were each placed in a 150 dm3 glass chamber with two holes, each 3
      cm in diameter in two opposite walls to provide unforced exchange of fresh air. A
      third hole was connected to an automatic smoking machine. The head of a
      commercial filter blond cigarette (13 mg Tar, 0.9 mg Nicotine) was introduced to
      the chamber through this later hole. Cigarettes were smoked by smoking machine at
      the rate and volume resembling human smoking and the mainstream smoke was
      separately collected and discarded. Each rat thus received the sidestream smoke
      self-diluted in the chamber air. Experiments were performed with either 1, 2, 3
      or 4 cigarettes/day during either first, second or third week of a total 21-day
      pregnancy period. The interval between smoking of cigarettes was 2 h. 3. COHb in
      blood of negative controls was about 1.2% and after exposure to 1 or 4 cigarettes
      were 6% and 12.2%, respectively. A dose-dependent reduction of birth weight was
      observed in newborns (P<0.001); bitemporal diameters and body lengths were
      reduced accordingly. No macroscopically visible gross anomaly could be observed.
      After removing the fat tissue and staining the skeleton with alizarin, a
      widespread ossification retardation could be observed in all exposed groups
      regardless of the dose. Such a retardation was not limited to a particular bone.
      4. These results support epidemiologic data on developmental toxicity of passive
      smoking and further provide evidence on an unfavorable osteopathic effect of
      sidestream exposure of mother on fetal development.

PMID- 10333313
TI  - Passive smoking and pregnancy outcome in central Poland.
AB  - 1. The present investigation was undertaken to evaluate the effect of
      environmental tobacco smoke (ETS) on the risk of preterm delivery (PD) and small
      for-gestational age (SGA) infants in a female non-smoking population of central
      Poland. 2. The study group were 1751 women classified as non-smokers in the
      comprehensive project on 'Socio-economic and environmental risk factors of
      preterm delivery and small-for-gestationaI-age babies in central Poland'
      conducted on a randomly selected population of 2080 women who gave birth to a
      child between June 1, 1996 and May 31, 1997. The PD group comprised 95 non
      smoking women who delivered before 37 weeks of pregnancy and the SGA group
      included 111 non-smoking mothers of babies with birthweight below the 10th
      percentile of the standard curves for central Poland. Passive exposure to tobacco
      smoke was determined based on a structured interview. 3. In the stepwise multiple
      logistic regression model maternal passive smoke exposure lasting 7 h or more was
      found to be a significant risk factor for preterm delivery. No significant effect
      of passive smoking on the risk of SGA was observed. 4. The information about the
      adverse effects of ETS exposure on pregnancy duration and outcome should be
      incorporated in the health promotion programmes for women.

PMID- 10333314
TI  - An experimental study of the influences of tobacco smoke on fertility and
      reproduction.
AB  - 1. The aim of this study was to evaluate the toxicological influence of tobacco
      smoke on fertility and reproduction of Wistar female rats. The influence of
      tobacco smoke from the Polish 'Popularne' cigarette brand was studied. The
      experiment was conducted on three generations of animals, each generation having
      two litters. The initial number of animals of the parent generation F0 was 192
      (128 females and 64 males). Animals were passively exposed to tobacco smoke in
      three different concentrations based on the content of carbon monoxide (500, 1000
      and 1500 mg of CO per cubic meter of air). Animals were exposed to tobacco smoke
      for 6 h a day, 5 days a week, during 11 weeks. 2. The analysis of indices of
      mating and fertility revealed the decrease in those indices with animals exposed
      to tobacco smoke. We also observed an increased number of mothers breading among
      animals exposed to tobacco smoke. In animals exposed to tobacco smoke, the dose
      effect or dose-response dependencies for mating, fertility and delivery indices
      were found. There was no influence of tobacco smoke on the duration of pregnancy.
      3. Tobacco smoke inhalation caused increased levels of carboxyhaemoglobin. 4.
      Tobacco smoke did not change the duration of pregnancy in rats.

PMID- 10333315
TI  - Hair analysis--a biological marker for passive smoking in pregnancy and
      childhood.
AB  - Passive smoking has been shown to adversely affect the health of infants and
      children. We used hair analysis for nicotine and its metabolite cotinine as a
      biological marker for exposure to smoking in these two groups. Using
      radioimmunoassay we measured maternal and fetal hair concentrations of nicotine
      and cotinine in the mother-infant pairs belonging to three different groups based
      on the mother's smoking habits. The three groups were: active smokers, passive
      smokers and nonsmokers. There was a significant correlation between maternal and
      neonatal hair concentration for both, nicotine and cotinine. Mothers and infants
      in the smoking groups, both active and passive, had significantly higher hair
      concentrations of both, nicotine and cotinine than in the control, nonsmoking
      group. In an older cohort, we compared two groups: 78 asthmatic children were
      compared to 86 healthy children exposed to similar degrees of passive smoking. By
      using objective, biological markers, our study aimed at verifying whether
      asthmatic children are different from nonasthmatic children in the way their
      bodies handle nicotine. Our results show, that, despite the fact that parents of
      asthmatic children tend to smoke a lower number of cigarettes per day, their
      children had an average twofold higher concentrations of cotinine in their hair
      then the control, nonasthmatic children. These studies document the importance of
      hair analysis as a tool for measuring exposure to cigarette smoke.

PMID- 10333316
TI  - Cotinine in meconium indicates risk for early respiratory tract infections.
AB  - 1. In order to identify potential risks for lower respiratory tract symptoms
      during early infancy, the concentration of cotinine was measured in meconium of
      91 newborns as a parameter of prenatal exposure to tobacco, and a questionnaire
      was performed with parents at birth. Infants were followed up for the first year
      of life by monthly telephone interviews. 2. Lower respiratory tract infections
      during the first 6 months of life were associated with a high concentration of
      cotinine in meconium (cotinine higher than median vs lower than median; odds
      ratio 4.9, 95% confidence interval 1.2 to 20.3), while none of the other
      variables tested including selfreport of parental, prenatal or postnatal tobacco
      consumption, parents history of atopy, maternal age, presence of siblings, socio
      economic status, duration of gestation, birth weight, gender, and duration of
      breast feeding were identified as independent risks. The occurrence of a lower
      respiratory tract infection during the first 6 months of life was predicted
      correctly in 77% of the infants by a cotinine excretion in meconium exceeding the
      group median. 3. In conclusion, quantification of cotinine in meconium is
      preferred to historical parameters as an estimate of the risk for early
      respiratory tract infections.

PMID- 10333317
TI  - Low level saliva cotinine determination and its application as a biomarker for
      environmental tobacco smoke exposure.
AB  - 1. The determination of personal exposures to environmental tobacco smoke (ETS)
      and respirable suspended particles (RSP) for housewives, and fixed site
      monitoring of their homes, have been undertaken by these authors throughout
      Europe, South East Asia and Australia. Median 24 h time weighted average (TWA)
      concentrations for ETS particles and nicotine were found to be significantly
      higher for housewives living in smoking households compared with those living in
      nonsmoking households. For Europe, median TWA concentrations of 4.1 and <0.26
      microg/ml for ETS particles and 0.63 and < 0.08 microg/m3 for nicotine were found
      for housewives living in smoking and nonsmoking households respectively. 2. In
      addition to the measurement of RSP, ETS particles and nicotine, saliva cotinine
      concentrations were determined using a radioimmunoassay method with a limit of
      quantitation of 1 ng/ml. Median saliva cotinine concentrations of 1.4 and <1
      ng/ml were determined for European housewives living in smoking and nonsmoking
      households respectively, which reflected the poor limit of quantitation of this
      methodology. A chromatographic method utilising tandem mass-spectrometric
      detection was developed and validated for the determination of both cotinine and
      3-hydroxycotinine, two of the main metabolites of nicotine, with lower limits of
      quantitation of 0.05 and 0.10 ng/ml respectively. This method was applied to
      samples collected from subjects with a known ETS exposure history and median
      cotinine concentrations of <0.05 ng/ml for self-reported unexposed nonsmokers,
      0.65 ng/ml for nonsmokers reporting some ETS exposure and 1.28 ng/ml for
      nonsmokers living with smokers were found. 3. In conclusion, the measurement of
      RSP and ETS concentrations derived from personal or fixed site monitors for
      housewives may provide some indication of potential exposures to dependent
      children. The recent development and application of a highly sensitive assay for
      the determination of cotinine in saliva has provided evidence to suggest that
      concentrations determined at sub-nanogram levels may be used as a biomarker for
      ETS exposure. This improved methodology, coupled with non-invasive sampling for
      saliva, may be of significance when considering the application of cotinine as a
      biomarker for ETS exposure in children.

PMID- 10333318
TI  - Assessment of the exposure of children to environmental tobacco smoke (ETS) by
      different methods.
AB  - 1. In order to elucidate the role of exposure to environmental tobacco smoke
      (ETS) in various acute and chronic illnesses in children, it is important to
      assess the degree of exposure by suitable methods. For this purpose, we
      determined the exposure to ETS in 39 children (4-15 years) and 43 adults (16+
      years) by questionnaires, personal diffusion samplers for nicotine, and cotinine
      measurements in saliva and urine. In addition, the influence of the smoking
      status and the location of the home (urban or suburban) on the benzene exposure
      of the children was investigated. 2. On average, the 24 children living in homes
      with at least one smoker were exposed to ETS for 3.1 h/d. This is significantly
      longer (P<0.001) than the daily exposure time of the 15 children from nonsmoking
      homes (0.3 h/d). The nicotine concentrations on the personal samplers worn over 7
      days were 0.615 and 0.046 microg/m3 for children from smoking and nonsmoking
      homes, respectively (P<0.001). Average salivary cotinine levels were 1.95 ng/ml
      in children from smoking homes and 0.11 ng/ml in children from nonsmoking homes
      (P< 0.01). The corresponding urinary cotinine levels were 29.4 and 4.5 ng/mg
      creatinine (P< 0.001). There was no difference in the extent of ETS exposure
      between children and adults from smoking households. Adults from nonsmoking homes
      tended to have higher ETS exposure than children from nonsmoking homes. 3.
      Exposure to benzene, which was determined by means of personal samplers,
      measurements of benzene in exhaled air and of the urinary benzene metabolite
      trans, trans-muconic acid, was not significantly related to the smoking status of
      the home but primarily dependent on the location of the home.

PMID- 10333319
TI  - Bisquinoline antimalarials: their role in malaria chemotherapy.
AB  - Quinoline compounds, such as chloroquine, are used widely to treat malaria;
      however, the malarial parasite is rapidly becoming resistant to the drugs
      currently available. Presently, rational drug design is hindered considerably due
      to the mode of action of chloroquine being poorly understood. We rely on
      serendipity, rather than solid structural evidence, to generate new
      antimalarials. Hence any insight into the possible modes of action of quinoline
      antimalarials, including the bisquinolines, would greatly aid rational drug
      design. The quinoline antimalarial drugs, chloroquine, quinine and mefloquine,
      are thought to act by interfering with the digestion of haemoglobin in the blood
      stages of the malaria life-cycle. These quinoline antimalarials traverse down the
      pH gradient to accumulate to millimolar concentrations in the acidic vacuole of
      the parasite. It has been suggested that this high intravacuolar concentration
      prevents haem sequestration, causing a build up of the toxic haem moiety and the
      death of the parasite by its own toxic waste. The actual mechanism by which the
      parasite sequesters haem and the drug target(s) during this process, however,
      still remains elusive. As a consequence, haem polymerisation and the efficiency
      of quinoline antimalarials, including the bisquinolines, as inhibitors of this
      process has been investigated. In this paper, the potential role of the
      bisquinolines in the fight against chloroquine-resistant malaria is addressed.

PMID- 10333320
TI  - The importance of systematics in parasitological research.
AB  - The discipline of systematics plays a central role in all branches of biology. In
      today's technology-orientated research world, it is important to realise the
      continuing value of systematics, the basic tenet of which is to combine diverse
      types of data to produce classifications that reflect the natural history of
      living organisms. Accurate classification systems are crucial in the field of
      parasitology, not only because they provide the means to identify species and
      strains of parasites, but also because they provide a framework around which a
      parasite's biology can be studied. The construction of such a classification
      system is often hampered by the parasite's biology, which may preclude the
      application of traditional techniques or concepts (such as morphological
      differentiation or the biological species concept) to delineate species. It is
      often the case that these difficulties can be overcome by the use of molecular
      systematic techniques. In this paper, it is proposed that a detailed
      understanding of the phylogeny of a group of organisms can be used as a basis to
      examine other aspects of their systematics. This is illustrated using the
      protozoan parasite Giardia intestinalis. Data gathered using the complementary
      techniques of allozyme electrophoresis and nucleotide sequencing have been used
      to infer the phylogenetic relationships of G. intestinalis isolated from various
      host species. The results, supported by biological data, suggest that G.
      intestinalis is a species-complex. As we move towards the year 2000, molecular
      systematics will play an increasingly important role in elucidating host-parasite
      relationships. However, its use as a taxonomic tool will require a general
      acceptance by parasitologists and the adoption of formal procedures to allow the
      description of new species by these methods. The aim of this approach is not to
      dismiss traditional methods, but to use them in combination with contemporary
      methods in the true spirit of the discipline of systematics.

PMID- 10333322
TI  - Grooming decisions by damselflies, age-specific colonisation by water mites, and
      the probability of successful parasitism.
AB  - We examined whether host damselflies (Ischnura verticalis) in different stages of
      development were differentially susceptible to parasitism by larval water mites
      (Arrenurus pseudosuperior). We found that mites were successful in reaching the
      parasitic phase more often if they colonised hosts closer to emergence. Thus, we
      predicted that more mites should colonise damselflies closer to emergence and
      damselflies closer to emergence should spend more time defending against mites.
      We found that mites colonised damselflies closer to emergence in one of two
      experiments, but that damselflies in different stages of development did not
      differ in time spent defending against mites.

PMID- 10333321
TI  - Peroxide-supported in-vitro cytochrome P450 activities in Haemonchus contortus.
AB  - The potential for cytochrome P450 from Haemonchus contortus to operate in the
      oxygen-poor intestinal environment was investigated by examining the ability of
      the cytochrome to act in vitro as a peroxygenase in utilising cumene
      hydroperoxide for substrate oxidations not requiring molecular oxygen.
      Peroxygenase and NADPH-supported monooxygenase activities were measured in
      microsomes prepared from L3 and adult nematodes. Both cumene hydroperoxide- and
      NADPH-supported ethoxycoumarin O-deethylase and aldrin epoxidase activities were
      detected in larval microsomes. Adult microsomes showed low levels of cumene
      hydroperoxide-supported ethoxycoumarin O-deethylase, as well as NADPH- and cumene
      hydroperoxide-supported aldrin epoxidase activities. The use of inhibitors in
      ethoxycoumarin O-deethylase assays with larval microsomes indicated that the
      peroxygenase pathway does not proceed via ferrous cytochrome P450 (no inhibition
      by carbon monoxide), did not require molecular oxygen, and did not depend on
      electron flow from cytochrome P450 reductase. Larval activity was inhibited by
      typical cytochrome P450 inhibitors (piperonyl butoxide, SKF-525A,
      chloramphenicol, metyrapone, n-octylamine) and was unaffected by the peroxidase
      inhibitor salicylhydroxamic acid. In contrast, adult microsomal cumene
      hydroperoxide-supported ethoxycoumarin O-deethylase activity was significantly
      inhibited by both cytochrome P450 inhibitors and salicylhydroxamic acid. Adult
      microsomes also contained potassium ferrocyanide peroxidase activity utilising
      cumene hydroperoxide. This activity showed a similar pattern of inhibition by
      both cytochrome P450 and peroxidase inhibitors. Whilst the ability of larval H.
      contortus cytochrome P450 to act as a peroxygenase in vitro was demonstrated, the
      inhibition results with adult microsomes showing both cytochrome P450 and
      peroxidase activities require further investigation to clarify the nature of the
      adult microsomal cumene hydroperoxide-supported O-deethylase activity.

PMID- 10333323
TI  - The effect of azadirachtin on Blastocrithidia triatomae and Trypanosoma cruzi in
      Triatoma infestans (Insecta, Hemiptera).
AB  - The effect of azadirachtin on Blastocrithidia triatomae and Trypanosoma cruzi,
      which colonise the intestinal tract of the blood-sucking bug Triatoma infestans,
      was investigated. In established infections of controls without azadirachtin
      treatment, the small intestine of fifth-instar T. infestans contained up to 7 x
      l0(6) B. triatomae and the rectum 3 x 10(6). In comparison to this homoxenous
      flagellate, the population densities of T. cruzi in the respective regions were
      99.3 and 76% lower. Treatment with azadirachtin (1 microg ml(-1)) via a blood
      meal and a concurrent infection with B. triatomae resulted in an increase of the
      population density (3 weeks p.i.), caused mainly by the mastigote stages in the
      rectum. In an established B. triatomae infection (12 weeks p.i.), feeding of
      azadirachtin did not affect the population density and composition. In an optimal
      T. cruzi-vector system, i.e. parasite and bug originate from the same locality,
      the treatment with azadirachtin at 20 weeks p.i. strongly reduced the population
      density in the small intestine of all bugs up to 100 days after treatment, but
      only in a minor percentage of the bugs in the rectum. Trypanosoma (cruzi
      incubated for up to 24 h in faeces of azadirachtin-treated bugs were not
      affected, indicating that the rectum of these bugs contained no toxic substances.
      The importance of these findings is that investigations of the mechanisms of
      action of azadirachtin offer a possibility to identify vector-derived compounds,
      which are necessary for the development of T. cruzi, thereby, giving us a
      possible new strategy to combat Chagas' disease.

PMID- 10333325
TI  - Actinosporeans (Myxozoa) with four developing spores within a pansporocyst:
      Tetraspora discoidea n.g. n.sp. and Tetraspora rotundum n.sp.
AB  - Two species of marine actinosporeans with spores that develop in groups of four
      rather than eight within a pansporocyst are described. In other respects,
      including triradial symmetry, three polar capsules each enclosing a coiled polar
      filament, parasitic in invertebrates, they conform with other actinosporeans.
      Both new species were found in the coelom of tubificid oligochaetes collected
      from Moreton Bay, Queensland, Australia. Spores of Tetraspora discoidea n.g.
      n.sp. are disc-like, almost round in apical view and dorso-ventrally compressed
      in side view, whereas spores of Tetraspora rotundum n.sp. are spherical. The
      novel development of these two marine actinosporeans may signify other variations
      in the life-cycles of marine Myxozoa.

PMID- 10333324
TI  - Schistosoma bovis: vaccine effects of a recombinant homologous glutathione S
      transferase in sheep.
AB  - The economic importance of the trematode Schistosoma bovis in African livestock
      has justified the development of a specific vaccine. Administered preventively to
      sheep, rSb28GST--the only molecule cloned from S. bovis which has demonstrated
      vaccine potentialities in goats and cattle--reduced the mean worm burden in
      vaccinated animals and improved their health status compared with that of non
      vaccinated controls. As in goats, but not in bovines, the fecundity of the
      settled worm pairs was not modified. Therefore, rSb28GST can be proposed as a
      universal tool for the prevention of clinical disorders engendered by the main
      schistosome species affecting domestic ruminants in the African continent.

PMID- 10333326
TI  - Human antibody responses to Brugia malayi antigens in brugian filariasis.
AB  - Human antibody responses to Brugia malayi antigens were studied with sera from a
      Brugia endemic area in South India. Patients with clinical filariasis had
      significantly higher IgE and lower IgG4 levels to adult worm antigens than people
      with asymptomatic microfilaraemia. Intermediate antibody levels were observed in
      endemic normals. A majority of sera from each clinical group contained IgG
      antibodies to surface antigens of infective larvae (L3) by IFAT. IgG immunoblot
      studies did not reveal group differences in L3 antigen recognition. IgE
      antibodies bound to a subset of antigens bound by IgG. IgE antibodies in sera
      from clinical filariasis patients preferentially bound to L3 antigens at 200, 97,
      68 and 58 kDa compared with sera from microfilaria carriers. These results are
      consistent with prior studies of antibody responses in filariasis and add new
      information on the targets of IgG and IgE antibodies to L3 antigens in brugian
      filariasis.

PMID- 10333327
TI  - Identification of novel 70-kDa heat shock protein-encoding cDNAs from Schistosoma
      japonicum.
AB  - A diverse range of organisms respond to a variety of chemical, physiological and
      temperature-associated stresses by a rapid and transient increase in the
      synthesis of heat shock proteins. We immunoscreened a Uni-ZAP XR cDNA library,
      prepared from mRNA isolated from the Philippine strain of the Asian bloodfluke,
      Schistosoma japonicum, using hyperimmune rabbit sera raised against soluble adult
      S. japonicum proteins. Six 70-kDa heat shock protein-encoding cDNA clones were
      identified which, upon further analysis, were separated into two distinct protein
      groups within the 70-kDa heat shock protein family, the 70-kDa heat shock
      proteins and the immunoglobulin heavy chain-binding proteins/glucose-related
      proteins (Grp78). A representative from both groups was fully sequenced and
      compared with homologous sequences available in the GenBank/EMBL database as the
      first stage in determining the role of their expression products in the
      regulation of S. japonicum development, in the induction of immunity, and whether
      they act as molecular chaperones capable of modulating the correct folding or
      repair of proteins within this species of schistosome.

PMID- 10333328
TI  - Codon usage in Plasmodium vivax nuclear genes.
AB  - Codon usage in Plasmodium vivax nuclear genes was analysed and compared with that
      in Plasmodium falciparum nuclear genes. Preferred codons were determined for P.
      vivax. Unlike P. falciparum, P. vivax genes are about 15% less A+T rich in the
      coding regions, with no obvious A+T bias at the third position of the codons. The
      amino-acid composition of P. vivax gene products is also different from that of
      P. falciparum. These results provide valuable information to facilitate gene
      cloning as well as expression and transfection studies for P. vivax.

PMID- 10333329
TI  - The intramammary inflammatory response of genetically resistant Merino ewes
      infected with Haemonchus contortus.
AB  - The mammary glands of 103 pasture-reared non-lactating, non-pregnant Merino ewes
      were infused via the teat canal with antigens prepared from the nematode
      Haemonchus contortus, and the inflammatory response to infusion assessed by
      washing the gland of its contents after 24 h and 14 days. The ewes were of two
      genotypes: one with proven high levels of resistance to infection with the
      nematode H. contortus, the other random-bred animals with relative susceptibility
      to infection. On day 0 of a H. contortus infection, one gland of the subgroups of
      both genotypes was infused with the antigen preparation. At the same time, the
      other gland of the random-bred ewes was infused with sterile physiological
      saline. A third group of infected random-bred ewes was infused with only sterile
      physiological saline. Similar infusions were performed on other subgroups on days
      12, 21 and 35 of infection, which was then terminated with anthelmintic. A fourth
      group of uninfected random-bred control ewes was given both infusions 35 days
      after the other groups were infected. Sheep of the resistant genotype had lower
      worm egg counts and smaller reductions in blood packed cell volumes from day 21
      of infection. Infusion of antigen had no effect on the course of infection and no
      effect on the response of the other gland, which had been infused with saline
      alone. The dominant leukocyte response from the antigen-infused gland was
      eosinophilia. On all days of infusion, and after both 24 h and 14 days,
      eosinophil counts from the resistant genotype were higher than those from their
      random-bred counterparts. The sheep mammary gland provides a source of
      eosinophils whose number is related to host genotype and stage of infection and
      may provide a model for the investigation of cellular responses in mucosal
      immunity to nematode infections.

PMID- 10333330
TI  - Studies on the role of mucus and mucosal hypersensitivity reactions during
      rejection of Trichostrongylus colubriformis from the intestine of immune sheep
      using an experimental challenge model.
AB  - Nematode-naive sheep and sheep immunised by truncated infections with
      Trichostrongylus colubriformis were fitted with intestinal cannulae to allow
      administration of challenge infection and collection of intestinal fluids. Sheep
      were slaughtered at various times after challenge and the distribution of larvae
      along the small intestine was determined. Results showed that immune sheep had
      significantly fewer larvae in their intestines and that some sheep could expel
      the challenge infection within 2 h. Mucus samples from immune sheep contained
      increased parasite-specific antibody, histamine and anti-parasite activity as
      measured by larval migration inhibition assay. Higher levels of antibody and
      histamine were seen in intestinal fluids of immune sheep after challenge.
      Immunisation of sheep by truncated infections stimulated serum IgE and resulted
      in significantly higher numbers of IgE-positive cells in gut tissue sections
      before challenge and at 2 h and 24 h after challenge. Immune sheep also had
      greater numbers of mucosal mast cells and globule leucocytes after challenge,
      compared with naive sheep. When challenge larvae were mixed with mucus from
      immune sheep and infused back into naive recipient sheep, there was a distinct
      displacement of the larval population towards the distal part of the intestine,
      compared with the profile of larval establishment after infusion with mucus from
      naive sheep. These results are further evidence for an immediate hypersensitivity
      reaction in the intestine of immune sheep, where challenge larvae are expelled
      within 2 h and confirm the direct anti-larval properties of mucus. The cannulated
      sheep challenge model described here will be a useful tool to unravel the
      mechanism of larval rejection from immune sheep and could lead to novel
      therapies.

PMID- 10333331
TI  - Characterisation of Ascaris from human and pig hosts by nuclear ribosomal DNA
      sequences.
AB  - The sequences of the nuclear ribosomal DNA region spanning the first internal
      transcribed spacer, the 5.8S rRNA gene and the second internal transcribed spacer
      were determined for Ascaris samples from pigs and humans from different
      geographical regions. The sequences of the 5.8S gene and the second internal
      transcribed spacer were the same for all samples examined, whereas all Ascaris
      samples from humans had six (1.3%) nucleotide differences in the first internal
      transcribed spacer compared with those from pigs. These differences provided some
      support for the existence of separate species of Ascaris or population variation
      within this genus. Using a nucleotide difference within a site for the
      restriction enzyme HaeIII, a PCR-linked restriction fragment length polymorphism
      method was established which allowed the delineation of the Ascaris samples from
      pigs and humans used herein. Exploiting the sequence differences in the first
      internal transcribed spacer, a PCR-based single-strand conformation polymorphism
      method was established for future analysis of the genetic structure of pig and
      human Ascaris populations in sympatric and allopatric zones.

PMID- 10333332
TI  - Long-term effects of short-term provision of protein-enriched diets on resistance
      to nematode infection, and live-weight gain and wool growth in sheep.
AB  - Weaner sheep that had been hand-fed on diets containing increasing concentrations
      of protein for a 9-week period (when uninfected, or infected with Haemonchus
      contortus) were studied during the next 69 weeks when put on to pasture as a
      single, unsupplemented flock. During the 9-week period, groups of 12 sheep (six
      infected, six uninfected) were offered one of five iso-energetic (9.0 MJ kg(-1))
      diets containing 10, 13, 16, 19 or 22% crude protein. All sheep were treated with
      anthelmintic at the end of the 9 weeks and then put out to pasture for 69 weeks,
      where they were all subject to the same environmental variables including
      nematode larval challenge. During the grazing period, animals that had previously
      received the higher protein diets consistently had higher live-weight gain and
      wool production, higher antibody responses to both H. contortus and
      Trichostrongylus colubriformis antigenic challenge in vitro, and lower faecal
      nematode egg counts than did the lambs previously offered the lower protein
      diets. Faecal egg counts of the grazing sheep that had been artificially infected
      with H. contortus while being hand-fed were similar to those of the uninfected
      sheep and there was no interaction between previous infection and dietary protein
      concentration. We conclude that short periods of enhanced post-weaning nutrition
      can have long-term and perhaps life-long effects on production.

PMID- 10333333
TI  - Antiparasite activity of sea-anemone cytolysins on Giardia duodenalis and
      specific targeting with anti-Giardia antibodies.
AB  - The killing activity of sea-anemone cytolysins on Giardia duodenalis was
      investigated. Three different toxins, sticholysin I and II from Stichodactyla
      helianthus (St I and St II) and equinatoxin II from Actinia equina (EqtII) were
      all found to be active in an acute test, with a C50 in the nanomolar range (St I,
      0.5 nM; St II, 1.6 nM; and EqtII, 0.8 nM). A method to target the cytolysin
      activity more specifically towards the parasite cells by using anti-Giardia
      antibodies was then investigated. Parasite cells were sensitised with a primary
      murine monoclonal or polyclonal antibody followed by a biotinylated secondary
      anti-mouse-IgG monoclonal antibody. Subsequently, avidin and a biotinylated EqtII
      mutant were added, either in two separate steps or as a pre-formed conjugate.
      When the monoclonal antibody was used, the C50 of biotinylated EqtII was 1.3 nM
      with sensitised cells and 5 nM with non-sensitised cells, indicating a four-fold
      enhancement of activity with the cell treatment. Treatment with the polyclonal
      antibody was somehow more effective than with the monoclonal antibody in an acute
      test. This indicates that sea-anemone cytolysins can efficiently kill Giardia
      cells, and that it is possible to improve, to a certain extent, the anti-parasite
      specificity of these toxins with anti-Giardia antibodies. However, the
      feasibility of this approach "in vivo" remains to be demonstrated.

PMID- 10333334
TI  - Ultrastructure of spermiogenesis and the spermatozoon of Mesocestoides litteratus
      (Cestoda, Mesocestoididae).
AB  - This paper constitutes the first ultrastructural study of spermiogenesis and the
      spermatozoon of a cestode belonging to the family Mesocestoididae, Mesocestoides
      litteratus. Spermiogenesis in M. litteratus is characterised by a flagellar
      rotation and a proximodistal fusion. The zone of differentiation presents
      striated roots associated with the centrioles and also an intercentriolar body.
      The most interesting ultrastructural feature found in the mature spermatozoon of
      M. litteratus is the presence of parallel cortical microtubules. The spermatozoon
      also exhibits a single crest-like body and granules of glycogen. The pattern of
      spermiogenesis and the parallel position of cortical microtubules reveal the lack
      of concordance between M. litteratus and cyclophyllidean species studied to date
      in spermiogenesis and in the ultrastructural organisation of spermatozoon. This
      study provides new spermatological data and calls into question the validity of
      the current systematic position of mesocestoidids.

PMID- 10333335
TI  - Ultrastructure of the eyes of the larva of Neoheterocotyle rhinobatidis
      (Platyhelminthes, Monopisthocotylea), and phylogenetic implications.
AB  - The oncomiracidium of Neoheterocotyle rhinobatidis (Monogenea, Monopisthocotylea,
      Monocotylidae) has two pairs of eyes, each eye with a lens and pigment cup. The
      anterior eyes have a single rhadomere; the posterior ones, two rhadomeres. Lenses
      are part of the pigment cup cells, as indicated by cytoplasmic connections
      between them and the pigment cups, and they are of mitochondrial origin because
      mitochondrial cristae are present in the periphery of the lenses. This is the
      first time that mitochondrial lenses have been shown to exist in a neodermatan.
      Such lenses may be a synapomorphy of a large taxon comprising the Neodermata and
      its turbellarian sister groups, or they may have evolved convergently in several
      not closely related groups as a result of strong selection pressure to find a
      suitable habitat or host.

PMID- 10333336
TI  - Immunohistochemical reactivity of polyclonal antibodies against Sphaerospora
      testicularis and Ceratomyxa labracis (Myxosporea: Bivalvulida), with other
      myxosporean parasites.
AB  - Immunological staining with rabbit antibodies raised against Sphaerospora
      testicularis and Ceratomyxa labracis was used to characterise their specificity
      and their reactivity towards other fish parasites. Polar capsules and valves of
      S. testicularis and C. labracis were labelled with their homologous antibody and
      cross reaction was observed with all the myxosporean parasites assayed from
      marine and freshwater fish hosts. All polar capsules were stained with both
      antibodies, except those of Zschokkella mugilis, which were not labelled with
      anti-S. testicularis serum. These observations suggest that polar capsules may be
      very conserved structures in myxosporean parasites from different hosts.

PMID- 10333337
TI  - Atherosclerotic renal artery stenosis: is it worth diagnosing?
AB  - Atherosclerotic renal artery stenosis (ARAS) is the commonest cause of secondary
      hypertension and is the cause of end stage renal failure in up to 20% of patients
      starting dialysis. Associated with it is a high morbidity and appalling
      mortality. The aetiology of ischaemic nephropathy is complex and is not simply
      related to renal artery narrowing. Captopril renography is sensitive and specific
      for diagnosing ARAS in patients with normal renal function. In those with renal
      impairment gadolinium-enhanced MRA or spiral CT angiography clearly define renal
      anatomy. Over 80% of ARAS is ostial. Studies of revascularisation with
      angioplasty show poor short and long term patency rates. Renal artery stenting
      leads to high initial technical success and long term patency. Recent randomised
      controlled trials in patients with renovascular hypertension demonstrate no clear
      benefit of adequate revascularisation over medical therapy. Renal artery stenting
      for renal protection in ARAS appears more encouraging and current randomised
      controlled trials are in progress to answer the question definitively.

PMID- 10333338
TI  - Hypertension in diabetes: a good opportunity to practise evidence-based medicine?
      A commentary on the UKPDS. United Kingdom Prospective Diabetes Study.

PMID- 10333339
TI  - Genetic epidemiology of essential hypertension.
AB  - This review article is intended to introduce the uninitiated clinician to the
      basic concepts, aims and early findings of the genetic epidemiology of
      hypertension. It separates the rare monogenic 'Mendelian' hypertensive disorders
      from the vast majority of patients with essential hypertension, which is a
      complex, polygenic, multifactorial disorder resulting from interaction of several
      genes with each other and with the environment. It highlights some clinical
      strategies used to enhance searches for 'candidates genes', such as subgrouping
      of populations into relatively homogenous groups or 'intermediate phenotypes'
      according to presumably heritable anthropometric, clinical or biochemical
      characteristics; and some applications of genetic epidemiologic techniques, such
      as linkage and association studies of certain gene polymorphisms with
      hypertension using affected sibling pairs and large sibships or wide genomic
      screens comparing affected and unaffected populations. Although so far there is
      no genotypic variation proven to be causally related to essential hypertension,
      its intermediate phenotypes or any of its complications, it is hoped that new,
      more efficient methods of genetic analysis will yield clinically meaningful
      information.

PMID- 10333341
TI  - Obesity and hypertension among college-educated black women in the United States.
AB  - It is established that obesity is an important risk factor for hypertension, but
      there is little information on this relationship among highly educated black
      women. We assessed the relationship of body mass index (weight (kg)/height2 (m))
      to prevalent hypertension among US black women who had completed college, and
      among less educated women as well. The data were collected in 1995 in the Black
      Women's Health Study: 64530 African-American women aged 21 to 69 years enrolled
      by completing mailed health questionnaires; 44% of the participants had completed
      college. We compared the 9394 participants who reported a diagnosis of
      hypertension treated with a diuretic or antihypertensive drug (cases) with 9259
      participants of similar ages who did not have hypertension (controls).
      Multivariate odds ratios were estimated by logistic regression. The odds ratio
      for treated hypertension increased with increasing body mass index at every
      educational level. Among college-educated women, the odds ratio for hypertension
      was 2.7 for overweight women (index 27.3-32.3) and 4.9 for severely overweight
      women (index > or =32.3), relative to women with a body mass index <22.8. The
      prevalences of obesity and hypertension were high among the college-educated
      women, although not as high as among women with fewer years of education. About a
      quarter of the difference in the prevalence of hypertension across educational
      levels was explained by the difference in the proportions who were overweight or
      severely overweight. These results document a high prevalence of obesity and
      hypertension, and a strong association of obesity with hypertension, among highly
      educated US black women.

PMID- 10333340
TI  - The lack of association between hypertension and hypothyroidism in a primary care
      setting.
AB  - This work examines the association between hypertension and hypothyroidism in
      geriatric patients seen at a primary care medical office. One hundred and twenty
      two geriatric patients with elevated thyroid stimulating hormone (TSH) levels
      were selected for the study. An equal number of euthyroid geriatric individuals
      were selected from the same clinic for comparison. We found no differences in
      mean diastolic blood pressure (DBP) in the euthyroid and hypothyroid groups (80.1
      mm Hg vs 78.9 mm Hg, P = 0.25). Additionally, there was no significant
      association between having hypertension (defined as having an elevated DBP or
      receiving treatment for hypertension at the time of the index visit) and level of
      TSH (P = 0.33). Logistic regression did show that race, gender, body mass index
      and renal function were significantly associated with the presence of
      hypertension. Lastly, there was not a significant association between level of
      TSH and DBP as determined by regression (P = 0.97). In conclusion, in this
      population of geriatric patients we did not find hypertension to be associated
      with the presence of hypothyroidism.

PMID- 10333342
TI  - Prevalence of cardiovascular risk factors in the Republic of Georgia.
AB  - BACKGROUND: Eastern Europe is experiencing an epidemic of deaths from
      cardiovascular diseases with an increase since the early 1990s approaching 50%.
      The ability to survey the risk factors associated with this striking rise is
      severely hampered by the current disarray of the area's public health system. We
      used a rapid survey method to describe the epidemiology of cardiovascular risk in
      the capital of the Republic of Georgia, Tbilisi. METHODS: A two-stage cluster
      design, 'rapid survey method' developed by the Chronic Disease Center was used to
      estimate the frequency of hypertension, a major cardiovascular risk factor. Local
      personnel were trained and certified in blood pressure measurement and rapid
      survey techniques. The training and survey were conducted over a period of 14
      days at which time a preliminary report of the survey was presented to the
      Ministry of Health. RESULTS: A total of 321 subjects were surveyed. The frequency
      of high blood pressure (>140/>90 mm Hg) at the time of the examination was 58% in
      men and 56% in women. The major correlates for blood pressure were gender and
      age. In addition we found that 31% of the population had a total cholesterol > or
      =220 mg% and a similar number had a low high density lipoprotein < or =35 mg%.
      Smoking was present in 60% of men and none were taking aspirin daily to prevent
      premature coronary artery disease. CONCLUSIONS: The rapid survey method is
      feasible in the former Soviet Union and can quickly provide estimates of the risk
      factors associated with the epidemic of cardiovascular disease in this area.

PMID- 10333343
TI  - Clinical presentation and management of patients with uncontrolled, severe
      hypertension: results from a public teaching hospital.
AB  - CONTEXT: There is relatively little data available on the management of patients
      with severe, uncomplicated hypertension and severe hypertension with stable
      hypertensive complications. OBJECTIVE: To determine the incidence, clinical
      features, acute management, and clinical course of severe, uncomplicated
      hypertension and severe hypertension with stable hypertensive complications
      presenting for emergency department care in a large public teaching hospital.
      DESIGN: Chart survey of consecutive emergency department visits. PATIENTS: Ninety
      one of 2898 consecutive visits to a public teaching hospital emergency department
      were specifically for severe, uncomplicated hypertension. RESULTS: Of 2898
      consecutive medical emergency department visits, there were 142 (4.9%) patient
      visits specifically for systolic blood pressure (SBP) > or =220 mm Hg or
      diastolic blood pressure (DBP) > or =120 mm Hg. Ninety-one of the 142 patient
      visits were for severe hypertension in the absence of acute target organ impact
      or neuroretinopathy. Eighty-nine patients received acute drug therapy. Twenty
      nine patients received two drugs, and 15 received three drugs. Sixty-eight
      patients (75%) received clonidine, and 15 (16.5%) received short-acting
      nifedipine despite widely published concerns about the safety of this practice.
      We found a wide variability of blood pressure response to treatment. The average
      decline in SBP was 50+/-31 mm Hg and the average decline of DBP was 34+/-20 mm Hg
      over 4.2+/-2.9 h. Forty-two patients (46%) had the SBP reduced to less than 160
      mm Hg, and 46 patients (50%) the DBP to less than 100 mm Hg. Long-term management
      and follow-up were suboptimal. Of 74 patients discharged from the emergency room,
      22 patients (30%) returned because of uncontrolled hypertension within an average
      of 33+/-28 days, 10 patients with hypertensive complications. CONCLUSIONS: Severe
      hypertension continues to present an important and common problem. Physicians
      appear to place a strong emphasis on acute lowering of the blood pressure to near
      normal levels. Patients are frequently lost to follow-up and have a very high
      rate of recurrent emergency department visits and hypertensive complications.
      This study points to a need for detailed, specific practice guidelines and
      comprehensive disease management protocols for severe, uncomplicated
      hypertension.

PMID- 10333344
TI  - Role of insulin resistance in the genesis of sodium sensitivity in essential
      hypertension.
AB  - We recently showed that cardiovascular morbidity was higher in sodium sensitive
      type of essential hypertension than in the non-sodium sensitive type. It was
      examined whether sodium sensitivity was associated with insulin resistance, an
      important atherosclerotic cardiovascular risk factor in essential hypertension.
      Fifty-three patients with essential hypertension, who had normal (n = 12) and
      impaired (n = 41) glucose tolerance, were placed on high (12-15 g NaCl/day) and
      low (1-3 g) sodium diets for 1 week each to determine sodium sensitivity. Fasting
      plasma glucose and insulin concentrations were measured on a regular sodium diet.
      The homeostasis model assessment insulin resistance index (fasting glucose
      [mmol/L] x fasting insulin [mU/L]/22.5) was 1.40+/-0.10 and 1.47+/-0.14 in non
      sodium sensitive and sodium sensitive groups. The insulin resistance index was
      positively correlated with the sodium sensitivity index, while was negatively
      correlated with fractional excretion of sodium (FE(Na)) obtained during a high
      sodium diet. In addition, the insulin resistance index had a positive
      relationship with overall creatinine clearance. Sodium sensitivity index was also
      negatively correlated with FE(Na) obtained during a high sodium diet. These
      results showed that insulin resistance might participate in the genesis of sodium
      sensitivity in essential hypertension by enhancing tubular sodium reabsorption,
      as reflected in decreased FE(Na) and augmented creatinine clearance. Insulin
      resistance seemed elevated in sodium sensitive state of essential hypertension,
      leading to future cardiovascular events.

PMID- 10333345
TI  - Acute hyperglycaemia in the forearm induces vasodilation that is not modified by
      hyperinsulinaemia.
AB  - OBJECTIVE: To evaluate whether acute elevations of local plasma glucose
      concentrations could influence forearm blood flow (FBF) and how this interacts
      with local hyperinsulinaemia in healthy volunteers. METHODS: Using the perfused
      forearm technique, in random order, glucose 20% or saline 0.9% as a control was
      infused in three dose steps (0.3, 1.0, and 3.0 ml/min) for 5 min each in eight
      healthy men. The infusion experiments were repeated, in random order, during
      local hyperinsulinaemia by intra-arterial infusion of insulin 0.05 mU/kg/min. The
      ratio of FBF of the infused over the FBF in the control arm (FR) was measured at
      15-sec intervals during the infusions. RESULTS: Glucose infusion increased the FR
      dose-dependently by 172%+/-39% (M+/-SE) at the highest dose (P < 0.01). During
      hyperinsulinaemia the glucose-induced increase in FR was significantly (P < 0.01)
      less, 96%+/-26%, however, when changes in FR or forearm vascular resistance were
      related to the plasma glucose concentrations both glucose infusions were
      equipotent. The saline infusions induced small increases in FR of 27+/-5% (P <
      0.01) and 24+/-11% (P > 0.05), without or with insulin respectively. The changes
      in FR during the saline infusions were much smaller than during the glucose
      infusions (P < 0.01). During the glucose infusions small but significant
      increases in FBF and venous plasma glucose in the non-infused forearm appeared,
      indicating carry-over effect and the possibility of a very low threshold for
      glucose-induced vascular effects. CONCLUSIONS: High, local levels of glucose in
      the forearm have a vasodilator effect on resistance vessels in skeletal muscle of
      the forearm that is not modified by local hyperinsulinaemia. Indications were
      found that the threshold for this glucose-induced vasodilation may be remarkably
      low, but this needs to be studied more formally.

PMID- 10333346
TI  - Studies on diurnal blood pressure variation in kidney diseases associated with
      excessive salt and water retention.
AB  - Salt and water retention, a cardinal feature of nephrotic syndrome, was suggested
      to be an important factor leading to reduced diurnal blood pressure (BP)
      variation in renoparenchymal disease. Twenty-four hour BP (SpaceLabs SL 90207),
      24-h urine excretion of catecholamines, plasma renin activity and plasma
      aldosterone concentration were therefore determined in 10 nephrotic patients with
      normal serum creatinine levels (group A, serum creatinine 1.0+/-0.2 mg/dl), in 10
      nephrotic patients with increased serum creatinine levels (group B, serum
      creatinine 2.4+/-0.9 mg/dl) and in 20 controls matched in respect of age and BP.
      To study the direct influence of fluid volume overload, diurnal BP variation was
      determined before and after volume depletion by ultrafiltration in 10 patients
      with end-stage renal failure. Diurnal BP variation was characterised by the
      difference of mean BP during daytime (10 pm to 8 am) and night-time (8 am to 10
      pm). In group A, the systolic and diastolic day-night difference was not changed
      when compared with the controls (NS). In contrast, in group B the day-night
      difference was significantly lower than in the controls (P < 0.01). Twenty-four
      hour urine catecholamine excretion and plasma aldosterone were comparable between
      the study groups. Plasma renin activity, however, was significantly increased in
      group A (P < 0.05). Nocturnal BP drop was not related to plasma renin activity in
      the nephrotic patients. The blunted diurnal blood pressure variation in end-stage
      renal failure was not influenced by ultrafiltration. The study demonstrates that
      the blunted diurnal BP variation in kidney disease is unaffected by marked
      changes in total exchangeable sodium and fluid volume, but is sensitive to
      changes in glomerular filtration rate.

PMID- 10333347
TI  - Dose-response efficacy of valsartan, a new angiotensin II receptor blocker.
AB  - OBJECTIVE: To study the efficacy and tolerability of a range of valsartan doses
      in patients with mild-to-moderate hypertension. DESIGN: 122 adult out-patients
      were randomised in equal numbers to receive valsartan 10 mg, 40 mg, 80 mg, 160 mg
      or placebo once daily (OD) for 4 weeks in this multicentre, double-blind, fixed
      dose, parallel trial. Patients were assessed at 0, 2 and 4 weeks. MAIN OUTCOME
      MEASURES: The primary efficacy variable was change from baseline in trough mean
      supine diastolic blood pressure (MSuDBP). Other variables included change from
      baseline in trough mean supine systolic blood pressure (MSuSBP), responder rates
      and trough/peak ratio. RESULTS: All treatments significantly reduced MSuDBP and
      MSuSBP at 4-week end-point compared to baseline (P < 0.001). The magnitude of
      blood pressure lowering was greater with increasing doses of valsartan (least
      square mean change from baseline for placebo, valsartan 10 mg, 40 mg, 80 mg, 160
      mg respectively: MSuDBP -4.4 mm Hg, -4.9 mm Hg, -6.5 mm Hg, -8.2 mm Hg, -9.1 mm
      Hg; MSuSBP -1.3 mm Hg, -3.6 mm Hg, -7.0 mm Hg, -11.1 mm Hg, -11.9 mm Hg). A
      fitted quadratic curve, to predict relationship between dose and change from
      baseline in trough MSuDBP, indicated a positive dose response. Responder rates
      were 16%, 24%, 33%, 46%, 54% for placebo, valsartan 10 mg, 40 mg, 80 mg, 160 mg
      respectively, which also indicated a positive dose response in the dose range of
      10 mg to 160 mg. Greater than 50% of the antihypertensive effect measured at peak
      persisted at trough for each of the four active treatment groups, confirming
      efficacy over a 24-h period. No dose-related adverse experiences were observed,
      with overall incidence (regardless of relationship to trial medication) of 44%
      with placebo and 44%, 36%, 22%, 21% for valsartan 10 mg, 40 mg, 80 mg, 160 mg
      respectively. The most common adverse experience reported was headache which
      occurred most frequently with placebo (12%). No trial drug-related cough was
      observed. Treatment with valsartan did not produce clinically significant
      orthostatic changes in diastolic or systolic blood pressure. One case of
      symptomatic orthostatic hypotension was observed on placebo. CONCLUSIONS: The
      results of this trial show valsartan to effectively lower blood pressure in
      patients with mild-to-moderate hypertension, and demonstrate that the reduction
      in blood pressure increases with increasing dose levels.

PMID- 10333348
TI  - Digital aortography showing extensive aneurysmal aortoiliac disease and severe
      proximal renal artery stenosis in a patient with a history of acute myocardial
      infarction.

PMID- 10333349
TI  - Erythrocyte deformability is related to fasting insulin and declines during
      euglycaemic hyperinsulinaemia in hypertensive patients.

PMID- 10333350
TI  - Isolation of the Ca2+ releasing component(s) of mammalian sperm extracts: the
      search continues.

PMID- 10333352
TI  - Novel transcripts of carbonic anhydrase II in mouse and human testis.
AB  - Intracellular and extracellular sources of bicarbonate are essential for sperm
      motility, sperm binding to the zona pellucida and the acrosome reaction. Carbonic
      anhydrase II, catalysing the synthesis of bicarbonate within spermatozoa, must
      play a significant role in these mechanisms. We report here the expression of
      carbonic anhydrase II during mouse spermatogenesis and the primary structure of
      testicular transcripts coding for carbonic anhydrase II isolated from adult mouse
      and human testes. The mouse carbonic anhydrase II (Car2) mRNA displays a 5'
      untranslated region (UTR) larger than the corresponding somatic sequence. The
      additional 5' sequence contains the 'TATA box' used in somatic tissues and other
      promoter sequences, suggesting the use of testis-specific promoters further
      upstream with read-through of downstream promoters. The 3'UTR of the Car2 mRNA is
      shorter in mature testicular cells than in somatic cells. Polysomal gradient
      analysis of carbonic anhydrase II transcripts isolated from adult mouse testis
      and kidney revealed different translation potential: most of the testicular
      transcripts were present in the non-polysomal fractions, whereas a considerable
      fraction of kidney transcripts were polysome-associated. These results suggest
      that specific transcriptional and post-transcriptional mechanisms regulate the
      expression of carbonic anhydrase II during mammalian spermatogenesis.

PMID- 10333351
TI  - Divergent mechanisms regulate proliferation/survival and steroidogenesis of theca
      interstitial cells.
AB  - Luteinizing hormone (LH) and insulin-like growth factor I (IGF-I) are recognized
      as major regulators of ovarian theca-interstitial (T-I) function. This study was
      designed to compare the effects of LH and IGF-I on T-I proliferation and
      steroidogenesis. Purified rat T-I cells were cultured in chemically-defined
      media. DNA synthesis was evaluated by a radiolabelled thymidine incorporation
      assay. The cells were also directly counted. Progesterone production was assessed
      using a specific radioimmunoassay. DNA synthesis of T-I cells was stimulated by
      IGF-I (10 nM) but modestly inhibited by LH (100 ng/ml). The inhibitory effect of
      LH was mimicked by 8Br-cAMP (10(-4) to 10(-3) M); forskolin (10(-5) M), cholera
      toxin (10 ng/ml) and 3-isobutyl-methylxanthine (10(-5) M). Stimulation of protein
      kinase C with phorbol 12-myristate 13-acetate (10(-7) M) had no significant
      effect on DNA synthesis. Furthermore, DNA synthesis was not affected by
      testosterone (10(-10) to 10(-9) M) or progesterone (10(-9) to 10(-8) M).
      Accumulation of progesterone was co-operatively stimulated by LH and IGF-I. These
      results suggest that LH-induced inhibition of T-I proliferation and/or survival
      is mediated via the cAMP system. IGF-I may be viewed as a co-gonadotrophin with
      respect to steroidogenesis but not with respect to proliferation/survival. The
      divergence of the effects on proliferation/survival versus steroidogenesis
      underscores the complexity of the interactions between LH and IGF-I signalling
      pathways.

PMID- 10333353
TI  - A quantitative sucrose gradient analysis of the translational activity of 18 mRNA
      species in testes from adult mice.
AB  - Sucrose gradients have been widely used to study the translational activity of
      mRNA species in meiotic and haploid spermatogenic cells in mammals.
      Unfortunately, the results of these studies have been very inconsistent. The
      purpose of the present study was to obtain accurate and reproducible measurements
      of the translational activity of a large number of testicular mRNA in sucrose
      gradients. Extracts of adult testes and cultured seminiferous tubules were
      sedimented on sucrose gradients, and the distribution of 18 mRNA species was
      quantified by phosphoimaging. The proportions of various mRNA species sedimenting
      with polysomes in meiotic and haploid cells (approximately 6-74%) is less than
      typical of efficiently translated mRNAs (85-90%), demonstrating that the
      initiation of translation of virtually all mRNA species is at least partially
      inhibited and that the extent of inhibition is mRNA-specific. Most mRNA species
      in meiotic and early haploid spermatogenic cells are translated on polysomes in
      which the ribosome spacing is somewhat wider than in somatic cells, 100-150
      verses 80-100 bases. However, the ribosome spacing on protamine mRNAs is
      unusually close (40-50 bases), and the spacing on poly(A) binding protein mRNA is
      unusually wide (212-272 bases), thus suggesting that the rate of translational
      initiation, termination and/or elongation is regulated on translationally active
      forms of certain mRNA.

PMID- 10333354
TI  - Detection of partial and complete acrosome reaction in human spermatozoa: which
      inducers and probes to use?
AB  - The acrosome reaction (AR), an essential step for achieving mammalian
      fertilization, was recently introduced as a means of clinical evaluation of male
      fertility. However, most of the available techniques for acrosomal status
      assessment (except those employing electron microscopy) do not define whether the
      measurements represent partial or complete AR. We, therefore, performed a
      crossover investigation of the types of inducers and probes required for
      detecting partial or complete AR in human spermatozoa. The acrosomal status
      before and after stimulation with four AR inducers was evaluated after incubation
      for 3 h in capacitating conditions. We used a fluorescence-activated cell sorter
      with fluorescein isothiocyanate-conjugated monoclonal antibody CD46 (FITC-CD46)
      targeting the inner acrosomal membrane for detecting a complete AR, and
      fluorescein isothiocyanate-Pisum sativum agglutinin (FITC-PSA) targeting the
      acrosomal content for detection of both partial and complete AR. Without
      stimulation or following stimulation with progesterone, follicular fluid (FF) or
      phorbol myristate ester (PMA), the AR could be detected with FITC-PSA but not
      with FITC-CD46. Following stimulation with the calcium ionophore A23187, the AR
      could be detected by both FITC-PSA and FITC-CD46. These results suggest that
      spontaneous AR as well as AR induced by progesterone, PMA and FF are partial. In
      contrast, the AR induced by A23187 is total, i.e. both partial and complete.
      These findings are valuable for both research and clinical purposes and are a
      step towards an international agreement on a standard test for human sperm AR,
      for which there is an urgent need.

PMID- 10333355
TI  - Seminal plasma components stimulate interleukin-8 and interleukin-10 release.
AB  - Human seminal plasma has potent anti-inflammatory properties which are thought to
      confer a survival advantage to the spermatozoa within the hostile female genital
      tract. In contrast, a profound pro-inflammatory leukocytosis has been observed
      post-coitus in animals and humans. Whether components of seminal plasma are
      involved in initiating this leukocytic reaction is not known. This study
      investigated the effect of human seminal plasma, a seminal plasma fraction and
      its principal constituent prostaglandins, prostaglandin E2 (PGE2) and 19-hydroxy
      PGE, on the release of the pro-inflammatory neutrophil chemotactic factor
      interleukin-8 (IL-8) and the anti-inflammatory cytokines interleukin-10 (IL-10)
      and secretory leukocyte protease inhibitor (SLPI). The tissues studied were non
      pregnant cervical explants, peripheral blood and the monocyte cell line U937.
      Seminal plasma fraction (SPF) significantly (P < 0.05) stimulated release of IL-8
      and inhibited release of SLPI from non-pregnant cervical explants. SPF, PGE2 and
      19-hydroxy PGE significantly (P< 0.005) stimulated IL-8 release from peripheral
      blood and U937 cells. 19-hydroxy PGE was significantly (P< 0.005) more effective
      than PGE2 in stimulating IL-8 release. Seminal plasma, SPF and PGE2 significantly
      (P < 0.05) stimulated IL-10 release from U937 cells. 19-hydroxy PGE stimulated IL
      10 release from U937 cells but this failed to reach significance. Release of IL
      10 by cervical explants and SLPI by peripheral blood and U937 cells were below
      the detection limit of the assays employed. We suggest that the anti- and pro
      inflammatory immune responses which seminal plasma induces might act in
      combination initially to promote sperm survival and then to facilitate their
      removal from the female genital tract.

PMID- 10333356
TI  - Effect of post-ovulatory age and calcium in the injection medium on the male
      pronucleus formation and metaphase entry following injection of human spermatozoa
      into golden hamster oocytes.
AB  - The occurrence of parthenogenetic activation is a major hurdle in obtaining sperm
      chromosome metaphases after heterospecific intracytoplasmic sperm injection
      (ICSI) of golden hamster oocytes with human spermatozoa. We addressed two
      potential contributors to parthenogenetic activation namely, post-ovulatory age
      of the oocyte and Ca2+ content of the injection medium. In serial experiments,
      hamster oocytes were retrieved at 11.5, 13, 16 and 21 h after the ovulatory dose
      of human chorionic gonadotrophin (HCG) and microinjected with human spermatozoa
      suspended alternately in a regular (1.9 mM Ca2+) or a Ca2+-free medium. A
      progressive decrease in the rates of male pronucleus (MPN) formation and
      metaphase entry and increase in the rates of parthenogenetic activation without
      male pronucleus occurred with increasing post-ovulatory age. The favourable
      influence of Ca2+-free injection medium on the mean rates of MPN and metaphase
      entry was restricted to the relatively older oocytes (MPN 16 h: 49.5 versus
      32.3%, P< 0.008; 21 h: 22.2 versus 11.1%, P< 0.001; metaphase entry 16 h: 36.8
      versus 25.1%, P< 0.02; 21 h: 13.3 versus 5.2%, P< 0.01 in the Ca2+-free and
      regular groups respectively). Our data confirm the increased activation
      sensitivity with post-ovulatory ageing and its adverse influence on the MPN
      formation and metaphase entry after heterospecific ICSI of hamster oocytes.

PMID- 10333357
TI  - GnRH mRNA and protein expression in human preimplantation embryos.
AB  - Gonadotrophin-releasing hormone (GnRH) regulates gonadotrophin biosynthesis and
      release in the anterior pituitary via specific receptors. Extrapituitary
      expression and action of GnRH have been demonstrated in several species. A
      possible role for GnRH in preimplantation embryonic development, endometrial
      preparation, and the implantation process has been previously suggested.
      Moreover, the presence of an immunoreactive GnRH in preimplantation embryos has
      been demonstrated in different species; however, there are no data for human
      embryos. We postulate that in humans GnRH may play a role in preimplantation
      embryonic development as well as in the implantation process. To examine this
      hypothesis, we assessed GnRH and GnRH-receptor mRNA and protein expression in
      human preimplantation embryos with three pronuclei. GnRH is expressed in peri
      implantation human embryos at both the mRNA and protein level. GnRH-receptor mRNA
      is also present in the embryos studied. Immunohistochemical localization of GnRH
      showed intense staining in all the blastomeres at morula stage as well as in the
      trophectoderm and inner cell mass of the blastocysts. The results of the present
      study challenge the widely held view that GnRH has a predominantly central
      action, and suggests a pathway to describe a local role for the GnRH system in
      successful preimplantation embryonic development and implantation.

PMID- 10333358
TI  - Interleukin-1 receptor-ligand interactions modulate interstitial collagenase-1
      production by human endometrial fibroblasts.
AB  - The expression of interstitial collagenase-1 in the cycling human endometrium is
      restricted to the perimenstrual phase and is a key event for matrix degradation
      that initiates menstruation. In the absence of ovarian steroids, collagenase
      production by endometrial fibroblasts is induced by epithelial cell-derived
      interleukin-1alpha. Media conditioned by endometrial epithelial cells were found
      to contain interleukin-1alpha but not interleukin-1beta, and their capacity to
      induce collagenase production by endometrial fibroblasts correlated with
      interleukin-1alpha concentration in a saturable manner. Collagenase induction by
      recombinant interleukin-1alpha was severely inhibited by interleukin-1 receptor
      antagonist alone and abolished by its combination with soluble interleukin-1 type
      II receptor. By contrast, the association of the receptor antagonist with soluble
      type-I receptor was less effective than each factor alone. Induction of
      collagenase by epithelial cell-conditioned media was severely inhibited by
      neutralizing interleukin-1alpha antibodies, whereas the combination of receptor
      antagonist with soluble type-II receptor proved less effective. We conclude that
      the collagenase response of endometrial fibroblasts to epithelial cell-derived
      interleukin-1alpha is effectively blocked in vitro by soluble members of the
      interleukin-1 family and can thus be modulated in vivo by these or other local
      factors.

PMID- 10333359
TI  - Inverse relationship between apoptosis and Bcl-2 expression in
      syncytiotrophoblast and fibrin-type fibrinoid in early gestation.
AB  - The purpose of this study was to assess the role of apoptosis and cell cycle
      arrest in the trophoblast during early gestation by determining the location of
      apoptotic cells and examining the expression of Bcl-2 and p21. Using the terminal
      deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL)
      method on human chorionic villi, a cluster of apoptotic nuclei was demonstrated
      in perivillous fibrin-type fibrinoid, but no apoptotic changes were identified in
      the syncytiotrophoblast or in other subtypes of the trophoblast. The
      syncytiotrophoblast was diffusely positive for Bcl-2, but fibrin-type fibrinoid
      was negative for Bcl-2. Hence, there was an inverse relationship between
      apoptosis and Bcl-2 expression in both fibrin-type fibrinoid and
      syncytiotrophoblast. Expression of p21 was present to some extent in the
      syncytiotrophoblast, but not in fibrin-type fibrinoid. These results suggest that
      Bcl-2 may play an important role in preventing apoptosis in the
      syncytiotrophoblast; this may be necessary to prevent any DNA degradation from
      being spread to other nuclei in a multinuclear cell like the syncytiotrophoblast.

PMID- 10333360
TI  - Effects of tumour necrosis factor-alpha, interleukin-1 alpha, macrophage colony
      stimulating factor and transforming growth factor beta on trophoblastic matrix
      metalloproteinases.
AB  - The aim of this study was to determine the effects of tumour necrosis factor
      alpha (TNF), interleukin-1 alpha (IL-1alpha), macrophage colony-stimulating
      factor (MCSF) and transforming growth factor beta (TGFbeta) on the secretion of
      matrix metalloproteinases (MMP), human chorionic gonadotrophin (HCG) and fetal
      fibronectin (fFN) by purified first trimester cytotrophoblastic cells (CTB) in
      vitro. CTB were obtained from legal abortions and cultured in vitro in the
      presence or absence of the different cytokines. Secreted gelatinases were
      analysed in the culture supernatants by zymography, by measurements of the total
      gelatinolytic activity and by enzyme immunoassays. HCG and fFN were measured by
      commercially available immunoassays. TNF increased the total gelatinolytic
      activity by increasing MMP-9 activity (P = 0.025-0.0177) but decreased MMP-2
      activity (P < 0.03) and immunoreactivity (P < 0.05), fFN (P < 0.02) and HCG (P <
      0.01). IL-1alpha significantly increased the secretion of fFN (P < 0.02), the
      activity (P < 0.02) and immunoreactivity (P < 0.05) of MMP-9 but had no effect on
      the other parameters. MCSF increased MMP-9 immunoreactivity (P < 0.05) and
      moderately decreased HCG. TGFbeta inhibited total gelatinolytic activity, MMP-9
      activity and immunoreactivity, but was without effect on MMP-2 concentrations and
      activity. TGFbeta decreased HCG (P < 0.041) and increased fFN (P < 0.042). Our
      results indicate that TGFbeta, TNF and IL-1alpha are important regulators of
      trophoblastic MMP secretion.

PMID- 10333362
TI  - Gestational changes in endothelin-1-induced receptors and myometrial contractions
      in rat.
AB  - The present experiments were performed to characterize the gestational changes in
      endothelin (ET)-1-induced myometrial contractions and ET receptors in rat. ET-1
      induced contractions were composed of two types: increases in resting tone and
      rhythmic contractions. The increase in resting tone was decreased at 7 days of
      gestation, but increased at 20 days. The increase in amplitude and frequency of
      rhythmic contractions remained unchanged during days 7-14 of gestation.
      Continuous rhythmic contractions were not produced by ET-1 near the term. Both
      contractions were inhibited by the antagonists BQ 123 and Ro 46-2005 but not by
      RES 701-1 or BQ 788. In binding studies, total binding sites of [1251]-ET-1 were
      unchanged, however higher affinity binding sites appeared during pregnancy in
      addition to the lower affinity sites. The specific [125I]-ET-1 binding in non
      pregnant and pregnant myometrium was completely inhibited by unlabelled ET-1 and
      Ro 46-2005. In contrast, the proportion which was inhibited by BQ 123 was
      decreased during pregnancy. In conclusion, characteristic gestational changes
      were the augmentation of ET-1-induced increased resting tone near term, and the
      appearance of high affinity ET-1 binding sites and an increase in BQ 123
      resistant ET-1 binding sites during pregnancy. Further investigations are needed
      to understand the physiological role of these changes.

PMID- 10333361
TI  - Binding of interleukin-8 to heparan sulphate enhances cervical maturation in
      rabbits.
AB  - Cervical ripening is a cytokine-triggered process with substantial remodelling of
      the cervical extracellular matrix. Interleukin-8 (IL-8) is an important cytokine
      in cervical maturation. Glycosaminoglycans are also included in this process, but
      their role in not clearly understood. The effects of heparan sulphate (HS),
      hyaluronic acid (HA), IL-8, HS + IL-8 and HA + IL-8 on biochemical properties of
      the cervix were examined in non-pregnant rabbits. The changes in vascular pattern
      with collagen structure of the cervices and immunohistochemical studies, together
      with the relative collagen concentrations, were determined. A reduction in
      relative collagen concentration was significant after HS + IL-8, IL-8 and HA + IL
      8 treatment (all P < 0.0001). Gel electrophoresis analysis showed that IL-8 bound
      preferentially to HS than to HA. Neutrophils were significantly increased in
      number (P < 0.0001) and located predominantly beneath the glandular epithelium
      and around the blood vessels after HS + IL-8 treatment. HS + IL-8 treatment
      caused cervices to increase their water content and become oedematous. The
      collagen fibres were considerably dissociated, the interfibrillar spaces markedly
      dilated, and the blood vessels notably increased and dilated. We conclude that
      binding to HS enhances the activity of IL-8 in inducing cervical maturation.

PMID- 10333364
TI  - Mutations in the promoter region of the androgen receptor gene are not common in
      males with idiopathic infertility.
AB  - Molecular studies on the role of the androgen receptor in male infertility have
      thus far concentrated solely on exonic regions of the androgen receptor gene. We
      have therefore screened for the first time the androgen receptor gene 5'
      untranslated region (nucleotides -153 to +237 ) in 240 males with idiopathic
      infertility for lesions which could potentially impair spermatogenesis. This
      region encompasses the androgen receptor gene promoter. DNA was extracted from
      blood leukocytes and the polymerase chain reaction was used to amplify the
      promoter region as two overlapping products. Single strand conformational
      polymorphism analysis was carried out on these products to screen for mutations.
      This analysis did not reveal the presence of any gross deletions or mutations.
      Our results thus preclude aberrations in the promoter region of the androgen
      receptor gene as a common factor in the aetiology of idiopathic male infertility.

PMID- 10333363
TI  - Temporal expression of inducible nitric oxide synthase in mouse and human
      placenta.
AB  - The aim of this study is to investigate the changes in expression and activity of
      inducible nitric oxide synthase (iNOS) in the developing murine embryo and mouse
      and human placenta. Using reverse transcription-polymerase chain reaction (RT
      PCR), Northern blotting, and in-situ hybridization (ISH) we identified iNOS mRNA
      in mouse placenta at 9.5, 12, 14, 16, 18 and 20 days post coitum. Northern blot
      analysis demonstrated that the quantity of murine iNOS transcript was expressed
      at a stable level between days 12-20 although the level of calcium-independent
      NOS activity declined with advancing gestation. RT-PCR detected iNOS-specific
      mRNA in murine embryonic stem cells, but not in embryos at later stages (4-cell
      or blastocyst). ISH failed to show iNOS-specific mRNA in either murine placenta
      or the underlying myometrium on day 7, but did so in the trophoblast by day 9.5.
      Later in gestation, extensive labelling was observed in both spongiotrophoblast
      and trophoblast giant cells. iNOS mRNA was also detected both in immature human
      placentae (16-18 weeks) and at term, predominantly in syncytiotrophoblasts and
      placental artery smooth muscle. In conclusion, iNOS is constitutively expressed
      in mouse and human placenta at a time and in a location that suggests a role in
      placentation.

PMID- 10333365
TI  - Current status of reproductive behaviour in Africa.
AB  - The current annual population growth rate of 3.2% in Africa will double the
      population by the year 2025. The majority of this population is below 15 years of
      age, and Africa concurrently also has the highest incidence of infertility in the
      world. Sexual behaviour, which has been poorly studied in Africa, has a direct
      impact on reproductive health [including fertility, infertility and sexually
      transmitted diseases (STDs)]. The multiple cultures and religions which
      characterize the African continent also affect reproductive health. Factors that
      have a significant effect on reproductive health in Africa include greater
      prevalence of extramarital/commercial sexual activity, polygamy, lower prevalence
      of contraceptives, reliance on traditional practices, high incidence of STDs and
      teenage pregnancies. High risk reproductive behaviours are predominantly
      displayed by adolescents, and the prevalence of STDs, including HIV (human
      immunodeficiency virus), is very high in this group. Pregnancy-related
      complications are the major cause of health-related problems in 15-19 year old
      girls. Maternal mortality rates in most countries remain high. Literacy rates
      affect these behaviours. It is apparent that changing the sexual behaviour of
      adolescents is one way of reversing the adverse trends, such as STD transmission,
      unwanted pregnancy and poor general reproductive health.

PMID- 10333366
TI  - Attitudes towards reproduction in Latin America. Teachings from the use of modern
      reproductive technologies.
AB  - The use of modern reproductive technology, such as in-vitro fertilization and its
      related procedures, has opened new areas of legal, religious and public concern.
      Thirty years ago, the development of effective methods to control procreation
      generated a debate on whether couples had the right to enjoy sex in the absence
      of its procreative effect. Today, assisted reproductive technology (ART) allows
      couples to have their own children in the absence of a direct intermediation of
      sex. The Catholic Church has reacted against both contraception and ART, and
      specific instructions have been directed to the public, the medical profession
      and legislators. In a recent survey, 88.4% of the population in Latin America
      claims to be Catholic; therefore, bioethical considerations and legal
      implications concerning intervention in reproduction are strongly permeated by
      the moral teachings of Catholicism. In 1996, 83 medical doctors and scientists,
      participating in the Latin American Network of Assisted Reproduction, produced a
      consensus document on ethical aspects and legal implications of ART. The document
      contains minimal ethical guidelines that Latin American professionals have
      decided to adhere to, even in the absence of legal regulations. This article
      examines how the medical profession, legislators and the public react to
      religious influence when confronted by difficult bioethical decisions such as the
      right to procreate.

PMID- 10333367
TI  - Social aspects in assisted reproduction.
AB  - In-vitro fertilization (IVF) and assisted reproductive techniques have become
      common practice in many countries today, regulated by established legislation,
      regulations or by committee-set ethical standards. The rapid evolution and
      progress of these techniques have revealed certain social issues that have to be
      addressed. The traditional heterosexual couple, nowadays, is not considered by
      many as the only 'IVF appropriate patient' since deviations from this pattern
      (single mother, lesbians) have also gained access to these treatments. Genetic
      material donation, age limitation, selective embryo reduction, preimplantation
      genetic diagnosis, surrogacy and cloning are interpreted differently in the
      various countries, as their definition and application are influenced by social
      factors, religion and law. Financial and emotional stresses are also often
      described in infertile couples. Information as deduced from the world literature
      regarding IVF regulation, as well as about the existing religious, cultural and
      social behaviours towards these new technologies, is presented in this article in
      relation to the social aspects of assisted reproduction.

PMID- 10333368
TI  - Endometriosis and unexplained recurrent spontaneous abortion: pathological states
      resulting from aberrant modulation of natural killer cell function?
AB  - The observation that natural killer (NK) cell activity is abnormally low in
      endometriosis patients and abnormally high in women with otherwise unexplained
      recurrent spontaneous abortion represents, at present, an intriguing curiosity.
      There is evidence suggesting that these conditions are associated with an
      opposite regulation of NK cell behaviour. This review discusses these
      observations and potential relationships.

PMID- 10333369
TI  - Leptin in human reproduction.
AB  - The recent discovery of the obese (ob) gene has provided new insight into the
      mechanism which controls body fat mass. Leptin, a product of the ob gene, serves
      as the link between fat and the brain. This protein, by acting at the level of
      the hypothalamus, decreases food intake and increases energy expenditure. Animals
      that lack leptin (ob/ob mice) develop profound obesity and become infertile.
      Treatment of these animals with leptin reduces food intake and restores normal
      fertility. Although leptin is important for the control of fat stores in certain
      species, the role of this substance in the development of human obesity remains
      obscure. However, it has been speculated that, in humans, obesity is related to
      leptin resistance. The relationship between fat and reproduction has been
      recognized for >20 years. This article discusses the relationship between leptin
      and human reproduction. In particular, recent knowledge about the possible role
      of leptin in various conditions such as puberty, polycystic ovary syndrome and
      pregnancy is reviewed. Also, the article discusses the possible role of leptin in
      ovarian function and the relationship of this protein with gonadal steroids. It
      is expected that future research will clarify the physiological importance of
      leptin in human reproductive function.

PMID- 10333370
TI  - Homocysteine--a pathophysiological cornerstone in obstetrical and gynaecological
      disorders?
AB  - Homocysteine, a product of the methionine cycle, is known to play an important
      role in cardiovascular diseases, neurological disorders and embryology, and in
      very important, fast growing fields concerning obstetrics and gynaecology.
      Therefore, we attempted an actual overview on possible obstetrical and
      gynaecological disorders as a consequence of an impaired methionine cycle. We
      tried to evaluate all mechanisms concerning homocysteine metabolism in order to
      look for hypothetical possibilities of therapeutic interventions. Using MEDLINE
      starting in January 1966, a search was conducted for articles published in which
      homocysteine was included as a subject heading or a text word. This search was
      also specified in combination with other key words such as obstetrics, pregnancy,
      gynaecology and cancer. Additional sources were identified through cross
      referencing. All sources found were examined with regard to providing substantial
      information on our topic. The information obtained was divided into articles
      dealing with homocysteine and the methionine cycle itself, homocysteine and
      pregnancy, and homocysteine and hormones, including menopause, hormone
      replacement therapy and oral contraceptives. Another group was concerned with
      other special gynaecological aspects of the methionine cycle. We suggest that
      elevated concentrations of homocysteine could be a marker and perhaps a cause of,
      or contributive to, a wide range of obstetrical and gynaecological disorders.

PMID- 10333371
TI  - Office mini-hysteroscopy.
AB  - The technique of diagnostic hysteroscopy has not yet been accepted generally as
      an ambulatory, well-tolerated office procedure. Especially in the infertile
      patient the standard hysteroscopic procedure is poorly tolerated in an office
      environment. Our prospective registration of 530 diagnostic office mini
      hysteroscopies in infertile patients demonstrates that using an atraumatic
      insertion technique, watery distention medium and the new generation of mini
      hysteroscopic endoscopes, hysteroscopy can be performed in an office set-up
      without any form of anaesthesia and with a high patient compliance. The
      significant number of abnormal findings (28.5%), the absence of complications and
      the low failure rate (2.3%) indicate that diagnostic office mini-hysteroscopy
      should be a first-line diagnostic procedure. Those results are compared with the
      registration of 4204 consecutive conventional diagnostic hysteroscopies in a
      routine gynaecological population performed between 1982 and 1989. We conclude
      that the mini-hysteroscopic system offers a simple, safe and efficient diagnostic
      method in the office for the investigation of abnormal uterine bleeding, to
      evaluate the cervix and uterine cavity in the infertile patient, for screening of
      endometrial changes in patients under hormone replacement therapy or anti
      oestrogens as (adjuvant) treatment and, lastly, it may be very helpful for the
      interpretation of uncertain findings in other diagnostic techniques such as
      ultrasound, magnetic resonance imaging, blind biopsy or hysterosalpingography.

PMID- 10333372
TI  - Sirenomelia. Pathological features, antenatal ultrasonographic clues, and a
      review of current embryogenic theories.
AB  - We aimed to discuss the prenatal diagnosis and pathological features of
      sirenomelia, and to review current embryogenic theories. We observed two
      sirenomelic fetuses that were at the 19th and 16th gestational week respectively.
      In the former, transvaginal ultrasound revealed severe oligohydramnios and
      internal abortion, whereas bilateral renal agenesis, absence of a normally
      tapered lumbosacral spine, and a single, dysmorphic lower limb were detected in
      the latter. In both cases, X-rays and autoptic examination allowed categorization
      on the basis of the skeletal deformity. Subtotal sacrococcygeal agenesis was
      present in both cases. Agenesis of the urinary apparatus and external genitalia
      and anorectal atresia were also found. Classification of sirenomelia separately
      from caudal regression syndrome is still debated. Recent advances in the
      understanding of axial mesoderm patterning during early embryonic development
      suggest that sirenomelia represents the most severe end of the caudal regression
      spectrum. Third-trimester ultrasonographic diagnosis is usually impaired by
      severe oligohydramnios related to bilateral renal agenesis, whereas during the
      early second trimester the amount of amniotic fluid may be sufficient to allow
      diagnosis. Early antenatal sonographic diagnosis is important in view of the
      dismal prognosis, and allows for earlier, less traumatic termination of
      pregnancy.

PMID- 10333373
TI  - Embryo transfer and uterine junctional zone contractions.

PMID- 10333374
TI  - Early human development.

PMID- 10333375
TI  - Brain metastases.
AB  - The topic of brain metastases has recently become a popular subject for review.
      The reasons for this most likely include technical advances in therapy, notably
      radiosurgery, as well as recently-published reports of phase III studies, which
      have addressed certain aspects of management, notably the combination of surgery
      and radiotherapy in the treatment of patients with a single metastasis. The main
      purpose of treatment is to reverse the patient's neurological deficits and
      prolong life. Nevertheless, opinions remain divided on whether meaningful
      clinical progress has been achieved overall. A clinician working in a tertiary
      referral center offering radiosurgery for a selected group of favorable patients
      may believe that the therapeutic nihilism of the past is no longer warranted,
      whereas another, whose experience is based on the management of patients dying
      from metastatic lung cancer, may still question the value of active treatment.
      The purpose of this review will be to try to reconcile these opinions by
      providing a critical analysis of the available evidence, identify current
      problems in management, and suggest future directions for clinical investigation.

PMID- 10333376
TI  - Effects of the CCK(B) antagonist CI-988 on responses to mCPP in generalized
      anxiety disorder.
AB  - In order to evaluate the effect of the CCK(B) antagonist CI-988 on behavioral,
      neuroendocrine, and physiologic responses to the mixed, post-synaptic serotonin
      (5-HT) agonist/antagonist mCPP, 16 patients with a principal DSM-III-R diagnosis
      of generalized anxiety disorder (GAD) were enrolled in a study that involved two
      challenge tests. On one day, patients received a single oral dose of CI-988
      followed 30 min later by an i.v. infusion of 0.1 mg/kg mCPP. On a second test day
      patients received placebo CI-988 followed 30 min later by active i.v. mCPP. The
      sequence of CI-988 was randomly assigned and the testing was conducted in double
      blind fashion. In an initial dose-finding phase (N = 6) with a dose of CI-988 of
      25 mg, there were no significant between-test differences in behavioral response
      to mCPP. Accordingly, the second phase of the study was conducted with a CI-988
      dose of 100 mg in another of patients (N = 10). CI-988 (100 mg) was well
      tolerated and had no significant effects on pretest anticipatory anxiety. There
      was no significant blunting of the anxiety response to mCPP as a result of CI-988
      administration, nor did CI-988 affect physiologic or neuroendocrine measures.
      Correlations between peak changes in plasma levels of CI-988 and mCPP-induced
      anxiety in the high-dose patient group were not significant. Overall, these
      findings did not provide evidence of anxiolytic effects of CI-988 in patients
      with GAD. The lack of effect of CI-988 on neuroendocrine and physiological
      measures further suggests that CI-988's pharmacological effects could be
      independent of 5-HT function. However, follow-up studies using higher doses of CI
      988 are indicated to confirm this preliminary finding as are studies more closely
      evaluating the interrelationship between CCK and 5-HT function in GAD.

PMID- 10333377
TI  - Behavioral effects of tryptophan depletion in seasonal affective disorder
      associated with the serotonin transporter gene?
AB  - There is some evidence that the neurotransmitter serotonin (5-hydroxytryptamine;
      5-HT) may be involved in the pathogenesis of seasonal affective disorder (SAD).
      Short-term tryptophan (TRP) depletion was carried out in 18 drug-free remitted
      patients who met DSM-IV criteria for SAD. Behavioral effects were measured with
      the Hamilton Depression Rating Scale (HDRS) both 24 h before and 24 h after TRP
      depletion. Some of the patients showed behavioral responses such as lowered mood,
      feelings of guilt, loss of interest, agitation, loss of energy, fatigue, social
      withdrawal, increased appetite, and carbohydrate craving. It was the aim of our
      study to investigate whether the genotypes of the serotonin transporter gene were
      associated with symptoms of transient depressive relapse after TRP depletion. In
      addition, we matched the SAD patients with healthy control subjects to see if
      alleles and genotypes of the serotonin transporter gene were associated with SAD.
      High molecular weight DNA was isolated from peripheral blood leukocytes using
      standard methods. For the 5-HTT receptor gene, a 17-bp repetitive element of
      intron 2 was genotyped (variable number tandem repeat, VNTR). Alterations in HDRS
      scores after TRP depletion showed no significant association with alleles or
      genotypes of the 5-HTT gene, although heterozygotes showed a trend toward
      increased HDRS scores. The serotonin transporter is known to play a critical role
      in the termination of serotonergic neurotransmission by sodium-dependent uptake
      of 5-HT into the presynaptic neuron. The present study in a small group of SAD
      patients was unable to demonstrate that the 5-HTT gene plays a role in the
      pathogenesis of SAD or in short-term depressive relapse after TRP depletion.

PMID- 10333378
TI  - Gender-specific mechanisms associated with outcome of depression: perception of
      emotions, coping and interpersonal functioning.
AB  - We proposed that a negative bias in the perception of facial expressions would
      affect the way in which deficient coping and interpersonal functioning influenced
      the risk of persistent depression. Furthermore, we hypothesised that cognitions,
      coping strategies, and interpersonal functioning would be more likely to
      contribute to the prediction of outcome of depression among women than among men.
      At admission, 60 in-patients with major depression judged 12 schematic faces with
      respect to the emotions that they expressed (fear, happiness, anger, sadness,
      disgust, surprise, rejection and invitation). In addition, difficulty in
      assertiveness and social distress, and coping strategies for dealing with
      stressful events were measured with self-report questionnaires. At admission and
      6 weeks later, the severity of depression was evaluated with the Beck Depression
      Inventory. Women who were inclined to perceive high levels of negative emotions
      from facial expressions and who reported high levels of social distress at
      admission were less likely to be improved after 6 weeks. Among women, these high
      levels of perception of negative emotions and high levels of social distress
      tended to predict the persistence of depression independently. A propensity to
      perceive negative facial expressions may underlie the unfavourable course of
      depression, especially among women.

PMID- 10333380
TI  - Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl
      esters of depressed patients.
AB  - Depression is associated with a lowered degree of esterification of serum
      cholesterol, an increased C20:4omega6/C20:5omega3 ratio and decreases in omega3
      fractions in fatty acids (FAs) or in the red blood cell membrane. The aims of the
      present study were to examine: (i) serum phospholipid and cholesteryl ester
      compositions of individual saturated fatty acids (SFAs), monounsaturated FAs
      (MUFAs) and polyunsaturated FAs (PUFAs) in major depressed patients vs. healthy
      volunteers; (ii) the relationships between the above FAs and lowered serum zinc
      (Zn), a marker of the inflammatory response in depression; and (iii) the effects
      of subchronic treatment with antidepressants on FAs in depression. The
      composition of the FAs was determined by means of thin layer chromatography in
      conjunction with gas chromatography. Lipid concentrations were assayed by
      enzymatic colorimetric methods. The oxidative potential index (OPI) of FAs was
      computed in 34 major depressed inpatients and 14 normal volunteers. Major
      depression was associated with: increased MUFA and C22:5omega3 proportions and
      increased C20:4omega6/C20:5omega3 and C22:5omega6/C22:6omega3 ratios; lower
      C22:4omega6, C20:5omega3 and C22:5omega3 fractions in phospholipids; lower
      C18:3omega3, C20:5omega3 and total (sigma)omega3 FAs, and higher
      C20:4omega6/C20:5omega3 and sigmaomega6/sigmaomega3 ratios in cholesteryl esters;
      lower serum concentrations of phospholipids and cholesteryl esters; and a
      decreased OPI. In depression, there were significant and positive correlations
      between serum Zn and C20:5omega3 and C22:6omega3 fractions in phospholipids; and
      significant inverse correlations between serum Zn and the
      sigmaomega6/sigmaomega3, C20:4omega6/C20:5omega3, and C22:5omega6/C22:6omega3
      ratios in phospholipids. There was no significant effect of antidepressive
      treatment on any of the FAs. The results show that, in major depression, there is
      a deficiency of omega3 PUFAs and a compensatory increase in MUFAs and C22:5omega6
      in phospholipids. The results suggest that: (i) there is an abnormal metabolism
      of omega3 PUFAs in depression; (ii) the FA alterations in depression are related
      to the inflammatory response in that illness; and (iii) the disorders may persist
      despite successful antidepressant treatment.

PMID- 10333379
TI  - Neurophysiologic predictors of treatment response to fluoxetine in major
      depression.
AB  - Treatment with antidepressants is marked by heterogeneity of response; predicting
      individual response to any given agent remains problematic. Neuroimaging studies
      suggest that response is accompanied by physiologic changes in cerebral energy
      utilization, but have not provided useful markers at pretreatment baseline. Using
      quantitative EEG (QEEG) techniques, we investigated pretreatment neurophysiologic
      features to identify responders and non-responders to fluoxetine. In a double
      masked study, 24 adult subjects with current major depression of the unipolar
      type were studied over 8 weeks while receiving fluoxetine (20 mg QD) or placebo.
      Neurophysiology was assessed with QEEG cordance, a measure reflecting cerebral
      energy utilization. Response was determined with rating scales and clinical
      interview. Subjects were divided into discordant and concordant groups based upon
      the number of electrodes exhibiting discordance. The concordant group had a more
      robust response than the discordant group, judged by lower final Hamilton
      Depression (HAM-D) mean score (8.0+/-7.5 vs. 19.6+/-4.7, P = 0.01) and final Beck
      Depression Inventory (BDI) mean score (14.0+/-9.4 vs. 27.8+/-3.7, P = 0.015), and
      by faster reduction in symptoms (HAM-D: 14.0+/-5.0 vs. 23.8+/-4.1, P = 0.004 at 1
      week). Groups did not differ on pretreatment clinical or historical features.
      Response to placebo was not predicted by this physiologic measure. We conclude
      that cordance distinguishes depressed adults who will respond to treatment with
      fluoxetine from those who will not. This measure detects a propensity to respond
      to fluoxetine and may indicate a more general responsiveness to antidepressants.

PMID- 10333381
TI  - Influence of psychological stress on immune-inflammatory variables in normal
      humans. Part II. Altered serum concentrations of natural anti-inflammatory agents
      and soluble membrane antigens of monocytes and T lymphocytes.
AB  - The effects of academic examination stress on serum concentrations of interleukin
      (IL)-1 receptor (R) antagonist (A), soluble(s) IL-2R, sIL-6R, soluble
      glycoprotein 130 (sgp130), Clara cell protein (CC16), sCD8 and sCD14 were
      evaluated in 38 university students. The relationships among changes in the above
      immune-inflammatory variables, levels of serum cortisol, and scores on the
      Perceived Stress Scale (PSS) or the State-Trait Anxiety Inventory (STAI) were
      examined. Academic examination stress was associated with significant increases
      in PSS and STAI scores, and in serum sgp130 and sCD8 values. Academic examination
      stress was associated with significantly decreased serum sCD14 concentrations in
      students with high, but not low, stress perception. There were stress-induced
      differences in serum IL-1RA, sIL-6R and CC16 concentrations between students with
      high vs. low stress-induced anxiety. The stress-induced increase in serum sCD8
      was significantly more pronounced in male students, whereas the increase in serum
      sgp130 was more pronounced in female students taking contraceptive drugs. These
      results suggest that: (1) psychological stress induces immune-inflammatory
      changes pointing toward complex regulatory responses in IL-6 signalling, a
      decreased anti-inflammatory capacity of the serum, and interactions with T cell
      and monocytic activation; and that (2) sex hormones may modify stress-induced
      immune-inflammatory responses.

PMID- 10333382
TI  - Characteristics of norepinephrine and clonidine displacement of [3H]yohimbine
      binding to platelet alpha2-adrenoreceptors in healthy volunteers.
AB  - Clonidine's estimates of platelet alpha2-adrenoreceptor (alpha2AR) density are
      substantially lower than yohimbine's. This discrepancy could have contributed to
      inconsistent results from studies on the role of alpha2AR in depression.
      Furthermore, few studies have investigated the relative distribution of alpha2AR
      between the high- and low-affinity states or their Gi protein coupling.
      [3H]yohimbine saturable binding to platelet alpha2AR, its displacement by
      norepinephrine and clonidine, and the effects of Gpp(NH)p on agonist displacement
      curves were investigated in 11 healthy volunteers. Clonidine estimates of
      alpha2AR density were close to norepinephrine estimates, and both were strongly
      correlated. Clonidine's K(L)/K(H) ratio was lower than norepinephrine's,
      consistent with its partial agonist nature. Norepinephrine and clonidine
      displacement curves revealed two affinity states. Gpp(NH)p induced a significant
      rightward shift to a single low-affinity state. When used in combination with a
      specific antagonist, clonidine's estimates of alpha2AR density were similar to
      those of norepinephrine's, and both were higher than previously reported, when
      clonidine was used alone. Re-evaluation of previous studies on alpha2AR in
      depression using clonidine is needed. The combined use of antagonist-saturation
      and agonist-displacement experiments to examine possible dysregulation in
      alpha2AR coupling to Gi protein in psychiatric disorders is recommended.

PMID- 10333383
TI  - Laboratory measures of aggression and impulsivity in women with borderline
      personality disorder.
AB  - To characterize how severe negative affect in women is reflected in objective
      measures of aggression and impulsivity, the aggressive and impulsive behavior of
      14 hospitalized women with borderline personality disorder (BPD) was compared
      with that of 17 controls. In an impulsivity task, subjects experienced two sets
      of 50 trials during which they could choose a smaller, immediate monetary reward
      or a larger but progressively delayed reward. In a separate task (PSAP), subjects
      earned monetary reinforcers with repeated button presses, and were provoked by
      the subtraction of money which was blamed on a fictitious other participant.
      Subjects could respond by ostensibly subtracting money from the fictitious
      subject (the aggressive response). While selection frequency of the short-delay
      responses was similar in patients and controls, BPD patients responded to avoid
      longer delay of reward across trials, and had higher Barratt Impulsiveness Scale
      total scores and attentional subscale scores. BPD patients responded to the money
      losses with roughly three times as many aggressive responses as controls and had
      higher Buss-Durkee Hostility Inventory (BDHI), Brown History of Violence, and
      Retrospective Overt Aggression Scale scores than controls. Aggressive responding
      rates correlated positively with BDHI scores. These results extend previous
      findings that negative affect in women is reflected in laboratory behavioral
      measures.

PMID- 10333384
TI  - Tracing steroid synthesis in plants.

PMID- 10333385
TI  - 19-Noraldosterone.

PMID- 10333386
TI  - Enzymology of phytosterol transformations.

PMID- 10333387
TI  - Isoprenoid biosynthesis in plants: carbon partitioning within the cytoplasmic
      pathway.

PMID- 10333388
TI  - Mevalonate biosynthesis in plants.

PMID- 10333389
TI  - Lanosterol analogs: dual-action inhibitors of cholesterol biosynthesis.
AB  - Drugs which suppress hepatic cholesterol biosynthesis are important therapeutic
      tools for lowering serum cholesterol, a major risk factor in coronary heart
      disease. With the goal of developing molecules that will effectively shut down
      cholesterol biosynthesis in hepatic tissue but allow for the buildup of the
      isoprenes needed for the biosynthesis of polyisoprenes other than sterols, we
      have designed and evaluated a series of lanosterol analogs to act as dual-action
      inhibitors of cholesterol biosynthesis. These sterols were predicted to act as
      competitive inhibitors of lanosterol 14alpha-methyl demethylase (P-450DM) and as
      partial suppressors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR),
      the rate-limiting enzyme in the pathway. Compounds which have been identified as
      dual-action inhibitors of cholesterol biosynthesis include analogs of the
      intermediates generated during the removal of the 14alpha-methyl group of
      lanosterol by P-450DM, aminolanosterols with the amine nitrogen placed in the
      vicinity of C-32, and lanosterol analogs with a ketone or oxime functionality at
      C-15. While some dual-action inhibitors require an active P-450DM for suppression
      of HMGR activity, others do not. The inability of some compounds to suppress HMGR
      activity in cells which lack P-450DM activity suggests either that these
      compounds require P-450DM for conversion to an active metabolite which then
      suppresses HMGR activity, or that they cause the accumulation of the natural
      demethylation intermediates resulting in the suppression of HMGR activity.
      Lanosterol analogs, in contrast to 25-hydroxycholesterol, do not inhibit
      transcription of the HMGR gene. Rather, they inhibit translation of the HMGR
      mRNA, and in most cases also accelerate the degradation of enzyme protein. The
      potential pharmacological utility of cholesterol biosynthesis inhibitors may be
      determined at least in part by their effects on LDL receptor (LDLR) activity. The
      transcriptional regulator 25-hydroxycholesterol suppresses both HMGR and LDLR
      activities, while the post-transcriptional regulatory lanosterol analogs exhibit
      a more desirable profile, lowering HMGR levels without suppressing LDLR
      expression, and in some cases actually enhancing cellular LDL metabolism.
      Lanosterol analogs which function as dual-action inhibitors of cholesterol
      biosynthesis promise to be useful not only as tools for dissecting the cellular
      regulation of cholesterol metabolism, but also as models for the development of
      safe, effective hypocholesterolemic agents.

PMID- 10333390
TI  - Prophylactic amnioinfusion in preganancies complicated by chorioamnionitis: a
      prospective randomized trial.
AB  - The objective of this article is to prospectively investigate the efficacy of
      amnioinfusion as a means to reduce febrile morbidity in pregnancies complicated
      by chorioamnionitis. All laboring patients with a temperature > or =100.1 degrees
      F were approached for study participation. Exclusion criteria included amnionitis
      diagnosed at greater than 8 cm dilation, multiple gestation, placental abruption,
      or a nonreassuring fetal heart rate tracing. Consenting patients were randomized
      to receive antibiotics (ampicillin or penicillin with gentamicin) and
      acetaminophen with or without amnioinfusion. All patients received intrauterine
      pressure catheter placement. For study patients, normal saline at room
      temperature was infused at 10 mL/min for 60 min, then 3 mL/min until delivery.
      Postpartum endometritis was defined as a temperature = 100.4 degrees F
      accompanied by uterine tenderness more than 12 hr after delivery. Statistical
      analysis was performed using the Student's t-test for continuous data and Chi
      square for discrete variables. Thirty-six patients were enrolled, and complete
      data were available for 34 patients (17 in each group). There were no differences
      between groups with respect to maternal age, gravidity, race, or gestational age.
      There were also no differences between groups in duration of rupture of
      membranes, temperature at randomization, interval from randomization to delivery,
      cesarean section rate, or umbilical cord arterial pH. The mean temperature at the
      time of delivery was 99.8+/-0.9 degrees F for the amnioinfusion group versus
      100.5+/-1.0 degrees F for the control group (p=0.046). Three of 17 amnioinfusion
      patients and 3 of 17 control patients had postpartum endometritis. There was 1
      neonatal infection in the treatment group and no neonatal infections among the
      control patients. Prophylactic amnioinfusion was associated with a decline in
      temperature at the time of delivery. No untoward effects from the amnioinfusion
      were identified.

PMID- 10333391
TI  - Aneurysm of the ductus arteriosus: a congenital lesion.
AB  - The objective of this study was to evaluate the clinical, radiological, and
      echocardiographic findings in 11 neonates with aneurysm of ductus arteriosus
      presented in our institutions between 1993 and 1996, and to postulate a new
      theory for the pathogenesis of this lesion. Medical records, radiographic
      studies, and echocardiograms were reviewed. All infants underwent follow-up
      echocardiograms every 2 to 3 days until the aneurysm spontaneously resolved or
      surgery was performed. The infants were predominantly term males; six had
      evidence of fetal distress, two were diagnosed prenatally by fetal
      echocardiogram, chest X ray evidenced mediastinal mass in six patients. The first
      echocardiogram showed structurally normal heart with an aneurysmal patent ductus
      arteriosus. In eight patients the aneurysm completely resolved by 5 to 10 days.
      One infant underwent surgical resection of the aneurysm after observation for 11
      days with no change in size. Thrombosis of the aneurysm was noted in two
      patients; both underwent surgery. Increasing reports of ductal aneurysms in
      infants may reflect the availability of high-resolution echocardiography and more
      frequent use of echocardiography in the neonatal intensive care unit. Spontaneous
      resolution occurred in the majority of cases as in previous reports. We postulate
      that, at least in some cases, aneurysm of the ductus arteriosus is a congenital
      lesion that may represent poststenotic dilation of the ductus due to turbulent
      flow through a stenotic segment at its pulmonary artery end during fetal life.
      The presence of aneurysm of the ductus arteriosus should be excluded in selected
      cases of fetal distress, by fetal echocardiography.

PMID- 10333392
TI  - Role of fetal echocardiography in the management of isolated fetal heart block
      with ventricular rate <55 bpm.
AB  - Persistent bradycardia is an uncommon cardiac problem in fetuses but carries a
      high mortality in those with a ventricular rate <55 bpm. Fetal heart block is one
      of the most common causes of persistent fetal bradycardia (PFB). An optimal
      method for assessing and monitoring cardiovascular compensation in the setting of
      PFB due to heart block has not been fully established. We report the application
      of two-dimensional and Doppler echocardiography in close monitoring of cardiac
      function and hemodynamics in a third-trimester fetus with a ventricular rate <55
      bpm due to heart block, which assisted in successful management of the pregnancy
      to term. Hemodynamic and cardiac adaptive changes in compromised fetuses,
      particularly due to heart block, are discussed.

PMID- 10333393
TI  - Perinatal monitoring of fetal well-being in the presence of congenital heart
      block.
AB  - We present a case of congenital complete heart block associated with maternal
      autoantibodies in which a normal labor and delivery could safely be allowed to
      proceed despite the absence of the usual tool of electronic fetal heart rate
      monitoring for fetal distress, by the technique of rupturing membranes and using
      a fetal scalp electrode electrocardiographic tracing to assess the fetal atrial
      rate.

PMID- 10333394
TI  - The need for delivery room intubation of thin meconium in the low-risk newborn: a
      clinical trial.
AB  - The delivery room management of meconium-stained amniotic fluid remains
      controversial. We attempted to determine if intubation of the low-risk newborn
      with thin meconium affects the incidence of respiratory symptoms. Exclusion
      criterion included moderate or thick meconium, fetal distress, neonatal
      depression, or prematurity. Eligible infants were randomized to either an
      intubation (group I) or to a nonintubation group (group II). The outcome was the
      presence of respiratory symptoms. Patients were studied from May 1994 to June
      1997. There were 8967 births during this period: 7.9% (708/8967) were delivered
      through meconium. Thin meconium was noted in 50.3% (356/708) of all births.
      24/356 infants with thin meconium were excluded for medical criterion. One
      hundred sixty-three infants were medically eligible but could not be randomized
      due to lack of consent, late arrival of the team, or obstetrician request. These
      were placed into intubation (group I B) and nonintubation (group II B) groups.
      Seventy-seven infants were randomized into group I and 92 infants into group II.
      From the intubation groups I and I B, one required supplemental oxygen and was
      weaned to room air in 7 hr. From the nonintubation groups II and II B, two
      infants required oxygen, weaning to room air in 11 and 46 hr. Comparing birth
      weight, gestational age, sex, mode of delivery and 5-min Apgar, there were no
      significant differences. However, the intubation groups had significantly lower 1
      min Apgar scores. There was no airway morbidity reported in the intubation
      groups. In the infant with thin meconium and an otherwise low-risk pregnancy, we
      were unable to demonstrate a difference in respiratory symptoms with intubation
      and intratracheal suctioning.

PMID- 10333395
TI  - Dual roles of amniotic fluid nitric oxide and prostaglandin E2 in preterm labor
      with intra-amniotic infection.
AB  - We hypothesized that induction of nitric oxide synthase and cyclo-oxygenase-2 by
      bacterial products in intra-amniotic infection could increase the production of
      proinflammatory nitric oxide and prostaglandin E2 (PGE2) and cause preterm labor.
      Thus, we sought to determine amniotic fluid levels of nitric oxide metabolites
      (NOx) and PGE2 in preterm labor patients with and without intra-amniotic
      infection. Amniotic fluid from 13 preterm labor patients with intra-amniotic
      infection and 24 without intra-amniotic infection were studied. Intra-amniotic
      infection was defined as the presence of a positive amniotic fluid culture.
      Amniotic fluid was tested for NOx, PGE2, glucose, leukocyte counts, Gram stains,
      creatinine, pH, and specific gravity. NOx was determined using Griess reagent
      after reduction of nitrate to nitrite with aspergillus nitrate reductase. PGE2
      was measured by an enzyme-linked immunoassay. Both amniotic fluid NOx and PGE2
      were normalized by amniotic fluid creatinine. We found that amniotic fluid
      concentrations of NOx and PGE2 were significantly higher in preterm labor
      patients with intra-amniotic infection compared to those without intraamniotic
      infection (NOx: median 1.8 micromol/mg creatinine, range 0.7 to 6.8 vs. 1.3
      micromol/mg creatinine, range 0.9 to 2.1, p=0.03; PGE2: median 33.5 ng/mg
      creatinine, range 0.0 to 1048.6 vs. 0.0 ng/mg creatinine, range 0.0 to 33.6,
      p=0.004). In addition, amniotic fluid NOx and PGE2 were positively correlated
      (r=0.343, p=0.0398). We conclude that there may be an interaction between the
      nitric oxide and prostaglandin pathways in intraamniotic infection. Increased
      production of amniotic fluid pro-inflammatory nitric oxide and PGE2 may play an
      important role in the pathogenesis of preterm labor in patients with intra
      amniotic infection.

PMID- 10333396
TI  - Congenital erythroleukemia in a neonate with severe hypoxic ischemic
      encephalopathy.
AB  - We report a case of a neonate who presented with hypoxic ischemic encephalopathy,
      persistent hypoglycemia and hypotension, intractable metabolic acidosis, renal
      failure and a coagulopathy but who, at autopsy, was found to have massive
      infiltration of nonhematopoietic tissues with blasts. The diagnosis of congenital
      erythroleukemia was confirmed by the detection of glycophorin A, a major
      erythrocyte membrane protein, on the surface of the blasts. The clinical
      presentation and course of the case described here have not previously been
      reported for this extremely rare condition.

PMID- 10333398
TI  - Stem cells and cloning: what's the difference and why the fuss?

PMID- 10333397
TI  - Prognostic factors and management in pregnancies complicated with severe kell
      alloimmunization: experiences of the last 13 years.
AB  - Because of the recent referral of an anti-Kell sensitized pregnant woman, whose
      fetus became severely anemic despite intensive antepartum surveillance, the
      prevalence and characteristics of fetal Kell isoimmunization were reviewed and
      analyzed. Cases with Kell and RhD alloimmunization requiring intrauterine
      intravascular transfusions (IUT) at the Mount Sinai Medical Center during the 13
      year period ending March 1998 were compared. Thirty-six fetuses with RhD and 5
      with Kell isoimmunization required IUTs. Lower fetal and neonatal hematocrit
      levels were observed in the RhD group. A significantly higher incidence of
      polyhydramnios was found among fetuses with Kell isoimmunization and the maternal
      serum titers were much lower than those in the RhD group. DeltaOD450 values did
      not reliably reflect the Kell sensitized fetus's condition. There were no
      intrauterine deaths or neonatal direct hyperbilirubinemia in the Kell group, and
      the hemolytic disease of the newborn was more severe in the RhD group. Although
      the course of the hemolytic disease in our cases of Kell isoimmunization showed a
      better prognosis than that in the RhD group, the importance of this condition
      should not be underestimated, and differences in the pathophysiology of Kell and
      RhD alloimmunization should be taken into consideration during the management of
      these cases.

PMID- 10333399
TI  - Development, evolution, and corroboration.
AB  - The cloning of genes involved in pathways fundamental to morphogenesis has opened
      the door to visualizing expression of developmental regulatory genes in many
      organisms. Expression data have become technical commonplace in analysis of
      mutants of Drosophila melanogaster and a handful of other genetic model systems.
      Many researchers have used probes and extended the logic from studies of D.
      melanogaster for comparisons of expression patterns to infer developmental bases
      for homologous structures among animals with diverse body plans. This research
      program has led to exciting but sweeping generalizations about how development
      evolves. Here we examine several underlying assumptions of this approach in terms
      of comparative and historical biology. First, we evaluate the logic that
      underlies the equation of gene expression similarity with homologous morphology.
      Second, we examine epistemological issues surrounding the descriptive
      visualization of gene expression patterns. We conclude by examining the role of
      phylogenetic coding and mapping of these patterns to examine the evolution of
      complex gene regulatory networks.

PMID- 10333401
TI  - Embryonic stem cell models of development.
AB  - Pluripotent mouse embryonic stem (ES) cell lines have provided a means to analyze
      gene function in development via gene targeting. At the same time, they provide
      an opportunity to directly probe gene function by assessing the in vitro
      differentiation capacity of the ES cells themselves. In addition to providing
      direct data on lineage decisions not accessible in the complex three-dimensional
      milieu of the early mouse embryo, controlled differentiation of ES into specific
      lineages may provide a source of cells for transplantation and gene therapy.

PMID- 10333400
TI  - Homeobox genes, fossils, and the origin of species.
AB  - Ever since Darwin there has been a history of debate on the tempo and mode of
      evolution. Is speciation a gradual process involving the accumulation of minute
      variations extant within a species, or is it rapid, the result of major
      organismal reorganization? Does one define a species on the basis of genes,
      morphology, or geographic or reproductive isolation? In this communication I
      present a model of evolutionary change that is based on the Mendelian inheritance
      of mutations in regulatory genes and the fact that most nonlethal mutations arise
      in the recessive state. Since the new recessive allele will spread through many
      generations without expression until there is a critical mass of heterozygotes
      capable of producing homozygotes for the mutation, the novel feature thus
      produced will appear abruptly in the population and in more than one individual.
      This picture of punctuation is consistent with the fossil record, which typically
      fails to provide evidence of smoothly transitional states of morphological
      change. Given that the first of their kind in the fossil record are organisms in
      which their novel characteristics are often more fully expressed or complex than
      in their descendants, it would seem that, after the mutation involving a
      regulatory gene is introduced, the general tendency is for its effects to become
      diminished. Among the implications for speciation is that this process does not
      depend on either reproductive isolation or genetic incompatibility. Rather,
      barring effects on reproductive organs or behavior, homozygotes for a novelty
      should be able to breed with heterozygotes and homozygotes for the wild state of
      the original population. This, in turn, suggests that the species barrier between
      individuals is probably a matter of mate recognition.

PMID- 10333402
TI  - Double staining of skeleton using microwave irradiation.
AB  - The fetal skeleton double staining method is used to reveal developmental
      abnormalities in the skeletal system. We used alizarin red S and alcian blue
      successfully with microwave irradiation for skeletal double staining. The
      fixation time was reduced from 4-7 days to 2-2.5 min and the staining time was
      reduced from 4 days to 23 min.

PMID- 10333404
TI  - Morphological analysis of the interaction of charged surfactant vesicles (SVs)
      with human cultured cells.
AB  - We analyzed the binding and fusogenic properties of surfactant vesicles (SVs),
      composed of ionic and nonionic surfactants and cholesterol, with the surface of
      different human lymphoid cells. The influence of charge on SVs-cell interaction
      was evaluated by monitoring the presence of fluorescent sodium calcein
      artificially entrapped in the vesicles using optical fluorescence microscopy and
      laser scanning confocal microscopy. Our results clearly indicate that only
      negatively charged vesicles bind and fuse with the plasma membrane of human
      lymphoid cells, and the number of SVs bound to the cell surface was variable
      among the positive cells. Thin section electron microscopy illustrated that the
      fusogenic events of SVs with the cell plasma membrane mostly occurred at smooth
      and nonvillous regions of the cell surface. Taken together, our results suggest
      that binding and fusion of SVs with the cell plasma membrane might be dependent
      on interactions with specific membrane components that preferentially recognize
      negatively charged SVs.

PMID- 10333403
TI  - Evaluating mitotic activity in canine and feline solid tumors: standardizing the
      parameter.
AB  - Three different methods for evaluating mitotic activity (mitotic count,
      mitoses/area, mitotic index) were applied to different types of canine and feline
      solid tumors to determine the method that is most objective and correlates best
      with other parameters of cell proliferation. Mitotic activity was evaluated on
      toluidine blue stained histological sections. Slides stained with histochemical
      (AgNOR proteins) and immunohistochemical (MIB1, PCNA) markers of cell
      proliferation were available for each case. Quantitation of mitotic activity and
      cell proliferation parameters was performed with an image analyzer. Mitotic
      activity assessment was compared with cell proliferation indices and its ability
      to discriminate tumors grouped on histologically based criteria including the
      histological type, malignant or benign characteristics, and grade. A significant
      correlation by linear regression analysis with other parameters assessing cell
      proliferation revealed that mitotic index correlated 1000% and mitoses/area and
      mitotic count correlated 40% of the time. In discriminating the proliferative
      activity of tumors grouped by histological criteria, mitotic index and mitotic
      count revealed 1000% concordance with the other parameters of cell proliferation,
      while mitoses/areas showed 80% concordance.

PMID- 10333405
TI  - Immunocytochemical detection of structural and regulatory proteins in rat adrenal
      nuclear matrix.
AB  - The nuclear matrix is a specific cell structure consisting of a residual
      nucleoskeleton that extends from the nucleoli to the nuclear envelope. The
      nuclear matrix of steroidogenic cells was isolated previously from a purified
      nuclear fraction. We present here an in situ extraction method, modified Lutz's
      method, for rat glandular adrenal cell nuclear matrix. This residual organelle
      was characterized and studied using immunocytochemical methods. The adrenal
      glands were removed, the cells prepared in suspension and deposited by cytospin
      onto Poly-L-lysine glass slides. The nuclear matrix was extracted with Nonidet P
      40, DNase I and high and low ionic strength buffers. Structural proteins, nuclear
      lamins, coilin and fibrillarin were detected immunocytochemically. The adrenal
      fasciculata cells were easily identified by this method because of their large
      nuclei and abundant lipid droplets in the cytoplasm. After immunocytochemical
      detection by antibodies against lamins A and C, a marked brown layer at the
      periphery of the nucleus was observed. The intensity of the staining was lower
      using the antibody against nuclear lamin B. Immunocytochemical detection of the
      protein coilin revealed punctuated stained areas, 2-6 per nucleus, that probably
      correspond to the coiled bodies. The protein fibrillarin was detected at the
      nucleolus and coiled bodies. Our technique is simple, reveals well preserved
      adrenal nuclear matrices, and may be a useful method for immunocytochemical
      analysis and in situ hybridization.

PMID- 10333406
TI  - Quantitative analysis of immunofluorescent signals for dystrophin, beta
      dystroglycan and myosin skeletal muscle by epifluorescence microscopy.
AB  - Quantitative analysis of signal intensities in immunostained sections has been
      performed in only a few studies owing to difficulties with quantifying amounts of
      antigen present. We determined correlations between fluorescent signal
      intensities and amounts of antigen in muscle cryosections by altering section
      thickness from 4 to 10 microm. Fluorescent signals of dystrophin. beta
      dystroglycan and myosin were detected with monoclonal and/or polyclonal primary
      antibodies using routine procedures. Confocal laser microscopy demonstrated that
      these signals were distributed uniformly along the z-axis suggesting that the
      antibodies permeated well through the sections. Epifluorescence microscopy with
      microfluorometry demonstrated a positive correlation between the optical density
      of signals and section thickness. These findings suggest that immunofluorescent
      signals can be quantitated by epifluorescence microscopy.

PMID- 10333407
TI  - An automated technique for double staining rat and rabbit fetal skeletal
      specimens to differentiate bone and cartilage.
AB  - Assessment of chemicals for their potential to cause developmental toxicity must
      include evaluation of the development of the fetal skeleton. The method described
      here is an improved and fully automated double staining method using alizarin red
      S to stain bone and alcian blue to stain cartilage. The method was developed on
      the enclosed Shandon Pathcentre, and the quality of specimens reported here will
      be reproduced only if carried out on a similar processor under the same
      environmental conditions. The staining, maceration and clearing process takes
      approximately 6 days. The personnel time, however, is minimal since solutions are
      changed automatically and the fetuses are not examined or removed from the
      processor until the procedure is completed. Upon completion of processing, the
      bone and cartilage assessment of the specimens can be carried out immediately if
      required. Full evaluation of skeletal development in both the rat and the rabbit
      is necessary to meet the requirements of safety assessment studies. This method
      allows this to be accomplished on a large scale with consistently clear specimens
      and in a realistic time.

PMID- 10333408
TI  - Diaminobenzidine as a myelin stain in semithin plastic sections.
AB  - A diaminobenzidine (DAB) stain for myelin in glutaraldehyde fixed, osmicated,
      semithin epoxy sections is described. One or 1.5 microm sections, dried onto
      slides, are first etched with a 1:2 dilution of saturated sodium
      ethoxide:absolute ethanol, then incubated in 0.05% aqueous DAB with 0.01%
      hydrogen peroxide. DAB specifically stains osmium fixed myelinated nerve fibers.
      This permits high resolution light microscopic study of myelinated nerve fibers
      in semithin sections of tissues that also can be studied by electron microscopy.

PMID- 10333409
TI  - Histopathological assessment of multidrug resistance in gastric cancer:
      expression of P-glycoprotein, multidrug resistance-associated protein, and lung
      resistance protein.
AB  - Because local recurrence is common after a curative resection for advanced
      gastric cancer, there has been significant interest in adjuvant chemotherapy.
      However, the overall effect of chemotherapy remains debatable regarding patients
      with advanced gastric adenocarcinoma. Multidrug resistance is thought to be a
      major cause of failure in cancer chemotherapy, and thus the expression of P
      glycoprotein (P-Gp), multidrug resistance-associated protein (MRP), and lung
      resistance protein (LRP) in tumor cells was evaluated by immunohistochemistry. In
      20 gastric adenocarcinomas, 11 (55%), 2 (10%), and 0 (0%) were positive for MRP,
      LRP, and P-Gp. In malignant lymphomas, only 3 out of 10 cases were positive for
      MRP (30%). The positive rate of MRP staining was significantly higher in well and
      moderately differentiated adenocarcinomas (80%) than in poorly differentiated
      adenocarcinomas (20%). With regard to the degree of MRP expression and
      histological cell type, higher grades (grade 2-3) were observed only in well and
      moderately differentiated adenocarcinomas. In terms of the positive-stained cells
      and staining intensity, heterogeneity was observed in the staining profile of
      MRP. The proliferative cell nuclear antigen labeling index (PCNA LI) of MRP
      positive and MRP-negative cases was 49.3% +/- 11.6% and 49.4 +/- 6.9%,
      respectively. No correlation was observed between the MRP expression and PCNA LI.
      In conclusion, the incidence of MRP expression in gastric cancer was the highest
      in three different multidrug resistance-related epitopes. An evaluation of the
      MRP expression thus seemed to be beneficial for determining the optimal strategy
      of chemotherapy.

PMID- 10333411
TI  - Repair of an acute type A dissection: fate of the remnant false lumen and
      preserved aortic valve.
AB  - From January 1992 through March 1997, 75 patients (DeBakey type I/II = 56/19)
      underwent a surgical repair of a type A acute dissection. The patients included
      37 men and 38 women ranging in age from 23 to 83 years with a mean of 65 years.
      All patients were admitted to our hospital with a mean interval of 2.2 days from
      the episode of onset. The overall hospital mortality rate was 25% (19/75). There
      were three late deaths among the 56 patients discharged from the hospital. The
      actuarial survival rate for the patients surviving the operation was 87% at 5
      years after repair. A subsequent aortic operation was necessary in 6 patients,
      while 3 other patients who had late aortic complications were put on medical
      therapy alone. As a result, the aortic event-free survival rate was 54% at 5
      years. For a type I dissection the false lumen was completely thrombosed after
      repair in 34%. The descending thoracic aorta with a patent false lumen was
      markedly enlarged in proportion to the follow-up time. After a conservative
      approach to the aortic valve, all but one patient demonstrated an adequate valve
      function throughout this study period. This experience with a midterm follow-up
      showed an acceptable durability of the preserved aortic valve and a progressive
      enlargement of the persistent false lumen with a high rate of aortic
      complications. Hence, all patients with a type A dissection need a close follow
      up to assess the aorta for complications of either recurrent or residual
      aneurysms and dissections.

PMID- 10333410
TI  - Immunohistochemical distribution of bombesin-positive pulmonary neuroendocrine
      cells in a congenital diaphragmatic hernia.
AB  - Morphometrical analyses of the immunohistochemical expression of bombesin, which
      is one of the peptides produced by pulmonary neuroendocrine (PNE) cells, were
      carried out on the bronchioles of human congenital diaphragmatic hernia (CDH)
      neonates, and the findings were then compared with those in a gestational and
      postnatal age-matched control group. As a result, no difference was found in the
      number of bombesin-positive cells between the lungs of the control group and the
      unaffected side lungs in the CDH group except for the ratio of the bombesin
      positive cells per unit of the bronchiolar surface area (P < 0.05). However,
      compared with the lungs in the control group, the affected side of the lungs in
      the CDH group showed a significant increase in the expression of bombesin,
      namely, the ratio of the bombesin-positive cells per bronchiole (P < 0.05), the
      ratio of the bombesin-positive cells per unit perimeter of the bronchioles (P <
      0.05), and the ratio of the bombesin-positive cells per unit of the bronchiolar
      surface area (P < 0.01). These results thus suggest that hyperplasia of the PNE
      cell system in the lungs of the CDH cases, especially on the affected side,
      exists in human fetuses. We also further speculate that PNE cells may thus play a
      role in the problems associated with CDH during intrauterine life in human
      beings.

PMID- 10333413
TI  - Successful surgical treatment of aortogastric fistula after an esophagectomy and
      subsequent endovascular graft placement: report of a case.
AB  - An aortogastric fistula is a rare but fatal complication after an esophagectomy
      and intrathoracic esophagogastric anastomosis. A 54-year-old man underwent an
      esophageal resection due to carcinoma in his lower esophagus. The alimentary
      tract continuity was restored by intrathoracic esophagogastric anastomosis. Forty
      six days later, he suffered a massive hematemesis due to an aortogastric fistula
      which had formed at the esophagogastric suture line. The fistula was surgically
      obliterated twice, but each operation was followed by pseudoaneurysm formation.
      The patient was finally successfully treated with an endovascular stent graft
      placement. This is the first report of a patient surviving after developing this
      complication.

PMID- 10333412
TI  - Improvement in the intestinal processes of hydroelectrolytic absorption and
      secretion in abdominal pathologies of surgical interest treated with SMS 201-995:
      experimental protocol.
AB  - The hypothesis that octreotide can improve the intestinal absorption and
      secretion processes in a mixed group of intestinal pathologies, and that this
      effect varies according to the pathology in question, was tested. One hundred and
      twenty Wistar rats were randomly assigned to six pathology groups consisting of
      three intestinal occlusions including (1) complete, (2) partial, and (3) complete
      with strangulation, and three mesenteric vascular occlusions including (4)
      partial permanent, (5) total permanent, and (6) total temporary. Each group
      contained ten control and ten treated rats. The treated animals received
      octreotide (100 microg/kg body weight) while the controls were given the same
      quantity of saline solution every 8 h. After the observation period, the contents
      of the small intestine were extracted and its volume measured before and after
      centrifugation; the concentration and total content of Na, K, Cl, and bicarbonate
      was then analyzed. Samples of all the intestines at specific distances from the
      lesion zone were treated and stained, and then evaluated according to a specific
      score to quantify the lesions. The concentration and contents of electrolytes in
      the intestine and its volume (before and after centrifugation) were lower in the
      treated animals, but varied according to the pathology. There was a nonadditive
      influence between the type of pathology and treatment for the four electrolytes
      and intestinal volume. The effects of the drug make it directly or indirectly
      possible to decrease the intestinal lesions to improve the absorption-secretion
      processes. Octreotide acts on intestinal secretion and absorption in all the
      pathologies analyzed except for total permanent intestinal ischemia. Its action
      also varies according to the type of pathology involved.

PMID- 10333414
TI  - Aortoduodenal fistula arising from the dilatation of a knitted Dacron graft:
      report of a case.
AB  - A fatal aortoduodenal fistula occurred in a 72-year-old man who underwent a
      repair of an abdominal aortic aneurysm 16 years previously with a 20 x 10 mm
      bifurcated knitted Dacron graft. The aortic part of his bifurcated graft had
      dilated to 40 mm in diameter, with a discrepancy of 20 mm in the diameter between
      the graft and infrarenal aorta. The fourth portion of the duodenum adhered to the
      left side of the anastomosis, where the aortoenteric fistula had occurred. We
      believe that the graft dilatation was the cause of the anastomotic failure,
      although other factors such as atherosclerotic degeneration of the host aorta
      should also be considered. Knitted Dacron grafts that have been implanted for
      more than 10 years should therefore be monitored carefully because they have an
      inherent tendency to dilate, especially those manufactured before 1981.

PMID- 10333415
TI  - Malignant hemangioendothelioma of the small intestine: report of a case.
AB  - A case of malignant hemangioendothelioma (MH) of the small intestine in a 27-year
      old woman is reported herein. The patient developed acute abdominal symptoms
      during investigations for anemia, weight loss, anorexia, and recurrent
      gastrointestinal bleeding. An emergency laparotomy revealed perforation of a
      jejunal tumor. The results of a histopathological study of the resected small
      bowel segment were interpreted as MH with lymph node involvement. Following this
      case report, a review of the relevant literature on small intestinal MH is
      presented.

PMID- 10333416
TI  - Successful transvaginal repair of a rectovaginal fistula developing after double
      stapled anastomosis in low anterior resection: report of four cases.
AB  - The management of postoperative rectovaginal fistula (RVF) after low anterior
      resection for rectal cancer is difficult and the results are often
      unsatisfactory. Among 140 patients with rectal cancer who underwent low anterior
      resection with a double-stapled anastomosis at our hospital between 1986 and
      1996, 4 (2.9%) developed RVF as a postoperative complication. The RVF developed
      gradually from 9 to 128 days after low anterior resection. We describe herein our
      technique of using a modified transvaginal approach for RVF repair with a
      diverting colostomy. In all four patients, the RVFs were completely eradicated
      with reestablishment of intestinal continuity and did not recur during the mean
      follow-up period of 29.5 months, ranging from 12 to 67 months. This report serves
      to demonstrate that emerging RVFs secondary to stapled anastomosis in low
      anterior resection for rectal cancer must be recognized, and that a modified
      transvaginal approach provides an effective method of repair.

PMID- 10333417
TI  - Laparoscopic ileocecal resection for Crohn's disease associated with intestinal
      stenosis and ileorectal fistula.
AB  - Although a complete remission of Crohn's disease can be induced by conservative
      therapy, surgical treatment is often required for patients with intestinal
      stenosis or fistulas, for whom minimally invasive laparoscopic surgery appears to
      be most appropriate. We herein report on a 26-year-old patient with Crohn's
      disease, who presented with an ileorectal fistula and severe stenosis of the
      terminal ileum and thus underwent laparoscopic surgery. The ileorectal fistula
      was divided intracorporeally using an autostapling device. The return to full
      activity after laparoscopic surgery is earlier than after open surgery, and the
      former approach is often beneficial for some patients with Crohn's disease. This
      is the first report of laparoscopic surgery for Crohn's disease associated with
      ileorectal fistula.

PMID- 10333418
TI  - Ovarian carcinoma with fistula formation to the sigmoid colon and ileum: report
      of a case.
AB  - We describe herein an extremely rare case of clear cell type ovarian carcinoma
      resulting in fistula formation into the colon and intestine. The patient was a 61
      year-old woman in whom a large tumor with extravasation from the sigmoid colon
      was found by barium enema examination. The tumor was preoperatively diagnosed as
      left ovarian cancer by angiography which showed the tumor feeder arising from the
      left ovarian and uterine arteries.

PMID- 10333419
TI  - Successful surgical treatment for implanted intraperitoneal metastases of
      ruptured small hepatocellular carcinoma: report of a case.
AB  - We report herein the case of a 53-year-old man with disseminated intraperitoneal
      metastases caused by the rupture of small hepatocellular carcinoma (HCC). He was
      admitted to our hospital in shock after suffering a trauma injury to the upper
      abdomen. Ultrasonography revealed a massive hemoperitoneum. At surgery, 4000 ml
      of blood was drained from the abdominal cavity and a ruptured tumor, 2 cm in
      diameter, was found in the right lobe of the liver. The tumor was resected with
      an adequate surgical margin and subsequent microscopic examination confirmed a
      diagnosis of moderately differentiated HCC without associated liver cirrhosis.
      The patient was readmitted 14 months later following the development of right
      lower quadrant pain. Ultrasonography and computed tomography revealed
      extrahepatic abdominal tumors, and abdominal angiography demonstrated four
      intraperitoneal tumors. At surgery, four implanted metastases adhered to the
      greater omentum were found and resected. No other tumors were detected.
      Microscopically, all four tumors were confirmed as moderately differentiated
      hepatocellular carcinoma. Ruptured HCC may lead to implanted intraperitoneal
      metastasis, but rupture of small HCC is very rare. While hepatic resection is the
      treatment of choice for ruptured HCC, according to our review of the literature,
      only a few patients have survived long-term after resection of implanted
      metastasis.

PMID- 10333420
TI  - Surgical approaches for pancreatic ascites: report of three cases.
AB  - Pancreatic ascites can occur in association with the rupture of a pseudocyst or
      the disruption of a pancreatic duct during the natural course of chronic
      pancreatitis. We report herein the successful treatment of three patients with
      pancreatic ascites by performing a surgical procedure after 4-6 weeks of total
      parenteral nutrition (TPN) proved ineffective. The principles of our surgical
      procedure for pancreatic ascites are as follows: (1) minimum pancreatic tissue is
      resected; (2) surgical intervention to repair leaking sites is not necessary; (3)
      pancreatic duct drainage is facilitated by an intestinal Roux-en-Y loop; (4) An
      external drainage tube is inserted through the Roux-en-Y loop into the main
      pancreatic duct. All three patients who underwent our surgical procedure had a
      good outcome. Although the mean follow-up time is still only 18.3 months, their
      condition has improved, with no evidence of recurrent ascites. Thus, our surgical
      procedure should be considered as an appropriate treatment for pancreatic ascites
      because it can be applied for all types of leakage, including leakage from the
      posterior wall of pancreas; it preserves pancreatic function, especially
      endocrine function; and it enables preservation of the spleen.

PMID- 10333421
TI  - Pancreatic arteriovenous malformation observed to bleed from the bile duct and a
      duodenal ulcer: report of a case.
AB  - A 48-year-old man with recurrent episodes of biliary colic and subsequent
      pancreatitis was admitted to undergo a cholecystectomy. A gastroduodenal
      fiberscopic examination was performed because of massive melena on the seventh
      day after admission. It revealed a shallow ulcer on the posterior wall of a
      duodenal bulbus with rubor and an exposed vessel, which was clipped
      endoscopically to stop the bleeding. Further observations showed the papilla of
      Vater to be bleeding from the papilla. A contrast-enhanced abdominal computed
      tomography scan demonstrated a dilatation of the common bile duct and several
      dilated vasculatures around the portal vein, some of which drained into the
      portal vein. Based on the angiography findings, a diagnosis of arteriovenous
      malformation in the pancreas head was obtained and an embolization of the
      gastroduodenal artery was performed. Although the melena subsided, he underwent a
      pylorus-preserving pancreatoduodenectomy to prevent the recurrence of
      hemorrhaging. The histopathological findings of the bile duct revealed
      inflammatory cell infiltration and a detachment of the epithelium, except in a
      small part of the bile duct. A rupture of a damaged vessel inside the bile duct
      was observed, which was thought to be the cause of hemobilia. Sections of the
      pancreatic head demonstrated an inflammatory lesion with fibrosis and
      saponification as well as a large degree of arteriovenous anastomosis. The
      patient was discharged on the 35th day after the operation following an
      uneventful postoperative course.

PMID- 10333422
TI  - Cystic lymphoepithelial lesions of the pancreas and peripancreatic region: report
      of two cases.
AB  - Two cases of an extremely rare cystic lymphoepithelial lesion of a lymph node
      associated with the pancreas are presented herein. The first patient was a 57
      year-old woman with a serous cystoadenoma who underwent resection of the body and
      tail of pancreas, and the other patient was a 75-year-old woman with cancer of
      the papilla of Vater who underwent pylorus-preserving pancreatoduodenectomy. Both
      lesions were incidentally found during pathologic examination of lymph nodes from
      the peripancreatic region. Histologically, there were many scattered nests of the
      lymphoepithelial lesion in the lymphoid stroma, each of which was lined with
      stratified squamous epithelium. The pathological structure was found to resemble
      the lymphoepithelial lesion of the pancreas. Although the histogenesis is
      unknown, we hypothesize that the lesion might have arisen from squamous
      metaplasia of a benign epithelial inclusion such as the pancreatic duct of an
      ectopic pancreas in a peripancreatic lymph node. Therefore, a cystic lesion
      formed as a result of keratinization of the squamous epithelium with invasion
      into the pancreas could become a lymphoepithelial cyst of the pancreas.

PMID- 10333423
TI  - Ectopic thyroid in the abdomen: report of a case.
AB  - Ectopic thyroid tissue can be seen anywhere along the path of the descending
      glands, but it is rarely seen in the abdominal cavity. An ectopic thyroid was
      encountered incidentally in the pancreas of a 50-year-old woman who underwent a
      bilateral truncal vagotomy and pyloroplasty for a duodenal ulcer. There were no
      signs or symptoms of a thyroid tumor.

PMID- 10333424
TI  - Fibromyxoma of the rib: report of a case.
AB  - We present herein the case of a 36-year-old man with fibromyxoma of the rib. At
      the age of 33 years, an abnormal shadow of the chest was found on a radiographic
      examination, subsequent to which the mass grew slowly into the intrathorax, and
      he was referred to our hospital. An X-ray film and computed tomography scan on
      admission showed an extrapleural mass, 7 x 5 cm in diameter, in the left sixth
      rib with no evidence of destruction, cortical expansion, or rupture. The patient
      underwent peripheral osteotomy of the sixth rib, which was resected with a 3-cm
      margin around the mass. Microscopically, a diagnosis of fibromyxoma was
      confirmed. To the best of our knowledge, this is the first reported case of
      fibromyxoma originating in a rib.

PMID- 10333425
TI  - A successful case of pulmonary thromboendarterectomy for chronic thromboembolic
      pulmonary hypertension with a thrombus in the right ventricle.
AB  - Chronic thromboembolism is a frequent cause of progressive hypertension and
      carries a poor prognosis. Medical treatment is not effective and surgery provides
      the only potential for a cure at present. We herein report a successful case of
      thromboendarterectomy treated via a median sternotomy with intermittent
      circulatory arrest. A 43-year-old man was admitted to our hospital complaining of
      progressive dyspnea, edema of the lower extremities, and a fever with an unknown
      origin. A subsequent definitive evaluation showed him to be suffering from
      surgically accessible chronic thromboembolic pulmonary hypertension with a
      thrombus in the right ventricle. He underwent a pulmonary thromboendarterectomy
      and thrombectomy via a median sternotomy with intermittent circulatory arrest on
      November 24, 1994. Postoperatively he showed a marked improvement in his
      hemodynamic status and blood gas analysis. He has also returned to work with no
      trouble. Deep vein thrombosis appeared to be the pathogenesis of this case, but
      we could not find the origin of his unknown fever. He is currently being
      controlled by treatment with methylprednisolone as before.

PMID- 10333426
TI  - High ligation of the inferior mesenteric artery with hypogastric nerve
      preservation in rectal cancer surgery.
AB  - We describe herein a technique of performing upward node dissection following
      high ligation of the inferior mesenteric artery for patients with T3 and T4
      rectal carcinomas. The course of the hypogastric nerve is confirmed
      macroscopically during the procedure to ensure its preservation. This technique
      offers both increased radicality and the prevention of ejaculatory dysfunction.

PMID- 10333427
TI  - Aortic stump tailoring with GRF glue and a felt strip.
AB  - We describe herein a new technique of aortic stump tailoring for aortic
      dissection. This method involves the application of gelatine-resorcin-formalin
      (GRF) glue and a felt strip, with manipulation using the balloon of an
      endotracheal tube. The conjoined wall consists of three layers, but it is
      completed like a single layer. This procedure facilitates anastomosis to the
      graft in the next step.

PMID- 10333428
TI  - Transabdominal inguinal hernioplasty combined with abdominal aortic aneurysm
      repair.
AB  - The number of patients being encountered with abdominal aortic aneurysm (AAA) and
      inguinal hernia is increasing. We describe herein a technique of performing a
      concomitant one-stage operation for both disorder. After conventional
      transperitoneal AAA repair, transabdominal preperitoneal hernia repair is carried
      out through the same incision using a prosthesis made from the same material as
      the graft used for AAA. The maneuver is similar to that of laparoscopic
      hernioplasty. We employed this technique in the treatment of four patients, none
      of whom developed any complications such as infection or recurrence of the
      inguinal hernia. Thus, we conclude that this one-stage operation for AAA and
      inguinal hernia may bring physical and economic benefits to patients who have
      both diseases concomitantly.

PMID- 10333429
TI  - Comparing measures of travel distances in primates: methodological considerations
      and socioecological implications.
AB  - Travel costs can influence numerous aspects of the lives of primates, including
      net energy balance (and therefore reproductive success of females) and maximum
      group size. Despite their potential impact, there has been no systematic
      comparison of different measures of travel distance. We compared three measures
      of travel distance in 30 min (actual distance of individuals, straight-line
      distance of individuals, and straight-line distance of groups) and their ratios
      in a small group and a large group of vervet monkeys (Cercopithecus aethiops) and
      between the large group of vervets and a group of patas monkeys (Erythrocebus
      patas) of roughly similar size. The large group of vervets traveled farther than
      the small group regardless of the measure used, but the ratios of the different
      measures were not significantly different between those groups. Patas monkeys
      traveled significantly farther than the large group of vervets regardless of the
      measure used. In both vervets and patas, straight-line distances of individuals
      (ISLD) and groups (GSLD) underestimated actual distances traveled by individuals
      (IAD), but the degree to which they did so differed between species. IAD is more
      accurate than the other two measures and is preferred for studies of energetics
      and individual reproductive success, although ISLD or GSLD may be substituted
      when the ratios of IAD/ISLD or IAD/GSLD do not differ between groups or species.
      The ratio of IAD/ISLD was larger in vervets than in patas, suggesting that
      individual vervets meander more over short periods of time than patas. The ratio
      of ISLD/GSLD was larger in patas than in vervets, suggesting that patas move at
      angles or across the group's center-of-mass whereas vervets move more
      consistently along with others in their group. This has implications for the
      formation of spatial subgroups and alliances within groups.

PMID- 10333430
TI  - Costs of infant-carrying in the cotton-top tamarin (Saguinus oedipus).
AB  - Infant-carrying behavior among callitrichids seems to be a costly activity. Costs
      have been related to the physical efforts of carrying the weight of very heavy
      infants and to the resulting reduction in foraging efficiency. However, the costs
      of carrying in terms of the physical consequences for carriers have not
      previously been assessed. In this study, we have regarded weight loss in infant
      carriers as a measure of costs. We studied five families of cotton-top tamarins
      (Saguinus oedipus) during the first 9 weeks following the birth of infants.
      Captive-breeding conditions were required so that body weight could be measured
      frequently. To avoid inflicting undue stress on the subject animals, we used a
      noninvasive method for weighing the tamarins. Differences in carrying
      contribution were found amongst fathers and male and female helpers, with female
      helpers contributing less. We have found that carrying infants in the cotton-top
      tamarins is an activity that produces a weight loss. Fathers and male helpers go
      through a maximal body weight loss. While carrying, the tamarins also decrease
      food intake. However, no relationship was found between contribution to carrying
      and feeding time or in energetic intake during feeding observations. Thus, it
      seems that a direct relation doesn't exist between the observations of feeding
      and weight loss. Fathers increase their contribution to carrying during mothers'
      periovulatory periods. In this period, male helpers and especially fathers go
      through a maximal body weight loss. We found body weight losses of up to 11.3% in
      one subadult male and 9.1% in a father during the fifth week. No changes occurred
      in food intake in fathers or other male helpers during this period. During
      periovulatory periods, mothers carried less frequently but did increase their
      food intake. They gained weight from the second week after birth onward,
      especially during the periovulatory period. It seems that the infant-carrying
      behavior of fathers and male helpers may contribute to the improvement of the
      mothers' physical condition after birth and therefore may support a consecutive
      pregnancy.

PMID- 10333431
TI  - Within-group vigilance in red colobus and redtail monkeys.
AB  - In theory, animals are expected to relax vigilance in the safety of large groups.
      Four controlled studies of primates have failed to detect relaxed vigilance as
      group size increases. The counter-intuitive behavior of primates might arise if
      another component of vigilance increases with group size, masking any decrease in
      outward, anti-predator vigilance. Surveillance of associates is a major component
      of primate vigilance and might be expected to increase with group size due to an
      increase in competitive interactions. The present analysis uses data on glances
      toward associates to determine if within-group surveillance is related to group
      size in wild red colobus and redtail monkeys of Uganda. Although males glance at
      associates more frequently during mating periods and females glance at associates
      more often when infants are young or out of contact, there was no evidence of a
      group-size effect on within-group surveillance. As with previous studies, primate
      vigilance patterns reflect reproductive strategies such as infant protection and
      mate defense. This study joins several others that indicate that primate
      vigilance is unresponsive to group size. New models that take into account
      association patterns below the level of the group may be needed.

PMID- 10333432
TI  - Mating system of Microcebus murinus.
AB  - Microcebus murinus, a small nocturnal lemur from Madagascar, has retained
      features of ancient primates. Based on these ancestral traits, its social
      organization has often been used as a model for early primate social systems. In
      captivity it breeds polygynously, i.e., one male mates with several females,
      while females usually copulate only with the dominant male. The present project
      tested whether or not sexual size dimorphism, spatial distribution, and relative
      testis size of M. murinus correspond with predictions of the sexual selection
      theory concerning polygynous mating systems. The study was combined with a mark
      recapture study and radio tracking of 12 animals in 1993 in a dry deciduous
      forest of western Madagascar at the end of the dry season. Large overlapping home
      ranges in males, lack of sexual size dimorphism, and relatively large testes
      suggest a multi-male mating system, i.e., one that is promiscuous rather than
      polygynous.

PMID- 10333433
TI  - Application of an enzyme immunoassay for urinary follicle-stimulating hormone to
      describe the effects of an acute stressor at different stages of the menstrual
      cycle in female laboratory macaques.
AB  - An enzyme-linked immunosorbent assay (ELISA) for human urinary beta follicle
      stimulating hormone (FSH) subunit was validated for use in the laboratory macaque
      (Macaca mulatta and Macaca fasicularis). This ELISA is based on the dissociation
      of the FSH heterodimer in urine and the subsequent measurement of the beta
      subunit as a representation of total urinary FSH. This assay was then used to
      describe the gonadotropin escape following ovarian senescence in post-menopausal
      macaques. In addition, the assay was used to observe the impact of an acute
      stressor on the pituitary-gonadal axis and how the impact of this stressor varies
      when experienced at different stages of the menstrual cycle. The study design
      involved the measurement of ovarian steroids and FSH in urine collected daily
      during a period of time when animals experienced a well-defined event on two
      occasions consisting of capture, restraint, and anesthesia. This unique study
      design was made possible by the ability to monitor both ovarian and pituitary
      function in the absence of confounding daily captures and restraint for blood
      collection. There was a high correlation between urinary FSH measured in macaques
      with the beta FSH subunit ELISA and serum FSH measured in paired blood samples by
      radioimmunoassay (n=39, r2=0.878, P<0.001) and the composite urinary FSH profile
      obtained from normal, premenopausal macaques exhibited the expected dynamics with
      a transient rise of FSH during the luteal-follicular transition as well as an
      acute rise of FSH at mid-cycle. This pattern was lost in castrate and post
      menopausal monkeys in which FSH levels were significantly increased (P<0.0001)
      above those of intact males and young females, respectively. In the stress study,
      we found that stressors occurring during the luteal-follicular transition not
      only resulted in acute perturbations of FSH but also led to abnormalities in the
      subsequent menstrual cycle in 50% of the cases.

PMID- 10333434
TI  - Taste difference thresholds for sucrose in two species of nonhuman primates.
AB  - The purpose of this study was to determine taste difference thresholds for
      sucrose in frugivorous spider monkeys and omnivorous baboons. Using a two-bottle
      preference test of brief duration, we presented four Ateles geoffroyi and four
      Papio hamdryas anubis with six different reference concentrations (RCs) of 25,
      50, 100, 200, 300, and 400 mM sucrose and tested their ability to discriminate
      these from lower concentrations of this carbohydrate. The just noticeable
      differences (JNDs), expressed as Weber ratios (delta/I), were found to range from
      0.075-0.25 in the spider monkeys, with a tendency for lower values with higher
      RCs. In contrast, the baboons showed the reverse trend, with the lowest Weber
      ratio of 0.10 at the two lowest RCs and higher values of up to 0.25 with the
      highest RC tested. Thus, the JNDs were found to be generally similar in both
      species and at least as low as in humans. The results support the assumption that
      both spider monkeys and baboons may use sweetness as a criterion for food
      selection. The different patterns of differential sensitivity for sucrose across
      the range of concentrations tested suggest a correlation between the ability to
      discriminate between different concentrations of sucrose and the dietary habits
      of the two species.

PMID- 10333436
TI  - Pathophysiology of variceal bleeding.
AB  - A review of the pathophysiology of variceal bleeding, with a discussion of the
      pathogenesis of portal hypertension, formation of varices, and bleeding from
      varices. Portal hypertension results from increases in portal flow and portal
      vascular resistance. The factors increasing portal blood flow are primarily
      humoral. Resistance to portal flow has fixed and variable components. Elevated
      portal pressure leads to variceal formation. Variceal bleeding is dependent on
      portal pressure, variceal size, and variceal wall thickness.

PMID- 10333435
TI  - A genome-wide search for linkage to asthma. German Asthma Genetics Group.
AB  - Asthma is among the most frequent chronic diseases in childhood. Although
      numerous environmental risk factors have already been identified, the basis for
      familial occurrence of asthma remains unclear. Previous genome screens for atopy
      in British/Australian families and for asthma in different American populations
      showed inconsistent results. We report a sib pair study of a sample of 97
      families, including 415 persons and 156 sib pairs. Following an extensive
      clinical evaluation, all participants were genotyped for 351 polymorphic
      dinucleotide markers. Linkage analysis for asthma identified four chromosomal
      regions that could to be linked to asthma: chromosome 2 (at marker D2S2298, P =
      0.007), chromosome 6 (around D6S291, lowest P = 0.008), chromosome 9 (proximal to
      D9S1784, P = 0.007), and chromosome 12 (D12S351, P = 0.010). These linkage
      regions could be reproduced for all loci by analysis of total or specific
      immunoglobulin E (minimum P values at these regions were 0. 003, 0.001, 0.010,
      and 0.015, respectively).

PMID- 10333437
TI  - Patient assessment and resuscitation.
AB  - The patient with acute variceal bleeding requires prompt attention and is best
      served by an organized approach to assessment and resuscitation. Knowledge of the
      differential diagnosis for acute bleeding from portal hypertension is essential.
      Special attention is needed during resuscitation regarding endotracheal
      intubation, intravenous resuscitation, and management of coagulopathy and
      thrombocytopenia. Carefully selected patients may be triaged into outpatient,
      overnight observation, routine inpatient, and intensive care settings.

PMID- 10333438
TI  - Endoscopic management of the acute variceal bleeding event.
AB  - An examination of the published literature with regard to background and
      endoscopic management. Methods that are reviewed include laser, polymer
      injection, sclerotherapy, ligation and novel new methods. Sclerotherapy is
      compared to other non-endoscopic management. Ligation and sclerotherapy are
      compared for effectiveness and complications. Information on endoscopic therapy
      of gastric varices is also reviewed.

PMID- 10333439
TI  - Variceal ligation with bands and clips.
AB  - While endoscopic sclerotherapy is effective for management of variceal bleeding,
      significant local and systemic side effects promoted the development of
      alternative endoscopic therapies. Endoscopic band ligation has emerged as a
      technique with equal or greater efficacy and fewer local and systemic
      complications. New multibanded ligation systems have enhanced the speed and
      efficiency of endoscopic variceal ligation therapy and eliminated the need for an
      esophageal overtube. Endoscopic hemostatic clipping is another means of achieving
      directed, mechanical endoscopic hemostasis that has a limited role in variceal
      bleeding.

PMID- 10333440
TI  - Injection therapy for variceal bleeding.
AB  - The role of injection therapies in the management of esophageal and gastric
      varices are reviewed. Available radiographic, pharmacologic and alternative
      endoscopic methods are compared and contrasted with sclerotherapy. Recent studies
      regarding a combination of endoscopic band ligation and low volume sclerotherapy
      to achieve best eradication of esophageal varices are reviewed.

PMID- 10333441
TI  - Long-term endoscopic management of variceal bleeding.
AB  - Recurrent hemorrhage from esophageal varices is a major source of morbidity and
      mortality in patients with portal hypertension. Esophageal sclerotherapy (EST)
      and more recently esophageal band ligation (EVL) can obliterate varices in 3-6
      treatment sessions. Multiple band ligators make the use of overtubes unnecessary
      and make the procedure faster and more tolerable for the patient. EVL has several
      advantages, including fewer complications, fewer treatment sessions to
      obliteration, lower rebleeding rates, and lower mortality as compared to EST; the
      other advantages of EVL make it the treatment of choice for bleeding varices and
      long term management. The recommendations and rational for long term EST and EVL
      are presented and combination therapy and EUS guided EVL are discussed.

PMID- 10333442
TI  - Endoscopic ultrasound in the evaluation of portal hypertension.
AB  - There is no question that EUS has a role in the imaging of gastric varices. EUS
      can be used to accurately differentiate thickened folds or submucosal lesions
      from varices. Its use in the evaluation of perigastric varices has progressed
      from the days in which EUS scopes were used, but were not as sensitive as
      endoscopy, to the current use of EUS probes, which very accurately measure the
      radius and the wall thickness (WT) of esophageal varices. These probes can locate
      varices not seen at endoscopy and can be used to calculate the variceal WT. EUS
      has been used to predict which patients will respond to therapy and which will
      not and it can be used to assess the results of therapeutic intervention. EUS of
      periesophageal varices may also be used to predict which patients will and will
      not respond to therapy. Although the use of EUS imaging in the evaluation of
      varices is still in its infancy, it holds great promise for the future.

PMID- 10333443
TI  - Pharmacologic intervention during the acute bleeding episode.
AB  - The risk of recurrent variceal bleeding after an acute episode of bleeding has
      been controlled in significant with rebleeding rates as high as 80% between one
      and two years. Pharmacologic therapy has a definite role in the prevention of
      recurrent variceal bleeding and should be started as soon as the acute bleeding
      event has been controlled. Serial hemodynamic measurements are critical for
      success. Non-selective beta-blocker therapy is a reasonable first line approach
      followed by the addition of a long-acting nitrate for patients not achieving a
      20% reduction in the hepatic venous pressure gradient. Most patients will require
      combination pharmacotherapy or combined endoscopic therapy with pharmacotherapy.

PMID- 10333444
TI  - Pharmacological prevention of rebleeding.
AB  - Pharmacologic therapy used during acute variceal bleeding may control the
      bleeding episode, minimized transfusion requirements, and prevent early
      rebleeding. Several options for pharmacologic therapy exist in this setting and
      include: vasopressin in combination with nitroglycerin, terlipressin,
      somatostatin, and octreotide. Metoclopramide and domperidone may also be useful
      but require additional study. At present, octreotide, administered intravenously
      as soon as variceal bleeding is suspected, is favored.

PMID- 10333445
TI  - Interventional radiology for the control and prevention bleeding.
AB  - Percutaneous treatment of patients with variceal hemorrhage began with
      transhepatic variceal embolization. These procedures proved to be ineffective as
      the absolute portal pressure remained elevated and varices recanalized with
      subsequent rebleeding. Transjugular intrahepatic portosystemic shunts (TIPS)
      promised the ability to effectively decompress the portal system without the need
      for general anesthesia. Initial enthusiasm for the procedure has waned as
      intrahepatic shunt durability proved to be less than adequate. Although it
      remains a powerful tool, TIPS is not a first line treatment for patients with
      variceal bleeding.

PMID- 10333446
TI  - The timing and role of non-transplant surgery in management of variceal bleeding.
AB  - Non-transplant surgery for variceal bleeding includes surgical shunts and
      devascularization procedures. The indication for such operation are good risk
      (Childs' A/B) patients who have failed endoscopic therapy. Undecided is the issue
      of TIPS versus surgical shunt.

PMID- 10333447
TI  - Liver transplantation for variceal hemorrhage.
AB  - Orthotopic liver transplantation should be considered as a treatment for end
      stage liver disease, which provides resolution to all its complications,
      including portal hypertensive-related bleeding. In the 1990s, variceal bleeding
      should be controlled primarily with endoscopy and, if this approach fails, with
      selective surgical shunting in those patients who have good hepatic function and
      with TIPS in those patients whose hepatic function is marginal and need bridging
      treatment until transplantation. Decompression of the portal system with either
      of these approaches allows for liver transplantation with challenges that can be
      overcome by experienced surgical teams.

PMID- 10333448
TI  - Diagnosis and treatment of carbon monoxide poisoning.
AB  - Carbon monoxide (CO) poisoning is a common occurrence in today's society. Most
      such poisonings are a direct consequence of inhaling the toxic byproducts of
      combustion. Exposure to toxic amounts of CO occurs most often during inhalation
      of automobile exhaust or smoke resulting either from faulty heating systems or
      industrial accidents. CO poisoning is associated primarily with injury to the
      brain and the heart because the gas binds to hemoglobin and interferes with these
      organs' need for a continuous supply of oxygen. Prompt recognition of CO
      poisoning and treatment of the patient with oxygen are essential to prevent long
      term damage and delayed neurologic sequelae.

PMID- 10333449
TI  - Hyperbaric oxygen in the treatment of life-threatening soft-tissue infections.
AB  - Necrotizing soft-tissue infections are rapidly spreading bacterial infections
      that account for a relatively small proportion of infections, but are aggressive
      in nature and nearly uniformly fatal if left untreated. Prompt recognition,
      antibiotic therapy, aggressive surgical debridement, and hyperbaric oxygen (HBO)
      therapy have reduced the mortality resulting from these infections. Oxygen, at
      increased pressures, augments tissue oxygen partial pressure, allowing increased
      bacterial killing by providing substrate for the formation of oxygen free
      radicals and augmenting respiratory burst. During the healing process, hyperoxia
      causes increased formation of capillaries for oxygen, nutrient, and antibiotic
      delivery, leading to increased efficacy of some antibiotics in the high oxygen
      environment, and possibly more rapid overall wound healing. Although there are no
      randomized trials of HBO in these infections, in vitro data and meta-analysis of
      clinical cases strongly support the use of HBO.

PMID- 10333450
TI  - Assessment of tissue oxygenation.
AB  - A continuous supply of oxygen to all tissues is necessary for the efficient
      production of ATP, and this supply is considered sufficient when aerobic
      metabolism is maintained. Nonhealing wounds, necrotizing infections, radiation
      induced necrosis, crush injury, decompression illness, and CO poisoning all
      exhibit impaired tissue oxygenation. The need for efficacy of HBO therapy in such
      conditions is in part determined by the prevailing state of tissue oxygen supply
      and demand. The methods currently available or under development for assessing
      the adequacy of tissue oxygenation include blood gas analysis, transcutaneous
      oxygen measurement, gastric tonometry, pulse oximetry, near-infrared
      spectroscopy, functional MR imaging, MR spectroscopy, electron paramagnetic
      resonance, positron emission tomography, and single photon emission computed
      tomography. The clinical and experimental applications of these methods are
      discussed and emphasis is placed on their role in hyperbaric medicine.

PMID- 10333451
TI  - Oxygen toxicity.
AB  - That hyperoxia induces "a profound modification in the metabolism of tissues" is
      an old observation. The mechanisms by which the physiologic, pathologic, and
      biomechanical perturbations caused by oxygen relate to the in vivo manifestations
      of oxygen toxicity, however, have not been explained fully. This article reviews
      cellular mechanisms of toxicity, outlines the clinical manifestations of oxygen
      toxicity, and discusses methods of monitoring and modifying oxygen tolerance.

PMID- 10333452
TI  - Appendix: education and information resources in hyperbaric medicine.
AB  - A comprehensive listing of hyperbaric medicine resources is provided. These
      resources serve the educational and information needs of those who wish to enter
      this medical specialty, as well as those who practice it. A selected hyperbaric
      specific bibliography is included, as is the methodology to stay current with the
      scientific and technological advances of this field.

PMID- 10333453
TI  - Ob-Gyn interactive case challenge--a case of sadness and anxiety 9 months
      postpartum.
AB  - If you were the primary care provider, how would you diagnose and treat
      postpartum anxiety and depression in this young, first-time mother? After a
      normal, uncomplicated pregnancy, this 27-year-old woman developed anxiety and
      depressed mood, which she was still struggling to control 9 months after the
      birth of her child. Among the diagnostic possibilities to consider are occult
      malignancy, diabetes mellitus, and thyroid disorder, as well as major
      depression/anxiety disorder and postpartum depression.

PMID- 10333454
TI  - In-vitro anti-proliferative effects of some anti-tumour drugs on feline mammary
      tumour cell lines.
AB  - Six anti-tumour drugs namely; doxorubicin, mitoxantrone, vincristine, cisplatin,
      recombinant human tumour necrosis factor alpha (rh-TNFalpha) and recombinant
      feline interferon gamma (rf-IFNgamma) were singly evaluated for their anti
      proliferative effects on two feline cell lines (FRM and NAC) derived from mammary
      adenocarcinoma and grown as monolayers. We obtained concentration response curves
      that enabled the determination of the concentration inhibiting growth by 50 per
      cent (IC50) for the chemotherapeutic agents with VCR exhibiting exponential
      plateau curves. Differences in anti-proliferative effects of drugs to a given
      cell line and between the cell lines were also observed. NAC cells were
      relatively more resistant compared with FRM cells. The relative resistances for
      NAC cells were 4.19, 12.96, 0.05 and 2.10-fold to doxorubicin, mitoxantrone,
      vincristine and cisplatin, respectively. FRM cells were more resistant to VCR at
      lower concentrations compared with NAC cells. The cells appeared, at least in
      vitro, least sensitive to rh-TNFalpha and rf-IFNgamma. rh-TNFalpha and rf
      IFNgamma were 23 and 29 per cent inhibitory to FRM cells and only 13 and 15 per
      cent inhibitory to NAC cells, respectively.

PMID- 10333455
TI  - Comparison of ultrasonographic and radiographic measurements of bladder
      dimensions and volume determinations.
AB  - The purpose of this study was to compare the linear dimensions of the bladder
      measured by ultrasonographic and radiographic methods and the accuracy of these
      methods for evaluation of bladder volume. Forty dogs were included in this study.
      Each dog was placed in right lateral recumbency and a plain lateral caudal
      abdominal radiograph was made. The bladder length and depth were measured in
      centimetres from the radiograph, taking into account magnification errors.
      Immediately after radiography was completed, ultrasonographic measurements of
      bladder length and depth on longitudinal section were measured in centimetres.
      The bladder was then emptied by catheterisation and the actual urine volume
      measured. 'Best subsets' analysis indicated that radiographic and
      ultrasonographic bladder lengths were the best predictors of actual bladder
      volume. Formulae were derived from radiographic and ultrasonographic bladder
      dimensions for estimating bladder volume. The formula using radiographic
      measurements was found to be a better predictor of actual bladder volume than the
      formula derived from ultrasonographic measurements, since it had higher F and
      lower error mean square values.

PMID- 10333456
TI  - An evaluation of iron-dextran supplementation in piglets administered by
      injection on the first, third or fourth day after birth.
AB  - The aims of the study were to evaluate the effect of iron-dextran injection given
      on the first, third or fourth day after birth on haematology in piglets. An
      advanced automated blood analyser; Technicon H*1, which performs a complete blood
      cell count and leukocyte differential counts was used to analyse the blood. Six
      litters of Norwegian Landrace x Yorkshire piglets were included in the study. The
      day after birth (day 1), half of the piglets in each litter (split litters) were
      injected subcutaneously with 180 mg iron as iron-dextran (1.5 ml Idofer). The
      untreated piglets from two of the litters were injected with the same amount of
      iron-dextran on day 3, and those from the remaining four litters on day 4. The
      piglets were weighed and blood samples collected on days 1, 3 or 4, 7, 14 and 21.
      Erythropoiesis, but not leukocyte count, responded to injection on day 1 compared
      with injection on the third or fourth day. The difference between groups in
      haematological parameters was greatest on day 7. The two groups of piglets
      treated on day 1 had a haemoglobin concentration (Hb) +/-SD of 92 g litre-1(+/-9)
      and 94 g litre-1(+/-9), and the piglets treated on day 3 had a Hb of 81 g litre
      1(+/-7) and the one treated on day 4 had a Hb of 78 g litre-1(+/-7) on day 7. On
      days 14 and 21 there were no differences between groups. This study indicates
      that some piglets were anaemic and responded to subcutaneous iron injection on
      day 1.

PMID- 10333457
TI  - Detection and measurement of canine alpha-macroglobulins by enzyme immuno-assay.
AB  - The alpha-macroglobulins are broad-specificity protease inhibitors important in
      the regulation and clearance from circulation of biologically active proteases.
      Inappropriate protease activation may be a feature of canine acute pancreatitis
      and the ability of the animal to clear these proteases may be important in
      determining survival. An enzyme immunoassay for the detection and measurement of
      canine alpha-macroglobulins in plasma samples was developed. A reference range
      for the canine alpha-macroglobulins of 1.20-2.72 mg ml-1 was established from a
      panel of canine plasma samples, and the stability of the alpha-macroglobulins in
      plasma samples stored at 4 degrees C was investigated. Changes in the level of
      the alpha-macroglobulins during disease states involving increased endogenous
      protease activity can now be investigated using a rapid, repeatable and
      quantifiable assay.

PMID- 10333458
TI  - Evaluation of an ELISA-PPD for the diagnosis of bovine tuberculosis in field
      trials in Brazil.
AB  - Bovine tuberculosis is a major health problem in Brazil. The intradermal
      tuberculin test is the standard test for its detection, but it can lack both
      sensitivity and specificity. The purpose of this study was to evaluate a bovine
      enzyme-linked immunosorbent assay- (ELISA - PPD) under field conditions in
      Brazil. A total of 1632 animals from 13 dairy farms were tested with the
      intradermal tuberculin test (ITT). Two hundred and seven cows gave a positive
      reaction, which represents 12.7 per cent of the cattle studied. The sensitivity
      and specificity rates to ITT were 87.7 per cent and 95.2 per cent, respectively.
      From the 1632 animals 15 per cent of each herd (220 in total) were selected to be
      tested by the ELISA. Differences between mean optical density (OD) of the control
      group, ITT -positive and ITT -negative groups were all significant (P<0.01). The
      sensitivity rates to ELISA - PPD were 86.7 per cent, while specificity was 90.6
      per cent. The use of ELISA - PPD is suggested for situations where the
      investigation of the whole herd is more important than the individual testing of
      each cow. In addition, the ELISA - PPD can also be helpful when a collective
      diagnosis is desired to elucidate clinical suspicions of disease, or in the first
      steps of a control program, for identification of foci.

PMID- 10333460
TI  - Expression of c-yes oncogene product in various animal tissues and spontaneous
      canine tumours.
AB  - An immunohistochemical study of various visceral organs of normal adult dogs,
      cats, pigs, horses, cows, and chickens (five of each species) and of 185
      spontaneous canine tumours was carried out using paraffin wax sections and a
      commercially available antibody to the human c- yes oncogene product. Among the
      adult normal tissues of six animal species, epithelial cells of the proximal and
      distal renal tubules, the myocardium, hepatocytes, cerebellar Purkinje cells and
      adrenal cortical cells were positive for c- yes product. Among the foetal tissues
      of dogs and chickens, a positive reaction was observed on canine chorionic villi
      cells and chick yolk sac surface epithelium, and on epithelial cells of the renal
      tubules, hepatocytes and the myocardium. These findings suggest that the c- yes
      proto-oncogene may play a physiological role in the cell growth and metabolism of
      these adult and foetal tissues. Of the 185 tumours tested, 59 (31.9 per cent)
      expressed the c- yes oncogene product. The c- yes -positive tumours accounted for
      44.4 per cent (12/27) of the skin tumours, 5.5 per cent (1/18) of the round cell
      tumours, 35. 7 per cent (10/28) of the soft tissue tumours, 21.4 per cent (3/14)
      of the testicular tumours, 29.1 per cent (23/79) of the mammary tumours, and 52.6
      per cent (10/19) of the other tumours types. Expression of the c- yes oncogene
      appeared to be common in spontaneously arising canine tumours, and the degree of
      expression varied considerably by tumour type.

PMID- 10333459
TI  - Macrolide antibiotics, drug interactions and microsomal enzymes: implications for
      veterinary medicine.
AB  - The macrolide group of antibiotics includes natural members, pro-drugs and semi
      synthetic derivatives, thus named because they are composed of a large aglycone
      ring (from 14 to 16 carbon atoms), to which are attached several sugars. Some of
      them are amino-sugars, containing a diethylamino, tertiary amine function. A
      number of antibiotics, including erythromycin, oleandomycin, triacetyl
      oleandomycin (troleandomycin), carbomycin, spiramycin, tylosin, rosamicin,
      azithromycin, clarithromycin, dirithromycin and others, are members of this
      group. On a comparative basis, erythromycin and oleandomycin are similar, with
      the same basic 14-carbon lactone ring and side chain sugars. The remaining
      compounds contain a basic 15- or 16-carbon lactone ring and one or two side-chain
      sugars. Most of the macrolides are produced by Streptomyces spp bacteria. An
      exception is rosamicin, which is produced by Micromonospora. Clarithromycin and
      azithromycin are new semi-synthetic derivatives of erythromycin.

PMID- 10333461
TI  - The angiographic anatomy of the portal venous system in the neonatal dog.
AB  - The angiographic anatomy of the portal venous system in 50 dead, neonatal
      Labrador/Retriever type puppies is described. Angiography was performed by the
      injection of radioopaque contrast media through a catheter placed within the
      umbilical vein. In 49 pups the ductus venosus was a straight vessel arising from
      the left main portal vein and terminating in an ampulla into which the left
      hepatic and left phrenic veins entered prior to the ampulla entering the caudal
      vena cava. The diameter of the ductus venosus was significantly narrower
      (P<0.001) in pups born alive (n=10) when compared to stillborn individuals
      (n=39). No discreet narrowing of the ductus venosus indicating a sphincter was
      found, with closure appearing to be uniform along the vessel's length. A well
      developed, patent portal venous system was present in the majority of
      individuals. One pup showed variation from the others studied having a vascular
      connection between the portal sinus and the vena cava within the liver. This may
      represent a normal variant of the ductus venosus, or may be an anatomical
      abnormality leading to the development of an intrahepatic portosystemic shunt. If
      this was an intrahepatic shunt, no concurrent ductus venosus was present.

PMID- 10333462
TI  - Thiamphenicol disposition in pigs.
AB  - Pharmacokinetic parameters of thiamphenicol (TAP) were determined after
      intravenous (i.v.) and intramuscular (i.m.) administration of 30 mg kg-1 of TAP
      in pigs. Plasma drug concentrations were determined by high performance liquid
      chromatography (HPLC) Intravenous TAP kinetics were fitted to a bi-exponential
      equation, with a first rapid disposition phase followed by a slower disposition
      phase. Elimination half-life was short, at 59.3 (29.4) minutes; volume of
      distribution at steady state was 0.62 (0.24) 1 kg-1; and plasma clearance was
      13.4 (4.5) ml min-1 kg-1. After i.m. administration, the peak plasma
      concentration (Cmax= 4.1 microg ml-1) was reached in about 60 minutes; these
      concentrations are lower than those reported in other species. The TAP
      elimination half-life after i.m. administration, 250.2 (107.1) minutes was longer
      after than i.v. administration, probably due to the slow rate of absorption from
      the muscle. The mean bioavailability value for i.m. administration was 76 (12)
      per cent.

PMID- 10333463
TI  - Differences in plasma and abomasal kinetics of albendazole and its metabolites in
      calves grazed on pasture or fed a grain-based diet.
AB  - We evaluated the comparative plasma and abomasal fluid disposition kinetics of
      albendazole (ABZ) and its metabolites in calves either grazing on pasture or fed
      a grain-based concentrate diet. Six male Holstein calves (weight 180 to 200 kg)
      were allowed to graze on lush pasture for three weeks before intraruminal
      administration of ABZ at 10 mg kg-1(pasture group). After a three-week wash-out
      period, the same animals were housed and fed on a grain-based concentrate diet
      for three weeks prior to receiving the same ABZ treatment (concentrate group).
      Jugular blood and abomasal fluid samples were collected over 120 hours post
      treatment. Plasma and abomasal fluid samples were analysed by high performance
      liquid chromatography (HPLC). The digesta transit time was measured using cobalt
      (Co) as a fluid marker; abomasal fluid and faecal samples were collected and Co
      concentrations measured by atomic absorption spectrophotometry. Complementary
      studies of the in vitro dissolution of ABZ particles at different pH values were
      also conducted. The pH of abomasal fluid collected from animals kept under both
      feeding conditions was registered. Increased concentrations of ABZ sulphoxide
      (ABZSO) and sulphone (ABZSO2) in plasma, resulting in significantly higher Cmax
      and area under the curve (AUC) values for both metabolites, were obtained in
      calves fed on the concentrate diet compared to those grazing on pasture. Enhanced
      abomasal fluid levels of ABZ and ABZSO were observed in concentrate-fed calves.
      The mean retention time of the digestive fluid marker in the gastrointestinal
      (GI) tract was significantly longer in the animals fed the grain-based diet. The
      in vitro dissolution of ABZ at a pH value equivalent to that obtained in the
      abomasum of the concentrate-fed calves (1.75) was significantly greater than that
      obtained at the pH registered in pasture-fed animals (2.00). The characterisation
      of the kinetic/metabolic behaviours and the resultant efficacy of antiparasitic
      drugs in animals reared under different management conditions may be relevant in
      increasing parasite control in livestock.

PMID- 10333464
TI  - Effects of vitamin D and retinoids on the differentiation and growth in vitro of
      canine osteosarcoma and its clonal cell lines.
AB  - Although canine osteosarcoma is one of the most malignant, aggressive and lethal
      neoplasms originating from undifferentiated bone cells, it may retain some
      capacity for normal differentiation. The purpose of this study was to ascertain
      if the residual capacity for differentiation could be used to suppress its
      malignant properties. We tested the efficacy of vitamin D and retinoids in
      inducing differentiation and inhibiting growth of the POS canine osteosarcoma and
      four of its clonal cell lines, POS 14A (fibroblast type), POS 53B (chondroblast
      type), POS 53C (undifferentiated type) and POS 53D (osteoblastic type). Treatment
      with 10(-10)to 10(-8)M concentrations of calcitriol, OCT, cholecalciferol, all
      trans retinoic acid (ATRA) and 9-cis retinoic acid for 48-120 hours changed the
      morphology of POS, POS 53B, POS 53C and POS 53D cells to cells that were
      elongated and spindle-shaped. Increased number of cytoplasmic organelles and
      pronounced nuclear activities were induced by concentrations of 10(-8)M and 10(
      7)M for 120 hours. All drugs at concentrations of 10(-10)to 10(-8)M for 72 hours
      inhibited POS growth dose-dependently. OCT significantly reduced the cell number
      in all cell lines when used at concentrations between 10(-9)and 10(-8)M for 72
      hours and exerted significant anti-proliferative effects for eight days culture.
      This study demonstrated that changed morphology and inhibition of growth was
      induced by treatment of the cells with these vitamins, that the loss of control
      of differentiation in the neoplasia was not irreversible and that these drugs may
      be useful in the clinic.

PMID- 10333465
TI  - Hepatic lesions in young rabbits experimentally infected with rabbit haemorrhagic
      disease virus.
AB  - Twenty young rabbits (eleven 2-week-old and nine 4-week-old) were experimentally
      infected with rabbit haemorrhagic disease virus (RHDV) to clarify susceptibility.
      They were killed chronologically up to 96 hours post-inoculation (PI) and
      examined for lesions. All inoculated rabbits were clinically normal, but grossly
      minute white or grey spots were detected throughout the liver. Histologically,
      the lesions consisted of aggregates of lymphocytes, macrophages and heterophils,
      with or without acidophilic bodies and necrotic hepatocytes.
      Immunohistochemically, RHDV antigens were found in the degenerated hepatocytes
      and in macrophages. The cellular aggregates were considered to be a reaction to
      necrotic hepatocytes infected with RHDV. It was concluded that some hepatocytes
      are susceptible to RHDV in young rabbits.

PMID- 10333466
TI  - Canine serum thyroglobulin autoantibodies in health, hypothyroidism and non
      thyroidal illness.
AB  - Thyroglobulin autoantibody (TGAA) was measured in serum from dogs with
      hypothyroidism (n = 42), non-thyroidal illness (NTI) (n = 77) and clinically
      healthy dogs (n = 70) using a commercially available enzyme immunoassay kit.
      Precision studies were consistent with good intra-assay and inter-assay
      repeatability. TGAA positive results occurred in 15 of the 42 (36 per cent)
      hypothyroid and four healthy dogs of the remaining 147 animals resulting in a
      lower incidence of false positive results than obtained with previous TGAA
      assays. The presence of TGAA was not influenced by age, sex, neutering or
      pedigree status. Of the four apparently healthy TGAA -positive dogs, two had
      additional clinicopathological evidence of hypothyroidism. TGAA was positive in
      43 per cent of hypothyroid dogs with unexpectedly normal serum c TSH
      concentrations and was particularly useful in the classification of these cases.

PMID- 10333468
TI  - Larval migration inhibition activity in abomasal mucus and serum from calves
      infected with Ostertagia ostertagi.
AB  - The present study investigated whether abomasal mucus from calves naturally
      infected with gastrointestinal nematodes possessed larval migration inhibition
      (LMI) activity in vitro, and whether LMI activity was greater in mucus from
      previously immunised animals, compared to primary infected and uninfected calves.
      LMI activity was also assessed in serum from calves during both natural and
      artificial Ostertagia ostertagi infections, in an attempt to monitor the
      development of acquired immunity. Both abomasal mucus and serum exhibited larval
      paralysing activity. Although the LMI capacity of the abomasal mucus was very
      variable, the highest paralysing activity was consistently observed in mucus from
      previously immunised calves. LMI activity in serum increased significantly during
      both artificial and natural Ostertagia infections. After a challenge infection,
      sera from immunised animals showed a significantly higher LMI capacity, compared
      to previously uninfected calves. Moreover, serum LMI activity was significantly
      negatively correlated with Ostertagia worm counts after the challenge infection.
      The present results suggest that LMI activity in serum and/or abomasal mucus
      reflects a protective immune response against O. ostertagi in the abomasal
      mucosa.

PMID- 10333467
TI  - Characterisation of monoclonal antibodies to epizootic hemorrhagic disease virus
      of deer (EHDV) and bluetongue virus by immunisation of mice with EHDV recombinant
      VP7 antigen.
AB  - Immunisation of mice with recombinant VP7 antigen of epizootic hemorrhagic
      disease virus of deer (EHDV) induced serum antibody responses to EHDV. However,
      from the 19 monoclonal antibodies (Mab) produced from these mice, 15 were
      specific for EHDV and four for bluetongue virus (BTV). No Mabs were identified
      with the specificity for an epitope of VP7 shared by both EHDV and BTV in spite
      of the fact that they share a large portion of homology in VP7 amino acids
      composition. These Mabs were divided into five groups based on their specificity
      and interaction with each other. Group II Mabs, consisting of 13 Mabs, recognises
      a potential serogroup specific, linear epitope of EHDV VP7 antigen. One of the
      Mabs to BTV (Group V) was identified as BTV VP7 specific with the possibility of
      being the serogroup specific and recognizes a potential conformational epitope.
      Two Mabs from these VP7 specific groups were further analysed and found to be
      useful in a competitive enzyme-linked immunosorbent assay (C - ELISA) for
      detection of specific antibodies against EHDV and BTV in bovine sera.

PMID- 10333469
TI  - Production of monoclonal antibodies and enzyme immunoassay to bovine retinol
      binding protein and determination of retinol-binding protein serum levels and
      retinol concentrations in serum and liver in dairy cows before and after
      parturition.
AB  - To study vitamin A transport in dairy cows and heifers around parturition, an
      enzyme immunoassay for bovine retinol binding protein (RBP) was developed and
      serum levels determined. Serum and liver concentrations of retinol were assayed
      by HPLC. Four weeks before expected calving the cows and heifers were divided
      into two groups each, and half of the animals received a protein supplementation
      during the dry period. The mean serum RBP concentration 4 weeks before calving
      was 42 mg l-1 for the cows and 44 mg l-1 for the heifers. The serum retinol
      concentrations were 0.53 mg l-1 for the cows and 0.42 mg l-1 for the heifers, and
      the liver retinol concentrations 0.30 mg l-1 and 0.13 mg g-1, respectively. In
      the groups without protein supplementation there was a significant decrease in
      serum RBP at sampling 1 week before parturition compared to initial values. The
      measurement of serum RBP may prove useful in assessment of amino acid
      availability in dairy cows.

PMID- 10333470
TI  - An immunohistochemical study of interstitial cells of Cajal (ICC) in the equine
      gastrointestinal tract.
AB  - The interstitial cells of Cajal (ICC) are c-kit immunoreactive cells of the
      gastrointestinal tract which are suggested to have a role in the control of
      intestinal motility. Cells with c-kit immunoreactivity have not been previously
      described in the gastrointestinal tract of the horse. Immunoreactivity for c-kit
      was revealed using immunohistochemical labelling with an anti-c-kit polyclonal
      antibody. Sections of normal gastrointestinal tissue were examined from 13
      anatomically defined sites from stomach to small colon taken from horses free
      from gastrointestinal disease. Three types of c-kit immunoreactive cells were
      identified: spindle-shaped cells in the region of the myenteric plexus, stellate
      or bipolar cells in the circular muscle layer, and round cells in the submucosa.
      The round cells were shown to be mast cells with the use of toluidine blue
      staining, whereas the other c-kit immunoreactive cells did not exhibit
      metachromasia and were classified as ICC. This study will serve as a basis for
      future pathological studies in the horse.

PMID- 10333471
TI  - Detection of high levels of canine herpes virus-1 neutralising antibody in kennel
      dogs using a novel serum neutralisation test.
AB  - It is widely held that only cells of canine origin support canine herpesvirus-1
      (CHV-1) replication and, that cytopathic effect (CPE) develops relatively slowly.
      Here we show that mink fetal lung cells (NBL-7 cell line) are permissive for CHV
      1 and can be used to produce a sensitive test for neutralising antibody by plaque
      reduction in the presence of complement. The test was applied to the
      investigation of CHV-1 virus neutralising antibody levels in three kennel
      populations. The results showed that 26 out of 28 dogs were neutralising antibody
      positive (titre >/=2), and, 11 out of 28 had titres of >/=1024. The serum samples
      were analysed by enzyme linked immunoassay (ELISA); 27 out of 28 were graded as
      ELISA IgG positive (titre >/=500) and 26 of 28 were graded as ELISA IgM positive
      (titre >/=50).

PMID- 10333472
TI  - Characterisation of equine T helper cells: demonstration of Th1- and Th2-like
      cells in long-term equine T-cell cultures.
AB  - The aim of this study was to characterise CD4+T-cells in equines, as these cells
      are pivotal in establishing immune responses or regulating established ones.
      Peripheral blood mononuclear cells from a pony immunised with ovalbumin were
      cultured in vitro in the presence of the specific antigen and autologous antigen
      presenting cells. During the antigen starvation phase, cells were maintained on
      recombinant equine IL-2. After 35 days of culture, most of the cells were CD4+,
      CD8-and sIg-. Cells proliferated specifically in the presence of antigen, as
      tested on day 42 of culture. These cells were analysed by in-situ hybridisation
      to detect m RNA for IL-2 and IL-4, the presence of which suggested the existence
      of of Th1- and Th2-like cells.

PMID- 10333473
TI  - Bioavailability of albendazole sulphoxide after netobimin administration in
      sheep: effects of fenbendazole coadministration.
AB  - After oral co-administration of two dosages of netobimin (7.5 and 20 mg kg-1 with
      fenbendazole (1.1 mg kg-1) to Merino sheep, the AUC0-infinity of albendazole
      sulphoxide at the lower dosage of netobimin, was significantly increased (75.5
      per cent) from control value (34.43 +/- 7.91 versus 60.33 +/- 11.93 microg h ml
      1). The pharmacokinetic parameters MRT and T1/2 were also increased: 18.96 +/-
      2.54 vs 26.44 +/- 4.69 h and 10.31 +/- 1.72 vs 22.28 +/- 6.75 h respectively. No
      data corresponding to the higher dosage of netobimin (20 mg kg-1) were
      statistically different from control values. It is concluded that fenbendazole
      increases the bioavailability of albendazole sulphoxide in sheep at the 7.5 mg kg
      1 dosage, and this may produce a potentiated anthelmintic action.

PMID- 10333474
TI  - Involvement of the core protein in the first beta-N-acetylgalactosamine transfer
      to the glycosaminoglycan-protein linkage-region tetrasaccharide and in the
      subsequent polymerization: the critical determining step for chondroitin sulphate
      biosynthesis.
AB  - alpha-Thrombomodulin (alpha-TM) with a truncated glycosaminoglycan-protein
      linkage tetrasaccharide, GlcAbeta1-3Galbeta1-3Galbeta1-4Xyl, was tested as an
      acceptor together with a sugar donor, UDP-N-[3H]acetylgalactosamine, using a cell
      free enzyme system prepared from the serum-free culture medium of a human
      melanoma cell line. The truncated tetrasaccharide on alpha-TM served as an
      acceptor, whereas the linkage tetrasaccharide-serine did not. Our
      characterization of the radioactively labelled product by enzymic digestion
      revealed that the N-[3H]acetylgalactosamine residue was transferred to alpha-TM
      through a beta1,4-linkage. The substrate competition experiments with the chondro
      hexasaccharide and alpha-TM reinforced our speculation that a common N
      acetylgalactosaminyltransferase catalysed the transfer of N-acetylgalactosamine
      to both the linkage tetrasaccharide and the longer chondroitin oligosaccharides.
      Moreover, chondroitin polymerization was demonstrated on the tetrasaccharide of
      alpha-TM using both UDP-glucuronic acid and UDP-N-acetylgalactosamine as sugar
      donors. Much longer chains were synthesized on alpha-TM than on the linkage penta
      and hexa-saccharide-serines. Together, these results indicated that the core
      protein is required for the transfer of the first N-acetylgalactosamine residue
      through a beta1,4-linkage and also for subsequent efficient chain polymerization
      reactions, and that the critical determining step for chondroitin sulphate
      biosynthesis is the transfer of the first N-acetylgalactosamine residue.

PMID- 10333475
TI  - Identification of centaurin-alpha1 as a potential in vivo phosphatidylinositol
      3,4,5-trisphosphate-binding protein that is functionally homologous to the yeast
      ADP-ribosylation factor (ARF) GTPase-activating protein, Gcs1.
AB  - Centaurin-alpha is a 46 kDa in vitro binding protein for the lipid second
      messenger PtdIns(3,4,5)P3. In this report we have addressed whether centaurin
      alpha1, a human homologue of centaurin-alpha, binds PtdIns(3,4,5)P3 in vivo and
      furthermore, identified a potential physiological function for centaurin-alpha1.
      Using confocal microscopy of live PC12 cells, transiently transfected with a
      chimera of green fluorescent protein (GFP) fused to the N-terminus of centaurin
      alpha1 (GFP-centaurin-alpha1), we demonstrated the rapid plasma membrane
      recruitment of cytosolic GFP-centaurin-alpha1 following stimulation with either
      nerve growth factor or epidermal growth factor. This recruitment was dependent on
      the centaurin-alpha1 pleckstrin homology domains and was blocked by the
      PtdIns(4,5)P2 3-kinase (PI 3-kinase) inhibitors wortmannin (100 nM) and LY294002
      (50 microM), and also by co-expression with a dominant negative p85.
      Functionally, we demonstrated that centaurin-alpha1 could complement a yeast
      strain deficient in the ADP-ribosylation factor (ARF) GTPase-activating protein
      Gcs1; a complementation that was blocked by mutagenesis of conserved cysteine
      residues within the ARF GTPase-activating protein analogous domain of centaurin
      alpha1. Taken together, our data demonstrated that centaurin-alpha1 could
      potentially function as an ARF GTPase-activating protein that, on agonist
      stimulation, was recruited to the plasma membrane possibly through an ability to
      interact with PtdIns(3,4,5)P3.

PMID- 10333476
TI  - Signal transduction pathway regulating prostaglandin EP3 receptor-induced neurite
      retraction: requirement for two different tyrosine kinases.
AB  - We reported previously that activation of the prostaglandin E receptor EP3
      subtype triggered neurite retraction through the small GTPase Rho-, and its
      target, RhoA-binding kinase alpha (ROKalpha)-, dependent pathway in EP3 receptor
      expressing PC12 cells. Here we examined the involvement of tyrosine kinases in
      this pathway in nerve growth factor-differentiated PC12 cells. Tyrphostin A25, a
      tyrosine kinase inhibitor, blocked neurite retraction and cell rounding induced
      by activation of the EP3 receptor, however, it failed to block neurite retraction
      and cell rounding induced by microinjection of constitutively active RhoA,
      RhoAV14, indicating that a tyrphostin-sensitive tyrosine kinase was involved in
      the pathway from the EP3 receptor to Rho activation. On the other hand,
      genistein, another tyrosine kinase inhibitor, blocked neurite retraction and cell
      rounding induced by both activation of the EP3 receptor and microinjection of
      RhoAV14. However, genistein did not block neuronal morphological changes induced
      by microinjection of a constitutively active mutant of ROKalpha. These results
      indicate that two different tyrosine kinases, tyrphostin A25-sensitive and
      genistein-sensitive kinases, are involved in the EP3 receptor-mediated neurite
      retraction acting upstream and downstream of Rho, respectively.

PMID- 10333477
TI  - The 5-lipoxygenase-activating protein (FLAP) inhibitor, MK886, induces apoptosis
      independently of FLAP.
AB  - The ability of various inhibitors of lipoxygenase (LOX) enzymes and 5
      lipoxygenase-activating protein (FLAP) to induce apoptosis has implicated these
      pathways in the mechanism(s) of this form of cell death. Although FLAP plays an
      important role in 5-LOX activity, this protein is found at high levels in some
      cells lacking LOX, suggesting it might mediate other effects. Furthermore, the
      concentration of MK886, a FLAP inhibitor, required to induce apoptosis is
      approximately 100-fold more than that required to inhibit LOX, and this compound
      remains effective in cells lacking LOX. The present study examines the role of
      FLAP in MK886-induced apoptosis. MK886 induced apoptosis in WSU cells, a human
      chronic lymphocytic leukaemia cell line that lacks FLAP protein and mRNA,
      suggesting that this agent is acting independently of FLAP. This conclusion was
      further supported by the fact that a more specific FLAP inhibitor, MK591, induced
      only minimal apoptosis in FL5.12 cells, a murine prolymphoid cell line containing
      FLAP. The role of FLAP was examined more directly by decreasing its expression by
      more than 50% in FL5.12 cells treated with 10 microM of an antisense
      oligonucleotide for 48h. This change in FLAP was not accompanied by any increase
      in apoptosis. Furthermore, FLAP-depleted cells exhibited the same level of
      apoptosis 8 h after treatment with 10 microM MK886, as did control cells. The
      increased fluorescence seen in MK886-treated cells loaded with
      carboxydichlorofluorescein indicates that oxidative reactions are stimulated by
      this compound, possibly via the release of fatty acids from fatty acid-binding
      proteins and their subsequent oxidation.

PMID- 10333478
TI  - Contribution of copper binding to the inhibition of lipid oxidation by
      plasmalogen phospholipids.
AB  - The role of plasmalogen phospholipids for copper-induced lipid oxidation was
      evaluated. Using 1H-NMR we observed that the copper (CuSO4)-promoted oxidative
      degradation of polyunsaturated fatty acids in micellar solution was dose
      dependently attenuated by the plasmalogen lysoplasmenylethanolamine from bovine
      brain (lysoBP-PtdEtn). This was due to a direct interaction of copper ions with
      the plasmalogen-specific enol ether double bond. The enol ether methine 1H signal
      decreased on the addition of copper, saturation being reached at a molar ratio of
      lysoBP-PtdEtn to copper of 1:1. The original 1H signal was recovered almost
      completely after the addition of EDTA. Enrichment of micelles and low-density
      lipoproteins (LDLs) with plasmalogen phospholipids led to a decrease in the
      Cu(II) concentration in the aqueous media. After loading of LDLs in vitro with BP
      PtdEtn, the LDL-dependent formation of Cu(I) was decreased, in particular in
      particles experimentally supplemented with alpha-tocopherol. The suppression of
      copper-promoted lipid oxidation that was observed in the presence of plasmalogen
      phospholipids plus alpha-tocopherol was greater than the sum of the protective
      effects elicited by the two substances alone. In conclusion, the formation of a
      complex between copper ions and the plasmalogens accounts partly for their
      inhibition of copper-induced lipid oxidation.

PMID- 10333479
TI  - Isolation and characterization of a novel antifreeze protein from carrot (Daucus
      carota).
AB  - A modified assay for inhibition of ice recrystallization which allows unequivocal
      identification of activity in plant extracts is described. Using this assay a
      novel, cold-induced, 36 kDa antifreeze protein has been isolated from the tap
      root of cold-acclimated carrot (Daucus carota) plants. This protein inhibits the
      recrystallization of ice and exhibits thermal-hysteresis activity. The
      polypeptide behaves as monomer in solution and is N-glycosylated. The
      corresponding gene is unique in the carrot genome and induced by cold. The
      antifreeze protein appears to be localized within the apoplast.

PMID- 10333480
TI  - Cationic liposome-encapsulated antisense oligonucleotide mediates efficient
      killing of intracellular Leishmania.
AB  - Antisense oligonucleotides have been considered as inhibitors of growth of
      intracellular parasites such as Leishmania, but only limited inhibition has been
      observed in vitro. We have encapsulated an antisense oligonucleotide,
      complementary to the Leishmania universal miniexon sequence, in cationic
      liposomes. Low concentrations (4 microM) of encapsulated oligonucleotides
      specifically reduced the amastigote burden within cultured macrophages by 80%.
      This result illustrates the importance of effective delivery for efficient
      antiparasitic activity of antisense oligonucleotides.

PMID- 10333481
TI  - Mechanism of ubiquitous expression of mouse uncoupling protein 2 mRNA: control by
      cis-acting DNA element in 5'-flanking region.
AB  - Uncoupling protein (UCP) 2 is a member of the uncoupling-protein family, and it
      appears to function as an uncoupler of oxidative phosphorylation. To identify cis
      acting regulatory elements controlling this gene's expression, we cloned an
      approx. 6.2-kb region upstream from the translation-initiation site of the mouse
      UCP2 gene and analysed its transcription activity using chimaeric mouse UCP2
      promoter-placental-alkaline-phosphatase (PLAP) reporter-gene constructs. Sequence
      analysis showed that the 5'-flanking region of the mouse UCP2 gene was not
      similar to those of mouse UCP1 or UCP3. For the mouse UCP2, the region near the
      transcription-initiation site lacked the typical TATA box, but was GC-rich,
      resulting in presence of several potential specificity protein 1 (Sp-1),
      activator protein (AP)-1 and AP-2 binding sites. The putative regulatory motifs
      for muscle-regulatory protein (MyoD), brown-fat regulatory element, CCAAT box,
      cAMP-response element and Y box were also found in the mouse UCP2 promoter region
      by computer-assisted analysis. From the results of Northern-blot analysis and
      transient expression assay, we found that the mouse UCP2 gene responded to the
      cAMP-dependent protein kinase alpha-catalytic subunit signal activation at the
      transcription level. Additionally, deletion analysis of the UCP2 promoter-PLAP
      constructs indicated that the minimal region exhibiting the promoter activity was
      located between nt -33 and +100, and that a strong enhancer was present within
      601 bp of the 5'-promoter region. In particular, the region from nt -233 to -34
      significantly induced PLAP activity in the cell lines derived from various
      tissues and in the primary culture cells of rat brown adipose tissue, suggesting
      that this region is most important for the ubiquitous expression of mouse UCP2
      mRNA. Furthermore, it was shown that two silencer elements were involved in the
      mouse UCP2 gene; one was located between nt -2746 and -602, and the other was
      identified in intron 1. These regions deprived the enhancer of the ability to
      induce PLAP activity. This study shows a fundamental role for positive and
      negative cis-acting DNA elements in regulating the basal and cAMP-induced
      transcription activity of the mouse UCP2 gene.

PMID- 10333482
TI  - Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP
      glucuronosyltransferase, UGT2B1, in the rat liver.
AB  - Bisphenol A, an environmental oestrogenic chemical, was found to conjugate highly
      with glucuronic acid in male rat liver microsomes studied in vitro. In the
      various isoforms tested (1A1, 1A3, 1A5, 1A6, 1A7 and 2B1), glucuronidation of
      bisphenol A and of diethylstilboestrol, a synthetic crystalline compound
      possessing oestrogenic activity and known to be glucuronidated by liver
      microsomes, was catalysed by an isoform of UDP-glucuronosyltransferase (UGT),
      namely UGT2B1, which glucuronidates some endogenous androgens. UGT activity
      towards bisphenol A in liver microsomes and in UGT2B1 expressed in yeast AH22
      cells (22.9 and 0.58 nmol/min per mg of microsomal proteins respectively) was
      higher than that towards diethylstilboestrol (75.0 and 4.66 pmol/min per mg of
      microsomal proteins respectively). UGT activities towards both bisphenol A and
      diethylstilboestrol were distributed mainly in the liver but were also observed
      at substantial levels in the kidney and testis. Northern blot analysis disclosed
      the presence of UGT2B1 solely in the liver, and about 65% of the male rat liver
      microsomal UGT activities towards bisphenol A were absorbed by the anti-UGT2B1
      antibody. These results indicate that bisphenol A, in male rat liver, is
      glucuronidated by UGT2B1, an isoform of UGT.

PMID- 10333483
TI  - Apoptosis induction via microtubule disassembly by an antitumour compound,
      pironetin.
AB  - We reported previously that pironetin and its derivatives were potent inhibitors
      of cell cycle progression at the M-phase and showed antitumour activity against a
      murine tumour cell line, P388 leukaemia, transplanted in mice. In this paper, we
      investigated the mechanism of action of pironetins in antitumour activity and
      cell cycle arrest at the M-phase. As reported previously for murine leukaemia
      P388 cells, pironetin showed antitumour activity in a dose-dependent manner in
      the human leukaemia cell line HL-60. Since DNA fragmentation was observed in both
      P388 and HL-60 cells, the antitumour activity of pironetin is thought to be due
      to the induction of apoptosis. Pironetin also induced the rapid phosphorylation
      of Bcl-2 before formation of the DNA ladder in HL-60 cells, as seen with several
      tubulin binders. These results suggest that the antitumour activity of pironetin
      is due to apoptosis caused by the phosphorylation of Bcl-2, and that pironetin
      targets the microtubules. Pironetin and demethylpironetin exhibited reversible
      disruption of the cellular microtubule network in normal rat fibroblast 3Y1
      cells. However, epoxypironetin, which contains epoxide instead of the double bond
      of pironetin, showed only weak activity. Since the concentrations that inhibit
      cell cycle progression at the M-phase were the same as those for disruption of
      the microtubule network, it was suggested that the mitotic arrest induced by
      pironetin was the result of the loss of the mitotic spindle. These compounds also
      inhibited the microtubule-associated protein-induced and glutamate-induced
      tubulin assembly in vitro. Pironetin inhibited the binding of [3H]vinblastine,
      but not that of [3H]colchicine, to tubulin, and the Kd values revealed that the
      affinity of pironetin for tubulin is stronger than that of vinblastine. These
      results suggest that pironetins are novel antitumour agents which inhibit
      microtubule assembly.

PMID- 10333484
TI  - Structural elements within the methylation loop (residues 112-117) and EF hands
      III and IV of calmodulin are required for Lys(115) trimethylation.
AB  - Calmodulin is trimethylated by a specific methyltransferase on Lys115, a residue
      located in a six amino acid loop (LGEKLT) between EF hands III and IV. To
      investigate the structural requirements for methylation, domain exchange mutants
      as well as single point mutations of conserved methylation loop residues (E114A,
      Glu114-->Ala; L116T, Leu116-->Thr) were generated. E114A and L116T activated
      cyclic nucleotide phosphodiesterase (PDE) and NAD+ kinase (NADK) similar to wild
      type calmodulin, but lost their ability to be methylated. Domain exchange mutants
      in which EF hand III or IV was replaced by EF hand I or II respectively (CaM1214
      and CaM1232 respectively) showed a modest effect on PDE and NADK activation (50
      to 100% of wild-type), but calmodulin methylation was abolished. A third domain
      exchange mutant, CaMEKL, has the methylation loop sequence placed at a
      symmetrical position between EF hands I and II in the N-terminal lobe [residues
      QNP(41-43) replaced by EKL]. CaMEKL activated PDE normally, but did not activate
      NADK. However, CaMEKL retained the ability to bind to NADK and inhibited
      activation by wild-type calmodulin. Site-directed mutagenesis of single residues
      showed that Gln41 and Pro43 substitutions had the strongest effect on NADK
      activation. Additionally, CaMEKL was not methylated, suggesting that the
      introduction of the methylation loop between EF hands I and II is not adequate
      for methyltransferase recognition. Overall the data indicate that residues in the
      methylation loop are essential but not sufficient for methyltransferase
      recognition, and that additional residues unique to EF hands III and IV are
      required. Secondly, the QNP sequence in the loop between EF hands I and II is
      necessary for NADK activation.

PMID- 10333485
TI  - Expression of the rat liver carnitine palmitoyltransferase I (CPT-Ialpha) gene is
      regulated by Sp1 and nuclear factor Y: chromosomal localization and promoter
      characterization.
AB  - Carnitine palmitoyltransferase (CPT)-I catalyses the transfer of long-chain fatty
      acids from CoA to carnitine for translocation across the mitochondrial inner
      membrane. Expression of the 'liver' isoform of the CPT-I gene (CPT-Ialpha) is
      subject to developmental, hormonal and tissue-specific regulation. To understand
      the basis for control of CPT-Ialpha gene expression, we have characterized the
      proximal promoter of the CPT-Ialpha gene. Here, we report the sequence of 6839
      base pairs of the promoter and the localization of the rat CPT-Ialpha gene to
      region q43 on chromosome 1. Our studies show that the first 200 base pairs of the
      promoter are sufficient to drive transcription of the CPT-Ialpha gene. Within
      this region are two sites that bind both Sp1 and Sp3 transcription factors. In
      addition, nuclear factor Y (NF-Y) binds the proximal promoter. Mutation at the
      Sp1 or NF-Y sites severely decreases transcription from the CPT-Ialpha promoter.
      Other protein binding sites were identified within the first 200 base pairs of
      the promoter by DNase I footprinting, and these elements contribute to CPT-Ialpha
      gene expression. Our studies demonstrate that CPT-Ialpha is a TATA-less gene
      which utilizes NF-Y and Sp proteins to drive basal expression.

PMID- 10333486
TI  - Involvement of Arg-328, Arg-334 and Arg-342 of DnaA protein in the functional
      interaction with acidic phospholipids.
AB  - We reported previously that three basic amino acids (Arg-360, Arg-364 and Lys
      372) of DnaA protein are essential for its functional interaction with
      cardiolipin. In this study, we examined the effect of mutation of some basic
      amino acids in a potential amphipathic helix (from Lys-327 to Ile-345) of DnaA
      protein on this interaction. ATP binding to the mutant DnaA protein, in which Arg
      328, Arg-334 and Arg-342 were changed to acidic amino acids, was less inhibited
      by cardiolipin than that of the wild-type protein, as was the case for mutant
      DnaA protein with mutations of Arg-360, Arg-364 and Lys-372. A mutant DnaA
      protein with mutations of all six basic amino acids showed the most resistance to
      the inhibition of ATP binding by cardiolipin. These results suggest that Arg-328,
      Arg-334 and Arg-342, like Arg-360, Arg-364 and Lys-372, are also involved in the
      functional interaction between DnaA protein and acidic phospholipids.

PMID- 10333487
TI  - Functional expression of rat thioredoxin reductase: selenocysteine insertion
      sequence element is essential for the active enzyme.
AB  - Mammalian thioredoxin reductase (TR) is a flavoprotein catalysing reduction of
      oxidized thioredoxin in an NADPH-dependent manner, and contains a selenocysteine
      (Sec) residue near the C-terminus. We observed that TR activity was decreased in
      A549 cells by the lowering of the fetal bovine serum content in the culture
      medium and was recovered by the addition of selenium. To study the role of Sec in
      TR activity, we have isolated a full-length clone of the rat TR cDNA (3.3 kb) and
      have expressed it in COS-1 cells in a transient-expression system. TR activities
      in COS-1 cells expressing rat TR were increased in accordance with supplemented
      sodium selenite concentrations, whereas levels of TR protein, examined by Western
      blotting, were not affected by sodium selenite concentrations. We introduced
      various deletions into the 3'-untranslated region of the TR cDNA to localize and
      examine the role of a Sec insertion-sequence (SECIS) element in the functional
      expression of TR. TR activities were observed only in COS-1 cells transfected
      with the TR cDNAs containing the putative SECIS element located between 1856 and
      1915 bp in the correct orientation. We also carried out radiolabelling of
      proteins by incubation of the cDNA-transfected cells with sodium [75Se]selenite.
      75Se was incorporated into the expressed TR protein of the cells transfected with
      the SECIS element-containing cDNAs, but not into those without the SECIS element
      or with an inverted SECIS element. These data clearly showed a requirement of
      selenium for the formation of functional TR protein.

PMID- 10333488
TI  - Partial replacement of bile salts causes marked changes of cholesterol
      crystallization in supersaturated model bile systems.
AB  - Cholesterol crystallization is a key step in gallstone formation and is
      influenced by numerous factors. Human bile contains various bile salts having
      different hydrophobicity and micelle-forming capacities, but the importance of
      lipid composition to bile metastability remains unclear. This study investigated
      the effect of bile salts on cholesterol crystallization in model bile (MB)
      systems. Supersaturated MB systems were prepared with an identical composition on
      a molar basis (taurocholate/phosphatidylcholine/cholesterol, 152 mM:38 mM: 24
      mM), except for partial replacement of taurocholate (10, 20, and 30%) with
      various taurine-conjugated bile salts. Cholesterol crystallization was
      quantitatively estimated by spectrophotometrically measuring crystal-related
      turbidity and morphologically scanned by video-enhanced microscopy. After partial
      replacement of taurocholate with hydrophobic bile salts, cholesterol
      crystallization increased dose-dependently without changing the size of vesicles
      or crystal morphology and the rank order of crystallization was
      deoxycholate>chenodeoxycholate>cholate (control MB). All of the hydrophilic bile
      salts (ursodeoxycholate, ursocholate and beta-muricholate) inhibited cholesterol
      precipitation by forming a stable liquid-crystal phase, and there were no
      significant differences among the hydrophilic bile-salt species. Cholesterol
      crystallization was markedly altered by partial replacement of bile salts with a
      different hydrophobicity. Thus minimal changes in bile-salt composition may
      dramatically alter bile lipid metastability.

PMID- 10333489
TI  - Relationship between cytochrome P450 catalytic cycling and stability: fast
      degradation of ethanol-inducible cytochrome P450 2E1 (CYP2E1) in hepatoma cells
      is abolished by inactivation of its electron donor NADPH-cytochrome P450
      reductase.
AB  - Ethanol-inducible cytochrome P450 2E1 (CYP2E1) involved in the metabolism of
      gluconeogenetic precursors and some cytotoxins is distinguished from other
      cytochrome P450 enzymes by its rapid turnover (in vivo half-life of 4-7 h), with
      ligands to the haem iron, both substrates and inhibitors, stabilizing the
      protein. CYP2E1 is also known to have a high oxidase activity in the absence of
      substrate, resulting in the production of reactive oxygen radicals. We suggested
      that the rapid intracellular turnover of the enzyme may be partly due to covalent
      modifications by such radicals or to other changes during catalytic cycling, in
      which case the inhibition of electron supply from NADPH-cytochrome P450 reductase
      would be expected to stabilize the protein. Fao hepatoma cells, where CYP2E1
      showed a half-life of 4 h upon serum withdrawal, were treated for 1 h with 0.3
      microM diphenylene iodonium (DPI), a suicide inhibitor of flavoenzymes, which
      resulted in approximately 90% inhibition of the microsomal NADPH-cytochrome P450
      reductase and CYP2E1-dependent chlorzoxazone hydroxylase activities. Subsequent
      cycloheximide chase revealed that the CYP2E1 half-life increased to 26 h. Neither
      the degradation rates of total protein, CYP2B1 and NADPH-cytochrome P450
      reductase nor the cellular ATP level were affected by DPI under the conditions
      employed. These results demonstrate for the first time that the short half-life
      of CYP2E1 in vivo may be largely due to the rapid destabilization of the enzyme
      during catalytic cycling rather than to the intrinsic instability of the protein
      molecule.

PMID- 10333490
TI  - Expression of hormone-sensitive lipase and its regulation by adrenaline in
      skeletal muscle.
AB  - The enzymic regulation of triacylglycerol breakdown in skeletal muscle is poorly
      understood. Western blotting of muscle fibres isolated by collagenase treatment
      or after freeze-drying demonstrated the presence of immunoreactive hormone
      sensitive lipase (HSL), with the concentrations in soleus and diaphragm being
      more than four times the concentrations in extensor digitorum longus and
      epitrochlearis muscles. Neutral lipase activity determined under conditions
      optimal for HSL varied directly with immunoreactivity. Expressed relative to
      triacylglycerol content, neutral lipase activity in soleus muscle was about 10
      times that in epididymal adipose tissue. In incubated soleus muscle, both neutral
      lipase activity against triacylglycerol (but not against a diacylglycerol
      analogue) and glycogen phosphorylase activity increased in response to adrenaline
      (epinephrine). The lipase activation was completely inhibited by anti-HSL
      antibody and by propranolol. The effect of adrenaline could be mimicked by
      incubation of crude supernatant from control muscle with the catalytic subunit of
      cAMP-dependent protein kinase, while no effect of the kinase subunit was seen
      with supernatant from adrenaline-treated muscle. The results indicate that HSL is
      present in skeletal muscle and is stimulated by adrenaline via beta-adrenergic
      activation of cAMP-dependent protein kinase. The concentration of HSL is higher
      in oxidative than in glycolytic muscle, and the enzyme is activated in parallel
      with glycogen phosphorylase.

PMID- 10333491
TI  - Stable expression of protective protein/cathepsin A-green fluorescent protein
      fusion genes in a fibroblastic cell line from a galactosialidosis patient. Model
      system for revealing the intracellular transport of normal and mutated lysosomal
      enzymes.
AB  - Fibroblastic cell lines derived from a galactosialidosis patient, stably
      expressing the chimaeric green fluorescent protein variant (EGFP) gene fused to
      the wild-type and mutant human lysosomal protective protein/cathepsin A (PPCA)
      cDNA, were first established as a model system for revealing the sorting and
      processing of lysosomal enzymes and for investigating the molecular bases of
      their deficiencies. In the cell line expressing the wild-type PPCA-EGFP chimaera
      gene (EGFP-PPwild), an 81 kDa form (27 kDa EGFP fused to the C-terminus of the 54
      kDa PPCA precursor) was produced, then processed into the mature 32/20 kDa two
      chain form free of the EGFP domain. The intracellular cathepsin A, alpha-N
      acetylneuraminidase and beta-galactosidase activities, which are deficient in the
      parent fibroblastic cells, could also be significantly restored in the cells. In
      contrast with the uniform and strong fluorescence throughout the cytoplasm and
      nucleus in the mock-cell line expressing only EGFP cDNA, weak reticular and
      punctate fluorescence was distributed throughout the EGFP-PPwild cell line.
      Bafilomycin A1, a potent inhibitor of vacuolar ATPase and intracellular
      acidification, induced the distribution of Golgi-like perinuclear fluorescence
      throughout the living and fixed cells, in which only the 81 kDa product was
      detected. After removal of the agent, time-dependent transport of the chimaeric
      protein from the Golgi apparatus to the prelysosomal structure in living cells
      was monitored with a confocal laser scanning microscope system. Leupeptin caused
      the distribution of lysosome-like granular fluorescence throughout the cytoplasm
      in the fixed cells, although it was hardly observed in living cells. The latter
      agent also dose-dependently induced an increase in the intracellular amount of
      the 81 kDa product containing the EGFP domain and inhibited the restoration of
      cathepsin A activity in the EGFP-PPwild cells after the removal of bafilomycin
      A1. In parallel, both the mature two-chain form and PPCA function disappeared.
      These results suggested that the chimaera gene product was transported to acidic
      compartments (endosomes/lysosomes), where proteolytic processing of the PPCA
      precursor/zymogen, quenching of the fluorescence, and random degradation of the
      EGFP portion occurred. A cell line stably expressing a chimaeric gene with a
      mutant PPCA cDNA containing an A1184-->G (Y395C) mutation, commonly detected in
      Japanese severe early-infantile type of galactosialidosis patients, showed an
      endoplasmic reticulum (ER)-like reticular fluorescence pattern. The PPCA
      immunoreactive gene product was hardly detected in this cell line. The mutant
      chimaeric product was suggested to be degraded rapidly in the ER before transport
      to post-ER compartments. A cell line expressing the chimaeric gene with a T746-
      >A (Y249N) PPCA mutation exhibited both ER-like reticular and granular
      fluorescence on the reticular structure that was stronger than that in the EGFP
      PPwild cells. Some of them contained large fluorescent inclusion-body-like
      structures. The ineffectiveness of transport inhibitors in the distribution
      changes in the two mutant chimaeric proteins suggested that they were not
      delivered to acidic compartments. Therefore this expression system can possibly
      be applied to the direct analysis of the sorting defects of mutant gene products
      in living cells and will be useful for the molecular investigation of lysosomal
      diseases, including galactosialidosis.

PMID- 10333493
TI  - Insulin and dexamethasone stimulation of cardiac lipoprotein lipase activity
      involves the actin-based cytoskeleton.
AB  - Lipoprotein lipase (LPL) activity in cultured ventricular cardiomyocytes from
      adult rat hearts was stimulated by the combination of insulin (100 nM) and
      dexamethasone (100 nM) during an overnight (16 h) incubation. Wortmannin (100
      nM), rapamycin (30 ng/ml) or PD98059 (50 microM) did not prevent this
      stimulation, suggesting that phosphatidylinositol 3-kinase, p70 S6 kinase and the
      mitogen-activated protein kinase cascade are not involved in transducing the
      hormonal signal. In contrast, cytochalasin D (2 microM) completely abolished the
      stimulatory effect of insulin and dexamethasone on both heparin-releasable LPL
      and total cellular LPL activities. The potential role of the actin cytoskeleton
      in the stimulation of LPL activity by insulin and dexamethasone appears to be
      distal to the initial signalling events since cytochalasin D is still effective
      in preventing the stimulation when added 2 h after the hormones.

PMID- 10333492
TI  - Neuronal expression of the rat M1 muscarinic acetylcholine receptor gene is
      regulated by elements in the first exon.
AB  - Muscarinic acetylcholine receptor genes are members of the G-protein coupled
      receptor superfamily. Each member of this family studied to date appears to have
      a distinct expression profile, however the mechanisms determining these
      expression patterns remain largely unknown. We have previously isolated a genomic
      clone containing the M1 muscarinic receptor gene and determined its gene
      structure [Pepitoni, Wood and Buckley (1997) J. Biol. Chem. 272, 17112-17117]. We
      have now identified DNA elements responsible for driving cell specific expression
      in transient transfection assays of immortalized cell lines. A region of the gene
      spanning 974 nucleotides and containing 602 nucleotides of the first exon is
      sufficient to drive specific expression in cell lines. Like the M4 and M2 gene
      promoters, the M1 promoter contains an Sp1 motif which can recruit transcription
      factor Sp1 and at least one other protein, although this site does not appear to
      be functionally important for M1 expression in our assay. We have identified a
      region within the first exon of the M1 gene that regulates expression in cell
      lines, contains several positive and negative acting elements and is able to
      drive expression of a heterologous promoter. A polypyrimidine/polypurine tract
      and a sequence conserved between M1 genes of various species act in concert to
      enhance M1 transcription and are able to activate a heterologous promoter. We
      show that DNA binding proteins interact in vitro with single-stranded DNA derived
      from these regions and suggest that topology of the DNA is important for
      regulation of M1 expression.

PMID- 10333494
TI  - 3-nitropropionic acid oxidase from horseshoe vetch (Hippocrepis comosa): a novel
      plant enzyme.
AB  - A novel enzyme that catalyses the oxygen-dependent oxidation of 3-nitropropionic
      acid (3NPA) to malonate semialdehyde, nitrate, nitrite and H2O2 has been purified
      from leaf extracts of the horseshoe vetch, Hippocrepis comosa, and named 3NPA
      oxidase. The enzyme is a flavoprotein with a subunit molecular mass of 36 kDa
      containing 1 molecule of FMN and exhibits little specificity for all nitroalkanes
      tested other than 3NPA (apparent Km 620 microM). The maximum enzyme activity in
      vitro was expressed at pH4.8 and was inhibited strongly by the products nitrate
      and nitrite. 3NPA oxidase activity was detected in green shoots, which also
      contain high concentrations of 3NPA, from plants grown with nitrate, ammonium or
      N2 as sources of nitrogen. Enzyme activity was absent from roots and cell
      cultures, neither of which accumulate high levels of 3NPA.

PMID- 10333495
TI  - Sepiapterin reductase producing L-threo-dihydrobiopterin from Chlorobium tepidum.
AB  - A novel type of NADPH-dependent sepiapterin reductase, which catalysed uniquely
      the reduction of sepiapterin to l-threo-dihydrobiopterin, was purified 533-fold
      from the cytosolic fraction of Chlorobium tepidum, with an overall yield of 3%.
      The native enzyme had a molecular mass of 55 kDa and SDS/PAGE revealed that the
      enzyme consists of two subunits with a molecular mass of 26 kDa. The enzyme was
      optimally active at pH8.8 and 50 degrees C. Apparent Km values for sepiapterin
      and NADPH were 21 and 6.2 microM, respectively, and the kcat value was 5.0 s-1.
      Diacetyl could also serve as a substrate, with a Km of 4.0 mM. The inhibitory
      effects of N-acetylserotonin, N-acetyldopamine and melatonin were very weak. The
      Ki value of N-acetyldopamine was measured as 400 microM. The N-terminal amino
      acid sequence was revealed as Met-Lys-His-Ile-Leu-Leu-Ile-Thr-Gly-Ala-Xaa-Lys -
      Lys - Ile - Xaa - Arg - Ala - Ile - Ala - Leu - Glu - Xaa - Ala - Arg - Xaa-Xaa
      Xaa-His-His-His-, which shared relatively high sequence similarity with other
      sepiapterin reductases.

PMID- 10333496
TI  - Mapping of a palmitoylatable band 3-binding domain of human erythrocyte membrane
      protein 4.2.
AB  - Evidence accumulated over the years suggests that human erythrocyte membrane
      protein 4.2 is one of the proteins involved in strengthening the cytoskeleton
      membrane interactions in the red blood cell. Deficiency of protein 4.2 is linked
      with a variety of hereditary haemolytic anaemia. However, the interactions of
      protein 4.2 with other proteins of the erythrocyte membrane remain poorly
      understood. The major membrane-binding site for protein 4.2 resides on the
      cytoplasmic domain of band 3 (CDB3). In order to carry out an initial
      characterization of its interaction with the CDB3, protein 4. 2 was subjected to
      proteolytic cleavage and gel renaturation assay, and the 23-kDa N-terminal domain
      was found to interact with band 3. This domain contained two putative
      palmitoylatable cysteine residues, of which cysteine 203 was identified as the
      palmitoylatable cysteine. Recombinant glutathione S-transferase-fusion peptides
      derived from this domain were characterized with respect to their ability to
      interact with the CDB3. Whereas these studies do not rule out the involvement of
      other subsites on protein 4.2 in interaction with the CDB3, the evidence suggests
      that the region encompassing amino acid residues 187-211 is one of the domains
      critical for the protein 4.2-CDB3 interaction. This is also the first
      demonstration that palmitoylation serves as a positive modulator of this
      interaction.

PMID- 10333497
TI  - Unique distance- and DNA-turn-dependent interactions in the human protein C gene
      promoter confer submaximal transcriptional activity.
AB  - Recent studies on the regulation of protein C gene transcription revealed the
      presence of three transcription-factor binding sites in the close proximity to
      the transcription start site. The proximal 40 bp upstream of the transcription
      initiation site contain two, partly overlapping, binding sites for the liver
      enriched hepatocyte nuclear factor (HNF)-3 and one binding site to which HNF-1
      and HNF-6 bind in a mutually exclusive manner. In order to examine the
      functionality of the tight alignment of transcription-factor binding sites around
      the transcription-initiation site, we performed insertional mutagenesis
      experiments. Sequences were inserted at position -21, separating both HNF-3
      binding sites from the HNF-1-HNF-6 binding site, and position -5, separating the
      HNF-3-HNF-1-HNF-6 complex from the transcription start site. All insertions were
      made in the context of the protein C gene -386/+107 promoter region and tested
      for activity by transient transfection experiments. Insertions at position -21
      resulted in a combined distance- and DNA-turn-dependent increase in protein C
      gene expression. Insertions of variable length at position -5 decreased protein C
      gene expression in a DNA-turn-dependent manner. However, this turn-dependent
      decrease was accompanied by a distance-dependent increase in promoter activity.
      This is the first report in which changing the spacing between adjacent
      transcription-factor binding sites results in enhanced transcription, indicating
      the submaximal alignment of promoter elements in the wild-type protein C gene
      promoter region.

PMID- 10333498
TI  - Ryanodine and inositol trisphosphate receptors are differentially distributed and
      expressed in rat parotid gland.
AB  - The present study examines the cellular distribution of the ryanodine
      receptor/channel (RyR) and inositol 1,4,5-trisphosphate receptor (InsP3R)
      subtypes in parotid acini. Using fluorescently labelled 4,4-difluoro-4-bora-3a,4a
      diaza-s-indacene-3-propionic acid glycyl-ryanodine (BODIPYtrade mark-ryanodine)
      and confocal microscopy, RyRs were localized primarily to the perinuclear region
      (basal pole) of the acinar cell. Ryanodine, Ruthenium Red, cAMP and cADP ribose
      (cADPR) competed with BODIPY-ryanodine, resulting in a reduction in the
      fluorescence signal. However, inositol 1,4, 5-trisphosphate [Ins(1,4,5)P3] did
      not alter the binding of BODIPY-ryanodine. Using receptor-subtype-specific
      antisera, InsP3Rs (types I, II and III) were located predominantly in the apical
      pole of the parotid cell. The presence of these three subtypes was confirmed
      using reverse transcriptase PCR with RNA-specific oligonucleotide probes. Binding
      studies using a parotid cell-membrane fraction identified and characterized RyRs
      and InsP3Rs in terms of binding affinity (Kd) and maximum binding capacity (Bmax)
      and confirmed that cADPR displaces ryanodine from its binding sites. Ruthenium
      Red and 8-Br-cADP-ribose blocked Ca2+ release in permeabilized acinar cells in
      response to cADPR and cAMP or forskolin, whereas Ins(1,4,5)P3-induced Ca2+
      release was unaffected. The localization of the RyRs and InsP3Rs in discrete
      regions endow broad areas of the parotid cell with ligand-activated Ca2+
      channels. The consequences of the dual activation of the RyRs and InsP3Rs by
      physiologically relevant stimuli such as noradrenaline (norepinephrine) are
      considered in relation to Ca2+ signalling in the parotid gland.

PMID- 10333499
TI  - Visualization of distinct patterns of subcellular redistribution of the
      thyrotropin-releasing hormone receptor-1 and gqalpha /G11alpha induced by agonist
      stimulation.
AB  - The rat thyrotropin-releasing hormone receptor-1 (TRHR-1) was modified by the
      addition of green fluorescent protein (GFP) and expressed stably in HEK293 cells.
      Extensive overlap of plasma membrane distribution of autofluorescent TRHR-1-GFP
      with that of the phosphoinositidase C-linked G-proteins Gqalpha/G11alpha,
      identified by indirect immunofluorescence, was monitored concurrently. Addition
      of thyrotropin-releasing hormone resulted in rapid separation of TRHR-1-GFP and
      Gqalpha/G11alpha signals as the receptor was internalized. This situation
      persisted for more than an hour. At longer time periods a fraction of the
      cellular Gqalpha/G11alpha was also internalized, although much of the
      Gqalpha/G11alpha immunoreactivity remained associated with the plasma membrane.
      Parallel experiments, in which the cellular distribution of TRHR-1-GFP and
      Gqalpha/G11alpha immunoreactivity were monitored in sucrose-gradient fractions
      following cell disruption, also demonstrated a rapid, agonist-induced movement of
      TRHR-1-GFP away from the plasma membrane to low-density vesicular fractions. At
      later time points, a fraction of the cellular Gqalpha/G11alpha immunoreactivity
      was also redistributed to overlapping, but non-identical, low-density-vesicle
      containing fractions. Pretreatment of the cells with cytochalasin D or nocodazole
      prevented agonist-induced redistribution of G-protein but not TRHR-1-GFP, further
      indicating resolution of the mechanics of these two processes. The combination of
      a GFP-modified receptor and immunostaining of the G-proteins activated by that
      receptor allows, for the first time, concurrent analysis of the varying dynamics
      and bases of internalization and redistribution of two elements of the same
      signal-transduction cascade.

PMID- 10333500
TI  - Hypochlorite-induced oxidation of proteins in plasma: formation of chloramines
      and nitrogen-centred radicals and their role in protein fragmentation.
AB  - Activated phagocyte cells generate hypochlorite (HOCl) via the release of H2O2
      and the enzyme myeloperoxidase. Plasma proteins are major targets for HOCl,
      although little information is available about the mechanism(s) of oxidation. In
      this study the reaction of HOCl (at least 50 microM) with diluted fresh human
      plasma has been shown to generate material that oxidizes 5-thio-2-nitrobenzoic
      acid; these oxidants are believed to be chloramines formed from the reaction of
      HOCl with protein amine groups. Chloramines have also been detected with isolated
      plasma proteins treated with HOCl. In both cases chloramine formation accounts
      for approx. 20-30% of the added HOCl. These chloramines decompose in a time
      dependent manner when incubated at 20 or 37 degrees C but not at 4 degrees C.
      Ascorbate and urate remove these chloramines in a time- and concentration
      dependent manner, with the former being more efficient. The reaction of fresh
      diluted plasma with HOCl also gives rise to protein-derived nitrogen-centred
      radicals in a time- and HOCl-concentration-dependent manner; these have been
      detected by EPR spin trapping. Identical radicals have been detected with
      isolated HOCl-treated plasma proteins. Radical formation was inhibited by excess
      methionine, implicating protein-derived chloramines (probably from lysine side
      chains) as the radical source. Plasma protein fragmentation occurs in a time- and
      HOCl-concentration-dependent manner, as evidenced by the increased mobility of
      the EPR spin adducts, the detection of further radical species believed to be
      intermediates in protein degradation and the loss of the parent protein bands on
      SDS/PAGE. Fragmentation can be inhibited by methionine and other agents
      (ascorbate, urate, Trolox C or GSH) capable of removing chloramines and reactive
      radicals. These results are consistent with protein-derived chloramines, and the
      radicals derived from them, as contributing agents in HOCl-induced plasma protein
      oxidation.

PMID- 10333501
TI  - CAT2-mediated L-arginine transport and nitric oxide production in activated
      macrophages.
AB  - Activated macrophages require l-arginine uptake to sustain NO synthesis. Several
      transport systems could mediate this l-arginine influx. Using competition
      analysis and gene-expression studies, amino acid transport system y+ was
      identified as the major carrier responsible for this activity. To identify which
      of the four known y+ transport-system genes is involved in macrophage-induced l
      arginine uptake, we used a hybrid-depletion study in Xenopus oocytes. Cationic
      amino acid transporter (CAT) 2 antisense oligodeoxyribonucleotides abolished the
      activated-macrophage-mRNA-induced l-arginine transport. Together with expression
      studies documenting that CAT2 mRNA and protein levels are elevated with increased
      l-arginine uptake, our data demonstrate that CAT2 mediates the l-arginine
      transport that is required for the raised NO production in activated J774
      macrophages.

PMID- 10333502
TI  - Chemical rescue of the catalytically disabled clostridial glutamate dehydrogenase
      mutant D165S by fluoride ion.
AB  - The catalytically disabled Asp165-->Ser mutant of clostridial glutamate
      dehydrogenase shows 100000-fold less activity than the wild-type (WT) enzyme in a
      standard glutamate oxidation assay and 1000-fold less activity in the reductive
      amination reaction. The large reduction in the rate has been attributed to
      removal of the negative charge and the postulated proton-donor capacity of the
      aspartate carboxyl group. However, fluoride ion (1 M NaF) causes a 1000-fold
      activation of the mutant enzyme while simultaneously inhibiting WT activity by 20
      fold in the forward reaction. For the reverse reaction, F- (1 M) activates the
      mutant 4-fold and inhibits WT activity to approx. 64%. The net result when 1 M F-
      is present is a decrease in the WT:mutant activity ratio from 100000 to 5 for the
      forward reaction. None of the other halides tested, nor NO3(-), CHCOO- or HCOO-,
      give comparable activation. Re-activation took 15-30 s under assay conditions,
      suggesting the possibility of conformational change; CD spectroscopy, however,
      provided no evidence of a substantial change and kinetics of modification using
      5,5'-dithiobis(2-nitrobenzoic acid) suggested only subtle structural
      rearrangement. This phenomenon is discussed in the light of available information
      about the structure of the mutant enzyme. It is suggested that the F- ion
      provides a fixed negative charge at the position of the missing aspartate
      carboxyl group. Therefore, this appears to be an example of 'chemical rescue'.

PMID- 10333504
TI  - Sound emission and the acoustic far field of a singing acridid grasshopper
      (Omocestus viridulus L.) 
AB  - An array of eight microphones, all at a distance of 15 cm, was used to make
      simultaneous recordings of the sounds emitted by courting male acridid
      grasshoppers of the species Omocestus viridulus. In this species, the movement
      pattern for sound production differs in the two hindlegs, and in most cases the
      leg facing the female moves with the larger amplitude. The sonic sound intensity
      (the total sound in the one-third octave bands with centre frequencies from 5 to
      20 kHz) is maximal ipsilateral to the leg stridulating with the larger amplitude
      (the dominant leg). A spontaneous switch of dominance to the other leg may cause
      a significant change in the emitted sound power. The sound intensities
      contralateral to the dominant leg and frontal to the animal are, on average,
      approximately half (-3 dB) of the ipsilateral value, whereas the mean sound
      intensities behind and above the singer are approximately one-fifth (-7 dB) of
      the ipsilateral value. In most singers, the patterns of sound radiation are close
      to these mean values, but in some singers the radiation patterns are radically
      different. The sound radiated in various directions differs not only in terms of
      sound intensity but also with respect to the frequency spectrum, which was
      studied up to the one-third octave band with a centre frequency of 31.5 kHz. In
      particular, the ratio between the ultrasonic and sonic components is much smaller
      in the forward direction than in other directions. This may allow the courted
      female to hear whether the courting male is oriented directly towards her.

PMID- 10333505
TI  - Auditory sensory cells in hawkmoths: identification, physiology and structure 
AB  - The labral pilifers are thought to contain auditory sensory cells in hawkmoths of
      two distantly related subtribes, the Choerocampina and the Acherontiina. We
      identified and analysed these cells using neurophysiological and neuroanatomical
      techniques. In the death's head hawkmoth Acherontia atropos, we found that the
      labral nerve carries the auditory afferent responses of a single auditory unit.
      This unit responds to ultrasonic stimulation with minimum thresholds of 49-57 dB
      SPL around 25 kHz. Ablation experiments and analyses of the neuronal activity in
      different regions of the pilifer revealed that the auditory afferent response
      originates in the basal pilifer region. The sensory organ was identified as a
      chordotonal organ that attaches to the base of the pilifer. This organ is the
      only sensory structure in the basal pilifer region and consists of a single
      mononematic scolopidium and a single sensory cell. In Choerocampina, a homologous
      scolopidium was also found and is probably the only sensory structure of the
      pilifer that might serve an auditory function. Since a pilifer chordotonal organ
      with only a single scolopidium has also been detected in a non-hearing hawkmoth
      species, hearing in the distantly related choerocampine and acherontiine
      hawkmoths presumably evolved from a single proprioceptive mechanoreceptor cell
      that is present in all hawkmoths.

PMID- 10333503
TI  - Identification of peroxisomal proteins by using M13 phage protein VI phage
      display: molecular evidence that mammalian peroxisomes contain a 2,4-dienoyl-CoA
      reductase.
AB  - To elucidate unknown mammalian peroxisomal enzymes and functions, we subjected
      M13 phage expressing fusions between the gene encoding protein VI and a rat liver
      cDNA library to an immunoaffinity selection process in vitro (biopanning) with
      the use of antibodies raised against peroxisomal subfractions. In an initial
      series of biopanning experiments, four different cDNA clones were obtained. These
      cDNA species encoded two previously identified peroxisomal enzymes, catalase and
      urate oxidase, and two novel proteins that contained a C-terminal peroxisomal
      targeting signal (PTS1). A primary structure analysis of these novel proteins
      revealed that one, ending in the tripeptide AKL, is homologous to the yeast
      peroxisomal 2,4-dienoyl-CoA reductase (EC 1.3.1.34; DCR), an enzyme required for
      the degradation of unsaturated fatty acids, and that the other, ending in the
      tripeptide SRL, is a putative member of the short-chain dehydrogenase/reductase
      (SDR) family, with three isoforms. Green fluorescent protein (GFP) fusions
      encoding GFP-DCR-AKL, GFP-DCR, GFP-SDR-SRL and GFP-SDR were expressed in
      mammalian cells. The analysis of the subcellular location of the recombinant
      fusion proteins confirmed the peroxisomal localization of GFP-DCR-AKL and GFP-SDR
      SRL, as well as the functionality of the PTS1. That the AKL protein is indeed an
      NADPH-dependent DCR was demonstrated by showing DCR activity of the bacterially
      expressed protein. These results demonstrate at the molecular level that
      mammalian peroxisomes do indeed contain a DCR. In addition, the results presented
      here indicate that the protein VI display system is suitable for the isolation of
      rare cDNA clones from cDNA libraries and that this technology facilitates the
      identification of novel peroxisomal proteins.

PMID- 10333506
TI  - Heat transfer from starlings sturnus vulgaris during flight 
AB  - Infrared thermography was used to measure heat transfer by radiation and the
      surface temperature of starlings (Sturnus vulgaris) (N=4) flying in a wind tunnel
      at 6-14 m s-1 and at 15-25 degrees C. Heat transfer by forced convection was
      calculated from bird surface temperature and biophysical modelling of convective
      heat transfer coefficients. The legs, head and ventral brachial areas (under the
      wings) were the hottest parts of the bird (mean values 6.8, 6.0 and 5.3 degrees
      C, respectively, above air temperature). Thermal gradients between the bird
      surface and the air decreased at higher air temperatures or during slow flight.
      The legs were trailed in the air stream during slow flight and when air
      temperature was high; this could increase heat transfer from the legs from 1 to
      12 % of heat transfer by convection, radiation and evaporation (overall heat
      loss). Overall heat loss at a flight speed of 10.2 m s-1 averaged 11. 3 W, of
      which radiation accounted for 8 % and convection for 81 %. Convection from the
      ventral brachial areas was the most important route of heat transfer (19 % of
      overall heat loss). Of the overall heat loss, 55 % occurred by convection and
      radiation from the wings, although the primaries and secondaries were the coolest
      parts of the bird (2.2-2.5 degrees C above air temperature). Calculated heat
      transfer from flying starlings was most sensitive to accurate measurement of air
      temperature and convective heat transfer coefficients.

PMID- 10333507
TI  - Many-legged maneuverability: dynamics of turning in hexapods 
AB  - Remarkable similarities in the vertical plane of forward motion exist among
      diverse legged runners. The effect of differences in posture may be reflected
      instead in maneuverability occurring in the horizontal plane. The maneuver we
      selected was turning during rapid running by the cockroach Blaberus discoidalis,
      a sprawled-postured arthropod. Executing a turn successfully involves at least
      two requirements. The animal's mean heading (the direction of the mean velocity
      vector of the center of mass) must be deflected, and the animal's body must
      rotate to keep the body axis aligned with the heading. We used two-dimensional
      kinematics to estimate net forces and rotational torques, and a photoelastic
      technique to estimate single-leg ground-reaction forces during turning. Stride
      frequencies and duty factors did not differ among legs during turning. The inside
      legs ended their steps closer to the body than during straight-ahead running,
      suggesting that they contributed to turning the body. However, the inside legs
      did not contribute forces or torques to turning the body, but actively pushed
      against the turn. Legs farther from the center of rotation on the outside of the
      turn contributed the majority of force and torque impulse which caused the body
      to turn. The dynamics of turning could not be predicted from kinematic
      measurements alone. To interpret the single-leg forces observed during turning,
      we have developed a general model that relates leg force production and leg
      position to turning performance. The model predicts that all legs could turn the
      body. Front legs can contribute most effectively to turning by producing forces
      nearly perpendicular to the heading, whereas middle and hind legs must produce
      additional force parallel to the heading. The force production necessary to turn
      required only minor alterations in the force hexapods generate during dynamically
      stable, straight-ahead locomotion. A consideration of maneuverability in the
      horizontal plane revealed that a sprawled-postured, hexapodal body design may
      provide exceptional performance with simplified control.

PMID- 10333510
TI  - Boron is required for zebrafish embryogenesis 
AB  - Boron is the only element known to be essential for plants, but only
      circumstantial evidence for essentiality exists in animals. We report here that
      boron is essential for the embryonic development of zebrafish (Danio rerio).
      Zebrafish were maintained in water with a boron concentration of 0.1 micromol l-1
      or supplemented to a concentration of 45 micromol l-1 using ultrapure boric acid.
      Both groups were fed boron-depleted brine shrimp. This procedure depleted the
      boron content of the blastulas from low-boron parents to only 5 % of the boron
      content of the blastulas from boron-supplemented parents. Sperm from low-boron
      males successfully fertilized eggs from low-boron females, but 92 % of the
      embryos died within 10 days. The early cleavage stage of development was the most
      sensitive to boron deficiency. Of the fertilized embryos, 46% did not live to
      complete the blastula stage. Repletion of low-boron embryos during the first hour
      after fertilization rescued them from death. These observations provide strong
      evidence that boron is essential for zebrafish development.

PMID- 10333508
TI  - An olfactory-specific glutathione-S-transferase in the sphinx moth Manduca sexta.
AB  - Insect antennae have a primary function of detecting odors including sex
      pheromones and plant volatiles. The assumption that genes uniquely expressed in
      these antennae have an olfactory role has led to the identification of several
      genes that are integral components of odorant transduction. In the present study,
      differential display polymerase chain reaction (ddPCR) was used to isolate 25
      antennal-specific mRNAs from the male sphinx moth Manduca sexta. Northern blot
      analyses revealed that one clone, designated G7-9, was antennal-specific and was
      highly enriched in male antennae relative to female antennae. In situ
      hybridization indicated that G7-9 expression was restricted to a spatial domain
      of the olfactory epithelium occupied exclusively by sex-pheromone-sensitive
      olfactory sensilla. Amino acid homology and phylogenetic analyses identified G7-9
      as a glutathione-S-transferase (GST); we have named the full-length clone GST
      msolf1. GSTs are known to function primarily in the detoxification of noxious
      compounds. Spectrophotometric and chromatographic analyses of total GST activity
      indicate that the endogenous GSTs of male and female antennae can modify trans-2
      hexenal, a plant-derived green leaf aldehyde known to stimulate the olfactory
      system of M. sexta. The restricted localization of GST-msolf1 to sex-pheromone
      sensitive sensilla, the fact that the sex pheromone of M. sexta consists of a
      complex mixture of aldehyde components, and the observation that antennal GSTs
      can modify an aldehyde odorant suggest that GST-msolf1 may have a role in signal
      termination. In the light of the more commonly observed role of GSTs in
      xenobiotic metabolism, we propose that GST-msolf1 may play a dual role of
      protecting the olfactory system from harmful xenobiotics and inactivating
      aldehyde odorants, especially components of the M. sexta sex pheromone.

PMID- 10333509
TI  - Influence of odour plume structure on upwind flight of mosquitoes towards hosts 
AB  - Both the concentration and the fine-scale plume structure of host odours
      influence the upwind flight of female mosquitoes Aedes aegypti (L.) (Diptera:
      Culicidae) in a wind tunnel. The attractive effects of carbon dioxide, human skin
      odour and l-(+)-lactic acid were tested in homogeneous, turbulent and filamentous
      odour plumes. With carbon dioxide, the percentage of upwind-flying mosquitoes
      increased with the increasing fluctuations in concentration that occur in
      turbulent and filamentous plumes. In homogeneous plumes, an initial activation
      effect was observed, but sustained upwind flights were less frequent than in the
      other plumes. The opposite was found with plumes of human skin odour: the highest
      number of mosquitoes flew upwind in the homogeneous plume, whereas in turbulent
      or filamentous plumes their numbers were significantly lower. Regardless of plume
      type, the percentage of upwind-flying mosquitoes increased with increasing
      concentrations of carbon dioxide and of skin odour. With l-(+)-lactic acid, the
      dose-response characteristics were not consistent, and the relative effects of
      different plume types upon upwind flights differed within different ranges of
      concentration. Even maximum reactions to this compound were modest compared with
      those to carbon dioxide or to skin odour. Our findings demonstrate (1) that
      mosquitoes are able to orient upwind under continuous odour stimulation and (2)
      that upwind flight is dependent upon plume structure in different ways for
      different host odour components.

PMID- 10333511
TI  - The role of orientation flights on homing performance in honeybees.
AB  - Honeybees have long served as a model organism for investigating insect
      navigation. Bees, like many other nesting animals, primarily use learned visual
      features of the environment to guide their movement between the nest and foraging
      sites. Although much is known about the spatial information encoded in memory by
      experienced bees, the development of large-scale spatial memory in naive bees is
      not clearly understood. Past studies suggest that learning occurs during
      orientation flights taken before the start of foraging. We investigated what
      honeybees learn during their initial experience in a new landscape by examining
      the homing of bees displaced after a single orientation flight lasting only 5-10
      min. Homing ability was assessed using vanishing bearings and homing speed. At
      release sites with a view of the landmarks immediately surrounding the hive,
      'first-flight' bees, tested after their very first orientation flight, had faster
      homing rates than 'reorienting foragers', which had previous experience in a
      different site prior to their orientation flight in the test landscape. First
      flight bees also had faster homing rates from these sites than did 'resident'
      bees with full experience of the terrain. At distant sites, resident bees
      returned to the hive more rapidly than reorienting or first-flight bees; however,
      in some cases, the reorienting bees were as successful as the resident bees.
      Vanishing bearings indicated that all three types of bees were oriented homewards
      when in the vicinity of landmarks near the hive. When bees were released out of
      sight of these landmarks, hence forcing them to rely on a route memory, the
      'first-flight' bees were confused, the 'reorienting' bees chose the homeward
      direction except at the most distant site and the 'resident' bees were
      consistently oriented homewards.

PMID- 10333512
TI  - Effects of anoxia on the extra- and intracellular acid-base status in the land
      snail helix lucorum (L.): lack of evidence for a relationship between pyruvate
      kinase down-regulation and acid-base status 
AB  - The aims of the present study were to describe a possible correlation between the
      regulation of the key glycolytic enzyme pyruvate kinase and the acid-base status
      in the haemolymph and in several other tissues of land snails during anoxia. To
      illustrate whether such a relationship exists, we determined (i) the acid-base
      variables in the haemolymph and tissues of the land snail Helix lucorum, (ii) the
      kinetic properties of pyruvate kinase from several tissues and (iii) the levels
      of the anaerobic end-products d-lactate and succinate in the haemolymph and
      tissues of aerobic and anoxic Helix lucorum. The results showed that the pH of
      haemolymph (pHe) decreased significantly over the first 20 h of anoxia and then
      recovered slowly towards control values. A similar pattern was observed for
      intracellular pH (pHi), which decreased significantly over the first 16 h of
      anoxia and slowly returned towards control levels. The reduction and recovery of
      pHi and pHe seem to reflect the rate of anaerobic metabolism. The main anaerobic
      end-products, d-lactate and succinate, accumulated rapidly during the initial
      stages of anoxia and more slowly as anoxia progressed. The decrease in the rate
      of accumulation of anaerobic end-products during prolonged anoxia was due to the
      conversion of tissue pyruvate kinase to a less active form. The results
      demonstrate a correlation between pyruvate kinase down-regulation and the
      recovery of acid-base status in the haemolymph and the tissues of land snails
      during anoxia.

PMID- 10333513
TI  - Blood pressure regulation during hypotension in two teleost species: differential
      involvement of the renin-angiotensin and adrenergic systems 
AB  - The stimulatory effects of angiotensin II (Ang II) on catecholamine release and
      the contributions of the renin-angiotensin system, humoral catecholamines and
      adrenergic nerves to blood pressure regulation were investigated in rainbow trout
      (Oncorhynchus mykiss) and American eel (Anguilla rostrata). In trout, bolus
      injections of homologous [Asn1,Val5]-Ang II (100 or 500 pmol kg-1) increased
      catecholamine secretion rates and plasma catecholamine concentrations from in
      situ posterior cardinal vein preparations and chronically cannulated fish,
      respectively. In contrast, in situ or in vivo injections of similar doses of Ang
      II in eel did not affect catecholamine release. &agr; -Adrenoceptor blockade
      (prazosin; 1 mg kg-1) reduced the pressor effect of exogenous Ang II (500 pmol kg
      1) in both species. In eel, intravenous injection of the smooth muscle relaxant
      papaverine (10 mg kg-1) elicited a rapid decrease in dorsal aortic pressure (PDA;
      58 %) followed by a gradual recovery back to the baseline value 85 min after the
      treatment. In trout, papaverine elicited a similar decrease in blood pressure (62
      %); however, PDA recovered fully 20 min after treatment. Blockade of either &agr;
      -adrenoceptors with prazosin or adrenergic nerves with bretylium (10 mg kg-1)
      prior to papaverine treatment did not alter PDA recovery in eel. In trout, &agr; 
      adrenoceptor and adrenergic nerve blockade prior to the papaverine treatment
      prevented and attenuated PDA recovery, respectively. In both species, papaverine
      treatment elicited significant increases in plasma catecholamine and Ang II
      concentrations. However, the increases in plasma catecholamine concentrations
      were markedly greater in trout than in eel. Similarly, the papaverine-elicited
      increase in plasma Ang II levels occurred earlier and was greater in trout than
      in eel. Thus, while Ang II stimulates humoral catecholamine release in trout,
      there is no evidence for a similar interaction in eel. Moreover, during
      hypotensive stress, although the renin-angiotensin system is recruited in both
      species, an essential involvement of adrenergic nerves and humoral catecholamines
      in the restoration of blood pressure is only apparent in trout.

PMID- 10333514
TI  - Experimental changes to limb muscles elicit contralateral reactions: the problem
      of controls 
AB  - The extensor digitorum longus muscle (EDL) or soleus muscle (SOL) in rats was
      mechanically overloaded on one side. The muscles were (i) untreated (normal) or
      (ii) self- or foreign-reinnervated (leading to persisting muscle fibres) or
      transplanted (leading to regenerating muscle fibres). The effects of the
      different procedures were studied in the treated and untreated muscles on the
      operated side and in the untreated muscles on the contralateral side. Overloading
      led to an absolute increase in mass (versus control values) in the normal muscles
      and to a relative increase in mass (versus the lower mass after reinnervation) in
      the treated muscles. The mechanism underlying this gain in mass was usually a
      compensatory hypertrophy. Overloading was followed by transformation of fibres
      from fast to slow in normal muscles. In the reinnervated muscles, the fibre
      distribution changed in response to the new nervous input and then remained
      constant. The majority of the experimental procedures elicited significant
      muscular changes in the contralateral muscles, including hyperplasia, fibre
      transformation and fibre hypertrophy or atrophy. The changes are interpreted as
      the consequence of a general compensatory neuromuscular activity designed to
      maintain a symmetrical posture during walking and running. These frequent and
      substantial muscular changes in the unoperated muscles clearly show that the
      muscles of the contralateral side cannot be used as normal controls.

PMID- 10333515
TI  - Hiding responses of locusts to approaching objects 
AB  - Locusts, Locusta migratoria, sitting on a plant stem hide from dark moving or
      expanding shapes in their environment. The fore- and middle legs perform this
      avoidance response by making lateral tilting movements, while the hindlegs slide
      laterally and guide rotation of the posterior body over the stem. During larger
      turns, the legs take lateral steps when lateral tilting is limited by the joints.
      Slow hiding movements of less than 300 degrees s-1 of angular velocity are
      induced by slowly changing (looming) shapes, and interposed stops or slowing of
      the movement can delay the progress of this hiding manoeuvre. Fast hiding
      movements with angular velocities between 120 degrees s-1 and 860 degrees s-1
      proceed continuously and rapidly in response to rapidly expanding stimuli. Hiding
      responses to expanding shapes occur only after the expanding image has exceeded a
      threshold visual angle of 8-9.5 degrees. Hiding response latencies range between
      220 ms and 1.2 s for fast hiding and are approximately 1.2 s for most slow hiding
      responses. Predator-avoidance responses such as freezing, jerking, crouching,
      walking backwards, dropping or jumping can be used instead of or in conjunction
      with hiding behaviour. We conclude that the fast hiding behaviour of locusts is a
      specific goal-directed type of optomotor behaviour requiring positional
      information from small-field detectors of shape expansion in the interneurone
      layers of the locust eye.

PMID- 10333516
TI  - Regulation of four genes encoding small, acid-soluble spore proteins in Bacillus
      subtilis.
AB  - Three genes (sspH, sspL, and tlp) encoding new, minor small, acid-soluble
      proteins (SASP) unique to spores of Bacillus subtilis are expressed only in the
      forespore compartment during sporulation of this organism. The sspH and sspL
      genes are monocistronic, whereas tlp is the second gene in an operon with a
      second small orf, which we have termed sspN. The sspH and sspL genes are
      recognized primarily by the forespore-specific sigma factor for RNA polymerase,
      sigmaG; the sspN-tlp operon is recognized equally well by sigmaG and the other
      forespore-specific sigma factor, sigmaF. Sequences centered 10 and 35nt upstream
      of the 5'-ends of sspH, sspL, and sspN mRNAs all show homology to -10 and -35
      sequences recognized by sigmaF and sigmaG, which are generally quite similar.
      Mutations disrupting the sspH, sspL, sspN-tlp, or tlp loci cause a loss of the
      appropriate SASP from spores, but have no discernible effect on sporulation,
      spore properties, or spore germination.

PMID- 10333518
TI  - Gene structure and polymorphism of an invertebrate nitric oxide synthase gene.
AB  - Nitric oxide synthases (NOSs) are ubiquitous in living organisms. However, little
      is known about the evolution of this large gene family. The first inducible NOS
      to be described from an invertebrate regulates malaria parasite (Plasmodium spp.)
      development in the mosquito Anopheles stephensi. This single copy gene shows the
      highest homology to the vertebrate neuronal isoforms, followed by decreasing
      homology to endothelial and inducible isoforms. The open reading frame of 1247
      amino acids is encoded by 19 exons, which span approximately 33 kilobases. More
      than 50% of the mosquito exons, distributed around the putative heme, calmodulin,
      and FAD/NADPH cofactor-binding domains, are conserved with those of the three
      human genes. Repetitive elements identified within the larger introns include a
      polymorphic dinucleotide repeat, two tandem repeats, and a putative miniature
      inverted repeat transposable element. Sequence analysis and primer extension
      indicate that the upstream promoter is 'TATA-less' with multiple transcription
      start sites within approximately 250 base pairs of the initiation methionine.
      Transcription factor binding sites in the 5'-flanking sequence demonstrate a
      bipartite distribution of lipopolysaccharide- and inflammatory cytokine
      responsive elements that is strikingly similar to that described for vertebrate
      inducible NOS gene promoters.

PMID- 10333517
TI  - Molecular evolution of immunoglobulin and fibronectin domains in titin and
      related muscle proteins.
AB  - The family of regulatory and structural muscle proteins, which includes the giant
      kinases titin, twitchin and projectin, has sequences composed predominantly of
      serially linked immunoglobulin I set (Ig) and fibronectin type III (FN3) domains.
      This paper explores the evolutionary relationships between 16 members of this
      family. In titin, groups of Ig and FN3 domains are arranged in a regularly
      repeating pattern of seven and 11 domains. The 11-domain super-repeat has its
      origins in the seven-domain super-repeat and a model for the duplications which
      gave rise to this super-repeat is proposed. A super-repeat composed solely of
      immunoglobulin domains is found in the skeletal muscle isoform of titin. Twitchin
      and projectin, which are presumed to be orthologs, have undergone significant
      insertion/deletion of domains since their divergence. The common ancestry of
      myomesin, skelemin and M-protein is shown. The relationship between myosin
      binding proteins (MyBPs) C and H is confirmed, and MyBP-H is proposed to have
      given rise to MyBP-C by the acquisition of some titin domains.

PMID- 10333519
TI  - Identification and characterization of G90, a novel mouse RNA that lacks an
      extensive open reading frame.
AB  - We describe the cloning and characterization of the murine G90 gene, identified
      by subtractive hybridization based on the differential presence of its transcript
      in large and small intestine. The full-length cDNA and genomic sequences were
      cloned and found to produce a 1.5kb transcript that is polyadenylated but has no
      open reading frame larger than 249bp. The G90 gene was mapped to the proximal
      region of mouse chromosome 6. Expression analysis by Northern blotting showed
      that G90 is transcribed at very high levels in the small intestine and at lower
      levels in large intestine, testis and kidney of the mouse. In situ hybridization
      analysis on sections of small and large intestine and testis showed that G90
      transcripts are present only in post-mitotic cells.

PMID- 10333520
TI  - Characterization of the biotin biosynthesis pathway in Saccharomyces cerevisiae
      and evidence for a cluster containing BIO5, a novel gene involved in vitamer
      uptake.
AB  - An engineered mutant of Saccharomyces cerevisiae affected in biotin biosynthesis
      has been isolated. This mutant allowed the characterization of a bio cluster
      (BIO3-4-5). We demonstrate that BIO3 (YNR058w) and BIO4 (YNR057c) encode,
      respectively, a 7, 8-diaminopelargonic acid aminotransferase and a dethiobiotin
      synthase, involved in the biotin biosynthesis pathway. A novel gene, BIO5
      (YNR056c), is present immediately downstream from BIO4. This gene encodes Bio5p,
      a protein with 11 putative transmembrane regions. Uptake experiments performed
      with labeled 7-keto 8-aminopelargonic acid indicate that Bio5p is responsible for
      transport into the cell of 7-keto 8-aminopelargonic acid.

PMID- 10333521
TI  - A new inducible protein expression system in fission yeast based on the glucose
      repressed inv1 promoter.
AB  - Studies of the fission yeast Schizosaccharomyces pombe have made major
      contributions towards understanding cell-cycle control and many other important
      aspects of cell biology. A series of pREP expression vectors that utilize the
      thiamine-repressible nmt1 promoter are used routinely to manipulate the
      expression of genes in fission yeast. A shortcoming of the nmt1 promoter is that
      it is very slowly induced following removal of thiamine from the growth medium,
      requiring approx. 16h for full induction. Invertase, an enzyme responsible for
      sucrose metabolism, is regulated transcriptionally by glucose derepression in S.
      pombe. Using the inv1 promoter, we have developed the pINV1 set of inducible
      protein expression vectors. A shift from glucose to sucrose-based culture medium
      leads to a very rapid induction of the inv1 promoter. Genes that are regulated by
      the inv1 promoter are fully induced within 1h of the shift to sucrose-based
      medium. The pINV1 vectors utilize a simple induction protocol and enable studies
      in fission yeast requiring tight and rapid regulation of protein synthesis.

PMID- 10333522
TI  - Molecular characterization of a chemotaxis operon in the oral spirochete,
      Treponema denticola.
AB  - A chemotaxis gene cluster from Treponema denticola (Td), a pathogenic spirochete
      associated with human periodontal diseases, was cloned, sequenced, and analyzed.
      The gene cluster contained three chemotaxis (che) genes (cheA, cheW, and cheY)
      and an open reading frame (cheX) that is homologous with Treponema pallidum (Tp)
      and Borrelia burgdorferi (Bb) cheX. The Td che genes have the same
      transcriptional orientation with a sigma 70-like promoter located upstream of
      cheA and a stem-loop structure characteristic of a Rho-independent
      transcriptional terminator downstream of cheY. Primer extension analysis
      identified a transcriptional start point six nucleotides (nt) downstream of the 
      10 (TAAAAA) promoter sequence. Reverse-transcriptase-polymerase chain reaction
      (RT-PCR) data indicated that cheA through cheY are co-transcribed and suggested
      that transcription is terminated after cheY. The gene organization of the Td che
      operon is identical to that of the Tp che operon. Southern blot analysis
      indicated the presence of one copy of each che gene on the Td genome. The cheA,
      cheW, cheX, and cheY genes are 2403, 1332, 462, and 438nt long, respectively, and
      encode proteins with predicted molecular masses of 88.2, 49.7, 16.8, and 16.
      0kDa, respectively. Functional domains of the T. denticola CheA and CheY proteins
      are highly conserved with those of the Escherichia coli (Ec) CheA and CheY
      proteins. Phylogenetic analysis of Td CheY indicated that it is closely related
      to Tp CheY and Bb CheY3.

PMID- 10333523
TI  - Toluene metabolism by the solvent-tolerant Pseudomonas putida DOT-T1 strain, and
      its role in solvent impermeabilization.
AB  - Pseudomonas putida DOT-T1E is a solvent-tolerant strain able to grow with toluene
      as the sole C-source. Tn5 mutagenesis was carried out and a mutant unable to use
      toluene as the sole C-source was isolated. DNA was sequenced upstream and
      downstream of the site where the Tn5 was inserted. Analysis of the DNA revealed
      13 open reading frames (ORFs) homologous to the tod genes for the toluene
      dioxygenase pathway of P. putida F1, which are organized in two operons:
      todXFC1C2BADEGIH and todST. The Tn5 was inserted at the todH gene. The role of
      the todXFC1C2BADEGIH operon in toluene metabolism was further confirmed in a
      todC1 mutant (generated by insertional inactivation), which was unable to use
      toluene as the sole C-source. Primer extension analysis identified a single
      promoter upstream from the todX gene. The -10 and -35 regions of this promoter
      showed no significant homology to known promoters. Expression from the todX
      promoter occurred in response to toluene, ethylbenzene, styrene, xylenes and
      other aromatic hydrocarbons. Expression from the todS gene was constitutive.
      Sensitivity to toluene of the todH and todC1 mutants was similar to that of the
      wild-type strain. This suggests that toluene metabolism is not involved in
      toluene tolerance.

PMID- 10333524
TI  - Molecular cloning and comparative sequence analyses of rRNA operons in
      Streptomyces nodosus ATCC 14899.
AB  - The genome of Streptomyces nodosus contains six ribosomal RNA (rRNA) operons.
      Four of the rRNA operons; rrnB, rrnD, rrnE and rrnF were cloned. We have
      completely sequenced all four operons, including a region 750 base pairs (bp)
      upstream of the 16S rRNA gene. The three rRNA genes present in each operon were
      closely linked in the order 16S-23S-5S. A sequence comparison of the four operons
      showed more than 99% sequence similarity between the corresponding 16S and 23S
      rRNA genes, and more than 97% similarity between 5S rRNA genes. The sequence
      differences observed between 23S rRNA genes appeared to be localized in two
      specific regions. Substantial sequence differences were found in the region
      upstream of the 16S rRNA gene as well as in the internal transcribed spacers. No
      tRNA gene was found in the 16S-23S spacer regions.

PMID- 10333526
TI  - Genomic organization and promoter characterization of the gene encoding the human
      telomerase reverse transcriptase (hTERT).
AB  - The enzyme telomerase plays a crucial role in cellular proliferation and
      tumorigenesis. By adding hexameric repeats to chromosome ends, it prevents
      telomeric loss and, thus, entry into senescence. Recent data suggest that
      expression of the human telomerase reverse transcriptase subunit (hTERT)
      represents the limiting factor for telomerase activity. To gain an insight into
      the mechanisms regulating hTERT expression, we have determined the complete
      genomic organization of the hTERT gene and isolated the 5'- and 3'- flanking
      region. The hTERT gene encompasses more than 37kb and consists of 16 exons. We
      show that all hTERT insertion and deletion variants described so far most likely
      result from the usage of alternative splice consensus sequences in intron or exon
      regions. Furthermore, we identified a new hTERT splice variant. Analysis of the
      DNA sequence surrounding the putative transcriptional start region revealed a
      TATA-less promoter located in a CpG island. A promoter fragment spanning the
      first 1100bp upstream of the initiating ATG start codon exhibited high-level
      activity in HEK-293 cells. Several consensus binding sites for the transcription
      factor Sp1 as well as a c-Myc binding site were identified in this promoter
      region. Altogether, these results provide the basis for more detailed studies on
      the regulation of telomerase activity in normal and cancer cells, and may lead to
      the development of new cancer therapies.

PMID- 10333525
TI  - Similarity in oligonucleotide usage in introns and intergenic regions contributes
      to long-range correlation in the Caenorhabditis elegans genome.
AB  - A method is presented which allows detection of a sequence correlation effect not
      related to patchiness in base composition or to preferences in codon usage.
      Recurrence plots providing local views of oligonucleotide recurrence regimen show
      that introns and intergenic regions are often characterised by a highly recurrent
      use of oligonucleotides. By window analysis it is possible to score a long
      sequence for the recurrence of a given subset of oligos while filtering away the
      effects of short-range correlations. Long-range exploration of chromosome III
      from Caenorhabditis elegans reveals that consistent use of recurrent
      oligonucleotides in introns and intergenic regions generates a correlation effect
      that extends over several megabases.

PMID- 10333527
TI  - Transcriptional analysis of levU operon encoding saccharolytic enzymes and two
      apparent genes involved in amino acid biosynthesis in Zymomonas mobilis.
AB  - Extracellular levansucrase (LevU) and sucrase (InvB) are two of the three
      saccharolytic enzymes involved in the sucrose metabolism of Zymomonas mobilis.
      The levU and invB genes were clustered with a 155bp interval on the chromosome.
      Both genes were transcribed constitutively at the basal level and the
      transcription of both genes was induced significantly when sucrose was added to
      the medium. These genes were transcribed as a bicistronic mRNA and the expression
      was modulated by a single promoter, which is located upstream of the levU gene.
      The transcriptional initiation site was mapped to -64bp from the translation
      start site of levU gene. These results indicated that two genes are most likely
      to constitute an operon. The glk operon, which encodes four glycolytic enzymes,
      was located close to the levU operon on the chromosome. Two apparent ORFs (ORF3
      and 4) were found at the intervening sequence located between the glk and levU
      operons. These ORFs were transcribed divergently and showed high homology at the
      amino acid level with the bacterial global regulatory protein (Lrp) and aspartate
      racemase.

PMID- 10333528
TI  - Genomic structure and chromosomal localization of the mouse Hsf2 gene and
      promoter sequences.
AB  - The mouse heat shock factor 2 (HSF2) cDNA was previously cloned by homology to
      HSF1, the heat shock factor involved in the cellular response to stress [Sarge,
      K.D., Zimarino, V., Holm, K., Wu, C., Morimoto, R.I., Cloning and
      characterization of two mouse heat shock factors with distinct inducible and
      constitutive DNA-binding ability. Genes Dev. 5 (1991) 1902-1911]. HSF2 is active
      in restricted cell types during pre- and post-implantation stages of development,
      and only in male germ cells of adult mice. However, the function of this factor
      remains elusive. We report here the cloning of the mouse Hsf2 gene and its
      genomic structure. We show that the gene is composed of 13 exons of variable
      sizes spanning at least 43kb in the genome. The transcription start site has been
      determined, and upstream sequences with promoter activity have been identified by
      their ability to direct the expression of a luciferase reporter gene in
      transfected cells. A preliminary analysis of the proximal promoter sequence
      determined that the TATA box is absent, but that a GC-rich region with several
      potential binding sites for transcription factors is present. The gene has been
      mapped to mouse chromosome 10 by in-situ hybridization on metaphase chromosomes.

PMID- 10333529
TI  - Enhancer function and novel DNA binding protein activity in the near upstream
      betaAPP gene promoter.
AB  - The role of betaAPP gene transcription and promoter regulation in modifying
      amyloid beta-peptide (Abeta) levels is not well understood. Increased production
      of Abeta or changes in Abeta42/Abeta40 ratio by fibroblasts occurs in the
      presence of mutant presenilin or betaAPP alleles in familial Alzheimer's disease
      subjects. Both betaAPP mRNA and Abeta levels are increased in trisomy 21. The APP
      gene promoter is in a class of housekeeping genes and contains two putative
      consensus sites for the binding of transcription factor AP1. Electrophoretic
      mobility shift (EMSA) and DNase protection assays using human fibroblast and HeLa
      nuclear extract identified specific protein binding with novel Sp1-like
      properties to both a near-upstream and a downstream domain of the betaAPP
      promoter. The upstream binding activity was localized to a putative AP1 consensus
      site and its immediate 5'-adjacent GC-rich element. However, c-Jun antibody and
      competition experiments had no effect on binding to this domain. A series of 5'
      deleted betaAPP promoter-reporter gene transfections in HeLa and fibroblast cells
      showed that the domain-containing region, n.t. -383 to -348, exerts a 2.9-fold
      activating influence on basal pbetaAPP-reporter transcription. When subcloned to
      test enhancer function, the 5'-GC element/'AP1 site' tandem construct conferred
      four-fold greater activity than either element alone and two-fold greater than
      the more 3'-situated HSE consensus sequence. Phorbol ester treatment had no
      effect in these reporter assays. This element shares homology and binding
      properties with a domain immediately 5' to the downstream E-box/USF element. An
      interaction model involving both domains and looping of interjacent DNA is
      proposed. We conclude that this newly described binding protein-enhancer complex
      is required for full betaAPP promoter activation.

PMID- 10333530
TI  - Induction of micronuclei in V79 cells by fractions of roofing asphalt fume
      condensate.
AB  - More than 50,000 workers in the United States are exposed to roofing asphalt
      fumes that may pose genotoxic and potential carcinogenic hazards. The Type III
      roofing asphalt is most frequently used in roof-application. Results of our
      previous studies showed that fume condensates of Type III roofing asphalts
      induced micronuclei (MN) in vitro in cultured V79 cells and DNA adduct formation
      in vivo in rat lung cells. In this study, the genotoxicity of whole fume
      condensates (WFC) of Type III roofing asphalt and its five chemical fractions (A,
      B, C, D and E) was determined by the micronucleus assay using V79 cells. Linear
      regressions were determined for the dose response of MN frequencies and percent
      of binucleated and multinucleated cells (MTC) following the treatment. Results
      showed that the numbers of micronucleated cells in cultures treated with Type III
      roofing asphalt WFC and its fractions B, C, D and E were significantly higher
      than that in the control culture, and that the slopes of the linear regression
      line for fractions B and C were greater than those for the WFC and fractions D
      and E. A clear dose response of binucleated cells was also induced by the WFC and
      fractions B and C. These findings indicate that: (1) WFC and all fractions,
      except fraction A, induced MN formation in cultured V79 cells; (2) fractions B
      and C possess the highest genotoxic activity; (3) the roofing asphalt WFC
      contains chemicals or chemical classes that induce not only chromosomal
      aberrations but also binucleation in V79 cells.

PMID- 10333531
TI  - Correcting for toxic inhibition in quantification of genotoxic response in the
      umuC test.
AB  - An improved procedure for quantification of results from the umuC tests for
      genotoxicity is presented. The calculation method better separates toxic growth
      inhibition (cytotoxicity) from genotoxic effects than currently used methods and
      therefore, greatly extends the applicability of genotoxicity tests on
      environmental samples. The basic principle is to normalize the genotoxic response
      compensating for both decreasing biomass and growth rate reduction that results
      from cytotoxicity. The improved method and the currently used method was compared
      for umuC tests on the pure compounds: methylmethanesulfonate (MMS), N-methyl-N'
      nitro-N-nitroguanidine (MNNG), sodium azide (NaN3), and 4-nitroquinoline-1-oxide
      (4-NQO). For compounds with no or low cytotoxicity, the two calculation methods
      gave practically identical results, while for highly cytotoxic compounds, the
      traditional method overestimated genotoxicity. umuC tests were also carried out
      on leachate polluted groundwater sampled downgradient of a landfill (Grindsted,
      Denmark). All polluted samples showed high cytotoxicity concomitant with high
      genotoxicity when the results were quantified in the traditional way. The new
      method showed that these results were in fact false positive, as the apparent
      genotoxicity was a result of cytotoxicity. Based on the mathematical analysis
      leading to the improved procedure for correction for cytotoxicity, it is
      suggested to alter the present test design of the umuC test in order to obtain
      well-defined exposure concentrations as well as mathematical consistency in the
      quantification of genotoxicity.

PMID- 10333533
TI  - Consumption of tea modulates the urinary excretion of mutagens in rats treated
      with IQ. Role of caffeine.
AB  - The present study was undertaken to investigate whether the consumption of green
      tea and black tea influences the excretion of mutagens and promutagens in rats
      treated orally with the food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline
      (IQ). Rats were maintained on aqueous extracts (2.5%, w/v) of green tea, black
      tea or decaffeinated black tea as their sole drinking liquid. After 4 weeks, the
      animals received, by gastric intubation, a single dose of IQ (5 mg/kg), and urine
      was collected for 48 h. Direct and indirect mutagenicity, in the presence of an
      activation system derived from Aroclor 1254-treated rats, was determined in the
      urine samples using the Ames mutagenicity assay. Consumption of green tea and
      black tea, but not of decaffeinated black tea, markedly decreased the urinary
      excretion of mutagens and promutagens. In a further study, supplementation of
      decaffeinated black tea with caffeine suppressed the excretion of mutagens and
      promutagens in the urine of rats pretreated with IQ. It is concluded that both
      green tea and black tea modulate the bioactivation and metabolism of IQ, and that
      caffeine is largely responsible for this effect.

PMID- 10333532
TI  - Griseofulvin-induced aneuploidy and meiotic delay in male mouse germ cells:
      detected by using conventional cytogenetics and three-color FISH.
AB  - Griseofulvin (GF) was tested in male mouse germ cells for the induction of
      meiotic delay and aneuploidy. Starved mice were orally treated with 500, 1000 and
      2000 mg/kg of GF in corn oil and testes were sampled 22 h later for meiotic delay
      analysis and chromosome counting in spermatocytes at the second meiotic metaphase
      (MMII). A dose-related increase in meiotic delay by dose-dependently arresting
      spermatocytes in first meiotic metaphase (MMI) or/and prolonging interkinesis was
      observed. Hyperhaploid MMII cells were not significantly increased. Sperm were
      sampled from the Caudae epididymes 22 days after GF-treatment of the males for
      three-color fluorescence in situ hybridization (FISH). The frequencies of
      diploidies were 0.01-0.02% in sperm of the solvent control animals and increased
      dose-dependently to 0.03%, 0.068% and 0.091%, respectively, for 500, 1000 and
      2000 mg/kg of GF. The frequencies of disomic sperm were increased significantly
      above the controls in all GF-treated groups but showed no dose response. The data
      for individual classes of disomic sperm indicated that MII was more sensitive
      than MI to GF-induced non-disjunction in male mice. A comparison of the present
      data from male mice and literature data from female mice suggests that mouse
      oocytes are more sensitive than mouse spermatocytes to GF-induced meiotic delay
      and aneuploidy.

PMID- 10333534
TI  - Substituent effect of a fluorine atom on the mutagenicity of nitroquinolines.
AB  - Some 16 nitroquinolines (NQs) and their fluorinated derivatives were tested for
      mutagenicity in Salmonella typhimurium TA100 without S9 mix to investigate the
      effect of fluorine-substitution on the mutagenicity. These NQs consist of 5-NQs,
      5-nitroquinoline N-oxides (5-NQOs), N-methyl-5-nitroquinolinium methanesulfonates
      (N-Me-5-NQs) and 8-NQs, including three ortho-F-NQs, one meta-F-NQ, four para-F
      NQs and four 3-F-NQs. For this purpose, eight F-NQs were newly synthesized. The
      data indicated that the ratio of the mutagenic activities (revertants/plate/nmol)
      of fluorinated NQs to those of the corresponding parent non-fluorinated compounds
      ranged from 0.6- to 119-fold. The fluorine atom located para to the nitro group
      markedly enhanced the mutagenicity (24-fold and more), while three ortho
      fluorinated derivatives showed no significant increase in mutagenicity
      (enhancement ratio were 0.6, 0.8 and 1.7). With respect to 8-NQs, its meta
      fluorinated derivative also had an enhanced mutagenicity over the parent compound
      (53-fold). In addition, although N-Me-5-NQ was less mutagenic than 5-NQ and 5
      NQO, the mutagenicity of N-Me-5-NQ was most significantly enhanced by fluorine
      substitution. These results suggest that introduction of a fluorine atom to the
      molecule in question may be a useful tool to modify their mutagenic potency and
      to better understand the mechanism of mutation.

PMID- 10333535
TI  - Single-cell gel electrophoresis assays with human-derived hepatoma (Hep G2)
      cells.
AB  - The purpose of the present study was the development of a protocol for detecting
      chemically-induced DNA damage, using the alkaline single-cell gel electrophoresis
      (SCGE) assay with human-derived, metabolically competent hepatoma (Hep G2) cells.
      Previous studies indicated that Hep G2 cells have retained the activities of
      certain phase I and phase II enzymes and reflect the metabolism of genotoxins in
      mammals better than other in vitro models which require addition of exogenous
      activation mixtures. The optimal trypsin concentration for the removal of the
      cells from the plates were found to be 0.1%. Dimethylsulfoxide, at concentrations
      up to 2%, was an appropriate solvent for water-insoluble compounds. To determine
      the optimal exposure periods for mutagen treatment, the time kinetics of comet
      formation was investigated with genotoxic chemicals representing various classes
      of promutagens namely benzo[a]pyrene (B[a]P), 2-amino-3-methylimidazo[4,5
      f]quinoline (IQ), and N-nitrosodimethylamine (NDMA) and with N-nitrosomethylurea
      (NMU). All compounds caused a statistically significant induction in DNA damage.
      With the promutagens, comet formation increased gradually as a function of the
      exposure duration, and reached maximum values between 20-24 h. With NMU, comet
      induction maximized already after a short exposure (1 h) and remained at a
      constant level for up to 24 h. Based on these results, the Hep G2/SCGE assay
      appears to be a suitable approach for investigating DNA damaging potential of
      chemicals. Further experiments with IQ and B[a]P showed that the assays are
      highly reproducible. Comparisons of the present results with those from earlier
      experiments in which other endpoints (induction of sister chromatid exchanges,
      micronuclei and chromosomal aberrations) were measured in Hep G2 cells, indicated
      that the sensitivity of the SCGE assays is more or less identical. Since the SCGE
      assay is less time consuming than other genotoxicity assays we anticipate that it
      might be a suitable approach to investigate DNA damaging effects of chemicals in
      the human-derived, metabolically competent cell line.

PMID- 10333536
TI  - Micronuclei in blood lymphocytes and genetic polymorphism for GSTM1, GSTT1 and
      NAT2 in pesticide-exposed greenhouse workers.
AB  - The frequency of micronuclei (MN) in cultured peripheral lymphocytes was used as
      a biomarker of genotoxic effects in 34 Italian pesticide-exposed greenhouse
      workers and 33 unexposed referents matched with the exposed workers for age and
      smoking habits. The possible influence of the genetic polymorphisms of xenobiotic
      metabolizing enzymes glutathione S-transferase M1 (GSTM1), T1 (GSTT1), and N
      acetyltransferase 2 (NAT2) was also evaluated. To restrict the analysis primarily
      to cells that have divided once in vitro, MN were scored only in cells showing
      label after a 42-h incubation with bromodeoxyuridine (BrdU), as detected by
      immunofluorescence (anti-BrdU technique). Two different concentrations of BrdU
      (0.5 and 1 microg/ml) were compared. Individual frequencies of micronucleated
      cells (MNCs) obtained with the two concentrations of BrdU significantly
      correlated with each other (r=0.55, P<0.001). Higher mean MNCs frequencies (per
      1000 cells) were detected among exposed smokers (9.0 at 0.5 microg/ml BrdU and
      7.8 at 1 microg/ml BrdU) than in smoking referents (6.3 and 5.9, respectively).
      In multiple regression analysis controlling for age, sex, smoking and genotypes,
      a significant elevation of MNC frequency (P=0.004 at 1 microg/ml BrdU; P=0.052 at
      0.5 microg/ml BrdU) was observed in greenhouse workers with a work history of
      extensive pesticide spraying (n=17). Increased MNC frequencies were also
      associated with ageing at 0.5 microg/ml BrdU, with the GSTM1-positive genotype at
      both 1 (P=0.028) and 0.5 (P=0.056) microg/ml BrdU in all subjects, and with the
      NAT2 fast acetylator genotype in smokers at 0.5 microg/ml BrdU (P=0.043). The
      results indicate that MN rates are increased in greenhouse workers, especially in
      those involved in pesticide spraying. The GSTM1 positive and NAT2 fast genotypes
      appear to be associated with elevated MNC frequencies, which contradicts with
      earlier results on elevated chromosomal aberration rates in GSTM1 null smokers
      and NAT2 slow subjects.

PMID- 10333537
TI  - Corticotropin-releasing hormone signals adversity in both the placenta and the
      brain: regulation by glucocorticoids and allostatic overload.
AB  - Glucocorticoids regulate corticotropin-releasing hormone (CRH) gene expression in
      the placenta and the brain. In both the placenta and two extrahypothalamic sites
      in the brain (the amygdala and the bed nucleus of the stria terminalis),
      glucocorticoids elevate CRH gene expression. One functional role of the elevation
      of CRH by glucocorticoids may be to signal adversity. When CRH is over-expressed
      in the placenta, it may indicate that the pregnancy is in danger, and preterm
      labor may result. When CRH is over-expressed in the brains of animals, they may
      become more fearful. Both situations possibly reflect allostatic mechanisms and
      vulnerability to allostatic overload, a condition in which biological tissue may
      be compromised.

PMID- 10333538
TI  - Pancreatic islet cell survival following islet isolation: the role of cellular
      interactions in the pancreas.
AB  - The purpose of this study was to characterize the trophic effect of pancreatic
      duct cells on the islets of Langerhans. Ductal epithelium and islets were
      isolated from hamster pancreata. In addition, duct-conditioned medium (DCM) was
      prepared from primary duct cultures that had been passaged twice to remove other
      cellular elements. Three experimental groups were then established: Group 1, 100
      islets alone; Group 2, 100 islets+80 duct fragments; and Group 3, 100 islets in
      25% DCM. All tissues were embedded in rat tail collagen for up to 12 days and the
      influence of pancreatic ductal epithelium on islet cell survival was examined. By
      day 12, 20.6+/-3. 0% (S.E.M.) of the islets cultured alone developed central
      necrosis, compared with 6.7+/-2.0% of the islets co-cultured with ducts and 5.6+/
      1.5% of the islets cultured in DCM (P<0.05). The presence of apoptotic cell death
      was determined by a TdT-mediated dUTP-biotin nick end labelling (TUNEL) assay and
      by a specific cell death ELISA. DNA fragmentation in islets cultured alone was
      significantly increased compared with islets cultured either in the presence of
      duct epithelium or in DCM (P<0.05). More than 80% of TUNEL-positive cells were
      situated in the inner 80% of the islet area, suggesting that most were beta
      cells. DCM was analysed for known growth factors. The presence of a large amount
      of IGF-II (34 ng/ml) and a much smaller quantity of nerve growth factor (4 ng/ml)
      was identified. When the apoptosis studies were repeated to compare islets alone,
      islets+DCM and islets+IGF-II, the cell death ELISA indicated that IGF-II produced
      the same beneficial result as DCM when compared with islets cultured alone. We
      conclude that pancreatic ductal epithelium promotes islet cell survival. This
      effect appears to be mediated in a paracrine manner by the release of IGF-II from
      cells in the ductal epithelium.

PMID- 10333539
TI  - Contribution of insulin-like growth factor (IGF)-I and IGF-binding protein-3 to
      mitogenic activity in bovine mammary extracts and serum.
AB  - Peripubertal development of the mammary gland is probably mediated by locally
      produced growth factors acting in concert with circulating mitogens. Our
      objective was to investigate the effect of recombinant human insulin-like growth
      factor-binding protein-3 (rhIGFBP-3) or insulin-like growth factor-I (IGF-I)
      antibodies on the IGF-I-related mitogenic activity of bovine serum and of mammary
      tissue extracts in primary mammary epithelial cell cultures. Cells were obtained
      from prepubertal female calf mammary tissue and cultured in three-dimensional
      collagen gels. An aqueous mammary parenchymal tissue extract (pooled from 20
      prepubertal heifers) or serum (pooled from 3 heifers) at a concentration of 5%
      was added to the medium containing either rhIGFBP-3 or monoclonal or polyclonal
      antibodies to human IGF-I. Cell proliferation was evaluated using [methyl
      3H]thymidine incorporation as a measure of DNA synthesis. Addition of mammary
      extracts stimulated DNA synthesis 545% compared with basal medium. Addition of
      serum stimulated DNA synthesis by 28%. Mitogenic activity of serum and added IGF
      I was abolished by addition of rhIGFBP-3 in equimolar concentrations with IGF-I.
      For mammary extracts, mitogenic activity was inhibited by 35%, 50%, and 82% by
      the addition of rhIGFBP-3 at, respectively, 1, 2 and 4 times the molar IGF-I
      concentration in the extract. Addition of rhIGFBP-3 to basal medium reduced DNA
      synthesis by 26%, whereas IGF-I antibodies had no consistent effect. These
      results indicate that circulating and mammary-synthesized IGF-I and IGFBPs
      probably play a critical role in prepubertal development of the bovine mammary
      gland.

PMID- 10333540
TI  - Effects of activin on hormone secretion by single female rat pituitary cells:
      analysis by cell immunoblot assay.
AB  - We investigated the effect of activin A on secretion of LH, FSH, and prolactin
      (PRL) by female cultured rat pituitary cells at the single-cell level by means of
      the cell immunoblot assay. Anterior pituitary cells from 8-week-old female rats
      were preincubated with or without activin A for 24 h, after which they were
      monodispersed and immediately used for cell immunoblot assay. The percentages of
      LH-, FSH- and PRL-immunoreactive cell blots detected were 5.5, 5.3 and 43.1%,
      respectively, of all pituitary cells applied to the transfer membrane. The
      percentage of LH-secreting cells and mean LH secretion per cell did not change
      after treatment with activin. In contrast, activin significantly increased the
      percentage of FSH-secreting cells and mean FSH secretion per cell to 136.0 and
      114. 5% respectively. In addition, activin significantly decreased the percentage
      of PRL-secreting cells and mean PRL secretion per cell to 52.2 and 72.0%
      respectively. These results suggest that (1) activin A has effects on female rat
      pituitary cells that increase not only the amount of FSH secretion per cell but
      also the number of FSH-secreting cells, and (2) activin A decreases both the
      amount of PRL secretion per cell and the number of PRL-secreting cells.

PMID- 10333541
TI  - Loss of sensitivity to insulin at early events of the insulin signaling pathway
      in the liver of growth hormone-transgenic mice.
AB  - Growth hormone (GH) excess is associated with secondary hyperinsulinemia, but the
      molecular mechanism and consequences of this alteration are poorly understood. To
      address this problem we have examined the levels and phosphorylation state of the
      insulin receptor (IR) and the insulin receptor substrate-1 (IRS-1), the
      association between IRS-1 and the p85 subunit of phosphatidylinositol 3-kinase
      (PI 3-kinase) as well as the PI 3-kinase activity in the livers of GH-transgenic
      mice. As expected, IR levels were reduced in the liver of GH-transgenic mice (55%
      of normal values) as determined by immunoblotting with an anti-IR beta-subunit
      antibody. IR and IRS-1 phosphorylation as determined by immunoblotting with
      antiphosphotyrosine antibody were increased in basal conditions by 315% and 560%
      respectively. After a bolus administration of insulin in vivo, IR phosphorylation
      increased by 40% while IRS-1 phosphorylation did not change. Insulin
      administration to control (normal) mice produced 670% and 300% increases in the
      IR and IRS-1 phosphorylation respectively. In the GH-transgenic animals, basal
      association of PI 3-kinase with IRS-1 as well as PI 3-kinase activity in liver
      was increased by 200% and 280% respectively, and did not increase further after
      administration of insulin in vivo, indicating a complete insensitivity to insulin
      at these levels. In conclusion, GH excess and the resulting secondary
      hyperinsulinemia were associated with alterations at the early steps of insulin
      action in liver. IR concentration was reduced, while IR and IRS-1
      phosphorylation, IRS-1/PI 3-kinase association, and PI 3-kinase activity appeared
      to be maximally activated under basal conditions, thus making this tissue
      insensitive to further stimulation by exogenous insulin in vivo.

PMID- 10333542
TI  - Gonadotropin-releasing hormone agonist has the ability to induce increased matrix
      metalloproteinase (MMP)-2 and membrane type 1-MMP expression in corpora lutea,
      and structural luteolysis in rats.
AB  - Gonadotropin-releasing hormone (GnRH) and its agonist analog (GnRHa) are well
      known to have luteolytic effects. We previously reported that prolactin (PRL)
      stimulated matrix metalloproteinase (MMP)-2 activity to degrade collagen type IV
      as a mechanism of structural luteolysis. The effects of GnRHa treatment on
      developed corpora lutea are unknown. In this study we assessed the effect of GnRH
      on MMP expression and induction of structural involution of developed corpora
      lutea of superovulated rats using GnRHa. Pregnant mare serum gonadotropin-human
      chorionic gonadotropin (hCG)-synchronized ovulation and luteinization were
      induced in immature female rats, followed by daily treatment with GnRHa from 5
      days after hCG treatment. GnRHa-induced involution of corpora lutea was evident 3
      days after the treatment, as shown by their markedly smaller size (60% of the
      control weight). Nine days after hCG injection, serum progesterone and 20alpha
      dihydroprogesterone concentrations were as low as those associated with
      structural luteolysis. These findings revealed that GnRHa has the ability to
      induce structural luteolysis in superovulated rats in the same way that PRL does.
      To gain information on mechanisms of luteal involution induced by GnRHa, we
      performed gelatin zymography. This showed a significant increase in the active
      form of MMP-2 in the luteal extract of GnRHa-treated rats (more than twofold that
      of the control). Activation of pro-MMP-2 by membrane type-MMP (MT-MMP) is
      reported to be a rate-limiting step for catalytic function. Another function of
      MT-MMP is to degrade collagen types I and III. The plasma membrane fraction of
      corpora lutea of GnRHa-treated rats activated pro-MMP-2 of fetal calf serum,
      resulting in a marked shift of the 68-kDa band to the 62-kDa band in the
      zymogram. A Northern hybridization study also revealed simultaneous significant
      increases in expression of MMP-2 mRNA and MT1-MMP mRNA in corpora lutea of GnRHa
      treated rats (more than threefold the control level). In summary, hormonal and
      histological features of corpora lutea of GnRHa-treated superovulated rats
      correspond to those of structural luteolysis. GnRHa stimulated the expression of
      MMP-2 and MT1-MMP in developed corpora lutea associated with involution. These
      findings support the conclusion that MMP-2, activated by MT1-MMP, and MT1-MMP
      itself, remodel the extracellular matrix during structural luteolysis induced by
      GnRHa.

PMID- 10333543
TI  - Up-regulation of oxytocin receptors in non-pregnant rat myometrium by
      isoproterenol: effects of steroids.
AB  - The objective of the present study was to further elucidate our previous
      observation that beta2-adrenoceptor activation induces oxytocin receptor (OTR)
      expression in rat myometrium. We wanted to investigate whether the mechanism
      behind this effect was under the influence of gonadal steroids. Ovariectomized
      non-pregnant rats were treated with estrogen, progesterone or a combination of
      both for 3 days. Some rats were concomitantly treated with isoproterenol.
      Estrogen treatment increased both OTR mRNA production and maximal binding of [3H]
      oxytocin to isolated myometrial plasma membranes, but it did not affect
      contractility of isolated uterine strips challenged with oxytocin. When the
      estrogen regimen was combined with isoproterenol treatment, an augmented maximal
      contractile response (Emax) to oxytocin was observed although no further increase
      in OTR mRNA and binding was seen. Progesterone treatment did not in itself alter
      OTR mRNA, OTR binding or Emax. However, OTRs were induced at the level of gene
      expression when progesterone was supplemented with isoproterenol infusion.
      Finally, progesterone suppressed the effect of estrogen on OTR mRNA production
      and binding when the two compounds were administered together. However, when
      isoproterenol treatment was added this effect was abolished and Emax was enhanced
      more than that seen following treatment with estrogen alone. These data suggest
      that beta2-adrenoceptor activation represents an important regulator of OTR
      expression/function in estrogen- and progesterone-dominated rat myometrium.

PMID- 10333544
TI  - Effects of GH, prolactin and cortisol on hepatic heat shock protein 70 expression
      in a marine teleost Sparus sarba.
AB  - Heat shock protein 70 (HSP70) expression was assessed in hepatic tissue of a
      marine teleost Sparus sarba after exogenous hormone administration. Using a PCR
      amplified, homologous HSP70 cDNA clone, as a probe in Northern analysis, we
      detected a 2.3 kb transcript which was elevated after exposure to a temperature 7
      degrees C above the ambient. For our studies on hormonal effects on HSP70
      expression, groups of fish were administered recombinant bream GH (rbGH), ovine
      prolactin (oPRL) or cortisol daily over a 7-day period. Quantification of hepatic
      HSP70 transcript revealed that the administration of GH and PRL significantly
      reduced HSP70 mRNA abundance by 42% and 54% from saline-injected fish
      respectively. Also hepatic HSP70 levels were reduced by 76% and 64% as determined
      by immunoblotting after rbGH and oPRL treatment respectively. The administration
      of exogenous cortisol did not alter hepatic HSP70 mRNA or protein levels in S.
      sarba. The results obtained in this study are the first evidence for hormonal
      modulation of heat shock protein expression in fish. The significance of these
      results is discussed within the context of current knowledge on the roles of
      these hormones in teleostean stress response.

PMID- 10333545
TI  - Changes in the expression of neurohypophyseal prolactins during the estrous cycle
      and after estrogen treatment.
AB  - Estrogens are recognized regulators of the expression of neurohypophyseal
      hormones and of anterior pituitary prolactin (PRL). Here we have investigated
      whether the levels of PRL mRNA and of 23 and 14 kDa PRL variants present in the
      hypothalamo-neurohypophyseal system change during the estrous cycle or in
      response to estrogen treatment. The reverse transcription polymerase chain
      reaction (RT-PCR) was performed to examine PRL mRNA expression in isolated
      paraventricular (PVN) and supraoptic (SON) hypothalamic nuclei. In both nuclei
      PRL mRNA levels appeared higher in cycling females than in male rats, with the
      highest level occurring at estrus. This increase may involve estrogen action,
      since estrogen administration to ovariectomized rats was associated with
      apparently higher PRL mRNA levels in both the PVN and SON. Expression of the PRL
      gene at these sites may occur via both transcriptional factor Pit-1-dependent and
      -independent mechanisms. RT-PCR detected the mRNA for Pit-1 in the PVN but only
      at estrus. The concentration of the 23 kDa immunoreactive PRL determined in the
      neurohypophysis was significantly higher during estrus and after estrogen
      treatment. However, no difference was detected in the levels of the
      neurohypophyseal 14 kDa PRL-like fragment along the estrous cycle nor after
      estrogen administration. This lack of parallelism between neurohypophyseal PRLs
      could relate to an estrogen-induced inhibition of the proteolysis of 23 kDa PRL
      at this site, since estrogen treatment reduced the activity of neurohypophyseal
      proteolytic enzymes able to cleave PRL. Altogether our results are consistent
      with estrogens having a stimulatory effect on PRL gene expression in the
      hypothalamo-neurohypophyseal system and a concomitant inhibitory action on PRL
      proteolysis at this site.

PMID- 10333546
TI  - Direct effects of the prostaglandins E2 and f2alpha on progesterone release by
      the corpus luteum of the marmoset monkey (Callithrix jacchus) studied by in vitro
      microdialysis.
AB  - The effects of the prostaglandins (PG) E2 and F2alpha on progesterone secretion
      in luteal tissue (32 corpora lutea) explanted from the mid-luteal ovary of the
      marmoset monkey (n=13) were investigated using an in vitro microdialysis system.
      Consecutive applications of 1, 10 and 100 microg/ml PGE2 resulted in a
      significant increase in secretion of progesterone at the maximum dose of 100
      microg/ml, which was shown to be the stimulatory dose in both long-period and 20
      min pulse (time to collect one fraction) applications. The response varied
      individually between 1.4- and 3. 4-fold above the baseline concentrations.
      Application of 500 microg/ml PGF2alpha led to similar hormone responses. In
      contrast, lower doses of PGF2alpha (0.5, 5 and 50 microg/ml) resulted in
      significantly increased levels of secretion of progesterone, to approximately 1.4
      fold baseline values, only after the application was terminated (echo effect).
      Responses were less variable when a short pulse of 20 min duration was applied,
      instead of long applications of 1-2 h. On the basis of the passage rates measured
      for tritiated PGF2alpha, transfer through the dialysis membrane was assumed to be
      in the range of 1% for both PGs. Ultrastructurally, luteal cells lying in a
      sheath of five to seven cell layers around the dialysis tubing appeared intact
      and were interconnected by gap junctions. Vesiculation of the smooth endoplasmic
      reticulum was more prominent after PG treatment, indicating a stimulation of
      cellular synthesis/secretory activities that was in accordance with the
      stimulatory action of both PGs on progesterone release under these in vitro
      conditions.

PMID- 10333547
TI  - Kangaroo IGF-II is structurally and functionally similar to the human [Ser29]-IGF
      II variant.
AB  - Kangaroo IGF-II has been purified from western grey kangaroo (Macropus
      fuliginosus) serum and characterised in a number of in vitro assays. In addition,
      the complete cDNA sequence of mature IGF-II has been obtained by reverse
      transcription polymerase chain reaction. Comparison of the kangaroo IGF-II cDNA
      sequence with known IGF-II sequences from other species revealed that it is very
      similar to the human variant, [Ser29]-hIGF-II. Both the variant and kangaroo IGF
      II contain an insert of nine nucleotides that encode the amino acids Leu-Pro-Gly
      at the junction of the B and C domains of the mature protein. The deduced
      kangaroo IGF-II protein sequence also contains three other amino acid changes
      that are not observed in human IGF-II. These amino acid differences share
      similarities with the changes described in many of the IGF-IIs reported for non
      mammalian species. Characterisation of human IGF-II, kangaroo IGF-II, chicken IGF
      II and [Ser29]-hIGF-II in a number of in vitro assays revealed that all four
      proteins are functionally very similar. No significant differences were observed
      in the ability of the IGF-IIs to bind to the bovine IGF-II/cation-independent
      mannose 6-phosphate receptor or to stimulate protein synthesis in rat L6
      myoblasts. However, differences were observed in their abilities to bind to IGF
      binding proteins (IGFBPs) present in human serum. Kangaroo, chicken and [Ser29]
      hIGF-II had lower apparent affinities for human IGFBPs than did human IGF-II.
      Thus, it appears that the major circulating form of IGF-II in the kangaroo and a
      minor form of IGF-II found in human serum are structurally and functionally very
      similar. This suggests that the splice site that generates both the variant and
      major form of human IGF-II must have evolved after the divergence of marsupials
      from placental mammals.

PMID- 10333548
TI  - Characterization of 11beta-hydroxysteroid dehydrogenase activity and
      corticosteroid receptor expression in human osteosarcoma cell lines.
AB  - Studies in vitro and in vivo have shown that corticosteroids play an important
      role in bone physiology and pathophysiology. It is now established that
      corticosteroid hormone action is regulated, in part, at the pre-receptor level
      through the expression of isozymes of 11beta-hydroxysteroid dehydrogenase (11beta
      HSD), which are responsible for the interconversion of hormonally active cortisol
      to cortisone. In this report we demonstrate 11beta-HSD activity in human
      osteoblast (OB) cells. Osteosarcoma-derived OB cell lines TE-85, MG-63 and SaOS-2
      and fibrosarcoma Hs913T cells express the type 2 isoform of 11beta-HSD, as
      determined by reverse transcription polymerase chain reaction (RT-PCR) and
      specific enzyme assays. Enzyme activity was shown to be strictly NAD dependent
      with a Km of approximately 71 nM; 11beta-HSD type 1 mRNA expression and enzyme
      activity were not detected. All four cell lines expressed mRNA for the
      glucocorticoid receptor (GR) and mineralocorticoid receptor, but specific binding
      was only detectable with radiolabelled dexamethasone (Kd=10 nM) and not
      aldosterone. MG-63 cells had two to three times more GR than the other OB cells,
      which correlated with the higher levels of 11beta-HSD 2 activity in these cells.
      In contrast to the osteosarcoma cell studies, RT-PCR analysis of primary cultures
      of human OB cells revealed the presence of mRNA for 11beta-HSD 1 as well as
      11beta-HSD 2. However, enzyme activity in these cells remained predominantly
      oxidative, i.e. inactivation of cortisol to cortisone (147 pmol/h per mg protein
      at 500 nM cortisol) was greater than cortisone to cortisol (10.3 pmol/h per mg
      protein at 250 nM cortisone). Data from normal human OB and osteosarcoma cells
      demonstrate the presence of an endogenous mechanism for inactivation of
      glucocorticoids in OB cells. We postulate that expression of the type 1 and type
      2 isoforms of 11beta-HSD in human bone plays an important role in normal bone
      homeostasis, and may be implicated in the pathogenesis of steroid-induced
      osteoporosis.

PMID- 10333549
TI  - Tri-iodothyronine increases insulin-like growth factor binding protein-2
      expression in cultured hepatocytes from hypothyroid rats.
AB  - Previous evidence suggests the existence of a thyroid hormone-IGF axis in the
      liver and changes in hepatic insulin-like growth factor binding protein (IGFBP)
      expression in rats with altered thyroid status have been previously reported. The
      aim of this study was to check if the higher IGFBP-2 mRNA levels observed in
      liver of hypothyroid rats could be due to a direct effect of thyroid hormone on
      the IGFBP-2 gene. In our experiments, cultured hepatocytes isolated from normal
      and hypothyroid adult rats were used. Northern blot analysis revealed barely
      detectable IGFBP-2 mRNA in normal rat hepatocytes, but easily detectable signal
      in hypothyroid rat cells. Therefore, the effect of tri-iodothyronine (T3) was
      investigated using cultured hepatocytes from hypothyroid rats as an in vitro
      model. The IGFBP-2 message was increased in a dose-dependent manner in
      hepatocytes cultured for 12-24 h in the presence of T3. A similar increase
      occurred in accumulation of IGFBP-2 in the culture medium, as measured by RIA.
      The effect of T3 on IGFBP-2 transcript levels appeared to consist of enhanced
      gene transcription and was independent of ongoing protein synthesis, but it was
      completely abolished by the incubation of hepatocytes with insulin. The latter
      result confirmed the dominant role of insulin in regulating IGFBP-2 expression by
      cultured hepatocytes. In vivo experiments confirmed an increase in hepatic IGFBP
      2 mRNA and serum IGFBP-2 levels in hypothyroid rats and demonstrated, in
      addition, a significant increase in these measures in T3-treated rats. Taken
      together, our in vitro and in vivo results support a role for a thyroid hormone
      IGF axis in the liver and suggest that other factors, such as insulin, interact
      in vivo with thryoid hormone in regulating hepatic IGFBP-2 expression.

PMID- 10333550
TI  - The differential processing of proenkephalin A in mouse and human breast tumour
      cell lines.
AB  - We have carried out an investigation into the processing of the enkephalin-like
      immunoreactivity reported in breast tissue using two human breast tumour cell
      lines and a mouse tumour cell line. A 46 kDa form of proenkephalin (PE) has been
      observed in the cell lysates of two human breast tumour cell lines (MCF-7, ZR-75
      1) and the mouse androgen-responsive Shionogi breast carcinoma cell line (SC115).
      PE processing in the cell lysates of these cells was assessed by a specific met
      enkephalin RIA. The basal levels of processed PE in the MCF-7, ZR-75-1 and SC115
      cell lysates were 30, 30 and 76% respectively. The processing enzymes PC1 and
      PC2, which have been implicated in the differential processing of PE, were
      detected by immunoblot analysis in these cells. PC1 was found within the cell
      extracts of all three cell lines. PC2 was only observed in the SC115 cell line,
      which may account for the higher percentage of processed PE measured. The cDNA of
      PC2 has been transfected into ZR-75-1 cells and this was accompanied by an
      increase in the level of processed PE from 30 to 76%. These breast tumour cell
      lines may provide a useful insight into the function of enkephalin-containing
      peptides in breast cancer.

PMID- 10333551
TI  - Metabolic effects of IGF-I in the growth retarded fetal sheep.
AB  - It has been shown that IGF-I has an anabolic effect in the normal fetus. However,
      there is evidence to suggest that there may be IGF-I resistance in the growth
      retarded fetus. Therefore, we investigated the effects of acute IGF-I infusion to
      chronically catheterised fetal sheep. At 128 days gestation, fetuses underwent a
      4 h infusion of IGF-I (50 microg/kg/h). Three groups of animals were studied.
      Nine normally grown fetuses were studied as controls. Embolised animals (n=8)
      received microspheres into the uterine vasculature, and animals with spontaneous
      intra-uterine growth retardation (IUGR animals) (n=6) were fetuses found at post
      mortem to be spontaneously growth restricted. The effects of IGF-I infusion on
      feto-placental carbohydrate and protein metabolism were similar in our control
      group to previous similar experiments. IGF-I infusion decreased fetal blood
      glucose, oxygen, urea and amino-nitrogen concentrations, and inhibited placental
      lactate production. The same fetal blood metabolite concentrations also fell
      during IGF-I infusion in the embolised fetuses, but the effect on placental
      lactate production was not seen. The only effect of IGF-I infusion in the
      spontaneous IUGR animals was a fall in fetal blood amino-nitrogen concentrations.
      We conclude that fetal IGF-I infusion does not have the same anabolic effects in
      the growth retarded fetus as the normal fetus. In addition, the effects of IGF-I
      were different in the two growth retarded groups. Our data support previous
      evidence that the growth retarded fetus has altered IGF-I sensitivity, and this
      may vary depending on the cause, severity and duration of growth retardation.

PMID- 10333552
TI  - A missense mutation in the GHR gene of Cornell sex-linked dwarf chickens does not
      abolish serum GH binding.
AB  - Sex-linked dwarfism (SLD) in chickens is characterized by impaired growth despite
      normal or supranormal plasma growth hormone (GH) levels. This resistance to GH
      action is thought to be due to mutations of the GH receptor (GHR) gene that
      reduce or prevent GH binding to target sites. The genetic lesion causing GH
      resistance in Cornell SLD chickens is, however, not known. Previous studies have
      shown that hepatic GH-binding activity is abnormally low in these birds, yet the
      GHR gene is transcribed into a transcript of appropriate size and abundance.
      Point mutations or defects in translation could therefore account for the
      impaired GHR activity in this strain. These possibilities were addressed in the
      present study. A missense mutation resulting in the substitution of serine for
      the conserved phenylalanine was identified in the region of the GHR cDNA encoding
      the extracellular domain. Translation of this mutant transcript was indicated by
      the presence of GHR/GH-binding protein (GHBP)-immunoreactive proteins in liver
      (55, 70 and 100 kDa) and serum (70 kDa) of normal (K) and SLD birds.
      Radiolabelled GH did not, however, bind to the hepatic membranes of most SLD
      chickens. Serum GH-binding activity, in contrast, was readily detectable,
      although at significantly lower levels than in normal birds. The missense
      mutation in the SLD GHR gene may thus affect targeting of GHRs to hepatic plasma
      membranes.

PMID- 10333553
TI  - Growth hormone directly inhibits leptin gene expression in visceral fat tissue in
      fatty Zucker rats.
AB  - Growth hormone (GH) is known to interact with adipose tissue and to induce
      lipolysis. Adipocytes produce leptin which regulates appetite and energy
      expenditure. In order to elucidate the role of GH in leptin production, we
      studied the effect of GH on leptin gene expression and body fat in fatty Zucker
      rats, a model of obesity with resistance to both leptin and insulin. Recombinant
      human GH administered subcutaneously at 0.5 mg/kg per day (low dose) as well as
      at 1.65 mg/kg per day (high dose) reduced leptin mRNA levels in epididymal fat
      tissue but not in subcutaneous fat tissue after 7 days. GH administration only at
      the high dose reduced percentage body fat. Insulin-like growth factor-I infusion
      (200 microg/kg per day) did not change percentage body fat or leptin mRNA levels
      in epididymal fat. These observations suggest that GH directly interacts with
      adipose tissue and reduces leptin gene expression in visceral fat tissue.

PMID- 10333554
TI  - Regulation of differentiation of sheep subcutaneous and abdominal preadipocytes
      in culture.
AB  - Factors regulating the differentiation of sheep subcutaneous and abdominal
      (omental or perirenal) preadipocytes from foetal lambs, suckling lambs and
      fattening sheep have been investigated using a serum-free cell culture system.
      Differentiation was assessed by changes in the activity of the enzyme glycerol 3
      phosphate dehydrogenase. Insulin or IGF-I was essential for differentiation.
      Dexamethasone, a lipid supplement (Excyte) and the thiazolidinedione,
      rosiglitazone (BRL 49653) (a peroxisome proliferator-activated receptor-gamma
      (PPAR-gamma) agonist) all enhanced preadipocyte differentiation, whereas
      fibroblast growth factor and GH were inhibitory. The most effective combination
      was insulin, triiodothyronine, dexamethasone and rosiglitazone. Under suboptimal
      conditions, preadipocytes from fattening sheep differentiated less well than
      cells from suckling and foetal lambs. Also, under suboptimal conditions,
      abdominal preadipocytes did not differentiate as well as subcutaneous
      preadipocytes. However, age and depot differences were minimised when cells were
      cultured with insulin, triiodothyronine, rosiglitazone and either dexamethasone
      or lipid. The results suggest that variation in the ability to produce the
      natural ligand for PPAR-gamma contributes to depot- and age-specific differences
      in the ability of preadipocytes to differentiate.

PMID- 10333555
TI  - Novel procedure for the detection of 5-methylcytosine.
AB  - Bisulfite converts non-methylated cytosine in DNA to uracil leaving 5
      methylcytosine unaltered. In this communication, we present a new approach
      omitting the conventional PCR amplification step. Bisulfite-converted methylated
      DNA is directly sequenced. The effectiveness of the new protocol is demonstrated
      by using it for the detection of 5-methylation of cytosine residues introduced by
      three different DNA methyltransferases (M.HaeIII, M.HpaII and M.HhaI). A simple
      experimental system useful to determine the sequence specificity of DNA
      methyltransferases is also presented.

PMID- 10333556
TI  - Characterisation of a new host-vector system for fast-growing mycobacteria.
AB  - In this paper we describe the development of a host-vector system for genetic
      studies of fast-growing mycobacteria able to biotransform sterols. A wild strain
      Mycobacterium smegmatis SN38 and a biotechnological mutant Mycobacterium vaccae
      B3805 were transformed by electroporation with the pSMT3 E. coli-Mycobacterium
      shuttle plasmid harbouring the hygromycin resistance gene. Both, the pSMT3
      plasmid and its derivative pSMT3-ksdD carrying the 3-ketosteroid-delta 1
      dehydrogenase gene (ksdD) from Arthrobacter simplex were stably maintained in M.
      vaccae B3805. The presence of the pSMT3 vector did not affect biotransformation
      activities of the host strain. We consider the M. vaccae B3805 strain and the
      pSMT3 plasmid to be a good host-vector system for cloning in mycobacteria genes
      coding enzymes involved in steroid degradation pathway.

PMID- 10333557
TI  - Cloning, sequencing and characterisation of a downstream region of ksdDI operon
      of Arthrobacter simplex.
AB  - An 8-kb region downstream of the ketosteroid dehydrogenase (ksdD)-ketosteroid
      isomerase (ksdI) genes of Arthrobacter simplex was cloned. The nucleotide
      sequence of the first 3-kb segment downstream of ksdD-ksdI operon was determined.
      Three open reading frames (ORFs) preceded by Shine-Dalgarno (SD) sequences have
      been found. Homology search revealed that the putative product encoded by ORF3
      has high level of similarity with the 3-oxosteroid dehydrogenases from A. simplex
      and P. testosteroni (90% identity in their putative active sites). The role of
      ORF3 product as a FAD-containing dehydrogenase in steroid degradation pathway is
      discussed.

PMID- 10333558
TI  - Simultaneous production of catalase, glucose oxidase and gluconic acid by
      Aspergillus niger mutant.
AB  - The production of gluconic acid, extracellular glucose oxidase and catalase in
      submerged culture by a number of biochemical mutants has been evaluated.
      Optimization of stirrer speed, time cultivation and buffering action of some
      chemicals on glucose oxidase, catalase and gluconic acid production by the most
      active mutant, AM-11, grown in a 3-L glass bioreactor was investigated. Three
      hundred rpm appeared to be optimum to ensure good growth and best glucose oxidase
      production, but gluconic acid or catalase activity obtained maximal value at 500
      or 900 rpm, respectively. Significant increase of dissolved oxygen concentration
      in culture (16-21%) and extracellular catalase activity were obtained when the
      traditional aeration was employed together with automatic dosed hydrogen
      peroxide.

PMID- 10333559
TI  - Some kinetic studies on cytidine aminohydrolase activity from Aspergillus niger
      NRRL3.
AB  - Cell free extract of nitrate-grown Aspergillus niger NRRL3 catalyzed the
      hydrolytic deamination of cytidine out of the tested bases, their nucleosides and
      nucleotides to uridine maximally at pH 7 and at 50 degrees C. The deaminating
      activity seems to be specific for cytidine, as the extracts could not deaminate
      AMP, GMP, CMP, adenosine, guanosine, adenine, guanine, and cytosine. Maximum
      activity of cytidine deaminase was achieved in Tris-HCl buffer at concentration
      of 0.15 M. Incubation of the extracts at 70 degrees C for 30 minutes in absence
      of cytidine caused about 70% loss in its activity, while dialysis, freezing and
      thawing has no effect on the activity. Results indicated the absence of the
      involvement of SH group(s) in the catalytic site of cytidine deaminase. Uridine
      competitively inhibited the enzyme activity, while ammonia had no effect. The
      apparent K(m) value of this enzyme for cytidine was 2.6 x 10(-3) and the Ki value
      for uridine was 10.06 x 10(-3).

PMID- 10333560
TI  - Molecular analysis of the human cytomegalovirus strains isolated from infected
      infants.
AB  - Polymerase chain reaction (PCR) techniques were developed to facilitate the study
      of the molecular epidemiology of human cytomegalovirus (HCMV). In the present
      study analysis of HCMV DNA was applied for the determination of the reinfection
      frequency and genotypes of HCMV strains isolated from infected infants, treated
      with ganciclovir and non-treated. Urines from 92 infants, aged 1 to 5 months,
      were investigated. Isolates were analysed by PCR method using primers for a-seq
      and glycoprotein B (gB) HCMV genes. PCR products of gB gene were digested with
      RsaI and HinfI endonucleases (PCR-RFLP). A-seq gene amplified products were
      visualized on agarose gels and analysed by densitometry. Genotyping based on
      hypervariable a-seq region in comparison with restriction analysis of gB gene
      fragment allowed better differentiation and discrimination of particular HCMV
      strains. Analysis of the a-sequence PCR products allowed to distinguish 9 profile
      groups. The patterns obtained consisted of fragments with different size (100 bp
      to 350 bp), suggesting considerable diversity of HCMV strains. A-sequence
      analysis revealed that 5 (15.6%) of treated children and 14 (20.7%) of those non
      treated, excreted virus of stable genotype. Twenty one (65.6%) of treated and 32
      (52.5%) of non-treated children excreted HCMV with a-sequence product of
      different size, suggesting that in these cases reinfection was caused by
      genetically distinct strains. Results suggest that reinfection is more frequent
      in children treated with ganciclovir.

PMID- 10333561
TI  - Channeling of vanadium in two species of fungi.
AB  - Aspergillus flavus and Penicillium italicum were cultivated on Dox medium amended
      with different concentrations of a vanadium salt; vanadium pentoxide (V2O5). The
      fungal isolates were found to absorb considerable quantities of vanadium. Fungal
      contents of carbohydrates and proteins were decreased by the presence of vanadium
      in the growth environment. Vanadium was incorporated into several types of low
      and high molecular weight protein(s) and peptides. In case of P. italicum,
      lysine, tyrosine, glycine, methionine, valine, alanine, proline, glutamic acid
      and histidine were detected in the fungal cell free extract. While in case of A.
      flavus, the following amino acids were detected: cystine, methionine, leucine,
      phenylalanine, glycine, alanine, tyrosine, lysine, histidine, arginine and
      valine.

PMID- 10333562
TI  - Sensitivity of the restriction endonucleases HaeIII, BsrI, EaeI and CfrI to
      cytosine N4-methylation.
AB  - HaeIII, BsrI and NgoII are isochizomers that recognize the sequence GGCC while
      EaeI and CfrI recognize the overlapping sequence YGGCCR. It has previously been
      shown that all these enzymes are inhibited by cytosine C5-methylation within the
      recognition sequence. The methylation sensitivities of these enzymes to cytosine
      N4-methylation have not been previously reported. In this paper we present data
      demonstrating that all these enzymes, except NgoII, are inhibited by cytosine N4
      methylation of the second 5' cytosine residue within the recognition sequence.

PMID- 10333563
TI  - Application of polymerase chain reaction for determination of toxins in
      Escherichia coli strains isolated from pigs with diarrhea.
AB  - The PCR method was used for the determination of LTI, STI, STII enterotoxins and
      Stx2e toxin genes in E. coli strains isolated from pigs with diarrhea. It was
      shown that most of the strains (77.3%) were enterotoxigenic, producing mainly LTI
      and STII (30.8%) or STI and STII (21.3%) toxins. It was found that 10.6% of
      isolates possessed the stx2e genes responsible for the elaboration of shiga toxin
      2e.

PMID- 10333564
TI  - The euryarchaeotes, a subdomain of Archaea, survive on a single DNA polymerase:
      fact or farce?
AB  - Archaea is now recognized as the third domain of life. Since their discovery,
      much effort has been directed towards understanding the molecular biology and
      biochemistry of Archaea. The objective is to comprehend the complete structure
      and the depth of the phylogenetic tree of life. DNA replication is one of the
      most important events in living organisms and DNA polymerase is the key enzyme in
      the molecular machinery which drives the process. All archaeal DNA polymerases
      were thought to belong to family B. This was because all of the products of pol
      genes that had been cloned showed amino acid sequence similarities to those of
      this family, which includes three eukaryal DNA replicases and Escherichia coli
      DNA polymerase II. Recently, we found a new heterodimeric DNA polymerase from the
      hyperthermophilic archaeon, Pyrococcus furiosus. The genes coding for the
      subunits of this DNA polymerase are conserved in the euryarchaeotes whose genomes
      have been completely sequenced. The biochemical characteristics of the novel DNA
      polymerase family suggest that its members play an important role in DNA
      replication within euryarchaeal cells. We review here our current knowledge on
      DNA polymerases in Archaea with emphasis on the novel DNA polymerase discovered
      in Euryarchaeota.

PMID- 10333565
TI  - Molecular structure of the copia-like retrotransposable element Yokozuna on the W
      chromosome of the silkworm, Bombyx mori.
AB  - We discovered a novel retrotransposable element, designated Yokozuna, on the W
      chromosome of Bombyx mori. The size of this element is 4738 bp, including a 208
      bp long terminal repeat (LTR) on one side and a 183-bp LTR on the other. This
      retrotransposable element is flanked by a 5-bp target site duplication, TAATT.
      Yokozuna contains a single long open reading frame (ORF) and the whole deduced
      amino acid sequence of ORF reveals strong homology with copia of Drosophila.
      Moreover, an alignment analysis of the reverse transcriptase (RT) sequences
      suggested that the Yokozuna element is the first Bombyx retrotransposable element
      belonging to the Ty1-copia group. The number of Yokozuna per haploid genome is
      approximately four copies. Although Yokozuna was discovered on the W chromosome,
      it is not specific for the W chromosome.

PMID- 10333566
TI  - A complete full-length non-LTR retrotransposon, BMC1, on the W chromosome of the
      silkworm, Bombyx mori.
AB  - In the silkworm, Bombyx mori, a non-long terminal repeat (non-LTR)
      retrotransposon, BMC1, is considered to be a LINE (long interspersed nuclear
      element)-like element. So far, a BMC1 containing two intact open reading frames
      (ORFs) has not been found. However, we discovered a complete full-length BMC1 on
      the W chromosome. This BMC1 is 5091 bp and contains a 5' untranslated region (5'
      UTR), two intact ORFs, and 3'-UTR which terminates in a poly(A) tail. ORF1
      encodes a putative nucleic acid-binding protein, while ORF2 encodes a protein
      containing an endonuclease domain and a reverse transcriptase domain.

PMID- 10333567
TI  - Isolation and characterization of the yeast las21 mutants, which are sensitive to
      a local anestheticum, tetracaine.
AB  - We isolated and characterized yeast mutants whose growth is sensitive to a local
      anestheticum tetracaine and, at the same time, temperature sensitive. These
      mutants were collectively called las mutants (local anestheticum sensitive). The
      las21 mutants were analyzed in this study. The wild type LAS21 gene was cloned by
      exploiting temperature sensitivity of the las21 mutants and we found that LAS21
      encodes ORF YJL062w which has not been analyzed before. Las21p is putative
      membrane protein belonging to the major facilitator super family containing
      plural membrane spanning domains. Complete elimination of the LAS21 ORF did not
      kill the cells but made their growth temperature sensitive. Interestingly, the
      complete loss of the LAS21 gene canceled the sensitivity to tetracaine. The
      ability of the las21 mutants to grow at a higher temperature was recovered in the
      various media containing an osmotic stabilizer or salts. Furthermore, temperature
      sensitivity of the las21 mutants was partially suppressed by introduction of
      PKC1, encoding protein kinase C, on a high copy vector. We found some genetic
      interactions between LAS21 and Ras/cAMP cascade genes. These results suggest that
      LAS21 defines unknown pathway regulating the stress response of yeast.

PMID- 10333568
TI  - Molecular identification of the active ninja retrotransposon and the inactive
      aurora element in Drosophila simulans and D. melanogaster.
AB  - How transposable elements evolve is a key facet in understanding of spontaneous
      mutation and genomic rearrangements in various organisms. One of the best ways to
      approach this question is to study a newly evolved transposable element whose
      presence is restricted to a specific population or strain. The retrotransposons
      ninja and aurora may provide insights into the process of their evolution,
      because of their contrasting characteristics, even though they show high sequence
      identity. The ninja retrotransposon was found in a Drosophila simulans strain in
      high copy number and is potent in transposition. On the other hand, aurora
      elements are distributed widely among the species belonging to the Drosophila
      melanogaster species complex, but are immobile at least in D. melanogaster. In
      order to distinguish the two closely resembled retrotransposons by molecular
      means, we determined and compared DNA sequence of the elements, and identified
      characteristic internal deletions and nucleotide substitutions in 5'-long
      terminal repeats (LTR). Analyses of the structure of ninja homologs and LTR
      sequences amplified from both genomic and cloned DNA revealed that the actively
      transposable ninja elements were present only in D. simulans strains, but
      inactive aurora elements exist in both D. melanogaster and D. simulans.

PMID- 10333569
TI  - The molecular basis of the instability of a crp- mutation in Escherichia coli.
AB  - We have described a rapid spontaneous conversion in the stationary phase of
      Escherichia coli strain DOO (crp-) cells as a whole population to crp+ state
      (Sugino and Morita, 1994). In this paper we have tried to elucidate the molecular
      basis of this unidirectional conversion by cloning and sequencing of the crp gene
      in their crp+ and crp- states. We have found that in the original crp- strain, an
      IS2 element has been inserted between its original promoter and the coding region
      of the crp gene in the so-called orientation II (Ahmed et al., 1981), accompanied
      by an 11 bp deletion. Unexpectedly, the crp+ "revertants" derived from the crp-
      mutant had no difference in sequence from the crp-, either in the coding or the
      regulatory region. This suggests that a change at another locus, such that this
      change somehow activates the expression of the crp gene to the level of a normal
      crp+, is responsible for the apparent reversion from crp- to crp+.

PMID- 10333570
TI  - Aberrant splicing of the Drosophila melanogaster phenylalanine hydroxylase pre
      mRNA caused by the insertion of a B104/roo transposable element in the Henna
      locus.
AB  - We report the insertion of the transposable element B104 in the Phenylalanine
      hydroxylase gene of the Drosophila mutant Henna-recessive 3. Its presence alters
      the Phenylalanine hydroxylase splicing pattern, producing at least two aberrant
      mRNAs which contain part of the B104 sequence interrupting the coding region.
      This aberrant splicing is provoked by the use of a cryptic donor site encoded by
      the B104 3' long terminal repeat in combination with either the gene intron 3
      acceptor site or a novel acceptor site generated by the target duplication caused
      by transposition. One of them, referred as mRNA type 1, encodes a truncated
      protein that could be predictably non-functional. In mRNA type 2, in spite of a
      42 nt insertion, the Phenylalanine hydroxylase reading frame is not altered and
      it would encode for a protein with 14 extra amino acids which would be able to
      account for the low enzyme activity detected in this mutant. These results
      demonstrated that Henna locus encodes the enzyme phenylalanine hydroxylase
      providing direct evidence of its participation in pteridine synthesis. Moreover,
      it constitutes an example of the ability of transposable elements to generate
      protein variation in populations with the evolutionary consequences that this
      implies.

PMID- 10333571
TI  - A peritrophin-like protein expressed in the embryonic tracheae of Drosophila
      melanogaster.
AB  - We have cloned and sequenced a cDNA from Drosophila melanogaster that encodes a
      protein homologous to the peritrophins, a family of chitin-binding proteins from
      the peritrophic matrix of insects. Unexpectedly, the gene, Gasp, is expressed in
      the embryonic tracheae. We suggest that this family of proteins may be present in
      other tissues than the peritrophic matrix, particularly where nutrient or gas
      exchange are important, and/or where invasion by parasites or viruses is
      possible. We have also mapped two similar genes that had been sequenced by the
      Berkeley Drosophila Genome Project, and find that these three very similar genes
      are not clustered, but are located on three different chromosomes.

PMID- 10333572
TI  - Oxidation of 3-hydroxykynurenine to produce xanthommatin for eye pigmentation: a
      major branch pathway of tryptophan catabolism during pupal development in the
      yellow fever mosquito, Aedes aegypti.
AB  - This study concerns the metabolic pathways of 3-hydroxykynurenine in Aedes
      aegypti mosquitoes during development with emphasis on its oxidation pathway to
      produce xanthommatin during eye pigmentation. Oxidation of tryptophan to 3
      hydroxykynurenine is the major pathway of tryptophan catabolism in Aedes aegypti,
      but 3-hydroxykynurenine oxidizes easily under physiological conditions, which
      stimulate the production of reactive oxygen species. Our data show that in Aedes
      aegypti, the chemically reactive 3-hydroxykynurenine is converted to the
      chemically stable xanthurenic acid by a transaminase-catalyzed reaction during
      larval development, while 3-hydroxykynurenine is transported to the compound eyes
      for eye pigmentation during pupal development. Our data suggest that (1) the
      transamination pathway of 3-hydroxykynurenine is down-regulated during the pupal
      development, (2) 3-hydroxykynurenine produced in other body tissues is actively
      transported to the compound eyes during the pupal stage, (3) the compound eye is
      the place where ommochromes are produced, and (4) formation of ommochromes
      results from nonenzymatic oxidation of 3-hydroxykynurenine in the compound eyes.

PMID- 10333573
TI  - Diapause-associated transcription of BmEts, a gene encoding an ETS transcription
      factor homolog in Bombyx mori.
AB  - To understand the molecular mechanism of diapause determination in early
      embryogenesis of the silkworm, Bombyx mori, mRNA from diapause and non-diapause
      eggs was compared using the differential display technique. A 1.2 kbp
      differentially amplified cDNA fragment was cloned and sequenced. Northern blot
      analysis confirmed that the mRNA corresponding to this clone, D1, was
      specifically induced in diapause eggs from 20 h after oviposition, and decreased
      gradually but was clearly detectable until 40 days after oviposition. On the
      other hand, if diapause eggs were activated by HCl treatment 20 h after
      oviposition, the mRNA corresponding to D1 vanished 72 h after HCl treatment. In
      pnd (pigmented and non-diapausing egg) homozygous embryos, which never enter into
      diapause, the RNA was not transcribed at any stage, whereas, in pnd-2 homozygous
      embryos which also have no diapause, similar results were obtained to those for
      HCl treated eggs. The deduced amino acid sequence of D1 was most highly related
      to the identified Drosophila and vertebrate ETS proteins, within the
      approximately 85 amino acid ETS domain. ETS proteins play an important role in
      transcription activation during a variety of biological processes and can be
      grouped into sub-families, based on sequence similarity in the ETS domain which
      has been shown to be a DNA-binding domain. Therefore, we have called the gene
      corresponding to D1 BmEts. These observations suggest that BmEts encodes a novel
      ETS family member which is strongly associated with the embryonic diapause.
      Moreover, BmEts probably acts downstream of the pnd gene in the regulatory
      hierarchy of diapause determination, alternatively BmEts itself might be the pnd
      gene.

PMID- 10333574
TI  - The Drosophila homologue of ribosomal protein L8.
AB  - We have cloned the gene encoding the Drosophila melanogaster homologue of
      ribosomal protein L8. It contains two introns: one in the 5' untranslated region
      and the second in the beginning of the ORF, and encodes a 256-residue protein
      which is highly conserved when compared with RpL8 proteins of other organisms.
      The gene is present as a single copy in the Drosophila genome and maps at
      position 62E6-7 on polytene chromosomes. It is expressed ubiquitously at all
      stages of development. It is located close to the gene encoding RpL12 and both
      are candidate targets of the Minute mutation, M(3)LS2, mapped in the region 62E
      63A.

PMID- 10333575
TI  - Identification and characterisation of a cytochrome P450 gene and processed
      pseudogene from an arachnid: the cattle tick, Boophilus microplus.
AB  - We isolated and sequenced the first known cytochrome P450 gene and pseudogene
      from an arachnid, the cattle tick, Boophilus microplus. Both the gene and
      pseudogene belong to the family CYP4, but a new subfamily, CYP4W, had to be
      created for these genes because they are substantially different to other CYP4
      genes. The gene, CYP4W1, has greatest homology with CYP4C1 from a cockroach,
      Blaberus discoidalis. The predicted molecular weight of the protein encoded by
      CYP4W1 (63 KDa) is greater than that of the other CYP4 genes. The pseudogene,
      CYP4W1P, is probably a processed pseudogene derived from the functional gene
      CYP4W1. This is only the third CYP processed pseudogene to be identified. The
      pseudogene is 98% identical to the functional gene, CYP4W1, therefore we
      hypothesise that this pseudogene evolved recently from the functional gene. The
      CYP4 genes from arthropods have diverged from each other more than those of
      mammals; consequently the phylogeny of the arthropod genes could not be resolved.

PMID- 10333576
TI  - Mechanisms of insecticide resistance in the aphid Nasonovia ribisnigri (Mosley)
      (Homoptera: Aphididae) from France.
AB  - Nasonovia ribisnigri, a main pest of salad crops, has developed resistance to
      various insecticides in southern France, including the carbamate pirimicarb and
      the cyclodiene endosulfan, two insecticides widely used to control this aphid.
      Here we have investigated the mechanisms of resistance to these two insecticides
      by studying cross-resistance, synergism, activity of detoxifying enzymes, and
      possible modifications of the target proteins. Resistance to pirimicarb was shown
      to be mainly due to a decreased sensitivity of the target acetylcholinesterase;
      this modification conferred also, resistance to propoxur but not to methomyl and
      the two tested organophosphates (acephate and paraoxon). Endosulfan resistance
      was associated with a moderate level of resistance to dieldrin, and resistance to
      both insecticides was due, in part, to increased detoxification by glutathione S
      transferases (GST). The endosulfan resistant strain displayed the same amino acid
      at position 302 of the Rdl gene (GABA receptor) as susceptible aphids (e.g. Ala),
      indicating that the Ala to Ser (or to Gly) mutation observed among dieldrin
      resistant strains of other insect species was not present.

PMID- 10333577
TI  - Differentiation-related changes in the cell cycle traverse.
AB  - This review examines recent developments relating to the interface between cell
      proliferation and differentiation. It is suggested that the mechanism responsible
      for this transition is more akin to a "dimmer" than to a "switch," that it is
      more useful to refer to early and late stages of differentiation rather than to
      "terminal" differentiation, and examples of the reversibility of differentiation
      are provided. An outline of the established paradigm of cell cycle regulation is
      followed by summaries of recent studies that suggest that this paradigm is overly
      simplified and should be interpreted in the context of different cell types. The
      role of inhibitors of cyclin-dependent kinases in differentiation is discussed,
      but the data are still inconclusive. An increasing interest in the changes in
      G2/M transition during differentiation is illustrated by examples of
      polyploidization during differentiation, such as megakaryocyte maturation.
      Although the retinoblastoma protein is currently maintaining its prominent role
      in control of proliferation and differentiation, it is anticipated that equally
      important regulators will be discovered and provide an explanation at the
      molecular level for the gradual transition from proliferation to differentiation.

PMID- 10333578
TI  - Nitric oxide and endothelin-1 in coronary and pulmonary circulation.
AB  - Since the discovery of the vasorelaxant properties of nitric oxide and the
      vasoconstrictor effect of endothelin-1, there have been many studies of the
      distribution and functional significance of these agents in various vascular
      beds. In the coronary and pulmonary circulation nitric oxide and endothelin-1
      actions have been largely investigated in terms of an imbalance between the
      opposing effects of these vasoactive agents leading to pathophysiological
      conditions. This article review functional and immunocytochemical studies with
      emphasis on the ultrastructural localization of nitric oxide synthase and
      endothelin-1 in the coronary and pulmonary vascular beds. Localization of nitric
      oxide synthase (type III or I or II) has been shown in endothelial cells, smooth
      muscle, and perivascular nerves of the coronary and pulmonary vascular beds and
      in the neurons, nerve fibers, and the small granule-containing cells within
      cardiac ganglia. Endothelin-1 was mainly localized in subpopulations of coronary
      and pulmonary endothelial cells. These immunocytochemical studies provide
      information about the sources of nitric oxide and endothelin-1 that contribute to
      the vasomotor control of cardiac and pulmonary circulation under normal and
      pathophysiological conditions.

PMID- 10333579
TI  - Phosphoinositide kinases and the synthesis of polyphosphoinositides in higher
      plant cells.
AB  - Phosphoinositides are a family of inositol-containing phospholipids which are
      present in all eukaryotic cells. Although in most cells these lipids, with the
      exception of phosphatidylinositol, constitute only a very minor proportion of
      total cellular lipids, they have received immense attention by researchers in the
      past 15-20 years. This is due to the discovery that these lipids, rather than
      just having structural functions, play key roles in a wide range of important
      cellular processes. Much less is known about the plant phosphoinositides than
      about their mammalian counterparts. However, it has been established that a
      functional phosphoinositide system exists in plant cells and it is becoming
      increasingly clear that inositol-containing lipids are likely to play many
      important roles throughout the life of a plant. It is not our intention to give
      an exhaustive overview of all aspects of the field, but rather we focus on the
      phosphoinositide kinases responsible for the synthesis of all phosphorylated
      forms of phosphatidylinositol. Also, we mention some of the aspects of current
      phosphoinositide research which, in our opinion, are most likely to provide a
      suitable starting point for further research into the role of phosphoinositides
      in plants.

PMID- 10333580
TI  - Cellular aspects of trophic actions in the nervous system.
AB  - During the past three decades the number of molecules exhibiting trophic actions
      in the brain has increased drastically. These molecules promote and/or control
      proliferation, differentiation, migration, and survival (sometimes even the
      death) of their target cells. In this review a comprehensive overview of small
      diffusible factors showing trophic actions in the central nervous system (CNS) is
      given. The factors discussed are neurotrophins, epidermal growth factor,
      fibroblast growth factor, platelet-derived growth factor, insulin-like growth
      factors, ciliary neurotrophic factor and related molecules, glial-derived growth
      factor and related molecules, transforming growth factor-beta and related
      molecules, neurotransmitters, and hormones. All factors are discussed with
      respect to their trophic actions, their expression patterns in the brain, and
      molecular aspects of their receptors and intracellular signaling pathways. It
      becomes evident that there does not exist "the" trophic factor in the CNS but
      rather a multitude of them interacting with each other in a complicated network
      of trophic actions forming and maintaining the adult nervous system.

PMID- 10333581
TI  - Conformational changes of contractile proteins and their role in muscle
      contraction.
AB  - The review summarizes the results of studies on conformational changes in
      contractile proteins that occur during muscle contraction. Polarized fluorescence
      of tryptophan residues in actin and of fluorescent probes bound specifically to
      different sites on actin, myosin, or tropomyosin in muscle fibers was measured.
      The results show that the transition of actomyosin complex from the weak to the
      strong-binding state is accompanied by a change in the orientation of F-actin
      subunits with the C and N termini moving opposite to a large part of the subunit.
      Myosin light chains and some areas in the 20-kDa domain of myosin head move in
      the same direction as the C- and N-terminal regions of actin. It is established
      that troponin, caldesmon, calponin, and myosin systems of regulation of muscle
      contraction modify intramolecular actomyosin rearrangements in a Ca(2+)-dependent
      manner. The role of intramolecular movements of contractile proteins in muscle
      contraction is discussed.

PMID- 10333583
TI  - Characterization and biosynthesis of non-degradable polymers in plant cuticles.
AB  - The structure and monomeric composition of the highly aliphatic and non
      saponifiable fraction of cutans isolated from the leaf cuticles of Agave
      americana L. and Clivia miniata Reg. have been elucidated. Spectroscopic Fourier
      transform infrared and 13C-nuclear magnetic resonance, calorimetric and X-ray
      diffraction studies, together with biopolymer analysis after exhaustive
      ozonolysis, showed that the cutan fraction consists of an amorphous three
      dimensional network linked by ether bonds containing double bonds and free
      carboxylic acid functions. Data obtained from fatty acid sorption indicated that
      the new biopolymer investigated here has a highly hydrophobic character
      constituting an additional barrier biopolymer in those cuticles where it is
      present. Labelled [14C]linoleic acid was preferentially incorporated into the non
      ester part of C. miniata leaf disks in comparison with the cutin fraction of the
      cuticular membrane. This indicates that the cis-pentadiene system of
      polyunsaturated fatty acids is involved in the formation of intramolecular
      linkages, mainly ether bonds, of the aliphatic biopolymer.

PMID- 10333582
TI  - Structure and regulation of OPR1 and OPR2, two closely related genes encoding 12
      oxophytodienoic acid-10,11-reductases from Arabidopsis thaliana.
AB  - The genes of two closely related 12-oxophytodienoic acid reductases (EC
      1.3.1.42), OPR1 and OPR2, were identified on a 7079-bp-long genomic fragment from
      Arabidopsis thaliana (L.) Heynh. The organization of these two genes was
      determined and putative cis elements were identified. Promoter-beta-glucuronidase
      (GUS) fusions expressed in transgenic Arabidopsis thaliana and Nicotiana tabacum
      L. plants revealed differences in OPR-promoter-driven GUS expression in flowers.
      While the OPR1 promoter directed GUS expression in young seeds, the OPR2 promoter
      directed pollen-specific expression. Both OPR1 and OPR2, were predominantly
      expressed in roots. Stress treatments, like local and systemic wounding, UV-C
      illumination and coldness, resulted in transient changes in steady-state OPR mRNA
      levels, but no concurrent changes in polypeptide level or enzyme activity were
      detected.

PMID- 10333584
TI  - Localization of pyrophosphatase in membranes of cauliflower inflorescence cells.
AB  - Using a polyclonal antiserum specific for the tonoplastic H(+)-pyrophosphatase
      (tPPase), significant amounts of antigenic polypeptides of the correct molecular
      mass were detected in Western blots of plasma membrane isolated from cauliflower
      (Brassica oleracea L.) inflorescence by phase-partitioning and subsequent sucrose
      density centrifugation. Potassium iodide-stripped plasma membranes continued to
      give a strong positive signal, indicating that the PPase antigen detected was not
      a result of contamination through soluble PPase released during homogenisation.
      The same preparation contained negligible vacuolar (v)H(+)-ATPase activity and
      the A subunit of the vATPase could not be detected by immunoblotting. Plasma
      membrane fractions exhibited a proton-pumping activity with ATP as substrate, but
      such an activity was not measurable with pyrophosphate, although the hydrolysis
      of this substrate was recorded. By contrast, pyrophosphate supported proton
      pumping in tonoplast-containing fractions. Immunogold electron microscopy
      confirmed the presence of PPase at the plasma membrane as well as at the
      tonoplast, trans Golgi network, and multivesicular bodies. The density of
      immunogold label was higher at the plasma membrane than at the tonoplast, except
      for membrane fragments occurring in the lumen of the vacuoles which stained very
      conspicuously.

PMID- 10333585
TI  - The Arabidopsis extensin gene is developmentally regulated, is induced by
      wounding, methyl jasmonate, abscisic and salicylic acid, and codes for a protein
      with unusual motifs.
AB  - A single-copy extensin gene (atExt1) has been isolated from Arabidopsis thaliana
      (L.) Heynh. The deduced amino acid sequence consists of 374 amino acids which are
      organised into highly ordered repeating blocks in which Ser(Pro)4 and Ser(Pro)3
      motifs alternate. Two copies of the Tyr-X-Tyr-Lys motif and 13 copies of the Val
      Tyr-Lys motif are present, showing that this extensin may be highly cross-linked,
      possessing the capacity for both intra and inter-molecular bond formation. The
      gene atExt1 is normally expressed in the root and is silent in the leaf; wounding
      reverses this pattern, turning on the gene in the leaf and repressing it in the
      root. The promoter contains motifs which have been found to activate plant
      defence genes in response to salicylic acid, abscisic acid and methyl jasmonate;
      when these compounds are applied to the roots, the atExt1 gene is activated in
      the leaf.

PMID- 10333586
TI  - Programme of senescence in petals and carpels of Pisum sativum L. flowers and its
      control by ethylene.
AB  - The role of ethylene in the control of senescence of both petals and unpollinated
      carpels of pea was investigated. An increase in ethylene production accompanied
      senescence, and the inhibitors of ethylene action were effective in delaying
      senescence symptoms in different flower verticils. Pollination did not seem to
      trigger the senescence syndrome in the corolla as deduced from the observation
      that petals from pollinated and unpollinated flowers and from flowers whose
      carpels had been removed senesced at the same time. A cDNA clone encoding a
      putative ethylene-response sensor (psERS) was isolated from pea flowers, and the
      pattern of expression of its mRNA was studied during development and senescence
      of different flower tissues. The levels of psERS mRNA paralleled ethylene
      production (and also levels of 1-aminocyclopropane-1-carboxylic acid oxidase
      (ACO) mRNA) in both petals and styles. Silver thiosulfate treatments were
      efficient at preventing ACO and psERS mRNA induction in petals. However, the same
      inhibitor showed no ability to modify expression patterns in pea carpels around
      the anthesis stage, suggesting different controls for ethylene synthesis and
      sensitivity in different flower organs.

PMID- 10333587
TI  - The effect of ethylene and cytokinin on guanosine 5'-triphosphate binding and
      protein phosphorylation in leaves of Arabidopsis thaliana.
AB  - Binding of [alpha-32P]guanosine 5'-triphosphate ([alpha-32P]GTP) has been
      demonstrated in a Triton X-100-solubilised membrane fraction from leaves of
      Arabidopsis thaliana (L.) Heynh. Binding was stimulated by 1 h pre-treatment of
      leaves with ethylene and this effect was antagonised by the inclusion of N6
      benzyladenine in the medium used for homogenisation. The ethylene-insensitive
      mutants eti 5 and etr showed contrasting responses. In eti 5 the constitutive
      level of GTP binding was higher than in the wild type whereas in etr the level
      was much lower. Neither ethylene nor cytokinin affected GTP binding in the
      mutants. The GTP-binding activity was localised in two bands at 22 and 25 kDa,
      both of which were immunoprecipitated by anti-pan-Ras antibodies, indicating that
      the activity is due to small GTP-binding proteins. In a similar membrane
      fraction, ethylene was shown to increase protein phosphorylation and
      benzyladenine antagonised this effect. In eti 5 the constitutive level of protein
      phosphorylation was higher than in the wild type, but benzyladenine increased
      activity substantially while ethylene was without effect. In etr, protein
      phosphorylation was lower than in the wild type, ethylene was without effect, but
      cytokinin increased activity. A protein of M(r) 17 kDa was detected on gels using
      antibodies to nucleoside diphosphate kinase. Phosphorylation of this protein was
      upregulated by ethylene but nucleoside diphosphate kinase activity was
      unaffected. The results are compared with the effect of the two hormones on the
      senescence of detached leaves and discussed in relation to pathways proposed for
      ethylene signal transduction.

PMID- 10333588
TI  - Polyamines and pectins. II. Modulation of pectic-signal transduction.
AB  - A previous study had shown that polyamines adsorb selectively on plant cell walls
      according to the valence of the polyamine (Messiaen et al. 1997, Plant Physiol.
      113: 387-395). In this study, the adsorption of polyamines onto isolated carrot
      cell walls and onto pure polygalacturonic acid was investigated in the presence
      of competing mono- and divalent cations (Na+ and Ca2+). Putrescine (Put2+) was
      unable to remove all the calcium (Ca2+) from cell walls or from polygalacturonic
      acid. Spermidine (Spd3+) and spermine (Spm4+) adsorbed on all galacturonates and
      were able to remove Ca2+ completely from both the walls and the pure
      polygalacturonates. Therefore, Spd3+ and Spm4+, unlike Put2+, prevented
      polygalacturonic acid from adopting the Ca(2+)-induced supramolecular
      conformation recognized by the 2F4 anti-pectin monoclonal antibody. We show that
      the signal transduction cascade otherwise initiated in plant cells by Ca(2+)
      bound alpha-1,4-oligogalacturonides was indeed blocked by both Spd3+ and Spm4+,
      but not by Put2+. The mobilization of cytosolic free Ca2+ and the cytosolic
      acidification usually observed after treatment with pectic fragments did not
      occur and the subsequent activation of phenylalanine ammonia-lyase was
      suppressed. It is hypothesized that the disruption by Spd3+ and Spm4+ of the
      Ca(2+)-induced supramolecular conformation of pectic fragments was the cause of
      the inhibition of the pectic signal. We conclude that polyamines can act on plant
      cell physiology by modulating the transduction of the pectic signal.

PMID- 10333589
TI  - Control of hypocotyl elongation in Arabidopsis thaliana by photoreceptor
      interaction.
AB  - In order to test the interaction of different phytochromes and blue-light
      receptors, etiolated seedlings of wild-type Arabidopsis thaliana (L.) Heynh., a
      phytochrome (phy) B-overexpressor line (ABO), and the photoreceptor mutants phyA
      201, phyB-5, hy4-2.23n, fha-1, phyA-201/phyB-5, and phyA-201/hy4-2.23n were
      exposed to red and far-red light pulses after various preirradiations. The
      responsiveness to the inductive red pulses is primarily mediated by phyB which is
      rather stable in its far-red-absorbing form as demonstrated by a very slow loss
      of reversibility. Without preirradiation the red pulses had an impact on
      hypocotyl elongation only in PHYA mutants but not in the wild type. This
      indicates a suppression of phyB function by the presence of phyA. Preirradiation
      with either far-red or blue light resulted in an inhibition of hypocotyl
      elongation by red pulses in the wild type. Responsiveness amplification by far
      red light is mediated by phyA and disappears slowly in the dark. The extent of
      responsiveness amplification by blue light was identical in the wild type and in
      the absence of phyA, or the cryptochromes cryl (hy4-2.23n) or cry2 (fha-1).
      Therefore, we conclude that stimulation of phyB by blue light preirradiation is
      either mediated by an additional still-unidentified blue-light-absorbing pigment
      or that phyA, cry1 and cry2 substitute for each other completely. Both blue and
      red preirradiation established responsiveness to red pulses in phyA-201/phyB-5
      double mutants. These results demonstrate that inhibition of hypocotyl elongation
      by red pulses is not only mediated by phyB but also by a phytochrome(s) other
      than phyA and phyB.

PMID- 10333590
TI  - Light-induced absorbance changes in Phycomyces: evidence for cryptochrome
      associated flavosemiquinones.
AB  - Light-induced absorbance changes (LIACs), which are associated with early
      photochemical events of blue-light transduction, were detected in growing zones
      of Phycomyces sporangiophores. The novel LIACs meet all the essential
      requirements for a spectrophotometric photoreceptor assay which was previously
      unavailable for blue-light receptors (cryptochromes). In-vivo absorption spectra
      of growing zones were derived from reflection spectra which were measured with a
      novel rapid-scan spectrophotometer. To detect photoreceptor-associated absorbance
      changes white mutants were employed which lack the interfering bulk pigment beta
      carotene. Blue and white light, not however red light, induced in these strains
      absorbance changes near 460-490 and 600-620 nm. The LIACs were absent in light
      insensitive mutants with defects in the genes madA, madB and madC. Because these
      genes affect photosensory adaptation and the blue-light receptor itself, the
      novel in-vivo LIACs must be associated with photochemical events which occur
      early in the transduction chain. The spectral characteristics of the LIACs are in
      accordance with a blue- and red-light absorbing flavosemiquinone which is
      generated upon light absorption by an oxidized flavin receptor. It is proposed
      that the flavosemiquinone functions itself as photoreceptor which mediates
      several red-light responses of Phycomyces.

PMID- 10333591
TI  - Purification, characterization, and cDNA structure of isoamylase from developing
      endosperm of rice.
AB  - Isoamylase (EC 3.2.1.68) in rice (Oryza sativa L.) was efficiently purified
      within a day to homogeneity, as confirmed by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE), from developing endosperm by
      sequential use of Q Sepharose HP anion-exchange chromatography, ammonium sulfate
      fractionation, and TSKgel G4000SWXL and G3000SWXL gel filtration chromatography.
      Although the protein exhibited a molecular size of ca. 83 kDa on SDS-PAGE, the
      apparent size of the native enzyme was approximately 340 and 490 kDa on TSKgel
      G3000SWXL and G4000SWXL gel filtration chromatograms, respectively, suggesting
      that rice isoamylase exists in a homo-tetramer to homo-hexamer form in developing
      endosperm. The purified rice isoamylase was able to debranch glycogen,
      phytoglycogen and amylopectin but could not attack pullulan. The optimum pH and
      temperature for isoamylase activity were found to be pH 6.5 to 7.0 and 30 degrees
      C, respectively. The enzyme activity was completely inhibited by HgCl2 and p
      chloromercuribenzoate at 1 mM. These results indicate that rice isoamylase
      possesses properties which are distinct from those reported for bacterial
      isoamylase. Complementary-DNA clones for rice endosperm isoamylase were isolated
      with a polymerase-chain-reaction product as probe which was generated by primers
      designed from nucleotides conserved in cDNA for maize Sugary-1 isoamylase (M.G.
      James et al., 1995. Plant Cell 7: 417-429) and a Pseudomonas amyloderamosa gene
      encoding isoamylase (A. Amemura et al. 1988, J Biol Chem 263: 9271-9275). The
      nucleotide sequence and deduced amino acid sequence of the longest clone showed a
      high similarity to those of maize Surgary-1 isoamylase, but a lesser similarity
      to those of Pseudomonas amyloderamosa isoamylase. Southern blot analysis and gene
      mapping analysis indicated that the isoamylase gene exists as a single copy in
      the rice genome and is located on chromosome 8 of cv. Nipponbare which belongs to
      the Japonica rice group. Phylogenetic analysis indicated that isoamylases from
      maize and rice are more closely related to a number of glgX gene products of the
      blue green alga Synechocystis and various bacteria than to isoamylases from
      Pseudomonas and Flavobacterium. Hence, it is proposed that glgX proteins are
      classified as isoamylase-type debranching enzymes. Our tree also showed that all
      starch- and glycogen-debranching enzymes from plants and bacteria tested can be
      classified into two distinct types, an isoamylase-type and a pullulanase-type.

PMID- 10333592
TI  - Interleukin-10 and liver diseases.

PMID- 10333593
TI  - Colorectal villous tumors accuracy of the preoperative biopsies.
AB  - This study was undertaken to assess the reliability of the endoscopic biopsies in
      the evaluation of colorectal villous tumors (CRVT). In 163 consecutive patients
      referred for surgical treatment of CRVT, preoperative evaluation had been
      routinely done by colonoscopy and multiple biopsies. Tumors were classified in 3
      groups: low grade tumors, high grade tumors and adenocarcinomas. Infiltration in
      depth was staged on the postoperative specimens according to the Dukes-Aster
      Coller's classification. All the tumors were completely resected by surgery and
      definitive pathological diagnosis was established. An exact correlation between
      the pre- and postoperative staging was observed in 48% of the cases. Accuracy
      averaged 54% in the group-by-group comparison, with an overstaging rate of 6.7%,
      and an understaging rate of 39%. The incidence of adenocarcinomas was 22% in the
      group with clearly benign preoperative biopsies and 50% in the other cases. There
      were significantly more B2 and C tumors among the patients referred after 3 or
      more endoscopic attempts (33%) than after one or two sessions (10%) (p < 0.0003).
      We confirm that in spite of multiple endoscopic biopsies, only a complete
      resection permits an exact staging and an appropriate therapeutic choice.

PMID- 10333594
TI  - Prevalence of hepatitis G virus in a haemodialysis unit.
AB  - BACKGROUND: Recently, a novel blood-borne virus has been identified and named
      hepatitis G virus. Transfusion is the main route of transmission. It is known
      that patients on maintenance dialysis are more susceptible to infections with
      parenterally-transmitted viruses than the general population. The aim of the
      present study was to determine the prevalence of hepatitis G infection in a
      Belgian dialysis unit. METHODS: The entire population of our dialysis unit (82
      patients) was tested for the presence of hepatitis G virus (HGV) by reverse
      transcriptase polymerase chain reaction. History of transfusion or renal
      transplantation, coinfections with hepatitis B and C viruses, and serum
      aminotransferase levels were also tested. RESULTS: Thirteen patients (16%) were
      found positive for HGV-RNA. Among these patients, 69.2% were infected by the G
      virus alone, 15.4% were coinfected with B virus, and 15.4% with C virus. All but
      one patient had a history of transfusion. Ten of the thirteen infected patients
      (77%) had normal aminotransferase (< 30 UI/l). Three patients had elevated
      aminotransferase levels (23%); one was coinfected with B virus, one with C virus,
      and the last one had a diabetes-induced fatty liver infiltration. No liver
      biopsies were performed. CONCLUSIONS: It is concluded that infection with G virus
      is common among dialyzed patients. This high rate of infection could be related
      to previous transfusions, but may as well be due to nosocomial transmission. In
      our series, at least one patient has been contaminated by another road than
      transplantation or transfusion. Finally, it does not appear clearly that chronic
      infection with hepatitis G virus induces liver disease, as defined by elevated
      aminotransferase level.

PMID- 10333595
TI  - Influence of body mass index, sex and age on serum alanine aminotransferase (ALT)
      level in healthy blood donors.
AB  - BACKGROUND AND AIM: Serum alanine aminotransferase (ALT) level is the most common
      screening test as part of a routine evaluation of liver damage. In order to
      determine the factors influencing this liver function test in normal subjects,
      the relationship between ALT level and gender, age and body mass index (BMI) was
      studied in a large population of healthy blood donors. METHODS: This population
      included 9,420 volunteer blood donors (4,488 men and 4,932 women aged from 18 to
      70 years) selected on the basis of negative answers to a detailed medical
      questionnaire including past medical history, drug and alcohol consumption, on
      the absence of clinical signs of liver disease, on the negativity of serological
      testing for hepatitis B and C virus and HIV. RESULTS: In the overall population,
      the mean serum ALT value was 21.8 I.U./L and the mean BMI was 24.4 kg/m2. There
      was a positive significant correlation between serum ALT level and BMI (Pearson r
      = 0.54; p < 0.001) and between ALT and age (Pearson r = 0.25; p < 0.001). A major
      sex-difference in ALT value was observed, the mean ALT value being higher in men
      than in women (26.8 +/- 13.6 vs. 17.2 +/- 8.1 I.U./L, p < 0.0001). In both sexes,
      ALT level was significantly correlated with BMI (Pearson r = 0.45 in men and r =
      0.37 in women; p < 0.001). In women a consistent rise in BMI and ALT value with
      increasing age was observed whereas in men BMI and ALT level only increased with
      age up to the fifth decade. IN CONCLUSION: There was a significant positive
      correlation between ALT and BMI regardless the gender in a population of healthy
      volunteer blood donors. Moreover, at the same age and the same BMI, ALT was
      significantly lower in women than in men suggesting that the normal range for ALT
      value should be adjusted for gender. So gender and BMI have to be considered in
      the interpretation of ALT values.

PMID- 10333596
TI  - Viral hepatitis and pregnancy.
AB  - This paper reviews data on the mutual relationship between pregnancy and viral
      hepatitis and the mother-to-infant transmission of the virus. In the western
      world, hepatitis A, B or C do not seem to influence the course of pregnancy, or
      to be associated with foetal risks. In contrast, women who contract a hepatitis E
      infection in their third trimester of pregnancy have a relatively high
      probability to develop a fulminant hepatitis. Mother-to-infant transmission of
      hepatitis A seems to be very uncommon. On the contrary, HBsAg and HBeAg positive
      mothers have a 80-90% risk to transmit the disease to their offspring, more than
      85% of these becoming chronic carriers of HBsAg. The risk depends on the level of
      viral replication. In HBsAg positive and HBeAg negative mothers the rate of
      transmission is only 2-15%, these babies rarely become carriers. A possible
      explanation is the transplacental passage of the HBeAg making the infant tolerant
      to the hepatitis B virus. As most of the infections occur during or directly
      after delivery, the neonates are suitable for postexposure prophylaxis. It is
      recommended by the Centers for Disease Control and Prevention and the American
      Academy of Pediatrics that newborns of HBsAg positive mothers should receive
      hepatitis B immunoglobulins within 12 hours after birth concurrently with the
      first paediatric dose of the vaccine. Vaccination should be completed at 1 and 6
      months. This regimen confers a protective efficacy of > or = 90%. Vertical
      transmission of hepatitis C is considered to be relatively rare, around 11% when
      HCV-RNA is positive. The highest rates of vertical transmission of HCV are noted
      in women with high HCV-RNA level or concurrent HIV infection. The risk is
      extremely low when no HCV-RNA is detected. There is currently no treatment to
      prevent this vertical transmission; routine screening of all mothers is
      unwarranted, and pregnancies among HCV-positive mothers should not be
      discouraged, but their infants should be tested for anti-HCV at 1 year and
      followed for the development of hepatitis. Breast feeding does not seem to play
      an important role in the transmission of hepatitis B and C.

PMID- 10333597
TI  - Treatment of chronic hepatitis C.

PMID- 10333598
TI  - The treatment of ascites.

PMID- 10333599
TI  - Acute renal failure requiring haemodialysis after high doses percutaneous acetic
      acid injection for hepatocellular carcinoma.
AB  - Recently, ultrasound-guided percutaneous acetic acid injection has been proposed
      in the treatment of hepatocellular carcinoma as an alternative to percutaneous
      ethanol injection. We report the case of severe renal failure requiring
      haemodialysis which occurred in a patient with 4 cm hepatocellular carcinoma
      treated adequately by high dose percutaneous acetic acid injection. The risk of
      such a serious side effect, likely related to a direct toxic effect of acetic
      acid, should be of concern when considering percutaneous treatment of
      hepatocellular carcinoma. Acute renal failure has been reported as a complication
      of acetic acid poisoning, but to our knowledge, we report here the first case of
      acute renal failure following high dose percutaneous acetic acid injection.

PMID- 10333600
TI  - [Proposals for the development of home care].

PMID- 10333601
TI  - [Palliative care in primary care: the opinion of professionals].
AB  - OBJECTIVES: To find the views and attitudes of primary care professionals to the
      setting-up of a palliative treatments programme. DESIGN: A qualitative research
      study with discussion groups. SETTING: Primary care. PARTICIPANTS: 60 primary
      care professionals, 30 doctors and 30 nurses, selected at random and placed in 6
      discussion groups. MEASUREMENTS AND MAIN RESULTS: Collection and analysis of the
      views expressed in the discussion groups. The professionals saw as problems: poor
      communication between levels of care, inadequate organisation and communication
      within the primary care teams and difficulties in obtaining opiates at pharmacy
      offices. Lack of training was not seen as a problem. The care organisation models
      suggested varied from those based on the first care level to those exclusively
      dependent on specialist units. CONCLUSIONS: The proper development of palliative
      treatment is subject to various problems identified by the professionals. These
      have to be tackled before the programmes are set up.

PMID- 10333602
TI  - [The validation of a questionnaire for measuring the organizational climate in
      health centers].
AB  - OBJECTIVE: To check the reliability and to analyse the validity of a
      questionnaire on organisational atmosphere (OA). DESIGN: Crossover and
      observational. SETTING: Primary care teams (PCTs). PARTICIPANTS: Two
      questionnaires were offered to all the doctors, nurses and social workers (548
      professionals) from the 29 PCTs in an autonomous community. One questionnaire was
      on the OA and the other was a subjective assessment of satisfaction with the
      structure and functioning of their own team. MEASUREMENTS AND MAIN RESULTS: When
      the results were analysed (initial factorial analysis), 3 items with only slight
      discrimination were eliminated from the OA questionnaire. Construction validity
      (factorial analysis with varimax method), reliability of the questionnaire
      (Cronbach's alpha and Spearman-Brown coefficient) and of criterion (correlation
      between OA and variables in the subjective assessment questionnaire) were
      calculated. The overall response rate was 77.5% (402 professionals). Three
      dimensions which explained 57% of total variability and which confirmed adequate
      construction validity were identified: team-work, cohesion and commitment. "Team
      work" comprised 9 items and explained 27.18% of total variability. "Cohesion" had
      7 items, which explained 16.55% of variability. Lastly, "Commitment" explained
      13.47% of variability, with 5 items. The validity of criterion was adequate
      (close correlation between OA and subjective assessment of structure and
      operation). Reliability was high (0.89 alpha and 0.92 Spearman-Brown for the
      entire questionnaire and > 0.7 for the dimensions). CONCLUSIONS: The reliability
      and validity of the adapted questionnaire are sufficient and permit its routine
      primary care use in our health system to be recommended.

PMID- 10333603
TI  - [A comparison of 2 survey methods: the telephone versus the mails in the diabetic
      population of a health center].
AB  - OBJECTIVE: To find the differences between telephone and mail interview respect
      on answer rate, economic cost and characteristics of participants. To determine
      the knowledge of our diabetics about their disease. DESIGN: A descriptive
      transversal study. SETTING: Primary care Centro de San Gregorio, Telde, Las
      Palmas. PATIENTS: The diabetics type 1 and 2 (n = 566) of our centre, whose ages
      were 18-70 years. In order to apply the same health questionnaire through two
      different ways, we divided the sample into two random groups: mail group (n =
      283) and telephone group (n = 283). RESULTS: The global answer rate was 51.6%
      (292 patients), 48% in the mail group (136 patients) and 55% in the telephone
      group (156 patients). The total cost of the mail survey was 41,000 pts. (104 pts.
      per mail), and the cost of telephone survey was 5.100 pts. (25.5 pts. per useful
      call). In the whole sample, we observed women more frequently in the answer group
      (56% of 292) than in the no answer group (44% of 274) (CI 95% 8.1-12.8). Also, in
      the answer group, the age was greater than in the no answer group (58.8 +/- 9.8
      yr vs. 55.8 +/- 12.5 yr) (CI 95% 1.14-4.8). When we analyzed gender and age in
      each group, we observed the same differences in the telephone group but not in
      the mail group. More than the half questionnaire were correctly answer by 64%
      (167 patients). In the telephone group the "fit" rate was greater (70.6% of 153)
      than in the mail group (55.7% of 106) (CI 95% 3.2-26.6). CONCLUSIONS: A suitable
      answer rate was reached through both methods of interview, but telephone survey's
      was smaller. In the mail group, both genders and all ages groups answered in the
      same way. The knowledge of our diabetics about their disease was like as the
      found in another studies.

PMID- 10333604
TI  - [The evaluation of the quality of so-called "clinical protocols" in primary care
      developed in the Autonomous Community of Murcia. The Group for the Evaluation and
      Improvement of Clinical Protocols].
AB  - OBJECTIVE: To evaluate the quality of the design (structural) of the clinical
      protocols worked out in the Murcia region. DESIGN: Descriptive evaluation.
      Retrospective, over 8 years. SETTING: Primary health care. PARTICIPANTS: The
      professionals from the 31 health centres in the Murcia Region with activities
      covered by protocols. MEASUREMENTS AND MAIN RESULTS: The 519 documents written
      between January 1985 and January 1994, of which 470 were obtained and classified,
      were the object of the study. 11 criteria for the design quality of the protocols
      were worked out, based on the bibliography and a previous experiment. The inter
      observer reliability of these criteria were assessed and two of them were
      rejected. Then the quality of the protocols design was evaluated through rates of
      compliance with the 9 standard and previously validated explicit criteria. 55.1%
      (259) of the documents fitted the accepted definition of protocol. 42.3% (199)
      had a recording system. 20.2% (95) had foreseen their evaluation. 41.7% (196) had
      some algorithm. 38.1% (179) had an anamnesis and/or examination page. 88.9% (418)
      were under 20 pages. Only 11.9% (56) had an index. 57.7% (271) had no formal
      defects of hand-writing or legibility. Only 14.7% (69) had a bibliography. Only
      three of the nine criteria were satisfied in over 50% of cases; three more, in
      under 30%. Overall, the clinical protocols had 2488 defects, with an average per
      protocol of 5.29. CONCLUSIONS: The formal quality of the primary care clinical
      protocols worked out in the Autonomous Community of Murcia is very low.
      Corrective measures to improve this situation should be taken.

PMID- 10333606
TI  - [Anti-ulcer drug consumption in Spain].
AB  - OBJECTIVE: To check whether therapy to eradicate Helicobacter pylori has
      succeeded in reducing the consumption of traditional ulcer medication. DESIGN: A
      longitudinal, retrospective study of the use of medication. SETTING: Spain in the
      decade from 1988 to 1997. PARTICIPANTS: Pharmaceutical products belonging to the
      anatomical therapeutic group AO2B (for ulcers) and dispensed at the Social
      Security's expense. MEASUREMENTS AND MAIN RESULTS: Despite the widespread use of
      treatments to eradicate H. pylori, it was found that consumption of ulcer
      medication continued to increase markedly, from 5 daily doses per 1000
      inhabitants in 1988 to 19 in 1997. In 1997 the two most frequently taken active
      principles in the group were omeprazole and ranitidine. Drugs indicated for
      gastric protection were also used much more. However, in absolute values, they
      stayed well below anti-H2 drugs and proton pump inhibitors. CONCLUSION: The
      introduction into Spain of therapy to eradicate H. pylori has failed to reduce
      the use of ulcer medication. The use of anti-H2 drugs and proton pump inhibitors
      for gastric protection may explain a part of the increase in consumption
      experienced by these two pharmacological groups.

PMID- 10333605
TI  - [The prevalence of serological markers of the hepatitis B virus in the hospital
      and primary health care workers of the Jerez area (Cadiz)].
AB  - OBJECTIVE: To know the magnitude the HBV infection on the staff of the hospital
      and primary care centres in Jerez (Spain) and its area. This work was carried out
      from a study on the seroprevalence of virus markers. DESIGN: Cross-sectional
      study. SETTING: Jerez and its sanitary area. PARTICIPANTS: The workers of the
      hospital and primary care centres in Jerez and its area who agreed to
      participate, who had not been vaccinated previously and had no known hepatic
      pathology were studied. INTERVENTIONS: Determinations of anti-HBs, anti-HBc and
      HbsAg were made, and the statuses of carrier (AgHBs and anti-HBC positives),
      immune (anti-HBs and anti-HBc positives), isolated marker (anti-HBs or anti-HBc
      positive), and impregnated group (all the previous situations) were taken into
      consideration. The global prevalence +/- CI 95% for each serological state was
      calculated, and associated factors such as age, sex and professional category
      were studied by means of the prevalence ratio (PR) +/- CI 95%. RESULTS: 1189
      hospital staffers and 341 primary-care workers with majority of women, were
      studied. The hospital group was younger than that of the primary care centres.
      The most frequent professional category was that of nurse in both settings. The
      global prevalence of autoimmmunes was higher in primary care centres (11.1 vs
      9.2), but the number of impregnated subjects was a bit bigger in the hospital.
      The total number of carriers, nevertheless was similar in both settings. The PR
      were higher in men in both settings, and an increase in age was observed in
      almost all serological statuses. Physicians and health workers without probable
      risk where those who presented the highest PR in both settings. We included the
      cleaning employees in the second group. CONCLUSIONS: Although there were not
      great differences in the serological statuses of the staff in both settings, an
      important percentage of immune and impregnated subjects was observed. This
      indicates a previous contact with HBV and the necessity in both sittings of
      vaccination and other available preventive measures.

PMID- 10333607
TI  - [The use of antitubercular drugs in primary care].
AB  - OBJECTIVES: To quantify the consumption of tuberculosis medication prescribed
      through the National Health Service in Spain during 1996. To calculate the
      prevalence of tuberculosis from this consumption. To analyse possible
      inequalities between autonomous communities. To analyse the cost of these drugs.
      DESIGN: A crossover, retrospective and observational study. SETTING: Primary
      care. MEASUREMENTS AND RESULTS: 5533233 DDDs were taken in 1996. 2215890 of these
      DDDs belonged to the rifinah association (rifampicin + isoniazid), followed by
      the active principle rifampicin with 973510 DDDs. Amikacin at 8,078 DDDs
      represented the lowest dose. DID (dose per inhabitant per day) in Spain was 0.37.
      Dosage was greater in Galicia (0.66) and Ceuta (0.52). The Canaries (0.19) and
      Balearics (0.27) were below the national average. Use was 40.05% for rifinah,
      followed by 17.59% for rifampicin. The least common active principles were
      amikacin (0.14%) and streptomycin (0.74%). The number of cases of tubercular
      disease in Spain calculated was 11,211; its prevalence was 27.7 cases per 100,000
      inhabitants. Total medication cost was 863275147 pesetas (0.1% of total
      pharmaceutical expenditure). The attributable cost was rifinah, 40.26%, the
      rifater association, 21.68%, and rifampicin, 18.34%. CONCLUSIONS: The most often
      prescribed drug is the rifampicin + ilsoniazid association. Use varies between
      autonomous communities. We think that the prevalence calculated is high for a
      developed country.

PMID- 10333608
TI  - [The factors that condition the efficacy of and indications for statins in
      cardiovascular prevention].

PMID- 10333609
TI  - [The professional profile of the family physician. The Working Group of the
      Sociedad Espanola de Medicina Familiar y Comunitaria].

PMID- 10333610
TI  - [Do not remain indifferent to temporary incapacity].

PMID- 10333611
TI  - [Evidently, the translation is not the problem].

PMID- 10333612
TI  - [Pharmacoeconomics: a new activity for the drug adviser in primary care?].

PMID- 10333613
TI  - [Family medicine residents and hospital emergencies].

PMID- 10333614
TI  - [The diagnostic classification in mental diseases].

PMID- 10333615
TI  - Acquired scalp alopecia. Part II: A review.
AB  - The neutrophil-associated and infiltrative scarring alopecias are reviewed
      including folliculitis decalvans, tufted folliculitis, dissecting cellulitis of
      the scalp, acne keloidalis and follicular degeneration syndrome. The management
      of acquired scalp alopecia is also reviewed including newer, promising therapies.
      More specific agents targeting components of the androgen system will make the
      treatment of androgenetic alopecia more rewarding. Similarly new immunomodulatory
      therapies show great promise for the lymphocyte-associated alopecias and include
      a new generation of macrolide immunosuppressives (tacrolimus, SDZ ASM 981, and
      SDZ 281-240), some of which appear to have good transcutaneous absorption.

PMID- 10333616
TI  - The descriptive epidemiology of atopic dermatitis in the community.
AB  - Atopic dermatitis (AD) is a common condition in the community, particularly
      amongst children. Although comparison of prevalence data between surveys is made
      difficult by differences in methodology, the available data suggest that there
      has been a substantial rise in the prevalence of AD, and that social,
      geographical and racial variation in disease frequency exists. There is a lack of
      quality data relating to the prognosis of AD. Recently a reliable set of
      diagnostic criteria has been developed and a number of severity scoring systems
      have been proposed for use in epidemiological studies.

PMID- 10333617
TI  - Do people who apply sunscreens, re-apply them?
AB  - Little is known about Australians' practices regarding sunscreen re-application,
      yet it is routinely advised and has recently been shown to increase the
      protective efficacy of sunscreens. A baseline survey of sunscreen application and
      re-application behaviour was therefore conducted in a Queensland community using
      a standard self-administered questionnaire. Other sun protection methods were
      also assessed. Of a total of 669 adult respondents, 76% reported using sunscreen
      and of those, 61% reported re-applying sunscreen. Significantly more women (66%)
      than men (55%) reported re-applying sunscreen and re-application was inversely
      related to age (79% of those aged less than 45, 57% of those 45-59 years old and
      46% of those over 60 years). Increased rates of re-application were reported
      during times of increased sun exposure, as well as by those with greater
      knowledge of the benefits of sunscreen re-application. A recent personal history
      of non-melanoma skin cancer did not lead to improved rates of sunscreen
      application, sunscreen re-application, or most forms of physical sun protection.

PMID- 10333618
TI  - The use of gloves in Australian dermatological practice.
AB  - Dermatologists use gloves as a major tool in universal precautions to prevent
      transmission of infections particularly human immunodeficiency virus (HIV) and
      hepatitis. We need to know how much protection is conferred by gloves and what
      problems are associated with glove use. This paper looks at these issues and
      reports the results of a survey on glove use by Australian dermatologists. The
      survey found a lack of awareness regarding gloves as a protective measure,
      suggesting the need to improve knowledge in this area so that realistic
      precautions can be adopted. Dermatologists have a high rate of glove use and
      reactions to gloves were noted by 13% of respondents. The authors recommend the
      use of non-powdered, low-allergen latex gloves. Handwashing prior to using non
      powdered latex gloves needs further investigation. Handwashing after wearing
      latex gloves may decrease sensitization risk.

PMID- 10333619
TI  - Molluscum contagiosum, swimming and bathing: a clinical analysis.
AB  - The link between swimming and bathing behaviour, and molluscum contagiosum (MC),
      in a sample of 198 patients with clinically confirmed MC was investigated.
      Results show that of all the swimming behaviour variables tested, only one
      (swimming in a school swimming pool) was significant. In relation to the bathing
      variables tested, only two (sharing a bath sponge with a MC-infected person, and
      sharing a bath towel with a MC-infected person), were significant. No
      relationship was found between MC and swimming in a private (home) pool, swimming
      in a public pool, swimming at the beach, sharing a bath tub with a MC-infected
      person, and using a private (home) spa. The Relative Risk (RR) ratio of a person
      sharing a bath sponge with an infected person is three times more at risk of
      procuring a severe case of MC infection (i.e. > 26 lesions) than a person who
      does not share a bath sponge with an infected person (r = 0.5; P < 0.01). There
      was a correlation found between the mode of MC acquisition by site location (r =
      0.63; P < 0.05). The anatomical position of MC lesions was shown to be highly
      dependent on the way the patient was primarily infected. There was also an
      additive effect with the mode of transmission in that patients who were in the
      upper extremes in terms of the total number of lesions (average, 124 lesions;
      mean diameter size, 4.2 mm; n = 42), were those patients who shared a number of
      fomites (bath sponge, bath towel) with a known MC-infected person, and also swam
      at the school swimming pool.

PMID- 10333621
TI  - Oestrogen dermatitis.
AB  - A 56-year-old woman presented with a recurrent itchy eruption mainly involving
      her face and upper trunk for 5 years. The rash flared cyclically 3 days before
      her menstruation and improved 5-10 days after the onset of her period.
      Examination revealed erythematous maculopapules, vesicles and crusting mainly on
      her face and upper trunk. Biopsy from a papule revealed spongiotic dermatitis.
      Intradermal testing with oestrogen was positive. There was marked improvement
      with tamoxifen. Sensitivity to oestrogen and progesterone is rare in women and
      the clinical presentation may be similar. Positive intradermal testing is
      diagnostic. Tamoxifen is effective in treating oestrogen sensitivity.

PMID- 10333620
TI  - Comparison of combination of cimetidine and levamisole with cimetidine alone in
      the treatment of recalcitrant warts.
AB  - Various immunomodulating agents have been used in the treatment of recalcitrant
      warts, but none is uniformly effective. Drugs like cimetidine and levamisole have
      been tried with varying success rates. Given the different target activities of
      immunomodulation by levamisole and cimetidine, we questioned whether the
      combination might be more effective and conducted this double-blind comparative
      trial of a combination of cimetidine and levamisole versus cimetidine alone.
      Forty-eight patients with multiple recalcitrant warts were assigned to two
      treatment groups (A and B) in double-blind fashion. Of the 48 patients, 22 in
      group A and 21 in group B were able to be evaluated. At the end of therapy, cure
      rates obtained were 45.5% (10/21) in cimetidine treated patients (group A) and
      85.7% (18/21) in combination treated patients (group B). A statistically
      significant improvement was seen in patients treated with the combination of
      levamisole and cimetidine (P < 0.01). A similar statistically significant result
      was obtained on using intention to treat analysis (P < 0.02). The rate of
      regression was faster in group B (average regression period of 7 weeks compared
      with 10 weeks in group A). The present study demonstrated that the combination of
      cimetidine with levamisole is more effective than cimetidine alone and is a
      highly effective therapy for the treatment of recalcitrant warts.

PMID- 10333623
TI  - Primary cutaneous nocardiosis.
AB  - A case of primary cutaneous nocardiosis due to Nocardia asteroides occurring in a
      steroid-dependent asthmatic with no history of trauma is presented. He had a 5
      month history of painful nodules on his right shin and calf. He was initially
      treated with a 6 week course of oral cephalexin 500 mg four times daily, followed
      by a 2 week course of minocycline 100 mg twice daily with worsening of the
      infection. A 12 week course of oral clarithromycin 500 mg twice daily led to
      complete resolution. A discussion of the problems associated with antimicrobial
      susceptibility testing and nocardia resistance is presented.

PMID- 10333622
TI  - Radiation-induced localized scleroderma in breast cancer patients.
AB  - Radiation-induced scleroderma in breast cancer patients appears to occur in
      approximately one out of every 500 patients. We report four cases that developed
      within 3 months of conservative breast surgery and postoperative radiation
      treatment. The reaction was contained entirely within the treatment field and
      demonstrated the typical features of this condition where the breast becomes
      erythematous, violaceous, indurated, retracted, and progressively pigmented. The
      breast tends to soften and become more comfortable over 1-4 years; however,
      significant induration, retraction and pigmentary changes remain. There appears
      to be no predictive factors. Radiation-induced scleroderma must be differentiated
      from cellulitis and recurrent breast cancer.

PMID- 10333624
TI  - Primary tuberculosis of the glans penis.
AB  - A 60-year-old man presented with multiple superficial ulcers on the glans penis.
      Histopathology, a positive tuberculin test result, and therapeutic response to
      antituberculous therapy confirmed the diagnosis of penile tuberculosis.
      Examination was otherwise normal except for a solitary enlarged reactive lymph
      node on the right side. There was no evidence of coexistent tuberculous infection
      elsewhere.

PMID- 10333625
TI  - Acquired perforating dermatosis in diabetes mellitus: an unusual case.
AB  - A case of elastosis perforans serpiginosa in a patient who presented with insulin
      dependent diabetes mellitus secondary to pancreatic insufficiency in a background
      of common variable immunodeficiency and endocrinopathy, as evidenced by
      pernicious anaemia and growth hormone deficiency, is described. In acquired
      perforating dermatosis occurring in patients with diabetes or renal failure,
      there is a spectrum of changes that may show an overlap of histological features
      of the four classic perforating diseases. The biopsy changes of the patient
      described in the present study most closely resembled those of elastosis
      perforans serpiginosa.

PMID- 10333626
TI  - Cardiofaciocutaneous (CFC) syndrome.
AB  - An 11-year-old boy affected by mental retardation and seizures demonstrates
      congenital heart defect, many dysmorphic features and dry skin. His hair is
      sparse over the vertex with alopecia of the eyebrows and eyelashes. There are
      horny small papules evident in those areas. The diagnosis of cardiofaciocutaneous
      syndrome has been made. The relationship between cardiofaciocutaneous and Noonan
      syndrome is discussed.

PMID- 10333627
TI  - Necrobiotic xanthogranuloma with paraproteinaemia.
AB  - A 51-year-old woman developed multiple periorbital nodules. The subsequent
      demonstration of IgG lambda paraproteinaemia and the histological features of
      necrobiotic xanthogranulomatous inflammation confirmed the clinical diagnosis of
      necrobiotic xanthogranuloma with paraproteinaemia.

PMID- 10333628
TI  - Reactions causing reactions: allergic contact dermatitis to an isocyanate
      metabolite but not to the parent compound.
AB  - Industrial use of isocyanate resins rarely causes allergic contact dermatitis. We
      report a patient who developed allergic contact dermatitis to a transitory
      chemical breakdown product of the isocyanate 4,4'-diphenylmethane diisocyanate
      (MDI), diaminodiphenylmethane (DDM), although he was not sensitized to the
      suspected parent compound MDI.

PMID- 10333629
TI  - The subgaleal pulley suture.
AB  - The repair of scalp defects is often complicated by moderate tension on the wound
      edges. A subgaleal version of the 'pulley' suture, which may be helpful in
      closing wounds in this setting, is described.

PMID- 10333630
TI  - Unusual reactions to paint-on tattoos.

PMID- 10333631
TI  - Positive para-phenylene diamine (PPD) reactions following paint-on tattoos.

PMID- 10333632
TI  - Collecting a verbal history.

PMID- 10333633
TI  - Overcoming failed local anaesthesia.

PMID- 10333634
TI  - Complete denture quality.

PMID- 10333635
TI  - Electronic dental discussion lists.

PMID- 10333636
TI  - Are graduates as good as they used to be?
AB  - A theme runs through discussions on dental undergraduate education, that 'they
      are not as good as they used to be'. Based largely on anecdotal evidence, we
      question whether this is true. Dentistry is changing. Today's graduates are
      different, but not worse. Graduates must qualify with basic competencies--agreed
      between all those responsible for their education. We maintain that vocational
      trainers are teachers, just as we are, and as such they have similar
      responsibilities. Close liaison between training practices and dental schools is
      essential.

PMID- 10333637
TI  - Adhesive techniques.
AB  - This paper describes the use of adhesive techniques to restore teeth previously
      affected by tooth surface loss so avoiding the need to remove sound tooth tissue.

PMID- 10333639
TI  - Direct referral day case oral surgery for dental practitioners: a pilot
      investigation.
AB  - Direct referral of patients for day case surgery by general medical practitioners
      (without hospital assessment) has become widely accepted but few facilities exist
      for this form of referral from general dental practice. In order to evaluate
      whether direct access day surgery is applicable to dentistry, the quality of
      referral by GDPs and hospital consultant clinics was compared in a prospective
      study (1994-1997) involving 1581 patients.

PMID- 10333638
TI  - The development of resin-bonding for amalgam restorations.
AB  - Adhesive techniques are now used for many dental restorative materials, including
      amalgam. Several generations of dentine bonding agents have been developed,
      mainly for bonding composite resins. When bonding is used with amalgam
      restorations, the need for retention and resistance form is reduced, the seal is
      improved, and some procedures, such as amalgam sealants, which were not
      previously possible, can be considered.

PMID- 10333640
TI  - Aspects of panoramic radiography in general dental practice.
AB  - OBJECTIVES: To gather information on the types of panoramic x-ray equipment used
      in NHS dental practice and whether dentists satisfy the legal requirements for
      safety, to determine which practice personnel take panoramic radiographs and to
      assess the prevalence of the practice of 'routine' panoramic radiography among
      NHS dentists. DESIGN: Postal questionnaire survey of general dental practitioners
      carried out during 1997 in selected FHSAs in England and Wales. RESULTS: 542
      dentists returned the questionnaire, a 73.3% response. Panoramic x-ray equipment
      ranged in age from 27 years old to new, with 42.2% exceeding 10 years in age. The
      overwhelming majority of GDPs satisfied the requirement for regular maintenance
      and surveying of equipment. Almost all dentists (95.9%) performed a history and
      clinical examination prior to panoramic radiography but 42% practised 'routine
      screening' of new adult patients. A substantial proportion (36.7%) of dentists
      used unqualified personnel to take panoramic radiographs. CONCLUSIONS: While some
      aspects of this study give reassurance about the prevalence of good practice,
      widespread panoramic screening and using unqualified staff to take radiographs
      causes concern. These findings have implications for educators and for those
      involved in maintaining clinical standards.

PMID- 10333641
TI  - Barriers to the use of a diagnostic oral microbiology laboratory by general
      dental practitioners.
AB  - OBJECTIVE: To identify barriers on the use of diagnostic microbiology facilities
      in general dental practice. DESIGN: A cross-sectional survey using a postal
      questionnaire. SETTING: Primary/secondary care interface between the diagnostic
      oral microbiology laboratory, University of Glasgow Dental Hospital and School,
      Glasgow and dental practitioners within the surrounding health boards, 1998.
      SUBJECTS: All GDPs (797) within Argyll and Clyde, Ayrshire and Arran, Lanarkshire
      and Greater Glasgow Health Boards. MAIN OUTCOME MEASURES: The responses were
      expressed as both absolute and relative frequencies. RESULTS: Responses were
      received from 430 (55%). The most frequent reason for failure to use the service
      was lack of information, with more than half of the respondents claiming to be
      unaware of the facility. Lack of request forms and sampling equipment were also
      viewed as barriers to using the service. CONCLUSIONS: The laboratory is failing
      to successfully communicate its role in addressing the growing burden of
      antibiotic resistance in the community and must be more proactive in encouraging
      appropriate use and increasing accessibility of the service to GDPs.

PMID- 10333642
TI  - Relating personality to interview results and performance in the first year of
      the dental course.
AB  - The aim of this paper is to relate personality measures of Year 1 undergraduate
      dental students to their performance at admissions interview and during the first
      year of their course. The personality profiles of 58 first year dental students,
      were statistically related to results of the first year examinations and to the
      results of 54 of the students' structured admissions interviews. A relationship
      was found to exist which related personality to interview results and performance
      in the first year of their dental course.

PMID- 10333643
TI  - [Familial eosinophilia: contribution of parasitology to its diagnosis].
AB  - It has been observed, at the turn of the century, that members of some families
      showed a peripheral blood hypereosinophilia. Despite all possible investigations
      at that time, it was not possible to link it up with a known and well established
      disease. It was named "family acquired eosinophilia" by Di Guglielmo. nowadays,
      it has been established that some congenital defects such as the Omenn syndrome
      and the Wiskott-Aldrich syndrome are associated with hypereosinophilia.
      Eosinophilia is well known as a sign of allergy, but contaminations with
      helminths are an important cause of familial hypereosinophilia. In a case of
      familial distomatosis by Fasciola hepatica, several members of the same family
      were infected after eating wild cress. An epidemiological study was carried out
      on 22 families whose several members in a same family had an hypereosinophilia, a
      parasitosis was serologically diagnosed using such methods as
      immunoelectrophoresis, Elisa or Western blot. Among these 22 families, 10 had
      contracted fascioliasis and 4 who had eaten contaminated horse meat contracted
      trichinosis. For some other families, eosinophilia was not well documented, it
      concerned cysticercosis for 3 couples after eating meat of raw pork, one family
      with intestinal distomatosis to F. buski after consumption of aquatic plants and
      lastly toxocarosis, zoonosis whose contamination is acquired by geophagy but also
      by eating raw vegetables (salad), fruit (strawberries) and by drinking
      contaminated water, affected 5 families. In one family, anisakiasis with
      hypereosinophilia had been contracted by eating raw fish. In another one,
      trichostrongyloidiasis was contracted by eating raw vegetables from the family
      garden. The diagnosis is often oriented, for the members of a same family, who
      are asymptomatic or pauci-symptomatic, by the blood cell count that shows an
      hypereosinophilia. Furthermore, a collective outbreak of strongyloidiasis
      epidemic among 115 individuals by oral route is reported, showing that such a way
      of transmission is possible.

PMID- 10333644
TI  - [Aberrant expression of the GIP (Gastric Inhibitory Polypeptide) receptor in an
      adrenal cortical adenoma responsible for a case of food-dependent Cushing's
      syndrome].
AB  - A 33 year old woman was investigated for an atypical case of Cushing's syndrome
      with suppressed early morning plasma cortisols. Chronic hypercortisolism was
      confirmed by classical biological criteria (24 h urinary cortisol excretion,
      dexamethasone suppression tests); more detailed dynamic and pharmacological tests
      revealed unanticipated features: spontaneous circadian plasma cortisol variations
      showed post prandial peaks; they could be induced by oral--but not intravenous-
      glucose tolerance tests, and were inhibited by the concomitant administration of
      Sandostatin (a somatostatin analog). Adrenal CT scan identified a 2 cm unilateral
      adenoma with ipsilateral and contralateral atrophy. Surgical removal of the tumor
      cured the hypercortisolism with hypocortisolism. Comparative analysis of the
      tumoral and normal tissues showed that only the former responded in vitro to GIP
      (Gastric Inhibitory Polypeptide) and contained the specific mRNA of the GIP
      receptor. This case illustrates a new pathophysiological mechanism of
      tumorigenesis due to the aberrant expression of a seven transmembrane domain
      receptor in a tumoral tissue. The nature of the given receptor induced a
      particular clinical phenotype related to food intake.

PMID- 10333646
TI  - Escherichia coli O157 associated with eating unpasteurised cheese--update.

PMID- 10333645
TI  - [Development of a model which makes it possible to test injectable bone
      substitutes and evaluation of a calcium phosphate cement].
AB  - New percutaneous filling techniques are beginning to be used in bone tumor
      pathology. The purpose of this study was to develop a reproducible model for
      testing new injectable bone substitutes. A closed cancellous bone defect was
      created in the distal femoral condyles of rabbit. Bone defect was filled by a
      percutaneous injection. Several situations were tested: spontaneous evolution of
      unfilled cavities, evolution of cavities filled either with a conventional
      orthopedic cement (PMMA), either with a mixed collagen-hydroxyapatite material,
      either with a biomaterial derived from the vegetal protein zein, either with a
      calcium phosphate cement brushite type. The new bone formation was quantified in
      the defect for each group in which several delays were tested. A bone defect of
      reproducible size was obtained consistently. A partial bone formation was
      observed in the unfilled group. The best bone formation rate was obtained in the
      phosphate cement group. This model showed the interest of injectable biomaterials
      and more precisely the interest of the phosphate calcium cements as brushite.

PMID- 10333648
TI  - Overview of communicable diseases 1999.

PMID- 10333647
TI  - Avian strain of influenza A virus isolated from humans in Hong Kong.

PMID- 10333649
TI  - The effects of maternal-child health service utilization on subsequent
      contraceptive use in Morocco.
AB  - There are a number of reasons for anticipating that contact by women in
      developing country settings with modern maternal-child health (MCH) services will
      lead to increased use of family planning services. Indeed, the expectation of
      such a relationship underlies the integrated service delivery strategy that has
      been adopted on a more or less global basis. However, the available empirical
      evidence in support of this proposition is inconclusive. This study re-examines
      this issue in Morocco. Household survey data and data on the supply environment
      for health and family planning services gathered in 1992 are analysed in the
      study. A full-information maximum likelihood estimator is used to control for the
      possible endogeneity of health care and contraceptive choices. The findings
      indicate a substantial and apparently causal relationship between the intensity
      of MCH service use and subsequent contraceptive use. Policy simulations indicate
      that sizeable increases in contraceptive prevalence might be realized by
      increasing the coverage and intensity of use of MCH services.

PMID- 10333650
TI  - Probabilities of marriage in two outer Hebridean islands, 1861-1990.
AB  - A study has been made of the probabilities of marriage of females and males aged
      15-49 (either as a whole or in 5-year age groups) in two Outer Hebridean islands,
      Harris and Barra. The results were compared with ages of marriage and with the
      frequencies of permanent celibacy. The marriages took place between 1861 and
      1990. Median ages of marriage rose to maxima in the 1930s and 1940s, then fell
      steeply, levelling out latterly. Permanent celibacy was consistently high among
      females, but rose from much lower levels in males to maxima in the 1970s and
      1980s. It is concluded that in these populations age at marriage and the extent
      of permanent celibacy are largely independent of one another. In both islands the
      overall probabilities of females marrying fell until the 1920s, and then rose.
      The last decades showed stability (Barra) and a fall (Harris). Males showed only
      slight falls to about 1910; data were absent for between 1911 and 1960, but
      subsequently there was little rise in probability. These overall changes seemed
      to be associated with reciprocal variations in probabilities in the younger and
      older age groups. Declining overall probabilities were associated with declines
      in younger and increases in older age-group probabilities, and vice versa. Non
      parametric correlations between median ages of marriage and probability of
      marriage were negative and generally significant for the 15-19 age group. Among
      the older age groups coefficients were generally positive. There was some
      evidence of an association between probability of marriage and sex ratio in any
      group of potential mates. The effect appeared more marked among 15- to 19-year
      old females. Local factors which might explain at least part of the decline in
      nuptiality for the greater part of the period under study include the decline in
      the fishing industry and the 'land hunger' which existed until the late 1920s.
      This decline is interpreted as a 'Malthusian' response to economic and social
      conditions, but it coexisted with a 'neo-Malthusian' strategy, in the shape of
      declining marital fertility. The 'Malthusian' strategy seems to have been largely
      abandoned around the 1950s, but it may have reappeared during the 1980s.

PMID- 10333651
TI  - Beliefs about children's illness.
AB  - Beliefs about child illness were investigated using semi-structured interviews
      with mothers and providers in four rural Guatemalan communities. The two most
      common forms of child illness in Guatemala--diarrhoea and respiratory disease-
      were focused upon. These illnesses are particularly difficult to prevent and
      treat, especially with the rudimentary health services available in rural areas
      of developing countries. Comparisons with other ethnographic studies in Guatemala
      suggest that some traditional models of illness causation identified in these
      earlier investigations are relatively unimportant in the communities studied
      here. This finding, in conjunction with frequent responses related to hygiene and
      water, suggests that traditional explanations may be co-existing with biomedical
      views of illness causation to a greater degree today than in the past.

PMID- 10333652
TI  - Lateralized ultradian rhythms of the right and left brain: temporal variations of
      tactile discrimination tested in German subjects.
AB  - Endogenous ultradian rhythms with a periodicity of 2-3 hours operate separately
      in the right and left hemispheres of the human brain and modulate physiological
      functions, perception and cognition. Since sensory pathways from either hand
      terminate in the contralateral hemisphere, ultradian rhythms of the right and
      left brain can be monitored by variations in the tactile discrimination of the
      left and right hand, respectively. Thirteen right-handed German males were tested
      every 15 minutes for 8 hours. Time series of the tactile error rate determined
      for the right and left hands oscillate with significantly different ultradian
      periodicities. Whereas cycles in tactile discrimination of the right hand (left
      hemisphere) have a periodicity of about 2 hours, tactile discrimination of the
      left hand (right hemisphere) is modulated by longer periods of about 3 hours.
      This is interpreted in terms of the overall functional asymmetry of the human
      brain. Since the left brain is the specialized locus for verbal processing and
      the right brain for visual-spatial processing, lateralized ultradian rhythms
      operating in the hemispheres may provide a distinct frame for long-term timing of
      neuronal processes underlying semantic and spatial mapping of the environment.
      This is particularly important for interpreting biosocial behavioural rhythms
      seen in humans living under natural conditions.

PMID- 10333653
TI  - Lateralized ultradian rhythms in time and space: a chronobiological field study
      in Kenyan Maasai.
AB  - Lateralized ultradian rhythms oscillating separately in the right and left
      hemispheres of the human brain can be monitored by variations in the tactile
      discrimination of either hand. A previous study in male German subjects has shown
      that the tactile error rates determined for the right and left hands oscillate
      with significantly different periodicities. In the present study, a group of
      Kenyan Maasai shepherds was tested while the subjects were leading herds on daily
      feeding routes. The Maasai exhibit considerable ultradian rhythms of about 2
      hours in tactile error rates of either hand, but in contrast to the German
      subjects there is no significant difference between the right and left side.
      While an individual is en route, his hemispheres proceed through alternating
      states in matching segments of the path. Ultradian rhythms thus 'scan' not only
      the time of day but also the space, and might provide an intrinsic time-frame for
      neuronal processes of cognitive mapping.

PMID- 10333654
TI  - Insurance ovulation, embryo mortality and twinning.
AB  - The 'insurance ova' hypothesis (Anderson, 1990) views dizygotic twinning as a by
      product of selection for multiple ovulation which sometimes--in error--results in
      the birth of twins. From this viewpoint, polyovulation is a mechanism which
      reduces the risks of fertilization failure or embryo defect/mortality. If DZ twin
      births are a 'side-effect' of a mechanism which compensates for defective embryos
      one might predict that embryo defect rates and twinning rates will covary. This
      prediction is tested using national-level data on twinning rates and rates of
      trisomy-21 (Down's syndrome), and a strong positive correlation is found, even
      when controlling for maternal age. One suggestion that follows from this finding
      is that intra- and interpopulation variation in both twinning rates and Down's
      syndrome rates may result, in part, from individual variation in pre-implantation
      rejection of embryos in the very early stages of pregnancy. In this paper it is
      proposed that the 'insurance ova' explanation for twinning in humans could be
      expanded to incorporate a model of rejection of anomalous embryos, be they
      anomalies of number or type. Variation in the efficiency of an embryo rejection
      mechanism, combined with variation in frequency of polyovulation, would have
      consequences for individual reproductive success.

PMID- 10333656
TI  - Positive and negative life changes and LDL cholesterol.
AB  - Epidemiological studies have revealed that stressful changes in social
      environment increase the risk of cardiovascular mortality. In this study, the
      influence of major negative and positive life changes on serum cholesterol was
      examined in middle-aged men to determine a possible biochemical link between life
      changes and cardiovascular mortality. The results showed no influence of negative
      life changes on serum cholesterols. However, positive life changes significantly
      predicted a reduction in total and LDL (low-density lipoprotein) cholesterol
      levels after adjustment for the baseline cardiovascular health status, baseline
      cholesterol level, diet, body mass index, waist-to-hip ratio and
      cardiorespiratory fitness. The odds ratio for lowering LDL cholesterol was 5.2 in
      the men reporting positive events compared with those reporting none. The
      findings suggest a predictive value of positive life changes for atherogenic
      lipid profile in middle-aged men.

PMID- 10333655
TI  - Secular trend in age at menarche in China: a case study of two rural counties in
      Anhui Province.
AB  - There is increasing evidence that age at menarche has decreased in Europe and the
      United States during the last century and in Japan over the last several decades.
      Data from a community-based survey conducted in two rural counties of Anhui
      Province in China indicate a similar, downward secular trend in age at menarche
      for Chinese women. The present study shows the mean age at menarche decreased by
      2.8 years, from 16.5 to 13.7, over an approximate 40-year time interval. This
      rapid decrease in age at menarche may partly be due to better nutrition and
      living standards reflected by the improved socioeconomic standards experienced in
      China over the past few decades. To test this hypothesis, a number of
      determinants of age at menarche were assessed; year of birth, literacy status,
      county of residence, amount of physical labour, general health status, pesticide
      exposure before age at menarche, and drinking water source were all found to be
      associated with age at menarche.

PMID- 10333657
TI  - The hierarchical genetic structure of an urban town, Kidlington, Oxfordshire,
      examined by the coefficient of relationship by isonymy.
AB  - The surnames of the 3443 males registered to vote in Kidlington in 1977 yield a
      Coefficient of Relationship by Isonymy of 0.000564 {Ri = sigma(n(n-1))/2 N(N-1),
      in which n = the number of men of each surname and N = sigma n}. Those of the
      four wards separately average 0.000722. However, if one includes only one male of
      any one surname in each residence, the values are, respectively, 0.000534 and
      0.000535. That is, the only structure seen between the two levels is in the
      influence of men of the same surname resident in the same house. An analysis of
      relationship by residence on the same street yields a value of Ri somewhat higher
      than that for the ward as a whole, however, suggesting that even within a ward
      there may be a tendency for the house of relatives occasionally to lie close
      together.

PMID- 10333658
TI  - Palliative care Canada 1999--a question period.

PMID- 10333659
TI  - Terminal HIV disease and extreme poverty: a review of 307 home care files.
AB  - This retrospective study of 307 patients with advanced HIV disease residing in
      downtown Montreal was carried out to examine the nature and consequences of the
      services they received according to their degree of poverty. The findings showed
      that, between 1 April 1991 and 31 March 1997, patients living in extreme poverty
      were more likely to complain of uncontrolled pain during the final week of home
      visits and were more likely to die in hospital than were their more financially
      secure counterparts. This held true even though the poorer group had a similar
      clinical profile at diagnosis and were provided with practically the same
      services. Thus there is a need to seek better understanding of the nature of
      palliative care services offered to underprivileged clienteles and to see if the
      services now provided are adequately adapted to the specific needs of
      impoverished patients.

PMID- 10333660
TI  - A profile of bereaved caregivers following provision of terminal care.
AB  - Caregivers are often overwhelmed by the strain of terminal caregiving. We wished
      to better understand the needs of terminal caregivers and to supply a basis for
      tailoring interventions to them during caregiving and early bereavement. This
      report provides a profile of 124 bereaved caregivers interviewed within three
      months of their patient's death. Three quarters were female and married to the
      patient. Four major areas were assessed: psycho-spiritual, personal-social,
      health status, and financial status. Caregivers reported higher than average
      depressive symptomatology (mean CES-D = 17.6), moderate levels of positive
      outlook, low negative reactions to caring, and relatively high levels of
      spirituality. Caregivers were highly involved in their patient's activities of
      daily living, providing an average of 10.8 hours/day of direct care and 8.9
      hours/day of companionship. Caregivers reported low utilization of health
      services and relatively high personal health status. 45% of the sample reported
      lower income since the patient's death and 44% reported out-of-pocket expenses
      not covered by insurance. Suggestions for interventions that target emotional,
      physical, and financial concerns are discussed.

PMID- 10333661
TI  - Comparison of palliative care needs of English- and non-English-speaking
      patients.
AB  - This study examined whether patients who are not fluent in English receive less
      than optimal palliative care. The subjects were 130 consecutive patients (24 non
      English speakers, NE, and 106 English speakers, E) with advanced malignant
      disease who were admitted to three metropolitan-area hospitals and followed for 6
      months or until death. 92% of patients who were unaware of their diagnosis were
      NE. Control of non-pain symptoms was worse for NE patients than for E patients
      during their last two months. There was an increased prevalence of mood
      disturbance in NE patients during their first two months in the study. Of the 102
      (83 E, 19 NE) patients who died during the study period, no NE patients died at
      home. These results suggest that patients not fluent in English received less
      optimal palliative care. Communication of the diagnosis and prognosis requires
      the cooperation of the patients' families as well as the use of professional
      interpreters. Further research is necessary to identify the differences in
      cultural attitudes that may have contributed to these findings.

PMID- 10333662
TI  - End-of-life decision making among Aboriginal Canadians: interpretation,
      mediation, and discord in the communication of "bad news".

PMID- 10333663
TI  - A preceptor model for introducing undergraduate medical students to palliative
      medicine.

PMID- 10333664
TI  - A model for delivery of palliative care in India--the Calicut experiment.

PMID- 10333665
TI  - Hospice Uganda: 1993-1998.

PMID- 10333666
TI  - Is this patient palliative?

PMID- 10333667
TI  - Organ and tissue donation and transplantation.

PMID- 10333668
TI  - Breast cancer screening in underserved women in the Bronx.
AB  - This article reports the results of mammography screening among socioeconomically
      disadvantaged women in Bronx, NY using a federally funded low-cost or no-cost
      cancer screening service. The New York State Department of Health provided funds
      for the uninsured through the Bronx Breast Health Partnership. All women < or =
      40 years underwent screening mammography using both a mobile van unit and
      hospital-based mammographic x-ray unit, both American College of Radiology (ACR)
      accredited. Return visits were coordinated by a follow-up clinic at Montefiore
      Medical Center using a patient navigator who acted as an advocate for patients
      with abnormal screening findings. The overall detection rate of 12.9 per 1000
      women screened was significantly higher than the New York State detection rate of
      6 per 1000 and 5.1 per 1000 nationally. Availability of a patient navigator was
      an essential factor in the effectiveness of the work-up of problem cases. Low
      cost or no-cost breast cancer screening programs can improve the availability,
      accessibility, acceptability, and utilization of mammography among underserved
      and uninsured women who are least likely to be screened otherwise.

PMID- 10333669
TI  - Racial bias in federal nutrition policy, Part II: Weak guidelines take a
      disproportionate toll.
AB  - Many diet-related chronic diseases take a disproportionate toll among members of
      racial minorities. Research shows the prevalence of diabetes, hypertension,
      cancer, and heart disease is higher among various ethnic groups compared with
      whites. The Guidelines and the Food Guide Pyramid, however, promote the use of
      multiple servings of meats and dairy products each day and do not encourage
      replacing these foods with vegetables, legumes, fruits, and grains. The Dietary
      Guidelines for Americans encourage a 30% caloric reduction in fat intake and make
      no provision for further reductions for those who wish to minimize health risks.
      Abundant evidence has shown that regular exercise combined with diets lower in
      fat and richer in plant products than is encouraged by the Dietary Guidelines for
      Americans are associated with reduced risk of these chronic conditions. While
      ineffective Dietary Guidelines potentially put all Americans at unnecessary risk,
      this is particularly true for those groups hardest hit by chronic disease.

PMID- 10333670
TI  - Seroprevalence of herpes simplex virus-type 2 in African-American college women.
AB  - This study examines the relationship between sexual behaviors and prevalence of
      herpes simplex virus-type 2 (HSV-2) among African-American college women.
      Subjects (n = 138) were recruited randomly from a state university to participate
      in a study regarding sexual attitudes and behaviors and to have their blood drawn
      for type-specific HSV seroprevalence. Sera were analyzed for 96 college women
      with a mean age of 21 years. Of the 96 women, 29 (30%) were HSV-2 seropositive.
      The results of this study revealed that a history of sexually transmitted disease
      was predictive of HSV-2 infection. Number of lifetime partners, however, was not
      related to HSV-2 seropositivity. Four (31%) of the 13 women who reported only one
      lifetime partner were seropositive. These findings indicate that for young
      African-American college women, the risk of being infected with HSV-2 is high
      even with only one lifetime partner. Behavioral strategies focused on decreasing
      the number of sexual partners are not likely to be sufficient in preventing the
      spread of HSV-2 infection among young African-American women. The development and
      use of alternative approaches to prevent the spread of HSV-2 among young African
      Americans should be considered.

PMID- 10333671
TI  - Marfan syndrome and sudden death.

PMID- 10333672
TI  - Minimally invasive parathyroidectomy utilizing a gamma detecting probe
      intraoperatively.
AB  - The most common pathologic finding in primary hyperparathyroidism is a single
      adenoma. Traditionally, all four glands have been explored during surgery for
      primary hyperparathyroidism. With the advent of accurate localizing diagnostic
      studies, such as the sestamibi scan, some surgeons are now recommending single
      gland exploration. In addition, when a sestamibi scan is performed the day of
      surgery, a gamma detecting probe can be used intraoperatively to direct the
      dissection. Although an experienced surgeon will successfully locate the abnormal
      gland 95% of the time with the traditional approach, this new technique results
      in a smaller incision with better cosmetic results as well as decreased operative
      time. Our initial experience with eight cases utilizing this technique is
      presented.

PMID- 10333673
TI  - Posterior mediastinal mass in a young male with chronic hepatitis B infection.

PMID- 10333674
TI  - The impact of a geriatrics evaluation and management unit compared to standard
      care in a community teaching hospital.
AB  - A prospective, controlled trial was initiated to determine whether an acute
      inpatient geriatrics unit located in a community-based teaching hospital provides
      better care for frail elderly patients at less cost than conventional medical
      surgical units.

PMID- 10333675
TI  - Incidence rates of Lyme disease in Maryland: 1993 through 1996.
AB  - The incidence rate per 100,000 population by gender and age group was calculated
      for the 24 Maryland jurisdictions using 1,392 cases reported to the Lyme Disease
      Registry during 1993 to 1996. The overall incidence rate for the state was 7.0
      cases per 100,000 inhabitants. Males (incidence rate = 7.7) were 1.2 times more
      affected than females (incidence rate = 6.2) (p < 0.001). The bimodal overall age
      distribution shows a peak in the 10 to 19 age category (incidence rate = 8.5) and
      in the 50 to 59 age group (incidence rate = 8.9), and in the 20 to 29 age group
      (incidence rate = 3.9). The incidence rate by jurisdiction ranged from 0.7 in
      Allegany County from Western Maryland to 88.3 in Kent County on the Upper Eastern
      Shore. Results from this study show that counties from the Upper Eastern Shore
      region had the highest specific incidence rate by age group/gender/jurisdiction
      while counties from Western Maryland had the lowest specific incidence rates and
      have not reported Lyme disease patients younger than 10 or older than 59 years of
      age. This difference might be explained primarily by the kind of outdoor
      activities in which the different age groups are involved and the relative
      abundance of Ixodes scapularis infected with the etiologic agent of Lyme disease,
      Borrelia burgdorferi, in these two regions.

PMID- 10333676
TI  - A 70-year-old man with atrial fibrillation and stroke.

PMID- 10333677
TI  - Emergency open heart surgery under World War II combat conditions.

PMID- 10333678
TI  - Let's get the lead out.

PMID- 10333679
TI  - Boxing and the fight to ban it.

PMID- 10333680
TI  - Radiology quiz. Horseshoe kidney.

PMID- 10333681
TI  - Erythema chronica migrans (ECM). Ticks and Lyme disease in Missouri.

PMID- 10333682
TI  - A multi-station hip joint simulator study of the performance of 22 mm diameter
      zirconia-ultra-high molecular weight polyethylene total replacement hip joints.
AB  - The commissioning of a new form of 10-station hip joint simulator is described
      and the results of a study of the performance of zirconia-ultra-high molecular
      weight polyethylene (UHMWPE) total replacement hip joints in the familiar
      Charnley head size of 7/8 inch (22.225 mm) diameter are presented. The head size
      is referred to as 22 mm for brevity and consistency throughout the paper. The
      simulator provided very consistent and repeatable results and the new machine,
      together with the methods of investigation adopted, offer an excellent facility
      for the further evaluation of existing and new prostheses. The findings are
      compared with the outcome of previous laboratory simulator and clinical studies
      of ceramic-polyethylene implants of similar diameter. It was found that a
      relatively rapid penetration of the head into the cup was followed by a very low,
      steady, long-term penetration rate after about two million loading cycles. The
      mean long-term volumetric penetration rate was 6.28 mm3/10(6) loading cycles.
      When the linear penetration rates were assessed by direct measurement on a
      coordinate measuring machine, or deduced from the tunnelling expression, the
      resulting values were very similar and small at 0.019 and 0.016 mm/10(6) loading
      cycles respectively. It is generally assumed that one million loading cycles is
      equivalent to about one year of service in the body and if this equivalence is
      accepted, these penetration rates compare very favourably with a clinical
      evaluation of alumina heads of the same diameter, which yielded a mean long-term
      penetration rate of 0.022 mm/year.

PMID- 10333683
TI  - Estimation of blood perfusion using ultrasound.
AB  - Ways to measure blood perfusion using ultrasound techniques such as continuous
      wave Doppler, pulsed Doppler, colour Doppler and power Doppler will be reviewed.
      From a certain standpoint, blood perfusion may be defined as the difference
      between arterial inflow and arterial outflow from a considered volume, i.e.
      capillary flow. The low velocities and small blood volumes involved make the
      signal-to-noise ratio, dynamic range and frequency resolution critical factors in
      the detection system. Another limiting factor is tissue motion which obscures the
      blood signal. Perfusion may still under certain conditions be estimated with the
      first moment of the Doppler power spectrum, as obtained with any Doppler
      ultrasound method. Modern flow mapping techniques also make it possible to
      estimate perfusion by counting the number of pixels that indicate flow, but low
      flow velocities cannot be included in the estimate. Future high-frequency systems
      may, however, provide very detailed images of minute flow distributions in
      superficial layers. Contrast agents are widely used today to enhance the blood
      signal, and a technique named harmonic imaging can suppress movement artefacts
      from surrounding tissue. Transient signals from disrupting contrast agent
      particles in an ultrasound field can potentially be used for perfusion
      quantification. Future developments to extract the blood flow signal from its
      noisy environment, aside from contrast agents, may be multiple sample volumes,
      frequency compounding and/or improved signal processing. The lack of an adequate
      perfusion phantom for verification of measurements of microcirculatory flow
      becomes, however, more apparent with improved detectability of slow flows.

PMID- 10333684
TI  - A review of metallic, ceramic and surface-treated metals used for bearing
      surfaces in human joint replacements.
AB  - A review of established and advanced materials used for the bearing surfaces of
      total hip replacements (THRs), their standards, methods of manufacture and
      corrosion testing is presented. Some account is also taken of parallel
      developments in femoral components used in total knee replacements (TKRs).
      Metallic, ceramic and surface-modified metallic materials are separately
      reviewed, but wherever possible common practices are collated. Coated implant
      bearing surfaces are in an advanced state of development and some designs are
      receiving clinical evaluation. To date, however, no standard methods of
      manufacturing and testing these materials have been agreed. Accordingly,
      corrosion and other key quality test methods suitable for surface-modified
      implant bearing materials are reviewed.

PMID- 10333685
TI  - The effects of design and configuration on the biomechanical response of an
      internal spinal fixator.
AB  - This study examines the biomechanical performance of an internal spinal fixator
      and the effects of specific design features under a range of loading modes. The
      commercial device was mounted on plastic vertebrae in a corpectomy injury model
      and attached by a series of experimental jigs to an appropriate material testing
      machine and tested under axial compression, torsion and flexion and extension
      moments. Results from the torsional tests indicated that increasing the clamp
      tightening torque from 5 to 15 N m significantly increased the rigidity of the
      fixation system. The inclusion of the transverse elements resulted in a
      significant increase in the torsional stiffness, with the increase largely
      overriding the effect of clamp tightening torque. By contrast, under compressive
      and both flexion and extension loads, neither of the design features of the
      fixator had a marked effect on the overall measured stiffness of the system.
      However, under extension loads, there were specific interactions between the two
      design parameters. The present study clearly indicates the need for the
      optimization of the design of the clamps and for alternative configurations of
      the transverse elements to enhance their performance under sagittal loads.

PMID- 10333687
TI  - The influence of lubricant on the morphology of ultra-high molecular weight
      polyethylene wear debris generated in laboratory tests.
AB  - Since the implication of polyethylene wear debris as a major cause of osteolysis
      in total joint replacements, there has been much interest in polyethylene wear
      studies and in cell culture studies using ultra-high molecular weight
      polyethylene (UHMWPE) wear debris. Studies have shown that particles in the 0.1
      10 microns size range are particularly important in causing adverse cellular
      reactions resulting in osteolysis. The morphology, the mass and size
      distributions, and the number of wear particles produced at the joint surfaces
      are influenced by the tribological conditions at the joint. Laboratory wear tests
      are used to investigate the wear properties of prosthetic joint materials and
      different research groups have used different lubricants in these tests. This
      paper shows that the volumetric wear and morphology of UHMWPE particles generated
      in vitro are influenced by the type of lubricant used. This study compared,
      quantitatively, UHMWPE wear debris generated in deionized water to debris that
      was generated in a system lubricated by bovine serum which was diluted to 25 per
      cent. The wear factors of UHMWPE in water and serum lubricants were significantly
      different (p < 0.05). UHMWPE wore 14 times more in water than in serum.
      Quantitative analysis of the wear particles showed that the debris that was
      generated in serum was morphologically different from debris that was produced in
      a water-lubricated system. Furthermore, the particles produced in serum showed a
      closer similarity to those found in retrieved acetabular tissues.

PMID- 10333686
TI  - The role of acetabular component screw holes and/or screws in the development of
      pelvic osteolysis.
AB  - Anecdotal reporting of osteolysis around cementless modular acetabular components
      with holes through the metal shell and/or iliac fixation screws has raised
      concern that such designs may generate excessive particulate debris and/or permit
      direct access of particulate debris to iliac bone. To address this issue,
      incidence data are reported on 513 total hip replacements from six different
      single-surgeon series of total hip arthroplasties performed with six different
      porous ingrowth acetabular components. With follow-up ranging from 40 to 108
      months, a total of 45 pelvic osteolytic lesions were observed (8.8 per cent).
      Pelvic osteolysis was seen nearly as frequently in the ischium and pubis (21
      lesions) as it was in the ilium (24 lesions). It was not possible to explain
      ischial and pubic osteolysis by holes and/or screws through the acetabular
      component shell. There was no direct correlation between the presence of screw
      holes or screws and the incidence of pelvic osteolysis. The incidence of pelvic
      osteolysis around modular components with holes through the shell was 4.5 per
      cent (14 of 313 hips). The incidence of pelvic osteolysis with solid-shell
      components was 15.5 per cent (31 of 200). The incidence of pelvic osteolysis
      around acetabular reconstructions with screws was 2.3 per cent (3 of 133). The
      incidence of pelvic osteolysis in reconstructions without screws was 11.1 per
      cent (32 of 380). The incidence of pelvic osteolysis in one-piece acetabular
      components (polyethylene pre-fixed in the metal shell) was 12.7 per cent (21 of
      165) and the incidence of pelvic osteolysis with the modular components was 6.9
      per cent (24 of 348). In each comparison, the incidence of pelvic osteolysis was
      actually lower in the group assumed to be at increased risk. Based on this review
      there does not appear to be a direct relationship between holes and/or screws
      through an acetabular component and the development of pelvic osteolysis. The
      incidence of pelvic osteolysis was associated with larger head diameters and
      longer follow-up. While screw holes may provide an access channel in specific
      cases, the present data indicate that the simple elimination of holes through the
      acetabular shell will not eliminate pelvic osteolysis. Regardless of other
      acetabular component design features, joint fluid and polyethylene wear particles
      from the femoral-acetabular articulation can gain access to bone behind an
      acetabular component via the peripheral implant-bone interface through regions
      without sufficient contact or tissue ingrowth. The development of pelvic
      osteolysis is multifactorial and includes the total volumetric wear of
      polyethylene as well as specific features of the acetabular component design and
      reconstruction technique.

PMID- 10333688
TI  - Cross-sectional geometry of the human femur in the mid-third region.
AB  - The design of a medical implant requires that the geometry and anatomy of the
      host region is fully understood. For any prosthesis to be located in the mid
      third of the human femur it is therefore vitally important that an in-depth
      understanding of this region is obtained. This study focuses on the geometry of
      the medulla and the cortex and the relationship between them in the diaphyseal
      region of the human femur. Sixteen femora obtained from the Human Biology
      Department of the University of Leeds were sectioned at 10 mm intervals along the
      shaft and scaled photographs of each section were taken. These photographs then
      provided the raw data to enable the variation in long bone cross-sectional
      geometry to be evaluated. The results show that the medulla is almost cylindrical
      in the mid-third region, being most cylindrical between 35 and 50 per cent of the
      total bone length. The medullary width is found to be greater in the antero
      posterior direction (> 90 per cent maximum diameter) than in the medio-lateral
      direction (78-88 per cent maximum diameter) along the studied femoral length. The
      cortex is also analysed and it is found that the mean cortical thickness on the
      anterior side is significantly smaller than the medial cortex and the lateral
      cortex, with the posterior cortex being the thickest. All the above findings
      suggest that the medulla does not lie centrally within the femur but is
      positioned slightly anteriorly. Anatomical characteristics such as this can have
      profound effects on the design of prostheses to be implanted in this region.

PMID- 10333689
TI  - [Gastric motility disorders].

PMID- 10333691
TI  - Evaluation of cardiopulmonary involvement in Gaucher's disease.

PMID- 10333690
TI  - [Epidemiological and evolutionary profile of childhood celiac disease (report of
      118 cases)].

PMID- 10333692
TI  - [Cardiovascular risk evaluation in three exposed populations].

PMID- 10333693
TI  - [Pump metastasis of the bone].

PMID- 10333694
TI  - [Air pollution and bronchial hyperresponsiveness].

PMID- 10333695
TI  - [Epidural analgesia used in childbirth: comparative analysis of 132 cases].

PMID- 10333696
TI  - [Ketoconazole foaming gel in tinea versicolor (report of 60 cases)].

PMID- 10333697
TI  - [Hemifacial spasm and its treatment with botulinum toxin].

PMID- 10333698
TI  - [Neurologic cryptococcosis: meningitis of the immunosuppressed patient].

PMID- 10333699
TI  - [Revascularization of an accidental amputation of the glans by cavernous-balanic
      shunt].

PMID- 10333700
TI  - [Leiomyoma of the female urethra (case report and review of the literature].

PMID- 10333702
TI  - [Juvenile rheumatoid arthritis (study of 30 cases)].

PMID- 10333701
TI  - [Adjuvant chemotherapy after curative surgery for non-metastatic colorectal
      carcinomas (2-year results of 52 cases)].

PMID- 10333703
TI  - [Neonatal mortality in the pediatric ward of the regional hospital of Sokode
      (Togo) during 1984-1985 and 1994-1995].

PMID- 10333704
TI  - [Clinical and biological data of acute lymphoblastic leukemia in children
      (retrospective study of 87 cases)].

PMID- 10333705
TI  - [Indications and results of abdominal hysterectomies (report of 250 cases)].

PMID- 10333706
TI  - [Ender nailing of trochanteric fractures (report of 100 cases)].

PMID- 10333707
TI  - [Treatment of cervical dystonia with botulinum toxin].

PMID- 10333708
TI  - [Leg ulcer associated with sickle cell disease (report of 5 cases)].

PMID- 10333709
TI  - [Refractory cardiac insufficiency developing from a chronic constrictive
      pericarditis in a 13-year-old child].

PMID- 10333710
TI  - [Vesico-uterine fistula after cesarean section].

PMID- 10333711
TI  - Clinicopathologic characteristics of mucinous gastric adenocarcinoma.
AB  - There has been considerable controversy over the prognosis of mucinous gastric
      adenocarcinoma (MGC). In this study we analyzed the clinicopathologic differences
      between MGC and non-mucinous gastric carcinoma (NMGC). In addition, the
      relationship between mucin content and other clinicopathologic variables,
      including prognosis in MGC, was also investigated. We reviewed 2118 patients with
      pathologically-confirmed gastric cancer who underwent gastrectomy at the
      Department of Surgery, Yonsei University College of Medicine, during the period
      between Jan. 1987 and Dec. 1993. Among them, 130 patients had gastric carcinoma
      with extracellular mucin (MGC) and 1988 patients had gastric carcinoma without
      extracellular mucin (NMGC). We placed the MGC patients into two groups according
      to mucin content: mucin content involving over 50% of the tumor (dominant type, n
      = 94) and mucin content involving less than 50% of the tumor area (partial type,
      n = 36). The results were as follows: MGC was more common in males than NMGC. The
      size of the tumor in MGC (mean 5.3 cm) was larger than that of NMGC (mean 4.4
      cm). The patients with MGC had a higher incidence of Borrmann type IV (MGC:
      16.1%, NMGC: 9.9%), more frequent serosal invasion (MGC: 75.4%, NMGC: 48.6%),
      lymph-node metastasis (MGC: 75.4%, NMGC: 50.7%), and peritoneal metastasis (MGC:
      10.0%, NMGC: 3.5%) than patients with NMGC. The patients with MGC were more
      advanced in stage at the time of diagnosis and had a worse overall 10-year
      survival rate (44.9%) than patients with NMGC (54.7%). However, the 10-year
      survival rate according to the stage of MGC was similar to that of NMGC. There
      were no significant differences between the mucin content and other pathologic
      variables, including prognosis, i.e. similar biologic behavior between dominant
      type MGC and partial type MGC. In conclusion, we suggest that MGC was more
      frequently diagnosed in advanced stage than NMGC with a poorer prognosis and that
      it is reasonable to consider the carcinoma with mucin content involving more than
      30% of the tumor area as MGC.

PMID- 10333712
TI  - Incidence and possible reasons for discordant results between positive FDP and
      negative D-dimer latex assays in clinical specimens.
AB  - In general, FDP and D-dimer values have a correlation in clinical conditions
      associated with disseminated intravascular coagulation(DIC) or coagulation
      activation. However, there are some patients with discordant results who
      demonstrate elevated FDP and negative D-dimer results by latex agglutination
      assays. The incidence and possible reasons for the discordance between FDP and D
      dimer results were investigated through simultaneous measurements (n = 763) from
      clinical patients with suspected DIC or coagulation activation. 24.8% (189/763)
      of samples with elevated FDP were negative for D-dimer assays by the latex
      agglutination method. Further detailed analysis on randomly-selected discordant
      samples (n = 41) revealed that the most common reason for the discordance was the
      lower sensitivity of the semiquantitative latex agglutination method for D-dimer,
      compared with quantitative enzyme or other latex immunoassay. The other
      contributing factors to the discordance were accelerated fibrinogenolysis without
      secondary fibrinolysis, elevated soluble fibrin monomer and rheumatoid factor.

PMID- 10333713
TI  - 4-Aminopyridine (4-AP) augments Ca(2+)-dependent action potential and changes
      oscillatory firing patterns in rat cerebellar Purkinje cells.
AB  - Intracellular recordings in cerebellar slice preparation showed that applications
      of 4-AP altered the pattern of oscillatory firing activity in Purkinje cells
      (PCs), especially yielding pronounced changes in action potential shape. 4-AP
      increased the amplitude and duration of action potential significantly and
      decreased the spike frequency. After 4-AP application, the duration of bursting
      was prolonged and the duration of after-burst hyperpolarization was progressively
      shortened. In all PCs tested, the rhythmicity of oscillatory firing activity was
      abolished completely at the steady state. These results suggest that 4-AP
      sensitive currents determine the shape and frequency of individual Ca(2+)
      dependent action potentials as well as maintaining oscillatory firing activity in
      PCs.

PMID- 10333714
TI  - The loss of expression of transforming growth factor-beta receptors correlates
      with the histopathologic tumor grade in bladder transitional cell carcinoma
      patients.
AB  - Transforming growth factor-beta (TGF-beta), a pleiotropic growth factor, is a
      potent inhibitor of cellular proliferation in cells of epithelial origin.
      Recently, it has been suggested that a loss of sensitivity to TGF-beta through a
      loss of expression of TGF-beta receptors T beta R-I and T beta R-II--is
      associated with tumor initiation and progression. Therefore, to investigate the
      relationship between TGF-beta receptors expression and carcinogenesis of bladder
      TCC, this study examined the expression of T beta R-I and T beta R-II in 46
      bladder TCC patients using immunohistochemistry. Since histopathological grade is
      a widely accepted marker of prognosis, the results were compared in relation to
      the three grades of bladder TCC. The results demonstrated that the loss of TGF
      beta receptors expression is associated with increasing histopathological grades
      of bladder TCC. Specifically, both T beta R-I and T beta R-II were readily
      detected in all 10 normal bladder mucosa specimens. Likewise, all 6 specimens of
      grade I TCC samples expressed high levels of both TGF-beta receptors. However,
      among grade II TCC samples, T beta R-I and T beta R-II were detected in 78% and
      89%, respectively: among grade III TCC samples, T beta R-I and T beta R-II were
      detected in 45% and 41%, respectively. These results suggested that loss of
      sensitivity to TGF-beta may play a role in the progression of TCC from low to
      high grade disease.

PMID- 10333715
TI  - Effects of exposure conditions to footshocks early in life on spontaneous
      locomotor activity at maturity in rats.
AB  - Both genetic and environmental factors are involved in establishing a behavior.
      An animal study was done to determine the characteristics of interaction between
      genetic (nature) and environmental (nurture) factors. Delivery of footshocks (0.8
      mA x 60 times, at random) early in life was used as the environmental stimulus.
      As the footshock was delivered repeatedly, a rat showed helplessness behavior and
      the number of shocks necessary to elicit helplessness was measured to quantify
      the trait of an animal in coping with the aversive environmental stimulus. The
      nocturnal ambulatory activity at adulthood was measured as a behavioral
      expression of the nature-nurture interaction. Although the experience of
      footshocks early in life did not significantly alter average activity levels at
      adulthood, the activity was positively correlated with the number of shocks
      necessary to elicit helplessness (nature) while receiving footshocks (nurture) on
      postnatal day 14. Additionally, a second exposure to identical shock parameters
      on postnatal day 21 reversed the relationship. These results clearly showed that
      an interaction between nature and nurture during infancy leads to substantial
      behavioral alterations later in life, and suggest that the nature-dependent
      determination of an adult behavior can be modified in different directions by the
      conditions of an environmental experience early in life.

PMID- 10333716
TI  - Expression of eosinophil chemotactic factors in stomach cancer.
AB  - We have occasionally experienced eosinophilic abscess of the liver in patients
      with gastric carcinoma, suggesting that some eosinophil mobilizing (chemotactic
      and proliferative) factors might be produced by carcinoma cells. The aim of this
      study was to determine whether or not gastric carcinoma expresses the well-known
      eosinophil chemotactic factors (ECFs) and whether or not the expression is
      related to the histologic subtypes. Seventeen consecutive surgically removed
      tumor-bearing stomachs were collected: 7 signet ring cell type, 7 poorly
      differentiated tubular adenocarcinoma, and 3 moderately differentiated tubular
      adenocarcinoma. Hematoxylin-eosin stained sections were re-evaluated for
      eosinophil and mast cell infiltration. The expression of IL-2, IL-5 and
      granulocyte-macrophage colony stimulating factor (GM-CSF) were examined by
      immunocytochemical stain. There was no available frozen tissue for IL-2 and IL-5
      in one case. Gastric carcinoma expressed IL-2 in all 16 cases, IL-5 in 12 of 16
      cases and GM-CSF in 10 of 17 cases. Of particular interest, 7 of 10 GM-CSF
      expressing carcinomas were signet ring cell type. Even in the remaining 3 cases,
      most GM-CSF-positive cells were signet ring cells scattered within tubular
      adenocarcinoma. No correlation of ECF expression between either eosinophil/mast
      cell infiltration or peripheral blood eosinophilia was identified. In conclusion,
      most gastric carcinomas express the well-known ECFs and the expression of GM-CSF
      is specific for signet ring carcinoma cells.

PMID- 10333717
TI  - Clinical characteristics of metachronous bilateral testicular tumors in the
      chemotherapeutic era.
AB  - We wanted to present the results of our experience with bilateral testis tumor
      and to suggest the effects of chemotherapy in suppressing the development of
      second primary testicular tumors. Between 1978 and 1997, 2,345 patients were
      treated for testicular tumor at The University of Texas M. D. Anderson Cancer
      Center. Of these, 2,107 had germ cell cancers. There were 22 (0.94%) cases of
      bilateral testicular tumor in the overall patient population and 21 (1.0%) cases
      among patients with germ cell cancer. We reviewed the medical records to
      determine the incidence of the histological subtype, the incidence of
      metachronous versus synchronous formation of contralateral tumors, and tumor
      stage in this patient population. We also examined the effect of chemotherapy in
      treating the first tumor and preventing the occurrence of a second tumor.
      Finally, we compared the effect of ultrasonography, serum tumor marker elevation,
      and physical examination in detecting second tumors. Only one contralateral germ
      cell tumor developed synchronously; all others developed metachronously. Fifty
      percent of first tumors were seminomas, compared to 55% of second tumors. The
      histologic concordance rate for first and second tumors was 35%. Tumor stage was
      higher among first tumors than second tumors. The majority of second tumors in
      patients who received chemotherapy for first malignancies tended to be
      metachronous seminomas. Ultrasonography detected 6 of 21 (28.6%) contralateral
      tumors before they were evident by physical examination or serum tumor marker
      elevation. Seminomas were more prevalent among patients with bilateral germ cell
      disease than patients with unilateral disease. Chemotherapy, when used as
      treatment for first tumors, may have some effect in preventing the development of
      nonseminomatous germ cell tumors in the contralateral testicle. Close follow-up
      of the contralateral testis with ultrasonography is essential for early detection
      of second tumors. The outcome for patients with bilateral testicular germ cell
      cancer is excellent, secondary to early detection.

PMID- 10333718
TI  - Fluoxetine inhibits L-type Ca2+ and transient outward K+ currents in rat
      ventricular myocytes.
AB  - The most common cardiovascular side effects of antidepressants are cardiac
      arrhythmias and orthostatic hypotension. Little is known, however, about the
      mechanisms by which these adverse reactions may occur, especially with regard to
      newer drugs such as fluoxetine. We hypothesized that these side effects may have
      an electrophysiological basis at the level of the cardiac myocyte. Thus, we
      investigated the effects of fluoxetine and other antidepressants on action
      potentials and ionic currents of rat ventricular myocytes using the amphotericin
      B perforated patch clamp technique. Fluoxetine (10 microM) prolonged the action
      potential duration (APD50) to 146.7 +/- 12.9% of control value without altering
      resting membrane potential. Fluoxetine and sertraline potently inhibited the L
      type Ca2+ current (IC50 = 2.82 and 2.31 microM, respectively), but did not
      significantly modify the steady-state inactivation. Amitriptyline and imipramine
      had similar, but slightly weaker, effects (IC50 = 3.75 and 4.05 microM,
      respectively). Fluoxetine attenuated the peak transient outward K+ current and
      also altered current kinetics, as shown by accelerated decay. Fluoxetine did not
      change the voltage-dependence of the steady-state inactivation. Sertraline,
      amitriptyline and imipramine inhibited the transient outward K+ current with
      potencies very similar to fluoxetine. In contrast to the other antidepressants
      tested, trazodone weakly inhibited the Ca2+ and K+ currents and moclobemide had
      no detectable effect. Our comparative pharmacology data suggest that selective
      serotonin reuptake inhibitors, such as fluoxetine, are as potent as tricyclic
      antidepressants in inhibiting L-type Ca2+ and transient outward K+ currents.
      These inhibitory effects may contribute to cardiovascular complications such as
      arrhythmias and orthostatic hypotension.

PMID- 10333719
TI  - Behcet's disease sera containing antiendothelial cell antibodies promote adhesion
      of T lymphocytes to cultured human dermal microvascular endothelial cells.
AB  - Antiendothelial cell antibodies (AECA) have been detected in the sera of patients
      of autoimmune diseases showing vasculitis. Using IgM-ELISA, we found AECA in 42
      (56%) of 75 sera samples from patients with Behcet's disease in a previous study.
      All of the 15 AECA-positive sera of Behcet's disease patients had an increased
      expression of the intercellular cell adhesion molecule-1 (ICAM-1), 93.3% of the
      sera induced the vascular cell adhesion molecule-1 (VCAM-1), and 100% of the
      serum induced the E-selectin molecule on human dermal microvascular endothelial
      cells (HDMEC). After stimulation of HDMEC with AECA-positive sera of Behcet's
      disease patients, the expression of ICAM-1 and VCAM-1 on HDMEC increased
      significantly at 4 hours, reaching a peak at 16 hours. Expression of E-selectin
      was induced at 1 hour after stimulation with a peak at 4 hours and it decreased
      thereafter. Adherence of T lymphocytes to HDMEC increased significantly after
      stimulation with AECA-positive sera from Behcet's disease patients. Also, the
      adherence of T lymphocytes to HDMEC increased at 4 hours and returned to its
      normal level at 48 hours. These results show that AECA-positive sera of Behcet's
      disease patients are capable of activating HDMEC to promote the adherence of T
      lymphocytes to increase the expression of ICAM-1, VCAM-1, and E-selectin on the
      cell surfaces. The whole process may play an important role in the pathogenesis
      of vasculitis in Behcet's disease.

PMID- 10333720
TI  - Evaluation of the degree of cross-linking in UV irradiated porcine valves.
AB  - A porcine heart valve was irradiated by Ultraviolet (UV) rays (10 W, 254 nm) for
      2, 4, 8 and 24 hours at 4 degrees C to cross-link the structural collagen matrix.
      The degree of cross-linking was evaluated by assaying the released amount of
      hydroxyproline (Hyp) from the matrix, and comparing it with the positive controls
      of valves treated by glutaraldehyde (GA) solution (0.625 wt%) and the negative
      controls of non-treated fresh valves. The undigested weight ratio of the
      specimens increased by increasing the UV irradiation time. The undigested weight
      of the leaflets, tunica interna and tunica externa of the fresh, GA-treated and
      UV-irradiated specimens after collagenase digestion was compared. As UV
      irradiation increased, the amount of released hydroxyproline was gradually
      decreased until 8 hours of irradiation, after which the released hydroxyproline
      reduction occurred slightly until 24 hours of irradiation time in this system. A
      total 47.68% of the hydroxyproline in the valve was cross-linked by UV
      irradiation after 24 hours, while 73.74% of the hydroxyproline in the positive
      control was crossed-linked. Light microscopic observation revealed that the
      typical crimp pattern of collagen fibers decreased and was rearranged into a
      dense flattened pattern as the UV irradiation induced interfibrilar cross
      linking. GA-treated valves demonstrated a denser matrix pattern than the UV
      irradiated specimens. Cross-linked collagenous tissue prepared by UV irradiation
      would be useful for improving durability and reducing the disadvantages related
      to using a chemical cross-linking agent.

PMID- 10333721
TI  - Intermittent parathyroid hormone treatment can promote linear growth in the
      ovariectomized growing rat.
AB  - To compare the effect of intermittent parathyroid hormone (PTH) treatment with
      that of estrogen treatment on epiphyseal growth in ovariectomized rats, 46
      Sprague-Dawley female rats aged 9-10 weeks (about 200-220 g) were either
      ovariectomized or sham operated. From 6 weeks after ovariectomy (ovx), rats were
      daily injected with subcutaneous human recombinant PTH (1-84)-dosed 30
      micrograms/kg (the low dose PTH-treated group) or 300 micrograms/kg (the high
      dose PTH-treated group), 17 beta-estradiol (the 17 beta-estradiol-treated group,
      30 micrograms/kg) or vehicle (the ovx-alone group), 5 times a week for 4 weeks.
      The decalcified sections of the distal femoral epiphyseal plate were analyzed on
      light microscopy after H&E stain, and the lengths of the zones of proliferation,
      maturing and hypertrophic chondrocytes were measured. The length of the growth
      plate, the zone of proliferation and the zone of hypertrophic chondrocyte in the
      ovx-alone group were significantly shorter than those of the sham-operated group.
      The treatment of 17 beta-estradiol speeded up the differentiation of cells from
      proliferating chondrocytes to maturing and hypertrophic chondrocytes even though
      the length of the growth plate was comparable to that of the sham-operated group.
      Both low and high dose PTH treatments increased the length of the growth plate,
      and those lengths were comparable to that of the sham-operated group. The
      fractions of proliferating, maturing and hypertrophic zone in the low dose PTH
      treated group were also comparable to those of the sham-operated group. However,
      high dose PTH treatment slowed down the differentiation of cells from
      proliferating chondrocytes to maturing and hypertrophic chondrocytes to a greater
      extent, and therefore the fraction of proliferating chondrocytes of the high dose
      PTH-treated group was larger than that of the low dose PTH-treated group (73.8 +/
      1.8 Vs 63.3 +/- 1.3%, p < 0.005). From these results, we showed that
      intermittent PTH treatment could promote linear growth in the ovariectomized
      growing rat. We propose that PTH may be an alternative drug candidate for
      promoting linear growth of long bones without the risk for early closure of the
      growth plate.

PMID- 10333722
TI  - Antibodies to human T-cell lymphotropic virus type I (HTLV-I) by particle
      agglutination (PA) test in Korean blood donors.
AB  - HTLV-I infection is a recently recognized disease entity that is common in some
      tropical and subtropical areas, including the southwestern district of Japan.
      Despite the geographical proximity and frequent cultural exchanges between Korea
      and Japan, it is understood that Korea is not an endemic area and HTLV-I
      associated illnesses are very rare in Korea. This study was designed to evaluate
      the positive rate of anti-HTLV-I antibodies in Korean blood donors and its
      regional distribution. Sera were obtained from blood donors from various
      districts around Korea. Anti-HTLV-I antibodies were detected by using the
      microtiter particle agglutination test employing an indirect agglutination
      technique. A total of 9,281 donors were tested and 12 donors (0.13%) were
      positive for anti-HTLV-I antibodies, 10 (0.11%) out of 8,845 males and 2 (0.46%)
      out of 436 females, with relative female predominance. A relatively high
      incidence of anti-HTLV-I positive donors was observed in Cheju Island (0.80%),
      Kyungnam (0.31%), and Chonnam (0.15%). In conclusion, the positive rate of anti
      HTLV-I antibodies seemed to be very low in Korea, but the highest positive rate
      of anti-HTLV-I antibodies was noticed on Cheju Island, warranting further
      research for confirmation.

PMID- 10333723
TI  - Identification of IgE-reacting Clonorchis sinensis antigens.
AB  - Clonorchis sinensis is a liver fluke and it is the most prevalent human parasite
      in Korea at present. The parasite infection induces immune responses,
      characteristically an increased production of parasite-specific IgE in the host.
      Major IgE-reacting C. sinensis antigens in infected humans have been protein
      bands with MWs of 15, 28, 37, 45, 51, 56, 62, 66, 74, 97 and 160 KD identified by
      immunoblot analysis. Individual variations of the IgE binding pattern to C.
      sinensis antigens have also been documented. Using immune BALB/c mouse sera, IgE
      reacting protein bands have been visualized with MWs of 28, 74, 86, 160 and
      several > 200 KD. One of the most strongly reacted C. sinensis antigenic proteins
      with a molecular weight of 28 KD was purified by gel filtration and preparative
      electrophoresis. Using a monoclonal antibody produced against the antigenic
      protein, the protein was localized in the parasite's intestine, and also found to
      be contained in excretory-secretory antigens.

PMID- 10333724
TI  - Viability and enzymatic activity of cryopreserved porcine heart valve.
AB  - Fibroblast viability of a natural tissue valve for replacing a defective heart
      valve through allograft or xenograft has been suggested to affect its clinical
      durability. In this study, the cell viability and enzymatic activity of porcine
      heart valve leaflets were examined in regard to concerning to the preservation
      process [variable warm ischemic time (WIT), cold ischemic time (CIT), and
      cryopreservation]. Porcine heart enblocs were obtained and valve dissection was
      performed after 2, 12, 24, or 36 hours, in respective groups A, B, C, and D, as
      WIT. Each group was stored for 24 hours as CIT and cryopreserved. Leaflets were
      dissected from a valved conduit after each process, and cell viability and
      enzymatic activity in the leaflet were investigated using trypan blue staining
      and API ZYM kits. WIT extension significantly decreased fibroblast viability (p <
      0.05, 92.25 +/- 2.7% at 2 hours, 84.9 +/- 6.7% at 12 hours, 57.0 +/- 10.2% at 24
      hours, 55.9 +/- 7.9% at 36 hours), while CIT for 24 hours was also influenced
      significantly (p < 0.05), whereas cryopreservation demonstrated no effect on
      cellular viability. In enzyme activity observation, several enzymes related to
      lipid or nucleotide degradation (esterase, esterase lipase, particularly
      phosphatase, phosphohydrolase) were remarkably changed following the valve
      fabrication process. After 24 hours CIT, these enzymatic activities in groups B,
      C and D significantly increased, but the activities decreased after
      cryopreservation. Particularly, both the viability and enzymatic activity showed
      remarkable changes after CIT in group B (WIT = 12 hours). These results suggest
      that WIT is more important than CIT in maintaining viability of the valve, and
      that completing all the cryopreservation process within 12 hours after
      acquisition is recommended.

PMID- 10333726
TI  - Mammalian sperm-egg recognition: does fertilin beta have a major role to play?
AB  - The advent of simple in vitro fertilisation techniques has provided the
      reproductive biologist with an invaluable system for assaying sperm fertilising
      ability. In particular, they provide a useful way of identifying and
      characterising gamete-specific proteins that play a role in sperm-egg
      interactions, and in recent years, a growing number of sperm surface proteins
      have been identified that appear to be involved in these processes. Fertilin beta
      was one of the first sperm membrane proteins to be implicated in egg interactions
      and it has been proposed that this is mediated by means of binding of its
      disintegrin-like domain to cognate integrin receptors on the egg plasma membrane.
      A recent paper in Science by Cho and colleagues [Cho et al. 1998. Fertilisation
      defects in sperm from mice lacking fertilin beta. Science 281: 1857-1859 (Ref.
      1)] provides preliminary data on a fertilin beta knockout mouse. Whilst fertilin
      beta null males had greatly reduced fertility, somewhat surprisingly, this could
      be largely attributed to causes other than impaired binding to the egg plasma
      membrane.

PMID- 10333727
TI  - On the origin of sex chromosomes.
AB  - In all living forms, the organization of the genetic material must enable two
      universally fundamental functions: the elaboration of biological properties and
      their transmission. In spite of these inexorable commonalties, genomes have a
      bewildering variety of forms, with differences occurring not only among distant
      taxa but also, in many instances, between members of the opposite sex within
      species. The rapidly growing field of comparative genomics offers a powerful tool
      for unraveling the evolutionary pathways that led to these karyotypic
      differences. This new method of genetic analysis [Fridolfsson et al, Proc Nat
      Acad Sci USA 1998; 95: 8147-8152. (Ref. 1)] complements still valuable,
      traditional experimental approaches.

PMID- 10333725
TI  - Obstructive jaundice and acute cholangitis due to papillary stenosis.
AB  - Papillary stenosis is characterized by fixed fibrosis leading to structural
      outflow obstruction and it is usually secondary to inflammation and fibrosis from
      the chronic passage of gallstones, episodes of acute pancreatitis, chronic
      pancreatitis, sclerosing cholangitis, peptic ulcer disease, and cholesterolosis.
      However, obstructive jaundice with or without acute cholangitis which leads the
      physician to suspect the presence of malignancy as a cause is a rare
      manifestation of papillary stenosis. We report here a case of papillary stenosis
      presenting with obstructive jaundice and acute cholangitis. The lesion was so
      difficult to exclude the presence of malignancy preoperatively and
      intraoperatively that a pylorus-preserving pancreaticoduodenectomy was performed.
      Histologic examination of the resected specimen revealed fibrosis, adenomatoid
      ductal hyperplasia, and mild chronic inflammation of the papilla of Vater and
      distal common bile duct.

PMID- 10333728
TI  - WT1: what has the last decade told us?
AB  - When positionally cloned in late 1989, it was anticipated that mutations within
      the Wilms' tumour suppressor gene (WT1) would prove responsible for this common
      solid kidney cancer of childhood. Characterisation of the WT1 expression pattern
      and of the structure of the encoded protein isoforms and their mode of action has
      now spanned almost a decade. WT1 proteins act as nucleic acid-binding zinc finger
      containing transcription factors involved in both transactivation and repression.
      These activities are facilitated and constrained by interactions with other
      proteins. Expression analyses and knockout mice indicate that WT1 protein plays a
      critical role in normal kidney and gonad development. Specific constitutional WT1
      mutations results in several urogenital anomaly syndromes. While only 10% of
      sporadic Wilms' tumours do display WT1 mutation, WT1 is mutated in other cancers,
      including acute myeloid leukaemia. Much is still to be determined in WT1 biology.
      The next decade will see at least three streams of attention. The first two,
      elucidation of the role of WT1 in RNA metabolism and the characterisation of
      further protein partners, may together explain the distinct tissue-specific
      functions of WT1. Finally, further research into the role of WT1 in
      haematopoiesis will improve our understanding of WT1 in leukaemia.

PMID- 10333729
TI  - Do human eggs attract spermatozoa?
AB  - A key process in human fertilization is bringing the two gametes together, so
      that the complex molecular events involved in sperm and egg interaction can
      begin. Does nature allow fertilization to occur only as a consequence of a chance
      collision, or is there a precontact sperm-egg communication? This review
      summarizes the bioassays used in testing human spermatozoa for chemotaxis,
      emphasizing the necessity to distinguish between chemotaxis and other
      accumulation-causing processes, and the results obtained. It demonstrates that
      human sperm chemotaxis to a follicular factor(s) does occur, at least in vitro,
      and that only capacitated spermatozoa are chemotactically responsive. Substances
      that have been proposed as attractants for human spermatozoa are reassessed. The
      potential role of sperm chemotaxis in vivo is discussed. Faulty precontact sperm
      egg communication may be one of the causes of male infertility, female
      infertility, or both. On the other hand, interfering with human sperm chemotaxis
      may represent an exciting new approach to contraception.

PMID- 10333730
TI  - Cadherins and tissue formation: integrating adhesion and signaling.
AB  - Cadherins and other cell-substrate and cell-cell adhesion molecules play an
      essential role during development. Through their cytoplasmic interaction with the
      cytoskeleton, cell adhesion molecules physically link cells with the
      extracellular matrix and/or with each other. These interactions create
      architectural and structural entities that enable the tissues in the embryo to
      restrain the physical forces encountered during development. Regulated cell
      adhesion is also often the driving force of morphogenetic movements. This review
      goes beyond the adhesive aspect of cadherins, focusing on their roles as
      signaling molecules in development. We discuss how cadherins, through their
      effects on cell proliferation, cell death, cell polarization, and
      differentiation, play a role in the formation of tissues and organs in the
      developing embryo.

PMID- 10333731
TI  - E2F target genes and cell-cycle checkpoint control.
AB  - In this review, we will focus on the role played by transcription factors of the
      E2F/DP family in controlling the expression of genes that carry out important
      cell-cycle control functions, thereby ensuring ordered progression through the
      mammalian cell division cycle. The emerging picture is that cell-cycle
      progression depends on the execution of a regulatory cascade of gene expression,
      driven by E2F/DP transcription factors, which are in turn regulated by the
      products of some of these genes. That E2F factors are potent regulators of cell
      cycle checkpoints in mammalian cells is supported by experiments demonstrating
      that ectopic expression of individual E2F family members is sufficient to
      modulate cell proliferation and apoptosis. It is also clear that deregulation of
      E2F activity will result in the loss of particular checkpoint controls, thereby
      predisposing cells to malignant conversion.

PMID- 10333732
TI  - Orphan selenoproteins.
AB  - Selenoproteins contain selenium in stoichiometric amounts. Most are synthesized
      by a process that decodes UGA codons as selenocysteine. Twelve animal
      selenoproteins have been characterized, and biochemical functions have been
      described for all but three. Two of these "orphan" selenoproteins are discussed
      in this paper. Selenoprotein P is an extracellular glycoprotein that contains
      multiple selenocysteines. It binds heparin and associates with endothelial cells.
      Two isoforms have been identified. Plasma concentration of selenoprotein P
      correlates with protection against diquat liver injury, suggesting that the
      protein protects against oxidant injury. Selenoprotein W is a small intracellular
      protein that contains one selenocysteine. It binds glutathione and has been
      suggested to function in oxidant defense. The postulated oxidant defense
      properties of these selenoproteins are consistent with the facile thiol-redox
      properties of selenocysteine. It can be predicted that more proteins will be
      discovered that take advantage of the chemical properties of selenium.

PMID- 10333733
TI  - Oxidative DNA damage, antioxidants, and cancer.
AB  - Oxidised bases, such as 8-oxo-guanine, occur in cellular DNA as a result of
      attack by oxygen free radicals. The cancer-protective effect of vegetables and
      fruit is attributed to the ability of antioxidants in them to scavenge free
      radicals, preventing DNA damage and subsequent mutation. Antioxidant supplements
      (e.g., beta-carotene, vitamin C) increase the resistance of lymphocytes to
      oxidative damage, and a negative correlation is seen between antioxidant
      concentrations in tissues and oxidised bases in DNA. Large-scale intervention
      trials with beta-carotene have, however, led to increases in cancer. Recent
      measurements of the frequency of oxidised DNA bases indicate that earlier
      estimates were greatly exaggerated; there may be only a few thousand 8-oxo
      guanines per cell. Convincing evidence for mutations resulting from oxidative
      damage, in tumours or cultured cells, is lacking. It seems that efficient
      antioxidant defences together with DNA repair maintain a steady-state level of
      damage representing minimal risk to cell or organism.

PMID- 10333734
TI  - Origin, genetic diversity, and genome structure of the domestic dog.
AB  - Comparative analysis of mammalian genomes provides important insight into the
      structure and function of genes. However, the comparative analysis of gene
      sequences from individuals of the same and different species also provides
      insight into the evolution of genes, populations, and species. We exemplify these
      two uses of genomic information. First, we document the evolutionary
      relationships of the domestic dog to other carnivores by using a variety of DNA
      based information. A phylogenetic comparison of mitochondrial DNA sequences in
      dogs and gray wolves shows that dogs may have originated from multiple wolf
      populations at a time much earlier than suggested by the archaeologic record. We
      discuss previous theories about dog development and evolution in light of the new
      genetic data. Second, we review recent progress in dog genetic mapping due to the
      development of hypervariable markers and specific chromosome paints. Extensive
      genetic homology in gene order and function between humans and dogs has been
      discovered. The dog promises to be a valuable model for identifying genes that
      control morphologic differences between mammals as well as understanding
      genetically based disease.

PMID- 10333735
TI  - Animal antimicrobial peptides: an overview.
AB  - Antibiotic peptides are a key component of the innate immune systems of most
      multicellular organisms. Despite broad divergences in sequence and taxonomy, most
      antibiotic peptides share a common mechanism of action, i.e., membrane
      permeabilization of the pathogen. This review provides a general introduction to
      the subject, with emphasis on aspects such as structural types, post
      translational modifications, mode of action or mechanisms of resistance. Some of
      these questions are treated in depth in other reviews in this issue. The review
      also discusses the role of antimicrobial peptides in nature, including several
      pathological conditions, as well as recent accounts of their application at the
      preclinical level.

PMID- 10333736
TI  - Antimicrobial peptides from amphibian skin: what do they tell us?
AB  - Amphibian skin secretions contain many biologically active compounds, such as
      biogenic amines, complex alkaloids, or peptides. Within the latter class of
      molecules, a large number of peptide antibiotics has been isolated and
      characterized from different amphibian species. Antimicrobial peptides are
      considered the effector molecules of innate immunity, acting as a first line of
      defense against bacterial infections, by perturbing the phospholipid bilayer of
      the target cell membrane. These gene-encoded molecules are synthesized as
      inactive precursors and in several cases their proparts were shown to have highly
      conserved structures. It has also been demonstrated that the promoter regions of
      inducible peptide antibiotics are often regulated by the transcriptional control
      machinery NF-kappa B/I kappa B alpha. In amphibia of Rana and Bombina genera,
      inhibition of transcription of the genes encoding antimicrobial peptides has been
      obtained by glucocorticoid treatment, which causes an increase of I kappa B alpha
      synthesis. Moreover, determination of the structure of a number of genes coding
      for antimicrobial peptides in amphibia has actually shown that their promoter
      regions contain recognition sites for nuclear factors.

PMID- 10333737
TI  - Mode of action of linear amphipathic alpha-helical antimicrobial peptides.
AB  - The increasing resistance of bacteria to conventional antibiotics resulted in a
      strong effort to develop antimicrobial compounds with new mechanisms of action.
      Antimicrobial peptides seem to be a promising solution to this problem. Many
      studies aimed at understanding their mode of action were described in the past
      few years. The most studied group includes the linear, mostly alpha-helical
      peptides. Although the exact mechanism by which they kill bacteria is not clearly
      understood, it has been shown that peptide-lipid interactions leading to membrane
      permeation play a role in their activity. Membrane permeation by amphipathic
      alpha-helical peptides can proceed via either one of the two mechanisms: (a)
      transmembrane pore formation via a "barrel-stave" mechanism; and (b) membrane
      destruction/solubilization via a "carpet-like" mechanism. The purpose of this
      review is to summarize recent studies aimed at understanding the mode of action
      of linear alpha-helical antimicrobial peptides. This review, which is focused on
      magainins, cecropins, and dermaseptins as representatives of the amphipathic
      alpha-helical antimicrobial peptides, supports the carpet-like rather the barrel
      stave mechanism. That these peptides vary with regard to their length, amino acid
      composition, and next positive charge, but act via a common mechanism, may imply
      that other linear antimicrobial peptides that share the same properties also
      share the same mechanism.

PMID- 10333738
TI  - Cysteine-rich antimicrobial peptides in invertebrates.
AB  - Antimicrobial peptides are pivotal elements of the innate immune defense against
      bacterial and fungal infections. Within the impressive list of antimicrobial
      peptides available at present, more than half have been characterized in
      arthropods. Cysteine-rich antimicrobial peptides represent the most diverse and
      widely distributed family among arthropods and, to a larger extent, among
      invertebrates. Proeminent groups of cysteine-rich peptides are peptides with the
      CS alpha beta motif and peptides forming an hairpin-like beta-sheet structure.
      Although these substances exhibit a large structural diversity and a wide
      spectrum of activity, they have in common the ability to permeabilize microbial
      cytoplasmic membranes. Drosophila has proved a remarkable system for the analysis
      of the regulation of expression of gene encoding antimicrobial cysteine-rich
      peptides. These studies have unraveled the striking parallels that exist between
      insect immunity and innate immunity in mammals that point to a common ancestry of
      essential aspects of innate immunity.

PMID- 10333739
TI  - Plant defense peptides.
AB  - Eight families of antimicrobial peptides, ranging in size from 2 to 9 kD, have
      been identified in plants. These are thionins, defensins, so-called lipid
      transfer proteins, hevein- and knottin-like peptides, MBP1, IbAMP, and the
      recently reported snakins. All of them have compact structures that are
      stabilized by 2-6 disulfide bridges. They are part of both permanent and
      inducible defense barriers. Transgenic overexpression of the corresponding genes
      leads to enhanced tolerance to pathogens, and peptide-sensitive pathogen mutants
      have reduced virulence.

PMID- 10333740
TI  - Molecular insights into the RNA world.

PMID- 10333741
TI  - On the role of magnesium ions in RNA stability.
AB  - Divalent cations, like magnesium, are crucial for the structural integrity and
      biological activity of RNA. In this article, we present a picture of how
      magnesium stabilizes a particular folded form of RNA. The overall stabilization
      of RNA by Mg2+ is given by the free energy of transferring RNA from a reference
      univalent salt solution to a mixed salt solution. This term has favorable
      energetic contributions from two distinct modes of binding: diffuse binding and
      site binding. In diffuse binding, fully hydrated Mg ions interact with the RNA
      via nonspecific long-range electrostatic interactions. In site binding,
      dehydrated Mg2+ interacts with anionic ligands specifically arranged by the RNA
      fold to act as coordinating ligands for the mental ion. Each of these modes has a
      strong coulombic contribution to binding; however, site binding is also
      characterized by substantial changes in ion solvation and other nonelectrostatic
      contributions. We will show how these energetic differences can be exploited to
      experimentally distinguish between these two classes of ions using analyses of
      binding polynomials. We survey a number of specific systems in which Mg(2+)-RNA
      interactions have been studied. In well-characterized systems such as certain
      tRNAs and some rRNA fragments these studies show that site-bound ions can play an
      important role in RNA stability. However, the crucial role of diffusely bound
      ions is also evident. We emphasize that diffuse binding can only be described
      rigorously by a model that accounts for long-range electrostatic forces. To fully
      understand the role of magnesium ions in RNA stability, theoretical models
      describing electrostatic forces in systems with complicated structures must be
      developed.

PMID- 10333742
TI  - New developments in structure determination of pseudoknots.
AB  - Recently, several high-resolution structures of-RNA pseudoknots have become
      available. Here we review the progress in this area. The majority of the
      structures obtained belong to the classical or H-type pseudoknot family. The most
      complicated pseudoknot structure elucidated so far is the Hepatitis Delta Virus
      ribozyme, which forms a nested double pseudoknot. In particular, the structure
      function relationships of the H-type pseudoknots involved in translational
      frameshifting have received much attention. All molecules considered show
      interesting new structural motifs.

PMID- 10333743
TI  - Saccharide-RNA recognition.
AB  - Among saccharides, the antibiotics of the aminoglycoside family are the best
      studied class of molecules interacting with RNA. By binding to RNA targets,
      aminoglycosides act as inhibitors of protein biosynthesis, they interfere with
      protein-RNA interaction of retroviral regulatory elements, and they inhibit the
      catalytic action of ribozymes. Here, we survey the available data on molecular
      structural details of aminoglycoside-RNA interaction.

PMID- 10333744
TI  - RNA recognition by arginine-rich peptide motifs.
AB  - A ubiquitious class of RNA-binding proteins is distinguished by an arginine-rich
      motif. Such proteins function in transcription, translation, RNA trafficking, and
      packaging. Peptide models are derived from viral regulatory proteins, including
      the virulence factors Tat and Rev of mammalian immunodeficiency viruses.
      Structures of model peptide-RNA complexes exhibit diverse strategies of
      recognition based in each case on structural transitions. Induced RNA structures
      contain noncanonical elements such as purine-purine mismatches, base triples, and
      flipped bases. Such elements enlarge and extend the RNA major groove to create
      specific peptide-binding pockets and surfaces. The repertoire of bound peptide
      structures--beta-hairpin, alpha-helix, and helix-bend-helix-reflects the
      diversity of induced RNA architectures. This repertoire, reminiscent of
      primordial exon-encoded peptides, may recapitulate early events in the transition
      between RNA and protein worlds. Peptide-directed changes in modern RNA structures
      can provide a mechanism of signaling in higher-order RNA-protein assemblies.

PMID- 10333745
TI  - Protein-RNA recognition.
AB  - The x-ray structure of the glutamine aminoacyl tRNA synthetase bound to its
      cognate tRNA(Gln) and ATP was reported by Steitz and co-workers in 1989,
      providing the first high resolution structure of a protein-RNA complex. Since
      then, high resolution structures have been reported for RNA complexes with five
      other tRNA synthetases, the elongation factor Tu, the bacteriophage MS2 coat
      protein, the human spliceosomal U1A and U2B"-U1A' proteins, and the HIV-1
      nucleocapsid protein. Although the number of high resolution structures of
      protein-RNA complexes are rather small, some general themes have begun to emerge
      regarding the nature and mechanisms of protein-RNA recognition.

PMID- 10333746
TI  - Morphometric analysis of LPS-stimulated human monocytes by computer-assisted
      image analysis.
AB  - This report describes the results of applying the computer-assisted image
      analysis system for the measurement of some cytological parameters of LPS
      stimulated and nonstimulated human monocytes. The experiments were carried out by
      means of the digital cell image analysis of haematoxilyn stained monocytes. Five
      different parameters describing the morphology of monocytes and their nuclei were
      selected to quantitate the differences between control and activated cells area,
      perimeter, elongation, dispersion, and extension of images of cell projections.
      The results suggest that all of the analysed parameters can be used to
      discriminate stimulated from nonstimulated monocytes which permits detailed
      monitoring of the changes in cell morphology during monocyte activation.

PMID- 10333747
TI  - The effect of carbachol on the phase of free-running locomotor activity rhythm
      under constant darkness (DD) and constant light (LL) in mice.
AB  - Carbachol chronically and peripherally administered, depending on the circadian
      time, caused a phase shift in the free-running locomotor activity rhythm,
      resynchronized the rhythm, or had a masking effect of this rhythm in mice. In the
      discussion it is stressed that the drug affects the rhythmicity of this activity,
      probably by acting on the mechanism of suprachiasmatic nuclei.

PMID- 10333748
TI  - Phospholipid content and lamellar structures in the epididymal epithelial cells
      of rats treated chronically with lead acetate [Pb(II)].
AB  - The electron-microscopic observations accomplished covered epididymal epithelial
      cells of rats receiving lead acetate for five times longer than the duration of
      one spermatogenesis. These cells were found to possess a large number of vacuoles
      and conglomerates containing plicated membranes or tightly packed myelin-like
      lamellar formations. Further observations also revealed the formation of lamellar
      structures in mitochondria, dilatation of cisternae in the Golgi apparatus, and
      increased phagocytosis of spermatozoa by epithelial cells. The presence of a
      large amount of membranous material correlated with the increased content of
      phospholipids in epididymal epithelial cells. It may be suggested that the
      presence of such a great quantity of lamellar structures in epididymal epithelial
      cells of rats treated chronically with lead is the result of several processes,
      including the augmented synthesis of membranes associated with encircling the
      deposits of lead, autophagy in the cells, as well as intensified phagocytosis of
      spermatozoa.

PMID- 10333749
TI  - Independent selection of multiple mechanisms for pyrethroid resistance in
      Guatemalan Anopheles albimanus (Diptera: Culicidae).
AB  - Isofemale lines were established containing either, both, or neither of the
      elevated esterase and oxidase resistance mechanisms conferring pyrethroid
      resistance in a Guatemalan strain of Anopheles albimanus (Wiedemann). Plots of
      esterase and oxidase levels for individual mosquitoes from these single families
      correlated with data obtained using oxidase and esterase synergists in bioassays
      run in the bottle format. Mixed populations of pyrethroid-resistant A. albimanus
      adult females were selected using DDT, permethrin, or malathion; and the esterase
      and oxidase levels of the individual progeny were plotted. These data showed that
      the 3 classes of insecticide selected the 2 mechanisms differently. These results
      are discussed in terms of the problem of multiresistance surveillance in the
      field, especially concerning pyrethroid insecticides and the interaction of
      agricultural and public health insecticide application.

PMID- 10333750
TI  - Mass rearing methods for Galerucella calmariensis and G. pusilla (Coleoptera:
      Chrysomelidae), biological control agents of Lythrum salicaria (Lythraceae).
AB  - Purple loosestrife, Lythrum salicaria L., an invasive Eurasian perennial, is
      degrading wetlands across temperate North America. Because conventional control
      methods have proven ineffective, current emphasis is on the introduction and
      release of host-specific biological control agents. To increase the availability
      of control agents for distribution and thus the potential for faster control,
      mass rearing techniques for 2 leaf beetles, Galerucella calmariensis L. and G.
      pusilla Duftschmidt, were developed under greenhouse and field conditions. To
      evaluate the success of various rearing techniques on the number of beetles
      produced and the effect of these methods on offspring quality, female fecundity,
      larval development, and adult survival were monitored. Survival of adults
      maintained at 4 degrees C was approximately 60% and was independent of the type
      of material used for storage, duration of overwintering, and number of beetles
      per container. Survival rates increased with increasing numbers of dry stems
      offered as an overwintering substrate. Females in smaller cages had significantly
      higher oviposition rates, and with an increase in the number of beetles per cage,
      female fecundity doubled. Continuous rearing in the greenhouse reduced female
      fecundity. Allowing beetles to overwinter significantly improved fecundity and
      rearing efficiency, independent of whether beetles overwintered in a controlled
      environment or in the field. Field rearings consistently produced 2-5 times more
      offspring with higher survival than greenhouse rearings.

PMID- 10333751
TI  - Estimating economic thresholds for pest control: an alternative procedure.
AB  - An alternative methodology to determine profit maximizing economic thresholds is
      developed and illustrated. An optimization problem based on the main biological
      and economic relations involved in determining a profit maximizing economic
      threshold is first advanced. From it, a more manageable model of 2
      nonsimultaneous reduced-from equations is derived, which represents a simpler but
      conceptually and statistically sound alternative. The model recognizes that
      yields and pest control costs are a function of the economic threshold used.
      Higher (less strict) economic thresholds can result in lower yields and,
      therefore, a lower gross income from the sale of the product, but could also be
      less costly to maintain. The highest possible profits will be obtained by using
      the economic threshold that results in a maximum difference between gross income
      and pest control cost functions.

PMID- 10333752
TI  - Effect of airflow on house fly (Diptera: Muscidae) distribution in poultry
      houses.
AB  - Numbers of fecal and vomit spots deposited by house flies, Musca domestica L., on
      spot cards were about twice as high on cards placed on the downwind sides as on
      the upwind sides of building support posts in caged-layer poultry houses with
      tunnel ventilation in Brooksville, FL. This trend was stronger at the ends of the
      houses where airflow is faster than in the relatively still-air center of the
      houses. A similar evaluation conducted in a pullet house (Zephyrhills, FL) with
      an evaporative cooling ventilation system revealed significantly higher fly
      counts on spot cards and sticky cards in downwind compared with upwind
      orientations. Flies in the pullet house were concentrated in both ends of the
      house and in the center, with comparatively fewer flies in the intermediate
      regions. There was a high degree of correlation between spot card and sticky card
      counts in the pullet house.

PMID- 10333753
TI  - Thermal treatments to increase acoustic detectability of Sitophilus oryzae
      (Coleoptera: Curculionidae) in stored grain.
AB  - Hidden infestations of stored-product insect larvae are detected most rapidly by
      acoustic techniques when the larvae are highly active. Larval activity is
      periodic, however, and it tends to decrease after the larvae are disturbed or
      cooled. Because of the practical need for rapid inspection of grain at commercial
      elevators, several heat treatments were tested as potential methods of increasing
      larval activity and improving the speed and reliability of acoustic detection
      under adverse conditions. Samples of grain infested with 4th instars of
      Sitophilus oryzae (L.) were exposed to different radiant and convective heat
      treatments after they had been conditioned at 11 degrees C, 17 degrees C, or room
      temperature for 12-24 h. Relative activity levels were evaluated over periods of
      0-12 h based on the mean levels in a 15-min interval, 2 h after the beginning of
      a trial. In comparisons among treatments with precooled larvae, relative activity
      levels 5-10 min after brief heat pulses were 2-30 times higher than activity
      levels in precooled controls exposed only to ambient temperatures (25 degrees C).
      After 15-25 min, the relative activity levels of these heated larvae remained 2-5
      times higher than those of the ambient controls. Brief movement disturbances
      inhibited activity for approximately 20 min at any temperature. These results
      suggest that, in general, larval detectability is enhanced if cool grain samples
      are warmed and all samples are left undisturbed for 15-20 min before inspection.

PMID- 10333754
TI  - Molecular-based approach to the differentiation of mealybug (Hemiptera:
      Pseudococcidae) species.
AB  - The rDNA internal transcribed spacer (ITS) region of 4 mealybug species,
      Pseudococcus viburni (Signoret), P. longispinus (Targiono-Tozzetti), P.
      calceolariae (Maskell), and P. similans (Lidgett), was isolated by polymerase
      chain reaction (PCR) amplification, cloned, and sequenced. In this region of the
      genome there were numerous differences, including nucleotide substitutions,
      insertions, or deletions between P. viburni, P. longispinus, and P. calceolariae,
      whereas P. calceolariae and P. similans were very similar. Based on sequence
      differences between the ITS regions, we designed PCR primers that were able to
      differentiate the 4 mealybug species and that correlated with morphological
      differences found between adult females of these species. The PCR amplification
      by using the species-specific primers enabled the differentiation of not only
      adult females but also eggs, juveniles, and adult males, which was not previously
      possible by using conventional identification methods.

PMID- 10333755
TI  - Host status of fresh prunes by potential quarantine pests in laboratory tests and
      evaluation of packinghouse culls.
AB  - The status of fresh prunes, Prunus domestica L., as a host for codling moth,
      Cydia pomonella (L.) (Lepidoptera: Tortricidae); peach twig borer, Anarsia
      lineatella Zeller (Lepidoptera: Gelechiidae); omnivorous leafroller, Platynota
      stultana Walshingham (Lepidoptera: Tortricidae); oriental fruit moth, Grapholita
      molesta (Busck) (Lepidoptera: Tortricidae); navel orangeworm, Amyelois
      transitella (Walker) (Lepidoptera: Pyralidae); and walnut husk fly, Rhagoletis
      completa Cresson (Diptera: Tephritidae), was investigated in laboratory tests and
      by examination of packinghouse culls. In laboratory no-choice tests, the mean
      number of adults reared per fruit was 0.01 for codling moth, 0.08 for omnivorous
      leafroller, 0 for oriental fruit moth, and 1.6 for navel orangeworm. In choice
      tests the mean number of adults reared per apple or fresh prune was for codling
      moth, 0.78 and 0.02 (significantly different); for omnivorous leafroller, 0.05
      and 0.02; and for oriental fruit moth, 2.07 and 0 (significantly different),
      respectively. Walnut husk fly oviposited in fresh prunes in no-choice tests but
      pupae did not develop from the fruit. In choice tests, walnut husk fly did not
      oviposit in fresh prunes when caged with its normal host, green walnuts, in which
      large numbers of pupae developed. Inspection of packinghouse culls for immature
      insects showed that fresh prunes with possible larval feeding sites in the form
      of frass or fruit gum extrusions were lighter in weight, significantly less firm,
      similar in color, and had significantly higher soluble solids than noninfested
      fruit. Based on packinghouse cull samples, 1 fresh prune per 133 harvested fruit
      would be expected to show possible insect damage. Eleven peach twig borer larvae
      were found in fresh prune cull samples (213.9 kg) removed from a 16,744.5-kg
      harvest. The calculated level of infestation was 1 infested fruit per 8,501.8
      fruit harvested or per 21.7 cartons of medium-sized packed fruit. Based on our
      results, the risk of infestation of fresh prunes by the insects in this study
      would be minimal in fruit exported from the San Joaquin Valley of California.

PMID- 10333756
TI  - Violent behavior preceding hospitalization among persons with severe mental
      illness.
AB  - The need to better understand and manage risk of violent behavior among persons
      with severe mental illness (SMI) in community care is increasingly being
      recognized. Of particular concern is a subset of the SMI population characterized
      by a "revolving door" pattern of institutional recidivism and poor adherence to
      outpatient treatment. Little empirical research exists which examines the
      specific dimensions of violent incidents and their surrounding context in this
      population. The present paper describes characteristics of violent behavioral
      events in a sample of 331 people with psychotic or major mood disorders who were
      placed on involuntary outpatient commitment in North Carolina. By pooling
      baseline data from respondents' self-report, collateral informant interviews, and
      hospital records, the study found violent behavior to be a problem affecting over
      half the sample in a 4-month period preceding hospitalization. The study also
      found considerable variability in the frequency of violent events, severity,
      weapon use, subjective state when incidents occurred, initiation of fights,
      settings, relationship to others involved, and associated threat of
      victimization. Multivariable analyses showed that cooccurring substance abuse
      problems, history of criminal victimization, and age (being younger) were
      significantly associated with violent behavior when all sources of data were
      taken into account. Clinical diagnosis and symptom variables were not related to
      violence in this sample. Implications of these findings for service delivery
      priorities and future research are discussed.

PMID- 10333757
TI  - Psychopathy (PCL-R) predicts violent recidivism among criminal offenders with
      personality disorders in Sweden.
AB  - Psychopathy as conceptualized with Hare's Psychopathy Checklist Revised, PCL-R,
      has attracted much research during the 1990s. In the Scandinavian countries, few
      studies that empirically support the validity of North American risk assessment
      techniques in our regional context have been published. The purpose of this paper
      is to explore the predictive power of the PCL-R in a population of personality
      disordered violent offenders subjected to forensic psychiatric evaluation in
      Sweden. Following release from prison (n = 172), discharge from forensic
      psychiatric treatment (n = 129), or probation (n = 51), a total of 352
      individuals were followed for up to 8 years (mean = 3.7 years) with reconviction
      for violent crime as endpoint variable (base rate 34%). As the estimate of
      predictive power, the area under the curve of a receiver operating characteristic
      (AUC of ROC) analysis was calculated. For PCL-R scores to predict 2-year violent
      recidivism, AUC of ROC was .72 (95% CI: .66-.78). In addition, the personality
      dimension of psychopathy (Factor 1) and the behavioral component (Factor 2) both
      predicted 2-year recidivism significantly better than random: AUC of ROC .64 (95%
      CI: .57-.70) and .71 (95% CI: .65-.77), respectively. We conclude that
      psychopathy is probably as valid a predictor of violent recidivism in Swedish
      forensic settings as seen in previous North American studies.

PMID- 10333758
TI  - Assessing violence risk among discharged psychiatric patients: toward an
      ecological approach.
AB  - This paper draws upon data from the Pittsburgh site of the MacArthur Foundation's
      Risk Assessment Study, a large-scale study of violence risk among persons
      discharged from psychiatric hospitals, to examine the effect of the neighborhood
      context on risk of violence. This paper has two purposes: (1) to assess the
      extent to which the inclusion of neighborhood characteristics enhances violence
      prediction models-models that traditionally only include individual-level
      characteristics; and (2) to assess the consistency of individual level risk
      factors across different neighborhood contexts. Results indicate that
      neighborhood poverty has an impact over and above the effects of individual
      characteristics in identifying cases with violence. These findings support
      efforts to include neighborhood context in the assessment and management of
      violence risk among discharged psychiatric patients.

PMID- 10333759
TI  - Brief research report: age factors affecting the believability of repressed
      memories of child sexual assault.
AB  - Two experiments investigated how mock jurors react to testimony involving claims
      of a repressed memory in a case involving child sexual assault. Participants read
      a fictional civil trial summary presented in one of three conditions: (a)
      immediate condition--the alleged victim testified immediately after the incident;
      (b) repressed condition--the alleged victim reported the assault 1-39 years
      later, after remembering it for the first time; or (c) not-repressed condition-
      the alleged victim reported the assault 1-39 years later, but the memory of the
      assault had been present for those years. When there was any type of delayed
      reporting, either the age of the alleged victim at the time of the assault was
      constant and her age at reporting varied (Experiment 1) or the age of the alleged
      victim at the time of the assault varied and her age at reporting remained
      constant (Experiment 2). The results showed that (1) a delay in reporting an
      incident adversely affected believability of the alleged victim and led to fewer
      rulings in support of the plaintiff compared to reporting it immediately, (2)
      longer delays in reporting generally led to lower alleged victim believability
      and fewer decisions in support of the plaintiff than shorter delays, (3) the age
      of the alleged victim at the time of the incident was a critical variable in
      determining belief of the alleged victim, and (4) men generally rated
      believability of the alleged victim lower and ruled in favor of the plaintiff
      less often than women. The results are discussed in terms of the psychosocial
      factors affecting the perception of delayed reporting in a child sexual assault
      trial.

PMID- 10333760
TI  - Influence of phage proteins on formation of specific UV DNA photoproducts in
      phage T7.
AB  - Phage T7 can be used as a biological UV dosimeter. Its reading is proportional to
      the inactivation rate expressed in HT7 units. To understand the influence of
      phage proteins on the formation of DNA UV photoproducts, cyclobutane pyrimidine
      dimers (CPD) and (6-4)photoproducts ((6-4)PD) were determined in T7 DNA exposed
      to UV radiation under different conditions: intraphage T7 DNA, isolated T7 DNA
      and heated phage. To investigate the effects of various wavelengths, seven
      different UV sources have been used. The CPD and (6-4)PD were determined by
      lesion-specific antibodies in an immunodot-blot assay. Both photoproducts were
      HT7 dose-dependently produced in all three objects by every irradiation source in
      the biologically relevant UV dose range (1-10 HT7). The CPD to (6-4)PD ratios
      increased with the increasing effective wavelength of the irradiation source and
      were similar in intraphage T7 DNA, isolated DNA and heated phage with all
      irradiation sources. However, a significant decrease in the yield of both
      photoproducts was detected in isolated T7 DNA and in heated phage compared to
      intraphage DNA, the decrease was dependent on the irradiation source. Both
      photoproducts were affected the same way in isolated T7 DNA and heated phage,
      respectively. The yield of CPD and (6-4)PD was similar in B, C-like and A
      conformational states of isolated T7 DNA, indicating that the conformational
      switch in the DNA is not the decisive factor in photoproduct formation. The most
      likely explanation for modulation of photoproduct frequency in intraphage T7 DNA
      is that the presence of bound phage proteins induces an alteration in DNA
      structure that can result in an increased rate of dimerization and (6-4)PD
      production of adjacent based in intraphage T7 DNA.

PMID- 10333761
TI  - Deletion of alloantigen-activated cells by aminolevulinic acid-based photodynamic
      therapy.
AB  - Protoporphyrin IX (PpIX), an endogenously synthesized photosensitizer, can
      transiently accumulate in activated lymphocytes following administration of the
      heme precursor 5-aminolevulinic acid (ALA). One possible mechanism of this in
      lymphocyte accumulation is that actively dividing cells use intracellular iron
      stores for cytochrome and DNA synthesis and thus do not inactivate PpIX, the
      photoactive precursor of heme, by iron incorporation. This selective accumulation
      in activated cells should allow targeting by photodynamic therapy (PDT). To
      determine the effect of this accumulation, we studied PDT effects on the in vitro
      correlate of transplantation rejection: the one-way mixed lymphocyte reaction
      (MLR). Selective phototoxicity was determined by photoirradiating ALA-treated,
      MLR-activated cells and measuring subsequent stimulation either in a secondary
      MLR or with phytohemagglutinin (PHA). We found that proliferation of MLR
      activated lymphocytes incubated with ALA and treated with light was only 12-20%
      of controls (ALA+, no light) after rechallenge with the stimulator cells (P <
      0.05), although their response to nonspecific PHA stimulation was similar to
      controls. Thus alloantigen-specific depletion was shown. The data suggest a role
      for ALA-PDT in the treatment of diseases that require the selective elimination
      of activated lymphocytes and possibly as an immunomodulator.

PMID- 10333762
TI  - Evaluation of UVA-mediated oxidative damage to proteins and lipids in
      extracorporeal photoimmunotherapy.
AB  - The combination of UVA and 8-methoxypsoralen (8-MOP) is known for the ability to
      produce reactive oxygen species (ROS) that react subsequently with DNA, lipids
      and proteins. In most studies concerned with UVA effects mediated by free
      radicals, UVA doses higher than those exhibiting beneficial clinical results in
      extracorporeal photoimmunotherapy (ECPI) were used. The present study was
      undertaken to determine markers of oxidative stress in plasma and cells from the
      buffy coat using conditions relevant for ECPI (cumulative UVA dose at the sample
      level < or = 2 J/cm2). Plasma exposed to UVA of 20 J/cm2 resulted in protein
      oxidation as well in crosslinking and fragmentation revealed by electrophoresis.
      Exposure of the buffy coat and plasma to considerably lower doses of UVA (up to 2
      J/cm2) combined with various 8-MOP concentrations resulted neither in an increase
      of malondialdehyde as a marker of lipid peroxidation nor in a changed
      electrophoretic protein pattern. In these same experiments the total
      antioxidative capacity decreased to 65% of the initial value, suggesting that the
      antioxidative defense of plasma is able to cope with oxidative stress under ECPI
      conditions. These results were confirmed by data from 10 patients with
      scleroderma or cutaneous T-cell lymphoma during ECPI treatment. The present
      results suggest that, although ROS are formed during ECPI, gross oxidative damage
      does not occur. It is, however, possible, that specific effects mediated by
      oxygen radicals may co-trigger the photoimmunomodulatory effects of ECPI.

PMID- 10333764
TI  - Role of the immune system in mediating the antitumor effect of benzophenothiazine
      photodynamic therapy.
AB  - The role of the host immune system in contributing to tumor regression following
      benzophenothiazine photodynamic therapy (PDT) was examined. Photodynamic therapy
      with 2-iodo-5-ethylamino-9-diethylaminobenzo[a]-phenothiazinium chloride (2I
      EtNBS) eradicated EMT-6 mammary fibrosarcomas in 75-100% of treated mice. In
      contrast, PDT failed to inhibit tumor growth in T-cell-deficient nude mice.
      Furthermore, T-cell depletion studies with anti-CD8 antibody revealed that the
      CD8+ T-cell population was critical for an effective PDT response (tumor volume
      14 days post-PDT: 262 mm3 vs 59 mm3 in controls; P < 0.01). Because anti-CD4
      antibody inhibited tumor growth in the absence of PDT, the role of CD4+ T cells
      remains unclear. Depletion of natural killer (NK) cells in vivo with anti-asialo
      GM1 antibody significantly reduced a suboptimal PDT effect relative to vehicle
      controls (tumor volume 13 days post-PDT: 513 mm3 vs 85 mm3, respectively; P <
      0.001). However, splenic NK cells obtained from PDT-treated tumor-bearing mice
      were not cytotoxic in vitro against EMT-6 cells, suggesting that NK cells
      contribute to the PDT effect in vivo by an indirect mechanism. In addition, when
      mice with complete tumor regression following PDT were rechallenged 28 days later
      with 5 x 10(5) EMT-6 cells, tumor growth was significantly inhibited as compared
      to controls (tumor volume 40 days postrechallenge: 137 mm3 vs 833 mm3 in
      controls; P < 0.03; percent animals without tumor in five experiments: 67% vs 8%
      in controls). Collectively, these results demonstrate that CD8+ T cells are
      required to prevent tumor regrowth after 2I-EtNBS-PDT, NK cells contribute to
      this response and such PDT can elicit protective antitumor immunity.

PMID- 10333763
TI  - Direct comparison of DNA damage, isomerization of urocanic acid and edema in the
      mouse produced by three commonly used artificial UV light sources.
AB  - Exposure to sunlight can result in a number of harmful effects, including
      sunburn, erythema, premature aging of the skin, immune suppression and skin
      cancer. Studies designed to understand the underlying mechanisms often depend
      upon the use of artificial sources of UV radiation. Unfortunately, conclusions
      from different laboratories using different lamps often conflict, and it is
      entirely possible that the different spectra of sunlights used in each may be a
      source of conflict. To minimize confounding variables, we employed two of the
      more commonly used UV light sources, fluorescent sunlamps, such as the FS-40 and
      Kodacel-filtered FS-40 sunlamps, and a xenon arc solar simulator and compared, in
      one series of standardized experiments, the effects of each light source on DNA
      damage, urocanic acid isomerization and edema formation. The dose-response
      curves, calculated by linear regression or curve fitting were compared. The data
      indicate that DNA damage and urocanic acid isomerization were more sensitive to
      shorter wavelengths of UV than longer wavelengths, and the biological endpoint of
      edema most closely correlated with the induction of DNA damage. The results
      emphasize the dominance of shorter wavelengths within the UV spectrum in damaging
      biological tissues, even when the solar simulator, which contains significant
      amounts of UVA, was used and demonstrate that each light source has a
      characteristic pattern of induction of biochemical and biological endpoints.

PMID- 10333765
TI  - Antisense bcl-2 retrovirus vector increases the sensitivity of a human gastric
      adenocarcinoma cell line to photodynamic therapy.
AB  - The bcl-2 oncoprotein directly prolongs cellular survival by blocking apoptosis
      and its overexpression is associated with cellular resistance to killing by
      chemotherapeutic drugs and gamma-irradiation. Meanwhile, it has been shown that
      bcl-2 antisense oligonucleotide can induce apoptosis or increase toxicity of the
      treatment in tumors in vivo and in vitro. However, it is difficult to obtain
      stable transfection by this approach and there are no reports about the effect of
      an antisense bcl-2 on the sensitivity to oxidative stress induced by photodynamic
      therapy (PDT). Here we investigated the effect of an antisense bcl-2 RNA
      retrovirus vector transfer on the sensitivity of 2-butylamino-2-demethoxy
      hypocrellin A (2-BA-2-DMHA) photosensitization in a human gastric adenocarcinoma
      MGC803 cell line. The results indicate that antisense bcl-2-infected MGC803 cells
      expressed exogenous antisense bcl-2 mRNA measured by reverse transcription
      polymerase chain reaction and significantly reduced bcl-2 protein determined by
      western blotting analysis. The decreased expression of bcl-2 protein was
      accompanied by increased phototoxicity and susceptibility to apoptosis induced by
      2-BA-2-DMHA PDT. Our finding suggests that reduction of bcl-2 protein in gastric
      cancers, and possibly also in a variety of other tumors, may be a novel and
      rational approach to improve photosensitivity and the treatment outcome.

PMID- 10333766
TI  - Toxicology of a boronated porphyrin in dogs.
AB  - Among the most important characteristics of any therapeutic agent are efficacy
      and an acceptable toxicity. Prior to human use, toxicity studies are performed in
      both small and large animal models. Our laboratory has developed a new binary
      therapy agent, a boronated porphyrin (BOPP), with excellent potential efficacy.
      The purpose of this study is to examine the toxicology of this compound in dogs.
      Sixteen dogs were given 35 mg/kg of BOPP intravenously and evaluated for up to 28
      days following administration. Clinical and pathologic responses were measured.
      BOPP was clinically well tolerated with some cases of weight loss, vomiting and
      mild photosensitivity. Adverse effects were limited primarily to thrombosis at
      the administration site in several subjects and three cases of mild, possibly
      transient, liver injury. Clinical pathologic tests found reversible changes in
      white blood cell counts and platelets, with neither change being clinically
      significant. The low toxicity associated with BOPP as shown in this study
      provides valuable evidence supporting the use of BOPP in binary therapy.

PMID- 10333767
TI  - Ultraviolet irradiation (UVB) interrupts calcium cell signaling in lens
      epithelial cells.
AB  - A preliminary study was undertaken to establish whether low-dose UV irradiation
      (UVB) affects calcium cell signaling in rabbit lens epithelia. In a suspension of
      lens epithelial cells (line NN1003A), changes in intracellular Ca2+ were measured
      by Fura-2 fluorescence in response to exogenously added ATP. The cellular
      response to ATP, referred to as the calcium signal, is characterized by a brief
      increase and subsequent decrease in cytosolic Ca2+ levels. Ultraviolet B
      irradiation (1.8-9 mJ/cm2) was found to reduce the magnitude of the Ca2+ signal
      in a dose-dependent manner. A 5 min UVB exposure (9 mJ/cm2) completely altered
      the biphasic nature of the calcium signal, causing only an immediate and steady
      rise in cytosol Ca2+ levels. Lower fluences of UVB irradiation (2 min exposure
      times or 3.6 mJ/cm2) induced a 50% reduction in the calcium signal. When
      irradiated cells were returned to culture for 3 h after irradiation, calcium
      signals induced by ATP were normal. In view of the photooxidative nature of UVB
      irradiation, the oxidative state of cells was assessed by measuring glutathione
      (GSH) levels. Ultraviolet B irradiation caused a rapid 20% decline in GSH levels
      that returned to near-control values after a 3 h postirradiation incubation. The
      results of this study indicate that fluences lower than previously found to be
      cataractogenic can perturb calcium cell signaling in cultured lens epithelial
      cells.

PMID- 10333768
TI  - Stability of the fluorescence measurement of Foscan in the normal human oral
      cavity as an indicator of its content in early cancers of the esophagus and the
      bronchi.
AB  - Photodynamic therapy (PDT) with Foscan (mTHPC) is used to cure early cancers of
      the esophagus or the tracheobronchial tree. However, fixed PDT parameters (drug
      dose, light dose, etc.) do not permit an accurate prediction of the tissue
      damage. Large interpatient fluctuations in tissue drug level, at the time of
      light application, suggest that the light dose must be adjusted to the drug dose
      shortly before the PDT. This drug dose can be measured endoscopically by light
      induced fluorescence spectroscopy, but this measurement is inconvenient and
      somewhat difficult. A better test site, yielding comparable information, is
      needed. The oral cavity seems ideal. However, it first had to be established to
      what extent the estimation of the drug dose was dependent upon the location of
      the measurement and the pressure applied to the probe. These measurements prove
      to be not only correlated to similar measurements in the esophagus or the bronchi
      but also more consistent and less sensitive to the location and the applied
      pressure. The buccal mucosa is therefore recommended as a test site for measuring
      the Foscan fluorescence signal at the time of PDT in the esophagus or the
      bronchi. This measurement is accurate enough for use in light-dose adjustment.

PMID- 10333769
TI  - Cell cycle delay, mitochondrial stress and uptake of hydrophobic cations induced
      by sunscreens in cultured human cells.
AB  - Reports of systemic absorption of sunscreens prompted a study of the effects of
      emulsions of 3 commonly used sunscreens on cultured human cells; vegetable oil
      and paraffin oil were used as controls. Ethylhexyl p-methoxycinnamate (EHMC),
      octyl p-dimethylaminobenzoate (PABA) and oxybenzone (OB) inhibited cell growth
      and DNA synthesis and retarded cycle progression from G1 in the dose range 25-100
      micrograms/mL. An extended period of exposure (up to 24 h) was required for
      maximum uptake of sunscreens and for inhibition of cell growth. Melano-cytes and
      fibroblasts tended to be more resistant than tumor cell lines (melanoma, cervical
      carcinoma). Sunscreens had no major effects on the transcription of certain
      genes, as judged by the activity of reporter constructs driven by the p53, c-fos
      and metal response (sheep metallothionein Ia promoter) elements and transfected
      into a human melanoma cell line (MM96L). The activity of the cytomegalovirus
      promoter was also not affected. A cell line (CI80-13S) with mitochondrial
      dysfunction was significantly more sensitive to growth inhibition by EHMC and
      PABA than the other cell lines tested. Treatment of MM96L with the mitochondrial
      inhibitor ethidium bromide sensitized the cells to killing by cotreatment with
      sunscreens, in association with increased cellular uptake of ethidium bromide.
      These results established conditions for studying the action of sunscreens on
      cultured human cells. Further studies are required to determine whether the
      mitochondrial stress and changes in drug uptake associated with sunscreens in the
      above cell lines are relevant to their action in vivo.

PMID- 10333770
TI  - Lactose and other intake prohibitions in small-bowel syndrome.

PMID- 10333771
TI  - SBS diet needs to address individual physiology.

PMID- 10333772
TI  - Is herbal therapy helpful or hazardous?

PMID- 10333773
TI  - How to design your professional development 2001 portfolio.

PMID- 10333774
TI  - The value of lifelong learning: key element in professional career development.

PMID- 10333775
TI  - A dietitian-delivered group nutrition program leads to reductions in dietary fat,
      serum cholesterol, and body weight: the Worcester Area Trial for Counseling in
      Hyperlipidemia (WATCH).
AB  - OBJECTIVE: To assess the effectiveness of a dietitian-based nutrition counseling
      and education program for patients with hyperlipidemia. DESIGN: A 4-session
      program implemented as a complement to a randomized physician-delivered
      intervention. SUBJECTS/SETTING: From 12 practice sites of the Fallon Clinic,
      1,162 subjects with hyperlipidemia were recruited, 645 of whom had data
      sufficient for our primary analyses. INTERVENTION: Two individual and 2 group
      sessions conducted over 6 weeks. MAIN OUTCOME MEASURES: Total and saturated fat
      levels; serum low-density lipoprotein cholesterol levels; and body weight,
      measured at baseline and after 1 year. STATISTICAL ANALYSES: Multiple linear
      regression was used to evaluate changes in outcome measures. RESULTS: After 1
      year, there were significant reductions in outcome measures for subjects
      attending 3 or 4 nutrition sessions vs subjects attending fewer than 3 sessions
      or those never referred to a nutrition session. Reductions (mean +/- standard
      error) in saturated fat (measured as percent of energy) were 2.7 +/- 0.5%, 2.1 +/
      0.5%, and 0.3 +/- 0.1%, respectively. These reductions correspond to roughly a
      22% relative change from baseline in those attending 3 or 4 sessions. Corollary
      reductions were observed for total fat (measured as percent of energy): 8.2 +/-
      1.4%, 5.0 +/- 1.4%, and 0.7 +/- 0.4%; low-density lipoprotein cholesterol: 0.48
      +/- 0.11 mmol/L, 0.13 +/- 0.11 mmol/L, and 0.02 +/- 0.03 mmol/L; and body weight:
      4.5 +/- 0.9 kg, 2.1 +/- 0.8 kg, and 1.1 +/- 0.2 kg. The specified changes were
      additive to those of the physician-delivered intervention.
      APPLICATIONS/CONCLUSIONS: This investigation provides empirical data
      demonstrating the effectiveness of a dietitian-delivered intervention in the care
      of patients with hyperlipidemia.

PMID- 10333776
TI  - Education and certification influence the nutrition and management knowledge of
      long-term-care foodservice managers.
AB  - OBJECTIVES: To describe nutrition knowledge, attitude toward nutrition, and
      management knowledge of long-term-care foodservice managers and to determine the
      relationship between these variables and the foodservice managers' personal and
      facility characteristics. DESIGN: Nutrition knowledge, management knowledge, and
      attitudes toward nutrition were measured using survey methodology designed for
      this study by modifying an instrument developed by the Nutrition Education
      Training Program for the Texas Department of Human Services. SUBJECTS/SETTING:
      Surveys were mailed to a random sample of 300 long-term-care foodservice
      directors from the 1,092 directors listed in the 1996 Ohio Department of Health
      Directory of Nursing Homes. The participants were 123 of the 300 foodservice
      directors (41%). STATISTICAL ANALYSES PERFORMED: Descriptive statistics, Spearman
      rank correlations, 1-way analysis of variance, and post hoc variance were
      calculated. RESULTS: Mean scores of respondents were 21.2 out of a possible 29
      (73%) for the nutrition knowledge assessment, and 18.2 out of 26 (70%) for
      management knowledge. Dietitians and dietetic technicians scored significantly
      better than others on these tests. The mean score of attitudes toward nutrition
      was 4 on a 5-point scale (where 1 = strongly disagree to 5 = strongly agree). All
      participants requested more training in computers, nutrition terminology, and
      preparing appealing foods. APPLICATIONS: Dietitians and dietetic technicians are
      prepared with a wide scope of knowledge in nutrition and management. Thus, they
      are in an ideal position to take advantage of job opportunities in the area of
      foodservice management.

PMID- 10333777
TI  - Development of a soy food frequency questionnaire to estimate isoflavone
      consumption in US adults.
AB  - OBJECTIVE: To develop a dietary assessment instrument to measure soy food
      consumption and isoflavone intake and test it for reliability. DESIGN: A soy food
      frequency questionnaire, designed for use in this study, was administered twice
      to participants, separated by a 2-week interval. The questionnaire was tested for
      reproducibility of estimates of soy food consumption and isoflavone (genistein
      and daidzein) intake. SUBJECTS/SETTING: A convenience sample of 51 faculty,
      staff, and students was recruited from a naturopathic university. STATISTICAL
      ANALYSES PERFORMED: Intraclass correlation coefficients were used to assess
      reproducibility of estimates of soy food intake and genistein and daidzein
      intake. RESULTS: Correlation coefficients comparing mean soy food servings per
      month between the 2 administrations of the questionnaire ranged from 0.50 for soy
      yogurt to 0.89 for tempeh. Correlation coefficients for genistein and daidzein
      intake estimated by the 2 administrations of the questionnaire were the same:
      0.89. Mean intake (+/- standard deviation) of genistein and daidzein was 7 +/- 10
      and 4 +/- 6 mg/day, respectively. Fifteen soy foods contributed 95% of the total
      genistein and daidzein intake: tofu, soy yogurt, tempeh, soy milk, low-fat tofu,
      soy flour, miso, soy protein isolate, low-fat soy milk, veggie soy burger,
      textured vegetable protein, miso soup, cooked soybeans, soy hot dogs, and natto
      (fermented soy beans). APPLICATIONS: The soy food frequency questionnaire
      developed in this study provided highly reproducible estimates of soy food
      consumption and isoflavone intake. This instrument may be a useful tool in
      studies of the associations between isoflavone exposure and risk for chronic
      disease.

PMID- 10333778
TI  - Nutrient intakes and adequacy among an older population on the eastern shore of
      Maryland: the Salisbury Eye Evaluation.
AB  - OBJECTIVE: To describe the reported usual dietary intakes of the participants in
      the Salisbury Eye Evaluation (SEE) project and to estimate the prevalence of
      inadequate nutrient intakes using the probability approach. SUBJECTS/SETTING: A
      representative sample of elderly residents (aged 65 to 85 years) of Salisbury,
      Md. DESIGN: Cross-sectional survey, using a food frequency questionnaire to
      obtain nutrient intakes. We estimated energy and protein; percent of energy
      intake from carbohydrates, fat, and protein; as well as usual intakes of
      cholesterol, vitamin A, carotenoids, vitamin C, thiamin, riboflavin, vitamin B-6,
      vitamin E, niacin, iron, calcium, zinc, and folate. Estimates of prevalence of
      inadequate nutrient intakes were calculated using the probability approach among
      the 2,655 participants with complete nutrient intake information. STATISTICAL
      ANALYSES PERFORMED: The chi 2 test for independence and analysis of variance. A P
      < .05 was considered significant in a 2-sided test. RESULT: On average, white
      participants of both genders reported higher mean energy and nutrient intakes
      than did black participants. Zinc had the highest estimated prevalences of
      inadequacy across all gender and race categories, followed by calcium, vitamin E,
      and vitamin B-6. Vitamin C, with estimated prevalences of inadequacy lower than
      13%, and folate, with prevalences lower than 17%, had the lowest estimated
      prevalences of inadequacy across all gender, race, and age categories.
      CONCLUSIONS: In this population, there are race differences in estimated
      prevalences of inadequate nutrient intake. According to the current nutrient
      requirements for adults aged 51 years and older, many elderly persons have
      inadequate dietary intakes of key nutrients.

PMID- 10333779
TI  - Comparison of energy and nutrient sources of elderly Hispanics and non-Hispanic
      whites in New Mexico.
AB  - OBJECTIVE: Identification and comparison of frequently consumed foods and
      important food sources of energy, protein, total fat, vitamin A, vitamin C,
      vitamin E, vitamin B-6, folate, and calcium of elderly Hispanics and non-Hispanic
      whites. DESIGN: Dietary intake data were collected using a modified Health Habits
      and History Questionnaire (a food frequency questionnaire) for 735 subjects who
      participated in the New Mexico Elder Health Survey. SUBJECTS: The sample
      consisted of 330 Hispanics (176 men and 154 women) and 405 non-Hispanic whites
      (214 men and 191 women) between the ages of 65 and 96 years. Subjects were those
      with food frequency data among 883 participants who completed the clinical visit
      of the New Mexico Elder Health Survey. RESULTS: Results show the top-ranked
      frequently consumed foods by gender and ethnicity and top-ranked food sources of
      energy and 8 nutrients. Regional foods were important sources of nutrients in the
      diets of both Hispanics and non-Hispanic whites, however, more so for the
      Hispanics. Chile sauces were notable sources of vitamin A, vitamin C, and folate
      among both groups. Both ethnic groups demonstrated selection of low-fat and skim
      milk and moderation in consumption of red meat. APPLICATIONS: These data will be
      useful for designing nutrition education programs, for studying the relationship
      between diet and disease among elderly Hispanics and non-Hispanic whites, and for
      designing assessment instruments for the elderly and other ethnic populations.

PMID- 10333780
TI  - Using disease-state management as the key to promoting employer sponsorship of
      medical nutrition therapy (continuing education credit).
AB  - The purpose of this project was to design, implement, and improve a nationwide
      medical nutrition therapy (MNT) intervention program for nutritionally at-risk
      employees and their dependents and retirees (hereinafter referred to as clients)
      with a Fortune 100 company (Texas Instruments, Dallas, Tex) with a dispersed
      population of 80,000. Preferred Nutrition Therapists (PNT), a network of
      registered dietitians, with the assistance of the Texas Instruments Health
      Promotion and Benefits Department, identified International Classification of
      Diseases, 9th ed (ICD-9), codes for which MNT intervention was appropriate. PNT
      then negotiated a contract with the Texas Instruments Health Promotion and
      Benefits Department and implemented clients' self-referral process. The main
      challenge was to promote utilization of a new service from an outside vendor
      (PNT) and to measure outcomes in meaningful ways. The goal was to use MNT as a
      tool to prevent the progression of clients' diseases to states that require more
      costly treatments. PNT used a continuous quality improvement process to refine
      the system and improve information gathering and reporting, by providing
      quarterly reports to the Health Promotion and Benefits Department. These reports
      summarized the outcomes for all clients seen at least 3 times during the quarter.
      The cost was less than $0.35 per member per month (less than the employer spent
      on advertising the program), and 0.5% of the population requested MNT during the
      first year of implementation (about what was expected for a new carveout
      benefit).

PMID- 10333781
TI  - Calcium supplementation and exercise increase appendicular bone density in
      anorexia: a case study.

PMID- 10333782
TI  - Oral creatine supplementation in male collegiate athletes: a survey of dosing
      habits and side effects.

PMID- 10333783
TI  - Vegetarianism among US women physicians.

PMID- 10333784
TI  - Two small surveys, 25 years apart, investigating motivations of dietary choice in
      2 groups of vegetarians in the Boston area.

PMID- 10333785
TI  - Child feeding strategies in low-income Latino households: focus group
      observations.

PMID- 10333786
TI  - The Professional Development 2001 Portfolio.

PMID- 10333787
TI  - Medicare: victim of rhetoric?

PMID- 10333788
TI  - Nursing and Wit.

PMID- 10333789
TI  - Similar name, different diagnosis. When two patients shouldn't be in the same
      room.

PMID- 10333790
TI  - Protecting the latex sensitive from chemotherapy.

PMID- 10333791
TI  - Real world drug monitoring.

PMID- 10333792
TI  - Provider-to-patient transmission.

PMID- 10333793
TI  - Epidural analgesia in children.

PMID- 10333794
TI  - When gambling becomes a losing battle.

PMID- 10333795
TI  - Tears for Stephanie. Knowing when a methodical response is appropriate--and when
      to express sorrow.

PMID- 10333796
TI  - AEDs. Changing the way you respond to cardiac arrest. Automatic external
      defibrillators.

PMID- 10333797
TI  - When faith is used to justify abuse. Helping victims of domestic violence.

PMID- 10333798
TI  - Sickle cell anemia.

PMID- 10333799
TI  - Getting to the heart of denial.

PMID- 10333800
TI  - Nurses at risk. A call to mobilize.

PMID- 10333801
TI  - Emergency! Methemoglobinemia.

PMID- 10333802
TI  - Case Management. Its value for staff nurses.

PMID- 10333803
TI  - Performance improvement in everyday clinical practice.

PMID- 10333804
TI  - ANA puts nursing in media spotlight.

PMID- 10333805
TI  - Detecting Hodgkin's disease.

PMID- 10333807
TI  - Preventing back injuries.

PMID- 10333806
TI  - The value of lab values.

PMID- 10333808
TI  - Improving care for the elderly.

PMID- 10333809
TI  - Dictation and the patient.

PMID- 10333810
TI  - Adverse effects of selective serotonin reuptake inhibitors.

PMID- 10333811
TI  - Relationship between use of the intrauterine device and pelvic inflammatory
      disease.

PMID- 10333812
TI  - Clinical guidelines.

PMID- 10333813
TI  - Diagnosis of migraine.

PMID- 10333814
TI  - The Supreme Court addresses physician-assisted suicide. Can its rulings improve
      palliative care?
AB  - In June 1997, the US Supreme Court unanimously decided that competent, terminally
      ill patients have no general constitutional right to commit suicide or to obtain
      assistance in committing suicide. Thus, the broad prohibitions against any kind
      of suicide assistance that almost every state has enacted do not violate the
      constitution. While many of the rulings and the bulk of the reaction to them
      focused on the Supreme Court's resolution of important legal controversies
      regarding physician-assisted suicide, this article focuses on the resulting
      potential for change in physicians' opinions on palliative care. The Court's
      reasoning may help physicians resolve substantial ethical dilemmas regarding the
      provision of narcotics given in high dosages, the care of incompetent patients,
      and the suffering caused by symptoms other than pain. For example, the Court
      concluded that a physician's intent can distinguish permissible acts of
      aggressive pain relief from impermissible acts of hastening death. This
      distinction has clinical uses and can help physicians develop ethical guidelines
      and practice standards to improve palliative care near the end of life.

PMID- 10333815
TI  - Effectiveness of assistive technology and environmental interventions in
      maintaining independence and reducing home care costs for the frail elderly. A
      randomized controlled trial.
AB  - CONTEXT: Home environmental interventions (EIs) and assistive technology (AT)
      devices have the potential to increase independence for community-based frail
      elderly persons, but their effectiveness has not been demonstrated. OBJECTIVE: To
      evaluate a system of AT-EI service provision designed to promote independence and
      reduce health care costs for physically frail elderly persons. DESIGN: Randomized
      controlled trial. SETTING AND PARTICIPANTS: A total of 104 home-based frail
      elderly persons living in western New York were assigned to 1 of 2 groups (52
      treatment, 52 control). INTERVENTION: All participants underwent a comprehensive
      functional assessment and evaluation of their home environment. Participants in
      the treatment group received AT and EIs based on the results of the evaluation.
      The control group received "usual care services." MAIN OUTCOME MEASURES:
      Functional status as measured by the Functional Independence Measure (FIM) and
      the Craig Handicap Assessment and Reporting Technique; pain as measured by the
      Functional Status Instrument; and health care costs including the costs. RESULTS:
      After the 18-month intervention period, the treatment groups showed significant
      decline for FIM total score and FIM motor score, but there was significantly more
      decline for the control group. Functional Status Instrument pain scores increased
      significantly more for the control group. In a comparison of health care costs,
      the treatment group expended more than the control group for AT and EIs. The
      control group required significantly more expenditures for institutional care.
      There was no significant difference in total in-home personnel costs, although
      there was a large effect size. The control group had significantly greater
      expenditures for nurse visits and case manager visits. CONCLUSION: The frail
      elderly persons in this trial experienced functional decline over time. Results
      indicate rate of decline can be slowed, and institutional and certain in-home
      personnel costs reduced through a systematic approach to providing AT and EIs.

PMID- 10333816
TI  - Evaluating interviewing techniques for the sexual practices history. Use of video
      trigger tapes to assess patient comfort.
AB  - BACKGROUND: Although physicians recognize the importance of assessing a patient's
      risk for human immunodeficiency virus (HIV) infection, many are reluctant to
      explore a person's sexual history, a principal determinant of this risk.
      OBJECTIVE: To examine the feasibility of a research design that uses responses to
      viewing a videotaped interview as a proxy for how patients might feel if they
      were interviewed using a specific approach, and to determine comfort levels with
      a variety of interview approaches for conducting HIV risk assessment. METHODS:
      Individuals responded to a videotape of several interviewing approaches for HIV
      risk assessment. Responses to the following aspects were collected: introduction
      of HIV risk assessment, assessment of patient comfort with the topic, techniques
      for collecting HIV risk and sexual information, and exploration of sensitive
      issues not previously identified. Participants expressed levels of comfort by
      means of a Likert scale to rate their comfort with each approach. RESULTS:
      Participants expressed higher comfort levels with an introduction that used a
      ubiquity statement or lifestyle bridge question. Also, they expressed greater
      comfort when the interviewer addressed how they felt about responding to
      questions about their HIV risk. Participants reported highest levels of comfort
      with both patient-centered and closed-ended interviewing techniques. Women were
      less comfortable with an open-ended interviewing technique. CONCLUSIONS:
      Individuals have different comfort levels for approaches used to assess HIV risk.
      This trigger tape experimental design to assess comfort levels for interview
      techniques is feasible for exploring other aspects of physician-patient
      communication; additional validation studies are recommended.

PMID- 10333817
TI  - Primary care physician perceptions of the nurse practitioner in the 1990s.
AB  - OBJECTIVE: To evaluate factors associated with primary care physician attitudes
      toward nurse practitioners (NPs) providing primary care. DESIGN: A mailed survey
      of primary care physicians in Iowa. SETTING AND PARTICIPANTS: Half (N = 616) of
      the non-institutional-based, full-time, primary care physicians in Iowa in spring
      1994. Although 360 (58.4%) responded, only physicians with complete data on all
      items in the model were used in these analyses (n = 259 [42.0%]). MAIN OUTCOME
      MEASURES: There were 2 principal dependent measures: physician attitudes toward
      NPs providing primary care (an 11-item instrument) and physician experience with
      NPs in this role. Bivariate relationships between physician demographic and
      practice characteristics were evaluated by chi 2 tests, as were both dependent
      variables. Ordinary least-squares regression was used to determine factors
      related to physician attitudes toward NPs. RESULTS: In bivariate analyses,
      physicians were significantly more likely to have had experience with an NP
      providing primary care if they were in pediatrics or obstetrics-gynecology (78.3%
      and 70.0%, respectively; P < .001), had been in practice for fewer than 20 years
      (P = .045), or were in practices with 5 or more physicians. The ordinary least
      squares regression indicated that physicians with previous experience working
      with NPs providing primary care (P = .01), physicians practicing in urban areas
      with populations greater than 20,000 but far from a metropolitan area (P = .03),
      and general practice physicians (P = .04) had significantly more favorable
      attitudes toward NPs than did other primary care physicians. CONCLUSIONS: The
      association between previous experience with a primary care NP and a more
      positive attitude toward NPs has important implications for the training of
      primary care physicians, particularly in community-based, multidisciplinary
      settings.

PMID- 10333818
TI  - Predictors and mediators of successful long-term withdrawal from antihypertensive
      medications. TONE Cooperative Research Group. Trial of Nonpharmacologic
      Interventions in the Elderly.
AB  - BACKGROUND: National guidelines recommend consideration of step down or
      withdrawal of medication in patients with well-controlled hypertension, but
      knowledge of factors that predict or mediate success in achieving this goal is
      limited. OBJECTIVE: To identify patient characteristics associated with success
      in controlling blood pressure (BP) after withdrawal of antihypertensive
      medication. DESIGN: The Trial of Nonpharmacologic Interventions in the Elderly
      tested whether lifestyle interventions designed to promote weight loss or a
      reduced intake of sodium, alone or in combination, provided satisfactory BP
      control among elderly patients (aged 60-80 years) with hypertension after
      withdrawal from antihypertensive drug therapy. Participants were observed for 15
      to 36 months after attempted drug withdrawal. MAIN OUTCOME MEASURES: Trial end
      points were defined by (1) a sustained BP of 150/90 mm Hg or higher, (2) a
      clinical cardiovascular event, or (3) a decision by participants or their
      personal physicians to resume BP medication. RESULTS: Proportional hazards
      regression analyses indicated that the hazard (+/- SE) of experiencing an end
      point among persons assigned to active interventions was 75% +/- 9% (weight
      loss), 68% +/- 7% (sodium reduction), and 55% +/- 7% (combined weight loss/sodium
      reduction) that of the hazard for those assigned to usual care. Lower baseline
      systolic BP (P < .001), fewer years since diagnosis of hypertension (P < .001),
      fewer years of antihypertensive treatment (P < .001), and no history of
      cardiovascular disease (P = .01) were important predictors of maintaining
      successful nonpharmacological BP control throughout follow-up, based on logistic
      regression analysis. Age, ethnicity, baseline level of physical activity baseline
      weight, medication class, smoking status, and alcohol intake were not
      statistically significant predictors. During follow-up, the extent of weight loss
      (P = .001) and urinary sodium excretion (P = .04) were associated with a
      reduction in the risk of trial end points in a graded fashion. CONCLUSIONS:
      Withdrawal from antihypertensive medication is most likely to be successful in
      patients with well-controlled hypertension who have been recently (within 5
      years) diagnosed or treated, and who adhere to life-style interventions involving
      weight loss and sodium reduction. More than 80% of these patients may have
      success in medication withdrawal for longer than 1 year.

PMID- 10333819
TI  - Early postpartum discharges. Impact on distress and outpatient problems.
AB  - OBJECTIVE: To determine the impact of shortened postpartum hospital stays on
      common clinical phenomena in a sociodemographically diverse, unselected group of
      general maternity patients. DESIGN: Observational cohort study in which the
      preapproved hospital stay duration of either 1 or 2 nights was set by third-party
      payers before each mother's admission. SETTING: Yale-New Haven Hospital, New
      Haven, Conn, from June 19 through August 10, 1995. PATIENTS: Two hundred forty
      four volunteers from among 400 eligible deliveries. MAIN OUTCOME MEASURES:
      Readmission within 1 month of hospital discharge, report of outpatient morbidity
      and use of outpatient health services within 1 week of discharge, status of
      breast-feeding during the first post-discharge week, and patient satisfaction.
      RESULTS: At discharge from the hospital, the hospital stay was regarded as "too
      short" by 80 (47%) of 171 mothers and 19 (26%) of 73 mothers in the 1- and 2
      night groups, respectively (P = .002). Although readmission rates were similar
      (5% vs 3%, P = .48), the 1-night group reported significantly more morbidity in
      the newborns (31% vs 16%, P = .03) and averaged more pediatric visits (96 vs 54
      per 100 newborns, P = .002). Mothers in the 1-night group also reported more
      fatigue (49% vs 29%, P = .001) and more worries about their newborns' health (24%
      vs 11%, P = .02). They were less likely to start breast-feeding (64% vs 77%, P =
      .06), and, if they started, were somewhat more likely to stop prematurely (14% vs
      8%, P = .43). A series of disturbing events was reported only in the 1-night
      group. CONCLUSIONS: In a relatively unselected group, mothers who stayed 1 night
      after routine vaginal delivery reported more distress and more pediatric problems
      and had greater use of outpatient health services than mothers who stayed 2
      nights.

PMID- 10333820
TI  - Loperamide-simethicone vs loperamide alone, simethicone alone, and placebo in the
      treatment of acute diarrhea with gas-related abdominal discomfort. A randomized
      controlled trial.
AB  - CONTEXT: Acute diarrhea with gas-related abdominal discomfort is a common,
      usually self-limited disorder with substantial social and economic impact.
      OBJECTIVE: To compare the efficacy and safety of a loperamide hydrochloride
      simethicone combination product with those of loperamide alone, simethicone
      alone, and placebo in treating acute diarrhea with gas-related abdominal
      discomfort. DESIGN: Randomized, placebo-controlled, double-blind trial of 48
      hours' duration. SETTING: A primary care, ambulatory practice in Acapulco,
      Mexico. PATIENTS: A total of 493 outpatient adults aged 18 to 63 years, with
      acute nonspecific diarrhea with at least moderately severe abdominal discomfort.
      INTERVENTIONS: Each patient was randomly assigned to receive 2 chewable tablets
      containing loperamide hydrochloride, 2 mg, and simethicone, 125 mg (n = 124);
      loperamide hydrochloride, 2 mg (n = 123); simethicone, 125 mg (n = 123); or
      placebo (n = 123). This was followed by 1 tablet after each unformed stool, up to
      4 tablets in any 24-hour period. MAIN OUTCOME MEASURES: Time to last unformed
      stool and time to complete relief of gas-related abdominal discomfort were the
      protocol-specified primary outcomes. Secondary outcomes included time to complete
      relief of diarrhea, number of unformed stools, and patient-assessed variables at
      the end of the study (overall illness relief, diarrhea relief, and abdominal
      discomfort relief). RESULTS: Patients who received loperamide-simethicone had
      significantly (P < .001) shorter time to last unformed stool and faster relief of
      gas-related abdominal discomfort than patients who received loperamide,
      simethicone, or placebo alone. Loperamide-simethicone was significantly (P < or =
      .01) more effective than the other 3 treatments for all end-of-study patient
      assessed outcomes and all clinically important secondary outcomes. No significant
      differences in adverse events were found among treatment groups. CONCLUSIONS: The
      loperamide-simethicone combination chewable product provides faster and more
      complete relief of acute nonspecific diarrhea and associated gas-related
      abdominal discomfort (gas pain, cramps, gas pressure, and bloating) than either
      of its components or placebo. The combination is well tolerated.

PMID- 10333821
TI  - Attitudes, knowledge, and behavior of family physicians regarding depression in
      late life.
AB  - OBJECTIVES: To assess self-reported knowledge, attitudes, and behaviors of
      practicing community family physicians regarding identification and management of
      depression in late life. DESIGN: We sent a 3-page "fax-back" survey to 768 active
      physician members of the Maryland Academy of Family Physicians, Baltimore.
      MEASUREMENTS: We asked physicians to rate how confident they felt in evaluating
      several common medical conditions of late life, including depression. The
      questionnaire included items related to knowledge and treatment practices for
      depression in older adults. RESULTS: Two hundred fifteen usable surveys were
      returned. In general, physicians took responsibility for diagnosing and treating
      depression. Few physicians reported that they routinely referred the older
      patient to a psychiatrist to treat depression, and only half thought that
      consultation was helpful. Physicians responding to the survey were generally
      aware of alternative presentations of depression in elderly persons, and were
      well informed about the duration of treatment with medications for depression.
      Most were using selective serotonin reuptake inhibitors as first-line agents to
      treat depression. Physicians though that medications for depression were as
      effective for older patients as for younger patients, but were less optimistic
      about the effectiveness of psychotherapy. The barriers to identifying and
      treating depression in older patients most often mentioned by physicians were
      related to the atypical presentation of depression in older adults. More than
      half of the physicians rated themselves as "very confident" in evaluating
      depression. There were few differences in the responses of physicians with and
      those without a Certificate of Added Qualifications in geriatrics. CONCLUSIONS:
      Depression in late life remains a difficult clinical challenge for primary care
      physicians. These findings are particularly relevant in the face of recent
      efforts to increase collaboration between primary care physicians and mental
      health professionals.

PMID- 10333822
TI  - Current status of testosterone replacement therapy in men.
AB  - Testosterone plays an essential role in the development of the normal male and in
      the maintenance of many male characteristics, including muscle mass and strength,
      bone mass, libido, potency, and spermatogenesis. Androgen deficiency occurs with
      disorders that damage the testes, including traumatic or surgical castration
      (primary testicular failure) or disorders in which the gonadotropin stimulation
      of the testes is reduced (hypogonadotropic hypogonadism). The clinical
      manifestations of androgen deficiency depend on the age at onset and the severity
      and duration of the deficiency. In adult males, these manifestations may include
      reduced body hair, decreased muscle mass and strength, increased fat mass,
      decreased hematocrit, decreased libido, erectile dysfunction, infertility,
      osteoporosis, and depressed mood. The forms of androgen replacement currently
      available in the United States are intramuscular depot injections of testosterone
      esters, oral tablets of testosterone derivatives, and transdermal patches. For
      most patients, androgen replacement therapy with testosterone is a safe,
      effective treatment for testosterone deficiency.

PMID- 10333823
TI  - Trigeminal neuralgia. New treatment options for a well-known cause of facial
      pain.
AB  - Trigeminal neuralgia is an idiopathic disorder of unilateral facial pain that is
      characterized by lancinating paroxysms of pain in the lips, gums, cheek, or chin.
      Pain in trigeminal neuralgia is associated with physical triggers. Much of the
      treatment has been unchanged for more than 10 years, with cabamazepine being the
      standard first-line treatment. There are several promising new medications
      available, such as pimozide, tizanidine hydrochloride, and topical capsaicin.
      Surgical management is also effective.

PMID- 10333824
TI  - The management of troubling feelings toward patients.

PMID- 10333825
TI  - Chiropractic and medicine blended at clinic.

PMID- 10333826
TI  - False-positive results in antenatal HIV screening.

PMID- 10333827
TI  - Compulsory HIV tests.

PMID- 10333828
TI  - Where there's smoke.

PMID- 10333829
TI  - King Tut's curse, take 2.

PMID- 10333830
TI  - Prevalence of gestational diabetes mellitus among James Bay Cree women in
      northern Quebec.
AB  - BACKGROUND: The prevalence of gestational diabetes mellitus has been reported to
      vary widely in aboriginal populations. Most of the data have come from the United
      States. To help determine the extent of gestational diabetes in Canada's
      aboriginal population, the authors assessed the prevalence in a population of
      Cree women in northern Quebec. METHODS: A cross-sectional study was conducted
      using the National Diabetes Data Group (NDDG) criteria. Information was obtained
      from patient charts on pregnancies between January 1995 and December 1996 among
      women residing in 9 Cree communities in the eastern James Bay region of northern
      Quebec. Women who were not Cree, had pre-existing diabetes, had spontaneous
      abortion or were receiving glucocorticoid treatment were excluded. RESULTS: Data
      on 654 pregnancies that met the inclusion criteria were available. Results of the
      screening oral glucose challenge test were available for 579 of the pregnancies;
      the remaining 75 were excluded. The mean gestational age at screening was 28.3
      (standard deviation 2.6) weeks. The prevalence of gestational diabetes was 12.8%
      (74/579) (95% confidence interval [CI] 10.1%-15.5%). The prevalence in the inland
      communities was twice as high as that in the coastal communities (18.0% v. 9.3%,
      p = 0.002). Women with gestational diabetes or impaired glucose tolerance tended
      to be older, have had more pregnancies, weigh more before pregnancy and have
      heavier babies than those with a normal glycemic status. INTERPRETATION: The
      prevalence of gestational diabetes among James Bay Cree women in northern Quebec
      is twice as high as that among women in the general North American population and
      the second highest reported in an aboriginal group worldwide.

PMID- 10333831
TI  - Prevalence of gestational diabetes mellitus among Swampy Cree women in Moose
      Factory, James Bay.
AB  - BACKGROUND: Although high rates of gestational diabetes mellitus have been
      documented in native populations, few studies have examined rates of the disease
      among native Indians in Canada. The authors conducted a study to estimate the
      prevalence of gestational diabetes among Swampy Cree women, to identify factors
      predictive of the occurrence of gestational diabetes, and to identify delivery
      and infant outcomes related to the presence of the disease. METHODS: Information
      on Swampy Cree women who gave birth at Weeneebayko Hospital, Moose Factory, James
      Bay, Ont., between 1987 and 1995 was obtained from medical charts. Patients with
      and without gestational diabetes were compared. Logistic regression analysis was
      used to identify independent predictors of gestational diabetes. Delivery and
      infant outcomes that occurred secondary to gestational diabetes were also
      identified by means of logistic regression. RESULTS: A total of 1401 deliveries
      occurred at Weeneebayko Hospital over the study period, of which 1298 were
      included in the study. Gestational diabetes was diagnosed in 110 (8.5% [95%
      confidence interval (CI) 6.9%-9.9%]) of the 1298 pregnancies. Factors predictive
      of gestational diabetes were age 35 years or more (relative risk [RR] 4.1, 95% CI
      1.5-11.7), a history of gestational diabetes in a previous pregnancy (RR 6.4, 95%
      CI 3.5-11.7), diastolic blood pressure of 80 mm Hg or higher at the first
      prenatal visit (RR 1.7, 95% CI 1.1-2.8), weight greater than 80 kg at the first
      prenatal visit (RR 4.9, 95% CI 1.8-12.9) and having a first-degree relative with
      diabetes (RR 3.0, 95% CI 1.4-6.1). The only delivery outcome independently
      associated with the presence of gestational diabetes was an increased likelihood
      of needing assisted delivery (forceps or vacuum extraction) (RR 2.8, 95% CI 1.1
      7.0). Shoulder dystocia was indirectly associated with gestational diabetes owing
      to increased infant birth weight. Infant outcomes associated with the presence of
      gestational diabetes were birth weight greater than 4500 g (RR 2.4, 95% CI 1.4
      3.8), hyperbilirubinemia (RR 2.9, 95% CI 1.4-6.1), hypoglycemia (RR 7.3, 95% CI
      3.7-14.4) and hypocalcemia (RR 8.9, 95% CI 2.3-33.7). INTERPRETATION: Gestational
      diabetes occurred in a significant minority of Swampy Cree women and was
      associated with a number of adverse outcomes.

PMID- 10333832
TI  - Intermittent compression units for severe post-phlebitic syndrome: a randomized
      crossover study.
AB  - BACKGROUND: Although uncommon, severe post-phlebitic syndrome may be associated
      with persistent, intractable pain and swelling that interfere with work and
      leisure activities. This study was performed to determine whether intermittent
      compression therapy with an extremity pump benefits patients with this condition
      and, if so, whether the benefit is sustained. METHODS: The study was a randomized
      crossover trial. Over the period 1990 to 1996, all patients in the clinical
      thromboembolism program of an Ontario teaching hospital who had a history of deep
      vein thrombosis and intractable symptoms of post-phlebitic syndrome were
      recruited into the study. The study involved using an extremity pump twice daily
      for a total of 2 months (20 minutes per session). The patients were randomly
      assigned to use either a therapeutic pressure (50 mm Hg) or a placebo pressure
      (15 mm Hg) for the first month. For the second month, the patients used the other
      pressure. A questionnaire assessing symptoms and functional status served as the
      primary outcome measure and was administered at the end of each 1-month period. A
      symptom score was derived by summing the scores for individual questions. At the
      end of the 2-month study, patients were asked to indicate their treatment
      preference and to rate the importance of the difference between the 12 pressures.
      Treatment was considered successful if the patient preferred the therapeutic
      pressure and stated that he or she would continue using the extremity pump and
      that the difference between the therapeutic and placebo pressures was of at least
      slight importance. All other combinations of responses were considered to
      represent treatment failure. Patients whose treatment was classified as
      successful were offered the opportunity to keep the pump and to alter pressure,
      frequency and duration of pump use to optimize symptom management. In July 1996
      the authors contacted all study participants whose treatment had been classified
      as successful to determine whether they were still using the pump and, if so,
      whether they were still deriving benefit. RESULTS: In total 15 consecutive
      patients (12 women and 3 men) were enrolled in the study. The symptom scores were
      significantly better with the therapeutic pressure (mean 16.5) than with the
      placebo pressure (mean 14.4) (paired t-test, p = 0.007). The treatment for 12 of
      the patients (80%, 95% confidence interval 52% to 96%) was considered successful.
      Of these, 9 patients continued to use the pump beyond the crossover study and to
      derive benefit. INTERPRETATION: The authors conclude that a trial of pump therapy
      is worthwhile for patients with severe post-phlebitic syndrome and that a
      sustained beneficial response can be expected in most such patients.

PMID- 10333833
TI  - Radiofrequency radiation in five Vancouver schools: exposure standards not
      exceeded.

PMID- 10333834
TI  - Alleviating nausea and emesis by Pavlovian conditioning.

PMID- 10333835
TI  - Ironies most bittersweet.

PMID- 10333836
TI  - Optimizing the duration of anticoagulation therapy for venous thrombosis.

PMID- 10333837
TI  - Radiofrequency radiation exposure and other environmental concerns.

PMID- 10333838
TI  - Informed consent in a different key: physicians' practice profiles and the
      patient's right to know.

PMID- 10333839
TI  - Reporting medical mistakes and misconduct.

PMID- 10333841
TI  - Lifestyle changes to prevent and control hypertension: do they work? A summary of
      the Canadian consensus conference.

PMID- 10333840
TI  - Recent advances in refractive surgery.
AB  - Refractive errors are some of the most common ophthalmic abnormalities world-wide
      and are associated with significant morbidity. Tremendous advances in treating
      refractive errors have occurred over the past 20 years. The arrival of the
      excimer laser has allowed a level of accuracy in modifying the cornea that was
      unattainable before. Although refractive surgery is generally safe and effective,
      it does carry some risks. Careful patient selection, meticulous surgical
      technique and frequent follow-up can avoid most complications. The experience of
      a surgical team can also affect the outcome and the incidence of complications.
      The future should bring continued improvement in outcomes, fewer complications
      and exciting new options for treating refractive errors.

PMID- 10333842
TI  - Tuberculosis: 4. Pulmonary disease.

PMID- 10333843
TI  - The impact of a split-second error.

PMID- 10333844
TI  - New federal office will spend millions to regulate herbal remedies, vitamins.
AB  - The new Office of Natural Health Products promises better regulation of herbal
      remedies, but its creation raises many questions.

PMID- 10333845
TI  - Surgeons find themselves on trial in forum featuring CMPA lawyers.
AB  - During a recent forum, Ontario surgeons learned that the courtroom requires a
      much different form of behaviour than the operating room. These lessons hit home
      during a mock trial featuring CMPA lawyers.

PMID- 10333846
TI  - A physician's struggle to close Pandora's box.

PMID- 10333847
TI  - Lifestyle modifications to prevent and control hypertension. 1. Methods and an
      overview of the Canadian recommendations. Canadian Hypertension Society, Canadian
      Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for
      Disease Control at Health Canada, Heart and Stroke Foundation of Canada.
AB  - OBJECTIVE: To provide updated, evidence-based recommendations for health care
      professionals on lifestyle changes to prevent and control hypertension in
      otherwise healthy adults (except pregnant women). OPTIONS: For people at risk for
      hypertension, there are a number of lifestyle options that may avert the
      condition--maintaining a healthy body weight, moderating consumption of alcohol,
      exercising, reducing sodium intake, altering intake of calcium, magnesium and
      potassium, and reducing stress. Following these options will maintain or reduce
      the risk of hypertension. For people who already have hypertension, the options
      for controlling the condition are lifestyle modification, antihypertensive
      medications or a combination of these options; with no treatment, these people
      remain at risk for the complications of hypertension. OUTCOMES: The health
      outcomes considered were changes in blood pressure and in morbidity and mortality
      rates. Because of insufficient evidence, no economic outcomes were considered.
      EVIDENCE: A MEDLINE search was conducted for the period January 1996 to September
      1996 for each of the interventions studied. Reference lists were scanned, experts
      were polled, and the personal files of the authors were used to identify other
      studies. All relevant articles were reviewed, classified according to study
      design and graded according to level of evidence. VALUES: A high value was placed
      on the avoidance of cardiovascular morbidity and premature death caused by
      untreated hypertension. BENEFITS, HARMS AND COSTS: Lifestyle modification by
      means of weight loss (or maintenance of healthy body weight), regular exercise
      and low alcohol consumption will reduce the blood pressure of appropriately
      selected normotensive and hypertensive people. Sodium restriction and stress
      management will reduce the blood pressure of appropriately selected hypertensive
      patients. The side effects of these therapies are few, and the indirect benefits
      are well known. There are certainly costs associated with lifestyle modification,
      but they were not measured in the studies reviewed. Supplementing the diet with
      potassium, calcium and magnesium has not been associated with a clinically
      important reduction in blood pressure in people consuming a healthy diet.
      RECOMMENDATIONS: (1) It is recommended that health care professionals determine
      the body mass index (weight in kilograms/[height in metres]2) and alcohol
      consumption of all adult patients and assess sodium consumption and stress levels
      in all hypertensive patients. (2) To reduce blood pressure in the population at
      large, it is recommended that Canadians attain and maintain a healthy body mass
      index. For those who choose to drink alcohol intake should be limited to 2 or
      fewer standard drinks per day (maximum of 14/week for men and 9/week for women).
      Adults should exercise regularly. (3) To reduce blood pressure in hypertensive
      patients, individualized therapy is recommended. This therapy should emphasize
      weight loss for overweight patients, abstinence from or moderation in alcohol
      intake, regular exercise, restriction of sodium intake and, in appropriate
      circumstances, individualized cognitive behaviour modification to reduce the
      negative effects of stress. VALIDATION: The recommendations were reviewed by all
      of the sponsoring organizations and by participants in a satellite symposium of
      the fourth international Conference on Preventive Cardiology. They are similar to
      those of the World Hypertension League and the Joint National committee, with the
      exception of the recommendations on stress management, which are based on new
      information. They have not been clinically tested. SPONSORS: The Canadian
      Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention
      and Control, the Laboratory Centre for Disease Control at health Canada, and the
      Heart and Stroke Foundation of Canada.

PMID- 10333848
TI  - Lifestyle modifications to prevent and control hypertension. 2. Recommendations
      on obesity and weight loss. Canadian Hypertension Society, Canadian Coalition for
      High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control
      at Health Canada, Heart and Stroke Foundation of Canada.
AB  - OBJECTIVE: To provide updated, evidence-based recommendations concerning the
      effects of weight loss and maintenance of healthy weight on the prevention and
      control of hypertension in otherwise healthy adults (except pregnant women).
      OPTIONS: The main options are to attain and maintain a healthy body weight (body
      mass index [BMI] 20-25 kg/m2) or not to do so. For those at risk for
      hypertension, weight loss and maintenance of healthy weight may prevent the
      condition. For those who have hypertension, weight loss and maintenance of
      healthy weight may reduce or obviate the need for antihypertensive medications.
      OUTCOMES: The health outcome considered was change in blood pressure. Because of
      insufficient evidence, no economic outcomes were considered. EVIDENCE: A MEDLINE
      search was conducted for the years 1992-1996 with the terms hypertension and
      obesity in combination and antihypertensive therapy and obesity in combination.
      Other relevant evidence was obtained from the reference lists of the articles
      identified, from the personal files of the authors and through contacts with
      experts. The articles were reviewed, classified according to study design and
      graded according to level of evidence. VALUES: A high value was placed on the
      avoidance of cardiovascular morbidity and premature death caused by untreated
      hypertension. BENEFITS, HARMS AND COSTS: Weight loss and the maintenance of
      healthy body weight reduces the blood pressure of both hypertensive and
      normotensive people. The indirect benefits of a health body weight are well
      known. The negative effects of weight loss are primarily the frustrations
      associated with attaining and maintaining a healthy weight. The costs associated
      with weight loss programs were not measured in the studies reviewed.
      RECOMMENDATIONS: (1) It is recommended that health care professionals determine
      weight (in kilograms), height (in metres) and BMI for all adults. (2) To reduce
      blood pressure in the population at large, it is recommended that Canadians
      attain and maintain a healthy BMI (20-25). (3) All overweight hypertensive
      patients (BMI greater than 25) should be advised to reduce their weight.
      VALIDATION: These recommendations are similar to those of the World Hypertension
      League, the National High Blood Pressure Education Program Working Group on
      Primary Prevention of Hypertension, the Canadian Hypertension Society and the
      Canadian Coalition for High Blood Pressure Prevention and Control. They have not
      been clinically tested. SPONSORS: The Canadian Hypertension Society, the Canadian
      Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre
      for Disease Control at Health Canada, and the Heart and Stroke Foundation of
      Canada.

PMID- 10333849
TI  - Lifestyle modifications to prevent and control hypertension. 3. Recommendations
      on alcohol consumption. Canadian Hypertension Society, Canadian Coalition for
      High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control
      at Health Canada, Heart and Stroke Foundation of Canada.
AB  - OBJECTIVE: To provide updated, evidence-based recommendations concerning the
      effects of alcohol consumption on the prevention and control of hypertension in
      otherwise healthy adults (except pregnant women). OPTIONS: There are 2 main
      options for those at risk for hypertension: avert the condition by limiting
      alcohol consumption or by using other nonpharmacologic methods, or maintain or
      increase the risk of hypertension by making no change in alcohol consumption. The
      options for those who already have hypertension include decreasing alcohol
      consumption or using another nonpharmacologic method to reduce hypertension;
      commencing, continuing or intensifying antihypertensive medication; or taking no
      action and remaining at increased risk of cardiovascular disease. OUTCOMES: The
      health outcomes considered were changes in blood pressure and in morbidity and
      mortality rates. Because of insufficient evidence, no economic outcomes were
      considered. EVIDENCE: A MEDLINE search was conducted for the period 1966-1996
      with the terms ethyl alcohol and hypertension. Other relevant evidence was
      obtained from the reference lists of articles identified, from the personal files
      of the authors and through contacts with experts. The articles were reviewed,
      classified according to study design, and graded according to the level of
      evidence. VALUES: A high value was placed on the avoidance of cardiovascular
      morbidity and premature death caused by untreated hypertension. BENEFITS, HARMS
      AND COSTS: A reduction in alcohol consumption from more than 2 standard drinks
      per day reduces the blood pressure of both hypertensive and normotensive people.
      The lowest overall mortality rates in observational studies were associated with
      drinking habits that were within these guidelines. Side effects and costs were
      not measured in any of the studies. RECOMMENDATIONS: (1) It is recommended that
      health care professionals determine how much alcohol their patients consume. (2)
      To reduce blood pressure in the population at large, it is recommended that
      alcohol consumption be in accordance with Canadian low-risk drinking guidelines
      (i.e., healthy adults who choose to drink should limit alcohol consumption to 2
      or fewer standard drinks per day, with consumption not exceeding 14 standard
      drinks per week for men and 9 standard drinks per week for women). (3)
      Hypertensive patients should also be advised to limit alcohol consumption to the
      levels set out in the Canadian low-risk drinking guidelines. VALIDATION: These
      recommendations are similar to those of the World Hypertension League, the
      National High Blood Pressure Education Program Working Group on Primary
      Prevention of Hypertension and the previous recommendations of the Canadian
      Coalition for High Blood Pressure Prevention and Control and the Canadian
      Hypertension Society. They have not been clinically tested. The low-risk drinking
      guidelines are those of the Addiction Research Foundation of Ontario and the
      Canadian Centre on Substance Abuse. SPONSORS: The Canadian Hypertension Society,
      the Canadian Coalition for High Blood Pressure Prevention and Control, the
      Laboratory Centre for Disease Control at Health Canada, and the Heart and Stroke
      Foundation of Canada. The low-risk drinking guidelines have been endorsed by the
      College of Family Physicians of Canada and several provincial organizations.

PMID- 10333850
TI  - Lifestyle modifications to prevent and control hypertension. 4. Recommendations
      on physical exercise training. Canadian Hypertension Society, Canadian Coalition
      for High Blood Pressure Prevention and Control, Laboratory Centre for Disease
      Control at Health Canada, Heart and Stroke Foundation of Canada.
AB  - OBJECTIVE: To provide updated, evidence-based recommendations for health care
      professionals concerning the effects of regular physical activity on the
      prevention and control of hypertension in otherwise healthy adults. OPTIONS:
      People may engage in no, sporadic or regular physical activity that may be of
      low, moderate or vigorous intensity. For sedentary people with hypertension, the
      options are to undertake or maintain regular physical activity and to avoid or
      moderate medication use; to use another lifestyle modification technique; to
      commence or continue antihypertensive medication; or to take no action and remain
      at increased risk of cardiovascular disease. OUTCOMES: The health outcomes
      considered were changes in blood pressure and in morbidity and mortality rates.
      Because of insufficient evidence, no economic outcomes were considered. EVIDENCE:
      A MEDLINE search was conducted for the period 1966-1997 with the terms exercise,
      exertion, physical activity, hypertension and blood pressure. Both reports of
      trials and review articles were obtained. Other relevant evidence was obtained
      from the reference lists of these articles, from the personal files of the
      authors and through contacts with experts. The articles were reviewed, classified
      according to study design and graded according to level of evidence. VALUES: A
      high value was placed on avoidance of cardiovascular morbidity and premature
      death caused by untreated hypertension. BENEFITS, HARMS AND COSTS: Physical
      activity of moderate intensity involving rhythmic movements with the lower limbs
      for 50-60 minutes, 3 or 4 times per week, reduces blood pressure and appears to
      be more effective than vigorous exercise. Harm is uncommon and is generally
      restricted to the musculoskeletal injuries that may occur with any repetitive
      activity. Injury occurs more often with jogging than with walking, cycling or
      swimming. The costs include the costs of appropriate shoes, garments and
      equipment, but these were not specifically measured. RECOMMENDATIONS: (1) People
      with mild hypertension should engage in 50-60 minutes of moderate rhythmic
      exercise of the lower limbs, such as brisk walking or cycling, 3 or 4 times per
      week to reduce blood pressure, (2) Exercise should be prescribed as an adjunctive
      therapy for people who require pharmacologic therapy for hypertension, especially
      those who are not receiving beta-blockers. (3) People who do not have
      hypertension should participate in regular exercise as it will decrease blood
      pressure and reduce the risk of coronary artery disease, although there is no
      direct evidence that it will prevent hypertension. VALIDATION: These
      recommendations agree with those of the World Hypertension League, the American
      College of Sports Medicine, the report of the US Surgeon General on physical
      activity and health, and the US National Institutes of Health Consensus
      Development Panel on Physical Activity and Cardiovascular Health. These
      guidelines have not been clinically tested. SPONSORS: The Canadian Hypertension
      Society, the Canadian Coalition for High Blood Pressure Prevention and Control,
      the Laboratory Centre for Disease Control at Health Canada, and the Heart and
      Stroke Foundation of Canada.

PMID- 10333851
TI  - Lifestyle modifications to prevent and control hypertension. 5. Recommendations
      on dietary salt. Canadian Hypertension Society, Canadian Coalition for High Blood
      Pressure Prevention and Control, Laboratory Centre for Disease Control at Health
      Canada, Heart and Stroke Foundation of Canada.
AB  - OBJECTIVE: To provide updated, evidence-based recommendations concerning the
      effects of dietary salt intake on the prevention and control of hypertension in
      adults (except pregnant women). The guidelines are intended for use in clinical
      practice and public education campaigns. OPTIONS: Restriction of dietary salt
      intake may be an alternative to antihypertensive medications or may supplement
      such medications. Other options include other nonpharmacologic treatments for
      hypertension and no treatment. OUTCOMES: The health outcomes considered were
      changes in blood pressure and in morbidity and mortality rates. Because of
      insufficient evidence, no economic outcomes were considered. EVIDENCE: A MEDLINE
      search was conducted for the period 1966-1996 using the terms hypertension, blood
      pressure, vascular resistance, sodium chloride, sodium, diet, sodium or sodium
      chloride dietary, sodium restricted/reducing diet, clinical trials, controlled
      clinical trial, randomized controlled trial and random allocation. Both trials
      and review articles were obtained, and other relevant evidence was obtained from
      the reference lists of the articles identified, from the personal files of the
      authors and through contacts with experts. The articles were reviewed, classified
      according to study design and graded according to level of evidence. In addition,
      a systematic review of all published randomized controlled trials relating to
      dietary salt intake and hypertension was conducted. VALUES: A high value was
      placed on the avoidance of cardiovascular morbidity and premature death caused by
      untreated hypertension. BENEFITS, HARMS AND COSTS: For normotensive people, a
      marked change in sodium intake is required to achieve a modest reduction in blood
      pressure (there is a decrease of 1 mm Hg in systolic blood pressure for every 100
      mmol decrease in daily sodium intake). For hypertensive patients, the effects of
      dietary salt restriction are most pronounced if age is greater than 44 years. A
      decrease of 6.3 mm Hg in systolic blood pressure and 2.2 mm Hg in diastolic blood
      pressure per 100 mmol decrease in daily sodium intake was observed in people of
      this age group. For hypertensive patients 44 years of age and younger, the
      decreases were 2.4 mm Hg for systolic blood pressure and negligible for diastolic
      blood pressure. A diet in which salt is moderately restricted appears not to be
      associated with health risks. RECOMMENDATIONS: (1) Restriction of salt intake for
      the normotensive population is not recommended at present, because of
      insufficient evidence demonstrating that this would lead to a reduced incidence
      of hypertension. (2) To avoid excessive intake of salt, people should be
      counselled to choose foods low in salt (e.g., fresh fruits and vegetables), to
      avoid foods high in salt (e.g., pre-prepared foods), to refrain from adding salt
      at the table and minimize the amount of salt used in cooking, and to increase
      awareness of the salt content of food choices in restaurants. (3) For
      hypertensive patients, particularly those over the age of 44 years, it is
      recommended that the intake of dietary sodium be moderately restricted, to a
      target range of 90-130 mmol per day (which corresponds to 3-7 g of salt per day).
      (4) The salt consumption of hypertensive patients should be determined by
      interview. VALIDATION: These recommendations were reviewed by all of the
      sponsoring organizations and by participants in a satellite symposium of the
      fourth International Conference on Preventive Cardiology. They have not been
      clinically tested. SPONSORS: The Canadian Hypertension Society, the Canadian
      Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre
      for Disease Control at Health Canada, and the Heart and Stroke Foundation of
      Canada.

PMID- 10333853
TI  - Lifestyle modifications to prevent and control hypertension. 7. Recommendations
      on stress management. Canadian Hypertension Society, Canadian Coalition for High
      Blood Pressure Prevention and Control, Laboratory Centre for Disease Control at
      Health Canada, Heart and Stroke Foundation of Canada.
AB  - OBJECTIVE: To provide updated evidence-based recommendations for health care
      professionals concerning the effects of stress management on the prevention and
      control of hypertension in otherwise healthy adults (except pregnant women).
      OPTIONS: Alternatives to stress management include other nonpharmacologic
      interventions and medical therapy; these options are not mutually exclusive.
      OUTCOMES: The health outcome considered was reduction of blood pressure. There is
      little evidence to date that stress management prevents death or vascular events.
      Because of insufficient evidence, no economic outcomes were considered. EVIDENCE:
      A systematic search of the literature (which yielded, among other sources, 3 meta
      analyses) was conducted for the period 1966-1997 with the terms essential
      hypertension, treatment, psychological, behavioural, cognitive, relaxation,
      mediation, biofeedback and stress management. Other relevant evidence was
      obtained from the reference lists of the articles identified, from the personal
      files of the authors and through contacts with experts. The articles were
      reviewed, classified according to study design and graded according to level of
      evidence. VALUES: A high value was placed on the avoidance of cardiovascular
      morbidity and premature death caused by uncontrolled hypertension. BENEFITS,
      HARMS AND COSTS: The magnitude of the reduction in blood pressure obtained with
      multicomponent, individualized cognitive behavioural intervention for stress
      management was comparable in some studies to that obtained with weight loss or
      drugs; single-component interventions such as biofeedback or relaxation were less
      effective. The adverse effects of stress-management techniques are minimal, but
      the cost for effective interventions is substantial, similar initially to drug
      costs; continuing costs are probably minimal. RECOMMENDATIONS: (1) In patients
      with hypertension, the contribution of stress should be considered. (2) For
      hypertensive patients in whom stress appears to be an important issue, stress
      management should be considered as an intervention. Individualized cognitive
      behavioural interventions are more likely to be effective than single-component
      interventions. VALIDATION: These recommendations were reviewed by all of the
      sponsoring organizations and by participants in a satellite symposium of the
      fourth International Conference on Preventive Cardiology. They have not been
      clinically tested. SPONSORS: The Canadian Hypertension Society, the Canadian
      Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre
      for Disease Control at Health Canada, and the Heart and Stroke Foundation of
      Canada.

PMID- 10333854
TI  - Environmental Mutagen Society 30th annual meeting. Washington, DC, USA. March 27
      April 1, 1999. Abstracts.

PMID- 10333855
TI  - Nursing administration research.

PMID- 10333852
TI  - Lifestyle modifications to prevent and control hypertension. 6. Recommendations
      on potassium, magnesium and calcium. Canadian Hypertension Society, Canadian
      Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for
      Disease Control at Health Canada, Heart and Stroke Foundation of Canada.
AB  - OBJECTIVE: To provide updated, evidence-based recommendations on the consumption,
      through diet, and supplementation of the cations potassium, magnesium and calcium
      for the prevention and treatment of hypertension in otherwise healthy adults
      (except pregnant women). OPTIONS: Dietary supplementation with cations has been
      suggested as an alternative or adjunctive therapy to antihypertensive
      medications. Other options include other nonpharmacologic treatments for
      hypertension. OUTCOMES: The health outcomes considered were changes in blood
      pressure and in morbidity and mortality rates. Because of insufficient evidence,
      no economic outcomes were considered. EVIDENCE: A MEDLINE search was conducted
      for the period 1966-1996 with the terms hypertension and potassium, magnesium and
      calcium. Reports of trials, meta-analyses and review articles were obtained.
      Other relevant evidence was obtained from the reference lists of articles
      identified, from the personal files of the authors and through contacts with
      experts. The articles were reviewed, classified according to study design, and
      graded according to the level of evidence. VALUES: A high value was placed on the
      avoidance of cardiovascular morbidity and premature death caused by untreated
      hypertension. BENEFITS, HARMS AND COSTS: The weight of the evidence from
      randomized controlled trials indicates that increasing intake of or supplementing
      the diet with potassium, magnesium or calcium is not associated with prevention
      of hypertension, nor is it effective in reducing high blood pressure. Potassium
      supplementation may be effective in reducing blood pressure in patients with
      hypokalemia during diuretic therapy. RECOMMENDATIONS: For the prevention of
      hypertension, the following recommendations are made: (1) The daily dietary
      intake of potassium should be 60 mmol or more, because this level of intake has
      been associated with a reduced risk of stroke-related mortality. (2) For
      normotensive people obtaining on average 60 mmol of potassium daily through
      dietary intake, potassium supplementation is not recommended as a means of
      preventing an increase in blood pressure. (3) For normotensive people, magnesium
      supplementation is not recommended as a means of preventing an increase in blood
      pressure. (4) For normotensive people, calcium supplementation above the
      recommended daily intake is not recommended as a means of preventing an increase
      in blood pressure. For the treatment of hypertension, the following
      recommendations are made. (5) Potassium supplementation above the recommended
      daily dietary intake of 60 mmol is not recommended as a treatment for
      hypertension. (6) Magnesium supplementation is not recommended as a treatment for
      hypertension. (7) Calcium supplementation above the recommended daily dietary
      intake is not recommended as a treatment for hypertension. VALIDATION: These
      guidelines are consistent with the results of meta-analyses and recommendations
      made by other organizations. They have not been clinically tested. SPONSORS: The
      Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure
      Prevention and Control, the Laboratory Centre for Disease Control at Health
      Canada, and the Heart and Stroke Foundation of Canada.

PMID- 10333856
TI  - The final chapter in the nursing administration research priorities saga: the
      state of the state.

PMID- 10333857
TI  - Longitudinal evaluation of professional nursing practice redesign.
AB  - OBJECTIVES: The authors describe a 5-year study at a western university teaching
      hospital that evaluated the effect of organizational redesign on nurse job
      satisfaction, autonomy, and patient satisfaction. BACKGROUND: Change in
      institutional status from public to private authority stimulated this hospital to
      map a new direction for professional nursing practice, to strengthen autonomy and
      job satisfaction while improving quality care outcomes. Evaluating redesign
      changes systematically provided significant longitudinal trended data to guide
      nurse executive actions. METHODS: Phase-I evaluation, from 1992 to 1995, was a
      quasi-experimental design comparing pre- and poststudy outcomes of facilitator
      led activities on units receiving interventions compared with control units. Of
      12 outcome variables measured, 3 were sustained longitudinally into Phase II:
      nursing job satisfaction using the McCloskey Mueller Satisfaction Scale (MMSS),
      autonomy using Schutzenhofer's Scale, and patient satisfaction using the Picker
      Institute survey. Data were trended across units and departments over a 5-year
      period. RESULTS: Phase-I results reported that control units held higher nursing
      documentation scores than the experimental units. There were no significant
      differences in aggregate nurse job satisfaction scores. Nurse autonomy scores
      significantly improved. Other results are reported descriptively. Phase II
      continued the evaluation, reporting no differences in nurse job satisfaction
      aggregate scores a decline in autonomy, and decreased patient satisfaction
      scores. There were significant differences by units and across departments.
      CONCLUSIONS: Longitudinal evaluation provides significant data to guide nurse
      executives in an uncertain healthcare environment. Of theoretical interest is the
      absence of congruence in nurse job satisfaction and autonomy scores, suggesting
      more independence between these variables than previously reported.

PMID- 10333858
TI  - The effect of patient-focused redesign on midlevel nurse managers' role
      responsibilities and work environment.
AB  - OBJECTIVE: The authors determine the effect of patient-focused redesign on
      midlevel nurse managers' role responsibilities and perceptions of work
      environment. BACKGROUND: Patient-focused redesign models have been initiated in a
      number of hospitals over the past 10 years. Few studies of the impact of these
      models on nurse leaders' roles and work responsibilities have been conducted.
      METHODS: Nine midlevel nurse managers were interviewed about their redesigned
      leadership roles and the challenges they experienced in implementing patient
      focused redesign. RESULTS: Several themes emerged from the data. These themes
      focused on role change, ambiguity, position power, and environmental uncertainty
      and turbulence. Each of the nurse managers described feelings of frustration,
      disconnectedness, and inadequacy and spoke of how difficult it was to be the
      central figure in the eye of the storm. They noted that previously successful
      administrative strategies were not producing the same effect as in the past.
      CONCLUSION: This study provides beginning information about the magnitude of the
      impact of organizational redesign on midlevel nurse managers. Midlevel managers
      in this study struggled to keep up with the demands of the change and their own
      recognition of the importance of remaining committed to the uncertain goals of
      the institution. They were frustrated by their perceived inability to fix the
      situation and to meet the multiple needs of the staff. Nonetheless, they
      supported senior executives and attempted reasonable solutions to the problem.

PMID- 10333859
TI  - Leader behavior impact on staff nurse empowerment, job tension, and work
      effectiveness.
AB  - OBJECTIVE: The authors tested a model linking specific leader-empowering
      behaviors to staff nurse perceptions of workplace empowerment, occupational
      stress, and work effectiveness in a recently-merged Canadian acute care hospital.
      SUMMARY BACKGROUND DATA: An integration of Kanter's organizational empowerment
      theory and Conger and Kunungo's model of the leader empowerment process
      constituted the theoretical framework for the study. Few published studies were
      found in which specific leader behaviors were linked empirically to staff nurses'
      workplace empowerment. METHODS: Staff nurses (n = 537) were surveyed shortly
      after a merger of two large tertiary hospitals. Structural equation modeling
      techniques were used to test the proposed model. RESULTS: Leader-empowering
      behaviors significantly influenced employees perceptions of formal and informal
      power and access to empowerment structures (information support, resources, and
      opportunity). Higher perceived access to empowerment structures predicted lower
      levels of job tension and increased work effectiveness. The amount of explained
      variance in the final model was 42%. CONCLUSIONS: Support for the model tested in
      this study highlights the importance of nurse managers' leadership behaviors
      within current turbulent healthcare organizations.

PMID- 10333860
TI  - Nursing in the nineties: managing the uncertainty.
AB  - OBJECTIVE: This study examined qualitative data on nurses' work lives from 53
      hospitals that participated in the National Institutes of Health (NIH)-funded
      Outcomes Research in Nursing Administration Project (ORNA). BACKGROUND: The ORNA
      project examines the impact of nursing unit organizational structure on outcomes.
      The information reported in this article amplifies the quantitative data with
      qualitative data that enhances understanding of nurses' work lives. METHODS: Site
      coordinators at all participating hospitals were requested to send monthly
      journal entries for 6 months. Data were documented according to an agreed-on
      content outline that consisted of critical incidents and implications. Data were
      collected from 53 of the 65 study site coordinators (response rate 81.5%).
      Content analysis of all collected data was conducted by the research team.
      RESULTS: Study site coordinators in 53 hospitals characterize the acute care
      environment as turbulent and uncertain. Contributing factors include: 1) work
      load (fluctuating census, staff preparation, turnover); 2) loss of workplace
      identity (unit consolidation, hospital buy-outs, and system mergers); and 3) re
      engineering (skill mix, new equipment/system changes, new documentation systems,
      rumored changes). CONCLUSIONS: This study adds to the growing body of literature
      that portrays environmental uncertainty from the narrative perspective. Although
      there is an ongoing need for the employment of fiscally accountable, quality
      enhancing organizational/management strategies, all initiatives are at risk
      unless personnel needs are attended to and seen as unique in each care setting.
      Some strategies are offered to meet this dual imperative.

PMID- 10333861
TI  - Outcomes for community health nursing practice.
AB  - OBJECTIVE: The purpose of this study was to develop an easy, practical list of
      outcomes amenable to community health nursing interventions. This study sought to
      answer the following question: What outcomes are sensitive to nursing
      interventions in the community health setting? SUMMARY BACKGROUND DATA: Nursing
      literature discusses many client outcomes. However, available outcome lists are
      not always sensitive to nursing interventions by community health nurses. Nurses
      need a precise list to measure client outcomes resulting from contact between
      nurses and clients in a variety of community health settings. METHODS AND
      SUBJECTS: The study used a modified Delphi technique to ensure adequate response
      from the subjects. Initially, focus groups generated items for the Delphi
      questionnaires. Using items from the focus groups, the researchers developed
      three rounds of questionnaires. In each round, nurses stated a level of agreement
      with each item as an outcome for community health nurses. Twenty-two community
      health nurses in one Southeastern state participated in four focus groups. One
      hundred fifty-two community health nurses returned round 1 questionnaires, 68
      nurses returned round 2 questionnaires, and 48 nurses returned round 3
      questionnaires. RESULTS: The researchers grouped the outcomes into four domains:
      client's psychosocial components of care, client's physiologic components of
      care, nursing intervention/implementation components of care, and
      environmental/community safety components of care. CONCLUSIONS: The findings
      produced an easy, practical list of 48 nursing outcomes for use in decision
      making and research by community health nurses in all settings.

PMID- 10333863
TI  - [80th German Congress of Radiology. Wiesbaden, Germany, 12-15 May 1999.
      Abstracts].

PMID- 10333862
TI  - Assessing the impact of reengineering on nursing.
AB  - OBJECTIVES: This study assessed the impact of organizational re-engineering on
      nursing in a large community teaching hospital in the Midwest, using an
      observational repeated measures design. Time, clinical unit, and nurse
      characteristics were incorporated as covariates. A second objective was to
      compare two sampling approaches for robustness and efficiency. BACKGROUND:
      Economic and technological changes are having an enormous impact on acute care
      hospitals, which often attempt to adapt by re-engineering or restructuring their
      systems. Despite the difficulty of conducting research in a constantly changing
      setting, it is imperative that nursing evaluate its reactions and contributions
      to new delivery models. METHODS AND SUBJECTS: During a hospital-wide
      reorganization, mail surveys were conducted to assess nurses' perceptions of
      their authority and autonomy in a new nursing model, commitment to a new
      philosophy (patient-focused care), and satisfaction with their ability to deliver
      care. To validate the findings, patient satisfaction was evaluated through a
      survey of 227 hospitalized patients. Over a 1-year period, two sampling
      approaches were used: three independent samples of nurses were surveyed at three
      dates, and a panel of nurses were surveyed repeatedly over the same three dates.
      Response rates were approximately 45% across the independent samples and 67% for
      the panel. RESULTS: Comparison of nursing units that underwent re-engineering and
      units in which re-engineering was delayed showed no obvious effects. Data also
      showed that the estimates of effects of re-engineering were not subject to
      confounding from nursing unit, date, or nurses' experience, although there was
      evidence that the measures were sensitive to these covariates. No biases were
      found due to the two sampling schemes, yet the panel data was three to five times
      more efficient--that is, they produced more information--than the data from the
      independent samples. CONCLUSIONS: This study reinforces the need to build
      evaluation research into organizational activities such as re-engineering. It
      also argues for the commitment of resources to organizational research so that
      information valuable to nursing and the healthcare system is not lost.

PMID- 10333864
TI  - 43rd Symposium of the German Society of Endocrinology (DGE). Kiel, Germany, March
      10-13, 1999. Abstracts.

PMID- 10333865
TI  - [Francophone meeting on Digestive Pathology. Nantes, France, 20-24 March 1999.
      Abstracts].

PMID- 10333866
TI  - The Physiological Society of Japan 75th annual meeting. Kanazawa, Japan, March 27
      29, 1998. Abstracts.

PMID- 10333868
TI  - Oncology Nursing Society 24th annual conference. Atlanta, Georgia, USA. April 28
      May 1, 1999. Abstracts.

PMID- 10333867
TI  - 2nd Annual Congress of the European College of Sport Science. Copenhagen,
      Denmark, 20-23 August 1997. Abstracts.

PMID- 10333869
TI  - XIXth Annual Conference on Peritoneal Dialysis. Charlotte, North Carolina, USA.
      February 28-March 2, 1999. Abstracts.

PMID- 10333870
TI  - 1999 AAHPERD National Convention. Boston, Massachusetts, USA. April 1999.
      Abstracts.

PMID- 10333871
TI  - 5th Congress of the Asian Pacific Society of Respirology. Sydney, Australia, 9-12
      October 1998. Abstracts.

PMID- 10333872
TI  - Swedish Association of Urology annual meeting. Goteborg, November 24-26, 1998.
      Abstracts.

PMID- 10333873
TI  - 1999 Scientific Session of the Society of American Gastrointestinal and
      Endoscopic Surgeons (SAGES). San Antonio, Texas, USA. March 24-27, 1999.
      Abstracts.

PMID- 10333874
TI  - Meniscal reconstruction. Part II: Outcome, potential complications, and future
      directions.
AB  - Currently, magnetic resonance imaging and second-look arthroscopy are the only
      methods available to objectively evaluate the outcome of meniscal reconstruction.
      While clinical studies indicate progressively improving outcomes of meniscal
      reconstruction, longer follow-up is needed to determine whether the natural
      history of joint degeneration can be altered. Part I of this comprehensive
      review, published in the April 1999 issue, discussed the anatomy and function of
      the meniscus, followed by the indications, techniques, and graft considerations
      for meniscal allograft reconstruction. Part II reviews the results, potential
      complications, and future directions of meniscal allograft reconstruction.

PMID- 10333875
TI  - Scaphoid position angles: a clinical study.
AB  - This study sought to describe the oblique orientation of the scaphoid relative to
      the anatomic planes of the wrist in terms of two position angles. Longitudinal
      axes of the scaphoid are defined on posteroanterior (p.a.) and lateral
      radiographs. These axes, together with the corresponding longitudinal axes of the
      distal radius, are used to define the frontal and lateral radioscaphoid angles.
      These angles are called the scaphoid yaw and pitch, respectively. A database
      representing the normal variation of the scaphoid position angles is obtained
      from a set of 100 PA and lateral radiographs of structurally normal wrists in a
      rigorously defined neutral position. To the nearest whole number, the mean
      scaphoid yaw is 35 degrees with a standard deviation of 6 degrees, and the mean
      scaphoid pitch is 50 degrees with a standard deviation of 7 degrees.

PMID- 10333876
TI  - Successful infiltration of the flexor tendon sheath.
AB  - Twenty cadaveric fingers and five thumbs were injected through a midaxial
      approach, a palmar approach superficial to the flexor tendon, and a palmar
      approach deep to the tendon, to assess the ability of these approaches to
      infiltrate the flexor tendon sheath successfully. With care to observe proper
      positioning of the needle, we were able to achieve essentially equivalent success
      in infiltration with most of these approaches. However, the midaxial approach to
      the thumb flexor sheath was unsuccessful.

PMID- 10333877
TI  - Open clavicle fractures: a case report.
AB  - Open fractures of the clavicle are rare, whereas closed fractures are quite
      common. Presented here is a case report of a grade IIIA open clavicle fracture.
      After reviewing the literature, there appears to be little information on the
      treatment or outcome of these fractures. One can only surmise that the outcome
      and complications are similar to those of other open fractures.

PMID- 10333878
TI  - Aneurysm of the small saphenous vein presenting as a popliteal mass: a case
      report.
AB  - This report describes an aneurysm in the superficial small saphenous vein in a 44
      year-old woman who presented with a popliteal mass. A venous aneurysm in this
      area is rare but should be among the differential diagnoses for a popliteal mass
      for optimal treatment and outcome.

PMID- 10333879
TI  - Distal tibial epiphyseal fractures in adolescents.
AB  - The characteristic pattern of fusion of distal tibial epiphysis explains the
      special configuration of the fragments in the triplane fracture and the
      "juvenile" fracture of Tillaux in adolescents. The application of external
      rotation force produces Tillaux and triplane fractures of the lateral portion of
      the distal tibial epiphysis in patients with a mean age of 13.5 years. Eight
      patients, 13 to 15 years of age, with distal tibial epiphyseal fractures were
      treated in the last 12 years. Three of the fractures were classified as
      "juvenile" Tillaux fractures and five were triplane fractures. Open reduction and
      fixation of the tibia was accomplished by using either malleolar screws or K
      wires. Follow-up time ranged from 1.5 to 11 years. All patients were evaluated
      subjectively and objectively after surgery. Objective evaluation included
      clinical assessment and radiographic evaluation. All patients regained full range
      of motion and no one complained of pain or joint stiffness. Radiographs confirmed
      that all fractures have healed without articular incongruity.

PMID- 10333880
TI  - The scapulohumeral line revisited.
AB  - Routine observation of the scapulohumeral line in the true anteroposterior
      radiographic view of the shoulder will allow a higher level of confidence in
      ruling out posterior dislocation of the glenohumeral joint. It will also
      facilitate evaluation of the relationship between the proximal humerus and the
      scapula (especially the acromion and the glenoid fossa) in (1) abnormal
      conditions of the subacromial space; (2) fractures and dislocations of the
      proximal humerus; and (3) proximal humerus prosthesis insertion and assessment.

PMID- 10333881
TI  - The Orthologic/'A' Company Award 1997.

PMID- 10333882
TI  - A modification to enable controlled progressive advancement of the Twin Block
      appliance.
AB  - A modification of the Twin block appliance has been developed to facilitate
      controlled gradual advancement of the mandibular position during the treatment of
      Class II division I malocclusions. This features the incorporation of stainless
      steel screws with conical heads into the blocks of the upper appliance to provide
      the inclined plane effect. Advancement is by the addition of polyacetal spacers
      between the screw heads and the upper blocks. The system is designed to improve
      the clinical flexibility of the appliance and to enhance patient acceptance in
      cases where mandibular protrusion is limited initially. Another possible
      application is gradual reactivation for Class III correction. Other advantages
      are reduced laboratory and clinical time during reactivation of the appliance,
      and perhaps a more physiological response to the growth modification process. The
      design and construction of the advancement system is illustrated, and its
      clinical use discussed.

PMID- 10333883
TI  - Assessment of clinical case presentations for the Membership in Orthodontics,
      Royal College of Surgeons of England 1995, 1996.
AB  - The cases presented and treated at successive examinations by the candidates for
      the Membership Examination in Orthodontics in 1995 and 1996 at The Royal College
      of Surgeons of England, were of a very high standard and demonstrated a wide
      range of treatment modalities. All cases had fixed appliances, predominantly with
      pre-adjusted Edgewise appliances. IOTN confirmed that most cases were in great
      need of treatment, with PAR scores showing them to be treated to a high standard.

PMID- 10333884
TI  - The genetic control of early odontogenesis.

PMID- 10333885
TI  - Rare earth magnets in orthodontics: an overview.
AB  - Magnets have been used in dentistry for many years. They can be made to push or
      pull teeth. The force they deliver can be directed, and they can exert their
      force through mucosa and bone, as well as within the mouth. In orthodontics they
      are used for intrusion of teeth, tooth movement along archwires, expansion,
      retention, in functional appliances, and in the treatment of impacted teeth. New
      'high energy' magnets are capable of producing very high forces relative to their
      size. Although magnets are potentially very useful there are a number of problems
      that severely affect their performance; the force produced between any two
      magnets falls dramatically with distance, significant irreversible loss in force
      is seen if the magnets are heated and a dramatic reduction in force is seen if
      the magnets are not ideally aligned to one another. In addition, magnets corrode
      badly in the mouth and a robust coating is required to protect them. This paper
      outlines the background to high energy magnets used in orthodontics, discusses
      the relevant physical and biological properties of them, and reviews their
      applications.

PMID- 10333886
TI  - An evaluation of the changes in maxillary pulpal blood flow associated with
      orthognathic surgery.
AB  - The objective of this study was to evaluate the use of the Laser Doppler
      Flowmeter (LDF) in the measurement of pulpal blood flow following orthognathic
      surgery and to conduct an initial study of the effects of a Le Fort I osteotomy
      on the pulpal blood flow of the maxillary central incisors. The design consisted
      of a preliminary prospective controlled consecutive clinical trial undertaken at
      the Orthodontic Clinic, University Dental Hospital NHS Trust, Wales, 1994. The
      study group consisted of 15 consecutive patients who were to receive a standard
      advancement Le Fort I osteotomy. Seven patients who were to undergo a mandibular
      advancement only acted as a control. A further 20 separate patients participated
      in a study for the assessment of measurement error. The blood flow in relative
      perfusion unit v. time, was measured using a Laser Doppler Flowmeter. Measurement
      error for flowmeter recordings with hand-held application and custom-made splint
      support showed no consistent difference or significant random variation between
      the two methods for holding the probe against the teeth (pooled S.D. of
      reproducibility 1/1 = 1.91/1.39 for custom splint location as opposed to
      0.96/1.07 for hand-held/fixed bracket location). For the surgical patients under
      investigation no significant differences for maxillary pulpal blood flow were
      found in the control group (mandibular osteotomy) over time. However, in the
      maxillary osteotomy patients there was a tendency for an initial rise in the
      maxillary perfusion post-surgery as measured at the central incisor pulps,
      followed by an overall reduction at 6 months. As an example, the mean value for
      the upper right central showed a significant increase in blood flow during the
      immediate post-operative period (P < 0.05), but at 6 months after surgery
      demonstrated a statistically significant overall reduction in comparison with the
      presurgical reading (P < 0.001). The laser Doppler flowmeter is not an easy
      instrument to use in the clinical assessment of pulpal blood flow. However, it
      would appear from these longitudinal series of readings, taken over a 6-month
      period on 15 patients, that the maxillary perfusion recorded at the central
      incisor pulps may be permanently affected in many Le Fort I osteotomy patients.
      For patients that already have a prejudiced blood supply this could lead to
      devitalization and discoloration of incisors. It is not known if this affect on
      the perfusion of the pulp continues beyond 6 months post-surgery.

PMID- 10333887
TI  - An ex vivo investigation into the bond strength of orthodontic brackets and
      adhesive systems.
AB  - The aim of this study was to compare the shear bond strength of Adhesive
      Precoated Brackets (APC) with that of two types of uncoated bracket bases,
      Straight-Wire and Dyna-Lock. Two types of orthodontic adhesives were used,
      Transbond XT and Right-On. Three different curing times were evaluated with the
      APC brackets in order to find the best. Adhesive remnants on the enamel surface
      following debond were evaluated using the Adhesive Remnant Index (Artun and
      Bergland, 1984). Bond strengths ranged from 11.00 to 22.08 MPa. For both types of
      brackets Transbond produced a significant increase in bond strength compared to
      Right-On. The Dyna-Lock/Right-On combination produced the poorest results. APC
      brackets cured for 40 s had similar bond strengths to uncoated brackets fixed by
      means of Transbond. Overall, 79 per cent of specimens had less than half the
      tooth surface covered with adhesive following debond. Significantly more adhesive
      remained on tooth surfaces following debond of the Straight-Wire/Right-On group
      than any other bracket/adhesive combination. Bond strengths were higher with
      light-cured Transbond than with chemically-cured Right-On. When Transbond is used
      in association with APC brackets a 40-second cure time is recommended.

PMID- 10333888
TI  - Linear and angular changes in dento-facial dimensions in the third decade.
AB  - The object of the study was to examine changes in dento-facial dimensions and
      relationships during the third decade of life, and consisted of a prospective
      cephalometric study. The data used consisted of 90 degree left lateral
      cephalometric radiographs of 21 males and 26 females at ages 18 years (T1) and 21
      years (T2), and for 15 of the males and 22 of the females at 28 years (T3).
      Various dimensions representative of dento-facial morphology were measured and
      the changes in dimensions over time were calculated and tested for significance
      with the one sample t-test. In general, skeletal and dental relationships
      remained relatively stable. Face height and jaw length dimensions increased by
      small amounts.

PMID- 10333889
TI  - Specialist training--where is it going?

PMID- 10333891
TI  - Straumann Orthosystem.

PMID- 10333890
TI  - Study model boxes--what's available?

PMID- 10333892
TI  - Undergraduate and postgraduate orthodontics in Australia.
AB  - Undergraduate orthodontic education in Australian university dental schools
      reflects a strong British influence. The Australian Dental Council is now
      responsible for undergraduate course accreditation and the development of a more
      distinctly Australian model might be expected, although not in isolation from the
      traditional British and American influences. Postgraduate specialty training has
      been more directly influenced by the North American dental schools, and
      specialist registers in the states and territories reflect that influence. The
      Australian Dental Council will commence accreditation of postgraduate specialty
      courses in 1999.

PMID- 10333893
TI  - Braces for blowers?

PMID- 10333894
TI  - Sources of stress for orthodontic practitioners.
AB  - This paper aims to examine and highlight the difference between sources of stress
      and burn-out. The first part of the paper examines stress and the second part
      looks at the concept of burn-out with reference to how orthodontists compare with
      other dental professionals.

PMID- 10333895
TI  - Renal assessment practices and the effect of nurse case management of health
      maintenance organization patients with diabetes.
AB  - OBJECTIVE: To examine baseline renal screening practices and the effect of nurse
      case management of patients with diabetes in a group model health maintenance
      organization (HMO). RESEARCH DESIGN AND METHODS: We performed both 1-year
      retrospective and 1-year prospective studies of renal assessment practices and
      ACE inhibitor usage in a cohort of 133 diabetic patients enrolled in a randomized
      controlled trial of a diabetes nurse case management program in a group model
      HMO. In accordance with American Diabetes Association recommendations, urine
      dipstick and quantitative protein and microalbuminuria testing rates were
      calculated. RESULTS: At baseline, 77% of patients were screened for proteinuria
      with dipsticks or had quantitative urine testing. Of patients with negative
      dipstick findings, 30% had appropriate quantitative protein or microalbumin
      follow-up at baseline. Baseline ACE inhibitor usage was associated with decreased
      follow-up testing (relative risk = 0.47). Nurse case management was associated
      with increased quantitative protein or or microalbumin testing and increased
      follow-up testing (relative risk = 1.65 and 1.60, respectively). CONCLUSIONS: We
      found a higher degree of adherence to recommendations for renal testing than has
      been reported previously. Nurse case management intervention further increased
      renal screening rates. The inverse association between ACE inhibitor usage and
      microalbumin testing highlights a potentially ambiguous area of current clinical
      pathways.

PMID- 10333896
TI  - Effectiveness of a prevention program for diabetic ketoacidosis in children. An 8
      year study in schools and private practices.
AB  - OBJECTIVE: To shorten the period of carbohydrate intolerance preceding the
      diagnosis of IDDM in children. RESEARCH DESIGN AND METHODS: The incidence of
      diabetic ketoacidosis (DKA) was studied in newly diagnosed diabetic children aged
      6-14 years, in the area of Parma, Italy, 8 years after an information program on
      DKA was introduced to teachers, students, parents, and pediatricians. Information
      was provided by displaying a poster with a few practical messages in 177 primary
      and secondary public schools. The pediatricians working in the same area were
      given equipment for the measurement of both glycosuria and blood glucose levels,
      as well as cards listing guidelines for the early diagnosis of diabetes, to be
      given to patients. A toll-free number was also provided. Clinical and laboratory
      features of 24 young diabetic patients diagnosed in the Parma area (group 1) were
      compared with those of 30 patients coming from two nearby areas in which no
      campaign for the prevention of DKA had been carried out (group 2). RESULTS: From
      1 January 1991 to 31 December 1997, DKA was diagnosed in 3 children from group 1
      (12.5%) and in 25 children from group 2 (83.0%) (chi 2 = 26.8; P = 0.0001). The
      three cases of DKA in group 1 were observed in 1991 (n = 1) and in 1992 (n = 2).
      No patients from the Parma area who had DKA were admitted to our unit after 1992.
      The duration of symptoms before diagnosis was 5.0 +/- 6.0 and 28.0 +/- 10.0 days
      (P < 0.0001), in groups 1 and 2, respectively, Metabolic derangements were less
      severe in patients of group 1 than in those of group 2. Hospitalization for the
      treatment of overt diabetes and for the teaching of self-management of the
      disease lasted 5.4 +/- 1.2 days in group 1 and 13.3 +/- 2.4 days in group 2 (P =
      0.002). The total cost of the 8-year campaign was $23,470. CONCLUSIONS: The
      prevention program for DKA in diabetic children aged 6-14 years, carried out in
      the Parma area during the last 8 years, was successful. Thanks to this program,
      cumulative frequency of DKA in new-onset IDDM decreased from 78% during 1987-1991
      to 12.5% during 1991-1997. None of the newly diagnosed diabetic children aged 6
      14 years and from the Parma area were ever admitted to the hospital for DKA after
      1992.

PMID- 10333897
TI  - Improved glycemic control and lipid profile and normalized fibrinolytic activity
      on a low-glycemic index diet in type 2 diabetic patients.
AB  - OBJECTIVE: To evaluate the effects of varying the glycemic index (GI) of
      carbohydrate-rich foods on metabolic control in type 2 diabetic patients.
      RESEARCH DESIGN AND METHODS: In a randomized crossover study, 20 patients, 5
      women and 15 men, were given preweighed diets with different GIs during two
      consecutive 24-day periods. Both diets were composed in accordance with dietary
      recommendations for people with diabetes. The macronutrient composition and type
      and amount of dietary fiber were identical. Differences in GI were achieved
      mainly by altering the structure of the starchy foods. RESULTS: Peripheral
      insulin sensitivity increased significantly and fasting plasma glucose decreased
      during both treatment periods. There was a significant difference in the changes
      of serum fructosamine concentrations between the diets (P < 0.05). The
      incremental area under the curve for both blood glucose and plasma insulin was
      approximately 30% lower after the low- than after the high-GI diet. LDL
      cholesterol was significantly lowered on both diets, with a significantly more
      pronounced reduction on the low-GI diet. Plasminogen activator inhibitor-1
      activity was normalized on the low-GI diet, (-54%, P < 0.001), but remained
      unchanged on the high-GI diet. CONCLUSIONS: A diet characterized by low-GI
      starchy foods lowers the glucose and insulin responses throughout the day and
      improves the lipid profile and capacity for fibrinolysis, suggesting a
      therapeutic potential in diabetes.

PMID- 10333898
TI  - Prediction of cardiovascular events in clinically selected high-risk NIDDM
      patients. Prognostic value of exercise stress test and thallium-201 single-photon
      emission computed tomography.
AB  - OBJECTIVE: We evaluated the prognostic value of an exercise stress test and
      thallium-201 scintigraphy for the prediction of cardiac events in selected high
      risk NIDDM patients. RESEARCH DESIGN AND METHODS: NIDDM patients (n = 158, 105
      men, aged 63 +/- 9 years) with two or more of the following criteria were
      prospectively included: age > or = 65 years, active smoking, hypertension >
      160/95 mmHg, hypercholesterolemia (cholesterol > 5.70 mmol/l or LDL > 3.10
      mmol/l), peripheral artery disease, abnormal rest electrocardiogram, or
      microalbuminuria (20-200 micrograms/min). An exercise-stress scintigraphy was
      performed in 77 patients able to exercise, while a dipyridamole scintigraphy was
      performed in 80 patients unable to exercise. Follow-up was 23 +/- 17 months.
      Major end points were cardiac deaths or nonfatal myocardial infarction. RESULTS:
      The annual event rate was 7.31% (deaths: 8, myocardial infarction: 14).
      Independent predictors of events were as follows: an age > 60 (P = 0.02), an
      abnormal rest electrocardiogram (P = 0.02), microalbuminuria (P = 0.001), the
      inability to exercise (P = 0.009), and the presence of more than two defects on
      scintigraphy (P = 0.001). A cardiac death occurred in 1.3% of patients able to
      exercise versus 8.8% of patients unable to exercise (odds ratio = 6.8, P =
      0.001). Among patients unable to exercise, large perfusion defects corresponded
      to an annual mortality rate of 22.3%. Conversely, the negative predictive value
      of a normal scintigraphy for the occurrence of death was 97%. CONCLUSIONS:
      Inability to exercise and large perfusion defects on thallium-201 scan are major
      predictors of future death and myocardial infarction in high-risk NIDDM patients.

PMID- 10333899
TI  - Lispro or regular insulin for multiple injection therapy in adolescence.
      Differences in free insulin and glucose levels overnight.
AB  - OBJECTIVE: Regular insulin given with the evening meal could contribute to the
      risk of nocturnal hypoglycemia in adolescents with type 1 diabetes using a
      multiple injection regimen. To test this hypothesis, we compared glucodynamics
      and free insulin levels on two separate study nights. RESEARCH DESIGN AND
      METHODS: A total of 14 adolescents were recruited. On both nights, identical
      doses of regular insulin or insulin lispro were administered 30 min or 10 min,
      respectively, before the evening meal, using a double-blind randomized crossover
      study design. Doses of NPH insulin and carbohydrate content of the evening meal
      and snack were kept identical. Blood samples were taken every 15 min for blood
      glucose and every 60 min for free insulin and ketones. RESULTS: After insulin
      lispro administration, glucose levels were significantly lower between the
      evening meal and the bedtime snack (analysis of variance [ANOVA] P = 0.02), and
      four hypoglycemic episodes were recorded. This corresponded to a higher (458 +/-
      48 vs. 305 +/- 33 pmol/l, P = 0.02), earlier (64 +/- 4.6 vs. 103 +/- 12 min, P =
      0.01), and shorter-lasting (245 +/- 21 vs. 365 +/- 39 min, P = 0.01) insulin peak
      in contrast to regular insulin. After the bedtime snack, glucose levels increased
      dramatically during the lispro night and stayed higher, up to 0300 in the morning
      (ANOVA P = 0.01), corresponding to lower mean insulin levels (146 +/- 20 vs. 184
      +/- 27 pmol/l, P = 0.04). No differences were seen in glucose and insulin levels
      between 0300 and 0800. Four episodes of nocturnal hypoglycemia were documented
      after the bedtime snack during the regular insulin night, in contrast to one
      episode after insulin lispro. No differences in ketone levels were observed.
      CONCLUSIONS: The replacement of regular insulin with insulin lispro may reduce
      the risk of late hypoglycemia, but redistribution of the evening carbohydrate may
      be needed to ensure good metabolic control and prevent early postprandial
      hypoglycemia.

PMID- 10333900
TI  - Efficacy of metformin in the treatment of NIDDM. Meta-analysis.
AB  - OBJECTIVE: The results differ concerning randomized controlled trials of the
      effects of metformin on blood glucose regulation and body weight. To get a
      systematic overview, a meta-analysis of the efficacy of metformin was performed
      by comparing metformin with placebo and sulfonylurea. RESEARCH DESIGN AND
      METHODS: All randomized controlled trials published since 1957 were selected by
      searching the Current List of Medical Literature, Cumulated Index Medicus,
      Medline, and Embase, Meta-analysis was performed calculating weighted mean
      difference (WMD) of fasting blood glucose, glycosylated hemoglobin, and body
      weight. RESULTS: Nine randomized controlled trials comparing metformin with
      placebo and ten comparing metformin with sulfonylurea were identified. The WMD
      between metformin and placebo after treatment for fasting blood glucose was -2.0
      mmol/l (95% CI -2.4 to -1.7) and for glycosylated hemoglobin -0.9% (95% CI -1.1
      to -0.7). Body weight WMD was not significant after treatment. Sulfonylurea and
      metformin lowered blood glucose and glycosylated hemoglobin equally, while there
      was a significant WMD of body weight (-2.9 kg [95% CI -4.4 to -1.1]) because of a
      1.7-kg mean increase after sulfonylurea and a 1.2-kg mean decrease after
      metformin. CONCLUSIONS: Metformin lowers blood glucose and glycosylated
      hemoglobin significantly, compared with placebo. Metformin and sulfonylurea have
      an equal effect on fasting blood glucose and glycosylated hemoglobin, but the
      body weight is significantly lower after metformin compared with sulfonylurea
      treatment because of an increase in body weight after sulfonylurea treatment.

PMID- 10333901
TI  - First 20 months' experience with use of metformin for type 2 diabetes in a large
      health maintenance organization.
AB  - OBJECTIVE: To assess adherence to prescribing guidelines, continuation rates,
      population effects on glycemic control, and occurrence of lactic acidosis during
      the first 20 months of the availability of metformin in a large health
      maintenance organization. RESEARCH DESIGN AND METHODS: A retrospective cohort
      study was performed in the 90,000-member diabetes registry of Kaiser Permanente,
      northern California. Principal study measures were the proportions of patients
      started on metformin who met prescribing guidelines (previously on sulfonylureas,
      HbA1c, obesity, creatinine), the change in HbA1c at 6 months after starting
      metformin, and hospitalization rates for lactic acidosis. RESULTS: A total of
      9,875 patients received metformin during this interval. At least 74% were
      previously treated with sulfonylureas alone, 81% had baseline HbA1c > or = 8.5%,
      71% were obese, and 99% had a serum creatinine < or = 1.5 mg/dl. Among patients
      on sulfonylureas at baseline, those starting metformin had significantly lower
      HbA1c levels 6 months later than those not started, after adjustment for age,
      sex, and the higher baseline levels in those started (adjusted difference: 0.5%,
      P < 0.0001). Patients starting metformin as initial monotherapy also improved
      significantly, but patients previously treated with insulin (with or without
      sulfonyl-ureas) had slightly higher follow-up HbA1c levels than similar patients
      not starting metformin. Continuation of metformin at 12 months was significantly
      higher for patients previously treated with sulfonylureas than other groups. One
      probable case of lactic acidosis was identified during 4,502 person-years on
      metformin. CONCLUSIONS: Adherence to prescribing guidelines was relatively high
      during metformin's first 20 months of availability. Glycemic control improved
      substantially for patients previously treated with sulfonylureas. Lactic acidosis
      was rare.

PMID- 10333902
TI  - Fasting blood glucose: an underestimated risk factor for cardiovascular death.
      Results from a 22-year follow-up of healthy nondiabetic men.
AB  - OBJECTIVE: Because of the available conflicting epidemiological data, we
      investigated the possible impact of fasting blood glucose as a risk factor for
      cardiovascular death in nondiabetic men. This study reports the results from a 22
      year prospective study on fasting blood glucose as a predictor of cardiovascular
      death. RESEARCH DESIGN AND METHODS: Of the 1,998 apparently healthy nondiabetic
      men (aged 40-59 years), a total of 1,973 with fasting blood glucose < 110 mg/dl
      were included in the study in which also a number of conventional risk factors
      were measured at baseline. RESULTS: After 22 years of follow-up, 483 men had
      died, 53% from cardiovascular diseases. After dividing men into quartiles of
      fasting blood glucose level, it was found that men in the highest glucose
      quartile (fasting blood glucose > 85 mg/dl) had a significantly higher mortality
      rate from cardiovascular diseases compared with those in the three lowest
      quartiles. Even after adjusting for age, smoking habits, serum lipids, blood
      pressure, forced expiratory volume in 1 s, and physical fitness (Cox model), the
      relative risk of cardiovascular death for men with fasting blood glucose > 85
      mg/dl remained 1.4 (95% CI 1.04-1.8). Noncardiovascular deaths were unrelated to
      fasting blood glucose level. CONCLUSIONS: Fasting blood glucose values in the
      upper normal range appears to be an important independent predictor of
      cardiovascular death in nondiabetic apparently healthy middle-aged men.

PMID- 10333903
TI  - Clinical, immunological, and genetic heterogeneity of diabetes in an Italian
      population-based cohort of lean newly diagnosed patients aged 30-54 years.
      Piedmont Study Group for Diabetes Epidemiology.
AB  - OBJECTIVE: In lean diabetic patients, the presentation of the disease does not
      allow one to easily distinguish between type 1 and type 2. Aims of this study
      were to describe clinical, immunological, and genetic features of lean newly
      diagnosed diabetic patients. RESEARCH DESIGN AND METHODS: A population-based
      cohort of 130 lean (BMI < 25 kg/m2) newly diagnosed patients, aged 30-54 years,
      was identified among residents of the province of Turin. Islet cell antibodies
      (ICAs), anti-GAD, fasting and glucagon-stimulated C-peptide values, and HLA DQA1
      DQB1 susceptibility genotypes were assessed within 2 months of the diagnosis.
      RESULTS: A total of 45 (34.6%) and 29 (22.3%) patients were, respectively, ICA+
      and anti-GAD+, with 15 (11.5%) having both antibodies. In 59 patients, ICAs
      and/or anti-GAD antibodies were detected, giving a high prevalence of
      autoimmunity (45.4%, 95% Cl 36.8-54.0); relative to patients without markers (n =
      71), they were younger (40.8 +/- 7.5 vs. 45.0 +/- 6.5 years, P < 0.001) and
      showed lower values of fasting C-peptide (0.56 +/- 0.33 vs. 0.79 +/- 0.41 nmol/l,
      P < 0.001) and stimulated C-peptide (1.03 +/- 0.56 vs. 1.42 +/- 0.69 nmol/l, P <
      0.001). The lowest stimulated C-peptide values were found in patients with both
      ICA and anti-GAD antibodies. Frequencies of adult-onset type 1 and type 2
      diabetes were, respectively, 49.2 and 50.8%. Clinical and genetic features were
      not useful in the classification of patients. CONCLUSIONS: Almost 50% of lean
      young and middle-aged patients were ICA+ and/or anti-GAD+, suggesting a high
      prevalence of a slowly evolving form of type 1 diabetes. The evaluation at
      diagnosis of both beta-cell secretory capacity and markers of autoimmunity is
      recommended to provide a pathogenetic classification of the disease.

PMID- 10333904
TI  - Increased health burden associated with comorbid depression in older diabetic
      Mexican Americans. Results from the Hispanic Established Population for the
      Epidemiologic Study of the Elderly survey.
AB  - OBJECTIVE: To examine the health burden associated with concomitant depressive
      symptoms and diabetes in older Mexican Americans. RESEARCH DESIGN AND METHODS:
      Data from the Hispanic Established Population for the Epidemiologic Study of the
      Elderly were used to assess the association between high levels of depressive
      symptoms, measured with the Center for Epidemiologic Studies of Depression scale,
      and comorbid chronic health conditions, diabetic complications, functional
      disability, health service use, and medication use among 636 older diabetic
      Mexican Americans, in comparison with 2,196 older nondiabetic Mexican Americans.
      RESULTS: Overall, 31.1% of the older diabetic individuals reported high levels of
      depressive symptoms. The risks of comorbid myocardial infarction, hypertension,
      arthritis, and angina were significantly higher in the presence of concomitant
      depressive symptoms, as were the risks of diabetic complications, functional
      disability, incontinence, vision impairment, poorer perceived health status, and
      health service use among both diabetic and nondiabetic individuals. Rates were
      substantially higher among depressed diabetic individuals, however, in comparison
      to depressed nondiabetic individuals. Importantly, this increased health burden
      was evident even when controlling for sociodemographic risk factors, including
      sex, age, level of education, marital status, immigrant status, and living
      arrangements. CONCLUSIONS: The presence of concomitant depressive symptoms among
      older diabetic Mexican Americans is associated with a substantially greater
      health burden than is seen among diabetic individuals without depression or
      depressed individuals without diabetes. This association of depression with
      higher rates of chronic conditions, poorer functioning, and increased health
      service use is particularly significant in that this study was conducted among
      community-dwelling adults and was not confounded by the potential association of
      health care-seeking behavior that might occur in a medically ill sample.

PMID- 10333905
TI  - Association between baseline plasma leptin levels and subsequent development of
      diabetes in Japanese Americans.
AB  - OBJECTIVE: Plasma leptin levels correlate strongly with increased total adipose
      tissue, a known risk factor for type 2 diabetes, yet the role of leptin in the
      etiology of diabetes remains unclear. We sought to determine whether leptin is a
      risk factor for development of diabetes in Japanese Americans. RESEARCH DESIGN
      AND METHODS: We compared baseline leptin levels in 370 nondiabetic Japanese
      Americans who remained nondiabetic for 5-6 years of follow-up with those of 40
      nondiabetic Japanese Americans who developed diabetes during follow-up. All
      participants had computed tomography measurements of baseline subcutaneous chest,
      abdomen, thigh, and intra-abdominal fat, with total fat defined as the sum of all
      these measurements. RESULTS: The mean age was 51.7 +/- 11.7 years for men and
      51.9 +/- 12.0 years for women. The 23 men who developed diabetes had
      significantly higher leptin levels than the 212 men who remained nondiabetic (P <
      0.01). Among men, baseline leptin levels predicted diabetes risk independent of
      baseline total fat, insulin, insulin resistance, glucose, or age in separate
      multiple logistic regression models (relative risk adjusted for baseline total
      fat = 1.80 per SD increase [2.7 ng/ml], 95% CI 1.02-3.17). This association was
      particularly strong among men in the top decile for intra-abdominal fat. In
      contrast, the 17 women who developed diabetes had leptin levels similar to those
      of the 158 women who remained nondiabetic (P = 0.31). CONCLUSIONS: Among Japanese
      Americans, increased baseline leptin levels are associated with increased risk of
      developing diabetes in men but not in women.

PMID- 10333906
TI  - Sex differences in African-Americans regarding sensitivity to insulin's
      glucoregulatory and antilipolytic actions.
AB  - OBJECTIVE: The purpose of this study was to determine if there are sex
      differences in African-Americans regarding the effect of obesity on sensitivity
      to insulin as a glucoregulatory and antilipolytic hormone. RESEARCH DESIGN AND
      METHODS: Data from study participants, 127 nondiabetic African-Americans (mean
      age 32 +/- 4 years), included anthropometric measurements, an oral glucose
      tolerance test (OGTT), a 2-h euglycemic-hyperinsulinemic clamp, and a fasting
      triglyceride level. Sensitivity to insulin as a glucoregulatory hormone was
      determined by M/FFM, where M is the mean glucose infusion rate during the second
      hour of the clamp and FFM is fat-free mass. Sensitivity to insulin's
      antilipolytic action was assessed during the OGTT by the percent suppression of
      free fatty acid (FFA) concentrations between 0 and 120 min. The higher the
      suppression of FFAs, the greater the sensitivity to insulin's antilipolytic
      action. RESULTS: The participants were classified by BMI into three groups:
      nonobese (31 men, 24 women), obese (17 men, 14 women), and severely obese (12
      men, 29 women). The women had higher percentages of body fat (P < 0.001), and the
      men had greater FFM (P < 0.001). The M/FFM values for men versus women in each
      BMI group were nonobese, 8.8 +/- 2.8 vs. 10.8 +/- 4.4; obese, 7.2 +/- 3.4 vs. 8.5
      +/- 3.4; and severely obese, 4.7 +/- 2.1 vs. 6.1 +/- 2.2. The difference between
      the BMI groups was significant (P < 0.001), as was the difference between men and
      women (P < 0.01). In addition, there was a significant sex difference in percent
      suppression of FFAS (P < 0.001). The men and women had similar fasting insulin
      and FFA concentrations; however, in the men only, the percent suppression of FFA
      declined with increasing obesity (nonobese, 83 +/- 15%; obese, 73 +/- 18%; and
      severely obese, 69 +/- 19%; P = 0.02). The women in all three BMI groups had
      lower FFA levels of 86-88%. CONCLUSIONS: Obese African-American men and women are
      resistant to insulin as a glucoregulatory hormone, but only obese men are
      resistant to insulin's antilipolytic action; obese African-American women are
      sensitive to insulin's antilipolytic action. The combined presence of sensitivity
      to insulin's antilipolytic action with resistance to insulin's glucoregulatory
      action in obese African-American women may contribute to their high prevalence of
      obesity and type 2 diabetes.

PMID- 10333907
TI  - Social environment and year of birth influence type 1 diabetes risk for African
      American and Latino children.
AB  - OBJECTIVE: Credible epidemiological data, primarily from European-origin
      populations, indicate that environmental factors play an important role in the
      incidence of type 1 diabetes. RESEARCH DESIGN AND METHODS: A population-based
      registry of incident cases of type 1 diabetes among African-American and Latino
      children in Chicago was used to explore the influence of individual and
      neighborhood characteristics on diabetes risk. New cases of insulin-treated
      diabetes in African-American and Latino Chicagoans aged 0-17 years for 1985-1990
      (n = 400) were assigned to one of 77 community areas based on street address.
      Census tables provided denominators, median household income, percentage of
      adults > or = 25 years old who had completed high school and college, and a
      crowding variable for each community area individual-level data were birth
      cohort, sex, and ethnicity. Outcomes in Poisson regression were sex-, ethnic-,
      and birth cohort-specific incidence rates. RESULTS: Significant univariate
      associations between diabetes risk and ethnicity, birth cohort, crowding, and the
      percentage of adults in each community area who had completed high school and
      college were observed. African-Americans had a relative risk (RR) of 1.42 (95%
      CI, 1.14-1.76) compared with Latinos. Risk varied significantly by birth cohort
      in both ethnic groups. For every 10% increase in the proportion of adults who
      completed college, the RR for diabetes increased by 25% (RR, 1.25 [95% CI, 1.09
      1.44]). Social class variables were significant determinants of risk for African
      Americans, but not for Latinos. CONCLUSIONS: The strong birth cohort and social
      class associations observed in this study implicate an infectious exposure linked
      with age.

PMID- 10333908
TI  - Hyperinsulinemia cluster predicts the development of type 2 diabetes
      independently of family history of diabetes.
AB  - OBJECTIVE: The aim of this prospective study was to determine risk factor
      clusters predicting type 2 diabetes in subjects with and without family history
      of diabetes by applying factor analyses. RESEARCH DESIGN AND METHODS: The study
      population consisted of 309 siblings of diabetic (DM+) or nondiabetic (DM-)
      probands. Risk factors, including lipids, lipoproteins, blood pressure, and
      glucose tolerance status, were measured at the baseline study and 8 years later.
      RESULTS: Siblings in the DM+ group had a significantly higher risk of diabetes
      (odds ratio [OR] = 3.25; P = 0.002) than siblings in the DM- group. Altogether,
      factor analyses revealed four significant factors in both the DM+ and DM- groups
      (the percentage of cumulative variance explained 62-66%). Of these, factor 1
      (percentage of variance, 27-29%) was characterized by high loadings for BMI,
      hypertension, glucose area, insulin area (the highest loading), and triglycerides
      in both the DM+ and DM- groups; therefore, factor 1 can be interpreted as a
      hyperinsulinemia factor. Also, other factors were essentially similar in both
      groups. Hyperinsulinemia factor was similarly associated with the risk of
      developing diabetes in the DM+ group (OR = 4.33, 95% CI 2.29-8.19; P < 0.001) and
      the DM- group (OR = 4.22, 95% CI 2.02-8.81; P < 0.001) in logistic regression
      analyses. CONCLUSIONS: Our results indicate that a cluster of cardiovascular risk
      factors around hyperinsulinemia is an important predictor of diabetes in 8-year
      follow-up independent of family history of diabetes.

PMID- 10333909
TI  - Peripheral atherosclerosis and serum lipoprotein(a) in diabetes.
AB  - OBJECTIVE: Serum lipoprotein(a) [Lp(a)] is strongly associated with
      atherosclerosis in nondiabetic individuals. To see if atherosclerosis is also
      associated with serum Lp(a) in both IDDM and NIDDM, we determined the correlation
      between the toe systolic blood pressure index (TSPI) and serum Lp(a) in tightly
      controlled diabetic patients without nephropathy. RESEARCH DESIGN AND METHODS:
      Cross-sectional study of 57 IDDM and 35 NIDDM patients. All patients had been
      under strict glycemic control for at least 6 months. The main outcome measure was
      TSPI of both lower extremities. In addition, we measured serum Lp(a) and other
      serum lipids, serum uric acid, total plasma homocysteine, plasma C-peptide,
      HbA1c, albumin excretion rate, glomerular filtration rate, BMI, abdominal fat
      distribution, left ventricular hypertrophy, probabilities for cardiovascular
      disease (CVD), and routine clinical parameters. RESULTS: TSPI was closely and
      independently related to serum Lp(a) in IDDM patients: R2 = 0.2999, partial P =
      0.0005, and in NIDDM patients: R2 = 0.7326, partial P = 0.0030. TSPI was
      associated with symptoms of CVD. Median serum Lp(a) concentration was normal in
      IDDM (45 mg/l [range 10-870]) and NIDDM (72 mg/l [11-803]) patients. CONCLUSIONS:
      Systemic atherosclerosis measured as the degree of peripheral occlusive arterial
      disease is strongly associated with serum Lp(a) in both IDDM and NIDDM patients.
      Serum Lp(a), however, is normal in both types of diabetic patients. Thus, it is
      indicated that serum Lp(a) should be measured in diabetic patients when assessing
      their risk profile for atherosclerosis.

PMID- 10333910
TI  - Epidemiology of Diabetes Interventions and Complications (EDIC). Design,
      implementation, and preliminary results of a long-term follow-up of the Diabetes
      Control and Complications Trial cohort.
AB  - OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) demonstrated the
      powerful impact of glycemic control on the early manifestations of microvascular
      complications. Contemporary prospective data on the evolution of macrovascular
      and late microvascular complications of type 1 diabetes are limited. The
      Epidemiology of Diabetes Interventions and Complications (EDIC) study is a
      multicenter, longitudinal, observational study designed to use the well
      characterized DCCT cohort of > 1,400 patients to determine the long-term effects
      of prior separation of glycemic levels on micro- and macrovascular outcomes.
      RESEARCH DESIGN AND METHODS: Using a standardized annual history and physical
      examination, 28 EDIC clinical centers that were DCCT clinics will follow the EDIC
      cohort for 10 years. Annual evaluation also includes resting electrocardiogram.
      Doppler ultrasound measurements of ankle/arm blood pressure, and screening for
      nephropathy. At regular intervals, a timed 4-h urine is collected, lipid profiles
      are obtained, and stereoscopic fundus photographs are taken. In addition, dual B
      mode Doppler ultrasound scans of the common and internal carotid arteries will be
      performed at years 1 and 6 and at study end. RESULTS: Written informed consent
      was obtained from 96% of the DCCT subjects. The participants, compared with
      nonparticipants, tended to have better glycemic control at the completion of the
      DCCT and were more likely to have their diabetes care provided by DCCT personnel.
      The EDIC baseline measurement stratified by sex delineates multiple
      cardiovascular disease risk factor differences such as age (older in men), waist
      to-hip ratio (higher in men). HDL cholesterol (lower in men), hypertension (more
      prevalent in men), and maximum intimal-medial thickness of common and internal
      carotid arteries (thicker in men). Of the original conventional treatment group,
      69% have changed to continuous subcutaneous insulin infusion or multiple daily
      injections. Although the mean HbA1c difference between the intensive and
      conventional treatment groups narrowed at EDIC years 1 and 2, HbA1c remained
      significantly lower in the intensive group. Of all expected clinic visits, 95%
      were completed, and the quality of EDIC data is very similar to that observed in
      the DCCT. CONCLUSIONS: Although obvious problems exist in extended follow-up
      studies of completed clinical trials, these are balanced by the value of
      continued systematic observation of the DCCT cohort. In contrast to other
      epidemiologic studies, EDIC will provide 1) definitive data on type 1 as distinct
      from type 2 diabetes; 2) reliance on prospective rather than on cross-sectional
      analysis; 3) long-term follow-up in a large population; 4) consistent use of
      objective, reliable measures of outcomes and glycemia; and 5) observation of
      patients from before the onset of complications.

PMID- 10333911
TI  - Metabolic alterations in middle-aged and elderly obese patients with type 2
      diabetes.
AB  - OBJECTIVE: We conducted this study to assess the metabolic alterations in middle
      aged and elderly obese patients with type 2 diabetes. RESEARCH DESIGN AND
      METHODS: Healthy control subjects (9 middle-aged, aged 42 +/- 2 years, BMI 33 +/-
      1 kg/m2; 10 elderly, aged 71 +/- 1 years, BMI 29 +/- 1 kg/m2) and patients with
      type 2 diabetes (11 middle-aged, aged 43 +/- 2 years, BMI 34 +/- 2 kg/m2; 23
      elderly, aged 73 +/- 1 years; BMI 30 +/- 1 kg/m2) underwent a 3-h oral glucose
      tolerance test (OGTT), a 2-h hyperglycemic glucose clamp, and a 3-h euglycemic
      glucose clamp study with tritiated glucose methodology to measure hepatic glucose
      production and peripheral disposal rates. RESULTS: Middle-aged and elderly
      control subjects and patients with diabetes were similar in percentage of body
      fat. Waist-to-hip ratio was greater in elderly patients with diabetes than in
      elderly control subjects (P < 0.01), but was similar in both middle-aged groups.
      VO2max was less in control subjects than in both middle-aged and elderly patients
      with diabetes (P < 0.05). Insulin responses during the OGTT were similar in
      elderly control subjects and patients with diabetes, but were less in middle-aged
      patients with diabetes than in control subjects (305 +/- 49 vs. 690 +/- 136
      pmol/l, P < 0.01). Patients with type 2 diabetes had absent first-phase insulin
      responses during the hyperglycemic clamp. Second-phase (80-120 min) insulin
      values were similar in elderly patients and control subjects, but were reduced in
      middle-aged patients with diabetes compared with control subjects (285 +/- 35 vs.
      894 +/- 143 pmol/l, P < 0.0001). During the euglycemic clamp, basal and steady
      state (150-180 min) hepatic glucose output values were less in middle-aged
      control subjects than in patients with diabetes (basal, 3.03 +/- 0.10 vs. 3.69 +/
      0.09 mg.kg-1 lean body mass.min-1, P < 0.0001; steady-state, 0.72 +/- 0.10 vs.
      1.84 +/- 0.20 mg.kg-1 lean body mass.min-1, P < 0.0001). Basal and steady-state
      hepatic glucose output values were similar in elderly patients and control
      subjects. Finally, steady-state (150-180 min) glucose disposal rates were higher
      in control subjects than in patients with diabetes in both the middle-aged (7.51
      +/- 0.85 vs. 4.62 +/- 0.24 mg.kg-1 lean body mass.min-1, P < 0.01) and elderly
      (9.91 +/- 0.61 vs. 6.78 +/- 0.60 mg.kg-1 lean body mass.min-1, P < 0.01) groups.
      CONCLUSIONS: We conclude that type 2 diabetes in obese middle-aged subjects is
      characterized by impaired glucose-induced insulin release, altered regulation of
      hepatic glucose output, and resistance to insulin-mediated glucose disposal. In
      contrast, the primary defect in elderly obese patients with type 2 diabetes is
      resistance to insulin-mediated glucose disposal. Our findings may have important
      therapeutic implications for these patient populations.

PMID- 10333912
TI  - Effect of repaglinide addition to metformin monotherapy on glycemic control in
      patients with type 2 diabetes.
AB  - OBJECTIVE: To compare the effect of repaglinide in combination with metformin
      with monotherapy of each drug on glycemic control in patients with type 2
      diabetes. RESEARCH DESIGN AND METHODS: A total of 83 patients with type 2
      diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the
      antidiabetic agent metformin were enrolled in this multicenter, double-blind
      trial. Subjects were randomized to continue with their prestudy dose of metformin
      (n = 27), to continue with their prestudy dose of metformin with the addition of
      repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients
      receiving repaglinide, the optimal dose was determined during a 4- to 8-week
      titration and continued for a 3-month maintenance period. RESULTS: In subjects
      receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9%
      (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No
      significant changes were observed in subjects treated with either repaglinide or
      metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting
      plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively).
      Subjects receiving repaglinide either alone or in combination with metformin, had
      an increase in fasting levels of insulin between baseline and the end of the
      trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02).
      Gastrointestinal adverse events were common in the metformin group. An increase
      in body weight occurred in the repaglinide and combined therapy groups (2.4 +/-
      0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05). CONCLUSIONS: Combined metformin
      and repaglinide therapy resulted in superior glycemic control compared with
      repaglinide or metformin monotherapy in patients with type 2 diabetes whose
      glycemia had not been well controlled on metformin alone. Repaglinide monotherapy
      was as effective as metformin monotherapy.

PMID- 10333914
TI  - Optimal administration of lispro insulin in hyperglycemic type 1 diabetes.
AB  - OBJECTIVE: Lispro is a new rapidly absorbed insulin analog. At present, there are
      no recommendations for the optimal injection time of lispro insulin in
      hyperglycemic patients. In contrast to normoglycemic patients with diabetes, we
      hypothesized that injection of lispro insulin 15-30 min before meal ingestion
      would improve postprandial glucose excursion in hyperglycemic diabetic subjects.
      RESEARCH DESIGN AND METHODS: In 48 randomized overnight studies, 12 healthy adult
      type 1 diabetic patients received lispro insulin 0.15 U/kg admixed with human
      ultralente 0.2 U/kg (as background insulin) subcutaneously at minutes (-30, -15,
      0, and +15) relative to the ingestion of an American Diabetes Association
      breakfast of 8.6 kcal/kg. Pre-breakfast hyperglycemia of 10.2 +/- 0.2 mmol/l was
      established before the study by continuous overnight infusion of intravenous
      insulin, which was stopped 30 min before lispro insulin injection. Glucose and
      insulin levels were measured every 30 min for 5 h after breakfast. RESULTS:
      Results demonstrated that postprandial glucose excursion was reduced when lispro
      insulin was administered 15 or 30 min before the meal compared with lispro
      insulin injected at the meal (P < 0.002). The postprandial glucose excursion
      (millimoles per liter per hour) was -6.4 +/- 3 for the -30-min group, -5.1 +/-
      2.9 for the -15-min group, 3.4 +/- 4.1 for the 0-min group, and 5.7 +/- 4.4 for
      the +15-min group. Although injecting lispro insulin at 30 min before the meal
      resulted in a significant reduction in postprandial glycemia, it was accompanied
      by loss of glucose control at 4 h postmeal in two subjects. CONCLUSIONS:
      Optimization of lispro insulin in hyperglycemic patients requires timing of the
      insulin injection at least 15 min before the meal.

PMID- 10333913
TI  - Fasting and post-methionine homocysteine levels in NIDDM. Determinants and
      correlations with retinopathy, albuminuria, and cardiovascular disease.
AB  - OBJECTIVE: The increased cardiovascular risk in subjects with NIDDM is partly
      explained by an association with established risk factors like hypertension,
      dyslipidemia, and obesity. Mild hyperhomocysteinemia has emerged as a new risk
      factor for cardiovascular disease. The purpose of this study was to assess its
      role in NIDDM. RESEARCH DESIGN AND METHODS: We studied predictors of homocysteine
      levels and correlations between homocysteine and (micro-)albuminuria,
      retinopathy, and history of cardiovascular disease in normotensive NIDDM subjects
      under stable metabolic control. This was done in 85 NIDDM subjects by measuring
      fasting and post-methionine-loading homocysteine levels together with blood
      pressure, BMI, serum cholesterol, triglyceride, HDL cholesterol, folate, vitamin
      B12, pyridoxal-5-phosphate, HbA1c, and (micro-)albuminuria and creatinine
      clearance in triplicate 24-h urine samples. The relationship between micro- and
      macrovascular complications and fasting homocysteine only was studied in an
      additional 65 subjects, giving a total of 150 subjects. RESULTS: In multiple
      regression analysis, significant (P < 0.05) predictors of fasting homocysteine
      were low-normal values of creatinine clearance (threshold effect at < 80 ml.min-1
      .1.73 m-2), folate (< 20 nmol/l), and vitamin B12 (< 350 pmol/l), and
      postmenopausal status in women. Determinants of post-methionine homocysteine were
      pyridoxal-5-phosphate levels < 80 nmol/l, creatinine clearance, and sex (higher
      levels in women). Hyperhomocysteinemia did not cluster with other cardiovascular
      risk factors, like hypertension, obesity, or dyslipidemia. Regarding
      cardiovascular complications, fasting homocysteine, but not post-methionine
      homocysteine, was higher in subjects with a history of cardiovascular disease.
      There was a stepwise increase in the prevalence of subjects with cardiovascular
      disease with increasing fasting homocysteine. The prevalence of cardiovascular
      disease was 19.4% in the bottom quartile of fasting homocysteine, versus 55.0% in
      the top quartile (P for trend < 0.01). Neither fasting homocysteine nor post
      methionine homocysteine correlated with (micro-)albuminuria or with retinopathy.
      CONCLUSIONS: The findings suggest that homocysteine levels in NIDDM rise even
      with modest deterioration of renal function and when vitamin status is in the low
      to low-normal range. Fasting homocysteine correlates with macrovascular disease,
      but we found no evidence of a correlation with retinopathy or (micro
      )albuminuria. Post-methionine homocysteine levels do not show a correlation with
      micro- or macrovascular complications.

PMID- 10333915
TI  - Accuracy of pen injectors versus insulin syringes in children with type 1
      diabetes.
AB  - OBJECTIVE: To compare the accuracy and precision of insulin syringes and pen
      devices used by children with type 1 diabetes and their parents. RESEARCH DESIGN
      AND METHODS: There were 48 subjects (32 patients, a parent of an additional 16
      patients) instructed to measure out morning insulin doses three times from vials
      and/or cartridges containing saline mixed with small amounts of [14C]glucose
      (solution used as regular insulin) and [3H]glucose (solution used as NPH insulin)
      and to dispense the contents into a scintillation vial. Statistical analysis was
      used to determine the accuracy and precision of both methods of insulin delivery.
      RESULTS: The absolute error in measuring out doses of regular insulin < 5 U was
      greater with insulin syringes compared with pen injection devices (9.9 +/- 2.4
      vs. 4.9 +/- 1.6%, respectively). Both were comparable for regular insulin doses >
      5 U (3.2 +/- 0.6 vs. 2.2 +/- 0.4% for syringes and pens, respectively). The
      accuracy in drawing up NPH doses was similar for low and high insulin doses (mean
      percent error of 7.5 +/- 1.5 vs. 5.6 +/- 1.1%). CONCLUSIONS: Pen devices are more
      accurate than insulin syringes in measuring out insulin at low insulin doses. The
      accuracy of insulin syringes improves when higher doses of regular insulin are
      measured out and becomes comparable to pen devices.

PMID- 10333916
TI  - Prevalence of impaired glucose tolerance and diabetes in women with polycystic
      ovary syndrome.
AB  - OBJECTIVE: NIDDM occurs commonly among women with polycystic ovary syndrome
      (PCOS). The prevalence and natural history of its precursor, impaired glucose
      tolerance (IGT), is less well known. The objective of this study was to
      characterize the prevalence and incidence of glucose intolerance in a large
      cohort of women with well-characterized PCOS. RESEARCH DESIGN AND METHODS: A
      total of 122 women with clinical and hormonal evidence of PCOS were recruited
      from the Medicine, Endocrinology, Gynecology, and Pediatrics Clinics at the
      University of Chicago. All women had a standard oral glucose tolerance test
      (OGTT) with measurement of glucose and insulin levels. A subset of 25 women were
      subsequently restudied with the aim of characterizing the natural history of
      glucose tolerance in PCOS. RESULTS: Glucose tolerance was abnormal in 55 (45%) of
      the 122 women: 43 (35%) had IGT and 12 (10%) had NIDDM at the time of initial
      study. The women with NIDDM differed from those with normal glucose tolerance in
      that they had a 2.6-fold higher prevalence of first-degree relatives with NIDDM
      (83 vs. 31%, P < 0.01 by chi 2) and were significantly more obese (BMI 41.0 +/-
      2.4 vs. 33.4 +/- 1.1 kg/m2, P < 0.01). For the entire cohort of 122 women, there
      was a significant correlation between fasting and 2-h glucose concentrations (r =
      0.76, P < 0.0001); among the subset with IGT, the fasting glucose concentration
      was poorly predictive of the 2-h level (r = 0.25, NS). After a mean follow-up of
      2.4 +/- 0.3 years (range 0.5-6.3), 25 women had a second OGTT. The glucose
      concentration at 2 h during the second glucose tolerance test was significantly
      higher than the 2-h concentration during the first study (161 +/- 9 vs. 139 +/- 6
      mg/dl, P < 0.02). CONCLUSIONS: The prevalence of IGT and NIDDM in women with PCOS
      is substantially higher than expected when compared with age- and weight-matched
      populations of women without PCOS. The conversion from IGT to NIDDM is
      accelerated in PCOS. The fasting glucose concentration does not reliably predict
      the glucose concentration at 2 h after an oral glucose challenge, particularly
      among those with IGT, the subgroup at highest risk for subsequent development of
      NIDDM. We conclude that women with PCOS should periodically have an OGTT and must
      be closely monitored for deterioration in glucose tolerance.

PMID- 10333917
TI  - Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of
      diabetic foot ulcers.
AB  - OBJECTIVE: The present study was undertaken to compare the predictive values of
      transcutaneous oxygen tension (TcPO2) and toe blood pressure (TBP) measurements
      for ulcer healing in patients with diabetes and chronic foot ulcers. RESEARCH
      DESIGN AND METHODS: Investigated prospectively were 50 diabetic patients (37 men)
      with chronic foot ulcers. The age was 61 +/- 12 (mean +/- SD), and the diabetes
      duration was 26 +/- 14 years. TBP (mmHg) was measured in dig I and TcPO2 (mmHg)
      at the dorsum of the foot. Ulcer healing was continuously evaluated by measuring
      the ulcer area every 4-6 weeks. After a follow-up time of 12 months, the patients
      were divided into three groups according to clinical outcome: healed with intact
      skin, improved ulcer healing, or impaired ulcer healing. RESULTS: Of the 13
      patients who deteriorated, 11 had TcPO2 < 25 mmHg, while 34 of the 37 patients
      who improved had TcPO2 > or = 25 mmHg. The sensitivity and specificity for TcPO2
      were 85 and 92%, respectively, when a cutoff level of 25 mmHg was used for
      determination of outcome of ulcer healing (healing or nonhealing). The
      corresponding values for TBP at 30 mmHg were 15 and 97%. Measurement of TcPO2
      provided a higher positive predictive value (79%) than TBP (67%). CONCLUSIONS:
      The results indicate that TcPO2 is a better predictor for ulcer healing than TBP
      in diabetic patients with chronic foot ulcers, and that the probability of ulcer
      healing is low when TcPO2 is < 25 mmHg.

PMID- 10333918
TI  - Elevated remnant-like lipoprotein particles in impaired glucose tolerance and
      type 2 diabetic patients.
AB  - OBJECTIVE: Impaired glucose tolerance (IGT) in association with insulin
      resistance is considered to be a risk factor for atherosclerosis. Thus, patients
      with IGT may have abnormal lipid and lipoprotein profiles. The purpose of this
      study was to investigate presence of remnant-type hyperlipoproteinemia in
      patients with IGT. RESEARCH DESIGN AND METHODS: Serum levels of remnant-like
      lipoprotein particles (RLP) were measured in 541 subjects (362 men and 179 women,
      age 53 +/- 7.9 years) who visited our health center for routine medical
      examinations. We measured RLP cholesterol (RLP-C) and RLP triglycerides (RLP-TG)
      using immunoaffinity gel containing monoclonal anti-human apoproteins A-I (H-12)
      and B-100 (JI-H) antibodies. After a 75-g oral glucose tolerance test, subjects
      were divided into three groups: normal, IGT, and type 2 diabetic. RESULTS: After
      matching for sex, age, and body weight, serum RLP-C in normal, IGT, and diabetic
      groups were 4.2 +/- 1.7, 6.2 +/- 3.4, and 6.2 +/- 4.2 mg/dl, respectively. The
      corresponding RLP-TG values were 16.7 +/- 9.2, 28.0 +/- 19.1, and 29.0 +/- 27.2
      mg/dl. We found that RLP-C and RLP-TG values were significantly higher in the IGT
      and diabetic groups compared with the normal group (P < 0.001). In the same
      order, total serum cholesterol levels were 206 +/- 29, 205 +/- 34, and 206 +/- 34
      mg/dl and LDL cholesterol levels were 127 +/- 27, 124 +/- 34, and 123 +/- 34
      mg/dl, showing no marked difference in these groups. However, serum levels of
      triglyceride were higher in the IGT and diabetes groups (155 +/- 76 and 151 +/-
      81 mg/dl vs. 106 +/- 41 mg/dl; P < 0.0001). Further, the incidence of remnant
      hyperlipoproteinemia in normocholesterolemic subjects was up to four times higher
      in IGT and diabetic groups compared with the normal group. CONCLUSIONS: High
      serum RLP-C and RLP-TG levels in IGT and diabetic patients may represent an
      increased risk of atherosclerosis in these patients.

PMID- 10333919
TI  - Causal pathways for incident lower-extremity ulcers in patients with diabetes
      from two settings.
AB  - OBJECTIVE: To determine the frequency and constellations of anatomic,
      pathophysiologic, and environmental factors involved in the development of
      incident diabetic foot ulcers in patients with diabetes and no history of foot
      ulcers from Manchester, U.K., and Seattle, Washington, research settings.
      RESEARCH DESIGN AND METHODS: The Rothman model of causation was applied to the
      diabetic foot ulcer condition. The presence of structural deformities, peripheral
      neuropathy, ischemia, infection, edema, and callus formation was determined for
      diabetic individuals with incident foot ulcers in Manchester and Seattle.
      Demographic, health, diabetes, and ulcer data were ascertained for each patient.
      A multidisciplinary group of foot specialists blinded to patient identity
      independently reviewed detailed abstracts to determine component and sufficient
      causes present and contributing to the development of each patient's foot ulcer.
      A modified Delphi process assisted the group in reaching consensus on component
      causes for each patient. Estimates of the proportion of ulcers that could be
      ascribed to each component cause were computed. RESULTS: From among 92 study
      patients from Manchester and 56 from Seattle, 32 unique causal pathways were
      identified. A critical triad (neuropathy, minor foot trauma, foot deformity) was
      present in > 63% of patient's causal pathways to foot ulcers. The components
      edema and ischemia contributed to the development of 37 and 35% of foot ulcers,
      respectively. Callus formation was associated with ulcer development in 30% of
      the pathways. Two unitary causes of ulcer were identified, with trauma and edema
      accounting for 6 and < 1% of ulcers, respectively. The majority of the lesions
      were on the plantar toes, forefoot, and midfoot. CONCLUSIONS: The most frequent
      component causes for lower-extremity ulcers were trauma, neuropathy, and
      deformity, which were present in a majority of patients. Clinicians are
      encouraged to use proven strategies to prevent and decrease the impact of
      modifiable conditions leading to foot ulcers in patients with diabetes.

PMID- 10333920
TI  - Care of children with diabetes in the school and day care setting. American
      Diabetes Association.

PMID- 10333921
TI  - Management of diabetes at diabetes camps. American Diabetes Association.

PMID- 10333922
TI  - American Diabetes Association Annual Meeting, 1998. Treatment of type 2 diabetes.

PMID- 10333923
TI  - GAD65 antibodies in classification of Asian Indian diabetic subjects with onset
      between 20 and 40 years.

PMID- 10333924
TI  - Thrifty gene and hunting as a way of life are evident in a Paleoindian burial.

PMID- 10333925
TI  - Diabetic ketoacidosis associated with clozapine treatment.

PMID- 10333926
TI  - Heterozygous hemoglobin Hamadan affects HbA1c assay.

PMID- 10333927
TI  - Lactic acidosis with therapeutic metformin blood level in a low-risk diabetic
      patient.

PMID- 10333928
TI  - Beneficial impact of ramipril on left ventricular hypertrophy in normotensive
      nonalbuminuric NIDDM patients.

PMID- 10333929
TI  - Metformin and fatty acids.

PMID- 10333930
TI  - Prevalence of deafness is increased in patients with type 2 diabetes in The
      Netherlands.

PMID- 10333931
TI  - Health promotion and diabetes risk factors in children.

PMID- 10333932
TI  - Multicenter randomized trial of a comprehensive prepared meal program in type 2
      diabetes.
AB  - OBJECTIVE: To evaluate the clinical effects of a comprehensive prepackaged meal
      plan, incorporating the overall dietary guidelines of the American Diabetes
      Association and other national health organizations, relative to those of a self
      selected diet based on exchange lists in free-living individuals with type 2
      diabetes. RESEARCH DESIGN AND METHODS: A total of 202 women and men (BMI < or =
      42 kg/m2) whose diabetes was treated with diet alone or an oral hypoglycemic
      agent were enrolled at 10 medical centers. After a 4-week baseline period,
      participants were randomized to a nutrient-fortified prepared meal plan or a self
      selected exchange-list diet for 10 weeks. On a caloric basis, both interventions
      were designed to provide 55-60% carbohydrate, 20-30% fat, and 15-20% protein. At
      intervals, 3-day food records were completed, and body weight, glycemic control,
      plasma lipids, and blood pressure were assessed. RESULTS: Food records showed
      that multiple nutritional improvements were achieved with both diet plans. There
      were significant overall reductions in body weight and BMI, fasting plasma
      glucose and serum insulin, fructosamine, HbA1c, total and LDL cholesterol, and
      blood pressure (P < 0.001 or better for all). In general, differences in major
      end points between the diet plans were not statistically significant.
      CONCLUSIONS: Glycemic control and cardiovascular risk factors improve in
      individuals with type 2 diabetes who consume diets in accordance with the
      American Diabetes Association guidelines. The prepared meal program was as
      clinically effective as the exchange-list diet. The prepared meal plan has the
      additional advantages of being easily prescribed and eliminating the complexities
      of meeting the multiple dietary recommendations for type 2 diabetes management.

PMID- 10333933
TI  - Walking training for intermittent claudication in diabetes.
AB  - OBJECTIVE: Walking training (WT) is an established treatment for patients with
      intermittent claudication (IC). Abnormalities specific to diabetes, such as a
      relative preponderance of distal lesions and the contribution of microcirculatory
      disease, might well influence the results of WT. We compared changes in walking
      distance during WT in diabetic patients with those in nondiabetic control
      subjects. RESEARCH DESIGN AND METHODS: In consecutive patients with limiting IC
      and proven peripheral vascular disease, 33 patients with diabetes were compared
      with 136 control subjects during a half-year supervised WT program. Walking
      parameters were determined every 2 months, while vascular parameters were
      obtained at the start and end of the program. RESULTS: Of the 33 diabetic
      patients, 25 (76%) completed the program, as did 87 of the 136 (64%) control
      subjects. Thereafter, the symptom-free walking distance and the maximum walking
      distance (MWD) were significantly increased in diabetic patients from 142 +/- 30
      to 339 +/- 57 m and from 266 +/- 39 to 603 +/- 52 m, respectively, and in control
      subjects from 126 +/- 8 to 400 +/- 39 m and from 292 +/- 18 to 628 +/- 36 m,
      respectively. The relative gain in MWD was 88% greater in those with diabetes.
      The vascular parameters were comparable for both groups before and after WT.
      CONCLUSIONS: WT is an effective treatment for IC, with a greater relative gain in
      diabetic patients.

PMID- 10333934
TI  - Diabetes risk factors in low-income Mexican-American children.
AB  - OBJECTIVE: To learn if Mexican-American children from low income neighborhoods
      have excess diabetes risk factors. RESEARCH DESIGN AND METHODS: The study
      involved 173 Mexican-American children aged 9 years. This is the age before type
      2 diabetes usually develops in youths and where the disparity in body fat between
      Mexican-American and non-Hispanic white children is evident. The study also
      targets poor children because diabetes and being overweight are more common in
      Mexican-American adults from a lower than from a higher socioeconomic status. The
      diabetes risk factors measured were percent body fat, dietary fat intake, daily
      fruit and vegetable intake, and physical fitness. Body fat was measured by
      bioelectric impedance, dietary intake was measured by three 24-h dietary recalls,
      and physical fitness was measured by a modified Harvard step test. RESULTS:
      According to self-reported dietary recalls, Mexican-American children ate higher
      than recommended fat servings and had higher percent energy from fat and
      saturated fat. On the other hand, their reported daily fruit and vegetable intake
      was half of that recommended by national dietary guidelines. A large percentage
      of these children were at unacceptable physical fitness levels. Percent body fat
      was higher in these Mexican-American children than that reported for non-Hispanic
      white children. Finally, 60% of the children had a first- or second-degree
      relative with diabetes. CONCLUSIONS: Because diabetes is highly prevalent in
      Mexican-American adults, type 2 diabetes in increasing in Mexican-American
      youths, and diabetes risk factors are more common in Mexican-American children, a
      prudent measure would be to explore early-age diabetes risk factor prevention
      programs in this population.

PMID- 10333935
TI  - Risk and protective factors associated with screening for complications of
      diabetes in a health maintenance organization setting.
AB  - OBJECTIVE: To identify risk and protective factors associated with screening for
      complications of diabetes, we performed a cross-sectional study of 3,612 diabetic
      members enrolled in CaliforniaCare, a large network-model health maintenance
      organization (HMO). RESEARCH DESIGN AND METHODS: We used the Health Plan and
      Employer Data Information Set (HEDIS) 3.0 technical definition to identify all
      members (aged > or = 31 years) receiving any diabetes medication(s) during a 12
      month period. Using a telephone survey instrument, identified members were
      interviewed about their diabetes care and screening, patient, and provider
      history. Survey data were supplemented with HMO claims and demographic
      information. Multivariate analysis was performed to identify demographic,
      clinical, and utilization characteristics that affect the odds of diabetic
      members receiving annual retinal examination, foot examination, and HbA1c
      testing. RESULTS: While results varied by screening category, the odds of
      obtaining screening were higher for diabetic members who were older, spoke
      English, received diabetes nutrition counseling, visited a diabetes specialist
      physician, belonged to a diabetes association or support group, used insulin,
      performed glycemic level self-examination at least once a day, and had higher
      overall prescription drug use (suggesting higher comorbidity). Since this study
      is a cross-sectional review, these results do not imply a cause-and-effect
      relationship between dependent and independent variables. CONCLUSIONS: Results of
      this study suggest barriers, risks, and protective factors associated with
      screening for complications of diabetes. Diabetic members who do not possess
      these characteristics may be at increased risk.

PMID- 10333936
TI  - Performance of a predictive model to identify undiagnosed diabetes in a health
      care setting.
AB  - OBJECTIVE: To develop a predictive model to identify individuals with an
      increased risk for undiagnosed diabetes, allowing for the availability of
      information within the health care system. RESEARCH DESIGN AND METHODS: A sample
      of participants from the Rotterdam Study (n = 1,016), aged 55-75 years, not known
      to have diabetes completed a questionnaire on diabetes-related symptoms and risk
      factors and underwent a glucose tolerance test. Predictive models were developed
      using stepwise logistic regression analyses with the absence or presence of newly
      diagnosed diabetes as the dependent variable and various items with a plausible
      connection to diabetes as the independent variables. The models were evaluated in
      another Dutch population-based study, the Hoorn Study (n = 2,364), in which the
      participants were aged 50-74 years. Performances of the predictive models were
      compared by using receiver-operator characteristics (ROC) curves. RESULTS: We
      developed three predictive models (PMs), PM1 contained information routinely
      collected by the general practitioner, while PM2 also contained variables
      obtainable by additional questions. The third predictive model, PM3, included
      variables that had to be obtained from a physical examination. These latter
      variables did not have additive predictive value, resulting in a PM3 similar to
      PM2. The area under the ROC curve was higher for PM2 than for PM1, but the 95%
      Cls overlapped (0.74 [0.70-0.78] and 0.68 [0.64-0.72], respectively).
      CONCLUSIONS: Using only information normally present in the files of a general
      practitioner, a predictive model was developed that performed similarly to one
      supplemented by information obtained from additional questions. The simplicity of
      PM1 makes it easy to implement in the current health care setting.

PMID- 10333937
TI  - Diabetes and automobile crashes in the elderly. A population-based case-control
      study.
AB  - OBJECTIVE: The aim of this study was to estimate the association between diabetes
      and its complications and at-fault automobile crashes among older drivers.
      RESEARCH DESIGN AND METHODS: This was a population-based case-control study. Case
      subjects were drivers aged > or = 65 years who had been involved in a crash
      during 1996 in which they were at fault. Two control groups were selected: 1)
      crash-involved not-at-fault subjects and 2) non-crash-involved subjects.
      Telephone interviewers collected information on demographic characteristics,
      driving habits, diabetes sequelae and treatment, other chronic medical
      conditions, and visual function. RESULTS: Overall, there was no association
      between diabetes and at-fault crash involvement. The adjusted odds ratio (OR) for
      diabetes was 1.1 (CI 0.7-1.9) when case subjects were compared with either
      control group. However, the adjusted OR for diabetes was 2.5 (0.9-7.2) among
      subjects who had been involved in a crash in the 4 years preceding 1996, while it
      was only 0.9 (0.5-1.7) among those who had not. There was no evidence of an
      association between treatment modalities and at-fault crash involvement. Case
      subjects were, although not significantly (P = 0.25), more likely (OR 2.4) to
      report neuropathy compared with both control groups, and retinopathy was not
      associated with increased crash risk. CONCLUSIONS: This study provides no
      evidence that older drivers with diabetes are at increased risk for automobile
      crashes. There remains the possibility that those with diabetes who have more
      severe disease or have had multiple crashes are at increased risk.

PMID- 10333938
TI  - Impaired fasting glucose and the risk of hypertension in Japanese men between the
      1980s and the 1990s. The Osaka Health Survey.
AB  - OBJECTIVE: To determine whether impaired fasting glucose (IFG) increased the risk
      for hypertension in two large Japanese cohorts during the different time periods.
      RESEARCH DESIGN AND METHODS: We prospectively investigated two Japanese cohorts:
      a 1980s population, comprising 4,130 normotensive and nondiabetic men aged 35-60
      years entered between 1981 and 1983, and a 1990s population, comprising 4,319
      normotensive and nondiabetic men aged 35-60 years entered between 1991 and 1992.
      Data on lifestyle factors were obtained from questionnaires. IFG was defined as a
      fasting plasma glucose level > or = 110 and < 126 mg/dl. RESULTS: During the 4
      year observation period, 708 cases of hypertension were confirmed in the 1980s
      and 848 cases were confirmed in the 1990s. In both the 1980s and 1990s
      populations, IFG was associated with the risk of hypertension. The frequency of
      IFG in men in the 1990s group was twice as high as that in the 1980s group. The
      multivariate-adjusted odds ratio (OR) of hypertension was 1.54 (95% CI, 1.01
      2.34) for men with IFG in the 1980s population and 1.73 (1.31-2.29) in the 1990s
      population, compared with those without IFG in the two populations. In the 1990s
      population, among lean men with a BMI < or = 23 kg/m2, men with IFG had a
      multivariate-adjusted OR of hypertension of 2.31 (1.46-3.65) compared with those
      without IFG. CONCLUSIONS: This study demonstrated direct correlation between IFG
      and hypertension and greater incidence of this hypertension in the 1990s group
      than in the 1980s group.

PMID- 10333939
TI  - The relationship between glucose and incident cardiovascular events. A
      metaregression analysis of published data from 20 studies of 95,783 individuals
      followed for 12.4 years.
AB  - OBJECTIVE: To assess the relationship between nondiabetic glucose levels and
      cardio vascular risk. RESEARCH DESIGN AND METHODS: Three independent searches
      using MEDLINE (1966-1996), followed by a manual search of the references from
      each retrieved article, were conducted by two physicians and one medical
      librarian. Data had to be reported in at least three quantiles or intervals so
      that the nature of the relationship between glucose and cardiovascular events
      (i.e., linear or nonlinear) could be explored, and to ensure that any incremental
      cardiovascular risk was consistent across quantiles or intervals. RESULTS:
      Analyzed studies comprised 95,783 people (94% male) who had 3,707 cardiovascular
      events over 12.4 years (1,193,231 person-years). Studies reporting fasting
      glucose levels (n = 6), 2-h glucose levels (n = 7), 1-h glucose levels (n = 5),
      and casual glucose levels (n = 4) were included. The glucose load used varied
      from 50 to 100 g. The highest glucose interval for most studies included glucose
      values in the diabetic range. The relationship between glucose levels and the
      risk of a cardiovascular event was modeled for each study and the beta
      coefficients were combined. Compared with a glucose level of 4.2 mmol/l (75
      mg/dl), a fasting and 2-h glucose level of 6.1 mmol/dl (110 mg/dl) and 7.8 mmol/l
      (140 mg/dl) was associated with a relative cardiovascular event risk of 1.33 (95%
      CI 1.06-1.67) and 1.58 (95% CI 1.19-2.10), respectively. CONCLUSIONS: The
      progressive relationship between glucose levels and cardiovascular risk extends
      below the diabetic threshold.

PMID- 10333940
TI  - Prevalence of diabetes and ethnic differences in cardiovascular risk factors. The
      1992 Singapore National Health Survey.
AB  - OBJECTIVE: The purpose of the 1992 Singapore National Health Survey was to
      determine the current distribution of major noncommunicable diseases and their
      risk factors, including the prevalence of diabetes and dyslipidemia, in
      Singapore. RESEARCH DESIGN AND METHODS: A combination of disproportionate
      stratified sampling and systematic sampling were used to select the sample for
      the survey. The final number of respondents was 3,568, giving a response rate of
      72.6%. All subjects fasted for 10 h and were given a 75-g glucose load, except
      those known to have diabetes. Blood was taken before and 2 h after the glucose
      load. Diagnosis of diabetes was based on 2-h glucose alone. RESULTS: The age
      standardized prevalence of diabetes in Singapore residents aged 18-69 years was
      8.4%, with more than half (58.5%) previously undiagnosed. Prevalence of diabetes
      was high across all three ethnic groups. The prevalence of impaired glucose
      tolerance was 16.1%, that of hypertension was 6.5%, and 19.0% were regular
      smokers. The total cholesterol (mean +/- SD) of nondiabetic Singaporeans was 5.18
      +/- 1.02 mmol/l; 47.9% had cholesterol > 5.2 mmol/l, while 15.4% had levels > 6.3
      mmol/l. Mean LDL cholesterol was 3.31 +/- 0.89 mmol/l; HDL cholesterol was 1.30
      +/- 0.32 mmol/l, and triglyceride was 1.23 +/- 0.82 mmol/l. CONCLUSIONS:
      Prevalence of diabetes was high across all three ethnic groups. Ethnic
      differences in prevalence of diabetes, insulin resistance, central obesity,
      hypertension, smoking, and lipid profile could explain the differential coronary
      heart disease rates in the three major ethnic groups in Singapore.

PMID- 10333941
TI  - Mortality and hormone-related exposures in women with diabetes.
AB  - OBJECTIVE: Hormone-related events and exposures are related to mortality and
      especially to cardiovascular disease in women. We evaluated whether such
      exposures influenced risk in a well-defined group of women with diabetes.
      RESEARCH DESIGN AND METHODS: Women with younger- and older-onset diabetes who
      were identified during a population-based study were queried about number of
      pregnancies, age at menarche, use of oral contraceptives, use of estrogen
      replacement therapy, and menopausal status at examinations in 1984-1986. Analyses
      are limited to women aged > or = 18 years (n = 398 and 542 in those with younger-
      and older-onset diabetes, respectively). Cohort mortality was monitored
      carefully, and causes of death were abstracted from death certificates. RESULTS:
      There were 58 deaths in the first group and 338 deaths in the second group since
      the 1984-1986 examination. The number of pregnancies was significantly associated
      with all-cause mortality (hazard ratio, 0.96 [95% CI 0.92-1.00]) in older-onset
      women only. CONCLUSIONS: These data suggest and are compatible with the notion
      that the hormone exposures examined are unrelated to cardiovascular mortality in
      women with diabetes, with the exception of a minimal effect of the number of
      pregnancies in older-onset women. Whether there is a difference in these exposure
      outcome relationships between women with diabetes and those without diabetes is
      uncertain and requires further investigation.

PMID- 10333943
TI  - Fasting proinsulin concentrations predict the development of type 2 diabetes.
AB  - OBJECTIVE: The development of specific assays allows the different molecules in
      the proinsulin processing pathway to be measured separately. 32,33 Split
      proinsulin is the predominant form of proinsulin and accounts for the
      disproportionate hyperproinsulinemia seen in individuals with prevalent type 2
      diabetes. This study was established to examine whether the concentration of this
      molecule predicts diabetes. RESEARCH DESIGN AND METHODS: A population-based
      longitudinal cohort study was conducted in Ely, Cambridgeshire. At baseline,
      1,122 individuals completed a 75-g oral glucose tolerance test (OGTT). At the 4.5
      year follow-up study, repeat OGTTs were performed on 937 of the cohort of 1,071
      individuals who had been nondiabetic at baseline. RESULTS: A total of 26 people
      progressed to diabetes as determined by the OGTTs. The risk of progression was
      strongly related to the fasting glucose concentration (relative risk [RR]
      comparing top with bottom quartile 17.6 [95% CI 2.4-130.4]) and fasting 32,33
      split proinsulin (RR 16.4 [2.2-121.9]), but less strongly to the fasting insulin
      (RR 4.41 [1.5-12.9]) or intact proinsulin (RR 5.2 [1.5-17.3]). In multivariate
      analyses, these associations were independent of age, sex, BMI, and baseline
      glucose tolerance category. Subjects in the top quartile for fasting glucose and
      total proinsulin with a family history of diabetes were a high-risk subgroup
      (incidence 65.8 per 1,000 person-years of follow-up [pyfu]); 30% of them
      progressed to diabetes at follow-up. CONCLUSIONS: Fasting 32,33 split proinsulin
      independently predicts the development of diabetes. This prediction was better
      than that observed for either the insulin or intact proinsulin concentrations.
      The combination of family history, fasting glucose, and total proinsulin
      identified a subgroup of individuals at high risk of progression who might
      benefit from targeted interventions.

PMID- 10333942
TI  - Phenotypic characteristics of early-onset autosomal-dominant type 2 diabetes
      unlinked to known maturity-onset diabetes of the young (MODY) genes.
AB  - OBJECTIVE: To investigate whether there are forms of early-onset autosomal
      dominant type 2 diabetes that are distinct from typical maturity-onset diabetes
      of the young (MODY) and to characterize their phenotypic characteristics.
      RESEARCH DESIGN AND METHODS: The study included 220 affected subjects from 29
      families in which early-onset type 2 diabetes occurred in multiple generations
      and was not linked to known MODY genes (MODY gene-negative families). All
      individuals underwent an oral glucose tolerance test and other clinical
      measurements aimed at investigating the underlying metabolic defect and the
      presence of diabetic complications. For comparison, 79 affected carriers of MODY3
      (hepatocyte nuclear factor [HNF]-1 alpha) mutations were similarly examined.
      RESULTS: Subjects from MODY gene-negative pedigrees were diagnosed with diabetes
      at an older age (36 +/- 17 vs. 21 +/- 10 years, P = 0.0001) and were more
      frequently obese (52 vs. 18%, P = 0.0001) than MODY3 individuals. MODY gene
      negative patients who were insulin treated required more exogenous insulin than
      did MODY3 subjects (0.7 +/- 0.4 vs. 0.45 +/- 0.2 U.kg-1.day-1, P = 0.04), despite
      similar C-peptide levels. Among subjects not treated with insulin, MODY gene
      negative subjects had significantly higher serum insulin levels, both fasting
      (16.5 +/- 15 vs. 6.5 +/- 5 microU/ml, P = 0.027) and 2 h after a glucose load (53
      +/- 44 vs. 11 +/- 10, P = 0.002). They also had higher serum triglycerides (P =
      0.02), higher cholesterol levels (P = 0.02), more hypertension (P = 0.0001), and
      more nephropathy (P = 0.001). Differences persisted when families were matched
      for age at diagnosis. CONCLUSIONS: Our findings indicate the existence of forms
      of early-onset autosomal-dominant type 2 diabetes that are distinct from MODY and
      are frequently characterized by insulin resistance, similar to later-onset type 2
      diabetes. Because of the Mendelian pattern of inheritance, the goal of
      identifying the genes involved in these forms of diabetes appears to be
      particularly feasible.

PMID- 10333944
TI  - HDL cholesterol subfractions and risk of developing type 2 diabetes among Pima
      Indians.
AB  - OBJECTIVE: To examine the relationships between HDL cholesterol subfractions and
      the incidence of type 2 diabetes and to evaluate potential sex differences in
      these relationships. RESEARCH DESIGN AND METHODS: Proportional hazards analyses
      were performed to examine the relationships between HDL subfractions and the
      development of type 2 diabetes in Pima Indian women and men. Results were
      controlled for age, BMI, systolic blood pressure, and 2-h glucose. RESULTS: Some
      54 of 123 women and 25 of 50 men developed type 2 diabetes during a mean follow
      up of 10 (2-19) years. For women, in separate models, high levels of total HDL,
      HDL2a, and HDL3 were negatively associated with incidence of type 2 diabetes;
      results were unchanged in models further controlled for fasting insulin level or
      alcohol consumption. For men, the results were inconsistent and associated with
      wide confidence intervals; high total HDL and HDL3 were positively associated
      with incidence of type 2 diabetes in models further controlled for fasting
      insulin level, but the risk estimates were attenuated in models further
      controlled for alcohol consumption. CONCLUSIONS: High levels of total HDL, HDL2a,
      and HDL3 were potential protective factors against type 2 diabetes in women after
      accounting for alcohol consumption and insulin resistance. High levels of total
      HDL and HDL3 were predictive of type 2 diabetes in men; the relationship in men
      appeared to be due to an association with alcohol consumption. The sex
      differences in the effects of HDL cholesterol may be related to the effects of
      sex hormones or lipoproteins.

PMID- 10333945
TI  - Capillary whole blood measurement of islet autoantibodies.
AB  - OBJECTIVE: Islet cell antibody (ICA) measurements in serum are used for large
      scale screening to identify subjects who are at high risk of developing type 1
      diabetes. The aim of this study was to adapt measurements to capillary whole
      blood samples to facilitate and reduce screening costs. RESEARCH DESIGN AND
      METHODS: GAD65, IA-2, and combined GAD65/IA-2 antibody tests were performed on
      patients with type 1 diabetes, first-degree relatives of patients, and control
      subjects, and results from serum, plasma, whole venous blood, and capillary whole
      blood lysates were compared. Measurements obtained in serum and eluates from
      dried capillary blood spots from 36 ICA+ first-degree relatives were also
      compared. RESULTS: GAD65, IA-2, and combined GAD65/IA-2 antibody levels were
      completely concordant with measurements obtained from serum, plasma, whole venous
      blood, and capillary whole blood lysates. Antibody levels obtained in eluates
      from dried capillary blood spots were lower than corresponding serum samples, and
      weak antibodies were not detected. CONCLUSIONS: Initial screening for diabetes
      risk can be performed using one drop of capillary whole blood without further
      processing to separate serum. This method should be considered as a way to
      simplify and reduce costs of screening programs.

PMID- 10333946
TI  - alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations
      and improves glucose effectiveness in lean and obese patients with type 2
      diabetes.
AB  - OBJECTIVE: We examined the effect of lipoic acid (LA), a cofactor of the pyruvate
      dehydrogenase complex (PDH), on insulin sensitivity (SI) and glucose
      effectiveness (SG) and on serum lactate and pyruvate levels after oral glucose
      tolerance tests (OGTTs) and modified frequently sampled intravenous glucose
      tolerance tests (FSIGTTs) in lean (n = 10) and obese (n = 10) patients with type
      2 diabetes. RESEARCH DESIGN AND METHODS: FSIGTT data were analyzed by minimal
      modeling technique to determine SI and SG before and after oral treatment (600
      mg, twice a day, for 4 weeks). Serum lactate and pyruvate levels of diabetic
      patients after glucose loading were compared with those of lean (n = 10) and
      obese (n = 10) healthy control subjects in which SI and SG were also determined
      from FSIGTT data. RESULTS: Fasting lactate and pyruvate levels were significantly
      increased in patients with type 2 diabetes. These metabolites did not exceed
      elevated fasting concentrations after glucose loading in lean patients with type
      2 diabetes. However, a twofold increase of lactate and pyruvate levels was
      measured in obese diabetic patients. LA treatment was associated with increased
      SG in both diabetic groups (lean 1.28 +/- 0.14 to 1.93 +/- 0.13; obese 1.07 +/-
      0.11 to 1.53 +/- 0.08 x 10(-2) min-1, P < 0.05). Higher SI and lower fasting
      glucose were measured in lean diabetic patients only (P < 0.05). Lactate and
      pyruvate before and after glucose loading were approximately 45% lower in lean
      and obese diabetic patients after LA treatment. CONCLUSIONS: Treatment of lean
      and obese diabetic patients with LA prevents hyperglycemia-induced increments of
      serum lactate and pyruvate levels and increases SG.

PMID- 10333947
TI  - Effects of a thiazolidinedione compound on body fat and fat distribution of
      patients with type 2 diabetes.
AB  - OBJECTIVE: To examine the effects of a thiazolidinedione (600 mg troglitazone)
      insulin-sensitizing treatment on total body fat measured by underwater weighing,
      on intra- and extra-abdominal fat mass using magnetic resonance imaging (MRI),
      and on anthropometric measures. RESEARCH DESIGN AND METHODS: Type 2 diabetic
      outpatients were studied in a double-blind randomized trial carried out at
      Glasgow Royal Infirmary, Scotland. RESULTS: Groups who received troglitazone (8
      men, 3 women) and placebo (8 men, 2 women) were well matched for age, BMI, total
      body fat percentage by underwater weighing, and intra-abdominal fat (kilograms)
      by MRI. After 12 weeks, body weight changes in the troglitazone group (mean +0.66
      kg [95% CI -0.71 to 2.04], P = 0.31) and the placebo group (mean +0.25 kg [-0.64
      to 1.13], P = 0.55) were not statistically different. Changes in total body fat
      with troglitazone (mean +1.02% body wt [-1.13 to 3.17], P = 0.32) and placebo
      (mean -0.54% body wt [-1.68 to 0.59], P = 0.31) were not significantly different.
      There was, however, a decrease in intra-abdominal fat mass in the troglitazone
      treated group (mean -0.47 kg [-0.79 to -0.13], P = 0.01), and this was
      significantly different (P = 0.03) from placebo treatment (mean -0.41 kg [-0.77
      to -0.05]). CONCLUSIONS: Treatment with the thiazolidinedione troglitazone in
      human patients with type 2 diabetes decreases intra-abdominal fat mass but does
      not affect total body fat or weight. This potentially valuable effect points to a
      differential action on insulin sensitivity in different adipose tissue depots.

PMID- 10333948
TI  - Correlation of imaging techniques to histopathology in patients with diabetic
      foot syndrome and clinical suspicion of chronic osteomyelitis. The role of high
      resolution ultrasound.
AB  - OBJECTIVE: To investigate the role of ultrasound in the diagnosis of
      osteomyelitis in the diabetic foot compared with magnetic resonance imaging
      (MRI), bone scintigraphy (BS), and plain film radiography (PFR). RESEARCH DESIGN
      AND METHODS: We investigated 19 consecutive diabetic patients (2 women, 17 men,
      age 60.7 +/- 9.8 years, BMI 27.0 +/- 3.8 kg/m2) with clinical suspicion of bone
      infection of the foot. A high-resolution ultrasound system (Esaote/Biosound,
      Munich) with a linear array transducer up to 13.0 MHz was used. The prospective
      and blinded results of each method were compared with histopathology as the
      reference method after metatarsal resection. RESULTS: In 14 of 19 patients,
      histopathology confirmed osteomyelitis. Ultrasound showed a sensitivity of 79%
      (PFR, 69%; BS, 83%; MRI, 100%), a specificity of 80% (PFR, 80%; BS, 75%; MRI,
      75%), a positive predictive value of 92% (PFR, 90%; BS, 91%; MRI, 93%), and a
      negative predictive value of 57% (PFR, 50%; BS, 60%; MRI, 100%). CONCLUSIONS: Our
      data indicate that ultrasound might have a better diagnostic power for detecting
      chronic osteomyelitis in the diabetic foot than PFR and has similar sensitivity
      and specificity as BS. MRI is superior to the other three methods. We conclude
      that the use of ultrasound in the management of the diabetic foot is worthy of
      further investigation.

PMID- 10333949
TI  - Effect of oxidized lipids in the diet on oxidized lipid levels in postprandial
      serum chylomicrons of diabetic patients.
AB  - OBJECTIVE: To determine whether humans with type 2 diabetes have increased levels
      of oxidized fatty acids in their serum chylomicron fraction after the ingestion
      of dietary oxidized fatty acids. RESEARCH DESIGN AND METHODS: The study was
      performed on 31 male type 2 diabetic patients and 24 age-matched control
      subjects. Among the diabetic patients, 22 had poor glycemic control, defined as
      HbA1 > 10% (normal value < 7.7%). Nine patients had good glycemic control (HbA1 <
      or = 10). Heated corn oil containing low or high levels of oxidized fatty acids
      was used as a test meal. At 2.5 h after the test meal, 50-ml blood samples were
      obtained from all subjects, and the chylomicron fraction (Sf > 1,000) was
      isolated. The degree of oxidation in chylomicrons was determined by measuring
      conjugated dienes. For determining the postprandial levels of triglycerides and
      of oxidized lipids in serum chylomicrons over an extended time period, blood
      samples were obtained at 0, 2.5, 5.0, and 7.5 h for isolation of chylomicrons and
      determination of fatty acid oxidation. RESULTS: We found that at 2.5 h after the
      consumption of the test meal containing either a low or high oxidized fatty acid
      content, conjugated dienes in serum chylomicrons in diabetic subjects in poor
      glycemic control were increased compared with those in control subjects. Diabetic
      patients in good glycemic control had similar levels of oxidized lipid in their
      chylomicrons when compared with control subjects. Additionally, in diabetic
      patients in poor glycemic control, the levels of oxidized lipids in chylomicrons
      remained elevated for an extended post-prandial period. CONCLUSIONS: In diabetic
      subjects with poor glycemic control, dietary oxidized lipids induce an
      exaggerated and sustained increase in the levels of oxidized lipids in
      chylomicrons when compared with either control subjects or diabetic patients with
      good glycemic control. These increased postprandial levels of potentially
      atherogenic oxidized lipids may contribute to the accelerated atherosclerosis
      associated with diabetes.

PMID- 10333950
TI  - Detection of microalbuminuria. Receiver operating characteristic curve analysis
      favors albumin-to-creatinine ratio over albumin concentration.
AB  - OBJECTIVE: To compare albumin-to-creatinine ratio (ACR) and albumin concentration
      (ALB) for detection of microalbuminuria using precise data on CIs for sensitivity
      and specificity and to determine sex- and age-specific discriminator values for
      ACR. RESEARCH DESIGN AND METHODS: All consecutive patients investigated for the
      presence of microalbuminuria with timed overnight urine collection were included
      in the study. Results from 1.171 men and 1,223 women were eligible for
      evaluation. Albumin excretion rate (the reference procedure), ALB, and ACR were
      compared by receiver operating characteristic (ROC) curve analysis. Age- and sex
      specific discriminator values were established. Sensitivity and specificity were
      determined, and their CIs were compared with those calculated from data presented
      in the literature. RESULTS: Sensitivity and specificity were 89% (range, 85-92)
      and 90% (88-92), respectively, for women, and 90% (87-93) and 89% (86-91),
      respectively, for men, at a discriminator value of 15 mg/l for the ALB. This
      discriminator value did not show any relationship to sex or age. For the ACR,
      which depends on sex, the sensitivity and specificity were 94% (92-96) and 92%
      (91-94), respectively, at 2.5 g/mol for women and 94% (92-97) and 93% (91-95),
      respectively, at 1.8 g/mol for men. The discriminator value for the ACR appears
      to depend on age in both men and women. CONCLUSIONS: ROC curve analysis clearly
      shows that the ACR performs better than the ALB in screening for
      microalbuminuria. However, in contrast to the ALB, the ACR needs sex- and age
      specific discriminator values.

PMID- 10333951
TI  - Severity of glomerulopathy predicts long-term urinary albumin excretion rate in
      patients with type 1 diabetes and microalbuminuria.
AB  - OBJECTIVE: To investigate whether the degree of glomerular structural lesions in
      young patients with type 1 diabetes and microalbuminuria was associated with
      urinary albumin excretion rate (AER) 6 years later and whether the AER level was
      influenced by blood glucose control, blood pressure, or glomerular filtration
      rate (GFR). RESEARCH DESIGN AND METHODS: There were 17 young adults with type 1
      diabetes and microalbuminuria, 8 men and 9 women with mean age 20 years (95% CI:
      18-22) and duration of diabetes of 11 years (10-13), who participated in a 6-year
      prospective study. Kidney biopsies (measurements of basement membrane thickness
      [BMT] and mesangial and matrix volume fractions) and GFR were performed at
      baseline. AER and HbA1c were measured at least three times a year and blood
      pressure once a year. RESULTS: In a multivariate analysis, baseline BMT and mean
      6-year HbA1c contributed significantly to AER at the end of the study (R2 = 0.69,
      P < 0.01). When mesangial volume fraction replaced BMT as the independent
      variable, this parameter and AER at baseline predicted the AER at 6 years (R2 =
      0.55, P < 0.55). Mesangial volume fraction and BMT (in separate analysis)
      contributed significantly to change in AER during the study. During the study,
      neither AER (30 micrograms/min [19-40] to 16 micrograms/min [7-90]) nor blood
      pressure (96 mmHg [92-102] to 95 mmHg [91-98]) changed significantly in the
      group. However, HbA1c was reduced from 10.3 (9.6-11.0) to 8.4% (7.8-9.1) (P <
      0.01). CONCLUSIONS: In young patients with microalbuminuria, the long-term
      urinary AER was predicted by the degree of glomerular structural changes and
      associated with blood glucose control, but not with blood pressure or GFR.

PMID- 10333952
TI  - Lipids increase after solitary pancreas transplantation.
AB  - OBJECTIVE: The aims of this study were to determine 1) changes in lipids after
      solitary pancreas transplantation (SPTX) in patients with type 1 diabetes and 2)
      factors that influence those changes. RESEARCH DESIGN AND METHODS: Lipids were
      evaluated prospectively in 24 patients who underwent SPTX. Three were excluded
      because of early graft failure. The remaining patients (n = 21; 13 men, 8 women)
      were studied for changes in lipids over time (pre-SPTX, 0-2, 3-6, 7-12, and > 12
      months). Glycohemoglobin, serum creatinine, BMI, and medications were also
      analyzed for their effects on lipid changes. RESULTS: Cholesterol, HDL, and LDL
      decreased in the immediate postoperative period (0-2 months), whereas
      triglycerides (TGs) increased (P < 0.05). At 3-6 months, cholesterol, HDL, and TG
      were higher than before the SPTX, whereas LDL returned to pre-SPTX levels. After
      12 months, HDL and TG remained higher than their pre-SPTX levels (P < 0.05).
      During the study, systolic and diastolic blood pressure increased, renal function
      decreased, glyco-hemoglobin improved, and weight was unchanged. Changes in
      cholesterol/HDL ratio, HDL, and TG correlated with changes in prednisone dose (P
      < 0.05), and changes in TG correlated with changes in creatinine (P < 0.05). The
      same pattern of lipids occurred in patients prescribed or not prescribed
      hypolipidemic agents. CONCLUSIONS: Lipids do not improve within the 1st year
      after SPTX, despite improved glycemic control and blood pressure control, and
      renal function is worse. These results are in contrast to those reported for
      combined kidney-pancreas transplantation, where lipids, blood pressure, and renal
      function improved immediately after transplant. Further studies are needed to
      determine whether lipids continue to change with time after SPTX. The impact of
      these changes after SPTX on overall cardiovascular risk is unknown.

PMID- 10333953
TI  - Postural characteristics of diabetic neuropathy.
AB  - OBJECTIVE: To explore the posturographic correlates of diabetic neuropathy by
      comparing the performances of three groups of diabetic patients (severe,
      moderate, and absent neuropathy) with those of normal subjects and four clinical
      control groups. RESEARCH DESIGN AND METHODS: Using the Interactive Balance System
      (Tetrax, Ramat Gan, Israel), based on the assessment of the interaction of
      vertical pressure fluctuations on four independent platforms, one for each heel
      and toe part, respectively, posturographic examinations were given to 28 diabetic
      patients (8 with severe, 12 with moderate, and 8 with no peripheral neuropathy),
      30 normal control subjects, and a clinical control group of 52 patients (14 with
      stage II Parkinson's disease, 13 with brain damage, 7 with whiplash, and 19 with
      peripheral vestibular pathology). The following posturographic parameters were
      evaluated; 1) general stability; 2) Fourier analysis showing patterns of sway
      intensity within eight frequency bands between 0.1 and 3 Hz; 3) weight
      distribution; 4) synchronization of sway; and 5) performance patterns for eight
      positions, requiring closure of eyes and standing on an elastic surface, as well
      as left, right, back, and downward head turns. RESULTS: For positions with closed
      eyes, diabetic patients with severe and moderate neuropathy were significantly
      less stable than normal subjects and diabetic patients without neuropathy, but
      diabetic patients with severe and moderate neuropathy turned out to be as equally
      unstable as clinical control subjects. However, for sway intensity within the
      band of 0.5 to 1.00 Hz on positions with lateral head turn with occluded vision,
      neuropathic diabetic patients performed significantly worse than did both normal
      and clinical control subjects. The same posturographic parameter also differed
      significantly between normal subjects and diabetic patients without neuropathy.
      CONCLUSIONS: As reported in previous studies, general instability in diabetic
      neuropathy is not a sufficiently characteristic correlate of the syndrome. On the
      other hand, spectral analysis of sway on stressful positions involving head
      turning appears to differentiate diabetic neuropathy from other disorders
      involving postural disturbances.

PMID- 10333954
TI  - Increased intimal-medial thickness in newly detected type 2 diabetes: risk
      factors.
AB  - OBJECTIVE: To examine carotid intimal-medial thickness (IMT) and its determinants
      in newly detected type 2 diabetic subjects, classified according to the new
      criteria of the American Diabetes Association, in comparison with age- and sex
      matched control subjects with normal glucose tolerance. RESEARCH DESIGN AND
      METHODS: This study was case-controlled, with matched pairs for 71 newly
      diagnosed type 2 diabetic individuals. Subjects aged 40-70 years were recruited
      from a risk population for diabetes seen in the Risk Factors in IGT for
      Atherosclerosis and Diabetes (RIAD) Study. Standard risk factors, 75-g oral
      glucose tolerance test with real insulin, proinsulin, and C-peptide, and
      ultrasound measurement of the IMT of the common carotid artery were performed.
      RESULTS: The diabetic subjects, both men and women, displayed carotid intimal
      medial thickening, even in the subgroup with fasting plasma glucose between 7.0
      and 7.8 mmol/l. HbA1c was significantly increased in the diabetic patients (6.33
      vs. 5.48%). Insulin, proinsulin, and C-peptide were also significantly higher.
      Among the coronary risk factors, triglycerides and plasminogen activator
      inhibitor were significantly increased. After age and sex adjustment. IMT in the
      diabetic group was correlated to triglycerides and the total-to-HDL cholesterol
      ratio. In the total group, IMT was significantly correlated to blood pressure, 2
      h glucose in oral glucose tolerance testing, triglycerides, albuminuria, and the
      total-to-HDL cholesterol ratio, and inversely correlated to HDL cholesterol. No
      independent determinant of IMT was found in the diabetic group by multivariate
      analysis. CONCLUSIONS: Newly detected type 2 diabetic patients exhibit a higher
      degree of early atherosclerosis than normal glucose-tolerant subjects matched for
      age and sex. Our data suggest that hyperglycemia, together with a clustering of
      risk factors, and in particular dyslipidemia, may cause intimal-medial thickening
      in the early phases of diabetes.

PMID- 10333955
TI  - Hyperglycemia attenuates the gastrokinetic effect of erythromycin and affects the
      perception of postprandial hunger in normal subjects.
AB  - OBJECTIVE: The major aims of this study were to determine in normal subjects
      whether the effects of erythromycin on gastric emptying, postprandial hunger, and
      fullness are modified by the blood glucose concentration. RESEARCH DESIGN AND
      METHODS: A total of 10 normal subjects (aged 20-39 years) underwent concurrent
      measurements of gastric emptying, blood glucose, hunger, and fullness on four
      separate occasions: twice during euglycemia (approximately 4 mmol/l) and twice
      during hyperglycemia (approximately 15 mmol/l). Either erythromycin (3 mg/kg) or
      saline (0.9%) was administered intravenously immediately before ingestion of a
      radioisotopically labeled solid meal. RESULTS: Gastric emptying was slower (P <
      0.0001) during hyperglycemia when compared with euglycemia after both
      erythromycin and saline administration. During hyperglycemia, erythromycin
      reduced the lag phase (77.8 +/- 12.6 vs. 20.3 +/- 7.3 min; P < 0.05) but had no
      effect on the postlag emptying rate (0.32 +/- 0.077% per min vs. 0.24% per min).
      Hunger decreased (P < 0.001) and fullness increased (P < 0.001) after the meal.
      Postprandial hunger was less during hyperglycemia after saline infusion (P <
      0.05) but not after erythromycin. Hunger was greater after erythromycin during
      both hyperglycemia and euglycemia (P < 0.05). CONCLUSIONS: At a blood glucose
      concentration of approximately 15 mmol/l, 1) gastric emptying of a solid meal is
      slower, when compared with euglycemia, even after administration of erythromycin;
      2) the effect of erythromycin on gastric emptying of a solid meal is attenuated;
      and 3) the perception of postprandial hunger is reduced.

PMID- 10333956
TI  - Emerging epidemic of type 2 diabetes in youth.
AB  - This review considers the epidemiologic evidence of an increasing incidence of
      type 2 diabetes in youth, the classification and diagnostic issues related to
      diabetes in young populations, pathophysiologic mechanisms relevant to the
      increasing incidence, the role of genetics and environment, and the community
      challenge for prevention and treatment. Type 2 diabetes in youth has been
      recognized to be frequent in populations of native North Americans and to
      comprise some 30 percent of new cases of diabetes in the 2nd decade of life,
      largely accounted for by minority populations and associated with obesity. Among
      Japanese schoolchildren, type 2 diabetes is seven times more common than type 1,
      and its incidence has increased more than 30-fold over the past 20 years,
      concomitant with changing food patterns and increasing obesity rates. The forms
      of diabetes seen in children and youth include typical type 1, occurring in all
      races; type 2, seen predominantly in minority youth; atypical diabetes, seen as
      an autosomal dominantly transmitted disorder in African-American populations; and
      maturity-onset diabetes of the young (MODY), seen rarely and only in Caucasians.
      Of the nonautoimmune forms of diabetes seen in youth, only type 2 diabetes is
      increasing in incidence. Proper classification requires consideration of onset
      (acute/severe versus insidious), ethnicity, family history, presence of obesity,
      and if necessary, studies of diabetes related autoimmunity. Insulin resistance
      predicts the development of diabetes in Pima Indians, in offspring of parents
      with type 2 diabetes, and in other high-risk populations. African-American
      children and youth have greater insulin responses during glucose tolerance
      testing and during hyperglycemic clamp study than do whites. There is also
      evidence of altered beta-cell function preceding the development of
      hyperglycemia. Of particular interest is the evidence that abnormal fetal and
      infantile nutrition is associated with the development of type 2 diabetes in
      adulthood. The thrifty phenotype hypothesis states that poor nutrition in fetal
      and infant life is detrimental to the development and function of the beta-cells
      and insulin sensitive tissues, leading to insulin resistance under the stress of
      obesity. The thrifty genotype hypothesis proposes that defective insulin action
      in utero results in decreased fetal growth as a conservation mechanism, but at
      the cost of obesity-induced diabetes in later childhood or adulthood. The vast
      majority of type 2 diabetes in adults is polygenic and associated with obesity.
      Monogenic forms (MODY, maternally transmitted mitochondrial mutations) are rare,
      but are more likely to appear in childhood. Linkage studies of the common
      polygenic type 2 diabetes have emphasized the heterogeneity of the disorder. The
      prevention and treatment of type 2 diabetes in children and youth is a daunting
      challenge because of the enormous behavioral influence, difficulty in reversing
      obesity, and typical nonadherence in this age-group. The emerging epidemic of
      type 2 diabetes in the pediatric population, especially among minorities whose
      proportion in the U.S. population is increasing, presents a serious public health
      problem. The full effect of this epidemic will be felt as these children become
      adults and develop the long-term complications of diabetes.

PMID- 10333957
TI  - Troglitazone directly increases HDL cholesterol levels.

PMID- 10333958
TI  - American Diabetes Association Annual Meeting, 1998. More on the treatment of type
      2 diabetes.

PMID- 10333959
TI  - Publication of abstracts presented at diabetes meetings.

PMID- 10333960
TI  - Influence of glycemic control on zinc urinary excretion in patients with type 1
      diabetes.

PMID- 10333961
TI  - High levels of circulating proinflammatory cytokines and leptin in urban, but not
      rural, Indians. A potential explanation for increased risk of diabetes and
      coronary heart disease.

PMID- 10333962
TI  - Enteroviral RNA and IgM antibodies in early pregnancy and risk for childhood
      onset IDDM in offspring.

PMID- 10333963
TI  - American Diabetes Association criteria for diabetes diagnosis. Another
      perspective.

PMID- 10333964
TI  - Pneumatosis cystoides intestinalis after treatment with an alpha-glucosidase
      inhibitor.

PMID- 10333965
TI  - Do the new screening and diagnostic criteria of diabetes proposed by the American
      Diabetes Association really match?

PMID- 10333966
TI  - HbA1c determination in patients with hemoglobinopathies.

PMID- 10333967
TI  - Fasting glucose and progression of impaired glucose tolerance.

PMID- 10333968
TI  - Meningeal syndrome in diabetic ketoacidosis. Consider cerebral edema.

PMID- 10333969
TI  - Analytic accuracy of calculated low-density lipoprotein cholesterol
      concentrations.

PMID- 10333970
TI  - American Diabetes Association: clinical practice recommendations 1999.

PMID- 10333971
TI  - An appreciation of molecular biology: signals, receptors, conveyors and
      processors.

PMID- 10333972
TI  - Commentary on medical specialties.

PMID- 10333973
TI  - Medicine at the Rubicon.

PMID- 10333974
TI  - Approximate entropy and point correlation dimension of heart rate variability in
      healthy subjects.
AB  - The contribution of nonlinear dynamics to heart rate variability in healthy
      humans was examined using surrogate data analysis. Several measures of heart rate
      variability were used and compared. Heart rates were recorded for three hours and
      original data sets of 8192 R-R intervals created. For each original data set (n =
      34), three surrogate data sets were made by shuffling the order of the R-R
      intervals while retaining their linear correlations. The difference in heart rate
      variability between the original and surrogate data sets reflects the amount of
      nonlinear structure in the original data set. Heart rate variability was analyzed
      by two different nonlinear methods, point correlation dimension and approximate
      entropy. Nonlinearity, though under 10 percent, could be detected with both types
      of heart rate variability measures. More importantly, not only were the
      correlations between these measures and the standard deviation of the R-R
      intervals weak, the correlation among the nonlinear measures themselves was also
      weak (generally less than 0.6). This suggests that in addition to standard linear
      measures of heart rate variability, the use of multiple nonlinear measures of
      heart rate variability might be useful in monitoring heart rate dynamics.

PMID- 10333975
TI  - The theory of the organism-environment system: I. Description of the theory.
AB  - The theory of the organism-environment system starts with the proposition that in
      any functional sense organism and environment are inseparable and form only one
      unitary system. The organism cannot exist without the environment, and the
      environment has descriptive properties only if it is connected to the organism.
      Although for practical purposes we do separate organism and environment, this
      common-sense starting point leads in psychological theory to problems which
      cannot be solved. Therefore, separation of organism and environment cannot be the
      basis of any scientific explanation of human behavior. The theory leads to a
      reinterpretation of basic problems in many fields of inquiry and makes possible
      the definition of mental phenomena without their reduction either to neural or
      biological activity or to separate mental functions. According to the theory,
      mental activity is activity of the whole organism-environment system, and the
      traditional psychological concepts describe only different aspects of
      organization of this system. Therefore, mental activity cannot be separated from
      the nervous system, but the nervous system is only one part of the organism
      environment system. This problem will be dealt with in detail in the second part
      of the article.

PMID- 10333976
TI  - The theory of the organism-environment system: II. Significance of nervous
      activity in the organism-environment system.
AB  - The relation between mental processes and brain activity is studied from the
      point of view of the theory of the organism-environment system. It is argued that
      the systemic point of view leads to a new kind of definition of the primary tasks
      of neurophysiology and to a new understanding of the traditional
      neurophysiological concepts. Neurophysiology is restored to its place as a part
      of biology: its task is the study of neurons as living units, not as computer
      chips. Neurons are living units which are organised as metabolic systems in
      connection with other neurons; they are not units which would carry out some
      psychological functions or maintain states which are typical only of the whole
      organism-environment system. Psychological processes, on the other hand, are
      processes always comprising the whole organism-environment system.

PMID- 10333977
TI  - Stability of heartbeat interval distributions in chronic high altitude hypoxia.
AB  - Recent studies of nonlinear dynamics of the long-term variability of heart rate
      have identified nontrivial long-range correlations and scale-invariant power-law
      characteristics (l/f noise) that were remarkably consistent between individuals
      and were unrelated to external or environmental stimuli (Meyer et al., 1998a).
      The present analysis of complex nonstationary heartbeat patterns is based on the
      sequential application of the wavelet transform for elimination of local
      polynomial nonstationary behavior and an analytic signal approach by use of the
      Hilbert transform (Cumulative Variation Amplitude Analysis). The effects of
      chronic high altitude hypoxia on the distributions and scaling functions of
      cardiac intervals over 24 hr epochs and 4 hr day/nighttime subepochs were
      determined from serial heartbeat interval time series of digitized 24 hr
      ambulatory ECGs recorded in 9 healthy subjects (mean age 34 yrs) at sea level and
      during a sojourn at high altitude (5,050 m) for 34 days (Ev-K2-CNR Pyramid
      Laboratory, Sagarmatha National Park, Nepal). The results suggest that there
      exists a hidden, potentially universal, common structure in the heterogeneous
      time series. A common scaling function with a stable Gamma distribution defines
      the probability density of the amplitudes of the fluctuations in the heartbeat
      interval time series of individual subjects. The appropriately rescaled
      distributions of normal subjects at sea level demonstrated stable Gamma scaling
      consistent with a single scaled plot (data collapse). Longitudinal assessment of
      the rescaled distributions of the 24 hr recordings of individual subjects showed
      that the stability of the distributions was unaffected by the subject's exposure
      to a hypobaric (hypoxic) environment. The rescaled distributions of 4 hr
      subepochs showed similar scaling behavior with a stable Gamma distribution
      indicating that the common structure was unequivocally applicable to both day and
      night phases and, furthermore, did not undergo systematic changes in response to
      high altitude. In contrast, a single function stable over a wide range of time
      scales was not observed in patients with congestive heart failure or patients
      after cardiac transplantation. The functional form of the scaling in normal
      subjects would seem to be attributable to the underlying nonlinear dynamics of
      cardiac control. The results suggest that the observed Gamma scaling of the
      distributions in healthy subjects constitutes an intrinsic dynamical property of
      normal heart function that would not undergo early readjustment or late
      acclimatization to extrinsic environmental physiological stress, e.g., chronic
      hypoxia.

PMID- 10333978
TI  - A decade of antidepressant development: the SSRIs and beyond.

PMID- 10333979
TI  - Mechanism of action of serotonin selective reuptake inhibitors. Serotonin
      receptors and pathways mediate therapeutic effects and side effects.
AB  - Serotonin selective reuptake inhibitors (SSRIs) are currently among the most
      frequently prescribed therapeutic agents in all of medicine. Their therapeutic
      actions are diverse, ranging from efficacy in depression to obsessive-compulsive
      disorder, panic disorder, bulimia and other conditions as well. The plethora of
      biological substrates, receptors and pathways for serotonin are candidates to
      mediate not only the therapeutic actions of SSRIs, but also their side effects.
      Specifically, the immediate actions of SSRIs are mostly side effects, and may be
      mediated by the initiating actions of SSRIs, namely negative allosteric
      modulation of the serotonin transporter. A leading hypothesis to explain these
      immediate side effects is that serotonin is increased at specific serotonin
      receptor subtypes in discrete regions of the body where the relevant physiologic
      processes are regulated. Desensitization of post-synaptic receptors in these same
      discrete brain regions may explain the development of tolerance to these same
      side effects. The explanation for therapeutic effects characteristic of SSRIs may
      be found in delayed neurochemical adaptations. A leading hypothesis for this
      action is desensitization of somatodendritic serotonin 1A autoreceptors in the
      midbrain raphe. The hypothesis to explain why SSRIs have such diverse therapeutic
      actions is that somatodendritic 5HT1A autoreceptor desensitization increases
      serotonin in those critical brain regions and at those key serotonin receptor
      subtype(s) which may mediate the pathophysiologies of the various disorders.
      Understanding the topography of serotonin receptor subtypes in discrete
      anatomical pathways may enhance our understanding of both the therapeutic actions
      and side effects of these important pharmaceutical agents.

PMID- 10333980
TI  - Mechanisms of action and clinical characteristics of three atypical
      antidepressants: venlafaxine, nefazodone, bupropion.
AB  - Tricyclic antidepressants have multiple sites of pharmacological actions which
      are responsible for their tolerability and toxicological problems as well as
      their efficacy. That fact has prompted the search for antidepressants with fewer
      sites of action. That search resulted in the serotonin selective reuptake
      inhibitors (SSRIs), with presumably only one site of action. Although the SSRIs
      are safer and better tolerated than the TCAs, a significant percentage of
      patients do not benefit from SSRIs. A group of "atypical antidepressants"
      including bupropion, nefazodone, and venlafaxine are known to have multiple sites
      of antidepressant action but do not interact at sites associated with side
      effects or tolerance. Thus this group of antidepressants present an important
      alternative to the SSRIs in the pharmacological therapy of depression. The basic
      pharmacological properties of bupropion, nefazodone, and venlafaxine are
      presented along with clinical profiles and the role of these three
      antidepressants in the pharmacotherapy of depression is discussed.

PMID- 10333981
TI  - Acute and long-term actions of the antidepressant drug mirtazapine on central 5
      HT neurotransmission.
AB  - Mirtazapine (ORG 3770, Remeron) is a new alpha 2-adrenoceptor antagonist which
      has been shown to be an effective antidepressant drug. The aims of the studies
      were to assess, using an in vivo electrophysiological paradigm in the rat, the
      effects of acute and long-term treatment with mirtazapine on pre- and
      postsynaptic alpha 2-adrenoceptors and to determine whether this drug could
      modulate serotonin (5-HT) neurotransmission. Acute administration of mirtazapine
      produced a transient increase of the firing activity of dorsal raphe 5-HT
      neurons. This effect was mediated via norepinephrine (NE) neurons because it was
      abolished in NE-lesioned rats. In fact, this increased firing rate of 5-HT
      neurons was due to their activation by the enhanced release of NE resulting from
      the blockade of alpha 2-adrenergic autoreceptors of locus coeruleus neurons.
      Furthermore, acute mirtazapine injection transiently enhanced the firing activity
      of locus coeruleus NE neurons and attenuated the suppressant effect of the alpha
      2-adrenoceptor agonist clonidine on these NE neurons. Sustained administration of
      mirtazapine for 21 days (5 mg/kg/day, s.c., using minipumps) lead to a marked
      increase in the firing rate of 5-HT neurons (75%) but a more modest increase in
      the firing rate of NE neurons (30%), as well as to a desensitization of alpha 2
      adrenergic heteroreceptors on 5-HT terminals in the hippocampus. The
      desensitization of these heteroreceptors, resulting from an increased synaptic
      availability of NE induced by mirtazapine would free 5-HT terminals from the
      inhibitory influence of NE on 5-HT release. These modifications of 5-HT neurons
      lead to an increased tonic activation of postsynaptic 5-HT1A receptors. The
      latter conclusion was based on the capacity of the selective 5-HT1A receptor
      antagonist WAY 100635 to enhance the firing activity of dorsal hippocampus CA3
      pyramidal neurons in mirtazapine-treated rats but not in controls. This enhanced
      5-HT neurotransmission may underlie to the antidepressant effect of mirtazapine.

PMID- 10333982
TI  - Review of the results from clinical studies on the efficacy, safety and
      tolerability of mirtazapine for the treatment of patients with major depression.
AB  - Mirtazapine is a presynaptic alpha-2 antagonist that has dual action by
      increasing noradrenergic and serotonergic neurotransmission. The enhancement of
      serotonergic neurotransmission is specifically mediated via 5-HT1 receptors
      because mirtazapine is a postsynaptic serotonergic 5-HT2 and 5-HT3 antagonist. In
      addition, mirtazapine has only a weak affinity for 5-HT1 receptors and has very
      weak muscarinic anticholinergic and histamine (H1) antagonist properties. As a
      consequence of its unique pharmacodynamic properties, mirtazapine is an
      effective, safe and well-tolerated addition to the antidepressant armamentarium.
      Mirtazapine is well absorbed from the gastrointestinal tract following oral
      administration, and it is extensively metabolized in the liver to four
      metabolites via demethylation and hydroxylation, followed by glucuronide
      conjugation. The unconjugated desmethyl metabolite is pharmacologically less
      active than the parent compound. Mirtazapine lacks auto-induction of hepatic
      isoenzymes. Although mirtazapine is a substrate of P450 isoenzymes 1A2, 2D6 and
      3A4, in vitro studies show that it is not a potent inhibitor or inducer of any of
      these enzymes. Mirtazapine has been evaluated in a worldwide clinical development
      program involving approximately 4500 patients. Controlled clinical trials
      involving almost 2800 mirtazapine-treated patients have demonstrated the compound
      to be effective for the treatment of moderate-to-serve major depression.
      Mirtazapine was consistently superior to placebo, and equivalent in efficacy to
      the tricyclic antidepressants amitriptyline, doxepin and clomipramine, but with
      an improved tolerability profile. Mirtazapine has shown a rapid onset of action
      in patients with predominantly severe depressive illness in a comparative study
      against fluoxetine. Mirtazapine has a unique tolerability profile, since the
      specific postsynaptic 5-HT2 and 5-HT3 receptor blockade of mirtazapine provides
      early antidepressant effects without causing unwanted serotonin-related side
      effects. Transient somnolence, hyperphagia and weight gain are the most commonly
      reported adverse events, which may be attributed to the antihistaminic (H1)
      activity of mirtazapine at low doses. Somnolence, the most commonly reported side
      effect, appears to be less frequent at higher dosages. Mirtazapine also
      demonstrates important anxiolytic and sleep-improving effects, which may be
      related to its pharmacodynamic properties. In addition, mirtazapine does not
      appear to be associated with sexual dysfunction. Mirtazapine has shown no
      significant cardiovascular adverse effects at multiples of 7 to 22 times the
      maximum recommended dose. Mirtazapine is a unique addition to the antidepressant
      armamentarium as first-line therapy in patients with major depression and
      symptoms of anxiety/agitation or anxiety/somatization or complaints of insomnia
      and as a useful alternative in depressed patients who do not adequately respond
      to or are intolerant of tricyclic antidepressants or serotonin-specific reuptake
      inhibitors.

PMID- 10333983
TI  - Preclinical profile of befloxatone, a new reversible MAO-A inhibitor.
AB  - Befloxatone, a novel oxazolidinone derivative, is a potent, selective and
      reversible monoamine oxidase A (MAO-A) inhibitor in vitro (K1A = 1.9-3.6 nM) and
      ex vivo (ED50 MAO-A = 0.02 mg/kg, p.o.). It does not interact with a large number
      of receptors, monoamine transporters or other amine oxidases. Binding studies
      with [3H]-befloxatone in rat brain sections show that it labels with high
      affinity (Kd = 1.3 nM) a single population of sites with the pharmacological
      characteristics and regional distribution of MAO-A. In the rat brain, befloxatone
      (0.75 mg/kg, i.p.) increases tissue levels of monoamines and decreases levels of
      their deaminated metabolites. Acute administration of befloxatone (0.75 mg/kg,
      i.p.) induces an increase in extracellular striatal dopamine and cortical
      norepinephrine but not cortical serotonin levels in the rat. Befloxatone (1
      mg/kg, i.p.) potently inhibits the firing rate of serotonergic neurons, partially
      decreases the firing of noradrenergic neurons and has no effect on the firing of
      dopaminergic neurons (a mirror image of its effects on monoamine release in
      terminal regions), suggesting that the relative effects of befloxatone on
      monoamine release may be governed by autoreceptor-mediated control of
      monoaminergic neurons at the cell body level. Befloxatone (0.03-0.3 mg/kg, p.o.)
      exhibits potent activity in behavioural models predictive of antidepressant
      activity. Befloxatone (up to 1.5 mg/kg, p.o.) does not potentiate the pressor
      effects of orally administered tyramine at centrally active doses and duodenal
      [3H]-befloxatone binding is displaced by increasing doses of orally administered
      tyramine (0.1-40 mg/kg, i.p.). These results suggest that befloxatone is a potent
      reversible MAO-A inhibitor with antidepressant potential and a wide safety margin
      with regard to the potentiation of the pressor effect of tyramine.

PMID- 10333984
TI  - Clinical pharmacology of befloxatone: a brief review.
AB  - Clinical pharmacology studies of befloxatone, a new selective reversible
      inhibitor of monoamine oxidase-A (MAO-A), have addressed safety, with special
      emphasis on tyramine interactions, and have also investigated pharmacokinetics
      (PK) and pharmacodynamics in terms of both MAO-A inhibition (using 3,4
      dihydroxyphenylglycol, DHPG, as a pharmacological activity marker) and effects on
      psychomotor and cognitive function, in young and elderly healthy volunteers.
      Clinical and laboratory safety data were satisfactory in healthy volunteers given
      single doses of up to 160 mg or repeated doses of up to 80 mg/day for 7 days.
      Tyramine interaction studies showed that the expected potentiation of the
      tyramine pressor effect occurred with a safety margin that was so wide as to make
      dietary restrictions unnecessary with dosages of up to 20 mg once daily in
      clinical settings. Absorption was rapid (tmax = 2 h), terminal halflife was about
      11 h, and PK parameters increased linearly with the dose. Befloxatone induced a
      dose-dependent decrease in plasma DHPG levels from 2.5 mg upwards, and a 10-mg
      dose provided sub-maximal activity (80% DHPG decrease) of 24 h duration. No
      sedative or stimulant effects were detected using several batteries of
      psychometric tests. Befloxatone was devoid of deleterious effects on memory in
      young volunteers, and exhibited the EEG profile of a non-sedative antidepressant.
      In summary, available clinical pharmacology studies confirm that befloxatone is a
      safe and potent RIMA with no potential for inducing deleterious CNS effects.

PMID- 10333985
TI  - The clinical pharmacologic profile of reboxetine: does it involve the putative
      neurobiological substrates of wellbeing?
AB  - Following a review of the clinical trials of reboxetine, a new nonadrenegic
      reuptake inhibitor antidepressant, this paper presents a heuristic theoretical
      framework to better understand selective antidepressant action. For over three
      decades, the dominant views of antidepressant action have seen these agents
      active across all constitutional types and regardless of social setting. An
      increasing number of studies using quality of life methods are at odds with this
      view. This paper summarizes several of these studies, along with two studies of
      the effects of reboxetine on the quality of life, which reveal differential
      effects of selective agents that demand alternative explanations to the
      conventional monoamine theories. The authors submit that any revisions in our
      understanding of what is happening will have to pay attention to temperamental
      inputs that antedate affective episodes and to the sense of wellbeing and level
      of residual symptoms patients have on treatment after the acute phase of their
      illness has remitted. Obviously much more research needs to be done in this area.
      This invited paper sketches out, in very general terms, some provocative
      possibilities of how future understanding of antidepressants, temperament and
      their neurobiologic substrates could lead to better matching of specific
      antidepressants to specific temperament types.

PMID- 10333986
TI  - Pharmacotherapy of dysthymic and chronic depressive disorders: overview with
      focus on moclobemide.
AB  - Chronic depression was once considered untreatable pharmacologically. Open
      studies conducted around 1980 demonstrated efficacious results with tricyclics,
      classical MAOIs and lithium in 45% of cases. The subsequent delineation of
      dysthymia in DSM-III and its future editions as well as ICD.10, facilitated
      controlled trials in subjects with "pure dysthymia" and those with superimposed
      major depression (so-called "double-depression"). TCAs, SSRIs, RIMA, and
      benzamides have all proven effective in an average of 65% vs. an average of 25%
      with placebo. Well tolerated compounds--e.g. moclobemide, sertraline and
      desipramine--may permit the long-term clinical management of this spectrum of
      dysthymic and related conditions. Patients with "lifetime pure dysthymia" tend to
      respond more slowly to antidepressants than those with concurrent major
      depression ("double-depression") or those with "pure dysthymia" but with history
      of major depressive episodes. Chronicity is now well established: indeed
      discontinuation of antidepressants in a 4-year maintenance study has resulted in
      89% rate of relapse. Dysthymia is a disabling condition and high doses of
      antidepressants are needed to achieve full recovery.

PMID- 10333988
TI  - The scientific, quasi-scientific and popular literature on the use of St. John's
      Wort in the treatment of depression.
AB  - St. John's Wort, also known as Hypericum, is an herbal product that is available
      in health food stores as an allegedly 'safe' alternative to antidepressants
      developed by the pharmaceutical industry. Recently it has received extensive
      coverage through the media, especially in the United States. To the best of our
      knowledge, Germany is the only country where it has been formally approved for
      clinical use. We reviewed both the vulgar and the scientific literature on this
      product. Although the few controlled studies that have been conducted pertain to
      adjustment disorder with depressed mood, several books and the media advocate its
      use for clinical and/or chronic depression. The high placebo rate in these
      studies, often in the 50% range, does indeed suggest that the controlled trials
      have been conducted on mild transient depressions; extrapolation to more serious
      or chronic depressions would therefore be unwarranted. We could not find any
      published literature comparing the efficacy of Hypericum to a standard
      antidepressant versus placebo. Furthermore, the studies claiming safety and
      freedom from potentially serious side effects appear flawed methodologically.
      Actually, little is known about the putative mechanism of action of Hypericum in
      depression; if indeed it does involve serotonergic mechanisms or monoamine
      oxidase inhibition, it invites caution with concurrent use with an SSRI and, of
      course, with a MAOI. A skeptic might conclude that St. John's Wort should not be
      used until more definitive data are available. A less conservative view would be
      that, while its current widespread use is not warranted, the product may still
      have some merit for mild nonchronic depressive states below the clinical
      threshold. If this were conclusively proven, it would indeed constitute an
      important development in the field of antidepressants.

PMID- 10333987
TI  - Lamotrigine as a promising approach to borderline personality: an open case
      series without concurrent DSM-IV major mood disorder.
AB  - BACKGROUND: Borderline personality disorder (BPD) has long defined definitive
      treatment. Such failure is reflected in repeated suicidal crises, often
      associated with dysphoric symptoms of a chronic fluctuating nature, whose labile
      intermittent character does suggest a subthreshold bipolar depressive mixed
      state. For all these reasons, we hypothesized that the anticonvulsant
      lamotrigine, touted to be a mood stabilizer with antidepressant properties, might
      be uniquely beneficial for these patients. METHODS: From a base rate of about 300
      patients in a community mental health center, we identified eight patients
      meeting seven or more of the DSM-IV criteria for BPD without concurrent major
      mood disorders. All patients presented with history of severe suicidal behavior,
      hostile depression and/or labile moods, stimulant and alcohol abuse, as well as
      multiple unprotected sexual encounters; one patient was actually HIV positive.
      All had failed previous trials with different antidepressants and mood
      stabilizers. All current medications were gradually withdrawn--and when necessary
      -patients kept on a low dose of a conventional neuroleptics for a few weeks,
      while lamotrigine was being gradually introduced in 25-mg weekly increments until
      the patient responded (up to 300 mg/day maximum). RESULTS: Consistent with
      previous work by us and others, bipolar family history could be documented in
      three of eight BPD patients, and worsening on antidepressants in four of eight,
      providing indirect support to our conceptualization of BPD as a bipolar variant.
      One patient developed a rash on 25 mg and was dropped from the lamotrigine trial,
      while another patient was noncompliant. Three who failed lamotrigine,
      subsequently responded, respectively, to sertraline, lithium-thioridazine
      combination, and valproate. The remaining three patients showed a robust response
      to lamotrigine, ranging from 75 to 300 mg/day: their functioning jumped from a
      mean baseline DSM-IV GAF score in the 40's to the 80's during 3-4 months. Among
      all responders impulsive sexual, drug-taking and suicidal behaviors disappeared
      and no longer met the criteria for BPD. At an average follow-up of 1 year, they
      no longer meet criteria for BPD. LIMITATIONS: Open uncontrolled results on a
      small number of patients in a tertiary care center may not generalize to BPD
      patients at large. CONCLUSIONS: Overall, the BPD response to pharmacotherapy in
      the present case series was 75%. The fact that five of six pharmacotherapy
      responders required mood stabilizers, argues against the prevalent view that the
      depressions of borderline patients belong to unipolarity. Of BPD patients who
      completed the trial, 50% achieved sustained remission from their personality
      disorder with lamotrigine monotherapy. The dramatic nature of the response in
      patients refractory to all previous medication trials and maintenance of a robust
      response over 1 year, argue against a placebo effect. Controlled systematic
      investigation of lamotrigine in BPD is indicated.

PMID- 10333989
TI  - New techniques for understanding Huntington's disease.

PMID- 10333991
TI  - Conventional and quantitative electroencephalography in psychiatry.
AB  - Electrical activity of each brain region is homeostatically regulated, resulting
      in predictable frequency composition of the background EEG. Replicated normative
      databases have established that the EEG power spectrum is independent of ethnic
      background. Artifact-free EEG evaluated relative to such norms displays few
      deviant values in healthy, normally functioning individuals. In subjects with
      psychiatric disorders, high proportions of abnormal findings have been reported
      with good concordance and high specificity and sensitivity across numerous
      studies, distinctive within a wide variety of disorders and often contributing to
      differential diagnosis and selection of treatment. New three-dimensional QEEG
      imaging methods offer an economical alternative to other functional brain imaging
      modalities.

PMID- 10333990
TI  - Pharmacologic efficacy in neuropsychiatry: a review of placebo-controlled
      treatment trials. A report of the ANPA Committee on Research.
AB  - Psychiatric disorders frequently compound the disability and complicate the
      management of neurologic conditions. These disorders result in increased
      morbidity for the person afflicted, stress for the caregiver, and financial
      burden. This study reviews the randomized double-blind placebo-controlled
      pharmacologic treatment trials of psychosis, depression, anxiety, and agitation
      in neurologic conditions from 1966 to 1998. Ten studies involving psychosis, 13
      involving depression, and 20 involving anxiety-agitation meeting the committee's
      criteria were identified. Relatively few randomized double-blind placebo
      controlled pharmacologic treatment trials of psychiatric disorders complicating
      neurologic disease have been conducted. These trials do not strongly support one
      specific pharmacologic approach to treatment. Further study of newer psychotropic
      agents, augmentation strategies, and novel use of other agents may help improve
      the treatment of psychiatric disorders observed in patients with neurologic
      disease.

PMID- 10333992
TI  - The EEG and cocaine sensitization: a hypothesis.
AB  - The author presents the hypothesis that reduced delta EEG power observed in
      cocaine withdrawal is related to changes in dopamine (DA) transmission related to
      cocaine sensitization. Evidence for this hypothesis includes the topographic
      anatomical correspondence between the putative site of delta generation and the
      cortical terminal field of the mesotelencephalic DA system, as well as the
      laminar distribution and ultrastructural features of DA terminals in frontal
      cortex that appear to be adapted to the modulation of the delta rhythm, a global
      forebrain EEG mode. The effect of DA on membrane conductances of individual
      pyramidal neurons also suggests that DA exerts a significant influence on delta
      power by modulating the transition between global and local EEG modes. Access to
      a neural correlate of sensitization via noninvasive EEG methodology could be
      useful in investigating the relationship of stimulant sensitization to the
      clinical syndrome of cocaine dependence.

PMID- 10333993
TI  - Patterns of relative cerebral blood flow in minor cognitive motor disorder in
      human immunodeficiency virus infection.
AB  - Individuals infected with HIV are at risk to develop cognitive impairment during
      the course of their disease. Although many patients develop an HIV-associated
      dementia, others may develop the less severe minor cognitive motor disorder
      (MCMD). In this study, relative cerebral blood flow was measured with PET imaging
      in HIV+ MCMD patients, HIV+ control subjects, and HIV- control subjects; analyses
      were performed by using statistical parametric mapping. Comparing a short-term
      memory task versus a rest state yielded activation in superior temporal cortex,
      postcentral gyrus, and cerebellum in all three subject groups. Comparing long-
      and short-term memory tasks yielded activation throughout the frontal cortex,
      including BA46. Activation in this area was reduced in the HIV+ control subjects
      and further reduced in the MCMD+ patients. Thus, brain activation associated with
      lower-level, automatic processing appears normal in HIV+ MCMD+ subjects, but
      activation associated with effortful retrieval and organizational processes is
      abnormal.

PMID- 10333995
TI  - CNS Sjogren's syndrome: an underrecognized and underappreciated neuropsychiatric
      disorder.
AB  - Sjogren's syndrome is a common medical condition that may produce psychiatric
      symptoms. Untreated deficits can become permanent, sometimes resulting in death.
      The hypothesized mechanism involves CNS vasculitis. Psychoactive medications
      treat psychiatric symptoms but leave the underlying medical process unaffected.
      Laboratory tests to diagnose Sjogren's syndrome and specific treatments for this
      condition are improving.

PMID- 10333994
TI  - The role of precise conceptualization in the treatment of a complicated HIV-1
      infected neuropsychiatric patient.
AB  - Patients infected with human immunodeficiency virus, type 1, may present with
      neuropsychiatric manifestations across all stages of disease. Frequently, these
      patients may present with more than one neuropsychiatric disorder concomitantly.
      The case presented highlights the utility of detailed clinical observation,
      careful use of medical terminology, and a neuropsychiatric organizing paradigm in
      the diagnosis and treatment of a patient presenting over time with delirium,
      aphasia, mania, and a complex partial seizure disorder.

PMID- 10333996
TI  - Vasopressin treats the persistent feeling of coldness after brain injury.
AB  - In this pilot study, 6 patients who complained of persisting coldness after brain
      injury were treated with intranasal vasopressin (DDAVP) twice daily for 1 month.
      Response was assessed after 1 month of treatment, DDAVP was discontinued, and
      response was reassessed 1 month later. Five of the 6 patients had a dramatic
      response to DDAVP, as soon as 1 week after initiating treatment, and no longer
      complained of feeling cold. Response persisted even after discontinuation of
      treatment. Patients denied any side effects from treatment with DDAVP. The
      experience of persisting coldness can respond dramatically to brief treatment
      with intranasal DDAVP. The authors discuss possible mechanisms of action to
      explain this phenomenon.

PMID- 10333997
TI  - Involuntary laughter and inappropriate hilarity.
AB  - Laughter is a particularly human behavior. Neuropsychiatrists are faced with
      disorders of laughter, yet the nature of this behavior and its disturbances
      remains obscure. The authors report an unusual patient with involuntary and
      unremitting laughter for 20 years and review the literature. The nature of
      laughter suggests that it has a unique role in human communication, particularly
      in the social exploration of incongruous information. The disorders of laughter
      suggest a neuroanatomical circuitry that includes the anterior cingulate gyrus,
      caudal hypothalamus, temporal-amygdala structures, and a pontomedullary center.
      Treatment includes the use of antidepressant and antimanic agents for disorders
      of laughter.

PMID- 10333998
TI  - Attitudes toward neurosurgical procedures for Parkinson's disease and obsessive
      compulsive disorder.
AB  - Similar neurosurgical procedures exist for Parkinson's disease (PD) and obsessive
      compulsive disorder (OCD). Because PD is seen as a brain disease and OCD as a
      disease of the mind, neurologists and psychiatrists may be more aware of and more
      optimistic toward neurosurgery for PD than for OCD. A questionnaire was sent to
      randomized American Psychiatric Association and American Academy of Neurology
      members, and 569 of 1,188 eligible members (47.9%) responded. Some 82.8% of the
      psychiatrists and 27.4% of the neurologists were aware of neurosurgical
      procedures for OCD, whereas 84.7% of psychiatrists and 99.4% of neurologists were
      aware of neurosurgery for PD (P < 0.001). Of psychiatrists, 74.1% would refer
      appropriate patients for OCD neurosurgery, 67.4% for PD neurosurgery (P = 0.15);
      of neurologists, 25.6% would refer for OCD, 94.3% for PD (P < 0.001). Specialty
      affected willingness to refer for OCD neurosurgery. Specialty and degree of
      contact with neurosurgeons affected willingness to refer for PD neurosurgery.
      There is poor physician awareness of neurosurgical options for OCD compared with
      PD, as well as a risk-benefit bias against OCD surgery by the neurologists
      surveyed.

PMID- 10333999
TI  - Use of donepezil for vascular dementia: preliminary clinical experience.

PMID- 10334001
TI  - Is the reduction of mental phenomena an attainable goal?

PMID- 10334000
TI  - Moclobemide treatment in multiple sclerosis patients with comorbid depression: an
      open-label safety trial.
AB  - Depression is common in multiple sclerosis (MS) patients, but tricyclic compounds
      are not well tolerated and newer antidepressants have not been studied. Effects
      of 150-400 mg/day of moclobemide, a reversible monoamine oxidase A inhibitor,
      were studied in a 3-month open design in 10 MS patient with DSM-IV-diagnosed
      depression. Nine patients reached complete remission. No adverse effects were
      noted. Four patients reported side effects including nausea and insomnia. The
      authors conclude that moclobemide is a well tolerated and efficient treatment for
      depression comorbid with MS.

PMID- 10334002
TI  - Frontal lobe function: Mr. Phineas Gage's famous injury.

PMID- 10334003
TI  - Passage of an iron rod through the head. 1848.

PMID- 10334004
TI  - Paroxetine treatment in alcohol amnestic disorder.

PMID- 10334005
TI  - Neurosyphilis in elderly patients.

PMID- 10334006
TI  - Evidence-based practice.

PMID- 10334007
TI  - Conflicting responses: the experiences of fathers of infants diagnosed with
      severe congenital heart disease.
AB  - PURPOSE: To explore the experiences of fathers of infants newly diagnosed with
      severe congenital heart disease. DESIGN: An analysis of qualitative data
      collected as part of a larger longitudinal study of parenting the medically
      fragile infant. PARTICIPANTS: Eight fathers whose infants were hospitalized for
      severe congenital heart disease, were technology dependent at time of enrollment,
      and were expected to have serious chronic health problems at discharge. DATA
      COLLECTION MEASURES: Semistructured interviews in the hospital and the home until
      the child reached 15 months adjusted age. RESULTS: Findings indicate that fathers
      experience four interrelated conflicting reactions: the joy of seeing the child
      born and becoming a father, plus the sadness and loss associated with the baby's
      illness; the challenge of becoming attached while dealing with fears about the
      infant's vulnerability and potential death; the need to try to maintain control
      while feeling a loss of control; and the struggle to remain strong for others
      while hiding their intense emotions. These findings extend the previous limited
      research about fathers by identifying the unique conflicts fathers of seriously
      ill infants experience in coping with the child's diagnosis and treatment.
      Findings have implications for intervening with fathers during the early
      diagnostic phase of a serious illness, particularly serious congenital heart
      disease.

PMID- 10334008
TI  - Broken past, fragile future: personal stories of high-risk adolescent mothers.
AB  - PURPOSE: To uncover what adolescent mothers view as their childhood struggles,
      their transition to the role of motherhood following a childhood of
      abuse/neglect, and their important relationships after they became parents.
      DESIGN: Qualitative, phenomenological. SETTING: Community-based parenting program
      for first-time mothers at risk for abusing or neglecting their children.
      PARTICIPANTS: Seven first-time mothers, ages 13 to 20, who reported they had been
      abused and/or neglected as children. All had healthy newborns. RESULTS: Five
      themes emerged from the data: impoverished past, disintegration of relationships,
      emotional distance, problem fixing, and reconnecting. Participants described a
      process of using the experience of pregnancy and parenting as a mechanism for
      growth. Becoming a parent provided an opportunity to receive support from family
      members and to build more positive relationships. They viewed the experience as a
      second chance for a successful and fulfilling life.

PMID- 10334009
TI  - Using parents' concerns to detect and address developmental and behavioral
      problems.
AB  - PURPOSE: Half of all children with disabilities are not identified before school
      entrance, precluding their participation in early intervention programs with
      known value in reducing high school dropout rates, increasing employment,
      delaying child-bearing, and reducing criminal behavior. Screening tests that can
      greatly improve detection rates have not been popular in primary care. This
      article describes an alternative approach in an evidence-based technique relying
      on professional elicitation and interpretation of parents' concerns. POPULATION:
      971 children from pediatric practices, day-care centers, public schools, and
      their siblings. CONCLUSIONS: Research shows that parents' concerns are as
      accurate as quality screening tests and that parents are equally able to raise
      important concerns regardless of differences in education and child-rearing
      experience. Parents' concerns can be elicited quickly, and 92% of parents can
      answer questions in writing while in exam or waiting rooms. Parents' concerns can
      help make a range of other important decisions about children's developmental and
      behavioral needs.

PMID- 10334010
TI  - Clinical pathways: a tool to evaluate clinical learning.
AB  - Clinical pathways are a means by which an instructor can objectively and
      effectively evaluate student learning and progress toward clinical outcomes. An
      advantage to use of pathways in one-time experiences is that the pathway serves
      as a criterion-based frame of reference for both student and instructor, since
      the criteria are the same as for other clinical experiences in that course. The
      faculty member thus has an objective measure of student learning and performance,
      and the student always knows the measure on which she or he will be evaluated.
      Clinical pathways are limited to brief experiences and are not designed to show
      professional growth and progress in learning over time. A pathway could be
      designed, however, to appraise critical thinking and professional behaviors
      associated with spontaneous incidents, such as a problem patient. Nurse educators
      can use pathways as a creative means to address student responses in a variety of
      situations.

PMID- 10334012
TI  - Behaviour of adult hamsters subjected to hypergravity.
AB  - We studied vestibular function in 20 adult hamsters (3 months old) subjected to
      either prolonged hypergravity (n = 10) or normal gravity (n = 10) for 2 months.
      Locomotion and swimming of the hypergravity hamsters under light conditions were
      normal. Equilibrium maintenance was severely disturbed; only 6 of 10 hypergravity
      hamsters managed to walk on the small tube after 2 months, whereas all 10
      controls were able to walk on the tube. The air-righting reflex was severely
      disturbed; the hypergravity hamsters made 30% correct air-righting responses,
      while the control hamsters made 88% correct responses. Finally, 5 of 8
      hypergravity hamsters had to be saved from drowning when swimming in total
      darkness. Histological examination of the utricular otoconial layers afterwards,
      using energy dispersive X-ray element (EDAX) analysis and scanning electron
      microscopy, did not reveal any differences in calcium content, shape and size
      distribution of the otoconia between hypergravity hamsters and controls. We
      suggest that adult hamsters adapt to hypergravity, leading to problems in normal
      functioning when tested in 1 G, especially in tasks in which sensory input of the
      vestibular system is important for spatial orientation. These disturbances were
      more severe in adult hamsters than in young ones, tested in previous experiments.
      Therefore, we assume that age is a factor for adaptation to altered gravity
      conditions.

PMID- 10334011
TI  - Effects of body orientation and rotation axis on pitch visual-vestibular
      interaction.
AB  - Spatial transformations of the vestibular-optokinetic system must account for
      changes in head position with respect to gravity in order to produce compensatory
      oculomotor responses. The purpose of this experiment was to study the influence
      of gravity on the vestibulo-ocular reflex (VOR) in darkness and on visual
      vestibular interaction in the pitch plane in human subjects using two different
      comparisons: (1) Earth-horizontal axis (EHA) rotation about an upright versus a
      supine body orientation, and (2) Earth-horizontal versus Earth-vertical (EVA)
      rotation axes. Visual-vestibular responses (VVR) were evaluated by measuring the
      slow phase velocity of nystagmus induced during sinusoidal motion of the body in
      the pitch plane (at 0.2 Hz and 0.8 Hz) combined with a constant-velocity vertical
      optokinetic stimulation (at +/- 36 degrees/s). The results showed no significant
      effect on the gain or phase of the VOR in darkness or on the VVR responses at 0.8
      Hz between EHA upright and EHA supine body orientations. However, there was a
      downward shift in the VOR bias in darkness in the supine orientation. There were
      systematic changes in VOR and VVR between EHA and EVA for 0.2 Hz, including a
      reduced modulation gain, increased phase lead, and decreased bias during EVA
      rotation. The same trend was also observed at 0.8 Hz, but at a lesser extent,
      presumably due to the effects of eccentric rotation in our EVA condition and/or
      to the different canal input across frequencies. The change in the bias at 0.2 Hz
      between rotation in darkness and rotation with an optokinetic stimulus was
      greater than the optokinetic responses without rotation. During EHA, changes in
      head position relative to gravity preserve graviceptor input to the VVR
      regardless of body orientation. However, the modifications in VVR gain and phase
      when the rotation axis is aligned with gravity indicate that this graviceptive
      information is important for providing compensatory eye movements during visual
      vestibular interaction in the pitch plane.

PMID- 10334013
TI  - Postural compensation after intratympanic gentamicin treatment of Meniere's
      disease.
AB  - We have treated 93 patients with severe Meniere's disease with gentamicin (GM)
      applied with 1 to 4 or intratympanic injections in a prospective study. The
      patients were tested at frequent intervals and followed up for two years.
      Postural stability was evaluated on posturography. Unsteadiness and gait between
      attacks, working capacity and vertigo were scored. Before commencing the
      treatment 47 of the patients complained from moderate to severe postural
      instability. After treatment moderate to severe postural instability was met in
      19 patients. Initially the sway velocity was 27 mm/s on average being
      significantly worse than in referents. Two weeks after treatment the sway
      velocity increased to 33 mm/s. Thereafter the sway velocity slowly started to
      decline to 31 mm/s after two years. Patients with severe attacks of rotatory
      vertigo had a good postural outcome with GM treatment. In logistic regression
      analysis the most significant risk factor for poor recovery after GM treatment
      was severely reduced gait before commencing the treatment with odds ratio of 2.0.
      Subjectively, after two years, the patients rated their postural stability
      significantly improved when compared to pretreatment values. The good subjective
      rating of postural stability is related to postural training program where in the
      absence of attacks, the patients have learned to cope with daily tasks.

PMID- 10334014
TI  - Contribution of the otoliths to the human torsional vestibulo-ocular reflex.
AB  - The dynamic contribution of the otolith organs to the human ocular torsion
      response was examined during passive sinusoidal body roll about an earth
      horizontal axis (varying otolith inputs) and about an earth-vertical axis
      (invariant otolith inputs). Torsional eye movements were registered in 5 subjects
      by means of video-oculography. At a fixed amplitude of 25 degrees, the stimulus
      frequency was varied from 0.05 to 0.4 Hz. Additionally, at a fixed frequency of
      0.2 Hz, the response was also measured at the amplitudes to 12.5 degrees and 50
      degrees. The results showed that the gain and phase of the torsional slow
      component velocity (SCV) did not depend on stimulus amplitude, indicating a
      linear response. Contribution of the otoliths affected the ocular torsion
      response in three different ways. First, the gain of the SCV was slightly, but
      consistently, higher during rotation about an earth-horizontal axis than during
      rotation about an earth-vertical axis. With invariant otolith inputs the average
      gain increased from 0.10 at 0.05 Hz to 0.26 at 0.25 Hz. With varying otolith
      inputs, the average gain increased from 0.14 to 0.37. Second and more
      substantially, contribution of the otoliths improved the response dynamics by
      reducing the phase lead at frequencies up to 0.02 Hz. Third, the nystagmus showed
      considerably less anticompensatory saccades in upright conditions than in supine
      conditions, even though the SCV gain was lower in the latter. As a consequence,
      the average excursion of torsional eye position was highest during earth
      horizontal rotation. This effect was observed in the entire frequency range.
      Thus, the otoliths controlled the human torsional VOR not only at low stimulus
      frequencies by keeping the slow component in phase with head motion, but also in
      a wider frequency range by modulating the saccadic behavior as to increase the
      amplitude of ocular torsion. We conclude that the primary concern of the otolith
      oculomotor system during head tilt is to stabilize eye position in space, rather
      than to prevent retinal blur.

PMID- 10334015
TI  - Spatial performance of unilateral vestibular defective patients in nonvisual
      versus visual navigation.
AB  - The purpose of this study was to investigate the effects of unilateral vestibular
      neurotomy on humans ability to perform navigation tasks. These tasks provided
      self-motion feedback by way of either locomotor activity only (nonvisual
      navigation or "locomotor task") or visual motion cues only (visually simulated
      navigation or "visual task"). After exploration of an environment in which 4
      locations were marked by different objects, subjects attempted to navigate to
      those locations either by reproducing the same paths as those followed during
      exploration, by reversing routes, or by making spatial inferences (shortcuts).
      Vestibular defective patients were tested one day before surgical treatment and
      during the recovery time course following unilateral vestibular nerve lesion (1
      week, 1 month, and 3 month later). Their performance was assessed by measuring
      turn error and distance error in both navigation tasks and was compared to that
      of control subjects tested 4 times at similar time intervals. Turn error in the
      reproduction of previously explored routes in the locomotor task was lower in
      patients before surgery than in controls, suggesting the existence of
      compensatory processes. In the acute stage (1 week) after unilateral vestibular
      lesion, turn error was greater in patients than in controls for the highest level
      of mental representation (spatial inferences or reversing routes); impairment at
      making accurate rotations had disappeared by 1 month after vestibular lesion in
      both navigation tasks. These results point to the role of vestibular cues, in
      interaction with other sensory modalities, in the elaboration of an accurate
      internal representation of the environment. In addition, they suggest that
      unilateral suppression of vestibular information would induce transitory spatial
      memory disorganization at a high level of information processing.

PMID- 10334016
TI  - Dynamic visual acuity while walking in normals and labyrinthine-deficient
      patients.
AB  - We describe a new, objective, easily administered test of dynamic visual acuity
      (DVA) while walking. Ten normal subjects and five patients with histories of
      severe bilateral vestibular dysfunction participated in this study. Subjects
      viewed a visual display of numerals of different font sizes presented on a laptop
      computer while they stood still and while they walked on a motorized treadmill.
      Treadmill speed was adapted for 4 of 5 patients. Subjects were asked to identify
      the numerals as they appeared on the computer screen. Test results were
      reasonably repeatable in normals. The percent correct responses at each font size
      dropped slightly while walking in normals and dropped significantly more in
      patients. Patients performed significantly worse than normals while standing
      still and while walking. This task may be useful for evaluating post-flight
      astronauts and vestibularly impaired patients.

PMID- 10334017
TI  - Does habitual, vigorous optokinetic stimulation alter optokinetic nystagmus and
      sensitivity to circularvection?
AB  - Previous studies have shown that experience with optokinetic stimulation can
      alter a subject's sensitivity to illusions such as circularvection (CV). The aim
      of the present experiment was to compare optokinetic nystagmus (OKN), optokinetic
      afternystagmus (OKAN), and sensitivity to CV between 2 groups of sportspeople: 1)
      squash players (n = 16), who regularly experience vigorous optokinetic
      stimulation while engaging in their sporting activity, and 2) weightlifters (n =
      16), whose sport does not involve the same degree of optokinetic stimulation as
      squash, but who nevertheless have to achieve a high degree of physical skill.
      OKN, OKAN (frequency, slow phase velocity, and timeconstant), and latency to CV
      (Stage 2 and Stage 3) were measured using electro-oculographic recording inside
      an optokinetic drum. Contrary to predictions, there were no significant
      differences in OKN, OKAN, or latency to CV between the 2 groups. These results
      suggest that 1) the practice effects that alter the sensitivity to CV may decay
      relatively quickly, and 2) differences in recreational sporting activities
      between subjects may not be a significant confounding factor in visual-vestibular
      interaction experiments.

PMID- 10334018
TI  - A factor analytic study of the dizziness handicap inventory: does it assess
      phobic avoidance in vestibular referrals?
AB  - Panic disorder and agoraphobia have been associated with increased functional
      disability in individuals who have vestibular problems. The Dizziness Handicap
      Inventory (DHI), a 25-item self-report questionnaire with three rationally
      derived subscales, was designed to measure functional, emotional, and physical
      disability associated with vestibular disturbance. Despite the apparent
      usefulness of the DHI, there have been few studies of its psychometric
      properties. The primary purpose of the present study was to assess the factor
      structure of the DHI. A principal components analysis with oblique rotation was
      conducted on data collected from 95 patients referred to a tertiary-care
      vestibular disorders clinic for assessment of vestibular disturbance. Both 2
      factor and 3-factor solutions are reported. The 2-factor solution was indicative
      of General Functional Limitations and Postural Difficulties. In the 3-factor
      solution, General Functional Limitations was split into factors indicative of
      Disability in Activities of Daily Living and Phobic Avoidance, while the Postural
      Difficulties factor remained stable. We also characterized the 3-factor solution
      by assessing the correlation of factor scores with measures of vestibular
      symptoms, mood, and anxiety. The general pattern of results does not support the
      validity of the original subscale structure of the DHI. Implications for revising
      the DHI to provide a more comprehensive and factorially valid assessment of
      disability associated with vestibular disturbance are discussed.

PMID- 10334019
TI  - We do not know what we do not know.

PMID- 10334020
TI  - LASIK for the correction of residual refractive errors from previous surgical
      procedures.
AB  - BACKGROUND AND OBJECTIVE: To evaluate laser assisted in situ keratomileusis
      (LASIK) efficacy in correcting residual refractive errors after corneal or
      intraocular surgery (penetrating keratoplasty, radial keratotomy, photorefractive
      keratectomy, phacoemulsification with intraocular lens (IOL) implantation,
      penetrating ocular trauma and phakic IOL implantation). MATERIAL AND METHODS: We
      performed LASIK in 87 eyes of 62 patients previously operated by means of other
      surgical techniques to completely correct the residual refractive error. We
      report the mean refractive error (in terms of spherical equivalent refraction),
      uncorrected visual acuity (UCVA) and spectacle corrected visual acuity (SCVA)
      before and after the surgical procedure. We also analyze safety and stability, in
      these results with a minimum of 12 months follow-up. RESULTS: Mean preoperative
      spherical equivalent was -5.25 +/- 2.1 diopters (D). Postoperatively, mean
      spherical equivalent was -0.70 +/- 0.65 D, 76% of eyes were between plano and 
      1.00 D and 99% were between plano and -2.25 D. At 12 months follow-up the change
      in the refractive result was equal or less than 0.5 D in 94% of eyes.
      Preoperatively SCVA was 1.0 or better in 24.13% of cases, and 0.5 or better in
      89.65%. Postoperative SCVA was 1.0 or better in 26.43% and 0.5 or better in 95%.
      Preoperative UCVA was 0.1 in 2 eyes, 0.05 in 4 eyes and count fingers in the rest
      of the cases. Postoperative UCVA was 1.0 or better in 1.1% and 0.5 or better in
      70.1%. We had an extremely low complication rate in this particular group of
      patients. CONCLUSIONS: LASIK can be successfully used to correct residual
      refractive errors after other surgical procedures.

PMID- 10334021
TI  - Reproducibility of corneal flap thickness in LASIK.
AB  - BACKGROUND: The purpose of the microkeratome in laser assisted in situ
      keratomileusis (LASIK) is to create a corneal flap of desired thickness, thus
      exposing the stroma. The accuracy and repeatability of intended flap thickness
      with the current microkeratome system has not been documented. The purpose of
      this study was to determine the precision and consistency of creating a corneal
      flap thickness of 160 microns with the Moria LSK-One microkeratome (distributed
      by Microtech, Inc., Doylestown, PA). PATIENTS AND METHODS: The records of 93 eyes
      from 67 patients who underwent LASIK were reviewed. The central corneal thickness
      was measured at baseline. The microkeratome using a "130" footplate was used to
      create an intended flap 160 microns thick, and the corneal thickness was then
      remeasured. RESULTS: The mean flap thickness for both eyes combined was 159
      microns (S.D. = 28). There was no significant correlation between pre-flap
      corneal thickness or average K and the corneal flap thickness. CONCLUSION: This
      study provides evidence that the Moria LSK-One microkeratome creates reproducible
      LASIK flaps consistently near the intended 160 microns corneal flap thickness.
      This knowledge enables the surgeon to make a corneal flap with great confidence
      in the thickness of the excision. In addition, this study provides a clinical, in
      vivo model for testing corneal flap thickness.

PMID- 10334022
TI  - Refractive results of post penetrating keratoplasty photorefractive keratectomy.
AB  - BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the safety,
      effectiveness, and predictability of photorefractive keratectomy (PRK) for severe
      myopia and astigmatism following penetrating keratoplasty. PATIENTS AND METHODS:
      PRK was performed on 42 eyes, and 33 eyes were followed up for at least 6 months.
      RESULTS: Mean preoperative spherical equivalent was -8.29 +/- 4.01 diopters (D),
      which decreased to -2.96 +/- 3.26 D in manifest refraction at 6 months.
      Keratometric power reduced from 48.06 +/- 3.32 D preoperatively to 43.97 +/- 3.40
      D. Refractive and keratometric astigmatism attained the reduction of 31.0% and
      13.56% in average respectively. Twenty three eyes had improved uncorrected visual
      acuity. CONCLUSION: PRK was effective in reducing post-keratoplasty myopia and
      astigmatism, but the predictability was not as good as in the non-grafted eye.

PMID- 10334023
TI  - Initial trabeculectomy with intraoperative mitomycin-C application in primary
      glaucomas.
AB  - PURPOSE: This is a prospective randomized study designed to compare the overall
      efficacy of intraoperative application of mitomycin-C (MMC) in eyes with no
      previous ocular surgery versus standard trabeculectomy without MMC. METHODS:
      Twenty-five patients with primary glaucoma had been treated with trabeculectomy
      in one eye and trabeculectomy with MMC in the other eye. Patients were followed
      up for 18 months. RESULTS: Intraocular pressure (IOP) was 20 mm Hg or less in 23
      eyes (92%) in the treatment group after a mean follow up of 17.8 +/- 1.1 months
      and 17 control eyes (68%) after mean follow up period of 17.8 +/- 1.2 months
      (range, 16.7-19 months). Wound leaks occurred in 10 (40%) of the treatment group
      and 3 (12%) of control group. Bleb scarring developed in 1 eye (4%) of the
      treatment group and 6 (24%) of the control group. Hypotony maculopathy developed
      in 3 (12%) of the MMC group. Postoperatively, laser suture lysis was needed in 13
      (52%) of the treatment group and 21 (84%) of the control group. Additional filter
      was needed in (4%) of the treatment group, while additional filters were needed
      in 7 (28%) of the control group. CONCLUSION: Intraoperative MMC application may
      increase the success rate of glaucoma surgery, but close follow-up and meticulous
      management of patients are needed, especially in the early postoperative period.

PMID- 10334024
TI  - Comparison of phacotrabeculectomy with 5-fluorouracil, mitomycin-C, and without
      antifibrotic agents.
AB  - BACKGROUND AND OBJECTIVE: To evaluate the potential benefits, complications, and
      prognostic risk factors for failure of phacotrabeculectomy performed with or
      without 5-fluorouracil (5-FU) and mitomycin-C (MMC). PATIENTS AND METHODS:
      Retrospective chart review of 78 patients who underwent phacotrabeculectomy
      during a 2-year period. Patients were divided into 3 groups, those who received 5
      FU (N = 28). MMC (N = 29), or no antifibrotic agent (N = 21). RESULTS: All 3
      groups had statistically significant lower intraocular pressures (IOP) on fewer
      antiglaucomatous medications at 6-month, 12-month, and last follow-up compared to
      preoperative levels (P < .05). Intraocular pressures were lower in the group that
      received MMC compared to the 5-FU group, but not in the group that did not
      receive antimetabolites, at all time intervals measured (P < .05). Black race was
      a strong predictor of failure of trabeculectomy (P = 009). No differences in
      final visual acuity or complications were found between groups. CONCLUSIONS:
      Phacotrabeculectomy is effective regardless of antimetabolite use. Race is a
      strong predictor of failure.

PMID- 10334025
TI  - Combined lensectomy, vitrectomy and scleral fixation of intraocular lens implant
      after closed-globe injury.
AB  - PURPOSE: To describe our experience in the surgical management of cataracts in
      patients with complications of closed-globe injury using pars plana lensectomy
      (PPL), pars plana vitrectomy (PPV), and scleral fixation of posterior chamber
      intraocular lens (PCIOL). METHODS: We retrospectively reviewed charts of all
      patients with closed-globe injury who underwent PPL, PPV and scleral fixation of
      PCIOL at our institution between January 1991 and July 1997. We identified 28
      eyes; because of less than 2 weeks follow-up, 4 eyes were excluded from the
      current study. All eyes had lens subluxation/dislocation and visually significant
      cataract. Additional indications for surgery included secondary glaucoma (10
      eyes), vitreous hemorrhage (3 eyes) and retinal detachment (1 eye). RESULTS: The
      postoperative follow-up interval ranged from 6 to 61 months (mean 18.5 months).
      Preoperative visual acuity (VA) ranged from 20/60 to hand motion and was 20/100
      or better in 6 eyes (25%). Postoperatively, 19 eyes (79%) improved to 20/100 or
      better. Five eyes had subsequent surgery for the following indications: retinal
      detachment (2 eyes), poorly controlled glaucoma (2 eyes), and epiretinal membrane
      formation (1 eye). CONCLUSIONS: In patients undergoing PPL, PPV and scleral
      fixation of PCIOL for cataract after a closed-globe injury, a substantial visual
      improvement occurred in a majority of the involved eyes.

PMID- 10334026
TI  - Effect of diclofenac sodium and dexamethasone on cultured human Tenon's capsule
      fibroblasts.
AB  - BACKGROUND AND OBJECTIVE: To investigate the effect of diclofenac sodium and
      dexamethasone on cultured human Tenon's capsule fibroblasts. MATERIALS AND
      METHODS: Two experiments were conducted. In the first experiment, fibroblasts
      were treated with either diclofenac sodium or dexamethasone at different
      concentrations, and the cell growth was quantified by using Coulter counter and
      hexosaminidase methods at 1, 3, 5, and 7 days after adding the drugs. In the
      second experiment, the cells were treated with each drug for 24 hours and then
      the cultures were switched to a drug-free medium. The cell growth was quantified
      at day 7 after removing the drugs from the medium. RESULTS: In the first
      experiment, inhibition of fibroblast growth in a dose-dependent manner was
      observed from days 1 to 7 in the cultures treated with each drug. The inhibitory
      was more pronounced in the diclofenac treated cultures. The typical spindle
      shaped fibroblasts treated with higher concentrations of the drugs became
      spherical cells. In the second experiment, inhibition was not observed when the
      cultures were switched to a drug-free medium. The spherical cells recovered to
      spindle-shaped cells and proliferated as normal cells. CONCLUSION: Our results
      have shown that diclofenac sodium and dexamethasone can significantly inhibit
      human Tenon's capsule fibroblast growth in a cell culture model. The inhibitory
      effect was not observed when the cultures were switched after 24 hours to a drug
      free culture medium.

PMID- 10334027
TI  - Endocapsular hematoma: report of a case following glaucoma surgery in a
      pseudophakic eye.
AB  - The authors describe a case of an endocapsular hematoma that occurred in a 69
      year-old pseudophakic diabetic male following mitomycin C (MMC) augmented
      trabeculectomy for neovascular glaucoma (NVG). The clinical course of the patient
      is described, and the unique features of this case are presented and discussed.
      The endocapsular hematoma absorbed in 6 weeks with conservative management. The
      patient regained the preoperative visual acuity of 20/30, and his intraocular
      pressure was controlled without any glaucoma medication. The iris
      neovascularization regressed. This case is the first report of an endocapsular
      hematoma following glaucoma filtering surgery in a pseudophakic eye with
      neovascular glaucoma.

PMID- 10334028
TI  - Primary eyelid mucinous adenocarcinoma of eccrine origin.
AB  - To report a case of mucinous adenocarcinoma of the eyelid. A 70-year-old man
      presented with a lesion of his lower left eyelid, which had been growing over the
      past few years. An excisional biopsy was performed. The lesion was incompletely
      excised and recurrence at the excision site was observed at a 3-month follow-up
      visit. A histopathological examination of the excised specimen showed it to be a
      mucinous adenocarcinoma of eccrine origin. Primary mucinous adenocarcinoma of the
      eye lid is a rare malignant sweat gland tumor with a high incidence of local
      recurrence. It has to be differentiated from other adenocarcinomas which may
      rarely metastasize to the skin.

PMID- 10334029
TI  - Acquired Pseudo-Brown's syndrome immediately following Ahmed valve glaucoma
      implant.
AB  - A 76-year-old woman noted vertical and horizontal diplopia one day following
      placement of an Ahmed valve in the superonasal quadrant of her left eye. She was
      unable to elevate her left eye, especially in adduction. She refused implant
      removal and strabismus surgery alone failed to satisfactorily resolve her
      problem. On forced duction testing, the implant became wedged between the globe
      and orbit superonasally. Subsequent repositioning of the valve resulted in
      resolution of her motility problem. Implant-orbital disproportion can produce a
      pseudo-Brown's syndrome. Surgeons are encouraged to perform forced duction
      testing at the time of glaucoma implant placement to detect and prevent this
      complication.

PMID- 10334030
TI  - A simplified technique for stable transscleral suture fixation of posterior
      chamber intraocular lenses.
AB  - We describe a technique for implanting ciliary sulcus posterior chamber
      intraocular lenses (PCIOLs). This technique uses radial keratotomy (RK) markers
      to facilitate PCIOL centration, 2-point scleral suture fixation for each haptic
      to prevent PCIOL tilt, and partial thickness sclerotomies to prevent suture
      erosion. Postoperative results of 20 eyes with PCIOLs sutured to the ciliary
      sulcus were reviewed. Suture placement was determined using a Mendez degree gauge
      with Bores axis marker (Katena USA, Denville, NJ). Two-point scleral suture
      fixation without a scleral flap was used for each haptic. Average follow-up was
      17.1 months. Postoperative best corrected visual acuity was 20/40 or better in
      95% of eyes. Average best-corrected post-operative visual acuity was 20/29. One
      patient with a previous retinal disease lost 3 lines of visual acuity. This
      technique results in excellent postoperative visual acuity without PCIOL
      decentration, tilt, or suture erosion.

PMID- 10334031
TI  - Wrapping hydroxyapatite implants.
AB  - Hydroxyapatite (HA) implants currently are most commonly wrapped in fresh
      unprocessed human donor sclera before implantation to facilitate entry into the
      orbital space and allow extraocular muscle attachment. Autologous temporalis
      fascia or autologous fascia lata are alternatives, but prolong surgery time and
      require a second operative site. Recently, a number of other wraps, such as
      processed human pericardium, processed human fascia lata, processed human sclera,
      bovine pericardium and expanded polytetrafluoroethylene [e-PTFE], have being
      marketed. Although they also facilitate implant placement, they can be costly.
      Polygalactin (Vicryl, Ethicon, Somerville, NJ) mesh is another readily available
      wrap that is easy to use and cost effective. To obtain a high success rate with
      this wrap, the polygalactin mesh wrapped HA implant must be moistened and seated
      into the orbit properly. If it is not, exposure may occur, which may explain why
      some surgeons shy away from its use. The proper technique is reviewed in this
      paper.

PMID- 10334032
TI  - Matching set of enucleation retractor and scissors.
AB  - Many surgeons encounter difficulty transecting the optic nerve during the
      enucleation procedure. An inadequate specimen may be obtained or the surrounding
      orbital tissue may be traumatized. A matching set of enucleation instruments have
      been developed to improve the visualization and division of the optic nerve while
      protecting the nearby orbital structures. The new enucleation instruments have
      been employed in 130 consecutive enucleation procedures. There have been no
      complications associated with these instruments. These instruments have
      facilitated the visualization and transection of the optic nerve during the
      enucleation procedure.

PMID- 10334033
TI  - Factors affecting image acquisition during scanning laser polarimetry: authors'
      response.

PMID- 10334034
TI  - Identification of genes directly and indirectly involved in the insect
      transmission of African cassava mosaic geminivirus by Bemisia tabaci.
AB  - The inability to transmit progeny virus resulting from the cloned components of
      an isolate of African cassava mosaic virus originating from Kenya (ACMV-K) has
      been shown to be due to defects in both genomic components. This was achieved by
      the production of infectious pseudorecombinants between ACMV-K and the cloned
      components of a whitefly-transmissible ACMV isolate originating from Nigeria
      (ACMV-NOg). The exchange of gene fragments between ACMV-K and ACMV-NOg has been
      used to demonstrate that the defects responsible for lack of transmissibility
      reside on the coat protein and DNA B C1 gene of ACMV-K. The significance of these
      finding with respect to the present understanding of the function of these gene
      products are discussed.

PMID- 10334035
TI  - Computational sequence analysis of mammalian reovirus proteins.
AB  - In the present study, computer-assisted searches for sequence similarities were
      performed with amino acid sequences from mammalian reovirus proteins. These
      analysis revealed that many proteins of reovirus are partially similar to known
      viral or cellular proteins. Consensus sequences have been identified that are in
      accordance with already suspected functions of reovirus proteins. The analysis
      has also revealed unexpected similarities of some reovirus proteins with specific
      classes of proteins which sequences are present in the databases. This could
      suggest yet unidentified activities for some of the reovirus proteins.

PMID- 10334036
TI  - Capsid protein-encoding genes of hamster polyomavirus and properties of the viral
      capsid.
AB  - On the basis of its genome organization the hamster polyomavirus (HaPV) is
      closely related to the murine polyomavirus Py. But HaPV infection, in contrast to
      Py infection, gives rise to two different tumor types; depending on the hamster
      strain used for infection, HaPV induces either epitheliomas or lymphomas.
      Although the HaPV virions were shown to be similar to those of Py and SV40, more
      precise information about the structure and protein composition of the HaPV
      capsid was still missing. Here we describe the primary structure of the capsid
      protein-encoding HaPV genes and the structure and protein composition of the HaPV
      capsid. Virions isolated from epitheliomas in HaPV-infected hamsters were shown
      by electron microscopy to be spherical particles with the typical icosahedral
      structure of polyomaviruses. However, in contrast to the capsids of SV40 and Py,
      a T = 7 laevo symmetry of HaPV capsids was observed. Separation of HaPV virions
      in SDS polyacrylamide gels and Western blotting with VP1-specific antisera
      identified VP1 as the major capsid protein species corresponding in its molecular
      weight to the predicted value of 41.8 kDa. Because of the presence of two
      potential translational initiation sites in the VP1 gene, the N-terminal amino
      acid sequence of virion VP1 was determined and found to start at the second
      initiation site. The amino acid homologies of HaPV capsid proteins shared with Py
      varied between 65.5% (VP1), 45.4% (VP3) and 44.6% (VP2), whereas the homologies
      to the relevant proteins of other polyomaviruses were found to range between 49.6
      57.9% for VP1 and 28.9-41% for VP2/VP3.

PMID- 10334037
TI  - Genetic interrelationships and genome organization of double-stranded RNA
      elements of Fusarium poae.
AB  - The similar sized double-stranded RNA (dsRNA) elements present in vegetatively
      compatible strains of Fusarium poae were always genetically related, while
      vegetatively incompatible strains of the fungus contained either homologous or
      non-homologous dsRNAs of the same size. Electron microscopic observations
      revealed the co-existence of encapsidated and naked dsRNA elements in the same
      host. A mycovirus, named FUPO-1 was purified from strain A-11 and was found to
      contain two kinds of dsRNA segments, dsRNA 1 and dsRNA 2. The dsRNA genome of
      these segments was converted to cDNA clones by reverse transcription and the
      clones were subjected to sequence analysis. The single long open reading frame
      deduced from the sequence of dsRNA 1 showed similarities to the putative coat
      protein genes known from other mycoviruses, while conserved motifs of an RNA
      dependent RNA polymerase were identified in the predicted amino acid sequence of
      dsRNA 2. The genome organization and certain sequence motifs of FUPO-1 show
      similarities to that of the Atkinsonella hypoxylon 2H virus and the FusoV
      mycovirus, members of the Partitiviridae family.

PMID- 10334038
TI  - The interaction of mitogen-activated protein kinases to Epstein-Barr virus
      activation in Akata cells.
AB  - To understand the mechanism by which Epstein-Barr virus (EBV) is activated in
      Akata cells by cross-linking of surface immunoglobulin, the interaction between
      mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase
      (ERK) and EBV activation was investigated. Immunoblotting using an anti
      phosphoMAPK antibody (Ab) revealed that anti-IgG Ab induced rapid phosphorylation
      of MAPK in the cells. The phosphorylation was inhibited by MAPK/ERK kinase
      specific inhibitor, PD98059. The expressions of the EBV immediate early BZLF1
      mRNA and its protein product ZEBRA, and early antigen were also inhibited by the
      inhibitor. These results indicate that MAPK is involved in the pathways of EBV
      activation.

PMID- 10334039
TI  - Molecular and phylogenetic analysis of SRS 19-6 murine leukemia virus.
AB  - The complete nucleotide sequence of the genome of Solid-type Reticulum cell
      Sarcoma 19-6 murine leukemia virus (SRS 19-6 MuLV) was determined. This virus was
      isolated in mainland China from laboratory mice that had been separated from
      western mice since the 1930s. The genome is 8,256 nucleotides in length and
      exhibits a genetic organization characteristic of replication competent MuLVs.
      Phylogenies constructed from reverse transcriptase (RT) domains showed that SRS
      19-6 MuLV is closely related to other MuLV-related retroviruses; however, it has
      clearly diverged from previously isolated MuLVs. Comparative sequence analysis of
      the env sequences indicated that SRS 19-6 MuLV encodes a surface (SU)
      glycoprotein that is related to other ecotropic MuLVs in the VR-A and VR-B
      variable regions. However, SRS 19-6 MuLV env glycoprotein was distinct from all
      other MuLVs (ecotropic and non-ecotropic) in the proline-rich hypervariable
      region. No evidence for recombination with endogenous MuLV env sequences in
      generation of SRS 19-6 MuLV was observed. Comparisons of long terminal repeat
      (LTR) sequences revealed that the GV 1.4 molecular clone of Graffi MuLV contained
      96% sequence identity to SRS 19-6 MuLV's LTR with 99% identity when comparisons
      were restricted to the U3 regions of the two viruses. The consensus enhancer
      binding motifs contained in the U3 regions of the two viruses were nearly
      identical. Nevertheless the two viruses have previously been shown to induce
      distinct patterns of disease. Comparisons between 196 and Graffi GV1.4 MuLVs may
      provide insights into the mechanisms of disease specificity induced by MuLVs.

PMID- 10334041
TI  - [Intestinal transplant: present and future].

PMID- 10334040
TI  - Glycoprotein K of herpes simplex virus: a transmembrane protein encoded by the
      UL53 gene which regulates membrane fusion.
AB  - Glycoprotein K (gK) encoded by the UL53 gene is the ninth out of eleven HSV
      glycoproteins (gps). The precursor gK (pgK) is a transmembrane protein with four
      hydrophobic domains, which consists of 338 amino acids. The UL53 gene has two
      initiation codons: the upper overlaps with the UL52 ORF, while the lower is
      located 55 codons downstream and specifies a truncated precursor of the gK
      polypeptide. The UL53 gene and the upstream located UL52 gene have a common
      polyadenylation signal downstream from the UL53 stop codon so that the UL53 mRNA
      is completely nested within the UL52 transcript. The syn1 mutations in several
      KOSsyn mutants and in the MPsyn virus, which had been fine mapped to DNA
      coordinates 0.735-0.740, were later on located to the UL53 gene, especially to
      its portion which specifies the first 120 amino acids (aa) from the N-terminus
      (most frequently residue 40) and to a less precisely defined locus between aa 301
      310 (close to the C-terminus). Point mutations in the N-terminal ectodomain of
      gK, which are related to syn formation, impair the putative ability of this
      region to down-regulate membrane fusion. The two N-glycosylated mannose core
      oligosaccharides are attached to the Asn residues of the gK polypeptide at
      positions 48 and 58, respectively. In infected cells, gK is localized mainly in
      the nuclear and endoplasmic reticulum (ER) membranes. It is not clear, whether gK
      becomes incorporated into the envelope of mature HSV particles. Studies with the
      insertion/deletion gK mutants showed the importance of gK for capsid envelopment,
      for the transportation and egress or virions from infected cells. It seems that
      gK has an essential role in virion egress, even though this glycoprotein acts in
      accord with gH and with another membrane protein encoded by the UL20 gene.

PMID- 10334042
TI  - [Donation and transplantation in the Spanish pediatric population: current
      status].

PMID- 10334043
TI  - [International nomenclature and classification of osteochondrodysplasias (1997)].

PMID- 10334044
TI  - [Epidemiology of breast feeding in north-central Spain].
AB  - OBJECTIVE: Our aim was to investigate the prevalence of breastfeeding in the
      north-central region of Spain and to study its prenatal and perinatal factors.
      PATIENTS AND METHODS: From October 1992 December 1992, 1175 infants were selected
      from fifteen maternity units in Aragon, Pais Vasco, Cantabria, La Rioja, Navarra
      and Soria and follow up during a one year period. RESULTS: At the time of
      discharge from the nursery unit, 79.9% of the newborns were exclusively
      breastfed, 8.5% were breast and bottle-fed and 11.8% were bottle-fed. At six
      months of life, we found that only 3.9% (43 babies) of the infants continue with
      breastfeeding. The mean period of breastfeeding in our area is 1.1 months. Of the
      mothers studied, 58.2% were from cities areas and 50% had basic academic studies,
      while 36.1% had intermediate studies. Approximately half of the mothers did
      receive prenatal preparation and 78% of them did no received a free sample of
      infant formula. Half of the mothers were housewives. Normal delivery occurred in
      79.6% and 68.8% were without their husbands. Placement of the baby to the breast
      occurred late in 79.5% and 97% of the babies received glucose or water in the
      nursery. Most of the newborns (81.7%) were with the mother 24 hours a day.
      CONCLUSIONS: Breastfeeding in the north-central region of Spain fits level 1 of
      the WHO classification. However, the prevalence at 3 and 6 months of life is
      lower. Protocols in the maternity units of this area are at a distance from those
      of the Baby-friendly Hospital Initiative.

PMID- 10334045
TI  - [Dental plaque in Helicobacter pylori infection].
AB  - OBJECTIVE: The aim of this study was to determine the role of Helicobacter pylori
      infection in dental plaque from 53 children, between 3 and 17 years of age, with
      recurrent abdominal pain and/or upper gastrointestinal bleeding. PATIENTS AND
      METHODS: Dental plaque was analyzed by using polymerase chain reaction (PCR) for
      a specific internal urease gene (as described by Clayton). Esophago-gastro
      duodenoscopy was performed after the dental plaque was obtained and biopsies were
      taken from the gastric antrium and fundus and analyzed by PCR. An individual
      interview was performed to know the customs and attitudes about bucodental
      hygiene. RESULTS: None of the children were positive with the PCR test in dental
      plaque, while 35 children (66%) had a positive gastric PCR result. CONCLUSIONS:
      This study does not confirm the hypothesis that dental plaque might act as a
      reservoir for this microorganism.

PMID- 10334046
TI  - [The pediatrician and the child with sleep disorders].
AB  - OBJECTIVE: The purpose of this study was to better understand the sleeping habits
      and its most frequent alterations in a general pediatric population and to
      propose a systematic study of ambulatory attendance. PATIENTS AND METHODS: A
      questionnaire of closed questions, multiple choice and unique answers was sent to
      an infantile population constituted of 240 children between 6 and 11 months of
      age and 894 children between 1 and 6 years of age. Data was collected in the 4
      different seasons of the year when concluding the control of health. The answers
      came from the closest relative. RESULTS: 1. There was a high incidence of sleep
      interruptions during the first semester of life (53.3%). 2. Starting from the
      third year of life, an important decrease in night awakenings took place. In
      spite of this, until 6 years of age, 18.6% of the children interrupted their
      family's sleep at least 3 times per week. 3. At 6 years of age 12.1% of the
      children had not learned how to fall asleep. CONCLUSIONS: Our study confirms a
      high incidence of alterations of sleep and the necessity of insisting in its
      prevention during health revisions.

PMID- 10334047
TI  - [Effect of inhaled nitric oxide on the first 24 hours of assisted respiration in
      the critically ill child].
AB  - OBJECTIVE: Our aim was to analyze if inhaled nitric oxide (NO) allows a reduction
      in respiratory assistance during the first 24 hours of treatment of children with
      acute respiratory distress syndrome (ARD) and/or pulmonary hypertension (PHT).
      PATIENTS AND METHODS: We studied 53 children with ARDS and/or PHT refractory to
      conventional therapy who were treated with inhaled nitric oxide at least 24 hours
      at 1.5 to 45 ppm. We compared respiratory assistance (peak pressure, PEEP and
      FiO2) and oxygenation parameters (PaO2/FiO2 ratio and oxygenation index) before
      and after 6 and 24 hours of treatment. RESULTS: In 45 of 53 children NO improved
      oxygenation (increase of PaO2/FiO2 > 20%). At six hours of treatment the
      PaO2/FiO2 ratio increased 31 points, the oxygenation index diminished 4.5 points,
      and the FiO2 was decreased 11 points without significant changes in peak pressure
      and PEEP. At 24 hours the PaO2/FiO2 ratio was increased 4 points, the oxygenation
      index diminished 7.3 points and the FiO2 decreased 18 points in relationship to
      the initial parameters. CONCLUSIONS: The effect of inhaled nitric oxide on
      oxygenation remains during the first 24 hours and permits a decrease in the FiO2.

PMID- 10334048
TI  - [Complications of varicella in children].
AB  - OBJECTIVE: The purpose of this study was to describe varicella complications that
      result in the hospitalization of children in our hospital, as well as the
      associated cost. PATIENTS AND METHODS: A retrospective study involving 84
      children hospitalized for complications due to varicella between January 1993 and
      December 1997 was carried out. Oncology patients were excluded. Data about age,
      sex, previous health conditions, complications developed, days of admission and
      treatments, amongst others, was collected and descriptive statistics performed.
      We also estimated the costs of hospitalization. RESULTS: We identified 84
      children hospitalized for complications of varicella, which represents 2.67% of
      the total cases of varicella attended in the Emergency Room (3,135). Of these
      children, 72.6% were healthy before the onset of varicella. The mean age was 3.3
      +/- 2.6 years. Skin or soft tissue infections were the most common complication,
      with all of the cases occurring in children under 5 years of age. Central nervous
      system complications were found in 19.27%, with involvement of the cerebellum
      accounting for the majority of the cases of encephalitis. Bilateral facial palsy
      was observed in one patient. Respiratory complications (14.45%) included
      pneumonia, bronchitis and croup. Other types of complications, such as
      gastrointestinal (9.63%), musculo-skeletal (4.76%) and hematological were less
      frequent. The mean hospital stay was 7.7 +/- 4.8 days. The cost associated with
      the admission of these children was 43,681,528 pesetas. CONCLUSIONS: Varicella
      complications represent an important morbidity for a disease that has long been
      considered benign and inevitable in children. The implementation of a varicella
      vaccine program for healthy children would be beneficial for the prevention of
      complications and the reduction in their associated cost to the health care
      system.

PMID- 10334049
TI  - [Vascular complications in pediatric renal transplant: echographic diagnosis].
AB  - OBJECTIVE: The purpose of this study was to assess the incidence of vascular
      complications in pediatric renal transplant patients and to evaluate the accuracy
      and limitations of duplex-Doppler color ultrasound (US) in their diagnosis.
      PATIENTS AND METHODS: The US studies of 89 transplants performed in 76 patients
      were reviewed. Ages of the patients ranged from 11 months to 23 years (mean 13
      years). The US exams were performed every 24 hours during the first week post
      transplantation, once a week during the hospital stay and whenever graft
      dysfunction occurred. A vascular map of the graft was performed with color
      Doppler and maximum systolic velocity, systolic acceleration time, resistive
      index and flow velocity in the renal vein were determined with pulsed Doppler. An
      angiography was performed in all patients with US diagnosis of vascular
      thrombosis, stenosis or arteriovenous fistula. RESULTS: Seventeen grafts (15%)
      showed vascular complications including renal artery stenosis (8 cases), renal
      artery thrombosis (4 cases), arteriovenous fistula (4 cases) and one renal vein
      thrombosis. US studies were able to detect six renal artery stenosis (false
      negative results in two cases), seven renal artery thrombosis (false positive
      results in three grafts), all of the arteriovenous fistulas and one renal vein
      thrombosis. CONCLUSIONS: Doppler-duplex color US has a high sensitivity and
      specificity in diagnosis of vascular complications and should be the first
      approach for their diagnosis. The presence of false positive and false negative
      results makes it necessary to perform angiography when symptomatic thrombosis,
      arteriovenous fistula or stenosis is suspected.

PMID- 10334050
TI  - [High-frequency oscillatory ventilation as salvage strategy in the newborn
      infant. Spanish multicenter study. I].
AB  - OBJECTIVE: The aim of this study was to evaluate the results of high frequency
      ventilation (HFV) used as a rescue strategy in newborn infants with severe lung
      disease who either failed conventional mechanical ventilation (CMV) or had an air
      block. PATIENTS AND METHODS: From April 1995 to June 1998, 241 infants with
      severe lung disease and managed according to a common protocol of HFV used as a
      rescue strategy were prospectively evaluated in the nine participating level III
      Spanish Neonatal Intensive Care Units. The most frequent diagnoses were
      respiratory distress syndrome (119), meconium aspiration (24), pneumonia (19) and
      congenital diaphragm hernia (18). RESULTS: Mean +/- SD gestational age and birth
      weight were 32.0 +/- 5.5 weeks and 1,187 +/- 1,071 g, respectively. All babies
      were previously manages with CMV for a mean of 59 hours. HFV was started at a
      mean postnatal age of 82 hrs, with a mean oxygenation index (OI) of 28.3 +/- 15.3
      and an a/A DO2 of 0.10 +/- 0.08. Initial mean HFV settings were: mean airway
      pressure 12.8 +/- 3.4 mbar, frequency 8.3 +/- 1.4 Hz, amplitude 53 +/- 20
      percent, tidal volume 2.2 +/- 0.7 ml/kg and FiO2 0.88 +/- 0.2. At two hours of
      HFV there was a significant increase in the mean PaO2 (from 48 to 80 mmHg), with
      a concomitant decrease in FiO2 (from 0.88 to 0.79), PaCO2 (from 60 to 46 mmHg)
      and OI (from 28 to 18). Mean a/A DO2 increased from 0.10 to 0.19; these changes
      remained similar thereafter. HFV was suspended after a mean of 95 hrs because of
      improvement in 70%, death in 19% and failure to improve the clinical condition in
      the remaining 19%. Intrahospital death rate was 32%. The following complications
      were observed: pneumothorax (10%), interstitial emphysema (4%), intraventricular
      hemorrhage grades III and IV (14.5%) and bronchopulmonary dysplasia (35%).
      CONCLUSIONS: HFV is an effective rescue strategy that improves pulmonary gas
      exchange within two hours of its initiation.

PMID- 10334051
TI  - [Morbidity of the newborn infant born to a diabetic mother in relation to
      macrosomia].
AB  - OBJECTIVE: A descriptive study of an infant of a diabetic mother was carried out
      in order to analyze if macrosomia (weight greater than P90 for gestational age)
      is a good criteria in order to predict associated complications. PATIENTS AND
      METHODS: A total of 382 diabetic mothers were attended between January 1994 and
      December 1996. RESULTS: Most of the complications were similar to those reported
      in the literature. In infants of diabetic mothers there is a significant increase
      in malformations (7.1%), sepsis (10.7%), hypertrophic cardiomyopathy (12.1%),
      respiratory distress (12.7%), hypoglycemia (50%), polyglobulia (30.4%) and
      jaundice (7.1%). We did not find any differences for traumatisms (8.25%), acute
      fetal suffering (19.6%) or hypocalcemia (1.8%). Respiratory distress was related
      to gestational age. CONCLUSIONS: The high weight for gestational age is a good
      parameter to predict complications in the infants of diabetic mothers.

PMID- 10334052
TI  - [Continuous arteriovenous hemofiltration in the newborn infant].
AB  - OBJECTIVE: We present 12 newborns with acute renal failure (ARF) of different
      etiologies that were treated with continuous arterio-venous hemofiltration
      (CAVH). PATIENTS AND METHODS: Gestational age and birth weight ranged from 26-42
      weeks and 700-4, 700 grams, respectively. The umbilical artery and vein were most
      frequently used as vascular accesses. Two types of filters were used: Gambro FH
      22 and Amicon Minifilter. RESULTS: Treatment lasted from 8 to 120 hours. We
      obtained an ultrafiltration median of 25 ml/h ranging from 10.75 mL/h to 82.8
      mL/h (4.1-31.8 mL/k/h). The volume balance was negative in all patients.
      Treatment was well tolerated. Complications included hypotension when the system
      was started and hypoglycemia. CAVH was stopped because of normalization of renal
      function in 6 cases and death in the other 6. In the latter, cardiac malformation
      was the cause of death in 3 cases and multiple organ failure in the other 3.
      CONCLUSIONS: CAVH is useful is the treatment of ARF in the oligoanuric newborn.

PMID- 10334053
TI  - [Fetal encephalopathy secondary to maternal shock].

PMID- 10334054
TI  - [Magnetic resonance in Ebstein anomaly].

PMID- 10334055
TI  - [Cholestasis associated with parenteral nutrition in the critically ill child].

PMID- 10334056
TI  - [Acute myocarditis: a forgotten diagnosis in pediatric emergencies?].

PMID- 10334057
TI  - [What is your diagnosis? A child that limps].

PMID- 10334058
TI  - [Epidemiology and scientific methodology applied to pediatrics (IV): diagnostic
      tests].

PMID- 10334059
TI  - [Advances in pediatric nephrology].

PMID- 10334060
TI  - [Anglicisms in medicine].

PMID- 10334061
TI  - 5th Africlen Regional Scientific Conference. 1998. Abstracts.

PMID- 10334062
TI  - Infectious diseases in England and Wales: October to December 1998.

PMID- 10334063
TI  - Unvaccinated child dies of Haemophilus influenzae type b infection.

PMID- 10334064
TI  - Vaccine research: new vaccines and evidence of vaccine safety.

PMID- 10334065
TI  - VTEC O157 infection in three nurseries in Preston.

PMID- 10334066
TI  - [Critical review of current indications in hormone replacement therapy for
      menopause].

PMID- 10334067
TI  - [Treatment of micturation troubles].

PMID- 10334068
TI  - [Management of abnormal cervical smears: management of ASCUS cervical smears].

PMID- 10334069
TI  - [For or against non-stop hormone replacement therapy?].

PMID- 10334070
TI  - [After how long should hormone replacement therapy be interrupted?].

PMID- 10334071
TI  - [Contraception during the first sexual intercourse: a survey concerning 467
      female teenagers, 13 to 21 years in the Nantes area].
AB  - More than 30 years after the legalization of contraception in France (Neuwirth
      law) it was interesting to access the sexual behavior and the practice of
      contraception of French female teenagers. It is with this purpose that this
      survey has been done in the city of Nantes in Loire Atlantique. 467 female
      teenagers, 13 to 21 years old, were concerned. Results point out that more of 75%
      of young girls who replied to this survey used one contraceptive method during
      the first sexual intercourse and condom is predominantly used. A few ambivalences
      stake out this life period, so preventive strategies have to be very specific in
      order to fight sexual transmitted diseases (STD) and AIDS.

PMID- 10334072
TI  - [Induced ovarian follicular development: theoretical basis and therapeutic
      applications].
AB  - The fine mechanisms involved in human follicular growth in the ovary are not
      completely elucidated yet. The morphometric parameters are, by far, better
      understood than the metabolic ones. However, new data on the steroidogenic
      follicular human activity and their ability to respond to endogenous and
      exogenous gonadotropins lead to a better understanding of the results of our
      different therapeutic schemes. On the other hand, the selection criteria of
      patients have been modified, dealing now with the ovarian age much more than the
      real age. A precise determination of the ovarian age allows us to better drive
      our stimulation protocols and helps us to switch to other alternatives rather
      than multiplying useless and ineffective stimulations. This is of major
      importance in term of psychological aspects as well as in term of public health
      costs for the society.

PMID- 10334073
TI  - [Mechanical and metabolic complications of hysteroscopic surgery: report of a
      retrospective study of 352 procedures].
AB  - Our objective was to determine, in a retrospective study of 352 operative
      hysteroscopies: (a) the rates and the types of complications and (b) the risk
      factors of peroperative perforations. The most important complications
      represented 1.7% including two haemorrhage, one symptomatic metabolic
      abnormalities and three uterine perforations with bowel injuries (0.8%).
      Furthermore, minor complications were observed in 9.3% including non symptomatic
      metabolic abnormalities (5.5%) and uterine perforations without visceral injury.
      Among mechanical complications, the majority were uterine perforations (4%). No
      relation was found between menopausal status of the patients and the occurrence
      of uterine perforation. In contrast, the perforation rate was statistically
      greater in patients treated for synechia than those found for myoma (p < 0.0001).
      Furthermore, the perforation rate was statistically higher for resection of
      myomas as compared with endometrial resection (p < 0.0001) or polyp resection (p
      < 0.0008). Moreover, in our experience, the perforation rate depended on
      hysteroscopic experience of surgical operators.

PMID- 10334074
TI  - [Atypical mammary hyperplasia: interpretation, therapeutic strategy, and post
      therapeutic survey].
AB  - Defining elements leading to atypical hyperplasia's diagnosis, interpreting
      histological diagnosis of atypical hyperplasia and determining therapeutic
      strategy.

PMID- 10334075
TI  - [Amnio-infusion during labor: experience and review of the literature].
AB  - OBJECTIVES: Evaluation of amnioinfusion results during labour in case of thick
      meconial amniotic fluid or in case of oligo-hydramnios associated with variable
      deceleration of the fetal heart response. PATIENTS AND METHODS: Prospective non
      randomized study. Amnioinfusion was applied to 47 cases of thick meconial
      amniotic fluid and to 18 cases of variable fetal heart decelerations associated
      with oligo-hydramnios. Obstetrical and neonatal data were compared with a similar
      group without amnioinfusion (n = 32). RESULTS: Comparing both groups shows that
      amnioinfusion offers a better fetal well-being during labour, according to Kreb's
      fetal heart evaluation during labour (8.53 +/- 1.06 vs 6.56 +/- 0.35--p < 0.01),
      lows the cesarean section rate (8.5% vs 31.2%--p < 0.01). Amnioinfusion is also
      associated with a higher Apgar's score at one minute after delivery (9.4 +/- 0.8
      vs 8.7 +/- 1.7--p = 0.01) and a lower rate of thick meconium inhalation (13.7% vs
      40.7%--p < 0.01). There was no difference for children's first days of life. We
      found no serious complication following amnioinfusion. CONCLUSION: We confirm
      general agreement about amnioinfusion, according to international literature.
      Amnioinfusion needs an acute care to prevent classically described complications.
      In case of thick meconial amniotic fluid or variable decelerations associated
      with oligo-hydramnios, amnioinfusion during labour offers a better fetal well
      being.

PMID- 10334076
TI  - [Sexual fantasies and sexual dreams: a sexoanalytical exploration].
AB  - Nowadays there are more and more empirical studies of sexual fantasies. Fewer are
      researches on sexual dreams. Even less common are the data on the relation
      between sexual fantasies and sexual dreams. A lot of questions can be brought up.
      Is there a correlation between the frequency in fantasies and sexual dreams? Is
      there a concordancy or discrepancy between these two? What would be the
      differences between the persons whom sexual fantasies and dreams concord from
      those who don't concord? Finally is there an interaction between fantasies and
      sexual dreams? Based on our preliminary results, we present our mains hypothesis
      and few illustrations.

PMID- 10334077
TI  - [Folic acid supplementation by 200 microgram per day during the periconceptional
      period: a necessary public health approach to reducing incidence of spina
      bifida].
AB  - The incidence of neural tube closure abnormalities, and particularly Spina-bifida
      is correlated with a low dietary intake of folic acid, for which the marker is
      the erythrocyte folate concentration. Initially, preventive policies concerned
      women treated with anticonvulsant agents and those with a known family history of
      Spina-bifida. This constituted secondary prevention. The objective of this study
      was to demonstrate the methods and respective role of secondary and primary
      prevention in 1998. The evolution away from secondary prevention towards primary
      prevention, i.e. aimed at all women who intend to conceive has been based upon
      the fundamental epidemiological estimate that 95% of cases of Spina-bifida occur
      in babies born to women without a known family history of this type of disorder.
      The idea that dietary measures alone may suffice to ensure effective prevention
      is invalid. However, if used in addition to a mean dietary intake of 200
      micrograms folic acid a day, the only use of pharmacological or synthetic
      supplementation of 200 micrograms/day makes it possible to achieve the desired
      threshold of Dietary Folate Equivalents of 600 micrograms/day. The dose of 200
      micrograms/day has been judged by the authors as being the most effective and
      safe for use on a large scale in the general population. Today, in 1998, the
      primary prevention of neural tube closure abnormalities is the subject of an
      international consensus which recommends folate supplementation of 100 to 200
      micrograms/day during the periconceptional period. Implementation of this
      solution in the context of a health education campaign would meet the
      expectations of many women, in as much as 66% of them have declared that they
      would be ready to comply with such primary preventive measures.

PMID- 10334078
TI  - [The effect of smoking on the spread and frequency of periodontal disease].
AB  - In recent years substantial data accumulated in the literature supporting the
      direct detrimental effect of tobacco smoking on periodontal health. The
      significantly inferior periodontal condition of smokers cannot be solely
      attributed to poor oral hygiene, increased calculus formation and altered
      subgingival microflora. Smoking imposes a direct threat to the periodontal
      tissues. Smokers with excellent oral hygiene show significantly less periodontal
      bone height and attachment level than matches non-smokers. Smoking entails a 2.5
      to 3.5 risk ratio for severe periodontal attachment loss. Smoking also interferes
      with the outcome of nonsurgical and surgical periodontal treatment and impairs
      periodontal regeneration. The pathomechanism of the tobacco smoking related
      periodontal destruction is just partly understood. Tobacco products can alter
      normal host responses to neutralize infections and can also stimulate pathologic
      mechanisms to destroy the surrounding tissues. Tobacco products can directly
      impair polymorphonuclear leukocyte functions. Smokers have less salivary IgA and
      decreased serum IgG concentration as well as depressed number of helper T
      lymphocytes. Consequently smoking today is considered as one of the major risk
      factors for destructive periodontitis. Periodontitis is also considered as a
      decisive risk factor for systemic diseases especially for cardiovascular
      disorders. A strong association has been shown between periodontal disease and
      coronary heart diseases, as well as between periodontal disease and
      cerebrovascular diseases (stroke). The subgingival microflora and the continuous
      latent bacteremia and endotoxemia originated from the periodontal pockets might
      be responsible for the damage of the vascular endothelial integrity, platelet
      functions and blood coagulation. Modern periodontal epidemiology rediscovered the
      old ide of "focal infections" and indicated that the general health has a crucial
      impact on the periodontal health and periodontal disease has also a major impact
      on the general health status of the patient.

PMID- 10334079
TI  - [In vitro comparison of marginal adaptation of different filling materials. II.
      Effect of the site and method of preparation on the marginal adaptation].
AB  - In a two-month in vitro experiment we examined the marginal adaptation of ten
      dental materials. Fifty Class II restorations were prepared extending to the
      cemento-enamel junction. The cavities of the composite restorations were bevelled
      at the vestibulo-occlusal and -approximal enamel margins, on the other side
      enamel and gingival margins were prepared conventionally. The specimens were
      thermocycled and examined with SEM. The microleakage was measured at the
      vestibulo-occlusal and -approximal tooth-filling junction, where adhesive
      technique was used, and at the gingival, oroocclusal and -approximal margins,
      which were not bevelled before. The obviously most important conclusion of the
      study is, that in the case of deep Class II cavities the amalgam has a better
      adaptation at the gingival margin than the examined composite resins.

PMID- 10334081
TI  - Cumulative index, 1932-1997.

PMID- 10334080
TI  - [Interface between Ni-Cr alloy and ceramic studied by scanning electron
      microscopy].
AB  - In this investigation we observed the interface between Wiron 99 (Bego) dental Ni
      Cr alloy and Vision (Wohlwend AG) ceramic opaquer with SEM. In the system there
      are intermediate phases coming from a solid phase rection which play an essential
      role in the metal-ceramic bond. The analytical methods showed that in this phases
      the content of Ni and Cr charge not monotonously from alloy to ceramic which
      shows strong chemical effects (the selective affinity of Cr and Ni). The
      concentration of Cr after the alloy surface increases in a 1-1.5 microns layer,
      where its concentration is higher than at the alloy, while the concentration of
      Ni decrease in this layer. Than at the ceramic side of the reaction zone the
      concentration of Ni increases in a 1-1.5 microns wide layer where its
      concentration is near upon that one in the alloy.

PMID- 10334082
TI  - Childhood obesity: addressing the issue.
AB  - Childhood obesity is a major health issue in pediatric practice. The old idea
      that "a chubby baby is a healthy baby" is not necessarily the case. Social
      stigmas and recidivism surrounding obesity make addressing families and their
      children difficult; however, with early intervention, treatment can be
      successful. Prevention of obesity with health maintenance surveillance and family
      focused behavior modification is the foundation for a healthy lifestyle and may
      prove the most effective way of avoiding long-term obesity-related morbidity.

PMID- 10334083
TI  - Advances in the understanding and treatment of obesity.
AB  - The epidemic of obesity in the United States has major consequences for society.
      Healthcare providers need to have an appreciation for obesity's complexity and
      related multiple comorbid medical problems. This article reviews the
      epidemiology, definitions, and assessment of obesity with emphasis on its
      clinical consequences. In addition, current techniques in evaluating and treating
      the obese patient are also described.

PMID- 10334084
TI  - Issues and principles in dietary management.
AB  - Obesity is a widely pervasive disease resulting in $45 million in healthcare
      costs. The contribution of genes in the etiology of obesity is quite convincing.
      It is becoming increasingly apparent also that diet can have an influential
      effect on gene expression. Dietary management remains the mainstay of treatment
      and can be tailored to meet the individual needs of patients.

PMID- 10334085
TI  - The role of physical activity in the management of obesity.
AB  - Sedentary lifestyle is associated with obesity and obesity-related chronic
      diseases. Increased physical activity can produce clinically significant changes
      in body composition and a reduction in risk of obesity-related chronic diseases
      in obese people. Because a great proportion of a primary care physician's patient
      population will be obese, it is essential that physicians know the scientific
      facts about the role of physical activity in the treatment of obesity and how to
      effectively prescribe it. This article summarizes significant research
      conclusions about the relationship between physical activity, obesity, and
      health. It also provides practical strategies for helping obese patients
      integrate physical activity into their lives.

PMID- 10334086
TI  - 27th Annual International Neuropsychological Society Conference. Boston,
      Massachusetts, USA. February 10-13, 1999. Abstracts.

PMID- 10334087
TI  - Births: final data for 1997.
AB  - OBJECTIVES: This report presents 1997 data on U.S. births according to a wide
      variety of characteristics. Data are presented for maternal demographic
      characteristics including age, live-birth order, race, Hispanic origin, marital
      status, and educational attainment; maternal lifestyle and health characteristics
      (medical risk factors, weight gain, and tobacco and alcohol use); medical care
      utilization by pregnant women (prenatal care, obstetric procedures, complications
      of labor and/or delivery, attendant at birth, and method of delivery); and infant
      health characteristics (period of gestation, birthweight, Apgar score, abnormal
      conditions, congenital anomalies, and multiple births). Also presented are birth
      and fertility rates by age, live-birth order, race, Hispanic origin, and marital
      status. Selected data by mother's State of residence are shown including teenage
      birth rates and total fertility rates, as well as data on month and day of birth,
      sex ratio, and age of father. Trends in fertility patterns and maternal and
      infant characteristics are described and interpreted. METHODS: Descriptive
      tabulations of data reported on the birth certificates of the 3.9 million births
      that occurred in 1997 are presented. RESULTS: Birth and fertility rates declined
      very slightly in 1997. Birth rates for teenagers fell 3 to 5 percent. Rates for
      women in their twenties changed very little, whereas rates for women in their
      thirties rose 2 percent. The number of births and the birth rate for unmarried
      women each declined slightly in 1997 while the percent of births that were to
      unmarried women was unchanged. Smoking by pregnant women overall dropped again in
      1997, but continued to increase among teenagers. Improvements in prenatal care
      utilization continued. The cesarean delivery rate increased slightly after
      declining for 7 consecutive years. The proportion of multiple birth continued to
      rise; higher order multiple births (e.g., triplets, quadruplets) rose by 14
      percent in 1997, following a 20 percent rise from 1995 to 1996. Key measures of
      birth outcome--the percents of low birthweight and preterm births--increased,
      with particularly large increases in the preterm rate. These changes are in large
      part the result of increases in multiple births.

PMID- 10334088
TI  - The discrimination of heading from optic flow is not retinally invariant.
AB  - Three experiments were conducted to determine whether the discrimination of
      heading from optic flow is retinally invariant and to determine the importance of
      acuity in accounting for heading eccentricity effects. In the first experiment,
      observers were presented with radial flow fields simulating forward translation
      through a three-dimensional volume of dots. The flow fields subtended 10 degrees
      of visual angle and were presented at 0 degree, 10 degrees, 20 degrees, and 40
      degrees of retinal eccentricity. The observers were asked to indicate whether the
      simulated movement was to the right or the left of a target that appeared at the
      end of the display sequence. Eye movements were monitored with an
      electrooculogram apparatus. In a second experiment, static acuity thresholds were
      derived for each of the observers at the same retinal eccentricities. There was a
      significant increase in heading detection thresholds with retinal eccentricity
      (from 0.92 degree at 0 degree retinal eccentricity to 3.47 degrees at 40
      degrees). An analysis of covariance indicated that the variation in sensitivity
      to radial flow, as a function of retinal eccentricity, is independent of acuity.
      Similar results were obtained when the Vernier acuity of observers was measured.
      These results suggest that the discrimination of heading from radial flow is not
      retinally invariant.

PMID- 10334089
TI  - Is the anisotropy of perceived 3-D shape invariant across scale?
AB  - A number of studies have resulted in the finding of a 3-D perceptual anisotropy,
      whereby spatial intervals oriented in depth are perceived to be smaller than
      physically equal intervals in the frontoparallel plane. In this experiment, we
      examined whether this anisotropy is scale invariant. The stimuli were L shapes
      created by two rods placed flat on a level grassy field, with one rod defining a
      frontoparallel interval, and the other, a depth interval. Observers monocularly
      and binocularly viewed L shapes at two scales such that they were projectively
      equivalent under monocular viewing. Observers judged the aspect ratio
      (depth/width) of each shape. Judged aspect ratio indicated a perceptual
      anisotropy that was invariant with scale for monocular viewing, but not for
      binocular viewing. When perspective is kept constant, monocular viewing results
      in perceptual anisotropy that is invariant across these two scales and presumably
      across still larger scales. This scale invariance indicates that the perception
      of shape under these conditions is determined independently of the perception of
      size.

PMID- 10334090
TI  - Visual selection mediated by location: feature-based selection of noncontiguous
      locations.
AB  - Experiments using two different methods and three types of stimuli tested whether
      stimuli at non-adjacent locations could be selected simultaneously. In one set of
      experiments, subjects attended to red digits presented in multiple frames with
      green digits. Accuracy was no better when red digits appeared successively than
      when pairs of red digits occurred simultaneously, implying allocation of
      attention to the two locations simultaneously. Different tasks involving oriented
      grating stimuli produced the same result. The final experiment demonstrated split
      attention with an array of spatial probes. When the probe at one of two target
      locations was correctly reported, the probe at the other target location was more
      often reported correctly than were any of the probes at distractor locations,
      including those between the targets. Together, these experiments provide strong
      converging evidence that when two targets are easily discriminated from
      distractors by a basic property, spatial attention can be split across both
      locations.

PMID- 10334091
TI  - Flanker recall and the flanker validity effect may reflect different attentional
      processes.
AB  - High flanker recall in the correlated flanker task suggests a failure of
      selective attention. We used a dissociation approach to examine the role of
      attentional processing of the flankers' identities in the flanker validity effect
      (FVE). In three experiments, flanker recall decreased as flanker duration
      decreased, but the FVE was not affected by flanker duration. Masking also
      produced a dissociation, in that masking decreased flanker recall but the FVE was
      not affected. Examination of on-line flanker identification suggested that
      flanker recall was an adequate measure of attentional processing of the flankers'
      identities on most trials. The results suggest that attentional processing of the
      flankers' identities is not related to the magnitude of the FVE and is not
      necessary for it to obtain. Because there is a failure of selective attention,
      the dissociations suggest that flanker recall and the FVE may reflect different
      attentional processes.

PMID- 10334092
TI  - Facilitative and inhibitory effects of location and frequency cues: evidence of a
      modulation in perceptual sensitivity.
AB  - The possibility that facilitative and inhibitory effects of auditory cues result
      because of a modulation in perceptual sensitivity was examined. Listeners were
      presented with a cue followed by a target, with the time period between the two
      varied at stimulus onset asynchronies (SOAs) of 150, 450, or 750 msec. In two
      conditions, the cue and target were either the same or different in location or
      frequency. In both conditions, listeners were required to identify the rise time
      of the target. Whereas the cue was presented in isolation, the target was
      presented in a wide-band noise background such that the required discrimination
      was made relatively difficult. In both conditions, a facilitative effect was
      apparent at the 150-msec SOA and an inhibitory effect was apparent at the 750
      msec SOA for both accuracy and response time measures of performance. That these
      results were apparent for a judgment unrelated to the manipulated cue-target
      relation suggests strongly that both location-based and frequency-based auditory
      inhibition of return result primarily because of changes in perceptual
      sensitivity.

PMID- 10334093
TI  - Wheatstone-Panum limiting case: occlusion, camouflage, and vergence-induced
      disparity cues.
AB  - We examined effects of binocular occlusion, binocular camouflage, and vergence
      induced disparity cues on the perceived depth between two objects when two
      stimuli are presented to one eye and a single stimulus to the other (Wheatstone
      Panum limiting case). The perceived order and magnitude of the depth were
      examined in two experimental conditions: (1) The stimulus was presented on the
      temporal side (occlusion condition) and (2) the nasal side (camouflage condition)
      of the stimulus pair on one retina so as to fuse with the single stimulus on the
      other retina. In both conditions, the separation between the stimulus pair
      presented to one eye was systematically varied. Experiment 1, with 16 observers,
      showed that the fused object was seen in front of the nonfused object in the
      occlusion condition and was seen at the same distance as the nonfused object in
      the camouflage condition. The perceived depth between the two objects was
      constant and did not depend on the separation of the stimulus pair presented to
      one eye. Experiment 2, with 45 observers, showed that the disparity induced by
      vergence mainly determined the perceived depth, and the depth magnitude increased
      as the separation of the stimulus pair was made wider. The results suggest that
      (1) occlusion provides depth-order information but not depth-magnitude
      information, (2) camouflage provides neither depth-order nor depth-magnitude
      information, and (3) vergence-induced disparity provides both order and magnitude
      information.

PMID- 10334094
TI  - Weakening the robustness of perspective: evidence for a modified theory of
      compensation in picture perception.
AB  - Viewed from the center of projection, a perspective picture presents the
      pictorial depth information of a scene. Knowing the center of projection, one can
      reconstruct the depicted scene. Assuming another viewpoint is the center of
      projection will cause one to reconstruct a transformed scene. Despite these
      transformations, we appreciate pictures from other viewpoints. The compensation
      hypothesis states that the visible picture surface allows observers to compensate
      for transformations by locating the center of projection and experiencing
      pictorial space from there. We show that observers neither completely compensate
      for nor experience transformations of space as geometry would predict. We propose
      a modified compensation hypothesis according to which different degrees of
      visibility of the picture surface invoke different degrees of compensation.

PMID- 10334095
TI  - Binocular vision enhances phase discrimination by filtering the background.
AB  - Previous studies have shown that the detectability of a noise-masked target can
      be enhanced under stereoscopic viewing when the target's interocular disparity
      differs from that of the noise. This enhanced detectability can be accounted for
      by a model postulating that the binocular system linearly sums the left-eye and
      right-eye views of a visual scene. This model also predicts enhanced phase
      discrimination under specifiable interocular disparities of target and noise. Two
      experiments were conducted in which subjects were asked to discriminate between
      two luminance patterns (target and foil) that differed only in phase. The target
      patterns were constructed by summating two vertical sinusoidal gratings in which
      the phase difference between the higher and the lower spatial frequency gratings
      was 45 degrees. The foils contained the same two component frequencies, with a
      phase difference of -45 degrees. Thus, targets and foils were mirror images of
      one another. The ability of subjects to discriminate between these
      stereoscopically viewed mirror-image patterns was investigated under two sets of
      interocular disparities: those that, according to our model, would unmask one or
      both spatial frequency components, and those that would leave both components
      masked by the noise. Phase discrimination was enhanced only when both component
      frequencies of the target and foil were unmasked. The implications of these
      findings for template-matching and phase-discrimination models of pattern
      discrimination are considered.

PMID- 10334096
TI  - The role of eye height in perceiving affordances and object dimensions.
AB  - In four experiments on perceived object height and width, the effects of shifting
      participants' effective eye height (EEH) on affordance (intrinsic) and apparent
      size (extrinsic) judgments were contrasted. In Experiment 1, EEH shifts produced
      comparable overestimations of height in intrinsic and extrinsic tasks. A similar
      result was found with a more abstract extrinsic height task (Experiment 2).
      However, Experiment 3 revealed a dissociation between intrinsic and extrinsic
      tasks of perceived width. Affordance judgments were affected by EEH shifts,
      whereas apparent size judgments were not. Experiment 4 compared participants'
      performance on comparable extrinsic tasks of height and width. Height judgments
      were affected by EEH shifts, but width judgments were again unaffected. It is
      concluded that eye height may be a more natural metric for object height than for
      width. Moreover, this difference reflects a basic flexibility within the human
      visual system for selectively attuning to the most accessible sources of size
      information.

PMID- 10334097
TI  - Are there critical bands in kinesthesia?
AB  - The effect of changing the bandwidth of noise on the ability of human subjects to
      detect a 10-Hz sinusoidal movement signal was measured in two experiments. The
      objective of these studies was to investigate whether critical bands exist for
      the kinesthetic system, as has been demonstrated for the auditory and tactile
      systems. It was found that subjects' ability to detect a 10-Hz sinusoidal
      movement stimulus embedded in noise was not influenced by the bandwidth of the
      noise over a range of 4-10 Hz. These findings suggest that, if a critical filter
      does exist for this system, it would have to be greater than 10 Hz.

PMID- 10334098
TI  - Analysis of recent empirical challenges to an account of interceptive timing.
AB  - How do we perceive how long it will be before we reach a certain place when
      running, driving, or skiing? How do we perceive how long it will be before a
      moving object reaches us or will arrive at a place where it can be hit or caught?
      These are questions of how we temporally coordinate our actions with a dynamic
      environment so as to control collision events. Much of the theoretical work on
      the control of these interceptive actions has been united in supposing that (1)
      timing is functionally separable from positioning and the two are controlled
      using different types of information; (2) timing is controlled using special
      purpose time-to-arrival information; (3) the time-to-arrival information used for
      the timing of fast interceptive actions is a first-order approximation to the
      actual time-to-arrival, which does not take accelerations into account.
      Challenges to each of these suppositions have recently emerged, suggesting that a
      complete rethinking of how interceptions are controlled may be necessary. These
      challenges are analyzed in detail and it is shown that they are readily
      accommodated by a recent theory of interceptive timing based on the points just
      noted.

PMID- 10334099
TI  - Detecting deviations from metronomic timing in music: effects of perceptual
      structure on the mental timekeeper.
AB  - The detectability of a deviation from metronomic timing--of a small local
      increment in interonset interval (IOI) duration--in a musical excerpt is subject
      to positional biases, or "timing expectations," that are closely related to the
      expressive timing (sequence of IOI durations) typically produced by musicians in
      performance (Repp, 1992b, 1998c, 1998d). Experiment 1 replicated this finding
      with some changes in procedure and showed that the perception-performance
      correlation is not the result of formal musical training or availability of a
      musical score. Experiments 2 and 3 used a synchronization task to examine the
      hypothesis that participants' perceptual timing expectations are due to
      systematic modulations in the period of a mental timekeeper that also controls
      perceptual-motor coordination. Indeed, there was systematic variation in the
      asynchronies between taps and metronomically timed musical event onsets, and this
      variation was correlated both with the variations in IOI increment detectability
      (Experiment 1) and with the typical expressive timing pattern in performance.
      When the music contained local IOI increments (Experiment 2), they were almost
      perfectly compensated for on the next tap, regardless of their detectability in
      Experiment 1, which suggests a perceptual-motor feedback mechanism that is
      sensitive to subthreshold timing deviations. Overall, the results suggest that
      aspects of perceived musical structure influence the predictions of mental
      timekeeping mechanisms, thereby creating a subliminal warping of experienced
      time.

PMID- 10334100
TI  - Aging and judgments of duration: effects of task complexity and method of
      estimation.
AB  - The effects of aging on judgments of short temporal durations were explored using
      the prospective paradigm and the methods of verbal estimation and production.
      Younger and older adults performed a perceptual judgment task at five levels of
      complexity for periods of 30, 60, and 120 sec. Participants either continued to
      perform the task for a specified interval (production) or were stopped and then
      verbally estimated the interval. Older adults gave shorter verbal estimates and
      longer productions than did younger adults. The methods of verbal estimation and
      production yielded approximately equal duration judgment ratios once range
      effects were taken into account. Task complexity had little effect. The major
      conclusion is that duration judgment ratios decrease from younger to older adults
      when the intervals are filled with a mental task.

PMID- 10334101
TI  - Adults' perception of native and nonnative vowels: implications for the
      perceptual magnet effect.
AB  - Two experiments were conducted to evaluate the perceptual magnet effect. In
      Experiment 1, American English speakers representing diverse dialects were
      presented with a fine-grained set of stimuli (varying in just noticeable
      differences for F1 and F2) and indicated whether they heard "/i/" or "not/i/,"
      thus delimiting the /i/ portion of the vowel space for individual subjects. Then
      these same subjects selected their own /i/ prototype with a method-of-adjustment
      procedure. The data from this experiment were used to synthesize customized
      prototype and nonprototype stimulus sets for Experiment 2. In Experiment 2, 24 of
      our original 37 subjects completed a discrimination task for each of three
      conditions, in which vector stimuli varied from the subject's prototype, the
      nonprototype, or a foreign vowel (/y/) in 15-mel steps. Subjects displayed higher
      discrimination, as indexed by d', for the nonprototype condition than they did
      for both the prototype and the foreign conditions. In addition, discrimination
      was better for variants further away from the referent in each condition.
      However, discrimination was not especially poor for stimuli close to subjects'
      individual prototypes--a result that would have yielded the strongest support for
      the operation of a magnet effect. This negative finding, together with other
      aspects of our results, raises problems for any theory of vowel perception that
      relies solely on "one-size-fits-all" prototype representations.

PMID- 10334102
TI  - Effect of combined transient androgen deprivation and irradiation following
      radical prostatectomy for prostatic cancer.

PMID- 10334103
TI  - Association of free PSA percent, total PSA, age, and gland volume in the
      detection of prostate cancer.
AB  - BACKGROUND: Measurement of the free fraction of total prostate-specific antigen
      (fPSA%) has been proposed as a useful addition to total PSA for the detection of
      prostate cancer. METHODS: We assessed the performance of fPSA% in differentiating
      men with prostate cancer from men without cancer in a group of 1,709 subjects
      studied in five institutions. RESULTS: On the basis of PSA testing, digital
      rectal examination, and ultrasound examination conducted at one or more visits,
      229 cancers were diagnosed. The mean fPSA% in men with cancer was 9.1% compared
      to 18.9% in men without cancer. The fPSA% varied by age, with men under 60 having
      a mean fPSA of 13.9% compared to 17.5% in men 60-69 years old and 19.8% in men
      over age 70. Significant associations of fPSA% with gland volume and PSA level
      were also observed. The sensitivity, specificity, and positive predictive value
      of different fPSA% cutoff levels were assessed in 513 men who underwent sextant
      biopsy. Sensitivity of 85.4%, 32.1% specificity, and a 39.2% positive predictive
      value were observed using an fPSA cutoff of 15% in men with PSA in the 4.0-9.9
      ng/ml range. Sensitivity of 96.9%, 12.3% specificity, and a 36.2% positive
      predictive value were observed using an fPSA cutoff of 20% in the same men. If
      15% fPSA had been used as a biopsy criterion in men with PSA of 4.0-9.9 ng/ml,
      the number of biopsies performed could have been reduced by 21.2%, with a
      concomitant reduction in cancer detection of 14.6%. Using a 20% fPSA criterion,
      biopsies would have been reduced 12.7%, with a 3.1% reduction in cancer
      detection. CONCLUSIONS: These results provide some evidence that the detection of
      prostate cancer is enhanced by measuring fPSA% in addition to the established
      measure of total PSA level. Further research is needed to identify other markers
      that have better sensitivity and specificity.

PMID- 10334104
TI  - Macrophage migration inhibitory factor in the human prostate: identification and
      immunocytochemical localization.
AB  - BACKGROUND: Macrophage migration inhibitory factor (MIF) is a lymphokine
      originally identified for its capacity to inhibit the random migration of
      macrophages. Recent data have further extended knowledge of the physiological
      role of this protein, showing that MIF is produced by several human organs and
      tissues. The present study was intended to evaluate the expression and tissutal
      localization of MIF in the human prostate. METHODS: Prostate tissues were
      obtained from patients undergoing surgical adenomectomy for benign prostatic
      hyperplasia and were analyzed by Western blot, reverse transcriptase-polymerase
      chain reaction, immunohistochemistry, and immunoelectron microscopy. RESULTS. The
      presence of both MIF protein and mRNA was demonstrated in the prostate.
      Immunocytochemical studies localized MIF protein in the secretory luminal
      epithelial and basal layer cells. CONCLUSIONS: The present study demonstrated
      that the human prostate is a site of MIF synthesis. Macrophages populate the
      human prostate and represent an important mechanism of defense of integrity and
      functionality of the gland. It is speculated that MIF might play a role in
      preserving prostate physiological activity by maintaining its macrophage
      population.

PMID- 10334105
TI  - High frequency of alterations in DNA methylation in adenocarcinoma of the
      prostate.
AB  - BACKGROUND: Alterations of DNA methylation have been reported in many human
      cancers. In prostatic carcinoma, hypermethylation of the GST P gene promoter and
      an overall decrease in methylcytosine content have been reported. The aim of the
      present study was to investigate the frequency and extent of these alterations in
      relation to tumor stage and grade, in order to explore their clinical relevance
      and to determine their relationship to each other. METHODS: DNA from 32
      histologically verified adenocarcinomas of the prostate was analyzed for GST P
      hypermethylation by a semiquantitative PCR method and for overall DNA methylation
      by quantitative Southern blot analysis or LM-PCR of LINE-1 repetitive sequence
      methylation. RESULTS: GST P hypermethylation was detected in 24/32 (75%)
      specimens, and LINE-1 hypomethylation in 17/32 (53%). Both alterations tended to
      increase in frequency and extent with tumor stage. All but 1 of 8 carcinomas with
      lymph node involvement were positive for GST P hypermethylation. Six of these as
      compared to 2 out of 24 showed strong hypomethylation (P = 0.005).
      Hypermethylation and hypomethylation did not show a quantitative correlation, but
      all except two samples with weak LINE-1 hypomethylation also displayed GST P
      hypermethylation. CONCLUSIONS: GST P hypermethylation is an extremely frequent
      change in prostatic carcinoma which most probably precedes genome-wide
      hypomethylation. It appears useful for sensitive detection of prostatic
      carcinoma, whereas pronounced LINE-1 hypomethylation may be associated with
      progressive tumors.

PMID- 10334106
TI  - Pretreatment plasma testosterone and estradiol levels in patients with locally
      advanced or metastasized prostatic cancer. FINNPROSTATE Group.
AB  - BACKGROUND: Studies concerning pretreatment plasma hormonal environment in
      relation to stage of prostatic cancer have given conflicting results. The aim of
      the present study was to compare the pretreatment plasma testosterone (T), free T
      (fT), estradiol (E2), and free E2 (fE2) levels in patients with locally advanced
      (T3-4 M0) and metastatic (T1-4 M1) prostatic cancer, and to further examine the
      effect of the patients' general condition on these levels. METHODS: The present
      series consisted of 238 patients (Finnprostate 6 study). The variables analyzed
      were E2, fE2, T, fT, age, body mass index (BMI), sex hormone binding globulin
      capacity (SHBG), prostate-specific antigen (PSA), alkaline phosphatase (ALP),
      hemoglobin concentration (Hb), erythrocyte sedimentation rate (ESR), and
      performance status (PS). RESULTS: The E2 and fE2 levels were significantly higher
      in M0 patients than in M1 patients, with no significant differences in T and fT
      levels. In multivariate analyses, a decline in performance status (PS), an
      increase in ESR, or a decrease in Hb, were related to a decrease in T, fT, E2, or
      fE2 levels. CONCLUSIONS: Pretreatment plasma estradiol was significantly lower in
      M1 patients than in M0 patients, but there were no significant differences in T
      levels, although the poor general condition was related to a decrease in the
      pretreatment levels of both testosterone and estradiol.

PMID- 10334107
TI  - High-malignancy orthotopic nude mouse model of human prostate cancer LNCaP.
AB  - BACKGROUND: An animal model of human prostate cancer LNCaP demonstrating high
      rates of spontaneous metastasis from the orthotopic site after tumor implantation
      would be very valuable for mechanistic and drug discovery studies. We previously
      developed microsurgical techniques to implant histologically intact tumor tissues
      orthotopically in nude mice in order to develop high metastatic mouse models of
      human cancer. METHODS: Intact tissue of the androgen-dependent human prostate
      cancer cell line, LNCaP, was implanted on the ventral lateral lobes of the
      prostate gland by surgical orthotopic implantation (SOI) in a series of 20 nude
      mice. Mice were autopsied, and histopathological examination of primary tumors
      and relevant organs was done to identify and quantitate micrometastasis. RESULTS:
      Eighteen of 20 animals transplanted with LNCaP by SOI had tumor growth. Mean
      primary tumor weight in the prostate was 9.24 g at time of necropsy. Sixty-one
      percent of the transplanted animals had lymph node metastasis. Forty-four percent
      had lung metastasis. Mean survival time was 72 days, indicating a high degree of
      malignancy of the tumor. CONCLUSIONS: The extensive and widespread lung
      metastasis as well as lymph node metastasis following orthotopic implantation of
      LNCaP in nude mice and the short survival time provide a high-malignancy nude
      model of the LNCaP human prostate tumor.

PMID- 10334108
TI  - Skeletal metastasis of prostate adenocarcinoma in rats: morphometric analysis and
      role of parathyroid hormone-related protein.
AB  - BACKGROUND: Prostate cancer frequently metastasizes to bone, where it induces
      osteoblastic lesions. Parathyroid hormone-related protein (PTHrP), a product of
      normal and neoplastic prostate cells, may promote growth and bone metastasis of
      certain types of cancer. In this study, we investigated the: 1) pathogenesis and
      morphology of bone metastases in the MATLyLu rat prostate adenocarcinoma model,
      and 2) effect of PTHrP overexpression on tumor growth and incidence of bone
      metastasis. METHODS: MATLyLu cells were stably transfected with a PTHrP
      expression vector or control plasmid. PTHrP expression was determined in vitro by
      immunoradiometric assay and Northern blot analysis. MATLyLu cells were injected
      into the left ventricle of Copenhagen rats to induce bone metastases. Histology
      and radiography were used to quantify the size and number of bone metastases.
      Serum alkaline phosphatase isoenzyme concentrations and histomorphometric
      analysis were used to evaluate bone formation and resorption. RESULTS: All rats
      developed osteolytic metastases in long bones and vertebrae. There was no
      evidence of increased intramedullary bone formation. PTHrP overexpression by
      MATLyLu cells was not associated with any difference in the incidence of bone
      metastasis, size of metastatic foci or tumor-cell proliferation. CONCLUSIONS: The
      MATLyLu intracardiac injection model of prostate carcinoma is an aggressive tumor
      model with a high incidence of osteolytic skeletal metastases, and is not altered
      by increased PTHrP production by neoplastic prostate epithelial cells.

PMID- 10334109
TI  - Artificial neural network analysis (ANNA) of prostatic transrectal ultrasound.
AB  - BACKGROUND: Our purpose was to determine the diagnostic potential of a new,
      computerized method of interpreting transrectal ultrasound (TRUS) information by
      artificial neural network analysis (ANNA). This method was developed to resolve
      the current dilemma of visual differentiation between benign and malignant tissue
      on TRUS. To train and objectively evaluate ANNA, a new precise method of
      computerized virtual correlation of preoperative ultrasound findings and radical
      prostatectomy histopathology was devised. After training with this pathologically
      confirmed digitized TRUS information, ANNA was tested in a blinded study.
      METHODS: Following radical prostatectomy, 289 pathology whole-mount sections of
      61 patients were correlated digitally with the corresponding TRUS slices.
      Specific selection of TRUS areas unequivocally identified on the correlated
      digitized pathohistology resulted in 553 pathology-confirmed representations
      (samples). Of these, 53 were used for training and 500 were subjected to blind
      analysis by ANNA. RESULTS: ANNA classified 378 (99%) of the 381 benign pathology
      confirmed samples correctly as benign. The false-positive rate was 1% (n = 3). Of
      the 119 pathology-confirmed malignant samples, 94 (79%) were classified
      correctly; 25 (21%) were falsely classified as normal. Out of all 119 cancers,
      ANNA classified 60 (71%) of the hypoechoic cancers as malignant and 24 (29%) as
      benign. Surprisingly, 34 (97%) of the isoechoic cancers were correctly classified
      by ANNA, missing only one sample. CONCLUSIONS: The introduction of ANNA enhanced
      the accuracy of TRUS prostate cancer identification. Although not all malignant
      areas were detected, cancer was detected in each patient. The ability to detect
      isoechoic cancerous lesions appears to be the essential innovation over
      conventional TRUS interpretation.

PMID- 10334110
TI  - The rat prostatic epithelial cell line NRP-152 can differentiate in vivo in
      response to its stromal environment.
AB  - BACKGROUND: The clonally derived rat prostatic epithelial cell line NRP-152 was
      examined to determine its ability to differentiate in a tissue recombination
      model. METHODS: NRP-152 cells alone, or combined with urogenital mesenchyme (UGM)
      or 10T1/2 fibroblasts, were grafted beneath the renal capsule of athymic rodent
      hosts. After 1 and 3 months, grafts were examined grossly and
      immunohistochemically. RESULTS: NRP-152 cells grafted alone formed small (10-25
      mg) grafts without recognizable architecture. NRP-152 cells recombined with UGM
      formed larger grafts (50-100 mg after 28 days) containing glandular epithelium.
      Columnar luminal cells expressed cytokeratins 8 and 18 and rat prostatic
      secretory markers (DP-1 and DP-2). The epithelial ducts were surrounded by well
      differentiated smooth muscle. The glandular epithelial cells were shown to be of
      rat origin. NRP-152 + 10T1/2 tissue recombinants formed small grafts (10-40 mg
      wet weight) after 1 month. The epithelial component of these grafts formed solid
      unbranched cords expressing cytokeratins 5 and 14; no glandular epithelial
      structures were observed. The stromal matrix was densely packed with a few cells
      expressing alpha-actin. CONCLUSIONS: A clonally derived prostatic epithelial cell
      line can form structurally and functionally normal prostatic tissue. This
      suggests that prostatic basal and luminal epithelial cells can be derived from a
      common progenitor.

PMID- 10334111
TI  - Bioimpedance: novel use of a minimally invasive technique for cancer localization
      in the intact prostate.
AB  - BACKGROUND: Prostate cancer is presently diagnosed by transrectal ultrasound
      (TRUS)-guided sextant needle biopsy. While echo texture of the tissue can prompt
      localization of tumor, it is presently imprecise. From 50-75% of men biopsied,
      based on an abnormal digital rectal examination (DRE) or elevated prostate
      specific antigen (PSA) level, have negative biopsy results. Improvements in tumor
      localization during TRUS-guided prostate biopsy are greatly needed. Bioimpedance
      is an electrical property of biologic tissue. Electric current is limited in
      living tissue by highly insulating cell membranes; however, different tissue
      architecture such as cancer may impede current differently and allow detection of
      differences between normal and abnormal or malignant prostate tissue. Our goal
      was to assess the utility of bioimpedance measurements in differentiating tumor
      from normal prostatic tissue in an ex vivo model. METHODS: Bioimpedance was
      measured in six ex vivo prostates, which were removed for clinically localized
      prostate cancer. Two bioimpedance needles, 1 mm apart, were inserted 3 mm into
      the posterior surface of the prostate an average of 16 times per gland.
      Frequencies ranging from 100 kHz-4 MHz were used to obtain 594 bioimpedance
      measurements from the six glands. These measurements were then correlated with
      histology to determine the presence or absence of prostate cancer. RESULTS:
      Prostate cancer was found to have a higher impedance, of 932+/-170 ohms, compared
      to areas of no cancer within the same prostate, 751+/-151 ohms, P < 0.0001, at 2
      MHz. This phenomenon was observed across all frequencies tested. CONCLUSIONS:
      This study demonstrates for the first time application of bioimpedance to
      distinguish areas of prostate cancer from areas of normal prostate. This
      technology may improve identification and localization of cancer within the
      prostate. Moreover, bioimpedance can potentially guide needle placement during
      prostate biopsy and thus improve sampling of tumors. Currently, our ex vivo model
      is limited by variables such as temperature and lack of blood flow. Further
      studies in an in vivo model will be needed to assess their effect.

PMID- 10334112
TI  - Cognitive impairment and intracranial calcification in chronic
      hypoparathyroidism.
AB  - BACKGROUND: Intracranial calcification is associated with chronic
      hypoparathyroidism. The relationship between intracranial calcification,
      neurological abnormalities and cognitive deficits in this disorder is unknown.
      The purpose of this study was to determine whether chronic hypoparathyroidism is
      associated with cognitive impairment. METHODS: We studied 11 hypoparathyroid
      patients and compared them with a sex-, age-, and education-matched control
      group. The hypoparathyroidism was postsurgical in nine and idiopathic in two. All
      patients underwent nonenhanced head computed tomography, detailed neurological
      examinations, and a battery of cognitive tests. These tests were performed
      separately and individual examiners were blinded to the results of the other
      components of the study. RESULTS: The mean age of the patients was 55 years; the
      duration of hypoparathyroidism was at least 9 years. Neuropsychological testing
      revealed cognitive impairment in 65% of hypoparathyroid subjects, and the
      presence of significant differences between the hypoparathyroid and control
      groups. Computed tomography showed intracranial calcification in 6 of 10
      hypoparathyroid subjects tested, and neurological (motor) examination revealed 5
      of 11 with abnormal findings. There were positive correlations between the
      presence of cognitive deficits and cerebral calcification (r = 0.59, P = 0.07),
      between abnormal motor findings and cerebral calcification (r = 0.77, P < 0.01)
      and between abnormal motor findings and the degree of cognitive deficit (r =
      0.83, P < 0.01). CONCLUSIONS: We conclude that cognitive and neurological
      deficits commonly occur in patients with chronic hypoparathyroidism and may be
      pathophysiologically related to the presence of intracranial calcification.

PMID- 10334113
TI  - Patients in the intensive care unit suffer from severe lack of sleep associated
      with loss of normal melatonin secretion pattern.
AB  - BACKGROUND: Patients hospitalized in the intensive care unit (ICU) tend to become
      agitated and confused, and many even develop temporary psychoses (the ICU
      syndrome). We wondered whether the regulation of sleep and the secretion of
      melatonin is abnormal in ICU patients. Therefore, we studied the association of
      sleep-wake pattern in patients hospitalized in the ICU, their melatonin secretion
      rates, and profile compared with a control group of patients in general medical
      wards. METHODS: Sleep was assessed by actigraphy. Urine was collected every 3
      hours for 24 hours. Melatonin secretion was assessed by measuring the melatonin
      metabolite 6-sulphatoxymelatonin by enzyme-linked immunosorbent assay. RESULTS:
      Actigraphy suggested that the ICU patients lacked normal sleep behavior for the
      entire study period, except for occasional short naps. Compared with controls,
      the nocturnal peak of melatonin secretion was absent, except in two patients in
      the nonventilated group, and showed a flat curve. CONCLUSIONS: Our results
      suggest that lack of sleep is indeed a severe problem in ICU patients and is
      accompanied by impairment of normal melatonin secretion. The possibility that
      melatonin administration may prove useful in improving sleep patterns in ICU
      patients deserves further study.

PMID- 10334114
TI  - Hepatic insulin clearance increases after weight loss in obese children and
      adolescents.
AB  - BACKGROUND: Obesity is a rapidly increasing health problem among US youth.
      Hyperinsulinemia is associated with obesity and has been found to be a
      contributory factor for the development of cardiovascular disease in the obese.
      It has been suggested that hyperinsulinemia of obesity is a result of increased
      insulin secretion caused by insulin resistance. However, it has been shown in
      adults that decreased hepatic insulin clearance (HIC) is the primary cause of
      hyperinsulinemia in this population. METHODS: We studied 15 obese children and
      adolescents (11 F, 4 M; 8.6 to 18.1 years) before and 10 weeks after their
      enrollment in a multidisciplinary weight reduction program, which included a
      protein-sparing modified fast, a moderate intensity progressive exercise program,
      and a behavior-modification intervention. RESULTS: All patients lost weight (P <
      0.05). Measurements of immunoreactive insulin (IRI) and C-peptide reactivity
      (CPR) were performed before the program and at 10 weeks. IRI levels dropped
      significantly, whereas CPR levels did not change. CPR/IRI molar ratios,
      considered an indirect estimation of HIC, rose significantly after weight loss.
      CONCLUSIONS: Our data suggest that hyperinsulinemia seen in obese children and
      adolescents is caused by decreased HIC. The cause for this decrease remains
      unknown, but it is reversible upon weight loss.

PMID- 10334115
TI  - Dietary compliance among salt-sensitive and salt-insensitive normotensive adults.
AB  - Little is known about the customary level of sodium intake by salt-sensitive
      people and the nature of obstacles they face in the adoption of a reduced-sodium
      diet. These issues were addressed with 12 salt-sensitive (SS) and 9 salt
      insensitive (SI) normotensive adults. Information about sodium consumption,
      taste, and blood pressure and concerns about following a diet reduced in sodium
      were collected at baseline and monthly while participants followed a 100 mmol
      Na/day diet for 4 months. Mean sodium intakes of both groups were comparable at
      baseline and were reduced significantly during diet. The principal dietary
      concerns were reduced food availability, increased food costs, and reduced food
      palatability. There were no group differences. Ratings declined over time, but
      only the food palatability issue did so significantly because of a shift by the
      SI only. While the predictive value of SS classification remains uncertain, these
      data indicate that dietary change is feasible in SS subjects.

PMID- 10334116
TI  - The exercise-induced oxidative stress paradox: the effects of physical exercise
      training.
AB  - BACKGROUND: Although physical exercise training is highly recommended, physical
      exercise causes oxidative stress, which is potentially injurious. This study
      evaluates this 'exercise paradox' by evaluating the effect of physical exercise
      on exercise-induced lipid peroxidation. METHODS: Measurement of lipid
      peroxidation (ie, expired ethane and pentane and plasma malondealdehyde) taken
      during cardiopulmonary exercise stress testing were compared between a group of
      10 cardiac patients who underwent physical exercise training in a cardiac
      rehabilitation setting and a group of 10 nonexercising cardiac patients. RESULTS:
      Our findings indicate that physical exercise training increased physical work
      capacity without a concomitant increase in expired markers of lipid peroxidation
      (ethane and pentane) and decreased malondealdehyde levels. CONCLUSIONS: Because
      physical exercise-trained people can perform more intense physical work with less
      oxidative stress, we conclude that physical exercise training can reduce
      potential chronic health effects associated with daily activities by contributing
      to an overall reduction in exercise-induced free radical production.

PMID- 10334118
TI  - Isoniazid drug and food interactions.
AB  - Isoniazid inhibits the metabolism of several drugs, resulting in clinically
      significant interactions in some patients. Clinical trials and case reports have
      documented that isoniazid can cause increased phenytoin and carbamazepine serum
      concentrations and toxicity. In relatively high doses, isoniazid can also cause
      increased effect of theophylline and warfarin. Isoniazid inhibits metabolism of
      selected benzodiazepines and vitamin D. Inhibition of monoamine oxidase and
      histaminase by isoniazid can cause significant drug-food interactions. Food
      greatly decreases isoniazid bioavailability. Although probably best recognized as
      an inhibitor of drug metabolism, isoniazid has a biphasic effect of inhibition
      induction on one cytochrome P450 isozyme, CYP2E1, which partially explains the
      interaction with acetaminophen and increased risk of hepatotoxicity. Continued
      investigations will likely result in discovery of new isoniazid interactions.

PMID- 10334117
TI  - Comparison of oral and tympanic temperatures in a Veterans Administration
      outpatient clinic.
AB  - BACKGROUND: To examine the accuracy of noncontact tympanic (NCT) temperatures in
      outpatients, we conducted a prospective study comparing NCT temperature with
      temperatures obtained by oral mercury thermometers. METHODS: The study included
      410 patients in whom oral and NCT temperatures were obtained. RESULTS: Mean oral
      temperature was 36.47 +/- 0.44 degrees C and mean NCT temperature was 36.36 +/-
      0.49 degrees C. On paired-sample, two-sided t-testing, oral temperature differed
      significantly from NCT temperature, with a P-value < 0.0001. The difference
      between simultaneous oral and NCT temperatures was > or = 1 degree F; in 63
      cases, oral temperature was higher than NCT temperature. CONCLUSION: We conclude
      that NCT temperature measurement is not reliable in an internal medicine
      outpatient clinic setting.

PMID- 10334119
TI  - New treatment strategies in patients with impaired left ventricular systolic
      function. Part II: Treatment of moderate to severe cardiac dysfunction.

PMID- 10334120
TI  - Cytomegalovirus retinitis in the era of highly active antiretroviral therapy
      (HAART).

PMID- 10334121
TI  - Nitrofurantoin-induced immune-mediated lung and liver disease.
AB  - A 60-year-old woman with multiple sclerosis and recurrent urinary tract
      infections (UTI) was evaluated for the recent onset of a dry cough, dyspnea on
      exertion, and jaundice. Investigation demonstrated interstitial lung disease with
      bilateral infiltrates and unilateral effusion, as well as a severe chronic active
      hepatitis with marked fibrosis. Other notable features were positive antinuclear
      antibodies and anti-smooth-muscle antibodies and the absence of any possible
      cause except for nitrofurantoin treatment (Macrodantin, 100 mg/day), which the
      patient had been taking for the previous 3 years as a prophylactic measure
      against UTI. The patient died of pneumococcal septicemia less than 30 days after
      presentation. Pulmonary or hepatic injury caused by nitrofurantoin treatment is
      rare; their combined occurrence is hardly ever described. Combined drug-induced
      pulmonary and hepatic toxicity is reviewed and should be considered early in the
      differential diagnosis to allow reversibility and avoid serious outcomes.

PMID- 10334122
TI  - Double heterozygosity for the codon beta 39 C-to-T nonsense mutation and a
      triplicate alpha-globin gene locus can cause "dominantly" inherited beta
      thalassemia intermedia.
AB  - BACKGROUND: A beta-thalassemia intermedia phenotype can be caused by multiple
      genotypes. METHODS: We studied a family where the mother was hematologically
      normal and both father and daughter had beta-thalassemia intermedia. RESULTS:
      Both affected individuals were heterozygous for a codon 39 CAG-to-TAG mutation.
      They also were heterozygous for a triplicate alpha-globin gene locus
      (alphaalphaalpha(anti 3.7)). CONCLUSIONS: This compound heterozygous condition of
      a beta39 C-to-T mutation and triplicate alpha-globin gene increases alpha:beta
      globin chain imbalance and accounts for the presence of beta-thalassemia
      intermedia. The proband received both an abnormal beta-globin gene and a
      triplicate alpha-globin locus from her father. Although the phenotype seems to be
      dominantly inherited, because of independent segregation of the alpha- and beta
      globin genes, it is more accurately an example of polygenic inheritance.

PMID- 10334123
TI  - Multiple endocrine neoplasia type 1 concomitant with Prader-Willi syndrome: case
      report and genetic diagnosis.
AB  - A case of multiple endocrine neoplasia type 1 (MEN 1) accompanied with Prader
      Willi syndrome (PWS) was reported. Diagnosis of both diseases have been
      genetically confirmed. Delay in the diagnosis and management for PWS made surgery
      for endocrine tumors difficult. This is the first report on the concomitance of
      MEN 1 with PWS.

PMID- 10334124
TI  - Massive intracerebral hemorrhage in an amphetamine addict.
AB  - A case of massive intracerebral hemorrhage, a rare but often fatal complication
      of amphetamine abuse, is described along with the review of the literature. There
      has been resurgence in the abuse of amphetamine. Amphetamine or other illicit
      drug abuse should be considered in young patients with cerebrovascular events.

PMID- 10334126
TI  - The results are not perfect.

PMID- 10334125
TI  - When physicians are not physicians.

PMID- 10334127
TI  - MEDLINE-induced blindness.

PMID- 10334128
TI  - Perioperative fluid therapy and postoperative pulmonary edema: cause-effect
      relationship?

PMID- 10334129
TI  - Acinetobacter baumannii infections in the ICU: customization is the key.

PMID- 10334130
TI  - Technique, complications, and improvements in percutaneous dilatational
      tracheostomy.

PMID- 10334131
TI  - Bronchial artery chemotherapy--a future?

PMID- 10334132
TI  - Lung cancer in patients < 50 years of age: the experience of an academic
      multidisciplinary program.
AB  - OBJECTIVE: To determine if the clinicopathologic features and survival of lung
      cancer patients < 50 years of age differ from those of older patients. DESIGN:
      Retrospective review of patients with primary bronchogenic carcinoma diagnosed at
      a single, multidisciplinary cancer center. SETTING: A National Cancer Institute
      designated comprehensive cancer center in urban Detroit, MI. PATIENTS: All
      patients with primary bronchogenic carcinoma evaluated in the Multidisciplinary
      Lung Cancer Clinic at the Barbara Ann Karmanos Cancer Institute between 1990 and
      1993. RESULTS: Of 1,012 patients with lung cancer, 126 (12.5%) were < 50 years
      old at diagnosis, with a median age of 44 years. The median age of the 886
      patients > or = 50 years of age was 65 years. The gender (p = 0.08) and racial (p
      = 0.12) characteristics of the younger and older patient groups were not
      significantly different. More than 90% of patients in both groups were smokers.
      The incidence of adenocarcinoma was significantly higher in younger patients
      (48.4% vs 36.0%, p < 0.001), and early-stage disease was less frequently
      diagnosed in younger patients (4.8% vs 19.7%, p < 0.001). Younger patients were
      more likely than older patients to undergo treatment, including surgery and
      combined-modality therapy (p < 0.001). Median survival was 13 months in younger
      and 9 months in older patients, while overall survival was similar in younger and
      older patients (p = 0.13). CONCLUSIONS: Although younger patients with lung
      cancer present with more advanced-stage disease, their overall survival is
      similar to that of older patients, suggesting that lung cancer is not an
      inherently more aggressive disease in patients < 50 years of age.

PMID- 10334133
TI  - Utility of transbronchial needle aspiration in the diagnosis of endobronchial
      lesions.
AB  - BACKGROUND: The utility of transbronchial needle aspiration (TBNA) in visible
      endobronchial lesions presenting as either an exophytic mass lesion (EML) or
      submucosal and peribronchial disease (SPD) is not well established. OBJECTIVE: To
      compare the yield of conventional diagnostic procedures (CDP) (bronchial washing,
      bronchial brushing, and endobronchial forceps biopsy) with that obtained from a
      combination of CDP and TBNA (CDP + TBNA). DESIGN: Prospective study of 55
      patients. SETTING: Tertiary-care referral hospital. RESULTS: Of the 55 patients
      in whom malignancy was confirmed, CDP + TBNA identified 53 (96%) vs 42 (76%)
      identified by CDP (p = 0.001). The highest yield from any individual procedure
      was obtained by TBNA. Of the 23 patients with SPD, 22 (96%) were diagnosed using
      CDP + TBNA compared with 15 (65%) by CDP (p = 0.016); the yield from TBNA alone
      (22 of 23) in this group surpassed the combined yield from all other procedures.
      Although no statistically significant difference in yield was observed for EML,
      the use of TBNA identified four additional patients compared with CDP.
      CONCLUSION: We conclude that the addition of TBNA to CDP increases diagnostic
      yield in patients with visible endobronchial lesions.

PMID- 10334134
TI  - B-cell pulmonary lymphoma: gene rearrangement analysis of bronchoalveolar
      lymphocytes by polymerase chain reaction.
AB  - STUDY OBJECTIVES: Non-Hodgkin's lymphomas (NHLs) are clonal proliferation of B or
      T lymphocytes. Assessment of clonality in lymphoid proliferations uses
      immunochemistry and, recently, molecular biology. The aim of our study is to
      assess the role of immunoglobulin gene rearrangement analysis on bronchoalveolar
      lymphocytes to aid in the diagnosis of B-cell pulmonary NHL. PATIENTS AND
      METHODS: The study took place in a university hospital. There were seven
      consecutive patients with B-cell-type pulmonary lymphoma and nine control
      subjects. Gene rearrangement analysis using polymerase chain reaction (PCR)
      technique was performed on alveolar lymphocytes recovered by BAL. RESULTS:
      Analysis of the immunoglobulin heavy chain gene rearrangement showed a
      predominant clonal alveolar lymphocyte population in six of seven patients while
      all control subjects showed germline pattern. CONCLUSIONS: Gene rearrangement
      analysis by PCR of alveolar lymphocytes would appear to be sensitive in patients
      with B-cell pulmonary NHL (six of seven patients) and specific (zero of nine in
      the control group). This simple test should be added only in the analysis of
      cells recovered by BAL in patients with suspected primary and secondary B-cell
      pulmonary NHL.

PMID- 10334135
TI  - The validity of medical history, classic symptoms, and chest radiographs in
      predicting pulmonary tuberculosis: derivation of a pulmonary tuberculosis
      prediction model.
AB  - STUDY OBJECTIVE: To improve the respiratory isolation policy for patients with
      suspected pulmonary tuberculosis (TB). DESIGN: Prospective, descriptive, French
      multicenter study. SETTING: Emergence of nosocomial outbreaks of TB. PATIENTS:
      All consecutive patients admitted with suspicion of pulmonary TB. MEASUREMENTS
      AND RESULTS: Medical history, social factors, symptoms, and chest radiograph
      (CXR) pattern (symptoms and CXR both scored as typical of pulmonary TB,
      compatible, negative, or atypical) were obtained on admission. Serial morning
      sputa were collected. Of the 211 patients, 47 (22.3%) had culture-proven
      pulmonary TB, including 31 (14.7%) with a positive smear. Mean age was 46.2
      years; 52 patients were HIV positive (24.6%). The sensitivity of the respiratory
      isolation policy was 71.4%, specificity was 51.7%, negative predictive value
      (NPV) was 88.2%, and positive predictive value (PPV) was 26.3%. On univariate
      analysis, predictive factors of culture-proven pulmonary TB were CXR (p <
      0.00001), symptoms (p = 0.0004), age (mean, 40.8 years for TB patients vs 47.5
      years for non-TB patients; p = 0.04), absence of HIV infection (89.4% vs 71.3%; p
      = 0.01), immigrant status (72% vs 55%; p = 0.03), and bacillus Calmette-Guerin
      status (p = 0.025). On multivariate analysis, CXR pattern (p < 0.00001), HIV
      infection (p = 0.002), and symptoms (p = 0.009) remained independently
      predictive. Based on these data, a model was proposed using a receiver operating
      characteristics curve. In the derivation cohort, the sensitivity and NPV of the
      model in detecting smear-positive pulmonary TB would have been 100%. The
      specificity and PPV would have been 48.4% and 25%, respectively. The model
      performed less well when evaluated on two retrospective groups, but its
      sensitivity remained above that of the current respiratory isolation policy
      (91.1% and 82.4% for the retrospective groups vs 71.1% for the current policy).
      CONCLUSIONS: Improved interpretation of clinical and radiologic data available on
      patient admission could improve adequacy of respiratory isolation. A prediction
      model is proposed.

PMID- 10334136
TI  - Clinical manifestations of Bordetella pertussis infection in immunized children
      and young adults.
AB  - STUDY OBJECTIVES: The incidence and prevalence of pertussis in adults have
      increased in recent years. It has been shown that previously immunized adults and
      adolescents are the main sources of transmission of Bordetella pertussis. The aim
      of this study was to describe the clinical presentation and the clinical course
      of pertussis in children and young adults who were immunized previously against B
      pertussis. DESIGN: Retrospective study. SUBJECTS: Children and young adults who
      were reported by local physicians to the Department of Epidemiology in the
      Israeli Ministry of Health with serologically confirmed pertussis and who were
      immunized previously were included. Information sought included personal data,
      epidemiologic data, signs and symptoms, laboratory results, initial diagnosis,
      and treatment. RESULTS: In the 95 previously immunized patients with
      serologically confirmed pertussis (mean age [+/- SD], 8.9 +/- 4.4 years old;
      range, 5 to 30 years old), the mean duration from onset of symptoms until the
      final diagnosis of pertussis was 23 +/- 15 days. The disease was usually atypical
      and generally mild. All the described patients had cough, usually prolonged,
      lasting 4 +/- 3.6 weeks. Only 6% had the classic whoop. The mean WBC count was
      8.7 +/- 2.6 cells/mm6, and the lymphocyte count was 40 +/- 12%. Two patients were
      admitted to the hospital for severe pneumonia. Among the reported cases, the
      proportion of patients between the ages of 10 and 45 years increased from 6.5%
      during the period from 1971 to 1980, to 26% during the period from 1980 to 1990,
      and to 38% during a 1989 outbreak. CONCLUSIONS: Pertussis in previously immunized
      individuals is usually characterized by an atypical and relatively mild clinical
      course. Patients suffer mainly from a prolonged and persistent cough. Early
      diagnosis may lead to prompt administration of therapy. Prophylaxis of exposed
      persons might be effective in decreasing both severity and transmission of the
      disease.

PMID- 10334137
TI  - The association between occupation and asthma in general medical practice.
AB  - BACKGROUND: In general practice settings, the proportion of adult asthma
      attributable to occupational factors is not known. OBJECTIVE: The goal of this
      study was to estimate the proportion of adult asthma cases that can be attributed
      to occupational factors initiating new disease onset and exacerbating preexisting
      disease. METHODS: We performed a cross-sectional analysis of interview data for
      150 adults with asthma recruited from a random sample of family practice
      specialists. We ascertained the asthma and work histories of the subjects and
      estimated the proportion with likely work-initiated asthma and work-related
      asthma recrudescence. RESULTS: Seventy-four subjects (49%) reported adult-onset
      asthma while employed; an additional 25 (17%) reported recrudescence of
      previously quiescent childhood-onset asthma during employment. Of those with new
      onset asthma while employed, 15 (10% of the study group; 95% confidence interval,
      5 to 15%) were employed in occupations at increased risk of occupational asthma
      initiation on the basis of an independent job scoring matrix. Of those with
      asthma recrudescence in adulthood, seven (5% of the study group; 95% confidence
      interval, 2 to 8%) were employed in occupations at increased risk of exposures
      aggravating asthma. CONCLUSIONS: Among adults with asthma treated in general
      practice settings, > 1 in 10 patients has a work history strongly suggestive of a
      potential relationship between exposure and disease.

PMID- 10334138
TI  - Validation of a standardized version of the Asthma Quality of Life Questionnaire.
AB  - BACKGROUND: In the original 32-item Asthma Quality of Life Questionnaire (AQLQ),
      five activity questions are selected by patients themselves. However, for long
      term studies and large clinical trials, generic activities may be more
      appropriate. METHODS: For the standardized version of the AQLQ, the AQLQ(S), we
      formulated five generic activities (strenuous exercise, moderate exercise, work
      related activities, social activities, and sleep) to replace the five patient
      specific activities in the AQLQ. In a 9-week observational study, we compared the
      AQLQ with the AQLQ(S) and examined their measurement properties. Forty
      symptomatic adult asthma patients completed the AQLQ(S), the AQLQ, the Medical
      Outcomes Survey Short Form 36, the Asthma Control Questionnaire, and spirometry
      at baseline, 1, 5, and 9 weeks. RESULTS: Activity domain scores (mean +/- SD)
      were lower with the AQLQ (5.7 +/- 0.9) than with the AQLQ(S) (5.9 +/- 0.8; p =
      0.0003) and correlation between the two was moderate (r = 0.77). However, for
      overall scores, there was minimal difference (AQLQ, 5.4 +/- 0.8; AQLQ(S), 5.5 +/-
      0.8; r = 0.99). Reliability (AQLQ intraclass correlation coefficient, 0.95;
      AQLQ(S) intraclass correlation coefficient, 0.96) and responsiveness (AQLQ, p <
      0.0001; AQLQ(S), p < 0.0001) were similar for the two instruments. Construct
      validity (correlation with other measures of health status and clinical asthma)
      was also similar for the two instruments. CONCLUSIONS: The AQLQ(S) has strong
      measurement properties and is valid for measuring health-related quality of life
      in asthma. The choice of instrument should depend on the task at hand.

PMID- 10334139
TI  - A randomized controlled trial on the effect of inhaled corticosteroids on airways
      inflammation in adult cigarette smokers.
AB  - STUDY OBJECTIVE: To determine whether inhaled corticosteroid treatment can reduce
      airways inflammation in adult cigarette smokers. DESIGN: This was a randomized,
      placebo-controlled, double-blinded clinical trial. SETTING: The subjects were
      recruited from the community by advertising. PARTICIPANTS: Seventy-one adults
      with a > or = 5 pack-year history who were current smokers, had a normal FEV1,
      and produced sputum daily. INTERVENTION: Sixty subjects were randomized to
      receive four puffs of placebo or beclomethasone dipropionate ([BDP]; total
      dosage, 1,000 microg/d) using a metered-dose aerosol inhaler with a valved
      holding chamber (AeroChamber; Trudell Medical; London, Ontario, Canada) for 28
      days. MEASUREMENTS AND RESULTS: Eleven subjects were not randomized because of
      poor compliance. The primary outcome was fractional airway neutrophilia, as
      assessed by a differential cell count of sputum. Additional outcome measures were
      spirometry, measurement of airway responsiveness by methacholine challenge, and
      lung epithelial permeability measured by the clearance of radiolabeled
      diethylenetriamine pentaacetic acid. There were no significant differences
      between the two groups in any outcome measurement after 4 weeks of treatment.
      CONCLUSIONS: With normal spirometry, we found no benefit of treatment with
      inhaled BDP, 1,000 microg/d, on noninvasive measures of airways inflammation in
      adult smokers. This indicates that cigarette smoke-induced inflammation in its
      early stages (before a demonstrable airflow obstruction) is not steroid
      sensitive. This may occur because the site of involvement is not accessible to
      inhaled medications or because the inflammatory process is resistant to moderate
      doses of inhaled corticosteroids.

PMID- 10334140
TI  - Systemic bioavailability and potency of high-dose inhaled corticosteroids: a
      comparison of four inhaler devices and three drugs in healthy adult volunteers.
AB  - OBJECTIVES: To compare the systemic bioavailability (assessed by cortisol
      suppression) of high-dose budesonide when given by four inhaler devices and
      orally. Also studied are the relative systemic potencies of three inhaled
      steroids (budesonide, fluticasone propionate, and beclomethasone dipropionate)
      when given by metered-dose inhaler (MDI) with a large volume spacer. DESIGN:
      Double-blind, crossover, placebo-controlled trial. PARTICIPANTS: Sixteen healthy,
      steroid-naive adult volunteers. METHODS: On separate occasions, each subjects
      took 4 mg of budesonide through the following devices: MDI alone, MDI with 750
      mL. spacer, dry-powder inhaler and nebulizer; 4 mg of budesonide was also taken
      orally to assess the effects of GI absorption. For the drug comparison, each
      subject took 4 mg of budesonide, fluticasone, and beclomethasone, and 2 mg of
      budesonide and fluticasone by MDI and spacer. RESULTS: Greatest percent
      suppression (95% confidence interval) of 9:00 AM cortisol with budesonide was
      observed with MDI alone (73% [57 to 90]) and turbohaler (72% [58 to 86]) compared
      with MDI spacer (42% [22 to 64]) and oral administration (14% [+6- to -34]).
      Nebulized budesonide produced an insignificant rise in 9:00 AM cortisol level.
      The most suppressive drug (given by MDI spacer) was fluticasone at 4 mg (86% [82
      to 91]) and at 2 mg (72% [59 to 85]). The least suppressive drug was budesonide
      at 4 mg (43% [22 to 64]) and at 2 mg (25% [3 to 47]). The effects of 4 mg of
      beclomethasone were intermediate (66% [49 to 82%]). CONCLUSIONS: The choice of
      delivery device for administration of budesonide can lead to important
      differences in systemic bioavailability. Fluticasone has greater systemic potency
      than budesonide or beclomethasone when given at microgram equivalent dosage. The
      systemic potency ratio of fluticasone propionate to budesonide in normal human
      volunteers in the present study is similar to the therapeutic potency ratio of
      the drug in asthmatic patients (approximately 2:1).

PMID- 10334141
TI  - Reduction in ventilator response to CO2 with relaxation feedback during CO2
      rebreathing in normal adults.
AB  - BACKGROUND: Previous studies have shown that relaxation biofeedback reduced time
      on the ventilator for the difficult-to-wean patients. OBJECTIVE: To test the
      hypothesis that the underlying mechanism of biofeedback ventilator weaning was
      the reduction of neural respiratory drive (NRD). DESIGN: Prospective, linear
      regression analysis. SETTING: Critical care medicine department in tertiary
      health care hospital. SUBJECTS: Fifteen healthy adult volunteers were randomly
      assigned to the biofeedback group, and 15 healthy adult volunteers were randomly
      assigned to a control group. INTERVENTIONS: Relaxation feedback was administered
      while a single variable, PaCO2, was inputted to the respiratory control system
      and the output measured. While rebreathing 7% CO2/93% O2, the biofeedback group
      received a baseline session and a relaxation feedback session and the control
      group received a baseline session and a no feedback session. MEASUREMENTS AND
      RESULTS: During relaxation feedback, there was a significant (p < 0.001 to p <
      0.05) reduction in the slope of minute ventilation (VI), mean inspiratory flow
      (VT/TI), occlusion pressure in 0.1 s from onset of inspiration (P100),
      respiration rate (RR), and diaphragm (DA) EMG compared to baseline. We also found
      the above breathing parameters decreased significantly for relaxation feedback (p
      < 0.001-0.05), compared to baseline, at maximum end-tidal CO2 (64 +/- 1.2 mm Hg)
      (all data are expressed as mean +/- SE). The decrease for VI = -4.65 +/- 1.17
      L/min, DA EMG = -0.4 +/- 0.21 microV, P100 = -1.13 +/- 0.56 cm H2O, VT/ TI = -144
      +/- 82.91 ml/s, and RR = -3.1 +/- 0.79 breaths/min. No significant changes
      occurred in these parameters for the control group. CONCLUSIONS: We conclude that
      the addition of the behavioral input of relaxation feedback results in decreasing
      the values of respiratory parameters that reflect NRD.

PMID- 10334143
TI  - Antifungal prophylaxis during the early postoperative period of lung
      transplantation. Valencia Lung Transplant Group.
AB  - INTRODUCTION: Fungal infections occur frequently in lung transplant patients,
      with the highest risk being in the early postoperative period (the initial
      hospitalization after lung transplantation). Aspergillus is responsible for more
      than half of all fungal infections, and Aspergillus has even been considered a
      contraindication for lung transplantation because of its difficult therapy and
      frequently fatal outcome. The aim of this article is to evaluate the success of
      an antifungal prophylaxis protocol to prevent fungal infection in the immediate
      postoperative period in lung transplant recipients. MATERIAL AND METHODS: From
      March 1994 to March 1997, we performed 52 lung transplants in 31 men and 21 women
      who received antifungal prophylaxis with fluconazole, 400 mg/d, and aerosolized
      amphotericin B, 0.6 mg/kg/d, during the postoperative period. RESULTS: The mean
      (+/- SD) postoperative period duration was 49 +/- 27.5 days. No fungal infections
      were observed during this period, and all patients provided negative cultures. We
      also found no toxicity related to antifungal drugs. The dose of cyclosporine was
      easily adjusted in every recipient according to blood levels so that effective
      immunosuppression was not compromised. DISCUSSION: In our study, the removal of
      the lungs and antifungal prophylaxis with fluconazole and aerosolized
      amphotericin B prevented fungal infection in the postoperative period in all 52
      lung transplant recipients.

PMID- 10334142
TI  - Ventilatory drive at rest and perception of exertional dyspnea in severe COPD.
AB  - BACKGROUND: The reasons for exertional dyspnea in severe COPD are not well
      established, but they are not solely related to the mechanical load. We tested
      the hypothesis that breathlessness may be determined, in part, by the response of
      an individual's central output. METHODS: In 26 patients with severe COPD (FEV1 <
      50% predicted) and 22 matched control subjects, we assessed at rest the
      ventilatory and mouth occlusion pressure (P0.1) response to hyperoxic progressive
      hypercapnia. At rest and during a symptom-limited exercise test, routine
      cardiopulmonary variables were measured, and respiratory muscle function was
      evaluated using esophageal and gastric pressure. Dyspnea was assessed with a
      visual analog scale. RESULTS: Dyspnea with or without leg discomfort limited
      exercise in 73% of patients. Peak exercise dyspnea correlated only with dyspnea
      at rest (r = 0.5, p < 0.008) and P0.1 response to CO2 (deltaP0.1/delta[end-tidal
      PCO2]PETCO2) (r = 0.48, p = 0.02). Multiple regression analysis including resting
      and exercise data as independent variables revealed that 47% of the variance for
      dyspnea at peak exercise was explained by a model including dyspnea at rest and
      deltaP0.1/deltaPETCO2. Again, deltaP0.1/deltaPETCO2 was the only predictor for
      the change in dyspnea from rest to peak exercise (delta Dyspnea, r2 = 0.28, p =
      0.005). There was no correlation between exercise dyspnea and any metabolic
      variable, pulmonary function, or respiratory muscle function test. CONCLUSION: In
      severe COPD, exertional dyspnea is not simply related to respiratory muscle load
      or mechanical impairment, but also to an individual's central motoneural output
      to the respiratory system.

PMID- 10334144
TI  - Ventilatory and diffusion abnormalities in long-term survivors after orthotopic
      heart transplantation.
AB  - OBJECTIVE: To investigate the long-term development of pulmonary diffusion
      abnormalities after orthotopic heart transplantation (oHT). DESIGN: Retrospective
      analysis of pulmonary function test results of different patient groups at
      different time intervals after oHT was performed. PATIENTS: This investigation
      included 642 patients who had undergone oHT for chronic heart failure. Patients
      were grouped according to the time elapsed after transplantation (group 1: n =
      164; age, 47 +/- 14 years; days after oHT, 324 +/- 101; group 2: n = 100; age, 48
      +/- 15 years; days after oHT, 723 +/- 104; group 3: n = 106; age, 52 +/- 12
      years; days after oHT, 1,092 +/- 98; group 4: n = 84; age, 51 +/- 13 years; days
      after oHT, 1,442 +/- 99; group 5: n = 61; age, 50 +/- 14 years; days after oHT,
      1,819 +/- 105; group 6: n = 101; age, 53 +/- 12 years; days after oHT, 2,463 +/-
      303; and group 7: n = 26; age, 54 +/- 14 years; days after oHT, 3,478 +/- 246).
      In 56 (group 8) of the 642 patients, follow-up measurements were performed with
      tests before and at two time points after oHT (6.5 +/- 1.7 and 12.5 +/- 9.3
      months). RESULTS: Of all patients, 39% showed restrictive and obstructive
      abnormalities with no differences between the groups. No significant differences
      in lung transfer factor for carbon monoxide (DLCO) were observed (61.2 vs 63.7 vs
      65.5 vs 65.6 vs 64.5 vs 65.7 vs 67.6% predicted). Differences in transfer
      coefficient for carbon monoxide (Kco) were significant between group 1 and 4
      (58.7 vs 64.1% predicted), and group 1 and 6 (58.7 vs 63.4% predicted). No
      differences occurred in the rate with which patients exhibited pathologic
      abnormalities for DLCO and KCO. After oHT, a marked reduction in diffusion
      capacity occurred in group 8. On follow-up, these measurements were only slightly
      restored in terms of the predicted DLCO percentage. No such improvement was
      observed in KCO or in the rate of pathologic changes for both DLCO and KCO. We
      conclude, therefore, that the impairment of diffusion does not improve even after
      a significant period has passed after the oHT. Whether this has any effect on
      symptoms and/or the prognosis for these patients is extremely unclear.

PMID- 10334145
TI  - Empyema complicating successful lung transplantation.
AB  - OBJECTIVE: To assess the prevalence and etiology of empyema complicating
      successful lung transplantation. DESIGN: Retrospective review. SETTING:
      University medical center transplant service. PATIENTS: All recipients (n = 392)
      of single-lung, double-lung, and heart-lung transplantation between May 1984 and
      April 1997. RESULTS: Of the 392 transplant recipients, empyema was documented in
      14 patients (3.6%) at a mean time (+/- SD) of 46 days after transplantation
      (range, 14 to 167 days). Of these 14 recipients with empyema, 4 recipients
      (28.6%) died of infectious complications related to empyema. Empyema was seen
      secondary to Gram-positive, Gram-negative, and saprophytic organisms; however,
      there was no predominance of a particular organism recovered from the empyemic
      fluid (chi2 = 0.53; p = 0.75). The development of empyema was not related to
      whether the transplant was performed secondary to a septic or nonseptic lung
      disorder (chi2 = 1.06; p = 0.67), nor was it related to the type of transplant
      procedure performed (ie, single-lung, double-lung, or heart-lung allografts; chi2
      = 4.39; p = 0.30). CONCLUSION: Empyema, a relatively uncommon complication of
      lung transplantation, is not related to the type of allograft received or to
      whether the recipient had a septic or a nonseptic lung disorder. If empyema does
      occur, the mortality associated with this infection is substantial.

PMID- 10334146
TI  - Determination of hemoglobin saturation in patients with acute sickle chest
      syndrome: a comparison of arterial blood gases and pulse oximetry.
AB  - STUDY OBJECTIVES: To evaluate three different methods of measuring oxygen
      saturation in patients suffering from acute sickle chest syndrome. DESIGN: A
      prospective, descriptive study of 9 months' duration. SETTING: A tertiary care
      university hospital. PATIENTS: Adult patients with acute sickle chest syndrome
      scheduled to undergo RBC exchange transfusion. INTERVENTIONS: None. MEASUREMENTS:
      Baseline hemoglobin oxygen saturation was determined simultaneously by (1)
      calculation based on PaO2 and an oxyhemoglobin dissociation curve algorithm, (2)
      co-oximetry, and (3) pulse oximetry. These same measures were repeated after
      exchange transfusion. Baseline and postexchange hemoglobin electrophoresis was
      performed in all patients. RESULTS: Baseline calculated saturation overestimated
      true saturation (determined by co-oximetry) with a baseline mean bias (co
      oximetry minus calculated saturation) of -6.78 +/- 2.63% (95% confidence interval
      for bias: -8.37% to -5.19%). Pulse oximetry was not different than co-oximetry at
      baseline with a baseline bias of +1.86 +/- 3.25% (95% confidence interval: -0.1%
      to 3.82%). After exchange transfusion, there was no bias between either co
      oximetry and calculated saturation (mean difference: -0.17 +/- 1.31% [95%
      confidence interval: -0.95% to 0.61%]), or co-oximetry and pulse oximetry (mean
      difference: +0.3 +/- 1.53% [95% confidence interval: -0.62% to 1.22%]).
      CONCLUSIONS: Calculated saturation overestimates true saturation during acute
      sickle chest syndrome. This discrepancy abates after exchange transfusion. Pulse
      oximetry more closely follows co-oximetry than does calculated saturation during
      acute sickle chest syndrome.

PMID- 10334147
TI  - Pulmonary hypertension and cardiac function in adult cystic fibrosis: role of
      hypoxemia.
AB  - STUDY OBJECTIVES: To determine (1) the prevalence of pulmonary hypertension and
      cardiac dysfunction in adult cystic fibrosis (CF) patients with severe lung
      disease, (2) the relationship between these cardiovascular abnormalities and
      hypoxemia, and (3) the impact of subclinical pulmonary hypertension on survival.
      DESIGN: Single-blind, cross-sectional study. SETTING: Ambulatory clinic of the
      Adult CF program at a tertiary-level hospital. PATIENTS: Clinically stable
      patients with severe lung disease (FEV1 < 40% of predicted normal value) who were
      not receiving supplemental oxygen. A second cohort of patients in stable
      condition with less severe lung disease (FEV1 40 to 65% predicted) was also
      recruited to enable multivariate analysis for the determinants of pulmonary
      hypertension. MEASUREMENTS AND RESULTS: Eighteen patients with severe lung
      disease (FEV1 28 +/- 7% of predicted normal value) were initially studied. Each
      patient had overnight polysomnography, pulmonary function tests, and Doppler
      echocardiography. Arterial oxygen saturation (SaO2) was reduced during
      wakefulness (87.1 +/- 6.1%) and fell during sleep (84.0 +/- 6.6%) while
      transcutaneous PCO2 was normal during wakefulness (41.1 +/- 6.9 mm Hg) and
      increased during sleep (46.6 +/- 4.7 mm Hg). Left ventricular size, systolic
      function, and diastolic function were normal except in one patient who had had a
      previous silent myocardial infarction due to coronary artery disease. Qualitative
      assessment of right ventricular function was normal in all patients. Pulmonary
      artery systolic pressure (PASP) was increased (> 35 mm Hg) in seven patients
      without clinical evidence of cor pulmonale. Regression analysis was performed by
      combining these data with data from an additional 15 CF patients with moderately
      severe lung disease (FEV1 56.3 +/- 8.9% predicted normal) who were recruited to a
      modified study protocol that included overnight oximetry, pulmonary function
      tests, and Doppler echocardiography. None of these patients had evidence of
      hypoxemia and only three had mild elevation of PASP (36, 37, and 39 mm Hg).
      Linear regression analysis revealed that PASP was significantly correlated with
      FEV1 (r = -0.44; p = 0.013), and SaO2 during wakefulness (r =-0.60; p = 0.0003),
      during sleep (r = -0.56; p = 0.0008), and after 6 min of exercise (r = -0.75; p <
      0.0001). Multivariate analysis revealed that awake SaO2 was a significantly
      better predictor of PASP than FEV1 (p = 0.0104). Clinical follow-up of the
      original cohort for up to 5 years revealed that mortality was significantly
      higher in those with pulmonary hypertension than those without pulmonary
      hypertension (p = 0.0129). CONCLUSIONS: In adult CF patients with severe stable
      lung disease, left and right ventricular function is well maintained in the
      absence of significant coronary artery disease; pulmonary hypertension develops
      in a significant proportion of patients and is strongly correlated with oxygen
      status, independent of lung function; and subclinical pulmonary hypertension is
      associated with an increased mortality.

PMID- 10334148
TI  - Leukocytosis in acute pulmonary embolism.
AB  - PURPOSE: The purpose of this investigation is to assess the level of leukocytosis
      in acute pulmonary embolism (PE). BACKGROUND: Limited data exist regarding
      leukocytosis in acute PE. One reason that the prevalence of leukocytosis in acute
      PE is unknown, despite an extensive number of investigations of PE, may relate to
      the fact that acute PE is usually associated with other conditions that
      themselves may cause leukocytosis. METHODS: Hospital records of 386 patients with
      a diagnosis of acute PE were reviewed retrospectively. Patients with no other
      possible or definite cause of leukocytosis were analyzed separately. A diagnosis
      of PE was made by a high-probability interpretation of the ventilation/perfusion
      lung scan or pulmonary angiogram. RESULTS: Among patients with PE in whom other
      possible or defined causes for leukocytosis were eliminated, 52 of 266 (20%) had
      a WBC count > 10,000/mm3. None had a WBC count that was > or = 20,000/mm3.
      Patients with the pulmonary hemorrhage/infarction syndrome had an increased WBC
      count in 32 of 183 (17%) vs 20 of 83 (24%) in patients who did not have pulmonary
      hemorrhage/infarction syndrome (not significant). CONCLUSION: A modest
      leukocytosis may accompany (and possibly be caused by) PE. Its presence should
      not dissuade the clinician from objectively pursuing the diagnosis of PE.

PMID- 10334149
TI  - Accuracy of respiratory inductive plethysmography for the diagnosis of upper
      airway resistance syndrome.
AB  - OBJECTIVE: To determine the sensitivity and specificity of quantitative
      respiratory inductive plethysmography (RIP) compared with the "gold standard,"
      nocturnal esophageal pressure (Pes) measurement, in the diagnosis of upper airway
      resistance syndrome (UARS) in adults. METHODS: Fourteen consecutive patients
      without obstructive sleep apnea and suspected of having UARS underwent
      simultaneous measurement of Pes with a catheter and standard nocturnal
      polysomnography along with RIP. UARS events (RERAs, respiratory effort-related
      arousals) were identified by observing crescendo changes in Pes with a Pes nadir
      < or = -12 cm H2O, followed by an arousal or microarousal. UARS was defined as >
      or = 10 RERAs per hour. For each patient, the ratio of peak inspiratory flow to
      mean inspiratory flow (PIFMF) measured by RIP was performed during quiet
      wakefulness and with 40 randomly selected breaths in the supine position for two
      conditions: stage 2 sleep, immediately prior to arousals in any sleep stage. The
      mean PIFMF (wake-sleep) was calculated for each condition. RESULTS: The
      sensitivities and specificities, respectively, of RIP to distinguish UARS
      patients from non-UARS patients are from stage 2 sleep (67%, 80%), immediately
      prior to arousals (100%, 100%). For breaths occurring immediately prior to
      arousals, the mean PIFMF (wake-sleep) is > or = 0.13 for UARS patients and < 0.13
      for non-UARS patients. CONCLUSION: The PIFMF measured by RIP allows for the most
      accurate identification of UARS patients when breaths are selected for analysis
      immediately prior to arousals.

PMID- 10334150
TI  - Effect of ipratropium bromide treatment on oxygen saturation and sleep quality in
      COPD.
AB  - STUDY OBJECTIVES: Patients with COPD are at risk of experiencing a deterioration
      in arterial oxygen saturation (SaO2) during sleep, which is generally most
      pronounced during rapid eye movement (REM) sleep. Increased cholinergic tone has
      been suggested as a contributing factor to this decrease in SaO2. Therefore, we
      investigated whether 4-week treatment with ipratropium bromide inhalation
      solution 0.02% (qid) could improve sleep characteristics in COPD. DESIGN:
      Randomized, placebo-controlled, double-blind, two-arm parallel study of 4 weeks
      of treatment with ipratropium bromide solution or placebo. SETTING: Multicenter
      investigation. PATIENTS: Thirty-six patients with moderate-to-severe COPD (FEV1 <
      65% of predicted). MEASUREMENTS AND RESULTS: Evaluation included
      polysomnographic, pulmonary function, and subjective quality of sleep (visual
      analog scale [VAS]) assessments. It was found that 4 week of treatment with
      ipratropium bromide solution in patients with COPD led to the following: (1) a
      significant (p = 0.05) improvement in mean nocturnal SaO2 with the more severe
      the nocturnal desaturation, the greater the improvement in SaO2; (2) significant
      (p = 0.03) improvement in perceived sleep quality (VAS: 5.5 +/- 0.5 after
      placebo; 7.2 +/- 0.5 after ipratropium); (3) a significant (p = 0.05) increase in
      REM sleep time (48.6 +/- 6.3 min after placebo; 66.5 +/- 6.4 min after
      ipratropium) with no effect on other sleep stages or total sleep time; and (4) a
      significant (p = 0.01) increase in pre-sleep FVC and flow rate at 50% of the
      vital capacity. CONCLUSIONS: These findings demonstrate that ipratropium bromide
      therapy can improve sleep SaO2 as well as sleep quality in patients with moderate
      to-severe COPD.

PMID- 10334151
TI  - Immunoglobulins and cellular constituents of the BAL fluid of patients with
      sulfur mustard gas-induced pulmonary fibrosis.
AB  - STUDY OBJECTIVE: The acute heavy exposure to sulfur mustard gas can lead to
      pulmonary fibrosis (PF). This study was performed to determine the cellular and
      protein content of BAL fluid in 24 patients with sulfur mustard gas-induced PF.
      PATIENTS: Twenty-four veterans with sulfur mustard gas-induced PF and 18
      nonexposed veterans serving as control subjects were enrolled into the study.
      MEASUREMENTS: Chest roentgenograms, pulmonary function tests (PFTs), tests for
      carbon monoxide diffusing capacity of the lung (DLCO), high-resolution CT scans
      of the chest, BAL via fiberoptic bronchoscopy, analyses of BAL fluids for
      cellular and protein constituents, and determinations of serum albumin and Ig
      levels were performed in all cases. A transbronchial lung biopsy was done in all
      patients following BAL. RESULTS: Neutrophilic alveolitis was the predominant
      feature. Neutrophils (p = 0.0001) and eosinophils (p = 0.0001) were the
      predominant cell types in the BAL fluid of patients with PF. There was a strong
      correlation between the BAL fluid neutrophil count (p = 0.76; p = 0.0003) or its
      percentage (p = 0.77; p = 0.0003) and the degree of fibrosis. Of the BAL fluid Ig
      levels, only the IgG level in the study group was significantly higher than the
      IgG level of the control group (p = 0.0001). Of the PFT physiologic parameters,
      only the percentage of DLCO showed a significant correlation with the degree of
      fibrosis (p = -0.76; p < 0.001). CONCLUSION: The cellular constituents of BAL
      fluid in patients with sulfur mustard gas-induced PF are very similar to the
      cellular constituents seen in patients with idiopathic PF, and this finding
      indicates the presence of an ongoing active alveolitis in PF.

PMID- 10334152
TI  - Exhaled nitric oxide is increased in active fibrosing alveolitis.
AB  - STUDY OBJECTIVES: Interstitial inflammation is a major aggravating factor in
      fibrosing lung disease associated with scleroderma (FASSc) and cryptogenic
      fibrosing alveolitis (CFA). Exhaled nitric oxide (NO) production is increased in
      asthma and bronchiectasis and reflects the degree of inflammation. We
      investigated whether measuring levels of exhaled NO is valuable in assessing
      disease activity in patients with CFA and patients with FASSc. MEASUREMENTS AND
      RESULTS: NO levels were measured in 11 patients with CFA (mean age +/- SEM, 58 +/
      12 years old; 5 were male) and 17 patients with FASSc (mean age, 48 +/- 9 years
      old; 5 were male), and they were compared to BAL cell counts and lung function.
      Patients with CFA and FASSe had elevated NO levels (11.2 +/-1.0 parts per billion
      [ppb] and 9.8 +/- 1.0 ppb, respectively; p > 0.05), whereas in a group of 13
      nonsmoking normal subjects, the NO levels were not elevated (6.9 +/- 0.5 ppb; p <
      0.05). Patients with FASSc (n = 8) who had active BAL (defined as either
      lymphocytes > 14%, neutrophils > 4%, or eosinophils > 3%) had significantly
      higher NO levels (13.2 +/- 1.8 ppb), and neutrophil (16.5 +/- 4.0%) and
      lymphocyte (26.8 +/- 3.4%) BAL cell counts than did patients with FASSc who had
      inactive BAL (6.7 +/- 1.2 ppb; 1.3 +/- 1.0% and 7.5 +/- 1.3%, respectively; p <
      0.05). There was a significant correlation between exhaled NO and lymphocyte cell
      count in patients with FASSc (r = 0.58; p < 0.05). All patients with CFA had
      active BAL; however, those treated with corticosteroids (12.9 +/- 1.0% ppb, p <
      0.05) had lower NO levels (9.0 +/- 1 ppb) and higher BAL lymphocyte cell couits
      (16.6 +/- 2.0%) than did those not treated with corticosteroids (7.2 +/- 1.7%; p
      < 0.05). CONCLUSIONS: We conclude that exhaled NO may be a useful addition to BAL
      cell counts in disease monitoring.

PMID- 10334153
TI  - Tracheobronchial foreign bodies: presentation and management in children and
      adults.
AB  - STUDY OBJECTIVES: To compare the clinical and management aspects of
      tracheobronchial aspirated foreign body (AFB) removal in children and adults; to
      assess the influence of the operator's experience on the outcome of the
      procedure. DESIGN: A retrospective review of a 20-year experience (from 1976 to
      1996). SETTING: A 900-bed university hospital. PATIENTS: Eighty-four children up
      to 8 years old (the child group) and 28 adult patients (the adult group).
      RESULTS: The peak incidence of foreign body aspiration occurred during the second
      year of life in the child group and during the sixth decade in the adult group.
      The symptoms at presentation were similar in both age groups, but the diagnosis
      was significantly delayed in the adults. The AFBs were lodged preferentially in
      the right bronchial tree only in the adults; a central location was predominant
      (but not at all exclusive) in the children. Atelectasis was more common in the
      adults, and air trapping was more common in the children. The most frequent
      procedure was rigid bronchoscopy; when a flexible bronchoscope was used, it was
      always in the adult patients. When the operator was less experienced, a failed
      first attempt at bronchoscopy and the need for a second procedure were
      significantly more frequent. CONCLUSIONS: At presentation, the symptoms seen with
      AFBs do not differ according to the age of the patient; however, the delay to
      diagnosis, the location of the AFBs, and the radiographic images differ between
      child and adult populations. The removal of AFBs in patients of all ages can be
      performed by the same operators. Because the outcome associated with these
      procedures improves when the operator is experienced, the removal of AFBs should
      be performed in medical centers that are capable of acquiring and maintaining the
      necessary expertise.

PMID- 10334154
TI  - Thrombocytopenia in a surgical ICU.
AB  - STUDY OBJECTIVES: To assess the incidence of thrombocytopenia in surgical ICU
      patients, the factors associated with thrombocytopenia, the outcome of
      thrombocytopenic patients, and the possible mechanisms involved. DESIGN:
      Prospective study. SETTING: An 8-bed surgical ICU in an 885-bed teaching
      hospital. PATIENTS: 147 consecutive patients admitted to the surgical ICU during
      a 6-month period. MAIN OUTCOME MEASURES: Incidence of thrombocytopenia (defined
      by a platelet count < 100,000/mm3), risk factors for thrombocytopenia, or death
      in thrombocytopenic patients identified by a stepwise logistic regression
      analysis, as well as the mechanisms involved. RESULTS: Thrombocytopenia occurred
      in 52 patients (35%) with a mortality rate of 38%, compared with a 20% mortality
      rate in nonthrombocytopenic patients (p = 0.02). Sepsis, episodes of bleeding or
      transfusions, and an acute physiology and chronic health evaluation (APACHE) II
      score of > 15 were the independent risk factors identified for thrombocytopenia.
      The correction of thrombocytopenia was a protective factor reducing the risk of
      mortality in thrombocytopenic patients. Disseminated intravascular coagulation
      was found in 40% of thrombocytopenic patients, elevated platelet-associated IgG
      in 33%, and hemophagocytic histiocytes in 67%. Combinations of two of these
      mechanisms were demonstrated in one quarter of thrombocytopenic patients.
      CONCLUSIONS: Sepsis was the major independent risk factor identified.
      Thrombocytopenic patients had a higher ICU mortality due to the severity of
      overall clinical status. Bone marrow examination could be diagnostic when no
      obvious causes are demonstrated. Thrombocytopenia probably reflects the severity
      and course of an underlying pathologic condition, as its correction appears to be
      a good prognostic factor.

PMID- 10334155
TI  - Fatal postoperative pulmonary edema: pathogenesis and literature review.
AB  - STUDY OBJECTIVES: Pulmonary edema is a known postoperative complication, but the
      clinical manifestations and danger levels for fluid administration are not known.
      We studied (1) 13 postoperative patients (11 adult, 2 pediatric) who developed
      fatal pulmonary edema, and (2) one contemporaneous year of inpatient operations
      at two university teaching hospitals to determine the clinical manifestations,
      causes, epidemiology, and guidelines for fluid administration. DESIGN:
      Retrospective analysis of 13 patients with fatal postoperative pulmonary edema
      and one contemporaneous year of major inpatient surgery. PATIENTS AND METHODS:
      Thirteen patients had net fluid retention of at least 67 mL/kg in the initial 24
      postoperative hours and developed pulmonary edema. Ten were generally healthy
      while three had serious associated medical conditions. MEASUREMENTS AND RESULTS:
      There was no measurement, laboratory value, or clinical finding predictive of
      impending pulmonary edema. The most common clinical manifestation following the
      onset of pulmonary edema was cardiorespiratory arrest (n = 8). Patients had
      metabolic acidosis (pH = 7.15 +/- .33), hypoxia (PO2 = 45 +/- 18 mm Hg), and
      normal electrolytes. The diagnosis of pulmonary edema was established by chest
      radiograph and confirmed by autopsy and pulmonary artery pressure (21 +/- 4 mm
      Hg). The mean net fluid retention was 7.0 +/- 4.5 L (90 +/- 36 mL/kg/d) and
      exceeded 67 mL/kg/d in all patients. Autopsy revealed pulmonary edema with no
      other cause of death. Among 8,195 major operations, 7.6% developed pulmonary
      edema with a mortality of 11.9%. Extrapolation to the 8.2 million annual major
      surgeries in the United States yields a projection of 8,000 to 74,000 deaths.
      CONCLUSIONS: Pulmonary edema can occur within the initial 36 postoperative hours
      when net fluid retention exceeds 67 mL/kg/d. There are no known predictive
      warning signs and cardiorespiratory arrest is the most frequent clinical
      presentation. The monitoring systems currently in use neither detect nor predict
      impending pulmonary edema, and as yet, there are no known panic values for
      excessive fluid administration or retention.

PMID- 10334156
TI  - Risk factors for an outbreak of multi-drug-resistant Acinetobacter nosocomial
      pneumonia among intubated patients.
AB  - INTRODUCTION: Acinetobacter baumanii is a Gram-negative coccobacillus that is
      normally a commensal pathogen but can be a nosocomial pathogen. An epidemiologic
      study was performed to investigate an outbreak of A baumanii that occurred in our
      medical intensive care unit (MICU) from March to September 1995. METHODS: A case
      control study was performed by retrospective chart review, comparing case
      patients to randomly selected patients who were mechanically ventilated in the
      MICU for at least 1 week during the outbreak. A case patient was defined as any
      patient with an Acinetobacter infection in which the epidemic strain was
      considered to be a pathogen. The epidemic strain was defined by its antibiogram.
      Case patients and control patients were compared for age, gender, underlying
      disease, acute physiology and chronic health evaluation III score, length of MICU
      stay, prior antibiotic use, presence of fever, sepsis, type of pulmonary
      infiltrate, and outcome. Environmental and hand-washing studies also were
      performed during the period of the outbreak. Molecular typing was performed on
      available bloodstream isolates. RESULTS: There were 15 cases of A baumanii
      nosocomial pneumonia. Fifty percent were bacteremic; one chart was unavailable
      for review. Twenty-nine patients were identified as control patients. The mean
      age for case patients was 50 (range, 21 to 84). The mean duration of time from
      admission to the ICU to infection was 12.8 days (range, 4 to 40). Sepsis
      developed in 35% of the case patients. Forty-three percent of the case patients
      died during their hospitalization, with two of those deaths attributed to
      Acinetobacter infection. Univariate analysis showed that prior use of ceftazidime
      was associated with infection with Acinetobacter (11/14 case patients compared to
      11/29 control patients; p < 0.01). Pulsed-field gel electrophoresis revealed two
      strains to be responsible for the outbreak. Hand washing was performed before
      patient contact by only 10% of health-care workers, and only 32% washed their
      hands after patient contact. CONCLUSION: The use of ceftazidime was associated
      with an increased risk of nosocomial pneumonia with resistant strains of
      Acinetobacter. Health-care workers need to improve compliance with hand-washing
      recommendations.

PMID- 10334157
TI  - Posterior tracheal wall perforation during percutaneous dilational tracheostomy:
      an investigation into its mechanism and prevention.
AB  - OBJECTIVES: Part 1: To describe the complication of posterior tracheal wall
      injury and perforation associated with the percutaneous dilational tracheostomy
      (PDT). Part 2: To determine the mechanism of posterior tracheal wall injury
      during PDT. DESIGN: Prospective observational study. SUBJECTS: Part 1: Medical
      surgical ICU patients requiring tracheostomy. Part 2: Swine and cadaver models.
      INTERVENTIONS: Part 1: Consecutive medical-surgical ICU patients undergoing
      tracheostomy tube insertion via the percutaneous dilation technique with
      bronchoscopic guidance were enrolled in the study. Demographic data and
      complications were recorded. Part 2: Tracheostomy tubes were inserted via the
      percutaneous dilational technique in the swine model with concomitant
      bronchoscopic video recording from the proximal and distal airways. Tracheostomy
      tubes were inserted via the percutaneous dilational technique in the cadaver
      model followed by anatomic inspection of the airway. RESULTS: Part 1: Seven (29%)
      of 24 medical-surgical ICU patients sustained complications associated with PDT.
      Three patients (12.5%) sustained posterior tracheal wall perforations followed by
      the development of tension pneumothoraces. Part 2: The swine model demonstrated
      that posterior tracheal wall perforation may occur during PDT when the guiding
      catheter is withdrawn into the dilating catheters. Five-centimeter posterior
      tracheal wall mucosal lacerations occurred when the guidewire and the guiding
      catheter were not properly stabilized during PDT. CONCLUSION: Percutaneous
      dilational tracheostomy was associated with a 29% complication rate in this
      observational study. Of concern was the high rate (12.5%) of posterior tracheal
      wall perforation. The swine and cadaver models suggest that posterior tracheal
      wall injury or perforation may occur if the guidewire and guiding catheter are
      not properly stabilized. To avoid posterior tracheal wall injury, the guidewire
      and guiding catheter should be firmly stabilized during PDT.

PMID- 10334158
TI  - Persistent gastric intramucosal ischemia in patients with sepsis following
      resuscitation from shock.
AB  - STUDY OBJECTIVES: (1) To determine the effects of resuscitation of patients with
      severe sepsis to conventional hemodynamic end points and normal blood lactate
      levels on postresuscitation sequential assessments of gastric intramucosal pH
      (pHi). (2) To determine whether trends in pHi are reflected in trends in systemic
      hemodynamic, oxygen utilization, and acid-base assessments. DESIGN: Prospective
      cohort study. SETTING: Medical ICU in an inner-city, university-based medical
      center. PATIENTS: Twelve recently admitted patients with severe sepsis and signs
      of circulatory shock who were successfully resuscitated to normal hemodynamic end
      points and lactate levels and who were also monitored with pulmonary artery
      catheters and gastric tonometers. INTERVENTIONS: Because of the observational
      nature of this study, no specific interventions were employed. The physician
      staff administered i.v. fluids and pharmacologic agents, during and after the
      resuscitative period, to treat infection and to achieve and maintain hemodynamic
      stability. Mechanical ventilation and supplemental oxygen were provided as
      needed. The hemodynamic and physiologic monitoring employed was determined by the
      managing physicians and established medical ICU routines. MEASUREMENTS AND
      RESULTS: A total of 12 patients were studied. Systemic hemodynamic, oxygen
      utilization, and acid-base assessments and pHi were recorded following
      resuscitation, and every 12 h thereafter. pHi decreased from 7.33 +/- 0.08 (mean
      +/- SD) following resuscitation to 7.26 +/- 0.04 at 24 h, 7.20 +/- 0.07 at 36 h
      (p < 0.05), and 7.24 +/- 0.08 at 48 h. Corresponding statistically significant
      and clinically relevant changes in systemic hemodynamic, oxygen utilization, and
      acid-base variables were not observed. The hospital mortality of this patient
      group was high (10 of 12; 83%). CONCLUSIONS: Gastric intramucosal acidosis
      develops and persists for at least 48 h in patients resuscitated from septic
      shock to conventional resuscitative end points, including the normalization of
      lactate levels. These regional changes were not reflected in corresponding
      changes in systemic acid-base and oxygen utilization variables. Direct
      determinations of pHi and therapy directed toward the resolution of splanchnic
      ischemia may be required to improve the outcome in these patients.

PMID- 10334159
TI  - Role of peripheral serotonin in the regulation of central sleep apneas in rats.
AB  - STUDY OBJECTIVES: The aim of our study was to determine the effects of serotonin
      (5-HT), which does not penetrate the blood-brain barrier (BBB), and GR38032F, a 5
      HT3 receptor antagonist that may cross the BBB, on spontaneous apneas in adult
      Sprague-Dawley rats. MEASUREMENTS AND RESULTS: Rats were implanted with
      electrodes for EEG and electromyographic recording to monitor sleep, with a
      radiotelemetry transmitter for monitoring aortic BP and heart period (HP) and
      were placed inside a single chamber plethysmograph for monitoring respiration.
      Sleep, BP, HP, and respiration were monitored for 6 h following administration of
      drugs. Intraperitoneal injection of 5-HT (0.79 mg/kg) to rats increased
      spontaneous central apneas during rapid eye movement (REM) sleep by > 250% in
      comparison to control recording (p = 0.01). GR38032F (0.1 mg/kg), which produced
      no effect on apnea expression, completely blocked the 5-HT-induced increase in
      REM apneas. Administration of 5-HT did not affect apnea expression in non-REM
      sleep and had no effect on sleep or BP. CONCLUSIONS: From these observations, we
      conclude that binding at 5-HT3 receptors in the peripheral nervous system
      promotes REM-related apnea genesis in rats. These findings further suggest that
      endogenous 5-HT, acting at least at peripheral 5-HT3 receptors, may play a
      baseline physiologic role in the expression of spontaneous central apneas in
      rats.

PMID- 10334160
TI  - A pharmacologic study on CO2 responsiveness of intracranial pressure in rats with
      chronic hypercapnia.
AB  - STUDY OBJECTIVES: To investigate intracranial pressure (ICP) changes and their
      mechanisms in chronic hypercapnia. DESIGN: After 12 male Wistar rats were
      maintained in CO2-mixed air (mean PaCO2, 71.0 mm Hg) for 21 weeks, their ICP
      levels were measured during the breathing of 0, 5, 10, 12, and 14% CO2-mixed air
      before and after the i.v. administration of nitro-L-arginine methyl ester (L
      NAME). The ICP responses to i.v. norepinephrine and i.v. adenosine were also
      tested. Ten rats that were maintained in room air served as the control group.
      RESULTS: The mean ICP in the study group (5.9 mm Hg) was not significantly
      different from the mean ICP in the control group. In the study group, the ICP
      response to changes in PaCO2 was significantly blunted when compared to the
      response seen in the control group. In both groups, i.v. norepinephrine
      significantly increased the ICP. In the control group but not in the study group,
      i.v. L-NAME suppressed the ICP response to changes in PaCO2. In both groups, i.v.
      adenosine significantly increased the ICP. CONCLUSIONS: The ICP response to PaCO2
      was blunted in rats with chronic hypercapnia, and the mechanism of this reduced
      response may involve nitric oxide.

PMID- 10334161
TI  - Nitric oxide in adult lung disease.
AB  - Advances in the understanding of nitric oxide as a biological mediator and a
      therapeutic tool continue to accumulate at a rapid rate. This review provides an
      update on recent developments pertinent to the role of nitric oxide in adult lung
      disease. After a brief review of basic nitric oxide biochemistry and physiology,
      the evidence supporting the role of nitric oxide in the regulation of vascular
      and airway tone in the normal lung is considered. Clinical studies addressing the
      pathophysiological role of nitric oxide in pulmonary hypertension, airway
      disease, and lung injury are reviewed, and the application of inhaled nitric
      oxide therapy is discussed.

PMID- 10334162
TI  - Clinical uses of low-molecular-weight heparins.

PMID- 10334163
TI  - Bronchial arterial infusion is an effective therapeutic modality for centrally
      located early-stage lung cancer: results of a pilot study.
AB  - OBJECTIVE: This pilot study was done to assess the effectiveness of bronchial
      arterial infusion (BAI) as a therapeutic modality for centrally located early
      stage lung cancer. PATIENTS AND METHODS: Seven patients who had endoscopically
      evaluated, centrally located early-stage squamous cell lung carcinoma, including
      three patients with synchronous multiple primary lung cancers, were offered BAI
      with cis-diamminedichloroplatinum (CDDP; dosage, 50 to 150 mg/body, 35 to 100
      mg/m2), a radical therapeutic method, as an alternative to a resection. RESULTS:
      All early-stage lesions showed complete remission within 1 to 6 weeks (median,
      3.3 weeks) after BAI. In the three patients with multiple lung cancers, BAI was
      used to treat accessible early-stage lesions, although a surgical resection was
      required for advanced lesions. Three of the seven patients suffered from severe
      bronchial ulcers after BAI. Six of the patients in the study had no disease
      relapse to date at a median follow-up time of 19.8 months (range, 11 to 32
      months), but the other patient died of a pulmonary hemorrhage 3 months after BAI.
      CONCLUSION: Based on our findings, BAI with CDDP should be reappraised as an
      effective therapeutic modality for centrally located early-stage lung cancer and
      as an acceptable primary treatment.

PMID- 10334164
TI  - Realizing the promise: delivering pulmonary continuing medical education over the
      Internet.
AB  - STUDY OBJECTIVES: Continuing medical education (CME) is meant to bridge the gap
      between new scientific observations and clinical practice. However, traditional
      CME has not been effective at altering the behaviors of physicians. One reason
      for this failure of traditional CME programs may be their inflexibility. In
      traditional CME, the clinician does not choose the topic, the pace of the
      program, or the place of learning, and the CME material cannot be easily
      delivered to the point of care where the clinician needs the information.
      Computers and computer networks have the potential to accomplish these goals. CME
      has begun to appear on the Internet; however, there have been few evaluations of
      its usefulness, acceptance, and effectiveness. Over the last 18 months, we have
      developed three on-line pulmonary CME programs, and we have delivered them on the
      Virtual Hospital, the University of Iowa's digital health sciences library on the
      Internet. We report our initial experience with this CME material. DESIGN: We
      measured the frequency with which the Internet-delivered CME is accessed by
      monitoring page accessions and by using a log file analysis program (Analog
      1.2.3; University of Cambridge Statistical Laboratory; Cambridge, UK). In
      addition, we collected all completed CME examinations and evaluation forms
      submitted by registered users. MEASUREMENTS AND RESULTS: We have found that the
      frequency with which the Internet-delivered CME is accessed has continued to
      increase with time (2.3-fold increase over 18 months), that evaluations of
      technical and content issues are strongly favorable, and that some clinicians
      have been willing to pay to receive CME through the medium of the Internet.
      CONCLUSIONS: We feel that with adequate peer review and quality control,
      physicians will use the Internet-delivered CME. However, several obstacles to
      wide use remain. These obstacles include issues regarding training in using the
      Internet for physicians, reluctance of physicians to participate in on-line
      commerce, and the current unavailability of CME to be delivered in small-grained
      quantities to the point of care. As these issues are addressed, we feel that on
      line CME will represent an increasingly important CME medium for clinicians.

PMID- 10334165
TI  - Patient satisfaction with conscious sedation for bronchoscopy.
AB  - STUDY OBJECTIVE: Bronchoscopic technique is not standardized. Controversies exist
      with regard to premedication with sedatives before the test. To evaluate safety
      and efficacy of conscious sedation, we studied 100 randomized patients undergoing
      diagnostic bronchoscopy; patients received premedication with lidocaine spray and
      atropine sulfate i.m. (nonsedation group; 50 patients) or lidocaine spray,
      atropine i.m. and diazepam i.v. (sedation group; 50 patients). METHODS AND
      RESULTS: Monitoring during flexible fiberoptic bronchoscopy included continuous
      ECG and pulse oximetry. The procedure could not be completed in six patients.
      None received premedication with diazepam; among the patients who ended the
      examination, tolerance to the examination (visual analogue scale, 0 to 100; 0 =
      excellent; 100 = unbearable) was better in the sedation group. Low anxiety, male
      sex, but not age were also associated with improved patient tolerance to the
      test. Oxygen desaturation occurred in 17% of patients, and it was not more
      frequent after diazepam treatment. CONCLUSIONS: In our study, sedation had a
      beneficial effect on patient tolerance and rarely induced significant alterations
      in cardiorespiratory monitoring parameters.

PMID- 10334166
TI  - Thoracoscopic resection of solitary lung metastases from colorectal cancer is a
      viable therapeutic option.
AB  - STUDY OBJECTIVES: The reported 5-year survival rate after pulmonary
      metastasectomy from colorectal carcinoma, usually accomplished through
      thoracotomy or median sternotomy, ranges from 9 to 47%. Video-assisted
      thoracoscopy (VAT) is employed routinely for many thoracic surgical procedures,
      but the main concern about this approach for resection of lung metastases is that
      VAT does not allow complete lung palpation to identify and remove metastases not
      detected by preoperative radiologic examinations. DESIGN: In this study, we
      reviewed our experience with thoracoscopic resection of single peripheral lung
      metastases from colorectal carcinoma with potentially curative intent. PATIENTS
      AND INTERVENTIONS: From July 1992 to September 1998, 24 patients (15 male, 9
      female) with a mean age of 56 years, who previously had undergone resection for
      colorectal carcinoma and had a single limited and peripheral lung lesion
      identified by high-resolution CT, underwent thoracoscopic wedge resection of the
      lesions. RESULTS: No intraoperative complications developed. Three patients had
      minor postoperative complications successfully treated. In one case, we found a
      benign lesion, and this patient was excluded from the analysis. In the remaining
      cases, metastases from colorectal cancer were confirmed. The median follow-up was
      29 months, ranging from 3 to 67 months. Thirteen patients (56.5%) developed
      recurrence of the disease, and 5 of them (21.7%) had local recurrence. Cumulative
      5-year survival estimated by Kaplan-Meier method was 49.5%, not really different
      from the data reported in the literature. CONCLUSIONS: Thoracoscopic resection of
      single peripheral lung metastases from colorectal cancer with potentially
      curative intent seems effective and justified since the ultimate outcome of this
      highly selected group of patients seems to be not different from that obtained
      after a more invasive approach.

PMID- 10334167
TI  - A 77-year-old man with worsening shortness of breath.

PMID- 10334168
TI  - A 27-year-old homeless man with mental obtundation and a metabolic acidosis.

PMID- 10334169
TI  - An 87-year-old man with hypotension and confusion after cystoscopy.

PMID- 10334170
TI  - Pulmonary Langerhans' cell histiocytosis: radiologic resolution following smoking
      cessation.
AB  - We describe two patients with histologically proven pulmonary Langerhans' cell
      histiocytosis in whom radiologic improvement occurred following smoking
      cessation. The patients had 23- and 25-pack-year smoking histories, respectively.
      High-resolution CT revealed multiple small nodules, located predominantly in the
      upper and middle lung fields. There was a close temporal relationship between
      smoking cessation and radiologic improvement.

PMID- 10334171
TI  - Hyperbaric oxygen therapy in deep sternal wound infection after heart
      transplantation.
AB  - The results of orthotopic heart transplantation (OHTx) are still burdened with
      considerable early mortality due to graft rejection or infection. Sternum
      osteomyelitis is an infrequent postoperative complication. We report a case of
      deep sternal wound infection (2 months after OHTx) that was treated with
      hyperbaric oxygen therapy in addition to local surgical treatment.

PMID- 10334172
TI  - Successful double lung transplantation with a graft obtained from a methanol
      poisoned donor.
AB  - A 25-year-old woman developed "brain death" 48 h after acute methanol poisoning.
      After the elimination of methanol and the correction of metabolic disorders,
      organ donation was discussed. The lungs were transplanted into a 46-year-old
      woman suffering from cystic "emphysematous-like" lesions as a complication of
      lymphangioleiomyomatosis. The procedure was not complicated, and we have an
      uneventful follow-up of > 12 months. In addition to the lungs, the kidneys and
      the liver were also removed and transplanted with success.

PMID- 10334173
TI  - Photopheresis in the treatment of refractory bronchiolitis obliterans
      complicating lung transplantation.
AB  - Photopheresis has been successfully used to treat heart allograft rejection and
      has had some initial success in the treatment of bronchiolitis obliterans (BO)
      following lung transplantation. This report describes five patients treated with
      photopheresis after the failure of augmented immunosuppression for BO. Four
      patients had a temporary stabilization of their airflow obstruction, and minimal
      side effects of the procedure were noted, although there were consequences from
      additional augmented immunosuppression (principally sepsis). Photopheresis may
      provide a safe modality for the treatment of BO that is unresponsive to standard
      and augmented immunosuppression.

PMID- 10334174
TI  - Witnessed embolization of a right atrial mass during transesophageal
      echocardiography: implications regarding the safety of esophageal intubation.
AB  - A patient with chronic lung disease and a right atrial density that was difficult
      to distinguish on a transthoracic echocardiogram underwent transesophageal
      echocardiography (TEE) that demonstrated two mobile masses attached to the
      anterior right atrial wall. During the TEE procedure, the patient experienced
      coughing and retching due to the esophageal intubation, and the embolization of
      one of the right atrial masses was observed. This case is the first to document
      this mechanism of pulmonary embolism (a mechanism that was suspected in two prior
      reports), and it questions the safety of procedures that induce retching and
      coughing in patients with mobile right atrial masses.

PMID- 10334175
TI  - Successful treatment of refractory bronchorrhea by inhaled indomethacin in two
      patients with bronchioloalveolar carcinoma.
AB  - Bronchorrhea in patients with bronchioloalveolar carcinoma is not uncommon.
      However, to our knowledge, an effective treatment for bronchorrhea in these
      patients has not been established. Recently, we have confirmed the efficacy of
      inhaled indomethacin in severe refractory bronchorrhea in comparison to that of
      other medications in two patients with bronchioloalveolar carcinoma. Despite the
      administration of a macrolide and corticosteroid, sputum volume increased to 700
      mL/d in case 1 and to 200 mL/d in case 2 and hypoxemia and dyspnea deteriorated.
      Within a few days after the initiation of treatment with inhaled nebulized
      indomethacin (75 mg/d), sputum volume started to decrease and was controlled to <
      100 mL/d, associated with alleviation of dyspnea and hypoxemia. To our knowledge,
      this is the first report of successfully treated refractory bronchorrhea
      associated with bronchioloalveolar carcinoma by inhaled indomethacin, resulting
      in markedly reduced sputum volume, improved quality of life, and prolonged
      survival.

PMID- 10334176
TI  - Late onset of subcutaneous emphysema and hypercarbia following laparoscopic
      cholecystectomy.
AB  - Laparoscopic surgical techniques are increasingly being applied to treat
      intraperitoneal abnormalities. These minimally invasive techniques potentially
      offer decreased operation time, decreased morbidity, and decreased length of
      hospitalization stays. These procedures, however are not without potential
      morbidity. Herein we describe two patients treated with laparoseopic
      cholecystectomy whose cases were complicated with subcutaneous emphysema and
      hyperearbia without pneumothorax. In each of these cases, carbon dioxide gas was
      used to induce pneumoperitoneum. In one of the cases, the hypercarbia was a late
      event occurring during the surgery, and in the second case, the first such
      description in the literature (to our knowledge), hypercarbia developed after
      termination of the induced pneumoperitoneum.

PMID- 10334177
TI  - Respiratory distress due to minocycline-induced pulmonary lupus.
AB  - Minoeycline, a semisynthetic tetracycline, is often used to treat acne and
      rheumatoid arthritis. It has been considered an unlikely drug to be associated
      with systemic lupus erythematosus; however, many cases of drug-induced lupus
      related to minocycline have been reported. Some of those reports included
      pulmonary lupus, but none of the patients described developed respiratory
      distress. We describe a patient treated with minocycline for 2 years who
      presented with progressive dyspnea, severe hypoxia, and pulmonary infiltrates
      necessitating hospitalization and oxygen supplementation.

PMID- 10334178
TI  - Positive antineutrophil cytoplasmic antibodies-associated vasculitis presenting
      with hemoptysis and a mediastinal mass.
AB  - A patient with end-stage renal failure, due to IgA nephropathy, was found to have
      a mediastinal mass. Biopsy specimen of the mass showed a necrotizing vasculitis.
      Antineutrophil antibodies to myeloperoxidase were strongly positive. To our
      knowledge, no case of a mediastinal mass due vasculitis has been reported in the
      literature, and our observation should lead to broadening of the spectrum of
      clinical manifestations of vasculitis.

PMID- 10334179
TI  - A case of endobronchial endometriosis treated by subsegmentectomy.
AB  - We present a case of endobronchial endometriosis with catamenial hemoptysis. The
      lesion was diagnosed as endobronchial endometriosis using helical CT, and the
      patient underwent a subsegmentectomy of the upper part of the lateral basal
      segment. A histopathologic examination of the resected specimen revealed findings
      typical of endobronchial endometriosis with intimal hyperplasia within the
      bronchus. Since the operation, the patient has been asymptomatic for 11 months
      with no recurrence of hemoptysis.

PMID- 10334180
TI  - Duplicate publication.

PMID- 10334181
TI  - Tuberculosis and sarcoidosis.

PMID- 10334182
TI  - The fourth heart sound.

PMID- 10334183
TI  - Infective exacerbations of COPD.

PMID- 10334184
TI  - Ipratropium bromide in acute asthma: small beneficial effects?

PMID- 10334185
TI  - Continuous gastric mucosal capnometry is affected by enteral nutrition: potential
      for misinterpretation of tissue oxygenation.

PMID- 10334186
TI  - Code 99--an international perspective.

PMID- 10334187
TI  - Brachial artery puncture for blood sampling.

PMID- 10334188
TI  - Metalloptysis expulsion of wire stent fragments.

PMID- 10334189
TI  - Glutathione S-transferase M1 and T1 null genotypes as risk factors for oral
      leukoplakia in ethnic Indian betel quid/tobacco chewers.
AB  - Oral cancer is the most common cancer in males and third most common in females
      in India, the main causative agent being the use of chewing tobacco with or
      without betel quid (BQ). However, nothing is known about the role of the host
      metabolic genes in oral cancer in ethnic Indian population. In this study, the
      prevalence of GSTM1 and GSTT1 null genotypes (GSTM1*2 and GSTT1*2) in oral
      premalignant leukoplakia cases and controls was ascertained in genomic DNA by a
      multiplex PCR technique. Biopsies taken from 98 oral leukoplakia patients and
      exfoliated cells from 82 healthy controls both of Indian ethnicity were analysed.
      GSTM1*1 (active) was present in 83% and GSTT1*1 (active) was present in 78% of
      all control subjects, while prevalence of GSTM1*2 and GSTT1*2 null genotypes was
      significantly higher among oral leukoplakia cases. The prevalence of GSTM1*2 in
      leukoplakia cases was 81.6% compared with 17% in controls [odds ratio (OR), 22;
      95% confidence interval (CI), 1047] and GSTT1*2 was 75.5% in the cases versus 22%
      in controls (OR, 11; 95% CI, 5-22). Combined null genotypes of GSTM1 and GSTT1
      prevailed in 60.2% of the cases with none detected in controls. Glutathione S
      transferase M1 and T1 enzymes are both known to catalyse detoxification of
      reactive oxygen species, lipid peroxidation products and tobacco-derived
      carcinogens that have been found in the saliva of BQ/tobacco chewers. Our
      results, still requiring confirmation by a larger study, demonstrate that the
      null genotypes of both GSTM1 and GSTT1 increase with high penetrance, separately
      or in combination, the risk for developing leukoplakia in an Indian ethnic
      population.

PMID- 10334190
TI  - Loss of basement membrane type IV collagen is associated with increased
      expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human
      colorectal tumorigenesis.
AB  - Breakdown of basement membrane (BM) is believed to be an essential step for tumor
      invasion and metastases. We have previously demonstrated that matrix
      metalloproteinase-9 (MMP-9), the 92 kDa collagenase expression correlates with
      metastases in human colorectal cancer (CRC). This study explores the relationship
      between the 72 and 92 kDa type IV collagenase (MMP-2 and MMP-9) activities and
      pattern of type IV collagen expression during human colorectal tumorigenesis.
      Thirty-four CRC patients, including four synchronous adenomas and one synchronous
      liver metastases, were involved in this study. By immunohistochemical staining,
      type IV collagen expression was noted to be continuous in the BM of normal
      mucosa, adenoma and in two cases of carcinoma in situ. Limited or absent type IV
      collagen staining pattern was seen in 100 (19/19) and 23% (3/13) of CRC with and
      without metastases, respectively. By double immunostaining, MMP-9 protein
      expression was noted to localize within areas of limited type IV collagen
      staining. Similarly, type IV collagen staining was noted to be greatest in areas
      devoid of MMP-9 expression. Gelatin zymography detected both 92 and 72 kDa
      proenzyme forms in all CRC and normal mucosa extracts examined. The mean
      tumor/normal fold increases of the proMMP-2 and proMMP-9 enzyme forms were 1.6+/
      0.1 (mean +/- SE) and 2.4+/-0.5 in adenomas, and 2.1+/-0.2 and 4.1+/-0.7 in CRC,
      respectively. The 62 and 82 kDa bands were present in 63 (12/19) and 74% (14/19)
      of CRC with metastases, compared with only 20 (3/15) and 33% (5/15) of CRC
      without metastases, respectively. These differences were significant (P = 0.045
      and P = 0.030, respectively). Our results demonstrate that loss of BM type IV
      collagen along with elevations in MMP-2 and MMP-9 expression, especially the
      activated forms, occur during colorectal tumorigenesis. Our data suggest that
      control of type IV collagenase activation may be beneficial in preventing human
      colorectal tumor progression.

PMID- 10334191
TI  - Perturbations in the control of cellular arachidonic acid levels block cell
      growth and induce apoptosis in HL-60 cells.
AB  - Our previous studies demonstrated that inhibitors of arachidonate-phospholipid
      remodeling [i.e. the enzyme CoA-independent transacylase (CoA-IT)] decrease cell
      proliferation and induce apoptosis in neoplastic cells. The goal of the current
      study was to elucidate the molecular events associated with arachidonate
      phospholipid remodeling that influence cell proliferation and survival. Initial
      experiments revealed the essential nature of cellular arachidonate to the
      signaling process by demonstrating that HL-60 cells depleted of arachidonate were
      more resistant to apoptosis induced by CoA-IT inhibition. In cells treated with
      CoA-IT inhibitors a marked increase in free arachidonic acid and AA-containing
      triglycerides were measured. TG enrichment was likely due to acylation of
      arachidonic acid into diglycerides and triglycerides via de novo glycerolipid
      biosynthesis. To determine the potential of free fatty acids to affect cell
      proliferation, HL-60 cells were incubated with varying concentrations of free
      fatty acids; exogenously provided 20-carbon polyunsaturated fatty acids caused a
      dose-dependent inhibition of cell proliferation, whereas oleic acid was without
      effect. Blocking 5-lipoxygenase or cyclooxygenases had no effect on the
      inhibition of cell proliferation induced by arachidonic acid or CoA-IT
      inhibitors. An increase in cell-associated ceramides (mainly in the 16:0-ceramide
      fraction) was measured in cells exposed to free arachidonic acid or to CoA-IT
      inhibitors. This study, in conjunction with other recent studies, suggests that
      perturbations in the control of cellular arachidonic acid levels affect cell
      proliferation and survival.

PMID- 10334192
TI  - Influence of p53 tumor suppressor protein on bias of DNA repair and apoptotic
      response in human cells.
AB  - A network of interacting cellular components is known to mediate the regulatory
      role of tumor suppressor protein p53 in genomic stability. DNA repair machinery
      is considered to be one of these vital cellular components. To investigate the
      modulatory function of p53 on the repair of DNA damage and related effects, we
      have studied the responses of human p53-wild-type (p53-WT), p53-mutant (p53-Mut)
      and p53-nullizygous (p53-Null) cells following exposure to UV irradiation.
      Absence of wild-type p53 function coincided with an enhanced sensitivity to UV,
      as well as induction of apoptosis. However, the lack of wild-type p53 expression
      did not affect the response of its signal transducer protein, p21. Repair
      analysis of specific genomic sequences, at a single nucleotide resolution,
      revealed that the removal of cyclobutane pyrimidine dimers in a non-transcribed
      strand was significantly slower in p53-Mut and p53-Null cell lines compared with
      the normal p53-WT cells. However, the repair of the transcribed strand was
      comparable in the three cell lines. Thus, p53 is required for the efficient
      nucleotide excision repair (NER) of the global genomic DNA, but not for the
      transcription-coupled repair of the essential genes. The decreased global NER,
      due to the lost p53 function, seems to be responsible for the conjoined
      cytotoxicity and apoptosis of human cells subjected to DNA stress damage.

PMID- 10334193
TI  - Asbestos induction of extended lifespan in normal human mesothelial cells:
      interindividual susceptibility and SV40 T antigen.
AB  - Normal human mesothelial cells from individual donors were studied for
      susceptibility to asbestos-induction of apoptosis and generation of an extended
      lifespan population. Such populations were generated after death of the majority
      of cells and arose from a subset of mesothelial cultures (4/16) whereas
      fibroblastic cells (5/5) did not develop extended lifespan populations after
      asbestos exposure. All mesothelial cultures were examined for the presence of
      SV40 T antigen to obtain information on (i) the presence of SV40 T antigen
      expression in normal human mesothelial cells and (ii) the relationship between
      generation of an extended lifespan population and expression of SV40 T antigen.
      Immunostaining for SV40 T antigen was positive in 2/38 normal human mesothelial
      cultures. These cultures also had elevated p53 expression. However, the two
      isolates expressing SV40 T antigen did not exhibit enhanced proliferative
      potential or develop an extended lifespan population. Asbestos-generated extended
      lifespan populations were specifically resistant to asbestos-mediated but not to
      alpha-Fas-induced apoptosis. Deletion of p16Ink4a was shown in 70% of tumor
      samples. All mesothelioma cell lines examined showed homozygous deletion of this
      locus which extended to exon 1beta. Extended lifespan cultures were examined for
      expression of p16Ink4a to establish whether deletion was an early response to
      asbestos exposure. During their rapid growth phase, extended lifespan cultures
      showed decreased expression of p16Ink4a relative to untreated cultures, but
      methylation was not observed, and p16Ink4a expression became elevated when cells
      entered culture crisis. These data extend the earlier observation that asbestos
      can generate extended lifespan populations, providing data on frequency and cell
      type specificity. In addition, this report shows that generation of such
      populations does not require expression of SV40 T antigen. Extended lifespan
      cells could represent a population expressing early changes critical for
      mesothelioma development. Further study of these populations could identify such
      changes.

PMID- 10334194
TI  - Carcinogen and dietary lipid regulate ras expression and localization in rat
      colon without affecting farnesylation kinetics.
AB  - Epidemiological and experimental data suggest that dietary fiber and fat are
      major determinants of colorectal cancer. However, the mechanisms by which these
      dietary constituents alter the incidence of colon cancer have not been
      elucidated. Evidence indicates that dominant gain-of-function mutations short
      circuit protooncogenes and contribute to the pathogenesis of cancer. Therefore,
      we began to dissect the mechanisms whereby dietary fat and fiber, fed during the
      initiation, promotion and progression stages of colon tumorigenesis, regulate ras
      p21 localization, expression and mutation frequency. Male Sprague-Dawley rats
      (140) were provided with corn oil or fish oil and pectin or cellulose plus or
      minus the carcinogen azoxymethane (AOM) in a 2 x 2 x 2 factorial design and
      killed after 34 weeks. We have previously shown adenocarcinoma incidence in these
      animals to be 70.3% (52/74) for corn oil + AOM and 56.1% (37/66) for fish oil +
      AOM (P < 0.05). Total ras expression as well as ras membrane:cytosol ratio was 4-
      to 6-fold higher in colon tumors than in mucosa from AOM- or saline-injected
      rats. Expression of ras in the mucosal membrane fraction was 13% higher for
      animals fed corn oil compared with fish oil feeding (P < 0.05), which is
      noteworthy since ras must be localized at the plasma membrane to function. The
      elevated ras membrane:cytosol ratio in tumors was not due to increased farnesyl
      protein transferase activity or prenylation state, as nearly all detectable ras
      was in the prenylated form. Phosphorylated p42 and p44 mitogen activated protein
      kinase (ERK) expression was two-fold higher in tumor extracts compared with
      uninvolved mucosa from AOM- and saline-injected rats (P < 0.05). The frequency of
      K-ras mutations was not significantly different between the various groups, but
      there was a trend toward a greater incidence of mutations in tumors from corn oil
      fed rats (85%) compared with fish oil fed rats (58%). Our results indicate that
      the carcinogen-induced changes in ras expression and membrane localization are
      associated with the in vivo activation of the ERK pathway. In addition,
      suppression of tumor development by dietary n-3 polyunsaturated fatty acids may
      be partly due to a combined effect on colonic ras expression, membrane
      localization, and mutation frequency.

PMID- 10334195
TI  - Dietary glycine inhibits the growth of B16 melanoma tumors in mice.
AB  - Dietary glycine inhibited hepatocyte proliferation in response to the carcinogen
      WY-14,643. Since increased cell replication is associated with hepatic cancer
      caused by WY-14,643, glycine may have anti-cancer properties. Therefore, these
      experiments were designed to test the hypothesis that dietary glycine would
      inhibit the growth of tumors arising from B16 melanoma cells implanted
      subcutaneously in mice. C57BL/6 mice were fed diet supplemented with 5% glycine
      and 15% casein or control diet (20% casein) for 3 days prior to subcutaneous
      implantation of B16 tumor cells. Tumor volume was estimated from tumor diameter
      for 14 days. Tumors were excised, weighed and sectioned for histology post
      mortem. B16 cells and endothelial cells were cultured in vitro to assess effects
      of glycine on cell growth. Statistical tests were two-sided and a P-value of 0.05
      was defined as a significant difference between groups. Weight gain did not
      differ between mice fed control and glycine-containing diets. B16 tumors grew
      rapidly in mice fed control diet; however, in mice fed glycine diet, tumor size
      was 50-75% less. At the time of death, tumors from glycine-fed mice weighed
      nearly 65% less than tumors from mice fed control diet (P < 0.05). Glycine (0.01
      10 mM) did not effect growth rates of B16 cells in vitro. Moreover, tumor volume
      and mitotic index of B16 tumors in vivo did not differ 2 days after implantation
      when tumors were small enough to be independent of vascularization. After 14
      days, tumors from mice fed dietary glycine had 70% fewer arteries (P < 0.05).
      Furthermore, glycine (0.01-10 mM) inhibited the growth of endothelial cells in
      vitro in a dose-dependent manner (P < 0.05; IC50 = 0.05 mM). These data support
      the hypothesis that dietary glycine prevents tumor growth in vivo by inhibiting
      angiogenesis through mechanisms involving inhibition of endothelial cell
      proliferation.

PMID- 10334196
TI  - Combined mismatch and nucleotide excision repair defects in a human cell line:
      mismatch repair processes methylation but not UV- or ionizing radiation-induced
      DNA damage.
AB  - Interaction between long patch mismatch repair (MMR) and persistent DNA O6
      methylguanine or 6-thioguanine (6-TG) is implicated in the cytotoxicity of
      methylating agents and 6-TG, respectively. Human cells with defective MMR
      tolerate DNA methylation damage and are cross-resistant to 6-TG. To determine
      whether MMR contributes to the lethal effects of persistent UV-induced DNA
      lesions, MMR deficiency was introduced into nucleotide excision repair (NER)
      defective XP12RO cells. The doubly repair-defective cells, designated XP12ROB4,
      did not express detectable hMSH2 protein. They had the mutator phenotype, N
      methyl-N-nitrosourea and 6-TG resistance typical of MMR-defective cells. Active
      MMR was not required for the cytotoxicity of UV light, and the hMSH2 defect did
      not detectably alter the survival of XP12ROB4. The level of spontaneous or UV
      induced SCE was also similar in XP12RO and XP12ROB4, indicating that hMSH2 is not
      required for this recombination process. The combined deficiency in MMR and NER
      did not confer a significant degree of tolerance to ionizing radiation, and the
      survival of XP12RO and XP12ROB4 after gamma-radiation was similar. Although it
      recognizes and processes some persistent damaged or modified DNA base pairs, MMR
      is unlikely to serve as a general sensor of DNA damage.

PMID- 10334197
TI  - Intestinal tumorigenesis in the Apc1638N mouse treated with aspirin and resistant
      starch for up to 5 months.
AB  - The Apc1638N mouse model, which carries a targeted mutant allele within the
      adenomatous polyposis (Apc) gene and develops intestinal tumours spontaneously,
      predominantly in the small bowel, was used to investigate the effects of two
      potential chemopreventive agents, aspirin and alpha-amylase resistant starch
      (RS). Heterozygous Apc+/Apc1638N mice were fed semi-purified diets rich in animal
      fat, animal proteins and sucrose and low in dietary fibre (Western style diets)
      from approximately 6 weeks up to 6 months of age. Two of the diets contained
      aspirin (300 mg/kg diet) and two RS (1:1 mixture of raw potato starch: Hylon VII
      at 200 g/kg diet) in a 2 x 2 factorial design. A fifth treatment group were fed a
      conventional rodent chow diet. The mice fed the Western style diets became almost
      three times as fat as the chow-fed mice but this did not affect tumour yield.
      Treatment with RS resulted in significantly more intestinal tumours whereas
      aspirin alone had no effect. However, there was a significant aspirin x RS
      interaction, which suggests that aspirin could prevent the small intestine tumour
      enhancing effects of RS in this Apc-driven tumorigenesis model. The possibility
      that large amounts of purified forms of resistant starch may have adverse effects
      within the small bowel is a novel observation that requires further investigation
      since greater intakes of starchy foods (and of RS) are being encouraged as a
      public health measure in compensation for reduced dietary fat intake. However, it
      remains possible that any increased risk is restricted to carriers of germline
      mutations in APC.

PMID- 10334198
TI  - Increased chromosomal instability in peripheral lymphocytes and risk of human
      gliomas.
AB  - Brain tumors exhibit considerable chromosome instability (CIN), suggesting that
      genetic susceptibility may contribute to brain tumorigenesis. To test this
      hypothesis, in this pilot study, we examined for CIN in short-term lymphocyte
      cultures from 25 adult glioma patients and 28 age-, sex- and ethnicity-matched
      healthy controls (all Caucasian). We evaluated CIN by a multicolor fluorescence
      in situ hybridization assay using two probes: a classic satellite probe for a
      large heterochromatin breakage-prone region of chromosome 1 and an alpha
      satellite probe for a smaller region adjacent to the heterochromatin probe. Our
      results showed a significant increase in the mean number of spontaneous breaks
      per 1000 cells in glioma patients (mean +/- SD, 2.4+/-0.8) compared with controls
      (1.4+/-0.9; P < 0.001). By using the median number of breaks per 1000 cells in
      the controls as the cutoff value, we observed a crude odds ratio (OR) of 8.5 [95%
      confidence interval (CI) = 2.05-34.9, P < 0.001] for spontaneous breaks and brain
      tumor risk. After adjustment for age, sex and smoking status, the adjusted OR was
      15.3 (95% CI, 2.71-87.8). A significant increase in cells with chromosome 1
      aneuploidy (in the form of hyperdiploidy) (P < 0.001) was also observed in the
      glioma cases, with an adjusted OR of 6.6 (95% CI = 1.5-30, P < 0.05). These
      findings suggest that CIN can be detected in the peripheral blood lymphocytes of
      brain tumor patients and may be a marker for identifying individuals at risk.

PMID- 10334199
TI  - Histopathology and gene expression changes in rat liver during feeding of
      fumonisin B1, a carcinogenic mycotoxin produced by Fusarium moniliforme.
AB  - Fumonisin B1 (FB1) is a carcinogenic mycotoxin produced by the fungus Fusarium
      moniliforme in corn. Feeding of FB1 to rats causes acute liver injury, chronic
      liver injury progressing to cirrhosis, and sometimes terminates in hepatocellular
      carcinoma or cholangiocarcinoma. This study describes the histolopathology and
      changes in gene expression in the rat liver during short-term feeding of FB1.
      Male Fischer rats were fed either FB1 250 mg/kg or control diet, and were killed
      weekly for 5 weeks. FB1 caused a predominantly zone 3 'toxic' liver injury, with
      hepatocyte death due to necrosis and apoptosis. Hepatocyte injury and death were
      mirrored by hepatic stellate cell proliferation and marked fibrosis, with
      progressive disturbance of architecture and formation of regenerative nodules.
      Despite ongoing hepatocyte mitotic activity, oval cell proliferation was noted
      from week 2, glutathione S-transferase pi-positive hepatic foci and nodules
      developed and, at later time points, oval cells were noted inside some of the
      'atypical' nodules. Northern blot (mRNA) analysis of liver specimens from weeks 3
      to 5 showed a progressive increase in gene expression for alpha-fetoprotein,
      hepatocyte growth factor, transforming growth factor alpha (TGF-alpha) and
      especially TGF-beta1 and c-myc. Immunostaining with LC(1-30) antibody
      demonstrated a progressive increase in expression of mature TGF-beta1 protein by
      hepatocytes over the 5 week feeding period. The overexpression of TGF-beta1 may
      be causally related to the prominent apoptosis and fibrosis seen with FB1-induced
      liver injury. Increased expression of c-myc may be involved in the cancer
      promoting effects of FB1.

PMID- 10334201
TI  - Analysis of 8-hydroxyguanine in rat kidney genomic DNA after administration of a
      renal carcinogen, ferric nitrilotriacetate.
AB  - The frequency of oxidative base damage, such as 8-hydroxyguanine (8-OH-Gua), was
      determined at the nucleotide level of resolution using the ligation-mediated PCR
      technique. Administration of a renal carcinogen, ferric nitrilotriacetate (Fe
      NTA), is known to induce oxidative stress and subsequent formation of 8-OH-Gua in
      the rat kidney. Whole genomic DNA was isolated from the rat kidney after or
      without Fe-NTA treatment and then cleaved with hot piperidine. In order to assess
      the frequency of 8-OH-Gua formation, we chose three genes, the tumor suppressor
      gene p53, the heat shock protein 70 (HSP70-1) gene and the Na,K-ATPase alpha1
      subunit gene. No alteration in the cleavage profile was observed in the p53 and
      HSP70 genes after Fe-NTA treatment. In the case of the p53 gene, a low incidence
      of point mutations has been observed in this carcinogenesis system. On the other
      hand, time-dependent alterations, corresponding to the time course of overall 8
      OH-Gua formation and repair, were detected in the promoter region of the Na,K
      ATPase alpha1 subunit gene. GpG and GpGpG in specific regions seem to be hotspots
      for the formation of 8-OH-Gua. These results were confirmed by
      formamidopyrimidine-DNA glycosylase-dependent DNA cleavage patterns. Thus,
      oxidative base damage, such as 8-OH-Gua, was not distributed uniformly along the
      whole genome, but seemed to be restricted to particular genes and regions.

PMID- 10334200
TI  - Diffusion of dialkylnitrosamines into the rat esophagus as a factor in esophageal
      carcinogenesis.
AB  - To indicate how readily nitrosamines (NAms) diffuse into the esophagus, we
      measured diffusion rate (flux) through rat esophagus of dialkyl-NAms using side
      by-side diffusion apparatuses. Mucosal and serosal flux at 37 degrees C of two
      NAms, each at 50 microM, was followed for 90 min by gas chromatography-thermal
      energy analysis of NAms in the receiver chamber. Mucosal flux of one or two NAms
      at a time gave identical results. Mucosal flux was highest for the strong
      esophageal carcinogens methyl-n-amyl-NAm (MNAN) and methylbenzyl-NAm. Mucosal
      esophageal flux of 11 NAms was 18-280 times faster and flux of two NAms through
      skin was 13-28 times faster than that predicted for skin from the molecular
      weights and octanol:water partition coefficients, which were also measured.
      Mucosal: serosal flux ratio was correlated (P < 0.05) with esophageal
      carcinogenicity and molecular weight. For seven NAms tested for carcinogenicity
      by Druckrey et al. [(1967) Z. Krebsforsch., 69, 103-201], mucosal flux was
      correlated with esophageal carcinogenicity with borderline significance (P =
      0.07). The MNAN:dipropyl-NAm ratio for mucosal esophageal flux was unaffected
      when rats were treated with phenethylisothiocyanate and was similar to that for
      forestomach, indicating no involvement by cytochromes P450. Mucosal esophageal
      flux of MNAN and dimethyl-NAm was reduced by >90% on enzymic removal of the
      stratum corneum, was unaffected by 0.1 mM verapamil and was inhibited 67-94% by
      1.0 mM KCN and 82-93% by 0.23% ethanol. NAm flux through rat skin and jejunum was
      5-17% of that through esophagus. Flux through skin increased 5-13 times after
      enzymic or mechanical removal of the epidermis; the histology probably explained
      this difference from esophagus. Hence, NAms could be quite rapidly absorbed by
      human esophagus when NAm-containing foods or beverages are swallowed, the
      esophageal carcinogenicity of NAms may be partly determined by their esophageal
      flux and NAm flux probably occurs by passive diffusion.

PMID- 10334203
TI  - Oxidative damage to cellular and isolated DNA by metabolites of a fungicide ortho
      phenylphenol.
AB  - ortho-Phenylphenol (OPP) and its sodium salt, which are used as fungicides and
      antibacterial agents, have been found to cause carcinomas in the urinary tract of
      rats. To clarify the carcinogenic mechanism of OPP, we compared the DNA damage
      inducing ability of an OPP metabolite, phenyl-1,4-benzoquinone (PBQ) with that of
      another metabolite, phenylhydroquinone (PHQ). Pulsed field gel electrophoresis
      showed that PBQ and PHQ induced DNA strand breakage in cultured human cells, but
      PBQ did it more efficiently than PHQ. Significant increases in 8-oxo-7,8-dihydro
      2'-deoxyguanosine (8-oxodG) were observed in cells treated with PBQ and PHQ, and
      the increase of 8-oxodG induced by PBQ was significantly higher than that induced
      by PHQ. Using 32P-5'-end-labeled DNA fragments obtained from human p53 tumor
      suppressor gene and c-Ha-ras-1 protooncogene, we showed that PBQ plus NADH, and
      also PHQ, induced DNA damage frequently at thymine residues, in the presence of
      Cu(II). The intensity of DNA damage by PBQ was stronger than that by PHQ, showing
      higher importance of PBQ than other OPP metabolites. Catalase and bathocuproine
      inhibited Cu(II)-mediated DNA damage by PBQ plus NADH and PHQ, suggesting that
      H2O2 reacts with Cu(I) to produce active species causing DNA damage. Electron
      spin resonance and UV-visible spectroscopic studies have demonstrated generation
      of semiquinone radical and superoxide from the reaction of PBQ with NADH or the
      Cu(II)-mediated autoxidation of PHQ. The present results suggest that these OPP
      metabolites cause oxidative DNA damage through H2O2 generation in cells, and the
      damage may lead to mutation and carcinogenesis. It is concluded that PBQ may play
      a more important role in the expression of OPP carcinogenicity than other OPP
      metabolites.

PMID- 10334202
TI  - Cutaneously applied 4-hydroxytamoxifen is not carcinogenic in female rats.
AB  - Tamoxifen is widely used to treat oestrogen-dependent carcinoma of the breast.
      Previous long-term studies have shown that oral administration of tamoxifen
      induces hepatoproliferative lesions and hepatocellular tumours in rats. 4
      hydroxytamoxifen is an active metabolite of tamoxifen undergoing clinical
      evaluation for the treatment of various non-malignant breast diseases by topical
      application. In the present study, 4-hydroxytamoxifen was administered daily by
      cutaneous application for 101 weeks to groups of 50 female Sprague-Dawley rats at
      20, 140 or 1000 microg/kg/day. The product was applied with no occlusive bandage
      and oral ingestion was avoided by application of an Elizabethan collar for 6 h
      after administration. Treatment with 4-hydroxytamoxifen was clinically well
      tolerated and induced changes such as decreased food consumption and body weight
      gain, uterine and ovarian atrophy, mucification of vaginal epithelium and reduced
      mammary development, all of which were attributed to its pharmacological action.
      Mortality was significantly lower in the treated animals. The number of animals
      with palpable masses was similarly reduced. The incidence of mammary tumours and
      hypophyseal tumours was markedly lower in 4-hydroxytamoxifen-treated animals. The
      incidence of chronic tubulo-interstitial nephropathies, a common cause of
      mortality, was also lowered. There was no evidence of a carcinogenic action of 4
      hydroxytamoxifen on the liver, genital organs or skin. Plasma levels of 4
      hydroxytamoxifen were stable over the duration of the study and were proportional
      to the administered dose, exceeding clinical plasma levels by 60-fold at the high
      dose-level. In conclusion, 4-hydroxytamoxifen is not carcinogenic in the rat and
      reduces the incidence of spontaneous mammary and hypophyseal tumours.

PMID- 10334204
TI  - The level of DNA modification by (+)-syn-(11S,12R,13S,14R)- and (-)-anti
      (11R,12S,13S,14R)-dihydrodiol epoxides of dibenzo[a,l]pyrene determined the
      effect on the proteins p53 and p21WAF1 in the human mammary carcinoma cell line
      MCF-7.
AB  - The polycyclic aromatic hydrocarbon (PAH) dibenzo[a,l]pyrene (DB[a,l]P), the most
      carcinogenic PAH tested in rodent bioassays, exerts its pathobiological activity
      via metabolic formation of electrophilically reactive DNA-binding fjord region
      (+)-syn-(11S,12R,13S,14R)- or (-)-anti-(11R,12S,13S,14R)-DB[a,l]P-dihydrodiol
      epoxides (DB[a,l]-PDEs). DB[a,l]P is metabolized to these DB[a,l]PDEs which bind
      to DNA in human mammary carcinoma MCF-7 cells. The molecular response of MCF-7
      cells to DNA damage caused by DB[a,l]PDEs was investigated by analyzing effects
      on the expression of the tumor suppressor protein p53 and one of its target gene
      products, the cyclin-dependent kinase inhibitor p21WAF1. Treatment of MCF-7 cells
      with (+)-syn- and (-)-anti-DB[a,l]PDE at a concentration range of 0.001-0.1
      microM resulted in DB[a,l]PDE-DNA adduct levels between 2 and 30, and 3 and 80
      pmol/mg DNA, respectively, 8 h after exposure. (-)-anti-DB[a,l]PDE exhibited a
      higher binding efficiency that correlated with a significantly stronger p53
      response at low concentrations of the dihydrodiol epoxides. The level of p53
      increased by 6-8 h after treatment. The p21WAF1 protein amount exceeded control
      levels by 12 h and remained elevated for 96 h. At a dose of 0.01 microM (+)-syn
      DB[a,l]PDE, an increase in p21WAF1 was observed in the absence of a detectable
      change in p53 levels. The results indicate that the increase in p53 induced by
      DB[a,l]PDEs in MCF-7 cells requires an adduct level of approximately 15 pmot/mg
      DNA and suggest that the level of adducts rather than the specific structure of
      the DB[a,l]PDE-DNA adduct formed triggers the p53 response. The PAH-DNA adduct
      level formed may determine whether p53 and p21VAF1 pathways respond, resulting in
      cell-cycle arrest, or fail to respond and increase the risk of mutation induction
      by these DNA lesions.

PMID- 10334205
TI  - Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in
      F344/N rats and B6C3F1 mice and comparison of dose-response with 1,3-butadiene in
      mice.
AB  - Chloroprene (2-chloro-1,3-butadiene) is a high production chemical used almost
      exclusively in the production of polychloroprene (neoprene) elastomer. Because of
      its structural similarity to 1,3-butadiene, a trans-species carcinogen,
      inhalation studies were performed with chloroprene to evaluate its carcinogenic
      potential in rats and mice. Groups of 50 male and female F344/N rats and 50 male
      and female B6C3F1 mice were exposed to 0, 12.8, 32 or 80 p.p.m. chloroprene (6
      h/day, 5 days/week) for 2 years. Under these conditions, chloroprene was
      carcinogenic to the oral cavity, thyroid gland, lung, kidney and mammary gland of
      rats, and to the lung, circulatory system (hemangiomas and hemangiosarcomas),
      Harderian gland, kidney, forestomach, liver, mammary gland, skin, mesentery and
      Zymbal's gland of mice. Survival adjusted tumor rates in mice were fit to a
      Weibull model for estimation of the shape of the dose-response curves, estimation
      of ED10 values (the estimated exposure concentration associated with an increased
      cancer risk of 10%) and comparison of these parameters with those for 1,3
      butadiene. Butadiene has been identified as a potent carcinogen in mice and has
      been associated with increased risk of lymphatic and hematopoietic cancer in
      exposed workers. Shape parameter values for most of the neoplastic effects of
      chloroprene and 1,3-butadiene were consistent with linear or supralinear
      responses in the area near the lowest tested exposures. The most potent
      carcinogenic effect of 1,3-butadiene was the induction of lung neoplasms in
      female mice, which had an ED10 value of 0.3 p.p.m. Since the ED10 value for that
      same response in chloroprene exposed mice was also 0.3 p.p.m., we conclude that
      the carcinogenic potency of chloroprene in mice is similar to that of 1,3
      butadiene. Cancer potency of chloroprene is greater in the mouse lung than in the
      rat lung, but greater in the rat kidney than in the mouse kidney and nearly
      equivalent in the mammary gland of each species.

PMID- 10334206
TI  - Suppression of cell proliferation and telomerase activity in 4
      (hydroxyphenyl)retinamide-treated mammary tumors.
AB  - The detection of telomerase activity has been proposed as a biomarker of breast
      cancer development and progression. In this study, we used cell proliferation and
      telomerase in MNU (N-methyl-N-nitrosourea)-induced mammary carcinomas as targets
      for assessing the response of tumor cells to 4-(hydroxyphenyl)retinamide (4-HPR),
      a known inhibitor of mammary carcinogenesis in animal models and premenopausal
      women. In mammary tumors of rats treated for 1, 2, 4 or 6 weeks with 4-HPR, we
      observed that telomerase activity decreased progressively with the extension of 4
      HPR administration. A marked reduction in telomerase activity was already
      observed by 2 weeks after treatment and the lowest level was found at 6 weeks
      after initiation of 4-HPR treatment. The changes in telomerase activity were
      preceded and accompanied by a significant decrease in the percentage of
      proliferating cells as evaluated by 5-bromodeoxyuridine (BrdU)-labeling. However,
      when the values of telomerase activity in the individual tumors were compared
      with the percentage of proliferating cells, no significant correlation was found.
      These data suggest that the decreased telomerase activity in the animals treated
      with 4-HPR is not a simple consequence of the changes in cell proliferation, but
      a more complex phenomenon involving different cellular mechanisms and pathways.
      The time-dependent and consistent decrease of telomerase activity in the tumors
      treated with 4-HPR suggests that, in addition to the percentage of proliferating
      cells, telomerase activity could also be used as an endpoint in breast cancer
      chemotherapy studies.

PMID- 10334207
TI  - Expression of cytochrome P450 2A3 in rat esophagus: relevance to N
      nitrosobenzylmethylamine.
AB  - N-nitrosobenzylmethylamine (NBzMA) must be metabolically activated to exert its
      carcinogenic potential and is a potent inducer of tumors in the rat esophagus.
      The activation is believed to occur in the esophagus. Although the pathways of
      NBzMA metabolism are well studied, the principal cytochrome P450 enzyme(s) (P450)
      responsible for catalyzing its activation is unknown. Several preliminary studies
      have suggested that this enzyme may belong to the P450 2A family. We report here
      that P450 2A3 expressed in a baculovirus system metabolizes NBzMA, predominantly
      by methylene hydroxylation. To determine whether or not P450 2A3 is present in
      the rat esophagus, the relative level of P450 2A3 mRNA was determined by reverse
      transcriptase-polymerase chain reaction (RT-PCR). The mRNA levels of P450 2A3
      were compared with the levels of P450 2A1 and 2A2 mRNA in the esophagus, liver,
      lung and nasal mucosa. P450 2A3 mRNA was detected in rat nasal mucosa, lung and
      esophagus, but not in liver, whereas P450 2A1 and 2A2 mRNAs were detected only in
      the liver. To determine the relative expression of P450 2A3 in each tissue,
      quantitative RT-PCR with PCR-MIMICS used as internal standards was performed. The
      expression level in the nasal mucosa was by far the greatest. The expression in
      the lung and esophagus was 60- and 1600-fold less, respectively. Using antibodies
      to P450 2A4/5 and P450 2A10/11 a 50 kDa immunoreactive protein was detected in
      all three tissues by western blot analysis. This is consistent with the
      expression of P450 2A3 in these tissues. However, the amount of protein detected
      in the nasal mucosa was much greater than that in the esophagus or lung. The
      expression of P450 2A protein was similar in the lung and esophagus. The rate of
      coumarin 7-hydroxylation in cultured rat esophagus was very low. This is a
      reaction efficiently catalyzed by P450 2A5, 2A6 and 2A10. In summary, our results
      clearly demonstrate the presence of P450 2A3 protein and mRNA in the esophagus,
      but the amounts are low and may not be sufficient to account for NBzMA activation
      in this tissue.

PMID- 10334208
TI  - Effects of Ni(II) and Cu(II) on DNA interaction with the N-terminal sequence of
      human protamine P2: enhancement of binding and mediation of oxidative DNA strand
      scission and base damage.
AB  - Epidemiological evidence suggests that certain paternal exposures to metals may
      increase the risk of cancer in the progeny. This effect may be associated with
      promutagenic damage to the sperm DNA. The latter is packed with protamines which
      might sequester carcinogenic metals and moderate the damage. Human protamine P2
      has an amino acid motif at its N-terminus that can serve as a heavy metal trap,
      especially for Ni(II) and Cu(II). We have synthesized a pentadecapeptide modeling
      this motif, Arg-Thr-His-Gly-Gln-Ser-His-Tyr-Arg-Arg-Arg-His-Cys-Ser-Arg-amide
      (HP21-15) and described its complexes with Ni(II) and Cu(II), including their
      capacity to mediate oxidative DNA degradation [Bal et al. (1997) Chem. Res.
      Toxicol., 10, 906-914 and 915-921]. In the present study, effects of HP21-15 on
      Ni(II)- and Cu(II)-mediated DNA oxidation by H2O2 at pH 7.4 were investigated in
      more detail using the circular plasmid pUC19 DNA as a target, and the
      single/double-strand breaks and production of oxidized DNA bases, as end points.
      Ni(II) alone was found to promote oxidative DNA strand scission (mostly single
      strand breaks) and base damage, while Cu(II) alone produced the same effects, but
      to a much greater extent. Both metals were relatively more damaging to the
      pyrimidine bases than to purine bases. HP21-15 tended to increase the Ni(II)/H2O2
      induced DNA breakage. In sharp contrast, the destruction of DNA strands by
      Cu(II)/H2O2 was almost completely prevented by HP21-15. The effect of HP21-15 on
      the oxidative DNA base damage varied from a limited enhancement (5
      hydroxyhydantoin and thymine glycol) to slight suppression (5-hydroxycytosine, 5
      hydroxyuracil, 8-oxoguanine, 8-oxoadenine, 2-hydroxyadenine, fapyguanine and
      fapyadenine) toward Ni(II)/H2O2. HP21-15 strongly suppressed the oxidative
      activity of Cu(II)/H2O2 in regard to all bases in DNA. Consistently with the
      above, the electron spin resonance/spin trap measurements revealed greater and
      more persistent generation of OH* and O2-*-like oxidants from H2O2 by the Ni(II)
      HP21-15 complex than by the Cu(II)-HP21-15 complex (no O2-* was detected). Both
      complexes were also found to bind to DNA more strongly than HP21-15 alone. The
      results indicate that protamine P2 is capable of binding Ni(II) and Cu(II) and,
      in this way, attenuating the mediation of oxidative DNA damage by Cu(II), but not
      Ni(II). The effects found may be mechanistically involved in the reproductive
      toxicity and carcinogenicity of metals.

PMID- 10334209
TI  - Effect of 26 week magnetic field exposures in a DMBA initiation-promotion mammary
      gland model in Sprague-Dawley rats.
AB  - Several studies have suggested that exposure to 50 Hz magnetic fields promote
      chemically induced breast cancer in rats. Groups of 100 female Sprague-Dawley
      rats were initiated with a single 10 mg gavage dose of 7,12
      dimethylbenz[a]anthracene (DMBA) at 50 days of age followed by exposure to
      ambient fields (sham exposed), 50 Hz magnetic fields at either 1 or 5 Gauss (G)
      field intensity or 60 Hz fields at 1 G for 18.5 h/day, 7 days/week for 26 weeks.
      A vehicle control group without DMBA was included. Rats were palpated weekly for
      the presence of tumors. There was no effect of magnetic field exposure on body
      weight gains or the time of appearance of mammary tumors. At the end of 26 weeks,
      the animals were killed and the mammary tumors counted and measured. Mammary
      gland masses found grossly were examined histologically. The mammary gland
      carcinoma incidence was 96, 90, 95 and 85% (P < 0.05, decrease) for the DMBA
      controls, 1 G 50 Hz, 5 G 50 Hz and 1 G 60 Hz groups, respectively. The total
      numbers of carcinomas were 649, 494 (P < 0.05, decrease), 547 and 433 (P < 0.05,
      decrease) for the DMBA controls, 1 G 50 Hz, 5 G 50 Hz and 1 G 60 Hz groups,
      respectively. The number of fibroadenomas varied from 276 to 319, with the lowest
      number in the 1 G 60 Hz exposure group. Measurement of the tumors revealed no
      difference in tumor size between groups. In this breast cancer initiation
      promotion study in female Sprague-Dawley rats, there was no evidence that 50 or
      60 Hz magnetic fields promoted breast cancer under the conditions of this assay.
      This study does not support the hypothesis that magnetic field exposure can
      promote breast cancer in this rat model.

PMID- 10334210
TI  - A study of endonuclease III-sensitive sites in irradiated DNA: detection of alpha
      particle-induced oxidative damage.
AB  - An important difference between chemical agents that induce oxidative damage in
      DNA and ionizing radiation is that radiation-induced damage is clustered locally
      on the DNA. Both modelling and experimental studies have predicted the importance
      of clustering of lesions induced by ionizing radiation and its dependence on
      radiation quality. With increasing linear energy transfer, it is predicted that
      complex lesions will be formed within 1-20 bp regions of the DNA. As well as
      strand breaks, these sites may contain multiple damaged bases. We have compared
      the yields of single strand breaks (ssb) and double strand breaks (dsb) along
      with those produced by treatment of irradiated DNA with the enzyme endonuclease
      III, which recognizes a number of oxidized pyrimidines in DNA and converts them
      to strand breaks. Plasmid DNA was irradiated under two different scavenging
      conditions to test the involvement of OH* radicals with either 60Co gamma-rays or
      alpha-particles from a 238Pu source. Under low scavenging conditions (10 mM Tris)
      gamma-irradiation induced 7.1 x 10(-7) ssb Gy/bp, which increased 3.7-fold to 2.6
      x 10(-6) ssb Gy/bp with endo III treatment. In contrast the yields of dsb
      increased by 4.2-fold from 1.5 x 10(-8) to 6.3 x 10(-8) dsb Gy/bp. This equates
      to an additional 2.5% of the endo III-sensitive sites being converted to dsb on
      enzyme treatment. For alpha-particles this increased to 9%. Given that endo III
      sensitive sites may only constitute approximately 40% of the base lesions induced
      in DNA, this suggests that up to 6% of the ssb measured in X- and 22% in alpha
      particle-irradiated DNA could have damaged bases associated with them
      contributing to lesion complexity.

PMID- 10334211
TI  - Relation of structure of curcumin analogs to their potencies as inducers of Phase
      2 detoxification enzymes.
AB  - A series of naturally occurring as well as synthetic structural analogs of the
      dietary constituent curcumin were examined in order to elucidate which portions
      of the molecule are critical for the ability to induce Phase 2 detoxification
      enzymes in murine hepatoma cells, and hence to assess the chemoprotective
      potential of these compounds. Two groups of compounds were studied: classical
      Michael reaction acceptors such as curcumin and related beta-diketones such as
      dibenzoylmethane which lack direct Michael reactivity. The presence of two
      structural elements was found to be required for high inducer potency: (i)
      hydroxyl groups at ortho-position on the aromatic rings and (ii) the beta
      diketone functionality. All curcuminoids elevate the specific activity of quinone
      reductase in both wild type and mutant cells defective in either the aryl
      hydrocarbon (Ah) receptor or cytochrome P4501A1 activity. This indicates that
      neither binding to this receptor, nor metabolic activation by P4501A1 are
      required for the signaling process originating from this family of electrophiles
      and ultimately resulting in Phase 2 enzyme induction.

PMID- 10334212
TI  - Polyethylene-glycol, a potent suppressor of azoxymethane-induced colonic aberrant
      crypt foci in rats.
AB  - Bulking fibers and high water intake may decrease colon carcinogenesis in rats,
      and the risk of colorectal cancer in humans. We speculated that a non-fermented
      polymer, polyethylene-glycol (PEG) 8000, which increases stool moisture, might
      protect rats against colon carcinogenesis. Thirty female F344 rats were given a
      single injection of azoxymethane (20 mg/kg), and 7 days later randomized to AIN76
      diets containing PEG (to provide 3 g/kg body wt/day), or no PEG (control). Diets
      were given ad libitum for 105 days, then colon carcinogenesis was assessed by the
      aberrant crypt foci (ACF) test. ACF were scored blindly by a single observer.
      Dietary feeding of PEG almost suppressed ACF larger than one crypt, and
      strikingly decreased the total number of ACF per rat. PEG-fed rats had 100 times
      less large ACF than controls (0.8 and 83 respectively, P = 0.00001). PEG-fed rats
      had 20 times less total ACF than control (six and 107 ACF/rat, respectively; P <
      0.0001). Two treated rats had no detectable ACF. PEG is 10 times more potent than
      other chemopreventive agents in this model. Since PEG is generally recognized as
      safe, its cancer-preventive features could be tested in humans.

PMID- 10334213
TI  - Radiofrequency energy tissue ablation for the treatment of nasal obstruction
      secondary to turbinate hypertrophy.
AB  - OBJECTIVE/HYPOTHESIS: We hypothesized that the success rate of radiofrequency
      energy (RFe) tissue ablation of the inferior turbinate for nasal obstruction
      achieved by previous investigators would be improved by using a longer needle
      electrode and creating two lesions per turbinate. METHODS: Ten patients with
      nasal obstruction secondary to inferior turbinate hypertrophy were prospectively
      enrolled. A 40-mm needle delivered RFe to two sites in each inferior turbinate.
      Patients used a visual analog scale (VAS) to grade nasal obstruction
      preoperatively and at 1 week and 8 weeks after surgery. Preoperative and
      postoperative digital images of the nasal cavity were graded for obstruction (0%
      to 100%) in a blinded manner. RESULTS: All patients (100%) were subjectively
      improved at 8 weeks. Mean obstruction (VAS) improved from 50%+/-21% to 16%+/-15%
      (right side) and from 53%+/-29% to 13%+/-13% (left side). Mean improvements were
      68% (right side) (P = .004) and 75% (left side) (P = .001). Mean obstruction
      graded during blinded review of nasal cavity images improved from 73.5%+/-8% to
      51%+/-8% (right side) and from 76%+/-6% to 64%+/-7% (left side). Of nine patients
      using medications for nasal obstruction before treatment, eight (89%) noted no
      further need for medications at 8 weeks. CONCLUSION: The use of RFe for
      submucosal tissue ablation in the hypertrophied inferior turbinate is an
      effective modality for reducing symptoms of nasal obstruction. Improved results
      may occur by using a longer needle and creating two lesions per turbinate. Of
      patients in this study, 100% reported improvement of nasal obstruction.

PMID- 10334214
TI  - Role of angiogenic factors: coexpression of interleukin-8 and vascular
      endothelial growth factor in patients with head and neck squamous carcinoma.
AB  - OBJECTIVE/HYPOTHESIS: Angiogenesis has been used as a prognostic indicator in a
      variety of cancers and is believed to be controlled by angiogenic factors,
      including the cytokines interleukin-8 (IL-8) and vascular endothelial growth
      factor (VEGF). We hypothesized that the in vivo coexpression of both IL-8 and
      VEGF in head and neck tumors contributes to perpetuating tumor growth and
      metastasis by enhancing angiogenesis. METHODS: Immunohistochemical analysis for
      IL-8 and VEGF was performed using specimens from 33 cancer patients and 6 control
      patients. We quantitatively evaluated levels of IL-8 and VEGF in tumor tissue
      homogenates from those same patients using enzyme-linked immunosorbent assay and
      radioimmunoassay. Comprehensive histories of each patient were taken and later
      analyzed for clinical correlations with IL-8 or VEGF levels. RESULTS: IL-8 and
      VEGF were found to be colocalized within the head and neck squamous cell
      carcinoma (HNSCCA) tumor cells. In the head and neck tumor specimens, IL-8 levels
      ([38,152+/-1.8]x10(5) pg/mg total protein [TP]) were 22-fold greater than
      controls (1,721+/-2,122 pg/mg TP). The tumor levels of VEGF (1,304+/-6,037 pg/mg
      TP) were nearly fourfold higher than the controls (317+/-400 pg/mg TP.
      Interleukin-8 and VEGF levels were found to have a positive correlation (P< or =
      .0001). Patients exhibiting high levels in picograms per milligram of TP and/or
      number of moles of IL-8 and VEGF were found to clinically have more aggressive
      disease manifested by higher TNM stage, more recurrences, and shorter disease
      free intervals (P< or =.03) CONCLUSIONS: Marked increase in HNSCCA of IL-8 and
      VEGF underscores the importance of these angiogenic factors in this disease.
      Understanding the roles and interplay of angiogenic factors such as IL-8 and VEGF
      may have value in the treatment of HNSCCA.

PMID- 10334215
TI  - Paroxysmal laryngospasm after laryngeal nerve injury.
AB  - OBJECTIVE: Describe a clinical syndrome of laryngeal hypersensitivity following
      laryngeal nerve injury. STUDY DESIGN: Retrospective review of six patients with
      laryngeal paralysis sustained during neck surgery who presented with paroxysms of
      coughing and stridor, progressing to brief episodes of complete airway occlusion.
      METHODS: Chart review. RESULTS: Superior laryngeal nerve blockade temporarily
      improved symptoms in four of five patients. Botulinum toxin relieved spasm in two
      of three patients and reduced symptoms in the third. Symptoms gradually
      diminished or resolved in four patients from 1 to 2.5 years later. One patient
      underwent arytenoidectomy and one patient has a tracheostomy. CONCLUSIONS:
      Patients with laryngeal injury may present with stridor and acute airway
      obstruction secondary to paroxysmal laryngospasm. The authors have found that
      superior laryngeal nerve blockade or botulinum toxin may be effective in
      temporary relief of symptoms.

PMID- 10334216
TI  - Vocal function after vertical partial laryngectomy with glottic reconstruction by
      false vocal fold flap: durational and frequency measures.
AB  - OBJECTIVE: Compare vocal function following vertical partial laryngectomy (VPL)
      with or without glottic reconstruction by false vocal fold (FVF) mucosal flap.
      STUDY DESIGN: Twenty-seven patients with Tla squamous cell carcinoma (SCC) of the
      glottis were included in a prospective randomized clinical study. All patients
      were treated by frontolateral partial laryngectomy (FLPL). Glottic reconstruction
      with FVF mucosal flap was performed in 14 patients at the time of the FLPL,
      whereas 13 patients had standard FLPL. METHODS: Objective voice assessment was
      based on computerized acoustic recordings performed before and 1 year after
      surgery. When possible, additional recordings were performed at 3 months, 6
      months, and 2 years postoperatively. Incidence of postoperative granuloma and
      anterior neoglottic web were noted. Repeated analysis of variance (ANOVA) was
      used to compare the durational (maximum phonation time, speech rate) and
      frequency measurements (average fundamental frequency [Fo], standard deviation of
      Fo, jitter, shimmer, noise-to-harmonics ratio, degree of voice breaks) between
      patients with or without glottic reconstruction, postoperative granuloma, and
      anterior neoglottic web. Linear regression was used to study the evolution over
      time of the durational and frequency measurements. RESULTS: Frequency
      measurements improved with time and were significantly better in patients treated
      with glottic reconstruction. In addition, glottic reconstruction decreased
      incidence of postoperative granuloma and anterior neoglottic web. CONCLUSIONS:
      The FVF mucosal flap technique can improve vocal results in selected cases of Tla
      SCC of the glottis when FLPL is the adequate surgical treatment. false vocal
      folds; glottic reconstruction; vertical partial laryngectomy; vocal function.

PMID- 10334217
TI  - Evidence for recurrent laryngeal nerve contribution in motor innervation of the
      human cricopharyngeal muscle.
AB  - OBJECTIVE: To study the functional motor nerve supply of the upper esophageal
      sphincter in humans. STUDY DESIGN: Intraoperative electromyographic study.
      METHODS: The contribution of the recurrent laryngeal nerve and the pharyngeal
      plexus in the motor nerve innervation of the cricopharyngeal muscle and the
      inferior pharyngeal constrictor muscle was examined intraoperatively. RESULTS:
      Electromyography showed that there is a considerable overlap in the innervation
      of the cricopharyngeal muscle and the inferior pharyngeal constrictor muscle. The
      recurrent laryngeal nerve functionally contributes to the motor innervation of
      the cricopharyngeal muscle in all patients and contributes to the motor
      innervation of the inferior pharyngeal constrictor muscle in most patients. The
      pharyngeal plexus functionally contributes to the motor innervation of the
      inferior pharyngeal constrictor muscle but does not always contribute to the
      motor innervation of the cricopharyngeal muscle. CONCLUSIONS: This is the first
      report which provides evidence that the recurrent laryngeal nerve functionally
      contributes to the motor innervation of the cricopharyngeal and inferior
      pharyngeal constrictor muscle. Furthermore, this study shows that intraoperative
      electromyography in humans is a feasible method to analyze the physiology of the
      motor innervation of the upper esophageal sphincter.

PMID- 10334218
TI  - Functional results of Plastipore prostheses for middle ear ossicular chain
      reconstruction.
AB  - OBJECTIVE: Assessment of plastipore prostheses for middle ear ossicular chain
      reconstruction. Hearing results with total and partial Plastipore ossicular
      replacement prostheses (TORP and PORP) were evaluated in open- and closed-cavity
      operations. STUDY DESIGN: A retrospective review of 237 patients who underwent
      operation for chronic ear disease as well as ossiculoplasty with plastipore
      prostheses. In order to assess the functional results, only 156 of 237 patients
      were included in the study. Follow-up ranged from 6 to 46 months. METHODS: Canal
      wall up and canal wall down operations were performed. Either TORP or PORP
      ossiculoplasty was performed in each operation. An airbone gap closure to within
      20 dB was considered successful. RESULTS: With TORPs, the airbone gap closure to
      within 20 dB was achieved in 43.1%, and similar results were obtained with PORPs
      in 63.3%. In canal wall down and canal wall up operations, the success rates were
      55.8% and 55.7%, respectively. The best results were obtained with PORPs in canal
      wall down operations, with a success rate of 82%. The extrusion rate of the
      prostheses was 4.2%. CONCLUSION: Hearing results of PORPs are better than TORPs.
      In canal wall up and canal wall down operations similar hearing results are
      obtained. PORP ossiculoplasty in a canal wall down operation yields the most
      favorable hearing result.

PMID- 10334219
TI  - Tympanic membrane/middle ear pathologic correlates in chronic otitis media.
AB  - OBJECTIVE: To correlate pathologic findings of the tympanic membrane with
      pathologic changes in the middle ear cleft in chronic otitis media. STUDY DESIGN:
      Retrospective. MATERIAL AND METHODS: One hundred-fifty temporal bones from 97
      subjects with chronic otitis media (defined as middle ear pathologic changes
      including granulation tissue, fluid, cholesteatoma, cholesterol granuloma,
      tympanosclerosis, and ossicular changes) were selected to correlate the presence
      of these middle ear pathologies with histopathologic changes of the tympanic
      membrane. The tympanic membrane pathologies included perforation,
      myringosclerosis, retraction, hemorrhage, fluid-filled cystic spaces, or dilated
      vessels. Temporal bones were also assessed for atelectasis. Fifty-six normal
      temporal bones were taken as controls for measurements. RESULTS: Significant
      correlations between tympanic membrane and middle ear pathology included
      myringosclerosis and granulation tissue, myringosclerosis and ossicular
      pathology, retraction and cholesterol granuloma, retraction and cholesteatoma,
      retraction and ossicular pathology, perforation and ossicular pathology, and
      hemorrhage and granulation tissue. Additive effects of some pathologies were also
      observed. Almost half the bones with middle ear pathology had no associated
      tympanic membrane pathology, whereas multiple pathologic changes in the tympanic
      membrane generally showed underlying multiple pathologic changes in the middle
      ear. CONCLUSION: When tympanic membrane pathology is detected otoscopically, its
      presence, alone or in combination, can be a strong indicator of underlying middle
      ear pathology. However, a normal-appearing tympanic membrane does not exclude the
      possibility of middle ear pathology. These findings suggest the need for other
      diagnostic tools such as multifrequency tympanometry and otoacoustic emissions to
      complement otoscopy for diagnosis of middle ear pathology, especially in a
      tympanic membrane that appears "normal."

PMID- 10334220
TI  - Anatomical and theoretical observations on otolith repositioning for benign
      paroxysmal positional vertigo.
AB  - OBJECTIVE: To determine if there is an anatomic basis for the assumption that
      loose, "rogue" otoliths presumed to arise from the utricular macula and theorized
      to cause benign paroxysmal positional vertigo (BPPV) by impinging on semicircular
      canal ampullae could be returned to their original site by a series of changes in
      the position of the head called particle repositioning maneuvers (PRMs). Further,
      if such otolith movement were possible, once they were replaced into the utricle,
      would they adhere to the utricular macula? STUDY DESIGN: Kodachrome photographs
      of 2-mm-thick macrosections of human temporal bones were available for
      evaluation. The bones were sectioned in horizontal, coronal, and sagittal planes.
      Rice grains were placed on the photographs of the cross-sections to demonstrate
      the possible paths taken by loose otoliths under the influence of gravity in
      different positions of the head. RESULTS: A study of cross-sections of the
      temporal bone shows that loose macular otoliths after PRMs would tend to fall
      into the lumen of the utricle. Once the patient assumes the erect position,
      however, repositioned otoliths would tend to fall into the near or utriculopetal
      side of the cupula of the posterior semicircular canal, which opens directly into
      the inferior portion of the utricle, and could cause labyrinth stimulation and
      BPPV by the same mechanism of misplaced otoliths on the opposite or far side of
      the cupula. Loose otoliths in the utricle could also stimulate the horizontal
      ampullae. CONCLUSIONS: PRMs do not remove or fix otoliths in any specific site in
      the labyrinth. Repositioning of loose otoliths onto the original site in the
      macula of the utricle, which lies superiorly in the vestibule, could not be
      accomplished by any of the repositioning maneuvers. If otoliths were to be
      repositioned on the utricular macula, there is no evidence that the otoliths
      would adhere to the macula when the patient assumes the erect position. The good
      results obtained by physiotherapeutic procedures suggest that some other
      mechanism than repositioning of otoliths is responsible for the relief of BPPV.

PMID- 10334221
TI  - Bone modeling dynamics in acute otitis media.
AB  - OBJECTIVE: A number of middle ear diseases are associated with pathologic bone
      modeling, either formative or resorptive. As such, the pathogenesis of a
      sclerotic mastoid has been controversial for decades. Experimental studies on
      acute middle ear infection have shown varying degrees of both osteoresorption and
      osteoneogenesis. This study presents data on the dynamics of bone modeling in a
      rat model of acute pneumococcal otitis media, studied longitudinally from day 1
      through 6 months after inoculation. RESULTS: Qualitative, as well as quantitative
      histopathology revealed initial osteoresorption, followed by increasing
      apposition of new bone in the middle ear cavity, initiated at the outer
      periosteum. Measured bone thickness in four anatomically distinct locations
      peaked 3 months after inoculation, followed by some degree of normalization.
      However, bone thickness was still massively increased 6 months after the acute
      incident. Except in perilymphatic spaces of the otic capsule, resorptive and
      formative activity were found in all bone tissue structures surrounding the
      middle ear cavity, including the bony external auditory canal and the ossicles.
      CONCLUSION: These findings may support the existence of a perilymphatic barrier
      of specialized bone and suggest that even a single episode of acute infection may
      alter properties of ossicular chain conduction. The authors conclude that acute
      otitis media is accompanied by massive and progressing net osteoneogenesis,
      already evident at 3 days and peaking 3 months after inoculation, followed by
      some degree of normalization. This is conceivably in support of the environmental
      theory of mastoid pneumatization, claiming inflammatory disease as the cause of a
      sclerotic mastoid.

PMID- 10334222
TI  - Clinical evidence for dystrophin dysfunction as a cause of hearing loss in locus
      DFN4.
AB  - OBJECTIVE: Locus DFN4 is an X-linked nonsyndromic hearing loss locus originally
      mapped to Xp21.2. Recently, we have mapped deafness in a second family from
      Turkey to the same region, refining the location to within the Duchenne muscular
      dystrophy (DMD) locus. The objective of this study was to characterize the
      clinical phenotype of the Turkish family with comprehensive audiovestibular
      testing and high-resolution temporal bone computerized tomography. METHODS:
      Fourteen members of a three-generation family were studied in detail including
      two deaf affected males. Members of the family underwent general physical and
      otologic examination, vestibular testing, pure-tone audiometry, otoacoustic
      emissions, and immitance testing. An affected male underwent high-resolution
      computerized tomography of the temporal bone, electroretinogram (ERG),
      electromyography, electroneurography, and determination of serum creatinine
      phosphokinase level. RESULTS: Affected males were congenitally deaf with normal
      vestibular function. Carrier females showed a mild sensorineural hearing loss
      affecting all frequencies and absent otoacoustic emissions. Otoacoustic emissions
      in a younger, 3-year-old carrier girl were normal. In an affected male, ERG
      demonstrated subnormal scotopic b-wave typically seen in DMD. Computerized
      tomography of the temporal bone was normal. With the exception of the ERG
      finding, there was no clinical or laboratory evidence of DMD or Becker muscular
      dystrophy (BMD). CONCLUSION: The abnormal ERG in the Turkish family in
      conjunction with mapping of the DFN4 locus to within DMD strongly suggests that a
      defect in dystrophin is responsible for the hearing loss in this family. Patients
      with DMD and BMD should be screened systematically for sensorineural hearing
      loss. This family provides additional evidence for the critical role of
      cytoskeletal proteins in normal hearing.

PMID- 10334223
TI  - Incidence of vestibular schwannomas.
AB  - OBJECTIVE: To determine the incidence of vestibular schwannoma (VS) in Denmark in
      a period of 191/2 years. STUDY DESIGN: Retrospective review of prospective
      registered data on all patients with VS operated on by the translabyrinthine,
      lateral suboccipital, or middle cranial fossa approach, as well as patients who
      were allocated to the "wait-and-scan" group. METHODS: Charts were reviewed and
      tabulated for age, extrameatal tumor extension, and date of diagnosis. The
      available data were divided into three periods: June 1976 to June 1983, July 1983
      to June 1990, and July 1990 to December 1995. RESULTS: The number of newly
      diagnosed tumors in the first period was 278, corresponding to an incidence of
      7.8 tumors/million population per year; in the second period 337, corresponding
      to an incidence of 9.4 tumors/million population per year; and in the third
      period 355, corresponding to an incidence of 12.4 tumors/million population per
      year. A significant increase in incidence of the newly diagnosed intracanalicular
      tumors in the second and third periods was observed. CONCLUSION: The increase in
      incidence of VS can probably be explained by the awareness among
      otolaryngologists of the diagnosis of VS and better access to computed tomography
      and magnetic resonance imaging scans. The observed increase in the diagnosis of
      the small and intrameatal tumor creates a clinical dilemma, whether to operate on
      tumors in this early stage or to allocate patients to the wait-and-scan group.
      This problem will still be relevant in the upcoming years, since the incidence of
      intrameatal and small VS is expected to increase.

PMID- 10334224
TI  - Relationship between cochleovestibular disorders in hemifacial spasm and
      neurovascular compression.
AB  - OBJECTIVE: To investigate the evolution of cochleovestibular symptoms before,
      during, and after microvascular decompression (MVD) of the facial nerve in
      hemifacial spasm. STUDY DESIGN: Prospective study in patients with hemifacial
      spasm. Among our 13 patients who underwent MVD of the facial nerve from 1995 to
      1997, 6 had associated cochleovestibular disorders confirmed by neurotologic
      tests. RESULTS: In four of these patients, a concomitant compression of the
      eighth and facial nerves was found at surgery. Preoperative magnetic resonance
      angiography studies had shown three cases of this double neurovascular
      compression. Intraoperative auditory brainstem response monitoring showed that
      interposition of Teflon between vessel and facial nerve was highly critical to
      the auditory function. Auditory brainstem response monitoring was used to guide
      the surgeon during this critical phase. Surgery improved at least one
      cochleovestibular symptom in each patient. CONCLUSIONS: The authors propose two
      pathophysiologic hypotheses. First, the concomitant facial and cochleo-vestibular
      symptoms may be due to a hyperactivity of both the facial and vestibular nuclei.
      According to theories about cryptogenic hemifacial spasm, the origin of this
      hyperactivity could be an ectopic excitation focus. However, the two nerves may
      have different sites of ectopic excitation. According to the second hypothesis, a
      pulsatile compression of the facial nerve may be transmitted to the eighth nerve.
      This could take place even if only the facial nerve is in contact with a vascular
      loop.

PMID- 10334225
TI  - Prevalence of Meniere disease in Finland.
AB  - OBJECTIVES: To assess the prevalence of Meniere disease in the population of 5
      million in Finland according to the criteria of the Committee on Hearing and
      Equilibrium of the American Academy of Otolaryngology-Head and Neck Surgery (AAO
      HNS) recommendation. STUDY DESIGN: Retrospective investigation based on patient
      records of 306 patients treated for Meniere disease and recognized as such
      according to the International Statistical Classification of Diseases and Related
      Health Problems (ICD-9 or ICD-10) in seven Finnish hospitals serving a population
      of 1.5 million people. METHODS: Patients were selected from the computerized
      patient registers of outpatients and inpatients having received an appropriate
      diagnosis during the period from 1992 to 1996 and re-evaluated. Definite cases
      according to AAO-HNS guidelines were identified to calculate the prevalence of
      Meniere disease in Finland at the end of 1996. RESULTS: A total of 131 definite
      cases of Meniere disease were identified. The prevalence of at least 43 per
      100,000 and an average annual incidence of 4.3 per 100,000 were obtained. The
      prevalence turned out to be higher (P<.001) in Northern areas (49/100,000) than
      in the south (38/100,000). The prevalence did not differ in the areas of
      university hospitals (44/100,000) from those of central hospitals (42/100,000).
      CONCLUSIONS: The prevalence and incidence in Finland is lower than could be
      expected from previous international surveys, most of which provide inadequate
      data for forming a real picture of the epidemiology of Meniere disease. Uniform
      diagnostic criteria are indispensable for further research.

PMID- 10334226
TI  - Postparotidectomy facial nerve paralysis: possible etiologic factors and results
      with routine facial nerve monitoring.
AB  - OBJECTIVE: Analyze the incidence and factors responsible for postparotidectomy
      facial nerve paralysis when the surgery is performed with the routine use of
      facial nerve monitoring. STUDY DESIGN: A prospective, nonrandomized study.
      METHODS: Seventy consecutive patients underwent parotidectomy with intraoperative
      facial nerve monitoring. Two devices were used: a custom mechanical transducer
      and a commercial electromyograph-based apparatus. All patients were analyzed,
      including those with cancer and those with deliberate or accidental sectioning of
      facial nerve branches. The outcome variables were the motor facial nerve function
      according to the House-Brackmann grading scale (HB) at 1 week (temporary
      paralysis) and 6 to 12 months (definitive paralysis). Facial nerve grading was
      performed blindly from reviewing videotapes. RESULTS: The overall incidence of
      facial paralysis (HB>1) was 27% for temporary and 4% for permanent deficits. Most
      of the deficits were partial, most often concerning the marginal mandibular
      branch. Temporary deficits with HB scores of greater than 2 were only present in
      patients with parotid cancer or infection. Permanent deficits were present in
      three patients, including one patient with facial nerve sacrifice. Factors
      significantly associated with an increased incidence of temporary facial
      paralysis include the extent of parotidectomy, the intraoperative sectioning of
      facial nerve branches, the histopathology and the size of the lesion, and the
      duration of the operation. CONCLUSIONS: Despite a stringent accounting of
      postoperative facial nerve deficits, these data compare favorably to the
      literature with or without the use of monitoring. An overall incidence of 27% for
      temporary facial paralysis and 4% for permanent facial paralysis was found.
      Although the lack of a control group precludes definitive conclusions on the role
      of electromyograph-based facial nerve monitoring in routine parotidectomy, the
      authors found its use very helpful.

PMID- 10334227
TI  - A new technique for laser-assisted uvulopalatoplasty: decision-tree analysis and
      results.
AB  - OBJECTIVE: Report a new technique of laser-assisted uvulopalatoplasty (LAUP) for
      snoring performed as a one-stage procedure. STUDY DESIGN: A decision-tree was
      used in a prospective study of 89 patients from April 1994 to May 1997. It
      included a fiberscopy and Muller's maneuver, rhinomanometry, pH monitoring,
      computed tomography scan to measure the pharyngeal lumen, pulse oximetry, and
      polysomnography in case of sleep apnea syndrome was suspected. METHODS: The
      authors performed their LAUP technique on 43 patients (48.5%) whose snoring was
      mainly caused by the velum. This technique consists of scarifying the velum by
      vaporizing the mucosa and the submucosa along a rectangle extending from the
      palatal dimple to the uvula and having a width of 1.5 to 2 cm. Vaporization of
      the palatal arches follows without exceeding the junction of the anterior and
      posterior pillars in height. The uvula is cut if necessary, preserving a length
      of at least 0.5 cm. The other patients underwent different procedures according
      to the cause of snoring. RESULTS: There was no significant difference between
      LAUP and uvulopalatoplasty (UPPP) regarding pain. No permanent phonatory
      disorders and no regurgitation occurred. Satisfaction evaluated on a scale
      ranging from 0 to 10 was equivalent for the two techniques: mean value = 7.68 (+/
      2.18) for LAUP and 8.60 (+/-2.27) for UPPP. The mean follow-up was 17 months
      (range, 1-37 mo). Satisfaction was also identical for all techniques. CONCLUSION:
      Our LAUP technique combined with other procedures according to a decision-tree is
      efficient and safe.

PMID- 10334228
TI  - Efficacy of endoscopic static pressure/area assessment of the passive pharynx in
      predicting uvulopalatopharyngoplasty outcomes.
AB  - OBJECTIVES/HYPOTHESIS: Although uvulopalatopharyngoplasty (UPPP) is an attractive
      surgical treatment for obstructive sleep apnea (OSA), the unpredictable outcome
      limits application of the procedure. Since UPPP corrects only retropalatal airway
      (RP) patency, we hypothesized that response to UPPP is determined by
      collapsibility of the retroglossal airway (RG), where UPPP does not correct.
      METHODS: We estimated closing pressure (Pclose) for each pharyngeal segment by
      endoscopically obtaining the static pressure/area relationship of the passive
      pharynx in completely paralyzed and anesthetized patients with sleep-disordered
      breathing (n = 41) before UPPP. Preferable response to UPPP was defined as the
      number of oxygen dips (ODI), obtained by nocturnal oximetry, less than 10 h(-1)
      after UPPP. RESULTS: Patients with negative Pclose at RG responded to UPPP
      significantly better than those with positive Pclose at RG (22/30 [73%] vs. 3/11
      [27%], P<.05). ODI after UPPP was significantly correlated with age, Pclose at
      RP, and Pclose at RG. CONCLUSIONS: Endoscopic assessment of anatomic abnormality
      of the pharynx in paralyzed patients with sleep-disordered breathing under
      general anesthesia has clinical value for the improvement of UPPP outcome.

PMID- 10334229
TI  - Comparison of the sensitivity of lateral neck radiographs and computed tomography
      scanning in pediatric deep-neck infections.
AB  - OBJECTIVE: To compare the sensitivity of lateral neck films and computed
      tomography (CT) scanning with contrast in evaluating children with a high index
      of suspicion for a deep-neck infection, either retropharyngeal, parapharyngeal,
      or combined based in clinical presentation. STUDY DESIGN: A retrospective chart
      review of children presenting to the Children's Hospital of Buffalo, New York,
      with the diagnosis of a deep-neck infection between January 1991 and November
      1997 was conducted. In total, 57 children were included in the study, ranging in
      age from 12 to 119 months (1-10 y). METHODS: Charts were reviewed for presenting
      signs, symptoms, and laboratory values and included only those children with the
      presence of fever, limited neck range of motion, a lateral neck mass, dysphagia,
      and a leukocyte count greater than 15,000 cells/mm3. Results of lateral neck
      radiographs and CT scanning with contrast were evaluated and compared when
      available. RESULTS: Lateral neck radiographs were found to have a sensitivity of
      83% for determining the presence of a pediatric deep-neck infection, whereas CT
      scanning with contrast had a sensitivity of 100. CONCLUSION: Lateral neck
      radiographs were found to offer no benefit in the workup of children strongly
      suspected of having a deep-neck infection based on clinical presentation. Despite
      the higher cost, CT scanning with contrast is the recommended radiologic test in
      such cases. This single study allows the determination of size, type, and
      location of the infectious process and is invaluable in treatment planning for
      pediatric patients with infection in deep-neck spaces.

PMID- 10334230
TI  - Nasal dilator strips increase maximum inspiratory flow via nasal wall
      stabilization.
AB  - OBJECTIVE: Inspiratory flow limitation associated with collapse of the nasal
      vestibular walls is a feature of nasal breathing at high ventilatory levels. We
      examined whether an external nasal dilator strip (ENDS) device (Breathe Right,
      CNS Inc., Chanhassen, MN) influences maximum inspiratory and expiratory flow
      rates. STUDY DESIGN: Prospective, randomized. METHODS: We studied 20 Caucasian
      subjects (13 female, 7 male; age range, 16-49 y) performing maximum-effort nasal
      flow-volume loop studies with (ENDS) and without ENDS (control) and following
      topical nasal decongestant (oxymetazoline hydrochloride, 0.2 mg per nostril).
      RESULTS: ENDS increased peak inspiratory flow from 2.55+/-0.24 L/s (mean+/
      standard error [SE]) to 2.86+/-0.25 L/s and forced inspiratory flow at 50% of
      vital capacity from 2.23+/-0.24 L/s to 2.53+/-0.24 L/s (both, P<.0001), but had
      no effect on maximum expiratory flows. Nasal decongestant increased the forced
      expiratory volume in 1 second from 3.39+/-0.22 L/s to 3.59+/-0.22 L/s and the
      average forced expiratory flow over 25% to 75% of vital capacity from 3.31+/-0.31
      L/s to 3.61+/-0.28 L/s (both, P< or = .008), but had no effect on maximum
      inspiratory flows. The combination of decongestant and ENDS increased both
      inspiratory and expiratory maximum flows. CONCLUSION: Since ENDS selectively
      increases maximum nasal inspiratory flow rates, we conclude that ENDS increases
      inspiratory nasal patency during maximum inspiratory efforts through the nose by
      supporting the lateral nasal vestibular walls and making them more resistant to
      collapse.

PMID- 10334232
TI  - Approaches to the sellar and parasellar region: anatomic comparison of the
      microscope versus endoscope.
AB  - OBJECTIVE: Traditionally, surgical approaches to the sellar region require the
      use of the operating microscope. Over the past decade endoscopic surgery has
      gained much popularity because of advances in optics and illumination. Endoscopic
      surgery of the sellar region has been performed successfully. The goal of the
      present study was to quantify the amount of exposure to the sellar and
      suprasellar region that the endoscope provides versus the microscope, with three
      different anterior approaches to the sellar region. METHODS: The transethmoidal,
      endonasal-transsphenoidal, and sublabial-transsphenoidal approaches were
      performed on 14 formalin-fixed cadaver heads with a 0 degrees endoscope and
      repeated with the operative microscope. The distances of relevant surgical
      landmarks and the amount of exposure superior and anterior to the dorsum sella,
      as well as the lateral exposure, were measured. The mean distances were then used
      to calculate the volume of exposure for each of the approaches. RESULTS: It was
      found that the endoscope provided greater view than the operating microscope in
      all three approaches. The difference was statistically significant using a paired
      Student t test and a signed-rank test (P<.001). CONCLUSION: The authors believe
      that endoscopic surgery of the sellar region can be performed safely and
      effectively, while providing the surgeon with a view that is superior to that
      afforded by the operating microscope.

PMID- 10334231
TI  - Do corticosteroids induce apoptosis in nasal polyp inflammatory cells? In vivo
      and in vitro studies.
AB  - OBJECTIVE/HYPOTHESIS: Corticosteroids are an effective treatment for nasal
      polyposis. The exact mechanism of action is not certain. Recent research
      demonstrates that apoptosis (programmed cell death) in inflammatory cells is an
      important factor in the resolution of inflammation, and apoptosis is induced in
      eosinophils in cell culture with steroids. We hypothesized that inflammatory cell
      apoptosis is a key feature of regression of nasal polyps on exposure to steroids
      and examined this hypothesis in vivo and in vitro. METHODS: A double-blind,
      placebo-controlled pilot study of fluticasone propionate aqueous nasal spray
      (FPANS) in nasal polyposis in humans in vivo was undertaken, and the effect of
      treatment on indices of cell death and proliferation measured. In addition,
      explants of nasal polyp tissue were maintained in vitro in short-term tissue
      culture with dexamethasone at increasing doses (0.1-50 micromol) over varying
      time intervals and then analyzed for similar indices of proliferation and cell
      death. RESULTS: Apart from a marginal increase in apoptotic:mitotic ratio in
      epithelium, little difference between the effect of FPANS and placebo was
      demonstrated in vivo. However, in vitro, apoptotic index was significantly
      increased in the stromal layers in relation to time of incubation (P = .0169),
      and a significant dose-response relationship was demonstrated at 24 hours between
      stromal cell apoptosis and dexamethasone concentration (P = .001). Eosinophil
      apoptosis was confirmed by in situ end labeling and transmission electron
      microscopy. No steroid or time effect on epithelial cells was demonstrated in
      vitro. CONCLUSION: Corticosteroids induce apoptosis in inflammatory cells in
      human nasal polyps in vitro. This is not reflected by a similar response to FPANS
      at 14 days in vivo, but may still play a part in regression of polyps with other
      forms of administration or at other time points.

PMID- 10334233
TI  - Predictive factors of nodal metastases in oral cavity and oropharynx carcinomas.
AB  - OBJECTIVE: To estimate the value of tumor (T)-related parameters (singly or in
      association) in predicting the presence of occult metastases in oral cavity and
      oropharynx carcinomas. STUDY DESIGN: We considered tumor size (T size), Broders'
      grading of histologic differentiation (G), invasive cell grading (ICG), and
      thickness. For every single factor, we evaluated the correlation between the
      parameter and occult metastases in N0 neck disease, the correlation between the
      parameter and metastases independently from node (N) class, and the relation
      between the parameter and extracapsular spread. On the basis of previous results,
      we gave a score to each parameter that showed higher significativity the sum of
      which we called global score (GS). We compared the predictivity of metastasis of
      the GS to that of the single parameters to obtain a more efficacious index.
      METHODS: Sixty-one patients with carcinomas of the oral cavity and oropharynx who
      underwent surgery on T and N were examined. RESULTS: Our preliminary results have
      highlighted a significant correlation between G, ICG, and the presence of occult
      metastases. No correlation between T size and metastases was highlighted. The GS
      obtained from G and ICG turned out to be highly significant. A strong correlation
      was found between the ICG score and extracapsular spread: a high risk of
      extracapsular spread was found in patients with an ICG score > or =13.
      CONCLUSION: We perform elective neck dissection in T1-T2 N0 neck disease with ICG
      > or =13 and GS1 > or =9.

PMID- 10334234
TI  - A retrospective comparison of the morbidity and cost of different reconstructive
      strategies in oral and oropharyngeal carcinoma.
AB  - PURPOSE: Evaluate and compare the morbidity and costs of different reconstructive
      strategies in oral and oropharyngeal carcinoma. STUDY DESIGN: Retrospective cross
      sectional. PATIENTS AND METHODS: One hundred twenty-seven consecutive patients
      treated surgically for oral and oropharyngeal carcinoma between 1990 and 1996
      were evaluated. Sixty-three patients had segmental mandibulectomies with 30 plate
      soft tissue reconstructions and 33 bone-soft tissue flaps. Sixty-four patients
      had soft-tissue-only reconstructions. The following outcome parameters were
      analyzed: operative time, intraoperative blood loss, postoperative admission
      length, ICU and coronary care unit admission length, surgical interventions for
      complications, re-admissions, and prolonged (>6 mo) gastrostomy tube feeding, and
      all costs within the disease-free interval. Means and standard deviations were
      calculated for continuous parameters. Differences among the three groups were
      analyzed using one-way analysis of variance. For discontinuous parameters, the
      chi-square test was applied. RESULTS: Longer operative time (1.8 h) and more
      blood loss (150 mL) for bone-soft tissue flaps were the only statistically
      significant findings (P<.05) between the three groups. CONCLUSION: There is no
      rationale for allowing presumed factors of morbidity or cost select for type of
      reconstruction in patients with oral and oropharyngeal carcinoma.

PMID- 10334235
TI  - Stereotactic radiotherapy for locally recurrent nasopharyngeal carcinoma.
AB  - OBJECTIVE: To determine the efficacy of stereotactic radiotherapy (SRT) in the
      treatment of recurrent nasopharyngeal carcinoma. STUDY DESIGN: A retrospective
      review of the outcome of SRT for patients with recurrent nasopharyngeal
      carcinomas following definitive conventional radiation therapy. METHODS: Five
      patients were treated with daily static multiportal irradiation. Two Gy was
      administered with eight isocentric portals in a single plane 5 days a week, and
      the plane was changed for every 20 to 30 Gy. Of these patients, three had poorly
      differentiated squamous cell carcinoma. Tumor sizes ranged from 1 to 15 cm3, with
      a median size 3.2 cm3. Median follow-up time from SRT was 34 months (range, 4-61
      mo). RESULTS: Four of five recurrent tumors responded well and achieved complete
      regression. Three patients have survived without evidence of local recurrence
      with a median follow-up time of 34 months. Marginal recurrence was observed at
      the posterosuperior wall in a patient with adenoid cystic carcinoma at 30 months
      after SRT. One patient who received SRT after the two complete courses of
      radiation therapy died 6 months after SRT as a result of rupture of a branch of
      the left carotid artery, but autopsy revealed no local residual tumor.
      CONCLUSIONS: Stereotactic radiotherapy with isocentric multiportals in one plane,
      which is changed at every 20 to 30 Gy, can provide local control with acceptable
      toxicity in patients with recurrent nasopharyngeal carcinoma, but increased
      clinical experience and longer follow-up will be necessary to evaluate the
      overall role of this technique in nasopharyngeal carcinoma.

PMID- 10334236
TI  - Association of vascular endothelial growth factor expression with angiogenesis
      and lymph node metastasis in nasopharyngeal carcinoma.
AB  - OBJECTIVE: Recent experimental evidence indicates that angiogenesis affects tumor
      growth and metastasis. Vascular endothelial growth factor (VEGF) is considered to
      be an important regulator of tumor angiogenesis. The present study was designed
      to examine the role of VEGF on angiogenesis and lymph node metastasis in primary
      nasopharyngeal carcinomas (NPCs). STUDY DESIGN: Formalin-fixed paraffin-embedded
      biopsy specimens were obtained from 29 primary NPCs that consisted of 22
      differentiated nonkeratinizing carcinomas and seven undifferentiated carcinomas.
      METHODS: Microvessels were highlighted by staining endothelial cells with von
      Willebrand factor (VWF) using immunohistochemical techniques, and were counted
      (per x 400 field) in the most active area of angiogenesis on light microscopy.
      The expression of VEGF was also studied with immunohistochemistry. Positive ratio
      for VEGF was graded on a scale of 1 and 2. Scale 1 represents patients with less
      than the mean value of the positive ratio, and scale 2 represents patients with
      more than the corresponding value. RESULTS: There was a significant correlation
      between increased microvessel count and the progression of regional lymph node
      involvement. The microvessel counts and the progression of N factor were
      significantly higher in scale 2 patients than in scale 1 patients. CONCLUSION:
      These results suggest that VEGF plays an important role in lymph node metastasis
      through induction of angiogenesis in NPCs.

PMID- 10334237
TI  - Expression of protein p27 is associated with progression and prognosis in
      laryngeal cancer.
AB  - OBJECTIVE: A cyclin-dependent kinase inhibitor, p27kip1, is recognized as a
      negative regulator of the cell cycle. To clarify whether immunohistochemical
      detection of p27 might provide prognostic information, we investigated the
      expression of p27 in laryngeal squamous cell carcinoma (SCC). STUDY DESIGN: A
      retrospective study of patients was performed in 109 cases of laryngeal SCC. In
      addition, we investigated the expression of p53 and granulocyte colony
      stimulating factor receptor (GCSF-R) to examine the prognostic significance of
      them in the same samples. METHODS: Immunohistochemical staining by specific
      monoclonal antibodies was performed using the avidin-biotin-peroxidase complex
      technique. RESULTS: Advanced tumor size and clinical stage and the occurrence of
      lymph node metastasis were associated with the absence of p27 expression, but not
      correlated with p53 expression and GCSF-R expression. The overall 5-year survival
      rate in the p27-positive group was significantly higher than that in the p27
      negative group. In the Cox proportional hazard model, p27 was demonstrated to be
      the most powerful prognostic factor among gender, tumor size, lymph node
      metastasis, stage of disease, and p53 and GCSF-R expression. CONCLUSIONS: We
      concluded that assessment of p27 expression is useful as a prognostic factor for
      laryngeal SCC and of value in selecting patients with laryngeal SCC for
      aggressive therapy.

PMID- 10334238
TI  - Nerve cell adhesion molecule expression in squamous cell carcinoma of the head
      and neck: a predictor of propensity toward perineural spread.
AB  - OBJECTIVE: To evaluate head and neck squamous cell carcinomas (SCCAs) for the
      expression of nerve cell adhesion molecule (N-CAM). We propose that expression of
      N-CAM by tumor cells may be associated with perineural invasion in SCCA of the
      head and neck. METHODS: Seventy-six archived specimens of histologically proven
      SCCA were analyzed by immunohistochemistry for the expression of N-CAM. Positive
      and negative controls were used to assess staining. Two sections of each specimen
      were reviewed for the presence of perineural invasion. A retrospective chart
      review was performed for each patient that corresponded to the above specimens.
      RESULTS: Perineural invasion was present in 28 (37%) of the 76 patients evaluated
      for the expression of N-CAM. N-CAM expression was demonstrated in 38 (50%) of the
      76 specimens. The incidence of N-CAM expression was significantly associated with
      perineural invasion (P = .002). There was no significant association between the
      presence of staining or the presence of perineural invasion and the incidence of
      locoregional recurrence, distant metastasis, or survival status; however, the
      mean follow-up was only 13.6 months (range, 1-49 mo). CONCLUSION: There is a
      positive correlation between the presence of N-CAM expression and perineural
      invasion in SCCA of the head and neck. The expression of this adhesion molecule
      by tumor cells may facilitate both homophilic cell-to-cell and heterophilic cell
      to-substrate adhesion, thereby enabling the tumor cells to use the perineural
      tissues or neural cells, or both as a conduit for perineural spread.

PMID- 10334239
TI  - Age-related changes in orofacial force generation in women.
AB  - OBJECTIVES: This study was designed to assess the effect of age on orofacial
      force generation. STUDY DESIGN: Forty women participated in a cross-sectional
      design, with 10 in each age group from 20 to 39, 40 to 59, 60 to 79, and 80 to
      100 years of age. METHODS: Measures of force generation were obtained for the
      upper lip, lower lip, tongue, and jaw. RESULTS: There were no statistical
      differences among age groups, probably because of large individual variability
      within groups. Trends indicated a decline, particularly after age 80 years.
      CONCLUSION: Although trends in the data suggest some decline in the function of
      orofacial structures with age, it is unlikely that these changes would noticeably
      affect functional communication.

PMID- 10334240
TI  - Improved method of isolation of DNA from celloidin-embedded tissue.

PMID- 10334241
TI  - Arytenoid fixation surgery for the treatment of arytenoid fractures and
      dislocations.

PMID- 10334242
TI  - Bipolar scissor division of tongue-tie under tubeless anesthesia.

PMID- 10334243
TI  - Meatoplasty: the cartilage of the floor of the ear canal.

PMID- 10334244
TI  - Role of computed tomography scan in the diagnosis and treatment of deep neck
      infections in children.

PMID- 10334245
TI  - Is smallpox history?

PMID- 10334246
TI  - Coronary heart disease: where have we been and where are we going?

PMID- 10334247
TI  - Facing up to re-emergence of urban yellow fever.

PMID- 10334248
TI  - What is "hypertension"?

PMID- 10334249
TI  - Controlled clinical evaluation of diacetyl morphine for treatment of intractable
      opiate dependence.

PMID- 10334250
TI  - What is in store after stem-cell transplantation?

PMID- 10334251
TI  - Prospects for therapy of nitrate tolerance.

PMID- 10334252
TI  - Contribution of trends in survival and coronary-event rates to changes in
      coronary heart disease mortality: 10-year results from 37 WHO MONICA project
      populations. Monitoring trends and determinants in cardiovascular disease.
AB  - BACKGROUND: The WHO MONICA (monitoring trends and determinants in cardiovascular
      disease) Project monitored, from the early 1980s, trends over 10 years in
      coronary heart disease (CHD) across 37 populations in 21 countries. We aimed to
      validate trends in mortality, partitioning responsibility between changing
      coronary-event rates and changing survival. METHODS: Registers identified non
      fatal definite myocardial infarction and definite, possible, or unclassifiable
      coronary deaths in men and women aged 35-64 years, followed up for 28 days in or
      out of hospital. We calculated rates from population denominators to estimate
      trends in age-standardised rates and case fatality (percentage of 28-day
      fatalities=[100-survival percentage]). FINDINGS: During 371 population-years,
      166,000 events were registered. Official CHD mortality rates, based on death
      certification, fell (annual changes: men -4.0% [range -10.8 to 3.2]; women -4.0%
      [-12.7 to 3.0]). By MONICA criteria, CHD mortality rates were higher, but fell
      less (-2.7% [-8.0 to 4.2] and -2.1% [-8.5 to 4.1]). Changes in non-fatal rates
      were smaller (-2.1%, [-6.9 to 2.8] and -0.8% [-9.8 to 6.8]). MONICA coronary
      event rates (fatal and non-fatal combined) fell more (-2.1% [-6.5 to 2.8] and 
      1.4% [-6.7 to 2.8]) than case fatality (-0.6% [-4.2 to 3.1] and -0.8% [-4.8 to
      2.9]). Contribution to changing CHD mortality varied, but in populations in which
      mortality decreased, coronary-event rates contributed two thirds and case
      fatality one third. INTERPRETATION: Over the decade studied, the 37 populations
      in the WHO MONICA Project showed substantial contributions from changes in
      survival, but the major determinant of decline in CHD mortality is whatever
      drives changing coronary-event rates.

PMID- 10334253
TI  - Urbanisation of yellow fever in Santa Cruz, Bolivia.
AB  - BACKGROUND: Reinvasion by Aedes aegypti of cities in the Americas poses a threat
      of urbanisation of yellow fever. After detection of yellow-fever infection in a
      resident of the city of Santa Cruz, Bolivia, in December, 1997, we investigated
      all subsequent suspected cases. METHODS: We introduced active surveillance of
      yellow fever in the Santa Cruz area. Hospitals and selected urban and rural
      health centres reported all suspected cases. Patients were serologically screened
      for yellow fever, dengue, hepatitis A and B, and leptospirosis. We collected
      clinical and epidemiological information from patients' records and through
      interviews. We also carried out a population-based serosurvey in the
      neighbourhood of one case. FINDINGS: Between December, 1997, and June, 1998,
      symptomatic yellow-fever infection was confirmed in six residents of Santa Cruz,
      five of whom died. Five lived in the southern sector of the city. Two had not
      left the city during the incubation period, and one had visited only an area in
      which sylvatic transmission was deemed impossible. Of the 281 people covered in
      the serosurvey 16 (6%) were positive for IgM antibody to yellow fever. Among five
      people for whom this result could not be explained by recent vaccination, there
      were two pairs of neighbours. INTERPRETATION: Urban transmission of yellow fever
      in Santa Cruz was limited in space and time. Low yellow-fever immunisation
      coverage and high infestation with A. aegypti in the city, and the existence of
      endemic areas in the region present a risk for future urban outbreaks. We
      recommend immediate large-scale immunisation of the urban population, as well as
      tightened surveillance and appropriate vector control.

PMID- 10334254
TI  - Influence of abdominal-wound closure technique on complications after surgery: a
      randomised study.
AB  - BACKGROUND: Wound complications that occur after closure of midline laparotomy
      remain challenging. A new continuous double-loop closure (CDLC) technique was
      developed to avoid wound rupture through resistance to high intra-abdominal
      pressure and continued approximation of wound edges. We investigated the efficacy
      of this technique. METHODS: We randomly assigned 390 patients undergoing midline
      laparotomy-wound closure with the commonly used continuous running suture (CRS)
      technique (n=204) or with the CDLC technique (n=186). We assessed the influence
      of closure technique on the rate of wound and other complications, with emphasis
      on wound dehiscence, pulmonary complications, and death. FINDINGS: The rate of
      wound complications did not differ significantly between groups. Pulmonary
      complications were seen in 11 patients (5.4%) in the CRS group, and in 32
      patients (17.2%) in the CDLC group (p=0.0002). In the CRS group, 17 (8.3%)
      patients died, compared with 39 (21.0%) patients in the CDLC group (p=0.0004).
      INTERPRETATION: The CDLC technique should not be used. The lessened compliance of
      the abdominal wall, which raises intra-abdominal pressure for long periods, may
      increase the risk of postoperative pulmonary complications and death. The ideal
      closure technique should combine strength to prevent wound rupture with
      elasticity to adapt to increased intra-abdominal pressure.

PMID- 10334255
TI  - Comparison of combination therapy with single-drug therapy in early rheumatoid
      arthritis: a randomised trial. FIN-RACo trial group.
AB  - BACKGROUND: The treatment of rheumatoid arthritis should aim at clinical
      remission. This multicentre, randomised trial with 2-year follow-up sought
      evidence on the efficacy and tolerability of combination therapy (sulphasalazine,
      methotrexate, hydroxychloroquine, and prednisolone) compared with treatment with
      a single disease-modifying antirheumatic drug, with or without prednisolone, in
      the treatment of early rheumatoid arthritis. METHODS: 199 patients were randomly
      assigned to two treatment groups. 195 started the treatment (97 received
      combination and 98 single drug therapy). Single-drug therapy in all patients
      started with sulphasalazine; in 51 patients methotrexate was later substituted.
      Oral prednisolone was required by 63 patients. The primary outcome measure was
      induction of remission. Analyses were intention to treat. FINDINGS: 87 patients
      in the combination group and 91 in the single-therapy group completed the trial.
      After a year, remission was achieved in 24 of 97 patients with combination
      therapy, and 11 of 98 with single-drug therapy (p=0.011). The remission
      frequencies at 2 years were 36 of 97 and 18 of 98 (p=0.003). Clinical improvement
      (American College of Rheumatology criteria of 50% clinical response) was achieved
      after 1 year in 68 (75%) patients with combination therapy, and in 56 (60%) using
      single-drug therapy (p=0.028), while at the 2-year visit 69 and 57 respectively
      (71% vs 58%, p=0.058) had clinically improved. The frequencies of adverse events
      were similar in both treatment groups. INTERPRETATION: Combination therapy was
      better and not more hazardous than single treatment in induction of remission in
      early rheumatoid arthritis. The combination strategy as an initial therapy seems
      to increase the efficacy of the treatment in at least a proportion of patients
      with early rheumatoid arthritis.

PMID- 10334256
TI  - Efficacy and acceptability of intranasal 17 beta-oestradiol for menopausal
      symptoms: randomised dose-response study. Aerodiol Study Group.
AB  - BACKGROUND: The benefit of oestrogen therapy for menopause symptoms is well
      recognised. However, the means of delivery currently available have
      disadvantages, including variable bioavailability, intestinal and hepatic first
      pass effects, and dermatological reactions. An intranasal 17beta-oestradiol
      spray, S21400, which bypasses such drawbacks, has been developed. We studied the
      efficacy and tolerability of S21400 in the treatment of postmenopausal symptoms.
      METHODS: In this double-blind study, 420 postmenopausal women were randomly
      allocated to receive intranasal placebo or S21400 in doses of 100 microg, 200
      microg, 300 microg, or 400 microg, or oral oestradiol valerate in doses of 1 mg
      or 2 mg, daily for 12 weeks. The primary outcomes were the Kupperman Index (KI)
      and the incidence of hot flushes. Tolerability assessments included rhinoscopy
      and ciliary function tests. FINDINGS: S21400 dose-dependently decreased KI
      (p<0.001), with a lowest effective dose of 300 microg/day at 4 weeks (p<0.05) and
      200 microg/day at 12 weeks (p<0.01). The incidence of hot flushes decreased by a
      maximum of 75% (S21400 lowest effective dose 200 microg/day at 4 weeks and 100
      microg/day at 12 weeks). S21400 increased serum oestradiol exposure dose
      dependently, to concentrations similar to those achieved with oral oestradiol 1-2
      mg, with lower intra-patient and inter-patient variability. There was no
      significant difference in ear, nose, and throat function or adverse events
      between the S21400 and the placebo or oral oestradiol groups, except for a
      greater incidence of sneezing and application site reaction (99% mild or
      moderate) in the S21400 groups. S21400 was thought to be effective and convenient
      by the patients, and compliance was high. INTERPRETATION: Intranasally
      administered 17beta-oestradiol is significantly better than placebo; its
      effectiveness at reducing menopausal symptoms is similar to that of oral
      oestradiol and is also well-tolerated. Intranasal administration avoids first
      pass metabolism and provides a reproducible, easily adjustable dosing mechanism
      that represents a new option for hormone replacement therapy.

PMID- 10334257
TI  - Non-invasive diagnosis of hepatic cirrhosis by transit-time analysis of an
      ultrasound contrast agent.
AB  - BACKGROUND: Hepatic cirrhosis is accompanied by several haemodynamic changes
      including arterialisation of the liver, intrahepatic shunts, pulmonary
      arteriovenous shunts, and a hyperdynamic circulatory state. We postulated that
      the hepatic first pass of a bolus of an ultrasound contrast agent injected into a
      peripheral vein is accelerated in patients with cirrhosis. We investigated this
      first pass in patients with diffuse liver disease and in normal controls to
      assess whether it provides useful differential diagnostic information. METHODS:
      We enrolled 15 patients with biopsy-proven cirrhosis, 12 patients with biopsy
      proven non-cirrhotic diffuse liver disease, and 11 normal controls. We carried
      out continuous spectral doppler ultrasonography of a hepatic vein from 20 s
      before to 3 min after a peripheral intravenous bolus injection of 2.5 g Levovist.
      The intensity of the doppler signal was measured and used to plot time-intensity
      curves. FINDINGS: Patients with cirrhosis showed a much earlier onset of
      enhancement (arrival time; mean 18.3 s) and peak enhancement (mean 55.5 s) than
      controls (49.8 s and 97.5 s) or patients with non-cirrhotic diffuse liver disease
      (35.8 s and 79.7 s). All patients with cirrhosis had an arrival time of the bolus
      of less than 24 s, whereas the arrival time was 24 s or more in 22 of the 23
      other participants. Peak enhancement was higher in patients with cirrhosis (mean
      48.7 units) than in the other two groups (12.5 and 12.3 units, respectively). We
      found highly significant differences between the patients with cirrhosis and each
      of the other two groups for all variables (p<0.005), whereas we found no
      significant differences between non-cirrhotic patients and controls.
      INTERPRETATION: Our preliminary study suggests that analysis of liver transit
      time of a bolus of ultrasound contrast agent provides useful information about
      haemodynamic changes in patients with cirrhosis. Measurement of the arrival time
      of the bolus allows discrimination of patients with cirrhosis from controls and
      from patients with non-cirrhotic diffuse liver disease, and has potential as a
      non-invasive test for cirrhosis.

PMID- 10334258
TI  - Pregnant, vomiting, and coma.

PMID- 10334259
TI  - Impervious wound-edge protector to reduce postoperative wound infection: a
      randomised, controlled trial.

PMID- 10334260
TI  - Outbreak of rare serotype of group A streptococcus pharyngitis in a boarding
      college.

PMID- 10334261
TI  - Homocysteine in cerebral macroangiography and microangiopathy.

PMID- 10334262
TI  - Vancomycin in surgical infections due to methicillin-resistant Staphylococcus
      aureus with heterogeneous resistance to vancomycin.

PMID- 10334263
TI  - Induction of type 2 Shiga toxin synthesis in Escherichia coli O157 by 4
      quinolones.

PMID- 10334264
TI  - A non-HLA gene within the MHC in psoriasis.

PMID- 10334265
TI  - Ciprofloxacin-resistant Salmonella typhi and treatment failure.

PMID- 10334266
TI  - Detection of ErbB2 oversignalling in a majority of breast cancers with
      phosphorylation-state-specific antibodies.

PMID- 10334267
TI  - Bias against European journals in medical publication Databases.

PMID- 10334269
TI  - The healthy home of the future comes to Japan.

PMID- 10334270
TI  - Zuma defends decision to make AIDS a notifiable disease.

PMID- 10334268
TI  - Crumbling bones yield to molecular biology.

PMID- 10334271
TI  - Thailand attacks AIDS with two-pronged approach.

PMID- 10334272
TI  - Neurobehavioural sequelae of cardiopulmonary bypass.
AB  - The development of coronary artery bypass grafting (CABG) and its effect on
      angina is the product of a series of technical and scientific advances. Despite
      these advances, however, adverse neurobehavioural outcomes continue to occur.
      Stroke is the most serious complication of CABG, but studies that have identified
      demographic and medical risk factors available before surgery are an important
      advance. Short-term cognitive deficits are common after CABG, but may not be
      specific to this procedure. However, deficits in some cognitive areas such as
      visuoconstruction persist over time, and may reflect parieto-occipital watershed
      area injury secondary to hypoperfusion or embolic factors. Risk factors for
      cognitive decline may be time dependent, with short-term studies identifying
      factors that differ from those of long-term studies. Patients with depression
      before surgery are likely to have persistent depression afterwards. However,
      depression does not account for the cognitive decline after CABG. Since CABG is
      increasingly done in older patients with more comorbidity, the challenge is to
      identify patients at risk of adverse neurocognitive outcomes and to protect them
      by modification of the surgical procedure or by effective medical therapy.

PMID- 10334273
TI  - Pain: an overview.
AB  - Until the 1960s, pain was considered an inevitable sensory response to tissue
      damage. There was little room for the affective dimension of this ubiquitous
      experience, and none whatsoever for the effects of genetic differences, past
      experience, anxiety, or expectation. In recent years, great advances have been
      made in our understanding of the mechanisms that underlie pain and in the
      treatment of people who complain of pain. The roles of factors outside the
      patient's body have also been clarified. Pain is probably the most common
      symptomatic reason to seek medical consultation. All of us have headaches, burns,
      cuts, and other pains at some time during childhood and adult life. Individuals
      who undergo surgery are almost certain to have postoperative pain. Ageing is also
      associated with an increased likelihood of chronic pain. Health-care expenditures
      for chronic pain are enormous, rivalled only by the costs of wage replacement and
      welfare programmes for those who do not work because of pain. Despite improved
      knowledge of underlying mechanisms and better treatments, many people who have
      chronic pain receive inadequate care.

PMID- 10334274
TI  - The neurobiology of pain.
AB  - Understanding the plasticity of pain and analgesia exhibited in different pain
      states may improve therapies for the two major types of pain, neuropathic and
      inflammatory pain, in which nerve and tissue damage leads to alterations at both
      peripheral and central levels. At the level of the peripheral nerve, drugs that
      act on particular sodium channels may target only pain-related activity. Agents
      that act on some of the peripheral mediators of pain may control peripheral nerve
      activity. A new generation of non-steroidal anti-inflammatory drugs, cyclo
      oxygenase 2 inhibitors, that lack gastric actions are becoming available. In the
      spinal cord, the release of peptides and glutamate causes activation of multiple
      receptors, particularly, the N-methyl-D-aspartate receptor for glutamate, which,
      in concert with other spinal systems, generates spinal hypersensitivity. Blocking
      the generation of excitability is one approach, but increasing inhibitions may
      also provide analgesia. Opioid actions are via presynaptic and post-synaptic
      inhibitory effects on central and peripheral C fibre terminals, spinal neurones,
      and supraspinal mechanisms. Our knowledge of brain mechanisms of pain is still,
      however, limited. Other new targets have been revealed by molecular biology and
      animal models of clinical pain, but the possibility of a "magic bullet" is
      doubtful. Thus, another approach could be single molecules with dual drug
      actions, that encompass targets where additive or synergistic effects of
      different mechanisms may enable pain relief without major adverse effects.

PMID- 10334275
TI  - Mental health care for refugees from Kosovo: the experience of Medecins Sans
      Frontieres.

PMID- 10334276
TI  - Hydrocortisone and chronic fatigue syndrome.

PMID- 10334277
TI  - Hydrocortisone and chronic fatigue syndrome.

PMID- 10334278
TI  - Hydrocortisone and chronic fatigue syndrome.

PMID- 10334279
TI  - Hydrocortisone and chronic fatigue syndrome.

PMID- 10334280
TI  - Thromboprophylaxis for atrial fibrillation.

PMID- 10334281
TI  - Evidence and primary care.

PMID- 10334282
TI  - Evidence and primary care.

PMID- 10334283
TI  - Evidence and primary care.

PMID- 10334284
TI  - Evidence and primary care.

PMID- 10334285
TI  - Methylene blue and fatal encephalopathy from ackee fruit poisoning.

PMID- 10334286
TI  - Methylene blue and fatal encephalopathy from ackee fruit poisoning.

PMID- 10334287
TI  - Methylene blue and fatal encephalopathy from ackee fruit poisoning.

PMID- 10334288
TI  - Preoperative fasting.

PMID- 10334289
TI  - Ageing eyes retain their mystery.

PMID- 10334290
TI  - Closing the gap in drug therapy.

PMID- 10334291
TI  - Racism in Australia's medical establishment.

PMID- 10334292
TI  - What are human rights?

PMID- 10334294
TI  - The Nobel chronicles. 1953: Hans Adolf Krebs (1900-81) and Fritz Albert Lipmann
      (1899-1986).

PMID- 10334293
TI  - Funding clinical research.

PMID- 10334295
TI  - Rewriting the book of the body.

PMID- 10334296
TI  - Sketches from the Lancet. Pollution.

PMID- 10334297
TI  - Islet amyloid: a long-recognized but underappreciated pathological feature of
      type 2 diabetes.
AB  - Islet amyloid has been recognized as a pathological entity in type 2 diabetes
      since the turn of the century. It has as its unique component the islet beta-cell
      peptide islet amyloid polypeptide (IAPP), or amylin, which is cosecreted with
      insulin. In addition to this unique component, islet amyloid contains other
      proteins, such as apolipoprotein E and the heparan sulfate proteoglycan perlecan,
      which are typically observed in other forms of generalized and localized amyloid.
      Islet amyloid is observed at pathological examination in the vast majority of
      individuals with type 2 diabetes but is rarely observed in humans without
      disturbances of glucose metabolism. In contrast to IAPP from rodents, human IAPP
      has been shown to form amyloid fibrils in vitro. Because all human subjects
      produce and secrete the amyloidogenic form of IAPP, yet not all develop islet
      amyloid, some other factor(s) must be involved in islet amyloid formation. One
      hypothesis is that an alteration in beta-cell function resulting in a change in
      the production, processing, and/or secretion of IAPP is critical to the initial
      formation of islet amyloid fibrils in human diabetes. This nidus of amyloid
      fibrils then allows the progressive accumulation of IAPP-containing fibrils and
      the eventual replacement of beta-cell mass by amyloid and contributes to the
      development of hyperglycemia. One factor that may be involved in producing the
      changes in the beta-cell that result in the initiation of amyloid formation is
      the consumption of increased dietary fat. Dietary fat is known to alter islet
      beta-cell peptide production, processing, and secretion, and studies in
      transgenic mice expressing human IAPP support the operation of this mechanism.
      Further investigation using this and other models should provide insight into the
      mechanism(s) involved in islet amyloidogenesis and allow the development of
      therapeutic agents that inhibit or reverse amyloid fibril formation, with the
      goal being to preserve beta-cell function and improve glucose control in type 2
      diabetes.

PMID- 10334298
TI  - Troglitazone, an antidiabetic agent, inhibits cholesterol biosynthesis through a
      mechanism independent of peroxisome proliferator-activated receptor-gamma.
AB  - Troglitazone is an antidiabetic agent of the thiazolidinedione family. It is
      generally believed that thiazolidinediones exert their insulin-sensitizing
      activity through activation of peroxisome proliferator-activated receptor-gamma
      (PPAR-gamma), a member of the steroid nuclear receptor superfamily. In the
      present study, we examined the effect of troglitazone on cholesterol biosynthesis
      in cultured Chinese hamster ovary (CHO) cells. Troglitazone inhibited
      biosynthesis of cholesterol, but not that of total sterols, in a dose-dependent
      manner, with a half-maximal concentration (IC50) value of 8 micromol/l. At 20
      micromol/l, troglitazone inhibited cholesterol biosynthesis by more than 80%,
      resulting in the accumulation of lanosterol and several other sterol products.
      This inhibitory effect observed in CHO cells was also reproduced in HepG2, L6,
      and 3T3-L1 cells, suggesting that there is a common pathway for this troglitazone
      action. One hour after removal of troglitazone from the culture medium,
      disappearance of the accumulated sterols was accompanied by restored cholesterol
      synthesis, indicating that those accumulated sterols are precursors of
      cholesterol. PPAR-gamma reporter assays showed that PPAR-gamma activation by
      troglitazone was completely blocked by actinomycin D and cycloheximide. In
      contrast, the inhibition of cholesterol synthesis by troglitazone remained
      unchanged in the presence of the above compounds, suggesting that this inhibition
      is mechanistically distinct from the transcriptional regulation by PPAR-gamma.
      Like troglitazone, two other thiazolidinediones, ciglitazone and englitazone,
      exhibited similar inhibitory effect on cholesterol synthesis; however, other
      known PPAR-gamma ligands such as BRL49653, pioglitazone, and 15-deoxy
      delta(12,14)-prostaglandin J2 showed only weak or no inhibition. The dissociation
      of PPAR-gamma binding ability from the potency for inhibition of cholesterol
      synthesis further supports the conclusion that inhibition of cholesterol
      biosynthesis by troglitazone is unlikely to be mediated by PPAR-gamma.

PMID- 10334300
TI  - Altered energy balance causes selective changes in melanocortin-4(MC4-R), but not
      melanocortin-3 (MC3-R), receptors in specific hypothalamic regions: further
      evidence that activation of MC4-R is a physiological inhibitor of feeding.
AB  - We have examined the effects of underfeeding and obesity on the density of
      hypothalamic melanocortin MC3 and MC4 receptors (MC3-R and MC4-R, respectively),
      which may mediate the hypophagic effects of alpha-melanocyte-stimulating hormone
      (MSH) in the rat. MC3-R and MC4-R were measured by quantitative autoradiography
      in brain sections using 125I-labeled Nle4-D-Phe7-alpha-MSH (125I-NDP-MSH) and
      discriminated by masking MC3-R with excess unlabelled gamma2-MSH. High densities
      of MC4-R occurred in the ventromedial (VMH) and arcuate (ARC) nuclei, median
      eminence (ME), and medial habenular nucleus (MHb), with lower densities in the
      dorsomedial hypothalamus (DMH) and forebrain regions. MC3-R were confined to the
      VMH, ARC, and MHb. After 10-days of food restriction (14% weight loss), density
      of MC4-R was significantly increased by 20-65% in the VMH, ARC, ME, and DMH, with
      no changes elsewhere. Similarly, obese (fa/fa) Zucker rats showed 43-98%
      increases in MC4-R in the same regions. By contrast, rats with diet-induced
      obesity (18% heavier than controls) showed significantly decreased binding to MC4
      R, especially in the VMH, ARC, and ME. MC3-R showed no significant alterations in
      any model. We suggest that increased density of MC4-R with food restriction and
      in obese Zucker rats reflects receptor upregulation secondary to decreased
      release of alpha-MSH, consistent with increased hunger in these models.
      Conversely, downregulation of MC4-R in diet-induced obesity may indicate
      increased alpha-MSH secretion in an attempt to limit overeating. This alpha
      MSH/MC4-R system may be inhibited by leptin and/or insulin. MC3-R are not
      apparently involved in regulating feeding.

PMID- 10334299
TI  - Renal glucose production during insulin-induced hypoglycemia in humans.
AB  - We investigated the effects of hypoglycemia on renal glucose production (RGP) and
      renal glucose uptake (RGU) using arteriovenous balance combined with tracer
      technique in humans. Our 14 healthy subjects had arterialized hand veins (artery)
      and renal veins (under fluoroscopy) catheterized after an overnight fast.
      Systemic and renal glucose kinetics were measured with infusion of [6
      (2)H2]glucose, and renal plasma flow was measured by para-aminohippurate
      clearance. After a 150-min equilibration period, artery and renal vein samples
      were obtained between -30 and 0 min, and subjects received a 180-min peripheral
      insulin infusion (0.250 mU kg(-1) x min(-1)) with a variable infusion of [6
      (2)H2]dextrose adjusted to maintain plasma glucose at either approximately 60
      mg/dl (hypoglycemic clamp) or approximately 90 mg/dl (euglycemic clamp). Blood
      samples were obtained between 150 and 180 min during the study period. Insulin
      increased from 49 +/- 14 to 130 +/- 25 (hypoglycemia) and to 102 +/- 10
      (euglycemia) pmol/l. Glucose decreased from 5.32 +/- 0.11 to 3.58 +/- 0.07
      micromol/ml during hypoglycemia, but it did not change during euglycemia (5.20 +/
      0.19 vs. 5.05 +/- 0.15 micromol/ml). Endogenous glucose production decreased
      (9.30 +/- 0.70 vs. 5.65 +/- 0.50) during euglycemia but not during hypoglycemia
      (9.80 +/- 0.50 vs. 10.25 +/- 0.60 micromol x kg(-1) x min(-1)). During
      hypoglycemia, net renal glucose output increased from 0.54 +/- 0.30 to 2.31 +/-
      0.40, RGP increased from 1.88 +/- 0.70 to 3.65 +/- 0.50 (P < 0.05), and RGU did
      not change (1.34 +/- 0.50 vs. 1.34 +/- 0.60 micromol x kg(-1) x min(-1)). During
      euglycemia, renal glucose balance switched from a net output of 0.72 +/- 0.20 to
      a net uptake of 1.70 +/- 0.92, RGP decreased from 2.31 +/- 0.50 to 1.20 +/- 0.58,
      and RGU increased from 1.59 +/- 0.50 to 2.90 +/- 0.70 micromol x kg(-1) x min(-1)
      (P < 0.05). During hypoglycemia, arterial glucagon increased from 105 +/- 6 to
      129 +/- 8, epinephrine increased from 116 +/- 28 to 331 +/- 33, norepinephrine
      increased from 171 +/- 9 to 272 +/- 9 (all P < 0.05), and renal vein
      norepinephrine increased from 236 +/- 13 to 426 +/- 50 (P < 0.001). These data
      indicate that, in addition to counterregulatory hormones, activation of the
      autonomic nervous system during hypoglycemia stimulates glucose production by the
      kidney, which may represent an important additional component of the body's
      defense against hypoglycemia in humans.

PMID- 10334301
TI  - Regulation of ob gene expression and leptin secretion by insulin and
      dexamethasone in rat adipocytes.
AB  - Leptin, the ob gene product, is produced by adipocytes, and it acts to decrease
      caloric intake and increase energy expenditure. To better understand the
      molecular mechanisms of hormone-regulated leptin synthesis and secretion, we
      assessed the ability of insulin and dexamethasone to acutely modulate ob gene
      expression and leptin secretion in rat adipocytes. Incubation of rat adipocytes
      with 100 nmol/l insulin for 2 h had no effect on ob mRNA levels, but it
      stimulated a twofold increase in leptin secretion. Dexamethasone (100 nmol/l)
      stimulated both a two- to fourfold increase in ob mRNA and a twofold increase in
      leptin secretion. Consonant with a posttranscriptional and transcriptional
      regulatory mechanism for insulin- and dexamethasone-stimulated leptin secretion,
      respectively, actinomycin D blocked dexamethasone-stimulated leptin secretion but
      did not affect insulin-stimulated leptin secretion. Cycloheximide treatment did
      not significantly affect ob mRNA accumulation, but it reduced total secreted
      leptin. Interestingly, however, insulin was still able to stimulate a twofold
      increase in leptin secretion. These data suggest that insulin, but not
      dexamethasone, is able to stimulate leptin secretion from a preexisting
      intracellular pool, although de novo protein synthesis is required for the full
      insulin-stimulated effect. Signaling pathways involved in leptin
      synthesis/secretion were also evaluated. The phosphatidylinositol 3-kinase
      inhibitor LY294002, the Map/Erk kinase inhibitor PD98059, and the
      immunosuppressant rapamycin had no effect on basal levels of leptin secretion.
      However, all three inhibitors markedly decreased both insulin- and dexamethasone
      stimulated leptin secretion. These findings suggest a complex set of signaling
      pathways involved in mediating insulin- and dexamethasone-stimulated leptin
      synthesis and secretion.

PMID- 10334302
TI  - Functional properties of leptin receptor isoforms: internalization and
      degradation of leptin and ligand-induced receptor downregulation.
AB  - Long (ObRb) and short (ObRa) leptin receptor isoforms are thought to play
      essential roles in mediating leptin signaling and the transport and degradation
      of leptin, respectively. Although the capacity of these cloned receptor species
      to mediate signal transduction has been reported, there is no information on the
      ability of individual receptor species to mediate leptin internalization and
      degradation or to undergo ligand-induced downregulation. We therefore studied
      these parameters in Chinese hamster ovary (CHO) cells stably expressing either
      ObRa or ObRb isoforms of the leptin receptor. We determined that both ObRa and
      ObRb mediated internalization of 125I-labeled leptin by a temperature- and coated
      pit-dependent mechanism. Both ObRa and ObRb also mediated degradation of 125I
      leptin by a lysosomal mechanism, and this was more efficiently mediated by ObRa
      in these cells. Neither leptin internalization nor degradation by ObRa was
      affected by mutation of the conserved Box 1 motif. By studying deletion mutants
      of ObRa, we found that efficient internalization was dependent on a motif located
      between amino acids 8 and 29 of the intracellular domain of ObRa. Exposure of
      cells expressing ObRa or ObRb to unlabeled leptin for 90 min at 37 degrees C
      produced downregulation of available surface receptors, and this effect was of
      greater magnitude in cells expressing ObRb. Whereas CHO cells expressing the
      growth hormone receptor showed marked downregulation of ligand binding after
      exposure to dexamethasone (DEX) or phorbol myristic acid (PMA), PMA had no effect
      on expression of ObRa or ObRb, and DEX reduced binding to cells expressing ObRb
      by 15%. Thus, the two leptin receptor isoforms, ObRa and ObRb, mediate leptin
      internalization by a coated pit-dependent mechanism, leptin degradation by a
      lysosomal pathway, and ligand-induced receptor downregulation. The differential
      capacity of the two receptor isoforms may relate to the different roles of the
      receptor isoforms in the biology of leptin.

PMID- 10334303
TI  - Microinjection of leptin into the ventromedial hypothalamus increases glucose
      uptake in peripheral tissues in rats.
AB  - We studied the effects of microinjection of leptin into the ventromedial
      hypothalamus (VMH) and lateral hypothalamus (LH) on glucose uptake in peripheral
      tissues in unanesthetized rats. The rate of glucose uptake was assessed in vivo
      by 2-[3H]deoxyglucose incorporation. Single injection of leptin into VMH
      increased glucose uptake in brown adipose tissue (BAT), heart, skeletal muscles,
      and spleen but not in white adipose tissue or skin. On the other hand,
      microinjection of leptin into LH had little effect on glucose uptake in those
      tissues. The plasma concentrations of glucose and insulin were unaltered by
      intrahypothalamic injection of leptin into either VMH or LH. Among skeletal
      muscles, the increase in glucose uptake induced by intrahypothalamic injection of
      leptin was greater in the soleus than in the extensor digitorum longus. Likewise,
      the increased glucose uptake in the gastrocnemius in response to leptin was more
      prominent in the red part than in the white part of the tissue. When surgical
      sympathetic denervation of the interscapular BAT was performed, the enhanced
      glucose uptake by BAT in response to intrahypothalamic leptin was completely
      suppressed. These findings suggest that intrahypothalamic injection of leptin
      preferentially increases glucose uptake by some peripheral tissues through
      activation of the VMH-sympathetic (or its neighboring medial hypothalamus
      sympathetic) nervous system, thereby contributing to the maintenance of energy
      balance.

PMID- 10334304
TI  - Contributions by kidney and liver to glucose production in the postabsorptive
      state and after 60 h of fasting.
AB  - Contributions of renal glucose production to whole-body glucose turnover were
      determined in healthy individuals by using the arteriovenous balance technique
      across the kidneys and the splanchnic area combined with intravenous infusion of
      [U-13C6]glucose, [3-(3)H]glucose, or [6-(3)H]glucose. In the postabsorptive
      state, the rate of glucose appearance was 11.5 +/- 0.6 micromol x kg(-1) x min(
      1). Hepatic glucose production, calculated as the sum of net glucose output (9.8
      +/- 0.8 micromol x kg(-1) x min(-1)) and splanchnic glucose uptake (2.2 +/- 0.3
      micromol x kg(-1) x min(-1)) accounted for the entire rate of glucose appearance.
      There was no net exchange of glucose across the kidney and no significant renal
      extraction of labeled glucose. The renal contribution to total glucose production
      calculated from the arterial, hepatic, and renal venous 13C-enrichments (glucose
      M+6) was 5 +/- 2%. In the 60-h fasted state, the rate of glucose appearance was
      8.2 +/- 0.3 micromol x kg(-1) x min(-1). Hepatic glucose production, estimated as
      net splanchnic output (5.8 +/- 0.7 micromol x kg(-1) x min(-1)) plus splanchnic
      uptake (0.6 +/- 0.3 micromol x kg(-1) x min(-1)) accounted for 79% of the rate of
      glucose appearance. There was a significant net renal output of glucose (0.9 +/-
      0.3 micromol x kg(-1) x min(-1)), but no significant extraction of labeled
      glucose across the kidney. The renal contribution to whole-body glucose turnover
      calculated from the 13C-enrichments was 24 +/- 3%. We concluded that 1) glucose
      production by the human kidney in the postabsorptive state, in contrast to recent
      reports, makes at most only a minor contribution (approximately 5%) to blood
      glucose homeostasis, but that 2) after 60-h of fasting, renal glucose production
      may account for 20-25% of whole-body glucose turnover.

PMID- 10334305
TI  - Cellular immune responses against proinsulin: no evidence for enhanced reactivity
      in individuals with IDDM.
AB  - Investigations of humans and nonobese diabetic mice suggest that proinsulin
      and/or a fragment of the region spanning C-peptide and the B-chain of insulin
      (i.e., proinsulin peptide) may serve as key autoantigens in IDDM. Therefore, we
      analyzed cellular immune reactivities against these molecules in people with or
      at varying risks for the disease to clarify their role in the pathogenesis of
      IDDM. In vitro peripheral blood mononuclear cell (PBMC) responses against these
      antigens, a control antigen (tetanus toxoid), and phytohemaglutinin were
      determined in 60 individuals with newly diagnosed IDDM (< or = 1 day from
      diagnosis) in 34 islet cell cytoplasmic autoantibody- and/or insulin autoantibody
      negative first-degree relatives of the IDDM subjects, and in 28 autoantibody
      negative control subjects. Unlike previous reports suggesting diabetes-associated
      elevations in cellular immunity to other beta-cell antigens (e.g., GAD, IA-2,
      etc.), we observed equivalent levels of phytohemaglutinin stimulation and
      cellular proliferation in all groups against these antigens (all P values were
      not significant). The mean stimulation index +/- SD and frequency of reactivity
      to proinsulin for healthy control subjects and IDDM patients, respectively, were
      as follows: 1 microg/ml (1.5 +/- 1.0, 1 out of 17 [6%]; 1.9 +/- 1.4, 4 out of 33
      [12%]); 10 microg/ml (1.7 +/- 1.3, 1 out of 17 [6%]; 1.2 +/- 0.6, 0 out of 28
      [0%]); and 50 microg/ml (1.2 +/- 0.6, 1 out of 16 [6%]; 1.1 +/- 0.6, 1 out of 27
      [4%]). The response in healthy control subjects, autoantibody-negative relatives,
      and IDDM patients, respectively, against the proinsulin peptide fragment were as
      follows: 1 microg/ml (0.9 +/- 0.4, 1 out of 12 [8%]; 1.3 +/- 1.1, 4 out of 34
      [11%]; 1.1 +/- 0.3, 2 out of 28 [7%]); 10 microg/ml (0.9 +/- 0.6, 1 out of 12
      [8%]; 1.2 +/- 0.6, 3 out of 34 [9%] 1.4 +/- 1.7, 2 out of 28 [7%]); and 50
      microg/ml (1.0 +/- 0.7, 1 out of 12 [8%]; 1.2 +/- 0.5, 2 out of 34 [6%]; 1.3 +/-
      0.5, 2 out of 28 [7%]). Taken together with previous studies reporting relatively
      infrequent occurrences of autoantibodies to proinsulin, the role of immunity to
      this molecule in the pathogenesis of IDDM in humans remains unclear.

PMID- 10334306
TI  - Genes expressed during the differentiation of pancreatic AR42J cells into insulin
      secreting cells.
AB  - Pancreatic AR42J cells have the feature of pluripotency of the common precursor
      cells of the pancreas. Dexamethasone (Dx) converts them to exocrine cells,
      whereas activin A (Act) converts them into endocrine cells expressing pancreatic
      polypeptide. A combination of Act and betacellulin (BTC) converts them further
      into insulin-secreting cells. The present study identifies some of the genes
      involved in the process of differentiation that is induced by these factors,
      using the mRNA differential display and screening of the cDNA expression array.
      The expression levels of 7 genes were increased by Act alone, and a combination
      of Act and BTC increased the expression of 25 more genes. Of these, 16
      represented known genes or homologues of genes characterized previously. Nine of
      the identified genes were unrelated to any other sequences in the database. An
      inhibitor of the mitogen-activated protein kinase pathway, PD098059, which blocks
      the differentiation into insulin-secreting cells, inhibited the expression of 18
      of the 25 genes, suggesting that the proteins encoded by these genes are
      associated with the differentiation into insulin-producing cells. These include
      known genes encoding extracellular signaling molecules, such as parathyroid
      hormone-related peptide, cytoskeletal proteins, and intracellular signaling
      molecules. Identification and characterization of these differentially expressed
      genes should help to clarify the molecular mechanism of differentiation of
      pancreatic cells and the gene products that enable the beta-cells to produce
      insulin.

PMID- 10334307
TI  - Glucosamine infusion in rats rapidly impairs insulin stimulation of
      phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B
      in skeletal muscle.
AB  - Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway,
      potently induces insulin resistance in skeletal muscle by impairing insulin
      induced GLUT4 translocation to the plasma membrane. Activation of
      phosphoinositide (PI) 3-kinase is necessary for insulin-stimulated GLUT4
      translocation, and the serine/threonine kinase Akt/protein kinase B (PKB) is a
      downstream mediator of some actions of PI 3-kinase. To determine whether
      glucosamine-induced insulin resistance could be due to impaired signaling, we
      measured insulin receptor substrate (IRS)-1 and insulin receptor tyrosine
      phosphorylation; PI 3-kinase activity associated with IRS-1, IRS-2, and
      phosphotyrosine; and Akt activity and phosphorylation in skeletal muscle of rats
      infused for 2 h with glucosamine (6.0 mg x kg(-1) x min(-1)) or saline.
      Euglycemic-hyperinsulinemic clamp studies (12 mU x kg(-1) x min(-1) insulin) in
      awake rats showed that glucosamine infusion resulted in rapid induction of
      insulin resistance, with a 33% decrease in glucose infusion rate (P < 0.01).
      Tissues were harvested after saline alone (basal), 1 min after an insulin bolus
      (10 U/kg), or after 2 h of insulin clamp in saline- and glucosamine-infused rats.
      After 1 min of insulin stimulation, phosphorylation of IRS-1 and insulin receptor
      increased 6- to 8-fold in saline-infused rats and 7- to 10-fold in glucosamine
      infused rats. In saline-infused rats, 1 min of insulin stimulation increased PI 3
      kinase activity associated with IRS-1, IRS-2, or phosphotyrosine 7.6-, 6.4-, and
      10-fold, respectively. In glucosamine-infused rats treated for 1 min with
      insulin, PI 3-kinase activity associated with IRS-1 was reduced 28% (P < 0.01)
      and that associated with phosphotyrosine was reduced 43% (P < 0.01). Insulin for
      1 min stimulated Akt/PKB activity approximately 5-fold in both saline- and
      glucosamine-infused rats; insulin-induced hyperphosphorylation of Akt/PKB was not
      different between groups. Glucosamine infusion alone had no effect on tyrosine
      phosphorylation of the insulin receptor or IRS-1 or on stimulation of PI 3-kinase
      or Akt/PKB activity. However, 2 h of insulin clamp reduced PI 3-kinase activity
      associated with IRS-1, IRS-2, or phosphotyrosine to <30% of that seen with 1 min
      of insulin. No effect of glucosamine was seen on these signaling events when
      compared with 2 h of insulin clamp without glucosamine. Our data show that 1)
      glucosamine infusion in rats is associated with an impairment in the early
      activation of PI 3-kinase by insulin in skeletal muscle, 2) this insulin
      resistant state does not involve alterations in the activation of Akt/PKB, and 3)
      prolonged insulin infusion under clamp conditions results in a blunting of the PI
      3-kinase response to insulin.

PMID- 10334308
TI  - Phosphorylated insulin-like growth factor binding protein 1 is increased in
      pregnant diabetic subjects.
AB  - During pregnancy, IGFs and their binding proteins (IGFBPs) are important for the
      growth of fetal and maternal tissues. IGFBP-1 normally circulates as a single,
      highly phosphorylated species (hpIGFBP-1). However, in pregnancy there are lesser
      phosphorylated isoforms (lpIGFBP-1) with decreased affinity for IGF-I, allowing
      for increased IGF bioavailability. Because regulation of IGFBP-1 is abnormal in
      type 1 diabetes, we examined the impact of this on IGFBP-1 and its
      phosphorylation status in diabetic pregnancy. We assessed IGFBP-1 in relation to
      birth weight, maternal weight gain, duration of diabetes, glycemic control, and
      the presence or absence of retinopathy in 44 diabetic and 11 nondiabetic
      subjects. We found that in type 1 diabetic patients there was a significant
      negative relationship between hpIGFBP-1 and birth weight (r = -0.42, P < 0.01)
      and between the ratio of hpIGFBP-1 to lpIGFBP-1 and birth weight (r = -0.38, P =
      0.02) by week 18 of gestation. Multiple regression analysis confirmed that
      hpIGFBP-1 was the best single predictor of birth weight (R2 = 0.3, P = 0.001) in
      diabetic subjects using models including other parameters known to influence
      fetal size. In contrast to hpIGFBP-1 levels, lpIGFBP-1 levels were not associated
      with birth weight, but were significantly related to initial maternal BMI and
      maternal weight throughout gestation in diabetic subjects (r = -0.57, P < 0.001).
      hpIGFBP-1 levels were positively related to duration of diabetes (r = 0.38, P <
      0.01). Diabetic subjects had significantly higher hpIGFBP-1 and lpIGFBP-1 levels
      than nondiabetic subjects (hpIGFBP-1: 215 +/- 21 vs. 108 +/- 13 microg/l, P =
      0.01; lpIGFBP-1: 139 +/- 12 vs. 66 +/- 5 microg/l, P < 0.001), but the ratio of
      hpIGFBP-1 to lpIGFBP-1 was similar in both groups (2.1 +/- 0.3 [diabetic] vs. 1.7
      +/- 0.2 [nondiabetic], NS). In summary, maternal IGFBP-1 levels were higher in
      diabetic than in normal pregnancies. Diabetic subjects with prolonged duration of
      diabetes and retinopathy had higher total IGFBP-1 levels than those with shorter
      disease duration. Thus hpIGFBP-1 in diabetic pregnancy is positively related to
      the duration of diabetes and inversely related to fetal growth, with lpIGFBP-1
      being related to maternal weight and BMI. The ratio of hpIGFBP-1 to lpIGFBP-1 may
      be a more robust indicator of fetal outcome, since it was consistent between
      diabetic and nondiabetic subjects. Measurement of the different phosphorylated
      isoforms of IGFBP-1 may increase the usefulness of IGFBP-1 as a predictor of
      fetal growth in both normal and diabetic pregnancy.

PMID- 10334309
TI  - 13C nuclear magnetic resonance study of glycogen resynthesis in muscle after
      glycogen-depleting exercise in healthy men receiving an infusion of lipid
      emulsion.
AB  - In healthy individuals, glycogen recovery after a strong depletion is known to be
      rapid and insulin independent during the initial phase, and subsequently, slow
      and insulin dependent. Free fatty acids (FFAs) as a putative source of insulin
      resistance (IR) could thus impair glycogen recovery during the second period.
      Using in vivo 13C nuclear magnetic resonance (NMR), we studied the effect of long
      chain triglyceride emulsion on gastrocnemius glycogen resynthesis during a 3-h
      recovery period after 90 min of moderate exercise consisting of plantar flexion
      on overnight-fasted healthy men (n = 8). In separate experiments, each subject
      was infused with 10% Ivelip (0.015 ml x kg(-1) x min(-1)) or 10% glycerol (0.13
      mg x kg(-1) x min(-1)). NMR spectra were acquired before and at the end of the
      exercise and during the recovery period. Whole-body glucose and lipid oxidation
      rates (indirect calorimetry), plasma insulin, C-peptide, glucose, lactate, beta
      hydroxybutyrate, triglycerides, and FFAs were determined. Glycogen consumption
      was 47.6 +/- 4.5% (glycerol) and 49.7 +/- 4.8% (Ivelip) of the initial glycogen.
      An acquired IR in the Ivelip group was significant at the onset of the recovery
      period by homeostasis model assessment (P = 0.002). Glycogen resynthesis in the
      glycerol group appeared faster during the 1st h than during the subsequent 2nd h
      of the postexercise period. The glycogen resynthesis level was significantly
      lower in the Ivelip group than in the glycerol group during the recovery period
      (P = 0.04 during the 1st h and P = 0.001 during the next 2 h). During the
      recovery, plasma lactate and whole-body oxidation rates were similar in the two
      groups, whereas glycemia was significantly higher in the Ivelip group. A
      decreased cellular uptake of glucose as a substrate for glycogenosynthesis,
      rather than a competition between oxidation of carbohydrate and FFA, is
      discussed.

PMID- 10334310
TI  - High-fat meals reduce 24-h circulating leptin concentrations in women.
AB  - Leptin induces weight loss in rodents via its effects on food intake and energy
      expenditure. High-fat diets induce weight gain, but the mechanism is not well
      understood. Previous studies have not found an effect of dietary fat content on
      fasting leptin. There is a nocturnal increase of leptin, however, which is
      related to insulin responses to meals. We have reported that adipocyte glucose
      utilization is involved in insulin-induced leptin secretion in vitro.
      Accordingly, high-fat, low-carbohydrate (HF/LC) meals, which induce smaller
      insulin and glucose responses, would produce lower leptin concentrations than low
      fat, high-carbohydrate (LF/HC) meals. Blood samples were collected every 30-60
      min for 24 h from 19 normal-weight (BMI, 24.2 +/- 0.7 kg/m2; percent body fat =
      31 +/- 1%) women on 2 days (10 days apart) during which the subjects were
      randomized to consume three isocaloric 730-kcal meals containing either 60/20 or
      20/60% of energy as fat/carbohydrate. Overall insulin and glycemic responses (24
      h area under the curve [AUC]) were reduced by 55 and 61%, respectively, on the
      HF/LC day (P < 0.0001). During LF/HC feeding, there were larger increases of
      leptin 4-6 h after breakfast (38 +/- 7%, P < 0.001) and lunch (78 +/- 14%, P <
      0.001) than after HF/LC meals (both P < 0.02). During LF/HC feeding, leptin
      increased from a morning baseline of 10.7 +/- 1.6 ng/ml to a nocturnal peak of
      21.3 +/- 1.3 ng/ml (change, 10.6 +/- 1.3 ng/ml; percent change, 123 +/- 16%; P <
      0.0001). The amplitudes of the nocturnal rise of leptin and the 24-h leptin AUC
      were 21 +/- 8% (P < 0.005) and 38 +/- 12% (P < 0.0025) larger, respectively, on
      the LF/HC day. In summary, consumption of HF/LC meals results in lowered 24-h
      circulating leptin concentrations. This result may be a consequence of decreased
      adipocyte glucose metabolism. Decreases of 24-h circulating leptin could
      contribute to the weight gain during consumption of high-fat diets.

PMID- 10334311
TI  - Hepatic glucose cycling does not contribute to the development of hyperglycemia
      in Zucker diabetic fatty rats.
AB  - Hepatic glucose cycling, whereby glucose is taken up by the liver, partially
      metabolized, then recycled to glucose, makes a substantial contribution to the
      development of hyperglycemia in IDDM. This stimulation of glucose cycling appears
      to be associated with elevated rates of fatty acid oxidation. Whether hepatic
      glucose cycling also contributes to the development of hyperglycemia in NIDDM is
      unclear. Using a model of NIDDM, the Zucker diabetic fatty (ZDF) rat, we
      determined whether glucose cycling was enhanced. Hepatocytes from ZDF rats
      exhibited higher rates of glucose phosphorylation and glycolysis, but there was
      no increase in the rate of cycling between glucose and glucose-6-phosphate or
      between glycolytically derived pyruvate and glucose. Despite the increased rates
      of glycolysis, the production of CO2 in liver cells from ZDF rats was no
      different from rates measured in cells from control animals. Instead, there was a
      large increase in the accumulation of lactate and pyruvate in the ZDF liver
      cells. The addition of 2-bromopalmitate, an inhibitor of fatty acid oxidation
      that inhibited glucose cycling in hepatocytes from IDDM rats, had no effect on
      glucose cycling in cells from ZDF rats. We therefore conclude that, unlike in
      IDDM, hepatic glucose cycling does not contribute to the development of
      hyperglycemia in the NIDDM Zucker rat.

PMID- 10334312
TI  - Plasma leptin and insulin levels in weight-reduced obese women with normal body
      mass index: relationships with body composition and insulin.
AB  - Obesity is a complex disease with multiple features that has confounded efforts
      to unravel its pathophysiology. As a means of distinguishing primary from
      secondary characteristics, we compared levels of fasting plasma leptin and
      insulin in a cohort of weight-reduced obese women who have attained and
      maintained a normal BMI for more than 1 year with the levels in cohorts of never
      obese and currently obese women. Weight-reduced obese women showed decreased
      plasma concentrations of leptin and insulin compared with obese women, but these
      levels remained significantly higher than those of never-obese women. Plasma
      leptin levels were highly correlated with plasma insulin levels (r = 0.60, P <
      0.001). To further explore relationships with body composition, total body fat
      was determined by dual-energy X-ray absorptiometry and body fat distribution by
      computed tomography in subsets of these groups. Weight-reduced obese women had a
      significantly greater percent body fat and subcutaneous abdominal fat mass than
      did the never-obese women, and these were highly correlated with plasma leptin (r
      = 0.90, P < 0.001, and r = 0.52, P < 0.001, respectively). In these weight
      reduced obese women, visceral fat mass was similar to that of the never-obese.
      The insulin sensitivity index and first-phase insulin response were also
      comparable. These results demonstrate that higher leptin levels in weight-reduced
      obese women are related to the higher total fat and particularly the subcutaneous
      fat masses. Normalization of visceral fat mass in the weight-reduced obese was
      accompanied by normalization of insulin sensitivity index and first-phase insulin
      response. This study suggests that increases in plasma leptin and insulin in
      obesity are secondary features of the obese state.

PMID- 10334313
TI  - An insulin sensitizer improves the free radical defense system potential and
      insulin sensitivity in high fructose-fed rats.
AB  - Recently there has been growing interest in the effects of antioxidants on
      insulin activity. In the present study, we investigated the effect of metformin
      on free radical activity and insulin sensitivity in high fructose-fed rats, a
      diet that leads to insulin resistance. The animals were divided into four groups
      (n = 16 per group; experiment duration = 6 weeks): the control (C) group received
      a standard diet; the control metformin (CM) group was fed a control diet and
      received metformin (200 mg x kg(-1) x day(-1) in water); the fructose control
      (FT) group was fed a diet in which fructose composed 56.8% of the total
      carbohydrates; and the fructose metformin (FM) group received high-fructose diet
      and metformin (200 mg x kg(-1) x day(-1) in water). The glucose clamp technique
      was used to determine insulin sensitivity in eight animals per group. Metabolic
      and oxidative stress parameters were measured in the remaining rats. In the FT
      rats, insulin resistance, lower red cell CuZn superoxide dismutase activity and
      lower blood reduced glutathione were observed. Metformin treatment improved both
      the insulin activity and the antioxidant defense system. In the CM group,
      metformin had no effect on metabolic parameters, but improved red cell
      antioxidant enzyme activities and the blood GSH level, which suggests that it has
      an antioxidant activity independent of its effect on insulin activity.

PMID- 10334314
TI  - Rapid impairment of skeletal muscle glucose transport/phosphorylation by free
      fatty acids in humans.
AB  - The initial effects of free fatty acids (FFAs) on glucose
      transport/phosphorylation were studied in seven healthy men in the presence of
      elevated (1.44 +/- 0.16 mmol/l), basal (0.35 +/- 0.06 mmol/l), and low (<0.01
      mmol/l; control) plasma FFA concentrations (P < 0.05 between all groups) during
      euglycemic-hyperinsulinemic clamps. Concentrations of glucose-6-phosphate (G-6
      P), inorganic phosphate (Pi), phosphocreatine, ADP, and pH in calf muscle were
      measured every 3.2 min for 180 min by using 31P nuclear magnetic resonance
      spectroscopy. Rates of whole-body glucose uptake increased similarly until 140
      min but thereafter declined by approximately 20% in the presence of basal and
      high FFAs (42.8 +/- 3.6 and 41.6 +/- 3.3 vs. control: 52.7 +/- 3.3 micromol x kg(
      1) x min(-1), P < 0.05). The rise of intramuscular G-6-P concentrations was
      already blunted at 45 min of high FFA exposure (184 +/- 17 vs. control: 238 +/-
      17 micromol/l, P = 0.008). At 180 min, G-6-P was lower in the presence of both
      high and basal FFAs (197 +/- 21 and 213 +/- 18 vs. control: 286 +/- 19
      micromol/l, P < 0.05). Intramuscular pH decreased by -0.013 +/- 0.001 (P < 0.005)
      during control but increased by +0.008 +/- 0.002 (P < 0.05) during high FFA
      exposure, while Pi rose by approximately 0.39 mmol/l (P < 0.005) within 70 min
      and then slowly decreased in all studies. In conclusion, the lack of an initial
      peak and the early decline of muscle G-6-P concentrations suggest that even at
      physiological concentrations, FFAs primarily inhibit glucose
      transport/phosphorylation, preceding the reduction of whole-body glucose disposal
      by up to 120 min in humans.

PMID- 10334315
TI  - Induction of obesity and hyperleptinemia by central glucocorticoid infusion in
      the rat.
AB  - It has been claimed that factors favoring the development or maintenance of
      animal or human obesity may include increases in glucocorticoid production or
      hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats,
      glucocorticoids have been shown to be necessary for chronic
      intracerebroventricular infusion of neuropeptide Y to produce obesity and related
      abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering
      effect of leptin. Such dual action of glucocorticoids may occur within the
      central nervous system, since both neuropeptide Y and leptin act within the
      hypothalamus. The aim of this study was to determine the effects of
      glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on
      body weight homeostasis and hypothalamic levels of neuropeptide Y and
      corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3
      days resulted in marked sustained increases in food intake and body weight
      relative to saline-infused controls. The infusion abolished endogenous
      corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and
      hyperleptinemia, three salient abnormalities of obesity syndromes. Central
      glucocorticoid infusion also produced a marked decrease in the expression of
      uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle.
      Finally, chronic central glucocorticoid administration increased the hypothalamic
      levels of neuropeptide Y and decreased those of corticotropin-releasing hormone.
      When the same dose of glucocorticoids was administered peripherally, it resulted
      in decreases in food intake and body weight, in keeping with the decrease in
      hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids
      induce an obesity syndrome in rodents by acting centrally and not peripherally.

PMID- 10334316
TI  - Hyperglycemia-induced embryonic dysmorphogenesis correlates with genomic DNA
      mutation frequency in vitro and in vivo.
AB  - Congenital malformations affecting multiple organ systems are at least three
      times more common in infants of mothers with IDDM than in infants born to
      nondiabetic mothers. Numerous studies have confirmed the teratogenic effect of
      hyperglycemia on the developing embryo, although no direct mechanism has been
      determined. In this study, we aimed to correlate the frequency of lacI mutations
      with degree of hyperglycemic exposure and severity of malformations in mouse
      embryos from in vitro cultures. Day 8 transgenic mouse embryos cultured in 30 or
      50 mmol/l glucose for 48 h exhibited a higher incidence of morphological
      abnormalities, as well as an increase in lacI mutation frequency, compared with
      embryos cultured in 10 mmol/l glucose with no abnormalities and a lower frequency
      of lacI mutations. We also used a transgenic lacI rat system to evaluate the
      relationship between abnormal embryonic development and DNA mutation frequency in
      day 11 embryos of severely diabetic rats (serum glucose >20 mmol/l). Compared
      with control embryos, the embryos from diabetic rats displayed significantly more
      malformations, shorter crown-rump lengths, fewer somites, and more than six times
      greater genomic DNA mutation frequency. Genetic analysis of the mutated lacI gene
      from both in vitro cultured mouse embryos and in vivo developed rat embryos
      revealed that the majority of mutations were due to base substitutions
      (transitions and transversions), but that the rate of large DNA mutations tended
      to increase in embryos exposed to a diabetic environment. Our results support the
      interrelationship between increased rates of congenital malformations and DNA
      mutations in the offspring of diabetic pregnancy.

PMID- 10334317
TI  - Inhibitory effect of a growth hormone receptor antagonist (G120K-PEG) on renal
      enlargement, glomerular hypertrophy, and urinary albumin excretion in
      experimental diabetes in mice.
AB  - Growth hormone (GH) and IGFs have a long and distinguished history in diabetes,
      with possible participation in the development of renal complications. To
      investigate the effect of a newly developed GH receptor (GHR) antagonist (G120K
      PEG) on renal/glomerular hypertrophy and urinary albumin excretion (UAE),
      streptozotocin-induced diabetic and nondiabetic mice were injected with G120K-PEG
      every 2nd day for 28 days. Placebo-treated diabetic and nondiabetic animals were
      used as reference groups. Placebo-treated diabetic animals were characterized by
      growth retardation, hyperphagia, hyperglycemia, increased serum GH levels,
      reduced serum IGF-I, IGF-binding protein (IGFBP)-3, and liver IGF-I levels,
      increased kidney IGF-I, renal/glomerular hypertrophy, and increased UAE when
      compared with nondiabetic animals. No differences were seen between the two
      diabetic groups with respect to body weight, food intake, blood glucose, serum
      GH, IGF-I, and IGFBP-3 levels or hepatic IGF-I levels. Kidney IGF-I, kidney
      weight, and glomerular volume were normalized, while the rise in UAE was
      partially attenuated in the G120K-PEG-treated diabetic animals. No effect of
      G120K-PEG treatment on any of the parameters mentioned above was seen in
      nondiabetic animals. In conclusion, administration of a GHR antagonist in
      diabetic mice has renal effects without affecting metabolic control and
      circulating levels of GH, IGF-I, or IGFBP-3, thus indicating that the effect of
      G120K-PEG may be mediated through a direct inhibitory effect on renal IGF-I
      through the renal GHR. The present study suggests that specific GHR blockade may
      present a new concept in the treatment of diabetic kidney disease.

PMID- 10334319
TI  - Effect of acute ketosis on the endothelial function of type 1 diabetic patients:
      the role of nitric oxide.
AB  - In type 1 diabetic patients, acute loss of metabolic control is associated with
      increased blood flow, which is believed to favor the development of long-term
      complications. The mechanisms for inappropriate vasodilation are partially
      understood, but a role of endothelium-derived nitric oxide (NO) production can be
      postulated. We assessed, in type 1 diabetic patients, the effect of the acute
      loss of metabolic control and its restoration on forearm endothelial function in
      13 type 1 diabetic patients who were studied under conditions of mild ketosis on
      two different occasions. In study 1, after basal determination, a rapid
      amelioration of the metabolic picture was obtained by insulin infusion. In study
      2, seven type 1 diabetic patients underwent the same experimental procedure,
      except that fasting plasma glucose was maintained constant throughout. Basal
      plasma venous concentrations of nitrites/nitrates (NO2- + NO3-) were determined
      both before and after intravenous insulin infusion. Endothelium-dependent and 
      independent vasodilation of the brachial artery was assessed by an intra-arterial
      infusion of N(G)-monomethyl-L-arginine (L-NMMA) and sodium nitroprusside (SNP),
      respectively. The same parameters were determined in 13 control subjects at
      baseline conditions and during a hyperinsulinemic-euglycemic glucose clamp.
      Baseline forearm blood flow (4.89 +/- 0.86 vs. 3.65 +/- 0.59 ml x (100 ml
      tissue)(-1) x min(-1)) and NO2- + NO3- concentration (30 +/- 8 vs. 24 +/- 3
      micromol/l) were higher in type 1 diabetic patients than in control subjects (P <
      0.05). Insulin infusion was associated with lower forearm blood flow and plasma
      (NO2- + NO3-) concentration (P < 0.05), irrespective of the prevailing glucose
      levels, as compared with patients under ketotic conditions. The responses to L
      NMMA were significantly lower in type 1 diabetic patients during euglycemia and
      hyperglycemic hyperinsulinemia (-11 +/- 5 and -10 +/- 4%, respectively, of the
      ratio of the infused arm to the control arm) than in control subjects at baseline
      (-18 +/- 6%, P < 0.05) and during hyperinsulinemia (-32 +/- 11%, P < 0.01). We
      conclude that the acute loss of metabolic control is associated with a functional
      disturbance of the endothelial function characterized by hyperemia and increased
      NO release during ketosis and blunted NO-mediated vasodilatory response during
      restoration of metabolic control by intravenous insulin. This functional
      alteration is unlikely to be explained by hyperglycemia itself.

PMID- 10334318
TI  - Effect of intensive diabetes treatment on carotid artery wall thickness in the
      epidemiology of diabetes interventions and complications. Epidemiology of
      Diabetes Interventions and Complications (EDIC) Research Group.
AB  - The Epidemiology of Diabetes Interventions and Complications (EDIC) is a
      multicenter longitudinal observational study of the Diabetes Control and
      Complications Trial (DCCT) cohort. One of the major objectives of EDIC is to
      study the development and progression of atherosclerotic cardiovascular disease
      in type 1 diabetes. In this study, we evaluated the role of cardiovascular risk
      factors and antecedent therapy in the DCCT on carotid intima-media wall thickness
      (IMT) in type 1 diabetes. At approximately 18 months after the end of the DCCT,
      high-resolution B-mode ultrasonography was used to assess the carotid arteries of
      1,325 patients with type 1 diabetes, 19-51 years of age, with duration of
      diabetes ranging from 6.3 to 26.1 years. An age- and sex-matched nondiabetic
      population (n = 153) was studied with the same protocol. The ultrasound protocol
      was carried out in 28 EDIC clinics by centrally trained and certified
      sonographers using one of three scanning systems. Determination of IMT from
      videotaped images was performed by a single reader at the Central Ultrasound
      Reading Unit. Univariate associations with greater IMT were strongest for older
      age and longer diabetes duration, greater waist-to-hip ratio (men only), higher
      blood pressure, higher LDL cholesterol, and smoking. The DCCT therapy group
      (intensive versus conventional) and HbA1c, measured at the time of the ultrasound
      or the mean HbA1c during the DCCT, were not significantly related to IMT.
      Multivariate analyses suggest that age, height, smoking, and BMI were the major
      predictors of common carotid IMT, whereas age, smoking, and LDL cholesterol
      predicted internal carotid IMT. There were significant differences between the
      IMT values of the internal carotid artery in the EDIC male cohort and similarly
      aged male nondiabetic control subjects. There were no significant differences
      between the IMT values in the EDIC female cohort and similarly aged female
      nondiabetic control subjects. At this point in the planned 10-year follow-up of
      the DCCT cohort, neither intensive therapy nor HbA1c level appears to influence
      the early signs of atherosclerosis. Traditional risk factors, including age,
      smoking, and LDL cholesterol, were related to IMT. As the cohort is only now
      entering the age interval during which rapid progression and clinical expression
      of atherosclerosis are expected, further follow-up will help to determine the
      role of hyperglycemia, and its interaction with other risk factors, on the
      development of atherosclerosis.

PMID- 10334320
TI  - A sib-pair analysis study of 15 candidate genes in French families with morbid
      obesity: indication for linkage with islet 1 locus on chromosome 5q.
AB  - As part of an ongoing search for susceptibility genes in obese families, we
      performed linkage analyses in 101 French families between qualitative and
      quantitative traits related to morbid obesity and polymorphisms located in or
      near 15 candidate genes whose products are involved in body weight regulation.
      These included cholecystokinin A and B receptors (CCK-AR and CCK-BR), glucagon
      like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-1 gene (Isl-1), the
      caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta3
      adrenoceptor (beta3-AR), the fatty acid-binding protein 2 (FABP-2), the hormone
      sensitive lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2),
      the insulin receptor substrate-1 (IRS-1), the peroxisome proliferator-activated
      receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the
      liver carnitine palmitoyltransferase-1 (CPT-1). Phenotypes related to obesity
      such as BMI, adult life body weight gain, fasting leptin, insulin, fasting
      glycerol, and free fatty acids were used for nonparametric sib-pair analyses. A
      weak indication for linkage was obtained between the Isl-1 locus and obesity
      status defined by a z score over one SD of BMI (n = 226 sib pairs, pi = 0.54 +/-
      0.02, P = 0.03). Moreover, a suggestive indication for linkage was found between
      the Isl-1 locus and BMI and leptin values (P = 0.001 and 0.0003, respectively)
      and leptin adjusted for BMI (P = 0.0001). Multipoint analyses for leptin trait
      with Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logarithm
      of odds (LOD) score is 1.73, coinciding with the Isl-1 locus. Although marginally
      positive indications for linkage in subgroups of families were found with IRS-1,
      CPT-1, and HSL loci, our data suggested that these genes are not major
      contributors to obesity. Whether an obesity susceptibility gene (Isl-1 itself or
      another nearby gene) lies on chromosome 5q should be determined by further
      analyses.

PMID- 10334321
TI  - Mutational analysis of the coding regions of the genes encoding protein kinase B
      alpha and -beta, phosphoinositide-dependent protein kinase-1, phosphatase
      targeting to glycogen, protein phosphatase inhibitor-1, and glycogenin: lessons
      from a search for genetic variability of the insulin-stimulated glycogen
      synthesis pathway of skeletal muscle in NIDDM patients.
AB  - The finding of a reduced insulin-stimulated glucose uptake and glycogen synthesis
      in the skeletal muscle of glucose-tolerant first-degree relatives of patients
      with NIDDM, as well as in cultured fibroblasts and skeletal muscle cells isolated
      from NIDDM patients, has been interpreted as evidence for a genetic involvement
      in the disease. The mode of inheritance of the common forms of NIDDM is as yet
      unclear, but the prevailing hypothesis supports a polygenic model. In the present
      study, we tested the hypothesis that the putative inheritable defects of insulin
      stimulated muscle glycogen synthesis might be caused by genetic variability in
      the genes encoding proteins shown by biochemical evidence to be involved in
      insulin-stimulated glycogen synthesis in skeletal muscle. In 70 insulin-resistant
      Danish NIDDM patients, mutational analysis by reverse transcription-polymerase
      chain reaction-single strand conformation polymorphism-heteroduplex analysis was
      performed on genomic DNA or skeletal muscle-derived cDNAs encoding glycogenin,
      protein phosphatase inhibitor-1, phophatase targeting to glycogen, protein kinase
      B-alpha and -beta, and the phosphoinositide-dependent protein kinase-1. Although
      a number of silent variants were identified in some of the examined genes, we
      found no evidence for the hypothesis that the defective insulin-stimulated
      glycogen synthesis in skeletal muscle in NIDDM is caused by structural changes in
      the genes encoding the known components of the insulin-sensitive glycogen
      synthesis pathway of skeletal muscle.

PMID- 10334322
TI  - A point mutation inactivating the sulfonylurea receptor causes the severe form of
      persistent hyperinsulinemic hypoglycemia of infancy in Finland.
AB  - Mutations in genes encoding the ATP-regulated potassium (K(ATP)) channels of the
      pancreatic beta-cell (SUR1 and Kir6.2) are the major known cause of persistent
      hyperinsulinemic hypoglycemia of infancy (PHHI). We collected all cases of PHHI
      diagnosed in Finland between 1983 and 1997 (n = 24). The overall incidence was
      1:40,400, but in one area of Central Finland it was as high as 1:3,200. Haplotype
      analysis using polymorphic markers spanning the SUR1/Kir6.2 gene cluster
      confirmed linkage to the 11p region. Sequence analysis revealed a novel point
      mutation in exon 4 of SUR1, predicting a valine to aspartic acid change at amino
      acid 187 (V187D). Of the total cases, 15 affected individuals harbored this
      mutation in heterozygous or homozygous form, and all of these had severe
      hyperinsulinemia that responded poorly to medical treatment and required subtotal
      pancreatectomy. No K(ATP) channel activity was observed in beta-cells isolated
      from a homozygous patient or after coexpression of recombinant Kir6.2 and SUR1
      carrying the V187D mutation. Thus, the mutation produces a nonfunctional channel
      and, thereby, continuous insulin secretion. This unique SUR1 mutation explains
      the majority of PHHI cases in Finland and is strongly associated with a severe
      form of the disease. These findings provide diagnostic and prognostic utility for
      suspected PHHI patients.

PMID- 10334323
TI  - Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the
      Japanese.
AB  - NeuroD/BETA2, a transcription factor of the insulin gene, also plays an important
      role in the development of pancreatic beta-cells. Recently, the NeuroD/BETA2 gene
      has been mapped to the long arm of human chromosome 2 (2q32) where the IDDM7 gene
      has previously been mapped, implying its involvement in diabetes. To identify
      mutations in the NeuroD/BETA2 gene that may predispose patients to develop
      diabetes, we studied the gene in 50 Japanese subjects with diabetes (4 with type
      1 and 46 with type 2) by the polymerase chain reaction (PCR) followed by single
      strand conformation polymorphism and sequencing analyses. Further analysis was
      performed in 392 Japanese subjects (60 with type 1 and 158 with type 2 diabetes
      and 174 healthy control subjects) by mismatch PCR restriction fragment length
      polymorphism. We found a DNA polymorphism of the NeuroD/BETA2 gene. A nucleotide
      G-to-A transition results in the substitution of alanine to threonine at codon 45
      (Ala45Thr). The frequencies of heterozygotes for the Ala45Thr variant were 9.8%
      in the control subjects, 9.5% in the patients with type 2 diabetes, and 25.0% in
      the patients with type 1 diabetes, a significant difference (P = 0.006). Because
      the variant of the NeuroD/BETA2 gene (Ala45Thr) is associated with type 1 but not
      type 2 diabetes, it may be implicated in the loss of pancreatic beta-cells in
      type 1 diabetes.

PMID- 10334324
TI  - Diabetic nephropathy is not associated with the dinucleotide repeat polymorphism
      upstream of the aldose reductase (ALR2) gene but with erythrocyte aldose
      reductase content in Japanese subjects with type 2 diabetes.

PMID- 10334325
TI  - Mutation in the HNF-4alpha gene affects insulin secretion and triglyceride
      metabolism.

PMID- 10334326
TI  - Leptin promotes aggregation of human platelets via the long form of its receptor.
AB  - Plasma leptin levels are elevated in most obese individuals, and obesity is
      accompanied by a high incidence of cardiovascular disease. Therefore, leptin
      could be involved in the pathogenesis of cardiovascular disease. In the present
      study, the role of leptin was explored in the regulation of platelet function.
      The expression of the long form of the leptin receptor was detected in human
      platelets. At 50 ng/ml, human leptin induced phosphorylation of several proteins
      of platelets at the tyrosine residue. Neither leptin at concentrations < or = 100
      ng/ml nor ADP at concentrations > or = 1 micromol/l affected platelet
      aggregation. However, after pretreatment with 100 ng/ml leptin for 5 min, 1
      micromol/l ADP caused aggregation. Thus, leptin and ADP acted synergistically. At
      a concentration of 2 micromol/l, ADP induced platelet aggregation, which was
      markedly enhanced by 30-100 ng/ml leptin in a concentration-dependent manner.
      This concentration range corresponds to that of plasma leptin levels in obese
      individuals. At the lower concentrations (< 10 ng/ml) that are observed in normal
      individuals, leptin had no effect on platelet aggregation. In conclusion, leptin
      at high concentrations has the novel function of promoting platelet aggregation,
      which may be a key coupling factor between obesity and the cardiovascular disease
      associated with syndrome X and diabetes.

PMID- 10334327
TI  - Streptozotocin treatment upregulates uncoupling protein 3 expression in the rat
      heart.
AB  - Diabetic rats have a deficiency in their heart ATP concentrations, and although
      the mechanism remains to be elucidated, this deficiency may involve increased
      uncoupling of oxidative phosphorylation. To investigate whether heart uncoupling
      proteins (UCPs) are subject to transcriptional regulation in diabetes, we
      examined changes in UCP mRNA expression in the heart of streptozotocin-induced
      diabetic (STZ-DM) rats. Heart UCP3 mRNA expression significantly increased by 9.4
      fold in STZ-DM rats, while levels of UCP2 mRNA expression were not significantly
      altered. Insulin supplementation in STZ-DM rats returned UCP3 mRNA concentrations
      to control levels. The expression of UCP3 mRNA was similarly elevated in the
      heart of fasted rats, which also have hypoinsulinemia and hyper-free fatty
      acidemia but, unlike the STZ-DM rats, are hypoglycemic. Since hyperinsulinemia
      alone was previously reported to not affect UCP3 gene expression in the muscle,
      these results indicate that hyper-free fatty acidemia is a potent enhancer of
      UCP3 gene expression in the diabetic rat heart. Interestingly, we found no
      changes in UCP3 mRNA levels in Zucker fatty (fa/fa) rats with excessive chronic
      hyper-free fatty acidemia, which suggests that upregulation of heart UCP3 mRNA
      may depend on an acute change in free fatty acid concentrations rather than on
      their sustained elevation. High-energy ATP deficiencies in the diabetic rat heart
      may primarily result from proton leakage due to the upregulation of UCP3
      expression.

PMID- 10334328
TI  - Post-starvation gene expression of skeletal muscle uncoupling protein 2 and
      uncoupling protein 3 in response to dietary fat levels and fatty acid
      composition: a link with insulin resistance.
AB  - UCP2 and UCP3 are two recently cloned genes with high sequence homology to the
      gene for uncoupling protein (UCP)-1, which regulates thermogenesis in brown
      adipose tissue. In the context of the current debate about whether UCP2 and UCP3
      in the skeletal muscle may also function as mediators of thermogenesis or as
      regulators of lipids as fuel substrate, we have examined their mRNA expressions
      in rat gastrocnemius muscle in response to dietary manipulations known to
      differentially affect thermogenesis during the phase of weight recovery after
      starvation. Compared with ad libitum-fed control rats, the refeeding of
      isocaloric amounts of a low-fat (high-carbohydrate) diet resulted in lower energy
      expenditure and lower mRNA levels of muscle UCP2 and UCP3. This downregulation of
      UCP homologs was abolished by the refeeding of a high-fat diet, even though
      energy expenditure was significantly lower during refeeding on the high-fat than
      on the low-fat diet. Furthermore, major alterations in the fatty acid composition
      of the refeeding diet in favor of n-6 polyunsaturated or medium-chain fatty acids
      resulted in significant increases in energy expenditure, but with no significant
      changes in the expression of skeletal muscle UCP homologs. Regression analysis of
      gastrocnemius UCP mRNA levels against parameters that included body composition,
      energy expenditure, and plasma levels of free fatty acids (FFAs), insulin, and
      glucose as well as the increase in plasma glucose after a glucose load, revealed
      that only the latter (an index of insulin resistance) could explain the
      variability in muscle UCP2 and UCP3 mRNA expressions (r = 0.41, P < 0.02; r =
      0.45, P < 0.01, respectively). Taken together, these data are at variance with a
      role for skeletal muscle UCP2 and UCP3 in dietary regulation (or modulation) of
      thermogenesis. However, they are consistent with the notion that these UCP
      homologs may function as regulators of lipids as fuel substrate and raise the
      possibility that high-fat induced upregulation of muscle UCP2 and UCP3 may be
      more closely linked to insulin resistance than to changes in circulating FFAs.

PMID- 10334330
TI  - An approximation of loop free energy values of RNA H-pseudoknots.
AB  - A set of free energy values is suggested for RNA H-pseudoknot loops. The
      parameters are adjusted to be consistent with the theory of polymer
      thermodynamics and known data on pseudoknots. The values can be used for
      estimates of pseudoknot stabilities and computer predictions of RNA structures.

PMID- 10334329
TI  - Peptidyl transferase activity catalyzed by protein-free 23S ribosomal RNA remains
      elusive.

PMID- 10334331
TI  - More mistakes by T7 RNA polymerase at the 5' ends of in vitro-transcribed RNAs.

PMID- 10334332
TI  - Insertional RNA editing in metazoan mitochondria: the cytochrome b gene in the
      nematode Teratocephalus lirellus.

PMID- 10334333
TI  - Two distinct SECIS structures capable of directing selenocysteine incorporation
      in eukaryotes.
AB  - Translation of UGA as selenocysteine requires specific RNA secondary structures
      in the mRNAs of selenoproteins. These elements differ in sequence, structure, and
      location in the mRNA, that is, coding versus 3' untranslated region, in
      prokaryotes, eukaryotes, and archaea. Analyses of eukaryotic selenocysteine
      insertion sequence (SECIS) elements via computer folding programs, mutagenesis
      studies, and chemical and enzymatic probing has led to the derivation of a
      predicted consensus structural model for these elements. This model consists of a
      stem-loop or hairpin, with conserved nucleotides in the loop and in a non-Watson
      Crick motif at the base of the stem. However, the sequences of a number of SECIS
      elements predict that they would diverge from the consensus structure in the loop
      region. Using site-directed mutagenesis to introduce mutations predicted to
      either disrupt or restore structure, or to manipulate loop size or stem length,
      we show that eukaryotic SECIS elements fall into two distinct classes, termed
      forms 1 and 2. Form 2 elements have additional secondary structures not present
      in form 1 elements. By either insertion or deletion of the sequences and
      structures distinguishing the two classes of elements while maintaining
      appropriate loop size, conversion of a form 1 element to a functional form 2-like
      element and of a form 2 to a functional form 1-like element was achieved. These
      results suggest commonality of function of the two classes. The information
      obtained regarding the existence of two classes of SECIS elements and the
      tolerances for manipulations of stem length and loop size should facilitate
      designing RNA molecules for obtaining high-resolution structural information
      about these elements.

PMID- 10334334
TI  - Long-distance RNA-RNA interactions and conserved sequence elements affect potato
      virus X plus-strand RNA accumulation.
AB  - Conserved octanucleotide sequences located upstream of two major potato virus X
      (PVX) subgenomic RNAs (sgRNAs), as well as elements in the 5' end of the genome,
      affect accumulation of sgRNA. To determine if complementarity between these
      sequences is important for PVX RNA accumulation, we analyzed the effects of
      mutations within these elements and compensatory mutations in a tobacco
      protoplast system and in plants. Mutations in the 5' nontranslated region (NTR
      mutants) that reduced complementarity resulted in lower genomic RNA (gRNA) and
      sgRNA levels, whereas mutations to the octanucleotide elements affected only the
      corresponding sgRNA levels. However, for both the NTR and octanucleotide mutants,
      the extent of reductions in RNA levels did not directly correlate with the degree
      of complementarity, suggesting that the sequences of these elements are also
      important. Mutants containing changes in the NTR and compensatory changes in one
      of the octanucleotide elements restored levels of gRNA and the other sgRNA
      species with an unaltered octanucleotide element to those of wild-type. Although
      compensatory changes significantly increased levels of the sgRNA species with the
      modified octanucleotide element, levels were not restored to those of wild-type.
      Our data indicate that long distance RNA-RNA interactions and the sequences of
      the interacting elements are required for PVX plus-strand RNA accumulation.

PMID- 10334335
TI  - The folding of large RNAs studied by hybridization to arrays of complementary
      oligonucleotides.
AB  - Folding pathways of large RNAs are poorly understood. We have addressed this
      question by hybridizing in vitro transcripts, which varied in size, to an array
      of antisense oligonucleotides. All transcripts included a common sequence and all
      but one shared the same start-point; the other had a small deletion of the 5'
      end. Minimal free energy calculations predicted quite different folds for these
      transcripts. However, hybridization to the array showed predominant features that
      were shared by transcripts of all lengths, though some oligonucleotides that
      hybridized strongly to the short transcripts gave weak interaction with longer
      transcripts. A full-length RNA fragment that had been denatured by heating and
      allowed to cool slowly gave the same hybridization result as a shorter
      transcript. Taken together, these results support theories that RNA folding
      creates local stable states that are trapped early in the transcription or
      folding process. As the transcript elongates, interactions are added between
      regions that are transcribed early and those transcribed late. The method here
      described helps in identifying regions in the transcripts that take part in long
      range interactions.

PMID- 10334336
TI  - In vitro uridine insertion RNA editing mediated by cis-acting guide RNAs.
AB  - Uridine (U) insertion/deletion editing of mitochondrial mRNAs in kinetoplastid
      protozoa is a posttranscriptional process mediated by guide RNAs (gRNAs). The
      gRNAs direct the precise insertion and deletion of Us by a cleavage-ligation
      mechanism involving base pairing. We show that a cognate gRNA in cis at the 3'
      end of a preedited NADH dehydrogenase 7 (ND7) mRNA substrate can direct U
      insertions at editing site 1 when incubated with a mitochondrial lysate from
      Leishmania tarentolae. The efficiency of gRNA-dependent U insertion mediated by a
      cis-acting gRNA is greater on a molar basis than that for a trans-acting gRNA, as
      expected for a unimolecular gRNA:mRNA interaction. Blocking the 3' end of a cis
      acting gRNA lacking a 3' oligo[U] tail has no effect on gRNA-dependent U
      insertions, nor does providing the gRNA in cis upstream of the mRNA, confirming
      the previous observation that the terminal 2'- and 3'-hydroxyls of the gRNA are
      not involved in U insertion activity. These results also establish that the
      oligo[U] tail is not required for U insertion in vitro. Increasing the extent of
      base pairing between the 3' end of the gRNA and the 5' end of the mRNA
      significantly increases in vitro gRNA-dependent U insertion at site 1, presumably
      by maintaining the mRNA 5' cleavage fragment within the editing complex. We
      speculate that, in vivo, protein:RNA and/or protein:protein interactions may be
      responsible for maintaining the mRNA 5' cleavage fragment in close proximity to
      the mRNA 3' cleavage fragment, and that such interactions may be rate limiting in
      vitro.

PMID- 10334337
TI  - Crystal structure of acceptor stem of tRNA(Ala) from Escherichia coli shows
      unique G.U wobble base pair at 1.16 A resolution.
AB  - The acceptor stem of Escherichia coli tRNA(Ala), rGGGGCUA.rUAGCUCC (ALAwt),
      contains the main identity element for the correct aminoacylation by the alanyl
      tRNA synthetase. The presence of a G3.U70 wobble base pair is essential for the
      specificity of this reaction, but there is a debate whether direct minor-groove
      contact with the 2-amino group of G3 or a distortion of the acceptor stem induced
      by the wobble pair is the critical feature recognized by the synthetase. We here
      report the structure analysis of ALAwt at near-atomic resolution using twinned
      crystals. The crystal lattice is stabilized by a novel strontium binding motif
      between two cis-diolic O3'-terminal riboses. The two independent molecules in the
      asymmetric unit of the crystal show overall A-RNA geometry. A comparison with the
      crystal structure of the G3-C70 mutant of the acceptor stem (ALA(C70)) determined
      at 1.4 A exhibits a modulation in ALAwt of helical twist and slide due to the
      wobble base pair, but no recognizable distortion of the helix fragment distant
      from the wobble base pair. We suggest that a highly conserved hydration pattern
      in both grooves around the G3.U70 wobble base pair may be functionally
      significant.

PMID- 10334338
TI  - The 5' end of the 18S rRNA can be positioned from within the mature rRNA.
AB  - In yeast, the 5' end of the mature 18S rRNA is generated by endonucleolytic
      cleavage at site A1, the position of which is specified by two distinct signals.
      An evolutionarily conserved sequence immediately upstream of the cleavage site
      has previously been shown to constitute one of these signals. We report here that
      a conserved stem-loop structure within the 5' region of the 18S rRNA is
      recognized as a second positioning signal. Mutations predicted to either extend
      or destabilize the stem inhibited the normal positioning of site A1 from within
      the 18S rRNA sequence, as did substitution of the loop nucleotides. In addition,
      these mutations destabilized the mature 18S rRNA, indicating that recognition of
      the stem-loop structure is also required for 18S rRNA stability. Several
      mutations tested reduced the efficiency of pre-rRNA cleavage at site A1. There
      was, however, a poor correlation between the effects of the different mutations
      on the efficiency of cleavage and on the choice of cleavage site, indicating that
      these involve recognition of the stem-loop region by distinct factors. In
      contrast, the cleavages at sites A1 and A2 are coupled and the positioning
      signals appear to be similar, suggesting that both cleavages may be carried out
      by the same endonuclease.

PMID- 10334341
TI  - Goniocurettage for removing trabecular meshwork: clinical results of a new
      surgical technique in advanced chronic open-angle glaucoma.
AB  - PURPOSE: To elucidate the long-term outcome of goniocurettage as a new technique
      in trabecular microsurgery for advanced open-angle glaucoma. METHODS: In a
      prospective, nonrandomized clinical trial, 25 eyes of 25 patients with a mean age
      +/- SD of 72.7+/-10.1 years (range, 50 to 89 years) with uncontrolled chronic
      open-angle glaucoma that had undergone failed filtering procedures were treated
      by goniocurettage. Trabecular tissue was scraped away from the chamber angle by
      means of an instrument similar to a microchalazion curette (diameter, 300
      microm). RESULTS: Before surgery, intraocular pressure ranged from 29 to 48 mm Hg
      (mean +/- SD, 34.7+/-7.1 mm Hg), and mean number of antiglaucoma medications was
      2.2+/-0.56. Follow-up averaged (+/-SD) 32.6+/-8.1 months (range, 30 to 45
      months). Overall success, defined as postoperative intraocular pressure of 19 mm
      Hg or less with one pressure-reducing agent, was attained in 15 eyes (60%), with
      five eyes (20%) being controlled without medication. Considering all successfully
      treated patients, the mean intraocular pressure was 17.7+/-3.1 mm Hg (range, 10
      to 19 mm Hg) at the final visit. Mean intraocular pressure reduction was 17.1+/
      7.1 mm Hg in these eyes, representing a net decrease from baseline of 49%. Number
      of antiglaucoma medications dropped to 0.63+/-0.29. Complications included
      localized Descemet membrane detachment in five eyes (20%) and moderate anterior
      chamber bleeding in four eyes (16%). CONCLUSIONS: This new surgical technique can
      effectively control intraocular pressure for long periods of time in patients
      with open-angle glaucoma and a history of failed filtering procedures.
      Goniocurettage may be a suitable alternative to surgical treatment of glaucoma
      patients with excessive conjunctival scarification.

PMID- 10334339
TI  - Combinatorial control of a neuron-specific exon.
AB  - The mouse c-src gene contains a short neuron-specific exon, N1. N1 exon splicing
      is partly controlled by an intronic splicing enhancer sequence that activates
      splicing of a heterologous reporter exon in both neural and nonneural cells. Here
      we attempt to dissect all of the regulatory elements controlling the N1 exon and
      examine how these multiple elements work in combination. We show that the 3'
      splice site sequence upstream of exon N1 represses the activation of splicing by
      the downstream intronic enhancer. This repression is stronger in nonneural cells
      and these two regulatory sequences combine to make a reporter exon highly cell
      type specific. Substitution of the 3' splice site of this test exon with sites
      from other exons indicates that activation by the enhancer is very dependent on
      the nature of the upstream 3' splice site. In addition, we identify a previously
      uncharacterized purine-rich sequence within exon N1 that cooperates with the
      downstream intronic enhancer to increase exon inclusion. Finally, different
      regulatory elements were tested in multiple cell lines of both neuronal and
      nonneuronal origin. The individual splicing regulatory sequences from the src
      gene vary widely in their activity between different cell lines. These results
      demonstrate how a simple cassette exon is controlled by a variety of regulatory
      elements that only in combination will produce the correct tissue specificity of
      splicing.

PMID- 10334340
TI  - Corneal sensitivity after photorefractive keratectomy and laser in situ
      keratomileusis for low myopia.
AB  - PURPOSE: To evaluate and compare the recovery of postoperative corneal
      sensitivity after laser in situ keratomileusis and photorefractive keratectomy
      for the correction of low myopia. METHODS: In a prospective study, 17 consecutive
      eyes (17 patients) underwent laser in situ keratomileusis to correct myopia
      ranging from -3.25 to -6.75 diopters, and another 18 consecutive eyes (18
      patients) underwent photorefractive keratectomy to correct myopia from -3.12 to 
      7.00 diopters. Corneal sensitivity was tested preoperatively and 1 week and 1, 3,
      and 6 months postoperatively using the Cochet-Bonnet esthesiometer. Corneal
      sensitivity was tested at the center of the cornea, and in four additional
      central points 2 mm from the corneal center (nasal, inferior, temporal, and
      superior). RESULTS: Corneal sensitivity after laser in situ keratomileusis was
      reduced at the ablated zone during the first 3 months after surgery (Wilcoxon
      rank sum test, P < .05), and only after 6 months it returned to its preoperative
      values. However, corneal sensitivity recovered its preoperative values 1 month
      after photorefractive keratectomy (Wilcoxon rank sum test, P > .05), except for
      the central corneal point, where 3 months were required. Comparing both groups,
      corneal sensitivity was more depressed after laser in situ keratomileusis than
      after photorefractive keratectomy during the first 3 months (Mann-Whitney test, P
      < .05), except for the nasal central point, although no differences were found
      between both groups at 6 months (P > .05). CONCLUSIONS: In the correction of low
      myopia, corneal sensitivity at the ablated zone was more depressed after laser in
      situ keratomileusis than after photorefractive keratectomy during the first 3
      months after surgery. Only after 6 months were corneal sensitivity values similar
      in both groups.

PMID- 10334342
TI  - Long-term brimonidine therapy in glaucoma patients with apraclonidine allergy.
AB  - PURPOSE: To report the use of brimonidine in patients with a documented ocular
      allergy to apraclonidine. METHODS: We conducted a prospective, open-label study
      on the use of long-term brimonidine therapy in 57 patients with chronic glaucoma
      with documented allergy to apraclonidine. The study patients were placed on
      brimonidine tartrate 0.2%, 1 drop three times daily in one or both eyes, either
      as additive therapy to a medical regimen devoid of apraclonidine for further
      lowering of intraocular pressure (25 patients) or as a replacement for
      apraclonidine at the time of diagnosis of apraclonidine ocular allergy for
      maintenance of intraocular pressure control (32 patients). Clinical symptoms and
      signs of ocular allergy to brimonidine were monitored for up to 18 months.
      RESULTS: During the treatment period of up to 18 months, six (10.5%) of 57
      patients developed slit-lamp biomicroscopic findings and subjective symptoms of
      an ocular allergic reaction that led to discontinuation of brimonidine treatment.
      All six patients developed ocular allergy to topical brimonidine 0.2% during the
      first 4 months of therapy. The addition of brimonidine 0.2% topical medication or
      the replacement of apraclonidine with brimonidine resulted in a significant
      decrease in mean intraocular pressure from 20.5+/-5.3 to 16.5+/-4.2 mm Hg (P <
      .0001) at the mean treatment period of 10.6+/-4.6 months (range, 0.5 to 18.0
      months in all 57 patients: 5 to 18 months in the 51 patients without brimonidine
      allergy and 0.5 to 3.8 months in the six patients who developed brimonidine
      allergy. CONCLUSIONS: The incidence of ocular allergy after the use of
      brimonidine 0.2% topical medication for up to 18 months was 10.5% in patients
      with a documented history of apraclonidine allergy. Therefore, it is generally
      safe as well as efficacious to administer brimonidine to patients with an ocular
      allergy to apraclonidine.

PMID- 10334343
TI  - Optic nerve blood flow in glaucoma: effect of systemic hypertension.
AB  - PURPOSE: To investigate optic nerve head blood flow in patients with glaucoma and
      to assess the effect of systemic hypertension. METHODS: This study included 24
      eyes of 24 patients with primary open-angle glaucoma. Eleven of these patients
      had a history of systemic hypertension. Results in patients with glaucoma were
      compared with those of 13 eyes of 13 age-matched normal controls. Determinations
      of relative optic nerve head blood velocity, volume, and flow were obtained with
      laser Doppler flowmetry in the superotemporal and inferotemporal neuroretinal rim
      and also in the cup. Means of the velocity, volume, and flow of these three
      measurement sites were calculated for each subject. RESULTS: Mean overall optic
      nerve head blood flow was 29% lower in glaucoma patients than in normal controls
      (t test, P < .001). This decrease in flow was mainly caused by a decrease of 23%
      in mean blood velocity (P < .001). Mean flow in glaucoma patients without
      systemic hypertension was 26% lower than that of glaucoma patients with
      hypertension (Tukey honest significant difference test, P = .05). A significant
      direct correlation was observed between mean flow and mean blood pressure (R =
      0.51, P < .02). CONCLUSIONS: Optic nerve blood flow is reduced in glaucoma
      patients. Glaucoma patients without systemic hypertension have lower optic nerve
      blood flow than those with hypertension. Our results raise concerns that
      treatment of systemic hypertension may further decrease optic nerve blood flow in
      glaucoma patients.

PMID- 10334344
TI  - Optic disk morphology in experimental central retinal artery occlusion in rhesus
      monkeys.
AB  - PURPOSE: To evaluate longitudinally the optic disk morphology of nonglaucomatous
      optic nerve damage secondary to retinal nerve fiber damage, using experimental
      central retinal artery occlusion in rhesus monkey eyes as a model. METHODS: This
      prospective study included 24 eyes of 16 monkeys. In eight eyes of eight animals,
      central retinal artery occlusion was produced by clamping the central retinal
      artery in the retrobulbar space. Occlusion was verified by fluorescein fundus
      angiography. The same eyes at baseline as well as the eight contralateral healthy
      eyes and eight monkey eyes with experimental high-pressure glaucoma served as
      control groups. Serially taken optic disk photographs were morphometrically
      evaluated. RESULTS: The area and shape of the neuroretinal rim and alpha zone and
      beta zone of parapapillary chorioretinal atrophy of eyes after central retinal
      artery occlusion did not vary significantly (P > .30) from the same eyes before
      central retinal artery occlusion nor from the normal contralateral eyes. In the
      glaucomatous eyes, the neuroretinal rim was significantly (P < .001) smaller and
      parapapillary atrophy significantly (P = .01) larger than in the eyes after
      central retinal artery occlusion. CONCLUSIONS: Experimental central retinal
      artery occlusion, in contrast to glaucoma, does not markedly change the size and
      shape of parapapillary atrophy and neuroretinal rim; this confirms previous
      clinical studies. Thus, assessment of parapapillary atrophy and neuroretinal rim
      may be helpful to differentiate between glaucomatous optic neuropathy and
      nonglaucomatous optic neuropathy secondary to retinal nerve fiber damage.
      Parapapillary atrophy is independent of decreased retinal blood perfusion and
      development of nonglaucomatous optic nerve atrophy following experimental central
      retinal artery occlusion.

PMID- 10334345
TI  - Latanoprost increases the severity and recurrence of herpetic keratitis in the
      rabbit.
AB  - PURPOSE: To determine whether topically applied latanoprost increases the
      severity of acute herpes simplex keratitis, the rate of recurrence of herpes
      keratitis, or both, in the rabbit. METHODS: To determine the effect on severity
      of acute herpetic keratitis, the corneas of New Zealand white rabbits were
      infected with either the less-corticosteroid-sensitive McKrae strain or the
      corticosteroid-sensitive F(MP)E strain of herpes simplex virus type 1. Rabbits
      were randomly assigned to twice-a-day treatment with latanoprost 0.005%,
      dexamethasone sodium phosphate 0.1%, or balanced saline solution within 3 days of
      infection and evaluated daily for up to 13 days after infection. The severity of
      keratitis was graded in a masked manner. To determine the effect on recurrences
      of herpetic keratitis, animals infected with McKrae strain herpes simplex virus
      type 1 that survived to day 32 after infection were randomized to treatment with
      latanoprost 0.005% or balanced saline solution and evaluated for the presence of
      corneal lesions from postinfection day 32 to day 47. RESULTS: In the severity
      studies, treatment of F(MP)E-infected corneas with latanoprost or dexamethasone
      significantly worsened herpetic keratitis; by postinfection day 5, F(MP)E
      infected eyes treated with dexamethasone or latanoprost demonstrated
      significantly higher severity scores than the eyes treated with balanced saline
      solution (P = .0001 and .008, respectively). Scores of McKrae-infected corneas
      treated with latanoprost or dexamethasone were not significantly different from
      scores of balanced saline solution-treated corneas. In the recurrence study,
      treatment with latanoprost significantly increased the appearance of clinical
      recurrences in McKrae-infected eyes, compared with balanced saline solution
      treatment (P = .0064). CONCLUSION: Latanoprost may worsen acute herpetic
      keratitis in the rabbit eye and increase the risk of recurrences in latently
      infected animals.

PMID- 10334346
TI  - Controlled evaluation of loteprednol etabonate and prednisolone acetate in the
      treatment of acute anterior uveitis. Loteprednol Etabonate US Uveitis Study
      Group.
AB  - PURPOSE: To compare the safety and efficacy of loteprednol etabonate 0.5%
      ophthalmic suspension with prednisolone acetate 1.0% ophthalmic suspension in
      reducing the ocular signs and symptoms associated with acute anterior uveitis.
      METHODS: Two prospective studies were conducted in sequence. Both were parallel,
      randomized, double-masked, active-controlled comparisons conducted at academic or
      private practice clinics in the United States. Efficacy was evaluated by the
      proportion of patients with a score of 0 for key signs and symptoms of uveitis.
      Intraocular pressure was increased regularly. The first study involved up to 42
      days of treatment, starting with a dose of eight times per day. The second study
      involved up to 28 days of treatment, starting with a dose of 16 times per day.
      RESULTS: In the first study (N = 70), the proportion of patients achieving
      resolution by the final visit was anterior chamber cell (74% loteprednol
      etabonate, 88% prednisolone acetate, P = .194) and flare (71% loteprednol
      etabonate, 81% prednisolone acetate, P = .330). In the second study (N = 175),
      the proportion of patients achieving resolution by the final visit was anterior
      chamber cell (72% loteprednol etabonate, 87% prednisolone acetate, P = .015) and
      flare (66% loteprednol etabonate, 82% prednisolone acetate, P = .017). In both
      studies, intraocular pressure increase of more than 10 mm Hg was observed more
      frequently in patients receiving prednisolone acetate (seven patients) than those
      receiving loteprednol etabonate (one patient). CONCLUSIONS: Although a clinically
      meaningful reduction of signs and symptoms was noted in both treatment groups,
      loteprednol etabonate was less effective than prednisolone acetate in both of
      these controlled studies. However, the more favorable profile of loteprednol
      etabonate with respect to intraocular pressure increase may make it useful in
      many patients.

PMID- 10334348
TI  - Cytomegalovirus retinitis in immunosuppressed children.
AB  - PURPOSE: To describe the ocular and systemic features of children with
      cytomegalovirus retinitis and their disease outcomes. METHODS: Review of all
      cases of cytomegalovirus retinitis diagnosed or treated at a tertiary care
      pediatric hospital during a 10-year period. RESULTS: Nine immunocompromised
      children younger than 16 years were diagnosed as having cytomegalovirus
      retinitis. The underlying causes of immunocompromise were severe combined
      immunodeficiency syndrome (n = 2), severe combined immunodeficiency syndrome
      after bone marrow transplantation (n = 1), acquired immunodeficiency syndrome
      (AIDS) (n = 2), AIDS and previous bone marrow transplantation for leukemia (n =
      1), immunosuppressive therapy after renal transplantation (n = 1), chemotherapy
      for leukemia (n = 1), and congenital cytomegalovirus infection (n = 1). Five
      children (56%) had symptomatic extraocular cytomegalovirus infection. Only two
      children reported visual symptoms with cytomegalovirus retinitis at initial
      examination. Cytomegalovirus retinitis was bilateral in eight children (89%) and
      involved the posterior pole in at least one eye of all nine children. Four
      children (44%) died within 10 months of being diagnosed with cytomegalovirus
      retinitis. The remaining five children were alive, with follow-up ranging from 14
      to 70 months. Successful bone marrow transplantation in one child and
      discontinuation of immunosuppressive medications in two children improved
      systemic immune function and permitted discontinuation of anticytomegaloviral
      therapy. CONCLUSION: Pediatric cytomegalovirus retinitis is often asymptomatic
      and bilateral and involves the posterior pole at initial examination. Recovery of
      systemic immune function may occur in some children. Evaluation of children at
      risk and prompt treatment of cytomegalo. virus retinitis are important to prevent
      long-term visual morbidity.

PMID- 10334347
TI  - The treatment of refractory uveitis with intravenous immunoglobulin.
AB  - PURPOSE: To study the treatment of uveitis that has not responded to
      immunosuppressive medication. Intravenous immunoglobulin (IVIg) effectively
      treats a variety of autoimmune diseases, but it has not been adequately studied
      in the treatment of uveitis. METHODS: The trial included patients who satisfied
      criteria that included noninfectious uveitis, active inflammatory disease, and a
      failure to respond adequately to immunosuppressive medication. We treated two
      patients with IVIg (0.5 gm/day, 3 days/mo initial dosage) as a pilot study and
      then treated an additional eight patients with a similar dosage as part of a
      formal but uncontrolled protocol. RESULTS: Patients on the protocol have been
      followed for a median of 11 months and have received a median of 7.5 treatment
      cycles. Five of 10 patients have had a clinically important and sustained
      improvement in visual acuity, and two of eight protocol patients have markedly
      reduced their immunosuppressive medication. CONCLUSIONS: Intravenous
      immunoglobulin can benefit some patients with uveitis that is otherwise
      refractory to immunosuppressive therapy. Although our preliminary experience is
      encouraging, the use of IVIg for uveitis should be limited because of cost,
      toxicity, the requirement for repeated administration, and the absence of
      controlled trials that demonstrate efficacy.

PMID- 10334349
TI  - Abnormal focal macular electroretinograms in eyes with idiopathic epimacular
      membrane.
AB  - PURPOSE: To study the functional state of the retina beneath an epimacular
      membrane by means of focal macular electroretinography. METHODS: Focal macular
      electroretinograms of 30 consecutive patients (age 25 to 75 years) with
      unilateral idiopathic epimacular membrane were recorded prospectively. The
      amplitudes and implicit times of the a and b waves and the oscillatory potentials
      (O1, O2, O3) recorded from the eye with idiopathic epimacular membrane were
      compared with those of the normal fellow eye. RESULTS: There was a statistically
      significant reduction in the amplitude of the a wave (P < .001), the b wave (P <
      .001), and the oscillatory potentials (O1 + O2 + O3; P < .001) of the affected
      eyes. The reduction of the b-wave amplitude was significantly greater than that
      of the a wave, resulting in a lower b/a wave ratio (P = .003) in the affected
      eyes. The reduction in the amplitude of the oscillatory potentials was
      significantly greater than that of the other two components (P < .001). The
      implicit times were significantly prolonged for the a wave (P < .001), the b wave
      (P = .004), and 03 (P < .001). There was a significant correlation between
      relative b-wave amplitude (affected/normal fellow eye) and the visual acuity (r =
      -0.50, P = .007). These findings were similar to those we reported for eyes with
      aphakic cystoid macular edema. CONCLUSIONS: The focal macular electroretinograms
      in eyes with epimacular membrane disclosed abnormalities that were similar to
      those of eyes with cystoid macular edema. This suggests that the epimacular
      membrane probably induced damage to the neurons in the inner retinal layers.
      Dysfunction of these neurons is one possible cause of visual impairment in this
      disease.

PMID- 10334350
TI  - Association of antiretinal antibodies and cystoid macular edema in patients with
      retinitis pigmentosa.
AB  - PURPOSE: To report the association of antiretinal antibodies in patients with
      bilateral cystoid macular edema and retinitis pigmentosa. METHODS: In a
      prospective study, 30 consecutive patients with bilateral cystoid macular edema
      and retinitis pigmentosa were tested for antiretinal antibodies. As control
      subjects, 30 consecutive patients with retinitis pigmentosa who did not have
      cystoid macular edema and 50 normal subjects without retinitis pigmentosa or
      cystoid macular edema were tested for antiretinal antibodies. Laboratory
      personnel performing the antiretinal antibody testing were masked regarding the
      diagnosis of each patient. RESULTS: Twenty-seven (90%) of 30 patients with
      retinitis pigmentosa with cystoid macular edema had antiretinal protein antibody
      activity, compared with three (6%) of 50 normal controls (P < .001) and only four
      (13%) of 30 control patients with retinitis pigmentosa (P < .001). CONCLUSIONS:
      We found a significant association between cystoid macular edema and the presence
      of circulating antiretinal antibodies in patients who presented with retinitis
      pigmentosa and cystoid macular edema. This study suggests that patients with
      retinitis pigmentosa with cystoid macular edema may have an autoimmune process
      that is contributing to the formation of cystoid macular edema in retinitis
      pigmentosa, but to date, there is no direct evidence that the cystoid macular
      edema is caused by the antiretinal antibodies.

PMID- 10334351
TI  - Randomized trial of radiation for age-related macular degeneration.
AB  - PURPOSE: To assess external beam radiation efficacy for subfoveal
      neovascularization associated with age-related macular degeneration. METHODS: All
      patients were evaluated in the same institution. In this prospective trial, 27
      eyes (27 patients) with subfoveal neovascularization associated with age-related
      macular degeneration were randomized to either single fraction radiation (750
      centigray) or observation. Endpoints were assessed by fluorescein angiography and
      Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity. Examiners were
      masked to patient treatment status. Parametric and nonparametric statistical
      analyses were performed. RESULTS: Twenty-seven patients were entered into the
      trial with a mean age of 76 years (range, 64 to 89) and a mean follow-up of 17
      months (range, 7 to 32). The visual acuity loss was slightly less in the
      irradiated group, a finding of borderline significance (P < .046). There was no
      significant difference in fluorescein angiographic evidence of subretinal
      neovascular membrane change in the control group vs the irradiated group.
      CONCLUSIONS: External beam radiation, at this dose and fractionation, did not
      appear harmful. There was slightly less visual loss in irradiated eyes. No
      difference in fluorescein angiographic characteristics of subfoveal
      neovascularization size or progression in eyes with age-related macular
      degeneration was noted.

PMID- 10334352
TI  - Radiation complications and tumor control after plaque radiotherapy of choroidal
      melanoma with macular involvement.
AB  - PURPOSE: To determine the outcome of plaque radiotherapy in the treatment of
      macular choroidal melanoma and to identify the risk factors associated with the
      development of radiation complications, tumor recurrence, and metastasis.
      METHODS: Chart analysis of 630 consecutive patients (630 eyes) with macular
      choroidal melanoma managed by plaque radiotherapy between July 1976 and June
      1992. RESULTS: The median largest basal tumor diameter was 10 mm, and the median
      tumor thickness was 4 mm. By means of Kaplan-Meier estimates, visually
      significant maculopathy developed at 5 years in 40% of the patients, cataract in
      32%, papillopathy in 13%, and tumor recurrence in 9%. Vision decrease by 3 or
      more Snellen lines was found in 40% of the patients at 5 years. Sixty-nine eyes
      (11%) were enucleated because of radiation complications and recurrence. Twelve
      percent of the patients developed metastasis by 5 years and 22% by 10 years.
      Results of multivariate Cox proportional hazards analyses showed that the
      significant predictors for tumor recurrence were a distance of tumor margin from
      the optic disk of less than 2 mm (P = .003) and retinal invasion (P = .009). The
      significant variables that were predictive of metastasis included tumor thickness
      greater than 4 mm (P = .02) and largest basal tumor diameter greater than 10 mm
      (P = .03). CONCLUSIONS: Plaque radiotherapy offers a 91% 5-year local tumor
      control rate for macular choroidal melanoma. Despite good local tumor control,
      the risk for metastasis is 12% at 5 years and 22% at 10 years. In 11% of the
      patients, enucleation eventually became necessary because of radiation
      complications and tumor recurrence.

PMID- 10334353
TI  - Prevalence and predictors of undercorrected refractive errors in the Victorian
      population.
AB  - PURPOSE: To investigate the prevalence and predictors of undercorrected
      refractive errors in the Victorian population. METHODS: In this prospective
      study, a population-based sample of residents was recruited. The improvement in
      visual acuity with subjective refraction was assessed. Several individual
      characteristics were investigated as predictors of undercorrected refractive
      error. RESULTS: There were 5,615 eligible residents, of which 4,735 (84%)
      participated in the study (53% were women). In all, 466 participants (10%) had
      significant undercorrected refractive error leading to an improvement of 1 or
      more lines of visual acuity with refraction. Age was the most important
      predisposing factor. The risk of undercorrected refractive error increased by 1.8
      times for every decade of life starting at 40 years of age. The next most
      important factor was the absence of distance refractive correction. These
      individuals were 6.8 times more at risk compared with those who wore distance
      spectacles. Other significant predictors of undercorrected refractive error were
      the presence of cataract and European or Middle Eastern languages spoken at home.
      People with tertiary education or hypermetropia were less likely to need
      refractive error improvement. Gender, country of birth, and employment status did
      not have any statistically significant effect after controlling for confounders.
      CONCLUSIONS: The results of this study disclose people in the community who are
      more at risk of compromising their vision because of undercorrected refractive
      errors. A campaign is warranted to alert people that it may be possible to
      improve their vision.

PMID- 10334354
TI  - New corticosteroids for the treatment of ocular inflammation.

PMID- 10334355
TI  - Endothelium and pachymetry of clear corneal grafts 15 to 33 years after
      penetrating keratoplasty.
AB  - PURPOSE: To evaluate long-term endothelial cell count and thickness of clear
      corneal grafts after penetrating keratoplasty. METHODS: Specular microscopy and
      ultrasonic pachymetry were performed in 20 eyes (14 eyes that were keratoconus,
      three aphakic/pseudophakic bullous keratopathy, one Fuchs dystrophy, one had
      herpetic keratitis, and one avascular scar after injury) of 18 patients (mean age
      +/- SD 58+/-15 years; range, 34 to 82 years) with a mean follow-up of 22+/-6
      years (range, 15 to 33 years). RESULTS: Mean endothelial cell count was 808+/-194
      cells per mm2 (range, 575 to 1243 cells/mm2), and thickness was 608+/-75 microm
      (range, 430 to 751 microm). Endothelial cell count was neither correlated with
      thickness (P = .25, r2 = .08) nor with follow-up interval (P = .31, r2 = .028).
      We observed predominantly enlarged endothelial cells and mild polymegethism. No
      graft rejections were recorded. CONCLUSION: Despite a reduced cell density, the
      dehydration function of the endothelium may still be sufficient in corneal grafts
      up to 33 years after penetrating keratoplasty.

PMID- 10334357
TI  - Hypertrophic discoid lupus erythematosus of the conjunctiva.
AB  - PURPOSE: To report the ophthalmic manifestations of hypertrophic discoid lupus
      erythematosus of the conjunctiva. METHOD: Case report and review of biopsy
      results. RESULTS: A 58-year-old woman with a history of chronic
      blepharoconjunctivitis presented with an unusual raised conjunctival lesion.
      Previous biopsy slides were reviewed and interpreted as diagnostic of discoid
      lupus erythematosus, hypertrophic or verrucous type. Both blepharoconjunctivitis
      and the raised conjunctival lesion resolved with hydroxychloroquine therapy.
      CONCLUSIONS: A raised conjunctival mass in the context of refractory
      blepharoconjunctivitis should elicit suspicion for discoid lupus erythematosus.
      The hypertrophic variant of this disease can affect the conjunctiva.

PMID- 10334356
TI  - Latanoprost and herpes simplex keratitis.
AB  - PURPOSE: To report three cases in which herpes simplex keratitis developed after
      initiation of latanoprost therapy. METHODS: Case report. RESULTS: One patient
      with a history of herpes simplex keratitis had recurrence of herpes simplex
      keratitis with latanoprost treatment, resolution when latanoprost was stopped,
      and another recurrence when rechallenged with latanoprost. A second patient with
      a history of herpes simplex keratitis had bilateral recurrence with initiation of
      latanoprost; antiviral therapy could not eradicate herpes simplex keratitis until
      the latanoprost was discontinued. The third patient with latanoprost-associated
      herpes simplex keratitis cleared with the discontinuation of latanoprost and
      start of antiviral therapy; reinstitution of latanoprost with prophylactic
      antiviral medication kept the cornea clear, but as soon as the antiviral
      suppression was discontinued, herpes simplex keratitis reappeared. CONCLUSION:
      Latanoprost, among its diverse pharmacologic effects, may mediate inflammation in
      the eye. Prostaglandins may be a final common pathway for stimulating recurrence
      of herpes simplex keratitis. Clinicians should be aware of this possible
      association.

PMID- 10334358
TI  - Capsular block syndrome with external blockage of the capsular opening by a
      ciliary sulcus fixated posterior chamber lens.
AB  - PURPOSE: To report capsular block syndrome with external blockage of the capsular
      opening by a posterior chamber lens fixated in the ciliary sulcus. METHOD: Case
      report. RESULTS: In an 89-year-old man who had undergone cataract surgery, a
      posterior chamber lens was accidentally fixated in the ciliary sulcus after
      continuous curvilinear capsulohhexis and phacoemulsification/aspiration. The next
      day, capsular block syndrome was noted along the posterior chamber lens optic,
      which was blocking the capsular opening from the outside. CONCLUSION: In all
      previously reported eyes with capsular block syndrome, the posterior chamber lens
      had been placed inside the lens capsule to block the continuous curvilinear
      capsulorhexis opening from the inside.

PMID- 10334359
TI  - Ultrasound biomicroscopy in peripheral retinovitreal toxocariasis.
AB  - PURPOSE: To report ultrasound biomicroscopic features in peripheral retinovitreal
      Toxocara uveitis. METHODS: Three patients with unilateral vitreitis suspected to
      be caused by peripheral toxocariasis were referred for ultrasound biomicroscopic
      examination of the peripheral retina, pars plana, and adjacent vitreous. RESULTS:
      In two of the three patients, characteristic pseudocystic transformation of the
      peripheral vitreous was seen. In both patients, Toxocara serology was positive
      and eosinophilia was present. In the third patient, no pseudocystic
      transformation of the peripheral vitreous was seen; however, there was the dense
      thickening adjacent to the pars plana usually seen by ultrasound biomicroscopy in
      pars planitis and corresponding to clinically visible snowbanks. The third
      patient had a negative Toxocara serology and later developed bilateral
      intermediate uveitis of the pars planitis type. In none of 48 patients with
      diverse inflammatory conditions of the retroiridal space that were examined by
      ultrasound biomicroscopy were the characteristic Toxocara-associated pseudocystic
      images seen. CONCLUSIONS: Pseudocystic transformation of the peripheral vitreous
      appears to be a rather specific and sensitive ultrasound biomicroscopic sign in
      patients with presumed peripheral toxocariasis that will likely aid diagnosis in
      difficult cases.

PMID- 10334360
TI  - Interstitial nephritis and uveitis syndrome presenting with bilateral optic disk
      edema.
AB  - PURPOSE: To report a rare presentation of the tubulointerstitial nephritis and
      uveitis syndrome. METHOD: Case report. A 34-year-old woman underwent extensive
      clinical and laboratory evaluation of bilateral intermediate uveitis and optic
      nerve edema. RESULTS: Laboratory evaluation and nephrology consultation led to a
      diagnosis of tubulointerstitial nephritis. The condition resolved with the use of
      topical and systemic corticosteroids and the discontinuation of ibuprofen.
      CONCLUSIONS: Tubulointerstitial nephritis and uveitis syndrome is uncommon. It
      may present with anterior or intermediate uveitis. Chronic intermediate uveitis
      can cause optic nerve and macular edema. A thorough medical evaluation of any
      patient presenting with uveitis and systemic disease is essential to the
      diagnosis and management of uveitis.

PMID- 10334361
TI  - Features of amiodarone-induced optic neuropathy.
AB  - PURPOSE: To report clinical features of amiodarone-induced optic neuropathy and
      outline the differentiation of amiodarone optic neuropathy from nonarteritic
      anterior ischemic optic neuropathy. METHOD: We reviewed data from 73 patients
      reported to have developed an optic neuropathy while taking amiodarone. RESULTS:
      Amiodarone optic neuropathy is characterized by an insidious onset, slow
      progression, bilateral visual loss, and protracted disk swelling that tends to
      stabilize within several months of discontinuing the medication. Nonarteritic
      ischemic optic neuropathy is characterized by acute, unilateral visual loss that
      is usually complete at onset, with resolution of disk edema over several weeks.
      CONCLUSION: Unique clinical features of amiodarone-induced optic neuropathy may
      help clinicians diagnose and distinguish between amiodarone-induced optic
      neuropathy and nonarteritic anterior ischemic optic neuropathy.

PMID- 10334362
TI  - Cutaneous melanoma-associated paraneoplastic retinopathy: histopathologic
      observations.
AB  - PURPOSE: To describe the retinal histopathology of paraneoplastic retinopathy
      associated with cutaneous melanoma. METHODS: A 59-year-old man had visual loss
      attributable to paraneoplastic retinopathy and died of metastatic cutaneous
      melanoma. His eyes were studied by conventional histopathologic techniques.
      RESULTS: Histopathologic examination of both eyes disclosed a marked reduction in
      the density of bipolar neurons in the inner nuclear layer; photoreceptor cell
      neurons in the outer nuclear layer were normal. Ganglion cells were present,
      although many showed evidence of transsynaptic atrophy. CONCLUSION: The
      histopathologic changes observed are consistent with clinical, immunologic, and
      electrophysiologic data that implicate the bipolar cell as the major site of the
      paraneoplastic process in cutaneous melanoma-associated retinopathy.

PMID- 10334363
TI  - Histologic and clinical evaluation of combined eyelid erbium: YAG and CO2 laser
      resurfacing.
AB  - PURPOSE: To report the histopathologic and clinical effects of eyelid resurfacing
      that combines two different lasers. METHODS: A case series of 23 patients who
      underwent eyelid resurfacing with two passes of the Erbium:YAG laser followed by
      one pass of the CO2 laser. With the Student t test, we compared skin re
      epithelialization time and duration of erythema with those of a previous group of
      25 patients who had undergone eyelid resurfacing with only the CO2 laser (two
      passes). A pathologist evaluated all skin biopsy specimens. RESULTS: Combining
      both lasers shortened re-epithelialization time (7 vs 12 days, P = .04) and the
      duration of erythema (2.5 vs 7.0 weeks, P = .02). Histopathologic examination
      disclosed less coagulative dermal damage with the combined laser protocol.
      CONCLUSION: The different biophysical properties of these two lasers can be
      combined in a periorbital resurfacing protocol to minimize both clinical and
      histopathologic morbidity.

PMID- 10334364
TI  - Factors affecting the success of nasolacrimal duct probing for congenital
      nasolacrimal duct obstruction.
AB  - PURPOSE: To ascertain the effect of certain parameters on nasolacrimal duct
      probing. METHODS: In a retrospective study of 142 infants and children who
      underwent nasolacrimal duct probing for congenital nasolacrimal duct obstruction,
      age at time of probing, gender, symptom severity, presence of mucous discharge,
      and history of probing were correlated with success of nasolacrimal probing.
      Success of probing was defined as complete resolution of signs and symptoms of
      nasolacrimal duct obstruction. Chi-square test was used to analyze covariance.
      RESULTS: Success of nasolacrimal duct probing was negatively correlated with
      increasing age: 92%, 89%, 80%, 71%, and 42% at age 12, 24, 36, 48, and 60 months,
      respectively (P = .001 at each interval). Increasing severity of epiphora was
      correlated with increased failure of nasolacrimal duct probing (P = .05).
      CONCLUSIONS: Although the success of nasolacrimal duct probing declines with age,
      probing in older children can remain the first line of treatment. Because
      increasing frequency of epiphora correlates with failure of nasolacrimal duct
      probing, children with daily epiphora should undergo early nasolacrimal duct
      probing.

PMID- 10334365
TI  - Isolated inferior rectus paresis secondary to a mesencephalic cavernous angioma.
AB  - PURPOSE: To report a case of recurrent binocular, vertical diplopia presenting as
      an isolated, unilateral inferior rectus paresis occurring in a patient with a
      mesencephalic tegmental cavernous angioma. METHOD: Case report. A 30-year-old man
      with recurrent vertical diplopia underwent neuro-ophthalmic examination,
      laboratory examination, pharmacologic testing, and magnetic resonance imaging and
      angiography. RESULTS: Magnetic resonance imaging disclosed a lesion in the
      mesencephalon consistent with a cavernous angioma. Magnetic resonance angiography
      was negative. CONCLUSIONS: Isolated inferior rectus paresis is a rare phenomenon.
      This unique case involved a patient with recurrent inferior rectus paresis
      secondary to a mesencephalic cavernous angioma. The disparity between the extent
      of the lesion and the neuro-ophthalmologic consequences is remarkable.

PMID- 10334366
TI  - Orbital chondrosarcoma developing in a patient with Paget disease.
AB  - PURPOSE: To describe the radiologic, histopathologic, and cytogenetic features of
      an orbital chondrosarcoma developing in a patient with Paget disease. METHODS: A
      64-year-old woman presented with rapidly progressive proptosis of her right eye.
      Computed tomographic scans, histopathologic examination, and cytogenetic analysis
      were performed. RESULTS: Computed tomographic scans disclosed osseous changes of
      the temporal and frontal bones, with areas of high density consistent with Paget
      disease. A soft-tissue tumor in the right lateral orbital wall was consistent
      with Paget sarcoma. On histology, a chondrosarcoma was diagnosed, which was
      confirmed by fluorescent in situ hybridization. CONCLUSION: This is a unique case
      of orbital chondrosarcoma developing in a patient with Paget disease.

PMID- 10334367
TI  - Reconstruction of the irradiated contracted socket with an expanded superficial
      temporalis fascial flap.
AB  - PURPOSE: To describe the reconstruction of an irradiated contracted socket with
      an expanded superficial temporalis fascial flap and oral mucosa. METHODS: A
      superficial temporalis fascial flap was first expanded with tissue expansion
      techniques and then rotated into the orbit to revascularize the socket. The
      mucosal surface of the socket was secondarily grafted with buccal and hard palate
      mucosa. RESULTS: The expanded superficial temporalis fascial flap was used to
      revascularize the socket for grafting with hard palate and buccal mucosa. This
      resulted in the successful retention of an ocular prosthesis. CONCLUSION: The
      expanded superficial temporalis fascial flap is a useful technique in
      reconstruction of the contracted socket.

PMID- 10334368
TI  - Comparison of glaucomatous progression between untreated patients with normal
      tension glaucoma and patients with therapeutically reduced intraocular pressures.
      The effectiveness of intraocular pressure reduction in the treatment of normal
      tension glaucoma.

PMID- 10334369
TI  - Comparison of glaucomatous progression between untreated patients with normal
      tension glaucoma and patients with therapeutically reduced intraocular pressures.
      The effectiveness of intraocular pressure reduction in the treatment of normal
      tension glaucoma.

PMID- 10334370
TI  - Glaucomatocyclitic crisis in a child.

PMID- 10334371
TI  - Heroin addiction and methadone maintenance: when will we ever learn.

PMID- 10334372
TI  - Access to narcotic addiction treatment and medical care: prospects for the
      expansion of methadone maintenance treatment.
AB  - Methadone maintenance treatment (MMT) for opioid addiction is safe and effective
      but underutilized because of inaccessibility, under-financing and the stigma
      generally attached to maintenance therapies. In addition, cumbersome regulation
      of methadone prescription and treatment impedes the delivery of care and retards
      expansion of methadone maintenance into office practice settings. Exaggeration of
      the problem of methadone diversion further hinders development of MMT. Despite
      obstacles, methadone maintenance has been successfully expanded and extended into
      primary care settings abroad. Initial trials in the U.S. have shown that
      methadone maintenance in physician office-based settings yields positive results
      with some advantages over care in large methadone clinics. Alternatives to
      methadone, such as buprenorphine, are also being explored in primary care
      settings. With implementation of the NIH Consensus Statement on Effective Medical
      Treatment of Heroin Addiction, including training of primary care physicians,
      methadone maintenance treatment could reach many more patients, achieve higher
      success rates, and substantially reduce the deleterious effects of opioid
      addiction in the U.S.

PMID- 10334373
TI  - Physician substance use by medical specialty.
AB  - Self-reported past year use of alcohol, tobacco, marijuana, cocaine, and two
      controlled prescription substances (opiates, benzodiazepines); and self-reported
      lifetime substance abuse or dependence was estimated and compared for 12
      specialties among 5,426 physicians participating in an anonymous mailed survey.
      Logistic regression models controlled for demographic and other characteristics
      that might explain observed specialty differences. Emergency medicine physicians
      used more illicit drugs. Psychiatrists used more benzodiazepines. Comparatively,
      pediatricians had overall low rates of use, as did surgeons, except for tobacco
      smoking. Anesthesiologists had higher use only for major opiates. Self-reported
      substance abuse and dependence were at highest levels among psychiatrists and
      emergency physicians, and lowest among surgeons. With evidence from studies such
      as this one, a specialty can organize prevention programs to address patterns of
      substance use specific to that specialty, the specialty characteristics of its
      members, and their unique practice environments that may contribute risk of
      substance abuse and dependence.

PMID- 10334374
TI  - Use of standardized patients to evaluate the physicians in residence program: a
      substance abuse training approach.
AB  - The purpose of this study was to evaluate the efficacy of the Physician in
      Residence (PIR) program at the Hazelden Residential Program of New York City as a
      substance abuse training approach using standardized patients (SP) and self
      report ratings. Using an objective rating scale, two experienced drug counselors
      evaluated four videotaped interviews carried out by housestaff pre- and post
      enrollment in the PIR program. In addition, housestaff completed self-report
      ratings regarding their knowledge, attitudes, and skills of substance abuse. Of
      the 23 housestaff who completed both pre- and post-PIR program videotape
      sessions, significant improvements were noted in both observer and self-reported
      ratings. Overall, self-report ratings showed a greater percent improvement than
      the counselor ratings. The PIR program may be an efficacious approach to teach
      substance abuse clinical skills to housestaff.

PMID- 10334375
TI  - Carisoprodol (soma): abuse potential and physician unawareness.
AB  - Carisoprodol is a noncontrolled skeletal muscle relaxant whose active metabolite
      is meprobamate, a Schedule IV controlled substance. Although several case reports
      have shown that carisoprodol has abuse potential, it continues to be widely
      prescribed. The usage patterns of 40 patients who had taken carisoprodol for
      three or more months (20 of whom had no history of substance abuse and 20 of whom
      carried a diagnosis of substance abuse or dependence) were reviewed and compared
      and a survey was conducted to assess physician awareness of the abuse potential
      of the drug. Findings showed that some patients using carisoprodol for over three
      months may abuse the medication, especially those individuals with a history of
      substance abuse. A significant percentage of the physician population is unaware
      of the potential of carisoprodol for abuse and of its metabolism to meprobamate,
      a controlled substance. Physicians should exercise caution when prescribing
      carisoprodol, especially if the patient has a history of substance abuse.

PMID- 10334376
TI  - LSD use and flashbacks in alcoholic patients.
AB  - Lysergic Acid Diethylamide (LSD) is a hallucinogenic drug that received
      considerable attention in the 1960's and early 1970's. It produced a wide variety
      of psychological phenomena, including a variety of perceptual disturbances which
      would manifest among some users long after the drug had left the system. These
      phenomena were commonly referred to as "flashbacks" and may have been largely
      responsible for the drug falling out of favor among recreational drug users. This
      report describes histories of LSD use among alcoholism treatment facility
      inpatients and reports specific characteristics of flashbacks and the degree of
      subjective distress experienced during flashbacks. Findings indicate a
      statistically significant relationship between number of doses and incidence of
      flashbacks.

PMID- 10334377
TI  - Primary care and addiction treatment: lessons learned from building bridges
      across traditions.
AB  - A primary care unit combined with residential addiction treatment allows patients
      with addictive disease and chronic medical or psychiatric problems to
      successfully complete the treatment. These are patients who would otherwise fail
      treatment or fail to be considered candidates for treatment. Health care
      providers should have a background in primary care and have the potential to
      respond professionally to clinical problems in behavioral medicine. Ongoing
      professional training and statistical quality management principles can maintain
      morale and productivity. Health education is an integral part of primary care.
      The costs of such concurrent care when viewed in the context of the high societal
      and economic costs of untreated addictive disease and untreated chronic medical
      problems are low. The principles used to develop this primary care unit can be
      used to develop health care units for other underserved populations. These
      principles include identification of specific health care priorities and
      continuity of rapport with the target population and with addiction treatment
      staff.

PMID- 10334378
TI  - Screening of substance abuse in public welfare and child protective service
      clients: a comparative study of rapid assessment instruments vs. the SASSI.
AB  - In light of new welfare reforms, it is essential that public welfare workers move
      individuals from welfare to work in an expedient fashion. Client alcohol and/or
      drug use/abuse is one barrier that may inhibit this process. The following study
      (N = 93) administered both the Hudson Index of Alcohol Involvement, the Hudson
      Index of Drug Involvement (rapid assessment instruments) and the Miller Substance
      Abuse Subtly Screening Inventory (SASSI) to public welfare and Child Protection
      system clients. Results indicated that the two rapid assessment measures strongly
      correlated with the advanced, commonly used SASSI measure. It is suggested that
      public welfare workers should institute these rapid assessment instruments at
      intake to screen clients for alcohol and drug use/abuse. When indicated, the
      client could then be referred to the appropriate agency for further assessment
      and treatment, to better prepare them for employment as mandated by new welfare
      reforms. The rapid assessment instruments were found to be shorter than the
      SASSI, easily administered, and able to detect alcohol and/or drug use/abuse
      effectively and efficiently in these populations.

PMID- 10334379
TI  - Selective guide to current reference sources on topics discussed in this issue.

PMID- 10334380
TI  - The human 2',5'-oligoadenylate synthetase family: interferon-induced proteins
      with unique enzymatic properties.
AB  - 2',5'-Oligoadenylate synthetase (2',5'-OAS) was discovered and characterized as
      an interferon (IFN)-induced enzyme that in the presence of double-stranded (ds)
      RNA converts ATP into 2',5'-linked oligomers of adenosine with the general
      formula pppA(2'p'A)n, n > or = 1. The product is pppG2'p5'G when GTP is used as a
      substrate. Now, 20 years later, this activity is attributed to several well
      characterized, homologous, and IFN-induced proteins in human cells. Three
      distinct forms of 2',5'-OAS exist, small, medium, and large, which contain 1, 2,
      and 3 OAS units, respectively, and are encoded by distinct genes clustered on the
      2',5'-OAS locus on human chromosome 12. Recently, other IFN-induced proteins
      homologous to the OAS unit but devoid of the typical 2',5'-OAS catalytic activity
      have been described. These OAS-related proteins are encoded by a gene located at
      the proximity of the 2',5'-OAS locus. These findings illustrate the apparent
      structural and functional complexity of the human 2',5'-OAS family.

PMID- 10334381
TI  - Human type I interferons differ greatly in their effects on the proliferation of
      primary B cells.
AB  - We examined the effects of eight subtypes of human interferon-alpha (IFN-alpha)
      and human IFN-beta on primary human B cells. In costimulation with antibodies to
      IgM (but not to CD40), some of these induced the cells to proliferate (but not to
      differentiate). Individual IFN differed greatly in their relative proliferative
      effects. IFN-alpha8 at 0.1-0.5 ng/ml induced proliferation, whereas most other
      subtypes were active only at concentrations >5 ng/ml, and IFN-alpha1 was
      inactive. These marked differences were not due to a selective overall increase
      in B cell response only to some IFN subtypes, as all those tested similarly
      induced the IFN-inducible genes 6-16 and HLA class I. Our results show that human
      B cells must respond to type I IFN via two distinct pathways. One is specific for
      IFN-alpha8 but can be activated by other IFN at relatively high concentrations.
      The other responds to them all and causes activation of IFN-inducible genes.

PMID- 10334382
TI  - Antigenic characterization of recombinant, lymphoblastoid, and leukocyte IFN
      alpha by monoclonal antibodies.
AB  - To gain more insight into similarities of different interferon-alpha (IFN-alpha)
      species, we evaluated neutralization and immunoactivity of a variety of IFN
      preparations with various monoclonal antibodies (IFN-alpha mAb). Nine IFN-alpha
      mAb obtained through immunization with recombinant IFN-alpha (rmAb),
      lymphoblastoid IFN-alpha (LY mAb), and leukocyte IFN-alpha (LE mAb) were tested.
      The IFN-alpha mAb were evaluated for their ability to neutralize the antiviral
      activity of 11 recombinant IFN-alpha subtypes, two recombinant IFN-alpha hybrids,
      and lymphoblastoid and leukocyte IFN-alpha preparations. The same IFN-alpha mAb
      were also used in immunoblotting, and some of them were used in immunoaffinity
      chromatography. The results of the neutralization assay reveal that the IFN-alpha
      mAb significantly differ in their ability to neutralize the individual IFN-alpha
      species. Interestingly, none of the IFN-alpha mAb was able to neutralize all the
      IFN-alpha species. In particular, rmAb were unable to neutralize LE-IFN-alpha or
      LY-IFN-alpha, whereas LE mAb and LY mAb efficiently neutralized rIFN-alpha2. In
      some cases, the epitopes to which IFN-alpha mAb are directed were identified
      through the use of synthetic fragments of IFN-alpha2 or by evaluating the
      selectivity in binding to IFN-alpha subtypes.

PMID- 10334383
TI  - Transforming growth factor-beta suppresses proliferation of rabbit corneal
      endothelial cells in vitro.
AB  - Corneal endothelial cells in vivo appear to be inhibited in G1 phase of the cell
      cycle. Studies were carried out to determine whether cultured rabbit corneal
      endothelium expresses transforming growth factor-beta (TGF-beta) receptor types
      I, II, and III, suggesting they would be sensitive to a TGF-beta-induced signal.
      In addition, we explored if TGF-beta might mediate this G1 phase inhibition by
      implementing flow cytometry and 5-bromo-2'-deoxyuridine (BrdU)
      immunofluorescence. Reverse transcription-polymerase chain reaction (RT-PCR)
      products of the expected size were obtained for all three TGF-beta receptor
      types. Flow cytometry revealed a dose-dependent suppression in the percentage of
      S phase cells in cultures treated with TGF-beta1 or TGF-beta2. The lowest
      percentage of S phase cells was found for 10 ng/ml TGF-beta1 and 0.1 ng/ml TGF
      beta2. BrdU, an S phase marker, was immunolocalized, and semiquantitative
      analysis of stained cells showed a maximum suppression of S phase entry at 18 h
      for 10 ng/ml of TGF-beta11 and 24 h for 10 ng/ml of TGF-beta2. In rabbit, the
      corneal endothelium expresses TGF-beta receptor types I, II, and III, permitting
      a TGF-beta signal to be transduced. Flow cytometry reveals a dose-dependent
      response to both TGF-beta1 and TGF-beta2, and the cells are more sensitive to TGF
      beta2. At optimal TGF-beta concentrations, the percentage of S phase cells is
      comparable to that of a non-proliferating culture, suggesting TGF-beta prevents
      the cells from proceeding through the G1/S phase transition. This suppression was
      also seen with BrdU labeling. Together, these results indicate that TGF-beta
      could be one of the pathways that leads to G1 phase arrest in corneal endothelial
      cells.

PMID- 10334384
TI  - IFN-alpha stimulates proliferation and cytokine secretion of CD40-stimulated B
      cell chronic lymphocytic leukemia cells in vitro.
AB  - Interferon (IFN)-alpha has a therapeutic effect in several B cell malignancies,
      including low-grade non-Hodgkin's lymphoma (NHL), multiple myeloma, and hairy
      cell leukemia, whereas its efficacy in the treatment of B cell chronic
      lymphocytic leukemia (B-CLL) is rather limited. In the present study, we
      investigated the effect of IFN-alpha on the biologic functions of B-CLL cells,
      which were stimulated by cross-linking of the CD40 antigen. In cell samples from
      16 B-CLL patients, the addition of IFN-alpha to CD40-stimulated purified B-CLL
      cells caused a significant increase in [3H]thymidine uptake (p < 0.003). In B-CLL
      cells maximally activated by CD40 cross-linking and interleukin-2 (IL-2)/IL-10,
      proliferation was not further enhanced or inhibited by IFN-alpha. In contrast,
      proliferation of normal tonsillar B cells stimulated by the combination CD40/IL
      2/IL-10 was significantly inhibited by IFN-alpha. Because B-CLL activation might
      be enhanced by induction of the autocrine growth factor tumor necrosis factor
      alpha (TNF-alpha), we investigated the effect of IFN-alpha on the secretion of B
      cell tropic cytokines. In fact, IFN-alpha significantly stimulated the secretion
      of IL-6 and TNF-alpha in CD40-activated B-CLL cells (p < 0.01). Although
      exogenous addition of TNF-alpha did not influence activation of CD40-stimulated B
      CLL cells, neutralization of TNF-alpha by polyclonal antibodies led to a complete
      inhibition of CD40-mediated proliferation of B-CLL cells, suggesting that
      enhanced proliferation and increased cytokine production by CD40-activated B-CLL
      cells are independent IFN-alpha-mediated events. The studies presented here
      provide evidence that IFN-alpha mediates costimulatory signals in the context of
      T cell-mediated B-CLL cell activation.

PMID- 10334385
TI  - RANTES stimulates cell-mediated transmission of HIV-1 infection.
AB  - We wished to determine the effects of the beta-chemokine RANTES in an established
      system of cell-mediated transmission of HIV-1, that is, normal human umbilical
      vein endothelial cells (HUVEC) nonproductively infected with HIV-1, cocultivated
      with CD4+ T cells to rescue productive infection. The results indicate that the
      addition of RANTES to HUVEC, either before or after HIV-1 infection, stimulates
      HIV-1 rescue by CD4+ T cells. However, viral DNA is not increased in HUVEC,
      suggesting that the stimulation exerted by RANTES could be mediated by events
      following HUVEC infection. The mechanisms of increase seem to be related to the
      rescue phase, involving membrane interaction of abortively infected HUVEC with
      permissive T cells. In fact, a strong upregulation and polarization of
      intercellular adhesion molecule-1 (ICAM-1) is induced in HUVEC by RANTES, and
      antibodies against ICAM-1 inhibit HIV-1 rescue by T cells. These results indicate
      that RANTES, similarly to other inflammatory cytokines, may favor HIV-1 spreading
      and crossing of blood-tissue barriers by indirect mechanisms involving membrane
      interactions between nonproductively infected and permissive cells.

PMID- 10334387
TI  - Proteases involved in the metabolic degradation of human interleukin-1beta by rat
      kidney lysosomes.
AB  - The in vitro metabolic degradation of human interleukin (IL)-1beta was studied
      using lysates of rat kidney lysosomes, and proteases involved in the degradation
      were identified. In the study of IL-1beta degradation, fluorescein isothiocyanate
      (FITC)-labeled IL-1beta was used as a substrate. The maximal degradation of IL
      1beta occurred at pH 3.0, and the reaction was proportional to the lysosomal
      protein concentration and time of incubation. The degradation was stimulated by
      the addition of L-cysteine. The reaction was not inhibited by
      phenylmethanesulfonyl fluoride or EDTA, indicating that serine proteases or
      metalloproteases do not play a major role in the degradation process. N
      Ethylmaleimide, leupeptin and E-64, inhibitors of thiol protease, inhibited the
      degradation of IL-1beta, by 59%-70%. Pepstatin A, an inhibitor of carboxyl
      protease, inhibited the degradation by 58%. Combinations of thiol and carboxyl
      protease inhibitors nearly completely inhibited the degradation. Bio-Gel P-10 gel
      filtration chromatography of in vitro reactants confirmed the ability of
      lysosomal proteases to degrade IL-1beta and revealed four to five peaks of
      degradation products. Taken together, these results indicate that thiol protease
      and carboxyl protease play an important role in the IL-1beta degradation process
      by kidney lysosomes. Leupeptin and E-64 dose dependently inhibited both cathepsin
      B and cathepsin L activities, and pepstatin A strongly inhibited cathepsin D
      activity in rat kidney lysosomes. The present results suggest that cathepsin B,
      cathepsin L, and cathepsin D in kidney lysosomes are involved in the metabolic
      degradation of human IL-1beta.

PMID- 10334386
TI  - Expression of interleukin-10 in isolated CD8+ T cells and monocytes from growth
      factor-mobilized peripheral blood stem cell products: a mechanism of immune
      dysfunction.
AB  - Previous reports showed the abnormal activation of immune cells in growth factor
      mobilized peripheral blood stem cell (PBSC) products, which might be responsible
      for depressed T cell responsiveness to mitogens compared with normal peripheral
      blood mononuclear cells (PBMC). In the present study, the mRNA expression levels
      of interleukin (IL)-2, IL-4, IL-10, and interferon-gamma (IFN-gamma) were
      significantly higher in CD4+ and CD8+ T cells from mobilized PBSC products
      compared with CD4+ and CD8+ cells from normal peripheral blood (PB). The mRNA
      expression levels of IL-4 and IL-10 were significantly higher in CD8+ compared
      with CD4+ cells from PBSC products. However, the expression of IL-2 and IFN-gamma
      mRNA transcripts was similar in the CD4+ and CD8+ T cells from PBSC products. The
      levels of IL-10, IL-8, and tumor necrosis factor (TNF)-alpha mRNA were also
      significantly higher in monocytes isolated from PBSC products compared with
      monocytes isolated from normal PB. Expression of IL-10-specific mRNA in monocytes
      also was significantly higher than the levels observed in CD8+ cells from PBSC
      products. We suggest that both CD4+ and CD8+ cells in the PBSC products are
      highly activated. However, their response to phytohemagglutinin (PHA) mitogenesis
      is depressed in part because of IL-10 expression by CD8+ cells and monocytes in
      addition to the higher levels of monocyte-dependent T cell inhibitory activity.
      These data demonstrate that aberrant IL-10 expression in the CD8+ T cells and
      monocytes present in PBSC products may represent a possible mechanism of immune
      dysfunction in patients after high-dose chemotherapy (HDT) and peripheral blood
      stem cell transplantation (PBSCT).

PMID- 10334388
TI  - Serum erythropoietin and interleukin-6 levels in hemodialysis patients with
      hepatitis virus infection.
AB  - The influence of hepatitis B (HBV) and hepatitis C virus (HCV) infection on blood
      hemoglobin (Hb) and serum erythropoietin (Epo) and interleukin-6 (IL-6)
      concentrations was studied in 48 anemic patients on regular hemodialysis. They
      were grouped as follows: (I) 19 patients whose Hb values improved after infection
      (Hb > 85 g/L), (II) 10 patients with persisting anemia after infection (Hb < 75
      g/L), and, without hepatitis virus markers (III) 8 patients with Hb > 85 g/L and
      (IV) 11 patients with Hb < 75 g/L. Serum immunoreactive Epo levels were
      significantly higher in group I (34.4+/-47.1 U/L) than in the other groups (II,
      10.8+/-6.0; III, 7.9+/-3.2; IV, 8.4+/-4.3). Serum IL-6 was higher in group I than
      group III (7.7+/-7.8 pg/ml vs. 3.6+/-2.4; p = 0.05) but similar to the other
      groups. Hb levels in group I were maximal at the time of serum alanine
      aminotransferase normalization. Red cell production increases as a result of
      elevated circulating Epo during hepatic regeneration after HBV or HCV infection.

PMID- 10334389
TI  - Tyrosine kinase regulatory action on ileal muscarinic effects of IFN-gamma.
AB  - Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that has a large number of
      immunologic and nonimmunologic functions. We have described that IFN-gamma could
      activate muscarinic cholinergic receptors (mAchR) of rat intestine, stimulating
      ileal motility. We also observed that mAchR activation induced inhibition of cAMP
      levels and stimulation of cGMP formation. The objectives of our work were to
      clarify the signal transduction pathways involved in regulation of ileal motility
      through mAchR activation by IFN-gamma. Our results demonstrate that this cytokine
      produces an ileal cholinergic response through tyrosine kinase activity. The
      activation of tyrosine kinase mediates ileal contractility, phosphoinositide
      hydrolysis by phospholipase C, nitric oxide synthase via protein kinase C, and
      cGMP synthesis. The increment in ileal motility is probably due to
      hyperproduction of prostaglandin E2 (PGE2) by ileal tissue. This prostanoid is an
      important mediator because it stimulates ileal motility. We conclude that IFN
      gamma not only immunomodulates the gut microenvironment but also exerts a local
      nonimmunologic regulation on intestinal motility.

PMID- 10334390
TI  - Recombinant chicken IFN-gamma expressed in Escherichia coli: analysis of C
      terminal truncation and effect on biologic activity.
AB  - Interferon-gamma (IFN-gamma) possesses potent immunostimulatory properties, and
      it has recently been shown to have potential therapeutic properties. Recombinant
      protein technology is frequently used for commercial production of therapeutics,
      such as IFN. Biologically active recombinant chicken IFN-gamma (rChIFN-gamma)
      constructs bearing an N-terminal poly-His tag were expressed in Escherichia coli.
      Preparations of rChIFN-gamma contained varying ratios of a full-length and a
      truncated protein species (18 and 16 kDa, respectively). Amino acid sequence
      analysis of the full-length protein corroborated the sequence previously
      predicted from the cDNA sequence. Full-length rChIFN-gamma contains two cysteine
      residues at the C-terminus, and these were labeled by reduction and subsequent
      specific alkylation with fluorescent tag (5-I-AEDANS) to distinguish between full
      length and C-terminally truncated forms of rChIFN-gamma. Comparative peptide
      mapping, amino acid sequencing, and mass spectrometry revealed that the 16 kDa
      protein was truncated at Lys133. It was also observed that the 18 kDa rChIFN
      gamma protein was infrequently contaminated with small quantities of protein
      truncated at Arg141. A truncated recombinant construct (His1-Lys133) was also
      expressed in E. coli and had biologic activity comparable with that of the full
      length construct. The 3-D structure of rChIFN-gamma was deduced by comparative
      modeling with bovine and human IFN-gamma crystallographic structures. Analysis of
      sequences and comparison of structures have revealed that the 3-D structure of
      rChIFN-gamma is similar to those of bovine and human molecules despite an overall
      amino acid identity of only 32%.

PMID- 10334391
TI  - Transcriptional basis for the differences in inducible nitric oxide synthase
      (iNOS) expression between nonmetastatic and metastatic murine melanoma cell
      lines.
AB  - An inverse correlation exists between expression of the inducible nitric oxide
      synthase (iNOS) gene and the ability of cloned K1735 murine melanoma cell lines
      to metastasize. We have analyzed the basis for the difference in iNOS induction
      by interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) in metastatic and
      non-metastatic K1735 cells. Nuclear run-on (NRO) assays revealed an upregulation
      of iNOS transcription on treatment with IFN-gamma plus LPS in nonmetastatic cells
      but not in a metastatic line. Transcription factors IFN regulatory factor 1 (IRF
      1) and NF-kappaB were induced and functional in both metastatic and nonmetastatic
      K1735 lines treated with IFN-gamma plus LPS. Furthermore, a reporter construct
      driven by the wild-type iNOS promoter was transcriptionally activated in both
      nonmetastatic and metastatic cells. The iNOS-inducible phenotype was dominant in
      somatic cell hybrids generated by the fusion of nonmetastatic and metastatic
      cells, suggesting that no inhibitors of iNOS expression are present in metastatic
      cells. We conclude that the selective block in iNOS transcription in metastatic
      K1735 cells is likely due to an alteration in iNOS gene regulatory sequences.
      However, no such alteration was detected within the 1.7 kb iNOS promoter region
      in metastatic cells.

PMID- 10334392
TI  - Retinoids synergize with interleukin-2 to augment IFN-gamma and interleukin-12
      production by human peripheral blood mononuclear cells.
AB  - We have demonstrated previously that cells from both the skin and peripheral
      blood from patients with cutaneous T cell lymphoma (CTCL) have elevated levels of
      protein and mRNA for Th2 cytokines, interleukin-4 (IL-4) and IL-5, and depressed
      levels of Thl cytokines, IL-2 and interferon-gamma (IFN-gamma). Furthermore, IL
      12 in vitro can restore IFN-gamma production by these patients' cells to near
      normal levels. Because retinoids exert therapeutic activity in CTCL and are
      potent modulators of growth and differentiation of hematopoietic cells, we
      investigated the role of retinoids in modulating Thl cytokine production.
      Peripheral blood mononuclear cells (PBMC) from normal donors and patients with
      CTCL were cultured with medium, IL-2, 13-cis-retinoic acid, all-trans-retinoic
      acid, acetretin or etretinate alone, or IL-2 plus the retinoids for 24 h, and
      levels of IFN-gamma were determined using ELISA. IL-2 or retinoids alone could
      induce low but significant levels of IFN-gamma. However, when IL-2 was cultured
      with each retinoid, a synergistic augmentation of IFN-gamma levels (4-fold to 90
      fold) was observed except in the case of etretinate. All-trans-retinoic acid
      (ATRA) was the most potent IFN-y inducer. Similar studies performed using PBMC
      from CTCL patients indicated the IFN-gamma augmentation occurred but in a blunted
      manner. The IFN-y-inducing effect of ATRA and 13-cis-retinoic acid could be
      abrogated by addition of anti-IL-12 antibodies, suggesting that IL-12 plays a
      role in the synergistic upregulation of IFN-gamma. Using an IL-12 p40-specific
      radioimmunoassay (RIA), we confirmed the presence of IL-12 in IL-2 plus retinoid
      treated culture supernatants. Purified monocytes cultured with IL-2 plus ATRA did
      not secrete IL-12. Only when monocytes were cocultured with lymphocytes was there
      an increase in IL-12 production, suggesting the involvement of a paracrine
      feedback loop requiring both monocytes and lymphocytes. These data suggest that
      retinoids can induce Th1 cytokines from normal and CTCL PBMC and that this
      induction may be mediated through IL-12 production.

PMID- 10334394
TI  - Functional brain imaging in neuropsychiatric disorders of childhood.
AB  - This review article presents a summary of the current state-of-the-art of
      functional brain imaging, with a primary focus on childhood neuropsychiatric
      disorders. Coverage is emphasized for developments that appear to be of current
      or potential future importance for the child neurologist and related pediatric
      specialist, and also from the perspective of the developmental neuroscientist.
      Emphasis is placed on the modalities of single photon emission computed
      tomography (SPECT), positron emission tomography (PET), and both "conventional"
      and "functional" magnetic resonance imaging, (MRI) including reference to the
      major new radiopharmaceutical and magnetic resonance-based imaging agents and
      techniques. The fundamental physicochemical processes underlying such studies are
      outlined, with citation of sources of more detailed information for the
      interested reader. A variety of imaging studies are reviewed for selected groups
      of childhood neuropsychiatric disorders, designed to illustrate the achievements
      and future promise of these imaging modalities. Areas of concentration are
      suggested for future imaging research in the field of childhood behavioral
      disorders, where these methods seem critical to improved understanding of
      pathogenetic mechanisms, as well as development of more effective treatment
      strategies.

PMID- 10334393
TI  - Direct comparison of the effects of CSF-1 (M-CSF) and GM-CSF on human monocyte
      DNA synthesis and CSF receptor expression.
AB  - There is evidence that a proportion of human monocytes can proliferate in vitro
      in response to colony-stimulating factor-1 (CSF-1, also known as M-CSF) and
      granulocyte-macrophage CSF (GM-CSF). To determine whether there are differences
      in DNA synthesis responses to these CSF, a large study using purified human
      peripheral blood monocytes from 45 donors was performed under optimized culture
      conditions. In contrast to the consistent response to CSF-1, approximately 20% of
      donors have monocytes that do not respond or have a minimal DNA synthesis
      response to GM-CSF stimulation. However, analysis demonstrated that no
      statistically significant differences exist in the levels of CSF-1 and GM-CSF
      stimulated proliferation in monocytes. In addition, CSF-1 receptor (CSF-1R)
      blocking experiments indicated that a proportion of the GM-CSF-induced DNA
      synthesis is due to endogenous levels of CSF-1. As a further comparison of the
      actions of the two CSFs, CSF-1R and GM-CSFR levels were measured by flow
      cytometry, and it was shown that GM-CSFR levels decreased within 5 days of
      culture, independent of the conditions examined. In contrast, CSF-1R levels at
      day 5 approximated those measured in uncultured monocytes. Whether the
      proliferating subpopulation(s) express one or both CSF receptors at the beginning
      or at the end of culture is as yet unknown. The information obtained in this
      study will be useful for the design of strategies to enrich for the subpopulation
      in question based on CSF receptor expression.

PMID- 10334395
TI  - Slow progression of juvenile metachromatic leukodystrophy 6 years after bone
      marrow transplantation.
AB  - Metachromatic leukodystrophy refers to a group of genetic neurologic diseases
      caused by deficiencies of the enzyme arylsulfatase A and the resulting
      accumulation of sulfatides in white matter. Bone marrow transplantation has been
      advocated as a treatment in an attempt to correct the enzyme deficiency. Such a
      transplant was performed in 1991 in a 16-year-old girl with a form of late
      juvenile metachromatic leukodystrophy caused by a homozygous P426L mutation in
      the arylsulfatase A gene. Engraftment was prompt and resulted in constant
      enzymatic normalization of circulating lymphocytes. The elevated urinary
      excretion of sulfatides remained unaffected. Clinical findings up until
      transplantation consisted of gait disturbances, impairment of cognitive
      functioning, and deterioration in school performance over several years. During a
      6-year follow-up period, the patient's condition was subject to major
      fluctuations but, on the whole, findings showed slow neurologic and
      neurophysiologic deterioration. The clinical course observed after bone marrow
      transplantation probably more or less reflects the natural course expected in
      this form of late-onset metachromatic leukodystrophy.

PMID- 10334396
TI  - Respiratory sinus arrhythmia of brainstem lesions.
AB  - In this pilot study we investigated the hypothesis that intrinsic and extrinsic
      brainstem lesions situated within the pontomedullary region would effect the
      integrity of respiratory sinus arrhythmia. The study sample consisted of three
      patients with anatomic brainstem abnormalities associated with isolated Chiari I
      malformation, Chiari II malformation with syringobulbia, and achondroplasia with
      cervicomedullary compression. They were compared to an age- and sex-matched
      control group of nine patients. Each subject's electrocardiogram was recorded in
      a quiet room and digitized by a personal computer during five 1-minute periods. R
      R intervals within each 1-minute period were converted to heart rate in 120
      successive 0.5-second intervals. The resultant heartrate time series was
      converted to its underlying frequency composition by a fast Fourier transform and
      averaged across minutes. Respiratory sinus arrhythmia was defined as the
      variability in the time series over a frequency range (0.096 to 0.48 Hz)
      corresponding to a range of respiratory rates from 6 to 30 breaths per minute.
      Analysis revealed a significant reduction in respiratory sinus arrhythmia (P <
      .05), defined as the summated area under the curve, with a mean for controls of
      35.42+/-28.13 SD and for subjects of 17.20+/-11.50 SD. There was a gradient of
      abnormality noted, with the mildest deviation in respiratory sinus arrhythmia for
      the patient with isolated Chiari I malformation and maximum deviation seen in the
      patient with extrinsic cervicomedullary compression.

PMID- 10334397
TI  - Case report of fibromuscular dysplasia presenting as stroke in a 16-year-old boy.
AB  - Fibromuscular dysplasia of the carotid artery is uncommon, but not rare. Although
      the true incidence and prevalence of the disease are not known, reported figures
      in adults range between 0.6% by angiography and 1.1% at autopsy. Most case
      reports of stroke caused by carotid fibromuscular dysplasia describe findings in
      adult subjects, although there are a few reports of the disease in children. In
      the present case, we describe a 16-year-old boy with fibromuscular dysplasia
      confined to one internal carotid artery and its branches, and in whom the disease
      declared itself by stroke. This case serves as a basis for considering diagnostic
      methods, treatment options, and future research in pediatric patients with
      cerebrovascular disease caused by fibromuscular dysplasia.

PMID- 10334398
TI  - Clinical experience of three pediatric and one adult case of spike-and-wave
      status epilepticus treated with injectable valproic acid.
AB  - Subclinical or nonconvulsive status epilepticus may cause severe postmorbid
      neurologic dysfunction. It is, therefore, critical to rapidly identify and treat
      these cases. The recent availability of injectable valproic acid (Depacon)
      provides an additional method for treatment of status epilepticus, although
      studies concerning its effectiveness are not widely available in the literature.
      We report four cases (three pediatric, one adult) of patients who presented to us
      in status epilepticus. All had previously failed more than one other common
      method of treatment for this condition. Treatment with injectable valproic acid
      resulted in the elimination of all clinical indications of status epilepticus as
      well as a return to the baseline EEG condition in all four cases. Seizure types
      included focal, multifocal, and generalized spike and wave forms, suggesting
      potential benefit from injectable valproic acid treatment in a wide range of
      status epilepticus patients. We present these cases for review.

PMID- 10334399
TI  - Clinical utility of the judgment of line orientation test and facial recognition
      test in children with acquired unilateral cerebral lesions.
AB  - In unselected adult patients with brain damage, the Judgment of Line Orientation
      Test and the Facial Recognition Test are considered valid instruments for
      detecting right cerebral hemisphere lesions. It is unknown, however, whether this
      applies to children as well. Performance levels on the Judgment of Line
      Orientation Test and the Facial Recognition Test of 18 children with acquired
      left cerebral lesions and 14 children with acquired right cerebral lesions were
      reviewed. Subjects were unselected for age, sex, or etiology. Age-related norms
      were obtained in 81 normal controls, aged 7 to 14 years. Judgment of Line
      Orientation Test and Facial Recognition Test performance levels did not predict
      the presence of cerebral pathology per se in our unselected groups with
      demonstrated unilateral cerebral lesions, nor did they contribute to the
      prediction of the side of the lesion within the two groups with cerebral lesions.
      These results cast serious doubt on an important aspect of the clinical utility
      of both tests in children, namely their discriminative validity in the assessment
      of etiologically unselected populations with brain damage.

PMID- 10334400
TI  - Clinical diversity in acute necrotizing encephalopathy.
AB  - Acute necrotizing encephalopathy is a novel disease entity, proposed by Mizuguchi
      et al in 1995, that shows a characteristic selective and symmetric involvement of
      the thalamus, brain stem, and cerebellum. It usually leaves sequelae. The
      etiology of acute necrotizing encephalopathy is unknown. We describe here six
      patients aged 6 months to 5 years (four boys and two girls). Four cases were
      typical, and the patients' cranial computed tomographic scans and magnetic
      resonance imaging showed irreversible symmetric involvement of the thalamus,
      brain stem, and cerebellum. Three of the patients died, and one was left with
      severe sequelae. In the other two patients, who had selective reversible thalamic
      involvement, the disease was mild; one also showed transient unilateral thalamic
      involvement. These patients recovered completely. We consider the illness in
      these two patients to fit the criteria of the mild form of acute necrotizing
      encephalopathy. We believe that acute necrotizing encephalopathy has some
      clinical diversity, as is seen in other neurologic disorders, and that a mild
      form could exist.

PMID- 10334401
TI  - Paul Dyken Lecture of the Southern Pediatric Neurology Society. Inherited
      neurodegenerative disease: the evolution of our thinking.
AB  - The past 3 decades have witnessed impressive progress in our understanding of
      inherited neurometabolic diseases, promoted by the rapid development and
      application of molecular genetic strategies. Such progress has required the
      juxtaposition of clinical evaluations and basic science techniques. The central
      role of careful and complete assessment of affected children cannot be
      overemphasized and in no way has been diminished by technologic advances. Indeed,
      enhanced clinical and laboratory evaluations have led to important conceptual
      advances. Molecular genetics has elucidated those disorders with known metabolic
      defects through functional cloning and explained the variability of disease
      expression based on specific mutational events. Alternatively, positional cloning
      has identified molecular defects for those disorders with clear phenotypic
      patterns, but lacking a defined metabolic abnormality. Regarding heterogeneous
      expression, disorders with clearly different phenotypes can arise from different
      mutations within the same gene. The multiple variants of beta-hexosaminidase
      deficiency (Tay-Sachs disease) are, arguably, the best examples. Conversely,
      disorders with similar phenotypes are explainable by quite different mutational
      events. In addition, the identification of specific diseases exhibiting both
      biochemical abnormalities and disturbed organogenesis has blurred conventional
      dogma regarding separation of genetic disorders into strict metabolic and
      structural categories. Disorders of peroxisomal function and the neuronal ceroid
      lipofuscinoses are prototypes for the points noted above and raise important
      issues regarding our approaches to children with these disorders. These issues
      include a high index of suspicion for an inherited neurometabolic disease and an
      open mind to possible interrelations with other known and seemingly dissimilar
      conditions.

PMID- 10334402
TI  - Jury finds pharmacy's misfilling of prescription caused child's brain damage.

PMID- 10334403
TI  - Possible dynamic neurotransmitter metabolism surrounding the fetus.
AB  - Human amniotic epithelial cells express makers of glial and neural stem cells.
      These cells also synthesize and release acetylcholine and catecholamines. This
      study of amniotic fluid demonstrated that acetylcholine and catecholamines can be
      readily identified in the fluid. Norepinephrine was the major catecholamine
      present, although dopamine and DOPAC could also be detected. The physiologic role
      of these amniotic fluid neurotransmitters in fetal-placental interactions and
      nervous system development is currently under investigation.

PMID- 10334404
TI  - Marin-Amat syndrome: case report and review of the literature.
AB  - We report a 10-year-old girl with Marin-Amat syndrome, a rare facial synkinesis
      sometimes referred to as the inverted Marcus Gunn phenomenon. Symptoms were
      apparent 6 months following unilateral peripheral facial nerve palsy. Her facial
      synkinesis failed to improve, despite improvement in her facial palsy consistent
      with an aberrant regeneration of the facial nerve. The clinical Several
      neurologic syndromes feature abnormal interactions, or synkinesis, between
      anatomically proximate muscle groups. Among these, the Marcus Gunn phenomenon
      (trigemino-oculomotor synkinesis) is one of the best described in children. The
      Marcus Gunn phenomenon, or 'jaw-winking phenomenon,' consists of unilateral
      congenital ptosis and retraction of the ptotic lid upon moving of the lower jaw.
      Although many adults have been reported with this synkinesis, it is usually most
      prominent in newborn infants, in whom rapid spasmodic movements of the lid are
      seen during periods of nursing. In general, the Marcus Gunn phenomenon is
      unilateral and sporadic although familial and bilateral cases have been reported.
      Marin-Amat syndrome (or 'inverse Marcus Gunn phenomenon') is a rarely reported
      synkinesis in which one eyelid closes upon full opening of the jaw or movement of
      the jaw laterally. We now report a 10-year-old patient who began to develop
      features of Marin-Amat syndrome involving the right eyelid 1 month following
      right facial nerve palsy. This is the first documented report of this syndrome in
      a child.

PMID- 10334405
TI  - Moyamoya syndrome in a patient with congenital human immunodeficiency virus
      infection.
AB  - A 10-year-old boy with congenital human immunodeficiency virus (HIV) infection
      developed recurrent episodes of left hemiparesis at age 7 years. The progression
      of his disease was followed by computed tomography, magnetic resonance imaging,
      magnetic resonance angiography, and cerebral angiography. The series of images
      showed progressive stenosis of both carotid arteries at the suprasellar origin
      with involvement of his anterior and middle cerebral arteries, while prominent
      collateral vessels developed from his external carotid supply through ophthalmic
      and middle meningeal arteries. The pattern of cerebrovascular disease is
      consistent with moyamoya syndrome. We suggest that further studies on the
      pathophysiology of cerebrovascular disease in patients with HIV could be helpful
      in understanding the cause of moyamoya disease as well. Also, with the various
      advances in treatment of HIV, neurovascular complications could be seen more
      frequently as the long-term survival in these patients improves.

PMID- 10334406
TI  - 50th anniversary historical article. Surgical treatment of acute myocardial
      infarction.

PMID- 10334407
TI  - Racial heterogeneity in coronary artery vasomotor reactivity: differences between
      Japanese and Caucasian patients.
AB  - Japanese investigators have provided a substantial contribution in the
      understanding of coronary vasomotor reactivity. On occasions, their findings have
      been at variance with those undertaken on caucasian patients, raising speculation
      that vasomotor differences between races may exist. In a comparative review of
      the published literature, we evaluated the vasoreactive differences among
      Japanese and caucasian patients with variant angina or myocardial infarction. In
      variant angina, Japanese patients appear to have diffusely hyperreactive coronary
      arteries compared with caucasian people, manifested by their segmental rather
      than focal spasm, hyperreactive nonspastic vessels and multivessel spasm. These
      differences may reflect the increased basal tone among Japanese variant angina
      patients and may relate to controversial differences in endothelial nitric oxide
      production or autonomic nervous system activity. Provocative vasomotor studies of
      Japanese patients with a recent myocardial infarction report a higher incidence
      of inducible spasm than caucasian studies, an observation recently supported by a
      controlled study. Furthermore, the hyperreactivity was diffuse, occurring in both
      non-infarct- and infarct-related vessels. These observations support the
      existence of racial coronary vasomotor reactivity differences but require
      confirmation in further prospectively conducted studies.

PMID- 10334408
TI  - The Women's Ischemia Syndrome Evaluation (WISE) study: protocol design,
      methodology and feasibility report.
AB  - OBJECTIVES: The Women's Ischemia Syndrome Evaluation (WISE) is a National Heart,
      Lung and Blood Institute-sponsored, four-center study designed to: 1) optimize
      symptom evaluation and diagnostic testing for ischemic heart disease; 2) explore
      mechanisms for symptoms and myocardial ischemia in the absence of epicardial
      coronary artery stenoses, and 3) evaluate the influence of reproductive hormones
      on symptoms and diagnostic test response. BACKGROUND: Accurate diagnosis of
      ischemic heart disease in women is a major challenge to physicians, and the role
      reproductive hormones play in this diagnostic uncertainty is unexplored.
      Moreover, the significance and pathophysiology of ischemia in the absence of
      significant epicardial coronary stenoses is unknown. METHODS: The WISE common
      core data include demographic and clinical data, symptom and psychosocial
      variables, coronary angiographic and ventriculographic data, brachial artery
      reactivity testing, resting/ambulatory electrocardiographic monitoring and a
      variety of blood determinations. Site-specific complementary methods include
      physiologic and functional cardiovascular assessments of myocardial perfusion and
      metabolism, ventriculography, endothelial vascular function and coronary
      angiography. Women are followed for at least 1 year to assess clinical events and
      symptom status. RESULTS: In Phase I (1996-1997), a pilot phase, 256 women were
      studied. These data indicate that the WISE protocol is safe and feasible for
      identifying symptomatic women with and without significant epicardial coronary
      artery stenoses. CONCLUSIONS: The WISE study will define contemporary diagnostic
      testing to evaluate women with suspected ischemic heart disease. Phase II (1997
      1999) is ongoing and will study an additional 680 women, for a total WISE
      enrollment of 936 women. Phase III (2000) will include patient follow-up, data
      analysis and a National Institutes of Health WISE workshop.

PMID- 10334409
TI  - Dobutamine stress echocardiography in women with chest pain. Pilot phase data
      from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome
      Evaluation (WISE).
AB  - OBJECTIVES: The aim of this project was to assess the utility of dobutamine
      stress echocardiography (DSE) for evaluation of women with suspected ischemic
      heart disease. BACKGROUND: Most investigations addressing efficacy of diagnosis
      and treatment of coronary artery disease (CAD) have been performed in
      predominantly male populations. As part of the Women's Ischemia Syndrome
      Evaluation (WISE) study, DSE was assessed in women participating at the
      University of Florida clinical site. METHODS: Women with chest pain or other
      symptoms suggestive of myocardial ischemia and clinically indicated coronary
      angiography were eligible for the WISE study. Enrolled subjects underwent DSE
      using a modified protocol. Coronary stenosis was assessed by core laboratory
      quantitative coronary angiography (QCA). RESULTS: The 92 women studied ranged in
      age from 34 to 82 years (mean 57.5). All women had > or = 1 major risk for CAD,
      and most (89, 97%) had > or = 2 risk factors. In 78 women (85%), left ventricular
      wall motion was normal at baseline and during peak infusion. The remaining 14
      women had wall motion abnormalities during DSE. By QCA, 25 women (27%) had > or =
      50% coronary stenosis, including 10 with single-vessel obstruction. Dobutamine
      stress echocardiography was abnormal in 10 of these 25 women, yielding overall
      sensitivity of 40%, and 60% for multivessel stenosis. Exclusion of women with
      inadequate heart rate response yielded overall sensitivity of 50%, and 81.8% for
      multivessel stenosis. Dobutamine stress echocardiography was normal in 54 of the
      67 women with < 50% coronary narrowing, specificity 80.6%. CONCLUSIONS:
      Dobutamine stress echocardiography reliably detects multivessel stenosis in women
      with suspected CAD. However, DSE is usually negative in women with single-vessel
      stenosis, and in the larger subset without coronary stenosis. Ongoing protocols
      of the WISE study are expected to improve diagnostic accuracy in women with
      single-vessel disease, as well as provide important data in the substantial
      number of women with chest pain but without epicardial coronary artery stenosis.

PMID- 10334410
TI  - Coronary flow velocity response to adenosine characterizes coronary microvascular
      function in women with chest pain and no obstructive coronary disease. Results
      from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study.
AB  - OBJECTIVES: We sought to develop and validate a definition of coronary
      microvascular dysfunction in women with chest pain and no significant epicardial
      obstruction based on adenosine-induced changes in coronary flow velocity (i.e.,
      coronary velocity reserve). BACKGROUND: Chest pain is frequently not caused by
      fixed obstructive coronary artery disease (CAD) of large vessels in women.
      Coronary microvascular dysfunction is an alternative mechanism of chest pain that
      is more prevalent in women and is associated with attenuated coronary volumetric
      flow augmentation in response to hyperemic stimuli (i.e., abnormal coronary flow
      reserve). However, traditional assessment of coronary volumetric flow reserve is
      time-consuming and not uniformly available. METHODS: As part of the Women's
      Ischemia Syndrome Evaluation (WISE) study, 48 women with chest pain and normal
      coronary arteries or minimal coronary luminal irregularities (mean stenosis = 7%)
      underwent assessment of coronary blood flow reserve and coronary flow velocity
      reserve. Blood flow responses to intracoronary adenosine were measured using
      intracoronary Doppler ultrasonography and quantitative angiography. RESULTS:
      Coronary volumetric flow reserve correlated with coronary velocity reserve
      (Pearson correlation = 0.87, p < 0.001). In 29 (60%) women with abnormal coronary
      microcirculation (mean coronary flow reserve = 1.84), adenosine increased
      coronary velocity by 89% (p < 0.001) but did not change coronary cross-sectional
      area. In 19 (40%) women with normal microcirculation (mean flow reserve = 3.24),
      adenosine increased coronary velocity and area by 179% (p < 0.001) and 17% (p <
      0.001), respectively. A coronary velocity reserve threshold of 2.24 provided the
      best balance between sensitivity and specificity (90% and 89%, respectively) for
      the diagnosis of microvascular dysfunction. In addition, failure of the
      epicardial coronary to dilate at least 9% was found to be a sensitive (79%) and
      specific (79%) surrogate marker of microvascular dysfunction. CONCLUSIONS:
      Coronary flow velocity response to intracoronary adenosine characterizes coronary
      microvascular function in women with chest pain in the absence of obstructive
      CAD. Attenuated epicardial coronary dilation response to adenosine may be a
      surrogate marker of microvascular dysfunction in women with chest pain and no
      obstructive CAD.

PMID- 10334411
TI  - Relationship among mental stress-induced ischemia and ischemia during daily life
      and during exercise: the Psychophysiologic Investigations of Myocardial Ischemia
      (PIMI) study.
AB  - OBJECTIVES: The purposes of this database study were to determine: 1) the
      relationship between mental stress-induced ischemia and ischemia during daily
      life and during exercise; 2) whether patients who exhibited daily life ischemia
      experienced greater hemodynamic and catecholamine responses to mental or physical
      stress than patients who did not exhibit daily life ischemia, and 3) whether
      patients who experienced daily life ischemia could be identified on the basis of
      laboratory-induced ischemia using mental or exercise stress testing. BACKGROUND:
      The relationships between mental stress-induced ischemia in the laboratory and
      ischemia during daily life and during exercise are unclear. METHODS: One hundred
      ninety-six stable patients with documented coronary disease and a positive
      exercise test underwent mental stress testing and bicycle exercise testing.
      Radionuclide ventriculography and electrocardiographic (ECG) monitoring were
      performed during the mental stress and bicycle tests. Patients underwent 48 h of
      ambulatory ECG monitoring. Hemodynamic and catecholamine responses were obtained
      during mental stress and bicycle tests. RESULTS: Ischemia (reversible left
      ventricular dysfunction or ST segment depression > or = 1 mm) developed in 106 of
      183 patients (58%) during the mental stress test. There were no significant
      differences in clinical characteristics of patients with, compared with those
      without, mental stress-induced ischemia. Patients with mental stress ischemia
      more often had daily life ischemia than patients without mental stress ischemia,
      but their exercise tests were similar. Patients with daily life ischemia had
      higher ejection fraction and cardiac output, and lower systemic vascular
      resistance during mental stress than patients without daily life ischemia. Blood
      pressure and catecholamine levels at rest and during the mental stress tests were
      not different in patients with, compared with those without, daily life ischemia.
      Patients with daily life ischemia had a higher ejection fraction at rest and at
      peak bicycle exercise compared with patients without daily life ischemia, but
      there were no other differences in peak hemodynamic or catecholamine responses to
      exercise. The presence of ST segment depression during routine daily activities
      was best predicted by ST segment depression during mental or bicycle exercise
      stress, although ST segment depression was rare during mental stress.
      CONCLUSIONS: Patients with daily life ischemia exhibit a heightened generalized
      response to mental stress. ST segment depression in response to mental or
      exercise stress is more predictive of ST segment depression during routine daily
      activities than other laboratory-based ischemic markers. Therapeutic management
      strategies might therefore focus on patients with these physiologic responses to
      stress and on whether lessening such responses reduces ischemia.

PMID- 10334412
TI  - Supine bicycle versus post-treadmill exercise echocardiography in the detection
      of myocardial ischemia: a randomized single-blind crossover trial.
AB  - OBJECTIVES: We sought to determine the comparative accuracy of supine bicycle
      exercise echocardiography (SBE) and posttreadmill exercise echocardiography (TME)
      in detecting myocardial ischemia in patients with known or suspected coronary
      artery disease (CAD). BACKGROUND: Supine bicycle echocardiography and TME have
      been used for evaluation of CAD. However, the comparative accuracy of these
      modalities in the detection of ischemia in the same patients is not known.
      METHODS: Seventy-four patients (age 59 +/- 9 years [mean +/- SD]) referred for
      evaluation of coronary disease underwent SBE (starting at 25 to 50 W with 25-W
      increment every 3 min) and post-TME (Bruce protocol) in a random sequence.
      Digitized images at baseline and maximal exercise were interpreted in a random
      and blinded fashion. RESULTS: Maximal heart rate was higher during TME, whereas
      systolic blood pressure was higher during SBE, resulting in a similar double
      product. At quantitative angiography (n = 67), 57 patients had coronary stenosis
      (>50%). During SBE, ischemia was detected in 47 patients compared with 38
      patients by TME (p < 0.001). Wall motion score index at maximal exercise was
      higher with SBE than with TME (1.48 +/- 0.51 vs. 1.38 +/- 0.43; p < 0.001). The
      extent of myocardial ischemia (number of ischemic segments) was higher during SBE
      compared with TME (3.3 +/- 3.4 vs. 2.3 +/- 2.9 segments; p = 0.004), whereas
      severity of abnormal wall motion was similar. The sensitivity of SBE and TME for
      CAD was 82% and 75% with a specificity of 80% and 90%, respectively. Image
      quality was similar with both techniques. Patients and sonographers favored SBE
      over TME. CONCLUSIONS: During SBE and TME exercise, patients achieve a similar
      double product. During SBE, however, the detection of ischemia is more frequent
      and more extensive which, along with patient and sonographer preference, makes
      supine bicycle exercise a valuable stress echocardiographic modality.

PMID- 10334413
TI  - Parental history of premature coronary heart disease mortality and signs of
      ischemia on the resting electrocardiogram.
AB  - OBJECTIVES: Here we explore the association between a family history of premature
      coronary heart disease (CHD) death and ischemic electrocardiogram (ECG) findings
      in the offspring. BACKGROUND: In the general population, signs of ischemia are
      found on the resting ECG in about 10% of middle-aged men and women. Their
      independent predictive value for CHD morbidity and mortality has been shown in
      several studies. METHODS: Our results are based on cross-sectional data from
      three large epidemiological studies performed in Belgium during the past two
      decades: the Belgian Heart Disease Prevention Project (n = 8,145), the Belgian
      Interuniversity Research on Nutrition and Health survey (n = 7,625) and the
      MONICA project (n = 3,193). A parental history of fatal CHD was considered
      premature if the father died from CHD before age 60 or the mother before age 70.
      Ischemic ECG findings were defined according to Minnesota Code criteria I(1-3),
      IV(1-3), V(1-3) or VII1. RESULTS: Subjects with a parental history of premature
      CHD death were found to have experienced significantly more frequently
      symptomatic CHD. After exclusion of symptomatic individuals, no major differences
      in lifestyle-related risk factors were found between the groups with and without
      a parental history of premature fatal CHD. After multivariate adjustment for age,
      smoking, body mass index and sex, the odds ratios (and 95% confidence interval
      [CI]) for ECG ischemia associated with a positive parental history of premature
      death were 1.42 (1.10-1.82), 1.47 (1.16-1.88) and 1.37 (0.78-2.41) in the three
      studies. Additional adjustment for systolic blood pressure, total cholesterol
      and, if available, lifestyle-related factors did not alter the magnitude of the
      odds ratios. Overall, in men aged 45 to 64 years, ECG ischemia was significantly
      more frequent (36% excess) in those with positive parental history. CONCLUSIONS:
      Subjects in whom one or both parents died prematurely from cardiac-related
      diseases have signs of ischemia more frequently on their electrocardiogram, and
      this is independent of other risk factors.

PMID- 10334414
TI  - Alpha-adrenoceptor blockade prevents exercise-induced vasoconstriction of
      stenotic coronary arteries.
AB  - OBJECTIVES: The study aimed to evaluate the role of alpha-adrenergic mechanisms
      during dynamic exercise in both normal and stenotic coronary arteries.
      BACKGROUND: Paradoxical vasoconstriction of stenotic coronary arteries has been
      reported during dynamic exercise and may be due to several factors such as alpha
      adrenergic drive, a decreased release of nitric oxide, platelet aggregation with
      release of serotonin, or a passive collapse of the vessel wall. METHODS: Twenty
      six patients were studied at rest, during two levels of supine bicycle exercise
      and after 1.6 mg sublingual nitroglycerin. The alpha-blocker phentolamine was
      given to 16 patients before exercise, five of whom had also taken a beta
      adrenergic-blocker the same morning. Ten patients served as controls. The cross
      sectional areas of a normal and a stenotic coronary vessel were determined by
      biplane quantitative coronary arteriography. RESULTS: In the normal vessel
      segments, coronary cross-sectional area did not change after phentolamine
      injection, but increased in all patient groups similarly during exercise.
      Although coronary vasoconstriction existed in stenotic vessel segments in control
      patients, phentolamine-treated patients showed exercise-induced vasodilation
      without difference in patients with and without chronic beta-blockade.
      CONCLUSIONS: Exercise-induced vasoconstriction of stenotic coronary arteries is
      prevented by intracoronary administration of phentolamine. There was no
      difference in coronary vasomotion between patients receiving phentolamine alone
      and patients receiving phentolamine in addition to a beta-blocker. This finding
      suggests that exercise-induced vasoconstriction is mediated not only by
      endothelial dysfunction but also by alpha-adrenergic mechanisms.

PMID- 10334415
TI  - Improvement in endothelial function by angiotensin-converting enzyme inhibition
      in non-insulin-dependent diabetes mellitus.
AB  - OBJECTIVES: The aim of this study was to assess the effect of angiotensin
      converting enzyme (ACE) inhibition with enalapril on forearm endothelial function
      in subjects with type II diabetes mellitus. BACKGROUND: Endothelial function is
      depressed in the presence of conventional risk factors for atherosclerosis, and
      various therapies, such as lipid-lowering therapy in hypercholesterolemia, can
      improve endothelial-mediated vasodilation. ACE inhibition has improved such
      function in several conditions including type I diabetes, but there is no
      evidence for a beneficial effect in type II diabetes. METHODS: The influence of
      enalapril (10 mg twice daily for 4 weeks) on endothelium-dependent and 
      independent vasodilator function was determined in 10 type II diabetic subjects
      using a double-blinded placebo-controlled crossover protocol. Forearm blood flow
      was measured using strain-gage plethysmography and graded intrabrachial infusion
      of acetylcholine (ACh), N(G)-monomethyl-L-arginine (LNMMA) and sodium
      nitroprusside (SNP). RESULTS: Enalapril increased the response to the endothelium
      dependent vasodilator, ACh (p < 0.02) and the vasoconstrictor response to the
      nitric oxide (NO) synthase inhibitor, LNMMA (p < 0.002). No difference was
      evident in the response to SNP. CONCLUSIONS: In type II diabetic subjects without
      evidence of vascular disease, the ACE inhibitor enalapril improved stimulated and
      basal NO-dependent endothelial function. The study extends the spectrum of
      beneficial effects demonstrated to result from ACE inhibition in diabetes.

PMID- 10334416
TI  - Improvement of endothelial vasomotor dysfunction by treatment with alpha
      tocopherol in patients with high remnant lipoproteins levels.
AB  - OBJECTIVES: This study sought to examine whether oral intake of alpha-tocopherol,
      an antioxidant, could improve endothelium-dependent vasorelaxation in patients
      with high remnant lipoproteins levels. BACKGROUND: Remnant lipoproteins are known
      to be atherogenic and impair endothelium-dependent arterial relaxation, but the
      underlying mechanisms remain unclear. Oxidative stress is a common feature of
      various risk factors for atherosclerosis. METHODS: Flow-mediated vasodilation of
      the brachial artery during reactive hyperemia was examined by high resolution
      ultrasound technique before and at the end of 4 weeks treatment with oral
      administration of alpha-tocopherol acetate (300 IU/day) or placebo, which was
      randomly assigned, in 40 patients with high serum levels of remnants and in 30
      patients with low remnants levels in the fasting state (>75th percentile and
      <25th percentile, respectively, of the distribution of remnants levels in 150
      consecutive hospitalized patients). RESULTS: Before treatment, flow-mediated
      vasodilation was lower in patients with high remnants levels than in those with
      low levels (4.1 +/- 0.3% vs. 6.0 +/- 0.5%, p < 0.01). Treatment with alpha
      tocopherol but not with placebo significantly increased flow-mediated dilation in
      patients with high remnants levels (7.5 +/- 0.4% after alpha-tocopherol vs. 4.2
      +/- 0.4% after placebo, p < 0.01). In patients with low remnants levels, alpha
      tocopherol was not effective. The beneficial effect with alpha-tocopherol in high
      remnants patients was associated with decrease in plasma levels of thiobarbituric
      acid reactive substances, an indicator of lipid peroxidation (6.6 +/- 0.3 nmol/ml
      before alpha-tocopherol vs. 4.6 +/- 0.3 after alpha-tocopherol, p < 0.05).
      CONCLUSIONS: Alpha-tocopherol improved impairment of endothelium-dependent
      vasodilation in patients with high remnants levels. The increase in oxidative
      stress may at least partly contribute to endothelial vasomotor dysfunction, in
      patients with high remnants levels.

PMID- 10334417
TI  - Admission risk assessment by cardiac troponin T in unstable coronary artery
      disease: additional prognostic information from continuous ST segment monitoring.
      TRIM study group. Thrombin Inhibition in Myocardial Ischemia.
AB  - OBJECTIVES: We investigated whether the addition of 24 h of continuous
      vectorcardiography ST segment monitoring (cVST) for an early (within 24 h of the
      latest episode of angina) determination of cardiac troponin T (cTnT) could
      provide additional prognostic information in patients with unstable coronary
      artery disease (UCAD), i.e., unstable angina and non-Q wave myocardial
      infarction. BACKGROUND: Determination of cTnT at admission and cVST are
      individually reported to be valuable techniques for the risk assessment of
      patients with UCAD. METHODS: Two hundred and thirty-two patients suspected of
      UCAD were studied. Patients were followed for 30 days, and the occurrence of
      cardiac death or acute myocardial infarction (AMI) were registered. RESULTS: One
      ST segment episode or more (relative risk [RR] 7.43, p = 0.012), a cTnT level >
      or = 0.20 microg/liter (RR 3.85, p = 0.036) or prestudy medication with calcium
      antagonists (RR 3.31, p = 0.041) were found to carry independent prognostic
      information after multivariate analysis of potential risk variables. By combining
      a cTnT determination and subsequent cVST for 24 h, subgroups of patients at high
      (25.8%) (n = 31), intermediate (3.1%) (n = 65) and low risk (1.7%) (n = 117) of
      death or AMI could be identified. CONCLUSIONS: Twenty-four hours of cVST provides
      additional prognostic information to that of an early cTnT determination in
      patients suspected of having UCAD. The combination of biochemical and
      electrocardiographic methods provides powerful and accurate risk stratification
      in UCAD.

PMID- 10334418
TI  - Abciximab in the treatment of acute myocardial infarction eligible for primary
      percutaneous transluminal coronary angioplasty. Results of the Glycoprotein
      Receptor Antagonist Patency Evaluation (GRAPE) pilot study.
AB  - OBJECTIVES: We sought to study the effect of early infusion of abciximab on
      coronary patency before primary angioplasty in patients with acute myocardial
      infarction. BACKGROUND: Glycoprotein IIb/IIIa antagonists have proved to be
      effective in reducing ischemic events associated with coronary angioplasty. The
      present study explores whether abciximab alone, without administration of
      thrombolytic therapy, may induce reperfusion in patients with acute myocardial
      infarction. METHODS: In the Glycoprotein Receptor Antagonist Patency Evaluation
      pilot study 60 patients with less than 6 h signs and symptoms of acute myocardial
      infarction eligible for primary angioplasty received in the emergency room a
      bolus of abciximab 250 microg/kg followed by a 12-h infusion of 10 microg/min.
      All patients were also treated with an oral dose of 160 mg aspirin and 5,000 IU
      of heparin intravenously. As soon as possible a diagnostic angiography was
      performed to evaluate the patency of the infarct-related artery. RESULTS: The
      median time between onset of symptoms and the administration of the abciximab
      bolus was 150 min (range 45 to 345), and the median time between abciximab bolus
      and first contrast injection in the infarct-related artery was 45 min (range 10
      to 150). In 24 patients (40%, 95% confidence interval 28% to 52%) Thrombolysis in
      Myocardial Infarction (TIMI) flow grade 2 or 3 was observed at a median time of
      45 min (range 10 to 150) after abciximab bolus; TIMI flow grade 3 was observed in
      11 patients (18%, 95% confidence interval 9% to 28%). There was no difference in
      percentage of TIMI flow grade 2 or 3 between patients who received abciximab
      within 2.5 h after onset of symptoms or thereafter. CONCLUSIONS: Abciximab
      therapy given in the emergency room in patients awaiting primary angioplasty is
      associated with full reperfusion (TIMI flow grade 3) in about 20% and with TIMI
      flow grade 2 or 3 in about 40% of the patients at a median time of 45 min. These
      figures are higher than those in primary angioplasty trials without such
      pretreatment. Randomized controlled trials of very early infusion of abciximab,
      either prehospital or in-hospital, in patients eligible for angioplasty are
      warranted.

PMID- 10334420
TI  - We have journeyed far.

PMID- 10334419
TI  - A two-decades (1975 to 1995) long experience in the incidence, in-hospital and
      long-term case-fatality rates of acute myocardial infarction: a community-wide
      perspective.
AB  - OBJECTIVES: The purpose of the present study is to describe changes over two
      decades (1975 to 1995) in the incidence, in-hospital and long-term case-fatality
      rates associated with acute myocardial infarction (AMI) from a multihospital
      community-wide perspective. BACKGROUND: Despite the magnitude of, and mortality
      associated with acute myocardial infarction (AMI), relatively limited population
      based data are available to describe recent and temporal trends in the attack and
      case-fatality rates associated with AMI from a representative population-based
      perspective. METHODS: The community-based study included 5,270 residents of the
      Worcester, Massachusetts, metropolitan area hospitalized with confirmed initial
      AMI in all metropolitan Worcester, Massachusetts, hospitals (1990 census
      population = 437,000) in 10 one-year periods between 1975 and 1995. RESULTS: The
      age-adjusted incidence rates of initial AMI increased between 1975 (244 per
      100,000) and 1981 (272 per 100,000), after which time these rates declined
      through 1995 (184 per 100,000). The crude and multivariable-adjusted in-hospital
      case-fatality rates exhibited a consistent decline between 1975/1978 (17.8%),
      1986/1988 (17.0%) and 1993/1995 (11.7%). Although there were no statistically
      significant differences in the unadjusted long-term case-fatality rates of
      discharged hospital survivors over the periods under study, declines in the
      multivariable-adjusted risk of dying within the first year after hospital
      discharge were observed between the earliest and most recently discharged
      patients with AMI. CONCLUSIONS: The results of this population-based study of
      patients with validated initial AMI provide encouragement for efforts directed at
      the primary and secondary prevention of AMI given declining incidence and case
      fatality rates.

PMID- 10334421
TI  - Prognostic significance of elevated hemostatic markers in patients with acute
      myocardial infarction.
AB  - OBJECTIVES: The purpose of this study was to determine whether the elevated
      levels of hemostatic markers in the early phase of myocardial infarction may
      serve as risk factors for subsequent cardiac mortality. BACKGROUND: Increased
      plasma hemostatic markers were noted in acute myocardial infarction, indicating
      that the blood coagulation system is highly activated in those patients. However,
      there are few clinical data concerning the association between the elevated
      hemostatic markers and survival in patients with myocardial infarction. METHODS:
      Blood samples were obtained from 64 patients (mean age 67 +/- 11 years; 49 male)
      with acute myocardial infarction within 12 h after the onset of symptoms and
      before the initiation of any antithrombotic treatment. We measured plasma
      concentrations of fibrinopeptide A (FPA), prothrombin fragment 1+2 (F1+2) and
      thrombin-antithrombin complex (TAT) using the enzyme-linked immunosorbent assay
      method, and examined the associations between the level of these markers and
      survival with Cox proportional hazards models. RESULTS: The follow-up time was 27
      +/- 17 months, and 19 patients died of cardiac causes during the follow-up.
      Univariate survival analysis identified Killip class IV (hazard ratio 4.86; 95%
      confidence interval [CI] 1.55-15.19), left ventricular ejection fraction (hazard
      ratio 0.94; 95% CI 0.90-0.99), FPA (hazard ratio 1.54; 95% CI 1.13-2.10), F1+2
      (hazard ratio 2.03; 95% CI 1.17-3.53) and TAT (hazard ratio 1.88; 95% CI 1.27
      2.79) as significant factors associated with cardiac mortality. In multivariate
      analyses, only FPA level (hazard ratio 1.84; 95% CI 1.03-3.30) and left
      ventricular ejection fraction (hazard ratio 0.93; 95% CI 0.88-0.98) were
      independent predictors of cardiac mortality. CONCLUSIONS: Elevated FPA in the
      early phase of myocardial infarction identifies patients with increased risk for
      subsequent cardiac death. This association appears to be independent of residual
      left ventricular function after infarction.

PMID- 10334422
TI  - Lack of effect of coenzyme Q on left ventricular function in patients with
      congestive heart failure.
AB  - OBJECTIVES: This study evaluated the effects of oral therapy with coenzyme Q on
      echocardiographic and hemodynamic indexes of left ventricular function and on
      quality of life in patients with chronic left ventricular dysfunction.
      BACKGROUND: Coenzyme Q is a coenzyme for oxidative phosphorylation and an
      antioxidant and free radical scavenger. It has been claimed to improve symptoms,
      quality of life, left ventricular ejection fraction and prognosis in patients
      with cardiac failure. METHODS: Thirty patients with ischemic or idiopathic
      dilated cardiomyopathy and chronic left ventricular dysfunction (ejection
      fraction 26 +/- 6%) were randomized to a double-blind crossover trial of oral
      coenzyme Q versus placebo, each for 3 months. Right heart pressures, cardiac
      output and echocardiographic left ventricular volumes were measured at baseline
      and after each treatment phase, and quality of life was assessed using the
      Minnesota "Living With Heart Failure" questionnaire. It was calculated that to
      demonstrate an increase in left ventricular ejection fraction from 25% to 30%
      with a standard deviation of 5% using 95% confidence intervals with a power of
      80% we would require 17 patients. RESULTS: Twenty-seven completed both treatment
      phases. There was no significant difference in left ventricular ejection
      fraction, cardiac volumes or hemodynamic and quality of life indices after
      treatment with coenzyme Q or placebo, although plasma coenzyme Q levels increased
      from 903 +/- 345 nmol/l(-1) to 2,029 +/- 856 nmol/l(-1). CONCLUSIONS: In patients
      with left ventricular dysfunction, treatment for three months with oral coenzyme
      Q failed to improve resting left ventricular systolic function or quality of life
      despite an increase in plasma levels of coenzyme Q to more than twice basal
      values.

PMID- 10334423
TI  - Antiadrenergic effect of chronic amiodarone therapy in human heart failure.
AB  - OBJECTIVES: The aim of the present study was to evaluate the influence of
      amiodarone on neurochemical parameters of sympathetic nervous activity in
      patients with congestive heart failure. BACKGROUND: Unlike most antiarrhythmic
      agents, amiodarone has been shown to exert a beneficial effect on survival in
      some studies of patients with congestive heart failure. The pharmacology of this
      agent is complex, and as such, the mode of its action is unclear in humans. Some
      experimental studies suggest that amiodarone exerts a sympatholytic effect.
      METHODS: To evaluate the effect of amiodarone on sympathetic nervous activity, we
      measured the total systemic and cardiac norepinephrine (NE) spillover rate by
      isotope dilution in 58 patients with severe heart failure (left ventricular
      ejection fraction 20 +/- 1%), 22 of whom were receiving chronic amiodarone
      treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE),
      and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG,
      intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to
      assess sympathetic neuronal integrity. RESULTS: Amiodarone-treated patients had
      significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p
      < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients
      not treated with amiodarone. Hemodynamic assessment of amiodarone-treated
      patients revealed higher cardiac output (4.4 +/- 0.2 vs. 3.7 +/- 0.2 liters/min,
      p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 +/- 2 vs. 22
      +/- 1, p = NS) than in untreated patients. After correction for the potential
      confounding effect of hemodynamic differences, amiodarone-treated patients
      continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG
      from the heart. CONCLUSIONS: These data indicate that amiodarone may exert
      beneficial effects on the failing human heart through a sympatholytic process,
      and this action appears to be relatively cardioselective.

PMID- 10334424
TI  - Prediction of hospital readmission for heart failure: development of a simple
      risk score based on administrative data.
AB  - OBJECTIVES: The purpose of this study was to develop a convenient and inexpensive
      method for identifying an individual's risk for hospital readmission for
      congestive heart failure (CHF) using information derived exclusively from
      administrative data sources and available at the time of an index hospital
      discharge. BACKGROUND: Rates of readmission are high after hospitalization for
      CHF. The significant determinants of rehospitalization are debated. METHODS:
      Administrative information on all 1995 hospital discharges in New York State
      which were assigned International Classification of Diseases-9-Clinical
      Modification codes indicative of CHF in the principal diagnosis position were
      obtained. The following were compared among hospital survivors who did and did
      not experience readmission: demographics, comorbid illness, hospital type and
      location, processes of care, length of stay and hospital charges. RESULTS: A
      total of 42,731 black or white patients were identified. The subgroup of 9,112
      patients (21.3%) who were readmitted were distinguished by a greater proportion
      of blacks, a higher prevalence of Medicare and Medicaid insurance, more comorbid
      illnesses and the use of telemetry monitoring during their index hospitalization.
      Patients treated at rural hospitals, those discharged to skilled nursing
      facilities and those having echocardiograms or cardiac catheterization were less
      likely to be readmitted. Using multiple regression methods, a simple methodology
      was devised that segregated patients into low, intermediate and high risk for
      readmission. CONCLUSIONS: Patient characteristics, hospital features, processes
      of care and clinical outcomes may be used to estimate the risk of hospital
      readmission for CHF. However, some of the variation in rehospitalization risk
      remains unexplained and may be the result of discretionary behavior by physicians
      and patients.

PMID- 10334425
TI  - Losartan improves exercise tolerance in patients with diastolic dysfunction and a
      hypertensive response to exercise.
AB  - OBJECTIVES: The aim of the study was to test the hypothesis that angiotensin II
      (Ang II) blockade would improve exercise tolerance in patients with diastolic
      dysfunction and a marked increase in systolic blood pressure (SBP) during
      exercise. BACKGROUND: Diastolic dysfunction may be exacerbated during exercise,
      especially if there is a marked increase in SBP. Angiotensin II may contribute to
      the hypertensive response to exercise and impair diastolic performance. METHODS:
      We performed a randomized, double-blind, placebo-controlled, crossover study of
      two weeks of losartan (50 mg q.d.) on exercise tolerance and quality of life. The
      subjects were 20 patients, mean age 64 +/- 10 years with normal left ventricular
      systolic function (EF >50%), no ischemia on stress echocardiogram, mitral flow
      velocity E/A <1, normal resting SBP (<150 mm Hg), and a hypertensive response to
      exercise (SBP >200 mm Hg). Exercise echocardiograms (Modified Bruce Protocol) and
      the Minnesota Living With Heart Failure questionnaire were administered at
      baseline, and after each two-week treatment period, separated by a two-week
      washout period. RESULTS: Resting blood pressure (BP) was unaltered by placebo or
      losartan. During control, patients were able to exercise for 11.3 +/- 2.5 (mean
      +/- SD) min, with a peak exercise SBP of 226 +/- 24 mm Hg. After two weeks of
      losartan, baseline BP was unaltered, but peak SBP during exercise decreased to
      193 +/- 27 mm Hg (p < 0.05 vs. baseline and placebo), and exercise time increased
      to 12.3 +/- 2.6 min (p < 0.05 vs. baseline and placebo). With placebo, there was
      no improvement in exercise duration (11.0 +/- 2.0 min) or peak exercise SBP (217
      +/- 26 mm Hg). Quality of life improved with losartan (18 +/- 22, p < 0.05)
      compared to placebo (22 +/- 26). CONCLUSIONS: In patients with Doppler evidence
      of diastolic dysfunction at rest and a hypertensive response to exercise, Ang II
      receptor blockade blunts the hypertensive response to exercise, increases
      exercise tolerance and improves quality of life.

PMID- 10334426
TI  - Low incidence of transplant coronary artery disease in Chinese heart recipients.
AB  - OBJECTIVES: This study sought to assess the incidence of transplant coronary
      artery disease (CAD) in Chinese heart recipients. BACKGROUND: The prevalence of
      transplant CAD detected by angiography at 1, 2 and 4 years after heart
      transplantation was 11%, 22% and 45%, respectively. The incidence of transplant
      CAD in Chinese heart recipients has not been reported. METHODS: For those
      recipients surviving for more than 1 year after transplantation, coronary
      angiography was performed annually for surveillance of transplant CAD. The
      recipient characteristics, donor characteristics, rejection episodes, medication
      and human leukocyte antigen (HLA) mismatches were recorded. RESULTS: Fifty
      patients were included in this study. Thirteen (26%) recipients had ischemic
      heart disease. Two patients (4%) had active cytomegalovirus (CMV) infection after
      transplantation. The mean number of rejection episodes in the 1st year after
      transplantation was 1.15. Among 47 patients with complete data of donor and
      recipient histocompatibility antigens, there were seven patients (14.9%) with two
      or fewer HLA mismatches. Among 74 angiograms of 50 patients reviewed, only one
      patient had discrete stenosis less than 50% in the middle portion of the left
      anterior descending artery at 1 year after transplantation. The cumulative
      incidence of transplant CAD was 2% at 1 year and 2% at 2 and 4 years after
      transplantation. CONCLUSIONS: The incidence of transplant CAD was low in Chinese
      heart transplant recipients. Low percentage of ischemic heart disease in
      recipients, low occurrence of active CMV infection and rejection episodes after
      transplantation, less racial disparity, and lower HLA mismatches may be the
      important factors.

PMID- 10334427
TI  - Marked elevation of myocardial trace elements in idiopathic dilated
      cardiomyopathy compared with secondary cardiac dysfunction.
AB  - OBJECTIVES: We sought to investigate the possible pathogenetic role of myocardial
      trace elements (TE) in patients with various forms of cardiac failure.
      BACKGROUND: Both myocardial TE accumulation and deficiency have been associated
      with the development of heart failure indistinguishable from an idiopathic
      dilated cardiomyopathy. METHODS: Myocardial and muscular content of 32 TE has
      been assessed in biopsy samples of 13 patients (pts) with clinical, hemodynamic
      and histologic diagnosis of idiopathic dilated cardiomyopathy (IDCM), all without
      past or current exposure to TE. One muscular and one left ventricular (LV)
      endomyocardial specimen from each patient, drawn with metal contamination-free
      technique, were analyzed by neutron activation analysis and compared with 1)
      similar surgical samples from patients with valvular (12 pts) and ischemic (13
      pts) heart disease comparable for age and degree of LV dysfunction; 2) papillary
      and skeletal muscle surgical biopsies from 10 pts with mitral stenosis and normal
      LV function, and 3) LV endomyocardial biopsies from four normal subjects.
      RESULTS: A large increase (>10,000 times for mercury and antimony) of TE
      concentration has been observed in myocardial but not in muscular samples in all
      pts with IDCM. Patients with secondary cardiac dysfunction had mild increase (<
      or = 5 times) of myocardial TE and normal muscular TE. In particular, in pts with
      IDCM mean mercury concentration was 22,000 times (178,400 ng/g vs. 8 ng/g),
      antimony 12,000 times (19,260 ng/g vs. 1.5 ng/g), gold 11 times (26 ng/g vs. 2.3
      ng/g), chromium 13 times (2,300 ng/g vs. 177 ng/g) and cobalt 4 times (86,5 ng/g
      vs. 20 ng/g) higher than in control subjects. CONCLUSIONS: A large, significant
      increase of myocardial TE is present in IDCM but not in secondary cardiac
      dysfunction. The increased concentration of TE in pts with IDCM may adversely
      affect mitochondrial activity and myocardial metabolism and worsen cellular
      function.

PMID- 10334428
TI  - Maternally inherited cardiomyopathy: clinical and molecular characterization of a
      large kindred harboring the A4300G point mutation in mitochondrial
      deoxyribonucleic acid.
AB  - OBJECTIVES: The purpose of this study was to describe the clinical and molecular
      features of a large family with maternally inherited cardiomyopathy (MICM).
      BACKGROUND: Recently, several mitochondrial deoxyribonucleic acid (mtDNA) point
      mutations have been associated with MICM. However, the distinctive clinical and
      morphologic features of MICM are not fully appreciated. This is partially due to
      the small size of the reported pedigrees, often lacking detailed clinical and
      laboratory information. METHODS: Clinical and genetic analysis of the family was
      carried out. RESULTS: Echocardiography showed mostly symmetrical hypertrophic
      cardiomyopathy in 10 family members. The illness had an unfavorable course.
      Progressive heart failure occurred in three subjects, who eventually died; one
      individual underwent heart transplantation. Electrocardiographic or
      echocardiographic signs of cardiac hypertrophy in the absence of significant
      clinical complaints were observed in five subjects. Neurologic examination was
      normal. The mutation was detected in blood from all available subjects. Abundance
      of mutated molecules ranged between 13% and 100% of total mtDNA genomes. The
      severity of the disease could not be foreseen by the proportion of mutation in
      blood. CONCLUSIONS: This report contributes a better description of the clinical
      aspects of MICM and provides important clues to distinguish it from hypertrophic
      cardiomyopathy. We suggest that mtDNA mutations, particularly in the transfer
      ribonucleic acid for isoleucin, should be systematically searched in patients
      with MICM. The identification of an underlying maternally inherited mitochondrial
      DNA defect in familial cases of cardiomyopathy may considerably influence the
      management and genetic counseling of affected patients.

PMID- 10334429
TI  - Clinical profile of hypertrophic cardiomyopathy identified de novo in rural
      communities.
AB  - OBJECTIVES: The purpose of this study was to assess the extent to which
      hypertrophic cardiomyopathy (HCM) exists unsuspected and undetected in the
      general population. BACKGROUND: Hypertrophic cardiomyopathy is a disease with
      diverse natural history for which the potential to produce adverse consequences
      has been emphasized. However, the possibility of this disease remaining
      clinically dormant for many years has not been as widely appreciated. Certainly,
      the clinical recognition of previously undiagnosed patients with HCM may be
      advantageous by permitting risk stratification for sudden cardiac death or for
      timely pharmacologic therapy when symptoms intervene. METHODS: We prospectively
      conducted an echocardiographic survey in 64 primarily rural communities within
      Minnesota (populations < 10,000) over a 33-month period. RESULTS: A total of
      15,137 echocardiograms were performed at the request of primary care physicians
      for the purpose of excluding cardiovascular abnormalities. Hypertrophic
      cardiomyopathy was identified in 44 patients during the survey (0.29%), and 29 of
      these patients (0.19% of the 15,137 echocardiograms) had not been previously
      identified as having cardiac disease or HCM. At diagnosis, ages were 16 to 87
      years (mean 57); 14 patients were > or = 60 years of age, and only two were < 30
      years. Twenty-four patients (83%) had either no or only mild or transient
      symptoms; 5 (17%) evidenced severe functional limitation; in eight patients the
      onset of symptoms had been deferred until > or = 70 years of age. Basal left
      ventricular outflow obstruction (gradients 20 to 82 mm Hg) was evident in 11
      patients (38%). Relatively mild phenotypic expression of the disease was
      substantiated by localized patterns of left ventricular wall thickening occurring
      more commonly than diffusely distributed hypertrophy (48% vs. 7%, respectively),
      and electrocardiograms that were frequently normal (about 25%) and rarely showed
      evidence of left ventricular hypertrophy (10%). CONCLUSIONS: These prospectively
      assembled data show that HCM may remain clinically dormant and undetected within
      community-based rural populations for many years (often to advanced ages) with a
      not inconsequential prevalence similar to that of HCM in the general population.

PMID- 10334430
TI  - Survival after cardiac arrest or sustained ventricular tachycardia in patients
      with hypertrophic cardiomyopathy.
AB  - OBJECTIVES: The aim of this study was to evaluate the survival of patients with
      hypertrophic cardiomyopathy (HCM) after resuscitated ventricular fibrillation or
      syncopal sustained ventricular tachycardia (VT/VF) when treated with low dose
      amiodarone or implantable cardioverter defibrillators (ICDs). BACKGROUND:
      Prospective data on clinical outcome in patients with HCM who survive a cardiac
      arrest are limited, but studies conducted before the widespread use of amiodarone
      and/or ICD therapy suggest that over a third die within seven years from sudden
      cardiac death or progressive heart failure. METHODS: Sixteen HCM patients with a
      history of VT/VF (nine male, age at VT/VF 19 +/- 8 years [range 10 to 36]) were
      studied. Syncopal sustained ventricular tachycardia/ventricular fibrillation
      occurred during or immediately after exertion in eight patients and was the
      initial presentation in eight. One patient had disabling neurologic deficit after
      VT/VF. Before VT/VF, two patients had angina, four had syncope and six had a
      family history of premature sudden cardiac death. After VT/VF all patients were
      in New York Heart Association class I or II, three had nonsustained VT during
      ambulatory electrocardiography and 11 had an abnormal exercise blood pressure
      response. After VT/VF eight patients were treated with low dose amiodarone and
      six received an ICD. Prophylactic therapy was declined by two patients. RESULTS:
      Mean follow-up was 6.1 +/- 4.0 years (range 0.5 to 14.5). Cumulative survival
      (death or ICD discharge) for the entire cohort was 59% at five years (95%
      confidence interval: 33% to 84%). Thirteen (81%) patients were alive at last
      follow-up. Two patients died suddenly while taking low dose amiodarone, and one
      died due to neurologic complications of his initial cardiac arrest. Three
      patients had one or more appropriate ICD discharges during follow-up; the times
      to first shock after ICD implantation were 23, 197 and 1,124 days. CONCLUSIONS:
      This study shows that patients with HCM who survive an episode of VT/VF remain at
      risk for a recurrent event. Implantable cardioverter defibrillator therapy
      appears to offer the best potential benefit regarding outcome.

PMID- 10334432
TI  - Acute and long-term cost implications of coronary stenting.
AB  - OBJECTIVES: We compared the acute and one year medical costs and outcomes of
      coronary stenting with those for balloon angioplasty (percutaneous transluminal
      coronary angioplasty) in contemporary clinical practice. BACKGROUND: While
      coronary stent implantation reduces the need for repeat revascularization, it has
      been associated with significantly higher acute costs compared with coronary
      angioplasty. METHODS: We studied patients treated at Duke University between
      September 1995 and June 1996 who received either coronary stent (n = 384) or
      coronary angioplasty (n = 159) and met eligibility criteria. Detailed cost data
      were collected initially and up to one year following the procedure. Our primary
      analyses compared six and 12 month cumulative costs for coronary angioplasty- and
      stent-treated cohorts. We also compared treatment costs after excluding nontarget
      vessel interventions; after limiting analysis to those without prior
      revascularization; and after risk-adjusting cumulative cost estimates. RESULTS:
      Baseline clinical characteristics were generally similar between the two
      treatment groups. The mean in-hospital cost for stent patients was $3,268 higher
      than for those receiving coronary angioplasty ($14,802 vs. $11,534, p < 0.001).
      However, stent patients were less likely to be rehospitalized (22% vs. 34%, p =
      0.002) or to undergo repeat revascularization (9% vs. 26%, p = 0.001) than
      coronary angioplasty patients within six months of the procedure. As such, mean
      cumulative costs at 6 months ($19,598 vs. $19,820, p = 0.18) and one year
      ($22,140 vs. $22,571, p = 0.26) were similar for the two treatments. Adjusting
      for baseline predictors of cost and selectively examining target vessel
      revascularization, or those without prior coronary intervention yielded similar
      conclusions. CONCLUSIONS: In contemporary practice, coronary stenting provides
      equivalent or better one-year patient outcomes without increasing cumulative
      health care costs.

PMID- 10334431
TI  - Verapamil acutely reduces ventricular-vascular stiffening and improves aerobic
      exercise performance in elderly individuals.
AB  - OBJECTIVES: We tested the hypothesis that acute intravenous verapamil acutely
      enhances aerobic exercise performance in healthy older individuals in association
      with a combined reduction of ventricular systolic and arterial vascular
      stiffnesses. BACKGROUND: Age-related vascular stiffening coupled with systolic
      ventricular stiffening may limit cardiovascular reserve and, thus, exercise
      performance in aged individuals. METHODS: Nineteen healthy volunteers with mean
      age 70 +/- 10 years underwent maximal-effort upright ergometry tests on two
      separate days after receiving either 0.15 mg/kg i.v. verapamil or 0.5 N saline in
      a double-blind, randomized, crossover study. RESULTS: Baseline vascular
      stiffness, indexed by arterial pulse-wave velocity (Doppler) and augmentation
      index (carotid tonometry) declined with verapamil (-5.9 +/- 2.1% and -31.7 +/-
      12.8%, respectively, both p < 0.05). Preload-adjusted maximal ventricular power,
      a surrogate for ventricular end-systolic stiffness, also declined by -9.5 +/-
      3.6%. Peripheral resistance and peak filling rate were unchanged. With verapamil,
      exercise duration prior to the anaerobic threshold (AT) increased by nearly 50%
      (260 +/- 129 to 387 +/- 176 s) with a corresponding 13.4 +/- 4.7% rise in oxygen
      consumption (VO2) at that time (both p < 0.01). Total exercise duration prolonged
      by +6 +/- 2.7% (p < 0.05) with no change in maximal VO2. Baseline
      cardiodepression from verapamil reversed by peak exercise with net increases in
      stroke volume and cardiac output (p < 0.05). CONCLUSIONS: Acute intravenous
      verapamil reduces ventriculovascular stiffening and improves aerobic exercise
      performance in healthy aged individuals. This highlights a role for heart
      arterial coupling in modulating exertional capacity in the elderly, suggesting a
      potentially therapeutic target for aged individuals with exertional limitations.

PMID- 10334433
TI  - N-3 fatty acids do not prevent restenosis after coronary angioplasty: results
      from the CART study. Coronary Angioplasty Restenosis Trial.
AB  - OBJECTIVES: The aim of the study was to investigate whether omega-3 fatty acids
      (n-3 FA) reduce the occurrence of restenosis after percutaneous transluminal
      coronary angioplasty. BACKGROUND: Meta-analyses have shown significant reduction
      of restenosis after coronary angioplasty upon supplementation with n-3 FA.
      METHODS: In a prospective, placebo-controlled, double-blind study, 500 patients
      were randomly allocated to treatment with n-3 FA (Omacor, Pronova AS, Oslo,
      Norway) 5.1 g/day or corn oil (placebo) starting at least two weeks prior to
      elective coronary angioplasty. The treatment was continued until restenosis
      evaluation by quantitative coronary angiography after six months. Stenosis was
      defined as a minimal luminal diameter (MLD) < 40% of the reference diameter.
      Successful coronary angioplasty was defined as > or = 20% acute gain in MLD and a
      residual stenosis < 50%. Restenosis was defined as > or = 20% late loss of
      diameter and stenosis > 50% or an increase in stenosis of > or = 0.7 mm. Three
      hundred ninety-two patients fulfilled the criteria for initial stenosis and
      successful coronary angioplasty, and, except four patients who died, none were
      lost for follow-up. RESULTS: Restenosis occurred in 108/266 (40.6%) of the
      treated stenoses in the Omacor group and in 93/263 (35.4%) in the placebo group
      (odds ratio [OR] 1.25, 95% confidence interval [CI] [0.87-1.80] p = 0.21). In the
      Omacor group one or more restenoses occurred in 90/196 (45.9%) patients as
      compared with 86/192 (44.8%) in the placebo group (OR 1.05, 95% CI [0.69-1.59] p
      = 0.82). CONCLUSIONS: Supplementation with 5.1 g n-3 FA/day for six months,
      initiated at least two weeks prior to coronary angioplasty did not reduce the
      incidence of restenosis.

PMID- 10334434
TI  - Is a strategy of intended incomplete percutaneous transluminal coronary
      angioplasty revascularization acceptable in nondiabetic patients who are
      candidates for coronary artery bypass graft surgery? The Bypass Angioplasty
      Revascularization Investigation (BARI).
AB  - OBJECTIVES: Our objective was to determine whether a strategy of intended
      incomplete percutaneous transluminal coronary angioplasty revascularization (IR)
      compromises long-term patient outcome. BACKGROUND: Complete angioplasty
      revascularization (CR) is often not planned nor attempted in patients with
      multivessel coronary disease, and the extent to which this influences outcome is
      unclear. METHODS: Before randomization, in the Bypass Angioplasty
      Revascularization Investigation, all angiograms were assessed for intended CR or
      IR via angioplasty. Outcomes were compared among patients with IR intended if
      assigned to angioplasty, randomized to coronary artery bypass graft surgery
      (CABG) versus angioplasty; and within angioplasty patients only, among patients
      with IR versus CR intended. RESULTS: At 5 years, there was a trend for higher
      overall (88.6% vs. 84.0%) and cardiac survival (94.5% vs. 92.1%) in CABG versus
      angioplasty patients with IR intended. The excess mortality in angioplasty
      patients occurred solely in diabetic subjects; overall and cardiac survival were
      similar among nondiabetic CABG and angioplasty patients. Freedom from myocardial
      infarction (MI) at 5 years was higher in nondiabetic CABG versus angioplasty
      patients (92.4% vs. 85.2%, p = 0.02), vet was similar to the rate observed (85%)
      in nondiabetic CABG and angioplasty patients with CR intended. Five-year rates of
      death, cardiac death, repeat revascularization and angina were similar in all
      angioplasty patients with IR versus CR intended. However, a trend for greater
      freedom from subsequent CABG was seen in CR patients (70.3% vs. 64.0%, p = 0.08).
      CONCLUSIONS: Intended incomplete angioplasty revascularization in nondiabetic
      patients with multivessel disease who are candidates for both angioplasty and
      CABG does not compromise long-term survival; however, subsequent need for CABG
      may be increased with this strategy. Whether the risk of long-term MI is also
      increased remains uncertain.

PMID- 10334435
TI  - Dose-dependent fetal complications of warfarin in pregnant women with mechanical
      heart valves.
AB  - OBJECTIVES: The purpose of this study was to assess the incidence of warfarin
      fetal complications and whether they are dose-dependent. BACKGROUND: Gravid
      patients with mechanical heart valves require long-term anticoagulant therapy.
      Controversy exists concerning the appropriate treatment of these patients.
      METHODS: Forty-three women on warfarin carrying out 58 pregnancies were studied.
      For each patient with full-term pregnancy a caesarian section was scheduled for
      the 38th week during brief warfarin discontinuation. Maternal and fetal
      complications were evaluated. Fetal complications were divided according to the
      warfarin dosage < or = 5 mg and > 5 mg necessary to keep an international
      normalized ratio (INR) of 2.5 to 3.5, and analyzed subsequently. RESULTS: A total
      of 58 pregnancies were observed: 31 healthy babies (30 full term, 1 premature)
      and 27 fetal complications (22 spontaneous abortions, 2 warfarin embryopathies, 1
      stillbirth, 1 ventricular septal defect, 1 growth retardation) were recorded. Two
      maternal valve thromboses occurred. No fetal or maternal bleeding was observed
      during caesarian sections or premature vaginal delivery. Patients whose warfarin
      doses during pregnancy were > 5 mg had 22 fetal complications, whereas those
      taking a dose < or = 5 mg had only five fetal complications (p = 0.0001). For an
      increase of the warfarin dose there was a substantially increased probability of
      fetal complications (p < 0.0001; p < 0.7316). CONCLUSIONS: There is a close
      dependency between warfarin dosage and fetal complications. Patients on warfarin
      anticoagulation may be delivered by planned caesarian section at the 38th week
      while briefly interrupting anticoagulation.

PMID- 10334436
TI  - Pregnancy through a prosthetic heart valve.

PMID- 10334437
TI  - Three-dimensional color Doppler: a clinical study in patients with mitral
      regurgitation.
AB  - OBJECTIVES: The purpose of this study was to assess the clinical feasibility of
      three-dimensional (3D) reconstruction of color Doppler signals in patients with
      mitral regurgitation. BACKGROUND: Two-dimensional (2D) color Doppler has limited
      value in visualizing and quantifying asymmetric mitral regurgitation. Clinical
      studies on 3D reconstruction of Doppler signals in original color coding have not
      yet been performed in patients. We have developed a new procedure for 3D
      reconstruction of color Doppler. METHODS: We studied 58 patients by
      transesophageal 3D echocardiography. The jet area was assessed by planimetry and
      the jet volumes by 3D Doppler. The regurgitant fractions, the volumes, and the
      angiographic degree of mitral regurgitation were assessed in 28 patients with
      central jets and compared with those of 30 patients with eccentric jets. RESULTS:
      In all patients, jet areas and jet volumes significantly correlated with the
      angiographic grading (r = 0.73 and r = 0.90), the regurgitant fraction (r = 0.68
      and r = 0.80) and the regurgitant volume (r = 0.66 and r = 0.90). In patients
      with central jets, significant correlations were found between jet area and
      angiography (r = 0.86), regurgitant fraction (r = 0.64) and regurgitant volume (r
      = 0.78). No significant correlations were found between jet area and angiography
      (r = 0.53), regurgitant fraction (r = 0.52) and regurgitant volume (r = 0.53) in
      the group of patients with eccentric jets. In contrast, jet volumes significantly
      correlated with angiography (r = 0.90), regurgitant fraction (r = 0.75) and
      regurgitant volume (r = 0.88) in the group of patients with eccentric jets.
      CONCLUSIONS: Three-dimensional Doppler revealed new images of the complex jet
      geometry. In addition, jet volumes, assessed by an automated voxel count,
      independent of manual planimetry or subjective estimation, showed that 3D Doppler
      is also capable of quantifying asymmetric jets.

PMID- 10334438
TI  - "Overestimation" of catheter gradients by Doppler ultrasound in patients with
      aortic stenosis: a predictable manifestation of pressure recovery.
AB  - OBJECTIVES: This study sought to evaluate whether pressure recovery can cause
      significant differences between Doppler and catheter gradients in patients with
      aortic stenosis, and whether these differences can be predicted by Doppler
      echocardiography. BACKGROUND: Pressure recovery has been shown to be a source of
      discrepancy between Doppler and catheter gradients across aortic stenoses in
      vitro. However, the clinical relevance of this phenomenon for the Doppler
      assessment of aortic stenosis has not been evaluated in patients. METHODS: Twenty
      three patients with various degrees of aortic stenosis were studied with Doppler
      echocardiography and catheter technique within 24 h. Using an equation previously
      validated in vitro, pressure recovery was estimated from peak transvalvular
      velocity, aortic valve area and cross-sectional area of the ascending aorta and
      compared with the observed differences between Doppler and catheter gradients.
      Doppler gradients were also corrected by subtracting the predicted pressure
      recovery and then were compared with the observed catheter gradients. RESULTS:
      Predicted differences between Doppler and catheter gradients due to pressure
      recovery ranged from 5 to 82 mm Hg (mean +/- SD, 19 +/- 16 mm Hg) and 3 to 54 mm
      Hg (12 +/- 11 mm Hg) for peak and mean gradients, respectively. They compared
      well with the observed Doppler-catheter gradient differences, ranging from -5 to
      75 mm Hg (18 +/- 18 mm Hg) and -7 to 48 mm Hg (11 +/- 13 mm Hg). Good correlation
      between predicted pressure recovery and observed gradient differences was found
      (r = 0.90 and 0.85, respectively). Both the noncorrected and the corrected
      Doppler gradients correlated well with the catheter gradients (r = 0.93-0.97).
      However, noncorrected Doppler gradients significantly overestimated the catheter
      gradients (slopes, 1.36 and 1.25 for peak and mean gradients, respectively),
      while Doppler gradients corrected for pressure recovery showed good agreement
      with catheter gradients (slopes, 1.03 and 0.96; standard error of estimate [SEE]
      8.1 and 6.9 mm Hg; mean difference +/- SD 0.4 +/- 8.0 mm Hg and 1.1 +/- 6.8 mm Hg
      for peak and mean gradients, respectively). CONCLUSIONS: Significant pressure
      recovery can occur in patients with aortic stenosis and can cause discrepancies
      between Doppler and catheter gradients. However, pressure recovery and the
      resulting differences between Doppler and catheter measurements may be predicted
      from Doppler velocity, aortic valve area and size of the ascending aorta.

PMID- 10334439
TI  - Range of tricuspid regurgitation velocity at rest and during exercise in normal
      adult men: implications for the diagnosis of pulmonary hypertension.
AB  - OBJECTIVES: The aim of this study was to explore the full range of tricuspid
      valve regurgitation velocity (TRV) at rest and with exercise in disease free
      individuals. Additionally we examined the relationship of stroke volume (SV),
      cardiac output (CO) and TRV to exercise capacity. BACKGROUND: Doppler evaluation
      of TRV can be used to estimate pulmonary artery systolic pressure (PASP). Most
      studies have assumed TRV < or = 2.5 m/s as the upper limits of normal. The full
      range of TRV with exercise has been incompletely defined. METHODS: Highly
      conditioned athletes (n = 26) and healthy, active, young male volunteers (n = 14)
      underwent standardized recumbent bicycle exercise. Exercise parameters included:
      TRV, SV, CO, systolic (SBP) and diastolic (DBP) systemic blood pressure. RESULTS:
      Tricuspid valve regurgitation, SV, HR and CO were significantly higher in
      athletes than in nonathletes over all workloads, including rest. Systolic blood
      pressure and DBP did not show significant differences between the two groups.
      CONCLUSIONS: This study defines the upper physiologic limits of TRV at rest and
      during exercise in normals and provides a noninvasive standard for the diagnosis
      of pulmonary hypertension.

PMID- 10334440
TI  - Narrowing of the superior vena cava-right atrium junction during radiofrequency
      catheter ablation for inappropriate sinus tachycardia: analysis with intracardiac
      echocardiography.
AB  - OBJECTIVES: The study explored the potential for tissue swelling and venous
      occlusion during radiofrequency (RF) catheter ablation procedures using
      intracardiac echocardiography (ICE). BACKGROUND: Transient superior vena cava
      occlusion has been reported following catheter ablation procedures for
      inappropriate sinus tachycardia (IST). Presumably, venous occlusion could occur
      owing to thrombus formation or tissue swelling with resultant narrowing of the
      superior vena cava-right atrial (SVC-RA) junction. METHODS: Intracardiac
      echocardiography (9 MHz) was used to guide ablation catheter position and for
      continuous monitoring during RF application in 13 ablation procedures in 10
      patients with IST. The SVC-RA junction was measured prior to and following
      ablation. Successful ablation was marked by abrupt reduction in the sinus rate
      and a change to a superiorly directed p-wave axis. RESULTS: Eleven of 13
      procedures were successful, requiring 29 +/- 20 RF lesions. Prior to the delivery
      of RF lesions, the SVC-RA junction measured 16.4 +/- 2.9 mm. With RF delivery,
      local and circumferential swelling was observed, causing progressive reduction in
      the diameter of the SVC-RA junction to 12.6 +/- 3.3 mm (24% reduction, p =
      0.0001). A reduction in SVC-RA orifice diameter of > or = 30% compared to
      baseline was observed in five patients. CONCLUSIONS: The delivery of multiple RF
      ablation lesions, often necessary for cure of IST, can cause considerable atrial
      swelling and resultant narrowing of the SVC-RA junction. Smaller venous
      structures, such as the coronary sinus and the pulmonary veins, would also be
      expected to be vulnerable to this complication. Thus, ICE imaging may be helpful
      in preventing excessive tissue swelling leading to venous occlusion during
      catheter ablation procedures.

PMID- 10334441
TI  - Pacemaker lead extraction with the laser sheath: results of the pacing lead
      extraction with the excimer sheath (PLEXES) trial.
AB  - OBJECTIVES: The purpose of this study was to evaluate the safety and
      effectiveness of pacemaker lead extraction with the excimer sheath in comparison
      to nonlaser lead extraction. BACKGROUND: Fibrotic attachments that develop
      between chronically implanted pacemaker leads and to the venous, valvular and
      cardiac structures are the major obstacles to safe and consistent lead
      extraction. Locking stylets and telescoping sheaths produce a technically
      demanding but effective technique of mechanically disrupting the fibrosis.
      However, ultraviolet excimer laser light dissolves instead of tearing the tissue
      attachments. METHODS: A randomized trial of lead extraction was conducted in 301
      patients with 465 chronically implanted pacemaker leads. The laser group patients
      had the leads removed with identical tools as the nonlaser group with the
      exception that the inner telescoping sheath was replaced with the 12-F excimer
      laser sheath. Success for both groups was defined as complete lead removal with
      the randomized therapy without complications. RESULTS: Complete lead removal rate
      was 94% in the laser group and 64% in the nonlaser group (p = 0.001). Failed
      nonlaser extraction was completed with the laser tools 88% of the time. The mean
      time to achieve a successful lead extraction was significantly reduced for
      patients randomized to the laser tools, 10.1 +/- 11.5 min compared with 12.9 +/-
      19.2 min for patients randomized to nonlaser techniques (p < 0.04). Potentially
      life-threatening complications occurred in none of the nonlaser and three of the
      laser patients, including one death (p = NS). CONCLUSIONS: Laser-assisted
      pacemaker lead extraction has significant clinical advantages over extraction
      without laser tools and is associated with significant risks.

PMID- 10334442
TI  - Adenosine causes the release of active renin and angiotensin II in the coronary
      circulation of patients with essential hypertension.
AB  - OBJECTIVES: The aim of the study was to evaluate whether adenosine infusion can
      induce production of active renin and angiotensin II in human coronary
      circulation. BACKGROUND: Adenosine can activate angiotensin production in the
      forearm vessels of essential hypertensive patients. METHODS: In six normotensive
      subjects and 12 essential hypertensive patients adenosine was infused into the
      left anterior descending coronary artery (1, 10, 100 and 1,000 microg/min x 5 min
      each) while active renin (radioimmunometric assay) and angiotensin II
      (radioimmunoassay after high performance liquid chromatography purification) were
      measured in venous (great cardiac vein) and coronary arterial blood samples. In
      five out of 12 hypertensive patients adenosine infusion and plasma samples were
      repeated during intracoronary angiotensin-converting enzyme inhibitor
      benazeprilat (25 microg/min) administration. Finally, in adjunctive hypertensive
      patients, the same procedure was applied during intracoronary sodium
      nitroprusside (n = 4) or acetylcholine (n = 4). RESULTS: In hypertensive
      patients, but not in control subjects, despite a similar increment in coronary
      blood flow, a significant (p < 0.05) transient increase of venous active renin
      (from 10.7 +/- 1.4 [95% confidence interval 9.4 to 11.8] to a maximum of 13.8 +/-
      2.1 [12.2 to 15.5] with a consequent drop to 10.9 +/- 1.8 [9.7 to 12.1] pg/ml),
      and angiotensin II (from 14.6 +/- 2.0 [12.7 to 16.5] to a maximum of 20.4 +/- 2.7
      [18.7 to 22.2] with a consequent drop to 16.3 +/- 1.8 [13.9 to 18.7] pg/ml) was
      observed under adenosine infusion, whereas arterial values did not change.
      Calculated venous-arterial active renin and angiotensin II release showed a
      strong correlation (r = 0.78 and r = 0.71, respectively; p < 0.001) with
      circulating active renin. This adenosine-induced venous angiotensin II increase
      was significantly blunted by benazeprilat. Finally, both sodium nitroprusside and
      acetylcholine did not affect arterial and venous values of active renin and
      angiotensin II. CONCLUSIONS: These data indicate that exogenous adenosine
      stimulates the release of active renin and angiotensin II in the coronary
      arteries of essential hypertensive patients, and suggest that this phenomenon is
      probably due to renin release from tissue stores of renally derived renin.

PMID- 10334443
TI  - Familial predisposition of left ventricular hypertrophy.
AB  - OBJECTIVES: The study evaluated the contribution of familial predisposition to
      the risk of left ventricular hypertrophy (LVH). BACKGROUND: Left ventricular
      hypertrophy is a multifactorial condition that serves as an important predictor
      of cardiovascular mortality. At present it is unclear whether familial
      predisposition contributes to the manifestation of LVH. Thus, we determined
      whether siblings of subjects with LVH are at increased risk to present with an
      elevation of LV mass or an abnormal LV geometry. METHODS: Echocardiographic and
      anthropometric measurements were performed in 2,293 individuals who participated
      in the echocardiographic substudies of population-based MONICA Augsburg surveys.
      In addition, a total of 319 siblings of survey participants with
      echocardiographic evidence of LVH were evaluated. The risk of these siblings to
      present with LVH or abnormal LV geometry was estimated by comparison with 636
      subjects matched for gender and age that were selected from the entire
      echocardiography study base. RESULTS: Blood pressure, body mass index, age, and
      gender (i.e., known determinants of LV mass) were comparable in LVH-siblings and
      the matched comparison group. However, septal and posterior wall thicknesses,
      relative wall thickness as well as LV mass index were significantly elevated in
      LVH-siblings (p < 0.001, each) whereas LV dimensions did not differ. Likewise,
      the prevalence of LVH was raised in LVH-siblings, as was the relative risk of LVH
      after adjustment for confounders (p < 0.05). More specifically, LVH-siblings
      displayed increased prevalences of concentric remodeling and concentric LVH (p <
      0.05) but not of eccentric LVH. CONCLUSIONS: Familial predisposition appears to
      contribute to increased LV wall thickness, to the development of LV hypertrophy
      and abnormal LV geometry.

PMID- 10334444
TI  - Pregnancy among women with congenitally corrected transposition of great
      arteries.
AB  - OBJECTIVES: The outcome of pregnancy in congenitally corrected transposition of
      the great vessels was studied in 22 women. BACKGROUND: Women with congenitally
      corrected transposition of the great vessels often reach childbearing age.
      Although reports on the outcome of pregnancy in these women are available, the
      number of patients is small. METHODS: The medical and surgical databases at the
      Mayo Clinic were reviewed, and 36 women >16 years old with congenitally corrected
      transposition of the great vessels were identified. All of them were contacted,
      and 22 who had pregnancies were identified and the outcome of pregnancy was
      evaluated. RESULTS: Twenty-two women had 60 pregnancies resulting in 50 live
      births (83%). Forty-four deliveries (88%) were vaginal and 6 (12%) were by
      cesarean section. One delivery was premature at 29 weeks. There was one
      successful twin pregnancy. There were 11 unsuccessful pregnancies. One patient
      developed congestive heart failure late in pregnancy because of systemic
      atrioventricular valve regurgitation and required valve replacement in the early
      postpartum period. One patient had a total of 12 pregnancies, including 1 twin
      pregnancy and 2 unsuccessful pregnancies. She had multiple pregnancy-related
      complications, including toxemia, congestive heart failure, endocarditis and
      myocardial infarction (single coronary artery). No other serious pregnancy
      related maternal complications and no pregnancy-related deaths occurred. The mean
      birth weight of the infants (n = 32) was 3.2 +/- 0.4 kg. None of the 50 live
      offspring have been diagnosed with congenital heart disease. CONCLUSIONS:
      Successful pregnancy can be achieved in most women with congenitally corrected
      transposition of the great arteries. The rate of fetal loss and maternal
      cardiovascular morbidity is increased. Because of the small number of births, the
      risk of congenital heart disease in offspring of women with congenitally
      corrected transposition of the great arteries is uncertain.

PMID- 10334445
TI  - Accuracy of prenatal echocardiographic diagnosis and prognosis of fetuses with
      conotruncal anomalies.
AB  - OBJECTIVES: The purpose of the study was to determine the accuracy of the
      prenatal echocardiographic diagnosis and prognosis of fetuses with conotruncal
      anomalies. BACKGROUND: The accuracy of prenatal echocardiographic diagnoses of
      cardiac lesions has been reported, but no previous reports specifically address
      fetal conotruncal anomalies. METHODS: Medical records of 61 fetuses, in which a
      fetal diagnosis of a conotruncal anomaly was made, were reviewed. Disease
      entities included were tetralogy of Fallot (TOF), double outlet right ventricle
      (DORV), transposition of the great arteries (TGA), and truncus arteriosus (TA).
      RESULTS: Fetal diagnosis was established at a median of 24.5 weeks' gestation.
      Termination of pregnancy was chosen in 31% (19/61) of cases. Postnatal assessment
      of the diagnosis was not obtained in 12 cases. Excluding two sets of conjoined
      twins, accurate prenatal diagnosis including definition of the great artery
      orientation was achieved in 36 of 47 cases (77%). Seven of 17 fetuses with DORV
      anatomy, of which 6 were thought to have a subpulmonary ventricular septal defect
      (VSD), had incorrect prenatal assessment of the great artery relationships. One
      fetus thought to show features of TA had aortic atresia with VSD and normal-sized
      left ventricle. Of the 42 pregnancies that continued, 15 had major extracardiac
      malformations and/or chromosomal abnormalities of which one died in utero with
      trisomy-13 and TA. A further nine died within the neonatal period. Among the 27
      fetuses without a documented chromosomal or major extracardiac anomaly, 13 (48%)
      died. Overall, the survival rate beyond 28 days of life was 52% (22/42). In
      contrast, 75% (6/8) of fetuses with TOF, excluding the absent pulmonary valve
      syndrome, survived. CONCLUSIONS: Conotruncal anomalies can be diagnosed by
      prenatal echocardiography with a high degree of accuracy. Defining the exact
      spatial relationship of the great arteries is problematic in some fetuses. The
      overall prognosis for fetuses with a conotruncal anomaly is poor, with the
      exception of uncomplicated TOF.

PMID- 10334446
TI  - Evolution of risk factors influencing early mortality of the arterial switch
      operation.
AB  - OBJECTIVES: The present study was undertaken to determine the independent risk
      factors for early mortality in the current era after arterial switch operation
      (ASO). BACKGROUND: Prior reports on factors affecting outcome of the ASO
      demonstrated that abnormal coronary arterial patterns were associated with
      increased risk of early mortality. As diagnostic, surgical and perioperative
      management techniques continue to evolve, the risk factors for the ASO may have
      changed. METHODS: All patients who underwent the ASO at Children's Hospital,
      Boston between January 1, 1992 and December 31, 1996 were included. Hospital
      charts, echocardiographic and cardiac catheterization data and operative reports
      of all patients were reviewed. Demographics and preoperative, intraoperative and
      postoperative variables were recorded. RESULTS: Of the 223 patients included in
      the study (median age at ASO = 6 days and median weight = 3.5 kg), 26 patients
      had aortic arch obstruction or interruption, 12 had Taussig-Bing anomaly, 12 had
      multiple ventricular septal defects, 8 had right ventricular hypoplasia and 6
      were premature. There were 16 early deaths (7%), with 3 deaths in the 109
      patients considered "low risk" (2.7%). Coronary artery pattern was not associated
      with an increased risk of death. Compared with usual coronary anatomy pattern,
      however, inverted coronary patterns and single right coronary patterns were
      associated with increased incidence of delayed sternal closure (p = 0.003) and
      longer duration of mechanical ventilation (p = 0.008). In a multivariate logistic
      regression model using only preoperative variables, aortic arch repair at a
      separate procedure before ASO and smaller birth weight were independent
      predictors of early mortality. In a second model that included both pre- and
      intraoperative variables, circulatory arrest time and right ventricular
      hypoplasia were independent predictors of early death. CONCLUSIONS: The ASO can
      be performed in the current era without excess early mortality related to
      uncommon coronary artery patterns. Aortic arch repair before ASO, right
      ventricular hypoplasia, lower birth weight and longer intraoperative support
      continue to be independent risk factors for early mortality after the ASO.

PMID- 10334447
TI  - The snare-assisted technique for transcatheter coil occlusion of moderate to
      large patent ductus arteriosus: immediate and intermediate results.
AB  - OBJECTIVES: The purpose of this study was to evaluate the feasibility, safety and
      efficacy of using a snare-assisted technique to coil occlude the moderate to
      large size patent ductus arteriosus (PDA). BACKGROUND: Transcatheter occlusion of
      small PDAs using Gianturco coils is safe and effective. However, in larger size
      PDAs and/or those with short PDA length, the procedure still carries risks of
      coil embolization, incomplete occlusion and failure to implant the coil. METHODS:
      From January 1994 to June 1997, the records of 104 consecutive snare-assisted
      coil occlusions of moderate to large PDAs (minimum diameter >2.0 mm) were
      reviewed. Immediate and intermediate outcomes including complete and partial
      occlusion, failure to implant and complications were analyzed with respect to
      ductal type and size. RESULTS: Patient age ranged from 0.1 to 70.1 years (median
      3.3 years). Minimum PDA diameter ranged from 2.1 to 6.8 mm (mean 3.0 +/- 0.9 mm).
      Angiographic types were A-62, B-13, C-6, D-14 and E-9. Using the snare-assisted
      technique, coil placement was successful in 104/104 patients (100%), irrespective
      of size or angiographic type. Immediate complete closure was observed in 73/104
      (70.2%) and was related to smaller PDA size, but not to angiographic type.
      Complete closure was documented in 102/104 (98.1%) at 2- to 16-month follow-up.
      Successful closure was unrelated to PDA size or type. Coil embolization to the
      pulmonary artery occurred in 3/104 (2.9%) patients and was not related to PDA
      size or type. The need for multiple coils was found in 28/104 patients (26.9%),
      and was related to larger PDA size, but not to angiographic type. CONCLUSIONS:
      The snare-assisted delivery technique allows successful occlusion of moderate to
      large PDAs up to 6.8 mm, irrespective of angiographic type. This technique
      permits improved control and accuracy of coil placement, and facilitates delivery
      of multiple coils.

PMID- 10334448
TI  - Troponin-I for prediction of early postoperative course after pediatric cardiac
      surgery.
AB  - OBJECTIVES: It was the aim of the study to test the prognostic value of cardiac
      troponin-I (cTnI) concerning the early postoperative course after pediatric
      cardiac surgery. BACKGROUND: Cardiac troponin-I is a very specific and sensitive
      marker of myocardial damage in adults and children. As perioperative myocardial
      damage may be a significant factor of postoperative cardiac performance, serial
      cTnI values were analyzed in children undergoing open heart surgery. METHODS:
      Seventy-three children undergoing elective correction of congenital heart disease
      including atrial and ventricular surgical manipulation were studied. Cardiac
      troponin-I levels were measured serially and correlated with intra- and
      postoperative parameters (such as doses and length of inotropic support, renal
      and hepatic function, duration of intubation). Patients with prolonged
      postoperative recovery were analyzed with special attention to the cTnI levels.
      RESULTS: The cutoff point for the definition of a high and a low risk group of
      cTnI values was set at 25 microg/liter, 4 h after admission to the intensive care
      unit (ICU) and at 35 microg/liter considering the maximal value of cTnI in the
      first 24 h in the ICU. The results showed a highly significant correlation
      between the need for inotropic support, the severity of renal dysfunction and the
      duration of intubation in relation to the serum levels of cTnI. CONCLUSIONS:
      Cardiac troponin-I serum levels after open heart surgery in children and infants
      4 h after admission to the ICU allowed anticipation of the postoperative course
      and correlated with the incidence of significant postoperative complications.

PMID- 10334449
TI  - Volume overload hypertrophy of the newborn heart slows the maturation of enzymes
      involved in the regulation of fatty acid metabolism.
AB  - OBJECTIVES: The purpose of this study was to determine the effect of volume
      overload hypertrophy in the newborn heart on the cardiac enzymes controlling
      fatty acid metabolism. BACKGROUND: Shortly after birth, a rise in 5'-adenosine
      monophosphate-activated protein kinase (AMPK) activity results in the
      phosphorylation and inhibition of acetyl coenzyme A (CoA) carboxylase (ACC), and
      a decline in myocardial malonyl CoA levels with increased fatty acid oxidation
      rates. Whether the early onset of hypertrophy in the newborn heart alters this
      maturational increase in fatty acid oxidation is unknown. METHODS: Newborn
      piglets underwent endovascular stenting of the ductus arteriosus on day 1 of life
      with a 4.5-mm diameter stent, resulting in a left to right shunt, and left
      ventricular (LV) volume loading. Left ventricular and right ventricular samples
      from fetal, newborn, three-week control and three-week stented animals were
      compared. RESULTS: Stenting resulted in echocardiographic evidence of volume
      overload and myocardial hypertrophy. In control animals, left ventricular ACC
      activity declined from 274 +/- 30 pmol/mg/min on day 1 to 115 +/- 12 after three
      weeks (p < 0.05), but did not display this maturation drop in hypertrophied
      hearts, remaining elevated (270 +/- 50 pmol/mg/min, p < 0.05). At three weeks,
      malonyl CoA levels remained 2.8-fold higher in hypertrophied hearts than in
      control hearts. In control hearts, LV AMPK activity increased 178% between day 1
      and three weeks, whereas in hypertrophied hearts AMPK activity at three weeks was
      only 71% of control values, due to a significant decrease in expression of the
      catalytic subunit of AMPK. CONCLUSIONS: Early onset LV volume overload with
      hypertrophy results in a delay in the normal maturation of fatty acid oxidation
      in the newborn heart.

PMID- 10334451
TI  - Training programs in interventional cardiology.

PMID- 10334450
TI  - Mapping of regional myocardial strain and work during ventricular pacing:
      experimental study using magnetic resonance imaging tagging.
AB  - OBJECTIVES: The purpose of this study was to determine the spatial distribution
      of myocardial function (myofiber shortening and work) within the left ventricular
      (LV) wall during ventricular pacing. BACKGROUND: Asynchronous electrical
      activation, as induced by ventricular pacing, causes various abnormalities in LV
      function, perfusion and structure. These derangements may be caused by
      abnormalities in regional contraction patterns. However, insight into these
      patterns during pacing is as yet limited. METHODS: In seven anesthetized dogs,
      high spatial and temporal resolution magnetic resonance-tagged images were
      acquired in three orthogonal planes. Three-dimensional deformation data and LV
      cavity pressure and volume were used to determine midwall circumferential strain
      and external and total mechanical work at 192 sites around the left ventricle.
      RESULTS: During ventricular pacing, systolic fiber strain and external work were
      approximately zero in regions near the pacing site, and gradually increased to
      more than twice the normal value in the most remote regions. Total mechanical
      work, normalized to the value during right atrial pacing, was 38 +/- 13% (right
      ventricular apex [RVapex] pacing) and 61 +/- 23% (left ventricular base [LVbase]
      pacing) close to the pacing site, and 125 +/- 48% and 171 +/- 60% in remote
      regions, respectively (p < 0.05 between RVapex and LVbase pacing). The number of
      regions with reduced work was significantly larger during RVapex than during
      LVbase pacing. This was associated with a reduction of global LV pump function
      during RVapex pacing. CONCLUSIONS: Ventricular pacing causes a threefold
      difference in myofiber work within the LV wall. This difference appears large
      enough to regard local myocardial function as an important determinant for
      abnormalities in perfusion, metabolism, structure and pump function during
      asynchronous electrical activation. Pacing at sites that cause more synchronous
      activation may limit the occurrence of such derangements.

PMID- 10334452
TI  - President's page: personalizing continuing medical education.

PMID- 10334453
TI  - Guidelines for 22q11 deletion screening of patients with conotruncal defects.

PMID- 10334454
TI  - Role of nitric oxide in venous and arterial graft failure.

PMID- 10334455
TI  - AHA/ACC scientific statement: consensus panel statement. Guide to preventive
      cardiology for women. American Heart Association/American College of Cardiology.

PMID- 10334456
TI  - ACC/AHA guidelines for coronary angiography. A report of the American College of
      Cardiology/American Heart Association Task Force on practice guidelines
      (Committee on Coronary Angiography). Developed in collaboration with the Society
      for Cardiac Angiography and Interventions.

PMID- 10334457
TI  - Protective effects of Gingko biloba extract EGb 761 on myocardium of
      experimentally diabetic rats. I: ultrastructural and biochemical investigation on
      cardiomyocytes.
AB  - Chronic diabetes in man and animal models develops cardiomyopathic alterations
      which cannot be absolutely avoided by insuline therapy. Since diabetic damage is
      partly attributed to oxidative stress antioxidative treatment could be able to
      reduce the alterations. Aim of this study was to investigate the cardioprotective
      effects of EGb 761, known as a radical scavenger, against diabetic alterations in
      rats. The diabetes was induced by i.p. injection of 60 mg/kg body weight
      streptozotocin. Duration of diabetes was 4 months, the protected group received
      100 mg/kg body weight EGb 761 with the drinking water over 3 months. Electron and
      light microscopic morphometry of left-ventricular samples revealed typical
      diabetic alterations consisting in decrease of volume fraction of myofibrils, SR
      and t-tubules and diminishing of cardiomyocyte diameter, increase of interstitial
      volume, mitochondrial size and volume fraction, and of vacuoles and of lipid
      drops. EGb treatment could gradually prevent the loss of myofibrils and reduction
      of myocyte diameter but has only little influence on interstitial and
      mitochondria volume. The diabetic-induced increase of lipid and vacuoles and the
      decrease of SR and t-tubules were not influenced. Biochemical parameters of
      oxidative stress: malondialdehyde (MDA) was only insignificantly altered by
      diabetes and EGb. The superoxide dismutase (SOD) activity was increased by
      diabetes and more increased by EGb treatment. Creatine kinase (CK) activity was
      diminished by diabetes but slightly increased by EGb. The polymerase chain
      reaction (PCR) of i-NOS was not different between the diabetic and protected
      diabetic groups.

PMID- 10334458
TI  - Differential effect of CCl4 on renal function in cirrhotic and non-cirrhotic
      rats.
AB  - The pathogenesis of renal function alteration associated with liver disease
      remains to be elucidated. Although different experimental animal models have been
      utilized in order to explain such pathophysiological state, none of them have
      completely explained the mechanisms involved. In this study we performed
      differential hemodynamic, hepatic and renal function alteration studies after
      induction of acute liver damage via intragastric administration of a single dose
      of CCl4 to cirrhotic and non-cirrhotic rats. Cirrhotic rats with acute liver
      damage exhibited a significant decrease in mean arterial pressure followed by a
      decreased glomerular filtration rate, urinary sodium concentration and an
      induction of plasma renin concentration and activity. At the same time, a
      significant association between oliguria and mortality was observed. The renal
      histopathological studies revealed glomeruli with mesangial hypercellularity and
      thickening of capillary wall, but not tubular epithelial injury. All these
      alterations were not detected in the control group, i.e. by non-cirrhotic rats
      with acute liver damage. This study suggests that the effect of CCl4 on kidney
      structure and function depends on the functional state of the liver. Since this
      experimental model of acute liver damage in cirrhotic rats presents hemodynamics
      and renal function alterations similar to those observed in the hepatorenal
      syndrome in man, it could be utilized to study the pathogenesis of renal function
      alterations associated with liver damage.

PMID- 10334459
TI  - Effect of prostacyclin on gastric mucosal RNA-content in the rat.
AB  - We investigated changes in gastric (antral and fundic) mucosal RNA contents in
      single-dose and in long-term (10 weeks) treatment of rats with receiving oral
      graded doses of prostacyclin. Long-term application of prostacyclin evoked no
      significant changes, while in the single-dose experiments there was a dose
      dependent elevation in RNA-content in both parts of the gastric mucosa. The
      results are interpreted as convincing signs of the gastro-protective effect of
      prostacyclin.

PMID- 10334460
TI  - Prevention of apoptosis reperfusion renal injury by calcium channel blockers.
AB  - Apoptosis has been shown in the literature to be the form of cell death occurring
      in renal tubular epithelial cells during the reperfusion phase after brief
      periods of renal ischaemia. In the present study apoptosis was examined in the
      rat kidney in the first 24 hours after 30 min ischaemia and apoptosis was
      influenced by administration of the Ca channel blockers Verapamil, Bepridil,
      Nifedipin and Sensit. Apoptosis was observed in the renal tubular cells two hours
      after the start of reperfusion and reached in maximum at hour 6. All above
      mentioned Ca channel blockers decreased the occurrence and degree of apoptosis.

PMID- 10334461
TI  - Protective effects of Ginkgo biloba extract EGb 761 on the myocardium of
      experimentally diabetic rats. II. Ultrastructural and immunohistochemical
      investigation on microvessels and interstitium.
AB  - Interstitial and microvascular disorders are known as a characteristic part of
      the diabetic cardiomyopathy and to resist partly insulin therapy. Aim of this
      study was to demonstrate structure-protecting effects of Ginkgo Extract EGb 761
      known as a natural radical scavenger in streptozotocin-diabetic rats on the
      microvascular compartment. Wistar rats (n = 5) were made diabetical by i.p.
      injection of 60 mg/kg body mass streptozotocin for 4 months. Rats of the
      protected group (n = 5) received daily 100 mg/kg body mass EGb 761 for 3 months,
      starting 1 month after induction of diabetes. 5 age-matched rats served as
      control. The volume fraction of interstitium was slightly but significantly
      increased only in the unprotected diabetic group. Diminishing of the capillary to
      the myocyte ratio was seen in the diabetic but not in the protected group.
      Immunostaining of collagen revealed a slight increase of type III, type IV, and
      type VI fibres in the interstitium, more expressed in the unprotected group.
      Ultrastuctural morphometry revealed significant thickening of endothelial and
      muscular basement membranes in diabetic animals, less expressed in the EGb-
      protected group. The capillary diameter was slightly increased in the diabetic
      and slightly decreased in the protected group. The number of plasmalemmal
      vesicles was tendentially more decreased, that of lysosomes more increased in the
      diabetic than in the protected group. It is concluded that EGb 761 can diminish
      partly interstitial fibrosis and reduce endothelial and muscular basement
      membrane thickening of the diabetic myocardium. It may contribute to prevent late
      diabetic complications.

PMID- 10334463
TI  - Cell cultures from cryopreserved renal biopsies and other tissue samples.
AB  - Answering questions regarding research or clinical aspects, histological and
      histochemical examinations of tissue specimens are playing an increasing role.
      The same is true for cell cultures obtained from organ specimens. In most cases,
      tissue samples are obtained only once and have to be examined immediately. This
      is often impracticable and therefore, it is necessary to store tissue samples or
      cells from established cell cultures so as to be able to continue examinations at
      a later time. Very rare reports exist on the preservation of tissue for
      performing cell culture examinations and they exclusively refer to tumour tissue
      and bone marrow, but not to normal organ tissue and biopsy samples. Therefore, in
      this study cell cultures from several organs have been prepared immediately after
      obtaining the tissue and compared with those established after cryopreservation
      several months later. The tissue specimens were obtained from rats (kidney, skin,
      heart) and from humans (kidney, placenta) or were biopsy specimens from the
      kidney and skin. From all these cryopreparations, typical cells were cultured.
      There was no significant difference in the mean population doubling time (MPD)
      and regarding morphological cell criteria between cell cultures obtained from
      fresh tissue samples after biopsy and those prepared several months after
      cryopreservation. There was nearly the same ratio between most cell types present
      in the tissue. From these results we can conclude that in the examined organs
      cells from cryopreserved tissue can be cultured even months or more than one year
      later. At least, these results make it possible to answer new questions and
      repeat different experiments at any time.

PMID- 10334462
TI  - The influence of low doses 131I-induced maternal hypothyroidism on the
      development of rat embryos.
AB  - The aim of our research was to create and verify a model for studying the effects
      of a low dose of 131I and 131I-induced maternal hypothyroidism on the development
      of the embryo's thyroid gland and brain. The given dose (150 microCi) corresponds
      to the absorbed dose of 0.5 Gy. This dose is similar to that dose received by
      large numbers of the population of the C.I.S. regions polluted by radioactive
      isotopes of iodine as a result of the Chernobyl accident in 1985. Thirty-five
      female Wistar rats and their 168 newborn pups were used for observation. The
      females were divided into a control group and four experimental groups (each
      distinguished by the time of 131I injection: group I - no less than 12 days
      before mating; groups II, III and IV - on 5th, 10th and 16th days of gestation,
      respectively). In all the experimental female groups the incorporate dose of 131I
      led to hypothyroidism accompanied by a 43% reduction in the thyroxin level and by
      a nearly 8-fold increase in the TSH level. However, the influence of maternal
      hypothyroidism on the development of the thyroid gland and brain of embryos
      depends on the time when 131I took effect. There is a reduction in the weight of
      the newborns' brain and thyroid gland, total body mass. The hormonal status of
      the newborns' thyroid gland also changes. The proposed model will allow us to
      study many aspects of induced changes in the brain and thyroid gland of the
      embryos which develop under conditions of maternal hypothyroidism resulting from
      a low dose of 131I, administered at the critical times of development.

PMID- 10334465
TI  - Decreased biosynthesis of glycosaminoglycans in the skin of rats with chronic
      diabetes mellitus.
AB  - The skin of rats with experimental (streptozotocin-induced) chronic diabetes
      mellitus exhibits significant decrease in glycosaminoglycans (GAGs) content. In
      the present study we asked the question whether the decrease in GAGs content is a
      result of decline in GAG biosynthesis or an increase in their degradation. We
      demonstrated by a pulse-labeling experiments that diabetes results in a decrease
      of [14C]-glucosamine incorporation into both hyaluronic acid and sulphated GAGs.
      During the chase period, there was no significant degradation of the pulse
      labeled GAGs, suggesting that the reduction of GAGs content in the skin of
      diabetic rats is a result of decrease in GAG biosynthesis. Especially the
      biosynthesis of sulphated GAGs is deeply reduced. This phenomenon may be one of
      the factors which impairs the wound healing in diabetic subjects.

PMID- 10334464
TI  - Changes of the calcium tolerance in anthracycline treated mice.
AB  - Anthracyclines are effective antineoplastic agents inducing cardiomyopathy as a
      side effect. The mechanism of the anthracycline cardiotoxicity is not completely
      understood, but a disturbance of the Ca2+ -homeostasis seems to be involved. In
      our study we investigated the Ca2+ -tolerance in mice after a single
      administration of 2 mg/kg violamycin bI (vbI). Isolated hearts were perfused with
      increasing concentrations of Ca2+ until cardiac arrest. In the hearts of control
      animals the highest tolerable concentration was about 19 mM. 4 and 8 days after
      the vbI application 8 and 12 mM Ca2+, respectively, induced cardiac arrest. On
      the 12th day the Ca2+ tolerance was similar to control organs. 16 and 20 days
      after the vbI injection the highest tolerable Ca2+ -concentration sank again. On
      the 24th day the Ca2+ -tolerance was nearly the same as in controls.

PMID- 10334466
TI  - The protective effect of lipoxygenase inhibitor FLM 5011 on mitochondria
      ultrastructure of ischemic and reperfused cardiomyocytes.
AB  - Lipoxygenase inhibitor FLM 5011 was used in experimental ischemia and reperfusion
      with dogs to investigate its ultrastructure-preserving effects on the
      mitochondria of myocardium. Ischemic and non-ischemic areas of the heart were
      ultrastructural-morphometric analysed, which revealed that FLM 5011 was able to
      diminish ischemic damage especially of mitochondria. The protective effects on
      mitochondria consisted mainly in reduction of defective intramitochondrial areas
      and in excellent protection of the structural integrity of cristae and matrix.
      The injury of mitochondria by ischemia/reperfusion in unprotected condition was
      partly more pronounced in the non-ischemic than in the ischemic area of the
      hearts probably caused by compensatory overload of the residual myocardium.

PMID- 10334467
TI  - Alternations in free radical erythrocyte-defense mechanisms in streptozotocin
      induced diabetic rats - effect of antioxidant treatment.
AB  - The activities of superoxide dismutase, glutathione peroxidase and the contents
      of glutathione, malondialdehyde were examined in erythrocytes of streptozotocin
      induced diabetic rats. The above mentioned antioxidant systems of erythrocyte
      were determined after treatment of diabetic rats with superoxide dismutase,
      trolox, catalase and allopurinol. In erythrocytes of streptozotocin induced
      diabetic rats the activities of superoxide dismutase, glutathione peroxidase as
      well as the levels of reduced glutathione were lower whereas the contents of
      oxidized glutathione and malondialdehyde were higher than in controls. Superoxide
      dismutase and trolox treatment of diabetic rats resulted in an increase of
      erythrocyte glutathione peroxidase activities and in reduced glutathione levels.
      However the levels of oxidized glutathione decreased after treatment of diabetic
      rats with superoxide dismutase and trolox. Catalase and allopurinol
      administration did not have any influence on the activities of the investigated
      enzymes nor on the levels of glutathione in diabetic rats. The antioxidants under
      study did not cause any changes in the increased level of malondialdehyde in
      erythrocytes.

PMID- 10334468
TI  - Transcription factors in dysmorphology.

PMID- 10334469
TI  - Beginning of a molecular era in hearing and deafness.

PMID- 10334471
TI  - Confirmation of linkage in X-linked infantile spasms (West syndrome) and
      refinement of the disease locus to Xp21.3-Xp22.1.
AB  - The syndrome of infantile spasms, hypsarrhythmia, and mental retardation (West
      syndrome) is a classical form of epilepsy, occurring in early infancy, which is
      etiologically heterogeneous. In rare families, West syndrome is an X-linked
      recessive condition, mapped to Xp11.4-Xpter (MIM 308350). We have identified a
      multi-generation family from Western Canada with this rare syndrome of infantile
      spasms, seen exclusively in male offspring from asymptomatic mothers, thereby
      confirming segregation as an X-linked recessive trait. Using highly polymorphic
      microsatellite CA-repeat probes evenly distributed over the entire X chromosome,
      linkage to markers DXS7110, DXS989, DXS1202, and DXS7106 was confirmed, with a
      maximum LOD score of 3.97 at a theta of 0.0. The identification of key
      recombinants refined the disease-containing interval between markers DXS1226 and
      the adrenal hypoplasia locus (AHC). This now maps the X-linked infantile spasms
      gene locus to chromosome Xp21.3-Xp22.1 and refines the interval containing the
      candidate gene to 7.0 cM. Furthermore, this interval overlaps several loci
      previously linked with either syndromic or non-syndromic X-linked mental
      retardation (XLMR), including one recognized locus implicated in neuroaxonal
      processing (radixin, RDXP2). Collectively, these studies lend strong support for
      the presence of one or more genes intrinsic to brain development and function,
      occurring within the critical interval defined between Xp21.3-Xp22.1.

PMID- 10334470
TI  - Additive effect of three noradrenergic genes (ADRA2a, ADRA2C, DBH) on attention
      deficit hyperactivity disorder and learning disabilities in Tourette syndrome
      subjects.
AB  - Halperin et al. (Halperin JM. Newcorn JH, Koda VH, Pick L, McKay KE, Knott P.
      Noradrenergic mechanisms in ADHD children with and without reading disabilities:
      a replication and extension. J Am Acad Child Adolesc Psychiatry 1997: 36: 1688
      1696) reported a significant increase in plasma norepinephrine (NE) in attention
      deficit hyperactivity disorder (ADHD) children with reading and other cognitive
      disabilities compared to ADHD children without learning disabilities (LD). We
      examined the hypothesis that ADHD + LD was associated with NE dysfunction at a
      molecular genetic level by testing for associations and additive effects between
      polymorphisms at three noradrenergic genes the adrenergic alpha2A receptor
      (ADRA2A), adrenergic alpha2C receptor (ADRA2C), and dopamine beta-hydroxylase
      (DBH) genes. A total of 336 subjects consisting of 274 individuals with Tourette
      syndrome (TS) and 62 normal controls were genotyped. Regression analysis showed a
      significant correlation between scores for ADHD, a history of LD, and poor grade
      school academic performance that was greatest for the additive effect of all
      three genes. Combined, these three genes accounted for 3.5% of the variance of
      the ADHD score (p = 0.0005). There was a significant increase in the number of
      variant NE genes progressing from subjects without ADHD (A-) or learning
      disorders (LD-) to A + LD - to A - LD + to A + LD + (p = 0.0017), but no
      comparable effect for dopamine genes. These data support an association between
      NE genes and ADHD, especially in ADHD + LD subjects.

PMID- 10334472
TI  - Interpupillary distance in a normal black population.
AB  - This report expands on a study by Pryor [Pryor HB. Objective measurement of
      interpupillary distance. Pediatrics 1969: 44: 973 977] that related normal values
      of inner canthal distance (ICD), outer canthal distance (OCD) and interpupillary
      distance (IPD) for Whites, Asians and Mexican Americans. To date, no similar
      values have been reported for Blacks. Utilizing a sample (n = 931: 485 males; 446
      females) of black people (range, birth 24 years), OCD, ICD, and head
      circumference (HC) were measured and tabulated. We calculated mean IPD according
      to Pryor's formulation and report that the general mean OCD and ICD in our sample
      differed significantly from, and were consistently higher than, Pryor's reported
      measurements for White males and females at each age level (p < 0.001). However,
      ICD in our sample was significantly lower at birth in both sexes, appeared to
      increase at a more rapid rate relative to Whites during the first 3 months of
      life, and reached and maintained a higher value beyond the age of 3 months, with
      most age groups showing a significant difference in mean ICD measurements. At
      each age level, the mean IPD values in Whites and Blacks were significantly
      higher (p < 0.001). Based upon these findings, we suggest that interpupillary
      distance of Black children and adults be assessed according to the mean
      proportions for their race.

PMID- 10334473
TI  - Effect of vitamin E on chromosomal aberrations in lymphocytes from patients with
      Down's syndrome.
AB  - A possible protective effect of vitamin E (DL-alpha-tocopherol) on chromosomal
      damage was evaluated in lymphocytes from patients with Down's syndrome (DS) and
      from controls. This included the analysis of the basal and G2 chromosomal
      aberration frequencies in lymphocytes cultured with and without 100 microM
      vitamin E. The chromosomal damage in G2 was determined by scoring the number of
      chromosomal aberrations in lymphocyte cultures treated with 5 mM caffeine, 2 h
      before harvesting. Vitamin E treatment decreased the basal and G2 chromosomal
      aberrations both in control and DS lymphocytes. In DS cells, this protective
      effect, expressed as a decrease in the chromosomal damage, was greater (50%) than
      in controls (30%). These results suggest that the increment in basal and G2
      aberrations yield in DS lymphocytes may be related to the increase in oxidative
      damage reported in these patients.

PMID- 10334474
TI  - Accurate determination of the number of CAG repeats in the Huntington disease
      gene using a sequence-specific internal DNA standard.
AB  - We have developed a sequence-specific internal DNA size standard for the accurate
      determination of the number of CAG repeats in the Huntington disease (HD) gene by
      cloning key fragments (between 15 and 64 CAG repeats) of the HD gene. These
      fragments, pooled to produce a sequence-specific DNA ladder, enabled us to
      observe the true number of CAG repeats directly, with no need for calculations.
      Comparison of the calculated numbers of CAG repeats in the HD gene using this
      sequence-specific DNA standard with a commercially available standard (GENESCAN
      500 TAMRA) showed that the latter underestimated the number of CAG repeats by
      three when analyzed by capillary electrophoresis on the ABI 310 Genetic Analyzer
      (POP4 polymer). In contrast, the use of the same standard overestimated the
      number of CAG repeats by one when the samples were analyzed by denaturing
      polyacrylamide electrophoresis on ABI 377 DNA Sequencer (6% denaturing
      polyacrylamide gel). This suggests that our sequence-specific standard provides
      greater accuracy for the determination of the true number of CAG repeats in the
      HD gene than commercially available standards. The sequence-specific standard can
      be radioactively labeled and successfully replace conventional DNA size standards
      when analyzing polymerase chain reaction (PCR)-amplified HD alleles by denaturing
      polyacrylamide electrophoresis.

PMID- 10334475
TI  - An extra idic(21)(q22.1) in a child with some features of Down's syndrome.
AB  - A 30-month-old boy with mental retardation, hypotonia, joint hyperlaxity,
      Brushfield spots, open mouth, distal axial triradius t", and ulnar loops on both
      forefingers was found to have a 47,XY, + psu idic(21)(q22.1).ish psu
      idic(21)(q22.1)(D13Z1/D21Z1 + + ,ETS2-) karyotype. The patient's phenotype, with
      only some Down's syndrome (DS) features, is probably related to his disomy for
      most or all of the critical region 21q22.2 q22.3 and agrees with the current
      notion that certain DS features may also result from 21q proximal duplications.
      The phenotypical comparison with 2 other patients with a similar extra idic(21)
      reveals some discrepancies, which may be related to the inherent clinical
      variability of similar imbalances: yet, a real difference between the tetrasomic
      segments cannot be excluded. Noticeably, all 3 patients with 21q proximal
      tetrasomy did not have cardiac defect and exhibited none or just one out of the
      five other DS phenotypic features attributed to a single gene or cluster on
      distal 21q22.

PMID- 10334476
TI  - A brief review of cryptic duplications of 21q as an emerging cause of Down
      syndrome: practical considerations for accurate detection.
AB  - We review five cryptic duplications of 21q in patients with Down syndrome (DS)
      that were inherited from parental balanced translocations. All cases were
      identified by fluorescence in situ hybridization (FISH) and or DNA diagnosis
      because the phenotype was inconsistent with the initial cytogenetic studies.
      These rearrangements seem to escape detection without expanded testing and are
      probably more frequent than expected. For this reason we propose a series of
      steps combining objective clinical diagnostic criteria, FISH and DNA methods to
      achieve an accurate ascertainment.

PMID- 10334477
TI  - Rapid detection of polymorphisms in exons 10, 11 and 12 of the low density
      lipoprotein receptor gene (LDLR) and their use in a clinical genetic diagnostic
      setting.

PMID- 10334478
TI  - Mutations in the endothelin-receptor B gene in Hirschsprung disease in Sweden.

PMID- 10334479
TI  - Nebulin is normally expressed in nemaline myopathy.
AB  - Since the nebulin gene is located in the candidate gene locus of autosomal
      recessive nemaline myopathy, 2q21.2-q22, we examined five muscle biopsy specimens
      with monoclonal and polyclonal antibodies against nebulin in combination with the
      modified Gomori trichrome stain. We were able to demonstrate
      immunohistochemically that there was no abnormality in nebulin in the muscle
      fibers both with and without nemaline bodies. Although the molecular weight of
      nebulin was normal, it was slightly reduced in amount on immunoblotting.

PMID- 10334480
TI  - In vitro synaptotrophic effects of Cerebrolysin in NT2N cells.
AB  - Recent studies have shown that Cerebrolysin can enhance synaptic function and
      ameliorate synaptodendritic alterations in animal models of neurodegeneration,
      suggesting a synaptotrophic effect. We hypothesize that Cerebrolysin might exert
      this effect, in part, by regulating the expression of amyloid precursor protein
      (APP). We studied the patterns of expression of synaptic proteins during
      differentiation of human teratocarcinoma cell line NTera 2 (NT2) in the presence
      or absence of Cerebrolysin. This study showed that the terminally differentiated
      neurons (NT2N) expressed a wide variety of synaptic markers and that expression
      of these synaptic-associated proteins coincided with the shift in expression from
      APP770/751 to APP695. Furthermore, APP immunoreactivity was colocalized with
      synaptophysin-immunoreactive neuritic varicosities in NT2N neurites, and
      Cerebrolysin treatment of NT2N cells resulted in an augmented and earlier
      expression of synaptic-associated proteins. This increased synaptic protein
      expression coincided with an increase in APP695 over APP770/751. These results
      support the possibility that synaptotrophic effects of Cerebrolysin might be
      mediated via regulation of APP expression.

PMID- 10334481
TI  - Expression of transforming growth factor-beta1, 2, 3 isoforms and type I and II
      receptors in acute focal cerebral ischemia: an immunohistochemical study in rat
      after transient and permanent occlusion of middle cerebral artery.
AB  - Transforming growth factor beta (TGF-beta) is involved in the modulation of cell
      growth, differentiation and repair following injury of various organs. Previous
      studies on human autopsy material have indicated that TGF-beta isoforms-beta1, 
      beta2 and -beta3, and TGF-beta receptor type I are expressed in various cells of
      necrotizing brain lesions like infarction and abscess. The present
      immunohistochemical study was designed to investigate changes that may occur with
      regard to TGF-beta and its receptors type I and II in a rat model of focal brain
      ischemia induced by transient or permanent occlusion of the middle cerebral
      artery. Our findings indicate that at days 1 and 3 following such transient and
      permanent ischemia there is an up-regulation of TGF-beta isoforms -beta1, -beta2
      and -beta3, and TGF-beta receptor types I and II mainly in the perifocal neurons,
      reactive astroglial cells, endothelial cells and macrophages.

PMID- 10334482
TI  - Quantification of pathological lesions in the frontal and temporal lobe of ten
      patients diagnosed with Pick's disease.
AB  - The densities of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and
      neurofibrillary tangles (NFT) in the frontal and temporal lobe were determined in
      ten patients diagnosed with Pick's disease (PD). The density of PB was
      significantly higher in the dentate gyrus granule cells compared with the cortex
      and the CA sectors of the hippocampus. Within the hippocampus, the highest
      densities of PB were observed in sector CA1. PC were absent in the dentate gyrus
      and no significant differences in PC density were observed in the remaining brain
      regions. With the exception of two patients, the densities of SP and NFT were low
      with no significant differences in mean densities between cortical regions. In
      the hippocampus, the density of NFT was greatest in sector CA1. PB and PC
      densities were positively correlated in the frontal cortex but no correlations
      were observed between the PD and AD lesions. A principal components analysis
      (PCA) of the neuropathological variables suggested that variations in the
      densities of SP in the frontal cortex, temporal cortex and hippocampus were the
      most important sources of heterogeneity within the patient group. Variations in
      the densities of PB and NFT in the temporal cortex and hippocampus were of
      secondary importance. In addition, the PCA suggested that two of the ten patients
      were atypical. One patient had a higher than average density of SP and one
      familial patient had a higher density of NFT but few SP.

PMID- 10334483
TI  - Immunoreactivity of beta-amyloid precursor protein in amyotrophic lateral
      sclerosis.
AB  - We investigated the localization and extent of beta-amyloid precursor protein
      (beta-APP695) immunoreactivity as a sensitive marker for impairment of fast
      axonal transport in the spinal cords of 21 patients with amyotrophic lateral
      sclerosis (ALS), paying special attention to anterior horn neurons. Specimens
      from 18 patients without neurological disease served as controls. Increased beta
      APP immunoreactivity was frequently recognized in the anterior horns of the ALS
      patients with short clinical courses or with mild depletion of anterior horn
      cells, while no beta-APP immunoreactivity was demonstrated in those with severe
      depletion of anterior horn neurons or with long-standing clinical courses.
      Increased beta-APP immunoreactivity in the anterior horn neurons was mainly
      confined to the perikarya and no immunoreactivity was recognized in the dendrites
      or proximal axons directly emanating from the somata, except some spheroids
      (proximal axonal swellings) which showed increased immunoreactivity of beta-APP.
      Increased beta-APP immunoreactivity was spotted or focally aggregated in the
      perikarya of normal-looking large anterior horn neurons, while it was frequently
      diffuse in that of degenerative neurons such as central chromatolytic cells and
      or those with simple atrophy. On the other hand, the controls showed no
      immunostaining with beta-APP in the spinal cord. These findings suggest that
      increased immunoreactivity of beta-APP in neuronal perikarya of the anterior horn
      cells and in some proximal axonal swellings is an early change of ALS, and may be
      a response of the increased synthesis of beta-APP resulting from neuronal damage,
      or the impairment of fast axonal transport.

PMID- 10334484
TI  - Increased density of oligodendrocytes in childhood ataxia with diffuse central
      hypomyelination (CACH) syndrome: neuropathological and biochemical study of two
      cases.
AB  - We report neuropathological, biochemical and molecular studies on two patients
      with childhood ataxia with diffuse central nervous system hypomyelination (CACH)
      syndrome, a leukodystrophy recently defined according to clinical and
      radiological criteria. Both had severe cavitating orthochromatic leukodystrophy
      without atrophy, predominating in hemispheric white matter, whereas U-fibers,
      internal capsule, corpus callosum, anterior commissure and cerebellar white
      matter were relatively spared. The severity of white matter lesions contrasted
      with the rarity of myelin breakdown products and astroglial and microglial
      reactions. In the white matter, there was an increase in a homogeneous cell
      population with the morphological features of oligodendrocytes, in many instances
      presenting an abundant cytoplasm like myelination glia. These cells were negative
      for glial fibrillary acidic protein and antibodies PGM1 and MIB1. Some were
      positive for myelin basic protein, proteolipid protein (PLP), and myelin
      oligodendrocyte glycoprotein, but the majority were positive for human 2'-3'
      cyclic nucleotide 3' phosphodiesterase and all were positive for carbonic
      anhydrase II, confirming that they are oligodendrocytes. Myelin protein and lipid
      content were reduced. The PLP gene, analyzed in one case, was not mutated or
      duplicated. The increased number of oligodendrocytes without mitotic activity
      suggests an intrinsic oligodendroglial defect or an abnormal interaction with
      axons or other glial cells. This neuropathological study supports the notion that
      CACH syndrome constitutes a specific entity.

PMID- 10334485
TI  - The CD34 epitope is expressed in neoplastic and malformative lesions associated
      with chronic, focal epilepsies.
AB  - The etiology and pathogenesis of complex focal lesions associated with chronic,
      intractable epilepsy are largely unknown. Some data indicate that malformative
      changes of the central nervous system may precede the development of
      gangliogliomas and other epilepsy-associated neoplasms. In the present
      immunhistochemical study, we have examined epilepsy-associated lesions for CD34,
      a stem cell marker transiently expressed during early neurulation. Surprisingly,
      most tissue samples from patients with chronic epilepsy (n = 262) revealed neural
      cells immunoreactive for CD34. Prominent immunoreactivity was detected in
      gangliogliomas (74%), low-grade astrocytomas (62%) and oligodendrogliomas (59%).
      Only 52% of non-neoplastic, malformative pathologies, such as glio-neuronal
      hamartias or hamartomas showed solitary or small clusters of CD34-immunoreactive
      cells. None of the adult control tissues (n = 22), none of the specimens obtained
      from the developing human brain (n = 44) and none of those tumor samples from
      patients without epilepsy (n = 63) contained CD34-immunoreactive neural cells.
      However, a malignant teratoma with microscopic features of early neural
      differentiation displayed a focal CD34-immunoreactive staining pattern. The
      majority of CD34-immunoreactive cells co-localized with S-100 protein and a small
      subpopulation was also immunoreactive for neuronal antigens. CD34 may, thus,
      represent a valuable marker for the diagnostic evaluation of neoplastic and/or
      malformative pathological changes in epilepsy patients. The CD34 immunoreactivity
      of these lesions indicates an origin from dysplastic or atypically differentiated
      neural precursors. Further studies may elucidate the functional significance of
      CD34 expression during the pathogenesis of epilepsy-related focal lesions as well
      as during neurogenesis.

PMID- 10334486
TI  - Is traumatic axonal injury (AI) associated with an early microglial activation?
      Application of a double-labeling technique for simultaneous detection of
      microglia and AI.
AB  - The aim of the present study was to determine whether axonal injury (AI) induces
      a microglial reaction within 15 days after brain trauma. In 40 selected cases of
      confirmed AI, the topographical relation of AI and microglial reaction was
      assessed using an immunohistochemical double-labeling technique for simultaneous
      demonstration of AI using beta-amyloid precursor protein (beta-APP) antibody and
      of microglia using CD68 antibody. Although traumatic injury was usually followed
      by a moderate early diffuse rise in the number of CD68-reactive cells in the
      white matter, increases in macrophages in areas of AI accumulation were only
      sporadic and did not occur until after 4 days. At survival intervals of 5-15 days
      a moderate microglial reaction in regions of beta-APP-positive injured axons was
      detected, at maximum, in half of the case material. During this interval AI
      associated satellitosis-like clusters or stars described by other authors after a
      survival time of more than 7 weeks were an isolated phenomenon. The prolonged
      microglial reaction as well as the reduction of beta-APP-positive AI during
      longer survival periods supports the hypothesis that AI is not primarily
      chemotactically attractive and that the damage to a portion of beta-APPstained
      axons may be partly reversible. Most cases clearly require a prolonged interval
      of more than 15 days before initiation of the final scavenger reaction. For
      forensic purposes the increase in the number of microglial cells within the
      region of AI accumulation after a survival time of more than 5 days and the
      multiple and distinct demonstration of star-like microglial reactions within the
      white matter after survival times exceeding 7 weeks may provide valuable
      postmortem information on the timing of a traumatic event.

PMID- 10334487
TI  - The effect of rapid preconditioning on the microglial, astrocytic and neuronal
      consequences of global cerebral ischemia.
AB  - Previous studies indicated preconditioning of the brain with sublethal ischemic
      insults separated by many hours, protected tissues from a subsequent lethal
      insult. We recently reported neuroprotection by a rapid preconditioning paradigm
      where a sublethal ischemic insult preceded test ischemia by only 30 min. We
      hypothesize that neuroprotection caused by the rapid ischemic preconditioning
      (IPC) will result in lowered microglial, reactive astrocytes and increased normal
      neuronal cell counts. Wistar rats underwent normothermic (36.5-37 degrees C)
      global cerebral ischemia, produced by bilateral carotid artery ligation after
      lowering mean systemic blood pressure. The preconditioning ischemic insult lasted
      2 min and was associated with a sufficient amount of time to provoke anoxic
      depolarization. After a 30-min reperfusion period, 10-min test ischemia was
      produced, and histopathology was assessed 3 and 7 days later. Normal neuronal
      cell counts for control rats at 3 days survival were significantly lower (by 58%)
      than in IPC animals. Although there was a trend toward protection in IPC rats at
      7 days, the difference in normal neuronal cell count between the IPC and control
      groups was not significant. IPC rats at 3 days but not 7 days of survival showed
      a significantly lower microglial cell count (by 56%) than control rats. These
      results showed that the protection induced through IPC at 3 days of survival
      produced lower numbers of microglia, while maintaining normal neuronal cells. No
      significant differences between control and IPC groups were found in astrocytic
      cell count at any time of reperfusion in any region of the hippocampus studied.
      The beneficial effects of IPC may, therefore, involve anti-inflammatory processes
      that target microglial activation after cerebral ischemia.

PMID- 10334488
TI  - The neuropathology of intestinal failure and small bowel transplantation.
AB  - The aim of this study was to elucidate the neuropathological substrate of
      intestinal failure before and after small bowel transplantation (SBT).
      Retrospective analysis of complete autopsy or brain biopsy specimens of 17
      patients with intestinal failure (12 children and 5 adults) were studied.
      Patients were divided into two groups. Group I (transplanted group; n = 13)
      included those patients who underwent intestinal transplantation under tacrolimus
      and steroids immunosuppressive therapy. Group II (control group) included 4
      children with intestinal failure who were candidates for SBT and died while
      awaiting an intestinal allograft. Central nervous system (CNS) abnormalities were
      seen in 92% of the SBT recipients and in 100% of SBT candidates. The
      neuropathological lesions of SBT recipients included: (a) vascular lesions:
      global brain ischemia, infarcts, intracranial hemorrhage and edema (7 children/2
      adults; 69%); (b) cerebral atrophy (6 children; 46%); (c) Alzheimer type II
      gliosis (5 children/4 adults; 69%); (d) infection (3 patients; 23%) due to
      cytomegalovirus (1 child), Aspergillus fumigatus (1 adult) and progressive
      multifocal leukoencephalopathy (PML)-like (1 adult); (e) Epstein-Barr virus
      related cerebral post-transplant lymphoproliferative disorder (2 children; 15%);
      and (f) central pontine and extrapontine myelinolysis (1 child; 7.5%). The
      neuropathological lesions of SBT candidates were Alzheimer type II astrocytosis
      (4 patients), vascular changes (4 patients), brain atrophy (4 patients) and
      cerebral candidiasis (1 patient). CNS vascular, metabolic and infectious
      pathology are significant causes of morbidity and mortality in patients suffering
      intestinal failure, both before and after SBT. Brain atrophy was a frequent
      finding and may be related to nutritional and developmental inadequacy of long
      term total parenteral nutrition.

PMID- 10334489
TI  - Familial inclusion body myopathy with desmin storage.
AB  - We report two adult familial cases of inclusion body myopathy (IBM) with desmin
      storage in skeletal muscle. Clinically, both patients presented late-onset,
      progressive, symmetrical, both proximal and distal muscle weakness. Muscle biopsy
      findings were identical in both cases and consisted of marked variability in
      fiber size, increased number of central nuclei and vacuolation involving 10% of
      fibers. Single or multiple vacuoles were located subsarcolemmally or in the
      center, and were rimmed by basophilic material. At the ultrastructural level,
      tubulofilamentous nuclear and cytoplasmic inclusions of 16-21 nm in diameter were
      frequently observed. In addition, large subsarcolemmal and central deposits
      composed of electron-dense granular material were present in many fibers.
      Immunocytochemistry revealed staining for desmin, vimentin and ubiquitin within
      both inclusions and vacuolated fibers. Possible structural and functional
      associations between these two types of muscle changes remain unclear. They may
      either represent two coexistent disease processes or merely reflect an abnormal
      form of muscle fiber degradation, with unidentifiable specificity.

PMID- 10334490
TI  - Changes in the cytoskeletal proteins, sarcoplasmic reticulum, and capillaries in
      acute relaxant-steroid myopathy (ARSM) in contrast to the corticosteroid
      myopathy.
AB  - Since we reported a case of acute relaxant-steroid myopathy (ARSM) in 1994, we
      continued histological studies and compared the findings with those in a case of
      corticosteroid myopathy (CM). It was revealed that (1) dystrophin, spectrin, beta
      dystroglycan, and sarcoglycans on the cell surface were decreased, (2) regular
      arrangement of the sarcoplasmic reticulum was lost, and (3) some capillaries were
      degenerated. Since none of these changes were seen in CM, it became clear that
      ARSM is different from CM. It was estimated that continuous administration of non
      depolarizing muscle relaxant produces a state akin to denervation. Combination of
      denervation, immobilization and circulatory disturbance in ARSM not only augments
      the effects of corticosteroids, but they produce changes different from CM,
      namely impairment of the cell membrane system (both internal and external) and
      capillary degeneration.

PMID- 10334491
TI  - MELAS with prominent white matter gliosis and atrophy of the cerebellar granular
      layer: a clinical, genetic, and pathological study.
AB  - This report concerns an autopsy case of mitochondrial myopathy, encephalopathy,
      lactic acidosis, and stroke-like episodes (MELAS) with unusual neuropathological
      findings. The patient was a Japanese woman who was 21 years old at the time of
      death. Her mother is a patient with genetically confirmed MELAS. Her clinical
      manifestations included convulsions and lactic acidosis in the latter half of the
      first decade of life, followed by deafness, dementia, muscle weakness in the
      lower extremities, slight ataxia in the upper and lower extremities, and diabetes
      mellitus. Muscle biopsy revealed ragged-red fibers, and genetic study showed a
      point mutation at nucleotide pair 3243 in mitochondrial DNA. She died of lactic
      acidosis. In the clinical course, she did not develop stroke-like episodes. The
      neuropathological examination revealed not only minute to small necrotic foci in
      the cerebral cortex, amygdala, hippocampus, and cerebellum, but also prominent
      white matter gliosis in the central nervous system and cerebellar cortical
      degeneration of granular cell type. Our neuropathological findings, including
      prominent white matter gliosis of the central nervous system and cerebellar
      cortical degeneration of granular cell type, may indicate morphologically
      widespread cellular dysfunction, not restricted to either neuronal or vascular
      derangement, in the brain pathology of MELAS.

PMID- 10334492
TI  - A case history of glioma progression.
AB  - Low-grade diffuse astrocytomas have an intrinsic tendency for malignant
      progression but the factors determining the kinetics of this process are still
      poorly understood. We report here the case of a male patient who developed a
      fibrillary astrocytoma at the age of 33 years and who underwent six surgical
      interventions over a period of 17 years without radiotherapy or chemotherapy. The
      first three biopsies spanned a period of 11 years and led to the diagnosis of low
      grade, diffuse astrocytoma (WHO grade II), with a growth fraction (MIB-1 labeling
      index) of 2.3-3.7%. The fourth to sixth biopsies showed histological features of
      anaplastic astrocytoma (WHO grade III), with growth fractions between 5.0 and
      10.5%. The fraction of gemistocytic neoplastic astrocytes also increased, from
      0.3% in the first biopsy to 17.5% in the last biopsy and preceded the increase in
      proliferative activity and transition to anaplastic astrocytoma. The fraction of
      tumor cells immunoreactive to BCL-2 increased from 0.3% to 8.2%. A p53 mutation
      in codon 273 (CGT-->TGT, Arg-->Cys) was identified in the first biopsy and
      persisted throughout the course of the disease. However, the fraction of cells
      with p53 protein accumulation increased significantly during progression, from
      3.2% in the first biopsy to 13.7% in the last. The absence of additional genetic
      alterations (PTEN mutations, loss of chromosome 10 and 19q) may be responsible
      for the slow progression and lack of glioblastoma features even after a 17-year
      disease duration.

PMID- 10334493
TI  - Numerous and widespread alpha-synuclein-negative Lewy bodies in an asymptomatic
      patient.
AB  - Lewy bodies (LB) and pale bodies (PB), their putative precursors, can be found in
      a spectrum of diseases characterized by parkinsonism and/or dementia.
      Furthermore, LB are occasionally observed in some other neurodegenerative
      diseases and in normal aging. Classical LB are typically found in the brain stem,
      especially in the substantia nigra, where these inclusions are associated with
      neuronal loss and clinical signs of idiopathic Parkinson's disease (PD). The so
      called cortical LB occur in the cerebral cortex, amygdala and claustrum with
      little or no neuronal loss and are clinically associated with dementia in
      dementia with LB (DLB). We describe a patient without apparent clinical signs of
      parkinsonism and/or dementia, whose brain contained numerous classical-like LB,
      pale inclusions with features of PB and transitions between these two. These
      inclusions had similar immunohistological (ubiquitin positive; neurofilament
      positive; tau negative) and ultrastructural features as the LB in PD and DLB
      except for the lack of immunoreactivity for alpha-synuclein. The pons and
      cerebral cortex showed the highest number of LB, up to 165/1.76 mm2. These
      numbers were contrasted by the lack of obvious neuronal loss or gliosis. The
      absence of alpha-synuclein reactivity in the LB in this symptomless patient
      corroborates the hypothesis that alpha-synuclein accumulation in LB is an
      important step in neurodegeneration in PD and DLB, but tones down the role of
      alpha-synuclein in LB formation in general. This patient seems to represent a new
      variant in the spectrum of diseases associated with LB.

PMID- 10334494
TI  - Concerning report by Nagao et al.

PMID- 10334495
TI  - 5-HT receptor ligands differentially affect operant oral self-administration of
      ethanol in the rat.
AB  - The present study evaluated the effects of the selective serotonin (5
      hydroxyhyptamine; 5-HT) reuptake inhibitor, fluoxetine, the 5-HT1B receptor
      agonist, tetrahydro-4-pyridyl[3,2-b]pyridine, CP-94,253 the preferential 5-HT2A
      receptor agonist, 1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane, DOI and the
      mixed 5-HT2C/1B receptor agonist, 1-(3-chlorophenyl)piperazine, mCPP, on oral
      ethanol (10% v/v) self-administration in a two-lever, fixed-ratio:1, water vs.
      ethanol choice procedure in the rat. All compounds affected operant behavior,
      with varying degrees of specificity, that is, the extent to which a reduction of
      ethanol-reinforced lever pressing coincided with a reduction of ethanol
      preference, and selectivity, that is, the extent to which a reduction of ethanol
      reinforced lever pressing could be dissociated from an effect on total responding
      on both levers. Fluoxetine (5-20 mg/kg, i.p.) and CP-94,253 (1-10 mg/kg, i.p.)
      induced a nonselective disruption of operant behavior; the profile being weakly
      specific for CP-94,253. DOI (0.1-0.3 mg/kg, i.p.) and mCPP (0.3-1 mg/kg, i.p.)
      induced a specific effect; the profile being more selective for DOI. These
      findings suggest that operant ethanol self-administration can be suppressed in a
      specific manner by activation of 5-HT2A and, possibly, 5-HT2C receptors, and in a
      nonselective manner by activation of 5-HT1B receptors. As fluoxetine indirectly
      stimulates these receptors and its behavioral profile resembles more that of a 5
      HT1B receptor agonist, activation of 5-HT1B receptors may underlie its effects on
      operant ethanol self-administration.

PMID- 10334496
TI  - Two novel sigma receptor ligands, BD1047 and LR172, attenuate cocaine-induced
      toxicity and locomotor activity.
AB  - The ability of cocaine to interact with sigma receptors indicates that these
      sites may mediate the negative properties associated with cocaine use, such as
      toxicity and addiction. Previous studies have shown that the novel sigma receptor
      ligand, BD1008 (N-[2-(3,4-dicholophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylam
      ine), effectively protects against cocaine-induced convulsions and locomotor
      activity in mice. Therefore, BD1047 ([2-(3,4-dichlorophenyl)ethyl]-N-methyl-2
      (diamino)ethylamine) and LR172 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1
      homopiperidinyl)eth ylamine), two analogs of BD1008, were tested to determine if
      they also have anti-cocaine properties. Receptor binding assays showed that
      BD1047 and LR172 both have high affinities for a receptors, but low to negligible
      affinities for dopamine, opioid, phencyclidine, and 5-HT2 sites. In behavioral
      studies, pretreatment of mice with BD1047 or LR172 reduced the convulsions,
      lethality, and locomotor activity produced by cocaine. The data indicates a
      possible role for sigma receptor ligands in the treatment of cocaine overdose and
      addiction.

PMID- 10334497
TI  - Increased motivation for beer in rats following administration of a cannabinoid
      CB1 receptor agonist.
AB  - A series of experiments examined the effects of the cannabinoid CB1 receptor
      agonist CP 55,940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3
      hyd roxypropyl)cyclohexanol) on the motivation to consume beer, near-beer (a beer
      like beverage containing <0.5% ethanol) and sucrose solutions in rats. The
      experiments employed a 'lick-based progressive ratio paradigm' in which an ever
      increasing number of licks had to be emitted at a tube for each successive fixed
      unit of beverage delivered. Break point, the lick requirement at which responding
      ceased, was used as an index of motivation. In the first experiment, CP 55,940
      (10, 30 or 50 microg/kg) caused a dose-dependent increase in break points for
      beer (containing 4.5% ethanol v/v) and for near-beer. The highest (50 microg/kg)
      dose of CP 55,940 also significantly decreased locomotor activity. In the second
      experiment, CP 55,940 (10 or 30 microg/kg) dose-dependently increased break
      points in rats licking for 'light' beer (containing 2.7% ethanol v/v) or for a
      sucrose solution (8.6% w/v) containing the same number of calories as the beer.
      In the third experiment, the facilitatory effects of CP 55,940 (30 microg/kg) on
      responding for beer and near-beer were reversed by both the cannabinoid CB1
      receptor antagonist SR 141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4
      dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride) (1.5 mg/kg)
      and the opioid receptor antagonist naloxone (2.5 mg/kg). Naloxone had a
      proportionally greater effect on rats licking for beer compared to near-beer,
      consistent with previous reports of opioid receptor mediation of alcohol craving.
      These results show that cannabinoids modulate the motivation for beer via both
      cannabinoid CB1 receptors and opioid receptors. The similar effect of CP 55,940
      on the motivation for beer, near-beer and sucrose suggests that the drug effect
      may reflect a general stimulatory effect on appetite for palatable beverages,
      although a more specific effect on the desire for alcohol cannot be ruled out.

PMID- 10334499
TI  - AMPA/kainate-related mechanisms contribute to convulsant and proconvulsant
      effects of 3-nitropropionic acid.
AB  - The role of the glutamatergic system in the convulsant and proconvulsant action
      of a mitochondrial toxin, 3-nitropropionic acid, was studied in mice. The
      occurrence of 3-nitropropionic acid-induced seizures was inhibited by the alpha
      amino-2,3-dihydro-5-methyl-3-oxo-isoxazole-propionate (AMPA)/kainate receptor
      antagonists, 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione disodium (NBQX)
      and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine HCI (GYKI
      52466), with ED50 of 14.1 (7.9-25.2) and 7.2 (5.3-9.6) mg/kg, respectively. The N
      methyl-D-aspartate (NMDA) receptor antagonists, dizocilpine (MK-801) and 3-(2
      carboxypiperazine-4-yl)propenyl-1-phosphonic acid (CPPene), were ineffective.
      Moreover, 3-nitropropionic acid given in a subthreshold dose potently enhanced
      seizures generated by intracerebroventricular administration of AMPA and kainate,
      lowering their CD50 from 0.98 (0.83-1.17) and 0.73 (0.64-0.83) to 0.55 (0.45
      0.66) (P<0.001) and 0.58 (0.51-0.65) (P<0.05) nmol, respectively. In contrast,
      NMDA action was not changed by 3-nitropropionic acid application. We conclude
      that AMPA/kainate-mediated events are involved in proconvulsive and convulsive
      effects of 3-nitropropionic acid.

PMID- 10334498
TI  - Chronic haloperidol alters dopamine receptors: effects of cocaine exposure during
      the preweaning period.
AB  - The effect of cocaine exposure during the preweaning period on the function of
      the central dopaminergic systems was determined in adult rats. The present study
      investigated the alterations in dopamine receptors in 93-day-old male and female
      rats treated with cocaine (50 mg kg(-1) day(-1)), 1-[2-[bis(4
      fluorophenyl)methoxyl]-4-[3-phenylpropyl]piperazine (GBR 12909) (50 mg kg(-1)
      every other day) or water during postnatal days 11-20. Haloperidol (2 mg kg(-1)
      day) or saline was injected during postnatal days 76-90 and the rats were killed
      on postnatal day 93. Quantitative receptor autoradiography with [3H]R-(+)-7
      chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-b enzazepine ([3H]SCH
      23390) for the dopamine D1 receptor and [3H]raclopride for the dopamine D2
      receptor was carried out. The results show that haloperidol increased
      [3H]raclopride binding in many forebrain regions. Preweaning cocaine treatment in
      males increased the area showing this effect. Males generally were more
      responsive to haloperidol than females. However, in GBR 12909-treated females,
      raclopride binding showed widespread increases following haloperidol injection.
      For SCH 23390 binding, most regions showed a significant interaction between
      haloperidol, sex and preweaning treatment group. This was due primarily to the
      GBR 12909-treated males, which showed elevated basal dopamine D1 receptor binding
      levels and a haloperidol-induced reduction in dopamine D1 receptor binding in
      most regions evaluated. These data suggest that inhibition of the dopamine
      transporter during ontogeny produces long-term alterations in dopamine receptor
      regulation but that selective inhibitors of the dopamine transporter produced
      greater effects than cocaine on both raclopride and SCH 23390 binding following
      chronic haloperidol injection.

PMID- 10334500
TI  - The effect of acute administration of risperidone on local cerebral glucose
      utilization in the rat.
AB  - Risperidone (R 64 766, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1
      pyperidinyl]ethyl )-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one)
      has superior effects in treating negative symptoms of schizophrenia and causes
      less extrapyramidal side effects than traditional antipsychotics. In this study,
      we employed the [14C]2-deoxy-D-glucose method to map local cerebral metabolic
      activity of rats acutely administrated i.p. with 0.0, 0.1, 0.5, 1.0 and 2.0 mg
      kg(-1) risperidone. Risperidone in the highest dose produced a reduction of
      glucose utilization in 11 of the 38 regions examined. The results showed that the
      regions with metabolic change are somewhat different from those results studied
      with microdialysis and the Fos immunohistochemistry. Among the nuclei with
      metabolic changes, the hippocampus and the mediodorsal nucleus of the thalamus
      may be related to the therapeutic action of risperidone and require further
      study.

PMID- 10334501
TI  - The effects of perhexiline on the rat coronary vasculature.
AB  - The predominant site and mechanism(s) of perhexiline-induced coronary
      vasodilatation were investigated in the rat heart. Perhexiline was more potent in
      the Langendorff perfused heart than in the left anterior descending coronary
      artery (EC50; 0.27 microM, confidence limits 0.19-0.39: 2.7 microM, 2.0-3.4,
      respectively). Selective endothelial inactivation with Triton X-100 in the
      perfused heart, reduced the response to perhexiline 1 microM (76+8% to 30+3% of
      control). 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) 3 microM, Nomega
      nitro-L-arginine 100 microM, or a combination of the latter with indomethacin 10
      microM, had no significant effect on responses to perhexiline in the perfused
      heart. Unlike bradykinin-induced vasodilatation, responses to perhexiline were
      not inhibited by tetrabutylammonium 1 mM, or charybdotoxin 20 nM. SKF525A 5
      microM inhibited both perhexiline and bradykinin responses, while apamin 1 microM
      and glibenclamide 3 microM inhibited neither. Perhexiline exerts partially
      endothelium-dependent coronary vasodilator effects in the rat, predominantly on
      small coronary arteries, which appear to be independent of nitric oxide (NO),
      prostacyclin and the endothelium-derived hyperpolarising factor (EDHF) released
      by bradykinin.

PMID- 10334502
TI  - Effect of glucocorticoids on renal dopamine production.
AB  - This study assess the effects of glucocorticoids on dopamine excretion and
      evaluates the participation of renal dopamine in the effects of glucocorticoids
      on renal function and Na+ excretion. Dexamethasone (i.m.; 0.5 mg/kg) was
      administered to male Wistar rats on day 2 or on days 2 and 5. Daily urinary
      excretions of Na+, dihydroxyphenylalanine (DOPA), dopamine and
      dihydroxyphenylacetic acid were determined from day 1 to day 7. Renal function
      was evaluated 8 h after dexamethasone administration in a separate group. The
      first dose of dexamethasone increased about 100% diuresis and natriuresis,
      increased urinary DOPA and renal plasma flow, and did not affect urinary dopamine
      or the other parameters evaluated. These effects were not affected by previous
      administration of haloperidol. The second dexamethasone dose increased about 200%
      diuresis and natriuresis, increased urinary dopamine, DOPA, dihydroxyphenylacetic
      acid, Uosm x V and both glomerular filtration rate and renal plasma flow.
      Carbidopa administered before the second dexamethasone dose blunted both the
      diuretic and the natriuretic response whereas haloperidol abolished or blunted
      all the effects of the second dexamethasone dose. These results show that
      modifications in renal dopamine production produced by corticoids may contribute
      to the effects of these hormones on Na+ balance and diuresis and suggest that
      regardless the factor that promotes an increase in renal perfusion and glomerular
      filtration rate during long term administration of glucocorticoids, a
      dopaminergic mechanism is actively involved in the maintenance of these
      hemodynamic changes.

PMID- 10334504
TI  - N(G)-nitro-L-arginine methylester is protective against ethanol-induced gastric
      damage in cholestatic rats.
AB  - In this study the effect of nitric oxide (NO) synthesis inhibition on ethanol
      induced gastric damage was evaluated in bile duct-ligated, sham-operated and
      unoperated rats. The animals were injected intraperitoneally with saline, L
      arginine (200 mg/kg) or N(G)-nitro-L-arginine methylester (L-NAME) in doses of 5,
      15 and 30 mg/kg, 30 min before ethanol administration. The animals were killed 1
      h after ethanol administration and their stomachs were removed for measurement of
      gastric mucosal damage. The results showed that L-NAME significantly enhanced the
      development of gastric mucosal lesions in sham-operated and unoperated rats,
      while in bile duct-ligated animals, L-NAME decreased and L-arginine enhanced the
      potentiation of ethanol-induced gastric mucosal damage. The plasma level of
      nitrite and nitrate was also measured and was significantly higher in bile duct
      ligated rats than in control groups. The results suggest that inhibition of NO
      synthase with L-NAME has different effects on ethanol-induced gastric damage in
      cholestatic groups and in normal rats and that these effects can be explained by
      overproduction of NO in bile duct-ligated animals.

PMID- 10334503
TI  - Lack of anticholinergic effect of N(G)-nitro-L-arginine methylester in the small
      intestine.
AB  - The nitric oxide (NO)-synthase inhibitor, N(G)-nitro-L-arginine methylester (L
      NAME), has been reported to have an atropine-like action. We compared the effects
      of L-NAME (1 mM) and atropine on isolated small intestinal preparations of the
      guinea-pig, rat, rabbit and mouse. Half-maximal longitudinal contractions in
      response to acetylcholine (50-100 nM) were not influenced by L-NAME, but were
      strongly suppressed by atropine (1 nM). Cholinergic 'twitch' contractions of the
      guinea-pig ileum were slightly enhanced by L-NAME; this effect was prevented by
      pretreatment with N(G)-nitro-L-arginine (L-NOARG, 100 microM), another NO
      synthase inhibitor. 'Twitch' contractions were concentration dependently
      inhibited by atropine (1-100 nM). We conclude that L-NAME is free of atropine
      like activity in isolated intestinal preparations.

PMID- 10334505
TI  - Effects of U-69,593, a kappa-opioid receptor agonist, on carrageenin-induced
      peripheral oedema and Fos expression in the rat spinal cord.
AB  - In an attempt to study the anti-inflammatory and the antinociceptive effects of a
      kappa1-opioid receptor agonist (U-69,593: trans-3,4-dichloro-N-methyl-N-[7-(1
      pyrrolidinyl)cycloexil]benzene acetamide methanesulfonate), we used a combination
      of the measurement of peripheral oedema (with a calliper) and Fos immunodetection
      in the carrageenin model of inflammation. The intraplantar injection of
      carrageenin-induced the development of a peripheral oedema, associated with an
      increase in Fos-like immunoreactivity at the level of the dorsal horn of the
      spinal cord. U-69,593 administered intravenously (i.v.) 10 min before carrageenin
      administration over the dose range 0.75, 1.5 and 3 mg/kg, reduced both paw and
      ankle oedema in a non dose-dependent manner. The maximal decrease was observed at
      the highest dose and did not exceed 21% and 20% for the paw and the ankle
      respectively. These effects were kappa-opioid receptor specific since the anti
      inflammatory effect of 1.5 mg/kg i.v. of U-69,593 was antagonised by a specific
      kappa-opioid receptor antagonist nor-binaltorphimine. Pre-treatment with U-69,593
      strongly decreased the number of Fos-like Immunoreactive neurones of the spinal
      cord in a dose-dependent, antagonist reversible manner; maximal effect was 65%.
      The disparate results between the anti-inflammatory effects and the depressive
      effects on Fos expression suggest that anti-inflammatory effects of kappa-opioid
      receptor agonist are of minor importance for the antinociceptive effects of this
      compound.

PMID- 10334507
TI  - Enzymatic inactivation of major circulating forms of atrial and brain natriuretic
      peptides.
AB  - We compared the enzymatic inactivation of major circulating forms of atrial
      natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Both ANP and BNP
      induced a significant increase in cyclic GMP (cGMP) formation in cultured
      epithelial cell line derived from porcine kidney, LLC-PK1. The cGMP formation
      stimulated by ANP in LLC-PK1 cells was significantly decreased by pre-treatment
      of the peptide with rat renal brush-border membranes, and the inactivation of ANP
      was inhibited by neutral endopeptidase inhibitors, phosphoramidon and S
      thiorphan. BNP exhibited greater resistance to enzymatic inactivation than did
      ANP. In addition, phosphoramidon potentiated the natriuresis with a low dose (7.5
      pmol min(-1) kg(-1)) of ANP but not of BNP in rats. These results suggest that
      enzymatic degradation of natriuretic peptides is highly dependent on peptide
      structure, and that the affinity of BNP to neutral endopeptidase is less than
      that of ANP.

PMID- 10334506
TI  - Esculetin suppresses proteoglycan metabolism by inhibiting the production of
      matrix metalloproteinases in rabbit chondrocytes.
AB  - The possible mechanism of the chondroprotective effect of 6,7-dihydroxycoumarin
      (esculetin) was investigated using primary cultures of rabbit articular
      chondrocytes. Esculetin (EST) significantly suppressed the proteoglycan depletion
      and the release of pulse-labeled [35S]proteoglycan from the matrix layer of
      rabbit chondrocytes treated with recombinant human interleukin-1alpha. The matrix
      metalloproteinase inhibitor, 1,10-phenanthroline, also blocked the proteoglycan
      depletion and [35S]proteoglycan release. From these results, it is likely that
      recombinant human interleukin-1alpha-induced proteoglycan depletion is mediated
      by matrix metalloproteinases. Although esculetin did not directly inhibit
      collagenolytic activity in the culture media, it significantly suppressed the
      production of pro-matrix metalloproteinase-1/interstitial procollagenase and pro
      matrix metalloproteinase-3/prostromelysin 1, accompanied by a decrease in the
      steady-state levels of their mRNAs. These results suggest that esculetin is a
      therapeutically effective candidate for inhibition of cartilage destruction in
      osteoarthritis and rheumatoid arthritis.

PMID- 10334508
TI  - Mechanism of adrenomedullin-stimulated hyaluronic acid release in rat mesangial
      cells.
AB  - Adrenomedullin is a potent vasodilatory peptide that increases cAMP in a number
      of different systems including rat mesangial cells. Since mesangial cells play a
      significant role in glomerular matrix production, we evaluated the effects and
      molecular mechanisms of adrenomedullin action on hyaluronic acid release, an
      important extracellular matrix component. Adrenomedullin increased hyaluronic
      acid release in mesangial cells in a concentration-dependent manner. Forskolin,
      an adenylate cyclase activator, and dibutyryl-cAMP, a cell permeable cAMP analog,
      also increased hyaluronic acid release significantly. Adrenomedullin-stimulated
      hyaluronic acid release was inhibited by the adrenomedullin receptor antagonist,
      adrenomedullin-(22-52). Inhibition of protein kinase A with H89 [[N-[2-(( p
      Bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide, hydrochloride)]], a potent
      protein kinase A inhibitor did not affect adrenomedullin-stimulated hyaluronic
      acid release; however, H89 [[N-[2-(( p-Bromocinnamyl)amino)ethyl]-5
      isoquinolinesulfonamide, hydrochloride]] inhibited forskolin- and dibutyryl-cAMP
      induced hyaluronic acid production. In addition, SB203580 [[4-(4-fluorophenyl)-2
      (4-methylsulfinylphenyl)-5-(4-pyridyl)1H-im idazole), a P38 mitogen-activated
      protein kinase (P38 MAPK) inhibitor attenuated adrenomedullin-, forskolin-, and
      dibutyryl-cAMP-stimulated hyaluronic acid release. Hyaluronic acid release
      induced by adrenomedullin, forskolin and dbcAMP was also inhibited by wortmannin
      [[1S-(1alpha, 6balpha, 9abeta, 11alpha, 11bbeta)]-11-(Acetyloxy)-1, 6b, 7, 8, 9a,
      10, 11, 11b-octahydro-1-(methoxymethyl)-9a, 11b-dimethyl-3H-furo[4, 3, 2
      de]indeno[4, 5-h]-2-benzopyran-3, 6, 9-trione]. We conclude that adrenomedullin,
      forskolin and dbcAMP cause an increase in hyaluronic acid release in rat
      mesangial cells through a pathway that involves activation of wortmannin
      sensitive kinase and P38 MAPK. Although cAMP stimulation and protein kinase A
      activation can induce hyaluronic acid release. adrenomedullin-stimulated
      hyaluronic acid release appears to be independent of protein kinase A activation.
      These data provide the first demonstration of the involvement of P38 MAPK- and
      wortmannin-sensitive kinase pathways in the stimulation of hyaluronic acid
      production by rat mesangial cells.

PMID- 10334509
TI  - Inhibition of cardiac inward-rectifier K+ current by terodiline.
AB  - The antispasmodic agent terodiline has cardiotoxic effects that include QT
      lengthening. To determine whether inhibition of inwardly-rectifying K+ current
      (I(K1)) might be a factor in the cardiotoxicity, we measured I(K1) in guinea pig
      ventricular myocytes. Terodiline reduced outward I(K1) with an IC50 of 7 microM;
      maximal reduction was 60% with 100-300 microM concentration. Inhibition was
      independent of current direction, and persisted after removal of the drug.
      Terodiline (3-5 microM) lengthened action potentials in guinea pig papillary
      muscles by ca. 10%, primarily by slowing phase 3 repolarization; higher
      concentrations abbreviated the plateau and markedly slowed late repolarization.
      Terodiline washout provoked an extra lengthening, consistent with persistent
      inhibition of I(K1) and rapid recovery of net inward plateau current. The results
      suggest that inhibition of I(K1) is a likely factor in the cardiotoxicity of the
      drug.

PMID- 10334510
TI  - Tissue-specific effect of clofibrate on rat lipogenic enzyme gene expression.
AB  - Fibrate derivatives are commonly used to treat hyperlipidaemia; however, the
      mechanism of the antilipidaemic action of these drugs is still unknown. The
      effect of clofibrate (fibrate derivative) administration for 14 days on
      lipogenesis and on malic enzyme (EC 1.1.1.40) and fatty acid synthase (EC
      2.3.1.85) gene expression in brown and white adipose tissues and in the liver was
      examined in rats. The rate of brown adipose tissue lipogenesis in the clofibrate
      treated animals was significantly lower than that of the control rats. The rate
      of liver and white adipose tissue lipogenesis was not affected significantly by
      clofibrate. In brown adipose tissue, the drug treatment resulted in a depression
      of fatty acid synthase and malic enzyme mRNA levels. The fatty acid synthase mRNA
      level did not change significantly in the liver, whereas the malic enzyme mRNA
      level increased approximately 6-fold in this organ after clofibrate treatment.
      The malic enzyme mRNA level in white adipose tissue increased about 2-fold, while
      the fatty acid synthase mRNA level was unchanged after clofibrate feeding. The
      results presented in this paper provide further evidence that the hypolipidaemia
      caused by treatment of rats with clofibrate cannot be related to the inhibition
      of fatty acid synthesis in the liver and white adipose tissue. These data also
      indicate that clofibrate exhibits tissue specificity.

PMID- 10334511
TI  - Human cloned alpha1A-adrenoceptor isoforms display alpha1L-adrenoceptor
      pharmacology in functional studies.
AB  - The recombinant alpha1A-adrenoceptor displays a distinct pharmacological profile
      ('classical alpha1A-adrenoceptor') in homogenate binding assays, but displays the
      properties of the so-called alpha1L-adrenoceptor in functional studies in whole
      cells at 37 degrees C. As three splice variants of the human alpha1A-adrenoceptor
      have been described previously (alpha1A-1, alpha1A-2 and alpha1A-3), we have
      compared their functional pharmacological profiles, when expressed stably in
      Chinese hamster ovary (CHO-K1) cells (antagonist inhibition of noradrenaline
      stimulated [3H]inositol phosphates accumulation). A fourth, novel isoform
      (alpha1A-4) has also been studied: alpha1A-4 mRNA predominates in several human
      tissues including prostate, liver, heart and bladder. In homogenate binding
      studies, all four isoforms displayed essentially identical affinity profiles,
      with prazosin (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl)piperazine),
      tamsulosin (5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-2-methoxybenzen
      esulfonamide), RS-17053 (N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro
      alpha,alphad imethyl-1H-indole-3-ethanamine hydrochloride), WB 4101 ((2,6
      dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride) and 5-Me
      urapidil (5-methyl-6[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]amino]-1,3-d
      imethyuracil) all displaying subnanomolar affinities. In functional studies,
      noradrenaline accelerated [3H]inositol phosphates production with potencies
      (p[A]50) of between 5.8 and 6.6. The affinities of prazosin, RS-17053, WB 4101
      and 5-Me-urapidil, at antagonizing responses to noradrenaline, were reduced by
      approximately 10-fold (cf. binding data), while those for tamsulosin and
      indoramin (N-[1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl]benzamide) remained
      constant or increased, consistent with the previously described alpha1L
      adrenoceptor. Thus, all four human recombinant alpha1A-adrenoceptor isoforms
      display the pharmacology of the alpha1L-adrenoceptor when studied in functional
      assays, consistent with the hypothesis that the putative alpha1L-adrenoceptor
      represents a functional phenotype of the alpha1A-adrenoceptor.

PMID- 10334512
TI  - A threonine residue in the M2 region of the beta1 subunit is needed for
      expression of functional alpha1beta1 GABA(A) receptors.
AB  - Although there is a high degree of homology in the M2 transmembrane segments of
      alpha1 and beta1 subunits, subunit-specific effects were observed in alpha1beta1
      GABA(A) receptors expressed in Spodoptera frugipedra (Sf9) cells when the
      conserved 13' threonine residue in the M2 transmembrane region was mutated to
      alanine. When threonine 263 (13') was mutated to alanine in the beta1 subunit,
      high-affinity muscimol binding and the response to GABA were abolished. This did
      not occur when the threonine 263 (13') was mutated to alanine in the alpha1
      subunit, but the rate of desensitisation increased and the effect of bicuculline,
      a competitive inhibitor, was reduced. The results show differential effects of
      subunits on receptor function and support a role for M2 in desensitisation.

PMID- 10334513
TI  - Evidence for the differential sensitivity to hypoxia of basal and agonist-induced
      nitric oxide release.
AB  - Rat pulmonary arterial rings (phenylephrine pre-contracted), were relaxed by
      carbachol or thapsigargin, or were contracted by Nomega-nitro-L-arginine methyl
      ester (L-NAME). Mild hypoxia (41 mm Hg) attenuated the carbachol-induced
      relaxation, whereas the relaxant and contractile effects produced by thapsigargin
      and L-NAME were unaffected. More severe hypoxia (20 mm Hg) abolished thapsigargin
      induced relaxation, with no further change in responses to carbachol or L-NAME.
      At 7 mm Hg, carbachol-induced relaxation was completely inhibited, and the L-NAME
      induced contraction was attenuated but not abolished. The present data is
      consistent with the conclusion that nitric oxide (NO) synthase activity is less
      susceptible to oxygen deprivation under basal conditions than during activation.

PMID- 10334514
TI  - Neighboring glycine residues are essential for P2X2 receptor/channel function.
AB  - The roles of a glycine-rich region in the cloned P2X2 receptor/channel were
      evaluated by site-directed mutagenesis. Responsiveness to ATP was lost when
      Gly247 was replaced by alanine. The sensitivity to ATP was reduced when Gly248
      was replaced by alanine, and the responsiveness to ATP was lost when Gly248 was
      replaced by valine. The results suggest that the neighboring glycine residues are
      essential for P2X2 receptor/channel function.

PMID- 10334515
TI  - Concurrent chemotherapy and radiation: a major advance for women with cervical
      cancer.

PMID- 10334516
TI  - The tea leaves of small trials.

PMID- 10334517
TI  - Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an
      adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with
      negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest
      Oncology Group study.
AB  - PURPOSE: In 1986, a protocol comparing primary radiation therapy (RT) plus
      hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was
      activated by the Gynecologic Oncology Group (GOG) for the treatment of patients
      with locally advanced cervical carcinoma. The goals were to determine the
      superior chemoradiation regimen and to quantitate the relative toxicities.
      METHODS: All patients had biopsy-proven invasive squamous cell carcinoma,
      adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients
      underwent standard clinical staging studies and their tumors were found to be
      International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA.
      Negative cytologic washings and para-aortic lymph nodes were required for entry.
      Patients were randomized to receive either standard whole pelvic RT with
      concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS: Of
      388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to
      HU. Adverse effects were predominantly hematologic or gastrointestinal in both
      regimens. Severe or life-threatening leukopenia was more common in the HU group
      (24%) than in the CF group (4%). The difference in progression-free survival
      (PFS) was statistically significant in favor of the CF group (P = .033). The
      sites of progression in the two treatment groups were not substantially
      different. Survival was significantly better for the patients randomized to CF (P
      = .018). CONCLUSION: This study demonstrates that for patients with locally
      advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers
      patients better PFS and overall survival than HU, and with manageable toxicity.

PMID- 10334519
TI  - Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer.
      International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2)
      Investigators.
AB  - PURPOSE: The goal of this analysis was to determine whether fluorouracil (FU) and
      folinic acid (leucovorin, LV) is an effective adjuvant therapy for patients after
      potentially curative resection of colon cancer in patients with B2 tumors.
      PATIENTS AND METHODS: One thousand sixteen patients with B2 colon cancer entered
      onto five separate trials were randomized to FU + LV or observation. A pooled
      analysis for event-free (EFS) and overall survival (OS) using a stratified log
      rank and Cox model was performed. RESULTS: The median follow-up duration was 5.75
      years. Patients receiving FU + LV did not experience a significant increase in
      EFS or OS. The hazards ratio at 5 years was 0.83 (90% confidence interval, 0.72
      to 1.07) for EFS and 0.86 (90% confidence interval, 0.68 to 1.07) for OS. The 5
      year EFS was 73% for controls and 76% for FU + LV. The 5-year OS was 80% for
      controls and 82% for FU + LV. Increasing age and poorly differentiated tumors
      were significant indicators of poor prognosis (P < .02). CONCLUSION: This data
      set does not support the routine use of FU + LV in all patients with B2 colon
      cancer. Longer follow-up may identify a small benefit. At present, studies in B2
      colon cancer designed with a no-treatment control arm should be considered
      appropriate.

PMID- 10334518
TI  - Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus
      Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and
      Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04)
AB  - PURPOSE: Although the benefit from adjuvant chemotherapy has been clearly
      established in patients with Dukes' C colon cancer, such benefit has been
      questioned in patients with Dukes' B disease. To determine whether patients with
      Dukes' B disease benefit from adjuvant chemotherapy and to evaluate the magnitude
      of the benefit, compared with that observed in Dukes' C patients, we examined the
      relative efficacy of adjuvant chemotherapy according to Dukes' stage in four
      sequential National Surgical Adjuvant Breast and Bowel Project trials (C-01, C
      02, C-03, and C-04) that compared different adjuvant chemotherapy regimens with
      each other or with no adjuvant treatment. PATIENTS AND METHODS: The four trials
      included Dukes' B and C patients and were conducted between 1977 and 1990. The
      eligibility criteria and follow-up requirements were similar for all four trials.
      Protocol C-01 compared adjuvant semustine, vincristine, and fluorouracil (5-FU)
      (MOF regimen) with operation alone. Protocol C-02 compared the perioperative
      administration of a portal venous infusion of 5-FU with operation alone. Protocol
      C-03 compared adjuvant 5-FU and leucovorin (LV) with adjuvant MOF. Protocol C-04
      compared adjuvant 5-FU and LV with 5-FU and levamisole (LEV) and with the
      combination of 5-FU, LV, and LEV. RESULTS: Forty-one percent of the patients
      included in these four trials had resected Dukes' B tumors. In all four studies,
      the overall, disease-free, and recurrence-free survival improvement noted for all
      patients was evident in both Dukes' B and Dukes' C patients. When the relative
      efficacy of chemotherapy was examined, there was always an observed reduction in
      mortality, recurrence, or disease-free survival event, irrespective of Dukes'
      stage, and in most instances, the reduction was as great or greater for Dukes' B
      patients as for Dukes' C patients. When data from all four trials were examined
      in a combined analysis, the mortality reduction was 30% for Dukes' B patients
      versus 18% for Dukes' C patients. The mortality reduction in Dukes' B patients
      occurred irrespective of the presence or absence of adverse prognostic factors.
      CONCLUSION: Patients with Dukes' B colon cancer benefit from adjuvant
      chemotherapy and should be presented with this treatment option. Regardless of
      the presence or absence of other clinical prognostic factors, Dukes' B patients
      seem to benefit from chemotherapy administration.

PMID- 10334520
TI  - Analysis of the p53/BAX pathway in colorectal cancer: low BAX is a negative
      prognostic factor in patients with resected liver metastases.
AB  - PURPOSE: To determine the prognostic value of the central downstream apoptosis
      effector BAX in relation to its upstream regulator p53 in R0-resected hepatic
      metastases of colorectal cancer. PATIENTS AND METHODS: Retrospective analysis of
      41 patients who underwent potentially curative resection of liver metastases from
      colarectal cancer was performed. Tumor DNA was screened for p53 mutations by
      single-stranded conformational polymorphism polymerase chain reaction and for BAX
      frameshift mutations by fragment length analysis. Protein expression of BAX, p21,
      and p53 was investigated by immunohistochemistry. RESULTS: Overall median
      survival was 40.2 months. Tumors with BAX frameshift mutations were considered
      microsatellite mutator phenotype-positive and were excluded from further
      prognostic analyses. Patients with high BAX protein expression had a median
      survival of 53.6 months compared with 35.4 months for patients with low BAX
      expression (P < .05). The negative prognostic value of low BAX expression was
      more evident in those patients with wild-type p53 (median survival, 54.0 v 23.3
      months for BAX-negative tumors; P < .01). Low BAX expression was an independent
      negative prognostic marker in multivariate regression analysis for all patients
      independent of the p53 status (relative risk, 3.03, P = .03), especially for p53
      wild-type tumors (relative risk, 8.21; P = .0095). CONCLUSION: We conclude that
      low BAX expression is an independent negative prognostic marker in patients with
      hepatic metastases of colorectal cancer. The best survival was seen in patients
      with an intact p53-to-BAX pathway; ie, wild-type p53- and BAX-positive tumors.
      Thus, analysis of apoptosis signaling pathways (here, p53 in concert with its
      downstream death effector, BAX) might yield more prognostic power in future
      studies as compared with analysis of single genes such as p53 alone.

PMID- 10334521
TI  - p53 and K-ras gene mutations correlate with tumor aggressiveness but are not of
      routine prognostic value in colorectal cancer.
AB  - PURPOSE: p53 gene and K-ras mutations are among the most common genetic
      alterations present in colorectal cancer. The prognostic utility of such
      mutations remains controversial. The purpose of this study was to prospectively
      evaluate the prognostic significance of p53 and K-ras gene mutations in
      colorectal cancer. PATIENTS AND METHODS: One hundred forty patients were
      analyzed. Tumors belonging to the microsatellite mutator phenotype were excluded
      (n = 8). Mutations at the K-ras and p53 genes were detected and characterized by
      restriction fragment length polymorphism, single-strand conformation
      polymorphism, and sequencing, as appropriate. RESULTS: p53 mutations were
      detected in 66 (50%) and K-ras mutations were detected in 54 (41%) of the 132
      patients. In 26 cases (20%), ras and p53 mutations coexisted; in 38 cases (29%),
      neither mutation was found. Multivariate analysis of the whole population
      analyzed (n = 132) showed that survival was strongly correlated with the presence
      of p53 mutations alone or in combination with K-ras mutations (P = .002; log-rank
      test). When only patients undergoing a radical resection were considered (R0; n =
      101), p53 mutations were no longer of prognostic significance. CONCLUSION: p53
      mutations alone or in combination with K-ras mutations are correlated with a
      worse outcome. However, the routine use of these mutations as prognostic markers
      in the clinical setting is not recommended.

PMID- 10334522
TI  - Prognostic significance of angiogenesis and Ki-67, p53, and p21 expression: a
      population-based endometrial carcinoma study.
AB  - PURPOSE: For endometrial carcinoma patients, there is a need for improved
      identification of high-risk groups that may benefit from postoperative adjuvant
      therapy. We therefore studied the prognostic impact of markers for cell
      proliferation, cell-cycle regulation, and angiogenesis among endometrial
      carcinoma patients in a population-based setting. PATIENTS AND METHODS: All
      patients diagnosed with endometrial carcinoma between 1981 and 1985 in Hordaland
      County, Norway, were studied. The median follow-up for the survivors was 11.5
      years (range, 8 to 15 years), with no patient lost because of insufficient follow
      up information. Paraffin-embedded tumor tissue, available in 96% of the cases (n
      = 142), was studied immunohistochemically for microvessel density (MVD) and
      expression of Ki-67, p53, and p21 proteins. We used the hot spot method for
      calculation of MVD, and expression of Ki-67 and p21 protein, because this
      approach may increase the probability of detecting small aggressive clones of
      possible prognostic relevance. The importance of these tumor markers was
      investigated in univariate survival analyses and Cox regression analysis.
      RESULTS: The majority of traditional clinicopathologic variables was
      significantly associated with the tumor biomarkers. Age, International Federation
      of Gynecology and Obstetrics (FIGO) stage, histologic type, histologic grade,
      MVD, as well as Ki-67, p53, and p21 protein expression, all significantly
      influenced survival in univariate analyses (P < or = .05). In the Cox regression
      analysis, age, FIGO stage, MVD, Ki-67 expression, and p53 expression were the
      only variables with independent prognostic impact (P < or = .05), whereas
      histologic type, histologic grade, and p21 expression had no independent
      influence. A group of high-risk patients with more than one unfavorable marker
      was identified. CONCLUSION: In addition to age and FIGO stage, MVD, Ki-67, and
      p53 protein expression showed an independent prognostic impact. Thus, information
      derived from routine histologic specimens identified a subgroup of high-risk
      endometrial carcinoma patients in this population-based study.

PMID- 10334523
TI  - Detection of human papillomavirus types 16 and 18 mRNA in peripheral blood of
      advanced cervical cancer patients and its association with prognosis.
AB  - PURPOSE: To evaluate the feasibility of detecting human papillomavirus E6 (HPVE6)
      gene mRNA in the peripheral blood of patients with locally advanced cervical
      cancer, and the relationship of the circulating HPV viral-specific mRNA with
      clinicopathologic factors and prognosis of locally advanced cervical cancer.
      PATIENTS AND METHODS: The presence of types 16 and 18 HPVE6 gene mRNA was
      determined by reverse transcription followed by nested polymerase chain reaction.
      Thirty-five patients with locally advanced cervical cancer who were positive for
      HPV type 16 or 18 DNA were included in the study. All patients received external
      beam radiation therapy followed by intracavitary brachytherapy. RESULTS: Eighteen
      (51.4%) of 35 HPV DNA-positive cervical cancer patients had HPV-specific mRNA in
      their peripheral blood cells, compared with none of 17 HPV DNA-negative cervical
      cancer patients and none of 12 control volunteers. The presence of HPVE6 gene
      mRNA in peripheral blood was associated with bulky tumor volume (> 4 cm) and
      pelvic lymph node metastasis (tumor volume, P = .03; lymph node status, P = .03).
      After a median follow-up of 22 months, patients who were positive for peripheral
      blood HPVE6 gene mRNA had a significantly higher risk of recurrence than those
      who were negative (10 of 18 v three of 17, P = .02; mean recurrent time, 20.7
      months v 12.6 months, P = .02). There was also a statistically significant
      association of peripheral-blood HPVE6 gene mRNA positivity with distant
      metastasis (eight of 18 vone of 17; P = .01). CONCLUSION: Results of this study
      seem to suggest that the presence of HPVE6 gene mRNA in peripheral blood may
      provide an early marker that identifies patients who are at risk for metastasis.

PMID- 10334524
TI  - Safety and efficacy of using a single agent or a phase II agent before
      instituting standard combination chemotherapy in previously untreated metastatic
      breast cancer patients: report of a randomized study--Cancer and Leukemia Group B
      8642.
AB  - PURPOSE: We undertook a prospective, randomized phase III trial to evaluate the
      safety and efficacy of using a phase II agent before initiating therapy with
      standard combination chemotherapy in metastatic breast cancer patients. PATIENTS
      AND METHODS: A total of 365 women with measurable metastatic breast cancer,
      previously untreated with chemotherapy for their metastatic disease, were
      randomized to receive either immediate chemotherapy with cyclophosphamide,
      doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five
      sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide,
      carboplatin, or elsamitrucin, followed by CAF. RESULTS: The toxicity of each
      single agent followed by CAF was comparable to that of CAF alone. The cumulative
      response rates for the single agent followed by CAF were not statistically
      different from those of CAF alone (44% v 52%; P = .24). However, in the
      multivariate analysis, patients with visceral disease had a trend toward lower
      response rates on the phase II agent plus CAF arm (P = .078). Although survival
      and response duration also were not statistically significantly different between
      the two study arms (P = .074 and P = .069, respectively), there was a suggestion
      of benefit for the CAF-only arm. CONCLUSION: The brief use of a phase II agent,
      regardless of its efficacy, followed by CAF resulted in response rates,
      toxicities, durations of response, and survival statistically equivalent to those
      seen with the use of CAF alone. These findings support the use of a new paradigm
      for the evaluation of phase II agents in the treatment of patients with
      metastatic breast cancer.

PMID- 10334525
TI  - Infusional paclitaxel and weekly vinorelbine chemotherapy with concurrent
      filgrastim for metastatic breast cancer: high complete response rate in a phase I
      II study of doxorubicin-treated patients.
AB  - PURPOSE: We investigated 96-hour paclitaxel infusion combined with weekly (days
      eight and 15) vinorelbine as salvage therapy for metastatic breast cancer in
      anthracycline-exposed patients. All patients received scheduled support with
      granulocyte colony-stimulating factor (G-CSF; filgrastim). Tumor response,
      toxicity, time to progression (TTP), and survival were assessed. PATIENTS AND
      METHODS: This single-center nonrandomized trial enrolled 32 patients.
      Anthracycline exposure and subsequent progression were common to all patients.
      Paclitaxel and vinorelbine were escalated over three dosing levels, stratified by
      liver function. RESULTS: Seven patients (22%) achieved a complete response and
      nine patients achieved a partial response for an overall response rate of 50%.
      The median TTP was 6.1 months, and median survival time was 14.1 months. Dose
      limiting toxicity was neutropenia, with dose delay or reduction in seven of 32
      patients. Febrile neutropenia requiring hospitalization was uncommon (three of 32
      patients; 9%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia
      occurred in two patients (6%), and 13 patients (41%) required RBC transfusions
      for anemia. Grade 3 nausea and vomiting was seen in one patient, who was found to
      be Addisonian. Despite potentially overlapping neurologic toxicities of the two
      agents, only two patients (6%) were removed from the study because of progressive
      peripheral neuropathy. CONCLUSION: Administration of 96-hour paclitaxel infusion
      and subsequent weekly vinorelbine with G-CSF support is well tolerated. The
      response rate, TTP, and survival data are encouraging for therapy given to
      anthracycline pretreated patients with metastatic breast cancer. If these results
      can be verified in multi-institution trials, this or a similar combination of
      drugs would merit investigation as first-line therapy in this patient population.

PMID- 10334526
TI  - Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in
      patients with metastatic breast cancer progressing despite previous anthracycline
      containing chemotherapy. 304 Study Group.
AB  - PURPOSE: This phase III study compared docetaxel with mitomycin plus vinblastine
      (MV) in patients with metastatic breast cancer (MBC) progressing despite previous
      anthracycline-containing chemotherapy. PATIENTS AND METHODS: Patients (n=392)
      were randomized to receive either docetaxel 100 mg/m2 intravenously (i.v.) every
      3 weeks (n=203) or mitomycin 12 mg/m2 i.v. every 6 weeks plus vinblastine 6 mg/m2
      i.v. every 3 weeks (n=189), for a maximum of 10 3-week cycles. RESULTS: In an
      intention-to-treat analysis, docetaxel produced significantly higher response
      rates than MV overall (30.0% v 11.6%; P < .0001), as well as in patients with
      visceral involvement (30% v 11%), liver metastases (33% v 7%), or resistance to
      previous anthracycline agents (30% v 7%). Median time to progression (TTP) and
      overall survival were significantly longer with docetaxel than MV (19 v 1 weeks,
      P=.001, and 1 1.4 v 8.7 months, P=.0097, respectively). Neutropenia grade 3/4 was
      more frequent with docetaxel (93.1 % v62.5%; P < .05); thrombocytopenia grade 3/4
      was more frequent with MV (12.0% v 4.1%; P < .05). Severe acute or chronic
      nonhematologic adverse events were infrequent in both groups. Withdrawal rates
      because of adverse events (MV, 10.1%; docetaxel, 13.8%) or toxic death (MV, 1.6%;
      docetaxel, 2.0%) were similar in both groups. Quality-of-life analysis was
      limited by a number of factors, but results were similar in both groups.
      CONCLUSION: Docetaxel is significantly superior to MV in terms of response, TTP,
      and survival. The safety profiles of both therapies are manageable and tolerable.
      Docetaxel represents a clear treatment option for patients with MBC progressing
      despite previous anthracycline-containing chemotherapy.

PMID- 10334527
TI  - Phase II trial of liposome-encapsulated doxorubicin, cyclophosphamide, and
      fluorouracil as first-line therapy in patients with metastatic breast cancer.
AB  - PURPOSE: To determine the efficacy and safety profile, including the risk for
      cardiac toxicity, of liposome-encapsulated doxorubicin (TLC D-99), fluorouracil
      (5-FU), and cyclophosphamide as first-line chemotherapy in patients with
      metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-one women were
      registered in this phase II study. All patients had measurable disease and no
      previous chemotherapy for MBC. Treatment consisted of TLC D-99 60 mg/m2 and
      cyclophosphamide 500 mg/m2 on day 1 and 5-FU 500 mg/m2 on days 1 and 8 every 3
      weeks. Serial cardiac monitoring, including endomyocardial biopsies, was
      performed. RESULTS: The overall response rate was 73% (95% confidence interval,
      57% to 86%). The median duration of response was 11.2 months, the median time to
      treatment failure was 8.1 months, and the median overall survival duration was
      19.4 months. The median number of cycles per patient was 10. The median
      cumulative dose of TLC D-99 was 528 mg/m2. Ten patients required hospitalization
      for febrile neutropenia. Nausea/vomiting, stomatitis, and fatigue higher than
      grade 2 occurred in 12%, 15%, and 41% of patients, respectively. Twenty-one
      patients reached a cumulative doxorubicin dose greater than 500 mg/m2. Three
      patients (7%) were withdrawn from the study due to protocol-defined cardiac
      toxicity, two because of a decrease in left ventricular ejection fraction to < or
      = 40%, and one because her endomyocardial biopsy result was grade 1.5. One
      patient had congestive heart failure that was probably nonanthracycline related.
      CONCLUSION: This chemotherapy regimen, including TLC D-99, was highly active
      against MBC and associated with low cardiac toxicity despite high cumulative
      doses of doxorubicin.

PMID- 10334528
TI  - Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte
      colony-stimulating factor in metastatic breast cancer. TLC D-99 Study Group.
AB  - PURPOSE: To estimate the toxicity and response rate of high-dose liposome
      encapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company Inc, Princeton,
      NJ) in patients with advanced breast cancer. PATIENTS AND METHODS: Fifty-two
      breast cancer patients with bidimensionally measurable metastatic disease and no
      prior chemotherapy for metastatic disease received a 135 mg/m2 intravenous (i.v.)
      bolus of TLC D-99 with 5 microg/kg of granulocyte colony-stimulating factor via
      subcutaneous injection every 21 days. RESULTS: The median number of treatment
      cycles of TLC D-99 was three (range, one to 10 cycles), and the median total
      cumulative dose of TLC D-99 was 405 mg/m2 (range, 135 to 1,065 mg/m2). Grade IV
      neutropenia, thrombocytopenia, and mucositis were experienced by 48 (92%), 46
      (88%), and 10 (19%) patients, respectively. Twenty (38%) of patients experienced
      cardiac toxicity: four (8%) experienced a decrease of 20% or more in left
      ventricular ejection fraction (LVEF) to a final value > or = 50%, nine (17%)
      experienced a decrease of 10% or more in LVEF to a final value less than 50%, and
      seven (13%) developed symptomatic congestive heart failure (CHF), including one
      patient who died of cardiomyopathy after receiving a total dose of 1,035 mg/m2.
      In a stepwise logistic regression model, the significant risk factors for the
      development of CHF were the cumulative dose of prior adjuvant doxorubicin (P =
      .007) and the total cumulative dose of TLC D-99 (P = .032). The overall response
      rate was 46% (95% confidence interval [CI], 32% to 61%) on an intent-to-treat
      basis. The median duration of response was 7.4 months (95% CI, 6.1 to 19.6
      months) and the median progression-free survival was 6.1 months (95% CI, 5.4 to
      7.5 months). CONCLUSION: There was no added therapeutic benefit to the dose
      escalation of TLC D-99 in this study. A high rate of cardiotoxicity was also
      observed, especially among patients who had received prior adjuvant doxorubicin.
      This was probably attributable to the dose and schedule of TLC D-99 used in this
      trial, as well as the patient's lifetime cumulative doxorubicin dose.
      Administration of high-dose TLC D-99 at 135 mg/m2 every 3 weeks by i.v. bolus
      infusion does not warrant further investigation.

PMID- 10334529
TI  - Tumor characteristics and clinical outcome of tubular and mucinous breast
      carcinomas.
AB  - PURPOSE: To comprehensively characterize the clinical and biologic features of
      tubular and mucinous carcinomas in a large cohort of patients and to relate this
      to clinical outcome and management. PATIENTS AND METHODS: The clinical and
      biologic features of 444 patients with tubular and 1,221 patients with mucinous
      carcinomas were compared with those of 43,587 patients with infiltrating ductal
      carcinoma, not otherwise specified (NOS). Disease-free survival (DFS) and overall
      survival (OS) for patients with tubular and mucinous carcinomas were compared
      with those of patients with NOS carcinomas and with age-matched sets from the
      general population. RESULTS: Tubular and mucinous carcinomas were more likely to
      occur in older patients, be smaller in size (tubular only), have substantially
      less nodal involvement, be estrogen receptor- and progesterone receptor-positive,
      have a lower S-phase fraction, be diploid, and be c-erbB-2- and epidermal growth
      factor receptor-negative compared with NOS carcinomas. Axillary node involvement
      was a poor prognostic feature in mucinous but not tubular carcinomas. Mucinous
      carcinomas < or = 1 cm had a < or = 5% incidence of node involvement. The 5-year
      DFS and OS were 94% and 88% for tubular, 90% and 80% for mucinous, and 80% and
      77% for NOS carcinoma, respectively (P < .001 for differences among all three
      types for both DFS and OS). The 5-year OS of females from the general population
      age-matched to the patients with tubular and mucinous carcinomas was 89% and 82%,
      respectively, which is not different from the OS of patients with tubular or
      mucinous carcinomas. CONCLUSION: The biologic phenotype of tubular and mucinous
      carcinomas is quite favorable. Consistent with this observation, the survival of
      patients with tubular and mucinous carcinomas is similar to that of the general
      population. Systemic adjuvant therapy and node dissection may be avoided in many
      patients with these special types of carcinoma.

PMID- 10334530
TI  - Breast-conserving therapy: proteases as risk factors in relation to survival
      after local relapse.
AB  - PURPOSE: To evaluate whether cathepsin D, urokinase-type plasminogen activator
      (uPA), its inhibitor, plasminogen activator inhibitor-1 (PAI-1), or clinical
      factors can predict which patients are at risk for developing distant metastases
      after local recurrence (LR). PATIENTS AND METHODS: Of 1,630 patients treated with
      breast-conserving surgery and radiotherapy of the breast between 1980 and 1992,
      LR developed in 171 as a first event. From the available primary tumor tissues,
      we determined the cytosolic levels of cathepsin D, uPA and PAI-1. RESULTS: In
      patients with LR, a short (< or = 2 years) disease-free interval (DFI) and skin
      involvement of LR were associated with poor postrelapse distant metastasis-free
      survival (PR-DMFS, P = .001, both) and postrelapse overall survival (PR-OS; P <
      .0001 and P < .0002, respectively). The primary tumor levels of uPA and PAI-1
      were elevated for patients with a short DFI (P < .01), but such a relation was
      not observed for patients with skin involvement. In univariate analyses, high
      levels of uPA and PAI-1 in the primary tumor were associated with poor PR-OS (P =
      .038 and P = .040, respectively) but not PR-DMFS. In Cox multivariate analyses
      for PR-DMFS and PR-OS, only a short DFI and skin involvement of the LR were
      independently associated with a poor clinical outcome. CONCLUSION: In patients
      treated with breast-conserving therapy who had LR as a first event, a short DFI
      and skin involvement were strong indicators for poor PR-DMFS and PR-OS. The
      proteases studied did not contribute significantly to the final multivariate
      model.

PMID- 10334531
TI  - Time trends in systemic adjuvant treatment for node-negative breast cancer.
AB  - PURPOSE: We conducted a population-based study in Quebec, Canada, to assess
      longitudinal changes in systemic adjuvant therapy for node-negative breast
      cancer. MATERIALS AND METHODS: A stratified random sample was selected among
      women with newly diagnosed node-negative breast cancer in 1988, 1991, and 1993.
      Information on the patient, her tumor, source of care, and treatment was
      abstracted from medical charts. Patients were classified as being at minimal,
      moderate, or high risk of recurrence on the basis of criteria proposed at the 4th
      International Conference on Adjuvant Therapy of Primary Breast Cancer (St.
      Gallen, Switzerland, 1992), and systemic adjuvant treatment received was
      dichotomized as being consistent or not consistent with consensus
      recommendations. RESULTS: Overall, 1,578 cases of invasive breast carcinoma were
      reviewed. The proportion of patients who were given hormonal or cytotoxic
      treatment increased from 51.7% to 73.1% from 1988 to 1993. Virtually all women at
      minimal risk were treated in 1991 and 1993 according to the consensus statement.
      The proportions of women so treated were 75.0% and 65.4% in the moderate- and
      high-risk categories, respectively, in 1991. In 1993, these proportions were
      71.4% and 67.0%, respectively. Omission of chemotherapy, especially in high-risk
      women with estrogen receptor-negative tumors who were 50 to 69 years of age, was
      the most frequent inconsistency with guidelines. CONCLUSION: Systemic adjuvant
      therapy for node-negative breast cancer has gained acceptance. Better
      understanding of the decision-making process, of the perception of the risks and
      benefits involved, and of the impact of alternative strategies for the
      dissemination of consensus recommendations are needed to promote the use of
      chemotherapy in specific categories of women who are at high risk of recurrence.

PMID- 10334532
TI  - Is axillary lymph node dissection indicated for early-stage breast cancer? A
      decision analysis.
AB  - PURPOSE: Axillary lymph node dissection (ALND) has been a standard procedure in
      the management of breast cancer. In a patient with a clinically negative axilla,
      ALND is performed primarily for staging purposes, to guide adjuvant treatment.
      Recently, the routine use of ALND has been questioned because the results of the
      procedure may not change the choice of adjuvant systemic therapy and/or the
      survival benefit of a change in adjuvant therapy would be small. We constructed a
      decision model to quantify the benefits of ALND for patients eligible for breast
      conserving therapy. METHODS: Patients were grouped by age, tumor size, and
      estrogen receptor (ER) status. The model uses the Oxford overviews and three
      combined Cancer and Leukemia Group B studies. We assumed that patients who did
      not undergo ALND received axillary radiation therapy and that the two procedures
      are equally effective. All chemotherapy combinations were assumed to be equally
      efficacious. RESULTS: The largest benefits from ALND are seen in ER-positive
      women with small primary tumors who might not be candidates for adjuvant
      chemotherapy if their lymph nodes test negative. Virtually no benefit results in
      ER-negative women, almost all of whom would receive adjuvant chemotherapy. When
      adjusted for quality of life (QOL), ALND may have an overall negative impact. In
      general, the benefits of ALND increase with the expected severity of adjuvant
      therapy on QOL CONCLUSION: Our model quantifies the benefits of ALND and assists
      decision making by patients and physicians. The results suggest that the routine
      use of ALND in breast cancer patients should be reassessed and may not be
      necessary in many patients.

PMID- 10334533
TI  - Estrogen receptor status by immunohistochemistry is superior to the ligand
      binding assay for predicting response to adjuvant endocrine therapy in breast
      cancer.
AB  - PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the
      estrogen receptor (ER) status of breast cancers, with the potential to overcome
      many of the shortcomings associated with the traditional ligand-binding assay
      (LBA). The purpose of this study was to evaluate the ability of ER status
      determination by IHC, compared with LBA, to predict clinical outcome-especially
      response to adjuvant endocrine therapy-in a large number of patients with long
      term clinical follow-up. PATIENTS AND METHODS: ER status was evaluated in 1,982
      primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue
      sections, using antibody 6F11 and standard methodology. Slides were scored on a
      scale representing the estimated proportion and intensity of positive-staining
      tumor cells (range, 0 to 8). Results were compared with ER values obtained by the
      LBA in the same tumors and to clinical outcome. RESULTS: An IHC score of greater
      than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to
      define ER positivity on the basis of a univariate cut-point analysis of all
      possible scores and disease-free survival (DFS) in patients receiving any
      adjuvant endocrine therapy. Using this definition, 71% of all tumors were
      determined to be ER-positive by IHC, and the level of agreement with the LBA was
      86%. In multivariate analyses of patients receiving adjuvant endocrine therapy
      alone, ER status determined by IHC was better than that determined by the LBA at
      predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214,
      respectively) and equivalent at predicting overall survival (0.379/.0001 and
      0.381/.0003, respectively). CONCLUSION: IHC is superior to the LBA for assessing
      ER status in primary breast cancer because it is easier, safer, and less
      expensive, and has an equivalent or better ability to predict response to
      adjuvant endocrine therapy.

PMID- 10334534
TI  - Estrogen replacement therapy after localized breast cancer: clinical outcome of
      319 women followed prospectively.
AB  - PURPOSE: To determine whether estrogen replacement therapy (ERT) alters the
      development of new or recurrent breast cancer in women previously treated for
      localized breast cancer. PATIENTS AND METHODS: Potential participants (n = 319)
      in a trial of ERT after breast cancer were observed prospectively for at least 2
      years whether they enrolled onto the randomized trial or not. Of 319 women, 39
      were given estrogen and 280 were not given hormones. Tumor size, number of lymph
      nodes, estrogen receptors, menopausal status at diagnosis, and disease-free
      interval at the initiation of the observation period were comparable for the
      trial participants (n = 62) versus nonparticipants (n = 257) and for women on ERT
      (n = 39) versus controls (n = 280). Cancer events were ascertained for both
      groups. RESULTS: Patient and disease characteristics were comparable for the
      trial participants versus nonparticipants, as well as for the women on ERT versus
      the controls. One patient in the ERT group developed a new lobular estrogen
      receptor-positive breast cancer 72 months after the diagnosis of a ductal
      estrogen receptor-negative breast cancer and 27 months after initiation of ERT.
      In the control group, there were 20 cancer events: 14 patients developed new or
      recurrent breast cancer at a median time of 139.5 months after diagnosis and six
      patients developed other cancers at a median time of 122 months. CONCLUSION: ERT
      does not seem to increase breast cancer events in this subset of patients
      previously treated for localized breast cancer. Results of randomized trials are
      needed before any changes in current standards of care can be proposed.

PMID- 10334535
TI  - Effect of tamoxifen on sexual functioning in patients with breast cancer.
AB  - PURPOSE: To define the incidence of sexual dysfunction in a population of women
      with breast cancer treated with tamoxifen. PATIENTS AND METHODS: Breast cancer
      patients with a performance status of 0 to 2 who had been treated with tamoxifen
      for 2 to 24 months completed the following measures: the Center for Epidemiologic
      Studies-Depression Scale, the Sexual History Form, and the Breast Cancer
      Prevention Trial Symptom Checklist. Forty-nine of the participants underwent
      gynecologic examinations with vaginal smears for determination of estrogen
      effect. RESULTS: Fifty-seven women were entered onto the trial. Sexual desire,
      arousal, and ability to achieve orgasm were comparable to norms established in
      participants in the Tamoxifen Prevention Trial (National Surgical Adjuvant Breast
      and Bowel Project P-01). Pain, burning, or discomfort with intercourse was
      reported in 54% of patients and did not correlate with age, surgical treatment of
      the primary cancer, or chemotherapy. Estrogen effect was seen on the vaginal
      smears of 34 of 49 participants and was more common in older patients (P = .054).
      The presence of estrogen effect correlated with negative reactions during sex (P
      = .02) and vaginal dryness or tightness (P = .046). CONCLUSION: Women treated
      with tamoxifen in the adjuvant setting experienced symptoms of sexual
      dysfunction. The individual contributions of chemotherapy and tamoxifen to sexual
      dysfunction warrant prospective study.

PMID- 10334536
TI  - Testicular function after cytotoxic chemotherapy: evidence of Leydig cell
      insufficiency.
AB  - PURPOSE: To evaluate testicular function in men after treatment with cytotoxic
      chemotherapy. PATIENTS AND METHODS: We measured testosterone, sex hormone-binding
      globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)
      levels in 209 men after treatment with mechlorethamine, vinblastine,
      procarbazine, and prednisone, hybrid chemotherapy, or high-dose chemotherapy and
      in 54 healthy age-matched controls. RESULTS: The mean age of the patients was 38
      years (range, 19 to 68 years), and all patients had received chemotherapy between
      1 and 22 years previously. Patients had significantly higher mean LH (7.9 v 4.1
      IU/L; P < .0001) and FSH levels (18.8 v 3.1 IU/L; P < .0001) than controls. There
      was no significant difference in mean total testosterone level between the
      patients and controls, but there was a trend toward a lower mean
      testosterone/SHBG ratio in the patients (0.63 v 0.7; P = .08). Analysis of the
      hormonal parameters using a model that allowed for the effects of increasing age
      on testicular function showed evidence of significant recovery of gonadal
      function in the first 10 years after treatment. Fifty-two percent of patients had
      LH levels at or above the upper limit of normal, and 32% of patients had
      increased LH with testosterone levels in the lower half of the normal range,
      suggesting a degree of Leydig cell impairment. CONCLUSION: In a significant
      proportion of men, there is good evidence of Leydig cell dysfunction after
      cytotoxic chemotherapy. The clinical significance of this Leydig cell dysfunction
      is not clear, but some of these men may benefit from testosterone replacement.
      Further studies are warranted.

PMID- 10334537
TI  - Postoperative nomogram for disease recurrence after radical prostatectomy for
      prostate cancer.
AB  - PURPOSE: Although models exist that place patients into discrete groups at
      various risks for disease recurrence after surgery for prostate cancer, we know
      of no published work that combines pathologic factors to predict an individual's
      probability of disease recurrence. Because clinical stage and biopsy Gleason
      grade only approximate pathologic stage and Gleason grade in the prostatectomy
      specimen, prediction of prognosis should be more accurate when postoperative
      information is added to preoperative variables. Therefore, we developed a
      postoperative nomogram that allows more accurate prediction of probability for
      disease recurrence for patients who have received radical prostatectomy as
      treatment for prostate cancer, compared with the preoperative nomogram we
      previously published. PATIENTS AND METHODS: By Cox proportional hazards
      regression analysis, we modeled the clinical and pathologic data and disease
      follow-up for 996 men with clinical stage T1a-T3c NXM0 prostate cancer who were
      treated with radical prostatectomy by a single surgeon at our institution.
      Prognostic variables included pretreatment serum prostate-specific antigen level,
      specimen Gleason sum, prostatic capsular invasion, surgical margin status,
      seminal vesicle invasion, and lymph node status. Treatment failure was recorded
      when there was either clinical evidence of disease recurrence, a rising serum
      prostate-specific antigen level (two measurements of 0.4 ng/mL or greater and
      rising), or initiation of adjuvant therapy. Validation was performed on this set
      of men and a separate sample of 322 men from five other surgeons' practices from
      our institution. RESULTS: Cancer recurrence was noted in 189 of the 996 men, and
      the recurrence-free group had a median follow-up period of 37 months (range, 1 to
      168 months). The 7-year recurrence-free probability for the cohort was 73% (95%
      confidence interval, 68% to 76%). The predictions from the nomogram appeared to
      be accurate and discriminating, with a validation sample area under the receiver
      operating characteristic curve (ie, a comparison of the predicted probability
      with the actual outcome) of 0.89. CONCLUSION: A postoperative nomogram has been
      developed that can be used to predict the 7-year probability of disease
      recurrence among men treated with radical prostatectomy.

PMID- 10334538
TI  - Prospective study of fluorodeoxyglucose-positron emission tomography imaging of
      lymph node basins in melanoma patients undergoing sentinel node biopsy.
AB  - PURPOSE: To prospectively compare positron emission tomography (PET) imaging of
      regional lymph node basins to sentinel node biopsy (SNB) in patients with
      American Joint Committee on Cancer (AJCC) stage I, II, and III melanoma localized
      to the skin. METHODS: Patients with cutaneous melanoma with Breslow's depth
      greater than 1 mm (AJCC T2-4N0M0) or localized regional cutaneous recurrence
      (TxN2bM0) underwent whole-body imaging of glucose metabolism with
      fluorodeoxyglucose (FDG) PET followed by SNB. PET scans were interpreted in a
      blinded fashion and compared with histologic analyses of SNB specimens and
      clinical follow-up examination. Nodal tumor volumes were estimated. RESULTS:
      Eighty-nine lymph node basins were evaluated by FDG-PET and SNB in 70 assessable
      patients. Eighteen patients (25.7%) had lymph node metastases at the time of FDG
      PET imaging: 17 proved by SNB (24.3%) and one by follow-up examination (1.4%).
      Median tumor volume in positive sentinel node basins was 4.3 mm3 (range, 0.07 to
      523 mm3). Sensitivity of SNB for detection of occult regional lymph node
      metastases was 94.4%, specificity was 100%, positive predictive value (PPV) was
      100%, and negative predictive value (NPV) was 98.6%. Sensitivity of FDG-PET was
      16.7%, specificity was 95.8%, PPV was 50%, and NPV was 81.9%. At a median follow
      up duration of 16.6 months, seven patients (10%) developed recurrent disease. PET
      predicted one recurrence (14.3%) in a node basin missed by SNB. CONCLUSION: FDG
      PET is an insensitive indicator of occult regional lymph node metastases in
      patients with melanoma because of the minute tumor volumes in this population.
      FDG-PET does not have a primary role for staging regional nodes in patients with
      clinically localized melanoma.

PMID- 10334539
TI  - Irinotecan therapy in adults with recurrent or progressive malignant glioma.
AB  - PURPOSE: To determine the activity, toxicity, and pharmacokinetics of irinotecan
      (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults
      with progressive, persistent, or recurrent malignant glioma. PATIENTS AND
      METHODS: Patients with progressive or recurrent malignant gliomas were enrolled
      onto this study between October 1996 and August 1997. CPT-11 was given as a 90
      minute intravenous (i.v.) infusion at a dose of 125 mg/m2 once weekly for 4 weeks
      followed by a 2-week rest, which comprised one course. Plasma concentrations of
      CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined
      in a subset of patients. RESULTS: All 60 patients who enrolled (36 males and 24
      females) were treated with CPT-11 and all were assessable for toxicity, response,
      and survival. Pharmacokinetic data were available in 32 patients. Nine patients
      (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and
      33 patients (55%) achieved stable disease lasting more than two courses (12
      weeks). Toxicity observed during the study was limited to infrequent neutropenia,
      nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma
      concentration-time curves through infinite time values in these patients were
      approximately 40%, 25%, and 25%, respectively, of those determined previously in
      patients with metastatic colorectal cancer not receiving antiepileptics or
      chronic dexamethasone treatment. CONCLUSION: Response results document that CPT
      11, given with a standard starting dose and treatment schedule, has activity in
      patients with recurrent malignant glioma. However, the low incidence of severe
      toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this
      patient population suggest that concurrent treatment with anticonvulsants and
      dexamethasone enhances drug clearance.

PMID- 10334540
TI  - Cisplatin, gemcitabine, and vinorelbine combination therapy in advanced non-small
      cell lung cancer: a phase II randomized study of the Southern Italy Cooperative
      Oncology Group.
AB  - PURPOSE: In a previous phase I study cisplatin (CDDP), gemcitabine (GEM), and
      vinorelbine (VNR) combination therapy was safe and very active in patients with
      non-small-cell lung cancer (NSCLC). This study was aimed at better defining the
      activity and toxicity of this regimen. PATIENTS AND METHODS: One hundred eleven
      chemotherapy-naive patients, age < or = 70 years, with stage IIIB or IV NSCLC and
      a performance status of 0 or 1 (Eastern Cooperative Oncology Group scale) were
      randomized to two treatment arms. Patients on arm A received CDDP 50 mg/m2, GEM
      1,000 mg/m2, and VNR 25 mg/m2 on days 1 and 8 of an every-3-weeks cycle (57
      patients). Patients on arm B received CDDP 80 mg/m2, epirubicin 80 mg/m2, and
      vindesine 3 mg/m2, all delivered on day 1 every 4 weeks, plus lonidamine orally
      150 mg three times daily (54 patients). In December 1996, randomization was
      stopped early, and an additional 30 patients were treated with the experimental
      regimen to obtain a more accurate estimation of its activity rate. RESULTS: Among
      87 patients who received the CDDP-GEM-VNR combination, four complete responses
      (CRs) and 46 partial responses (PRs) were observed, for an overall response rate
      of 57% (95% confidence interval [CI], 46% to 68%). Two CRs and 18 PRs were
      recorded among 54 patients on arm B, giving a 37% activity rate (95% CI , 24% to
      51%). After a median follow-up duration of 19 months, the median progression-free
      and overall survival durations were 32 and 50 weeks in arm A, and 18 and 33 weeks
      in arm B, respectively. World Health Organization grade 3 to 4 neutropenia and
      thrombocytopenia occurred in 46% and 14% of patients in arm A and in 22% and 11%
      of those in arm B, respectively. Severe nonhematologic toxicity was uncommon in
      both arms. CONCLUSION: The CDDP-GEM-VNR combination is a highly effective
      treatment for patients with advanced NSCLC and has a manageable toxicity. A phase
      III trial comparing this new combination with both CDDP-VNR and CDDP-GEM regimens
      is underway.

PMID- 10334541
TI  - Expression of MUC-1 epitopes on normal bone marrow: implications for the
      detection of micrometastatic tumor cells.
AB  - PURPOSE: The expression of the carcinoma-associated mucin MUC-1 is thought to be
      restricted to epithelial cells and is used for micrometastatic tumor cell
      detection in patients with solid tumors, including those with breast cancer.
      Little is known, however, about the expression of MUC-1 epitopes in normal
      hematopoietic cells. MATERIALS AND METHODS: MUC-1 expression was analyzed by flow
      cytometry and immunocytology on bone marrow (BM) mononuclear cells and purified
      CD34+ cells from healthy volunteers, using different anti-MUC-1-specific
      monoclonal antibodies. In addition, Western blotting of MUC-1 proteins was
      performed. RESULTS: Surprisingly, 2% to 10% of normal human BM mononuclear cells
      expressed MUC-1, as defined by the anti-MUC-1 antibodies BM-2 (2E11), BM-7,
      12H12, MAM-6, and HMFG-1. In contrast, two antibodies recognizing the BM-8 and
      the HMFG-2 epitopes of MUC-1 were not detected. MUC-1+ cells from normal BM
      consisted primarily of erythroblasts and normoblasts. In agreement with this,
      normal CD34+ cells cultured in vitro to differentiate into the erythroid lineage
      showed a strong MUC-1 expression on day 7 proerythroblasts. Western blotting of
      these cells confirmed that the reactive species is the known high molecular
      weight MUC-1 protein. CONCLUSION: Our data demonstrate that some MUC-1 epitopes
      are expressed on normal BM cells and particularly on cells of the erythroid
      lineage. Hence the application of anti-MUC-1 antibodies for disseminated tumor
      cell detection in BM or peripheral blood progenitor cells may provide false
      positive results, and only carefully evaluated anti-MUC-1 antibodies (eg, HMFG-2)
      might be selected. Furthermore, MUC-1-targeted immunotherapy in cancer patients
      might be hampered by the suppression of erythropoiesis.

PMID- 10334542
TI  - Improved outcome with T-cell-depleted bone marrow transplantation for acute
      leukemia.
AB  - PURPOSE: To eliminate the risk of rejection and lower the risk of relapse after T
      cell-depleted bone marrow transplants in acute leukemia patients, we enhanced
      pretransplant immunosuppression and myeloablation. PATIENTS AND METHODS:
      Antithymocyte globulin and thiotepa were added to standard total-body
      irradiation/cyclophosphamide conditioning. Donor bone marrows were depleted ex
      vivo of T lymphocytes by soybean agglutination and E-rosetting. This approach was
      tested in 54 consecutive patients with acute leukemia who received transplants
      from HLA-identical sibling donors or, in two cases, from family donors mismatched
      at D-DR. No posttransplant immunosuppressive treatment was given as graft-versus
      host disease (GVHD) prophylaxis. RESULTS: Neither graft rejection nor GVHD
      occurred. Transplant-related deaths occurred in six (16.6%) of 36 patients in
      remission and in seven (38.8%) of 18 patients in relapse at the time of
      transplantation. The probability of relapse was .12 (95% confidence interval
      [CI], 0 to .19) for patients with acute myeloid leukemia and .28 (95% CI, .05 to
      .51) for patients with acute lymphoblastic leukemia who received transplants at
      the first or second remission. At a median follow-up of 6.9 years (minimum follow
      up, 4.9 years), event-free survival for patients who received transplants while
      in remission was .74 (95% CI, .54 to .93) for acute myeloid leukemia patients and
      .59 (95% CI, .35 to .82) for acute lymphoblastic leukemia patients. All surviving
      patients have 100% performance status. CONCLUSION: Adding antithymocyte globulin
      and thiotepa to the conditioning regimen prevents rejection of extensively T-cell
      depleted bone marrow. Even in the complete absence of GVHD, the leukemia relapse
      rate is not higher than in unmanipulated transplants.

PMID- 10334543
TI  - Plasmablastic morphology is an independent predictor of poor survival after
      autologous stem-cell transplantation for multiple myeloma.
AB  - PURPOSE: To study the prognostic value of plasmablastic morphology after
      autologous stem-cell transplantation for relapsed or primary refractory myeloma.
      PATIENTS AND METHODS: Seventy-five patients were studied. Investigators blinded
      to the clinical details of the individual cases reviewed bone marrow aspirate
      slides to determine plasmablastic classification. Plasmablasts were defined using
      strict, well-described criteria. Plasmablastic morphology was considered to be
      present (plasmablastic myeloma) when 2% or more plasmablasts were present in the
      plasma-cell population. RESULTS: Patients underwent transplantation 5 to 88
      months (median, 20 months) after the initial diagnosis of myeloma. Twenty-eight
      percent of patients had plasmablostic morphology. A significantly greater
      proportion of patients with plasmablastic morphology had abnormal cytogenetics
      compared with those with nonplasmablastic classification (73% v 31%,
      respectively; P = .003). The overall survival rate measured from the time of
      transplantation was significantly worse in patients with plasmablastic morphology
      compared with those without (median survival time, 5 months v 24 months,
      respectively; P < .001). Progression-free survival time was shortened also, with
      a median time of 4 months compared with 12 months, respectively (P < .001). In
      the multivariate analysis, plasmablastic classification was the most powerful
      prognostic factor after transplantation for both overall (P = .001) and
      progression-free survival rates (P < .001). We also identified three risk groups
      based on plasmablastic morphology: plasma-cell labeling index, lactate
      dehydrogenase, and cytogenetics. The median overall survival time was 38 months
      when none of these factors was abnormal, 17 months with one abnormal factor, and
      8 months with two or more abnormal factors (P < .001). CONCLUSION: Plasmablastic
      morphology is a powerful independent predictor of poor survival rate after
      autologous stem-cell transplantation for relapsed or primary refractory myeloma.

PMID- 10334544
TI  - Small noncleaved, non-Burkitt's (Burkit-Like) lymphoma: cytogenetics predict
      outcome and reflect clinical presentation.
AB  - PURPOSE: To correlate cytogenetic abnormalities with clinical presentation and
      outcome in Burkitt-like, small noncleaved non-Burkitt's lymphoma (SNC-NB).
      PATIENTS AND METHODS: Thirty-nine patients with SNC-NB lymphoma and a clonal
      karyotype were evaluated between January 1989 and January 1996. All were from
      British Columbia, Canada, underwent uniform clinical staging, and were treated on
      investigational protocols by a small group of clinicians. RESULTS: Three groups
      of patients were identified by clonal karyotype on cytogenetic analysis: (1)
      those with a c-myc translocation (n = 11); (2) those with dual translocation of c
      myc and bcl-2 (n = 13); and (3) those with other cytogenetic abnormalities (n =
      15). The c-myc group was younger, presented with earlier stage de nova disease,
      and had a better clinical prognostic factor profile. The dual-translocation and
      other groups were older and presented in advanced stage with poorer prognostic
      features, and a larger proportion of the dual-translocation group patients had
      transformed from previously diagnosed follicular lymphoma. The median overall
      survival (OS) time for all patients was 5 months. The median OS time for the dual
      translocation group was only 2.5 months, as compared with 7 months and 8 months
      for the c-myc and other group, respectively (P < .001). There were no survivors
      beyond 7 months among the dual-translocation group, as opposed to 32% and 25% 2
      year OS rates in the c-myc and other group. CONCLUSION: SNC-NB lymphoma is a
      clinically and cytogenetically heterogenous disease. Dual translocation of c-myc
      and bcl-2 is characterized by a rapid clinical course and extremely poor outcome.
      This latter entity may represent the most clinically aggressive lymphoma thus far
      characterized and warrants intensive investigational treatment where feasible.

PMID- 10334545
TI  - Cerebrospinal fluid asparagine concentrations after Escherichia coli asparaginase
      in children with acute lymphoblastic leukemia.
AB  - PURPOSE: The CNS is an important sanctuary site in childhood acute lymphoblastic
      leukemia (ALL). CSF asparagine concentration reflects asparaginase systemic
      pharmacodynamics. We evaluated the time course of CSF asparagine depletion in
      children with ALL during and after a course of Escherichia coli asparaginase.
      PATIENTS AND METHODS: Thirty-one children (24 newly diagnosed and seven at
      relapse) received E coli asparaginase 10,000 IU/m2 intramuscularly three times
      weekly for six and nine doses, respectively, as part of multiagent induction
      chemotherapy. CSF asparagine levels were measured before, during, and after
      asparaginase dosing. RESULTS: The percentage of patients with undetectable (<
      0.04 micromol/L) CSF asparagine was 3.2% (one of 31 patients) at baseline, 73.9%
      (17 of 23) during asparaginase therapy, and 56.3% (nine of 16) 1 to 5 days, 43.8%
      (seven of 16) 6 to 10 days, 20.0% (two of 10) 11 to 30 days and 0% (zero of 21)
      more than 30 days after asparaginase therapy. The proportion of patients with
      depleted CSF asparagine was higher during asparaginase therapy than at baseline
      (P < .001), 11 to 30 days (P = .003), and more than 30 days after asparaginase
      therapy (P < .001). Median CSF asparagine concentrations were 4.42 micromol/L
      before, less than 0.04 micromol/L during, and less than 0.04 micromol/L at 1 to 5
      days, 1.63 micromol/L at 6 to 10 days, 1.70 micromol/L at 11 to 30 days, and 5.70
      micromol/L at more than 30 days after asparaginase therapy, respectively. CSF
      depletion was more common in patients with low baseline CSF asparagine
      concentrations (P = .003). CONCLUSION: CSF asparagine concentrations are depleted
      by conventional doses of E coli asparaginase in the majority of patients, but
      they rebound once asparaginase therapy is completed.

PMID- 10334546
TI  - Pharmacokinetic study of single doses of oral fludarabine phosphate in patients
      with "low-grade" non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia.
AB  - PURPOSE: Fludarabine phosphate (F-AMP), a purine analog, requires daily
      intravenous administration. A pharmacokinetic study of an oral formulation (10 mg
      immediate-release tablet) was undertaken in patients with "low-grade" non
      Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia. PATIENTS AND METHODS:
      Oral F-AMP was incorporated into the "conventional" treatment schedule. Single
      oral trial doses of 50, 70, and 90 mg of F-AMP were given on the first day of
      three cycles of treatment; a comparative 50-mg intravenous trial dose was given
      on the first day of the fourth cycle. Intravenous F-AMP (25 mg/m2) was given on
      days 2 to 5 at 4-week intervals. Pharmacokinetic samples taken after each trial
      dose were analyzed for plasma 2-fluoro-arabinofuranosyladenine (2F-ara-A)
      concentration (its main metabolite); area under the curve 0 to 24 hours (AUC(0
      24h)) and maximum concentration (Cmax) were calculated. Eighteen patients
      received all three oral trial doses, and bioavailability was determined in 15
      patients who completed four courses of therapy. RESULTS: Oral administration of F
      AMP resulted in a dose-dependent increase in Cmax and AUC(0-24h) of 2F-ara-A and
      achieved an AUC(0-24h) similar to intravenous administration, although at a lower
      Cm. The linear increase in mean AUC(0-24h) by factors of 1.36 +/- 0.22 (mean +/-
      SD) and 1.72 +/- 0.31 corresponded well with the increase in oral dose from 50 to
      70 mg (factor of 1.4) and 90 mg (factor of 1.8), respectively. Bioavailability
      (approximately 55%, with low intraindividual variation) and time to Cmax were
      dose independent. CONCLUSION: Oral doses of F-AMP can achieve an AUC(0-24h) of 2F
      ara-A similar to intravenous administration, with dose-independent
      bioavailability. The tablet will greatly enhance the use of F-AMP in a palliative
      setting.

PMID- 10334547
TI  - Tumor, normal tissue, and plasma pharmacokinetic studies of fluorouracil
      biomodulation with N-phosphonacetyl-L-aspartate, folinic acid, and interferon
      alfa.
AB  - PURPOSE: To evaluate the effect of N-phosphonacetyl-L-aspartate (PALA), folinic
      acid (FA), and interferon alfa (IFN-alpha) biomodulation on plasma fluorouracil
      (5FU) pharmacokinetics and tumor and liver radioactivity uptake and retention
      after [18F]-fluorouracil (5-[18F]-FU) administration. PATIENTS AND METHODS:
      Twenty-one paired pharmacokinetic studies were completed on patients with
      colorectal, gastric, and hepatocellular cancer, utilizing positron emission
      tomography (PET), which allowed the acquisition of tumor, normal tissue, and
      plasma pharmacokinetic data and tumor blood flow (TBF) measurements. The first
      PET study was completed when the patient was biomodulator-naive and was repeated
      on day 8 after the patient had been treated with either PALA, FA, or IFN-alpha in
      recognized schedules. RESULTS: TBF was an important determinant of tumor
      radioactivity uptake (r = .90; P < .001) and retention (r = .96; P < .001), for
      which radioactivity represents a composite signal of 5-[18F]-FU and [18F]-labeled
      metabolites and catabolites. After treatment with PALA, TBF decreased (four of
      four patients; P = .043), as did tumor radioactivity exposure (five of five
      patients; P = .0437), with no change in plasma 5FU clearance. With FA treatment,
      there were no differences observed in whole-body metabolism, plasma 5FU
      clearance, or tumor and liver pharmacokinetics. IFN-alpha had measurable effects
      on TBF and 5-[18F]-FU metabolism but had no apparent affect on liver blood flow.
      CONCLUSION: The administration of PALA and IFN-alpha produced measurable changes
      in plasma, tumor, and liver pharmacokinetics after 5-[18F]-FU administration. No
      changes were observed after FA administration. In vivo effects may negate the
      anticipated therapeutic advantage of 5FU biomodulation with some agents.

PMID- 10334548
TI  - High-dose leucovorin as sole therapy for methotrexate toxicity.
AB  - PURPOSE: Hemodialysis, hemoperfusion, thymidine, and carboxypeptidase have been
      recommended together with high-dose (HD) leucovorin (LV) to treat patients at
      risk for methotrexate (MTX) toxicity. To elucidate the efficacy of high LV rescue
      as the sole salvage modality for severe MTX intoxication, we studied 13 patients
      who were treated in this fashion at Memorial Sloan-Kettering Cancer Center (New
      York, NY). PATIENTS AND METHODS: To identify patients at high risk for severe MTX
      toxicity, we performed a retrospective review of all patients with MTX levels
      greater than 100 micromol/L at 24 hours and greater than 10 micromol/L at 48
      hours after HD MTX. RESULTS: A total of 13 patients were identified. The median
      MTX concentration was 164 micromol/L at 24 hours (range, 102 to 940 micromol/L),
      16.3 micromol/L at 48 hours (range, 10.5 to 190 micromol/L), and 6.2 micromol/L
      at 72 hours (range, 1.35 to 39 micromol/L). MTX levels remained greater than 0.1
      micromol/L for an average of 11 +/- 3 days (mean +/- SD) (range, 7 to 17 days).
      In addition to supportive treatment with hydration and sodium bicarbonate
      administration, all patients were treated solely with HD LV, which was started
      within the first 24 hours in nine patients, 48 hours in three patients, and 72
      hours in one patient in doses that varied from 0.24 to 8 g/d. Significant
      neutropenia (neutrophil count < 1,000/ microL) occurred in eight patients and
      lasted for 1 to 5 days. Thrombocytopenia (platelet count < 100,000/microL)
      occurred in seven patients and lasted for 5 to 10 days. Other toxic
      manifestations included mucositis of varying degrees, diarrhea, and neutropenic
      fever, but all patients recovered. CONCLUSION: In the range of MTX levels
      observed, HD LV can be used as a sole therapy for MTX toxicity without the need
      for extracorporeal removal and with tolerable morbidity.

PMID- 10334549
TI  - Moral concerns of different types of patients in clinical BRCA1/2 gene mutation
      testing.
AB  - PURPOSE: Implementing predictive genetic testing for a severe and common chronic
      disease such as breast cancer may raise unique ethical problems. Here we report
      on moral concerns experienced by patients in the setting of genetic counseling
      based on BRCA1/2 gene testing. PATIENTS AND METHODS: Patients were members of
      breast or breast/ovarian cancer families in a consecutive series of 100 families
      who received counseling at a familial cancer clinic. The patients' moral concerns
      were identified using the grounded theory approach in the qualitative analysis of
      verbal transcripts of 45 counseling sessions. Included were sessions with
      patients who had breast and ovarian cancer, as well as their male and female
      relatives, before and after the specific BRCA1/2 gene mutation was identified in
      the family, and before and after those who opted for mutation analysis were
      informed of their carrier status. RESULTS: There is an association of BRCA1/2
      gene mutation carrier status and specific topics of moral concern. The moral
      preoccupations of patients with breast and ovarian cancer (probable carriers)
      related to their being instrumental in the detection of the specific mutation
      segregating in the family. The preoccupations of possible carriers concerned
      their own offspring. Individuals who tested positive (proven carriers) were
      concerned with issues of confidentiality. Patients who tested negative (proven
      noncarriers) were concerned with helping siblings and other relatives.
      CONCLUSION: Knowledge of the moral concerns of subjects in the study sample may
      help health care providers be aware of the moral concerns of their own patients.
      This report may also contribute to the debate on predictive testing for familial
      adult-onset diseases from the patient's perspective.

PMID- 10334550
TI  - Impact of therapeutic research on informed consent and the ethics of clinical
      trials: a medical oncology perspective.
AB  - PURPOSE: To create a more meaningful understanding of the informed consent
      process as it has come to be practiced and regulated in clinical trials, this
      discussion uses the experience gained from the conduct of therapeutic research
      that involves cancer patients. DESIGN: After an introduction of the ethical
      tenets of the consent process in clinical research that involves potentially
      vulnerable patients as research subjects, background that details the use of
      written consent documents and of the term "informed consent" is provided. Studies
      from the cancer setting that examine the inadequacies of written consent
      documents, and the outcome of the consent process itself, are reviewed. Two
      ethically challenging areas of cancer clinical research, the phase I trial and
      the randomized controlled trial, are discussed briefly as a means of highlighting
      many dilemmas present in clinical trials. Before concluding, areas for future
      research are discussed. RESULTS: Through an exclusive cancer research
      perspective, many current deficiencies in the informed consent process for
      therapeutic clinical trials can be critically examined. Also, new directions for
      improvements and areas of further research can be outlined and discussed
      objectively. The goals of such improvements and research should be prevention of
      further misguided or ineffective efforts to regulate the informed consent
      process. CONCLUSION: To ignore this rich and interesting perspective potentially
      contributes to continued misunderstanding and apathy toward fulfilling the
      regulatory and ethically obligatory requirements involved in an essential
      communication process between a clinician-investigator and a potentially
      vulnerable patient who is considering clinical trial participation.

PMID- 10334552
TI  - Review of the efficacy of individualized chemotherapy selected by in vitro drug
      sensitivity testing for patients with cancer.
AB  - PURPOSE: The purpose of this study is to review the potential efficacy of
      individualized chemotherapy selected by in vitro drug sensitivity testing (DST)
      compared with empiric regimens for patients with cancer. METHODS: MEDLINE and
      CANCERLIT were searched for articles published (in English) about prospective
      clinical trials in which patients were treated with chemotherapy that was
      selected with the use of in vitro DST. RESULTS: We identified 12 prospective
      studies that examined the benefit of chemotherapy selected by DST. Five hundred
      six patients (33%) were treated with chemotherapy that was selected with the use
      of in vitro DST. The mean response rate for patients treated with in vitro
      selected therapy was 27% (range, 10% to 100%; n = 12 studies) compared with 18%
      (range, 0% to 100%; n = 7 studies) for patients treated with empiric therapy.
      Five studies (only one randomized) evaluated the impact of chemotherapy selected
      by in vitro DST on patient survival. Three studies showed that survival was 1 to
      4 months longer for the 238 patients treated with empiric chemotherapy compared
      with that of the 65 patients treated with chemotherapy that was selected by in
      vitro testing. Two nonrandomized studies showed that survival was 4 or 19 months
      longer for 27 patients treated with chemotherapy selected by in vitro testing
      compared with that of 80 patients who were treated with empiric chemotherapy.
      CONCLUSION: Only one third of patients entered in prospective trials of in vitro
      DST were actually treated with an in vitro best regimen. The response rates seem
      to be better with in vitro selected chemotherapy regimens than with empiric
      regimens, but the impact on survival has not been adequately addressed.

PMID- 10334551
TI  - Role of FHIT in human cancer.
AB  - Through investigation of hemizygous and homozygous deletions in common human
      cancers, including lung cancer, we have cloned and characterized a gene at
      chromosome region 3p14.2, FHIT, that is inactivated in epithelial tumors,
      particularly in tumors resulting from exposure to environmental carcinogens. In
      some tumors, particularly those associated with environmental carcinogens,
      alterations in the FHIT gene occur quite early in the development of cancer. In
      other cancers, Fhit inactivation seems to be a later event, possibly associated
      with progression to more aggressive neoplasias. Thus, detection of Fhit
      expression by immunohistochemistry in premalignant and malignant tissues may
      provide important diagnostic and prognostic information.

PMID- 10334553
TI  - National Surgical Adjuvant Breast and Bowel Project breast cancer prevention
      trial: a reflective commentary.

PMID- 10334554
TI  - Uncommon sites of presentation of hematologic malignancies. Case 1: localized
      primary non-Hodgkin's lymphoma of the patella.

PMID- 10334555
TI  - Uncommon sites of presentation of hematologic malignancies. Case 2: diffuse
      muscle infiltration by granulocytic sarcoma seven years after acute
      myelomonocytic leukemia.

PMID- 10334556
TI  - Quality of life in advanced colorectal cancer.

PMID- 10334557
TI  - Misleading title and abstract in recent granulocyte-macrophage colony-stimulating
      factor trial.

PMID- 10334558
TI  - Prostate-specific antigen doubling time: a potential surrogate end point in
      hormone-refractory prostate cancer.

PMID- 10334559
TI  - Meta-analyses of published results are unreliable.

PMID- 10334560
TI  - Cardiotoxicity associated with paclitaxel/trastuzumab combination therapy.

PMID- 10334561
TI  - Use of placebos in delayed-emesis studies.

PMID- 10334562
TI  - Immunohistochemical assays for HER2 overexpression.

PMID- 10334563
TI  - Nephron number: variability is the rule. Causes and consequences.

PMID- 10334564
TI  - Suppression of T1-receptor expression by antisense RNA abrogates differentiation
      of osteogenic osteosarcoma cells.
AB  - Soluble and membrane-associated variants of the orphan T1-receptor, a homolog of
      interleukin-1 receptor type I, are expressed in proliferating preosteoblasts in
      differentiating bone. Recent evidence reveals that T1-receptor synthesis is
      retained in osteogenic osteosarcoma cells. Here we report that the suppression of
      T1-receptor expression by mouse osteosarcoma cells using a T1 -antisense
      expression vector results in the abrogation of the osteogenic potential of the
      tumor cells. T1-antisense-expressing tumor cells formed anaplastic tumors in vivo
      and failed to express the osteoblast-specific genes collagen type 1, alkaline
      phosphatase, and osteocalcin when cultured in a 3-dimensional collagen type I
      matrix in vitro. Suppression of T1-receptor synthesis did not affect the
      expression of the essential bone cell-specific transcription factor AML3/CBFA1 in
      the osteosarcoma cells. These data provide the first evidence that T1-receptor
      plays a key role in osteogenic differentiation.

PMID- 10334565
TI  - Trefoil factor-2, human spasmolytic polypeptide, promotes branching morphogenesis
      in MCF-7 cells.
AB  - Members of the trefoil factor (TFF) family are highly expressed in endodermal
      ulcerative wound healing and selectively in neoplastic proliferation of various
      glandular epithelia. There is some evidence that TFF1 and TFF3 affect cell
      motility, are indirectly involved in growth suppression, and are associated with
      mucin expression. TFF2 is co-expressed with TFF1 in gastric surface epithelial
      cells, but its potential role in vivo is unclear. We analyzed potential effects
      on cell proliferation and morphogenesis of TFF2 on a panel of epithelial and
      mesenchymal cell lines. TFF2 had no measurable effect on the proliferation of any
      of the cell lines tested. In type 1 collagen lattices, TFF2 at a low
      concentration (25-100 nM) induced the formation of highly complex branched
      structures in the breast carcinoma cell line MCF-7 over a period of 14 to 42
      days. No significant effect was shown with other cell lines. This morphogenic
      effect was abolished by monoclonal antibodies specific for either TFF2 or TFF1.
      TFF2 did not affect cell motility in MCF-7 cells as measured by videomicroscopy,
      in contrast to previous studies using TFF1. TFF2-treated MCF-7 colonies showed a
      30% reduction in the number of apoptotic bodies, corroborated by trypan blue
      exclusion and DNA fragmentation ELISA, indicating TFF2 promotes cell survival via
      inhibition of apoptosis and can act as a morphogen in the presence of TFF1. These
      properties may complement the actions of TFF1 as a motogen and may explain
      differential expression in endodermal wound healing.

PMID- 10334566
TI  - Frequent chromosomal DNA unbalance in thyroid oncocytic (Hurthle cell) neoplasms
      detected by comparative genomic hybridization.
AB  - Thyroid oncocytic (Hurthle cell) neoplasms represent a distinct subset of
      follicular thyroid tumors characterized by abnormal accumulation of mitochondria,
      whose chromosomal abnormalities have never been systematically analyzed. We have
      used comparative genomic hybridization to investigate chromosomal DNA alterations
      in 11 thyroid oncocytic tumors (7 adenomas and 4 carcinomas). Unbalanced
      chromosomal DNA profiles were detected in 6 of 7 adenomas and 3 of 4 carcinomas,
      numerical chromosomal aberrations being the dominant feature. Comparative genomic
      hybridization findings are compatible with two separate groups of tumors with
      karyotypic abnormalities, one characterized by multiple chromosomal gains with
      polysomy of chromosomes 5 and 7, the other by loss of chromosome 2. Pathologic
      and clinical features were similar in the two groups with no difference observed
      between adenomas and carcinomas. Activating H-, K-, or N-Ras mutations are
      commonly detected in follicular adenomas and carcinomas of the thyroid gland.
      However, Ras mutational analysis demonstrated that only one of the tumors in this
      series, an oncocytic carcinoma with a balanced karyotype, had activating Ras
      mutations (at codon 13 of K-Ras). The lack of Ras mutations in the 9 oncocytic
      neoplasms exhibiting chromosomal aneuploidy indicates that numerical chromosomal
      abnormalities are independent of activating Ras mutations in oncocytic tumors.

PMID- 10334568
TI  - Histology and ultrastructure of liver and kidney following blood exchange with
      ultrapurified, polymerised bovine hemoglobin in comparison with hydroxyethyl
      starch.
AB  - Because of their oxygen binding capacity, cell-free hemoglobin solutions are
      promising blood substitutes. However, their clinical use has so far been limited
      by toxic side effects on liver and kidney until ultrapurification and chemical
      modifications have been established in the production process of hemoglobin-based
      oxygen carriers. The present study has been designed to examine structural
      changes of liver and kidney by light and electron microscopy after complete
      isovolemic blood exchange with a new ultrapurified bovine hemoglobin solution
      (UPBH-2) in eight beagle dogs. The results have been compared with a sham
      operated control and eight animals having undergone blood exchange with
      hydroxyethyl starch (HES), a clinically used colloidal volume substitute. In the
      kidney, no changes were observed after blood exchange with UPBH-2 as compared
      with the sham control. These findings indicate sufficient tissue oxygenation and
      lack of renal toxicity. In contrast, histological signs of severe proximal
      tubular damage, eg, wide lumina, cytoplasmic protrusions, brush-border defects,
      and tubular necroses, were seen after blood exchange with HES. These changes are
      consistent with hypoxic tissue damage. In the liver, a slight increase in the
      number of single cell necroses was observed after UPBH-2 treatment as well as
      after blood exchange with HES. At the ultrastructural level, partial loss of
      microvilli and cytoplasmic protrusions of hepatocytes as well as swelling of
      endothelial cells were present in both groups, but slightly more pronounced in
      the UPBH-2 group. In all UPBH-2-treated animals, a marked diminution of glycogen
      granula in hepatocytes was observed indicating an influence of UPBH-2 upon
      glycogen metabolism. Whereas the alterations of hepatocytes after nearly complete
      blood exchange with HES can be interpreted as a consequence of tissue hypoxia,
      the ultrastructural changes after UPBH-2 treatment cannot be attributed to
      hypoxic conditions, because improved tissue oxygenation has been demonstrated
      during treatment with UPBH-2. Hepatocyte damage was very discrete and comparable
      with the alterations observed after HES treatment. Hence, major hepatotoxicity
      can be excluded. The absence of significant adverse effects on the
      ultrastructural integrity of the kidney indicates that UPBH-2, owing to
      ultrapurification and polymerization, is an oxygen-carrying hemoglobin without
      acute renal toxicity.

PMID- 10334569
TI  - Pleomorphic adenoma gene 1 is expressed in cultured benign and malignant salivary
      gland tumor cells.
AB  - The pleomorphic adenoma gene 1 (PLAG1) is activated by reciprocal chromosomal
      translocations involving 8q12 in a subset of salivary gland pleomorphic adenomas.
      PLAG1 encodes a zinc finger protein and was initially reported to be expressed in
      placenta and fetal tissues, with no detectable expression in other normal adult
      tissues. By Northern blotting we have detected PLAG1 expression in a wide set of
      normal adult tissues, including heart, placenta, spleen, prostate, testis, ovary,
      and small intestine. We have performed reverse transcriptase-PCR and Northern
      blot analyses to study the expression of PLAG1 in normal salivary gland tissues
      and in primary cultures and cell lines derived from salivary gland tumors. PLAG1
      was expressed in all tumor-derived primary cultures and cell lines, irrespective
      of their histological type or the presence of genomic rearrangements involving
      PLAG1, but was not detected by our assays in normal salivary glands. Our data
      indicate that the presence or absence of PLAG1 expression is not an unequivocal
      marker for the differential diagnosis of benign versus malignant salivary gland
      tumors, and that a simple de novo activation of this gene does not fully explain
      the involvement of this gene in salivary gland tumors.

PMID- 10334567
TI  - Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 act as
      "epitheliotrophins" in murine skin.
AB  - Nerve growth factor (NGF) is produced by keratinocytes and modulates their
      proliferation and apoptosis. However, it is as yet unknown whether other members
      of the NGF family of neurotrophins, brain-derived neurotrophic factor (BDNF),
      neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), also modulate keratinocyte
      proliferation in situ. We determined by ELISA and reverse transcriptase-PCR that
      BDNF, NT-3, and NT-4 are expressed in C57BL/6 mouse skin. By immunofluorescence,
      the subcutaneous panniculus carnosus muscle and arrector pili muscle showed
      strong NT-3 immunoreactivity, whereas BDNF-IR was found only in skin nerve
      bundles. NT-4 immunoreactivity was noted in single epidermal keratinocytes. The
      high affinity receptor for both BDNF and NT-4, TrkB, was detected in basal and
      suprabasal epidermal keratinocytes, whereas the high affinity NT-3 receptor,
      TrkC, was observed in skin nerve bundles. Compared with the corresponding age
      matched wild-type mice, BDNF or NT-3-overexpressing transgenic mice showed a
      significantly increased epidermal thickness and enhanced number of Ki-67-positive
      (ie, proliferating) epidermal keratinocytes in vivo, whereas the number of these
      cells was substantially reduced in BDNF knockout mice. In skin organ culture of
      C57BL/6 mice, BDNF, NT-3, and NT-4 all significantly increased 5-bromo-2'
      deoxyuridine incorporation into epidermal keratinocytes. Co-administration of NGF
      neutralizing antibody failed to abrogate the stimulatory effect of NT-3 on
      keratinocyte proliferation in skin organ culture. This demonstrates that normal
      murine epidermal keratinocytes in situ are direct or indirect target cells for
      these neurotrophins. Therefore, BDNF, NT-3, and NT-4 can also act as
      "epitheliotrophins" and may thus be intimately involved in the control of
      epidermal homeostasis.

PMID- 10334570
TI  - Involvement of growth-related protein in lipopolysaccharide-induced rabbit
      arthritis: cooperation between growth-related protein and IL-8, and interrelated
      regulation among TNFalpha, IL-1, IL-1 receptor antagonist, IL-8, and growth
      related protein.
AB  - We investigated the functional role of a CXC chemokine, growth-related protein
      (GRO), in the recruitment of neutrophils in lipopolysaccharide (LPS)-induced
      rabbit arthritis. The amounts of GRO in the synovial fluids (SF) reached the
      first peak (major) at 2 hours and the second peak (minor) at 9 hours after
      injection of LPS into the knee joints. Administration of anti-GRO mouse
      monoclonal antibody inhibited 54% of the peak leukocyte accumulation at 9 hours
      (neutrophils greater than 95%), which was similar to the inhibition by anti-IL-8
      IgG (48%). Co-administration of these inhibitors increased the inhibition up to
      70% at 9 hours and also inhibited 65% of the initial phase of leukocyte
      infiltration at 2 hours (neutrophils greater than 99%), which was not affected by
      a single administration of each inhibitor. The amounts of GRO in SF at 2 hours
      were not altered by either anti-TNFalpha mAb or anti-IL-8 IgG, but reduced by
      rabbit recombinant IL-1 receptor antagonist (rrlL-1Ra) by 39%. The inhibition by
      rrlL-1 Ra was augmented further to 59% with coadministered anti-TNFalpha mAb. In
      contrast, the amounts of GRO at 9 hours were reduced by rrlL-1Ra by 67%. There
      was no additional reduction in the amounts of GRO at 9 hours by either
      combination of rrlL-1Ra with anti-TNFalpha mAb or anti-IL-8 IgG. Administration
      of anti-GRO mAb did not alter TNFalpha or IL-8 contents in SF at their peak (2
      hours), but reduced the amounts of IL-1beta at 6 hours and IL-1Ra at 9 hours by
      42% and 49%, respectively. These results provide evidence for the following: (a)
      GRO as well as IL-8 are important mediators involved in the recruitment of
      neutrophils both in the early and the late phase of LPS-induced arthritis, (b) IL
      1 produced in the early phase stimulates GRO production, (c) GRO plays a role in
      the later induction of IL-1beta and IL-1Ra, and (d) induction of GRO is not
      regulated by IL-8.

PMID- 10334572
TI  - Vitamin E prevents apoptosis in hippocampal neurons caused by cerebral ischemia
      and reperfusion in stroke-prone spontaneously hypertensive rats.
AB  - Cerebral ischemia followed by oxygen reperfusion induced apoptosis in hippocampal
      neurons in stroke-prone spontaneously hypertensive rats (SHRSP) but not in Wistar
      Kyoto rats. Oxygen radicals were involved in reoxygenation injury after hypoxia
      in hippocampal slices. Vitamin E inhibited the reoxygenation injury in cultured
      cortical neurons. In addition, the temporal cortices in Alzheimer's disease have
      increased sensitivity to oxygen radicals, and Vitamin E slowed the progression of
      the disease. Thus we fed Wistar Kyoto and SHRSP rats either a normal diet or a
      high Vitamin E diet for 3 weeks. We measured Vitamin E concentrations of plasma
      and brain by applying the HPLC method. Vitamin E increased its concentration in
      plasma, cerebral cortex, and hippocampus (p < 0.01) during a 3-week pretreatment.
      In addition, we clipped both common carotid arteries in these rats for 30
      minutes. After the blocking, the rats were reperfused for 6 and 9 days,
      respectively, and then killed. We cut the brains coronally, removed the
      hippocampal CA1 regions, and examined the neurons using an electron microscope.
      SHRSP rats with normal cerebral circulation had 30.4+/-8.0 apoptotic neurons per
      1000 neurons. Cerebral ischemia followed by 6 and 9 days of reperfusion,
      respectively, increased apoptotic neurons in SHRSP rats fed a normal diet (6
      days: 542.5+/-154.1 per 1000 neurons; 9 days: 657.5+/-110.2 per 1000 neurons). In
      contrast, apoptotic neurons in SHRSP rats fed a high Vitamin E diet were
      significantly (p < 0.01) small in number (6 days: 41.3+/-27.5 per 1000 neurons; 9
      days: 35.5+/-19.7 per 1000 neurons) even though the rats were treated in the same
      way. These data demonstrate that oxygen radical generation occurs after
      reperfusion and that free radicals heavily damage the neurons in SHRSP rats.
      Vitamin E reacts with the radicals and prevents neuronal apoptosis caused by
      cerebral ischemia and reperfusion. Therefore, Vitamin E seems to be an important
      agent in lowering radical damage to hippocampal neurons.

PMID- 10334571
TI  - Integrins alpha4beta7 and alphaEbeta7 are expressed on epidermotropic T cells in
      cutaneous T cell lymphoma and spongiotic dermatitis.
AB  - Integrin alpha4beta7 has been associated with tissue-specific homing of malignant
      and inflammatory lymphocytes to gastrointestinal mucosa, whereas integrin
      alphaEbeta7 has been associated with intraepithelial lymphocytes in both the gut
      and the skin. This prompted us to examine the expression of alpha4beta7 on skin
      infiltrating lymphocytes in 12 cases of patch/plaque stage cutaneous T cell
      lymphoma (CTCL) and in 4 cases of spongiotic dermatitis, which also display
      intraepidermal T cell accumulation. alpha4beta7 was found to be expressed on
      64.8+/-7.4% of intraepidermal and 39.1+/-5.0% of intradermal T lymphocytes in
      CTCL. There was a significant positive correlation (r=0.58) between the degree of
      epidermotropism and the percentage of intraepidermal T cells expressing
      alpha4beta7. Similar findings were observed in spongiotic dermatitis, indicating
      that this result is not unique to malignant T cells. We evaluated staining of T
      cells in the same specimens for presence of alphaEbeta7 and observed a strong
      correlation between the expression of both beta7 integrins in each specimen.
      Staining with antibodies directed against the known ligands of alpha4beta7 was
      also performed on skin biopsies from CTCL patients. There was significantly
      increased dermal microvascular endothelial expression of vascular cell adhesion
      molecule-1 in lesional compared with nonlesional skin, and in nonlesional skin
      compared with skin of normal control subjects. Dermal and epidermal expression of
      the CS-1 domain of fibronectin was present but not increased in lesional biopsies
      compared with nonlesional or normal controls, whereas expression of mucosal
      addressin cell adhesion molecule-1 was not detectable in any skin biopsy
      specimens. In summary, alpha4beta7, like alphaEbeta7, is expressed at high levels
      on epidermotropic T cells and may interact with endothelial cell vascular cell
      adhesion molecule-1 as part of stepwise recruitment of lymphocytes from the blood
      to the epidermis.

PMID- 10334573
TI  - Improved detection of K-ras codon 12 mutations in fecal exfoliated cells.

PMID- 10334574
TI  - Fractin immunostaining for the detection of apoptotic cells and apoptotic bodies
      in formalin-fixed and paraffin-embedded tissue.

PMID- 10334575
TI  - More on-line publishing.

PMID- 10334576
TI  - Review of historical monitoring data on Techa River contamination.
AB  - The Mayak Production Association was the first Russian site for the production
      and separation of plutonium. The extensive increase in plutonium production
      during 1948-1955, as well as the absence of reliable waste-management technology,
      resulted in significant releases of liquid radioactive effluent into the rather
      small Techa River. This resulted in chronic external and internal exposure of
      about 30,000 residents of riverside communities; these residents form the cohort
      of an epidemiologic investigation. Analysis of the available historical
      monitoring data indicates that the following reliable data sets can be used for
      reconstruction of doses received during the early periods of operation of the
      Mayak Production Association: Temporal pattern of specific beta activity of river
      water for several sites in the upper Techa region since July 1951; average annual
      values of specific beta activity of river water and bottom sediments as a
      function of downstream distance for the whole river since 1951; external gamma
      exposure rates near the shoreline as a function of downstream distance for the
      whole Techa River since 1952; and external gamma-exposure rate as a function of
      distance from the shoreline for several sites in the upper and middle Techa since
      1951.

PMID- 10334577
TI  - Plutonium fecal and urinary excretion functions: derivation from a systemic whole
      body retention function.
AB  - Liver-bile secretion directly influences the content of plutonium in feces. To
      assess the reliability of plutonium metabolic models and to improve the accuracy
      of interpreting plutonium fecal data, we developed a compartmental model that
      simulates the metabolism of plutonium in humans. With this model, we can describe
      the transport of plutonium contaminants in the systemic organs and tissues of the
      body, including fecal and urine excretions, without using elaborate kinetic
      information. The parameter values of the models, which describe the translocation
      rates and recycling of plutonium in the body, can be derived from a multi-term
      exponential systemic function for whole-body retention. The analytical
      derivations and algorithms for solving translocation parameter values are
      established for the model and illustrated by applying them to the biokinetics and
      bioassay of plutonium. This study describes how to (1) design a physiological
      model for incorporating liver biliary secretion and for obtaining a fecal
      excretion function, (2) develop an analytical solution for identifying the
      translocation-parameter values incorporating the recycling of plutonium in the
      body, and (3) derive a set of urinary and fecal excretion-functions from a
      published systemic whole-body retention function, generally acknowledged to be
      accurate, as a real and practical example.

PMID- 10334578
TI  - Solubility of various forms of strontium titanate in lungs: in vitro and in vivo
      studies.
AB  - At the In-Tank Precipitation Facility of the Savannah River Site, strontium and
      other radionuclides are removed from high-level radioactive waste and sent to the
      Defense Waste Processing Facility. Strontium removal is accomplished by
      adsorption using a slurry that includes monosodium titanate, which forms
      strontium titanate with unknown lung solubility characteristics. The purpose of
      this study was to determine the solubility of strontium titanate in the form
      created at the In-Tank Precipitation facility. An in vitro dissolution study was
      done with a slurry simulant and with several types of strontium titanate, and the
      results were compared. An in vivo study was also performed with high-fired SrTiO3
      in rats. Strontium and titanium were measured by inductively-coupled
      plasma/atomic emission spectrometry. The data from both studies were used
      independently to assign the compounds to an absorption type based on criteria
      specified in ICRP 71. Results of the in vitro studies showed that the Defense
      Waste Processing Facility simulant should be assigned to Type M and the strontium
      titanate should be assigned to Type S. Results of the in vivo study verified that
      SrTiO3 should be assigned to Type S. Lung clearance data of SrTiO3 from rats
      showed that 85% cleared within the first 24 h and the remaining 15% cleared with
      a half-time of 130 d. The initial rapid clearance is attributed to deposition in
      airways as compared to the alveolar region.

PMID- 10334580
TI  - Absorbed dose from traversing spherically symmetric, Gaussian radioactive clouds.
AB  - If a large radioactive cloud is produced, sampling may require that an airplane
      traverse the cloud. A method to predict the absorbed dose to the aircrew from
      penetrating the radioactive cloud is needed. Dose rates throughout spherically
      symmetric Gaussian clouds of various sizes, and the absorbed doses from
      traversing the clouds, were calculated. Cloud size is a dominant parameter
      causing dose to vary by orders of magnitude for a given dose rate measured at
      some distance. A method to determine cloud size, based on dose rate readings at
      two or more distances from the cloud center, was developed. This method, however,
      failed to resolve the smallest cloud sizes from measurements made at 1,000 m to
      2,000 m from the cloud center.

PMID- 10334579
TI  - A method to detect low-level 63Ni activity for estimating fast neutron fluence
      from the Hiroshima atomic bomb.
AB  - The Hiroshima and Nagasaki atomic bombs resulted in the worst reported exposure
      of radiation to the human body. The data of survivors have provided the basis for
      the risk estimation for ionizing radiation, and thus are widely used as the basis
      of radiation safety. In this report we have studied a new method to detect the
      low-level 63Ni activity in copper samples in order to estimate the fast neutron
      fluence from the Hiroshima atomic bomb. Only 0.8 x 10(-3) Bq g(-1) of 63Ni is
      expected to be produced by the atomic bomb in a copper sample with the 63Cu(n,
      p)63Ni reaction at a distance of 500 m from the hypocenter. Our method has the
      required level of sensitivity for determination of the fast neutron fluence out
      to distances of at least 500 m, and perhaps as far as 1,000 m. We have already
      investigated and collected some bomb-irradiated copper samples for further study.

PMID- 10334581
TI  - Comparison of four 90Sr groundwater analytical methods.
AB  - Data are presented for 45 Long Island groundwater samples each measured for 90Sr
      using four different analytical methods. 90Sr levels were first established by
      two New York State certified laboratories, one of which used the U.S.
      Environmental Protection Agency Radioactive Strontium in Drinking Water Method
      905.0. Three of the 90Sr methods evaluated at Brookhaven National Laboratory can
      reduce analysis time by more than 50%. They were (a) an Environmental
      Measurements Laboratory Cerenkov technique and (b) two commercially available
      products that utilize strontium-specific crown-ethers supported on either a resin
      or membrane disk. Method independent inter-laboratory bias was <12% based on 90Sr
      results obtained using both U.S. Department of Energy/Environmental Measurements
      Laboratory and U.S. EPA/National Environmental Radiation Laboratory samples of
      known activity concentration. Brookhaven National Laboratory prepared a National
      Institute of Standards and Technology traceable 90Sr tap-water sample used to
      quantify test method biases. With gas proportional or liquid scintillation
      counting, minimum detectable levels (MDLs) of 37 Bq m(-3) (1 pCi L(-1)) were
      achievable for both crown-ether methods using a 1-L processed sample beta counted
      for 1 h. The primary radiological contaminants of the Brookhaven National
      Laboratory groundwater samples were 3H (14.8-518 kBq m(-3)) and 90Sr/Y (37 Bq m(
      3)-18.5 kBq m(-3)). Thirty samples were above the U.S. EPA drinking water
      standard of 300 Bq m(-3) for beta emitting 90Sr. Regression of paired data sets
      showed that both crown-ether methods quantified 90Sr levels to within 5% of the
      "EPA method results" for samples greater than the drinking water standard and
      within 30-40% for samples less than the drinking water standard. The Cerenkov
      method, with a minimum detectable level of 150 Bq m(-3), was only useful for
      samples greater than the drinking water standard and underestimated 90Sr levels
      by 13%. Precision, as measured by the relative percent difference and mean
      difference statistics, was acceptable for both crown-ether methods when compared
      to the paired "EPA method" results. Cerenkov method precision exceeded pre
      defined acceptance criteria for 12 of 33 samples analyzed.

PMID- 10334582
TI  - The usability of wood as a volume trap for the purpose of retrospective radon
      exposure assessment.
AB  - The possibility of using wood samples as a retrospective radon monitor was
      investigated. Retrospective radon monitors are based on the analysis of the
      enhanced 210Po content of the bulk of the sample as a result of radon exposure.
      Several wood samples in different sizes and shapes were tested for their radon
      penetrability and the speed at which radon can diffuse throughout the material.
      Also, the volume ratio of air to solid material and the natural occurring 210Po
      background were determined. It was seen that only in fairly exceptional cases
      wood can be used as an acceptable volume trap. This is mostly due to the high and
      variably occurring natural 210Po background in wood samples with respect to the
      expected increase in radon-related 210Po due to common radon concentrations in
      dwellings.

PMID- 10334583
TI  - Measurement of surface alpha contamination using electret ion chambers.
AB  - Electret ion chambers are inexpensive, light-weight, commercially available,
      passive charge-integrating devices for accurate measurement of different
      radiations. Performance of electret ion chambers for surface alpha contamination
      measurement was evaluated. Ion chambers of two types and electrets of three
      thicknesses were used for the study. Calibration of the electret ion chambers was
      performed using reference alpha standards of different energies and
      radioactivities. Effects of various parameters such as chamber dimensions,
      electret thickness, alpha particle energy, position of alpha source from the
      chamber centerline, source localized or uniformly distributed, level of alpha
      contamination, Mylar window covering the chamber, and ambient radon and gamma
      radiation on the response of the electret ion chambers were determined. Suitable
      combinations of chambers and electrets to measure surface alpha contamination
      were determined.

PMID- 10334584
TI  - Radon emanation of building material--impact of back diffusion and difference
      between one-dimensional and three-dimensional tests.
AB  - Small-scale chamber experiments were conducted to investigate the radon emanation
      rates of commonly used building materials such as bare concrete, granite, red
      brick, and sand brick. It has been found that back diffusion caused by the
      accumulation of radon in the indoor environment has significant influence on the
      radon emanation rate. The radon emanation rate can be expressed as the summation
      of an initial emanation rate and the product of a specific back diffusion
      coefficient and the indoor radon level. In some occasions the radon emanation
      rate can be significantly lower than its initial value. A database was developed
      summarizing results from 26 samples. The influence of relative humidity on the
      radon emanation characteristics has also been discussed. Separate tests were done
      by coating the four sides of the building material with silicone gel to simulate
      a one-dimensional radon diffusion geometry. The results show that a factor has to
      be included when the three-dimensional test results are used to describe one
      dimensional geometry, such as radon emanation from building wall surfaces.

PMID- 10334585
TI  - Penetration of solar erythemal UV radiation in the shade of two common Australian
      trees.
AB  - The penetration of solar erythemal ultraviolet radiation has been measured in the
      shade of a gum (Eucalyptus sp.) and a she oak (Casaurina) tree, both on a
      horizontal plane and with polysulphone dosimeters to human anatomical sites. This
      has provided new data useful for protection strategies against harmful
      ultraviolet radiation. For larger solar zenith angles, the relative penetration
      of solar erythemal ultraviolet in the shade of the trees is higher. On a
      horizontal plane, at noon, in winter, the shade erythemal ultraviolet ranged from
      44 to 55% of that in the sun whereas in spring it ranged from 29 to 37% of the
      irradiances in the sun. Similarly, at 9:00 EST and 15:00 EST, the shade erythemal
      ultraviolet in winter ranged from 51 to 81% of the irradiances in the sun whereas
      in spring and summer they ranged from 35 to 51% of the unshaded irradiances. The
      shade ratios for specific body sites provided by the shade of the two trees were
      0.05 to 0.45 for the solar zenith angles in this research. The shade ratios
      ranged from 0.14 to 0.45 for the gum tree and from 0.05 to 0.28 for the she oak.
      The denser foliage of the she oak provided higher ultraviolet protection compared
      to that of the gum tree.

PMID- 10334587
TI  - Cancer death rates and background radiation.

PMID- 10334586
TI  - Optimization of radon measurements with active charcoal.
AB  - This paper examines the possibilities for improving the integration
      characteristics of active charcoal by using finite elements method simulation.
      Two different modes were considered separately: the period of active adsorption,
      when the activity of radon in charcoal increases, and the saturation period, when
      the activity is constant. The time when saturation begins depends on the
      thickness of the layer of charcoal. It was found that the peak amortization is 24
      h in active adsorption and 36 h in saturation period for examined charcoal and
      canister.

PMID- 10334588
TI  - Antibiotic use for the control of sexually transmitted infections in developing
      countries--too much or not enough?

PMID- 10334589
TI  - Glycosaminoglycan-binding microbial proteins in tissue adhesion and invasion: key
      events in microbial pathogenicity.
AB  - Glycosaminoglycans such as heparin, heparan sulphate and dermatan sulphate, are
      distributed widely in the human body. Several glycosaminoglycans form part of the
      extracellular matrix and heparan sulphate is expressed on all eukaryotic
      surfaces. The identification of specific binding to different glycosaminoglycan
      molecules by bacteria (e.g., Helicobacter pylori, Bordetella pertussis and
      Chlamydia trachomatis), viruses (e.g., herpes simplex and dengue virus), and
      protozoa (e.g., Plasmodium and Leishmania), is therefore of great interest.
      Expression of glycosaminoglycan-binding proteins depends on growth and culture
      conditions in bacteria, and differs in various phases of parasite development.
      Glycosaminoglycan-binding microbial proteins may mediate adhesion of microbes to
      eukaryotic cells, which may be a primary mechanism in mucosal infections, and are
      also involved in secondary effects such as adhesion to cerebral endothelia in
      cerebral malaria or to synovial membranes in arthritis caused by Borrelia
      burgdorferi. It has been suggested that they may enhance intracellular survival
      in macrophages. Microbial binding of heparin may interfere with heparin-dependent
      growth factors. Whether or not glycosaminoglycan-binding proteins mediate
      invasion of epithelial cells is a matter of controversy. Heparin and other
      glycosaminoglycans may have potential uses as therapeutic agents in microbial
      infections and could form part of future vaccines against such infections.

PMID- 10334590
TI  - Cationic currents induced by Clostridium perfringens type A enterotoxin in human
      intestinal CaCO-2 cells.
AB  - Clostridium perfringens type A produces an enterotoxin that induces diarrhoea
      experimentally in man and animals. The enterotoxin causes increased membrane
      permeability in susceptible cells which is thought to be due to pore formation in
      the host cell membrane. The effect of purified C. perfringens enterotoxin on
      intact intestinal CaCO-2 monolayers was examined in Ussing chambers and on single
      cells by whole-cell patch clamp. Mucosal application of C. perfringens
      enterotoxin resulted in prompt increases in short-circuit current coupled with a
      reduction in transepithelial resistance consistent with movement of sodium and
      other cations smaller than diethanolamine from mucosa to serosa. These changes
      were independent of extracellular calcium. Increases in short-circuit current
      were also observed in the apical membranes of CaCO-2 monolayers permeabilised
      across the basolateral membrane with nystatin. Currents were blocked by
      subsequent exposure to mucosal barium and zinc. Zinc also prevented the
      development of the current increases in apical membranes. Cationic currents were
      also observed following exposure of single CaCO-2 cells in whole-cell patch clamp
      recordings. These data indicate that C. perfringens enterotoxin is able to form
      cation permeant pores in the apical membrane of human intestinal CaCO-2 epithelia
      and the increases in short-circuit current can be prevented by pre-exposure to
      zinc ions.

PMID- 10334591
TI  - Identification and partial characterisation of an extracellular activator of
      fatty acid modifying enzyme (FAME) expression in Staphylococcus epidermidis.
AB  - Fatty acid modifying enzyme (FAME) is an extracellular enzyme that inactivates
      bactericidal fatty acids by esterifying them to cholesterol. Inactivation of
      these fatty acids may allow Staphylococcus epidermidis to live for long periods
      of time on the skin. This study describes the identification and partial
      characterisation of an extracellular activator of FAME production. Addition of
      FAME-free concentrated culture filtrate (activator) to S. epidermidis cultures
      (OD600 = 0.05) caused a 3-5-fold increase in FAME activity. Addition of the
      activator did not increase the amount of exopolysaccharide produced by S.
      epidermidis. The mol. wt of this activator was <3000 kDa and it was quite
      resistant to boiling. Treatment of the activator with proteinase K did not
      destroy its ability to induce FAME expression. Addition of S. aureus activator to
      S. epidermidis cultures also increased FAME expression. However, when S.
      epidermidis activator was added to S. aureus cultures no increase or inhibition
      in FAME production was observed.

PMID- 10334592
TI  - Effect of pH, temperature and surface contact on the elaboration of fimbriae and
      flagella by Salmonella serotype Enteritidis.
AB  - Survival of enteric pathogens exposed to various environmental stresses depends
      upon a number of protective responses, some of which are associated with
      induction of virulence determinants. Flagella and fimbriae are putative virulence
      determinants of Salmonella spp. and ELISAs specific for the detection of flagella
      and SEF21, SEF14 and SEF17 fimbriae were used to assess the effect of temperature
      and pH upon their elaboration by isolates of Salmonella serotype Enteritidis in
      planktonic growth and on the surface of two-dimensional gradient agar plates. For
      three phage type 4 isolates of Enteritidis of comparative clinical provenance,
      similar phenotypes for the elaboration of these surface antigens were observed.
      SEF14 fimbriae were elaborated in planktonic growth at 37 degrees C, but not 20
      degrees C, at pH 4.77 and above but not at pH 4.04; whereas on agar gradient
      plates SEF14 fimbriae were elaborated poorly but with best yields at pH 4.04.
      SEF17 fimbriae were elaborated in planktonic growth at 20 degrees C, but not at
      37 degrees C, at pH 6.18 and above but not at pH 5.09 or below; whereas on agar
      gradient plates SEF17 fimbriae were elaborated well even at pH 4.65. SEF21
      fimbriae were expressed very poorly under all conditions tested. Planktonic
      growth at 37 degrees C induced least flagella whereas growth at 20 degrees C, and
      particularly surface growth at lower pH values, induced a 'hyper-flagellate'
      phenotype. Single colonies allowed to form on gradient agar plates were shown to
      generate different colonial morphologies which were dependent on initial pH.
      These results demonstrate that the physicochemical environment is an important
      determinant of bacterial response, especially the induction of putative virulence
      factors.

PMID- 10334593
TI  - Presence of eubacteria in biopsies from Crohn's disease inflammatory lesions as
      determined by 16S rRNA gene-based PCR.
AB  - The aim of this study was to search for putative microbial agents in Crohn's
      disease (CD) tissues by bacterial broad-range 16S rDNA PCR combined with genus-
      and species-specific DNA hybridisation analysis. Biopsies taken both surgically
      and endoscopically from the terminal ileum of 11 CD patients and 11 control
      patients were investigated. Significant amounts of eubacteria were demonstrated
      in biopsies taken endoscopically from both affected and unaffected individuals;
      the biopsies taken at surgery from control patients were negative. Three of five
      biopsies taken surgically from CD patients harboured Helicobacter spp.-,
      Mycobacterium paratuberculosis-, Listeria monocytogenes- and Escherichia coli
      like 16S rDNA sequences. These findings show the importance of the sampling
      method chosen when combined with molecular typing of eubacteria in intestinal
      tissues. The mixed bacterial flora found in the surgical biopsies from CD
      patients supports the idea that the enteric microflora enters primary lesions
      where secondary bacterial colonisers may elicit a chronic inflammatory syndrome.

PMID- 10334594
TI  - Molecular typing of Legionella pneumophila serogroup 1 by pulsed-field gel
      electrophoresis with SfiI and comparison of this method with restriction fragment
      length polymorphism analysis.
AB  - A panel of 131 well-characterised Legionella pneumophila serogroup 1 strains,
      previously used to evaluate a restriction fragment-length polymorphisms (RFLP)
      typing scheme, was examined by pulsed-field gel electrophoresis (PFGE) with the
      restriction endonuclease SfiI. The data obtained show that PFGE with SfiI is a
      highly discriminatory method yielding an index of discrimination (IOD) of 0.992
      and 0.975, with 100% and 90% similarity thresholds respectively, compared with an
      IOD of 0.909 for the RFLP typing method. Reproducibility of PFGE profiles within
      gels was excellent and it was possible to compare the profiles visually. However,
      the reproducibility of the technique between gels was poor and visual comparison
      of the patterns was extremely difficult. Computer-aided analysis assisted the
      assessment of inter-gel reproducibility. Of 11 duplicates examined only four
      pairs showed 100% similarity, although 9 of 11 showed > or =90% similarity. In an
      attempt to determine if the PFGE banding patterns were sufficiently unambiguous
      to allow the method to be used as a definitive typing method, 20 coded strains
      were examined. At a 90% similarity level, 16 of these were placed in the correct
      PFGE type and four were not allocated to a type. Partial digestion of DNA by SfiI
      was noted despite careful control of DNA and enzyme concentrations, suggesting
      that an alternative enzyme might give more reproducible results.

PMID- 10334595
TI  - Genomic DNA restriction site heterogeneity in bovine Pasteurella multocida
      serogroup A isolates detected with an rRNA probe.
AB  - A total of 81 Pasteurella multocida isolates from healthy and diseased dairy and
      beef cattle originating from various geographical locations was examined by rRNA
      gene restriction site polymorphism analysis (ribotyping), restriction
      endonuclease analysis (REA), SDS-PAGE analysis of whole-cell (WCP) and outer
      membrane (OMP) proteins, and capsule and somatic serotyping. Bacterial strains
      were isolated from nose, lung and in one case testicle, of Holstein and cross
      bred beef cattle. The isolates represented for the most part serogroup A3 (88%).
      Ribotyping was performed on DNA digested with HaeII, electrophoresed and then
      hybridised with 32P-labelled 16S-23S rRNA from Escherichia coli. Six ribotypes
      (R1-R6) and 10 REA types were found among the 81 isolates with similar
      discrimination index (DI) of c. 0.60. Protein profiles revealed reproducibility
      and high levels of polymorphisms among lung isolates. Isolates were compared
      according to their geographical habitat, their isolation from dairy or from beef
      cattle and from nasal cavities or lungs. No correlation was apparent between
      geographical locations and ribotypes. Overall, isolates obtained from dairy
      cattle were predominantly R1, whereas those obtained from beef cattle were
      equally distributed between R1 and R2. R1 was more representative of lung
      isolates. For some strains, particularly the single isolate ribotypes, good
      correlation was achieved between WCP analysis, REA types and ribotypes. For
      others, REA to some extent and WCP profiles were able to discriminate among
      isolates within ribotypes. The data suggest that a combination of ribotyping, REA
      and WCP analysis is useful for investigating the epidemiology of bovine P.
      multocida serogroup A.

PMID- 10334596
TI  - Genotypic and phenotypic similarity of multiresistant Acinetobacter baumannii
      isolates in the Czech Republic.
AB  - The diversity of 103 clinical isolates of the Acinetobacter calcoaceticus
      Acinetobacter baumannii complex obtained between 1991 and 1997 from 17 Czech
      hospitals was studied by ribotyping, biotyping, plasmid profiling and antibiotic
      susceptibility testing. According to the EcoRI ribotypes, all but one of these
      isolates were identified to the DNA group level: 77 isolates were allocated to
      DNA group 2 (A. baumannii), 14 to DNA group 3, 10 to DNA group 13 sensu Tjernberg
      and Ursing and one to DNA group 1 (A. calcoaceticus). In total, 50 different
      EcoRI ribotypes and 10 biotypes were observed. Plasmids were found in 92% of the
      isolates and a high variability in plasmid profiles was found in isolates of the
      same DNA group. The combination of typing profiles allowed two predominant groups
      (termed A and B) to be distinguished among the A. baumannii isolates (37 and
      eight isolates, respectively) that shared a specific ribotype and were highly
      similar in other properties. These two groups comprised both sporadic and
      outbreak isolates and were found in most localities. Group A and B isolates were
      markedly more resistant to antibiotics than most of the remaining isolates, thus
      representing 85% of all multiresistant isolates. The features of groups A and B
      corresponded to those of two epidemic clones identified recently among hospital
      strains in north-western Europe.

PMID- 10334597
TI  - Subtyping of methicillin-resistant Staphylococcus aureus isolates from the North
      West of England: a comparison of standardised pulsed-field gel electrophoresis
      with bacteriophage typing including an inter-laboratory reproducibility study.
AB  - Bacteriophage typing is currently the recognised methodology for the typing of
      methicillin-resistant Staphylococcus aureus (MRSA) in the UK. Bacteriophage
      typing is less discriminatory and does not type all isolates compared with some
      molecular methods for typing MRSA. Chromosomal genotyping by pulsed-field gel
      electrophoresis (PFGE) is increasingly recognised as an improved method for
      typing MRSA, providing increased discrimination and typability. In this study the
      results of a comparison of bacteriophage typing and PFGE typing and subtyping are
      presented for a large collection of isolates from the North-West of England.
      Isolates belonging to the most frequently isolated epidemic methicillin-resistant
      Staphylococcus aureus (EMRSA) bacteriophage types 15 and 16 were typed by PFGE
      with further discrimination of common PFGE types possible into a number of
      subtypes. These results for a large collection of isolates demonstrate the
      improved typing of MRSA with PFGE. The widespread acceptance of PFGE for typing
      MRSA isolates has been hampered by the lack of standardised methodologies.
      Recently, a standardised PFGE strain typing system, known as the GenePath system
      has become available. The results of an inter-laboratory comparison of PFGE
      typing for a collection of isolates demonstrated good reproducibility with this
      system.

PMID- 10334598
TI  - Emergence of mupirocin resistance in multiresistant Staphylococcus aureus
      clinical isolates belonging to Brazilian epidemic clone III::B:A.
AB  - Mupirocin is a topical antimicrobial agent that has been successfully used to
      eradicate methicillin-resistant Staphylococcus aureus from the anterior nares and
      other sites of patients and health care personnel. This report describes the
      acquisition of a novel mupirocin resistance gene (ileS) by an epidemic MRSA clone
      that is geographically widespread in Brazil.

PMID- 10334599
TI  - Relationship between morphological changes and endotoxin release induced by
      carbapenems in Pseudomonas aeruginosa.
AB  - The relationship between morphological changes and endotoxin release induced in
      vitro by carbapenems in a clinical isolate of Pseudomonas aeruginosa was
      examined. The time-course and magnitude of endotoxin release induced varied among
      imipenem, panipenem, meropenem and biapenem and related to the morphological
      changes caused by these agents which variously affected cell shape, cell-wall
      disintegration and cell lysis. The amount of endotoxin released by carbapenem
      treated cells correlated with both the cell-wall morphology and bacterial shape
      immediately before lysis. Meropenem and biapenem caused markedly increased
      endotoxin release during cell lysis and cell-wall disintegration, whereas
      imipenem and panipenem caused much less release of endotoxin.

PMID- 10334601
TI  - Management of first-trimester spontaneous abortion.

PMID- 10334600
TI  - Identification by PCR of Helicobacter pylori in subgingival plaque of adult
      periodontitis patients.
AB  - The PCR was used to detect the presence of Helicobacter pylori in subgingival
      plaque samples from patients with adult periodontitis. Primers based upon the 16S
      ribosomal RNA (rRNA) gene sequence of H. pylori were used in a single round of
      PCR to amplify a 295-bp DNA fragment and the identity of the amplified products
      was confirmed by Southern blot hybridisation to a digoxigenin-labelled H. pylori
      probe. Further confirmation of product identity was obtained by DNA sequencing of
      a proportion of the amplified products. The assay was demonstrated to be specific
      for H. pylori with a lower limit of detection of 100 fg of bacterial genomic DNA.
      In all, 73 samples from 29 patients were analysed, of which 24 (33%) were H.
      pylori-positive by PCR; the proportion of patients carrying H. pylori in at least
      one sampled site was 38% (11 of 29). This is the first study to demonstrate the
      presence of H. pylori in the subgingival plaque of patients with adult
      periodontitis and indicates that, in this patient group at least, subgingival
      plaque may be a reservoir for H. pylori infection.

PMID- 10334602
TI  - EMLA cream for the debridement of venous leg ulcers.

PMID- 10334603
TI  - Omeprazole or ranitidine for intermittent treatment of GERD?

PMID- 10334604
TI  - Mediterranean diet for heart disease.

PMID- 10334605
TI  - Amiodarone for the treatment of persistent atrial fibrillation.

PMID- 10334606
TI  - Incorporating right precordial leads in exercise electrocardiography.

PMID- 10334607
TI  - Comparing troponin I with creatinine kinase.

PMID- 10334608
TI  - Bed rest for sciatica?

PMID- 10334609
TI  - POEMs as a paradigm shift in teaching, learning, and clinical practice. Patient
      Oriented Evidence that Matters.

PMID- 10334610
TI  - Evidentiary medicine lacks humility.

PMID- 10334611
TI  - Finding POEMs in the medical literature.
AB  - Articles about primary care topics that measure patient-oriented outcomes (eg,
      morbidity, mortality, quality of life) should change practice, if the reported
      results are valid. We call these types of articles POEMs--Patient-Oriented
      Evidence that Matters. The extent and distribution of POEMs in the medical
      literature is unknown. We identified 85 medical journals of potential interest to
      primary care physicians, and counted 8085 original research articles over a 6
      month period; 211 of those articles were POEMs (2.6%). Ten journals accounted for
      50% of the POEMs identified during the study period: Journal of the American
      Medical Association, Annals of Internal Medicine, New England Journal of
      Medicine, Archives of Internal Medicine, Lancet, British Medical Journal,
      Obstetrics and Gynecology, Arthritis and Rheumatology, American Journal of
      Obstetrics and Gynecology, and Journal of the American College of Cardiology.
      Other journals with a high percentage of POEMs were: Journal of Family Practice,
      Journal of the American Board of Family Practice, and American Journal of
      Emergency Medicine. Half the journals we surveyed published 0 or 1 POEMs during
      the study period. Not all clinicians have the time, inclination, or access to
      review a large number of journals on a regular basis. By focusing on POEMs and
      the journals that publish them, busy physicians can avoid reading 98% of the
      original research published each month. This will not only drastically cut
      physicians' reading time, but also help them obtain the information that is most
      valuable for their patients.

PMID- 10334613
TI  - Use of hormone replacement therapy in Washington State: is prevention being put
      into practice?
AB  - BACKGROUND: American women are using hormone replacement therapy (HRT) for long
      term disease prevention, as well as symptom control, in increasing numbers. Our
      study examined the role of prevention in women's decisions to initiate HRT and
      their intended duration of therapy. METHODS: We analyzed the mailed survey
      responses of 2023 women aged 50 to 70 years from the practices of 46 physicians
      in the Puget Sound region for knowledge and attitudes about HRT, current use, and
      intended duration of therapy. Multiple logistic regression was used to model
      current HRT use and intended treatment length. RESULTS: A total of 71% of our
      respondents were using HRT. Women with osteoporosis, coronary heart disease
      (CHD), or risk factors for CHD were not more likely to be using HRT, and women
      with CHD or risk factors for CHD were not targeted by their physicians for
      discussion of HRT. Of women using HRT, 77% expected lifelong use, and this was
      not more common among women initiating HRT for disease prevention. CONCLUSIONS:
      Despite the high rates of HRT use and expected lifelong duration, use of HRT for
      prevention was neither higher among women most likely to benefit nor a major
      determinant of expected lifetime use.

PMID- 10334612
TI  - A randomized controlled trial of facilitating information giving to patients with
      chronic medical conditions: effects on outcomes of care.
AB  - BACKGROUND: The purpose of this study was to assess the impact of an intervention
      to facilitate information giving to patients with chronic medical conditions on
      outcomes of care. METHODS: A consecutive sample of 276 eligible patients with
      chronic medical conditions at a family medicine clinic was randomized to control
      and experimental interventions. A total of 205 completed the study. Experimental
      group patients received copies of their medical record progress notes, and they
      completed question lists for physician review, while control group patients
      received health education sheets and completed suggestion lists for improving
      clinic care. Self-reported physical functioning, global health, and patient
      satisfaction and adherence were measured at enrollment and after the
      interventions. Visit lengths and patient response to medical record sharing after
      the interventions were also measured. RESULTS: After the intervention,
      experimental group patients reported 3.7% better overall physical functioning
      than did control patients (mean = 83.6, standard deviation [SD] = 17.6 vs mean =
      79.9, SD = 25.3; P = .005 after adjusting for covariates). The experimental group
      was more satisfied with their physician's care (mean = 31.4, SD = 4.6 vs mean =
      31.3, SD = 5.2; P = .045 after adjusting for covariates). They were also more
      interested in seeing their medical records than were control patients (mean =
      12.0, SD = 2.8 vs mean = 11.2, SD = 2.8; P = .002 after adjusting for
      covariates). Experimental group patients also reported an 8.3% improvement in
      overall health status (postintervention mean = 3.0, SD = 1.1) compared with their
      pre-intervention health status (mean = 2.8, SD = 1.0; P =.001). Visit lengths for
      patients in the experimental group did not differ from those of the control
      group. CONCLUSIONS: A simple patient-centered intervention to facilitate
      information giving in the primary health care of patients with chronic medical
      conditions can improve self-reported health, physical functioning, and
      satisfaction with care.

PMID- 10334614
TI  - Is lower income associated with greater biopsychosocial morbidity? Implications
      for physicians working with underserved patients.
AB  - BACKGROUND: Previous studies have established a powerful relationship between
      socioeconomic position and health. However, there has been little attention given
      to the association between income, biopsychosocial morbidity, and decline in
      health over time among primary care patients. METHODS: Data were collected using
      a survey mailed to patients receiving care at a family medicine center and
      through a follow-up survey mailed 2 years later. The independent association
      between various biopsychosocial measures and family income was assessed through
      stepwise linear regression. After controlling for baseline health status, the
      effect of family income on health status at follow-up was assessed. RESULTS: Data
      were available from 922 active family medicine patients who responded to the
      initial survey and from 655 who responded to the follow-up survey. In bivariate
      analyses, lower family income was significantly associated with poorer health
      status, greater psychological distress, more family dysfunction, less social
      support, more behavioral risk factors, higher rates of obesity and uncontrolled
      blood pressure, poorer physical and mental health status, and more medical
      diagnoses. In a multivariate analysis, age, sex, marital status, race, social
      network, family criticism, smoking, fat consumption, and health status were
      independently associated with family income. After controlling for covariates,
      including baseline health status, family income was a significant predictor of
      health status at follow-up. CONCLUSIONS: Family income is associated with
      biopsychosocial morbidity and health decline. Physicians who care for poorer
      patients will likely be confronted by challenging and complex biopsychosocial
      problems.

PMID- 10334615
TI  - Brief physician advice for alcohol problems in older adults: a randomized
      community-based trial.
AB  - BACKGROUND: Alcohol use in older adults is common. It is associated with
      depression, hypertension, diabetes, drug interactions, accidents, and increased
      rates of emergency department visits and hospitalizations. METHODS: A controlled
      clinical trial (Project GOAL--Guiding Older Adult Lifestyles) tested the efficacy
      of brief physician advice in reducing the alcohol use and use of health care
      services of older adult problem drinkers. Twenty-four community-based primary
      care practices in Wisconsin (43 family physicians and internists) participated in
      the trial. Of the 6073 patients screened, 105 men and 53 women met inclusion
      criteria and were randomized into a control group (n = 71) or an intervention
      group (n = 87). Intervention group patients received two 10- to 15-minute
      physician-delivered counseling sessions that included advice, education, and
      contracting using a scripted workbook. A total of 146 patients (92.4%)
      participated in the 12-month follow-up procedure. RESULTS: No significant
      differences were found between the control and intervention groups at baseline in
      alcohol use, age, socioeconomic status, depression, onset of alcohol use, smoking
      status, activity level, or use of mood-altering drugs. The older adults who
      received the physician intervention demonstrated a significant reduction in 7-day
      alcohol use, episodes of binge drinking, and frequency of excessive drinking (P
      <.005) compared with the control group at 3, 6, and 12 months after the
      intervention. There was a 34% reduction in 7-day alcohol use, 74% reduction in
      mean number of binge-drinking episodes, and 62% reduction in the percentage of
      older adults drinking more than 21 drinks per week in the intervention group
      compared with the control group. There were no significant changes in health
      status. Patterns of health care utilization were not extensively analyzed because
      of the small number of events. CONCLUSIONS: This study provides the first direct
      evidence that brief physician advice can decrease alcohol use by older adults in
      community-based primary care practices.

PMID- 10334616
TI  - Are the best doctors sued more?

PMID- 10334617
TI  - Appointments, procedures, and lawsuit frequency?

PMID- 10334618
TI  - Spirituality and medicine.

PMID- 10334619
TI  - Fish p53 as a possible biomarker for genotoxins in the aquatic environment.
AB  - The p53 gene is a tumour suppressor gene which has a fundamental role in cell
      cycle control and division, and in mammals certain genotoxic agents induce
      specific mutations in p53, leading to tumourigenesis. Fish have been investigated
      as models for studying carcinogens, but as yet very little data exists that links
      exposure to specific chemicals with the aetiology of tumours found in wild
      populations. In this study, p53 was sequenced from five species of fish with a
      view to the possible use of mutations in the highly conserved domains of p53 to
      identify genotoxins in the aquatic environment. A 0.8 kb fragment of the cDNA
      encompassing the conserved DNA-binding domain of p53 was sequenced in three
      Oncorhynchus salmonid fish: coho (O. kisutch), chum (O. keta), and chinook (O.
      tshawytscha) and full-length p53 cDNAs were sequenced in the puffer fish
      (Tetraodon miurus) and the barbel (Barbus barbus). The full-length puffer fish
      and barbel p53 cDNAs were 1834 bp and 1790 bp in length, encoding a 367 aa
      protein and a 369 aa protein, respectively. The deduced aa sequences of the p53
      cDNA in the Oncorhynchus salmon shared a 100% identity in the five conserved
      regions (I-V). Comparisons of the deduced aa sequences for puffer fish and barbel
      p53 with other fish p53s revealed a high homology within the conserved DNA
      binding domain (68-86% for puffer fish and between 66-88% for barbel).
      "Conserved" domain I was not highly conserved in fish, as it is in mammals, and,
      therefore, conserved domains II-V are most likely to provide the valuable
      sequences in fish p53 for use in mutational studies to fingerprint genotoxins in
      the aquatic environment.

PMID- 10334620
TI  - Mutation spectrum in Salmonella induced by environmental tobacco smoke.
AB  - Environmental tobacco smoke (ETS) is a major source of indoor air pollution.
      Extractable-respirable particulate (ERP) from the ETS-contaminated indoor air
      (ERP-ETS) was collected from six passenger train cars and one control room. The
      mutagenicity of ERP-ETS was tested in the Ames/Salmonella test in the presence of
      male rat liver microsomal fraction S9. The mutation spectrum of ERP-ETS was
      determined by colony probe hybridization and polymerase chain reaction/DNA
      sequence analysis in approximately 2,370 His+ revertants. The results indicate
      that the majority of ERP-ETS-induced mutations were a two-base deletion of GC or
      CG within the hotspot sequence of CGCGCGCG at the frameshift hisD3052 allele in
      strain TA98. The ERP-ETS from the control room induced approximately 94.3% such
      deletions, while the ERP-ETS collected from the passenger cars induced
      approximately 89.6% such deletions. The ERP-ETS either from the control room or
      from the passenger cars induced approximately 74% C/G --> A/T transversions, and
      approximately 23% C/G --> T/A transitions within the primary target CCC at the
      hisG46 allele in strain TA100.

PMID- 10334621
TI  - Singlet oxygen is the major species participating in the induction of DNA strand
      breakage and 8-hydroxydeoxyguanosine adduct by lead acetate.
AB  - To investigate DNA damage induced by Pb2+ and its prevention by scavengers, we
      determined DNA strand breakage and the formation of 8-hydroxydeoxyguanosine (8
      OHdG) in DNA using plasmid relaxation assay and HPLC with electrochemical
      detection, respectively. Lead acetate induced DNA strand breakage in 10 mM of
      Hepes buffer, pH 6.8, in a time- and dose-dependent manner. Compared with lead,
      zinc acetate did not significantly induce DNA breakage. The singlet oxygen
      scavengers NaN3 and 2,2,6,6-tetramethyl-4-piperidone (TEMP) inhibited lead
      induced DNA breakage more efficiently than the hydroxyl radical scavengers
      mannitol and DMPO. Deuterium oxide (D2O), a singlet oxygen enhancer, potentiated
      lead-induced DNA breakage. At low ratios to Pb2+, NADPH, glutathione, and 2
      mercaptoethanol enhanced lead-induced DNA breakage, whereas high ratios of these
      agents protected it. Catalase and superoxide dismutase (SOD) did not protect DNA
      breaks induced by Pb2+. Lead-induced DNA breakage was markedly enhanced by H2O2,
      and this induction was inhibited by NaN3, TEMP, EDTA, catalase, BSA, and
      glutathione. In contrast, mannitol and SOD potentiated Pb2+/H2O2-induced DNA
      breaks. The results indicate that singlet oxygen, lead, and H2O2 are all involved
      in the reaction system, whereas hydroxyl radical and superoxide did not. Lead
      could cause a small amount of 8-OHdG formation in calf thymus DNA and dose
      dependently induced the formation of this adduct in the presence of H2O2. Singlet
      oxygen scavengers were more effective than hydroxyl radical scavengers in
      protection from lead/H2O2-induced 8-OHdG adducts. Taken together, these results
      suggest that lead may induce DNA damage through a Fenton-like reaction and that
      singlet oxygen is the principal species involved.

PMID- 10334622
TI  - Combinations of chlorocatechols and heavy metals cause DNA degradation in vitro
      but must not result in increased mutation rates in vivo.
AB  - Chlorocatechols introduced into the environment directly or as a result of
      degradation processes are highly toxic, particularly when combined with heavy
      metals. With in vitro DNA degradation assays, the high reactivity of
      chlorocatechols combined with heavy metals could be shown, whereby copper was
      shown to be more active than iron. Structure-activity analysis showed that the
      degradation potential of the chlorocatechols decreased with an increasing number
      of chloratoms. The addition of reactive oxygen species scavengers allowed the
      identification of hydrogen peroxide as an important agent leading to DNA damage
      in this reaction. The potential of other reactive compounds, however, can neither
      be determined nor excluded with this approach. Exposure of Escherichia coli and
      Salmonella typhimurium cultures to the same mixtures of chlorocatechols and
      copper surprisingly did not lead to an enhanced mutation rate. This phenomenon
      was explained by doing marker gene expression measurements and toxicity tests
      with E. coli mutants deficient in oxidative stress defense or DNA repair. In
      catechol-copper-exposed cultures an increased peroxide level could indeed be
      demonstrated, but the highly efficient defense and repair systems of E. coli
      avoid the phenotypical establishment of mutations. Increased mutation rates under
      chronic exposure, however, cannot be excluded.

PMID- 10334623
TI  - Nickel subsulfide is similar to potassium dichromate in protecting normal human
      fibroblasts from the mutagenic effects of benzo[a]pyrene diolepoxide.
AB  - The cellular response to multiple carcinogen treatment has not been extensively
      studied, even though the effect of individual carcinogens is, in many cases, well
      known. We have previously shown that potassium dichromate can protect normal
      human fibroblasts from the mutagenic effects of benzo[a]pyrene diolepoxide
      (BPDE), and that this effect may be via an oxidative stress mechanism [Tesfai et
      al. (1998) Mutat Res 416:159-168]. Here, we extend our previous work by showing
      that nickel subsulfide can produce the some effect. Normal human fibroblasts,
      preincubated with nickel subsulfide for 46 hr followed by a coincubation of
      nickel subsulfide and BPDE for 2 hr, showed a dramatic reduction in the mutant
      frequency of the hypoxanthine (guanine)phosphoribosyl-transferase (HPRT) gene
      when compared to cells treated only with BPDE. The preincubation period with
      nickel subsulfide was necessary to see the antagonistic effect, since it was not
      observed if the cells were simply incubated with both carcinogens for 2 hr. The
      extent of the antagonistic effect was nickel subsulfide dose-dependent and also
      appeared to be species-specific, since the effect was not observed when Chinese
      hamster fibroblasts were tested. Finally, the antagonistic effect of the nickel
      subsulfide was eliminated by vitamin E, suggesting that production of reactive
      oxygen species by the nickel may be required. This data, along with our previous
      work, suggest that the antagonistic effect we observe is not chromium-specific,
      and that it could be species-specific.

PMID- 10334624
TI  - Feasibility of micronucleus methods for monitoring genetic damage in two feral
      species of small mammals.
AB  - Peromyscus leucopus (white-footed mouse) and Cryptotis parva (least shrew)
      possess desirable attributes for biomonitoring contamination of terrestrial
      ecosystems, but few studies have examined the potential use of these species for
      monitoring exposure to genotoxic contaminants. The susceptibility of laboratory
      reared C. parva, P. leucopus, and Mus musculus (house mouse, strain CD-1) to
      micronucleus (MN) induction by known clastogens was evaluated. Animals were
      exposed for 24 hr to methyl methanesulfonate (MMS; 12.5, 25, and 50 mg/kg), 4
      nitroquinoline 1-oxide (4-NQO; 7.5, 15, and 30 mg/kg), or mercuric chloride
      (HgCl2; 6, 12, and 24 mg/kg). Both MMS and 4-NQO induced dose-related increases
      in micronucleated polychromatic erythrocytes (MNPCE) in all three species,
      whereas HgCl2 induced a weak response only in P. leucopus. P. leucopus and C.
      parva were more sensitive than M. musculus to MMS. Similar micronucleus responses
      to 4-NQO were seen in each of the species. The feasibility of using blood for MN
      assessment was evaluated by comparing MN frequencies in bone marrow (BM) PCE, and
      blood PCE and normochromatic erythrocytes (NCE) in untreated animals, and
      following daily treatment for 1, 2, 3, and 10 days with 0.4 mg/kg
      triethylenemelamine (TEM). The results indicated that micronucleated erythrocytes
      were removed from the circulating blood in P. leucopus, but not in C. parva.
      Measurement of BM and blood MN levels appears feasible for monitoring exposure to
      genotoxic agents in C. parva and P. leucopus, and for distinguishing between
      acute and chronic exposure in C. parva.

PMID- 10334625
TI  - Computer-aided analysis of mutagenicity and cell transformation data for
      assessing their relationship with carcinogenicity.
AB  - Using a computer-aided approach, the tests for Salmonella mutagenicity and
      transformation in established cell lines were compared for the qualitative bases
      of their carcinogenicity predictions. For this purpose, a database of 145
      chemicals was prepared in which rodent carcinogenicity data and results of the
      Ames' and transformation tests were available. Using a software program for
      connectivity analysis (previously developed and validated by us), we assayed the
      molecular structures of these chemicals for the presence of fragments relatable
      to their positive (i.e., biophores) or negative (i.e., biophobes) response to the
      tests in question. These fragments were then studied for their association with
      genotoxic and nongenotoxic carcinogenicity. The philosophy adopted was that the
      type and number of molecular fragments chosen by the software to describe the
      chemicals correctly predicted by the tests could be related to the type of
      carcinogenic effects to which the tests themselves were sensitive. The
      classifications made by the software were interpreted by human expertise and the
      biophores found were compared with the acknowledged structural alerts to DNA
      reactivity as formalized by Ashby and co-workers [(1991): Mutat Res 257:229-306;
      (1993): Mutat Res 286: 3-74]. The results show that, in quantitative terms, the
      overall ability to predict carcinogenicity is about the same for both the
      Salmonella and transformation tests. However, in qualitative terms the
      transformation test appears to be sensitive to effects that are more
      heterogeneous than those inducing mutation, some of which are presumably related
      to nongenotoxic carcinogenic activities. This study illustrates a possible,
      innovative model of analysis of chemical structures that, using an automated
      approach along with the biologist's judgment, could contribute to the detection
      of complementarities among short-term test endpoints.

PMID- 10334626
TI  - VITOTOX bacterial genotoxicity and toxicity test for the rapid screening of
      chemicals.
AB  - The VITOTOX test is a new bacterial genotoxicity test that was previously shown
      to be very rapid and sensitive. Initially only one Salmonella typhimurium strain
      (TA104 recN2-4) was used in the test. In this paper we introduce a second strain
      (TA104pr1) that can be used as an internal control to further enhance the
      reliability of the test. We demonstrate the usefulness of this pr1 strain in
      genotoxicity and toxicity testing. We also report on the results of a study where
      the VITOTOX test was performed on newly synthesized pharmaceutical compounds, or
      intermediate products in the synthesis of drug candidates. We demonstrate that
      the test gives identical results when performed independently in two different
      laboratories and that it correlates well with either the Ames test or SOS
      chromotest.

PMID- 10334628
TI  - Recent progress in insulin signal transduction.

PMID- 10334627
TI  - Comparison of mutant frequencies at the transgenic lambda LacI and cII/cI loci in
      control and ENU-treated Big Blue mice.
AB  - We compared the lambda cII/cI transgenic mutation assay described by Jakubczak et
      al. [(1996): Proc Natl Acad Sci USA 93:9073-9078] to the previously established
      Big Blue assay. Genomic DNA isolated from liver, spleen, and lung tissue of
      control or ethylnitrosourea (ENU)-treated Big Blue mice (100 mg/kg i.p., single
      dose) was packaged into phage (five animals, two packagings per DNA sample) which
      were simultaneously plated for lacI and cII/cI mutant frequency (MF) and titer.
      Mean MF of control animals was higher for cII/cI than lacI for all three tissues
      examined (spontaneous cII/cI MF divided by spontaneous lacI MF = 2.9, 3.1, and
      1.7 for liver, spleen, and lung, respectively). The differences were
      statistically significant for liver and spleen, but not lung. The ENU-induced MF
      measured by subtracting control MFs from ENU-treated MFs was higher in the cII/cI
      assay than lacI (liver = 23.0 x 10(-5) for cII/cI vs. 15.1 x 10(-5) for lacI;
      spleen = 64.8 x 10(-5) for cII/cI vs. 36.1 x 10(-5) for lacI; lung = 17.1 x 10(
      5) for cII/cI vs. 15.8 x 10(-5) for lacI). Fold increase over control values
      measured by dividing MF of ENU-treated animals by appropriate control values was
      higher for lacI than cII/cI (liver = 4.4-fold for lacI vs. 2.7 for cII/cI; spleen
      = 13.1-fold for lacI vs. 8.4 for cII/cI; and lung = 5.6-fold for lacI vs. 4.0 for
      cII/cI). Despite these differences, overall results were similar for the two
      mutational endpoints. These results suggest that the cII/cI assay may be an
      acceptable alternative to lacI where transgenic mutation studies are indicated.

PMID- 10334629
TI  - Application of microcalorimetry for recording basal metabolic and Na+, K+-ATPase
      activity in LLC-PK1 cells, a model for the renal tubular epithelial cell.
AB  - In the present study we have employed a microcalorimetric procedure to measure
      the heat generated by a porcine renal tubule cell line (LLC-PK1) and its Na+, K+
      ATPase. Microplates with an area of 2.2 cm2 were found to be optimal in terms of
      producing sufficient heat and a steady-state power curve. We compared the rate of
      heat production by cells in suspension and on monolayers and found a much lower
      value in suspension, that is, 1.42+/-0.2 versus 2.54+/-0.19 microW/microg DNA.
      Ouabain, the specific Na+, K+-ATPase inhibitor, caused a reduction in this heat
      output. The maximal inhibition in cell suspensions was 40% and remained unchanged
      with as much as 100 microM ouabain, the highest concentration tested. With cells
      cultured on microplates, ouabain in the concentration interval 0.1-3 microM
      caused a 25% inhibition of heat output. With 25-100 microM ouabain, a 50%
      inhibition was observed and at higher concentrations, no further inhibition
      occurred. Furthermore, upon removal of ouabain, full recovery of the Na+, K+
      ATPase was observed, a process that could easily be monitored by using cell
      monolayers cultured on microplates.

PMID- 10334630
TI  - Water permeation barrier in isolated cutaneous newborn rat epidermis.
AB  - Abnormal water barrier function occurs in irritated skin and certain cutaneous
      diseases. Methods have been compared for separating the epidermis (site of the
      barrier) from the whole skin without disturbing the barrier function. The
      epidermis was separated from newborn rat skin by (1) exposure to 10% trypsin at 4
      degrees C for 16 h, (2) exposure to 0.2% dispase at 4 degrees C for 16 h, (3)
      heating for 50 s at 55 degrees C, (4) or heating for 40 s at 50 degrees C after
      the whole skin was kept in medium at the air-liquid interface for 1 day at 35
      degrees C. Water permeation of the isolated epidermis was then measured
      immediately or after 3, 5, 8, and 10 days of maintenance at the air-liquid
      interface. The water permeation barrier constant (kp) was 1.9+/-0.9 cm/h in
      intact rat skin. At 0 day of maintenance, the kp of the epidermis was 2.1+/-0.9
      after treatment with trypsin, 3.8+/-1.2 after dispase, and 4.3+/-1.4 after
      immediate heating, or 2.2+/-0.7 cm/h after culture and heating. The dispase and
      heating methods disrupted the barrier to a greater extent than did the trypsin
      and culture-heating methods. The latter two methods allowed the kp to be
      maintained at low levels for 8 days (kp for trypsin 2.8+/-0.9 and 2.5+/-0.8 for
      culture-heating). Epidermis isolated by the trypsin or culture-heating techniques
      and maintained at the air-liquid interface can be used to study the mechanism by
      which barrier function is disrupted by chemicals.

PMID- 10334631
TI  - A study on seasonal variation in the development of morphine dependence in rats.
AB  - The possibility that naloxone-precipitated opiate withdrawal behaviors varied
      qualitatively over the course of the year was investigated. The experiments were
      carried out at monthly intervals over a 2-year period using rats treated with a
      morphine-containing slow-release emulsion. The results obtained from these
      experiments were equivocal, neither providing support for seasonal variance in
      the expression of the opiate abstinence syndrome, nor showing a complete lack of
      time-related differences. Although some behavioral signs of opiate abstinence
      showed seasonally related alterations in frequency over one of the years, this
      was not consistent from one year to another. It was therefore concluded that no
      significant relationship between the severity of the abstinence syndrome and the
      time of the year in which the experiment carried out could be demonstrated.

PMID- 10334632
TI  - Absorption of morphine from a slow-release emulsion used to induce morphine
      dependence in rats.
AB  - This study was performed to measure absorption of morphine from the injection
      site following treatment of rats with slow-release emulsions formulated with
      morphine hydrochloride and morphine base. Samples of emulsion were collected from
      the injection site of halothane anesthetized animals at 24 and 48 h following
      emulsion treatment and concentrations of morphine remaining in the emulsion were
      analyzed using high-performance liquid chromatography (HPLC). In another group of
      morphine-treated rats, at times equivalent to collecting samples of emulsion, the
      intensity of naloxone-precipitated withdrawal behaviors was monitored. Both
      morphine base- and hydrochloride-containing emulsions induced a high degree of
      physical dependence in animals treated over 48 h. Release of morphine from
      emulsions containing morphine base was slower than that from the hydrochloride
      formulations. In the 24-h morphine base-treated animals, approximately 45% was
      absorbed from the injection site as opposed to 99% in the 24-h morphine
      hydrochloride-treated animals. These results suggest that morphine base
      containing emulsions provide a more sustained exposure to the opioid.

PMID- 10334633
TI  - Erdosteine enhances mucociliary clearance in rats with and without airway
      inflammation.
AB  - Erdosteine is a new homocysteine-derived expectorant and has been reported to
      have many mucolytic effects. In this report, we studied the activities of
      erdosteine on mucociliary clearance in normal and airway-inflammation-induced
      rats. In normal rats, erdosteine at doses of 100-600 mg/kg significantly promoted
      mucociliary clearance. However, erdosteine did not change the concentrations of
      mucopolysaccharides in bronchoalveolar lavage fluid (BALF). In the LPS
      instillated rats, the mucociliary clearance was inhibited and the number of
      inflammatory cells, albumin concentration, and mucopolysaccharides concentration
      in BALF were increased. Erdosteine at doses of 100-600 mg/kg significantly
      attenuated the inhibition of mucociliary clearance and the increase of
      inflammatory cells, however, it did not prevent the increase of albumin and
      mucopolysaccharides. Other mucolytic drugs which are ambroxol and S
      carboxymethylcysteine, had no effect. These results indicate that erdosteine
      promotes the mucociliary clearance in normal and airway-inflammation-induced
      rats.

PMID- 10334634
TI  - Curative effect of picroliv on primary cultured rat hepatocytes against different
      hepatotoxins: an in vitro study.
AB  - Picroliv, the standardized active principle from the plant Picrorhiza kurrooa
      showed significant curative activity in vitro in primary cultured rat hepatocytes
      against toxicity induced by thioacetamide (200 microg/mL), galactosamine (400
      microg/mL), and carbon tetrachloride (3 microl/mL). Activity was assessed by
      determining the change in hepatocyte viability and rate of oxygen uptake and
      other biochemical parameters (GOT, GPT, and AP). The toxic agents alone produced
      a 40-62% inhibition of cell viability and a reduction of biochemical parameters
      after 24 h of incubation at 37 degrees C which (on removal of the toxic agents)
      was reversed after further incubation for 48 h. Incubation of damaged hepatocytes
      with picroliv exhibited a concentration- (1-100 microg/mL) dependent curative
      effect in restoring altered viability parameters. The results warrant the use of
      this in vitro system as an alternative for in vivo assessment of hepatoprotective
      activity of new agents.

PMID- 10334635
TI  - Epidural analgesia for postoperative pain control following spinal surgery:
      paucity of evidence and need for studies.

PMID- 10334636
TI  - Serum organochlorine pesticides and PCBs and breast cancer risk: results from a
      prospective analysis (USA).
AB  - OBJECTIVE: To prospectively evaluate relationships of organochlorine pesticides
      and polychlorinated biphenyls (PCBs) with breast cancer, we conducted a case
      control study nested in a cohort using the Columbia, Missouri Breast Cancer Serum
      Bank. METHODS: Women donated blood in 1977-87, and during up to 9.5 years follow
      up, 105 donors who met the inclusion criteria for the current study were
      diagnosed with breast cancer. For each case, two controls matched on age and date
      of blood collection were selected. Five DDT [2,2-bis(p-chlorophenyl)-1,1,1
      trichloroethane] analogs, 13 other organochlorine pesticides, and 27 PCBs were
      measured in serum. RESULTS: Women in the upper three quartiles of
      hexachlorobenzene were at twice the risk of breast cancer compared to those in
      the lowest quartile. However, there was no evidence for a dose-response
      relationship, and the association was limited to women whose blood was collected
      close to the time of diagnosis. Women with higher serum levels of other
      organochlorine pesticides and PCBs showed no increased risk of breast cancer
      overall, although positive associations were suggested for PCB-118 and PCB-138
      when blood was collected close to the time of diagnosis. CONCLUSIONS: Results of
      this study do not support a role for organochlorine pesticides and PCBs in breast
      cancer etiology.

PMID- 10334637
TI  - Visual impairment and cancer: a population-based cohort study in Finland.
AB  - OBJECTIVES: To describe the cancer risk pattern of Finnish persons with visual
      impairment. METHODS: A cohort of 17,557 persons identified from the Finnish
      Register of Visual Impairment was followed-up for cancer through the Finnish
      Cancer Registry from 1983-95. The degree of visual impairment ranged from
      moderate low vision with visual acuity less than 0.3, to total blindness with no
      perception of light. The standardized incidence ratios (SIR) and 95% confidence
      intervals (CI) were calculated by primary site; the expected rates were based on
      national cancer incidence rates. RESULTS: The SIR for overall cancer among
      totally blind men was 2.2 (CI = 1.3-3.5) while in the entire cohort the incidence
      was increased by only 15% (1,255 cancers observed cf 1,093 expected). Excesses
      were observed in both genders in cancers of the liver (SIR = 1.8, CI = 1.2-2.5)
      and lung (SIR = 1.5, CI = 1.3-1.7); in females in cancers of the stomach (SIR =
      1.5, CI = 1.2-1.9) and the colorectum (SIR = 1.3, CI = 1.1-1.6); and in males in
      cancers of the kidney (SIR = 1.8, CI = 1.1-2.6) and the eye (5.8, CI = 1.9-13).
      The excess in lung cancer was entirely attributable to age-related macular
      degeneration (which is most common among smokers). CONCLUSIONS: Cancer incidence
      among the visually impaired tended to be increased for most cancer types.
      Attention should be paid to lifestyle factors underlying the observed risk
      increases, such as unbalanced diet.

PMID- 10334638
TI  - A case-control study of melanomas of the soles and palms (Australia and
      Scotland).
AB  - OBJECTIVES: Because the factors that influence risk of acral melanomas on the
      soles and palms in White populations are unknown, we investigated these in a
      multi-center case-control study. METHODS: Cases of melanoma of the feet and hands
      diagnosed from 1987-93 in persons aged over 18 years were ascertained in eastern
      Australia and western Scotland. There were 275 cases of melanoma on the soles and
      palms matched to 496 controls (selected from the electoral roll) in Australia,
      and 36 cases matched to 72 controls (nominated by general practitioners) in
      Scotland. RESULTS: Acral melanoma was strongly associated with high total body
      nevus counts (adjusted relative risk [RR] = 6.3, 95% confidence interval [CI] =
      2.5-15.6), and with nevi on the soles (RR = 7.5, CI = 3.0-18.6). There were also
      significant positive associations with a penetrative injury of the feet or hands
      (RR = 5.0, CI = 3.0-8.6) and with heavy exposure to agricultural chemicals (RR =
      3.6, CI = 1.5-8.3). Sun-sensitive complexions, cumulative sun exposure and a past
      history of nonmelanoma skin cancer were also associated with increased risk of
      acral melanoma. Current cigarette smoking was inversely related to acral melanoma
      (RR = 0.6, CI = 0.4-0.9). CONCLUSIONS: Melanomas of the soles and palms resemble
      other cutaneous melanomas in their association with sun exposure, but are
      distinguished from them by their strong positive associations with nevi on the
      soles, previous penetrative injury, and exposure to agricultural chemicals, and
      by their inverse association with smoking.

PMID- 10334639
TI  - Tobacco and alcohol use and oral cancer in Puerto Rico.
AB  - OBJECTIVES: To determine risk for oral cancer in Puerto Rico associated with use
      of alcohol and tobacco. METHODS: In Puerto Rico, alcohol and tobacco use were
      compared among nonsalivary gland cancers of the mouth and pharynx (n = 342),
      cancers of major and minor salivary glands (n = 25) and 521 population-based
      controls. RESULTS: Alcohol (usual use, Ptrend < 0.0001 for men and Ptrend = 0.02
      for women) and tobacco (usual use, Ptrend < 0.0001, for both men and women) were
      strong independent risk factors for oral cancer in Puerto Rico, with a
      multiplicative effect from combined exposures. Risks did not vary systematically
      by use of filter vs. nonfilter cigarettes. Risks with use of other forms of
      smoked tobacco were about sevenfold among both men and women. Risks decreased
      only gradually after cessation of tobacco and alcohol use. Tobacco use, but not
      alcohol, was linked to cancers of the salivary glands. The burden of oral cancer
      due to alcohol and tobacco use in Puerto Rico (76% for men, 52% for women) agreed
      closely with earlier estimates for the mainland US population, while about 72% of
      salivary gland cancer (men and women, combined) was due to tobacco use.
      CONCLUSIONS: Excess risks for oral cancer in Puerto Rico are largely explained by
      patterns of alcohol and tobacco use. Smoking filter vs. nonfilter cigarettes does
      not alter risk, while cessation of alcohol and tobacco use appears to reduce risk
      only gradually.

PMID- 10334640
TI  - Leukemias and lymphomas: time trends in the UK, 1984-93.
AB  - OBJECTIVE: To investigate recent time trends of some selected and common
      neoplasms of the blood and lymphatic tissues. METHODS: A specialist population
      based register of hematological and related neoplasms was set up in parts of the
      UK in 1984. Secular changes over the first 10 years were investigated using log
      linear Poisson modeling. The results are presented in tabular and graphical form.
      RESULTS: The analyses of 26,899 cases revealed a decline in incidence of acute
      myeloid leukaemia (AML), the myeloproliferative disorders (MPD) including chronic
      myeloid leukaemia (CML) and, in males only, Hodgkin's disease (HD). No secular
      trends for acute lymphoblastic leukaemia (ALL) were observed at any age. A marked
      increase in incidence in non-Hodgkin's disease (NHL) and the pre-leukemia group
      of myeloid dysplasias (MDS) was found. CONCLUSIONS: The rise in MDS and decline
      in AML and related conditions are most likely to reflect diagnostic changes.
      Changes in NHL may reflect, in part, a similar phenomena, but an underlying
      upward trend cannot be excluded. The decline in HD is in one gender only and the
      significance of this remains to be investigated.

PMID- 10334641
TI  - Childbearing at older age and endometrial cancer risk (Sweden).
AB  - OBJECTIVES: Several studies have found an inverse association between older age
      at last birth and endometrial cancer risk. A nested case-control study was
      undertaken to examine the influence of this and other aspects of reproductive
      patterns on the risk of developing endometrial cancer. METHODS: Among women born
      in 1925 and later, 4,839 eligible patients were identified in the Swedish Cancer
      Register. For each case, five individually age-matched controls were randomly
      selected from a population-based Fertility Register. Relative risks were
      estimated from odds ratios obtained from conditional logistic regression
      analyses. RESULTS: Compared to uniparous women, childless women were at a higher
      risk of endometrial cancer (odds ratio [OR] = 1.38, 95% confidence interval [CI]
      = 1.25-1.52). This association was stronger in younger (< 50 years) than in older
      (50+ years) women. At all ages of first birth, a delivery was associated with a
      reduced risk of endometrial cancer that slowly diminished with time. Among parous
      women, the risk decreased by almost 20% for each additional live birth (OR =
      0.81, CI = 0.78-0.84). In an analysis limited to women with two or more births
      that compared the independent effects of age at first and at last birth, only
      older age at last birth was associated with a lowered risk of endometrial cancer.
      The risk decreased at a rate of about 15% per five-year delay of last birth.
      CONCLUSIONS: Endometrial cancer is often referred to as the prototype hormonally
      determined disease in women. However, our findings give further support to the
      hypothesis that a birth may not only affect risk through hormonal influences, but
      possibly also through mechanical shedding of cells that have undergone malignant
      transformation.

PMID- 10334642
TI  - Incidence of cancer among Finnish patients with asbestos-related pulmonary or
      pleural fibrosis.
AB  - OBJECTIVES: To study the asbestos-associated risk of lung cancer according to the
      histological type of cancer, the time of and time since diagnosis of asbestosis,
      the asbestos-associated risk for cancers other than lung cancer or mesothelioma,
      and the predictive value of asbestos-related pleural abnormalities as regards the
      risk of cancer. METHODS: Finnish patients with asbestosis (n = 1,376) or asbestos
      related benign pleural disease (n = 4,887) notified as an occupational disease
      since 1964 were followed-up through the Finnish Cancer Registry for cancer in
      1967-95. RESULTS: Compared with the total cancer incidence in Finland, men with
      asbestosis had a raised risk of lung cancer (standardized incidence ratio [SIR] =
      6.7; 95% confidence interval [CI] = 5.6-7.9), mesothelioma (SIR = 32, CI = 14-60)
      and cancer of the larynx (SIR = 4.2, CI = 1.4-9.8). The risk of lung cancer was
      similarly raised for all histological types of lung cancer (the highest in
      insulators) and did not change markedly over time of notification or duration of
      follow-up. Men with benign pleural disease had a raised risk of mesothelioma (SIR
      = 5.5, CI = 1.5-14) and a slightly elevated risk of lung cancer (SIR = 1.3, CI =
      1.0-1.8). Among women with asbestosis, significant excess was found for lung
      cancer and mesothelioma. CONCLUSION: Asbestosis and asbestos-related benign
      pleural disease seem to possess different predictive values as regards the risk
      of lung cancer.

PMID- 10334643
TI  - Mortality and cancer incidence among laboratory technicians in medical research
      and routine laboratories (Sweden).
AB  - OBJECTIVES: To investigate cancer incidence and mortality among laboratory
      employees. METHODS: Mortality and cancer incidence were investigated among 2553
      female and male laboratory workers employed at the Karolinska Institute and
      Karolinska Hospital in Stockholm between 1950 and 1989. Mortality was followed
      from 1952-1993 and cancer incidence from 1958-1992. Expected numbers were based
      on the general population in Stockholm, standardizing for age, gender, and
      calendar period. RESULTS: The overall mortality and cancer incidence in the
      cohort was lower than expected. There were in all 10 cases of hemato-lymphatic
      malignancies (three acute myeloid leukemias, four non-Hodgkin lymphomas, two
      Hodgkin's lymphomas, and one multiple myeloma) in the cohort. The standardized
      incidence ratio (SIR) for hematolymphatic tumors was increased among workers who
      had ever been employed in laboratories with a high probability for chemical
      exposure, SIR 224 (95% CI 108-412). The risk of breast cancer among women was
      increased after more than 10 years of work in high-exposure laboratories, SIR 225
      (128-365). The number of malignant melanomas exceeded those expected.
      CONCLUSIONS: The findings support earlier observations of an increased risk of
      hematolymphatic cancer among laboratory workers. The routine for handling
      chemicals and functionality of ventilatory equipment must be under continuous
      supervision.

PMID- 10334644
TI  - Genetic polymorphism of glutathione S-transferase P1 gene and lung cancer risk.
AB  - OBJECTIVES: The human GSTTP1 gene is polymorphic with an A-->G transition in exon
      5 causing a replacement 105 Ile-->Val in the GSTP1 protein. The two isoforms,
      encoded by the alleles GSTP1*A and GSTP1*B, respectively, show different
      catalytic efficiencies towards some carcinogenic epoxides. In this study we have
      addressed the possible role of the Ile105Val GSTP1 polymorphism in lung cancer
      susceptibility. METHODS: The polymorphic site was genotyped by RFLP in a group of
      lung cancer patients (n = 164) and in two control groups (healthy smokers, n =
      132; general population, n = 200). All patients and controls were Northwestern
      Mediterranean Caucasians of the same ethnic origin. RESULTS AND CONCLUSIONS: The
      cancer patients showed frequencies of GSTP1*A/A; GSTP1*A/B and GSTP1*B/B (50%,
      38%, 11%, respectively) very similar to those of both control groups (healthy
      smokers: 48%, 41%, 11%). After adjusting for age, sex and smoking status, no
      association was found between the GSTP1*B allele and lung cancer risk (OR: 1.18;
      95% CI: 0.67-2.07). The Ile105val GSTP1 polymorphism was also analysed in
      combination with the GSTM1 and GSTT1 genes. The results showed that allelism at
      GSTP1 did not increase the risk associated with the GSTM1 or GSTT1 deletions.

PMID- 10334645
TI  - Intake of specific carotenoids and flavonoids and the risk of gastric cancer in
      Spain.
AB  - OBJECTIVES: To investigate the relationship between gastric cancer and the intake
      of specific carotenoids (alpha-carotene, beta-carotene, lutein, and lycopene) and
      flavonoids (quercetin, kaempferol, myricetin, and luteolin) using new data on
      their concentration in foods. METHODS: Case-control study carried out in Spain
      that included 354 cases of gastric cancer and 354 controls, matched by age,
      gender, area of residence and hospital. Usual food intake was assessed using a
      dietary history questionnaire. RESULTS: In a multivariate model adjusted for
      several dietary factors, no association was found between intake of any of the
      studied carotenoids and the risk of gastric cancer. The adjusted OR of gastric
      cancer for the highest quartile of total flavonoid intake versus the lowest
      quartile was 0.44 (95 percent confidence interval [CI] = 0.25-0.78; P for trend =
      0.003). Kaempferol intake was found to be protective (OR = 0.48; CI = 0.26-0.88;
      P for trend = 0.04) comparing the highest versus the lowest quartile of intake. A
      trend toward lower risk of stomach cancer with higher intake of quercetin was
      also found. CONCLUSIONS: The results of this study support the hypothesis that
      the well-established protective effect of fruit and vegetables against gastric
      cancer could, in part, be due to the presence of flavonoids.

PMID- 10334646
TI  - The incidence of gastric carcinoma in Asian migrants to the United States and
      their descendants.
AB  - OBJECTIVES: We examined the incidence of gastric carcinoma in Chinese, Japanese,
      and Filipino residents of the United States to obtain additional information
      about the etiology of this disease. METHODS: The age, race, and birthplace of
      residents of Hawaii, San Francisco/Oakland, and northwestern Washington who were
      diagnosed with gastric carcinoma during the period 1973-1986 were obtained from
      population-based registries, and a special tabulation from the 1980 Census was
      used to estimate the number of person-years at risk for each category of
      resident. RESULTS: The incidence of gastric carcinoma in Japanese-Americans was
      three to six times higher than that of US-born whites, with the highest rates
      occurring in those persons born in Japan. The rate in US-born Chinese and Chinese
      men who immigrated to the US was similar to that of whites, whereas the rate in
      Chinese female migrants was twice that of white American women. Filipino men,
      regardless of birthplace, were only at 60% the risk of US-born white men, while
      their female counterparts had a rate very similar to that of US-born white women.
      The high incidence observed among Japanese-Americans and Chinese female
      immigrants was largely restricted to sites other than the gastric cardia.
      CONCLUSIONS: Our findings suggest that dietary and other lifestyle differences
      between the different generations of Japanese-Americans, and between Japanese
      residents of the US and Japan may provide clues regarding the etiologies of
      stomach cancers that arise beyond the gastric cardia.

PMID- 10334647
TI  - Characteristics of pregnancy and birth and malignancy in the offspring (Sweden).
AB  - OBJECTIVES: The aim of the study was to investigate whether factors of pregnancy
      and birth influence the risk of malignancy in the offspring. METHODS: Data on all
      deliveries (248,701 births) in two counties in Sweden 1955-90 were extracted from
      two birth registries. The follow-up period closed at the end of 1994 and the
      subjects were followed up to early middle-age at most (39 years). Incidence rates
      of malignancy were obtained from the Cancer Register 1958-1994. Standardized
      incidence ratios (SIR) and relative risks (RR) were calculated. RESULTS: Overall,
      few associations were detected. A significantly increased standardized incidence
      ratio (SIR) of 50.00 (95% CI = 13.45-99.99) was found for the relationship
      between Down's syndrome and lymphatic leukaemia. Elder maternal age (> or =35
      years) and lymphatic leukaemia were associated with a significantly enhanced risk
      (SIR = 2.00; 95% CI, 1.16-3.20). Maternal age 25-34 years, compared to younger
      age, was associated with a reduced risk of cervical cancer (RR = 0.47; 95% CI =
      0.26-0.86). CONCLUSIONS: Although some associations, the consistent pattern of
      non-association indicated a low impact of intrauterine environment or changed
      genetic material on the future development of malignancy in the offspring up to
      early middle-age.

PMID- 10334648
TI  - The glycaemic index of potatoes: the effect of variety, cooking method and
      maturity.
AB  - OBJECTIVE: The aim of this study was to determine the impact of variety, cooking
      method and maturity on the GI of potatoes, it was hypothesised that new potatoes
      may have a relatively lower GI. DESIGN AND SUBJECTS: Ten healthy volunteers were
      recruited as subjects through advertising on the campus of the University of
      Sydney. Equal (50 g) carbohydrate portions of eight potato meals (three
      varieties, four cooking methods, two states of maturity) and two reference white
      bread meals were fed in random order to each of the subjects over a period of 10
      weeks. Capillary blood samples were taken in the fasting state and then at 15,
      30, 45, 60, 90 and 120 min from the start of each meal. Samples were analysed for
      plasma glucose concentrations and incremental areas under plasma glucose curves
      were calculated. The GI of the potato was calculated as the AUC of the potato
      expressed as a percentage of the individual's average AUC of the white bread.
      This was then multiplied by 0.7 to index the GI to glucose as the reference food.
      RESULTS: GI values (mean +/- s.e.m.) ranged from 65+/-9 (canned new potatoes) to
      10+/-15 (boiled Desiree potatoes), glucose = 100. No significant difference was
      found among the three varieties of potato tested (P = 0.38) or among the four
      different cooking methods (P = 0.55). The GI values of the canned new potato and
      boiled Desiree potato were significantly different (P = 0.047). The average size
      of the tuber was found to correlate with the GI (r = 0.83, P<0.05). CONCLUSIONS:
      Potatoes, regardless of variety, cooking method and maturity, have exceptionally
      high GI values. New potatoes have relatively lower GI values which is attributed
      to differences in starch structure.

PMID- 10334649
TI  - The effect of magnesium supplementation on biochemical markers of bone metabolism
      or blood pressure in healthy young adult females.
AB  - OBJECTIVES: To investigate the effects of increasing Mg intakes, above the usual
      dietary intake, on blood pressure and on biomarkers of bone metabolism in healthy
      young adult females. DESIGN: A double-blind, placebo-controlled, randomised
      crossover Mg intervention trial. SETTING: The study was conducted in the
      Department of Nutrition, University College, Cork, Ireland. SUBJECTS: Twenty-six
      healthy (normotensive) adult females aged 20-28 y were recruited from University
      College, Cork. INTERVENTION: Subjects were randomly assigned to their self
      selected diets (approximately 11 mmol Mg/d) or their self-selected diet with a 10
      mmol/d Mg supplement as Mg(OH)2 (approximately 22 mmol Mg/d) for 28 d followed by
      cross-over to the alternative diet for a further 28 d. During each dietary period
      urines (last 3 d) and blood (morning of 27 d) were collected and blood pressure
      was measured on the morning of 28 d. RESULTS: Increasing Mg intake from the usual
      level (11 mmol/d) to 22 mmol/d for 28d increased urinary excretion of Mg by 36%
      and erythrocyte Mg content by 5% but had no effect on serum Mg, Ca, PTH,
      osteocalcin or bone-specific alkaline phosphatase (biomarkers of bone formation),
      urinary pyridinium crosslinks of collagen (biomarkers of bone resorption), or on
      blood pressure. CONCLUSION: Increasing the mean Mg intake in healthy young adult
      females above the usual dietary intake, which is currently above the US EAR
      (estimated average requirement), but below the US RDA for Mg, does not affect
      blood pressure or the rate of bone turnover.

PMID- 10334651
TI  - Dietary and lifestyle factors affecting plasma vitamin D levels in Asian children
      living in England.
AB  - OBJECTIVE: To determine the vitamin D status of a sample of young Asian children
      living in England by measurement of plasma 25-hydroxycholecalciferol levels; to
      relate biochemical measurements with parameters of diet, lifestyle and iron
      status in this population. DESIGN: The 'Infant Feeding in Asian Families' survey
      covered infants born to mothers of Bangladeshi, Indian or Pakistani origin, plus
      a sample of children born to White mothers in 41 local authority areas. The
      current study describes vitamin D values in a sub sample of Asian children from
      that survey. SETTING: Forty-one local authority areas which covered 95% of the
      Asian population at the time of the 1991 Census and include areas with the
      highest and lowest density of Asians. SUBJECTS: Seventy-one percent (2382) of
      mothers who were originally eligible were interviewed on four occasions up to the
      time their infant was 15 months. One thousand, seven hundred and thirty-eight of
      these children were followed up for this current study. Of these 618 had a blood
      sample analysed for vitamin D. OUTCOME MEASURES: Previous day's food intake,
      normal dietary intake, indicators of iron status and plasma vitamin D levels.
      RESULTS: Plasma vitamin D values are lower in the three groups of Asian children
      than values reported for children of a similar age in the National Diet and
      Nutrition Survey. Between one third and a half of children with a low haemoglobin
      also had low plasma vitamin D values; there was a significant association between
      failure to take a vitamin supplement, chapati consumption and low vitamin D
      values. CONCLUSIONS: It is particularly important that pre-school Asian children
      receive a vitamin D supplement. Children with low haemoglobin values should be
      screened for vitamin D deficiency.

PMID- 10334650
TI  - Rye bread decreases postprandial insulin response but does not alter glucose
      response in healthy Finnish subjects.
AB  - OBJECTIVE: To compare if postprandial glucose and insulin responses to
      wholekernel rye bread are lower than to wheat bread, and to see if these
      responses to two types of rye breads are different. To explore starch digestion
      in more detail, rate of starch hydrolysis of same breads was measured in vitro.
      DESIGN: Subjects were given test breads (43-61 g available carbohydrates by
      analysis) with standardized breakfast in a random order after a fast. Eight
      postprandial blood samples were collected during the following three hours. Rate
      of starch hydrolysis was determined by an in vitro enzymatic hydrolysis method.
      SUBJECTS: 10 men and 10 women, aged 32+/-3 and 27+/-5 y, BMI 24.5+/-2.2 and
      20.3+/-1.1 kg/m2, respectively, all had normal glucose tolerance. RESULTS: Plasma
      insulin response to wholekernel rye bread was lower than to wheat bread (45 min P
      = 0.025, 60 min P = 0.002, 90 min P = 0.0004, 120 min P = 0.050, 150 min P =
      0.033), but there was no difference in glucose responses. In comparison of two
      types of rye breads, glucose response to wholemeal rye bread at 150 and 180 min
      was higher (P = 0.018 and P = 0.041, respectively) and insulin response at 60 min
      was lower (P = 0.025) than those to wholemeal rye crispbread. Total sugar
      profiles in vitro were similar for all breads. When free reducing sugars were
      subtracted, starch in wholekernel and wholemeal rye breads appeared to be
      hydrolysed slower than starch in wholemeal rye crispbread and wheat bread.
      CONCLUSIONS: Wholekernel rye bread produces lower postprandial insulin response
      than wheat bread, but there is no difference in glucose response. The latter is
      in accordance with in vitro results. Postprandial glucose and insulin may also be
      affected by type of rye bread. Characteristics of different types of rye breads
      must be further investigated to develop health properties of rye breads.

PMID- 10334652
TI  - Effect of the energy density and volume of high carbohydrate meals on short term
      satiety in preschool children.
AB  - OBJECTIVE: To investigate the effect of energy density and food volume intakes in
      one meal (lunch-time) on food and energy intakes in the subsequent meal (tea
      time). DESIGN: During lunch, two meals with different energy densities (1.26 and
      0.69 kcal/g) were offered to preschool children using normal foods and
      maintaining a similar energy, carbohydrate, and fat intakes. In the subsequent
      meal a varied type of high acceptability foods were served in higher amounts than
      those that children usually consume. SETTING: A day care center where the
      children were fed during lunch-time and tea-time. SUBJECTS: Two hundred and
      thirty-four normal preschool children, 108 males and 126 females, according to
      the weight for height index using the NCHS standards. METHODS: Chemical analysis
      of the meals served using the AOAC methods and determination of food and energy
      intakes by differential weighing of the foods. RESULTS: The preschool children
      had a similar energy intake at lunch but a significantly higher food intake when
      they consumed the meal with the lower energy density (313 vs. 290.7 kcal) (P =
      0.001). There were no differences in the food intakes at the subsequent meal
      times. CONCLUSIONS: The results of this present work demonstrate that under the
      conditions of the study, there is an inverse relationship between the energy
      density of the meals consumed at the first meal-time and the energy intakes at
      the subsequent meal in normal preschool children; and a direct relationship with
      the short-term satiety. It is possible that differences in satiety reflect, in
      part, effects from the characteristics of the normal food used in the dietary
      treatments. These conclusions suggest that future research must be carried out in
      order to investigate the separate effects of food and the dietary variables
      commonly used in the studies of food and energy regulations in humans.

PMID- 10334653
TI  - Yoghurt enriched with Lactobacillus acidophilus does not lower blood lipids in
      healthy men and women with normal to borderline high serum cholesterol levels.
AB  - OBJECTIVE: To investigate whether intake of Lactobacillus acidophilus strain L-1
      lowers serum cholesterol in healthy men and women. DESIGN: Randomised, placebo
      controlled parallel trial. SETTING: Subjects were free-living. Blood sampling and
      distribution of yoghurts were administered at a local hospital. SUBJECTS: Seventy
      eight adult men and women with cholesterol levels of 3.9-7.8 mmol/L (mean +/-
      s.d., 5.4+/-0.7). INTERVENTIONS: Subjects consumed 500 mL of control yoghurt
      daily for two weeks. They were then randomly allocated to receive 500 mL per day
      of control yoghurt or of yoghurt enriched with Lactobacillus acidophilus L-1 for
      another six weeks. The yoghurts were spiked with a trace of lithium; compliance
      as assessed by plasma lithium was excellent. RESULTS: Energy and nutrient intake
      was constant, and identical for the two groups. Mean body weight was stable.
      Baseline blood lipid concentrations in the control and treatment groups were
      highly similar. The effect of consumption of Lactobacillus acidophilus L-1 vs.
      control on total cholesterol was -0.02 mmol/L (95% CI, -0.18-0.15) after three
      weeks and 0.04 mmol/L (95% CI, -0.12-0.20) after six weeks. Serum LDL and HDL
      cholesterol and triacylglycerol levels were also unaffected. CONCLUSIONS: Yoghurt
      enriched with Lactobacillus acidophilus L-1 does not lower serum cholesterol in
      men and women with normal to borderline high cholesterol levels.

PMID- 10334654
TI  - Comparison of three methods for estimating daily individual discretionary salt
      intake: 24 hour recall, duplicate-portion method, and urinary lithium-labelled
      household salt excretion.
AB  - OBJECTIVE: To compare methods for estimating discretionary salt intake, that is,
      salt added during food preparation and consumption in the home. SETTING: The
      study was carried out in a rural Guatemalan village. SUBJECTS: Subjects were
      selected non-randomly, based on their willingness to cooperate. Nine mother-son
      dyads participated; the sons were aged 6-9 y. INTERVENTIONS: Three approaches for
      estimating the discretionary salt consumption were used: 24 h recall; collection
      of duplicate portions of salt; and urinary excretion of lithium during
      consumption of lithium-labelled household salt. Total salt intake was assessed
      from the excretion of chloride over 24 h. RESULTS: The mean discretionary salt
      consumption based on lithium excretion for mothers was 3.9+/-2.0 g/d (mean +/-
      s.d.) and for children 1.3+/-0.6 g/d. Estimates from the 24 h recalls and from
      the duplicate portion method were approximately twice and three times those
      measured with the lithium-marker technique respectively. The salt intake
      estimated from the recall method was associated with the lithium-marker technique
      for both mothers and children (Spearman correlation coefficient, 0.76 and 0.70
      respectively). The mean daily coefficient of variation in consumption of
      discretionary salt measured by the three methods, for mothers and boys
      respectively, were: lithium marker, 51.7 and 43.7%; 24 h recall, 65.8 and 50.7%;
      and duplicate portion, 51.0 and 62.6%. CONCLUSIONS: We conclude that an interview
      method for estimating discretionary salt intake may be a reasonable approach for
      determining the relative rank-order in a population, especially among female food
      preparers themselves, but may grossly overestimate the actual intake of salt
      added during food preparation and consumption.

PMID- 10334655
TI  - Who has a high vitamin A intake from plant foods, but a low serum retinol
      concentration? Data from women in Indonesia.
AB  - OBJECTIVE: To examine whether the relationship between vitamin A intake, from
      plant and animal foods, and vitamin A status is the same throughout a population.
      DESIGN: Analysis of cross-sectional data on vitamin A intake, vitamin A status,
      physiological condition and socio-economic status. SETTING: Central Java,
      Indonesia. SUBJECTS: Women with a child < or =24 months old (n = 600). RESULTS:
      Mean serum retinol concentration of women with animal vitamin A intake below or
      above the median (50 RE/d) was 1.28 and 1.38 micromol/L, respectively (P<0.05).
      For those with intake above the median the distribution curve for serum retinol
      concentration was shifted towards the right, to higher concentrations. Serum
      retinol concentration of women with plant vitamin A intake below or above the
      median (279 RE/d) was 1.30 and 1.36 micromol/L, respectively (P<0.05). Again, the
      distribution curve for serum retinol was shifted towards higher concentrations
      for women with an intake above the median, except for the subgroup of 25% with
      the lowest serum retinol concentration (<1.10 micromol/L). These women did not
      seem to benefit from their relatively high vegetable intake. They also had the
      lowest socio-economic status. CONCLUSIONS: The subgroup that was most in need of
      vitamin A could not obtain it from plant foods. It may well be that, because of
      their lower socio-economic status, their hygiene conditions were worse and
      therefore host-related factors that affect carotene bioavailability, such as
      parasitic infestation, were less favourable in this group. They depended on
      supplements and, if affordable, on animal foods, fruits and/or fortified
      products.

PMID- 10334656
TI  - Development of a general nutrition knowledge questionnaire for adults.
AB  - OBJECTIVE: This paper describes the development of a reliable and valid
      questionnaire to provide a comprehensive measure of the nutritional knowledge of
      UK adults. The instrument will help to identify areas of weakness in people's
      understanding of healthy eating and will also provide useful data for examining
      the relationship between nutrition knowledge and dietary behaviour which, up
      until now, has been far from clear. DESIGN: Items were generated paying
      particular attention to content validity. The initial version of the
      questionnaire was piloted and assessed on psychometric criteria. Items which did
      not reach acceptable validity were excluded, and the final 50 item version was
      administered to two groups differing in nutritional expertise on two occasions to
      assess the construct validity and test-retest reliability. SETTING: The
      questionnaire was developed in 1994 in the UK. SUBJECTS: Three hundred and ninety
      one members of the general public, recruited via their places of work, completed
      the questionnaire at the piloting stage. The final version was administered to
      168 dietetics and computer science students following a university lecture.
      RESULTS: The internal consistency of each section was high (Cronbach's alpha =
      0.70-0.97) and the test-retest reliability was also well above the minimum
      requirement of 0.7. Nutrition experts scored significantly better than computer
      experts [F(1167) = 200.5, P<0.001], suggesting good construct validity.
      CONCLUSIONS: The findings demonstrate that the instrument meets psychometric
      criteria for reliability and construct validity. It should provide a useful scale
      with which to reassess the relationship between knowledge and dietary behaviour.

PMID- 10334657
TI  - How optimal are computer-calculated optimal diets?
AB  - OBJECTIVE: This paper aims at clarifying the meaning of 'optimal diets'. DESIGN:
      Two different optimization approaches are considered. Both depart from people's
      actual diets which in general do not meet all their nutrient requirements. In the
      first case (non fuzzy approach) the actual diets are modified such that all
      nutrient intake recommendations are met and the resulting changes in the persons'
      food habits are as little as possible. In the second case (fuzzy approach) the
      actual diets are modified such that the persons' food habits undergo little
      change and the nutrient intake recommendations are met as well as possible. Both
      approaches are evaluated using data on the actual diets of three randomly chosen
      participants of the Bavarian Food Intake Survey. RESULTS: With both approaches
      feasible solutions can be found. The optimal diets computed with the non fuzzy
      approach satisfy all the persons' nutrient requirements, but make it necessary to
      change the persons' food habits considerably. When compared to the subjects'
      actual diets, the optimal diets computed with the fuzzy approach yield
      improvements for the intake of many nutrients, but in some cases deteriorations
      also occur (for example, concerning folate, calcium and iodine). So, the process
      and the results of the fuzzy approach are not 'Pareto efficient'. But it has the
      advantage that the corresponding optimal diets deviate from the actual diets by
      no more than about 3-5 kitchen units per day. CONCLUSIONS: The term 'optimal'
      does not have a general meaning. An 'optimal diet' does not necessarily meet all
      the nutrient requirements of a person. Optimality only depends on the respective
      conditions any optimization is based on.

PMID- 10334658
TI  - Spreads enriched with three different levels of vegetable oil sterols and the
      degree of cholesterol lowering in normocholesterolaemic and mildly
      hypercholesterolaemic subjects.
AB  - OBJECTIVE: To investigate the dose-response relationship between cholesterol
      lowering and three different, relatively low intake levels of plant sterols
      (0.83, 1.61, 3.24 g/d) from spreads. To investigate the effects on lipid-soluble
      (pro)vitamins. DESIGN: A randomized double-blind placebo controlled balanced
      incomplete Latin square design using five spreads and four periods. The five
      study spreads included butter, a commercially available spread and three
      experimental spreads fortified with three different concentrations of plant
      sterols. SUBJECTS: One hundred apparently healthy normocholesterolaemic and
      mildly hypercholesterolaemic volunteers participated. INTERVENTIONS: Each subject
      consumed four spreads, each for a period of 3.5 week. RESULTS: Compared to the
      control spread, total cholesterol decreased by 0.26 (CI: 0.15-0.36), 0.31 (CI:
      0.20-0.41) and 0.35 (CI: 0.25-0.46) mmol/L, for daily consumption of 0.83, 1.61
      and 3.24 g plant sterols, respectively. For LDL-cholesterol these decreases were
      0.20 (CI: 0.10-0.31), 0.26 (CI: 0.15-0.36) and 0.30 (CI: 0.20-0.41). Decreases in
      the LDL/HDL ratio were 0.13 (CI: 0.04-0.22), 0.16 (CI: 0.07-0.24) and 0.16 (CI:
      0.07-0.24) units, respectively. Differences in cholesterol reductions between the
      plant sterol doses consumed were not statistically significant. Plasma vitamin K1
      and 25-OH-vitamin D and lipid standardized plasma lycopene and alpha-tocopherol
      were not affected by consumption of plant sterol enriched spreads, but lipid
      standardized plasma (alpha + beta)-carotene concentrations were decreased by
      about 11 and 19% by daily consumption of 0.83 and 3.24 g plant sterols in spread,
      respectively. CONCLUSIONS: The three relatively low dosages of plant sterols had
      a significant cholesterol lowering effect ranging from 4.9-6.8%, 6.7-9.9% and 6.5
      7.9%, for total, LDL-cholesterol and the LDL/HDL cholesterol ratio, respectively,
      without substantially affecting lipid soluble (pro)vitamins. No significant
      differences in cholesterol lowering effect between the three dosages of plant
      sterols could be detected. This study would support that consumption of about 1.6
      g of plant sterols per day will beneficially affect plasma cholesterol
      concentrations without seriously affecting plasma carotenoid concentrations.

PMID- 10334659
TI  - Household budget survey nutritional data in relation to mortality from coronary
      heart disease, colorectal cancer and female breast cancer in European countries.
      DAFNE I and II projects of the European Commission. Data Food Networking.
AB  - OBJECTIVE: We have undertaken a study to examine whether Household Budget Survey
      (HBS)-derived nutritional patterns are related to mortality from diseases with
      strong nutritional components, namely coronary heart disease, colorectal cancer
      and cancer of the female breast. DESIGN: Ecological correlation study. In the
      context of the Data Food Networking projects of the European Union, raw data from
      the national HBS of 10 European countries were provided. For each of the 10
      participating countries, daily food availability per capita around 1990 was
      calculated. Individual foods were aggregated into 12 major food groups that were
      linked with the diseases under consideration. Mortality data were available from
      a World Health Organisation database. We have used a composite score to summarise
      the postulated influence of diet. SETTING: Ten European countries circa 1990.
      RESULTS: The correlation coefficients between the composite score and the age
      adjusted mortality from each of the studied diseases were: + 0.51 (P
      approximately 0.14) for colorectal cancer; +0.72 (P approximately 0.02) for
      female breast cancer; and +0.60 (P approximately 0.07) for coronary heart
      disease, after adjustment for tobacco smoking. CONCLUSIONS: We conclude that
      dietary information from HBS is sufficiently reliable to reveal correlations with
      mortality rates from chronic diseases with fairly strong nutritional roots. HBS
      data could be used, with little cost, for monitoring secular trends in dietary
      patterns with a view to their health implications.

PMID- 10334660
TI  - Sex-related influence of body size and sexual maturation on blood pressure in
      adolescents.
AB  - OBJECTIVE: This study is aimed at investigating the influence of body size, body
      fat and sexual maturation on blood pressure (BP) in adolescents. DESIGN: A cross
      sectional study. SETTING: A suburban student population of Southern Italy.
      SUBJECTS: One hundred ninety students attending the first and second year of a
      secondary school. Five were excluded because they were affected by major
      diseases. The remaining were 98 M and 87 F (mean age for either group = 12.0+/
      0.8 y). METHODS: Blood pressure was measured by a mercury sphygmomanometer, body
      weight by a platform beamscale, other measurements included height, biceps,
      triceps, subscapular and suprailiac skinfolds by a caliper; sexual maturation was
      evaluated according to Tanner. RESULTS: Body size was greater than in Tanner's
      population: in particular body weight (but not height) in our sample markedly
      exceeded that of the children of the same age in Tanner's population. Boys had
      higher systolic blood pressure (SBP) than girls (BP = 109/64+/-12/10 vs. 103/63+/
      11/8 mm Hg, P<0.02 for SBP), while heart rate and waist/hip ratio were lower.
      During puberty evaluated on the basis of pubic hair growth BP in girls was higher
      than in the prepubertal phase (107/66+/-9/7 vs. 99/61+/-10/7, P<0.01). Pubertal
      boys showed a reduced percent of body fat (calculated from four skinfold
      measurements) in comparison to prepubertal ones (21.0%+/-4.5 vs. 24.5%+/-7.1,
      P<0.01). In linear correlation analysis, height, BW, BMI and lean body mass were
      found to be significantly associated with SBP in both sexes and to diastolic
      blood pressure (DBP) in girls. Percent body fat was correlated with SBP in boys,
      while sexual maturation was associated to SBP and DBP in girls only. Multiple
      regression analysis indicated a significant contribution of body size to BP
      variability, particularly in the girls. Sexual maturation was excluded from the
      final regression equations when height, BW or lean body mass were present.
      CONCLUSIONS: These data indicate that body weight in these adolescents is greater
      that in Tanner's population of the same age and sex. Body size appears to be a
      major determinant of BP, whereas sexual maturation seems to influence BP levels
      mainly through body growth. The influence of percent body fat on BP setting seems
      to be of limited importance.

PMID- 10334661
TI  - The role of excitotoxicity in neurodegenerative disease: implications for
      therapy.
AB  - Glutamic acid is the principal excitatory neurotransmitter in the mammalian
      central nervous system. Glutamic acid binds to a variety of excitatory amino acid
      receptors, which are ligand-gated ion channels. It is activation of these
      receptors that leads to depolarisation and neuronal excitation. In normal
      synaptic functioning, activation of excitatory amino acid receptors is
      transitory. However, if, for any reason, receptor activation becomes excessive or
      prolonged, the target neurones become damaged and eventually die. This process of
      neuronal death is called excitotoxicity and appears to involve sustained
      elevations of intracellular calcium levels. Impairment of neuronal energy
      metabolism may sensitise neurones to excitotoxic cell death. The principle of
      excitotoxicity has been well-established experimentally, both in in vitro systems
      and in vivo, following administration of excitatory amino acids into the nervous
      system. A role for excitotoxicity in the aetiology or progression of several
      human neurodegenerative diseases has been proposed, which has stimulated much
      research recently. This has led to the hope that compounds that interfere with
      glutamatergic neurotransmission may be of clinical benefit in treating such
      diseases. However, except in the case of a few very rare conditions, direct
      evidence for a pathogenic role for excitotoxicity in neurological disease is
      missing. Much attention has been directed at obtaining evidence for a role for
      excitotoxicity in the neurological sequelae of stroke, and there now seems to be
      little doubt that such a process is indeed a determining factor in the extent of
      the lesions observed. Several clinical trials have evaluated the potential of
      antiglutamate drugs to improve outcome following acute ischaemic stroke, but to
      date, the results of these have been disappointing. In amyotrophic lateral
      sclerosis, neurolathyrism, and human immunodeficiency virus dementia complex,
      several lines of circumstantial evidence suggest that excitotoxicity may
      contribute to the pathogenic process. An antiglutamate drug, riluzole, recently
      has been shown to provide some therapeutic benefit in the treatment of
      amyotrophic lateral sclerosis. Parkinson's disease and Huntington's disease are
      examples of neurodegenerative diseases where mitochondrial dysfunction may
      sensitise specific populations of neurones to excitotoxicity from synaptic
      glutamic acid. The first clinical trials aimed at providing neuroprotection with
      antiglutamate drugs are currently in progress for these two diseases.

PMID- 10334662
TI  - Twelve centuries of nephrological writings in the Graeco-Roman world of the
      Eastern Mediterranean (from Hippocrates to Aetius Amidanus).

PMID- 10334663
TI  - Towards the millennium: a history of renal anaemia and the optimal use of
      epoetin.

PMID- 10334664
TI  - The molecular biology of erythropoietin.
AB  - Erythropoietin (Epo) controls the proliferation, differentiation and survival of
      the erythroid progenitors. Epo exerts its effects by binding to a cell surface
      receptor. The Epo receptor includes a p66 chain, which is dimerized upon Epo
      activation, and two accessory proteins, which have been defined by cross-linking.
      Epo binding induces stimulation of the Jak2 tyrosine kinase. Jak2 activation
      leads to the tyrosine phosphorylation of several proteins, including the Epo
      receptor itself. Different intracellular pathways are activated: Ras/MAP kinase,
      phosphatidylinositol 3-kinase and STAT transcription factors. However, the exact
      mechanisms by which the proliferation and/or differentiation of erythroid cells
      are regulated after Epo stimulation are not known. Target disruption of both Epo
      and Epo receptors showed that Epo is not involved in the commitment of the
      erythroid lineage; it seems to act mainly as a survival factor. Epo is
      synthesized largely by the kidney and the liver, and sequences required for
      tissue-specific expression have been localized in the Epo gene. A 3' enhancer is
      responsible for hypoxia-inducible Epo gene expression. Hypoxia-induced factor-1
      (HIF-1) protein binds to this enhancer. In addition to anaemia of renal failure,
      the indication for treatment with epoetin has been extended to the anaemia of
      chronic diseases.

PMID- 10334665
TI  - What are the short-term and long-term consequences of anaemia in CRF patients?
AB  - There is a clear relationship between anaemia and cardiovascular risk in chronic
      renal failure (CRF) patients. Left ventricular hypertrophy (LVH) is present in
      about three-quarters of patients starting dialysis, and is a strong predictor of
      mortality. Anaemia contributes to the development of LVH, mainly via increased
      cardiac output. In some patients, anaemia results in an increase in LV mass,
      while in others it also results in LV end-diastolic volume dilatation. These
      changes increase the risk of arrhythmias, myocardial infarction and myocardial
      fibrosis. The lower the haemoglobin, the more likely it is that LVH and heart
      failure will develop. Furthermore, a haemoglobin of < 11 g/dl is associated with
      increased morbidity and mortality. Partial correction of anaemia with epoetin
      leads to a partial, but not complete, reversal of LVH. One large prospective
      study (Lombardy Registry) found that epoetin treatment was accompanied by a 30%
      reduction in crude relative risk of mortality. A progressive reduction in the
      relative risk of general and cardiovascular mortality was found with increasing
      haematocrit, with and without adjustment for co-morbid conditions. Mean
      hospitalizations also decreased with increasing haematocrit. The long-term
      effects of normalized haematocrit/haemoglobin values in uraemic patients have not
      yet been evaluated exhaustively in prospective, randomized, multicentre studies.
      Epoetin treatment has been shown to induce lasting improvements in patients'
      sense of well-being, reduce fatigue, increase appetite and work capacity, and
      improve exercise tolerance, libido and work performance. Further studies are
      needed to demonstrate whether greater haemoglobin concentrations are associated
      with greater improvements in quality of life during epoetin treatment.

PMID- 10334666
TI  - Should anaemia in subtypes of CRF patients be managed differently?
AB  - In patients with cardiovascular disease, partial correction of anaemia with
      epoetin improves quality of life and exercise capacity, and reduces left
      ventricular hypertrophy. The currently recommended haemoglobin in these patients
      is 11-12 g/dl. The optimal haemoglobin in patients with diabetes mellitus does
      not differ from that in non-diabetic patients; however, haemoglobin should be
      increased slowly. There is no difference in the recommended haemoglobin between
      children and adults. However, epoetin sensitivity is lower in children who,
      therefore, typically need the same absolute dose of epoetin as adults. Epoetin
      treatment may delay the progression of chronic renal failure (CRF) in paediatric
      patients. Elderly patients obtain similar benefits from epoetin as younger
      adults; moreover, there are no differences in the doses of epoetin required or
      the optimal haemoglobin. There are very few data available on the effects of
      epoetin in patients with CRF and chronic obstructive pulmonary disease. At
      present, a haemoglobin of 11 g/dl seems appropriate. In sickle-cell anaemia
      patients with CRF, a high haemoglobin could precipitate painful crises;
      consequently, the recommended haemoglobin is the pre-CRF concentration of 6-9
      g/dl. There is no convincing evidence of any effect of previous epoetin treatment
      on the long-term outcome of renal transplantation. In patients with a failing or
      failed transplant, the required dose of epoetin may be higher than in pre
      transplantation patients. In such cases, transplant nephrectomy might be
      considered.

PMID- 10334667
TI  - Effects of epoetin on vascular biology.
AB  - In addition to promoting erythropoiesis, chronic administration of epoetin
      frequently increases blood pressure, ameliorates uraemic platelet dysfunction,
      enhances platelet production and elevates resting and stimulated cytosolic
      [Ca2+]. In addition, in vivo and in vitro studies have demonstrated that epoetin
      may modify production and activity of certain vasoactive factors and may promote
      vascular cell growth. Many of the latter effects of epoetin appear to be
      unrelated to the associated erythropoietic action of the hormone and must,
      therefore, involve other mechanisms. The present article is intended to provide a
      brief overview of the effects of epoetin on vascular and haemostatic systems.

PMID- 10334669
TI  - European best practice guidelines for the management of anaemia in patients with
      chronic renal failure.
AB  - Best practice guidelines recommend management strategies and attempt to set
      standards for optimal patient care. The momentum towards formulating guidelines
      comes not only from health care professionals, but also from health care
      management organizations, who need some way of measuring the quality of the
      services they purchase. The European Best Practice Guidelines for the Management
      of Anaemia in Patients with Chronic Renal Failure have been drawn up by a Working
      Party including representatives of the European Renal Association/European
      Dialysis and Transplantation Association (ERA-EDTA) and the national nephrology
      societies of a cross-section of European countries. The guidelines draw on the
      National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI)
      Clinical Best Practice Guidelines for the Treatment of Anemia in Chronic Renal
      Failure, but reflect European clinical practice and experience. They include
      additional publications, and new analysis and interpretation of the evidence
      base. Topics covered in the European guidelines include diagnosis of the anaemia
      of chronic renal failure, indications for starting treatment with epoetin,
      recommended minimum target haemoglobin concentrations, epoetin dosage and route
      of administration, assessing and optimizing iron stores, causes and management of
      epoetin resistance, and possible adverse effects of epoetin treatment. The
      guidelines are not intended to be prescriptive but rather to provide clinical
      guidance based on the best available evidence. The evidence supporting each
      guideline is graded, so that physicians may judge its reliability.

PMID- 10334668
TI  - Is there a role for adjuvant therapy in patients being treated with epoetin?
AB  - Adjuvant therapy may allow patients being treated with epoetin to derive greater
      clinical benefits. Iron supplementation is currently the most widely used form of
      adjuvant therapy; intravenous (i.v.) iron is required by the majority of
      haemodialysis patients receiving epoetin. Measurement of hypochromic red blood
      cells is the most direct way of assessing iron supply to the bone marrow. During
      the correction phase, a dose of i.v. iron equivalent to 50 mg/day is recommended,
      with the total dose not exceeding 3 g. When subclinical vitamin C deficiency is
      suspected, ascorbic acid may be given orally (1-1.5 g/week) or i.v. (300 mg three
      times weekly at the end of dialysis). The active vitamin D metabolites
      alfacalcidol and calcitriol may, under some circumstances, improve anaemia and
      reduce epoetin dosage requirements. Vitamin B6 requirements are increased during
      epoetin therapy, and supplementation at a dose of 100-150 mg/week is recommended.
      Supplementation of vitamin B12 is optional. Folic acid is supplemented routinely
      in haemodialysis patients, though evidence that it increases the efficacy of
      epoetin is limited. Low doses (2-3 mg/week) should normally be sufficient to
      maintain optimal folic acid stores in epoetin-treated patients, although higher
      doses are necessary for patients with hyperhomocysteinaemia. L-Carnitine
      supplementation may be appropriate in some patients with anaemia of chronic renal
      failure (CRF) unresponsive to, or requiring large doses of, epoetin. Androgens
      potentially could reduce epoetin costs in countries with limited resources, but
      should only be used in men older than 50 years with a remnant kidney. Recent
      animal studies indicate that the combination of epoetin and insulin-like growth
      factor 1 might be beneficial in CRF patients. High doses of angiotensin
      converting enzyme (ACE) inhibitors should be reserved for dialysis patients who
      have hypertension that cannot be controlled by other agents, or who require an
      ACE inhibitor for treatment of heart failure.

PMID- 10334670
TI  - How should anaemia be managed in pre-dialysis patients?
AB  - Anaemia is a common problem in patients with renal failure, whether or not they
      are on dialysis. There is a continuum of declining renal function. In addition,
      the creatinine clearance at which dialysis is initiated varies widely between
      institutions and between studies. The term 'progressive renal insufficiency' is
      therefore preferable to 'pre-dialysis'. The adverse effects of renal anaemia on
      left ventricular mass become apparent early in the course of progressive renal
      insufficiency; 75% of patients starting dialysis already have left ventricular
      hypertrophy (LVH). Correction of anaemia in patients with progressive renal
      insufficiency has been shown to improve physical function and anaemia-related
      symptoms, but no controlled studies have yet been conducted to determine its
      effects on LVH. Although one animal study generated some concern that epoetin may
      exacerbate a decline in renal function, there is no evidence from human studies
      for any such effect. Treatment of anaemia with epoetin in anaemic patients with
      progressive renal insufficiency is therefore recommended, provided blood pressure
      is controlled. To date, however, there are insufficient data to determine whether
      normalization of haemoglobin is advisable in this patient group. Detection and
      correction of iron deficiency is important to achieve the full benefits of
      epoetin, though recommendations cannot yet be made regarding the optimum route
      and timing of iron supplementation in patients with progressive renal
      insufficiency. In these patients the role of other adjuvant therapies, such as L
      carnitine, vitamin B6, vitamin B12 and folic acid, also requires further
      investigation.

PMID- 10334671
TI  - Normalization of haemoglobin: why not?
AB  - It has been suggested that normalization of haemoglobin with epoetin in anaemic
      chronic renal failure (CRF) patients might result in even greater benefits than
      those currently achieved with partial haemoglobin correction. Four prospective
      randomized trials recently examined this hypothesis. The Scandinavian Multicentre
      Trial, which was completed in February 1998, included 416 haemodialysis,
      continuous ambulatory peritoneal dialysis and pre-dialysis patients. Preliminary
      analysis of the data found no differences with respect to safety between patients
      treated to achieve subnormal haemoglobin (9.0-12.0 g/dl) and those in whom
      haemoglobin was normalized (13.5-16.0 g/dl). The Canadian Multicentre Trial
      included 159 haemodialysis patients with asymptomatic left ventricular (LV)
      dysfunction. In patients with a normal LV cavity volume at enrolment, the change
      in LV cavity volume at 48 weeks was significantly greater in the control group
      (target haemoglobin 9.5-10.5 g/dl) than in the intervention group (target
      haemoglobin 13.0-14.0 g/dl). The Normal Hematocrit Cardiac Trial in the US
      included 1233 haemodialysis patients with clinically evident ischaemic heart
      disease or congestive heart failure. The trial was stopped in 1996 after an
      interim analysis showed increased mortality in the intervention group (target
      haematocrit 42%) compared with the control group (target haematocrit 30%). The
      higher haematocrit values themselves, however, did not appear to be responsible
      for the differences in mortality, as the mortality rates within each group
      decreased with increasing haematocrit. Nonetheless, until evidence is available
      from other trials demonstrating a benefit of normalizing haemoglobin, it has been
      recommended that a target haematocrit value of 42% be avoided in haemodialysis
      patients with clinically evident ischaemic heart disease or congestive heart
      failure. Further studies are also required to determine whether increasing
      haemoglobin to normal may prove to be beneficial in other patient groups. The
      Spanish Quality of Life Study of 134 haemodialysis patients found a significant
      improvement in all quality-of-life parameters when haemoglobin was increased to a
      mean of 12.5 g/dl. The investigators suggested that in patients without severe co
      morbidity, the target haemoglobin should be as close to normal as possible.

PMID- 10334672
TI  - New epoetin molecules and novel therapeutic approaches.
AB  - Erythropoietin (EPO) is a 34 kDa protein that is the primary regulator of red
      blood cell production. EPO facilitates its effect by binding to the cell surface
      EPO receptor which initiates the JAK-STAT signal transduction cascade. The search
      for small mimetic molecules of EPO has led to the discovery of a family of
      peptides that demonstrate EPO mimetic activity. A member of this peptide family,
      EMP1 (EPO mimetic peptide 1), was used to solve the crystal structure of the
      soluble EPO receptor in complex with this peptide. The structure revealed a 2:2
      stoichiometry of receptor to peptide, with each peptide contacting both receptor
      molecules in a symmetrical fashion. The potency of the EMPs could be improved
      through the covalent dimerization of two peptide molecules. Further
      investigations of EMP EPO receptor complex structures revealed the formation of a
      non-productive receptor dimer using an inactive peptide. An alternative approach
      towards the identification of an EPO-like mimetic is to target an intracellular
      signalling molecule such as haematopoietic cell phosphatase (HCP), also known as
      SHP1. Inhibiting HCP causes responsive cells to be hypersensitive to EPO. The
      cloned HCP protein has been utilized in screening assays to identify small
      molecule inhibitors of HCP.

PMID- 10334673
TI  - Epoetin in cancer-related anaemia.
AB  - Cancer-related anaemia has a number of causes, not least the underlying
      malignancy itself which plays a role in suppressing erythropoiesis. Anaemia is
      often exacerbated by cancer treatments, in particular routinely used cytotoxic
      chemotherapy. Chronic anaemia of cancer is often characterized by inappropriately
      low levels of endogenous erythropoietin for the degree of anaemia, and manifests
      clinically with generalized hypoxia and resultant severe fatigue. Epoetin alfa is
      one recombinant form of erythropoietin, the primary human growth factor
      responsible for promoting proliferation and survival of erythroid progenitor
      cells. Epoetin alfa has been widely studied for the treatment of anaemia
      associated with renal failure and is now recognized as having significant
      potential in the management of cancer-related anaemia. Studies suggest that
      epoetin alfa is an effective treatment in a proportion of cancer patients with
      symptomatic anaemia. It also appears useful for the prevention of chemotherapy
      induced anaemia. Studies in a number of different cancer settings have shown that
      epoetin alfa significantly increases haemoglobin and haematocrit, reduces
      transfusion requirements and improves quality of life for the patient.

PMID- 10334675
TI  - Does economic evaluation have anything to offer the rheumatologist?

PMID- 10334676
TI  - Glucocorticosteroids in the management of rheumatoid arthritis.
AB  - Glucocorticosteroids are used frequently in the management of patients with
      rheumatoid arthritis. Data supporting their efficacy and safety are still meagre.
      Glucocorticosteroids may be used systemically with different routes of
      administration (oral, i.m. and i.v.), in different doses and for different
      periods of time. The effectiveness of glucocorticosteroids in reducing
      inflammation in the short term has been shown for oral treatment in a dose of 7.5
      mg prednisolone daily or more, for i.m. pulses (120 mg methylprednisolone every 4
      weeks) and for i.v. methylprednisolone pulses. For longer periods of treatment,
      the evidence suggesting effectiveness of low-dose oral glucocorticosteroids is
      more limited. Some data suggest that different regimens of glucocorticosteroids
      may retard the development of erosions in patients with rheumatoid arthritis. The
      toxicity of short-term treatment is relatively low. For long-term treatment, the
      development of osteoporosis is a serious problem. Concomitant therapy with either
      calcitriol or bisphosphonates may reduce this risk.

PMID- 10334677
TI  - Bibliometric methods for the evaluation of arthritis research.
AB  - This study uses bibliometric methods to evaluate the magnitude and quality of
      publications in arthritis research in the UK and compare this with that of other
      countries. Arthritis research was defined by publication in a specialist journal
      or by specific title key words or address. Outputs from 13 countries between 1988
      and 1995 were analysed by number, research level (from clinical to basic) and
      potential impact on other researchers (from low to high). The UK has a strong
      presence in arthritis research and the highest relative commitment of all the
      countries studied. UK output was more clinical than that of other countries,
      except Spain, and was of relatively high impact. A second study examined UK
      arthritis papers supported by different funding sources, including government,
      private-non-profit and industry. Papers with funding acknowledgements were of
      significantly higher impact and less clinical than those without. The Arthritis
      Research Campaign was the leading funder in the UK with high-impact papers which,
      over the 8 yr period, have become more clinical than those supported by other
      funding sources, except hospital trusts.

PMID- 10334678
TI  - Relationship between urinary pyridinium cross-links, disease activity and disease
      subsets of ankylosing spondylitis.
AB  - OBJECTIVE: In this study, we aimed to determine the urinary levels of pyridinium
      cross-links and urinary beta-isomerized fragments derived from the C-telopeptide
      of the alpha1 chain of type I collagen (beta-CTX) as markers of bone resorption
      in patients with ankylosing spondylitis (AS), and to study their relationship to
      markers of disease activity [erythrocyte sedimentation rate (ESR)] and to disease
      subsets of this condition. METHODS: The serum calcium, osteocalcin (OC),
      parathormone (PTH), 25 OHD3 levels, beta-CTX and the urinary combined free
      pyridinolines (f-Pyr + f-Dpyr), urinary free deoxypyridinoline (f-Dpyr) and
      urinary free pyridinoline (f-Pyr) were evaluated and compared in 32 AS patients
      and 25 controls. Bone mineral density (BMD) was evaluated at the lumbar spine and
      the femoral neck. RESULTS: The serum markers of bone metabolism (serum calcium,
      PTH, 25 OHD3 and OC) were in the normal range in the AS group. AS patients had a
      lowered lumbar spine BMD (P = 0.01) (corresponding T score: P = 0.03), but
      femoral neck BMD did not differ significantly between AS and controls (P = 0.08)
      (corresponding T score: P = 0.11). There was no difference in the urinary levels
      of pyridinium cross-links and beta-CTX between AS patients and controls. A
      positive correlation between ESR, (f-Pyr + f-Dpyr) (r = 0.42; P = 0.018) and f
      Dpyr (r = 0.49; P = 0.005) was observed. In the different disease subsets of AS,
      we found that patients with peripheral involvement had higher (f-Pyr + f-Dpyr) (P
      = 0.04) and f-Dpyr levels (P = 0.04), patients with early disease had elevated (f
      Pyr + f-Dpyr) (P = 0.01), f-Dpyr (P = 0.02) and f-Pyr (P = 0.01) levels, and that
      those with raised ESR had enhanced f-Dpyr (P = 0.009) excretion. Patients were
      then stratified according to disease duration, peripheral involvement and sex,
      and this allowed us to observe that only urinary f-Dpyr remained elevated in
      patients independently from these variables and that raised ESR is the more
      relevant parameter for explaining this high level of excretion. CONCLUSION: We
      conclude that there was no difference in the levels of urinary pyridinium cross
      links and beta-CTX between AS and controls. However, urinary excretion of some of
      these collagen compounds was enhanced in subgroups of AS, mainly in patients with
      raised ESR. Thus, AS patients with laboratory evidence of active disease could
      have a higher risk of bone loss.

PMID- 10334679
TI  - Glomerular and tubular proteinuria as markers of nephropathy in rheumatoid
      arthritis.
AB  - OBJECTIVE: We examined the prevalence of nephropathy in unselected patients with
      rheumatoid arthritis (RA) by measurement of marker proteins for glomerular and
      tubular damage in urine. METHODS: A highly sensitive immunoluminometric assay was
      used to measure albumin, immunoglobulin G and alpha1-microglobulin in 24 h urines
      of 44 RA patients and a control group of 46 patients with generalized
      osteoarthritis (OA). RESULTS: Fifty-five per cent of RA patients were found to
      have proteinuria as a symptom of renal disease. Drug therapy or vasculitis were
      identified as possible reasons for proteinuria in only 25% of these patients; in
      most patients (75%), no reason for proteinuria was found. Tubular and mixed
      proteinuria were more frequent than glomerular proteinuria. Only 15% of the
      control group exhibited mild proteinuria, which was attributable to nephrotoxic
      factors. The renal function of RA patients and the control group did not differ
      significantly. CONCLUSIONS: Proteinuria is a frequent symptom of nephropathy in
      RA. Screening for renal disease in RA should not only include creatinine
      measurement and dipstick examination of urine, but also more sensitive methods to
      detect tubular and glomerular proteinuria as a marker of tubular and early stages
      of glomerular damage.

PMID- 10334680
TI  - Collagenase, cathepsin B and cathepsin L gene expression in the synovial membrane
      of patients with early inflammatory arthritis.
AB  - OBJECTIVE: To examine the expression of the matrix metalloproteinase, MMP-1, and
      the cysteine proteases, cathepsin B (CB) and cathepsin L (CL), in the synovial
      membrane (SM) of patients with early inflammatory arthritis. METHODS: Samples of
      SM were obtained by blind needle biopsy or needle arthroscopy from inflamed knees
      of 28 patients with early inflammatory arthritis (mean disease duration 10.2
      months, range 2 weeks-18 months). Sixteen patients had rheumatoid arthritis (RA),
      nine psoriatic arthritis and there was one each with ankylosing spondylitis, gout
      and an undifferentiated arthritis. Comparison was made with tissue from two
      patients with established erosive RA and three normal synovial tissue samples. In
      situ hybridization was performed using digoxigenin-labelled RNA probes. RESULTS:
      MMP-1, CB and CL were expressed in all patients with early arthritis and in
      established erosive RA, whereas normal synovium showed only scanty expression.
      The three proteases were prominent in perivascular infiltrates and endothelial
      cells of early arthritis tissue. MMP-1 was observed primarily in the lining
      layer, but was also evident in the sublining area. CB and CL were expressed to a
      lesser extent in the lining layer, and were present mainly in the subintima. The
      three proteases were not found in lymphoid aggregrates. No differences were
      observed between the disease categories. CONCLUSIONS: The detection of MMP-1, CB
      and CL in the synovium shortly after symptom onset implies that the potential for
      joint destruction exists at a very early stage in the disease. In addition, the
      perivascular and endothelial cell expression suggests a role for these proteases
      in mononuclear cell influx to the inflamed synovium and in angiogenesis.

PMID- 10334681
TI  - The therapeutic response to D-penicillamine in rheumatoid arthritis: influence of
      glutathione S-transferase polymorphisms.
AB  - OBJECTIVES: To investigate whether the therapeutic response of rheumatoid
      arthritis (RA) patients to D-penicillamine is associated with polymorphisms in
      genes of the glutathione S-transferase (GST) supergene family. METHODS: Disease
      activity in 81 patients with RA treated with D-penicillamine monotherapy was
      assessed using the Stoke Index, a validated index of disease activity, prior to
      treatment and at 6 months. GST typing was performed using a polymerase chain
      reaction-based approach and a logistic regression model was used to investigate
      any possible association between the therapeutic response to D-penicillamine and
      the GST genotype. RESULTS: A poor therapeutic response was associated with the
      GSTM1 null genotype [odds ratio (OR) 3.94], and in particular with the
      GSTM1*0/GSTM3*A haplotype (OR 7.63). CONCLUSIONS: Our results suggest that GST
      polymorphisms may influence the response to D-penicillamine in RA, and that
      patients in possession of the GSTM1*0/GSTM3*A haplotype are significantly less
      likely to show a beneficial response to the drug.

PMID- 10334682
TI  - A patient-derived disease activity score can substitute for a physician-derived
      disease activity score in clinical research.
AB  - OBJECTIVE: Joint counts have a central role in assessing disease activity in
      rheumatoid arthritis (RA). They are usually undertaken by physicians or nurses.
      We investigated whether joint counts can be devolved to patients and evaluated
      the use of a patient-derived Disease Activity Score (DAS). METHODS: One hundred
      RA patients attending a specialist unit were evaluated, comparing joint counts by
      a physician with patient-assessed joint counts and DAS derived from both methods.
      They were related to other measures of disease activity in the European League
      Against Rheumatism (EULAR) core data set and with the Rheumatoid Arthritis
      Disease Activity Index (RADAI; a validated patient self-assessment index).
      RESULTS: Regression analysis showed no significant differences between a
      physician's and patient's joint counts and DAS. There were middle to high
      correlations between patient and physician assessments of tender joints and
      swollen joints; using R2, this explained 70% of the variance for tender joints
      and 40% for swollen joints. Kappa analysis showed good agreement between
      physician and patient assessments of individual joint tenderness (kappa values
      0.49-0.84). There was lower agreement for individual swollen joints (kappa values
      0.02-0.61). Physician DAS and patient DAS had a similar correlation with the
      Health Assessment Questionnaire (HAQ) (r = 0.50 and r = 0.48, respectively).
      CONCLUSION: The agreements between physician and patient assessments are
      sufficient to allow patients' assessments to be used for clinical research. This
      is especially the case with a patient-derived DAS. However, the results are not
      directly interchangeable and further studies are needed before patients'
      assessments are used to guide clinical practice.

PMID- 10334683
TI  - The influence of a partially HLA-matched blood transfusion on the disease
      activity of rheumatoid arthritis.
AB  - OBJECTIVE: Based on the immunosuppressive effects of blood transfusions in organ
      transplantation, we determined the effect of a blood transfusion on disease
      activity of rheumatoid arthritis (RA). METHOD: In this double-blind pilot study,
      40 patients with active RA were randomly assigned to receive a HLA-DRB1-matched
      blood transfusion (n = 30) or placebo (n = 10). Disease activity was scored
      according to the American College of Rheumatology response criteria during 6
      months of follow-up. RESULTS: After 1 month and 6 months, respectively, 6 and 16%
      of patients fulfilled the response criteria in the blood transfusion group
      compared to none and 30%, respectively, in the placebo group. Following
      correction for the increase in haemoglobin levels, a majority of the response
      parameters in the blood transfusion group showed significant improvement compared
      to the placebo group. CONCLUSION: A DRB1-matched blood transfusion shows
      improvement of symptoms in several RA patients. Additional studies are required
      to identify blood transfusion regimens that enhance the potential for therapeutic
      responses.

PMID- 10334684
TI  - Three year follow-up of body composition changes in pre-menopausal women with
      systemic lupus erythematosus.
AB  - OBJECTIVES: To measure the change in body composition in a pre-menopausal female
      systemic lupus erythematosus (SLE) population over 3 yr, and to identify
      predictors of change in body composition including the effects of disease-,
      corticosteroid (CS)- and patient-related variables. METHODS: All 55 pre
      menopausal females with SLE who participated in a cross-sectional study of body
      composition in 1994 were invited to undergo interview, examination, medical
      record review, and body composition assessment by dual-energy X-ray
      absorptiometry (DXA). RESULTS: Twenty-eight subjects participated with a mean
      (S.E.M.) age of 34.4 (1.6) yr, duration of SLE of 6.8 (0.8) yr and mean (range)
      time to follow-up of 3.2 (2.9-3.4) yr. Seventeen subjects were exposed to CS
      during the study period with a mean (range) daily dose of prednisolone of 12.0
      (2.8-22.9) mg. There was a significant increase in body mass index (BMI) (24.53+/
      0.83 vs 25.37+/-1.04, P = 0.03) and fat-free mass (41.04+/-0.83 vs 41.53+/-0.92,
      P = 0.05) over the 3 yr period. Univariate analysis revealed that change in fat
      free mass was significantly associated with change in total body bone mineral
      density (BMD) (P = 0.03). Stepwise multiple linear regression analysis revealed a
      significant independent association of disease activity with increases in both
      BMI (r2 = 0.41, P = 0.006) and fat mass (r2 = 0.39, P = 0.007), and of exercise
      and Modified Health Assessment Questionnaire with an increase in fat-free mass
      (r2 = 0.51, P = 0.007). Age at SLE diagnosis and smoking were significant
      independent predictors for loss of total body BMD, while CS duration was
      predictive of an increase in total body BMD (r2 = 0.80, P < 0.0001). CONCLUSION:
      In this SLE population, disease activity was predictive of deleterious changes in
      body composition, including increases in BMI and fat mass. Patient-related
      variables were also important predictors of body composition change with exercise
      independently predicting an increase in fat-free mass, and smoking predictive of
      loss of total body BMD. In contrast, CS-related variables were not found to have
      harmful effects on body composition. Change in fat-free mass, and not fat mass,
      was predictive of change in total body BMD.

PMID- 10334685
TI  - Finger joint synovitis in rheumatoid arthritis: quantitative assessment by
      magnetic resonance imaging.
AB  - OBJECTIVE: To assess quantitatively, by magnetic resonance imaging (MRI), the
      synovial membrane volume in second to fifth metacarpophalangeal (MCP) joints in
      patients with rheumatoid arthritis and healthy controls, and to compare the
      synovial membrane volumes with a more easily obtained semi-quantitative score for
      hypertrophic synovial membrane. PATIENTS AND METHODS: MCP joints of the dominant
      hand of 37 patients and five controls were examined clinically and by MRI.
      Laboratory assessments were performed. RESULTS: Median synovial membrane volumes
      were considerably larger in clinically active rheumatoid arthritis (RA) joints
      (e.g. 0.97 ml in the second MCP joint) than in clinically inactive joints (0.54
      ml) and control joints (0.04 ml). Nevertheless, group distributions overlapped
      and marked volume differences were found within clinically uniform groups. The
      semi-quantitative score was highly correlated with the synovial volumes (Spearman
      rho = 0.79; P < 0.00001). Synovial membrane volumes were poorly related to the
      presence of rheumatoid factor and to laboratory markers of inflammation.
      CONCLUSION: These findings suggest that synovial membrane volumes, as determined
      by MRI, in finger joints are related to clinical signs of synovitis, but also
      that the volumes may vary more than what can be accounted for by the clinical
      appearances. A semi-quantitative score may be sufficient for more routine
      purposes.

PMID- 10334686
TI  - Knee replacement surgery for osteoarthritis: effectiveness, practice variations,
      indications and possible determinants of utilization.

PMID- 10334687
TI  - Catastrophic antiphospholipid syndrome associated with anti-beta-2-glycoprotein I
      IgA.

PMID- 10334689
TI  - Psoriatic arthritis associated with chondrolysis and osteolysis.

PMID- 10334688
TI  - Oral desensitization in patients with chronic tophaceous gout and allopurinol
      hypersensitivity.

PMID- 10334690
TI  - Transmission of psoriatic arthritis by allogeneic bone marrow transplantation for
      chronic myelogenous leukaemia from an HLA-identical donor.

PMID- 10334691
TI  - Sacral insufficiency fractures: an unsuspected cause of low back pain.

PMID- 10334692
TI  - Sacral insufficiency fractures as an unsuspected cause of low back pain.

PMID- 10334693
TI  - The rates of alcohol-related deaths from accidents and violence in subjects with
      ankylosing spondylitis and rheumatoid arthritis.

PMID- 10334694
TI  - What is a podiatric surgeon?

PMID- 10334695
TI  - Cadaveric allograft as adjunct therapy for nonhealing ulcers.
AB  - The objective of this study was to describe the results of a retrospective survey
      of 27 patients who were treated with cadaveric skin allograft as an adjunct
      therapy for wound management. The evolution, benefits, indications, and future of
      cadaveric skin allografts are also discussed. Glycerin-preserved, frozen,
      cadaveric split-thickness skin allograft was sutured to excised wounds and held
      in place with a stent dressing. Retrospective data recovered from wound
      assessment forms and progress reports were used to evaluate the effectiveness of
      this treatment. The etiology, pre- and postexcisional volume, depth of
      debridement, time taken for granulation tissue to first appear, allograft life
      span, volume post allograft removal, healing time, time expired from allograft to
      skin grafting, and reported pain were documented and presented. A total of 34
      ulcers in 27 patients of various etiologies were evaluated. Pre-excisional volume
      averaged 6448.2 mm3, while the volume post allograft debridement averaged 9159.0
      mm3. The length of time the biologic dressing remained in place averaged 29.1
      days. Granulation tissue became first apparent through the fenestrations in the
      graft at an average of 13.4 days. Pain was notably reduced in 53% of the
      patient's post debridement with application of allograft. Only 12% of the
      patients experienced an increase in pain and 35% related no change. Most (65%) of
      the patients healed via secondary intention. The rest (35%) underwent split
      thickness skin grafting. The average healing time was 113.9 days. No infections
      occurred while the allograft was in place. Lower extremity wounds present many
      challenges that may lengthen the course of treatment. As healing time increases,
      so too does the risk of various complications such as infection, desiccation, and
      damage to underlying soft tissues. The benefits of allograft treatment are
      particularly noteworthy in areas where bone and/or tendon are exposed. In these
      cases it becomes especially difficult to promote granulation tissue growth.
      Cadaveric skin allografts aid in preventing desiccation, help to control
      infection, and can substantially reduce patient discomfort.

PMID- 10334696
TI  - Injuries of the foot and ankle in occupational medicine: a 1-year study.
AB  - With occupational injuries, both the employee and employer are impaired by
      monetary or physical damages. Administrative and clinical data can assist in
      identifying risks for these injuries. While musculoskeletal injuries are well
      known, foot and ankle injuries are not as frequently described as back and hand
      injuries. Changes in the workplace may then be implemented dependent on the risk
      factors identified. A retrospective study was completed on all foot and ankle
      injuries that were reported to the Oakwood Hospital Downriver Center Occupational
      Medicine Clinics over 1 year. Of 3851 new injuries, 245 (6.4%) were due to foot
      and ankle injuries. The mean age was 36.7+/-9.2 (mean +/- S.D.) years and 64%
      men. No seasonal variation was seen. Most commonly the ankle (46.9%) was injured.
      A diagnosis of sprain was most frequent (40.8%), followed by contusions (26.5%).
      A twisting mechanism of injury was seen 27.3% of the time. Medical charges ranged
      from $100 to $6414, although over two thirds of the patients had expenses between
      $250 and $749. Eleven patients required surgery, costing $9125+/-2321. Most often
      injured were operators, fabricators, and laborers. Workers were restricted for
      20.5+/-21.4 days, although they were allowed light duty most of the time (16.8+/
      16.5 days).

PMID- 10334697
TI  - An examination of plantar pressure measurements to identify the location of
      diabetic forefoot ulceration.
AB  - The purpose of this study was to evaluate pressure-time parameters on the sole of
      the foot in order to predict sites of pathology in diabetics. Mid-gait walking
      steps from 36 subjects diagnosed with diabetes and ulceration to the forefoot
      were analyzed using the Pedar in-shoe pressure analysis system. The time that
      weight was loaded on the hallux and lesser digits was found to be significantly
      shorter on the feet with ulceration compared to those without. A combination of
      five pressure measure reports could significantly differentiate between the three
      common locations of forefoot ulcerations. The significant pressure measure
      reports were the pressure-time integral measured over the whole foot and pressure
      time integral and peak pressure measured separately at the first and combined
      lesser metatarsophalangeal joint regions. A preliminary model was developed using
      discriminate analysis that was accurate to 72.7% in identifying the location of
      the subjects' ulceration. Sensitivity and specificity formulas were calculated to
      demonstrate the diagnostic value of the model. The model accurately identified
      ulceration locations to a sensitivity of 83% and a specificity of 69%. Further
      refinement and testing is underway to refine the model to develop a screening
      tool to identify the site of potential foot ulceration and to prevent it and its
      sequelae of lower limb ulceration in the diabetic population.

PMID- 10334699
TI  - The Valenti procedure for hallux limitus: a long-term follow-up and analysis.
AB  - A retrospective analysis of the long-term efficacy of the Valenti procedure for
      hallux limitus was performed from 1989 to 1997. A total of 33 patients (36
      procedures) were selected, surveyed, and examined. Preoperative and postoperative
      radiographic evaluations and levels of function and pain were obtained from
      medical records. Complications and patient satisfaction data were collected and
      reviewed. The patients were evaluated clinically and radiographically. The
      average age of the patient at the time of surgery was 50.6 years (range, 35-75
      years) with an average follow-up of 4.16 years (range, 1-9 years). The average
      grade of hallux limitus/rigidus was grade II. Five patients were classified as
      grade I, 23 as grade II, five as grade III, and none as grade IV, based on the
      modified Drago/Regnauld grading system. Subjective results were calculated based
      on the American Orthopedic Foot and Ankle Society clinical rating system. Twenty
      two patients were rated as having an excellent result, 11 had good results, two
      had fair results, and one patient had a poor result. We conclude that the Valenti
      arthroplasty for symptomatic hallux rigidus/limitus is a good procedure for
      arthritic and degenerated first metatarsophalangeal joints where implant
      arthroplasty, osteotomy, or arthrodesis are not viable options. Advantages
      include increased range of motion, decreased postoperative pain, technical ease
      of performance, maintenance of intrinsic musculature, and rapid return to closed
      footgear.

PMID- 10334698
TI  - Talonavicular joint arthrodesis and Evans calcaneal osteotomy for treatment of
      posterior tibial tendon dysfunction.
AB  - The purpose of this study was to evaluate the combination of talonavicular fusion
      and Evans calcaneal osteotomy for the treatment of posterior tibial tendon
      dysfunction. This was a retrospective study of 10 patients, mean age 48.7 years,
      who had continued pain despite 6 months of conservative treatment and a minimum
      Johnson and Strom stage II deformity. Patients completed a detailed
      questionnaire, were physically examined, and their postoperative improvement was
      graded according to the American Orthopedic Foot and Ankle Society Ankle-Hindfoot
      Rating Scale. At a mean of 35 months (range 8-72 months) after surgery, patients
      demonstrated a significant improvement (p<.001) both in their subjective
      discomfort and in the structural alignment and function of their feet. The
      authors feel that this combination of procedures allows greater correction and
      stability than either procedure performed alone, and provides a viable
      alternative to triple arthrodesis.

PMID- 10334700
TI  - Subtalar joint arthrodesis for postpoliomyelitis valgus foot deformity.
AB  - The purpose of this study was to evaluate the results of full versus partial
      subperiosteal fibular bone graft for subtalar joint arthrodesis in patients with
      pes planovalgus foot deformity associated with residual polio myelitis. A
      prospective study was carried out on 16 patients with postpoliomyelitis valgus
      foot deformity secondary to invertor muscle paralysis. All patients were treated
      by peroneal tendon transfer to the medial metatarsals and subtalar extra
      articular arthrodesis. In 12 patients, subperiosteal partial fibular graft was
      used, while four patients received a full fibular graft. Patients were followed
      for an average of 2.5 years following surgery and were assessed using Axer's
      criteria. Partial fibular subperiosteal bone grafts (n = 12) were not associated
      with any major biomechanical sequalae of the ankle and foot, while full fibula
      grafts had 75% (n = 4) adverse sequelae.

PMID- 10334701
TI  - Plexiform fibrohistiocytic tumor of the foot.
AB  - The first case of plexiform fibrohistiocytic tumor in the foot is presented in
      this article. The tumor developed on the dorsum of the left foot in a 14-year-old
      female. This tumor was originally described in 1988 by Enzinger and Zhang. Their
      study indicated that this tumor has a female predominance, median age of 14.5
      years, 63% located in the upper extremities, 37.5% recurrence rate, and 3%
      metastasis rate. These tumors are very unique with a nodular pattern and a
      cellular component of histiocytes, fibroblasts, and multinucleated giant cells.
      Typically they are located within the deep dermis and subcutaneous tissue.
      Immunohistochemical preparations show that the tumor does not stain for S-100
      protein, desmin, cytokeratin, factor VIII-related protein, or lysozyme. However,
      it does stain for alpha-1-antitrypsin, alpha-1-antichymotrypsin, alpha-smooth
      muscle-specific actin, vimentin, and CD68 antibody.

PMID- 10334703
TI  - Progressive macrodactyly.
AB  - A case of progressive macrodactyly in an adult is presented with MRI and CT
      imaging to illustrate the extent of the deformity.

PMID- 10334702
TI  - Enchondroma as a cause of midfoot pain.
AB  - Enchondroma is a common bone tumor of the foot. It is often reported in the
      phalanges and distal metatarsals. The authors, however, present a rare case study
      of two patients with enchodromas as the cause of midfoot pain. One case presented
      in the lateral cuneiform which to the authors' knowledge is the first reported
      case in the literature. Two cases are presented with their surgical management
      including autogenous calcaneal graft and follow-up.

PMID- 10334704
TI  - An unusual complication of an ankle arthroscopy and its management.
AB  - This report describes a case of a routine ankle arthroscopy which went awfully
      wrong. In trying to excise a loose body the surgeon had excised the distal
      fibula. A reasonable solution to the problem now facing the patient would have
      been an ankle fusion. The authors, however, performed an osteoarticular fibular
      grafting. At 34 months, this has been a success so far clinically and
      radiologically. Both the complication and its treatment have not been described
      before.

PMID- 10334705
TI  - Asymptomatic accessory soleus muscle.
AB  - The accessory soleus muscle has been infrequently seen and reported clinically.
      Most of the cases reported have been associated with symptomatology. Yet there
      are cases in which the patient presents with only asymptomatic swelling. Such a
      case is presented as well as a review of previously reported cases of the
      accessory soleus muscle.

PMID- 10334706
TI  - Talar neck fractures and rates of avascular necrosis.
AB  - Talar neck fractures are unique and potentially debilitating injuries. Their
      successful treatment requires an understanding of talar anatomy and arterial
      blood supply, as well as knowledge of the sequelae of these injuries,
      particularly avascular necrosis of the talar body. Presented is an extensive
      literature review on talar neck fractures and Hawkins' classification, with
      special emphasis on the rates of avascular necrosis as determined by selected
      researchers on the topic.

PMID- 10334707
TI  - Lesser metatarsophalangeal joint capsular release utilizing the #66 mini-blade.

PMID- 10334708
TI  - Hammer toe syndrome. American College of Foot and Ankle Surgeons.

PMID- 10334709
TI  - Bioelectromagnetics, Carl Durney, and dosimetry: some historical remarks.
AB  - The contributions of Carl Durney to dosimetry have decisively advanced the
      bioelectromagnetics field and led to significant revisions of relevant health
      standards. Three items come to mind while studying his work: 1. The work of Carl
      Durney and his colleagues in dosimetry has advanced the bioelectromagnetics field
      most significantly whereas more abundant work of a biomedical nature has had less
      impact. More biophysics work is desirable. 2. The rationale for the specific
      absorption rate as a basis of health standards needs further elaboration. The
      need for scaling animal results is stressed. 3. Dosimetry at the cellular level
      (microdosimetry) is essential if one cares to discuss direct field interactions
      at the cellular and macromolecular level. Carl Durney's recognition of this need
      is stated. Carl Durney's wide range of productive interests is indicated by
      several tables. They summarize his many contributions to electrical engineering,
      education, bioelectromagnetic dosimetry, hyperthermia, NMR, and field-induced
      biophysical phenomena at the molecular and cellular level. His scientific work is
      summarized, including how his interest changed with time. His scientific
      accomplishment and productive interaction with students, colleagues, and society
      sets an example to be admired.

PMID- 10334710
TI  - The Radiofrequency Radiation Dosimetry Handbook: reminiscences.
AB  - This paper traces the history of the development of the Radiofrequency Radiation
      Dosimetry Handbook and its subsequent impact on radio frequency radiation
      exposure standards. The author's recollections are used to illustrate the behind
      the scenes efforts of the individuals involved in this project. The development
      of models at the University of Utah and confirmation of these results by various
      experimenters led to the publication of four editions of the Radiofrequency
      Radiation Dosimetry Handbook, i.e., "The RFR Experimenters Bible."

PMID- 10334711
TI  - Human exposure at two radio frequencies (450 and 2450 MHz): similarities and
      differences in physiological response.
AB  - Thermoregulatory responses of heat production and heat loss were measured in two
      different groups of seven adult volunteers (males and females) during 45-min
      dorsal exposures of the whole body to 450 or 2450 MHz continuous-wave radio
      frequency (RF) fields. At each frequency, two power densities (PD) were tested at
      each of three ambient temperatures (T(a) = 24, 28, and 31 degrees C) plus T(a)
      controls (no RF). The normalized peak surface specific absorption rate (SAR),
      measured at the location of the subject's center back, was the same for
      comparable PD at both frequencies, i.e., peak surface SAR = 6.0 and 7.7 W/kg. No
      change in metabolic heat production occurred under any exposure conditions at
      either frequency. The magnitude of increase in those skin temperatures under
      direct irradiation was directly related to frequency, but local sweating rates on
      back and chest were related more to T(a) and SAR. Both efficient sweating and
      increased local skin blood flow contributed to the regulation of the deep body
      (esophageal) temperature to within 0.1 degrees C of the baseline level. At both
      frequencies, normalized peak SARs in excess of ANSI/IEEE C95.1 guidelines were
      easily counteracted by normal thermophysiological mechanisms. The observed
      frequency-related response differences agree with classical data concerning the
      control of heat loss mechanisms in human beings. However, more practical
      dosimetry than is currently available will be necessary to evaluate realistic
      human exposures to RF energy in the natural environment.

PMID- 10334712
TI  - A quarter century of in vitro research: a new look at exposure methods.
AB  - The specific absorption rate (SAR) distributions in radio frequency-exposed
      solutions containing suspended or plated cells in vessels used for in vitro
      research were calculated by the finite-difference-time-domain method, graphed in
      color, and statistically analyzed in terms of uniformity for application to
      research on safety of wireless devices. The uniformity of SAR was quantified by
      visual inspection of colored plots, histograms, means, standard deviations, and
      maximums for the cell suspensions exposed in test tubes, Petri dishes, and
      rectangular flasks. Exposure sources included plane waves, transverse
      electromagnetic (TEM) cells, and striplines used at frequencies of 837, 2450, or
      3,000 MHz. The results demonstrated that the most nonuniform SARs for plated or
      suspended cells in solution occurred for exposures of test tubes and rectangular
      flasks with plane waves, polarized for maximal absorption. The most uniform SARs
      for a layer of cells occurred for exposure of Petri dishes oriented for weakest
      coupling to the fields in a TEM cell. Additional improvement in uniformity was
      found to be possible by restricting the edge of the layer of cells from being too
      near the edges of the dish. It was not possible to achieve satisfactory
      uniformity in the SAR in cell suspensions exposed in standard vessels to any of
      the sources. The best but not satisfactory SAR uniformity was observed for cells
      suspended in the lowest 1-ml volume of the liquid contained in a test tube
      exposed at the bottom in a TEM cell. Experimental measurements of average SAR by
      temperature change for this case varied from 18% higher to 26% lower than finite
      difference time domain-derived values. The most uniform SAR distribution for cell
      suspensions in nonstandard containers was found for a rectangular slab
      configuration exposed in a stripline with the plates separated from the media by
      a thin layer of insulation. It is possible to experimentally implement this model
      by placing a fluid-filled thin-wall rectangular container tightly between the
      plates of a stripline.

PMID- 10334713
TI  - Dielectric behaviour of frozen DNA in solution.
AB  - In this article, measurements are reported on ice and frozen DNA solutions
      between 100 Hz-10 MHz. Pure ice is shown to exhibit single relaxation behaviour,
      which confirms previous work taken over a more restricted frequency range. The
      frozen DNA solution displays double-dispersion behaviour. One dispersion centred
      around 3 kHz is due to a defect mechanism while the other, centred around 2 MHz,
      may be attributed to counterion flow through the water immediately adjacent to
      the DNA molecule.

PMID- 10334715
TI  - Thermal models for microwave hazards and their role in standards development.
AB  - We consider the thermal response of the body to radiofrequency (RF) energy, with
      emphasis on partial-body exposure, to assess potential thermal hazards. The
      thermal analysis is based on Pennes' bioheat equation. In this model, the thermal
      response is governed by two time constants. One (tau1) pertains to heat
      convection by blood flow and is (for physiologically normal perfusion rates) on
      the order of 3 min. The second (tau2) characterizes heat conduction, and varies
      as the square of a distance that characterizes the spatial extent of the heating.
      We examine three idealized cases. The first is a region of tissue with an
      insulated surface, subject to irradiation with an exponentially decreasing SAR,
      which models a large surface area of tissue exposed to microwaves. The second is
      a region of tissue in contact with a hemispherical electrode that passes current
      into it, which models exposure from contact with a conductor. The third is a
      region of tissue with an insulated surface, subject to heating from a dipole
      located close to it. In all three cases, we estimate the maximum steady-state
      temperature increase as a function of the relevant electrical and thermal
      parameters and the thresholds for thermal hazard. We conclude that thermal models
      are a potentially fruitful but underutilized means of analyzing thermal hazards
      from RF fields. A quantitative analysis of such hazards enables the development
      of data-based uncertainty factors, which can replace arbitrary "safety factors"
      in developing exposure limits. Finally, we comment on the need to marry
      quantitative modeling of data and risk assessment, and to incorporate
      contemporary approaches to risk assessment into RF standards development.

PMID- 10334714
TI  - Luminescent radio frequency radiation dosimetry.
AB  - Thermoluminescent dosimetry has been the industry standard for ionizing radiation
      dosimetry because it is inexpensive, sensitive, and accurate. No such system
      exists for radio frequency radiation. This paper describes the state of the art
      of efforts toward developing such a system. Thermochemiluminescent (TCL)
      dosimetry, first reported in 1991, is a first step toward achieving this goal.
      However, it has had problems in the production of TCL materials and in conversion
      of the luminescent signal into specific absorption rate (SAR). The former problem
      has been solved by the development of a genetically engineered Escherichia coli
      bacterium (JM 109/plC20RNR1.1), described herein, that produces the TCL material
      in a fermentation process. The latter problem stems from the difficulty in
      determining the structure of the currently best TCL material diazoluminomelanin.
      A theoretical approach for the solution of this problem has been achieved by
      combining equations for delayed fluorescence, temperature determination by TCL,
      and the free energy equation for equilibrium reactions. It has led to an
      explanation for the stable display of steady-state energy disposition,
      illustrated by TCL, in phantoms without the expected disruption by thermal
      conduction or convection, at frequencies ranging from 2.06 GHz to 35 GHz.

PMID- 10334716
TI  - Behavioral evaluation of microwave irradiation.
AB  - Establishing safe exposure levels for microwave irradiation is important since
      new, more powerful emitters are developed and the potential for accidental
      exposure is increasing. Analysis of the behavior of exposed laboratory animals
      has proven to be an accurate and repeatable metric for assessing the effects of
      microwave irradiation. Determining the specific absorption rate (SAR) at which an
      animal will cease an ongoing behavior has proven useful in the development of
      safe exposure levels for humans. Behaviors that have been used are simple tasks,
      and the point at which behavior changes significantly or ceases has often been
      referred to as "work stoppage." The tasks have been used to evaluate the
      overwhelming effects of heating produced by microwave irradiation. Both whole
      body exposures and partial-body exposures with hotspots have been evaluated.
      Recent studies have suggested that microwave effects on specific cognitive
      aspects of behavior such as attention, learning, memory, discrimination, and time
      perception may occur at SAR levels far below the SARs needed to cause work
      stoppage. New research studies are underway to evaluate microwave-induced
      cognitive effects.

PMID- 10334717
TI  - Development of a rat head exposure system for simulating human exposure to RF
      fields from handheld wireless telephones.
AB  - The aim of this project was to develop an animal exposure system for the
      biological effect studies of radio frequency fields from handheld wireless
      telephones, with energy deposition in animal brains comparable to those in
      humans. The finite-difference time-domain (FDTD) method was initially used to
      compute specific absorption rate (SAR) in an ellipsoidal rat model exposed with
      various size loop antennas at different distances from the model. A 3 x 1 cm
      rectangular loop produced acceptable SAR patterns. A numerical rat model based on
      CT images was developed by curve-fitting Hounsfield Units of CT image pixels to
      tissue dielectric properties and densities. To design a loop for operating at
      high power levels, energy coupling and impedance matching were optimized using
      capacitively coupled feed lines embedded in a Teflon rod. Sprague Dawley rats
      were exposed with the 3 x 1 cm loop antennas, tuned to 837 or 1957 MHz for
      thermographically determined SAR distributions. Point SARs in brains of
      restrained rats were also determined thermometrically using fiberoptic probes.
      Calculated and measured SAR patterns and results from the various exposure
      configurations are in general agreement. The FDTD computed average brain SAR and
      ratio of head to whole body absorption were 23.8 W/kg/W and 62% at 837 MHz, and
      22.6 W/kg/W and 89% at 1957 MHz. The average brain to whole body SAR ratio was 20
      to 1 for both frequencies. At 837 MHz, the maximum measured SAR in the restrained
      rat brains was 51 W/kg/W in the cerebellum and 40 W/kg/W at the top of the
      cerebrum. An exposure system operating at 837 MHz is ready for in vivo biological
      effect studies of radio frequency fields from portable cellular telephones. Two
      tenths of a watt input power to the loop antenna will produce 10 W/kg maximum
      SAR, and an estimated 4.8 W/kg average brain SAR in a 300 g medium size rat.

PMID- 10334718
TI  - Comparison of numerical and experimental methods for determination of SAR and
      radiation patterns of handheld wireless telephones.
AB  - Some recent developments in both the numerical and experimental methods for
      determination of SARs and radiation patterns of handheld wireless telephones are
      described, with emphasis on comparison of results using the two methods. For
      numerical calculations, it was possible to use the Pro-Engineer CAD Files of
      cellular telephones for a realistic description of the device. Also, we used the
      expanding grid formulation of the finite-difference time-domain (FDTD) method for
      finer-resolution representation of the coupled region, including the antenna, and
      an increasingly coarser representation of the more-distant, less-coupled region.
      Together with the truncation of the model of the head, this procedure led to a
      saving of computer memory needed for SAR calculations by a factor of over 20.
      Automated SAR and radiation pattern measurement systems were used to validate
      both the calculated 1-g SARs and radiation patterns for several telephones,
      including some research test samples, using a variety of antennas. Even though
      widely different peak 1-g SARs were obtained, ranging from 0.13 to 5.41 W/kg,
      agreement between the calculated and the measured data for these telephones, five
      each at 835 and 1900 MHz, was excellent and generally within +/-20% (+/-1 dB). An
      important observation was that for a maximum radiated power of 600 mW at 800/900
      MHz, which may be used for telephones using AMPS technology, the peak 1-g SARs
      can be higher than 1.6 W/kg unless antennas are carefully designed and placed
      further away from the head.

PMID- 10334719
TI  - Membrane potential and time requirements for detection of weak signals by voltage
      gated ion channels.
AB  - The question of minimum detection limits for biological processes sensitive to
      membrane potential perturbations has arisen in various contexts. Of special
      interest are the prediction of theoretical limits for sensory perception
      processes and for possible biological effects of environmental or therapeutic
      electric and magnetic fields. A new method is presented here, addressing the
      particular case in which perturbations of membrane potential affect the gating
      rate probability of voltage-sensitive ion channels. Using a two-state model for
      channel gating, the influence of the perturbing potential on the mean fraction of
      open channels is approximated by a Boltzmann distribution, and integrated over
      time to obtain a quantity proportional to the net change in expected charge
      transfer through the membrane. This change in net charge transfer (the signal, S)
      is compared to the expected root mean variance in charge transfer (the noise, N)
      due to random channel gating. Using a nominal criterion of S/N = 1, a model is
      developed for predicting the minimum time and number of ion channels necessary to
      detect a given membrane potential. Example calculations, carried out for a gating
      charge of 6, indicate that a 1 microV induced membrane potential can be detected
      after 10 ms by an ensemble of less than 10(8) ion channels.

PMID- 10334720
TI  - Modeling the nuclear magnetic resonance behavior of lung: from electrical
      engineering to critical care medicine.
AB  - The present article reviews the basic principles of a new approach to the
      characterization of pulmonary disease. This approach is based on the unique
      nuclear magnetic resonance (NMR) properties of the lung and combines experimental
      measurements (using specially developed NMR techniques) with theoretical
      simulations. The NMR signal from inflated lungs decays very rapidly compared with
      the signal from completely collapsed (airless) lungs. This phenomenon is due to
      the presence of internal magnetic field inhomogeneity produced by the alveolar
      air-tissue interface (because air and water have different magnetic
      susceptibilities). The air-tissue interface effects can be detected and
      quantified by magnetic resonance imaging (MRI) techniques using temporally
      symmetric and asymmetric spin-echo sequences. Theoretical models developed to
      explain the internal (tissue-induced) magnetic field inhomogeneity in aerated
      lungs predict the NMR lung behavior as a function of various technical and
      physiological factors (e.g., the level of lung inflation) and simulate the
      effects of various lung disorders (in particular, pulmonary edema) on this
      behavior. Good agreement has been observed between the predictions obtained from
      the mathematical models and the results of experimental NMR measurements in
      normal and diseased lungs. Our theoretical and experimental data have important
      pathophysiological and clinical implications, especially with respect to the
      characterization of acute lung disease (e.g., pulmonary edema) and the management
      of critically ill patients.

PMID- 10334721
TI  - Catheter microwave ablation therapy for cardiac arrhythmias.
AB  - This article describes three microwave catheter antennas for percutaneous cardiac
      ablation. A particular design feature of these antennas is that there is no
      reflected microwave current from the antenna flowing up the transmission line.
      Thus, it minimizes heating of the coaxial cable. The power reflection
      coefficients are very low (4% or less) in phantom equivalent materials. These
      antennas can also serve as bipolar electrodes for sensing endocardiac
      electrograms. Our studies in dogs, during both cardiopulmonary bypass and closed
      chest operations via the femoral vein, have shown microwave energy greater than
      200 joules (J) delivered to the heart through a split-tip dipole catheter antenna
      can produce irreversible block of the heart rhythms. This energy was achieved
      either by increasing the delivered power from 20 to 40 watts or by increasing the
      treatment duration from 7 to 11 s (210 to 330 J per application). It produced an
      endocardium temperature of about 65 degrees C. We found that the percutaneous,
      transcatheter microwave system is capable of inducing AV blocks consistently in
      dogs using the flexible, curved tip, split-tip catheter antenna. In addition, our
      studies have shown that the width and height of SAR distributions for cap-choke
      and split-tip catheter antennas are similar for the same antenna length. The cap
      slot design had a much longer SAR distribution compared to the others. Moreover,
      a longer (4 mm) split-tip antenna can also induce larger lesions. These results
      suggest that it could be possible to ablate a ventricular tachycardia focus using
      the 4 mm split-tip as well as the cap-slot microwave catheter antennas.

PMID- 10334722
TI  - 25 years of dosimetry: what now?

PMID- 10334723
TI  - Hyponatraemia after orthopaedic surgery.

PMID- 10334724
TI  - Dietary management of hepatic encephalopathy.

PMID- 10334725
TI  - New rules for expert witnesses.

PMID- 10334726
TI  - Prevention of corticosteroid induced osteoporosis.

PMID- 10334728
TI  - Thorough cancer surgery may make radiation unnecessary 

PMID- 10334727
TI  - Waiting in the dark: cataract surgery in older people.

PMID- 10334730
TI  - In brief 

PMID- 10334729
TI  - Children who sleep with light on may damage their sight 

PMID- 10334731
TI  - Hungarians spurn private health insurance 

PMID- 10334733
TI  - Doctors resist adopting clinical guidelines.

PMID- 10334732
TI  - Welsh assembly appoints health secretary 

PMID- 10334734
TI  - Pennsylvania plans to reward organ donation.

PMID- 10334735
TI  - BMA calls for halt on GM crops.

PMID- 10334736
TI  - Langlands defends NHS information technology strategy 

PMID- 10334737
TI  - Fluid intake affects the risk of bladder cancer in men 

PMID- 10334738
TI  - Belgium is to regulate complementary medicine.

PMID- 10334739
TI  - Dyslexia may be associated with cerebellar abnormalities 

PMID- 10334741
TI  - Savage challenges irvine for GMC presidency 

PMID- 10334740
TI  - Warning letter not seen by relevant body, Bristol inquiry told.

PMID- 10334742
TI  - US survey reveals deficits in women's health care.

PMID- 10334743
TI  - Women with epilepsy are not getting pregnancy advice.

PMID- 10334744
TI  - Ashworth announces its reform plan 

PMID- 10334745
TI  - Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic
      review.
AB  - OBJECTIVE: To evaluate the efficacy of vitamin B-6 in the treatment of
      premenstrual syndrome. DESIGN: Systematic review of published and unpublished
      randomised placebo controlled trials of the effectiveness of vitamin B-6 in the
      management of premenstrual syndrome. SUBJECTS: Nine published trials representing
      940 patients with premenstrual syndrome. MAIN OUTCOME MEASURES: Proportion of
      women whose overall premenstrual symptoms showed an improvement over placebo. A
      secondary analysis was performed on the proportion of women whose premenstrual
      depressive symptoms showed an improvement over placebo. RESULTS: Odds ratio
      relative to placebo for an improvement in overall premenstrual symptoms was 2.32
      (95% confidence interval 1.95 to 2.54). Odds ratio relative to placebo for an
      improvement in depressive symptoms was 1.69 (1.39 to 2.06) from four trials
      representing 541 patients. CONCLUSION: Conclusions are limited by the low quality
      of most of the trials included. Results suggest that doses of vitamin B-6 up to
      100 mg/day are likely to be of benefit in treating premenstrual symptoms and
      premenstrual depression.

PMID- 10334747
TI  - Commentary: how experienced should a colorectal surgeon be?

PMID- 10334746
TI  - Influence of hospital and clinician workload on survival from colorectal cancer:
      cohort study.
AB  - OBJECTIVE: To determine whether clinician or hospital caseload affects mortality
      from colorectal cancer. DESIGN: Cohort study of cases ascertained between 1990
      and 1994 by a region-wide colorectal cancer register. OUTCOME MEASURES: Mortality
      within a median follow up period of 54 months after diagnosis. RESULTS: Of the
      3217 new patients registered over the period, 1512 (48%) died before 31 December
      1996. Strong predictors of survival both in a logistic regression (fixed follow
      up) and in a Cox's proportional hazards model (variable follow up) were Duke's
      stage, the degree of tumour differentiation, whether the liver was deemed clear
      of cancer by the surgeon at operation, and the type of intervention (elective or
      emergency and curative or palliative intent). In a multilevel model, surgeon's
      caseload had no significant effect on mortality at 2 years. Hospital workload,
      however, had a significant impact on survival. The odds ratio for death within 2
      years for cases managed in a hospital with a caseload of between 33 and 46 cases
      per year, 47 and 54 cases per year, and >/=55 cases per year (compared to one
      with </=23 cases per year) were respectively 1.48 (95% confidence interval 1.03
      to 2.13), 1.52 (1.08 to 2.13), and 1.18 (0.83 to 1.68). CONCLUSIONS: There was no
      detectable caseload effect for surgeons managing colorectal cancer, but survival
      of patients treated in hospitals with caseloads above 33 cases per year was
      slightly worse than for those treated in hospitals with fewer caseloads.
      Imprecise measurement of clinician specific "events rates" and the lack of
      routinely collected case mix data present major challenges for clinical audit and
      governance in the years ahead.

PMID- 10334748
TI  - Systematic review of the effectiveness of planned short hospital stays for mental
      health care.
AB  - OBJECTIVE: To determine the effectiveness of planned short hospital stays versus
      standard care for people with serious mental illness. DESIGN: Systematic review
      of all randomised controlled trials comparing planned short hospital stay versus
      long hospital stay or standard care for people with serious mental illness.
      SUBJECTS: Four trials enrolled 628 patients. MAIN OUTCOMES MEASURES: Relapse;
      readmission; death (suicides and all causes); violent incidents (self, others,
      property); lost to follow up; premature discharge; delayed discharge; mental
      state (not improved); social functioning; patient satisfaction, quality of life,
      self esteem, and psychological wellbeing; family burden; imprisonment; employment
      status; independent living; total cost of care; and average length of hospital
      stay. RESULTS: Patients allocated to planned short hospital stays had no more
      readmissions (in four trials, odds ratio 0.93, 95% confidence interval 0.66 to
      1.29 with no heterogeneity between trials), no more losses to follow up (in three
      trials of 404 patients, 1.09, 0.62 to 1.91 with no heterogeneity between trials),
      and more successful discharges on time (in three trials of 404 patients, 0.47,
      0.27 to 0.85) than patients allocated long hospital stays or standard care. Some
      evidence showed that patients allocated planned short hospital stay were no more
      likely to leave hospital prematurely and had a greater chance of being employed
      than those allocated long hospital stay or standard care. Data on mental, social,
      and family outcomes could not be summated, and there were few or no data on
      patient satisfaction, deaths, violence, criminal behaviour, and costs.
      CONCLUSION: The effectiveness of care in mental hospitals is important to
      patients, carers, and policy makers. Despite inadequacies in the data, this
      review suggests that planned short hospital stays do not encourage a "revolving
      door" pattern of care for people with serious mental illness and may be more
      effective than standard care. Further pragmatic trials are needed on the most
      effective organisation and delivery of care in mental hospitals.

PMID- 10334749
TI  - Dietary management of hepatic encephalopathy in cirrhotic patients: survey of
      current practice in United Kingdom.

PMID- 10334751
TI  - Treatment of shoulder complaints in general practice: long term results of a
      randomised, single blind study comparing physiotherapy, manipulation, and
      corticosteroid injection.

PMID- 10334752
TI  - Email submissions from outside the united kingdom 

PMID- 10334750
TI  - Effect on hospital attendance rates of giving patients a copy of their referral
      letter: randomised controlled trial.
AB  - OBJECTIVES: To investigate whether sending patients a copy of their referral
      letter can reduce non-attendance at outpatient departments. DESIGN: Blinded
      randomised controlled trial. SETTING: 13 general practices in Exeter, Devon.
      SUBJECTS: 2078 new consultant referrals from 26 doctors. MAIN OUTCOME MEASURES:
      Non-attendance at outpatient departments. RESULTS: The doctors excluded 117
      (5.6%) referrals, and 100 (4.8%) received no appointment. Attendance data were
      available for 1857 of the 1861 patients sent an appointment (99.8%). The receipt
      of a copy letter had no effect on the non-attendance rate: copy 50/912 (5.5%)
      versus control 50/945 (5.3%). CONCLUSION: Copy letters are ineffective in
      reducing non-attendance at outpatient departments.

PMID- 10334753
TI  - Recent advances: occupational disease.

PMID- 10334754
TI  - Evidence based cardiology: prevention of congestive heart failure and management
      of asymptomatic left ventricular dysfunction.

PMID- 10334755
TI  - ABC of labour care: care of the newborn in the delivery room.

PMID- 10334756
TI  - Ethical issues in the design and conduct of cluster randomised controlled trials.

PMID- 10334757
TI  - Psychotherapy for severe personality disorder: exploring the limits of evidence
      based purchasing.

PMID- 10334759
TI  - Is nail-cutting a surgical operation? 

PMID- 10334758
TI  - Economics notes: measuring outcomes in economic evaluations.

PMID- 10334760
TI  - Antepartum risk factors for newborn encephalopathy. Intrapartum risk factors are
      important in developing world.

PMID- 10334761
TI  - Backdoor euthanasia. Withholding food and fluids is justifiable only for
      terminally ill.

PMID- 10334762
TI  - Widening screening to detect Chlamydia trachomatis is more important than using
      DNA methods.

PMID- 10334763
TI  - Audit of implantable cardioverter-defibrillators in a single UK centre.

PMID- 10334764
TI  - Vitamin D concentrations in Asian children living in England. Limited vitamin D
      intake and use of sunscreens may lead to rickets.

PMID- 10334765
TI  - Income distribution, socioeconomic status, and self rated health in US. Authors
      ignored data in their study.

PMID- 10334766
TI  - Prediction of cardiovascular risk. Program is not suitable for diabetic patients.

PMID- 10334767
TI  - Secondary prevention in coronary heart disease. Effects of statins have been in
      addition to those of aspirin and beta blockers.

PMID- 10334768
TI  - Minimisation is much better than the randomised block design in certain cases.

PMID- 10334769
TI  - Is there a clinical future for the general practitioner?

PMID- 10334770
TI  - Role of general practitioners in NHS must not be undervalued. Author
      underestimated figures.

PMID- 10334771
TI  - Noise trauma after inflation of air bags in low speed car crashes. Article was
      unclear and possibly misleading.

PMID- 10334772
TI  - Every hospital must improve in-hospital resuscitation.

PMID- 10334773
TI  - Head lice can be controlled without application of insecticide lotions.

PMID- 10334774
TI  - WHO should undertake full inquiry into Gulf war illness.

PMID- 10334775
TI  - GP surgeries were hard to contact over Christmas.

PMID- 10334776
TI  - Frederick baar 

PMID- 10334777
TI  - Government condemned over juniors' hours 

PMID- 10334778
TI  - Matters of life and death 

PMID- 10334779
TI  - The aesculapian 

PMID- 10334781
TI  - Website of the week 

PMID- 10334780
TI  - The Painter's Eye 

PMID- 10334783
TI  - Bookcase 

PMID- 10334782
TI  - Email contact between doctor and patient 

PMID- 10334784
TI  - The soho bomb 

PMID- 10334785
TI  - Class list 

PMID- 10334786
TI  - On being scientific about organising care 

PMID- 10334788
TI  - Surgical experience should not be defined by workload 

PMID- 10334787
TI  - Benefits are likely from vitamin B-6 in premenstrual syndrome 

PMID- 10334789
TI  - Copying referral letters to patients has no effect on non-attendance 

PMID- 10334790
TI  - Short planned hospital stays are more effective for patients with mental illness 

PMID- 10334792
TI  - Treatments for shoulder complaints do not show long term effects 

PMID- 10334791
TI  - Many patients with hepatic encephalopathy are on damaging diets 

PMID- 10334793
TI  - Hypertension : the present years 

PMID- 10334794
TI  - Race and diurnal blood pressure patterns. A review and meta-analysis.
AB  - Investigators have reported variable findings regarding the role of race in
      diurnal blood pressure patterns. We performed a review and meta-analysis of this
      literature to identify the overall effect of race on circadian blood pressure
      patterns. Eighteen studies involving 2852 participants were reviewed. Meta
      analyses were conducted using effect sizes calculated from the data provided
      directly in the study reports. Separate meta-analyses were conducted on effect
      sizes for differences between blacks and whites in daytime and nighttime systolic
      and diastolic blood pressure and nocturnal dip in systolic and diastolic blood
      pressure. To evaluate discrepancies in findings from studies involving American
      versus non-American blacks, overall meta-analyses as well as within-subset meta
      analyses of black/white differences were conducted for comparisons involving
      American and non-American blacks. Results of overall meta-analyses indicate that
      blacks experience higher levels of systolic and diastolic blood pressure, both at
      night and during the day. These differences were significantly greater at night
      than during the day (P<0.05). Results of within-subset analyses involving
      American blacks mirrored those for all black/white comparisons, except that the
      effect of race on nocturnal dip, ie, that American blacks experienced less of a
      dip in both systolic and diastolic blood pressure at night, was significant
      (P<0.05). In contrast, the effect of race on nocturnal dip was not significant
      for comparisons involving non-American blacks. These results suggest a consistent
      difference in the chronobiology of blood pressure, particularly in American
      blacks.

PMID- 10334795
TI  - Effect of magnesium deficiency on blood pressure and mechanical properties of rat
      carotid artery.
AB  - The purpose of this study was to determine the effect of dietary Mg deficiency
      (80 mg/kg versus control diet: 960 mg/kg) on blood pressure and mechanical
      properties of the rat common carotid artery. The internal diameter and intra
      arterial pressure of carotid artery were measured continuously with an echo
      tracking device. At 19 weeks, systolic, diastolic, and mean blood pressures were
      higher in Mg-deficient rats. Histological examination showed an increase in cross
      sectional area, intima-media thickness, and media-to-lumen ratio in carotid
      artery of Mg-deficient rats. Mg deficiency did not modify the arterial
      distensibility-blood pressure curve. At mean blood pressure, arterial
      distensibility was significantly less in 19-week-old rats than in 5-week-old rats
      of both control and Mg-deficient groups. A significant interaction between age
      and Mg-deficient diet on arterial distensibility (P<0.04) indicates an
      accelerated age-dependent decreased arterial distensibility with Mg deficiency.
      At 19 weeks, the artery was stiffer in hypertensive Mg-deficient rats, as
      illustrated by a shift to higher levels of the incremental elastic modulus-stress
      curve. In conclusion, the increased blood pressure and the vascular morphological
      alterations observed in Mg-deficient rats may contribute to an accelerated
      alteration of the wall material, which in turn leads to a stiffening of the
      carotid artery.

PMID- 10334796
TI  - Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive
      patients.
AB  - Large artery damage is a major contributory factor to cardiovascular morbidity
      and mortality of patients with hypertension. Pulse wave velocity (PWV), a classic
      evaluation of arterial distensibility, has never been ascertained as a
      cardiovascular risk marker. To determine the factors influencing aortic PWV and
      the potential predictor role of this measurement, we studied a cohort of 710
      patients with essential hypertension. Atherosclerosis alterations (AA) were
      defined on the basis of clinical events. Calculation of cardiovascular risks, by
      use of Framingham equations, was performed in subjects without AA. PWV was higher
      in the presence of AA (14.9+/-4.0 versus 12.4+/-2.6 m/s, P<0.0001), even after
      adjustments on confounding factors and was the first determinant (P<0.0001) of
      the extent of atherosclerosis assessed as the sum of the atherosclerotic sites.
      In patients without AA, all cardiovascular risks increased constantly with PWV.
      Furthermore, at a given age, aortic PWV was the best predictor of cardiovascular
      mortality. The odds ratio of being in a high cardiovascular mortality risk group
      (>5% for 10 years) for patients in the upper quartile of PWV was 7.1 (95%
      confidence intervals 4.5 to 11.3). The presence of a PWV >13 m/s, taken alone,
      appeared as a strong predictor of cardiovascular mortality with high performance
      values. This study shows that aortic PWV is strongly associated with the presence
      and extent of atherosclerosis and constitutes a forceful marker and predictor of
      cardiovascular risk in hypertensive patients.

PMID- 10334797
TI  - Diminished wave reflection in the aorta. A novel physiological action of insulin
      on large blood vessels.
AB  - Epidemiological data suggest that insulin may have direct effects on large-vessel
      function, but thus far insulin has only been shown, after prolonged infusions, to
      slowly decrease peripheral vascular resistance by increasing muscle blood flow.
      We determined whether physiological doses of insulin affect function of large
      arteries, before any changes in peripheral blood flow, in vivo using pulse wave
      analysis. Nine normal men were studied on 2 occasions: once during a 6-hour
      infusion of saline and once under normoglycemic hyperinsulinemic conditions
      (sequential 2-hour insulin infusions of 1, 2, and 5 mU/kg. min). Central aortic
      pressure waves were synthesized from those recorded in the periphery with the use
      of applanation tonometry and a validated reverse transfer function every 30
      minutes. This allowed determination of central aortic augmentation (the pressure
      difference between early and late systolic pressure peaks) and augmentation index
      (augmentation expressed as a percentage of pulse pressure). Both augmentation and
      augmentation index decreased significantly within 1 hour after administration of
      insulin (P<0.001) but not saline. Systolic and diastolic blood pressure and heart
      rate remained unchanged for the first 2 hours. A significant increase in
      peripheral (forearm) blood flow was not observed until 2.5 hours after start of
      the insulin infusion. These data demonstrate that insulin, in normal subjects,
      rapidly decreases wave reflection in the aorta. This beneficial effect is
      consistent with increased distensibility or vasodilatation of large arteries. In
      contrast to the effect of insulin on peripheral blood flow, this action of
      insulin is observed under conditions in which both the insulin dose and duration
      of insulin exposure are physiological. Resistance to this action of insulin could
      provide a mechanism linking insulin resistance and conditions such as
      hypertension at the level of large arteries.

PMID- 10334798
TI  - Descriptive epidemiology of blood pressure response to change in body position.
      The ARIC study.
AB  - The epidemiology of a common measure of cardiovascular reactivity, the change in
      systolic blood pressure (DeltaSBP) from the supine to the standing position, is
      described in a cohort of 13 340 men and women aged 45 to 65 years enrolled in the
      Atherosclerosis Risk in Communities (ARIC) Study. The distribution of DeltaSBP
      was found to be symmetrical and unimodal, with a mean value near zero (-0.45 mm
      Hg). The range of DeltaSBP was from -63.2 to 54.3 mm Hg, and the standard
      deviation was 10.8. Stratification of DeltaSBP by race and gender shows a slight
      shift in distribution toward higher values for black men and women. DeltaSBP was
      categorized into deciles. Participants in the top 30% and bottom 30% of the
      distribution were compared with individuals in the middle 40% of the
      distribution, who had little or no change in SBP on standing. Participants in the
      bottom 30% (ie, SBP decreased on standing) were significantly older, had a
      greater prevalence of hypertension and peripheral vascular disease, had higher
      values of SBP, and had more cigarette-years of smoking. Among participants in the
      top 30% (ie, SBP increased on standing), a significantly larger proportion were
      black, mean seated SBP was higher, and the predicted risk of developing coronary
      heart disease after 8 years was greater. The response of SBP to change in posture
      showed considerable variability in a population sample of middle-aged adults.
      Cardiovascular morbidity, sociodemographic factors, and cigarette smoking were
      associated with the magnitude and direction of the postural change.

PMID- 10334799
TI  - Diabetes and cardiovascular events in hypertensive patients.
AB  - To determine the relation of self-reported history of diabetes as well as
      baseline and in-treatment blood sugar to subsequent cardiovascular disease (CVD)
      in treated hypertensive patients, we assessed the experience of 6886 participants
      in a systematic treatment program. The presence or absence of a history of
      diabetes was known for all patients, who were then stratified into 3 groups
      according to blood sugar at baseline and in treatment (<6.11, 6.11 to 7.74, and
      >/=7.75 mmol/L). Some 7.4% of all patients reported history of diabetes, and the
      overall prevalence of blood sugar >/=7. 75 mmol/L was 7.7% and 10.4% at baseline
      and in treatment, respectively. Patients with a history of diabetes were 10 or 8
      times as likely to have blood sugar >/=7.75 mmol/L at baseline (47.2% versus
      4.5%) or in treatment (55.0% versus 6.8%), as were patients without history.
      During an average 6.3 years of follow-up, patients with history of diabetes had a
      cardiovascular event incidence 2-fold higher than those without history (20.8
      versus 8.6/1000 person-years). Age-gender-adjusted CVD incidence rate but not non
      CVD was twice as high in the highest compared with the lowest blood sugar stratum
      (baseline 16.6 versus 8.4/1000 person-years; in treatment 15.2 versus 8.2). Three
      separate models of Cox multivariate analysis revealed that history of diabetes
      (with no history as reference) had a greater association with CVD events (hazard
      ratio 2.37, 95% confidence interval 1.80 to 3.11) than did baseline (1.75, 1.31
      to 2.33) or in-treatment blood sugar (1.55, 1. 19 to 2.02). Furthermore, in the
      presence of history of diabetes (2. 15, 1.58 to 2.92), neither baseline nor in
      treatment blood sugar was independently associated with CVD risk. In the elevated
      (>/=7.75 mmol/L) in-treatment blood sugar group, the age-gender-adjusted rate of
      CVD events in frequent diuretic users (30.79/1000 person-years) was significantly
      higher than in moderate (13.34, P=0.004) and rare users (13.25, P=0.008). These
      data affirm that the coincidence of diabetes and hypertension is common, that
      evidence of diabetes substantially increases CVD risk, that self-reported history
      is a more powerful predictor of CVD events than any measure of blood sugar, and
      that CVD increases in hypertensive diuretic users who develop hyperglycemia even
      when blood pressure is well controlled.

PMID- 10334800
TI  - Metformin attenuates salt-induced hypertension in spontaneously hypertensive
      rats.
AB  - Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes
      mellitus, lowers blood pressure in humans and experimental animals. We recently
      demonstrated that short-term administration of metformin may lower blood pressure
      by reducing sympathetic neural outflow. The present studies were initiated to
      determine whether long-term administration of metformin blunts salt-induced
      hypertension, a condition characterized by elevated sympathetic activity. Male
      spontaneously hypertensive rats, in which radiotelemeters had been implanted for
      continuous monitoring of heart rate and blood pressure, were randomly assigned to
      groups that received vehicle (drinking water) or metformin (500 mg/kg per day)
      and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin
      and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not
      affect blood pressure in the animals that ate the normal-salt diet (vehicle,
      130+/-3 mm Hg; metformin, 133+/-5 mm Hg; mean+/-SEM), drug treatment blunted the
      rise in pressure caused by a high-salt diet (vehicle, 153+/-4 mm Hg; metformin,
      140+/-5 mm Hg; P<0.001). In agreement, during direct pressure recordings in
      anesthetized rats, the animals that ate the high-salt diet had higher pressures
      (136+/-13 mm Hg) than those in the control (98+/-5 mm Hg, P<0.01), metformin
      (100+/-7 mm Hg, P<0.01), and metformin/high-salt groups (92+/-3 mm Hg, P<0.01).
      Finally, metformin lowered heart rate in rats that ate the normal- and high-salt
      diets (310+/-3 and 305+/-4 bpm) compared with rats that ate normal- and high-salt
      diets given vehicle (332+/-3 and 324+/-2 bpm, P<0.01). These data indicate that
      the chronic depressor actions of metformin are enhanced in animals with
      hypertension exacerbated by a high-salt diet.

PMID- 10334801
TI  - Diastolic dysfunction and baroreflex sensitivity in hypertension.
AB  - The determinants of diastolic dysfunction in patients with systemic hypertension
      are not completely known. To evaluate the possible role of age, arterial blood
      pressure, and baroreflex heart rate response impairment in causing diastolic
      dysfunction, we studied 61 patients (42 male; mean+/-SD age, 43.9+/-12 years)
      with newly recognized and therefore previously untreated systemic hypertension.
      Diastolic dysfunction was evaluated by means of Doppler echocardiography (and
      diagnosed as such when the early to atrial peak velocity ratio corrected to heart
      rate was <1), arterial blood pressure by 24-hour ambulatory monitoring, and
      baroreflex heart rate response by means of the spectral technique (alpha index)
      during paced (0.27 Hz) and spontaneous breathing (in a supine position and during
      tilt). Nineteen patients had diastolic dysfunction, the most powerful predictor
      of which was age (r=-0.63, P<0.001). The patients with diastolic dysfunction had
      significantly lower values for spectral baroreflex gain in the high-frequency
      band than those without (5.2+/-3 versus 8.4+/-5 ms/mm Hg during paced breathing,
      P<0.05; 7. 4+/-4 versus 13.3+/-7 ms/mm Hg in a supine position, P<0.05; 4.3+/-4
      versus 5+/-2 ms/mm Hg during tilt, P<NS). Ambulatory blood pressure values were
      not significantly different in the patients with (137+/-14 and 89+/-9 mm Hg) and
      without (144+/-11 and 82+/-24 mm Hg) diastolic dysfunction. In conclusion, age
      and impaired baroreflex heart rate response (but not pressure overload) are
      determinants of left ventricular diastolic dysfunction in patients with newly
      recognized and untreated systemic hypertension.

PMID- 10334802
TI  - Ventricular adrenomedullin levels correlate with the extent of cardiac
      hypertrophy in rats.
AB  - We investigated the pathophysiological significance of adrenomedullin (AM) in the
      development of left ventricular hypertrophy (LVH). LVH was produced by aortic
      banding (AB) in rats. The left ventricular weight/body weight (LV/BW) ratio,
      ventricular AM peptide and mRNA levels, and hemodynamics were measured at 1, 3,
      7, and 21 days after the operation. Both LV/BW ratio and ventricular AM levels
      showed a significant increase from 1 day after the operation in the AB rats
      versus the sham-operated rats. Both increased in a time-dependent manner. The
      ventricular AM levels correlated with the LV/BW ratio (r=0.76, P<0.01). The AM
      mRNA levels were highly expressed at 1 day after the operation in the AB rats but
      showed no difference from 3 to 21 days after the operation between the AB and
      sham groups. The plasma AM levels showed a peak at 1 day after the operation in
      both groups. Then, we treated AB rats with an angiotensin-converting enzyme
      inhibitor (quinapril) in 2 doses (1 and 10 mg. kg-1. d-1) for 21 days. The
      quinapril treatment attenuated similarly both the LV/BW ratio and the ventricular
      AM levels. We also assessed the effects of AM and hydralazine administration for
      7 days on the LV/BW ratio and hemodynamics of AB rats. Both AM and hydralazine
      administration reduced the blood pressure by approximately 10% compared with the
      nontreated AB rats, but a reduction of the LV/BW ratio was observed only in the
      AM-treated group (P<0.05). These results suggest that ventricular AM levels are
      elevated by chronic pressure overload in a time-dependent manner concomitant with
      the extent of LVH and that AM may play a pathophysiological role in the
      development of LVH in chronic pressure overload.

PMID- 10334803
TI  - Human obesity is characterized by a selective potentiation of central chemoreflex
      sensitivity.
AB  - The chemoreflexes are an important mechanism for regulation of both breathing and
      autonomic cardiovascular function. Obesity is associated with an increased risk
      of alveolar hypoventilation and carbon dioxide retention, suggesting that
      abnormalities in chemoreflex control mechanisms may be implicated. We tested the
      hypothesis that chemoreflex function is altered in obesity. We compared
      ventilatory, sympathetic, heart rate, and blood pressure responses to
      hypercapnia, hypoxia, and the cold pressor test in 14 obese subjects and 14
      normal-weight subjects matched for age and gender. During hypercapnia, the
      increase in minute ventilation was significantly greater in obese subjects (7.0+/
      0.3 L/min) than in normal-weight subjects (3.3+/-1.1 L/min; P=0.03). Despite
      higher minute ventilation during hypercapnia in obese subjects, the increase in
      muscle sympathetic nerve activity was similar in obese and normal-weight
      subjects. When the inhibitory influence of breathing during hypercapnia was
      eliminated by apnea, the increase in sympathetic nerve activity in obese subjects
      (99+/-16%) was greater than in normal-weight subjects (44+/-16%; P=0.02). The
      magnitude of the ventilatory and autonomic responses to hypoxia and the cold
      pressor test was similar in obese and normal-weight subjects. We conclude that
      chemoreflex responses to hypercapnia are potentiated in eucapnic obese subjects.
      In contrast, responses to hypoxia and to the excitatory cold pressor stimulus in
      obese subjects are similar to those in normal-weight subjects. Thus, obesity is
      characterized by selective potentiation of central chemoreflex sensitivity.

PMID- 10334804
TI  - Relation between body fat-corrected ECG voltage and ambulatory blood pressure in
      patients with essential hypertension.
AB  - Because adipose tissue has high electric resistance, the amount of body fat
      influences ECG voltage. In this study, body fat weight of patients with essential
      hypertension was measured by means of the impedance method and was used to
      correct mean ECG voltage. Then the relation between body fat-corrected mean ECG
      voltage (Vfm) and ambulatory blood pressure (BP) was investigated. The subjects
      were 172 patients with essential hypertension (88 men, 84 women, none receiving
      medication) between the ages of 30 and 75 years. Ambulatory BP was measured by a
      multi-biomedical recorder. Minimum sleep-time BP (base BP) was calculated to
      correspond with minimum sleep-time heart rate. The tetrapolar bioelectric
      impedance method was used to measure body fat (kg). Left ventricular mass (LVM)
      was obtained by echocardiography. Then comparisons were made with standard 12
      lead ECG, and the statistical mean ECG voltage (Vm) and Vfm were derived by
      multivariate statistical analysis. The following formula was devised to obtain
      Vfm resulting from the multivariate analysis that demonstrated a high correlation
      with LVM (r=0.85): Vfm=0.175(Body Fat)1/3xVm+0.5 (mV). The coefficient of
      correlation (r) between Vfm and ambulatory BP was not smaller than that between
      LVM and ambulatory BP. Base systolic BP demonstrated a significantly higher r
      value (r=0.83) with Vfm/BSA1/2 (where BSA is body surface area) than mean daytime
      SBP (r=0.65). In many subjects with white-coat hypertension, Vfm/BSA1/2 was <1.33
      mV/m (34 of 38 cases; sensitivity, 89%; specificity, 89%). These results indicate
      that Vfm is a better indicator of hypertensive left ventricular hypertrophy and
      that it may be useful in estimating minimum sleep-time systolic BP and in
      diagnosing white-coat hypertension in the outpatient clinic.

PMID- 10334805
TI  - DD angiotensin-converting enzyme gene polymorphism is associated with endothelial
      dysfunction in normal humans.
AB  - A polymorphism within the angiotensin-converting enzyme (ACE) gene may increase
      the risk of myocardial infarction in individuals previously thought to be at low
      cardiovascular risk. The mechanism through which it exerts this effect is unknown
      but may be due to increased angiotensin II-induced nitric oxide (NO) breakdown
      and/or reduced bradykinin-mediated NO release. We investigated whether
      endothelial function was different between different ACE genotypes. We performed
      a cross-sectional study comparing the endothelial function of the 3 genotypes
      (II: n=25; ID: n=31; DD: n=12). Mean+/-SD ages of the subjects were 24+/-4 (II),
      25+/-6 (ID), and 25+/-6 (DD) years. We assessed the impact of the genotypes on
      endothelial function and found that the DD genotype was associated with a
      significant blunting in endothelial-dependent vasodilatation (forearm blood flow
      data are presented as mean+/-SD ratio of blood flow in response to 3
      incrementally increasing doses of each vasoactive agent in the test arm to blood
      flow in the control arm; the comparison is between DD versus ID versus II; the P
      value is an expression of an overall difference by ANOVA, and the 95% CIs are of
      a pairwise comparison between genotypes): acetylcholine, 2.88+/-1.45 versus
      3.81+/-1.93 versus 4.23+/-2.37 (P=0.002; 95% CI [II versus ID], -0.19 to 0.91;
      95% CI [II versus DD], 0.36 to 1.80; 95% CI [ID versus DD], 0.02 to 1.42). There
      was also a significant difference with the endothelial-independent vasodilator
      sodium nitroprusside, with values of 2.11+/-1.00 versus 2.55+/-1.36 versus 2.75+/
      1.18 (P<0.05; 95% CI [II versus ID], -0.15 to 0.51; 95% CI [II versus DD], 0.03
      to 0.89; 95% CI [ID versus DD], -0.13 to 0.71), but not with verapamil. There was
      no effect of the ACE genotype on endothelial-dependent or -independent
      vasoconstrictors NG-monomethyl-L-arginine or norepinephrine. Investigating the
      effects of cigarette smoking on each genotype demonstrated that for II and DD
      genotypes, acetylcholine responses were further blunted if subjects smoked. These
      data demonstrate that the DD ACE genotype in a young population is associated
      with a blunting of stimulated endothelial NO and donated NO responses but not to
      non-NO vasodilators or vasoconstrictors.

PMID- 10334806
TI  - The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood
      pressure in overweight people.
AB  - There is accumulating evidence that endothelin-1 plays an important role in
      vascular pathophysiology. Our objective was to examine whether molecular
      variations at the endothelin-1 locus were involved in susceptibility to
      myocardial infarction and variation in blood pressure. The entire coding sequence
      and 1.4 kb of the 5' flanking region were screened. Five polymorphisms were
      detected, which were genotyped in the ECTIM (Etude Cas-Temoin de l'Infarctus du
      Myocarde) Study, a multicenter study comparing 648 male patients who had survived
      a myocardial infarction and 760 population-based controls. The polymorphisms were
      not associated with myocardial infarction, nor did they contribute to blood
      pressure levels in the population at large. However, a G/T polymorphism
      predicting an Lys/Asn change (ET1/C198) strongly interacted (P<0.001) with body
      mass index in the determination of blood pressure levels. There was a steeper
      increase of blood pressure with body mass index in carriers of the T allele than
      in GG homozygotes. As a consequence, the T allele was associated with an increase
      of blood pressure in overweight subjects (body mass index >/=26 kg/m2), while no
      significant effect was observed in lean subjects (body mass index <26 kg/m2). To
      determine whether this finding could be replicated, the ET1/C198 was genotyped in
      the Glasgow Heart Scan Study, a population-based study including 619 men and 663
      women. Subjects homozygous for the T allele had higher resting blood pressure
      levels than others (P<0.05). A similar interaction between the T allele and body
      mass index was observed on the maximum blood pressure achieved during a treadmill
      exercise test (P<0.001). In conclusion, results from 2 independent studies
      suggest that the ET1/C198 polymorphism is associated with blood pressure levels
      in overweight people.

PMID- 10334807
TI  - The 825C/T polymorphism of the G-protein subunit beta3 is not related to
      hypertension.
AB  - A polymorphism at position 825 (C-->T) of the cDNA that encodes the beta3 subunit
      (GNB3) of the pertussis toxin-sensitive G protein was recently shown to be
      associated with human hypertension. To verify this finding and to investigate
      whether this polymorphism could also be associated with coronary heart disease,
      we analyzed the GNB3 variant in subjects from 2 previously described studies:
      Projet d'Etude des Genes de l'hypertension Arterielle Severe a moderee
      Essentielle (PEGASE), a case-control study of moderate to severe hypertension
      (681 cases and 308 controls), and Etude Cas-Temoins de l'Infarctus du Myocarde
      (ECTIM), a case-control study of myocardial infarction (MI) (564 cases and 633
      controls). Genotyping was performed with allele-specific oligonucleotides.
      Genotype and allele frequencies were in Hardy-Weinberg equilibrium in all groups.
      Allele and genotype frequencies did not differ significantly between case
      patients with essential hypertension or MI and control subjects. In the ECTIM
      study, the 825T allele frequencies in cases and controls from Belfast, Northern
      Ireland, were 0.31 and 0.30 (P=0.79), respectively; the corresponding frequencies
      in cases and controls from France were 0.33 and 0.31 (P=0.30), respectively. In
      the PEGASE study, the 825T allele frequency was 0.35 in female and male cases and
      0.31 in male normotensive controls (P=0.12). The odds ratios for hypertension
      (PEGASE) and MI (ECTIM) associated with T-allele carrying were 1.23 (95%
      confidence interval, 0.94 to 1.62; P=0.13) and 1.11 (95% confidence interval,
      0.88 to 1.39; P=0.37), respectively. There was no association of the GNB3
      polymorphism with early onset of hypertension, familial history of hypertension,
      or blood pressure level. We conclude that the 825C/T polymorphism of the GNB3
      gene did not contribute in any important way to the risk of essential
      hypertension or MI in these studies.

PMID- 10334808
TI  - 11beta-hydroxysteroid dehydrogenase in cultured human vascular cells. Possible
      role in the development of hypertension.
AB  - 11beta-Hydroxysteroid dehydrogenases (11beta-HSD) interconvert cortisol, the
      physiological glucocorticoid, and its inactive metabolite cortisone in humans.
      The diminished dehydrogenase activity (cortisol to cortisone) has been
      demonstrated in patients with essential hypertension and in resistance vessels of
      genetically hypertensive rats. 11beta-Hydroxysteroid dehydrogenase type 2 (11beta
      HSD2) catalyzes only 11beta-dehydrogenation. However, a functional relationship
      between diminished vascular 11beta-HSD2 activity and elevated blood pressure has
      been unclear. In this study we showed the expression and enzyme activity of
      11beta-HSD2 and 11beta-HSD type 1 (which is mainly oxoreductase, converting
      cortisone to cortisol) in human vascular smooth muscle cells. Glucocorticoids and
      mineralocorticoids increase vascular tone by upregulating the receptors of
      pressor hormones such as angiotensin II. We found that physiological
      concentrations of cortisol-induced increase in angiotensin II binding were
      significantly enhanced by the inhibition of 11beta-HSD2 activity with an
      antisense DNA complementary to 11beta-HSD2 mRNA, and the enhancement was
      partially but significantly abolished by a selective aldosterone receptor
      antagonist. This may indicate that impaired 11beta-HSD2 activity in vascular wall
      results in increased vascular tone by the contribution of cortisol, which acts as
      a mineralocorticoid. In congenital 11beta-HSD deficiency and after administration
      of 11beta-HSD inhibitors, suppression of 11beta-HSD2 activity in the kidney has
      been believed to cause renal mineralocorticoid excess, resulting in sodium
      retention and hypertension. In the present study we provide evidence for a
      mechanism that could link impaired vascular 11beta-HSD2 activity, increased
      vascular tone, and elevated blood pressure without invoking renal sodium
      retention.

PMID- 10334809
TI  - Proadrenomedullin N-terminal 20 peptide (PAMP), acting through PAMP(12-20)
      sensitive receptors, inhibits Ca2+-dependent, agonist-stimulated secretion of
      human adrenal glands.
AB  - Proadrenomedullin N-terminal 20 peptide (PAMP) is a 20-amino acid hypotensive
      peptide expressed in the adrenal medulla. We investigated the localization and
      function of PAMP receptors in the human adrenal gland. Autoradiography showed the
      presence of [125I]PAMP-binding sites in both zona glomerulosa and adrenal medulla
      that were displaced by cold PAMP and PAMP(12-20) but not by other
      preproadrenomedullin-derived peptides. PAMP, but not PAMP(12-20), counteracted,
      in a concentration dependent manner, both aldosterone response of zona
      glomerulosa cells and catecholamine response of adrenal medulla cells to BAYK
      8644, the selective agonist of voltage-activated Ca2+ channels, as well as to K+
      and angiotensin II. PAMP(12-20) partially reversed this antisecretagogue effect
      of PAMP. Collectively, these findings suggest (1) that PAMP inhibits Ca2+
      dependent, agonist-stimulated aldosterone and catecholamine secretion, acting via
      specific receptors and through a mechanism involving the impairment of Ca2+
      influx; and (2) that PAMP(12-20) acts as a weak antagonist of PAMP receptors,
      thereby suggesting that both C- and N-terminal sequences of the PAMP molecule are
      required for this peptide to exert its antisecretagogue action on the human
      adrenal gland.

PMID- 10334810
TI  - Estradiol with or without progesterone and ambulatory blood pressure in
      postmenopausal women.
AB  - The purpose of this study was to determine whether transdermal estradiol and
      intravaginal progesterone given in doses to mimic the premenopausal state would
      lower blood pressure (BP) in postmenopausal women. Fifteen healthy postmenopausal
      women were studied in each of 3 conditions: on placebo, after 8 weeks of
      transdermal estradiol 0.2 mg twice per week, and again 2 weeks after addition of
      intravaginal progesterone 300 mg/d. Women were studied at each point after 2 days
      of 100 mmol/d sodium intake. Twenty-four-hour ambulatory BP monitoring was
      performed, and blood was assayed for estradiol, progesterone, and hormones of the
      renin-angiotensin-aldosterone system (RAAS). ANOVA with pairwise comparisons was
      used for analysis. Urinary sodium excretion was similar at each time point.
      Levels of estrogen and progesterone similar to those in premenopausal women were
      achieved. On estradiol, nocturnal systolic BP (110+/-3 mm Hg), diastolic BP (63+/
      2 mm Hg), and mean BP (77+/-2 mm Hg) fell significantly (P<0.02) compared with
      placebo systolic BP (116+/-2 mm Hg), diastolic BP (68+/-2 mm Hg), and mean BP
      (82+/-2 mm Hg). Daytime BP followed the same trend but was significantly lower
      only for mean BP. There was no activation of the RAAS. The addition of
      progesterone resulted in no further fall in BP but a significant activation of
      the RAAS. Thus, contrary to what is often assumed, administration of estradiol
      with or without progesterone not only did not raise BP but rather substantially
      lowered BP. This BP-lowering effect may be responsible for the lower incidence of
      hypertension in premenopausal than in postmenopausal women.

PMID- 10334812
TI  - Brain mineralocorticoid receptor control of blood pressure and kidney function in
      normotensive rats.
AB  - Brain mineralocorticoid receptors appear to contribute to mineralocorticoid
      hypertension and may be involved in blood pressure control in normotensive rats.
      We examined the effect of blockade of central mineralocorticoid receptors with
      the use of a selective antagonist (RU28318) on cardiovascular and renal function
      in conscious normotensive rats. The contribution of renal innervation was
      evaluated in rats with bilaterally denervated kidneys. Young adult, male Wistar
      rats were trained for systolic blood pressure measurement by a tail
      sphygmographic method and accustomed to metabolic cages for collection of urine.
      One week before experimentation, an intracerebroventricular cannula was
      implanted. Systolic blood pressure was diminished 30 minutes after an
      intracerebroventricular dose of 10 ng of RU28318. The effect was maximal at 8
      hours and was still present after 24 hours. Blood pressure returned to the basal
      level by 48 hours. During the period 0 to 8 hours after intracerebroventricular
      injection, rats treated with the antagonist showed an increase in diuresis and
      urinary electrolyte excretion. No significant effect on plasma renin activity,
      measured 8 and 30 hours after administration of RU28318, was observed. In
      denervated rats, the decrease in systolic blood pressure after administration of
      RU28318 was reduced. The difference was statistically significant compared with
      controls at 2 hours but not at 8 hours, and blood pressure returned to the basal
      value by 24 hours. The increases in diuresis and urinary electrolyte excretion
      induced by RU28318 were abolished in denervated rats. These results show that
      brain mineralocorticoid receptors are involved in blood pressure regulation and
      kidney function homeostasis in conscious normotensive rats. The renal nerves
      appear to participate in the brain mineralocorticoid receptor control of blood
      pressure.

PMID- 10334813
TI  - Pressor response to compression of the ventrolateral medulla mediated by
      glutamate receptors.
AB  - The rostral ventrolateral medulla (RVLM) is considered a major center for the
      regulation of sympathetic and cardiovascular activities. Several clinical studies
      have indicated a possible causal relationship between neurovascular contact of
      the left RVLM and essential hypertension, and some investigators have suggested
      that the left RVLM is more sensitive to pulsatile compression than the right
      RVLM. Previously, we reported that pulsatile compression of the RVLM elevates
      arterial pressure by enhancing sympathetic outflow in rats; however, we have not
      investigated the laterality of the responses to the compression. In addition, it
      remains to be elucidated whether RVLM neurons are activated by compression and,
      if so, how they are activated. Therefore, we performed compression experiments in
      rats to investigate these issues. Pulsatile compression was performed on the
      unilateral RVLM with a pulsating probe in anesthetized and artificially
      ventilated rats. Pulsatile compression of the unilateral RVLM increased arterial
      pressure, heart rate, and sympathetic nerve activity. The pressor response to
      compression was inhibited significantly after local microinjection of glutamate
      receptor antagonists. Pulsatile compression of the RVLM increased Fos
      immunoreactivitiy, a marker of neuronal activation, within the nuclei of
      postsynaptic RVLM neurons. All results were observed symmetrically. The data
      indicate that the responses to pulsatile compression of the unilateral RVLM are
      similar on both sides. They also suggest that pulsatile compression of the RVLM
      increases sympathetic and cardiovascular activities by activating postsynaptic
      RVLM neurons through the stimulation of the local glutamate receptors in rats.

PMID- 10334811
TI  - Effects of age and gender on autonomic control of blood pressure dynamics.
AB  - Both age and gender influence cardiovascular autonomic control, which in turn may
      influence the ability to withstand adverse cardiac events and respond to
      orthostatic stress. The purpose of this study was (1) to quantify age- and gender
      related alterations in autonomic control of blood pressure (BP) and (2) to
      examine the impact of these autonomic alterations on BP response to orthostatic
      stress. We measured continuous BP and R-R intervals and vasoactive peptide levels
      in the supine and 60 degrees head-up tilt positions during paced respiration
      (0.25 Hz) in 89 carefully screened healthy subjects (41 men, 48 women, aged 20 to
      83 years). Data were analyzed by gender (age adjusted) and by age group (gender
      adjusted). During tilt, women had greater decreases in systolic BP than men (
      10.2+/-2 versus -1.2+/-3 mm Hg; P=0.02) and smaller increases in low-frequency
      (sympathetically mediated) BP power (P=0.02). Upright plasma norepinephrine was
      lower in women (P=0.02). Women had greater supine high-frequency R-R interval
      power than men (P=0.0001). In elderly subjects, the tilt-induced increase in low
      frequency BP power was also diminished (P=0.01), despite higher supine (P=0.02)
      and similar upright norepinephrine levels compared with younger subjects. Thus,
      healthy women have less sympathetic influence on BP and greater parasympathetic
      influence on R-R interval than men. Elderly subjects also have reduced
      sympathetic influence on BP, but this appears to be more consistent with a
      reduction in vasomotor sympathetic responsiveness.

PMID- 10334814
TI  - Long-term effects of angiotensin-converting enzyme inhibition on renal medullary
      neutral lipid in spontaneously hypertensive rats.
AB  - Short-term treatment of young spontaneously hypertensive rats (SHR) with
      angiotensin-converting enzyme (ACE) inhibitors reduces systolic blood pressure.
      Renal medullary neutral lipids (RMNLs) have vasodilator properties that may
      explain the effects of ACE inhibition. We measured RMNL levels of SHR treated
      between 6 and 10 weeks of age with (1) vehicle, (2) ramipril 1 mg. kg-1. d-1, (3)
      the bradykinin B2 receptor antagonist icatibant 0.5 mg. kg-1. d-1, or (4)
      icatibant 0.5 mg. kg-1. d-1 plus ramipril 1 mg. kg-1. d-1. RMNLs were quantified
      by oil red O fluorescence at 10 and 20 weeks of age. Systolic blood pressure (BP)
      was measured by tail-cuff plethysmography. Ramipril reduced BP at 10 weeks of age
      and increased RMNLs compared with controls (0.99+/-0.07% versus 0.56+/-0. 06%,
      P<0.01). Icatibant alone had no significant effect on RMNLs (0.55+/-0.04%) but
      attenuated the increase in RMNLs by ramipril (0. 81+/-0.05%). In control SHR, the
      increase in BP between 10 and 20 weeks of age was associated with a significant
      increase in RMNLs (0.79+/-0.09%). SHR that had received ramipril had
      significantly lower BP than controls at 20 weeks of age, but RMNL was not
      significantly different (0.92+/-0.10%). Therefore, in young SHR, ACE inhibition
      increases RMNLs and reduces blood pressure, an effect that appears to depend on
      bradykinin. The changes in RMNLs at the age of 10 weeks paralleled long-term BP
      effects and may be involved in setting the BP track in SHR.

PMID- 10334815
TI  - Systemic administration of lipopolysaccharide induces release of nitric oxide and
      glutamate and c-fos expression in the nucleus tractus solitarii of rats.
AB  - There is increasing recognition that communication pathways exist between the
      immune system and brain, which allows bidirectional regulation of immune and
      brain responses to infection. The endotoxin lipopolysaccharide (LPS) has been
      reported to elicit release of cytokines and expression of inducible nitric oxide
      synthase (iNOS) in peripheral organs. Whereas LPS given systemically causes
      endotoxic shock, little is known about its central nervous system action,
      particularly the induction of iNOS. Nitric oxide (NO) and glutamate in the
      nucleus tractus solitarii (NTS) are important mediators of central cardiovascular
      regulation. We have previously demonstrated that intravenous injections of LPS
      increased the NO precursor L-arginine-induced depressor effect in the NTS. The
      present study investigated further the effects of LPS on the release of NO and
      glutamate in the NTS and the expression of c-fos, an immediate early response
      gene product, in neural substrates for central cardiovascular control. In vivo
      microdialysis coupled with chemiluminescence and electrochemical detection
      techniques were used to measure extracellular levels of NO and glutamate in the
      rat NTS. Immunohistochemistry was used for the examination of c-fos protein
      expression. We found that intravenous infusion of LPS (10 mg/kg) produced a
      biphasic depressor effect, with an early, sharp hypotension that partially
      recovered in 15 minutes and a secondary, more prolonged hypotension. In the NTS,
      a progressive increase of extracellular glutamate and NO levels occurred 3 and 4
      hours after LPS was given, respectively. The effects of LPS on the induction of
      delayed hypotension and NO formation in the NTS were abolished by pretreatment
      with the iNOS inhibitor aminoguanidine. Finally, c-fos protein expression in the
      NTS and related structures for cardiovascular regulation was observed after LPS
      challenge. Taken together, these data suggest that an endotoxin given
      systemically can elicit delayed increases of glutamate release and iNOS-dependent
      NO production in the NTS and activate the central neural pathway for modulating
      cardiovascular function.

PMID- 10334817
TI  - Type 2 bradykinin-receptor antagonism does not modify kinin or angiotensin
      peptide levels.
AB  - Type 2 bradykinin (B2)-receptor antagonists have been used to define the role of
      endogenous kinin peptides. However, interpretation of the effects of B2-receptor
      antagonists has been limited by lack of information concerning the effects of
      these antagonists on endogenous kinin and angiotensin peptide levels. If kinin
      levels were subject to short-loop-feedback regulation mediated through B2
      receptors, then a reactive increase in kinin levels might blunt the effects of B2
      receptor antagonism and stimulate type 1 bradykinin receptors. Moreover, kinins
      have been implicated in the control of renin secretion. We investigated whether
      endogenous kinin levels are subject to short-loop-feedback regulation mediated by
      the B2 receptor and whether endogenous kinins acting through the B2 receptor
      influence plasma renin levels and circulating and tissue angiotensin peptide
      levels. The B2-receptor antagonist icatibant (1 mg/kg) was administered to rats
      by intraperitoneal injection, and circulating and tissue levels of angiotensin
      and kinin peptides were measured after 4 hours. Icatibant produced 75% occupancy
      of B2 receptors in the inner stripe of the renal medulla. Icatibant did not
      influence plasma levels of renin, angiotensinogen, angiotensin-converting enzyme,
      neutral endopeptidase, or circulating or tissue levels of angiotensin and
      bradykinin peptides. This study demonstrated that kinin levels are not subject to
      short-loop-feedback regulation mediated through B2 receptors and that endogenous
      kinin levels acting through the B2 receptor do not modulate the renin-angiotensin
      system.

PMID- 10334816
TI  - Paracrine role of adventitial superoxide anion in mediating spontaneous tone of
      the isolated rat aorta in angiotensin II-induced hypertension.
AB  - The relationship between vascular generation of superoxide anion and spontaneous
      tone observed in the isolated aorta was studied in hypertensive rats infused with
      angiotensin II. Aortic rings from hypertensive, but not from sham-operated rats,
      demonstrated oscillatory spontaneous tone that represented 52+/-5.6% of the
      maximal contraction to KCl. Spontaneous tone was prevented by calcium-free buffer
      or by blocking calcium influx through L-type calcium channels with nifedipine.
      The production of superoxide anion measured by lucigenin chemiluminescence was up
      to 15-fold higher than in sham-operated rat aorta. The adventitial site of
      production of superoxide anion was suggested by the fact that lucigenin
      chemiluminescence was 5.5-fold higher from the adventitia than from the intima.
      This was confirmed histochemically by demonstrating that the adventitia was the
      site of reduction of nitroblue tetrazolium as well as immunohistochemical
      staining of NAD(P)H oxidase subunit proteins. A causal link between superoxide
      anion production by NAD(P)H oxidase and the spontaneous tone is suggested by the
      fact that superoxide dismutase or the inhibitor of NAD(P)H oxidase, diphenylene
      iodonium, decreased both superoxide anion production and spontaneous tone. L-NAME
      or removal of the endothelium from the aorta had no significant effect on
      superoxide anion levels or spontaneous tone. However, although superoxide
      dismutase decreased superoxide anion levels in the presence of L-NAME or in
      endothelium-denuded rings, it no longer inhibited the tone. This suggests that
      the effect on tone of superoxide anion originating in the adventitia is mediated
      by inactivating endothelium-derived nitric oxide, which promotes smooth muscle
      calcium influx and spontaneous tone. The adventitia is not a passive bystander
      during the development of hypertension, but rather it may have an important role
      in the regulation of smooth muscle tone.

PMID- 10334820
TI  - Correction 

PMID- 10334818
TI  - Protective role of the angiotensin AT2 receptor in a renal wrap hypertension
      model.
AB  - We evaluated the role of the renal angiotensin II type 2 (AT2) receptor in blood
      pressure regulation in rats with 2-kidney, 1 figure-8 wrap (Grollman)
      hypertension. Renal wrapping increased systolic blood pressure (SBP). Renal
      interstitial fluid (RIF) bradykinin (BK), nitric oxide end-products (NOX), and
      cGMP were higher in the contralateral intact kidney than in the wrapped kidney.
      In rats with Grollman hypertension, losartan normalized SBP and increased renal
      function, RIF BK, NOX, and cGMP only in contralateral kidneys. In contrast, PD
      123319, a specific AT2-receptor antagonist, significantly increased SBP and
      decreased RIF BK, NOX, and cGMP in both kidneys. Combined administration of
      losartan and PD 123319 prevented the decrease in SBP and the increase in RIF BK,
      NOX, and cGMP levels observed with losartan alone. BK-receptor blockade caused a
      significant increase in RIF BK and a decrease in RIF NOX and cGMP in both kidneys
      similar to that observed during administration of PD 123319. In rats that
      underwent sham operation, RIF BK increased in response to angiotensin II, an
      effect that was blocked by PD 123319. These data demonstrate that angiotensin II
      mediates renal production of BK, which, in turn, releases nitric oxide and cGMP
      via stimulation of AT2 receptors. The increase in blood pressure and the decrease
      in renal BK, nitric oxide, and cGMP during AT2-receptor blockade suggests that
      the AT2 receptor mediates counterregulatory vasodilation in Grollman hypertension
      and prevents a further increase in blood pressure.

PMID- 10334819
TI  - Role of increased production of superoxide anions by NAD(P)H oxidase and xanthine
      oxidase in prolonged endotoxemia.
AB  - Superoxide anions (O2-) are supposedly involved in the pathogenesis of
      endothelial dysfunction. We investigated whether the enhanced formation of O2- is
      involved in the attenuation of endothelium-dependent relaxation induced by
      lipopolysaccharide (LPS). Rats were injected with LPS (10 mg/kg IP), the aorta
      was removed after 12 or 30 hours, and generation of O2-, H2O2, and ONOO- was
      measured using chemiluminescence assays. Protein tyrosine nitration and
      expression of xanthine oxidase (XO), NAD(P)H oxidase, and manganese superoxide
      dismutase were determined by Western or Northern blotting, and endothelium
      dependent relaxation in aortic rings was studied. LPS treatment increased
      vascular O2- (from 35+/-2 cpm/ring at baseline to 166+/-21 cpm/ring at 12 hours
      and 225+/-16 cpm/ring at 30 hours) and H2O2 formation, which was partially
      sensitive to the NAD(P)H oxidase inhibitor diphenylene iodonium at both time
      points studied and to the XO inhibitor oxypurinol only 30 hours after LPS
      treatment. Expression of XO and NAD(P)H oxidase (p22phox, p67phox, and gp91phox)
      were increased by LPS in a time-dependent manner, as were protein tyrosine
      nitration and ONOO- formation. LPS also induced expression of the oxidative
      stress-sensitive protein manganese superoxide dismutase. Endothelium-dependent
      relaxation was impaired after LPS treatment and could not be restored by
      inhibition of inducible NO synthase. Inhibition of O2- with superoxide dismutase,
      oxypurinol, tiron, or the superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic
      acid)porphyrin chloride did not restore but further deteriorated the relaxation
      of LPS-treated rings. In summary, treatment of rats with LPS enhances vascular
      expression of XO and NAD(P)H oxidase and increases formation of O2- and ONOO-.
      Because removal of O2- compromised rather than restored endothelium-dependent
      relaxation, a direct role of O2- in the induction of endothelial dysfunction is
      unlikely. Other mechanisms, such as prolonged protein tyrosine nitration by
      peroxynitrite (which is formed from NO and O2-) or downregulation of the NO
      effector pathway, are more likely to be involved.

PMID- 10334821
TI  - Ligand-induced downregulation of receptors for TGF-beta in human osteoblast-like
      cells from adult donors.
AB  - High concentrations of transforming growth factor b (TGF-beta) are found in the
      bone matrix, reflecting a pivotal role of this growth factor in the coupling of
      bone resorption and formation. TGF-beta strongly stimulates the synthesis of
      extracellular matrix proteins, but in vitro studies show an inhibitory effect on
      the final mineralization process, which in vivo occurs despite high
      concentrations of TGF-beta. Little is known about how bone-forming cells respond
      to different concentrations of TGF-beta and if they can transiently adapt
      receptor numbers in order to modulate cellular activity. Against this background,
      we studied the cell-surface expression of TGF-beta receptors (TbetaR) I, II and
      III (betaglycan) on human osteoblast-like cells from adult donors, and examined
      the TbetaR presentation on these cells after a preceding exposure to TGF-beta1.
      Affinity crosslinking studies with disuccinimidylsuberate showed the presence of
      all three receptor types. Preincubation with TGF-beta1 markedly reduced 125I-TGF
      beta1 binding in a time-dependent and dose-dependent manner and revealed a 95%
      reduction after an 18-h preincubation with 200 pM TGF-beta1. In parallel,
      Scatchard analysis showed that the binding affinity did not change as a
      consequence of TGF-beta1 preincubation. Immunoblotting analyses revealed an
      almost complete disappearance of immunoreactive TbetaR-II and TbetaR-III proteins
      after a 24-h preincubation with TGF-beta1. Using semi-quantitative reverse
      transcription PCR, no effect of TGF-beta1 on the expression of TbetaR-II mRNA was
      observed. These studies demonstrate a ligand-induced downregulation of TbetaRs-II
      and -III on human osteoblast-like cells, without any evidence for recovery within
      the first 24 h, both in the presence and after the removal of the ligand. The
      underlying mechanism appears to be based on post-transcriptional events. The
      results suggest that high concentrations of active TGF-beta1 decrease the
      responsiveness of osteoblasts towards this growth factor.

PMID- 10334822
TI  - TWODEE: the Health and Safety Laboratory's shallow layer model for heavy gas
      dispersion. Part 1. Mathematical basis and physical assumptions.
AB  - The Major Hazard Assessment Unit of the Health and Safety Executive (HSE)
      provides advice to local planning authorities on land use planning in the
      vicinity of major hazard sites. For sites with the potential for large scale
      releases of toxic heavy gases such as chlorine this advice is based on risk
      levels and is informed by use of the computerised risk assessment tool RISKAT [C.
      Nussey, M. Pantony, R. Smallwood, HSE's risk assessment tool RISKAT, Major
      Hazards: Onshore and Offshore, October, 1992]. At present RISKAT uses consequence
      models for heavy gas dispersion that assume flat terrain. This paper is the first
      part of a three part paper. Part 1 describes the mathematical basis of TWODEE,
      the Health and Safety Laboratory's shallow layer model for heavy gas dispersion.
      The shallow layer approach used by TWODEE is a compromise between the complexity
      of CFD models and the simpler integral models. Motivated by the low aspect ratio
      of typical heavy gas clouds, shallow layer models use depth-averaged variables to
      describe the flow behaviour. This approach is particularly well suited to assess
      the effect of complex terrain because the downslope buoyancy force is easily
      included. Entrainment may be incorporated into a shallow layer model by the use
      of empirical formulae. Part 2 of this paper presents the numerical scheme used to
      solve the TWODEE mathematical model, and validated against theoretical results.
      Part 3 compares the results of the TWODEE model with the experimental results
      taken at Thorney Island [J. McQuaid, B. Roebuck, The dispersion of heavier-than
      air gas from a fenced enclosure. Final report to the US Coast Guard on contract
      with the Health and Safety Executive, Technical Report RPG 1185, Safety
      Engineering Laboratory, Research and Laboratory Services Division, Broad Lane,
      Sheffield S3 7HQ, UK, 1985].

PMID- 10334823
TI  - TWODEE: the Health and Safety Laboratory's shallow layer model for heavy gas
      dispersion. Part 2: outline and validation of the computational scheme.
AB  - Part 1 of this three part paper described the mathematical and physical basis of
      TWODEE, the Health and Safety Laboratory's shallow layer model for heavy gas
      dispersion. In this part, the numerical solution method used to simulate the
      TWODEE mathematical model is developed. The boundary conditions for the leading
      edge, discussed in part 1, make demanding requirements on the computational
      scheme used. The flux correction scheme of Zalesak [S.T. Zalesak, Fully
      multidimensional flux-corrected transport algorithms for fluids, Journal of
      Computational Physics, 31 (1979) 335-362] is used in TWODEE as this has all the
      required properties. The TWODEE code is then tested against a number of
      theoretical and computational benchmark problems.

PMID- 10334825
TI  - Detoxifying chlorine rich gas streams using solid supported nickel catalysts.
AB  - Catalytic hydrogen treatment is presented as a viable low energy means of
      treating/detoxifying concentrated chlorinated gas streams to generate recyclable
      raw materials. Nickel (1.5% w/w and 15.2%) loaded silica and nickel (2.2% w/w)
      exchanged Y zeolite catalysts have been used to hydrotreat a range of
      chlorophenols (CPs), dichlorophenols (DCPs), trichlorophenols (TCPs) and
      pentachlorophenol (PCP) over the temperature interval 473 K</=T</=573 K. In every
      instance the nickel catalysts were 100% selective in cleaving the chlorine
      component from the ring, leaving the aromatic nucleus and hydroxyl substituent
      intact. The effects of varying process time and temperature are considered in
      terms of phenol yield and the ultimate partitioning of chlorine in the parent
      organic and product inorganic hosts. Chlorine removal rates, hydrodechlorination
      selectivity and apparent activation energies are also provided. Prolonged
      exposure of the catalysts to the concentrated chlorine gas streams resulted in an
      irreversible loss of activity which is related to the total concentration of
      chlorine that had been hydroprocessed. Hydrodechlorination proceeds via
      irreversible stepwise and/or concerted routes as is illustrated for the treatment
      of 2,3,5-TCP. Increasing the nickel content was found to raise the overall
      detoxification efficiency while the use of a zeolite support introduced spatial
      constraints which had a strong bearing on process selectivity.

PMID- 10334824
TI  - TWODEE: the Health and Safety Laboratory's shallow layer model for heavy gas
      dispersion. Part 3: experimental validation (Thorney Island).
AB  - Part 1 of this three-part paper described the mathematical and physical basis of
      TWODEE, the Health and Safety Laboratory's shallow layer model for heavy gas
      dispersion. In part 2, the numerical solution method used to simulate the TWODEE
      mathematical model was developed; the flux correction scheme of Zalesak [S.T.
      Zalesak, Fully multidimensional flux-corrected transport algorithms for fluids,
      Journal of Computational Physics, 31 (1979) 335-362.] was used in TWODEE. This
      paper compares results of the TWODEE model to the experimental results taken at
      Thorney Island [J. McQuaid, B. Roebuck, The dispersion of heavier-than-air gas
      from a fenced enclosure. Final report to the U.S. Coast Guard on contract with
      the Health and Safety Executive. Technical Report RPG 1185, Safety Engineering
      Laboratory, Research and Laboratory Services Division, Broad Lane, Sheffield S3
      7HQ, UK, 1985.]. There is no evidence to suggest that TWODEE predictions could be
      improved by changing any of the entrainment parameters from generally accepted
      values [R.K.S. Hankin, Heavy gas dispersion over complex terrain, PhD thesis,
      Cambridge University, 1997.]. The TWODEE model was broadly insensitive to the
      exact values of the entrainment parameters.

PMID- 10334826
TI  - Surrogate burns in deactivation furnace system.
AB  - The deactivation furnace system at the Deseret Chemical Depot in Utah is designed
      for processing explosive components from munitions containing nerve and mustard
      agents. The system was installed during the period of 1989 through 1993. The Utah
      Division of Solid and Hazardous Waste (UDSHW) required that trial burns be
      conducted using surrogate chemicals prior to introducing chemical agents into the
      system. The selected surrogate chemicals were monochlorobenzene and
      hexachloroethane based on the criteria established by the UDSHW. Three surrogate
      runs were conducted in October, 1995. The gaseous emissions and liquid and solid
      effluents were sampled and analyzed using approved EPA methods. The trial burns
      demonstrated the desirable destruction and removal efficiency for the selected
      surrogate chemicals. The pollution abatement system demonstrated the desired
      scrubbing efficiency for acid gases generated during incineration of chlorinated
      surrogate chemicals. The particulate removal efficiency during the trial burns
      was also considerably higher than required by regulations. After comprehensive
      review of the performance of the deactivation furnace system during the surrogate
      trial burns, UDSHW approved introduction of GB nerve agent into the system to
      prepare it for agent trial burns.

PMID- 10334827
TI  - Magnitude of effect of reaction parameters on 2-chlorophenol decomposition by
      ultrasonic process.
AB  - In the present work, decomposition of o-chlorophenol (2-cp) was carried out using
      an ultrasonic process. The extent of 2-cp decomposition depends on several
      parameters such as ultrasound wave energy (ultrasonic amplitude), addition of
      hydrogen peroxide (H2O2), pH value (H+ concentration), ionic strength, and
      initial concentration of 2-cp. The experimental results showed that the
      decomposition of 2-cp was affected by the various reaction conditions. The
      profiles of 2-cp decomposition fitted well with the first-order kinetic equation.
      A linear relationship was obtained between the rate constants of 2-cp
      decomposition and the varying reaction parameters. The magnitude of effect of
      reaction parameters such as ultrasonic amplitude, H+ concentration, ionic
      strength, H2O2 and 2-cp initial concentration on 2-cp decomposition were 0.60,
      0.48, 0.19, 0.09 and -0.06, respectively.

PMID- 10334829
TI  - A new Hazardous Waste Index.
AB  - Hazardous wastes, once generated, have to be stored, transported, treated,
      disposed off, recycled, depending upon the situation. With laws being tightened,
      all of the above operations have to be done safely without causing harm to people
      and environment. Before any operation is carried out, it is vital to know the
      hazardous characteristics of the waste to be handled. Because waste, generally,
      is a mixture instead of a pure compound, its hazardous characteristics are
      difficult to determine and generalize because each waste is specific. A new
      Hazardous Waste Index (HWI) is proposed in this paper. The index measures hazards
      related to flammability, reactivity, toxicity and corrosivity as well as the pH
      value for a hazardous waste. Two examples are given for its use. The index can be
      modified to include radioactive or mixed waste.

PMID- 10334831
TI  - Heat transfer in large-scale heavy-gas dispersion.
AB  - Heavy-gas dispersion of practical interest is usually cold gas dispersion with
      the enthalpy deficit as the main cause of the density effect. New analysis of
      existing field experiment data suggests that heat transfer from the ground
      sometimes reduces this thermally induced density effect considerably. The limited
      heat capacity of the ground implies that heat transfer to a gas plume must
      disappear eventually, and our interpretation of Desert Tortoise measurements
      indicates that the surface heat flux decreased by 38% during a 3-min long release
      period.

PMID- 10334832
TI  - Wet air oxidation of oily wastes generated aboard ships: kinetic modeling.
AB  - Ships are floating industrial plants which generate great amounts of toxic and
      hazardous wastes. Nevertheless, a feasible model for the management of such
      wastes has not been developed yet. This work studies the feasibility of treating
      those wastes aboard the ship by means of aqueous oxidation at high pressures and
      temperatures. Wet air oxidation has proved to be a very efficient technology for
      the treatment of those residual currents, resulting in destruction efficiencies
      of greater than 90% of initial COD and 99.9% of oil/greases content. A kinetic
      model for the oxidation process, based on a series-parallel reaction pathway, is
      proposed and is shown to fit the experimental results.

PMID- 10334830
TI  - Dispersion and thermodynamics of clouds generated from spills of SO3 and oleum.
AB  - A new model describing the dispersion behaviour and the processes that occur in a
      cloud generated from accidental spills of SO3 and oleum has been developed. Such
      a cloud may initially behave as a dense gas, with several chemical and physical
      processes occurring in it. There is not usually enough atmospheric moisture in
      the air passing immediately above the pool for complete and rapid reaction to
      sulphuric acid mist. Therefore in the early stages, SO3 vapour, H2SO4 vapour and
      H2SO4 aerosol will be present. At some distance downwind, transition to passive
      dispersion behaviour will take place and only sulphuric acid aerosol will be
      present in the cloud. The dense gas model is based on a box type dispersion
      model. The passive behaviour is described by a Gaussian model that takes into
      account deposition of the aerosol particles. The model results suggest a number
      of lines of experimental investigation that are required to provide data for
      model validation.

PMID- 10334834
TI  - Factors influencing suspended solids concentrations in activated sludge settling
      tanks.
AB  - A significant fraction of the total mass of sludge in an activated sludge process
      may be in the settling tanks if the sludge has a high sludge volume index (SVI)
      or when a hydraulic overload occurs during a rainstorm. Under those conditions,
      an accurate estimate of the amount of sludge in the settling tanks is needed in
      order to calculate the mean cell residence time or to determine the capacity of
      the settling tanks to store sludge. Determination of the amount of sludge in the
      settling tanks requires estimation of the average concentration of suspended
      solids in the layer of sludge (XSB) in the bottom of the settling tanks. A widely
      used reference recommends averaging the concentrations of suspended solids in the
      mixed liquor (X) and in the underflow (Xu) from the settling tanks (XSB=0.
      5{X+Xu}). This method does not take into consideration other pertinent
      information available to an operator. This is a report of a field study which had
      the objective of developing a more accurate method for estimation of the XSB in
      the bottom of the settling tanks. By correlation analysis, it was found that only
      44% of the variation in the measured XSB is related to sum of X and Xu. XSB is
      also influenced by the SVI, the zone settling velocity at X and the overflow and
      underflow rates of the settling tanks. The method of averaging X and Xu tends to
      overestimate the XSB. A new empirical estimation technique for XSB was developed.
      The estimation technique uses dimensionless ratios; i.e., the ratio of XSB to Xu,
      the ratio of the overflow rate to the sum of the underflow rate and the initial
      settling velocity of the mixed liquor and sludge compaction expressed as a ratio
      (dimensionless SVI). The empirical model is compared with the method of averaging
      X and Xu for the entire range of sludge depths in the settling tanks and for SVI
      values between 100 and 300 ml/g. Since the empirical model uses dimensionless
      ratios, the regression parameters are also dimensionless and the model can be
      readily adopted for other activated sludge processes. A simplified version of the
      empirical model provides an estimation of XSB as a function of X, Xu and SVf and
      can be used by an operator when flow conditions are normal.

PMID- 10334833
TI  - Determination of the effect of exposure to gasoline components on a high density
      polyethylene geomembrane using the comprehensive test system.
AB  - The comprehensive testing system (CTS) for geomembranes was used to test the
      compatibility of high-density polyethylene (HDPE) geomembrane landfill liner
      material with chemicals typically found in motor vehicle fuel. The CTS is a
      testing apparatus specifically designed to test the effects of simultaneously
      applying mechanical load, fluid head, and chemical exposure on the geomembrane. A
      combination of these factors is present on the geomembrane material in service,
      and the CTS provides a laboratory reproduction of actual field conditions. The
      article provides a description of gasoline based upon the desirable qualities of
      gasoline and provides background on testing of rubbers used in gasoline-powered
      engine parts. The test's chemicals were gasoline, motor oil, benzene,
      ethylbenzene, toluene, xylenes, and iso-octane (2,2,4 trimethyl pentane). This
      work found that gasoline had an effect on the geomembrane greater than the effect
      of any of the pure chemicals except ethylbenzene. Benzene, and the other aromatic
      compounds (ethylbenzene, toluene, and xylenes) are typically the primary
      regulatory concerns at fuel contaminated sites. The fact that gasoline had a
      greater effect on the performance of the HDPE geomembrane indicated that
      chemicals are present in gasoline which can decrease the performance of the
      containment structures used to hold gasoline, while not having a significant
      health risk. The clear implication is that risk assessments conducted on
      facilities must not only include the health risks of chemicals placed in a
      facility, but must also consider the effect of the chemical on a containment
      structure. The fact that low-health-risk chemicals may have a great impact on the
      effectiveness of containment structures leads to a possible synergistic mechanism
      where the low-health-risk chemicals enable a pathway for greater-health-risk
      chemicals to enter the environment.

PMID- 10334835
TI  - Immobilized sample amplification for quantitative determination of retroviruses.
AB  - Immobilized sample amplification (ISA) is a novel method for amplification,
      detection, monitoring, and quantitative determination of nucleic acids from a
      minute amount of sample. We present here a novel quantitative ISA assay for
      retroviruses using a replication-defective recombinant retrovirus as a model
      retrovirus. Samples, as small as 5 to 10 microl or as large as 1 ml or more in
      volume, are readily immobilized on a nylon or polyester matrix. Retroviral RNA is
      directly amplified following the rehydration of the immobilized samples, thus
      eliminating the needs for retroviral RNA extraction. An ISA assay of a 10-microl
      viral sample generates results equal to or better than that of RT-PCR on
      equivalent amount RNA isolated from larger sample volumes. Recovery of RNA from
      small volumes, such as 10 microl, is almost impossible, whereas ISA assay detects
      retroviruses from as small as 1 to 5 microl of viral samples containing 10(4)
      cfu/ml determined by colony-forming assay. Extraction of RNA from a small amount
      of infectious viral samples not only is a difficult, biohazardous procedure, but
      also introduces random errors which contribute to variability in viral
      quantitation. Since the ISA method eliminates the isolation/extraction of the
      nucleic acids, it significantly shortens the handling time for the biohazardous
      materials and simplifies the procedure for analyzing small quantities of
      biological samples. This method detects less than 10 infectious retroviral
      particles as determined by both colony-forming assay and electron microscope
      studies. The format and protocol of this quantitative ISA assay can be easily
      automated to fit into numerous platforms, thus making it attractive for
      laboratory automation.

PMID- 10334836
TI  - A microplate assay for DNA damage determination (fast micromethod).
AB  - A rapid and convenient procedure for DNA damage determination in cell suspensions
      and solid tissues on single microplates was developed. The procedure is based on
      the ability of commercially available fluorochromes to interact preferentially
      with dsDNA in the presence of ssDNA, RNA, and proteins at high pH (>12.0), thus
      allowing direct measurements of DNA denaturation without sample handling or
      stepwise DNA separations. The method includes a simple and rapid 40-min sample
      lysis in the presence of EDTA, SDS, and high urea concentration at pH 10,
      followed by time-dependent DNA denaturation at pH 12.4 after NaOH addition. The
      time course and the extent of DNA denaturation is followed in a microplate
      fluorescence reader at room temperature for less than 1 h. The method requires
      only 30 ng DNA per single well and could conveniently be used whenever fast
      analysis of DNA integrity in small samples has to be done, e.g., in patients'
      lymphocytes after irradiation or chemotherapy (about 3000 cells per sample), in
      solid tissues or biopsies after homogenization (about 25 microg tissue per well),
      or in environmental samples for genotoxicity assessment.

PMID- 10334837
TI  - Kinetic analysis of analyte binding by optical biosensors: hydrodynamic
      penetration of the analyte flow into the polymer matrix reduces the influence of
      mass transport.
AB  - I examined the penetration of the hydrodynamic flow into a polymer matrix
      immobilized by grafting to a surface, such as used in optical biosensors designed
      to measure binding reactions in real time. I show that the flow penetrates with
      an appreciable velocity into a region located at the tip of such a polymer brush,
      corresponding to about 10 to 15% of the total mass of the grafted polymer.
      Furthermore, under the conditions recommended for kinetic measurements, the
      concentrations of both polymer and immobilized ligands are low in these regions
      of the matrix, where crowding effects are negligible. Under such conditions, the
      hydrodynamic flow penetrating into the dextran matrix flow will bring the
      analytes close to their targets, thus considerably reducing transport problems.

PMID- 10334838
TI  - A standardized protocol for assessing regulators of pigmentation.
AB  - Varied effects of chemical or biological compounds on mammalian pigmentation have
      been reported by many groups, but to date, no standardized method has established
      necessary and/or optimal parameters for testing such agents. A standardized
      method has been developed to screen compounds with potential effects on
      pigmentation. The protocol comprises basic parameters to analyze melanogenic
      effects and allows for further characterization of candidate compounds, providing
      important insights into their mechanism of action. In this protocol (termed
      STOPR, for standardized testing of pigmentation regulators), compounds are
      initially screened using purified tyrosinase and are then tested on melanocytes
      in culture. After treatment of melanocytes with potentially bioactive compounds,
      cell proliferation and viability, total melanin accumulated, and melanogenic
      potential are measured. This protocol is an important first step in
      characterizing chemical regulation of effects on melanogenesis. When bioactive
      candidate compounds are identified, testing may proceed for pharmacological or
      otherwise commercial applications in coculture and/or organ culture models
      followed by in vivo testing. As an application of this method, results for
      compounds known to stimulate and/or inhibit melanogenesis (including arbutin,
      hydroquinone, kojic acid, melanocyte-stimulating hormone, and thymidine dimers)
      as well as some commercial skin whiteners are reported.

PMID- 10334839
TI  - Characterization of metabolites in intact Streptomyces citricolor culture
      supernatants using high-resolution nuclear magnetic resonance and directly
      coupled high-pressure liquid chromatography-nuclear magnetic resonance
      spectroscopy.
AB  - A novel NMR spectroscopic approach to the direct biochemical characterization of
      bacterial culture broths is presented. A variety of one- and two-dimensional 1H
      NMR spectroscopic methods were used to characterize low-molecular-weight organic
      components of broth supernatants from cultures of Streptomyces citricolor. By
      applying 1H NMR spectroscopy to analyze whole, untreated culture supernatants, it
      was possible to identify and monitor simultaneously a range of media substrates
      and excreted metabolites. Identified metabolites include 2-phenylethylamine,
      trehalose, succinate, acetate, uridine, and aristeromycin, a secondary metabolite
      with antibiotic properties. Directly coupled HPLC-NMR spectroscopy was also
      applied to the analysis of broth supernatants for the first time, to aid spectral
      assignments, especially where signals were extensively overlapped in the 1H NMR
      spectra of the whole broth mixtures. Two-dimensional NMR methods such as 1H-1H
      correlation spectroscopy, 1H-13C heteronuclear single quantum correlation, and 1H
      13C heteronuclear multiple bond correlation aided the structure elucidation and
      peak assignments of individual components in the mixtures by providing
      information on 1H-1H coupling networks and 13C chemical shifts. This work shows
      that high-resolution NMR spectroscopic methods provide a rapid and efficient
      means of investigating microbial metabolism directly without invasive or
      destructive sample pretreatment.

PMID- 10334840
TI  - Investigations of S-transnitrosylation reactions between low- and high-molecular
      weight S-nitroso compounds and their thiols by high-performance liquid
      chromatography and gas chromatography-mass spectrometry.
AB  - S-Transnitrosylation reactions are supposed to be the basic principle by which
      nitric oxide-related biological activities are regulated in vivo. Mechanisms of S
      transnitrosylation reactions are poorly understood and equilibria constants for
      physiological S-nitroso compounds and thiols are rare. In the present study we
      investigated S-transnitrosylation reactions of the thiols homocysteine, cysteine,
      glutathione, N-acetylcysteine, N-acetylpenicillamine, and human plasma albumin
      and their corresponding S-nitroso compounds SNhC, SNC, GSNO, SNAC, SNAP, and
      SNALB utilizing high-performance liquid chromatographic and gas chromatographic
      mass spectrometric techniques. These methods allowed to study S
      transnitrosylation reactions in mixtures of several S-nitroso compound/thiol
      pairs, to determine equilibria constants, and to elucidate the mechanism of S
      transnitrosylation reactions. We obtained the following order for the equilibria
      constants in aqueous buffered solution at pH 7.4: SNhC approximately SNAC > GSNO
      approximately SNALB > SNAP > SNC. Our results suggest that the mechanism of S
      transnitrosylation reactions of these S-nitroso compounds and their thiols
      involve heterolytic cleavage of the S&sbond;N bond. Incubation of SNC with human
      red blood cells resulted in a dose-dependent formation of GSNO in the cytosol
      through S-transnitrosylation of intracellular GSH by the SNC transported into the
      cells. This reaction was accompanied with an almost complete disappearance of the
      SNC fraction transported into the cells. This finding is in full agreement with
      the equilibrium constant Keq of 1.9 for the reaction SNC + GSH <--> Cys + GSNO in
      aqueous buffer.

PMID- 10334841
TI  - Chimeric G proteins allow a high-throughput signaling assay of Gi-coupled
      receptors.
AB  - G-protein-coupled receptors are a major target for potential therapeutics; yet, a
      large number of these receptors couple to the Gi pathway, generating signals that
      are difficult to detect. We have combined chimeric G proteins, automated sample
      handling, and simultaneous 96-well fluorometric imaging to develop a high
      throughput assay system for Gi signaling. The chimeric G proteins alter receptor
      coupling so that signaling can occur through Gq and result in mobilization of
      intracellular calcium stores. An automated signaling assay device, the
      fluorometric imaging plate reader (FLIPR), can simultaneously measure this
      response in real time in 96-well microplates, allowing two people to process more
      than 10,000 points per day. We used the chimeric G protein/FLIPR system to
      characterize signaling by the Gi-coupled human opioid receptors. We show that the
      mu, delta, and kappa opioid receptors and the related nociceptin receptor, ORL1,
      each couple to Galphaqi5, Galphaqo5, and Galpha16 (Galphaqi5 and Galphaqo5 refer
      to Galphaq proteins containing the five carboxyl-terminal amino acids from
      Galphai and Galphao, respectively) and that different receptor/G protein
      combinations show different levels of maximal activation. We tested 31 opioid
      ligands for agonist activity at the opioid receptors (124 ligand-receptor
      combinations); all 31 activated at least one receptor type, and several activated
      multiple receptors with differing potencies. This high-throughput assay could be
      useful for dissecting the complex ligand-receptor relationships that are common
      in nature.

PMID- 10334842
TI  - Development of internal controls for probe-based nucleic acid diagnostic assays.
AB  - A method is described for the design, evaluation, and application of internal
      control targets and probes for use in probe-based nucleic acid diagnostic assays
      (i.e., PCR-ELISA). The technique is a modified version of oligonucleotide
      directed mutagenesis in conjunction with PCR amplification to develop a novel
      probe-annealing sequence in a cloned IS1111a gene fragment of Coxiella burnetii.
      The internal control probe-recognition site with its complementary probe was
      identical to the wild-type-specific probe in length, base composition, location,
      and annealing temperature. Neither the internal control nor the wild-type probes
      annealed to the recognition sequence of the other. As both of the amplified
      nucleic acid fragments, internal control and wild type, were identical in length
      and base composition, the amplification conditions for the diagnostic assay were
      not affected. This allowed small copy numbers of the internal control clone to be
      loaded into a diagnostic assay without negatively affecting it. In a single
      reaction we were able to differentiate between an assay reporting a true or false
      negative signal. A negative signal is defined as the absence of detectable
      pathogen genetic material (true) or inhibition/failure of the reaction (false).

PMID- 10334843
TI  - Detection of DBD-carbamoyl amino acids in amino acid sequence and D/L
      configuration determination of peptides with fluorogenic Edman reagent 7-[(N,N
      dimethylamino)sulfonyl]-2,1,3-benzoxadiazol-4-yl isothiocyanate.
AB  - A method for amino acid sequence and D/L configuration identification of peptides
      by using fluorogenic Edman reagent 7-[(N, N-dimethylamino)sulfonyl]-2,1,3
      benzoxadiazol-4-yl isothiocyanate (DBD-NCS) has been developed. This method was
      based on the Edman degradation principle with some modifications. A peptide or
      protein was coupled with DBD-NCS under basic conditions and then cyclized/cleaved
      to produce DBD-thiazolinone (TZ) derivative by BF3, a Lewis acid, which could
      significantly suppress the amino acid racemization. The liberated DBD-TZ amino
      acid was hydrolyzed to DBD-thiocarbamoyl (TC) amino acid under a weakly acidic
      condition and then oxidized by NaNO2/H+ to DBD-carbamoyl (CA) amino acid which
      was a stable and had a strong fluorescence intensity. The individual DBD-CA amino
      acids were separated on a reversed-phase high-performance liquid chromatography
      (RP-HPLC) for amino acid sequencing and their enantiomers were resolved on a
      chiral stationary-phase HPLC for identifying their D/L configurations.
      Combination of the two HPLC systems, the amino acid sequence and D/L
      configuration of peptides could be determined. This method will be useful for
      searching D-amino-acid-containing peptides in animals.

PMID- 10334845
TI  - An attachment for nondestructive, fast quenching of samples in rapid-mixing
      experiments.
AB  - The present paper describes a quenching-and-washing chamber (QWC) to be used with
      a rapid-mixing apparatus (RMA) for the study of processes in the millisecond time
      scale. The QWC enables fast, nondestructive quenching by cooling and dilution of
      reactants in particulate systems that can be trapped on a filter. The reaction
      mixture (e.g., at 25 degrees C) is injected from the RMA into the QWC where it is
      immediately mixed with a stream of ice-cold solution flowing at a rate of 15-40
      ml s-1. Quenching requires that the process studied is slowed considerably by
      cooling to 0-2 degrees C and/or by removal of reactants by dilution. The
      equipment was characterized through a study of the tight binding (occlusion) of
      86Rb+ to purified, membrane-bound Na+/K+-ATPase. Millipore filters of 0.22-0.80
      microm pore size trapped close to 100% of the enzyme protein. Enzyme with
      occluded 86Rb+ was formed in the RMA under conditions where the rate constant for
      release of Rb+ at 25 degrees C is up to 25 s-1 and then injected into the QWC.
      The high off-rate constant is due to the presence of 2.5 mM ATP, which
      accelerates release of Rb+. The recovery of occluded 86Rb+ on the filter was at
      least 90%, indicating that both cooling of the reactants and dilution of ATP are
      fast enough to stop the reaction. The quenching time was 3-4 ms.

PMID- 10334844
TI  - A continuous spectrophotometric assay for the hepatitis C virus serine protease.
AB  - The hepatitis C virus (HCV) encodes a chymotrypsin-like serine protease
      responsible for the processing of HCV nonstructural proteins and which is a
      promising target for antiviral intervention. Its relatively low catalytic
      efficiency has made standard approaches to continuous assay development only
      modestly successful. In this report, four continuous spectrophotometric
      substrates suitable for both high-throughput screening and detailed kinetic
      analysis are described. One of these substrates, Ac-DTEDVVP(Nva)-O-4
      phenylazophenyl ester, is hydrolyzed by HCV protease with a second-order rate
      constant (kcat/Km) of 80,000 +/- 10,000 M-1 s-1. Together with its negligible
      rate of nonenzymatic hydrolysis under assay conditions (0.01 h-1), analysis of as
      little as 2 nM protease can be completed in under 10 min.

PMID- 10334846
TI  - Molecular weights of CTLA-4 and CD80 by sedimentation equilibrium
      ultracentrifugation.
AB  - Proteins that are heavily glycosylated pose unique challenges in their
      biophysical characterization. In particular, molecular weight analysis is
      exacerbated by such glycosylation. For example, glyoproteins are refractory to
      careful mass spectrum analysis and often give anomalous retention times using
      size exclusion chromatography. We combine several approaches to characterize the
      molecular weights of the extracellular domains of the glycoproteins CTLA-4 and
      CD80 using carbohydrate analysis, electrospray mass spectrometry, size exclusion
      chromatography, and analytical ultracentrifugation. In addition, we have applied
      a method described previously, using sedimentation equilibrium analysis to
      calculate the contribution of carbohydrates to the molecular masses of CTLA-4 and
      CD80. It is important to understand the oligomeric states of these protein
      domains because the interaction between these lymphocyte receptors plays an
      important costimulatory role in the Th-cell antigenic response. It is thought
      that extracellular interactions between these receptors may regulate both the
      self-association of these receptor proteins and the oligomeric state of the
      heterocomplex; this regulation has important consequences for potentiating the
      signaling mechanism between Th-cells and antigen-presenting cells.

PMID- 10334847
TI  - Determination of norepinephrine in microdialysis samples by microbore column
      liquid chromatography with fluorescence detection following derivatization with
      benzylamine.
AB  - A microbore column liquid chromatographic method is described for the
      determination of norepinephrine (NE) in microdialysis samples from rat brain. The
      method is based on precolumn derivatization of NE with benzylamine in the
      presence of potassium hexacyanoferrate(III) resulting in a highly fluorescent and
      stable benzoxazole derivative. Typically, a 10-microl sample was mixed with 10
      microl derivatization reagent containing 0.45 M Caps buffer (pH 12.0), 0.2 M
      benzylamine, 10 mM potassium hexacyanoferrate(III), and N,N-dimethylformamide
      (1:1:1:15, v/v). The derivatization was carried out at 50 degrees C for 20 min.
      Under these conditions only NE and epinephrine produced high fluorescence yields
      at excitation and emission wavelengths of 345 and 480 nm, respectively, while
      fluorescence of other catechols and 5-hydroxyindoles was quenched by 10-100
      times. The NE derivative was separated on a reversed-phase column (100 x 1.0 mm
      i.d., packed with C18 silica, 5 microm) within 10 min with no late eluting peaks.
      The mobile phase consisted of 40 mM Britton-Robinson buffer (pH 7.5) containing 1
      mM didodecyldimethylammonium bromide and acetonitrile (34%, v/v), the flow rate
      was 40 microl/min. The limit of detection (signal-to-noise ratio of 3) for NE was
      90 amol in 10 microl sample injected. Microdialysis samples were collected in 5
      min intervals from the probes implanted in the hippocampus, frontal cortex, or
      hypothalamus of awake rats. The basal extracellular NE levels in the respective
      areas were 4.7 +/- 0.9, 1.8 +/- 0.3, and 0.8 +/- 0.2 fmol/10 microl (mean +/- SE,
      n = 7). Perfusion with a Ringer solution containing 100 mM K+ increased
      hippocampal NE levels by 700%, while NE uptake inhibitors maprotiline and
      amitriptyline administered orally or subcutaneously increased extracellular NE in
      the frontal cortex by about 300%. On the other hand, reserpine (5 mg/kg) reduced
      cortical NE levels by 40% 3 h after the administration. This new fluorescence
      derivatization method provides better selectivity, sensitivity, and speed for NE
      determination than the electrochemical detection since no late-eluting compounds
      such as dopamine, serotonin, and their metabolites are detectable in the
      chromatograms of the microdialysis samples.

PMID- 10334848
TI  - Development of an assay for phospholipase C using column-reconstituted, extruded
      phospholipid vesicles.
AB  - The reconstitution of heterotrimeric G proteins into phospholipid vesicles has
      been widely used for the measurement of PLC-beta activity in vitro. We have
      developed an improved and sensitive method for the assay of PLC-beta activity.
      This approach involves reconstitution of purified betagamma dimers into extruded
      phospholipid vesicles containing phosphatidylinositol 4, 5-bisphosphate and using
      a gel-filtration technique to separate the reconstituted vesicles from
      monodispersed betagamma dimers and the detergent used to solubilize G proteins.
      The method provides physical information about the partitioning of betagamma
      dimers into phospholipid vesicles and was used to examine the effect of different
      prenyl groups on the gamma subunits in the activation of PLC-beta. The
      beta1gamma1 dimer (containing the farnesyl group) and the beta1gamma2 dimer
      (containing the geranylgeranyl group) were purified from baculovirus-infected Sf9
      insect cells and were found to partition equally into phospholipid vesicles. The
      beta1gamma2 dimer is more potent and effective in stimulating PLC-beta activity
      than the beta1gamma1 dimer. The EC50 values of betagamma dimers for the
      activation of PLC-beta determined with this method were lower than those
      determined by previous methodology, showing that betagamma subunits have a
      subnanomolar affinity for PLC-beta.

PMID- 10334849
TI  - Core-branching pattern and sequence analysis of mannitol-terminating
      oligosaccharides by neoglycolipid technology.
AB  - The occurrence of mannitol-terminating oligosaccharides (2-substituted or 2,6
      disubstituted) among the O-glycans released by alkaline borohydride treatment
      from glycoproteins of the nervous system has prompted the development of a
      microscale method to analyze the core-branching pattern and sequence by the
      neoglycolipid (NGL) technology, analogous to a method previously described for
      GalNAcol-terminating oligosaccharides (M. S. Stoll, E. F. Hounsell, A. M. Lawson,
      W. Chai, and T. Feizi, Eur. J. Biochem. 189, 499-507, 1990). The approach
      involves the selective cleavage at the core mannitol by mild periodate treatment
      and analysis of the reaction products as NGLs by in situ TLC/liquid secondary ion
      mass spectrometry. Oxidation conditions have been optimized using as reference
      compounds 2-, 3-, 4-, or 6-monosubstituted mannobi-itols, 3,6-disubstituted
      mannitol-terminating pentasaccharides, and 2-mono- and 2,6-disubstituted mannitol
      terminating neutral and sialylated oligosaccharides isolated from brain
      glycopeptides. When a 2:1 molar ratio of periodate to alditol is used, the core
      mannitol is cleaved at the C3-C4 threo-diol bond and in the absence of a threo
      diol cleavage occurs to a lesser extent at erythro-diols. Saccharide ring diols
      are not cleaved under these conditions, and it is also shown that the side chain
      of sialic acid on the oligosaccharide is largely unaffected. Substituents at 2-
      and 6-positions of the core mannitol can be identified, and the method is
      applicable to neutral and sialylated oligosaccharide alditols. Typically, the
      starting material is 5 nmol of oligosaccharide and 0.5-1 nmol of derivatives is
      applied for analysis. By this strategy, the core-branching pattern and position
      of sialic acid of two branched monosialylated mannitol-terminating
      oligosaccharide isomers have been determined.

PMID- 10334850
TI  - A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and
      hydroxynonenal-modified proteins by epitope-bound casein matrix method.
AB  - A simple and rapid enzyme-linked immunosorbent assay (ELISA) method for
      quantitation of acrolein and 4-hydroxy-2-nonenal (HNE)-modified proteins was
      developed. Microtiter plate wells were precoated and blocked simultaneously with
      epitope-bound bovine caseins as matrix proteins, and aldehyde-modified proteins
      were quantitated by a competition assay with a monoclonal antibody specific for
      acrolein-modified lysine or HNE-modified histidine epitopes. Minimal reaction
      times required for the coating/blocking; first monoclonal antibody and the
      peroxidase-conjugated second antibody binding steps were 3, 3, and 7 min,
      respectively, the former two steps being found to be or akin to diffusion-rate
      limiting reactions. The convenient ELISA should find an application for analyses
      of the intricate processes involved in oxidative stress and carcinogenic insult.
      The epitope-attachment methodology may also be advantageous for the quantitation
      of various other biologically important haptenic molecules.

PMID- 10334851
TI  - Fluorometric determination of aminopolycarboxylates using Fluo-3.

PMID- 10334852
TI  - Direct dye terminator sequencing of lambda DNA and phage suspensions.

PMID- 10334853
TI  - GFPcre fusion vectors with enhanced expression.

PMID- 10334854
TI  - A simple method to measure the absolute heat capacity of proteins.

PMID- 10334855
TI  - A low-volume, short-path length dynamic light scattering sample cell for highly
      turbid suspensions.

PMID- 10334856
TI  - Stimulation of aggrecan synthesis in cartilage explants by cyclic loading is
      localized to regions of high interstitial fluid flow.
AB  - Chondrogenesis in cartilage development and repair and cartilage degeneration in
      arthritis can be regulated by mechanical-load-induced physical factors such as
      tissue deformation, interstitial fluid flow and pressure, and electrical fields
      or streaming potentials. Previous animal and tissue explant studies have shown
      that time-varying dynamic tissue loading can increase the synthesis and
      deposition of matrix molecules in an amplitude-, frequency-, and spatially
      dependent manner. To provide information on the cell-level physical factors which
      may stimulate chondrocytes to increase production and export of aggrecan, the
      main proteoglycan component of the cartilage matrix, we characterized local
      changes in aggrecan synthesis within cyclically loaded tissue explant disks and
      compared those changes to values of predicted local physical factors. Aggrecan
      synthesis following a 23-h compression/radiolabel protocol was measured with a
      spatial resolution of approximately 0.1 mm across the 1.5-mm radius of explanted
      disks using a quantitative autoradiography method. A uniform stimulation of
      aggrecan synthesis was observed at an intermediate frequency of 0.01 Hz, while,
      at a higher frequency of 0.1 Hz, stimulation was only seen at peripheral radial
      positions. Profiles of radial solid matrix deformation and interstitial fluid
      pressure and velocity predicted to be occurring across the radius of the disk
      during sinusoidal loading were estimated using a composite poroelastic model.
      Tissue regions experiencing high interstitial fluid velocities corresponded to
      those displaying increased aggrecan synthesis. These results reinforce the role
      of load-induced flow of interstitial fluid in the stimulation of aggrecan
      production during dynamic loading of cartilage.

PMID- 10334857
TI  - Purification and characterization of a histidine-rich glycoprotein that binds
      cadmium from the blood plasma of the bivalve Mytilus edulis.
AB  - An unusual cadmium-binding protein was purified for the first time from the blood
      plasma of the blue mussel, Mytilus edulis. The protein was isolated and purified
      to homogeneity using ammonium sulfate precipitation and immobilized metal-ion
      affinity chromatography. It was identified as a glycoprotein with an apparent Mr
      of 63 kDa and a pI of 4.8. Electrophoresis of the protein under denaturing
      conditions on polyacrylamide gels produced four bands of 35, 37, 39 and 29 kDa.
      Isoelectric focusing under denaturing conditions produced 12 closely spaced bands
      with pIs of 4.2 to 5.8, revealing charge microheterogeneity. Molecular proterties
      (Mr and pI), carbohydrate content (11.6%) and composition, high histidine content
      (13.7%), as well cadmium-binding property of the protein (approximate log K >/=
      5.4) indicated that it is similar to the mammalian histidine-rich glycoprotein,
      hitherto unreported in aquatic invertebrates. The cadmium-binding ability of the
      protein was retained even after heat denaturation and polyacrylamide gel
      electrophoresis.

PMID- 10334858
TI  - Glyoxalase II in Saccharomyces cerevisiae: in situ kinetics using the 5,5'
      dithiobis(2-nitrobenzoic acid) assay.
AB  - The determination of glyoxalase II (S-(2-hydroxyacyl)glutathione hydrolase, EC
      3.1.2.6) activity is usually accomplished by monitoring the decrease of
      absorbance at 240 nm due to the hydrolysis of S-d-lactoylglutathione. However, it
      was not possible, using this assay, to detect any enzyme activity in situ, in
      Saccharomyces cerevisiae permeabilized cells. Glyoxalase II activity was then
      determined by following the formation of GSH at 412 nm using 5,5'-dithiobis(2
      nitrobenzoic acid). Using this method we characterized the kinetics of glyoxalase
      II in situ using S-d-lactoylglutathione as substrate and compared the results
      with those obtained for cell-free extracts. The specific activity was found to be
      (4.08 +/- 0.12) x 10(-2) micromol min-1 mg-1 in permeabilized cells and (3.90 +/-
      0.04) x 10(-2) micromol min1 mg-1 in cell-free extracts. Kinetic parameters were
      Km 0.36 +/- 0.09 mM and V (7.65 +/- 0.59) x 10(-4) mM min-1 for permeabilized
      cells and Km 0.15 +/- 0.10 mM and V (7.23 +/- 1.04) x 10(-4) mM min-1 for cell
      free extracts. d-Lactate concentration was also determined and increased in a
      linear way with permeabilized cell concentration. gamma-Glutamyl transferase (EC
      2.3.2.2), which also accepts S-d-lactoylglutathione as substrate and hence could
      interfere with glyoxalase II assays, was found to be absent in Saccharomyces
      cerevisiae permeabilized cells.

PMID- 10334859
TI  - Binding interactions and conformational changes induced by sulfonated aluminum
      phthalocyanines in human serum albumin.
AB  - Phthalocyanines (Pc), which are extensively studied as tumor localizing
      photosensitizers for photodynamic therapy, are transported by the blood
      circulatory system to target tissues. Binding interactions between human serum
      albumin and differently sulfonated aluminum phthalocyanines (AlPcSn; n = 1-4)
      were studied using optical and ESR spectroscopy. AlPcSn (n = 1-3) occupy one
      strong binding site and eight weaker sites. The high affinity binding site
      interactions differ with respect to the degree of sulfonation and isomeric
      composition of the Pc. Phthalocyanines without SO-3 groups on adjacent iso-indole
      rings exhibit a high affinity binding site constant of K approximately 3-4 x
      10(7) M-1, while Pc with two or three adjacent SO-3 groups show binding for this
      high affinity site that is no longer independent, but cooperative (alpha = 2),
      with K approximately 2-6 x 10(6) M-1. Binding isotherms for AlPcS4 and its close
      analog, tempoyl spin-labeled SL-AlPcS3, do not approach saturation at high ligand
      concentrations. Competition analyses between AlPcSn and spin-labeled fatty acids
      (5- and 16-doxyl stearate isomers) reveal that all compounds participate in
      cooperative (allosteric) interactions with the high affinity binding site of 16
      DS, while extruding 5-DS isomer from certain sites and increasing the binding
      affinity for the remaining. Protein conformational dynamics was studied by ESR
      spectroscopy using covalent (alkylation of Cys34 residue) and noncovalent spin
      labeling (employing SL-AlPcS3). Phthalocyanines perturb conformational dynamics
      parameters (tauc and S) depending on the degree of sulfonation and isomeric
      composition corresponding to the type of sites, i.e., independent or cooperative,
      occupied on the HSA molecule.

PMID- 10334860
TI  - Electrostatically mediated interactions between cationic lipid-DNA particles and
      an anionic surface.
AB  - In an effort to model the interaction of lipid-based DNA delivery systems with
      anionic surfaces, such as a cell membrane, we have utilized microelectrophoresis
      to characterize how electrokinetic measurements can provide information on
      surface charge and binding characteristics. We have established that cationic
      lipids, specifically N-N-dioleoyl-N,N-dimethylammonium chloride (DODAC),
      incorporated into liposomes prepared with 1, 2-dioleoyl-i-glycero-3
      phosphoethanolamine (DOPE) or 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) at
      50 mol%, change the inherent electrophoretic mobility of anionic latex
      polystyrene beads. Self-assembling lipid-DNA particles (LDPs), prepared at
      various cationic lipid to negative DNA phosphate charge ratios, effected no
      changes in bead mobility when the LDP charge ratio (+/-) was equal to or less
      than 1. Increasing the LDP concentration in a solution of 0.1% (w/v) anionic
      beads resulted in a charge reversal effect when a net charge of LDP to total bead
      charge ratio (+/-) of 1:1 was observed. LDP formulations, utilizing either DOPE
      or DOPC, showed similar titration profiles with a charge reversal observed at a
      1:1 net LDP to bead charge ratio (+/-). It was confirmed through centrifugation
      studies that the DNA in the LDP was associated with the anionic latex beads
      through electrostatic interactions. LDP binding, rather than the binding of
      dissociated cationic lipids, resulted in the observed electrophoretic mobility
      changes of the anionic latex beads.

PMID- 10334861
TI  - Purification and characterization of thermostable aspartase from Bacillus sp.
      YM55-1.
AB  - A thermostable aspartase was purified from a thermophile Bacillus sp. YM55-1 and
      characterized in terms of activity and stability. The enzyme was isolated by a 5
      min heat treatment at 75 degrees C in the presence of 11% (w/v) ammonium sulfate
      and 100 mM aspartate, followed by Q-Sepharose anion-exchange and AF-Red Toyopearl
      chromatographies. The native molecular weight of aspartase determined by gel
      filtration was about 200,000, and this enzyme was composed of four identical
      monomers with molecular weights of 51,000 determined by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis. Unlike Escherichia coli aspartase, the enzyme
      was not activated by the presence of magnesium ion at alkaline pH. At the optimum
      pH, the Km and Vmax were 28.5 mM and 700 units/mg at 30 degrees C and 32.0 mM and
      2200 units/mg at 55 degrees C, respectively. The specific activity was four and
      three times higher than those of E. coli and Pseudomonas fluorescens enzymes at
      30 degrees C, respectively. Eighty percent of the activity was retained after a
      60-min incubation at 55 degrees C, and the enzyme was also resistant to chemical
      denaturants; 80% of the initial specific activity was detected in assay mixtures
      containing 1.0 M guanidine hydrochloride. The purified enzyme shared a high
      sequence homology in the N-terminal region with aspartases from other organisms.

PMID- 10334862
TI  - Overlapping between fluorescence modifications and activation of prostate
      transglutaminase induced by sodium dodecyl sulfate.
AB  - The transglutaminase from rat coagulating gland secretion has been proposed as a
      new member of the transglutaminase family. Its basal activity is about 11-fold
      lower than those of other transglutaminases (e.g., the cytosolic tissue
      transglutaminase), but reaches levels comparable to those of other
      transglutaminases on addition of specific surfactant agents. There is no study
      devoted to understanding the molecular basis of this apparently anomalous
      activation, which is maximal at approximately 1.5 mM sodium dodecyl sulfate. We
      provide evidence that in the presence of this detergent modifications of the
      intrinsic fluorescence as well as energy transfer of the protein fluorescence to
      a micellar probe parallel the activation of the enzyme. As the sodium dodecyl
      sulfate concentration inducing maximal activation equals the critical micellar
      concentration, the biological activity of this transglutaminase appears to be
      modulated by the binding of micellar aggregates. In fact, the enzyme is modified
      by posttranslational modifications consisting of some lipid tails. At least two
      of these tails could act as aggregation nuclei of the enzyme with detergents.
      This behavior is different from that typical of molecular forms purified from
      other sources.

PMID- 10334863
TI  - Peroxyvanadium compounds inhibit glucose-6-phosphatase activity and glucagon
      stimulated hepatic glucose output in the rat in vivo.
AB  - The present investigation was undertaken to characterize the direct inhibitory
      action of the peroxyvanadium compounds oxodiperoxo(1, 10-phenanthroline)
      vanadate(V) (bpV(phen)) and oxodiperoxo(pyridine-2-carboxylate) vanadate(V)
      (bpV(pic)) on pig microsomal glucose-6-phosphatase (G-6-Pase) activity and on
      glucagon stimulated hyperglycemia in vivo. Both bpV(phen) and bpV(pic) were found
      to be potent competitive inhibitors of G-6-Pase with Ki values of 0.96 and 0.42
      microM (intact microsomes) and 0.50 and 0.21 microM (detergent-disrupted
      microsomes). The corresponding values for ortho-vanadate were 20.3 and 20.0
      microM. Administration of bpV(phen) to postprandial rats did not affect the basal
      glucose level although a modest and dose-dependent increase in plasma lactate
      levels was seen. Injection of glucagon raised the plasma glucose level from 5.5
      mM to about 7.5 mM in control animals and this increase could be prevented dose
      dependently by bpV(phen). The inhibition of the glucagon-mediated blood glucose
      increase was accompanied by a dose-dependent increase in plasma lactate levels
      from 2 mM to about 11 mM. In conclusion, the finding that vanadate and bpV
      compounds are potent inhibitors of G-6-Pase suggests that the blood-glucose
      lowering effect of these compounds which is seen in diabetic animals may be
      partly explained by a direct effect on this enzyme rather than, as presently
      thought, being the result of inhibition of phosphoprotein tyrosine phosphatases
      and thereby insulin receptor dephosphorylation.

PMID- 10334864
TI  - Mechanism of free radical-induced hemolysis of human erythrocytes: comparison of
      calculated rate constants for hemolysis with experimental rate constants.
AB  - We previously developed a simple competitive reaction model between lipid
      peroxidation and protein oxidation in erythrocyte membranes that accounts for
      radical-induced hemolysis of human erythrocytes. In this study, we compared the
      rate constants calculated from the hemolysis curves of erythrocytes in the
      presence of radical initiators with those obtained from experiments using
      erythrocyte ghosts treated with radicals. 2,2'-Azobis(amidinopropane)
      dihydrochloride and 2,2'-azobis(2,4-dimethylvaleronitrile) were used as radical
      initiators. Plots of the logarithm of concentration of the radical initiator
      against the logarithm of the rate constant gave straight lines. The slope of the
      lines for the calculated lipid peroxidation was nearly equal with the
      experimental value. Similar results were obtained for oxidation of membrane
      proteins, except for band 3 oxidation. The values for the rate constants
      calculated from hemolysis curves seem to be accurate. The slope of the lines for
      the calculated rate constants for proteins was larger than the experimental value
      for band 3 oxidation, because band 3 oxidation is accompanied by aggregation or
      redistribution of band 3 proteins to form hemolytic holes. These results indicate
      that the competitive reaction model may be useful for analyzing radical-induced
      hemolysis.

PMID- 10334865
TI  - Characterization of the spectroscopic properties of the Cu,Co cluster in a
      prokaryotic superoxide dismutase.
AB  - A Cu,Co derivative of the Cu,ZnSOD from Photobacterium leiognathi, in which
      cobalt has been selectively substituted for zinc, has been prepared and
      spectroscopically investigated. The derivative shows three bands in the visible
      region at 530, 566, and 600 nm when copper is in the oxidized state. Reduction or
      depletion of the copper ion produce a shift of the band absorbing at 600 to 590
      nm because of the detachment from copper of the imidazolate bridging the two
      metals when copper is in the oxidized state. Numerous isotropically shifted 1H
      NMR lines are observed when copper is oxidized, confirming the presence of the
      imidazolate bridge between the two metals. Comparison of the optical and the NMR
      spectra with those observed for the eukaryotic enzyme reveals the occurrence of
      slight but unambiguous differences diagnostic of a different degree of distortion
      of the metal cluster between the prokaryotic and eukaryotic enzymes.

PMID- 10334866
TI  - Purification and characterization of stachyose synthase from lentil (Lens
      culinaris) seeds: galactopinitol and stachyose synthesis.
AB  - Stachyose synthase (STS) (EC 2.4.1.67) was purified 313-fold from mature seeds of
      lentil. The final preparation had a specific activity of 9.09 nkat stachyose
      formed per milligram of protein. The enzyme was a monomeric protein with a
      molecular mass of 88.6 kDa (SDS-PAGE) and an isoelectric point of 4.8
      (chromatofocusing). Western analysis revealed cross-reactivity of polyclonal
      antibodies raised against STS from adzuki bean with the lentil enzyme. The
      purified enzyme catalyzed a range of different galactosyl transfer reactions. In
      addition to the genuine STS reaction (raffinose + galactinol --> stachyose + myo
      inositol), the enzyme catalyzed the reversible galactosyl transfer from
      galactinol to d-pinitol (1d-3-O-methyl-chiro-inositol), yielding galactopinitol A
      (O-alpha-d-galactopyranosyl-(1 --> 2)-4-O-methyl-d-chiro-inositol) and myo
      inositol. Galactopinitol A could be further galactosylated by STS to give
      ciceritol (O-alpha-d-galactopyranosyl-(1 --> 6)-O-alpha-d-galactopyranosyl-(1 -->
      2)-4-O-methyl-d-chiro-inositol). Enzymatic synthesis of galactopinitol A and
      ciceritol is a new observation. However, STS was not only able to utilize
      galactopinitol A as galactosyl acceptor, but also as galactosyl donor to form
      stachyose from raffinose. The role of STS in the metabolism of galactosyl
      cyclitols and oligosaccharides in plant seeds is discussed.

PMID- 10334867
TI  - Tyrosine modifications and inactivation of active site manganese superoxide
      dismutase mutant (Y34F) by peroxynitrite.
AB  - Recent studies from this laboratory have demonstrated that human manganese
      superoxide dismutase (MnSOD) is a target for tyrosine nitration in several
      chronic inflammatory diseases including chronic organ rejection, arthritis, and
      tumorigenesis. Furthermore, we demonstrated that peroxynitrite (ONOO-) is the
      only known biological oxidant competent to inactivate enzymatic activity, nitrate
      critical tyrosine residues, and induce dityrosine formation in MnSOD. To
      elucidate the differential contributions of tyrosine nitration and oxidation
      during enzymatic inactivation, we now compare ONOO- treatment of native
      recombinant human MnSOD (WT-MnSOD) and a mutant, Y34F-MnSOD, in which tyrosine 34
      (the residue most susceptible to ONOO--mediated nitration) was mutated to
      phenylalanine. Both WT-MnSOD (IC50 = 65 microM, 15 microM MnSOD) and Y34F-MnSOD
      (IC50 = 55 microM, 15 microM Y34F) displayed similar dose-dependent sensitivity
      to ONOO--mediated inactivation. Compared to WT-MnSOD, the Y34F-MnSOD mutant
      demonstrated significantly less efficient tyrosine nitration and enhanced
      formation of dityrosine following treatment with ONOO-. Collectively, these
      results suggest that complete inactivation of MnSOD by ONOO- can occur
      independent of the active site tyrosine residue and includes not only nitration
      of critical tyrosine residues but also tyrosine oxidation and subsequent
      formation of dityrosine.

PMID- 10334868
TI  - Differential catalytic efficiency of allelic variants of human glutathione S
      transferase Pi in catalyzing the glutathione conjugation of thiotepa.
AB  - Alkylating agents are extensively used in the treatment of cancer. The clinical
      usefulness of this class of anticancer drugs, however, is often limited by the
      emergence of drug-resistant tumor cells. Increased glutathione (GSH) conjugation
      through catalysis by GSH S-transferases (GSTs) is believed to be an important
      mechanism in tumor cell resistance to alkylating agents. In the present study, we
      report that the allelic variants of human Pi class GST (hGSTP1-1), which differ
      in their primary structures at amino acids in positions 104 and/or 113, exhibit
      significant differences in their activity in the GSH conjugation of alkylating
      anticancer drug thiotepa. Mass spectrometry revealed that the major product of
      the reaction between thiotepa and GSH was the monoglutathionyl-thiotepa
      conjugate. While nonenzymatic formation of monoglutathionyl-thiotepa was
      negligible, the formation of this conjugate was increased significantly in the
      presence of hGSTP1-1 protein. The hGSTP1-1-catalyzed GSH conjugation of thiotepa
      was time and protein dependent and followed Michaelis-Menten kinetics. The
      catalytic efficiency of hGSTP1-1(I104, A113) variant was approximately 1.9- and
      2.6-fold higher compared with hGSTP1-1(V104,A113) and hGSTP1-1(V104,V113)
      isoforms, respectively. The results of the present study indicate that the hGSTP1
      1 polymorphism may be an important factor in GST-mediated tumor cell resistance
      to thiotepa, and that subjects homozygous for the hGSTP1-1(I104,A113) allele,
      which is most frequent in human populations, are likely to be at a greater risk
      for developing GST-mediated resistance to thiotepa than heterozygotes or
      homozygotes with valine 104 background.

PMID- 10334869
TI  - Molecular and functional characterization of the intestinal Na+-dependent
      multivitamin transporter.
AB  - We have cloned a Na+-dependent multivitamin transporter from rabbit intestine
      (riSMVT). The cDNA codes for a protein of 636 amino acids with 12 putative
      transmembrane domains. When expressed in mammalian cells, the cDNA induces Na+
      dependent uptake of the vitamins pantothenate and biotin. Lipoate is also a
      substrate for the cDNA-induced uptake process. The affinity constant for the cDNA
      specific transport of pantothenate and biotin is approximately 2 and
      approximately 8 microM, respectively. The Na+:vitamin stoichiometry is greater
      than 1, indicating that the transport process is electrogenic. The SMVT-specific
      transcripts of 3.2 kbp are equally distributed throughout the small intestine. We
      have also cloned SMVT from the human intestinal cell line Caco-2. The Caco-2 SMVT
      cDNA codes for a protein of 635 amino acids which is homologous to riSMVT and is
      identical to the SMVT expressed in the human choriocarcinoma cell line JAR. Caco
      2 SMVT also catalyzes Na+-dependent uptake of pantothenate, biotin, and lipoate.
      In oocytes expressing Caco-2 SMVT, all three vitamins evoke inward currents,
      confirming the electrogenicity of the transport process.

PMID- 10334870
TI  - Signal presequences increase mitochondrial permeability and open the multiple
      conductance channel.
AB  - We have reported that the signal presequence of cytochrome oxidase subunit IV
      from Neurospora crassa increases the permeability of isolated rat liver
      mitochondria [P. M. Sokolove and K. W. Kinnally (1996) Arch. Biochem. Biophys.
      336, 69] and regulates the behavior of the mutiple conductance channel (MCC) of
      yeast inner mitochondrial membrane [T. A. Lohret and K. W. Kinnally (1995) J.
      Biol. Chem. 270, 15950]. Here we examine in greater detail the action of a number
      of mitochondrial presequences from various sources and of several control
      peptides on the permeability of isolated rat liver mitochondria and on MCC
      activity monitored via patch-clamp techniques in both mammalian mitoplasts and a
      reconstituted yeast system. The data indicate that the ability to alter
      mitochondrial permeability is a property of most, but not all, signal peptides.
      Furthermore, it is clear that, although signal peptides are characterized by
      positive charge and the ability to form amphiphilic alpha helices, these two
      characteristics are not sufficient to guarantee mitochondrial effects. Finally,
      the results reveal a strong correlation between peptide effects on the
      permeability of isolated mitochondria and on MCC activity: peptides that induced
      swelling of mouse and rat mitochondria also activated the quiescent MCC of mouse
      mitoplasts and induced flickering of active MCC reconstituted from yeast
      mitochondrial membranes. Moreover, relative peptide efficacies were very similar
      for mitochondrial swelling and both types of patch-clamp experiments. We propose
      that patch-clamp recordings of MCC activity and the high-amplitude swelling
      induced by signal peptides reflect the opening of a single channel. Based on the
      selective responsiveness of that channel to signal peptides and the dependence of
      its opening in isolated mitochondria on membrane potential, we further suggest
      that the channel is involved in the mitochondrial protein import process.

PMID- 10334871
TI  - Effects of human cytochrome b5 on CYP3A4 activity and stability in vivo.
AB  - Cytochrome P450s (P450) form a superfamily of membrane-bound proteins that play a
      key role in the primary metabolism of both xenobiotics and endogenous compounds
      such as drugs and hormones, respectively. To be enzymically active, they require
      the presence of a second membrane-bound protein, NADPH P450 reductase, which
      transfers electrons from NADPH to the P450. Because of the diversity of P450
      enzymes, much of the work on individual forms has been carried out on purified
      proteins, in vitro, which requires the use of complex reconstitution mixtures to
      allow the P450 to associate correctly with the NADPH P450 reductase. There is
      strong evidence from such reconstitution experiments that, when cytochrome b5 is
      included, the turnover of some substrates with certain P450s is increased. Here
      we demonstrate that allowing human P450 reductase, CYP3A4, and cytochrome b5 to
      associate in an in vivo-like system, by coexpressing all three proteins together
      in Escherichia coli for the first time, the turnover of both nifedipine and
      testosterone by CYP3A4 is increased in the presence of cytochrome b5. The
      turnover of testosterone was increased by 166% in whole cells and by 167% in
      preparations of bacterial membranes. The coexpression of cytochrome b5 also
      resulted in the stabilization of the P450 during substrate turnover in whole E.
      coli, with 109% of spectrally active CYP3A4 remaining in cells after 30 min in
      the presence of cytochrome b5 compared with 43% of the original P450 remaining in
      cells in the absence of cytochrome b5.

PMID- 10334873
TI  - Ethanol potentiates the mitogenic effects of sphingosine 1-phosphate by a zinc-
      and calcium-dependent mechanism in fibroblasts.
AB  - In mouse embryo NIH 3T3 fibroblasts, ethanol (60-80 mM) was found to enhance the
      stimulatory effects of sphingosine 1-phosphate (S1P) on both DNA synthesis and
      cell proliferation. Well-detectable potentiating effects of ethanol on S1P
      induced mitogenesis required the presence of calcium (>1 mM) and zinc (20-40
      microM) in the incubation medium. The amphibian tetrapeptide bombesin, which is
      known to mobilize intracellular calcium in fibroblasts, had no effect alone, but
      it approximately doubled the combined stimulatory effects of ethanol and S1P on
      DNA synthesis. The synergistic mitogenic effects of ethanol and S1P were also
      slightly enhanced, rather than inhibited, by the alcohol dehydrogenase inhibitor
      4-methylpyrazole (5 mM). Of the various growth regulatory enzymes examined,
      ethanol detectably enhanced the stimulatory effects of S1P on the
      phosphosphorylation (activation) of p42/p44 mitogen-activated protein (MAP)
      kinases, but not of p38 MAP kinase. Cotreatment of fibroblasts with ethanol for
      10 min also enhanced the stimulatory effects of S1P on the activities of c-Raf-1
      kinase and p70 S6 kinase, but neither S1P nor ethanol had effects on
      phosphatidylinositol 3'-kinase and Akt/PKB kinase activities. Ethanol-plus-S1P
      induced DNA synthesis was partially inhibited by both PD 98059 (50 microM) and
      rapamycin (10 nM), inhibitors of p42/p44 MAP kinase kinase and mTOR/p70 S6
      kinases, respectively. The results indicate that in NIH 3T3 fibroblasts, ethanol
      can enhance the mitogenic effects of S1P by a zinc- and calcium-dependent
      mechanism involving both the rapamycin-sensitive p70 S6 kinase-dependent and the
      c-Raf-1/MAP kinase-dependent growth regulatory pathways.

PMID- 10334872
TI  - Neutrophil myeloperoxidase is a potent and selective inhibitor of mast cell
      tryptase.
AB  - Myeloperoxidase (MPO) is an important component of the neutrophil response to
      microbial infection. In this paper we report an additional activity of MPO, the
      potent and selective inhibition of human mast cell tryptase. MPO inhibits human
      mast cell tryptase in a time-dependent manner with an IC50 of 16 nM at 1 h. In
      contrast, MPO does not inhibit trypsin, thrombin, plasmin, factor Xa, elastase,
      or cathepsin G. It is the native protein conformation of MPO and not its enzyme
      activity that is responsible for tryptase inhibition. Heparin, at high
      concentrations, can prevent the inhibition of tryptase by MPO. We have shown by
      size-exclusion chromatography that MPO promotes the dissociation of active
      tryptase tetramer to inactive monomer. These data suggest that MPO inhibits
      tryptase by interfering with the heparin stabilization of tryptase tetramer. We
      have previously shown that lactoferrin (another neutrophil-associated protein)
      also inhibits tryptase activity by a similar mechanism. The finding that MPO is a
      potent inhibitor of tryptase lends further support to the hypothesis that
      neutrophil proteins, such as MPO and lactoferrin, may play a regulatory role as
      endogenous suppressers of tryptase enzyme activity.

PMID- 10334874
TI  - Interaction of talin with actin: sensitive modulation of filament crosslinking
      activity.
AB  - Talin is an adhesion plaque protein believed important in linking actin filaments
      to the plasma membrane. The nature of a direct talin-actin interaction, however,
      is complex and has remained unclear. We have systematically characterized the
      effects of pH, ionic strength, temperature, and protein molar ratio on the
      interaction between highly purified talin and actin. The ability of talin to
      increase viscosity of F-actin at 25 degrees C and low ionic strength increased
      with decreasing pH from 7.3 to 6.4 and increasing molar ratio of talin to actin.
      At pH 6.4 and low ionic strength, talin could extensively crosslink actin
      filaments into ordered bundles as shown by negative staining and could cosediment
      with F-actin at molar ratios as high as one talin to two actin monomers. Talin
      crosslinked prepolymerized actin filaments to a similar extent as actin filaments
      polymerized in its presence. The 190-kDa calpain-generated proteolytic fragment
      of talin bound poorly to actin under conditions favorable for intact talin, but
      was able to crosslink actin filaments at a lower pH. Increasing the ionic
      strength within a relatively narrow range significantly decreased ability of
      talin to bind to actin, regardless of pH. The effects of pH and ionic strength on
      the talin-actin interaction were rapid and reversible. Low-shear-viscosity
      studies revealed a strong temperature dependence in the talin-actin interaction
      with significant crosslinking activity at physiological-like ionic conditions and
      temperature (37 degrees C). Our results consistently demonstrated that talin
      crosslinks actin filaments and that this direct interaction is highly sensitive
      to, and dependent upon, ionic conditions and temperature.

PMID- 10334875
TI  - Organization and chromosomal mapping of mouse Gh/tissue transglutaminase gene
      (Tgm2).
AB  - The mouse Gh/tissue transglutaminase gene (Tgm2), coding a dual-function protein
      that both binds guanosine triphosphate (GTP) and catalyzes the posttranslational
      modification of proteins by transamidation of glutamine residues, has been
      cloned. Sequence analysis of Tgm2 and comparison with the TGase sequences of
      other species allowed correction of several apparent sequencing artifacts in the
      Tgm2 cDNA. Tgm2 spans approximately 34 kb and has 13 exons and 12 introns.
      Although the structure of Tgm2 shows similarity to that of other transglutaminase
      genes, with introns ranging from 921 bp to >5 kb, several introns differ
      considerably in size from those of the human Gh gene, TGM2. Tgm2 maps to the
      distal region of mouse chromosome 2, a region syntenic to human chromosome 20q
      containing TGM2. Tgm2 is in the vicinity of two uncloned mouse mutations,
      diminutive (dm) and blind-sterile (bs). Genomic DNA from dm mice was unavailable;
      however, Southern blot analysis of bs DNA showed no gross rearrangements of Tgm2.

PMID- 10334876
TI  - Effects of coenzyme Q10 on changes in the membrane potential and rate of
      generation of reactive oxygen species in hydrazine- and chloramphenicol-treated
      rat liver mitochondria.
AB  - Effects of CoQ10 and cycloheximide (CHX) on hydrazine- and chloramphenicol (CP)
      induced morphological and some functional changes of mitochondria using cultured
      rat hepatocytes and effects on the process of recovery from CP intoxication using
      mouse liver were examined. Results obtained are summarized as follows: (1) The
      formation of megamitochondria induced in the hepatocytes cultured for 22 h in the
      presence of 2 mM hydrazine or CP (300 microgram/ml) was suppressed by
      pretreatment of hepatocytes with CoQ10 (1 microM) or CHX (0.5 microgram/ml). This
      was proved by electron microscopic analysis of mitochondria. (2) Treatment of
      hepatocytes with hydrazine for 48 h or longer caused decreases in the membrane
      potential of mitochondria, which were suppressed by CoQ10. (3) Treatment of
      hepatocytes with hydrazine for 22 h or longer caused remarkable increases in
      intracellular levels of reactive oxygen species in hepatocytes, which were
      suppressed by CoQ10. (4) The process of recovery from the CP-induced changes of
      mitochondria in mouse liver was accelerated by CoQ10 and CHX.

PMID- 10334877
TI  - Effect of substitution inert metal complexes on calcineurin.
AB  - As a substitute for M(H2O)2+6, Co(NH3)3+6 was found to activate calcineurin with
      para-nitrophenyl phosphate as substrate. Kinetics for calcineurin catalyzed
      hydrolysis of para-nitrophenyl phosphate at pH 7.0 with Mn2+, Mg2+, Co2+, and
      Co(NH3)3+6 were compared. Although kcat and Km were different with the metals,
      values of kcat/Km were nearly identical for Mn2+ and Mg2+, but lower for Co2+ and
      Co(NH3)3+6. The concentration of each metal providing half-maximal activation,
      designated Kact, was evaluated as 15.9 mM for Co(NH3)3+6, compared to Kact = 0.17
      mM for Mn2+ and Co2+ and 6.3 mM for Mg2+, respectively. Comparing kcat/Kcat
      showed that Co(NH3)3+6 was a 170-fold poorer activator of calcineurin than was
      Mn2+, but only 1.5-fold poorer than Mg2+. Activation by Co(NH3)3+6 indicated that
      activation of calcineurin by exogenous metal ions can proceed via an outer
      coordination sphere reaction mechanism with no requirement for the direct
      coordination of substrate by metal. Because Co(NH3)3+6 was found to support
      calcineurin activity, the related compound [Co-(ethylenediamine)3]3+ (or
      Co(en)3+3) was tested as a possible activator. Co(en)3+3 did not support
      calcineurin activity but did inhibit calcineurin. Co(en)3+3 showed competitive
      inhibition kinetics with either Mn2+ or pNPP as the varied ligand and the other
      at a fixed, subsaturating concentration. Inorganic phosphate was used as a known
      competitive inhibitor to pNPP (B. L. Martin and D. J. Graves, J. Biol. Chem. 261,
      14545-14550, 1986) and showed uncompetitive inhibition with Mn2+ as the varied
      ligand. These patterns are consistent with the mechanism of ligand binding to
      calcineurin being ordered with metal preceding substrate. Prior formation of a
      metal-substrate complex was not required for association with calcineurin.

PMID- 10334878
TI  - Phonotactic and prosodic effects on word segmentation in infants.
AB  - This research examines the issue of speech segmentation in 9-month-old infants.
      Two cues known to carry probabilistic information about word boundaries were
      investigated: Phonotactic regularity and prosodic pattern. The stimuli used in
      four head turn preference experiments were bisyllabic CVC.CVC nonwords bearing
      primary stress in either the first or the second syllable (strong/weak vs.
      weak/strong). Stimuli also differed with respect to the phonotactic nature of
      their cross-syllabic C.C cluster. Clusters had either a low probability of
      occurring at a word juncture in fluent speech and a high probability of occurring
      inside of words ("within-word" clusters) or a high probability of occurring at a
      word juncture and a low probability of occurring inside of words ("between-word"
      clusters). Our results show that (1) 9-month-olds are sensitive to how
      phonotactic sequences typically align with word boundaries, (2) altering the
      stress pattern of the stimuli reverses infants' preference for phonotactic
      cluster types, (3) the prosodic cue to segmentation is more strongly relied upon
      than the phonotactic cue, and (4) a preference for high-probability between-word
      phonotactic sequences can be obtained either by placing stress on the second
      syllable of the stimuli or by inserting a pause between syllables. The
      implications of these results are discussed in light of an integrated multiple
      cue approach to speech segmentation in infancy.

PMID- 10334879
TI  - Food for thought: cross-classification and category organization in a complex
      real-world domain.
AB  - Seven studies examined how people represent, access, and make inferences about a
      rich real-world category domain, foods. The representation of the category was
      assessed by category generation, category ratings, and item sortings. The first
      results indicated that the high-level category of foods was organized
      simultaneously by taxonomic categories for the kind of food (e.g., vegetables,
      meats) and script categories for the situations in which foods are eaten (e.g.,
      breakfast foods, snacks). Sortings were dominated by the taxonomic categories,
      but the script categories also had an influence. The access of the categories was
      examined both by a similarity rating task, with and without the category labels,
      and by a speeded priming experiment. In both studies, the script categories
      showed less access than the taxonomic categories, but more than novel ad hoc
      categories, suggesting some intermediate level of access. Two studies on
      induction found that both types of categories could be used to make a wide range
      of inferences about food properties, but that they were differentially useful for
      different kinds of inferences. The results give a detailed picture of the use of
      cross-classification in a complex domain, demonstrating that multiple categories
      and ways of categorizing can be used in a single domain at one time.

PMID- 10334880
TI  - Intrathymic immunomodulation and the "infectious" tolerance pathway in allograft
      recipients.
AB  - BACKGROUND: We have previously shown that >75% of LEW cardiac allografts survive
      indefinitely in BUF rats pretreated at Day -21 intrathymically (IT) with donor
      alloantigen in conjunction with a single intravenous dose of ALS. Spleen cells
      can adoptively transfer the tolerant state to new cohorts of test recipients.
      This study was designed to analyze cellular and humoral events contributing to
      the "infectious" tolerance pathway in this model. METHODS: Spleen cells (25 x
      10(6)) harvested from BUF recipients bearing long-term cardiac allografts were
      injected intravenously into lightly irradiated (450 R) secondary BUF rats,
      followed 24 h later by transplantation of LEW of ACl hearts. Cardiac allografts
      were then analyzed serially by reverse transcription polymerase chain reaction
      for Th1 and Th2 cytokine gene expression. Donor-specific IgM and IgG alloantibody
      responses in host serum were screened by flow cytometry. RESULTS: Transfer of
      regulatory spleen cells harvested between Days 80 and 140 from tolerant hosts
      induced tolerance to heart grafts in a donor-specific manner. In the early
      posttransplant period, selective sparing of Th2 cytokines was noted. Adoptively
      transferred hosts showed overall depression of IgM, but a vigorous IgG1 and IgG2a
      alloantibody response. CONCLUSION: IT + ALS-induced tolerance can be transferred
      in a donor-specific "infectious" manner to new cohorts of engrafted recipients.
      The development of tolerance is nontemporally bound, and associates with an early
      Th2-type immune deviation at the graft site. The elevated levels of T cell
      dependent IgG1 and IgG2 may interfere with the antigen reactivity and
      alloresponsive effector functions, contributing to graft acceptance in the
      "infectious" tolerance pathway.

PMID- 10334881
TI  - Role of nitric oxide, vasoactive intestinal polypeptide, and ATP in inhibitory
      neurotransmission in human jejunum.
AB  - BACKGROUND: Inhibitory neurotransmission in the human intestine is poorly
      understood. This study was undertaken to determine the role of nitric oxide (NO),
      adenosine triphosphate (ATP), and vasoactive intestinal polypeptide (VIP) in
      inhibitory neurotransmission in human jejunal circular muscle strips. METHODS: In
      vitro response of precontracted (10(-5) M substance P) normal human jejunal
      muscle strips to electric field stimulation (EFS) under adrenergic and
      cholinergic receptor blockade was evaluated. Selective neural blockade was
      obtained by the NO synthase inhibitor l-NG-nitroarginine methyl ester (l-NAME,
      10(-3) M), VIP receptor antagonist (4-Cl-d-Phe6Leu17-VIP, 10(-7) M), P2
      purinergic receptor blocker suramin (3 x 10(14) M), or the calcium-dependent
      potassium channel blocker apamin (10(-6) M). Force generated in response to EFS
      was quantitated and analyzed statistically. RESULTS: Exogenous NO and ATP dose
      dependently inhibited contractile activity and relaxed muscle strips with a
      concentration yielding a 50% effect (ED50) of 4.5 +/- 2.9 x 10(-6) M and 3.3 +/-
      1.3 x 10(-4) M, respectively. EFS resulted in relaxation of precontracted muscle
      strips in all groups. When compared with controls, relaxation was decreased but
      not abolished by l-NAME (-0.12 +/- 0.03 vs -0.33 +/- 0. 05, -0.07 +/- 0.03 vs 
      0.34 +/- 0.05, and 0.04 +/- 0.03 vs -0.30 +/- 0.04 at 2, 5, and 10 Hz,
      respectively, P < 0.011). d-NAME (inactive stereoisomer of l-NAME), 4-Cl-d
      Phe6Leu17-VIP, suramin, and apamin did not alter EFS-induced relaxation.
      CONCLUSIONS: Inhibition of NO synthesis by l-NAME reduced the inhibitory response
      to EFS, whereas blocking ATP and VIP receptors or other effector pathways had no
      effect. Our findings indicate that although NO plays a predominant role in
      inhibitory neurotransmission in human jejunal circular muscle, another
      neurotransmitter(s) appears to be involved as well. These data may impact on
      understanding mechanisms of disorders of gut dysmotility.

PMID- 10334882
TI  - Glutamine-enriched total parenteral nutrition preserves respiratory immunity and
      improves survival to a Pseudomonas Pneumonia.
AB  - BACKGROUND: Addition of 2% glutamine (GLN), a specific lymphocyte fuel, prevents
      deleterious effects of TPN on gut-associated lymphoid tissue and IgA while
      preserving IgA-mediated upper respiratory immunity to influenza virus. We
      examined whether a 2% GLN-enhanced TPN solution preserves respiratory immunity to
      a lethal and clinically relevant pneumonia challenge. MATERIALS AND METHODS: Male
      ICR mice were randomized to chow (n = 20), TPN (n = 20), or an isonitrogenous,
      isocaloric TPN-2% GLN solution (n = 17). All groups were immunized 10 days before
      surgery with Pseudomonas polysaccharide-containing liposomes (LIP) to confer
      immunity except for a nonimmune chow-fed LIP control group (n = 21) which
      received LIP without Pseudomonas. Mice received 5 days of diet and then were
      given an LD90 dose of 1.2 x 10(8) intratracheal Pseudomonas bacteria, and
      mortality was recorded. RESULTS: Immunization reduced mortality compared with LIP
      alone. TPN impaired immunity and reduced survival while GLN maintained
      immunization effectiveness. CONCLUSIONS: Pseudomonas immunization reduces
      mortality to Pseudomonas pneumonia, but this immunity is lost with TPN. Addition
      of 2% GLN to TPN preserves immunity in the respiratory tract and reduces
      mortality to a lethal bacterial challenge compared with standard TPN.

PMID- 10334883
TI  - Tracheal ligation increases mitogen-activated protein kinase activity and
      attenuates surfactant protein B mRNA in fetal sheep lungs.
AB  - BACKGROUND: Tracheal ligation has been shown to accelerate fetal pulmonary growth
      in normal and hypoplastic lungs. Our aim was to study the effects of tracheal
      ligation on established molecular markers of growth and differentiation [mitogen
      activated protein (MAP) kinase] and maturity [surfactant protein B (SPB) and
      fatty acid synthase (FAS)]. MATERIALS AND METHODS: Tracheal ligation was
      performed on four 100-day-gestation fetal sheep, with four age-matched fetuses
      undergoing maternal laparotomy and hysterotomy as control. Lungs from surviving
      fetuses (n = 2 in each group) were harvested after 4 days and frozen in liquid
      nitrogen. Protein lysates were prepared, and MAP kinase enzymatic assays
      [extracellular signal regulated protein kinase (ERK)-1 and -2] and Western blots
      were performed. Total RNA was isolated, and a fetal sheep lung cDNA library was
      created. The sheep SPB and FAS genes were cloned and sequenced. Northern blots
      were performed with the new clones, normalizing to beta-actin. RESULTS: Tracheal
      ligation lungs contained a larger volume of fluid (40 ml) compared with age
      matched controls (8 ml). MAP kinase enzymatic ERK-1 activity was increased and
      SPB mRNA expression was reduced in fetal lungs after tracheal ligation. Neither
      ERK-2 enzymatic activities and FAS mRNA nor ERK protein levels were affected by
      tracheal ligation, by Western blot analysis. CONCLUSION: Tracheal ligation
      induced fetal lung growth may be mediated in part via the MAP kinase pathway.
      Expression of SPB mRNA is attenuated by tracheal ligation, whereas FAS, one of
      the key enzymes that synthesizes the lipid portion of surfactant, is not
      affected.

PMID- 10334884
TI  - Neutrophil priming state predicts capillary leak after gut ischemia in rats.
AB  - BACKGROUND: Multiple organ failure after serious injury or illness is a major
      determinant of mortality. An initial insult is believed to "prime" circulating
      neutrophils and induce systemic inflammation. Thereafter, a second insult will
      precipitate distant organ injury. The aim of these studies was to evaluate
      circulating neutrophil function after mesenteric ischemia-reperfusion to
      determine the neutrophil "priming state," a quantitative and clinically useful
      predictor of multiple organ failure. MATERIALS AND METHODS: Anesthetized Sprague
      Dawley rats underwent superior mesenteric artery occlusion for 30 min or sham
      operation and were euthanized after 2, 6, or 24 h of reperfusion. Control animals
      had blood taken without any intervention. To determine changes in lung capillary
      permeability, another group of rats received Evan's blue, a dye that binds
      albumin, 1 h before sacrifice. Flow cytometric analysis was performed on 5
      million white blood cells after removal of red cells by lysis and centrifugation.
      Neutrophil number, oxidative burst, and CD18 expression were measured. RESULTS:
      The number of circulating neutrophils was elevated similarly in rats subjected to
      sham operation or ischemia-reperfusion. Oxidative burst potential was increased
      at 2 h, maximum at 6 h, and normal at 24 h after reperfusion, but not in sham
      rats. CD18 expression was similar in all groups. There was a significant temporal
      correlation between the "priming state" of the circulating neutrophil, defined as
      the product of the neutrophil number times oxidative burst, and lung leak.
      CONCLUSIONS: The neutrophil "priming state" may allow the clinician to better
      predict those patients at greatest risk for multiple organ failure.

PMID- 10334885
TI  - Stromelysin-1-deficient fibroblasts display impaired contraction in vitro.
AB  - Targeted disruption of the stromelysin-1 gene in mice causes a delay in
      excisional wound healing due to a failure in wound contraction. Therefore, we
      postulated that stromelysin-1 activity is responsible for initiating contraction.
      To test this hypothesis, we compared the contractile capacity of fibroblasts from
      stromelysin-1 knockout mice (strom-1 KO) with that of normal fibroblasts using a
      collagen gel contraction model. Fibroblast cultures were established from
      explants of skin and lung parenchyma from strom-1 KO and wild-type mice, then
      transferred to the surface of collagen gels. The extent of contraction was
      determined by measuring greatest gel diameter. Results demonstrated that (1) all
      fibroblasts contracted collagen gels in a uniform concentric fashion, (2) skin
      fibroblasts from both sets of mice exhibited greater gel contraction than did
      lung fibroblasts, and (3) strom-1 KO fibroblasts demonstrated significantly less
      contraction (21-23%) than wild-type fibroblasts. These data support the
      hypothesis that absence of stromelysin-1 results in defective fibroblast
      contraction that may contribute to delayed wound healing.

PMID- 10334886
TI  - Ascorbic acid prevents cigarette smoke injury to endothelium-dependent arterial
      relaxation.
AB  - BACKGROUND: Arterial endothelium-dependent acetylcholine relaxation is impaired
      by smoking, and this injury may be mediated by oxygen free radicals. The purpose
      of this study was to examine the effect of ascorbic acid (AA) treatment on this
      injury. MATERIALS AND METHODS: New Zealand White rabbits (n = 6, each group) were
      placed in a 240-ft3 airflow chamber for 3 h per day, 5 days per week over an 8
      week period. Animals were divided into four groups and fed rabbit chow and water
      or rabbit chow and AA (250 ml/kg)-supplemented water. The control-smoke rabbit
      group and the ascorbic acid-smoke rabbit group were exposed to mainstream
      cigarette smoke from a robotic smoke generator for the 3-h period, while the
      control-no smoke rabbit group and ascorbic acid-no smoke rabbit group were
      similarly placed in the chamber without smoke. At the end of 8 weeks, rabbits
      were sacrificed and segments of their superficial femoral arteries were suspended
      from tension transducers and the maximal contraction was determined. The
      remaining rings were contracted to 50% of the maximum and relaxation was
      determined by adding acetylcholine. Groups were compared using one-way ANOVA.
      RESULTS: Rings from control-smoke (5.13 +/- 0.21 g) and AA-smoke rabbits (6. 24
      +/- 0.46 g) exhibited increased mean contraction to KCl (P < 0. 05) compared to
      control-no smoke rabbits (3.86 +/- 0.40 g). Acetylcholine-dependent relaxation
      was significantly reduced in the rings from the control-smoke rabbits compared to
      control-no smoke rabbits (acetylcholine, 5 x 10(-7) M: 24.7 +/- 2.7% versus 55.3
      +/- 8.0%; acetylcholine, 7 x 10(-7) M: 27.5 +/- 2.3% versus 56.3 +/- 9. 2%). The
      AA-smoke group (acetylcholine, 5 x 10(-7) M: 61.8 +/- 12. 4%; 7 x 10(-7) M: 67.9
      +/- 11.4%) had significantly increased relaxation compared to the control-smoke
      group (P < 0.05). There was no statistical difference in the mean percentage ring
      relaxation between the control-no smoke, AA-no smoke, and AA-smoke groups.
      CONCLUSIONS: Ascorbic acid protected the artery from cigarette smoke-induced
      endothelial injury.

PMID- 10334887
TI  - Functional characterization of alpha1-adrenergic receptors in experimental vein
      grafts.
AB  - BACKGROUND: Studies on the pharmacology of the smooth muscle cells in vein bypass
      grafts suggest that the function of G-proteins and adrenergic receptors is
      altered. This study examines the alpha-adrenergic responsiveness of smooth muscle
      cells in vein bypass grafts as compared with those in the common carotid arteries
      and external jugular veins. METHODS: New Zealand White rabbits received jugular
      vein interposition bypass grafts of the common carotid. Vessel segments of the
      vein bypass grafts harvested after 28 days, common carotid arteries, and external
      jugular veins were sectioned into 5-mm rings (four per vessel) for studies of
      isometric tension in response to phenylephrine (10(-10) to 10(-4) M) alone and in
      the presence of prazosin, an alpha1-adrenergic antagonist; WB4101 and 5
      methylurapidil (5-MU), alpha1A antagonists; chloroethylclonidine (CEC); an
      alpha1B antagonist; or the Gi/o G-protein inhibitor pertussis toxin (PTx).
      RESULTS: All vessels had prazosin-sensitive responses. The jugular veins appear
      to have functional alpha1A receptors (WB4101 and 5-MU sensitive, CEC insensitive)
      which are associated with pertussis toxin-sensitive G-proteins. Carotid arteries
      appear to have atypical alpha1 receptors (WB4101 and 5-MU insensitive, CEC
      insensitive) associated with pertussis toxin-insensitive G-proteins. Vein grafts
      appear to have functional alpha1B receptors (WB4101 and 5-MU insensitive, CEC
      sensitive) which are associated with pertussis toxin-insensitive G-proteins.
      CONCLUSIONS: These results show that placement of a vein into the arterial
      circulation induces a change in alpha1-adrenergic receptor subtypes (alpha1A to
      alpha1B) and in the G-protein coupling of the receptors (PTx sensitive to PTx
      insensitive), reflecting a signficant phenotypic change in smooth muscle cell
      signal transduction.

PMID- 10334888
TI  - Cardiopulmonary bypass increases coronary IL-8 in diabetic patients without
      evidence of reperfusion injury.
AB  - BACKGROUND: Endothelin-1 (ET-1) has been shown to be a potent agonist for
      monocyte production of the neutrophil chemotactic cytokine interleukin-8 (IL-8).
      We have shown that diabetic patients demonstrate elevated coronary ET-1 after
      coronary artery bypass grafting (CABG). We hypothesized that these same diabetic
      patients would manifest elevated coronary IL-8 and conjugated diene
      concentrations (an index of reperfusion injury). METHODS: Sixteen patients [9
      nondiabetics and 7 type II diabetics] underwent nonemergent CABG. The two groups
      did not differ significantly in preoperative ejection fraction, number of vessels
      bypassed, or cross-clamp time. Coronary sinus samples were obtained prior to
      cardioplegic arrest (baseline) and at 1 and 15 min after reperfusion periods A
      and B (A, reperfusion of native coronaries + LIMA; B, reperfusion of saphenous
      vein grafts in addition to native coronary system + LIMA). Plasma samples were
      analyzed for IL-8 (ELISA) and conjugated dienes (spectrophotometry). RESULTS:
      Initially after reperfusion, IL-8 in both groups was significantly lower than
      precardioplegia values. In reperfusion B, only the diabetic group demonstrated a
      significant increase in IL-8 concentrations at 1 and 15 min compared to
      nondiabetics. Conjugated diene levels were significantly higher in diabetics at
      each time point than nondiabetics. CONCLUSIONS: This study demonstrates an early
      decrease in IL-8 in both groups, most likely related to depressed production
      secondary to hypothermia. The subsequent elevation in IL-8 only in the diabetic
      group was seen without concomitant conjugated diene elevation. While no evidence
      of reperfusion injury was demonstrated in this time frame, the elevation of IL-8
      in diabetics after CABG may contribute to later infiltration and associated
      oxidative damage.

PMID- 10334890
TI  - Glucose and glutamine gavage increase portal vein nitric oxide metabolite levels
      via adenosine A2b activation.
AB  - INTRODUCTION: Postprandial intestinal hyperemia is a complex vascular response
      during nutrient absorption. Many mediators have been studied including enteric
      reflexes, GI hormones, and absorption-stimulated metabolic mediators such as pH
      and adenosine. We have shown that nitric oxide (NO) mediates premucosal
      arteriolar dilation during glucose absorption and that glucose-induced portal
      vein NO metabolite production requires adenosine A2b receptor activation. We
      hypothesize that Na+-linked absorption of l-glutamine or l-glycine might also
      stimulate NO release in the enteroportal circulation via adenosine A2b receptors.
      METHODS: Male Sprague-Dawley rats (190-220 g) were anesthetized with
      urethane/alpha-chloralose and cannulated for hemodynamic monitoring and blood
      sampling. A right paramedian abdominal incision was made for access to both the
      stomach (gavage) and the portal vein (blood sampling). Animals received
      intragastric nutrient gavage (saline, d-glucose, l-glutamine, racemic glycine, or
      oleic acid) with and without adenosine A2b receptor blockade. NO metabolites
      (NOx) were measured by a fluorescent modified-Greiss assay at baseline and 30 min
      after nutrient gavage. RESULTS: Glucose and glutamine gavage increased portal NOx
      levels compared to baseline, while glycine and oleic acid gavage did not.
      Adenosine A2b antagonism returned NOx levels to baseline in both glucose and
      glutamine gavage animals, but did not alter portal NOx levels in glycine- or
      oleic acid-treated animals. CONCLUSIONS: These data suggest that nutrient-induced
      adenosine is involved in a signaling process from the intestinal epithelium to
      nitric oxide-producing cells elsewhere in the vasculature. Adenosine A2b
      receptors are required for NO production during Na+-linked glucose or glutamine
      absorption.

PMID- 10334889
TI  - The effect of phospholipase A2 inhibitors on proliferation and apoptosis of
      murine intestinal cells.
AB  - BACKGROUND: Group II phospholipase A2 (PLA2) enzymes, the rate controlling
      enzymes in arachidonic acid metabolism, have been well characterized and
      subdivided into secretory 14-kDa PLA2 (sPLA2) and cytoplasmic 85-kDa PLA2
      (cPLA2). Previous research has demonstrated increased PLA2 in colorectal tumors.
      The present study was performed to determine the effect of specific PLA2
      inhibitors on the proliferation and induction of apoptosis of intestinal
      epithelial cells. METHODS: A continuously proliferating rat small intestinal cell
      line (IEC-18) and a mouse colon cancer cell line (WB-2054-M4) were utilized for
      these experiments. The cells were placed in microwells with serum-free or serum
      supplemented media. The effects of serum on proliferation were then evaluated in
      the presence of the cPLA2 inhibitor, methylarachidonyl fluorophosphate (MAFP), or
      the sPLA2 inhibitor p-bromophenacyl bromide (BPB). The sPLA2 and cPLA2 protein
      was estimated by Western blotting. Proliferation of intestinal cells was
      quantitated by incorporation of [3H]thymidine into DNA and PLA2 activity was
      evaluated by quantitating arachidonic acid formation and prostaglandin E2
      production. RESULTS: Western blotting of IEC-18 and WB-2054 cell protein
      demonstrated sPLA2 and cPLA2 enzyme in cells incubated in media containing 10%
      serum. Spontaneous DNA synthesis was present in both cell lines and serum
      consistently increased proliferation. In IEC-18 cells [3H]thymidine incorporation
      stimulated by serum was inhibited by MAFP and BPB, while in the malignant cell
      line, proliferation was inhibited only by BPB. BPB, but not MAFP, produced a dose
      dependent increase in apoptotic ratios in both cell lines. Arachidonic acid and
      PGE2 formation, stimulated by serum, was inhibited by MAFP and BPB. CONCLUSIONS:
      A differential effect on intestinal cell mitogenesis was seen with different PLA2
      inhibitors. The sPLA2 inhibitor, but not the cPLA2 inhibitor, significantly
      inhibited [3H]thymidine incorporation in the malignant cell line. This occurred
      with an induction of apoptosis. sPLA2 inhibitors may be specific inhibitors of
      growth of malignant cells. The inhibition of arachidonic acid and PGE2 production
      did not correlate with the inhibition of proliferation, suggesting that the two
      processes may be unrelated.

PMID- 10334891
TI  - Ethanol inhibits basal and flow-induced vascular smooth muscle cell migration in
      vitro.
AB  - BACKGROUND: Alcohol consumption protects against coronary heart disease by as yet
      unclear mechanisms. The aim of this study was to determine the effect of ethanol
      on vascular smooth muscle cell (SMC) migration which plays an important role in
      the pathogenesis of atherosclerosis. MATERIALS AND METHODS: Cultures of human SMC
      under static (no flow) or pulsatile flow conditions (perfused transcapillary
      culture system) were pretreated in the absence or presence of ethanol (EtOH)
      whereupon their random migration (chemokinesis) was assessed by Transwell assay.
      RESULTS: Ethanol pretreatment (24 h) dose dependently inhibited migration of
      HuSMC from static cultures with a maximal inhibition of 60.8 +/- 4.4% observed at
      40-80 mM, in the absence of any effect on cell adhesion or cell viability as
      assessed by trypan blue exclusion. In HuSMC exposed to pulsatile flow (0.3 to 25
      ml/min, 24 h), there was a flow-dependent increase in migration ranging from a
      1.3 +/- 0.16- to 2.67 +/- 0.26-fold increase, compared to static cells,
      concomitant with a significant increase in urokinase-type plasminogen activator
      (uPA) mRNA levels. Ethanol pretreatment (20-80 mM, 24 h) dose dependently
      inhibited the flow-induced increase in SMC migration but did not affect uPA mRNA
      expression. CONCLUSIONS: The inhibitory effect of ethanol on basal and flow
      stimulated SMC migration may be relevant to its cardiovascular effects in vivo.

PMID- 10334892
TI  - Enhanced bradykinin-stimulated prostaglandin release in the acutely inflamed
      guinea pig gallbladder is due to new synthesis of cyclooxygenase 1 and
      prostacyclin synthase.
AB  - BACKGROUND: Our previous studies have shown that acute gallbladder (GB)
      inflammation increases endogenous bradykinin (BK)-stimulated prostaglandin (PG)
      release and inhibits guinea pig (GP) GB contractility. This study examines the
      hypothesis that exaggerated PG release following BK stimulation in the inflamed
      guinea pig GB is due to new protein synthesis of cyclooxygenase 1 (COX-1) and
      prostacyclin synthase (PS). MATERIALS AND METHODS: Male Hartley GPs (450-550 g)
      were anesthetized and underwent common bile duct ligation (BDL, a model of acute
      inflammation). GBs were harvested after 3 days from BDL and control groups.
      Tissue slices were prepared and placed in oxygenated tissue culture medium at 37
      degrees C for 1 h (basal) and for a second hour in medium alone (carrier, Car),
      medium plus 10(-6) M BK, or medium plus 10(-6) M BK plus cycloheximide 100
      microgram/ml (BK + CX). The medium was assayed for net release of 6-keto
      PGF1alpha (PGI2 metabolite), thromboxane B2 (TxB2), PGE2, leukotriene B4 (LTB4),
      and C4 (LTC4) by enzyme immunoassay and data are reported as nanograms per
      milligram of protein. GB tissue from control and BDL groups was examined for COX
      1, COX-2, PS, and inducible nitric oxide synthase (iNOS) content by Western blot
      analysis, analyzed by densitometry, and reported as densitometry units. RESULTS:
      All data were analyzed by ANOVA and t test and reported as means +/- SEM, N >/=
      5.BK increased the release of PGI2 and PGE2 from the control group and markedly
      exaggerated release of PGI2 and PGE2 from the BDL GP gallbladder. This
      exaggerated PGI2 and PGE2 release was greatly diminished by inhibition of new
      protein synthesis with cycloheximide. TxB2, LTB4, and LTC4 showed no significant
      differences between any groups. COX-1 and PS contents were significantly elevated
      in the BDL group compared with control. COX-2 and iNOS were not present in
      control or BDL GBs. CONCLUSIONS: These data suggest that the enhanced BK
      stimulated PG release seen in the acutely inflamed GP gallbladder is due to the
      synthesis of new COX-1 and PS enzymes.

PMID- 10334893
TI  - Overexpression of Fas ligand does not confer immune privilege to a pancreatic
      beta tumor cell line (betaTC-3).
AB  - BACKGROUND: Fas ligand (Fas-L) is thought to provide immune privilege to specific
      tissues and tumors by inducing an apoptotic signal of cytotoxic T cells
      expressing its Fas receptor. Purpose. The purpose of this work was to evaluate
      whether an immortalized insulin-secreting cell line (betaTC-3) gains immune
      privilege by inducing overexpression of Fas-L. METHODS: A lipofection technique
      was used to transfect a betaTC-3 tumor cell line with a plasmid (pcDNA3.1/Zeo)
      carrying the Fas-L gene and a zeocin resistance gene. Insertion of Fas-L into
      betaTC was characterized by reverse transcription polymerase chain reaction (RT
      PCR) and the ability of transfectants (betaTC-3/Fas-L) to induce apoptosis of Fas
      sensitive T cells. Transfectants and control cells were tested for insulin
      secretion following which 1 x 10(6) insulin-secreting betaTC-3 and betaTC-3/Fas-L
      cells were subcutaneously implanted into syngeneic, allogeneic, and Fas mutant
      (lpr) syngeneic mice. Survival of the insulin-secreting cells was then determined
      by monitoring serum glucose levels in recipients. RESULTS: Successful
      transfection of vector resistance gene was achieved in the transfected betaTC-3
      cells, which was confirmed by zeocin resistance. RT-PCR in resistant Fas-L clones
      confirmed the transcription of Fas-L, which was absent in controls. Fas-L
      transfectants induced 20 +/- 4.2% apoptosis of Fas-sensitive T cells, while
      controls induced 3.47 +/- 2.3% by flow cytometry (P = 0.04, n = 3). Insulin
      secretion was equivalent in both betaTC-3 and betaTC-3/Fas-L cells. Syngeneic
      mice implanted with control betaTC-3 cells died within 3 weeks from hypoglycemia
      due to overgrowth of betaTC-3 tumor. Implanted Fas-L transfected betaTC-3 cells
      were killed and had no effect on glycemic status except in Fas mutant hosts,
      where tumors formed in two of three mice. CONCLUSIONS: Despite the ability of
      transfected betaTC-3 cells to induce apoptosis of T cells in vitro, expression of
      Fas-L provided no immune privilege to these cells in vivo, but paradoxically
      induced killing of betaTC-3 cells even in syngeneic hosts.

PMID- 10334894
TI  - Fas-mediated induction of hepatocyte apoptosis in a neuroblastoma and hepatocyte
      coculture model.
AB  - BACKGROUND: We have previously demonstrated an increase in hepatocyte apoptosis
      when they are cocultured with neuroblastoma cells. Death receptors in the tumor
      necrosis factor (TNF) family such as TNFR1 and Fas have been identified as
      regulators of apoptosis and may be responsible for the altered regulation of
      apoptosis seen in our coculture model. To evaluate the effects of released
      factors and remove the potential alterations induced by direct contact, a
      noncontact coculture system was used to study the interaction between hepatocytes
      and neuroblastoma cells. METHODS: Human Chang hepatocytes (HC) were plated onto
      Falcon cell culture inserts with 0.45-micrometer pores in the permeable membrane.
      Human neuroblastoma cells (NB-IMR-32) were seeded into wells of the Falcon
      companion plate. After 24 h, inserts containing HC were placed into wells
      containing NB cells and incubated for 4 days. This provided a coculture
      environment without actual cellular contact. Immunohistochemical staining for
      TNFalpha, Fas, and Fas ligand (Fas-L) was performed. Apoptosis was detected via
      the TUNEL method. Images were analyzed with ImagePro-Plus. Statistical analyses
      were done with significance determined at P < 0.05. RESULTS: Chang hepatocytes
      demonstrated a significant increase in the levels of TNF, Fas, and Fas-L when
      cocultured with neuroblastoma cells (P < 0.005). In addition, the cocultured
      hepatocytes had a 20-fold increase in the apoptotic rate (P < 0.001).
      Neuroblastoma cells had no demonstrable level of Fas or TNF when grown alone and
      in cocultures. Neuroblastoma cells that were grown alone had an elevated level of
      Fas-L, but this level diminished by 44% when cocultured with hepatocytes (P <
      0.001). CONCLUSION: An upregulated TNF/Fas receptor-ligand system may be
      responsible for increased apoptosis in hepatocytes when cocultured with
      neuroblastoma. This upregulation may be due to release of neuroblastoma-derived
      Fas ligand into the media. Tumors may alter the regulation of apoptosis in
      surrounding tissues via the death receptors.

PMID- 10334895
TI  - Chromosome 9p21 loss and p16 inactivation in primary sclerosing cholangitis
      associated cholangiocarcinoma.
AB  - BACKGROUND: Cholangiocarcinoma is a frequent complication of primary sclerosing
      cholangitis and is a leading cause of mortality in patients with this disease.
      The tumor suppressor gene p16 is commonly inactivated in many neoplasms; however,
      the role of p16 in the pathogenesis of cholangiocarcinoma is unclear. Therefore,
      we examined the role of p16 inactivation in the pathogenesis of
      cholangiocarcinoma associated with primary sclerosing cholangitis. MATERIALS AND
      METHODS: Paraffin-embedded sections from 10 patients who developed
      cholangiocarcinoma in the setting of primary sclerosing cholangitis were
      examined. Chromosomal loss at 9p21 was determined using microsatellite analysis.
      Methylation of a CpG island in the promoter region of the p16 gene was determined
      using methylation-specific polymerase chain reaction. p16 inactivation was also
      determined using immunohistochemistry. RESULTS: Allelic loss at chromosome 9p21
      was present in 9 of 10 tumors (90%). Methylation of the p16 promoter was present
      in 2 of the 8 tumors examined (25%). Four of seven tumors (57%) analyzed by
      immunohistochemistry demonstrated an absence of p16 nuclear staining.
      CONCLUSIONS: Loss of chromosome 9p21 and inactivation of the p16 tumor suppressor
      gene are common events in primary sclerosing cholangitis-associated
      cholangiocarcinoma and may play a role in the high incidence of
      cholangiocarcinoma in patients with primary sclerosing cholangitis.

PMID- 10334896
TI  - Small bowel adaptation is dependent on site of massive enterectomy.
AB  - BACKGROUND: Changes in amino acid transport after massive enterectomy occur in a
      nutrient-dependent fashion and may affect long-term outcome. Epidermal growth
      factor (EGF) can enhance nutrient transport and a defective epidermal growth
      factor receptor (EGF-R) has been noted to attenuate adaptation. Most animal
      studies, however, have examined only a single site of resection. This does not
      mimic the clinical situation where disease dictates the site of resection leading
      to proximal, middle, or distal enterectomies. We hypothesize that the site of
      massive enterectomy will alter nutrient transport and EGF-R levels in the
      residual gut. MATERIALS AND METHODS: New Zealand White rabbits were randomized to
      control, midgut division, or 70% resection (proximal, midgut, or distal). After 1
      week, sodium-dependent transport of glucose, glutamine, alanine, and leucine into
      brush border membrane vesicles was quantitated. EGF-R protein was determined by
      Western blot analysis. RESULTS: At baseline, amino acid transport was greater in
      ileum than jejunum. Surgery alone elevated glutamine and leucine jejunal
      transport by 130 and 97%, respectively, over controls (P < 0.05). Midgut
      resection increased jejunal glutamine transport 61% over control (P < 0.05). In
      contrast, distal resection increased jejunal alanine transport by 150% over
      controls with no change in glutamine (P < 0.05). After midgut resection, EGF-R
      was significantly greater (124%) in ileum then in jejunum in whole mucosa
      homogenates. Proximal resection significantly lowered ileal EGF-R compared to
      that seen in midgut resected residual ileum. CONCLUSIONS: Site of massive
      resection is important in determining postoperative changes in nutrient transport
      and EGF-R.

PMID- 10334897
TI  - Hypophosphorylated retinoblastoma protein is associated with G2 arrest in
      esophageal squamous cell carcinoma.
AB  - Hypophosphorylated retinoblastoma (Rb) gene product binds critical transcription
      factors, leading to G1 arrest in a number of conditions, including following DNA
      damage. We have previously shown that irradiated esophageal squamous cell
      carcinoma (ESSC) cells undergo predominantly G2 arrest, with increases in
      inhibitors of Rb phosphorylation. We thus hypothesized that this G2 arrest would
      be accompanied by increases in hypophosphorylated Rb protein (pRb). We sequenced
      the Rb genes of three human ESSC lines (KYSE) following reverse transcription
      polymerase chain reaction of exons A-E. Western gels were performed on protein
      extracts for pRb. Cells were irradiated at 6 Gy, and protein was extracted at 6
      h. ELISA was used to measure hypophosphorylated pRb in radiated versus control
      cells. Student's t test was used to compare results. All lines had wild-type Rb
      genes. Western gels confirmed the presence of pRb. There were significant
      increases in hypophosphorylated pRb in all three lines following irradiation (no
      line with less than a 100% increase). We have thus shown that irradiation-induced
      G2 arrest occurs in association with wild-type Rb genes and that there is
      associated hypophosphorylation of pRb. This supports our data describing a
      further role for other G1 mediators, such as p21, in G2 arrest. Further
      investigations into therapies to expoit this cell cycle checkpoint are warranted
      and planned.

PMID- 10334898
TI  - The effect of the duration and structure of a surgery clerkship on student
      performance.
AB  - The emphasis on a generalist professional education has led to shortening and
      restructuring of the surgery clerkship in the curricula of many medical schools.
      Little data exist regarding the effect of these changes on student performance.
      Therefore, we examined the effect of the length, timing, and content of the third
      year surgery rotation on several clerkship and postclerkship performance measures
      of 487 students from July 1994 to July 1998. In addition, students' perceptions
      regarding their ability to understand surgical disease topics were surveyed. The
      8-week clerkship (n = 232) was associated with higher NMBE surgery test scores
      (510.5 +/- 6.3 versus 457.4 +/- 10.0, P < 0.05) resulting in higher final
      clerkship grades (5.15 +/- 0.04 versus 4.87 +/- 0.03, P < 0.05). Although
      clerkship length had no significant effect on USMLE step 2 total or surgery
      subsection scores, the longer clerkship was associated with higher total (70.6 +/
      0.37 versus 68. 8 +/- 0.50, P < 0.05) and abdominal pain station (81.87 +/- 0.71
      versus 79.54 +/- 0.73, P < 0.05) OCSE scores. Students rotating on surgery during
      the second half of third year (n = 233) had higher NMBE surgery test scores
      (513.1 +/- 8.9 versus 460.5 +/- 11.2, P < 0. 05) and final grades (5.17 +/- 0.03
      versus 4.81 +/- 0.04, P < 0.05). Although the timing of the surgery clerkship did
      not significantly affect total OSCE scores, students who rotated on surgery in
      the second half of third year performed significantly better year on the
      abdominal pain OSCE station (80.47 +/- 0.92 versus 76.49 +/- 1.27, P < 0.05).
      Students who rotated on general surgery (n = 298) performed significantly better
      on the NBME surgery test (525.6 +/- 6.0 versus 459.6 +/- 9.1, P < 0.05), although
      this did not significantly affect the final grade. Although general versus
      subspecialty surgery rotation did not significantly affect total OSCE scores,
      students rotating on general surgery performed significantly better on the
      abdominal pain OSCE station (81.21 +/- 0.91 versus 78.17 +/- 0.32, P < 0.05). The
      length, timing, and content of the third year surgery rotation had no significant
      effect on performance on the oral examination. Students who had a 6-week
      clerkship and students who lacked exposure to general surgery felt their surgery
      rotation failed to prepare them to understand a number of surgical topics as well
      as students who had an 8-week clerkship or students who rotated on general
      surgery. The length, timing, and content of the surgery clerkship affect some
      clerkship performance measures and student perceptions of their understanding of
      surgical disease topics. While cognitive differences related to clerkship length
      are no longer detectable at the end of the third year of medical school,
      differences related to the acquisition of some clinical skills persist after the
      surgery clerkship.

PMID- 10334899
TI  - Cholesterol enhances membrane-damaging properties of model bile by increasing the
      intervesicular-intermixed micellar concentration of hydrophobic bile salts.
AB  - Bile salts are potent detergents that, at concentrations attained in bile and
      intestine, can disrupt cell membranes. Hepatic secretion of vesicles containing
      lecithin and cholesterol appears to be critical in preventing bile salt damage to
      hepatobiliary epithelia. We hypothesize that the protective effect of biliary
      lipids results from lowering of the bile salt intervesicular intermixed micellar
      bile salt concentration (IMMC) to which epithelial membranes are exposed. We
      further hypothesize that increases in biliary cholesterol, by reducing
      association of bile salts with vesicles and mixed micelles, may increase bile
      toxicity by raising the bile salt IMMC. METHOD: Large unilamellar lecithin
      vesicles (100 nm) with varying cholesterol:lecithin molar ratios (C:L) of 0, 0.5,
      and 1 were added to taurochenodeoxycholate (TCDCA), taurocholate (TCA), or
      taurodeoxycholate (TDCA) in Tris-buffered saline, pH 7.4. Human erythrocyte
      ghosts (model target membrane), prepared by osmotic hemolysis and resealed with
      [14C]inulin trapped inside, were added and incubated at 37 degrees C for 30 min
      and 4 h. Plasma membrane disruption was quantified by [14C]inulin release and
      bile salt IMMC was determined by ultrafiltration. RESULTS: Membrane disruption
      started at a concentration of 0.5 mM for TDCA, 1 mM for TCDCA, and 2 mM for TCA
      and was complete within 4 h at concentrations of 1, 2, and 4 mM, respectively.
      Addition of 2 mM lecithin to 2 mM TDCA, 4 mM TCDCA, or 5 mM TCA reduced or
      eliminated membrane leakage and lowered the IMMC. For TDCA and TCDCA, the
      protective effect of vesicles was entirely attributable to reduction in IMMC; in
      contrast for TCA, the protective effect exceeded that which would have been
      expected based solely on reduction of the IMMC. Inclusion of cholesterol
      attenuated the binding of bile salts to vesicles and raised the IMMC, thereby
      reducing the protective effect of lecithin over the time course of these studies.
      Although there was loss of phospholipid and cholesterol from the erythrocyte
      membranes on addition of bile acids even in the presence of vesicles, the ratio
      of cholesterol to phospholipid in the erythrocyte membrane did not change.
      CONCLUSION: Lecithin protects against membrane disruption by hydrophobic bile
      salts by lowering the IMMC. Cholesterol added to lecithin raises the bile salt
      IMMC and reduces or eliminates this protective effect. This mechanism of
      potentiation of bile salt toxicity by cholesterol may be an important contributor
      to the pathogenesis of gallbladder disease in cholesterol cholelithiasis.

PMID- 10334900
TI  - A functional anatomy of anticipatory anxiety.
AB  - Anticipatory anxiety is a complex combination of a future-oriented cognitive
      state, negative affect, and autonomic arousal. A dual-task paradigm of
      anticipation of electric shocks and a motor-learning task was used to examine the
      changes in neural patterns of activation associated with modulation of the
      cognitive state in anxiety by a distracting motor task. We used positron emission
      tomography (PET) and 15O-water to measure regional cerebral blood flow (rcbf) in
      10 healthy male volunteers. A 2x2 factorial design-(shock vs no shock) x (low vs
      high distraction) was used with three scans per condition. Twelve PET scans were
      performed on each subject. In six of these scans, subjects were given electric
      shocks. In all scans, subjects also simultaneously performed a motor repetition
      (low distraction) or learning (high distraction) task. Galvanic skin conductance
      (GSR), Spielberger State and Trait Anxiety Inventory (STAI), and self-report data
      were also collected. In comparisons between the shock and no-shock conditions,
      the main finding was of increased rcbf in the left insula (-38,8,8) (z = 4.85,
      P<0.05 corrected) and a homologous area in the right insula at a lower threshold
      (z =3.20, P = 0.001 uncorrected). Other areas activated were the right superior
      temporal sulcus, left fusiform, and left anterior cingulate. Using the STAI-state
      scores as a covariate of interest, significant correlations with rCBF were seen
      in the left orbitofrontal cortex, left insula, and left anterior cingulate
      cortex. There was no significant distraction effect as measured by the STAI, self
      report, GSR response or interactional analysis of the PET data. These findings
      support the role of paralimbic structures as neural substrates of anticipatory
      anxiety. The failure to demonstrate behavioral and neurophysiological changes
      with the distractor task may reflect the modest increases in anxiety with the
      shock, the relatively simple distractor task, and small sample size.

PMID- 10334901
TI  - Stimulus-dependent BOLD and perfusion dynamics in human V1.
AB  - Blood oxygenation level-dependent (BOLD) fMRI signals often exhibit pronounced
      over- or undershoot upon changes in stimulation state. Current models postulate
      that this is due to the delayed onset or decay of perfusion-dependent attenuating
      responses such as increased cerebral blood volume or oxygen consumption, which
      are presumed to lag behind the rapid adjustment of blood flow rate to a new
      steady-state level. If this view is correct, then BOLD overshoot amplitudes in a
      specific tissue volume should be correlated with steady-state increases in
      perfusion, independent of stimulus type. To test this prediction, we
      simultaneously recorded BOLD and relative perfusion signals in primary visual
      cortex while inducing graded perfusion increases with three types of visual
      stimulus. Two of these, a diffuse chromatic stimulus with no luminance variation
      and a very high spatial frequency luminance grating, did not produce detectable
      BOLD overshoot (or undershoot) when an equal mean luminance baseline was used.
      Radial checkerboard stimuli, however, caused pronounced over/undershoot of both
      BOLD and perfusion signals even when temporal mean luminance was held constant
      and stimulus contrast was adjusted to produce the same steady-state blood flow
      increases evoked by the other stimuli. Transient amplitudes were relatively
      invariant in spite of large changes in steady-state response, demonstrating
      nonlinear BOLD and perfusion step responses in human V1. These findings suggest
      that, rather than a purely tissue-specific biomechanical or metabolic phenomenon,
      BOLD overshoot and undershoot represent transient features in the perfusion
      signal whose effects may be amplified by slowly evolving blood volume changes.

PMID- 10334902
TI  - Localizing age-related changes in brain structure between childhood and
      adolescence using statistical parametric mapping.
AB  - Volumetric studies have consistently shown reductions in cerebral gray matter
      volume between childhood and adolescence, with the most dramatic changes
      occurring in the more dorsal cortices of the frontal and parietal lobes. The
      purpose of this study was to examine the spatial location of these changes
      employing methods typical of functional imaging studies. T1-weighted structural
      MRI data (1.2 mm) were analyzed for nine normally developing children and nine
      normal adolescents. Validity and reliability of the tissue segmentation protocol
      were assessed as part of several preprocessing analyses prior to statistical
      parametric mapping (SPM). Using SPM96, a simple contrast of average gray matter
      differences between the two age groups revealed 57 significant clusters (SPM[Z]
      height threshold, P<0.001, extent threshold 50, uncorrected). The pattern and
      distribution of differences were consistent with earlier findings from the
      volumetric assessment of the same subjects. Specifically, more differences were
      observed in dorsal frontal and parietal regions with relatively few differences
      observed in cortices of the temporal and occipital lobes. Permutation tests were
      conducted to assess the overall significance of the gray matter differences and
      validity of the parametric maps. Twenty SPMs were created with subjects randomly
      assigned to groups. None of the random SPMs approached the number of significant
      clusters observed in the age difference SPM (mean number of significant clusters
      = 5.8). The age effects observed appear to result from regions that consistently
      segment as gray matter in the younger group and consistently segment as white
      matter in the older group. The utility of these methods for localizing relatively
      subtle structural changes that occur between childhood and adolescence has not
      previously been examined.

PMID- 10334903
TI  - The role of the fusiform gyrus in successful encoding of face stimuli.
AB  - PET was used to measure regional cerebral blood flow (rCBF) while memorizing
      pictures of unfamiliar human faces presented one at a time (FaceMemory). Other
      conditions included: (1) FaceRepeat-memorization of four individual faces
      presented repeatedly; (2) FaceWatching-viewing passively single faces without
      overt memory demands; and (3) Scrambled-counting dots superimposed on pictures of
      scrambled faces. After each FaceMemory condition and after the final FaceWatching
      condition scan, recall was tested by measuring face recognition. Contrasting
      FaceMemory and Scrambled conditions revealed several temporal activations: right
      midfusiform and bilateral anterior fusiform gyri. Contrasting FaceWatching and
      Scrambled conditions showed bilateral activation in the temporal poles and in the
      anterior fusiform gyri. No hippocampal activation arose from any contrast. Region
      of interest analyses on the above areas showed correlations with performance: (1)
      only rCBF in the right midfusiform correlated positively with encoding during the
      FaceMemory and FaceWatching conditions; (2) in the right temporal polar cortex
      rCBF decreased during FaceMemory and correlated positively with performance,
      whereas rCBF increased during FaceWatching and correlated negatively with
      incidental performance; and (3) activity in the anterior fusiform gyri remained
      constant across the conditions of FaceMemory, FaceRepeat, FaceWatching, and
      Scrambled and was uncorrelated with performance. These data suggest an expanded
      mnemonic role for the right midfusiform in depth of processing/encoding of face
      information, temporal polar cortex in face perception and recognition, and
      anterior fusiform activity in featural visual feature processing.

PMID- 10334904
TI  - MRI of functional deactivation: temporal and spatial characteristics of
      oxygenation-sensitive responses in human visual cortex.
AB  - Magnetic resonance imaging (MRI) of neuronal "activation" relies on the elevation
      of blood flow and oxygenation and a related increase of the blood oxygenation
      level-dependent (BOLD) MRI signal. Because most cognitive paradigms involve both
      switches from a low degree of activity to a high degree of activity and vice
      versa, we have undertaken a baseline study of the temporal and spatial
      characteristics of positive and negative BOLD MRI responses in human visual
      cortex. Experiments were performed at 2.0 T using a multislice gradient-echo EPI
      sequence (TR = 1 s, mean TE = 54 ms, flip angle 50 degrees) at 2x2-mm2 spatial
      resolution. Activation and "deactivation" processes were accomplished by
      reversing the order of stimulus presentations in paradigms using homogeneous gray
      light and an alternating checkerboard as distinct functional states. For
      sustained stimulation (> or = 60 s) the two conditions resulted in markedly
      different steady-state BOLD MRI signal strengths. The transient responses to
      brief stimulation (< or = 18 s) differed insofar as activation processes
      temporally separate positive BOLD and negative undershoot effects by about 10 s,
      whereas negative BOLD effects and undershoot contributions overlap for
      deactivation processes. Apart from differences in stimulus features (e.g.,
      motion) the used activation and deactivation protocols revealed similar maps of
      neuronal activity changes.

PMID- 10334905
TI  - High-dimensional image registration using symmetric priors.
AB  - This paper is about warping a brain image from one subject (the object image) so
      that it matches another (the template image). A high-dimensional model is used,
      whereby a finite element approach is employed to estimate translations at the
      location of each voxel in the template image. Bayesian statistics are used to
      obtain a maximum a posteriori (MAP) estimate of the deformation field. The
      validity of any registration method is largely based upon the constraints or, in
      this instance, priors incorporated into the model describing the transformations.
      In this approach we assume that the priors should have some form of symmetry, in
      that priors describing the probability distribution of the deformations should be
      identical to those for the inverses (i.e., warping brain A to brain B should not
      be different probabilistically from warping B to A). The fundamental assumption
      is that the probability of stretching a voxel by a factor of n is considered to
      be the same as the probability of shrinking n voxels by a factor of n(-1). In the
      Bayesian framework adopted here, the priors are assumed to have a Gibbs form,
      where the Gibbs potential is a penalty function that embodies this symmetry. The
      penalty function of choice is based upon the singular values of the Jacobian
      having a lognormal distribution. This enforces a continuous one-to-one mapping. A
      gradient descent algorithm is presented that incorporates the above priors in
      order to obtain a MAP estimate of the deformations. We demonstrate this approach
      for the two-dimensional case, but the principles can be extended to three
      dimensions. A number of examples are given to demonstrate how the method works.

PMID- 10334906
TI  - Cartilage-derived growth factor and antitumor factor: past, present, and future
      studies.

PMID- 10334907
TI  - Pulsatile stretch activates mitogen-activated protein kinase (MAPK) family
      members and focal adhesion kinase (p125(FAK)) in cultured rat cardiac myocytes.
AB  - Recently, we demonstrated that pulsatile mechanical stretch induced rapid
      secretion of vascular endothelial growth factor (VEGF) by cultured rat cardiac
      myocytes in vitro. To investigate whether pulsatile stretch activates
      intracellular signaling in cardiac myocytes, we examined the activation of
      mitogen-activated protein kinase (MAPK) family members and focal adhesion kinase
      (p125(FAK)) in cultured rat cardiac myocytes. We found that pulsatile stretch
      rapidly phosphorylated p44/p42 MAPKs (extracellular signal-regulated protein
      kinase [ERK] 1/2), stress-activated protein kinase (SAPK), p38MAPK, and
      p125(FAK). The stretch-induced activation of ERKs was at least partly mediated by
      VEGF, which was shown to be induced by transforming growth factor (TGF)-beta, and
      was also partly dependent on tyrosine kinases as well as protein kinase C (PKC).
      These data provide the direct evidence that pulsatile stretch can activate
      intracellular signaling in cardiac myocytes and that this was at least partly
      mediated by VEGF, which may play a role in cardiac adaptation to mechanical
      overload.

PMID- 10334908
TI  - HSF1 activation occurs at different temperatures in somatic and male germ cells
      in the poikilotherm rainbow trout.
AB  - The heat shock factor 1 (HSF1) is the central actor of the response to
      hyperthermia in eukaryotic cells. In mammals, male germ cells are an exception
      among all cellular populations for their HSF1 activation occurs at low
      temperature. This feature was believed to be specific of homeotherms whose
      testicular compartment is located outside the main body cavity, where temperature
      is lower. In the present study, we show that in the poikilotherm rainbow trout,
      the maximal heat shock response of male germ cells, that are located in the same
      body compartment than the other organs, occurs also at a significantly lower
      temperature (22 degrees C) than for somatic cells (28 degrees C), regardless of
      culture conditions before heat shock. In addition, the acquisition of the HSE
      binding activity of HSF1 upon heat shock is not associated with the classical
      hsp70 mRNA accumulation. Taken together, these results strongly suggest the
      existence of a particular mode of heat shock response that could be specific of
      male germ cells but not restricted to homeotherms.

PMID- 10334909
TI  - Phosphorylation/dephosphorylation of androgen receptor as a determinant of
      androgen agonistic or antagonistic activity.
AB  - Protein phosphorylation/dephosphorylation is an important posttranslational
      modification that plays a critical role in signal transduction. The androgen
      receptor (AR) is under such control. We demonstrate that androgen receptor
      phosphorylation determines whether or not AR ligands perform as agonists or
      antagonists in LNCaP cells. Androgen receptor ligands (such as
      dihydrotestosterone and beta-estradiol) stimulate receptor expression and
      phosphorylation and, as a result, they act as agonists or partial agonists. In
      contrast, agents such as bicalutamide and estramustine inhibit the receptor
      phosphorylation and act as antagonists. This model is supported by gene
      expression and transactivation assays. Significant increases in levels of both
      mRNA and protein of prostate-specific antigen (PSA), a natural AR target gene,
      occur following the treatment of LNCaP cells with DHT, beta-estradiol, or
      hydroxyflutamide. In contrast, exposure of LNCaP cells to bicalutamide or
      estramustine results in a sharp decrease of PSA expression. Agonistic or
      antagonistic effect of these compounds on PSA expression parallels the level of
      phosphorylated, but not dephosphorylated androgen receptors. These agonistic or
      antagonistic effects are also observed in HeLa cells transfected with wild-type
      AR expression plasmid (pAR0) and AR-driven luciferase expression plasmid GRE-tk
      LUC in the presence of different groups of AR blockers. Our data indicate that
      the functional status of androgen receptors is strongly correlated with the
      phosphorylation status of the receptors, and that the phosphorylated androgen
      receptor is the form of the receptor transcriptionally active in regulation. Thus
      the androgen receptor phosphorylation/dephosphorylation may serve as a new
      molecular target for screening androgen antagonists for the treatment of prostate
      cancer.

PMID- 10334910
TI  - Developmentally regulated expression of a nonmuscle myosin heavy chain IIB
      inserted isoform in rat brain.
AB  - The alternatively spliced isoform of the nonmuscle myosin II heavy chain B (MHC
      B) with an insert of 21 amino acids at the 50- to 20-kDa junction of the globular
      region of myosin has been demonstrated to be expressed specifically in the
      central nervous system (CNS) in chicken. To explore the role of this B2 inserted
      isoform (MHC-B(B2)), immunoblot and immunoprecipitation analyses were performed
      using specific antibodies and extracts from rat tissues. MHC-B(B2) is present
      throughout the CNS, but is less abundant in the cerebrum and not expressed in the
      olfactory lobe at all. In the developing rat brain, MHC-B(B2) is expressed from
      postnatal day 10 (P10) in the cerebellum and increases markedly from P14. The
      appearance of MHC-B(B2) in the cerebrum (P28) is later than in the cerebellum.
      Additionally, we show that myosin IIB(B2) is homodimeric in its heavy chain
      subunit composition. These results suggest that myosin IIB(B2) might participate
      in cell motility in the neuronal cells of the mature CNS.

PMID- 10334911
TI  - Identification of three alternatively spliced variants of human CD28 mRNA.
AB  - CD28, expressed by T cells, plays a central role in providing costimulatory
      signals to T cells. The cd28 gene is organized into 4 exons. An alternatively
      spliced CD28 mRNA lacking most of the exon 2 has been previously evidenced. We
      report here that non stimulated human T cells express three additional
      alternatively spliced variants of CD28 mRNA (CD28a-c) in. The CD28a variant,
      expressed at similar levels to that of the full length CD28 mRNA encoding for the
      membrane form, lacks exon 3. This deletion introduces (i) a frame shift resulting
      in the addition of two extra amino acids and a premature stop codon and, (ii)
      induces the loss of the transmembrane region, suggesting that it could encodes
      for a soluble monomeric molecule which conserves the binding sites of CD28. The
      CD28b and CD28c variants, expressed at a low level compared with CD28a, are
      generated by deletion of most of the 3' end of exon 2 plus exon 3 and exon 2 plus
      exon 3, respectively. Activated T cells express only the membrane CD28 mRNA.
      These results suggest that resting human T cells may constitutively express both
      membrane and soluble CD28 which can differentially regulate the outcome of the T
      cell response.

PMID- 10334912
TI  - Phosphorylation induces conformational changes in the leukocyte NADPH oxidase
      subunit p47(phox).
AB  - The leukocyte NADPH oxidase of neutrophils is a membrane-bound enzyme that
      catalyzes the reduction of oxygen to at the expense of NADPH. The enzyme is
      dormant in resting neutrophils but becomes active when the cells are exposed to
      appropriate stimuli. During oxidase activation, the highly basic cytosolic
      oxidase component p47(phox) becomes phosphorylated on several serines and
      migrates to the plasma membrane. We report here that phosphorylation of p47(phox)
      with protein kinase C induces conformational changes, as reflected by a
      fluorescence change of N, N'-di-methyl-N(iodoacetyl)-N'-(7-nitrobenz-2-oxa-1,3
      diazol-4-yl) ethyleneamine (IANBD)-labeled p47(phox). We propose that this
      alteration in conformation results in the appearance of a binding site through
      which p47(phox) interacts with cytochrome b558 during the activation process. In
      addition, the present study indicates that other oxidase components, such as
      p67(phox) and p22(phox), influence the conformation of p47(phox).

PMID- 10334913
TI  - Multidrug-resistant phenotype influences the differentiation of a human colon
      carcinoma cell line.
AB  - The human colon carcinoma cell line HT29-D4, which constitutively expresses a
      very low level of the MDR1 gene product, was made multidrug resistant by
      transfection with a human MDR1 cDNA from the pHaMDR1/A expression vector and
      selection by colchicine. Resistant clones were 3- to 15-fold resistant to
      colchicine and were cross-resistant to doxorubicin (3- to 4-fold). MDR1 gene
      expression was associated with the expression of functional P-glycoprotein (gp
      170); the function was reversed by verapamil and cyclosporin A. HT29-D4 cells are
      able to differentiate in vitro by replacement of glucose by galactose in the
      culture medium and also to release the carcinoembryonic antigen (CEA). Under
      these culture conditions, MDR1 mRNA and gp-170 were always expressed and the
      protein remained functional. Upon galactose treatment, resistant clones were less
      differentiated since they showed a heterogeneous monolayer organization
      accompanied by heterogeneous staining of cell-surface CEA and a high decrease (60
      90%) of CEA release.

PMID- 10334914
TI  - The requirement of both intracellular reactive oxygen species and intracellular
      calcium elevation for the induction of heparin-binding EGF-like growth factor in
      vascular endothelial cells and smooth muscle cells.
AB  - Heparin-binding EGF-like growth factor (HB-EGF), which is a potent mitogen for
      vascular smooth muscle cells (SMC) and fibroblasts, has been reported to be
      strongly implicated in atherosclerosis and wound healing. HB-EGF mRNA is known to
      be induced by thrombin, angiotensin-II, basic fibroblast growth factor (bFGF),
      platelet-derived growth factor (PDGF), and HB-EGF itself in SMC. In vascular
      endothelial cells (EC), its mRNA is induced by tumor necrosis factor-alpha and
      interleukin-1beta. Only phorbol 12-myristate 13-acetate is a common inducer for
      HB-EGF mRNA. The present study shows that calcium ionophore A23187 also induced
      HB-EGF mRNA in both SMC and in EC and that both intracellular reactive oxygen
      species (ROS) and an increase in calcium levels were essential for the induction
      of this growth factor mRNA. While HB-EGF caused an increase in both intracellular
      ROS and calcium in SMC, it increased only calcium, but not the intracellular ROS
      in EC. When the intracellular ROS was elevated by treatment with hydrogen
      peroxide (H2O2) or by depletion of glutathione by buthionine sulfoxamine, both HB
      EGF and thrombin were observed to upregulate HB-EGF mRNA in EC. These data
      suggest that H2O2, produced by activated leukocytes in inflammatory lesions,
      upregulates HB-EGF mRNA by cooperating with thrombin, angiotensin-II, and the
      above growth factors. Since activated macrophages under the EC are thought to
      elevate the ROS in neighboring EC, this mechanism might play a major role in the
      progression of atherosclerosis and for wound healing.

PMID- 10334915
TI  - A detailed study on the role of sex steroid milieu in determining plasma leptin
      concentrations in adult male and female rats.
AB  - We examined the effects of sex steroid milieu on plasma leptin levels in adult
      male and female rats. Since the body weight is known to influence leptin
      concentrations, the hormone was measured in rats with a very similar body weight
      (about 250 g) throughout this study. Plasma leptin levels were significantly
      higher in female than in male rats. Orchidectomy (ODX) caused a significant rise
      in leptin, and replacement of a physiological dose of testosterone (T) completely
      abolished the effect of ODX. Since the effect of tamoxifen (estrogen antagonist)
      coadministered with T on leptin levels in ODX rats was the same as that of T
      alone, it was suggested that the suppressive effect of T on leptin may be
      mediated by the androgenic potency of T, but not by its aromatized product,
      estradiol. In female rats, plasma leptin concentrations did not change
      significantly during the estrous cycle. Furthermore, leptin levels were not
      affected either by ovariectomy alone or by the administration after ovariectomy
      of physiological doses of estradiol, progesterone, or both. This is the first
      study to demonstrate in rats with a very similar body weight the existence of a
      clear sexual difference in plasma leptin levels, and also a suppressive action of
      T on the adipocyte hormone concentrations.

PMID- 10334916
TI  - Cloning and characterization of SOB1, a new testis-specific cDNA encoding a human
      sperm protein probably involved in oocyte recognition.
AB  - A human sperm-oocyte binding protein, SOB1, was purified by two dimensional gel
      electrophoresis and sequenced. This protein was selected because it was
      recognized by a monoclonal antibody that inhibited the binding of human sperm to
      zona-free hamster oocytes. The sequences of the tryptic peptides were used to
      design degenerate primers. These were used to amplify a specific fragment from
      human testis cDNA by the polymerase chain reaction. This 1233 bp fragment was
      extended in 3' and 5' by RACE to obtain the 3 kb full length SOB1 cDNA. Sequence
      analysis indicated that the deduced open reading frame encodes a 853 amino acid
      protein, with a molecular mass of 94. 7 kDa. This is a new testis-specific cDNA.
      It is 27, 32.8 and 34.4% homologous to three sperm proteins, HI, Fsc1 and AKAP82
      respectively. A single 3kb transcript was demonstrated only in the testis by
      northern blot analysis. It is a single copy gene, well conserved among mammals
      and located on human chromosome 12 at band p13.

PMID- 10334917
TI  - Loss of the bcl-2 phosphorylation loop domain increases resistance of human
      leukemia cells (U937) to paclitaxel-mediated mitochondrial dysfunction and
      apoptosis.
AB  - The impact of ectopic expression of an N-terminal phosphorylation loop deletant
      Bcl-2 protein (Bcl-2Delta32-80) on the response of U937 monoblastic leukemia
      cells to paclitaxel was examined. In contrast to recent findings in HL-60 cells
      (Fang et al., Cancer Res. 58, 3202, 1998), U937 cells overexpressing Bcl-2Delta32
      80 were significantly more resistant than those overexpressing full-length
      protein to caspase-3 and -9 activation, PARP degradation, and apoptosis induced
      by paclitaxel (500 nM; 18 h). Bcl-2Delta32-80 was also more effective than its
      full-length counterpart in opposing paclitaxel-mediated mitochondrial
      dysfunction, e.g., loss of mitochondrial membrane potential (Deltapsim) and
      cytochrome c release into the cytoplasm. Enhanced resistance of U937/Bcl-2Delta32
      80 cells to paclitaxel was observed primarily in the G2M population. Together,
      these findings demonstrate that deletion of the Bcl-2 phosphorylation loop domain
      increases resistance of U937 leukemia cells to paclitaxel-mediated mitochondrial
      damage and apoptosis and suggest that factors other than, or in addition to,
      phosphorylation contribute to Bcl-2-related cytoprotectivity against paclitaxel
      in this model system.

PMID- 10334918
TI  - Direct microsensor measurement of nitric oxide production by the osteoclast.
AB  - Nitric oxide (NO) triggers marked osteoclast retraction which closely resembles
      that due to Ca2+. The effect of Ca2+ has been attributed to a stimulated release
      of NO. Here, we show for the first time, by direct measurement with a
      microsensor, that osteoclasts do indeed produce NO and that this production is
      enhanced by a high Ca2+. We also show that the Ca2+ ionophore, A23187, mimics the
      latter. Furthermore, osteoclasts on dentine produce more NO than osteoclasts on
      glass and NO release from dentine-plated osteoclasts is much less sensitive to
      stimulation by Ca2+. Finally, the microsomal Ca2+ store-depleting agent,
      thapsigargin, attenuates NO release only from osteoclasts on glass, suggesting
      that stored Ca2+ has the dominant effect in modulating NO release from non
      resorbing cells. NO is a powerful inhibitor of bone resorption: a direct
      demonstration of its production is therefore strong evidence for a role in
      modulating osteoclast function.

PMID- 10334919
TI  - Activation of Gi1 by lysophosphatidic acid receptor without ligand in the
      baculovirus expression system.
AB  - Lysophosphatidic acid (LPA) receptor has been attracting many neuroscientists'
      concerns, since it was reported to have a potential role in the neurogenesis,
      which occurs in the ventricular zone of the developing and adult brain. In the
      present experiments using baculovirus expression system, the LPA receptor encoded
      by ventricular zone gene 1 (Edg-2/Vzg-1) was found to be functionally coupled to
      Gi1, Goa, and G11, but not to GS. The coexpression of LPA receptor markedly
      decreased the expression of G protein alphai1 or alphaoa subunit, while the basal
      [35S]GTPgammaS binding significantly increased in the Gi1-preparation. The
      Scatchard Plot analysis indicates that the expression of LPA-receptor (Edg-2/Vzg
      1) showed stimulation of Gi1 without agonist. These results suggest the Edg-2/Vzg
      1 has an intrinsic acctivity on Gi1.

PMID- 10334920
TI  - Increased uncoupling protein2 mRNA in white adipose tissue, and decrease in
      leptin, visceral fat, blood glucose, and cholesterol in KK-Ay mice fed with
      eicosapentaenoic and docosahexaenoic acids in addition to linolenic acid.
AB  - The effects of n-3 polyunsaturated fatty acids (n-3PUFA) on obesity and diabetes
      were examined using KK-Ay mice fed with perilla oil (P), soybean oil (S), or lard
      (L), and those containing 30% fish oil (PF, SF, or LF), containing
      eicosapentaenoic acid (EPA = 9.9%) and docosahexaenoic acid (DHA = 18.0%).
      Perilla oil contained the largest proportion of linolenic acid (LNA = 61.9%).
      Computerized tomography (CT) scans showed narrower areas of visceral fat in the
      abdominal cross sections of groups given fish oil (PF, SF, and LF) and lower
      leptin levels (p < 0.05-p < 0.001) compared with controls (P, S, and L), without
      significant changes in energy intake and body weight. The highest plasma n-3PUFA
      content (21.31 +/- 0.35%) was attained with PF. This group contained 2.6-fold
      more plasma DHA (p < 0.001), and expressed 2.7-fold more UCP2 mRNA in white
      adipose tissue (p < 0.01) than in the P group. The epididymal fat pad (p < 0.05)
      weighed less, and levels of blood glucose (p < 0.05) and total cholesterol (p <
      0.01) were reduced in PF compared with P.

PMID- 10334921
TI  - Induction of heme oxygenase-1 in the rat brain by kainic acid-mediated
      excitotoxicity: the dissociation of mRNA and protein expression in hippocampus.
AB  - Heme oxygenase-1 (HO-1) is induced under various stresses. Here we report the
      induction and localization of HO-1 in the rat brain by intraperitoneal
      administration of kainic acid (KA). Both mRNA and protein of HO-1 were markedly
      induced by KA treatment, and each maximal induction was observed 24 h after KA
      administration. In situ hybridization analysis showed that HO-1 mRNA appeared
      predominantly in glial cells, and confined neurons were positive in the cerebral
      cortex, basal ganglia, and hippocampal pyramidal cell layer. Immunohistochemical
      analysis showed that the positive cells in the cerebral cortex and hippocampus
      were mainly astrocytes and microglia, whereas neurons in the basal ganglia showed
      intense immunoreactivity. We also demonstrate the dissociation between HO-1 mRNA
      and protein level in the hippocampal pyramidal neurons, which is known to be
      vulnerable against excitotoxicity, and discuss the correlation between this
      dissociation and the vulnerability of hippocampal pyramidal neurons.

PMID- 10334922
TI  - Bone morphogenetic protein-2 enhances osteoclast formation mediated by
      interleukin-1alpha through upregulation of osteoclast differentiation factor and
      cyclooxygenase-2.
AB  - Bone morphogenic protein-2 (BMP-2) is a member of the transforming growth factor
      beta (TGF-beta) superfamily. While BMP-2 is capable of inducing bone formation
      ectopically, little is known about its role on osteoclastogenesis. In this study,
      we examined the effect of BMP-2 on osteoclast-like multinucleated cell (OCL)
      formation in cocultures of osteoblast-like cells and hematopoietic cells of bone
      marrow origin. BMP-2 alone did not stimulate OCL formation in this culture
      system; however, it strongly enhanced OCL formation in a dose-dependent fashion
      in the presence of interleukin-1alpha (IL-1alpha). Western blot analysis showed
      that a simultaneous addition of BMP-2 and IL-1alpha synergistically enhanced
      cyclooxygenase-2 (COX-2) expression in osteoblast-like cells. Moreover, Northern
      blot analysis revealed that the level of osteoclast differentiation factor (ODF)
      mRNA increased by treatment with BMP-2 and IL-1alpha in osteoblast-like cells. It
      is noted that BMP-2 alone did cause an increase in the expression of both COX-2
      and ODF genes. The stimulatory effect of BMP-2 was abolished by adding
      nonsteroidal anti-inflammatory drugs, such as indomethacin and a selective COX-2
      inhibitor NS-398. Addition of NS-398 inhibited the expression of the ODF gene in
      osteoblast-like cells treated with BMP-2 and IL-1alpha. These results indicated
      that the combination of BMP-2 and IL-1alpha stimulated osteoblast-like cells to
      elevate the expression of both COX-2 and ODF genes, resulting in an enhanced OCL
      formation. Since BMP-2 alone induced the expression of COX-2 and ODF genes in
      osteoblast-like cells, it appears to be one of the regulating factors of
      osteoclastogenesis.

PMID- 10334923
TI  - In vivo interaction of AF-6 with activated Ras and ZO-1.
AB  - AF-6 contains two putative Ras-associating domains (RA domains) which are seen in
      several Ras effectors such as RalGDS and RIN1. We previously showed that an AF-6
      fragment containing the amino-terminal (N-terminal) RA domain directly binds to
      activated Ras and ZO-1 in vitro. In this study, we showed that a single amino
      acid mutation in the N-terminal RA domain of AF-6 abolished the interaction of AF
      6 with activated Ras and that the sites of this critical amino acid residue were
      similar to those for Raf-1 and RalGDS. The overexpression of the N-terminal RA
      domain of AF-6 inhibited the Ras-dependent c-fos promoter/enhancer stimulation in
      NIH3T3 cells. Endogenous AF-6 was coimmunoprecipitated with activated Ras from
      Rat1 cells expressing activated Ras. Moreover, we showed that AF-6 was
      coimmunoprecipitated with ZO-1 from Rat1 cells. Taken together, these results
      indicate that the Ras-interacting region on AF-6 is structurally similar to that
      on Raf-1 and on RalGDS and that AF-6 interacts with activated Ras and ZO-1 in
      vivo.

PMID- 10334924
TI  - Fragments from actin binding protein (ABP-280; filamin) insert into reconstituted
      lipid layers.
AB  - Previous computer analyses suggested two possible lipid binding sites, residues
      49-71 and 131-155, of the primary amino acid sequence on ABP-280 (filamin), which
      could facilitate membrane attachment/insertion. We expressed these regions as
      fusion proteins with schistosomal GST and investigated their interaction with
      mixtures of zwitterionic (dimyristoyl-l-alpha-phosphatidylcholine, DMPC) and
      anionic (dimyristoyl-l-alpha-phosphatidylglycerol, DMPG) phospholipids in
      reconstituted lipid bilayers by differential scanning calorimetry (DSC). Using
      vesicles of mixed DMPC/DMPG with increasing fusion protein concentrations, we
      established in calorimetric assays a decrease of the main chain transition
      enthalpy, DeltaH, and a shift in chain melting temperature. This is indicative of
      the insertion of these fragments into the hydrophobic region of lipid membranes.
      We confirmed these findings by the film balance technique using lipid monolayers
      (DMPG). The binding judged from both methods was of moderate affinity.

PMID- 10334925
TI  - Sequence analysis identifies a ras-associating (RA)-like domain in the N-termini
      of band 4.1/JEF domains and in the Grb7/10/14 adapter family.
AB  - RA (RalGEF/AF6 or Ras-associating) domains are found in a wide variety of
      proteins, several of which are known to be Ras-GTP effectors. The three
      dimensional structure of the RA domain has been experimentally determined in Ral
      guanine nucleotide exchange factor (Ral-GEF) and found to be similar to that of
      the Ras-binding domain of c-Raf1, in spite of a very low level of sequence
      identity. Using various approaches of sequence analysis, including automatic
      procedures such as BLAST2, profilescan, and hidden Markov models (HMM), as well
      as the bidimensional hydrophobic cluster analysis (HCA), here we found that a
      region with a similar structure is also present at the N-terminus of the band
      4.1/JEF domain of KIAA0316 (a human cDNA open reading frame) and H09G03.2 (a
      related protein sequence predicted from C. elegans genome cloning), as well as in
      a particular class of adapter proteins including Grb7, Grb10, Grb14, MIG-10, and
      PRP48. Although the structural conservation of this motif does not necessarily
      imply a conservation of its ability to bind small GTPases of the Ras superfamily,
      several proteins with a band 4.1/JEF domain and adapters of the Grb7 group have
      close functional relationships with such small GTPases. Thus, our finding raises
      the intriguing possibility of a direct interaction between members of these two
      groups of proteins and Ras-like GTP-binding proteins.

PMID- 10334926
TI  - Mapping regions of the beta1 integrin cytoplasmic domain involved in migration
      and survival in primary oligodendrocyte precursors using cell-permeable
      homeopeptides.
AB  - The mapping of regions within integrin cytoplasmic domains responsible for the
      different effects on cell behaviour is an important part of an analysis of
      integrin-mediated signalling. In order to facilitate this analysis in primary
      cells, we have used cell-permeable homeopeptides to deliver sequences mimicking
      parts of the integrin beta1 cytoplasmic domain into the cell. In a study using
      oligodendrocyte precursors, the cells that give rise to myelin-forming
      oligodendrocytes during CNS development, we show that these peptides can be used
      to manipulate beta1 integrin signalling and that the regions of the cytoplasmic
      domain involved in migration and survival are distinct. Peptides mimicking the N
      terminal portion of the cytoplasmic domain previously implicated in binding to
      Focal Adhesion Kinase (FAK) induce apoptosis, while peptides mimicking more C
      terminal sequences do not cause cell death. In contrast they show that the NPIY
      sequence, the N-terminal one of two NPXY motifs previously implicated in
      signalling, is involved in migration. Peptides containing this sequence promote
      migration while alteration of NPIY to NPIA makes the peptide inhibitory to
      migration. Our results show that these peptides represent a novel approach to
      integrin signalling that allow rapid definition of critical cytoplasmic sequences
      in primary cells.

PMID- 10334927
TI  - Glycated serum albumin-induced nitric oxide production in vascular smooth muscle
      cells by nuclear factor kappaB-dependent transcriptional activation of inducible
      nitric oxide synthase.
AB  - Glycated proteins, including serum albumin, may be involved in the pathogenesis
      of diabetic vasculopathy. Recent evidence suggests that expression of inducible
      nitric oxide synthase (iNOS) in vascular smooth muscle cells (VSMC) may, in part,
      promote atherosclerosis by increasing local oxidative stress. We therefore
      investigated whether VSMC exposed to glycated human serum albumin (GHSA) produce
      nitric oxide (NO) by increasing iNOS expression through transcriptional
      activation of the iNOS gene and whether this process is dependent on nuclear
      factor kappaB (NF-kappaB) activation. Treatment of VSMC with GHSA causes
      activation of NF-kappaB and the iNOS promoter. Induction of NF-kappaB and the
      iNOS promoter by GHSA exhibited dose-dependent kinetics at concentrations ranging
      from 3 to 1000 microgram/ml. GHSA alone was a weak inducer of NO production in
      VSMC as measured by determining nitrite levels, and interferon-gamma alone was
      totally ineffective, whereas the combination of GHSA and interferon-gamma was a
      strong stimulus. This synergy for NO production corresponded to Northern blot
      analyses of iNOS mRNA expression. Thus, GHSA may promote atherosclerosis in part
      by activation of NF-kappaB and upregulation of iNOS, thereby fostering local
      inflammation and oxidative stress.

PMID- 10334928
TI  - No metal cofactor in orotidine 5'-monophosphate decarboxylase.
AB  - Orotidine 5'-monophosphate decarboxylase (OMP decarboxylase, ODCase) is an
      important enzyme that catalyzes the final step of de novo pyrimidine nucleotide
      biosynthesis. The mechanism of this unique enzyme and whether metal ions play any
      role in catalysis have been topics of intense research interest. In this report,
      the role of Zn in ODCase was reexamined. Atomic absorption (AA) and X-ray
      absorption (XAS) spectroscopic studies did not detect zinc in active enzyme
      samples at high concentration. The XAS results also indicated the absence of
      other transition metal ions in ODCase.

PMID- 10334929
TI  - Role of tryptophanyl residues in tobacco acetolactate synthase.
AB  - Acetolactate synthase (ALS) catalyzes the first common step in the biosynthesis
      of valine, leucine, and isoleucine. ALS is the target of three classes of
      herbicides, the sulfonylureas, the imidazolinones, and the triazolopyrimidines.
      Five mutants (W266F, W439F, W490F, W503F, and W573F) of the ALS gene from
      Nicotiana tabacum were constructed and expressed in Escherichia coli, and the
      enzymes were purified. The W490F mutation abolished the binding affinity for
      cofactor FAD and inactivated the enzyme. The replacement of Trp573 by Phe yielded
      a mutant ALS resistant to the three classes of herbicides. The other three
      mutations, W266F, W439F, and W503F, did not significantly affect the enzymatic
      properties and the sensitivity to the herbicides. These results indicate that the
      Trp490 residue is essential for the binding of FAD and that Trp573 is located at
      the herbicide binding site. The data also suggest that the three classes of
      herbicides bind ALS competitively.

PMID- 10334930
TI  - Porcine guanylin and uroguanylin: cDNA sequences, deduced amino acid sequences,
      and biological activity of the chemically synthesized peptides.
AB  - Guanylin and uroguanylin are structurally related intestinal peptide hormones
      which were purified from a limited number of mammals and are capable of
      activating the particulate guanylate cyclase-C. Although the biological functions
      of guanylin and uroguanylin are not yet clarified in detail, they are involved in
      the regulation of the intestinal water and electrolyte balance. In order to
      verify the general importance of this hormone system in mammals, we cloned the
      corresponding cDNAs from pig. Here, we present the nucleotide sequences and the
      deduced amino acid sequences representing porcine guanylin and uroguanylin. The
      expression patterns of the corresponding genes, as shown by Northern
      hybridization and RT-PCR analysis, resemble those of the human homologues.
      Further, we demonstrate the bioactivity of both porcine peptide hormones by
      inducing the intracellular cGMP production in human T84 cells and by ion
      transport experiments using porcine intestinal mucosa in the Ussing chamber.

PMID- 10334931
TI  - Molecular and histological evaluation of pancreata from patients with a
      mitochondrial gene mutation associated with impaired insulin secretion.
AB  - A mutation in mitochondrial DNA, which was originally identified in patients with
      mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes
      (MELAS), can be associated with a subtype of diabetes mellitus. To determine the
      molecular and histological basis of impaired insulin secretion in the subjects
      with this mutation, we studied autopsy pancreata specimens from eight subjects
      diagnosed as having MELAS. The 3243 bp mutation was identified in seven out of
      eight pancreata examined. Immunohistochemical studies demonstrated a reduction in
      total islet mass, and in the numbers of both B and A cells. No evidence of
      insulitis or apoptosis was found. These data suggested that the 3243 bp mutation
      may cause the reduction of islet cells, mainly through mechanisms other than
      autoimmune destruction.

PMID- 10334932
TI  - gamma-tocopherol decreases ox-LDL-mediated activation of nuclear factor-kappaB
      and apoptosis in human coronary artery endothelial cells.
AB  - gamma-Tocopherol, produced by many plants, is the major form of tocopherol in the
      United States diet. It is an effecient protector of lipids against peroxidative
      damage. Epidemiologic studies show that supplementation of diet with gamma
      tocopherol is inversely related to the risk of death from cardiovascular disease.
      This study was conducted to examine the role of gamma-tocopherol in oxidized LDL
      (ox-LDL)-induced nuclear factor (NF)-kappaB activation and apoptosis in human
      coronary artery endothelial cells (HCAECs). Cultured HCAECs were treated with ox
      LDL (10-40 microgram/ml). Incubation of HCAECs with ox-LDL resulted in apoptosis
      of HCAECs, as determined by TUNEL and DNA laddering. Ox-LDL degraded IkappaB
      protein and activated NF-kappaB in HCAECs (both P < 0.01 vs control), as
      determined by Western blot. Treatment of cells with gamma-tocopherol attenuated
      ox-LDL-mediated degradation of IkappaB and activation of NF-kappaB (both P < 0.01
      vs ox-LDL alone). The presence of gamma-tocopherol also reduced ox-LDL-induced
      apoptosis (P < 0.01 vs ox-LDL alone). A high concentration of gamma-tocopherol
      (50 micromol/L) was more effective than the low concentration of gamma-tocopherol
      (10 micromol/L) in this process. These observations show that ox-LDL induces
      apoptosis of HCAECs at least partially by activation of NF-kappaB signal
      transduction pathway. gamma-Tocopherol significantly decreases ox-LDL-induced
      apoptosis of HCAECs by inhibiting the activation of NF-kappaB.

PMID- 10334933
TI  - Mapping of the antigenic regions of streptokinase in humans after streptokinase
      therapy.
AB  - Streptokinase (SK) is efficaciously used as a thrombolytic drug for the treatment
      of myocardial infarction. Being a bacterial protein, SK is immunogenic in humans.
      Therefore, resulting from SK therapy, patients become immunized and anti-SK
      antibody (Ab) titers rise post-treatment. High Ab titers might provoke severe
      immune reactions during SK therapy and neutralize SK activity, preventing
      effective thrombolysis. Spot synthesis combined with peptide library techniques
      is a useful tool for studying protein-peptide interactions on continuous
      cellulose membranes. Here, we report on the mapping of antigenic regions of SK
      using a spot-synthesized peptide library and human total sera from patients
      receiving SK therapy. All tested samples have high anti-SK Ab titers and most of
      them show significant SK neutralizing capacity. Individual variations in peptide
      recognition were detected. However, patients treated with SK tend, in general, to
      show a common regional binding pattern, including residues 1-20, 130-149, 170
      189, and 390-399. This is the first study reporting the probing of a cellulose
      bound set of peptides with total human sera.

PMID- 10334934
TI  - Complexation of 1,2,4-benzenetriol with inorganic and ferritin-released iron in
      vitro.
AB  - The reactive metabolite(s) responsible for the expression of benzene toxicity is
      not clearly known despite extensive information on the metabolism and
      hematotoxicity of benzene. It is now widely believed that hematotoxicity of
      benzene is due to the concerted action of several metabolites which arise from
      multiple pathways of benzene. In our earlier study, we proposed iron polyphenol
      chelates as possible toxic metabolites of benzene due to their prooxidant
      activity. In continuation, we demonstrate the formation of an iron and 1,2,4
      benzenetriol (BT) complex, when added together in an acetate buffer, 0.1 M, pH
      5.6, by sephadex G-10 column chromatography. It was also observed that iron
      released from ferritin in the presence of BT formed a complex with BT.

PMID- 10334935
TI  - Interleukin-17 induces rapid tyrosine phosphorylation and activation of raf-1
      kinase in human monocytic progenitor cell line U937.
AB  - Interleukin-17 is a T cell derived pro-inflammatory cytokine exhibiting multiple
      biological activities in a variety of cells and believed to fine tune all general
      phases of hematopoietic response. However, the signaling mechanism of this novel
      cytokine remains unknown. The purpose of this study was to determine whether
      Interleukin-17 induces tyrosine phosphorylation of proteins and to find out
      whether the raf-1 kinase signaling pathway is involved in mediating its
      signaling. Using immunoblotting and immunocomplex kinase assays, we report that
      the early signaling events triggered by rhIL-17 involves rapid tyrosine
      phosphorylation of several cellular proteins including raf-1 within 0.5 to 30
      min. Optimal stimulation of tyrosine phosphorylation was observed with 0.5 to 1.0
      ng/ml of Interleukin-17. Further, Interleukin-17 stimulates rapid activation of
      raf-1 kinase. These findings provide the first evidence that the mechanism of IL
      17 signaling involves rapid tyrosine phosphorylation and activation of raf-1
      serine/threonine kinase.

PMID- 10334936
TI  - Regulation of angiogenin expression in human HepG2 hepatoma cells by mediators of
      the acute-phase response.
AB  - Angiogenin is a potent inducer of neovascularization in vivo. However, like other
      angiogenic molecules, its specific physiologic roles and mechanisms regulating
      its expression remain to be elucidated. Angiogenin is a liver-derived component
      of normal serum whose concentration can increase in various disease states. This
      suggests that it might participate in the acute-phase response. In an initial
      study we showed that angiogenin protein and mRNA levels transiently increased in
      mice following an acute inflammatory stimulus. We now report that IL-6, a major
      inducer of acute-phase proteins, stimulates the synthesis and secretion of
      angiogenin protein in human HepG2 cells within 24 hr following treatment, an
      effect enhanced by dexamethasone. IL-6 also increases the amount of angiogenin
      mRNA without altering its half-life. This increase, suppressible by
      cycloheximide, peaks at 12 hr following stimulation and returns to basal levels
      by 48 hr. IL-1 alone slightly decreases the basal production of angiogenin
      protein and mRNA, but essentially abolishes the response to IL-6 in the absence
      or presence of dexamethasone. This antagonistic effect by IL-1 on IL-6 activity
      is not a result of changes in mRNA stability nor is it dependent on new protein
      synthesis. Thus, the combined effects of IL-6, IL-1, glucocorticoids, and perhaps
      other related factors may specifically control angiogenin expression. Since
      angiogenin is regulated in a manner similar to that of acute phase proteins both
      in vitro and in vivo, it may play a role in the host response to injury.

PMID- 10334937
TI  - Reduction of lipid hydroperoxides by apolipoprotein B-100.
AB  - We have previously isolated two proteins which can reduce phosphatidylcholine
      hydroperoxide (PC-OOH) from human blood plasma and identified one of the proteins
      as apolipoprotein A-I (Mashima, R. , et al. (1998) J. Lipid Res. 39, 1133-1140).
      In the present study we have identified the other protein as apolipoprotein B-100
      (apo B-100) by amino acid sequence analysis of its tryptic peptides. The
      reactivity of lipid hydroperoxides with apo B-100 decreased in the order of PC
      OOH > linoleic acid hydroperoxide > cholesteryl ester hydroperoxide under our
      experimental conditions. Pretreatment of apo B-100 with chloramine T, an oxidant
      of methionine, diminished the PC-OOH-reducing activity, indicating that some of
      78 methionines are responsible for the reduction of PC-OOH. Despite the presence
      of 6 methionines in albumin, albumin was inactive to reduce PC-OOH. Free
      methionine was also inactive. These data suggest that the accessibility and
      binding of lipid hydroperoxides to the protein methionine residues are crucial
      for reduction of lipid hydroperoxides.

PMID- 10334938
TI  - Transcribed dinucleotide microsatellites and their associated genes from channel
      catfish Ictalurus punctatus.
AB  - The presence of trinucleotide microsatellites within genes is a well-known cause
      for a number of genetic diseases. However, the precise distribution of
      dinucleotide microsatellites within genes is less well documented. Here we report
      15 unique cDNAs containing dinucleotide repeats from the channel catfish
      Ictalurus punctatus. Gene identities of nine of the 15 cDNAs were determined, of
      which three encode structural genes, and six encode regulatory proteins. Five
      cDNAs harbored dinucleotide repeats in the 5' untranslated region (5'-NTR), nine
      in the 3'-NTR, and one in the coding region. The presence of these transcribed
      dinucleotide repeats and their potential expansion in size within coding regions
      could lead to disruption of the original protein and/or formation of new genes by
      frame shift. The low number of dinucleotide repeats within coding regions
      suggests that they were strongly selected against. All the transcribed
      microsatellite loci examined were polymorphic making them useful for gene mapping
      in catfish.

PMID- 10334939
TI  - Glutathione-dependent oxidative modification of protoporphyrin and other
      dicarboxylic porphyrins by mammalian and plant peroxidases.
AB  - Protoporphyrin, an intermediate in heme and chlorophyll biosynthesis, can
      accumulate in human and plant tissues under certain pathological conditions and
      is a photosensitizer used in cancer phototherapy. We previously showed that
      protoporphyrin and the related non-natural dicarboxylic porphyrin
      deuteroporphyrin are rapidly oxidized by horseradish peroxidase in the presence
      of some thiols, especially glutathione. This study reports that bovine
      lactoperoxidase, but not leucocyte myeloperoxidase, can also catalyze this
      reaction and that Tween and ascorbic acid are inhibitors. Exogenous hydrogen
      peroxide is not required and cannot replace glutathione. Deuteroporphyrin was
      oxidized to a unique green chlorin product with two oxygen functions added
      directly to the characteristic reduced pyrrole ring of the chlorin. Spectroscopic
      and chromatographic results suggest that protoporphyrin was oxidized not to a
      green chlorin, but to a much more polar red porphyrin modified by oxidative
      addition to the two vinyl side chains. Two related nonnatural dicarboxylic
      porphyrins, with ethyl or hydroxyethyl instead of vinyl side chains, are not
      substrates or products for this enzymatic conversion.

PMID- 10334940
TI  - Interindividual differences in hepatic expression of CYP3A4: relationship to
      genetic polymorphism in the 5'-upstream regulatory region.
AB  - Cytochrome P450 3A4, the most abundant P450 form in human liver, exhibits a very
      broad substrate specificity and is of great importance for drug metabolism. The
      interindividual difference in the hepatic expression of CYP3A4 is considerable.
      In order to investigate possible genetic factor(s) causing this variation, the
      rate of 6beta-hydroxylation of testosterone in human liver microsomes prepared
      from 46 different human liver samples was determined and the 5'upstream region
      (+10 to -490 bp) was sequenced from genomic DNA isolated from 39 of these livers.
      We found a 31-fold variation of the testosterone hydroxylase activity between the
      samples. However, a very high sequence homology between the CYP3A4 5'-upstream
      regions sequenced from the 78 different alleles was found. In fact, only three
      variant nucleotide exchanges were identified, all causing a -290 A-->G mutation
      (CYP3A4-V) in a so called nifedipine specific element (NFSE). The importance of
      this element and the polymorphism was evaluated by gel shift analysis.
      Competition experiments revealed that the binding of nuclear proteins, although
      having lower affinity to the CYP3A4-V form of the element, was unspecific in
      nature. In accordance, no influence of this polymorphism was seen on the
      microsomal testosterone hydroxylase activity in vitro. It is concluded that the
      promoter region of CYP3A4 is highly conserved, the only polymorphism being in the
      NFSE, which however does not influence the enzyme expression in liver to a
      significant degree. This casts doubt of a previously described relationship
      between the CYP3A4-V allele and cancer in the prostate and leukaemia.

PMID- 10334941
TI  - Cloning and characterization of the promoter region of the Wilson disease gene.
AB  - Wilson disease (WD), an autosomal recessive disorder of copper transport, is
      marked by impaired biliary excretion and incorporation of copper into
      ceruloplasmin. Molecular mechanism regulating the expression of the WD gene was
      studied. We isolated, sequenced, and characterized approximately 1.3 kb of the 5'
      flanking region of the WD gene from the human genomic library. The approximately
      1.3 kb of the WD sequence directed high level of luciferase activity in HepG2
      cells. Interestingly, the 5'-flanking region contained four metal response
      elements (MREs) and six MRE-like sequences (MLSs), usually found in the
      metallothionein genes. It also contained a number of putative regulatory elements
      such as Sp1, AP-1, AP-2, and E-box, but lacked TATA box. The transcription start
      site was located at 335 base pairs upstream of the translation initiation site.
      Successive 5'-deletion analyses suggested that the 159-base pair region from -811
      to -653, which includes MLS2 (-802 to -796) and MLS3 (-785 to -779), contained
      one or more positive regulatory element(s). A negative element was also
      identified at region -1038 to -812. A protein-MLS complex was identified through
      electrophoretic mobility shift and competition assay using MLS2/MLS3 and HepG2
      cell nuclear proteins.

PMID- 10334942
TI  - Coupling of manganese peroxidase-mediated lipid peroxidation with destruction of
      nonphenolic lignin model compounds and 14C-labeled lignins.
AB  - Linoleic acid, the predominant unsaturated fatty acid (UFA) in the lipids of wood
      rotting fungi, was oxidized by manganese peroxidase (MnP) from the white-rot
      fungus Phlebia radiata through a peroxidation mechanism. The peroxidation was
      markedly stimulated by hydrogen peroxide. UFAs that are substrates for lipid
      peroxidation and surfactants that emulsify water-insoluble components were
      essential for the MnP-catalyzed destruction of a nonphenolic beta-O-4-linked
      lignin model compound (LMC). Moreover, both components stimulated the MnP
      catalyzed mineralization of 14C-labeled synthetic lignin and 14C-labeled wheat
      straw. A high level of destruction was obtained in reaction systems with Tween 80
      acting both as surfactant and source of UFAs. The presence of the linoleic acid
      in reaction systems with MnP and Tween 80 additionally enhanced rate and level of
      LMC destruction and lignin mineralization. The results indicate that lipid
      peroxidation may play an important role in lignin biodegradation by wood-rotting
      basidiomycetes and support the hypothesis of coupling between the processes.

PMID- 10334943
TI  - Allylic or benzylic stabilization is essential for catalysis by bacterial benzyl
      alcohol dehydrogenases.
AB  - Benzyl alcohol dehydrogenase from Acinetobacter calcoaceticus (AC-BADH) and TOL
      plasmid-encoded benzyl alcohol dehydrogenase from Pseudomonas putida (TOL-BADH)
      have previously been shown to oxidize a variety of aromatic alcohols but not
      aliphatic substrates. Here, we have expressed the genes for AC-BADH and TOL-BADH
      in Escherichia coli, purified the resulting over-expressed enzymes, and shown
      that each is an effective catalyst of both benzylic and allylic alcohol
      oxidation, but not of oxidation of nonallylic analogs. Enzyme specificity
      (kcat/Km) for both enzymes was higher with an aliphatic, allylic alcohol (3
      methyl-2-buten-1-ol) than with benzyl alcohol. These results suggest that
      bacterial benzyl alcohol dehydrogenases use the resonance stabilization provided
      by allylic and benzylic alcohols to promote catalysis.

PMID- 10334944
TI  - Overexpression of wild-type and catalytically inactive forms of GRK2 and GRK6
      fails to alter the agonist-induced phosphorylation of the C5a receptor (CD88):
      evidence that GRK6 is autophosphorylated in COS-7 cells.
AB  - The G protein-coupled receptor kinase family comprises six members (GRK1 to GRK6)
      that phosphorylate and desensitize a number of agonist-occupied G protein-coupled
      receptors. Overexpression of the dominant negative mutant GRK2-K220R is often
      accompanied by an inhibition of the agonist-mediated phosphorylation of G protein
      coupled receptors. In the case of the C5a receptor (C5aR), the overexpression of
      wild-type GRK2 or GRK6 as well as of catalytically inactive forms of these
      kinases (GRK2-K220R and GRK6-K215R) failed to increase or to inhibit the agonist
      mediated phosphorylation of C5aR, respectively. Replacement of Lys215 by an
      arginine residue in GRK6 yielded a protein with a relative molecular mass of 63
      kDa, whereas wild-type GRK6 had a relative molecular mass of 66 kDa on
      polyacrylamide gel. The mutations S484D and T485D in the catalytically inactive
      mutant GRK6-K215R resulted in a protein (GRK6-RDD) with the same electrophoretic
      mobility as wild-type GRK6. Furthermore, in the absence of phosphatase
      inhibitors, GRK6 was rapidly converted into the 63 kDa species, whereas GRK6-RDD
      was not. Overepression of GRK6-RDD failed to alter the agonist-mediated
      phosphorylation of C5aR. Taken together, the results suggest that C5aR is not a
      substrate for either GRK2 or GRK6 and that GRK6 is very likely autophosphorylated
      on Ser484 and Thr485 in vivo.

PMID- 10334948
TI  - Multiprobe fluorescence imaging and microspectrofluorimetry of cell
      transformation and differentiation: implications in terms of applied biochemistry
      and biotechnology.
AB  - The dichotomy of cellular transformation versus differentiation does not preclude
      the hypothesis of a unified underlying mechanism that can switch either way as a
      result of growth factors, cell-membrane receptors, secondary messengers,
      integrating switch kinases and/or nuclear receptors. Its study for
      biopharmaceutical and biotechnological applications requires a methodology
      capable of dealing with such pleiotropy. In the multiprobe-multiparameter
      approach, one must remain wary of cumulative toxic effects and
      misinterpretations. 'Smart' instrumentation does not mean 'smart' probes. It
      turns out that the cell's own endogenous probes, the fluorescent coenzymes, may
      be akin to 'smart' probes, open to study in situ of many-fold interrelated
      pathways in cell energetics and dynamics. Resolution at the micro- and even nano
      compartment levels is not altogether impossible. Thus an innovative search in
      terms of what may be called 'intracellular reconnaissance with fluorescent probes
      and biopharmaceuticals' necessitates recourse to multiple tentative probings
      along the pleiotropic mechanisms as far in resolution as one can go. Among the
      characteristic findings using this approach are: (i) morphometric alterations in
      the mitochondria and melanosomes of melanoma cells treated with azelaic acid;
      (ii) deregulation of mitochondrial control and extramitochondrial metabolism in
      similarly treated cells; (iii) considerable acceleration of NAD(P) transient
      kinetics in atractylate-treated L sarcoma cells; (iv) alterations of mitochondria
      and Golgi in fusion-deficient myoblasts; (v) tentative recognition of beta
      glucosidase deficiency in Gaucher disease cells by the use of fluorescent and
      fluorogenic lysosomal probes; and (vi) UVA-induced accumulation of Schiff bases
      (a kind of accelerated photo-aging) in yeast and kidney epithelial cells. Because
      these studies utilize probing at whatever points along the concerned pathways
      become accessible, at first glance they may look disconnected. What and where is
      the connecting thread, for instance, between studying melanoma metabolism,
      melanosome morphometry, hepatocyte organelle morphogenesis and transformation,
      myotube organelle morphogenesis and fusion-non-fusion, and lysosomal activity in
      gene-deficient cells? In the mapping of the regulatory and deregulatory
      mechanisms involved in the switching of differentiation or transformation, each
      of the above topics carries an information content towards resolution of the
      pleiotropic puzzle. The integration of such information with increasing
      resolution and access to intracellular microdomains may ultimately allow focus on
      the precise target, the switch from differentiation to transformation or vice
      versa.

PMID- 10334949
TI  - Cofactor recycling in a coupled enzyme oxidation-reduction reaction: conversion
      of omega-oxo-fatty acids into omega-hydroxy and dicarboxylic acids.
AB  - Aldehydes are reduced to alcohols by the enzyme alcohol dehydrogenase (ADH),
      whereas the enzyme aldehyde dehydrogenase (AldDH) oxidizes aldehydes to
      carboxylic acids. ADH and AldDH require, respectively, the reduced and oxidized
      forms of the cofactor NAD (NAD+/NADH). By combining both oxidation and reduction
      reactions into one process, it is possible to produce alcohols and carboxylic
      acids simultaneously from aldehydes by continuous recycling of the NAD+/NADH
      cofactor. However, both enzymes need to be active within the same pH region and
      buffer system. To test this hypothesis, the pH profile (Vmax and Vmax/Km) as well
      as the pKa of the prototropic groups involved in catalysis for both
      dehydrogenases were determined using (Z,Z)-nona-2,4-dienal as a model substrate.
      The pH profile (Vmax and Vmax/Km) of both enzymes overlapped in the pH range of 6
      8 in potassium phosphate buffer. When the coupled enzyme system was used at pH 7
      with 10% NAD+ cofactor, over 90% of the starting aldehyde was converted to its
      corresponding acid and alcohol derivatives in a 1:1 ratio. The sequential action
      of the enzymes lipoxygenase and hydroperoxide lyase converts polyunsaturated
      fatty acids to aldehydic fatty acids. The products arising from the oxidation or
      reduction of the aldehydic functionality are of industrial interest. It was found
      that 13-oxo-9-(Z),11-(E)-tridecadienoic acid, the product of the sequential
      reaction of soya bean lipoxygenase and hydroperoxide lyase from Chlorella
      pyrenoidosa on linoleic acid, is also a substrate in this coupled enzyme system.

PMID- 10334950
TI  - Effect of alpha-tocopherol and silibin dihemisuccinate on the proliferation of
      human skin fibroblasts.
AB  - Cell proliferation is a complex and important event in atherosclerosis, aging and
      cancer, and is under the control of signalling pathways. These signalling
      pathways in turn are effected by the presence of a number of chemicals. For this
      purpose, we have checked the effect of two chemicals on the proliferation of skin
      fibroblasts. alpha-Tocopherol and silibin dihemisuccinate (SDH) negatively
      regulate proliferation of human skin fibroblasts. To check the cell-cycle time
      intervals, a [3H]thymidine incorporation assay was performed, showing DNA
      replication at around 24 h; this indicated the time required for the incubation
      with the chemicals. When alpha-tocopherol was added to the growth medium at a
      physiological concentration of 50 microM, cell proliferation was inhibited by 40%
      in 72 h. A similar inhibitory effect of cell proliferation was achieved when 500
      microM SDH was used (39% inhibition in 72 h). From the dose-response curves
      obtained it was concluded that both duration of treatment and the concentration
      of the chemicals are important parameters. The actual mechanism of the inhibition
      of cell proliferation may be due to the anti-oxidative potential of these
      chemicals as well as another mechanism effecting signal transduction pathways.

PMID- 10334951
TI  - Production of cholesterol oxidase by Rhodococcus equi No. 23 in a jar fermenter.
AB  - Rhodococcus equi No. 23 was grown in a batch fermenter. The effects of
      cultivation temperature, pH of the culture medium, aeration rate and agitation
      speed on the production of cholesterol oxidase (CholOx) by the test organism were
      examined. Results revealed that the cultivation temperature, the pH of the
      medium, the aeration rate and the agitation speed all affected the production of
      CholOx by R. equi No. 23. Adjusting the operation variables during the
      cultivation period increased the production of CholOx effectively and prevented
      the occurrence of overflow of foam during the fermentation period. A maximum
      CholOx activity of 0.34 unit/ml with a volumetric production rate of 0.011 unit/h
      per ml could be achieved in 30 h of cultivation at an aeration rate of 5.0 l/min,
      if the pH of the culture medium, the cultivation temperature and the agitation
      speed were controlled at 6.5, 39 degrees C and 200 rev. /min respectively during
      the first 24 h of cultivation, then shifted to 7.5, 37 degrees C and 300 rev./min
      respectively.

PMID- 10334952
TI  - Generation of a highly immunogenic recombinant enolase of the human opportunistic
      pathogen Candida albicans.
AB  - Enolase, a 46 kDa glycolytic enzyme, is an immunodominant antigen of Candida
      albicans, an important human opportunistic pathogen. The full-length coding
      sequence of C. albicans enolase gene was subcloned into the prokaryotic
      expression vector pDS56/RBSII,His6/E- under the control of an inducible promoter
      to produce a His6-tagged enolase. The recombinant protein was purified to
      homogeneity by one-step nickel-chelate affinity chromatography. It was recognized
      by a monoclonal antibody specific for C. albicans enolase, as well as by anti
      enolase antibodies present in human sera (IgG). The recombinant protein promptly
      elicited antibody in mice and detected immune responses in normal human subjects
      that were comparable to those generated by the native C. albicans enolase. Thus
      this new recombinant enolase constitutes a valuable reagent for studying the
      possible role of this protein in anti-Candida immune response.

PMID- 10334953
TI  - Enzymic acylation of 506U78 (2-amino-9-beta-D-arabinofuranosyl-6- methoxy-9H
      purine), a powerful new anti-leukaemic agent.
AB  - A practical enzymic approach for acylation of 506U78 (2-amino-9-beta-D
      arabinofuranosyl-6-methoxy -9H-purine), a powerful anti-leukaemic agent, is
      described. Novozyme-435, an immobilized preparation of Candida antarctica lipase,
      was used to acylate 506U78 regioselectively at the 5'-position. This rendered the
      compound more soluble and bioavailable. Vinyl acetate was used as the acyl donor
      and reactions were carried out in anhydrous 1,4-dioxane with up to 100 g/l of
      substrate input. Bioconversions were optimised to achieve impurity (3'-mono- and
      di-acetates) levels of less than 0.5%.

PMID- 10334954
TI  - Purification and characterization of alkaline phosphatase from Bacillus
      stearothermophilus.
AB  - Soluble alkaline phosphatase from the thermophilic bacterium Bacillus
      stearothermophilus was purified by a combination of chromatographic methods, and
      its properties were examined. The purified enzyme had specific activity of 4.43
      micromol p-nitrophenol/min per mg of protein and seemed to be a single band on
      SDS/PAGE with a molecular mass of 32 kDa. Its apparent Km for p-nitrophenyl
      phosphate was 1.114 mM. The enzyme exhibited an optimal pH of approx. 9.0 and
      exhibited its highest activity at 60-70 degrees C. It also showed a bivalent
      cation requirement for activity, with maximal enhancement in the presence of
      Mg2+. In addition, significant thermal stability was observed in comparison with
      counterparts from mesophiles. Its partial N-terminal sequence was
      T1FSIVAFDPATGELGIAVQ19 as estimated by automated Edman degradation method. A
      search on the SwissProt database did not reveal any similar protein sequences
      from other sources.

PMID- 10334955
TI  - Colorimetric capture assay for human-immunodeficiency-virus-I reverse
      transcriptase activity.
AB  - The development of a colorimetric capture assay for HIV-1 reverse transcriptase
      (RT) activity is described. This assay consisted of three basic steps: enzyme
      purification, RT reaction and product detection, which were all performed in the
      same microtitre plate. Mouse monoclonal anti-RT antibodies of subclass G2a were
      bound by polyclonal goat anti-(mouse IgG2a) immobilized in the wells of a
      microtitre plate. The monoclonal antibodies (mAbs) were selected for their
      ability to bind HIV-1 RT without hampering the polymerase activity. The assay
      system first involved the RT's adherence to the immobilized mAbs. Non-specific
      enzymes and other impurities were removed by a simple wash, after which an RT
      reaction mixture containing BrdUTP as nucleotide substrate was added. After the
      RT reaction substrate and product had been separated by washing of the plate, the
      amount of BrdUMP-DNA in the wells was finally detected with alkaline-phosphatase
      conjugated mouse anti-BrdU antibodies of subclass IgG1. The background signal in
      this system was similar to the signals obtained with control wells coated with
      BSA only. A detection limit of 1.2 micro-units of RT activity, corresponding to
      0.3 pg of RT protein, was obtained for the capture assay when applying
      colorimetric product detection. The assay detected RTs from HIV-1 subtypes A and
      B and one of the two D type isolates tested. None of the five non-HIV-1 RTs
      tested was found positive. At least 50 microl of human serum or plasma per sample
      could be included in the capture assay without adverse effects on the recovery of
      the RT activity.

PMID- 10334956
TI  - Accumulation of fibrinogen-coated microparticles at a fibrin(ogen)-rich
      inflammatory site.
AB  - We have developed methods for coating with fibrinogen both liposomes and
      microscopic droplets of olive oil. Because the fibrinogen bound to them is
      functional in the classic sense of fibrin gelation, the coated microparticles may
      have potential as vehicles for the targeted delivery of various molecules to
      sites of fibrin(ogen) deposition in vivo. So that we could assess directly this
      potential, we first established a method for eliciting reproducibly a focal,
      fibrin(ogen)-rich, inflammatory lesion in a hind footpad of mice. We then
      monitored the tissue distribution of fibrinogen-coated microparticles following
      their injection into the tail vein of mice bearing this well-defined lesion. As
      happens with most microparticles following their intravenous administration,
      liposomes and oil droplets, whether coated with fibrinogen or not, accumulate
      rapidly in the liver and spleen of treated animals. Indeed, in the case of oil
      droplets, accumulation of fibrinogen-coated microparticles in those organs and in
      the lungs is even greater than that of fibrinogen-free microparticles. However,
      as distinct from fibrinogen-free liposomes and oil droplets, fibrinogen-coated
      microparticles also accumulate in the inflamed hind footpad. We conclude that
      fibrinogen-coated liposomes and oil droplets do have potential as vehicles for
      delivering molecules to sites of fibrin(ogen) deposition in vivo.

PMID- 10334957
TI  - Purification and characterization of a levanbiose-producing levanase from
      Pseudomonas sp. No. 43.
AB  - A levanbiose-accumulating levanase from Pseudomonas sp. No. 43 was purified to a
      homogeneous state by (NH4)2SO4 fractionation and by chromatography on DEAE
      Toyopearl 650 M and phenyl-Toyopearl 650 M columns. The molecular mass and
      isoelectric point of the enzyme were estimated to be 36 kDa and 5.7 respectively;
      the optimal pH and temperature for the enzyme reaction were pH 7.0 and 40 degrees
      C respectively. The purified enzyme was stable in the pH range 6.0-8.0 at 20
      degrees C and stable up to 50 degrees C at pH 7.0. The enzyme's activity was
      inhibited by MnCl2, CoCl2, AlCl3, EDTA and potassium permanganate. The levanase
      was specific towards the 2, 6-beta-D-fructosidic linkages of levan and did not
      hydrolyse other polysaccharides among those examined. The enzyme is an
      exohydrolase of levan and produced levanbiose as a sole product; the limits of
      hydrolysis of levans from Zymomonas mobilis and Serratia sp. were 65% and 80%
      respectively.

PMID- 10334958
TI  - Use of herpes simplex virus type 1 for transgene expression within the nervous
      system.
AB  - Gene therapy might provide a useful treatment for a number of neurological
      diseases and a great deal of effort is going into the development of vector
      systems which will allow the delivery of potentially therapeutic genes to
      terminally differentiated neurons within the intact mammalian brain. The ability
      of herpes simplex virus type 1 (HSV-1) to establish a lifelong latent infection
      within neurons has led to interest in its use as a neuronal gene delivery vector.
      During HSV latency no viral proteins are produced and transcription from the
      latent viral genome is limited to a family of nuclear RNAs, the latency
      associated transcripts, whose function is not well understood. Obtaining
      prolonged expression of a transgene in latently infected neurons has proven
      difficult due to transcriptional silencing of exogenous promoters introduced into
      the latent viral genome. For this reason there is a great deal of interest in
      utilizing the HSV latency-associated promoter to drive the expression of
      therapeutic genes in latently infected neurons of both the peripheral and central
      nervous systems. In this review we describe a strategy which allows the latency
      associated promoter to drive long-term reporter gene expression in the mammalian
      nervous system. These observations open up the possibility of using similar HSV
      based vectors to express therapeutic transgenes within the brain and investigate
      the potential of gene therapy in a range of neurological disorders.

PMID- 10334959
TI  - Elevated plasma levels of adrenomedullin in congenital cyanotic heart disease.
AB  - Adrenomedullin is a novel hypotensive peptide originally isolated from human
      pheochromocytoma. Accumulating evidence suggests the possible involvement of
      adrenomedullin in the physiology of the pulmonary circulation and the
      pathophysiology of hypoxaemia. The aim of the present study was to investigate
      the pathophysiological significance of adrenomedullin in hypoxaemia caused by
      congenital cyanotic heart disease. Subjects were 16 patients with congenital
      cyanotic heart disease aged 0.8-10 years (Group C) and 12 age-matched control
      subjects (patients with coronary artery dilatation after Kawasaki disease; Group
      N). Plasma adrenomedullin concentrations were measured, using radioimmunoassay,
      in femoral venous, pulmonary arterial and pulmonary venous blood obtained during
      cardiac catheterization. Plasma adrenomedullin concentrations in Group C were
      significantly (3-fold) higher than those in Group N at all sampling sites. In
      Group C, plasma adrenomedullin concentrations in pulmonary venous blood were
      significantly lower than those in pulmonary arterial blood. Pulmonary uptake of
      adrenomedullin in Group C was significantly greater than that in Group N.
      Patients with congenital cyanotic heart disease showed elevated plasma
      adrenomedullin concentrations and an increased uptake of adrenomedullin in the
      pulmonary circulation, which may act to dilate pulmonary vessels and increase
      pulmonary blood flow to alleviate hypoxaemia. Intrinsically increased
      adrenomedullin levels may function as a compensatory mechanism for hypoxaemia in
      congenital cyanotic heart disease.

PMID- 10334960
TI  - Effects of adrenaline on glucose and glutamine metabolism and superoxide
      production by rat neutrophils.
AB  - Despite the large body of information on the role of corticosteroids in
      regulating lymphocyte and phagocyte function, the role of the hormone adrenaline
      in immunoregulation is an under-investigated topic. The present study has
      addressed the effects of adrenaline on the rates of utilization and oxidation of
      glucose and glutamine, the phagocytic capacity and the rate of superoxide
      production by rat neutrophils. Incubation of rat neutrophils in the presence of
      50 microM adrenaline caused a marked elevation in glucose metabolism, an effect
      that could be blocked by propranolol. Adrenaline caused a partial inhibition of
      glutamine utilization by neutrophils, an effect that was also blocked by
      propranolol. These effects of adrenaline could be mimicked by 100 microM
      dibutyryl cAMP. Phosphate-dependent glutaminase activity was significantly
      elevated in neutrophils incubated in the presence of 50 microM adrenaline or 100
      microM dibutyryl cAMP for 1 h, whereas glutamine oxidation was significantly
      depressed (P<0.05) under these conditions. The elevation in enzyme activity was
      only partially blocked by propranolol. The phagocytic activity of rat neutrophils
      was not altered by adrenaline in the presence of either glucose or glutamine. The
      rate of phorbol 12-myristate 13-acetate-induced superoxide production in the
      presence of glucose was potently reduced by the addition of 5 nM or 50 microM
      adrenaline. This effect could be mimicked by dibutyryl cAMP. However, when rat
      neutrophils were incubated in the presence of glutamine plus adrenaline (5 nM or
      50 microM), the rate of superoxide production was only marginally reduced. These
      findings support the proposition that adrenaline may deviate the flux of glucose
      from the NADPH-producing pentose phosphate pathway, thus reducing substrate
      availability for the superoxide-generating NADPH oxidase. However, glutamine
      metabolism may still give rise to substantial quantities of NADPH from the
      glutaminolysis pathway. We postulate that glutamine metabolism may thus provide a
      protective mechanism against the inhibitory effect of adrenaline on superoxide
      production by neutrophils.

PMID- 10334961
TI  - Dissociation between microneurographic and heart rate variability estimates of
      sympathetic tone in normal subjects and patients with heart failure.
AB  - The concept that spectral analysis of heart rate variability (HRV) can estimate
      cardiac sympathetic nerve traffic in subjects with both normal and impaired left
      ventricular systolic function has not been validated against muscle sympathetic
      nerve activity (MSNA). We used coarse-graining spectral analysis to quantify the
      harmonic and non-harmonic, or fractal, components of HRV and to determine low
      frequency (0.0-0.15 Hz; PL) and high-frequency (0.15-0.5Hz; PH) harmonic power.
      To test the hypothesis that MSNA and HRV representations of sympathetic nerve
      activity (PL and PL/PH) increase in parallel in heart failure, we recorded heart
      rate and MSNA during supine rest in 35 patients (age 52.4+/-2 years; mean+/-S.
      E.M.), with a mean left ventricular ejection fraction of 22+/-2%, and in 34 age
      matched normal subjects. Power density was log10 transformed. Mean MSNA was
      52.9+/-2.6 bursts/min in heart failure patients and 34.9+/-1.9 bursts/min in
      normal subjects (P<0.0001). In normal subjects, but not in heart failure
      patients, total power (PT) (r=-0.41; P=0.02) and fractal power (PF) (r=-0.36;
      P=0.04) were inversely related to age. In heart failure patients, total and
      fractal power were reduced (P<0.009 for both), and were inversely related to MSNA
      burst frequency (r=-0.55, P=0.001 and r=-0.60, P=0. 0003 respectively). In normal
      subjects, there was no relationship between MSNA and either PL or PH. In heart
      failure patients, as anticipated, PH was inversely related to MSNA (r=-0.41;
      P<0.02). However, PL was also inversely rather than directly related to MSNA
      (r=0.44 for 1/log10 PL; P<0.01). There was no relationship between other
      sympathetic (PL/PH) or parasympathetic (PH/PT) indices and MSNA in either heart
      failure patients or normal subjects. The lack of concordance between these direct
      and indirect estimates of sympathetic nervous system activity indicates that this
      component of HRV cannot be used for between-subject comparisons of central
      sympathetic nervous outflow. It is the absence of low-frequency power that
      relates most closely to sympathetic activation in heart failure.

PMID- 10334962
TI  - Cardiovascular control and plasma catecholamines during rest and mental stress:
      effects of posture.
AB  - In order to understand the complex autonomic adjustments that occur during the
      psychological challenges of normal daily life, autonomic responses to
      psychological stress were studied by evaluating the effects of body posture on
      various indices of sympathetic and parasympathetic regulation during performance
      of a psychological task. Twelve male subjects were studied in various postures
      (supine, sitting and standing), and during performance of the Colour Word Test
      (CWT) when sitting and then when standing. This procedure was subsequently
      repeated in reverse order (first standing and then sitting) after 15 min of
      supine rest. Blood samples for assay of plasma catecholamines were obtained
      before and during each CWT. Spectral analysis of beat-to-beat variations of heart
      rate (HR) and blood pressure (BP) was applied in order to obtain non-invasive
      indices of sympathetic and parasympathetic regulation. HR, diastolic BP, mid
      frequency band power (0.07-0.14 Hz) of HR and systolic BP, and plasma adrenaline
      and noradrenaline concentrations showed significant increases when changing from
      supine to sitting to standing posture, whereas high-frequency band power (0.15
      0.50 Hz) of HR decreased in a posture-dependent fashion. In the sitting position,
      the CWT caused significant increases in HR, BP and plasma adrenaline levels, and
      decreased HR and BP variability indices. In the standing posture, the CWT
      responses differed significantly from those during sitting for HR (a mild
      decrease during standing), high-frequency band power of HR (decreased more while
      sitting), high-frequency band power of BP (decreased more while standing), and
      plasma adrenaline responses (larger during sitting). Posture-related differential
      effects were observed on indices of sympatho-adrenomedullary activation during
      performance of a psychological challenge, whereas indices of parasympathetic
      activity indicated primarily less vagolytic effects when the task was performed
      in the standing posture. Our findings therefore underline the complexity of the
      adjustments that occur in neurohumoral and haemodynamic parameters during the
      psychological challenges of daily life.

PMID- 10334963
TI  - Cardiovascular responses evoked by mild cool stimuli in primary Raynaud's
      disease: the role of endothelin.
AB  - In control subjects and in subjects with primary Raynaud's disease, sudden sound
      evokes the pattern of the alerting response, which includes cutaneous
      vasoconstriction and vasodilatation in forearm muscle. However, whereas this
      pattern of response habituates on repetition of the sound stimulus in control
      subjects, both cutaneous vasoconstriction and muscle dilatation persist in
      subjects with primary Raynaud's disease. The aim of the present study was to test
      whether a similar disparity exists between control subjects and those with
      primary Raynaud's disease for the response to mild cool stimuli, and whether the
      cutaneous response is accompanied by the release of endothelin-1 (ET-1). In nine
      subjects with primary Raynaud's disease and in nine matched controls, the left
      hand was placed in cool water at 16 degrees C for 2 min five times on each of
      three experimental sessions on days 1, 3 and 5, with blood being taken from the
      venous drainage of the cooled hand before and at the end of the second session.
      In response to the first cool stimulus in Session 1, the subjects with primary
      Raynaud's disease showed a decrease in digital cutaneous vascular conductance
      (DCVC) in both the right and left hands, as indicated by a laser Doppler
      recording of erythrocyte (red cell) flux divided by arterial pressure, and six of
      the nine subjects showed an increase in forearm vascular conductance (FVC), as
      indicated by forearm blood flow measured by plethysmography divided by arterial
      pressure. On repetition of the stimulus in Session 1, there was no change in the
      magnitude of the increase in FVC, but the evoked decreases in DCVC became more
      prolonged in both the right and the left hand. Similar responses occurred in
      Sessions 2 and 3; in Session 2, the ET-1 concentration increased from a baseline
      value of 2.15+/-0.26 fM to 2.72+/-0.37 fM after five stimuli. There was no
      habituation of the increase in FVC over Sessions 1, 2 and 3, judging from the
      mean changes in each session. Control subjects also showed a decrease in DCVC in
      both hands, and in eight out of nine subjects there was an increase in FVC in
      response to the first cool stimulus in Session 1. However, on repetition of the
      stimulus in Session 1, the increase in FVC habituated, while there was no
      prolongation of the decrease in DCVC; in addition, the ET-1 concentration did not
      change in Session 2 in response to the stimulus (2.07+/-0.28 compared with 2.29+/
      0.30 fM). Further, the increase in FVC habituated over the three sessions, such
      that there was a mean decrease in FVC in Session 3. These results indicate that,
      in subjects with primary Raynaud's disease, there is impairment of the ability of
      the central nervous system to allow habituation of the cardiovascular components
      of the alerting response evoked by mild cooling, as with the response to sound.
      We propose that persistence of the cutaneous vasoconstriction of the alerting
      response, coupled with increased release of ET-1 secondary to vasoconstriction,
      prolongs such vasoconstriction and eventually leads to vasospasm.

PMID- 10334964
TI  - Circulating stress hormone and insulin concentrations in acute coronary
      syndromes: identification of insulin resistance on admission.
AB  - We re-examined, in the context of modern practice, plasma insulin and stress
      hormone concentrations in patients admitted to hospital with acute coronary
      syndromes. Venous blood sampling was carried out prior to anti-thrombotic therapy
      in 148 patients with myocardial infarction (MI); 76 patients with unstable angina
      (UA) pectoris were also studied, together with 27 patients with non-cardiac chest
      pain (NCP). There were significant progressive increases in the concentrations of
      catecholamines, cortisol, glucose and insulin from NCP to UA to MI patients.
      Hyperglycaemia (glucose >8 mmol/l) was present in over 50% of MI patients. The
      plasma cortisol and insulin levels were both significantly positively correlated
      with the glucose concentration on admission. Only the cortisol concentration was
      correlated with peak cardiac enzyme levels. The glucose and insulin
      concentrations on admission in 141 MI and UA patients were related to insulin
      resistance, as judged from subsequent insulin and glucose concentrations measured
      while fasting and during a glucose tolerance test. The product of admission
      insulinxglucose (divided by 25; the admission insulin-resistance index, or AIRI)
      was significantly correlated with indices of insulin resistance, and was
      significantly higher (approximately double) in the MI group (7. 81+/-0.76) and
      the UA group (6.88+/-1.19) than in the control NCP group (3.59+/-0.06; Kuskul
      Wallis: P=0.0001), implying that the insulin levels in the first two groups were
      approximately twice as high as is appropriate for the glucose levels. The ethnic
      origin of 20% of the patients was the Indian subcontinent; admission insulin and
      glucose levels in this subgroup were higher than in the non-Asians across all the
      groups with chest pain. Cortisol was the only stress hormone that was raised in
      proportion to the size of the infarct, and is a likely partial cause of the
      elevation in blood glucose. The high insulin levels were related to the
      prevalence of insulin resistance, and this was particularly important in the
      Asian subgroup presenting with MI and UA. Thus it appears feasible to identify
      acute coronary syndrome patients who are insulin-resistant at a time (on
      admission) when alternative early therapeutic strategies can be instituted.

PMID- 10334965
TI  - Effect of adenosine on heart rate variability in humans.
AB  - By stimulating afferent nerve endings in skeletal muscle, heart, kidney and the
      carotid body, adenosine infusion evokes a receptor-specific sympatho-excitatory
      reflex in humans that overrides its direct negative chronotropic effect. We
      tested the hypothesis that adenosine increases heart rate by suppressing
      parasympathetic and augmenting sympathetic components of heart rate variability.
      High-frequency (PH; 0.15-0.50 Hz) and low-frequency (PL; 0.05-0.15 Hz) components
      of heart rate variability total power (PT) were determined by spectral analysis.
      The ratios PH/PT and PL/PH respectively were used to estimate parasympathetic and
      sympathetic input to the sino-atrial node. Heart rate was recorded before and
      during a 5 min intravenous infusion of adenosine (140 micrograms.min-1.kg-1) in
      seven healthy men. Adenosine did not affect blood pressure, but increased heart
      rate by 33+/-6 beats/min, and reduced PT, PH, PL and PH/PT. In contrast, there
      was an increase in PL/PH. In a second experiment in nine men, brachial artery
      infusion of adenosine (15 micrograms.min-1.100 ml-1 forearm tissue) increased
      heart rate by 3 beats/min, had no effect on PT, PH, PL or PH/PT, yet increased
      PL/PH. Intra-arterial adenosine exerts a modest effect on heart rate by
      modulating cardiac sympathetic indices, without affecting parasympathetic
      indices, of heart rate variability, whereas intravenous infusion of adenosine
      reduces heart rate variability and raises heart rate by decreasing
      parasympathetic and increasing cardiac sympathetic tone. These reflex effects may
      become clinically relevant during adenosine stress testing, or when endogenous
      adenosine is increased, such as during ischaemia, exercise or vasodepressor
      reactions, or in heart failure.

PMID- 10334966
TI  - Apoptosis and Bcl-xs in the intimal thickening of balloon-injured carotid
      arteries.
AB  - We performed balloon injury in the rat carotid artery and identified intimal
      thickening after injury. Balloon-injured carotid arteries showed maximum
      thickness of the neointima on the 14th day before complete endothelial cell
      regeneration. In this lesion we identified apoptosis of vascular smooth muscle
      cells (VSMCs) by in situ DNA labelling and electron microscopy in the neointima
      on the 14th day after injury. mRNA expression levels of bcl-2, bax, bcl-x, p53
      and caspase-1 were determined by the reverse transcriptase-polymerase chain
      reaction method both in injured and uninjured carotid arteries. Neither bcl-2 nor
      bcl-xl mRNA expression was detected in either injured or uninjured arteries,
      whereas bax and p53 mRNA expression was identified and their mRNA levels were not
      altered after balloon injury. In contrast, both bcl-xs and caspase-1 mRNA was
      detected and was markedly induced only in the injured carotid artery. Positive
      staining for immunoreactive Bcl-x was observed specifically in the injured
      arterial wall and co-localized with positive staining of nuclei identified by in
      situ DNA labelling. We conclude that two opposite cellular responses, VSMC
      proliferation and apoptosis, exist together in the neointima of the rat carotid
      artery after balloon injury, and selective induction of Bcl-xs expression is a
      key regulator of VSMC apoptosis in the process of vascular remodelling.

PMID- 10334967
TI  - Short-term variability of blood pressure and heart rate in Guillain-Barre
      syndrome without respiratory failure.
AB  - The effect of Guillain-Barre syndrome (GBS) on the short-term variability of
      blood pressure and heart rate was evaluated in six patients presenting with a
      moderate form of the syndrome, i.e. unable to stand up unaided and without
      respiratory failure, at the height of the disease and during recovery. The
      patients were compared with six age-matched healthy volunteers. During the acute
      phase of the syndrome, GBS patients exhibited a significant heart rate elevation
      (+26 beats/min compared with healthy subjects), but the acceleratory response to
      atropine, or to 60 degrees head-up tilt, was maintained. Resting plasma
      noradrenaline levels were high in acute GBS, but the secretory response to tilt
      was preserved. Desensitization to noradrenaline was observed in acute GBS with a
      reduced pressor action of this alpha-adrenoceptor agonist. Blood pressure levels
      were normal and head-up tilt did not induce orthostatic hypotension in this
      moderate form of GBS. Power spectral analysis demonstrated marked alterations in
      cardiovascular variability. The overall heart period variability was markedly
      reduced with the reduction predominantly in the high-frequency (respiratory)
      range (-73%). The low-frequency component of heart period variability was also
      reduced (-54%). This cardiovascular profile of moderate GBS at the height of the
      disease could result from a demyelination of the reflex loop controlling
      respiratory oscillations in heart rate and from a desensitization of the arterial
      tree to an elevated plasma noradrenaline. Sympathetic nervous activation may
      contribute to the high resting heart rate in acute GBS.

PMID- 10334968
TI  - Physiological control of splanchnic blood flow by adrenaline: studies during
      acute hypoglycaemia in man.
AB  - Superior mesenteric artery blood flow (SMABF) increases significantly during and
      after the hypoglycaemia reaction in healthy humans. To investigate the mechanisms
      controlling this phenomenon, SMABF and plasma catecholamines were measured in
      healthy human volunteers. In 10 controls, hypoglycaemia was induced by insulin
      infusion (2.5 m-units.min-1.kg-1). In six subjects, beta-blockade by propranolol
      infusion (0.7 microgram.min-1.kg-1) preceded insulin infusion and was continued
      throughout the study. Following the hypoglycaemia reaction, the glucose nadir was
      similar in both groups. In controls, increases in SMABF [42.4+/-6.1% (mean+/
      S.E.M.); P<0. 001], cardiac output (34.3+/-2.3%; P<0.001) and pulse rate (from
      63. 9+/-2.7 to 82.5+/-3.1 beats/min; P<0.001) occurred. Superior mesenteric
      artery resistance fell by 32.4+/-3.3% (P<0.001). Under beta-blockade, decreases
      in SMABF (34.8+/-2.9%; P<0.001) and pulse rate (from 59.5+/-0.2 to 51.8+/-2.2
      beats/min; P<0.001) occurred. Superior mesenteric artery resistance increased
      (peak +30.8+/-12.3%; not significant). Subjects showed greater increases in
      adrenaline (P<0.006) and noradrenaline (P<0.022) concentrations than controls.
      Mesenteric hyperaemia associated with hypoglycaemia in man appears to be mediated
      by a beta-adrenergic mechanism that is activated by increased circulating levels
      of adrenaline.

PMID- 10334969
TI  - Does potassium channel opening contribute to endothelium-dependent relaxation in
      human internal thoracic artery?
AB  - Opening of potassium channels can cause hyperpolarization and relaxation of
      vascular smooth muscle cells. The aim of this work was to investigate the
      contribution of potassium channel activation to vasorelaxation in internal
      thoracic artery taken from patients undergoing coronary artery bypass graft
      surgery. Relaxations to carbachol and sodium nitroprusside were studied in
      isolated rings of internal thoracic artery in the absence and presence of nitric
      oxide synthase inhibitors and potassium channel blockers. The nitric oxide
      synthase inhibitors Nomega-nitro-L-arginine methyl ester and NG-monomethyl-L
      arginine abolished relaxations to carbachol. Relaxations to both carbachol and
      sodium nitroprusside were attenuated in the presence of raised extracellular
      potassium and the potassium channel blockers charybdotoxin, iberiotoxin and
      tetraethylammonium. Neither apamin nor glibenclamide modified relaxation. ODQ (1H
      [1,2,4]oxadiazolol-[4,3a] quinoxalin-1-one), an inhibitor of soluble guanylate
      cyclase, abolished relaxation to carbachol in rings from some but not all
      subjects. These results suggest that potassium channel opening may make a small
      contribution to endothelium-dependent vasorelaxation in internal thoracic artery.
      The potassium channels had characteristics consistent with those of large
      conductance calcium-dependent potassium channels.

PMID- 10334970
TI  - Effects in vivo of decreased plasma and intracellular muscle glutamine
      concentration on whole-body and hindquarter protein kinetics in rats.
AB  - Glutamine is considered to be a 'conditionally' essential amino acid. During
      situations of severe stress like sepsis or after trauma there is a fall in plasma
      glutamine levels, enhanced glutamine turnover and intracellular muscle glutamine
      depletion. Under these conditions, decreased intramuscular glutamine
      concentration correlates with reduced rates of protein synthesis. It has
      therefore been hypothesized that intracellular muscle glutamine levels have a
      regulatory role in muscle protein turnover rates. Administration of the glutamine
      synthetase inhibitor methionine sulphoximine (MSO) was used to decrease glutamine
      levels in male Wistar rats. Immediately after the MSO treatment (t=0 h), and at
      t=6 h and t=12 h, rats received intraperitoneal injections (10 ml/100 g body
      weight) with glutamine (200 mM) to test whether this attenuated the fall in
      plasma and intracellular muscle glutamine. Control animals received alanine and
      saline after MSO treatment, while saline was also given to a group of normal
      rats. At t=18 h rats received a primed constant infusion of L-[2,6
      3H]phenylalanine. A three-pool compartment tracer model was used to measure whole
      body protein turnover and muscle protein kinetics. Administration of MSO resulted
      in a 40% decrease in plasma glutamine and a 60% decrease in intracellular muscle
      glutamine, both of which were successfully attenuated by glutamine infusions. The
      decreased intracellular muscle glutamine levels had no effect on whole-body
      protein turnover or muscle protein kinetics. Also, glutamine supplementation did
      not alter these parameters. Alanine supplementation increased both hindquarter
      protein synthesis and breakdown but the net balance of phenylalanine remained
      unchanged. In conclusion, our results show that decreased plasma and muscle
      glutamine levels have no effect on whole-body protein turnover or muscle protein
      kinetics. Therefore, it is unlikely that, in vivo, the intracellular muscle
      concentration of glutamine is a major regulating factor in muscle protein
      kinetics.

PMID- 10334971
TI  - Predicting composition of leg sections with anthropometry and bioelectrical
      impedance analysis, using magnetic resonance imaging as reference.
AB  - Magnetic resonance imaging (MRI) was used to evaluate and compare with
      anthropometry a fundamental bioelectrical impedance analysis (BIA) method for
      predicting muscle and adipose tissue composition in the lower limb. Healthy
      volunteers (eight men and eight women), aged 41 to 62 years, with mean (S.D.)
      body mass indices of 28.6 (5.4) kg/m2 and 25.1 (5.4) kg/m2 respectively, were
      subjected to MRI leg scans, from which 20-cm sections of thigh and 10-cm sections
      of lower leg (calf) were analysed for muscle and adipose tissue content, using
      specifically developed software. Muscle and adipose tissue were also predicted
      from anthropometric measurements of circumferences and skinfold thicknesses, and
      by use of fundamental BIA equations involving section impedance at 50 kHz and
      tissue-specific resistivities. Anthropometric assessments of circumferences,
      cross-sectional areas and volumes for total constituent tissues matched closely
      MRI estimates. Muscle volume was substantially overestimated (bias: thigh, -40%;
      calf, -18%) and adipose tissue underestimated (bias: thigh, 43%; calf, 8%) by
      anthropometry, in contrast to generally better predictions by the fundamental BIA
      approach for muscle (bias: thigh, -12%; calf, 5%) and adipose tissue (bias:
      thigh, 17%; calf, -28%). However, both methods demonstrated considerable
      individual variability (95% limits of agreement 20-77%). In general, there was
      similar reproducibility for anthropometric and fundamental BIA methods in the
      thigh (inter-observer residual coefficient of variation for muscle 3.5% versus
      3.8%), but the latter was better in the calf (inter-observer residual coefficient
      of variation for muscle 8.2% versus 4.5%). This study suggests that the
      fundamental BIA method has advantages over anthropometry for measuring lower limb
      tissue composition in healthy individuals.

PMID- 10334972
TI  - Insulin gene polymorphism and premature male pattern baldness in the general
      population.
AB  - Insulin is found in hair follicles and may play a role in the regulation of
      androgen metabolism and the hair growth cycle, which are relevant to the loss of
      scalp hair known as male pattern baldness. An excess of dihydrotestosterone on
      balding scalp indicates that the condition is androgen dependent. Premature male
      pattern baldness may be the male phenotype of familial polycystic ovary syndrome,
      a condition characterized by high levels of androgens and insulin that has been
      linked to insulin gene polymorphism. Therefore, we studied possible associations
      between relevant insulin gene polymorphisms and premature male pattern baldness
      in the general community. We examined the distribution of three dimorphic
      restriction fragment length polymorphisms: HphI, PstI and FokI in cases
      consisting of 56 men aged 18-30 years with significant baldness, and in 107
      control men aged 50 years or more with no indication of baldness. No significant
      differences between cases and controls in allele, genotype or haplotype
      frequencies were identified. We conclude that, in the general population, the
      insulin gene is not associated with premature male pattern baldness.

PMID- 10334973
TI  - Sympathetic activation and myocardial ischaemia: a role for cold adaptation?

PMID- 10334974
TI  - Interleukin-4 and interleukin-4 receptor polymorphisms in minimal change
      nephropathy.
AB  - Minimal change nephropathy (MCN) is an important cause of nephrotic syndrome,
      especially in children, that is strongly associated with atopy and IgE
      production. The immunogenetics of MCN are poorly understood. Interleukin-4 (IL-4)
      is the critical cytokine involved in the development of atopy. Polymorphic
      regions in the genes encoding IL-4 itself and the IL-4 receptor have been
      demonstrated that may predispose to increased activity. We have analysed these
      polymorphisms in 149 patients with MCN and 73 controls to test the hypothesis
      that these loci are involved in genetic predisposition to MCN. In our populations
      there were no polymorphisms in the IL-4 promoter. We did confirm allelic
      variation in a dinucleotide repeat in the second intron of the IL-4 gene, but
      there was no significant difference between allele distributions in MCN and
      controls. Similarly, allele frequencies for the IL-4 receptor alpha chain
      polymorphism were similar in patients and controls. Genetic loci which are
      believed to influence IL-4 responsiveness and to predispose to atopy do not
      appear to be associated with susceptibility to MCN.

PMID- 10334975
TI  - Regulation of 11beta-hydroxysteroid dehydrogenase type 2 by diuretics and the
      renin-angiotensin-aldosterone axis.
AB  - In the kidney and colon 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2)
      inactivates cortisol to cortisone, thereby protecting the non-selective
      mineralocorticoid receptor from cortisol. Deficiency of 11beta-HSD2 results in
      cortisol-mediated sodium retention and hypertension, suggesting that the
      physiological regulation of 11beta-HSD2 in mineralocorticoid target tissues may
      be important in modulating sodium homoeostasis and blood pressure control. Using
      the human epithelial colon cell line SW-620, reverse transcriptase-polymerase
      chain reaction and enzyme kinetic analysis indicated expression of only 11beta
      HSD2 (Km for cortisol 66 nmol/l). Bradykinin (10(-8) to 10(-12) mol/l), frusemide
      (10(-4) to 10(-9) mol/l), benzamiloride hydrochloride (10(-5) to 10(-10) mol/l)
      and atrial natriuretic peptide (10(-6) to 10(-10) mol/l) had no effect on 11beta
      HSD2 expression. Using a range of concentrations of angiotensin II (2x10(-8) to
      2x10(-5) mol/l) a significant reduction in activity was seen but only at supra
      physiological concentrations, [e.g. 2x10(-6) mol/l at 4 h pretreatment: 36.7+/
      2.0 pmol cortisone. h-1.mg-1 (mean+/-S.E.M.) compared with 45.1+/-1.7 pmol.h-1.mg
      1 in control; P<0.05]. The angiotensin-converting enzyme inhibitors captopril,
      enalapril, lisinopril, perindopril, quinapril and trandolapril at 10(-7) mol/l,
      but not fosinopril, significantly increased 11beta-HSD2 activity after
      pretreatment for 16 or 24 h (P<0.05-P<0.01 compared with control). No effects
      were seen at 4 h pretreatment. Hydrochlorothiazide (10(-7) mol/l) significantly
      decreased 11beta-HSD2 activity (P<0.05 compared with control) at 4 h
      pretreatment. Commonly used diuretics, atrial natriuretic peptide and
      physiological concentrations of angiotensin II and bradykinin do not alter 11beta
      HSD2 activity. In contrast, a series of angiotensin-converting enzyme inhibitors
      significantly increase 11beta-HSD2 activity in vitro. This may explain how
      intrarenal infusions of angiotensin-converting enzyme inhibitors increase renal
      sodium excretion independent of circulating concentrations of angiotensin II. The
      interaction between angiotensin-converting enzyme inhibitors and 11beta-HSD2 may
      be an additional mechanism by which the former can lower blood pressure.

PMID- 10334976
TI  - Weight fluctuations could increase blood pressure in android obese women.
AB  - Recent studies have documented a relationship between increased morbidity and
      mortality from cardiovascular diseases and a history of weight cycling (WC) in
      obese subjects. We performed a cross-sectional analysis in 96 weight-cycling
      android obese women, matched with 96 non-weight-cycling android obese women by
      age, body mass index (BMI) and waist-to-hip ratio (WHR), to evaluate any increase
      in blood pressure (BP) levels in association with WC. The patients were all
      between 20 and 45 years old, were non-menopausal, did not smoke, did not take any
      medication, had normal glucose tolerance and were otherwise healthy. A history of
      WC was established on the basis of at least five weight losses in the previous 5
      years due to dieting, with a weight loss of at least 4.5 kg per cycle. We
      documented higher levels of casual BP in the weight-cycling obese compared with
      the non-weight-cycling subjects: 147+/-12/90+/-8 mmHg versus 125+/-14/79+/-8 mmHg
      (P<0.001). The women with WC showed a statistically significant positive
      correlation between BP and age, weight, BMI, waist circumference, WHR, total
      weight regained and weight cycling index (WCI). However, in a multiple regression
      model only the WHR and WCI contributed significantly to the BP variability. These
      findings could support the hypothesis that it is the combined exposure of central
      type obesity and WC that strongly raises the prediction of hypertension.

PMID- 10334977
TI  - The search for unrecognized pathogens.
AB  - The distribution and diversity of microorganisms in the world are far greater
      than have been previously appreciated. Molecular, cultivation-independent methods
      have played a key role in this insight. To what extent do humans remain ignorant
      of microbial diversity within the human body and the settings in which
      microorganisms cause human disease? In addition to implicating microbial agents
      in nontraditional infectious diseases, the use of methods such as broad-range
      polymerase chain reaction, representational difference analysis, expression
      library screening, and host gene expression profiling may force a reassessment of
      the concepts of microbial disease causation.

PMID- 10334978
TI  - Emerging infectious diseases: public health issues for the 21st century.
AB  - Infectious diseases are the third leading cause of death in the United States and
      the leading cause worldwide. As the new millennium approaches, the public health
      community must replenish capacity depleted during years of inadequate funding
      while simultaneously incorporating new technologies and planning for the longer
      term. Among the challenges facing the public health community is the need for
      coordinated, global, multisectoral approaches to preventing and controlling
      complex infectious disease problems.

PMID- 10334979
TI  - Phylogenetic perspectives in innate immunity.
AB  - The concept of innate immunity refers to the first-line host defense that serves
      to limit infection in the early hours after exposure to microorganisms. Recent
      data have highlighted similarities between pathogen recognition, signaling
      pathways, and effector mechanisms of innate immunity in Drosophila and mammals,
      pointing to a common ancestry of these defenses. In addition to its role in the
      early phase of defense, innate immunity in mammals appears to play a key role in
      stimulating the subsequent, clonal response of adaptive immunity.

PMID- 10334980
TI  - Bacterial biofilms: a common cause of persistent infections.
AB  - Bacteria that attach to surfaces aggregate in a hydrated polymeric matrix of
      their own synthesis to form biofilms. Formation of these sessile communities and
      their inherent resistance to antimicrobial agents are at the root of many
      persistent and chronic bacterial infections. Studies of biofilms have revealed
      differentiated, structured groups of cells with community properties. Recent
      advances in our understanding of the genetic and molecular basis of bacterial
      community behavior point to therapeutic targets that may provide a means for the
      control of biofilm infections.

PMID- 10334981
TI  - Type III secretion machines: bacterial devices for protein delivery into host
      cells.
AB  - Several Gram-negative pathogenic bacteria have evolved a complex protein
      secretion system termed type III to deliver bacterial effector proteins into host
      cells that then modulate host cellular functions. These bacterial devices are
      present in both plant and animal pathogenic bacteria and are evolutionarily
      related to the flagellar apparatus. Although type III secretion systems are
      substantially conserved, the effector molecules they deliver are unique for each
      bacterial species. Understanding the biology of these devices may allow the
      development of novel prevention and therapeutic approaches for several infectious
      diseases.

PMID- 10334982
TI  - Helicobacter pylori virulence and genetic geography.
AB  - Isolated for the first time in 1982 from human gastric biopsy, Helicobacter
      pylori is responsible for gastritis, peptic ulcer, and gastric cancer. A
      pathogenicity island acquired by horizontal transfer, coding for a type IV
      secretion system, is a major determinant of virulence. The infection is now
      treated with antibiotics, and vaccines are in preparation. The geographic
      distribution suggests coevolution of man and Helicobacter pylori.

PMID- 10334983
TI  - Large magnetoresistance of electrodeposited single-crystal bismuth thin films 
AB  - Single-crystal bismuth thin films 1 to 20 micrometers thick were fabricated by
      electrodeposition and suitable annealing. Magnetoresistance up to 250 percent at
      300 kelvin and 380,000 percent at 5 kelvin as well as clean Shubnikov-de Haas
      oscillations were observed, indicative of the high quality of these films. A
      hybrid structure was also made that showed a large magnetoresistive effect of 30
      percent at 200 oersted and a field sensitivity of 0.2 percent magnetoresistance
      per oersted at room temperature.

PMID- 10334984
TI  - Cracks faster than the shear wave speed 
AB  - Classical dynamic fracture theories predict the surface wave speed to be the
      limiting speed for propagation of in-plane cracks in homogeneous, linear elastic
      materials subjected to remote loading. This report presents experimental evidence
      to the contrary. Intersonic shear-dominated crack growth featuring shear shock
      waves was observed along weak planes in a brittle polyester resin under far-field
      asymmetric loading. When steady-state conditions were attained, the shear cracks
      propagated at speeds close to 2 times the material shear wave speed. These
      observations have similarities to shallow earthquake events where intersonic
      shear rupture speeds have been surmised.

PMID- 10334985
TI  - Carbon nanotube actuators 
AB  - Electromechanical actuators based on sheets of single-walled carbon nanotubes
      were shown to generate higher stresses than natural muscle and higher strains
      than high-modulus ferroelectrics. Like natural muscles, the macroscopic actuators
      are assemblies of billions of individual nanoscale actuators. The actuation
      mechanism (quantum chemical-based expansion due to electrochemical double-layer
      charging) does not require ion intercalation, which limits the life and rate of
      faradaic conducting polymer actuators. Unlike conventional ferroelectric
      actuators, low operating voltages of a few volts generate large actuator strains.
      Predictions based on measurements suggest that actuators using optimized nanotube
      sheets may eventually provide substantially higher work densities per cycle than
      any previously known technology.

PMID- 10334986
TI  - The magnetic excitation spectrum and thermodynamics of high-Tc superconductors 
AB  - Inelastic neutron scattering was used to study the wave vector- and frequency
      dependent magnetic fluctuations in single crystals of superconducting
      YBa2Cu3O6+x. The spectra contain several important features, including a gap in
      the superconducting state, a pseudogap in the normal state, and the much
      discussed resonance peak. The appearance of the pseudogap determined from
      transport and nuclear resonance coincides with formation of the resonance in the
      magnetic excitations. The exchange energy associated with the resonance has the
      temperature and doping dependences as well as the magnitude to describe
      approximately the electronic specific heat near the superconducting transition
      temperature (Tc).

PMID- 10334987
TI  - 26Al in eucrite piplia kalan: plausible heat source and formation chronology 
AB  - Aluminum-magnesium isotopic analysis of plagioclase in the eucrite Piplia Kalan,
      with 27Al/24Mg ratio between 2000 to 7000, reveals the presence of excess
      magnesium-26 resulting from in situ decay of the short-lived nuclide aluminum-26.
      This observation confirms aluminum-26 as a plausible heat source for melting and
      differentiation of the eucrite parent body in particular and for planetesimals in
      general. The inferred initial abundance of 26Al/27Al of (7.5 +/- 0.9) x 10(-7)
      indicates that melting, differentiation, and crust formation in the parent body
      of Piplia Kalan was complete within 5 million years of the formation of the solar
      system.

PMID- 10334988
TI  - Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor
      antigen.
AB  - In an effort to identify tumor-specific antigens recognized by CD4(+) T cells, an
      approach was developed that allows the screening of an invariant chain
      complementary DNA fusion library in a genetically engineered cell line expressing
      the essential components of the major histocompatibility complex (MHC) class II
      processing and presentation pathway. This led to the identification of a mutated
      form of human CDC27, which gave rise to an HLA-DR4-restricted melanoma antigen. A
      mutated form of triosephosphate isomerase, isolated by a biochemical method, was
      also identified as an HLA-DR1-restricted antigen. Thus, this approach may be
      generally applicable to the identification of antigens recognized by CD4(+) T
      cells, which could aid the development of strategies for the treatment of
      patients with cancer, autoimmune diseases, or infectious diseases.

PMID- 10334989
TI  - BRCA1 inhibition of estrogen receptor signaling in transfected cells.
AB  - Mutations of the breast cancer susceptibility gene BRCA1 confer increased risk
      for breast, ovarian, and prostatic cancers, but it is not clear why the mutations
      are associated with these particular tumor types. In transient transfection
      assays, BRCA1 was found to inhibit signaling by the ligand-activated estrogen
      receptor (ER-alpha) through the estrogen-responsive enhancer element and to block
      the transcriptional activation function AF-2 of ER-alpha. These results raise the
      possibility that wild-type BRCA1 suppresses estrogen-dependent transcriptional
      pathways related to mammary epithelial cell proliferation and that loss of this
      ability contributes to tumorigenesis.

PMID- 10334990
TI  - Self-organization of microtubule asters induced in Xenopus egg extracts by GTP
      bound Ran.
AB  - The nucleotide exchange activity of RCC1, the only known nucleotide exchange
      factor for Ran, a Ras-like small guanosine triphosphatase, was required for
      microtubule aster formation with or without demembranated sperm in Xenopus egg
      extracts arrested in meiosis II. Consistently, in the RCC1-depleted egg extracts,
      Ran guanosine triphosphate (RanGTP), but not Ran guanosine diphosphate (RanGDP),
      induced self-organization of microtubule asters, and the process required the
      activity of dynein. Thus, Ran was shown to regulate formation of the microtubule
      network.

PMID- 10334991
TI  - Stimulation of microtubule aster formation and spindle assembly by the small
      GTPase Ran.
AB  - Ran, a small guanosine triphosphatase, is suggested to have additional functions
      beyond its well-characterized role in nuclear trafficking. Guanosine triphosphate
      bound Ran, but not guanosine diphosphate-bound Ran, stimulated polymerization of
      astral microtubules from centrosomes assembled on Xenopus sperm. Moreover, a Ran
      allele with a mutation in the effector domain (RanL43E) induced the formation of
      microtubule asters and spindle assembly, in the absence of sperm nuclei, in a
      gammaTuRC (gamma-tubulin ring complex)- and XMAP215 (Xenopus microtubule
      associated protein)-dependent manner. Therefore, Ran could be a key signaling
      molecule regulating microtubule polymerization during mitosis.

PMID- 10334992
TI  - Identification of a nuclear receptor for bile acids.
AB  - Bile acids are essential for the solubilization and transport of dietary lipids
      and are the major products of cholesterol catabolism. Results presented here show
      that bile acids are physiological ligands for the farnesoid X receptor (FXR), an
      orphan nuclear receptor. When bound to bile acids, FXR repressed transcription of
      the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting
      enzyme in bile acid synthesis, and activated the gene encoding intestinal bile
      acid-binding protein, which is a candidate bile acid transporter. These results
      demonstrate a mechanism by which bile acids transcriptionally regulate their
      biosynthesis and enterohepatic transport.

PMID- 10334993
TI  - Bile acids: natural ligands for an orphan nuclear receptor.
AB  - Bile acids regulate the transcription of genes that control cholesterol
      homeostasis through molecular mechanisms that are poorly understood.
      Physiological concentrations of free and conjugated chenodeoxycholic acid,
      lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR;
      NR1H4), an orphan nuclear receptor. As ligands, these bile acids and their
      conjugates modulated interaction of FXR with a peptide derived from steroid
      receptor coactivator 1. These results provide evidence for a nuclear bile acid
      signaling pathway that may regulate cholesterol homeostasis.

PMID- 10334994
TI  - Modulation of polyketide synthase activity by accessory proteins during
      lovastatin biosynthesis.
AB  - Polyketides, the ubiquitous products of secondary metabolism in microorganisms,
      are made by a process resembling fatty acid biosynthesis that allows the
      suppression of reduction or dehydration reactions at specific biosynthetic steps,
      giving rise to a wide range of often medically useful products. The lovastatin
      biosynthesis cluster contains two type I polyketide synthase genes. Synthesis of
      the main nonaketide-derived skeleton was found to require the previously known
      iterative lovastatin nonaketide synthase (LNKS), plus at least one additional
      protein (LovC) that interacts with LNKS and is necessary for the correct
      processing of the growing polyketide chain and production of dihydromonacolin L.
      The noniterative lovastatin diketide synthase (LDKS) enzyme specifies formation
      of 2-methylbutyrate and interacts closely with an additional transesterase (LovD)
      responsible for assembling lovastatin from this polyketide and monacolin J.

PMID- 10334995
TI  - UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation.
AB  - Modification of cell surface molecules with sialic acid is crucial for their
      function in many biological processes, including cell adhesion and signal
      transduction. Uridine diphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2
      epimerase) is an enzyme that catalyzes an early, rate-limiting step in the sialic
      acid biosynthetic pathway. UDP-GlcNAc 2-epimerase was found to be a major
      determinant of cell surface sialylation in human hematopoietic cell lines and a
      critical regulator of the function of specific cell surface adhesion molecules.

PMID- 10334996
TI  - The burden of asthma: weighing the community risk against individual risk.

PMID- 10334997
TI  - Screening older patients for obstructive airways disease.

PMID- 10334998
TI  - A quagmire for clinicians: when technological advances exceed clinical knowledge.

PMID- 10334999
TI  - Geographical and socioeconomic variation in the prevalence of asthma symptoms in
      English and Scottish children.
AB  - BACKGROUND: There has been controversy over the relation between poverty and
      asthma in the community. The aim of this analysis was to disentangle geographical
      and socioeconomic variation in asthma symptoms. METHODS: The analysis is based on
      parental reports of symptoms from data collected in 1990 and 1991. Children aged
      5-11 years from three populations (English representative sample, Scottish
      representative sample, and an English inner city sample) were included. Of 17 677
      eligible children, between 14 490 (82.0%) and 15 562 (88.0%) children were
      available for analysis according to symptom group. RESULTS: Wheezy symptoms were
      less prevalent in the Scottish sample than in the English samples and asthma
      attacks were most prevalent in the English representative sample. Asthma attacks
      were less prevalent in inner city areas than in the English representative sample
      (OR 0.79, 95% CI 0.66 to 0.95), but persistent wheeze and other respiratory
      symptoms were more prevalent (OR 1.95, 95% CI 1.65 to 2.32 and OR 1.67, 95% CI
      1.52 to 1.84, respectively). The prevalence of persistent wheeze was higher in
      children whose father's social class was low and in those living in areas with a
      high Townsend score (an index of poverty) than in other children (p<0.001). Of
      the 14 areas with the highest Townsend score, 13 had an OR above 1 and six had an
      OR significantly higher than the reference area. CONCLUSIONS: Persistent wheeze
      is more prevalent in poor areas than in less deprived areas. This may indicate
      that poverty is associated with severe asthma or that a high percentage of
      persistent asthma symptoms in inner city areas are unrecognised and untreated.

PMID- 10335000
TI  - Randomised trial of an inhaled beta2 agonist, inhaled corticosteroid and their
      combination in the treatment of asthma.
AB  - BACKGROUND: Although many asthmatic patients are treated with a combination of
      beta2 agonist and corticosteroid inhalers, the clinical effects of combining the
      drugs are unknown. Studies on the early asthmatic response to allergen suggest
      that beta2 agonists may reduce the benefit of inhaled corticosteroids. A study of
      the effects of combining the drugs on asthma control was undertaken. METHODS:
      Sixty one subjects with mild to moderate asthma were randomised to a double blind
      crossover comparison of inhaled budesonide (200-400 microg twice daily),
      terbutaline (500-1000 microg four times daily), combined treatment, and placebo.
      Each treatment was given for six weeks following a four week washout period.
      Ipratropium was used for symptom relief. Treatments were ranked from worst (1) to
      best (4) based on need for oral steroid, mean morning peak flow, nocturnal
      awakening, ipratropium use, and asthma symptoms. Lung function and bronchial
      hyperresponsiveness were measured before and after each treatment. RESULTS:
      Evaluable data for all four treatments were obtained from 47 subjects. The mean
      rank of each treatment was: placebo = 2.05; terbutaline = 2.13; budesonide =
      2.48; combined treatment = 3.34. Combined treatment was ranked significantly
      better than any other treatment (p<0.01). Mean (95% CI) morning and evening peak
      flows were 14 (5 to 23) and 24 (15 to 34) l/min higher, respectively, during
      combined treatment than during budesonide, and 27 (17 to 37) and 15 (7 to 23)
      l/min higher than during terbutaline. Asthma symptoms tended to be least frequent
      during combined treatment but were not significantly different from budesonide
      alone. There was no significant difference between combined treatment and
      budesonide alone for lung function and bronchial hyperresponsiveness.
      CONCLUSIONS: In this group of mild to moderate asthmatic subjects the combination
      of beta2 agonist and corticosteroid gave better asthma control than either
      treatment alone. There was no evidence that regular beta2 agonist treatment
      impaired the beneficial effect of inhaled corticosteroid.

PMID- 10335001
TI  - Effects of inhaled beta agonist and corticosteroid treatment on nuclear
      transcription factors in bronchial mucosa in asthma.
AB  - BACKGROUND: Inhaled corticosteroids and beta agonists are the most commonly used
      treatments in asthma and are often used together. Recent evidence suggests that
      many of the anti-inflammatory actions of corticosteroids are mediated by cross
      talk between the activated glucocorticoid receptor (GR) and other transcription
      factors such as the pro-inflammatory nuclear factor kappa B (NFkappaB). Beta
      agonists can activate the transcription factor cAMP response element binding
      protein (CREB). A mutual inhibition between GR and CREB occurs in vitro which
      raises the possibility of a negative interaction between corticosteroid and beta
      agonist drugs. A study was undertaken to determine whether these interactions
      occur during treatment with beta2 agonists and corticosteroids in asthma.
      METHODS: Seven subjects who were participating in a randomised, placebo
      controlled, crossover study of six weeks treatment with inhaled budesonide (400
      microg twice daily), terbutaline (1 mg four times daily), and combined treatment
      were recruited. Biopsy samples of the bronchial mucosa were obtained after each
      treatment and analysed for the DNA binding activity of GR, CREB, and NFkappaB.
      RESULTS: Budesonide increased GR activity (p<0.05) and decreased NFkappaB
      activity (p<0.05). No treatment combination altered CREB activity and terbutaline
      had no significant effects on any transcription factor. CONCLUSIONS: Inhaled
      corticosteroids have significant effects on GR and NFkappaB activity in bronchial
      mucosa. A negative interaction between inhaled corticosteroids and beta agonists
      was not found.

PMID- 10335002
TI  - Evaluation of a randomised controlled trial of adult asthma education in a
      hospital setting.
AB  - BACKGROUND: Although patient education is a key step in the Australian Asthma
      Management Plan, its impact has not been assessed in a hospital outpatient asthma
      clinic. METHODS: A controlled trial was undertaken in 125 adults with asthma
      recruited from the Alfred Hospital Asthma and Allergy Clinic and randomly
      allocated to an intervention (n = 64) or control (n = 61) group. Subjects in the
      intervention group attended three education sessions, each of 90 minutes
      duration, spread over three successive weeks. Asthma knowledge, quality of life,
      self-management skills, and attitudes and beliefs about asthma were assessed by
      questionnaires at baseline and after six months. The intervention group was also
      assessed immediately after the three education sessions. The control group was
      evaluated after six months of usual care. RESULTS: Asthma knowledge improved
      significantly in the intervention group after three education sessions (p =
      0.0001) and this was retained six months later (p = 0.03). The impact of asthma
      on quality of life decreased significantly immediately after intervention (p =
      0.03) but this was not maintained six months later (p = 0.35). On the other hand,
      the intervention had little impact on self-management skills or attitudes and
      beliefs about asthma. However, the control group had also improved their
      knowledge, quality of life and self-management skills after six months of usual
      care. The difference in mean change in knowledge score at six months between the
      intervention and control groups was not significant (p = 0.51). CONCLUSIONS: In
      contrast to some other studies, a limited asthma education programme in a
      hospital outpatient setting had a positive impact on patients' knowledge of
      asthma, but not on their quality of life, self-management skills, or attitudes
      and beliefs about asthma.

PMID- 10335003
TI  - Screening older patients for obstructive airways disease in a semi-rural
      practice.
AB  - BACKGROUND: Obstructive airways disease in older patients is reported to be not
      only common, but frequently overlooked and untreated by general practitioners.
      This study examines the value of screening elderly patients in a large semi-rural
      general practice for potentially treatable asthma and chronic obstructive
      pulmonary disease (COPD). METHODS: A random sample of 353 patients aged 60-75
      years attended a nurse run screening clinic for pulmonary function testing,
      serial peak flow recording, and completion of a symptom questionnaire. Patients
      with a low forced expiratory volume in one second (below the fifth centile of
      their predicted value) or >15% mean diurnal variation in peak flow were referred
      to a doctor's clinic for further diagnostic assessment and/or to discuss possible
      treatment where appropriate. RESULTS: Fifty eight patients (16.4%) had
      obstructive airways disease, the prevalence of asthma being 6.5% and that of COPD
      9.9%. Of these, 30 had no previous diagnosis of airways disease and were not on
      treatment; eight of them had significant airways reversibility and 10 were
      current smokers. No newly diagnosed patients had severe disease as measured by
      pulmonary function or quality of life assessment, and six patients accepted
      treatment. CONCLUSION: Few older patients benefited from a screening programme
      for obstructive airways disease in a semi-rural general practice.

PMID- 10335004
TI  - Nasal pressure recording in the diagnosis of sleep apnoea hypopnoea syndrome.
AB  - BACKGROUND: Nasal pressure tracing is now being used to measure breathing in
      ambulatory screening devices for sleep apnoea but it has not been compared with
      other methods of assessment. METHODS: Sleep induced breathing disorders were
      scored by three different methods of analysis (thermistry, inductive
      plethysmography, and nasal pressure tracing) in 193 consecutive patients referred
      to our sleep laboratory. With the conventional thermistry method an apnoea was
      defined as the absence of oronasal flow on the thermistor signal for >/=10 s and
      a hypopnoea as a 50% decrease in the sum signal of inductive plethysmography
      tracing for >/=10 s associated with an arousal and/or a 2% decrease in SaO2.
      Nasal pressure was measured via nasal prongs connected to a pressure transducer.
      Using the thermistor signal alone, a hypopnoea was defined as a 50% decrease in
      the signal for >/=10 s associated with an arousal and/or a 2% decrease in SaO2. A
      similar definition of apnoea and hypopnoea was used for nasal pressure, the fall
      in pressure being substituted for the thermistor reading. RESULTS: Impaired nasal
      ventilation prevented adequate measurements of nasal pressure in 9% of subjects.
      According to the conventional method of interpretation 107 subjects were
      identified as having the sleep apnoea hypopnoea syndrome (SAHS). The apnoea +
      hypopnoea index (AHI) was significantly lower using the thermistry method than
      with conventional analysis (mean difference -4.3/h, 95% CI -5.3 to -3.2, p<10(
      4)); 39% of conventional hypopnoeic events were scored as apnoeas using nasal
      pressure scoring. Apnoeic and hypopnoeic events could also be observed without
      any change in thermistor and sum Respitrace signals that resumed with the
      occurrence of arousals or awakenings. The AHI was significantly higher with nasal
      pressure scoring than with the conventional method (mean difference 4.5, 95% CI
      3.4 to 5.6, p<10(-4)). The mean difference in apnoea index between conventional
      and nasal pressure scoring was -7.5/h (95% CI -8.9 to -6.1). In the 78 patients
      who did not have SAHS according to the conventional method of analysis there was
      a significant positive relationship between the arousal index and AHI measured by
      nasal pressure tracing (R = 0.51, p<10(-4)). Seventeen of the 78 patients had an
      AHI of >15/h by the nasal pressure method of analysis. CONCLUSIONS: Nasal
      pressure recording provides a simple and reliable measurement of nocturnal
      breathing abnormalities and may identify breathing abnormalities associated with
      arousals that are missed by other diagnostic methods.

PMID- 10335005
TI  - Tracheobronchial malacia and stenosis in children in intensive care: bronchograms
      help to predict oucome.
AB  - BACKGROUND: Severe tracheobronchial malacia and stenosis are important causes of
      morbidity and mortality in children in intensive care, but little is known about
      how best to diagnose these conditions or determine their prognosis. METHODS: The
      records of all 62 children in whom one or both of these conditions had been
      diagnosed by contrast cinetracheobronchography in our intensive care unit in the
      period 1986-95 were studied. RESULTS: Seventy four per cent of the 62 children
      had congenital heart disease; none was a preterm baby with airways disease
      associated with prolonged ventilation. Fifteen of the children had airway
      stenosis without malacia; three died because of the stenosis and two died from
      other causes. Twenty eight of the 47 children with malacia died; only eight
      children survived without developmental or respiratory handicap. All children
      needing ventilation for malacia for longer than 14 consecutive days died if their
      bronchogram showed moderate or severe malacia of either main bronchus (15 cases),
      or malacia of any severity of both bronchi (three additional cases); all children
      needing ventilation for malacia for longer than 21 consecutive days died if their
      bronchogram showed malacia of any severity of the trachea or a main bronchus
      (three additional cases). These findings were strongly associated with a fatal
      outcome (p<0.00005); they were present in 21 children (all of whom died) and
      absent in 26 (of whom seven died, six from non-respiratory causes). They had a
      positive predictive value for death of 100%, but the lower limit of the 95%
      confidence interval was 83.9% so up to 16% of patients meeting the criteria might
      survive. CONCLUSION: In this series the findings on contrast
      cinetracheobronchography combined with the duration of ventilation provided a
      useful guide to the prognosis of children with tracheobronchomalacia. The
      information provided by bronchoscopy was less useful.

PMID- 10335006
TI  - Oxidative stress during acute respiratory exacerbations in cystic fibrosis.
AB  - BACKGROUND: Patients with cystic fibrosis experience chronic systemic oxidative
      stress. This is coupled with chronic inflammation of the lung involving bronchial
      polymorphonuclear neutrophil accumulation and activation. We hypothesised that,
      during periods of acute respiratory exacerbation, free radical activity and
      consequent damage would be most marked and that intensive treatment of the
      infection would result in improvement towards values found during stable periods.
      METHODS: Plasma and red blood cells were collected from 12 healthy normal
      volunteers and from 12 patients with cystic fibrosis with an acute respiratory
      exacerbation (increased respiratory symptoms, reduction in forced expiratory
      volume in one second (FEV1) of more than 10%, and a decision to treat with
      intravenous antibiotics). Further samples were collected from patients following
      two weeks of treatment. Samples were analysed for inflammatory markers, markers
      of free radical damage, and aqueous and lipid phase scavengers. RESULTS: During
      respiratory exacerbations FEV1 and forced vital capacity (FVC) were lower than in
      controls (mean differences -2.82 (95% CI -2.12 to -3.52) and -3. 79 (-3.03 to 
      4.55) l, respectively) but improved following treatment (mean change 0.29 (95% CI
      0.18 to 0.40) and 0.33 (0.23 to 0.43) l, respectively). Inflammatory markers
      during exacerbations were significantly higher in patients than in controls with
      the following mean (95% CI) differences: C reactive protein (CRP), 46 (17 to 75)
      g/l; neutrophil elastase alpha1-antiprotease complexes (NEAPC), 4.4 (1.77 to
      7.07) mg/l; white cell count (WCC), 5.3 (4.7 to 5.9) x 10(9)/l. These markers
      decreased significantly following treatment with the following mean (95% CI)
      changes: CRP -26 (-10 to -42) g/l; NEAPC -3.1 (-1.3 to -4.9) mg/l; WCC -1.5 (-1.3
      to -1.7) x 10(9)/l. Malondialdehyde (MDA) as a marker of free radical activity
      was significantly higher in patients during exacerbations than in controls with a
      mean (95% CI) difference of 193 (107 to 279) which improved with treatment (mean
      change -56 (95% CI -28 to -84) nmol/mmol cholesterol). Red blood cell
      polyunsaturated fatty acids were significantly lower in patients than in controls
      with a mean difference of -4.4(95% CI -2.6 to -6.2) moles percent, but did not
      improve significantly after treatment. Protein carbonyls during exacerbations
      were not different from controls but did increase with treatment compared with
      levels during the exacerbation (mean change 0.39 (95% CI 0.11 to 0.67) micromol/g
      protein). Aqueous and lipid phase scavengers in patients during exacerbations
      were significantly lower than in controls with the following mean (95% CI)
      differences: ascorbate, -19.0 (-2.7 to -35.3) micromol/l; sulphydryls, -122 (-77
      to -167) micromol/l; retinol, -237 (-47 to -427) nmol/mmol cholesterol; beta
      carotene, -52.8 (-11.8 to -93.8) nmol/mmol cholesterol; luteine, -50.4 (-10.4 to 
      90.4) nmol/mmol cholesterol; lycopene, -90.1 (-30.1 to -150.1) nmol/mmol
      cholesterol. Treatment resulted in improvement with the following mean (95% CI)
      changes: sulphydryls, 50 (32 to 68) micromol/l; retinol, 152 (47 to 257)
      nmol/mmol cholesterol; alpha- and beta-carotene, 0.6 (0.0 to 1.2) and 7.6 (0.0 to
      15.2) nmol/mmol cholesterol, respectively; alpha-tocopherol, 839 (283 to 1405)
      nmol/mmol cholesterol; and lycopene, 8.2 (0.0 to 16.2) nmol/mmol cholesterol.
      CONCLUSIONS: Abnormalities of markers of inflammation, free radical activity, and
      radical scavengers were significantly more extreme during acute respiratory
      exacerbations and showed improvement with treatment. The need to provide
      protection from inflammation and free radical damage should therefore be dynamic
      and related to the inflammatory and oxidative processes.

PMID- 10335007
TI  - Inter-relationship between tumour necrosis factor-alpha (TNF-alpha) and TNF
      soluble receptors in pulmonary sarcoidosis.
AB  - BACKGROUND: The importance of tumour necrosis factor-alpha (TNF-alpha) in the
      pathogenesis of pulmonary sarcoidosis has remained uncertain because of the
      paucity of clinical features associated with excessive levels of this cytokine.
      Increased levels of soluble TNF receptors (TNF-R), which are known to inhibit TNF
      alpha activity, were recently described in the lungs of subjects with
      sarcoidosis. We hypothesised that TNF-alpha bioactivity may be inhibited in
      sarcoidosis by the presence of TNF-R. A study was therefore undertaken to
      investigate for the first time the relationship between soluble receptors and TNF
      alpha bioactivity in the lungs of subjects with sarcoidosis. METHODS: Alveolar
      macrophages (AMs) from 16 subjects with histologically proven sarcoidosis and 13
      healthy controls were cultured in the presence and absence of lipopolysaccharide
      (LPS). The subjects with sarcoidosis were grouped by radiological assessment into
      stage I (n = 6) and stage II/III (n = 10). The cell culture supernatants and
      bronchoalveolar lavage (BAL) fluid were assayed for TNF bioactivity using the
      WEHI 164 clone 13 assay. Immunoreactive (bound and free) TNF-alpha and free TNF
      Rs (p55 and p75) were determined by ELISA. RESULTS: Bioactive TNF-alpha was
      undetectable in the BAL fluid of all the subjects with sarcoidosis and most of
      the healthy controls. However, there was significantly more immunoreactive TNF
      alpha in the BAL fluid from subjects with sarcoidosis than from the controls
      (median values 0.304 ng/ml and 0.004 ng/ml, respectively, 95% CI 0. 076 to 0.455,
      p<0.001). The levels of both p55 and p75 in the BAL fluid were higher in both
      sarcoidosis groups than in the controls (p<0.0005 and p<0.001, respectively). In
      LPS stimulated AM supernatants reduced TNF-alpha bioactivity was seen in subjects
      with stage I sarcoidosis compared with those with stage II/III disease and
      healthy controls (median 0.333 ng/ml vs 1.362 ng/ml and 2.385 ng/ml,
      respectively, p<0.01). This contrasted with increased p55 levels in the AM
      supernatants derived from subjects with stage I sarcoidosis compared with those
      with stage II/III disease and healthy controls (median 0.449 ng/ml vs 0.058 ng/ml
      and 0.078 ng/ml, respectively, p<0.01). The levels of p75 were increased in
      unstimulated AM cultures in subjects with stage II/III disease compared with
      those with stage I disease and healthy controls (median 0.326 ng/ml vs 0.064
      ng/ml and 0.102 ng/ml, p<0.05). CONCLUSIONS: These results indicate that TNF
      alpha bioactivity may be inhibited by increased soluble TNF-R in the lungs of
      subjects with sarcoidosis, and this inhibition may be greater in patients with
      stage I sarcoidosis than in those with stage II/III disease. This may represent a
      homeostatic mechanism which protects the lung from excessive TNF production
      characteristic of chronic inflammation.

PMID- 10335008
TI  - Muscarinic blockade of methacholine induced airway and parenchymal lung responses
      in anaesthetised rats.
AB  - BACKGROUND: It has previously been shown that M1 cholinergic receptors are
      involved in the parenchymal response to inhaled methacholine in puppies using the
      M1 selective antagonist pirenzepine. Although M3 receptors are responsible for
      acetylcholine induced bronchoconstriction in isolated rat lung, the role of M1
      receptors has not been determined in the rat in vivo. METHODS: Anaesthetised,
      paralysed, open chested Brown Norway rats were mechanically ventilated and the
      femoral vein cannulated for intravenous injection of drugs. Low frequency forced
      oscillations were applied to measure lung input impedance (ZL) and computerised
      modelling enabled separation of ZL into airway and parenchymal components.
      Atropine (500 microg/kg iv) and pirenzepine (50, 100 or 200 microg/kg iv) were
      administered during steady state constriction generated by continuous inhalation
      (1 mg/ml) or intravenous (10 or 15 microg/kg/min) administration of methacholine.
      RESULTS: Continuous inhalation of methacholine produced a 185% increase in
      frequency dependent tissue resistance (G) which was effectively inhibited by
      atropine 500 microg/kg iv (p<0.01, n = 6). Pirenzepine (50, 100 or 200 microg/kg)
      had a minimal effect on the parenchymal response to inhaled methacholine. A 258%
      increase in airway resistance (Raw) was induced by continuous intravenous
      infusion of methacholine and this response was effectively abolished by
      pirenzepine (p<0.001, n = 5). Cutting the vagi in the cervical region did not
      alter baseline airway mechanics. Vagotomy did not affect lung responses to
      intravenous methacholine nor the ability of pirenzepine to reduce these
      responses. CONCLUSIONS: In the rat, M1-subtype receptors are functional in
      airways but not in the tissue.

PMID- 10335009
TI  - Issues at the interface between primary and secondary care in the management of
      common respiratory disease. Introduction.

PMID- 10335010
TI  - Issues at the interface between primary and secondary care in the management of
      common respiratory disease. 1. The challenge of improving the delivery of lung
      cancer care.

PMID- 10335014
TI  - Pulmonary eosinophilia associated with montelukast.
AB  - Antileukotriene drugs are new therapeutic agents that have recently been approved
      for the treatment of asthma. Several cases of eosinophilic conditions including
      Churg-Strauss syndrome have been reported to be associated with zafirlukast, a
      cysteinyl leukotriene type 1 receptor antagonist. So far no other leukotriene
      modifier has been associated with the syndrome. The case history is presented of
      a man with allergic rhinitis and asthma who had received intermittent pulse
      therapy with oral corticosteroids. Pulmonary eosinophilia developed while he was
      receiving treatment with montelukast, a chemically distinct cysteinyl leukotriene
      type 1 receptor antagonist. After discontinuation of montelukast therapy and
      administration of systemic corticosteroids the patient's symptoms reversed
      rapidly and there was prompt resolution of the pulmonary infiltrates. We believe
      that cysteinyl leukotriene type 1 receptor antagonists are safe and effective
      drugs for most patients with asthma but caution is needed for those with more
      severe disease who require systemic corticosteroids, especially if they show
      characteristics of the atypical allergic diathesis seen in the prodromal phase of
      Churg-Strauss syndrome.

PMID- 10335012
TI  - New immunosuppressive drugs and lung transplantation: last or least?

PMID- 10335011
TI  - Prevention of nosocomial bacterial pneumonia.

PMID- 10335013
TI  - Immunomodulation by interference with co-stimulatory molecules: therapeutic
      perspectives in asthma.

PMID- 10335015
TI  - Epithelioid haemangioendothelioma.
AB  - Epithelioid haemangioendothelioma is a rare pulmonary neoplasm with less than 40
      cases described world wide. We describe the only case to have presented with
      hypertrophic pulmonary osteoarthropathy who has been treated with azathioprine
      and has remained alive and well with no deterioration in pulmonary function since
      being diagnosed 16 years ago. The progression of the chest radiograph and spiral
      CT appearances of this rare neoplasm are described, and current views regarding
      the cellular origin of the neoplasm, its cytological appearance, clinical
      presentation and prognosis are discussed.

PMID- 10335016
TI  - Internal and temporal reliability estimates for informant ratings of personality
      using the NEO PI-R and IAS. NEO Personality Inventory. Interpersonal Adjective
      Scales.
AB  - This study examines the internal consistency and temporal stability of informant
      ratings from two widely used instruments for normal personality assessment, the
      revised NEO Personality Inventory (NEO PI-R) and the Interpersonal Adjective
      Scales (IAS). Well-known adult targets were selected by 109 undergraduate
      students and rated on two occasions separated by a 6-month interval. With few
      exceptions, estimates of internal consistency are adequate to good for both
      instruments. NEO PI-R domain scores yield coefficient alphas ranging from .89 to
      .96, with a median of .80 for the 30 facet scales. IAS octant scales show
      coefficient alphas ranging from .83 to .92. Retest Pearson correlations are above
      .70 for each of the NEO PI-R domain scores and both IAS axis coordinates, and
      intraclass correlations are above .60 for all scales from both instruments. Score
      changes were small but statistically significant for three of the five NEO PI-R
      domains at retest. The retest stability of IAS type classifications varies as a
      function of the extremity of the associated octant scores.

PMID- 10335017
TI  - Methodological issues in evaluating Rorschach validity: a comment on Burns and
      Viglione (1996), Weiner (1996), and Ganellen (1996)
AB  - The old controversy regarding the Rorschach Inkblot Test has recently revived.
      The present article suggests that the debate will be most productive if careful
      attention is paid to methodological issues. Three recent examples illustrate how
      incorrect conclusions regarding Rorschach validity may occur if methodological
      issues are not evaluated carefully. The present article examines (a) Burns and
      Viglione s (1996) conclusion that the Rorschach Human Experience Variable (HEV)
      is a predictor of interpersonal relatedness among adults; (b) Weiner s (1996)
      conclusion that the D score and Morbid Responses (MOR) are valid measures of
      experienced distress in Posttraumatic Stress Disorder (PTSD); and (c) Ganellen s
      (1996a, 1996b) conclusion that the Rorschach Depression Index (DEPI) and the
      Minnesota Multiphasic Personality Inventory (MMPI) are comparable in their power
      to identify diagnoses of depression.

PMID- 10335018
TI  - Short forms of the Schedule for Nonadaptive and Adaptive Personality (SNAP) for
      self- and collateral ratings: development, reliability, and validity.
AB  - Researchers and clinicians alike increasingly seek brief, reliable, and valid
      measures to obtain personality trait ratings from both selves and peers. We
      report the development of a paragraph-descriptor short form of a full-length
      personality assessment instrument, the Schedule for Nonadaptive and Adaptive
      Personality (SNAP) with both self- and other versions. Reliability and validity
      data were collected on a sample of 294 college students, from 90 of whom we also
      obtained parental ratings of their personality. Internal consistency reliability
      was good in both self- and parent data. The factorial structures of the self
      report short and long forms were very similar. Convergence between parental
      ratings was moderately high. Self-parent convergence was variable, with lower
      agreement on scales assessing subjective distress than those assessing more
      observable behaviors; it also was stronger for higher order factors than for
      scales.

PMID- 10335019
TI  - Norms for letter and category fluency: demographic corrections for age,
      education, and ethnicity.
AB  - Letter and category fluency tasks are used to assess semantic knowledge,
      retrieval ability, and executive functioning. They appear to be useful in
      detecting different types of dementia, but accurate detection of
      neuropsychological impairment relies on appropriate normative data. Multiple
      regression analysis was used to develop demographically corrected norms for
      letter and category fluency in 768 normal adults. T-score equations were
      developed on a base subsample of 403, and crossvalidated on a separate subsample
      (n = 365). Participants ranged in age from 20 years to 101 years; in educational
      level from 0 to 20 years; 55% were Caucasian and 45% were African American.
      Together, age, education, and ethnicity were significant predictors of letter and
      category fluency performance, accounting for 15% and 25% of variance,
      respectively. Formulas and tables for converting raw fluency scores to
      demographically corrected T scores are presented.

PMID- 10335020
TI  - Performance on the Wisconsin Card Sorting Test after traumatic brain injury.
AB  - The performance of 100 patients with traumatic brain injury (TBI) on the
      Wisconsin Card Sorting Test (WCST) was examined to determine the underlying
      latent structure as well as profile subtypes. Exploratory factor analysis with
      oblique rotation identified three factors: response accuracy, learning, and
      failure to maintain set. Marker variables from each factor were then included in
      a two-stage cluster analysis, which identified two reliable subtypes. Level of
      performance differences between these subtypes were meaningfully related to both
      demographic background and length of coma. It is concluded that interpretation of
      the WCST results of patients with TBI should consider the multifactorial nature
      of the instrument in combination with injury severity characteristics and
      demographic variables.

PMID- 10335023
TI  - [Renal hypertension in children and adolescents].

PMID- 10335021
TI  - A new measure of conversational experience: the speaking extent and comfort scale
      (SPEACS).
AB  - Few measures exist which directly assess aspects of conversational experience. We
      present and provide a psychometric assessment of the Speaking Extent and Comfort
      Scale (SPEACS), a new 20-item measure which assesses four aspects of past
      conversational experience: the extent and comfort of both general conversations
      and in conversations specifically about the self. All four SPEACS subscales
      exhibited good test-retest reliability. As predicted, the subscales related
      positively to social competence, disclosure, assertiveness, and perceived
      availability of someone to talk to, and negatively to social avoidance and social
      anxiety, providing support for their construct validity. Internal consistency
      data demonstrated that people tend to vary in how often and how comfortable they
      feel having conversations with different people. SPEACS offers a range of
      potential applications in areas with a focus on social networks, social
      experience and interaction, and the possibility of extension to other dimensions
      of conversational experience.

PMID- 10335024
TI  - [The influence of salmon calcitonin on changes in thyroid hormone concentration
      and on TSH secretion. I].
AB  - The aim of this investigation was determination of salmon calcitonin (sCT)
      influence on changes of thyroid hormones levels in serum. The investigation was
      carried out on a group of 26 patients. The group was divided in two different
      ways: into people younger and older than 65 years, and into men and women.
      Investigation protocol consists of 4 days. On the 1st day patients received 100U
      of SC, on the 2nd day--100U of SC and 0.4 mg TRH, on the 3rd day--0.4 mg TRH, on
      the 4th day--0.9% solution of NaCl and 5% solution of human albumin. T3, T4 fT3
      and fT4 concentrations in serum were determined by RIA method.

PMID- 10335025
TI  - [Influence of salmon calcitonin on changes in thyroid hormone concentration and
      on TSH secretion. II].
AB  - The aim of this investigation was determination of salmon calcitonin (SC)
      administration influence on hypothalamus-pituitary-thyroid axis. The
      investigation was carried out on a group of 26 patients. The group was divided in
      two different ways: into people younger and older than 65 years, and into men and
      women. Investigation protocol consists of 4 days. On the 1st day patients
      received 100U of SC, on the 2nd day--100U of SC and 0.4 mg TRH, on the 3rd day-
      0.4 mg TRH, on the 4th day--0.9% solution of NaCl and 5% solution of human
      albumin. TSH serum concentrations were determined by RIA method. Infusion of SC
      caused TSH serum concentration increase in all groups. This effect is
      qualitatively similar but quantitatively different in investigated groups.
      Administration of SC with TRH causes significantly smaller growth of TSH
      concentration than observed after infusion of TRH alone. The mechanism of SC
      influence on pituitary may be similar to the one of TRH.

PMID- 10335026
TI  - [The influence of testosterone replacement therapy on well-being, bone mineral
      density and lipids in elderly men].
AB  - The aim of this study was to determine the influence of testosterone replacement
      therapy in elderly men on mood, bone mineral density, and lipids. We investigated
      thirty men (mean +/- SD; age 61.1 +/- 5.6 yr) with testosterone concentrations
      (mean +/- SEM) 2.1 +/- 0.2 ng/ml. Testosterone deficiency was replacement by
      intramuscular injections of testosterone enanthate 200 mg every second week from
      1.5 to 6 yr. (mean +/- SD; 3.35 +/- 1.6 yr.). During the treatment serum
      testosterone increased reaching normal levels (mean +/- SEM; 6.6 +/- 0.2 ng/ml).
      This was associated with significant increase in positive mood parameters and a
      decrease in negative mood parameters. Also self assessment of libido, potence and
      dream were improved. Bone mineral density (BMD) of lumbar spine increased. We
      noticed significant decrease in total cholesterol, and LDL-cholesterol.
      Hematocrit was increase Prostate-specific antigen concentration statistically
      increased from 0.65 +/- 0.1 to 1.35 +/- 0.1 ng/ml (mean +/- SEM), but in the
      cases of its levels were in normal range. Patients with coronary heart disease
      demonstrated decreasing ing symptoms of angina pectoris and nitrate requirement.
      In summary, long-term testosterone replacement therapy in elderly men may have
      beneficial effects on well-being, libido, potence, dream, bone mineral density,
      lipids, blood cell count and body mass (BMI). This therapy appears to be safe and
      there is no adverse effection on prostate.

PMID- 10335028
TI  - [Risk factors of the incidence of late vascular complications of diabetes].
AB  - From the follow-up examination of 1329 out of 4420 type 2 (non-insulin-dependent)
      diabetes followed for 17 years, the incidence of micro and macrovascular
      complications (proteinuria and nephropathy, symptoms of leg vascular disease,
      ischemic heart disease, and cerebrovascular events, was estimated and related to
      the levels of baseline-risk variables using logistic regression. For new cases of
      proteinuria and heavy proteinuria, hyperglycemia was the common predictor
      (alongside diastolic hypertension, smoking and overweight); hyperglycemia and
      glycosuria were among significant predictors of leg vascular disease (with
      duration of diabetes, smoking, male sex, diastolic hypertension, and
      proteinuria). On the other hand, systolic hypertension and male sex prevailed
      among factors predicting both ischemic heart disease (with high cholesterol and
      overweight), and stroke. The data confirm the higher involvement of diabetic
      milieu in micro than macrovascular incidents, with diabetic foot disease placed
      in between.

PMID- 10335027
TI  - [Clinical efficacy and safety of spiramycin and clarithromycin in the treatment
      of outpatients with lower respiratory tract infections].
AB  - Macrolide antibiotics have a broad spectrum of activities against the common
      pathogens responsible for lower respiratory tract infections, therefore for over
      40 years they have been useful in treatment of these diseases. The aim of this
      open randomised multicentre trial is to compare the efficacy and safety of
      spiramycin, one of the first macrolides, to clarithromycin, a new generation
      macrolide, in their normal condition of use in patient presenting with acute non
      complicated lower respiratory tract infections. 55 adult non-hospitalised
      patients with clinical diagnosis of bronchitis or pneumonia were randomised to
      receive either spiramycin 3 MIU twice daily or clarithromycin 500 mg twice daily
      for 7 or 10 days. For clinical evaluable patients, successful outcome was noted
      for 96.15% (25/26) spiramycin-treated patients and 96.43% (27/28) clarithromycin
      treated patients. Clinically significant improvement in signs and symptoms was
      comparable between treatment groups. 2 patients in the spiramycin group (7.69%)
      and 3 in clarithromycin group (10.71%) complained of adverse events which
      severity was mild or moderate and did not require interruption of conducting
      antibioticotherapy. Efficacy and safety analysis showed that the two macrolides
      were equally effective and well-tolerated, at the given doses, for the treatment
      of lower respiratory tract infections and may play important role in out-patient
      therapy of these diseases.

PMID- 10335030
TI  - [Toxic reaction induced by Hymenoptera stings].
AB  - Clinical symptoms of toxic reactions occurred in two patients following multiple
      stinging by bees and wasps respectively. The first cause is that of 76-year old
      woman attacked by a swarm of bees (about 200 stings), the other case presents a
      69-year old man who was stung by several dozen of wasps. In the first case the
      toxic reaction was manifested by shock, acute renal failure, tissue damage of the
      skin, muscles and liver and haemolysis which resulted in the patients death.
      These symptoms occur as a results of the cytotoxic effects of bee venom
      components such as melittin, phospholipase and kinins. In the course of the
      disease, noteworthy are: the initial phase mimicking an anaphylactic shock,
      haemolysis and rhabdomyolysis which lead to acute renal failure with tubular
      necrosis. In the second case skin symptoms prevailed. Additionally, laboratory
      tests showed increased CPK as a results of myolysis caused by components of
      insect venom. The progress of toxic reactions following multiple stinging
      especially by bees, calls for hospital observation of stung patients with careful
      monitoring of renal function.

PMID- 10335031
TI  - [Multiple myeloma nephropathy as a cause of renal failure--diagnostic
      difficulties and prospects for treatment].
AB  - We describe two patients admitted to our hospital because of renal failure. We
      diagnosed multiple myeloma in both. One patient had high peripheral blood
      eosinophilia, that normalized during therapy. The patients were treated with
      melphalan and prednisone, hemodialysis and one patient with recombinant human
      erythropoietin. Both patients responded to that treatment: after 7 months the
      number of plasma cell in bone marrow decreased from 65 to 10% in the first
      patient, and from 38 to 4% in the second patient. They returned to work and were
      on maintenance hemodialysis 2 times weekly. The patients have been observed for
      21 months.

PMID- 10335029
TI  - [The results of research on the prevalence of allergy to Hymenoptera venom in
      Southwestern Poland].
AB  - A questionnaire designed to estimate the prevalence of allergic reactions to
      Hymenoptera venom was posted to 1000 inhabitants of south west Poland. 881
      persons responded to the questionnaire. 255 (28.9%) reported allergic reactions
      to stinging insects venom 141 persons (16%) report large local reactions (LL) and
      114 (12.9%) systemic reactions (SYS) after stinging. At the second stage of the
      study 95 persons, out of the 255, were examined by a physician and tested with
      the intracutaneous skin test. Anamnesis carried out by the physician initially
      confirmed venom allergy in 87% of the LL group and 77.5% of the SYS group. Skin
      test results verified the above assessments confirming venom allergy in 38%
      persons initially reporting LL reactions and in 55% of those initially reporting
      SYS reaction.

PMID- 10335032
TI  - [Inclusion body myositis].

PMID- 10335033
TI  - [Myopathy in the course of corticosteroid treatment--new aspects].

PMID- 10335034
TI  - [Churg-Strauss syndrome].

PMID- 10335035
TI  - [Dr. of Medicine Primoz Vidali awarded the Medal of the Polish Society in
      Internal Medicine].

PMID- 10335036
TI  - [Poisoning with Coprinus atramentarius, a previously unknown hallucinogenic
      mushroom: report of two cases].

PMID- 10335037
TI  - [Chemotherapy of malignant melanoma].

PMID- 10335038
TI  - [The role of beta1 integrins in renal failure accompanied by multiple myeloma].
AB  - Clinical features of multiple myeloma are linked with immunological phenotype of
      myeloma cells. The interactions between malignant plasma cells and proteins of
      ECM (extracellular matrix) or different cells results from the influence of
      adhesion molecules. In our study the expression of CD49b, CD49d, CD49e, CD49f on
      the myeloma cells has been estimated. These cells were obtained from bone marrow
      of 33 just diagnosed patients. Immunophenotyping was performed with flow
      cytometry method. Malignant plasma cells were identified by monoclonal antibody
      anti-CD138 (B-B4) directed against Syndecan-1. We have observed that in patients
      with high expression of laminin receptors CD49b, CD49f and lack of fibronectin
      receptors CD49d, CD49e more often renal failure has been confirmed.

PMID- 10335039
TI  - [The effect of growth hormone replacement therapy on markers of bone formation
      and bone mineral density in elderly men].
AB  - OBJECTIVE: Decline in growth hormone (GH) secretion and serum levels of insulin
      like growth factor-1 (IGF-1) during ageing may be a causal factor in the
      development of osteopenia. The purpose of this study was to test the effects of
      GH-replacement therapy on bone metabolism and mineral density in healthy men over
      40 years old. MATERIAL: 18 healthy men aged 60.2 +/- 2.4 (avg +/- SEM) with mean
      body weight 78.6 +/- 4.6 kg and body mass index (BMI) 26.5 +/- 1.4 kg/m2.
      Diagnosis of growth hormone deficiency was based on serum IGF-1 levels below 200
      micrograms/L (138.1 +/- 9.2), abolished GH nocturnal surge and diminished
      glucagon-stimulated GH secretion compared to reference group of young men (16.2
      +/- 1.8 to 30.6 +/- 4.7 micrograms/L/hour; p < 0.02 and 10.8 +/- 1.0 to 44.1 +/-
      15.3 micrograms/L/hour; p < 0.02 respectively). Nine healthy men aged 27.5 +/-
      1.3 were recruited as a control subjects. Their body weight was 76.3 +/- 2.2 kg
      and BMI 21.3 +/- 0.6 kg/m2. METHODS: The subjects received human, recombinant GH
      (rhGH) daily subcutaneously during 12 months in dose individually adjusted to
      maintain optimal (280-350 micrograms/L) serum IGF-1 level. Initial dose was 0.125
      IU/kg b.w./week. Before and after 6 and 12 months of therapy clinical and
      laboratory exams, including serum GH, IGF-1, calcium, phosphate, osteocalcin,
      glucose, insulin levels and alkaline phosphatase (AP) activity were obtained.
      Lumbar spine and femoral neck bone mineral density (BMD) were measured by dual
      energy X-ray absorptiometry. RESULTS: rhGH administration for 12 months led to a
      significant increase in mean serum IGF-1 levels, from 138.1 +/- 9.2 to 279.4 +/-
      26.3 micrograms/L (p < 0.001). Mean serum osteocalcin concentration rose from
      19.4 +/- 1.7 to 34.4 +/- 4.7 micrograms/L (p < 0.004), and serum AP activity
      changed nearly significantly, from 78.0 +/- 4.8 to 88.1 +/- 7.2 U/L. Lumbar spine
      and femur neck BMD increased significantly after 12 months, from 1.092 +/- 0.05
      to 1.119 +/- 0.06 g/cm2 (p < 0.05) and from 0.886 +/- 0.04 to 0.905 +/- 0.04
      g/cm2 (p < 0.05), respectively. CONCLUSION: Growth hormone replacement therapy in
      elderly men may be regarded as a method useful to protect against osteoporosis
      progression.

PMID- 10335040
TI  - [Levels of neuropeptide Y and thromboxane B2 in patients with variant angina].
AB  - One of the causes of coronary artery spasm in patients with variant angina could
      be a disturbed interaction between the vasodilating action of endothelial derived
      relaxing factor and the vasospastic action of neuropeptide Y and thromboxane B2.
      The aim of this study was a verification of the participation of neuropeptide Y
      and thromboxane B2 in etiopathogenesis of the coronary artery spasm in patients
      with variant angina. The survey was made in 38 patients with variant angina and
      in 18 patients with chronic stable angina pectoris. The control group consisted
      of 20 healthy persons. Before the hyperventilation test, during which the person
      under test has been breathing with a frequency of 40/minute through 5 minutes,
      the Tris (tromethamol) of pH = 10.5 has been given in intravenous infusion
      lasting for 5 minutes. The neuropeptide Y and thromboxane B2 plasma levels have
      been determined just before the hyperventilation test, just after the termination
      of the test and 10 minutes after the termination of the test. Neuropeptide Y and
      thromboxane B2 plasma levels have been determined with a radioimmunologic method.
      It has been recorded that during the hyperventilation test in all of the 38
      patients with variant angina the clinical and the electrocardiographic symptoms
      of the coronary artery spasm have appeared--but these have not appeared in
      patients with chronic stable angina pectoris and in healthy persons. The level of
      neuropeptide Y in patients with variant angina before the test, just at its end
      and as well as 10 min. after completing of the hyperventilation test, was
      significantly higher compared with the level in patients with chronic stable
      angina pectoris and controls. Contrary to chronic stable angina pectoris patients
      and controls, in variant angina group the level of neuropeptide Y increased
      rapidly at the end of the test and further elevation in neuropeptide Y level was
      observed 10 min. after the test. There was no difference in basal thromboxane B2
      levels between angina patients and controls. At the end of hyperventilation test
      in variant angina group thromboxane B2 level significantly increased and remained
      on this level until 10 min. after the test. Significant increase of neuropeptide
      Y and thromboxane B2 plasma levels in variant angina patients during artery
      coronary spasm induced by hyperventilation test suggests the contribution of
      these humoral factors to the pathogenesis of vasospastic episodes in angina
      patients.

PMID- 10335041
TI  - [Asymptomatic bacteriuria in women diagnosed with systemic lupus erythematosus
      (SLE)].
AB  - The aims of our research were: estimation of asymptomatic bacteriuria (a.b.)
      incidence in population of women with systemic lupus erythematodes (SLE),
      evaluation its clinical significance and examination of bacterial colonisation of
      nostrils and pharynx in SLE patients with a.b. 85 women aged 24-77 (mean 49.3)
      with mean SLE duration 7.8 (range 1-32) years were examined. All of them
      fulfilled ARA criteria for the classification of SLE. Among group of patients
      with a.b. were counted women who had significant bacteriuria > or = 10(4) in ml
      urine in two cultures. Asymptomatic bacteriuria was found in 14 cases of 85 women
      with SLE (16.5%). In two following urine cultures bacteria from family
      Enterobacteriaceae were dominated: the same types of bacteria were in 85.7%-
      bacteriuria persistens, in others 14.3% were observed change of bacteria-
      bacteriuria transistens. In 9 from 14 patients with (64.3%) a.b. very massive
      growth of Staphylococcus aureus in culture from vestibulae of the nose swab was,
      in other cultures very massive growth of physiological flora was seen. All
      patients with a.b. were in clinical remission of SLE and they had no clinical
      symptoms of infection in urinary tract in 5 months of observation. However
      clinical significance of asymptomatic bacteriuria and pathogenic bacteria
      colonisation of nostrils as a precedence to symptomatic infections needs further
      investigations.

PMID- 10335043
TI  - [Diagnostic difficulties in Gaucher disease: report of two cases].
AB  - Diagnostic difficulties of Gaucher disease, a disorder resulted from a deficient
      activity of glucocerebrosidase is reported. Gaucher disease was described in the
      16 year old male, 5 years after manifestation of the very first symptoms
      (fracture and osteomyelitis). At the age of 14, the cirrhosis due to viral
      hepatitis accompanied with splenomegaly was diagnosed. This findings was not
      associated with the earlier osseous disorders. Histopathologic examination of the
      removed spleen facilitate the diagnosis. The second case refers to 20 year old
      female. Clinical symptoms and additional test pointed to malignant neoplasm of
      thyroid, the reproductive organs or cancer of indistinguishable primary focus
      with metastases in the liver. Trepanobiopsy of bone marrow had made an accurate
      diagnosis possible, while determination of beta-glucosidase activity in
      peripheral white blood cells, chitotriosidase activity, and molecular
      investigations of gene specific to beta-glucocerebrosidase proved it.

PMID- 10335042
TI  - [The impact of 2-year rehabilitation on exercise tolerance and transcutaneous
      oxygen saturation during exercise in patients with chronic obstructive pulmonary
      disease].
AB  - We compared results of symptom-limited exercise test (ET) and percutaneous oxygen
      saturation (SaO2) during ET in rehabilitated COPD patients (R) and in control
      COPD patients (C) before and after 2 years of study. Group of R consisted of 27
      patients (FVC 2.15 l, FEV1 1.17 l, mean age 58, range 32-76 years) who underwent
      comprehensive, in-hospital and domestic R, group C consisted of 19 patients (FVC
      1.95 l, FEV1 1.42 l, mean age 68, range 55-83 years). The studied groups did not
      differ in their FVC and FEV1, but R patients were younger (p = 0.05), had more
      sustained ET (p = 0.0002) and greater number of METs achieved during ET (p =
      0.0008). After study we found increased number of METs during ET from 3.94 to
      4.77, p = 0.003, improved 10 grade Borg score in 3' ET from 4.0 to 2.5, p = 0.05
      and tendency to decrease maximal drop of SaO2 during ET from 6.8 to 3.1% (NS).
      Patients in C group failed to improve results of ET: from 2.7 to 2.5 METs (NS),
      and pulse oximetry: maximal drop in SaO2 during ET from 3.1 to 3.07%, NS) and
      also 10-grade Borg score in 3'ET (from 2.0 to 2.8, NS). In conclusion, although
      differences in age and in initial exercise tolerance between studied groups could
      influence the results of this study, it seems that long term rehabilitation can
      improve both exercise tolerance and oxygen saturation during exercise in COPD
      patients.

PMID- 10335044
TI  - [Can peak serum digoxin concentration be a sign of acute poisoning severity?
      Analysis of two cases of digoxin poisoning].
AB  - Contrary to cardiac glycoside poisoning often seen in medical practice,
      intentional digoxin poisoning is rather rare and its course is serious only if
      very high doses have been ingested. Ventricular arrhythmias and severe conduction
      disturbances are the most threatening sings may need the use of antiarrhythmic
      agents, temporally endocardial stimulation or digoxin specific antibody Fab
      fragments. The course and the management of digitalis poisoning is described in
      two young patients (female aged 37 and male aged 26). Before admission to the
      hospital they were healthy, without any heart problem. Only one patient (female)
      had short spell of nausea and vomiting as well as green vision phenomenon. This
      patient developed transitory non-life threatening conduction disturbances (degree
      and II degree a-v block). The second patient had nausea and vomiting but no
      serious cardiac symptoms. In both patients very high digoxin plasma levels were
      found (19.88 ng/ml and 9.63 ng/ml), but no one of them had serious poisoning
      symptoms and did not require any specific therapy. After 3 (male) and 4 (female)
      days both patients left the hospital.

PMID- 10335045
TI  - [Protein glycosylation end products].

PMID- 10335046
TI  - [Hypothetical pathogenetic mechanisms of hepatic encephalopathy].

PMID- 10335047
TI  - [Hepatic veno-occlusive disease--a growing clinical problem].

PMID- 10335048
TI  - [Good manners in science. A collection of rules and principles. The committee on
      ethics in science from the executive board of the Polish Academy of Science].

PMID- 10335049
TI  - Should people with nocturnal leg cramps drink tonic water and bitter lemon?
AB  - A literature search from 1993 to 1997 using MEDLINE and key-words beverages,
      muscle cramp, and quinine was performed. Three beverages containing quinine were
      examined in grocery stores. Analysis indicate that leg cramps are a common
      phenomenon associated with many comorbid disorders especially peripheral vascular
      and neurologic disorders. Thus, evaluation of a patient's complaining of leg
      cramps appropriately includes vascular, neurologic, and musculoskeletal
      examinations. Laboratory investigation of the symptom of leg cramps warrants as a
      minimum, assessment of thyroid function and determination of platelet counts and
      serum levels of electrolytes, calcium, and magnesium. A few small studies suggest
      that quinine is effective in decreasing the frequency of nocturnal leg cramps but
      not their severity or duration. Quinine consumed in commercial beverages has been
      reported to cause potentially fatal immunologically mediated hypersensitivity
      reactions. The concentration of quinine in commercial beverages varies greatly.
      Although commercial beverages containing quinine generally are labeled "Contains
      quinine," they typically lack both nutritional information about the amount of
      quinine and warnings of the health risks. It appears that 325 milligrams of
      quinine taken by mouth at bedtime typically relieves nocturnal leg cramps, but
      lower starting doses are appropriate for senior citizens and individuals with
      impaired renal function. In general, quinine in any form should be avoided by
      pregnant women and people with hepatic failure. Quinine consumed for the
      treatment of leg cramps should be prescribed and monitored by physicians, and
      people who consume quinine in commercial beverages must be warned of the health
      risks.

PMID- 10335050
TI  - Perceived competence, social anxiety about physique, and enjoyment in testing
      situations among groups of mixed sex and girls only.
AB  - The purpose of the present study was to assess whether there are differences in
      agility and coordination performance, anxiety about physique, perceived
      competence, and enjoyment between girls (n = 56) performing within mixed-sex
      versus all-female high school classes in physical education. A series of between
      group comparisons yielded no significant differences between groups on measures
      of performance, perceived competence, and anxiety about physique; however, the
      mixed-sex group reported significantly greater enjoyment on both psychomotor
      tests than the all-female group (ps < or = .05). Results are discussed within
      other contexts such as sport motivation and Weiss and Chaumeton's (1992) theory
      of youth sport development.

PMID- 10335051
TI  - The detection of malingering.
AB  - A 60-item paper-and-pencil inventory showed a 98% "hit-rate" in distinguishing
      between honest and simulated malingering protocols produced by 29 nonclinical
      subjects who took the inventory in both the honest and faked conditions. When
      instructed to take the Wildman Symptom Cheklist "as if applying for some kind of
      disability compensation," subjects endorsed a significantly higher number of the
      self-statements which appear clinically unbelievable. Independent replication is
      now required.

PMID- 10335052
TI  - Reliability and validity of the functional assessment rating scale.
AB  - The Functional Assessment Rating Scale was developed as a measure of psychiatric
      symptomatology and psychosocial impairments. This study was designed to report
      estimates of reliability and validity with a population of schizophrenic
      patients. The scale showed very good interrater agreement, test-retest
      reliability, construct validity, and concurrent validity, so the scale seems a
      useful measure of psychopathology which may be used to assess and monitor
      patients displaying severe mental illnesses.

PMID- 10335053
TI  - Why do women treated for breast cancer report good health despite disease or
      disability? A pilot study.
AB  - Few studies have explained the basis on which people with acknowledged physical
      pathology or disability report good self-perceived health. This limited
      qualitative study of 13 women identified two common pathways to subjective health
      taken by women treated for breast cancer, each involving a shift in emphasis from
      being healthy physically to being whole emotionally, relationally, or
      spiritually.

PMID- 10335054
TI  - Native American suicide rates, acculturation stress and traditional integration.
AB  - In 18 Native American tribes, suicide rates were positively associated with
      acculturation stress and negatively with traditional integration.

PMID- 10335055
TI  - High school students' perceptions of nursing homes: before and after experience.
AB  - 86 high school students considering entering a health care profession indicated
      that they would not likely choose to work in a nursing home even though they
      found them in general to be more pleasant than expected.

PMID- 10335056
TI  - Maturity fears during recovery from cocaine dependency.
AB  - The present study explored the incidence of maturation fears among 22 cocaine
      dependent individuals who were at various levels of recovery ranging from 3 mo.
      to 4 yr. From clinical observation and prior research it is known that cocaine
      dependency commonly produces feelings of empowerment and confidence and thus, it
      was predicted that cocaine-dependent individuals would report more extreme
      maturation fears, measured by the Maturity Fears subscale of the Eating Disorders
      Inventory. The findings indicated that the cocaine-dependent group had
      significantly higher scores than a group of individuals not dependent on cocaine.

PMID- 10335057
TI  - Self-perception profile in children with cancer: self vs parent report.
AB  - Self-perception about competence, behaviour, and self-worth were examined in 30
      children (8 to 14 years) recently diagnosed as having cancer and were compared
      with that of their parents' perception. The poor agreement between parents' and
      children's ratings on physical appearance and social acceptance is noteworthy in
      that these two domains are particularly vulnerable in children with cancer, given
      the effect of chemotherapy on physical appearance and children's tendency to view
      themselves as socially undesirable or a burden to others. This finding, if
      replicated, can have implications for therapeutic intervention since the
      discrepancy score could be used to challenge children's negative views in the
      context of cognitive therapy to improve their self-esteem.

PMID- 10335058
TI  - Association of heart rate and heart-rate variability with scores on the emotion
      profile index in patients with acute coronary heart disease.
AB  - We investigated the link between the eight basic emotions named by Plutchik and
      heart rate, heart-rate variability in the 114 patients, 86 men and 28 women (M =
      53.8 yr., SD = 8.0) with acute coronary heart disease during the initial 24-hr.
      stay in the coronary care unit and again at hospital discharge. Variability in
      heart rate was significantly positively associated with scores on Trust (the
      emotional state acceptance) at hospital admission and discharge in the patients
      with unstable angina and non-Q-wave infarction, on Aggression in the patients
      with unstable angina at hospital discharge and at hospital admission in the
      patients with non-Q-wave infarction. There was inverse relation on Timid (the
      emotional state fear) and Gregarious (joy) at hospital admission and on Distrust
      (disgust or rejection), Depressed (sadness), and Dyscontrol (impulsiveness) at
      hospital discharge in the patient with non-Q-wave infarction. There was no
      significant association between heart-rate variability and the scores on the
      Emotion Profile Index in the patients with anterior and posterior myocardial
      infarction. There was no statistically significant association between heart rate
      and scores on the Emotion Profile Index in the patients with acute coronary
      disease at hospital admission and discharge. Our results suggest psychological
      interventions that enhance emotional states represented by the Trust and
      Aggression scales and minimize those represented by Depressed, Dyscontrol, Timid,
      and Distrust scales could have a beneficial effect on cardiovascular function in
      the patients with unstable angina and non-Q-wave infarction in a hospital
      setting.

PMID- 10335059
TI  - Next stage of burnout research and applications.
AB  - This note introduces a holistic estimate of burnout, which can be used to extend
      bivariate designs such as that of Turnipseed. The "phase model" builds on but
      also transcends the widely accepted approach to burnout via three separate
      subdomains. Here, these subdomains generate eight progressively intense phases
      that covary regularly with differences in a wide range of variables. Also, the
      phase model permits diagnoses on which ameliorative designs have been based.

PMID- 10335060
TI  - Significant others: Italian adolescents' rankings compared with their parents.
AB  - In a study of social context in which adolescents live from an intergenerational
      perspective, the purpose was comparison of significant others of the generation
      of Italian adolescents (n = 595) and their parents' recalled others significant
      during adolescence (397 fathers and 416 mothers). Analysis showed the
      predominance of parents and above all the mother as the most significant others
      for both generations during adolescence. Further, today's adolescent generation
      attributed less importance to other unrelated adults than their parents recalled.

PMID- 10335061
TI  - Ginkgo biloba and memory for a maze.
AB  - A number of sources suggest that the natural herb ginkgo biloba enhances mental
      sharpness by increasing blood flow to the brain. A preliminary study was designed
      to examine whether memory for a maze would be enhanced in 5 mice who received a
      dietary supplement containing ginkgo biloba. The mice showed an improved memory
      for the maze as evidenced by a decrease in the number of errors in reaching the
      goal box when they received gingko biloba as a dietary supplement.

PMID- 10335062
TI  - Teachers' personalities and students' behavior in referrals for special
      education.
AB  - 84 regular classroom teachers completed four self-report personality scales (self
      concept, tolerance, locus of control, and teachers' efficacy) and reviewed
      hypothetical records of three types of students (withdrawn, acting-out, and
      neutral) and made decisions for referral for each student to special education.
      Scores for self-concept, tolerance, locus of control, and teachers' efficacy were
      not related to their decisions to refer across types of students.

PMID- 10335063
TI  - Reliability of the State-Trait Anxiety Inventory, Form Y in Japanese samples.
AB  - The internal consistency of the State-Trait Anxiety Inventory, Form Y was
      examined using data collected from Japanese participants by five diverse surveys,
      in which one included American university students. Cronbach coefficient alpha
      was calculated separately for state and trait items as well as for anxiety
      present and absent items. The internal consistency was higher for the anxiety
      absent items than those of the state and trait anxiety items, but this tendency
      was not clear for the anxiety-present items. The trait anxiety items showed the
      lowest internal consistency for all Japanese groups, whereas the anxiety-present
      items showed the lowest alpha for American university students. It can be
      considered that this difference might induce the difference in two--factor
      structure between Japanese and people in Western countries.

PMID- 10335064
TI  - Hardiness and major personality factors.
AB  - This study tested Maddi and Khoshaba's 1994 hypothesis that Hardiness is an index
      of mental health. A sample of 241 undergraduates (103 men and 138 women)
      completed the Dispositional Resilience Scale, the Revised NEO Personality
      Inventory, and the Psychopathology-5 Scales. Using the individual median scores
      on the three subscales (Commitment, Control, and Challenge) of the Dispositional
      Resilience Scale, the High Hardiness group was obtained by identifying the
      individuals who scored above the medians on all the three subscales, whereas the
      Low Hardiness group were those who scored consistently below the medians on all
      the three subscales. Multivariate analysis of variance performed for the two
      hardiness groups using the scales from each personality inventory indicated that
      the two groups had significantly different mean profiles on the NEO Personality
      Inventory as well as the Psychopathology-5 Scales. Combined discriminant function
      analysis performed for the two hardiness groups using all the 10 scales from the
      two personality inventories indicated that the two groups had significantly
      different mean profiles and that the standard discriminant function coefficients
      were substantial (> .3) for the NEO Personality Inventory Openness (.65) and
      Conscientiousness (.49) scales and the Psychopathology-5 Positive Emotionality
      (.56) and Psychoticism (-.36) scales, supporting the tested hypothesis.

PMID- 10335065
TI  - Ethnic similarities and differences in the association of emotional autonomy and
      adolescent outcomes: comparing Euro-American and Asian-American adolescents.
AB  - This study has conducted an ethnic comparison on the strength of the association
      between Individuation, a subscale from the Emotional Autonomy construct presented
      originally by Steinberg and Silverberg in 1986, and adolescent outcomes in terms
      of self-esteem and susceptibility to negative peer pressure. Consistent with what
      was expected, the association between Individuation and lowered self-esteem was
      more salient among 287 Asian-American adolescent boys than among 1,353 Euro
      American adolescent boys. Contrary to what was hypothesized, the association
      between Individuation and susceptibility to negative peer pressure was more
      pronounced among 1,573 Euro-American adolescent girls than among 292 Asian
      American adolescent girls.

PMID- 10335066
TI  - Correlates of empathic understanding among neophyte trainees in psychotherapy.
AB  - Results are summarized of an empirical study testing the associations among
      various academic, demographic, and personal characteristics and rated empathic
      understanding among 93 neophyte psychotherapy trainees from six universities.
      Multiple regression analyses suggested that completion of a graduate group
      counseling course with a specific personal growth component was the only
      characteristic significantly correlated with ratings of empathic understanding.

PMID- 10335067
TI  - Perceived functional health of disabled elderly persons in a follow-up program
      for primary care.
AB  - 180 disabled elderly persons were followed in a home care program after acute
      care rehabilitation in order to correlate subjective and objective ratings of
      medical, physical, and social functioning. To assess the benefits of case
      management services, 95 test patients receiving such care at home were compared
      with 85 controls who did not receive services. Both groups reported gains in
      functional health and their reports were verified with objective measures. There
      was no difference, however, between the groups in outcome. Our findings indicated
      that self-assessments correlate highly with measures of functional health.
      Procedures for self-ratings should be developed as important complements to
      objective functional health measures.

PMID- 10335068
TI  - Correlations of self-ratings of attitude towards violent groups with measures of
      personality, self-esteem, and moral reasoning.
AB  - Relations of self-rated positive attitudes towards violent groups were examined
      among 273 adolescents with scores on self-esteem, moral reasoning, and self
      perceptions of personality. Moral reasoning, measured by the Rest Defining Issues
      Test, correlated -.18 but not with self-esteem scores. There were significant
      correlations of .18 or .19 between the self-rated attitudes and Materialism,
      Conformity, Conservatism, Obstinance, Anxiety, and Thoughtlessness, but rs
      accounted for very little common variance.

PMID- 10335069
TI  - Assessing multiple facets of gender identity: the gender identity questionnaire.
AB  - 314 men and 451 women participated in a study to assess the reliability and
      validity of the multifaceted Gender Identity Questionnaire. Reliability
      coefficients of the (sub)scales varied between .67 and .80; content, criterion,
      and construct validity were satisfactory.

PMID- 10335070
TI  - K-ABC simultaneous processing, DAS nonverbal reasoning, and Horn's expanded fluid
      crystallized theory.
AB  - Horn's distinction between--fluid intelligence (Gf) and visualization (Gv) was
      investigated with two Nonverbal Reasoning subtests from the Differential Ability
      Scales and three Simultaneous Processing subtests from the Kaufman Assessment
      Battery for Children. The sample comprised a predominantly Euro-American groups
      of 57 normal boys and girls between the ages of 6 and 12 years. Principal factor
      analysis yielded clear-cut Gf and Gv dimensions. The Gf factor was composed both
      of Differential Ability Scales and Kaufman-ABC subtests, suggesting that the
      construct of simultaneous processing is not merely a measure of Gv, as
      researchers have hypothesized, but also measures Horn's Gf fluid intelligence to
      a considerable extent.

PMID- 10335071
TI  - Sex differences on the MMPI-2 substance abuse scales in psychiatric inpatients.
AB  - Sex differences on the MMPI-2 addiction scales (MacAndrew Alcoholism Scale
      Revised, Addiction Acknowledgement Scale, Addiction Potential Scale) and their
      ability to distinguish between substance-abusing and nonabusing psychiatric
      inpatients were examined. Men obtained higher mean raw scores than women on the
      MacAndrew Alcoholism Scale-Revised and the Addiction Acknowledgement Scale, and
      substance abusers scored higher on all three scales. Even relatively low cutoff
      scores, however, on the MacAndrew Alcoholism Scale-Revised resulted in false
      negative rates of 37 to 39%. The results support the utility of the MMPI-2
      substance abuse scales; however, lower cutoff scores should be used with women
      and within a psychiatric population.

PMID- 10335073
TI  - Do students studying therapy have more problems?
AB  - This study examined several questions on whether graduate students studying
      therapy reported more personal counseling or traumas than other students. The 66
      students studying therapy did not report significantly different experiences or
      attitudes than 52 students in other areas, indicating that they did not seem to
      have more emotional problems or traumas than others.

PMID- 10335072
TI  - Filial therapy: effects on two children's behavior and mothers' stress.
AB  - Due to patients' continual and natural contact with their children, as well as
      shortages of professionals, parents are increasingly being asked to play a
      significant role in treatment for the children's emotional and behavior problems.
      Filial therapy is a treatment that involves parents by teaching parents to
      conduct child-centered play therapy sessions with their children. The current
      study sought to examine filial therapy effectiveness by measuring changes in
      children's behavior and parental stress in parenting. Mothers of two preschool
      children were administered the Behavior Assessment for Children and the Parenting
      Stress Index prior to, following completion of, and 2 mo. after participating in
      a 10-wk. filial therapy training program. Results suggest significant decreases
      in externalizing behaviors and decreased parenting stress for one parent of the
      two children. Informal parental reports of changes suggest that parents saw
      improved relationships with their children, their own confidence increased,
      generalization of skills, and improvements with regard to behavior problems.

PMID- 10335074
TI  - Overgeneralization of validity generalization in personality inventories: applied
      issues in testing.
AB  - Generalization of validity asserts that a predictor or criterion generalizes
      across studies and will continue to show similar parameters when the situation
      changes. Kurt Lewin explored situation-behavior relationships, and Mischel
      examined the situation-behavior association showing predictive accuracy between
      behaviors and contexts. Investigators have critically reproached the assumed
      generalization of assessment instruments that ignore contextual variance. The
      validity hypothesis confirmed that using nonsituation-specific scales does not
      focus on the contextual effects relevant to the criterion measured and
      consequently has no practical application for focused evaluation in clinical and
      employment settings. This study describes a model and technique for the
      measurement of contextual variance in personality dimensions thereby introducing
      situation-specificity in evaluation for more focused research, treatment, and a
      more specific job fit in employment settings.

PMID- 10335075
TI  - Cross-cultural similarity in the love attitudes scale: short form.
AB  - Recently, Hendrick, Hendrick, and Dicke presented two short forms of the Love
      Attitudes Scale, the first using 24 items with 4 items for each subscale and the
      second using 18 items with 3 items for each subscale. Their data indicated that
      the two short versions have even stronger psychometric properties than the
      original scale. This study reports an 18-item short form of the scale developed
      independently in Taiwan using 460 graduate and undergraduate students in the fall
      semester of 1997. The results demonstrated a remarkable cross-cultural similarity
      in the development and response to the short form of the scale and its
      applicability to a broader cultural setting.

PMID- 10335076
TI  - Defining elder care.
AB  - This study was a beginning effort to clarify the different types of elder care
      and to understand which type of elder care, i.e., giving time or giving money,
      might be more closely associated with employed persons' health. Giving time,
      compared to giving money, to provide care may be weakly associated with emotional
      health (r = .05) and physical health (r = .04) as N = 2,269 (cf. rs of .00, .01);
      giving money may not be associated with either. Investigations of elder care and
      its consequences should be very specific when measuring this construct.

PMID- 10335077
TI  - Cognitive bias of optimism and its influence on psychological well-being.
AB  - An investigation of the cognitive bias observed in optimism and the influence of
      optimism on psychological well-being was conducted. The cognitive bias was
      assumed to be related to the repressive style of information processing,
      represented by the trait scale of the State-Trait Anxiety Inventory and the
      Social Desirability scale. Optimism and well-being were measured by the Life
      Orientation Test and the Social Optimism scale as well as by the Life
      Satisfaction and Depression scales, respectively. These scales were applied to a
      sample of 200 individuals. Trait Anxiety and Social Desirability led to a high
      multiple correlation with the Life Orientation Test (R = .54) and a moderate
      multiple correlation with the Social Optimism scale (R = .30). Higher
      correlations were obtained for the expectation of a positive than of a negative
      future. Both the Life Orientation Test and the Social Optimism scale contributed
      to the high multiple correlation with psychological well-being (R = .52).

PMID- 10335078
TI  - Family size and intelligence revisited: the role of emotional intelligence.
AB  - Studies examining the link between family size and intelligence have consistently
      found a negative relationship. Children born into larger families tend to score
      lower on intelligence tests than children raised in smaller families. One
      recurrent but unexplained finding is that the relation between intelligence and
      number of siblings is consistently significant for verbal intelligence but
      inconsistent for nonverbal intelligence. Here, we conceptualize emotional
      intelligence as one facet of nonverbal intelligence. The research develops a
      measure of emotional intelligence and uses it to test the hypothesis that
      emotional intelligence is positively correlated with family size. The results,
      based upon a sample of graduate students, support the hypothesized relationship.
      Implications for the study of family size and intelligence, for refining the
      conceptualizations and measures of nonverbal intelligence, and for leadership
      theory, are discussed.

PMID- 10335079
TI  - Zen and happiness.
AB  - In a sample of 69 undergraduates, a Taoist orientation was associated with less
      depression and hopelessness.

PMID- 10335080
TI  - Specific intervention for multiplication skill with learning-disabled students.
AB  - A multiple baseline design was used to assess the intervention of individual
      tutoring to help two learning-disabled students (15 and 16 years old) improve
      their multiplication of 1-digit numbers over nine days of 10-min. instruction.
      Observation or visual analysis indicated 40 to 50% improvement after the
      intervention, and a nonparametric test of randomization showed that the students'
      improvement was retained during the 2-wk. follow-up.

PMID- 10335081
TI  - Description and validation of a measure of received support specific to HIV.
AB  - Validation data are described for the Social Support Inventory for People who are
      HIV Positive or Have AIDS. This inventory was developed specifically for use with
      individuals who are HIV-positive to assess three types of received support
      (instrumental, informational, emotional) for each of four dimensions: whether
      support is received or wanted, satisfaction with support, and source of the
      support. It was validated in the context of a larger cross-sectional study of 120
      adults with HIV who completed a set of questionnaires. Descriptive statistics,
      internal consistency coefficients, and evidence of construct validity for the
      original inventory are presented. An improved, revised version based on the
      validation data for the original one is also briefly described, but not tested.

PMID- 10335082
TI  - Counselors' and clients' ethnic similarity and therapeutic alliance in time
      limited outcomes of counseling.
AB  - 51 pairs of clients and counselors at a Southwestern university counseling and
      research training clinic were assessed for ethnic similarities in relation to the
      therapeutic alliance and counseling outcomes in 6 sessions of counseling.
      Analysis showed after 6 sessions symptom distress was reduced. Also, counselors
      and clients who had similar ethnicity had significantly more positive counseling
      outcomes than ethnically dissimilar pairings, but ethnic similarity was not
      related to the nature of the therapeutic alliance and therapeutic alliance was
      not a correlate of counseling outcomes.

PMID- 10335083
TI  - Development and validation of an inventory to measure satisfaction of users of
      family medicine clinics in Mexico.
AB  - The object of this study was to construct and validate an inventory to measure
      the satisfaction of users of Family Medicine Clinics. The satisfaction construct
      was theoretically developed, then the semantic network technique was applied to
      write 45 items with a dichotomized response. The scale was validated for 4,134
      users. Cronbach coefficient alpha was .78. In a factor analysis, 8 factors were
      obtained, which explained 43.3% of the variance. The content of the first factor
      referred to the Family Physician dimension, Factors 3, 4, and 5 to the Family
      Medicine Clinic, and Factors 2, 6, 7, and 8 to Other Services of the Clinic. The
      questionnaire is being integrated to the Quality of Care Evaluation System to
      assess satisfaction of users. It may be useful in other venues to assess cultural
      and organizational aspects of satisfaction with health care.

PMID- 10335085
TI  - Loss, death, bereavement: where are the empirical studies?
AB  - The periodical literature on loss, death, bereavement, and grieving, as reported
      in PsycLIT for 1990-1998, was classified as empirical, theoretical, review of the
      literature, descriptive, or case report. Striking was the lack of empirical
      studies on psychotherapy and counseling.

PMID- 10335084
TI  - Environmental and possible genetic contributions to character dimensions of
      personality.
AB  - The relationship between dimensions of personality characteristics and the
      perceived rearing attitude of parents in the Japanese population were
      investigated. The scores on a measure of perceived parental attitude of 153
      normal female students, measured on the Parker Parental Bonding Instrument, were
      correlated with personality features from the Japanese version of the Cloninger
      Temperament and Character Inventory. Self-directedness, especially the subclasses
      of Responsibility vs Blaming and Congruent Second Nature vs Incongruent Habits,
      was significantly related to high scores on Maternal Care and low scores on
      Maternal Overprotection. The subscale of Self-acceptance vs Self-striving
      correlated only with low scores on Maternal Overprotection. Paternal Care was
      only related to the total scale scores on Self-directedness. Results suggest that
      some personality traits may be related to the perceived attitudes of parents,
      especially of the mother, during childhood.

PMID- 10335086
TI  - [The implantation of VDD pacemakers with a single electrode--a comparative study.
      The experience of the last 5 years].
AB  - OBJECTIVE: To compare the epidemiological characteristics and immediate results
      of all first single lead VDD pacemaker (PM) implantations with those of an equal
      number of dual chamber DDD PM, implanted during a 5-year period in a tertiary
      care hospital. POPULATION AND METHODS: A total of 41 patients (pts) (25 males,
      mean age of 69.0 +/- 11.8 years) underwent a VDD PM implantation, from 30-11-92
      to 15-9-97. This group was compared with an equal number of patients (28 males,
      mean age of 69.9 +/- 7.31 years) with a DDD PM implanted in the same period,
      selected by a criterion of immediate temporal proximity of procedure. For each
      patient we collected the clinical and electrocardiographic (ECG) indications for
      PM implantation, parameters of atrial (AS) and ventricular (VS) sensing and
      ventricular pacing (VP), X-ray exposure time (XRT) and complications. RESULTS: In
      the VDD group, 46.3% of the patients had syncope, 51.2% had complete AV block on
      the ECG, and 14.6% were PM-dependent. Analyzed procedure-related parameters were
      as follows: P-wave amplitude: 2.1 +/- 0.6 V; AS threshold: 1.2 +/- 0.7 V; R-wave
      amplitude: 9.1 +/- 3.3 V; VS threshold: 7.0 +/- 2.0 V; VP thresholds: 0.68 +/-
      0.24 mA, 0.43 +/- 0.12 V (for a spike duration of 0.5 ms); ventricular impedance:
      644.9 +/- 132.0 ohm; XRT; 7' 43" +/- 8' 23". There were two minor complications,
      for an incidence of 4.9% (one local hematoma and a vagal reaction). In the DDD
      group the clinical and ECG characteristics were similar, but there was a 22.0%
      prevalence of sinus-node dysfunction, VS 0% in the VDD group). The P-wave
      amplitude and AS threshold were significantly (p < 0.005) better (2.8 +/- 0.9 V
      and 2.8 +/- 0.9 V respectively). The other parameters were similar to those of
      the VDD group. CONCLUSIONS: The immediate results of VDD PM implantation are good
      and comparable with those of DDD PM, although with worse acute AS parameters.

PMID- 10335087
TI  - [The persistence of the left vena cava superior and the absence of the right vena
      cava superior: the implications in the implantation of a definitive pacemaker].
AB  - Persistent left superior vena cava and associated absence of the right superior
      vena cava is exceedingly rare. The authors present a case, diagnosed when a DDD
      pacemaker system was being implanted, and point out its rarity, possibility of
      diagnosis by non invasive methods and technical implications in transvenous
      electrode implantation.

PMID- 10335089
TI  - [The percutaneous closure of the ductus arteriosus in adults].
AB  - From May 1990 to June 1998, 116 patients were submitted to percutaneous closure
      of patent ductus arteriosus. There were 18 adult patients, aged 18 to 61 years.
      Two patients had residual ductus after an attempted surgical ligation and two
      other patients had a calcified ductus. A device was not implanted in three
      patients, two of whom because of pulmonary hypertension being considered
      irreversible. Another patient, with a very large duct, underwent attempted
      occlusion, but the device embolized to the pulmonary artery and was retrieved
      percutaneously in the same session. This patient was operated later. Complete
      duct occlusion, confirmed by color Doppler echocardiography, was achieved in 14
      of the remaining 15 patients (93%; 95% CL: 81-100). This was performed with a
      single catheterization in 12 cases, with implantation of one or more detachable
      coils in 8 patients; with a Rashkind device in 3, and a combination of a Rashkind
      device and coils in 1. In two cases complete duct occlusion required a second
      catheterization for implantation of additional detachable coils, including one
      patient with intravascular hemolysis in whom resolution of this problem was
      achieved with additional coils. In recent years, we have preferentially used
      detachable coils implanted through 5 Fr catheters, with a controlled release
      mechanism. This is a safer and less expensive device. Patients with pulmonary
      hypertension can be submitted to a trial occlusion of the duct with a balloon
      catheter to evaluate the response of pulmonary artery pressures. Percutaneous
      closure of the patent ductus arteriosus can be performed with excellent results
      in adults. Complete occlusion was achieved in 14 of the 15 patients (93%) without
      pulmonary hypertension or extremely large ductus. This is similar to our results
      in the pediatric population.

PMID- 10335088
TI  - [The Internet as a solution facilitating the identification of patients with a
      suspected acute myocardial infarct].
AB  - The current steps for diagnosing heart disease are very time consuming, delaying
      the correct identification of the problem, therefore, delaying the right
      treatment. In this study we have developed an experimental method using e-mail in
      order to identify patients with "rule out myocardial" condition and reduce the
      time lag for thrombolysis or coronary angioplasty in this clinical setting. Three
      different locations linked to the Internet by ISDN lines were used. Each line was
      connected with a computer. A pager and a dedicated phone line were also used. The
      following steps were performed for each situation: filling out of a
      questionnaire, ECG recording, questionnaire mailing and ECG by e-mail as
      attachment, pager warning that an urgent cardiology consultation was requested,
      including the doctor and patient's phone number, time to open the message and
      reply by e-mail, phone call for additional comments. A total of 24 attempts of
      interactive communication were performed. In 22 of those, an answer was obtained
      in less than 30 minutes. Two failures were recorded. One was due to a delay in
      the pager message, which did not arrive within the first hour; the second was due
      to a computer break down. This report shows that it is possible to establish a
      fast communication between the out patient clinic and the hospital (less than 30
      minutes in most cases) at a very low cost and in a simple manner.

PMID- 10335090
TI  - [The variability of the heart rate in the first 24 hours after fibrinolytic
      therapy in acute myocardial infarct].
AB  - AIM OF THE STUDY: The role of heart rate variability changes in the appraisal of
      reperfusion after fibrinolytic therapy in acute myocardial infarction is still
      controversial. The aim of this study was to analyze the influence of reperfusion
      and infarct site on heart rate variability within 24 hours after infarction.
      PATIENTS AND METHODS: We studied 45 patients with a mean age = 56.3 +/- 12.4
      years, 25 with anterior infarction and 20 with inferior infarction. The
      reperfusion was defined by the simultaneous presence of three classic noninvasive
      criteria (fast relief of pain, fast regression of ST segment elevation and early
      peak of CK). We studied heart rate variability parameters in time-domain and
      frequency-domain on a 24-hour Holter ECG started at the same time as fibrinolytic
      therapy. RESULTS: Thirty-three patients showed reperfusion. We did not find
      significant differences in the several parameters of heart rate variability
      between patients with reperfusion and patients without reperfusion, but the
      patients with anterior wall infarction showed a significant reduction in SDNN in
      comparison with patients with inferior wall infarction (84 +/- 28 ms vs 102 +/-
      30 ms; p = 0.05). pNN50 (5.3 +/- 7.2 ms vs 10.5 +/- 9.8 ms; p = 0.04), LF (618 +/
      591 ms2 vs 1374 +/- 1761 ms2; p = 0.05) and TP (1415 +/- 1199 ms2/Hz vs 3015 +/-
      4243 ms2/Hz). CONCLUSION: These data suggest a relationship between infarct
      severity and sympathetic activation and/or reduction of vagal modulation, but a
      potential beneficial effect of reperfusion on autonomic nervous system
      alterations was not evident in the first day of acute myocardial infarction.

PMID- 10335091
TI  - [The patient with palpitations: from the clinical picture to the therapeutic
      decision].
AB  - Palpitations are a common complaint in a medical consultation. The initial
      approach to the patient his based on the history, physical examination and 12
      lead electrocardiogram (ECG). The history is very important because most patients
      are initially seen by physicians after the episode of palpitations. The analysis
      of the characteristics of the episode, the presence of cardiac pathology and the
      effects of previous treatments are very important. Physical examination during
      the episode can provide some physical signs that may suggest a certain etiology.
      The physical examination after an episode can diagnose a certain cardiac disease.
      The ECG during the episode is very important and can provide the diagnosis. A
      normal ECG outside an episode does not exclude an arrhythmia. The initial
      diagnostic evaluation is complemented with other examinations, such as
      echocardiography or coronariography, to analyse a cardiac disease. Some other
      investigations are necessary, such as ECG Holter, Transtelephonic monitoring of
      cardiac rhythm or electrophysiological investigation to complement an initial
      diagnosis. This therapeutic decision is based on the type of arrhythmias, the
      associated symptomatology, the cardiac structural disease and the activity of the
      patient.

PMID- 10335092
TI  - [The nonpharmacological treatment of atrial fibrillation].
AB  - The authors describe the main forms of nonpharmacological treatment of atrial
      fibrillation considering catheter ablation and surgical therapy. A new
      methodology to modify atrioventricular conduction is discussed as well its long
      term results. All studies are non-randomised with selected patients, which makes
      the development of a therapeutical algorithm difficult. However, the results have
      shown that it is possible to recover sinus rhythm through surgery or catheter
      ablation and to control the ventricular rate either by His ablation or
      modification of atrioventricular conduction.

PMID- 10335093
TI  - [The new indications for permanent cardiac pacing].
AB  - In spite of conflicting data from several studies, pacing is being used in
      several indications beyond the classic ones, namely to treat patients with
      hypertrophic cardiomyopathy, severe heart failure and to prevent atrial
      fibrillation. In this article the authors briefly review the new indications for
      this therapeutic intervention and discuss the utilization criteria, the technical
      details and the results of trials with dual-chamber pacing in patients with
      hypertrophic cardiomyopathy and severe heart failure. In obstructive hypertrophic
      cardiomyopathy, dual-chamber pacing significantly reduces the gradient and
      improves symptoms. Criteria suggested for the application of pacemaker therapy
      are: 1) persistent symptoms in spite of an adequate medical therapy trial (i.e.,
      B-blockers, calcium antagonists, disopyramide): 2) left ventricular tract
      gradients of > 30 mmHg at rest or > 50 mmHg with provocation. In heart failure
      (NYHA class III ou IV with ejection fraction < 35) only a small percentage seems
      to benefit from this new therapeutic approach. They are those with a long PR
      interval on the surface electrocardiogram, with presystolic mitral regurgitation
      and with abbreviated diastolic filling period on the mitral inflow velocity on
      Doppler echocardiography. On the basis of some preliminary results, it appears
      that pacing may decrease the frequency of paroxysms of atrial fibrillation in
      some patients with vagal mediated fibrillation, chronotropic incompetence and
      those with long interatrial conduction times. Noninvasive detection of acute
      cardiac allograft rejection in heart transplant recipients by the analysis of
      some pacing parameters with telemetry is, at present, in an experimental stage.

PMID- 10335095
TI  - [Pacing electrocardiography (from the normal to the pathological)].

PMID- 10335094
TI  - [Advances in the technology of pacing].
AB  - It has been nearly four decades since the first asynchronous simple-chamber
      permanent pacemaker was implanted. At this time the only indication for pacemaker
      implantation was heart block associated with syncope. Since then, pacemaker
      technology has improved. In this article we provide an overview of recent
      technological advances in cardiac pacing. Those related to both generators
      (dimensions, multiprogrammability, protecting algorithms, automatization, sensors
      and others) and leads (polarity, dual chamber pacing with a single lead and
      others). With all these improvements in pacemaker technology, we now witness a
      relative simplification in the implantation procedures and in the follow-up
      evaluation of new systems. Due to all these improvements, current indications for
      cardiac pacing were expanded (non conventional indications). Despite all these
      recent engineering improvements, formal monitoring of the pacemaker system is
      still warranted to detect, pacemaker malfunctions as soon as possible.

PMID- 10335096
TI  - [The therapeutic approach in refractory supraventricular tachycardias].
AB  - In recent years, considerable progress has been achieved on the understanding of
      the mechanisms of the different supraventricular tachyarrhythmias. These advances
      have led to the development of rational procedures that can effectively cure most
      of the patients. Radiofrequency catheter ablation is highly effective in
      supraventricular tachycardia, with favorable cost-benefit analysis compared to
      lifelong antiarrhythmic drug therapy and should be considered as an initial
      option. In atrial fibrillation, only few patients are currently considered for
      non-pharmacologic therapeutic modalities, but this number should grow as this is
      the area of most promising research and the one expected to make more progress in
      the years to come.

PMID- 10335097
TI  - Intermediate-term outcome of mitral reconstruction in cardiomyopathy.

PMID- 10335098
TI  - [A giant aneurysm of the interatrial septum simulating cystic masses of the right
      atrium].

PMID- 10335099
TI  - [New genetics and medicine].

PMID- 10335100
TI  - [Friedreich's ataxia: recent developments and prospects for treatment].
AB  - Friedreich's ataxia (FRDA) is the most frequent cause of recessive ataxias.
      Neurological examination shows oculo-motor ataxia, dysarthria, limbs ataxia,
      tendon areflexia, pyramidal signs and sensory deficits. Extra-neurological
      involvement consists in osteoarticular deformities, cardiomyopathy and diabetes
      mellitus. Neurological deficits and osteoarticular deformities both contribute to
      the gait disorder, which is the main disabling deficit. In 98% of the cases, a
      trinucleotide repeat is found in chromosome 9. Gene implicated in FRDA codes for
      a protein called frataxin. Experimental studies have revealed iron accumulation
      in mitochondria of neurons and cardiomyocytes, suggesting that frataxin plays a
      determinant role in intramitochondrial iron homeostasis. These discoveries are
      now considered as a clue for new strategies of treatment in this hereditary
      disease.

PMID- 10335101
TI  - [Twins: interpretation of height-weight curves at birth].
AB  - Weight, head circumference and body length curves were established with the data
      at birth of 770 twins born alive in our hospital. Those curves were compared with
      the Gairdner-Pearson curves realized on a population of singleton newborns. The
      twin weight curve shows the expected fall down from 32 weeks of gestation. More
      than 50% of twins would have been qualified as small for dates on the Gairdner
      standard for singletons. The head circumference and the body length curves show
      few differences, except a late fall down, significant from 39 weeks. So the
      normal twin shows usually an "asymmetrical" hypotrophy if compared with a general
      newborn population standard. The general weight standards do not allow to assess
      the normality of a twin and to suspect other reasons of fetal growth restriction
      that could also be present. These considerations plead for the use of specific
      twin charts. Yet the evaluation of twins on the general standards has still a
      place to estimate the immediate and at long-term adverse outcomes of fetal growth
      restriction. The evaluation of twin measurements would not be completed without
      the assessment of the weight discordancy inside the twin couple, as a risk factor
      of morbidity and mortality.

PMID- 10335102
TI  - [Maternal mortality in adolescents at the university hospital of Ouagadougu].
AB  - This retrospective study evaluates the adolescent mortality rate at the
      University Hospital of Ouagadougou in the year 1995. Twenty lethal cases were
      collected amongst 646 deliveries giving birth to 490 children. The in-hospital
      adolescent maternal mortality rate come to be 4081 for 100,000 living births
      (4.08%) and represented 16.3% of all maternal deaths occurring during the study
      period. The most frequent causes of death were related to clandestine abortion
      (30%) and chronic anemia due to malnutrition (30%). Pregnancy in an adolescent
      girl is a high-risk event that requires special care due to a precarious global
      health status.

PMID- 10335103
TI  - [Post-traumatic carotid-cavernous sinus fistula].
AB  - The authors report the case of a 51 year-old man who developed a carotid
      cavernous sinus fistula after a blunt trauma. In view of an exophthalmia, an
      impressive chemosis, a pupillary dilatation due to parasympathetic paralysis and
      a bruit over the right orbit, a carotid-cavernous sinus fistula was diagnosed.
      The existence of the fistula was confirmed by a brain CT scan and a cerebral
      angiogram. Carotid-cavernous sinus fistulas are rare. They are spontaneous or
      posttraumatic. Cerebral angiography is the diagnostic procedure of choice. The
      authors review the signs and symptoms, diagnostic procedures, treatment, and
      prognosis of this complication.

PMID- 10335104
TI  - [Nevirapine (Viramune): a new HIV inhibitor].
AB  - Nevirapine is the first member of a new therapeutic class (NNRTI: non nucleoside
      inhibitors of the reverse transcriptase) in the treatment against human
      immunodeficiency virus (HIV). In association with two other antiretroviral
      products, it reduces significantly the viral load and increases the CD4-cells
      count, especially in naive patients. Results at six months show that a tritherapy
      including nevirapine and 2 nucleoside inhibitors of the reverse transcriptase
      (NRTIs) has a similar efficacy than an association including 1 anti-protease and
      two NRTIs. Nevirapine is easy to take (1 tablet 2x/day, irrespective of the
      meals). Its tolerance profile is favourable. The principal side effect is a rash,
      which can be severe in rare cases.

PMID- 10335105
TI  - [Tympanosclerosis. Radio-anatomic correlation].

PMID- 10335106
TI  - [Massive skeletal metastasis: difficulties of bone scintigraphy, contribution of
      medullary scintigraphy].

PMID- 10335107
TI  - [Palliative and continuous care in a public hospital. Experience at C.H.U.
      Brugmann].

PMID- 10335108
TI  - [How does one diagnosis gastroesophageal reflux?].

PMID- 10335109
TI  - [How does one evaluate the severity of gastroesophageal reflux and what are the
      therapeutic objectives?].

PMID- 10335110
TI  - [What are the results of medical treatments?].

PMID- 10335111
TI  - [What are the results of surgical treatments?].

PMID- 10335112
TI  - [What are the therapeutic strategies?].

PMID- 10335113
TI  - [The muse of medicine].

PMID- 10335114
TI  - Diamond necklaces: perspectives on power and the language of "community".
AB  - The relationship between power and the language of "community" is considered
      through findings from research conducted in a clinic in which clinic personnel
      and women who used the clinic discussed their understanding of "community."
      Analysis of the data was informed by critical social theory such as the work of
      Foucault which was used to understand "community" as a place of oppression, while
      feminist theory was applied in order to understand "community" as a place of
      resistance. Women who used the clinic were created and defined consonant with
      clinic practices. The exercise of power was evident through the types of
      objectives pursued by the clinic, the establishment of power relations, the
      system of differentiation between clinic personnel and users, and the forms of
      institutionalization. Counter-discourses were also constructed that served as
      points of resistance. "Community" became a mechanism by which clinic users
      challenged various enactments of clinic power through their health care choices
      and the stories they shared among each other. Findings point to "community" as
      emphasizing boundaries and divisions rather than similarities and unity.

PMID- 10335115
TI  - A conceptual model of collaborative nurse-physician interactions: the management
      of traditional influences and personal tendencies.
AB  - In this article, the phenomena of "collaborative nurse-physician interactions"
      are analyzed as such encounters may be conceptualized in modern healthcare
      practice settings. The author observes that many writers have used either
      nonclinical or incomplete definitions when discussing nurse-physician
      collaboration, often paying little attention to the research which indicates that
      members of both groups consistently possess very different perspectives of what
      usually comprises collaboration. A conceptual model is presented to
      comprehensively illustrate the salient variables that have been suggested in the
      professional literature as affecting the quality, rate, and outcomes of the
      fundamental unit of nurse-physician collaboration: the collaborative interaction.
      The author asserts that although many of the peculiarities of the traditional
      nurse-physician relationship are generations old, contemporary patients' needs
      and modern practice conditions now mandate further conceptual development and
      research regarding these work encounters.

PMID- 10335116
TI  - Language, ideology, and nursing practice.
AB  - This article explores the ways in which nursing practice is shaped by language
      and ideology. It is based on an ethnographic study conducted at two general
      surgical units in one of the main acute care hospitals in Iceland. The data used
      were qualitative: transcribed semistructured interviews with registered nurses on
      two acute care units, field notes from a participant observation on the two units
      and contextual information from written documents, such as yearly reports from
      the hospital and newspaper articles. The main findings revealed a stark contrast
      between the two discourses noticed. The public discourse, observed at team
      meetings in giving reports and in the written documentation, was characterized by
      objectivity and distancing from patients' personal understandings. The style of
      presentation was distant and mechanical. The private discourse, which emerged in
      private discussions between staff on the units and in interviews with the
      researcher, reflected the nurses' attempts to understand each patient's situation
      and outlook on life. This discourse was much more engaged, reflecting the nurses'
      energy and interest in being of assistance. By highlighting the difference
      between private and public discourses, this study provides important insight into
      the complex ways in which language and power interact to create different
      conditions for nursing practice. Based on these findings inferences are made as
      to how nursing practice is shaped by ideology.

PMID- 10335117
TI  - Reflections on "Structuring the nursing knowledge system: a typology of four
      domains".

PMID- 10335118
TI  - [Clinical application of photodynamic method to the treatment of malignancies.
      Part II].
AB  - The successfully finished experimental studies in an animal model became the
      foundation for starting clinical trials with the use of photodynamic therapy in
      the treatment of malignancies in humans. The data presented in the literature
      worldwide include mainly early results of such studies. This method seems to be
      of particular usefulness in the treatment of neoplasma with location accessible
      to various light sources, including the use of endoscopic techniques. Several
      thousand patients with various degrees of disease progression were subjected to
      the treatment. Among others, oesophagal, gastric and large bowel cancers were
      treated as well as malignancies of the pancreas and bile ducts, lungs, brain,
      breasts skin and bladder. The results of the presented clinical trials point to
      the possibility of the use of photodynamic therapy as the main treatment, and
      also as an element of supportive therapy e.g. in classical surgical treatment.

PMID- 10335119
TI  - [Reduced pulsatility index and elevated ankle systolic pressure as a risk factor
      for foot ulceration in diabetic patients with autonomic neuropathy].
AB  - The contribution of peripheral autonomic neuropathy to development of foot ulcers
      in diabetic patients has been emphasized recently. The purpose of this study was
      to demonstrate the association between the sympathetic denervation of the limb
      and changes of pulsatility index (PI), to compare the blood flow curve in
      diabetics with neuropathic foot ulcer and in patients after surgical
      sympathectomy and to asses the value of PI and ankle systolic pressure in
      identification of diabetic patients with increased risk of foot ulceration. The
      changes in blood flow curve and in PI in arteries of upper limb in patients after
      thoracic sympathectomy (group 1) were recorded. The blood flow curve, PI and
      ankle systolic pressure were also examined in patients with neuropathic foot
      ulcer and diabetes (group 2), in patients without foot ulcer and with diabetes
      (group 3) and in patients without foot ulcers and without diabetes (group 4). The
      blood flow curve in group 1 was similar to that observed in diabetic patients,
      especially from group 2. In patients from group 1 the PI was reduced
      postoperatively. In patients from groups 2, 3 and 4 PI differed significantly
      with the lowest values in group 2. Ankle systolic pressure also differed in
      examined groups with the highest values in group 2. We concluded were was
      sympathetic denervation of the extremity results in lowering of PI and in changes
      in blood flow curve similar to those observed in neuropathic diabetic foot and
      that the combined evaluation of PI and ankle systolic pressure could be helpful
      in identification of diabetic patients with increased risk of neuropathic foot
      ulceration.

PMID- 10335120
TI  - [Chosen function of peripheral blood neutrophils in workers operating X-ray
      equipment].
AB  - Examinations were carried out in 44 persons (29 women and 15 men) who operated X
      ray equipment in radiology departments. Neutrophil adherence and spontaneous
      migration of leukocytes were estimated in this group. Investigations' results
      were compared with the results in the control group. In the group of employees
      who operated X-ray units, the examinations were additionally performed taking sex
      into consideration. In the persons employed in radiology departments
      statistically significant reduction of neutrophil adherence was shown, which
      especially in the subgroup of men was observed. Statistically significant
      reduction of spontaneous migration area of leukocytes was revealed and it
      concerned both the subgroup of men and subgroup of women. On the basis of the
      obtained results the following conclusions were drawn: leukocyte spontaneous
      migration estimated in three-hour test decreases in employees who operated X-ray
      units; it may be used as the estimation test of influence of the X-ray on
      employees operating X-ray equipment when the routine tests are in the normal
      range.

PMID- 10335121
TI  - [Bronchial hyperreactivity in chemical plant workers employed in the production
      of dust pesticides].
AB  - The staff of two chemical plant divisions producing dust pesticides, 131
      employees exposed to dust containing 28-65% SiO2 at an average dust concentration
      of 4.8-5.2 mg/m3 were examined. In the first division (group I, 38 males and 35
      females) captan, carbamates, dodine and chlorinated hydrocarbons active
      substances. In the second division (group II, 26 males and 32 females) the active
      substances included: carbamates, triazine compounds, cupric oxychloride, captan,
      lindane, carboxine. Chronic bronchitis was diagnosed in 51.5% of males and 14.9%
      of females, none had history of asthma. Spirography showed frequent occurrence of
      impaired maximal endexpiratory flow and elevated residual volume; in about a
      quarter of the examined subjects a decreased one-second forced expiratory volume
      was found. The rate of bronchial hyperreactivity to histamine in the examined
      workers (group I-9.6%, group II-10.3%) did not differ significantly from the
      control group of 31 healthy inhabitants of the region, professionally unexposed
      to dust and chemical noxes (6.5%).

PMID- 10335122
TI  - [The effect of various occupational exposures to microwave radiation on the
      concentrations of immunoglobulins and T lymphocyte subsets].
AB  - The immunoglobulins' concentrations and T lymphocyte subsets during occupational
      exposures to microwave radiation were assessed. In the workers of retransmission
      TV center and center of satellite communications on increased IgG and IgA
      concentration and decreased count of lymphocytes and T8 cells was found. However,
      in the radar operators IgM concentration was elevated and a decrease in the total
      T8 cell count was observed. The different behaviour of examined immunological
      parameters indicate that the effect of microwave radiation on immune system
      depends on character of an exposure. Disorders in the immunoglobulins'
      concentrations and in the T8 cell count did not cause any clinical consequences.

PMID- 10335123
TI  - [The assessment of thyroid gland function in patients with non-insulin dependent
      diabetes mellitus (type II)].
AB  - The aim of the study was to assess thyroid gland function in non-insulin
      dependent diabetes mellitus patients under different therapeutic regimens. There
      were examined 75 patients with type II diabetes mellitus, age range 33-80 years
      (average 65.24 +/- 14.32 years) including 46 women and 29 men. Group I was
      treated with insulin, group II--with diet, and group III--with sulfonylurea
      derivatives oral antidiabetic agents. Control group consisted of 91 healthy
      persons in appropriate age. The highest glucose levels were in insulin treated
      group--174.17 +/- 40.31 mg%, and were significantly higher from the values
      observed in oral antidiabetic agents treated group (169.89 +/- 41.34 mg%), and in
      diet treated group, where glucose levels were the lowest--134.57 +/- 25.06 mg%.
      In both groups--patients treated with insulin and with oral antidiabetic agents a
      positive correlation between fT4 and glycated hemoglobin levels were observed.
      Performed experiments and investigations suggest: 1. There are no differences in
      thyroid gland function in patients with non-insulin dependent diabetes mellitus.
      2. Different therapies (diet, insulin therapy, oral antidiabetic agents) have no
      influence on thyroid gland function.

PMID- 10335124
TI  - [Prevention and principles of management in case of cardiac tamponade after
      catheterisation of the subclavian vein in parenteral nutrition].
AB  - The authors described different complications after the subclavian vein
      catheterisation, focusing on the cardiac tamponade. The authors presented the
      prevention and treatment principles respectively in case of the cardiac tamponade
      and reported experiences in this field.

PMID- 10335125
TI  - [Losartan: angiotensin II type 1 receptor antagonist].
AB  - The angiotensin II (A II) type 1 receptor (AT1) antagonists represent a new
      pharmacologic class of drugs. These drugs antagonize A II induced biologic
      actions. Initial clinical trials suggest that these drugs are effective in the
      treatment of essential hypertension and hypertensive patients with renal disease.
      Losartan becomes the first potent, orally active and longacting nonpeptide A II
      receptor antagonist to be used in humans. Antihypertensive efficacy appears to be
      dependent on an activation of renin-angiotensin system, since bilateral
      nephrectomy and/or volume expansion abolishes the blood pressure lowering effect.
      Blood pressure is lowered without a significant change in heart rate or cardiac
      output. In hypertensive patient with renal disease, losartan has been reported to
      have no clinically important effect on glomerular filtration rate. To date, no
      specific AT1 antagonists' side effect has been reported. The potential widespread
      use of this new class of antihypertensive drugs will depend on whether AT1
      receptor antagonists can be differentiated clinically from ACE inhibitors, and if
      such differentiation has clinically significant benefits.

PMID- 10335126
TI  - [Chronic paroxysmal hemicrania].
AB  - The article deals with chronic paroxysmal hemicrania which is a special type of
      headache described for the first time by Sjaastad and Dale in 1974. The author
      presents the symptoms and signs of the disease, its the most frequent
      manifestations and diagnostic methods. The probable etiology of the disease and
      the most effective methods of its treatment are discussed.

PMID- 10335127
TI  - [The use of visual evoked potentials in clinical diagnostics].
AB  - In the presented work the use of visual evoked potentials in the diagnostics of
      multiple sclerosis, optic neuritis, vitamin deficiency, neurotoxic substance
      intoxication, brain tumours, Parkinson's and Alzheimer's disease and migraine was
      discussed.

PMID- 10335128
TI  - [Hereditary long QT syndrome: our own experience].
AB  - We report the case of 16-year old girl who was admitted to our Department after
      the episode of ventricular fibrillation. We diagnosed the hereditary long QT
      syndrome. The patient's family was investigated and complex therapy was started
      in affected individuals including cardioselective beta-blocker (atenolol) and
      permanent cardiac pacing (VVIR and DDDR). This therapy is effective in prevention
      of life-threatening cardiac arrhythmias in our patients.

PMID- 10335129
TI  - [The choice of treatment in multiple pancreatic pseudocysts].
AB  - The authors present their own experience in the treatment of 4 patients (3F, IM)
      with multiple pancreatic pseudocysts. The diagnosis was based on ultrasound and
      CT. In 4 patients 2, 2, 3, and 3 pseudocysts were found respectively. One
      patients was cured using two pig-tail catheters within 3-5 days. Two patients had
      internal drainage. One of them had 3 pseudocysts, two were anastomosed with the
      stomach (Jurasz operation) and the third one with jejuneum. The other patient had
      cystocystostomy and so created cyst was then anastomosed with the stomach
      applying Jurasz's method. In the 3rd patient with 3 pseudocysts pancreatectomy
      was done. This case was complicated by pancreatic fistula, but finally good
      result was achieved. In the follow up time (2, 3, 5 years and 5 months) there was
      no recurrence of the pseudocysts and the patient's condition was good.

PMID- 10335130
TI  - [Minor blunt abdominal trauma can be dangerous].
AB  - Four cases with apparently mild abdominal trauma were presented. Finally, all but
      one were operated. On laparotomy ruptured spleen was found in two patients, the
      third had hematoma of the ileal mesentery. The fourth patient with subcapsular
      kidney hematoma was treated conservatively. All patients had initially denied any
      abdominal trauma. Sonography seems to be the most reliable and non-invasive
      investigation in making the diagnosis.

PMID- 10335131
TI  - [Mirizzi syndrome caused by the gallstone in long remnant of a cystic duct].
AB  - It is the case of a 53-year-old woman diagnosed during the operation on Mirizzi
      syndrome type I caused by the gallstone in a cystic ducts' remnant, 20 years
      after cholecystectomy.

PMID- 10335132
TI  - [Medical associations in the period of Polish enlightenment].
AB  - The author presents the beginnings of scientific medical associations in Poland
      in the 18th century. The associations contributed significantly to popularization
      of the achievements of medicine and were uniting the medical circle when medical
      schools were closed. Medical magazines edited and published by these associations
      were the platform of the exchange of scientific experiences what approached
      Polish science to European level.

PMID- 10335133
TI  - [Social diseases in Poland during the in-between wars period].
AB  - In the paper the methods of prevention and control of social diseases
      (tuberculosis, trachoma, increased infantile and maternal mortality, alcoholism)
      in Poland of interwar period were presented. A considerable prevalence of these
      diseases was connected with social and economic conditions, in which broad
      classes of society had to live. The most effective methods in reducing the
      incidence of the diseases were prophylaxis and organization of free health care.

PMID- 10335134
TI  - [Good manners code in scientific publications].

PMID- 10335135
TI  - Using the health belief model in understanding prostate cancer in African
      American men.
AB  - Research studies show that African American men or more likely to develop and die
      of prostate cancer than any other ethnic group. The disparity is partially
      associated with the motivators of behaviors in African American men. In
      particular, perception of outcomes in relationship to behavioral performances
      influences whether a task will be initiated. This paper examines prostate cancer
      in African American men using components of the Health Belief Model.
      Implications, for professional nurses in designing interventions to encourage
      early screening and treatment for prostate cancer, are included.

PMID- 10335136
TI  - Technology in nurse education: a communication teaching strategy.
AB  - This article focuses on the topic of technology in nurse education as a
      communication learning tool. Nurses are very interested in learning more about
      telehealth through the application of technology--computer-managed instruction
      (CMI), computer adaptive testing (CAT), computer stimulation testing (CST),
      telenursing, telemedicine and the Internet as it relates to improving health care
      delivery. With the current technology, there are many clinical implications,
      faculty concerns, and student issues in documentation and the explosion of
      knowledge and research as a direct source of information. This technology may
      also serve as a catalyst in bringing positive changes in the practice and the
      profession of nursing in collaboration with other health disciplines. Although
      there are limitations that cost may be a major deterrent in some schools of
      nursing, it is a fact that technology has invaded today's health care delivery
      system and the society, and is here to stay.

PMID- 10335138
TI  - Empowerment: a tool for black nursing faculty.
AB  - This article explores the concept of power and applies it to Black nursing
      faculty members. Recognizing that although the number of Black Americans teaching
      in schools of nursing is not proportional to the number in the general
      population, the authors state that the number entering the teaching field is
      increasing. With so few in nursing and subsequently in teaching, problems are
      inherent in the teaching role. The authors address some of these problems and
      offer suggestions for how Black nursing faculty members can empower themselves.

PMID- 10335137
TI  - Health promoting behaviors of urban African American female heads of household.
AB  - Nurse practitioners' understanding of the health status and health promoting
      behavior of African American women is only in its infancy. This study utilized
      the Health Promoting Lifestyle Profile to examine these behaviors in 198 females
      (73% African American) in an urban setting who were heads of household. The
      purpose was to identify their health promoting lifestyles. Such knowledge could
      be the basis for health promotion programs to meet the needs of these women.
      Findings revealed that being head of household had no significant relationship to
      health promoting behavior. Religiosity and education were positively associated
      with health promoting behavior, while smoking and ethnic background were
      inversely correlated. Age and marital status also influenced specific health
      promoting behaviors. Implications for development of programs to foster
      involvement of African American women in health promotion programs were
      presented.

PMID- 10335139
TI  - The "kaleidoscope" experience for elderly women living with coronary artery
      disease.
AB  - In recent years, there has been a rapid increase in the number of elderly women,
      over the age of 60 years, who experience manifestations of coronary artery
      disease (CAD) such as angina and myocardial infarction (MI). While quantitative
      research has indicated some significant findings concerning the risk factors and
      symptoms of CAD in men and women within hospital settings, the majority of
      studies have had under representative samples of elderly women. Little research
      has been conducted regarding the complex relationships that exist between the
      contexts, contingencies and conditions that influence the meaning that elderly
      women attach to cardiac illness. This qualitative study, which used a grounded
      theory approach, provides a theoretical analysis of the meaning that elderly
      women with CAD attach to their illness, home convalescence and social support
      needs. Eight women, between the ages of 61 and 87 years, who experienced acute
      exacerbations of CAD, were interviewed in their homes during the early home
      convalescence period (2 weeks and 4 weeks post discharge). In the theoretical
      analysis, finding a voice, the core variable, represents the basic social process
      employed by these elderly women during hospitalization and the early home
      convalescence period. Struggling for a new self is the transcending process that
      influences all aspects and interactions of this social process. The major
      supporting interlinkages of the transcending process include living with loss,
      conforming to tradition, striving for respect and blending the gaps. These women
      blended all of these transcending processes to find a voice that reflected their
      unique perceptions, past experiences, coping strategies and personal identity.
      This paper will discuss the salient issues arising from the literature on elderly
      women and heart disease, the theoretical analysis of the meaning these women
      attach to their illness, home convalescence and social support needs, and
      implications for future research, practice and educational pursuits.

PMID- 10335140
TI  - Women's heart health--an integrated approach to prevention.
AB  - The major causes of death and disability in women include in order: heart
      disease, cancer, stroke, fractures, pneumonia, osteoarthritis, and cataracts.
      This paper discusses common preventive approaches that have the potential to
      reduce women's risk of atherosclerotic cardiovascular disease as well as cancer,
      osteoporosis, and fractures. These preventive approaches include smoking
      cessation or prevention, physical activity, weight control and consuming a
      healthy diet.

PMID- 10335141
TI  - An overview of commonly used antiplatelet agents.
AB  - Several agents inhibiting platelet function are commonly used in clinical
      practice, each having a unique mechanism of action. The complex cascade of events
      ultimately resulting in thrombus formation has several areas that pharmacologic
      agents can affect. The resultant effects range from being relatively non-specific
      with aspirin, ticlopidine, and clopidogrel to being specific with the
      glycoprotein IIb/IIIa receptor antagonists such that platelet aggregation will be
      inhibited irregardless of the metabolic pathway responsible for initiating
      aggregation. The clinical indications for these agents are vast, as platelet
      aggregation has been widely implicated in cardiovascular events. The degree of
      platelet inhibition is related to the frequency of bleeding. Aspirin is a
      relatively weak inhibitor of platelet function, ticlopidine has been said to have
      moderate activity, while the glycoprotein IIb/IIIa receptor antagonists are the
      most potent inhibitors of platelet aggregation. As our knowledge of the
      mechanisms of platelet aggregation expands, so will our treatment regimens.
      Clearly, we will await the results of future clinical trials to further define
      the role of antiplatelet agents.

PMID- 10335142
TI  - Writing abstracts for peer review.

PMID- 10335143
TI  - Necessity for CNS skills.

PMID- 10335144
TI  - Adults' experience with asthma and their reported uncertainty and coping
      strategies.
AB  - This study examined the uncertainty experienced by persons with asthma and the
      coping strategies they used. The sample of 99 adults was interviewed by the
      investigators. Subjects responded to demographic and illness-related questions
      and completed the Mishel Uncertainty in Illness Scale and the Jalowiec Coping
      Scale. Subjects who had asthma for a longer duration reported lower levels of
      uncertainty. Those who were hospitalized because of asthma and those for whom
      pollen was a trigger experienced greater uncertainty. Females, individuals who
      went to an emergency department because of asthma, and those who attended
      pulmonary support groups used more coping strategies. Understanding the sources
      of perceived uncertainty may assist individuals to cope with and manage the
      chronic and acute phases of asthma.

PMID- 10335145
TI  - Stages of change theory and the nicotine-dependent client: direction for decision
      making in nursing practice.
AB  - Clinical practice is the basic purpose of nursing. Nursing's evolving
      professional development calls for the application of theory to direct decision
      making in nursing practice. Therefore, in an attempt to bridge what has been
      described as the "theory-practice gap," the author demonstrates how Prochaska and
      DiClemente's stages of change theory is relevant to nursing practice. According
      to Prochaska and DiClemente, behavioral change, such as smoking cessation,
      involves a process of five identified stages: precontemplation, contemplation,
      preparation, action, and maintenance. The author discusses each stage of change
      and the framework it provides for decision making in nursing practice. The
      concept of relapse is described and highlighted as a valuable learning
      experience. Finally, using the criteria set by Chinn and Kramer, systematic
      evaluation of the stages of change theory pinpoints strengths and discusses
      integration of the theory into nursing practice.

PMID- 10335146
TI  - CNS impact in nontraditional settings.

PMID- 10335147
TI  - The role of a CNS in a memory clinic.
AB  - The advent of medications to treat the symptoms associated with mild to moderate
      Alzheimer's disease has added to the critical need for early diagnosis of
      dementia. Yet diagnosis and treatment of Alzheimer's disease require specialized
      assessment and knowledge. To address the needs of patients and families coping
      with Alzheimer's disease, an ambulatory care memory clinic was established in
      Fredericton, New Brunswick, Canada. This article describes the four components of
      the clinical nurse specialist role in this clinic that reflect the essential
      characteristics of advanced nursing practice.

PMID- 10335148
TI  - The clinical nurse specialist's role in school health.
AB  - This article explores the role of the clinical nurse specialist (CNS) in school
      health. School nurse roles and responsibilities are expanding from their original
      emphasis on providing direct care and education to children and their parents to
      community-oriented care. CNS roles and practice areas have expanded to fill needs
      in a variety of settings, with a variety of clients. The identified CNS roles of
      clinician, educator, consultant, researcher, and leader/manager provide a
      comprehensive approach to providing school health services directly to
      individuals and indirectly through community-oriented care. A CNS's expertise is
      essential to assist with providing comprehensive care to students, their
      families, and the community through comprehensive school health services.

PMID- 10335150
TI  - Efficiency in communication.

PMID- 10335149
TI  - Collaboration? Supervision? Direction? Independence? What is the relationship
      between the advanced practice nurse and the physician? States' Legislative and
      Regulatory Forum III.

PMID- 10335151
TI  - Outcome evaluation: an essential component for CNS practice.
AB  - Tumultuous changes in healthcare costs, delivery, and service are requiring
      revolutionary new approaches by healthcare professionals to meet current and
      future needs. Multidisciplinary teams are creating many innovative care delivery
      models. It is essential that healthcare professionals evaluate the cost
      effectiveness and impact of their care and service on both patient and system
      outcomes. Clinical nurse specialists (CNSs) are an integral component in these
      models and are uniquely qualified both to implement and to evaluate care delivery
      and systems changes. The purpose of this article is to describe the role of the
      CNS in outcomes evaluation. Specifically, various types of outcomes are
      delineated, with a differentiation between nurse-sensitive and medical and
      collaborative care outcomes. Examples of valid and reliable measurement tools
      that are easy to use and have wide comparability are described, and implications
      for CNS practice are posed.

PMID- 10335152
TI  - Preventing secondary pregnancy in adolescents: a model program.
AB  - The Dollar-A-Day program in Greensboro, North Carolina, was established in 1990
      to prevent subsequent pregnancies in girls under 16 years of age who had already
      given birth to one child. Conceptualized by nursing professors and using
      principles from theories of adolescent development and social exchange, the
      program was planned and implemented in collaboration with nurses from the local
      health department. Weekly meetings featured food, an informal program focused on
      needs identified by members, setting of short-term goals, and an award of a
      dollar for each day they remained nonpregnant. After five years of operation with
      a series of small grants, only 15% of the 65 girls who had been enrolled in the
      program experienced subsequent pregnancies. The success of the program convinced
      health department officials to incorporate Dollar-A-Day into their budget as a
      permanent service to the population of adolescents they serve. It remains as a
      model program for others to emulate.

PMID- 10335153
TI  - Abnormal Papanicolaou smears, genital tract infections, and contraception.
AB  - Cervical cancer ranks second among all cancers in women world-wide, and the rate
      of invasive cervical cancer among women under 50 is rising in the United States.
      Risk factors for abnormal Papanicolaou (Pap) smears and invasive cervical cancer
      include genital tract infections. This study was designed to compare the rates of
      genital tract infections and the contraceptive choices of a random sample of 800
      women, using an ex post facto design. The Pap positive women had a significantly
      higher rate of genital tract infections than did the Pap negative women but did
      not differ significantly in use of contraceptive methods. Findings support those
      of other researchers suggesting genital tract infections as risk factors for
      abnormal Pap smears and are consistent with the literature in suggesting a role
      for oral contraceptive pills (OCPs) in acquisition of the human papillomavirus
      (HPV). Caregivers can help empower women to reduce their risks through informed
      choices about protection and sexual behaviors.

PMID- 10335154
TI  - Women's experiences of preterm labor: a feminist critique.
AB  - Using a feminist perspective, women's experiences of preterm labor (PTL) were
      critiqued and compared with the medical establishment's perspective on PTL as
      described in the medical literature. Interview data from 29 women who
      participated in a larger study on the PTL experience were revisited and examined
      based on principles of feminist theory. The persistent "medicalization" of
      women's bodies was discussed and used as a framework to explore several issues:
      (a) the diagnosis of PTL and what it means to be at risk for this phenomenon; and
      (b) the treatment of PTL including the role of medications, activity, and home
      monitoring for uterine contractions. Based on the differences that emerged when
      PTL--was examined from two divergent standpoints--the women's perspective and the
      physician's perspective--some alternative approaches to PTL management that place
      women's lives at the center of the treatment process were suggested.

PMID- 10335155
TI  - Use of indigenous explanations and remedies to further understand nausea and
      vomiting during pregnancy.
AB  - Professional and indigenous midwives are rich and appropriate sources of
      information about antenatal comfort measures. Midwives from a variety of
      geographic and cultural areas were interviewed to further our understanding of
      the phenomenon of nausea and vomiting during pregnancy (NVP). The midwives
      offered general physiological, psychological, and socioeconomic etiological
      theories that were, at times, inconsistent with their recommended remedies. The
      remedies generally included alterations in maternal nutrition, activity, and
      environment. Commonalities in the midwives theories of etiology and treatment
      were found across culturally and geographically diverse groups. Much of the
      variation that was noted in the midwives recommendations for treatment was
      related to (a) availability of a specific remedy and (b) the midwife's
      willingness to either support or discourage intuitive responses that women have
      to their pregnancies (e.g., encourage either additional rest or exercise and
      productive activity; social withdrawal or usual social interaction; and pica and
      food cravings or a balanced diet with high nutritive value).

PMID- 10335156
TI  - Pregnancy during residency--an Israeli survey of women physicians.
AB  - The objective is to assess the impact of workload on pregnancy among women
      physicians in public hospitals in Israel. A self-administered, cross-sectional
      study of pregnancies among women physicians in public hospitals was conducted. An
      82-item questionnaire was mailed to women physicians in the three largest
      university hospitals in Israel. The questionnaire assessed demographic data,
      pregnancy course, perceived stress, and complications during pregnancy. Response
      rate was 52% (207/400). The complication rates were compared with rates in the
      Jewish population and expressed as mean +/- SD. Mean number of pregnancies during
      residency was 1.3 +/- 1.2. Mean age at the first delivery was 27 +/- 3.2 years.
      There was a significant difference in the rates of stillbirth (32/1000 births
      versus 3.7/1000, p < 0.001) and premature delivery (12.4% versus 7.6%, p =
      0.0014) between women physicians and the general population. There was no
      significant difference in the proportion of spontaneous abortions (12.7%),
      pregnancy induced hypertension (3.2%), hyperemesis gravidarum (3.2%), and
      diabetes (1%). Seven percent of women physicians changed their specialty due to
      pregnancy while in residency. Our results suggest that working long hours in a
      stressful occupation in a hospital environment has an adverse effect on pregnancy
      course and is associated with increased rates of stillbirth and premature
      delivery.

PMID- 10335157
TI  - Predictors of rape in the Central African Republic.
AB  - This is a study of women in the Central African Republic (CAR) whose first sexual
      encounter was the result of rape. The analyses presented here are based on a
      national HIV/AIDS survey conducted in 1989. Respondents were selected through
      multistage cluster sampling, where census districts and households within
      districts were randomly selected. A total of 1307 females responded to the
      question regarding the circumstances of their first intercourse. Nearly 22% of
      female respondents reported that their first experience with intercourse was
      rape. Bivariate analyses found that rape during first intercourse was
      significantly related to the following respondent characteristics at the time of
      the survey: age, marital status, having a child, education, occupation, urban
      versus rural living, ethnic group, age at first date, and consumption of alcohol.
      Rape was not significantly related to ability to read, religion, and years in
      current village or town. Rape during first intercourse was found in a stepwise
      logistic regression to be related to age, marital status, occupation, and ethnic
      group. These data indicate that the incidence of rape is higher than previously
      reported in Africa, there are specific risk factors, and there are serious
      negative consequences.

PMID- 10335158
TI  - Information sources, menopause beliefs, and health complaints of midlife
      Filipinas.
AB  - Although the perimenopausal transition is a universal experience for women who
      live long enough, its cross-cultural variations have been explored only recently.
      In this study, we investigated some of the expectations and health beliefs of 165
      midlife Filipina Americans using focus groups and a short-answer questionnaire.
      Participants reported on (a) how they learned about menopause, (b) who they
      talked to about menopause symptoms or issues, (c) how Filipino women and men feel
      about menopause, and (d) the most common health complaints of midlife Filipinas.
      Findings revealed that midlife Filipina Americans primarily obtain their
      information from and talk about menopause with female relatives and friends. They
      usually viewed menopause as a normal life phase, yet knew less about how Filipino
      men feel about menopause. Health complaints of midlife Filipinas were mainly
      estrogen-related menopause symptoms and negative affect symptoms.

PMID- 10335159
TI  - HIV-positive mothers and stigma.
AB  - Our purpose in this paper is to demonstrate how stigma pervades the lives of
      human immunodeficiency virus (HIV)-positive mothers and their children. Data from
      a grounded theory study on HIV-positive mothers are used to illustrate Goffman's
      theory of stigma. This research is an example of "emergent fit," where extant
      theory is discovered by the interpretive researchers to fit much of the data. The
      sample included 18 HIV-positive mothers who participated in in-depth interviews.
      The HIV-positive mothers valued being perceived as normal but acknowledged that
      normalcy was lost for them because of the stigma of HIV. Consequently, they tried
      to pass as normal by managing information and manipulating their environment.
      They attempted to cover up their illness by lying and pretending. Health care
      professionals can provide quality, client-centered care when they understand the
      power that stigma holds over these women and the strategies that effectively
      mitigate the stigma.

PMID- 10335160
TI  - An integrated dialysis delivery network in Ontario.
AB  - In August 1995, the Ontario Ministry of Health (MOH) issued a request for
      proposal (RFP) for the establishment of new and expanded dialysis services.
      London Health Sciences Centre (LHSC) was successful in expanding its integrated
      dialysis delivery network with satellites in Stratford, Woodstock and Owen Sound.
      This achievement required collaboration of LHSC and host hospital staff to meet
      the challenging RFP requirements. With final approval received in January 1997,
      efforts were required to establish an operational model supporting self-care and
      full-care patients, to train satellite staff and patients, and to manage the
      resulting clinical impact. A balanced scorecard (Kaplan & Norton, 1992)
      evaluation model was developed. Initial outcome data indicate that full-care
      patients in satellites require more fallback support to London units, experience
      more hypotensive episodes during dialysis and, in some cases, demonstrate lower
      levels of dialysis adequacy and nutritional status when compared to satellite
      self-care patients. Findings from these data will assist in revising patient
      inclusion criteria and processes to optimize community-based dialysis.

PMID- 10335161
TI  - Incidence of sleep pattern disturbance (SPD) in a hemodialysis sample.
AB  - Personal experience suggests that sleep pattern disturbance (SPD) is a serious
      problem for the patients we serve. The purpose of this study was to identify the
      scope of sleep problems among all willing patients in a medium-sized hemodialysis
      unit in a university teaching centre. This descriptive study examined SPD through
      the use of a sleep diary that subjects were asked to complete each morning for a
      week. Subjects were asked to describe sleep latency, sleep quantity, number of
      arousals, whether they awoke feeling rested, factors that interfered with sleep
      the night before, and sleep inducers employed the night before. They were also
      asked to record their dialysis schedule. Each subject's chart was reviewed with
      respect to medications and evidence of other medical problems that interfered
      with sleep. Findings were benchmarked with results from the literature.
      Information regarding facilitators and barriers to sleep has provided some basis
      for an interdisciplinary plan of care to address this distressing problem.

PMID- 10335162
TI  - Pregnancy and the dialysis patient.
AB  - Pregnancy in the dialysis patient is a rare occurrence. When pregnancy does
      occur, the risk of spontaneous abortion, stillbirth and neonatal complications
      such as prematurity and growth retardation are fairly high. This paper discusses
      issues surrounding pregnancy and the dialysis patient. It also follows the
      pregnancy of one hemodialysis patient at The Toronto Hospital. Guidelines for the
      care of pregnant dialysis patients are reviewed.

PMID- 10335163
TI  - [Assessment clinic and pre-dialysis information].
AB  - The objectives for the predialysis clinic were to help patients and their
      families cope with chronic renal failure and to provide information so that
      patients could choose the method of dialysis that best suited their lifestyle.
      The clinic was started on April 26, 1995. The patients' visits were divided into
      three phases. Phase one consisted of three visits to complete a biophysical,
      psychosocial assessment. A multidisciplinary team provided information to assist
      the patient and family understand renal disease as well as the options available
      for dialysis. The patients learned about continuous ambulatory peritoneal
      dialysis (CAPD), self-care hemodialysis, and in-centre hemodialysis. Criteria to
      start this phase one were chronic renal failure with a creatinine clearance rate
      of 20 ml/min. Phase one usually lasted two to three weeks.

PMID- 10335164
TI  - How to organize a professional portfolio for staff and career development.
AB  - Professional portfolio development is an innovative way for staff development
      departments to assist staff nurse in showcasing their professional
      accomplishments. Whether preparing staff for their annual performance appraisal,
      the human resources portion of a Joint Commission on Accreditation of Healthcare
      Organizations survey, personal career development, or career transitions in the
      volatile healthcare job market, the staff development department plays a pivotal
      role in portfolio development. Although the literature describes the types of
      documents to include in a professional portfolio, missing is practical
      information on how to organize a professional portfolio. In this article, the
      authors describe how to organize a professional portfolio, identify the most
      useful components, and outline the role the staff development department plays in
      professional portfolio development.

PMID- 10335165
TI  - Preparing readable patient education handouts.
AB  - Printed health educational materials, such as patient information handouts,
      booklets, pamphlets, and information sheets are among the most common and
      extensively used teaching tools (Rankin & Stallings, 1996). In this article, the
      author reports (1) the readability of patient information handouts developed by
      the nursing division and (2) the effect on the patient-teaching task force
      members of instruction on the readability of patient information handouts at a 79
      bed community hospital in Southern Ontario.

PMID- 10335166
TI  - Continuing education: an aspect of staff development relating to the nurse
      manager's role.
AB  - Continuing education programs are an important part of staff development. The
      purpose of this article is to indicate how the nurse manager can promote a
      successful continuing education program. The authors present arguments for the
      implementation of mandatory, continuing education.

PMID- 10335167
TI  - The ABCs of highly effective presentations: a customer-centered approach.
AB  - In the world of adult education where the learners have complex expectations, the
      educator must make an extra effort to meet the customers' (learners') needs. This
      article describes how an educator can make every presentation customer-centered
      by knowing the ABCs of highly effective presentations. The ABCs, when applied,
      can jump-start presentations and help the presenter meet or exceed learners'
      expectations.

PMID- 10335168
TI  - Teaching pain management: how to make it work.
AB  - What are effective strategies for teaching and molding attitudes toward pain
      management? Nursing responsibility for pain management involves a complex
      decision-making process affected by many variables. Traditional pain management
      classes omit critical content and strategies that may affect implementation of
      the information. Techniques and resources for the educator planning pain
      management programs are presented in this article. Achieving positive changes in
      behavior related to pain management requires a well-developed plan that
      incorporates model-based instruction in both cognitive and affective domains.

PMID- 10335169
TI  - Colliding of cultures in a therapeutic regimen.

PMID- 10335170
TI  - Caring and cultural maintenance and transformation for secondary urban family
      caregivers of persons with stroke.
AB  - An ethnographic study examined secondary urban family caregivers' caring and
      cultural maintenance and transformation as it influences their capacity to care
      for persons with stroke within African American family systems. Caring as
      experience was demonstrated by two domains: caring actions and caring family
      functions. Caring as meaning was centered in one domain: caring expressions.
      Cultural patterns were evidenced in the experience and meaning of caring and
      focused on cultural maintenance that the caregivers and their families developed
      to survive the caring situation. Culture transformation such as being open to
      more options could occur only if the caregivers' circumstances changed. For the
      most part, they were doing everything in their power to maintain their family
      system.

PMID- 10335171
TI  - From recipes to recetas: health beliefs and health care encounters in the rural
      Dominican Republic.
AB  - With the growing influx of immigrants from the Dominican Republic entering the
      U.S. yearly, it is important for nurses to become familiar with their traditional
      health beliefs and health care experiences. The purpose of this study was: (a) to
      identify health beliefs of rural Dominicans and (b) to describe health care
      encounters between rural Dominicans and a visiting team of U.S. nurses. The data
      on health beliefs were collected in six focus groups and were analyzed using
      content analysis techniques. Health encounter data were collected from 693
      Dominicans as they presented to mobile clinics for care. Findings from the focus
      group interviews suggested that health beliefs fall into two major categories:
      physical and spiritual/mystical. The most frequently occurring health problems,
      summaries of medications dispensed, treatments provided, referrals made, and
      health teaching information are presented.

PMID- 10335172
TI  - Meaning of filial piety in the Chinese parent-child relationship: implications
      for culturally competent health care.
AB  - To work with Chinese/Chinese-American clients more effectively, health care
      providers must know how to work with them within their value system of filial
      piety. This paper focuses on Chinese parent-child relationships with respect to
      this value system from the perspective of young adult Chinese immigrants in the
      United States. Using an ethnographic approach, in-depth interviews were conducted
      with six immigrants from Taiwan. Domain analysis and content analysis revealed
      ten domains, five of which are reported in this paper. The findings suggest that
      filial piety continues to operate in Chinese immigrant families. Implications for
      cross-cultural health care and research are addressed.

PMID- 10335173
TI  - Reuse of single-use equipment. The intravenous nurse specialist's role in
      institutional policy development.
AB  - The controversial issues and numerous regulatory, ethical, financial, and
      liability risks that must be considered when a healthcare organization evaluates
      implementation of a program to reuse single-use equipment are discussed. A role
      for the well-informed intravenous nurse specialist in institutional policy
      development regarding reuse of infusion equipment is suggested. Numerous
      resources on this topic are referenced.

PMID- 10335174
TI  - Positive outcome after looped peripherally inserted central catheter malposition.
      A case study.
AB  - Tip malposition of peripherally inserted central catheters (PICCs) is a
      frequently encountered problem. Invasive and noninvasive techniques for
      resolution of malpositions described in the literature are reviewed. A positive
      outcome using non-invasive techniques after a looped malposition in the axillary
      vein is discussed.

PMID- 10335175
TI  - Patient education. Understanding the process to maximize time and outcomes.
AB  - The role of teacher is inherent to the profession of nursing. According to the
      Joint Commission on the Accreditation of Healthcare Organizations, the goal of
      patient and family education is to improve patient health outcomes by promoting
      healthy behavior and involving the patient in care and care decisions. Infusion
      therapy encompasses a variety of therapies, equipment, and techniques that often
      must be taught to the patient or provider of care. Education involves assessment,
      goals, allocation of resources, maximizing patients self-care skills, enhancing
      patient participation in continuing care, and promoting interactive communication
      between patients and providers. This article focuses on tools for better
      assessments, fine tuning goal setting, creative teaching strategies, and four
      levels of evaluation that lead to positive patient outcomes.

PMID- 10335176
TI  - Clinical factors associated with the development of phlebitis after insertion of
      a peripherally inserted central catheter.
AB  - A descriptive comparison study was conducted to determine if there were any
      coagulation, immune, nutritional, or insertion-related differences between 64
      adult hospitalized clients who experienced phlebitis after insertion of a
      peripherally inserted central catheter (PICC) compared with a matched group of 64
      adult hospitalized clients who did not develop phlebitis. Factors that
      significantly decreased the development of phlebitis in this study included
      smaller catheter gauge, placement in the basilic vein, tip location in the
      superior vena cava, no manipulation or movement at the exit site, and higher
      platelet levels.

PMID- 10335177
TI  - Clinical and ethical considerations of fluid and electrolyte management in the
      terminally ill client.
AB  - Modern medicine has at its disposal a vast array of technology to provide support
      for basic human functions that have been compromised by trauma or disease. These
      are frequently referred to as life-support interventions, without which life
      could not be sustained beyond either an immediate or relatively short period of
      time. This includes support for basic physiologic activities such as respiration,
      circulation, kidney function, and food and fluid needs. Among the many medical
      interventions available to circumvent life-threatening situations that jeopardize
      these basic functions, artificial nutrition/hydration poses the greatest
      challenges. Various factors must be considered and weighed in coming to a
      decision about the appropriateness or inappropriateness of using the technology
      available to provide nutrition and hydration. These factors include clinical,
      ethical, legal and emotional considerations.

PMID- 10335178
TI  - Going the extra mile for organ donation. 1998 NN&I Quality of Life Award
      recipient joins '93 and '96 winners in Miami-area crusade to improve organ
      donation.

PMID- 10335179
TI  - Patient perspectives. Hemodialysis.

PMID- 10335180
TI  - Patient perspectives. Peritoneal dialysis.

PMID- 10335181
TI  - Patient perspectives. Kidney transplantation.

PMID- 10335182
TI  - Internet access for ESRD patients gives new meaning to "sleepless in Seattle".
      Northwest kidney centers wire all stations at newest unit.

PMID- 10335184
TI  - Changing roles in the evolution of the renal care team.

PMID- 10335183
TI  - Signing on. DIALYSIS mailing list allows patients to share the ups and downs of
      treatment.

PMID- 10335185
TI  - The role of the physician assistant in nephrology.

PMID- 10335186
TI  - Technician training and certification: a legislative update.

PMID- 10335187
TI  - A model for patient participation in quality of life measurement to improve
      rehabilitation outcomes.
AB  - Health-related quality of life (HRQOL) measurement is being used to assess end
      stage renal disease (ESRD) patients' functional status and well-being from the
      patient's perspective. Research shows that HRQOL can screen for patients at high
      risk for death, hospitalization, treatment adherence, and depression. This study
      investigated whether patient goal setting and interdisciplinary collaboration and
      support could increase HRQOL scores in ESRD patients on chronic maintenance
      hemodialysis. Differences were found to be statistically significant in two of
      the MOS Short Form 36 (SF-36) categories (role physical and role emotional)
      following the intervention at the 95% confidence interval using a t-test
      statistic. This indicates that the intervention had a positive impact on patient
      perceptions of their health status. Eighty-seven percent indicated that there had
      been at least some progress made in reaching the goal. The results of this study
      support the utilization of HRQOL data at the facility level to improve patient's
      perceptions of their health status. A further study is needed to examine the long
      term impact on HRQOL and other patient outcome measures through consistent use of
      this intervention.

PMID- 10335188
TI  - Searching for the optimal renal prescription. Fresenius, Kaiser Permanente team
      up to offer new options in dialysis care.
AB  - The goals are simple: Improve well-being of the dialysis patient and reduce
      hospitalizations. The tools are diverse: Ultrapure dialysate. On-line blood
      monitoring. Biocompatible membranes. No reuse. Daily, in-center dialysis and
      possibly nocturnal dialysis at home. Reimbursement: Full-risk capitation, With
      Medicare and commercial payor rates varying on a patient-by-patient basis. Create
      an incubator with approximately 1,000 end-stage renal disease patients, treated
      at both capitated payment-exclusive dialysis units and mingled in at traditional
      fee-for-service clinics. Establish a team of nurses and renal care staff to
      direct the care plan, and put the program in place. After the first year, analyze
      the data and see if the end--hopefully, improved outcomes and resulting reduced
      hospitalizations--justifies the means--the higher cost for "optimal
      technologies."

PMID- 10335189
TI  - Clinical governance: where does nurse education fit?

PMID- 10335190
TI  - Assessment of mental health nursing competence using level III academic marking
      criteria: the Eastbourne assessment of practice scale.
AB  - The assessment of clinical competence in nursing represents a challenge to the
      profession. There is a need for assessment of practice skills through evaluative
      observation of performance but unfortunately such methods are not regularly used
      as a basis for assessment within most academic nursing institutions. Instead
      there is still a reliance upon more traditional types of academic assessment
      usually done through a written medium. Such methods whilst academically rigorous
      do not easily assess actual real life competence. This paper will describe how
      this tension was addressed through the development of a tool that combines
      observation of real life practice and viva style questioning with an assessment
      marking grid whose descriptors represent level III practice. Its inter rater
      reliability (rs = 0.88, P < 0.01) was established by 14 clinical nurse
      specialists in cognitive behaviour therapy who assessed a single video taped
      recording of a post-registration students performance whilst undergoing training
      in cognitive behaviour therapy.

PMID- 10335191
TI  - Continuing education needs of community nurses, midwives and health visitors for
      supervising and assessing students.
AB  - The objective of this study was to ascertain the changing educational needs of
      community nurses, midwives and health visitors in relation to the teaching,
      supervising and assessing of pre- and post-registration students. A questionnaire
      was sent to all education institutions providing community nursing experience in
      England (Whittaker et al. 1997), which allowed identification of three centres
      for in-depth study. Questionnaires were sent to practitioners (community nurses
      and midwives, health visitors and school nurses), their managers, and teachers of
      community courses in the three centres: 314 were returned. Eight semi-structured
      interviews were undertaken with volunteers in each of the study centres (n = 24).
      Extensive demands are being made on community staff to provide learning
      experiences for students on a wide range of courses. Practitioners reported that
      in order to fulfil their teaching and assessing functions they needed continuing
      education in matters which would assist them to provide research-based practice
      and education, teaching and assessing in the community and personal skills, for
      example assertiveness and counselling. Less than a quarter of practitioners were
      undertaking continuing education courses. However, opportunities for further
      academic study varied enormously and most practitioners had to study in their own
      time at their own expense.

PMID- 10335192
TI  - Preparing for the future: the status of genetics education in diploma-level
      training courses for nurses in the UK.
AB  - This paper offers new information about genetics education provided by diploma
      level training programmes for nurses in the UK. Those responsible for the
      development and provision of curricula were asked to complete a questionnaire
      that attempted to assess the nature of genetics education and their attitudes
      towards it. The response rate was 84%. Whist genetics teaching is included on all
      but two training courses, variation in content, delivery and timetable allocation
      indicates disparity. Genetics is taught for 10 hours or less on most courses,
      utilizing a limited number of approaches. Most courses do not have compulsory
      assessment. The majority of respondents (81%) agreed that genetics will have a
      major impact on health care, and will become an increasingly important issue in
      education. A small majority (58%) agreed that genetics should have a higher
      profile in professional training yet many respondents (68%) felt that the
      teaching they were already offering was appropriate to meet patients' needs. In
      the absence of any clear national framework for delivery and assessment of
      genetics education, the author questions whether current training is sufficient
      to provide nurses with the basic genetic literacy needed to respond to
      developments in genetics as they impact on health care.

PMID- 10335193
TI  - This little piggy went to market: using a health education market as a learning
      strategy for preregistration Bachelor of Nursing students.
AB  - In the academic year 1997/98 at the University of Tasmania, students undertaking
      the research unit in their second year of the Bachelor of Nursing (BN) took part
      in producing a health education market for the staff and students on the
      Launceston campus of the University. The cafeteria and outside grassed areas were
      transformed into a network of information stalls, displays and activities. The
      students reported a constant flow of interested and enthusiastic people to their
      stalls. Integrating research findings, technical and interpersonal skills and
      creative ability, students were encouraged to synthesize many areas of theory in
      the nursing programme in order to present high quality, informative and engaging
      stalls. Formal evaluation of both group and individual work was integrated into
      the process in such a way as to provide prompt feedback and encouragement,
      ongoing quality control and to generate a final grade for each student.

PMID- 10335194
TI  - Nursing students' perceptions of their first mental health placement.
AB  - The way in which the theory and practice of mental health nursing is presented to
      students is of particular importance, especially at a time when recruitment into
      the profession is falling. This study sought to examine how nursing students
      experience their first mental health placement. A pre-/post-test design was used
      with a standardized instrument (Attitude Towards Psychiatry questionnaire) to
      assess the influence of their mental health placements on nursing students'
      attitudes towards mental health nurses, mental health nursing practice and
      education and theoretical aspects of mental health nursing. Results suggest that
      the placements were effective in improving students' regard in each of these
      areas. Though no generalizable conclusions can be inferred from this study some
      interesting insights are provided by nursing students into their perceptions of
      current mental health nursing practice.

PMID- 10335195
TI  - Some important limitations of competency-based education with respect to nurse
      education: an Australian perspective.
AB  - Issues concerning competency-based education (CBE) have recently promoted much
      discussion and debate throughout most developed countries. This paper provides an
      Australian perspective and adds to the wider debate about CBE by deliberating on
      the part professional competency standards should play in a university
      curriculum, specifically the undergraduate nurse education curriculum. A position
      is developed by addressing the following thesis statement: the competency-based
      approach to nursing education is an indisputable reality but nursing competencies
      must not be allowed to control the curriculum. Some background material is
      briefly reviewed in order to situate CBE, nurse education, and nursing
      competencies in their Australian economic and sociopolitical context. The
      position is then explicated through an examination of some intersections between
      nursing competencies and aspects of undergraduate nurse curriculum making.

PMID- 10335196
TI  - Integrating information literacies into an undergraduate nursing programme.
AB  - The development of support for a more research-based approach to care has created
      the imperative for nursing education to tackle the issue of information literacy.
      Information literacy means the ability to locate, evaluate and apply information
      in critical thinking and problem solving. This paper outlines and provides a
      rationale for a curriculum-integrated information literacy programme, implemented
      in the pre-registration Bachelor of Nursing course at the University of
      Wollongong, NSW, Australia. It also describes a multidimensional evaluation
      process for determining nursing students' growth in cognitive and affective
      domains. Results of the programme evaluation will be featured in a future paper.

PMID- 10335197
TI  - Discontinuation, leaving reasons and course evaluation comments of students on
      the common foundation programme.
AB  - There is considerable financial incentive, at all levels, to reduce student nurse
      wastage and maintain recruitment to a workforce of professional nurses. This
      strategy is being pursued in a period following major educational change, when
      the attrition levels and leaving reasons of students need to be reassessed.
      Previous reports have identified a high voluntary loss of students on the common
      foundation programme (CFP) of the pre-registration nursing course. In order to
      achieve a better understanding of the basic problems faced by student nurses who
      consider leaving the CFP, questionnaires were distributed to three groups of
      students: current CFP students; students who had completed the CFP; and students
      who had discontinued training. The questionnaire responses show that course-based
      problems, identified as prime leaving reasons by the current and completed
      student groups, differ from the actual leaving reasons of discontinued students
      obtained by exit questionnaire. The attitudes of participating and discontinued
      students to theory, clinical and pastoral components of the CFP are not
      dissimilar. Some trends in attrition rate relate significantly to student
      category. Our results have implications for the management of student nurse
      attrition.

PMID- 10335198
TI  - Present tense commentary: a qualitative research technique.
AB  - This paper describes Present Tense Commentary (PTC) as a technique to gather rich
      data which satisfies the requirements of a hermeneutic phenomenological approach
      to research. Using PTC, the informant is encouraged to relieve significant events
      by conveying them to the researcher as if they are happening now. This process
      demands greater cognitive ability, greater exposure to the event and more
      thorough grammatical correctness than in a standard interview situation. The
      reward, however, is insight for the informant and the researcher into the meaning
      and understanding, otherwise concealed within the experience. PTC was used as the
      third phase of data collection in a study involving eight student nurses
      undertaking the Diploma in Higher Education, Nursing Studies Course (Project
      2000). The intention of the study is to illuminate the student's development and
      their socialization into nursing and to portray the total learning milieu for the
      students as they describe it. The technique has enabled the students to record
      experiences in clinical practice, reflect upon them and identify their own
      development during the course. PTC contrasts with traditional interview methods
      because it empowers the informant and addresses their agenda and not the
      researcher's. This paper gives a brief rationale for selecting PTC and describes
      the process of preparing informants and conducting the technique. The paper
      focuses upon issues related to philosophical and ethical considerations and
      recommends that the technique is recognized as a valuable phenomenological tool.

PMID- 10335199
TI  - Controversial issues: a case for neutrality?
AB  - Controversial issues are defined, in this discussion, as those in relation to
      which contrary views can be held without those views being contrary to reason.
      Such issues arise in the range of courses constituting nurse education,
      especially, but not exclusively, where ethical questions are discussed. The nurse
      educator may, therefore, have to decide whether or not to say what she thinks, in
      particular she may have to decide whether or not to assert her own view as
      correct. Where professional beliefs and values are involved, to assert a view as
      correct may seem to be required. Might this, though, detract from the aim of
      developing students' capacity for autonomous reflection? The discussion assesses
      whether neutrality, in the sense either of not stating one's view or not
      asserting it as correct, is desirable, by examining arguments both for and
      against, and highlights ways in which a neutral stance both is, and is not, an
      option.

PMID- 10335200
TI  - Contracting for nurse education: nurse leader experiences and future visions.
AB  - The integration of nurse education into higher education establishments following
      Working for Patients, Working Paper 10 (DOH 1989a) has seen changes to the
      funding and delivery of nurse education. The introduction of contracting for
      education initiated a business culture which subsumed previous relationships,
      affecting collaborative partnerships and shared understanding. Discourse between
      the providers and purchasers of nurse education is vital to achieve proactive
      curriculum planning, which supports the development of nursing practitioners who
      are fit for award and fit for purpose. Research employed philosophical
      hermeneutics to guide the interviewing of seven nurse leaders within one region.
      Data analysis occurred within a hermeneutic circle and was refined using NUDIST.
      Two key themes were seen as impacting on the development of an effective
      educational strategy. Firstly, the development of collaborative working was
      thought to have been impeded by communication difficulties between the Trusts and
      higher education provider. Secondly, there was concern that curriculum
      developments would support the future evolution of nursing, acknowledging the
      professional issues impacting on nursing roles. The research findings suggest
      purchasers and providers of nurse education must move towards achieving mutual
      understanding and collaborate in developing a curriculum which will prepare
      nurses for practice and for award.

PMID- 10335201
TI  - Assessing the effectiveness of an online program.

PMID- 10335202
TI  - Bringing nursing theory to life: the poster presentation.

PMID- 10335203
TI  - The journey.

PMID- 10335204
TI  - From expert to novice: doctorally prepared nursing faculty retooling for the
      future.

PMID- 10335205
TI  - Transcultural nursing experience in the Philippines.

PMID- 10335206
TI  - A unique strategy for pediatric community health nursing for ADN students.
AB  - Students were overwhelmingly positive when given the opportunity to evaluate the
      pilot project and the model of pediatric community health nursing. According to
      the students, the strong points of the model were the orientation before the
      community experience, the presence of faculty of the community, the ability to
      contact faculty when needed, and the postclinical conference. The students'
      comments confirmed the faculty's belief that a clinical experience in community
      health nursing must place more emphasis on the specialty of community health
      nursing to be meaningful for students. To do the of job of educating tomorrow's
      nurses, ADN faculty should develop new strategies for teaching the pediatric
      clinical component of community health nursing. Clearly, hospitals are no longer
      the exclusive sites where students learn about patient and family needs and
      nursing care delivery. Community-based and community-focused experiences will
      continue to be required so that nursing students are prepared to practice in a
      dynamic and changing healthcare environment.

PMID- 10335207
TI  - Using CD-ROM technology to enhance clinical nursing education.

PMID- 10335208
TI  - An innovative education strategy in a migrant farm community.

PMID- 10335209
TI  - Introduction to nursing. Creative strategies for generating interest in the
      major.
AB  - Beginning nursing students have a limited understanding of nursing as a major and
      a profession. Evaluation of previous Introduction to Nursing courses led faculty
      to a redesign which included classroom exercises and assignments that actively
      engage students in a wider variety of experiences. Increased student involvement
      had the effect of presenting a more realistic picture of nursing as a profession.

PMID- 10335210
TI  - Assessing students' perceived threats to safety in the community: instrument
      refinement.
AB  - The shift to community-based practice presents challenges to traditional nursing
      education. One such challenge is that of student safety. The authors discuss the
      continuing efforts to develop an instrument to assess student perceptions of
      threats in the community as well the findings of a pilot study. Analysis of the
      data indicates that the Environmental Comfort Scale III is valid, reliable, and
      easy to administer and interpret.

PMID- 10335211
TI  - The integration of problem-based learning strategies in distance education.
AB  - The authors explore the redesign of a traditional distance nursing program to
      integrate problem-based learning (PBL) strategies. Using pre- and postcourse
      questionnaires, learning satisfaction was compared between students who attended
      the PBL course face-to-face and those who received the course via audio
      teleconferencing. Tutor and student perceptions of PBL via audio-teleconferencing
      are also described. Study results suggest that audio-teleconferencing is an
      effective means of delivering PBL by distance education.

PMID- 10335212
TI  - The serendipity of faculty practice: strategies for success.
AB  - The contemporary social issues impacting healthcare coupled with the increasing
      demands for academic units to generate income have contributed to the emergence
      of faculty practice as an integral component of the nurse educator's role. As a
      result, faculty are encouraged increasingly to assume entrepreneurial joint
      appointments with the service industry. For nurse educators who engage in faculty
      practice, serendipity occurs when they immerse themselves in situations and
      emerge from the experience making unexpected discoveries. The author shares
      practical recommendations and strategies resulting from a successful 9-month
      faculty practice.

PMID- 10335213
TI  - Using technology-based assignments to promote critical thinking.
AB  - The authors describe the use of technology-based active and collaborative
      learning assignments to promote critical thinking. Although the innovative
      assignments are part of a nursing transition course required for returning
      registered nurses, they have the potential for use in traditional generic nursing
      programs as well. The assignments are aimed at developing skill in collaboration,
      promoting creativity in solving problems, and actively engaging students in their
      learning.

PMID- 10335214
TI  - Mentoring new faculty.
AB  - This is a report of the process and evaluation of 12 years of mentoring new
      faculty in a university nursing faculty of 48 members. Each new faculty member is
      paired with an experienced faculty member who serves as a mentor for a year.
      Evaluations completed by both new faculty and mentors at the end of the year are
      positive.

PMID- 10335215
TI  - Back to basics.

PMID- 10335216
TI  - Can advanced practice nurses succeed in the primary care market?
AB  - In the mid-1980s the Columbia University School of Nursing (CUSN) reconfigured
      its mission to once again become the premier training ground for clinical experts
      in nursing. Its APN faculty members were expected to function as APN primary care
      providers in some of its affiliated clinics. Extensive studies at CUSN have
      validated the high quality and effectiveness of comprehensive APN-managed patient
      care when compared to a randomly selected group of patients managed by primary
      care MDs. The issue of APN-MD primary practice fee equity for professional
      services at Columbia Presbyterian Medical Center was settled by agreement to the
      same reimbursement per visit, while acknowledging that APNs would customarily
      have longer contact time with each patient, and therefore a lower number of
      visits per day. The studies concluded that the ideal configuration of
      professional health care services would see APNs with hospital admitting
      priviledges alongside primary care and specialty MDs working collectively to
      serve their patients together in the new system.

PMID- 10335217
TI  - Corporate compliance: critical to organizational success.
AB  - Operation Restore Trust (ORT) has focused increased governmental attention on
      health care fraud and abuse activities, making it more costly to be noncompliant,
      and thus has led to significant behavioral changes within the health care
      industry. Initially five states (California, Florida, Illinois, New York, &
      Texas) were included in the 1997 ORT pilot program. This has been expanded to
      include Arizona, Colorado, Georgia, Louisiana, Massachusetts, Missouri, New
      Jersey, Ohio, Pennsylvania, Tennessee, Virginia, and Washington. The author
      presents a road map for developing of a compliance program that includes
      suggested strategies for staff training in anticipation of heightened scrutiny of
      compliance standards and procedures. Effective Corporate Compliance Programs
      (CCPs) should include policies and procedures and monitoring systems that can
      provide reasonable assurance that fraud, abuse, and systematic billing errors are
      detected in a timely manner.

PMID- 10335218
TI  - Cost analysis of a nursing center for the homeless.
AB  - Single women and children now make up a third of the vulnerable U.S. homeless
      population who tend to seek health care only when their symptoms can no longer be
      ignored. The school of nursing at SUNY was one of the programs funded by HHS
      Division of Nursing to develop and implement a nursing center that would provide
      primary health services to the homeless. The cost of providing nursing services
      to homeless clients in nurse-managed centers was compared to costs for
      alternatives in the community including emergency department visits or care at
      the county supported nurse-run outpatient clinics. The four sites that served the
      homeless donated space for the SUNY project nurses to see patients. This enhanced
      accessibility, earlier intervention in health care problems, and decreased client
      cost (and time) for transportation to other service providers. The potential for
      earlier and less costly interventions confirmed the value of this humanistic
      nurse-run service for the homeless.

PMID- 10335219
TI  - The evolution of a hospital-based decentralized case management model.
AB  - The authors present a case study of a highly integrated case management program
      and the redefinition of the clinical practice model that evolved across the
      continuum of care as the integration process was achieved. The central leadership
      role of the clinical care coordinator (an advanced staff nurse role) as the front
      line link between the case manager and the staff nurses was seen as one key in
      the model's success. Success was further enhanced by: development of objective
      based versus time-oriented pathways; involvement of home health earlier,
      especially in the more complex discharge plans; and a refocus of the patient
      education process. Future initiatives include refocusing the patient education
      component as part of a "Steps to Recovery" approach that includes appropriate
      aspects of the objective-based clinical pathways and expanding the number of case
      management models to include currently underrepresented patient populations.

PMID- 10335220
TI  - A comparison of leadership vs. renovation in changing staff values.
AB  - The authors compared the effects of the staff's perceptions of the culture in a
      LTC facility pre and post-intervention(s). One unit had significant architectural
      modification (physical intervention). On the second unit, efforts were directed
      toward culture change through management modification (social intervention
      through goal setting and role modeling). Lastly, both were compared to a third
      control unit where there was no planned change. On the unit with the social
      intervention model there was an attempt to support a "neighborhood" sense for
      residents and staff that would encourage residents to become more self-directed
      and self-sufficient rather than remain in the passive "good patient" role.
      Significant staff training resources and time were devoted to this effort. On the
      second unit, the architectural renovation sought to provide a distinctly home
      like open, and relaxed atmosphere with a large, well-equipped day room. This
      encouraged closer resident and staff interactions and included a staff
      workstation that was part of the day room. On a third control unit, no changes
      were made.

PMID- 10335221
TI  - Financing strategies for a community nursing center.

PMID- 10335222
TI  - Managing data security: developing a plan to protect patient data.

PMID- 10335223
TI  - The tobacco settlement and 1999 forecasts.

PMID- 10335224
TI  - New methodology for analyzing fluctuating unit activity.

PMID- 10335225
TI  - Business etiquette.
AB  - As health care executives we must respect our business contacts whether at a
      meeting, a meal, or on the phone. Good etiquette can prove to be good business
      and yield the results desired.

PMID- 10335226
TI  - Creating the forgetting organization.

PMID- 10335227
TI  - Make do and mend ingenuity.

PMID- 10335228
TI  - In the hot seat. Interview by Graham Scott.

PMID- 10335229
TI  - Power to the nurses.

PMID- 10335230
TI  - Aromatherapy in practice.

PMID- 10335231
TI  - The hidden survivors.

PMID- 10335233
TI  - Treating the untreatable.

PMID- 10335232
TI  - Recognising nurses' potential and appreciating the value of nursing.

PMID- 10335234
TI  - Fondness for those good ol' days.

PMID- 10335235
TI  - Taking the right precautions.

PMID- 10335236
TI  - Reaching out to carers.

PMID- 10335237
TI  - Evaluation of multidisciplinary notes.
AB  - The introduction of multidisciplinary notes can provide benefits to staff and
      patients alike. In this report, Angela Clegg and Carolyn Meston outline their
      experiences at the Bradford Community NHS Trust.

PMID- 10335238
TI  - The essence of nursing. Part II.

PMID- 10335239
TI  - Nurses and nurse practitioners. 1: Priorities in care.
AB  - Some people perceive nurse practitioners (NPs) as 'mini doctors' concerned more
      with the biomedical and technical aspects of health care than with the holistic,
      psychosocial elements. In the first of two articles, these assertions are tested.
      The views of a group of nurse practitioner graduates and undergraduates are
      compared with the views of a group of other nurses taking continuing education
      courses. The results may surprise you.

PMID- 10335240
TI  - The importance of sleep.
AB  - Sleep is a complex function which nurses need to understand if they are to help
      patients to avoid sleep problems, in short- or long-term care settings. This
      article sets out the background anatomy and physiology behind sleep and the
      nurse's role in promoting sleep. It also explains the importance of nurses
      understanding sleep and sleeplessness in the broader context of health care.

PMID- 10335242
TI  - Managing your nursing career.

PMID- 10335243
TI  - Opportunities for E grade nurses. Interview by Frances Pickersgill.

PMID- 10335241
TI  - Antipsychotic drug treatment.
AB  - This article discusses the clinical use, action and effectiveness of
      antipsychotics and methods of improving compliance with treatment regimes.

PMID- 10335244
TI  - Nurses in the new biogenetics millennium?

PMID- 10335245
TI  - Reliability of three length measurement techniques in term infants.
AB  - PURPOSE: To describe and compare the intra- and interexaminer reliability of
      three length measurement techniques and to determine if the three measurement
      techniques yield significantly different measurements. METHOD: Two experienced,
      mother-baby nurses each obtained length measurements using the supine, paper
      barrier, and Auto-length measurement techniques twice each from 48 healthy term
      infants. The nurses were blind to their own and to each other's measurements. The
      order of the nurses and the order of the measurement techniques were randomized.
      RESULTS: For intraexaminer reliability, RN-1 had smaller mean absolute
      differences for the Auto-length measurements. RN-2 had similar mean absolute
      differences for all three measurement techniques. The percentage of differences <
      or = 1 cm were smallest for the supine measurements for RN-1 and not remarkably
      different between the measurement techniques for RN-2. For interexaminer
      reliability, the mean absolute differences between the pairs of measurements were
      smallest for the Auto-length measurements for Set-1 and for the paper-barrier
      measurements for Set-2. The percentage of differences < or = 1 cm between the
      pairs of measurements for Set-1 were not remarkably different and were lowest for
      the supine measurements for Set-2. The mean measurements obtained by the supine,
      paper-barrier, and the Auto-length measurements were respectively: 50.88, 50.33,
      and 49.67 cm. The differences between the means were statistically significant
      (X2 = 56.56, p = .0000). CONCLUSIONS: The differences between length measurements
      by individual examiners and pairs of examiners are relatively large. Clinicians
      should be aware of the magnitude of error in length measurements and should
      interpret length measurements with caution. These findings also demonstrate that
      all clinicians in any setting should use the same technique to obtain length
      measurements.

PMID- 10335246
TI  - Weight change of infants, age birth to 12 months, born to abused women.
AB  - Abuse to pregnant women can affect maternal health and infant birthweight. To
      examine the rate of weight change among infants, ages birth to 12 months, born to
      women abused by the male intimate, an ethnically stratified cohort of 121 infants
      and their mothers were followed. Infants were weighed on a beam balance scale at
      birth, 6, and 12 months of age. At the same time, abused mothers were asked if
      the abuse had ended. Rate of change in infant weight was calculated for birth to
      6 months and 6 months to 1 year. The rate of change in infant weight from birth
      to 6 months did not differ significantly based on whether or not the mother
      reported that the abuse had ended by 6 months or 12 months. However, the rate of
      change in infant weight from 6 to 12 months was significantly greater (p = .046)
      for those infants whose mothers reported the abuse had ended by 12 months and
      even greater (p = .019) if the mother reported that the abuse had ended by 6
      months. When controlling for ethnicity and parity, abuse ending at 6 months was a
      significant (p = .029, r2 = .102) predictor of the rate of infant weight change
      from 6 to 12 months. To maximize infant growth and the health and wellbeing of
      mother and child, routine screening and intervention for abuse of women is
      recommended during child health visits.

PMID- 10335247
TI  - Neonatal drug exposure: assessing a specific population and services provided by
      visiting nurses.
AB  - Historically, community health nurses have provided nursing services to infants
      who were exposed to licit and illicit drugs in utero and their mothers. The
      charts of 145 infants whose mothers had a history of drug and alcohol abuse and
      who were referred to a visiting nurse agency between 1988 and 1994 were reviewed
      for this study. Of the infants who were reported to have been exposed to drugs in
      utero, 69% were exposed to cocaine, 11% to heroin, and 6% to marijuana. The
      average age of the mothers was 26 years; 83.4% were single; 82.1% received Aid
      for Families of Dependent Children (AFDC); 92.4% were on Medicaid; and 95.9% were
      involved with child protective services. The most frequent nursing problems
      identified were (a) maternal-child attachment, (b) sleep patterns, (c) infant
      feeding, and (d) infant development. Nursing interventions included nutritional
      management, physical assessment, monitoring growth and development, and education
      in parenting skills. Fifty percent of the infants increased their weight by at
      least one percentile and 31% increased two percentiles. Resolution of nursing
      problems occurred in 50% of the cases.

PMID- 10335248
TI  - Accuracy of tympanic temperature readings in children under 6 years of age.
AB  - PURPOSE: Infrared tympanic thermometry (ITT) is increasingly used as a
      convenient, noninvasive assessment method for febrile children. However, the
      accuracy of ITT for children has been questioned, particularly in relation to
      specificity and sensitivity. This study was designed to (a) determine the
      correlation and extent of agreement between rectal temperature (RT) readings
      obtained by electronic thermometer and ear-based temperature readings obtained by
      ITT, and (b) determine the accuracy of detecting fever in children under 6 years
      of age. METHODS: This correlational study used a sample of 241 paired ear and
      rectal temperatures obtained in the emergency department (ED) of a 920-bed
      regional hospital. All children under the age of 6 years who routinely received a
      rectal temperature measurement were eligible to participate. According to the ED
      protocol, rectal temperatures were obtained on all patients less than 3 years or
      patients 3-6 years that presented with a complaint of fever. For the study,
      tympanic measurements were also taken. RESULTS: Correlation between rectal and
      tympanic temperature readings was statistically significant (r = 0.84, p < .001).
      The mean difference between rectal and tympanic temperatures was -0.60 degrees C.
      Threshold-adjusted accuracy in screening for fever was determined by sensitivity
      (80%), specificity (85%), positive predictive value (87%), and negative
      predictive value (85%). CONCLUSIONS: Sensitivity, specificity, positive
      predictive value, and negative predictive value are unacceptably low and the
      number of children with fever who would be missed by screening with a tympanic
      thermometer is unacceptable. Findings of this study do not support the use of
      tympanic thermometers to detect fever in children under 6 years of age.

PMID- 10335249
TI  - School-age child and adolescent perception of the pain intensity associated with
      three word descriptors.
AB  - This study examined children's and adolescents' perceptions of the descriptors
      hurt, ache, and pain. Nonhospitalized subjects (N = 198) between 8 and 19 years
      of age from three schools rated the levels of intensity associated with each of
      the descriptors on a word-graphic rating scale and matched each to one of three
      drawings depicting painful experiences. Subjects ranked pain highest; hurt
      middle; and ache lowest intensity. Significant preferences for matching
      descriptors to painful experiences was not demonstrated except for the word ache.
      These findings indicate that children and adolescents associate similar levels of
      intensity with pain, hurt, and ache but associate different experiences with
      each.

PMID- 10335250
TI  - Promoting family-centered care with foster families.
AB  - There has been a tremendous increase in the need for foster families since the
      1980s largely because of the effects of drug abuse on the child and the
      biological family. As many as 500,000 children are currently living with foster
      families. Many children living with foster families were exposed to drugs before
      birth. Even those not exposed before birth demonstrate the effects of having
      lived with drug-abusing family members. Family life for these children is very
      often chaotic and unpredictable. There are increased health care needs for foster
      children due to drug-exposure and neglect. Yet, research suggests that the health
      care needs of foster children are often neglected. Foster families report that
      their concerns and needs are, frequently, neither recognized nor addressed by
      health professionals. Pediatric nurses can improve health care by increasing
      their awareness of the special needs of foster families and foster children.

PMID- 10335251
TI  - Genetic testing of children: an issue of ethical and legal concern.

PMID- 10335253
TI  - The adolescent gynecologic exam.
AB  - The first gynecologic exam for adolescents can be a positive experience in which
      they learn about their own body, or it can be a traumatic event. For the
      practitioner who may not do frequent gynecologic exams it can also be anxiety
      producing. The exam begins with a complete patient history including menstrual
      history, sexual history, and contraceptive history. The physical exam includes
      examination of thyroid, heart, lungs, breasts, abdomen, and genitalia. The
      nurse's approach can provide the tools the adolescent needs to make it a positive
      experience.

PMID- 10335252
TI  - Commentary on genetic testing of children: maintaining an open future.
AB  - Pediatric nurses have the opportunity to facilitate genetic testing decisions
      made by parents on behalf og their children. When facilitating and evaluating the
      genetic testing decision, the pediatric nurse should consider whether the
      decision is in the best interest of the child and protects the child's right to
      an open future. Pediatric nurses should take advantage of the various formal and
      informal educational genetic and ethics resources available.

PMID- 10335254
TI  - Asthma clinical pathway: an interdisciplinary approach to implementation in the
      inpatient setting.
AB  - Asthma is a leading cause of admission to the pediatric inpatient setting.
      Despite advances in the treatment of this chronic condition, morbidity and
      mortality continue to increase. It is also a source of significant variation in
      clinical practice and redundancy of care elements across various disciplines
      involved in the management of patients with asthma. A clinical pathway was
      developed and implemented by a multidisciplinary team at The Children's Hospital
      of Philadelphia. The unique approach used to strategize implementation combined
      the expertise of registered nurses, respiratory therapists, medical staff, and
      case managers and was a significant factor in the pathway's ultimate success. The
      result was a more standardized and efficient approach to care. Outcome
      measurements revealed decreased length of stay with no increase in the re
      admission rate and cost savings.

PMID- 10335256
TI  - Bibliotherapy: using fiction to help children in two populations discuss
      feelings.
AB  - PURPOSE: To identify whether bibliotherapy will help children with short stature
      and diabetes discuss their feelings and to explore themes that may help children
      cope with short stature and diabetes. METHOD: Twenty-seven children, referred to
      a pediatric endocrinologist, aged 7-16 years, participated in interviews after
      reading a work of fiction. A semi-structured interview guide was used in both
      groups to elicit feelings about the work of fiction, feelings of self-esteem, and
      attitudes toward the condition. FINDINGS: Children freely discussed their
      feelings about school experiences and condition-related issues. Several themes
      emerged from data analysis including the child's development of compensatory
      attributes, responses to teasing, and management of diabetes. CONCLUSION: This
      study confirmed that bibliotherapy is an effective nursing intervention in
      children with short stature and diabetes. Bibliotherapy can be used by nurses to
      facilitate open discussion between nurses, children, and families.

PMID- 10335255
TI  - Cleaner air and lungs may be in store for our children's future.

PMID- 10335257
TI  - Building a case for evidence-based practice: inhalers vs. nebulizers.

PMID- 10335258
TI  - Pediatric management problems: sinusitis.

PMID- 10335259
TI  - Monicagate and male bashing.

PMID- 10335260
TI  - Rage and women's sexuality after childhood sexual abuse: a phenomenological
      study.
AB  - TOPIC: One common long-term effect of childhood sexual abuse is rage. This
      phenomenological study deals with such rage as it is expressed through women's
      sexuality. METHODS: A guided interview method (N = 7). The constant comparative
      method was used for data analysis. FINDINGS: Results provide information about
      ways rage and maladaptive behaviors are learned in childhood and carry over into
      adult relationships. CONCLUSIONS: Healthcare professionals need to be sensitive
      to the sometimes devastating effects of sexual abuse on women in our society.
      There is a need to create treatment programs that empower survivors to avoid
      revictimization.

PMID- 10335261
TI  - The psychotherapeutic needs of women who have been sexually assaulted.
AB  - PROBLEM: Despite the significant emotional repercussions of sexual assault, women
      survivors often avoid formal mental health treatment. Little is known about why
      survivors are reluctant to use professional services to facilitate recovery.
      METHODS: A descriptive study used content analysis to describe the therapy
      experiences and self-perceived psychotherapeutic needs of 33 women who survived
      sexual assault by male intimates. FINDINGS: With regard to professional services,
      the participants were most concerned about the quality of the therapeutic
      relationship and advised clinicians to appreciate the strengths and resources
      women bring to their own recovery. The participants' specific psychotherapeutic
      needs were influenced by the pervasiveness of the violence in their lives.
      CONCLUSIONS: Clinicians should not focus exclusively on the amelioration of
      symptoms but should provide support, validation, and empowerment for sexual
      assault survivors who seek treatment.

PMID- 10335262
TI  - A qualitative study of factors influencing psychiatric nursing practice in
      Australian prisons.
AB  - TOPIC: Factors influencing the practice of psychiatric nursing in Australian
      prisons. METHODS: A qualitative study of psychiatric nurses (N = 30) working in a
      prison. FINDINGS: The psychiatric nurses identified the following factors as
      influencing their work: challenging patients, threats to personal survival of
      patients, the technology and artifice of confinement, conflicting values of
      nurses and corrections staff, stigma by association, and prisoner identification
      of the nurses with prison administration. CONCLUSIONS: Psychiatric nurses who
      work in forensic settings must adapt to less than optimal practice conditions.

PMID- 10335263
TI  - Synthesis, DNA-cleaving properties and cytotoxicity of intercalating chelidamic
      acid derivatives.
AB  - We have explored the potential antitumour activity of DNA-intercalating free
      radical generators based on compounds constructed from 9-anilinoacridine and
      chelidamic acid as an iron (II) binding centre. Here we describe their synthesis,
      DNA cleaving ability and activity against a panel of human tumour cell lines in
      culture. We also investigate their potential for use as DNA footprinting agents.
      Previous work has shown that the parent compound, FTP1, cleaves DNA in an
      essentially sequence neutral fashion and has modest cytotoxicity [Searcey, M.,
      McClean, S., Madden, B. & Wakelin, L.P.G. (1997) Journal of the Chemical Society.
      Perkin Transactions, 2, 523]. Here we have equipped the acridine chromophore with
      an N,N-dimethylaminoethyl-4-carboxamide substituent, giving the threading agent
      FTP2, which confers selectivity for cleaving in GC-rich sequences, avoidance for
      binding to AT-tracts and 8-fold enhanced cytotoxicity compared with FTP1.
      Although this side chain bestows slow dissociation kinetics on DNA complexes of 9
      anilinoacridines, it does not enhance the overall cutting efficiency of FTP2,
      implying that free-radical generation, DNA hydrogen abstraction and sugar
      fragmentation are fast compared with DNA-ligand complex lifetimes. FTP2 does not
      appear to be susceptible to resistance by the mdr phenotype in human ovarian
      carcinoma cells. We also report that FTP2 is an effective footprinting agent for
      GC-selective binding ligands and that it has some advantages over FTP1 in this
      regard.

PMID- 10335264
TI  - DNA minor groove targeted alkylating agents based on bisbenzimidazole carriers:
      synthesis, cytotoxicity and sequence-specificity of DNA alkylation.
AB  - A series of bisbenzimidazoles bearing a variety of alkylating agents [ortho- and
      meta-mustards, imidazolebis(hydroxymethyl), imidazolebis(methylcarbamate) and
      pyrrolebis(hydroxymethyl)], appended by a propyl linker chain, were prepared and
      investigated for sequence-specificity of DNA alkylation and their cytotoxicity.
      Previous work has shown that, for para-aniline mustards, a propyl linker is
      optimal for cytotoxicity. Alkaline cleavage assays using a variety of different
      labelled oligonucleotides showed that the preferred sequences for adenine
      alkylation were 5'-TTTANANAANN and 5'-ATTANANAANN (underlined bases show the drug
      alkylation sites), with AT-rich sequences required on both the 5' and 3' sides of
      the alkylated adenine. The different aniline mustards showed little variation in
      alkylation pattern and similar efficiencies of DNA cross-link formation despite
      the changes in orientation and positioning of the mustard, suggesting that the
      propyl linker has some flexibility. The imidazole- and pyrrolebis(hydroxymethyl)
      alkylators showed no DNA strand cleavage following base treatment, indicating
      that no guanine or adenine N3 or N7 adducts were formed. Using the PCR-based
      polymerase stop assay, these alkylators showed PCR blocks at 5'-C*G sites (the *
      nucleotide indicates the blocked site), particularly at 5'-TAC*GA 5'-AGC*GGA, and
      5'-AGCC*GGT sequences, caused by guanine 2-NH2 lesions on the opposite strand.
      Only the (more reactive) imidazolebis(methylcarbamoyl) and
      pyrrolebis(hydroxymethyl) alkylators demonstrated interstrand cross-linking
      ability. All of the bifunctional mustards showed large (approximately 100-fold)
      increases in cytotoxicity over chlorambucil, with the corresponding
      monofunctional mustards being 20- to 60-fold less cytotoxic. These results
      suggest that in the mustards the propyl linker provides sufficient flexibility to
      achieve delivery of the alkylator to favoured (adenine N3) sites in the minor
      groove, regardless of its exact geometry with respect to the bisbenzimidazole
      carrier. The 'targeted' bisbenzimidazole bis(hydroxymethyl)pyrrole- and imidazole
      analogues showed very similar patterns of alkylation to the corresponding
      'untargeted' compounds, with little evidence of additional selectivity imposed by
      this AT-preferring carrier.

PMID- 10335265
TI  - Synthesis of flavone-2'-carboxylic acid analogues as potential antitumor agents.
AB  - Some flavone-2'-carboxylic acid analogues are described. Direct in vitro toxicity
      of the synthesized compounds was evaluated towards four tumoral cell lines, and
      the ability of these compounds to stimulate mouse peritoneal macrophages in
      culture to become tumoricidal (indirect toxicity) was also studied. Direct
      cytotoxic activity was very low for all derivatives. However, almost all
      compounds showed a remarkable increase of indirect cytotoxicity. In particular,
      compound 3i, which has an F atom in the 7 position of the flavone ring, was able
      to increase significantly the macrophage's lytic properties, and has been
      selected for further investigations.

PMID- 10335266
TI  - Synthesis and antiproliferative properties of 4-aminoquinazoline derivatives as
      inhibitors of EGF receptor-associated tyrosine kinase activity.
AB  - The mitogenic action of EGF is mediated by ligand-induced autophosphorylation of
      the EGF receptor (EGF-R), which is commonly overexpressed in numerous human
      cancers. Inhibitors of receptor tyrosine kinase (RTK) activity could therefore be
      considered as effective potential antitumor agents. For this purpose, 4
      aminoquinazoline derivatives were prepared and evaluated for their ability to
      inhibit RTK activity and the autophosphorylation of EGF-R. In addition, these
      compounds were tested on A431 cell growth to estimate their antiproliferative
      effect. The results showed that the substituent at the 4-position of the
      quinazoline ring must be an aromatic amine carrying small lipophilic electron
      withdrawing groups on the 3- (or 2-) position of the phenyl ring. This aromatic
      moiety might be far from the quinazoline provided that the linking group is
      conformationally restricted, such as with piperazine. Hydrophilic and non
      aromatic substituents such as morpholine gave completely inactive compounds.
      Introduction of a bulk at the 2-position of the quinazoline ring in 2,4
      diaminoquinazolines or tricyclic compounds led to inactive products. This study
      reports additional structure-activity relationships of a well-characterized
      series to develop new inhibitors of EGF-R-associated tyrosine kinase activity.

PMID- 10335267
TI  - The role of structural factors of anthraquinone compounds and their quinone
      modified analogues in NADH dehydrogenase-catalysed oxygen radical formation.
AB  - Anthraquinone compounds belong to the most important class of clinical antitumour
      agents. However, their use is limited by their peroxidating activity, being the
      consequence of free radical formation initiated by three oxyreductases. This
      activity is considered to be the main cause of cardiotoxic effects. The affinity
      of anthraquinone compounds to these enzymes is an essential factor governing the
      rate of one-electron transfer and the generation of oxygen radicals. A series of
      novel derivatives and analogues of natural and synthetic anthraquinones has been
      examined with the aim of identifying the structural factors essential for the
      ability to stimulate oxygen radical formation catalysed by NADH dehydrogenase.
      Functional groups and moieties favouring or disfavouring the interaction of the
      compounds with the enzyme have been determined. The quinonoid moiety as well as
      at least two phenolic groups in peri positions favoured the affinity of these
      compounds for NADH dehydrogenase. The modification of the quinonoid structure to
      iminoquinonoid or carboquinonoid forms dramatically decreased interaction with
      the enzyme. The O'-substitution by a bulky group in the sugar moiety of
      daunorubicin decreased the ability of the derivatives to stimulate oxygen radical
      formation. It has also been shown that the presence of an ionizable amino group
      on the sugar moiety of daunorubicin favours interaction with the NADH
      dehydrogenase. However, its location is not essential for this effect.

PMID- 10335268
TI  - Binding of polybenzamides to DNA: studies by DNase I and chlorambucil
      interference footprinting and comparison with Hoechst 33258.
AB  - The DNA sequence-specific binding ability of polybenzamide minor groove binding
      ligands was investigated. These ligands were compared with the known minor groove
      binder Hoechst 33258, using both DNase I footprinting and chlorambucil
      interference footprinting. The monocationic derivative showed some sequence
      specific binding to A/T-rich sequences, as shown by DNase I footprinting, but
      results for the biscationic polybenzamide were inconclusive. A general non
      specific inhibition of cleavage at high drug concentrations was observed,
      suggesting these compounds had a low DNA binding affinity compared to Hoechst
      33258. Using a complementary technique, chlorambucil interference footprinting,
      the biscationic derivative displayed a clear preference for sites containing at
      least three consecutive adenines and in contrast with the monocationic analogue,
      a lesser affinity for mixed A/T sequences.

PMID- 10335269
TI  - Doxorubicin prodrugs with reduced cytotoxicity suited for tumour-specific
      activation.
AB  - The three new hydrophilic prodrugs 2, 3 and 4 have been prepared from methyl (4
      hydroxymethyl-2-nitrophenyl 2,3,4-tri-O-acetyl-beta-D-glucopyranosid)uronate (5)
      and doxorubicin. Their low cytotoxicity, efficient release of doxorubicin after
      hydrolysis by beta-D-glucuronidase, and in the cases of 2 and 3 stability at pH
      7.2 fulfil the preliminary requirement for their use in antibody-directed enzyme
      prodrug therapy or prodrug monotherapy.

PMID- 10335270
TI  - Synthesis and antiproliferative activity of some N-sulphonated-2-substituted
      benzimidazoles and imidazo[4,5-b]pyridines.
AB  - Some N-sulphonated-2-substituted benzimidazoles and imidazo[4,5-b]-pyridines were
      synthesized and tested in vitro for antiviral and antiproliferative activity.
      None of the compounds had antiviral properties. However, three of them inhibited
      the proliferation of leukaemia and lymphoma cell lines at micromolar
      concentrations. The maximum potency of antiproliferative activity is correlated
      with the presence of an ethylenic spacer between the two heterocycles.

PMID- 10335271
TI  - Antineoplastic agents 393. Synthesis of the trans-isomer of combretastatin A-4
      prodrug.
AB  - The (E)-stilbene isomer (2a) of the (Z)-combretastatin A-4 prodrug (1b) was
      efficiently prepared from (E)-combretastatin A-4 by a reaction sequence employing
      phosphorylation (dibenzyl chlorophosphite), cleavage (trimethyliodosilane) of the
      benzyl ester and reaction of the resulting phosphoric acid with sodium methoxide.
      The sodium phosphate product (2c) was also found to be an important side-product,
      presumably from iodine-catalyzed isomerization, when the analogous synthetic
      route was used to obtain the combretastatin A-4 prodrug (1b). The phosphoric acid
      precursor of prodrug 1b derived from (Z)-combretastatin A-4 (1a) was converted
      into a series of metal cation and ammonium cation salts to evaluate effects on
      human cancer cell growth, antimicrobial activities and solubility behavior.

PMID- 10335272
TI  - Synthesis of self-immolative glucuronide-based prodrugs of a phenol mustard.
AB  - The design and synthesis of the mustard pro-prodrugs which can be used in ADEPT
      is reported. Prodrugs 1 and 2 include a glucuronide group which is connected to
      the drug via an aromatic and/or aliphatic bis-carbamate spacer. The design of
      these new prodrugs takes advantage of a spontaneous 1,6-elimination and/or an
      intramolecular cyclization reaction after enzymatic cleavage. Thus, enzymatic
      catalyzed hydrolysis of the glucuronyl moiety of 1 by Escherichia coli beta
      glucuronidase results in the liberation of the parent mustard drug 20 with
      formation of CO2, 2-nitro-4-hydroxymethylphenol 19 and dimethylimidazolidinone
      21. Surprisingly, prodrug 2 was not cleaved under the same conditions. According
      to in vitro experiments, prodrugs 1 and 2 were approximately 50- and 80-fold less
      cytotoxic than the parent drug and, when treated with beta-glucuronidase, the
      level of cytotoxic activity of 1 became comparable to that of the drug. Stability
      of 1 in phosphate buffer was satisfactory. These results demonstrate that 1 is a
      prodrug that can be specifically activated to release the cytotoxic agent.

PMID- 10335273
TI  - Myocardial abscess with perforation of the heart following Staphylococcal pyemia.
      1943.

PMID- 10335274
TI  - Justifications and needs for diversity in orthopaedics.
AB  - America is founded on high humanitarian, democratic ideals. The historic facts of
      slavery, discrimination, and segregation challenge and taint these democratic
      principles. Although progress has been made, serious racial problems remain. In
      1997, the United States had 474 active hate groups, up 20% from 1996. African
      American males who have the same education as white males doing the same work
      earn approximately 75% of what their white counterparts earn. America, as
      predicted by the Kerner Commission Report, is two societies: black and white,
      separate, and unequal. Some astonishing disparities in healthcare exist. Peer
      reviewed medical literature documents that African Americans have higher infant
      mortality rates, shorter life expectancies, fewer joint replacements, and more
      amputations than whites. Communications within a diverse group of students and
      teachers enriches the educational experience. The late Supreme Court Justice
      Lewis Powell, LLD, asserted that a medical student from a particular background
      may enrich classmates' understanding of people whose cultures are different from
      their own, and improve their ability to serve a heterogeneous patient population.
      Diversity on clinical teams can enhance rapport between patient and physician,
      and can diminish unthinking insults to patients, born of physician ethnic
      insensitivity. Healthcare facilities with diverse staffs are more likely than
      homogeneous facilities to attract and successfully serve the nation's diverse
      population. A University of California at Davis School of Medicine study showed
      that diversity can be achieved without compromising quality of patient care.
      Clinically and ideologically, diversity in orthopaedics is good for patients and
      for the country.

PMID- 10335275
TI  - Challenges and opportunities of racial diversity in medical education.
AB  - Racial and cultural diversity in the physician workforce (in orthopaedics this
      includes women) is an essential if the best healthcare for the American people is
      to be provided. The percentage of minorities to the white population is
      increasing yet their representation in medical schools and the practicing
      community has not risen at that same pace. Affirmative Action efforts continue to
      be challenged as lowering standards and depriving better qualified students
      admission to medical schools. Admissions committees and orthopaedic residency
      directors should recognize that grade point averages and test scores may not be
      the best predictors of how well a physician or surgeon cares for patients. How
      far a person has come and what obstacles they have had to overcome, their
      demonstrated caring and compassion for people, their understanding of diverse
      cultures and languages may be a far better predictor of the quality of care
      physicians give to their patients. Affirmative Action should not be looked on as
      lowering standards, but using all available information in the selection process
      for medical school and residency training to ensure that the medical profession
      more closely mirrors the diverse racial and ethnic background of the United
      States population. How far a person has come and the adversity they have overcome
      may have far greater impact on making the correct diagnosis and setting out a
      proper treatment plan that the patient will accept than mastering test taking in
      the biologic and physical sciences. Obtaining racial and cultural diversity in
      the medical profession should be a national imperative.

PMID- 10335276
TI  - Current diversity in orthopaedics. Issues of race, ethnicity, and gender.
AB  - The size and diversity of the United States orthopaedic workforce continues to
      interest academic graduate medical education analysts. Numerous medical groups
      have expressed the need for diversity in orthopaedics and in general medicine.
      The Association of American Medical Colleges has had two policies since the early
      1970s concerning minorities in medicine. It was thought that special attention
      should be given to minority groups underrepresented in medicine and that the
      minority groups should be represented in medicine in the same proportion as in
      the population as a whole. The purpose of this paper was to examine the selection
      of orthopaedic residents during the past 12 years based on the candidates
      documented race, ethnicity, and gender. The diversity of orthopaedic residents
      changed minimally during the period of the study. The percentage of African
      American, Hispanic, Native American, Puerto Rican, and Mexican American
      orthopaedic residents essentially has remained unchanged. The percentage of Asian
      and Pacific Islander women has remained unchanged whereas the percentage of Asian
      and Pacific Islander men has quadrupled (2.2% in 1983 to 9.8% in 1995) during the
      12 years of the study. The percentage of white women has remained virtually
      unchanged whereas that of white men has declined in direct relation to the
      increase in Asian or Pacific Islander men.

PMID- 10335277
TI  - Barriers to minorities in the orthopaedic profession.
AB  - The rapidly growing population of the United States is becoming more diversified
      in its ethnicity. Conversely, the orthopaedic profession has not kept pace with
      this increase. Although 1/3 of the total population is comprised of Latinos,
      African Americans, and Native Americans, only 7% of all orthopaedic surgeons
      represent these minorities. There is a widespread need for minority orthopaedic
      surgeons who can communicate with and understand these patients to provide them
      with competent cultural care. Minority students face significant barriers,
      intrinsic and extrinsic, which impede them in choosing orthopaedics as a career.
      Recognizing that these barriers are rooted in the early years of education,
      solutions such as mentoring activities, good guidance counseling, and accessible
      role models should be advocated and adopted. Misconceptions on the part of the
      minority students, medical school admissions committees, and directors of
      orthopaedic residency training programs may lead to negative impressions and
      results. The purpose of this paper is to make the orthopaedic community aware of
      this disparity and the barriers that underrepresented minority students
      encounter. Hopefully an appropriate positive response by those who have the
      ability to make a difference will result, thus facilitating the pathway for the
      minority student to become an orthopaedic surgeon.

PMID- 10335278
TI  - Barriers to minority participation in the orthopaedic profession. Personal
      perspectives.
AB  - A brief summary of one individual's pathway and the challenges encountered along
      the road to becoming an orthopaedic surgeon are outlined. Beginning with the
      decision to pursue a career in medicine, and chronicling the subsequent decisions
      made along the way, key elements that facilitated this individual's success are
      reviewed. Some of the difficulties encountered from the perspective of a minority
      candidate also are discussed and what perhaps may be deemed an indirect pathway
      to an orthopaedic career. The importance of institutional support, mentorship,
      and recruitment are essential to facilitate and secure the success of minority
      candidates.

PMID- 10335279
TI  - Quality and fairness: achieving the paradigm. A personal perspective.
AB  - African Americans and those traditionally underrepresented and discriminated
      against by society face particular roadblocks in achieving success. In the case
      of training for orthopaedic surgery selection, this paper presents fundamental
      concepts addressing misconceptions regarding the pool of underrepresented
      applicants for positions in orthopaedic surgery residency and the notion and
      definition of the terms qualified and best qualified regarding the residency
      applicant pool. The paper underscores the fact, that despite advances in the
      century, racism continues to be pervasive in America, and efforts at leveling the
      playing field should be used.

PMID- 10335280
TI  - Minorities and the orthopaedic profession.
AB  - Orthopaedic surgery represents a specialty in which applicants are abundant,
      residency slots are limited, and all candidates presumably are qualified.
      Orthopaedic residency programs have members of the resident selection committee
      review medical school performance measures for the purpose of screening
      candidates to interview and, subsequently, include on their rank order lists for
      the residency match process. The performance measures universally reviewed
      include the United States Medical Licensing Examination scores, Alpha Omega Alpha
      distinction, grade point averages, class rank, personal statements and letters of
      recommendation. A significant percentage of the residency positions available for
      orthopaedic training continue to be reserved for candidates who participate in
      the National Residency Matching Program. Although the selection process is open
      to any medical student or medical school graduate, the process fails to make any
      substantive strides in addressing the diminutive representation of certain ethnic
      and racial minorities within the profession. The intent of this manuscript is to
      expatiate on the effect various dynamics have on the orthopaedic profession,
      relative to underrepresented minorities in the profession. Those dynamics
      comprise (1) the size of the applicant pool; (2) the applicant screening
      criteria; (3) the underrepresented minority specialty preference; and (4) the
      perception underrepresented minorities have of orthopaedic surgeons.

PMID- 10335281
TI  - African Americans and women in orthopaedic residency. The Johns Hopkins
      experience.
AB  - At the Johns Hopkins Department of Orthopaedic Surgery, African Americans have
      comprised 22.9% of all residents admitted through the match program between
      enrollment years 1992 and 1998, and women have comprised 14.3%. The number of
      African American residents within the Orthopaedic program during any given
      academic year has been as high as 32%, and the number of female residents has
      been as high as 20%. These numbers have been achieved even though African
      Americans comprise only 1.5% of all United States orthopaedists, whereas women
      comprise only 2.3%. This achievement has been the result of a commitment by the
      chairman of the Johns Hopkins Department of Orthopaedic Surgery to develop
      diversity within the department's residency program.

PMID- 10335282
TI  - Predictors of success in medicine.
AB  - Many different variables have been used in an attempt to predict performance in
      medical school, residency, and practice. The extensive literature on this subject
      has been reviewed and evaluated. Admission to medical school should not be based
      solely on grade point average and Medical College Admission Test scores because
      these offer no measure of extremely important noncognitive attributes. Although
      performance in the preclinical years is predicted by the grade point average and
      Medical College Admission Test scores, no such correlation exists for
      achievements in the clinical years, for postgraduate training, or as physicians.
      Thus, even though underrepresented minority applicants to medical school tend to
      have lower grade point averages and Medical College Admission Test scores than
      majority applicants, ultimate success in postgraduate training and as practicing
      physicians is equivalent to that attained by majority students.

PMID- 10335283
TI  - Clinical experience and minority group students. A perspective from Harvard
      Medical School.
AB  - Medical educators realize that there are no simple predictors for student
      performance in the clinical training years. College grades and Medical College
      Admission Test scores may suggest the strength of a student's achievement in the
      basic sciences but cannot be relied on to predict efficacy in patient care. There
      is no fool proof way of assessing noncognitive abilities critical to clinical
      competence. However, in admissions, extracurricular activities, community
      service, leadership abilities, recommendations, and interviews are examined to
      assess personal strengths. The author's observations suggest that noncognitive
      attributes are important in the success of disadvantaged students. Although some,
      but not all, with low Medical College Admission Test scores may not excel in the
      basic sciences, once they reach the clinical years, a leveling of the playing
      field gives them an opportunity to show their special competence with patients.
      Minority students, perhaps because of their own life experiences, often are alert
      to the needs and sensitivities of patients. As a group, they are respectful of
      the dignity of patients. Many embrace the dictum: treat every patient as you
      would want a family member to be treated. Most minority students, despite
      pressures of being a minority in predominantly white environments, perform at a
      very high level in the clinical years and thereafter.

PMID- 10335284
TI  - Diversity in orthopaedics.
AB  - There is little doubt that women, African Americans, and Hispanics, have fewer
      opportunities to enter, or once in, to become contributing members of orthopaedic
      programs in the United States. The expressed reasons for this by faculty members
      sometimes sound reasonable, but on analysis all are spurious. It is the
      responsibility of the chief of service and the faculty members to change this
      pattern and offer all individuals equal opportunity and treat them identically to
      anyone in the program or on the faculty. Some guidelines are provided.

PMID- 10335285
TI  - Pioneering efforts for minority appointments and academic surgery. A narrative.
AB  - The author gives a narrative chronologic explanation for the early inclusion of
      African Americans and other minorities into the Yale University Orthopaedic
      Surgical Residency Training Program. The author's early isolation from racial
      problems living in rural Nebraska and the paucity of racial friction at the
      University of Nebraska gave him a more neutral or positive view of other
      cultures. Sudden exposure to the racial tension and police brutality toward
      African Americans in Boston followed by the well defined racial bias in the
      Southern city of Baltimore showed the plight of minorities. At that same time the
      author encountered many gentle and extremely intelligent African Americans who
      performed outstanding medical tasks for the Johns Hopkins Hospital hospital with
      little educational background. The author's experience with Shirley Moore and
      Augustus White at Yale made it possible to recruit a diverse group of gifted and
      loyal resident staff. The high number of academic appointments in minority and
      majority residents has evolved from the Academic Training and Research Program
      and a special selection process for choosing residents.

PMID- 10335286
TI  - Perspectives from the historic African American medical institutions.
AB  - The historically African American medical schools have been at the center of
      medical education for African American physicians in the United States since the
      Howard University College of Medicine opened in 1868. Although there were more
      than a dozen African American medical schools established during the next few
      decades, as propriety or church affiliated schools, only two survived the Flexner
      Report in 1910. Howard University (1868) and Meharry (1876) survived and trained
      generations of African Americans. These two schools educated approximately 85% of
      all African American physicians whereas the majority medical schools educated 15%
      for more than half of the twentieth century. As the result of a series of
      lawsuits filed by the National Association for the Advancement of Colored People,
      civil rights legislation and affirmative action programs, the numbers of the
      schools that now admitted African Americans increased and the total numbers of
      African American medical students increased when discrimination was prohibited in
      1966. The percentage of African American medical students attending predominantly
      white institutions increased by 25% in 1948, by 47% in 1968, by 61% in 1983 and
      to 84% in 1990. Two additional predominantly African American medical schools
      were established: the Charles R. Drew Medical School, Los Angeles (affiliated
      with the University of California, Los Angeles) in 1966, and Morehouse Medical
      School, Atlanta, which admitted its first class in 1978. Recent court decisions
      prohibiting schools from considering race as factor in admission and the end of
      affirmative action programs have resulted in a drop in total minority enrollment.
      The historically African American medical schools, that admitted approximately
      15% of the African American medical students during the era of affirmative action
      programs, will see this percentage decrease as the majority institutions admit
      fewer African American medical students and minority students. In the United
      States this trend already has been observed in admission data and graduation data
      for 1996 and 1997.

PMID- 10335287
TI  - The moral imperatives for diversity.
AB  - The debate over diversity and affirmative action remains contentious at best and
      divisive or polarizing at worst. The profession of orthopaedics, like all elite
      professions, is very much involved in this debate. Starting with the assumption
      that there are reasonable arguments on both sides of this question, this paper
      will search for common ground by focusing on three issues: the ethical and
      pragmatic reasons for overcoming the present effects of past discrimination; the
      importance of ensuring the clinical and cultural competence of the specialty of
      orthopaedics in taking care of a diverse population; and the value of preserving
      a commitment to equality.

PMID- 10335288
TI  - Leadership perspectives on the philosophy and rationale of diversity in the
      United States.
AB  - The uneasy civil rights consensus of the 1960s and 1970s has become frayed in
      civic and legal culture, and now it somehow must be mended. Defining
      discrimination, condemning it, regulating it, and remedying it are complicated
      issues. To find a solution is not rocket science; it is harder than rocket
      science. What is the moral cost of making decisions about people based on
      immutable characteristics like race and gender? In a 1995 review of affirmative
      action conducted by the author for President William Clinton, one issue was that
      discrimination can take place without the victim being aware of it. Victims of
      discrimination cannot litigate what they cannot see. This is but one
      justification for voluntary affirmative action. The debate about such measures,
      however, is fueled by sharp differences regarding basic questions of values, and
      perceptions of how much discrimination exists. Not many prejudices will be
      abandoned when people are presented with rational, social science evidence about
      crime, victimization, and the extent of discrimination. Experiences, including
      experiences with people who are different, are the most powerful tool for
      changing people's sense of community and people's values.

PMID- 10335289
TI  - African Americans and orthopaedic surgery. A resident's perspective.
AB  - Orthopaedic surgery, like many other medical specialties, suffers from a lack of
      representation in its professional ranks from groups other than Caucasian males.
      This not only has measurable impact on the quantity and quality of care delivered
      to underrepresented groups, but also affects research and policy decisions.
      Orthopaedic care as perceived by many in the African American community is
      primarily for salvage procedures such as amputations. Evolving the current system
      to produce more efficacious and fair healthcare delivery requires training more
      orthopaedic surgeons of African American extraction. Department chiefs of
      residency programs must be enlisted to achieve this goal.

PMID- 10335290
TI  - The coordinate movement of the interphalangeal joints. A cinematic study.
AB  - No agreement exists on how coordinate flexion and extension movements of the
      interphalangeal joints of the long fingers of the hand are performed. A cinematic
      study in 18 healthy volunteers was done to assess the objective sequence of
      beginning and ending of movement in the eight free movements of the hand in which
      these joints flex and extend. The results show that the proximal interphalangeal
      joint is the one that first initiates the four analyzed movements in which these
      interphalangeal joints flex and the four movements in which these interphalangeal
      joints extend. The distal interphalangeal joint is the one that ends first in
      these two groups of movements. These results confirm that the coordinated
      movements of the interphalangeal joints may be explained based exclusively on the
      tendinous system and especially on the setup and balance that exists between the
      components of the extensor apparatus (longitudinal sliding of the central slip
      and lateral bands and either the dorsal to palmar or palmar to dorsal
      displacement of the lateral bands with respect to the rotation axis of the
      proximal interphalangeal joint).

PMID- 10335292
TI  - Minimum 10-year results of a tapered cementless hip replacement.
AB  - Seventy-one total hip arthroplasties with a cementless, wedge fit, cobalt chrome
      femoral component were reviewed in 60 patients at a minimum 10-year followup
      (mean, 11.5 years). For the femoral component, the mechanical failure rate was 5%
      and the revision rate for aseptic loosening was 0%. The mean Charnley scores for
      pain, function, and motion changed from preoperative mean values of 3.0, 2.7, and
      3.2 to followup mean values of 5.7, 5.5, and 5.2, respectively. The followup mean
      Harris hip Score was 91. The incidence of thigh pain was 1.4% at 10-year
      followup. Ninety-five percent of femoral components showed radiologic evidence of
      stable, bone ingrowth fixation, whereas loosening was seen in 5% of stems.
      Despite the high incidence of acetabular osteolysis, no osteolysis was seen on
      the femoral side distal to the lesser trochanter. Nonmodularity of the femoral
      component led to unavoidable revision of stably fixed femoral components in seven
      (9.8%) hips during the revision of a loose socket. Design features (collarless,
      tapered, wedge fit, and circumferentially porous coated) were thought to be
      crucial to the superlative results with the cobalt chrome femoral component.

PMID- 10335291
TI  - Mueller roof reinforcement rings. Medium-term results.
AB  - Short term results of cemented acetabular reconstruction with the use of the
      Mueller reinforcement ring in 30 hips in 29 patients have been reported
      previously. The indications for reinforcement were primary and postrevision
      segmental, cavitary, and combined acetabular deficiencies. The current study
      reports the medium term clinical and radiologic results of 20 of the 29 patients
      who were surgically treated (18 primary and eight postrevision hips) and who
      underwent followup with detailed clinical and radiographic analysis within an
      average of 9 years (range, 7-12 years). In the latest followup, there has been a
      statistically insignificant decrease in clinical scores compared with those
      obtained immediately after surgery; the changes probably are a result of the
      patients' aging. The radiologic scores at the latest followup were lower,
      although not statistically significant, than those at the short term followup.
      The causes of the three ring failures that occurred 5, 8, and 8.5 years after
      surgery and required revision arthroplasty were either acute trauma or
      tuberculous arthritis. Three additional hips (two primary and one revision) had
      evidence of loosening in the ring and socket associated with symptomatology and
      were considered as hips with impending revision. The rate of success of primary
      implantation was 94% at 7 years, 86% at 10 years, and 86% at 12 years and was not
      statistically different from that of revision implantation, which was 86% in all
      three followup periods. In this small series this surgical technique was
      successful and effective and followed by good medium term clinical and
      radiographic results in primary and revision implantation in segmental, cavitary,
      or complex acetabular deficiencies and in osteoporotic or deficient acetabular
      bone.

PMID- 10335293
TI  - Mechanism of failure in hips with an uncemented, all polyethylene socket.
AB  - The outcome of 32 patients with 33 primary total hip replacements performed using
      noncemented uncoated polyethylene acetabular cups (RM cup) with cemented titanium
      alloy monoblock stems (STH-2 stem) was reviewed. At a mean followup of 6.3 years
      (range, 6 months-10 years), the failure rate was 57%, more than 14 times higher
      than the rate typically seen with cemented polyethylene acetabular cups used with
      the STH stem. Failure was characterized by rapidly progressive acetabular or
      femoral osteolytic lesions that resulted in extensive bone loss, often in
      patients who had no symptoms. In addition to the debris that typically is
      generated by a metal on plastic bearing couple, an abundance of polyethylene
      particles of submicron size were produced at the cup-bone interface. Tissues
      retrieved from areas of osteolysis revealed the presence of intracellular
      submicron polyethylene particles in macrophages. It is recommended that patients
      with no symptoms who have RM noncemented, uncoated acetabular cups be followed up
      yearly and undergo early revision surgery when faced with osteolysis to prevent
      extensive bone loss.

PMID- 10335294
TI  - Lateral approach with osteotomy of the tibial tubercle in primary total knee
      arthroplasty.
AB  - In a prospective study of 51 patients (61 cases) with primary total knee
      arthroplasty (valgus knees and/or knees that had undergone previous
      nonarthroplasty surgery), a lateral approach with osteotomy of the tibial
      tubercle was performed. In a lateral approach, lateral release techniques form
      part of the approach. In addition, the medial blood supply to the patella is
      preserved. An additional tibial osteotomy grants wide exposure with little
      tension on the extensor mechanism during eversion of the patella. The patients
      were followed up clinically (51 patients, 61 cases) and radiologically (44
      patients, 52 cases) for 1 year. No postoperative tibial fractures, no delayed
      unions, and no nonunions at the site of the osteotomy were seen. No patellar
      necrosis occurred. The results after 1 year were good or excellent in 45 (88%)
      patients, fair in four (8%), and poor in two (4%). Complications related to
      technique were hematoma (four patients) and compartment syndrome (one patient).
      These complications occurred early in the series and were eliminated by technical
      modifications.

PMID- 10335295
TI  - Anteroposterior and rotational movement of femur during knee flexion.
AB  - This study was designed to analyze anteroposterior and rotational movement of
      femoral condyles during knee flexion from 15 degrees to 90 degrees using magnetic
      resonance imaging. After a pilot study, scans were made in 10 healthy male
      Japanese volunteers. When centers of the circular profiles of posterior femoral
      condyles were used as reference points, the medial and lateral femoral condyles
      displaced posteriorly 1.9 +/- 0.8 mm and 2.3 +/- 0.5 mm, respectively (mean +/-
      standard error). Duplicate examinations on two separate occasions revealed the
      accuracy of this procedure was in the range of 1 to 2 mm. These results have
      confirmed that femoral rollback occurs in the unloaded normal knee during flexion
      from 15 degrees to 90 degrees, but its magnitude is small (2 mm). The results
      obtained in this in vivo measurement of anteroposterior movement of the femoral
      condyles have relevance for total knee replacement design.

PMID- 10335296
TI  - Pelvic reconstruction for severe periacetabular metastatic disease.
AB  - The functional outcome of acetabular reconstruction in 21 patients with severe
      acetabular deficiency was examined. The surgical indications were pain,
      immobility, and loss of indepedence. Surgical reconstruction included curettage,
      placement of an acetabular roof ring with screws crossing the defect, cementation
      of the defect, and cemented hip arthroplasty. Although three patients died within
      the first month, the mean postoperative survival was 14.5 +/- 4.0 months, with a
      10.4 +/- 3.0-month period of independent living. Statistically significant
      postoperative improvements were seen in pain and mobility scores. Using the
      Musculoskeletal Tumor Society score for the lower extremity, a mean postoperative
      score of 14.2 of a total 30 was calculated. Low scores were attributed to the
      patients' overall disease, including the requirement of continued narcotic pain
      control, occupational restriction, and the presence of Trendelenburg limp.
      Surgical complications occurred in six patients and included three early
      postoperative deaths, two related to poor preoperative pulmonary function; two
      dislocations, one related to a late infection; one femoral nerve palsy; and one
      foot drop. Although associated with a high complication rate, acetabular
      reconstruction for metastatic disease can lead to marked improvement in pain
      control, function, independence, and quality of life in carefully selected
      patients.

PMID- 10335297
TI  - Malignant lesions arising in chronic osteomyelitis.
AB  - Neoplasia occurring in a sinus tract is a well known complication of chronic
      osteomyelitis. Previous series have been too small to permit survival analysis.
      Fifty-three consecutive patients (44 men and 9 women) from the authors'
      institution were reviewed, including 24 who previously were reported. There were
      50 patients with squamous cell carcinomas, one with fibrosarcoma, one with
      myeloma, and one with lymphoma. Mean age was 59 years. One patient sought
      treatment elsewhere and was lost to followup. Forty-four patients underwent
      amputation, and eight underwent limb salvage. Followup averaged 9 years. Of 50
      patients with squamous cell carcinoma, five died of disease. Overall survival in
      this group was not statistically different from that expected for age matched
      controls. Despite the low grade nature of most of these lesions, amputation often
      is chosen as the most reliable means of treating the tumor and the chronic
      infection.

PMID- 10335298
TI  - Outcome of surgical treatment of congenital muscular torticollis.
AB  - Eighty-four patients with congenital muscular torticollis were treated surgically
      in a 10-year period with a mean followup of 5 years (range, 2-13 years). All
      patients were classified into subgroups according to the type of congenital
      torticollis, the limitation of passive rotation of the neck, and other
      parameters, including head tilt and craniofacial asymmetry. Twenty-two (26.2%)
      patients underwent surgery before they were 1 year of age, 22.6% were between 1
      and 3 years of age, 38.1% were between 3 and 10 years, and 13.1% were older than
      10 years. Postoperative management included physiotherapy for 3 to 4 months and
      the application of a multiply adjustable torticollis brace for 10 weeks in
      children older than 2 years of age. Loss of the sternomastoid column was found in
      82.6%, poor scar in 2.4%, lateral band in 47.2% and 1.2% required a second
      operation. The final overall score showed excellent results in 88.1%, good
      results in 8.3%, and fair to poor results in 3.6%. The most important factor
      affecting the overall result and outcome was found to be the age of the patient
      at the time of operation. However, this series also showed that for patients who
      were 10 years or older at the time of surgery, 63.6% had excellent results and
      81.8% had good to excellent results, indicating the benefit of surgery even in
      the late cases.

PMID- 10335299
TI  - Risk factors for osteonecrosis in patients with type 1 Gaucher's disease.
AB  - This study investigated 51 patients with Type 1 Gaucher's disease clinically and
      radiographically for the presence of osteonecrosis. Twenty-five female and 26
      male patients with a mean age of 37 years were evaluated retrospectively for
      osteonecrosis of the proximal and distal femur, proximal tibia, and proximal
      humerus. All patients were examined before enzyme replacement therapy. Gender,
      age at diagnosis, prior splenectomy, hematocrit, platelet count, acid phosphatase
      level, radiographs of the long bones, and magnetic resonance quantitative
      chemical shift imaging of the spine were analyzed to see if any of these values
      or findings were associated with the presence of osteonecrosis. Splenectomy was
      an independent risk factor for the presence of osteonecrosis in three of the four
      major sites and was a multivariate risk factor for osteonecrosis of the proximal
      femur and tibia. Male gender was the other significant multivariate risk factor
      for osteonecrosis of the humerus and distal femur when all sites were taken into
      account.

PMID- 10335300
TI  - Peripheral nerve palsies in victims of the Hanshin-Awaji earthquake.
AB  - On January 17, 1995, the Hanshin-Awaji earthquake directly hit a metropolis and
      destroyed approximately 120,000 houses. Many people were buried under the debris
      of the Japanese style wooden houses or were injured by falling furniture. Twenty
      five patients (35 extremities) with earthquake associated peripheral nerve palsy
      were studied and followed up for 2 years. The characteristic feature of
      earthquake associated palsies was combined nerve palsy induced by prolonged
      compression. There were 11 extremities with brachial plexus palsy; two
      extremities with combined radial, median, and ulnar nerve palsy; two extremities
      with combined median and ulnar nerve palsy; two extremities with radial nerve
      palsy; two extremities with ulnar nerve palsy; 10 extremities with combined
      femoral and sciatic nerve palsy; one extremity with combined tibial and peroneal
      nerve palsy; and five extremities with compartment syndrome of the leg. Many
      peripheral nerve palsies were induced by nerve ischemia. Most patients had good
      spontaneous recovery. The prognosis of these palsies generally was good.

PMID- 10335301
TI  - Remobilization does not fully restore immobilization induced articular cartilage
      atrophy.
AB  - The recovery of articular cartilage from immobilization induced atrophy was
      studied. The right hind limbs of 29-week-old beagle dogs were immobilized for 11
      weeks and then remobilized for 50 weeks. Cartilage from the immobilized knee was
      compared with tissue from age matched control animals. After the immobilization
      period, uncalcified articular cartilage glycosaminoglycan concentration was
      reduced by 20% to 23%, the reduction being largest (44%) in the superficial zone.
      The collagen fibril network showed no significant changes, but the amount of
      collagen crosslinks was reduced (13.5%) during immobilization. After
      remobilization, glycosaminoglycan concentration was restored at most sites,
      except for in the upper parts of uncalcified cartilage in the medial femoral and
      tibial condyles (9% to 17% less glycosaminoglycans than in controls). The
      incorporation of 35SO4 was not changed, and remobilization also did not alter the
      birefringence of collagen fibrils. Remobilization restored the proportion of
      collagen crosslinks to the control level. The changes induced by joint unloading
      were reversible at most sites investigated, but full restoration of articular
      cartilage glycosaminoglycan concentration was not obtained in all sites, even
      after remobilization for 50 weeks. This suggests that lengthy immobilization of a
      joint can cause long lasting articular cartilage proteoglycan alterations at the
      same time as collagen organization remains largely unchanged. Because
      proteoglycans exert strong influence on the biomechanical properties of
      cartilage, lengthy immobilization may jeopardize the well being of articular
      cartilage.

PMID- 10335302
TI  - Micromotion measurements with hip center and modular neck length alterations.
AB  - Hip center relocation often is necessary because of acetabular deformity or in
      revision surgery. Superolateral relocation of the acetabular component increases
      the hip joint reaction forces and has been associated with early femoral implant
      loosening. In addition, relocation can necessitate the use of extended femoral
      neck lengths. The purpose of this study was to compare the initial stability
      (micromotion) of an anatomically placed femoral component with that of a
      superolaterally relocated component and with a component having an extended neck
      length. A six-degree of freedom device was constructed to measure three
      dimensional micromotion at the proximal and distal regions of the femoral
      component. The instrumented femur was loaded using a unique loading device that
      included musculature necessary to simulate stairclimbing. Results showed that
      superolateral relocation of the hip center (25 mm) only moderately increased
      femoral component micromotion (13%). However, it was found that extending the
      neck length 12.5 mm produced a dramatic increase in micromotion (38%). Clinically
      this suggests that hip center lateralization and the use of long modular neck
      lengths should be avoided.

PMID- 10335304
TI  - Large medial knee mass in a 61-year-old man.

PMID- 10335305
TI  - A managed care world. Can academic activities survive?
AB  - As a guest speaker at the Brown University Medical School Graduation, the author
      described some aspects of managed care that impact on academics and more
      specifically teaching and research. The issues for education included the
      reduction in numbers of residents and fellows; the rapidity with which the
      patients must be treated; the reduction in monies for educational activities; and
      consuming and at times needless paperwork. As far as research is concerned the
      reduction in time and money have had a negative effect on this important aspect
      of academic life for physicians. Several proposals are put forth to maintain the
      quality of these educational and investigational pursuits, and the students soon
      to be residents and, hopefully, academicians are advised to maintain the highest
      standards and appreciation for quality care, education, and research.

PMID- 10335303
TI  - Development of a biodegradable antibiotic delivery system.
AB  - Antibiotic beads have been used as a drug delivery system for the treatment of
      various surgical infections. In this study, the copolymer 50:50 poly(DL
      lactide):co-glycolide was mixed with vancomycin powder and hot compressing molded
      at 55 degrees C to form five types of biodegradable antibiotic beads. The beads
      were placed in 1 mL of phosphate buffered saline and incubated at 37 degrees C.
      The phosphate buffered saline was changed daily, and the removed buffer solutions
      were stored at -70 degrees C until the antibiotic concentration in each sample
      was determined by high performance liquid chromatography system assay. The
      concentration of vancomycin in each sample was well above the breakpoint
      sensitivity concentration (the antibiotic concentration at the transition point
      between bacterial killing and resistance to the antibiotic) for more than 32
      days. The release was most marked during the first 48 hours. All copolymer 50:50
      poly(DI lactide):co-glycolide biodegradable beads released high concentrations of
      the antibiotics in vitro for the time needed to treat bone infections (4 to 6
      weeks). The diameter of the sample inhibition zone ranged from 6.5 mm to 10 mm,
      and the relative activity of vancomycin ranged from 12.5% to 100%. Copolymers
      with low heat of formation temperatures are required for making a controlled
      release system to prevent antibiotic decomposition, which occurs when using the
      hot compressing molded method. The rate and duration of release from the
      antibiotic beads can be adjusted by varying the diameter of the beads. This
      offers a convenient method to adjust the release rate to meet the specific
      antibiotic requirements for different patients.

PMID- 10335306
TI  - Medicare "premium supports".

PMID- 10335307
TI  - Franchise issues--exclusivity of territory.

PMID- 10335308
TI  - Health insurance choices in two-worker households: determinants of double
      coverage.
AB  - Understanding how households make health insurance choices is of critical
      importance in evaluating issues of equity and efficiency in health care markets.
      We consider a largely neglected aspect of such decision making: the decision of
      families with two working spouses to obtain double coverage. Using data from the
      1987 National Medical Expenditure Survey, we find that household decisions to
      obtain double coverage are especially sensitive to a couple's out-of-pocket
      premium costs. Our analysis also reveals that households with double coverage
      have more generous insurance, as reflected in their higher coverage rates for
      specific types of benefits. We also demonstrate that the presence of duplicate
      health benefits in double-covered households is not random, possibly reflecting a
      systematic attempt by working spouses to obtain more extensive coverage.

PMID- 10335309
TI  - Who gains and who loses with community rating for small business?
AB  - This paper compares community rating with experience rating for small businesses
      using a microsimulation model to determine what firms offer and who within these
      firms purchases insurance. We generate four years of data and find that our
      results are remarkably stable through time. Both offer and purchase rates are
      about five percentage points higher under experience rating, but community rating
      leads to more stable offerings. Under community rating, high-risk firms and
      families purchase insurance, whereas under experience rating, it is the low-risk
      firms and families who are the purchasers. Young families and poor families have
      the lowest purchase rates, with these rates being disproportionately low under
      community rating.

PMID- 10335311
TI  - Cost implications of regionalizing open heart surgery units.
AB  - This study calculated the potential change in costs from regionalizing open heart
      surgery units in a geographic network of the Department of Veterans Affairs (VA).
      It used data from the VA's cost accounting system, and the authors conducted a
      sensitivity analysis. Under consolidation, savings from closing an open heart
      surgery unit would be partially offset by the costs of treating nonemergency
      cases at other VAs, treating emergency cases at non-VA hospitals, and
      transporting patients to regionalized facilities. Nevertheless, the potential
      savings from consolidation would exceed $3 million, or 18% of the network's costs
      of treating open heart surgery patients.

PMID- 10335310
TI  - An alternative approach to measuring the effects of insurance market reforms.
AB  - Reforms in the small group and individual insurance markets could make it easier
      for the currently insured to keep their coverage, and could expand coverage by
      making insurance more accessible to the currently uninsured. We use data from the
      1989 through 1995 Current Population Survey to measure the impact of these
      reforms on state-level rates of uninsurance and private health insurance
      coverage. Instead of examining the effect of each of the various types of
      insurance marker reforms, we estimate the impact of packages of reforms on
      insurance coverage, reflecting how policies were implemented. We find that small
      group reforms have done little to affect insurance coverage. Individual market
      reforms, on the other hand, appear to increase uninsurance rates and reduce
      private coverage. Our findings suggest that small group reforms may have
      prevented erosion of private coverage, but have not reduced the numbers of
      uninsured people.

PMID- 10335312
TI  - Does managed care affect the supply and use of ICU services?
AB  - This paper analyzes use of hospital intensive care units (ICUs) by adult patients
      who are under age 65 and not covered by Medicaid; it allows for variation in
      indicators of the patient's condition, severity of illness, type of admission,
      emergency status, and degree of constraint on the total hospital ICU supply. We
      use data for Massachusetts and Florida in 1992. In neither state is there a
      significant difference in ICU admission rates between managed care patients and
      other privately insured patients. In Massachusetts, we find that the length of
      stay in the ICU is somewhat less for managed care and uninsured patients than for
      other privately insured patients. In both states, a hospital's ratio of total
      annual supply of ICU services to expected demand has a strong effect. In
      Massachusetts, the differences across payer groups in length of stay disappear
      for hospitals where the total ICU supply is relatively constrained.

PMID- 10335313
TI  - Recent determinants of new entry of HMOs into a Medicare risk contract: a
      diversification strategy.
AB  - This study provides knowledge of more recent entry of health maintenance
      organizations (HMOs) into the Medicare risk program than earlier analyses. Based
      on a diversification framework, this study examines new market entry from three
      dimensions: attractiveness of the market, market area attributes, and
      organizational attributes. The analysis uses a 1994-1995 cross-sectional, lagged
      time sample with 440 HMOs that did not have a Medicare risk contract as of
      January 1994; it defines an HMO's market as its service area. HMO enrollment
      growth in the market, individual HMO enrollment size, and adjusted average per
      capita cost (AAPCC) rates are found to be significant in predicting new market
      entry.

PMID- 10335314
TI  - Utilization of physician services at the end of life: differences between the
      United States and Canada.
AB  - This study draws on physician claims for the elderly from the U.S. Medicare
      program and the Canadian provinces of Quebec and British Columbia to compare
      physician service use by people with fewer than six months to live relative to
      those who liver longer. Physician service quantities are expressed in relative
      value units (RVUs), and aggregated into clinical type-of-service categories.
      Relative to survivors, those in the United States approaching death receive about
      the same amount of evaluation and management services as those in Quebec and
      British Columbia, though less in absolute value; they also receive about the same
      amount of procedures as those nearing death in British Columbia, but half as much
      in proportion as people nearing death in Quebec. Further analyses of
      appropriateness of care to the dying appear no less necessary in Canada than in
      the United States.

PMID- 10335316
TI  - Are routine office procedures still worth your while?

PMID- 10335315
TI  - Consumer protection and the HMO backlash: are HMOs to blame for drive-through
      deliveries?
AB  - This study used patient discharge data from New Jersey to examine differences in
      length of stay for normal, uncomplicated deliveries between patients in health
      maintenance organizations (HMOs) and those not in HMOs. The percentage of one-day
      stays increased from less than 4% for all payers in 1990 to 48.1% for HMO
      patients, and 31.5% for non-HMO patients in 1994. Controlling for other factors,
      the odds of an HMO patient staying one day were nearly twice as great as a non
      HMO patient by 1994; for all patients, regardless of payer, the odds of a one-day
      stay in 1994 were more than 18 times the odds of a one-day stay in 1990. The
      strong secular trend suggests that legislation and regulations should be targeted
      at particular policies rather than insurers.

PMID- 10335317
TI  - Reclaiming your desktop space. Are your gadgets pushing you aside?

PMID- 10335318
TI  - Insulin versus oral agents for 'steroid-induced' diabetes.

PMID- 10335319
TI  - Evaluating pleural effusions. How should you go about finding the cause?
AB  - Although many pulmonary and systemic diseases are known to cause pleural
      effusions, analysis of the pleural fluid pinpoints the cause in most cases.
      Distinguishing pleural transudates from exudates is an important step. Transudate
      effusions are caused by a small, well-defined group of illnesses (e.g.,
      cirrhosis, congestive heart failure). Exudative effusions, on the other hand, are
      associated with a wide variety of causes, including pneumonia, malignancy, TB,
      drug-induced reactions, and many others. Some effusions remain unexplained
      despite extensive tests. Surgical approaches may be appropriate for some of these
      patients, but the risks must be carefully weighed against the benefits.

PMID- 10335320
TI  - Maximizing the exercise stress test. Critical factors that enhances its validity.
AB  - The maximal exercise stress test continues to be an important diagnostic and
      prognostic tool in the primary care office setting. But are you getting the most
      accurate information possible? Drs Driggers and Marchant discuss several factors
      that are crucial to the test's validity--and thus to its usefulness in your
      clinical practice.

PMID- 10335321
TI  - Improving survival in metastatic carcinoma of unknown origin.
AB  - Metastatic carcinoma from an unknown primary site accounts for 3% to 5% of all
      newly diagnosed malignant lesions. Although 85% of patients who receive this
      diagnosis are dead within a year, 5% to 10% may be long-term survivors. Close
      cooperation between an experienced pathologist and the referring physician is
      essential in the management of these patients. One important task for the
      physician is to recognize those subgroups of patients who may have a better
      prognosis and thus may be treated in a different fashion. A second challenge is
      not to overinvestigate or overtreat patients who fall into the poor prognosis
      category. Empirical chemotherapy should not be given simply for the sake of doing
      something. Rather, proper emphasis should be placed on regional therapy,
      symptomatic treatment, and the best palliative care. Patients may be confused and
      frustrated when confronted with the news that the source of their tumor is not
      apparent. They should be reassured that this lack does not preclude development
      of a rational treatment plan and that those cancers for which highly effective
      systemic therapy exists have been excluded. A caring, informed physician may help
      empower the patient to make educated and informed choices.

PMID- 10335322
TI  - Turning up the heat on hypertension. It's time to be more aggressive in finding
      and treating this silent killer.
AB  - Treatment of high blood pressure can be challenging. Most patients have no
      symptoms and are unlikely to appreciate the value of antihypertensive
      medications. Unless acute target organ involvement is already present, there are
      no compelling reasons to lower blood pressure quickly. Instead, beginning with
      relatively low doses of medications and slowly bringing the blood pressure to
      goal helps avoid troublesome medication side effects. This is especially
      important in elderly patients with isolated systolic hypertension who are
      susceptible to orthostatic hypotension, dizziness, and confusion, despite little
      change in blood pressure. Use of long-acting agents and combination medications
      may improve compliance with the medical regimen.

PMID- 10335323
TI  - Controlling isolated systolic hypertension. No time to be complacent.
AB  - Isolated systolic hypertension (ISH) is the most common form of hypertension in
      the elderly. It is an even better predictor of morbidity and mortality than is
      diastolic blood pressure. Several large trials have documented a clear benefit to
      treating ISH. Therapy should be initiated only after careful evaluation of the
      patient's overall medical status, because the elderly are at increased risk of
      adverse effects from medications. Pharmacologic therapy should be started at a
      low dose and increased slowly, if necessary. If hypertension is still present
      after the addition of two or three medications, a cause other than essential
      hypertension should be considered, such as white coat hypertension, secondary
      hypertension, or pseudohypertension.

PMID- 10335324
TI  - Hypertensive crisis. How to tell if it's an emergency or an urgency.
AB  - Hypertensive crisis occurs when critically elevated blood pressure is accompanied
      by diastolic pressure greater than 120 to 130 mm Hg. The presence of acute or
      ongoing end-organ damage constitutes a hypertensive emergency, which requires
      reduction of blood pressure within minutes to hours to avoid catastrophic
      outcomes. Critically elevated blood pressure without end-organ damage is known as
      a hypertensive urgency, which is generally treated over 24 to 48 hours in a
      closely monitored outpatient setting. Although hypertensive crises are relatively
      rare, most primary care physicians will eventually encounter them. Thus, for
      optimal patient outcomes, it is important to be aware of appropriate treatment
      options as well as the impact of potential complications on management.

PMID- 10335326
TI  - Coping with panic disorder.
AB  - Have you ever had a spell when your heart suddenly began to pound and you felt
      light-headed and shaky? You may have had a panic attack. These episodes are very
      frightening. People often think they have some life-threatening problem, are
      going crazy, or are utterly losing control, but these calamities don't really
      happen. The attack usually lasts only a few minutes and then gradually fades and
      it completely gone within an hour. THe following information may help you
      understand and cope with dismaying episodes.

PMID- 10335325
TI  - Blocking the cycle of panic disorder. Ways to gain control of the fear of fear.
AB  - Panic disorder is a common and potentially debilitating anxiety disorder that can
      adversely affect patients' personal, social, work, and academic lives. It may go
      unrecognized for long periods, because physical symptoms may mimic other
      conditions. Typical onset is during late adolescence and early adulthood.
      Stressors (e.g., new environments, loss of social support, relationship
      difficulties, academic pressure, substance use) may trigger or exacerbate panic
      symptoms. Evaluation by a healthcare professional paying close attention to
      medical and psychological aspects of panic disorder can lead to a proper
      diagnosis and effective management with medication (e.g., SSRIs) and
      psychotherapy.

PMID- 10335327
TI  - Crusted (Norwegian) scabies. A simple office test demystifies the 'great
      imitator'.

PMID- 10335328
TI  - Successful methods of treating leg ulcers. The tried and true, plus the novel and
      new.
AB  - The cause of a leg ulcer should be determined before a course of treatment is
      undertaken, and this often can be accomplished through history taking, physical
      examination, and use of simple noninvasive testing. Most leg ulcers are caused by
      venous disease, arterial insufficiency, neuropathy, or a combination of these
      factors. Complete management should address the patient's general health as well
      as specific findings, and treatment of any underlying cause is paramount. In
      venous ulcers, compression is the cornerstone of treatment, and a variety of
      effective stockings and other compression devices are available. Arterial ulcers
      usually require reestablishment of an adequate vascular supply, often through
      surgery. Neuropathic ulcers need thorough debridement to allow good granulation
      and epithelialization. Five types of occlusive dressings are available that
      achieve debridement less painfully but also more slowly than the surgical
      approach. Several adjunctive methods are now available that facilitate successful
      therapy in these ulcers, which have often been considered nonhealing wounds.

PMID- 10335329
TI  - Uncomplicated urinary tract infection in women. Diagnostic and therapeutic
      recommendations by the Institute for Clinical Systems Integration.

PMID- 10335330
TI  - More than a mouth ulcer. Oral ulcer due to Wegener's granulomatosis.

PMID- 10335331
TI  - Monitoring your blood pressure.
AB  - About 60 million Americans have high blood pressure, also known as hypertension.
      It occurs when the pressure of your blood against the artery walls is higher than
      normal. Hypertension is often referred to as a "silent killer" because it causes
      no symptoms but greatly increases the risk of stroke, heart attack, and kidney
      disease.

PMID- 10335332
TI  - Transgenic xenotransplants.

PMID- 10335333
TI  - The Human Genome Project: promise versus reality.

PMID- 10335334
TI  - [Human rights and genetics: the fundamental principles of the Universal
      Declaration on the Human Genome and Human Rights].
AB  - The Universal Declaration on the Human Genome and Human Rights sets out generally
      agreed criteria in response to the human rights challenges posed by advances in
      molecular biology and genetics. The lynchpin of these criteria is respect for
      human dignity, a premise from which other principles are derived. The author
      examines and gives the justification for these principles, and refers to another
      crucial bioethics text, the recent Council of Europe Convention on the protection
      of human rights and the dignity of the human person in regard to applications of
      biology and medicine.

PMID- 10335335
TI  - [Genetic expertise and the penal process].
AB  - The author reflects on the major forensic biology issues related to human genome
      analysis. He also discusses, from the comparative law perspective, the extent to
      which genetic test evidence is binding on judges. He concludes with a discussion
      of the influence of genetic research on people's fundamental rights.

PMID- 10335336
TI  - [Human cloning. The biological fundamentals and an ethical-legal assessment].
AB  - Following a description of the cloning process and how this might be used in
      humans, the authors examine the possibility of human cloning in the light of
      recognised ethical principles. They also address the question of whether current
      national and international laws are sufficient to prevent such practices.

PMID- 10335337
TI  - [The legal limits to a change in the genetic heritage of human beings (I)].
AB  - Special laws on assisted reproduction techniques appear to expressly prohibit
      research and experimentation on human beings, particularly cloning. However, in
      some countries such laws have yet to be prepared, while in others they might be
      enacted in the future. This situation shows the urgent need for generally agreed
      legal principles in all legislation to limit the aforementioned practices and for
      general mechanisms to safeguard human genetic heritage. Against this background,
      the present article discusses two possible ways of limiting modifications to
      human genetic heritage, namely, the principle of respect for human dignity and
      the designation of this dignity as "a legal interest of humankind".

PMID- 10335338
TI  - UNESCO's Universal Declaration on the Human Genome and Human Rights, 11 November
      1997.

PMID- 10335339
TI  - [Patent rights and biotechnological inventions].
AB  - In spite of all the controversy surrounding it and the problems encountered in
      the process leading to its adoption, the Directive on the legal protection of
      biotechnology inventions does not feature anything substantially new compared to
      the criteria used by patent offices in determining whether inventions of this
      type can be patented. The Directive's originality stems not so much from the
      interpretation given of patenting requirements but rather from the legal
      importance attached to issues of public policy or morality. It sets out and
      interprets for the member states of the European Union what is meant by the term.
      However, in our opinion this regulation of morality reflects above all else an
      attempt to satisfy the views of sectors opposed to the Directive. Clearly, there
      is some doubt as to whether in practice patents for genetic material can be
      turned down because they run counter to morality, except in blatant cases of
      immorality (applications for patents for human embryos, etc).

PMID- 10335340
TI  - [The right not to know in German legislation (II)].

PMID- 10335341
TI  - [A commentary on the Ruling of the Tribuna Constitucional 212/1996 of 19 December
      1996 (I)].
AB  - This article is a commentary on Spain's Constitutional Court's ruling of 19
      December 1996 (STC 212/1996), on the challenge (596/89) on grounds of alleged
      unconstitutionality made against Law 42/1988, 28 December, which regulates the
      donation of human embryos and foetuses or the cells, tissues and organs
      therefrom. The article is structured as follows: it opens with a summary of Law
      42/1988, since this is felt necessary to understand the subsequent challenge made
      on grounds of alleged unconstitutionality. We then provide specific details of
      the challenge and the resulting ruling, before concluding with some critical
      remarks on the aforementioned Law and ruling.

PMID- 10335342
TI  - [Genetic research as a means of proof in the German penal trial after the reform
      of the Court Rules of Procedure of 17 March 1997 (I)].
AB  - The authors reviews genetic fingerprinting practice and cases in Germany
      following the adoption of the new specific regulatory measures in the StPO, and
      looks at German case law on the subject. Also examined are the way in which the
      issue of human rights and some doubts which have arisen among authors and the
      courts have been resolved. The positive aspects of the new regulations are
      underlined and the author concludes with some proposals for application of these,
      lege ferenda, in Spain.

PMID- 10335343
TI  - International policy-making in genetic sciences.

PMID- 10335344
TI  - Ethical questions raised by human genetics. A personal contribution to the
      preparation of a legal instrument of the Council of Europe on human genetics
      (Part II).

PMID- 10335346
TI  - Proposed International Guidelines on Ethical Issues in Medical Genetics and
      Genetic Services (Part II). World Health Organization, Human Genetics Programme.

PMID- 10335347
TI  - [An additional protocol to the Convention for the Protection of Human Rights and
      Human Dignity with regard to the Application of Biology and Medicine on the
      prohibition of the cloning of human beings, 6 November 1997].

PMID- 10335348
TI  - [The Ibero-Latin American declaration on ethics and genetics. The declaration of
      Manzanillo of 1996, revised in Buenos Aires in 1998].

PMID- 10335349
TI  - Twin differences and similarities of birthweight and term in the French Romulus
      population.
AB  - This study was performed to examine the main characteristics of the French
      Romulus twin population: zygosity, chorionicity, sex, term and birthweight. A
      sample of 104 pairs of twins was distinguished by zygosity, chorionicity and sex,
      and divided into concordant and discordant birthweight groups. Fifty-three % (n =
      55) of the fetus pairs studied were born at "ideal term" (35-38 weeks), and 25%
      (n = 26) were delivered at "preterm" (28-34 weeks). The very preterm (< 28
      weeks), and "postterm" (> 38 weeks) represented altogether 22% (n = 23) of the
      sample. Of the 104 twin pairs, 68% (n = 71) differ by less than 15% in
      birthweight, and 32% (n = 33) have a birthweight difference higher than 15%. In
      dizygotic (DZ) pairs females had more tendency to be in the discordant group (p =
      0.01) while in monochorionic-monozygotic (MC-MZ) pairs males were more discordant
      (p = 0.07). We found a significant interaction between sex and zygosity type (p =
      0.02). Males had a birthweight difference significantly weaker than that of
      females in dichorionic-monozygotic (DC-MZ) and DZ twins whereas it was higher
      than that of females in MC-MZ twins. There were no MZ twin pairs with DC
      placentation over than 15% birthweight difference. Log linear analysis
      demonstrated a three-way interaction (p < 0.05) between term type, zygosity type
      and hypotrophy. Our data indicate that in the group of twins born between 35 and
      38 weeks' gestation the crucial question still remains unsettled on how term and
      birthweight are related to zygotism and/or chorionicity.

PMID- 10335350
TI  - Level of anxiety in parents of high-risk premature twins.
AB  - We attempted to define parental anxiety in a population of parents of high-risk
      premature twins (mean birth weight 1,493 +/- 227 kg; mean gestational age 33 +/-
      3.5 weeks), admitted to III level NICU. We specifically examined the following
      factors; gestational age of the twins, whether or not the twins had ventilatory
      support, pulmonary sequelae, major malformations or intra-ventricular hemorrhage,
      parental gender and highest level of education obtained by the parent. In the
      immediate pre-discharge period and a month later, a questionnaire (State-Trait
      Anxiety Inventory) was given to all parents of premature twins presenting for the
      discharge. The parents of 30 twins entered the study twice, at the discharge of
      their first twin (mean postnatal age 40 +/- 32 days), and one month later. They
      included 15 mothers and 11 fathers, aged 33 +/- 5.5 and 33 +/- 4.2 years, and at
      the second evaluation 11 mothers and 10 fathers, respectively. As case-controls
      we examined parental anxiety of fifteen consecutive singleton high-risk
      prematures, with equal gestational age, discharged immediately after. Our results
      indicate that the parents of high-risk twin and singleton prematures present an
      elevated, lasting state-trait anxiety level. Pre- and post-discharge parental
      anxiety is more elevated (not significant) in twinning with respect to the
      prematurity alone. When assessed separately by parental gender, in both these
      groups an increased (not significant) anxiety was persistently found in the
      mothers. We recommend that, although neonatologists generally define the
      discharge of the high-risk premature based upon the acquired stabilization of
      vital parameters, they pay special attention to the twin group we have identified
      which is at increased risk for predischarge parental anxiety.

PMID- 10335351
TI  - Yearly changes in stillbirth rates of zygotic twins in Japan, 1975-1994.
AB  - The stillbirth rates decreased to 2/3 for MZ male twins, 1/2 for MZ female twins,
      and under 1/2 for DZ twins for both sexes during the 19-year period from 1975 in
      Japan. The stillbirth rate was significantly higher in MZ males than MZ females
      in each year, whereas stillbirth rates of DZ twins for both sexes indicated
      similar values during that period. After 1986, stillbirth rates were more than 2
      times higher in MZ twins than in singletons and in DZ twins. The higher
      stillbirth rate of MZ twins as opposed to DZ twins could be related to
      monochorionic twin pairs in MZ twins. The stillbirth rate decreased more
      drastically in twins for both zygosities than in singleton births during the 34
      year period from 1960. However, declining rates of stillbirths may be attributed
      to medical care during twin pregnancies. Recommendation of an optimum day to give
      birth for twin pregnancy is 37-38 weeks for Japanese women.

PMID- 10335352
TI  - Sex differences in genetic determinants of craniofacial variations--a study based
      on twin kinships.
AB  - Race, sex, nutritional status and cultural factors affect craniofacial
      morphogenesis. Out of these, sex is a major factor in craniofacial
      differentiation, because it can be stronger in one ethnic group and weaker in
      another. In this study, sex differences in genetic variance and heritability of
      13 craniofacial traits are investigated. The study is based on a sample of 45 MZ
      and 101 DZ twin pairs and their 125 singleton siblings, 104 fathers and 103
      mothers in 146 families drawn from an urban population of Chandigarh. Results of
      t-tests for equality of the means reveal association of zygosity with the mean
      value of bigonial diameter in female twins and for none in males. Heterogeneity
      of variance is observed in about 50% traits in females as compared to 15% in
      males. This invalidates conventional within-pair genetic variance estimates for
      these traits. The revised genetic variance ratios are higher on an average in
      males than in females. However, there is greater MZ environmental covariance in
      male twins than their female counterparts. Family data indicate higher maternal
      effect for ear height, nasal height and frontal breadth, while greater paternal
      effect is seen in cranial traits. Sex-wise midparent-child regression
      coefficients show greater heritability in daughters for nasal traits and bigonial
      breadth, while sons show higher genetic component for head size measures.

PMID- 10335353
TI  - [Three sets of twins in three successive generations through the maternal line].
AB  - It is generally held that there are genetic factors for dizygotic (DZ) twinning,
      but the pattern of inheritance is far from clear. We report on a rare pedigree
      with three sets of spontaneous DZ female twin births in three successive
      generations. To our knowledge no similar pedigrees have been reported in
      literature. Zygosity determination in three pairs of twins was performed with
      ABO, MN and Rh blood groups from erythrocytes and with STR analysis from samples
      of saliva. In our pedigree, the direct transmission of the DZ twinning through
      the maternal line seems show an autosomal dominant pattern of inheritance. We
      believe that the inheritance of DZ twinning appears to be recessive in most case
      and autosomal dominant only in rare instances. It is plausible with the
      hypothesis that the expression of the dizygotic twinning trait in a mother shows
      a genetic heterogeneity.

PMID- 10335354
TI  - Etiology and management of monoamniotic twin discordant for anencephaly.
AB  - A case of monoamniotic monochorionic (MAMC) female twins, with one twin being
      anencephalic, and the co-twin being normal, is reported. Twin to twin transfusion
      syndrome was also noted. The reasons for anencephaly in association with
      monozygotic (MZ) twinning are discussed. The management of such a case is
      presented.

PMID- 10335355
TI  - [A brief history of twin study methods 2--actual formulation of methods].

PMID- 10335356
TI  - Premature implantation may be prevented by an inhibitory system regulated by
      epidermal growth factor.
AB  - Using immunohistochemical methods at both light and electron microscopical
      levels, we have studied epidermal growth factor in the uterine epithelium during
      early pregnancy and up to the time of blastocyst implantation. We report that the
      distribution of this growth factor changed markedly over the period of study and
      that it was gradually de-expressed across the entire uterine epithelium as
      pregnancy advanced towards the time of implantation. At the electron
      microscopical level, immunogold labelling clearly showed label associated with
      both lateral and basal plasma membranes very early in pregnancy but not by the
      time of implantation. We suggest that the de-expression of this molecule may
      indicate its role in the removal of mechanisms which inhibit uterine receptivity
      for implantation.

PMID- 10335358
TI  - Junctional plaque proteins shift to the apical surface of uterine epithelial
      cells during early pregnancy in the rat.
AB  - Antibodies against the cytoplasmic plaque molecules, plectin and plakoglobin, and
      cytokeratin, the molecular component of intermediate filaments (IFs), were used
      to examine the distribution of these molecules in rat uterine epithelial cells
      during early pregnancy including the period of blastocyst implantation. On day 1
      of pregnancy plectin was detected in concentrated bands along the apical and
      basal plasma membranes, and diffusely throughout the cytoplasm. Plakoglobin was
      found along the entire lateral plasma membrane on day 1. By day 6, the time of
      blastocyst implantation, plectin was localised along the apical and basal
      membranes and reduced in the basal cytoplasm, and plakoglobin was seen
      exclusively at the apical-most quarter of the lateral plasma membrane.
      Cytokeratin was detected throughout the cytoplasm on day 1, but by day 6, was
      localised to the apical region of the cytoplasm only. These results show a
      redistribution of plectin, plakoglobin and cytokeratin away from the basal region
      of the uterine epithelial cells. The change in distribution of these molecules
      may contribute to the adhesion of the blastocyst to the apical and lateral
      surfaces of uterine epithelial cells and the subsequent detachment of the uterine
      epithelium from the basal lamina.

PMID- 10335357
TI  - Glycohistochemical investigation of canine and feline zonae pellucidae of
      preantral and antral oocytes.
AB  - Glycoconjugate modifications were analysed in the zona pellucida during
      development of oocytes in dog and cat using conventional histochemical staining
      methods with or without previous carbohydrate digestion. A series of lectins
      combined with desulphation and sialic acid degradation were applied. No
      differences were observed between dog and cat follicles using conventional
      histochemical staining methods. In both species, the zona pellucida and
      follicular fluid/intercellular matrix strongly reacted with PAS and high iron
      diamine stain (HID) and reacted moderately with low iron diamine stain (LID).
      Treatment with testicular hyaluronidase, chondroitinase ABC, chondroitinase AC
      and chondroitinase B treatment diminished HID and LID positivity of follicular
      fluid and intercellular matrix. Lectins that gave the most intense staining of
      the zona pellucida of both species were SBA, PNA, RCA-I, GSA-IB4 and WGA,
      indicating the presence of beta-D-GalNAc, D-Gal and GlcNAc residues. Sulpho- and
      asulpho-carbohydrates were identified in terminal and/or subterminal positions
      linked to sialic acid residues. In conclusion, the results indicate that
      glycosaminoglycans are not present in the zona pellucida of both species.
      Differences were observed in carbohydrate residues and in their spatial
      distribution, depending on species and developmental stage of the follicles. The
      similarity in lectin affinity between ooplasm and zona pellucida of oocytes
      present in follicles at different stages of development confirm the involvement
      of oocytes in zona pellucida production.

PMID- 10335359
TI  - Human autoantibodies identify a protein in dense fibrillar and granular
      components of the nucleolus.
AB  - A novel nucleolar protein of an approximate molecular weight of 60 kDa was
      identified by immunoprecipitation in human cells with an autoimmune sclerodermic
      serum. It maps at the ultrastructural level to nucleolar granular and dense
      fibrillar components. This 60 kDa protein could not be demonstrated in Western
      blots suggesting that the epitope structure is complex and/or is sensitive to the
      treatment of cells. The immunoprecipitation results indicate that the 60 kDa
      protein is not a phosphoprotein and is not associated with a nucleolar RNA
      containing particle. The identified protein represents a new autoimmune marker in
      the field of systemic connective tissue diseases.

PMID- 10335360
TI  - The silver reaction of nucleolar proteins in the main structural compartments of
      ring-shaped nucleoli in smear preparations.
AB  - The present study was undertaken to provide more information on the conditions
      which result in preferential silver staining of the main nucleolar structural
      compartments using silver stainable proteins as their markers at the light
      microscopic level. For this study the mostly used method in cytology and
      pathology in which the nucleolar silver-positive structures are "developed" with
      the colloidal developer (Howell and Black, 1980; Ploton et al., 1986) was
      selected as silver reaction. Ring-shaped nucleoli of mature human lymphocytes
      represent a convenient model for such a study because they consist of one large
      fibrillar center, adjacent nucleolar regions with dense fibrillar components and
      the nucleolar peripheral shell with dense granular components. All these
      nucleolar compartments are known to possess characteristic silver stainable
      proteins. The results demonstrated that proteins of the fibrillar center and
      possibly adjacent nucleolar regions reacted preferentially with silver after a
      relatively long fixation with formaldehyde or methanol in unwashed specimens
      before the silver reaction. In contrast, the preferential staining of proteins in
      the nucleolar peripheral shell with silver was achieved after the fixation with
      acidified methanol or ethanol as well as after short fixation with formaldehyde
      vapors. In addition, the commonly used fixation before the silver reaction are
      not necessary and may be omitted for the visualization of all silver stainable
      proteins present in the fibrillar center as well as in the adjacent nucleolar
      regions and the nucleolar peripheral shell. In addition, similar results were
      achieved for the simultaneous visualization of proteins in the fibrillar center
      and nucleolar peripheral shell after fixation with ethanol.

PMID- 10335361
TI  - Immunochemical analysis of laminin during postnatal development of the rat
      submandibular gland.
AB  - Anti-laminin serum was used to investigate distribution patterns and chain
      composition of laminin during postnatal development of rat submandibular gland.
      Immunohistochemical analysis showed that in glands of newborn rats laminin was
      not uniformly present around growing acini. Staining was frequently weak or
      absent in clefts formed between adjacent cells. This irregular staining pattern
      decreased progressively over the subsequent periods, and in 30-day-old animals
      immunoreactivity was observed only at the periphery of glands. Immunoblot
      analysis showed that laminin was composed of bands corresponding to the alpha 1,
      beta 1 and gamma 1 polypeptides. The correlation between the pattern of laminin
      expression and gland maturation suggests a role of laminin in the functional
      maturation of acinar cells.

PMID- 10335362
TI  - Motor neuron degeneration due to aluminium deposition in the spinal cord: a light
      microscopical study.
AB  - For a long time, aluminium has been considered as an indifferent element from a
      toxicological point of view. In recent years, it became clear that aluminium is a
      potential toxic agent in humans and has been implicated in the pathogenesis of
      several clinical disorders, such as dementia, respiratory tract disorders and
      allergic reactions. Chronic exposure to aluminium fumes, inhalation of aluminium
      and aluminium-oxide powder increase the risk to develop serious central nervous
      system pathology, in particular Alzheimer's disease and amyotrophic lateral
      sclerosis (ALS). In the present study, 3 experimental and 1 control group of rats
      were used to study the effects of aluminium on the central nervous system.
      Aluminium was injected intracisternally as a single dose (50 micrograms for group
      I, 100 micrograms for group II and 300 micrograms for group III) to the
      experimental groups (n = 5 in each group). The same dose was given at 3 months
      after the first injection to all groups. The control group (n = 5) was
      intracisternally given a physiological salt solution. Electromyography (EMG) was
      applied to the rats of the experimental groups. Rats were decapitated at 3 months
      after the second injections. Spinal cord samples from lumbar and cervical regions
      were removed and histological examination was performed. Light microscopical
      investigations revealed severe degeneration in motor neurons of the rats treated
      with 300 micrograms. Neurofibrillary tangle formation, chromatolysis and abnormal
      localization of the nuclei were found in swollen perikarya. Extreme loss of motor
      neurons with "ghost cell" appearance was found in that group. Sections of spinal
      cords of rats treated with lower doses of aluminium showed a moderate degree of
      motor neuron damage. EMGs of rats treated with the high dose of aluminium
      revealed severe acute denervation whereas treatment with lower doses resulted in
      moderate denervation. We conclude that aluminium may cause severe motor neuron
      damage in rat spinal cord resembling ALS.

PMID- 10335363
TI  - Mechanical compression of a fibrous membrane surrounding bone causes bone
      resorption.
AB  - Early micromovement and migration of a prosthesis of a hip or knee predicts late
      clinical loosening of the prosthesis. Such migration is likely to be associated
      with mechanical compression of the fibrous membrane interpositioned between bone
      and prosthesis during movement. Compression of the fibrous membrane by loading
      may lead to locally high fluid pressures reaching the underlying bone tissue. It
      has been established that high fluid pressures can lead to bone resorption. This
      resorption may eventually lead to clinical loosening of the prosthesis. We
      developed an experimental model to study the effects of compression of a soft
      tissue layer located between a titanium implant and cortical bone. In twelve
      rabbits, this device was implanted in the proximal tibia and allowed to
      osseointegrate. Next, a layer of soft tissue was allowed to form between titanium
      and bone. Subsequently, in six rabbits a cyclic load of 60 times in 2 min per day
      during 2 weeks was applied, leading to compression of the interpositioned soft
      tissue layer only. In the other six rabbits no load was applied. In all six
      loaded specimens, osteocyte death and bone resorption was observed underneath the
      area where compression of the fibrous membrane was exerted to a depth exceeding
      the amplitude of the loading device. Furthermore, formation of fibrocartilage was
      observed in the loaded areas. Formation of fibrocartilage, osteocyte death or
      bone resorption did not occur in the controls. Our results indicate that
      compression of a fibrous membrane surrounding bone can lead to resorption of the
      underlying bone primarily because of osteocyte death and subsequent resorption of
      dead bone tissue. This may explain the observation that early migration of a hip
      or knee prosthesis is predictive of clinical loosening of the prosthesis.

PMID- 10335365
TI  - Consumer perceptions and concerns about food contaminants.
AB  - More consumers are concerned about microbiological hazards than any other area.
      Pesticide residues generate concern, especially among low income consumers with
      less formal education. Use of antibiotics and hormones in animal production is
      considered a serious hazard by fewer consumers. Consumer attitudes are influenced
      by media coverage. An increasing number of consumers expect food producers and
      retailers to assume a major role in providing safe food. A majority of consumers
      express interesting in purchasing irradiated food when specific benefits are
      described and the percentage increases when irradiation is more fully described.
      In actual market experiences, irradiated produce and poultry have been well
      received. Similarly, most consumers are positive toward biotechnology, with
      greatest support for environmental applications. The scientific community should
      use the media to reach the public with information identifying risks and
      protective strategies, including the use of new technology.

PMID- 10335366
TI  - Microorganisms and microbial toxins.
AB  - The primary concern in food safety issues focuses on microorganisms and microbial
      toxins. Effective food preservation requires that the growth and proliferation of
      hazardous microorganisms be well controlled, and that the presence of significant
      quantities of microbial toxins in foods be prevented. The traditional effective
      preservation methodologies, such as canning, are being supplemented by new
      technologies which are less destructive of the food qualities. New strategies are
      therefore needed to prevent the transmission of microbial contamination or to
      prevent the formation of microbial toxins which remain in food. This paper
      discusses the role of modern processing methodologies in helping protect
      consumers from hazards of microbial origin.

PMID- 10335364
TI  - Immunohistochemical detection of collagen type III and IV in relation with
      transformation of Ito cells in liver sinusoids of patients with reactive biliary
      hepatitis.
AB  - Reactive biliary hepatitis is a defined morphological entity, which is a result
      of chronic diseases of the gall bladder, biliary ducts or pancreas. The aim of
      the present study was to describe the morphology of reactive biliary hepatitis
      and its significance for progression of liver fibrosis, and in particular Ito
      cell (fat storing cell) transformation and occurrence of collagen type III and IV
      in the liver. Liver tissue from 19 patients with reactive biliary hepatitis was
      investigated light microscopically and immunohistochemically. Histologically, the
      liver showed features of mild to severe portal and lobular inflammation. The
      number of Ito cells increased periportally and pericentrally. Deposition of
      collagen type III and IV was increased in portal tracts, septa and perisinusoidal
      spaces, mainly in periportal zones of the lobules. Ultrastructurally, collagen
      type III immunoreactive fibrillar networks were found to be increased in the
      space of Disse around transitional cells. Collagen type IV immunoreactive
      deposits were detected around newly proliferating bile ducts in portal stroma and
      in the space of Disse. Ito cells were mainly transformed into transitional and
      myofibroblast-like cells. We discuss here the role of Ito cells and certain
      cytokines in the process of fibrosis of the liver in the course of reactive
      biliary hepatitis. It is proposed that bile acid retention in bile ducts during
      non-specific reactive inflammation or a gut endotoxin may cause transformation of
      Ito cells and increased collagen type III and IV in this type of hepatitis.

PMID- 10335367
TI  - Food processing and lipid oxidation.
AB  - Food lipids are principally triacylglycerides, phospholipids and sterols found
      naturally in most biological materials consumed as food and added as functional
      ingredients in many processed foods. As nutrients, lipids, especially
      triglycerides, are a concentrated caloric source, provide essential fatty acids
      and are a solvent and absorption vehicle for fat-soluble vitamins and other
      nutrients. The presence of fat significantly enhances the organoleptic perception
      of foods, which partly explains the strong preference and market advantage of fat
      rich foods. As a class, lipids contribute many desirable qualities to foods,
      including attributes of texture, structure, mouthfeel, flavor and color. However,
      lipids are also one of the most chemically unstable food components and will
      readily undergo free-radical chain reactions that not only deteriorate the lipids
      but also: (a) produce oxidative fragments, some of which are volatile and are
      perceived as the off-flavors of rancidity, (b) degrade proteins, vitamins and
      pigments and (c) cross-link lipids and other macromolecules into non-nutritive
      polymers. Free-radical chain reactions are thermodynamically favorable, and as a
      result, evolutionary selection has strongly influenced the chemistry, metabolism
      and structure of biological cells to prevent these reactions kinetically.
      However, the loss of native structure and the death of cells can dramatically
      accelerate the deteriorative reactions of lipid oxidation. The effects of all
      processing steps, including raw product selection, harvesting, storage, refining,
      manufacturing and distribution, on the quality of lipids in the final commodity
      are considerable. Certain key variables now known to influence oxidative
      processes can be targeted to increase food lipid stability during and after
      processing. Retention of or addition of exogenous antioxidants is a well-known
      consideration, but the presence and activity of catalysts, the integrity of
      tissues and cells, the quantity of polyunsaturated lipids and the structural
      properties of the final food product, including total surface area of lipids, and
      the nature of surfactant materials all play important roles in final product
      stability.

PMID- 10335368
TI  - Impact of processing on formation of trans fatty acids.
AB  - Trans fatty acids are formed during hydrogenation which is done to improve the
      functionality and oxidative stability of oils. Several process conditions affect
      the content of trans fatty acids in hydrogenated oil. There is conflicting
      evidence as to whether intake of trans fatty acids, in foods such as margarine,
      affects the types and levels of cholesterol produced in the blood.
      Epidemiological studies have shown associated increases in total cholesterol and
      low density lipoproteins, as well as decreased levels of high density lipo
      proteins in the blood. It is unknown whether these effects are related directly
      to trans fatty acids or to the decrease of unsaturated fatty acids in the diet.
      This chapter will cover the recent nutritional status of trans fatty acids and
      the effect of processing on the levels of trans fatty acids in foods.

PMID- 10335369
TI  - Impact of high-temperature food processing on fats and oils.
AB  - Fats and oils are heated at high temperatures during baking, grilling and pan
      frying; however, deep fat frying is the most common method of high temperature
      treatment. Deep fat frying is a popular food preparation method because it
      produces desirable fried food flavor, golden brown color and crisp texture. For
      example, in the U.S. in 1994, approximately 12 billion pounds of fats and oils
      were used with 5.5 billion pounds used for frying and baking (USDA, 1995). Fried
      snack foods accounted for 2.9 billion pounds of oil, whereas 2 billion pounds
      were used for frying in restaurants (USDA, 1995). Because of such large
      consumption of frying oils and fats, the effects of high temperatures on these
      oils and fats is of major concern both for product quality and nutrition. This
      chapter will discuss the process of frying and the chemical and physical
      reactions that occur. The products formed from these reactions will be reviewed
      as well as information on the effects of the products and the control of these
      deteriorative reactions.

PMID- 10335370
TI  - Cholesterol oxidation products. Their occurrence and detection in our foodstuffs.
AB  - The structural similarity of cholesterol oxidation products (COP) to native
      cholesterol and their xenobiotic effects prompt researchers to study the long
      term effects of the assimilation of these compounds into our tissues. COP are
      present in our food system. The level of exposure changes as our food products
      and our food choices alter. Therefore, the presence of COP in our food system has
      to be carefully monitored and their presence in processed foods minimized by
      optimizing processing and storage conditions. This review will briefly discuss
      the chemistry of some commonly-occurring COP and their biological significance. A
      more in-depth survey of the literature on the pitfalls of COP determination is
      included. It is the intention of the author to impress the readers that
      'exogenous' COP can easily form during sample preparation. These artifacts will
      hinder our understanding of factors that promote COP formation in foods. The
      effects of heating, dehydrating, packaging and the presence of highly unsaturated
      lipids on the levels of COP in cholesterol-containing foods are evaluated to
      gauge the levels of exposure to different consumer groups.

PMID- 10335371
TI  - The impact of food processing on the nutritional quality of vitamins and
      minerals.
AB  - Processing (including preparation) makes food healthier, safer, tastier and more
      shelf-stable. While the benefits are numerous, processing can also be
      detrimental, affecting the nutritional quality of foods. Blanching, for example,
      results in leaching losses of vitamins and minerals. Also, milling and extrusion
      can cause the physical removal of minerals during processing. The nutritional
      quality of minerals in food depends on their quantity as well as their
      bioavailability. The bioavailability of key minerals such as iron, zinc and
      calcium is known to be significantly affected by the fiber, phytic acid, and
      tannin content of foods. Concentrations of these constituents are altered by
      various processing methods including milling, fermentation, germination
      (sprouting), extrusion, and thermal processing. Vitamins, especially ascorbic
      acid, thiamin and folic acid, are highly sensitive to the same processing
      methods. The time and temperature of processing, product composition and storage
      are all factors that substantially impact the vitamin status of our foods.

PMID- 10335372
TI  - Impact of processing on food allergens.
AB  - In general, allergenic foods are resistant to processes commonly used in food
      manufacturing. Nearly all the causative proteins (allergens) retain their
      allergenicity after treatment by heat and/or proteolysis. Notable exceptions
      exist; for example, the allergenicity of many fresh fruits and vegetables is
      decreased or removed by relatively mild processes such as gentle heating or
      mashing. The use of proteolytic enzymes to remove allergenicity is successfully
      used in the production of hypoallergenic infant formulas, but this approach with
      other allergenic foods has resulted in only limited success. Processing effects
      can result in decreased or complete removal of allergenic qualities of a food,
      such as the removal of proteins in oilseed processing, which renders the oils
      hypoallergenic and safe for consumption by allergic individuals. This discussion
      will address the different allergenic foods and processes which can affect or
      decrease their allergenicity.

PMID- 10335373
TI  - Postharvest changes in glycoalkaloid content of potatoes.
AB  - Potatoes contain antinutritional and potentially toxic compounds including
      inhibitors of digestive enzymes, hemagglutinins, and glycoalkaloids. Solanum
      glycoalkaloids are reported to inhibit cholinesterase, disrupt cell membranes,
      and induce teratogenicity. In this overview, we describe the role of potatoes in
      the human diet, reported changes in glycoalkaloid content of fresh and processed
      potatoes during storage, under the influence of light and radiation, following
      mechanical damage, and as a result of food processing. Also covered are safety
      aspects and suggested research needs to develop a protocol that can be adopted by
      the potato producers and processors to minimize post-harvest synthesis of
      glycoalkaloids in potatoes. Reducing the glycoalkaloid content of potatoes will
      provide a variety of benefits extending from the farm to processing, shipping,
      marketing, and consumption of potatoes and potato products. A commercially
      available ELISA kit is described which permits rapid assay of glycoalkaloid
      content of parts of the potato plant including leaves, tubers, and peel, as well
      as processed potato products including french fries, chips, and skins.
      Understanding the multiple overlapping aspects of glycoalkaloids in the plant and
      in the diet will permit controlling postharvest glycoalkaloid production for the
      benefit of the producer and consumer.

PMID- 10335374
TI  - Lysinoalanine in food and in antimicrobial proteins.
AB  - Heat and alkali treatment of food proteins widely used in food processing results
      in the formation of crosslinked amino acids such as lysinoalanine,
      ornithinoalanine, lanthionine, and methyl-lanthionine and concurrent racemization
      of L-amino acid isomers to D-analogues. The mechanism of lysinoalanine formation
      is a two-step process: first, hydroxide ion-catalyzed elimination of cysteine and
      serine residues to a dehydroalanine intermediate; second, reaction of the double
      bond of dehydroalanine with the epsilon-NH2 group of lysine to form a
      lysinoalanine crosslink. The corresponding elimination-addition reaction of
      threonine produces methyl-dehydroalanine, which then reacts with the NH2 and SH
      groups to form methyl-lysinoalanine and methyl-lanthionine, respectively. The
      crosslinked amino acids lanthionine and methyl-lanthionine are formed by
      analogous nucleophilic addition reactions of the SH group of cysteine to
      dehydroalanine and methyl-dehydroalanine, respectively. Processing conditions
      that favor these transformations include high pH, temperature and exposure time.
      Factors which minimize lysinoalanine formation include the presence of SH
      containing amino acids such as cysteine, N-acetyl-cysteine, and glutathione,
      dephosphorylation of O-phosphoryl esters, and acylation of epsilon-NH2 groups of
      lysine side chains. The presence of lysinoalanine residues along a protein chain
      decreases digestibility and nutritional quality in rodents but enhances
      nutritional quality in ruminants. Protein-bound and free lysinoalanines are
      reported to induce enlargement of nuclei of rat kidney cells. All of the
      mentioned dehydro and crosslinked amino acids also occur naturally in certain
      peptide and protein antibiotics. These include duramycin, cinnamycin, epidermin,
      subtilin and the widely used food preservative nisin. Mechanistic
      rationalizations are offered for the observed antimicrobial activities of these
      compounds in relation to their structures. The cited findings and new research to
      better define the chemistry and dietary and antimicrobial roles of lysinoalanine
      and related compounds should lead to better and safer foods.

PMID- 10335375
TI  - Influence of feeding alkaline/heat processed proteins on growth and protein and
      mineral status of rats.
AB  - Effects of feeding alkaline (0.1 N NaOH) and heat treated (75 degrees C for 3 h)
      proteins (lactalbumin and soybean protein isolate, SPI) on growth, and protein
      and mineral status of rats have been determined. The untreated and alkaline/heat
      treated lactalbumin contained 0.10 and 4.42 g lysinoalanine (LAL)/100 g protein,
      respectively. Similarly, the untreated and treated SPI contained 0.03 and 1.94 g
      LAL/100 g protein, respectively. The formation of LAL in the treated proteins was
      accompanied with a loss of cystine (73-77%), threonine (35-45%), serine (18-30%)
      and lysine (19-20%). The alkaline/heat treatments caused significant (P < 0.05)
      reductions in protein digestibility of lactalbumin (99 vs. 73%) and SPI (96 vs.
      68%). The processing treatments also caused a drastic negative effect on protein
      quality, as measured by rat growth methods such as relative protein efficiency
      ratio (RPER) and relative net protein ratio (RNPR). The RPER and RNPR values of
      untreated lactalbumin and SPI were 89-91 and 56-64%, respectively. But the RPER
      and RNPR values of the treated lactalbumin and SPI were 0%. The mineral status of
      rats was also compromised by feeding alkaline/heat treated proteins. Liver iron
      levels in male rats (165-180 micrograms/g dry weight) and female rats (306-321
      micrograms/g dry weight) fed the treated proteins were about half the levels in
      male rats (229-257 micrograms/g dry weight) and female rats (578-697 micrograms/g
      dry weight) fed the untreated proteins. The kidney iron contents of rats fed the
      treated proteins were also lower than that of rats fed the untreated proteins.
      Liver copper levels of male and female rats fed the treated proteins were up to
      three fold higher than those found in rats fed the untreated proteins. The data
      suggested that LAL, an unnatural amino acid derivative formed during processing
      of foods, may produce adverse effects on growth, protein digestibility, protein
      quality and mineral bioavailability and utilization. The antinutritional effects
      of LAL may be more pronounced in sole-source foods such as infant formulas and
      formulated liquid diets which have been reported to contain significant amounts
      (up to 2400 ppm of LAL in the protein) of LAL.

PMID- 10335376
TI  - Food heating and the formation of heterocyclic aromatic amine and polycyclic
      aromatic hydrocarbon mutagens/carcinogens.
AB  - Heterocyclic aromatic amines (HAA) and polycyclic aromatic hydrocarbons (PAH) are
      mutagens and animal carcinogens sometimes formed when foods are heated or
      processed. Determining their role in cancer etiology depends on comparing human
      exposures and determining any significant dose-related effects. Chemical analysis
      of foods shows that flame-grilling can form both PAH and HAA, and that frying
      forms predominantly HAA. With detection limits of about 0.1 ng/g, amounts found
      in commercially processed or restaurant foods range from 0.1 to 14 ng/g for HAA,
      and levels of PAH up to 1 ng/g in a liquid smoke flavoring. Laboratory fried
      samples have greater amounts of PAH, up to 38 ng/g in hamburgers, and high levels
      of HAA, over 300 ng/g, are measured in grilled chicken breast. Understanding the
      processing conditions that form PAH and HAA can lead to methods to greatly reduce
      their occurrence in processed foods.

PMID- 10335377
TI  - Effects of processing of heavy metal content of foods.
AB  - Metals occur in all foodstuffs. Of particular concern is the presence of toxic
      metals, which include lead, cadmium, arsenic and mercury. The toxic metal content
      of foods is influenced by many factors ranging from environmental conditions
      during growth to post-harvest handling, processing, preparation and cooking
      techniques. For example, metal content increases in some commodities grown in
      contaminated soils or atmospheres while post-harvest handling steps such as
      washing generally remove metal contaminants. Cooking may reduce metal content
      although some foods can absorb metals if the cooking water is contaminated.
      Metals used in food processing equipment or food packaging material may
      contribute to food contamination. Contamination may also occur during kitchen
      preparation and storage. This paper will review the effects of processing of
      foods on toxic metal content. A broad interpretation of processing, to include
      aspects of food production from growth through cooking, will be taken in
      discussing the toxic metal content of foods. Specific examples of changes in
      metal content due to processing will be discussed.

PMID- 10335378
TI  - Polychlorinated biphenyls, polybrominated biphenyls, and dioxin reduction during
      processing/cooking food.
AB  - This chapter presents information on the levels of environmental contaminants
      found in recent market basket surveys as well as the effect of processing and
      cooking on the reduction of these contaminants. Although consumers have expressed
      concern over the level of environmental contaminants in the food supply, market
      basket surveys involving over 8,000 analyses of foods ready-to-eat, found
      measurable amounts (ppb levels) of PCBs in only 24 foods. Processing/cooking has
      been shown to reduce PCBs by 20-100%. Although PBBs got into the food chain as
      the result of one incredible accident and thus are not expected to be found in
      foods today, cooking/processing was also effective in reducing PBBs. Dioxins are
      the result of combustion processes and chemical manufacturing processes. TCDD
      levels found in Great Lakes fish were in the low part per trillion level. Again,
      cooking and processing resulted in substantially less TCDD in fish as eaten.

PMID- 10335379
TI  - The effect of processing on veterinary residues in foods.
AB  - Heat stability of antibiotics in foods to cooking has been determined by a
      variety of methods. These include heating in such liquid media as milk, water,
      buffers and meat extracts, and in solids such as buffered meat homogenates and
      various sausages. Inactivation of incurred residues in tissues and eggs was also
      studied. Time and temperature of heating were more easily controlled in liquid
      media, but results in actual meat products are more indicative of actual cooking
      processes. Ordinary cooking procedures for meat, even to "well-done", cannot be
      relied on to inactivate even the more heat sensitive compounds such as
      penicillins and tetracyclines. More severe heating as for canning or prolonged
      cooking with moist heat can inactivate the more heat sensitive compounds. The
      relevance to food safety is uncertain since the nature of the degradation
      products is unknown in most cases.

PMID- 10335381
TI  - Novel chemicals from plants via bioengineering. An overview.
AB  - Novel chemicals were traditionally extracted from medicinal plants or produced
      synthetically. However, new development in the field of bioengineering has
      allowed production of novel products from plants such as edible and industrial
      oils as well as specific chemicals which could be used as foods with remedial
      effects.

PMID- 10335380
TI  - Effect of processing on Fusarium mycotoxins.
AB  - Mycotoxins are secondary metabolites produced by a wide variety of fungal species
      that contaminate food or feed. Fumonisins (FUM), deoxynivalenol (DON) and
      zearalenone (ZEN) are examples of common mycotoxins in grains that have been
      shown to affect human and/or animal health. Physical, chemical and biological
      methods have been used for decontaminating grains containing these toxins. Some
      treatments reduce the concentration of mycotoxins while others are ineffective.
      For example, removal of damaged grain by density segregation can reduce DON and
      ZEN concentrations in corn and wheat. In contrast, thermal processing is usually
      ineffective for reducing the FUM and ZEN content of foods. More work is needed to
      identify effective methods for detoxifying mycotoxin contaminated food.

PMID- 10335382
TI  - Recent progress in agricultural biotechnology and opportunities for contract
      research and development.
AB  - The global market for agriculture products and agriculture-based value-added
      products is undergoing change as the top players in agriculture and agricultural
      biotechnology face increased consolidation and ultimately form alliances in
      development, production and marketing. Transgenic plants for human consumption
      and industrial applications are entering the marketplace. Novel, genetically
      engineered, plant-based organisms (GMO) designed for resistance to herbicides,
      pesticides and environmental stress or for the production of valuable chemicals,
      pharmaceuticals and vaccines are available. A growing demand for bioprocessing,
      test production, scale-up or providing data for registration has created new
      opportunities for contract research and development (CR&D) firms.

PMID- 10335383
TI  - Manipulation of plant oil composition for the production of valuable chemicals.
      Progress, problems, and prospects.
AB  - The first transgenic crop with a modified seed oil composition was released for
      commercial use in 1995. Many additional transgenic rapeseed varieties expressing
      novel seed oils or proteins are now under development. Recent research advances
      in Arabidopsis molecular genetics and the emerging relatedness between the
      Arabidopsis and Brassica genomes will enable more radical manipulation of many
      key agronomic traits in rapeseed. These will range from greatly improved seed oil
      yield to the production of seed oils with defined fatty acid contents ranging
      from C8 to C24 chain lengths and including many desirable functionalities
      including double bonds, triple bonds, hydroxy and epoxide groups. Much of the
      technology currently being development in rapeseed and soybean oil modification
      will be directly applicable to other oil crops including high yield tropical
      perennials such as oil palm.

PMID- 10335384
TI  - Biosynthesis of ricinoleate in castor oil.
AB  - Castor oil is 90% ricinoleate (12-hydroxyoleate) and has numerous industrial
      uses. Components of castor bean (Ricinus communis L.) pose serious problems to
      processors. Other researchers have cloned the gene for the oleoyl hydroxylase,
      but transgenic plants produce only about 20% hydroxy fatty acid. To improve such
      transgenic substitutes for castor, we are using HPLC analysis of castor bean
      microsomal suspensions to follow the hydroxylase reaction and the movement of 14C
      ricinoleate through phospholipid into triacylglycerol. Most labeled ricinoleate
      is rapidly removed from the phospholipid fraction as free fatty acid and
      incorporated into triacylglycerol, with triricinolein predominating. Elucidation
      of the basis for high incorporation of ricinoleate and exclusion of oleate from
      triacylglycerols will identify genes that can be used to engineer high
      ricinoleate production in transgenic plants.

PMID- 10335385
TI  - Monoterpenes in essential oils. Biosynthesis and properties.
AB  - Monoterpenes are compounds found in the essential oils extracted from many
      plants, including fruits, vegetables, spices and herbs. These compounds
      contribute to the flavor and aroma of plant from which they are extracted.
      Monoterpenes are acyclic, monocyclic, or bicyclic C30 compounds synthesized by
      monoterpene synthases using geranyl pyrophosphate (GPP) as substrate. GPP is also
      the precursor in the synthesis of farnesyl pyrophosphate (FPP) and geranyl
      geranyl pyrophosphate (GGPP), two important compounds in cell metabolism of
      animals, plants and yeast. Monoterpene cyclases produce cyclic monoterpenes
      through a multistep mechanism involving a universal intermediate, a terpinyl
      cation which can be transformed to several compounds. Experimental studies, using
      animal cancer models, have demonstrated that some monoterpenes possess
      anticarcinogenic properties, acting at different cellular and molecular levels.
      From these discoveries it seems clear that monoterpenes could be considered as
      effective, nontoxic dietary antitumorigenic agents that hold promise as a novel
      class of anticancer drugs.

PMID- 10335387
TI  - Towards the production of salt-tolerant crops.
AB  - Crop production is affected by numerous environmental factors, with soil salinity
      and drought having the most detrimental effects. Attempts to improve yield under
      stress conditions by plant breeding have been unsuccessful, primarily due to the
      multigenic origin of the adaptive responses. The transfer of genes through
      genetic engineering of crop plants appears more feasible. Important adaptive
      mechanisms targeted for potential gene transfer would be the tonoplast Na+/H+
      antiport, compatible solute synthesis and, regulation of water channel activity
      and expression, mechanisms involved in cellular osmoregulation. In this review we
      discuss recent advances in our understanding of these adaptive mechanisms.

PMID- 10335386
TI  - Biochemical and molecular tools for the production of useful terpene products
      from pepper (Capsicum annuum).
AB  - Among other natural products such as colorants and flavorants, natural fungicides
      like the pepper phytoalexin capsidiol, and the related biochemical pathways, may
      be used for practical approaches. Key enzymes such as 3-hydroxy-3-methylglutaryl
      Coenzyme A: reductase, the farnesyl pyrophosphate synthase and and farnesyl
      pyrophosphate cyclases are known and some related genes have been isolated.
      However, specific enzymes for important and final modifications as methylation
      and others, are still to be studied. Construction of chimeric enzymes allowed
      already the synthesis of different products and the possibilities of designing
      new enzymes by gene manipulation to produce unknown and useful chemicals are
      open.

PMID- 10335388
TI  - Combinatorial chemistry and its applications in agriculture and food.
AB  - Combinatorial chemistry has become a major focus of research activity in the
      pharmaceutical industry for development new therapeutic compounds. The same
      techniques could be potentially applied to benefit agricultural and food
      research. This article reviews the various procedures used in combinatorial
      chemistry, outlines some of the strengths and limitations of the various methods,
      and proposes potential areas in agriculture and food that could be benefited by
      this technology. These areas include developing new antimicrobial agents,
      antioxidants, and other additives, creating antigen-binding molecules for the
      detection or removal of food pathogens or toxicants, engineering food proteins
      and enzymes for specific functions, and modifying biosynthetic pathways for the
      production of novel natural products.

PMID- 10335389
TI  - Biological nitrogen fixation and future challenges of agriculture. The endophytic
      connection.
AB  - Feeding the growing global population, anticipated to be 8 billion by the year
      2020, is one of the most important recent challenges of agriculture. The increase
      in cereal grain yield, to cope with this demand, directly implies a dramatic
      increase in the use of nitrogen-based fertilizers and agrochemicals. Some of
      these intensive agricultural practices have progressive detrimental effects on
      the environment. This review is focused on some novel insights gained into the
      understanding of associative and symbiotic interactions of plants with nitrogen
      fixing organisms that makes Biological Nitrogen Fixation (BNF) a viable answer to
      this compelling dilemma.

PMID- 10335390
TI  - Molecular strategies to improve the nutritional quality of legume proteins.
AB  - Legume proteins are relatively deficient in the sulfur amino acids. Among the
      different strategies to increase the sulfur amino acid contents of legumes, we
      have chosen to increase the biosynthesis of endogenous, non-abundant sulfur-rich
      proteins we have identified in soybean seed. We identified and isolated an 8 kDa
      sulfur-rich protein from the albumin fraction of soybean seed. Subsequently, a
      cDNA designated Gm2S-1, has been isolated and characterized. The Gm2S-1 cDNA
      encodes a pre-proprotein that contains a signal peptide and a precursor protein
      that undergoes post-translational processing to yield the mature 8 kDa protein
      containing 7.8% methionine and 7.8% cysteine. The Gm2S-1 gene is an ideal
      candidate for overexpression to improve the nutritional quality of soybean and
      other legumes.

PMID- 10335391
TI  - Molecular farming of industrial proteins from transgenic maize.
AB  - Recombinant egg white avidin and bacterial B-glucuronidase (GUS) from transgenic
      maize have been commercially produced. High levels of expression were obtained in
      seed by employing the ubiquitin promoter from maize. The recombinant proteins had
      activities that were indistinguishable from their native counterparts. We have
      illustrated that down-stream activities in the production of these recombinant
      proteins, such as stabilizing the germplasm and processing for purification, were
      accomplished without any major obstacles. Avidin (A8706) and GUS (G2035) are
      currently marketed by Sigma Chemical Co.

PMID- 10335392
TI  - Improvements in human health through production of human milk proteins in
      transgenic food plants.
AB  - Plants are particularly suitable bioreactors for the production of proteins, as
      their eukaryotic nature frequently directs the appropriate post-translational
      modifications of recombinant proteins to retain native biological activity. The
      autotrophic growth of plants makes this in vivo biosynthesis system economically
      competitive for supplementation or replacement of conventional production systems
      in the future. For the production of biologically active proteins, food plants
      provide the advantage of direct delivery via consumption of transformed plant
      tissues. Here we describe the production of recombinant human milk proteins in
      food plants for improvements in human nutrition and health, with emphasis on
      enhanced nutrition for non-breast fed infants as well as children and adults.
      Nutritional improvements in edible plants generated through advancements in
      recombinant DNA technology are rapidly repositioning the world for enjoyment of a
      more healthful diet for humans in all age groups.

PMID- 10335393
TI  - Food plant-delivered cholera toxin B subunit for vaccination and
      immunotolerization.
AB  - Developments in recombinant DNA technology have enabled molecular biologists to
      introduce a variety of novel genes into plant species for specific purposes. From
      crop improvement to vaccine antigen and antibody production, plants are
      attractive bioreactors for production of recombinant proteins, as their
      eukaryotic nature often permits appropriate post-translational modification of
      recombinant proteins to retain native biological activity. The autotrophic growth
      of plants requires only soil minerals, water, nitrogen, sunlight energy and
      carbon dioxide for the synthesis of constituent proteins. Furthermore, production
      of biologically active proteins in food plants provides the advantage of direct
      delivery through consumption of edible transformed plant tissues. The production
      of cholera toxin B subunit in potato plants and applications for prevention of
      infectious and autoimmune disease are explained in this contribution.

PMID- 10335394
TI  - Autoantigens produced in plants for oral tolerance therapy of autoimmune
      diseases.
AB  - Oral administration of protein antigens can induce antigen-specific immune
      hyporesponsiveness and may be useful in treating autoimmune diseases or
      preventing transplant rejection. However, the therapeutic value of oral tolerance
      may be limited when candidate autoantigens cannot be produced by conventional
      system in quantities sufficient for clinical studies. Plants may be ideally
      suited for this purpose, as they can produce hugh quantities of functional
      mammalian proteins at extremely competitive cost. Furthermore, transgenic food
      plants could provide a simple and direct method of autoantigen delivery for oral
      tolerance. Here we show that the diabetes-associated autoantigen glutamic acid
      decarboxylase (GAD) is efficiently expressed in both tobacco and potato plants,
      and that mice, when fed with fresh transgenic potato tubers, are fully protected
      from diabetes.

PMID- 10335396
TI  - Production of recombinant blood factors in transgenic plants.
AB  - The production of recombinant proteins for therapeutic use in transgenic plants
      has become an alternative to the isolation of these molecules from natural or
      other recombinant sources. Plant bioreactors offer the possibility of an
      inexpensive large scale production of high volumes of recombinant proteins with
      increased safety concerning contaminations with human pathogens. Several
      laboratories are involved in the commercial production of the first recombinant
      products, such as antibodies or recombinant human hemoglobin, from transgenic
      plants.

PMID- 10335397
TI  - Recent progress in biotechnology of Mexican medicinal plants.
AB  - Based on traditional medicinal knowledge, it was possible to identify the plant
      species Solanum chrysotrichum as the source of a new antimycotic agent designated
      SC-1. Cell suspension batch cultures from this plant were established in shake
      flasks, in which the production of SC-1 was optimized, reaching values fifty
      times higher than those registered in field grown plants. Large-scale cultivation
      of the active biomass from S. chrysotrichum was established in 10 l airlift
      bioreactors, and productivity levels of SC-1 were increased by 60% when using a
      draw-fill mode in the bioreactors.

PMID- 10335395
TI  - Production of food related colorants by culture of plant cells. The case of
      betalains.
AB  - Betalains are vacuole pigments produced solely by Caryophyllales plants and few
      superior fungi. For many years, betalains have been used as food colorants. The
      aim of the present chapter is to present relevant aspects related to betalains
      characteristics and feasibility of their industrial production in bioreactors.

PMID- 10335398
TI  - Chemicals from roots, hairy roots, and their application.
AB  - Plants produce thousands of different compounds through the secondary metabolism
      pathways. Since many of these products are obtained by direct extraction from
      plants that are cultivated in the field or some times even collected in their
      original habitat several factors can alter their yield. The use of plant cell
      cultures has overcome several inconveniences for the production of secondary
      metabolites. Organized cultures, and especially root cultures, can make a
      significant contribution to our understanding of secondary metabolism.
      Furthermore, a new alternative has arisen: transformed root cultures. Until now,
      hairy roots have been obtained from more than 100 different species. The products
      that they are able to produce range from alkaloids to aromatic compounds and
      dyes. These kinds of cultures have turned out to be an invaluable tool to study
      the biochemistry and the gene expression of the metabolic pathways in order to
      elucidate the intermediaries and enzymes involved in the biosynthesis of
      secondary metabolites.

PMID- 10335399
TI  - Human immunodeficiency virus type 1 entry and chemokine receptors: a new
      therapeutic target.
AB  - After the identification of CD4 as the primary receptor for human
      immunodeficiency virus (HIV) type 1 entry into cells of the immune system, it
      soon became clear that CD4 alone was not sufficient to establish a productive
      infection. The search for the second receptors or co-receptors started over 10
      years ago, and it was not until 1996 that G protein-coupled 7-transmembrane
      receptors, CXCR4 and CCR5 were finally identified as the co-receptors for HIV-1
      entry. The 7-transmembrane receptor family is a familiar therapeutic target for a
      number of diseases, and therefore these recent findings represent an exciting
      opportunity for new therapeutic approaches to the treatment of HIV-1 infection.

PMID- 10335400
TI  - Isolation and characterization of novel human immunodeficiency virus integrase
      inhibitors from fungal metabolites.
AB  - We have identified a series of novel inhibitors of human immunodeficiency virus
      type 1 (HIV-1) integrase by randomly screening natural product extracts using an
      in vitro biochemical assay designed to identify inhibitors of integrase-catalysed
      strand transfer. Equisetin recovered from the fungus Fusarium heterosporum and a
      novel enantiomeric homologue of equisetin from Phoma sp. were isolated as
      inhibitors of HIV-1 integrase in vitro. Two additional analogues, a novel decalin
      derivative, integric acid, and oteromycin were also discovered to be inhibitors
      of integrase. Equisetin and related compounds inhibit 3' end-processing and
      strand transfer as well as disintegration catalysed by either the full-length
      enzyme or the truncated integrase core domain (amino acids 50-212). These
      compounds also inhibit strand transfer reactions catalysed by stable complexes
      assembled in vitro and integration reactions catalysed by pre-integration
      complexes isolated from HIV-1-infected cells. The compounds described in this
      report are structurally novel and mechanistically distinct from many previously
      described inhibitors of HIV-1 integrase. These results demonstrate the utility of
      using an appropriately configured assay to identify compounds that are effective
      post-assembly and the potential of isolating novel integrase inhibitors from
      complex natural product extracts.

PMID- 10335401
TI  - Inhibition of human immunodeficiency virus replication by RD6-Y664, a novel
      benzylhydroxylamine derivative.
AB  - We have examined novel benzylhydroxylamine derivatives for their inhibitory
      effects on the replication of human immunodeficiency virus (HIV) in cell
      cultures. Among the series, O-(2-chloro-6-fluorobenzyl)hydroxylamine (RD6-Y664)
      was found to be the most potent inhibitor of HIV-1. The EC50 for HIV-1 strain
      IIIB was 1.6 micrograms/ml with a selectivity index greater than 38 in MT-4
      cells. It also inhibited the replication of other HIV strains including a non
      nucleoside reverse transcriptase (RT) inhibitor-resistant mutant, a nucleoside RT
      inhibitor-resistant mutant and HIV-2, in acutely infected cells. However, the
      compound did not affect HIV-1 production in chronically infected cells. A time-of
      addition experiment and detection of proviral DNA synthesis suggested that RD6
      Y664 targeted an early step of the viral replication cycle, presumably a process
      prior to reverse transcription. In fact, an assay for HIV-1 RT revealed that the
      compound did not suppress enzyme activity. Furthermore, RD6-Y664 did not show any
      inhibition of gp120-CD4 interaction, or binding of anti-CXCR4 antibody to CXCR4.

PMID- 10335402
TI  - Pyrido [1,2a] indole derivatives identified as novel non-nucleoside reverse
      transcriptase inhibitors of human immunodeficiency virus type 1.
AB  - Pyrido [1,2a] indole derivatives were identified as potent inhibitors of human
      immunodeficiency virus type 1 (HIV-1) replication during a random screening
      programme. The compounds showed no antiviral activity against HIV-2 or in cells
      chronically infected with HIV-1, but had good inhibitory effect against purified
      HIV-1 reverse transcriptase (RT) in an in vitro assay. They were therefore
      classified as non-nucleoside RT inhibitors (NNRTI). The synthesis of additional
      compounds of the same class revealed a structure-activity relationship. The most
      potent compound of the series, BCH-1, had similar antiviral activity to the
      licensed NNRTI nevirapine against laboratory strains of HIV-1 cultured in cell
      lines and primary clinical isolates of HIV-1 cultured in peripheral blood
      mononuclear cells. However, BCH-1 showed greater cytotoxicity, providing a narrow
      selectivity index in the order of 35. BCH-1 had equivalent antiviral activity
      against viruses resistant to the nucleoside RT inhibitors zidovudine, didanosine
      and lamivudine and maintained better activity (less than threefold change in
      IC50) than nevirapine against viruses resistant to a range of NNRTIs with the
      single amino acid changes L100I, K103N, E138K or Y181C in the RT. Viruses with
      single V106A or Y188C amino acid changes showed five- and 10-fold resistance to
      BCH-1, respectively, in contrast to nevirapine, which had a > 100-fold change in
      IC50. However, virus with both V106A and Y188C amino acid changes showed higher
      level resistance (> 15-fold) to BCH-1. Virus with > 10-fold resistance to BCH-1
      was rapidly selected for after growth in increasing concentrations of compound
      and was shown to be cross-resistant to nevirapine. Sequencing of this virus
      revealed two amino acid changes at positions 179 (V to D) and 181 (Y to C) in the
      RT. BCH-1 represents a new class of NNRTI, which may act as a lead to identify
      more selective compounds.

PMID- 10335403
TI  - Synthesis and antiviral activity of 6-benzoyl-benzoxazolin-2-one and 6-benzoyl
      benzothiazolin-2-one derivatives.
AB  - The synthesis and antiviral activity of an original series of 6-benzoyl
      benzoxazolin-2-one and 6-benzoyl-benzothiazolin-2-one derivatives are described.
      Several compounds were found to have a selective inhibitory activity against
      human cytomegalovirus (HCMV) and varicella-zoster virus (VZV) in vitro, being
      inactive against a variety of other DNA and RNA viruses. 6-(3
      fluorobenzoyl)benzoxazolin-2-one, 6-(3-fluorobenzoyl)benzothiazolin-2-one, 6-(3
      bromobenzoyl)benzothiazolin-2-one, 6-(3-iodobenzoyl)benzothiazolin-2-one, 3
      methyl-6-(3-fluorobenzoyl)benzothiazolin-2-one, 3-benzyl-6-benzoyl-benzothiazolin
      2-one, 3-benzyl-6-(3-fluorobenzoyl)benzothiazolin-2-one and 3-benzoyl-6-(3
      fluorobenzoyl)benzothiazolin-2-one were the most active of the series against
      HCMV and VZV with a selectivity index (CC50/IC50) ranging from 10 to 20. They
      displayed similar activity against thymidine kinase competent (TK+) and deficient
      (TK-) VZV strains, and also proved to be active against clinical HCMV isolates
      that were resistant to ganciclovir (GCV). Time-of-addition experiments revealed a
      site of interaction with the HCMV replicative cycle that may be close or similar
      to that of GCV and cidofovir (HPMPC). The compounds showed poor, if any, activity
      against herpes simplex virus type 1 (HSV-1) and HSV-2, and were not inhibitory
      against human immunodeficiency virus and other DNA and RNA viruses. Therefore,
      these compounds may represent a novel lead for the development of specific HCMV
      and VZV drugs.

PMID- 10335404
TI  - [Chemical synthesis of cytochrome P-450-dependent metabolites of arachidonic
      acid].
AB  - Approaches to the chemical synthesis of cytochrome P-450-dependent metabolites of
      arachidonic acid and the biological role of novel metabolites in the arachidonic
      acid cascade are discussed.

PMID- 10335405
TI  - [Study of the antigenic structure of tick-borne encephalitis virus using
      synthetic peptides].
AB  - A number of peptides, fragments of the envelope protein E of the tick-borne
      encephalitis virus (Sofjin strain), were synthesized. Their binding to the
      polyclonal antiserum to protein E was studied. Rats were immunized with both the
      free peptides and their KLH-conjugates, and the resulting antisera were tested
      for their reactivity toward protein E and for their neutralizing activity toward
      the virus in cell culture. The only peptide corresponding to the 98-113 sequence
      of protein E was shown to be bound by the protein E antiserum in EIA. Two-fold
      immunization of rats with KLH-conjugates of the peptides corresponding to the 98
      113, 130-143, and 394-403 sequences of protein E resulted in antipeptide
      antibodies capable of binding the native protein E, and the antibodies to the 98
      113 and 394-403 peptides were capable of neutralizing the virus.

PMID- 10335408
TI  - [Long terminal repeat of the human endogenous retrovirus HERV-K in the intron of
      the ZNF91 gene].
AB  - The relative positions of the ZNF91 gene (exon-intron organization) and the HERV
      K human endogenous virus long terminal repeat (LTR), which was earlier found to
      be located in the ZNF91 gene locus, on the EcoRI restriction metric map of the
      human chromosome 19 were determined with a high resolution. The direction of the
      ZNF91 gene transcription relative to the chromosome 19 telomeres was determined.
      The HERV-K LTR was localized to the ZNF91 gene intron 19. The role of retroviral
      sequences in the evolution of the ZNF91 gene family is discussed.

PMID- 10335407
TI  - [Structural-functional characteristics of the Schizosaccharomyces pombe rpb8+
      gene, coding the subunit of RNA polymerase I-III, specific only for eukaryotes].
AB  - A full-length cDNA of the rpb8+ gene encoding a common subunit Rpb8 of nuclear
      RNA polymerases I-III only specific for Eucarya was isolated from an expression
      library of the fission yeast Schizosaccharomyces pombe. The primary structure of
      the corresponding fragment of the Sz. pombe genome was also established. The
      rpb8+ gene contains two short introns, 59 and 48 bp long. Only short segments of
      homology were found upon comparing the Rpb8 subunit homologs from various
      eukaryotic species, and substantial differences exist between the corresponding
      proteins of unicellular and multicellular organisms. Subunit Rpb8 of Sz. pombe
      proved to be the smallest one among the known related proteins: it lacks the 21
      aa fragment corresponding to amino acids residues 68-88 of the central part of
      the homologous subunit ABC14.5 of Saccharomyces cerevisiae. Accordingly, subunit
      Rpb8 of the fission yeast was not capable of substituting in vivo subunit ABC14.5
      in nuclear RNA polymerases of the baker's yeast.

PMID- 10335406
TI  - [Isolation of trypsin PC from the Kamchatka crab Paralithodes camtschatica and
      its properties].
AB  - Trypsin PC from the hepatopancreas of the king crab Paralithodes camtschatica was
      isolated and purified to apparent homogeneity by ion-exchange chromatography on
      Aminosilochrom and DEAE-Sephadex and affinity chromatography on arginine-agarose.
      The yield of the enzyme was 37.7%, and the purification degree was 21. Trypsin PC
      has a molecular mass of 29 kDa and pI < 2.5. It hydrolysis N-benzoyl-L-arginine p
      nitroanilide at the optimum pH of 7.5-8.0 and at the temperature optimum of 55
      degrees C (K(m) = 0.05 mM). Trypsin PC retained its activity within the pH range
      of 5.8-9.0 in the presence of Ca2+. The enzyme was inhibited by the specific
      inhibitors of serine proteases diisopropyl fluorophoshate and
      phenylmethylsulfonyl fluoride, by the trypsin inhibitor N-tosyl-L
      lysylchloromethylketone, and by the trypsin inhibitors from soybean and potato.
      Trypsin PC was found to hydrolyze amide bonds formed by carboxylic groups of
      lysine and arginine in peptide substrates. The N-terminal sequence of this enzyme
      is IVGGTEVTPG.

PMID- 10335409
TI  - [Interactions of derivatives of short oligonucleotides with nucleic acids. VII.
      Effect of conformation changes in the duplex structure on on the specificity and
      efficacy of modification of target DNA by alkylating oligonucleotide
      derivatives].
AB  - The modification of a target DNA by alkylating oligonucleotide derivatives
      possessing various capacities for complex formation was studied. The binding
      properties of oligonucleotides were changed either by increasing their length
      (tetra-, octa-, and dodecamers) or by introducing a point substitution and/or an
      N-(2-hydroxyethylphenazinium) residue. It was found that conformational changes
      occurring in the structure of the target.reagent complex upon elevating the
      reaction temperature affect the efficiency and site-specificity of the
      alkylation. In the case of complete saturation of the target with the reagent, an
      increase in the hybridization ability of the reagent reduced the efficiency of
      the target modification. It was found that the modification by the
      tetranucleotide reagent (in the presence of an effector adjacent to the 3' end)
      occurs exclusively at an intracomplex target base. In the case of the dodecamer,
      which forms a stable, highly cooperative complex with the target, several bases
      of the target undergo alkylation, and an increase in temperature changes the site
      specificity of alkylation. In this process, the redistribution of the target
      modification sites toward stronger nucleophilic centers enhances alkylation at
      temperatures near the melting temperature of the target.dodecanucleotide complex
      despite a decrease in the extent of target association.

PMID- 10335410
TI  - [Ser/Thr-phosphatases from bovine retina: detection of cDNA coding for the
      catalytic subunit of the gamma-isoform PP2B and two homologs of rdgC/PPEF].
AB  - The expression of genes for Ser/Thr phosphatases of the PP1/2A/2B class in the
      bovine retina was analyzed using PCR on cDNA. The mRNAs were found for the
      following phosphatases: PP1 (alpha- and gamma-isoforms), PP2A (alpha- and beta
      isoforms), PPV, and PP2B (beta- and gamma-isoforms). Earlier, PP2B gamma-isoform
      was considered testis-specific. cDNAs of two phosphatases related to rdgC/PPEF
      were also detected. Thus, there are mRNAs of at least four phosphatases in retina
      that may be regulated by Ca2+.

PMID- 10335411
TI  - Homeopathy--the new orthodoxy.

PMID- 10335412
TI  - Homeopathy in HIV infection: a trial report of double-blind placebo controlled
      study.
AB  - OBJECTIVE: This study was aimed to evaluate the immuno-modulator role of
      homeopathic remedies in Human Immunodeficiency Virus (HIV) infection.
      METHODOLOGY: A randomised double blind clinical trial was conducted to compare
      the effect of homeopathic remedies with placebo, on CD4+ve T-lymphocytes in HIV
      infected individuals, conforming to Centres for Disease Control (CDC) stage II &
      III. 100 HIV+ve individuals between 18-50 y (71% males) were included in the
      study. 50 cases conformed to CDC stage II--Asymptomatic HIV infection, and 50
      cases to CDC stage III--Persistent Generalised Lymphadenopathy (PGL). Cases were
      stratified according to their clinical status and CD4+ve lymphocyte counts. The
      randomisation charts were prepared much before the start of the trial by randomly
      assigning placebo and verum codes to registration numbers from 1 to 50. A single
      individualised homeopathic remedy was prescribed in each case and was followed up
      at intervals of 15 d to one month. A six months study was performed for each
      registered case. Assessment of progress was made by evaluation of CD+ve
      lymphocyte counts, which was the prospectively-defined main outcome measure of
      the study; the results were compared with the base line immune status. RESULTS:
      In PGL, a statistically significant difference was observed in CD+ve T-lymphocyte
      counts between pre and post trial levels in verum group (P < 0.01). In the
      placebo group a similar comparison yielded non-significant results. (P = 0.91).
      Analysis of change in the pre and post trial counts of CD4+ve cells between
      groups was also statistically significant (P = 0.04). In asymptomatic HIV
      infection, differences in absolute CD4+ve lymphocyte counts between pre and post
      trial levels were not significant. Analysis of changes in pre and post trial CD4
      levels of placebo and verum groups for combined strata of asymptomatic and PGL
      groups was also not significant. CONCLUSION: The study suggests a possible role
      of homeopathic treatment in HIV infection in symptomatic phase, as evidenced by a
      statistically significant elevation of base line immune status in persistent
      generalised lymphadenopathy.

PMID- 10335413
TI  - Reduction of alcohol induced sleep time in albino mice by potentized Nux vomica
      prepared with 90% ethanol.
AB  - Male adult albino mice were administered potentized Nux vomica 30 c (Nux v). The
      drug was mixed with sterile distilled water at 0.05 ml/2 ml water and given at
      0.05 ml/individual. Control consisted of blank ethanol solution. Ethanolic
      extract from the seeds of Strychnos nuxvomica L was mixed with 90% ethanol 1:100
      and sonicated for 30 s at 20 KHz. This was further diluted and sonicated in 30
      steps to produce Nux v 30 c. Six hours after treatment, mice were given 25%
      ethanol i.p. at 4 g/kg body wt. The duration of sleep time starting from the loss
      of righting reflex until its restoration was recorded for each mouse. The
      duration of sleep time with ethanol was recorded in four sessions for the same
      group of mice with an interval of 10 d between sessions. TREATMENTS: session 1
      with control solution, 2 with Nux v (oral), 3 with control solution and 4 with
      Nux v (i.p.). Nux v (oral) produced the shortest sleep time as compared to other
      treatments which did not differ from each other significantly with respect to
      sleep time. In another experiment Nux v 30 c was prepared with distilled water
      and pure absolute ethanol by the above process of successive dilution and
      sonication. These two preparations together with Nux v 30 c, prepared with 90%
      ethanol, were tested on mice for their effect on alcohol-induced sleep time. Only
      Nux v 30 c prepared with 90% ethanol was effective in reducing the sleep time in
      mice. It is concluded that the solution structure of ethanol/water mixture
      carries the specificity of the Nux v at ultra high dilution. It is further
      concluded that the effect is mediated through oral receptors.

PMID- 10335414
TI  - The toxicology of the Chironex fleckeri jelly fish: the Australian sea wasp.

PMID- 10335415
TI  - How to prescribe Medorrhinum: the frequency of symptoms and signs in homeopathic
      patients.
AB  - Medorrhinum is an important, but under-prescribed, homeopathic medicine. This
      paper discusses how to prescribe Medorrhinum on the basis of symptoms, signs and
      family history.

PMID- 10335416
TI  - Was Kent a Hahnemannian?
AB  - This article voices concern at the trend among an influential section of
      homeopaths the world over, to jettison Hahnemann's similimum principle and
      replace it with Kent's almost exclusive concentration on mental and psychic
      symptoms. This concern raises the question whether Kent was a true Hahnemannian.
      In order to discuss this question, two schools of thoughts are investigated. The
      first argues that Hahnemann's theories were scientific whereas Kent's were
      metaphysical. The second criticises Kent's more severely for being metaphysical.
      At the same time, it accuses Hahnemann himself of increasingly losing his way,
      with increasing age, into metaphysical homeopathy. The author believes there was
      no break in Hahnemann's thinking as alleged, but a gradual development with
      increasing experience, together with judicious use of rational insight, when
      scientific explanation was not yet available. The yardstick used to accuse
      Hahnemann of being metaphysical is crudely empirical and long outdated.

PMID- 10335417
TI  - 20 years ago. The British Homoeopathic Journal, April 1979.

PMID- 10335418
TI  - The St Vincent Declaration. A long march for significant changes.

PMID- 10335420
TI  - Propranolol in hypoglycaemia unawareness.
AB  - The effect of propranolol on the occurrence of hypoglycaemic symptoms was
      assessed in insulin-dependent diabetic patients with hypoglycaemia unawareness. A
      double-blind, randomised parallel group study (2:1 fashion) was conducted over 4
      week period. The propranolol group (n = 9) received 20 mg (week 1 and 2) and 30
      mg (week 3 and 4) twice daily, and the other group (n = 5) a matched placebo for
      4 weeks. Patients included had experienced at least two severe hypoglycaemic
      episodes (coma or seizures) during the previous year, which were characterised by
      a lack of adrenergic symptoms and required the assistance of another person. The
      mean number of hypoglycaemias during the study period was similar in both groups
      (placebo: 13 +/- 2 propranolol: 11 +/- 1), whereas the number of totally
      asymptomatic hypoglycaemias (< 0.6 g/l) was lower on propranolol than on placebo
      (3 +/- 1 vs 8 +/- 3, NS) and the number of symptomatic hypoglycaemias was higher
      (7.2 +/- 2 vs 4.6 +/- 1, NS). Subjective evaluation of treatment by the
      investigators showed 0/5 successes in the placebo group and 5/9 in the
      propranolol group (chi2 = 4.32, p = 0.038). The main advantage of propranolol
      over placebo was an increased incidence of sweating. The ratio [number of
      hypoglycaemias with sweating/total number of hypoglycaemias] being higher with
      propranolol (0.28 +/- 0.08 vs 0.06 +/- 0.02, p = 0.06). This pilot study suggests
      that beta-blockers may be useful in restoring adrenergic symptoms during
      hypoglycaemia in insulin-dependent diabetic patients without warning symptoms of
      hypoglycaemia. This beneficial effect seems to be predominantly related to an
      increase in hypoglycaemia-induced sweating. A larger study is needed to confirm
      or invalidate these preliminary results.

PMID- 10335419
TI  - Development of beta 3-adrenoceptor agonists for the treatment of obesity and
      diabetes--an update.
AB  - Beta 3-adrenoceptor (beta 3-AR) agonists were found to have remarkable anti
      obesity and anti-diabetic effects in rodents shortly after their discovery in the
      early 1980s. Despite these promising qualities, several pharmaceutical problems
      and theoretical concerns have slowed the development of these products as
      therapeutic agents in humans during the last 15 years. To date, the
      pharmaceutical industry has not been successful in developing a beta 3-AR agonist
      for use in the treatment of human obesity and type 2 diabetes. Pharmaceutical
      problems in this area concern important differences between rodent and human beta
      3-AR and the difficulty in finding a compound with sufficient bioavailability
      that is a highly selective and full agonist at the human receptor. Some of these
      problems seem to have been solved with the cloning of the human beta 3-AR, which
      has made it possible to develop novel compounds directly and specifically against
      the human receptor. However, several theoretical concerns still remain. These
      include the major question as to whether the number of biologically active beta 3
      ARs in adult humans is sufficient to produce relevant metabolic effects and, if
      so, whether their long-term stimulation is safe and free of unwarranted side
      effects. In addition, the mechanisms of action of beta 3-AR agonists remain
      poorly understood. Recent studies using CL 316,243, a highly selective beta 3
      adrenergic compound, have provided new insights into the potential mechanisms of
      action of these drugs in rodents as well as the first evidence that treatment
      with a highly selective beta 3-AR agonist exerts relevant metabolic effects in
      humans. It appears that chronic beta 3-adrenergic stimulation in white adipose
      tissue increases the expression of newly discovered mitochondrial uncoupling
      proteins (UCP 2 and 3) and a "reawakening" of dormant brown adipocytes. In
      addition, beta 3-ARs may be present in skeletal muscle where ectopic expression
      of UCP-1 has been reported. If these findings are confirmed, tissues other than
      brown fat may play an important role in mediating beta 3-adrenergic effects on
      thermogenesis and substrate oxidation. In humans, treatment with CL 316,243 for 8
      weeks, in spite of limited bioavailability, induced marked plasma concentration
      dependent increases in insulin sensitivity, lipolysis, and fat oxidation in lean
      volunteers, without causing beta 1-, or beta 2-mediated side effects. These
      results clearly indicate that favourable metabolic effects can be achieved by
      selective beta 3-AR stimulation in humans. The compounds of the next generation
      currently emerging from preclinical development are full agonists at the human
      beta 3-AR. These agents have demonstrated promising results in non-human
      primates. It will be interesting to see whether their efficacy in clinical trials
      is superior to that achieved with previous (rodent) beta 3-AR agonists and, if
      so, whether their effects will eventually translate into weight loss and improved
      metabolic control that could facilitate their use as effective drugs for the
      treatment of obesity and Type 2 diabetes in humans.

PMID- 10335421
TI  - Combined analysis of long-term anti-beta-cell humoral reactivity in type 1
      diabetes with and without thyroid disease.
AB  - The prevalence and levels of islet-cell antibodies (ICA) decrease in the years
      following diabetes onset but may persist, particularly in patients with
      concomitant autoimmune disease. The aim of this cross-sectional study was to
      investigate the frequencies, associations and levels of the major anti-beta-cell
      antibodies in long-standing diabetic patients (median duration: 14 years; range 5
      47 years) with and without autoimmune thyroid disease (ATD) in order to consider
      the specific antipancreatic immunologic features associated with endocrine
      autoimmunity. Both ICA and glutamic acid decarboxylase (GAD) antibody (GAD-A)
      frequencies were increased in diabetic patients with ATD (38 vs 23%, p = 0.03 and
      70 vs 21%, p < 10(-4) respectively). Although IA2-A frequency tended to be higher
      in diabetic patients with ATD, no significant difference was seen (37 vs 26%, p =
      0.14). GAD median level was significantly higher in the diabetic group with ATD
      (15 vs 5 units, p < 10(-4)). IA2-A and ICA median levels were similar in both
      groups. Regardless of the combined analysis performed (ICA/GAD-A, ICA/IA2-A or
      GAD-A/IA2-A), the prevalence of combined antibody positivity was higher in
      diabetic patients with than without ATD. In both diabetic populations, ICA and GA
      DA were significantly associated (p < 10(-4), and their levels were correlated (r
      = 0.42, p < 10(-4) and r = 0.584, p < 10(-4) respectively). No significant
      correlation was seen between IA2-A levels and either ICA or GAD-A titres. It is
      concluded that Type 1 diabetes mellitus with ATD is characterised by increased
      persistent humoral islet-related reactivity, particularly directed towards GAD.

PMID- 10335422
TI  - Relationship between neuropathy, hypertension and red blood cell Na/K ATPase in
      patients with insulin-dependent diabetes mellitus.
AB  - Hypertension has been proposed as an independent risk factor for diabetic
      neuropathy. In insulin-dependent diabetic (IDDM) patients suffering from
      neuropathy, red blood cell (RBC) Na/K ATPase is decreased. Such a decrease might
      be involved in the physiopathology of hypertension and therefore be the link
      between hypertension and neuropathy. To confirm this hypothesis, we studied 104
      IDDM patients with a long duration of disease by looking at the association
      between neuropathy and hypertension and by comparing RBC Na/K ATPase activity in
      subgroups. The independent risk factors associated with neuropathy were
      hypertension, triglyceride level, diabetes duration and low RBC Na/K ATPase
      activity. Contrary to our expectations, Na/K ATPase was not decreased in
      hypertensive patients (294 +/- 16 nmol Pi/mg prot/h vs 303 +/- 9), but those
      treated with angiotensin converting enzyme (ACE) inhibitor had higher RBC Na/K
      ATPase activity than those treated with calcium blockers (355 +/- 15 nmol Pi/mg
      prot/h vs 216 +/- 10). These results confirm the association between neuropathy
      and hypertension, on the one hand, and neuropathy and decreased Na/K ATPase, on
      the other, and show that hypertension in IDDM patients was not associated with
      decreased RBC Na/K ATPase. Moreover, ACE inhibitor treatment in IDDM patients,
      whether hypertensive or not, was associated with higher levels of RBC Na/K
      ATPase, which could account for its beneficial effect on diabetic neuropathy.

PMID- 10335424
TI  - Cooperation between general practitioners and diabetologists and clinical audit
      improve the management of type 2 diabetic patients.
AB  - A programme was set up in the Essonne (France) between 1994 and 1998 to improve
      the quality of care for Type 2 diabetic patients. A consensus panel of general
      practitioners and diabetes specialists established guidelines based on the French
      St. Vincent recommendations. An audit involving 73 volunteer general
      practitioners (out of 965 in the Essonne) then evaluated compliance with these
      guidelines. Care and outcome were assessed in 505 (1995) and 604 (1996) Type 2
      diabetic patients. The first audit cycle showed that defined standards were not
      met for several criteria and also revealed a lack of standardisation of HbA1c
      measurements and delayed intervention when blood glucose control was inadequate.
      Corrective measures were adopted: cooperative protocols for foot care, prevention
      of nephropathy and retinopathy, standardisation of HbA1c, and an educational
      programme at the primary health care level. The second audit cycle showed
      improvement in foot care (+33.6%), quality (+39.9%), prescription of HbA1c
      (+11.9%), and control of blood pressure (+11.9%) and blood lipids (+12.8%). The
      proportion of early interventions in case of inadequate glucose control increased
      significantly (+10.5%). However, some gaps persisted, mainly regarding screening
      for complications, diet counselling and patient education. This study shows that
      cooperation between general practitioners and diabetes specialists is feasible
      and effective in the context of a district-wide approach, and that it facilitates
      the adoption of international guidelines by local physicians. A project has been
      developed to provide structured diabetes care in general practice and better
      access to specialist services in order to improve the outcome of Type 2 diabetic
      patients.

PMID- 10335423
TI  - Comparison of the cost-effectiveness of three approaches to screening for and
      treating sight-threatening diabetic retinopathy.
AB  - The purpose of this study was to analyse and compare the costs involved in
      screening for and treating sight-threatening diabetic retinopathy in three
      different clinical settings. In the first setting, diabetologists screened using
      ophthalmoscopy and color photography, according to the St. Vincent Declaration
      guidelines, and selected patients for further assessment by a visiting
      ophthalmologist and for treatment in another hospital. In the second setting, all
      patients were regularly referred to ophthalmologists, either in the same hospital
      or elsewhere, for all aspects of eye care. In the third setting, screening was
      done again with ophthalmoscopy alone by diabetologists who followed the St.
      Vincent Declaration guidelines; however, further assessment and treatment were
      carried out in the eye department of the same hospital. Costs to the Italian
      National Health Service and to patients were calculated per screening performed
      and per patient subjected to laser treatment as a result of screening. A
      sensitivity analysis was then performed to simulate the costs of standardised
      patient populations going through the three different settings. It is concluded
      that absolute costs would be lower, both for the Italian National Health Service
      and for patients, if screening, assessment and treatment were all carried out in
      the same hospital. Equipping a diabetic clinic specially for screening would not
      be more expensive than delegating eye care to external parties, even for a
      hospital without an eye department. Moreover, delegating eye care more than
      doubles costs for patients. Screening for, assessing and treating sight
      threatening diabetic retinopathy may be a cost-effective procedure for society as
      a whole in Italy.

PMID- 10335425
TI  - Microalbuminuria: relationships with clinical and biological parameters. A study
      of diabetic patients admitted to the University Hospital in Guadeloupe.

PMID- 10335426
TI  - [Perception and understanding of insulin-dependent diabetes and its treatment by
      the child from 2 to 12 years].

PMID- 10335427
TI  - [Diagnosis and classification of diabetes mellitus: the new criteria].

PMID- 10335428
TI  - [Diabetes in the elderly].

PMID- 10335429
TI  - [NMR of (129)Xe, dissolved in tissues of animals and plants in vitro. Effect of
      tissue damage by cancer].

PMID- 10335430
TI  - [Liquid crystalline phases of DNA complexes with synthetic polycations].

PMID- 10335431
TI  - [Spermatogenesis in SAMP1 inbred mice, predisposed to accelerated aging].

PMID- 10335433
TI  - [Informative role of tremor in the physiology of vision].

PMID- 10335432
TI  - [Differences in properties and structure of hemagglutinins from influenza virus
      variants, adapted to lungs of mice and beta-inhibitors from murine serum].

PMID- 10335434
TI  - [Effect of water deprivation on serotonin metabolism in rat brain].

PMID- 10335435
TI  - Microsomes, drug oxidation, and clinical pharmacology. Proceedings of a satellite
      symposium of the 2nd Congress of the European Association for Clinical
      Pharmacology and Therapeutics. Berlin, Germany, September 20-21, 1997. Dedicated
      to Alfred George Hildebrandt on the occasion of his 60th birthday.

PMID- 10335436
TI  - Alfred Hildebrandt: from basic research to clinical application and drug
      regulation.

PMID- 10335437
TI  - Discovering the functions of cytochrome P450 in drug metabolism: the role of
      Alfred Hildebrandt.

PMID- 10335438
TI  - Biochemical diversity of peptide-hormone-dependent regulation of steroidogenic
      P450s.

PMID- 10335439
TI  - Peroxynitrite inactivates prostacyclin synthase by heme-thiolate-catalyzed
      tyrosine nitration.
AB  - Previous work has shown a sensitive inhibition of prostacyclin synthase activity
      by peroxynitrite as well as by superoxide in the presence of NO donors. Neither
      superoxide nor NO alone nor decomposed peroxynitrite is effective. The inhibition
      of activity was paralleled by a nitration of a tyrosine residue and both could be
      prevented by a stable substrate analog. The same IC50 value for peroxynitrite was
      also found for the cellular prostacyclin activity in endothelial and kidney
      mesangial cells, indicating that the antioxidant potential of the cell cannot
      prevent the inactivation. Aortic tissue shows a co-localization of prostacyclin
      synthase and nitrotyrosine staining after treatment of the tissue with 1 microM
      peroxynitrite. It can be speculated that this pathway of enzyme nitration is of
      pathophysiological significance.

PMID- 10335440
TI  - Interactions between cytochrome P450 and cytochrome b5.

PMID- 10335441
TI  - Phenobarbital-mediated changes in gene expression in the liver.

PMID- 10335442
TI  - Induction of CYP1A by various benzimidazoles and its significance in
      administrative drug regulation.

PMID- 10335443
TI  - Regulation of endoplasmic reticulum biogenesis in response to cytochrome P450
      overproduction.

PMID- 10335444
TI  - Functions and transcriptional regulation of PAH-inducible human UDP
      glucuronosyltransferases.
AB  - Functions and regulation of selected human UDP-glucuronosyltransferases (UGT1A1,
      UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15) are summarized. Evidence for at least
      two PAH-inducible UGTs (UGT1A6 and UGT1A9) is presented, which, however, are also
      constitutively expressed in a tissue- and cell-specific manner. These isoforms
      have recently been characterized to conjugate planar and bulky phenols,
      respectively. Using a selective RT-PCR method, UGT1A6 expression was detected in
      a variety of tissues (liver, kidney, lung, intestine, and pharyngeal mucosa). PAH
      inducible UGTs may cooperate in the metabolism of phenolic metabolites of
      benzo(a)pyrene. Studies with stably expressed isoforms suggest that UGT1A9 is
      responsible for the formation of benzo(a)pyrene-3.6-diphenol diglucuronide, the
      major biliary metabolite of benzo(a)pyrene.

PMID- 10335445
TI  - Molecular studies on the toxifying effects by genetically engineered cytochromes
      P450.

PMID- 10335446
TI  - Cytochrome P450-null mice.

PMID- 10335447
TI  - Duplication, multiduplication, and amplification of genes encoding drug
      metabolizing enzymes: evolutionary, toxicological, and clinical pharmacological
      aspects.

PMID- 10335448
TI  - Genetic epidemiology of environmental toxicity and cancer susceptibility: human
      allelic polymorphisms in drug-metabolizing enzyme genes, their functional
      importance, and nomenclature issues.
AB  - Pharmacogenetics is the study of idiosyncratic drug responses that have an
      hereditary basis and usually reflect differences in drug-metabolizing enzymes
      (DMEs) and the receptors that control DME levels. The purpose of this review is
      to provide a brief overview of recent findings concerning more than a dozen
      clinically important polymorphisms and to emphasize the need to standardize the
      nomenclature of these alleles in each polymorphism, as quickly as possible. This
      nomenclature system should be consistent with the Human Gene Nomenclature
      Guidelines. Because DMEs have existed before divergence of prokaryotes and
      eukaryotes more than 2 billion years ago, it is clear that DME genes first must
      have evolved for critical life functions and that, more recently in animals, DME
      genes expanded to include the role of detoxification of dietary products,
      evolving plant metabolites, and, of course, pharmaceutical drugs. Many human DME
      polymorphisms are relevant to clinical problems in that they represent the basis
      of risk factors in the development of cancer, toxicity, and other diseases
      associated with drug, chemical, or dietary exposure. The study of the
      relationship among human genetic polymorphisms, cancer susceptibility, toxicity,
      and environmental exposure is a new and exciting area of research--which will
      undoubtedly have increasingly important implications for risk assessment and the
      prevention, early diagnosis, and intervention of clinical disease.

PMID- 10335449
TI  - Arylamine N-acetyltransferase activity in man.

PMID- 10335450
TI  - Cytochrome P450-based cancer gene therapy: recent advances and future prospects.
AB  - Cytochrome P450-based cancer gene therapy is a novel prodrug activation strategy
      for cancer treatment that has substantial potential for improving the safety and
      efficacy of cancer chemotherapeutics. The primary goal of this strategy is to
      selectively increase tumor cell exposure to cytotoxic drug metabolites generated
      locally by a prodrug-activating P450 enzyme. This strategy has been exemplified
      for the alkylating agents cyclophosphamide and ifosfamide, which are bioactivated
      by select P450 enzymes whose expression is generally high in liver and deficient
      in tumor cells. Transduction of tumors with a prodrug-activating P450 gene,
      followed by prodrug treatment, greatly increases intratumoral formation of
      activated drug metabolites. This leads to more efficient killing of the
      transduced tumor cells without a significant increase in host toxicity. P450 gene
      therapy is accompanied by substantial bystander cytotoxicity which greatly
      enhances the therapeutic effect by extending it to nearby tumor cells not
      transduced with the therapeutic P450 gene. Although endogenous P450 reductase is
      not expected to be a limiting factor in prodrug activation in tumor cells that
      express moderate levels of an exogenous P450 gene, P450 reductase transduction
      has recently been found to substantially enhance intratumoral prodrug activation
      and its associated therapeutic effects. Using this gene combination, an overall
      50- to 100-fold increase in tumor cell kill in vivo over that provided by hepatic
      drug activation alone has been observed. Striking improvements in therapeutic
      effects can thus be achieved using an established anticancer drug in an
      intratumoral prodrug activation strategy based on the combination of a cytochrome
      P450 gene with the gene encoding NADPH-P450 reductase. This strategy is readily
      extendable to several other widely used P450-activated cancer chemotherapeutic
      prodrugs, as well as to prodrugs that undergo P450 reductase-dependent
      bioreductive activation and which may exhibit synergy when combined with P450
      activated prodrugs in a P450/P450 reductase-based cancer gene therapeutic
      regimen.

PMID- 10335451
TI  - Merits and limitations of recombinant models for the study of human P450-mediated
      drug metabolism and toxicity: an intralaboratory comparison.
AB  - A wide variety of pharmacological and toxicological properties of drugs are
      determined by cytochrome P450-mediated metabolism. Characterization of these
      pathways and of the P450 isoenzymes involved constitutes an essential part of
      drug development. Similarly, because P450s are catalyzing the toxication and
      detoxication of environmental pollutants, an understanding of these reactions
      facilitates risk assessment in environmental toxicology. Recently, a variety of
      recombinant expression systems has been employed to study the role of human P450s
      in these reactions. These include insect, bacterial, yeast, and mammalian models.
      As these were developed and characterized by different laboratories, evaluation
      of their merits and limitations is inherently difficult. To resolve this problem,
      we have established and characterized the latter three systems and present the
      key results here. In general, the catalytic properties of P450 isozymes in the
      various models were rather similar. However, taking technical considerations into
      account as well as the high level of functional expression of P450s achieved in
      bacteria make this system ideally suited for drug metabolism research, including
      the generation of milligram quantities of metabolites for structural
      determinations. For toxicological studies, however, expression of P450s in
      mammalian cells was most appropriate. This is exemplified here by studies into
      the role of human P450s in the activation and inactivation of chemotherapeutic
      drugs.

PMID- 10335452
TI  - Extrapolating in vitro data on drug metabolism to in vivo pharmacokinetics:
      evaluation of the pharmacokinetic interaction between amitriptyline and
      fluoxetine.
AB  - Recently, models have been proposed to extrapolate in vitro data on the influence
      of inhibitors on drug metabolism to in vivo decrement in drug clearance. Many
      factors influence drug clearance such as age, gender, habits, diet, environment,
      liver disease, heredity, and other drugs. In vitro investigation of hepatic
      cytochrome P450 activity has generally centered on genetic influences and
      interactions with other drugs. This group of enzymes is involved in many,
      although not all, drug interactions. The interaction of amitriptyline and
      fluoxetine is an example. Of the different in vitro paradigms, interaction
      studies utilizing human liver microsomal preparations have proved to be the most
      generally applicable for in vitro scaling models. Assuming Michaelis-Menten
      conditions and applying nonlinear regression, a hybrid inhibition constant (Ki)
      can be generated that allows classification of the inhibitory potency of an
      inhibitor toward a specific reaction. This constant is largely independent of the
      substrate concentration, but in vivo relevance is critically dependent on the
      inhibitor concentration in the site of metabolic activity, the liver cell
      cytosol. Many lipophilic drugs are extensively bound to plasma protein but,
      nonetheless, demonstrate extensive partitioning into liver tissue. This is not
      compatible with diffusion only of the unbound drug fraction into liver cells. The
      introduction of a partition factor, based on data from a number of possible
      sources, provided a reasonable basis for the scaling of in vitro data to in vivo
      conditions. Many interactions could be reconstructed or predicted with greater
      accuracy and clinical relevance for interactions such as terfenadine or midazolam
      and ketoconazole. Even for less marked interactions such as amitriptyline and
      fluoxetine, this model provides a forecast consistent with the clinically
      observed range of 22-45% reduction in oral clearance, although this interaction
      is complicated by the presence of two inhibitors, fluoxetine and norfluoxetine.
      The concept of in vitro-in vivo scaling is promising and might ultimately yield a
      fast and more cost-effective screening for drug interactions with reduced human
      drug exposure and risk.

PMID- 10335453
TI  - Energy balance and cancer.

PMID- 10335456
TI  - Height, weight and gastrointestinal cancer: a follow-up study in Norway.
AB  - It has been suggested that components of our diet play an essential role in
      carcinogenesis. Anthropometric indices, such as body weight and height, have
      often been considered as measurements of prevailing diet and nutrition in
      childhood respectively. To investigate to what extent height and body weight are
      associated with the risk of gastrointestinal cancer, data from a Norwegian
      screening programme for tuberculosis were analysed. More than 1,100,000
      individuals, aged 30-69 years at the time of examination, were included in the
      study. Body weight, expressed as Quetelet's index (QI), and height records were
      linked with vital status data from Statistics Norway and the Cancer Registry of
      Norway. The analysis shows that individuals in the first quintile of height had a
      lower relative risk than later quintiles for colon cancer, independent of sex and
      stage of disease at completion of follow-up. The association between height and
      rectal cancer is similar, but weaker. Men in the fifth quintile of QI have a
      relative risk of 1.39 for colon cancer, compared with the first quintile, and
      they also have a slightly elevated risk for rectal cancer. Among women, the
      pattern is unclear, but we observed a significant relationship between high QI
      and cancer of the gallbladder. Our results indicate that prevailing diet and
      living conditions in early life do play a role, and seem to support the
      hypothesis that anthropometric indices could be of importance as indirect markers
      for the risk of colon cancer and, to some extent, for cancer of the rectum and
      gallbladder.

PMID- 10335455
TI  - Intervention studies on cancer.
AB  - This paper (and an extensive supplementary report) considers how far cancer/risk
      factor associations based on epidemiology have been confirmed by evidence from
      226 studies involving interventions other than smoking. Many are small,
      uncontrolled, of unrepresentative populations, concern cancer markers not cancer,
      and may involve combinations of agents. Many agents suspected of causing cancer
      are untested by intervention trials. For seven of 16 agents tested (fibre, folic
      acid, low-fat diet, riboflavin, zinc, vitamin Bs, and vitamin D), the evidence is
      clearly inadequate to confirm or deny the epidemiology, while the evidence
      relating to calcium only concerns biomarkers. For other agents, the evidence
      relating to cancer itself is weak. In studies where cancer is the endpoint, only
      three effects have been replicated: (a) selenium supplementation and decreased
      liver cancer incidence, (b) treatment by the retinoid etretinate and reduced
      bladder tumours in susceptible individuals, and (c) beta-carotene supplementation
      and increased lung cancer incidence. Studies involving pre-cancerous conditions
      as the endpoint, which have a number of practical advantages, more frequently
      report benefits of intervention. Thus, oral pre-cancerous lesions can certainly
      be reduced by beta-carotene, vitamin A, and other retinoids, and possibly by
      vitamin E. It also seems that retinoids can reduce pre-cancerous cervix, skin and
      lung lesions, that vitamin C and the NSAID sulindac can reduce colonic polyps,
      and that sunscreens can reduce solar keratoses. Our findings clearly show that
      the great majority of causal relationships suggested by epidemiology have not
      been validated by intervention trials. This may be partly due to lack of suitable
      studies of adequate size or duration, or to using single dietary compounds as
      agents that are by themselves not responsible for the epidemiologically-observed
      associations between diet and cancer. However, this lack of validation must cause
      concern in view of the markedly conflicting evidence on beta-carotene and lung
      cancer between epidemiological and intervention studies. More intervention
      studies are needed, but in their absence, caution in interpreting epidemiological
      findings is warranted.

PMID- 10335454
TI  - Energy balance and cancers.
AB  - Energy balance results from the exact equilibrium between caloric intake and
      caloric expenditure. A caloric intake larger than caloric expenditure results in
      overweight, even obesity, but other determinants, like hormonal dysfunction
      and/or genetic traits may play a part in obesity syndrome. Obesity, and even
      overweight, have been recognized as risk factors for the development of cancers.
      Human epidemiological studies, which have tended to establish the nature of the
      relationship between energy balance and cancer, are summarized first, with the
      influence of the various factors which act both on obesity and on cancer risk.
      Among these factors are the macronutrients responsible for the caloric intake,
      and some lifestyle factors (physical activity, drinking habits and tobacco use).
      Second, the animal studies help to distinguish between different relevant
      factors, and to understand some of the underlying mechanisms. However, the
      insulin-resistance syndrome, which appears to underlie the relationship between
      obesity and hormone-dependent cancers, and possibly colon cancer, is only
      relevant to human physiology because hormonal alterations are part of it.
      Prevention of hyperinsulinemia, insulin resistance and the accompanying visceral
      obesity appears to be a major public health task for the prevention of cancers.

PMID- 10335457
TI  - Height, weight and cancer of the oesophagus and stomach: a follow-up study in
      Norway.
AB  - Epidemiological studies have suggested that socioeconomic conditions, including
      dietary factors, can affect the risk of several gastric cancers. Anthropometric
      indices, such as body weight and adult height, have been considered as
      measurements of prevailing diet and nutrition, respectively, in early life. The
      objective of this study was to evaluate the association between body mass and
      height and the risk of cancer of the oesophagus and stomach. The analysis was
      based on data from a national Norwegian screening programme for tuberculosis,
      which ran from 1963 to 1975, screening more than 1,100,000 individuals, aged 30
      69 years at the time of examination. The participants were followed until
      December 1989. Body weight (expressed as Quetelet's index (QI) and height records
      were linked with vital status data from Statistics Norway and the Cancer Registry
      of Norway. Individuals in the first quintile of height appear to have an
      increased risk of oesophageal cancer in both sexes. Low QI was found to increase
      the risk for oesophageal squamous cell carcinoma, whereas high QI was linked to
      an elevated risk of oesophageal adenocarcinoma. The analysis reveals a
      relationship between low QI and the risk of stomach cancer. There were no
      associations between stomach cancer and height. These associations indicate that
      prevailing and early life conditions could play a role in later cancer
      development; they support the hypothesis that anthropometric indices are
      important as markers for the risk of oesophageal cancer and, to some extent, for
      cancer of the stomach.

PMID- 10335458
TI  - Hormone replacement therapy and risk of benign proliferative epithelial disorders
      of the breast.
AB  - Use of hormone replacement therapy (HRT) has been associated with increased risk
      of breast cancer, and it is possible that this reflects a positive association
      between HRT use and risk of proliferative forms of benign breast disease (BBD),
      conditions which are thought to have pre-malignant potential. The purpose of the
      present investigation was to study the association between HRT use and risk of
      benign proliferative epithelial disorders of the breast (BPED). The study was
      undertaken using the 56,837 women within the Canadian National Breast Screening
      Study (NBSS) who completed self-administered lifestyle and dietary
      questionnaires. (The NBSS is a randomized controlled trial of screening for
      breast cancer in women aged 40-59 at recruitment.) During the course of the
      follow-up period, a total of 691 women in the dietary cohort were diagnosed with
      biopsy-confirmed incident BPED. For comparative purposes, a sub-cohort consisting
      of a random sample of 5681 women (including 65 of the subjects with BPED) was
      selected from the full dietary cohort. After exclusions for various reasons, the
      analyses were based on 691 cases and 5443 non-cases. In post-menopausal women, in
      whom most of the reported use occurred, there was a positive association between
      duration of HRT use and risk of BPED, the adjusted incidence rate ratio (95%
      confidence interval) in those who had used HRT for more than 8 years being 1.70
      (1.06-2.72). There were too few cases of atypical BPED for meaningful analysis,
      but results for those whose BPED showed no atypia were similar to the overall
      results. Further analyses conducted separately in the screened and control arms
      of the NBSS were similar to those observed overall, as were those conducted
      separately for screen-detected and interval-detected BPED.

PMID- 10335459
TI  - Interval cancers in a community-based programme of colorectal cancer screening
      with faecal occult blood test.
AB  - Interval cancers represent the major limitation of screening for colorectal
      cancer with the faecal occult blood test. The aim of this study was to describe
      the characteristics of interval cancers and the sensitivity of the screening
      programme in a well-defined French population. During five screening rounds, 398
      cancers were diagnosed in those of the population having performed at least one
      screening test; 57.8% of them were interval cancers. The proportion of interval
      cancers was higher among cancers of the rectal ampulla (72.2%) than among cancers
      of other sites (52.9%) (P < 0.001). The proportion of TNM stage I and II were
      higher among screen-detected cancers (73.8%) than among interval cancers (57.4%).
      The overall sensitivity of the screening programme was 62.9% within 1 year, and
      48.7% within 2 years. An improvement in the sensitivity of the faecal occult
      blood test for colorectal cancer screening is needed, without an unacceptable
      loss of specificity.

PMID- 10335460
TI  - European registry comparisons provide evidence of shared risk factors for renal,
      colon and gallbladder cancer development.
AB  - In order to assess links between renal cell cancer (RCCs) and transitional cell
      cancers (TCCs) of the kidney and cancer development in other organs of the
      abdominal cavity, incidence data from the Cancer Incidence in Five Continents
      (Vol VII) were compared between various cancer registries in Europe. Significant
      correlations which persisted on partial analysis were observed between RCCs and
      carcinomas of the colon and gallbladder, as well as between the latter
      themselves. Kidney TCCs, in contrast, were associated with tumours of the urinary
      bladder. In addition, significant correlations between hepatocellular, but not
      cholangiocellular carcinomas, and gallbladder and colon cancers were observed.
      Data for pancreas and gallbladder neoplasms also correlated. Prostate cancer
      incidences, while positively linked to RCCs, negatively correlated with
      gallbladder rates. The results point to shared risk factors for RCCs and
      adenocarcinomas in a number of organs, suggesting a role for humoral agents. The
      present findings also underline the necessity of distinguishing between tumour
      types within organs in epidemiological investigations of causal influences.

PMID- 10335461
TI  - Interaction between selected environmental factors and familial propensity for
      colon cancer.
AB  - Using data of a case-control study conducted in Italy between 1992 and 1996 on
      1225 cases of colon cancer and 4154 controls, we have evaluated the effect of
      selected established risk factors in subjects with, and in those without,
      familial propensity (134 cases, 146 controls); there were non-significant
      associations between education and meal frequency and colon cancer risk. Physical
      activity, high energy and low vegetable intake were significantly related to
      colon cancer risk in subjects without familial predisposition, but showed no
      relationship in those with family history of colorectal cancer: the ORs were 1.1
      for the lowest level of physical activity, 0.7 for the highest tertile of energy
      intake, and 1.0 for the lowest one of vegetable intake. These findings would
      suggest that genetic predisposition can make the influence of environmental
      factors for defining the risk of colon cancer weak and/or difficult to estimate.

PMID- 10335462
TI  - Country comparisons provide evidence of links between specific circulatory
      disease and gastric, rectal, prostate and breast cancers.

PMID- 10335464
TI  - The Vahouny Symposium on Dietary Fibre in Health and Disease, Adelaide, 3
      December 1998.

PMID- 10335463
TI  - Effect of vitamin D3 on carcinogen-modified liver enzymes and tumour incidence in
      experimental rat mammary carcinogenesis.
AB  - The anticarcinogenic effect of vitamin D3 in relation to biochemical and
      morphological markers in 7,12-dimethylbenz(alpha)anthracene (DMBA)-induced
      mammary carcinogenesis was investigated in two different sets of experiments. For
      each set, female Sprague-Dawley rats were divided into four groups, to allow
      comparison among treated and non-treated groups. At 50 days of age, animals of
      group B and C were given DMBA injection (0.5 mg/100 g body weight) through the
      tail vein, and normal control (group A) animals received the oil emulsion vehicle
      alone. Vitamin D3 at the dose of 0.3 microgram/0.1 ml propylene glycol was given
      orally twice a week, in carcinogen as well as non-carcinogen treated animals
      (group C and c), until the termination of the experiments (22-24 weeks for
      biochemical markers, and 35 weeks for morphology). At approximately 22-24 weeks,
      when marked lobular hyperplasia in DMBA control groups were confirmed through
      histology, the biochemical markers were modulated towards normal value for
      vitamin D3 in the treatment group, in comparison to the disturbed values caused
      by carcinogen administration in group B animals. Again, vitamin D3
      supplementation was effective in reducing the tumour incidence (70% in comparison
      to 90% in group B). The results thus clearly concluded the antineoplastic
      potential of vitamin D3, and the existing correlation between biological and
      biochemical markers.

PMID- 10335465
TI  - Proper chewing.

PMID- 10335466
TI  - Incidence and perinatal outcome of multiple pregnancies after intracytoplasmic
      sperm injection compared to standard in vitro fertilization.
AB  - PURPOSE: Our purpose was to assess the incidence of multiple pregnancies and
      their obstetric outcome after intracytoplasmic sperm injection. METHODS: The
      study group comprised women who delivered twins or triplets after
      intracytoplasmic sperm injection and standard in vitro fertilization. The
      incidence and main perinatal outcome of 140 multiple pregnancies resulting from
      intracytoplasmic sperm injection or standard in vitro fertilization treatment
      were analyzed. RESULTS: A total of 60 multiple pregnancies was obtained after
      intracytoplasmic sperm injection (3.4 +/- 1.1 embryos/cycle) and 80 after
      standard in vitro fertilization (3.3 +/- 2.0 embryos/cycle). The incidence of
      multiple pregnancy, i.e., 22.6 compared to 20.7%, respectively, was calculated.
      The obstetric outcome of 47 multiple pregnancies after intracytoplasmic sperm
      injection was 39 twin deliveries at between 27 and 37 weeks of gestation (mean,
      36 +/- 3.3) and 8 successful triplet deliveries between 26 and 36 weeks of
      gestation (mean 32.6 +/- 2.4). The outcome after regular in vitro fertilization
      was similar. No major malformations were observed. CONCLUSIONS: The results of
      this study showed that the incidence of multiple pregnancies after
      intracytoplasmic sperm injection was similar to that after standard, conventional
      in vitro fertilization. The perinatal outcome did not differ between both groups.

PMID- 10335467
TI  - A retrospective follow-up study on intracytoplasmic sperm injection.
AB  - PURPOSE: Genetic aspects of male subfertility and the novelty of intracytoplasmic
      sperm injection (ICSI) as a new technique can influence the development of
      zygotes and children born after ICSI. Therefore, we evaluated the outcome of ICSI
      compared to in vitro fertilization (IVF). METHODS: Data from medical records of
      233 total pregnancies and the follow-up of 132 children born after IVF and 120
      after ICSI were retrospectively analyzed. RESULTS: No differences were found
      between ICSI and IVF for early embryonic development and obstetric outcome. In
      both groups the rate of women undergoing prenatal chromosomal diagnosis was low,
      30.0%. The congenital malformation rate was 3.0% after IVF and 1.7% after ICSI,
      which was not significantly different. Follow-up on development of children born
      after IVF and ICSI also showed no significant differences. CONCLUSIONS: Our
      results indicate that at this moment ICSI is a safe procedure. However, a
      consistent prospective follow-up is still mandatory to exclude possible risks.

PMID- 10335468
TI  - Dexamethasone supplementation to gonadotropin stimulation for in vitro
      fertilization in polycystic ovarian disease.
AB  - PURPOSE: This study was conducted to determine whether glucocorticoid
      supplementation for patients with polycystic ovarian disease during ovulation
      induction with gonadotropins for in vitro fertilization (IVF) therapy is
      beneficial. METHODS: Seventy-one cycles of patients undergoing first attempts at
      IVF, with classical polycystic ovarian disease and hyperandrogenemia, who
      enrolled in the IVF-embryo transfer program, were evaluated retrospectively. In
      20 cycles (20 patients) glucocorticoid supplementation was noted and compared to
      51 cycles (51 patients) without glucocorticoid as adrenal androgen suppression.
      Ovaries were stimulated by gonadotropin releasing hormone agonist, human
      menopausal gonadotropin, and dexamethasone. Ovarian responsiveness and IVF-embryo
      transfer outcome were analyzed and included the number of follicles > 17 mm in
      diameter, serum estradiol concentration on the day of human chorionic
      gonadotropin administration, number of human chorionic gonadotropin ampoules
      administered, number of oocytes retrieved, percentage of oocytes fertilized,
      number of embryos transferred, implantation rate, and number of clinical
      pregnancies and their outcome. RESULTS: The results showed that the pregnancy
      rate in patients who received glucocorticoid was 22.1%, compared to 26% in the
      controls (statistically insignificant). The IVF cycle variables studied revealed
      no statistically significant differences. CONCLUSIONS: Our observations did not
      support the notion that adrenal androgen suppression by glucocorticoid, or as an
      adjuvant therapy, is beneficial to patients with polycystic ovarian disease who
      enrolled in an IVF-embryo transfer program.

PMID- 10335469
TI  - In vitro fertilization outcome according to age and follicle-stimulating hormone
      levels on cycle day 3.
AB  - PURPOSE: In a retrospective study, the prognostic factors of in vitro
      fertilization outcome were studied in women of 39 years of age or older, with an
      elevated cycle day 3 follicle-stimulating hormone (FSH) level. METHODS: Ovarian
      stimulation was achieved with a combination of gonadotropin-releasing hormone
      agonist/human menopausal gonadotropin in a short protocol. All patients underwent
      FSH dosage on cycle day 3 prior to stimulation. The pregnancy rate was studied
      according to age, FSH levels, and stimulation parameters. RESULTS: There was a
      negative correlation between day 3 FSH levels and the number of ovocytes
      retrieved. Cycles canceled because of the absence of ovarian response had a
      significantly higher mean FSH value (18.2 mlU/ml) than cycles ending in ovocyte
      retrieval (14.6 mlU/ml). Patients with three or more growing follicles during
      stimulation achieved a significantly higher pregnancy rate per egg retrieval
      (16%) compared to patients with fewer than three growing follicles (6%). Eighty
      percent of those pregnancies were obtained during the first two IVF cycles. Even
      with an elevated FSH level, some patients developed three or more follicles after
      stimulation. In such cases, the number of embryos available for transfer was the
      only significant limiting factor to achieving pregnancy. CONCLUSIONS: As our
      results suggest, there is a discrepancy between biological and chronological
      ovarian age. In patients with an elevated cycle day 3 FSH level and over 40 years
      of age, alternatives to fertility treatments (ovum donation, adoption, or no
      treatment) should not be considered as first choices. Indeed, even with elevated
      FSH levels, a 16% pregnancy rate per egg retrieval may be obtained if three or
      more growing follicles can be seen during ovarian stimulation. However, in the
      presence of fewer than three growing follicles during ovarian stimulation, the
      patient should be informed about the discouraging prognosis of the running cycle.

PMID- 10335470
TI  - Serum progesterone before and after human chorionic gonadotropin injection
      depends on the estradiol response to ovarian hyperstimulation during in vitro
      fertilization-embryo transfer cycles.
AB  - PURPOSE: Our purpose was to assess if periovulatory serum progesterone is
      reflective of ovarian responsiveness in controlled ovarian hyperstimulation
      (COH). METHODS: One-hundred forty-two in vitro fertilization-embryo transfer
      cycles in women using GnRH-a suppression and human menopausal gonadotropin (hMG)
      stimulation were evaluated. Responses were studied according to ovarian response
      to hMG and age. Outcome measures included peak serum estradiol, serum
      progesterone and estrogen/progesterone ratios on the day of hCG injection, number
      of harvested oocytes, fertilization rates, and delivered pregnancy rates.
      RESULTS: A periovulatory rise in serum progesterone (> 0.9 ng/ml) occurred only
      among younger women (< 40 years old) with a good response (P < 0.05). Though the
      number of oocytes was greater in good responders, fertilization and pregnancy
      rates were similar among all women regardless of age and ovarian response.
      CONCLUSIONS: Periovulatory levels of serum progesterone vary according to ovarian
      response to COH. Elevations in progesterone do not appear to be a manifestation
      of poor responders. Reduced periovulatory progesterone may reflect inadequate
      steroidogenesis.

PMID- 10335472
TI  - Implications of sperm chromosome abnormalities in recurrent miscarriage.
AB  - PURPOSE: Our purpose was to assess the existence of sperm chromosome
      abnormalities in recurrent pregnancy loss in an assisted reproduction program.
      METHODS: In this prospective study, 12 sperm samples from couples undergoing in
      vitro fertilization with two or more first-trimester spontaneous abortions were
      analyzed. Diploidy and disomy in decondensed sperm nuclei were assessed for
      chromosomes 13, 18, 21, X, and Y using two- and three-color fluorescence in situ
      hybridization. RESULTS: Sex chromosome disomy in sperm samples from recurrent
      abortion couples was significantly increased compared to that from internal
      controls (0.84% vs 0.37%). In a subpopulation of seven couples who underwent
      oocyte donation, mean frequencies for sex chromosome disomy (1%) were even higher
      and diploidy (0.43%) was also significantly increased. CONCLUSIONS: These results
      suggest an implication of sperm chromosome abnormalities in some cases of
      recurrent pregnancy loss.

PMID- 10335471
TI  - Cytokines in older patients undergoing in vitro fertilization: the relationship
      to the response to controlled ovarian hyperstimulation.
AB  - PURPOSE: Our purpose was to assess the endocrine, autocrine, and paracrine milieu
      in follicles of older women undergoing stimulated cycles, comparing normal (NR)
      and low (LR) responses, based on the measurement of interleukin (IL)-1 beta, IL
      6, and vascular endothelial growth factor (VEGF) in serum and follicular fluid
      (FF). METHODS: A total of 40 women entered the study, divided into three groups:
      (1) older patients (> 37 years) with NR (age-NR; n = 18); (2) older women with LR
      (age-LR; n = 11); and (3) normal controls, aged < 35 years (control; n = 11). IL
      1 beta, IL-6, and VEGF measured in serum (day of ovum pickup) and FF, employing
      ELISAs. RESULTS: Follicular fluid IL-6 was significantly (P < 0.05) higher in age
      LR compared to the other two groups. IL-6 and VEGF showed a 4- to 20-fold
      increase in FF compared to blood, suggesting the ovary as an additional source of
      both cytokines. IL-1 beta levels remained unchanged in FF compared to blood and,
      also, among groups. CONCLUSIONS: These data provide further evidence that the
      endocrine, paracrine, and/or autocrine status in vivo of older patients is
      different from that of younger women and suggest that cytokines, specifically IL
      6, may be involved in the changes observed during senescence within the ovary.

PMID- 10335473
TI  - Detection of azoospermic factor genes in Chinese men with azoospermia or severe
      oligozoospermia.
AB  - PURPOSE: We investigated the prevalence of deletions in the azoospermic factor
      (AZF) region of chromosome Yq11 in Chinese men with infertility due to idiopathic
      azoospermia or severe oligozoospermia. The DAZ gene cluster was also examined for
      mutations. METHODS: Sixty-eight men with azoospermia or severe oligozoospermia
      taking part in an intracytoplasmic sperm injection program were recruited. Four
      loci specific for AZFa, AZFb, and AZFc were amplified from genomic DNA via
      polymerase chain reaction to determine whether deletions were present in the AZF
      region. Direct DNA sequencing of amplified products was also performed to look
      for mutations or polymorphism from exon 2 to exon 6 of the DAZ gene cluster.
      RESULTS: Six (9%) of the 68 patients had AZF deletions. None had mutations in
      exons 2 to 6 of DAZ. CONCLUSIONS: The prevalence of AZF deletions in our study
      was similar to those in Western reports, as was the lack of DAZ mutations.

PMID- 10335475
TI  - Tumor vascular pattern and blood flow impedance in the differential diagnosis of
      leiomyoma and adenomyosis by color Doppler sonography.
AB  - PURPOSE: Our objective was to evaluate the differences between leiomyoma and
      adenomyosis by color Doppler sonography with new criteria. METHODS: A total of 78
      patients with symptomatic uterine nodularities who were sonographically suspected
      to have leiomyoma or adenomyosis without other coexisting pathologic conditions
      was enrolled in the study. All patients underwent transvaginal color Doppler
      sonography (7.0-MHz vaginal probe) or transabdominal color Doppler sonography
      (5.0 MHz) during the early follicular phase. The morphology, tumor vascular
      pattern, and blood flow impedance of the uterine tumors were measured. All of the
      patients underwent surgery and the pathologic reports were used as references.
      RESULTS: The mean age was not statistically significant in patients with
      adenomyosis versus leiomyoma (P > 0.05). The morphologic criteria for adenomyosis
      and leiomyoma by sonography detected 79% of adenomyosis and 84% of leiomyoma.
      Adenomyosis had 87% randomly scattered vessels or intratumoral signals and 88% of
      leiomyomas showed peripheral scattered vessels or outer feeding vessels. Eighty
      two percent of adenomyosis had a pulsitility index (PI) of arteries within or
      around uterine tumors > 1.17 and 84% of leiomyomas had a PI < or = 1.17. The
      reliability test of tumor vascular pattern and blood flow impedance were better
      than that of using morphological criteria alone. CONCLUSIONS: With the aid of
      color Doppler sonography, tumor vascular pattern and blood flow impedance of the
      arteries within or around uterine tumors could more accurately diagnose
      adenomyosis and leiomyoma in addition to the morphologic criteria on transvaginal
      sonography.

PMID- 10335474
TI  - DNA flow cytometric quantification and DNA polymorphism analysis in the case of a
      complete mole with a coexisting fetus.
AB  - PURPOSE: Our purpose was to investigate whether DNA flow cytometric
      quantification and DNA polymorphism analysis are useful for cytogenetic diagnosis
      in the case of a complete hydatidiform mole that coexists with a living fetus.
      METHODS: Flow cytometric analysis of the nuclear DNA content and polymerase chain
      reaction (PCR) amplification of the minisatellite locus with the MCT118 probe
      were performed on the tissues (fetus, placenta and mole) obtained at the initial
      evacuation. RESULTS: DNA histograms of placental, fetal, and molar tissues showed
      diploid peaks. PCR products demonstrated that the allele of the mole was
      homozygous and inherited solely from the husband and that the mole differed
      genetically from the fetus and the placenta. CONCLUSIONS: These results suggested
      that DNA flow cytometry and DNA polymorphism analysis may be useful for the
      cytogenetic diagnosis of a complete hydatidiform mole and a coexisting fetus.

PMID- 10335476
TI  - Effect of intracellular Ca2+ chelation with the acetoxymethyl ester-derived form
      of bis(o-aminophenoxy)ethane-N,N,N,N',N'-tetraacetic acid on meiotic division and
      chromosomal segregation in mouse oocytes.
AB  - PURPOSE: Our purpose was to ascertain the effect of intracellular Ca2+ chelation
      on the chromosomal distribution and segregation of mouse oocytes during
      maturation in vitro. METHODS: Germinal vesicle oocytes were loaded with the
      acetoxymethyl ester-derived form of bis(o-aminophenoxy)-ethane-N,N,N',N'
      tetraacetic acid (BAPTA-AM). Chromosomal distribution and segregation of control
      and BAPTA-AM-treated metaphase II (MII) oocytes were evaluated at 16 hr, and
      intracellular ATP content at 0, 1, and 16 hr after BAPTA-AM loading. RESULTS:
      BAPTA-AM treatment decreased (P < or = 0.05) the potential for in vitro
      maturation, increased (P < or = 0.0001) the percentage of oocytes displaying an
      abnormal distribution of metaphase II chromosomes in the meiosis II spindle and
      aneuploidy, and decreased (P < or = 0.005) the ATP content at 0, 1, and 16 hr of
      culture compared to the control groups. CONCLUSIONS: These findings raise some
      concern about any other condition/drug that may directly or indirectly decrease
      the intracellular Ca2+ concentration in human oocytes.

PMID- 10335477
TI  - Ongoing pregnancy after intracytoplasmic sperm injection of epididymal
      spermatozoa into cryopreserved human oocytes.

PMID- 10335478
TI  - Endothelial cells as targets for tumor therapy.

PMID- 10335479
TI  - Tumor angiogenesis and endothelial cell modulatory factors.
AB  - Angiogenesis is the ability of preexisting vasculature to send out capillary
      sprouts leading to the formation of new vasculature. It is now a well-accepted
      idea that progression of solid tumors is intrinsically dependent on angiogenesis
      for growth of the primary tumor and metastatic lesions. Investigations into tumor
      angiogenesis have focused on inhibition of tumor neovasculature as yet another
      possible mechanism for impairing tumor progression. Numerous studies have
      characterized cellular and molecular factors important to vascular formation and
      development and have led to the identification and understanding of requisite
      interactions between endothelium, angiogenic cytokines, and the supporting
      matrix. These studies have also led to the identification of cytokines involved
      in the proteolytic disruption of the basement membrane, the migration of
      endothelial cells, and the proliferation and formation of neoendothelium into
      functional vasculature. As therapies based on antiangiogenic strategies continue
      to evolve and clinical trials are conducted, these agents may become an important
      part of the arsenal against tumor proliferation, especially given their favorable
      toxicity profile. This review discusses the angiogenic cytokines which have been
      most intensely studied and the receptors they act upon. Additionally, we discuss
      select proteases and their importance in the development of neovasculature. A
      better understanding of these components will help in the development of novel
      therapeutic strategies.

PMID- 10335480
TI  - Human papillomavirus vaccines for cervical cancer.
AB  - Cervical cancer is one of the most common causes of cancer-related death in
      women. As a result of several recent advances in molecular biology, the
      association between human papillomavirus (HPV) infection and cervical cancer has
      been firmly established, and the oncogenic potential of certain HPV types has
      been clearly demonstrated. Several lines of evidence suggest the importance of
      the host's immune response, especially cellular immune response, in the
      pathogenesis of HPV-associated cervical lesions. These observations form a
      compelling rationale for the development of vaccine therapy to combat HPV
      infection. Both prophylactic and therapeutic HPV vaccine strategies are being
      developed. Prophylactic strategies currently under investigation focus on the
      induction of effective humoral immune responses against subsequent HPV infection.
      In this respect, impressive immunoprophylactic effects have been demonstrated in
      animals using papillomavirus-like particles (VLPs). VLPs are antigenic and
      protective, but are devoid of any viral DNA that may be carcinogenic to the host.
      For treatment of existing HPV infection, techniques to improve cellular immunity
      by enhancing viral antigen recognition are being studied. For this purpose, the
      oncogenic proteins E6 and E7 of HPV-16 and -18 are the focus of current clinical
      trials for cervical cancer patients. The development of successful HPV-specific
      vaccines may offer an attractive alternative to existing screening and treatment
      programs for cervical cancer.

PMID- 10335481
TI  - High-resolution HLA-A*0201 subtyping using directed heteroduplex analysis.
AB  - HLA-A02* has become an important target for cytotoxic T lymphocyte-based
      immunotherapy reflecting the high prevalence of this allele in patient
      populations. There are at least 26 different A*02 alleles, and their subtype
      specificity has significant functional implications for T-cell-mediated
      recognition of immunologic targets. We have developed a novel method for HLA-A*02
      allelic screening using directed heteroduplex analysis (DHDA). DNA samples from
      Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines (EBV-B)
      representing 10 different HLA-A*02 alleles (0201, 0202, 0204, 0205, 0206, 0208,
      0210, 0211, 0216, 0217) were prepared. In addition, DNA was prepared from 81
      individuals representing a wide variety of A*02 subtypes previously determined by
      sequence specific primer (SSP) polymerase chain reaction (PCR) including
      individuals heterozygous for two A*02 specificities. Probes and samples were
      generated by PCR amplification using HLA-A*02 specific primers encompassing exons
      2 and 3, where most of the functionally significant allelic polymorphism is
      clustered. DHDA was performed by generating heteroduplex molecules composed of a
      fluorescein-labeled allelic probe sequence and an unlabeled allelic PCR product.
      Gel retardation was consistent for allele-probe combinations. We were able to
      identify several A*02 alleles prepared from EBV-B cell lines that, when used as
      probes, had very impressive specificity and sensitivity. Combinations of two
      probes were identified (0205 + 0211 and 0208 + 0211) that allowed differentiation
      of A*0201 alleles from all other A*02 alleles tested. All samples typed by probe
      combinations had DHDA typing and SSP typing confirmed by DNA sequencing. This
      study expands the molecular typing repertoire available to the modern HLA
      laboratory, and shows that DHDA has significant promise as a reliable screening
      method for HLA A*02 subtyping.

PMID- 10335482
TI  - IL-13 can substitute for IL-4 in the generation of dendritic cells for the
      induction of cytotoxic T lymphocytes and gene therapy.
AB  - Immunization with tumor-associated antigen pulsed dendritic cells (DC) has been
      shown to elicit both protective and therapeutic antitumor immunity in a variety
      of animal models and is currently being investigated for the treatment of cancer
      patients in clinical trials. In this study we show that DC can be generated from
      peripheral blood mononuclear cells of healthy donors as well as breast and
      melanoma cancer patients using granulocyte-macrophage colony-stimulating factor
      (GM-CSF) and interleukin-13 (IL-13) and that these DC have many of the same
      characteristics as DC differentiated using GM-CSF and IL-4. The DC generated in
      GM-CSF and IL-13 are CD14- and express high levels of the cell surface markers
      CD86, HLA-DR, and CD58, as do DC generated in GM-CSF and IL-4. The purity and
      yield of both DC populations are not significantly different. Furthermore, both
      populations of DC are effective at presentation of alloantigen as determined in a
      mixed lymphocyte response, and both are able to process and present soluble
      tetanus toxoid antigen to CD4+ T cells. Because we are interested in the
      generation of DC for antigen-specific cytotoxic T lymphocyte (CTL) generation, we
      compared the ability of peptide-pulsed DC differentiated in GM-CSF and IL-4
      versus GM-CSF and IL-13 for the generation of influenza and MART-1 specific CTL.
      Both populations of DC induced CD3+ CD8+ CD4- and CD56- CTL, which could lyse the
      appropriate targets in an antigen-specific manner. Finally, both GM-CSF and IL-4
      DC and GM-CSF and IL-13 DC yielded similar beta galactosidase expression levels
      after transduction with recombinant adenovirus containing the LacZ gene. These
      results suggest that DC generated in GM-CSF and IL-13 may be useful for
      immunotherapy and gene therapy protocols.

PMID- 10335484
TI  - Antitumor activity of killer cells stimulated with both interleukin-2 and
      interleukin-12 on mouse glioma cells.
AB  - Interleukin-12 (IL-12), originally called natural killer cell stimulatory factor
      or cytotoxic lymphocyte maturation factor, has potential for use as an
      immunomodulator in cancer therapy because it significantly retards the growth of
      some murine tumors. In this study, we analyzed the antitumor effects of
      lymphocytes stimulated in vitro with both recombinant IL-2 (rIL-2) and rIL-12.
      When IL-12 was added to mouse splenocytes (SPCs) or human peripheral blood
      monocytes (PBMCs) incubated with IL-2 for > 4 days, IL-2-induced cytotoxicity
      against glioma cells was augmented. In contrast, IL-12 inhibited IL-2-induced
      lymphokine-activated killer (LAK) cell activity when added concurrently to
      cultures. The concentration of IL-10 induced by IL-12 increased in the
      supernatant of human PBMCs costimulated with IL-2 and IL-12. Endogenous IL-10
      augmented the cytotoxicity of SPCs stimulated with IL-2 or IL-12 or both.
      However, tumor-bearing mice treated with PBMCs stimulated with both IL-2 and IL
      12 did not survive longer than those treated with PBMCs stimulated with IL-2
      alone (LAK cells).

PMID- 10335483
TI  - Cytocidal activity of PBL, LAK, and IDEC-C2B8 and expression of HLA class 1, ICAM
      1, and CD20 in vincristine-resistant hematologic cell lines.
AB  - This study was designed to determine whether the cytocidal activity of
      immunotherapy such as cytotoxic peripheral blood lymphocytes (PBL), lymphokine
      activated killer (LAK) cells, and chimeric anti-CD20 mouse/human monoclonal
      antibody, IDEC-C2B8, overcome vincristine (VCR) resistance in cultured cell lines
      derived from human leukemia/lymphoma. In addition, the relation between the
      susceptibility to these immunotherapies and the expression levels of HLA class 1
      and ICAM-1 as well as CD20 on the cell surface was analyzed. Three of six VCR
      resistant cell lines were less susceptible to PBL cytotoxicity compared with wild
      type cells, whereas the susceptibility was kept in the other three VCR-resistant
      cell lines. Four of six VCR-resistant cell lines were less susceptible to LAK
      activity and the other two cell lines were as sensitive to LAK cells as their
      wild-type counterparts. There was no correlation between the susceptibility for
      PBL cytotoxicity and the expression of HLA class 1 in both wild and VCR-resistant
      cells. In contrast, ICAM-1 in the two cell lines that showed decreased
      susceptibility for LAK cytotoxicity disappeared, although that in one cell line
      increased. IDEC-C2B8 was effective only against B-cell lines expressing CD20. One
      cell line in which the expression of CD20 increased was nearly six times more
      sensitive to IDEC-C2B8 than wild type. Thus, we concluded that the resistance to
      VCR in some tumor cell lines is associated with modified susceptibility for
      immunotherapies by the different expression of target molecules from those of
      wild-type counterparts.

PMID- 10335485
TI  - Active specific immunotherapy for metastatic colorectal carcinoma: phase I study
      of an allogeneic cell vaccine plus low-dose interleukin-1 alpha.
AB  - A vaccine consisting of four allogeneic colon carcinoma cell lines (DLD-1,
      HCT116, WiDr, and T84) mixed with the adjuvant DETOX (Mycobacterium phlei cell
      wall and Salmonella minnesota lipid A) was administered to 25 patients with low
      volume metastatic colorectal carcinoma. The first eight patients received vaccine
      only, given intradermally on three occasions at 3-week intervals. Subsequent
      patients also received subcutaneous interleukin-1 alpha (IL-1 alpha), 0.3-0.5
      microgram/m2 per day for 8 days after each vaccination in an outpatient setting.
      Vaccine alone caused local erythema, induration, and pruritus. IL-1 caused
      fevers, chills, and rigors that started in 4 h and lasted 1-2 h. One patient
      developed a brief loss of consciousness with a rigor that resolved without
      sequelae. One episode of mild hypotension occurred. Fatigue occurred by day 8 of
      IL-1. A substantial increase in the number of patients with positive skin tests
      to DLD-1 and HCT116 occurred after vaccine treatment both without and with IL-1
      alpha. An allogeneic cell vaccine plus subcutaneous IL-1 was administered safely
      to outpatients with some evidence of in vivo effect observed.

PMID- 10335486
TI  - Immunological changes in peripheral blood mononuclear cells of patients with
      metastatic renal cell carcinoma after low doses of subcutaneous immunotherapy
      with IFN-alpha-2b and IL-2.
AB  - To elucidate the immunologic changes induced by low doses of subcutaneous
      interferon (IFN)-alpha-2b plus interleukin-2 (IL-2) in patients with metastatic
      renal cell cancer, we have studied a group of eight patients undergoing two
      cycles of immunotherapy after radical nephrectomy. Natural killer (NK) cytotoxic
      activity, proliferative response to T-lymphocyte mitogens, and phenotypic profile
      of T and NK cells were determined in peripheral blood mononuclear cells (PBMCs)
      before and after each cycle. No significant differences were found in either of
      the studies realized between untreated patients and their counterpart healthy
      controls. However, after the first cycle, there was a significant increase in NK
      cytotoxic activity and in the number of CD16+/CD56+ cells that parallelled a
      significant decrease in the percentage of CD3+ and CD4+ lymphocytes with no
      changes in the proliferative response to T-cell mitogenic signals. Individual
      analysis of each patient on the basis of their clinical response to treatment
      showed that after the first cycle of immunotherapy there were no significant
      differences in the immunological profiles analyzed between patients with complete
      or partial responses and those who did not respond to treatment, whereas, at the
      end of the second cycle, patients who achieved complete or partial clinical
      responses had higher NK-cytotoxic activity that those who remained in disease
      progression. We conclude that subcutaneous immunotherapy with IFN-alpha-2b and IL
      2 induces a systemic immunomodulatory effect on PBMCs, manifested preferentially
      in a systemic NK activation and expansion that is related to the clinical
      outcome.

PMID- 10335487
TI  - Combination interleukin-2 and doxorubicin in advanced adult solid tumors:
      circumvention of doxorubicin resistance in soft-tissue sarcoma?
AB  - Based on the likelihood of antitumor interactions between cytokines and cytotoxic
      drugs, we designed a pilot study to evaluate feasibility, clinical,
      pharmacologic, and immunologic effects of concomitantly administered subcutaneous
      (SQ) recombinant interleukin-2 (r-IL-2) and doxorubicin (ADR) in patients with
      advanced solid tumors (AST). Patients received one injection of ADR alone (70
      mg/m2) and 3 weeks later a combination of r-IL-2 (18 MIU/m2 days 1-5 s.q.) and
      ADR at the same dose either 3-4 h after the first r-IL-2 injection (arm 1) or 2
      days after the last r-IL-2 injection (arm 2). The same combination was repeated
      every 4 weeks according to the evolution of the disease. Pharmacokinetics were
      assessed over 48 h after injection of ADR alone and after the first ADR-IL-2
      cycle and immunologic monitoring at days 1 and 8 of the first ADR-IL-2 cycle.
      Tumors were measured at baseline, after ADR alone, and after each ADR-IL-2 cycle
      until progression. Twenty-one adult patients with various AST including 14 soft
      tissue sarcomas (STS) entered the study, 11 in arm 1 and 10 in arm 2. All
      patients were heavily pretreated; 16 had received an anthracycline-containing
      chemotherapy regimen. Eleven patients were ADR refractory and 1 ADR resistant.
      Grade 4 neutropenia occurred in 28, 82, and 40% of patients after ADR alone, ADR
      IL-2 in arm 1 and ADR-IL-2 in arm 2, respectively. Mucitis was higher in arm 1 (7
      of 11 patients) compared with arm 2 (0 of 10) and ADR alone (0 of 21). SQ
      injections of r-IL-2 did not affect ADR pharmacokinetics. ADR injection in arm 1
      prevented IL-2-induced lymphocyte rebounds in all patients but did not alter
      qualitatively non-major histocompatibility complex-restricted cytotoxicity. There
      was no response after ADR alone. Two patients, one in each arm, experienced a
      prolonged (8 and 5 months) objective response after ADR-IL-2. Both had ADR
      refractory STS with a local relapse and metastatic metastases. Interestingly,
      both patients had unusually elevated TNF-alpha levels before and after the first
      ADR cycle. Combination ADR-IL-2, although toxic, is feasible and manageable with
      routine clinical support. r-IL-2 enhanced ADR hematologic and extrahematologic
      toxicities. The two objective responses observed in these heavily pretreated
      patients refractory to ADR supports the hypothesis of a modulation of ADR
      resistance, possibly mediated by means of a mechanism involving TNF-alpha.
      Elevated baseline TNF-alpha levels could be predictive of response to ADR-IL-2
      and deserves further investigation.

PMID- 10335488
TI  - Cell differentiation in the embryonic mammalian spinal cord.
AB  - The acquisition of cell type specific properties in the spinal cord is a process
      of a sequential restriction in developmental potential. Multipotent
      neuroepithelial stem cells (NEP cells) can give rise to all the major cell types
      in the central nervous system. The generation of these multiple cell types occurs
      via the generation of intermediate precursor cells, which are restricted in their
      differentiation potential, but are still able to give rise to more than one cell
      type. These intermediate precursor cells are different from NEP cells and are
      different from each other. We have identified neuronal restricted precursor cells
      (NRP's) which can only generate neurons but no longer glial cells and glial
      restricted precursor cells (GRP's), which give rise to glial cells but not to
      neurons. These intermediate precursor cells can be purified and expanded in vitro
      and might offer a new tool for gene discovery, drug screening and transplantation
      approaches.

PMID- 10335489
TI  - Myelin dysfunction/degradation in the central nervous system: why are myelin
      sheaths susceptible to damage?
AB  - In the central nervous system, myelin sheaths are produced to electrically
      insulate axons and to increase the velocity of axonal conduction. They are highly
      complex structures, which are often destructed in neurological disorders. One
      possible reason for the vulnerability of myelin sheaths to damage became apparent
      from analyses of animals with altered amounts of otherwise normal myelin
      components: Due to limited redundance in function between different myelin
      proteins, dysfunction or loss of one protein may cause loss of function and
      instability of the entire myelin sheath.

PMID- 10335490
TI  - Molecular mimicry and multiple sclerosis--a possible role for degenerate T cell
      recognition in the induction of autoimmune responses.
AB  - Multiple sclerosis is an inflammatory demyelinating disease of the central
      nervous system. The etiology is unknown, but several lines of evidence support
      the hypothesis that the pathogenesis is mediated by autoreactive T lymphocytes.
      Molecular mimicry has been proposed as a possible mechanism for the development
      of an autoimmune response to myelin antigens. According to this model, an immune
      reaction to self antigens could be initiated by T cells that cross-react with
      infectious agents that "mimic" the autoantigen, i.e. they share immunologic
      epitopes. It was previously thought that, in order for a cross-reaction of T
      cells to two different antigens to occur, a substantial amino acid sequence
      homology between the two antigens was required. More recent studies on the basic
      mechanisms of T cell antigen recognition have shown that, at least for some T
      cell clones, antigen recognition is more "degenerate" and sequence homology is
      not required for crossreactivity to occur. This article reviews the relevance of
      these recent advances in basic T cell receptor immunology to the occurrence of
      autoimmunity in the central nervous system.

PMID- 10335491
TI  - Dopamine agonists: what is the place of the newer compounds in the treatment of
      Parkinson's disease?
AB  - Three new dopamine agonists (cabergoline, pramipexole, ropinirole) have been put
      on to the market within the past months to treat patients with Parkinson's
      disease. Like any marketed dopamine agonists, the new compounds bind to the D2
      like receptors. Pramipexole and ropinirole appear to be quite close drugs. Both
      are selective non ergot D2 (and preferentially D3) agonists, with an elimination
      half-life of 5 to 10 hours. Conversely, cabergoline is an ergot derivative, less
      selective for the D2 receptors, with a much longer elimination half-life (60
      hours or more). In moderately advanced levodopa treated patients with Parkinson's
      disease and motor fluctuations, cabergoline, pramipexole and ropinirole all do
      significantly better than placebo in reducing UPDRS motor examination scores,
      time spent off and daily dose of levodopa. None of the 3 newer agonists proved to
      do significantly better than bromocriptine in this indication, at the cost of
      very similar adverse effects. In de novo levodopa naive patients, pramipexole and
      ropinirole did significantly better than placebo in short-term (few months)
      follow-up trials, at the cost again of classical dopaminergic adverse effects.
      Ropinirole was marginally more effective than bromocriptine, while its use
      induced the same risk of psychosis than the "old" reference agonist. Early
      treatment with cabergoline, compared with levodopa, in a long-term (5 year) study
      reduced the relative risk of developping motor complication by more than 50%. A
      similar study is presently on-going to compare ropinirole and levodopa. Clinical
      trials to assess putative neuroprotective effects are also on going with
      ropinirole and pramipexole. Up to now, the available clinical controlled data
      suggest that the newer dopamine agonists have very similar clinical effects with
      only minor superiority, if any, versus bromocriptine.

PMID- 10335492
TI  - Apomorphine has a potent antiproliferative effect on Chinese hamster ovary cells.
AB  - Apomorphine is a potent non selective agonist at the D1 and D2 dopamine receptors
      acting both pre- and post-synaptically. In this report we describe a novel
      function of apomorphine, independent from its dopaminergic activity. Apomorphine
      inhibits Chinese hamster ovary (CHO)-K1 cell proliferation in a dose-dependent
      manner. The EC50 of apomorphine-induced inhibition of CHO-K1 cell proliferation
      determined by cell counting was 3.24 +/- 0.07 microM. Remarkably, the dose
      response curve obtained by measuring the incorporation of [3H]thymidine was
      practically identical to the previous one giving an EC50 of 3.52 +/- 0.04 microM.
      The dopaminergic antagonists SCH23390 and spiperone at a concentration of 10
      microM (well beyond their Kd values for the dopamine D1- and D2-like receptors
      respectively) were not able to antagonize the effect of apomorphine on CHO-K1
      cell proliferation. Apomorphine exerts its effect early during incubation; CHO-K1
      cells exposed to apomorphine for a period as short as 1 h and then allowed to
      grow for three days were significantly reduced in number with respect to
      untreated control cells. After four hours of exposition to apomorphine (10
      microM) the antiproliferative effect was similar to that seen when this compound
      was present in the bath for all three days. Concentrations of apomorphine higher
      than 10 microM induced cell death, and the colony was completely destroyed at 50
      microM. Cytometric analyses showed a significant accumulation of CHO-K1 cells in
      the G2/M phase.

PMID- 10335493
TI  - Potent neuroprotective and antioxidant activity of apomorphine in MPTP and 6
      hydroxydopamine induced neurotoxicity.
AB  - Apomorphine is a potent radical scavenger and iron chelator. In vitro apomorphine
      acts as a potent iron chelator and radical scavenger with IC50 of 0.3 microM for
      iron (2.5 microM) induced lipid peroxidation in rat brain mitochondrial
      preparation, and it inhibits mice striatal MAO-A and MAO-B activities with IC50
      values of 93 microM and 241 microM. Apomorphine (1-10 microM) protects rat
      pheochromocytoma (PC12) cells from 6-hydroxydopamine (150 microM) and H2O2 (0.6
      mM) induced cytotoxicity and cell death. The neuroprotective property of (R)
      apomorphine, a dopamine D1-D2 receptor agonist, has been studied in the MPTP (N
      methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. (R)
      apomorphine (5-10 mg/kg, s.c.) pretreatment in C57BL mice, protects against MPTP
      (24 mg/kg, i.p.) induced loss of nigro-striatal dopamine neurons, as indicated by
      striatal dopamine content, tyrosine hydroxylase content and tyrosine hydroxylase
      activity. It is suggested that the neuroprotective effect of (R)-apomorphine
      against MPTP neurotoxicity derives from its radical scavenging and MAO inhibitory
      actions and not from its agonistic activity, since the mechanism of MPTP
      dopaminergic neurotoxicity involves the generation of oxygen radical species
      induced-oxidative stress.

PMID- 10335494
TI  - Neuroprotective effect of chronic inactivation of the subthalamic nucleus in a
      rat model of Parkinson's disease.
AB  - Several evidences showed that glutamate can be implicated in the degenerative
      process of dopaminergic neurons in Parkinson's disease. The treatment with NMDA
      antagonists have been shown to induce a neuroprotective effect in animal models
      of this disease. As subthalamic nucleus neurons send direct glutamatergic
      projections to the substantia nigra, we studied the effects of kainic acid lesion
      of this nucleus on the degeneration of dopaminergic neurons induced by
      microinjection of 6-hydroxydopamine in the striatum of rat done one week after
      the first lesion. Animals were killed 15 days after the injection of 6
      hydroxydopamine. Immunohistochemical study showed that lesion of the subthalamic
      nucleus can prevent the degeneration of substantia nigra dopaminergic somata when
      carried out one week prior to 6-hydroxydopamine injection in the striatum.
      Nevertheless neurochemical results showed that this lesion did not antagonize the
      striatal 6-hydroxydopamine-induced dopamine depletion in the striatum 15 days
      after 6-hydroxydopamine injection.

PMID- 10335495
TI  - Antiglutamate therapy of ALS--which is the next step?
AB  - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which
      was thought to be untreatable for a long time. However, recent evidence in men
      indicates that antiglutamatergic strategies are the first to have an influence on
      its pathogenesis and slow down the disease process. Since the effect of the drugs
      is still small, this progress cannot only be seen as a success of the present but
      most also be acknowledged as a starting point for the future. How will these
      future studies look like? They will have to take into account that ALS presumably
      has a long preclinical period and they will use a number of novel compounds and
      treatment strategies which have recently been shown to be effective in a
      transgenic animal model. This also implies that we are likely to use combination
      therapies and have to try to treat patients early. The latter will be necessarily
      connected with the demand for a novel clinical attitude to the diagnosis of the
      disease.

PMID- 10335496
TI  - Antiglutamate therapies in Huntington's disease.
AB  - Huntington's disease is an autosomal dominant neurodegenerative disorder caused
      by an unstable trinucleotide CAG repeat. The mechanism by which the genetic
      defect leads to neuronal injury and death is unknown, but is thought to include
      glutamate-mediated excitotoxicity and abnormalities of mitochondrial energy
      production. Both of these mechanisms may lead to a final common pathway of
      increased production of free radical species. Prior clinical trials in patients
      with Huntington's disease that have addressed these hypotheses have been limited
      by size. A current, NIH-funded trial of remacemide hydrochloride and Coenzyme Q10
      in 340 patients with Huntington's disease is described. This is the largest and
      longest multi-center trial in Huntington's disease to address the glutamate- and
      mitochondrial-mediated hypotheses of neurodegeneration.

PMID- 10335497
TI  - Neural transplantation in animal models of multiple system atrophy: a review.
AB  - Multiple system atrophy of the striatonigral degeneration (MSA-SND) type is
      increasingly recognized as major cause of neurodegenerative parkinsonism. Due to
      combined degeneration of substantia nigra pars compacta (SNC) and of striatum,
      antiparkinsonian therapy based on levodopa substitution eventually fails in more
      than 90% of patients. Animal models of MSA-SND are urgently required as test-bed
      for the evaluation of novel therapeutic interventions in this disorder such as
      neurotrophic factor delivery and neuronal transplantation. A number of well
      established rodent and primate models of Parkinson's (PD) and Huntington's (HD)
      disease replicate either nigral ("PD-like") or striatal ("HD-like") pathology and
      may therefore provide a useful baseline for the development of MSA-SND models.
      Previous attempts to mimick MSA-SND pathology in rodents have included sequential
      injections of 6-hydroxydopamine (6OHDA) and quinolinic acid (QA) into medial
      forebrain bundle and ipsilateral striatum, respectively ("double toxin-double
      lesion" approach). Preliminary evidence in rodents subjected to such lesions
      indicates that embryonic transplantation may partially reverse behavioural
      abnormalities. Intrastriatal injections of mitochondrial toxins such as 3
      nitropropionic acid (3NP) and 1-methyl-4-phenylpyridinium (MPP+) in rodents
      result in (secondary) excitotoxic striatal lesions and subtotal neuronal
      degeneration of ipsilateral SNC, thus producing MSA-SND-like pathology by a
      simplified "single toxin-double lesion" approach. Comparative studies of human
      SND pathology and rodent striatonigral lesions are required in order to determine
      the rodent model(s) most closely mimicking the human disease process.

PMID- 10335498
TI  - Striatal reconstruction by striatal grafts.
AB  - It is now well established that striatal lesions induce motor and cognitive
      deficits in rats, and that grafts of embryonic striatal tissue can survive,
      integrate into the lesioned host brain and alleviate the behavioural deficits in
      both motor and cognitive spheres. How? Since normal striatal function is
      dependent upon it's integration within a connected cortical-subcortical neuronal
      circuitry, and the deficits following striatal damage appear to reflect a
      "disconnexion" syndrome, the observation of recovery suggests that the grafts re
      establish a connected circuitry within the host brain. Evidence to corroborate or
      refute this hypothesis, in comparison with a less-specific mechanism (or
      mechanisms) of recovery, is considered, including anatomical,
      electrophysiological and neurochemical demonstrations of functional circuit
      reconstruction in the host brain by striatal tissue transplants.

PMID- 10335499
TI  - Somatic gene therapy in animal models of Parkinson's disease.
AB  - Gene therapy in Parkinson's disease (PD) emerged about 10 years ago but until
      now, no clinical trials are under way, because most approaches have failed to
      show long-term therapeutic effects in PD animal models and because safety
      concerns precluded the use in humans so far. This review tries to give an
      overview on the development of different strategies in gene therapy in PD animal
      models and point out new and possibly more successful directions, including the
      transplantation of neural precursor cells and pig tissue.

PMID- 10335500
TI  - [Computer-assisted diagnostic system based on the analysis of the rhythmic
      pattern of a radial artery pulse signal].
AB  - The paper outlines a computer-aided diagnostic system based on the analysis of
      the rhythmic pattern of a radial arterial pulse signal and the procedures of its
      analysis. Basic data on how to implement hardware and software are presented. The
      results of clinical studies conducted by using the presented system are given.

PMID- 10335502
TI  - [Functional role' of hemodialysis equipment in the bioengineering system of
      artificial purification].
AB  - The paper deals with hemodialysis equipment as a constituent of the
      bioengineering system for artificial blood purification. This approach allows us
      to objectively evaluate its functional capacities and the usefulness of objective
      results of hemodialysis and to provide scientific evidence for the structure of
      hemodialysis equipment. The artificial purification of the biological organism is
      presented as a variety of interrelated controlling and diagnostic processes in
      the controlling and actuating elements of extracorporeal artificial organs.

PMID- 10335501
TI  - [Effects of magnetic fields on the respiratory function].
AB  - The impact of a constant magnetic field on the blood oxygen and carbon dioxide
      linkage in the alive organism was studied. The action of the magnetic field was
      demonstrated to increase the oxygen capacity of hemoglobin by 20%. Furthermore,
      it makes carbon dioxide excretion difficult on air breathing and easy on oxygen
      breathing. The increased oxygen capacity is attributable to the formation of
      compounds of the type of hemochrome and the altered CO2 linkage change is
      accounted for by the Bore effect.

PMID- 10335503
TI  - [Assessment of the effectiveness of medical instruments sterilization by
      electrochemically activated solutions and computer modeling of the dynamics of
      hospital infections].
AB  - The paper sets a task of evaluating the efficiency of electrochemically activated
      solution sterilization of medical instruments, which is tackled by the computer
      aided simulation of time course of nosocomial HIV infection.

PMID- 10335505
TI  - [Water purification for hemodialysis].
AB  - An electrodialysis system has been designed to purify water. It comprises two
      units: a preliminary preparation unit and an electrodialysis one. The system
      consists of columns containing zeolite, activated carbon, and ion-exchange
      resins. Zeolite makes water free from mechanical impurities and iron, activated
      carbon adsorbs organic matter and chlorine ions, ion-exchange resins soften
      water. The electrodialysis unit is noted for its original design. Mathematical
      simulation has allowed the authors to optimize the design and to make a block
      that makes the process continuous without repolarization, which can decant the
      minimum levels of salt concentrates, thus decreasing energy supply to 2 W per
      liter. The unit is made as a pressure filter design having the platinum-titanium
      electrodes and membranes MK-40 and MK-45 made in Russia. The system operates
      automatically. Its all components are made in Russia.

PMID- 10335504
TI  - [Adaptation-reposition technological means in combination with a bioactive
      preparation Ximedon for stimulation of wound healing].
AB  - The paper proposes a working classification of devices for intra- and extrafocal
      transtissue vulnosynthesis with the concurrent use of the agents that enhance
      reparative regeneration. Evaluating wound closure with wound adapters or routine
      suture has shown the advantages of the techniques by employing the proposed
      devices: the latter accelerates and facilitates suture application reparative,
      increases atraumaticity, asepticity, creates conditions for forming a precision
      suture. The positive results of experimental studies and clinical observations
      suggest that wound adapters have promises in practical application, transtissue
      device-aided vulnosynthesis in combination with topical pyrimidine derivatives,
      such as ximedon, shows great opportunities in soft tissue lesions.

PMID- 10335506
TI  - [Information technologies in public health to simulate the processes of decision
      making based on medical monitoring data].
AB  - The paper considers how to enhance the efficiency of therapeutical-and
      therapeutical procedures and to choose the strategy for arranging medical
      measures at different levels of public health care, which is largely determined
      by the corrective use of computer-aided information technologies to apply
      monitoring approaches to assessing and predicting medical parameters by taking
      into account the space position of the objects under study and the ecological
      situation in a region. A procedure is proposed for decision making on the basis
      of experts' assessments and data imaging findings in arbitrary schematic images.
      This procedure serves as a basis of making various management decisions.

PMID- 10335507
TI  - [Features of the maintenance of automated developing machines].
AB  - Based on his long-term own experience the author gives recommendations on the
      assembly, adjustment, operation, and preventive maintenance of automatic
      developing machines. Procedures are presented for evaluating the quality of X-ray
      films and controlling the activity of operating qualities of a developer while
      machining photographic materials. Troubles and malfunction of equipment and
      procedures for their elimination are shown to affect the quality of development
      of films.

PMID- 10335508
TI  - [Second-generation self-moving wheelchairs: conception and prospects of
      production].
AB  - The paper proposes a conception of designing the self-moving wheeled chairs that
      meet the present-day consumers' requirements and corresponds to the up-to-date
      medical and transport building facilities. The conception mainly involves their
      electrification requirements, maximum maneuverability, good moving capacities,
      including self-climbing up and down stairs. The system of decision making and
      recommended modes for the wheeled chairs to move is designed up to the world
      novelty standards and can be manufactured both in Russia and foreign countries.

PMID- 10335509
TI  - [Supplying therapeutic equipment to tuberculosis departments and hospitals].
AB  - The paper provides evidence for that the development of new treatments of
      tuberculosis by using up-to-date technical means and their introduction into
      practice. It gives the data of the researches and developments made by the VNIIMP
      VITA close joint stock company, which are both aimed at providing tuberculous
      units and hospitals with necessary therapeutical equipment, such as devices for
      pneumothorax, endoscopic studies, etc.

PMID- 10335510
TI  - [Control of effective doses in x-ray studies].
AB  - Developing the controlling techniques for dose loads in patients has led to the
      introduction of methods for evaluating the new dosimetric value an effective
      dose. When it is determined, regular refinement of calculating multiples causes
      errors as hundredths of a percent. Therefore, in addition to tabulated techniques
      of evaluating the effective dose and direct measurement of the dose absorbed per
      radiation area, one can determine midpoint exposure of an X-ray feeding device
      and use a translating program implemented in the Indor-C indicating device
      designed by the authors. In going from 60 kW to 120 kW, changes in the
      superficial dose by 15-50%, the absorbed dose by 10-45%, the 5-cm depth dose by 3
      5 times can be neglected.

PMID- 10335511
TI  - [New types of multi-size cameras].
AB  - The paper provides a technical evaluation of the thermographic multi-sized
      chambers and recorders used in them, which have appeared on the market. It
      compares the control images obtained by employing thermographic and conventional
      multi-sized chambers.

PMID- 10335512
TI  - [A device for joining fractured fragments in unstable pelvic injuries].
AB  - In unstable injuries (dislocations and fractures) of the posterior and anterior
      semirings, clamp-type devices are used for emergency temporal (and prolonged)
      stabilization of the pelvis. In such pelvic injuries, a device for closing
      fractured fragments as double clamps that consist of two pairs of stands, fixed
      with bond beams, and long beams which compress the broken parts of the pelvis.
      The pairs of pushing screws in the lower part of the stands provides finishing
      compression. The device is kept assembled in a paraformalin chamber. It is
      assembled within 10 minutes. The device is superior to the other well-known
      devices in its functional capacities.

PMID- 10335513
TI  - Pathological laughing and crying in multiple sclerosis: a preliminary report
      suggesting a role for the prefrontal cortex.
AB  - As part of a wide ranging study investigating the prevalence, demographic and
      disease related characteristics of pathological laughing and crying (PLC) in
      multiple sclerosis (MS), a putative role for the prefrontal cortex was also
      explored. Eleven multiple sclerosis (MS) patients with carefully defined PLC were
      compared to a control group of 13 MS patients without PLC on various cognitive
      indices known to be sensitive to frontal lobe dysfunction. Although the two
      groups did not differ with respect to age, sex, physical disability, disease
      course, duration of MS, years of education, premorbid IQ, and depression, the PLC
      group performed more poorly on the Stroop test and a measure of verbal fluency.
      They also showed a trend to make more total errors on the Wisconsin Card Sort
      Test. The relevance of these findings to the pathogenesis of PLC is discussed, in
      particular whether the syndrome is, in part, mediated by dysfunction of the
      prefrontal cortex.

PMID- 10335514
TI  - Familial multiple sclerosis: volumetric assessment in clinically symptomatic and
      asymptomatic individuals.
AB  - A genetic basis for clustering of multiple sclerosis (MS) cases, based on studies
      of MS families, has been proposed for decades. Few reports provide detailed
      neurological as well as neuroradiological findings on these patients. We report
      total T2-weighted intracranial lesion volumes on members of three familial MS
      cohorts: a mother and father with conjugal MS with one affected son and a
      neurologically normal son and daughter, one pair of monozygotic twin sisters with
      MS, and a female sibling pair with MS. We hypothesized that asymptomatic siblings
      in a family with two affected parents and another affected child might
      demonstrate clinically silent T2-weighted lesions; and that monozygotic twins
      with MS are more likely to express similar T2-weighted lesion volumes than non
      twin sibling pairs. We found clinically silent lesions in unaffected children of
      the symptomatic parent couple, with a significant difference in total T2 lesion
      volume between these unaffected siblings and their parents, as well as their
      affected brother. In our other sibling pairs, T2 lesion volumes were similar
      between the twins and significantly different in the non-twin pair, despite
      similar levels of clinical functioning as determined by EDSS scoring. These
      results suggest that foci of demyelination might be expected in clinically normal
      offspring of parents with MS, possibly reflecting a genetic predisposition to
      subsequent development of MS.

PMID- 10335515
TI  - Survey of multiple sclerosis in northern California. Northern California MS Study
      Group.
AB  - A random sample of 493 multiple sclerosis (MS) patients registered with the
      Northern California Chapter of the National MS Society was surveyed by mail and
      subsequently interviewed with regard to their MS, life style, diet, medical
      treatment, family history, and insurance coverage. Of this sample, 168 patients
      (34%) returned completed questionnaires. The answers on the questionnaire were
      entered into a database and scores on the extended disability status scale
      (EDSS), the neurologic rating scale (NRS), the ambulation index (AI), and the
      mean disability scale (MDS) were determined from the patient's answers to a
      portion of the questionnaire using a previously validated conversion program.
      This survey population of 168 patients seemed to represent well both the random
      sample and the frame population from which it was drawn. Patients commonly
      experienced symptoms for which there are medical treatments currently available
      such as bladder symptoms, fatigue, spasticity, pain, and depression.
      Surprisingly, however, with the exception of spasticity, patients were only
      infrequently treated for these complaints. In addition, despite the recent
      approval of the beta-interferons and copolymer I in the treatment of MS, only 74%
      of the appropriate candidates for such treatment had these options discussed with
      them and only 45% ever actually received such treatment. Certain clinical
      features and dietary habits were strongly associated with both EDSS scores and
      total disability. Not unexpectedly, either a progressive disease course or the
      presence of neurological dysfunction in any one of a number of functional areas
      (e.g. bladder, vision, cognitive change, etc.) correlated with higher EDSS scores
      and greater total disability. Fatigue was also strongly correlated with
      disability. Indeed, fatigue accounted (in whole or in part) for 65% of the
      disability experienced by patients; an observation which only underscores the
      fact that fewer than one third of the patients who experience fatigue have ever
      been tried on medications. Interestingly, the only factors associated with lower
      EDSS scores and less total disability were exercise and alcohol consumption. Such
      associations from a single survey, however, do not establish causation. It is the
      purpose of this study to establish a baseline level of function within this
      survey population so that future surveys in the same set of individuals can allow
      a prospective assessment of how health outcome has influenced different aspects
      of the patient's medical care, lifestyle, and insurance coverage.

PMID- 10335516
TI  - Stress and coping in multiple sclerosis: exacerbation, remission and chronic
      subgroups.
AB  - Individuals with multiple sclerosis were asked to identify stressors they had
      experienced over a 6-month period and the coping mechanisms employed to deal with
      those stressors. Subjects who reported currently experiencing an exacerbation of
      symptoms were compared with those in remission or in the chronic phase of their
      illness. Of the 61 subjects who completed the Hassles Scale, Uplifts Scale, and
      Ways of Coping, those classified as being in an exacerbation phase of MS were
      found to have significantly higher hassles scores than those in the chronic
      phase. A significant difference was also found in terms of a factor labeled
      'passive avoidant and aggressive coping' derived through a factor analysis of the
      Ways of Coping subscales. Subjects in the exacerbation subgroup had higher scores
      on this coping factor than those in the chronic subgroup. The difference in
      hassles scores remained significant after between-group differences in length of
      illness and reported number of symptoms were controlled through an analysis of
      covariance, although the difference in coping fell short of significance in this
      covariance analysis.

PMID- 10335517
TI  - Multiple sclerosis: a preliminary study of selected variables affecting
      rehabilitation outcome.
AB  - PROBLEM: The diversity of physical and cognitive impairments seen in progressive
      multiple sclerosis (MS), make it difficult to identify the factors that influence
      neurorehabilitation outcome. Improvements in a motor disability scale must be
      considered in the context of the patient's physical and cognitive starting
      points, if the process of neurorehabilitation is to be properly understood.
      METHOD: Data was collected from 38 patients (mean age 41 years, 16 men and 22
      women) with clinically definite MS (of whom all but one were in the progressive
      phase of the disease), who were consecutively admitted to a neurorehabilitation
      unit. Patients' physical disability was assessed on the motor scale of the
      Functional Independence Measure (FIM) on admission and discharge. Cognitive and
      neurological assessments were completed on admission. The cognitive battery
      comprised the WAIS-R, NART, RMT, CVLT CMT, GNT, GDA, and VOSP (some in short
      form). Emotional measures were the STAI, STAXI and BDI. RESULTS: The mean
      improvement on the FIM was 6 points. A multiple regression analysis was performed
      to determine which cognitive and neurological variables related to reduced
      disability after neurorehabilitation. To take account of each patient's starting
      point, the model included their FIM admission score. This variable, together with
      vocabulary skills and cerebellar function accounted for 57% of the variance in
      the patients' improvements. These results suggest that verbal intelligence and
      cerebellar function are influential in determining rehabilitation outcome.
      Although these findings will be unsurprising to clinicians, this is the first
      quantitative demonstration of these effects.

PMID- 10335518
TI  - Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in
      multiple sclerosis.
AB  - Myelin-directed autoimmunity is considered to play a key role in the pathogenesis
      of multiple sclerosis (MS). Increased production of both pro- and anti
      inflammatory cytokines is a common finding in MS. Interleukin-17 (IL-17) is a
      recently described cytokine produced in humans almost exclusively by activated
      memory T cells, which can induce the production of proinflammatory cytokines and
      chemokines from parenchymal cells and macrophages. In situ hybridisation with
      synthetic oligonucleotide probes was adopted to detect and enumerate IL-17 mRNA
      expressing mononuclear cells (MNC) in blood and cerebrospinal fluid (CSF) from
      patients with MS and control individuals. Numbers of IL-17 mRNA expressing blood
      MNC were higher in patients with MS and acute aseptic meningoencephalitis (AM)
      compared to healthy individuals. Higher numbers of IL-17 mRNA expressing blood
      MNC were detected in MS patients examined during clinical exacerbation compared
      to remission. Patients with MS had higher numbers of IL-17 mRNA expressing MNC in
      CSF compared to blood. This increase in numbers of IL-17 mRNA expressing MNC in
      CSF was not observed in patients with AM. Our results thus demonstrate increased
      numbers of IL-17 mRNA expressing MNC in MS with higher numbers in CSF than blood,
      and with the highest numbers in blood during clinical exacerbations.

PMID- 10335519
TI  - Lack of association of transforming growth factor (TGF)-beta 1 and beta 2 gene
      polymorphisms with multiple sclerosis (MS) in Northern Ireland.
AB  - OBJECTIVE: To examine the influence of TGF-beta genes on MS susceptibility.
      BACKGROUND: TGF-beta, of which three homologous isoforms exist (1, 2 and 3), is a
      strongly immunosuppressive cytokine-inhibiting expression of pro-inflammatory
      cytokines and blocking cytokine induction of adhesion molecules. TGF-beta delays
      onset of EAE and TGF-beta 1 gene knockout mice develop fatal multifocal
      inflammatory disease. High TGF-beta levels exist during MS remission whilst E
      selectin, whose expression is inhibited by TGF-beta, is found at higher levels in
      primary progressive disease (PPMS) and it is postulated that the unremitting
      course of PPMS may be due to low levels of TGF-beta. METHODS: Gene association
      studies using separate polymorphic microsatellite markers for TGF-beta 1 and TGF
      beta 2 were performed, incorporating 151 relapsing-remitting or secondary
      progressive MS (RR/SPMS) patients, 104 PPMS patients and 159 normal controls
      (Nor). Forward primers were 5' end-labelled with 6-Fam, PCR products were
      analysed on an Applied Biosystems 373A fluorescent fragment analyser and Genescan
      672 software was used for allele sizing. RESULTS: No significant differences
      existed in allele frequencies between either MS group and controls regarding the
      TGF-beta 1 marker: RR/SPMS vs Nor (P = 0.48, df = 8); PPMS vs Nor (P = 0.34, df =
      8). Similarly there were no associations demonstrated with the TGF-beta 2 marker:
      RR/SPMS vs Nor (P = 0.24, df = 2); PPMS vs Nor (P = 0.53, df = 2). CONCLUSION:
      These data indicate that TGF-beta 1 and beta 2 genes are not loci influencing MS
      susceptibility, either RR/SPMS or PPMS, in this population.

PMID- 10335520
TI  - Recent developments in drug therapy for multiple sclerosis.
AB  - Symptomatic treatment of multiple sclerosis (MS) includes a diverse range of
      drugs intended to relieve the specific symptoms with which a patient may present
      at a particular point in the progression of the disease. These drugs, not
      specifically designed for the treatment of MS, may include antispastic agents
      (e.g. baclofen), drugs to reduce tremor (e.g. clonazepam), anticholinergics (e.g.
      oxybutynin) which relieve urinary symptoms, anti-epileptics (e.g. carbamazepine)
      to control neuralgia, stimulants to reduce fatigue (e.g. amantadine), and
      antidepressants (e.g. fluoxetine) to treat depression. The treatment of acute
      relapses or exacerbations is dominated by corticosteroids such as
      methylprednisolone. The most active area of current investigation is the
      development of drugs which will inhibit the progression of the disease process
      itself, and in this category the beta- and alpha-interferons are the most
      effective drugs currently available, although many new treatments are currently
      in trials, including immunoglobulin, copolymer-1. bovine myelin, T-cell receptor
      (TCR) peptide vaccines, platelet activating factor (PAF) antagonists, matrix
      metallo-proteinase inhibitors, campath-1, and insulin-like growth factor (IGF).

PMID- 10335521
TI  - Autoimmunity in multiple sclerosis: study of a wide spectrum of autoantibodies.
AB  - The aim of this study was to assess the frequency of organ- and nonorgan-specific
      autoantibodies in MS patients and evaluate whether the presence of autoantibodies
      is an indicator of disease activity and/or a prognosis factor. One hundred and
      five definite MS patients in different stages and with different course and 75
      blood donors were tested for the autoantibodies TgA, TMA/TPO-A, PCA, ANA, aCl,
      SMA, AMA and ANCA. All patients were screened for the LAC. Autoantibodies to at
      least one autoantigen were found in 66.6% MS patients and in 13.3% controls (P <
      0.001). The frequency of TgA, TMA/TPO-A, ANA, aCl and SMA was statistically
      higher in patients than in controls. Circulating ANCAs were found in seven MS, a
      never reported finding. An early onset of MS (< 20 years) was associated with a
      lower autoantibody frequency (P < 0.01) Primary and secondary progressive MS had
      a higher antibody frequency than relapsing-remitting (P < 0.05) or benign (P <
      0.001) MS. Up to 86% of patients were autoantibody-positive during the acute
      stage, but only 30% of them remained positive during the remission stage (P <
      0.001). A generalised immune dysregulation occurs in MS patients, mostly during
      the acute stages and in the progressive courses, involving activation of both
      autoreactive Th1-cells (mainly linked to CNS lesions) and B-cells via Th2 cells.

PMID- 10335524
TI  - [Hemophilia in orthopedics--severe complications can be avoided].

PMID- 10335523
TI  - Chromosome 19 locus apolipoprotein C-II association with multiple sclerosis.
AB  - We have used a PCR based method to analyze allelic frequencies in a (TG)n(AG)m
      microsatellite marker located in the first intron of the apolipoprotein C-II gene
      in French MS patients and controls. Samples were collected from 74 MS patients
      and from 102 controls. The distribution of microsatellite alleles differed
      between patients and controls (chi 2 = 7.82), showing a significant effect (P <
      0.04) with MS due to the increased frequency of the allele 6 and a decrease
      frequency (P < 0.03) of allele I. Our study confirms that the apolipoprotein C-II
      region may influence susceptibility to MS.

PMID- 10335522
TI  - Effects of phosphodiesterase inhibitors on cytokine production by microglia.
AB  - Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to
      suppress the production of TNF-alpha in several types of cells. In the present
      study, we have shown that all the types of PDEIs, from type I- to V-specific and
      non-specific, suppress the production of TNF-alpha by mouse microglia stimulated
      with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of
      three different types of PDEIs synergistically suppressed TNF-alpha production by
      microglia at a very low concentration (1 microM). Since some PDEIs reportedly
      pass through the blood-brain barrier (BBB), the combination of three PDEIs may be
      worth trying in neurological diseases, such as multiple sclerosis and HIV-related
      neurological diseases in which TNF-alpha may play a critical role. Some PDEIs
      also suppressed interleukin-I (IL-I) and IL-6 production by mouse microglia
      stimulated with LPS. In contrast, the production of IL-10, which is known to be
      an inhibitory cytokine, was upregulated by certain PDEIs. The suppression of TNF
      alpha and induction of IL-10 were confirmed at the mRNA level by RT-PCR. PDEIs
      may be useful anti-inflammatory agents by downregulating inflammatory cytokines
      and upregulating inhibitory cytokines in the central nervous system. (CNS).

PMID- 10335525
TI  - [Diagnosis and management of coagulation disorders in orthopedic surgery].
AB  - Patients suffering from von-Willebrand-disease or hemophilia A or B are the most
      common patients with coagulation disorders in orthopedic hospitals. Patients
      suffering from hemophilia A or B are treated with pure factor VIII or IX
      concentrates. We prefer recombinant products. The goals are normal levels of F
      VIII or F IX activity during the operation and postoperatively. In order to save
      costs the continuous infusion is recommended. Approximately 30% of products and
      costs may be saved. The prevalence of von-Willebrand-disease is very high in
      Europe and USA (1%). Typical presentation of these patients is the uncontrollable
      bleeding during an operation; typical is also the bleeding from mucous membranes.
      Patients with mild disorders are treated with DDAVP. Patients suffering from type
      3 need substitution therapy with von-Willebrand-factor containing concentrates
      (for example Humate P).

PMID- 10335526
TI  - [Pathology of synovitis and hemophilic arthropathy].
AB  - Hemophilia is an X chromosome linked disease characterized by an increased
      tendency to hemorrhage. Due to recurrent haemarthroses specific changes occur in
      synovium and cartilage. This process is called haemophilic arthropathy. The
      pathogenetic mechanisms involved are not precisely known. Current concepts, which
      are based on experimental in vitro studies and clinical experience, hold that the
      synovium becomes catabolically active because of the exposure to blood components
      and as a result induces cartilage destruction. A considerable amount of reports
      concerning blood induced joint damage suggest that synovial changes have a
      leading role in the development of the joint damage and therefore precede the
      changes in cartilage. However, there are also observations that question whether
      this is the only and the initiating mechanism of joint damage in hemophilia they
      hold that intra-articular blood has a direct harmful effect on cartilage before
      synovial changes and suggest that joint damage may occur before synovial
      inflammation is evident. Primarily there may be damage of articular cartilage
      with synovitis as a consequence. These studies show that synovitis is involved,
      but that it is not the only mechanism in the joint damage caused by intra
      articular bleeding. These findings do not contradict the current concept of blood
      induced cartilage damage in which synovial changes are thought to play an
      important role. Several pathological processes are possibly involved, some of
      them occurring in parallel and others sequentially. Possibly intra-articular
      blood first has an direct effect on cartilage, and then it affects the synovium.
      Thus, both processes occur in parallel, and while they influence each other they
      probably do not depend on each other. This concept resembles degenerative joint
      damage as found in osteoarthritis.

PMID- 10335527
TI  - [Diagnostic imaging of hemophilic osteoarthropathy].
AB  - Presently, the degree of the hemophilic arthropathy is estimated by the
      classification system of Pettersson, which is recommended by the Orthopedic
      Advisory Committee of the World Federation of Hemophilia. This classification
      system bases upon plain radiographs of the joints and analyses only those changes
      which represent the progression of the arthropathy. The value of this
      classification system has been established by inter-observer studies. However, it
      shows drawbacks at the exact definition of some parameters. Presently, it is more
      valuable for longitudinal than for transversal studies. Due to the possibilities
      of an adequate substitution therapy, only minor degrees of an arthropathy are
      observed in children. The ankle joints are more severly affected than the elbow
      joints and they more than the knee joints. This distribution is explained by an
      increasing sports activity in children. If more than 3 joint bleedings occur
      within a year the invent of an arthropathy must be presumed. Because the
      classification system of Pettersson analyses only osseous changes representing
      late changes, important early changes like hypertrophy of the synovialis and
      focal destruction of the joint cartilage are overlooked. Magnetic resonance
      imaging is suitable to show these early changes reliably. MRI can be recommended
      for the investigation of recurrently bleeding joints without evidence of major
      osseous changes and for decision making to perform a synovectomy.

PMID- 10335528
TI  - [Prevention of joint damage in hemophilic children with early prophylaxis].
AB  - Radiological and orthopaedic outcome in severe and moderate haemophilia A and B
      patients undergoing long-term prophylactic treatment were prospectively
      investigated focusing on the age of onset of prophylaxis and the number of joint
      bleedings prior to treatment. We report on 21 patients with severe and moderate
      haemophilia A and B receiving prophylactic treatment of between 3.1 and 16.1
      years duration. Three patient groups were evaluated according to the age at onset
      of prophylaxis. In group I (n = 8) prophylactic treatment was initiated in the
      first 2 years of life. Patients of group II (n = 6) received prophylaxis at the
      age of 3-6 years. Late-onset or secondary prophylactic treatment was started at
      the age of 6 years and above in 7 patients (group III). All patients received
      virus-inactivated F VIII or F IX concentrates at dosages of 30-40 IU, in some
      cases up to 50 IU/kg body weight i.v. three times per week for those with
      haemophilia A and twice per week for those with haemophilia B. Elbow, knee and
      ankle joints were investigated at 3-4 yearly intervals according to the
      radiological and orthopaedic scores recommended by the World Federation of
      Haemophilia (WFH). The total number of joint bleedings before and after start of
      prophylaxis were recorded in all patients. In group 17 out of 8 patients had
      unaffected joints with constant radiological and orthopaedic scores of zero or 1,
      after a median of 11.25 years of prophylactic treatment. One patient in this
      group demonstrated mild radiological alterations (score 4). Patients of group II
      showed neither radiological nor orthopaedic alterations at study entry. Worsening
      joint scores could be detected despite ongoing prophylaxis after the 3-year
      interval (median orthopaedic score 4, median radiological score 8). Treatment
      group III already showed considerable joint damage at study entry with a median
      radiological score of 11 (0-33) and a median orthopaedic score of 4 (0-11).
      Despite prophylactic treatment both, orthopaedic (median 8, range 2-12) and
      radiological scores (median 19.5, range 2-47) deteriorated after 3 years. Prior
      to onset of prophylaxis no or only one joint bleeding occurred in treatment group
      I. In group II, a median of 6 joint bleeds (range 1-8) were reported before
      prophylaxis was started. Patients of group III usually experienced a median of
      more than 10 joint haemorrhages (range 6-10 or more). Under prophylactic
      treatment the number of joint bleedings decreased significantly in groups II and
      III. However, radiological and orthopaedic scores increased as a sign of
      progressing osteoarthropathic alterations in patients reporting more than 6 joint
      haemorrhages before onset of prophylaxis whereas no joint alterations could be
      assessed in patients with no or only one joint bleeding episode prior to
      prophylaxis. Even a small number of joint bleedings seems to cause irreversible
      osteoarthropathic alterations leading to haemophilic arthropathy. Once apparent,
      further progression of joint damage could not be arrested despite of prophylactic
      treatment (group II and III). In order to prevent haemophilic arthropathy,
      effective prophylaxis should be started before or at least after the first joint
      bleeding in severe haemophilia A and B.

PMID- 10335529
TI  - [Conservative management of hemophilic arthropathy].
AB  - Intraarticular bleeding and muscle bleeding occur spontaneously or as a result of
      trauma in hemophilia A or B. The most common sites for hemarthrosis are the knees
      joints, elbows and ankles joints. Resorption of intraarticular blood induces
      reactive hemophilic synovitis Hyperplasia of the synovium can be followed by
      recurrent bleedings. These early reactions can change to a chronic synovitis and
      cause cartilage damage, finally resulting in a complete destruction of the joint.
      Since 1981 158 adults and 61 children with a hemophilia A or B were treated at
      the Center for hemophilic disorders Frankfurt in an interdisciplinary approach.
      Consequent prophylactic treatment with factor substitution can prevent the
      incidence of severe hemarthrosis. Minor joint bleedings are treated by adequate
      factor substitution, temporarily non-weight bearing of the extremity, application
      of ice-packs and physical therapy. More severe joint hemorrhages should be
      aspirated in order to reduce the acute synovitis. This is followed by a
      consequent physical therapy (joint and soft tissue techniques) and anti
      inflammatory drugs. The goal is a sufficient muscular balance of the joint, the
      improvement of the coordination, and the proprioception. The chronic synovitis is
      less painful and poorly responses to conservative interventions. Local ice
      application, systemic and local anti-inflammatory treatment support the physical
      therapy. Soft heel shock absorber, elastic and semi-rigid bandages prevent
      recurrent bleeding episodes by shock absorption and decrease of synovial
      impingement. Synovectomy is indicated in cases of chronic persistent synovitis.
      Radiosynoviorthesis (RSO), which is an alternative in certain cases, has been
      performed with great success in 12 cases in our hospital. In advanced arthropathy
      joint mobilization should be the emphasis of the physical therapy. Bandages,
      crutches and ortopaedic shoe devices improve the walking capacity.

PMID- 10335530
TI  - [Joint preserving operations and endoprosthetic joint substitutions in
      hemophiliacs. Indications and long term results].
AB  - Hemophilic arthropathy is the result of recurrent joint bleedings in patients
      with severe haemophilia A or B and von Willebrand Syndrome. Conservative
      orthopaedic treatment is preferred in every stage of the arthropathy. Synovectomy
      is indicated only after failure of the conservative regimen after 3 to 6 months
      in order to control synovitis and recurrent bleeding. This paper presents the
      indications, methods, and results of different joint preserving operations.
      Especially synovectomy of the elbow joint with or without radial head resection
      shows very good long term results. Radiosynoviorthesis is an alternative in
      certain cases. The end stages of hemophilic arthropathy are characterised by
      pronounced joint contractures. We achieved very good long term results by
      implanting total hip joints (n = 13) and total knee joints (n = 20) with a median
      follow up of 102 respectively 53 months. No perioperative complications like
      bleeding or infection were registrated. Only one aseptic loosening of a cemented
      cup occurred 14 years postoperatively as well as one septic loosening 14 months
      postoperatively in an HIV positive haemophilic. Another HIV positive patient
      developed a hematogenic abscess on both operated on hips without loosening of the
      endoprosthesis. Bicondylar prosthesis (n = 14) showed 6 very good, 6 good and 2
      fair results in the HSS-score. Only one subsidence of an uncemented tibia plateau
      without definitive loosening occurred 55 months later. The functional results of
      constrained knee endoprostheses (n = 6) were not as good (2 good, 2 fair, 2
      poor). However, these patients suffered preoperatively from severe contractures
      and malalignments. Aseptic loosening or late infections did not occur even in
      case of HIV infections.

PMID- 10335531
TI  - [Prevalence, pathophysiology, diagnosis and treatment of von Willebrand syndrome
      in orthopedic trauma patients].
AB  - The von Willebrand's Disease affects about 1-3% of the population and it is
      undiagnosed in most people. Originally described by the Finish physician Erik von
      Willebrand in 1926 this disorder is associated with mucous membrane bleeding
      including epistaxis, hypermenorhoea and excessive bleeding from surgery and
      dental procedures. In von Willebrands disease the patients have a quantitative or
      qualitative abnormality in the von Willebrand Factor (vWF) which has two major
      functions: it serves by bridging between platelets and injury site in the blood
      vessel wall, and it circulates as a complex with factor VIII, protecting it from
      rapid degradation. More than 20 different types and subtypes of vWD have been
      described but almost all patients can be classified as having 1 of the 2 most
      common types of vWD. About 70% of patients have type 1 and about 10-20% present
      themself with type 2A and 2B vWD type 3 in about 10%. By taking a clinical
      history of bleeding it is important to think about vWD and to make the
      appropriate diagnosis. If the vWD is suspected diagnostic tests should include an
      activated partial thromboplastin time, bleeding time, factor VIII:C, Ristocetin
      cofactor, and vWF antigen. Additional testing of ristocetin induced plattlet
      adhesion (RIPA), the multimeric structure and collagen binding test and
      genanalysis allow diagnosing the different types of v. Willebrand Disease. The
      treatment of choice in mild forms is the synthetic agent desmopressin. In
      patients with severe type 1, type 2B, 2N and type 3 or in people who do not
      response to desmopressin, the appropriate treatment is a factor VIII concentrate
      that is rich of vWF. Until now no recommendations in the orthopaedic literature
      have been found regarding diagnosis and treatment of vWS patients. Based on the
      experience with 43 orthopaedic patients presenting vWD over the last 15 years a
      contemporary guideline for the successful perioperative management of vWD in
      orthopaedic surgery is presented. In a close collaboration between the
      orthopaedic surgeon and the specialized haemostaseologist every invasive
      procedure in patients with vWD can be undertaken without the risk of excessive
      bleeding.

PMID- 10335532
TI  - [Chemotherapy of osteoarticular tuberculosis].
AB  - Bone and joint tuberculosis, as all other types of tuberculosis is generally
      treated with antituberculotic combination chemotherapy. This has to be continued
      for a minimum of six months, or nine months in case of extensive spreading. A two
      to three-month initial phase with four or five different drugs (H, R, Z, and
      additionally E and/or S) is followed by a four- to six-month therapy with H and R
      alone, provided the pathogen is fully susceptible to a standard regimen. The main
      side effects are hepatotoxic or allergic reactions. A frequent contra-indication
      is existing, often toxicity-induced, liver damage. The main local complications
      requiring surgery are spinal instability or neurologic deficiencies.

PMID- 10335533
TI  - [Cardiorespiratory monitoring in hospital and at home].
AB  - Apnoea become a medical problem when associated with a symptomatology cohort
      characterized by skin colour modifications, muscular tone modifications and
      consciousness. This syndrome named ALTE, from the acronym Apparent Life
      Threatening Event, well describes the near death sensation in the witnesses. Only
      60% of this events may be revealed in his etiopathogenesis, also even a strong
      diagnostic protocol is applied; the remaining part, called idiopathic represent a
      open doubt and stressing factor for the physicians. ALTE may be analyzed in his
      rising and resolving ways, throughout a complete and accurate report of the
      history and throughout his association with other several symptoms eventually
      associated, able to leading at diagnosis. The child must be investigated about
      his metabolic status near the crisis, particularly for each disease life
      threatening as cardiac arrhythmias, electrolytes alterations and hide or
      beginning infections. The use of instruments for domestic surveillance is based
      on old observations, denied by a lot of studies, there is an high relation
      between ALTE and SIDS. Really the monitoring has different rules in the
      management of child with ALTE: it is a useful tool to evaluate in continuous
      child's life parameters in order to be able to make a quick intervention in case
      of life threatening alterations for child. It also represents a diagnostic and
      prognostic way because it allows to evaluate respiratory and cardiac patterns and
      their modifications time related. There are some side effects as anxiety elicited
      in parents, cause of high frequency in false alarms. This allows the need of a
      strict relation between a SIDS Center and the family in order to increase the
      parents compliance.

PMID- 10335534
TI  - [Renal calculosis in pediatrics].
AB  - Urinary stones (calculi) are not a rare problem in pediatrics, presenting a
      prevalence of 1 case/20,000 children/year. Both nephrocalcinosis (deposition of
      calculi within the renal parenchyma) and urolithiasis (stone formation in the
      calyces, renal pelvis and bladder) may occur. Etiology of urinary stones involves
      metabolic, infectious, anatomic and idiopathic causes. Diagnosis and treatment
      require knowledge of a wide range of diseases. After urinary stones have been
      suspected, biohumoral tests and ultrasound examination should be routinely
      performed.

PMID- 10335535
TI  - [Physiopathologic findings and surgical treatment in transposition of great
      vessels: our experience].
AB  - Transposition of great vessels (TGV) is the most frequent neonatal cyanotic
      malformative cardiopathy. The Authors report their experience in surgical
      anatomical correction of transposition of the great arteries in 55 patients, 44
      male and 11 female. Minimum age was 2 days, maximum 6 months. TGV was simple in
      38 cases and associated with ventricular defect in 12 cases, with double outlet
      right ventricle in 3 cases, and with complex cardiopathy in 2 cases. There have
      been 11 deaths. The cause of death was: cardiac failure in 3 patients, myocardial
      infarct in 4 patients, respiratory insufficiency in 2 patients, and sepsis in 2
      patients. There was one death by myocardial infarction and 1 asymptomatic ostial
      left coronary stenosis during follow-up (from 1 to 104 months). There were
      neither anastomotic pulmonary stenosis nor aortic valve incompetence. The authors
      review the literature on functional and anatomic correction of TGV and underline
      the importance of precocious anatomic together with early diagnosis, percutaneous
      atrioseptostomy and pharmacologic (PGE1) therapy in determining further reduction
      of mortality and to improve late outcome.

PMID- 10335536
TI  - [Histiocytosis].
AB  - Histiocytosis are often hard to define clinically, due to a wide range of
      symptoms shown. Therefore, in order to display them, a deep knowledge of the
      symptoms is required and, above all, of their histological and histoclinical
      characteristics.

PMID- 10335537
TI  - [Follow-up of children included in the Italian Study on the Use of Low-Dose
      Aspirin During Pregnancy: development at 18 months of life and birth weight].
AB  - To assess the relationship between birthweight and the child's development at 18
      months of age, we sent a postal questionnaire to the parents of 861 singleton
      children, born in the framework of the Italian Study of Aspirin in Pregnancy, 18
      months after delivery. A total of 623 (72.4%) were returned. There were 94
      children weighing < 2500-1500 g at birth and 19 < 1500 g. Children with weight
      and height less than the 10th percentile at 18 months were significantly more
      frequent in the low birthweight group (p < 0.01). Motor problems were about six
      times more common in children with birthweight less than 2500 g than in those
      with birthweight > or = 2500 g (p < 0.001). A larger proportion of children with
      birthweight < 2500 g than > or = 2500 g had respiratory problems (15% vs 11%, p =
      ns). Finally admission to hospital was more common in children with birthweight
      less than 2500 g (p < 0.01). This study confirms the differences in growth and
      development for children in low and normal birthweight groups.

PMID- 10335538
TI  - [Diffuse axonal lesions in childhood].
AB  - OBJECTIVE: About 48% of all primary traumatic intracranial lesions are
      represented by so-called Diffuse Axonal Injury (DAI): a pathologic condition
      characterized by multiple microscopic lesions and hemorrhage at the level of
      midline cerebral structures, in the subcortical grey matter, and/or within the
      brainstem. The natural history of DAI is depressing: 100% of the patients
      deteriorate rapidly to coma and approximately 50% die, while 50% remain in a
      vegetative state or with severe neurological deficits. In the present report, we
      describe the results of a study aimed to evaluating the cerebral hemodynamics and
      the neuroradiological findings observed in four children (6, 8, 10 and 12 years
      old) affected by DAI. METHODS: All the patients had been admitted to the
      Pediatric Intensive Care Unit with Glasgow Coma Score (GCS) of 5. On admission,
      all patients underwent mechanical ventilation, antiedemigen and barbiturates
      therapy. Serial CT scan and Transcranial Doppler Sonography (TCD) examinations
      were carried out in all children. TCD of the middle cerebral arteries was
      performed through the temporal window. The children underwent insertion of a
      ventricular catheter for intracranial pressure monitoring. Follow-up time has
      been, respectively, 4 years, 3 years, 7 and 1 months. RESULTS: The Glasgow
      Outcome Score (GOS) of three children is 2 (persistent vegetative state), while
      the GOS of the one child is 3 (severe neurological deficits). CONCLUSION: DAI
      results in unfortunate prognosis and large health care costs. The proper medical
      management of this condition should be based on TCD and SjO2 and CEO2
      evaluations, in order to monitor efficaciously the cerebral blood flow.

PMID- 10335539
TI  - [Basal metabolism and respiratory quotient in obese children].
AB  - Childhood obesity represents an increasing dysmetabolic condition. The aim of our
      study was to evaluate the influence of Fat Mass (FM%) on Resting Metabolic Rate
      (RMR) and Respiratory Quotient (RQ) as indicator of substrate oxidation. FFM and
      FM were estimated by bioelectrical impedance analysis (BIA), using the Kushner
      equation. Resting metabolic rate was determined by open-circuit indirect
      calorimetry. The mean (SD) of RMR 1517.6 (236.8) was found to be different from
      predicted RMR 1470.6 (190) calculated using the Fleisch equations. The best
      predictors of RMR were weight (p = 0.000) and FFM (p = 0.000); whereas
      correlation between RMR and fat mass (FM%) was not significant. Therefore low RMR
      cannot be responsible of fat mass degree, in fact, it is not reduced in obese
      children. Different values of RQ were found suggesting different metabolic
      behaviours to oxidate substrates. These data indicate that genetics may play a
      significant role in the development of many types of obesity.

PMID- 10335540
TI  - [The adolescent and the choice of profession].
AB  - Is easy to understand that choice of profession in countries where there is no
      organized professional help for job guidance it is not based done of the
      recognitions of the aptitude necessary for a particular job or profession. But it
      is a result of a very different actual conditions: youthful fancies, parent's
      mistakes, influences of the surroundings, ets. The situation of this conditions
      that we find in other countries and in Italy would resulting a serious problem.
      If not overcome by positive judgment in the orientation. The fact of the average
      intelligence accompany by sufficient good will is needed to overcome most common
      difficulties which are meet in a job or a profession.

PMID- 10335541
TI  - [Idiopathic thrombocytopenic purpura and food allergy: a study on possible
      correlations].
AB  - Eight children affected by idiopathic chronic thrombocytopenia were studied for
      history of food allergy, anti-platelet antibodies, total IgE, prick test for food
      antigens, AGA and EMA. They were free of treatment for thrombocytopenia since at
      least six months before. Three children had in the first year of life intolerance
      to cow's milk proteins with atopic dermatitis and/or poor growth. None had AGA or
      EMA positivity. 6/8 had positivity for anti-platelet antibodies. A 15-days
      oligoantigenic diet was instituted in all of them. Platelet count was unaffected
      in all but one, in which a sharp increase was noted (from 19x 10(9)/l. to 150x
      10(9)/l.). He was a 12-year-old boy with a previous history of cow's milk
      intolerance and actual skin prick test positivity for casein and lactoglobulin. A
      one-year follow up for this case was instituted and he was put on two further 15
      days periods of oligoantigenic diet, but no change in platelet count was noted
      any more. CONCLUSION: we were not able to correlate chronic thrombocytopenia to
      food allergy.

PMID- 10335542
TI  - [Acquired methemoglobinemia: a case report].
AB  - When an infant presents severe cyanosis which is not associated with respiratory
      distress, methaemoglobinemia should always be suspected. In children its main
      inducers are contaminated water or vegetable broths with high nitrate levels
      (especially spinach and carrots) used to prepare powdered formula or soups.
      Children affected with methaemoglobinemia have a peculiar lavender colour. Blood
      from the heel sticks is chocolate-brown and does not become pink when exposed to
      room air. Diagnosis can be confirmed by excluding other causes of cyanosis and by
      spectrophotometric analysis of blood for methaemoglobin. When methaemoglobin's
      levels reach 60% or more, the patient will collapse and become comatose and may
      die. Therapy with methylene blue results in prompt relief. In this article we
      report a case of methaemoglobinemia due to the administration of powdered formula
      mixed with vegetable broths to a newborn aged 16 days. Furthermore we will
      present a short review of literature regarding methaemoglobinemia caused by toxic
      agents over the last 10 years.

PMID- 10335543
TI  - [A case report of drepanocytic anemia with "belt syndrome"].
AB  - Following article describes the case of a child with painful abdominal
      symptomatology showing characteristics of an acute abdomen. Following the
      laboratory tests abdominal crises have been classified as vessel occlusion crises
      with sickle cell anemia.

PMID- 10335544
TI  - [Peutz-Jeghers syndrome. Report of a family].
AB  - The Authors report on the clinical and instrumental findings of a 11 years old
      patient affected with Peutz-Jeghers syndrome, several component of her family
      were also affected. The Authors confirm clinical heterogeneity of the disease and
      the importance of a early diagnosis.

PMID- 10335545
TI  - Lack of genetic linkage or association between a functional serotonin transporter
      polymorphism and panic disorder.
AB  - Given the efficacy of medications that interact with the serotonin transporter (5
      HTT) in the treatment of panic disorder, we have used a family-based design to
      test for genetic association and linkage between panic disorder and a functional
      polymorphism in the promoter of the gene for 5-HTT. In this study, 340
      individuals in 45 families, as well as 74 haplotype relative risk 'trios' were
      genotyped at the polymorphic locus, which consists of a 44 base pair
      deletion/insertion. There were no significant differences in allele frequencies
      or occurrence of genotypes within the triads. No linkage between the 5-HTT
      polymorphism and panic disorder was observed in the multiplex families, using a
      variety of simulations for dominant and recessive models of inheritance. Recent
      reports suggest an association between the 5-HTT polymorphism and anxiety-related
      traits, as measured with personality assessment. The results reported here
      provide evidence that the genetic basis of panic disorder may be distinct from
      anxiety-related traits assessed by personality inventories in normal populations.

PMID- 10335546
TI  - Possible association between schizophrenia and a CAG repeat polymorphism in the
      spinocerebellar ataxia type 1 (SCA1) gene on human chromosome 6p23.
AB  - The gene for spinocerebellar ataxia type 1 (SCA1) is a potential candidate gene
      for schizophrenia because of previous positive linkage findings in this region
      (6p22-24), and because the reported correlation between SCA1 onset and the number
      of CAG repeats suggests anticipation. To test the involvement of this gene in the
      development of schizophrenia, we examined genotypes of the SCA1 CAG repeat
      polymorphism for 49 Caucasian patients with schizophrenia, and 88 Caucasian
      controls. We found a significant association between the frequencies of alleles
      of this gene and schizophrenia (chi 2 = 18.40, df = 8, P = 0.018). Among 13
      alleles, one allele (31 trinucleotide repeat) was significantly more frequent in
      patients with schizophrenia than in controls (chi 2 = 9.57, df = 1, P = 0.002).
      This association was sustained after applying a Bonferroni correction for
      multiple testing (P = 0.05/13 = 0.004), and the chi-square results were shown to
      be robust through Monte Carlo simulation. We observed no allelic association with
      three flanking microsatellite markers (D6S288, D6S1605, and D6S337), suggesting
      that our result was not due to population stratification. Further studies of this
      locus are needed to confirm this finding, and to determine a potential role for
      this gene in the development of schizophrenia.

PMID- 10335547
TI  - MAOA: association and linkage studies with lithium responsive bipolar disorder.
AB  - A number of association studies have investigated the role of the monoamine
      oxidase A (MAOA) gene in the susceptibility to bipolar disorder. Although some
      studies have reported positive findings, there remains some controversy, because
      results from different studies have not been consistent. A common explanation for
      inconsistencies between studies is genetic heterogeneity. We have focused on
      lithium responsive bipolar disorder as a way to reduce heterogeneity. In this
      study, we investigated the role of MAOA in lithium responsive bipolar patients
      using association and linkage study designs. The investigation used 138 patients
      and 108 normal controls. In addition, 25 families were also studied. Our results
      were not supportive of a major role of MAOA in the predisposition to bipolar
      disorder.

PMID- 10335548
TI  - Dopamine D3 receptor gene polymorphism and alcohol dependence: relation to
      personality rating.
AB  - Hereditary dopaminergic mechanisms have been implicated in the aetiology of
      alcoholism. For this study, the distribution of a dopamine D3 receptor gene
      polymorphism (Ball) has been investigated in patients suffering from alcohol
      dependence, and compared with non-dependent controls. The allele A1 occurred
      significantly more frequently among patients compared to controls. Patients with
      the genotype A1/A2 showed significantly higher novelty seeking (NS) scores in the
      tridimensional personality questionnaire (TPQ) than patients with the genotype
      A1/A1. The distribution of patients with high and low NS scores in heterozygotes
      (A1/A2) did not follow a random distribution. There were significantly more
      individuals with higher NS scores, and fewer individuals with lower NS scores
      than expected. The results of this study support the hypothesis of a genetically
      determined involvement of the dopaminergic system in alcohol dependence. This is
      probably related to the modulation of personality traits. The observed effects
      are relatively small, but statistically significant. Thus, the genetics of the
      dopaminergic neurotransmitter system alone cannot explain the aetiopathogenesis
      of alcoholism.

PMID- 10335549
TI  - A haplotype-based study of lithium responding patients with bipolar affective
      disorder on the Faroe Islands.
AB  - The Faroe Islands are a small group of islands in the North Atlantic Ocean,
      situated between Norway, Iceland and Scotland. The origin of the population is
      thought to be a mixture of Norwegian, Danish and British. The islands were
      populated at the same time as Iceland, i.e. around 1100 years ago, and the size
      of the population was around, and occasionally below, 4000 inhabitants until
      1800, after which it increased to its present-day level of around 45,000. The
      population is descended from Scandinavian and British ancestors. Because of the
      low number of founders and small size for many centuries, the Faroese population
      is perhaps the most valuable European population for genetic mapping of complex
      disease genes. The present study searched for haplotype sharing on chromosome 18
      among eight lithium responding patients with bipolar affective disorder related,
      on average, 6.2 generations ago, using 30 DNA markers. In order to obtain as
      homogeneous a sample as possible, strict inclusion criteria based on severity of
      phenotype, geography and treatment response, were applied. Evidence suggestive of
      increased haplotype sharing on the distal part of chromosome 18q23 in the region
      implicated by Freimer and co-workers was found. However, methods of genetic
      analysis which might provide a conclusive result are not yet available.

PMID- 10335550
TI  - Non-linear association between the serotonin transporter promoter polymorphism
      and neuroticism: a caution against using extreme samples to identify quantitative
      trait loci.

PMID- 10335551
TI  - Tests for linkage to MDI with a new trinucleotide repeat polymorphism in the 80K
      H gene on chromosome 19.

PMID- 10335552
TI  - Survey for CAG repeat polymorphisms in the human MAP-2 gene.
AB  - Microtubule-associated protein-2 (MAP-2) expression is altered in response to a
      number of physiological insults such as Alzheimer's disease, schizophrenia,
      stroke and AIDS-dementia. Changes include alteration in MAP-2 transcription,
      translation, and state of phosphorylation. Multiple MAP-2 transcripts exist
      within the nervous system and, as noted for a number of genes expressed in the
      central nervous system, MAP-2 contains a region of trinucleotide repeats located
      in exon 1 of the 5' untranslated region (5' UTR). Since expansion of CAG repeats
      are found in several neurodegenerative disorders, we analysed the CAG repeats in
      MAP-2 for polymorphisms in 31 controls, 35 chronic schizophrenics, and 20 with
      other neuropsychiatric illnesses. Genomic DNA samples from 86 individuals were
      used as templates in PCR amplifications with primers within exon 1. Sequencing of
      the PCR products, or short tandem repeat polymorphism (STRP) analysis,
      demonstrated consistency in the size of the CAG repeats. This study demonstrates
      that the seven copies of the CAG repeat located in the 5' UTR of the MAP-2 gene
      are highly conserved in the general population, and that there is no evidence for
      expansion of the CAG repeat.

PMID- 10335553
TI  - No association between schizophrenia and serotonin receptor type 2A gene in
      Korea.

PMID- 10335554
TI  - Health care professionals' familiarity with non-pharmacological strategies for
      managing cancer pain.
AB  - Many studies have confirmed unnecessary suffering among cancer patients, due to
      the inadequate use of analgesic medication and other effective interventions.
      While pharmacological treatments are appropriately the central component of
      cancer pain management, the under-utilization of effective nonpharmacological
      strategies (NPS) may contribute to the problem of pain and suffering among cancer
      patients. The purpose of this study was to determine health care professionals'
      familiarity with, and perceptions regarding, NPS for managing cancer pain, and to
      assess their interest in learning more about NPS as adjuncts to pharmacological
      analgesics. Two-hundred and fourteen health care professionals were surveyed at
      two cancer treatment centres in Ontario, Canada. The self-report questionnaire
      included questions regarding 11 psychological strategies (e.g. imagery) and eight
      other NPS (e.g. acupuncture). The response rate was 67% (141/214). Subjects were
      found to be the least familiar with autogenic training, operant conditioning, and
      cognitive therapy. Other than radiation and surgery, subjects most commonly
      reported recommending support groups (67%), imagery (54%), music or art therapy
      (49%) and meditation (43%) for managing cancer pain. Participants were most
      interested in learning more about acupuncture, massage therapy, therapeutic
      touch, hypnosis, and biofeedback. Participants were somewhat familiar with most
      of the 19 NPS presented; however, they use or recommend few NPS for managing
      cancer pain. Health professionals' interest in NPS has important implications for
      the supportive care of cancer patients.

PMID- 10335555
TI  - Utility of the theory of planned behavior for understanding exercise during
      breast cancer treatment.
AB  - Preliminary evidence indicates that physical exercise may be an effective
      strategy for helping cancer patients cope with the negative side-effects of their
      treatment. The purpose of the present study was to examine the utility of the
      theory of planned behavior in understanding cancer patients' motivation to
      exercise during treatment. A total of 164 women who had been diagnosed with
      breast cancer within the previous 2 years participated in the study. A
      retrospective design was used wherein these women were asked to recall their
      beliefs and exercise behavior during cancer treatment using a self-administered,
      mailed questionnaire. Results showed that: (1) the salient beliefs of breast
      cancer patients concerning exercise were different from those of the healthy
      population; (2) intention and perceived behavioral control were significant
      determinants of exercise during cancer treatment; and, (3) attitude and
      subjective norm were significant determinants of intention. It was concluded that
      the theory of planned behavior may be a viable framework on which to base
      interventions designed to promote exercise during cancer treatment. The results
      of this study are preliminary, however, and more sophisticated research designs
      to examine this question are warranted.

PMID- 10335557
TI  - Differences in perception of quality of life issues between health professionals
      and patients with pancreatic cancer.
AB  - During the initial stages of development of a pancreatic cancer quality of life
      (QoL) module to supplement the EORTC core QoL module, the QLQ-C30, a qualitative
      study was undertaken to explore observed differences in the health professionals'
      and patients' perception of the illness, treatment and care of pancreatic cancer.
      Semi-structured one-to-one interviews were conducted with a range of six health
      professionals and 21 pancreatic cancer patients from two acute general hospitals
      and one teaching hospital within the Wessex Region. Grounded theory guided data
      collection and analysis. There was good agreement between the content of issues
      generated by professionals and patients with 42 relevant and specific issues
      identified. However, subtle differences in perception were observed when the
      context of why such issues were important was examined between the two groups.
      Health professionals took a mechanistic view and saw the impact of each symptom
      or problem as directly affecting quality of life perception. Patients' perception
      of quality of life was mediated by the process of coping. This was grounded by
      two linked factors. First, the perceived threat of each symptom or problem to the
      patient and second, the success or otherwise of coping strategies employed to
      maintain control. Five main coping strategies were identified. This study
      highlighted that there are important and specific quality of life issues which
      warrant a need for a pancreatic cancer QoL module. This study emphasises the fact
      that patients are the best source to describe their quality of life. Health
      professionals should acknowledge the effect of coping strategies when assessing
      the impact of symptoms and their treatment on patients with pancreatic cancer.

PMID- 10335556
TI  - A long-term follow-up study of psychosocial functioning after autologous bone
      marrow transplantation in childhood.
AB  - Psychosocial functioning was assessed in 26 subjects treated with autologous bone
      marrow transplantation (ABMT) for leukaemia or lymphoma before the age of 18
      years. The median time from ABMT was 7 years (range 2-10 years), and the median
      age of the subjects at the evaluation was 16 years (range 7-24 years). Patients,
      parents and teachers were used as informants. Parents of subjects in the ABMT
      group reported more behaviour problems than in a normative sample of school
      children, in particular of the internalising problem type, a finding also
      supported by the teachers' report on the children's behaviour at school. The
      magnitude of the behaviour problems correlated positively to CNS treatment
      intensity. The parents rated their children's school competence as lower than did
      parents of a normative sample. All school children (n = 18) were in regular
      education, although five pupils were receiving individual tutorial help. Overall,
      the patients reported a positive view on their own functioning, in contrast to
      the higher levels of psychosocial problems reported by their parents and
      teachers. The results thus show, that the psychosocial functioning seen in
      children treated because of cancer is dependent on the type of informant used.

PMID- 10335558
TI  - Factors affecting presentation and delay in patients with testicular cancer:
      results of a qualitative study.
AB  - A qualitative study was undertaken with men treated for testicular tumours, to
      ascertain how they interpreted their symptoms and the factors which influenced a
      decision to consult a physician. The research was undertaken with six men who had
      been diagnosed as having testicular tumours. Interviews were also conducted with
      four wives and one mother. The findings showed that giving men information on
      testicular cancer may not guarantee early presentation. Symptoms were not
      generally attributed to cancer and the one patient who practised self-examination
      had delayed seeking help for 6 months. The extent to which symptoms affected the
      patient's lifestyle was also a factor in the decision-making process, as was the
      checking of symptoms with other family members. Wives were often pivotal in
      persuading men to seek help. The discovery of testicular symptoms produced
      emotional responses which included embarrassment and fear of both cancer and
      castration. There was evidence of strong feelings of masculine identity bound up
      with the appearance of 'normal' genitals. Provider-delay was identified in four
      cases and was associated with misattribution of symptoms by physicians and the
      failure to initiate specialist referral. Delay was under-recorded in the hospital
      notes in all cases where presentation was not immediate.

PMID- 10335559
TI  - Cancer patients' coping styles and doctor-patient communication.
AB  - Monitoring and blunting styles have become relevant concepts regarding their
      potential impact on patients' and doctors' behaviors. The present study aimed at
      investigating the relation between cancer patients' coping styles and doctor
      patient communication and global affect. Coping styles were assessed by means of
      the Threatening Medical Situations Inventory (TMSI). Since a shortened version of
      the TMSI was used, the validity of this instrument was also evaluated. First, it
      was examined whether the two factor structure of the original TMSI could be
      confirmed in our version. Then, the relation between coping style and patients'
      preferences for information and participation in decision-making was evaluated.
      Second, the relation between monitoring and blunting and patients' age, sex,
      education, quality of life and prognosis was investigated. Finally, the relation
      between patients' coping styles and communicative behaviors and global affect of
      both patients and physicians during the initial oncological consultation was
      examined. Patients (N = 123) visited their gynaecologist or medical oncologist
      for an initial discussion of possible treatment. Patients' coping styles, socio
      demographics, preference for information and participation in decision-making,
      quality of life and prognosis were assessed by postal questionnaire prior to the
      visit to the outpatient clinic. The consultation was audiotaped and analysed
      according to Roter's Interaction Analysis System, to identify instrumental and
      affective communicative behaviors of both patients and physicians. The two factor
      structure of the TMSI could be confirmed. A monitoring style was related to a
      preference for detailed information (r = 0.23) and participation in medical
      decision-making (r = 0.23). A monitoring style was also related to patient
      question-asking (r = 0.25) and patient dominance (r = 0.23). To conclude, the
      validity of the shortened TMSI is satisfactory. Also, cancer patients' coping
      styles are not related to other personal and disease characteristics. Further, a
      monitoring style seems to have an impact on patients' question-asking and
      dominance during the oncological consultation.

PMID- 10335560
TI  - Quality of life in patients surviving at least 12 months following high dose
      chemotherapy with autologous bone marrow support.
AB  - BACKGROUND: Over the past decade, high dose chemotherapy with autologous bone
      marrow (HDC-ABMT) support has been used increasingly in the treatment of patients
      with breast cancer. In evaluating the results of HDC-ABMT in patients with breast
      cancer, an assessment of quality of life can add to the traditional endpoints
      (toxicity, and disease-free and overall survival) that are routinely assessed in
      clinical trials. PURPOSE: This study evaluated the quality of life (QOL) of
      breast cancer patients who had survived 1 or more years following high dose
      chemotherapy with autologous bone marrow transplant (HDC-ABMT) support. METHODS:
      Eighty-two patients who had undergone HDC-ABMT were surveyed by written
      questionnaire and follow-up telephone interview at least 1 year following HDC
      ABMT. Patients were asked to complete the Functional Living Index-Cancer (FLIC),
      the Symptom Distress Scale (SDS), and a survey of sexual function developed as
      part of the study. RESULTS: The mean FLIC score among all patients was 130 +/-
      19.1 (possible range 22-154). FLIC scores were significantly lower in patients
      with evidence of recurrent disease than in patients who were free of disease. The
      most commonly reported symptoms after HDC-ABMT were insomnia, fatigue, and pain.
      Sexual interest and sexual activity were reported to be lower after participation
      in HDC-ABMT than prior to the procedure. The majority of patients who were
      employed outside the home prior to HDC-ABMT returned to work with a median time
      away from work of 48 weeks. CONCLUSIONS: Patients with breast cancer who survive
      1 or more years following HDC-ABMT rate their QOL at a relatively high level and
      frequently return to work. Less than one-third of patients who were interviewed
      reported moderate to severe symptoms. Problems with sexual functioning were
      common. IMPLICATIONS: Future research is needed on long-term outcomes after HDC
      ABMT and on specific areas of concern, such as sexual functioning.

PMID- 10335562
TI  - Organizing sexual abuse.

PMID- 10335561
TI  - Delivering a very brief psychoeducational program to cancer patients and family
      members in a large group format.
AB  - It is well established that brief psychoeducational programs for cancer patients
      will significantly improve mean quality of life. As this kind of adjunctive
      treatment becomes integrated into general cancer management, it will be necessary
      to devise cost-effective and efficacious programs that can be offered to
      relatively large numbers of patients. We have developed a very brief 4-session
      program that provides this service to 40-80 patients and family members per month
      (and seems capable of serving much larger numbers, depending on the capacity of
      the facility in which they assemble). Patients meet in a hospital auditorium for
      a large group, lecture-style program that offers training in basic coping skills:
      stress management, relaxation training, thought monitoring and changing, mental
      imagery and goal setting. Over the first year we have treated 363 patients and
      150 family members. Improvements were assessed by changes in the POMS-Short Form,
      and both patients and family members were found to improve significantly over the
      course of the program. While this is not a randomized comparison, it suggests
      that the benefits gained from a large group in a classroom are not substantially
      less than the improvements that have been documented in the usual small group
      format, where more interactive discussions are possible.

PMID- 10335563
TI  - Sexual offender treatment efficacy revisited.
AB  - Several authors have recently addressed current views of sexual offender
      treatment efficacy. Some maintain that offenders can gain from treatment while
      others argue that the vast majority cannot. Some researchers say that the field
      of sexual offender treatment is too new to be able to determine whether or not
      treatment works. This latter group notes that most studies in this field have not
      yet reached the point at which meta-analytic techniques can be applied; for this
      reason no definitive statements can be made about the utility of treatment. The
      present analysis examines the issues from a slightly different perspective. Data
      from a large group of studies are combined to identify patterns which can be
      examined later in more detail. More specifically, 79 sexual offender treatment
      outcome studies are reviewed, encompassing 10,988 subjects. Recidivism rates for
      treated versus untreated offenders are investigated according to age of offender,
      age of victim, offense type, type of treatment, location of treatment, decade of
      treatment, and length of follow-up. Each study is used as the unit of analysis,
      and studies are combined according to the number of treated versus untreated
      subjects who reoffended in each category. Clinical implications are drawn from
      these results.

PMID- 10335564
TI  - Pathways in the offending process of extrafamilial sexual child molesters.
AB  - The aim of the current study was to investigate specific pathways in the
      offending process of extrafamilial sexual child molesters. Forty-four men who had
      committed at least one sexual offense against a nonfamilial prepubescent child
      were included in this study and were classified using cluster analysis. Subjects
      using the coercive pathway (n = 30) had generally used psychoactive substances
      before their offenses. Furthermore, they had molested a female victim without
      perceived vulnerability and whom they had already well known. These molesters had
      not planned their offense, which was of short duration (less than 15 min), and
      involved coital activities and coercion (verbal and/or physical). Subjects using
      the noncoercive pathway (n = 14) had generally used pornography and deviant
      sexual fantasies before their offenses. Moreover, they had molested a male
      victim, in whom they perceived a psychosocial vulnerability and who was not
      familiar to them. These molesters had planned their offense, which was of longer
      duration (more than 15 min) and involved noncoital activities without coercion.
      These two pathways were compared to the two pathways in the offending process
      identified by Ward and his colleagues.

PMID- 10335565
TI  - The effect of alcohol on the responses of sexually coercive and noncoercive men
      to an experimental rape analogue.
AB  - This study examined the impact of the psychological and pharmacological effects
      of alcohol on the ability of sexually coercive and noncoercive men to
      discriminate when a female wants a partner to stop sexual advances. In a 2
      (alcohol vs. no alcohol) x 2 (expectancy vs. no expectancy) x 2 (sexually
      coercive vs. noncoercive status) randomized factorial design, male college
      students were exposed to an audiotape of a date rape. Participants who consumed,
      or expected to consume, alcohol took significantly longer to determine that the
      man should refrain from attempting further sexual contact. In addition,
      nonsexually coercive participants assigned to conditions in which they expected
      to consume alcohol responded similarly to their sexually coercive counterparts in
      their responses. The implications of these findings are discussed.

PMID- 10335566
TI  - Alcohol's possible covert role: brain dysfunction, paraphilias, and sexually
      aggressive behaviors.
AB  - A number of studies have suggested a relationship between sexually anomalous
      behavior and brain dysfunction. However, in most cases, the etiology of this
      dysfunction remains elusive. In this paper, alcohol exposure in utero (fetal
      alcohol syndrome) is offered as one possible explanation for the
      neurophysiological abnormalities that appear to characterize a notable proportion
      of individuals within the paraphilic and sexually aggressive populations. It is
      noteworthy that the teratogenic effects of alcohol upon humans and animals often
      leads to a number of the behavioral and physiological abnormalities exhibited by
      some of these individuals.

PMID- 10335567
TI  - Familial support as perceived by adult victims of childhood sexual abuse.
AB  - With the increasing popularity of family therapies in cases of childhood sexual
      abuse (CSA), many studies have discussed the importance of familial support in
      the successful recovery of victims. Therefore, a systematic study exploring
      family support of victims was undertaken to shed light on the level of family
      support perceived by adult victims of CSA. It was anticipated that victims of
      intrafamilial CSA would report more family dissatisfaction and perceive less
      family support than extrafamilial victims. As hypothesized, intrafamilial victims
      reported significantly more general family dissatisfaction and specifically,
      perceived significantly less father, parent, and brother support. Additionally,
      the gender of the victim played a significant role: Male victims reported less
      father, parent and sister support and less family protectiveness after disclosure
      when compared to female victims. Based on the results, clinicians should be aware
      that issues of gender and relatedness may play a significant part in the
      effectiveness of their CSA clients' family support systems.

PMID- 10335568
TI  - [The prognostic importance of cancer-associated proteins and apoptosis in
      glioblastomas of the cerebral hemispheres].
AB  - Clinical and morphological studies were undertaken to examine 168 patients with
      glioblastomas of the cerebral hemispheres. They revealed that the longevity of
      the hemispheres was substantially influenced by three immunobiological criteria:
      the proliferative potential defined as a labelling index (LI) of proliferative
      cell nuclear antigen (PCNA), the expression of intracellular domain of epidermal
      growth factor receptor (EGFR) and the rate of apoptosis identified by ISEL. The
      risk for shorter survivals increases with higher PCNA LI and with the EGFR
      expression in the tumor. In contrast, the rate of apoptosis is a good predictor
      since the risk for shorter postoperative survivals progressively reduces with
      high apoptotic indices. The expression of cancer proteins p53 and bc12 in the
      glioblastomas produces no noticeable effect on the patients survival.

PMID- 10335569
TI  - [Shunting operations in the hypertensive hydrocephalic syndrome in children with
      developmental defects of the central nervous system].
AB  - By analyzing the outcomes of surgical treatment of 105 children with hypertensive
      syndrome of various genesis, the authors present their data on the detection,
      diagnosis, and treatment of children with malformations of the central nervous
      system (CNS). The paper defines the present feasibilities of neurosonography,
      magnetic resonance imaging, neuroendoscopic verification of CNS malformations and
      their place in determining the policy and choice of a surgical treatment. The
      rationale for and the efficiency of cerebrospinal fluid corrective operations in
      children with these abnormalities are defined. Less good prognosis and a higher
      risk of surgery for hydrocephalic complications have been revealed and
      statistically evidenced.

PMID- 10335570
TI  - [Cerebral hemodynamics and metabolism in the acute stage of cerebral aneurysm
      rupture].
AB  - The relationship between lipid peroxidation products and the severity of arterial
      spasm was studied in 86 patients. For this, the level of radical production, the
      content of the end lipid peroxidation product malonic dialdehyde and the overall
      antioxidative activity of lumbar cerebrospinal fluid were determined during 24
      hour Doppler monitoring of blood flow in the middle cerebral and internal carotid
      arteries. Following subarachnoidal hemorrhage, the activation of lipid
      peroxidation processes was shown to correlate with the severity of arterial spasm
      and it is likely to contribute to the development of late ischemias. Nimotop used
      to treat patients with significant arterial spasm caused a reduction in the rate
      of free radical lipid peroxidation to that characteristic for patients with
      moderate spasm. The findings suggest that it is expedient of including
      antioxidants into the combined therapy of patients with acute subarachnoidal
      hemorrhage.

PMID- 10335571
TI  - [Changes in the somatosensory evoked potentials of patients with complicated
      spinal trauma after an omentomyelopexy operation].
AB  - The purpose of the study was to record somatosensory evoked potentials (SSEP) to
      objectify the results omentomyelopexy in late spinal cord injury. SSEP were
      recorded in 25 patients in leads of three levels of the somatosensory tract (from
      the popliteal fossa, from the lumbar enlargement of the spinal cord, and from the
      surface of the skull in the region of projection of leg presentation in cerebral
      hemispherical cortex) before and after surgery. The study indicated that there
      were no pre- or postoperative records of cortical evoked potentials. At the same
      time there was improvement in the magnitude of SSEP at the level of the lumbar
      enlargement (36%). In 4 (16%) and 5 (20%) cases of them SSEP changes were clear
      and unclear, respectively. The assessment of SSEP changes requires consideration
      of cases with unclear SSEP. Comparison of the results with clinical findings
      shows a correlation mainly with urological and urodynamic evidence. Thus, there
      are minor positive changes in the magnitude of SSEP after omentomyelopexy in the
      lumbar enlargement lead with unclearly pronounced evoked potentials.

PMID- 10335572
TI  - [The possibility of immunocorrection in spinal-spinal cord trauma by using
      intravenous laser irradiation].
AB  - The natural defense factors of the body and the cell factors of immunity were
      studied in 60 patients with acute and early spinal trauma. Immunodeficiency
      develops in 100% of cases with acute and early spinal trauma. Blood intravenous
      laser radiation at wave lengths of 632 and 830 nm was shown to produce an
      immunostimulating effect.

PMID- 10335573
TI  - [The permeability of the hemato-encephalic barrier in neurological cancer
      patients in the postoperative period].
AB  - The permeability of the blood-brain barrier was studied in 48 patients by
      examining the protein indices of cerebrospinal fluid. The types of changes in the
      indices were identified, which reflected the level of the permeability and
      correlate with good and poor postoperative outcomes. Possible ways of correcting
      hypertransudation across the barrier were defined.

PMID- 10335574
TI  - [Meningioma with a peritumoral abscess].
AB  - The paper presents a rare case of meningioma associated with peritumoral abscess
      formed in a 63-year-old female undergone right nephrectomy for abscessed
      pyelonephritis and drainage of gluteal abscesses 3 months before admission. Brain
      computed tomography revealed a left frontotemporal heterogeneous mass lesion with
      margin contrast accumulation. At surgery, convexity meningioma with peritumoral
      abscess was totally removed. Hematogenous spread of Staphylococcus aureus is most
      likely to be responsible for peritumoral abscess. The paper also gives a review
      of literature and a brief account of the case.

PMID- 10335575
TI  - [Chronic subdural hematoma of the posterior cranial fossa].
AB  - The 41-year-old patient experienced a trauma in childhood. Her examination
      revealed the hypertensive syndrome, truncal and cerebellar symptoms, suboccipital
      pain. Computed tomography indicated that in the posterior cranial fossa was a 48
      x 78 x 37-mm spreading from the tentorium of the cerebellum to the foramen magnum
      and descending along the clivus. At surgery, chronic subdural hematoma of the
      posterior cranial fossa was totally removed, the total volume of liquid and dense
      fractions was as high as 100 ml. After surgery, the patient recovered working
      capacity. The interest of this clinical case is due to a rare traumatic
      pathology, long disease, problematic preoperative diagnosis of chronic hematoma,
      a large formation, fair postoperative outcome.

PMID- 10335576
TI  - [The excessive drainage syndrome as a complication in the surgical treatment of
      hydrocephalus in children].

PMID- 10335578
TI  - [International standards in assessing the neurological disorders in spinal and
      spinal cord trauma].

PMID- 10335579
TI  - [A localizing helmet for optimizing the surgical approach].

PMID- 10335580
TI  - [A posterolateral approach to the area of the craniovertebral transition].
AB  - The paper presents a stepwise surgical technique of transcervical craniospinal
      posterolateral approach to the bulky processes of the craniovertebral region and
      the historical background. The access was modulated on cadavers (the head-neck
      region) in the project of a surgical intervention. In 1995-1998, clinical tests
      were made in 11 patients, 6 of whom had ventral craniospinal meningiomas, 2 cases
      had sand watch neuromas of the C2 root with extradural growth and 3 cases
      presented sand watch neurofibroma at the C1-C levels. The advantages and
      disadvantages of the approach are described.

PMID- 10335581
TI  - Nuclear magnetic resonance in environmental engineering: principles and
      applications.
AB  - This paper gives an introduction to nuclear magnetic resonance spectroscopy (NMR)
      and magnetic resonance imaging (MRI) in relation to applications in the field of
      environmental science and engineering. The underlying principles of high
      resolution solution and solid state NMR, relaxation time measurements and imaging
      are presented. Then, the use of NMR is illustrated and reviewed in studies of
      biodegradation and biotransformation of soluble and solid organic matter, removal
      of nutrients and xenobiotics, fate of heavy metal ions, and transport processes
      in bioreactor systems.

PMID- 10335582
TI  - Application of 13C NMR to investigate the transformations and biodegradation of
      organic materials by wood- and soil-feeding termites, and a coprophagous litter
      dwelling dipteran larva.
AB  - Solid-state 13C nuclear magnetic resonance spectroscopy has been used to
      characterize the C in samples of the food (wood), gut contents and faeces from
      the wood-feeding termite, Microcerotermes parvus; soil in the guts and mound
      material from the soil-feeding termite, Thoracotermes macrothorax; and the food
      and faeces from the litter-feeding, coprophagous larvae of the dipteran fly,
      Bibio marci. Spectra from the wood-feeding termite indicated preferential loss of
      polysaccharide and accumulation of lignin with some modification to the O
      aromatic-C and methoxyl-C (O-methyl-C) components during passage through the gut.
      Spectra for the soil-feeding termite indicated little change in the distribution
      of 13C between resonances following passage through the gut, except for some
      evidence of preferential polysaccharide loss. Interpretation of the spectra from
      these organisms was restricted by the relatively low C content of the soils and
      mound material, and by the large contribution to the NMR spectra from the gut
      tissue rather than the gut contents. Spectra for the litter-feeding dipteran
      larvae indicated preferential feeding on the polysaccharide-rich component of the
      litter and then overall loss of polysaccharide-C and accumulation of both
      aromatic-C and methoxyl-C in the gut. These changes were greater for the second
      passage than for the first passage through the gut, suggesting that principally
      mechanical and physical changes occurred initially and that chemical digestion
      was prevalent during the second passage.

PMID- 10335583
TI  - Thiomorpholine and morpholine oxidation by a cytochrome P450 in Mycobacterium
      aurum MO1. Evidence of the intermediates by in situ 1H NMR.
AB  - Spectrophotometric assays of Mycobacterium aurum MO1 cells extracts gave evidence
      of a soluble cytochrome P450, involved in the degradative pathway of morpholine,
      a waste product from the chemical industry. In order to get further information,
      the kinetics of the biodegradation of the sulfur analogue thiomorpholine was
      monitored by using in situ nuclear magnetic resonance (NMR). This technique
      allowed the identification of two intermediates: the sulfoxide of thiomorpholine
      resulting from S-oxidation and thiodiglycolic acid owing to ring cleavage. The S
      oxidation (S-->SO) represents one of the well-known reactions catalyzed by
      cytochromes P450. The inhibitory effect of metyrapone, a cytochrome P450
      inhibitor, on the thiomorpholine and morpholine degradative abilities of M. aurum
      MO1 confirmed the involvement of a cytochrome P450. These results and the
      decrease of the rate of formation of the first intermediate during the morpholine
      degradation, 2-(2-aminoethoxy) acetate, proved the key role of the cytochrome
      P450 in the early events of the biodegradation, i.e., in the C-N bond cleavage.

PMID- 10335584
TI  - In vivo 13C NMR study of glucose and cellobiose metabolism by four cellulolytic
      strains of the genus Fibrobacter.
AB  - The metabolism of glucose and cellobiose, products of cellulose hydrolysis, was
      investigated in four cellulolytic strains of the genus Fibrobacter: Fibrobacter
      succinogenes S85, 095, HM2 and Fibrobacter intestinalis NR9. In vivo 13C nuclear
      magnetic resonance was used to quantify the relative contribution of glucose and
      cellobiose to metabolite production, glycogen storage and cellodextrins synthesis
      in these four strains. The same features were found in all four strains of the
      genus Fibrobacter metabolizing simultaneously glucose and cellobiose: i)
      differential metabolism of glucose and cellobiose; glucose seems preferentially
      used for glycogen storage and energy production, while part of cellobiose seems
      to be diverted from glycolysis, ii) synthesis of cellodextrins, mainly from
      cellobiose not entering into glycolysis, iii) accumulation of glucose 6
      phosphate, iv) simultaneous presence of cellobiose phosphorylase and cellobiase
      activities. Although genetically diverse, the Fibrobacter genus appears to
      possess a marked homogeneity in its carbon metabolism.

PMID- 10335585
TI  - 19F NMR study on the biodegradation of fluorophenols by various Rhodococcus
      species.
AB  - Of all NMR observable isotopes 19F is the one perhaps most convenient for studies
      on biodegradation of environmental pollutants. The reasons underlying this
      potential of 19F NMR are discussed and illustrated on the basis of a study on the
      biodegradation of fluorophenols by four Rhodococcus strains. The results indicate
      marked differences between the biodegradation pathways of fluorophenols among the
      various Rhodococcus species. This holds not only for the level and nature of the
      fluorinated biodegradation pathway intermediates that accumulate, but also for
      the regioselectivity of the initial hydroxylation step. Several of the
      Rhodococcus species contain a phenol hydroxylase that catalyses the oxidative
      defluorination of ortho-fluorinated di- and trifluorophenols. Furthermore, it is
      illustrated how the 19F NMR technique can be used as a tool in the process of
      identification of an accumulated unknown metabolite, in this case most likely 5
      fluoromaleylacetate. Altogether, the 19F NMR technique proved valid to obtain
      detailed information on the microbial biodegradation pathways of fluorinated
      organics, but also to provide information on the specificity of enzymes generally
      considered unstable and, for this reason, not much studied so far.

PMID- 10335586
TI  - Application of 113Cd NMR to metallothioneins.
AB  - Metallothioneins constitute a class of ubiquitously occurring low molecular mass
      proteins (6-7 kDa) possessing two cysteine thiolate-based metal clusters usually
      formed by the preferential binding of d10 metal ions such as ZnII and CdII. The
      three-dimensional solution structure of mammalian proteins has been determined by
      two-dimensional NMR spectroscopy of 113Cd7-metallothionein. The structure shows
      two protein domains encompassing the M3(CysS)9- and M4(CysS)11-cluster with each
      metal ion being tetrahedrally coordinated by thiolate ligands. The application of
      113Cd NMR proved to be indispensable in the structural studies of
      metallothioneins. Thus, both homonuclear 113Cd decoupling studies and 113Cd-113Cd
      COSY of 113Cd7-metallothionein established the existence of two metal-thiolate
      clusters in this protein. The identification of sequence specific cysteine
      cadmium coordinative bonds came from heteronuclear 113Cd-1H COSY experiments.
      Independently, the 113Cd NMR characterization of the intermediate metal-protein
      complexes, leading to the cluster structure in 113Cd7-metallothionein, revealed a
      stepwise cluster formation process with the Cd4(CysS)11-cluster being formed
      first. The recent demonstration of a Karplus-like dependence between the
      heteronuclear3 J(113Cd, 1H) coupling constants for the cysteine C beta protons
      and the H beta-C beta-S gamma -Cd dihedral angles should allow to derive the
      geometry of the CD-(S-Cys) centers in various metallothioneins and related
      metalloproteins. A possible application of 113Cd NMR to the study of
      metallothioneins in the environment is discussed.

PMID- 10335587
TI  - Interaction between calcofluor white and carbohydrates of alpha 1-acid
      glycoprotein.
AB  - Interactions between the fluorescent probe, calcofluor white, and human serum
      albumin (HSA) and alpha 1-acid glycoprotein (orosomucoid) are compared. The two
      proteins have comparable isoelectric points, but alpha 1-acid glycoprotein is
      highly glycosylated (40% of glycans by weight), while the serum albumin is not.
      Binding of calcofluor to the proteins induces an increase in both the
      fluorescence anisotropy and the fluorescence intensity of the fluorophore. Also,
      we found that the calcofluor exhibits a fluorescence emission with a maximum
      located at 432, 415 or 445 nm, respectively, in the absence of proteins, in the
      presence of HSA, and in the presence of alpha 1-acid glycoprotein. The
      stoichiometries of the calcofluor-serum albumin and calcofluor-alpha 1-acid
      glycoprotein complexes are 2:1 and 1:1, respectively. The association constants
      are 0.04 and 0.15 microM-1, respectively. The calcofluor does not interact with
      Lens culinaris agglutinin (LCA), although the protein has a hydrophobic site.
      Nevertheless, one cannot exclude that the binding of the fluorophore to the HSA
      is nonspecific. Our results, when compared with those obtained with calcofluor
      dissolved in the hydrophobic solvent isobutanol, and with the fluorescent probe,
      potassium 6-(p-toluidino)-2-naphthalenesulfonate (TNS), bound to alpha 1-acid
      glycoprotein, indicate that the emission of calcofluor bound to HSA occurs from a
      hydrophobic state, while that of calcofluor bound to alpha 1-acid glycoprotein
      occurs from a hydrophilic state. The fluorescence intensity of calcofluor
      decreases in the presence of carbohydrates isolated from alpha 1-acid
      glycoprotein, while it increases in the presence of alpha 1-cellulose. Thus,
      calcofluor interacts mainly with the glycan moiety of alpha 1-acid glycoprotein,
      and its fluorescence is sensitive to the secondary structure of the glycans.

PMID- 10335588
TI  - Synthesis of the two monomethyl esters of the disaccharide 4-O-alpha-D
      galacturonosyl-D-galacturonic acid and of precursors for the preparation of
      higher oligomers methyl uronated in definite sequences.
AB  - Methyl (alpha-D-galactopyranosyluronic acid)-(1-->4)-D-galactopyranuronate and
      methyl alpha-D-galactopyranosyl-uronate-(1-->4)-D-galactopyranuronic acid have
      been synthesized by coupling methyl (benzyl 2,3-di-O-benzyl-beta-D
      galactopyranosid)uronate (3) or benzyl (benzyl 2,3-di-O-benzyl-beta-D
      galactopyranosid)uronate (4) with benzyl (phenyl 2,3,4-tri-O-benzyl-1-thio-beta-D
      galactopyranosid)uronate and methyl (phenyl 2,3,4-tri-O-benzyl-1-thio-beta-D
      galactopyranosid)uronate, respectively, using N-iodosuccinimide and
      trifluoromethanesulphonic acid as promoters, followed by removal of the benzyl
      groups. The 4'-OH unprotected dimers benzyl (methyl 2,3-di-O-benzyl-alpha-D
      galactopyranosyluronate)-(1-->4)-(benzyl 2,3-di-O-benzyl-beta-D
      galactopyranosid)uronate and methyl (benzyl 2,3-di-O-benzyl-alpha-D
      galactopyranosyluronate)-(1-->4)-(benzyl 2,3-di-O-benzyl-beta-D
      galactopyranosid)uronate were prepared from methyl (phenyl 2,3-di-O-benzyl-1-thio
      4-O-trimethylsilyl-beta-D-galactopyranosid) uronate and benzyl (phenyl 2,3-di-O
      benzyl-1-thio-4-O-trimethylsilyl-beta-D-galactopyranosid) uronate and acceptors 4
      or 3, respectively. These compounds have been designed to serve as precursors for
      the preparation of higher-membered D-galacturonic acid oligomers methyl
      esterified in definite positions.

PMID- 10335589
TI  - Structural heterogeneity of the sialic-acid-containing oligosaccharides from the
      lipopolysaccharide of Hafnia alvei strain 2 as detected by FABMS studies.
AB  - The structure of four oligosaccharide fractions from the Hafnia alvei strain 2
      lipopolysaccharide (LPS) have been assigned by FABMS. This approach corroborates
      data previously established by NMR spectroscopy for the major oligosaccharides in
      these fractions [A. Gamian, E. Romanowska, U. Dabrowski, J. Dabrowski,
      Biochemistry 30 (1991) 5032-5038; E. Katzenellenbogen, A. Gamian, E. Romanowska,
      U. Dabrowski, J. Dabrowski, Biochem. Biophys. Res. Commun. 194 (1993) 1058-1064;
      N. Ravenscroft, A. Gamian, E. Romanowska, Eur. J. Biochem. 227 (1995) 889-896].
      In addition, the MS/MS with B/E linked scan technique allowed the detection of an
      additional oligosaccharide with the structure: [formula: see text] lacking the
      branched O-6 linked glucopyranose residue at the 3-linked Gal unit, which
      indicates a structural heterogeneity for the major oligosaccharide fraction.

PMID- 10335590
TI  - Structure of an extracellular polysaccharide produced by Lactobacillus rhamnosus
      strain C83.
AB  - The extracellular polysaccharide produced by Lactobacillus rhamnosus strain C83
      was found to be composed of D-glucose and D-galactose in a molar ratio of 2:3.
      The primary structure of the polysaccharide was shown by sugar analysis,
      methylation analysis, FABMS, partial acid hydrolysis and nuclear magnetic
      resonance (NMR) spectroscopy to consist of a pentasaccharide repeating unit
      having the following structure: -->3)-alpha-D-Glcp-(1-->2)-beta-D-Galf-(1-->6)
      alpha-D-Galp-(1-->6 )-alpha-D -Glcp-(1-->3)-beta-D-Galf-(1-->

PMID- 10335591
TI  - Unsaturated oligogalacturonic acids are generated by in vitro treatment of pectin
      with human faecal flora.
AB  - Pectins with a degree of esterification (DE) of 95, 66, 34 and 0%, respectively,
      were incubated in vitro with human faecal flora (pH 7.8). The concentration and
      composition of oligogalacturonic acids (oligoGalA) generated were determined
      using high-performance thin-layer chromatography (HPTLC) with UV and colorimetric
      detection. In the first period of the anaerobic degradation, the pectin
      macromolecules were fragmented into unsaturated oligoGalA as intermediate
      products by the action of bacterial pectate lyases. Depending on the incubation
      time and the DE of pectin, the amount of unsaturated oligoGalA having different
      degrees of polymerization changed continuously. These oligoGalA were present in
      the cultures for some hours. Mixtures of unsaturated di-, tri- and tetraGalA were
      the end products of a pectate lyase action. Later, the oligoGalA disappear as a
      result of their further fermentation by the gastrointestinal microflora under
      formation of short-chain fatty acids (SCFA). Low-esterified pectins were
      depolymerized and fermented faster than the highly esterified by the human faecal
      flora in vitro. Furthermore, a mixture of unsaturated oligoGalA prepared from
      pectic acid by the action of pectate lyase from Erwinia carotovora was completely
      fermented by human faecal flora.

PMID- 10335592
TI  - Subtilisin-catalyzed esterification of di- and oligosaccharides containing a D
      fructose moiety.
AB  - Several di- and oligosaccharides containing a D-fructose moiety have been
      acylated by protease subtilisin in anhydrous dimethylformamide in the presence of
      the activated ester trifluoroethyl butanoate. Under the reaction conditions used,
      all the substrates were converted into the corresponding monobutanoates in ca.
      50% isolated yields. Structural determination of the products by 13C NMR
      indicated a strong preference of subtilisin towards the regioselective
      esterification of the primary hydroxyls of the fructose moiety and, specifically,
      of the C-1 OH, as already observed with sucrose.

PMID- 10335593
TI  - Access to tetrachlorophthalimide-protected ethyl 2-amino-2-deoxy-1-thio-beta-D
      glucopyranosides.
AB  - Ethyl 2-deoxy-2-tetrachlorophthalimido-1-thio-beta-D-glucopyranoside (7) was
      prepared from glucosamine hydrochloride in four steps with a 20-25% overall
      yield. Formation of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-tetrachlorophthalimido-beta
      D- glucopyranoside (5) was found to be crucial for this reaction sequence since
      the corresponding alpha-1-acetate did not react in Lewis-acid-catalyzed ethylthio
      glycosidations. Formation of the beta-1-acetate (5) was achieved by treatment of
      3,4,6-tri-O-acetyl-2-deoxy-2-tetrachlorophthalimido-alpha-D-glucop yranosyl
      bromide (4) with acetic acid under silver zeolite promotion. This was necessary
      because conditions normally used for beta-1-acetate formation were not tolerated
      by the tetrachlorophthalimido (TCP) group.

PMID- 10335594
TI  - Multigram syntheses of the disaccharide repeating units of chondroitin 4- and 6
      sulfates.
AB  - The multigram syntheses of beta-D-glucopyranosyluronic acid-(1-->3)-2-acetamido-2
      deoxy-4- and 6-O-sulfo-D-galactopyranose disodium salt, the disaccharide
      repeating units of chondroitin 4- and 6-sulfates, are described. The disaccharide
      benzyl methyl 2,3,4-tri-O-benzoyl-beta-D-glucopyranosyluronate- (1-->3)-2
      acetamido-2-deoxy-alpha-D-galactopyranoside was used as a common intermediate.
      Selective benzoylation at O-6 followed by O-sulfonation at C-4 of the aminosugar
      moiety, saponification and catalytic hydrogenation afforded the 4-O-sulfo
      derivative, whereas selective O-sulfonation at C-6 followed by similar
      deprotection steps provided the 6-O-sulfo derivative in high yield.

PMID- 10335596
TI  - A professionally led adoption triad group: an evolving approach to search and
      reunion.
AB  - In the field of postadoption services, counseling resources for reunited
      biological relatives are scarce. An adoption triad search and reunion pilot
      project at McGill University School of Social Work responded to this scarcity by
      providing the triad of adopted persons, biological parents, and adoptive parents
      with supportive counseling, and by conducting research on the outcomes. This
      article is an evaluative descriptive study of a mutualaid adoption triad group in
      search and reunion. The data were gathered through pre- and postintervention
      questionnaires and from process notes of the group meetings, which revealed five
      major themes. Results of the group experience, in terms of the feelings of the
      participants, were positive. The mutual-aid triad group can serve as a model for
      agencies and professionals seeking effective, affordable methods of providing
      postadoption search and reunion support services.

PMID- 10335595
TI  - The status of older adolescents at exit from out-of-home care.
AB  - Administrative data and case record reviews were used to assess the exit status
      of a sample of older youths leaving out-of-home care in one midwestern state.
      Results show that most left without a job or a high school diploma, and that many
      left with neither. The most common living arrangement at the time of exit was
      with relatives, some through planned reunification and some through unplanned
      reunification. The majority of the youths exited out-of-home care in unplanned
      ways. The number of placements and the completion of high school predicted
      employment status. High school completion was associated with age and a history
      of inpatient psychiatric care, running away, and mental retardation. Implications
      for independent living programs for older youths are discussed.

PMID- 10335598
TI  - Dynamics of Japanese encephalitis--a study in mathematical epidemiology.
AB  - An S-->I-->R-->S (susceptible-infective-recovered-susceptible) epidemiological
      model coupling the dynamics of the spread of Japanese encephalitis (JE) in two
      populations, human and reservoir animals (pigs, cattle, equines, birds, etc.)
      through a vector population (a particular species of mosquitos, Culex vishnui,
      Culex tritaeniorhynchus, etc.) is discussed. We assume that there is a constant
      recruitment rate of the susceptibles into both the populations, whereas the death
      rates are proportional to the population sizes, which are hence variables. We
      also assume that the human population is regulated by the disease. Conditions for
      the existence of a unique endemic equilibrium were found, and the endemicity of
      the disease is discussed. The threshold values determine whether the disease dies
      out or approaches an endemic equilibrium. The persistence of disease and disease
      related death can lead to a new equilibrium population size. The criteria for
      eradication of the disease have been worked out. The analytical results
      corresponding to the solutions of our system are verified by numerical analysis
      and computer simulation. The dynamics of disease transmission of JE during 1948
      1956 in Japan were also investigated with the help of available data.

PMID- 10335597
TI  - Using benefit-cost analysis to assess child abuse prevention and intervention
      programs.
AB  - Benefits and costs are discussed when child abuse prevention and intervention
      programs are proposed and evaluated, but systemic benefit-cost analysis as
      developed by economists has not been applied to such programs. This article
      presents the case for using benefit-cost analysis to structure evaluations of
      child abuse prevention and intervention programs. It presents the basic concept
      of benefit-cost analysis, its application in the context of assessing these types
      of child welfare programs, and limitations on its application to social service
      programs.

PMID- 10335599
TI  - Delay effect in a model for virus replication.
AB  - As biology becomes more quantitative, it appears that the increasing use of
      mathematics in this area is inevitable. In 1996, Nowak & Bangham (1996, Science
      272, 74-79) proposed three mathematical models to explore the relation between
      antiviral immune responses, virus load, and virus diversity. In this paper we
      investigate the delay effect in a model which considers the interaction between a
      replicating virus and host cells. We assume that there is a finite time lag
      between infection of a cell and the emission of viral particles. Even with the
      introduction of this delay, the steady states of the model--as suggested by Nowak
      & Bangham--remain stable. The result also gives a condition for how the parameter
      values should be chosen when analysing clinical data so that the model remains
      tenable.

PMID- 10335600
TI  - Modelling and simulation of chemotherapy of haematological and gynaecological
      cancers.
AB  - In this paper elaborate mathematical models and investigative computer
      simulations for the chemotherapy of haematological and gynaecological cancers are
      presented. The pharmacodynamics of the actions of the antineoplastic drugs are
      described by multicompartmental models with the associated model equations taking
      into account the drug dosage, type of delivery, route of delivery, the
      intercompartmental drug-transition constants, degradation parameters, and leakage
      coefficients. The cell-cycle phase-specific six-compartmental cytokinetic tumour
      growth model presented here incorporates the cell-cycle phase residence time,
      time lags associated with drug-induced cell-kill, or progression delays due to
      repair of cell damage. Investigative computer simulations are performed depicting
      the effects of cell-cycle phase-specific antineoplastic drugs on haematological
      and gynaecological cancer cells. The computer simulations are performed under
      various clinically plausible parametric configurations to elucidate the effects
      of certain critical variables such as tumour cell burden, mode of antineoplastic
      drug delivery, tumour cell loss and cell-cycle cytokinetic parameters.

PMID- 10335601
TI  - Toxicity in a water column following the stratification of a cyanobacterial
      population development in a calm lake.
AB  - Cyanobacteria, including the genera Anabaena, Aphanizomenon, Microcystis, and
      Oscillatoria, are known to release or have the potential to release phycotoxins
      into the water. Indeed, there are documented cases of both animal and human
      intoxication. Data obtained from field observations and laboratory experiments
      demonstrate a correlation between the development of the cyanobacterial
      population and the level of phycotoxin present in the water, though it should be
      noted that not all cyanobacterial blooms are toxic. The development of
      cyanobacterial populations is described by a dynamical model which accounts for
      factors that include algal growth, degradation, and light-driven buoyancy under
      the assumption of an isothermal, calm, and nutrient-abundant lake. A
      semiempirical mathematical model for water-column toxicity is developed and is
      used in conjunction with an improved result for the density of the cyanobacteria
      population obtained from the dynamical model. Light transfer through the water
      column, light absorption, the implication of the differentiated attenuation of
      light by the water, and its diurnal effect on the cyanobacteria population is
      considered. The result of which is a plausible description of the seasonal
      development of cyanobacteria populations and of the toxicity within the water
      body.

PMID- 10335602
TI  - Properties of adenosine deaminase from Candida albicans.
AB  - Adenosine deaminase (ADA; adenosine aminohydrolase, E.C. 3.5.4.4), a purine
      catabolic enzyme, was studied in Candida albicans, an opportunistic yeast that
      causes diseases ranging from superficial infections to the deep systemic disease,
      candidiasis, in immunosuppressed humans. The fungus was grown as a yeast form in
      LEE's synthetic medium, pH 4.5, at room temperature for various growth periods.
      Adenosine deaminase (ADA) activity was determined from the cell free extract by
      measuring the change in absorbance 265 nm resulting from the deamination of
      adenosine. In yeast form, maximum growth and ADA activity were found at 72 and 24
      hours, respectively, whereas in the mycelial form both the growth and ADA
      activity were maximum after 48 hours. Among the three media tested, tryptic soy
      broth supported maximum growth and enzyme production, compared to LEE synthetic
      medium or SABOURAUD dextrose broth. The enzyme was active over the pH range 4-8
      and the optimum temperature for ADA activity was found to be 37 degrees C.

PMID- 10335603
TI  - Miniaturization and application of the MTT assay to evaluate metabolic activity
      of protozoa in the presence of toxicants.
AB  - This paper describes a critical evaluation of a miniaturised colorimetric assay,
      using MTT (3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl-tetrazolium bromide)
      reduction, applied to protozoan viability testing. The toxic substances used were
      copper, zinc, Triton X-100 (a membrane surfactant) and cycloheximide (an
      inhibitor of the protein synthesis). The viability assay of the ciliate protozoan
      Tetrahymena pyriformis was optimised in terms of MTT concentration and incubation
      time. Since protozoa are non adherent cells the MTT assay was modified in order
      to maintain the medium in the well. MTT proved to be effective in the measurement
      of Tetrahymena pyriformis viability. Four hours of MTT incubation followed by 30
      minutes of incubation with DMSO were found to be the best incubation times for
      optical density reading. Furthermore, 10 mg/ml of MTT solution was the
      concentration that gave higher values of optical densities with minor medium
      interference.

PMID- 10335604
TI  - Removal of anthracene and phenanthrene by filamentous fungi capable of
      cortexolone 11-hydroxylation.
AB  - Nine fungal strains showing ability of cortexolone hydroxylation to epicortisol
      and/or cortisol were screened in this work for anthracene and phenanthrene
      elimination (250 mg/l). All of the strains (Cylindrocladium simplex IM 2358, C.
      simplex IM 2358/650, Monosporium olivaceum IM 484, Curvularia lunata IM 2901, C.
      lunata IM 2901/366, C. tuberculata IM 4417, Cunninghamella elegans IM 1785, C.
      elegans IM 1785/21Gp, C. elegans IM 1785/10Gi) significantly removed anthracene
      and phenanthrene. During incubation with anthracene formation of intermediate
      products was observed. The amount of the main intermediate product, identified as
      9, 10-anthraquinone, was not greater than 22.2% of the anthracene introduced to
      the fungal cultures. C. elegans IM 1785/21Gp was the best degrader of both
      anthracene and phenanthrene, removing 81.6 and 99.4% of these compounds after 7
      days, respectively. Phenanthrene removal by C. elegans IM 1785/21Gp was preceded
      by PAHs accumulation in mycelium and growth inhibition. Elimination of
      phenanthrene started after one day of incubation and was related to the fungus
      growth.

PMID- 10335605
TI  - Detection of a common genotype among strains of Taylorella equigenitalis isolated
      from thoroughbred horses in Japan between 1994 and 1996.
AB  - We examined whether or not the genotype J could be detected among 21 new strains
      of T. equigenitalis isolated between 1994 and 1996 in Japan since our previous
      report (MIYAZAWA et al. 1995). The respective pulsed-field gel electrophoretic
      profiles of the 21 Japanese strains, as well as those of an old EQ59 used as a
      reference strain after separate digestion with the two restriction enzymes, ApaI
      and NotI, were essentially identical but differed from those of T. equigenitalis
      NCTC11184T and KENTUCKY 188, respectively. Hence, the 21 strains and EQ59
      appeared to have a common genotype J. Consequently, no strains of T.
      equigenitalis with any genotype other than genotype J may have reached Japan from
      1980 to 1996 and strains with the genotype J have survived in Japan since the
      first invasion of contagious equine metritis into Japan.

PMID- 10335606
TI  - Effect of thioredoxin on the sensitivity of bacteria to chemical damage.
AB  - The ability of thioredoxin (Trx) to protect cells from chemical damage was
      determined by comparing the growth of a control strain of Escherichia coli JM101
      and isogenic strain transformed with the plasmid pKKTS1 containing the
      Streptomyces aureofaciens thioredoxin gene, in the presence of the nucleoside
      analogs arabinosylcytosine, 5-fluorouridine, ftorafur and carcinogen beta
      naftylamine. Arabinosylcytosine showed no effect on the growth of either of the
      two strains. 5-fluorouridine, ftorafur [1-((R,S)-tetrahydrofuran-2-yl)-5
      fluorouracil] and beta-naftylamine demonstrated lower inhibitory effects on the
      growth of the thioredoxin overproducing strain than on the growth of the control
      strain. These results suggested that Trx could protect the cells from chemical
      damage under certain metabolic conditions.

PMID- 10335608
TI  - Peptide separation in normal-phase liquid chromatography. Study of selectivity
      and mobile phase effects on various columns.
AB  - An experimental procedure for peptide separation by normal-phase liquid
      chromatography (NPLC) was proposed in previous papers. In the present study, the
      chromatographic behavior of amino, cyano, amide, diol and silica columns, which
      have been used in non-aqueous NPLC, is investigated anew. The amino column was
      not appropriate for peptide separation because of poor recovery. The cyano column
      could not be used due to lack of retention. The amide, diol and silica columns
      were useful for peptide separation. The chromatograms on amide, diol and silica
      columns were a little different when the mobile phase composition was changed.
      The recovery of peptides was good: diol > amide > silica. Repeatability and
      reproducibility using amide, diol and silica columns was satisfactory.

PMID- 10335607
TI  - Quantitation of clobazam in human plasma using high-performance liquid
      chromatography.
AB  - A rapid and simple reversed-phase high-performance liquid chromatographic (HPLC)
      method for the determination of clobazam concentrations in human blood samples is
      developed and validated. Solid-phase column extraction is performed to clean up
      blood samples before running the analytical HPLC system. The chromatography is
      isocratic with a mobile phase consisting of acetonitrile (20%, v/v), methanol
      (23%, v/v), and 0.1 M potassium hydrogen phosphate buffer (pH 3.6; 57%, v/v) at a
      constant flow rate of 2 mL/min. Clobazam is detected at 226 nm. Chromatography is
      completed within less than 25 min. The recovery rate is greater than 95% and
      linear over a wide range of drug concentrations. The intra-assay coefficient of
      variation percentage varies between 4.3 and 12. This method is used for
      therapeutic drug monitoring in patients undergoing antiepileptic therapy with
      clobazam. Plasma levels of clobazam ranged from 21 to 663 ng/mL. Other
      antiepileptic compounds, such as clonazepam and phenobarbital, did not interfere
      with the detection of clobazam.

PMID- 10335609
TI  - Preconcentration of quinolones by dialysis on-line coupled to high-performance
      liquid chromatography.
AB  - The parameters influencing dialytic separation of ciprofloxacin (CF)
      fluoroquinolone were investigated. Dialysis with a porous cellulose acetate
      membrane was on-line coupled with HPLC and the analysis of dialysate was made by
      isocratic ion-pairing liquid chromatography using a reversed-phase analytical
      column and fluorescence detection. Optimisation of the experimental conditions
      for selective dialytic enrichment are described and explanations of some
      phenomena affecting dialysis efficiency discussed. By the use of a neutral donor
      (pH approximately 7) and acidic acceptor solution (pH < 4) a substantial
      enrichment of quinolones was achieved. Accumulation of CF in the acidic acceptor
      phase is based on the protonation of the analyte in the acceptor compartment.
      Continuous-flow of donor solution and a stagnant acceptor solution gave high
      dialysis efficiency in 5-15 min. Effects of interfering substances present in
      real samples on the variation of dialysis efficiency can be minimised by
      successive dialysis runs of the original and spiked samples.

PMID- 10335610
TI  - Faster isolation of recombinant factor VIII SQ, with a superporous agarose
      matrix.
AB  - A superporous agarose matrix was compared with a corresponding homogenous matrix
      in the isolation of recombinant factor VIII SQ (r-VIII SQ) by immunoaffinity
      chromatography. As a reference, the commercially available Sepharose FastFlow,
      used for a similar purification in the industry, was also evaluated. Breakthrough
      curves are described for flows between 50 and 400 cm/h with pre-purified r-VIII
      SQ and with cell culture broth. The superporous gel gave the best performance and
      a 1000-fold purification was obtained in a one-step procedure. The superporous
      matrix made it possible to increase the throughput about four-fold, presumably
      due to its better mass transfer properties. The importance of the ligand
      distribution profile is discussed based upon immunofluorescence microscopy data.

PMID- 10335611
TI  - Separation of G structures formed by a 27-mer guanosine-rich
      oligodeoxyribonucleotide by dye-ligand affinity chromatography.
AB  - G-DNA structures, formed by a 27-mer guanosine-rich oligodeoxyribonucleotide,
      AACCCGGCGTTCGGGGGGTACCGGGTT, were isolated and studied by dye-ligand affinity
      chromatography, using a Reactive Green 19-agarose resin (RG19-aga) and gel
      electrophoresis. The experiments were performed in the presence of Li+, Na+ and
      K+, which are able to stabilise the G structures to different extents. Desalting
      procedures followed by affinity chromatography, performed in the presence of Li+,
      gave us information on the relationships among the species isolated and their
      stability. The results show that the more stable species were those obtained in
      the presence of K+, while in the presence of Li+, the formation of G structures
      was negligible and the oligonucleotide was almost exclusively present as a stem
      loop structure recognised by the RG19-aga affinity resin. Electrophoretic and
      denaturation and renaturation experiments supported the affinity chromatography
      results.

PMID- 10335612
TI  - Efficiency of supercritical fluid extraction for determining 4-nonylphenol in
      municipal sewage sludge.
AB  - When the sewage sludge containing the persistent, lipophilic, metabolite 4
      nonylphenol (4-NP) has been disposed of in the environment it's toxic nature can
      lead to serious health risks to human beings and can also affect plants and
      aquatic organisms. Supercritical fluid extraction (SFE) is a new and powerful
      technique for extracting the organic contaminants from the solid phase. The
      present study was conducted to investigate optimal conditions for the
      quantitative extraction of 4-NP by SFE and to determine the concentration of 4-NP
      in municipal sewage sludge. The effect of several parameters such as temperature,
      pressure, static extraction time, dynamic extraction time, CO2 flow-rate, sample
      mass and modifier on the extraction were investigated. The optimal conditions for
      the extraction of the spiked sample were fluid pressure 97 bar, temperature 40
      degrees C, flow-rate 3.0 ml/min, static extraction time 2 min, dynamic extraction
      time 5 min and modifier methanol (0.5 ml). Extracts were analyzed by gas
      chromatography-mass spectrometry. Concentration of 4-NP in the anaerobically
      degraded sludge of the De-Haw Sewage Treatment Plant in Taiwan was found to be
      243.9 mg/kg. The extraction efficiency of the SFE method was compared with the
      conventional Soxhlet extraction method. The overall recovery of the SFE method
      was found to be greater and the results indicate that SFE is an efficient method
      for extracting 4-NP from sewage sludge.

PMID- 10335613
TI  - Automated one-step supercritical fluid extraction and clean-up system for the
      analysis of pesticide residues in fatty matrices.
AB  - An automated supercritical fluid extraction and in-line clean-up system has been
      developed for organochlorine and organophosphate pesticide residues contained in
      fats. This procedure utilizes supercritical carbon dioxide modified with 3%
      acetonitrile at 27.58 MPa and 60 degrees C to extract and separate the pesticide
      residues from the fat on a C1 bonded phase preparative column at 95 degrees C.
      The automated C1 system recovers 86 of 117 nonpolar to moderately polar
      organochlorine and organophosphate pesticides from fats. Ten of the 31 pesticides
      not recovered through the system are not recovered through the conventional clean
      up sorbent, Florisil. Pesticide residues can be separated from 0.68 g of butter
      fat and 0.67 g corn oil, resulting in 2.9 mg of butterfat and 2.1 mg corn oil
      residue co-eluting into the pesticide fraction. Also, this integrated method can
      extract and clean-up a 5 g sample of fatty foods containing < 18% fat and 70%
      moisture. The automated C1 system is reproducible and the amount of co-extracted
      sample residue in the pesticide fraction yields results comparable to the current
      methodology, which uses organic solvent extraction and gel permeation
      chromatography, along with a final Florisil column clean-up step. This automated
      C1 system simplifies the extraction and clean-up step while reducing solvent
      usage and hazardous waste.

PMID- 10335614
TI  - Ambient temperature affects free-flight performance in the fruit fly Drosophila
      melanogaster.
AB  - To gain insight into how temperature affects locomotor performance in insects,
      the limits of flight performance have been estimated in freely flying fruit flies
      Drosophila melanogaster by determining the maximum load that a fly could carry
      following take-off. At a low ambient temperature of 15 degrees C, muscle
      mechanical power output matches the minimum power requirements for hovering
      flight. Aerodynamic force production rises with increasing temperature and
      eventually saturates at a flight force that is roughly equal to 2.1 times the
      body mass. Within the two-fold range of different body sizes, maximum flight
      force production during free flight does not decrease with decreasing body size
      as suggested by standard aerodynamic theories. Estimations of flight muscle
      mechanical power output yields a peak performance of 110 W kg-1 muscle tissue for
      short-burst flight that was measured at an ambient temperature of 30 degrees C.
      With respect to the uncertainties in estimating muscle mechanical power during
      free flight, the estimated values are similar to those that were published for
      flight under tethered flight conditions.

PMID- 10335615
TI  - Mycophagy by small mammals in the coniferous forests of North America:
      nutritional value of sporocarps of Rhizopogon vinicolor, a common hypogeous
      fungus.
AB  - We evaluated the nutritional value of sporocarps of Rhizopogon vinicolor, a
      common hypogeous fungus in the coniferous forests of North America, for two small
      mammal species: the Californian red-backed vole (Clethrionomys californicus) and
      the northern flying squirrel (Glaucomys sabrinus). Although the nitrogen
      concentration of sporocarps was high, much of it was in non-protein form or
      associated with cell walls, suggesting that it may be of low nutritional value or
      protected from mammalian digestive enzymes. Sporocarps also had high
      concentrations of cell wall constituents, indicating low availability of
      digestible energy. When fed a diet of this fungus alone in a controlled feeding
      experiment both mammal species lost a small amount of body mass. Digestibilities
      of dry matter, nitrogen, cell wall constituents and energy from sporocarps by
      both species were lower than the digestibilities of other food types by other
      similarly sized small mammals. Red-backed voles digested the various components
      of sporocarps at least as well as the flying squirrels, even though they were
      almost six-fold smaller in body mass. This observation supports the notion that
      red-backed voles, like other microtine rodents, have morphological and
      physiological adaptations of the digestive system that are postulated to permit
      greater digestion of fibrous diets than predicted on the basis of body size.
      Despite this, our results re-affirm previous conclusions that hypogeous fungi are
      only of moderate nutritional value for most small, hindgut-fermenting mammals.
      Future studies should focus on the importance of mixed-species of fungi in the
      diet of small mammalian mycophagists.

PMID- 10335616
TI  - Absorption of visible spectrum radiation by the wing membranes of living
      pteropodid bats.
AB  - The wing membranes of bats present a large surface area upon which radiation
      might be taken up, increasing heat load to the animals. This, combined with the
      high amount of heat produced during flight, has been advanced as one hypothesis
      explaining the fact that bats are almost exclusively nocturnal. The proportion of
      short-wave (visible) radiation absorbed by bat wing membrane has previously been
      measured at between 0.7 and 0.92. These measurements were made on pieces of
      membrane taken from the wings of dead, mainly insectivorous bats from temperate
      regions. Here we examined the amount of light transmitted through and reflected
      off the wing membranes of four species of live pteropodid bats. There were
      significant differences in wing reflection between species. At 0.68, the average
      proportion of light absorbed into the wing membranes was lower than previously
      reported. This might be because we worked with live animals or because ours were
      tropical bats which are routinely exposed to tropical sun when roosting.
      Variation in wing tension strongly affected light absorption. It was predicted
      that the relaxed state of wing membrane through part of the wing beat cycle would
      increase the absorption of light into the wings of day-flying bats. The
      proportion of light absorbed into wings was shown to be an important factor in
      the heat balance of hypothetical bats flying during the day. Our results raise
      the predicted temperature at which bats flying during the day might experience
      hyperthermia by approximately 2 degrees C and suggest that variation in albedo of
      wings between species may make some species more susceptible to overheating than
      others.

PMID- 10335617
TI  - Time-frequency analysis of the dispersion of Lamb modes.
AB  - Accurate knowledge of the velocity dispersion of Lamb modes is important for
      ultrasonic nondestructive evaluation methods used in detecting and locating flaws
      in thin plates and in determining their elastic stiffness coefficients. Lamb mode
      dispersion is also important in the acoustic emission technique for accurately
      triangulating the location of emissions in thin plates. In this research, the
      ability to characterize Lamb mode dispersion through a time-frequency analysis
      (the pseudo-Wigner-Ville distribution) was demonstrated. A major advantage of
      time-frequency methods is the ability to analyze acoustic signals containing
      multiple propagation modes, which overlap and superimpose in the time domain
      signal. By combining time-frequency analysis with a broadband acoustic excitation
      source, the dispersion of multiple Lamb modes over a wide frequency range can be
      determined from as little as a single measurement. In addition, the technique
      provides a direct measurement of the group velocity dispersion. The technique was
      first demonstrated in the analysis of a simulated waveform in an aluminum plate
      in which the Lamb mode dispersion was well known. Portions of the dispersion
      curves of the A0, A1, S0, and S2 Lamb modes were obtained from this one waveform.
      The technique was also applied for the analysis of experimental waveforms from a
      unidirectional graphite/epoxy composite plate. Measurements were made both along
      and perpendicular to the fiber direction. In this case, the signals contained
      only the lowest order symmetric and antisymmetric modes. A least squares fit of
      the results from several source to detector distances was used. Theoretical
      dispersion curves were calculated and are shown to be in good agreement with
      experimental results.

PMID- 10335618
TI  - Working gases in thermoacoustic engines.
AB  - The best working gases for thermoacoustic refrigeration have high ratios of
      specific heats and low Prandtl numbers. These properties can be optimized by the
      use of a mixture of light and heavy noble gases. In this paper it is shown that
      light noble gas-heavy polyatomic gas mixtures can result in useful working gases.
      In addition, it is demonstrated that the onset temperature of a heat driven prime
      mover can be minimized with a gas with large Prandtl number and small ratio of
      specific heats. The gas properties must be optimized for the particular
      application of thermoacoustics; it cannot be assumed that high specific heat
      ratio and low Prandtl number are always desirable.

PMID- 10335619
TI  - Photoacoustic detection and localization of small gas leaks.
AB  - Leak detection and localization are critical manufacturing quality-control
      processes. Many industrial and domestic machines use or convey pressurized gases
      or liquids. Unintended leaks from machine components may be detrimental to
      consumers, manufacturers, and the environment. This paper describes a leak
      detection technique based on photoacoustic sounds produced by the interaction of
      a carbon dioxide (CO2) laser tuned to 10.6 micrometers and a photoactive tracer
      gas, sulfur hexaflouride (SF6), emitted by calibrated leak sources. Acoustic
      signals generated by a high-speed scan of the laser beam through the cloud of
      tracer gas formed near the leak are recorded in a bandwidth from 3 to 52 kHz by
      multiple microphones. From the recorded signals, the presence or absence of a
      leak may be deduced by comparison with the background noise level at the signal
      frequencies, which occur at the harmonics of the scan rate. When a leak is
      present, its location is determined from a simple model of the acoustic
      environment and matched field processing (MFP). Current results show that a gas
      leak of 1 cm3 per day can be detected and localized to within +/- 3 mm in a few
      seconds using four microphones, placed 0.41 m from the leak location, and an
      incoherent average of the MFP ambiguity surfaces at eight signal frequencies.
      Comparisons of the Bartlett and minimum-variance-distortionless matched field
      processors are also presented.

PMID- 10335620
TI  - Counteracting moment device for reduction of earthquake-induced excursions of
      multi-level buildings.
AB  - A vibration-control mechanism for beams and columns was presented in our previous
      report in which the earthquake force was transformed into a vibration-control
      force by using a gear train mechanism. In our previous report, however, only the
      principle of transforming the earthquake force into the control force was
      presented; the discussion for real structures and the design method were not
      presented. The present article provides a theoretical analysis of the column
      which is used in multi-layered buildings. Experimental tests were carried out for
      a model of multi-layered buildings in the frequency range of a principal
      earthquake wave. Theoretical results are compared to the experimental data. The
      optimal design of the control mechanism, which is of importance in the column
      design, is presented. Numerical calculations are carried out for the optimal
      design. It is shown that vibrations of the column involving the mechanism are
      suppressed remarkably. The optimal design method and the analytical results are
      applicable to the design of the column.

PMID- 10335621
TI  - Circumferential waves on an immersed, fluid-filled elastic cylindrical shell.
AB  - The existence of various types of circumferential waves, both predominantly shell
      or fluid borne, and the repulsion of their dispersion curves is discussed here
      for an infinite, thin elastic, circular-cylindrical shell immersed in a fluid and
      filled with another fluid. The study is based on an analytic calculation of the
      partial-wave resonances in the acoustic scattering amplitude of a normally
      incident plane wave. A large number of cases of repulsion are found in the phase
      velocity dispersion curves of the various types of circumferential waves due to
      the shell-fluid coupling.

PMID- 10335622
TI  - Applications of the causality condition to one-dimensional acoustic reflection
      problems.
AB  - The causality condition is examined as a means of determining frequency-domain
      information about a submerged object from a partial knowledge of its acoustic
      reflection characteristics. A one-dimensional problem is considered in which an
      acoustic wave reflects from an object that is described by the impedance it
      presents to the fluid. Two new applications of the causality condition to the
      frequency-domain analysis of this problem are investigated and illustrated by
      numerical examples. In each application, the causality condition is used to find
      the object's complex impedance from a knowledge of the reflected wave's
      magnitude. The first application is to experimental studies where one desires a
      knowledge of an object's complex impedance but practical limitations only allow a
      measurement of the reflected wave amplitude. Analysis shows that the causality
      condition may be used to determine the phase of the reflected wave, and hence the
      object's impedance, if the reflection coefficient is minimum phase. When this is
      true, examples suggest that the phase of the reflection coefficient may be
      accurately determined from the causality condition even in the presence of noise
      and band-limited data. The second application is to design situations, where one
      wishes to create an object that reflects sound with a specified frequency
      dependent magnitude. The causality condition may aid the designer by providing a
      knowledge of all causal object impedances that produce the same reflection
      coefficient magnitude. A numerical example is presented in which a variety of
      causal object impedances produce the same reflection coefficient magnitude over
      an infinite frequency range.

PMID- 10335623
TI  - Fluid flow imaging by means of wide-band diffraction tomography.
AB  - The problem of reconstructing a two-dimensional distribution of fluid flow from
      wide-band scattering measurements is considered. Reciprocal scattering
      measurements are employed, meaning that scattered waves are recorded between a
      source and receiver, and again with the source and receiver interchanged. As
      shown, such measurements allow the reconstruction of a fluid flow image separate
      from that of a distribution of stationary acoustic velocity inhomogeneities.

PMID- 10335624
TI  - Group delays of distortion product otoacoustic emissions in the guinea pig.
AB  - This paper presents a comprehensive set of experimental data on group delays of
      distortion product otoacoustic emissions (DPOAEs) in the guinea pig. Group delays
      of the DPOAEs with frequencies 2f1-f2, 3f1-2f2, 4f1-3f2, and 2f2-f1 were measured
      with the phase gradient method. Both the f1- and the f2-sweep paradigm were used.
      Differences between the two sweep paradigms were investigated for the four
      DPOAEs, as well as the group delay differences between the DPOAEs. Analysis
      revealed larger group delays with the f2-sweep paradigm, but only for the lower
      sideband DPOAEs (with fdp < f1,f2). For the lower sideband cubic distortion
      product 2f1-f2, the f2-sweep delays were a factor of 1.17-1.54 larger than the f1
      sweep delays, depending on frequency. The upper sideband DPOAE 2f2-f1 showed no
      significant difference between f1- and f2-sweep group delays, except for the
      highest and lowest f2 frequencies. Comparing the group delays of the DPOAEs for
      each sweep paradigm separately, equal group delays were found for all four DPOAEs
      measured with the f1-sweep. With the f2-sweep paradigm on the other hand, the
      group delays of the three lower sideband DPOAEs occurred to be larger than the
      group delays of the upper sideband DPOAE 2f2-f1. A tentative interpretation of
      the data in the context of proposed explanatory hypotheses on DPOAE group delays
      is given.

PMID- 10335625
TI  - Response magnitude and timing of auditory response initiation in the inferior
      colliculus of the awake chinchilla.
AB  - Recent single-unit studies in anesthetized cats have revealed that the latency
      and strength of transient responses to tone burst stimuli are determined largely
      by stimulus events in the first few ms of the signal. The present study sought to
      extend these findings by studying the inferior colliculus potential (ICP) in
      unanesthetized chinchillas. The ICP magnitude and latency were studied as a
      function of the plateau amplitude and rise time of noise burst stimuli. ICP
      amplitude increased with stimulus amplitude and decreased with stimulus rise
      time. ICP latency decreased with stimulus amplitude and increased with stimulus
      rise time. The absolute values of the ICP latencies confirmed that it is only the
      first few ms of the stimulus which determine the timing of response initiation,
      and therefore, that it is not the plateau level of the stimulus that directly
      determines the latent period. These data constitute a direct link between earlier
      single-unit studies in anesthetized animals and brainstem-evoked potential data
      in animals and man.

PMID- 10335626
TI  - Influence of speech stimuli intensity on the activation of auditory cortex
      investigated with functional magnetic resonance imaging.
AB  - Understanding the impact of variations in the acoustic signal is critical for the
      development of auditory and language fMRI as an experimental tool. We describe
      the dependence of the BOLD signal and speech intelligibility on the intensity of
      auditory stimuli. Eighteen subjects were imaged on a 1.5-T MRI scanner. Speech
      stimuli were English monosyllabic words played at five intensity levels.
      Intrasubject reproducibility was measured on one subject by presenting the
      stimulus five times at the same intensity level. Intelligibility was measured
      during data acquisition as subjects signaled when hearing two targets. Each
      functional trial consisted of four cycles (30 s off-30 s on). Five oblique slices
      covering primary and association auditory areas were imaged. Activated voxels
      were identified by cross-correlation analysis and their percent signal change
      (delta S) was measured. Intersubject differences in activation extent, asymmetry,
      and dependence on intensity were striking. Volume of activation was significantly
      greater in the left than in the right hemisphere. Intrasubject reproducibility
      for delta S was higher than for volume of activation. delta S and intelligibility
      showed a similar dependence on intensity suggesting that not only intensity but
      also intelligibility affect the fMRI signal.

PMID- 10335627
TI  - Temporal resolution and temporal masking properties of transient stimuli: data
      and an auditory model.
AB  - Temporal resolution is often measured using the detection of temporal gaps or
      signals in temporal gaps embedded in long-duration stimuli. In this study,
      psychoacoustical paradigms are developed for measuring the temporal encoding of
      transient stimuli. The stimuli consisted of very short pips which, in two
      experiments, contained a steady state portion. The carrier was high-pass
      filtered, dynamically compressed noise, refreshed for every stimulus
      presentation. The first experiment shows that, with these very short stimuli, gap
      detection thresholds are about the same as obtained in previous investigations.
      Experiments II and III show that, using the same stimuli, temporal-separation
      thresholds and duration-discrimination thresholds are better than gap-detection
      thresholds. Experiment IV investigates the significance of residual spectral cues
      for the listeners' performance. In experiment V, temporal separation thresholds
      were measured as a function of the signal-pip sensation level (SL) in both
      forward- and backward-masking conditions. The separation thresholds show a strong
      temporal asymmetry with good separation thresholds independent of signal-pip SL
      in backward-masking conditions and increasing separation thresholds with
      decreasing signal-pip SL in forward-masking conditions. A model of the auditory
      periphery is used to stimulate the gap-detection and temporal-separation
      thresholds quantitatively. By varying parameters like auditory-filter width and
      transduction time constants, the model provides some insight into how the
      peripheral auditory system may cope with temporal processing tasks and thus
      represents a more physiology-related complement to current models of temporal
      processing.

PMID- 10335629
TI  - Two phase effects in roughness perception.
AB  - The respective influences of spectral and temporal aspects of sound in roughness
      perception are examined by way of phase manipulations. In a first experiment, the
      phase of the central component of three-component signals is shown to modify
      perceived roughness, for a given amplitude spectrum, regardless of whether it
      modifies the waveform envelope. A second experiment shows that the shape of the
      waveform envelope, for a given amplitude spectrum and a given modulation depth,
      also influences perceived roughness. We interpret both of these results by
      considering the envelope of an internal representation that is deduced from the
      physical signal by taking into account peripheral auditory processing. The
      results indicate that the modulation depth of such an internal representation is
      not the only determinant of roughness, but that an effect of temporal asymmetry
      is also to be taken into account.

PMID- 10335630
TI  - Syllable intelligibility for temporally filtered LPC cepstral trajectories.
AB  - The intelligibility of syllables whose cepstral trajectories were temporally
      filtered was measured. The speech signals were transformed to their LPC cepstral
      coefficients, and these coefficients were passed through different filters. These
      filtered trajectories were recombined with the residuals and the speech signal
      reconstructed. The intelligibility of the reconstructed speech segments was then
      measured in two perceptual experiments for Japanese syllables. The effect of
      various low-pass, high-pass, and bandpass filtering is reported, and the results
      summarized using a theoretical approach based on the independence of the
      contributions in different modulation bands. The overall results suggest that
      speech intelligibility is not severely impaired as long as the filtered spectral
      components have a rate of change between 1 and 16 Hz.

PMID- 10335628
TI  - Factors affecting the loudness of modulated sounds.
AB  - Loudness matches were obtained between unmodulated carriers and carriers that
      were amplitude modulated either periodically (rates between 2 and 32 Hz,
      modulation sinusoidal either on a linear amplitude scale or on a dB scale; the
      latter is called dB modulation) or with the envelope of the speech of a single
      talker. The carrier was a 4-kHz sinusoid, white noise, or speech-shaped noise.
      Both normally hearing subjects and subjects with cochlear hearing loss were
      tested. Results were expressed as the root-mean-square (rms) level of the
      modulated carrier minus the level of the unmodulated carrier at the point of
      equal loudness. If this difference is positive, this indicates that the modulated
      carrier has a higher rms level at the point of equal loudness. For normally
      hearing subjects, the results show: (1) For a 4000-Hz sinusoidal carrier, the
      difference was slightly positive (averaging about 0.7 dB). There was no
      significant effect of modulation rate or level over the range 20-80 dB SL. (2)
      For a speech-shaped noise or white noise carrier, the difference was close to
      zero, although for large modulation depths it tended to be negative. There was no
      clear effect of level (over the range 35-75 dB SPL) or modulation rate. For the
      hearing-impaired subjects, the differences were small, but tended to be slightly
      negative for both the 4000-Hz carrier and the noise carriers, when the modulation
      rate was above 2 Hz. Again, there was no clear effect of overall level. However,
      for dB modulation, the differences became more negative with increasing
      modulation depth. For modulation rates in the range 4-32 Hz, the results could be
      fitted reasonably well using the assumption that the loudness of modulated sounds
      is based on the rms value of the time-varying intensity of the response of the
      basilar membrane (taking into account the compression that occurs in the normal
      cochlea). The implications of the results for the fitting of multi-band
      compression hearing aids and for the design of loudness meters are discussed.

PMID- 10335631
TI  - Center frequency modulation detection for harmonic complexes resembling vowel
      formants and its interference by off-frequency maskers.
AB  - Vowels are characterized by peaks in their spectral envelopes: the formants. To
      gain insight into the perception of speech as well as into the basic abilities of
      the ear, sensitivity to modulations in the positions of these formants is
      investigated. Frequency modulation detection thresholds (FMTs) were measured for
      the center frequency of formantlike harmonic complexes in the absence and in the
      presence of simultaneous off-frequency formants (maskers). Both the signals and
      the maskers were harmonic complexes which were band-pass filtered with a
      triangular spectral envelope, on a log-log scale, into either a LOW (near 500
      Hz), a MID (near 1500 Hz), or a HIGH region (near 3000 Hz). They had a duration
      of 250 ms, and either an 80- or a 240-Hz fundamental. The modulation rate was 5
      Hz for the signals and 10 Hz for the maskers. A pink noise background was
      presented continuously. In a first experiment no maskers were used. The measured
      FMTs were roughly two times larger than previously reported just-noticeable
      differences for formant frequency. In a second experiment, no significant
      differences were found between the FMTs in the absence of maskers and those in
      the presence of stationary (i.e., nonfrequency modulated) maskers. However, under
      many conditions the FMTs were increased by the presence of simultaneous modulated
      maskers. These results indicate that frequency modulation detection interference
      (FMDI) can exist for formantlike complex tones. The FMDI data could be divided
      into two groups. For stimuli characterized by a steep (200-dB/oct) slope, it was
      found that the size of the FMDI depended on which cues were used for detecting
      the signal and masker modulations. For stimuli with shallow (50-dB/oct) slopes,
      the FMDI was reduced when the signal and the masker had widely differing
      fundamentals, implying that the fundamental information is extracted before the
      interference occurs.

PMID- 10335632
TI  - A binaural analog of gap detection.
AB  - The temporal resolution of the binaural auditory system was measured using a
      binaural analog of gap detection. A binaural "gap" was defined as a burst of
      interaurally uncorrelated noise (Nu) placed between two bursts of interaurally
      correlated noise (N0). The Nu burst creates a dip in the output of a binaural
      temporal window integrating interaural correlation, analogous to the dip created
      by a silent gap in the output of a monaural temporal window integrating
      intensity. The equivalent rectangular duration (ERD) of the binaural window was
      used as an index of binaural temporal resolution. In order to derive the ERD,
      both the shortest-detectable binaural gap and the jnd for a reduction in
      interaural correlation from unity were measured. In experiment 1, binaural-gap
      thresholds were measured using narrow-band noise carriers as a function of center
      frequency from 250 to 2000 Hz (fixed 100-Hz bandwidth) and a function of lower
      cutoff frequency from 100 to 400 Hz (fixed 500-Hz upper-cutoff frequency).
      Binaural-gap thresholds (1) increased significantly with increasing frequency in
      both tasks, and (2) at frequencies below 500 Hz, were shorter than corresponding
      silent-gap thresholds measured with the same N0 noises. In experiment 2,
      interaural-correlation jnd's were measured for the same conditions. The jnd's
      also increased significantly with increasing frequency. The results were analyzed
      using a temporal window integrating the output of a computational model of
      binaural processing. The ERD of the window varied widely across listeners, with a
      mean value of 140 ms, and did not significantly depend on frequency. This
      duration is about an order of magnitude longer than the ERD of the monaural
      temporal window and is, therefore, consistent with "binaural sluggishness."

PMID- 10335633
TI  - Sensitivity of human subjects to head-related transfer-function phase spectra.
AB  - Head-related transfer functions (HRTFs) for human subjects in anechoic space were
      modeled with modified phase spectra, including minimum-phase-plus-delay, linear
      phase, and reversed-phase-plus-delay functions. The overall (wide-band)
      interaural time delay (ITD) for the modeled HRTFs was made consistent with that
      of the empirical HRTFs by setting the position-dependent, frequency-independent
      delay in the HRTF for the lagging ear. Signal analysis of the minimum-phase-plus
      delay reconstructions indicated that model HRTFs deviate from empirical HRTF
      measurements maximally for contralateral azimuths and low elevations. Subjects
      assessed the perceptual validity of the model HRTFs in a four-interval, two
      alternative, forced-choice discrimination paradigm. Results indicate that
      monaural discrimination performance of subjects was at chance for all three types
      of HRTF models. Binaural discrimination performance was at chance for the linear
      phase HRTFs, was above chance for some locations for the minimum-phase-plus-delay
      HRTFs, and was above chance for all tested locations for the reversed-phase-plus
      delay HRTFs. An analysis of low-frequency timing information showed that all of
      these results are consistent with efficient use of interaural time differences in
      the low-frequency components of the stimulus waveforms. It is concluded that
      listeners are insensitive to HRTF phase spectra as long as the overall ITD of the
      low-frequency components does not provide a reliable cue. In particular, the
      minimum-phase-plus-delay approximation to the HRTF phase spectrum is an adequate
      approximation as long as the low-frequency ITD is appropriate. These results and
      conclusions are all limited to the anechoic case when the HRTFs correspond to
      brief impulse responses limited to a few milliseconds.

PMID- 10335634
TI  - Resolution of front-back ambiguity in spatial hearing by listener and source
      movement.
AB  - Normally, the apparent position of a sound source corresponds closely to its
      actual position. However, in some experimental situations listeners make large
      errors, such as indicating that a source in the frontal hemifield appears to be
      in the rear hemifield, or vice versa. These front-back confusions are thought to
      be a result of the inherent ambiguity of the primary interaural difference cues,
      interaural time difference (ITD) in particular. A given ITD could have been
      produced by a sound source anywhere on the so-called "cone of confusion." More
      than 50 years ago Wallach [J. Exp. Psychol. 27, 339-368 (1940)] argued that small
      head movements could provide the information necessary to resolve the ambiguity.
      The direction of the change in ITD that accompanies a head rotation is an
      unambiguous indicator of the proper hemifield. The experiments reported here are
      a modern test of Wallach's hypothesis. Listeners indicated the apparent positions
      of real and virtual sound sources in conditions in which head movements were
      either restricted or encouraged. The front-back confusions made in the restricted
      condition nearly disappeared in the condition in which head movements were
      encouraged. In a second experiment head movements were restricted, but the sound
      source was moved, either by the experimenter or by the listener. Only when the
      listener moved the sound source did front-back confusions disappear. The results
      clearly support Wallach's hypothesis and suggest further that head movements are
      not required to produce the dynamic cues needed to resolve front-back ambiguity.

PMID- 10335635
TI  - Articulatory tradeoffs reduce acoustic variability during American English /r/
      production.
AB  - The American English phoneme /r/ has long been associated with large amounts of
      articulatory variability during production. This paper investigates the
      hypothesis that the articulatory variations used by a speaker to produce /r/ in
      different contexts exhibit systematic tradeoffs, or articulatory trading
      relations, that act to maintain a relatively stable acoustic signal despite the
      large variations in vocal tract shape. Acoustic and articulatory recordings were
      collected from seven speakers producing /r/ in five phonetic contexts. For every
      speaker, the different articulator configurations used to produce /r/ in the
      different phonetic contexts showed systematic tradeoffs, as evidenced by
      significant correlations between the positions of transducers mounted on the
      tongue. Analysis of acoustic and articulatory variabilities revealed that these
      tradeoffs act to reduce acoustic variability, thus allowing relatively large
      contextual variations in vocal tract shape for /r/ without seriously degrading
      the primary acoustic cue. Furthermore, some subjects appeared to use completely
      different articulatory gestures to produce /r/ in different phonetic contexts.
      When viewed in light of current models of speech movement control, these results
      appear to favor models that utilize an acoustic or auditory target for each
      phoneme over models that utilize a vocal tract shape target for each phoneme.

PMID- 10335636
TI  - Perturbation-free measurement of the harmonics-to-noise ratio in voice signals
      using pitch synchronous harmonic analysis.
AB  - The measurement of the harmonics-to-noise ratio (HNR) in speech signals gives an
      indication of the aperiodicity of the speech waveform. This may be due to the
      presence of jitter, shimmer, additive noise, waveshape change, or some unknown
      combination of these factors. In order to estimate the HNR as a measure of the
      additive noise component only, the contaminating effects of the other
      contributory components must first be removed. A pitch synchronous harmonic
      analysis is proposed to overcome this problem. The procedure takes advantage of
      the time scale compression-frequency expansion property of the Fourier series in
      order to eliminate jitter and shimmer. Successive spectra are added by harmonic
      number as opposed to frequency location, and perturbation is removed due to the
      fact that the relative heights of the harmonic components remain the same for
      scaled signals. The technique is examined on synthetically generated voice
      signals. A discussion of the results is given in terms of human voice signals,
      characterization of jitter, vocal tract filtering effects, perturbation
      mechanisms, nonlinear dynamics, and the possibility of developing the method for
      use with inverse filtering strategies.

PMID- 10335637
TI  - Influences of pellet markers on speech production behavior: acoustical and
      perceptual measures.
AB  - Peri- and intraoral devices are often used to obtain measurements concerning
      articulator motions and placements. Surprisingly, there are few formal
      evaluations of the potential influence of these devices on speech production
      behavior. In particular, the potential effects of lingual pellets or coils used
      in x-ray or electromagnetic studies of tongue motion have never been evaluated
      formally, even though a large x-ray database exists and electromagnetic systems
      are commercially available. The x-ray microbeam database [Westbury, J. "X-ray
      Microbeam Speech Production Database User's Handbook, version 1" (1994)] includes
      several utterances produced with pellets-off and -on, which allowed us to
      evaluate effects of pellets for the utterance, She had your dark suit in greasy
      wash water all year, using acoustic and perceptual measures. Overall, there were
      no acoustic or perceptual measures that showed consistent effects of pellets
      across speakers, but certain effects were consistent either within a given
      speaker or in direction across a subgroup of the speakers. The results are
      discussed in terms of the general goodness of the assumption that point
      parameterization of lingual motion does not interfere with normal articulatory
      behaviors. A brief screening procedure is suggested to protect articulatory
      kinematic experiments from those individuals who may show consistent effects of
      having devices placed on perioral structures.

PMID- 10335638
TI  - Measuring the threshold for speech reception by adaptive variation of the signal
      bandwidth. I. Normal-hearing listeners.
AB  - An adaptive test has been developed to determine the minimum bandwidth of speech
      that a listener needs to reach 50% intelligibility. Measuring this speech
      reception bandwidth threshold (SRBT), in addition to the more common speech
      reception threshold (SRT) in noise, may be useful in investigating the factors
      underlying impaired suprathreshold speech perception. Speech was bandpass
      filtered (center frequency: 1 kHz) and complementary bandstop filtered noise was
      added. To obtain reference values, the SRBT was measured in 12 normal-hearing
      listeners at four sound-pressure levels, in combination with three overall
      spectral tilts. Plotting SRBT as a function of sound-pressure level resulted in U
      shaped curves. The most narrow SRBT (1.4 octave) was obtained at an A-weighted
      sound-pressure level of 55 dB. The required bandwidth increases with increasing
      level, probably due to upward spread of masking. At a lower level (40 dBA)
      listeners also need a broader band, because parts of the speech signal will be
      below threshold. The SII (Speech Intelligibility Index) model reasonably predicts
      the data, although it seems to underestimate upward spread of masking.

PMID- 10335639
TI  - Compression and expansion of the temporal envelope: evaluation of speech
      intelligibility and sound quality.
AB  - Sensorineural hearing loss is accompanied by loudness recruitment, a steeper-than
      normal rise of perceived loudness with presentation level. To compensate for this
      abnormality, amplitude compression is often applied (e.g., in a hearing aid).
      Alternatively, since speech intelligibility has been modeled as the perception of
      fast energy fluctuations, enlarging these (by means of expansion) may improve
      speech intelligibility. Still, even if these signal-processing techniques prove
      useful in terms of speech intelligibility, practical application might be
      hindered by unacceptably low sound quality. Therefore, both speech
      intelligibility and sound quality were evaluated for syllabic compression and
      expansion of the temporal envelope. Speech intelligibility was evaluated with an
      adaptive procedure, based on short everyday sentences either in noise or with a
      competing speaker. Sound quality was measured by means of a rating-scale
      procedure, for both speech and music. In a systematic setup, both the ratio of
      compression or expansion and the number of independent processing bands were
      varied. Individual hearing thresholds were compensated for by a listener-specific
      filter and amplification. Both listeners with normal hearing and listeners with
      sensorineural hearing impairment participated as paid volunteers. The results
      show that, on average, both compression and expansion fail to show better speech
      intelligibility or sound quality than linear amplification.

PMID- 10335640
TI  - Time-delay estimation of reverberated speech exploiting harmonic structure.
AB  - The relative time delay associated with a speech signal received at a pair of
      spatially separated microphones is a key component in talker localization and
      microphone array beamforming procedures. The traditional method for estimating
      this parameter utilizes the generalized cross correlation (GCC), the performance
      of which is compromised by the presence of room reverberations and background
      noise. Typically, the GCC filtering criteria used are either focused on the
      signal degradations due to additive noise or those due exclusively to multipath
      channel effects. There has been relatively little success at applying GCC
      weighting schemes which are robust to both of these conditions. This paper
      details an alternative approach which attempts to employ a signal-dependent
      criterion, namely, the estimated periodicity of the speech signal, to design a
      GCC filter appropriate for the combination of noise and multipath distortions.
      Simulations are performed across a range of room conditions to illustrate the
      utility of the proposed time-delay estimation method relative to conventional GCC
      filtering approaches.

PMID- 10335641
TI  - An acoustical study of sound production in biphonic singing, Xoomij.
AB  - A theory that the high melody pitch of biphonic singing, Xoomij, is produced by
      the pipe resonance of the rear cavity in the vocal tract is proposed. The front
      cavity resonance is not critical to the production of the melody pitch. This
      theory is derived from acoustic investigations on several three-dimensional
      shapes of a Xoomij singer's vocal tract measured by magnetic resonance imaging.
      Four different shapes of the vocal tract are examined, with which the melody
      pitches of F6, G6, A6, and C7 are sung, along with the F3 drone of a specific
      pressed voice. The second formant frequency calculated from each tract shape is
      close to the melody pitch within an error of 36 cents. Sounds are synthesized by
      convolving a glottal source waveform provided by the Rosenberg model with
      transfer functions calculated from the vocal tract shapes. Two pitches are found
      to be successfully perceived when the synthesized sounds are listened to. In a
      frequency range below 2 kHz, their spectra have a strong resemblance to those of
      the sounds actually sung. The synthesized sounds, however, fail to replicate the
      harmonic clustering at 4-5 kHz observed in the actual sounds. This is speculated
      to originate from the glottal source specific to the "pressed" timbre of the
      drone.

PMID- 10335642
TI  - Messa di voce: an investigation of the symmetry of crescendo and decrescendo in a
      singing exercise.
AB  - A classical vocal exercise called "messa di voce" (Italian for "placing the
      voice") was used to study the symmetry of intensity increase and decrease in six
      trained singers. Ideally, the exercise is performed as a symmetric triangle, a
      linear increase in loudness, followed by a linear decrease. Given that some
      physiologic variables, like lung volume, undergo unidirectional change rather
      than a symmetric reversal, there is reason to believe that symmetries may not
      exist. It was found that highly trained singers who use large SPL ranges tend to
      abbreviate the decrescendo phase in comparison with the crescendo phase. In a few
      other cases, a plateau in SPL is reached, but an increase in loudness may still
      be perceived on the basis of a stronger vibrato or changes in timbre.

PMID- 10335643
TI  - A solution to diffraction biases in sonoelasticity: the acoustic impulse
      technique.
AB  - Several methods have been proposed to estimate the viscoelastic properties of
      soft biological tissues using forced low-frequency vibrations (10-500 Hz). Those
      methods are based on the measurement of phase velocity of the shear waves
      (approximately 5 m/s). It is shown in this article that the measurements of
      velocity as well as attenuation are subjected to biases. These biases are related
      to reflected waves created at boundaries, to the nonnegligible size of the piston
      source which causes diffraction effects and to the influence of a low-frequency
      compressional wave. Indeed, a theoretical analysis of the field radiated by a
      point source explains how mechanical vibrations of a piston generate a shear wave
      with a longitudinal component and how this component can interfere with a low
      frequency compressional wave. However, by using a low-frequency transient
      excitation, these biases can be avoided. Then the precise numerical values of
      elasticity and viscosity can be deduced. Experiments in phantoms and beef muscles
      are shown. Moreover, a relative hardness imaging of a phantom composed of two
      media with different elasticities is presented.

PMID- 10335644
TI  - Ultrasound-induced cell lysis and sonoporation enhanced by contrast agents.
AB  - The enhancement of ultrasound-induced cell destruction, lysis, and sonoporation
      in low cell concentration suspensions (2 x 10(5)/mL) by the presence of contrast
      agents (gas bubble to cell ratio = 230) was demonstrated using cervical cancer
      cells (HeLa S3) suspensions containing micron-size denatured albumin microspheres
      filled with air (Albunex) or octafluoropropane (Optison). The suspensions were
      insonificated by 2-MHz continuous or tone burst ultrasound in near field. The
      spatial peak-pressure amplitude was 0.2 MPa. The enhancement of cell destruction
      due to Optison was shown to be much higher than that due to Albunex for similar
      bubble concentration and ultrasound conditions. For tone burst exposures,
      significant lysis and sonoporation only occurred in the presence of a contrast
      agent. The majority of the bioeffects observed occurred in the first 5 min of
      exposure. The relationship between the enhancement of bioeffects and duty cycle
      of tone burst ultrasound appears to indicate that both stable gas spheres of
      contrast agents and cavitation nuclei created by the disruption of the gas
      spheres play a significant role in causing the bioeffects.

PMID- 10335645
TI  - Acoustic flow perception in cf-bats: properties of the available cues.
AB  - Signal design in cf-bats is hypothesized to be commensurate with the evaluation
      of time-variant echo parameters, imposed by changes in the sound channel
      occurring as the bat flies by a target. Two such parameters, the proportional
      changes in Doppler frequency and sound pressure amplitude, are surveyed,
      employing a simplified acoustic model in order to assess their fitness for target
      localization given a translational movement within a plane. This is accomplished
      by considering the properties of the scalar fields given by the value of these
      putative sensory variables as a function of position in a plane. The considered
      criteria are: existence and extent of ambiguity areas (i.e., multiple solutions
      for target position), magnitude of the variables (relevant with regard to
      perceptual thresholds), as well as magnitude and orthogonality of the gradients
      (relevant to localization accuracy). It is concluded that these properties render
      the considered variables compatible with gross judgements of target position.
      This may be sufficient for behavioral contexts like obstacle avoidance, where
      adoption of suitable safety margins could compensate for the variance and bias
      associated with estimates of target location.

PMID- 10335646
TI  - Computer models for masked hearing experiments with beluga whales (Delphinapterus
      leucas).
AB  - Environmental assessments of manmade noise and its effects on marine mammals need
      to address the question of how noise interferes with animal vocalizations.
      Seeking the answer with animal experiments is very time consuming, costly, and
      often infeasible. This article examines the possibility of estimating results
      with software models. A matched filter, spectrogram cross-correlation, critical
      band cross-correlation, and a back-propagation neural network detected a beluga
      vocalization in three types of ocean noise. Performance was compared to masked
      hearing experiments with a beluga whale [C. Erbe and D. M. Farmer, Deep-Sea Res.
      II 45, 1373-1388 (1998)]. The artificial neural network simulated the animal data
      most closely and raised confidence in its ability to predict the interference of
      a variety of noise source with a variety of vocalizations.

PMID- 10335647
TI  - Abstract exercises in cochlear modeling: reply to "What should be the goals of
      cochlear modeling?" [J. Acoust. Soc. Am. 102, 3054 (1997)].

PMID- 10335648
TI  - On solution techniques for cochlear models: reply to "Comments on 'a method for
      forward and inverse solutions of a three-dimensional model of the cochlea'" [J.
      Acoust. Soc. Am. 103, 3729 (1998)].

PMID- 10335649
TI  - Discrimination of amplitude-modulation phase spectrum.

PMID- 10335650
TI  - FDTD simulation of finite-amplitude pressure and temperature fields for
      biomedical ultrasound.
AB  - Full wave simulations provide a valuable tool for studying the spatial and
      temporal nature of an acoustic field. One method for producing such simulations
      is the finite-difference time-domain (FDTD) method. This method uses discrete
      differences to approximate derivatives in the governing partial differential
      equations. We used the FDTD method to model the propagation of finite-amplitude
      sound in a homogeneous thermoviscous fluid. The calculated acoustic pressure
      field was then used to compute the transient temperature rise in the fluid; the
      heating results from absorption of acoustic energy by the fluid. As an example,
      the transient temperature field was calculated in biological tissue in response
      to a pulse of focused ultrasound. Enhanced heating of the tissue from finite
      amplitude effects was observed. The excess heating was attributed to the
      nonlinear generation of higher-frequency harmonics which are absorbed more
      readily than the fundamental. The effect of nonlinear distortion on temperature
      rise in tissue was observed to range from negligible at 1 MPa source pressure to
      an 80% increase in temperature elevation at 10 MPa source pressure.

PMID- 10335651
TI  - Molecular evolution of the nuclear von Willebrand factor gene in mammals and the
      phylogeny of rodents.
AB  - Nucleotide sequences of exon 28 of the von Willebrand Factor (vWF) were analyzed
      for a representative sampling of rodent families and eutherian orders, with one
      marsupial sequence as outgroup. The aim of this study was to test if inclusion of
      an increased taxonomic diversity in molecular analyses would shed light on three
      uncertainties concerning rodent phylogeny: (1) relationships between rodent
      families, (2) Rodentia monophyly, and (3) the sister group relationship of
      rodents and lagomorphs. The results did not give evidence of any particular
      rodent pattern of molecular evolution relative to a general eutherian pattern.
      Base compositions and rates of evolution of vWF sequences of rodents were in the
      range of placental variation. The 10 rodent families studied here cluster in five
      clades: Hystricognathi, Sciuridae and Aplodontidae (Sciuroidea), Muridae,
      Dipodidae, and Gliridae. Among hystricognaths, the following conclusions are
      drawn: a single colonization event in South America by Caviomorpha, a paraphyly
      of Old World and New World porcupines, and an African origin for Old World
      porcupines. Despite a broader taxonomic sampling diversity, we did not obtain a
      robust answer to the question of Rodentia monophyly, but in the absence of any
      other alternative, we cannot reject the hypothesis of a single origin of rodents.
      Moreover, the phylogenetic position of Lagomorpha remains totally unsettled.

PMID- 10335652
TI  - Correct and incorrect vertebrate phylogenies obtained by the entire mitochondrial
      DNA sequences.
AB  - Concatenated sequences of all protein-coding genes in mitochondria recovered a
      known phylogeny of 11 vertebrate species correctly with statistical significance.
      However, when it was rooted by lampreys or sea urchins, the root of the
      vertebrate tree was placed between the mammal cluster and the chicken-frog-fish
      cluster or between the mammal-chicken cluster and the frog-fish cluster,
      depending on the tree-making method used. Although the frog-fish or chicken-frog
      fish cluster was biologically incorrect, it was again supported with a
      significantly high bootstrap value. In this study, we investigated the reasons
      why this happened. It has been suggested that an incorrect phylogeny may be
      constructed due to a change of amino acid composition in different lineages or
      due to homoplasies at sites with hydrophobic amino acids. However, our results
      indicated that these were not the causes of the incorrect rooting of the
      vertebrate tree. Rather, it was important to take into account an extensive rate
      variation across sites and different probabilities of substitution among
      different amino acids. The substitution rates for mitochondrial sequences vary
      considerably for different vertebrate lineages. In such a case, it is known to be
      important to use the model that reflects the actual substitution probability to
      obtain a correct tree topology. The correct rooting of the vertebrate tree was
      recovered when rate variation across sites was properly accounted for.

PMID- 10335653
TI  - Distribution of dinucleotide microsatellites in the Drosophila melanogaster
      genome.
AB  - Microsatellites, a special class of repetitive DNA, have become one of the most
      popular genetic markers. The progress of various genome projects has made it
      possible to study the genomic distribution of microsatellites and to evaluate the
      potential influence of several parameters on their genesis. We report the
      distribution of dinucleotide microsatellites in the genome of Drosophila
      melanogaster. When considering only microsatellites with five or more repeat
      units, the average length of dinucleotide repeats in D. melanogaster is 6.7
      repeats. We tested a wide range of parameters which could potentially influence
      microsatellite density, and we did not detect a significant influence of
      recombination rate, number of exons, or total length of coding sequence. In
      concordance with the neutral expectation for the origin of microsatellites, a
      significant positive correlation between AT content and (AT/TA)n microsatellite
      density was detected. While this pattern may indicate that microsatellite genesis
      is a random process, we also found evidence for a nonrandom distribution of
      microsatellites. Average microsatellite density was higher on the X chromosome,
      but extreme heterogeneity was observed between different genomic regions. Such a
      clumping of microsatellites was also evident on a more local scale, as 38.9% of
      the contiguous sequences analyzed showed a deviation from a random distribution
      of microsatellites.

PMID- 10335654
TI  - Molecular genetic diversity and evolution at the MHC DQB locus in four species of
      pinnipeds.
AB  - Variation was investigated at exon 2 (including part of the putative peptide
      binding region) of the class II major histocompatibility complex (MHC) DQB locus
      for two congeneric phocid seal species and two congeneric otariid seal species.
      Polymorphism in one phocid species, the southern elephant seal (Mirounga
      leonina), was comparable to that seen in human populations, while the other
      phocid, the northern elephant seal (Mirounga angustirostris), has been through a
      severe population bottleneck and exhibited much less variation at this locus. A
      phylogenetic comparison of the four species was consistent with the trans
      specific pattern of evolution described for other taxa at this locus, and
      relative nonsynonymous and synonymous substitution rates suggest the maintenance
      of polymorphisms by natural selection. A comparison of sequence patterns also
      suggested that some variation could have been generated through recombinational
      events, primarily within genera. These results suggest a pattern of evolution of
      the immune response in pinnipeds similar to that in terrestrial mammal species.

PMID- 10335656
TI  - Biased amino acid composition in repeat regions of Plasmodium antigens.
AB  - Many malarial antigens contain extensive arrays of tandemly repeated short amino
      acid sequences, and much of the antibody response induced by malaria infections
      is directed against these repeats. Indeed, it has been hypothesized that these
      repeats function to elicit a relatively ineffective T-cell-independent antibody
      response by the host. In order to test this hypothesis, tandem repeats of
      Plasmodium species were examined for a bias in composition favoring amino acids
      likely to form epitopes for the antibody. The genome of Plasmodium is very A+T
      rich, and nucleotide compositional bias will, in itself, lead to a high
      proportion of hydrophilic amino acids. When this bias was controlled for,
      Plasmodium antigens did not show a higher proportion of hydrophilic amino acids
      than expected, but there was a significant reduction in the proportion of
      hydrophobic amino acids in the repeats of the antigens. The amino acid
      composition of the repeats was thus strikingly different from those seen both in
      the remainder of the antigens and in a sample of Plasmodium falciparum
      housekeeping genes.

PMID- 10335655
TI  - Molecular evolution of the COX7A gene family in primates.
AB  - COX VIIa is one of 10 nuclear-encoded subunits of the COX holoenzyme, and one of
      three that have isoforms with tissue-specific differences in expression. Analysis
      of nucleotide substitution rates revealed an accelerated rate of nonsynonymous
      substitutions relative to that of synonymous substitutions for the heart isoform
      gene (COX7AH) in six primate lineages. Rate accelerations have been noted for
      four other COX-related genes in this time period, suggesting that the COX
      holoenzyme has experienced an episode of adaptive evolution. A third member of
      the gene family, COX7AR, has recently been described. Although its function is
      currently unknown, low nonsynonymous substitution/synonymous substitution (N/S)
      ratios in mammalian evolution suggest that COX7AR is of functional importance.
      When the COX7A isoforms were divided into domains, examination of nucleotide
      substitution rates suggested that mitochondrial targeting residues experienced an
      accelerated nonsynonymous substitution rate in the period following gene
      duplication. In contrast, paralogous comparisons of the targeting residues of
      each isoform show they have been relatively conserved in mammalian evolution.
      This pattern is consistent with the evolution of tissue-specific function.

PMID- 10335657
TI  - Molecular characterization and phylogenetic analysis of SpBMP5-7, a new member of
      the TGF-beta superfamily expressed in sea urchin embryos.
AB  - TGF-beta ligands are probably pan-bilaterian in phylogenetic distribution. The
      family appears to have diversified greatly with the evolution of the vertebrates,
      but only a few invertebrate deuterostome TGF-beta molecules have so far been
      isolated. A search for members of this family expressed in sea urchin embryos,
      using canonical PCR primers, revealed a single-copy gene encoding a new TGF-beta
      protein. The sequence which it encodes is closely related to those of vertebrate
      bone morphogenetic proteins (BMPs) 5-7. No additional TGF-beta family members
      were uncovered other than univin, which had previously been reported.

PMID- 10335658
TI  - Evolution of the ascidian anural larva: evidence from embryos and molecules.
AB  - Most ascidians pass through a tadpole (urodele) larval stage, although some
      species have derived a tailless (anural) larva. New insights into the evolution
      of anural larvae in the Roscovita clade of molgulid ascidians were obtained from
      studing embryonic development of the transitional anural species Molgula bleizi
      and from phylogenetic analysis based on muscle and cytoskeletal actin gene
      sequences. By observing in vitro fertilized eggs, we found that M. bleizi,
      previously described as a typical anural developer, actually forms a short
      immotile tail during embryogenesis. The short tail contains notochord lineage
      cells, which undergo abbreviated morphogenetic movements but eventually arrest in
      development. Molgula bleizi tail muscle lineage cells produce the muscle enzyme
      acetylcholinesterase (AChE) but do not express muscle actin genes. The presence
      of a short tail, a vestigial notochord, and AChE-positive muscle cells suggest
      that M. bleizi is a recently derived anural species. An M. bleizi larval muscle
      actin gene (MbMA1) was isolated, sequenced, and shown to be a pseudogene based on
      critical deletions in its coding region that would result in a nonfunctional
      actin protein. The mutations in MbMA1 are distinct from and have evolved
      independent of the larval muscle actin pseudogenes MoccMA1a and MoccMA1b in
      Molgula occulta, another anural developer in the Roscovita clade. Pseudogene
      formation explains the absence of muscle actin mRNA in M. bleizi embryos. The 3'
      untranslated region of an M. bleizi cytoskeletal actin gene was also isolated and
      sequenced. Phylogenetic trees reconstructed using muscle and cytoskeletal actin
      sequences suggest that the anural developer M. bleizi evolved prior to the
      divergence of the urodele developer Molgula oculata and the anural developer M.
      occulta in the Roscovita clade. Since M. bleizi lives attached to hard substrata
      in the tidal zone, whereas M. oculata and M. occulta live buried in subtidal sand
      flats, our results suggest that the anural larva evolved at least twice in the
      Roscovita clade of molgulid ascidians as an adaptation to different habitats.

PMID- 10335659
TI  - Interspecies transfer of female mitochondrial DNA is coupled with role-reversals
      and departure from neutrality in the mussel Mytilus trossulus.
AB  - Mussels of the genus Mytilus have distinct and highly diverged male and female
      mitochondrial DNA (mtDNA) genomes with separate routes of inheritance. Previous
      studies of European populations of Mytilus trossulus demonstrated that 33% of
      males are heteroplasmic for a second mtDNA genome of increased length and that
      hybridization with Mytilus edulis does not block mtDNA introgression, in contrast
      to reports for American populations. Here, we demonstrate that the female mtDNA
      type of M. edulis has replaced the resident female mtDNA type of European M.
      trossulus. This is supported by COIII sequence data indicating that the female
      mtDNA of European M. trossulus is very similar to that of M. edulis and that in
      phylogenetic trees, the mtDNAs of these two species cluster together but
      separately from American M. trossulus sequences, the latter not being disturbed
      by introgressive hybridization. We also provide evidence that the mtDNA genome of
      increased length found in heteroplasmic males of European M. trossulus derives
      from a recent partition of an introgressed M. edulis female type into the male
      route of transmission. Neutrality tests reveal that European populations of M.
      trossulus display an excess of replacement polymorphism within the female mtDNA
      type with respect to conspecific American populations, as well as a significant
      excess of rare variants, of a similar magnitude to those previously reported for
      the invading European M. edulis mtDNA. Results are consistent with a nearly
      neutral model of molecular evolution and suggest that selection acting on
      European M. trossulus mtDNA is largely independent of the nuclear genetic
      background.

PMID- 10335660
TI  - G+C content variation along and among Saccharomyces cerevisiae chromosomes.
AB  - Past analyses of the genome of the yeast Saccharomyces cerevisiae have revealed
      substantial regional variation in G+C content. Important questions remain,
      though, as to the origin, nature, significance, and generality of this variation.
      We conducted an extensive analysis of the yeast genome to try to answer these
      questions. Our results indicate that open reading frames (ORFs) with similar G+C
      contents at silent codon positions are significantly clustered on chromosomes.
      This clustering can be explained by very short range correlations of silent-site
      G+C contents at neighboring ORFs. ORFs of high silent-site G+C content are
      disproportionately concentrated on shorter chromosomes, which causes a negative
      relationship between chromosome length and G+C content. Contrary to previous
      reports, there is no correlation between gene density and silent-site G+C content
      in yeast. Chromosome III is atypical in many regards, and possible reasons for
      this are discussed.

PMID- 10335661
TI  - Microevolution of the mitochondrial DNA control region in the Japanese brown bear
      (Ursus arctos) population.
AB  - We investigated nucleotide sequences of the mitochondrial DNA control region to
      describe natural genetic variations and to assess the relationships between
      subpopulations of the brown bear Ursus arctos on Hokkaido Island, Japan. Using
      the polymerase chain reaction product-direct sequencing technique, partial
      sequences (about 930 bases) of the control region were determined for 56 brown
      bears sampled throughout Hokkaido Island. A sequence alignment revealed that the
      brown bear control region included a variable sequence on the 5' side and a
      repetitive region on the 3' side. Phylogenetic trees reconstructed from the 5'
      variable region (696-702 bases) exhibited 17 haplotypes, which were clustered
      into three groups (Clusters A, B, and C). The distribution of each group did not
      overlap with those of the others, and the three different areas were located in
      separate mountainous forests of Hokkaido Island. Furthermore, most of the
      phylogenetically close haplotypes within each group were distributed
      geographically close to each other. In addition, the 3' repetitive region (arrays
      of 10 bases) exhibited a much faster mutation rate than the 5' variable region,
      resulting in heteroplasmy. Such mitochondrial DNA divergence in each group could
      have occurred after the brown bears migrated from the continent to Hokkaido and
      became fixed in the different areas.

PMID- 10335662
TI  - Rapid evolution of a primate sperm protein: relaxation of functional constraint
      or positive Darwinian selection?
AB  - Protamines are arginine-rich proteins that replace histones and bind sperm DNA
      during spermatogenesis in vertebrates. Previous studies have shown that protamine
      exons evolve faster than does the protamine intron. It has been suggested that
      this is a result of a relaxation of functional constraint. However, a more likely
      explanation is that the evolutionary rate of exons has been accelerated by
      positive Darwinian selection, because introns are generally believed to evolve in
      a neutral fashion. Therefore, we examined the possibility that positive selection
      has been acting on the protamine genes of three groups of placental mammals:
      primates (hominoids and Old World monkeys), rodents (mice, rats, and guinea
      pigs), and pecoran ruminants (deer and bovids). We found that the nucleotide
      substitution rate at nonsynonymous sites is significantly higher than the rate at
      synonymous and intron sites for protamine P1 of hominoids and Old World monkeys.
      This result suggests that positive selection has been operating on protamine P1
      of these species. In contrast, no clear-cut evidence of positive selection was
      found for protamine P1 of ruminants and rodents or protamine P2 of primates. The
      agent of positive selection on primate protamine P1 remains unknown, though sperm
      competition is a possibility. Further investigations on the function and
      intraspecific polymorphism of this protein are needed in order to identify the
      selection agent.

PMID- 10335663
TI  - Changes in ds/dn in the HIV-1 env gene.

PMID- 10335664
TI  - The evolutionary position of dormice (Gliridae) in Rodentia determined by a novel
      short retroposon.

PMID- 10335666
TI  - Psychoses in the elderly: a spectrum of disorders.
AB  - The incidence of psychoses increases with age with a number of factors leading to
      the increase in vulnerability and expression. They include comorbid physical
      illnesses, social isolation, sensory deficits, cognitive changes, polypharmacy,
      and substance abuse. Agitation and aggressiveness are also associated with
      psychosis in the elderly and frequently are the precipitating reasons for
      psychiatric consultation. A review of psychoses in the elderly must, therefore,
      consider psychotic symptoms within the context of the underlying etiologies of
      the psychotic symptoms. Elderly patients who present with psychotic symptoms
      require social, behavioral, and environmental interventions that are necessary
      for their safety and orientation. Given the likelihood of comorbid medical
      disorders and concomitant medications, the mere presence of delusions or
      hallucinations is not always an indication for additional medications. However,
      some patients may need pharmacologic intervention in order to manage the
      behavioral disturbance that often results from the psychotic symptoms. The
      atypical antipsychotics with their low propensity to produce extrapyramidal and
      cognitive side effects have greatly advanced the pharmacotherapy for elderly
      patients with psychoses.

PMID- 10335667
TI  - Treatment of agitation in dementia.
AB  - Behavioral and psychological signs and symptoms associated with dementia are
      common and often confusing because they do not meet criteria for typical discrete
      psychiatric disorders. Although the symptoms tend to occur in clusters, the
      clusters often vary with time and between patients. Recognizing the behavioral
      pathology associated with dementia is important because it can be distressing to
      the patient, lead to dangerous interactions with others or the environment, and
      result in the use of inappropriate psychotropic medications. A practical, general
      approach to the evaluation and management of agitation in dementia for
      psychiatric consultants confronted with such problems is proposed.

PMID- 10335668
TI  - Antipsychotics from theory to practice: integrating clinical and basic data.
AB  - The recent introduction of the atypical antipsychotics into the treatment arena
      for psychoses and related disorders comes with justifiable excitement. These
      newer antipsychotics offer several clinical benefits over the conventional
      antipsychotics, which have been the mainstays of care thus far. The primary
      advantage of these atypical agents is their superior side effect profiles,
      particularly with regard to extrapyramidal side effects (EPS). The implications
      from a reduction in EPS touch on virtually every aspect of pathology in
      schizophrenic illness, including short- and long-term movement disorders,
      negative symptoms, noncompliance, cognitive dysfunction, and dysphoria. It should
      be emphasized that while atypical antipsychotics share many clinical attributes,
      there are also substantial differences among them. This review will examine the
      pharmacology, clinical efficacy, and side effect profiles of the atypical
      antipsychotics and attempt to relate the attributes observed in clinical practice
      and clinical trials to their basic pharmacologic profiles. There is a fair, but
      not perfect, correspondence between the pharmacologic profiles of the different
      atypical antipsychotics and their respective clinical attributes. After a
      comparative overview of their receptor-binding profiles, a brief pharmacokinetic
      summary will be provided. Finally, the clinical profiles of these agents will be
      summarized with regard to both their efficacy and adverse effects.

PMID- 10335669
TI  - The efficacy, safety, and tolerability of antipsychotics in the elderly.
AB  - Antipsychotic medications are among the most widely prescribed class of
      medications for elderly patients. Despite their high use, few studies document
      the efficacy, safety, and tolerability of these agents in this patient
      population. This is unfortunate because, as a group, the elderly are
      exceptionally sensitive to the adverse effects associated with antipsychotics, in
      particular, the extrapyramidal side effects (EPS). The atypical antipsychotics
      with their lower propensity to cause EPS and lower need for augmenting
      anticholinergic medication have introduced new options for elderly patients who
      need antipsychotic therapy for a number of psychiatric and neurologic disorders
      with psychotic manifestations. This review covers the pharmacologic, clinical,
      and regulatory issues involving antipsychotic use in elderly patients that
      warrant consideration by the practicing psychiatrist.

PMID- 10335670
TI  - Management of psychotic aspects of Parkinson's disease.
AB  - Psychotic symptoms have become increasingly common in patients with idiopathic
      Parkinson's disease and other parkinsonian syndromes. This increased prevalence
      of psychoses is in part a reflection of the greater longevity of people with
      Parkinson's disease and, to a certain extent, is a consequence of our success in
      treating the motor symptoms of these syndromes. The psychotic symptoms associated
      with Parkinson's disease can be as varied as the motor symptoms. They stem from
      interactions between the underlying neuropathologies of the syndromes and the
      adverse effects associated with chronic antiparkinsonian drug administration. In
      patients with advanced Parkinson's disease, there is also a high prevalence of
      affective comorbidity. This increase in affective symptoms and the relatively
      high incidence of cognitive and affective side effects of the antiparkinsonian
      medications contribute to the increase in psychoses observed in these older
      patients. The most significant risk factors for developing psychosis in
      Parkinson's disease are (1) coexistence of dementia, (2) protracted sleep
      disturbances, and (3) nighttime use of long-acting dopaminomimetics. This article
      reviews the phenomenology, pathophysiology, and treatment of psychosis associated
      with parkinsonism and discusses how atypical antipsychotic medications have
      revolutionized the management of the symptoms and improved the quality of life of
      those affected.

PMID- 10335671
TI  - Pharmacologic management of psychosis in dementia.
AB  - Significant consequences of untreated psychosis in patients with dementia have
      led clinicians to seek improved therapeutic options. This review presents the
      scope of the problem, discusses some of the underlying neurobiology, and
      highlights the evidence for appropriate therapies. A range of potentially
      effective pharmacologic therapies is available and is discussed.

PMID- 10335673
TI  - The history, epidemiology, and differential diagnosis of social anxiety disorder.
AB  - Social anxiety disorder has only recently garnered recognition as a unique
      anxiety disorder. Although social anxiety disorder is distinguishable from other
      psychiatric disorders, there are several areas in which this distinction is not
      straightforward. Furthermore, social anxiety disorder is associated with
      considerable comorbidity with other disorders, which may render differential
      diagnosis a challenging endeavor. This article will review those disorders that
      must be differentiated from social anxiety disorder, including major depression,
      panic disorder with agoraphobia, generalized anxiety disorder, obsessive
      compulsive disorder, and body dysmorphic disorder. In addition, the fourth
      edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)
      provides specific examples of disorders, e.g., verbal dysfluency (stuttering) and
      Parkinson's disease, in the context of which social anxiety disorder is not to be
      diagnosed. Social anxiety disorder is also frequently comorbid with the Axis II
      avoidant personality disorder. Interestingly, this may present a prime example of
      "comorbidity by committee," because it is growing increasingly clear that much
      avoidant personality disorder as defined by DSM-IV merely denotes a subgroup of
      patients with generalized social anxiety disorder. Because social anxiety
      disorder has a chronic course and is associated with significant morbidity, it is
      critical that patients receive an accurate diagnosis and appropriate treatment.

PMID- 10335674
TI  - Gender differences in the presentation and management of social anxiety disorder.
AB  - Social anxiety disorder is associated with significant impairment in social and
      occupational functioning. Gender differences in social anxiety disorder are
      apparent for treatment seeking and symptom clusters, and hormonal influences may
      affect the natural course of illness. The lifetime prevalence rate is 13.3%, with
      rates of 15.5% in women and 11.1% in men. Although most studies indicate that
      more women suffer from social anxiety disorder, it appears that men are more
      likely to seek treatment. Gender differences in the presentation and management
      of social anxiety disorder may be influenced by fluctuations in levels of
      endogenous or exogenous reproductive hormones. Neurotransmitter systems
      implicated in the etiology of mood and anxiety disorders may be affected by both
      estrogen and progesterone. There are also issues with regard to pregnancy in
      women who have social anxiety disorder. It is not known if untreated social
      anxiety disorder represents a significant risk to the fetus. However, social
      anxiety disorder often is complicated by comorbid depression, panic disorder, or
      substance abuse, all of which may pose risks to the fetus if left untreated.
      Treatment strategies for patients with social anxiety disorder should consider
      gender differences in response to pharmacotherapy, psychiatric comorbidity, oral
      contraceptive use, pregnancy status, and the specific nature of symptoms in the
      individual patient.

PMID- 10335675
TI  - Cognitive-behavioral therapy for social anxiety disorder: model, methods, and
      outcome.
AB  - Cognitive-behavioral therapy for social anxiety disorder has typically emphasized
      cognitive-restructuring and exposure interventions, delivered alone or in
      combination, in either individual or group formats. Treatment programs
      emphasizing these interventions are associated with both acute improvements and
      longer term maintenance of treatment gains. In this article, the nature and
      application of these interventions are reviewed in relation to a cognitive
      behavioral model of the development and maintenance of social anxiety disorder.
      Strategies for change and outcome findings are discussed, with attention to both
      individual studies and meta-analytic reviews of the literature. Strategies for
      improving outcomes and future directions for research are also discussed.

PMID- 10335676
TI  - Social anxiety disorder: designing a pharmacologic treatment strategy.
AB  - Growing appreciation of the prevalence of and morbid sequelae associated with
      social anxiety disorder has focused increasing interest on the development of
      effective treatment strategies. A number of pharmacologic interventions,
      including the monoamine oxidase inhibitors, reversible inhibitors of monoamine
      oxidase A, beta-blockers, benzodiazepines, and selective serotonin reuptake
      inhibitors, have demonstrated efficacy for the treatment of social anxiety
      disorder. The choice of initial treatment depends on a variety of factors
      including comorbidity, prior treatment history, patient preference, and adverse
      effect profile. This article will examine the effectiveness of various
      pharmacologic agents for the treatment of social anxiety disorder, discuss
      considerations for long-term management, and review strategies for optimizing
      treatment in patients who are partially responsive or unresponsive to initial
      therapy.

PMID- 10335677
TI  - Comorbid social anxiety and body dysmorphic disorder: managing the complicated
      patient.
AB  - Patients with body dysmorphic disorder (BDD) have an obsessive preoccupation with
      an imagined defect in appearance or, if a slight physical abnormality exists, a
      grossly excessive concern with it. This preoccupation causes significant distress
      or impairment of social, occupational, or other functioning. Social anxiety is a
      prominent component of BDD, and social avoidance resulting from BDD symptoms may
      markedly impair social functioning. In severe cases, avoidance of social
      situations in combination with occupational and academic impairment may result in
      patients becoming housebound. The prevalence of BDD is 1% to 2% in the U.S.
      population and 11% to 12% in patients with social anxiety disorder. Behaviors
      associated with BDD include mirror checking, physician visits, hair grooming, use
      of cosmetics, and social avoidance. Distress over BDD may lead patients to
      undergo repeated cosmetic surgeries in futile attempts to conceal or correct
      perceived defects. Additionally, depression and suicide are frequent
      complications of BDD. Pharmacologic and nonpharmacologic treatments for the
      management of BDD with coexisting social anxiety are presented in this article.

PMID- 10335678
TI  - Type 2 diabetes mellitus: greater cardiovascular risks and greater benefits of
      therapy.

PMID- 10335679
TI  - Prognostic and therapeutic significance of low levels of high-density lipoprotein
      cholesterol: current perspectives.

PMID- 10335680
TI  - Clinical progress and the future of HIV exceptionalism.
AB  - In the 18 years since the first cases of the acquired immunodeficiency syndrome
      (AIDS) were reported by the Centers for Disease Control and Prevention (CDC), the
      epidemic has undergone profound transformations, and so, too, has the
      sociomedical context within which public health policy is fashioned and
      implemented. The early years of neglect and panic were also characterized by
      relative therapeutic impotence and deep uncertainty about the epidemiological
      course the new threat would take. In the United States and in other economically
      advanced nations, the threat of contracting the human immunodeficiency virus
      (HIV) has abated. The incidence of infection has declined, and the prevalence of
      infection has stabilized and, in some instances, begun to fall. The pattern of
      HIV spread, where it has continued, has been dramatically circumscribed to
      marginalized populations. The panic of the mid-1980s has passed, and in many
      nations, AIDS has lost its salience as a public issue. A sense of therapeutic
      impotence no longer prevails, and a new mood of triumphalism has taken hold. How
      have these crucial changes affected AIDS policies in America?

PMID- 10335681
TI  - New perspectives on the management of low levels of high-density lipoprotein
      cholesterol.
AB  - A low serum high-density lipoprotein cholesterol (HDL-C) level is a potent
      predictor of coronary heart disease (CHD). It has been estimated that 11% of US
      men have isolated low HDL-C levels, and there is uncertainty regarding the
      management of these patients. A cause-and-effect relationship between low HDL-C
      levels and CHD is supported by epidemiological, animal, and human clinical
      studies. We reviewed the structure and function of HDL-C and its role in
      preventing atherosclerosis. We then suggested an approach to the patient with
      isolated low HDL-C that may be useful to the primary care physician. An algorithm
      was proposed for use in patients with existing CHD, while the decision to treat
      patients without CHD was based on their score on the Framingham Heart Study risk
      prediction chart.

PMID- 10335682
TI  - Age at natural menopause and risk of cardiovascular disease.
AB  - BACKGROUND: Early natural menopause has been postulated to increase the risk of
      cardiovascular disease. OBJECTIVE: To examine the relation of age at natural
      menopause with risk of coronary heart disease (CHD) and stroke in the Nurses'
      Health Study. METHODS: Analysis was restricted to 35 616 naturally postmenopausal
      women who never used estrogen replacement therapy and with no diagnosed
      cardiovascular disease at baseline, followed up from 1976 to 1994. Information on
      menopausal status, age at menopause, and other risk factors was obtained in 1976
      and updated every 2 years by mailed questionnaires. RESULTS: During 354326 person
      years of follow-up, we documented 757 incident cases of CHD and 350 incident
      cases of stroke. After adjusting for age, smoking status, and other
      cardiovascular risk factors, the relative risks (RRs) across categories of age at
      natural menopause (<40, 40-44, 45-49, 50-54, and > or = 55 years) were 1.53,
      1.42, 1.10, 1.00 (reference), and 0.95, respectively; the RR for each 1-year
      decrease in age at natural menopause was 1.03 (95% confidence interval, 1.01
      1.05). Elevated risk with younger age at menopause was observed among current
      smokers (RR, 1.04 [95% CI, 1.01-1.07] for each 1-year decrease in age at natural
      menopause) but not among never smokers (RR, 1.00; 95% CI, 0.96-1.04). Age at
      natural menopause was not significantly associated with ischemic stroke (RR,
      1.01; 95% CI, 0.97-1.04) or hemorrhagic stroke (RR, 1.03; 95% CI, 0.97-1.10).
      CONCLUSIONS: We observed an overall significant association between younger age
      at menopause and higher risk of CHD among women who experienced natural menopause
      and never used hormone therapy. This increased risk was observed among current
      smokers but not among never smokers. The apparent elevated risk of CHD with
      decreased age at natural menopause among smokers might reflect residual
      confounding by smoking.

PMID- 10335683
TI  - Difficult patient encounters in the ambulatory clinic: clinical predictors and
      outcomes.
AB  - BACKGROUND: One sixth of patient encounters are perceived as difficult by
      clinicians. Our goal was to assess clinical predictors and outcomes from such
      encounters. METHODS: Five hundred adults presenting to a primary care walk-in
      clinic with a physical symptom completed surveys before the visit, immediately
      after the visit, at 2 weeks, and at 3 months. Patient measurements included
      mental disorders (PRIME-MD), functional status (Medical Outcomes Study Short-Form
      Health Survey [SF-6]), satisfaction (RAND 9-item survey), symptom resolution,
      visit costs, previsit and residual expectations of care, and health services
      utilization. Measurements from the 38 participating clinicians included the
      Physician's Belief Scale and physician perception of encounter difficulty
      (Difficult Doctor-Patient Relationship Questionnaire). RESULTS: Seventy-four
      patient encounters (15%) were rated as difficult. Patients in such encounters
      were more likely to have a mental disorder (odds ratio, 2.4; 95% confidence
      interval, 1.3-4.4), more than 5 somatic symptoms (odds ratio, 1.4; 95% confidence
      interval, 1.1-1.8), and more severe symptoms (odds ratio, 1.6; 95% confidence
      interval, 1.04-2.3). Difficult-encounter patients had poorer functional status,
      more unmet expectations (P=.005), less satisfaction with care (P=.03), and higher
      use of health services (P<.001). Clinicians with poorer psychosocial attitudes as
      reflected by higher scores on the Physician's Belief Scale experienced more
      encounters as being difficult (23% vs 8%; P<.001). CONCLUSIONS: Patients
      presenting with physical symptoms who are perceived as difficult are more likely
      to have a depressive or anxiety disorder, poorer functional status, unmet
      expectations, reduced satisfaction, and greater use of health care services.
      Physicians with poorer psychosocial attitudes are more likely to experience
      encounters as difficult.

PMID- 10335684
TI  - Nonfasting plasma total homocysteine levels and all-cause and cardiovascular
      disease mortality in elderly Framingham men and women.
AB  - BACKGROUND: Elevated fasting total homocysteine (tHcy) levels were recently shown
      to confer an independent risk for all-cause and cardiovascular disease (CVD)
      mortality among selected Norwegian patients with confirmed coronary heart
      disease. We examined whether elevated fasting plasma tHcy levels were predictive
      of all-cause and CVD mortality in a large, population-based sample of elderly US
      women and men. METHODS: Nonfasting plasma tHcy levels were determined in 1933
      elderly participants (mean age, 70 +/- 7 years; 58.9% women) from the original
      Framingham Study cohort, examined between 1979 and 1982, with follow-up through
      1992. Unadjusted and adjusted (ie, for age, sex, diabetes, smoking, systolic
      blood pressure, total and high-density lipoprotein cholesterol, and creatinine)
      relative risk estimates (with 95% confidence intervals [CIs]) for total and CVD
      mortality were generated by proportional hazards modeling, with tHcy levels
      (quartiles) as the independent variable. RESULTS: There were 653 total deaths and
      244 CVD deaths during a median follow-up of 10.0 years. Proportional hazards
      modeling revealed that tHcy levels of 14.26 micromol/L or greater (the upper
      quartile), vs less than 14.26 micromol/L (the lower three quartiles), were
      associated with relative risk estimates of 2.18 (95% CI, 1.86-2.56) and 2.17 (95%
      CI, 1.68-2.82) for all-cause and CVD mortality, respectively. The relative risk
      estimates after adjustment for age, sex, systolic blood pressure, diabetes,
      smoking, and total and high-density lipoprotein cholesterol levels attenuated
      these associations, but they remained significant: 1.54 (95% CI, 1.31-1.82) for
      all-cause mortality; 1.52 (95% CI, 1.16-1.98) for CVD mortality. CONCLUSION:
      Elevated nonfasting plasma tHcy levels are independently associated with
      increased rates of all-cause and CVD mortality in the elderly.

PMID- 10335685
TI  - Diagnosing pneumonia by physical examination: relevant or relic?
AB  - BACKGROUND: The reliability of chest physical examination and the degree of
      agreement among examiners in diagnosing pneumonia based on these findings are
      largely unknown. OBJECTIVES: To determine the accuracy of various physical
      examination maneuvers in diagnosing pneumonia and to compare the interobserver
      reliability of the maneuvers among 3 examiners. METHODS: Fifty-two male patients
      presenting to the emergency department of a university-affiliated Veterans
      Affairs medical center with symptoms of lower respiratory tract infection (cough
      and change in sputum) were prospectively examined. A comprehensive lung physical
      examination was performed sequentially by 3 physicians who were blind to clinical
      history, laboratory findings, and x-ray results. Examination findings by lung
      site and whether the examiner diagnosed pneumonia were recorded on a standard
      form. Chest x-ray films were read by a radiologist. RESULTS: Twenty-four patients
      had pneumonia confirmed by chest x-ray films. Twenty-eight patients did not have
      pneumonia. Abnormal lung sounds were common in both groups; the most frequently
      detected were rales in the upright seated position and bronchial breath sounds.
      Relatively high agreement among examiners (kappa approximately 0.5) occurred for
      rales in the lateral decubitus position and for wheezes. The 3 examiners'
      clinical diagnosis of pneumonia had a sensitivity of 47% to 69% and specificity
      of 58% to 75%. CONCLUSIONS: The degree of interobserver agreement was highly
      variable for different physical examination findings. The most valuable
      examination maneuvers in detecting pneumonia were unilateral rales and rales in
      the lateral decubitus position. The traditional chest physical examination is not
      sufficiently accurate on its own to confirm or exclude the diagnosis of
      pneumonia.

PMID- 10335686
TI  - Prosecutors and end-of-life decision making.
AB  - OBJECTIVE: To examine personal beliefs and professional behavior of state
      criminal prosecutors toward end-of-life decisions. DESIGN: Mail survey. SETTING:
      District attorney offices nationwide. PARTICIPANTS: All prosecuting attorneys who
      are members of the National District Attorneys Association. A total of 2844
      surveys were mailed with 2 follow-up mailings at 6-week intervals; 761 surveys
      were returned for a response rate of 26.8%. The majority of respondents were
      white men, Protestant, and served in rural areas. INTERVENTIONS: None. MAIN
      OUTCOME MEASURES: On the basis of 4 case scenarios, (1) professional behavior as
      determined by respondents' willingness to prosecute and what criminal charges
      they would seek; and (2) personal beliefs as determined by whether prosecutors
      believed the physicians' actions were morally wrong and whether they would want
      the same action taken if they were in the patient's condition. RESULTS: Most
      respondents would not seek prosecution in 3 of the 4 cases. In the fourth case,
      involving physician-assisted suicide, only about one third of the respondents
      said that they definitely would prosecute. Those who would prosecute would most
      often seek a charge of criminal homicide. A majority of respondents believed that
      the physicians' actions were morally correct in each of the 4 cases and would
      want the same action taken if they were in the patient's position. There was a
      strong correlation between personal beliefs and professional behaviors.
      CONCLUSIONS: A large majority of responding prosecutors were unwilling to
      prosecute physicians in cases that clearly fall within currently accepted legal
      and professional boundaries. In the case of physician-assisted suicide, results
      reflected a surprisingly large professional unwillingness to prosecute and an
      even greater personal acceptance of physician-assisted suicide.

PMID- 10335687
TI  - Risk factors for stroke in type 2 diabetes mellitus: United Kingdom Prospective
      Diabetes Study (UKPDS) 29.
AB  - OBJECTIVE: To investigate modifiable and nonmodifiable risk factors for stroke in
      type 2 diabetes mellitus. PATIENTS AND METHODS: A total of 3776 patients aged 25
      to 65 years newly diagnosed as having type 2 diabetes mellitus without known
      cardiovascular or other serious disease were studied for a median of 7.9 years.
      An initial stepwise evaluation of risk factors was done in 2704 patients with all
      risk factors measured, with the final Cox model analysis being of 3776 patients
      who had complete data on the selected variables. RESULTS: Of 3776 patients, 99
      (2.6%) had a stroke. Significant risk factors for stroke in a multivariate model
      were age (estimated hazard ratio [95% confidence interval], 4.78 [2.56-8.92] for
      > or =60 vs <50 years), male sex (1.63 [1.08-2.47)] vs female), hypertension
      (2.47 [1.64-3.74)] vs normotension), and in 3728 patients who had
      electrocardiography at study entry, atrial fibrillation (8.05 [3.52-18.44] vs
      sinus rhythm). Obesity, lack of exercise, smoking, poor glycemic control,
      hyperinsulinemia, dyslipidemia, and microalbuminuria were not significantly
      associated with stroke in the model. CONCLUSION: In patients with type 2
      diabetes, aggressive antihypertensive therapy and routine anticoagulation therapy
      for atrial fibrillation may reduce the risk of stroke.

PMID- 10335688
TI  - Clustering of metabolic factors and coronary heart disease.
AB  - BACKGROUND: The degree of clustering for common metabolic coronary disease risk
      factors is not well known, the antecedents of clustering are not well studied,
      and the impact of such clusters on coronary risk has not been assessed
      systematically. METHODS: Prospective community sample of 2406 men and 2569 women
      aged 18 to 74 years at baseline. The 6 metabolically linked risk factors
      considered were the lowest sex-specific quintile of high-density lipoprotein
      cholesterol and the highest quintiles of body mass index, systolic blood
      pressure, triglycerides, glucose, and serum total cholesterol. RESULTS: At
      baseline the risk factor sum, represented as integer values, ranged from 0 to 6,
      and clusters of 3 or more risk factors occurred at twice the rate predicted by
      chance. After adjustment for age and obesity level, a 2.25-kg (5-lb) weight
      increase over 16 years was associated with an increased risk factor sum in men
      (+20%; P=.002) and women (+37%; P<.001), and a 2.25-kg weight loss was associated
      with a decreased risk factor sum in men (-48%; P<.001) and women (-40%; P<.001).
      Clusters of 3 or more risk factors were associated with a 2.39 (95% confidence
      interval, 1.56-3.36) and 5.90 (95% confidence interval, 2.54-13.73) times greater
      risk of coronary heart disease in men and women, respectively (both P<.001).
      CONCLUSIONS: Atherogenic risk factor clustering is common in both sexes, worsens
      with weight gain, and is associated with greatly increased risk of coronary
      disease risk in both sexes.

PMID- 10335689
TI  - Predictors of sputum culture conversion among patients with tuberculosis in the
      era of tuberculosis resurgence.
AB  - BACKGROUND: Sputum culture conversion among patients with tuberculosis (TB) is
      the most important indicator for the effectiveness of treatment and the
      infectivity of the disease. We sought to investigate predictors for documented
      sputum culture conversion among TB cases reported in the surveillance system.
      METHODS: This study included 780 patients with pulmonary TB who were initially
      sputum culture positive in New Jersey in 1994-1995. These patients were followed
      up for at least 1 week and up to 1 year. Kaplan-Meier curves and Cox proportional
      hazards models were performed to analyze the data. RESULTS: Overall, 469 (60.1%)
      of the 780 patients had documented sputum culture conversion. The elderly (36%)
      and non-Hispanic whites (41.3%) were the least likely to have documented sputum
      conversion. Patients who were initially given 4 or more drugs were 36% more
      likely to have documented sputum conversion than those who were initially given
      fewer than 4 drugs, after adjusting for other factors. Patients who were under
      the care of chest clinics and the model TB center were about 3 times more likely
      to have documented sputum conversion than those under care of private physicians.
      Sex, recurrent TB, foreign-born status, homelessness, injecting drug use, human
      immunodeficiency virus infection and drug-resistant TB were not significantly
      associated with the documentation of sputum culture conversion. CONCLUSIONS: A
      substantial proportion of sputum culture-positive TB patients have no documented
      sputum culture conversion. The type of care provider was the predominant
      determinant for the documentation of sputum culture conversion.

PMID- 10335690
TI  - Lone atrial fibrillation in elderly persons: a marker for cardiovascular risk.
AB  - BACKGROUND: The risk of stroke in persons aged 60 years and younger with lone
      atrial fibrillation (LAF) is no greater than in the general population. The
      effect of older age on the risk of stroke in persons with LAF is less well
      established. PARTICIPANTS AND METHODS: The risk of stroke in persons with LAF and
      without substantial comorbidities was examined in a population-based study at a
      single institution in Olmsted County, Minnesota, and compared with that in an age
      and sex-matched population. The mean age was 74 years (range, 61-97 years). The
      median duration of follow-up was 9.6 years until death or last follow-up.
      RESULTS: Of 55 patients, 26 had 31 cardiovascular events during follow-up,
      occurring a median of 5.1 years after diagnosis (range, 0.7-18 years). Of 11
      cerebrovascular events, 6 were transient ischemic attacks and 5 were strokes. The
      event rates (percentage per person-year) were 0.9% for stroke, 1.1% for transient
      cerebral ischemia, and 2.6% for myocardial infarction, for a total cardiovascular
      event rate of 5.0% per person-year. The corresponding rates for the age- and sex
      matched control group were 0.2%, 0%, and 1.1%, for a total of 1.3% per person
      year. The incidence of total cardiovascular events was significantly greater (P<
      .01) in those with LAF, although there was no difference in survival. CONCLUSION:
      Lone atrial fibrillation occurring after age 60 years is a risk marker for a
      substantial increase in cardiovascular events that warrants consideration for
      antithrombotic therapy.

PMID- 10335691
TI  - Health and economic outcomes of antibiotic resistance in Pseudomonas aeruginosa.
AB  - BACKGROUND: Antimicrobial resistance is an increasing problem. OBJECTIVE: To
      examine the clinical and economic impact of antibiotic resistance in Pseudomonas
      aeruginosa. METHODS: In-hospital mortality, secondary bacteremia, length of stay,
      and hospital charges were examined in a cohort of 489 inpatients with positive
      clinical cultures for P aeruginosa. One hundred forty-four had a resistant
      baseline P aeruginosa isolate and 30 had resistance emerge during follow-up.
      Multivariable and survival analytic methods were used to adjust for confounding
      and effects of time. RESULTS: The overall in-hospital mortality rate was 7.6%,
      7.7% in patients with a resistant isolate at baseline (relative risk [RR], 1.3;
      95% confidence interval [CI], 0.6-2.8) and 27% in patients in whom resistance
      emerged (RR, 3.0; 95% CI, 1.2-7.8). Secondary bacteremia developed in 1.4% of
      patients in whom resistance did not emerge and in 14% of those in whom resistance
      emerged (RR, 9.0; 95% CI, 2.7-30). The median duration of hospital stay following
      the initial P aeruginosa isolate was 7 days. Emergence of resistance, but not
      baseline resistance, was significantly associated with a longer hospital stay
      (P<.001 and P=.71, respectively). The average daily hospital charge was $2059.
      Neither baseline resistance nor emergence of resistance had a significant effect
      on the daily hospital charge. In a matched cohort analysis, a trend was seen
      toward increased total charges in patients demonstrating emergence of resistance
      (difference, $7340; P=.14). CONCLUSIONS: Emergence of antibiotic resistance in P
      aeruginosa results in severe adverse outcomes. Efforts should be directed toward
      early detection and prevention of emergence of antibiotic resistance.

PMID- 10335692
TI  - Community physicians who provide terminal care.
AB  - BACKGROUND: Most dying patients are treated by physicians in community practice,
      yet studies of terminal care rarely include these physicians. OBJECTIVE: To
      examine the frequency of life-sustaining treatment use and describe what factors
      influence physicians' treatment decisions in community-based practices. METHODS:
      Family members and treating physicians for decedents 65 years and older who died
      of cancer, congestive heart failure, chronic lung disease, cirrhosis, or stroke
      completed interviews about end-of-life care in community settings. RESULTS:
      Eighty percent of eligible family and 68.8% of eligible physicians participated
      (N = 165). Most physicians were trained in primary care and 85.4% were primary
      care physicians for the decedents. Physicians typically knew the decedent a year
      or more (68.9%), and 93.3% treated them for at least 1 month before death. In
      their last month of life, 2.4% of decedents received cardiopulmonary
      resuscitation, 5.5% received ventilatory support, and 34.1% received hospice
      care. Family recalled a discussion of treatment options in 78.2% of deaths. Most
      discussions (72.1%) took place a month or more before death. Place of death,
      cancer, and having a living will were independent predictors of less aggressive
      treatment before death. Physicians believed that advanced planning and good
      relationships were the major determinants of good decision making. CONCLUSIONS:
      Community physicians use few life-sustaining treatments for dying patients.
      Treatment decisions are made in the context of long-term primary care
      relationships, and living wills influence treatment decisions. The choice to
      remain in community settings with a familiar physician may influence the dying
      experience.

PMID- 10335693
TI  - Outpatient protocols for treatment of venous thromboembolism using low-molecular
      weight heparin: to treat or not to treat at home.

PMID- 10335695
TI  - Weight watching in heparin.

PMID- 10335694
TI  - A surfeit of serotonin: sumatriptan and serotonergic antidepressants.

PMID- 10335696
TI  - Probable false authentication of herbal plants: ginseng.

PMID- 10335697
TI  - Carnitine stands on its own in HIV infection treatment.

PMID- 10335698
TI  - Cigarette smoking: risk factor for venous thromboembolic disease?

PMID- 10335699
TI  - Is bone mineral density paradoxically increased in early stage of diabetic
      nephropathy?

PMID- 10335700
TI  - Therapy of idiopathic sudden sensorineural hearing loss: antiviral treatment of
      experimental herpes simplex virus infection of the inner ear.
AB  - Experimental herpes simplex virus type 1 (HSV-1) labyrinthitis provides a model
      of idiopathic sudden sensorineural hearing loss (ISSHL). Corticosteroids improve
      the prognosis for hearing recovery in ISSHL, but the effects of acyclovir are
      unknown. To establish the therapeutic efficacy of acyclovir (Zovirax) and
      prednisolone in experimental HSV-1 viral labyrinthitis, we induced HSV-1
      labyrinthitis in 12 guinea pigs. Three animals received no treatment, 3 received
      prednisolone, 3 received acyclovir, and 3 received both. Four other animals
      served as controls, receiving culture medium only. Hearing, HSV-1 antibody
      titers, and cochlear damage were evaluated. The HSV-1 labyrinthitis caused
      hearing loss within 24 hours. Combination treatment consisting of prednisolone
      and acyclovir resulted in earlier hearing recovery and less extensive cochlear
      destruction compared to prednisolone or acyclovir as a monotherapy. The
      beneficial effect of this treatment modality remains to be demonstrated in ISSHL.

PMID- 10335701
TI  - Outcome of brain stem auditory electrophysiology in children who survive purulent
      meningitis.
AB  - Brain stem auditory electrophysiology was assessed in children long after
      purulent meningitis by examining the central components of brain stem auditory
      evoked response (BAER) at different presentation rates of clicks. Children with
      peripheral hearing loss were excluded from this study to avoid any possible
      influence of the loss on the measurements of BAER central components. Of the 70
      children who had recovered from meningitis 2 to 8 years earlier, 9 (12.9%) showed
      abnormalities in BAER central components--mainly a slight reduction of wave V
      amplitude, at the click presentation rate of 10/s. Of the remaining 61 children
      who did not show any obvious abnormalities in the BAER at 10/s, an abnormally
      prolonged I-V interval and a reduced amplitude of wave V were seen in 5 children
      (8.2%) at the click rate of 90/s. The total BAER abnormality rate was therefore
      20.0% (14/70 cases). The results suggest that most children who survive purulent
      meningitis have a favorable outcome for the brain stem auditory pathway, with
      about 1 in 5 having mild dysfunction or a suboptimal outcome in the pathway.

PMID- 10335702
TI  - Clinical presentation and management of labyrinthine fistula caused by chronic
      otitis media.
AB  - To describe the clinical presentation and surgical management of patients with
      chronic otitis media complicated by labyrinthine fistula and to determine
      clinical indicators that predict postoperative hearing outcome, I performed a
      retrospective analysis at an academic tertiary care center. Thirty-four patients
      with labyrinthine fistula as a complication of chronic otitis media, documented
      at mastoidectomy, underwent postoperative audiometry. The median age was 50
      years, and the duration of otologic symptoms ranged from 2 months to more than 40
      years. On presentation, 3 patients had anacusis in the affected ear, while in the
      others, the pure tone average for bone conduction at the 0.5-, 1-, 2-, and 4-kHz
      frequencies was 34 dB hearing level. Nineteen patients (56%) complained of
      dizziness on presentation. The fistula test was positive in 14 of 28 patients
      (50%). The fistula was detected radiologically in 10 of 24 patients (42%).
      Cholesteatoma was present in 33 of 34 patients (97%). The lateral semicircular
      canal was the most common site of labyrinthine fistula. The cholesteatoma matrix
      was completely removed in 29 of 33 cases and exteriorized in the remaining 4. Of
      the 31 patients with measurable hearing preoperatively, anacusis occurred in 8
      (26%). In 6 of these, the preoperative pure tone average for bone conduction was
      greater than 50 dB hearing level, and cholesteatoma matrix and granulation tissue
      invading the membranous labyrinth were found at surgery. I concluded that in
      chronic otitis media, labyrinthine fistulas occurred almost exclusively in the
      presence of a cholesteatoma. Postoperative hearing outcome correlated with the
      size of the fistula and the presence of granulation tissue invading the
      labyrinth. which could be predicted by the preoperative audiometry.

PMID- 10335703
TI  - Antibiotics in chronic suppurative otitis media: a bacteriologic study.
AB  - Conservative medical management of chronic suppurative otitis media (CSOM) is an
      important step in achieving a dry ear. Topical antibiotic ear drops and aural
      toilet form the mainstay of medical management of noncholesteatomatous CSOM. This
      study analyzes the causal organisms and their sensitivity to various antibiotics.
      Out of 382 swabs examined, the major organisms isolated were Pseudomonas
      aeruginosa (27.2%), followed by Staphylococcus aureus (23.6%). The sensitivity of
      P. aeruginosa was 100% to ceftazidime, 98.9% to ciprofloxacin, 96.3% to
      gentamicin, and 95.4% to polymyxin B, whereas the sensitivity of S. aureus was
      98.6% to ciprofloxacin, 97.4% to cloxacillin sodium, 96.5% to cotrimoxazole, and
      90.7% to gentamicin. Pseudomonas aeruginosa was almost completely resistant to
      ampicillin (97.6%) and chloramphenicol (96.6%), whereas S. aureus was almost
      completely resistant to ampicillin (73.8%) and polymyxin B (98.3%). Among the
      available topical antibiotic preparations for use in the ear, we found that
      ciprofloxacin and gentamicin are the best choices.

PMID- 10335704
TI  - Twenty-four-hour oscillations of facial electroneurography parameters and their
      relationship to body temperature.
AB  - The purpose of the present study was to assess the temporal variation of the
      facial electroneurography (ENoG) parameters recorded from the nasolabial crease
      and to compare it to the temporal oscillations of oral and facial cutaneous
      temperatures. Twelve healthy individuals were examined at 4-hour intervals for 2
      consecutive days. Twenty-four-hour rhythms of oral and facial cutaneous
      temperatures were found in all subjects (troughs on average at 4:20 and 4:00 AM,
      respectively). Significant 24-hour oscillations of ENoG amplitude were found in
      all subjects, which were positively correlated to the oscillations of oral and
      facial cutaneous temperatures (trough on average at 2:40 AM). The compound action
      potential (CAP) latency fluctuated during the day and was negatively correlated
      with local temperatures. However, these fluctuations and correlations did not
      reach statistical significance. We also found a significant reduction of ENoG
      amplitude in 5 patients with artificial cooling of the face near the facial
      nerve. Also, there was a small increase in CAP latency with facial cooling.
      Interpreting ENoG recordings in accordance with oral temperature and recording
      time of day reduce the intertest variation.

PMID- 10335706
TI  - Prospective application of a protocol for selective nonsurgical management of
      suspected orbital subperiosteal abscesses in children.
AB  - Goodwin et al (1982) and Souliere et al (1990) have proposed a protocol for the
      selective nonsurgical management of suspected orbital subperiosteal abscesses.
      This protocol has been routinely applied by the Temple Pediatric Otolaryngology
      and Ophthalmology services since 1990. During this period, children with computed
      tomography and physical examination findings consistent with orbital
      subperiosteal abscesses and visual acuity better than 20/60 were treated with
      intravenous antibiotics rather than immediate surgery. They were followed with
      frequent ophthalmologic examinations and operated upon if vision deteriorated or
      they failed to improve clinically within 48 hours. A review of patients admitted
      to St Christopher's Hospital for Children, the site of Temple University's
      pediatric activities in the years from 1991 to 1997, revealed 14 patients with
      clinical evidence of orbital subperiosteal abscesses. Twelve patients were
      treated in accordance with the Goodwin-Souliere protocol. All recovered
      completely without surgical intervention and without any adverse sequelae.
      Selective nonsurgical treatment of clinically diagnosed orbital subperiosteal
      abscesses in children is relatively safe and effective.

PMID- 10335705
TI  - Effect of platelet activating factor and its antagonist on the mucociliary
      clearance of the eustachian tube in guinea pigs.
AB  - The purpose of this study was to test whether platelet activating factor (PAF)
      impairs the mucociliary clearance function of the eustachian tube (ET) in a dose
      dependent manner and whether PAF antagonist can prevent the impairment of
      mucociliary function of the ET induced by PAF. Coomassie brilliant blue dye
      transport time (DTT) in normal guinea pigs was 69 seconds. The DTTs after the
      application of normal saline and PAF at I and 2 microg/mL into bullae were 66,
      74, and 157 seconds. The time was over 15 minutes when 4, 8, and 16 microg/mL of
      PAF were applied. The DTT was 62 seconds when the animals were pretreated with
      PAF antagonist (WEB 2170). There were significant delays of the DTTs after
      treatment with 2, 4, 8, and 16 microg/mL of PAF. Histopathologic examination of
      ETs from groups with a significant delay in DTTs showed intact cilia, mucous
      plugs, increased inflammatory cells, and exfoliation of cells. This study
      demonstrated that PAF impaired the mucociliary clearance function of the ET in a
      dose-dependent manner. This impairment of mucociliary clearance function was
      prevented by pretreatment with PAF antagonist. The findings of the study suggest
      that PAF plays an important role in the pathogenesis of otitis media with
      effusion by impairing the ET clearance function.

PMID- 10335707
TI  - Sinusitis with contiguous abscess involvement of the clivus and petrous apices.
      Case report.
AB  - A wide spectrum of diseases may involve the clivus, such as primary neoplasms,
      metastatic disease, and inflammatory, vascular, hematopoietic, and infectious
      processes. Of these, osteomyelitis of the skull base and/or clival-petrous
      abscess are unusual, but may occur as a result of contiguous spread from the
      paranasal sinuses, namely, the posterior ethmoid and sphenoid, as was
      demonstrated by this patient. In this case report we discuss the pertinent
      anatomy, imaging studies, pathogenesis, and medical and surgical management of
      this case.

PMID- 10335708
TI  - Comparative role of peptide leukotrienes and histamine in the development of
      nasal mucosal swelling in nasal allergy.
AB  - To evaluate the importance of histamine and peptide leukotrienes (LTs) in the
      development of nasal mucosal swelling in nasal allergy, H1 receptor antagonist
      (mequitazine, 6 mg, in 2 divided doses, Rhone-Poulenc Rorer, France) and LT
      receptor antagonist (ONO-1078, pranlukast, 450 mg, in 2 divided doses, Ono
      Pharmaceutical Co, Ltd, Osaka) were administered orally for 7 days to 16 subjects
      with perennial nasal allergy to house dust mites, and the effects of receptor
      blockers of these chemical mediators on the effective cross-sectional area of the
      nasal cavity (ECA) at rest, at exercise load, at antigen challenge, and at
      exercise load following antigen challenge were studied. After the administration
      of H1 receptor antagonist, ECAs at all measurement points slightly increased, but
      no statistical significance was observed. On the other hand, LT receptor
      antagonist inhibited ECAs 10 minutes after exercise load, just after the end of
      antigen challenge, 10 minutes later, and at exercise load following antigen
      challenge with statistical significance. These results suggest that LTs are
      involved markedly, and histamine slightly, in the development of nasal mucosal
      swelling in nasal allergy.

PMID- 10335709
TI  - Delayed irradiation effects on nasal epithelium in patients with nasopharyngeal
      carcinoma. An ultrastructural study.
AB  - The ostiomeatal complex is responsible for the clearance of most sinus
      secretions. To evaluate the delayed effects of irradiation. this study examined
      the infundibulum mucosa of 10 patients who developed sinusitis after receiving
      radiotherapy for nasopharyngeal carcinoma (NPC). Pathologic findings under the
      light microscope revealed an increased deposition of dense collagenous fibers in
      the lamina propria. The epithelial cells also transformed into a stratified
      arrangement and showed gradual reduction of cytoplasmic volume. Ultrastructural
      observations detected areas of ciliary loss, intercellular and intracellular
      vacuolation, and ciliary dysmorphism. Most of these pathologic findings were
      observed even in a patient 23 years after irradiation. The results presented
      herein suggest that radiotherapy may cause long-term damage to the nasal
      epithelium that may be responsible for the prolonged sinusitis of irradiated NPC
      patients.

PMID- 10335710
TI  - Flow cytometric analysis of BHRF1 expression prohibiting apoptosis induced by
      radiation.
AB  - The Epstein-Barr virus gene BHRFI has homology with proto-oncogene bcl-2, which
      can protect cells from apoptosis. In order to investigate the effect of BHRF1
      expression on the anti-apoptotic ability of nasopharyngeal carcinoma (NPC) cells
      after irradiation, a high-BHRF1 expression vector was constructed and transfected
      into the NPC cell line CNE2. Then, the alteration of proliferation and apoptosis
      in the cells was tested by flow cytometry after cobalt 60 irradiation. The
      results showed that BHRF1 expression could increase G1 delay and decrease the
      cell percentage in S phase before irradiation, and reduce the apoptotic rate of
      CNE2 cells and increase the cell percentage in S phase after irradiation. The
      results suggest that BHRF1 expression is able to alter the cell cycle and protect
      CNE2 cells from apoptosis induced by radiation.

PMID- 10335711
TI  - Glandular carcinoma of the larynx: the UCLA experience.
AB  - Glandular carcinomas of the larynx are rare tumors that constitute less than 1%
      of all laryngeal malignancies. A retrospective case review of 12 patients with
      glandular carcinomas of the larynx is presented to identify patient and tumor
      characteristics, therapeutic modalities, and treatment outcomes. Ten patients
      underwent surgical excision of the primary tumor, by either supraglottic
      laryngectomy, vertical partial laryngectomy, or total laryngectomy. Seven of
      these patients also received postoperative radiotherapy. After a median follow-up
      period of 23 months, 7 of the 12 patients (58.3%) died as a result of
      uncontrolled locoregional disease or distant metastases. The 5-year survival rate
      was 57% in patients who underwent combination therapy versus 50% for those
      patients who received surgery alone. Surgical resection is the primary treatment
      modality used in the majority of cases. Neck dissection is reserved for patients
      with clinically apparent adenopathy, adenocarcinoma, or high-grade mucoepidermoid
      carcinoma. Combination therapy with surgical resection and radiotherapy may be
      more effective in achieving tumor remission than is surgical resection alone.

PMID- 10335712
TI  - Carbon dioxide laser debulking for obstructing endolaryngeal carcinoma: a 10-year
      experience.
AB  - The results of the carbon dioxide (CO2) laser debulking procedure for obstructing
      endolaryngeal carcinoma were analyzed in terms of efficiency, complications,
      secondary tracheotomy rate, and peristomal recurrence rate in a series of 50
      patients consecutively managed at our department. The CO2 laser was used to
      reestablish a safe airway without resorting to tracheotomy and without performing
      a transoral resection. Our series included 42 patients in a pre-definitive
      treatment group (group 1) and 8 patients in a palliation group (group 2).
      Complications included death, pneumonia from inhalation, and cutaneous burns in 2
      patients, 1 patient, and 1 patient, respectively. Thirty-two percent of patients
      required a repeat laser treatment to maintain the airway. Overall success rates
      of 92.8% and 87.5% were achieved in group 1 and group 2 patients, respectively.
      None of the variables under analysis could predict the success of the CO2 laser
      debulking procedure. The overall incidences for secondary tracheotomy were 4.7%
      and 0% in group 1 and group 2 patients, respectively. Peristomal recurrence was
      not encountered in patients managed with definitive therapy with curative intent.

PMID- 10335713
TI  - Extramedullary solitary plasmacytoma of the head and neck. A clinicopathological
      study.
AB  - Monoclonal extramedullary plasmacytoma (EMP) is a rare, low-grade lymphoma found
      predominantly in the head and neck region. Only since the introduction of
      immunophenotyping techniques 2 decades ago has it been possible to differentiate
      EMP from benign polyclonal plasma cell proliferation. The purpose of this study
      was to trace the evolutionary profile of the disease under consideration of
      monoclonality assessment. The records of 24 patients with morphologically
      diagnosed EMP treated in a single institution underwent clinical and pathological
      review. Only 14 patients had true monoclonal plasmacytoma. No EMP-related deaths
      occurred. Two patients had local recurrence, and 2 patients developed multiple
      myeloma. Review of the literature confirms the low-grade malignancy of EMP.
      Diagnostic procedures must exclude benign polyclonal plasmacytoma, multiple
      myeloma, and solitary bone plasmacytoma. The slow natural progression of the
      disease and the rarity of secondary multiple myeloma favor nonmutilating local
      surgery whenever possible to avoid the long-term sequelae of radiotherapy.

PMID- 10335714
TI  - Substernal goiter: clinical experience of 72 cases.
AB  - The aim of this work was to study the clinical management and surgical approach
      of substernal goiters. We studied the clinical data, preoperative evaluation,
      surgical treatment, histopathologic data, complications, and follow-up of 72
      patients found to have substernal goiter over a period of 15 years, from a total
      of 780 patients with goiter who underwent surgery. In this group, 83% were women,
      and the mean age was 61 years. The most common symptoms were the existence of a
      palpable cervical mass (93% of cases) and dyspnea (40%). The most successful
      study to diagnose substernal goiter was computed tomography (100%), followed by
      chest radiography (75%), gammagraphy (19%), and ultrasound (15%). All but 7
      patients received a Kocher cervicotomy, and 49% of the cases underwent a total
      thyroidectomy. The histologic study revealed 3 carcinomas (4%). There was 1
      permanent unilateral recurrent laryngeal nerve injury (1.4%) and 1 instance of
      permanent hypoparathyroidism (1.4%). We regard surgery as the most successful
      treatment for patients with substernal goiter, even in those without compressive
      symptoms. We base our choice on the low morbidity and zero mortality obtained.

PMID- 10335715
TI  - Thoracic duct cyst: a case report and review of 29 cases.
AB  - Cysts of the thoracic duct are rare. We report a case of a cervical thoracic duct
      cyst and review 29 thoracic duct cysts reported previously (19 mediastinal, 9
      cervical, and 1 abdominal). The mean age of the patients was 47.6 years (range 17
      to 86 years). Fourteen (46.7%) of the patients were asymptomatic. When symptoms
      were present, they ranged from retrosternal pain, dysphagia, and dyspnea to
      respiratory insufficiency and superior vena cava compression. Diagnosis of the
      cyst can be made after computed tomography or ultrasonography. The cystic fluid
      contains T lymphocytes and triglycerides in excess. The symptoms in a patient
      with a thoracic duct cyst are related to compression of adjacent structures. The
      most profound symptoms are likely to be produced by mediastinal cysts above the
      aortic arch. Treatment consists of surgical removal of the cyst and ligation of
      all lymphatics connected to the cyst.

PMID- 10335717
TI  - Cervical anatomy of phrenic nerve roots in the rabbit. European Group for
      Research on the Larynx.
AB  - The cervical anatomy of the different nerve contributions that constitute the
      phrenic nerve (phrenic nerve roots and accessory phrenic nerve) were studied in
      rabbits. In 55 dissections, 6 main root arrangement types were observed. The
      roots that issued from the fourth and fifth cervical nerves (C4 and C5 roots)
      were constant. The C4 root was either short or long. The C6 root was at times
      absent, or sometimes double. An accessory phrenic nerve was present in 43% of the
      right and 28% of the left dissections. The distribution of the phrenic nerve
      roots often displayed left-right asymmetry. We conclude that a better knowledge
      of the cervical anatomy of the phrenic nerve is useful both in physiological
      studies involving diaphragm denervation and in experimental laryngeal
      reinnervation.

PMID- 10335716
TI  - Postnatal development of myosin heavy chain isoforms in rat laryngeal muscles.
AB  - The developmental transitions of myosin heavy chain (MHC) isoforms of rat
      posterior cricoarytenoid (PCA), thyroarytenoid (TA), cricothyroid (CT), and
      lateral cricoarytenoid (LCA) muscles were examined by means of sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot
      techniques. The muscles were microscopically dissected from animals on postnatal
      days 0, 3, 7, 10, 14, 21, 28, 35, 45, and 55 and from adult animals. Silver
      stained SDS-PAGE gels of each muscle were analyzed densitometrically to measure
      the composition of MHC isoforms, and Western blot was carried out to identify
      specific bands. Characterizations of the internal laryngeal muscles determined by
      the composition of MHCs were correlated with their function in the adult.
      Temporally, differentiation reflects onset of function. Differentiation of
      isoforms and transition to adult forms occur first in the TA muscle, followed by
      the PCA, LCA, and CT muscles. Expression of type IIL was observed only in muscles
      innervated by the recurrent laryngeal nerve. Postnatally observed developmental
      differences of myosin phenotypes suggest that regulation of MHC expression is
      influenced by neural activity or other environmental factors.

PMID- 10335718
TI  - Frontoethmoid osteoma.

PMID- 10335719
TI  - Beyond the mystique of prestige: measuring the quality of residency programs.

PMID- 10335720
TI  - Successful implementation of guidelines for encouraging the use of beta blockers
      in patients after acute myocardial infarction.
AB  - PURPOSE: To assess whether implementation of guidelines increases the
      prescription of drugs, particularly beta blockers, recommended for secondary
      prevention after acute myocardial infarction. SUBJECTS AND METHODS: Prescription
      patterns among 355 patients discharged from a public teaching hospital after
      recovery from myocardial infarction were prospectively monitored in a before
      after trial. The implementation strategies included educational interventions
      (large group meetings), placement of guidelines in patients' records, and
      bimonthly general reminders sent to physicians. RESULTS: Beta blockers were
      prescribed in 93 (38%) of 243 survivors of acute myocardial infarction before
      guideline implementation (12-month control period), as compared with 71 (63%) of
      112 patients (P <0.001) after their implementation (6-month period). During the
      entire study period, the prescription of beta blockers at a neighboring public
      teaching hospital, used as a comparison, was unchanged. After adjusting for
      potential confounders, implementation of the guidelines remained significantly
      associated with prescription of beta blockers at discharge [odds ratio (OR) = 10;
      95% confidence interval (CI), 3.2 to 33; P <0.001]. Other independent predictors
      of prescription of beta blockers were previous coronary artery bypass grafting
      (OR = 8.7; 95% CI, 2.5 to 31; P = 0.001), hypertension (OR = 2.5; 95% CI, 1.4 to
      4.5; P = 0.003), age per 10-year increase (OR = 0.82; 95% CI, 0.67 to 0.99; P =
      0.04), secular trend in prescription patterns expressed in months (OR = 0.9; 95%
      CI, 0.8 to 1.0; P = 0.02), a left ventricular ejection fraction < or = 40% (OR =
      0.2; 95% CI, 0.1 to 0.4; P <0.001), the presence of atrioventricular block (OR =
      0.1; 95% CI, 0.02 to 0.7; P = 0.02), and concomitant prescription of digoxin (OR
      = 0.2; 95% CI, 0.05 to 0.8; P = 0.02) or calcium antagonists (OR = 0.06; 95% CI,
      0.01 to 0.3; P = 0.001). CONCLUSION: When appropriately developed and implemented
      by local experts, literature-based guidelines may be effective in modifying use
      of recommended drugs for secondary prevention of coronary artery disease, such as
      prescription of beta blockers.

PMID- 10335721
TI  - Associations of elevated interleukin-6 and C-reactive protein levels with
      mortality in the elderly.
AB  - PURPOSE: To investigate whether interleukin-6 and C-reactive protein levels
      predict all-cause and cause-specific mortality in a population-based sample of
      nondisabled older people. SUBJECTS AND METHODS: A sample of 1,293 healthy,
      nondisabled participants in the Iowa 65+ Rural Health Study was followed
      prospectively for a mean of 4.6 years. Plasma interleukin-6 and C-reactive
      protein levels were measured in specimens obtained from 1987 to 1989. RESULTS:
      Higher interleukin-6 levels were associated with a twofold greater risk of death
      [relative risk (RR) for the highest quartile (> or = 3.19 pg/mL) compared with
      the lowest quartile of 1.9 [95% confidence interval, CI, 1.2 to 3.1]). Higher C
      reactive protein levels (> or = 2.78 mg/L) were also associated with increased
      risk (RR = 1.6; CI, 1.0 to 2.6). Subjects with elevation of both interleukin-6
      and C-reactive protein levels were 2.6 times more likely (CI, 1.6 to 4.3) to die
      during follow-up than those with low levels of both measurements. Similar results
      were found for cardiovascular and noncardiovascular causes of death, as well as
      when subjects were stratified by sex, smoking status, and prior cardiovascular
      disease, and for both early (<2.3 years) and later follow-up. Results were
      independent of age, sex, body mass index, and history of smoking, diabetes, and
      cardiovascular disease, as well as known indicators of inflammation including
      fibrinogen and albumin levels and white blood cell count. CONCLUSIONS: Higher
      circulating levels of interleukin-6 and C-reactive protein were associated with
      mortality in this population-based sample of healthy older persons. These
      measures may be useful for identification of high-risk subgroups for anti
      inflammatory interventions.

PMID- 10335722
TI  - A randomized, double-blind comparison of risedronate and etidronate in the
      treatment of Paget's disease of bone. Paget's Risedronate/Etidronate Study Group.
AB  - PURPOSE: To compare the efficacy and tolerability of oral risedronate and
      etidronate for treatment of Paget's disease of bone. PATIENTS AND METHODS:
      Patients from 12 centers in North America received risedronate 30 mg daily for 2
      months (62 patients) or etidronate 400 mg daily for 6 months (61 patients) in a
      prospective, randomized, double-blind study. Serum alkaline phosphatase (the
      primary variable), serum bone-specific alkaline phosphatase, and urinary
      deoxypyridinoline concentrations were monitored for 12 to 18 months. RESULTS:
      Serum alkaline phosphatase concentration normalized by month 12 in 73% of
      risedronate-treated patients, compared with 15% of those receiving etidronate (P
      <0.001). Median time to normalization was 91 days for risedronate-treated
      patients and >360 days for etidronate-treated patients (P <0.001); relapse rates
      were 3% in the risedronate group and 15% in the etidronate group (P <0.05). At
      month 18, 53% of the risedronate group and 14% of the etidronate group remained
      in biochemical remission. Urinary deoxypyridinoline normalized in 87% of patients
      on risedronate and 57% of patients receiving etidronate (P <0.01); serum bone
      specific alkaline phosphatase normalized in 73% of patients on risedronate and
      18% of patients on etidronate (P <0.001). Patients who had received etidronate
      previously had a blunted response to etidronate, but not to risedronate.
      Reductions in pain were statistically significant in the risedronate group, but
      not in the etidronate group. Both drugs were well tolerated. CONCLUSION: Although
      etidronate is effective, risedronate offers a shorter duration of therapy, better
      and longer-lasting remission, significant reductions in pain, and provides
      additional remission in subjects who exhibited an incomplete response to previous
      etidronate treatment.

PMID- 10335723
TI  - Telephone reporting of the results of cardiac procedures: feasibility and primary
      care physician preferences.
AB  - PURPOSE: We evaluated the feasibility and time required for routine telephone
      communication with primary care physicians after cardiac procedures and surveyed
      primary care physicians as to their preferences for the method and content of
      reports of cardiac procedures. SUBJECTS AND METHODS: A phone call was made within
      1 day of the procedure during normal working hours to the primary care physician
      for all 414 patients who underwent cardiac catheterizations or interventions
      during a 1-year period. Subsequently, all 211 primary care physicians were mailed
      a questionnaire on the effectiveness of phone calls as compared with other
      communication methods. RESULTS: The primary care physician was reached with one
      call for 51% of patients and could not be contacted with up to five calls to
      office, clinic, or hospital for 32% of patients. Mean (+/- SD) phone time per
      patient was 4.1 (+/- 2.0) minutes. Surveys were returned by 119 (56%) of 211
      referring physicians. Telephone communication was rated as "very helpful" by 69%.
      Most primary care physicians (86%) were "very" or "a little pleased" to receive
      phone calls. Survey respondents identified the summary of the results and the
      recommendations for treatment as the most important parts of the report.
      Respondents preferred personal phone calls or faxed reports to phone messages
      left with office staff, reports sent by electronic mail, or mailed written
      reports. CONCLUSIONS: Most primary care physicians find personal phone calls
      helpful and desirable, but the effectiveness of routine phone calls is limited by
      the availability of primary care physicians during working hours and the time
      required for phonereporting.

PMID- 10335724
TI  - Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with
      systemic vasculitis.
AB  - PURPOSE: To assess the value of serial determinations of antineutrophil
      cytoplasmic autoantibodies (ANCA) for monitoring disease activity in patients
      with systemic vasculitis. PATIENTS AND METHODS: Forty-three patients with
      histologically proven vasculitis (21 with Wegener's granulomatosis, 17 with
      microscopic polyangiitis, and 5 with renal-limited vasculitis) were studied for a
      median follow-up of 22 months. Disease activity was prospectively assessed and
      quantified by the Birmingham Vasculitis Activity Score. A total of 347 sera were
      analyzed for ANCA determination. RESULTS: Relapses occurred in 23 (54%) of 43
      patients. Diagnostic category (Wegener's granulomatosis vs micropolyangiitis and
      renal-limited vasculitis), severity of initial symptoms (mean vasculitis activity
      score, mean number of organs involved), and ANCA pattern [cytoplasmic-ANCA (c
      ANCA) vs perinuclear-ANCA (p-ANCA)] did not significantly differ between
      relapsers and nonrelapsers. Lung involvement was more frequent at onset among
      relapsers [16 of 23 (70%) vs 6 of 20 (30%); P = 0.02]. Relapses were slightly,
      but not significantly, more frequent in patients with Wegener's granulomatosis or
      a c-ANCA pattern. The percentage of relapsers was greater in patients with
      persistently positive ANCA than in patients with negative or decreasing ANCA
      titers (86% vs 20%, P = 0.0001). However, the predictive value of an increase in
      ANCA titers for the occurrence of a subsequent relapse was only 28% (4 of 14) for
      c-ANCA, 12% (2 of 17) for anti-proteinase 3-ANCA, and 43% (6 of 14) for anti
      myeloperoxidase-ANCA. An increase in ANCA occurred before or during relapse in
      33% (10 of 30) of cases for c-ANCA/anti-proteinase 3 antibodies, and 73% (11 of
      15) of cases for anti-myeloperoxidase antibodies. CONCLUSION: The persistence of
      ANCA positivity is strongly associated with relapses. However, an increase in
      ANCA titers has a poor value for the early prediction of a subsequent relapse and
      should not be used as a sole parameter for therapeutic intervention. In addition,
      our results suggest that serial anti-myeloperoxidase determination may be useful
      as a prognostic marker in patients who are p-ANCA positive.

PMID- 10335725
TI  - Reduced hypothalamic-pituitary and sympathoadrenal responses to hypoglycemia in
      women with fibromyalgia syndrome.
AB  - PURPOSE: To perform a detailed comparison of the hypothalamic-pituitary-adrenal
      axis and the sympathoadrenal system in women with and without fibromyalgia.
      SUBJECTS AND METHODS: Fifteen premenopausal women who met the 1990 American
      College of Rheumatology criteria for the diagnosis of fibromyalgia and 13
      healthy, premenopausal women were enrolled. We measured baseline 24-hour urinary
      free cortisol levels and evening and morning adrenocorticotropic hormone (ACTH)
      and cortisol levels, performed stepped hypoglycemic hyperinsulinemic clamp
      studies in which serum glucose levels were decreased from 5.0 to 2.2 mmol/L, and
      compared the effects of infusions of placebo and ACTH. RESULTS: Women with
      fibromyalgia had normal 24-hour urinary free cortisol levels and normal diurnal
      patterns of ACTH and cortisol. There was a significant, approximately 30%,
      reduction in the ACTH and epinephrine responses to hypoglycemia in women with
      fibromyalgia compared with controls. Prolactin, norepinephrine, cortisol, and
      dehydroepiandrosterone responses to hypoglycemia were similar in the two study
      groups. In subjects with fibromyalgia, the epinephrine response to hypoglycemia
      correlated (P = 0.01) inversely with overall health status as measured by the
      fibromyalgia impact questionnaire. Graded ACTH infusion revealed similar
      increases in cortisol in women with fibromyalgia and healthy controls.
      CONCLUSIONS: Patients with fibromyalgia have an impaired ability to activate the
      hypothalamic-pituitary portion of the hypothalamic-pituitary-adrenal axis as well
      as the sympathoadrenal system, leading to reduced ACTH and epinephrine responses
      to hypoglycemia.

PMID- 10335726
TI  - Association between angiotensin-converting enzyme gene polymorphisms and
      regression of left ventricular hypertrophy in patients treated with angiotensin
      converting enzyme inhibitors.
AB  - PURPOSE: An insertion/deletion (ID) polymorphism of the angiotensin-converting
      enzyme (ACE) gene is associated with left ventricular hypertrophy. The present
      study examined polymorphisms of the ACE gene in patients with essential
      hypertension and left ventricular hypertrophy who were participants in a long
      term trial of therapy with an ACE inhibitor. PATIENTS AND METHODS: ACE inhibitor
      therapy was administered for >2 years to 54 patients with hypertension who had
      moderate or severe left ventricular hypertrophy. Cardiac dimensions were
      monitored by echocardiography before the initiation of therapy and after 1 and 2
      years of treatment. Serum ACE activity and plasma concentrations of brain
      natriuretic peptide, a marker for left ventricular hypertrophy, were also
      monitored. RESULTS: Eighteen patients had the II genotype for the angiotensin
      converting enzyme gene, 19 had the ID genotype, and 17 had the DD genotype.
      Baseline (mean +/- SD) serum ACE activity was significantly greater (P <0.05) in
      the DD (18 +/- 7 IU/L) group than in the II (7 +/- 4 IU/L) or ID (12 +/- 6 IU/L)
      groups. ACE inhibitor therapy was effective in controlling blood pressure, and it
      reduced posterior and septal wall thickness, left ventricular mass index, and
      plasma brain natriuretic peptide concentration in all three groups. Despite
      similar blood pressure reductions, after 2 years, mean (+/- SD) regression in
      posterior wall thickness was significantly less (P <0.05) in the DD group (-9% +/
      5%) than in the ID (-21% +/- 7%) and II (-21% +/- 9%) groups. Similar results
      were seen for the reductions in brain natriuretic peptide levels. The magnitudes
      of regression of septal wall thickness and left ventricular mass index during
      therapy were less in the DD group than the II group (P <0.05). CONCLUSION:
      Hypertensive patients with the DD genotype are less likely to have regression of
      left ventricular hypertrophy when treated with ACE inhibitors than are patients
      with other ACE genotypes.

PMID- 10335728
TI  - Association between hepatitis C virus and non-Hodgkin's lymphoma, and effects of
      viral infection on histologic subtype and clinical course.
AB  - PURPOSE: Because an etiologic role for hepatitis C virus in non-Hodgkin's B-cell
      lymphoma has been suggested by several reports, we assessed the prevalence of
      hepatitis C virus infection in patients with non-Hodgkin's B lymphoma and in
      controls, and evaluated the influence of viral infection on histologic and
      clinical features of the lymphoma patients. PATIENTS AND METHODS: We
      prospectively investigated 175 consecutive patients with non-Hodgkin's lymphoma
      and 350 controls for serologic and molecular markers of hepatitis C virus
      infection. Controls were selected from inpatients (n = 175) and outpatients (n =
      175) cared for at our hospital. Patients with lymphoma who had hepatitis C virus
      infection were tested for mixed cryoglobulinemia. Aminotransferase levels were
      measured in all lymphoma patients at baseline and during and after chemotherapy.
      RESULTS: Hepatitis C virus prevalence in patients with non-Hodgkin's lymphoma was
      significantly greater than in control subjects (37% vs 9%, P = 0.0001). Among
      patients with lymphoma, viral infection was associated with older mean (+/
      standard deviation) age (67 +/- 14 vs 61 +/- 8 years, P = 0.001), and women (41
      of 87, 47%) were more likely than men (24 of 88, 27%) to have evidence of
      hepatitis C infection (P = 0.006). Thirteen of the 20 cases of immunocytoma were
      associated with hepatitis C virus infection, which was also more common in
      patients with orbital and conjunctival localization of lymphoma. Patients with
      mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach were less likely
      to have evidence of hepatitis C infection. Mixed cryoglobulinemia was much more
      common in patients with hepatitis C virus infection (14 of 65 vs 1 of 110, P =
      0.0001); it was not associated with the histologic type of lymphoma. Patients
      with and without hepatitis C virus infection underwent similar chemotherapy
      regimens and had no differences in response to chemotherapy or in overall and
      disease-free survival. Hepatic toxicity from chemotherapy was seen only in
      patients with hepatitis C virus infection, although all but one of these patients
      were able to complete their planned treatment. CONCLUSION: These findings suggest
      that the hepatitis C virus may have a role as an etiologic agent in non-Hodgkin's
      B-cell lymphoma. Some clinical and pathologic features of the disease are
      associated with hepatitis C virus infection, but the virus does not seem to
      affect prognosis.

PMID- 10335727
TI  - The effects of physical treatment on induced fever in humans.
AB  - PURPOSE: Initial treatments for fever include the amelioration of underlying
      causes and administration of antipyretic medications. However, patients who fail
      these treatments are often actively cooled, which may be counterproductive
      because decreasing skin temperature increases the thermoregulatory core target
      temperature. Cooling may also provoke metabolic and autonomic stress and thermal
      discomfort. SUBJECTS AND METHODS: We studied 9 subjects, each on 3 days. Fever
      was induced each day with 100,000 IU/kg of interleukin-2 administered
      intravenously (elapsed time zero). Randomly assigned treatments were 1) control
      (a cotton blanket), 2) cooling (forced air at 15 degrees C), or 3) self-adjust
      (forced-air warming adjusted to comfort). Treatments were maintained for 3 to 8
      elapsed hours. RESULTS: Peak core temperatures (mean +/- SD) were 38.4 +/- 0.5
      degrees C on the control day, 38.1 +/- 0.5 degrees C on the cooling day, and 38.5
      +/- 0.4 degrees C on the self-adjust day. Integrated core temperatures were 6.0
      +/- 1.6 degrees C x h on the control day, 5.7 +/- 2.2 degrees C x h on the
      cooling day, and 6.4 +/- 1.2 degrees C x h on the self-adjust day. Neither peak
      nor integrated core temperatures differed significantly on the 3 days. Shivering
      was common on the cooling day but otherwise rare. Oxygen consumption was normal
      on the control and self-adjust days but increased 35% to 40% during cooling (P =
      0.0001). Mean arterial pressure and plasma norepinephrine and epinephrine
      concentrations were significantly greater during cooling (P <0.05). On a self
      reported thermal comfort scale, the subjects were miserable during cooling and
      significantly more comfortable on the self-adjust than control day (P <0.05).
      CONCLUSION: We conclude that active cooling should be avoided in unsedated
      patients with moderate fever, because it does not reduce core temperature but
      does increase metabolic rate, activate the autonomic nervous system, and provoke
      thermal discomfort.

PMID- 10335729
TI  - Learning primary care in medical school: does specialty or geographic location of
      the teaching site make a difference?
AB  - PURPOSE: The Liaison Committee on Medical Education mandates a core curriculum in
      primary care but does not specify its content or structure. In this study, we
      explored the question of whether primary care specialty or geographic location
      affects student learning and satisfaction. METHODS: From 1994 to 1996, 294 third
      year medical students at one medical school in New York state were randomly
      assigned to multiple teaching sites for a required 5-week primary care clerkship.
      Independent predictor variables were primary care specialty of the preceptor
      (family medicine, medicine, pediatrics, or joint medicine and pediatrics) and
      geographic location of the site (urban, suburban, rural). Outcome measures
      included four areas of student satisfaction, one of patient volume, and two of
      student performance. RESULTS: Primary care specialty had no detectable
      association with the outcome measures, except for a lower rating of patient
      diversity in pediatric experiences (P <0.001). Geographic location of the site
      had a significant association with all measures of student satisfaction and
      patient volume (all P values <0.001). Students at rural sites rated the
      experience more highly and saw on average 15 more patients per rotation. Ratings
      of student satisfaction remained high after adjusting for patient volume. Primary
      care specialty and geographic location did not influence student performance in
      the clerkship or scores on standardized patient examination. CONCLUSIONS: Rural
      geographic location of teaching site, but not primary care specialty, was
      associated with higher student satisfaction. However, higher student satisfaction
      ratings did not correspond to better student performance. Provided that all sites
      meet the screening criteria for inclusion in a teaching program, these findings
      support the continued development of high-quality, heterogeneous,
      interdisciplinary, primary care experiences.

PMID- 10335730
TI  - Delirium: a symptom of how hospital care is failing older persons and a window to
      improve quality of hospital care.
AB  - Delirium, or acute confusional state, which often results from hospital-related
      complications or inadequate hospital care for older patients, can serve as a
      marker of the quality of hospital care. By reviewing five pathways that can lead
      to a greater incidence of delirium--iatrogenesis, failure to recognize delirium
      in its early stages, attitudes toward the care of the elderly, the rapid pace and
      technological focus of health care, and the reduction in skilled nursing staff-
      we identify how future trends and cost-containment practices may exacerbate the
      problem. Examining delirium also provides an opportunity to improve the quality
      of hospital care for older persons. Interventions to reduce delirium would need
      to occur at the local and national levels. Local strategies would include routine
      cognitive assessment and the creation of systems to enhance geriatric care, such
      as incentives to change practice patterns, geriatric expertise, case management,
      and clinical pathways. National strategies might include providing education for
      physicians and nurses to improve the recognition of delirium and the awareness of
      its clinical implications, improving quality monitoring systems for delirium, and
      creating environments to facilitate the provision of high-quality geriatric care.

PMID- 10335732
TI  - The role of cell adhesion molecules in ischemic acute renal failure.

PMID- 10335733
TI  - Success in translating guidelines for beta-blocker use in patients following
      acute myocardial infarction into improved clinical care.

PMID- 10335731
TI  - Postmenopausal hormone therapy and the risk of colorectal cancer: a review and
      meta-analysis.
AB  - PURPOSE: Colorectal cancer is the fourth most common cancer and the second
      leading cause of cancer death in the United States. Accumulating evidence
      indicates that postmenopausal hormone therapy may reduce the risk of colorectal
      cancer in women. METHODS: Through MEDLINE computer searches (January 1966 to
      September 1998) and a review of references, we identified English-language
      articles with quantitative data on the relation of postmenopausal hormone therapy
      to colorectal cancer. We reviewed the studies and made summary estimates of
      relative risks (RR) by weighting the results of each study in proportion to its
      precision, using a general variance-based, fixed-effects model. RESULTS: In our
      meta-analysis of 18 epidemiologic studies of postmenopausal hormone therapy and
      colorectal cancer, we found a 20% reduction [RR = 0.80, 95% confidence interval
      (CI), 0.74 to 0.86] in risk of colon cancer and a 19% decrease (RR = 0.81, 95%
      CI, 0.72 to 0.92) in the risk of rectal cancer for postmenopausal women who had
      ever taken hormone therapy compared with women who never used hormones. Much of
      the apparent reduction in colorectal cancer was limited to current hormone users
      (RR = 0.66, 95% CI, 0.59 to 0.74). CONCLUSION: Observational studies suggest a
      reduced risk of colorectal cancer among women taking postmenopausal hormones.
      There is biologic evidence to support this association.

PMID- 10335734
TI  - Primary care: beyond disciplines.

PMID- 10335735
TI  - Ominous sneezing.

PMID- 10335736
TI  - Withdrawal of Pneumocystis carinii pneumonia prophylaxis after combination
      antiretroviral therapy in patients with AIDS.

PMID- 10335737
TI  - A dopamine-secreting pheochromocytoma.

PMID- 10335738
TI  - Nimodipine treatment for intractable hiccups.

PMID- 10335739
TI  - Monitoring health outcomes among patients with arthritis using the SF-36 Health
      Survey: overview.
AB  - As shown here, general health measures cover much of the content included in
      arthritis-specific measures, but, are they equally sensitive to changes in
      disease condition? We reviewed the literature on the most widely used general
      health measure, the SF-36 Health Survey, to see if the empirical evidence
      supported its validity for use in arthritis patients. As of this writing, there
      was no documentation of the sensitivity of the SF-36 to short-term changes in
      arthritic condition over the course of clinical trials and few studies that
      compared the sensitivity of the SF-36 to arthritis-specific measures. The
      empirical research reported in this special supplement contributes to the
      literature on the use of the SF-36 in arthritis patients and demonstrates methods
      of studying the validity of general health measures to monitor change in specific
      conditions.

PMID- 10335740
TI  - The SF-36 Health Survey as a generic outcome measure in clinical trials of
      patients with osteoarthritis and rheumatoid arthritis: tests of data quality,
      scaling assumptions and score reliability.
AB  - OBJECTIVE: To evaluate the psychometric assumptions underlying the construction
      and scoring of SF-36 scales and summary measures among clinical trial
      participants with arthritis. METHODS: Cross-sectional SF-36 data from the
      baseline assessment of adult patients (n = 1,016) participating in four placebo
      controlled clinical trials of treatment for arthritis were analyzed with blinding
      as to treatment. Tests of the completeness of data, scaling assumptions, internal
      consistency reliability, and factor structure of SF-36 scales were performed for
      the combined sample. Eligible participants had at least a 6-month history of
      moderate to severe osteoarthritis or rheumatoid arthritis of the knee or hip.
      Participants meeting inclusion criteria had undergone a washout period of 3-14
      days before baseline assessment to bring about a flare state in osteoarthritis or
      rheumatoid arthritis symptoms. Baseline sample sizes for the three osteoarthritis
      trials were n = 121, n = 341, and n = 187. The baseline sample size for the
      rheumatoid arthritis trial was n = 367. The average age of participants was 60
      years, and the majority were females (72%). Measured were functional health and
      well-being scales and physical and mental health summary measures from the SF-36
      Health Survey acute form. RESULTS: Missing responses ranged from 0.0% to 1.5%
      across SF-36 items, and scale scores could be computed for 96.8% to 100% of
      participants across trials. In all four trials, item internal consistency tests
      were passed (91.4%-97.1%) and item discriminant validity tests were passed (96.9%
      100.0%). Across the four trials, internal-consistency reliability coefficients
      ranged from a low of 0.75 to a high of 0.91 for the eight scales (median = 0.84),
      exceeding the minimum standards for group comparisons. Ceiling effects were
      minimal for most scales, and floor effects were noteworthy for the role physical
      and role emotional scales. Physical and mental health factors identified in
      previous studies were replicated. CONCLUSION: The SF-36 Health Survey proved to
      be a psychometrically sound tool for the assessment of the health status of adult
      participants in clinical trials of arthritis.

PMID- 10335742
TI  - The SF-36 Arthritis-Specific Health Index (ASHI): I. Development and cross
      validation of scoring algorithms.
AB  - An arthritis-specific health index (ASHI) for the SF-36 Health Survey was
      developed by studying its responsiveness to changes in clinical indicators of
      arthritis severity. Longitudinal data from 1,076 patients participating in four
      placebo-controlled trials were analyzed. All had at least a 6-month history of
      moderate to severe osteoarthritis or rheumatoid arthritis of the knee or hip. All
      had undergone a washout period of 3 to 14 days before baseline assessment to
      bring about a flare state in osteoarthritis or rheumatoid arthritis symptoms.
      Their average age was 60 years and 72% were female. Change scores for the eight
      scale SF-36 health profile (acute version) and five arthritis-specific measures
      of disease severity (knee pain on weight bearing, time to walk 50 feet, physician
      global evaluation of symptom severity and impact, patient global evaluation of
      symptom severity and impact, and pain intensity visual analogue scale) were
      computed by subtracting scores before treatment from scores at two-week follow
      up. Canonical correlation methods were used to derive weights for changes in SF
      36 scales to score a single index (ASHI) that maximized its correlation with
      changes in the set of five clinical measures of arthritis severity. The weights
      used to score the ASHI were cross-validated in a 25% holdout group (N = 144) from
      the first two osteoarthritis trials and in two additional osteoarthritis and
      rheumatoid arthritis trials (N = 530). Only one SF-36 canonical variate (ASHI)
      correlated significantly (F = 4.69, P < 0.0001) with the clinical canonical
      variate that served as the "criterion" measure of change in the severity of
      arthritis. Changes in the ASHI and clinical canonical variate were substantially
      correlated in the developmental sample (r = 0.628, P < 0.0001) and on cross
      validation (r = 0.629, P < 0.0001). The clinical canonical variate correlated
      highly (r = 0.75-0.88) with changes in all but one of the five clinical measures
      (50-foot walk; r = 0.41). The pattern of correlations between changes in SF-36
      scales and the ASHI indicated that ASHI is primarily a measure of bodily pain (r
      = 0.92) and other aspects of physical and role functioning and well-being (r =
      0.69 for Role-Physical, r = 0.68 for Physical Functioning, r = 0.52 for Social
      Functioning, and r = 0.51 Vitality). The patterns of correlations between SF-36
      scales and the ASHI were very similar across developmental and cross-validation
      samples. This research demonstrates the feasibility and generalizability of a
      single ASHI scored from changes in responses to the SF-36 Health Survey. The
      generic SF-36 health profile, which has already been shown to be useful in
      comparing arthritis with other diseases and treatments, can also be scored
      specifically to make it more useful in studies of osteoarthritis and rheumatoid
      arthritis.

PMID- 10335741
TI  - The SF-36 Health Survey as a generic outcome measure in clinical trials of
      patients with osteoarthritis and rheumatoid arthritis: relative validity of
      scales in relation to clinical measures of arthritis severity.
AB  - OBJECTIVE: To evaluate the validity of SF-36 Health Survey (SF-36) scale scores
      and summary measure scores to describe the health burden of arthritis and to be
      responsive to clinical indicators of arthritis severity used in four clinical
      trials. METHODS: Adults participating in four double-blinded, placebo-controlled
      clinical trials of therapy for osteoarthritis or rheumatoid arthritis were
      administered the SF-36 concurrent with clinical measures of disease severity (n =
      1,016). Data were collected before treatment and 2 weeks after treatment. Mean SF
      36 scores for all patients with arthritis at baseline were compared to a
      sociodemographically equivalent national norm to test the ability of the SF-36 to
      describe the burden of arthritis. To test the responsiveness of SF-36 scores to
      clinical measures of arthritis severity, mean SF-36 scale scores were compared
      across patients differing in arthritis severity before treatment. Two-week mean
      SF-36 change scores were compared across patients who improved in arthritis
      severity (responders) versus patients who did not improve (nonresponders). F
      statistics and relative validity coefficients were computed to determine how well
      each SF-36 scale and summary measure discriminated among arthritis severity
      levels and distinguished treatment responders from nonresponders, relative to the
      best scale. RESULTS: Large and statistically significant differences in mean SF
      36 scale scores and summary measures were found such that trial participants
      scored in worse health than a sociodemographically equivalent US general
      population norm. In addition, the largest SF-36 scale scores were found to
      significantly differ across clinically defined levels of arthritis severity.
      Finally, it was found that the SF-36 scales that best discriminate among
      arthritis severity groups cross-sectionally were also best at discriminating
      treatment responders from nonresponders. CONCLUSION: Results of this study
      support the validity of the SF-36 to document the health burden of arthritis and
      as a measure of generic health outcome for clinical trials of alternative
      treatments for osteoarthritis and rheumatoid arthritis patients.

PMID- 10335743
TI  - The SF-36 Arthritis-Specific Health Index (ASHI): II. Tests of validity in four
      clinical trials.
AB  - OBJECTIVE: The SF-36 Arthritis-Specific Health Index (ASHI) was constructed to
      improve the responsiveness of the SF-36 Health Survey to changes in the severity
      of arthritis through the use of arthritis-specific scoring algorithms. This study
      compared the responsiveness of the ASHI and other generic scales and summary
      measures scored from the SF-36 in clinical trials of health outcomes for patients
      with arthritis. METHODS: Longitudinal data for patients (n = 835) participating
      in four placebo-controlled trials were analyzed. Study participants had at least
      a 6-month history of moderate to severe osteoarthritis or rheumatoid arthritis of
      the knee or hip. All had undergone a washout period of 3 to 14 days before
      baseline assessment to bring about a flare state in osteoarthritis or rheumatoid
      arthritis symptoms. Their average age was 60 years, and 72% were female.
      Responders and nonresponders were classified on the basis of physician
      assessments of changes in arthritis severity, with blinding as to treatment
      group; treated and untreated (placebo) groups were also compared. For the SF-36
      ASHI, generic physical (PCS) and mental (MCS) component summary measures and each
      of eight subscales scored from the SF-36 (acute version) change scores were
      computed by subtracting scores before treatment from scores at 2-week follow-up.
      To evaluate empirical validity, analyses of variance were performed. For each
      measure, an F-ratio was computed for the comparison between clinically defined
      groups of responders and nonresponders and between groups of patients assigned to
      placebo versus drug therapy. Relative validity (RV) coefficients were computed
      for the ASHI in comparison with PCS, MCS, and the best SF-36 scale to determine
      which was more responsive. RESULTS: In analyses of each of the four trials and
      all trials combined, RV coefficients for the ASHI were higher than those for both
      of the generic SF-36 summary measures and for the most valid SF-36 scale (Bodily
      Pain), with only one exception. Across 40 tests of validity in distinguishing
      treated from untreated patients, the ASHI was 5% to 19% more valid than the best
      SF-36 scale (RV = 1.05-1.19; RV = 1.10 in all trials combined). The generic
      summary measures (PCS and MCS) were much less valid in these tests (RV = 0.67 and
      0.27, respectively). In analyses of responders and nonresponders, RV coefficients
      for the ASHI ranged from 0.70 to 1.22 (RV = 1.04 in all trials combined), in
      comparison with the best SF-36 subscale, which was always Bodily Pain. RV
      coefficients were lower for PCS (RV = 0.75) and much lower than the MCS (RV =
      0.18) in comparisons of treatment outcomes based on all trials combined.
      CONCLUSION: The ASHI appears to be more valid than the eight SF-36 scales and PCS
      and MCS summary measures for purposes of distinguishing between treated and
      untreated patients and between clinical responders and nonresponders. This study
      demonstrates the feasibility of improving the validity of the SF-36 through the
      use of arthritis-specific scoring while retaining the option of generic scoring,
      which makes it possible to also compare results across diseases and treatments.

PMID- 10335744
TI  - A call to action: improving oncologic care information in the United States.

PMID- 10335745
TI  - Shrinking costs of inpatient mental health care.

PMID- 10335746
TI  - The sensitivity of Medicare claims data for case ascertainment of six common
      cancers.
AB  - BACKGROUND: Although Medicare claims data have been used to identify cases of
      cancer in older Americans, there are few data about their relative sensitivity.
      OBJECTIVES: To investigate the sensitivity of diagnostic and procedural coding
      for case ascertainment of breast, colorectal, endometrial, lung, pancreatic, and
      prostate cancer. SUBJECTS: Three hundred and eighty nine thousand and two hundred
      and thirty-six patients diagnosed with cancer between 1984 and 1993 resided in
      one of nine Surveillance Epidemiology and End Results (SEER) areas. MEASURES: The
      sensitivity of inpatient and Part B diagnostic and cancer-specific procedural
      codes for case finding were compared with SEER. RESULTS: The sensitivity of
      inpatient and inpatient plus Part B claims for the corresponding cancer diagnosis
      was 77.4% and 91.2%, respectively. The sensitivity of inpatient claims alone was
      highest for colorectal (86.1%) and endometrial (84.1%) cancer and lowest for
      prostate cancer (63.6%). However, when Part B claims were included, the
      sensitivity for diagnosis of breast cancer was greater than for other cancers
      (93.6%). Inpatient claim sensitivity was highest for earlier years of the study,
      and, because of more complete data and longer follow up, the highest sensitivity
      of combined inpatient and Part B claims was achieved in the late 1980s or early
      1990s. CONCLUSIONS: Medicare claims provide reasonably high sensitivity for the
      detection of cancer in the elderly, especially if inpatient and Part B claims are
      combined. Because the study did not measure other dimensions of accuracy, such as
      specificity and predictive value, the potential costs of including false positive
      cases need to be assessed.

PMID- 10335747
TI  - Use of Medicare hospital and physician data to assess breast cancer incidence.
AB  - OBJECTIVES: Health claims data have the potential of being an inexpensive,
      timely, and nationally representative source of information about cancer. This
      study examined the utility of Medicare hospital and physician data as an
      independent source to identify incident breast cancer cases. METHODS: Data came
      from Medicare and the National Cancer Institute's SEER cancer registries. From
      1992, for women residing in the SEER states (n = 659,260), Medicare hospital and
      physician claims were reviewed to identify women with a breast cancer diagnosis
      on a claim (n = 6,784). These women were matched with women in the SEER data who
      had been diagnosed with breast cancer in 1992 (n = 3,230). The sensitivity,
      specificity, and positive predictive value (PPV) of the Medicare data were
      calculated. Logistic regression models were used to identified cancer related
      procedures reported to Medicare that could distinguish true cases from false
      positive cases. Predicted values from these models were included to create plots
      of sensitivity versus false positive rates and sensitivity versus PPV. RESULTS:
      Medicare hospital data had 62% sensitivity, 99.9% specificity, and 88% PPV.
      Physician claims increased sensitivity by 14%, with specificity of 99.4%, and a
      PPV of 10%. Inclusion of additional cancer related diagnoses and procedures
      improved the ability to distinguish true cases from false positives, although the
      number of false positive cases remained high. CONCLUSIONS: The Medicare data
      overall offer limited potential to assess breast cancer incidence, largely
      because of low sensitivity and poor PPV. The Medicare data may have utility to
      identify women undergoing selected breast cancer treatments. In addition, the
      data may be used to help registries focus case-finding efforts, particularly for
      persons undergoing cancer related treatments.

PMID- 10335748
TI  - Changes in inpatient mental health utilization and costs in a privately insured
      population, 1993 to 1995.
AB  - BACKGROUND: Concerns over rising health care costs have led to pressure on health
      care providers to reduce inpatient costs. METHODS: Inpatient claims data were
      analyzed for adult users of mental health services (n = 45,579) from a national
      sample of over 3.8 million privately insured individuals between 1993 and 1995
      from the MarketScan database. Costs and annual hospital days per treated patient
      were compared across diagnostic groups and plan types. RESULTS: Inpatient mental
      health costs fell 30.5% over the period, driven primarily by decreases in the
      number of hospital days per treated patient per year (-20.0%), with smaller
      changes in the proportion of enrollees who received care (-0.2%), and per diem
      costs (-13.1%). Patients whose primary diagnosis was mild/moderate depression saw
      the largest decrease in costs per treated patient (44.5%), and those diagnosed
      with schizophrenia experienced the smallest decrease (23.5%). There was no
      evidence of substitution of medical for psychiatric care. CONCLUSIONS: Inpatient
      cost reductions have been substantial and are primarily caused by reductions in
      the number of inpatient mental health treatment days per treated patient. Further
      research is needed to evaluate the impact of these changes on outcome, quality of
      care, and patient satisfaction.

PMID- 10335749
TI  - Linking clinical relevance and statistical significance in evaluating intra
      individual changes in health-related quality of life.
AB  - OBJECTIVE: To compare the standard error of measurement (SEM) with established
      standards for clinically relevant intra-individual change in an evaluation of
      health-related quality of life. DESIGN: Secondary analysis of data from a
      randomized controlled trial. SUBJECTS: Six hundred and five outpatients with a
      history of cardiac problems attending the general medicine clinics of a major
      academic medical center. MEASURES: Baseline and follow-up interviews included a
      modified version of the Chronic Heart Failure Questionnaire (CHQ) and the SF-36.
      The SEM values corresponding to established standards for minimal clinically
      important differences (MCIDs) on the CHQ were determined. Individual change on
      the SF-36 was explored using the same SEM criterion. RESULTS: One-SEM changes in
      this population corresponded well to the patient-driven MCID standards on all CHQ
      dimensions (weighted kappas (0.87; P < 0.001). The distributions of outpatients
      who improved, remained stable, or declined (defined by the one-SEM criterion)
      were generally consistent between CHQ dimensions and SF-36 subscales.
      CONCLUSIONS: The use of the SEM to evaluate individual patient change should be
      explored among other health-related quality of life instruments with established
      standards for clinically relevant differences. Only then can it be determined
      whether the one-SEM criterion can be consistently applied as a proxy for
      clinically meaningful change.

PMID- 10335750
TI  - Associations between health status and utilities implications for policy.
AB  - BACKGROUND: If shape of a person's utility function is associated with his health
      status, as is predicted by Prospect Theory, the use of utilities from the healthy
      could result in 'de facto' discrimination against the sick. OBJECTIVES: To
      determine if patients' utilities for hypothetical states and for their current
      health were associated with their health status. DESIGN: A cross-sectional study
      of the health and values of patients with depressive illnesses. SETTING: Patients
      from three large primary care practices with various medical illnesses
      complicated by symptoms of depression. MEASURES: Short-Form 12 health status
      measurements, standard gamble, and visual analog scale preference measurements
      for patients' current health and for three hypothetical states. RESULTS: One
      hundred and forty nine patients enrolled in the study and 139 patients completed
      the survey. Utilities for the best and worst states were similar across different
      levels of health status; however, standard gamble utilities for intermediate
      health states were higher for patients in poorer health than patients in better
      health (P = 0.019,) suggesting utility functions with radically different shapes.
      Utilities for patients' current health were also associated with their health
      status. Patients in poor health tended to overvalue their current health relative
      to the most similar hypothetical state; whereas, patients in good health tended
      undervalue their current health state (P = 0.036). CONCLUSIONS: In patients with
      depressive illnesses, there were significant interactions between health and
      values, that were consistent with the predictions of Prospect Theory, and that
      could result in systematic under valuation of the health effects of treatments
      that primarily benefit more severely patients ill.

PMID- 10335751
TI  - Hospital readmissions and quality of care.
AB  - BACKGROUND: Readmission rates are often proposed as markers for quality of care.
      However, a consistent link between readmissions and quality has not been
      established. OBJECTIVE: To test the relation of readmission to quality and the
      utility of readmissions as hospital quality measures. SUBJECTS: One thousand,
      seven hundred and fifty-eight Medicare patients hospitalized in four states
      between 1991 to 1992 with pneumonia or congestive heart failure (CHF). DESIGN:
      Case control. MEASURES: Related adverse readmissions (RARs), defined as
      readmissions that indicate potentially sub-optimal care during initial
      hospitalization, were identified from administrative data using readmission
      diagnoses and intervening time periods designated by physician panels. We used
      linear regression to estimate the association between implicit and explicit
      quality measures and readmission status (RARs, non-RAR readmissions, and
      nonreadmissions), adjusting for severity. We tested whether RARs were associated
      with inferior care and performed simulations to determine whether RARs
      discriminated between hospitals on the basis of quality. RESULTS: Compared with
      nonreadmitted pneumonia patients, patients with RARs had lower adjusted quality
      measured both by explicit (0.25 standardized units, P = 0.004) and implicit
      methods (0.17, P = 0.047). Adjusted differences for CHF patients were 0.17 (P =
      0.048) and 0.20 (P = 0.017), respectively. In some analyses, patients with non
      RAR readmissions also experienced lower quality. However, rates of inferior
      quality care did not differ significantly by readmission status, and simulations
      identified no meaningful relationship between RARs and hospital quality of care.
      CONCLUSIONS: RARs are statistically associated with lower quality of care.
      However, neither RARs nor other readmissions appear to be useful tools for
      identifying patients who experience inferior care or for comparing quality among
      hospitals.

PMID- 10335752
TI  - Influenza and pneumococcal vaccine receipt in older persons with chronic disease:
      a population-based study.
AB  - OBJECTIVE: To identify factors associated with receipt of the pneumococcal and
      influenza vaccines among community-dwelling older persons with chronic disease.
      METHODS: A population-based sample of urban and rural Iowa adults age 65 years
      and older with one or more self-reported target medical conditions were
      interviewed by telephone. Information was obtained on aspects of health care
      access, which were examined as potential determinants of receipt of recommended
      vaccines. RESULTS: A total of 787 interviews were completed (response rate = 68%;
      completion rate for screened, eligible subjects = 91%). Two-thirds (n = 531, 68%)
      reported influenza vaccination in the last year, and one-half (51%, n = 393)
      reported ever receiving the pneumococcal vaccine. Both vaccines were received at
      recommended intervals by 347 subjects (44%). Multivariable logistic regression
      identified the following factors independently associated with receipt of both
      vaccines: age 70 or greater (OR = 1.64, CI95 = 1.15, 2.32); married (OR = 1.41,
      CI95 = 1.03, 1.92); self-owned residence (OR = 0.57, CI95 = 0.33, 0.97); working
      (OR = 2.94, CI95 = 1.38, 6.18); increased number of target medical conditions (OR
      = 1.3 for each, CI95 = 1.09, 1.54); current prescription medication (OR = 2.04,
      CI95 = 1.32, 3.14); and a physician visit in the last year (OR = 2.53, CI95 =
      1.52-4.19). Receipt of the vaccines was unrelated to geographic location in a
      rural area. CONCLUSIONS: Despite their proven safety and efficacy, many persons
      with at least two indications to receive either vaccine remain unvaccinated.
      Among the elderly with chronic disease, predisposing and need factors were
      independently associated with receipt of both vaccines. Enabling factors assessed
      appeared less important in this population. Targeting of the elderly and those
      with chronic disease to receive recommended vaccines is needed to adequately
      protect these populations at risk.

PMID- 10335753
TI  - Further validation and reliability testing of the Trust in Physician Scale. The
      Stanford Trust Study Physicians.
AB  - OBJECTIVES: To further validate and assess the reliability and validity of the
      Trust in Physician Scale. METHODS: Consecutive adult patients (n = 414) from 20
      community-based, primary care practices were enrolled in a prospective, 6-month
      study. At enrollment, subjects completed the 11-item Trust in Physician Scale
      plus measures of demographics, preferences for care, and satisfaction with care
      received from the physician. Continuity, satisfaction with care, and self
      reported adherence to treatment were measured at 6 months. Reliability, construct
      validity, and predictive validity were assessed using correlation coefficients
      and analysis of variance techniques. RESULTS: The Trust in Physician Scale showed
      high internal consistency (Cronbach's alpha = .89) and good 1-month test-retest
      reliability (intraclass correlation coefficient = .77). As expected, trust
      increased with the length of the relationship and was higher among patients who
      actively chose their physician, who preferred more physician involvement, and who
      expected their physician to care for a larger proportion of their problems (P <
      0.001 for all associations). Baseline trust predicted continuity with the
      physician, self-reported adherence to medication, and satisfaction at 6 months
      after adjustment for gender, age, education, length of the relationship, active
      choice of the physician, and preferences for care. After additional adjustment
      for baseline satisfaction with physician care, trust remained a significant
      predictor of continuity, adherence, and satisfaction. CONCLUSIONS: The Trust in
      Physician Scale has desirable psychometric characteristics and demonstrates
      construct and predictive validity. It appears to be related to, but still
      distinct from, patient satisfaction with the physician and, thus, provides a
      valuable additional measure for assessment of the quality of the patient
      physician relationship.

PMID- 10335754
TI  - Physicians' attitudes toward reclassifying drugs as over-the-counter.
AB  - OBJECTIVES: Releasing prescription drugs over-the-counter (OTC) has been a trend
      in many Western countries. The purpose of this study was to find out about
      Finnish physicians' attitudes towards OTC switches and to find out whether
      transfer of drugs that are used in a doctor's own area of specialty increases
      negative attitudes toward release. For the latter purpose, gynecologists'
      perceptions about the availability of vaginal antifungal OTC drugs was studied.
      METHODS: Postal questionnaire to a representative random sample of gynecologists
      (n = 169) and general practitioners (GPs) (n = 288) in six counties in Finland in
      1996. After a reminder, the response rate was 77% (n = 341). Multivariate
      logistic regression models were used to explore the relationship of factors to
      attitudes toward OTC drugs. RESULTS: The overall attitude toward the availability
      of OTC drugs was moderately positive but was more reserved toward those drugs
      only recently given OTC status. However, physicians were judged in many cases to
      be the most suitable source of information on OTC drugs. GPs working in health
      centers, more often than other physicians, found drugs suitable for self
      medication. Our hypothesis about gynecologists being against the release of
      vaginal antifungal drugs was not supported. CONCLUSIONS: Physicians' views about
      OTC drugs are influenced by the current OTC status of the drug and by public
      discussion. The place of work has an important influence on these opinions, most
      likely reflecting the effect of case mix and patient load.

PMID- 10335756
TI  - Serial volumetric intravascular ultrasound assessment of arterial remodeling in
      left main coronary artery disease.
AB  - Serial volumetric intravascular ultrasound (IVUS) was used to study de novo,
      nontreated left main coronary arteries (LMCAs) in 31 patients. Using an automated
      contour detection algorithm, analysis of 7.2 +/- 2.5 mm long segments included
      arterial, lumen, and plaque volumes and plaque burden (plaque/arterial volumes).
      During follow-up (7.7 +/- 2.4 months), the percent change in lumen volume
      correlated with the percent change in arterial volume (r = 0.897, p <0.0001), but
      not with the percent change in plaque volume (r = 0.066, p = 0.7263). Percent
      changes in arterial volume correlated with percent changes in plaque + media
      volume (r = 0.448, p = 0.0115), indicating arterial remodeling. However, there
      was a spectrum of responses ranging from inadequate remodeling (decrease in lumen
      volume despite no increase or a decrease in plaque volume: i.e., arterial
      shrinkage) to overcompensation (an increase in lumen volume despite an increase
      in plaque volume). Serial volumetric IVUS (1) confirms the existence of both
      positive and negative remodeling in LMCA, and (2) shows that in moderate LMCA
      disease, luminal changes resulted primarily from positive versus negative
      remodeling, not plaque progression and/or regression.

PMID- 10335755
TI  - Relation of QT dispersion to infarct size and left ventricular wall motion in
      anterior wall acute myocardial infarction.
AB  - Previous studies have shown that QT dispersion increases during acute myocardial
      infarction (AMI). However, the relation of QT dispersion to infarct size and left
      ventricular (LV) function in AMI has not yet been fully clarified. Accordingly,
      this study was conducted to elucidate this relation at 1 month after anterior
      wall AMI. We examined 94 patients with first anterior wall AMI (< or = 6 hours)
      who underwent coronary arteriography at admission, 1 month, and 6 months after
      AMI, and left ventriculography at 1 and 6 months after AMI. Mean QT dispersion on
      the chronic phase (about 1 month after AMI) electrocardiogram was 79 +/- 33 ms.
      There were no significant correlations between QT dispersion and peak creatine
      phosphokinase levels, LV ejection fraction, and regional wall motion in the
      infarct region at 1 month after AMI (r = 0.06, p = 0.57; r = 0.11, p = 0.29; r = 
      0.05, p = 0.63, respectively). In conclusion, the findings of this study suggest
      that QT dispersion on the resting electrocardiogram at 1 month after anterior
      wall AMI is unrelated to infarct size estimated by the peak creatine
      phosphokinase level and the degree of LV dysfunction.

PMID- 10335757
TI  - Pharmacodynamics, safety, tolerability, and pharmacokinetics of the 0.8-mg dose
      of cerivastatin in patients with primary hypercholesterolemia.
AB  - Cerivastatin is a third generation hydroxy-methyl-glutaryl-Co-enzyme A (HMG-CoA)
      reductase inhibitor proven to lower low-density lipoprotein (LDL) cholesterol 28%
      to 31% in patients with primary hypercholesterolemia when given at 0.3 mg/day.
      This study evaluates the safety, tolerability, pharmacodynamics, and
      pharmacokinetics of cerivastatin 0.8 mg once daily for 4 weeks. In this
      randomized, double-blind, placebo-controlled parallel group trial conducted at 2
      study centers, 41 patients (63% women) with primary hypercholesterolemia were
      placed on an American Heart Association Step 1 diet for 4 weeks. Single-blind
      placebo was administered for the final 2 weeks, before randomization. Patients
      received cerivastatin 0.8 mg (n = 28) or placebo (n = 13) once each evening for
      28 days. Cerivastatin at 0.8 mg daily was well tolerated. No discontinuations
      occurred during the study. Adverse events were mild and transient. One
      cerivastatin-treated patient experienced asymptomatic creatinine kinase, 8x the
      upper limit of normal (ULN) elevation on the last day of the study, which
      resolved 6 days after the completion of the study. Cerivastatin 0.8 mg daily
      significantly reduced LDL cholesterol compared with placebo (-44.0 +/- 2.0% vs
      2.2 +/- 2.8%, p <0.0001); total cholesterol (-30.8 +/- 1.4% vs 2.6 +/- 2.1%, p
      <0.0001), triglycerides (-11.2 +/- 5.9% vs 15.9 +/- 8.6%, p <0.02), but did not
      significantly alter high-density lipoprotein (HDL) cholesterol (3.2 +/- 2.1% vs 
      1.2 +/- 3.1%, p = NS). The pharmacokinetics of the 0.8-mg dose revealed dose
      proportional elevations in the 24-hour area under the curve and maximum plasma
      concentration relative to 0.3- and 0.4-mg doses with no change in time to maximum
      concentration or the elimination half-life in plasma. The increased efficacy and
      lack of clinically significant laboratory abnormalities or adverse events
      demonstrates a need for a large long-term study to confirm the safety and
      efficacy of this dose of cerivastatin.

PMID- 10335758
TI  - Radiofrequency ablation of atrioventricular junction and pacemaker implantation
      versus modulation of atrioventricular conduction in drug refractory atrial
      fibrillation.
AB  - Modulation of atrioventricular (AV) node conduction and radiofrequency ablation
      of AV junction are alternative approaches to control ventricular rate in drug
      refractory atrial fibrillation (AF). In 2 centers, 120 patients were treated
      either with AV junction ablation (center 1, group 1, 60 patients [30 men, aged 64
      +/- 11 years], paroxysmal AF in 24 patients) or with modulation (group 2, 60
      patients [32 men, aged 58 +/- 12 years], paroxysmal AF in 43 patients). In group
      1, complete AV block was achieved in all patients. In group 2, the procedure was
      performed in sinus rhythm (30 patients), prolonging the Wenckebach cycle length
      from 328 +/- 85 to 466 +/- 80 ms (p <0.01) or during AF (30 patients), decreasing
      ventricular rate from 178 +/- 35 to 96 +/- 35 beats/min (p <0.01), and to <100
      beats/min in 17 patients (61%). Complete AV block was induced in 9 of 60 patients
      (15%). In groups 1 and 2, at a follow-up of 27 +/- 7 and 26 +/- 6 months, there
      were 2 deaths (1 cardiac, 1 sudden death) and 1 death for end-stage heart
      failure, respectively. Hospital readmissions decreased from 3.2 to 0.2 and from
      4.2 to 0.2/year; late AF recurrences at of >120 beats/min were documented in 6%
      and 12%, respectively. Symptom score analysis including effort and rest dyspnea,
      exercise intolerance, weakness, and palpitation showed a significant improvement
      in both treatment groups, when acutely effective, in patients with paroxysmal
      and/or chronic AF. In conclusion, ablation of the AV junction shows a higher
      acute success rate compared with modulation of the AV node conduction in patients
      with drug refractory AF. Depending on the acute success, both approaches
      therefore were similarly effective in achieving long-term ventricular rate
      control and symptom score improvement.

PMID- 10335759
TI  - Subendocardial enhancement in gadolinium-diethylene-triamine-pentaacetic acid
      enhanced magnetic resonance imaging in aortic stenosis.
AB  - We investigated the usefulness of magnetic resonance imaging (MRI) with
      gadolinium-diethylene-triamine-pentaacetic acid (Gd-DTPA) in assessing myocardial
      damage from valvular aortic stenosis (AS). Cardiac catheterization and
      echocardiography were performed in 17 patients with AS. T1-weighted spin-echo
      sequence was used to obtain magnetic resonance images of short-axis planes of the
      left ventricle before and after intravenous Gd-DTPA injection in all patients
      using a 1.5 Tesla imager. Patients were divided into 2 groups according to the
      presence or absence of regional myocardial enhancement in the images. The Gd-DTPA
      enhanced magnetic resonance images of 7 patients showed circumferential
      subendocardial enhancement. All patients with enhancement had a history of heart
      failure and were in New York Heart Association functional class III or IV,
      whereas patients without enhancement were in New York Heart Association
      functional class I or II. Patients with enhancement had a smaller aortic valve
      area (0.28 +/- 0.09 vs 0.38 +/- 0.07 cm2/m2, p <0.05), a higher transvalvular
      pressure gradient (109 +/- 40 vs 68 +/- 18 mm Hg, p <0.05), greater elevation of
      left ventricular end-diastolic pressure (22 +/- 11 vs 12 +/- 2 mm Hg, p <0.05),
      and greater reduction in left ventricular ejection fraction (40 +/- 9 vs 59 +/-
      10%, p <0.05). Subendocardial enhancement by Gd-DTPA-enhanced MRI was thus shown
      to be closely related to the severity of AS. In conclusion, Gd-DTPA-enhanced MRI
      is a new noninvasive tool that can provide useful information about myocardial
      damage in AS.

PMID- 10335760
TI  - Insights into catheter/Doppler discrepancies in congenital aortic stenosis.
AB  - Despite inherent discrepancies between Doppler and catheter gradients in aortic
      stenosis, the simplified Bernoulli equation is still the accepted noninvasive
      technique to quantitate severity. The Reynolds number is a dimensionless
      parameter that characterizes the nature of flow as being viscous, turbulent, or
      transitional. Recently, in vivo and animal studies have successfully used a
      Reynolds number-based approach to reconcile Doppler-estimated and catheter
      measured discrepancies. At the midrange of Reynolds number, pressure recovery
      effects are most evident, resulting in "overestimation" of catheter gradients by
      Doppler. At the lower range of the Reynolds number viscous effects are important,
      whereas at a higher range, turbulent factors are dominant; both result in a
      tendency toward agreement. We recorded 18 peak instantaneous gradients from dual
      left ventricular catheters (15 to 95 mm Hg), while simultaneously recording
      Doppler velocities before and after intervention in 11 pediatric patients (ages
      0.5 to 16 years, mean 4.5). Doppler correlated but overestimated catheter
      measured peak instantaneous gradients (y = 0.84x + 18.4, r = 0.8, SEE +/- 15.2 mm
      Hg, mean percent difference 29.9 +/- 36) over the range of catheter gradients
      measured. Accounting for the Reynolds number successfully collapsed data onto a
      single curve. Our study confirms in a clinical setting the importance of applying
      fluid dynamic principles such as the Reynolds number to explain apparent
      discrepancies between catheter and Doppler gradients. These principles provide a
      foundation for developing clinically appropriate correction factors.

PMID- 10335761
TI  - Cardiovascular safety of fexofenadine HCl.
AB  - Fexofenadine HCl is the acid metabolite of terfenadine (Seldane). The effect of
      this recently approved nonsedating antihistamine on the corrected QT interval
      (QTc) was evaluated in dose-tolerance, safety, and drug-interaction studies with
      healthy volunteers, and in clinical studies in patients with seasonal allergic
      rhinitis (SAR). Twelve-lead electrocardiographic data were collected once before
      and after dosing or serially throughout these studies. Outliers were defined as
      QTc > 440 ms with a > or = 10 ms increase from baseline. The recommended
      fexofenadine HCl dose is 60 mg twice daily. Fexofenadine HCl doses up to 800 mg
      once daily or 690 mg twice daily for 28 days resulted in no dose-related
      increases in QTc. Longer term studies indicated no statistically significant QTc
      increases compared with placebo in patients receiving fexofenadine HCl 80 mg
      twice daily for 3 months, 60 mg twice daily for 6 months, or 240 mg once daily
      for 12 months. Interaction studies showed no significant increases in QTc when
      fexofenadine HCl 120 mg twice daily was administered in combination with
      erythromycin (500 mg 3 times daily) or ketoconazole (400 mg once daily) after
      dosing to steady state (6.5 days). Clinical trials in patients with SAR (n =
      1,160) treated with 40, 60, 120, or 240 mg twice-daily fexofenadine HCl or
      placebo indicated no dose-related increases in QTc and no statistically
      significant increases in mean QTc compared with placebo. In controlled trials
      with approximately 6,000 persons, no case of fexofenadine-associated torsades de
      pointes was observed. The frequency and magnitude of QTc outliers were similar
      between fexofenadine HCl and placebo in all studies. Based on a large clinical
      database, we conclude that fexofenadine HCl has no significant effect on QTc,
      even at doses > 10-fold higher than that is efficacious for SAR.

PMID- 10335762
TI  - Age as a risk factor: you are as old as your arteries.
AB  - Advancing age is a major risk factor for coronary heart disease and is an
      indicator of coronary plaque burden. Noninvasive assessment of subclinical
      atherosclerosis is a better measurement of plaque burden and can provide a better
      assessment of "arterial age."

PMID- 10335763
TI  - Robert Roberts, MD: a conversation with the editor. Interview by William Clifford
      Roberts.

PMID- 10335764
TI  - Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein
      cholesterol and apolipoprotein A-I.
AB  - A randomized, blinded, multicenter clinical trial was performed comparing low-
      and high-dose simvastatin (40 and 80 mg) with comparable doses of atorvastatin
      (20 and 40 mg) for effects on plasma concentrations of lipoproteins and
      apolipoprotein A-I over 12 weeks in 842 patients with elevated low-density
      lipoprotein cholesterol. The 2 agents reduced low-density lipoprotein cholesterol
      and triglycerides to a comparable degree, but simvastatin raised high-density
      lipoprotein cholesterol and apolipoprotein A-I more than atorvastatin, suggesting
      differences in metabolic effects of the 2 agents on plasma lipids and
      lipoproteins.

PMID- 10335765
TI  - Effects of cardiac rehabilitation and exercise training on peak aerobic capacity
      and work efficiency in obese patients with coronary artery disease.
AB  - Using cardiopulmonary stress testing in 76 lean and 99 obese coronary patients,
      we demonstrated significant improvements in both groups for anaerobic threshold,
      peak aerobic capacity (VO2), peak VO2 corrected for lean body mass, and work
      efficiency. Although anaerobic threshold and peak VO2 are adequate to describe
      exercise capacity in lean patients, baseline and post-training data are best
      exemplified by peak VO2 corrected for lean body mass and work efficiency in obese
      coronary patients.

PMID- 10335766
TI  - Effects of cardiac rehabilitation and exercise training programs in women with
      depression.
AB  - Depression is prevalent in women with coronary artery disease, and increases
      morbidity and mortality following major coronary events. We demonstrated that
      women with depression had markedly abnormal overall cardiovascular risk profiles
      and have marked benefits in exercise capacity, obesity indexes, behavioral
      characteristics (including depression), and quality of life following formal,
      outpatient phase II cardiac rehabilitation and exercise training programs.

PMID- 10335767
TI  - Initial results and long-term clinical and angiographic implications of coronary
      stenting in elderly patients.
AB  - Results of 378 consecutive elderly patients (> or = 65 years) undergoing coronary
      stenting were compared with those of 601 younger patients. Although the
      restenosis rate was similar in the 2 groups, age > or = 65 years was an
      independent predictor of in-hospital mortality (relative risk 5.4, 95% confidence
      interval 1.2 to 20.1) and follow-up mortality (relative risk 2.8, 95% confidence
      interval 1.3 to 6.1).

PMID- 10335768
TI  - Clinical and inflammatory effects of dietary L-arginine in patients with
      intractable angina pectoris.
AB  - We evaluated the effects of oral L-arginine on the clinical outcome and the
      inflammatory markers of patients with intractable angina pectoris. Our findings
      demonstrated a significant clinical improvement in 7 of 10 patients, which was
      associated with a significant decrease in cell adhesion molecule and
      proinflammatory cytokine levels. Dietary L-arginine may have clinical beneficial
      effects in patients with intractable angina pectoris, and may have anti
      inflammatory properties.

PMID- 10335769
TI  - Evidence that anticardiolipin antibodies are independent risk factors for
      atherosclerotic vascular disease.
AB  - Thrombophilic anticardiolipin antibodies (ACLAs) are independent risk factors for
      atherosclerotic vascular disease. We suggest that ACLAs IgG and IgM be routinely
      measured as ancillary atherothrombotic risk factors in all patients with
      atherosclerotic vascular disease events, in those at high risk for
      atherosclerotic vascular disease, and in those in whom thrombosis is a major
      pathoetiology.

PMID- 10335770
TI  - Face immersion in cold water induces prolongation of the QT interval and T-wave
      changes in children with nonfamilial long QT syndrome.
AB  - We investigated the relation between heart rate and the QT interval using face
      immersion in cold water in children with long QT syndrome (LQTS) without a family
      history of this condition, and in control children. The face immersion test
      revealed that all children with high probability of LQTS had a significantly
      longer QT interval than control children during face immersion, and that the test
      could induce T-wave alternans or a notched T-wave in all children with a high
      probability of LQTS.

PMID- 10335771
TI  - Additional reduction in blood pressure after cholesterol-lowering treatment by
      statins (lovastatin or pravastatin) in hypercholesterolemic patients using
      angiotensin-converting enzyme inhibitors (enalapril or lisinopril).
AB  - Blood pressure (BP) reduction was compared between patients receiving angiotensin
      converting enzyme inhibitors alone and patients receiving these medications plus
      statins after 3 months of dietary intervention. Although BP was similarly reduced
      at week 4, the statin-treated group had a greater reduction in BP and total
      cholesterol levels at week 16, suggesting a synergistic effect between
      cholesterol lowering with statins and angiotensin-converting enzyme inhibitor
      treatment for hypertensive patients.

PMID- 10335772
TI  - Elevated circulating levels and cardiac secretion of soluble Fas ligand in
      patients with congestive heart failure.
AB  - The circulating levels of soluble Fas ligand was increased in patients with
      advanced congestive heart failure. This study also indicates that the failing
      heart may contribute to the increased concentration of soluble Fas ligand in
      patients with congestive heart failure.

PMID- 10335773
TI  - Oxidative metabolism of the transplanted human heart assessed by positron
      emission tomography using C-11 acetate.
AB  - For investigation of the metabolic profile of the transplanted human heart,
      positron emission tomography with C-11 acetate was performed to compare global
      and regional oxidative metabolism in 14 transplant patients with that in 10
      healthy volunteers. Because no difference between transplants and normals could
      be observed, the results suggest that oxidative metabolism remains stable after
      transplantation, whereas cardiac work remains the major determinant.

PMID- 10335774
TI  - Regression of acromegalic left ventricular hypertrophy after lanreotide (a slow
      release somatostatin analog).
AB  - A group of 13 acromegalic patients was treated with lanreotide for 18 months and
      followed-up echocardiographically; these patients showed significant correlations
      between the decrease of both growth hormone (GH) and insulin-like growth factor-1
      and the decrease of left ventricular mass index. This documents a regression of
      left ventricular hypertrophy in acromegaly after lanreotide treatment, the degree
      of which is dependent on the magnitude of the decrease of GH and insulin-like
      growth factor-1 serum levels.

PMID- 10335775
TI  - Intracardiac Doppler hemodynamics and flow: new vector, phased-array ultrasound
      tipped catheter.
AB  - Comprehensive intracardiac Doppler examination under simultaneous direct
      ultrasound visualization has not been previously possible. This human feasibility
      study demonstrates that a new 10Fr, 3.2-mm diameter, 5.5- to 10-MHz frequency
      agile, phased, vector array, ultrasound-tipped catheter with 4-way tip
      articulation provides diagnostic, high-quality, intracardiac Doppler signals
      using pulsed and continuous-wave, color flow, and tissue Doppler.

PMID- 10335776
TI  - Chaos surrounds high-dose chemotherapy for breast cancer.

PMID- 10335777
TI  - Non-alcoholic steatohepatitis: another disease of affluence.

PMID- 10335778
TI  - Prevention of postherpetic neuralgia.

PMID- 10335779
TI  - Better coronary risk assessment in women.

PMID- 10335780
TI  - Prophylaxis against contrast-induced nephropathy.

PMID- 10335781
TI  - Public disclosure of performance data: does the public get what the public wants?

PMID- 10335783
TI  - Markers of inflammation and prediction of diabetes mellitus in adults
      (Atherosclerosis Risk in Communities study): a cohort study.
AB  - BACKGROUND: Type 2 diabetes mellitus and atherosclerotic cardiovascular disease
      have common antecedents. Since markers of inflammation predict coronary heart
      disease and are raised in patients with type 2 diabetes, we investigated whether
      they predict whether people will develop type 2 diabetes. METHODS: 12,330 men and
      women, aged 45-64 years, were followed up for a mean of 7 years. We analysed the
      association between different markers of acute inflammation and subsequent
      diagnosis of diabetes. In a subgroup of 610 individuals selected originally for
      an unrelated atherosclerosis case-control study, we also investigated diabetes
      associations with total sialic acid and orosomucoid, haptoglobin, and alpha1
      antitrypsin. FINDINGS: 1335 individuals had a new diagnosis of diabetes. Adjusted
      odds ratios for developing diabetes for quartile extremes were 1.9 (95% CI 1.6
      2.3) for raised white-cell count, 1.3 (1.0-1.5) for low serum albumin, and 1.2
      (1.0-1.5) for raised fibrinogen. In the subgroup analysis, individuals with
      concentrations of orosomucoid and sialic acid of more than the median had odds
      ratios of 7.9 (2.6-23.7) and 3.7 (1.4-9.8), respectively. Adjustment for body
      mass index and waist-to-hip ratio lessened the associations; those for white-cell
      count (1.5 [1.3-1.8]), orosomucoid (7.1 [2.1-23.7]), and sialic acid (2.8 [1.0
      8.1]) remained significant. INTERPRETATION: Markers of inflammation are
      associated with the development of diabetes in middle-aged adults. Although
      autoimmunity may partly explain these associations, they probably reflect the
      pathogenesis of type 2 diabetes.

PMID- 10335782
TI  - Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients
      given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c
      randomised trial.
AB  - BACKGROUND: Postmastectomy radiotherapy is associated with a lower locoregional
      recurrence rate and improved disease-free and overall survival when combined with
      chemotherapy in premenopausal high-risk breast-cancer patients. However, whether
      the same benefits apply also in postmenopausal women treated with adjuvant
      tamoxifen for similar high-risk cancer is unclear. In a randomised trial among
      postmenopausal women who had undergone mastectomy, we compared adjuvant tamoxifen
      alone with tamoxifen plus postoperative radiotherapy. METHODS: Between 1982 and
      1990, postmenopausal women with high-risk breast cancer (stage II or III) were
      randomly assigned adjuvant tamoxifen (30 mg daily for 1 year) alone (689) or with
      postoperative radiotherapy to the chest wall and regional lymph nodes (686).
      Median follow-up was 123 months. The endpoints were first site of recurrence
      (locoregional recurrence, distant metastases, or both), and disease-free and
      overall survival. FINDINGS: Locoregional recurrence occurred in 52 (8%) of the
      radiotherapy plus tamoxifen group and 242 (35%) of the tamoxifen only group
      (p<0.001). In total there were 321 (47%) and 411 (60%) recurrences, respectively.
      Disease-free survival was 36% in the radiotherapy plus tamoxifen group and 24% in
      the tamoxifen alone group (p<0.001). Overall survival was also higher in the
      radiotherapy group (385 vs 434 deaths; survival 45 vs 36% at 10 years, p=0.03).
      INTERPRETATION: Postoperative radiotherapy decreased the risk of locoregional
      recurrence and was associated with improved survival in high-risk postmenopausal
      breast-cancer patients after mastectomy and limited axillary dissection, with 1
      year of adjuvant tamoxifen treatment. Improved survival in high-risk breast
      cancer can best be achieved by a strategy of both locoregional and systemic
      tumour control.

PMID- 10335784
TI  - Brain structure and neurocognitive and behavioural function in adolescents who
      were born very preterm.
AB  - BACKGROUND: Infants born very preterm (<33 weeks) are at increased risk of
      neurocognitive deficits. Their neurodevelopmental outcome up to age 8 years can
      be predicted by neonatal ultrasonography, but little is known of their later
      function. We investigated the effect of very preterm birth on brain structure and
      neurocognitive and behavioural functioning in adolescence. METHODS: A cohort of
      105 infants born before 33 weeks of gestation in 1979-80 had ultrasonographic
      scans at University College Hospital, London, and were prospectively examined at
      1, 4, and 8 years. At age 14-15 years, 72 of those who remained in UK (cases) and
      21 age-matched full-term controls underwent brain magnetic resonance imaging
      (MRI), as well as neurological, cognitive, and behavioural assessment. MRI images
      were assessed by two neuroradiologists unaware of ultrasonographic findings or
      case or control status. FINDINGS: Of the 72 cases, 40 had unequivocally abnormal
      MRI and 15 had equivocal scans. Of the 21 controls, one had abnormal and five
      equivocal MRI. Abnormalities of ventricles, corpus callosum, and white matter
      were especially common in cases. More brain lesions were identified by MRI than
      by neonatal ultrasonography. The cases had significantly more reading,
      adjustment, and neurological impairments than controls, but their behaviour was
      significantly related to MRI abnormality. INTERPRETATION: Individuals born very
      preterm show an excess of neurocognitive and behavioural problems in adolescence,
      and more than half have abnormal MRI brain scans.

PMID- 10335785
TI  - Audio-computer interviewing to measure risk behaviour for HIV among injecting
      drug users: a quasi-randomised trial.
AB  - BACKGROUND: We aimed to assess audio-computer-assisted self-interviewing (audio
      CASI) as a method of reducing under-reporting of HIV risk behaviour among
      injecting drug users. METHODS: Injecting drug users were interviewed at syringe
      exchange programmes in four US cities. Potential respondents were randomly
      selected from participants in the syringe exchanges, with weekly alternate
      assignment to either traditional face-to-face interviews or audio-CASI. The
      questionnaire included items on sociodemographic characteristics, drug use, and
      HIV risk behaviours for 30 days preceding the interview. We calculated odds
      ratios for the difference in reporting of HIV risk behaviours between interview
      methods. FINDINGS: 757 respondents were interviewed face-to-face, and 724 were
      interviewed by audio-CASI. More respondents reported HIV risk behaviours and
      other sensitive behaviours in audio-CASI than in face-to-face interviews (odds
      ratios for reporting of rented or bought used injection equipment in audio-CASI
      vs face-to-face interview 2.1 [95% CI 1.4-3.3] p=0.001; for injection with
      borrowed used injection equipment 1.5 [1.1-2.2] p=0.02; for renting or selling
      used equipment 2.3 [1.3-4.0] p=0.003). INTERPRETATION: Although validation of
      these self-reported behaviours was not possible, we propose that audio-CASI
      enables substantially more complete reporting of HIV risk behaviour. More
      complete reporting might increase understanding of the dynamics of HIV
      transmission and make the assessment of HIV-prevention efforts easier.

PMID- 10335786
TI  - Association of abnormal cerebellar activation with motor learning difficulties in
      dyslexic adults.
AB  - BACKGROUND: In addition to their impairments in literacy-related skills, dyslexic
      children show characteristic difficulties in phonological skill, motor skill, and
      balance. There is behavioural and biochemical evidence that these difficulties
      may be attributable to mild cerebellar dysfunction. We wanted to find out whether
      there was abnormal brain activation when dyslexic adults undertook tasks known
      normally to involve cerebellar activation. METHODS: Brain activation was
      monitored by positron emission tomography in matched groups of six dyslexic
      adults and six control adults as they carried out either a prelearned sequence or
      learned a novel sequence of finger movements. FINDINGS: Brain activation was
      significantly lower (p<0.01) for the dyslexic adults than for the controls in the
      right cerebellar cortex and the left cingulate gyrus when executing the
      prelearned sequence, and in the right cerebellar cortex when learning the new
      sequence. INTERPRETATION: The results provided direct evidence that, for this
      group of dyslexic adults, the behavioural signs of cerebellar abnormality reflect
      underlying abnormalities in cerebellar activation.

PMID- 10335787
TI  - Development of a nurse-led sedation service for paediatric magnetic resonance
      imaging.
AB  - BACKGROUND: Children generally lie still enough for magnetic resonance imaging
      (MRI) only if they are asleep, either under sedation, which is deeper than
      conscious sedation, or under anaesthesia. Anaesthesia resources, however, are
      limited, and non-anaesthetists must use sedation frequently. Demand for MRI has
      increased and the failure of our sedation regimen led to an impractical demand
      for anaesthesia and unacceptable waiting times for scanning. We have therefore
      developed a nurse-led sedation service in a designated unit next to the scanner.
      This study assessed the safety and efficacy of this approach. METHODS: Children
      who required MRI were sedated in the unit by designated sedationist nurses, who
      used an oral drug regimen (according to weight and age from conception: weight <5
      kg, 50 mg/kg chloral hydrate; 5-10 kg, 100 mg/kg chloral hydrate; 10-20 kg, 1
      mg/kg temazepam plus 0.25 mg/kg droperidol; >20 kg temazepam and droperidol as
      directed by radiologist, maximum doses 20 mg and 5 mg respectively). Nurses
      checked patients for their suitability, charted and administered the drugs
      according to a protocol, and monitored the children throughout the sedation. We
      prospectively audited failure and complications of sedation. FINDINGS: During the
      30 month study, there were 1155 sedations. 61 (5%) were unsuccessful, and there
      were no adverse events relating to the airway or breathing. After scanning had
      finished all children, in response to gently pinching the nose, could open their
      mouths to maintain their airway. INTERPRETATION: This study suggests that it is
      possible to have a nurse-led sedation service for MRI of children that is both
      successful and safe.

PMID- 10335788
TI  - A sore anus for 6 months.

PMID- 10335789
TI  - Codon 129 prion protein genotype and sporadic Creutzfeldt-Jakob disease.

PMID- 10335790
TI  - Low 1-year prevalence of atopic eczema in very low birthweight infants.

PMID- 10335791
TI  - Alcohol injection: a new method of treating placental chorioangiomas.

PMID- 10335792
TI  - Relative eosinophilia and functional adrenal insufficiency in critically ill
      patients.

PMID- 10335793
TI  - Percutaneous radiofrequency interstitial thermal ablation of small hepatocellular
      carcinoma.

PMID- 10335794
TI  - Contribution of immediate and delayed ischaemic damage to the volume of final
      infarcts.

PMID- 10335795
TI  - Latent dysbetalipoproteinaemia precipitated by HIV-protease inhibitors.

PMID- 10335796
TI  - Neurological complications in heparin-induced thrombocytopenia.

PMID- 10335798
TI  - From effect size into number needed to treat.

PMID- 10335797
TI  - Liver transplantation in a Jehovah's witness.

PMID- 10335799
TI  - Public-health message about dioxin remains unclear.

PMID- 10335801
TI  - International consortium SN(i)Ps away at individuality.

PMID- 10335800
TI  - HIV-treatment guidelines.

PMID- 10335802
TI  - On leaving Florence Nightingale behind.

PMID- 10335803
TI  - When pharmaceutical wrangles cast a wide net.

PMID- 10335804
TI  - AIDS campaigner on trial for testing vaccine on people.

PMID- 10335805
TI  - BCG immunotherapy of bladder cancer: 20 years on.

PMID- 10335806
TI  - Management of cancer pain.
AB  - Patients with cancer have diverse symptoms, impairments in physical and
      psychological functioning, and other difficulties that can undermine their
      quality of life. If inadequately controlled, pain can have a profoundly adverse
      impact on the patient and his or her family. The critical importance of pain
      management as part of routine cancer care has been forcefully advanced by WHO,
      international and national professional organisations, and governmental agencies.
      The prevalence of chronic pain is about 30-50% among patients with cancer who are
      undergoing active treatment for a solid tumour and 70-90% among those with
      advanced disease. Prospective surveys indicate that as many as 90% of patients
      could attain adequate relief with simple drug therapies, but this success rate is
      not achieved in routine practice. Inadequate management of pain is the result of
      various issues that include: undertreatment by clinicians with insufficient
      knowledge of pain assessment and therapy; inappropriate concerns about opioid
      side-effects and addiction; a tendency to give lower priority to symptom control
      than to disease management; patients under-reporting of pain and non-compliance
      with therapy; and impediments to optimum analgesic therapy in the healthcare
      system. To improve the management of cancer pain, every practitioner involved in
      the care of these patients must ensure that his or her medical information is
      current and that patients receive appropriate education.

PMID- 10335807
TI  - Caring for ethnic Albanians in Macedonia's refugee camps.

PMID- 10335808
TI  - Transmyocardial laser revascularisation.

PMID- 10335809
TI  - Transmyocardial laser revascularisation.

PMID- 10335810
TI  - Transmyocardial laser revascularisation.

PMID- 10335811
TI  - Transmyocardial laser revascularisation.

PMID- 10335812
TI  - Transmyocardial laser revascularisation.

PMID- 10335813
TI  - Osteoporotic fractures in Cornwall.

PMID- 10335814
TI  - In-vitro spermatogenesis.

PMID- 10335815
TI  - Deep-vein thrombosis.

PMID- 10335816
TI  - Drug resistance among acid-fast bacilli.

PMID- 10335817
TI  - Provision of treatment for multiple sclerosis.

PMID- 10335818
TI  - Smoking and acute appendicitis.

PMID- 10335819
TI  - Smoking and acute appendicitis.

PMID- 10335820
TI  - Political correctness.

PMID- 10335821
TI  - Informed consent: what did the doctor say?

PMID- 10335822
TI  - Informed consent: what did the doctor say?

PMID- 10335823
TI  - Authorship criteria and academic reward.

PMID- 10335824
TI  - Randomised trials are not unethical.

PMID- 10335825
TI  - Typhoid Mary.

PMID- 10335826
TI  - Websites in brief.

PMID- 10335827
TI  - The Nobel Chronicles. 1954: John Franklin Enders (1897-1985); Thomas Huckle
      Weller (b 1915); and Frederick Chapman Robbins (b 1916).

PMID- 10335828
TI  - "Taking a line for a walk".

PMID- 10335829
TI  - Impure, maybe, but exemplary.

PMID- 10335830
TI  - 'Sell the message of research', Europe's cell biologists urged.

PMID- 10335831
TI  - US stem-cell pioneers buy 'Dolly' cloning company.

PMID- 10335832
TI  - Australia boosts medical research, but keeps other budgets level.

PMID- 10335833
TI  - Japan bids to catch up on gene sequencing.

PMID- 10335834
TI  - Drug company backs Africa's war on AIDS.

PMID- 10335835
TI  - Building the future of biocomputing.

PMID- 10335836
TI  - The right prescription for preclinical teaching.

PMID- 10335837
TI  - Cell signalling. Calmodulin at the channel gate.

PMID- 10335838
TI  - Excitatory synapses. Neither too loud nor too quiet.

PMID- 10335839
TI  - Myopia and ambient lighting at night.

PMID- 10335840
TI  - No role for colour in symmetry perception.

PMID- 10335841
TI  - Size and form in efficient transportation networks.
AB  - Many biological processes, from cellular metabolism to population dynamics, are
      characterized by allometric scaling (power-law) relationships between size and
      rate. An outstanding question is whether typical allometric scaling relationships
      -the power-law dependence of a biological rate on body mass--can be understood by
      considering the general features of branching networks serving a particular
      volume. Distributed networks in nature stem from the need for effective
      connectivity, and occur both in biological systems such as cardiovascular and
      respiratory networks and plant vascular and root systems, and in inanimate
      systems such as the drainage network of river basins. Here we derive a general
      relationship between size and flow rates in arbitrary networks with local
      connectivity. Our theory accounts in a general way for the quarter-power
      allometric scaling of living organisms, recently derived under specific
      assumptions for particular network geometries. It also predicts scaling relations
      applicable to all efficient transportation networks, which we verify from
      observational data on the river drainage basins. Allometric scaling is therefore
      shown to originate from the general features of networks irrespective of
      dynamical or geometric assumptions.

PMID- 10335843
TI  - The role of the anterior prefrontal cortex in human cognition.
AB  - Complex problem-solving and planning involve the most anterior part of the
      frontal lobes including the fronto-polar prefrontal cortex (FPPC), which is
      especially well developed in humans compared with other primates. The specific
      role of this region in human cognition, however, is poorly understood. Here we
      show, using functional magnetic resonance imaging, that bilateral regions in the
      FPPC alone are selectively activated when subjects have to keep in mind a main
      goal while performing concurrent (sub)goals. Neither keeping in mind a goal over
      time (working memory) nor successively allocating attentional resources between
      alternative goals (dual-task performance) could by themselves activate these
      regions. Our results indicate that the FPPC selectively mediates the human
      ability to hold in mind goals while exploring and processing secondary goals, a
      process generally required in planning and reasoning.

PMID- 10335842
TI  - Evolution of genetic mechanisms controlling petal development.
AB  - Molecular genetic studies in Arabidopsis thaliana and other higher-eudicot
      flowering plants have led to the development of the 'ABC' model of the
      determination of organ identity in flowers, in which three classes of gene, A, B
      and C, are thought to work together to determine organ identity. According to
      this model, the B-class genes APETALA3 (AP3) and PISTILLATA (PI) act to specify
      petal and stamen identity. Here we test whether the roles of these genes are
      conserved throughout the angiosperms by analysing the expression of AP3 and PI
      orthologues in the lower eudicot subclass Ranunculidae. We show that, although
      expression of these orthologues in the stamens is conserved, the expression
      patterns in the petals differ from those found in the higher eudicots. The
      differences between these expression patterns suggest that the function of AP3
      and PI homologues as B-class organ-identity genes is not rigidly conserved among
      all angiosperms. These observations have important implications for understanding
      the evolution of both angiosperm petals and the genetic mechanisms that control
      the identities of floral organs.

PMID- 10335844
TI  - Synaptic calcium transients in single spines indicate that NMDA receptors are not
      saturated.
AB  - At excitatory synapses in the central nervous system, the number of glutamate
      molecules released from a vesicle is much larger than the number of postsynaptic
      receptors. But does release of a single vesicle normally saturate these
      receptors? Answering this question is critical to understanding how the amplitude
      and variability of synaptic transmission are set and regulated. Here we describe
      the use of two-photon microscopy to image transient increases in Ca2+
      concentration mediated by NMDA (N-methyl-D-aspartate) receptors in single
      dendritic spines of CA1 pyramidal neurons in hippocampal slices. To test for NMDA
      receptor saturation, we compared responses to stimulation with single and double
      pulses. We find that a single release event does not saturate spine NMDA
      receptors; a second release occurring 10 ms later produces approximately 80% more
      NMDA-receptor activation. The amplitude of spine NMDA-receptor-mediated [Ca2+]
      transients (and the synaptic plasticity which depends on this) may thus be
      sensitive to the number of quanta released by a burst of action potentials and to
      changes in the concentration profile of glutamate in the synaptic cleft.

PMID- 10335845
TI  - Ca2+/calmodulin binds to and modulates P/Q-type calcium channels.
AB  - Neurotransmitter release at many central synapses is initiated by an influx of
      calcium ions through P/Q-type calcium channels, which are densely localized in
      nerve terminals. Because neurotransmitter release is proportional to the fourth
      power of calcium concentration, regulation of its entry can profoundly influence
      neurotransmission. N- and P/Q-type calcium channels are inhibited by G proteins,
      and recent evidence indicates feedback regulation of P/Q-type channels by
      calcium. Although calcium-dependent inactivation of L-type channels is well
      documented, little is known about how calcium modulates P/Q-type channels. Here
      we report a calcium-dependent interaction between calmodulin and a novel site in
      the carboxy-terminal domain of the alpha1A subunit of P/Q-type channels. In the
      presence of low concentrations of intracellular calcium chelators, calcium influx
      through P/Q-type channels enhances channel inactivation, increases recovery from
      inactivation and produces a long-lasting facilitation of the calcium current.
      These effects are prevented by overexpression of a calmodulin-binding inhibitor
      peptide and by deletion of the calmodulin-binding domain. Our results reveal an
      unexpected association of Ca2+/calmodulin with P/Q-type calcium channels that may
      contribute to calcium-dependent synaptic plasticity.

PMID- 10335846
TI  - Calmodulin supports both inactivation and facilitation of L-type calcium
      channels.
AB  - L-type Ca2+ channels support Ca2+ entry into cells, which triggers cardiac
      contraction, controls hormone secretion from endocrine cells and initiates
      transcriptional events that support learning and memory. These channels are
      examples of molecular signal-transduction units that regulate themselves through
      their own activity. Among the many types of voltage-gated Ca2+ channel, L-type
      Ca2+ channels particularly display inactivation and facilitation, both of which
      are closely linked to the earlier entry of Ca2+ ions. Both forms of
      autoregulation have a significant impact on the amount of Ca2+ that enters the
      cell during repetitive activity, with major consequences downstream. Despite
      extensive biophysical analysis, the molecular basis of autoregulation remains
      unclear, although a putative Ca2+-binding EF-hand motif and a nearby consensus
      calmodulin-binding isoleucine-glutamine ('IQ') motif in the carboxy terminus of
      the alpha1C channel subunit have been implicated. Here we show that calmodulin is
      a critical Ca2+ sensor for both inactivation and facilitation, and that the
      nature of the modulatory effect depends on residues within the IQ motif important
      for calmodulin binding. Replacement of the native isoleucine by alanine removed
      Ca2+-dependent inactivation and unmasked a strong facilitation; conversion of the
      same residue to glutamate eliminated both forms of autoregulation. These results
      indicate that the same calmodulin molecule may act as a Ca2+ sensor for both
      positive and negative modulation.

PMID- 10335847
TI  - A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and
      clk-1 mutants.
AB  - The dauer larva is an alternative larval stage in Caenorhabditis elegans which
      allows animals to survive through periods of low food availability. Well-fed
      worms live for about three weeks, but dauer larvae can live for at least two
      months without affecting post-dauer lifespan. Mutations in daf-2 and age-1, which
      produce a dauer constitutive (Daf-C) phenotype, and in clk-1, which are believed
      to slow metabolism, markedly increase adult lifespan. Here we show that a ctl-1
      mutation reduces adult lifespan in otherwise wild-type animals and eliminates the
      daf-c and clk-1-mediated extension of adult lifespan. ctl-1 encodes an unusual
      cytosolic catalase; a second gene, ctl-2, encodes a peroxisomal catalase. ctl-1
      messenger RNA is increased in dauer larvae and adults with the daf-c mutations.
      We suggest that the ctl-1 catalase is needed during periods of starvation, as in
      the dauer larva, and that its misexpression in daf-c and clk-1 adults extends
      lifespan. Cytosolic catalase may have evolved to protect nematodes from oxidative
      damage produced during prolonged dormancy before reproductive maturity, or it may
      represent a general mechanism for permitting organisms to cope with the metabolic
      changes that accompany starvation.

PMID- 10335848
TI  - Gene silencing in Neurospora crassa requires a protein homologous to RNA
      dependent RNA polymerase.
AB  - In plants and fungi, the introduction of transgenes can lead to post
      transcriptional gene silencing. This phenomenon, in which expression of the
      transgene and of endogenous genes containing sequences homologous to the
      transgene can be blocked, is involved in virus resistance and genome maintenance.
      Transgene-induced gene silencing has been termed quelling in Neurospora crassa
      and co-suppression in plants. Quelling-defective (qde) mutants of N. crassa, in
      which transgene-induced gene silencing is impaired, have been isolated. Here we
      report the cloning of qde-1, the first cellular component of the gene-silencing
      mechanism to be isolated, which defines a new gene family conserved among
      different species including plants, animals and fungi. The qde-1 gene product is
      similar to an RNA-dependent RNA polymerase found in the tomato. The
      identification of qde-1 strongly supports models that implicate an RNA-dependent
      RNA polymerase in the post-transcriptional gene-silencing mechanism. The presence
      of qde-1 homologues in a variety of species of plants and fungi indicates that a
      conserved gene-silencing mechanism may exist, which could have evolved to
      preserve genome integrity and to protect the genome against naturally occurring
      transposons and viruses.

PMID- 10335849
TI  - Start-up companies: out of the lab and into the marketplace.

PMID- 10335851
TI  - The unique vulnerability of diabetic subjects to hypertensive injury.

PMID- 10335852
TI  - Diabetes and hypertension: an era of clarity or confusion?
AB  - In light of recent data from the UKPDS and HOT trials, it appears that intensive
      combination therapies are essential in the treatment of patients with diabetes
      and hypertension. Appropriate treatment strategies, based on effective BP
      reductions, will usually require two or more different antihypertensives and the
      addition of lipid-lowering agents. There is also an urgent need to update
      existing guidelines and perhaps even provide specific guidelines for the
      treatment and long-term management of patients with diabetes and hypertension.

PMID- 10335853
TI  - Intensive blood pressure/glucose control in type 2 diabetes: why is it so
      difficult to decrease coronary heart disease?

PMID- 10335855
TI  - A novel deletion mutant of hepatitis B virus surface antigen.
AB  - HBsAg is the most important serological marker for acute or chronic hepatitis B.
      Nevertheless, there are reports of HBsAg-negative virus carriers, either with
      anti-HBc as the only marker for hepatitis B virus (HBV) infection or even
      positive for anti-HBs and anti-HBc. We report isolates from a patient, in which a
      deletion in the HBs-gene was associated with persisting viremia in the presence
      of anti-HBs. The 62-year-old female, infected most likely by her husband, had
      detectable markers of chronic active hepatitis B, such as HBsAg, HBeAg, and anti
      HBc-IgM, for 2 years. The patient then seroconverted to anti-HBs, although HBeAg
      and anti-HBc-IgM remained detectable. At this time, semiquantitative polymerase
      chain reaction showed about 10(4) viral genomes per milliliter of serum. Direct
      sequencing of the amplified products revealed a major population of DNA molecules
      with a deletion of nucleotide 31 of the HBs-gene, which up to now has not been
      described. This deletion led to a frame-shift and introduced a stop-codon after
      21 amino acids of the sHBsAg. We suspect that this deletion, and the resulting
      HBsAg lacking the major epitopes recognized by specific antibodies, could favor
      ongoing viral replication, despite the presence of anti-HBs. However, because the
      reading frame of the polymerase was also severely damaged by this deletion, it is
      assumed that a minor population of intact genomes was present to help in the
      formation of virus particles.

PMID- 10335856
TI  - Preimmunization epidemiology of hepatitis B virus infection in South African
      children.
AB  - The prevalence of hepatitis B surface antigen (HBsAg) was determined in a
      community-based, cross-sectional, age-stratified sample of children from 0 to 6
      years of age (n = 2,299) from the Eastern Cape Province of South Africa. The
      purpose of the study was to investigate the epidemiology and the age of
      acquisition of hepatitis B virus (HBV) infection in children, thus providing a
      preimmunization baseline measure of this infection in the population targeted for
      HBV immunization in South Africa. Overall, 10.4% (95% CI, 9.2-11.7) of the
      children tested were HBsAg-positive. There was a high rate of positivity in the 0
      6- and 7-12-month age groups at 8.1% (95% CI, 5.5-11.7) and 8.9% (95% CI, 6.1
      12.7), respectively, suggesting a higher rate of early acquisition of this
      infection than previously reported in South Africa. The proportion of HBsAg
      positive children increased significantly with increasing age (chi2trend = 5.9,
      df = 1, P = 0.02), reaching 15.7% in the 61-72-month age group. This is the
      highest rate of HBV infection reported in community-based children from South
      Africa, indicating a significant burden of this infection. The difference in
      HBsAg prevalence between urban and rural children was not statistically
      significant (chi2 = 0.32, df = 1, P = 0.57). There was also no difference in
      positivity between males (10.5%; 95% CI, 8.7-12.5) and females (9.8%; 95% CI, 8.1
      11.7), (chi2 = 0.006, df = 1, P = 0.94). This study provides the most recent
      preimmunization, community-based baseline investigation of the epidemiology of
      HBV infection in children targeted for universal immunization in South Africa.

PMID- 10335857
TI  - Multicenter study on hepatitis C virus infection in patients with dilated
      cardiomyopathy. North Italy Transplant Program (NITP).
AB  - Preliminary epidemiological and histological studies from Japan suggested that
      hepatitis C virus (HCV) infection has a role in the development of dilated
      cardiomyopathy (DCM). This multicenter study was conducted to verify this
      hypothesis on a large cohort of Italian patients with end-stage heart failure.
      Antibodies to HCV were determined in the 752 consecutive patients (608 males and
      144 females; age, 53 +/- 13 years) who entered the waiting list for cardiac
      transplantation from 1995 to 1997 at the six cardiac surgery centers
      participating in the North Italy Transplant program. Three hundred and nine
      patients (41%) had dilated, 9 (1%) restrictive, and 4 (0.5%) hypertrophic
      cardiomyopathy; 284 patients (38%) had ischemic, 65 (9%) valvular, and 22 (3%)
      congenital heart disease; 5 patients (0.5%) had primary pulmonary hypertension;
      54 patients (7%) had other or nonspecified heart disease. Overall, 41 of 752
      patients (5.4%) resulted anti-HCV-reactive. Serological evidence of HCV infection
      was found in 12 of 309 patients with DCM (3.9%; 95% CI, 1.7-6.0), and in 29 of
      443 without DCM (6.5%; 95% CI, 4.2-8.8), without statistical difference
      (difference of prevalence rate: 2.6%; 95% CI, -4.9 to 5.8). In conclusion, HCV
      does not seem to have a primary role in the pathogenesis of DCM. However, since
      our findings are in disagreement with those obtained in smaller series of
      patients of other ethnicity, large studies from different countries should be
      conducted.

PMID- 10335858
TI  - Quantification of hepatitis C virus by TaqMan PCR: comparison with HCV Amplicor
      Monitor assay.
AB  - The quantitation of serum levels of hepatitis C virus RNA in chronic hepatitis C
      has been regarded as one of the most important indicators for the outcome of
      interferon therapy. A new method was used for quantitating the copy number of
      hepatitis C virus RNA using TaqMan polymerase chain reaction and for comparing
      the ability and usefulness of this assay with Amplicor Monitor assay in 138
      patients. The detection range of hepatitis C virus RNA by TaqMan polymerase chain
      reaction was from 2 x 10(3) to 2 x 10(8) copies/ml. Hepatitis C virus RNA was
      detectable in 128 cases (92.8%) and undetectable in 10 cases (7.2%) by this
      method. The RNA levels measured by Amplicor Monitor assay correlated
      significantly with those measured by TaqMan polymerase chain reaction assay and
      the sensitivity of the two assays was almost equal. Thus, TaqMan polymerase chain
      reaction assay appears sufficiently sensitive for the evaluation of hepatitis C
      virus RNA and would be useful for the diagnosis and management of hepatitis C
      virus infection.

PMID- 10335859
TI  - The most prevalent hepatitis C virus genotypes in England and Wales are 3a and
      1a.
AB  - Hepatitis C virus (HCV) genotypes were assigned to 567 individuals by restriction
      fragment length polymorphism analysis of the 5' noncoding region of the HCV
      genome following reverse transcription-polymerase chain reaction. The groups of
      individuals in this study included hemophilia patients, injecting drug users
      (IDUs), blood donors, antenatal patients, those attending genitourinary medicine
      (GUM) clinics, and patients with chronic liver disease, all from England and
      Wales. The majority of HCV infections were types 1a (32%), 1b (15%), or 3a (37%).
      The genotype distribution in individual groups was similar to the overall
      genotype distribution except for hemophilia patients, in whom the frequencies
      were 1a (39%), 1b (23%), and 3a (21%). With the exception of hemophilia patients,
      subpopulations in England and Wales appear to share common modes of HCV
      transmission. There is a need for continued surveillance to monitor the spread of
      possibly more virulent or drug-resistant HCV genotypes.

PMID- 10335860
TI  - Decreased diversity of hepatitis C virus quasispecies during bone marrow
      transplantation.
AB  - To elucidate the role of host immune status in the evolution and complexity of
      hepatitis C virus (HCV) quasispecies, three chronic HCV-infected patients who
      underwent bone marrow transplantation (BMT) were studied. The three transplanted
      patients' sera were sampled at pre-BMT, 3 months after BMT, and 12 months after
      BMT and the nucleotide diversity and substitution of the hypervariable region
      (HVR) of HCV quasispecies were analyzed. The nucleotide diversity was high at the
      pre-BMT period (28.2-43.4 x 10(-2) nucleotide difference/site). HVR of HCV
      quasispecies then became homogeneous in the first 3 months after BMT (0.11-6.40 x
      10(-2) nucleotide difference/site). The nucleotide diversity of HVR at 12 months
      after BMT of all three patients was higher than that of 3 months after BMT but
      still lower than that of pre-BMT (2.09-6.40 x 10(-2) nucleotide difference/site).
      The analysis on nucleotide substitution rate showed a higher value between pre
      BMT and 3 months after BMT (0.624-0.708 nucleotide difference/site per year) than
      that between 3 months and 12 months after BMT (0.072-0.127 nucleotide
      difference/site per year). HCV RNA titer decreased when the host had a low white
      cell count and increased accordingly. It was concluded that the evolution of HVR
      of HCV quasispecies related to the immune status of the host during BMT: after
      immunosuppression, an initial increase of viral populations was followed by the
      emergence of a dominant strain while the quasispecies gradually recovered as the
      immunity of the host gained its competence.

PMID- 10335861
TI  - Molecular evidence for nosocomial transmission of hepatitis C virus in a French
      hemodialysis unit.
AB  - A systematic virological follow-up of hemodialysis patients identified 11 cases
      of de novo hepatitis C virus (HCV) infection in the same unit that were not due
      to blood transfusion. There were three groups of infection, each occurring within
      a period of 3 months: four infections with genotype 1b, two infections with
      genotype 1b, and five infections, four with genotype 1a and one with genotype 5a.
      The possibility of patient-to-patient transmission was addressed by sequencing
      the first hypervariable region of the HCV genome in sera taken shortly after
      infection. Phylogenetic analysis indicated clustering of most of the cases of de
      novo infections. Sequence homologies identified potential contaminators among
      already infected patients. All patients who were infected with closely related
      HCV isolates were found to have been treated in the same area and during the same
      shift or on the previous one. These infections could have been due to occasional
      breaches of the usual hygiene measures. Strict adhesion to hygiene standards and
      routines, continuously supervised, remains the key rule in the management of
      dialysis patients. Nevertheless, the isolation of patients with HCV could reduce
      the risk of infection because occasional lapses of preventive hygiene measures or
      unpredictable accidents can always take place in a hemodialysis unit. This policy
      needs to be evaluated by large-scale prospective studies.

PMID- 10335862
TI  - Diversity of GB virus C/hepatitis G virus isolates in Singapore: predominance of
      group 2a and the Asian group 3 variant.
AB  - The occurrence of GBV-C/HGV infection was studied in 160 individuals from two
      high-risk groups in Singapore. RT-PCR of the 5'-UTR detected GBV-C/HGV RNA in
      3/73 (4.1%) of patients undergoing maintenance hemodialysis for chronic renal
      failure, and in 17/87 (19.5%) of patients coinfected with HCV who tested positive
      for HCV RNA. Phylogenetic analysis of 5'-UTR sequences from these 20 samples
      showed that the Asian or group 3 variant was found in 45% of the samples
      sequenced, thus confirming the high frequency of this variant in the region.
      Group 2a variants accounted for 50% of the samples with a complete absence of
      group 2b. Our analysis also provided strong bootstrap support for the subdivision
      of group 2 into subgroups 2a and 2b. This study shows that isolates belonging to
      all three main groups of GBV-C/ HGV can be detected in Singapore, with the large
      majority belonging to groups 2a (50%) and 3 (45%). Only a single group 1-like
      sequence was detected within the 20 isolates. Of interest also is that all group
      3 isolates were identified in Chinese patients while group 2a was found in both
      Chinese and Malay.

PMID- 10335863
TI  - Etiology of sporadic acute viral hepatitis in Taiwan: the role of hepatitis C
      virus, hepatitis E virus and GB virus-C/hepatitis G virus in an endemic area of
      hepatitis A and B.
AB  - The etiology of sporadic acute hepatitis was studied in 334 consecutive patients
      from Taiwan (237 men and 97 women, aged 16-81 years), with emphasis on the role
      of hepatitis C virus (HCV), hepatitis E virus (HEV), and GB virus-C/hepatitis G
      virus (GBV-C/HGV) in acute non-A, non-B (NANB) hepatitis and in HBsAg carriers
      with superimposed acute hepatitis. According to the conventional diagnostic
      criteria, there were 12 cases (3.6%) of acute hepatitis A, 17 cases (5.1%) of
      acute hepatitis B, 128 cases (38.3%) of acute NANB hepatitis, and 177 cases
      (53.0%) of acute hepatitis in HBsAg carriers (those who were HBsAg positive but
      IgM anti-HBc negative). Among 128 cases of acute NANB hepatitis, 70 (54.7%) had
      acute hepatitis C (HCV RNA positive), 5 (3.9%) had acute hepatitis E (IgM anti
      HEV positive), and the other 53 (41.4%) were presumably acute hepatitis non-A-E.
      The prevalence of acute hepatitis A, B, E, and non-A-E showed no significant sex
      difference, whereas acute hepatitis C was significantly more prevalent in
      females. The prevalence of acute hepatitis A and B decreased and that of acute
      hepatitis C increased significantly with increasing age. In contrast, acute
      hepatitis E and non-A-E showed no significant age predominance. Of 177 HBsAg
      carriers with acute hepatitis, 64 (36.1%) demonstrated non-B hepatotropic virus
      superinfection, with HCV being the most common (60.9%), followed by hepatitis D,
      E, and A viruses, and the other 55 (31.1%) and 58 (32.8%) were presumed to have
      acute exacerbation of chronic hepatitis B or superimposed acute hepatitis non-A
      E, respectively. Serum GBV-C/HGV RNA was detected in 3-4% of acute hepatitis non
      A-E cases, suggesting its limited role in these cases.

PMID- 10335864
TI  - Is hepatitis G/GB virus-C virus hepatotropic? Detection of hepatitis G/GB virus-C
      viral RNA in liver and serum.
AB  - The recently identified hepatitis G virus (HGV, also named GB virus-C, GBV-C)
      appears to have similarities to hepatitis C virus and other flaviviridae. To
      better understand its clinical significance and hepatotropism, we collected liver
      tissue and matched serum samples from 56 patients undergoing liver
      transplantation. HGV/GBV-C RNA was detected by reverse transcription-nested PCR,
      using primers from the relatively conserved 5' noncoding region of the genome to
      detect HGV/GBV-C RNA and the amount was semiquantitatively estimated by serial 10
      fold endpoint dilution. The presence and amount of HCV RNA was estimated by the
      same methodology. Seventeen patients (30%) had HGV/GBV-C RNA detectable either in
      liver or in serum, including two of three with cryptogenic liver disease.
      Interestingly, 5 of 17 (29%) patients had HGV/GBV-C RNA in serum but not liver,
      even with repeated testing of hepatic RNA from different portions of the liver.
      Furthermore, the titer of HGV/GBV-C RNA was significantly lower in liver than in
      serum in most samples (mean log titer, 1.33 vs. 2.56, P < 0.05). In contrast, all
      21 patients with HCV RNA in serum also had the virus detectable in liver. In five
      patients coinfected with HCV and HGV/GBV-C, the mean titer of HCV RNA in liver
      was higher than that in serum (log titer, 2.8 vs. 3.0, P > 0.05). Thus, our
      results suggest that HGV/GBV-C is probably not hepatotropic and may replicate
      predominantly in sites other than the liver. These findings brings into question
      the role of HGV in causing significant liver disease.

PMID- 10335866
TI  - Detection of a novel DNA virus (TTV) sequence in peripheral blood mononuclear
      cells.
AB  - DNA sequences of a novel DNA virus (TTV) were examined in 81 peripheral blood
      mononuclear cell (PBMC) DNA samples from 48 children and 33 adults, 22 cord blood
      mononuclear cells (CBMC) DNA samples, and 7 autopsy liver tissue DNA samples by a
      hemi-nested polymerase chain reaction (PCR). The PCR was carried out using the
      published primers (NG059, NG061, NG063) to amplify TTV DNA sequences. The
      sequences were detected in 4 of 81 (5%) PBMC DNA samples, in none of 22 (0%) CBMC
      DNA samples, and in 2 of 7 (29%) liver tissue DNA samples by direct gel analysis.
      The PCR-amplified products were confirmed by direct sequencing. The sequencing
      showed considerable diversities, with differences of 0-55% in 6 TTV isolates,
      compared with the prototype sequence of TTV. These results suggest that TTV is a
      ubiquitous virus that produces asymptomatic infection in a large proportion of
      the general population without transfusion of blood-derived products. To our
      knowledge, this is the first report describing the detection of TTV DNA sequences
      in PBMCs.

PMID- 10335865
TI  - Unintegrated HIV-1 circular 2-LTR proviral DNA as a marker of recently infected
      cells: relative effect of recombinant CD4, zidovudine, and saquinavir in vitro.
AB  - Unintegrated HIV-1 proviral DNA is one of the earliest detectable forms of HIV-1,
      and the influence of an antiretroviral drug on its appearance may reflect the
      efficacy of that agent in preventing infection of new cells. We characterized the
      dynamics of HIV-1 p24 (p24) antigen production, HIV-1 gag DNA, tandem long
      terminal-repeat circular unintegrated proviral (2-LTR) HIV-1 DNA, HIV-1 tat mRNA,
      and cell viability in the presence of three antiretroviral agents: recombinant
      soluble CD4 (rsCD4), zidovudine, and saquinavir. Interference with HIV-1 entry by
      rsCD4 decreased p24 antigen levels modestly, decreased HIV-1 gag by twofold, and
      2-LTR was detectable at the end of the culture period. Inhibition of reverse
      transcription by zidovudine decreased p24 antigen levels modestly, decreased HIV
      1 gag by 19-fold, and inhibited detection of 2-LTR HIV-1 DNA. The protease
      inhibitor, saquinavir, had the greatest overall effect, with the lowest levels of
      p24 antigen and HIV-1 gag, and inhibition of 2-LTR. There was no detection of tat
      mRNA in the saquinavir-treated cultures. In addition, cell viability was
      significantly higher in cultures treated with saquinavir. In these experiments, 2
      LTR HIV-1 DNA was indicative of the relative inhibitory effects of three
      antiretroviral agents acting at different steps of the HIV-1 replication cycle.
      We demonstrated in vitro that 2-LTR HIV-1 DNA was a useful indicator of an
      antiretroviral drug in preventing new cell infection and could be utilized as a
      dynamic marker of drug efficacy in HIV-1-infected patients.

PMID- 10335867
TI  - Specific detection of echoviruses 22 and 23 in cell culture supernatants by RT
      PCR.
AB  - Reverse transcription-polymerase chain reaction (RT-PCR) methods are available
      for the rapid detection of enteroviruses in clinical specimens or virus isolates.
      Pan-enterovirus PCR primers, however, fail to amplify echovirus (E) type 22 or 23
      because of their extreme sequence divergence from the other enteroviruses. We
      have developed an RT-PCR method to detect specifically E22 and E23 RNA directly
      in tissue culture supernatants without a viral RNA purification step. The E22/E23
      primers successfully amplified 20 of 20 clinical isolates of E22 and 4 of 4 E23
      isolates representing viruses isolated in 15 states over a 19-year period, as
      well as E22 and E23 prototype strains isolated in the 1950s. The primers did not
      amplify any of the other 64 enterovirus prototype strains.

PMID- 10335868
TI  - Quantity of human cytomegalovirus (CMV) DNAemia as a risk factor for CMV disease
      in renal allograft recipients: relationship with donor/recipient CMV serostatus,
      receipt of augmented methylprednisolone and antithymocyte globulin (ATG).
AB  - A prospective longitudinal study of 87 renal allograft recipients identified 31
      patients with cytomegalovirus (CMV) viraemia. Previous studies have identified
      CMV viraemia, donor positivity, and CMV load in urine as independent risk factors
      for disease following renal transpl antation. We used quantitative-competitive
      polymerase chain reaction (QC-PCR) to quantify the CMV DNA load in blood from
      these patients, and report that it is a significant and independent risk factor
      for CMV disease. Patients with symptomatic CMV infection had significantly higher
      maximum CMV loads than those with no disease (P = .0003). We also found that peak
      loads were significantly higher in individuals experiencing primary CMV infection
      (P < .01), and CMV re-infection (P < .05) compared with recipients reactivating
      endogenous CMV. Univariate analysis revealed that CMV DNA load in blood, donor
      seropositivity, and receipt of antithymocyte globulin (ATG) were all
      significantly associated with disease (P = .005, .04, and .05, respectively).
      However, the association of donor/recipient serostatus, and receipt of ATG became
      nonsignificant in multivariate analyses whereas the significance of the quantity
      of CMV DNAemia was maintained, illustrating that CMV load plays a central role in
      the pathogenesis of CMV disease.

PMID- 10335869
TI  - L20B cells simplify culture of polioviruses from clinical samples.
AB  - Culture of polioviruses from clinical samples is the gold-standard method for
      virological surveillance in the world-wide initiative to eradicate wild-type
      polioviruses. Two poliovirus-sensitive cell lines of human origin were used
      originally by the laboratories of the World Health Organisation (WHO) global
      poliovirus network. However, the cell lines used, Hep2 and RD, also support
      cytopathic growth of a variety of non-poliovirus enteroviruses. This can make
      detection of polioviruses in samples with mixtures of viruses difficult and time
      consuming. The development of mouse cell lines that express the gene for the
      human cellular receptor for polioviruses allows selective poliovirus culture,
      because very few non-poliovirus enteroviruses grow in these murine cells. A WHO
      Collaborative Study was initiated to test one such cell line, L20B, and to
      compare under routine conditions the sensitivity and selectivity of L20B cells
      against RD and Hep2 cells. Five laboratories in countries endemic or recently
      endemic for wild polioviruses participated. A total of 425 samples were tested
      prospectively in all three cell lines and there was a clear and consistent trend
      for greater sensitivity for polioviruses in L20B cells. Overall, 148/160
      polioviruses were detected in L20B cells compared with 89/160 in RD and 98/ 160
      in Hep2. In part, this finding was due to detection in L20B cells of polioviruses
      from samples that also contained non-poliovirus enteroviruses in which the
      poliovirus was masked in RD or Hep2 cells. However, L20B cells were also
      significantly more sensitive for poliovirus than either RD or Hep2 cells in three
      of the five study laboratories. The L20B cells were completely selective for
      polioviruses, as 0/89 wild type non-poliovirus enteroviruses produced cytopathic
      effect in L20B cells. Finally, L20B cells provided a diagnosis of poliovirus
      infection in the same time as RD and Hep2 cells from samples that contained
      poliovirus only, but substantially more quickly for samples that contained
      another enterovirus. Taken together, these data indicate that L20B cells simplify
      primary diagnosis of poliovirus from clinical samples and as a result they have
      been introduced for routine use by laboratories of the WHO global poliovirus
      network.

PMID- 10335870
TI  - Introduction: current issues in high-dose chemotherapy and stem cell support.
AB  - In the 1980s it became clear that low numbers of primitive hematopoietic cells
      were present in the peripheral bloodstream. Early clinical trials by
      investigators in the USA, Australia, and Germany demonstrated that these cells
      could be collected and reinfused to support high-dose chemotherapy procedures in
      patients otherwise unable to undergo bone marrow collection, usually because of
      prior pelvic irradiation. It was, however, difficult to obtain adequate numbers
      of stem cells from patients in the steady state. It was not until the
      demonstration by Socinski in Boston and Gianni in Milan that these circulating
      cells were markedly increased following the administration of either cytokines,
      chemotherapy, or a combination of both that the use of peripheral blood stem
      cells over bone marrow began to be widely undertaken. Since that time, peripheral
      blood stem cell collection has become the preferred means of stem cell support
      for high-dose chemotherapy because of the reduction in time to neutrophil and
      platelet engraftment, reduction in the number of transfusions and hospital stay,
      and an apparent reduction in tumor cell contamination.

PMID- 10335871
TI  - Impact of stem cell dose on hematopoietic recovery in autologous blood stem cell
      recipients.
AB  - Hematopoietic recovery rates following high-dose chemotherapy in autologous blood
      stem cell recipients have been shown, in part, to be dependent on the source and
      quantity of hematopoietic stem cells infused. Mobilized blood stem cell quantity
      (identified by the surface expression of the CD34 antigen) has been demonstrated
      in multiple studies to be the strongest predictor of days to hematopoietic
      recovery (ie platelets and neutrophils) in autologous blood stem cell recipients.
      Additionally, data from four large studies confirm that prompt and sustained
      hematopoietic recovery will occur in the majority of patients treated with high
      dose chemotherapy if a stem cell dose > or = 5 x 10(6)/kg is administered.
      However, multiple aphereses are needed in the majority of patients to achieve
      these optimal stem cell doses. Problems associated with multiple aphereses
      procedures include hypocalcemia, anemia, thrombocytopenia, infection, thrombosis,
      increased costs, and malignant cell contamination of the apheresis product.
      Recent data indicate that less differentiated (eg CD33 ) stem and progenitor
      cells result in both early and sustained hematopoietic recovery in bone marrow
      and blood stem cell recipients. Future trials using new growth factors such as
      stem cell factor (which has been shown to increase CD34+/CD33 cell mobilization),
      as well as improvements in purging strategies are needed to ensure prompt,
      sustained, and malignant-cell-free engraftment for the majority of autologous
      blood stem cell recipients.

PMID- 10335872
TI  - The utilization of cytokines in stem cell mobilization strategies.
AB  - High-dose myeloablative chemotherapy supported by peripheral blood progenitor
      cell (PBPC) transplant is rapidly replacing bone marrow transplant to treat a
      number of chemosensitive cancers. Numerous investigators have studied the
      relationship of CD34+ cell dose and engraftment kinetics in an effort to help
      define minimum and optimum target stem cell doses. A number of studies suggest
      that reinfusion of > or = 5 x 10(6) CD34+ PBPCs results in prompt and durable
      platelet engraftment. Mobilization of stem cells can be accomplished through use
      of chemotherapy alone, colony-stimulating factors, or a combination of the two.
      Strategies to improve PBPC yields include filgrastim in combination with
      chemotherapy or with other hematopoietic growth factors. In this paper, the
      advantages and disadvantages of these strategies will be discussed, and the
      results of a recently conducted, randomized, controlled phase 3 clinical trial in
      breast cancer patients receiving either SCF plus filgrastim or filgrastim alone
      for PBPC mobilization will be reviewed.

PMID- 10335873
TI  - Economic considerations in the use of peripheral blood progenitor cells to
      support high-dose chemotherapy.
AB  - There has been increasing interest in the development of strategies to enhance
      the number of CD34+ cells obtained during harvesting of peripheral blood
      progenitor cells (PBPC) to support high-dose chemotherapy. The strategies have
      included the use of chemotherapy plus cytokine for mobilization, and the
      development of more effective mobilizing cytokine combinations, such as stem cell
      factor plus filgrastim. Although there are costs associated with the
      implementation of these strategies, there are also predictable cost savings to be
      realized from the enhanced PBPC yields. Available data suggest that these cost
      savings include: $2000 per apheresis prevented, $6000 per back-up bone marrow
      harvest prevented, and at least $10200 per remobilization and apheresis stage
      prevented. In addition, there is emerging evidence that the administration of
      optimal (> or = 5 x 10(6)/kg) as opposed to acceptable but suboptimal (>1 x
      10(6)/kg but <5 x 10(6)/kg) numbers of CD34+ PBPC will be associated with
      decreased supportive care needs and decreased costs of at least $4500-8000. These
      economic considerations should play a role, together with clinical data, in
      rational decision-making with respect to PBPC support.

PMID- 10335874
TI  - Management strategies for the hard-to-mobilize patient.
AB  - Delayed hematopoietic engraftment, particularly of platelets, is seen in 5-35% of
      patients undergoing high-dose chemotherapy with autologous stem cell
      transplantation. Studies indicate that delayed engraftment is related to low
      CD34+ cell dose, and that risk factors for poor mobilization of CD34+ cells
      relate primarily to the type and extent of prior therapy. Data indicating an
      appropriate strategy to ensure that 'hard-to-mobilize' patients will achieve
      adequate CD34+ cell numbers are limited. It is clear, however, that marrow
      harvesting (performed frequently by a number of centers), is of limited value.
      Remobilization, best accomplished with a regimen of high-dose chemotherapy and
      cytokines, is of benefit in selected patients, but has substantial costs and
      morbidity. Instead of ad hoc treatment of patients who have a poor first
      mobilization, high-risk groups should be identified prospectively, and strategies
      should be developed to ensure adequate mobilization in all high-risk patients.
      The first randomized trial utilizing this approach has recently been reported. In
      this trial, stem cell mobilization with granulocyte colony-stimulating factor (G
      CSF) alone was compared to mobilization with G-CSF combined with stem cell factor
      (SCF) in heavily pretreated patients with Hodgkin's and non-Hodgkin's lymphoma.
      The combination of G-CSF and SCF led to collection of a higher total CD34+ cell
      dose compared to G-CSF alone. Further, more patients in the combination group
      were able to mobilize an optimal CD34+ cell dose (ie 5 x 10(6)/kg). Additional
      trials are needed to determine long-term outcomes and the economic impact of
      achieving optimal stem cell mobilization in these patients, who would otherwise
      not be candidates for high-dose chemotherapy.

PMID- 10335875
TI  - Plasma lipids, lipoproteins and apolipoproteins and sudden cardiac death.
AB  - To investigate the risk factors for sudden cardiac death, in particular that
      triggered by coronary heart disease, we analysed 17 different lipids,
      lipoproteins and apolipoproteins in the plasma of patients who had suffered
      sudden death, including sudden cardiac death. Studies were carried out on 107
      cadavers comprising 78 subjects where the cause of death was diagnosed as sudden
      cardiac death and 29 subjects diagnosed with other causes of sudden death. All
      107 cases were classified into four groups according to the degree of coronary
      stenosis and the degree of cardiac hypertrophy. Plasma levels of total
      cholesterol (T-CHOL), triglyceride (TG), beta-lipoprotein (beta-LIPO), free fatty
      acid, phospholipid, free cholesterol, high density lipoprotein cholesterol,
      lipoprotein(a) [Lp(a)], lipoproteins (VLDL, LDL, HDL) and apolipoproteins (apoAI,
      apoAII, apoB, apoCII, apoCIII, apoE) were determined. The level of apoB showed a
      significant difference and positive correlation with the degree of coronary
      stenosis by two different statistical methods, while the levels of T-CHOL, TG,
      beta-LIPO, VLDL, apoCII, apoCIII and apoE showed significant differences with the
      degree of coronary stenosis by one statistical method. It was concluded that a
      high plasma level of apoB is a risk factor for coronary stenosis, with higher
      levels resulting in more severe degrees of coronary stenosis. Furthermore, a
      significant difference was found regarding only apoCIII both between the sudden
      cardiac death group and the sudden death from other causes group, and between
      each of the four groups classified according to the degree of coronary stenosis.
      It was thus concluded that a high plasma level of apoCIII indicates the
      possibility of a coronary stenotic origin for sudden cardiac death.

PMID- 10335876
TI  - The detection of dihydrocodeine and its main metabolites in cases of fatal
      overdose.
AB  - The levels of dihydrocodeine found in impaired individuals and in fatalities show
      a wide overlap in the ranges. Among other factors, the genetically controlled
      metabolism of dihydrocodeine should play an important role in dihydrocodeine
      toxicity. For the first time, the most important metabolites of dihydrocodeine
      were investigated in femoral blood from three fatal cases by simultaneous
      determination using HPLC and native fluorescence for detection. The amount of
      parent drug always exceeded dihydrocodeine-glucuronide formation and
      dihydromorphine concentrations ranged from 0.16-0.21 mg/L. The similar binding
      affinities of dihydromorphine and morphine to mu-opioid receptors suggest similar
      pharmacological effects and adverse reactions. The determination of the
      pharmacologically active metabolites should help to clarify the cause of death in
      fatal cases especially if a relatively low concentration of the parent drug is
      found.

PMID- 10335877
TI  - Estimation of wound age and VCAM-1 in human skin.
AB  - To estimate the age of skin wounds, the endothelial adhesion molecule VCAM-1 (CD
      106) was detected in paraffin sections after autoclaving and using the ABC
      technique. The percentage of VCAM-1 positive blood vessels was determined after
      the blood vessels had been marked with PECAM-1 (CD 31). Low positive staining
      reactions were observed for VCAM-1 on endothelial cells of uninjured skin in 18%
      of the samples. In injured skin, 51% of the cases investigated showed a VCAM-1
      expression. Strong positive staining reactions were observed 3 h at the earliest
      and 3.5 days at the latest after the time of injury. The immunohistochemical
      results for VCAM-1 differed significantly between the injured and uninjured skin
      (P < 0.01). In a few cases VCAM-1 was detected (n = 6) at low intensity in
      postmortem skin wounds and a moderate to strong expression of VCAM-1 is
      indicative of the vitality of the wound. The detection of VCAM-1 can be used for
      estimating the age of wounds in forensic applications if the degree of expression
      of further adhesion molecules, especially that of selectins, is taken into
      account.

PMID- 10335878
TI  - Diatom analysis in victim's tissues as an indicator of the site of drowning.
AB  - The diagnosis of drowning is one of the most difficult in forensic pathology and
      previously we proposed criteria for a positive tissue analysis according to the
      qualitative and quantitative diatom investigations. In the positive cases, we
      studied the reliability of determining the site of drowning by comparing the
      diatom taxa found in the lung samples with those of the water samples or in the
      absence of these samples with the results of the water diatom monitoring
      programme set up in our region. In this study, we present two series of cases,
      the first is one of 20 corpses who died from accidental or suicidal drowning with
      known drowning site, and the second of 20 corpses for which the drowning site was
      unknown. The results showed that a concordance of the abundance of the diatom
      taxa in tissues compared to the site of drowning and their distribution relative
      to one another was 65% in the group where the site of drowning was known and 35%
      in the other group. The concordance of the individual distribution in the lungs
      of water diatom taxa may be an interesting method to guide the investigations for
      determining the site of drowning. The two limiting factors are the concentration
      of diatoms in the lungs and the development of a river monitoring programme in
      the district of the study.

PMID- 10335879
TI  - Does the sequence of onset of rigor mortis depend on the proportion of muscle
      fibre types and on intra-muscular glycogen content?
AB  - We examined the postmortem changes in the levels of ATP, glycogen and lactic acid
      in two masticatory muscles and three leg muscles of rats. The proportion of fibre
      types of the muscles was determined with NIH image software. The ATP levels in
      the white muscles did not decrease up to 1 h after death, and the ATP levels 1
      and 2 h after death in the white muscles were higher than those in the red
      muscles with a single exception. The glycogen level at death and 1 h after death
      and the lactic acid level 1 h after death in masticatory muscles were lower than
      in the leg muscles. It is possible that the differences in the proportion of
      muscle fibre types and in glycogen level in muscles influences the postmortem
      change in ATP and lactic acid, which would accelerate or retard rigor mortis of
      the muscles.

PMID- 10335880
TI  - Mitochondrial DNA in human hair shafts--existence of intra-individual
      differences?
AB  - The sequences of the hypervariable region 1 (HV1) of the mitochondrial DNA
      control region from multiple hair shafts from 10 unrelated individuals were
      compared to determine the frequency of differences in hairs from one individual.
      The extraction method described herein showed an average success rate of 67% for
      all 150 hair shafts tested in HV1. The mtDNA sequences from the hair shafts
      matched the sequences from the corresponding blood and saliva samples taken from
      the same donor and no evidence of heteroplasmy was found. The results emphasize
      the reliability of DNA extraction and mtDNA typing from human hair shafts for
      forensic purposes.

PMID- 10335881
TI  - On the consequences of DNA profile mismatches for close relatives of an excluded
      suspect.
AB  - If the DNA profiles of a crime stain and the reference sample from the suspect do
      not match, the suspect is excluded as the donor of the crime stain. However, in
      some situations the DNA evidence can suggest that a close relative of the suspect
      might match the stain, in particular when the reference sample from the suspect
      and the crime stain share rare alleles. This finding can be important for the
      authorities. The forensic scientist has to decide whether or not to notify the
      authorities in these circumstances. To the best of our knowledge there is not yet
      an objective rule for making this decision. We propose such a decision rule for
      brothers of the suspect, investigate its performance and address some ethical,
      legal, and practical aspects. Our calculations can be simply adjusted for other
      relatives of the suspect.

PMID- 10335882
TI  - Human Y-chromosomal STR haplotypes in a Kurdish population sample.
AB  - In an Iraqi Kurdish population sample (n = 101), seven polymorphic STR loci of
      the Y-chromosome (DYS19, 389, 390, 391, 392, 393, and DXYS156-Y) were typed, with
      DYS389 being subtyped for its four segments. The haplotype diversity was 97.83%
      and 82 different haplotypes were observed. The Kurds shared some Y-types with
      neighbouring south Turks but strikingly few with Germans: it is 20-30 times more
      likely to find a sequence match in a random pair of Kurds than in a random Kurd
      German pair.

PMID- 10335883
TI  - The concentration of glutamate in cerebral tissue as a factor for the assessment
      of the emotional state before death. A preliminary report.
AB  - In this paper the concentration of glutamate in the hemispheres of the brain, the
      cerebellum and the brain stems of rats exposed to sensory stimulation before
      death and of control rats are presented. Statistically significant differences in
      the concentration of this neurotransmitter were found in the hemispheres of the
      brain in the cases of stress lasting 10 min and 1 min and in the cerebellum after
      a stress of 10 min. This suggests that it may be possible to diagnose the post
      mortem state of emotional tension related to sensoric aversive input which takes
      place directly before death.

PMID- 10335884
TI  - Physical activity following fatal injury from sharp pointed weapons.
AB  - Cases of suicide from sharp pointed weapons (n = 12) witnessed by one or more
      persons are reported with regard to the potential for physical activity. One case
      each involved the ulnar artery, the great saphenous vein and the periphery of the
      lung and liver and the physical activity following these injuries lasted for
      several hours. In one case, the left carotid and vertebral arteries were
      transected and the physical activity lasted for approximately 10 s. An
      extraordinary case involved a protracted incapacitation due to heart tamponade
      from a small myocardial injury caused by a cannula. In the remaining seven cases,
      a stab wound to the heart was present. With regard to the physical activity, a
      long-term group (2-10 min, n = 4) can be differentiated from a short-term group
      (approximately 10 s, n = 2) and one case of immediate incapacitation. The size of
      the myocardial perforation was 7-10 mm in length in the long-term group compared
      to 1.4-2 cm in the short-term group. So small perforations of the heart or
      incisions of the carotid artery offer a potential for considerable physical
      activity. Large perforations of the heart or a transection of the carotid and
      vertebral arteries can result in short-term activity.

PMID- 10335885
TI  - Mutation of the repeat number of the HPRTB locus and structure of rare
      intermediate alleles.
AB  - During routine paternity testing a mutation of a paternal allele at the HPRTB
      locus was observed. The opportunity was taken to analyse this mutation at a
      molecular level. The repeat sequence is flanked by an imperfect repeat sequence
      and this region could be involved in the mutation mechanism. For this reason, we
      also examined the structure of "intermediate" alleles. Sequencing confirmed the
      insertion of a perfect repeat motif and revealed a deletion of a dinucleotide
      some 50 nucleotides downstream from the repeat sequence for the intermediate
      alleles. It is likely that these intermediate alleles are rare biallelic deletion
      polymorphisms and are probably not involved in the mutation or variation
      mechanism of this locus.

PMID- 10335886
TI  - Recognition and significance of pulmonary bone embolism.
AB  - Embolism of bone marrow to the lungs is a quite frequent finding after trauma but
      transport and deposition of solid bone is rarely seen, which may simply be
      because pulmonary calcifications are not recognized as bone fragments. We report
      on three patients with embolism of bone spicules to small lung arteries of about
      0.5 mm in diameter which were plentiful in two of the patients on postmortem
      examination. However, the true nature of the emboli was only recognizable after
      decalcification of lung tissues. It appears that trauma occurring in a septic
      bone lesion has the greatest chance to provoke bone embolism. The bone spicules
      do not usually occlude vessel lumina and thus do not severely disturb the blood
      circulation in the lungs. The bone fragments become covered by endothelium and
      can remain recognizable for months or even years.

PMID- 10335887
TI  - Levels of paraquat in fatal intoxications.
AB  - We describe here fatal levels of paraquat in plasma of victims due to the
      ingestion of the herbicide, paraquat, and the relationship between those levels
      and survival times after ingestion. We determined paraquat levels in plasma of
      106 paraquat poisoning cases in Korea between June 1992 and December 1996 using a
      visible spectrophotometric method based on the alkali-dithionite reaction. Among
      55 cases with known survival times, plasma paraquat levels of victims who died
      within one day of ingestion ranged from 2.3 to 636.6 microg/ml (average 127.6
      microg/ml) while those of the victims who died between 1 approximately 4 days
      ranged from 0.9 to 25.1 microg/ml (average 7.0 microg/ml). Since preparations
      containing 24.5% paraquat dichloride are still used in Korea, our data for Korean
      victims who died within one day were 8.5 times higher than those in Baselt and
      Cravey's report for the same survival times. Our data also suggest that victims
      in whom a plasma paraquat concentration of more than 30 microg/ml was detected
      are likely to have died within 24 h after ingestion.

PMID- 10335888
TI  - Saliva from cheese bite yields DNA profile of burglar: a case report.
AB  - Physical evidence in the form of a high quality bite mark was discovered on a
      piece of yellow cheese found at the scene of a crime. The cheese had been frozen
      by police for 10 days after recovery and before submission to the laboratory for
      testing. The double swab technique was used to collect DNA samples. A sample of
      the suspect's blood was obtained. Using PCR-based DNA typing at ten STR loci,
      (Profiler Plus, Perkin Elmer-Applied Biosystems) it was determined that the DNA
      from the cheese originated from the suspect. This case illustrates the importance
      of a) always considering human bite marks as both physical and biological
      evidence, and b) attempting DNA recovery in any case in which minute traces of
      saliva may be present, even in situations involving bacteria-rich foods.

PMID- 10335889
TI  - Detection of additional structural variation at the FES/FPS system and population
      data from S. Tome e Principe and North Portugal.
AB  - Comparative analysis of heteroduplex patterns on the STR FES/FPS system led to
      the detection of a new non-consensus allele 10 in the African population of Sao
      Tome e Principe. Automated sequencing confirmed a T-->C substitution at position
      177 (1stT of the 6th repeat) which was exclusively found in haplotypic
      combination with base A in the previously described polymorphic position 34. The
      new substitution was not detected in a sample from North Portugal. Sequence
      analysis revealed a triplet of inverted bases, from positions 101 to 103,
      relative to the sequence described in the GeneBank (Accession No. X06292). This
      work confirms the capacity of heteroduplex analysis in the detection of DNA
      structural microvariation and emphasises the complementary utility of manual
      system analysis and semi-automated techniques for a full characterisation of the
      genetic variability of STRs.

PMID- 10335890
TI  - The Y-STRs DYS19 and DYS390 in a south-east Hungarian (Szeged area) population.
AB  - The allele frequencies of DYS19 and DYS390 located on the Y chromosomes were
      determined from male bloodstain samples of 308 (DYS19) and 268 (DYS390) unrelated
      male adults in south-east Hungary. Six alleles could be distinguished in both
      systems, yielding 22 DYS19/DYS390 halotypes in a subset of 239 males.

PMID- 10335891
TI  - Improved DNA typing of human urine by adding EDTA.
AB  - The effect of different EDTA concentrations on the DNA content of urine samples
      was examined and compared to untreated urine at various storage temperatures and
      times. The results indicate that adding EDTA increases the DNA stability for long
      time storage especially at low temperatures.

PMID- 10335892
TI  - Human Y-chromosomal STR types in north Thailand.
AB  - A north Thai Y-haplotype database consisting of the loci DYS19, DXYS156-Y,
      DYS390, DYS391, DYS392, DYS393, and the four subsegments of DYS389 is presented.
      We observed 44 Y-types in 50 unrelated Thais, and the haplotype diversity was
      calculated to be 97.36%. No Y-types were shared with a sample of 55 Japanese, but
      3 matches were found in a sample of 61 Han Chinese, and there was one Thai-German
      match in a larger west German sample (n = 179).

PMID- 10335893
TI  - Quantitation of intraepidermal T-cell subsets in formalin-fixed, paraffin
      embedded tissue helps in the diagnosis of mycosis fungoides.
AB  - Differentiation between mycosis fungoides (MF) and cutaneous inflammatory
      processes can usually be made on clinical and histologic grounds. In difficult
      cases, immunohistochemical studies can be helpful since MF infiltrates usually
      contain a predominance of CD4+ lymphocytes, while most inflammatory lesions
      usually have a mixture of CD4+ and CD8+ lymphocytes. However, this determination
      has traditionally required the use of frozen tissue, thus severely limiting its
      usefulness. Recently, antibodies that differentially label CD4+ and CD8+
      lymphocytes in formalin-fixed, paraffin-embedded tissue have become available
      (OPD4 and C8/144B respectively, DAKO (Carpinteria, CA, USA). This study tests the
      utility of these antibodies in the pathologic diagnosis of MF and inflammatory
      lesions with significant exocytosis. In 9 cases of MF for which both frozen and
      fixed tissues were available for comparison, the OPD4+ cell count in fixed tissue
      was significantly lower than the Leu-3a+ cell count in frozen tissue. Also, the
      C8/144B+ cell count in fixed tissue was higher than the Leu-2a+ cell count in
      frozen tissue, although this difference was not significant statistically. In a
      larger series for which only fixed tissue was available, epidermal CD4:CD8 ratios
      were significantly greater in 23 MF cases (mean 4.0+/-4.76) than in 35
      inflammatory cases (mean 0.6+/-0.42; p = 0.001). Thus, although the studied
      antibodies appear to detect different epitopes in frozen versus paraffin-embedded
      tissue, demonstration of an elevated CD4:CD8 ratio in fixed tissue supports the
      diagnosis of MF, and is a helpful adjunct to routine histopathology.

PMID- 10335895
TI  - Differences in sialyl-Tn antigen expression between keratoacanthomas and
      cutaneous squamous cell carcinomas.
AB  - Keratoacanthoma and squamous cell carcinoma are common skin tumors, especially in
      immunosuppressed transplant recipients, but the distinction between these two
      types of epidermal neoplasia may be difficult. Sialyl-Tn (Sia-GalNAc-O-Ser/Thr)
      is a cell surface carbohydrate associated with hyperplasia in squamous
      epithelium, and correlated with poor prognosis in several human adenocarcinomas.
      Twenty-seven keratoacanthomas and 29 cutaneous squamous cell carcinomas were
      examined for the expression of sialyl-Tn and of the Ki67 epitope, the latter a
      marker for cell proliferation. By immunohistochemistry, basaloid tumor cells at
      the periphery of tumor nests showed some degree of sialyl-Tn expression in 16
      keratoacanthomas (59%), while only three squamous cell carcinomas (10%) showed
      sialyl-Tn-positive basaloid tumor cells (p<0.001). Keratinized, differentiated
      tumor cells were more often sialyl-Tn-positive in keratoacanthomas (89%) than in
      squamous cell carcinomas (31%) (p<0.001). A striking sialyl-Tn-positivity in the
      basal cell layer was found in a border zone directly adjacent to most tumors of
      both types (88 and 88%). By immunohistochemical examination of parallel sections
      and by double immunofluorescence, sialyl-Tn antigen expression was primarily seen
      in cells that did not express Ki67, although some overlap was present.
      Keratoacanthomas from transplant recipients did not differ in sialyl-Tn
      expression compared to those from non-immunosuppressed patients. The results
      indicate that sialyl-Tn expression is not directly related to cell proliferation,
      but rather to cellular features of post-mitotic cells, and that sialyl-Tn is not
      associated with a malignant phenotype. Sialyl-Tn may be linked to tumor
      regression, as seen in keratoacanthomas.

PMID- 10335894
TI  - Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR/DGGE)
      based detection of clonal T-cell receptor gamma gene rearrangements in paraffin
      embedded cutaneous biopsies in cutaneous T-cell lymphoproliferative diseases.
AB  - Polymerase chain reaction (PCR)-based amplification of T-cell receptor (TCR)
      gamma genes is a novel technique that can detect a clone of T cells comprising
      less than 1% of the total T cells in a lymphoid infiltrate. Besides greater
      sensitivity than Southern blotting, this technique can be performed with smaller
      quantities of lower molecular weight genomic DNA as template. We retrospectively
      analyzed 12 paraffin-embedded biopsies of cutaneous T-cell lymphoma (CTCL), 1
      case suspicious for CTCL, 1 case of granulomatous slack skin, and 8 cases of
      inflammatory skin diseases to determine if PCR-denaturing gradient gel
      electrophoresis (PCR-DGGE) analysis can detect TCR-gamma gene rearrangements on
      paraffin-embedded specimens. We were able to amplify Vgamma1-8 TCR sequences in
      each case and detected a dominant clone in 9 of 12 cases of CTCL and in
      granulomatous slack skin. We analyzed Vgamma9 sequences in 9 cases of CTCL and
      detected a dominant clone in 4 cases. This study demonstrates that PCR-DGGE can
      easily be applied retrospectively to cutaneous biopsies of lymphoproliferative
      diseases when fresh tissue is not available.

PMID- 10335897
TI  - Three-dimensional reconstruction in dermatopathology--a personal computer-based
      system.
AB  - The purpose of the present study was to build a system for three-dimensional (3D)
      reconstruction of dermatopathological specimens using an easily available
      personal computer and graphic programs. A stereogram was generated by projecting
      thirty serial sections transferred into a Macintosh computer. The quality of the
      3D images obtained by this method were high enough to show the net-like structure
      of rete ridges in normal epidermis, the antler-like branching of dermal papillae
      in seborrheic keratosis, and the bulge-like proliferation of tumor nests in basal
      cell carcinoma. This method was also helpful to assess oblique sectioning of the
      specimens, which sometimes produces a strange appearance in dermatopathological
      sections. The method presented here would not only help to better understand the
      3D structures of dermatopathological specimens, but could also be used to examine
      3D patterns of tumor invasion, which may contribute to the differential diagnosis
      of malignant tumors.

PMID- 10335896
TI  - Ectopic breast tissue and breast-like sweat gland metaplasias: an overlapping
      spectrum of lesions.
AB  - There are many similarities in the morphology of benign and malignant lesions of
      the sweat glands and the breasts. The recently described cutaneous mammary-like
      sweat glands, also known as mixed sweat glands or apoeccrine glands, are also a
      likely source of selected proliferations that closely mimic those of the breast.
      We present three cases of breast-like lesions arising in the skin that
      demonstrate the ways in which the morphologic and pathologic continuum of the
      mammary glands, cutaneous mammary-like glands, and sweat glands can produce
      difficulties in precise diagnosis. The examples demonstrate that an anatomic
      location outside the milk line does not preclude the diagnosis of ectopic mammary
      tissue, and that lesions closely resembling those of the breast may also arise
      outside the milk line from conventional sweat glands or mixed sweat glands. The
      concept of homologous lesions of the breast, breast-like glands and sweat glands,
      in which morphology is partially mirrored by biochemical similarities, provides a
      perspective for classification of problematic cases of breast-like cutaneous
      lesions.

PMID- 10335898
TI  - Confocal reflectance imaging of folliculitis in vivo: correlation with routine
      histology.
AB  - Near-infrared confocal reflectance microscopy (CM) is a high-resolution: non
      invasive imaging technique with promising future in dermatology. A pustular
      lesion from a 35-year-old male with a known history of folliculitis was non
      invasively viewed with CM and later biopsied. Optical sections were correlated
      with routine histology. This optical technique allows us to view non-invasively
      transverse skin sections to a controlled depth in real time. In the CM images,
      tissue can be visualize with cellular and subcellular detail as shown by imaging
      infiltrating neutrophils (PMNs) within the subcorneal pustule of a superficial
      folliculitis in vivo.

PMID- 10335899
TI  - Angiomatosis of skin with local intravascular immunoglobulin deposits, associated
      with monoclonal gammopathy. A potential cutaneous marker for B-chronic
      lymphocytic leukemia. A report of unusual case with immunohistochemical and
      immunofluorescence correlation and review of the literature.
AB  - Reactive cutaneous vascular proliferation or angiomatosis is associated with
      various conditions, but is rarely seen secondary to vascular occlusion. We report
      an unusual case of a 79-year-old female who presented with 8 month history of
      purpuric facial plaques, with painful crusted ulceration of the nose, later
      developing similar eruptions on hands, thighs and trunk. Biopsies showed marked
      angioproliferation, with intravascular (IV) hyaline deposits (PAS+, fibrin+/-;
      IgM+, fibrinogen+, and C3+), associated with endothelial hyperplasia (Factor
      VIII+, Vimentin+). Immunofluorescence showed IV IgM, fibrinogen, and granular C3
      deposits within vessel walls. Initially, extensive investigations only showed
      minimal monoclonal gammopathy of undetermined significance (MGUS) and repeatedly
      negative cryoglobulins. After a 3-year follow-up, the patient developed chronic
      lymphocytic leukemia (B-CLL). This case illustrates a difficult diagnostic
      challenge. Although this condition resembles other forms of reactive
      angiomatosis, it shows distinct features and should be considered in the
      differential diagnosis of unusual vascular proliferations of the skin. The
      cutaneous lesions are also considered a potential marker for an underlying
      systemic condition, which may require prolonged clinical follow-up. We believe
      this condition to be related to other rare cutaneous vascular proliferations
      associated with plasma cell and lymphoproliferative disorders. Furthermore, we
      suggest a common pathogenetic pathway resulting from the IV immunoglobulin
      deposits causing vascular injury, finally leading to the angiomatosis.

PMID- 10335900
TI  - Cutaneous epithelioid schwannoma: an unusual benign neurogenic tumor.

PMID- 10335901
TI  - Variations among non-sedating antihistamines: are there real differences?
AB  - Most of the modern non-sedating H1 receptor antagonists (antihistamines)
      penetrate the brain poorly, allowing the use of doses large enough to counteract
      allergic processes in peripheral tissues without important central effects. The
      antihistamines reviewed here are acrivastine, astemizole, cetirizine, ebastine,
      fexofenadine, loratadine, mizolastine, and terfenadine. However, these drugs are
      not entirely free from central effects, and there are at least quantitative
      differences between them. Although psychomotor and sleep studies in healthy
      subjects in the laboratory may predict that an antihistamine does not cause
      drowsiness, the safety margin can be narrow enough to cause a central sedating
      effect during actual treatment. This might result from a patient's individual
      sensitivity, disease-induced sedation, or drug dosages that are for various
      reasons relatively or absolutely larger (patient's weight, poor response, reduced
      drug clearance, interactions). Mild to even moderate sedation is not necessarily
      a major nuisance, particularly if stimulants need be added to the regimen (e.g.
      in perennial rhinitis). Furthermore, patients can adjust doses themselves if
      needed. Sedating antihistamines are not needed for long-term itching, because
      glucocorticoids are indicated and more effective. It is wise to restrict or avoid
      using antihistamines (astemizole, terfenadine) that can cause cardiac
      dysrhythmias, because even severe cardiotoxicity can occur in certain
      pharmacokinetic drug-drug interactions. Histamine H1 receptor antagonists
      (antihistamines) are used in the treatment of allergic disorders. The therapeutic
      effects of most of the older antihistamines were associated with sedating effects
      on the central nervous system (CNS) and antimuscarinic effects causing dry mouth
      and blurred vision. Non-specific "quinidine-like" or local anaesthetic actions
      often led to cardiotoxicity in animals and man. Although such adverse effects
      varied from drug to drug, there was some degree of sedation with all old
      antihistamines. Non-sedating antihistamines have become available during the past
      15 years. Some of them also have antiserotonin or other actions that oppose
      allergic inflammation, and they are not entirely free from sedative effects
      either. In small to moderate "clinical" concentrations they are competitive H1
      receptor antagonists, although large concentrations of some of them exert non
      competitive blockade. Daytime drowsiness and weakness are seldom really
      important, and they restrict patients' activities less than the old
      antihistamines. Some new antihistamines share with old antihistamines quinidine
      like effects on the cardiac conducting tissues, and clinically significant
      interactions have raised the question of drug safety. This prodysrhythmic effect
      has also been briefly mentioned in comparisons of non-sedative H1 antihistamines.

PMID- 10335902
TI  - Antimicrobial efficacy of antiseptic mouthrinse solutions.
AB  - OBJECTIVE: To assess the activity of different mouthrinse solutions compared to
      sterile water and sage tea against aerobe bacteria in the oral cavity. METHODS:
      The extent and the duration of the salivary bacterial count reduction were
      determined using a uniform model that allows a direct comparison of the different
      products. In contrast to previous investigations the antimicrobial activity of
      the tested products was stopped by specific neutralizers immediately after
      sampling. RESULTS: The obtained results allowed us to classify four categories of
      mouthrinse solutions according to their antimicrobial properties: Products
      without any active antimicrobial effect (sterile water, sage tea, Fluomint
      Lysoform), products with a weak and temporary effect that does not exceed a
      salivary bacterial count reduction of 1.5 log of colony forming units (cfu)
      immediately and 1.0 log cfu 1 h after application (hydrogen peroxide, Meridol,
      Listerine, Lavasept), products with a strong immediate effect (> or =1.5 log cfu)
      but no prolonged activity (Betaisodona solution, acriflavine) and finally
      products that exert a sustained effect of at least 1.0 log cfu 1 h after
      application (Chloramine T, Gurfix, Skinsept mucosa, Corsodyl, Dobendan,
      Octenisept). CONCLUSION: The method used in this investigation allows an easy and
      reproducible evaluation of antimicrobial efficacy and may be part of a future
      test guideline for efficacy testing of antiseptics.

PMID- 10335903
TI  - Troglitazone has no effect on red cell mass or other erythropoietic parameters.
AB  - OBJECTIVE: Troglitazone is a new anti-diabetic agent for the treatment of type 2
      diabetes. In placebo-controlled trials troglitazone improves glycaemic control,
      reduces hyperinsulinaemia and has beneficial effects on blood lipids. However,
      minor, reversible reductions in erythrocyte count, haemoglobin and haematocrit
      with no associated clinical symptoms have been observed in some troglitazone
      treated patients. The primary objective of the present study was to determine if
      these changes could be explained by a decrease in red cell mass or change in
      plasma volume. METHODS: Twenty-four healthy males were randomized in a double
      blind manner to troglitazone (200 or 600 mg per day) or placebo for 6 weeks.
      Blood samples for the measurement of red cell mass and plasma volume were
      obtained in the 2 weeks prior to treatment and after 6 weeks of treatment.
      Reticulocyte and erythrocyte counts, haemoglobin and haematocrit were also
      measured. RESULTS: At the end of the treatment period there were no statistically
      significant changes in red cell mass. Similarly there were no changes in
      reticulocyte count, erythropoietin or soluble transferrin receptors. These data
      indicate that troglitazone does not affect erythropoiesis. In addition,
      troglitazone was not associated with increased red blood cell destruction or
      haemolysis. There was a trend towards increased plasma volume in the troglitazone
      groups: increases of 2.5 ml x kg(-1) (5.7% increase) in the troglitazone 200 mg
      group and 3.4 ml x kg(-1) (7.8% increase) in the troglitazone 600 mg group were
      observed compared with placebo. CONCLUSION: These data suggest that dilutional
      effects related to a modest increase in plasma volume may explain the
      haematological changes seen in other clinical trials with high doses of
      troglitazone, although this study has shown that the changes in plasma volume are
      not statistically significant.

PMID- 10335904
TI  - An open comparison of the diabetogenic effect of deflazacort and prednisone at a
      dosage ratio of 1.5 mg:1 mg.
AB  - OBJECTIVE: To compare the diabetogenic effects of deflazacort (D) versus
      prednisone (PN) using a dosage ratio of 1.5 mg deflazacort:1 mg prednisone.
      METHODS: Thirty-three patients suffering from various active connective tissue or
      chronic inflammatory diseases were randomized to be treated with D or PN,
      assuming a therapeutic equipotency ratio of 1.5 mg D:1 mg PN. Neither dosage nor
      glucocorticoid employed were modified during the study. Patients had not received
      steroid treatment during the month prior to their inclusion date. Fasting
      glucose, glycosylated haemoglobin and fructosamine were determined before and
      after 1 month of treatment. Non-diabetic patients were also submitted to an oral
      glucose tolerance test (OGTT) at entry and after 1 month. Results were compared
      by univariate, and multivariate tests to correct the effects of age, body mass
      index and diagnosis. RESULTS: After 1 month of treatment there were no
      differences between D and PN in fasting glucose, glycosylated haemoglobin, or
      fructosamine. OGTT performed after treatment showed similar glucose values for
      both treatment groups. Patients treated with D had insulin levels at min 60 of
      the post-treatment OGTT which were higher than those treated with PN [114.1
      (62.8) mcUI x ml(-1) versus 73.5 (32.7) mcUI x ml(-1), P = 0.049], but the
      difference lost its statistical significance in the multivariate analysis.
      CONCLUSION: D and PN have similar effects on glucose tolerance when an
      equipotency ratio of 1.5 mg D:1 mg PN is employed. Previous studies employing a
      ratio of 1.2:1 mg may have underestimated the adverse effects of D on glucose
      metabolism.

PMID- 10335905
TI  - Influence of beta-blockers on melatonin release.
AB  - OBJECTIVE: Melatonin is a mediator in the establishment of the circadian rhythm
      of biological processes. It is produced in the pineal gland mainly during the
      night by stimulation of adrenergic beta1- and alpha1-receptors. Sleep
      disturbances are common side-effects of beta-blockers. The influence of specific
      beta-blockade as well as that of combined alpha-and beta-blockade on melatonin
      production has not been investigated in humans before. METHODS: We performed a
      randomized, double-blind, placebo-controlled, cross-over study in 15 healthy
      volunteers. Subjects received single oral doses of 40 mg (R)-propranolol, 40 mg
      (S)-propranolol, 50 mg (R)-atenolol, 50 mg (S)-atenolol, 25 mg (R,S)-carvedilol,
      120 mg (R,S)-verapamil or placebo at 1800 hours. Urine was collected between 2200
      hours and 0600 hours, and 6-sulfatoxy-melatonin (aMT6s), the main metabolite of
      melatonin which is almost completely eliminated in urine, was determined by
      radioimmunoassay (RIA). RESULTS: Mean nocturnal excretion of aMT6s in urine after
      intake of the drugs was as follows (in microg): placebo 26; (R)-propranolol 24 (
      7%, NS); (S)-propranolol 5 (-80%, P < 0.001); (R)-atenolol 27 (+7%, NS); (S)
      atenolol 4 (-86%, P < 0.01); (R,S)-carvedilol 23 (-10%, NS); (R,S)-verapamil 29
      (+14%, NS). These data show that only the specifically beta-blocking (S)
      enantiomers of propranolol and atenolol decrease the nocturnal production of
      melatonin whereas the non-beta-blocking (R)-enantiomers have no effect.
      Unexpectedly, (R,S)-carvedilol which inhibits both alpha- and beta-adrenoceptors
      does not decrease melatonin production. CONCLUSION: These findings indicate that
      beta-blockers decrease melatonin release via specific inhibition of adrenergic
      beta1-receptors. Since lower nocturnal melatonin levels might be the reason for
      sleep disturbances, further clinical studies should investigate whether or not
      oral administration of melatonin might avoid this well-known side-effect of beta
      blockers. The reason why (R,S)-carvedilol does not influence melatonin production
      remains to be determined.

PMID- 10335906
TI  - Loop diuretics enhance the secretion of prostacyclin in vitro, in healthy
      persons, and in patients with chronic heart failure.
AB  - BACKGROUND: Previous studies suggest that the acute haemodynamic effects of loop
      diuretics are due to a direct dilation of blood vessels and are not related to
      diuretic properties, but possibly to prostaglandin secretion. OBJECTIVES: We
      investigated whether in vitro human endothelial and renal epithelial cells
      responded to torasemide or furosemide with enhanced secretion of the vasodilator
      prostaglandin prostacyclin (PGI2). We also investigated the effects of loop
      diuretics on plasma concentrations of PGI2 and its physiological antagonist
      thromboxane after 25 min of administration of drugs in 44 patients with
      congestive heart failure (CHF) and 44 healthy volunteers. METHODS: The PGI2
      levels were measured after extraction in ethyl acetate by RIA as levels of 6
      KetoPGF1alpha, a stable metabolite from a non-enzymatic degradation. TxB2
      concentration, the stable hydrolysis product of TxA2, was also measured by RIA.
      RESULTS: In human endothelial and renal epithelial cells, both loop diuretics
      induced an increase of 6-KetoPGF1alpha secretion that reached a peak after about
      5 min and remained stable for 30 min of exposure to the drugs. The magnitude of
      the phenomenon was lesser in epithelial than in endothelial cells. Moreover, in
      both cell lines, there was a significantly higher secretion of 6-KetoPGF1alpha to
      torasemide than furosemide (P < 0.05). Concentrations of 6-KetoPGF1alpha at
      baseline were similar between the groups of CHF patients receiving the two
      different drugs. After 25 min of both drugs, 6-Keto-PGF1alpha significantly
      increased (P < 0.01), and this was significantly higher in patients treated with
      10 mg of torasemide (P < 0.05 vs furosemide). Levels of PGI2 at baseline were
      lower in healthy controls than those reached by CHF patients and similar between
      groups. After 25 min of both drugs, PGI2 plasma levels were significantly
      increased (P < 0.01). Baseline values of TxB2 were significantly higher in CHF
      patients compared with controls (P < 0.01 vs respective groups). and, more
      importantly, furosemide but not torasemide increased TxB2 levels in patients and
      controls (P < 0.05 vs baseline). CONCLUSIONS: Our study is the first
      demonstration in human tissue of increased secretion of PGI2 both in vitro and in
      vivo, after torasemide or furosemide administration. This phenomenon, which may
      explain in part the vasodilatory effects of these drugs, was more evident with
      torasemide and was reached at lower concentrations of the drug. Accordingly, we
      also found that furosemide but not torasemide stimulated the release of the PGI2
      physiological antagonist thromboxane in CHF patients and healthy controls.

PMID- 10335907
TI  - Lack of influence of menstrual cycle and premenstrual syndrome diagnosis on
      pregnanolone pharmacokinetics.
AB  - OBJECTIVE: Pregnanolone is a 3alpha-hydroxylated-5beta-reduced metabolite of the
      female sex steroid hormone progesterone. The compound is currently being
      evaluated for anaesthetic purposes. Previous studies have indicated a
      differential physiological response across the menstrual cycle and a different
      response in patients with premenstrual syndrome (PMS). This study was undertaken
      to determine whether hormonal changes during the menstrual cycle influence
      pregnanolone pharmacokinetics and to compare PMS diagnosis-related differences in
      pregnanolone pharmacokinetics. METHODS: Seven patients with premenstrual syndrome
      and seven female controls were given three increasing doses of pregnanolone in
      the follicular and luteal phase of the menstrual cycle. RESULTS: Mean
      pregnanolone elimination half-life varied between 28.4 min and 31.8 min and
      clearance between 59.6 ml x min(-1) x kg(-1) and 64.0 ml x min(-1) x kg(-1),
      depending on diagnostic group and cycle phase. No significant differences in
      pregnanolone pharmacokinetic properties were found between PMS patients and
      controls in either phase of the menstrual cycle. Furthermore, no differences in
      pharmacokinetic variables were detected between cycle phases. CONCLUSION:
      Pregnanolone pharmacokinetics do not differ between follicular and luteal phase
      of the menstrual cycle, nor between PMS patients and control subjects.

PMID- 10335909
TI  - Drug use in first pregnancy and lactation: a population-based survey among Danish
      women. The EUROMAP group.
AB  - OBJECTIVE: To examine the drug prescription pattern in Danish women from 12 weeks
      prior to conception until 12 weeks post-partum. METHOD: A drug utilization study
      based on The North Jutland Prescription Database. The Danish pharmacies use a
      computerized accounting system for all subsidized drugs and this was linked to
      the Danish Medical Birth Registry concerning prescription patterns for all women
      who had given birth in the county of North Jutland from 1991 to 1996. RESULTS:
      The analysis included 16,001 primiparous women, who had redeemed 34,834
      prescriptions prior to, during and after pregnancy. During pregnancy 44.2% of the
      women received prescriptions for at least one drug. Users received 2.6
      prescriptions on average during pregnancy: 5% of the users redeemed 24.2% of all
      prescriptions. The proportion of women who redeemed prescriptions for more than
      three different drugs was 2.7%. The majority of prescriptions were for
      antibiotics (28.7%), gynaecological drugs (13.3%) and anti-asthma drugs (7.6%).
      The post-partum prescription proportion was 34.0% and the majority of the
      prescriptions during this period were for penicillins (20.1%), ophthalmologicals
      (15.5%) and corticosteroids for dermatological use (5.7%). CONCLUSION: A high
      proportion of the women received drugs during pregnancy. The pattern of drug use
      within the Anatomical Therapeutical Chemical (ATC) groups changed, i.e. the
      amount of broad spectrum antibiotics decreased and the proportion of
      prescriptions for local use increased. A small proportion of women redeemed
      prescriptions for more than three different drugs during pregnancy.

PMID- 10335908
TI  - Pharmacokinetics and tolerability of formoterol in healthy volunteers after a
      single high dose of Foradil dry powder inhalation via Aerolizer.
AB  - OBJECTIVE: The pharmacokinetics of the long-acting beta2-agonist formoterol
      fumarate, which is a racemate of the (S,S)- and (R,R)-enantiomers were evaluated
      in 12 healthy (eight male, four female) volunteers after a single inhaled high
      dose of 120 microg of formoterol fumarate. The tolerability and safety were also
      assessed. METHODS: Each volunteer inhaled the single 120-microg dose through the
      Aerolizer device within 2-5 min, using ten 12-microg dry powder capsules for
      inhalation. Formoterol, i.e., the sum of both enantiomers, was determined in
      plasma over 24 h, whereas the separate enantiomers were determined in urine over
      48 h. Incidence, seriousness and severity of adverse experiences,
      electrocardiogram (ECG), including the corrected QT interval (QTc) calculation,
      systolic blood pressure, heart rate, and plasma potassium levels were recorded.
      RESULTS: In nine of the 12 volunteers, the peak plasma concentration of
      formoterol was observed already at 5 min after inhalation. The absorption
      kinetics were complex, as depicted by multiple peaks or shoulders within 0.5-6 h
      after inhalation. Mean with (SD; n = 12) of maximum concentration (Cmax) and area
      under the curve (AUC) of formoterol in plasma were 266 (108) pmol x l(-1) and
      1330 (398) pmol x l(-1), respectively. The moderate inter-individual variability
      in systemic exposure of formoterol reflects the homogeneous pharmacokinetics of
      the drug. A predominant slow elimination of formoterol from plasma with a mean
      half-life (t1/2) of 10 h was demonstrated. Assuming linear kinetics in plasma
      suggested by urinary data, the steady-state trough plasma levels of formoterol
      for a b.i.d. dosing regimen are predicted to amount to 20% of Cmax. In urine,
      mean with (SD; n = 10) of the amount excreted over 48 h was 3.61 (0.89)% of dose
      for the pharmacologically active (R,R)-enantiomer and 4.80 (1.33)% of dose for
      the (S,S)-enantiomer. The terminal half-lives calculated from the excretion rate
      time curves, i.e., 13.9 h and 12.3 h for the (R,R)- and (S,S)-enantiomer,
      respectively, confirm the slow elimination of formoterol from plasma. The dose
      inhaled was 10 times the most frequently recommended dose (12 microg) and 5 times
      the highest recommended dose (24 microg). Ten of 12 subjects experienced mild and
      transient nervousness. Pulse readings demonstrated the maximum mean increase of
      25.8 beats x min(-1) at 6 h. The mean maximum QTc increase was 25 msec at 6 h.
      Pulse and QTc values returned to baseline or close to baseline values at 24 h or
      before. Potassium levels in plasma decreased in eight out of 12 subjects; the
      lowest mean value was 3.53 mmol x l(-1) at 2 h post-dose. The lowest individual
      potassium measurement was 2.95 mmol x l(-1) between 15 min and 6 h. By 8 h post
      dose all values had returned to within the normal ranges. CONCLUSIONS: The
      extremely fast appearance of formoterol in plasma shows the predominance of
      airways absorption shortly after inhalation. Due to a terminal elimination half
      life of about 10 h, sustained systemic concentrations of formoterol are predicted
      for a twice daily treatment regimen without noteworthy accumulation. The excreted
      amounts in percent of dose of the enantiomers in urine and the enantiomer ratio
      are similar to data reported previously after lower doses and suggest linear
      kinetics for doses between 12 microg and 120 microg of formoterol fumarate. The
      expected side effects on heart rate, QTc interval, and plasma potassium were
      small and had no clinical consequences in spite of the very high dose of 120
      microg (5 to 10 times the recommended therapeutic dose of Foradil). It should be
      noted that the impact of high doses may be greater in patients. Nevertheless
      these findings provide reassurance on the safety margin of formoterol after
      accidental and intentional overdosing.

PMID- 10335910
TI  - Compliance and medication knowledge among elderly Japanese home-care recipients.
AB  - OBJECTIVES: To investigate the risk factors for noncompliance in elderly home
      care recipients; and to evaluate to what extent regular home visits and drug
      counseling by a pharmacist contribute to compliance. SUBJECTS: One hundred and
      sixty-three elderly home-care recipients aged 62 years and over took part in this
      study. All subjects were cognitively normal, and taking a regimen of one or more
      prescribed drugs. Medication use was observed by pharmacist-conducted interviews
      during home visits. Compliance was estimated by comparing prescribed regimens
      with medications actually being taken at home. RESULTS: The mean age with (SD) of
      the subjects was 78.7 (8.3) years. Eighteen per cent were regularly counseled by
      a pharmacist about medication. Poor compliance with prescribed medications was
      associated with subjects aged 80 years and over, who were administering their own
      medication, consuming less than three meals a day, did not have one dose
      packages, and who were not receiving pharmacist counseling. In multiple logistic
      regression analyses, frequency of meals (OR 5.99; 95% CI 1.25-28.79), pharmacist
      counseling (OR 5.32; 95% CI 2.00-14.20), and age (OR 0.96; 95% CI 0.92-1.00) were
      independent predictors of good compliance for home-care recipients with physical
      disabilities. Compliance correlated inversely with knowledge of drug names, and
      drug purposes in the uncounseled group. Compliance, however, positively
      correlated with knowledge of drug purposes in the counseled group. CONCLUSION: In
      this study, compliance among elderly Japanese home-care recipients was found to
      be associated with receiving pharmacist counseling, frequency of meals, and age.

PMID- 10335911
TI  - Nimesulide and renal impairment.
AB  - OBJECTIVES: To analyse from spontaneous reporting data the renal adverse
      reactions associated with the use of nimesulide. METHODS: Case reports were
      obtained from a Northern Italian Regional database (Veneto Pharmacovigilance
      System), containing all the spontaneous reports filed between 1988 and 1997. The
      Veneto Region is the principal contributor to the Italian spontaneous reporting
      system, with an annual report rate of approximately 17 per 100,000 inhabitants.
      The clinical records of hospitalized patients were also analysed. RESULTS: Of the
      120 reports associated with oral nimesulide, 11 referred to suspected renal
      adverse reactions. The drug was taken by ten patients for a short period. All the
      patients discontinued the therapy and hospitalization was required in six cases.
      Other risk factors were identified in six cases. DISCUSSION: Together with the
      new insights into the possible consequences of renal cyclooxygenase-2 (COX-2)
      inhibition, the reported cases should draw the attention of doctors and patients
      to the importance of recognizing any possible signs of renal impairment during
      nimesulide therapy, although only extensive epidemiological data can define the
      real impact of its renal toxicity.

PMID- 10335912
TI  - Adverse drug events in hospitalized patients. A comparison of doctors, nurses and
      patients as sources of reports.
AB  - OBJECTIVE: This study investigated the relative value of adverse drug events
      reported by doctors, nurses and patients. METHODS: The study was conducted on a
      total of four wards: the paediatric and internal medicine wards (including
      geriatric patients) of two peripheral hospitals in The Netherlands. Adverse drug
      events were collected by spontaneous reporting (doctor and nurse reports) and by
      daily ward visits, during which the patients were interviewed by a hospital
      pharmacist (patient reports). Criteria for relative value of the reported adverse
      drug events were the number of potentially serious reactions, the number of
      reactions not mentioned in the patient information leaflet and the number of
      reactions reported to new drugs (5 years or less on the Dutch market). No formal
      causality assessment was applied. RESULTS: Over a period of 2 months in 1996
      (Hospital I) and 2 months in 1997 (Hospital II) a total of 620 patients were
      included in the study and adverse drug events were reported in 179 (29%) of these
      cases. Doctors reported a statistically significant larger number of serious (26%
      of all doctor reports; odds ratio (OR) 3.2; confidence interval (CI) 1.2-8.7) and
      unknown (39%; OR 2.5; CI 1.0-6.0) adverse drug events than patients themselves
      during the daily ward visit. Doctors also reported more serious and unknown
      adverse drug events than nurses. Adverse reactions to new drugs were reported
      during the daily ward visit only (8% of all daily ward visit reports).
      CONCLUSION: This study reconfirms that doctors are the main source for reports of
      serious and unknown adverse drug events in hospitalized patients. However,
      patients themselves seem to report more adverse reactions to new drugs (during
      the daily ward visit). By focusing on patients using new drugs, the daily ward
      visit might become cost-effective. This needs to be explored in future studies.

PMID- 10335913
TI  - Nicorandil and diabetes: a nested case-control study to examine a signal
      generated by prescription-event monitoring.
AB  - OBJECTIVE: To investigate a signal generated by an observational cohort study
      that treatment with the potassium channel opener drug, nicorandil, is associated
      with an increased incidence of diabetes mellitus (DM). METHODS: Nested case
      control study within cohorts used for prescription-event monitoring. RESULTS: The
      cohort study of nicorandil showed that there was a significant difference between
      the event rate for DM in the first month after starting nicorandil, compared to
      months 2-6 (difference in rates 1.93, 99% CI 0.7-3.1, per 1000 patient months of
      treatment). However, the adjusted odds ratio from the case-control study was 1.42
      (95% CI 0.66-3.07) for incidence of newly diagnosed DM in nicorandil versus four
      comparator drugs. CONCLUSIONS: The nested case-control study was used as a
      hypothesis-testing instrument for following up a signal of a possible drug
      reaction to nicorandil. It showed no evidence that nicorandil is associated with
      increased incidence of newly diagnosed DM.

PMID- 10335914
TI  - BP180/type XVII collagen: its role in acquired and inherited disorders or the
      dermal-epidermal junction.
AB  - BP180 is a member of the collagen protein family and is also referred to as type
      XVII collagen or BP antigen 2. It is a transmembrane protein constituent of the
      dermal-epidermal anchoring complex. The long-held hypothesis that BP180 functions
      as a cell-matrix adhesion molecule has been supported by recent investigations of
      human disorders of the dermal-epidermal junction in which BP180 is either
      genetically defective or targeted by the immune system. In generalized atrophic
      benign epidermolysis bullosa, mutations of BP180 result in an inherited
      subepidermal blistering disease. In bullous pemphigoid, herpes/pemphigoid
      gestationis, cicatricial pemphigoid, lichen planus pemphigoides and linear IgA
      disease, autoantibodies are directed to different epitopes on the BP180
      ectodomain. Recent molecular investigations have provided new insights, not only
      into the mechanism of autoantibody-mediated subepidermal blistering, but also
      into the biochemical structure and cell biological functions of BP180 and other
      components of the dermal-epidermal anchoring complex. These findings have
      suggested new directions for the development of diagnostic and therapeutic tools
      for these autoimmune and genetic diseases.

PMID- 10335915
TI  - Stratum corneum chymotryptic enzyme in psoriasis.
AB  - Stratum corneum chymotryptic enzyme (SCCE) is a serine protease which may
      function in the turnover of the stratum corneum by means of degradation of
      intercellular adhesive structures between corneocytes. It is also potentially an
      epidermal activating enzyme for cytokines such as interleukin-1beta. The aim of
      this work was to study the expression of SCCE in psoriatic epidermis by means of
      immunohistochemistry, and to elucidate the nature of the SCCE present in
      psoriatic scales by means of biochemical analyses. In comparison to normal skin
      the number of cell layers expressing SCCE in psoriatic lesions was consistently
      increased. In nonlesional psoriatic skin the pattern of SCCE expression varied.
      It was similar to the pattern in normal skin in some biopsies, whereas in other
      biopsies evidence of an increased expression of SCCE was found. By means of
      zymography and immunoblotting, extracts of psoriatic scales were found to contain
      active SCCE as well as enzymatically inactive SCCE precursor. Also the effects of
      inhibitors on the activity towards a chromogenic protease substrate in the
      extracts after partial purification by gel exclusion chromatography were
      compatible with the presence of enzymatically active SCCE. We conclude that the
      expression of SCCE in psoriasis may be upregulated, and that the conversion of
      inactive SCCE-precursor to active SCCE occurs in the psoriatic lesion. The
      possible role of SCCE in the pathophysiology of psoriasis remains to be
      elucidated, but should be considered in future studies.

PMID- 10335917
TI  - Reduced expression of CDKN2a/P16INK4a in mycosis fungoides.
AB  - Alterations in the CDKN2a gene have been demonstrated in a wide range of human
      tumors including hematopoietic malignancies. To verify whether altered CDKN2a
      expression is involved in the pathogenesis of mycosis fungoides (MF), we examined
      mRNA expression in 20 patients with MF by RT-PCR and dot blot hybridization.
      CDKN2a mRNA expression was undetectable in 5 of the 20 patients (25%),
      intermediate in 13 (65%) and high in 2 (10%). Immunohistochemical studies, which
      were performed in ten patients, revealed that in the four patients showing no
      mRNA, p16INK4a was expressed in <1% of neoplastic lymphocytes whereas in the four
      patients with an intermediate mRNA level, specific nuclear staining was present
      in 1-25% of tumor cells. In the two patients with high levels of CDKN2a mRNA,
      >25% of neoplastic lymphocytes stained positively. No direct correlation between
      clinicopathological and molecular findings was evident in our patients. DNA
      mutational analysis revealed no alterations in a total of six patients examined.
      Our results indicate that the lack of CDKN2a expression, as found in 25% of the
      patients, may have a pathogenetic role in MF even though the absence of CDKN2a
      mRNA was not associated with point mutations or minor gene deletions.

PMID- 10335916
TI  - Vasoactive intestinal polypeptide in allergic contact dermatitis: an
      immunohistochemical and radioimmunoassay study.
AB  - Vasoactive intestinal polypeptide (VIP) is a neuropeptide with immunomodulatory
      properties. To elucidate the possible role of VIP in the pathophysiology of
      cutaneous contact hypersensitivity, we compared involved with uninvolved skin of
      allergic contact dermatitis (ACD) from nickel-allergic patients. Assays included
      quantification of VIP-immunoreactive (VIP-IR) nerve fibres and cells bearing
      immunoreactivity for VIP1 and VIP2 receptors in skin biopsy specimens, and of the
      concentration of VIP-like immunoreactivity (VIP-LI) in extracts of biopsy
      specimens. VIP-IR nerve fibres were found in the deeper part of the dermis close
      to sweat glands and hair follicles. No difference in the presence of VIP-IR nerve
      fibres was found between involved and uninvolved skin of ACD. VIP1 and VIP2
      receptor immunoreactivity was seen on keratinocytes in the basal layer of the
      epidermis, with no difference between involved and uninvolved skin. Staining was
      also seen on vessel walls and mononuclear cells in the dermis. The highest
      staining intensity in the mononuclear cells was noted with the antibodies against
      the VIP2 receptor. While most of the mononuclear cells were stained in uninvolved
      skin, a minority of the cells showed a positive signal in involved skin. The
      concentration of VIP-LI in uninvolved skin was 1.53+/-0.790 pmol/g and in
      involved skin 1.41+/-0.735 pmol/g. It is concluded that there is no significant
      difference in either the distribution of VIP-IR fibres or the concentration of
      VIP-LI between involved and uninvolved skin of ACD. However, the number of dermal
      mononuclear cells showing VIP2 receptor immunoreactivity in skin of ACD was
      reduced.

PMID- 10335919
TI  - Quantitative digital image analysis applied to demonstrate the stratified
      distribution of involucrin in organ cultured human skin.
AB  - In this study, quantitative digital image analysis was utilized to measure the
      optical density of immunostains of involucrin at different depths in the
      epidermis to obtain reliable ordinal-scaled interpretations of the staining
      intensity. The distribution of involucrin within the epidermis was investigated
      in air-liquid interface and submerged skin organ cultures at different time
      points. A greyscale calibration procedure to standardize the optical units was
      used. By the 2nd day of culture, staining of involucrin had shifted markedly
      towards the mid or basal epidermis. Air-liquid interface cultures showed a less
      intensive shift than the submerged cultures. Up to the 7th day, involucrin
      staining remained in the upper epidermis in the air-liquid interface cultures,
      though weak staining was already observed in the basal epidermis. The results
      suggest that air-liquid interface conditions maintained physiological conditions
      better than submerged conditions which result in cultures that may have to
      increase their involucrin synthesis to improve the barrier function against the
      surrounding liquid during culture. Alternatively, changes in involucrin synthesis
      could reflect disturbed homeostasis. Concentrating measurements on certain cell
      layers might give more detailed information about changes in involucrin
      expression. Although the detection method was used to study the histochemistry of
      skin, it could easily be applied to other tissues as well.

PMID- 10335918
TI  - UV irradiation induces downregulation of bcl-2 expression in vitro and in vivo.
AB  - Recently, the proto-oncogenes bcl-2 and bax have emerged as important regulators
      of the apoptotic form of cell death. We examined UV irradiation-elicited
      apoptosis and regulation of bcl-2 and bax expression both in vivo in human skin
      and in vitro in HeLa cells. Using flow cytometric analysis, HeLa cells were found
      to undergo apoptosis at the 12-h time-point after exposure to UVB irradiation
      (100 mJ/cm2). The expression of bcl-2 mRNA was found to decrease after a single
      dose of UVB radiation (doses 10-200 mJ/cm2). In contrast, the expression of bax
      mRNA was not significantly changed. When human skin was irradiated with a single
      dose of solar-simulated radiation (40 mJ/cm2), Bcl-2-positive cells were
      significantly reduced in the epidermis at the 3- and 6-h time-points. Our results
      suggest that UV irradiation downregulates bcl-2 expression both in vitro at the
      mRNA level and in vivo at the protein level, and that downregulation of bcl-2
      constitutes a mechanism of potential importance in UV-induced apoptosis in human
      epidermis.

PMID- 10335920
TI  - Glucocorticoids inhibit proliferation and adhesion of the IL-3-dependent mast
      cell line, MC/9, to NIH/3T3 fibroblasts, with an accompanying decrease in IL-3
      receptor expression.
AB  - We investigated the effects of glucocorticoids on IL-3-dependent proliferation
      and c-kit expression of cells of the mouse mast cell line, MC/9. Glucocorticoids
      (dexamethasone, prednisolone, and hydrocortisone) inhibited IL-3-dependent MC/9
      cell proliferation, whereas sex steroids (progesterone, beta-estradiol, and
      testosterone) had no effect. Flow cytometric analysis revealed that
      glucocorticoids reduced the expression of the IL-3 receptor on MC/9 cells.
      Immunoblot and Northern blot analyses indicated that glucocorticoids also reduced
      the expression of both c-kit protein and c-kit mRNA transcript. Furthermore, the
      adhesion of MC/9 cells to stem cell factor-expressing NIH/3T3 cells was reduced
      following glucocorticoid treatment. Our results indicate that glucocorticoids
      inhibit IL-3-dependent MC/9 mast cell proliferation, with an accompanying
      decrease in IL-3 receptor expression. Glucocorticoids also reduced c-kit
      expression on MC/9 cells resulting in a decreased adhesion to NIH/3T3
      fibroblasts.

PMID- 10335921
TI  - Interaction of liposomes composed of phospholipids, GM1 ganglioside and
      cholesterol with human keratinocytes in culture.
AB  - We studied the possibility of supplementing human keratinocytes with exogenous
      lipids (phospholipids, sphingolipids and cholesterol) and evaluated their
      influence on cell proliferation, using cells cultured in vitro. Experiments
      carried out with liposomes composed of cholesterol/GM1 ganglioside and different
      phospholipids (5:1.5:10, M/M/M), showed that liposomes associated with cells more
      efficiently when they contained soya lecithin. The treatment with liposomes made
      of the ternary mixture did not modify the rate of cell proliferation, as assessed
      by the incorporation of [3H]-thymidine. In contrast, the proliferation rate
      strongly decreased (65% with respect to the control) using the same liposomes
      without GM1. Experiments carried out with GM1 alone showed a strong stimulation
      of the proliferation rate (144% with respect to the control). Fluorescence
      dequenching experiments, carried out with the probe octadecyl rhodamine B
      chloride, showed that fusion was the main mechanism of liposome-cell interaction.
      Metabolic studies established that exogenously administered GM1--either embedded
      in liposomes or as a pure glycolipid dispersion--led to the production of several
      products, including ceramide. Altogether, these results show that different,
      opposing effects can be exerted on cell proliferation by the administration of
      lipids, separately or in mixtures, to human keratinocytes, and indicate the
      importance of a correct formulation for supplementing human keratinocytes with
      exogenous lipids.

PMID- 10335922
TI  - Immunohistochemical localization of the neutral cysteine protease bleomycin
      hydrolase in human skin.

PMID- 10335923
TI  - Mouse Langerhans cells do not express the high-affinity receptor for IgE.

PMID- 10335924
TI  - Increased incidences of micronuclei in human lymphocytes in cultures exposed to
      cetirizine.

PMID- 10335925
TI  - Psychosocial research in supportive care: focusing the health care system.

PMID- 10335926
TI  - Unsuccessful pain relief: the relatives' perspective.

PMID- 10335927
TI  - Palliative care services in Belgium: benefits and shortcomings of a legal
      framework.
AB  - All health services dealing with the terminally ill are called upon to dispense
      palliative care. We shall, however, be making a distinction between palliative
      care services and other forms of services: in fact, the main activity of a
      palliative care service is palliative medicine, which is dispensed by its trained
      and experienced personnel. In Belgium, the first specialist palliative care
      services developed autonomously, and the absence of a planning policy isolated
      them from the rest of the health system. The Belgian health authorities decided
      to put an end to this situation by legislation: the laws introduced determine the
      number, mission and modus operandi of the various palliative care services, as
      well as the links to be established between them (interaction of the home care
      support team and the mobile function in hospitals or institutions for the elderly
      and association for cooperation). The following is a presentation and critical
      analysis of this legislation.

PMID- 10335928
TI  - Breaking bad news to patients: physicians' perceptions of the process.
AB  - The goal of this investigation was to gain a better understanding of the
      processes associated with communicating bad news to patients. A convenience
      sample of 38 physicians recalled a time when they delivered bad news and then
      answered a series of questions about what transpired. Data were also obtained
      about how well they thought the transaction had proceeded, how much stress they
      had experienced, and what they thought the experience was like from the patient's
      perspective. The majority of physicians reported following most of the published
      recommendations for delivering bad news. However, the number of recommendations
      followed was not correlated with self-reported stress and effectiveness in news
      delivery or with physicians' estimates of patients' distress. The number of
      recommendations followed could not be accounted for by the closeness of the
      relationship between physician and patient or by the gender composition of the
      bad news encounter. Overall, physicians reported that the transaction was
      moderately stressful for themselves, that the stress lasted beyond the recalled
      transaction, and that they were effective in delivering the news in a way that
      reduced patient distress. These findings suggest that the sampled physicians are
      generally following a substantial number of published recommendations when
      delivering very stressful news to patients. The primary weaknesses in the
      delivery process occur while preparing for the encounter. The fact that many of
      the physicians reported that their stress lasted beyond the transaction itself
      suggests that training in the delivery of bad news should include guidance on
      cognitive and behavioral coping strategies to help physicians deal with their own
      discomfort.

PMID- 10335929
TI  - Detecting psychological distress in cancer patients: validity of the Italian
      version of the Hospital Anxiety and Depression Scale.
AB  - The psychometric properties of the Italian version of the Hospital Anxiety and
      Depression Scale and its utility as a screening instrument for anxiety and
      depression in a non-psychiatric setting were evaluated. The questionnaire was
      administered twice to 197 breast cancer patients randomised in a phase III
      adjuvant clinical trial: before the start of chemotherapy and at the first follow
      up visit. The presence of psychiatric disorders was evaluated at the follow-up
      visit using the Structured Clinical Interview for DSM-III-R in 132 patients.
      Factor analyses identified two strictly correlated factors. Crohnbach's alpha for
      the anxiety and depression scales ranged between 0.80 and 0.85. At follow-up, 50
      patients (38%) were assigned a current DSM-III-R diagnosis, in most cases
      adjustment disorders (24%) or major depressive disorder (10%). Receiver operating
      characteristics (ROC) analysis was used to test the discriminant validity for
      both anxiety and depressive disorders. The comparison of the areas under the
      curve (AUC) between the two scales did not show any difference in identifying
      either anxiety (P = 0.855) or depressive disorders (P = 0.357). The 14-item total
      scale showed a high internal consistency (alpha = 0.89 and 0.88) and a high
      discriminating power for all the psychiatric disorders (AUC = 0.89; 95% CI = 0.83
      0.94). The cut-off point that maximised sensitivity (84%) and specificity (79%)
      was 10. These results suggest that the total score is a valid measure of
      emotional distress, so that the Italian version of HADS can be used as a
      screening questionnaire for psychiatric disorders. The use of the two subscales
      as a 'case identifier' or as an outcome measure should be considered with
      caution.

PMID- 10335930
TI  - The Palliative Prognostic Index: a scoring system for survival prediction of
      terminally ill cancer patients.
AB  - Although accurate prediction of survival is essential for palliative care, few
      clinical methods of determining how long a patient is likely to live have been
      established. To develop a validated scoring system for survival prediction, a
      retrospective cohort study was performed with a training-testing procedure on two
      independent series of terminally ill cancer patients. Performance status (PS) and
      clinical symptoms were assessed prospectively. In the training set (355
      assessments on 150 patients) the Palliative Prognostic Index (PPI) was defined by
      PS, oral intake, edema, dyspnea at rest, and delirium. In the testing sample (233
      assessments on 95 patients) the predictive values of this scoring system were
      examined. In the testing set, patients were classified into three groups: group A
      (PPI< or =2.0), group B (2.0<PPI< or =4.0), and group C (PPI>4.0). Group B
      survived significantly longer than group C, and group A survived significantly
      longer than either of the others. Also, when a PPI of more than 6 was adopted as
      a cut-off point, 3 weeks' survival was predicted with a sensitivity of 80% and a
      specificity of 85%. When a PPI of more than 4 was used as a cutoff point, 6
      weeks' survival was predicted with a sensitivity of 80% and a specificity of 77%.
      In conclusion, whether patients live longer than 3 or 6 weeks can be acceptably
      predicted by PPI.

PMID- 10335931
TI  - Domiciliary treatment of febrile episodes in cancer patients: a prospective
      randomized trial comparing oral versus parenteral empirical antibiotic treatment.
AB  - Hospitalization and empirical broad-spectrum, intravenous antibiotics are the
      standard treatment for febrile cancer patients. Recent evidence supports the
      suggestion that febrile episodes in a low-risk population can be managed
      successfully in an outpatient setting, but the optimal drug regimen is unknown.
      In a prospective randomized clinical trial we compared ciprofloxacin 750 mg p.o.
      twice a day with ceftriaxone 2 g i.v. as a single daily dose for the empiric
      domiciliary treatment of febrile episodes in low-risk neutropenic and
      nonneutropenic cancer patients. A total of 173 patients, accounting for 183
      febrile episodes, were enrolled in the study. Overall, successful outcomes were
      recorded for 76 of 93 (82%) febrile episodes in patients who were randomized to
      the oral regimen and for 68 of 90 (75%) febrile episodes in patients randomized
      to the i.v. regimen: this difference was not statistically significant. The
      success rate was similar in all subgroups of patients: neutropenic and
      nonneutropenic, with documented infection and with fever of unknown origin. There
      were 3 deaths in the group of patients treated with the parenteral regimen, and
      two of these were related to treatment failure. Both treatments were well
      tolerated, and the cost of the oral regimen was lower. This prospective study
      suggests that domiciliary antibiotic empiric monotherapy is feasible in febrile
      nonneutropenic or low-risk neutropenic outpatients in whom a bacterial infection
      is suspected, and that either an oral or a parenteral regimen can be used. A
      number of factors may influence the choice between an orally and an i.v.
      administered antibiotic, but owing to the easier administration and lower cost,
      the oral regimen seems to be preferable.

PMID- 10335932
TI  - Normative data and trends in quality of life from the Lung Cancer Symptom Scale
      (LCSS).
AB  - Normative data and trends for a disease- and site-specific quality of life (QL)
      instrument for individuals with lung cancer, the Lung Cancer Symptom Scale
      (LCSS), are presented to facilitate the user's interpretation of test scores.
      Data for patients enrolled in two large, identical, randomized trials of a new
      combination chemotherapy regimen for patients with stages III and IV non-small
      cell lung cancer (NSCLC) were combined into one dataset (n = 673). For these
      patients with a Karnofsky performance status (KPS) of 60-100%, QL had been
      prospectively measured at baseline, day 29 and every 6 weeks thereafter.
      Descriptive statistics for the LCSS are presented for three time points
      (baseline, day 29 and day 71) and for specific demographic and disease-related
      characteristics (age, gender, race, performance status and stage of disease) to
      provide expected values and their variability during chemotherapy. Data from a
      small dataset of 63 NSCLC inpatients with KPS scores of 20-50% are also presented
      for a comparison sample of supportive care for inpatients and hospice patients.
      For the 673 NSCLC patients at baseline there were no significant differences in
      QL by age, gender, or race. Major presenting lung cancer symptoms at baseline for
      this combined sample were dyspnea 87%, cough 86%, pain 81%, loss of appetite 75%,
      and hemoptysis 41%. Of these patients, 81% had three or more presenting symptoms
      at baseline (2% had no symptoms; 5%, one symptom; 12%, two symptoms; 18%, three
      symptoms; 27%, four symptoms; and 36%, five symptoms). The mean LCSS baseline
      score (best = 0; worst = 100) was 26.56 (SD 16.10). The mean scores for day 29
      and day 71 were 25.46 (SD 16.52) and 25.30 (SD 16.93), respectively, but follow
      up assessments on progressers were not obtained. Stage III patients had a mean
      LCSS score of 23.7 (SD 15.1), whereas stage IV patients reported a mean LCSS
      score of 27.3 (SD 16.3). The mean LCSS score for the group with KPS 60-70% was
      34.8 (SD 15.5), and that for the group with KPS 80-100% was 23.3 (SD 15.1). The
      mean LCSS score for the lower performance group, with KPS scores of 20-50% at
      baseline, was 46.85 (SD 17.65).

PMID- 10335933
TI  - Interaction of tamoxifen with concurrent cytotoxic adjuvant treatment affects
      lymphocytes and lymphocyte subsets counts in breast cancer patients.
AB  - The effects and interaction of endocrine and cytotoxic adjuvant treatment on
      measures of cellular immunity were assessed in 41 stage I-II breast cancer
      patients from International Breast Cancer Study Group trials. Counts of
      lymphocytes and lymphocyte subsets [(T, T4, T8, B, natural killer (NK) and
      activated T (AT) cells] were assessed by flow cytometry immediately before
      adjuvant therapy at baseline and on day 1 of the 3rd cycle. Twenty-two patients
      received cyclophosphamide, methotrexate and 5-fluorouracil (CMF), 7 CMF and
      tamoxifen (TAM), and 12 TAM alone. On day 1 of the 3rd cycle the counts of total
      lymphocytes (P = 0.003) and all lymphocyte subsets (P<0.05) except AT cells were
      significantly lower than baseline in the CMF treatment group. There was no
      significant change in the CMF+TAM or in the TAM treatment group. The combination
      of CMF and TAM resulted in less pronounced decrease in lymphocyte and subset
      counts from baseline to day 1 of the 3rd cycle. It seems possible that there is
      an interaction between TAM with CMF that affects lymphocyte and lymphocyte subset
      counts during cytotoxic treatment.

PMID- 10335934
TI  - Evaluation of a national breast cancer information service: the Iranian
      experience.
AB  - This descriptive study evaluates a newly established national breast cancer
      information service in Iran and reports data on the impact of contacting the
      service. Two instruments were used to collect data: a "call record form" and a
      "user survey" questionnaire. The call record was filled in after each inquiry,
      and during 1 year 1,000 forms were completed. The questionnaire was filled in 1
      week after each inquiry and was completed for a random sample of 400 callers.
      Thus, the results are presented in two parts. Analysis of the call record forms
      (part one) showed that 95% of the callers were female, mostly married (82%) and
      with secondary or higher education (80%). Most callers reported that they had
      heard about the service through the mass media (69%). Benign breast diseases,
      mastalgia and breast masses were the most common subjects of the inquiries (28%,
      27%, and 18%, respectively). The majority of callers (77%) said that the main
      reason for contacting the service was that they wanted more information about
      breast diseases. Examination of the questionnaires (part two) revealed that 97%
      of respondents described the service as "useful" or "very useful". The vast
      majority (80%) perceived the information given as "easy" or "very easy" to
      understand. When respondents were asked to compare their feelings before and
      after contacting the service, 86% said that they felt "much more" or "a little
      more cheerful" and 81% said that they felt "much less" or "a little less
      worried". Practically all (99%) were satisfied with the overall service provided.
      The findings indicate that the service is effective in providing information and
      support for patients, relatives and the general public. The real challenge is how
      to make the service more widely available, especially to breast cancer patients.

PMID- 10335936
TI  - Rifampicin as treatment for pruritus in malignant cholestasis: an example of an
      improper indication for anti-infective drugs.

PMID- 10335935
TI  - Skin necrosis in the presence of paclitaxel and fluorometholone.
AB  - Paclitaxel (Taxol) can induce full-thickness skin necrosis at sites distant from
      those of injection. This side effect may be potentiated in the presence of
      fluorometholone (FML).

PMID- 10335937
TI  - Diagnosis of gastric carcinoma: Japanese fairy tales or Western deficiency?

PMID- 10335938
TI  - Epithelial tumours of the adult kidney.
AB  - The epithelial tumours of the adult kidney, in particular renal cell carcinoma
      (RCC), are a variety of neoplasms that can be classified by morphology and
      genotype. Although most are well characterised, typical and less typical tumour
      variants are recognised. There is evidence to indicate that stage is one of the
      most important prognostic factors, irrespective of tumour subtype. However, the
      appropriate handling of nephrectomy specimens is essential for accurate
      evaluation of diagnostic and prognostic factors in RCC. The problem of how to
      achieve more objective nuclear grading is still unresolved. The use of diagnostic
      decision support systems offers the possibility of a flexible approach to this
      problem, while still utilising morphological criteria. The histopathological
      analysis remains important, but new techniques of molecular and cell biology will
      be providing new tools of extraordinary power to sharpen the diagnosis and give
      it a biological interpretation.

PMID- 10335939
TI  - High-grade carcinoma component in epithelial-myoepithelial carcinoma of salivary
      glands clinicopathological, immunohistochemical and flow-cytometric study of
      three cases.
AB  - Three cases of epithelial-myoepithelial carcinoma (EMC) with coexisting areas of
      high grade carcinoma are reported. In two of the cases there was a previous
      recurrence, and in all three patients there had been a sudden increase in size
      before final surgery. The typical ductal and myoepithelial components of EMC
      showed the usual biphasic pattern and the expected immunophenotypes, with
      expression of wide spectrum cytokeratins, Cam 5.2 and EMA in the ductal part, and
      muscle-specific actin, smooth muscle actin, S-100 protein, vimentin and
      cytokeratins in the myoepithelial component. These areas also had a low mitotic
      count and low proliferation rate as measured by immunohistochemistry and by flow
      cytometry. Conversely, areas of high-grade tumour had the features of a large
      cell carcinoma, with focal mucin secretion in two cases. This high-grade
      component showed an epithelial immunophenotype in two cases, and was negative for
      all tested markers in the third one. The mitotic counts and the proliferation
      rates were much higher in these anaplastic areas. One of the patients died 3
      months after treatment; another developed lymph node metastases 1 year later and
      was alive after 6 years of follow-up. The third patient was alive without
      evidence of disease 7 months after wide surgical resection of the tumour. The
      possibility of anaplastic transformation in EMC makes thorough sampling mandatory
      in this type of neoplasm.

PMID- 10335940
TI  - Proliferation not apoptosis as a prognostic indicator in retinoblastoma.
AB  - The balance between proliferation and cell death is the major determinant of
      tumour growth. We analysed the proliferative and apoptotic indices (PI and AI,
      respectively) of 33 children with retinoblastoma. PI and AI were assessed by
      immunohistochemistry for Ki-67 antigen and TUNEL staining, respectively. The mean
      PI was 21.0+/-21.1%, and higher PI was associated with more advanced tumour stage
      (P<0.0001) and poor clinical outcome (P<0.05). Patients in whom amplified N-myc
      oncogene was found (n=6) determined by the multiplex polymerase chain reaction
      tended to have a higher PI (37.6+/-27.2%) than those without amplified N-myc
      (n=27; PI=17.3+/-18.1). A PI value of over 40% was clearly associated with an
      unfavourable prognosis. The AI, however, did not correlate with any of the other
      variables analysed. The findings suggest that proliferation, but not apoptosis,
      is of critical significance in retinoblastoma biology. PI, as determined by the
      Ki-67 antigen labelling index, seems to be a relevant histopathological parameter
      that can predict the clinical outcome of retinoblastoma.

PMID- 10335941
TI  - Endometrial stromal sarcomas: immunohistochemical, electron microscopical and
      cytogenetic findings in two cases.
AB  - Uterine sarcomas are approximately 3% of all malignant uterine corpus tumours. Of
      these, the tumours that originate solely in the stromal elements of the uterine
      wall are infrequent and have not been well characterized cytogenetically. We
      report two cases of endometrial stromal sarcomas (ESS), one low grade and one
      high grade, diagnosed by conventional histology, immunocytochemistry, electron
      microscopy and cytogenetics. Morphologically clear-cut differential structures
      were seen at optical, immunohistochemical, and electron microscopic levels,
      permitting a clear differential diagnosis. The low-grade ESS expressed hormonal
      receptors and vimentin, whereas the high-grade ESS showed no hormone receptors,
      high Ki-67 activity, and occasional cytokeratin-positive cells.
      Ultrastructurally, no malignant epithelial differentiation was seen in the tumour
      cells, but cilia were found in both cases. Cytogenetic study of the low-grade ESS
      showed pseudodiploid karyotype with chromosomes 6 and 20 rearranged. The high
      grade ESS showed a complex karyotype with clonal numerical and structural
      anomalies. The chromosomes involved in the structural rearrangements were 1, 3,
      6, 7, 13, 14, 15, 17, 19, and 21.

PMID- 10335942
TI  - Lymphoepithelial duct lesions in Sjogren-type sialadenitis.
AB  - It is not clear, whether the so-called basal cells of the salivary striated ducts
      are an independent cell-type distinct from myoepithelial cells, making
      characterization of the cell proliferation typical of the duct lesions in Sjogren
      type sialadenitis/benign lymphoepithelial lesion (BLEL) difficult. An
      immunohistochemical investigation including different cytokeratin subtypes, alpha
      actin, Ki-67 and Bcl-2 was directed at the epithelial cytoskeleton in normal
      parotid parenchyma (n=8), BLEL (n=12), HIV-associated lymphoepithelial cysts
      (n=8) and palatine tonsils (n=8). There are profound morphological and functional
      differences between basal and myoepithelial cells in the normal salivary duct.
      Development of duct lesions in BLEL arises from basal cell hyperplasia of
      striated ducts with aberrant differentiation into a multi-layered and reticulated
      epithelium, characterized by profound alteration of the cytokeratin pattern. This
      functionally inferior, metaplastic epithelium is similar to the lymphoepithelial
      crypt epithelium of palatine tonsils. The often postulated participation of
      myoepithelial cells in duct lesions of Sjogren disease/BLEL cannot be supported.
      We regard the designations lymphoepithelial lesion and lymphoepithelial
      metaplasia as the most appropriate.

PMID- 10335944
TI  - The interaction of Bcl-2 and Bax regulates apoptosis in biliary epithelial cells
      of rats with obstructive jaundice.
AB  - A complex molecular network controls cell homeostasis by inducing apoptosis or
      proliferation. The balance of Bcl-2 and Bax, members of a protein family,
      determines whether a cell will become immortal (Bcl-2) or will undergo apoptosis
      (Bax). To determine the role of Bcl-2 and Bax during proliferation of biliary
      epithelial cells (BEC) after bile duct ligation (BDL) and their regression after
      biliary decompression we induced hyperplasia of BEC by BDL in male rats.
      Regression of hyperplastic BEC by way of apoptosis was induced by biliary
      decompression through a Roux-en-Y biliodigestive anastomosis. To quantify
      apoptosis a modified TUNEL assay was used. Expression of Bcl-2 and Bax was
      visualized by immunohistochemistry and quantified stereologically. BEC increased
      from <1% to >20% after BDL; this increase was associated with overexpression of
      Bcl-2 in up to 30% of hyperplastic BEC. After biliodigestive anastomosis,
      apoptotic BEC increased from <0.1% to a peak of 5.4% after 1 day to reach
      baseline again 1 week after decompression. This was associated with de novo
      appearance of Bax. The interaction between Bcl-2 and Bax triggers apoptosis in
      BEC and acts as a cell rheostat in BEC hyperplasia and its involution after
      biliary decompression.

PMID- 10335943
TI  - Expression of laminin-2 by normal and neoplastic rat C cells during the
      development of medullary thyroid carcinoma.
AB  - Medullary thyroid carcinoma (MTC) originates from C cells, which secrete
      calcitonin (CT), their specific marker. C cells are located in contact with the
      basement membrane (BM) of the thyroid follicles, which is partly made up of the
      laminin-2 isoform synthesized by thyrocytes. During oncogenesis, proliferation of
      the C cells, invading the centre of the follicles, leads to a break in their
      normal contact with the BM. As specific interactions of cells with BM components,
      especially laminins, are important for proliferation and differentiation, we
      investigated the relationships of normal and neoplastic C cells with laminin in
      the Wag/Rij rat model of human MTC. Immunocytochemical studies showed a
      progressive loss of the laminin layer underlying the hyperplastic C cell nodules
      around the large dedifferentiated tumours. The alpha2, beta1 and gamma1 chains of
      the laminin-2 isoform were synthesized and secreted by rat MTC 6-23 cell cultures
      and the tumours induced by subcutaneous injection of these cells. In situ
      hybridization combined with anti-CT immunocytochemistry showed a low expression
      of alpha2 mRNA on differentiated C cells and thyrocytes, but an overexpression on
      immunonegative spontaneous MTC and induced intrathyroid tumours. The high level
      of alpha2 gene expression, together with tumour dedifferentiation, suggests a
      relationship with malignancy.

PMID- 10335946
TI  - Angiosarcoma of the testis.
AB  - A primary angiosarcoma of the testis in a 74-year-old patient was a highly
      anaplastic epthelioid angiosarcoma, which was positive for endothelial markers
      immunohistochemically. The tumour was unrelated to testicular germ cell neoplasm;
      the patient had received no previous radiation or chemotherapy.

PMID- 10335945
TI  - Distribution of Tsc2 protein in various normal rat tissues and renal tumours of
      Tsc2 mutant (Eker) rat detected by immunohistochemistry.
AB  - Alterations in the rat tuberous sclerosis gene (Tsc2) are responsible for the
      hereditary renal carcinomas (RCs) of Eker rat. We examined protein distribution
      in various normal rat tissues and the Eker RCs by immunohistochemistry. Tsc2
      protein is expressed in the mammary ducts, salivary glands, gastric glands,
      parathyroid, small and large intestine, ovary and uterus. Specific expression of
      Tsc2 protein is found in the B cells of pancreatic islets and in the smooth
      muscle of lung veins. Interestingly, in the RCs of Eker rat, Tsc2 protein was
      detectable with some variation in reactivity.

PMID- 10335947
TI  - Unusual choristoma of the parotid gland in a girl. A possible trichoadenoma.
AB  - An 8-year-old girl had a painless circumscribed nodule in the right parotid gland
      for 4 weeks. A tumour (1.3 cm diameter) within the salivary gland parenchyma
      showed small cystic spaces with horn-like material macroscopically. The tumour
      tissue contained solid squamous cell formations and cystic spaces limited by
      multilayered squamous epithelium and covered by layers of ortho- and
      parakeratotic cells. The cystic spaces contained keratotic lamellae. In some
      areas pin-like epithelial proliferations were seen. All epithelial cells were
      characterized by uniform nuclei, and no atypical mitoses were seen. Keratinizated
      masses with partial calcification were occasionally located in the interstitial
      tissue and replaced by multinucleated giant cells. The tumour was classified as a
      choristoma and resembled a trichoadenoma. The ectodermally derived oral and
      salivary gland epithelium may be the source of skin-like or adnexal tumours.

PMID- 10335948
TI  - Unilateral aneuploid dedifferentiated acinic cell carcinoma associated with
      bilateral-low grade diploid acinic cell carcinoma of the parotid gland.
AB  - A dedifferentiated acinic cell carcinoma (AciCC) of the right parotid gland with
      lymph node metastases occurred in a 36-year-old woman. The tumour was associated
      with a bilateral well-differentiated AciCC. The two components of this tumour had
      different (high and low) proliferative activity measured by Mib-1 and different
      (aneuploid and diploid) DNA content. Despite the presence of a high-grade
      component, TP53 mutations, microsatellite instability (MSI) and/or loss of
      heterozygosity (LOH) at the p53 locus were not detected. Although the follow-up
      of the patient is very short, the aggressiveness of the tumour is shown by a
      recurrence in the right parotid within 4 months and by the rapid development of
      regional metastases.

PMID- 10335949
TI  - Primary epithelioid leiomyosarcoma of bone. Case report and literature review.
AB  - We describe an epithelioid leiomyosarcoma of bone located in the right knee of a
      51-year-old woman. Plain radiograph and CT scan revealed a poorly defined lytic
      and destructive mass in the upper metaepiphyseal right tibia which involved
      surrounding soft tissues. The lesion was composed of proliferating monotonous
      round cells with a high mitotic activity with scanty intersecting spindle cell
      fascicles. Immunohistochemistry of both areas demonstrated a strong positivity
      for actin (HHF-35 and alpha-SMA) and vimentin, and negative reactions for desmin,
      keratin (AE1 AE3), epithelial membrane antigen, S-100 protein, factor VIII
      related antigen, CD 31 and CD 34. Ultrastructural study confirmed a diagnosis of
      leiomyosarcoma. This is the first detailed description of the microscopic and
      radiological features of primary epithelioid leiomyosarcoma of bone.

PMID- 10335950
TI  - Infection, inflammation and sleep: more pieces to the puzzle of sudden infant
      death syndrome (SIDS).
AB  - Risk factors for sudden infant death syndrome (SIDS) parallel those for
      respiratory tract infections; however, infectious agents suggested to be involved
      in SIDS do not fulfil Koch's postulates. No single agent has been identified in
      all cases and there is no suitable animal model for SIDS which could be used to
      test the candidate organisms. Based on epidemiological and experimental work by
      our group and others, we suggested some SIDS deaths are due to pathophysiological
      responses elicited by combinations of microbial products and/or cigarette smoke
      during a developmental stage when infants' endocrine responses are less able to
      "damp down" the effects of inflammatory mediators. Here we review evidence from
      studies on interactions between developmental and environmental risk factors that
      could affect 1) mucosal colonization of infants by potentially pathogenic
      bacteria, and 2) induction and control of infants', inflammatory responses to
      infectious agents. New evidence suggests that there are genetic factors involved
      in the induction of inflammatory responses to some bacterial antigens implicated
      in SIDS. Further investigation of the role of infection, exposure to cigarette
      smoke and inflammation in infants, particularly differences in ethnic groups at
      increased risk of SIDS, could lead to new insights into the events leading to a
      fatal outcome and perhaps to new intervention schemes to reduce further the
      incidence of these deaths.

PMID- 10335951
TI  - Relationship between pinworm and urinary tract infections in young girls.
AB  - Urinary tract infection is particularly common in young girls and Enterobius
      vermicularis (pinworm) is one of the most prevalent worms found in children
      worldwide. Young girls, with or without urinary tract infection, were examined
      for pinworms in order to explore a possible relationship between these two
      problems. Of the 55 young girls with urinary tract infection, 20 (36.4%) had
      pinworm eggs in the perianal and/or perineal region monitored using the
      cellophane tape method, while 9 (16.4%) of 55 young girls who had never
      previously had a urinary tract infection were found to have Enterobius eggs in at
      least one of the cellophane tape tests, and the difference was found to be
      significant (p<0.05). These results suggested that urinary tract infections may
      be related to pinworms. When a urinary tract infection is diagnosed in young
      girls, cellulose tape should be applied to both the perianal and the perineal
      regions on at least three consecutive occasions.

PMID- 10335952
TI  - Evidence for an oral-faecal transmission of Helicobacter pylori infection in an
      experimental murine model.
AB  - An experimental murine model was used to evaluate the possible animal-to-animal
      transmission of Helicobacter pylori and the mechanism involved. Twenty-four
      Balb/C mice were infected with H. pylori type I strain culture and kept with 24
      noninoculated mice to evaluate the possible transmission of the microorganism.
      Twelve inoculated mice were housed with 12 noninoculated mice in a grated cage
      (supporting an oral-oral transmission); the remaining inoculated and
      noninoculated mice were housed in another cage without grating on the floor
      (supporting a faecal-oral transmission). The bacterial colonization was assessed
      by culture and immunohistochemistry. The systemic antibody response to H. pylori
      and the histopathological changes were evaluated; controls were examined at 2, 4,
      8, 12 weeks after the start of the experiment. Faecal samples were also collected
      from each mouse on the day before sacrifice, to assess the presence of H. pylori
      by culture and by immunohistochemistry. In the gastric mucosa of inoculated mice,
      histopathological changes were recorded at each control time and H. pylori was
      detected both by immunohistochemistry and by a systemic antibody response; the
      microorganism was also cultured at 2, 4, 8 weeks postinoculation. H. pylori was
      detected in noninoculated mice, housed in the cage without grating, using an
      immunoperoxidase technique at 2, 4, 8 weeks after starting the experiment, and
      these positive values were supported by histopathological changes, and, in one
      case, at 8 weeks, also by the serum immune response. No colonies of H. pylori
      were detected by culturing faecal samples from either noninoculated or inoculated
      mice. The results obtained in this study seem to support an oral-faecal route as
      the mode of transmission of H. pylori infection in this animal model.

PMID- 10335953
TI  - Transient Tat activation of the HIVLAV/Lai-1 LTR by primary HIV-1 phenotypic
      variants in HeLaT4LTRbeta-gal cells.
AB  - The rapid/high and slow/low phenotypic variants of primary HIV-1 isolates can be
      distinguished by their differential co-receptor utilization and their ability to
      productively infect established cell lines. To reveal possible differences in Tat
      mediated transactivation, the potential for primary isolate Tat proteins to
      transactivate the LTR from the laboratory strain HIVLAV/Lai-1 was examined. Using
      either cell-mediated or PEG-induced fusion of cells infected with primary HIV-1
      isolates and HeLaT4LTRbeta-gal cells, it was clear that the Tat protein encoded
      by all patient isolates efficiently activated transcription from the HIVLAV/Lai-1
      LTR. However, infection of HeLaT4LTRbeta-gal cells by primary HIV-1 isolates was
      transient, suggesting the development of a postpenetration host control of HIV-1
      replication at the level of tat activation, a feature not observed for the
      laboratory-adapted strain HIVIIIB. Although plasmid vectors based on the
      HIVLAV/Lai-1 LTR remain useful for the development of susceptible established
      cell lines for titrating primary HIV-1 isolates, the efficacy of such a system
      would depend upon the stability/duration of Tat activation.

PMID- 10335955
TI  - Postantibiotic effect and postantibiotic sub-mic effect of dirithromycin and
      erythromycin against respiratory tract pathogenic bacteria.
AB  - The postantibiotic effect (PAE) of dirithromycin and erythromycin against strains
      Streptococcus pyogenes group A M12, NCTC P1800, Streptococcus pneumoniae 23,
      Staphylococcus aureus Oxford strain 209, Moraxella catarrhalis 15616 and
      Haemophilus influenzae 5590 was investigated in vitro and in vivo by use of the
      tissue cage model in rabbits. By exposing strains to 2.5-5 x MIC levels for 6 h
      or 12 h, both compounds induced in vitro PAEs of 1-9 h, and in two cases >20 h.
      Cultures in the PAE-phase were then re-exposed to subinhibitory concentrations
      (0.25 x MIC and 0.5 x MIC) of antibiotic and prolonged suppression of regrowth
      was obtained for 2->20 h. Following i.v. antibiotic treatment of rabbits (10
      mg/kg or 20 mg/kg dirithromycin and 20 mg/kg or 40 mg/kg erythromycin) and
      bacterial infection of the implanted tissue cages in the same rabbit, the tissue
      cage fluid (TCF) was sampled 6 h after infection and regrowth was monitored by
      sampling from new tissue cages in untreated rabbits. These i.v. single doses of
      both antibiotics induced in vivo PAEs of >6 h, but <20 h against S. pyogenes.
      Suppression of regrowth in TCF was also obtained for > or = 20 h on infection
      with exposed S. pyogenes in the PAE-phase in newly implanted tissue cages in
      rabbits that had been treated with low doses of antibiotic to produce
      subinhibitory concentrations in the TCE Dirithromycin was in general as active as
      erythromycin in inducing PAE and in prolonging suppression of bacterial regrowth
      in the PAE phase.

PMID- 10335954
TI  - Bacterial binding to extracellular matrix proteins -- in vitro adhesion.
AB  - A binding assay was developed and used to study the binding of oral streptococcus
      to immobilized human fibronectin, laminin, vitronectin, fibrinogen, heparin, and
      collagen IV. The protein binding was dependent on the broth used for bacterial
      growth. The binding after growth in brain heart infusion broth, trypticase soy
      broth, Todd-Hewitt broth, and Dulbecco's modified Eagle's medium was examined.
      Most of the strains were able to bind to immobilized fibronectin and laminin, and
      to a minor extent vitronectin. Binding was not observed on immobilized
      fibrinogen, collagen IV, or heparin. Measured surface hydrophobicity correlated
      well with the bacterial binding strength to the proteins. Streptococcal
      incubation with putative inhibitors indicates multiple binding mechanisms of a
      lectin-like and protein nature, possibly involving protein receptors.

PMID- 10335956
TI  - Interrelations of clinicopathological variables, local immune response and
      prognosis in esophageal squamous cell carcinoma.
AB  - The purpose of this study was to investigate the relationship between the local
      immune response, clinicopathological variables and prognosis in esophageal
      squamous cell carcinoma (SCC). A total of 377 cases of esophageal SCC without
      preoperative radiotherapy, chemotherapy or immunotherapy were studied. Corrected
      5-year survival for pronounced, moderate and sparse immunocyte infiltration was
      66%, 43% and 24%, respectively. In multivariate survival analysis, the immunocyte
      infiltration was an independent prognostic factor for survival (p<0.001). A
      correlation was found between density of T-cell and macrophage infiltration,
      depth of tumor invasion and lymph node metastasis using immunohistochemical
      analysis of the expression of T-cell, B-cell and macrophage markers. The results
      indicate that the local immunocyte infiltration is a manifestation of the host
      defense against cancer. It is therefore reasonable to infer that the local
      immunocyte infiltration in and around the cancer stroma is an important factor in
      predicting the prognosis of patients with esophageal SCC.

PMID- 10335957
TI  - Synchronous occurrence of carcinoid tumour of the appendix and T-cell lymphoma of
      the ileum. A case report with review of the literature.
AB  - Carcinoid tumours of the gastrointestinal tract are often associated with other
      tumour types at various sites. However, only rarely has a lymphoma constituted
      the second tumour. In the present paper, we report the case of a 62-year-old
      woman who was operated on for a perforated T-cell lymphoma of the ileum and in
      whom an appendicular carcinoid tumour was incidentally discovered at surgery. It
      was possible to completely remove both tumours and postoperatively the patient
      underwent CHOP treatment. Ten months after surgery the patient is well, with no
      tumour manifestations. We also discuss problems concerning classification of the
      lymphoma on account of loss of the T-cell antigen CD45RO (UCHL-1).

PMID- 10335958
TI  - Apoptosis in acute pulmonary allograft rejection and cytomegalovirus infection.
AB  - Apoptosis is a form of programmed cell death, characterized by activation of
      endonucleases that cleave DNA into oligonucleosomal fragments, which can be
      identified by in situ terminal deoxyribonucleotide transferase-mediated dUTP nick
      end labeling (TUNEL). This process has recently been implicated in cardiac and
      hepatic allograft rejection, and we investigated its contribution to acute
      pulmonary allograft rejection and cytomegalovirus (CMV) pneumonitis by in situ
      TUNEL of transbronchial biopsy specimens. In situ TUNEL was performed on 70
      transbronchial biopsy samples collected from 25 pulmonary allograft recipients
      for diagnosis of acute rejection or CMV pneumonitis, and the number of apoptotic
      nuclei/mm2 was correlated with the rejection grade (International Society of
      Heart and Lung Transplantation classification). During acute pulmonary allograft
      rejection, apoptotic nuclei were demonstrated in pulmonary parenchymal cells and
      mononuclear infiltrating cells, and the number of apoptotic cells was positively
      correlated with the rejection grade. In addition, a marked increase in the
      density of apoptotic cells was found in pulmonary allografts with CMV
      pneumonitis. We conclude that apoptosis contributes to cell death during acute
      pulmonary allograft rejection and CMV infection.

PMID- 10335959
TI  - MR imaging of invasive carcinoma of the uterine cervix.

PMID- 10335960
TI  - Renal duplex Doppler ultrasonography as a predictor of preclinical diabetic
      nephropathy in children.
AB  - PURPOSE: To perform Doppler US in patients with insulin-dependent diabetes
      mellitus (IDDM) as a predictive method in diabetic nephropathy (DN). MATERIAL AND
      METHODS: Twenty-five patients with type I diabetes mellitus underwent renal
      Doppler US examination. Children were divided into three age groups: group I, 3-7
      years; group II, 8-10 years; and group III, 11-18 years. The age-matched control
      group consisted of 56 healthy children who underwent renal Doppler US only.
      RESULTS: The mean values of the resistive index (RI) were, respectively, 0.64+/
      0.03, 0.59+/-0.04, 0.59+/-0.02 in age groups I, II, and III for healthy children
      and 0.68+/-0.03, 0.62+/-0.04, 0.59+/-0.04 in age groups I, II, and III of the
      diabetic patients. There were no significant differences between the diabetic and
      healthy subjects. The mean RI value was not different in the patients with
      glomerular hyperfiltration compared to patients with normal filtration rate.
      Additionally, there were no significant differences between the mean RI value in
      patients with or without microalbuminuria. CONCLUSION: Renal Doppler US is not
      useful for prediction or for early diagnosis of DN.

PMID- 10335961
TI  - Gadolinium-enhanced MR imaging of normal renal transplants. An evaluation of a T1
      weighted dynamic echo-planar sequence.
AB  - PURPOSE: To evaluate the potential usefulness of dynamic MR with echoplanar
      imaging (EPI) in assessing the renal function in patients with renal allografts.
      MATERIAL AND METHODS: Using a T1-weighted sequence, EPI was performed after
      injection of a Gd-chelate in 17 patients with normally functioning renal
      allografts. Time-intensity curves were plotted from the signal intensity (SI)
      measurements of the cortex and the medulla. RESULTS: The pattern of
      corticomedullar differentiation (CMD) observed after contrast enhancement was
      divided into four phases using the T1-EPI. After a rapid decrease in the SI of
      cortical structures, and a subsequent return to precontrast levels, a gradual
      fall in the SI of the medulla was observed. The average time between the two
      periods of signal loss was 60 s. CONCLUSION: This study illustrated the potential
      use of dynamic T1-EPI to demonstrate contrast-induced CMD in renal allografts.

PMID- 10335962
TI  - Radiological diagnosis of acute stroke. Comparison of conventional MR imaging,
      echo-planar diffusion-weighted imaging, and spin-echo diffusion-weighted imaging.
AB  - PURPOSE: To compare conventional MR imaging, echo-planar diffusion-weighted
      imaging (EP-DWI) and spin-echo diffusion-weighted imaging (SE)-DWI at
      radiological diagnosis of acute stroke. MATERIAL AND METHODS: Twenty-seven
      patients (30-85 years old) were examined. Clinical examination was performed
      before MR imaging. All MR examinations were assessed by an experienced
      neuroradiologist blinded to clinical findings. RESULTS: In EP-DWI, every patient
      had a lesion corresponding to the clinical findings. EP-DWI was used as the gold
      standard. In conventional PD+T2 imaging, 23/59 focal lesions were interpreted as
      acute, which was false in 11 lesions, and 36/59 lesions were considered to be
      old, 6 were in fact acute. Nine acute lesions were only detected retrospectively
      and 12 acute lesions were not detected at all on PD+T2. SE-DWI including the
      apparent diffusion coefficient correlated fairly well with EP-DWI but the
      procedure was impractical. CONCLUSION: EP-DWI is reliable for diagnosis of early
      ischemic stroke, while SE-DWI performs reasonably well. Conventional PD+T2
      imaging is not reliable for diagnosis of early ischemia.

PMID- 10335963
TI  - Triggering in quantitative diffusion imaging with single-shot EPI.
AB  - PURPOSE: The aim of this study was to evaluate any possible effects of brain
      motion, CSF pulsations and other possible sources of physiological motion in
      electrocardiographic (ECG) triggered and non-triggered single-shot echo-planar
      imaging (EPI) measurements of diffusion. MATERIAL AND METHODS: Three different
      triggering protocols were evaluated in 6 healthy volunteers: 1) ECG triggering
      with time delay (TD) 100 ms; 2) ECG triggering with TD 400 ms; and 3) no
      triggering at all. RESULTS: The results obtained showed that white matter mean
      apparent diffusion coefficient (ADC) values were similar for all triggering
      protocols and that the reproducibility in ADC measurements using diffusion
      weighted (DW) EPI was good. The average standard deviation of the ADC values was,
      however, higher for ADC maps obtained without ECG triggering. CONCLUSION: The use
      of prospective diastolic ECG triggering significantly improves the accuracy of
      quantitative diffusion measurements but for routine clinical diffusion imaging,
      where quantitative data is of less importance, the accuracy obtained without ECG
      triggering can be considered adequate.

PMID- 10335964
TI  - Effect of an internal carotid stenosis on orbital blood velocity.
AB  - PURPOSE: To examine how an internal carotid artery (ICA) stenosis influences the
      orbital blood velocity and to determine which velocity parameters are most
      useful. MATERIAL AND METHODS: The study group comprised 94 randomly selected
      patients examined with orbital US; most of the patients had a carotid artery
      stenosis. There were 58 men and 36 women, ranging in age from 22 to 88 years with
      a mean age of 63.1 years. The ICA stenosis grade was determined with carotid US.
      Peak systolic (Vp) and end-diastolic blood velocities, systolic acceleration,
      mean velocity, pulsatile index (PI) and resistance index (RI) were measured
      within the central retinal artery (CRA) and the ophthalmic artery (OA), and peak
      velocity was measured within the central retinal vein (CRV). The area under the
      ROC curve was used to compare the outcome of diagnostic tests. RESULTS: Only a
      severe (> or =80%) ICA stenosis decreased orbital blood velocity significantly,
      while milder stenoses did not cause significant flow decrease or side
      differences. According to ROC curve analysis, the threshold values giving the
      highest accuracy in detecting a > or =80% ICA stenosis were Vp < or =0.08 cm/s
      for the CRA and Vp < or =0.14 cm/s for the OA. The sensitivities for detecting a
      > or =80% ICA stenosis were 45% for Vp CRA and 60% for Vp OA. Systolic
      acceleration also decreased in severe stenoses, but RI, PI and velocity in the
      CRV did not correlate with ICA pathology. Reversal of OA flow was seen in 92% of
      ICA occlusion and in 47% of severe ICA stenosis. CONCLUSION: Orbital Doppler
      combined with carotid Doppler can be helpful in the diagnosis of the ocular
      ischaemic syndrome and in the evaluation of whether the symptoms are related to
      occlusion of the ophthalmic or central retinal vessels or are a consequence of
      carotid artery stenosis.

PMID- 10335965
TI  - MR imaging of squamous cell carcinoma of the floor of the mouth. Appearance of
      the sublingual and submandibular glands.
AB  - PURPOSE: To determine the diagnostic value of MR imaging for tumors of the floor
      of the mouth and the effects of the tumors on the sublingual and submandibular
      glands. MATERIAL AND METHODS: Thirty-seven patients with proven squamous cell
      carcinoma of the floor of the mouth underwent MR imaging, including unenhanced T1
      weighted, T2-weighted, dynamic, and contrast-enhanced T1-weighted images. The
      appearance of the tumor and the sublingual and submandibular glands was assessed
      qualitatively and quantitatively. RESULTS: All tumors demonstrated replacement of
      the normal signal intensity in the adjacent sublingual gland. Twenty-one patients
      (57%) had abnormal signal intensity of the submandibular gland without tumor
      invasion, presumably secondary to submandibular duct obstruction by the tumor.
      Unenhanced T1-weighted images provided high contrast between tumor and sublingual
      gland. Tumors limited within the gland were well detected on unenhanced T1
      weighted images. Large tumors extending beyond the gland were well delineated on
      dynamic images, but no better than on T2-weighted images. CONCLUSION: At MR
      imaging for tumor of the floor of the mouth, one must carefully evaluate the
      appearance of the sublingual and submandibular glands. Contrast-enhanced studies
      are unnecessary when the tumor is limited within the sublingual gland on
      precontrast MR images.

PMID- 10335966
TI  - NC100150-enhanced 3D-SPGR MR angiography of the common carotid artery in a pig
      vascular stenosis model. Quantification of stenosis and dose optimization.
AB  - PURPOSE: NC100150 is a new type of ultra-small iron oxide (USPIO) blood pool
      agent. The aim of this study was to compare NC100150-enhanced MR angiography
      (MRA) to time-of-flight (TOF) MRA, phase-contrast (PC) MRA, and digital
      subtraction angiography (DSA) in experimental stenoses in pigs, and furthermore
      to determine the optimal dose of the contrast agent. MATERIAL AND METHODS: An
      experimental stenosis of the right and left common carotid artery (CCA) was
      applied surgically in 6 Yorkshire pigs. DSA was performed as the gold standard,
      followed by 3D-TOF, 3D-PC, and NC100150-enhanced MRA. RESULTS: Eleven stenoses of
      the CCA were successfully applied. The degree of the stenosis, determined by
      NC100150-enhanced MRA, did not differ significantly from DSA, whereas TOF and PC
      MRA underestimated it. The image quality of the NC100150-enhanced MRA was
      superior to both TOF and PC MRA. The optimal dose of NC100150 was 5-6 mg Fe/kg,
      since higher doses did not further increase signal-to-noise ratio or contrast-to
      noise ratio. There was a linear relationship between blood relaxation rate and
      contrast dose. CONCLUSION: NC100150-enhanced MRA has the potential for
      quantification of carotid stenoses and provides an alternative to DSA. The
      optimal dose of NC100150 was 5-6 mg Fe/kg.

PMID- 10335967
TI  - Comparison of iodixanol 270 with iohexol 300 in infrapopliteal arteriography.
      Digital densitometric analysis of angiographic opacification.
AB  - PURPOSE: To compare iodixanol 270 mg I/ml with iohexol 300 mg I/ml in
      infrapopliteal arteriography by measuring digital densitometric vessel
      opacification and by visually assessing angiographic enhancement. MATERIAL AND
      METHODS: In a double-blind, dual-balanced, 4-sequence cross-over design, 50
      claudicant patients received two contrast media injections (10 min interval) in
      the superficial femoral artery. Digital angiography was performed at 8 frames/s
      and time-density curves with a circular region of interest over a distal calf
      artery were generated. A mixed, linear model was used to identify effects
      influencing the density measurements. Subjective evaluation of the image quality
      was made independently by two observers. RESULTS: No statistically significant
      difference between the contrast media was revealed in the analysis of the
      densitometric measurements (p=0.14) nor in the subjective visual evaluation
      (p=0.74). However, the mean density at the time of maximum opacification was
      higher after the first injection than that after the second injection (p=0.02).
      There was a tendency towards lower intensity of warmth during injection of
      iodixanol 270 than during injection of iohexol 300. CONCLUSION: In patients with
      severe occlusive atherosclerotic disease, iodixanol yielded the same image
      quality as iohexol in infrapopliteal arteriography, in spite of the 30 mg I/ml
      lower iodine concentration.

PMID- 10335968
TI  - Clinical impact of MR arthrography of the shoulder.
AB  - PURPOSE: To evaluate the effect of MR arthrography of the shoulder on diagnostic
      thinking and therapeutic decisions by orthopedic shoulder surgeons. MATERIAL AND
      METHODS: Orthopedic surgeons completed a questionnaire before and after MR
      arthrography for 73 consecutive patients. The main indications were suspected
      rotator cuff abnormalities. The clinical diagnosis, the degree of confidence in
      this diagnosis, and the therapeutic decision were noted before and after MR
      imaging. Surgical reports were available for 34 patients. RESULTS: Thirty-four
      percent of the pre-MR imaging diagnoses were withdrawn after MR imaging, and new
      diagnoses were made after MR imaging in 13% of the cases. Confidence in the
      diagnosis increased significantly after MR imaging for supraspinatus and
      infraspinatus lesions (p<0.05). Changes of therapeutic decision after MR imaging
      were noted in 36 of the 73 patients (49%). In 23 patients, more invasive
      therapeutic procedures were initiated after MR imaging, and a more conservative
      treatment was implemented for 13 patients. Agreement of MR diagnoses with surgery
      was 94% for supraspinatus tears, 87% for infraspinatus tears, 77% for
      subscapularis tears, and 81% for biceps tendon lesions. Agreement of clinical
      diagnoses with surgery was 56%, 83%, 50%, and 64%, respectively. CONCLUSION: MR
      arthrography of the shoulder has a major effect on diagnostic thinking and
      therapeutic decisions by orthopedic shoulder surgeons.

PMID- 10335969
TI  - Ligaments and tendons of the ankle. Evaluation with low-field (0.2 T) MR imaging.
AB  - PURPOSE: To investigate the value of MR imaging using a low-field imaging unit
      (0.2 T) for the evaluation of ligaments and tendons of the ankle. MATERIAL AND
      METHODS: Twelve ankle specimens were studied using low-field MR imaging (0.2 T).
      The Achilles tendon, the tibialis posterior tendon, and the lateral collateral
      ligaments were evaluated for the presence of degenerative changes and partial and
      complete tears. Visibility and overall image quality were analyzed by qualitative
      evaluation. RESULTS: Low-field MR images of the 24 tendons were interpreted as
      normal in 11 cases, showing degenerative changes in 9 cases and a partial tear in
      1 case. Visualization was regarded as not sufficient for a diagnosis in 3 cases.
      Of the 36 ligaments, 14 were regarded as normal while degenerative changes were
      seen in 5 cases and a tear in 2 cases. In 13 cases, no diagnosis could be
      established, and in 2 cases only a probable diagnosis was established. The best
      overall quality was obtained with the use of T1 spin-echo (680/20/4) and T2 multi
      echo (3000/40/1) images. CONCLUSION: Optimized protocols for examination of the
      ankle using low-field MR imaging may allow evaluation of the Achilles and
      tibialis posterior tendons, but these protocols may not be as useful for
      diagnosing ligamentous changes.

PMID- 10335970
TI  - Sympathotropic drugs and the distribution of 99mTc-hydroxymethylene
      diphosphonate. Experimental studies in the mouse.
AB  - OBJECTIVE: The uptake of bone-seeking radiopharmaceuticals depends on the blood
      flow, which is influenced by the sympathetic nervous system. Our aim was to study
      the effect of sympathomimetic drugs on the distribution of bone-seeking agents.
      MATERIAL AND METHODS: Various sympathomimetic and beta-blocking drugs were
      injected in mice at different times in relation to the administration of 99mTc
      HDP. Three hours after this, venous blood and various organs were removed and
      their activities were related to the administered activity. A kinetic study of
      the whole-body activity retention after administration of terbutaline was also
      made. RESULTS: The biodistribution of 99mTc-HDP was similar after the
      administration of sympathomimetics and of beta-antagonists. All drugs gave rise
      to an increased soft tissue activity and a decreased bone activity, corresponding
      to a lowered quality of the potential bone scan. Terbutaline gave rise to an
      increased excretion of 99mTc-HDP. The mechanisms behind the findings cannot be
      entirely explained. CONCLUSION: Drug interference with the sympathetic nervous
      system causes undesirable effects on the biodistribution of 99mTc-HDP in the
      mouse. Studies in humans are necessary to evaluate whether clinical treatment
      with sympathotropic drugs affects the bone scintigram.

PMID- 10335971
TI  - Determination of tissue volumes. A comparison between CT and MR imaging.
AB  - PURPOSE: To evaluate MR imaging for tissue volume measurements. MATERIAL AND
      METHODS: Imaging was done with a spoiled gradient echo technique using the human
      lower leg as a simple model and CT as the reference technique. Areas of adipose
      tissue, muscle plus skin and bone tissue were evaluated in 5 volunteers using
      signal intervals (MR) and attenuation intervals (CT) defined by histograms.
      Volumes were determined from 7 images (MR-7, CT-7), from 70 contiguous images (MR
      70), and also from a commercially-available 3D program based on a seeding
      technique applied according to the operators' judgment (MR-op). RESULTS: The sum
      of bone tissue, muscle plus skin and adipose tissue were similar for CT and MR.
      Compared to CT-7, MR-7 and MR-70 overestimated adipose tissue (0-8%) and muscle
      plus skin (11-15%), while bone tissue was underestimated (61-78%). Determinations
      based on the contiguous images or the 7 images were similar (standard error 2
      5%). MR-op resulted in pronounced underestimation of muscle plus skin and bone
      tissue and a minor underestimation of adipose tissue. CONCLUSION: Valid
      determinations of adipose tissue volume are possible with MR but further
      technical development is required for other tissue volumes. The technique applied
      according to the operators' judgement, as used for 3D surface rendition, is
      unreliable for tissue volume determinations.

PMID- 10335972
TI  - MR imaging of the liver using an ultrafast 3D multi-shot EPI sequence. Comparison
      with four other T1-weighted sequences.
AB  - PURPOSE: To compare a 3D echo planar imaging (EPI) sequence with four other T1
      weighted sequences for imaging of the liver at 1 T. MATERIAL AND METHODS: Twenty
      volunteers were included in our imaging protocol. Spin-echo (SE), turbo SE (TSE),
      turbo field echo (TFE) in 2D and 3D acquisition mode, fast field echo (T1-FFE)
      and 3D EPI sequences were applied. Signal-to-noise (S/N) ratio of the liver,
      contrast-to-noise (C/N) ratio and relative contrast (ReCon) between the liver and
      the spleen, scanning time per slice and artifact levels were evaluated. RESULTS:
      3D EPI provided a statistically equivalent S/N ratio of the liver with SE and T1
      FFE sequences (p>0.05), while it provided a statistically higher S/ N ratio of
      the liver compared to TFE sequences (p<0.05). The TSE technique provided a
      statistically higher S/N ratio of the liver compared to 3D EPI (p<0.05). With
      regard to the liver-spleen C/N ratio, 3D EPI provided statistically equivalent
      results compared to all sequences except T1-FFE, where 3D EPI was superior. With
      regard to liver-spleen ReCon, 3D EPI was statistically equivalent to SE, TSE and
      T1-FFE, while it provided significantly higher liver-spleen ReCon than 3D TFE and
      significantly lower than 2D TFE. CONCLUSION: 3D EPI provided sufficient ReCon and
      C/N ratio and produced motion-free images in one breath-hold period. Further
      clinical studies are required to estimate the sensitivity, specificity and
      accuracy of the sequence.

PMID- 10335973
TI  - Hepatic alveolar echinococcosis. A case report.
AB  - Alveolar echinococcosis is a rare parasitic disease caused by Echinococcus
      multilocularis and most commonly involves the liver. Early diagnosis and precise
      evaluation of the localisation and the extent of the lesions are essential for
      treatment. In this report, we present US and CT findings in a patient with
      hepatic alveolar echinococcosis.

PMID- 10335974
TI  - Diaphragmatic haemangioma. A case report.
AB  - The case of a 4-year-old patient with a diaphragmatic haemangioma is reported.
      There were no symptoms and the only clinical finding was prominent subcutaneous
      vessels on the abdominal wall. The lesion was revealed by imaging and was
      excised. The findings and the differential diagnosis are discussed.

PMID- 10335975
TI  - CT measurement of lung density.
AB  - PURPOSE: The aim of this study was to obtain more accurate data on the electron
      density of the lungs in healthy subjects and to determine the factors that
      influence this value. MATERIAL AND METHODS: Single kVp quantitative CT was
      applied in 130 normal adults (61 men and 69 women) to study the electron density
      of the lung. RESULTS: The electron density of the lung in men was lower than that
      in women. In contrast, the area designated as lung in men was larger than that in
      women. The mean electron density decreased with increasing age in men, but not in
      women. The following parameters were not found to influence lung electron
      density: body mass, body height, smoking habits, and right or left lung. The
      electron density of the lung medial to the thoracic wall and close to the breast
      was lower than the density in the entire lung parenchyma. CONCLUSION:
      Quantitative CT provided the means to study noninvasively the electron density of
      the lung and the factors that influence this value.

PMID- 10335976
TI  - The tip of the needle--a trick of the trade.

PMID- 10335977
TI  - Single-shot diffusion-weighted echo-planar imaging of normal and cirrhotic livers
      using a phased-array multicoil.

PMID- 10335978
TI  - Capillary zone electrophoresis: an additional technique for the identification of
      hemoglobin variants.
AB  - Two capillary zone electrophoresis kits (Hb A2 and Hb A1c) were tested for
      confirmation and identification of hemoglobin variants. The capillary zone
      electrophoresis experiments were performed at pH 4.7 (Hb A1c kit) and 8.7 (Hb A2
      kit) in a 24 cm uncoated fused silica capillary tube (25 microm I.D.). Normal
      hemoglobins and common hemoglobin variants, including Hbs S, D-Punjab, C, E, O
      Arab, and G-Philadelphia, were successfully separated by both methods within a
      few minutes. Both systems provided completely different elution profiles of
      normal and abnormal hemoglobin fractions tested and were complementary. The inter
      assay coefficient of variations of the migration times of hemoglobin variants
      were less than 1.0 and 1.3% by the Hb A2 and Hb A1c, respectively. This permits a
      higher resolution of some hemoglobin variants in low concentrations, like Hb S in
      newborns, compared with conventional electrophoresis methods. The present
      capillary zone electrophoresis methods are sensitive, rapid, not labor intensive,
      and highly selective for the separation of hemoglobin variants. Combination of
      both methods with some conventional methods, such as isoelectrofocusing, allows
      identification of Hbs C, E, O-Arab, S, and D-Punjab, as well as their
      quantification. We have demonstrated that the conventional electrophoresis
      methods (electrophoresis at pH 6.5 in citrate agar gel and electrophoresis at pH
      8.6 on cellulose acetate) can be advantageously replaced by the present capillary
      zone electrophoresis methods in a clinical laboratory practice for the detection
      and quantification of hemoglobin variants.

PMID- 10335979
TI  - Hb Rainier [beta145(HC2)Tyr-->Cys] in Italy. Characterization of the amino acid
      substitution and the DNA mutation.
AB  - A high oxygen affinity hemoglobin variant was identified in a 53-year-old male
      patient from Napoli (Italy), suffering from pulmonary thromboembolism and
      polycythemia. A detailed structural characterization of the variant hemoglobin
      was carried out, both at the protein and DNA levels, by a combination of DNA
      sequencing and allele-specific amplification techniques with mass spectrometric
      procedures. The amino acid substitution was found to be Tyr-->Cys, and the
      corresponding DNA mutation was identified as A-->G at the second position of
      codon 145 of the beta chain. These variations indicated the presence of Hb
      Rainier. Haplotype analysis of DNA polymorphisms showed that the beta-globin gene
      from Hb Rainier was associated with haplotype II. Moreover, structural analyses
      provided direct identification of an intramolecular disulphide bridge joining the
      newly inserted beta145Cys with beta93Cys. This is the first report of the
      occurrence of Hb Rainier in Italy.

PMID- 10335980
TI  - Hb Chile [beta28(B10)Leu-->Met]: an unstable hemoglobin associated with chronic
      methemoglobinemia and sulfonamide or methylene blue-induced hemolytic anemia.
AB  - Among the causes of life-long cyanosis are congenital methemoglobinemia due to M
      hemoglobins, congenital methemoglobinemia due to methemoglobin reductase
      deficiency, a small number of low oxygen affinity hemoglobins, and a small number
      of unstable hemoglobins that spontaneously form methemoglobin in vivo at an
      accelerated rate. We report an unstable hemoglobin with these characteristics
      that was observed in a family of indigenous (native American) origin living near
      Santiago, Chile. This variant has the substitution beta28(B10)Leu-->Met,
      unambiguously corresponding to the DNA mutation of CTG-->ATG in beta-globin gene
      codon 28.

PMID- 10335981
TI  - Hb Nijkerk: a new mutation at codons 138/139 of the beta-globin gene inducing
      severe hemolytic anemia in a Dutch girl.
AB  - We describe a new structural mutant of the beta-globin chain in a 17-year-old
      Dutch Caucasian girl. The mutant is associated with a severe pathology as a
      consequence of hyper-instability of the hemoglobin tetramer. The proband, whose
      parents had no history of hemolysis, was admitted to the hospital at 5 months of
      age with hemolytic anemia and splenomegaly. No indications for autoimmune defects
      or enzymopathies were found. Repeated hemoglobin electrophoresis on cellulose
      acetate revealed no abnormalities. At the age of 17 years, a minor abnormal band
      of less than 1% was detected on starch gel electrophoresis, migrating slightly
      faster than Hb A2. Sequencing of the beta-globin gene revealed heterozygosity for
      a 4 bp deletion (GCTA) in combination with a 1 bp insertion (T) at codons
      138/139. This event eliminates two amino acids (Ala-Asn) and introduces a new
      residue (Tyr). We discuss the hematological and the pathophysiological
      consequences of this mutant, which is fully expressed as a gene product, and
      apparently assembled into unstable tetramers that precipitate shortly after.

PMID- 10335982
TI  - Characterization and locus assignment of two alpha-globin variants present in the
      Maltese population: Hb St. Luke's [alpha95(G2)Pro-->Arg] and Hb Setif
      [alpha94(G1)Asp-->Tyr].
AB  - Two types of alpha-globin variants were found in 0.2% of a large number of
      newborn from Malta. The two hemoglobins were identified from tryptic maps on a
      Vydac C18 column and by alpha-globin gene sequencing as Hb St. Luke's
      (isoelectric point = 7.18+/-0.017) and Hb Setif (isoelectric point = 7.26+/
      0.010). Hb St. Luke's [alpha95(G2)Pro-->Arg] was found to result from a C-->G
      mutation at the second position of codon 95 on an alpha1-globin gene, and Hb
      Setif [alpha94(G1) Asp-->Tyr] resulted from a G-->T mutation at the first
      position of codon 94 on an alpha2-globin gene. Quantification of Hb St. Luke's
      (11.1+/-1.12%) and Hb Setif (14.7+/-2.22%) in peripheral blood hemolysates
      indicated that, in the absence of either an alpha- or a beta-thalassemia allele,
      the protein products of the alpha1- and alpha2-globin genes were nearly equal in
      quantity.

PMID- 10335984
TI  - The beta+-thalassemia mutation [IVS-II-5 (G-->C] creates an alternative splicing
      site in the second intervening sequence.
AB  - We report a beta-thalassemia mutation [IVS-II-5 (G-->C)] in a Chinese family.
      Recently we cloned this beta-globin gene and studied its transient expression in
      murine erythroleukemia (MEL) cells. Both the thalassemic and normal beta-globin
      genes were isolated by polymerase chain reaction and TA-vector cloning. When the
      cloned beta-thalassemic globin gene was introduced into MEL cells, two kinds of
      spliced cytoplasmic beta-globin RNAs were detected. The predominant RNA was
      normally spliced, while the less abundant RNA contained an insertion of the first
      47 nucleotides of the second intervening sequence localized between exons 2 and
      3. These results suggest that the mutation [IVS-II-5 (G-->C)] causes a beta+
      thalassemia.

PMID- 10335983
TI  - A novel C-->A transversion within the distal CCAAT motif of the Ggamma-globin
      gene in the Algerian Ggammabeta+-hereditary persistence of fetal hemoglobin.
AB  - Hereditary persistence of fetal hemoglobin (HPFH) is a group of genetically
      heterogeneous conditions characterized by the continued expression of fetal
      hemoglobin in adulthood. These constitute natural models for understanding the
      mechanism(s) of the hemoglobin switch. Many large deletions in the beta-globin
      gene cluster and point mutations in one of the fetal globin gene promoters have
      been described before. In this study we describe a novel C-->A transversion (
      114) in the distal CCAAT box of the Ggamma-globin gene promoter associated with
      the Ggammabeta+-HPFH phenotype in an Algerian family. Individuals heterozygous
      for this mutation exhibit moderate raise in Hb F levels (0.6-3.5%). Much higher
      Hb F levels (3.8-11.2%) are observed when a beta(o)-thalassemia allele is present
      in trans to the hereditary persistence of fetal hemoglobin allele. This novel
      Algerian HPFH mutation further stresses the importance of the distal CCAAT box in
      the postnatal regulation of gamma-globin gene expression.

PMID- 10335985
TI  - Hb Rio Claro [beta34(B16)Val-->Met]: a novel electrophoretically silent variant
      found in association with Hb Hasharon [alpha47(CE5)Asp-->His] and alpha
      thalassemia-2(-alpha3.7).

PMID- 10335986
TI  - Identification of Hb J-Buda [alpha61(E10)Lys-->Asn] in a Thai female.

PMID- 10335987
TI  - Two new beta-thalassemia mutations: codon 88 (CTG-->C--) and codons 83-86
      (GGC/ACC/TTT/GCC-->GGCC).

PMID- 10335988
TI  - Haplotype analysis of two new, independent cases of Hb Osu-Christiansborg.

PMID- 10335990
TI  - Blood component recalls.

PMID- 10335989
TI  - Hb Siriraj: a G-->A substitution at codon 7 of the beta-globin chain creates an
      MboII cutting site.

PMID- 10335991
TI  - The predictive value of white cell or CD34+ cell count in the peripheral blood
      for timing apheresis and maximizing yield.
AB  - BACKGROUND: The collection of peripheral blood stem and progenitor cells (PBPCs)
      for transplantation can be time-consuming and expensive. Thus, the utility of
      counting CD34+ cells and white cells (WBCs) in the peripheral blood was evaluated
      as a predictor of CD34+ cell yield in the apheresis component. STUDY DESIGN AND
      METHODS: The WBC and CD34+ cell counts in the peripheral blood and the apheresis
      components from 216 collections were assessed. Sixty-three patients underwent
      mobilization with chemotherapy plus filgrastim, and 17 patients and 14 allogeneic
      PBPC donors did so with filgrastim alone. The relationship between the number of
      WBC and CD34+ cells in the peripheral blood and in the apheresis component was
      analyzed by using rank correlation and linear regression analysis. RESULTS: The
      correlation coefficient for CD34+ cells per liter of peripheral blood with CD34+
      cell yield (x 10(6)/kg) was 0.87 (n = 216 collections). This correlation existed
      for many patient and collection variables. However, patients with acute myeloid
      leukemia had fewer CD34+ cells in the apheresis component at any level of
      peripheral blood CD34+ cell count. Components collected from patients with CD34+
      cell counts below 10 x 10(6) per L in the peripheral blood contained a median of
      0.75 x 10(6) CD34+ cells per kg. When the WBC count in the blood was below 5.0 x
      10(9) per L, the median number of CD34+ cells in the peripheral blood was 5.6 x
      10(6) per L (range, 1.0-15.5 x 10(6)/L). A very poor correlation was found
      between the WBC count in the blood and the CD34+ cell yield (p = 0.12, n = 158
      collections). CONCLUSION: The number of CD34+ cells, but not WBCs, in the
      peripheral blood can be used as a predictor for timing of apheresis and
      estimating PBPC yield. This is a robust relationship not affected by a variety of
      patient and collection factors except the diagnosis of acute myeloid leukemia.
      Patients who undergo mobilization with chemotherapy and filgrastim also should
      undergo monitoring of peripheral blood CD34+ cell counts, beginning when the WBC
      count in the blood exceeds 1.0 to 5.0 x 10(9) per L.

PMID- 10335992
TI  - Improved progenitor assay standardization using peripheral blood progenitor cells
      from a donor treated with granulocyte-colony-stimulating factor.
AB  - BACKGROUND: Progenitor assays are the principal method for evaluating
      hematopoietic cell function. The magnitude of assay variability and the assay
      steps contributing to variability were determined, and modifications intended to
      increase assay consistency were evaluated. STUDY DESIGN AND METHODS: Assays were
      performed using a serum-free progenitor assay medium with cells plated at 5.0 x
      10(4) and 1.0 x 10(5) cells per plate. A peripheral blood progenitor cell
      component collected from a normal donor after administration of granulocyte
      colony-stimulating factor was divided into identical aliquots. Each experiment
      involved at least 5 technologists, each performing assays in duplicate on five
      aliquots, with each person scoring all assay plates. Three sample preparation
      methods were tested: 1) ficoll mononuclear cell enrichment and sample dilution,
      2) sample dilution without ficoll separation, and 3) sample dilution without
      ficoll separation, with cell counts performed before and after each dilution
      step, dilution volumes calculated on the basis of each cell count, automated
      electronic pipettors used in dilution steps, and colony frequency calculated on
      the basis of cell counts from the final specimen. RESULTS: Global variability for
      colony-forming units-granulocyte-macrophage, represented by the percentage of CV
      for all specimens and all technologists, was 89.6 percent at 5.0 x 10(4) cells
      per plate and 81.3 percent at 1.0 x 10(5), when ficoll separation was used.
      Subjective differences in scoring plates did not account for most of the
      variability observed, as results for any individual plate read by multiple
      technologists had a mean CV of 15.6 percent and 19.7 percent at the two plating
      concentrations. Method 3 resulted in the greatest improvement, reducing CV to
      24.4 percent at 5.0 x 10(4) cells per plate and to 24.2 percent at 1.0 x 10(5)
      cells per plate. Similar results were obtained for erythroid-burst-forming units.
      CONCLUSIONS: Baseline assay results were extremely inconsistent. Interindividual
      differences in colony interpretation did not contribute significantly to assay
      variability, although sample preparation and plating did. Improved control over
      cell concentration decreased assay variability by 70 to 73 percent.

PMID- 10335993
TI  - The transfusion needs of an autologous bone marrow transplant patient with IgA
      deficiency.
AB  - BACKGROUND: Transfusion management of the patient who is undergoing a marrow or
      peripheral blood stem and progenitor cell transplantation is often challenging.
      The situation is further complicated when the patient is IgA deficient with
      circulating anti-IgA. CASE REPORT: This report describes an approach to
      transfusion therapy primarily using red cells washed by automated techniques and
      cryopreserved autologous plateletpheresis components. Additional platelet support
      was provided with manually washed allogeneic plateletpheresis components.
      Autologous fresh-frozen plasma was collected concurrently, and IgA-deficient
      allogeneic units were ordered and kept in storage, but they were not needed
      during transplantation. The patient experienced no transfusion sequelae as a
      result of the IgA deficiency. CONCLUSION: With this approach, the transfusion
      needs of an IgA-deficient patient were adequately met during bone marrow
      transplantation.

PMID- 10335994
TI  - A feasibility evaluation of an automated blood component collection system
      platelets and red cells.
AB  - BACKGROUND: The purpose of these studies was to evaluate the functional
      properties of blood components collected with an automated collection system.
      STUDY DESIGN AND METHODS: Single-donor platelets (n = 44) and packed red cell
      (RBC) units (n = 10) were collected. In vitro and in vivo assays were used to
      assess the function of single-donor platelet components stored for 5 days and of
      packed RBC units after storage for 42 days at 4 degrees C. RESULTS: Adverse
      events observed in the 44 study subjects were minor. The mean 24-hour recovery
      value for the packed RBC units stored for 42 days was 83.6 +/- 5.4 percent, with
      a mean percentage of hemolysis on Day 42 at 0.46 +/- 0.19 percent. The 25
      patients receiving platelet components achieved a mean corrected count increment
      of 15.1 +/- 10.4 x 10(3). All platelet concentrates had less than 1 x 10(6) total
      white cells. CONCLUSION: Both in vitro and in vivo testing for the packed RBCs
      collected and stored for 42 days met the standards for both hemolysis and
      percentage of 51Cr 24-hour RBC recovery. The in vitro results and transfusion
      data on white cell-reduced platelet components transfused to thrombocytopenic
      patients were comparable to those on available platelet components.

PMID- 10335996
TI  - Blood component recalls in the United States.
AB  - BACKGROUND: United States blood suppliers are required to recall marketed blood
      components later found to be in violation of Food and Drug Administration (FDA)
      regulations for safety, purity, and potency. Many recalled units have already
      been transfused. Analysis of the frequency and nature of blood component recalls
      would be useful for blood suppliers, transfusion services, and physicians. STUDY
      DESIGN AND METHODS: Each blood component recall in the weekly FDA Enforcement
      Report from 1990 through 1997 was examined for the number of units, recall
      reason, and hazard class. Units for manufacturing were excluded. RESULTS: In 8
      years, an estimated 241,800 blood components were recalled, or approximately 1 in
      700 units available to US hospitals. Eighty-eight percent of recalled units were
      in 22 large recalls of over 1000 units each. The most common reasons were
      incorrect testing for syphilis (57% of units) or viral markers (19%), reactive or
      previously reactive donor viral markers (6-11%), and inadequate donor-history
      screening (4%). Twelve units were in the FDA's highest hazard Class I, 24 percent
      were in Class II, and 76 percent were in Class III. Over 43,900 units had HIV
      related problems, but only 3 units involved HIV transmission. Large recalls have
      declined since peaking in 1995, but units in small recalls increased 116 percent
      in 1997 over the previous 7-year average. CONCLUSIONS: Although high-risk recalls
      are rare, many blood component recalls pose medical concerns for physicians and
      patients. The recent decline in large recalls may be due to increased FDA
      oversight, stricter accreditation standards for quality improvement, and more
      centralized donor testing in large specialized laboratories. However, smaller
      recalls, which involve nearly all blood suppliers, were sharply higher in 1997.

PMID- 10335995
TI  - Oral or intravenous iron as an adjuvant to autologous blood donation in elective
      surgery: a randomized, controlled study.
AB  - BACKGROUND: This study was performed to evaluate the capacity of oral and
      intravenous (i.v.) iron administration during autologous blood donation (ABD) to
      improve the efficacy of ABD and to prevent the need for allogeneic blood
      transfusion in patients without iron deficiency who are undergoing major elective
      surgery for which a minimum of 3 autologous units have been ordered. STUDY DESIGN
      AND METHODS: One hundred twenty-three patients were enrolled in an open-labeled,
      randomized, controlled trial and assigned to three treatment groups: patients in
      Group 1 received 3 x 100 mg of Fe2+ per day given orally for 5 weeks before
      operation; patients in Group 2 received 200 mg of Fe3+ given intravenously after
      each donation combined with initial i.v. iron supplementation in patients with
      hemoglobin under 15 g per dL; and patients in Group 3 were in the control group
      that received no iron medication. A modest ABD program involving weekly
      phlebotomy and threshold hemoglobin values for donation of 11.5 g per dL in women
      and 12.0 g per dL in men was performed. RESULTS: Ninety patients, 15 women and 15
      men in each of the three groups, completed the study. The mean net red cell
      production during ABD was no higher (p>0.2) in the iron-treated groups (Group 1:
      473 +/- 178 mL; Group 2: 436 +/- 170 mL; Group 3 (controls): 397 +/- 174 mL). The
      mean number of autologous units donated per patient did not differ (p>0.7) among
      the groups (Group 1: 3.1 +/- 0.6; Group 2: 2.9 +/- 0.7; Group 3: 3.0 +/- 0.7).
      The proportion of patients who needed allogeneic blood transfusion showed no
      significant (p>0.4) advantage for iron treatment, (Group 1: 7%; Group 2: 20%;
      Group 3: 10%). CONCLUSION: In non-iron-deficient patients undergoing modest ABD
      without erythropoietin therapy, neither oral nor i.v. application of iron during
      the preoperative period enhances the success of preoperative ABD.

PMID- 10335997
TI  - Cost-effectiveness of transfusing virus-inactivated plasma instead of standard
      plasma.
AB  - BACKGROUND: Virus inactivation of plasma intended for transfusion avoids the
      transmission of hepatitis B virus, hepatitis C virus, and HIV. However, because
      most plasma recipients also receive other blood components concomitantly, the
      procedure reduces but cannot eliminate the risk of transfusion-transmitted
      infection. As virus-inactivated plasma has just been licensed in the United
      States and other countries, a cost-effectiveness analysis is pertinent. STUDY
      DESIGN AND METHODS: A Monte Carlo simulation of a Markov model representing the
      possible outcomes of plasma recipients was used to derive costs and utilities of
      transfusing virus-inactivated plasma instead of standard plasma. Probability
      distributions for patients' age and sex and for the number of blood components
      transfused per case were determined in 924 plasma recipients in a tertiary-care
      hospital. Other values were obtained from the medical literature. Results of the
      baseline and sensitivity analyses are the mean (+/- SD) of 10 simulations with
      10(7) patients per simulation. RESULTS: In the baseline analysis, transfusing
      virus-inactivated plasma instead of standard plasma prolonged the quality
      adjusted survival by 1 hour and 11 minutes per patient, at a cost-effectiveness
      ratio of $2,156,398 +/- $257,587 per quality-adjusted life year gained. Cost
      effectiveness was most sensitive to the patients' mean age, the incremental cost
      per unit of virus-inactivated plasma, the HIV and hepatitis C virus transmission
      rates, and the short-term mortality of plasma recipients due to their underlying
      diseases. CONCLUSIONS: Compared to most accepted medical procedures, the
      transfusion of virus-inactivated plasma produces little health benefit at a very
      high cost. This poor cost-effectiveness ratio is due to the low current risk of
      infection with transfusion-transmitted viruses and to the greater age and poor
      short-term prognosis of most plasma recipients.

PMID- 10335998
TI  - Effect of 24-hour whole-blood storage on plasma clotting factors.
AB  - BACKGROUND: The current requirements for the preparation of fresh-frozen plasma
      within 8 hours of whole-blood collection were designed to maintain clotting
      factor activities. These requirements, however, limit the production of fresh
      frozen plasma in a large blood center. There are few data on the effect of the
      extension of CPD whole-blood storage to 24 hours on clotting factor activity.
      STUDY DESIGN AND METHODS: A 500-mL unit of whole blood was collected from 10
      volunteer donors. At 1 hour after collection, a plasma sample was separated by
      centrifugation, and each unit was equally divided into 2 half-units, with 1 half
      unit stored at 4 degrees C (range, 1-6 degrees C) and 1 half-unit stored at 22
      degrees C (range, 20-24 degrees C) for 8 hours after collection. Each half-unit
      was then placed at 4 degrees C for further storage for 16 hours. At 8 and 24
      hours after collection, plasma samples were separated from each half-unit. All
      plasma samples were frozen at -18 degrees C. Factors V, VII, VIII, and X;
      fibrinogen; antithrombin III; protein C; and protein S were measured. RESULTS: No
      significant changes were noted in factors V, VII, and X; fibrinogen; antithrombin
      III; protein C; and protein S over the 24-hour storage period. Factor VIII in
      both half-units was significantly reduced, by 13 percent, from the baseline
      sample as compared to the level in the 8-hour storage sample (p<0.05). Factor
      VIII was further reduced by 15 to 20 percent after the 24-hour storage period
      (p<0.05). CONCLUSION: The coagulation factor activity for all factors measured,
      with the exception of factor VIII, showed no significant change over the 24-hour
      storage period. Factor VIII was significantly decreased by 13 percent in 8-hour
      storage and by an additional 15 to 20 percent in 24-hour storage. For clinical
      situations not requiring the replacement of factor VIII only, 24-hour frozen
      plasma has properties comparable to those of fresh-frozen plasma.

PMID- 10335999
TI  - Storage of whole blood before separation: the effect of temperature on red cell
      2,3 DPG and the accumulation of lactate.
AB  - BACKGROUND: Although whole blood intended for component preparation is commonly
      left to cool at ambient temperature, knowledge is insufficient as to the effects
      this may have on red cell quality, in particular after a prolonged hold. STUDY
      DESIGN AND METHODS: Whole blood collected in ACD-A (7% wt/wt) and CPD (12% wt/wt)
      was incubated at 4, 10, 15, 20, 25, and 30 degrees C for 24 hours. Blood gases,
      pH, bicarbonate, glucose, lactate, and red cell 2,3 DPG were investigated.
      RESULTS: When the blood was stored at 30 degrees C, the 2,3 DPG concentration
      decreased within 4 hours from 858 +/- 106 to 316 +/- 172 mmol per mol of
      hemoglobin (a 63% decrease); 99 percent was lost within 18 hours. At 25 degrees
      C, 46 percent was lost within 4 hours and 94 percent within 18 hours; at 20
      degrees C, the decrease at 18 hours was 62 percent and that at 15 degrees C was
      24 percent. No loss of 2,3 DPG was observed at 4 degrees C and 10 degrees C
      storage. No difference was attributable to the anticoagulant used. After 24
      hours, the lactate concentration at 15 degrees C was 2.9 times the original, that
      at 20 degrees C was 3.8 times the original, that at 25 degrees C was 7.0 times,
      and that at 30 degrees C was 9.2 times. CONCLUSIONS: With current anticoagulants,
      storage of whole blood at temperatures of 25 to 30 degrees C before separation
      causes a great and rapid loss of 2,3 DPG and an accumulation of acid metabolites.
      In a hold of blood for >4 hours, rapid cooling is desirable to avoid initial loss
      of 2,3 DPG.

PMID- 10336000
TI  - Effects of filtration and gamma radiation on the accumulation of RANTES and
      transforming growth factor-beta1 in apheresis platelet concentrates during
      storage.
AB  - BACKGROUND: Platelet-derived biologic response modifiers (BRMs) including RANTES
      and transforming growth factor (TGF)-beta1 accumulate in platelet components
      during storage because of platelet activation, and they may play a causative role
      in nonhemolytic febrile transfusion reactions. The majority of PCs with high unit
      values are provided by single donor apheresis in Japan. STUDY DESIGN AND METHODS:
      RANTES and TGF-beta1 levels in platelet units prepared from single-donor
      apheresis platelet concentrates (apheresis PCs) and units from whole blood (buffy
      coat PCs) were investigated. The effects of prestorage and poststorage filtration
      and gamma radiation on the levels of RANTES and TGF-beta1 in the supernatant of
      apheresis PCs during storage were also examined. RESULTS: The levels of RANTES
      and TGF-beta1 increased during storage from Day 0 to Day 5. The levels of RANTES
      and of TGF-beta1 correlated with the platelet concentration (p<0.01), but not
      with the residual white cell concentration in apheresis PCs that were not white
      cell reduced by filtration (p>0.05). In addition, there was a correlation between
      RANTES and TGF-beta1 levels (p<0.01). In white cell-reduced apheresis PCs using
      negatively charged filters as well as in gamma-radiated apheresis PCs, the levels
      of these two BRMs-did not differ at any storage time from those of untreated
      apheresis PCs. Filtration of apheresis PCs with negatively charged filters after
      3 days of storage significantly (p<0.05) reduced the levels of RANTES, but not of
      TGF-beta1. There was no reduction in the levels of RANTES and TGF-beta1 levels by
      positively charged filters. The RANTES levels in buffy coat PCs were slightly
      higher than but not significantly different from those of apheresis PCs during
      storage, except for the level on Day 1. There were no differences in the TGF
      beta1 levels in apheresis and buffy coat PCs during storage. CONCLUSION:
      Prestorage filtration and gamma radiation had neither preventive effects on the
      accumulation of RANTES and TGF-beta1 nor adverse effects on platelet activation.
      Negatively charged filters might be useful for the reducing the levels of RANTES
      in stored apheresis PCs.

PMID- 10336001
TI  - Effects of nitric oxide on platelet activation during plateletpheresis and in
      vivo tracking of biotinylated platelets in humans.
AB  - BACKGROUND: The use of platelet transfusions has risen considerably over the last
      few years, which leads to the collection and transfusion of a greater number of
      donor plateletpheresis units. Plateletpheresis activates platelets in platelet
      concentrates, which determines the degree of the storage lesion subsequently
      observed. STUDY DESIGN AND METHODS: As nitric oxide (NO) is a potent inhibitor of
      platelet aggregation and activation, a placebo-controlled crossover trial was
      performed in healthy young male volunteers to determine whether the NO-donating
      compound, sodium nitroprusside (SNP), decreases platelet activation during
      apheresis and whether activated (p-selectin+) platelets circulate in vivo after
      transfusion. The study also investigated whether nonradioactive biotin labeling
      of apheresis platelets is feasible for the study of platelet recovery after
      transfusion in humans. RESULTS: Platelet activation increased after
      plateletpheresis in the platelet components, but SNP did not inhibit platelet
      activation during apheresis, as measured by the percentage of p-selectin
      expression and the secretion of soluble p-selectin and RANTES. Only a minor
      increase in p-selectin+ platelets was seen in peripheral blood at 60 minutes
      after transfusion of the platelets, a rise that was considerably less than that
      calculated in p-selectin+ platelets if they all were recovered as activated
      platelets after transfusion. Biotin-labeled platelets averaged 1.5 percent at 10
      minutes after transfusion and increased slowly to 2.6 and 3.4 percent after 60
      minutes and 24 hours, respectively (p<0.05). CONCLUSION: SNP does not decrease
      platelet activation during apheresis and subsequent storage, and only a minor
      proportion of activated (p-selectin+) platelets circulate after transfusion in
      men. Moreover, biotin labeling of PCs can safely be used in humans for the study
      of platelet recovery after transfusion, and measuring recovery at 1 hour may lead
      to an underestimation of the true recovery when activated platelets are
      transfused.

PMID- 10336002
TI  - Evaluation by enzyme-linked immunosorbent assay of IgG anti-D and IgG subclass
      concentrations in immunoglobulin preparations.
AB  - BACKGROUND: Anti-D immunoglobulin preparations are injected to prevent hemolytic
      disease of the newborn. The concentration of IgG anti-D in these preparations is
      usually determined by an automated hemagglutination technique using as a
      reference a calibrated preparation of anti-D, but the method requires special
      equipment and cannot be routinely applied to measure the IgG subclasses of anti-D
      in these preparations. STUDY DESIGN AND METHODS: Taking advantage of a recently
      described enzyme-linked immunosorbent assay (ELISA) for the determination of the
      anti-D concentration in sera of alloimmunized pregnant women, IgG anti-D and IgG
      subclass concentrations were measured in the international reference preparation
      (IRP) coded 68/419, 10 anti-D immunoglobulin preparations, and sera of 15 D
      immunized volunteers. RESULTS: An IgG anti-D concentration of 61.5 +/- 4.8 microg
      per ampoule (mean +/- SD) was found by ELISA in IRP 68/419. This result was in
      agreement with previous determinations obtained by radioimmunoassay (60
      microg/ampoule). The IgG subclass concentration of anti-D in this preparation was
      48.4 microg of IgG1 (78.6%), 3.0 microg of IgG2 (4.8%), 9.7 microg of IgG3
      (15.8%), and 0.4 microg of IgG4 (0.7%). The mean proportion of IgG subclasses of
      anti-D in 10 immunoglobulin preparations was similar (81.7% for IgG1, 5.0% for
      IgG2, 12.7% for IgG3, and 0.6% for IgG4). In the sera of 15 immunized volunteers,
      the IgG anti-D concentration varied from 3.1 to 68.4 microg per mL. The mean IgG
      subclass composition of anti-D was 79.3 percent for IgG1, 2.2 percent for IgG2,
      18.1 percent for IgG3, and 0.4 percent for IgG4. The proportions of IgG3 anti-D
      in these sera were found to range between 1 percent and 87 percent, as in the
      sera of D-alloimmunized pregnant women. CONCLUSION: ELISA provides an alternative
      to the radioimmunoassay and the automated hemagglutination technique. In
      addition, it allows the evaluation of the absolute concentration of each IgG
      subclass of anti-D in immunoglobulin preparations and necessitates only the
      conventional equipment required for an immunoenzymatic assay.

PMID- 10336003
TI  - Infection by an unenveloped DNA virus associated with non-A to -G hepatitis in
      Japanese blood donors with or without elevated ALT levels.
AB  - BACKGROUND: An unenveloped, single-stranded DNA virus named TT virus has been
      found in association with elevated alanine aminotransferase (ALT) levels in
      recipients of transfusions and has been detected frequently in patients with
      acute or chronic hepatitis of non-A to -G etiology in Japan. DNA of the TT virus
      was searched for in blood donors with or without elevated ALT levels. STUDY
      DESIGN AND METHODS: A total of 861 blood donors without previous transfusions and
      who were negative for markers of hepatitis B or C virus infection were tested.
      DNA of the TT virus was detected by polymerize chain reaction with hemi-nested
      primers. RESULTS: TT virus DNA was detected in 62 of 280 (22.1% [95% CI: 18.1
      26.6]) donors with elevated ALT levels (mean +/- SD, 89.3 +/- 36.4 U/L; range, 61
      301 U/L), which is significantly more frequently (p<0.02) than its detection in
      91 of 581 (15.7% [95% CI: 13.2-18.4]) donors with normal ALT (< or = 45 U/L). The
      frequency of TT virus DNA increased with age, in donors with and without elevated
      ALT. CONCLUSION: The detection of TT virus DNA, at a frequency higher in donors
      with elevated ALT than in those without, strengthens the association of TT virus
      with non-A to -G hepatitis.

PMID- 10336004
TI  - Demonstration of drug-dependent antibodies in two patients with neutrophenia and
      successful treatment with granulocyte-colony-stimulating factor.
AB  - BACKGROUND: Many drugs have been reported as being capable of inducing immune
      neutropenia, but the causative drug-dependent antibodies were rarely
      demonstrated. STUDY DESIGN AND METHODS: This report describes the results of
      serologic testing and treatment in two children with immune neutropenia related
      to cefotaxime and metamizole, respectively. Serum samples were tested in the
      presence and the absence of the drugs using the granulocyte agglutination test
      (GAT), the granulocyte immunofluorescence test (GIFT), and the monoclonal
      antibody-specific immobilization of granulocyte antigens (MAIGA) assay. RESULTS:
      The serum of one child contained cefotaxime-dependent antibodies that were
      detectable by the GAT and the MAIGA assay, but not by the GIFT. The serum of the
      other child gave positive reactions in the GAT and GIFT due to HLA antibodies and
      in the MAIGA assay only in the presence of metamizole. While cefotaxime-dependent
      antibody was directed against CD16, the metamizole antibody was directed against
      CD11b and CD35. The administration of granulocyte-colony-stimulating factor led
      to an abrupt increase in circulating neutrophils in both cases. CONCLUSION: The
      use of more than one technique is necessary for detection of drug-dependent
      antibodies against neutrophils, and early administration of granulocyte-colony
      stimulating factor may result in fewer complications in these patients.

PMID- 10336005
TI  - Anti-G in a pregnant patient.
AB  - BACKGROUND: Anti-G is a red cell (RBC) antibody of the Rh system. It has been
      described in pregnant women only in association with anti-D or anti-C; therefore,
      the ability of this antibody alone to cause hemolytic disease of the newborn is
      uncertain. One case in which this antibody caused no clinical sequelae is
      reported. CASE REPORT: The patient was a 35-year-old primigravida with type O, D
      , C-, E-, c+ RBCs who was given 4 units of type O, D- allogeneic RBCs and 2 units
      of autologous RBCs 2 years antepartum. She was found to have anti-D and anti-C by
      an outside laboratory as part of a routine prenatal work-up. Further evaluation
      by our laboratory revealed the presence of anti-G and possible anti-C without
      anti-D. Titers at 22 weeks' gestation were 64 against r'r RBCs and 16 against
      R2R2 RBCs; these remained unchanged throughout the pregnancy. Amniocentesis
      performed at Weeks 28 and 32 showed no evidence of hemolytic disease of the
      newborn. A healthy 3.3-kg infant was delivered at 36 weeks' gestation.
      Prophylactic Rh immune globulin was administered antepartum and postpartum. The
      infant's RBCs were type O, D+, c+ C-, E-, and the direct antiglobulin test was
      positive. An acid eluate prepared from the baby's RBCs revealed anti-G. The total
      bilirubin was 5.5 mg per dL at birth, and the hematocrit was 66 percent. Total
      bilirubin peaked on Day 5 at 11.9 mg per dL, and no therapeutic intervention was
      required. CONCLUSIONS: Anti-G alone caused little if any fetal or neonatal
      hemolysis in this case. Although further study is needed, invasive fetal
      monitoring may be unnecessary if anti-G is the sole cause of fetomaternal RBC
      incompatibility.

PMID- 10336006
TI  - Transfusion medicine in philately.

PMID- 10336007
TI  - Mild hemolytic disease of the newborn due to anit-Go(a)

PMID- 10336008
TI  - Polyethylene glycol-induced immunoglobulin precipitation may cause invalidation
      of antiglobulin tests.

PMID- 10336009
TI  - False-positive and false-negative results of sterility testing of stored platelet
      concentrates.

PMID- 10336010
TI  - Creutzfeldt-Jakob disease targeted lookback.

PMID- 10336011
TI  - Unstable angina in a peripheral blood stem and progenitor cell donor given
      granulocyte-colony-stimulating factor.

PMID- 10336012
TI  - Acquired B antigen in a volunteer blood donor.

PMID- 10336013
TI  - The major histocompatibility complex: an important factor in every stage of
      pregnancy from preimplantation to birth? Part I.

PMID- 10336014
TI  - Influence of human leukocyte antigen and tumour necrosis factor genes on the
      development of pre-eclampsia.
AB  - Pre-eclampsia is a syndrome with a strong familial component. Autosomal recessive
      inheritance acting only in the mother is not consistent with the epidemiological
      data, and a more complex genetic susceptibility, involving interactions between
      maternal and fetal genomes, seems likely. The human leukocyte antigen (HLA)
      system has been implicated, but many of the findings reported have been
      inconsistent or contradictory. Pre-eclampsia is unlikely to be the simple result
      of excessive HLA-class II antigen sharing between mother and fetus, as was first
      thought, but a more complex mechanism involving feto-maternal compatibility
      cannot be excluded. The reported increase in HLA-DR4 in mothers and babies from
      pre-eclamptic pregnancies has not been independently confirmed for mothers, and
      no further studies have been conducted with babies. Consequently, the allegedly
      stronger relationship with HLA-DR4 sharing between mother and fetus has neither
      been confirmed nor refuted. Certain (B44-DR7)-containing haplotypes appear to
      confer increased risk for pre-eclampsia on the basis of independent analyses of
      American and Scottish populations. HLA-DR53 may be associated with the
      antiphospholipid antibody syndrome, which is itself a strong risk factor for pre
      eclampsia. The tumour necrosis factor (TNF)-alpha allele, TNF1, may be associated
      with pre-eclampsia and certainly elevated concentrations of the cytokine appear
      to be a feature of the disease. The inducibility of TNF-alpha is HLA-class II
      dependent, and the relevance of HLA-class II genes might be entirely in relation
      to TNF-alpha synthesis and secretion.

PMID- 10336015
TI  - Studies of HLA, fertility and mate choice in a human isolate.
AB  - The role of human leukocyte antigen (HLA) genes in pregnancy and in human mate
      choice has been investigated in the Hutterites, an inbred population of European
      origins. High-resolution HLA haplotypes were defined by alleles at 16 loci in
      >1000 Hutterites. Prospective studies of pregnancy outcome previously
      demonstrated increased fetal loss rates among Hutterite couples matching for HLA
      B antigens (P = 0.033) or for the entire 16-locus haplotype (P = 0.002). Among
      living children of couples matching for HLA-B or for the haplotype, there was a
      non-significant deficit of children who were heterozygous and compatible with the
      mother; the number of living children who were compatible and homozygous or
      incompatible and heterozygous was not different than expectations (HLA-B, P =
      0.095; haplotype, P = 0.376). Mate choice among 411 couples was non-random with
      respect to the HLA haplotype, assessed by a variety of methods (P = 0.020 to
      <0.001). These combined data indicate a role for HLA region genes in both
      pregnancy outcome and mate choice, and suggest that selection acting on these
      genes occurs pre-conceptually as well as during pregnancy. This review outlines
      previously published studies on HLA, fertility and mate choice in the Hutterites.

PMID- 10336016
TI  - Expression of mitochondrial marker proteins during spermatogenesis.
AB  - Spermatogenesis is a highly complex, hormonally regulated cytodifferentiation
      process finally leading to the production of spermatozoa. In addition to other
      events germ cell differentiation is characterized by a gradual structural
      modification of many organelles including mitochondria which play a unique role.
      The morphological and functional development of germ cell mitochondria is a
      reflection of the permanent change in the testicular microenvironment which
      occurs when the germ cells are slowly moving from the base of the seminiferous
      epithelium to the lumen. Concomitant with the structural changes, several
      mitochondrial proteins are known to be expressed and synthesized during distinct
      phases of the organelle's development. This review pays particular attention to
      these transiently expressed mitochondrial proteins such as hsp60, Lon protease,
      sulphydryl oxidase and cytochrome ct. Furthermore, the biological function of
      this stepwise gene activation during mitochondrial and germ cell development is
      discussed.

PMID- 10336017
TI  - Developmental and genetic disorders in spermatogenesis.
AB  - The most common cause of male infertility is idiopathic. Fresh insights based on
      genetic and molecular analysis of the human genome permit classification of
      formerly unexplained disorders in spermatogenesis. In this article, we review new
      procedures that expand diagnostic and therapeutic approaches to male infertility.
      Recombinant DNA technology makes it possible to detect specific chromosomal
      and/or genetic defects among infertile patients. The identification of genes
      linked to disorders in spermatogenesis and male sexual differentiation has
      increased exponentially in the past decade. Genetic defects leading to male
      factor infertility can now be explained at the molecular level, even though the
      germ cell profile of infertile patients is too variable to permit classification
      of the clinical phenotype. Increasing knowledge of genes that direct
      spermatogenesis provides important new information about the molecular and
      cellular events involved in human spermatogenesis. Molecular analysis of
      chromosomes and/or genes of infertile patients offers unique opportunities to
      uncover the aetiology of genetic disorders in spermatogenesis. Increasing numbers
      of cases, previously classified as idiopathic, can now be diagnosed to facilitate
      the treatment of infertile men. Advanced knowledge also poses ethical dilemmas,
      since children conceived with assisted reproductive technologies such as
      intracytoplasmic sperm injection (ICSI) are at risk for congenital abnormalities,
      unbalanced complements of chromosomes and male infertility.

PMID- 10336018
TI  - Recent biochemical approaches to post-testicular, epididymal contraception.
AB  - Results from recent animal models with implications for putative human male
      contraceptives acting on the epididymis are reviewed. Inducing sterility by
      enhancing sperm transport through the epididymis has not been achieved. The
      induction of infertility in males of several species is easier to achieve by
      direct actions of drugs on sperm function (e.g. inhibition of sperm-specific
      isoenzymes of the glycolytic pathway by chloro-compounds) than by indirectly
      reducing amounts of epididymal secretions normally present in high concentration
      (e.g. alpha-glucosidase, L-carnitine). The former show promise for the clinic
      since human spermatozoa are susceptible to inhibition. On the other hand, the
      infertile male mice of the c-ros knock-out model demonstrate the influence of
      even a small region of the epididymis on fertility, so that targeting the as yet
      unknown epididymal factors presumably secreted in limiting amounts by this
      epididymal segment, is a new lead for a contraceptive. Targeting a specific sperm
      protein acquired in the testis, but depleted in the epididymis by toxicants that
      induce rapid infertility, may also lead to the discovery of new contraceptives,
      but these will require developing new means of organ-specific delivery of
      contraceptive drugs.

PMID- 10336019
TI  - The role of intra-ovarian interactions in the regulation of follicle dominance.
AB  - The processes that precisely control the selection of ovulatory follicles from a
      growing cohort are poorly understood. This reduction in follicle number occurs
      through several phases of selection, consequently we limit the use of the term
      'selection' to the first major reduction of growing follicles, at the pre- to
      early antral stage. The final process of selection, achieving the appropriate
      ovulatory number, is referred to as 'dominance'. We discuss possible mechanisms
      that could bring about these reductions and highlight intra-ovarian involvement,
      particularly via follicle-follicle interactions. Analogies are drawn between
      local ovarian events and processes commonly reported in the determination of cell
      fate in developmental biology. Two facets of intra-follicular interactions are
      proposed: initially that follicle-follicle interactions mediate early selection
      processes at the preantral stage, and later that during antral development
      dominant follicles directly affect the fate of the subordinate cohort members.

PMID- 10336020
TI  - Leptin, polycystic ovaries and polycystic ovary syndrome.
AB  - As soon as leptin was discovered four years ago, its potential as a player in the
      polycystic ovary syndrome (PCOS) was explored in a primitive way, though little
      light was shed on the enigma that is PCOS. As a second wave of leptin research is
      now available, we review how the expanded role of the cytokine in reproduction
      might yet impact upon our understanding of PCOS.

PMID- 10336021
TI  - The role of sperm morphology in assisted reproduction.
AB  - This article attempts to evaluate the value of sperm morphology in assisted
      reproduction by summarizing a recent structured literature review covering the
      topic. New developments in the field of sperm morphology with emphasis on
      computer evaluation of morphology and its latest clinical application are
      highlighted, as well as the correlation between sperm functional tests and sperm
      morphology. Based on the correlation between the sperm functional tests and sperm
      morphology, as well as the latter's proven value as a predictor in in-vitro
      fertilization, one can assume that sperm morphology reflects function, although
      based on definition it is not a sperm functional test per se. The evaluation of
      sperm morphology by strict criteria is a simple, cost-effective method and can be
      used to guide the clinician and scientist on a day-to-day basis to make sound
      clinical decisions.

PMID- 10336022
TI  - The epidemiology of multiple births.
AB  - On the basis of MEDLINE and manual searches, we examined the main papers in the
      English literature regarding risk factors for spontaneous (i.e. not related to
      fertility drug use) multiple births. The constant frequency of monozygotic (MZ)
      pregnancies over time and in different geographical areas suggests that the
      determination of MZ twins is largely unchanged over time, and that a genetic
      mechanism may have a role. In contrast, temporal and geographical trends observed
      in dizygotic (DZ) pregnancies suggest that environmental factors play a role in
      determining this condition. At present, maternal age and hereditary components
      are the best-defined determinants for spontaneous multiple births.

PMID- 10336023
TI  - Central lamellar keratoplasty for optical indications.
AB  - PURPOSE: This study aims to evaluate the results of lamellar keratoplasty (LKP)
      for optical (nontectonic) indications over the past 19 years at our institution,
      noting the advantages and pitfalls of the procedure. METHODS: The study is a
      retrospective review of 52 central LKPs in 37 patients. Snellen visual acuity,
      preoperative clinical indications, and postoperative status of the cornea (donor
      graft, graft-host interface, and recipient cornea) were assessed. RESULTS:
      Postoperative follow-up ranged from 3 months to 18 years (median, 3 years). In
      descending order of frequency, corneal dystrophies, aniridic keratopathy, corneal
      scars, and keratoconus were the most common indications for surgery. After
      surgery, 38% of the eyes were able to achieve 20/50 or better visual acuity. The
      two most common causes of poor visual acuity were (1) opacification and/or blood
      vessel growth in the graft-host interface or on the graft surface and (2) high
      astigmatism. Persistent epithelial defects occurred in 21% of the eyes after LKP.
      CONCLUSION: Although LKP provides a safer alternative to penetrating
      keratoplasty, it is limited by vision-reducing graft-host interface problems,
      astigmatism, and difficult surgical technique. We postulate that the current
      results of LKP may be improved by (1) removing as much recipient corneal stroma
      as possible (e.g., dissecting down to Descemet's membrane) or, alternatively,
      using an automated microkeratome and (2) raising the currently used qualitative
      eyebank standards for accepting LKP donor tissue.

PMID- 10336024
TI  - Single culture media in infectious keratitis.
AB  - PURPOSE: To evaluate the usefulness of the various culture media used in the
      traditional workup in infectious keratitis. METHODS: Microbiology data sheets
      from all corneal cultures performed at the University of California Davis Medical
      Center over a 1-year period were reviewed retrospectively. RESULTS: Bacterial
      cultures were sent in 76 cases. In 19 cases, culture specimens from ulcers were
      plated onto blood, chocolate, and inhibitory mold agar and were inoculated into
      an anaerobic medium. In 58 cases, blood and chocolate agar were sent. In 70% of
      cases, blood and chocolate agar provided identical information. Inhibitory mold
      agar was positive twice in 39 plates sent. A fungal pathogen had been identified
      on chocolate agar plates sent for these cases. CONCLUSION: In the evaluation of
      infectious keratitis, plating onto chocolate agar or blood agar alone is a
      reasonable alternative to sending multiple cultures.

PMID- 10336025
TI  - Optical sector iridectomy in corneal opacities.
AB  - PURPOSE: To evaluate the visual outcome after optical sector iridectomy in cases
      of corneal opacities. METHODS: Seventeen eyes of 17 patients with preoperative
      visual acuity of <6/60 in the affected eye underwent sector iridectomy in a
      prospective clinical study at a tertiary eye care center. Of 17 cases, 11 had
      corneal opacities after healed keratitis, four after trauma, and one each due to
      alkali burns or trachoma. The sector iridectomy was undertaken in cases in which
      one sector of the cornea and lens was fairly clear. Success was defined as
      attainment of ambulatory visual acuity of 6/60 or better. RESULTS: Mean age of
      the patients was 32+/-2.3 years. Most eyes had deep vascularized corneal scars
      (13 eyes). Optical sector iridectomy was performed most frequently in the lower
      nasal quadrant (11 eyes) followed by the lower temporal quadrant (four eyes). Of
      17 eyes, 16 achieved a visual acuity of 6/60 or better. No intra-or postoperative
      complications were encountered. CONCLUSION: Optical sector iridectomy in cases of
      corneal opacities is a simple and safe procedure that can improve visual outcome
      and provide ambulatory vision to patients. It is a valuable alternative to
      penetrating keratoplasty if penetrating keratoplasty is not possible or not
      promising for various reasons.

PMID- 10336026
TI  - Corneal topography in atypical pellucid marginal degeneration.
AB  - PURPOSE: Pellucid marginal degeneration (PMD) is commonly described as a
      noninflammatory corneal ectasia typically involving the inferior cornea. Although
      reports of superior corneal changes in PMD exist, the topographic patterns of
      these PMD variants are not well characterized. We describe corneal topographic
      alterations seen in eyes with atypical PMD. METHODS: Computer-assisted
      videokeratography was performed in 10 eyes of five patients with PMD. RESULTS:
      Eight of the eyes studied had changes involving the superior cornea, with or
      without changes in the inferior cornea. Atypical presentations of PMD included
      extension of inferior peripheral thinning above the horizontal meridian and
      occurrence of superior corneal thinning and ectasia with or without typical
      inferior changes. Atypical PMD reveals topographic patterns similar to classic
      PMD, but corneal changes also involve the nasal, temporal, or superior quadrants
      or a combination of these. The topographic maps reflect the location of
      peripheral corneal thinning and extent of corneal protrusion. CONCLUSIONS:
      Corneal topographic changes in atypical PMD are similar to those seen in typical
      PMD but can involve the superior cornea.

PMID- 10336028
TI  - Perforating keratoplasty with an intracorneal ring.
AB  - PURPOSE: We evaluated the clinical feasibility of an intracorneal ring for
      penetrating keratoplasty (PKP) designed to decrease postoperative corneal
      astigmatism. MATERIAL AND METHODS: A steel alloy ring was used for 8-mm PKP. The
      prospective study was comprised of 15 consecutive patients who underwent PKP for
      different corneal pathologies. The mean age was 52 years (range, 20-74 years).
      The Guided Trephine System was used in all cases for the preparation of the donor
      button and the recipient bed to ensure identical dimensions. The donor button
      with the surrounding ring in place was sutured in place with a 10-0 nylon double
      running suture. RESULTS: Except for one patient who had an allergic reaction to
      alloy components, no significant complications were observed. Mean
      reepithelialization occurred within an average of 4 days (range, 3-5 days). In
      80% of the cases, stromal graft edema and Descemet's folds disappeared at 14 days
      after surgery. Average removal time of the intracorneal ring was 6 months (range,
      3-9 months). Mean corneal astigmatism was 2.71 (standard deviation [SD], 1.37)
      diopters (D) before surgery compared to 2.10 (SD, 1.09) D at 1 month, 2.07 (SD,
      1.26) D at 3 months, 2.29 (SD, 0.86) D at 6 months, and 2.94 (SD, 1.05) D at 12
      months. In four eyes (27%), ruptures of one of the double-running antitorque
      sutures required resuturing. CONCLUSION: The intracorneal ring prevented the
      donor button from distortions related to peripheral changes or suture traction. A
      sutured intracorneal ring appears to be a safe and effective aid in
      keratoplasties. Further evaluation in a multicenter study with larger patient
      numbers and indication-specific longer follow-ups is under way.

PMID- 10336027
TI  - Co-occurrence of pneumococcal keratitis and dacryocystitis.
AB  - PURPOSE: To evaluate the specific risk factors responsible for the development of
      pneumococcal keratitis. METHODS: In a retrospective analysis of 383 patients of
      culture-proven bacterial keratitis, seen between 1991 and 1995, 139 had
      monobacterial isolates on culture. We analyzed the various predisposing factors
      in these patients, with special emphasis on the patency of nasolacrimal drainage
      system. RESULTS: Of the 139 patients with monobacterial keratitis, 48 (group 1)
      grew Streptococcus pneumoniae in culture. In the remaining 91 patients (group 2),
      Pseudomonas (18), coagulase-negative Staphylococci (15), Staphylococcus
      epidermidis (23), Staphylococcus aureus (16), Corynebacterium species (12), and
      others (seven) were isolated. Trauma was found to be a predisposing factor in 12
      patients of group 1 and 27 patients of group 2 (p = 0.5601). Twelve (25%)
      patients of group 1 revealed chronic dacryocystitis, and nine of them underwent
      sac excision. On the contrary, only three patients of group 2 demonstrated
      dacryocystitis (p = 0.0003). CONCLUSION: These results underscore the importance
      of assessing the patency of lacrimal drainage system in patients with infectious
      keratitis, especially of pneumococcal origin.

PMID- 10336029
TI  - Ocular surface neoplasia masquerading as chronic blepharoconjunctivitis.
AB  - PURPOSE: To present the clinical characteristics and difficulties in the
      diagnosis of various ocular surface malignancies mimicking features of chronic
      blepharoconjunctivitis and to summarize the current therapeutic approach and
      prognosis of patients. METHODS: Six patients with slowly evolving signs of
      persistent inflammation underwent a conjunctival biopsy after a prolonged course
      of medical treatment. The medical records of the patients were reviewed. RESULTS:
      Histopathologic examination of the biopsy specimens revealed intraepithelial
      squamous neoplasia (one patient), invasive squamous cell carcinoma (one patient),
      sebaceous carcinoma (two patients), and conjunctival lymphoma (two patients).
      CONCLUSION: Although uncommon, ocular surface malignancies may involve the
      conjunctiva diffusely and present as chronic conjunctivitis. A high index of
      suspicion and an early histopathologic examination are essential to not delay
      diagnosis.

PMID- 10336030
TI  - Colonization of hydrogel lenses with Streptococcus pneumoniae: risk of
      development of corneal infiltrates.
AB  - PURPOSE: To report the association between colonization of contact lenses with
      Streptococcus pneumoniae and the observation of corneal infiltrative events in a
      group of patients wearing disposable hydrogel lenses on an extended-wear
      schedule. METHODS: In a prospective clinical trial, 330 patients wore disposable
      hydrogels on a 6-night extended-wear and replacement schedule. The contact lens,
      lid, and conjunctival microbiota of these subjects was analyzed at frequent
      intervals and at the time of an adverse event. RESULTS: Streptococcus pneumoniae
      was an uncommon isolate and was recovered from only one of the 3,763 conjunctival
      samples, five (0.1%) of the 3,764 lid samples, and 33 (0.8%) of the 4,315 contact
      lens samples. Of the 33 lens samples, 10 (30%) were associated with corneal
      infiltrative events. Many of the events were mild inflammatory responses and
      resolved rapidly on discontinuation of lens wear. The presence of S. pneumoniae
      on the contact lens was associated with a significant risk of development of
      corneal infiltrates (odds ratio, 3.0; p = 0.0227, logistic-regression analysis).
      CONCLUSIONS: Presence of S. pneumoniae on hydrogel lenses is a significant risk
      factor for the development of corneal infiltrates.

PMID- 10336031
TI  - Indications for pediatric keratoplasty in India.
AB  - PURPOSE: To study the associations and indications for pediatric keratoplasty.
      METHODS: We undertook a retrospective analysis of 415 grafts performed in 393
      children, aged 12 years or younger between January 1993 and December 1997. The
      parameters evaluated were demographic data, socioeconomic status, preoperative
      diagnosis, and any systemic or ocular associations. RESULTS: Of the 415 eyes
      operated on, 296 (71.32%) eyes underwent keratoplasty for acquired nontraumatic
      corneal opacities, 51 (12.28%) had congenital corneal conditions, 45 (10.85%)
      were regrafts, and 23 (5.54%) eyes had acquired traumatic corneal opacities. The
      cause of corneal opacification in the acquired nontraumatic group was infectious
      keratitis in 215 (72.63%) eyes and keratomalacia in 81 (27.36%) eyes. Systemic
      associations with the onset of the opacity in the acquired nontraumatic group
      were fever in 74 (25%) cases, diarrhea in 56 (18.9%) cases, and malnutrition in
      98 (33.1%) cases. Seventeen (4.32%) children belonged to the lower middle class,
      64 (16.28%) were in the upper lower class, and 312 (79.38%) were from the lower
      socioeconomic families based on the Kuppuswamy scale. CONCLUSIONS: Infectious
      keratitis is the major indication for pediatric keratoplasty in India. In the
      majority of the cases, the occurrence of corneal opacification is associated with
      poverty.

PMID- 10336032
TI  - Lateral tarsorrhaphy: is it preferable to patching?
AB  - PURPOSE: To evaluate the effectiveness of lateral tarsorrhaphy for the management
      of postkeratoplasty epithelial defects. METHOD: Thirty-six patients with
      persistent postkeratoplasty epithelial defects that did not heal despite topical
      medical therapy for a period of 96 hours were treated with either a lateral
      tarsorrhaphy (18 patients) or with tight patching (18 patients). All patients
      were evaluated daily by slit-lamp examination until complete reepithelialization
      occurred. RESULTS: The epithelial healing was significantly faster (7.61+/-0.91
      days vs. 12.6+/-1.61 days, p<0.5) in the lateral tarsorrhaphy group. Further, the
      patients with lateral tarsorrhaphies were significantly more comfortable when
      compared with those of the patching group (p<0.05). CONCLUSION: Lateral
      tarsorrhaphy provides quick symptomatic relief and faster corneal epithelial
      defect healing. Therefore, it may be of benefit in cases of postkeratoplasty
      persistent epithelial defects.

PMID- 10336033
TI  - Evaluation of anterior chamber inflammation after corneal refractive surgery.
AB  - PURPOSE: To prospectively evaluate inflammatory response by measuring aqueous
      flare in the anterior chamber after photorefractive keratectomy (PRK), laser in
      situ keratomileusis (LASIK), and intracorneal ring segments (ICRS) implantation.
      METHODS: Aqueous flare was measured pre- and postoperatively at days 1, 7, and 21
      with a laser flare meter (Kowa FM 500). Thirty-one patients (58 eyes) were
      randomized, only for low myopia, in three groups treated with PRK (myopia <-4.50
      D), LASIK (myopia range between -4.00 and -12.00 D), and ICRS (myopia <-4.50 D).
      RESULTS: Mean preoperative flare intensities were similar in the three groups (p<
      or =0.05; mean, 4.6 photons/ms). In the PRK group, flare increased significantly
      (mean day 2, 9.5 photons/ms), as it did in the LASIK group (mean day 1, 23.8
      photons/ms). In the ICRS group, there was no significant difference between pre-
      and postoperative levels of flare at any time (mean day 1, 4.9 photons/ms). In
      all three groups, flare intensity returned to baseline at day 7, except in the
      LASIK group, which remained at a significantly higher level (mean day 7, 7.7
      photons/ms) than the preoperative one. CONCLUSIONS: According to this method, the
      blood-aqueous barrier seems to be altered in laser procedures, particularly in
      LASIK, probably in correlation with the depth of photoablation. ICRS implantation
      did not increase the postoperative flare significantly.

PMID- 10336034
TI  - Effects of methylprednisolone and cyclosporine A on fungal growth in vitro.
AB  - PURPOSE: The management of corneal transplants after mycotic keratitis often
      poses a therapeutic dilemma. Clinicians are hesitant to use topical steroids
      because of their potential enhancement of fungal growth. This study seeks to
      evaluate the in vitro effects of methylprednisolone and cyclosporine A on the
      growth of various molds that often are responsible for keratomycoses. METHODS:
      Fusarium oxysporum, Fusarium solani, and Aspergillus fumigatus were grown in the
      presence of varying concentrations of methylprednisolone, cyclosporine A, and
      vehicle controls. Fungal growth was evaluated in a masked fashion based on the
      number of colonies and their morphologies. RESULTS: All tested concentrations of
      cyclosporine A (1%, 2%, 4%) had a statistically significant suppressive effect on
      the growth of F. oxysporum (p<0.001) and F. solani (p<0.001) compared with
      methylprednisolone and vehicle control solutions. A dose-dependent decrease in
      the number of colonies grown also was noted for F. oxysporum (p<0.001) and F.
      solani (p<0.001). In the case of A. fumigatus, cyclosporine A significantly
      decreased the colony size (p<0.015) in a dose-dependent fashion. CONCLUSIONS:
      Cyclosporine A appears to have an inhibitory effect on fungal growth in vitro.
      Cyclosporine A may be an important alternative to topical steroids for management
      of corneal transplants after mycotic keratitis.

PMID- 10336035
TI  - Protection of corneal allografts by CTLA4-Ig.
AB  - PURPOSE: CTLA4, a high-affinity ligand of B7, can, in soluble form, prevent
      antigen-driven T-cell activation by blocking CD28-B7 interaction and can thereby
      prevent immune graft rejection. In this study, we tested the capacity of soluble
      CTLA4-Ig alone or in combination with UV-B irradiation to suppress corneal
      allograft rejection in rabbits. METHODS: Corneas from Dutch belted rabbits were
      incubated in corneal storage medium containing 0, 1, 10, 25, or 250 microg/ml of
      CTLA4-Ig for 18 h and were then transplanted into the vascularized or
      nonvascularized corneas of New Zealand White rabbit recipients. A series of donor
      corneas were exposed to UV-B irradiation alone or a combination of irradiation
      and CTLA4-Ig to determine if these two treatments would have an additive effect
      in prolonging graft survival. The fate and clinical condition of the allografts
      were evaluated by slit-lamp photomicroscopic observation and corneal-thickness
      measurements. Grafts that were rejected were processed for histopathologic and
      immunohistochemical analysis to determine the characteristics of cells
      infiltrating the grafts. RESULTS: Grafts placed in nonvascularized corneas showed
      no differences in survival times, regardless of treatment. Among the grafts
      placed in vascularized corneas, those incubated with CTLA4-Ig at a concentration
      of 250 microg/ml failed within 7-14 days. Histopathologic and immunocytochemical
      examination revealed a dense accumulation of immune inflammatory cells,
      especially class II major histocompatibility complex (MHC)-expressing, antigen
      presenting cells, in the failed grafts. Grafts incubated with CTLA4-Ig at
      concentrations of 1 and 10 microg/ml had mean survival times greater than the
      control, untreated corneal allografts. Some of the grafts in these two treatment
      groups survived for the 100-day observation period, whereas none of the grafts in
      the other treatment groups survived to this end point. UV-B irradiated grafts
      incubated with CTLA4-Ig at a concentration of 1 microg/ml appeared to have longer
      survival times and fewer rejections compared with control, untreated grafts and
      grafts treated with UV-B or CTLA4-Ig alone. CONCLUSION: The results show that the
      CTLA4-Ig coreceptor blocking agent can prolong corneal allograft survival in
      vascularized graft sites and that UV-B irradiation followed by incubation in
      CTLA4-Ig may prolong graft survival better than either treatment alone. These
      results suggest that agents that prevent second-signal interaction between
      antigen-presenting cells and T lymphocytes may be useful for inhibiting corneal
      allograft rejection.

PMID- 10336036
TI  - Corneal transport of circulating glutathione in normal and galactosemic guinea
      pigs.
AB  - PURPOSE: To study synthesis and transport of glutathione (GSH) in guinea-pig
      cornea and to determine the effect of galactose feeding and growth on transport.
      METHODS: Steady-state level and maximal rate of synthesis of GSH (GSH-SR) were
      determined in guinea pigs fed 50% galactose diet for 10 days and in controls. By
      using a model of in situ eye perfusion, corneal transport of [35S]GSH (4 nM) and
      [14C]sucrose was measured as a function of time (1-10 min) in normal guinea pigs
      under gamma-glutamyltranspeptidase (GGT)-inhibited and uninhibited conditions.
      The unidirectional constant of GSH uptake was determined as a function of GSH
      concentration in the perfusate. The effect of galactose feeding on corneal uptake
      of tracer GSH was determined in control and 10-day galactose-fed guinea pigs.
      Levels of GSH and uptake of GSH also were measured in corneas from three
      different age groups: 10 days, 4 weeks, and 9 months. RESULTS: The mean GSH level
      (nmol/ mg protein) in corneas of control guinea pigs was 47.6, which decreased to
      36.4 (p<0.05) in 10-day galactose-fed animals. The GSH-SR was not significantly
      different in the two groups (1.98 vs. 2.27 nmol/min/mg protein, respectively; p =
      NS). Corneal uptake of tracer [35S]GSH (4 nM) was linear up to 10 min and was
      several-fold higher than that of the impermeable marker [14C]sucrose. The
      unidirectional rate constant (corrected for sucrose) for GSH was 4.03+/-0.21x10(
      3)/min. GSH uptake in normal guinea pigs occurred by a saturable process with a
      Km of 24+/-4 microM and Vmax of 92+/-14 pmol/min/g and was significantly
      inhibited by GSH and GSH monoethyl ester at 60 microM concentrations. Corneal
      uptake of tracer GSH in galactose-fed guinea pigs showed a dramatic decrease
      (almost to that of sucrose) as compared with control guinea pigs. GSH uptake was
      similar in corneas of 10-day and 4-week-old guinea pigs, whereas that in 9-month
      old guinea pigs showed a significant (approximately 80%) decrease in uptake.
      CONCLUSION: Cellular uptake of GSH by the cornea in the young, adult guinea pigs
      is carrier mediated via mechanism(s) that can be dissociated from the
      transpeptidation pathway. The reduced availability of circulating GSH may be an
      important factor in the development of corneal pathology associated with aging
      and corneal hydration due to relative GSH deficiency.

PMID- 10336037
TI  - Evaluation of the effect of lissamine green and rose bengal on human corneal
      epithelial cells.
AB  - PURPOSE: To examine the effects of lissamine green and rose bengal on
      proliferating human corneal epithelial (HCE) cells in vitro. METHODS: HCE cells
      derived from explants of discarded corneoscleral rims were cultured by the
      standard technique. Experimental cells were exposed to 1, 0.5, or 0.1% of either
      lissamine green or rose bengal for 10 min while control cells were exposed to a
      phosphate buffer solution (PBS). RESULT: Cell viability was 92% greater for 1%
      lissamine green (p = 0.013) and 81.2% greater for 0.5% lissamine green (p =
      0.006) compared to 1 and 0.5% rose bengal, respectively. The difference between
      the effect of 0.1% rose bengal and 0.1% lissamine green on cell viability was not
      statistically significant (p = 0.83). Rose bengal staining of HCE cells was
      immediate and readily detectable with unaided eyes at all three concentrations,
      whereas no observable staining of healthy HCE cells was noted with lissamine
      green. CONCLUSION: Rose bengal adversely affects HCE cell viability and stains
      normal proliferating HCE cells in contrast to lissamine green, which exhibited
      neither of these characteristics. Therefore, we recommend the use of lissamine
      green over rose bengal in evaluating ocular surface disorders.

PMID- 10336038
TI  - Corneal surface temperature change as the mode of stimulation of the non-contact
      corneal aesthesiometer.
AB  - PURPOSE: The non-contact corneal aesthesiometer (NCCA) assesses corneal
      sensitivity by using a controlled pulse of air, directed at the corneal surface.
      The purpose of this paper was to investigate whether corneal surface temperature
      change was a component in the mode of stimulation. METHODS: Thermocouple
      experiment: A simple model corneal surface was developed that was composed of a
      moistened circle of filter paper placed on a thermocouple and mounted on a glass
      slide. The temperature change produced by different stimulus pressures was
      measured for five different ambient temperatures. Thermal camera experiment:
      Using a thermal camera, the corneal surface temperature change was measured in
      nine young, healthy subjects after exposure to different stimulus air pulses.
      Pulse duration was set at 0.9 s but was varied in pressure from 0.5 to 3.5
      millibars. RESULTS: Thermocouple experiment: An immediate drop in temperature was
      detected by the thermocouple as soon as the air flow was incident on the filter
      paper. A greater temperature change was produced by increasing the pressure of
      the incident air flow. A relationship was found and a calibration curve plotted.
      Thermal camera experiment: For each subject, a drop in surface temperature was
      detected at each stimulus pressure. Furthermore, as the stimulus pressure
      increased, the induced reduction in temperature also increased. A relationship
      was found and a calibration curve plotted. CONCLUSION: The NCCA air-pulse
      stimulus was capable of producing a localized temperature change on the corneal
      surface. The principal mode of corneal nerve stimulation, by the NCCA air pulse,
      was the rate of temperature change of the corneal surface.

PMID- 10336039
TI  - Immunohistochemical and ultrastructural analysis of dysplastic epithelium of
      human ocular surface: basement membrane and intermediate filament.
AB  - PURPOSE: The dysplastic corneal epithelium is characterized by the abnormal
      proliferation of epithelial cells. The phenotypes of these cells have not been
      elucidated. We investigated whether such epithelium expresses the phenotypes of
      corneal or conjunctival epithelial cells. METHODS: The corneas and conjunctivae
      from four normal subjects and from one patient with epithelial dysplasia of the
      central cornea were immunostained for IV and VII collagens and for cytokeratins.
      Monoclonal antibodies against collagen IV reacted to the [alpha1(IV)]2alpha2(IV)
      or alpha5(IV) molecule. Anti-cytokeratin antibodies were used to define
      epithelial cell types. The ultrastructure of the basement membrane (BM) of each
      specimen also was examined. RESULTS: Type VII collagen immunoreactivity was
      detected in all the specimens of epithelial BM. The anti-collagen IV
      [alpha1(IV)]2alpha2(IV) antibody labeled the conjunctival BMs, not the BMs of the
      corneal epithelia, of each subject. The normal corneal epithelial BM, not the BM
      of the conjunctival or dysplastic corneal epithelium, was immunolabeled with anti
      alpha5(IV) antibody. The pattern of cytokeratin expression in the corneal
      epithelial dysplasia resembled that seen in the normal conjunctivae. Small breaks
      in the BM of dysplastic corneal epithelium were ultrastructurally revealed. The
      number of hemidesmosomes in the dysplastic corneal epithelium was decreased as
      compared with that in the normal BM. CONCLUSION: The composition of collagen
      types within the BM and the cellular phenotype of the dysplastic epithelium in
      the cornea resembled those of conjunctival epithelium, not of the cornea.

PMID- 10336040
TI  - Evaluation of prior photorefractive keratectomy in donor tissue.
AB  - PURPOSE: To describe a case in which an eye donor had prior bilateral
      photorefractive keratectomies and to elucidate possible methods of evaluation and
      screening of donor tissue. METHODS: Case report. A 62-year-old eye donor was
      reported to have received radial keratotomy before his death. Further
      investigation by the eye bank showed a history of photorefractive keratectomy
      (PRK), not radial keratotomy. The corneas were therefore not used for
      transplantation, and the eyes were evaluated by slit-lamp examination,
      photography, corneal topography, and histology. RESULTS: Slit-lamp and
      photographic examination did not indicate the presence of PRK ablations. Corneal
      topography mapping with the TMS-1 was relatively ambiguous for identifying PRK
      flattening, while multiple data formatting of the cornea with the Orbscan
      resulted in the strongest suggestion of prior PRK. Histologic analysis showed
      central corneal thinning and loss of Bowman's membrane consistent with PRK.
      CONCLUSIONS: In the absence of a positive donor history for PRK, current methods
      of screening donor tissue for prior PRK often are insufficient to exclude these
      corneas from use in transplantation. More refined placido imagery corneal
      topography or newer technologies such as the Orbscan may allow more sensitive and
      specific methods of donor tissue screening.

PMID- 10336041
TI  - Detection of herpes simplex virus in aqueous humor in iridocorneal endothelial
      (ICE) syndrome.

PMID- 10336043
TI  - Cyanoacrylate tissue adhesive augmented tenoplasty: a new surgical procedure for
      bilateral severe chemical eye burns.
AB  - PURPOSE: To report on cyanoacrylate tissue adhesive augmented tenoplasty, a new
      surgical procedure for bilateral severe chemical eye injuries. METHODS: A 26-year
      old man presented with bilateral severe (grade IV) chemical burns involving the
      eye, periorbital tissues, face, and neck. Despite adequate medical therapy,
      corneal, limbal, and scleral ulceration progressed in both eyes. Secondary
      Pseudomonas keratitis necessitated therapeutic penetrating keratoplasty in the
      right eye. Tenoplasty and glued-on rigid gas permeable contact lens were
      unsuccessful to arrest progression of corneolimboscleral ulceration in the left
      eye. We applied n-butyl cyanoacrylate tissue adhesive directly on the ulcerating
      corneal, limbal, and scleral surface to augment tenoplasty. RESULTS: The left
      ocular surface healed with resultant massive fibrous tissue proliferation and
      symblepharon on the nasal side. Ocular surface rehabilitation resulted in a
      vascularized leukomatous corneal opacity with upper temporal clear cornea. The
      patient achieved visual acuity of 6/36 in the left eye. CONCLUSION: We suggest
      that cyanoacrylate tissue adhesive-augmented tenoplasty can be undertaken to
      preserve ocular integrity and retain visual potential in a severe chemical eye
      injury.

PMID- 10336042
TI  - Staphylococcal infection under a LASIK flap.
AB  - PURPOSE: To report a staphylococcal infection under a laser in situ
      keratomileusis (LASIK) flap and to discuss the management of this rare and
      potentially devastating complication. METHODS: A patient was referred to our
      practice having had bilateral LASIK. She was found to have abscesses under the
      left corneal flap. Staphylococcus aureus was identified as the infecting organism
      by corneal scrape and treated with appropriate antibiotics. The cornea improved,
      and then the abscess recurred. The abscess was again scraped and intensive
      treatment reinstituted. RESULTS: After successful treatment, the patient
      recovered excellent visual acuity with only a minimal astigmatic error.
      CONCLUSION: The possible reasons for the apparent improvement and then recurrence
      of the abscess are discussed. The management of this case including the need for
      corneal scrape and antibiotic prophylaxis is discussed in relation to previously
      reported cases.

PMID- 10336044
TI  - Comparing videokeratoscopic systems.

PMID- 10336045
TI  - Preparticipation physical examinations: a collegiate experience.
AB  - OBJECTIVE: To determine the relative frequency of limiting conditions in
      collegiate preparticipation physical examinations. DESIGN: Prospective recording
      of physical examinations over a 2-year period. SETTING: West Virginia University
      Department of Intercollegiate Athletics. PARTICIPANTS: A total of 596 student
      athletes, including 405 men and 191 women, involved in 22 sports at the
      intercollegiate level. MAIN OUTCOME MEASURES: The number of all athletes that
      passed, passed with follow-up or restriction, and failed the preparticipation
      examinations were recorded along with the specific abnormalities that resulted in
      follow-up/restriction or failure. RESULTS: Of the athletes, 512 (85.9%) passed
      without significant medical or orthopedic abnormalities; 83 (13.9%) passed with a
      condition requiring follow-up or restriction; and one (0.2%) failed the
      examination. Medical and orthopedic abnormalities were responsible for 55.4% and
      44.6% of the restricted athletes, respectively. Elevated blood pressure was the
      most common medical condition (47.8%), and knee problems were the most common
      orthopedic abnormality (43.2%). CONCLUSION: Outcome results of collegiate
      preparticipation physical examinations compare favorably with results in high
      school students and support the need for detailed examinations before
      competition. The results also underscore the importance of proper rehabilitation
      of previous injuries.

PMID- 10336046
TI  - Skiing and snowboarding injuries in the children and adolescents of Southern
      Alberta.
AB  - OBJECTIVE: To identify injuries and profile the characteristics of injured skiers
      and snowboarders younger than 18 years of age in Southern Alberta, Canada.
      DESIGN: Case-series over one year. PARTICIPANTS: Injured skiers and snowboarders
      younger than 18 years of age presenting to the ski patrol members at each of
      seven ski areas in Southern Alberta. MAIN OUTCOME MEASURES: Information on
      injured individuals reporting to the ski patrol at the involved areas was
      documented on a standardized injury reporting form. Anonymous information was
      then copied and sent to the University of Calgary Sport Medicine Centre, where
      the data were analyzed. Proportions of injured skiers and snowboarders with
      specific characteristics or participating in specific environmental conditions
      are presented. RESULTS: There were a total of 832 (60.0%) injury reports filed
      for skiers and 557 (40.1%) for snowboarders, reflecting 1,635 separate injuries.
      Head injuries were the most frequently reported (19.1% of all regional injuries).
      The most commonly injured region was the knee among skiers (n = 213; 22.8%) and
      the wrist among snowboarders (n = 173; 27.8%). Lower extremity injuries in skiers
      and upper extremity injuries in snowboarders were most common. Younger male
      skiers and snowboarders reported high proportions of head, neck, and back
      injuries. CONCLUSION: The lower extremity in skiers and the upper extremity in
      snowboarders were most susceptible to injury. A cause for concern is the high
      proportion of head injuries reported for both male skiers and snowboarders of
      younger age groups. Further study into protective equipment design and function
      is required.

PMID- 10336047
TI  - Injuries in commercial whitewater rafting.
AB  - OBJECTIVE: To describe injuries sustained by participants in commercial
      whitewater rafting. DESIGN: Analysis of injury reports submitted by commercial
      outfitters to the West Virginia Division of Natural Resources. PARTICIPANTS:
      Customers of commercial rafting outfitters who sustained injuries in the 1995
      1997 whitewater seasons on the New, Gauley, Cheat, and Shenandoah Rivers and for
      whom injury reports were submitted as required by the West Virginia Legislative
      Rules. RESULTS: A total of 200 rafting injuries were reported from 1995 through
      1997, with a resulting overall injury incidence rate of 0.263 per 1,000 rafters.
      Incidence rates ranged from 0. 145 per 1,000 on the Shenandoah to 0.381 per 1,000
      on the Gauley River. The average age of injured persons was 33.14 years, 53.3%
      were male, and 59.8% had previous rafting experience. The body part most
      frequently injured was the face (33.3%), including the eye (12.1%), mouth (6.6%),
      other facial parts (5.1%), nose (4.5%), and teeth (4.0%), followed by the knee
      (15.3%), arm/wrist/hand (11.6%), other parts of the leg, hip, or foot (10.5%),
      ankle (7.4%), torso (6.8%), shoulder (6.3%), and head/neck (5.3%). Predominant
      injury types included lacerations (32.5%), sprains/strains (23.2%), fractures
      (14.9%), contusions/bruises (9.8%), dislocations (8.2%), and two deaths. On-site
      administration of first aid included bandages (29%), ice (26.9%),
      splinting/immobilization (17.7%), antiseptic (11.3%), direct pressure (4.2%),
      elevation (2.1%), cardiopulmonary resuscitation (1%), and treatment for shock
      (0.4%). No first aid was administered for 4.6% of injuries. Most injuries
      occurred in the raft (51.3%) as a result of collisions among passengers, being
      struck by a paddle or other equipment, or entanglement of extremities in parts of
      the raft; 40.3% of injuries occurred in the water after falling from the raft.
      Types of injuries were independent of where they occurred, but differences were
      found in injured body parts by location of occurrence. Injuries occurring in the
      raft more commonly were to the face, and injuries occurring in the water involved
      the extremities and face. Injuries requiring evacuation to an outfitter's base
      camp or to a medical facility occurred at a higher rate among persons without
      previous rafting experience. Gender differences were not found for types of
      reported injuries, but body part injured did vary by gender. Female boaters more
      frequently sustained facial injuries, whereas male boaters more frequently
      sustained injuries to the limbs and torso. CONCLUSION: Overall injury rates were
      low, but verification limitations render a determination of unreported injuries
      difficult. Because most injuries occur in the raft while running rapids, involve
      injuries to the face, and result from contact among passengers or paddling
      equipment, preventive measures such as attaching face protection to paddling
      helmets, carrying fewer passengers per raft, or portaging dangerous rapids are
      suggested. More research is needed to verify injury rates and severity, and to
      document related medical costs.

PMID- 10336048
TI  - Adolescent growth is not associated with changes in flexibility.
AB  - OBJECTIVE: To determine whether adolescent growth is associated with a decrease
      in flexibility. DESIGN: Longitudinal cohort study of urban high school students.
      MAIN OUTCOME MEASURES: Flexibility of hamstring muscles (popliteal angle),
      quadriceps muscles (quadriceps angle), lumbar extensor muscles (Schober test),
      and combined lower extremity-trunk muscles (Sit and Reach test). RESULTS: There
      was no relation between growth and changes in flexibility for the lumbar flexor
      muscles, hamstring muscles, or muscles involved in the Sit and Reach test.
      Although there was a slight decrease in flexibility of the quadriceps muscle with
      increases in growth, the very low r2adj value (0.01-0.06) strongly suggests that
      growth plays only a small role in determining the flexibility of individuals.
      CONCLUSION: These results strongly suggest that growth is not a cause of
      decreased flexibility during the peripubescent period.

PMID- 10336049
TI  - Intercollegiate ice hockey injuries: a causal analysis.
AB  - OBJECTIVE: The purpose of this study was to explore the relationships of
      position, mechanism of injury, type of injury, and body part injured to days
      lost. DESIGN: A causal analysis within a prospective cohort was used for this
      project. PARTICIPANTS: Seven schools from Hockey East and Eastern Collegiate
      Athletic Conference participated in this project for three consecutive
      competitive seasons. ASSESSMENT OF RISK FACTORS: The independent variables were
      position, mechanism of injury, and body part injured. MAIN OUTCOME MEASURES: The
      dependent variable was days lost due to injury. RESULTS: The entire causal model
      was statistically significant, with the variables of body part injured, mechanism
      of injury, and injury type accounting for 52% of the variance associated with
      days lost. The most important variable related to days lost was injury type and
      accounted for 43% of the variance associated with days lost. We found that
      fractures and dislocations resulted in an average of 22.22 days lost and sprains
      resulted in a mean of 13.61 days lost. CONCLUSION: The causal analysis
      demonstrated that body part injured, mechanism of injury, and injury type are
      important factors related to days lost. Those players who experience a
      fracture/dislocation or sprain of the lower extremity will tend to lose 2 weeks
      or more of participation. Studies such as this are useful in examining the
      multivariate circumstances surrounding an injury episode.

PMID- 10336050
TI  - Anabolic steroid-induced hepatotoxicity: is it overstated?
AB  - OBJECTIVE: There have been numerous reports of hepatic dysfunction secondary to
      anabolic steroid use based on elevated levels of serum aminotransferases. This
      study was conducted to distinguish between serum aminotransaminase elevations
      secondary to intense resistance training and anabolic steroid-induced
      hepatotoxicity in elite bodybuilders. DESIGN: This was a case-control study of
      serum chemistry profiles from bodybuilders using and not using anabolic steroids
      with comparisons to a cohort of medical students and patients with hepatitis.
      PARTICIPANTS: The participants were bodybuilders taking self-directed regimens of
      anabolic steroids (n = 15) and bodybuilders not taking steroids (n = 10). Blood
      chemistry profiles from patients with viral hepatitis (n = 49) and exercising and
      nonexercising medical students (592) were used as controls. MAIN OUTCOME
      MEASURES: The focus in blood chemistry profiles was aspartate aminotransferase
      (AST), alanine aminotransferase (ALT), gamma-glutamyltranspeptidase (GGT), and
      creatine kinase (CK) levels. RESULTS: In both groups of bodybuilders, CK, AST,
      and ALT were elevated, whereas GGT remained in the normal range. In contrast,
      patients with hepatitis had elevations of all three enzymes: ALT, AST, and GGT.
      Creatine kinase (CK) was elevated in all exercising groups. Patients with
      hepatitis were the only group in which a correlation was found between
      aminotransferases and GGT. CONCLUSION: Prior reports of anabolic steroid-induced
      hepatotoxicity based on elevated aminotransferase levels may have been
      overstated, because no exercising subjects, including steroid users, demonstrated
      hepatic dysfunction based on GGT levels. Such reports may have misled the medical
      community to emphasize steroid-induced hepatotoxicity when interpreting elevated
      aminotransferase levels and disregard muscle damage. For these reasons, when
      evaluating hepatic function in cases of anabolic steroid therapy or abuse, CK and
      GGT levels should be considered in addition to ALT and AST levels as essential
      elements of the assessment.

PMID- 10336051
TI  - Is stress radiography necessary in the diagnosis of acute or chronic ankle
      instability?
AB  - BACKGROUND: Clinicians often use the talar tilt (TT) and anterior drawer (AD)
      stress x-rays to diagnose acute or chronic mechanical ankle instability. However,
      the wide range of TT and AD values in normal and injured ankles makes
      interpretation of the test results difficult. OBJECTIVE: To critically review the
      literature and determine the accuracy of stress radiography in the diagnosis of
      mechanical ankle instability. DATA SOURCES: MEDLINE was searched for relevant
      articles published since 1966 using MEDLINE subject headings (MeSH) and textwords
      for English articles related to ankle injuries and radiography. Additional
      references were reviewed from the bibliographies of the retrieved articles. The
      total number of articles reviewed was 67. Of these, 8 studies met criteria for
      inclusion and were analyzed. STUDY SELECTION: Only clinical studies that used
      surgical exploration as the gold standard for diagnosing lateral ligament rupture
      were evaluated for this study. Cadaver or laboratory studies were excluded. DATA
      EXTRACTION AND SYNTHESIS: In reviewing the literature, pertinent strengths of the
      different study designs were emphasized. From these data, particular attention
      was paid to the diagnostic accuracy of each study in comparing TT and AD stress x
      rays to surgical confirmation of lateral ligament rupture. MAIN RESULTS: A total
      of eight prospective clinical series satisfied the inclusion criteria. Seven of
      the eight assessed acute ankle instability as the outcome and one assessed
      chronic ankle instability. Of the seven studies that focused on acute ankle
      injuries, only one concluded significant benefit in using stress views to
      diagnose lateral ligament rupture. Three of the seven reported a positive
      relationship between stress radiography and surgical findings, although all six
      studies concluded that TT and AD stress x-rays are not reliable enough to make
      the diagnosis. The authors who assessed chronic ankle instability stated that TT
      and AD stress views combined were not useful in defining ankle instability.
      CONCLUSION: The published data regarding TT and AD stress x-rays are too variable
      to determine accepted normal values compared with injured values. There are
      insufficient data for comparison of the use of mechanical versus manual
      techniques, or use of local anesthetic to facilitate the stress test. Because the
      treatment evolution of all acute ankle sprains is toward functional nonoperative
      treatment and because treatment does not depend on the degree of ankle
      instability on stress views, the TT and AD stress x-rays have no clinical
      relevance in the acute situation. In cases of chronic instability, the large
      variability in TT and AD values in both injured and noninjured ankles precludes
      their routine use.

PMID- 10336052
TI  - Exercise-associated hypogammaglobulinemia.

PMID- 10336053
TI  - Spontaneous rupture of plantar fascia.

PMID- 10336054
TI  - Elevated expression of p21ras is an early event in Alzheimer's disease and
      precedes neurofibrillary degeneration.
AB  - Alzheimer's disease is a chronic degenerative disorder characterized by the
      intracellular accumulation of "paired helical filaments" consisting of highly
      phosphorylated tau and by extracellular deposits of aggregated Abeta-peptide.
      Furthermore, neurodegeneration in Alzheimer's disease is associated with the
      appearance of neuritic growth profiles that are aberrant with respect to their
      localization, morphological appearance, and composition of cytoskeletal elements.
      During early stages of Alzheimer's disease, a variety of growth factors and
      mitogenic compounds are elevated. Most of these factors mediate their cellular
      effects through activation of the p21ras-dependent mitogen-activated protein
      kinase cascade, a pathway that is also involved in the regulation of expression
      and post-translational modification of the amyloid precursor protein and tau
      protein. We previously reported on the elevated expression of p21ras associated
      with paired helical filament formation and Abeta-deposits. However, the question
      arises as to whether induction of p21ras and the downstream mitogen-activated
      protein kinase cascade is an early event with rather primary importance in the
      pathogenetic chain or simply occurs as a cellular response to neurodegeneration.
      The present study shows that expression of p21ras is clearly elevated in very
      early stages of the disease, preceding both neurofibrillary pathology and
      formation of Abeta.

PMID- 10336055
TI  - Dynamic properties of corticothalamic excitatory postsynaptic potentials and
      thalamic reticular inhibitory postsynaptic potentials in thalamocortical neurons
      of the guinea-pig dorsal lateral geniculate nucleus.
AB  - The properties of postsynaptic potentials evoked by stimulation of cortical,
      retinal and GABAergic thalamic afferents were examined in vitro in
      thalamocortical neurons of the guinea-pig dorsal lateral geniculate nucleus.
      Brief trains of stimulation (2-10 stimuli) delivered to corticothalamic fibers
      led to a frequency-dependent increase in excitatory postsynaptic potential
      amplitude associated with an increase in activation of both N-methyl-D-aspartate
      and non-N-methyl-D-aspartate glutamate receptors. In addition, repetitive
      stimulation of corticothalamic fibers also gave rise to a slow excitatory
      postsynaptic potential that was blocked by local application of the glutamate
      metabotropic receptor antagonist alpha-methyl-4-carboxyphenylglycine. In
      contrast, repetitive stimulation of optic tract fibers resulted in monosynaptic
      excitatory postsynaptic potentials that did not potentiate and were not followed
      by the generation of a slow excitatory postsynaptic potential. Repetitive
      activation of the optic radiation also evoked both GABA(A) and GABA(B) receptor
      mediated inhibitory postsynaptic potentials. These inhibitory postsynaptic
      potentials exhibited frequency-dependent depression during repetitive activation.
      The presence of frequency-dependent facilitation of corticothalamic excitatory
      postsynaptic potentials and frequency-dependent decrement of inhibitory
      postsynaptic potentials, as well as the ability of corticothalamic fibers to
      activate glutamate metabotropic receptors, suggests that sustained activation of
      corticothalamic afferents in vivo may result in postsynaptic responses in
      thalamocortical cells that are initially dominated by GABAergic inhibitory
      postsynaptic potentials followed by prominent monosynaptic excitatory
      postsynaptic potentials as well as a slow depolarization of the membrane
      potential.Therefore, the corticothalamic system may inhibit or enhance the
      excitability and responsiveness of thalamocortical neurons, based both on the
      spatial and temporal features of thalamocortical interactions.

PMID- 10336056
TI  - Mu rhythm modulation during changes of visual percepts.
AB  - Cooperation between vision and somatomotor behavior, such as manual exploration
      of objects, suggests close functional coupling between the visual and
      sensorimotor systems. We observed this type of interaction in human volunteers
      during binocular rivalry while following the level of sensorimotor mu rhythm with
      a whole-scalp neuromagnetometer. The observers viewed a weak vertical grating in
      the lower visual field of one eye and a strong horizontal grating in the same
      spatial window of the other eye. When stationary, the weak grating was
      permanently invisible because of its low contrast and spatial frequency. A sudden
      brief drifting movement of the weak grating wiped out the dominant grating, and
      the weak grating became visible for less than the 3-s interval between the
      movements. The postcentral 8- to 15-Hz mu rhythm was found in six of nine
      observers, and its level increased transiently by 10-15%, starting about 450 ms
      after the beginning of the movement. The mu level was also enhanced by the actual
      disappearance of the stronger stimulus, when it occurred in random order with the
      rivalry stimuli. Identical visual motion, when not accompanied by a perceptual
      dominance change, produced only minor effects on the mu rhythm. Our results show
      that a change in visual percept, even with no real or imagined motor response, is
      associated with modified activity of the postcentral gyrus. This modification may
      reflect visuohaptic interactions and/or activity of the distributed cortical
      network implementing visually guided movements.

PMID- 10336057
TI  - Receptive field characteristics of neurons in the nucleus of the basal optic root
      in pigeons.
AB  - Optokinetic nystagmus is a reflex to stabilize an object image on the retina by
      compensatory eye movements. In lower vertebrates, the nucleus of the basal optic
      root participates in generating this reflex. Visual responses of 135 neurons were
      extracellularly recorded from the nucleus in pigeons and their receptive field
      properties were analysed on-line with a workstation. These cells could be
      categorized into slow (84%), intermediate (3%) and fast (13%) cells, preferring
      motion velocities of 0.25-8, 16 and 32-64 deg./s, respectively. Using whole-field
      gratings as stimuli revealed that 97% of the cells were selective for direction
      of motion and 3% were not. The directional cells preferred motion in the
      dorsoventral (35%), nasotemporal (34%), ventrodorsal (23%), or temporonasal (8%)
      directions. The omni-directional neurons were equally excited or inhibited by
      motion in all directions. The receptive field of basal optic neurons usually
      consisted of an excitatory receptive field and an inhibitory receptive field,
      both of which possessed opposite (heterodirectional) or identical
      (homodirectional) directionalities. In the case of homodirectional co-existence
      of both fields, whether whole-field gratings could produce visual responses from
      the cells would depend on the interaction between excitation and inhibition
      evoked in their excitatory and inhibitory receptive fields, respectively.
      Therefore, in some cases a single object was more effective than whole-field
      gratings in eliciting visual responses from basal optic neurons in pigeons. All
      of these receptive field properties revealed by on-line computer analysis may
      underlie the detection of optic flow and the induction of optokinetic responses.

PMID- 10336058
TI  - Developmental expression of calretinin immunoreactivity in the human retina and a
      comparison with two other EF-hand calcium binding proteins.
AB  - This paper reports the localization pattern of calretinin, a calcium-binding
      protein, in the human retina during development, as studied by
      immunohistochemistry. A comparison is made of the cellular distribution of
      calretinin with two other calcium-binding proteins, calbindin and parvalbumin,
      recently reported by us in the human retina, and by parallel labeling with both
      antisera in the same tissues. At 11-12 weeks of gestation, calretinin
      immunoreactivity was expressed in many prospective ganglion cells of the central
      inner neuroblastic zone. At 16-17 weeks of gestation, the immunoreactivity was
      localized in the ganglion cell layer, inner plexiform layer, and in most
      differentiated amacrine, horizontal and cone cells located in the central (1-2 mm
      temporal from optic disc) to midperipheral parts of the retina. By midgestation
      (20-21 weeks), calretinin immunoreactivity was strongly developed in the cone
      photoreceptors. Parallel labeling with calbindin and parvalbumin antisera
      revealed that the calretinin-positive horizontal cells were somewhat smaller and
      less frequent and less intense than the calbindin- and parvalbumin-positive
      counterparts, at 16-21 weeks of gestation. No horizontal cells were calretinin
      immunopositive in the postnatal (four-month-old infant) and adult retinas
      examined. Also, at both stages, a few bipolar and cone cells were weakly
      immunoreactive. These observations suggest a critical role for calretinin in the
      development and maturation of a select class of horizontal cells. The widespread
      expression of immunoreactivity in the early ganglion cells indicates that
      calretinin may be involved in their differentiation. The weak immunoreactivity
      pattern noted in the adult photoreceptor and bipolar cells, and an apparent lack
      of immunoreactivity in the mature horizontal cells, tends to indicate that,
      unlike calbindin and parvalbumin, calretinin plays little role in the transport
      and physiological buffering of Ca2+ in these neurons of the human retina. It
      appears, however, that calretinin is predominantly involved in both processes in
      amacrine cells.

PMID- 10336059
TI  - The parafascicular thalamic nucleus but not the prefrontal cortex facilitates the
      nitric oxide/cyclic GMP pathway in rat striatum.
AB  - We investigated whether the parafascicular thalamic nucleus and the prefrontal
      cortex, the two major excitatory inputs to the striatum, modulate the nitric
      oxide/cyclic GMP pathway in rat striatum. Electrical stimulation (10 pulses of
      0.5 ms, 10 V applied at 10 Hz, 140 microA) delivered bilaterally to the
      parafascicular thalamic nucleus for a total of 4, 10 and 20 min, time-dependently
      facilitated cyclic GMP output in the dorsal striatum of freely moving rats,
      assessed by trans-striatal microdialysis. Electrical stimulation to the
      prefrontal cortex for a total duration of 20 min did not affect striatal cyclic
      GMP levels. The facilitatory effect observed after electrical stimulation of the
      parafascicular thalamic nucleus was blocked by co-perfusion with tetrodotoxin,
      suggesting that the effect is mediated by neuronal process(es). The non
      competitive N-methyl-D-aspartate receptor antagonist, dizocilpine maleate (30
      microM infused into the dorsal striatum), and the competitive one, 3-[(R)
      carboxypiperazin-4-yl]-propyl-phosphonic acid (50 microM infused), but not local
      perfusion of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid
      antagonist, 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (15 microM perfused
      locally), abolished the cyclic GMP response in the striatum. The nitric oxide
      synthase inhibitor, 7-nitroindazole, applied locally (1 mM), blocked the
      electrically evoked increase in striatal extracellular cyclic GMP. This increase
      was also prevented by local application (100 and 300 microM) of 1H-(1,2,4)
      oxadiazolo-(4,3a)-quinoxalin-1-one, a selective inhibitor of soluble guanylyl
      cyclase. The results provide direct functional evidence of selective thalamic
      facilitation of the nitric oxide/cyclic GMP pathway in the dorsal striatum,
      through activation of N-methyl-D-aspartate receptors.

PMID- 10336060
TI  - Expression of N-methyl-D-aspartate receptor-dependent long-term potentiation in
      the neostriatal neurons in an in vitro slice after ethanol withdrawal of the rat.
AB  - To examine changes in corticostriatal synaptic transmission in rats with ethanol
      withdrawal syndrome, intracellular and extracellular responses to subcortical
      white matter stimulation were recorded in neostriatal slice preparations. The
      resting membrane potential, input resistance and depolarizing postsynaptic
      potentials to single cortical white matter stimulation were similar in the
      neostriatum of naive and ethanol withdrawal rats. Repetitive stimulation of the
      white matter induced more pronounced N-methyl-D-aspartate receptor-mediated
      postsynaptic potentials in ethanol withdrawal than naive rat neostriatum. In
      intracellular recording, tetanic stimulation (50 Hz, 20 s) induced more
      pronounced post-tetanic potentiation of depolarizing postsynaptic potentials in
      the neostriatum of ethanol withdrawal than naive rats. However, in extracellular
      recording, tetanic stimulation induced smaller post-tetanic depression of
      population spikes in the neostriatum of ethanol withdrawal than naive rats.
      Tetanic stimulation of the subcortical white matter induced long-term
      potentiation of postsynaptic potentials and population spikes in the ethanol
      withdrawal rat neostriatum, while long-term depression was evoked in the naive
      rat neostriatum. The induction of long-term potentiation was blocked by D-2-amino
      5-phosphonovaleric acid or 7-chlorokynurenic acid, N-methyl-D-aspartate receptor
      antagonists, but not by (RS)-methyl-4-carboxyphenyl-glycine, a metabotropic
      glutamate receptor antagonist. Dopamine also significantly depressed the
      induction of long-term potentiation in ethanol withdrawal rat neostriatum and
      this depressant effect was antagonized by the D2 antagonist L-sulpiride but not
      by the D1 antagonist SCH23390. These results indicate that the N-methyl-D
      aspartate component of the corticostriatal glutamatergic responses, which might
      be necessary for induction of long-term potentiation, was enhanced in ethanol
      withdrawal rats. The depression of long-term potentiation induction by activation
      of D2 receptor suggests that corticostriatal N-methyl-D-aspartate response or
      intracellular mechanisms involving in the induction of the long-term potentiation
      can be suppressed by D2 activation and that the D2 effects are inhibited in the
      neostriatum of ethanol withdrawal rats.

PMID- 10336061
TI  - Effects of nitric oxide inhibition on the spread of biotinylated dextran and on
      extracellular space parameters in the neostriatum of the male rat.
AB  - Volume transmission in the brain is mediated by the diffusion of
      neurotransmitters, modulators and other neuroactive substances in the
      extracellular space. The effects of nitric oxide synthase inhibition on
      extracellular space diffusion properties were studied using two different
      approaches, the histological dextran method and the real-time iontophoretic
      tetramethylammonium method. The spread of biotinylated dextran (mol. wt 3000) in
      the extracellular space was measured morphometrically following microinjection
      into the neostriatum of male rats. Two parameters were used to describe the
      spread of biotinylated dextran in brain tissue, namely, total volume of spread
      and the mean grey value. The nonspecific nitric oxide synthase inhibitors NG
      nitro-L-arginine methyl ester (10-100 mg/kg) and NG-monomethyl-L-arginine acetate
      (30-200 mg/kg) decreased the total volume of spread of dextran in a dose
      dependent manner. 7-Nitroindazole monosodium salt (50-100 mg/kg), a specific
      neuronal nitric oxide synthase inhibitor, did not change the total volume of
      spread of dextran. Using the tetramethylammonium method, the extracellular space
      diffusion properties can be described by the volume fraction (alpha =
      extracellular space volume/total tissue volume), tortuosity lambda (lambda2 =
      free diffusion coefficient/apparent diffusion coefficient in tissue), and non
      specific uptake kappa' [Nicholson C. and Sykova E. (1998) Trends Neurosci. 21,
      207-215]. Nitric oxide synthase inhibition by NG-nitro-L-arginine methyl ester
      (50 mg/kg) had relatively little effect on volume fraction and tortuosity, and no
      changes were observed after NG-monomethyl-L-arginine acetate (20 mg/kg) or 7
      nitroindazole monosodium salt (100 mg/kg) treatment. A substantial increase was
      found only in non-specific uptake, by 13% after NG-nitro-L-arginine methyl ester
      and by 16% after NG-monomethyl-L-arginine acetate, which correlates with the
      decreased total volume of spread of dextran observed with the dextran method. NG
      Nitro-L-arginine methyl ester treatment (100 mg/kg) decreased striatal blood flow
      and increased mean arterial blood pressure. The changes in dextran spread and non
      specific uptake can be explained by an increased capillary clearance following
      the inhibition of endothelial nitric oxide synthase, as neuronal nitric oxide
      synthase inhibition had no effect. The observed changes after non-specific nitric
      oxide synthase inhibition may affect the extracellular space concentration of
      neurotransmitters and modulators, and influence volume transmission pathways in
      the central nervous system by increased capillary and/or cellular clearance
      rather than by changes in extracellular space diffusion.

PMID- 10336062
TI  - The ascending serotonergic system in the hamster: comparison with projections of
      the dorsal and median raphe nuclei.
AB  - The ascending serotonergic projections are derived largely from the midbrain
      median and dorsal raphe nuclei, and contribute to the regulation of many
      behavioral and physiological systems. Serotonergic innervation of the hamster
      circadian system has been shown to be substantially different from earlier
      results obtained with other methods and species. The present study was conducted
      to determine whether similar differences are observed in other brain regions.
      Ascending projections from the hamster dorsal or median raphe were identified
      using an anterograde tracer, Phaseolus vulgans leucoagglutinin, injected by
      iontophoresis into each nucleus. Brains were processed for tracer
      immunoreactivity, and drawings were made of the median raphe and dorsal raphe
      efferent projection patterns. The efferents were also compared to the
      distribution of normal serotonergic innervation of the hamster midbrain and
      forebrain. The results show widespread, overlapping projection patterns from both
      the median and dorsal raphe, with innervation generally greater from the dorsal
      raphe. In several brain regions, including parts of the pretectum, lateral
      geniculate and basal forebrain, nuclei are innervated by the dorsal, but not the
      median, raphe. The hypothalamic suprachiasmatic nucleus is the only site
      innervated exclusively by the median and not by the dorsal raphe. The pattern of
      normal serotonin fiber and terminal distribution is generally more robust than
      would be inferred from the anterograde tracer material. However, there is good
      qualitative similarity between the two sets of data. The oculomotor nucleus and
      the medial habenula are unusual to the extent that each has a moderately dense
      serotonin terminal plexus, although neither receives innervation from the median
      or dorsal raphe. In contrast, the centrolateral thalamic nucleus and lateral
      habenula have little serotonergic innervation, but receive substantial other
      neural input from the raphe nuclei. The normal serotonergic innervation of the
      hamster brain is similar to that in the rat, although there are exceptions. The
      anterograde tracing of ascending median or dorsal raphe projections reveals a
      high, but imperfect, degree of correspondence with the serotonin innervation
      data, and with data from rats derived from immunohistochemical and
      autoradiographic tract-tracing techniques.

PMID- 10336063
TI  - Calcium changes induced by presynaptic 5-hydroxytryptamine-3 serotonin receptors
      on isolated terminals from various regions of the rat brain.
AB  - The serotonin 5-hydroxytryptamine-3 receptor is a ligand-gated ion channel that
      is distributed widely in the nervous system. Within the CNS, a significant
      portion of the 5-hydroxytryptamine-3 receptors appears to be present on
      presynaptic nerve terminals and, using an imaging approach, it was shown
      previously that presynaptic 5-hydroxytryptamine-3 receptors on individual
      isolated nerve terminals (synaptosomes) from rat corpus striatum display a
      distinctive set of properties-slow onset, little desensitization and high
      apparent permeability for Ca2+-when compared to those observed for 5
      hydroxytryptamine-3 receptors localized at postsynaptic sites on neuronal cell
      bodies. To consider whether their characteristic nature is a common feature of
      presynaptic 5-hydroxytryptamine-3 receptors across the brain, we used confocal
      microscopy to measure changes in intracellular Ca2+ concentration resulting from
      5-hydroxytryptamine-3 agonist-induced responses in synaptosomes from
      representative rat brain regions, ranging in expression of overall levels of 5
      hydroxytryptamine-3 receptors from relatively low (cerebellum) to intermediate
      (corpus striatum and hippocampus) to high (amygdala). Application of 100 nM m
      chlorophenyl biguanide, a specific 5-hydroxytryptamine-3 receptor agonist,
      induced changes in relative intracellular Ca2+ concentration in subsets of
      synaptosomes from the corpus striatum (approximately 6% of total), hippocampus
      (approximately 3% of total), amygdala (approximately 30% of total) and cerebellum
      (approximately 32% of total). In order to assure the viability of the
      synaptosomes that did not respond to 5-hydroxytryptamine-3 agonist stimulation,
      KCl (45 mM) was subsequently added to depolarize the same population of
      synaptosomes, and increases in intracellular Ca2+ concentration were then seen in
      80-90% of the synaptosomes from all four regions. The kinetics of the intra
      synaptosomal Ca2+ changes produced by K+-evoked depolarization were similar in
      all regions, showing a rapid rise to a peak followed by an apparent plateau
      phase. In contrast, the changes in intracellular Ca2+ concentration evoked by m
      chlorophenyl biguanide displayed substantially slower kinetics, similar to
      previous findings, but which varied among responding synaptosomes from one region
      to another. In particular, m-chlorophenyl biguanide-induced changes were notably
      slower in synaptosomes from the amygdala (rise time constant, tau = 25 s), when
      compared to responses in synaptosomes from other regions (striatum, tau = 12 s;
      hippocampus, tau= 9.6 s; cerebellum, tau = 7 s). To independently demonstrate the
      presence of 5-hydroxytryptamine-3 receptors on nerve terminals in the various
      regions using a molecular approach, we double-immunostained the synaptosomes for
      the 5-hydroxytryptamine-3 receptor and the synaptic vesicle protein
      synaptophysin, using, respectively, a polyclonal antibody raised against an N
      terminal peptide of the 5-hydroxytryptamine-3 receptor and a monoclonal anti
      synaptophysin antibody, and observed 5-hydroxytryptamine-3 receptors in varying
      subsets of the synaptosomes from each region, providing direct support for the
      results obtained in our functional experiments. These results suggest that the
      distinctive properties of presynaptic 5-hydroxytryptamine-3 receptors are found
      throughout the brain, with evident differences in the kinetics of the responses
      to agonist stimulation observed across the brain regions studied. As expected,
      the proportion of the synaptosomal population that responded on application of 5
      hydroxytryptamine-3 agonist varied in preparations from one region to another;
      however, the presence of a relatively high proportion of presynaptic 5
      hydroxytryptamine-3 receptors in the cerebellum contrasts with previous binding
      studies demonstrating a relatively low overall density of 5-hydroxytryptamine-3
      receptors in this region. We hypothesize that presynaptic 5-hydroxytryptamine-3
      receptors present on nerve terminals regulate the

PMID- 10336064
TI  - N-methyl-D-aspartate receptors are present in vagal afferents and their dendritic
      targets in the nucleus tractus solitarius.
AB  - N-Methyl-D-aspartate receptors are present in the nodose ganglion, which contains
      the cell bodies of vagal afferents, and in the nucleus tractus solitarius, where
      these afferent fibers terminate. This suggests that N-methyl-D-aspartate
      receptors are located presynaptically on visceral vagal afferents and/or their
      target neurons in the nucleus tractus solitarius. To test this hypothesis, we
      combined anterograde transport of biotinylated dextran amine, following
      injections into the left nodose ganglion, with electron microscopic immunogold
      labeling of antipeptide antiserum against the R1 subunit of the N-methyl-D
      aspartate receptor in the nucleus tractus solitarius of rat brain. Within the
      medial nucleus tractus solitarius, the N-methyl-D-aspartate receptor R1
      immunoreactivity was seen in dendrites (39% of 639 profiles), axons and axon
      terminals (41%), and a few neuronal perikarya and glia. Many vagal afferent axons
      and terminals (40% of 468 profiles) contained N-methyl-D-aspartate receptor R1
      immunogold labeling. In addition, 42% of the dendrites contacted by vagal
      afferent terminals (n = 206) contained N-methyl-D-aspartate receptor R1
      immunoreactivity. In axons and dendrites, the gold particles were occasionally
      seen within asymmetric postsynaptic junctions or at non-synaptic sites on the
      plasma membrane. More commonly, however, N-methyl-D-aspartate receptor R1
      labeling was seen on membranes of vesicular cytoplasmic organelles, suggesting
      that there is abundant N-methyl-D-aspartate receptor protein available for
      activity-dependent mobilization to the plasmalemma. Since many vagal afferents
      are glutamatergic, our results implicate N-methyl-D-aspartate receptors in
      autoregulation of the presynaptic release and postsynaptic responses to glutamate
      at the level of the first central synapse in the nucleus tractus solitarius.

PMID- 10336065
TI  - Sinusoidal amplitude modulation alters contralateral noise suppression of evoked
      otoacoustic emissions in humans.
AB  - It is well established that low-level broad band noise can elicit an amplitude
      decrease in evoked otoacoustic emissions recorded in the opposite ear. However,
      the influence of the temporal characteristics of the contralateral stimulus on
      this effect remains largely unknown. In the present study, otoacoustic emissions
      evoked by 60 dB SPL clicks were recorded in 19 normal-hearing subjects using the
      Otodynamics IL088, successively in absence and presence of a contralateral noise
      that was either steady or modulated sinusoidally in amplitude at different depths
      (from 25% to 100% in 25 point steps) and rates (from 50 Hz to 800 Hz in half
      octave steps). The energy was kept constant whatever the modulation depth. The
      results showed that the evoked otoacoustic-emission attenuation effect induced by
      contralateral stimulation varied depending on the modulation depth and frequency
      of the contralateral amplitude-modulated noise. The largest suppression effect
      was observed at the 100 Hz modulation frequency and the 100% modulation depth.
      The 50 Hz modulation resulted in less suppression than with unmodulated noise. An
      interpretation of these results in terms of the influence of temporal amplitude
      fluctuations falling within a certain range on medial olivocochlear bundle
      activity is discussed.

PMID- 10336066
TI  - Fos-like immunoreactivity in the auditory brainstem evoked by bipolar
      intracochlear electrical stimulation: effects of current level and pulse
      duration.
AB  - Fos-like immunoreactivity was used to compare the auditory brain stem excitation
      elicited by bipolar electrical stimulation of the cochlea at various current
      levels relative to the electrically evoked auditory brain stem response threshold
      for a 50-micros/phase monophasic pulse. Fos-like immunoreactive cells were
      labeled in primary auditory brain stem regions. The distribution of labeled cells
      was restricted to regions known to be cochleotopically related to the stimulated
      region of the scala tympani. Some labeled cells were observed at 2x electrically
      evoked auditory brain stem response threshold. The number, density and spatial
      distribution of labeled cells were quantified in the dorsal cochlear nucleus and
      inferior colliculus, and found to increase with increasing level of stimulation.
      For 50-micros pulses, the location of labeled neurons remained reasonably
      restricted to narrow bands within each region until the 1Ox level of stimulation
      (20 dB above electrically evoked auditory brain stem response threshold) was
      reached. While a monotonic increase in Fos-like immunoreactivity with increasing
      stimulus level was observed in most nuclei, for cells of the superficial layer of
      the dorsal cochlear nucleus, a non-monotonic change with increasing stimulus
      level was seen. This dorsal cochlear nucleus non-monotonicity may indicate that,
      at higher levels of stimulation, a secondary indirect inhibitory input, probably
      associated with activation of deep layer dorsal cochlear nucleus cells, reduces
      excitatory responses at the superficial layer of the dorsal cochlear nucleus.
      Electrically evoked auditory brain stem response and Fos expression showed
      parallel changes as a function of stimulus level and pulse duration. The data
      indicate that discrete activation of cell populations within the central auditory
      pathways can occur with bipolar electrical stimulation to the highest levels of
      stimulation typically useful in humans. The data also indicate a close, but not
      identical, quantitative relationship between Fos-like immunoreactivity and
      electrophysiological response amplitude. These findings support the view that a
      study of Fos-like immunoreactivity can provide a powerful and quantitative tool
      for study of the dynamic response characteristics of cells of the central
      auditory system to electrical stimulation at suprathreshold levels. The data
      suggest that there is a monotonic increase in the number of neurons responsive to
      intracochlear electrical stimulation as a function of stimulus level, at least
      through the upper half of the dynamic range, but that this increase does not
      result in a complete loss of spatial selectivity. Coupled with previous
      psychophysical studies, these results suggest that the increase in the number of
      activated neurons is functionally beneficial, resulting in improved
      discrimination of changes in the electrical signals.

PMID- 10336067
TI  - A new form of synaptic plasticity is transiently expressed in the developing rat
      visual cortex: a modulatory role for visual experience and brain-derived
      neurotrophic factor.
AB  - Synaptic plasticity has been implicated in the mechanisms contributing to the
      shaping of the cortical circuits responsible for the transmission of the visual
      input in the rat primary visual cortex. However, the degree of plasticity of the
      thalamocortical synapse may change during development, perhaps reflecting the
      degree of stabilization of the circuitry subserving it. We have chosen the
      ability of this synapse to be first depressed and then potentiated as a specific
      indicator of its plasticity. In this study we have investigated how this
      parameter changes during development and the factors controlling it.
      Extracellular field potentials in cortical layers 2/3 were evoked by stimulation
      of the white matter in rat primary visual cortex slices prepared at different
      postnatal ages. Low-frequency stimulation (900 pulses at 1 Hz) of the white
      matter was used to induce long-term depression of field potential amplitude,
      whereas long-term potentiation was evoked by high-frequency stimulation
      consisting of three trains at 100 Hz. We provide evidence that while it is
      possible to potentiate previously depressed synapses soon after eye opening
      (postnatal day 17) this synaptic characteristic decreases rapidly thereafter. The
      decrease in this form of cortical synaptic plasticity closely matches the
      stabilization of the cortical circuitry towards an adult pattern of connectivity
      and function. Depressed cortical synapses cannot be potentiated in normal rats at
      postnatal 23, but they can be potentiated in rats reared in the dark from
      postnatal days 17 to 29. Moreover, application of brain-derived neurotrophic
      factor, known to be expressed in an activity-dependent manner, was able to
      restore the ability of synapses to be potentiated after long-term depression,
      thus indicating its important modulatory role in brain development.

PMID- 10336068
TI  - Glycosylation of proteins during a critical time window is necessary for the
      maintenance of long-term potentiation in the hippocampal CA1 region.
AB  - This paper focuses on the role of glycoproteins in activity-dependent synaptic
      plasticity. The effect of the different inhibitors of protein glycosylation,
      Tunicamycin, Brefeldin A and Swainsonine, on long-term potentiation was studied
      in the CA1 region of rat hippocampal slices. Bath application of the inhibitors
      60 min before and during tetanization did not interfere with the induction of
      long-term potentiation of the field excitatory postsynaptic potential. However,
      the potentiation in inhibitor-treated slices decreased to baseline levels during
      90-180 min. Significant differences in the potentiation in non-treated slices
      were detectable 80 min (Tunicamycin), 60 min (Brefeldin A) and 75 min
      (Swainsonine) after tetanization, thus indicating the prevention of long-term
      potentiation maintenance. The application of Swainsonine 120 and 240 min after
      tetanization did not influence the potentiated field excitatory postsynaptic
      potential. These data demonstrate the need for undisturbed glycoprotein
      processing in a time window around long-term potentiation induction to maintain
      later phases of long-term potentiation and essential functional implications of
      protein glycosylation in mechanisms underlying synaptic plasticity.

PMID- 10336069
TI  - Diabetes mellitus preserves synaptic plasticity in hippocampal slices from middle
      aged rats.
AB  - Synaptic plasticity is generally believed to provide a cellular mechanism for
      learning and memory. One manifestation of synaptic plasticity, long-term
      potentiation in the CA1 region, was compared in hippocampal slices from young and
      older rats, both control animals and streptozotocin-treated diabetics with
      moderate hyperglycemia ( approximately 15 mM). Long-term potentiation of
      excitatory synaptic potentials, elicited by tetanic stimulation or by 2-deoxy-D
      glucose application, was readily obtained in slices from young (four-month-old)
      control and diabetic rats, but not in slices from middle-aged (12-month-old)
      control rats. Both forms of potentiation, however, could be elicited in slices
      from 12-month-old diabetics. The unexpected finding that long-term potentiation
      is restored in moderately hyperglycemic older rats suggests that the blood
      glucose level of older animals may be important for synaptic plasticity and
      perhaps for the ability to learn.

PMID- 10336070
TI  - Up-regulation of Eph tyrosine kinase receptors after excitotoxic injury in adult
      hippocampus.
AB  - The molecular mechanisms underlying the response to injury in the central nervous
      system are incompletely understood. Many cell activation systems may be involved.
      Tyrosine kinase receptors and their ligands play key roles in cell activation
      throughout life. The Eph family of tyrosine kinase receptors/ ligands are
      developmentally regulated and have been implicated in neural pathfinding.
      However, nothing is known about their role in the adult brain. We have used a
      model of central nervous system lesion in the rat, in which intraventricular
      injection of kainate was performed. This produced neuronal death in the CA3-CA4
      fields and glial activation in the hippocampus. Highly degenerate primers,
      corresponding to the catalytic domain of the tyrosine kinase family, were used
      for reverse transcription-polymerase chain reaction of pooled RNA extracted from
      injured hippocampi. The amplified products were cloned and 100 clones
      (arbitrarily named TK1-TK100) were examined and inserts sequenced. We obtained
      four clones containing inserts which belong to the Eph receptor family. Two of
      these inserts (TK17 and TK63) were EphA4 and the other were EphB2 (TK25) and
      EphA5 (TK23). We performed in situ hybridization, and we found our clones to be
      present in all fields of the hippocampus, their expression being mainly neuronal.
      Three days after lesion, prominent expression appeared in CA1 as compared to the
      same field in the non-treated contralateral hippocampus. We performed northern
      blot analysis for quantification, and found that, three days after injury, the
      values decreased to 33 +/- 4%, 33 +/- 1% and 46 +/- 1% of control values for TK63
      (EphA4), TK25 (EphB2) and TK23 (EphA5), respectively. Neuronal death in CA3-CA4
      might account for this fact. Later, five days post-injury, the expression
      increased to 63 +/- 3%, 71 +/- 1% and 111 +/- 5% of control values, respectively.
      This increase was due to an up-regulation of these genes in the hippocampal
      neurons that survive after the injury, as indicated by in situ hybridization.

PMID- 10336071
TI  - Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that
      correlates with spatial memory impairment.
AB  - The impact of chronic cerebral hypoperfusion on cognitive function and cerebral
      capillary morphology in the hippocampus was examined. Young adult Wistar rats
      were subjected to permanent ligation of both common carotid arteries (two-vessel
      occlusion). One month after vascular occlusion, a small but non-significant
      impairment in the acquisition of spatial information was registered compared with
      sham-operated controls. Two months after surgery, the occluded animals displayed
      an impaired performance throughout the training period. One year after surgery,
      the acquisition curves demonstrated a significant attenuation of the learning
      rate in the occluded rats group, whereas no significant differences in long-term
      retention were observed. Thus, chronic hypoperfusion induced by two-vessel
      occlusion gave rise to impairment of spatial memory. Following behavioural
      testing, the rats were killed at the age of 17 months, and capillaries in the CA1
      and dentate gyrus were examined using transmission electron microscopy. Typical
      age-related capillary abnormalities such as degenerative pericytes and thickened
      basement membranes (with or without fibrosis) were detected in the hippocampus of
      sham animals. In occluded rats, the occurrence of capillaries displaying such
      abnormalities almost doubled in the CA1 region, but was similar in the dentate
      gyrus, compared with sham controls. A highly significant correlation was found
      between the last Morris maze performance and the percentage of capillaries with
      deposits in the basement membrane in the hippocampal CA1 area of occluded rats,
      which was not present in the sham animals. We conclude that a long-term
      hypoperfusion accelerated the development of age-related ultrastructural
      aberrations of capillaries in the hippocampal CA1 area, but not in the dentate
      gyrus. Thus, not only neurons, but also capillaries in the hippocampal CA1 area
      are sensitive to an impaired microcirculation. Moreover, the cognitive
      performance of hypoperfused rats correlated closely with the condition of the
      capillaries in the CA1 area, suggesting that capillary integrity is one of the
      important determinants of brain function in conditions that compromise cerebral
      microcirculation.

PMID- 10336072
TI  - Corticosterone and phenytoin reduce neuronal nitric oxide synthase messenger RNA
      expression in rat hippocampus.
AB  - The production and release of the corticosteroids, namely the glucocorticoids and
      the mineralocorticoids, are regulated by various stimuli, including stress.
      Previous studies from our laboratory have shown that chronic exposure to stress
      or to stress levels of glucocorticoids produces atrophy of the apical dendrites
      of CA3 pyramidal neurons in the hippocampus. This stress-induced dendritic
      remodeling is blocked by the anti-epileptic drug phenytoin, which suppresses
      glutamate release, and also by N-methyl-D-aspartate receptor antagonists. These
      results suggest an interaction between glucocorticoids and excitatory amino acids
      in the development of stress-induced atrophy of CA3 pyramidal neurons. Since
      nitric oxide is proposed to play an important role in mediating both the
      physiological and pathophysiological actions of excitatory amino acids, we
      examined the regulation of neuronal nitric oxide synthase messenger RNA
      expression by corticosterone and phenytoin in the rat hippocampus. The expression
      of neuronal nitric oxide synthase messenger RNA in hippocampal pyramidal neurons
      and granule neurons of the dentate gyrus was unaffected by 21-day administration
      of corticosterone (40 mg/kg), phenytoin (40 mg/kg) or the combination of
      corticosterone and phenytoin. However, in hippocampal interneurons,
      corticosterone/ phenytoin co-administration led to a significant reduction in
      neuronal nitric oxide synthase messenger RNA levels when compared with vehicle
      controls. These results suggest that, during exposure to stress levels of
      corticosterone, phenytoin inhibits glucocorticoid-induced atrophy of CA3
      pyramidal neurons by reducing neuronal nitric oxide synthase expression in
      hippocampal interneurons. Moreover, these results may provide another example of
      synaptic plasticity in the hippocampus mediated by nitric oxide synthase.

PMID- 10336073
TI  - Transient hypoxia may lead to neuronal proliferation in the developing mammalian
      brain: from apoptosis to cell cycle completion.
AB  - Cerebral hypoxia/ischemia was shown to induce delayed, apoptotic neuronal death
      occurring through biochemical pathways potentially sharing common events with
      cell proliferation. This study was designed to test the hypothesis that a
      sublethal hypoxia may promote mitotic activity in developing central neurons.
      After six days in vitro, cultured neurons from the forebrain of 14-day-old rat
      embryos were exposed to hypoxia (95% N2/5% CO2) for 3 h and re-oxygenated for up
      to 96 h. Controls were kept in normoxia. As a function of time, cell viability
      was measured by diphenyltetrazolium bromide, and rates of DNA and protein
      synthesis were monitored using [3H]thymidine and [3H]leucine, respectively.
      Morphological features of apoptosis, necrosis and mitosis were scored under
      fluorescence microscopy after nuclear staining with 4,6-diamidino-2-phenylindole,
      and the expression profile of proliferating cell nuclear antigen, a cofactor for
      DNA polymerase, was analysed by immunohistochemistry. Data were compared to those
      obtained after transient hypoxia for 6 h followed by re-oxygenation for 96 h and
      which was shown to induce apoptosis. Whereas a 6-h insult reduced cell viability,
      with 23% of the neurons exhibiting apoptosis by the end of re-oxygenation, a 3-h
      hypoxia led to a cycloheximide-sensitive increase in the final number of living
      neurons compared to controls (13%, P < 0.01), with no signs of apoptosis,
      significantly increased thymidine incorporation into acid-precipitable fraction,
      and persistent over-expression of proliferating cell nuclear antigen.
      Accordingly, final score of mitotic nuclei was significantly enhanced. In
      addition, the cell cycle inhibitor olomoucine (50 microM) prevented apoptosis
      consecutive to a 6-h hypoxia, but impaired the stimulatory effects of a 3-h
      insult. These findings support the conclusion that some neurons exposed to
      sublethal hypoxia may dodge apoptotic death by fully achieving the cell cycle.

PMID- 10336074
TI  - Regulation of a novel pathway for cell death by lysosomal aspartic and cysteine
      proteinases.
AB  - PC12 cells undergo apoptosis when cultured under conditions of serum deprivation.
      In this situation, the activity of caspase-3-like proteinases was elevated, and
      the survival rate could be maintained by treatment with acetyl-DEVD-cho, a
      specific inhibitor of caspase-3. In a culture of PC12 cells treated with acetyl
      DEVD-cho, where caspase-3-like proteinases are not activated, CA074, a specific
      inhibitor of cathepsin B induced active death of the cells. Cathepsin B antisense
      oligonucleotides showed a similar effect to CA074 on the induction of active cell
      death. By double staining of terminal deoxynucleotidyl transferase-mediated
      deoxyuridine triphosphate-biotin nick end-labeling and activated caspase-3, the
      dying cells treated with CA074 were positive for terminal deoxynucleotidyl
      transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling staining
      but negative for activated caspase-3. Ultrastructurally, the cells were
      relatively large and had nuclei with chromatin condensation. The initiation of
      cell death by CA074 or the cathepsin B antisense were inhibited by the addition
      of pepstatin A, a lysosomal aspartic proteinase inhibitor, or by cathepsin D
      antisense. To examine whether this cell death pathway was present in cell types
      other than PC12 cells, we analysed dorsal root ganglion neurons obtained from rat
      embryos on the 15th gestational day, a time when they require nerve growth factor
      for survival and differentiation in culture. When cultured in the absence of
      nerve growth factor, the neurons survived in the presence of acetyl-DEVD-cho or
      acetyl-YVAD-cho. Under these conditions, CA074 reduced the survival rate of the
      neurons, which was subsequently restored by the further addition of pepstain A.
      These results suggest that a novel pathway for initiating cell death exists which
      is regulated by lysosomal cathepsins, and in which cathepsin D acts as a death
      factor. We speculate that this death-inducing activity is normally suppressed by
      cathepsin B.

PMID- 10336075
TI  - Electrically mediated regeneration and guidance of adult mammalian spinal axons
      into polymeric channels.
AB  - An extracellular electric field has been shown to influence the regeneration of
      nerve fibers within the adult mammalian spinal cord. However, in these studies,
      few axons were labeled by local application of intracellular markers relative to
      the number of axons transected. This has limited an evaluation of the robustness
      of the response, and the direction of growth of regenerating axons that might be
      influenced by the orientation of the applied voltage gradient. In this study, a
      hollow silicone rubber tube (c. 6 mm x 1 mm outside diameter) containing a
      cathodal (negative) electrode was inserted longitudinally into the dorsal half of
      the adult guinea-pig spinal cord. The electric field ( approximately 100
      microV/mm) was imposed within the damaged spinal cord with an implanted d.c.
      stimulator for about three weeks. Based on previous studies, this orientation of
      the electric field would be expected to both initiate axonal regeneration and
      guide growing axons to, and into, the silicone guidance channel. In experimental
      animals (n = 20), a robust regeneration of axons into the tube was observed in
      more than half the cases. These axons were traced from surrounding white and gray
      matter by anterograde and retrograde labeling using a tetramethylrhodamine
      conjugated dextran as an intracellular marker. Control animals (n = 16) received
      tubes with inactive electrodes. It was rare to find any axons within control
      guidance channels, since adult mammalian central nervous system axons do not
      regenerate. This report provides evidence for not only the facilitated
      regeneration of adult mammalian central axons, but also their guidance, by an
      imposed electric field.

PMID- 10336076
TI  - Focally administered nerve growth factor suppresses molecular regenerative
      responses of axotomized peripheral afferents in rats.
AB  - Effects of delivery of nerve growth factor, from a catheterized osmotic mini-pump
      to the proximal stump of a transected sciatic nerve, were compared with the
      effects of normal saline. A pilot measured retrograde axonal transport of nerve
      growth factor to determine a pump concentration which raised axonal transport
      ipsilaterally, but not contralaterally. The effects of this delivery over 12 days
      were then determined on expression of growth-associated protein-43, trkA, p75NTR
      and preprotachykinin A ipsilateral and contralateral to the pump in dorsal root
      ganglia at L4 and L5 (pooled). Ganglionic expression was measured both as
      messenger RNA and protein. Axotomy (saline pumps) increased growth-associated
      protein-43 messenger RNA (318 +/- 14%: all changes are percent of contralateral,
      non-axotomized ganglia with saline pumps) and immunoreactivity (431 +/- 43%). The
      increase was significantly less (P < 0.001) ipsilateral to nerve growth factor
      pumps (191 +/- 45%). Axotomy reduced expression of p75NTR (messenger RNA: 52 +/-
      17%, P < 0.01; immunoreactivity: 74 +/- 3%, P < 0.05). These decreases were
      converted to increases by nerve growth factor delivery (respectively 143 +/- 40%
      and 281 +/- 67%; both P < 0.01). With trkA, axotomy decreased the expression of
      the messenger RNA (68 +/- 40%, P < 0.01) and of the primary translation product-
      110,000 mol. wt protein (55 +/- 12%, P < 0.01)--but not the fully glycosylated
      trkA protein (mol. wt 145,000). Nerve growth factor delivery did not affect trkA
      expression. Axotomy reduced messenger RNA for the substance P precursor,
      preprotachykinin A, to 42 +/- 17% (P < 0.01) and this reduction was prevented by
      nerve growth factor treatment. We suggest that the primary effect of nerve growth
      factor on axotomized C-fibres is not to promote regeneration, although that may
      be its secondary effect via an action on Schwann cells. It is possible that
      reduced neuronal sensitivity to nerve growth factor during regeneration is
      advantageous in suppressing nociception.

PMID- 10336077
TI  - Re-expression of p75NTR by adult motor neurons after axotomy is triggered by
      retrograde transport of a positive signal from axons regrowing through damaged or
      denervated peripheral nerve tissue.
AB  - To investigate different types of potential signalling mechanisms that regulate
      neuronal reactions to axotomizing injury, we compared the re-expression of the
      low-affinity neurotrophin receptor, p75NTR, and the down-regulation of choline
      acetyltransferase expression, after various combinations of axotomy, crush injury
      and blockade of axonal transport in adult hypoglossal motor neurons in the rat.
      We found that pure axotomy in the absence of crush injury down-regulated choline
      acetyltransferase, but did not induce p75NTR re-expression. Blockade of axonal
      transport with colchicine had an identical effect. In contrast, both a crush
      injury on its own, or a crush injury proximal to a complete axotomy, induced
      p75NTR re-expression and down-regulated expression of choline acetyltransferase.
      Blockade of axonal transport with colchicine or tight ligation proximal to a
      crush prevented the crush injury-induced re-expression of p75NTR. Infusion of
      vehicle, nerve growth factor or ciliary neurotrophic factor induced low levels of
      p75NTR re-expression that were not significantly different from each other and
      were substantially lower than crush-induced levels. These findings confirm
      previous suggestions that the loss of choline acetyltransferase expression is due
      to the interruption of a constitutive retrograde signal, and show that the re
      expression of p75NTR by adult motor neurons after axotomy is triggered by the
      retrograde transport of a positive signal derived from axons that are regrowing
      through damaged or denervated peripheral nerve tissue. The precise source and
      nature of this signal are not yet clear.

PMID- 10336078
TI  - The kainate receptor antagonist 2S,4R-4-methylglutamate attenuates mechanical
      allodynia and thermal hyperalgesia in a rat model of nerve injury.
AB  - Opioids and receptor antagonists of excitatory amino acids attenuate mechanical
      allodynia and thermal hyperalgesia in animal models of neuropathic pain.
      Recently, a kainate receptor antagonist, 2S,4R-4-methylglutamate, has been
      developed but has not been tested for antinociceptive effects in animal models of
      neuropathic pain. We evaluated whether 2S,4R-4-methylglutamate attenuated
      responses to mechanical and thermal stimuli in uninjured (control) rats and
      increased responsiveness in rats with chronic constriction injury. Rats were
      tested for a number of withdrawal responses using a calibrated von Frey filament
      (mechanical stimulus) and withdrawal latencies from a radiant heat source
      (thermal stimulus). In control rats, 2S,4R-4-methylglutamate produced a small but
      significant decrease in responses from the mechanical stimulus (25 mg/kg) and
      significantly increased withdrawal latencies from the thermal stimulus at the
      highest dose administered (100 mg/kg). In addition, 2S,4R-4-methylglutamate
      greatly attenuated increased responsiveness in rats with chronic constriction
      injury. At four to eight days following chronic constriction injury, animals that
      displayed increased responsiveness to mechanical and thermal stimuli were
      injected intraperitoneally with either dizocilpine maleate (0.1 mg/kg), morphine
      (4 mg/kg), vehicle as controls, or 2S,4R-4-methylglutamate (25, 50, 75 or 100
      mg/kg). 2S,4R-4-Methylglutamate (25, 50, 75 and 100 mg/kg) significantly
      attenuated the frequency of responses to mechanical stimuli (Wilcoxon, P < 0.05)
      and the latency of responses to thermal stimuli (analysis of variance and
      Duncan's, P < 0.05). Dizocilpine maleate and morphine, as expected, also reduced
      these responses. These results suggest that, in addition to opioid and N-methyl-D
      aspartate receptors, kainate receptors may play a role in the maintenance of
      mechanical allodynia and thermal hyperalgesia associated with peripheral nerve
      injury.

PMID- 10336080
TI  - Cortical spreading depression reversibly disrupts convulsive motor seizure
      expression in amygdala-kindled rats.
AB  - To determine the role of the frontal cortex in the generalization of limbic
      seizures, we first produced unilateral cortical spreading depression to
      reversibly suppress neuronal activity in the motor cortex and then triggered an
      amygdala-kindled seizure. Three minutes following induction of unilateral
      spreading depression, stimulation of the ipsilateral kindled amygdala produced
      only a brief electrographic seizure, and completely failed to produce the
      bilateral electrographic and clonic convulsive seizures that were normally
      present during control trials. A very different outcome occurred when unilateral
      spreading depression was induced in the cortex contralateral to the kindled
      amygdala. In these cases, the electrographic amygdala seizures were normal and
      bilateral like control trials, yet the clonic convulsive seizures were
      lateralized and appeared to be controlled by the non-depressed, kindled
      hemisphere. These lateralized convulsions were identical to those observed
      following forebrain commissurotomy, when direct communication between the frontal
      cortices was permanently severed. The results of the present study further define
      the pathways of temporal lobe seizure propagation, and highlight the important
      contribution frontal cortical regions provide to both the electrographic and
      convulsive expression of amygdala-kindled seizures by amplifying local seizures
      and projecting them into downstream brainstem and spinal cord circuits.

PMID- 10336079
TI  - Neuroprotective effects of brain-derived neurotrophic factor in seizures during
      development.
AB  - Although the immature brain is highly susceptible to seizures, it is more
      resistant to seizure-induced neuronal loss than the adult brain. The developing
      brain contains high levels of neurotrophins which are involved in growth,
      differentiation and survival of neurons. To test the hypothesis that
      neurotrophins may protect the developing brain from seizure-induced neuronal
      loss, brain-derived neurotrophic factor up-regulation was blocked by
      intracerebroventricular infusion of an 18mer antisense oligodeoxynucleotide
      sequence to brain-derived neurotrophic factor in 19-day-old rats using micro
      osmotic pumps. Control rats were infused with sense or missense
      oligodeoxynucleotide. Status epilepticus was induced by intraperitoneal
      administration of kainic acid 24 h after the start of oligodeoxynucleotide
      infusion. Seizure duration was significantly increased in the antisense
      oligodeoxynucleotide plus kainic acid group compared to groups that received
      kainic acid alone or kainic acid plus sense or missense oligodeoxynucleotide.
      There was no difference between groups in the latency to forelimb clonus. A
      twofold increase in brain-derived neurotrophic factor levels was observed in the
      hippocampus 20 h following kainic acid-induced seizures. This kainic acid-induced
      increase was absent in animals receiving infusion of antisense
      oligodeoxynucleotide to brain-derived neurotrophic factor at time of seizure
      induction. Hippocampi of rats in this group (antisense oligodeoxynucleotide plus
      kainic acid) showed a loss of CA1 and CA3 pyramidal cells and hilar interneurons.
      This neuronal loss was not dependent upon seizure duration since animals injected
      with diazepam to control seizure activity in the antisense plus kainic acid group
      also showed similar neuronal loss. Administration of kainic acid or infusion of
      antisense alone did not produce any cell loss in these regions. Induction of
      seizures at postnatal day 20, in the presence or absence of antisense
      oligonucleotide, did not produce an impairment in learning and memory when tested
      15 days later in the Morris water maze. The hippocampi of these animals did not
      show any synaptic reorganization as assessed by growth-associated protein-43
      immunostaining and Timm staining. Our findings confirm prior studies
      demonstrating that seizures in the immature brain are associated with little, if
      any, cell loss. However, when seizure-induced increase in brain-derived
      neurotrophic factor is blocked, seizures do result in neuronal loss in the
      developing brain. Thus, brain-derived neurotrophic factor appears to provide
      protection against kainic acid seizure-induced neuronal damage in the developing
      brain.

PMID- 10336081
TI  - Vermectomy enhances parvalbumin expression and improves motor performance in
      weaver mutant mice: an animal model for cerebellar ataxia.
AB  - In the Weaver mutant mouse (wv/wv), an animal model for hereditary cerebellar
      ataxia, electrophysiological experiments have revealed a disorganized output of
      cerebellar Purkinje cells (the latter using GABA as an inhibitory transmitter)
      which, by a cascade of mechanisms, was thought to be the cause of the poor motor
      abilities. In Purkinje cell degeneration mice (pcd/pcd) lacking nearly all
      Purkinje cells and displaying milder motor deficiencies than wv, in comparison to
      wild-type mice, a strong increase in parvalbumin- and (co-localized with
      parvalbumin) glycine-immunopositive somata in the deep cerebellar and vestibular
      nuclei has recently been found. It was therefore intriguing to investigate
      whether motor performance in weaver mutants could be ameliorated by applying
      cerebellar lesions to eliminate the faulty output and to look for a change in
      transmitter weighting, indicated by a strong increase in parvalbumin-positive
      somata in areas (the respective target areas) which were formerly devoid of it.
      Ten Weaver mutants were subjected to cerebellar lesions. After removal of the
      vermis a total abolition of tremor, a definite improvement in the balance of
      affected body parts, an increase in locomotor activity when tested in an open
      field matrix, and a strong increase in parvalbumin expression in Weaver mutant
      deep cerebellar and vestibular nuclei in comparison to wild-types have indeed
      been found. Increase in motor activity (or explorative behaviour) has been placed
      in relation to learning mechanisms. The increase in parvalbumin expression and
      the observed improvement in motor abilities and mechanisms probably related to
      learning underline the hypothesis that any change in the physiological
      equilibrium of the brain function by removal of input or output related to an
      assembly of nerve cells leads to a cascade of changes at the transmitter and
      neuronal level in near or distant connected brain structures.

PMID- 10336082
TI  - Temporal and regional regulation of alpha1, beta2 and beta3, but not alpha2,
      alpha4, alpha5, alpha6, beta1 or gamma2 GABA(A) receptor subunit messenger RNAs
      following one-week oral flurazepam administration.
AB  - The effect of prolonged benzodiazepine administration on GABA(A) receptor subunit
      (alpha1-6, beta1-3, gamma2) messenger RNAs was investigated in the rat
      hippocampus and cortex, among other brain areas. Rats were orally administered
      flurazepam for one week, a protocol which results in benzodiazepine
      anticonvulsant tolerance in vivo, and in the hippocampus in vitro, in the absence
      of behavioral signs of withdrawal. Autoradiographs of brain sections, hybridized
      with [35S]oligoprobes in situ, were examined immediately (day 0) or two days
      after drug treatment, when rats were tolerant, or seven days after treatment,
      when tolerance had reversed, and were compared to sections from pair-handled,
      vehicle-treated controls. Alpha1 subunit messenger RNA level was significantly
      decreased in CA1 pyramidal cells and dentate granule cells at day 0, an effect
      which persisted only in CA1 neurons. Decreased "alpha1-specific" silver grain
      density over a subclass of interneurons at the pyramidal cell border suggested
      concomitant regulation of interneuron GABA(A) receptors. A reduction in beta3
      subunit messenger RNA levels was more widespread among hippocampal cell groups
      (CA1, CA2, CA3 and dentate gyrus), immediately and two days after treatment, and
      was also detected in the frontal and parieto-occipital cortices. Changes in beta2
      subunit messenger RNA levels in CA1, CA3 and dentate gyrus cells two days after
      ending flurazepam treatment suggested a concomitant up-regulation of beta2
      messenger RNA. There was a trend toward an increased level of alpha5, beta3 and
      gamma2 subunit messenger RNAs in CA1, CA3 and dentate gyrus cells, which was
      significant for the beta3 and gamma2 subunit messenger RNAs in the frontal cortex
      seven days after ending flurazepam treatment. There were no flurazepam treatment
      induced changes in any other GABA(A) receptor subunit messenger RNAs. The
      messenger RNA levels of three (alpha1, beta2 and beta3) of nine GABA(A) receptor
      subunits were discretely regulated as a function of time after ending one-week
      flurazepam treatment related to the presence of anticonvulsant tolerance, but not
      dependence. The findings suggested that a localized switch in the subunit
      composition of GABA(A) receptor subtypes involving these specific subunits may
      represent a minimal requirement for the changes in GABA(A) receptor-mediated
      function recorded previously at hippocampal CA1 GABAergic synapses, associated
      with benzodiazepine anticonvulsant tolerance.

PMID- 10336083
TI  - Effects of ATP and elevated K+ on K+ currents and intracellular Ca2+ in human
      microglia.
AB  - We have used whole-cell patch-clamp recordings and calcium microfluorescence
      measurements to study the effects of ATP and elevated external K+ on properties
      of human microglia. The application of ATP (at 0.1 mM) led to the activation of a
      transient inward non-selective cationic current at a cell holding potential of 
      60 mV and a delayed, transient expression of an outward K+ current activated with
      depolarizing steps applied from holding level. The ATP response included an
      increase in inward K+ conductance and a depolarizing shift in reversal potential
      as determined using a voltage ramp waveform applied from -120 to -50 mV. Fura-2
      microspectrofluorescence measurements showed intracellular calcium to be
      increased following the application of ATP. This response was characterized by an
      initial transient phase, which persisted in Ca2+-free media and was due to
      release of Ca2+ from intracellular storage sites. The response had a later
      plateau phase, consistent with Ca2+ influx. In addition, ATP-induced changes in
      intracellular Ca2+ exhibited prominent desensitization. Elevated external K+ (at
      40 mM) increased inward K+ conductance and shifted the reversal potential in the
      depolarizing direction, with no effect on outward K+ current or the level of
      internal Ca2+. The results of these experiments show the differential responses
      of human microglia to ATP and elevated K+, two putative factors associated with
      neuronal damage in the central nervous system.

PMID- 10336084
TI  - Internalization of the neurokinin 1 receptor in rat myenteric neurons.
AB  - Immunoreactivity for the neurokinin 1 receptor is contained in nerve cell bodies
      that have been deduced to be intrinsic primary afferent neurons in the myenteric
      plexus of the rat ileum. This study shows that neurokinin 1 receptor
      immunoreactivity on these neurons represents receptors that can bind agonist and
      undergo endocytosis, and explores the properties of that endocytosis. Segments of
      rat ileum were incubated in Hanks' balanced salt solution for 1 h at 4 degrees C,
      followed by 1 h at 37 degrees C in physiological saline solution with nicardipine
      and tetrodotoxin, in the presence or absence of substance P. Tissue was then
      fixed and whole-mount preparations were processed for fluorescence
      immunohistochemistry, using antibodies raised against the C-terminus of the
      neurokinin 1 receptor. The intracellular and surface distributions of receptor
      immunoreactivity were analysed using confocal microscopy and quantified by
      computer analysis. In tissue not exposed to substance P, most neurokinin 1
      receptor immunoreactivity was confined to the surfaces of nerve cells, and 29%
      was intracellular. Exogenous substance P (10(-6) M) caused an increase in the
      amount of intracellular receptor to 72%. This internalization was concentration
      dependent, and maximum receptor internalization was achieved between 10(-6) M and
      10(-5) M substance P (EC50 = 4.9 +/-1.6 x 10(-7) M). The specific neurokinin 1
      receptor antagonist, SR104333 (10(-6) M), inhibited substance P-induced
      endocytosis. In tissue that was incubated in 5 x 10(-5) M monensin (to trap
      endocytosed receptor in the cell), without the addition of substance P, a high
      level of intracellular neurokinin 1 receptor immunoreactivity (81%) was also
      present. We deduce that endocytosis in the presence of monensin was stimulated by
      the release of tachykinins from intrinsic nerve endings, based on the following
      evidence: when endogenous release of tachykinin was blocked using a high
      magnesium/low calcium solution, or binding of tachykinins to the receptor was
      prevented using 10(-6) M SR140333, the intracellular receptor immunoreactivity
      remained at approximately 40%. Incubation with hypertonic sucrose also trapped
      receptors on the cell surface. Use of these protocols that modify receptor
      trafficking showed that agonist induced the neurokinin 1 receptors to aggregate,
      accumulate in endocytotic vesicles, move to perinuclear organelles and recycle to
      the surface in less than 1 h. This study indicates that there is sufficient
      release of endogenous tachykinins in the rat ileum to cause receptor
      internalization and implies that these intrinsic primary afferent neurons are
      likely to be under continuous influence from tachykinins in the normal intestine.

PMID- 10336085
TI  - An anatomical study of brainstem projections to the trigeminal motor nucleus of
      lampreys.
AB  - This study was undertaken to identify and describe populations of brainstem
      neurons that project to the area of the nucleus motorius nervi trigemini in
      lampreys as a first step in the study of neurons that control feeding behavior in
      this species. To identify these neurons, the retrograde tracer cobalt-lysine was
      injected into the nucleus motorius nervi trigemini on one side of the in vitro
      isolated brainstem preparation of seven spawning adult lampreys (Petromyzon
      marinus). Transport times ranged from 42 to 48 h. Retrogradely labeled neurons
      were found within the rostral spinal cord, the rhombencephalon, the mesencephalon
      and the caudal diencephalon. This study concentrates on the labeled neurons in
      the rhombencephalon, since the essential circuits for mastication and swallowing
      are confined to this region in higher vertebrates. Within the rhombencephalon,
      labeled cells were in the nucleus sensibilis nervi trigemini on both sides. A
      densely packed column of labeled neurons was found medial to the nucleus motorius
      nervi trigemini on the ipsilateral side, extending further rostrally in the
      isthmic region. Continuous columns of labeled cells were observed in the lateral
      reticular formation on each side in the basal plate ventral to rhombencephalic
      cranial motor nuclei. They extended from the rostral trigeminal region down into
      the rostral spinal cord. A comparison with data from cats and rats shows that the
      distribution of neurons that project to the nucleus motorius nervi trigemini is
      very similar in mammals and in agnathes. We conclude that the organization of the
      motor command network of the trigeminal system is well preserved throughout
      phylogeny and that the in vitro isolated brainstem of lampreys should be a useful
      model for the study of vertebrate feeding behavior.

PMID- 10336086
TI  - A physiological study of brainstem and peripheral inputs to trigeminal
      motoneurons in lampreys.
AB  - The inputs to trigeminal motoneurons from sensory afferents and rhombencephalic
      premotor regions were studied in isolated brainstem preparations of adult
      lampreys (Petromyzon marinus). Stimulation of both trigeminal nerves,
      contralateral nucleus motorius nervi trigemini, nucleus sensibilis nervi
      trigemini and ipsilateral rostral reticular formation elicited large-amplitude
      excitatory postsynaptic potentials with short latencies. These were significantly
      attenuated by adding 6-cyano-7-nitroquinoxaline2,3-dione (10 microM) and 2-amino
      5-phosphonopentanoate (200 microM) to the bath, suggesting participation of both
      alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and N-methyl-D-aspartate
      receptors. The inputs from ipsilateral trigeminal afferents included a di- or
      oligosynaptic glycinergic inhibition. Sustained rhythmical membrane potential
      oscillations were observed in 52% of the recorded cells upon stimulation of
      trigeminal afferents or the contralateral nucleus sensibilis nervi trigemini. Two
      types of rhythm were obtained: (i) low-frequency oscillations (0.1-0.5 Hz), with
      peak-to-peak amplitudes between 8.5 and 17 mV; and (ii) higher frequency
      oscillations (1.0-2.8 Hz) with smaller amplitudes (1.8-5.1 mV). The two types of
      trigeminal rhythm could occur independently of fictive locomotion and fictive
      breathing. In a decerebrate semi-intact preparation, slow rhythmical trigeminal
      motoneuron potential oscillations were also evoked by stimulation of the oral
      disc. This study shows that trigeminal motoneurons receive excitatory synaptic
      inputs from several brainstem sites, and that membrane potential oscillations can
      be triggered upon stimulation of trigeminal afferents or the nucleus sensibilis
      nervi trigemini. We suggest that these oscillations recorded in vitro may
      represent the centrally generated components that underlie rhythmical feeding in
      lampreys.

PMID- 10336087
TI  - Sleep in the platypus.
AB  - We have conducted the first study of sleep in the platypus Ornithorhynchus
      anatinus. Periods of quiet sleep, characterized by raised arousal thresholds,
      elevated electroencephalogram amplitude and motor and autonomic quiescence,
      occupied 6-8 h/day. The platypus also had rapid eye movement sleep as defined by
      atonia with rapid eye movements, twitching and the electrocardiogram pattern of
      rapid eye movement. However, this state occurred while the electroencephalogram
      was moderate or high in voltage, as in non-rapid eye movement sleep in adult and
      marsupial mammals. This suggests that the low-voltage electroencephalogram is a
      more recently evolved feature of mammalian rapid eye movement sleep. Rapid eye
      movement sleep occupied 5.8-8 h/day in the platypus, more than in any other
      animal. Our findings indicate that rapid eye movement sleep may have been present
      in large amounts in the first mammals and suggest that it may have evolved in pre
      mammalian reptiles.

PMID- 10336088
TI  - Synaptic alterations in apolipoprotein E knockout mice.

PMID- 10336089
TI  - The eicosanoid generating capacity of isolated cell populations from the gills of
      the rainbow trout, Oncorhynchus mykiss.
AB  - Rainbow trout gill filaments generated a wide range of eicosanoid products
      following calcium ionophore challenge. The putative lipoxygenase products were
      separated by reverse phase high performance liquid chromatography (RP-HPLC),
      while prostanoids were quantified by enzyme immunoassay. Three main monohydroxy
      compounds containing conjugated dienes were observed after RP-HPLC namely 12-(S)
      hydroxyeicosatetraenoic acid (12-HETE), 12-(S) hydroxyeicosapentaenoic acid (12
      HEPE) and 14-(S) hydroxydocosahexaenoic acid (14-HDHE), derived from endogenous
      arachidonic, eicosapentaenoic and docosahexaenoic acids, respectively. Their
      identification was confirmed by mass spectrometry. A further five compounds
      containing conjugated trienes were also observed but in lesser amounts. One of
      these products was identified as 8,15-dihydroxyeicosatetraenoic acid (8,15
      DiHETE) based on its UV spectrum, co-elution with authentic standard on RP-HPLC
      and mass spectrometry. Overall, the generation of these products suggests the
      presence of 12- and possibly 15-lipoxygenase activities in trout gill acting on
      endogenous sources of fatty acid. To determine if the various cell types in trout
      gill had differing eicosanoid generating potential, gills were disrupted and the
      resultant cell suspensions separated by density gradient centrifugation.
      Following this three bands were formed on the gradients and the cell populations
      from these were characterised using periodic acid Schiff's (PAS) reactivity for
      mucosubstances, haematoxylin and eosin staining, and immunoreactivity with both
      monoclonal and polyclonal antibodies. The first band consisted of polygonal cells
      and other more minor cell types, the second cell band contained mainly polygonal
      and PAS-positive goblet epithelial cells, while the third band consisted of
      mainly erythrocytes. There were significant differences in the eicosanoid
      generating potential of the isolated cells, with cells from the second band
      generating significantly more 12-HETE and 8,15-DiHETE than those from both the
      first band and unfractionated populations. The eicosanoid generating activity of
      the trout gill epithelial cell line, RTG-W1, was also elucidated. It proved to be
      a modest generator of eicosanoids in that only low levels of thromboxane B2 and
      prostaglandin E2 were detected while no lipoxygenase products were observed.

PMID- 10336090
TI  - Comparison of the half-lives and regeneration rates of blood clotting factors II,
      VII, and X in anticoagulant-resistant and susceptible Norway rats (Rattus
      norvegicus Berk.).
AB  - The half-lives and regeneration rates of clotting factors II, VII, and X in the
      plasma of anticoagulant-resistant and susceptible rats were determined. There is
      little or no difference in the half-lives of factors II and X in anticoagulant
      resistant rats compared to susceptible rats, but the half-life of factor VII is
      longer in anticoagulant-resistant rats. In anticoagulant-resistant rats critical
      clotting factors appear to be carboxylated in preference to factor II, whereas
      the opposite occurs in susceptible rats; this may contribute to an animal's
      resistance status.

PMID- 10336092
TI  - Inhibition of sea urchin fertilization by fatty acid ethanolamides and
      cannabinoids.
AB  - The influence of saturated and unsaturated fatty acid ethanolamides as well as
      delta9-tetrahydrocannabinol (delta9-THC), WIN 55,212-2 and cannabinoid CB1
      receptor antagonist SR 141716 on sea urchin fertilization was studied. The
      ethanolamides of arachidonic, oleic and linoleic acids but not saturated fatty
      acid (C14-C20) derivatives inhibited fertilization when pre-incubated with sperm
      cells. Delta9-THC and WIN 55,212-2 also inhibited fertilization, delta9-THC being
      ten times as potent as WIN 55,212-2. Selective cannabinoid CB1 receptor
      antagonist SR 141716 also blocked fertilization and did not antagonize the action
      of delta9-THC. The obtained results indicate that different unsaturated fatty
      acid ethanolamides may control sea urchin fertilization, and that sea urchin
      sperm cell cannabinoid receptor may differ from the known cannabinoid receptor
      subtypes.

PMID- 10336091
TI  - Esterification and hydrolysis of vitamin A in the liver of brook trout
      (Salvelinus fontinalis) and the influence of a coplanar polychlorinated biphenyl.
AB  - Recent reports of extremely low retinoid stores in fish living in contaminated
      river systems prompted an initial investigation of the mechanisms of hepatic
      storage and mobilization in brook trout. Enzyme characterization in microsomes
      revealed a lecithin:retinol acyltransferase activity (LRAT) optimum in the
      alkaline range (pH 9.0; Vmax = 0.6 nmol per mg prot. h(-1); Km = 10.2 microM)
      which is not known to occur in mammals, in addition to a secondary optimum at pH
      6.5 typical of mammals. Acyl CoA:retinol acyltransferase (ARAT) kinetic
      parameters were quite different to those of mammals. The substrate affinity of
      trout ARAT (Km = 1.6 microM) was approximately 22-fold greater than that of the
      rat while maximal velocity (Vmax = 0.2 nmol per mg prot. h(-1)) was 18-fold less.
      Retinyl ester hydrolase activity (REH) was optimal under acid conditions (pH 4.2;
      Vmax = 6.6 nmol per mg prot. h(-1); Km = 0.6 mM), was inhibited by a bile salt
      analogue and was greater in males than females. This REH was tentatively
      categorized as a bile salt-independent, acid retinyl ester hydrolase (BSI-AREH).
      REH was inhibited in a dose-dependent manner following in vivo exposure to a
      representative environmental contaminant the coplanar polychlorinated biphenyl
      (PCB), 3,3',4,4'-tetrachlorobiphenyl (TCBP). Inhibition may be an indirect effect
      because enzyme activity was not affected by in vitro exposure of control
      microsomes. REH inhibition in the brook trout may affect the uptake of retinyl
      esters (REs) from chylomicron remnants as well as the mobilization of stored REs.

PMID- 10336093
TI  - Strain differences of the ability to hydroxylate methotrexate in rats.
AB  - Converting activity of methotrexate (MTX) to 7-hydroxymethotrexate (7-OH-MTX) was
      examined using eight strains of rats. Marked variability of the activity was
      found in liver cytosols from the rats. The highest activity was observed with
      Sea:SD rats, followed by LEW/Sea and Jcl:Wistar rats. The lowest activity was
      observed with WKA/Sea rats. The difference in the activity between Sea:SD and
      WKA/Sea strains was 104-fold. The variation was correlated to the strain
      difference of benzaldehyde oxidase activity in the rats. The cytosolic 7
      hydroxylase activities in other tissues of Sea:SD rats were much higher than
      those of WKA/Sea, similarly to the case in liver. The liver microsomes of Sea:SD
      rats exhibited no 7-hydroxylase activity toward MTX even in the presence of
      NADPH. The cytosolic 7-hydroxylating activity of the livers of Sea:SD rats was
      inhibited by menadione, beta-estradiol, chlorpromazine and disulfiram, inhibitors
      of aldehyde oxidase, but not oxypurinol, an inhibitor of xanthine oxidase. The
      purified aldehyde oxidase from the livers of Sea:SD rats exhibited a significant
      7-hydroxylating activity toward MTX. However, xanthine oxidase had no ability to
      hydroxylate MTX. These facts suggest that MTX hydroxylating activity in rats is
      predominantly due to aldehyde oxidase, and the strain differences are due to the
      variations of the flavoenzyme level.

PMID- 10336094
TI  - Some effects of the fungicide propiconazole on cytochrome P450 and glutathione S
      transferase in brown trout (Salmo trutta).
AB  - The fungicide propiconazole (1-(2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2
      ylmethyl) -1H-1,2,4-triazole) induced the hepatic cytochrome P4501A (CYP1A)
      activity towards ethoxyresorufin-O-deethylase (EROD), the content of CYP1A
      protein as quantified by enzyme-linked immunosorbent assay (ELISA) and the
      glutathione S-transferase (GST) activity towards the three commonly used
      substrates CDNB(1-chloro-2,4-dinitrobenzene), cumene hydroperoxide (CU) and
      ethachrynic acid (EA) in brown trout (Salmo trutta) depending on dose and body
      weight. An exponential dose response relationship existed between propiconazole
      exposure and CYP1A activity. A 2. order polynomial regression of the
      propiconazole concentration (square root transformed) on the data for CDNB, EU
      and CU revealed a bell-shaped pattern of the GST induction. Reverse-phase HPLC of
      the GSH-affinity chromatography purified GST isozymes in trout exposed to
      respectively 8.3, 23, 93, 313 and 606 microg l(-1) propiconazole in the water
      indicated that the propiconazole treatment may lead to changes in the composition
      of the subunits compared to the controls. Thus, propiconazole exposure through
      the water changed the properties of the brown trout hepatic CYP1A and GST, and
      these changes may be used as a bioindicator on the molecular level of exposure
      and effect of propiconazole in controlled experiments. The use in monitoring of
      propiconazole exposure under natural field conditions is possible, however needs
      further investigation.

PMID- 10336095
TI  - Kinetics of cadmium accumulation and elimination in carp Cyprinus carpio tissues.
AB  - Carp (Cyprinus carpio) were tested for cadmium accumulation and elimination
      during and after a simulated pollution exposure. Fish were distributed in two
      1000-l indoor concrete aquaria supplied with a continuous flow (8 l min(-1)) of
      well water. The cadmium concentration was maintained at 53 microg l(-1) in one
      aquarium and 443 microg l(-1) in the other aquarium for 127 days. The exposure
      phase was followed by a 43-day depuration period. The cadmium accumulation in
      liver, kidney and muscle was measured by means of ICP-MS. The data showed that
      cadmium exposure produces significant cadmium uptake in tissues. Cadmium
      concentrations increased sharply in kidney and liver, whereas the pollutant level
      in muscle was only significant after 106 days. After 127 days of Cd exposure (53
      microg l(-1)), the cadmium concentration in kidney was 4-fold higher than in
      liver and 50-fold higher than in muscle for a toxic level of 53 microg l(-1). At
      a Cd of 443 microg l(-1), kidney cadmium content was 2-fold higher than in liver
      and 100-fold higher than in muscle. In kidney and liver, the toxic concentration
      increased as the concentration of pollutant in water increased. During the 43
      depuration days, the loss of accumulated cadmium was rapid and immediate in
      muscle. Conversely, no loss of cadmium was observed in kidney and liver.

PMID- 10336096
TI  - Cholinesterases from the marine mussels Mytilus galloprovincialis Lmk. and M.
      edulis L. from the freshwater bivalve Corbicula fluminea Muller.
AB  - In order to improve the molecular basis for the use of bivalve cholinesterases as
      a reliable biomarker for aquatic pollution, the polymorphism and characterization
      of these enzymes in Mytilus edulis, Mytilus galloprovincialis and Corbicula
      fluminea were investigated. All results are consistent with the presence of only
      one pharmacological form of cholinesterase in each species. The molecular masses
      were 180 kDa for the two marine mussels and 240 kDa for C. fluminea. The
      cholinesterases are anchored to the membrane by a glycosyl inositol phosphate
      like the Ga form (type I) described in vertebrates. Surprisingly, these
      cholinesterases were poorly inhibited by organophosphorous compounds compared to
      enzymes from other sources. This suggests that these bivalves could be used as a
      biomarker for acute rather than chronic contaminations by anticholinesterase
      insecticides.

PMID- 10336097
TI  - Study of the relationship between thyroid hormones and lipid metabolism during
      KClO4-induced metamorphosis of landlocked lamprey, Petromyzon marinus.
AB  - This study examines the role of thyroid hormones (TH) (thyroxine and
      triiodothyronine) in regulating lipid metabolism of landlocked larval sea
      lampreys, Petromyzon marinus. Larvae were treated with either thyroxine (0.5 or 1
      mg l(-1) water) or triiodothyronine (0.25 or 1 mg l(-1) water) in the presence or
      absence of the goitrogen, potassium perchlorate (KClO4) (0.05% w/v), for 4, 8,
      and 16 weeks. Treatment with KClO4 alone, which induced metamorphosis after 8
      weeks and lowered plasma TH levels, reduced hepatic and renal total lipid content
      after 8 weeks of treatment. KClO4-induced lipid depletion after the 8-week
      treatment was supported by an increased rate of hepatic lipolysis, as indicated
      by increased triacylglycerol lipase activity. Furthermore, reduced lipogenesis in
      the liver was indicated by decreased hepatic acetyl-CoA carboxylase and
      diacylglycerol acyltransferase (DGAT) activities, and by decreased renal DGAT
      activity following 8 weeks of KClO4 treatment. Treatment of larvae for 4 weeks
      with TH alone resulted in either no change or a slight increase of lipid in the
      liver and kidney. TH treatments in combination with KClO4 failed to induce
      metamorphosis and, after up to 8 weeks, several TH treatments blocked changes in
      lipid content and enzyme activity associated with KClO4-induced metamorphosis.
      These experimental results suggest that TH deficiency during metamorphosis may
      promote lipid catabolism, while the presence of TH tends to protect/promote lipid
      reserves, perhaps favoring the larval condition. The actions of TH and KClO4 on
      metamorphosis-associated lipid metabolism in sea lampreys may be direct,
      permissive, and/or indirect via other factors.

PMID- 10336098
TI  - Development of a screening questionnaire for tobacco/nicotine dependence
      according to ICD-10, DSM-III-R, and DSM-IV.
AB  - A 10-item questionnaire (the Tobacco Dependence Screener; TDS) for screening of
      tobacco/nicotine dependence according to ICD-10, DSM-III-R, and DSM-IV was newly
      developed. The reliability and validity were assessed in three samples of smokers
      in Japan. A total of 58 male smokers completed the TDS and the Fagerstrom
      Tolerance Questionnaire (FTQ), and they were interviewed using the World Health
      Organization's Composite International Diagnostic Interview (Sample 1). A total
      of 118 male and 36 female smoking outpatients completed the TDS and the FTQ and
      provided a breath sample for carbon monoxide measurement (Sample 2). A total of
      194 male smokers joined a health education program using a health risk appraisal
      (HRA) and reported their smoking status and completed the TDS 6 months after
      receiving the HRA results (Sample 3). The Cronbach's alpha coefficients for the
      TDS ranged from .74 to .81 among the samples, whereas those for the FTQ ranged
      from .41 to .64. Receiver operator characteristic analyses indicated that the TDS
      had a better screening performance for ICD-10, DSM-III-R, and DSM-IV diagnoses
      than did the FFQ. The TDS score significantly and positively correlated with the
      severity of the diagnoses, the carbon monoxide levels, number of cigarettes
      smoked per day, and years of smoking. The TDS score was significantly lower in
      those who quit smoking than in those who did not quit smoking after the HRA. It
      is suggested that the TDS is a reliable and useful screening questionnaire for
      tobacco/nicotine dependence according to ICD-10, DSM-III-R, and DSM-IV.

PMID- 10336099
TI  - Metacognition and substance use.
AB  - Metacognition has been defined as cognition about cognition. Metacognition can
      include beliefs and attitudes about cognitive events such as thoughts, feelings,
      memories, images, sensations, and perceptions. Cognitive models of addictions
      have addressed the role of beliefs and attitudes in substance misuse, but the
      role of metacognition has been neglected. Metacognitive effects (beliefs about
      the effect of psychoactive substances on cognition) is differentiated from
      metacognitive consequences (beliefs about the effect of refraining from
      psychoactive substances on cognitive experience). In this study of 20 types of
      cognitive experience in 108 treatment-seeking substance abusers, the major
      metacognitive effects of drugs and alcohol were reduction, detachment from, and
      intensification of the cognitive event. The major metacognitive consequences of
      not consuming a substance included beliefs that the cognitive experience would be
      too uncomfortable, sleep would be disturbed, persistence of the cognitive event,
      and intensification of the cognitive event. An interaction between metacognitive
      effects and consequences and the type of cognitive event was found.

PMID- 10336100
TI  - Mood and forbidden foods' influence on perceptions of binge eating.
AB  - This study consists of two experiments investigating the effects of induced mood
      and food type on perceptions of eating in imagined and real eating situations. A
      total of 212 female undergraduates representing the continuum of bulimic
      symptomatology were induced with either elated or depressed moods using a
      standardized mood-induction procedure. They were then either asked to imagine
      themselves in a situation with either forbidden or non-forbidden foods
      (Experiment 1) or else were presented with a buffet of forbidden or non-forbidden
      foods and asked to eat (Experiment 2). Participants subsequently reported their
      perception of their eating behavior (i.e., amount of control, meal rating: from a
      snack to a binge; and meal feeling: from great to bad). Results revealed limited
      support for affect regulation models of bulimia nervosa when the participants
      consumed food, but no support for the theory when they imagined eating.
      Conversely, forbidden foods were found to influence perceptions in the imagined
      eating situation, but not when the participants ate. Implications of these
      results are discussed.

PMID- 10336101
TI  - Motivational profiles of polysubstance-dependent patients: do they differ from
      alcohol-dependent patients?
AB  - Changing addictive behaviors may be conceptualized as a stage phenomenon
      consisting of precontemplation, contemplation, preparation, action, and
      maintenance stages. Prior research has provided empirical support for the
      existence of two discrete motivational subtypes of alcohol-dependent patients
      (i.e., precontemplation and contemplation/action stage patients). The present
      study attempted to identify similar motivational profiles for polysubstance
      dependent patients and to provide empirical support for the validity of these
      profiles. Results from a sample of polysubstance-dependent VA patients revealed
      two clusters consistent with precontemplation (n = 62) and contemplation/action
      stage (n = 71) profiles, similar to findings from alcohol-dependent samples.
      Although, as expected, contemplation/action stage patients were more likely to
      complete treatment than were precontemplators, relatively few differences were
      noted between these two groups on several other theoretically relevant variables.
      These results suggest that these subtypes may not identify clinically similar
      types of patients across alcohol- and polysubstance-dependent samples.

PMID- 10336102
TI  - Stress-coping and other psychosocial risk factors: a model for smoking in grade 6
      students.
AB  - Smoking uptake by adolescents is best studied by a following a cohort of children
      as they proceed through adolescence. In this analysis of the first stage of such
      a study, several hypotheses about psychosocial factors that may modify the
      initiation of smoking in adolescents were examined in 1,552 11- and 12-year-olds
      in a school system in Scarborough, Canada. Investigation of the stress-coping
      hypothesis and other possible effect modifiers as they relate to ever-smoking
      revealed that stress (measured by number of life events) was important for both
      males and females (p = .0163 and .0056, respectively). However, the mechanisms
      underlying smoking appear to be different for males and females, even at this
      young age. In models adjusting for several factors simultaneously, rebelliousness
      was found to be the most important factor (p = .0001) followed by attitudes
      toward the effect of second-hand smoke (p = .0063) for males, whereas for
      females, mother smoking was the most important factor (p = .0001) followed by
      rebelliousness (p = .0102). Implications for design of prevention programs are
      discussed.

PMID- 10336103
TI  - Effects of exercise-focused versus weight-focused maintenance programs on the
      management of obesity.
AB  - This study examined the effects of two maintenance programs on exercise
      participation, energy expenditure, energy consumption, and weight change in 67
      obese adults undergoing behavioral weight-loss treatment. Following an initial 6
      month treatment phase which produced a mean weight loss of 8.8 kg, participants
      were assigned randomly to an exercise-focused maintenance program or to a weight
      focused maintenance program. Both maintenance programs included 6 months of
      biweekly group sessions. The exercise-focused program included supervised group
      walking sessions, individual and group contingencies for exercise completion, and
      relapse prevention training targeted specifically at the maintenance of physical
      activity. The weight-focused program contained a general focus on the maintenance
      of weight-loss through therapist-led group problem-solving of weight-related
      problems presented by individual participants. At the completion of the
      maintenance program and at long-term follow-up, there were no significant
      differences between conditions in exercise participation or energy expenditure.
      However, during the year following initial treatment, participants in the weight
      focused program demonstrated significantly greater reductions in fat consumption
      and significantly better maintenance of weight losses than subjects in the
      exercise-focused program.

PMID- 10336104
TI  - Expectancies and other psychosocial factors associated with alcohol use among
      early adolescent boys and girls.
AB  - Early experimentation with drinking increases the lifetime risk for substance
      abuse and other serious health and social problems. We studied factors associated
      with early alcohol experimentation by surveying 4,263 sixth- to eighth-grade
      students (67.1% White, 23.5% Black, 7.2% other races combined; 2.2% missing data)
      from seven schools in one suburban school district. The prevalence of drinking in
      the last 30 days was 12.1% for boys and 13.1% for girls (12.6% overall); 6.6%
      among sixth graders, 11.1% among seventh graders, and 19.5% among eighth graders.
      In multiple logistic regression analyses, controlling for grade, positive alcohol
      expectancies, perceived prevalence, and deviance acceptance were associated
      positively, self-control negatively, with drinking for both boys and girls. Among
      boys, grade point average was negatively associated with drinking. Among girls,
      propensity for risk-taking and problem-behaving friends were positively
      associated and high parental expectations were negatively associated with
      drinking. Alcohol use in our sample of early adolescent boys and girls was better
      explained by modifiable psychosocial factors such as alcohol expectancies,
      perceived prevalence, and self-control than by grade.

PMID- 10336105
TI  - Longitudinal patterns of tobacco smoking from childhood to middle age.
AB  - This study described the development of tobacco smoking of subjects between ages
      12 and 36 using prospectively collected self-reports of 212 Swedish men and women
      born in the 1950s. Smoking habits were studied in terms of stability,
      longitudinal patterns of smoking, and the relation between age of initiation and
      later smoking. Findings showed that light smoking (up to 6 cigarettes/day) did
      not remain stable after adolescence. Typical development patterns from age 15 to
      age 36 included staying a nonsmoker; smoking intensely (>10 cigarettes/day) and
      continuing into adulthood; smoking less intensely for some periods; or smoking
      intensely and quitting before age 36. Differences in age at smoking initiation
      were related to later habitual smoking only when participants reported initiation
      had occurred after age 12.

PMID- 10336106
TI  - Correlates of occasional cigarette and marijuana use: are teens harm reducing?
AB  - This paper examines characteristics that distinguish heavy and occasional
      cigarette and marijuana use among U.S. high school seniors. High school seniors
      who completed the 1994 Monitoring the Future survey (N = 15,929) were classified
      as nonusers, occasional users, and heavy users of cigarettes and marijuana. Level
      of use was examined with regard to degree of perceived risk of regular use,
      perceived risk of occasional use as well as several psychosocial factors
      previously shown to be associated with use (e.g., peer use, close friends'
      approval of use, and self-esteem). Involvement with other drugs and high-risk
      behaviors across levels of use was also examined. Heavy users of cigarettes or
      marijuana reported significantly lower perceived risk of regular use of each
      substance compared to occasional users. Heavy and occasional users did not
      generally differ with regard to perceived risk of occasional use. Compared to
      heavy users, occasional cigarette or marijuana users reported significantly lower
      rates of illicit drug use, heavy alcohol use, and high-risk driving behaviors as
      well as fewer problem behaviors and higher grades. Some adolescents may moderate
      their cigarette and marijuana use to minimize harmful effects they associate with
      heavier use (i.e., they may be practicing harm reduction). Additional research is
      needed to better understand controlled substance use, and incorporate this
      information into prevention and cessation programs.

PMID- 10336107
TI  - Untreated remissions from drug use: the predominant pathway.
AB  - Prior research has indicated that the majority of people who resolve an alcohol
      problem or from smoking cigarettes do so without treatment. However, no similar
      data have been available for other drug resolutions. This article explores the
      service use of former drug users employing data from the 1994 Canadian Alcohol
      and Drug survey. It is concluded that, as for alcohol and smoking, the majority
      of individuals stop their drug use without treatment.

PMID- 10336108
TI  - Reliability of children's self-reported cigarette smoking.
AB  - Youth who first smoke cigarettes during childhood are a high risk for habitual
      smoking. Evaluating the reliability of children's smoking initiation is essential
      to research efforts to explain or prevent smoking onset. The present study is the
      first to establish reliability of self-reported smoking behavior with
      questionnaire data from elementary school children (N = 1,184). Data from a
      longitudinal investigation are used to examine the consistency of children's self
      reported smoking across items and over time. Both cross-sectional and
      longitudinal analyses demonstrate that children report having tried smoking and
      lifetime use remarkably consistently. However, only about half the children
      reliably estimated their grade at first use. The study results suggest that some
      but not all standard questionnaire items yield reliable self-report data about
      initial smoking behavior from respondents as young as 8 to 11 years.

PMID- 10336109
TI  - College students' self-reported reasons for playing drinking games.
AB  - Two samples of college students who engage in drinking games completed questions
      about their drinking behavior, a set of items concerning their reasons for
      playing drinking games, and various self-report measures of personality.
      Principal components analysis using the first sample yielded four factors:
      Relaxation & Disinhibition, Fun & Celebration, Conformity, and Sexual
      Manipulation. A similar factor structure was also obtained in the second sample.
      In both samples, Fun & Celebration and Sexual Manipulation reasons were most
      strongly predictive of frequency of play and quantity of alcohol consumed while
      playing. In men, Sexual Manipulation reasons for play predicted frequency of
      taking sexual advantage of others during play. Endorsement of Conformity and
      Relaxation & Disinhibition reasons were associated with high social anxiety and
      low assertiveness. Reasons for play predicted consumption, both in drinking-game
      situations and overall, even after removing variance due to general reasons for
      drinking. Psychometric properties of the current measure are less than ideal, but
      the constructs identified appear to have important implications for prevention.
      Assessment of self-reported reasons for drinking in specific situations may be a
      generally useful strategy.

PMID- 10336111
TI  - "Ready to quit chew? " Smokeless tobacco cessation in rural Nebraska.
AB  - A quit-chew media campaign was conducted in a 10-county region of south-central
      Nebraska. The campaign involved television and radio appearances, newspaper
      articles, and paid billboard advertisements. Smokeless tobacco users who called a
      toll-free helpline were provided quitting resources. Twelve months after the
      campaign ended, follow-up contact was completed with 104/205 (51%) of chewers who
      received the quit kits. A majority (70%) reported making some change, such as
      using less or switching brands, and 49% had made a quit attempt. The point
      prevalence quit rate was 11.5%.

PMID- 10336110
TI  - Open trials as a method of prioritizing medications for inclusion in controlled
      trials for cocaine dependence.
AB  - This paper describes a rapid and systematic method of using open trials to
      identify medications that may be useful for the treatment of cocaine dependence.
      Results of these open trials can be used to prioritize medications for inclusion
      in subsequent double-blind, placebo-controlled trials. Preliminary results are
      presented from the evaluation of propranolol, nefazodone, and the combination of
      phentermine and fenfluramine (phen/fen). Each medication was evaluated in an open
      trial, and results were compared to results obtained from a group that received a
      multivitamin. Outcome measures included treatment retention, urine toxicology
      screens, self-reported cocaine use, and changes on the Addiction Severity Index
      (ASI). Treatment retention was significantly better in the propranolol group than
      in the multivitamin group. Concurrent alcohol abuse was associated with increased
      rates of attrition in the multivitamin group, and the phen/fen group, but not in
      the propranolol group. Neither the nefazodone nor the phen/fen groups showed any
      outcome advantages over the multivitamin group. We conclude that propranolol may
      enhance retention among cocaine-dependent patients, especially among those who
      also abuse alcohol. These results encourage a double-blind, placebo-controlled
      trial of propranolol.

PMID- 10336112
TI  - How many donuts is a "binge"? Women with BED eat more but do not have more
      restrictive standards than weight-matched non-BED women.
AB  - Theories of disordered eating suggest that binge eating may occur as a response
      to violations of unrealistically restrictive dietary standards, but there are few
      direct comparisons of the dietary standards of binge eaters and nonbinge eaters.
      In this study, we asked obese women with Binge Eating Disorder (BED) and weight-
      and age-matched women without BED to report the minimum amount of each of eight
      foods they considered a "binge" and "out of control" to determine whether binge
      eaters had stricter dietary standards than women without BED. Women with BED did
      not consider smaller amounts of food a "binge" or "out of control" than did women
      without BED; however, binge eaters did report that their "typical" and "largest
      ever" servings of each of the eight foods were larger than those reported by
      nonbinge eaters. This suggests that for this group of eating- disordered women,
      eating behaviors may be a more important intervention target than overly
      restrictive dietary standards.

PMID- 10336113
TI  - Noxious heat activates all capsaicin-sensitive and also a sub-population of
      capsaicin-insensitive dorsal root ganglion neurons.
AB  - A sub-population of primary afferent fibres comprising mainly Adelta and C
      polymodal nociceptors specifically detects high intensity heat stimuli. These
      fibres are also sensitive to high threshold mechanical stimulation and different
      chemicals including inflammatory mediators. C-polymodal nociceptors are also
      activated by capsaicin. Recent findings show that noxious heat induces inward
      currents in a sub-population of cultured dorsal root ganglion neurons by opening
      nonselective cation-channels. It has been suggested that noxious heat is
      transduced by the recently cloned capsaicin-gated ion-channel since oocytes and
      HEK 293 cells expressing this channel respond to heat as well as capsaicin. In
      agreement with this suggestion Kirschstein et al. found in a small sample of
      dorsal root ganglion cells that all heat-sensitive neurons were also sensitive to
      capsaicin. In this study we examine further, by whole-cell voltage-clamp
      recording from adult rat dorsal root ganglion neurons grown in culture, the
      relationship between heat- and capsaicin-sensitivity. Our results show the
      existence of two kinds of heat-sensitive neurons, distinguished by their
      temperature thresholds. The low-threshold cells, which comprise the small-medium
      diameter population, are capsaicin-sensitive, whereas the high-threshold (mainly
      large-diameter) cells are not, and we postulate the existence of a heat
      transducer distinct from capsaicin receptor in the latter group.

PMID- 10336114
TI  - Functional involvement of synaptotagmin I/II C2A domain in neurite outgrowth of
      chick dorsal root ganglion neuron.
AB  - Synaptotagmin I or II (Syt I/II) is involved in Ca2+-regulated exocytosis of
      secretory vesicles, probably serving as a Ca2+-sensor via its C2A domain.
      Synaptotagmin is also known to be expressed in neuronal growth cone vesicles, but
      its functional involvement in neurite outgrowth remains largely unknown. In this
      study, we examined the function of Syt I/II in neurite outgrowth in cultured
      chick dorsal root ganglion neurons using an anti-synaptotagmin I and II C2A
      domain (anti-STI/II-C2A) antibody that inhibits Ca2+-regulated exocytosis.
      Immunoblots confirmed the high specificity of the anti-STI/II-C2A antibody and
      showed the expression of synaptotagmin I or II in chick dorsal root ganglion
      neurons. Immunocytochemistry revealed that synaptotagmin I or II is enriched at
      the growth cone region of chick dorsal root ganglion neurons, in both
      lamellipodia and filopodia. Whole or Fab-fragment of the anti-STI/II-C2A antibody
      loaded into dorsal root ganglion neurons by trituration significantly inhibited
      neurite outgrowth, whereas preimmune immunoglobulin G had no effect. These
      results showed that the C2A domain of synaptotagmin I or II plays a crucial role
      in neurite outgrowth.

PMID- 10336116
TI  - Brain-derived neurotrophic factor regulates the expression of AMPA receptor
      proteins in neocortical neurons.
AB  - The role of the neurotrophins; nerve growth factor, brain-derived neurotrophic
      factor, neurotrophin-3 and neurotrophin-4/5, in synaptic development and
      plasticity has been extensively investigated. The neurotrophins regulate synaptic
      transmission as well as neural development in the brain. However, the mechanisms
      underlying these processes are unknown. In this study we show that brain-derived
      neurotrophic factor triggers an increase in alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid (AMPA)-type glutamate receptor (GluR) proteins without
      significant changes in their messenger RNA levels. Brain-derived neurotrophic
      factor treatment specifically increased the protein levels of GluR1 (193+/-22%)
      and GluR2/3 (182+/-11%) in cultured rat neocortical neurons. In contrast, nerve
      growth factor and neurotrophin-3 failed to alter the protein levels of these
      neurons, and brain-derived neurotrophic factor effects on N-methyl-D-aspartate
      type glutamate receptors were either modest or negligible. Immunocytochemical
      studies indicated that the increase in AMPA receptor proteins reflects the
      induction of their neuronal expression, but not selective neuronal survival. In
      agreement with these results, cortical neurons from brain-derived neurotrophic
      factor-knockout mice exhibited a reduction in AMPA receptor proteins in the
      cytoskeletal fraction containing postsynaptic proteins. Thus, the neurotrophin
      plays a crucial role in modulating the expression of AMPA receptors presumably at
      translational or post-translation levels and is implicated in synaptic
      development and plasticity.

PMID- 10336115
TI  - Activation of dopamine D2 receptors decreases DARPP-32 phosphorylation in
      striatonigral and striatopallidal projection neurons via different mechanisms.
AB  - The vast majority of striatal neurons are GABAergic medium-sized spiny neurons.
      These cells receive glutamatergic input from the cortex, thalamus and limbic
      areas and dopaminergic input from the mesencephalon. Most relevant evidence
      indicates that dopamine D1 receptors are located on striatonigral projection
      neurons, and that adenosine A2A receptors and most dopamine D2 receptors are
      located on striatopallidal projection neurons (see, however, Refs I and 13). Here
      we have utilized regulation of the phosphorylation of dopamine- and cyclic AMP
      regulated phosphoprotein of mol. wt 32,000 (DARPP-32) to study the possible
      interactions among nigrostriatal dopaminergic neurons and the two classes of
      dopaminoceptive target neurons. We show that, in striatal slices, the D2 receptor
      agonist, quinpirole, strongly inhibits the phosphorylation of DARPP-32 induced by
      either the D1 receptor agonist, SKF 81297, or the A2A receptor agonist, CGS
      21680. Tetrodotoxin abolished the effect of quinpirole on the D1 agonist-induced
      but not the A2A agonist-induced phosphorylation of DARPP-32. These data indicate
      that: (i) adenosine A2A and dopamine D2 receptors interact within the same
      striatopallidal neurons, and (ii) D2 receptors present on the striatopallidal
      neurons modulate the effects of D1 receptors on the striatonigral neurons. Thus,
      a single neurotransmitter is capable of activating distinct classes of receptors
      on distinct populations of target neurons, which, in turn, interact with each
      other through intercellular communication.

PMID- 10336117
TI  - An immunohistochemical study of the distribution of brain-derived neurotrophic
      factor in the adult human brain, with particular reference to Alzheimer's
      disease.
AB  - Brain-derived neurotrophic factor is a member of the family of neuronal
      differentiation and survival-promoting molecules called neurotrophins. Neuronal
      populations known to show responsiveness to the action of brain-derived
      neurotrophic factor include the cholinergic forebrain, mesencephalic
      dopaminergic, cortical, hippocampal and striatal neurons. This fact has aroused
      considerable interest in the possible contribution of an abnormal brain-derived
      neurotrophic factor function to the aetiology and physiopathology of different
      neurodegenerative disorders, such as Alzheimer's disease. This report describes
      the cellular and regional distribution of brain-derived neurotrophic factor in
      post mortem control human brain and in limited regions of the brain in patients
      with Alzheimer's disease, as was revealed by immunohistochemistry. Brain-derived
      neurotrophic factor is widely expressed in the control human brain, both by
      neurons and glia. In neurons, brain-derived neurotrophic factor was localized in
      the cell body, dendrites and axons. Among the structures showing the most intense
      immunohistochemical labeling were the hippocampus, claustrum, amygdala, bed
      nucleus of the stria terminalis, septum and the nucleus of the solitary tract. In
      the striatum, immunoreactivity was more intense in striosomes than in the matrix.
      Many labeled neurons were found in the substantia nigra pars compacta. The large
      putatively cholinergic neurons in the basal forebrain showed no immunoreactivity.
      The general pattern of labeling was similar in individuals with Alzheimer's
      disease. Brain-derived neurotrophic factor-immunoreactive material was found in
      senile plaques, and some immunoreactive cortical pyramidal neurons showed
      neurofibrillary tangles, suggesting that brain-derived neurotrophic factor may be
      involved in the process of neuronal degeneration and/or compensatory mechanisms
      which occur in this illness.

PMID- 10336118
TI  - Role of brain-derived neurotrophic factor and presynaptic proteins in passive
      avoidance learning in day-old domestic chicks.
AB  - The consolidation of a one-trial passive avoidance learning task in the day-old
      chick involves a number of transient and longer-term biochemical processes,
      including increased release of glutamate. This study demonstrated that brain
      derived neurotrophic factor, a proposed modulator of synaptic transmission and
      neurotransmitter release, is involved in the cascade associated with memory
      consolidation in the chick and that its actions were linked to modulation of
      expression of SNAP-25, syntaxin and synaptophysin, required for exocytosis.
      Intracerebral injections of 5 microl of antibodies to brain-derived neurotrophic
      factor into the left and right intermediate medial hyperstriatum ventrale
      resulted in a dose-dependent reduction in avoidance of an "aversive" bead by 3 h
      after training. Neurotrophin antibodies (0.5 microg/chick) administered between 1
      h before, and up to 30 min after, training induced amnesia by 3 h which was
      sustained for at least 24 h. Injections of recombinant brain-derived neurotrophic
      factor (50 microg/ml; 0.5 microg/chick) just before training maintained avoidance
      in birds trained with a weaker aversant (10% methylanthranilate), such that
      chicks showed enhanced recall at times (24 h) beyond that when shorter-term forms
      of memory have decayed. In lysed synaptosomal membranes prepared from chicks
      injected with antibodies to brain-derived neurotrophic factor there was a
      decrease in expression of SNAP-25 and syntaxin in the left, but not the right,
      intermediate medial hyperstriatum ventrale, a region known to be associated with
      memory formation, which correlated with the decrease in neurotrophin
      concentration. Thus, these data indicate that brain-derived neurotrophic factor
      is involved in the formation of a long-term memory for an aversive stimulus and
      may function as a modulator of presynaptic proteins associated with exocytosis,
      enabling increases in neurotransmitter release.

PMID- 10336119
TI  - Basic fibroblast growth factor in the primary olfactory pathway: mitogenic effect
      on ensheathing cells.
AB  - The mitogenic effect of basic fibroblast growth factor and nerve growth factor
      (2.5S) on olfactory ensheathing cell culture was examined by bromodeoxyuridine
      uptake. It was found that, at 10 ng/ml, basic fibroblast growth factor elicited
      about a three-fold increase in proliferation, while the stimulatory effect of
      nerve growth factor was considerably less. The increased proliferation resulting
      from basic fibroblast growth factor could be attributed to perlecan, which was
      shown to be expressed by ensheathing cell in culture. Perlecan is known to induce
      high-affinity binding of basic fibroblast growth factor to receptors on cell
      membranes. Immunohistochemical staining demonstrated that basic fibroblast growth
      factor was abundantly expressed in select regions of the lamina propria
      underlying the olfactory epithelium. In these regions, contiguous patches of
      olfactory epithelium also showed the presence of basic fibroblast growth factor.
      Although basic fibroblast growth factor was present on the periphery of nerve
      bundles in the olfactory nerve layer of the bulb, all other laminae did not
      demonstrate the presence of this factor. The immunohistochemistry and cell
      culture results show that regions of the lamina propria and small patches of the
      olfactory epithelium, by their presence of basic fibroblast growth factor, are
      potential sites of ensheathing cell proliferation in vivo.

PMID- 10336120
TI  - Visual input regulates the expression of basic fibroblast growth factor and its
      receptor.
AB  - Emerging evidence indicates that the expression of trophic factors in the brain
      is regulated in an activity-dependent manner, which suggests an involvement of
      trophic factors in events controlled by input activity. We have investigated the
      possibility that visual sensory input impacts the expression of basic fibroblast
      growth factor and its receptor in the brain. Rats were maintained for seven days
      in darkness and then re-exposed to normal illumination for 0, 1, 3 or 6 h. We
      assessed relative levels of basic fibroblast growth factor and fibroblast growth
      factor receptor messenger RNAs using nuclease protection assays, and examined
      possible changes in the phenotypic expression of basic fibroblast growth factor
      and its receptor using immunohistochemistry. There was a significant decrease in
      levels of basic fibroblast growth factor and fibroblast growth factor receptor
      messenger RNAs as a result of dark rearing, and levels of messenger RNAs
      increased progressively with light re-exposure. Changes in messenger RNAs were
      observed primarily in the cerebral cortex (caudal portion) and were accompanied
      by alterations in the staining intensity and density of cells exhibiting basic
      fibroblast growth factor and fibroblast growth factor receptor phenotypes.
      Regulation of the basic fibroblast growth factor system by sensory input suggests
      that basic fibroblast growth factor, and perhaps other trophic factors, are
      mediators of the effects of experience on the structure and function of the CNS.

PMID- 10336121
TI  - Fimbria-fornix transection and excitotoxicity produce similar neurodegeneration
      in the septum.
AB  - Fimbria-fornix transection produces neuronal injury in the septum. This cellular
      pathology is characterized by somatodendritic vacuolar abnormalities in neurons.
      Because these cellular changes are reminiscent of some of the morphological
      abnormalities seen with glutamate receptor-mediated excitoxicity, we tested
      whether excitotoxic injury to the septal complex of adult rats mimics the
      degeneration observed within the dorsolateral septal nucleus and medial septal
      nucleus following fimbria-fornix transection. The septal complex was evaluated at
      various time-points (6 h to 14 days) by light and electron microscopy following
      unilateral injection of the N-methyl-D-aspartate receptor agonist quinolinate or
      the non-N-methyl-D-aspartate receptor agonist kainate, and the morphological
      changes observed were compared to those abnormalities in the medial septal
      nucleus and dorsolateral septal nucleus at three to 14 days after fimbria-fornix
      transection. The patterns of cytoplasmic abnormalities and vacuolar injury were
      morphologically similar in the somatodendritic compartment of neurons following
      excitotoxicity and axotomy paradigms. These similarities were most evident when
      comparing the persistently injured neurons in the penumbral regions of the
      excitotoxic lesions at one to 14 days recovery to neurons in the medial septal
      nucleus and dorsolateral septal nucleus at seven and 14 days after fimbria-fornix
      transection. Pretreatment with the N-methyl-D-aspartate receptor antagonist
      dizocilpine maleate prior to unilateral fimbria-fornix transection attenuated the
      somatodentritic vacuolar damage found within the ipsilateral dorsolateral and
      medial septal nuclei at 14 days recovery. Because glutamate is the principal
      transmitter of hippocampal efferents within the fimbria-fornix, we conclude that
      postsynaptic glutamate receptor activation participates in the evolution of
      septal neuron injury following fimbria-fornix transection. Thus, excitotoxicity
      is a possible mechanism for transneuronal degeneration following central nervous
      system axotomy.

PMID- 10336122
TI  - Expression of C5a receptor in mouse brain: role in signal transduction and
      neurodegeneration.
AB  - In this study we explored the potential role of the complement derived
      anaphylatoxin C5a and the expression of its receptor in mouse brain. Using in
      situ hybridization, we found that C5a receptor messenger RNA is expressed in
      mouse brain. In response to intraventricular kainic acid injection, there was
      marked increase in the C5a receptor messenger RNA expression, particularly in
      hippocampal formation and cerebral cortex. C5a ligand-binding autoradiography
      confirmed the functional expression and elevation of the C5a receptor post
      lesioning. The expression of C5a receptor messenger RNA in brain was confirmed by
      northern blot hybridization of total RNA from neuronal and glial cells in vitro.
      Based on these findings we explored the role of C5a in mechanisms of signal
      transduction in brain cells. Treatment of primary cultures of mouse astrocytes
      with human recombinant C5a resulted in the activation of mitogen-activated
      extracellular signal-regulated protein kinase. This response appeared to be
      mediated by the C5a receptor since astrocyte cultures derived from C5a receptor
      knockout mice were not responsive to the treatment. Understanding the regulation
      of C5a receptor in brain and mechanisms by which pro-inflammatory C5a modulates
      specific signal transduction pathways in brain cells is crucial to studies of
      inflammatory mechanisms in neurodegeneration.

PMID- 10336123
TI  - Expression of the glutamate transporters in human temporal lobe epilepsy.
AB  - Glutamate is the major excitatory neurotransmitter in the central nervous system
      and is implicated in the pathogenesis of neurodegenerative diseases. Five human
      glutamate transporters have been cloned and are responsible for the removal of
      potentially excitotoxic excess glutamate from the extracellular space. In this
      study we consider whether there are selective changes in the expression of the
      glutamate transporters in the medial temporal cortex and hippocampus from
      temporal lobe epilepsy patients, which might contribute to the development or
      maintenance of seizures. Since disruption of the glial transporter excitatory
      amino acid transporter 2 in mice results in lethal spontaneous seizures, we were
      interested primarily in studying changes in this transporter. Using in situ
      hybridization we show that there was no reduction in the level of excitatory
      amino acid transporter 2 encoding messenger RNA in the temporal lobe epilepsy
      cases compared to post mortem controls and indeed there was a relative increase
      in content of excitatory amino acid transporter 2 messenger RNA per cell in
      temporal lobe epilepsy cases. Western blotting showed that there was no change in
      the excitatory amino acid transporter 2 protein content in temporal lobe epilepsy
      cases as compared to post mortem controls. A small reduction in the level of the
      second astroglial transporter protein, excitatory amino acid transporter 1, was
      observed in temporal lobe epilepsy cases. Surprisingly, immunohistochemical
      experiments using a polyclonal antiexcitatory amino acid transporter 2 antibody,
      showed a different localization of this protein in epilepsy derived tissue as
      compared to post mortem controls although glial markers such as glial fibrillary
      acidic protein and glutamine synthase showed similar patterns of staining.
      However, repeating this experiment using control tissue from non-temporal lobe
      epilepsy biopsies demonstrated that this change in the excitatory amino acid
      transporter 2 transporter localization occurred post mortem. These data suggest
      that major changes in the level of expression of the glutamate transporters do
      not play an important role in the development of human temporal lobe epilepsy but
      may be implicated the aetiology of other types of epilepsy.

PMID- 10336124
TI  - Expression of mu, kappa, and delta opioid receptor messenger RNA in the human
      CNS: a 33P in situ hybridization study.
AB  - The existence of at least three opioid receptor types, referred to as mu, kappa,
      and delta, is well established. Complementary DNAs corresponding to the
      pharmacologically defined mu, kappa, and delta opioid receptors have been
      isolated in various species including man. The expression patterns of opioid
      receptor transcripts in human brain has not been established with a cellular
      resolution, in part because of the low apparent abundance of opioid receptor
      messenger RNAs in human brain. To visualize opioid receptor messenger RNAs we
      developed a sensitive in situ hybridization histochemistry method using 33P
      labelled RNA probes. In the present study we report the regional and cellular
      expression of mu, kappa, and delta opioid receptor messenger RNAs in selected
      areas of the human brain. Hybridization of the different opioid receptor probes
      resulted in distinct labelling patterns. For the mu and kappa opioid receptor
      probes, the most intense regional signals were observed in striatum, thalamus,
      hypothalamus, cerebral cortex, cerebellum and certain brainstem areas as well as
      the spinal cord. The most intense signals for the delta opioid receptor probe
      were found in cerebral cortex. Expression of opioid receptor transcripts was
      restricted to subpopulations of neurons within most regions studied demonstrating
      differences in the cellular expression patterns of mu, kappa, and delta opioid
      receptor messenger RNAs in numerous brain regions. The messenger RNA distribution
      patterns for each opioid receptor corresponded in general to the distribution of
      opioid receptor binding sites as visualized by receptor autoradiography. However,
      some mismatches, for instance between mu opioid receptor receptor binding and mu
      opioid receptor messenger RNA expression in the anterior striatum, were observed.
      A comparison of the distribution patterns of opioid receptor messenger RNAs in
      the human brain and that reported for the rat suggests a homologous expression
      pattern in many regions. However, in the human brain, kappa opioid receptor
      messenger RNA expression was more widely distributed than in rodents. The
      differential and region specific expression of opioid receptors may help to
      identify targets for receptor specific compounds in neuronal circuits involved in
      a variety of physiological functions including pain perception, neuroendocrine
      regulation, motor control and reward.

PMID- 10336125
TI  - Postembedding immunogold labelling reveals subcellular localization and pathway
      specific enrichment of phosphate activated glutaminase in rat cerebellum.
AB  - Phosphate activated glutaminase is a key enzyme in glutamate synthesis. Here we
      have employed a quantitative and high-resolution immunogold procedure to analyse
      the cellular and subcellular expression of this enzyme in the cerebellar cortex.
      Three main issues were addressed. First, is phosphate activated glutaminase
      exclusively or predominantly a mitochondrial enzyme, as biochemical data suggest?
      Second, to what extent is the mitochondrial content of glutaminase dependent on
      cell type and transmitter identity? Third, can individual neurons maintain a
      subcellular segregation of mitochondria with different glutaminase content? An
      attempt was also made to disclose the intramitochondrial localization of
      glutaminase, and to correlate the content of this enzyme with that of glutamate
      and glutamine in the same mitochondria (by use of triple labelling). Antisera to
      the N- and C-termini of glutaminase revealed strong labelling of the putatively
      glutamatergic mossy fibre terminals. The vast majority of gold particles
      (approximately 96%) was associated with the mitochondria. Equally high labelling
      intensities were found in mitochondria of perikarya and dendrites in the pontine
      nuclei, a major source of mossy fibres. The level of glutaminase immunoreactivity
      in parallel and climbing fibres (which like the mossy fibres are thought to use
      glutamate as transmitter) was only about 20% of that in mossy fibres, and similar
      to that in non-glutamatergic neurons (Purkinje and Golgi cells). Glial cell
      mitochondria were devoid of specific glutaminase labelling and revealed a much
      lower glutamate:glutamine ratio than did the mitochondria of mossy fibres. As to
      the submitochondrial localization of glutaminase, immunogold particles were often
      found to be aligned with the cristae, suggesting an association of the enzyme
      with the inner mitochondrial membrane. However, the existence of a glutaminase
      pool in the mitochondrial matrix could not be excluded. The outer mitochondrial
      membrane was unlabelled. The present study provides quantitative evidence for a
      substantial heterogeneity in the mitochondrial content of glutaminase. This
      heterogeneity applies not only to neurons with different transmitter signatures,
      but also to different categories of glutamatergic pathways. In terms of the
      routes involved, the synthesis of transmitter glutamate may be less uniform than
      previously expected.

PMID- 10336126
TI  - High and low responders to novelty: effects of a catecholamine synthesis
      inhibitor on novelty-induced changes in behaviour and release of accumbal
      dopamine.
AB  - The purpose of the present study was two-fold: (i) to investigate to what extent
      novelty, i.e. a novel cage with slightly larger dimensions than the home cage and
      lacking the floor covering that was originally present, produced behavioural
      effects in high responders to novelty and low responders to novelty that could be
      correlated with the extracellular amount of accumbal dopamine, using the
      microdialysis technique, and (ii) to establish the ability of the catecholamine
      synthesis inhibitor alpha-methyl-p-tyrosine to inhibit the novelty-induced
      responses in high and low responders. The difference in the behavioural response
      to novelty between the high and low responders was limited to walking, which
      lasted significantly longer in high responders than in low responders. The
      novelty-induced increase in extracellular concentration of accumbal dopamine was
      significantly greater in high responders than in low responders; moreover, the
      shape of the growth curves differed between high and low responders. The
      behavioural changes did not correlate with the neurochemical effects, which
      outlasted the duration of the novelty-induced behavioural arousal. It is
      hypothesized that this long-lasting increase in accumbal dopamine produces
      "adaptive changes" that help and/or allow the animal to incorporate knowledge
      about the condition that it experienced. When the nucleus accumbens was perfused
      with alpha-methyl-p-tyrosine for a period of 40 min, given at the same time as
      the transfer of the rat to the novel cage, it reduced the novelty-induced
      increase in walking in the high responders, but did not alter the novelty-induced
      behaviour of low responders. Finally, alpha-methyl-p-tyrosine reduced the novelty
      induced increase in the release of accumbal dopamine in high responders, but
      enhanced it in low responders. The present neurochemical data are discussed in
      view of the outcome of earlier reported pharmacobehavioural studies on the
      neurochemical state of the nucleus accumbens of non-challenged versus challenged
      high and low responders. It is hypothesized that, in the high responder, exposure
      to novelty enhances the release of accumbal dopamine from reserpine-resistant,
      alpha-methyl-p-tyrosine-sensitive pools that are under the stimulatory control of
      beta-adrenergic receptors in the nucleus accumbens, and that, in the low
      responder, exposure to novelty enhances the release of accumbal dopamine from
      reserpine-sensitive, alpha-methyl-p-tyrosine-resistant pools that are under the
      inhibitory control of alpha-adrenergic receptors in the nucleus accumbens.

PMID- 10336127
TI  - Thalamic input to parvalbumin-immunoreactive GABAergic interneurons: organization
      in normal striatum and effect of neonatal decortication.
AB  - The neocortex and thalamus send dense glutaminergic projections to the
      neostriatum. The neocortex makes synaptic contact with spines of striatal
      projection neurons, and also targets a distinct class of GABAergic interneurons
      immunoreactive for the calcium-binding protein parvalbumin. We determined whether
      the parafascicular thalamic nucleus also targets striatal parvalbumin
      immunoreactive interneurons. The anterograde tracer biotinylated dextranamine was
      injected into the parafascicular nucleus of adult rats. Double-labeled
      histochemistry/immunohistochemistry revealed overlapping thalamic fibers and
      parvalbumin-immunoreactive neurons in the neostriatum. Areas of overlap within
      the sensorimotor striatum were analysed by electron microscopy. Of 311 synaptic
      boutons originating from the parafascicular nucleus, 75.9% synapsed with
      unlabeled dendrites, 22.5% with unlabeled spines, and 1.3% had parvalbumin
      immunoreactive dendrites as a postsynaptic target. Only 4% of all asymmetric
      synapses on parvalbumin-immunoreactive dendrites were derived from the
      parafascicular nucleus. A separate group of animals underwent bilateral
      neocortical deafferentation on the third postnatal day, prior to injection of
      anterograde tracer into the parafascicular nucleus of adult animals. These
      experiments were performed with the dual purpose of (i) reducing the possibility
      that thalamic inputs to parvalbumin-immunoreactive neurons are the result of
      transsynaptic uptake of tracer by a thalamo-cortico-striatal route, and (ii)
      determining whether competitive interactions between developing corticostriatal
      and thalamostriatal fibers may account for the relatively sparse thalamic input
      onto parvalbumin-immunoreactive interneurons. In decorticates, 219 striatal
      synaptic contacts derived from the parafascicular nucleus, out of which 77.2%
      were on unlabeled dendrites, 20.9% were upon unlabeled spines, and 0.9% targeted
      parvalbumin-immunoreactive dendrites. We conclude that the thalamic
      parafascicular nucleus indeed sends synaptic input to parvalbumin-immunoreactive
      striatal neurons. Parafascicular nucleus inputs to striatal parvalbumin
      immunoreactive interneurons are sparse in comparison to other asymmetric inputs,
      most of which are likely to be of cortical origin. The synaptic profile of
      thalamostriatal inputs to parvalbumin-immunoreactive neurons and unlabeled
      elements is unchanged following neonatal decortication. This suggests that
      competitive interaction between developing thalamostriatal and corticostriatal
      projections is not a major mechanism determining synaptic input to striatal
      subpopulations.

PMID- 10336128
TI  - Effect of arginine on basal and high potassium-induced efflux of [3H]D-aspartate
      from rat striatal slices.
AB  - There are conflicting reports in the literature regarding the effects of nitric
      oxide as well as the involvement of the cyclic GMP pathway on the transmitter
      release. To study the influence of the availability of the nitric oxide precursor
      arginine on the glutamate transmission process, rat striatal slices preloaded
      with the tritiated glutamate analogue D-aspartate were used. L-Arginine
      stimulated in a concentration-dependent way (0.01-10.0 mM) the high potassium
      induced efflux of [3H]D-aspartate. The basal release was increased only by 10 mM
      L-arginine. Neither the basal nor the depolarization-induced efflux of [3H]D
      aspartate was affected by D-arginine. The L-arginine effect was abolished by the
      nitric oxide synthase inhibitor L-arginine methyl ester and was not modified by
      cyclic GMP. Only at high concentrations of L-arginine (10 mM) could an elevation
      of cyclic GMP level be demonstrated. The results are discussed in terms of direct
      presynaptic action of nitric oxide on [3H]D-aspartate efflux and a possible
      modulation of glutamate release by the availability of arginine.

PMID- 10336129
TI  - Alpha2C-adrenoceptor overexpression disrupts execution of spatial and non-spatial
      search patterns.
AB  - We investigated the role of alpha2C-adrenoceptors in the modulation of spatial
      and non-spatial navigation behaviour. Alpha2C-adrenoceptor overexpressing mice
      developed an ineffective thigmotaxic search pattern characterized by swimming
      close to the pool walls during both spatial and non-spatial water maze training.
      A subtype-non-selective alpha2-adrenoceptor antagonist, atipamezole (1000
      microg/kg, s.c.), fully reversed this impairment in their search strategy.
      Withdrawal of atipamezole at the end of spatial training resulted in an immediate
      disruption of the search pattern in alpha2C-adrenoceptor overexpressing mice. The
      swimming pattern of alpha2C-adrenoceptor overexpressing mice during a five day
      free swimming period was normal, when no cognitive component was required.
      Diazepam (0.3 and 1.0 mg/kg, i.p.), neither improved the accuracy in finding the
      platform nor decreased thigmotaxis. These results suggest that alpha2C
      adrenoceptors may modulate the execution of complex navigation patterns.

PMID- 10336130
TI  - Phosphorylation of transcription factor cyclic-AMP response element binding
      protein mediates c-fos induction elicited by sustained hypertension in rat
      nucleus tractus solitarii.
AB  - We investigated the role of cyclic-AMP response element binding protein signaling
      in the induction of the immediate-early gene c-fos by baroreceptor activation in
      neurons of the nucleus tractus solitarii of anesthetized rats. Activation of the
      arterial baroreceptors with sustained hypertension significantly increased the
      number of neurons in the caudal nucleus tractus solitarii that were
      immunoreactive to an antiserum that detects Ser133-phosphorylated cyclic-AMP
      response element binding protein. This implied increase in phosphorylation of
      cyclic-AMP response element binding protein was subsequently followed by an
      elevation in the expression of Fos protein in neurons of the nucleus tractus
      solitarii. Microinjection bilaterally into the nucleus tractus solitarii of a
      phosphorothioated antisense oligonucleotide directed against the initiation site
      of cyclic-AMP response element binding protein messenger RNA discernibly reduced
      the manifested immunoreactivity of phosphorylated cyclic-AMP response element
      binding protein in response to baroreceptor activation. This was accompanied by a
      decline in the transcription of c-fos messenger RNA and the expression of Fos
      protein, along with an appreciable potentiation of the baroreceptor reflex
      response. Control injections of the sense oligonucleotide or artificial
      cerebrospinal fluid were ineffective. These findings suggest that phosphorylation
      of cyclic-AMP response element binding protein is crucial to Fos expression in
      the nucleus tractus solitarii elicited by sustained hypertension. As such,
      phosphorylation of cyclic-AMP response element binding protein may be an
      important early nuclear event that mediates the long-term inhibitory modulation
      of the baroreceptor reflex response by Fos protein at the nucleus tractus
      solitarii.

PMID- 10336131
TI  - A novel influence of adenosine on ongoing activity in rat rostral ventrolateral
      medulla.
AB  - We have investigated whether exogenously applied adenosine modulates neuronal
      activity in a region of the central nervous system crucial for cardiovascular
      regulation. Extracellular recordings were made from neurons in the rostral
      ventrolateral medulla of the anaesthetized rat. Ionophoretic application of
      adenosine altered ongoing activity in 91% of neurons, evoking either a long
      lasting depression or a short-lasting increase in firing rate. Both responses
      were blocked by application of the broad spectrum adenosine receptor antagonist 8
      sulphophenyltheophylline, indicating that the responses were mediated by specific
      cell surface receptors. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3
      dimethylxanthine blocked the increase, and partially blocked the decrease in
      firing rate in response to adenosine. The GABA(A) receptor antagonist bicuculline
      also blocked the increase in firing rate in response to adenosine, suggesting
      that adenosine may inhibit release of GABA from axon terminals in this region.
      The adenosine A2a receptor agonist CGS 21680 produced a long-lasting depression
      of ongoing activity. These results suggest that A1 receptors mediate an increase
      in firing rate, whilst A1 and A2a receptors mediate decreases in firing rate in
      some rostral ventrolateral medulla neurons. Thus, adenosine has been shown to
      modulate the ongoing activity of neurons in the rostral ventrolateral medulla by
      acting at both A1 and A2a receptors. Accordingly, we suggest, and provide some
      evidence to support the idea, that adenosine acts as an important neuromodulator
      in this region of the central nervous system, possibly by modulating the
      presynaptic release of neurotransmitters such as GABA.

PMID- 10336132
TI  - Immunolocalization of tripeptidyl peptidase II, a cholecystokinin-inactivating
      enzyme, in rat brain.
AB  - Tripeptidyl peptidase II (EC 3.4.14.10) is a serine peptidase apparently involved
      in the inactivation of cholecystokinin octapeptide [Rose C. et al. (1996) Nature
      380, 403-409]. We have compared its distribution with that of cholecystokinin in
      rat brain, using a polyclonal antibody raised against a highly purified
      preparation for immunohistochemistry at the photon and electron microscope
      levels. Tripeptidyl peptidase II-like immunoreactivity was mostly detected in
      neurons, and also in ependymal cells and choroid plexuses, localizations
      consistent with a possible participation of the peptidase in the inactivation of
      cholecystokinin circulating in the cerebrospinal fluid. Immunoreactivity was
      mostly detected in cell bodies, large processes and, to a lesser extent, axons of
      various neuronal populations. Their localization, relative to that of
      cholecystokinin terminals, appears to define three distinct situations. The first
      corresponds to neurons with high immunoreactivity in areas containing
      cholecystokinin terminals, as in the cerebral cortex or hippocampal formation,
      where pyramidal cell bodies and processes surrounded by cholecystokinin axons
      were immunoreactive. A similar situation was encountered in many other areas,
      namely along the pathways through which cholecystokinin controls satiety, i.e. in
      sensory vagal neurons, the nucleus tractus solitarius and hypothalamic nuclei.
      The second situation corresponds to cholecystokinin neuronal populations
      containing tripeptidyl peptidase II-like immunoreactivity, as in neurons of the
      supraoptic or paraventricular nuclei, axons in the median eminence or nigral
      neurons. In both situations, localization of tripeptidyl peptidase II-like
      immunoreactivity is consistent with a role in cholecystokinin inactivation. The
      third situation corresponds to areas with mismatches, such as the cerebellum, a
      region devoid of cholecystokinin, but in which Purkinje cells displayed high
      tripeptidyl peptidase II-like immunoreactivity, possibly related to a role in the
      inactivation of neuropeptides other than cholecystokinin. Also, some areas with
      cholecystokinin terminals, e.g., the molecular layer of the cerebral cortex, were
      devoid of tripeptidyl peptidase II-like immunoreactivity, suggesting that
      processes other than cleavage by tripeptidyl peptidase II may be involved in
      cholecystokinin inactivation. Tripeptidyl peptidase II-like immunoreactivity was
      also detected at the ultrastructural level in the cerebral cortex and
      hypothalamus using either immunoperoxidase or silver-enhanced immunogold
      detection. It was mainly associated with the cytoplasm of neuronal somata and
      dendrites, often in the vicinity of reticulum cisternae, Golgi apparatus or
      vesicles, and with the inner side of the dendritic plasma membrane. Hence,
      whereas a fraction of tripeptidyl peptidase II-like immunoreactivity localization
      at the cellular level is consistent with its alleged function in cholecystokinin
      octapeptide inactivation, its association with the outside plasma membrane of
      neurons remains to be confirmed.

PMID- 10336133
TI  - 5-Hydroxytryptamine and glutamate modulate velocity and extent of intercellular
      calcium signalling in hippocampal astroglial cells in primary cultures.
AB  - The effects of 5-hydroxytryptamine or glutamate treatment on mechanically induced
      intercellular calcium waves were studied in gap junction-coupled astroglial cells
      using rat astroglial-neuronal primary cultures from hippocampus. Imaging software
      was developed to study amplitude, velocity and extent of wave propagation.
      Velocity software was designed to find the cell contours automatically and to
      calculate travelled distance and time-delay of the calcium wave as it propagates
      from the stimulated cell to all other cells. Propagation analyses were performed
      to calculate the area of wave propagation. Mechanical stimulation of a single
      astroglial cell induced an intercellular calcium wave spreading from cell to cell
      in the astroglial syncytium. When registering the appearances of calcium signals
      in individual cells along the wave path upon re-stimulation of the same cell,
      44.7% of the cells responded with similar calcium signal appearances the second
      time as the first time. A second wave from the opposite direction resulted in
      similar calcium signal appearances in 27.3% of the studied cells. Both amplitude
      and velocity of the calcium signal decreased most prominently in the first part
      and showed a later flattening out. Treatment with 5-hydroxytryptamine or
      glutamate for 20-30 s before mechanical stimulation increased the velocity of the
      calcium waves. 5-Hydroxytryptamine treatment for varying times decreased the
      propagation area of the calcium waves. In contrast, glutamate treatment increased
      the propagation area.

PMID- 10336134
TI  - Localization of macrophage inflammatory protein: macrophage inflammatory protein
      1 expression in rat brain after peripheral administration of lipopolysaccharide
      and focal cerebral ischemia.
AB  - Macrophage inflammatory protein is a member of the C-C subfamily of chemokines,
      which exhibits, in addition to proinflammatory activities, a potent endogenous
      pyrogen activity. In this study, we analysed the time-course of expression and
      cellular source of macrophage inflammatory protein-1alpha and macrophage
      inflammatory protein-1beta, in inflammation of the rat brain associated with
      ischemia and endotoxemia. Using in situ hybridization histochemistry, we observed
      that intravenously injected bacterial lipopolysaccharide induced a transient
      expression of macrophage inflammatory protein-1alpha and macrophage inflammatory
      protein-1beta messenger RNAs throughout the brain, with maximal expression 8-12 h
      after lipopolysaccharide treatment. We also revealed an early increase in
      macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta
      messenger RNA levels, after permanent and transient middle cerebral artery
      occlusion, starting as early as 1 h after the occlusion and reaching a peak of
      expression 8-16 h after middle cerebral artery occlusion. The induction of
      macrophage inflammatory protein-1 messenger RNA was clearly stronger in the
      transient than in the permanent middle cerebral artery-occluded rat brains,
      showing that the reperfusion process influences the extent of the chemokine
      response after middle cerebral artery occlusion. In situ hybridization combined
      with immunohistochemistry for glial fibrillary acidic protein, a specific marker
      for astrocytes, excluded astrocytes as the cellular source of macrophage
      inflammatory protein-1 messenger RNAs after both middle cerebral artery ischemia
      and lipopolysaccharide treatment. Using immunohistochemistry, macrophage
      inflammatory protein-1alpha protein expression was shown to be induced in a time
      dependent manner after lipopolysaccharide treatment and middle cerebral artery
      occlusion. Macrophage inflammatory protein-1alpha immunopositive cells co
      localized with cells stained with OX-42 antibody, a microglia/macrophage marker.
      These results indicate that macrophage inflammatory protein-1 is implicated in
      the inflammatory reaction of the brain in response to ischemia or infection, and
      might modulate the host defence febrile response to a pathogenic stimulus.

PMID- 10336135
TI  - Inflammation-induced up-regulation of protein kinase Cgamma immunoreactivity in
      rat spinal cord correlates with enhanced nociceptive processing.
AB  - Activation of various second messengers contributes to long-term changes in the
      excitability of dorsal horn neurons and to persistent pain conditions produced by
      injury. Here, we compared the time-course of decreased mechanical nociceptive
      thresholds and the density of protein kinase Cgamma immunoreactivity in the
      dorsal horn after injections of complete Freund's adjuvant in the plantar surface
      of the rat hindpaw. Complete Freund's adjuvant significantly increased paw
      diameter and mechanical sensitivity ipsilateral to the inflammation. The changes
      peaked one day post-injury, but endured for at least two weeks. In these rats, we
      recorded a 75-100% increase in protein kinase Cgamma immunoreactivity in the
      ipsilateral superficial dorsal horn of the L4 and L5 segments at all time-points.
      Electron microscopy revealed that the up-regulation was associated with a
      significant translocation of protein kinase Cgamma immunoreactivity to the plasma
      membrane. In double-label cytochemical studies, we found that about 20% of the
      protein kinase Cgamma-immunoreactive neurons, which are concentrated in inner
      lamina II, contain glutamate decarboxylase-67 messenger RNA, but none stain for
      parvalbumin or nitric oxide synthase. These results indicate that persistent
      changes in protein kinase Cgamma immunoreactivity parallel the time-course of
      mechanical allodynia and suggest that protein kinase Cgamma contributes to the
      maintenance of the allodynia produced by peripheral inflammation. The minimal
      expression of protein kinase Cgamma in presumed inhibitory neurons suggests that
      protein kinase Cgamma-mediated regulation of excitatory interneurons underlies
      the changes in spinal cord activity during persistent nociception.

PMID- 10336136
TI  - Co-localization of substance P and dopamine beta-hydroxylase with growth
      associated protein-43 is lost caudal to a spinal cord transection.
AB  - After spinal cord injury, abnormal responses of spinal cord neurons to sensory
      input lead to conditions such as autonomic dysreflexia, urinary bladder
      dyssynergia, muscle spasticity and chronic pain syndromes. These responses
      suggest that the spinal cord undergoes marked reorganization after an injury. In
      previous studies, we demonstrated changes in individual patterns of
      immunoreactivity for growth-associated protein-43, dopamine beta-hydroxylase and
      substance P that suggest growth and/or changes in expression of neurotransmitter
      enzymes and peptides in the cord caudal to a transection injury. In the present
      study we determined whether (i) growth-associated protein-43 and dopamine beta
      hydroxylase or substance P were co-expressed in the same neurons prior to cord
      injury, and (ii) these patterns of expression changed after injury. A change in
      co-localization patterns caudal to an injury would suggest diversity in responses
      of different populations of spinal neurons. We used double-labelling
      immunocytochemistry to determine whether either dopamine beta-hydroxylase or
      substance P was co-localized with growth-associated protein-43 in control rats
      and in rats one, two or six weeks after spinal cord transection. We focused on
      the intermediate gray matter, especially the sympathetic intermediolateral cell
      column. In control rats, fibres travelling in a stereotyped ladder-like pattern
      in the thoracic gray matter contained growth-associated protein-43 co-localized
      with dopamine beta-hydroxylase or substance P. In spinal rats, such co
      localization was also observed in spinal cord segments rostral to the cord
      transection. In contrast, caudal to the transection, substance P and growth
      associated protein-43 were found in separate reticular networks. Immunoreactivity
      for dopamine beta-hydroxylase disappeared in fibres during this time, but was
      clearly present in somata. Immunoreactivity for growth-associated protein-43 was
      also found in somata, but never co-localized with that for dopamine beta
      hydroxylase. These observations demonstrated co-localization of growth-associated
      protein-43 with dopamine beta-hydroxylase and substance P in descending spinal
      cord pathways. Caudal to a cord transection, this co-localization was no longer
      found, although each substance was present either in an abundant neural network
      or in somata. One population of spinal neurons responded to cord injury by
      expressing the growth-associated protein, whereas two others changed in the
      intensity of their expression of neurotransmitter peptides or enzymes or in the
      abundance of fibres expressing them. Thus, three populations of spinal neurons
      had distinct responses to cord injury, two of them increasing their potential
      input to spinal sensory, sympathetic or motor neurons. Such responses would
      enhance transmission through spinal pathways after cord injury.

PMID- 10336137
TI  - Microtubule-associated protein-2 in the hypothalamo-neurohypophysial system: low
      molecular-weight microtubule-associated protein-2 in pituitary astrocytes.
AB  - Microtubule-associated protein-2 is the most abundant microtubule-associated
      protein in the brain and is responsible for morphogenesis and maintenance of the
      nervous system. In the present experiments, we have examined the localization of
      microtubule-associated protein-2 in the hypothalamo-neurohypophysial system of
      the rat using western blots and immunohistochemistry. Two monoclonal antibodies
      against microtubule-associated protein-2, antibody C and AP20, were used:
      antibody C recognizes both the high- and low-molecular-weight isoforms of
      microtubule-associated protein-2; antibody AP20 specifically detects high
      molecular-weight microtubule-associated protein-2 only. Western blot analysis
      revealed expression of high-molecular-weight microtubule-associated protein-2 in
      the whole brain, hippocampus and whole hypothalamus. While the supraoptic nucleus
      expressed only high-molecular-weight microtubule-associated protein-2, the adult
      posterior pituitary predominantly expressed low-molecular-weight microtubule
      associated protein-2, which was also seen in the embryonic whole brain. Light
      microscopic immunohistochemistry revealed that both antibody C and AP20 intensely
      stained dendrites of the dendritic and somatic zones in the supraoptic nucleus.
      Double labeling with antibodies against microtubule-associated protein-2 and
      oxytocin (or vasopressin) demonstrated that microtubule-associated protein-2 was
      localized in dendrites of magnocellular neurons in the supraoptic nucleus. In the
      posterior pituitary, however, antibody C stained fine processes and cell bodies
      of astrocytes, which were identified by an antibody against glial fibrillary
      acidic protein. Antibody AP20 also stained fine processes of some astrocytes in
      the posterior pituitary, but the intensity of immunoreactivity with antibody AP20
      was weaker than that with antibody C. This result suggests that microtubule
      associated protein-2 in astrocytes of the posterior pituitary is predominantly of
      the low-molecular-weight type. Moreover, western blots revealed low-molecular
      weight microtubule-associated protein-2 of the posterior pituitary at a molecular
      weight slightly higher than embryonically expressed low-molecular-weight
      microtubule-associated protein-2, indicating that low-molecular-weight
      microtubule-associated protein-2 in the posterior pituitary is possibly the
      isoform microtubule-associated protein-2d. The present results demonstrate that
      astrocytes in the posterior pituitary of adult rats still retain the ability to
      express the immature variant of microtubule-associated protein-2, low-molecular
      weight microtubule-associated protein-2, and its expression is probably linked to
      structural plasticity.

PMID- 10336138
TI  - Hypo-osmolarity stimulates and high sodium concentration inhibits thyrotropin
      releasing hormone secretion from rat hypothalamus.
AB  - The hypothalamic paraventricular nucleus, representing cell bodies in which
      thyrotropin-releasing hormone is synthesized, and the median eminence,
      representing nerve terminals, were incubated in vitro. Various hypo- and
      hyperosmotic solutions were tested to determine osmotic sensitivity of
      thyrotropin-releasing hormone secretion. High KCl (56 mM) causing membrane
      depolarization was used as a non-specific control stimulus to induce thyrotropin
      releasing hormone secretion. A 30% decrease of medium osmolarity (from 288 to 202
      mOsmol/l) increased thyrotropin-releasing hormone secretion from both the
      paraventricular nucleus and median eminence. A 30% decrease of medium NaCl
      content by its replacement with choline chloride did not affect basal thyrotropin
      releasing hormone secretion. Increasing medium osmolarity with biologically
      inactive L-glucose did not affect basal or KCl-induced thyrotropin-releasing
      hormone secretion from either structure. Medium made hyperosmotic (350-450
      mOsmol/l) by increasing the NaCl concentration resulted in a dose-dependent
      decrease of basal thyrotropin-releasing hormone secretion and abolished KCl
      induced thyrotropin-releasing hormone secretion. If an osmotically equivalent
      amount of choline chloride was substituted for NaCl, there was no effect on
      thyrotropin-releasing hormone secretion, indicating a specific action of Na+.
      This study indicates a specific sensitivity to high concentrations of Na+ ions of
      both thyrotropin-releasing hormone-producing parvocellular paraventricular
      neurons and thyrotropin-releasing hormone-containing nerve terminals in the
      median eminence.

PMID- 10336139
TI  - Dark Agouti and Fischer 344 rats: differential behavioral responses to morphine
      and biochemical differences in the ventral tegmental area.
AB  - We sought to identify behavioral and biochemical differences between Dark Agouti
      and Fischer 344 inbred rat strains to assess whether they could serve as a model
      of genetically determined differences in sensitivity to drugs of abuse. We
      compared the strains for the following traits: morphine-induced locomotor
      activity and sensitization; circadian variation in plasma levels of
      corticosterone, a hormone reported to affect sensitivity to drugs of abuse; and
      several biochemical parameters in the ventral tegmental area and nucleus
      accumbens, brain regions implicated in the locomotor activating and reinforcing
      actions of drugs of abuse. Fischer 344 rats exhibited greater initial locomotor
      responses to morphine but, unlike Dark Agouti rats, did not develop sensitization
      to a second morphine exposure. Fischer 344 rats displayed a marked rise in basal
      plasma corticosterone levels in the late light phase and early dark phase,
      whereas Dark Agouti rats showed no significant circadian variation in
      corticosterone levels. Relative to drug-naive Fischer 344 rats, drug-naive Dark
      Agouti rats showed higher levels of tyrosine hydroxylase and glial fibrillary
      acidic protein, and lower levels of neurofilament proteins, in the ventral
      tegmental area. In contrast, no strain differences were found in levels of
      tyrosine hydroxylase, specific G protein subunits or protein kinase A in the
      nucleus accumbens. Together, these results demonstrate that Dark Agouti rats and
      Fischer 344 rats exhibit differences in specific behavioral, endocrine and
      biochemical parameters related to sensitivity to drugs of abuse.

PMID- 10336140
TI  - Workshop on taste and smell in the elderly: an overview.
AB  - The purpose of the workshop entitled Taste and Smell in the Elderly: Behavioral
      and Nutritional Consequences was 1) to review the current state of knowledge in
      the area of taste and smell, with emphasis on age-related changes, 2) to identify
      existing gaps in our knowledge, and 3) to develop future research strategies.
      There was general agreement that the majority of scientific studies have found
      impairments in taste and smell acuity in the elderly. These losses may result
      from normal aging, certain disease states especially Alzheimer's disease,
      medications, surgical interventions, and environmental exposure. However, there
      are gaps in our knowledge of the basic mechanisms by which aging and
      environmental factors may impair the chemical senses in the elderly. Further
      research is also required in a variety of areas including chemosensory test
      procedures, food intake, and nutrition to understand fully the impact of
      chemosensory dysfunction on older individuals.

PMID- 10336141
TI  - Loss of olfactory function in dementing disease.
AB  - Alzheimer's (AD) patients show neuropathological changes in areas of the brain
      central to olfactory processing, suggesting the theoretical importance and
      potential diagnostic utility of investigating functional changes in olfaction in
      these patients. Persons with Down's Syndrome who live to the fourth decade
      develop neuropathological changes in the brain similar to those found in AD. A
      series of investigations have been conducted to assess olfaction function in both
      patients with Alzheimer's disease and persons with Down's Syndrome. Functional
      testing included olfactory threshold, odor identification, odor similarity
      judgements, odor recognition memory, odor recall, odor fluency. Both Alzheimer's
      patients and persons with Down's Syndrome showed significant impairment in
      olfactory function, with some measures showing more impairment than others in the
      early stages of the disease process. Longitudinal investigation of several of the
      measures indicated decreased function over time consonant with falling DRS
      scores. Normal controls who tested positive for the APOE4 allele showed impaired
      odor identification compared to those who were allele negative. Patients with
      Huntington's Disease showed olfactory functional impairments, although the degree
      of impairment differed from the cortical dementias for some of these tasks. The
      sensitivity and specificity of these assessments will be discussed in relation to
      analogous assessments in other sensory modalities.

PMID- 10336142
TI  - Effect of medications on taste: example of amitriptyline HCl.
AB  - Use of medications is a major factor that contributes to taste losses in the
      elderly. Epidemiological studies suggest that community-dwelling elderly over the
      age of 65 use an average of 2.9 to 3.7 medications, and this number increases
      significantly for elderly living in retirement and nursing homes. The tricyclic
      antidepressant amitriptyline HCl is used by at least half a million people aged
      65 years or more. In human studies performed here, amitriptyline HCl was found to
      have a bitter, unpleasant taste of its own. In addition, it blocked responses to
      other taste stimuli in both humans and gerbils. This blockage in humans was
      greater when amitriptyline HCl was applied continuously to the tongue than when
      it was applied intermittently. Continuous application of the drug affected all of
      the taste qualities to varying degrees, while intermittent application led to
      taste decrements only for salts. Electrophysiological studies in gerbils also
      revealed taste decrements after a short adaptation to amitriptyline HCl.

PMID- 10336143
TI  - Do chemosensory changes influence food intake in the elderly?
AB  - Food intake declines with age, and elderly individuals frequently report a
      decrease in appetite. Changes in chemosensory systems may partially explain this
      low intake. However, few data have directly linked changes in gustatory or
      olfactory function to food choice or intake. In two studies, taste perception and
      preference were unrelated to sodium chloride or sugar intakes. Olfaction may be
      more affected by age than taste. Olfactory dysfunction is associated with
      decreased enjoyment of food, and adding odors to foods can increase intake in
      some elderly individuals. The consumption of a varied diet depends in part on
      sensory-specific satiety (a decrease in the pleasantness of a food as it is
      consumed). Sensory-specific satiety diminishes with age, and this could be part
      of the explanation of why some elderly individuals have little variety in their
      diets. However, the impact of chemosensory deficits on nutritional status depends
      on a number of social and environmental factors. For example, despite their age,
      financially secure, free-living healthy older men and women consumed more varied
      diets than young adults. Changes in mechanisms regulating food intake can make it
      difficult for some elderly individuals to maintain energy balance. When
      chemosensory impairments are combined with changes in food intake regulatory
      mechanisms, the risk for nutritional deficiencies may be high. If we are to
      optimize food intake and nutritional status in the elderly, additional basic
      studies on how changes in chemosensory systems associated with aging affect food
      selection and intake are required.

PMID- 10336145
TI  - Alterations of chemosensory function in end-stage liver disease.
AB  - Taste and smell dysfunction has been documented in patients with both acute and
      chronic liver disease. The purpose of this study was to determine if chemosensory
      function is improved after restoration of hepatic function with liver
      transplantation. Nine subjects (seven women and two men) with end-stage liver
      disease participated in the study. Taste and smell detection and recognition
      thresholds were determined before and after transplantation. A significant
      improvement in detection of the taste of sodium chloride and the odor of
      phenethyl alcohol was found after transplantation. These findings may have
      clinical significance in food choices and nutritional status of these patients.

PMID- 10336144
TI  - Food aversion learning: a risk factor for nutritional problems in the elderly?
AB  - Food aversions that are acquired as a result of unpleasant experiences with foods
      represent a potent defense mechanism against poisoning. However, this powerful
      and durable form of conditioning can also contribute to avoidance of foods that
      are not poisonous, and are, in fact, quite nutritious. This is because such foods
      may be coincidentally associated with unpleasant gastrointestinal symptoms,
      sometimes due to transient, unrelated illness, or unpleasant drug side effects.
      Most of the studies of naturally occurring learned food aversions in humans have
      been focused on subjects of college age, so we have limited information about the
      extent to which such food aversions occur in the elderly. Additionally, most
      studies have employed questionnaire or interview methods that may have some
      significant limitations in the accurate assessment of the incidence of food
      aversions. Thus, although food aversion learning has been thoroughly documented
      in the animal laboratory, its role in everyday food selection in humans,
      including the elderly, remains relatively unclear.

PMID- 10336146
TI  - The influence of aging on oral health and consequences for taste and smell.
AB  - Oral diseases that are commonly seen in older adults can impair chemosensory
      function. Many stomatological conditions are preventable and treatable, yet
      unmanaged, they can cause significant morbidity and a diminished quality of life.
      Importantly, many oral diseases are not necessarily an inevitable consequence of
      growing old, and are frequently attributed to systemic diseases and their
      treatment. Although gustation may undergo mild age-related decrements, olfaction
      declines dramatically with greater age. The oral-facial region is intimately
      involved in the sensations of taste and smell, and diseases affecting this region
      in an older person could adversely affect an already compromised chemosensory
      system. Older adults with impaired taste and/or smell should be thoroughly
      evaluated for oral and pharyngeal diseases. It is reasonable to expect that a
      healthy adult can grow older with good oral health and function, and can continue
      to experience the hedonic pleasures of taste and smell associated with eating and
      drinking.

PMID- 10336147
TI  - Inhibitory effects of electroacupuncture on stress responses evoked by tooth-pulp
      stimulation in rats.
AB  - The mechanism of electroacupuncture (EA) on the stress responses induced by tooth
      pulp stimulation was investigated in anesthetized adult female Sprague-Dawley
      rats. The Hoku point in the Chinese meridian was used for acupuncture
      stimulation. Constant rectangular current (1 mA) pulses of 5-ms duration were
      delivered at 3 Hz through a pair of needles for 15 min. As for stress response
      indexes, we have monitored changes in arterial blood pressure and the levels of
      blood catecholamines, corticosterone, and ACTH. Arterial blood pressure was
      increased by high frequency stimulation (0.1 mA, 0.5 ms, 100 Hz for 15 s) of
      tooth-pulp in the control condition. After EA, we did not observe the same
      responses of the arterial blood pressure changes with the same stimuli. The tooth
      pulp stimulation increased the concentrations of plasma norepinephrine (NE),
      epinephrine (E), dopamine (DA), corticosterone, and ACTH significantly from the
      levels of those before stress. After treatment with EA, the stress-induced
      increase in NE, DA, corticosterone, and ACTH but not the rise in E, were
      inhibited. When naloxone, an opioid antagonist, was administered
      intraperitoneally before EA, the effects of EA on stress responses were reduced.
      In this study, it can be suggested that EA has not only an analgesic effect but
      also suppressive effects on the stress responses primarily through the mediation
      of an endogenous opioid.

PMID- 10336148
TI  - Inheritance of premeal stomach content influences on food intake in free living
      humans.
AB  - The heritability of the before-meal stomach content effects on food intake was
      investigated with 110 identical and 102 fraternal same-sex and 53 fraternal mixed
      gender adult twin pairs who were paid to maintain 7-day food intake diaries. From
      the diary reports, the total and meal intakes of food energy and the amounts of
      the macronutrients ingested were estimated. A simple computer model of stomach
      emptying was used to estimate the contents of the stomach at the beginning and
      end of the meals. Linear structural modeling was applied to investigate the
      nature and degree of genetic and environmental influences and revealed
      significant genetic influences on the amount of food energy and macronutrients
      estimated to be present in the stomach at the beginning and end of meals.
      However, these influences were found to be secondary to genetic influences on
      overall intake and meal size such that when these were considered in the model
      the heritabilities for stomach contents vanished. The genes were also found to
      affect the magnitude of the negative correlations between the before meal stomach
      contents and the amounts of nutrients ingested, and the magnitude of the negative
      slope of the best-fitting regression line between before meal stomach contents
      and meal size. These results suggest that although the amount in the stomach
      found at meal time is only affected indirectly by the genes, the impact of the
      content of the stomach on the amount ingested is to some extent inherited. This
      suggests that responses to internal stimuli are influenced by the genes and
      become part of the total package of genetically determined physiological and
      psychological processes that regulate energy balance.

PMID- 10336149
TI  - Chronic stress in dogs subjected to social and spatial restriction. I. Behavioral
      responses.
AB  - Six weeks of social and spatial restriction were used as a model to induce
      chronic stress in Beagles. Behavioral and physiological measurements were
      performed during a period of enriched spacious outdoor housing in groups (GH) and
      during a subsequent period of solitary housing in small indoor kennels (IH).
      Behavioral parameters that may indicate chronic stress in dogs are reported.
      During IH, the dogs showed significantly (comparison-wise error rate <0.05) lower
      postures than during GH. IH induced enduring increments in frequencies of
      autogrooming, paw lifting, and vocalizing, and was associated with incidents of
      coprophagy and repetitive behavior. So far, we interpret the behavioral changes
      as signs of chronic stress. Relatively low levels of walking, digging, intentions
      to change from one state of locomotion to another, and increments in circling are
      conceived as obvious adaptations to the specific features of the IH system. By
      challenging the dogs outside their home kennel we tested whether the dogs' coping
      abilities were affected by IH. Dogs that were challenged were introduced into a
      novel environment, given the opportunity to escape from their home kennel,
      restrained, walked down an unfamiliar corridor, presented a novel object, exposed
      to loud noise, given food, or confronted with a conspecific. During IH,
      challenged dogs exhibited higher postures, showed more tail wagging, nosing,
      circling, urinating, and defecating, and changed more often from one state of
      locomotion (or posture) to another than during GH. These behavioral changes were
      observed across the different types of challenges, with the exception of the
      noise administration test. In the presence of conspecifics, the socially and
      spatially restricted male dogs behaved more dominantly and aggressive than during
      the time that they were kept in groups. Such behavior manifested as increased
      performances of raised hairs, growling, paw laying, and standing over. Both sexes
      showed increases in paw lifting, body shaking, ambivalent postures, intentions to
      change from one state of locomotion to another, and trembling in any of the
      challenges, excluding the walking down the corridor test. In short, during a
      variety of challenges, socially and spatially restricted dogs exhibited a
      heightened state of aggression, excitement, and uncertainty. Behavioral
      differences between dogs that had experienced pleasant and bad weather conditions
      during GH, suggested that "pleasant-weather individuals" had experienced early
      stress during the control period, and, as a result, responded to the subsequent
      period of IH differently. Regardless of the housing conditions, challenged
      bitches showed stronger indications of acute stress than male dogs. Gender did
      not affect the chronic stress responses to social and spatial restriction. A low
      posture and increased auto-grooming, paw lifting, vocalizing, repetitive
      behavior, and coprophagy may indicate chronic stress in dogs, and as such, can
      help to identify poor welfare. When challenged, chronically stressed dogs may
      show increased excitement, aggression, and uncertainty, but the nonspecificity of
      such emotional behavior will complicate its practical use with regard to the
      assessment of stress.

PMID- 10336150
TI  - Chronic stress in dogs subjected to social and spatial restriction. II. Hormonal
      and immunological responses.
AB  - Two groups of beagles, accustomed to spacious group housing, were subjected to
      social and spatial restriction and studied for manifestations of chronic stress
      with a time interval of 7 weeks between the groups. The change from outside group
      housing (the control period) to individual housing in small indoor kennels
      resulted in sustained decreases in urinary adrenaline/creatinine and
      noradrenaline/creatinine ratios for the total group. Urinary dopamine/creatinine
      and noradrenaline/adrenaline ratios were statistically unaffected. Socially and
      spatially restricted dogs that had experienced pleasant weather during the
      control period showed (a) increased salivary and urinary cortisol concentrations,
      (b) a diminished responsiveness of the pituitary-adrenal axis to a sudden sound
      blast or exogenous CRH, (c) intact plasma ACTH and cortisol suppressions after
      dexamethasone administration, and (d) increased concanavalin A induced lymphocyte
      proliferations. When social and spatial restriction was preceded by a control
      period during which the weather was bad, these physiological responses were
      either augmented (lymphocyte proliferation), or offset (salivary and urinary
      cortisol), or directed oppositely (CRH-induced ACTH and cortisol responses).
      Together with the previously presented behavioral observations, these data
      suggest that bad weather conditions during spacious outdoor group housing induced
      early stress that attenuated the negative appraisal of the subsequent period of
      social and spatial restriction. In comparison to male dogs, bitches showed
      increased HPA responses to a sound blast or exogenous CRH. Their increased
      attenuations of the ACTH and cortisol responses to CRH after 5 weeks of
      restricted housing indicates that bitches are not only more susceptible to acute
      stress, but also to chronic housing stress. It is concluded that the quality of
      circumstances preceding a period of affected well-being determines the magnitude
      and even the direction of the behavioral and physiological stress responses.
      Basal salivary and urinary cortisol measurements are useful for the assessment of
      chronic stress, and of poor welfare in dogs. The use of urinary catecholamine,
      peripheral leucocyte, and lymphocyte proliferation measures requires further
      investigation.

PMID- 10336151
TI  - Role of the ventromedial hypothalamus in prolactin-induced hyperphagia in ring
      doves.
AB  - Prolactin (PRL) strongly stimulates feeding activity and body weight gain in ring
      doves, and of the brain loci tested to date, the ventromedial hypothalamus (VMH)
      is the most effective site of PRL action in promoting these changes. To determine
      if the VMH is essential for this response, we examined the effects of VMN
      destruction on spontaneous feeding and on changes in food intake induced by
      intracerebroventricular (i.c.v.) injections of PRL. Male birds were selectively
      destroyed by radiofrequency lesions (n = 6). A group of sham-lesioned males (n =
      6) served as controls. Lesioned birds exhibited a transient increase in food
      intake that peaked around the seventh postoperative day and declined to baseline
      levels by day 12. In contrast to this pattern, body weights of lesioned birds
      increased in parallel with food intake, but remained elevated throughout the 3
      week postoperative period. During the peak period of hyperphagia in the lesioned
      group, food intake and body weight increases were two to three times greater in
      lesioned birds than in controls. After postoperative feed intake had stabilized,
      each bird received 5 daily i.c.v. injections of ovine PRL. Food intake and body
      weight increased dramatically in both groups in response to PRL treatment, and no
      group differences were observed in response to magnitude. We conclude that VMH
      destruction strongly perturbs feeding and body weight regulation in doves.
      However, VMH integrity is not essential for the expression of PRL-induced
      hyperphagia.

PMID- 10336152
TI  - Effect of dopamine blockers on cerebral ischemia-induced hyperactivity in
      gerbils.
AB  - When common carotid arteries of Mongolian gerbils were clamped for 5 min,
      locomotor activity significantly increased the day after the ischemic insult.
      This hyperactivity induced by cerebral ischemia was evident in both light and
      dark periods. The significant increases in locomotor activity seen in both
      periods were noted for 3 and 9 days after occlusion, respectively. Effects of
      dopamine receptor antagonists on the ischemia-induced hyperactivity were
      investigated the day after the ischemia insult. Haloperidol, sulpiride, and
      eticlopride, all dopamine D2 receptor antagonists, decreased the ischemia-induced
      hyperactivity at doses that had no effects on locomotor activity in sham-operated
      animals. SCH23390, a dopamine D1 receptor antagonist, had no clear effects on the
      ischemia-induced hyperactivity. Clozapine, with not so high an affinity for the
      dopamine D2 receptor decreased the ischemia-induced hyperactivity when given in a
      relatively high dose. Thus, the ischemia-induced hyperactivity is apparently
      related to abnormalities in dopaminergic functions, particularly the dopamine D2
      receptor.

PMID- 10336153
TI  - Blood pressure and heart rate rhythmicity: differential effects of late
      pregnancy.
AB  - Arterial blood pressure (BP) and heart rate (HR) of 31 hospitalized pregnant
      women at low risk of hypertension were automatically monitored for 48 h at 15-min
      intervals. Each of the recorded 56 data series for systolic arterial pressure
      (SAP), diastolic arterial pressure (DAP), and HR was chronobiologically assessed
      by linear-nonlinear rhythmometry. The rhythm-adjusted mean (MESOR), circadian
      amplitude, circadian acrophase, and best-fitting period were grouped by pregnancy
      trimester and further subjected to analysis of variance. BP MESOR remained
      unaltered, whereas HR MESOR increased significantly in middle and late pregnancy.
      Ultradian rhythms, with an amplitude higher than that of the circadian rhythm,
      were found in 25% of the SAP records in the second and third trimester. Such
      ultradian rhythms were not detected in the simultaneously recorded HR. Finally,
      the group BP and HR circadian acrophases coincided in the first trimester, but
      were significantly apart in mid and late pregnancy. These observations support
      the notion that the coordination of BP and HR rhythmicity involves different
      physiological mechanisms. Analysis of the individual variability in the
      chronobiological end points (based on the records of nine women monitored in each
      pregnancy trimester) revealed that only the BP MESOR was well reproducible in the
      course of pregnancy and may be useful in early diagnosis of gestational
      hypertension.

PMID- 10336155
TI  - The orosensory recognition of long-chain fatty acids in rats.
AB  - To determine the selectivity of long-chain fatty acid (LCFA) in the oral cavity,
      short-term (5 min) two-bottle tests were conducted in rats. Fifteen male Wistar
      rats were given oleic acid, linoleic acid, linolenic acid, and their derivatives.
      All compounds used were 99% pure. The concentration of test fluids was made 1% in
      0.3% xanthan gum to minimize postingestive and textural effects. The rats
      preferred LCFA fluids to the control of 0.3% xanthan gum solution. The preference
      order of LCFA was linolenic acid > linoleic acid > oleic acid. Four LCFA
      derivatives (methyl oleate, oleyl alcohol, methyl linoleate, and linolyl
      alcohol), triolein, and capric acid were not preferred to LCFA, but LCFA
      derivatives were preferred to the control of xanthan gum solution. These studies
      suggest that rats select LCFA from olfactory or gustatory cues that are related
      to both the carbon chain and carboxylate group.

PMID- 10336154
TI  - Interactive effects of psychosocial stressors and gender on mouse mammary tumor
      growth.
AB  - We have previously demonstrated that social housing condition significantly
      affects the growth rate of the androgen-responsive Shionogi mouse mammary
      carcinoma (AR SC115) in male mice. The present study examined the effects of
      social housing condition and acute daily exposure to a novel environment on the
      growth rate of an androgen-independent variant of the AR SC115 carcinoma,
      designated SC115V, in male and female mice. Immediately following tumor cell
      injection, male and female mice that were reared as individuals (I) or in groups
      (G) of the same sex were rehoused either from individual to same-sex groups (IG)
      or from group to individual (GI), or remained in their group housing condition
      (GG). Approximately half the mice in each housing condition were subjected to
      acute daily exposure to novel environments (novelty stress), a treatment shown
      previously to increase the significant difference in tumor growth rates between
      male mice in the IG and GI housing conditions. The remaining mice were left
      undisturbed (no novelty stress). In the presence of acute daily novelty stress,
      the growth rate of the SC115V tumor was significantly increased in GI compared to
      IG males. However, no significant differences in SC115V tumor growth rates among
      nonstressed GI, IG, or GG males were observed. For females, in contrast to males,
      acute daily novelty stress significantly decreased tumor growth in GI compared to
      IG mice, whereas under nonstressed conditions, tumor growth rate was
      significantly increased in GI compared to IG females. Neither housing condition
      nor novelty stress altered estrous cyclicity, nor did the stage of the estrous
      cycle at the time of tumor cell injection influence tumor growth rates. These
      findings suggest that social housing condition and novelty stress may interact to
      produce differential effects on the growth rate of the SC115V tumor in male and
      female mice.

PMID- 10336156
TI  - Reduction in peripheral inflammation by changes in attention.
AB  - Peripheral inflammation in response to intra-articular injection of sodium urate
      was measured in birds showing pain-coping behaviour as well as in birds showing
      endogenous analgesia produced by changes in attention. Sixteen birds were
      injected with sodium urate into the left ankle joint. Eight birds were returned
      to their cages, and eight were placed in pairs into a novel pen. The birds placed
      into the novel pen showed significantly less pain coping behaviour in the 3-h
      period after injection than those birds returned to their cages. Both groups of
      birds showed elevated skin temperature over the inflamed joint, but in the birds
      in the novel pen this increase in temperature was significantly less than in the
      birds in cages. These results demonstrate that attentional shifts cannot only
      reduce the severe tonic pain of sodium urate arthritis, but also reduce
      peripheral inflammation.

PMID- 10336157
TI  - Periodic maternal deprivation induces gender-dependent alterations in behavioral
      and neuroendocrine responses to emotional stress in adult rats.
AB  - There is evidence that stressful events during the neonatal "stress
      hyporesponsive period" may influence both emotional behavior and the maturation
      of the hypothalamic-pituitary-adrenal (HPA) axis in rats. We tested whether
      periodic maternal deprivation (180 min daily on postnatal days 3-10, PMD) caused
      chronic changes in emotional behavior and HPA axis activity in either male or
      female adult rats, or both. In addition, HPA secretory responses to human/rat
      corticotropin-releasing factor (CRH, 50 ng/kg i.v.) were determined in the adult
      males. In the elevated plus-maze test, adult (4-5 months of age) PMD-treated
      animals of both sexes displayed increased anxiety-related behavior compared to
      control rats. This was indicated by a reduction in the number of entries (male:
      70% reduction, p < 0.01; female: 31% reduction, p < 0.01) and amount of time
      spent on the open arms (male: 86% reduction, p < 0.01; female: 40% reduction,
      NS). Neuroendocrine parameters were also altered in PMD-treated rats in a gender
      dependent manner. Whereas basal plasma adrenocorticotropin (ACTH) and
      corticosterone levels did not differ significantly between PMD and control groups
      of either sex, the ACTH response to elevated plus-maze exposure, a predominantly
      emotional stressor, was higher in male (p < 0.01), but not female, PMD animals
      than in the respective controls. In contrast, PMD had no effect on behavioral
      (duration of struggling) or HPA axis responses to forced swimming (90 s, 19
      degrees C), a complex and predominantly physical stressor, in either male or
      female rats. In response to CRH stimulation, PMD-treated males did not show
      differences in the ACTH secretion compared to controls, indicating alterations in
      HPA axis regulation at a suprapituitary level. Thus, PMD caused long-term changes
      in the emotional behavior of adult rats of both sexes, although to a differing
      degree in males and females, whereas it appeared to cause predominantly
      alterations in the HPA axis response in males, depending on the characteristics
      of the stressor used.

PMID- 10336158
TI  - Development of vasomotor control in lean (+/?) and genetically obese (fa/fa) rat
      pups.
AB  - Using laser Doppler flowmetry, we determined whether vasomotor control is already
      functional in 7-, 11-, and 16-day-old rat pups, and whether differences in
      vasomotor responses between 16-day-old lean (+/?) and fatty (fa/fa) pups occur.
      For 3 h, at the end of their daily light phase, the pups were exposed to 30-min
      step changes of ambient temperature (Ta) alternating between thermoneutrality and
      cold loads resulting in a 50-100% increase of metabolic rate (MR) above its
      thermoneutral value, while core temperature (Tc), skin blood flux at the hindpaw,
      and MR were recorded. In all age groups, blood flux changed significantly in
      response to these Ta changes. The time needed for a significant change in blood
      flux was shorter in the 7-day-old than in the 16-day-old lean pups, while the Ta
      dependency of Tc was more pronounced in the younger pups. Comparison of the
      responses of the 16-day-old fatty and lean pups showed a parallel shift to lower
      values in the correlation of Ta with MR in the fa/fa pups, but no difference in
      the correlation of Ta with blood flux. This demonstrates that the vasomotor
      control system in the rat is already functional by the age of 7 days, and that
      the fa/fa lesion influences the vasomotor control less than the metabolic cold
      defense.

PMID- 10336159
TI  - Plasma glucagon, glucose, insulin, and motilin in rats anticipating daily meals.
AB  - The circadian food entrainable oscillator (FEO) mediates an increase in activity
      preceding access to periodic meals. The FEO is anatomically independent of the
      suprachiasmatic nucleus (SCN), but its locus remains to be established. Whether
      the FEO is located in the central nervous system (CNS) or in the periphery, it
      seems reasonable to assume that there is a link of communication between the
      digestive system and the CNS because only nutritive meals entrain the FEO.
      Subdiaphragmatic vagotomy and visceral deafferentation with capsaicin do not
      eliminate food-anticipatory activity (FAA), indicating that a neural signal is
      not necessary. The present study investigates the hypothesis that humoral signals
      from the digestive system act upon the CNS to trigger or entrain FAA. Intact rats
      and rats with SCN lesions were entrained to daily meals and then sacrificed prior
      to FAA or during FAA, but before meal access. Average plasma concentrations of
      glucose and insulin were nearly identical in both groups. Plasma and duodenal
      mucosal motilin concentrations also were not different between the two times.
      Corticosterone was elevated during anticipation, but the difference was not
      statistically reliable. Glucagon concentration was decreased during FAA compared
      to concentration prior to FAA in both intact and SCN-lesioned subjects. This
      difference was not observed in control rats fasted for the same number of hours,
      but not previously entrained to a daily meal. Although the decrease in glucagon
      could be a signal that initiates FAA, a causal role remains to be established.

PMID- 10336160
TI  - Gustatory changes associated with the menstrual cycle.
AB  - We studied changes in the palatability and gustatory functions as they correlate
      with the menstrual cycle in 30 healthy females with regular menstrual cycles. The
      gustatory function was investigated by conducting electrogustometry and by the
      filter-paper disk method with taste solutions in the follicular and luteal phases
      of the same subjects. The responses to a questionnaire revealed that appetite was
      enhanced prior to menstruation in 14 cases (46.7%). The results of
      electrogustometry showed that the threshold in the domain of the chorda tympani
      nerve was 0.3 +/- 3.4 dB in the follicular phase and -0.9 +/- 2.8 dB in the
      luteal phase. Although the threshold in the luteal phase indicated a
      statistically significant decrease (p < 0.05), the difference was so small that
      the change could not be subjectively discriminated. The threshold in the domain
      of the glossopharyngeal nerve was 2.6 +/- 4.0 dB in the follicular phase and 1.7
      +/- 3.9 dB in the luteal phase, with no significant difference between the two
      values. Gustatory thresholds as obtained by the filter-paper disk testing were
      not significantly different between the follicular and luteal phases. Thus,
      although the taste function may change through the menstrual cycle, changes in
      gustatory thresholds are minimal and remain within the normal range.

PMID- 10336161
TI  - Environmental lighting has a selective influence on ethanol intake in rats.
AB  - The effect of lighting condition on levels of absolute ethanol intake were
      systematically examined in the present study. Wistar rats were exposed to one of
      three lighting conditions: constant light, constant dark, and a standard 12/12
      light/dark cycle. The animals were acclimatized to lighting conditions for 2
      weeks prior to ethanol (EtOH) acquisition with water and food available ad lib.
      EtOH was then presented in increasing concentrations from 2% (v/v; 95% with tap
      water) to 10% on alternate days in free choice with water. Immediately following
      the acquisition phase, a maintenance period was initiated that began with
      everyday presentations of 10% EtOH solution in free choice with water. After 10
      days, lighting conditions for the constant light and dark groups were switched to
      normal lighting (12/12 light/ dark). EtOH and water intake were recorded for an
      additional 10 days. Rats exposed to constant light during EtOH acquisition and
      maintenance consumed less EtOH during the maintenance period than rats exposed to
      normal lighting conditions. When lighting conditions were switched to a normal
      cycle, water consumption increased significantly but EtOH intake did not change.
      Rats living in constant dark during EtOH acquisition and maintenance consumed
      less EtOH during the acquisition period when compared with rats living in normal
      lighting conditions. Unlike animals trained under constant lighting, switching to
      normal lighting conditions had no effect on EtOH or water intake. There were no
      differences in water consumption levels among the groups during acquisition and
      maintenance, suggesting a specificity of the effects of lighting condition on
      EtOH intake. The present study, therefore, has attempted to show that an
      environmental variable such as lighting may exert a selective influence on EtOH
      self-selection in rats.

PMID- 10336162
TI  - Enhanced food-anticipatory circadian rhythms in the genetically obese Zucker rat.
AB  - This study examines the effects of the leptin receptor mutation in obese Zucker
      rats on entrainment of food-anticipatory rhythms to daily feeding schedules.
      Leptin is secreted by adipocytes in proportion to fat content, exhibits a daily
      rhythm in plasma that is synchronized to feeding time, and inhibits activity of
      arcuate neuropeptide Y neurons that stimulate feeding behavior and regulate
      metabolism. Activity within this neuropeptide Y system is enhanced by food
      deprivation and attenuated by overfeeding and diet-induced obesity. Diet-induced
      obesity, in turn, attenuates food-anticipatory rhythms. If the effects of obesity
      on food-entrained rhythms are mediated by leptin inhibition of neuropeptide Y
      neurons, then these rhythms may be enhanced in leptin-insensitive Zucker obese
      rats. Alternatively, if daily rhythms of leptin mediate the generation or
      entrainment of these rhythms, Zucker rats may fail to anticipate daily feedings.
      Zucker obese and lean rats received food for 3 h/day during the midlight period.
      Both groups exhibited significant food-anticipatory activity that persisted
      during three cycles of food deprivation, but this rhythm was significantly more
      robust in obese rats, when expressed as anticipation and persistence ratios, and
      as peak values. Anticipatory rhythms did not persist in either group when food
      was provided ad lib. These results indicate that central actions of leptin may
      mediate the inhibitory effects of obesity on the expression of food-anticipatory
      rhythms in rats, but do not mediate the inhibitory effects of ad lib food access,
      and do not serve as necessary internal entrainment cues or clock components for
      the food-entrainable circadian system.

PMID- 10336163
TI  - Behavioral and neuroanatomical consequences of chronic ethanol intake and
      withdrawal.
AB  - We have examined if long-term (13 months) alcohol consumption and the same
      treatment followed by a 6-week withdrawal period cause different
      neuropathological changes in rats. Spatial reference and working memory of
      alcohol-consuming and withdrawn rats were evaluated by comparison of their
      performance with age-matched controls in the Morris water maze. In the reference
      memory task we did not observe significant cognitive deficits in rats
      continuously exposed to ethanol, whereas withdrawn animals showed an obvious
      impairment of their overall performance. The reference memory deficit in
      withdrawn rats was evident in the spatial probe trial; these animals required
      significantly longer swimming distances to approach the former position of the
      platform when compared with controls and alcohol-consuming animals. In contrast,
      working memory was not significantly altered in either experimental group.
      Stereological methods were applied to compare the neurodegenerative changes
      produced by alcohol intake and withdrawal in the hippocampal formation. In the
      alcohol-consuming animals there was a significant cell loss in CA1 (18%) and CA3
      (19%) hippocampal regions. Moreover, in withdrawn rats there was a further decay
      in the total number of pyramidal neurons, which amounted to 15% relative to
      nonwithdrawn animals. In the granular layer of the dentate gyrus there was a
      trend in the same direction, but it did not reach significance. Thus, our
      findings indicate that withdrawn rats are cognitively impaired relative to
      animals submitted to continuous alcohol consumption and to age-matched controls,
      which fits the morphological data showing that withdrawal aggravates ethanol
      induced degenerative processes in the hippocampal formation.

PMID- 10336164
TI  - Beta-adrenoceptor blockade and open-field behavior in male golden hamsters.
AB  - Open-field behavior was compared between untreated, saline-treated, and
      butoxamine (a beta-2-adrenoceptor antagonist) treated (15 and 5 mg/kg body
      weight) male golden hamsters (Mesocricetus auratus). Butoxamine-treated males
      spent significantly more time self-grooming than saline-treated and untreated
      males. Especially, untreated males and very similar saline control males showed a
      clear time sequential structure of behavior with two axes: a grooming-grooming
      sequence and a highly organized flankmark followed by scrape axis. The degree of
      this organization was markedly decreased in the butoxamine-treated males, showing
      an increase in organization of the transition between grooming acts. In general,
      these males displayed a more stereotypic pattern of behavior than the other. To
      reveal a systematic relation between the flankmark-scrape response and the
      exposition to butoxamine and to keep the numbers of experimental animals low,
      mixed samples were created through consecutive summing of the individual
      transition matrices of six males treated with 5 mg/kg b.wt. butoxamine to the 15
      mg/kg b.wt. sample. By analyzing all samples separately, a positive linear
      relation between the number of low dosed males in the samples and the degree of
      organization of the flankmark-scrape sequence was found. The results suggest that
      the analysis of the transitional structure of behavior during short-term
      challenges can considerably contribute to an estimation of the coping style and
      seems to be a more sensitive method than comparing frequencies of behavioral
      indicators of stress.

PMID- 10336165
TI  - A rodent model of spontaneous stereotypy: initial characterization of
      developmental, environmental, and neurobiological factors.
AB  - Stereotypies are patterns of motor behavior that are repetitive, excessive,
      topographically invariant, and that lack any obvious function or purpose. In
      humans, stereotyped behaviors are associated with psychiatric, neurological, and
      developmental disorders. In animals, stereotypy has been frequently associated
      with adverse environmental circumstances and often related to alterations in
      striatal dopamine. To assess the development of stereotyped behaviors and to test
      the hypothesis that these behaviors are associated with environmental
      restriction, deer mice were housed in either standard laboratory cages or larger,
      enriched cages, and the development of stereotypy was followed from weaning over
      a 17-week period. Standard-caged deer mice engaged in stereotyped behaviors at a
      higher rate and developed these behaviors more quickly when compared to animals
      in enriched caging. Additionally, enriched caging was associated with higher
      rates of patterned running, whereas jumping and backward somersaulting were
      typically observed in standard cages. In addition, there was a significant effect
      of litter, but no effect of sex or cage, on the time to develop stereotypy. No
      differences were found in the density of either striatal D1 or D2 dopamine
      receptors or the concentration of striatal dopamine or its metabolites as a
      function of rearing condition or as a function of whether the animals developed
      stereotypy. These results characterize the development of stereotypies in this
      species, demonstrate the importance of environmental conditions in the genesis of
      stereotypy, and suggest that alterations in striatal dopamine content or dopamine
      receptor density do not account for the expression of stereotyped behaviors in
      this model.

PMID- 10336166
TI  - Peripheral heat loss: a predictor of the hypothermic response to melatonin
      administration in young and older women.
AB  - Core hypothermia following daytime melatonin administration typically displays
      significant interindividual variability. As this hypothermia has been associated
      with significant increases in skin temperature, the mechanism by which melatonin
      decreases core temperature may involve increasing peripheral heat loss. If so,
      the interindividual variability in this effect may reflect concomitant
      interindividual variability in heat loss capacity at the distal periphery. For
      six younger (mean +/- SEM: 23.4 +/- 0.3 years) and 10 older women (mean +/- SEM:
      65.6 +/- 0.7 years), the maximum decrease in core body temperature following a 5
      mg (p.o.) dose of melatonin was correlated with the capacity to lose heat. This
      was determined by the maximum increase in contralateral hand temperature
      following a mild positive thermal challenge (PTC). The regression analysis
      yielded a significant (p < 0.01) correlation of 0.80, suggesting that the
      individual magnitude of hypothermia following melatonin administration may
      reflect the capacity of an individual to dissipate heat at the distal periphery.

PMID- 10336167
TI  - Reduced femoral geometry but normal biomechanics in the dorsomedial hypothalamic
      nucleus-lesioned rat.
AB  - Bone geometry, structure, and biomechanical properties were investigated in a
      model of growth retardation, the dorsomedial hypothalamic nucleus-lesioned (DMNL)
      weanling rat. Male weanling Sprague-Dawley rats received bilateral electrolytic
      lesions in the dorsomedial hypothalamic nucleus (DMN) at age 27 days. Sham
      operated rats served as controls. All rats were maintained postoperatively for 40
      days. Upon sacrifice, DMNL rats weighed less (p < 0.01), were shorter (p < 0.01),
      and ate less (p < 0.01) when compared to controls, but their body composition was
      normal. The femora in DMNL were shorter (p < 0.01), had a smaller outer
      anteroposterior (AP) diameter (p < 0.04), polar moment of the area (p < 0.02),
      and maximal (p < 0.02) and minimal (p < 0.03) principal moment of the area when
      compared with sham-operated rats. Notably, mean torque at failure, torsional
      energy, stiffness, and maximal stress did not demonstrate statistically
      significant differences between the two groups. These data clearly show that
      despite the reduced size and bone growth, DMNL rats responded normally to the
      mechanical challenges applied to test bone biomechanical properties. The data,
      therefore, add to previous evidence and strengthen the hypothesis that DMNL rats
      are governed by an "organismic" set point.

PMID- 10336168
TI  - Effects of sweetness and energy in drinks on food intake following exercise.
AB  - Exercise is known to cause physiological changes that could affect the impact of
      nutrients on appetite control. This study was designed to assess the effect of
      drinks containing either sucrose or high-intensity sweeteners on food intake
      following exercise. Using a repeated-measures design, three drink conditions were
      employed: plain water (W), a low-energy drink sweetened with artificial
      sweeteners aspartame and acesulfame-K (L), and a high-energy, sucrose-sweetened
      drink (H). Following a period of challenging exercise (70% VO2 max for 50 min),
      subjects consumed freely from a particular drink before being offered a test meal
      at which energy and nutrient intakes were measured. The degree of pleasantness
      (palatability) of the drinks was also measured before and after exercise. At the
      test meal, energy intake following the artificially sweetened (L) drink was
      significantly greater than after water and the sucrose (H) drinks (p < 0.05).
      Compared with the artificially sweetened (L) drink, the high-energy (H) drink
      suppressed intake by approximately the energy contained in the drink itself.
      However, there was no difference between the water (W) and the sucrose (H) drink
      on test meal energy intake. When the net effects were compared (i.e., drink +
      test meal energy intake), total energy intake was significantly lower after the
      water (W) drink compared with the two sweet (L and H) drinks. The exercise period
      brought about changes in the perceived pleasantness of the water, but had no
      effect on either of the sweet drinks. The remarkably precise energy compensation
      demonstrated after the higher energy sucrose drink suggests that exercise may
      prime the system to respond sensitively to nutritional manipulations. The results
      may also have implications for the effect on short-term appetite control of
      different types of drinks used to quench thirst during and after exercise.

PMID- 10336169
TI  - Memory enhancement by the angiotensinergic system in the crab Chasmagnathus is
      mediated by endogenous angiotensin II.
AB  - In previous work with the crab Chasmagnathus, it was reported that either
      exogenous angiotensin II (ANGII) or angiotensin IV (ANGIV), have an enhancing
      effect on long-term memory, which involves an association between context and an
      iterative danger stimulus (context-signal memory, CSM). Present results indicate
      that Dival, an ANGIV antagonist, reverts the facilitatory effect of ANGIV but not
      that of ANGII, whereas saralasin but not Dival, disrupts CSM. These findings
      suggest that ANGII is the endogenous angiotensin that plays a significant role in
      long-term memory, while the ANGIV receptor would not be encompassed in the
      cascade of events related to crab's CSM.

PMID- 10336170
TI  - Pentylenetetrazol-induced seizures increase [3H]L-2-amino-4-phosphonobutyrate
      binding in discrete regions of the rat brain.
AB  - Convulsions were induced in rats by a single injection of pentylenetetrazol (PTZ)
      and [3H]L-2-amino-4-phosphonobutyrate ([3H]L-AP4) in vitro receptor
      autoradiography was used to evaluate the effects on the expression of group III
      metabotropic glutamate receptors. Significant increases by 60-80% in [3H]L-AP4
      binding was observed in the frontal parts of cortex (sensory, motor and cingulate
      cortex) and by 28% in the molecular layer of the cerebellar cortex 24 h after PTZ
      induced seizures. Since group III metabotropic glutamate receptors has an
      inhibitory effect on glutamatergic transmission, the observed increases in
      binding may indicate that these receptors serve as a mechanism for preventing
      further seizure activity.

PMID- 10336171
TI  - Potentiation and suppression of the histamine response by raising and lowering
      the temperature in canine visceral polymodal receptors in vitro.
AB  - It is well known that itch and inflammatory pain are enhanced when tissue is
      warmed, while they are suppressed when tissue is cooled. To see whether these
      changed sensations are based on the changed response of sensory receptors, the
      temperature dependency of the excitation of polymodal receptors induced by
      histamine, which plays an important role both in itch and inflammatory pain, was
      studied. Single nerve activities of polymodal receptors were recorded from canine
      testis-spermatic nerve preparations in vitro. Raising the temperature from 34 to
      40 degrees C, a temperature below the threshold for the heat response of
      polymodal receptors, facilitated the histamine-induced nerve discharge to 268% of
      that at 34 degrees C, while lowering the temperature to 28 degrees C decreased it
      to 25%. Facilitation of the histamine response was also observed in the noxious
      temperature range (48 and 51 degrees C). These results suggest that the
      potentiation of the histamine-induced sensation by increasing the tissue
      temperature, as well as its suppression by lowering tissue temperature, can be
      explained by a temperature-dependent response of peripheral sensory receptors to
      histamine. However, the suppression of itch by noxious heat reported by Bickford
      (Bickford, R.G., Experiments relating to the itch sensation, its peripheral
      mechanism, and central pathways, Clin. Sci. Incorp. Heart, 3 (1937) 377-386)
      cannot be explained by the noxious heat-induced facilitation of the peripheral
      receptor response reported in this paper.

PMID- 10336172
TI  - Immunohistochemical determination of the Wilson Copper-transporting P-type ATPase
      in the brain tissues of the rat.
AB  - Immunohistochemical localization of Copper-transporting P-type ATPase (ATP7B), a
      gene product responsible for Wilson disease, was visualized in the brain tissues
      of the Long-Evans agouti rat in detail using tissue-blotting technique and
      confocal laser microscopy. The ATP7B was intensely detected in neuronal cells of
      the hippocampal formation, olfactory bulbs, cerebellum, cerebral cortex and
      nuclei in the brainstem in which high amounts of copper and cuproenzymes,
      dopamine beta hydroxylase and Cu,Zn-superoxide dismutase (Cu,Zn-SOD) were
      detected. The present results suggest that ATP7B plays key roles in
      neurotransmissions of catecholamine pathway and preventing brain tissues from
      injury by superoxide radicals to regulate the cellular Cu concentration and/or
      activities of cuproenzymes related to neurotransmissions and a free radical
      metabolism. Furthermore, it is reasonable to assume that neurotoxicity due to
      abnormal copper accumulation or irregular regulation of cuproenzymes in the
      critical brain regions by mutation of the ATP7B gene leads to neurological
      failures of Wilson disease.

PMID- 10336173
TI  - Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and
      neuronal nicotinic acetylcholine receptor subunits in human mononuclear
      leukocytes and leukemic cell lines.
AB  - Previously, we reported that various levels of acetylcholine (ACh), currently
      known as a neurotransmitter, are detectable in the blood of several mammals
      including humans and that most blood ACh originates from T-lymphocytes. To
      investigate whether ACh in the blood acts on lymphocytes and participates in the
      modulation of immune responses, we have analyzed the expression of mRNA for
      muscarinic (Ms) ACh receptor subtypes and nicotinic (Nc) ACh receptor subunits
      using reverse transcription-polymerase chain reaction (RT-PCR) methods. The cells
      tested were human peripheral mononuclear leukocytes (MNLs) from seven healthy
      donors and eight leukemic cell lines, as models of lymphocytes. We detected mRNA
      expression for various neuronal Nc receptor subunits and Ms receptor subtypes in
      all of the MNL samples and in all of the cell lines tested. However, the
      expression pattern of mRNA for neuronal Nc receptor subunits (alpha2-alpha7 and
      beta2-beta4) and Ms receptor subtypes (m1-m5) varied among the individuals and
      cell lines. No expression of mRNA for three muscle-type Nc receptor subunits
      (alpha1, beta1 and epsilon) was observed in the MNLs and cell lines. These
      results indicate that both neuronal-type Nc and Ms ACh receptors are present on
      the surface of lymphocytes.

PMID- 10336174
TI  - Lowering barometric pressure aggravates mechanical allodynia and hyperalgesia in
      a rat model of neuropathic pain.
AB  - To examine the effects of meteorological change on the pain-related behaviors of
      neuropathic rats, animals with a chronic constriction injury (CCI) to the sciatic
      nerve were exposed to low barometric pressure (LP), 20 mmHg below the natural
      atmospheric pressure in a climate-controlled room. CCI caused a decreased hindpaw
      withdrawal threshold to von Frey hair (VFH) stimulation (mechanical allodynia)
      and prolonged duration of hindpaw withdrawal in response to pinprick stimulation
      (mechanical hyperalgesia). When the CCI rats were exposed to LP, both these pain
      related behaviors were aggravated, whereas no change was seen in a group of
      controls. In the CCI rats sympathectomy inhibited this LP-induced augmentation of
      pain-related behaviors. These results show that LP intensifies the abnormalities
      in the pain-related behaviors of neuropathic rats, and that sympathetic activity
      contributes to the LP effect.

PMID- 10336175
TI  - Do specific EEG frequencies indicate different processes during mental
      calculation?
AB  - EEG recordings during mental calculation and a control task (with presentation of
      stimuli with similar physical characteristics to the arithmetic symbols) were
      obtained in 10 subjects. Narrow band analyses of the EEG and distributed sources
      for each EEG frequency were calculated using variable resolution electromagnetic
      tomography. Significant differences between the sources for arithmetic and
      control tasks were observed at 3.9 Hz within Broca's and left parietotemporal
      cortices, suggesting that this frequency may be related with the production of
      internal speech, storage and rehearsal of verbal working memory. Differences at
      5.46 Hz within the right dorsolateral prefrontal cortex were considered to be
      associated to sustained attention. The decrease at 12.46 Hz within the left
      parietal cortex was interpreted as a sign of retrieval of arithmetic facts from
      long term memory.

PMID- 10336176
TI  - Day- and night-time contents of monoamines and their metabolites in the medial
      preoptic area of the rat hypothalamus.
AB  - The present study was conducted to investigate whether monoamines and their
      metabolites in the medial preoptic area (mPOA) of the rat hypothalamus exhibit
      differences in their contents between day and night. We therefore sampled the
      mPOA from adult animals of either sex at the middle of the light or dark period,
      respectively, and analyzed the tissue by means of high performance liquid
      chromatography with electrochemical detection. We found that, in female animals
      at mid-night, dopamine and 3,4-dihydroxyphenyl acetic acid (DOPAC) was reduced to
      43 and 30%, respectively, of daytime levels, while the norepinephrine content was
      doubled. No significant differences were observed in male animals. We also
      conducted immunohistochemistry of the catecholamine synthesizing enzymes,
      tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH), in sections from
      perfusion-fixed male rats and showed that TH is present in neuronal perikarya and
      processes in the anteroventral periventricular region of the mPOA, while DBH was
      only seen in fibers and terminals. Our results of sex-specific and day time
      dependent variations in dopamine and norepinephrine concentrations indicate that
      the two monoamines are candidate neurotransmitters that may transmit diurnal
      information to the mPOA.

PMID- 10336177
TI  - Characterization of pontine neurons which respond to hypoxia in fetal sheep.
AB  - Hypoxia causes apnea and postural muscle hypotonia in fetal sheep, a response
      thought to arise by descending inhibition from a group of lateral pontine neurons
      that express FOS protein after hypoxia. To determine the neurochemical phenotype,
      and whether these neurons project to the cervical spinal cord, the retrograde
      tracer CTB-gold was injected into the C5-C8 ventral horn of four fetal sheep at
      110 days gestation. Then, at 135 days each fetus was made hypoxic for 2 h by
      allowing the mother to breathe 7-8% O2. Immunocytochemistry showed that FOS
      positive neurons in the subcoeruleus and Kolliker-Fuse regions of the pons were
      catecholaminergic, but not cholinergic or GABAergic, and a proportion of them
      contained CTB-gold particles, indicating direct connection with the cervical
      spinal cord. We suggest that these pontine neurons inhibit respiratory and
      postural muscle activities during hypoxia in fetal sheep.

PMID- 10336178
TI  - Proliferation and apoptosis in the mouse vomeronasal organ during ontogeny.
AB  - Differential cell proliferation and apoptosis play a key role in organ
      morphogenesis. We have analyzed these two processes in the development of murine
      vomeronasal organ (VNO), an olfactory structure involved in the detection of
      pheromones. Using the TUNEL (TdT-mediated dUTP nick end labelling) method we
      demonstrate that dying cells are relatively more abundant in non sensory
      vomeronasal organ (NS-VNO) rather than in sensory epithelium (S-VNO),
      particularly in early stages of development. During ontogeny cell proliferation,
      studied with bromodeoxyuridine (BrdU) labelling, shows a broad pattern of
      localization, since proliferating cells are distributed throughout the VNO and
      not confined between NS-VNO and S-VNO. Quantification of BrdU-labelled cells
      indicates that proliferation is rather stable in both components.

PMID- 10336179
TI  - Quantitative evidence for increase in galanin-immunoreactive terminals in the
      hippocampal formation following entorhinal cortex lesions in the adult rat.
AB  - The projection from the entorhinal cortex to the dentate gyrus and hippocampus is
      severely affected in Alzheimer's disease and there is a depletion of cholinergic
      terminals but an upregulation of the neuropeptide galanin, which inhibits the
      release of acetylcholine. Evidence for changes to galanin-immunoreactive
      terminals in the hippocampal formation was therefore examined after unilateral
      entorhinal cortex lesions in the adult rat. An increase in the density of galanin
      immunoreactive terminals on the lesioned side was evident in the stratum
      lacunosum moleculare of the hippocampus and the outer molecular layer of the
      dentate gyrus at 17 days post-lesion, and it increased gradually until the last
      time point examined, at 40 days post-lesion. Thus we demonstrate that there is an
      increase in galanin-immunoreactive terminals in the hippocampal formation
      following entorhinal cortex lesions.

PMID- 10336180
TI  - Sensory threshold changes without initial pain or alterations in cutaneous blood
      flow, in the area of secondary hyperalgesia caused by topical application of
      capsaicin in humans.
AB  - Changes in von Frey hair perception, pricking pain, and vibration thresholds were
      examined in six healthy human adults, in the zone of secondary hyperalgesia, 45
      min following the topical application of capsaicin at concentrations of 0.05 and
      0.1 mg/ml. In two of these subjects, cutaneous blood flow was monitored at 10-min
      intervals, before, during and after capsaicin application, using laser Doppler
      perfusion imaging. Thresholds for all three parameters were significantly reduced
      after capsaicin treatment, in a dose-dependent manner. However, there was no
      visible skin flare, and no change in cutaneous blood flow at these doses of
      capsaicin. The effects on von Frey perception threshold and vibration threshold
      have not been demonstrated previously, and may be indicative of central changes,
      initiated by afferent fibres (presumably C fibres) that are not vasoactive.

PMID- 10336181
TI  - Morphologic investigation of rolling mouse Nagoya (tg(rol)/tg(rol)) cerebellar
      Purkinje cells: an ataxic mutant, revisited.
AB  - Rolling mouse Nagoya (rolling: tg(rol)) is a neurologic mutant mouse exhibiting
      severe ataxia. Two alleles of the rolling mutation, tottering (tg) and
      leaner(tg(la)), have been identified as mutations in the voltage-dependent
      calcium channel alpha1A subunit. No specific light and electron microscopic
      findings have been reported for the rolling mouse cerebellum except a decreased
      number of granule cells, while altered Purkinje cell/parallel fiber synapses have
      been observed in tottering and leaner cerebella. Rolling mouse cerebella were
      analyzed using anti-calbindin-D immunohistochemistry and transmission electron
      microscopy to investigate Purkinje cell morphology and synaptic contacts between
      Purkinje cell dendritic spines and parallel fiber varicosities. Multiple Purkinje
      cell dendritic spines synapsing with single parallel fiber varicosities were
      frequently observed in rolling cerebella. The correlation between the presence of
      altered Purkinje cell synapses and ataxia in rolling mice warrants further
      investigation.

PMID- 10336182
TI  - Expression of gicerin, a cell adhesion molecule, in the abnormal retina in silver
      plumage color mutation of Japanese quail (Coturnix japonica).
AB  - Silver plumage color mutant (B/B) quail has an abnormal retina characterizing the
      transdifferentiation of retinal pigment epithelium (RPE) following the retinal
      separation in the early developmental stage. In the present study; (i) the
      expression of gicerin, an immunoglobulin-superfamily cell adhesion molecule, was
      examined in the retina of B/B quail. In the wild-type quail, gicerin protein was
      enriched in the apical membrane (facing the neural retina, NR) of RPE cells on
      embryonic day (E) 4 and then appeared also in NR cells from E5. However, in the
      B/B retina, no gicerin expression was found in the transdifferentiation area of
      RPE prior to the retinal separation. (ii) In addition to this, microinjection of
      anti-gicerin polyclonal antibody into the eyeball of wild-type quail on E3 caused
      the retinal separation and induced the transdifferentiation of RPE into new NR.
      These observations suggest that the decrease of gicerin expression might
      participate in the retinal separation and RPE-transdifferentiation in B/B quail.

PMID- 10336183
TI  - Contingent negative variation indicates phasic arousal for externally cued
      unilateral eye blink in human subjects.
AB  - The contingent negative variation (CNV) as a slow cortical potential was used to
      investigate cortical processing of externally cued, voluntary unilateral eye
      blink. Probands blinked as a response within a modified two-stimulus reaction
      time paradigm. Reaction time and amplitudes of CNV were determined. The activity
      of the orbicularis oculi muscles (OO) was registered by surface electromyography
      (EMG). Probands who performed unilateral eye blinks with accurately inhibiting
      contralateral OO activity showed a significantly higher negativity of the early
      CNV component compared with the bilateral eye blink condition. This effect was
      confined to the beginning of unilateral blinking performance. It is suggested
      that the unilateral eye blink is a challenging motor task, initially requiring an
      increased cortically driven arousal and attention as revealed by increased early
      CNV components.

PMID- 10336184
TI  - Cyclosporin-A inhibits lipid peroxidation after spinal cord injury in rats.
AB  - Besides its immunosuppressive/anti-inflammatory activity, cyclosporin-A (CsA) may
      protect damaged tissues from lipid peroxidation (LP) by free radicals. To
      determine the effect of CsA on LP spinal cord (SC) injury, Wistar rats were
      treated with either vehicle or CsA (2.5 mg/kg per 12 h i.p.) 1, 2, 6 or 12 h
      after SC trauma by T8-T9 spinal cord contusion, analyzing LP 24 h after injury at
      the lesion site by the lipid fluorescent products formation method. CsA
      significantly diminished LP to levels below control values after contusion (P <
      0.05). The greater inhibition was observed when CsA was given during the first 6
      h after injury, furthermore, animals showed a significant clinical improvement.
      Results show that CsA may be beneficial to injured tissue by inhibiting the
      levels of LP.

PMID- 10336185
TI  - The mouse cpp32 mRNA transcript is early up-regulated in axotomized motoneurons
      following facial nerve transection.
AB  - In adult mice, axotomy of facial motoneurons induces apoptotic cell death. Cpp32,
      Bax and Bcl-xl are regulators of this type of cell death in the central nervous
      system. Using in situ hybridization, we have studied the kinetics of expression
      of cpp32, bax and bcl-xl mRNAs after a fatal lesion of the facial nerve in wild
      type and Bcl-2 transgenic mice, where cell death is known to be prevented. In
      both strains of mice, cpp32 mRNA was up-regulated by 12 h following axotomy
      whereas changes in bax mRNA expression occurred later (from 3 days). These
      results provide information on the timing of molecular processes involved in cell
      death and could be helpful in determining a critical period during which they may
      be blocked.

PMID- 10336186
TI  - Learning deficits in first generation OF1 mice deficient in (n-3) polyunsaturated
      fatty acids do not result from visual alteration.
AB  - The effects of (n-3) polyunsaturated fatty acids (PUFA) diet deficiency on
      learning, electroretinogram and retinal fatty acid composition were assessed for
      the first time in OF1 mice. Pups fed the same diets (deficient in alpha-linolenic
      acid or a control) as their dams were used aged 7 weeks for passive avoidance
      test and fatty acid analysis of retinal phospholipids. Visual function was
      measured by electroretinography in 4- and 7-week-old mice. The (n-3) PUFA
      deficient diet significantly decreased learning performance and retinal
      docosahexaenoic acid level in adult mice. The electroretinogram showed a
      significant alteration of b-wave amplitude in deficient mice at 4 weeks but not
      at 7 weeks. These results show that learning deficits in mice fed a diet
      deficient in (n-3) PUFA were not due to visual alteration.

PMID- 10336187
TI  - Cellular localization of prolactin-releasing peptide messenger RNA in the rat
      brain.
AB  - Prolactin-releasing peptide (PrRP), a novel peptide identified as the endogenous
      ligand for an orphan receptor isolated from the pituitary, is a potent stimulator
      of prolactin release. To get a clue of the functional roles of the peptide, we
      performed in situ hybridization histochemistry for PrRP mRNA to define the
      cellular localization of PrRP-producing cells in the brain of the cycling adult
      female rat during diestrus. The PrRP mRNA-containing cells were located in the
      caudal part of the dorsomedial nucleus of the hypothalamus. In the brainstem, the
      cells were found in the caudal part of the solitary tract nucleus and in the
      caudal ventrolateral medulla (ventrolateral intermediate reticular field).
      Specific signals for PrRP mRNA were not detected in other brain regions. Although
      PrRP is a candidate for being a hypophysiotropic specific releasing factor, the
      discrete distribution of PrRP in the extrahypothalamic area suggests that the
      peptide has other physiological functions in the central nervous system.

PMID- 10336188
TI  - Mammographic appearances of male breast disease.
AB  - Various male breast diseases have characteristic mammographic appearances that
      can be correlated with their pathologic diagnoses. Male breast cancer is usually
      subareolar and eccentric to the nipple. Margins of the lesions are more
      frequently well defined, and calcifications are rarer and coarser than those
      occurring in female breast cancer. Gynecomastia usually appears as a fan-shaped
      density emanating from the nipple, gradually blending into surrounding fat. It
      may have prominent extensions into surrounding fat and, in some cases, an
      appearance similar to that of a heterogeneously dense female breast. Although
      there are characteristic mammographic features that allow breast cancer in men to
      be recognized, there is substantial overlap between these features and the
      mammographic appearance of benign nodular lesions. The mammographic appearance of
      gynecomastia is not similar to that of male breast cancer, but in rare cases, it
      can mask malignancy. Gynecomastia can be mimicked by chronic inflammation. All
      mammographically lucent lesions of the male breast appear to be benign, similar
      to such lesions in the female breast.

PMID- 10336189
TI  - Imaging features of uncommon adrenal masses with histopathologic correlation.
AB  - Uncommon adrenal masses include cystic lesions (hydatid cyst, endothelial cyst),
      solid lesions (hemangioma, ganglioneuroma, angiosarcoma, primary malignant
      melanoma), and solid fatty lesions (myelolipoma, collision tumor). Most of these
      lesions do not have specific imaging features. The liquid content of adrenal
      cysts is clearly demonstrated on ultrasonographic scans, computed tomographic
      scans, and magnetic resonance images. Nevertheless, the histologic type cannot be
      predicted except at some stages of hydatid disease in which pathognomonic
      features are present. The most typical imaging features of hemangioma are
      phleboliths and enhancement of peripheral vascular lakes. Ganglioneuroma has
      nonspecific radiologic features, but this diagnosis should be considered in cases
      with early enhancement of fine septa and progressive filling. The radiologic
      features of angiosarcoma and primary malignant melanoma are nonspecific. A
      macroscopic lipid content within an adrenal mass is theoretically characteristic
      of myelolipoma. This diagnosis should be made with caution, especially when the
      lipid content is not predominant, because of the possible association with an
      adenoma.

PMID- 10336190
TI  - Cervicothoracic lesions in infants and children.
AB  - Cervicothoracic lesions are not uncommon in children. All cervicothoracic lesions
      except superficial lesions extend from the neck to the thorax through the
      thoracic inlet. Evaluation of this area involves multiple imaging modalities:
      plain radiography, ultrasonography, nuclear medicine, computed tomography, and
      magnetic resonance (MR) imaging. However, MR imaging is the method of choice for
      assessing the full extents of cervicothoracic lesions and their relationships to
      neurovascular structures. Cervicothoracic lesions can be classified as congenital
      lesions, inflammatory lesions, benign tumors, malignant tumors, and traumatic
      lesions. Lymphangioma is the most common cervicothoracic mass in children; other
      congenital lesions include hemangioma, thymic cyst, and vascular anomalies.
      Inflammatory adenopathy reactive to tuberculosis, mononucleosis, tularemia, cat
      scratch fever, infection with human immunodeficiency virus, or other upper
      respiratory tract infections can manifest as cervicothoracic lesions; tuberculous
      abscesses and abscesses of other origins can also be seen. Lipoma, lipoblastoma,
      aggressive fibromatosis, and nerve sheath tumors (either isolated lesions or
      those associated with neurofibromatosis) can also occur as cervicothoracic
      masses. Malignant cervicothoracic tumors include lymphoma, thyroid carcinoma,
      neuroblastoma, and chest wall tumors (rhabdomyosarcoma, Ewing sarcoma, and
      neuroectodermal tumor). Traumatic cervicothoracic lesions include
      pneumomediastinum of traumatic origin, traumatic pharyngeal pseudodiverticulum,
      esophageal foreign-body granuloma, and cervicothoracic hematoma.

PMID- 10336191
TI  - Parathyroid imaging with Tc-99m sestamibi planar and SPECT scintigraphy.
AB  - Technetium-99m sestamibi planar and single-photon-emission computed tomographic
      scintigraphy is useful in the diagnosis of parathyroid gland disease. To
      understand the various patterns of parathyroid disease, it is important to
      understand parathyroid embryology and anatomy. The spectrum of parathyroid
      disease demonstrated with Tc-99m sestamibi scintigraphy includes eutopic disease,
      ectopic disease, solitary adenoma, double or multiple adenomas, cystic adenoma,
      lipoadenoma, multiple endocrine neoplasia, hyperfunctioning parathyroid
      transplant, entities with atypical washout, and nonparathyroid entities that take
      up Tc-99m sestamibi. The diagnosis of parathyroid tumors with Tc-99m sestamibi
      scintigraphy is based on the difference in clearance rates between the thyroid
      and diseased parathyroid glands, and any condition that interferes with
      radiotracer clearance will limit the effectiveness of the study. The technique is
      most clearly indicated for the preoperative evaluation of recurrent or persistent
      hyperparathyroidism, but it is increasingly being used before the initial
      surgical exploration as well. Subtraction Tc-99m sestamibi and iodine-123
      scintigraphy may be helpful in difficult cases. Parathyroid hyperplasia,
      multisite parathyroid disease, and concomitant thyroid and parathyroid disease
      remain potential hurdles for this scintigraphic technique, and optimal handling
      of these problems still relies heavily on the skill and experience of the
      endocrine surgeon.

PMID- 10336193
TI  - Use of CT in detection of internal damage and repair and determination of
      authenticity in high-quality bowed stringed instruments.
AB  - Computed tomography (CT) was used to evaluate 17 high-quality violins and cellos
      crafted between 1633 and 1872 by master craftsmen such as Guarneri, Amati, and
      Stradivari. Multiple high-resolution CT scans were obtained in each instrument,
      and additional scans were obtained when defects or repair was detected. Varying
      degrees of internal damage (eg, wormholes, air gaps, plastic deformities of wood)
      or repair (eg, glue lines, filler material, wooden cleats and patches) not seen
      at visual inspection were detected in all 17 instruments. In addition, CT allowed
      noninvasive identification of the internal wood grain pattern unique to each
      instrument, thereby facilitating verification of authenticity to help protect
      against loss, theft, or forgery. The information provided by CT analysis of
      valuable bowed stringed instruments may prove useful to prospective buyers or to
      insurance companies that specialize in insuring such instruments against
      accidental loss or damage.

PMID- 10336192
TI  - Imaging of chest wall disorders.
AB  - Pathologic processes that may involve the chest wall include congenital and
      developmental anomalies, inflammatory and infectious diseases, and soft-tissue
      and bone tumors. Many of these processes have characteristic radiologic
      appearances that allow definitive diagnosis. Sternal deformities can be
      visualized at radiography and their severity quantified with computed tomography
      (CT). In cervical rib, CT with multiplanar reconstruction may demonstrate
      relevant anatomic detail and the relationship between bone deformity and arterial
      compression. In Poland syndrome, radiography reveals an area of hyperlucency on
      the affected side, whereas CT demonstrates the absence of the greater pectoral
      muscle and clearly depicts associated musculoskeletal anomalies. Tuberculosis
      typically manifests at radiography and CT as osseous and cartilaginous
      destruction and soft-tissue masses with calcification and rim enhancement.
      Aspergillosis involving the chest wall manifests as pulmonary consolidations and
      permeative osteolytic changes of the rib and spine at CT and as an area of
      increased signal intensity at T2-weighted magnetic resonance (MR) imaging.
      Neurogenic tumors and hemangiomas also typically have high signal intensity at T2
      weighted MR imaging. Apparent mass extension or unequivocal bone destruction seen
      at CT or MR imaging may indicate chest wall involvement by lymphoma.
      Radiologically, soft-tissue sarcomas typically appear as areas of soft-tissue
      density or attenuation, often associated with necrotic areas of low density or
      attenuation. At radiography, plasmacytoma typically manifests as well-defined,
      "punched-out" lytic lesions with associated extrapleural soft-tissue masses.
      Chondrosarcoma frequently appears as a large, lobulated excrescent mass arising
      from a rib with scattered flocculent calcifications characteristic of its
      cartilaginous mix. Familiarity with these radiologic features facilitates
      accurate diagnosis and optimal patient treatment.

PMID- 10336194
TI  - Therapeutic percutaneous injections in the treatment of malignant acetabular
      osteolyses.
AB  - Percutaneous injection of methylmethacrylate or ethanol may provide marked pain
      relief or bone strengthening in patients with malignant acetabular osteolyses who
      are unable to tolerate surgery. Injection of methylmethacrylate is usually
      indicated when osteolysis involves the weight-bearing part of the acetabulum (ie,
      the acetabular roof); in all other cases, ethanol injection is preferred. Ethanol
      and methylmethacrylate injections may be performed together if both weight
      bearing and nonweight-bearing parts of the acetabulum are involved or extensive
      soft-tissue involvement is present. Moreover, these injections may be performed
      prior to radiation therapy, which complements their action due to similar but
      delayed effects on pain, or after radiation therapy that failed to relieve pain
      or in cases of local recurrence. Radiography and computed tomography must be
      performed prior to therapeutic percutaneous injection to assess the location and
      extent of the lytic process, the presence of cortical destruction or fracture,
      and the presence of soft-tissue involvement. Fever and transitory worsening in
      pain may occur secondary to inflammatory reaction in the hours following
      injection; however, these side effects usually resolve spontaneously within 1-3
      days. The decision to perform therapeutic percutaneous injections should be made
      by a multidisciplinary team because the choice between this option and
      alternative methods of treatment depends on several factors including the
      location of the lesion, the local and general extent of the disease, the pain and
      functional disability experienced by the patient, and the patient's state of
      health and life expectancy.

PMID- 10336195
TI  - Have you been checked?

PMID- 10336196
TI  - Imaging features of avulsion injuries.
AB  - Avulsion injuries are common among participants in organized sports, especially
      among adolescent participants. Imaging features of both acute and chronic
      avulsion injuries of the pelvis, knee, ankle and foot, shoulder, and elbow were
      evaluated to help distinguish these injuries from more serious disease processes
      such as neoplasm and infection. At radiography, acute injuries (ie, those
      resulting from extreme, unbalanced, often eccentric muscular contractions) may be
      associated with avulsed bone fragments, whereas subacute injuries have an
      aggressive appearance that may include areas of mixed lysis and sclerosis.
      Chronic injuries (ie, those resulting from repetitive microtrauma or overuse) or
      old inactive injuries may be associated with a protuberant mass of bone and may
      bear a striking resemblance to a neoplastic or infectious process. Although not
      usually required, computed tomography is helpful in the diagnosis if radiographic
      findings are equivocal or if the injury is not in the acute phase. MR imaging is
      best suited for the evaluation of injuries to muscles, tendons, and ligaments.
      Recognition of characteristic imaging features and familiarity with
      musculotendinous anatomy will aid in accurate diagnosis of avulsion injuries.

PMID- 10336197
TI  - Collateral ligaments of the ankle: high-resolution MR imaging with a local
      gradient coil and anatomic correlation in cadavers.
AB  - Findings at high-resolution magnetic resonance (MR) imaging of the lateral and
      medial collateral ligaments of the ankle were compared with findings in anatomic
      sections from cadavers. MR imaging of six cadaveric feet was performed with a
      newly developed local gradient coil and axial and coronal T1-weighted spin-echo
      sequences. Axial imaging provided optimum views of the anterior and posterior
      talofibular ligaments, the deep layers of the medial collateral ligament, and the
      tibionavicular ligament. Coronal imaging allowed complete visualization of the
      calcaneofibular, posterior talofibular, tibiocalcaneal, and posterior tibiotalar
      ligaments. In both imaging planes, differentiation of the deep and superficial
      layers of the medial collateral ligament was possible. Differentiation between
      the syndesmotic complex and the lateral collateral ligament was accomplished
      easily; in particular, differentiation of the posterior tibiofibular ligament
      from the posterior talofibular ligament was not difficult because of the
      differing insertions of these ligaments. The inhomogeneous appearance of the
      medial collateral ligament and the posterior talofibular ligament on MR images
      correlated with areas of fatty tissue on corresponding microscopic sections. High
      resolution MR imaging with a newly developed local gradient coil allows excellent
      visualization of the lateral and medial collateral ligaments of the ankle.

PMID- 10336198
TI  - Rotator cuff: evaluation with US and MR imaging.
AB  - Magnetic resonance (MR) and ultrasound (US) imaging are currently touted for
      assessment of rotator cuff disease. Optimum clinical imaging techniques include
      use of (a) a 1.5-T MR imaging unit with small planar coils, proton-density
      weighted and T2-weighted fast spin-echo sequences, and 10-12-cm fields of view
      (yielding 400-470 x 500-625-microm in-plane spatial resolution) and (b) a state
      of-the-art commercial US unit with insonation frequencies of 9-13 MHz (yielding
      200-400-microm axial and lateral resolution). Proper diagnosis requires
      familiarity with normal anatomic characteristics and imaging pitfalls. Care must
      be taken to avoid sonographic tendon anisotropy and MR imaging magic angle
      effects, which can be misinterpreted as rotator cuff tear. At MR imaging, a
      complete cuff tear typically appears as either a hyperintense defect or a
      tendinous avulsion that extends from the bursal to the articular side of the
      cuff; a partial cuff tear typically appears as a focal hyperintense region that
      contacts only one surface of the cuff. Complete and partial tears manifest with a
      wide spectrum of findings at US. MR imaging and US are effective for evaluating
      rotator cuff injuries, with high reported accuracies for detection of complete
      tears but more disparate results for detection of partial tears.

PMID- 10336199
TI  - Illuminations. Typical bronchial carcinoid.

PMID- 10336200
TI  - Thoracic carcinoids: radiologic-pathologic correlation.
AB  - Carcinoids are neuroendocrine neoplasms. Bronchial carcinoids are unusual,
      malignant primary neoplasms that characteristically involve the central airways
      and typically exhibit well-defined margins and bronchial-related growth.
      Bronchial carcinoids include low-grade typical carcinoids and the more aggressive
      atypical carcinoids. These tumors usually affect patients in the 3rd through 7th
      decades of life who are often symptomatic with cough, hemoptysis, or obstructive
      pneumonia. Bronchial carcinoids radiologically manifest as hilar or perihilar
      masses, with or without associated atelectasis, pneumonia, bronchiectasis, or
      mucoid impaction. At computed tomography, an anatomic relationship of these
      tumors to a bronchus is usually seen, and they may show contrast material
      enhancement or calcification. In rare cases, carcinoids occur in the thymus; when
      they do, they are aggressive tumors that affect adults who usually present with
      chest pain, cough, and dyspnea. Thymic carcinoids manifest radiologically as
      anterior mediastinal masses and may mimic thymomas. Thoracic carcinoids are
      treated by surgical excision. The prognosis for patients with typical bronchial
      carcinoids is excellent; patients with atypical bronchial or thymic carcinoids
      have a worse prognosis.

PMID- 10336201
TI  - Three-dimensional volume rendering of spiral CT data: theory and method.
AB  - Three-dimensional (3D) medical images of computed tomographic (CT) data sets can
      be generated with a variety of computer algorithms. The three most commonly used
      techniques are shaded surface display, maximum intensity projection, and, more
      recently, 3D volume rendering. Implementation of 3D volume rendering involves
      volume data management, which relates to operations including acquisition,
      resampling, and editing of the data set; rendering parameters including window
      width and level, opacity, brightness, and percentage classification; and image
      display, which comprises techniques such as "fly-through" and "fly-around,"
      multiple-view display, obscured structure and shading depth cues, and kinetic and
      stereo depth cues. An understanding of both the theory and method of 3D volume
      rendering is essential for accurate evaluation of the resulting images. Three
      dimensional volume rendering is useful in a wide variety of applications but is
      just now being incorporated into commercially available software packages for
      medical imaging. Although further research is needed to determine the efficacy of
      3D volume rendering in clinical applications, with wider availability and
      improved cost-to-performance ratios in computing, 3D volume rendering is likely
      to enjoy widespread acceptance in the medical community.

PMID- 10336202
TI  - Counting statistics.
AB  - The low radiation dose rates used in nuclear medicine necessitate image formation
      and measurements that are severely count limited. This limitation may mask our
      ability to perceive contrast in an image or may affect our confidence in
      quantitative functional measurements. The randomness of the signal can be
      described by using the Poisson probability distribution with its associated mean
      and variance. The validity of a measurement and uncertainties in a result can be
      determined by examining the count statistics. If multiple measurements are used
      to derive a result, confidence levels can be determined by examination of the
      propagation of errors. The statistical properties of the detected signal can also
      be evaluated to determine if the equipment is functioning properly. For example,
      the chi2 test can be used to determine if there is too much or too little
      variability in count samples. Finally, image formation with limited numbers of
      photons results in noisy images that may be difficult to interpret. An
      understanding of the trade-offs between contrast, noise, and object size is
      required to set proper image acquisition parameters and thereby ensure that the
      information required to make a diagnosis is contained in the final image.

PMID- 10336203
TI  - Three-dimensional visualization and analysis methodologies: a current
      perspective.
AB  - Three-dimensional (3D) imaging was developed to provide both qualitative and
      quantitative information about an object or object system from images obtained
      with multiple modalities including digital radiography, computed tomography,
      magnetic resonance imaging, positron emission tomography, single photon emission
      computed tomography, and ultrasonography. Three-dimensional imaging operations
      may be classified under four basic headings: preprocessing, visualization,
      manipulation, and analysis. Preprocessing operations (volume of interest,
      filtering, interpolation, registration, segmentation) are aimed at extracting or
      improving the extraction of object information in given images. Visualization
      operations facilitate seeing and comprehending objects in their full
      dimensionality and may be either scene-based or object-based. Manipulation may be
      either rigid or deformable and allows alteration of object structures and of
      relationships between objects. Analysis operations, like visualization
      operations, may be either scene-based or object-based and deal with methods of
      quantifying object information. There are many challenges involving matters of
      precision, accuracy, and efficiency in 3D imaging. Nevertheless, 3D imaging is an
      exciting technology that promises to offer an expanding number and variety of
      applications.

PMID- 10336205
TI  - Breast imaging case of the day. Tubular carcinoma and fibroadenoma.

PMID- 10336204
TI  - Mucinous cystic neoplasm of the pancreas.

PMID- 10336206
TI  - US case of the day. Extralobar pulmonary sequestration.

PMID- 10336207
TI  - Gastrointestinal case of the day. Pyogenic liver abscess caused by perforation by
      a swallowed wooden toothpick.

PMID- 10336208
TI  - General case of the day. Ectopic retrosternal parathyroid adenoma.

PMID- 10336209
TI  - Neuroradiology case of the day. Malignant mixed germ cell tumor with yolk sac and
      teratomatous components.

PMID- 10336211
TI  - The nature of psychiatric classification: issues beyond ICD-10 and DSM-IV.
AB  - OBJECTIVE: The aim of this paper is to provide an overview of the methodological
      underpinnings of current classification systems in psychiatry, their impact on
      clinical and social practices, and likely scenarios for future development, as an
      introduction to a series of related articles in this issue. METHOD: The method
      involved a selective literature review. RESULTS: The role and significance of
      psychiatric classifications is placed in a broader social and cultural context;
      the 'goodness of fit' between ICD-10 and DSM-IV on one hand, and clinical reality
      on the other hand, is examined; the nature of psychiatric classification,
      compared to biological classifications, is discussed; and questions related to
      the impact of advances in neuroscience and genetics on psychiatric classification
      are raised for further discussion. CONCLUSIONS: The introduction of explicit
      diagnostic criteria and rule-based classification, a major step for psychiatry,
      took place concurrently with the ascent to dominance of a biomedical paradigm and
      the synergistic effects of social and economic forces. This creates certain risks
      of conceptual closure of clinical psychiatry if phenomenology, intersubjectivity
      and the inherent historicism of key concepts about mental illness are ignored in
      practice, education and research.

PMID- 10336210
TI  - Pediatric case of the day. Osteogenic sarcoma as a second malignancy with
      bilateral hereditary retinoblastoma.

PMID- 10336212
TI  - Classifications in psychiatry: a conceptual history.
AB  - BACKGROUND: Historical accounts of psychiatric classifications have hitherto been
      written in terms of a 'received view'. This contains two assumptions, that: (i)
      the activity of classifying is inherent to the human mind; and (ii) psychiatric
      'phenomena' are stable natural objects. OBJECTIVES: The aim of this article is to
      provide an outline of the evolution of psychiatric classifications from the
      perspective of conceptual history. This is defined as a theoretical and empirical
      inquiry into the principles, sortal techniques and contexts in which alienists
      carried out their task. It assumes that all psychiatric classifications are
      cultural products, and endeavours to answer the question of whether
      classificatory models imported from the natural sciences can be applied to man
      made constructs (such as mental illness) definitionally based on 'personalised
      semantics'. METHODS: Exemplars of classificatory activity are first mapped and
      contextualised. Then, it is suggested that in each historical period crafting
      classifications has been like playing a game of chess with each move being
      governed by rules. This is illustrated by offering an analysis of the 1860-1861
      French debate on classification. RESULTS AND CONCLUSIONS: (1) Medicine is not a
      contemplative but a modificatory activity and hence classifications are only
      valuable if they can release new information about the object classified. (2) It
      should not be inferred from the fact that psychiatric classifications are not
      working well (i.e. that they only behave as actuarial devices) that they must be
      given up. Conceptual work needs to continue to identify 'invariants' (i.e. stable
      elements that anchor classifications to 'nature'. (3) Because mental disorders
      are more than unstable behavioural epiphenomena wrapped around stable molecular
      changes, 'neurobiological' invariants may not do. Stability depends upon time
      frames. Furthermore, it is unlikely that gene-based classifications will ever be
      considered as classifications of mental disorders. For once, they would have low
      predictive power because of their lack of information about the defining codes of
      mental illness. 'Social' and 'psychological' invariants have problems of their
      own.

PMID- 10336213
TI  - Whither psychiatric diagnosis.
AB  - OBJECTIVE: The aim of this paper is to describe the development of the Diagnostic
      and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), its purposes
      and limitations, and the psychiatric nosologies which may emerge from advances in
      psychiatric research and which may supersede the current classification system.
      METHOD: A review of the methodology used to develop DSM-IV, considered in the
      context of current and future psychiatric, neurobiological, and genetic research,
      was undertaken. RESULTS: The DSM-IV is a descriptive nosology that has shaped
      psychiatric research and clinical practice by providing agreed-upon definitions
      of psychiatric disorders based on the current state of empirical data. Despite
      the critical importance of the DSM system of classification, this complex yet
      limited nosology will eventually be replaced by simpler, more incisive
      explanatory models of psychiatric illness that reflect the interplay of
      biological, psychological, environmental and social variables affecting the
      expression and treatment of psychiatric disorders. CONCLUSIONS: As we continue to
      understand the pathophysiology of brain disorders, as well as the biological
      effects of psychiatric interventions, we will be able to move from a descriptive
      model to an integrative, explanatory model of psychiatric illness.

PMID- 10336214
TI  - Reflections on the clinical utility of the ICD-10 and DSM-IV classifications and
      their diagnostic criteria.
AB  - OBJECTIVE: The change to non-theoretical, criteria-based diagnostic
      classification in ICD-10 and DSM-III/IV has presented a major innovation in
      clinical psychiatry. The aim of the present paper is to provide a provisional
      evaluation of their utility in clinical practice. METHOD: The method involved a
      close scrutiny of ICD-10 and DSM-IV with a view to identifying difficulties and
      problems in their use. RESULTS AND CONCLUSIONS: The criteria-based
      classifications are no longer just coding conventions, but have become part of
      the conceptual framework of the discipline itself. The advantages, particularly
      as to the quality and reliability of clinical diagnoses, outweigh the
      disadvantages with temptations to mechanistic and reductionistic applications of
      criteria and incomplete nosological evaluation. Comprehensive clinical
      evaluation, however, should work at two separate levels: one, the initial,
      syndromatical diagnostic level, followed by the other, the nosological level,
      with evaluation of factors possibly influencing course and outcome of the
      psychiatric disorders. Only when both the syndromatical diagnosis and nosological
      factors are taken into consideration, is it possible to get a full understanding
      of the disorder necessary for optimal treatment. In this way, clinical psychiatry
      can be kept as it was intended: a healing discipline.

PMID- 10336215
TI  - A new conceptual paradigm from genetics and psychobiology for the science of
      mental health.
AB  - OBJECTIVE: The assumptions and goals underlying current systems of classification
      are critically examined. METHOD: Current systems of classification are based on
      assumptions that health can be adequately defined as the absence of disorders and
      that psychiatric disorders are discrete disease entities that can be
      categorically defined. These assumptions appear to be inconsistent with available
      knowledge of the psychobiology, genetics, development and evolution of thoughts,
      emotions, and behaviour. RESULTS: An alternative psychobiologically based
      paradigm is described based on the model that mental health and its disorders are
      emergent properties of complex interactions among multidimensional neuroadaptive
      systems. CONCLUSIONS: This permits an explicit definition of optimum mental
      health and a descriptive system that is more effective for professionals,
      individuals, and society in understanding and achieving increased adaptive
      fitness.

PMID- 10336217
TI  - Qigong-induced mental disorders: a review.
AB  - OBJECTIVE: This review article aims to explore current opinions on Qigong-induced
      mental disorders, an entity which is unfamiliar to Western psychiatrists. METHOD:
      Relevant literature published in Chinese and English is reviewed. RESULTS: The
      review is divided into three sections: first, there is brief consideration of the
      historical development of Qigong in traditional Chinese medicine and its role in
      psychiatry; second, there is a review of the literature published on Qigong
      deviations and Qigong-induced mental disorders; and third, there is a discussion
      on the aetiological role of Qigong in these conditions. CONCLUSIONS: Qigong
      remained veiled in secrecy and available only to the elite until the early 1980s.
      Despite the widespread use of Qigong, there is a conspicuous lack of controlled
      data regarding its effects on mental health. Qigong, when practised
      inappropriately, may induce abnormal psychosomatic responses and even mental
      disorders. However, the ties between Qigong and mental disorders are manifold,
      and a causal relationship is difficult to establish. Many so-called 'Qigong
      induced psychoses' may be more appropriately labelled 'Qigong-precipitated
      psychoses', where the practice of Qigong acts as a stressor in vulnerable
      individuals.

PMID- 10336216
TI  - Brain imaging technologies: how, what, when and why?
AB  - OBJECTIVE: Innovations in physics and computing technology over the past two
      decades have provided a powerful means of exploring the overall structure and
      function of the brain using a range of computerised brain imaging technologies
      (BITs). These technologies offer the means to elucidate the patterns of
      pathophysiology underlying mental illness. The aim of this paper is to explore
      the current status and some of the future directions in the application of BITs
      to psychiatry. METHOD: Brain imaging technologies provide unambiguous measures of
      brain structure (computerised tomography and magnetic resonance imaging [MRI])
      and also index complementary measures of when (electroencephalography, event
      related potentials, magnetoencephalography) and where (functional MRI, single
      photon emission computed tomography, positron emission tomography) aspects of
      brain activity occur. RESULTS: The structural technologies are primarily used to
      exclude a biological cause in cases of a suspected psychiatric disorder. The
      functional technologies show considerable potential to delineate subgroups of
      patients (that may have different treatment outcomes), and evaluate objectively
      the effects of treatment on the brain as a system. What is seldom emphasised in
      the literature are the numerous inconsistencies, the lack of specificity of
      findings and the simplistic interpretation of much of the data. CONCLUSION: Brain
      imaging technologies show considerable utility, but we are barely scratching the
      surface of this potential. Simplistic over-interpretation of results can be
      minimised by: replication of BIT findings, judicious combination of complementary
      methodologies, use of appropriate activation tasks, analysis with respect to
      large normative databases, control for performance, examining the data'beyond
      averaging', delineating clinical subtypes, exploring the severity of symptoms,
      specificity of findings and effects of treatment in the same patients. The
      technological innovation of BITs still far outstrips the sophistication of their
      use; it is essential that the meaning and mechanisms underlying BIT measures are
      always evaluated with respect to prevailing models of brain function across
      disciplines.

PMID- 10336218
TI  - An integrated treatment algorithm for pharmacotherapy and psychotherapy.
AB  - OBJECTIVE: As in Australia, demand for psychotherapy is rising in Britain, and
      the wide variety of psychological treatments available within the National Health
      Service (NHS), the independent sector, and voluntary agencies leads to
      uncertainty about which patients are most suitable for which type of
      psychotherapy, as well as the appropriate balance between psychological and
      pharmacological interventions. This paper describes how Birmingham Health
      Authority (HA), the largest HA in England and Wales with a population of just
      under one million, developed and implemented an evidence-based strategy for the
      use of psychotherapy services. METHOD: A literature search and health needs
      assessment for psychotherapy in Birmingham was performed. RESULTS: It was
      possible to estimate the need for evidence-based psychotherapy services using
      routinely available epidemiological data. By matching specific techniques to
      individual diagnosis and estimating the size of the population for whom this was
      appropriate, demand for psychotherapy exceeded service provision by a factor of
      four. CONCLUSIONS: The following steps were undertaken: (i) setting priorities
      for the commissioning of psychotherapy on the basis of the scientific literature
      including greater use of brief and focused forms of integrative therapy from a
      variety of psychotherapeutic schools; (ii) targeting interventions on the basis
      of objective criteria to ensure that patients were referred for the appropriate
      level and intensity of psychological intervention using the full range of
      available services within the NHS, the independent sector, and voluntary
      agencies; (iii) agreeing on an integrated treatment algorithm (ITA) for the use
      of the most cost-effective treatments while ensuring that a range of alternative
      interventions was available for patients for whom a first line therapy was not
      suitable. Such an ITA could be adapted to assist general practitioners in their
      management and referral decisions; (iv) sharing skills between specialist
      psychotherapy services and members of primary and mental health teams through
      training, supervision and consultation-liaison.

PMID- 10336219
TI  - Sub-grouping non-melancholic major depression using both clinical and
      aetiological features.
AB  - OBJECTIVE: In previous papers we have considered the extent to which two
      contrasting analytic approaches, examining reported clinical symptom variables
      alone and aetiological variables alone, assist definition of subgroups of non
      melancholic major depression. Here, we address the same objective but combine
      both sets of variables, and contrast the combined solution with each of the
      contributing ones. METHOD: We study a sample of 185 subjects with a putative non
      melancholic major depressive disorder, with analyses involving 13 aetiological
      and 38 symptom variables. RESULTS: A four-class subgrouping was derived by use of
      a cluster analytic technique, with 'neurotic depression', non-anxious
      'depressed', 'situational' and 'residual' groups. The largest group comprised
      'neurotic depression' subjects, with characteristics compatible with a spectrum
      disorder encompassing both clinical features as well as an underlying temperament
      and personality style marked by anxiety. CONCLUSIONS: Comparative advantages and
      properties of the three differing analytic approaches to defining 'meaningful'
      non-melancholic major depressive subgroupings are considered. As a 'neurotic
      depressive' class has been consistently identified across those three approaches,
      but with quite varying numbers of subjects circumscribed, it is clearly a 'fuzzy'
      entity which may benefit from a dimensional approach to its measurement. As many
      of the non-melancholic groupings appear secondary to a substantive predisposing
      factor such as anxiety or disordered personality functioning, the clinical
      importance and treatment utility in identifying and circumscribing such classes
      are clearly supported.

PMID- 10336220
TI  - Gender differences in living skills and global assessment of functioning among
      outpatients with schizophrenia.
AB  - OBJECTIVE: The aims of this paper are to study skills in personal and domestic
      activities, and their associations with Global Assessment of Functioning (GAF)
      scale scores among outpatients with schizophrenia, and to study the impact of
      depressive mood on functional capacity in schizophrenia. METHOD: Three hundred
      and two outpatients with DSM-III-R schizophrenia completed the 13-item Beck
      Depression Inventory (BDI) and a questionnaire relating to their sociodemographic
      characteristics, and living and working conditions. Staff members completed the
      GAF scale and a questionnaire relating to the patient's medical history and
      current treatment. This questionnaire also included the staff's assessments on
      patient's skills in six personal or domestic activities (personal hygiene,
      homemaking, management of financial affairs, shopping, decision-making, getting
      about). RESULTS: Fifty-six percent of men and 33% of women (p < 0.001) with
      schizophrenia did not have independent skills in at least one personal or
      domestic activity but there was no difference in the mean GAF score between men
      and women. In men, the GAF score was independently and positively associated with
      all living skills studied and in women with homemaking, management of financial
      affairs, and decision-making, respectively. The BDI scores were not independently
      associated with functioning in personal and domestic activities except with
      getting about in women. CONCLUSIONS: The GAF scale is a simple and time-saving
      measure for assessing overall living skills among outpatients with schizophrenia.
      However, assessments on the GAF scale may be biased towards poor functioning in
      women. Moreover, psychosocial functioning and depression should be evaluated
      separately.

PMID- 10336221
TI  - Mental illness depictions in prime-time drama: identifying the discursive
      resources.
AB  - OBJECTIVE: The aim of this study was to determine how the mentally ill are
      depicted in prime-time television dramas. METHOD: Fourteen television dramas that
      included at least one character with a mental illness, shown in prime-time during
      a 1-year period, were systematically viewed and analysed. RESULTS: Fifteen of the
      20 mentally ill characters were depicted as physically violent toward self or
      others. Characters were also depicted negatively as simple or lacking in
      comprehension and appearing lost, unpredictable, unproductive, asocial,
      vulnerable, dangerous to self or others because of incompetent behaviours,
      untrustworthy, and social outcasts, and positively as caring or empathic.
      CONCLUSIONS: These data are consistent with an overwhelming negativity of
      depictions of the mentally ill found in other forms of media and settings, and
      contribute to the stigmatisation of this population.

PMID- 10336222
TI  - Constructing mental illness as dangerous: a pilot study.
AB  - OBJECTIVE: There is a dearth of studies examining how dangerousness is
      constructed in media depictions of mentally ill individuals who are frequently
      portrayed as acting violently. The aim of the present study was to identify the
      contribution of diverse technical, semiotic and discursive resources utilised in
      portraying a character with a mental illness in a prime-time drama as dangerous.
      METHOD: Discourse analytic techniques, involving systematic, repeated, critical
      viewings, were applied to a single program drawn from a sample of prime-time
      television drama episodes touching on mental illness. RESULTS: Nine devices
      (appearance, music and sound effects, lighting, language, intercutting, jump
      cutting, point of view shots, horror conventions and intertextuality) were
      identified as contributing to the signified dangerousness of person receiving
      care in the community for a mental illness. CONCLUSIONS: These techniques combine
      in signifying mental illness and a person suffering from it as dangerous. The
      findings suggest that mental health professionals working to reduce the stigma of
      mental illness need to have a reasonably sophisticated understanding of the
      practices and priorities of television production if they are to collaborate
      effectively with producers to create dramas that convey more human and
      sympathetic understandings of mental illness or to combat the negative effects of
      such portrayals.

PMID- 10336223
TI  - Measuring the quality of supervision and the training experience in psychiatry.
AB  - OBJECTIVE: The aim of this study was to develop and trial a method of trainee
      evaluation of the supervision and training experience. METHOD: A questionnaire
      was developed and applied at the end of each of four 6-month clinical rotations.
      RESULTS: The evaluation demonstrated areas of strength (punctuality and
      reliability, encouragement, educational value, clinical guidance) and weakness
      (journal club, clinical meetings). Many supervisors were not observing diagnostic
      or management interviews of trainees. Psychotherapy supervision received the
      highest ratings. CONCLUSIONS: Because of the privacy of supervision and the
      occasional nature of evaluations, reliability of scores cannot be demonstrated.
      However, within the context of a model of quality improvement, and supplemented
      by the education and supervision of supervisors, trainee evaluations can be
      useful in targeting specific areas of deficiency in training and supervision.

PMID- 10336224
TI  - A survey of suicide prevention curricula taught in Australian universities.
AB  - OBJECTIVE: The aim of this study was to survey Australian universities to
      determine the scope of suicide prevention curricula in a range of prevocational
      courses. METHOD: Coordinators of undergraduate and postgraduate university
      programs for medicine, nursing, psychology, social work, theology, education,
      pharmacy, law and journalism were asked to complete a survey instrument to
      determine whether specific knowledge, attitude and skills items were included in
      the course content. Additional information was sought concerning the dominant
      method of teaching. Data were compared by discipline. An arbitrary threshold of
      70% of courses within each discipline responding positively to each survey item
      was established as an adequate level of penetrance of that item into
      prevocational programs. RESULTS: Overall, knowledge and attitudes related to
      suicide prevention are taught more comprehensively than are skills. Knowledge and
      attitude items are taught most comprehensively in medical and nursing schools,
      somewhat less in psychology, social work, and pharmacy, uncommonly in theology
      and education. Law and journalism courses currently include very little material
      related to suicide and suicide prevention. Skills relevant to the management of
      suicidal individuals and their families are taught most comprehensively in
      psychology, nursing and medical courses, with low penetrance into other courses.
      CONCLUSION: The greatest opportunity to increase exposure to knowledge and
      attitudes relevant to suicide prevention exists within education, theology, law
      and journalism courses. Programs directed to the development of interpersonal
      skills relevant to the management of suicidal individuals and their families
      could be introduced across the board.

PMID- 10336225
TI  - Sex knowledge and sexual attitudes among medical and nursing students.
AB  - OBJECTIVES: The aim of this study was to assess the relationship between
      background and sociodemographic variables, attitudes toward controversial aspects
      of human sexuality and sex knowledge among medical and nursing students. METHOD:
      The study design was a questionnaire-based survey of medical and nursing students
      in Western Australia. Participants were first- through fifth-year medical
      students at the University of Western Australia and first- through third-year
      undergraduate nursing students at Edith Cowan University. Outcome measures were
      students' attitudes toward controversial aspects of human sexuality expressed on
      a five-point Likert scale and a modified version of the Kinsey Institute/Roper
      Organization National Sex Knowledge Test. RESULTS: A significant relationship was
      found between certain background and sociodemographic variables, sexual attitudes
      and sex knowledge. The background variable most strongly related to both
      attitudes and knowledge was frequency of attendance at religious services of any
      religious denomination during the past month, with those attending three or more
      times more likely to express negative attitudes and have lower sex knowledge
      scores. Lower sex knowledge was related to negative attitudes toward
      gay/lesbian/bisexual behaviour, masturbation, premarital sex and contraception.
      Other important background and sociodemographic variables related to negative
      attitudes were: never having experienced sexual intercourse; right-wing political
      orientation; lower family income; gender and ethnicity. CONCLUSIONS: Negative
      attitudes toward controversial aspects of human sexuality and lower sex knowledge
      scores among medical and nursing students can be predicted on the basis of
      background and sociodemographic variables. Education aimed at increasing sex
      knowledge and modifying negative attitudes may increase students' ability to
      function more effectively as sexual history takers and sex counsellors.

PMID- 10336226
TI  - Experience, knowledge and attitudes of mental health staff regarding patients'
      problematic drug and alcohol use.
AB  - OBJECTIVE: The aim of this study was to assess the experience, knowledge and
      attitudes of mental health staff regarding patients' problematic drug and alcohol
      use in order to provide direction for planned drug and alcohol education. METHOD:
      A 47-item questionnaire was developed and individually posted to all mental
      health staff employed by Central Sydney Area Health Service (n = 536). RESULTS:
      Three hundred and thirty-eight (63%) staff members completed the questionnaire.
      Thirty-six percent of respondents had received drug and alcohol training and 41%
      had drug and alcohol work experience. Drug and alcohol training and work
      experience were associated with increased drug and alcohol knowledge.
      Respondents' perception of their knowledge and competence was positively
      correlated with their actual knowledge. Most staff reported having regular
      contact with patients with psychotic illnesses and drug and alcohol problems. The
      majority considered the management of this patient group difficult and currently
      inadequate. Seventy percent believed that as mental health professionals they had
      a role to play in the management of their patients' drug and alcohol problems.
      Almost all (95%) were willing to participate in further education and training in
      this area. CONCLUSIONS: Mental health staff are often confronted with drug and
      alcohol problems in patients with psychotic illnesses. They perceive a need for
      drug and alcohol education and training specific to the management of these
      patients. Future research will need to evaluate outcomes of education and
      training programs for both staff and patients.

PMID- 10336227
TI  - Dexamethasone suppression test reversal in rapid transcranial magnetic
      stimulation-treated depression.
AB  - OBJECTIVE: The aim of this paper is to report the effect of rapid transcranial
      magnetic stimulation (rTMS) on the mood and dexamethasone suppression test (DST)
      of a patient with major depressive disorder (DSM-IV). CLINICAL PICTURE: A 36-year
      old woman with a past history of prolactinoma and recurrent major depressive
      disorder presented with major depression on three separate occasions over a 3
      month period. DST was positive on each occasion. TREATMENT: During each episode,
      a course of rTMS was given. Courses varied from seven to 13 once-daily treatment
      sessions depending on clinical response. These treatment sessions were 20 trains
      of 10 Hz for 5 s at 100% of motor threshold. OUTCOME: Remission was achieved,
      psychiatric rating scales improved and the DST status converted from positive to
      negative. There were no side effects. CONCLUSION: DST status in major depressive
      disorder can be converted from positive to negative by rTMS. This so far
      unreported observation increases our knowledge of rTMS.

PMID- 10336228
TI  - Nefazodone for patients with chronic fatigue syndrome.
AB  - OBJECTIVE: Patients with chronic fatigue syndrome (CFS) present with a variety of
      musculoskeletal, neurocognitive, sleep disturbance and mood symptoms. An open
      evaluation of the clinical utility of the novel antidepressant compound,
      nefazodone, was completed. METHOD: Ten patients with CFS presenting for
      assessment by a specialist psychiatrist were treated with nefazodone. Patients
      treated within this specialist service are also advised to engage in appropriate
      behavioural and sleep-wake cycle strategies to improve their level of
      functioning. RESULTS: Of the 10 patients, eight (80%) reported at least some
      improvement in the key symptom of fatigue, with four (40%) reporting moderate or
      marked symptom relief. Additionally, sleep disturbance and mood were both
      moderately or markedly improved in seven (70%) and eight (80%) of the patients,
      respectively. Five of the patients (50%) achieved at least a moderate improvement
      in overall functional outcome and were able to return to work or their previous
      level of role function. The mean dose of nefazodone was 370 mg/day (range = 200
      800 mg), with a strong preference for nocturnal dosing. Seven of the patients had
      previously failed to respond to moclobemide, while seven had previously failed to
      respond to conventional antidepressant therapy. CONCLUSION: Nefazodone appears to
      be worthy of further systematic investigation in patients with CFS. Given its
      effects on sleep, mood and anxiety symptoms, it may have particular advantages in
      patients with this disorder.

PMID- 10336229
TI  - Prescribing of psychotropic drugs in an acute inpatient unit.

PMID- 10336230
TI  - Multispeak in psychiatry.

PMID- 10336231
TI  - Cost-effectiveness of cyclic antidepressants in a developing country.

PMID- 10336232
TI  - Cardiotoxicity associated with use of intravenous haloperidol.

PMID- 10336233
TI  - International telepsychiatry: a link between New Zealand and Australia.

PMID- 10336234
TI  - The link between diabetes and schizophrenia: an immunological explanation.

PMID- 10336235
TI  - Microtitre plate and assay buffer alter detection of antiphosphatidylethanolamine
      antibodies in lupus anticoagulant positive plasma.
AB  - The ELISA for detection of anti-phosphatidylethanolamine antibodies in patients
      with lupus anticoagulant was studied. The influence of microtitre plate types,
      antigen concentration, antibody dilution, and buffer system was evaluated. Human
      albumin in the blocking buffer gave greater numbers of positive plasma samples
      than bovine serum. Comparison of simultaneous plasma and serum samples showed
      only minor variation in binding characteristics.

PMID- 10336236
TI  - Do antiphospholipid antibodies interfere with tissue factor pathway inhibitor?
AB  - This study was conducted to investigate whether antiphospholipid antibodies (APA)
      can interfere with the phospholipid-dependent inhibition of coagulation exerted
      by tissue factor pathway inhibitor (TFPI). Eleven patients with APA and eleven
      healthy controls matched for age and gender were enrolled. Blood samples were
      drawn before and 5 minutes after an intravenous injection of unfractionated
      heparin 5000 IE, which is known to cause TFPI release in healthy individuals. The
      preheparin samples showed significantly higher TFPI free antigen levels in the
      APA positive patients than in the controls (21.7 vs. 14.2 ng/ml, p = 0.03). TFPI
      activity as measured in a chromogenic substrate assay also was higher in
      patients, but this difference was not statistically significant (1.13 vs. 1.01
      U/ml, p = 0.2). The TFPI levels showed a considerable rise in both patients and
      controls after heparin injection. In both assays, the postheparin levels were
      significantly higher in patients than in controls (TFPI antigen: 179 vs. 153
      ng/ml, p = 0.05; TFPI activity: 3.26 vs. 2.51 U/ml, p = 0.03). A modified diluted
      prothrombin time assay (dPT) was used to measure TFPI anticoagulant activity. In
      this assay, samples from the patients with the strongest effect of lupus
      anticoagulants (LAs) on preheparin coagulation times showed little or no increase
      after heparin injection. This result may reflect an inhibition of TFPI
      anticoagulant activity by strong LAs. In conclusion, we have found that patients
      with APA have higher TFPI amidolytic activity/antigen level both before and after
      heparin stimulation of TFPI release. These observations do not explain the higher
      thrombotic risk in these patients but may reflect an upregulated tissue factor
      activity, which has been demonstrated in these patients. TFPI anticoagulant
      activity, however, as measured in a dPT assay, may be inhibited by strong LAs.

PMID- 10336237
TI  - CA-1 method, a novel assay for quantification of normal prothrombin using a Ca2+ 
      dependent prothrombin activator, carinactivase-1.
AB  - We established a novel prothrombin assay, designated CA-1 method, for
      quantification of normal prothrombin in application of a Ca2+ -dependent
      prothrombin activator, carinactivase-1 (CA-1), found in the venom of Echis
      carinatus leucogaster. On microplate, thrombin converted from normal prothrombin
      in plasma sample by CA-1 cleaves a thrombin specific chromogenic substrate, t
      butoxy-Val-Pro-Arg-p-nitroanilide and liberates p-nitroaniline. Then, the normal
      prothrombin level is decided by measuring the velocity of p-nitroaniline
      liberation. Normal prothrombin levels in plasma from warfarin-treated individuals
      were highly correlated with coagulant activities assayed by both prothrombin time
      and thrombotest. CA-1 method is not only a rapid and highly sensitive chromogenic
      microplate assay for quantification of normal prothrombin in the range of 10-200
      ng/100 microl in plasma samples but also suitable for analyses of many samples in
      a short time. In addition, normal prothrombin levels obtained by CA-1 method are
      not inhibited by EDTA and heparin, which reduce prothrombin time and thrombotest
      activities. CA-1 method is a novel assay for monitoring coagulant activity in
      warfarin-treated individuals.

PMID- 10336238
TI  - Antithrombotic effect of SM-20302, a nonpeptide GPIIb/IIIa antagonist, in a
      photochemically induced thrombosis model in guinea pigs.
AB  - SM-20302, a synthetic inhibitor of the fibrinogen receptor of platelets, has been
      shown to inhibit the platelet aggregation induced by various stimuli. In the
      present study, we performed ex vivo platelet aggregation studies by using
      heparinized platelet-rich plasma (PRP) as well as citrated PRP and compared the
      antiaggregatory activity with the in vivo antithrombotic efficacy of SM-20302.
      The oral administration of SM-20302 (0.3-10 mg/kg) to guinea pigs completely
      inhibited the ADP-induced ex vivo platelet aggregation in citrated PRP. In
      heparinized PRP, SM-20302 (1-10 mg/kg) showed a dose-dependent inhibition of ex
      vivo platelet aggregation, and it exhibited complete inhibition at a dose of 3
      and 10 mg/kg, respectively. The concentration of ionized calcium in the citrated
      samples was approximately 35 times lower than that in heparinized samples.
      Chelation of ionized calcium caused an enhancement of the antiaggregatory
      activity of SM-20302 in guinea pig heparinized PRP in vitro. And addition of
      CaCl2 to citrated PRP reversed the enhancement. Citrate therefore appeared to
      enhance the inhibitory activity of SM-20302 by lowering the ionized calcium
      levels. We also examined the in vivo efficacy of SM-20302 in a photochemically
      induced femoral artery thrombosis model in guinea pigs. The photochemical injury
      of the endothelium of femoral artery resulted in a progressive decline in the
      blood flow. The oral administration of SM-20302 (0.1-3 mg/kg) produced a dose
      dependent maintenance of the femoral artery patency and significantly prolonged
      the time to occlusive thrombus formation at a dose of 1 and 3 mg/kg,
      respectively. These results suggest that SM-20302 may be an orally active
      antithrombotic agent, and its in vivo antithrombotic efficacy appeared to
      correlate well with the ex vivo platelet inhibition in PRP prepared from
      heparinized blood but not in PRP anticoagulated with citrate.

PMID- 10336239
TI  - Effect of a micronized purified flavonoid fraction on in vivo platelet functions
      in the rat.
AB  - The aim of this study was to investigate the effects of a micronized purified
      flavonoid fraction (MPFF) on in vivo rat platelet functions. Platelet aggregation
      and disaggregation were evaluated by a noninvasive, automated isotope monitoring
      system (AimsPlus). Indium-labeled platelets were injected into anesthetized rats
      and stimulated by adenosine diphosphate (ADP) (10 microg/kg, i.v.) or collagen
      (50 microg/kg, i.v.). Fibrinogen binding to ex vivo ADP-activated platelets was
      determined by flow cytometry. MPFF (100 mg/kg, p.o.) significantly reduced ADP
      induced platelet aggregation (p<0.05) and increased platelet disaggregation
      (p<0.05) compared with controls. Moreover, MPFF inhibited collagen-induced
      platelet aggregation (p<0.001) and increased platelet disaggregation (p<0.01). In
      addition, fibrinogen binding to 2.5 or 5 microM ADP-stimulated platelets also was
      reduced significantly (p<0.05 and 0.01, respectively). These results show that
      MPFF inhibits in vivo rat platelet functions.

PMID- 10336240
TI  - Changes in the fibrinolytic system in patients with peripheral arterial occlusive
      disease undergoing percutaneous transluminal angioplasty.
AB  - We have investigated fibrinolytic parameters in 33 patients with peripheral
      arterial occlusive disease (PAOD) before and 6, 24, and 48 hours after
      percutaneous transluminal angioplasty (PTA) as well as in 35 gender-matched
      healthy controls, whose mean age was not significantly different from the mean
      age of the patients. PAOD patients had significantly higher plasma levels of t-PA
      antigen (12.0+/-4.9 vs. 9.2+/-5.5 ng/ml), PAI-1 antigen (34.8+/-22.1 vs. 27.2+/
      23.6 ng/ml), PAI-1 activity (10.0+/-6.5 vs. 8.0+/-8.0 U/ml), PCI (188.2+/-55.6
      vs. 134.1+/-75.5% as compared with normal human plasma), and fibrinogen (420.2+/
      92.6 vs. 261.9+/-32.7 mg/dl) as compared with controls. After angioplasty,
      fibrinolytic parameters and fibrinogen levels increased, reaching higher than
      preintervention levels 24 and 48 hours after the intervention. Six months after
      initially successful PTA, restenosis was demonstrated in 14 out of 33 patients
      (42%). Patients with late restenosis had significantly higher levels of PAI-1
      activity 24 and 48 hours after PTA, as compared with patients with late patency
      (24 hours: 16.1+/-8.0 vs. 10.0+/-7.4; 48 hours: 16.5+/-7.9 vs. 12.0+/-7.0; p<0.05
      for both time points). The results suggest that impaired fibrinolysis early after
      PTA might be a cause or marker of a disturbed repair process of vascular injury,
      leading to restenosis.

PMID- 10336241
TI  - Microheterogeneity in the distribution of the 844ins68 in the cystathionine beta
      synthase gene in Italy.
AB  - Cystathionine beta-synthase (CBS) is an important enzyme for methionine
      metabolism. A common 844ins68 insertion variant in the CBS gene has been
      described. This 68-bp duplication of the intron 7-exon 8 boundary within the CBS
      gene already has been reported to be associated in cis with the T833C mutation.
      Heterozygosity for CBS deficiency is considered an important cause of
      hyperhomocysteinemia that strongly relates to cardiovascular disease, as well as
      homozygosity for another common variant, the C677T mutation of 5,10-methylene
      tetrahydrofolate reductase. We analysed the prevalence of the 844ins68 variant in
      the CBS gene in 595 unrelated apparently healthy individuals from nine Italian
      regions and in 133 patients with coronary artery disease. Our data confirm that
      the T833C mutation cosegregates in cis with the 844ins68 in all carriers of the
      insertion. Furthermore, no statistical difference was found in the insertion
      variant allele frequency between controls and coronary artery disease patients.
      Our study indicates a microheterogeneity in the distribution of the 844ins68 in
      the Italian population.

PMID- 10336242
TI  - Comparative studies of rabbit and human recombinant tissue factor reagents.

PMID- 10336243
TI  - Exhaustive cycle exercise induces P-selectin expression, coagulation, and
      fibrinolysis activation in ultraendurance athletes.

PMID- 10336244
TI  - New source of vein graft for rabbit experimentation.
AB  - The present report introduces a new source of vein graft in rabbit
      experimentation which is long and of large caliber. The average length of
      available vein was 13.3+/-0.9 cm (mean+/-SD). The average external diameter of
      the vein was 1.8+/-0.2 mm (mean+/-SD), 1.4+/-0.4 mm (mean+/-SD), and 1.8+/-0.2 mm
      (mean+/-SD) at the proximal, middle, and distal portions, respectively. The
      average number of valves throughout the vein was 7+/-1. The vein is anatomically
      termed the lateral saphenous vein distally and the ischiadic vein proximally, and
      is superficially located on the lateral aspect of the pelvic limb. Therefore,
      this vein is easily harvested from the lower crus to the upper-thigh, providing a
      long length of vein graft for experimental study.

PMID- 10336245
TI  - Detection of free radicals in reperfused dog skin flaps using electron
      paramagnetic resonance spectroscopy: a pilot study.
AB  - This is a preliminary investigation of the usefulness of spin-trapping electron
      paramagnetic resonance (EPR) in detecting oxygen-derived free radicals after
      reperfusion of ischemic skin flaps. Fourteen island skin flaps approximately 12
      cm long by 6 cm wide based on the caudal superficial epigastric vessels were
      isolated in seven dogs. Seven of the paired skin flaps were subjected to 4 hours
      of arterial and venous occlusion. The opposite skin flap on each dog served as a
      perfused control. Spin trapping-EPR was able to detect radical adducts in five of
      the seven reperfused skin flaps. Hyperfine splitting constants of the radical
      adducts from the blood of three of the flaps confirmed biologically derived free
      radical production. Contaminating EPR signals from free radicals created in the
      manufacture of plastics probably masked any biologically derived radical adducts
      in the remaining flaps. The authors conclude that EPR-spin trapping may be a
      valuable tool in the study of the importance of oxygen-derived free radicals in
      the failure of skin flaps subjected to transient ischemia.

PMID- 10336246
TI  - Can vascularization improve the surgical outcome of the intercostal nerve
      transfer for traumatic brachial plexus palsy? A clinical comparison of
      vascularized and non-vascularized methods.
AB  - It is very difficult to design a well-controlled comparative study for clarifying
      the value of vascularized nerve grafting in clinical cases. In order to
      understand whether or not the vascularizing procedure has any clinical value in
      nerve transfer and in nerve grafting, we compared non-vascularized with
      vascularized intercostal nerve transfer in patients with brachial plexus injury.
      Factors that were likely to affect the results were controlled. We found there
      was no significant difference in the functional outcome and no difference in the
      regenerating rate of the nerves between nonvascularized and vascularized
      intercostal nerve transfer. We concluded that the vascularizing procedure had
      little clinical value not only in intercostal nerve transfer, but also in nerve
      grafting irrespective of the length of the gap, when the recipient bed had normal
      vascularity.

PMID- 10336247
TI  - Anatomic and physiologic evaluation of upper extremity ischemia.
AB  - This study assessed the accuracy of arteriography and laser Doppler perfusion
      imaging (LDPI) as predictors of digital ischemia and correlated upper extremity
      symptoms, function, and nutritional flow with arteriographic and laser Doppler
      assessments. Multiple-level occlusive disease was documented in 25 hands (23
      patients) by arteriography. LDPI demonstrated one or more hypoperfused digits in
      17 hands. Patient questionnaires were used to assess upper extremity symptoms,
      pain, cold sensitivity, and function. Spearman correlation coefficients indicated
      that arteriography is a poor indicator of nutritional perfusion as measured by
      LDPI. Neither arteriography or laser Doppler perfusion imaging served as an
      indicator of the severity of cold intolerance. However, upper extremity symptoms
      and functional status correlated with both laser Doppler measurements and the
      level of cold sensitivity. Laser Doppler perfusion imaging and arteriographic
      analysis provide complimentary data in the evaluation of upper extremity
      ischemia.

PMID- 10336248
TI  - Long-term result of arterial grafts interposed for arterial defects using the
      telescoping anastomotic technique: histological and angiographic study.
AB  - The arterial grafting model for arterial defects provides an ideal environment
      for the microvascular telescoping anastomosis because tension of the repaired
      vessel is maintained low and deformities of the inserted vessel end is minimal
      due to the thick arterial wall. The left femoral artery was grafted in 46 rats
      into the defect created in the right femoral artery using the telescoping
      anastomotic technique at both the proximal and distal anastomoses. The grafts
      were seen histologically and angiographically 3 to 4 months postoperatively in
      order to fairly evaluate the telescoping anastomosis in terms of long-term
      patency, stenosis, and changes in the outer and inner walls at the anastomosis.
      All arterial grafts were patent 3 to 4 months postoperatively and there were no
      aneurysms at the anastomoses. Enlargement of the graft diameter was minimal. The
      rate of stenosis at the anastomosis was smaller than that 1-day postoperatively.
      Even though the thick arterial wall was initially inserted and the intimal
      hyperplasia was still present at the anastomosis 3 to 4 months postoperatively,
      the long-term stenosis was relatively mild due to the atrophy in the overlapped
      walls.

PMID- 10336249
TI  - Postoperative changes in blood flow in free muscle flaps: a prospective study.
AB  - We used color Doppler ultrasound (US) to study postoperative changes in blood
      flow in 10 non-innervated free latissimus dorsi (LD) muscle flaps transplanted
      onto lower extremities. The peak, mean, and minimum velocities, resistance index,
      and diameter of the pedicle, and the recipient and control arteries were recorded
      preoperatively and on the 2nd, 5th, and 10th days after surgery. In the pedicle
      of the transplant, the peak and mean velocities increased but not significantly
      during the follow-up. The minimum velocity value in the thoraco-dorsal artery was
      (mean+/-SD) 4+/-5 cm/sec preoperatively, and was in the leg 19+/-9 cm/sec (P <
      0.05) on the 5th and 17+/-10 cm/sec (P < 0.05) on the 10th postoperative day. The
      preoperative value of the resistance index decreased from 0.92+/-0.12 to 0.79+/
      0.08 on the 10th postoperative day (P < 0.05). In the recipient artery, the peak
      (117+/-37) and mean (35+/-16 cm/sec) velocities increased significantly on the
      5th postoperative day compared to the preoperative value (79+/-22 and 14+/-6
      cm/sec, respectively). The minimum velocity increased but not significantly. The
      resistance index was preoperatively 1.23+/-0.09 and 0.88+/-0.16 (P < 0.05) on the
      10th postoperative day. This prospective clinical study demonstrates that blood
      flow in the pedicle and in the recipient artery of a free muscle flap increases
      after surgery. This phenomenon may be due to loss of vascular tone and decreased
      resistance after denervation. Increased blood flow helps to keep the
      microanastomosis open and also promotes wound healing.

PMID- 10336250
TI  - Effects of tension at the site of coaptation on recovery of sciatic nerve
      function after neurorrhaphy: evaluation by walking-track measurement,
      electrophysiology, histomorphometry, and electron probe X-ray microanalysis.
AB  - The effects of tension at the site of coaptation on recovery of sciatic nerve
      function after neurorrhaphy were studied by evaluating walking-track
      measurements, nerve conduction velocity measurements, histomorphometry, and
      electron probe X-ray microanalysis. Forty adult male Lewis rats underwent right
      sciatic nerve (SN) transection followed by one of four different nerve repair
      procedures (N = 10 rats per group). In Group 1, the gap was repaired by end-to
      end epineural coaptation. In Group 2, a 5-mm segment of SN was resected, and the
      defect was repaired under high tension by epineural neurorrhaphy. In Group 3, a 5
      mm segment of SN was resected, and the defect was repaired with a 5-mm
      interposition nerve graft. In Group 4, a 5-mm segment of SN was resected. Then,
      to lessen the tension that follows neurorrhaphy, an anchoring suture was added.
      Finally, end-to-end coaptation was performed. Walking-track analysis showed
      better functional recovery in Group 1 than in Group 2, and better recovery in
      Group 3 than in Group 2. Group 4 showed a tendency toward better recovery
      comparing with Group 2. Electron probe X-ray microanalysis revealed higher Na,
      Cl, and K peaks in axoplasm accompanied by increase in the endoneural fluid
      pressure (EFP) in Group 2 than those of Group 1. This higher level of Na, Cl and
      K may be due to impairment of axonal sodium and potassium transport mechanism in
      Group 2. Increase in EFP may affect nerve regeneration.

PMID- 10336251
TI  - Structural features of the rat GFAP gene and identification of a novel
      alternative transcript.
AB  - The glial fibrillary acidic protein (GFAP) is expressed in a cell-specific manner
      and represents the major subunit of intermediate filaments of astroglial cells.
      The knowledge of the gene structure is an important step for further
      understanding the mechanisms of cell-specific expression. In the present study,
      we report the complete sequence of the rat GFAP gene and provide evidence for the
      existence, in the rat brain, of a novel alternative transcript. Since three
      different transcripts, indicated as GFAPalpha, beta, and gamma, have been
      previously reported (Feinstein et al. [1992] J. Neurosci. Res. 32:1-14; Zelenika
      et al. [1995] Mol. Brain Res. 30:251-258), we called this novel mRNA isoform
      GFAPdelta. It is generated by the alternative splicing of a novel exon located in
      the classic seventh intron. This alternative exon (called VII+) contains a 101-bp
      coding sequence in frame with exon VII and interrupted by a stop codon TAA at
      position +5451. Therefore, the novel GFAPdelta transcript encodes for an
      hypothetical GFAP where the forty-two carboxy-terminal amino acids encoded by
      exon VIII and IX are replaced by thirty-three amino acids encoded by exon VII+.
      Northern blot analysis with a specific probe for exon VII+ revealed a 4.2-kb
      mRNA, expressed in several brain areas, but absent in extracerebral tissues
      (lung, heart, kidney, liver, spleen). The previously discovered GFAP isoforms
      (alpha, beta, and gamma) produce hypothetical translation products differing in
      the amino-terminal Head domain. The present data suggest, for the first time, the
      possible existence of GFAP isoforms differing in the carboxy-terminal Tail
      domain.

PMID- 10336253
TI  - Myelin basic protein isoforms in myelinating and remyelinating rat brain
      aggregate cultures.
AB  - Recent evidence suggests that myelin basic protein (MBP) exon-2-containing
      isoforms play a significant role in the onset of myelination because they are
      more abundant during early development. The pattern of expression of MBP exon-2
      containing isoforms was studied in rat brain aggregate cultures during
      myelination to draw comparisons with the developing brain and at remyelination
      after demyelinative treatment. The pattern of MBP isoform expression in the
      aggregate cultures was found to be similar to that of the brain and was
      recapitulated after demyelination with antimyelin antibodies. Macrophage
      enrichment, resulting in increased accumulation of total MBP in the cultures, did
      not alter the isoform distribution. Both control and enriched cultures expressed
      a 16-kDa protein (26+/-9.8% of total MBP for control samples) that reacted with
      MBP antisera at the onset of myelination (day in vitro 14) but was barely
      detectable by day in vitro 21. The expression of this protein, also present in
      postnatal day 6 rat brain but no longer by day 11, has been predicted by reverse
      transcription polymerase chain reaction in embryonic mouse brain. The results of
      the present study reinforce the value of the aggregate culture system as a
      versatile yet accurate model of myelination and remyelination.

PMID- 10336252
TI  - Regulation of hippocampal neuronal differentiation by the basic helix-loop-helix
      transcription factors HES-1 and MASH-1.
AB  - HES-1 is a vertebrate homologue of the Drosophila basic helix-loop-helix (bHLH)
      protein Hairy, a transcriptional repressor that negatively regulates neuronal
      differentiation. HES-1 expression in neuronal precursors precedes and represses
      the expression of the neuronal commitment gene MASH-1, a bHLH activator
      homologous to the proneural Achaete-Scute genes in Drosophila. Down-regulation of
      HES-1 expression in developing neuroblasts may be necessary for the induction of
      a regulatory cascade of bHLH activator proteins that controls the commitment and
      progression of neuronal differentiation. Here we show that the differentiation of
      embryonic day-17 rat hippocampal neurons in culture was coincident with a decline
      in HES-1 expression and DNA binding. Therefore, we examined the effect of forced
      expression of HES-1 and MASH-1 upon nerve growth factor (NGF) -induced
      differentiation in TrkA transfected hippocampal neurons. Expression of HES-1
      inhibited both the intrinsic and NGF-induced neurite outgrowth, whereas MASH-1
      expression increased neurite outgrowth. Strikingly, the increased hippocampal
      differentiation observed with MASH-1 expression is completely blocked by
      coexpression of HES-1. Furthermore, both wild-type HES-1 and a non-DNA binding
      mutant of HES-1 repressed MASH-1-dependent transcription activation. These
      results suggest that down-regulation of HES-1 is necessary for autonomous, growth
      factor-induced and MASH-1-activated hippocampal differentiation.

PMID- 10336254
TI  - Bone morphogenetic proteins-2 and -4 attenuate apoptosis in a cerebellar
      primitive neuroectodermal tumor cell line.
AB  - Similarities between primitive neuroectodermal tumors and central nervous system
      (CNS) progenitor cells have evoked interest in the response of these tumors to
      endogenous growth factors. The bone morphogenetic proteins (BMPs) have recently
      been found to regulate survival and differentiation of CNS progenitor cell
      populations. In this study, we investigated the effects of BMP-2, BMP-4, and BMP
      6 on the undifferentiated cerebellar primitive neuroectodermal tumor or
      medulloblastoma cell line DAOY. Analysis by reverse transcriptase-polymerase
      chain reaction showed that mRNAs for type IA and type II BMP receptors were
      present in control cultures. In cultures treated with BMP-2, mRNAs for BMP
      receptor type IB and the activin R-I receptor became evident. Cultures were
      analyzed for total cell counts, proliferating cell nuclear antigen (PCNA), and
      apoptotic DNA fragmentation. There was a significant increase in total cell
      number in the BMP-2 and BMP-4 treatment groups, without any change in PCNA
      reactivity, and a dramatic decrease in the proportion of apoptotic nuclei at
      concentrations of BMP-2 and BMP-4 above 5 ng/ml (P<0.001). These effects were not
      observed with BMP-6, TGF-beta1 or GDNF. These results suggest that the increase
      in total cell number is due to the attenuation of apoptosis by BMP-2 and BMP-4.
      The anti-apoptotic effect of BMP-2 and BMP-4 on this neuroectodermal cell line
      has potential clinical implications for neuroectodermal tumors.

PMID- 10336255
TI  - Developmental regulation of alternatively spliced isoforms of mRNA encoding MAP2
      and tau in rat brain oligodendrocytes during culture maturation.
AB  - Oligodendrocytes are responsible for the formation and maintenance of the myelin
      sheaths in the central nervous system (CNS), and microtubules essentially
      participate in the elaboration and stabilization of myelin-containing cellular
      processes. We have shown before that the two major groups of neuronal microtubule
      associated proteins (MAPs), MAP2 and tau, are expressed in the myelin forming
      cells of the CNS (Mueller et al. [1997] Cell Tissue Res. 288:239-249). Here we
      demonstrate for the first time that during culture maturation, changes in mRNA
      splicing and a shift from immature to mature MAP2 and tau mRNAs occur in
      oligodendrocytes. Similarly to neurons, a developmental shift from MAP2 isoforms
      with 3 microtubule (MT)-binding domains (3R) to the isoforms with 4 MT-binding
      domains (4R) is observable. MAP2c constitutes the major MAP2 isoform in
      oligodendrocytes. They contain tau mRNA splice products with both 3 and 4 MT
      binding repeats (3R, 4R) with no amino terminal insert or with exon 2, and do not
      express isoforms containing exon 3. The shortest form tau 1 (3R; no inserts)
      representing the immature tau isoform is most prominently expressed in early
      progenitor cells and gradually decreases during culture maturation, while tau 5
      (4R; with exon 2) appears later during in vitro differentiation. The product
      corresponding to tau 2 (3R; with exon 2) and tau 4 (4R; no inserts) remains
      approximately at the same level. Hence, the occurrence of MAPs in
      oligodendrocytes is developmentally regulated. While in progenitor cells, 3R- and
      4R-MAP2c are expressed at approximately the same level, in mature
      oligodendrocytes after 12 days in vitro, the ratio of 4R- to 3R-MAP2c is nearly
      2. In contrast, the ratio of 4R- to 3R-tau in progenitor cells is 1:3 and shifts
      to 1:1 after 12 days in culture.

PMID- 10336256
TI  - Regulation of tau phosphorylation in microtubule fractions by apolipoprotein E.
AB  - In Alzheimer's disease (AD), a family of proteins collectively named tau are
      displaced from their normal association with microtubules and are found in in a
      hyperphosphorylated state deposited into paired helical filaments (PHFs). PHFs
      are the hallmark cytoskeletal pathology of the disease, and the degree of PHF
      pathology correlates with the clinical severity of AD. Certain apolipoprotein E
      (apoE) isoforms have been identified as either risk or protective factors for AD,
      and one of the proposed mechanisms involves an interaction and potentially
      modulatory effects on tau hyperphosphorylation by the different apoE isoforms. In
      these studies, we directly tested the effects of apoE, E2, E3, and E4 on AD-like
      phosphorylation of tau in brain microtubule fractions. We found that apoE
      attenuates tau hyperphosphorylation in the fractions, but the pattern was
      indistinguishable for the different isoforms.

PMID- 10336257
TI  - Discoordinate regulation of different K channels in cultured rat skeletal muscle
      by nerve growth factor.
AB  - We investigated the effects of nerve growth factor (NGF) on expression of K+
      channels in cultured skeletal muscle. The channels studied were (1) charybdotoxin
      (ChTx)-sensitive channels by using a polyclonal antibody raised in rabbits
      against ChTx, (2) Kv1.5 voltage-sensitive channels, and (3) apamin-sensitive
      (afterhyperpolarization) channels. Crude homogenates were prepared from cultures
      made from limb muscles of 1-2-day-old rat pups for identification of ChTx
      sensitive and Kv1.5 channels by Western blotting techniques. Apamin-sensitive K+
      channels were studied by measurement of specific [125I]-apamin binding by whole
      cell preparations. ChTx-sensitive channels display a fusion-related increase in
      expression, and NGF downregulates these channels in both myoblasts and myotubes.
      Voltage-dependent Kv1.5 channel expression is low in myoblasts and increases
      dramatically with fusion; NGF induces early expression of these channels and
      causes expression after fusion to increase even further. NGF downregulates apamin
      sensitive channels. NGF increases the rate of fall of the action potential
      recorded intracellularly from single myotubes with intracellular microelectrodes.
      The results confirm and extend those of previous studies in showing a functional
      role for NGF in the regulation of membrane properties of skeletal muscle.
      Moreover, the findings demonstrate that the different K+ channels in this
      preparation are regulated in a discoordinate manner. The divergent effects of NGF
      on expression of different K+ channels, however, do not appear sufficient to
      explain the NGF-induced increase in the rate of fall of the action potential. The
      changes during the falling phase may rather be due to increases in channel
      properties or may result from an increased driving force on the membrane
      potential secondary to the NGF-induced hyperpolarization.

PMID- 10336258
TI  - p200, a collagen secreted by Schwann cells, is expressed in developing nerves and
      in adult nerves following axotomy.
AB  - Previously we reported that cultured rat Schwann cells secrete p200, a collagen
      like heparin-binding adhesive glycoprotein with a restricted pattern of
      expression. Here we report that p200 is secreted as a stable trimer, but only
      after treatment of Schwann cells with ascorbic acid, and was deposited in the
      fibrillar extracellular matrix. Heparin and heparitinase treatment inhibited
      incorporation of p200 into extracellular matrix, suggesting the involvement of
      Schwann cell heparan sulfate proteoglycans in this process. Pepsin digestion
      revealed that p200 secreted by ascorbate-treated cells contains a collagenous
      domain of approximately 140 kDa. Immunofluorescent staining of rat embryos at
      different ages showed that p200 first appeared between embryonic days 15 and 18,
      and was confined to peripheral nerves. Staining of adult peripheral nerve was
      negative, but p200 expression was induced in adult sciatic nerve following nerve
      transection. These data suggest that p200 carries out unique functions during
      peripheral nerve development and regeneration and that its expression by Schwann
      cells is regulated by axon-Schwann cell interaction.

PMID- 10336259
TI  - Characterization of acetylcholinesterase and butyrylcholinesterase forms in
      normal and dystrophic Lama2dy mouse heart.
AB  - In searching for possible differences in acetylcholinesterase (AChE) and
      butyrylcholinesterase (BuChE) forms of dystrophic heart, the properties of ChE
      species in normal (NH) and dystrophic Lama2dy mouse heart (DH) were investigated.
      BuChE predominated over AChE. Loosely- and tightly-bound ChEs were released with
      saline (extract S1) and saline-Triton X-100 buffers (S2). About 50% of AChE, and
      25% of BuChE, in NH or DH was measured in S1, and the rest in S2. Asymmetric AChE
      forms A12 (15%) and A8 (11%), globular hydrophilic G(H)4 (8%), amphiphilic G(A)4
      (15%), and G(A)2+G(A)1 (51%) AChE species, and BuChE forms G(H)4 (13%), G(A)4
      (3%), and G(A)2+G(A)1 (84%) were identified in NH and DH. Most of the asymmetric
      and G(A)4 AChE species were bound to Triticum vulgaris (WGA) or Ricinus communis
      (RCA) agglutinins. About half of G(H)4 and G(A)2+G(A)1 AChE were bound to WGA,
      and less (10%) to RCA. Variable amounts of G(H)4+G(A)4 (60%), and G(A)2+G(A)1
      (75%) BuChE bound to WGA, and 50 and 10% to RCA. The lack of structural
      differences between ChE species in NH and DH indicates that, in contrast to the
      ChE forms in mouse skeletal muscle, the biosynthesis of ChE components in heart
      is not disturbed by dystrophy.

PMID- 10336260
TI  - Age-changes of brain synapses and synaptic plasticity in response to an enriched
      environment.
AB  - Numerical synaptic density and synaptic vesicle density in rat frontal cortex
      were examined by electron microscopy as a function of age. The density of
      axospinous synapses, a major population of synapses, was found to peak at age 1
      month, and to gradually decrease with aging. The synaptic vesicle density in
      axospinous synapses was shown to rapidly increase to a peak during the first 3
      weeks and then decrease to the adult level, which remained unchanged in
      senescence. The time course of synaptic changes in aging is presented in this
      study. In a previous report (Saito et al. [1994] J. Neurosci. Res. 39:57-62), we
      showed that enriched rearing conditions restored the age-related decrease of
      synaptophysin contents. This might be due to increased numerical synaptic density
      or enhanced packing density of synaptic vesicles in synapses. The results of the
      present study support the latter explanation; that is, synaptic vesicle contents
      were increased without changes in synaptic density. Synaptic plasticity induced
      by environmental stimulation is shown to relate with synaptic strengthening, but
      not with the formation of new synapses.

PMID- 10336261
TI  - Detection of dopamine D2 receptor mRNA and binding sites in monkey amniotic
      epithelial cells.
AB  - Previous results from our laboratory showed that monkey amniotic epithelial cells
      (MAEC) possess the catecholamine synthesizing enzymes and have the capacity to
      synthesize and release CA. Recently, we also reported that these cells express
      dopamine D1 receptor mRNA and binding sites. This study was designed to
      investigate the presence of dopamine D2 receptors in MAEC. Using RT-PCR, we found
      that MAEC express dopamine D2 receptor mRNA that is having 98% homology with
      human dopamine D2 receptors. Radioligand saturation binding studies showed a 3H
      YM-09151-2 high-affinity binding site with a K(D) of 0.293+/-0.06 nM and Bmax of
      180.69+/-11.61 fmol/mg protein. Competition experiments with a variety of
      displacing drugs demonstrated that D2 antagonists potently compete with 3H-YM
      09151-2 binding, whereas D1 antagonists displayed a weaker competition for the
      binding sites. The rank order of potency of these compounds in competing with 3H
      YM-09151-2 for binding sites was consistent with the pharmacology of the dopamine
      D2 receptors. All competition curves were better fitted to a one-site model with
      a Hill coefficient around unity, indicating that 3H-YM-09151-2 is labeling a
      single population of receptors. These results provide, for the first time, a
      compelling evidence that MAEC natively express dopamine D2 receptor mRNA and
      binding sites, and they suggest that monkey amniotic epithelial cells (MAEC)
      could represent a source of primate dopamine receptors without the need for
      transformation or cloning procedures using nonprimate cells, as generally
      happens.

PMID- 10336264
TI  - Sustaining and renewing the federal research partnership with universities.

PMID- 10336266
TI  - [The founding of the Sociedade Portuguesa de Cardiologia].

PMID- 10336267
TI  - Viktor Mutt, 1923-1998.

PMID- 10336265
TI  - Precise quantitation of human parvovirus B19 DNA in biological samples by PCR.
AB  - An application of a quantitative PCR-based method was developed for the detection
      of human parvovirus B19 DNA. The procedure was characterised according to
      guidelines for the validation of analytical procedures. Furthermore, the
      reliability was demonstrated by the correct quantitation of samples of an
      international collaborative study. This application might be useful for studies
      focussed on removal and/or inactivation procedures of human parvovirus B19 as
      well as for general screening purposes of biological materials.

PMID- 10336268
TI  - "Stochastic" -40 years of use and abuse.

PMID- 10336269
TI  - Effect of complete remission on survival in patients with acute myelogenous
      leukemia receiving first salvage therapy.

PMID- 10336270
TI  - The 20210A allele of the prothrombin gene is an independent risk factor for
      perception deafness in patients with venous thromboembolic antecedents.

PMID- 10336271
TI  - Where does platelet factor V originate?

PMID- 10336272
TI  - Hormonal therapy after stem cell transplantation and risk of veno-occlusive
      disease.

PMID- 10336273
TI  - Is complicated celiac disease or refractory sprue an intestinal intra-epithelia
      cryptic T-cell lymphoma?

PMID- 10336274
TI  - Antioxidant effects of dopamine and related compounds.
AB  - The antioxidant and free radical scavenging effects of dopamine, noradrenaline,
      tyramine, and tyrosine were investigated and compared with alpha-tocopherol. The
      antioxidant effect of dopamine and its related compounds on peroxidation of
      linoleic acid were in the order of dopamine > alpha-tocopherol = tyramine >
      tyrosine > noradrenaline as measured by the thiocyanate method. These amine
      compounds had reducing power, and a scavenging effect on reactive oxygen species,
      i.e., superoxide anion and hydroxyl radical. The results for reducing power and
      scavenging effect of these amine compounds had a similar trend as their
      inhibition of linoleic acid peroxidation. The antioxidant activity of these amine
      compounds in soybean oil was also evaluated by the Rancimat method. The induction
      time to reach 100 meq/kg peroxide value (POV) of soybean oil for dopamine, alpha
      tocopherol, tyramine, tyrosine, noradrenaline, and control were 9.0, 8.2, 8.0,
      6.4, 4.6, and 4.3 h, respectively. The antioxidant efficacy of amine compounds
      seems to be correlated with the numbers of hydroxy groups and their position on
      the phenolic ring.

PMID- 10336275
TI  - Growth and differentiation of cultured fetal hepatocytes isolated various
      developmental stages.
AB  - We examined the relationship between cell proliferation and differentiation of
      cultured rat fetal and newborn hepatocytes isolated from various developmental
      stages. The albumin production rate increased along with cell growth under in
      vitro culture and became maximal two days after the growth cessation. AFP was
      secreted by both fetal and newborn hepatocytes with growth ability. Furthermore,
      the responses to HGF addition in fetal hepatocyte cultures were observed in terms
      of growth stimulation and down-regulated of the Met receptor. We also studied the
      changes in RB and liver enriched transcription factors (C/EBPs) for investigating
      the mechanism underlying proliferation and differentiation of fetal hepatocytes.
      Western blot analysis of hepatocytes taken from various gestation stages of rat
      liver showed that the expression of RB and C/EBP beta increased as gestation
      stage proceeded. When RB antisense S-oligonucleotide was added to the culture
      medium, proliferation and AFP expression increased, while C/EBP alpha and albumin
      expressions decreased. These results indicated that the tumor suppressor gene
      product RB had a profound role not only in cell proliferation but also hepatocyte
      differentiation.

PMID- 10336276
TI  - Proceedings of the 1st Workshop on Insulin-dependent Diabetes Mellitus in
      Children and Adolescents. Amman, Jordan, 26-28 October 1997.

PMID- 10336277
TI  - Postcoital testing. Male partner should be assessed.

PMID- 10336278
TI  - Postcoital testing. Postcoital test should be performed as routine infertility
      test.

PMID- 10336279
TI  - Value of breast imaging in women with painful breasts. Women with severe problems
      must be seen in specialist breast clinics.

PMID- 10336280
TI  - More on the Bristol affair. Audit was secret yet not confidential.

PMID- 10336281
TI  - More on the Bristol affair. Audit was not secret.

PMID- 10336282
TI  - More on the Bristol affair. Look at this case again.

PMID- 10336283
TI  - More on the Bristol affair. What went wrong and how can we move forward?

PMID- 10336284
TI  - Commentary: Chlamydia pneumoniae infection and ischaemic heart disease.

PMID- 10336285
TI  - Commentary: uncertainty over length of incubation tempers optimism.

PMID- 10336286
TI  - Commentary: weighing burdens and benefits rather than competence.

PMID- 10336287
TI  - Is general practice in need of a career structure? GPs' clinical sessions should
      be reduced.

PMID- 10336288
TI  - Is general practice in need of a career structure? SHO posts are important for
      registrar in general practice.

PMID- 10336289
TI  - Is general practice in need of a career structure? Training schemes after
      vocational training are useful and popular.

PMID- 10336290
TI  - Is general practice in need of a career structure? Future role of general
      practitioners must be clarified.

PMID- 10336291
TI  - Is general practice in need of a career structure? All three years of vocational
      training should be based on general practice.

PMID- 10336292
TI  - Is general practice in need of a career structure? Training in family practice in
      US has many strenghts.

PMID- 10336293
TI  - The Di Bella multitherapy trial. Criticism ignores standard methodology of cancer
      treatments.

PMID- 10336294
TI  - Hyperbaric oxygen therapy. Complication rates are much lower than author suggest.

PMID- 10336295
TI  - Proceedings of the Margaret E. Mahoney Symposium. The State of the Nation's
      Health.

PMID- 10336296
TI  - [Community acquired pneumonia in childhood. Conference proceedings. Pontault
      Combault, France, 5-7 June 1997].

PMID- 10336297
TI  - Risk factors versus mechanisms of death in subjects with asthma.

PMID- 10336298
TI  - [Analysis of risks: social and ecologic aspects].
AB  - The article deals with traditional and up-to-date post-Soviet view of risks
      theory, technical and democratic patterns for risks evaluation, structural
      description of social reformation of risks, risk-communication model. The article
      could be interesting for wide variety of specialists.

PMID- 10336299
TI  - Proceedings of the Ares-Serono Foundation 2nd International Workshop on Growth
      and Endocrine Complications and Reproduction in Thalassaemia. Ferrara, Italy.
      April 2-4, 1998.

PMID- 10336301
TI  - Clinical effectiveness: the issues for primary dental care.

PMID- 10336300
TI  - Structural view of cadherin-mediated cell-cell adhesion.
AB  - Following the multiplication of biochemical, biophysical and structural studies
      describing cadherin molecules and their interactions, several ideas have emerged
      to explain the mechanisms of cadherin-mediated cell adhesion. Although different
      models were proposed for cadherin interactions, a consensus has come forth
      considering lateral dimerization of cadherins as being a central component of the
      cell-cell adhesion process. This review summarizes the recent development in
      structural studies of cadherin.

PMID- 10336302
TI  - Proceedings of the International Symposium on Gut Dysfunction in Irritable Bowel
      Syndrome. Montreal, Quebec, Canada. October 4-5, 1997.

PMID- 10336303
TI  - Proceedings of the 10th International Congress on Circumpolar Health. Anchorage,
      Alaska, USA. May 19-24, 1996.

PMID- 10336304
TI  - Development of Supplementation Strategies for Milk-Producing Animals in Tropical
      and Sub-Tropical Environments. Proceedings of a meeting. Malang, Indonesia, 24-28
      March 1997.

PMID- 10336305
TI  - Comparing crystallographic and solution structures of nitrogenase complexes.

PMID- 10336306
TI  - Posterior tibial tendon insufficiency: diagnosis and treatment.
AB  - Posterior tibial tendon insufficiency is the most common cause of acquired adult
      flatfoot deformity. Although the exact etiology of the disorder is still unknown,
      the condition has been classified, on the basis of clinical and radiographic
      findings, into four stages. In stage I, there is no notable clinical deformity;
      patients usually present with pain along the course of the tendon and evidence of
      local inflammatory changes. Stage II is characterized by a dynamic deformity of
      the hindfoot. Stage III involves a fixed deformity of the hindfoot and typically
      also a fixed forefoot supination deformity but no obvious evidence of ankle
      abnormality. In stage IV, ankle involvement is secondary to long-standing fixed
      hindfoot deformities. The initial treatment of patients in any stage should be
      nonoperative, with immobilization, a nonsteroidal anti-inflammatory drug, and
      perhaps an orthotic device. Corticosteroid injections continue to be
      controversial. When nonoperative management fails, the treatment options consist
      of soft-tissue procedures alone or in combination with osteotomy or arthrodesis.
      Stage I insufficiency is generally treated with debridement and tenosynovectomy.
      Soft-tissue transfer does not appear to correct the underlying deformity in stage
      II disease; however, there is growing interest in joint-sparing operations that
      attempt to compensate for the underlying deformities with osteotomies or
      arthrodeses, supplemented with dynamic transfers to replace the insufficient
      posterior tibial tendon. Subtalar, double, or triple arthrodesis is the procedure
      of choice for stage III disease, frequently in conjunction with heel-cord
      lengthening. Tibiocalcaneal arthrodesis or pantalar arthrodesis is most commonly
      used to treat stage IV disease.

PMID- 10336307
TI  - [Anthroposophy, medicine and research. Meeting report on the 15th Gyllenberg
      Symposium "Research in Anthroposophical Medicine" of October 29-31 1998 in
      Hanasaairi, Finland].

PMID- 10336308
TI  - Is the antidepressant effect of Hypericum extracts depending on their hyperforin
      content?

PMID- 10336309
TI  - And again: is homeopathy a placebo response?

PMID- 10336310
TI  - A homeopathic nosode for influenza-like syndromes.

PMID- 10336311
TI  - Rhythmical electrical events as indicators for biological actions of homeopathic
      remedies.

PMID- 10336312
TI  - [Combined chemical and biomedicine: a new strategy in the development of
      antibiotics].

PMID- 10336313
TI  - [Evolution of resistance in the genus Enterococcus in strains isolated from
      blood].
AB  - The objective of this study was to determine the evolution of the species
      distribution and the prevalence of resistance to the Enterococcus genus. We
      studied 281 strains of enterococcus isolated from blood samples: 90 throughout
      1984 and 791 from the years 1994 to 1996. identification was made using PosCombo
      4Y Microscan-Baxter dehydrated panels and the Rapid ID 32 Strep system
      (bioMerieux). The MICs were calculated using the agar dilution method according
      to recommendations of the NCCLS for the following antibiotics: ampicillin,
      vancomycin, teicoplanin, gentamicin, kanamycin and streptomycin. The production
      of betalactamases were evaluated using a paper disk with nitrocefin for all the
      strains. The genotypes with resistance to glycopeptides were determined using
      PCR. The percentage of E. faecalis for 1984-1986/1994-1996 was 82.2/79.4; of E.
      faecium 4.4/16.4; and other species 12.214.3. The resistance to ampicillin went
      from 1.1% to 5.8%; high level resistance to glycopeptides went from 0% to 9.9%;
      for low level from 7.7% to 2.6%; resistance to a high charge of gentamicin went
      from 27.7% to 40.8%; and that for kanamycin from 45.5% to 62.8%. Resistance to
      streptomycin remained constant (45.5%). No strains produced betalactamases. For
      the species E. faecium, a statistically significant increase was detected for
      global resistance to ampicillin, gentamicin and kanamycin, with resistance to
      streptomycin remaining at similar percentages. No high level resistance to
      glycopeptides was detected in the first time period, but the low level resistance
      was greater.

PMID- 10336314
TI  - [In vitro activity of fluconazole against Candida albicans isolated from blood
      culture].
AB  - The in vitro activity of fluconazole against 65 Candida albicans isolated from
      blood culture in 1995, 1996 and 1997 was studied by macrodilution and disk
      diffusion methods. The MIC ranged from 0.03 to 64 microg/ml, with 93.6% of
      strains being inhibited with 1 microg/ml fluconazole; the mode MIC was 0.25
      microg/ml. Using this method, only one strain was resistant and another was
      susceptible depending on the dose. By diffusion, eight strains were susceptible,
      53 intermediate, and four resistant. The strains susceptible by dilution were
      also susceptible by diffusion, but the strains resistant by diffusion were not
      always resistant by dilution. We find it therefore useful to determine the MIC of
      fluconazole to the C. albicans resistant by diffusion.

PMID- 10336315
TI  - [Resistance of Streptococcus pneumoniae to antibiotics].

PMID- 10336316
TI  - [Inhibition mechanisms of permeability and XXXXX].

PMID- 10336317
TI  - [Mechanisms of inhibition of beta-lactamases].

PMID- 10336318
TI  - [Mechanisms of resistance to beta-lactam inhibitors of beta-lactamases].

PMID- 10336319
TI  - [Pharmacodynamics and non-enzymatic activity of beta-lactamase inhibitors].

PMID- 10336320
TI  - [Problems in the detection of resistance to beta-lactam inhibitors of beta
      lactamases in the laboratory].

PMID- 10336321
TI  - [Evolution of resistance to beta-lactam inhibitors of beta-lactamases].

PMID- 10336322
TI  - [Re-evaluation of the gastrointestinal effects of beta-lactam inhibitors of beta
      lactamase].

PMID- 10336323
TI  - [Inhibitors of beta-lactamases in the genus Haemophilus].

PMID- 10336324
TI  - [Inhibitors of beta-lactamases in Streptococcus pneumoniae].

PMID- 10336325
TI  - [Activity of beta-lactamase inhibitors against Acinetobacter baumannii].

PMID- 10336326
TI  - [Beta-lactam inhibitors of beta-lactamases in Mycobacterium].

PMID- 10336327
TI  - The American Society of Colon and Rectal Surgeons 100th Anniversary and
      Tripartite Meeting. Washington DC, USA. May 1-6, 1999. Abstracts.

PMID- 10336328
TI  - Steroid-induced pancreatitis.

PMID- 10336329
TI  - Cimetidine impairs the elimination of theophylline and antipyrine.

PMID- 10336330
TI  - Carcinoma of the gallbladder.

PMID- 10336331
TI  - C(Tr)/C(Cr) ratio in pancreatic disease.

PMID- 10336332
TI  - Use of a recombinant parvovirus to facilitate screening for human melanoma cell
      clones expressing tetracycline-responsive transactivators.
AB  - The tetracycline regulatory (TET) system provides a useful means of controlling
      foreign gene expression in mammalian cells. Exploiting this system in cultured
      cells requires the prior isolation, from the cells of interest, of transfectant
      clones expressing the necessary TET transactivator, tTA, or reverse
      transactivator, rtTA. We describe a simple screening procedure for identifying
      transfectant clones expressing a properly regulated transactivator, and the
      application of this method to isolating clones of human melanoma cells expressing
      either tTA or rtTA. Clones in multi-well plates are transduced by exposure to a
      recombinant parvovirus containing a luciferase reporter, under control of a
      promoter responsive to the TET system transactivators. Transactivation of
      reporter expression in the presence or absence of doxycycline (DOXY) is
      determined after one to two days, using a rapid luciferase assay. Screening is
      easier and more reproducible with this transduction method than with conventional
      transient transfection of analogous reporter plasmids. Clones of two human
      melanoma cell lines showing >100-200-fold transactivation after transfection with
      either tTA or rtTA were readily identified using this method.

PMID- 10336333
TI  - Phospholipase A2 and acute pancreatitis in rats.

PMID- 10336334
TI  - Effect of gastric acid suppressants on human gastric mucosa.

PMID- 10336335
TI  - Faecal elastase 1 in chronic pancreatitis.

PMID- 10336336
TI  - Regulation of ileal bile acid transport: desirability of measuring transport
      function as well as transporter activity.

PMID- 10336337
TI  - Sodium purine nucleoside transporter.

PMID- 10336338
TI  - Hemochromatosis C282Y mutation and histological fibrosis in patients with C virus
      chronic hepatitis.

PMID- 10336339
TI  - Flumazenil and hepatic encephalopathy.

PMID- 10336340
TI  - Splanchnic arterial Doppler parameters in portal hypertension.

PMID- 10336341
TI  - The International Commission of Occupational Health (ICOH) Working Group
      "Unemployment and Health". Proceedings. Paris, France, 25-26 September 1998.

PMID- 10336342
TI  - Author errata.

PMID- 10336343
TI  - Author errata.

PMID- 10336344
TI  - The AADS International Women's Leadership Conference. Proceedings and abstracts.

PMID- 10336345
TI  - Endocrinology and art.

PMID- 10336346
TI  - The Journal of Virology: a personal retrospective.

PMID- 10336347
TI  - X-ray analysis of hair reveals breast cancer.

PMID- 10336348
TI  - Needlestick injuries among French medical students.

PMID- 10336349
TI  - What is your diagnosis? Mouth neoplasms.

PMID- 10336350
TI  - Coagulation factor abnormalities after the Fontan procedure and its
      modifications.

PMID- 10336351
TI  - A word of caution in interpreting the ischemic time causing apoptosis in spinal
      cord ischemia.

PMID- 10336352
TI  - Cervicothoracic tumors: results of resection by the "hemi-clamshell" approach.

PMID- 10336353
TI  - Correction of cardiac defects through a right thoracotomy in children.

PMID- 10336354
TI  - Anterior approach to the superior sulcus tumors: the transmanubrial osteomuscular
      sparing approach.

PMID- 10336355
TI  - Homograft valve failure in children.

PMID- 10336356
TI  - Effect of normoxic cardiopulmonary bypass on leukocyte elastase release.

PMID- 10336357
TI  - The extracardiac Fontan procedure using a pedicled pericardial roll without
      cardiopulmonary bypass.

PMID- 10336358
TI  - Harry A. Blackmun and Mayo.

PMID- 10336359
TI  - Spousal liability for medical fees.

PMID- 10336360
TI  - Correction: Mutations of the cystic fibrosis gene in patients with chronic
      pancreatitis.

PMID- 10336361
TI  - Inadequate management of blood pressure in a hypertensive population.

PMID- 10336362
TI  - Inadequate management of blood pressure in a hypertensive population.

PMID- 10336363
TI  - Inadequate management of blood pressure in a hypertensive population.

PMID- 10336364
TI  - Noninvasive detection of coronary artery disease.

PMID- 10336365
TI  - Noninvasive detection of coronary artery disease.

PMID- 10336366
TI  - Chest-pain observation units.

PMID- 10336367
TI  - Chest-pain observation units.

PMID- 10336368
TI  - Mystery of the blue pigmentation.

PMID- 10336370
TI  - Attending-physician role models.

PMID- 10336369
TI  - Attending-physician role models.

PMID- 10336371
TI  - Wasted paper in pharmaceutical samples.

PMID- 10336372
TI  - 1st Joint meeting of the European Neuropeptide Club (8th annual meeting) and the
      Summer Neuropeptide Conference (8th annual meeting). Gent, Belgium, 6-9 May 1998.
      Abstracts.

PMID- 10336373
TI  - Alternative opinions.

PMID- 10336374
TI  - Respiratory care. A world of difference.

PMID- 10336375
TI  - Recognizing pneumonia.

PMID- 10336376
TI  - Arm-domain interactions in proteins: a review.

PMID- 10336377
TI  - Effect of alphabet size and foldability requirements on protein structure
      designability.
AB  - A number of investigators have addressed the issue of why certain protein
      structures are especially common by considering structure designability, defined
      as the number of sequences that would successfully fold into any particular
      native structure. One such approach, based on foldability, suggested that
      structures could be classified according to their maximum possible foldability
      and that this optimal foldability would be highly correlated with structure
      designability. Other approaches have focused on computing the designability of
      lattice proteins written with reduced two-letter amino acid alphabets. These
      different approaches suggested contrasting characteristics of the most designable
      structures. This report compares the designability of lattice proteins over a
      wide range of amino acid alphabets and foldability requirements. While all
      alphabets have a wide distribution of protein designabilities, the form of the
      distribution depends on how protein "viability" is defined. Furthermore, under
      increasing foldability requirements, the change in designabilities for all
      alphabets are in good agreement with the previous conclusions of the foldability
      approach. Most importantly, it was noticed that those structures that were highly
      designable for the two-letter amino acid alphabets are not especially designable
      with higher-letter alphabets.

PMID- 10336378
TI  - Structural basis for the activity of two muconate cycloisomerase variants toward
      substituted muconates.
AB  - We have refined to 2.3 A resolution two muconate cycloisomerase (MCIase) variant
      structures, F329I and I54V, that differ from each other and from wild-type in
      their activity toward cis,cis-muconate (CCM) and substituted CCMs. The working
      and free R-factors for F329I are 17.4/21.6% and for I54V, 17.6/22.3% with good
      stereochemistry. Except for the mutated residue, there are no significant changes
      in structure. To understand the differences in enzymatic properties we docked
      substituted CCMs and CCM into the active sites of the variants and wild type. The
      extra space the mutations create appears to account for most of the enzymatic
      differences. The lack of other structural changes explains why, although
      structurally equivalent changes occur in chloromuconate cycloisomerase (CMCIase),
      the changes in themselves do not convert a MCIase into a dehalogenating CMCIase.
      Reanalysis of the CMCIase structure revealed only one general acid/base, K169.
      The structural implication is that, in 2-chloro-CCM conversion by CMCIase, the
      lactone ring of 5-chloromuconolactone rotates before dehalogenation to bring the
      acidic C4 proton next to K169. Therefore, K169 alone performs both required
      protonation and deprotonation steps, the first at C5 as in MCIase, and the
      second, after ring rotation, at C4. This distinguishes CMCIase from alpha/beta
      barrel isomerases and racemases, which use two different bases.

PMID- 10336379
TI  - Prediction of membrane protein types and subcellular locations.
AB  - Membrane proteins are classified according to two different schemes. In scheme 1,
      they are discriminated among the following five types: (1) type I single-pass
      transmembrane, (2) type II single-pass transmembrane, (3) multipass
      transmembrane, (4) lipid chain-anchored membrane, and (5) GPI-anchored membrane
      proteins. In scheme 2, they are discriminated among the following nine locations:
      (1) chloroplast, (2) endoplasmic reticulum, (3) Golgi apparatus, (4) lysosome,
      (5) mitochondria, (6) nucleus, (7) peroxisome, (8) plasma, and (9) vacuole. An
      algorithm is formulated for predicting the type or location of a given membrane
      protein based on its amino acid composition. The overall rates of correct
      prediction thus obtained by both self-consistency and jackknife tests, as well as
      by an independent dataset test, were around 76-81% for the classification of five
      types, and 66-70% for the classification of nine cellular locations. Furthermore,
      classification and prediction were also conducted between inner and outer
      membrane proteins; the corresponding rates thus obtained were 88-91%. These
      results imply that the types of membrane proteins, as well as their cellular
      locations and other attributes, are closely correlated with their amino acid
      composition. It is anticipated that the classification schemes and prediction
      algorithm can expedite the functionality determination of new proteins. The
      concept and method can be also useful in the prioritization of genes and proteins
      identified by genomics efforts as potential molecular targets for drug design.

PMID- 10336380
TI  - The particle concept: placing discrete water molecules during protein-ligand
      docking predictions.
AB  - Water is known to play a significant role in the formation of protein-ligand
      complexes. In this paper, we focus on the influence of water molecules on the
      structure of protein-ligand complexes. We present an algorithmic approach, called
      the particle concept, for integrating the placement of single water molecules in
      the docking algorithm of FLEXX. FLEXX is an incremental construction approach to
      ligand docking consisting of three phases: the selection of base fragments, the
      placement of the base fragments, and the incremental reconstruction of the ligand
      inside the active site of a protein. The goal of the extension is to find water
      molecules at favorable places in the protein-ligand interface which may guide the
      placement of the ligand. In a preprocessing phase, favorable positions of water
      molecules inside the active site are calculated and stored in a list of possible
      water positions. During the incremental construction phase, water molecules are
      placed at the precomputed positions if they can form additional hydrogen bonds to
      the ligand. Steric constraints resulting from the water molecules as well as the
      geometry of the hydrogen bonds are used to optimize the ligand orientation in the
      active site during the reconstruction process. We have tested the particle
      concept on a series of 200 protein-ligand complexes. Although the average
      improvement of the prediction results is minor, we were able to predict water
      molecules between the protein and the ligand correctly in several cases. For
      instance in the case of HIV-1 protease, where a single water molecule between the
      protein and the ligand is known to be of importance in complex formation,
      significant improvements can be achieved.

PMID- 10336381
TI  - New general approach for determining the solution structure of a ligand bound
      weakly to a receptor: structure of a fibrinogen Aalpha-like peptide bound to
      thrombin (S195A) obtained using NOE distance constraints and an ECEPP/3 flexible
      docking program.
AB  - A new approach incorporating flexible docking simulations and NMR data is
      presented for calculating the bound conformation of a ligand that interacts
      weakly with an enzyme. This approach consists of sampling directly the
      conformation of a flexible ligand inside a receptor active site containing
      surrounding flexible loops. To make this sampling efficient, a ligand-growing
      procedure has been adopted. Optimization of the ECEPP/3-plus-NOE constraint
      function is carried out by using a collective variable Monte Carlo minimization
      technique. Numerous energy minimizations are made possible for such a large
      system by using a Bezier splines energy grid technique. This new flexible docking
      approach was applied to determine the structure of a fibrinogen Aalpha-like
      peptide (7DFLAEGGGVRGPRV20) bound to an active site mutant of thrombin
      [thrombin(S195A)]. Structure calculations of the bound ligand, using 2D
      transferred NOESY distance constraints in the DIANA program, showed that the N
      terminal portion of the peptide (D7-R16) involves a chain reversal, whereas the C
      terminal portion (G17-V20) adopts a fold that exists in several different
      orientations. In addition, the ECEPP/3 flexible docking package was used to
      assess the conformational variability of the ligand and surrounding 60D-insertion
      loop of thrombin. Amino acid residues (17-20) of the peptide interact with a
      region of the enzyme that exhibits broad specificity, with a preferred direction
      between the 60D-insertion loop and Pro37 of thrombin.

PMID- 10336382
TI  - Ligand solvation in molecular docking.
AB  - Solvation plays an important role in ligand-protein association and has a strong
      impact on comparisons of binding energies for dissimilar molecules. When
      databases of such molecules are screened for complementarity to receptors of
      known structure, as often occurs in structure-based inhibitor discovery, failure
      to consider ligand solvation often leads to putative ligands that are too highly
      charged or too large. To correct for the different charge states and sizes of the
      ligands, we calculated electrostatic and non-polar solvation free energies for
      molecules in a widely used molecular database, the Available Chemicals Directory
      (ACD). A modified Born equation treatment was used to calculate the electrostatic
      component of ligand solvation. The non-polar component of ligand solvation was
      calculated based on the surface area of the ligand and parameters derived from
      the hydration energies of apolar ligands. These solvation energies were
      subtracted from the ligand-receptor interaction energies. We tested the
      usefulness of these corrections by screening the ACD for molecules that
      complemented three proteins of known structure, using a molecular docking
      program. Correcting for ligand solvation improved the rankings of known ligands
      and discriminated against molecules with inappropriate charge states and sizes.

PMID- 10336383
TI  - Self-consistent estimation of inter-residue protein contact energies based on an
      equilibrium mixture approximation of residues.
AB  - Pairwise contact energies for 20 types of residues are estimated self
      consistently from the actual observed frequencies of contacts with regression
      coefficients that are obtained by comparing "input" and predicted values with the
      Bethe approximation for the equilibrium mixtures of residues interacting. This is
      premised on the fact that correlations between the "input" and the predicted
      values are sufficiently high although the regression coefficients themselves can
      depend to some extent on protein structures as well as interaction strengths.
      Residue coordination numbers are optimized to obtain the best correlation between
      "input" and predicted values for the partition energies. The contact energies
      self-consistently estimated this way indicate that the partition energies
      predicted with the Bethe approximation should be reduced by a factor of about 0.3
      and the intrinsic pairwise energies by a factor of about 0.6. The observed
      distribution of contacts can be approximated with a small relative error of only
      about 0.08 as an equilibrium mixture of residues, if many proteins were employed
      to collect more than 20,000 contacts. Including repulsive packing interactions
      and secondary structure interactions further reduces the relative errors. These
      new contact energies are demonstrated by threading to have improved their ability
      to discriminate native structures from other non-native folds.

PMID- 10336384
TI  - Ranking ligand binding affinities with avidin: a molecular dynamics-based
      interaction energy study.
AB  - The binding of 14 biotin analogues to avidin is examined to evaluate the
      viability of calculating binding free energy based on molecular dynamics (MD)
      trajectories. Two approaches were investigated in this work. The first one uses
      the linear interaction energy approximation, while the other approach utilizes
      the interaction free energy. The results obtained from these two methods were
      found to correlate well with the experimental binding free energy data for 10 out
      of 14 ligands. For the other four ligands, both methods overestimate their
      binding strength by more than 7 kcal/mol. Free energy calculations using the
      thermodynamic integration method are employed to understand this overestimation.
      The effect of protein flexibility on binding free energy calculation and the
      effect of charged or neutral ligands on the calculated results are discussed. MD
      simulations are shown to be able to provide insight into the interactions
      occurring in the active site and the origins of variations in binding free
      energy.

PMID- 10336385
TI  - Improved recognition of native-like protein structures using a combination of
      sequence-dependent and sequence-independent features of proteins.
AB  - We describe the development of a scoring function based on the decomposition
      P(structure/sequence) proportional to P(sequence/structure) *P(structure), which
      outperforms previous scoring functions in correctly identifying native-like
      protein structures in large ensembles of compact decoys. The first term captures
      sequence-dependent features of protein structures, such as the burial of
      hydrophobic residues in the core, the second term, universal sequence-independent
      features, such as the assembly of beta-strands into beta-sheets. The efficacies
      of a wide variety of sequence-dependent and sequence-independent features of
      protein structures for recognizing native-like structures were systematically
      evaluated using ensembles of approximately 30,000 compact conformations with
      fixed secondary structure for each of 17 small protein domains. The best results
      were obtained using a core scoring function with P(sequence/structure)
      parameterized similarly to our previous work (Simons et al., J Mol Biol
      1997;268:209-225] and P(structure) focused on secondary structure packing
      preferences; while several additional features had some discriminatory power on
      their own, they did not provide any additional discriminatory power when combined
      with the core scoring function. Our results, on both the training set and the
      independent decoy set of Park and Levitt (J Mol Biol 1996;258:367-392), suggest
      that this scoring function should contribute to the prediction of tertiary
      structure from knowledge of sequence and secondary structure.

PMID- 10336386
TI  - Tertiary and quaternary conformational changes in aspartate transcarbamylase: a
      normal mode study.
AB  - Aspartate transcarbamylase (ATCase) initiates the pyrimidine biosynthetic pathway
      in Escherichia coli. Binding of aspartate to this allosteric enzyme induces a
      cooperative transition between the tensed (T) and relaxed (R) states of the
      enzyme which involves large quaternary and tertiary rearrangements. The
      mechanisms of the transmission of the regulatory signal to the active site (60 A
      away) and that of the cooperative transition are not known in detail, although a
      large number of single, double, and triple site-specific mutants and chimeric
      forms of ATCase have been obtained and kinetically characterized. A previous
      analysis of the very low-frequency normal modes of both the T and R state
      structures of ATCase identified some of the large-amplitude motions mediating the
      intertrimer elongation and rotation that occur during the cooperative transition
      (Thomas et al., J. Mol. Biol. 257:1070-1087, 1996; Thomas et al., J. Mol. Biol.
      261:490-506, 1996). As a complement to that study, the deformation of the
      quaternary and tertiary structure of ATCase by normal modes below 5 cm(-1) is
      investigated in this article. The ability of the modes to reproduce the domain
      motions occurring during the transition is analyzed, with special attention to
      the interdomain closure in the catalytic chain, which has been shown to be
      critical for homotropic cooperativity. The calculations show a coupling between
      the quaternary motions and more localized motions involving specific residues.
      The particular dynamic behavior of these residues is examined in the light of
      biochemical results to obtain insights into their role in the transmission of the
      allosteric signal.

PMID- 10336387
TI  - Tobacco mosaic virus: pioneering research for a century. Proceedings of a
      meeting. 7-8 August 1998.

PMID- 10336388
TI  - Varmus circulates proposal for NIH-backed online venture.

PMID- 10336389
TI  - President revokes plan to destroy smallpox.

PMID- 10336390
TI  - New model for hereditary breast cancer.

PMID- 10336391
TI  - Are pathogens felling frogs?

PMID- 10336392
TI  - A trematode parasite causes some frog deformities.

PMID- 10336393
TI  - Assessing the decade of the brain.

PMID- 10336394
TI  - Fire use.

PMID- 10336395
TI  - Breast cancer detection.

PMID- 10336396
TI  - One signal or two?

PMID- 10336397
TI  - Free copper ions in the cell?

PMID- 10336398
TI  - A new look at MHC and autoimmune disease.

PMID- 10336399
TI  - Sir Alan Hodgkin (1914-1998).

PMID- 10336400
TI  - The science of signal transduction. Introduction.

PMID- 10336401
TI  - Symposium honouring the life and work of Sol Levine.

PMID- 10336402
TI  - [Proceedings of the 1st International Meeting on Hospital Toxicology. Liege, 22
      23 October 1998].

PMID- 10336403
TI  - Electromagnetic interference of an external temporary pacemaker during
      maxillofacial and neck surgery.
AB  - Indirect inhibition of an external temporary pacemaker by electrocautery is
      reported. Before induction of general anesthesia for a hemimaxillectomy and
      radical neck dissection, a temporary transvenous demand pacemaker was inserted
      into a patient with a first-degree atrioventricular block and complete left
      bundle-branch block. Although we provided common precautions to prevent
      electromagnetic interference by electrocautery, pacing failure still occurred. It
      was thought to be caused by current dispersing from the active electrocautery
      electrode. This case suggests that occipital placement of the electrocautery
      ground plate should be considered during neck surgery in a patient requiring a
      temporary pacemaker.

PMID- 10336404
TI  - Proceedings of the 2nd Conference on Catalytic Antibodies. Compiegne, France,
      October 14-18, 1996.

PMID- 10336405
TI  - Characterisation of immunological reactivity of patients with adverse effects
      during therapy with an aqueous mistletoe extract.
AB  - Drugs, which are effective are also bond to exert adverse effects. This is also
      true for mistletoe extracts. Extracts from European mistletoe (Viscum album, VAL)
      belong to the complementary therapeutic regimens and are used for adjuvant cancer
      therapy. This study was performed to characterise immunological reactivity of
      patients with adverse effects during treatment with an aqueous VAL extract
      (Helixor). VAL-stimulated proliferation and cytokine release of peripheral blood
      mononuclear cells (PBMC) and anti-mistletoe lectin (ML)-1 antibody production
      were investigated. 34 patients with proven adverse effects due to VAL therapy
      (group 1) and 9 patients with unproven relation (group 2) were studied and
      compared to 14 tumour patients treated with VAL for more than 2 years without
      side effects (TTP). VAL-stimulated proliferation of PBMC of group 1 was
      significantly enhanced as compared to group 2 patients and TTP. PBMC from
      patients with local manifestations proliferated significantly stronger than those
      from patients with systemic symptoms. Anti-ML-1 antibodies of the IgE type were
      produced in patients with proven adverse effects but not in patients without
      adverse effects. Production of Th1 and Th2 specific cytokines varied
      considerably, indicating that different mechanisms were involved in the induction
      of adverse effects. In conclusion, our study provide evidence that adverse
      effects towards VAL (Helixor) are seldom and are dominated by an application site
      reaction suggesting the involvement of delayed type hypersensitivity (DTH)
      reactions.

PMID- 10336406
TI  - Significant leukocyte and platelet retention during pulmonary passage after
      declamping of the aorta in CABG patients.
AB  - During reperfusion of the heart and the lungs in patients undergoing coronary
      artery bypass grafting, these organs have been shown to release inflammatory
      mediators. The present study was performed to quantitatively determine cellular
      retention or washout during pulmonary passage in early reperfusion. In 14
      consecutive patients undergoing coronary artery bypass grafting blood was
      simultaneously drawn from right atrium and pulmonary vein at 1, 10 and 20 min
      reperfusion. The counts for platelets, leukocytes and the leukocyte subsets
      polymorphonuclear neutrophils (PMN), lymphocytes and monocytes were determined.
      Pulmonary veno-right atrial (transpulmonary) differences are given in percent
      with respective right atrial values being considered as 100%. Before CPB
      leukocyte counts were 4.7 +/- 0.5 in right atrium and 4.2 +/- 0.4 in pulmonary
      vein, x10(9)/l, resp. (transpulmonary difference of -8 +/- 3%). During
      reperfusion, pulmonary retention was in the range of 20-23% (p <0.01 vs. right
      atrial value). The basal values for PMN were 2.4 +/- 0.3 in right atrium and 1.9
      +/- 0.3 in pulmonary vein, x10(9)/l, resp. (transpulmonary difference -15 +/-
      8%). Thereafter, retention was in the range of 25-30% (p <0.01 vs. right atrium).
      Basal values for lymphocytes were 1.5 +/- 0.2 in right atrium and 1.6+/-0.3 in
      pulmonary vein, x10(9)/l, resp. (transpulmonary difference +6 +/- 10%). A
      tendency towards a washout of lymphocytes at 1 min reperfusion (+1 +/- 12%) was
      followed by retention of these cells at 10 and 20 min reperfusion (-14 +/- 12%
      and -10 +/- 5%, p <0.05 vs right atrium). Before ischemia monocyte counts were
      0.7 +/- 0.2 in right atrium and 0.6 +/- 0.2 in pulmonary vein, x10(9)/l, resp.
      (transpulmonary difference -10 +/- 4%) and -9 +/- 9%, -27 +/- 12% (p <0.05 vs
      right atrium) and -22 +/- 14% at 1, 10 and 20 min reperfusion. During early
      reperfusion of the lungs after declamping of the aorta, significant amounts of
      leukocytes, platelets and the leukocyte subsets are retained in the pulmonary
      vascular bed. These retained cells may be responsible for the previously
      described pulmonary release of cytokines.

PMID- 10336407
TI  - Treatment of tension-type headache with botulinum toxin: a pilot study.
AB  - We studied if injections of botulinum toxin into multiple pericranial muscles
      reduce pain of patients with tension-type headache. Nine patients with tension
      type headache not sufficiently responding to physical therapy or to amitriptyline
      were studied. Patients kept a headache diary that was used to calculate the area
      under the headache curve (AUC) of 4 weeks before and after treatment. After a run
      in phase of 4 weeks equal doses of 25 units (0.25ml) of botulinum toxin type A
      (Dysport) were injected into both frontal, temporal, occipital, and
      sternocleidomastoid muscles. Mean AUC of the 8 patients who completed the study
      was significantly reduced from 404 to 196 (p = 0.039). No major side effects were
      reported by the patients. These results justify further studies of botulinum
      toxin therapy in patients with tension type headache. The presented scheme for
      injections of botulinum toxin into multiple pericranial muscles is a rational
      basis for the design of such studies.

PMID- 10336408
TI  - Is there a psoriatic osteopathy? -- the activity of bone resorption in psoriatics
      is related to inflammatory joint process.
AB  - The aim of this study was to examine former own histomorphological results by
      using biochemical markers of bone collagen catabolism in patients with psoriasis
      vulgaris and psoriatic arthritis and to compare these results with those from
      rheumatoid arthritis. - The diagnosis of PsA was made according to the diagnostic
      criteria of Moll and Wright modified by Bennet. Urine was collected from 99
      patients with PsA, 21 patients suffering from PS without articular
      manifestations, 154 patients with RA fulfilling the ACR criteria of 1987, and 80
      healthy controls. Pyridinoline and deoxypyridinoline in urine were analyzed by
      HPLC, levels of CrP and ESR were estimated using laboratory assessment. - Both
      crosslinks show a elevated excretion in PsA (particularly in active PsA / aPsA)
      as well as in RA. PS and Controls show no significant difference in the
      elimination of crosslinks. The levels of both crosslinks are higher in females
      than males in all groups. With the exception of Dpyd levels in urine which only
      show a tendency to correlate with ESR, there are positive correlations between
      measured crosslink-levels in urine and markers of inflammation. The Pyd/Dpyd
      ratio displays a significant correlation with ESR. - An increased breakdown of
      collagen I and II was found only in active forms of psoriatic arthritis and in
      rheumatoid arthritis. Our biochemical results do not demonstrate a complete
      agreement with former scintigraphic or histological investigations of other
      authors and own histomorphological results.

PMID- 10336409
TI  - Efficacy of sublingual verapamil in patients with severe essential hypertension:
      comparison with sublingual nifedipine.
AB  - Ninety patients, 50 males and 40 females, and their ages ranged between 42 and 70
      years, with severe hypertension were treated by either sublingual verapamil
      tablets 40 mg (30 patients) or 80 mg (30 patients) or sublingual nifedipine
      capsules 10 mg (30 patients). Blood pressure and heart rate were measured before
      and 15, 30, 60, 90 and 120 mins after administration of the drugs. - Results
      showed that sublingual verapamil 40 mg caused significant drop of blood pressure
      after 60 min (200 +/- 11.6 / 127 +/- 8.7 to 177 +/- 13.8 / 95.4 +/- 11.8, P
      <0.05) and in 10/30 patients blood pressure was less than 150/90 mmHg. Verapamil
      40 mg decreased heart rate in 16 patients, elevated in 5 patients and unchanged
      heart rate in 9 patients. Verapamil 80 mg caused significant reduction of blood
      pressure after 30 min (201 +/- 16 / 129 +/- 7.5 to 182 +/- 13 / 105 +/- 10.7, P
      <0.05) and the blood pressure was dropped to less than 150/90 mmHg in 18/30
      patients. Sublingual verapamil 80 mg caused significant decrease in heart rate in
      21/30 patients and peak decrease was recorded at 90 min (92.6 +/- 7.2 beats/min
      to 82 +/- 9, P <0.05). It alleviated headache in 8 patients including 2 patients
      with migraine. Sublingual nifedipine caused significant drop of elevated blood
      pressure at each time intervals and the peak drop was at 60 min (from 199 +/-
      13.8 / 126 +/- 13.2 to 142.8 +/- 15 / 80. 9 +/- 9, P <0.05). In 22/30 patients
      blood pressure dropped to less than 150/90 mmHg after 60 min. Nifedipine elevated
      heart rate in 22/30 patients and peak elevation was at 30 min (from 91.6 +/- 7.8
      to 105.6 +/- 6.1 beats/min, P <0.05). It caused headache in 8 patients and
      flushing in other 2 patients. Therefore, as compared to sublingual verapamil,
      sublingual nifedipine caused rapid lowering of elevated blood pressure and
      elevation of heart rate in most of the patients treated. The differences in
      proportions of patients whom blood pressure was dropped to less than 150/90 mmHg
      between nifedipine group and verapamil 40 mg group and between verapamil 80 mg
      and verapamil 40 mg groups were significant (P <0.05). - It might be concluded
      that sublingual verapamil caused significant lowering of blood pressure in
      hypertensive patients, decreased heart rate in most of the treated patients and
      alleviated headache in symptomatic hypertensive patients.

PMID- 10336410
TI  - Abstracts from the first symposium on the topic: liquid ventilation - 13th of
      march 1999, berlin 
AB  - Basic research: Perfluorocarbons and the Pulmonary Surfactant System -
      Perfluorocarbons in the Treatment of Pneumonia - Inertance of the Respiratory
      System during Partial Liquid Ventilation - Alveolar Dead Space and Partial Liquid
      Ventilation - Partial Liquid Ventilation and Prevention of Cerebral Damage - New
      therapies of old problems: Efficacy of Partial Liquid Ventilation (PLV) Compared
      to Mechanical Ventilation with High Levels of PEEP in Experimental Acute Lung
      Injury - Application of Nitric Oxide during Partial Liquid Ventilation in Acute
      Respiratory Failure with Pulmonary Hypertension in Piglets - Preparation for
      clinical application: Partial Liquid Ventilation and Filling Condition with
      Perfluorocarbon - The Influence of Different Positive End-expiratory Pressure
      Levels on Partial Liquid Ventilation in Acute Lung Injury in Piglets - Partial
      Liquid Ventilation and Filling Condition with Perfluorocarbon - Spontaneous
      Respiratory Effort during Partial Liquid Ventilation (PLV) - Combination of
      Kinetic Therapy and Partial Liquid Ventilation in the Therapy of Acute
      Respiratory Failure in Piglets - Level of clinical studies: Do We Need Liquid
      Ventilation (LV) in Neonatology?

PMID- 10336411
TI  - Erythema nodosum of dental origin.
AB  - This paper describes the case of a patient who had erythema nodosum which
      disappeared following teeth extraction.

PMID- 10336412
TI  - One-dimensional diffusion of proteins along DNA. Its biological and chemical
      significance revealed by single-molecule measurements.

PMID- 10336413
TI  - IKKgamma mediates the interaction of cellular IkappaB kinases with the tax
      transforming protein of human T cell leukemia virus type 1.
AB  - The Tax oncoprotein of human T cell leukemia virus type 1 constitutively
      activates transcription factor NF-kappaB by a mechanism involving Tax-induced
      phosphorylation of IkappaBalpha, a labile cytoplasmic inhibitor of NF-kappaB. To
      trigger this signaling cascade, Tax associates stably with and persistently
      activates a cellular IkappaB kinase (IKK) containing both catalytic (IKKalpha and
      IKKbeta) and noncatalytic (IKKgamma) subunits. We now demonstrate that IKKgamma
      enables Tax to dock with the IKKbeta catalytic subunit, resulting in chronic
      IkappaB kinase activation. Mutations in either IKKgamma or Tax that prevent
      formation of these higher order Tax.IKK complexes also interfere with the ability
      of Tax to induce IKKbeta catalytic function in vivo. Deletion mapping studies
      indicate that amino acids 1-100 of IKKgamma are required for this Tax targeting
      function. Together, these findings identify IKKgamma as an adaptor protein that
      directs the stable formation of pathologic Tax.IKK complexes in virally infected
      T cells.

PMID- 10336414
TI  - The TATA-binding protein and its associated factors are differentially expressed
      in adult mouse tissues.
AB  - We have investigated the expression levels of the TATA-binding protein (TBP) and
      several TBP-associated factors (TAFIIs) in differentiated adult mouse tissues.
      Immunoblots performed using monoclonal antibodies show that there are
      considerable variations in the levels of TBP and many TAFII proteins present in
      various tissues. Consequently, the relative levels of TAFIIs and TBP vary
      significantly from one tissue to another. TBP and several TAFIIs are
      overexpressed in both testis and small intestine, while in marked contrast, many
      of these proteins, including TBP itself, were substantially down-regulated in
      nervous tissues and in the heart. These tissues do, however, show a high
      expression level of the TBP-like factor, which thus may represent an alternative
      factor for the specialized transcription program in some differentiated tissues.
      While there are significant variations in the levels of TAFII28 protein, reverse
      transcription-coupled polymerase chain reaction shows similar expression of the
      TAFII28 mRNA in different tissues. The variations in TAFII28 protein levels
      therefore result from post-transcriptional regulatory events.

PMID- 10336415
TI  - Cloning, expression, and biochemical characterization of hexahistidine-tagged
      terminase proteins.
AB  - The terminase enzyme from bacteriophage lambda is composed of two viral proteins
      (gpA, 73.2 kDa; gpNu1, 20.4 kDa) and is responsible for packaging viral DNA into
      the confines of an empty procapsid. We are interested in the genetic,
      biochemical, and biophysical properties of DNA packaging in phage lambda and, in
      particular, the nucleoprotein complexes involved in these processes. These
      studies require the routine purification of large quantities of wild-type and
      mutant proteins in order to probe the molecular mechanism of DNA packaging.
      Toward this end, we have constructed a hexahistidine (hexa-His)-tagged terminase
      holoenzyme as well as hexa-His-tagged gpNu1 and gpA subunits. We present a
      simple, one-step purification scheme for the purification of large quantities of
      the holoenzyme and the individual subunits directly from the crude cell lysate.
      Importantly, we have developed a method to purify the highly insoluble gpNu1
      subunit from inclusion bodies in a single step. Hexa-His terminase holoenzyme is
      functional in vivo and possesses steady-state and single-turnover ATPase activity
      that is indistinguishable from wild-type enzyme. The nuclease activity of the
      modified holoenzyme is near wild type, but the reaction exhibits a greater
      dependence on Escherichia coli integration host factor, a result that is mirrored
      in vivo. These results suggest that the hexa-His-tagged holoenzyme possesses a
      mild DNA-binding defect that is masked, at least in part, by integration host
      factor. The mild defect in hexa-His terminase holoenzyme is more significant in
      the isolated gpA-hexa-His subunit that does not appear to bind DNA. Moreover,
      whereas the hexa-His-tagged gpNu1 subunit may be reconstituted into a holoenzyme
      complex with wild-type catalytic activities, gpA-hexa-His is impaired in its
      interactions with the gpNu1 subunit of the enzyme. The results reported here
      underscore that a complete biochemical characterization of the effects of
      purification tags on enzyme function must be performed prior to their use in
      mechanistic studies.

PMID- 10336416
TI  - Three amino acid residues determine selective binding of FK506-binding protein
      12.6 to the cardiac ryanodine receptor.
AB  - FK506-binding protein (FKBP12) has been found to be associated with the skeletal
      muscle ryanodine receptor (RyR1) (calcium release channel), whereas FKBP12.6, a
      novel isoform of FKBP, is selectively associated with the cardiac ryanodine
      receptor (RyR2). For both RyRs, the stoichiometry is 4 FKBP/RyR. Although
      FKBP12.6 differs from FKBP12 by only 18 of 108 amino acids, FKBP12.6 selectively
      binds to RyR2 and exchanges with bound FKBP12.6 of RyR2, whereas both FKBP
      isoforms bind to RyR1 and exchange with bound FKBP12 of RyR1. To assess the amino
      acid residues of FKBP12.6 that are critical for selective binding to RyR2, the
      residues of FKBP12.6 that differ with FKBP12 were mutated to the respective
      residues of FKBP12. RyR2 of cardiac sarcoplasmic reticulum, prelabeled by
      exchange with [35S]FKBP12.6, was used as assay system for binding/exchange with
      the mutants. The triple mutant (Q31E/N32D/F59W) of FKBP12.6 was found to lack
      selective binding to the cardiac RyR2, comparable with that of FKBP12.0. In
      complementary studies, mutations of FKBP12 to the three critical amino acids of
      FKBP12.6, conferred selective binding to RyR2. Each of the FKBP12.6 and FKBP12
      mutants retained binding to the skeletal muscle RyR1. We conclude that three
      amino acid residues (Gln31, Asn32, and Phe59) of human FKBP12.6 account for the
      selective binding to cardiac RyR2.

PMID- 10336417
TI  - Selective inhibition of protein kinase C isozymes by Fas ligation.
AB  - Activation of protein kinase C (PKC) can protect cells from apoptosis induced by
      various agents, including Fas ligation. To elucidate a possible interaction
      between Fas-mediated apoptotic signals and activation-related protective signals,
      we investigated the impact of Fas ligation on PKC activity. We demonstrate that
      engagement of Fas on human lymphoid Jurkat cells triggered apoptosis, and Fas
      ligation resulted in partial blockade of cellular PKC activity. The phorbol 12
      myristate 13-acetate-mediated translocation of PKCtheta from the cytoplasm to the
      membrane was inhibited by treatment with anti-Fas antibody, whereas the
      translocation of PKCalpha or epsilon was not affected. In vitro kinase assay of
      PKCalpha or epsilon phosphotransferase activity demonstrated that Fas ligation
      inhibited the ability of PKCalpha to phosphorylate histone H1 as substrate but
      did not inhibit epsilon isozyme activity. This inhibition of PKCalpha activity
      mediated by Fas ligation was reversed by okadaic acid, a phosphatase inhibitor,
      suggesting the involvement of a member of the protein phosphatase 2A subfamily in
      this component of Fas signaling. Identical patterns of PKC isozyme inhibition
      were obtained using mouse thymoma cells overexpressing the fas gene (LF(+)).
      These results suggest that the selective inhibition of a potentially protective,
      PKC-mediated pathway by Fas activation may, to some extent, contribute to Fas
      induced apoptotic signaling.

PMID- 10336418
TI  - A rat RuvB-like protein, TIP49a, is a germ cell-enriched novel DNA helicase.
AB  - We have isolated a novel nuclear protein with a molecular mass of 49 kDa (TIP49a)
      from rat liver. The rat TIP49a showed structural resemblance to several bacterial
      RuvBs and also displayed Walker A and B motifs. We overproduced the recombinant
      TIP49a in Escherichia coli and purified it to near homogeneity. Biochemical
      investigations demonstrated that TIP49a possessed ATPase activity that was
      stimulated by single-stranded DNA but neither by double-stranded DNA nor by any
      forms of RNA polymers tested. Moreover, a UV cross-linking assay indicated TIP49a
      specifically interacted with ATP. Interestingly, we found that DNA duplex was
      unwound by the recombinant TIP49a in the presence of ATP or dATP. Optimal
      concentrations of ATP and Mg2+ for the helicase activity were 1-2 mM and 0.25-1
      mM, respectively. Displacement of the DNA strand occurred in the 3' to 5'
      direction with respect to the single-stranded DNA flanking the duplex. Western
      blot analysis revealed that TIP49a was abundantly expressed in testes and
      moderately in spleen, thymus, and lung. In mouse seminiferous tubules, the
      protein was restrictively observed in germ lineages from late pachytene
      spermatocytes to round spermatids. From these observations, we propose that
      TIP49a is a novel DNA helicase and may play a role in nuclear processes such as
      recombination and transcription.

PMID- 10336419
TI  - Protein GRAB of streptococcus pyogenes regulates proteolysis at the bacterial
      surface by binding alpha2-macroglobulin.
AB  - In the molecular interplay between pathogenic microorganisms and their host,
      proteolytic mechanisms are believed to play a crucial role. Here we find that the
      important human pathogen Streptococcus pyogenes (group A Streptococcus) expresses
      a surface protein with high affinity (Ka = 2.0 x 10(8) M-1) for alpha2
      macroglobulin (alpha2M), the dominating proteinase inhibitor of human plasma. The
      immunoglobulin-binding protein G of group C and G streptococci also contains an
      alpha2M-binding domain and a gene encoding protein GRAB (protein G-related
      alpha2M-binding protein) was identified in the S. pyogenes Genome Sequencing data
      base. The grab gene is present in most S. pyogenes strains and is well conserved.
      Protein GRAB has typical features of a surface-attached protein of Gram-positive
      bacteria. It also contains a region homologous to parts of the alpha2M-binding
      domain of protein G and a variable number of a unique 28-amino acid-long repeat.
      Using Escherichia coli-produced protein GRAB and synthetic GRAB peptides, the
      alpha2M-binding region was mapped to the NH2-terminal part of protein GRAB, which
      is the region with homology to protein G. An isogenic S. pyogenes mutant lacking
      surface-associated protein GRAB showed no alpha2M binding activity and was
      attenuated in virulence when injected intraperitoneally in mice. Finally, alpha2M
      bound to the bacterial surface via protein GRAB was found to entrap and inhibit
      the activity of both S. pyogenes and host proteinases, thereby protecting
      important virulence determinants from proteolytic degradation. This regulation of
      proteolytic activity at the bacterial surface should affect the host-microbe
      relation during S. pyogenes infections.

PMID- 10336420
TI  - Singlet oxygen mediates the UVA-induced generation of the photoaging-associated
      mitochondrial common deletion.
AB  - Mutations of mitochondrial (mt) DNA accumulate during normal aging. The most
      frequent mutation is a 4,977-base pair deletion also called the common deletion,
      which is increased in photoaged skin. Oxidative stress may play a major role in
      the generation of large scale mtDNA deletions, but direct proof for this has been
      elusive. We therefore assessed whether the common deletion can be generated in
      vitro through UV irradiation and whether reactive oxygen species are involved in
      this process. Normal human fibroblasts were repetitively exposed to sublethal
      doses of UVA radiation and assayed for the common deletion employing a
      semiquantitative polymerase chain reaction technique. There was a time/dose
      dependent generation of the common deletion, attributable to the generation of
      singlet oxygen, since the common deletion was diminished when irradiating in the
      presence of singlet oxygen quenchers, but increased when enhancing singlet oxygen
      half-life by deuterium oxide. The induction of the common deletion by UVA
      irradiation was mimicked by treatment of unirradiated cells with singlet oxygen
      produced by the thermodecomposition of an endoperoxide. These studies provide
      evidence for the involvement of reactive oxygen species in the generation of
      aging-associated mtDNA lesions in human cells and indicate a previously
      unrecognized role of singlet oxygen in photoaging of human skin.

PMID- 10336421
TI  - Glucose uptake kinetics and transcription of HXT genes in chemostat cultures of
      Saccharomyces cerevisiae.
AB  - The kinetics of glucose transport and the transcription of all 20 members of the
      HXT hexose transporter gene family were studied in relation to the steady state
      in situ carbon metabolism of Saccharomyces cerevisiae CEN.PK113-7D grown in
      chemostat cultures. Cells were cultivated at a dilution rate of 0.10 h-1 under
      various nutrient-limited conditions (anaerobically glucose- or nitrogen-limited
      or aerobically glucose-, galactose-, fructose-, ethanol-, or nitrogen-limited),
      or at dilution rates ranging between 0.05 and 0.38 h-1 in aerobic glucose-limited
      cultures. Transcription of HXT1-HXT7 was correlated with the extracellular
      glucose concentration in the cultures. Transcription of GAL2, encoding the
      galactose transporter, was only detected in galactose-limited cultures. SNF3 and
      RGT2, two members of the HXT family that encode glucose sensors, were transcribed
      at low levels. HXT8-HXT17 transcripts were detected at very low levels. A
      consistent relationship was observed between the expression of individual HXT
      genes and the glucose transport kinetics determined from zero-trans influx of 14C
      glucose during 5 s. This relationship was in broad agreement with the transport
      kinetics of Hxt1-Hxt7 and Gal2 deduced in previous studies on single-HXT strains.
      At lower dilution rates the glucose transport capacity estimated from zero-trans
      influx experiments and the residual glucose concentration exceeded the measured
      in situ glucose consumption rate. At high dilution rates, however, the estimated
      glucose transport capacity was too low to account for the in situ glucose
      consumption rate.

PMID- 10336422
TI  - Identification of a novel class of retinoic acid receptor beta-selective retinoid
      antagonists and their inhibitory effects on AP-1 activity and retinoic acid
      induced apoptosis in human breast cancer cells.
AB  - Four candidate retinoid antagonists (LE135, LE511, LE540, and LE550) were
      designed on the basis of the ligand superfamily concept and synthesized. Analysis
      of these related retinoids by transient transfection assay demonstrated that
      LE135, LE540, and LE550 are effective retinoic acid receptor (RAR) antagonists,
      whereas LE511 selectively induced RARbeta transcriptional activity. Both LE135
      and LE540 inhibited retinoic acid (RA)-induced transcriptional activation of
      RARbeta, but not RARalpha, RARgamma or retinoid X receptor alpha (RXRalpha), on a
      variety of RA response elements. The retinoid antagonists also inhibited all
      trans-RA-induced transcriptional activation of RARbeta/RXRalpha heterodimers,
      although they did not show any effect on transactivation activity of RXR/RXR
      homodimers. In ZR-75-1 human breast cancer cells, cotreatment of LE135 and LE540
      with all-trans-RA inhibited all-trans-RA-induced apoptosis of the cells, further
      demonstrating that RARbeta plays a role in RA-induced apoptosis of breast cancer
      cells. We also evaluated the effect of these retinoids on AP-1 activity. Our data
      showed that LE135 and LE540 strongly repressed 12-O-tetradecanoylphorbol-13
      acetate-induced AP-1 activity in the presence of RARbeta and RXRalpha.
      Interestingly, LE550 induced AP-1 activity when RARbeta and RXRalpha were
      expressed in HeLa cells but not in breast cancer cells. These results demonstrate
      that LE135 and LE540 were a novel class of RARbeta-selective antagonists and anti
      AP-1 retinoids and should be useful tools for studying the role of retinoids and
      their receptors.

PMID- 10336423
TI  - ATP hydrolysis and DNA binding by the Escherichia coli RecF protein.
AB  - The Escherichia coli RecF protein possesses a weak ATP hydrolytic activity. ATP
      hydrolysis leads to RecF dissociation from double-stranded (ds)DNA. The RecF
      protein is subject to precipitation and an accompanying inactivation in vitro
      when not bound to DNA. A mutant RecF protein that can bind but cannot hydrolyze
      ATP (RecF K36R) does not readily dissociate from dsDNA in the presence of ATP.
      This is in contrast to the limited dsDNA binding observed for wild-type RecF
      protein in the presence of ATP but is similar to dsDNA binding by wild-type RecF
      binding in the presence of the nonhydrolyzable ATP analog, adenosine 5'-O-(3
      thio)triphosphate (ATPgammaS). In addition, wild-type RecF protein binds tightly
      to dsDNA in the presence of ATP at low pH where its ATPase activity is blocked. A
      transfer of RecF protein from labeled to unlabeled dsDNA is observed in the
      presence of ATP but not ATPgammaS. The transfer is slowed considerably when the
      RecR protein is also present. In competition experiments, RecF protein appears to
      bind at random locations on dsDNA and exhibits no special affinity for single
      strand/double strand junctions when bound to gapped DNA. Possible roles for the
      ATPase activity of RecF in the regulation of recombinational DNA repair are
      discussed.

PMID- 10336424
TI  - The iron sulfur protein AtsB is required for posttranslational formation of
      formylglycine in the Klebsiella sulfatase.
AB  - The catalytic residue of eukaryotic and prokaryotic sulfatases is a alpha
      formylglycine. In the sulfatase of Klebsiella pneumoniae the formylglycine is
      generated by posttranslational oxidation of serine 72. We cloned the atsBA operon
      of K. pneumoniae and found that the sulfatase was expressed in inactive form in
      Escherichia coli transformed with the structural gene (atsA). Coexpression of the
      atsB gene, however, led to production of high sulfatase activity, indicating that
      the atsB gene product plays a posttranslational role that is essential for the
      sulfatase to gain its catalytic activity. This was verified after purification of
      the sulfatase from the periplasm of the cells. Peptide analysis of the protein
      expressed in the presence of AtsB revealed that half of the polypeptides carried
      the formylglycine at position 72, while the remaining polypeptides carried the
      encoded serine. The inactive sulfatase expressed in the absence of AtsB carried
      exclusively serine 72, demonstrating that the atsB gene is required for
      formylglycine modification. This gene encodes a 395-amino acid residue iron
      sulfur protein that has a cytosolic localization and is supposed to directly or
      indirectly catalyze the oxidation of the serine to formylglycine.

PMID- 10336425
TI  - Domain identification of hormone-sensitive lipase by circular dichroism and
      fluorescence spectroscopy, limited proteolysis, and mass spectrometry.
AB  - Structure-function relationship analyses of hormone-sensitive lipase (HSL) have
      suggested that this metabolically important enzyme consists of several functional
      and at least two structural domains (Osterlund, T., Danielsson, B., Degerman, E.,
      Contreras, J. A., Edgren, G., Davis, R. C., Schotz, M. C., and Holm, C. (1996)
      Biochem. J. 319, 411-420; Contreras, J. A., Karlsson, M., Osterlund, T., Laurell,
      H., Svensson, A., and Holm, C. (1996) J. Biol. Chem. 271, 31426-31430). To
      analyze the structural domain composition of HSL in more detail, we applied
      biophysical methods. Denaturation of HSL was followed by circular dichroism
      measurements and fluorescence spectroscopy, revealing that the unfolding of HSL
      is a two-step event. Using limited proteolysis in combination with mass
      spectrometry, several proteolytic fragments of HSL were identified, including one
      corresponding exactly to the proposed N-terminal domain. Major cleavage sites
      were found in the predicted hinge region between the two domains and in the
      regulatory module of the C-terminal, catalytic domain. Analyses of a hinge region
      cleavage mutant and calculations of the hydropathic pattern of HSL further
      suggest that the hinge region and regulatory module are exposed parts of HSL.
      Together, these data support our previous hypothesis that HSL consists of two
      major structural domains, encoded by exons 1-4 and 5-9, respectively, of which
      the latter contains an exposed regulatory module outside the catalytic alpha/beta
      hydrolase fold core.

PMID- 10336427
TI  - Neuregulin stimulates myogenic differentiation in an autocrine manner.
AB  - During myogenesis, mononucleated myoblasts form multinucleated myotubes by
      membrane fusion. Efficiency of this intercellular process can be maximized by a
      simultaneous progress, with a time window, of other neighboring myoblasts in the
      differentiation program. This phenomenon has been described as the community
      effect. It proposes the existence of a molecule that acts as a differentiation
      inducing signal to a group of identical cells. Here, we show that neuregulin is a
      strong candidate for this molecule in myoblast differentiation. The expression of
      neuregulin increased rapidly but transiently at early stage of differentiation of
      rat L6 cells. Neuregulin showed a potent differentiation-promoting activity in
      membrane fusion and expression of myosin heavy chain. The antibodies raised
      against neuregulin and its cognate receptor ErbB3, which were capable of
      neutralizing the signal pathway, inhibited myotube formation and expression of
      myosin heavy chain in both L6 cells and primary rat myoblasts. The progress of
      differentiation was mostly halted after the expression of myogenin and cell cycle
      arrest. These results suggest that the activation of an autocrine signaling of
      neuregulin may provide a basic mechanism for the community effect observed in the
      differentiation of the embryonic muscle cells.

PMID- 10336426
TI  - Translocation of protein kinase Cepsilon and protein kinase Cdelta to membrane is
      required for ultraviolet B-induced activation of mitogen-activated protein
      kinases and apoptosis.
AB  - UV-induced signal transduction may be involved in tumor promotion and induction
      of apoptosis. The role of protein kinase C (PKC) in UVB-induced signal
      transduction is not well understood. This study showed that UVB markedly induced
      translocation of membrane-associated PKCepsilon and PKCdelta, but not PKCalpha,
      from cytosol to membrane. Dominant negative mutant (DNM) PKCepsilon or PKCdelta
      inhibited UVB-induced translocation of PKCepsilon and PKCdelta, respectively. UVB
      induced activation of extracellular signal-regulated protein kinases (Erks) and c
      Jun NH2-terminal kinases (JNKs) was strongly inhibited by DNM PKCepsilon and
      PKCdelta, whereas the DNM of PKCalpha was less effective on the UVB-induced
      phosphorylation of Erks and JNKs. Among the PKC inhibitors used only rottlerin, a
      selective inhibitor of PKCdelta, markedly inhibited the UVB-induced activation of
      Erks and JNKs, but not p38 kinases. Safingol, a selective inhibitor for PKCalpha,
      did not show any inhibitory effect on UVB-induced mitogen-activated protein
      kinase activation. GF109203X is a stronger inhibitor of classical PKC than novel
      PKC. Lower concentrations of GF109203X (<10 microM) had no effect on UVB-induced
      activation of Erks or JNKs. However, at higher concentrations (over 20 microM),
      GF109203X inhibited UVB-induced activation of JNKs, Erks, and even p38 kinases.
      Meanwhile, rottlerin and GF109203X markedly inhibited UVB-induced apoptosis of
      JB6 cells, whereas safingol had little inhibitory effect. DNM-Erk2 cells and
      PD98059, a selective inhibitor for mitogen-activated protein kinase/extracellular
      signal-regulated kinase 1 that directly activates Erks, inhibited UVB-induced
      apoptosis. DNM-JNK1 cells also blocked UVB-induced apoptosis, whereas SB202190, a
      specific inhibitor for p38 kinases, did not produce the inhibitory effect. These
      data demonstrate that PKCdelta and PKCepsilon, but not PKCalpha, mediate UVB
      induced signal transduction and apoptosis in JB6 cells through activation of Erks
      and JNKs.

PMID- 10336428
TI  - The A1 and A2 subunits of factor VIIIa synergistically stimulate factor IXa
      catalytic activity.
AB  - Factor VIIIa, the protein cofactor for factor IXa, is comprised of A1, A2, and A3
      C1-C2 subunits. Recently, we showed that isolated A2 subunit enhanced the kcat
      for factor IXa-catalyzed activation of factor X by approximately 100-fold (
      approximately 1 min-1), whereas isolated A1 or A3-C1-C2 subunits showed no effect
      on this rate (Fay, P. J., and Koshibu, K. J. (1998) J. Biol. Chem. 273, 19049
      19054). However, A1 subunit increased the A2-dependent stimulation by
      approximately 10-fold. The Km for factor X in the presence of A2 subunit was
      unaffected by A1 subunit, whereas the kcat observed in the presence of saturating
      A1 and A2 subunits ( approximately 15 min-1) represented 5-10% of the value
      observed for native factor VIIIa (approximately 200 min-1). An anti-A1 subunit
      antibody that blocks the association of A2 eliminated the A1-dependent
      contribution to factor IXa activity. Inclusion of both A1 and A2 subunits
      resulted in greater increases in the fluorescence anisotropy of fluorescein-Phe
      Phe-Arg factor IXa than that observed for A2 subunit alone and approached values
      obtained with factor VIIIa. These results indicate that A1 subunit alters the A2
      subunit-dependent modulation of the active site of factor IXa to synergistically
      increase cofactor activity, yielding an overall increase in kcat of over 1000
      fold compared with factor IXa alone.

PMID- 10336429
TI  - Role of protein kinase C isoforms in phorbol ester-induced vascular endothelial
      growth factor expression in human glioblastoma cells.
AB  - Aberrant expression of the potent angiogenic cytokine, vascular endothelial
      growth factor (VEGF), has been demonstrated to be associated with most human
      solid tumors. Both transcriptional and post-transcriptional mechanisms have been
      shown to modulate VEGF expression in a multitude of cell types. Here we report
      that when protein kinase C (PKC) pathways were activated in human glioblastoma
      U373 cells by phorbol 12-myristate 13-acetate (PMA), VEGF mRNA expression was up
      regulated via a post-transcriptional mRNA stabilization mechanism. PMA treatment
      exhibited no increase in VEGF-specific transcriptional activation as determined
      by run-off transcription assays and VEGF promoter-luciferase reporter assays.
      However, PMA increased VEGF mRNA half-life from 0.8 to 3.6 h which was blocked by
      PKC inhibitors but not by protein kinase A or cyclic nucleotide-dependent protein
      kinase inhibitors. When U373 cells were transfected with antisense
      oligonucleotide sequences to the translation start sites of PKC-alpha, -beta, 
      gamma, -delta, -epsilon, or -zeta isoforms, both PKC-alpha and -zeta antisense
      oligonucleotides showed substantial inhibition of PMA-induced VEGF mRNA. In
      addition, overexpression of PKC-zeta resulted in a strong constitutive up
      regulation of VEGF mRNA expression. This study demonstrates for the first time
      that specific PKC isoforms regulate VEGF mRNA expression through post
      transcriptional mechanisms.

PMID- 10336430
TI  - Functional and biochemical evidence for heteromeric ATP-gated channels composed
      of P2X1 and P2X5 subunits.
AB  - The mammalian P2X receptor gene family encodes two-transmembrane domain
      nonselective cation channels gated by extracellular ATP. Anatomical localization
      data obtained by in situ hybridization and immunocytochemistry have shown that
      neuronal P2X subunits are expressed in specific but overlapping distribution
      patterns. Therefore, the native ionotropic ATP receptors diversity most likely
      arises from interactions between different P2X subunits that generate hetero
      multimers phenotypically distinct from homomeric channels. Rat P2X1 and P2X5
      mRNAs are localized within common subsets of peripheral and central sensory
      neurons as well as spinal motoneurons. The present study demonstrates a
      functional association between P2X1 and P2X5 subunits giving rise to hybrid ATP
      gated channels endowed with the pharmacology of P2X1 and the kinetics of P2X5.
      When expressed in Xenopus oocytes, hetero-oligomeric P2X1+5 ATP receptors were
      characterized by slowly desensitizing currents highly sensitive to the agonist
      alpha,beta-methylene ATP (EC50 = 1.1 microM) and to the antagonist trinitrophenyl
      ATP (IC50 = 64 nM), observed with neither P2X1 nor P2X5 alone. Direct physical
      evidence for P2X1+5 co-assembly was provided by reciprocal subunit-specific co
      purifications between epitope-tagged P2X1 and P2X5 subunits transfected in HEK
      293A cells.

PMID- 10336431
TI  - Monoclonal antibodies that inhibit the transport function of the 190-kDa
      multidrug resistance protein, MRP. Localization of their epitopes to the
      nucleotide-binding domains of the protein.
AB  - Multidrug resistance in tumor cells is often accompanied by overexpression of
      multidrug resistance protein (MRP), a 190-kDa transmembrane protein that belongs
      to the ATP-binding cassette superfamily of transport proteins. MRP mediates ATP
      dependent transport of a variety of conjugated organic anions and can also
      transport several unmodified xenobiotics in a glutathione-dependent manner. To
      facilitate structure-function studies of MRP, we have generated a panel of MRP
      specific monoclonal antibodies (mAbs). Four of these mAbs, QCRL-2, -3, -4, and 
      6, bind intracellular conformation-dependent epitopes, and we have shown that
      they can inhibit the transport of several MRP substrates. Binding competition and
      immunoprecipitation assays indicated that mAbs QCRL-4 and -6 probably recognize
      the same detergent-sensitive epitope in MRP, whereas mAbs QCRL-2, -3, and -4 each
      bind distinct, non-overlapping epitopes. Fab fragments inhibit transport as
      effectively as the intact mAbs, suggesting that inhibition results from direct
      interactions of the mAbs with MRP. Immunodot blot and immunoprecipitation
      analyses revealed that the minimal regions of MRP sufficient for full reactivity
      of mAbs QCRL-2 and -3 are amino acids 617-858 and 617-932, respectively, which
      encompass the NH2-proximal nucleotide-binding domain (NBD). In contrast, the
      epitope bound by mAb QCRL-4 localized to amino acids 1294-1531, a region that
      contains the COOH-proximal NBD. However, none of the mAbs inhibited photolabeling
      of intact MRP with 8-azido-[alpha-32P]ATP. This suggests that rather than
      preventing nucleotide binding, the mAbs inhibit transport by interfering with
      substrate binding or by trapping MRP in a conformation that does not allow
      transport to occur. Our results also demonstrate for the first time that the NBDs
      of MRP can be expressed as soluble polypeptides that retain a native
      conformation.

PMID- 10336432
TI  - RAX, a cellular activator for double-stranded RNA-dependent protein kinase during
      stress signaling.
AB  - The double-stranded (ds) RNA-dependent protein kinase (PKR) regulates protein
      synthesis by phosphorylating the alpha subunit of eukaryotic initiation factor-2.
      PKR is activated by viral induced dsRNA and thought to be involved in the host
      antiviral defense mechanism. PKR is also activated by various nonviral stresses
      such as growth factor deprivation, although the mechanism is unknown. By
      screening a mouse cDNA expression library, we have identified an ubiquitously
      expressed PKR-associated protein, RAX. RAX has a high sequence homology to human
      PACT, which activates PKR in the absence of dsRNA. Although RAX also can directly
      activate PKR in vitro, overexpression of RAX does not induce PKR activation or
      inhibit growth of interleukin-3 (IL-3)-dependent cells in the presence of IL-3.
      However, IL-3 deprivation as well as diverse cell stress treatments including
      arsenite, thapsigargin, and H2O2, which are known to inhibit protein synthesis,
      induce the rapid phosphorylation of RAX followed by RAX-PKR association and
      activation of PKR. Therefore, cellular RAX may be a stress-activated, physiologic
      activator of PKR that couples transmembrane stress signals and protein synthesis.

PMID- 10336433
TI  - Involvement of RFX1 protein in the regulation of the human proliferating cell
      nuclear antigen promoter.
AB  - The proliferating cell nuclear antigen (PCNA) is an essential eukaryotic DNA
      replication factor that is transcriptionally regulated by the adenovirus
      oncoprotein E1A 243R. Inducibility of the human PCNA promoter by E1A 243R is
      conferred by the cis-acting PCNA E1A-responsive element (PERE), which associates
      with the ATF-1, cAMP response element-binding protein (CREB), and RFX1
      transcription factors and is modulated by cellular proteins such as the
      coactivator CREB-binding protein (CBP) and tumor suppressor p107 (Labrie, C.,
      Lee, B. H., and Mathews, M. B. (1995) Nucleic Acids Res. 23, 3732-3741; Lee, B.
      H., and Mathews, M. B. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 4481-4486; Lee,
      B. H., Liu, M., and Mathews, M. B. (1998) J. Virol. 72, 1138-1145). RFX1 also
      forms a complex with sequences in the PCNA promoter of mouse and rat that share
      homology with the RFX1 consensus site. To explore the role of RFX1 in regulating
      the PCNA promoter, we examined the effects of mutations in the human PERE on RFX1
      binding and gene expression. Mutations within the RFX1 consensus binding site
      reduced RFX1 binding, whereas mutations upstream of the site, or on its border,
      increased RFX1 binding. These mutations also affected the transcriptional
      activity of PCNA-chloramphenicol acetyltransferase reporter constructs in
      transient expression assays. The relative transcriptional activity of mutant PCNA
      promoters, both in the presence and absence of E1A 243R, was inversely related to
      their ability to complex with RFX1. These findings suggest that the binding of
      RFX1 is influenced by sequences outside its consensus binding site and that this
      transcription factor plays an inhibitory role in the regulation of PCNA gene
      expression.

PMID- 10336435
TI  - Interaction mapping of a dynein heavy chain. Identification of dimerization and
      intermediate-chain binding domains.
AB  - Cytoplasmic dynein is a multisubunit microtubule-based motor protein that is
      involved in several eukaryotic cell motilities. Two dynein heavy chains each form
      a motor domain that connects to a common cargo-binding tail. Although this tail
      domain is composed of multiple polypeptides, subunit organization within this
      region is poorly understood. Here we present an in vitro dissection of the tail
      forming region of the dynein heavy chain from Dictyostelium. Our work identifies
      a sequence important for dimerization and for binding the dynein intermediate
      chain. The core of this motif localizes within an approximately 150-amino acid
      region that is strongly conserved among other cytoplasmic dyneins. This level of
      conservation does not extend to the axonemal dynein heavy chains, suggesting
      functional differences between the two. Dimerization appears to occur through a
      different mechanism than the heavy chain-intermediate chain interaction. We
      corroborate the in vitro interactions with in vivo expression of heavy chain
      fragments in Dictyostelium. Fragments lacking the interaction domain express
      well, without an obvious phenotype. On the other hand, the region crucial for
      both interactions appears to be lethal when overexpressed.

PMID- 10336434
TI  - Mixed and non-cognate SNARE complexes. Characterization of assembly and
      biophysical properties.
AB  - Assembly of soluble N-ethylmaleimide-sensitive fusion attachment protein receptor
      (SNARE) proteins between two opposing membranes is thought to be the key event
      that initiates membrane fusion. Many new SNARE proteins have recently been
      localized to distinct intracellular compartments, supporting the view that sets
      of specific SNAREs are specialized for distinct trafficking steps. We have now
      investigated whether other SNAREs can form complexes with components of the
      synaptic SNARE complex including synaptobrevin/VAMP 2, SNAP-25, and syntaxin 1.
      When the Q-SNAREs syntaxin 2, 3, and 4, and the R-SNARE endobrevin/VAMP 8 were
      used in various combinations, heat-resistant complexes were formed. Limited
      proteolysis revealed that these complexes contained a protease-resistant core
      similar to that of the synaptic complex. All complexes were disassembled by the
      ATPase N-ethylmaleimide-sensitive fusion protein and its cofactor alpha-SNAP.
      Circular dichroism spectroscopy showed that major conformational changes occur
      during assembly, which are associated with induction of structure from
      unstructured monomers. Furthermore, no preference for synaptobrevin was observed
      during the assembly of the synaptic complex when endobrevin/VAMP 8 was present in
      equal concentrations. We conclude that cognate and non-cognate SNARE complexes
      are very similar with respect to biophysical properties, assembly, and
      disassembly, suggesting that specificity of membrane fusion in intracellular
      membrane traffic is not due to intrinsic specificity of SNARE pairing.

PMID- 10336436
TI  - Activation of the 9E3/cCAF chemokine by phorbol esters occurs via multiple signal
      transduction pathways that converge to MEK1/ERK2 and activate the Elk1
      transcription factor.
AB  - Using primary fibroblasts in culture, we have investigated the signal
      transduction mechanisms by which phorbol esters, a class of tumor promoters,
      activate the 9E3 gene and its chemokine product the chicken chemotactic and
      angiogenic factor. This gene is highly stimulated by phorbol 12,13-dibutyrate
      (PDBu) via three pathways: (i) a small contribution through protein kinase C (the
      commonly recognized pathway for these tumor promoters), (ii) a contribution
      involving tyrosine kinases, and (iii) a larger contribution via pathways that can
      be interrupted by dexamethasone. All three of these pathways converge into the
      mitogen-activated protein kinases, MEK1/ERK2. Using a luciferase reporter system,
      we show that although both the AP-1 and PDRIIkB (a NFkappaB-like factor in
      chickens) response elements are capable of activation in these normal cells,
      regions of the 9E3 promoter containing them are unresponsive to PDBu stimulation.
      In contrast, we show for the first time that activation by PDBu occurs through a
      segment of the promoter containing Elk1 response elements; deletion and mutation
      of these elements abrogates 9E3/chicken chemotactic and angiogenic factor
      expression. Electrophoretic mobility shift assays and functional studies using
      PathDetect systems show that stimulation of the cells by phorbol esters leads to
      activation of the Elk1 transcription factor, which binds to its element in the
      9E3 promoter.

PMID- 10336437
TI  - The p75(NTR)-induced apoptotic program develops through a ceramide-caspase
      pathway negatively regulated by nitric oxide.
AB  - SK-N-BE neuroblastoma cell clones transfected with p75(NTR) and lacking Trk
      neurotrophin receptors, previously reported to undergo extensive spontaneous
      apoptosis and to be protected by nerve growth factor (NGF) (Bunone, G., Mariotti,
      A., Compagni, A., Morandi, E., and Della Valle, G. (1997) Oncogene 14, 1463
      1470), are shown to exhibit (i) increased levels of the pro-apoptotic lipid
      metabolite ceramide and (ii) high activity of caspases, the proteases of the cell
      death cascade. In the p75(NTR)-expressing cells, these parameters were partially
      normalized by prolonged NGF treatment, which, in addition, decreased apoptosis,
      similar to caspase blockers. Conversely, exogenous ceramide increased caspase
      activity and apoptosis in both wild-type and p75(NTR)-expressing cells. A new
      p75(NTR)-expressing clone characterized by low spontaneous apoptosis exhibited
      high endogenous ceramide and low caspase levels. A marked difference between the
      apoptotic and resistant clones concerned the very low and high activities of
      nitric-oxide (NO) synthase, respectively. Protection from apoptosis by NO was
      confirmed by results with the NO donor S-nitrosoacetylpenicillamine and the NO
      trapping agent hemoglobin. We conclude that the p75(NTR) receptor, while free of
      NGF, triggers a cascade leading to apoptosis; the cascade includes generation of
      ceramide and increased caspase activity; and the protective role of NO occurs at
      step(s) in between the latter events.

PMID- 10336438
TI  - The compact conformation of fibronectin is determined by intramolecular ionic
      interactions.
AB  - Fibronectin exists in a compact or extended conformation, depending upon
      environmental pH and salt concentration. Using recombinant fragments expressed in
      bacteria and baculovirus, we determined the domains responsible for producing
      fibronectin's compact conformation. Our velocity and equilibrium sedimentation
      data show that FN2-14 (a protein containing FN-III domains 2 through 14) forms
      dimers in low salt. Experiments with smaller fragments indicates that the compact
      conformation is produced by binding of FN12-14 of one subunit to FN2-3 of the
      other subunit in the dimer. The binding is weakened at higher salt
      concentrations, implying an electrostatic interaction. Furthermore, segment FN7
      14+A, which contains the alternatively spliced A domain between FN11 and 12,
      forms dimers, whereas FN7-14 without A does not. Segment FN12-14+A also forms
      dimers, but the isolated A domain does not. These data imply an association of
      domain A with FN12-14, and the presence of A may favor an open conformation by
      competing with FN2-3 for binding to FN12-14.

PMID- 10336439
TI  - Synergism among lysophosphatidic acid, beta1A integrins, and epidermal growth
      factor or platelet-derived growth factor in mediation of cell migration.
AB  - GD25 cells lacking the beta1 integrin subunit or expressing beta1A with certain
      cytoplasmic mutations have poor directed cell migration to platelet-derived
      growth factor (PDGF) or epidermal growth factor (EGF), ligands of receptor
      tyrosine kinases, or to lysophosphatidic acid (LPA), a ligand of G-protein
      coupled receptors (Sakai, T., Zhang, Q., Fassler, R., and Mosher, D. F. (1998) J.
      Cell Biol. 141, 527-538 and Sakai, T., Peyruchaud, O., Fassler, R., and Mosher,
      D. F. (1998) J. Biol. Chem. 273, 19378-19382). We demonstrate here that LPA
      synergizes with signals induced by beta1A integrins and ligated EGF or PDGF
      receptors to modulate migration. When LPA was mixed with EGF or PDGF, migration
      was greater than with EGF or PDGF alone. The enhancement was greater for beta1A
      expressing cells than for beta1-null cells. Cells expressing beta1A with
      mutations of prolines or tyrosines in conserved cytoplasmic NPXY motifs had
      blunted migratory responses to mixtures of LPA and EGF or PDGF. The major effects
      on beta1A-expressing cells of LPA when combined with EGF or PDGF were to
      sensitize cells so that maximal responses were obtained with >10-fold lower
      concentrations of growth factor and increase the chemokinetic component of
      migration. Sensitization by LPA was lost when cells were preincubated with
      pertussis toxin or C3 exotransferase. There was no evidence for transactivation
      or sensitization of receptors for EGF or PDGF by LPA. EGF or PDGF and LPA caused
      activation of mitogen-activated protein kinase by pertussis toxin-insensitive and
      -sensitive pathways respectively, but activation was not additive. These findings
      indicate that signaling pathways initiated by the cytoplasmic domains of ligated
      beta1A integrins and tyrosine kinase receptors interact with signaling pathways
      initiated by LPA to facilitate directed cell migration.

PMID- 10336440
TI  - Biochemical characterization of human S-nitrosohemoglobin. Effects on oxygen
      binding and transnitrosation.
AB  - S-Nitrosation of cysteine beta93 in hemoglobin (S-nitrosohemoglobin (SNO-Hb))
      occurs in vivo, and transnitrosation reactions of deoxygenated SNO-Hb are
      proposed as a mechanism leading to release of NO and control of blood flow.
      However, little is known of the oxygen binding properties of SNO-Hb or the
      effects of oxygen on transnitrosation between SNO-Hb and the dominant low
      molecular weight thiol in the red blood cell, GSH. These data are important as
      they would provide a biochemical framework to assess the physiological function
      of SNO-Hb. Our results demonstrate that SNO-Hb has a higher affinity for oxygen
      than native Hb. This implies that NO transfer from SNO-Hb in vivo would be
      limited to regions of extremely low oxygen tension if this were to occur from
      deoxygenated SNO-Hb. Furthermore, the kinetics of the transnitrosation reactions
      between GSH and SNO-Hb are relatively slow, making transfer of NO+ from SNO-Hb to
      GSH less likely as a mechanism to elicit vessel relaxation under conditions of
      low oxygen tension and over the circulatory lifetime of a given red blood cell.
      These data suggest that the reported oxygen-dependent promotion of S-nitrosation
      from SNO-Hb involves biochemical mechanisms that are not intrinsic to the Hb
      molecule.

PMID- 10336441
TI  - beta-amyloid activates the O-2 forming NADPH oxidase in microglia, monocytes, and
      neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer's
      disease.
AB  - The deposition of beta-amyloid in the brain is the key pathogenetic event in
      Alzheimer's disease. Among the various mechanisms proposed to explain the
      neurotoxicity of beta-amyloid deposits, a new one, recently identified in our and
      other laboratories, suggests that beta-amyloid is indirectly neurotoxic by
      activating microglia to produce toxic inflammatory mediators such as cytokines,
      nitric oxide, and oxygen free radicals. Three findings presented here support
      this mechanism, showing that beta-amyloid peptides (25-35), (1-39), and (1-42)
      activated the classical NADPH oxidase in rat primary culture of microglial cells
      and human phagocytes: 1) The exposure of the cells to beta-amyloid peptides
      stimulates the production of reactive oxygen intermediates; 2) the stimulation is
      associated with the assembly of the cytosolic components of NADPH oxidase on the
      plasma membrane, the process that corresponds to the activation of the enzyme; 3)
      neutrophils and monocytes of chronic granulomatous disease patients do not
      respond to beta-amyloid peptides with the stimulation of reactive oxygen
      intermediate production. Data are also presented that the activation of NADPH
      oxidase requires that beta-amyloid peptides be in fibrillary state, is inhibited
      by inhibitors of tyrosine kinases or phosphatidylinositol 3-kinase and by
      dibutyryl cyclic AMP, and is potentiated by interferon-gamma or tumor necrosis
      factor-alpha.

PMID- 10336442
TI  - Paradoxical stimulation of a DEG/ENaC channel by amiloride.
AB  - Extracellular amiloride inhibits all known DEG/ENaC ion channels, including BNC1,
      a proton-activated human neuronal cation channel. Earlier studies showed that
      protons cause a conformational change that activates BNC1 and exposes residue 430
      to the extracellular solution. Here we demonstrate that, in addition to blocking
      BNC1, amiloride also exposes residue 430. This result suggested that, like
      protons, amiloride might be capable of activating the channel. To test this
      hypothesis, we introduced a mutation in the BNC1 pore that reduces amiloride
      block, and found that amiloride stimulated these channels. Amiloride inhibition
      was voltage-dependent, suggesting block within the pore, whereas stimulation was
      not, suggesting binding to an extracellular site. These data show that amiloride
      can have two distinct effects on BNC1, and they suggest two different interaction
      sites. The results suggest that extracellular amiloride binding may have a
      stimulatory effect similar to that of protons in BNC1 or extracellular ligands in
      other DEG/ENaC channels.

PMID- 10336443
TI  - Molecular chaperone-like properties of an unfolded protein, alpha(s)-casein.
AB  - All molecular chaperones known to date are well organized, folded protein
      molecules whose three-dimensional structure are believed to play a key role in
      the mechanism of substrate recognition and subsequent assistance to folding. A
      common feature of all protein and nonprotein molecular chaperones is the
      propensity to form aggregates very similar to the micellar aggregates. In this
      paper we show that alpha(s)-casein, abundant in mammalian milk, which has no well
      defined secondary and tertiary structure but exits in nature as a micellar
      aggregate, can prevent a variety of unrelated proteins/enzymes against thermal-,
      chemical-, or light-induced aggregation. It also prevents aggregation of its
      natural substrates, the whey proteins. alpha(s)-Casein interacts with partially
      unfolded proteins through its solvent-exposed hydrophobic surfaces. The absence
      of disulfide bridge or free thiol groups in its sequence plays important role in
      preventing thermal aggregation of whey proteins caused by thiol-disulfide
      interchange reactions. Our results indicate that alpha(s)-casein not only
      prevents the formation of huge insoluble aggregates but it can also inhibit
      accumulation of soluble aggregates of appreciable size. Unlike other molecular
      chaperones, this protein can solubilize hydrophobically aggregated proteins. This
      protein seems to have some characteristics of cold shock protein, and its
      chaperone-like activity increases with decrease of temperature.

PMID- 10336444
TI  - Fourier transform infrared spectroscopy study of the secondary and tertiary
      structure of the reconstituted Na+/Ca2+ exchanger 70-kDa polypeptide.
AB  - The secondary structure of the purified 70-kDa protein Na+/Ca2+ exchanger,
      functionally reconstituted into asolectin lipid vesicles, was examined by Fourier
      transform infrared attenuated total reflection spectroscopy. Fourier transform
      infrared attenuated total reflection spectroscopy provided evidence that the
      protein is composed of 44% alpha-helices, 25% beta-sheets, 16% beta-turns, and
      15% random structures, notably the proportion of alpha-helices is greater than
      that corresponding to the transmembrane domains predicted by exchanger hydropathy
      profile. Polarized infrared spectroscopy showed that the orientation of helices
      is almost perpendicular to the membrane. Tertiary structure modifications,
      induced by addition of Ca2+, were evaluated by deuterium/hydrogen exchange
      kinetic measurements for the reconstituted exchanger. This approach was
      previously proven as a useful tool for detection of tertiary structure
      modifications induced by an interaction between a protein and its specific
      ligand. Deuterium/hydrogen exchange kinetic measurements indicated that, in the
      absence of Ca2+, a large fraction of the protein (40%) is inaccessible to
      solvent. Addition of Ca2+ increased to 55% the inaccessibility to solvent,
      representing a major conformational change characterized by the shielding of at
      least 93 amino acids.

PMID- 10336445
TI  - Simultaneous presence of p47(phox) and flavocytochrome b-245 are required for the
      activation of NADPH oxidase by anionic amphiphiles. Evidence for an intermediate
      state of oxidase activation.
AB  - We have examined the kinetics of NADPH oxidase activation induced by arachidonic
      acid or SDS in a cell-free system using mixtures of recombinant Phox proteins and
      purified flavocytochrome b-245. Activation of oxidase activity required the
      simultaneous presence of p47(phox), flavocytochrome b-245, and the anionic
      amphiphile. The activation of electron transfer reactions was much more rapid
      when iodonitrotetrazolium violet was used as electron acceptor than when oxygen
      alone was the acceptor. We propose that this difference represents an
      intermediate activation state of NADPH oxidase in which electron flow can proceed
      from NADPH to enzyme flavin (and hence to iodonitrotetrazolium violet) but not
      from flavin to heme (or not between the hemes). A model for NADPH oxidase
      activation is presented that is consistent with these observations.

PMID- 10336446
TI  - An upstream regulator of the glycoprotein hormone alpha-subunit gene mediates
      pituitary cell type activation and repression by different mechanisms.
AB  - Targeting of alpha-subunit gene expression within the pituitary is influenced by
      an upstream regulatory region that directs high level expression to thyrotropes
      and gonadotropes of transgenic mice. The same region also enhanced the activity
      of the proximal promoter in transfections of pituitary-derived alpha-TSH and
      alpha-T3 cells. We have localized the activating sequences to a 125-bp region
      that contains consensus sites for factors that also play a role in proximal
      promoter activity. Proteins present in alpha-TSH and alpha-T3 cells as well as
      those from GH3 somatotrope-derived cells interact with this region. The upstream
      area inhibited proximal alpha-promoter activity by 80% when transfected into GH3
      cells. Repression in GH3 cells was mediated through a different mechanism than
      enhancement, as supported by the following evidence. Reversing the orientation of
      the area resulted in a loss of proximal promoter activation in alpha-TSH and
      alpha-T3 cells but did not relieve repression in GH3 cells. Mutation of proximal
      sites shown to be important for activation had no effect on repression. Finally,
      bidirectional deletional analysis revealed that multiple elements are involved in
      activation and repression and, together with the DNA binding studies, suggests
      that these processes may be mediated through closely juxtaposed or even
      overlapping elements, thus perhaps defining a new class of bifunctional gene
      regulatory sequence.

PMID- 10336447
TI  - Activation of the leukocyte NADPH oxidase by protein kinase C in a partially
      recombinant cell-free system.
AB  - The leukocyte NADPH oxidase is an enzyme present in phagocytes and B lymphocytes
      that when activated catalyzes the production of O-2 from oxygen at the expense of
      NADPH. A correlation between the activation of the oxidase and the
      phosphorylation of p47(PHOX), a cytosolic oxidase component, is well recognized
      in whole cells, and direct evidence for a relationship between the
      phosphorylation of this oxidase component and the activation of the oxidase has
      been obtained in a number of cell-free systems containing neutrophil membrane and
      cytosol. Using superoxide dismutase-inhibitable cytochrome c reduction to
      quantify O-2 production, we now show that p47(PHOX) phosphorylated by protein
      kinase C activates the NADPH oxidase not only in a cell-free system containing
      neutrophil membrane and cytosol, but also in a system in which the cytosol is
      replaced by the recombinant proteins p67(PHOX), Rac2, and phosphorylated
      p47(PHOX), suggesting that neutrophil plasma membrane plus those three cytosolic
      proteins are both necessary and sufficient for oxidase activation. In both the
      cytosol-containing and recombinant cell-free systems, however, activation by SDS
      yielded greater rates of O-2 production than activation by protein kinase C
      phosphorylated p47(PHOX), indicating that a system that employs protein kinase C
      phosphorylated p47(PHOX) as the sole activating agent, although more
      physiological than the SDS-activated system, is nevertheless incomplete.

PMID- 10336448
TI  - Mechanism of interaction of Acanthamoeba actophorin (ADF/Cofilin) with actin
      filaments.
AB  - We characterized the interaction of Acanthamoeba actophorin, a member of
      ADF/cofilin family, with filaments of amoeba and rabbit skeletal muscle actin.
      The affinity is about 10 times higher for muscle actin filaments (Kd = 0.5
      microM) than amoeba actin filaments (Kd = 5 microM) even though the affinity for
      muscle and amoeba Mg-ADP-actin monomers (Kd = 0.1 microM) is the same (Blanchoin,
      L., and Pollard, T. D. (1998) J. Biol. Chem. 273, 25106-25111). Actophorin binds
      slowly (k+ = 0.03 microM-1 s-1) to and dissociates from amoeba actin filaments in
      a simple bimolecular reaction, but binding to muscle actin filaments is
      cooperative. Actophorin severs filaments in a concentration-dependent fashion.
      Phosphate or BeF3 bound to ADP-actin filaments inhibit actophorin binding.
      Actophorin increases the rate of phosphate release from actin filaments more than
      10-fold. The time course of the interaction of actophorin with filaments measured
      by quenching of the fluorescence of pyrenyl-actin or fluorescence anisotropy of
      rhodamine-actophorin is complicated, because severing, depolymerization, and
      repolymerization follows binding. The 50-fold higher affinity of actophorin for
      Mg-ADP-actin monomers (Kd = 0.1 microM) than ADP-actin filaments provides the
      thermodynamic basis for driving disassembly of filaments that have hydrolyzed ATP
      and dissociated gamma-phosphate.

PMID- 10336449
TI  - Activation of retinal guanylyl cyclase-1 by Ca2+-binding proteins involves its
      dimerization.
AB  - Retinal guanylyl cyclase-1 (retGC-1), a key enzyme in phototransduction, is
      activated by guanylyl cyclase-activating proteins (GCAPs) if [Ca2+] is less than
      300 nM. The activation is believed to be essential for the recovery of
      photoreceptors to the dark state; however, the molecular mechanism of the
      activation is unknown. Here, we report that dimerization of retGC-1 is involved
      in its activation by GCAPs. The GC activity and the formation of a 210-kDa cross
      linked product of retGC-1 were monitored in bovine rod outer segment homogenates,
      GCAPs-free bovine rod outer segment membranes and recombinant bovine retGC-1
      expressed in COS-7 cells. In addition to recombinant bovine GCAPs, constitutively
      active mutants of GCAPs that activate retGC-1 in a [Ca2+]-independent manner and
      bovine brain S100b that activates retGC-1 in the presence of approximately 10
      microM [Ca2+] were used to investigate whether these activations take place
      through a similar mechanism, and whether [Ca2+] is directly involved in the
      dimerization. We found that a monomeric form of retGC-1 ( approximately 110 kDa)
      was mainly observed whenever GC activity was at basal or low levels. However, the
      210-kDa product was increased whenever the GC activity was stimulated by any Ca2+
      binding proteins used. We also found that [Ca2+] did not directly regulate the
      formation of the 210-kDa product. The 210-kDa product was detected in a purified
      GC preparation and did not contain GCAPs even when the formation of the 210-kDa
      product was stimulated by GCAPs. These data strongly suggest that the 210-kDa
      cross-linked product is a homodimer of retGC-1. We conclude that inactive retGC-1
      is predominantly a monomeric form, and that dimerization of retGC-1 may be an
      essential step for its activation by active forms of GCAPs.

PMID- 10336450
TI  - Phosphorylation of replication protein A middle subunit (RPA32) leads to a
      disassembly of the RPA heterotrimer.
AB  - Replication protein A (RPA), the major eukaryotic single-strand specific DNA
      binding protein, consists of three subunits, RPA70, RPA32, and RPA14. The middle
      subunit, RPA32, is phosphorylated in a cell cycle-dependent manner. RPA occurs in
      two nuclear compartments, bound to chromatin or free in the nucleosol. We show
      here that the chromatin-associated fraction of RPA contains the phosphorylated
      forms of RPA32. Treatment of chromatin with 0.4 M NaCl releases bound RPA and
      causes a separation of the large and the phosphorylated middle RPA subunit.
      Unmodified RPA in the nucleosolic fraction remains perfectly stable under
      identical conditions. Phosphorylation is most likely an important determinant of
      RPA desintegration because dialysis from 0.4 to 0.1 NaCl causes the reformation
      of trimeric RPA only under dephosphorylating conditions. Biochemical studies with
      isolated Cyclin-dependent protein kinases showed that cyclin A/CDK1 and cyclin
      B/CDK1, but not cyclin E/CDK2, can phosphorylate human recombinant RPA in vitro.
      However, only a small fraction of in vitro phosphorylated RPA desintegrated,
      suggesting that phosphorylation may be one, but probably not the only,
      determinant affecting subunit interaction. We speculate that phosphorylation and
      changes in subunit interaction are required for the proposed role of RPA during
      the polymerase switch at replication forks.

PMID- 10336451
TI  - The IIANtr (PtsN) protein of Pseudomonas putida mediates the C source inhibition
      of the sigma54-dependent Pu promoter of the TOL plasmid.
AB  - The gene cluster adjacent to the sequence of rpoN (encoding sigma factor sigma54)
      of Pseudomonas putida has been studied with respect to the C source regulation of
      the Pu promoter of the upper TOL (toluene catabolism) operon. The region includes
      four open reading frames (ORFs), two of which (named ptsN and ptsO genes) encode
      proteins similar to components of the phosphoenolpyruvate:sugar
      phosphotransferase system. Each of the four genes was disrupted with a nonpolar
      insertion, and the effects in the inhibition caused by glucose on Pu activity
      were inspected with a lacZ reporter system. Although cells lacking ORF102,
      ORF284, and ptsO did not display any evident phenotype under the conditions
      tested, the loss of ptsN, which encodes the IIANtr protein, made Pu unresponsive
      to repression by glucose. The ptsN mutant had rates of glucose/gluconate
      consumption identical to those of the wild type, thus ruling out indirect effects
      mediated by the transport of the carbohydrate. A site-directed ptsN mutant in
      which the conserved phospho-acceptor site His68 of IIANtr was replaced by an
      aspartic acid residue made Pu blind to the presence or absence of glucose, thus
      supporting the notion that phosphorylation of IIANtr mediates the C source
      inhibition of the promoter. These data substantiate the existence of a molecular
      pathway for co-regulation of some sigma54 promoters in which IIANtr is a key
      protein intermediate.

PMID- 10336452
TI  - Estrogen modulation of apolipoprotein(a) expression. Identification of a
      regulatory element.
AB  - Elevated plasma levels of the lipoprotein particle Lp(a) are a major risk factor
      for cardiovascular disease. Lp(a) plasma levels are determined by the level of
      expression of its characteristic protein component, apo(a). Apo(a) expression is
      modulated by several hormones, of which estrogens are the best known. The
      chromosomal region responsible for estrogen response was identified within an
      apo(a) enhancer located at approximately 26 kilobases from the apo(a) promoter.
      Although the estrogen-responsive unit contains a potential estrogen response
      element, binding of estrogen receptor-alpha to DNA was not necessary. The
      receptor, activated by bound estradiol, interacts through its transactivation
      domains with a transcription factor necessary for the function of the enhancer,
      preventing its binding to DNA.

PMID- 10336453
TI  - The role of STAT3 in granulocyte colony-stimulating factor-induced enhancement of
      neutrophilic differentiation of Me2SO-treated HL-60 cells. GM-CSF inhibits the
      nuclear translocation of tyrosine-phosphorylated STAT3.
AB  - The role of granulocyte colony-stimulating factor (G-CSF) on neutrophilic
      differentiation of Me2SO-treated HL-60 cells was studied. G-CSF augmented the
      functional maturation of Me2SO-treated HL-60 cells in terms of both O-2
      generating ability and expression of the formyl-methionyl-leucyl-phenylalanine
      receptor. G-CSF induced enhancement of cell growth in Me2SO-treated HL-60 cells.
      These results indicate that G-CSF is a potent enhancer for the differentiation
      and proliferation of Me2SO-treated HL-60 cells. G-CSF caused the activation of
      p70 S6 kinase but not mitogen-activated protein (MAP) kinase. On the other hand,
      G-CSF rapidly induced tyrosine phosphorylation of signal transducers and
      activators of transcription-3 (STAT3), but did not induce serine727
      phosphorylation. From the analysis of confocal laser scanning fluorescence
      microscopy and differential centrifugation, it was clearly demonstrated that G
      CSF induced nuclear translocation of tyrosine-phosphorylated STAT3. The G-CSF
      dependent enhancement of neutrophilic differentiation in Me2SO-HL-60 cells was
      reversely inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF).
      Notably, in the presence of GM-CSF, G-CSF induced the tyrosine phosphorylation of
      STAT3 but failed to induce the nuclear translocation of tyrosine-phosphorylated
      STAT3. GM-CSF induced activation of not only p70 S6 kinase, but also of MAP
      kinase. Furthermore, GM-CSF caused the rapid serine727 phosphorylation of STAT3,
      both in the presence and absence of G-CSF. PD98059, an MEK1 inhibitor, inhibited
      the G-CSF-dependent serine727 phosphorylation of STAT3 and blocked the inhibitory
      effect of GM-CSF on G-CSF-dependent nuclear translocation of STAT3. These results
      suggest that G-CSF-dependent nuclear translocation of STAT3 coordinates with the
      promotion of neutrophilic differentiation in Me2SO-treated HL-60 cells.

PMID- 10336454
TI  - Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in
      complex with NAD+ and a C16 fatty acyl substrate.
AB  - Enoyl-ACP reductases participate in fatty acid biosynthesis by utilizing NADH to
      reduce the trans double bond between positions C2 and C3 of a fatty acyl chain
      linked to the acyl carrier protein. The enoyl-ACP reductase from Mycobacterium
      tuberculosis, known as InhA, is a member of an unusual FAS-II system that prefers
      longer chain fatty acyl substrates for the purpose of synthesizing mycolic acids,
      a major component of mycobacterial cell walls. The crystal structure of InhA in
      complex with NAD+ and a C16 fatty acyl substrate, trans-2-hexadecenoyl-(N
      acetylcysteamine)-thioester, reveals that the substrate binds in a general "U
      shaped" conformation, with the trans double bond positioned directly adjacent to
      the nicotinamide ring of NAD+. The side chain of Tyr158 directly interacts with
      the thioester carbonyl oxygen of the C16 fatty acyl substrate and therefore could
      help stabilize the enolate intermediate, proposed to form during substrate
      catalysis. Hydrophobic residues, primarily from the substrate binding loop
      (residues 196-219), engulf the fatty acyl chain portion of the substrate. The
      substrate binding loop of InhA is longer than that of other enoyl-ACP reductases
      and creates a deeper substrate binding crevice, consistent with the ability of
      InhA to recognize longer chain fatty acyl substrates.

PMID- 10336455
TI  - Immediate upstream sequence of arrestin directs rod-specific expression in
      Xenopus.
AB  - Arrestins are a family of proteins that modulate G protein-coupled receptor
      responses with distinct arrestin genes expressed in rods and cones. To understand
      the regulatory mechanisms controlling rod-specific expression, the abundant
      Xenopus rod arrestin cDNA and a partial genomic clone, containing the immediate
      upstream region and amino terminus of the polypeptide, have been characterized.
      The deduced polypeptide has approximately 69% identity to other vertebrate rod
      arrestins. Southern blot analysis and polymerase chain reaction of intronic
      sequences demonstrated multiple alleles for rod arrestin. DNase I footprinting
      with retinal proteins revealed four major DNA binding sites in the proximal
      promoter, coinciding with consensus sequences reported in mammalian promoters.
      Purified bovine Crx homeodomain and mouse Nrl proteins protected a number of
      these sites. A dual approach of transient embryo transfections and transgenesis
      was used to locate transcriptional control sequences essential for rod-specific
      expression in Xenopus. Constructs containing -1287/+113 of 5' upstream sequence
      with or without intron 1 directed high level expression, specifically in rods. A
      construct containing only -287/+113 directed expression of green fluorescent
      protein solely in rod cells. These results suggest that the Crx and Nrl binding
      sites in the proximal promoter are the primary cis-acting sequences regulating
      arrestin gene expression in rods.

PMID- 10336456
TI  - Structure of the membrane domain of subunit b of the Escherichia coli F0F1 ATP
      synthase.
AB  - The structure of the N-terminal transmembrane domain (residues 1-34) of subunit b
      of the Escherichia coli F0F1-ATP synthase has been solved by two-dimensional 1H
      NMR in a membrane mimetic solvent mixture of chloroform/methanol/H2O (4:4:1).
      Residues 4-22 form an alpha-helix, which is likely to span the hydrophobic domain
      of the lipid bilayer to anchor the largely hydrophilic subunit b in the membrane.
      The helical structure is interrupted by a rigid bend in the region of residues 23
      26 with alpha-helical structure resuming at Pro-27 at an angle offset by 20
      degrees from the transmembrane helix. In native subunit b, the hinge region and C
      terminal alpha-helical segment would connect the transmembrane helix to the
      cytoplasmic domain. The transmembrane domains of the two subunit b in F0 were
      shown to be close to each other by cross-linking experiments in which single Cys
      were substituted for residues 2-21 of the native subunit and b-b dimer formation
      tested after oxidation with Cu(II)(phenanthroline)2. Cys residues that formed
      disulfide cross-links were found with a periodicity indicative of one face of an
      alpha-helix, over the span of residues 2-18, where Cys at positions 2, 6, and 10
      formed dimers in highest yield. A model for the dimer is presented based upon the
      NMR structure and distance constraints from the cross-linking data. The
      transmembrane alpha-helices are positioned at a 23 degrees angle to each other
      with the side chains of Thr-6, Gln-10, Phe-14, and Phe-17 at the interface
      between subunits. The change in direction of helical packing at the hinge region
      may be important in the functional interaction of the cytoplasmic domains.

PMID- 10336457
TI  - Kinetic and product distribution analysis of human eosinophil cationic protein
      indicates a subsite arrangement that favors exonuclease-type activity.
AB  - With the use of a high yield prokaryotic expression system, large amounts of
      human eosinophil cationic protein (ECP) have been obtained. This has allowed a
      thorough kinetic study of the ribonuclease activity of this protein. The
      catalytic efficiencies for oligouridylic acids of the type (Up)nU>p,
      mononucleotides U>p and C>p, and dinucleoside monophosphates CpA, UpA, and UpG
      have been interpreted by the specific subsites distribution in ECP. The
      distribution of products derived from digestion of high molecular mass
      substrates, such as poly(U) and poly(C), by ECP was compared with that of RNase
      A. The characteristic cleavage pattern of polynucleotides by ECP suggests that an
      exonuclease-like mechanism is predominantly favored in comparison to the
      endonuclease catalytic mechanism of RNase A. Comparative molecular modeling with
      bovine pancreatic RNase A-substrate analog crystal complexes revealed important
      differences in the subsite structure, whereas the secondary phosphate-binding
      site (p2) is lacking, the secondary base subsite (B2) is severely impaired, and
      there are new interactions at the po, Bo, and p-1 sites, located upstream of the
      P-O-5' cleavable phosphodiester bond, that are not found in RNase A. The
      differences in the multisubsites structure could explain the reduced catalytic
      efficiency of ECP and the shift from an endonuclease to an exonuclease-type
      mechanism.

PMID- 10336458
TI  - A pathway for conformational diversity in proteins mediated by intramolecular
      chaperones.
AB  - Conformational diversity within unique amino acid sequences is observed in
      diseases like scrapie and Alzheimer's disease. The molecular basis of such
      diversity is unknown. Similar phenomena occur in subtilisin, a serine protease
      homologous with eukaryotic pro-hormone convertases. The subtilisin propeptide
      functions as an intramolecular chaperone (IMC) that imparts steric information
      during folding but is not required for enzymatic activity. Point mutations within
      IMCs alter folding, resulting in structural conformers that specifically interact
      with their cognate IMCs in a process termed "protein memory." Here, we show a
      mechanism that mediates conformational diversity in subtilisin. During
      maturation, while the IMC is autocleaved and subsequently degraded by the active
      site of subtilisin, enzymatic properties of this site differ significantly before
      and after cleavage. Although subtilisin folded by Ile-48 --> Thr IMC (IMCI-48T)
      acquires an "altered" enzymatically active conformation (SubI-48T) significantly
      different from wild-type subtilisin (SubWT), both precursors undergo autocleavage
      at similar rates. IMC cleavage initiates conformational changes during which the
      IMC continues its chaperoning function subsequent to its cleavage from
      subtilisin. Structural imprinting resulting in conformational diversity
      originates during this reorganization stage and is a late folding event catalyzed
      by autocleavage of the IMC.

PMID- 10336459
TI  - Prostaglandin-endoperoxide H synthase-2 expression in human thyroid epithelium.
      Evidence for constitutive expression in vivo and in cultured KAT-50 cells.
AB  - Prostaglandin-endoperoxide H synthase (PGHS) (EC 1.14.99.1) expression was
      examined in human thyroid tissue and in KAT-50, a well differentiated human
      thyroid epithelial cell line. PGHS-1 is found constitutively expressed in most
      healthy tissues, whereas PGHS-2 is highly inducible and currently thought to be
      expressed, with few exceptions, only in diseased tissues. Surprisingly, PGHS-2
      mRNA and protein were easily detected in normal thyroid tissue. KAT-50 cells
      express high levels of constitutive PGHS-2 mRNA and protein under basal culture
      conditions. Compounds usually associated with PGHS-2 induction, including
      interleukin-1beta (IL-1beta), phorbol 12-myristate 13-acetate, and serum
      transiently down-regulated PGHS-2 expression. Human PGHS-2 promoter constructs (
      1840/+123 and -831/+123) fused to a luciferase reporter and transfected into
      untreated KAT-50 cells exhibited substantial activity. NS-398, a highly selective
      inhibitor of PGHS-2 could inhibit substantial basal prostaglandin E2 production.
      Exogenous IL-1 receptor antagonist or IL-1alpha neutralizing antibodies could
      attenuate constitutive PGHS-2 expression in KAT-50 cells, suggesting that
      endogenous IL-1alpha synthesis was driving PGHS-2 expression. Our findings
      suggest that normal thyroid epithelium expresses high constitutive levels of PGHS
      2 in situ and in vitro and this enzyme is active in the generation of
      prostaglandin E2. Thus, unprovoked PGHS-2 expression might be considerably more
      widespread in healthy tissues than is currently believed.

PMID- 10336460
TI  - A novel gene (PLU-1) containing highly conserved putative DNA/chromatin binding
      motifs is specifically up-regulated in breast cancer.
AB  - A novel human gene (PLU-1) has been identified which shows a highly restricted
      expression in normal adult tissues but which is consistently expressed in breast
      cancers. A fragment of the PLU-1 cDNA was identified by differentially screening
      a fetal brain library with cDNAs prepared from ce-1 cells (a human mammary
      epithelial cell line overexpressing c-ErbB2) treated or untreated with the
      antibody 4D5, which inhibits c-ErbB2 phosphorylation. Clones covering the full
      cDNA sequence of 6.4 kilobases were isolated from a breast cancer cDNA library.
      Although expression of PLU-1 in ce-1 cells is regulated by signaling from c
      ErbB2, the gene is expressed in all the breast cancer cell lines examined, in
      cells cultured from primary breast cancers, and in the invasive and in situ
      components of primary breast cancers. Translation of the open reading frame
      predicts a protein of 1544 amino acids, which contains three PHD/LAP motifs, a
      specific DNA-binding domain found in a Drosophila protein (dri) and novel domains
      showing extensive homology with other human and non human gene products.
      Transient transfection of cell lines with MYC-tagged PLU-1 showed the protein to
      be localized in the nucleus and associated with discrete foci. The presence of
      the dri motif and PHD/LAP fingers together with the clear nuclear localization
      and consistent expression in breast cancers, suggest a role for PLU-1 in
      regulating gene expression in breast cancers.

PMID- 10336461
TI  - A fluorescence investigation of the active site of Pseudomonas aeruginosa
      exotoxin A.
AB  - Single tryptophan mutant proteins of a catalytically active domain III
      recombinant protein (PE24) from Pseudomonas aeruginosa exotoxin A were prepared
      by site-directed mutagenesis. The binding of the dinucleotide substrate, NAD+, to
      the PE24 active site was studied by exploiting intrinsic tryptophan fluorescence
      for the wild-type, single Trp, and tryptophan-deficient mutant proteins. Various
      approaches were used to study the substrate binding process, including dynamic
      quenching, CD spectroscopy, steady-state fluorescence emission analysis, NAD+
      glycohydrolase activity, NAD+ binding analysis, protein denaturation experiments,
      fluorescence lifetime analysis, steady-state anisotropy measurement, stopped flow
      fluorescence spectroscopy, and quantum yield determination. It was found that the
      conservative replacement of tryptophan residues with phenylalanine had little or
      no effect on the folded stability and enzyme activity of the PE24 protein.
      Dynamic quenching experiments indicated that when bound to the active site of the
      enzyme, the NAD+ substrate protected Trp-558 from solvent to a large extent but
      had no effect on the degree of solvent exposure for tryptophans 417 and 466.
      Also, upon substrate binding, the anisotropy of the Trp-417(W466F/W558F) protein
      showed the largest increase, followed by Trp-466(W417F/W558F), and there was no
      effect on Trp-558(W417F/W466F). Furthermore, the intrinsic tryptophan
      fluorescence exhibited the highest degree of substrate-induced quenching for the
      wild-type protein, followed in decreasing order by Trp-417(W466F/W558F), Trp
      558(W417F/W466F), and Trp-466(W417F/W558F). These data provide evidence for a
      structural rearrangement in the enzyme domain near Trp-417 invoked by the binding
      of the NAD+ substrate.

PMID- 10336462
TI  - Crystal structure of carboxylase reaction-oriented ribulose 1, 5-bisphosphate
      carboxylase/oxygenase from a thermophilic red alga, Galdieria partita.
AB  - Ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco, EC 4.1.1. 39) obtained
      from a thermophilic red alga Galdieria partita has the highest specificity factor
      of 238 among the Rubiscos hitherto reported. Crystal structure of activated
      Rubisco from G. partita complexed with the reaction intermediate analogue, 2
      carboxyarabinitol 1,5-bisphosphate (2-CABP) has been determined at 2.4-A
      resolution. Compared with other Rubiscos, different amino residues bring the
      structural differences in active site, which are marked around the binding sites
      of P-2 phosphate of 2-CABP. Especially, side chains of His-327 and Arg-295 show
      the significant differences from those of spinach Rubisco. Moreover, the side
      chains of Asn-123 and His-294 which are reported to bind the substrate, ribulose
      1,5-bisphosphate, form hydrogen bonds characteristic of Galdieria Rubisco. Small
      subunits of Galdieria Rubisco have more than 30 extra amino acid residues on the
      C terminus, which make up a hairpin-loop structure to form many interactions with
      the neighboring small subunits. When the structures of Galdieria and spinach
      Rubiscos are superimposed, the hairpin region of the neighboring small subunit in
      Galdieria enzyme and apical portion of insertion residues 52-63 characteristic of
      small subunits in higher plant enzymes are almost overlapped to each other.

PMID- 10336463
TI  - Identification of a novel inhibitor of nuclear factor-kappaB, RelA-associated
      inhibitor.
AB  - Here we report the identification and characterization of a novel protein, RelA
      associated inhibitor (RAI), that binds to the NF-kappaB subunit p65 (RelA) and
      inhibits its transcriptional activity. RAI gene was isolated in a yeast two
      hybrid screen using the central region of p65 as bait. We confirmed the physical
      interaction in vitro using recombinant proteins as well as in vivo by
      immunoprecipitation/Western blot assay. RAI gene encodes a protein with homology
      to the C-terminal region of 53BP2 containing four consecutive ankyrin repeats and
      an Src homology 3 domain. RAI mRNA was preferentially expressed in human heart,
      placenta, and prostate. Despite its similarity to 53BP2, RAI did not interact
      with p53 in a yeast two-hybrid assay. RAI inhibited the action of NF-kappaB p65
      but not that of p53 in transient luciferase gene expression assays. Similarly,
      RAI inhibited the endogenous NF-kappaB activity induced by tumor necrosis factor
      alpha. RAI specifically inhibited the DNA binding activity of p65 when co
      transfected in 293 cells. RAI protein appeared to be located in the nucleus and
      colocalized with NF-kappaB p65 that was activated by TNF-alpha. These
      observations indicate that RAI is another inhibitor of NF-kappaB in addition to
      IkappaB proteins and may confer an alternative mechanism of regulation.

PMID- 10336464
TI  - Splice variants of intersectin are components of the endocytic machinery in
      neurons and nonneuronal cells.
AB  - We recently identified and cloned intersectin, a protein containing two Eps15
      homology (EH) domains and five Src homology 3 (SH3) domains. Using a newly
      developed intersectin antibody, we demonstrate that endogenous COS-7 cell
      intersectin localizes to clathrin-coated pits, and transfection studies suggest
      that the EH domains may direct this localization. Through alternative splicing in
      a stop codon, a long form of intersectin is generated with a C-terminal extension
      containing Dbl homology (DH), pleckstrin homology (PH), and C2 domains. Western
      blots reveal that the long form of intersectin is expressed specifically in
      neurons, whereas the short isoform is expressed at lower levels in glia and other
      nonneuronal cells. Immunofluorescence analysis of cultured hippocampal neurons
      reveals that intersectin is found at the plasma membrane where it is co-localized
      with clathrin. Ibp2, a protein identified based on its interactions with the EH
      domains of intersectin, binds to clathrin through the N terminus of the heavy
      chain, suggesting a mechanism for the localization of intersectin at clathrin
      coated pits. Ibp2 also binds to the clathrin adaptor AP2, and antibodies against
      intersectin co-immunoprecipitate clathrin, AP2, and dynamin from brain extracts.
      These data suggest that the long and short forms of intersectin are components of
      the endocytic machinery in neurons and nonneuronal cells.

PMID- 10336465
TI  - Structural and biochemical evaluation of the interaction of the
      phosphatidylinositol 3-kinase p85alpha Src homology 2 domains with
      phosphoinositides and inositol polyphosphates.
AB  - Src homology 2 (SH2) domains exist in many intracellular proteins and have well
      characterized roles in signal transduction. SH2 domains bind to phosphotyrosine
      (Tyr(P))-containing proteins. Although tyrosine phosphorylation is essential for
      protein-SH2 domain interactions, the binding specificity also derives from
      sequences C-terminal to the Tyr(P) residue. The high affinity and specificity of
      this interaction is critical for precluding aberrant cross-talk between signaling
      pathways. The p85alpha subunit of phosphoinositide 3-kinase (PI 3-kinase)
      contains two SH2 domains, and it has been proposed that in competition with
      Tyr(P) binding they may also mediate membrane attachment via interactions with
      phosphoinositide products of PI 3-kinase. We used nuclear magnetic resonance
      spectroscopy and biosensor experiments to investigate interactions between the
      p85alpha SH2 domains and phosphoinositides or inositol polyphosphates. We
      reported previously a similar approach when demonstrating that some pleckstrin
      homology domains show binding specificity for distinct phosphoinositides (Salim,
      K., Bottomley, M. J., Querfurth, E., Zvelebil, M. J., Gout, I., Scaife, R.,
      Margolis, R. L., Gigg, R., Smith, C. I., Driscoll, P. C., Waterfield, M. D., and
      Panayotou, G. (1996) EMBO J. 15, 6241-6250). However, neither SH2 domain
      exhibited binding specificity for phosphoinositides in phospholipid bilayers. We
      show that the p85alpha SH2 domain Tyr(P) binding pockets indiscriminately
      accommodate phosphoinositides and inositol polyphosphates. Binding of the SH2
      domains to Tyr(P) peptides was only poorly competed for by phosphoinositides or
      inositol polyphosphates. We conclude that these ligands do not bind p85alpha SH2
      domains with high affinity or specificity. Moreover, we observed that although
      wortmannin blocks PI 3-kinase activity in vivo, it does not affect the ability of
      tyrosine-phosphorylated proteins to bind to p85alpha. Consequently
      phosphoinositide products of PI 3-kinase are unlikely to regulate signaling
      through p85alpha SH2 domains.

PMID- 10336466
TI  - Cooperative transcriptional activation by serum response factor and the high
      mobility group protein SSRP1.
AB  - Serum response factor (SRF) is a MADS box transcription factor that controls a
      wide range of genes involved in cell proliferation and differentiation. The MADS
      box mediates homodimerization and binding of SRF to the consensus sequence
      CC(A/T)6GG, known as a CArG box, which is found in the control regions of
      numerous serum-inducible and muscle-specific genes. Using a modified yeast one
      hybrid screen to identify potential SRF cofactors, we found that SRF interacts
      with the high mobility group factor SSRP1 (structure-specific recognition
      protein). This interaction, which occurs in yeast and mammalian cells, is
      mediated through the MADS box of SRF and a basic region of SSRP1 encompassing
      amino acids 489-542, immediately adjacent to the high mobility group domain.
      SSRP1 does not bind the CArG box, but interaction of SSRP1 with SRF dramatically
      increases the DNA binding activity of SRF, resulting in synergistic
      transcriptional activation of native and artificial SRF-dependent promoters.
      These results reveal an important role for SSRP1 as a coregulator of SRF
      dependent transcription in mammalian cells.

PMID- 10336467
TI  - Morphological transformation induced by activation of the mitogen-activated
      protein kinase pathway requires suppression of the T-type Ca2+ channel.
AB  - Transformation of fibroblasts by various oncogenes, including ras, mos, and src
      accompanies with characteristic morphological changes from flat to round (or
      spindle) shapes. Such morphological change is believed to play an important role
      in establishing malignant characteristics of cancer cells. Activation of the
      mitogen-activated protein kinase (MAPK) pathway is a converging downstream event
      of transforming activities of many oncogene products commonly found in human
      cancers. Intracellular calcium is known to regulate cellular morphology. In
      fibroblasts, Ca2+ influx is primarily controlled by two types of Ca2+ channels (T
      and L-types). Here, we report that the T-type current was specifically inhibited
      in cells expressing oncogenically activated Ras as well as gain-of-function
      mutant MEK (MAPK/extracellular signal-regulated kinase (ERK) kinase, a direct
      activator of MAPK), whereas treatment of ras-transformed cells with a MEK
      specific inhibitor restored T-type Ca2+ channel activity. Using a T-type Ca2+
      channel antagonist, we further found that suppression of the T-type Ca2+ channel
      by the activated MAPK pathway is a prerequisite event for the induction and/or
      maintenance of transformation-associated morphological changes.

PMID- 10336468
TI  - Isolation and characterization of CA XIV, a novel membrane-bound carbonic
      anhydrase from mouse kidney.
AB  - Carbonic anhydrase (CA) is involved in various physiological processes such as
      acid-base balance and transport of carbon dioxide and ions. In this study, we
      have succeeded in the isolation of a novel CA from the mouse kidney by use of the
      signal sequence trap method. It is a 337-amino acid polypeptide with a calculated
      molecular mass of 37.5 kDa, consisting of a putative amino-terminal signal
      sequence, a CA domain, a transmembrane domain, and a short hydrophilic carboxyl
      terminus, which we designated CA XIV. The CA domain of CA XIV is highly
      homologous with those of known CAs, especially extracellular CAs including CA
      XII, IX, VI, and IV. The expression study of an epitope-tagged protein has
      suggested that CA XIV is located on the plasma membrane. When expressed in COS-7
      cells, CA XIV exhibits CA activity that is predominantly associated with the
      membrane fraction. By Northern blot analysis, the gene expression of CA XIV is
      most abundant in the kidney and heart, followed by the skeletal muscle, brain,
      lung, and liver. In situ hybridization has revealed that, in the kidney, the gene
      is expressed intensely in the proximal convoluted tubule, which is the major
      segment for bicarbonate reabsorption and also in the outer border of the inner
      stripe of the outer medulla. In conclusion, we have cloned a functional cDNA
      encoding a novel membrane-bound CA. This study will bring new insights into our
      understanding of carbon dioxide metabolism and acid-base balance.

PMID- 10336469
TI  - Kinetic properties and metal content of the metallo-beta-lactamase CcrA harboring
      selective amino acid substitutions.
AB  - The crystal structure of the metallo-beta-lactamase CcrA3 indicates that the
      active site of this enzyme contains a binuclear zinc center. To aid in assessing
      the involvement of specific residues in beta-lactam hydrolysis and susceptibility
      to inhibitors, individual substitutions of selected amino acids were generated.
      Substitution of the zinc-ligating residue Cys181 with Ser (C181S) resulted in a
      significant reduction in hydrolytic activity; kcat values decreased 2-4 orders of
      magnitude for all substrates. Replacement of His99 with Asn (H99N) significantly
      reduced the hydrolytic activity for penicillin and imipenem. Replacement of
      Asp103 with Asn (D103N) showed reduced hydrolytic activity for cephaloridine and
      imipenem. Deletion of amino acids 46-51 dramatically reduced both the hydrolytic
      activity and affinity for all beta-lactams. The metal binding capacity of each
      mutant enzyme was examined using nondenaturing electrospray ionization mass
      spectrometry. Two zinc ions were observed for the wild-type enzyme and most of
      the mutant enzymes. However, for the H99N, C181S, and D103N enzymes, three
      different zinc content patterns were observed. These enzymes contained two zinc
      molecules, one zinc molecule, and a mixture of one or two zinc molecules/enzyme
      molecule, respectively. Two enzymes with substitutions of Cys104 or Cys104 and
      Cys155 were also composed of mixed enzyme populations.

PMID- 10336470
TI  - The chaperoning activity of hsp110. Identification of functional domains by use
      of targeted deletions.
AB  - hsp110 is one of major heat shock proteins of eukaryotic cells and is a diverged
      relative of the hsp70 family. It has been previously shown that hsp110 maintains
      heat-denatured luciferase in a soluble, folding competent state and also confers
      cellular heat resistance in vivo. In the present study the functional domains of
      hsp110 that are responsible for its chaperoning activity are identified by
      targeted deletion mutagenesis using the DnaK structure as the model. The
      chaperoning activity of mutants is assessed based on their ability to solubilize
      heat-denatured luciferase as well as to refold luciferase in the presence of
      rabbit reticulocyte lysate. It is shown that these functions require only an
      internal region of hsp110 that includes the predicted peptide binding domain and
      two immediately adjacent C-terminal domains. It is also shown that although
      hsp110 binds ATP, binding can be blocked by its C-terminal region.

PMID- 10336471
TI  - Localization of functional prostaglandin E2 receptors EP3 and EP4 in the nuclear
      envelope.
AB  - The effects of prostaglandin E2 are thought to be mediated via G protein-coupled
      plasma membrane receptors, termed EP. However recent data implied that
      prostanoids may also act intracellularly. We investigated if the ubiquitous EP3
      and the EP4 receptors are localized in nuclear membranes. Radioligand binding
      studies on isolated nuclear membrane fractions of neonatal porcine brain and
      adult rat liver revealed the presence of EP3 and EP4. A perinuclear localization
      of EP3alpha and EP4 receptors was visualized by indirect immunocytofluorescence
      and confocal microscopy in porcine cerebral microvascular endothelial cells and
      in transfected HEK 293 cells that stably overexpress these receptors.
      Immunoelectron microscopy clearly revealed EP3alpha and EP4 receptors
      localization in the nuclear envelope of endothelial cells; this is the first
      demonstration of the nuclear localization of these receptors. Data also reveal
      that nuclear EP receptors are functional as they affect transcription of genes
      such as inducible nitric-oxide synthase and intranuclear calcium transients; this
      appears to involve pertussis toxin-sensitive G proteins. These results define a
      possible molecular mechanism of action of nuclear EP3 receptors.

PMID- 10336472
TI  - A predominant apoptotic death pathway of neuronal PC12 cells induced by activated
      microglia is displaced by a non-apoptotic death pathway following blockage of
      caspase-3-dependent cascade.
AB  - Activated microglia have been implicated in the regulation of neuronal cell
      death. However, the biochemical mechanism for neuronal death triggered by
      activated microglia is still unclear. When treated with activated microglia,
      neuronal PC12 cells undergo apoptosis accompanied by caspase-3-like protease
      activation and DNA fragmentation. Apoptotic bodies formed were subsequently
      phagocytosed by neighboring activated microglia. Pretreatment of the cells with
      the caspase-3-like protease inhibitor N-acetyl-Asp-Glu-Val-Asp-aldehyde did not
      reverse this cell death. Although Bcl-2 overexpression in the cells caused the
      inhibition of caspase-3-like protease activity and DNA fragmentation and the
      effective interference of apoptosis induced by deprivation of trophic factors, it
      could not suppress the activated microglia-induced neuronal death. At the
      electron microscopic level, degenerating cells with high levels of Bcl-2 were
      characterized by slightly condensed chromatins forming irregular-shaped masses,
      severely disintegrated perikarya, and marked vacuolation. Various protease
      inhibitors tested did not inhibit this cell death, whereas the radical oxygen
      species scavenger N-acetyl-L-cysteine significantly suppressed this death.
      Altogether, our study provides an alternative death pathway for the activated
      microglia-induced neuronal death by blockage of the caspase-3 protease cascade.

PMID- 10336473
TI  - Hypoxia and vascular endothelial growth factor selectively up-regulate
      angiopoietin-2 in bovine microvascular endothelial cells.
AB  - Recent studies have shown that the angiopoietin-Tie2 system is a predominant
      regulator of vascular integrity. In this study, we investigated the effect of two
      known angiogenic stimuli, hypoxia and vascular endothelial growth factor (VEGF),
      on these molecules. VEGF induced both a time- and concentration-dependent
      increase in angiopoietin-2 (Ang2) mRNA expression in bovine microvascular
      endothelial cells. This up-regulation was derived primarily from an increased
      transcription rate as evidenced by nuclear run-on assay and mRNA decay study. The
      increased Ang2 expression upon VEGF treatment was almost totally abolished by
      inhibition of tyrosine kinase or mitogen-activated protein kinase and partially
      by suppression of protein kinase C. Hypoxia also directly increased Ang2 mRNA
      expression. In contrast, Ang1 and Tie2 responded to neither of these stimuli. The
      enhanced Ang2 expression following VEGF stimulation and hypoxia was accompanied
      by de novo protein synthesis as detected by immunoprecipitation. In a mouse model
      of ischemia-induced retinal neovascularization, Ang2 mRNA was up-regulated in the
      ischemic inner retinal layer, and remarkable expression was observed in
      neovascular vessels. These data suggest that both hypoxia- and VEGF-induced
      neovascularization might be facilitated by selective induction of Ang2, which
      deteriorates the integrity of preexisting vasculature.

PMID- 10336474
TI  - Functional differences of two forms of the inhibitor of caspase-activated DNase,
      ICAD-L, and ICAD-S.
AB  - Caspase-activated DNase (CAD) is responsible for the DNA fragmentation that
      occurs during apoptosis. CAD is complexed with an inhibitor of CAD (ICAD) in non
      apoptotic, growing cells. Here, we report that mouse WR19L and human Jurkat T
      lymphoma cells express two alternative forms of ICAD, ICAD-L and ICAD-S, at
      similar levels. CAD was predominantly associated with ICAD-L in these cell lines.
      When CAD was expressed alone in Sf9 cells, it was found in insoluble fractions.
      However, when CAD was co-expressed with ICAD-L and ICAD-S, it was recovered as a
      soluble protein complexed predominantly with ICAD-L. In vitro transcription and
      translation of CAD cDNA did not produce a functional protein. Addition of ICAD-L
      but not ICAD-S to the assay mixture resulted in the synthesis of functional CAD.
      These results indicated that ICAD-L but not ICAD-S works as a specific chaperone
      for CAD, facilitating its correct folding during synthesis. Recombinant CAD, as a
      complex with ICAD-L, was then produced in Sf9 cells. The complex was treated with
      caspase 3, and CAD was purified to homogeneity. The purified CAD had DNase
      activity with a high specific activity.

PMID- 10336475
TI  - Signal transduction and hormone-dependent internalization of the thyrotropin
      releasing hormone receptor in cells lacking Gq and G11.
AB  - The thyrotropin-releasing hormone (TRH) receptor was expressed in embryonic
      fibroblasts from mice lacking the alpha subunits of Gq and G11 (Fq/11 cells) to
      determine whether G protein coupling is necessary for agonist-dependent receptor
      internalization. Neither TRH nor agonists acting on endogenous receptors
      increased intracellular calcium unless the cells were co-transfected with the
      alpha subunit of Gq. In contrast, temperature-dependent internalization of
      [3H]MeTRH in Fq/11 cells was the same whether Gqalpha was expressed or not. A
      rhodamine-labeled TRH analog and fluorescein-labeled transferrin co-localized in
      endocytic vesicles in Fq/11 cells, indicating that endocytosis took place via the
      normal clathrin pathway. Cotransfection with beta-arrestin or V53D beta-arrestin
      increased TRH-dependent receptor sequestration. Fq/11 cells were co-transfected
      with the TRH receptor and a green fluorescent protein (GFP)-beta-arrestin
      conjugate. GFP-beta-arrestin was uniformly distributed in the cytoplasm of
      untreated cells and quickly translocated to the periphery of the cells when TRH
      was added. A truncated TRH receptor that lacks potential phosphorylation sites in
      the cytoplasmic carboxyl terminus signaled but did not internalize or cause
      membrane localization of GFP-beta-arrestin. These results prove that calcium
      signaling by the TRH receptor requires coupling to a G protein in the Gq family,
      but TRH-dependent binding of beta-arrestin and sequestration do not.

PMID- 10336476
TI  - Hepatitis C virus core protein binds to a DEAD box RNA helicase.
AB  - Approximately 4 million Americans are infected with the hepatitis C virus (HCV),
      making it a major cause of chronic liver disease. Because of the lack of an
      efficient cell culture system, little is known about the interaction between HCV
      and host cells. We performed a yeast two-hybrid screen of a human liver cell cDNA
      library with HCV core protein as bait and isolated the DEAD box protein DBX. DBX
      has significant amino acid sequence identity to mouse PL10, an ATP-dependent RNA
      helicase. The binding of DBX to HCV core protein occurred in an in vitro binding
      assay in the presence of 1 M NaCl or detergent. When expressed in mammalian
      cells, HCV core protein and DBX were co-localized at the endoplasmic reticulum.
      In a mutant strain of Saccharomyces cerevisiae, DBX complemented the function of
      Ded1p, an essential DEAD box RNA helicase. HCV core protein inhibited the growth
      of DBX-complemented mutant yeast but not Ded1p-expressing yeast. HCV core protein
      also inhibited the in vitro translation of capped but not uncapped RNA. These
      findings demonstrate an interaction between HCV core protein and a host cell
      protein involved in RNA translation and suggest a mechanism by which HCV may
      inhibit host cell mRNA translation.

PMID- 10336477
TI  - C5a receptor activation. Genetic identification of critical residues in four
      transmembrane helices.
AB  - Hormones and sensory stimuli activate serpentine receptors, transmembrane
      switches that relay signals to heterotrimeric guanine nucleotide-binding proteins
      (G proteins). To understand the switch mechanism, we subjected 93 amino acids in
      transmembrane helices III, V, VI, and VII of the human chemoattractant C5a
      receptor to random saturation mutagenesis. A yeast selection identified 121
      functioning mutant receptors, containing a total of 523 amino acid substitutions.
      Conserved hydrophobic residues are located on helix surfaces that face other
      helices in a modeled seven-helix bundle (Baldwin, J. M., Schertler, G. F., and
      Unger, V. M. (1997) J. Mol. Biol. 272, 144-164), whereas surfaces predicted to
      contact the surrounding lipid tolerate many substitutions. Our analysis
      identified 25 amino acid positions resistant to nonconservative substitutions.
      These appear to comprise two distinct components of the receptor switch, a
      surface at or near the extracellular membrane interface and a core cluster in the
      cytoplasmic half of the bundle. Twenty-one of the 121 mutant receptors exhibit
      constitutive activity. Amino acids substitutions in these activated receptors
      predominate in helices III and VI; other activating mutations truncate the
      receptor near the extracellular end of helix VI. These results identify key
      elements of a general mechanism for the serpentine receptor switch.

PMID- 10336478
TI  - Induction of cell shape changes through activation of the interleukin-3 common
      beta chain receptor by the RON receptor-type tyrosine kinase.
AB  - The RON receptor-type tyrosine kinase, a member of the hepatocyte growth factor
      receptor family, is a receptor for macrophage-stimulating protein (MSP).
      Recently, we observed that MSP induces morphological changes in interleukin (IL)
      3-dependent Ba/F3 cells ectopically expressing RON. We show here that stimulation
      of those cells with either MSP or IL-3 increases tyrosine phosphorylation of
      proteins of 130, 110, 90, 62, and 58 kDa and induces similar morphological
      changes, accompanied by unique nuclear shape and redistribution of F-actin. A
      tyrosine kinase inhibitor, genistein, blocked both the increase in tyrosine
      phosphorylation and morphological changes. Upon stimulation with either MSP or IL
      3, prominent tyrosine-phosphorylated pp90 was similarly co-immunoprecipitated
      with the common beta chain of IL-3 receptor (betac). Unlike IL-3, stimulation
      with MSP increased tyrosine phosphorylation of betac without activation of JAK2,
      resulting in morphological changes with modest cell growth. Confocal
      immunofluorescence analyses showed colocalization of RON, betac, and tyrosine
      phosphorylated proteins. In vitro kinase assays revealed that autophosphorylated
      RON phosphorylated betac. These results suggest that the signaling pathway for
      morphological changes through betac and its associated protein pp90 is distinct
      from the pathway for cell growth in the IL-3 signal transduction system.

PMID- 10336479
TI  - Absence of spontaneous peroxisome proliferation in enoyl-CoA Hydratase/L-3
      hydroxyacyl-CoA dehydrogenase-deficient mouse liver. Further support for the role
      of fatty acyl CoA oxidase in PPARalpha ligand metabolism.
AB  - Peroxisomes contain a classical L-hydroxy-specific peroxisome proliferator
      inducible beta-oxidation system and also a second noninducible D-hydroxy-specific
      beta-oxidation system. We previously generated mice lacking fatty acyl-CoA
      oxidase (AOX), the first enzyme of the L-hydroxy-specific classical beta
      oxidation system; these AOX-/- mice exhibited sustained activation of peroxisome
      proliferator-activated receptor alpha (PPARalpha), resulting in profound
      spontaneous peroxisome proliferation in liver cells. These observations implied
      that AOX is responsible for the metabolic degradation of PPARalpha ligands. In
      this study, the function of enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase
      (L-PBE), the second enzyme of this peroxisomal beta-oxidation system, was
      investigated by disrupting its gene. Mutant mice (L-PBE-/-) were viable and
      fertile and exhibited no detectable gross phenotypic defects. L-PBE-/- mice
      showed no hepatic steatosis and manifested no spontaneous peroxisome
      proliferation, unlike that encountered in livers of mice deficient in AOX. These
      results indicate that disruption of classical peroxisomal fatty acid beta
      oxidation system distal to AOX step does not interfere with the inactivation of
      endogenous ligands of PPARalpha, further confirming that the AOX gene is
      indispensable for the physiological regulation of this receptor. The absence of
      appreciable changes in lipid metabolism also indicates that enoyl-CoAs, generated
      in the classical system in L-PBE-/- mice are diverted to D-hydroxy-specific
      system for metabolism by D-PBE. When challenged with a peroxisome proliferator, L
      PBE-/- mice showed increases in the levels of hepatic mRNAs and proteins that are
      regulated by PPARalpha except for appreciable blunting of peroxisome
      proliferative response as compared with that observed in hepatocytes of wild type
      mice similarly treated. This blunting of peroxisome proliferative response is
      attributed to the absence of L-PBE protein in L-PBE-/- mouse liver, because all
      other proteins are induced essentially to the same extent in both wild type and L
      PBE-/- mice.

PMID- 10336480
TI  - Angiogenesis activators and inhibitors differentially regulate caveolin-1
      expression and caveolae formation in vascular endothelial cells. Angiogenesis
      inhibitors block vascular endothelial growth factor-induced down-regulation of
      caveolin-1.
AB  - Angiogenesis is the process by which new blood vessels are formed via
      proliferation of vascular endothelial cells. A variety of angiogenesis inhibitors
      that antagonize the effects of vascular endothelial growth factor (VEGF) and
      basic fibroblast growth factor (bFGF) have recently been identified. However, the
      mechanism by which these diverse angiogenesis inhibitors exert their common
      effects remains largely unknown. Caveolin-1 and -2 are known to be highly
      expressed in vascular endothelial cells both in vitro and in vivo. Here, we
      examine the potential role of caveolins in the angiogenic response. For this
      purpose, we used the well established human umbilical vein endothelial cell line,
      ECV 304. Treatment of ECV 304 cells with known angiogenic growth factors (VEGF,
      bFGF, or hepatocyte growth factor/scatter factor), resulted in a dramatic
      reduction in the expression of caveolin-1. This down-regulation event was
      selective for caveolin-1, as caveolin-2 levels remained constant under these
      conditions of growth factor stimulation. VEGF-induced down-regulation of caveolin
      1 expression also resulted in the morphological loss of cell surface caveolae
      organelles as seen by transmission electron microscopy. A variety of well
      characterized angiogenesis inhibitors (including angiostatin, fumagillin, 2
      methoxy estradiol, transforming growth factor-beta, and thalidomide) effectively
      blocked VEGF-induced down-regulation of caveolin-1 as seen by immunoblotting and
      immunofluorescence microscopy. However, treatment with angiogenesis inhibitors
      alone did not significantly affect the expression of caveolin-1. PD98059, a
      specific inhibitor of mitogen-activated protein kinase and a known angiogenesis
      inhibitor, also blocked the observed VEGF-induced down-regulation of caveolin-1.
      Furthermore, we show that caveolin-1 can function as a negative regulator of VEGF
      R (KDR) signal transduction in vivo. Thus, down-regulation of caveolin-1 may be
      an important step along the pathway toward endothelial cell proliferation.

PMID- 10336481
TI  - Effect of transforming RNA on the synthesis of a protein with a secretory signal
      sequence in vitro.
AB  - U5 small nuclear RNA itself can act as a clastogenic and transforming agent when
      transfected into cells. In the previous work, the 3' half of the U5 small nuclear
      RNA first stem structure (designated RNA3S) was capable of driving normal cells
      into tumorigenic cells when expressed with a poly(A) tail (RNA3S+). This
      transformation critically depended upon the polypurine sequence GGAGAGGAA in
      RNA3S+. In this work, we first examined the pre-beta-lactamase and luciferase
      (model secretory and nonsecretory proteins) translation with the in vitro
      synthesized RNA3S in rabbit reticulocyte lysate. The capped RNA3S with a poly(A)
      tail suppressed the translation. In addition, the polypurine sequence played a
      crucial role in affecting the secretory protein synthesis, indicating a primary
      action of RNA3S+. Further studies revealed that the oligodeoxynucleotides,
      corresponding to the polypurine and its antisense sequences, directly contacted
      28 S rRNA in ribosome and 7SL RNA in signal recognition particle, respectively,
      and differentially affected the nascent chain elongation of secretory protein
      synthesis. These results suggest that RNA3S+ blocks a physiological regulatory
      function played by signal recognition particle and the ribosome in the secretory
      protein synthesis and support the idea that the transformation might result from
      a repressed cellular activity.

PMID- 10336482
TI  - Inhibitory effect of a self-derived peptide on glucosyltransferase of
      Streptococcus mutans. Possible novel anticaries measures.
AB  - Glucosyltransferase (GTF) plays an important role in the development of dental
      caries. We examined the possible presence of self-inhibitory segments within the
      enzyme molecule for the purpose of developing anticaries measures through GTF
      inhibition. Twenty-two synthetic peptides derived from various regions presumably
      responsible for insoluble-glucan synthesis were studied with respect to their
      effects on catalytic activity. One of them, which is identical in amino acid
      sequence to residues 1176-1194, significantly and specifically inhibited both
      sucrose hydrolysis and glucosyl transfer to glucan by GTF-I. Double-reciprocal
      analysis revealed that the inhibition is noncompetitive. Scramble peptides,
      composed of the identical amino acids in randomized sequence, had no effect on
      GTF-I activity. Furthermore, the peptide is tightly bound to the enzyme once
      complexed, even in the presence of sodium dodecyl sulfate (SDS). Kinetic analysis
      using an optical evanescent resonant mirror cuvette system demonstrated that the
      enzyme-peptide interaction was biphasic. These results indicate that the peptide
      directly interacts with the enzyme with high affinity and inhibits its activity
      in a sequence-specific manner. This peptide itself could possibly be an effective
      agent for prevention of dental caries, although its effectiveness may be improved
      by further modification.

PMID- 10336484
TI  - Brain myosin-V, a calmodulin-carrying myosin, binds to calmodulin-dependent
      protein kinase II and activates its kinase activity.
AB  - Myosin-V, an unconventional myosin, has two notable structural features: (i) a
      regulatory neck domain having six IQ motifs that bind calmodulin and light
      chains, and (ii) a structurally distinct tail domain likely responsible for its
      specific intracellular interactions. Myosin-V copurifies with synaptic vesicles
      via its tail domain, which also is a substrate for calmodulin-dependent protein
      kinase II. We demonstrate here that myosin-V coimmunoprecipitates with CaM-kinase
      II from a Triton X-100-solubilized fraction of isolated nerve terminals. The
      purified proteins also coimmunoprecipitate from dilute solutions and bind in
      overlay experiments on Western blots. The binding region on myosin-V was mapped
      to its proximal and medial tail domains. Autophosphorylated CaM-kinase II binds
      to the tail domain of myosin-V with an apparent Kd of 7.7 nM. Surprisingly,
      myosin-V activates CaM-kinase II activity in a Ca2+-dependent manner, without the
      need for additional CaM. The apparent activation constants for the
      autophosphorylation of CaM-kinase II were 10 and 26 nM, respectively, for myosin
      V versus CaM. The maximum incorporation of 32P into CaM-kinase II activated by
      myosin-V was twice that for CaM, suggesting that myosin-V binding to CaM-kinase
      II entails alterations in kinetic and/or phosphorylation site parameters. These
      data suggest that myosin-V, a calmodulin-carrying myosin, binds to and delivers
      CaM to CaM-kinase II, a calmodulin-dependent enzyme.

PMID- 10336483
TI  - Substrate recognition by Ca2+/Calmodulin-dependent protein kinase kinase. Role of
      the arg-pro-rich insert domain.
AB  - Mammalian Ca2+/CaM-dependent protein kinase kinase (CaM-KK) has been identified
      and cloned as an activator for two kinases, CaM kinase I (CaM-KI) and CaM kinase
      IV (CaM-KIV), and a recent report (Yano, S., Tokumitsu, H., and Soderling, T. R.
      (1998) Nature 396, 584-587) demonstrates that CaM-KK can also activate and
      phosphorylate protein kinase B (PKB). In this study, we identify a CaM-KK from
      Caenorhabditis elegans, and comparison of its sequence with the mammalian CaM-KK
      alpha and beta shows a unique Arg-Pro (RP)-rich insert in their catalytic domains
      relative to other protein kinases. Deletion of the RP-domain resulted in complete
      loss of CaM-KIV activation activity and physical interaction of CaM-KK with
      glutathione S-transferase-CaM-KIV (T196A). However, CaM-KK autophosphorylation
      and phosphorylation of a synthetic peptide substrate were normal in the RP-domain
      mutant. Site-directed mutagenesis of three conserved Arg in the RP- domain of CaM
      KK confirmed that these positive charges are important for CaM-KIV activation.
      The RP- domain deletion mutant also failed to fully activate and phosphorylate
      CaM-KI, but this mutant was indistinguishable from wild-type CaM-KK for the
      phosphorylation and activation of PKB. These results indicate that the RP-domain
      in CaM-KK is critical for recognition of downstream CaM-kinases but not for its
      catalytic activity (i.e. autophosphorylation) and PKB activation.

PMID- 10336485
TI  - Efficiency of importin alpha/beta-mediated nuclear localization sequence
      recognition and nuclear import. Differential role of NTF2.
AB  - Little quantitative, kinetic information is available with respect to the process
      of nuclear import of conventional nuclear localization sequence (NLS)-containing
      proteins, which initially involves recognition and docking at the nuclear pore by
      importin alpha/beta. This study compares the binding and nuclear import
      properties of mouse (m) and yeast (y) importin (IMP) subunits with respect to the
      NLSs from the SV40 large tumor antigen (T-ag), and the Xenopus laevis
      phosphoprotein N1N2. m- and y-IMPalpha recognized both NLSs, with y-IMPalpha
      exhibiting higher affinity. m-IMPbeta greatly enhanced the binding of m-IMPalpha
      to the T-ag and N1N2 NLSs, but y-IMPbeta did not significantly affect the
      affinity of y-IMPalpha for the T-ag NLS. In contrast, y-IMPbeta enhanced y
      IMPalpha binding to the NLS of N1N2, but to a lesser extent than the enhancement
      of m-IMPalpha binding by m-IMPbeta. NLS-dependent nuclear import was
      reconstituted in vitro using the different importin subunits together with the
      transport factors Ran and NTF2. Whereas T-ag NLS-mediated nuclear import did not
      exhibit an absolute requirement for NTF2, N1N2 NLS-mediated transport strictly
      required NTF2. High levels of NTF2 inhibited nuclear accumulation conferred by
      both NLSs. We conclude that different NLSs possess distinct nuclear import
      properties due to differences in recognition by importin and requirements for
      NTF2.

PMID- 10336486
TI  - Studies on the "insoluble" glycoprotein complex from human colon. Identification
      of reduction-insensitive MUC2 oligomers and C-terminal cleavage.
AB  - The "insoluble" glycoprotein complex was isolated from human colonic tissue and
      mucin subunits were prepared following reduction. Antibodies raised against
      peptide sequences within MUC2 revealed that virtually all of this mucin occurs in
      the insoluble glycoprotein complex. In addition, reduction released a 120-kDa C
      terminal MUC2 fragment, showing that proteolytic cleavage in this domain may
      occur and leave the fragment attached to the complex via disulfide bonds. The
      variable number tandem repeat region and the irregular repeat domain were
      isolated after trypsin digestion and shown to have molecular weights of 930,000
      and 180,000, respectively, suggesting a molecular weight for the entire MUC2
      monomer of approximately 1.5 million. Gel chromatography and agarose gel
      electrophoresis revealed several populations of MUC2 subunits, and analytical
      ultracentrifugation showed that these have molecular weights on the order of 2
      million, 4 million, and 5 million, corresponding to monomers, dimers, and
      trimers, respectively. Agarose gel electrophoresis of subunits from individuals
      expressing both a "long" and a "short" MUC2 allele revealed a larger number of
      populations, consistent with the presence of short and long monomers and
      oligomers arising from permutations of the two types of monomers. In addition to
      disulfide bonds, MUC2 monomers are apparently joined by a "novel," reduction
      insensitive bond.

PMID- 10336487
TI  - Down-regulation of melanocortin receptor signaling mediated by the amino terminus
      of Agouti protein in Xenopus melanophores.
AB  - Agouti protein and Agouti-related protein (Agrp) regulate pigmentation and body
      weight, respectively, by antagonizing melanocortin receptor signaling. A carboxyl
      terminal fragment of Agouti protein, Ser73-Cys131, is sufficient for melanocortin
      receptor antagonism, but Western blot analysis of skin extracts reveals that the
      electrophoretic mobility of native Agouti protein corresponds to the mature full
      length form, His23-Cys131. To investigate the potential role of the amino
      terminal residues, we compared the function of full-length and carboxyl-terminal
      fragments of Agrp and Agouti protein in a sensitive bioassay based on pigment
      dispersion in Xenopus melanophores. We find that carboxyl-terminal Agouti
      protein, and all forms of Agrp tested, act solely by competitive antagonism of
      melanocortin action. However, full-length Agouti protein acts by an additional
      mechanism that is time- and temperature-dependent, depresses maximal levels of
      pigment dispersion, and is therefore likely to be mediated by receptor down
      regulation. Apparent down-regulation is not observed for a mixture of amino
      terminal and carboxyl-terminal fragments. We propose that the phenotypic effects
      of Agouti in vivo represent a bipartite mechanism: competitive antagonism of
      agonist binding by the carboxyl-terminal portion of Agouti protein and down
      regulation of melanocortin receptor signaling by an unknown mechanism that
      requires residues in the amino terminus of the Agouti protein.

PMID- 10336488
TI  - Multiple enzymatic activities of the murein hydrolase from staphylococcal phage
      phi11. Identification of a D-alanyl-glycine endopeptidase activity.
AB  - Bacteriophage muralytic enzymes degrade the cell wall envelope of staphylococci
      to release phage particles from the bacterial cytoplasm. Murein hydrolases of
      staphylococcal phages phi11, 80alpha, 187, Twort, and phiPVL harbor a central
      domain that displays sequence homology to known N-acetylmuramyl-L-alanyl
      amidases; however, their precise cleavage sites on the staphylococcal
      peptidoglycan have thus far not been determined. Here we examined the properties
      of the phi11 enzyme to hydrolyze either the staphylococcal cell wall or purified
      cell wall anchor structures attached to surface protein. Our results show that
      the phi11 enzyme has D-alanyl-glycyl endopeptidase as well as N-acetylmuramyl-L
      alanyl amidase activity. Analysis of a deletion mutant lacking the amidase
      homologous sequence, phi11(Delta181-381), revealed that the D-alanyl-glycyl
      endopeptidase activity is contained within the N-terminal 180 amino acid residues
      of the polypeptide chain. Sequences similar to this N-terminal domain are found
      in the murein hydrolases of staphylococcal phages but not in those of phages that
      infect other Gram-positive bacteria such as Listeria or Bacillus.

PMID- 10336489
TI  - Nitric oxide inhibits c-Jun DNA binding by specifically targeted S
      glutathionylation.
AB  - This study addresses potential molecular mechanisms underlying the inhibition of
      the transcription factor c-Jun by nitric oxide. We show that in the presence of
      the physiological sulfhydryl glutathione nitric oxide modifies the two cysteine
      residues contained in the DNA binding module of c-Jun in a selective and distinct
      way. Although nitric oxide induced the formation of an intermolecular disulfide
      bridge between cysteine residues in the leucine zipper site of c-Jun monomers,
      this same radical directed the covalent incorporation of stoichiometric amounts
      of glutathione to a single conserved cysteine residue in the DNA-binding site of
      the protein. We found that covalent dimerization of c-Jun apparently did not
      affect its DNA binding activity, whereas the formation of a mixed disulfide with
      glutathione correlated well with the inhibition of transcription factor binding
      to DNA. Furthermore, we provide experimental evidence that nitric oxide-induced S
      glutathionylation and inhibition of c-Jun involves the formation of S
      nitrosoglutathione. In conclusion, our results support the reversible formation
      of a mixed disulfide between glutathione and c-Jun as a potential mechanism by
      which nitrosative stress may be transduced into a functional response at the
      level of transcription.

PMID- 10336490
TI  - Different mechanisms for thermal inactivation of Bacillus subtilis signal
      peptidase mutants.
AB  - The type I signal peptidase SipS of Bacillus subtilis is of major importance for
      the processing of secretory precursor proteins. In the present studies, we have
      investigated possible mechanisms of thermal inactivation of five temperature
      sensitive SipS mutants. The results demonstrate that two of these mutants, L74A
      and Y81A, are structurally stable but strongly impaired in catalytic activity at
      48 degrees C, showing the (unprecedented) involvement of the conserved leucine 74
      and tyrosine 81 residues in the catalytic reaction of type I signal peptidases.
      This conclusion is supported by the crystal structure of the homologous signal
      peptidase of Escherichia coli (Paetzel, M., Dalbey, R. E., and Strynadka, N. C.
      J. (1998) Nature 396, 186-190). In contrast, the SipS mutant proteins R84A, R84H,
      and D146A were inactivated by proteolytic degradation, indicating that the
      conserved arginine 84 and aspartic acid 146 residues are required to obtain a
      protease-resistant conformation. The cell wall-bound protease WprA was shown to
      be involved in the degradation of SipS D146A, which is in accord with the fact
      that SipS has a large extracytoplasmic domain. As WprA was not involved in the
      degradation of the SipS mutant proteins R84A and R84H, we conclude that multiple
      proteases are responsible for the thermal inactivation of temperature-sensitive
      SipS mutants.

PMID- 10336491
TI  - Incorporation of molybdenum into the iron-molybdenum cofactor of nitrogenase.
AB  - The biosynthesis of the iron-molybdenum cofactor (FeMo-co) of dinitrogenase was
      investigated using 99Mo to follow the incorporation of Mo into precursors. 99Mo
      label accumulates on dinitrogenase only when all known components of the FeMo-co
      synthesis system, NifH, NifNE, NifB-cofactor, homocitrate, MgATP, and reductant,
      are present. Furthermore, 99Mo label accumulates only on the gamma protein, which
      has been shown to serve as a chaperone/insertase for the maturation of
      apodinitrogenase when all known components are present. It appears that only
      completed FeMo-co can accumulate on the gamma protein. Very little FeMo-co
      synthesis was observed when all known components are used in purified forms,
      indicating that additional factors are required for optimal FeMo-co synthesis.
      99Mo did not accumulate on NifNE under any conditions tested, suggesting that Mo
      enters the pathway at some other step, although it remains possible that a Mo
      containing precursor of FeMo-co that is not sufficiently stable to persist during
      gel electrophoresis occurs but is not observed. 99Mo accumulates on several
      unidentified species, which may be the additional components required for FeMo-co
      synthesis. The molybdenum storage protein was observed and the accumulation of
      99Mo on this protein required nucleotide.

PMID- 10336492
TI  - Transient nuclear factor kappaB (NF-kappaB) activation stimulated by interleukin
      1beta may be partly dependent on proteasome activity, but not phosphorylation and
      ubiquitination of the IkappaBalpha molecule, in C6 glioma cells. Regulation of NF
      kappaB linked to chemokine production.
AB  - We previously reported that several stresses can induce cytokine-induced
      neutrophil chemoattractant expression in a nuclear factor kappaB (NF-kappaB)
      dependent manner. In this study, we focused further on the regulation of NF
      kappaB. The activation of NF-kappaB and the subsequent cytokine-induced
      neutrophil chemoattractant induction in response to interleukin-1beta (IL-1beta)
      were inhibited by proteasome inhibitors, MG132 and proteasome inhibitor I.
      Translocation of NF-kappaB into nuclei occurs by the phosphorylation, multi
      ubiquitination, and degradation of IkappaBalpha, a regulatory protein of NF
      kappaB. Nascent IkappaBalpha began to degrade 5 min after treatment with IL-1beta
      and disappeared completely after 15 min. However, IkappaBalpha returned to basal
      levels after 45-60 min. Interestingly, resynthesized IkappaBalpha was already
      phosphorylated at Ser-32. These results suggest that 1) the upstream signals are
      still activated, although the translocation of NF-kappaB peaks at 15 min; and 2)
      the regulated protein(s) acts downstream of IkappaBalpha phosphorylation. Western
      blotting showed that the resynthesized and phosphorylated IkappaB molecules were
      also upward-shifted by multi-ubiquitination in response to IL-1beta treatment. On
      the other hand, ATP-dependent Leu-Leu-Val-Tyr cleaving activity transiently
      increased, peaked at 15 min, and then decreased to basal levels at 60 min.
      Furthermore, the cytosolic fraction that was stimulated by IL-1beta for 15 min,
      but not for 0 and 60 min, could degrade phosphorylated and multi-ubiquitinated
      IkappaBalpha. These results indicate that the transient translocation of NF
      kappaB in response to IL-1beta may be partly dependent on transient proteasome
      activation.

PMID- 10336493
TI  - Activation of the murine dihydrofolate reductase promoter by E2F1. A requirement
      for CBP recruitment.
AB  - The E2F family of heterodimeric transcription factors plays an important role in
      the regulation of gene expression at the G1/S phase transition of the mammalian
      cell cycle. Previously, we have demonstrated that cell cycle regulation of murine
      dihydrofolate reductase (dhfr) expression requires E2F-mediated activation of the
      dhfr promoter in S phase. To investigate the mechanism by which E2F activates an
      authentic E2F-regulated promoter, we precisely replaced the E2F binding site in
      the dhfr promoter with a Gal4 binding site. Using Gal4-E2F1 derivatives, we found
      that E2F1 amino acids 409-437 contain a potent core transactivation domain.
      Functional analysis of the E2F1 core domain demonstrated that replacement of
      phenylalanine residues 413, 425, and 429 with alanine reduces both
      transcriptional activation of the dhfr promoter and protein-protein interactions
      with CBP, transcription factor (TF) IIH, and TATA-binding protein (TBP). However,
      additional amino acid substitutions for phenylalanine 429 demonstrated a strong
      correlation between activation of the dhfr promoter and binding of CBP, but not
      TFIIH or TBP. Finally, transactivator bypass experiments indicated that direct
      recruitment of CBP is sufficient for activation of the dhfr promoter. Therefore,
      we suggest that recruitment of CBP is one mechanism by which E2F activates the
      dhfr promoter.

PMID- 10336494
TI  - Sulfation of chondroitin sulfate in human articular cartilage. The effect of age,
      topographical position, and zone of cartilage on tissue composition.
AB  - The chondroitin ABC lyase digestion products of normal human femoral condyle
      articular cartilage and of purified aggrecan were analyzed for their mono- and
      nonsulfated disaccharide composition. Changes in the total tissue chemistry were
      most pronounced during the period from birth to 20 years of age, when the 
      [GlcAbeta,3GalNAc6]- disaccharide content increased from approximately 50% to 85%
      of the total disaccharide content and there was a concomitant decrease in the
      content of the 4-sulfated disaccharide. In general, the disaccharide content of
      the deeper layers of immature cartilage were richer in the 4-sulfated residue
      than the upper regions of the tissue. As the tissue aged and decreased in
      thickness, the disaccharide composition became more evenly 6-sulfated. The newly
      synthesized chondroitin sulfate chains had a similar composition to the
      endogenous chains and also underwent the same age and zonal changes. The
      monoclonal antisera 3B3(+) and 2B6(+) were used to immunolocalize the unsaturated
      6- and 4-sulfated residues generated at the reducing termini of the chondroitin
      sulfate chains by digestion with chondroitin ABC lyase, and these analyses
      indicated that the sulfation pattern at this position did not necessarily reflect
      the internal disaccharide composition of the chains. In summary, the sulfation
      pattern of chondroitin sulfate disaccharides from human normal articular
      cartilage varies with the age of the specimen, the position (topography) on the
      joint surface, and the zone of cartilage analyzed. Furthermore, these changes in
      composition are a consequence of both extracellular, post-translational
      processing of the core protein of aggrecan and changes in the sulfotransferase
      activity of the chondrocyte.

PMID- 10336495
TI  - Identification of nuclear receptor corepressor as a peroxisome proliferator
      activated receptor alpha interacting protein.
AB  - Nuclear receptor corepressor (NCoR) was demonstrated to interact strongly with
      peroxisome proliferator-activated receptor alpha (PPARalpha), and PPARalpha
      ligands suppressed this interaction. In contrast to the interaction of PPARalpha
      with the coactivator protein, p300, association of the receptor with NCoR did not
      require any part of the PPARalpha ligand binding domain. NCoR was found to
      suppress PPARalpha-dependent transcriptional activation in the context of a
      PPARalpha.retinoid X receptor alpha (RXRalpha) heterodimeric complex bound to a
      peroxisome proliferator-responsive element in human embryonic kidney 293 cells.
      This repression was reversed agonists of either receptor demonstrating a
      functional interaction between NCoR and PPARalpha.RXRalpha heterodimeric
      complexes in mammalian cells. NCoR appears to influence PPARalpha signaling
      pathways and, therefore, may modulate tissue responsiveness to peroxisome
      proliferators.

PMID- 10336496
TI  - High affinity interactions of nucleolin with G-G-paired rDNA.
AB  - Nucleolin is a very abundant eukaryotic protein that localizes to the nucleolus,
      where the rDNA undergoes transcription, replication, and recombination and where
      rRNA processing occurs. The top (non-template) strand of the rDNA is very guanine
      rich and has considerable potential to form structures stabilized by G-G pairing.
      We have assayed binding of endogenous and recombinant nucleolin to synthetic
      oligonucleotides in which G-rich regions have formed intermolecular G-G pairs to
      produce either two-stranded G2 or four-stranded G4 DNA. We report that nucleolin
      binds G-G-paired DNA with very high affinity; the dissociation constant for
      interaction with G4 DNA is KD = 1 nM. Two separate domains of nucleolin can
      interact with G-G-paired DNA, the four RNA binding domains and the C-terminal Arg
      Gly-Gly repeats. Both domains bind G4 DNA with high specificity and recognize G4
      DNA structure independent of sequence context. The high affinity of the
      nucleolin/G4 DNA interaction identifies G-G-paired structures as natural binding
      targets of nucleolin in the nucleolus. The ability of two independent domains of
      nucleolin to bind G-G-paired structures suggests that nucleolin can function as
      an architectural factor in rDNA transcription, replication, or recombination.

PMID- 10336497
TI  - Recombinant SFD isoforms activate vacuolar proton pumps.
AB  - The vacuolar proton pump of clathrin-coated vesicles is composed of two general
      sectors, a cytosolic, ATP hydrolytic domain (V1) and an intramembranous proton
      channel, V0. V1 is comprised of 8-9 subunits including polypeptides of 50 and 57
      kDa, termed SFD (Sub Fifty-eight-kDa Doublet). Although SFD is essential to the
      activation of ATPase and proton pumping activities catalyzed by holoenzyme, its
      constituent polypeptides have not been separated to determine their respective
      roles in ATPase functions. Recent molecular characterization of these subunits
      revealed that they are isoforms that arise through an alternative splicing
      mechanism (Zhou, Z., Peng, S.-B., Crider, B.P., Slaughter, C., Xie, X.S., and
      Stone, D.K. (1998) J. Biol. Chem. 273, 5878-5884). To determine the functional
      characteristics of the 57-kDa (SFDalpha)1 and 50-kDa (SFDbeta) isoforms, we
      expressed these proteins in Escherichia coli. We determined that purified
      recombinant proteins, rSFDalpha and rSFDbeta, when reassembled with SFD-depleted
      holoenzyme, are functionally interchangeable in restoration of ATPase and proton
      pumping activities. In addition, we determined that the V-pump of chromaffin
      granules has only the SFDalpha isoform in its native state and that rSFDalpha and
      rSFDbeta are equally effective in restoring ATPase and proton pumping activities
      to SFD-depleted enzyme. Finally, we found that SFDalpha and SFDbeta structurally
      interact not only with V1, but also withV0, indicating that these activator
      subunits may play both structural and functional roles in coupling ATP hydrolysis
      to proton flow.

PMID- 10336498
TI  - "Action-at-a-distance" mutagenesis. 8-oxo-7, 8-dihydro-2'-deoxyguanosine causes
      base substitution errors at neighboring template sites when copied by DNA
      polymerase beta.
AB  - 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), a common oxidative DNA lesion,
      favors a syn-conformation in DNA, enabling formation of stable 8-oxo-dG.A base
      mispairs resulting in G.C --> T.A transversion mutations. When human DNA
      polymerase (pol) beta was used to copy a short single-stranded gap containing a
      site-directed 8-oxo-dG lesion, incorporation of dAMP opposite 8-oxo-dG was
      slightly favored over dCMP depending on "downstream" sequence context.
      Unexpectedly, however, a significant increase in dCMP.A and dGMP.A mispairs was
      also observed at the "upstream" 3'-template site adjacent to the lesion. Errors
      at these undamaged template sites occurred in four sequence contexts with both
      gapped and primed single-stranded DNA templates, but not when pol alpha replaced
      pol beta. Error rates at sites adjacent to 8-oxo-dG were roughly 1% of the values
      opposite 8-oxo-dG, potentially generating tandem mutations during in vivo short
      gap repair synthesis by pol beta. When 8-oxo-dG was replaced with 8-bromo-2'
      deoxyguanosine, incorporation of dCMP was strongly favored by both enzymes, with
      no detectable misincorporation occurring at neighboring template sites.

PMID- 10336499
TI  - Comparison of paclitaxel-, 5-fluoro-2'-deoxyuridine-, and epidermal growth factor
      (EGF)-induced apoptosis. Evidence for EGF-induced anoikis.
AB  - Epidermal growth factor (EGF), a hormone that stimulates proliferation of many
      cell types, induces apoptosis in some cell lines that overexpress the EGF
      receptor. To evaluate the mechanism of EGF-induced apoptosis, MDA-MB-468 breast
      cancer cells were examined by microscopy, flow cytometry, immunoblotting, enzyme
      assays, and affinity labeling after treatment with EGF, paclitaxel, or 5-fluoro
      2'-deoxyuridine (5FUdR). Apoptosis induced by all three agents was accompanied by
      activation of caspases-3, -6, and -7, as indicated by disappearance of the
      corresponding zymogens from immunoblots, cleavage of substrate polypeptides in
      situ, and detection of active forms of these caspases in cytosol and nuclei using
      fluorogenic assays and affinity labeling. Further analysis indicated involvement
      of the cytochrome c/Apaf-1/caspase-9 pathway of caspase activation, but not the
      Fas/Fas ligand pathway. Interestingly, caspase activation was consistently lower
      after EGF treatment than after paclitaxel or 5FUdR treatment. Additional
      experiments revealed that the majority of cells detaching from the substratum
      after EGF (but not paclitaxel or 5FUdR) were morphologically normal and retained
      the capacity to readhere, suggesting that EGF-induced apoptosis involves cell
      detachment followed by anoikis. These observations not only indicate that EGF-
      and chemotherapy-induced apoptosis in this cell line involve the same downstream
      pathways but also suggest that detachment-induced apoptosis is responsible for
      the paradoxical antiproliferative effects of EGF.

PMID- 10336500
TI  - A di-acidic (DXE) code directs concentration of cargo during export from the
      endoplasmic reticulum.
AB  - Efficient export of vesicular stomatitis virus glycoprotein (VSV-G), a type I
      transmembrane protein, from the endoplasmic reticulum requires a di-acidic code
      (DXE) located in the cytosolic carboxyl-terminal tail (Nishimura, N., and Balch,
      W. E. (1997) Science 277, 556-558). Mutation of the DXE code by mutation to AXA
      did not prevent VSV-G recruitment to pre-budding complexes formed in the presence
      of the activated form of the Sar1 and the Sec23/24 complex, components of the
      COPII budding machinery. However, the signal was required at a subsequent
      concentration step preceding vesicle fission. By using green fluorescence protein
      tagged VSV-G to image movement in a single cell, we found that VSV-G lacking the
      DXE code fails to be concentrated into COPII vesicles. As a result, the normal 5
      10-fold increase in the steady-state concentration of VSV-G in downstream pre
      Golgi intermediates and Golgi compartments was lost. These results demonstrate
      for the first time that inactivation of the DXE signal uncouples early cargo
      selection steps from concentration into COPII vesicles. We propose that two
      sequential steps are required for efficient export from the endoplasmic
      reticulum.

PMID- 10336501
TI  - Specificity for fibroblast growth factors determined by heparan sulfate in a
      binary complex with the receptor kinase.
AB  - A divalent cation-dependent association between heparin or heparan sulfate and
      the ectodomain of the FGF receptor kinase (FGFR) restricts FGF-independent trans
      phosphorylation and supports the binding of activating FGF to self-associated
      FGFR. Here we show that in contrast to heparin, cellular heparan sulfate forms a
      binary complex with FGFR that discriminates between FGF-1 and FGF-2. FGFR type 4
      (FGFR4) in liver parenchymal cells binds only FGF-1, whereas FGFR1 binds FGF-1
      and FGF-2 equally. Cell-free complexes of heparin and recombinant FGFR4 bound FGF
      1 and FGF-2 equally. However, in contrast to FGFR1, when recombinant FGFR4 was
      expressed back in epithelial cells by transfection, it failed to bind FGF-2
      unless heparan sulfate was depressed by chlorate or heparinase treatment.
      Isolated heparan sulfate proteoglycan (HSPG) from liver cells in cell-free
      complexes with FGFR4 restored the specificity for FGF-1 and supported the binding
      of both FGF-1 and FGF-2 when complexed with FGFR1. In contrast, FGF-2 bound
      equally well to complexes of both FGFR1 and FGFR4 formed with endothelial cell
      derived HSPG, but the endothelial HSPG was deficient for the binding of FGF-1 to
      both FGFR complexes. These data suggest that a heparan sulfate subunit is a cell
      type- and FGFR-specific determinant of the selectivity of the FGFR signaling
      complex for FGF. In a physiological context, the heparan sulfate subunit may
      limit the redundancy among the current 18 FGF polypeptides for the 4 known FGFR.

PMID- 10336502
TI  - Expression, abundance, and RNA polymerase binding properties of the delta factor
      of Bacillus subtilis.
AB  - The delta protein is a dispensable subunit of Bacillus subtilis RNA polymerase
      (RNAP) that has major effects on the biochemical properties of the purified
      enzyme. In the presence of delta, RNAP displays an increased specificity of
      transcription, a decreased affinity for nucleic acids, and an increased
      efficiency of RNA synthesis because of enhanced recycling. Despite these profound
      effects, a strain containing a deletion of the delta gene (rpoE) is viable and
      shows no major alterations in gene expression. Quantitative immunoblotting
      experiments demonstrate that delta is present in molar excess relative to RNAP in
      both vegetative cells and spores. Expression of rpoE initiates from a single,
      sigmaA-dependent promoter and is maximal in transition phase. A rpoE mutant
      strain has an altered morphology and is delayed in the exit from stationary
      phase. For biochemical analyses we have created derivatives of delta and sigmaA
      that can be radiolabeled with protein kinase A. Using electrophoretic mobility
      shift assays, we demonstrate that delta binds core RNAP with an apparent affinity
      of 2.5 x 10(6) M-1, but we are unable to demonstrate the formation of a ternary
      complex containing core enzyme, delta, and sigmaA.

PMID- 10336503
TI  - B cell-specific activator protein prevents two activator factors from binding to
      the immunoglobulin J chain promoter until the antigen-driven stages of B cell
      development.
AB  - The immunoglobulin J chain gene is inducibly transcribed in mature B cells upon
      antigen recognition and a signal from interleukin-2 (IL-2). B cell-specific
      activator protein (BSAP), a transcription factor that silences J chain
      transcription, has been identified as a nuclear target of the IL-2 signal. The
      levels of BSAP progressively decrease in response to IL-2 and this change
      correlates with the differentiation of B cells into antibody secreting plasma
      cells. Here we report the binding of the upstream stimulatory factor (USF) to an
      E-box motif immediately upstream from the BSAP site on the J chain promoter.
      Mutations in the USF binding motif significantly decrease J chain promoter
      activity in J chain expressing B cell lines. We also show that a functional
      relationship exists between USF and a second J chain positive-regulating factor,
      B-MEF2, using co-immunoprecipitation assays and transfections. Finally, we
      provide evidence that the binding of BSAP prevents USF and B-MEF2 from
      interacting with the J chain promoter during the antigen-independent stages of B
      cell development. It is not until the levels of BSAP decrease during the antigen
      driven stages of B cell development that both USF and B-MEF2 are able to bind to
      their respective promoter elements and activate J chain transcription.

PMID- 10336504
TI  - Pharmacokinetic advantage of intra-arterial cyclosporin A delivery to vascularly
      isolated rabbit forelimb. I. Model development.
AB  - Effective antirejection therapy with minimal systemic morbidity is required if
      limb transplantation is to become a clinical reality. We investigated whether
      i.a. infusion of cyclosporin A (CSA) into the vascularly isolated rabbit forelimb
      will distribute drug homogeneously to the tissues and produce higher local drug
      levels than same-dose i.v. treatment, thereby improving the therapeutic index.
      CSA 4.0 mg/kg/day was infused continuously via osmotic minipump into either the
      right brachial artery (i.a. group) or jugular vein (i.v. group) of New Zealand
      rabbits. Ligation of all muscles at the right mid-arm level was performed in the
      i.a. group to eliminate collateral circulation and simulate allografting, while
      leaving bone and neurovasculature intact. On day 6, CSA concentrations were
      measured in skin, muscle, bone, and bone marrow samples taken from different
      compartments of the right and left forearms in the i.a. group and right forearm
      only in the i.v. group. There were no significant differences between
      compartmental CSA levels in all tissues examined on the locally treated, right
      side during i.a. infusion, indicating that drug streaming from the catheter tip
      is not occurring in our model. During i.a. infusion, mean CSA concentrations were
      4- to 7-fold higher in the right limb than in the left limb in all four tissues
      examined. Tissue CSA levels in the left limb were equivalent to those achieved
      during i.v. infusion, but CSA concentrations in blood, kidney, and liver were
      higher during i.a. infusion. These favorable, preliminary, single-dose
      pharmacokinetic results warrant further investigation in our novel rabbit model.

PMID- 10336505
TI  - Pharmacokinetic advantage of intra-arterial cyclosporin A delivery to vascularly
      isolated rabbit forelimb. II. Dose dependence.
AB  - A vascularly isolated rabbit forelimb model simulating conditions of composite
      tissue allografting was used to determine the regional pharmacokinetic advantage
      achievable in extremity tissue components during i.a. cyclosporin A (CSA)
      administration. CSA was infused continuously via osmotic minipump into the right
      brachial artery of New Zealand rabbits at multiple doses ranging from 1.0 to 8.0
      mg/kg/day. On day 6, CSA concentrations were measured in aortic whole blood, as
      well as in skin, muscle, bone, and bone marrow samples from both right and left
      forelimbs. The variation of right-sided mean CSA concentrations with dose was
      tissue dependent and saturable in the case of skin and bone, whereas left-sided
      tissue concentrations correlated significantly with systemic blood levels. At 1.0
      mg/kg/day, there were no significant differences between right and left mean CSA
      concentrations for all four tissues examined. However, with a doubling of the
      i.a. dose, huge increases in local tissue CSA concentrations were produced with
      only very modest increases in systemic whole-blood and tissue drug levels,
      resulting in a 4-fold regional advantage (right/left ratio of CSA concentrations)
      in bone and bone marrow, 7-fold in muscle, and 14-fold in skin. With further dose
      increases to 8.0 mg/kg/day, the regional advantage decreased to 4-fold in skin,
      increased to 9-fold in bone marrow, remained relatively constant in bone, and
      initially decreased and then increased to 9-fold in muscle. These favorable
      pharmacokinetic results suggest that reduced, local doses of CSA might be useful
      in preventing extremity composite tissue allograft rejection with decreased
      systemic drug exposure.

PMID- 10336506
TI  - Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated
      rabbit forelimb.
AB  - A vascularly isolated rabbit forelimb model simulating conditions of composite
      tissue allografting was used to determine the regional pharmacokinetic advantage
      achievable in extremity tissue components during i.a. tacrolimus (FK506)
      administration. FK506 was infused continuously via osmotic minipump into the
      right brachial artery of New Zealand rabbits at 0.05, 0.1, and 0.2 mg/kg/day. On
      day 6, FK506 concentrations were measured in aortic whole blood, heart, lung,
      liver, kidney, spleen, and fat, as well as in skin, muscle, bone, and bone marrow
      samples from both right and left forelimbs. The relative tissue concentrations of
      FK506 in descending order were [spleen approximately lung approximately kidney] >
      [heart approximately skin approximately muscle] > [fat approximately bone marrow]
      > [liver approximately bone approximately blood]. In marked contrast to previous
      results with i.a. cyclosporin A infusion, only a minimal regional advantage of
      local FK506 delivery (mean right/left concentration ratios 1.0-1.4) was obtained
      in all forearm tissues over the dose range studied. For each limb tissue, left
      sided FK506 concentrations significantly correlated with systemic blood levels,
      and the left-sided tissue-to-whole-blood concentration ratio did not vary
      significantly with dose. We conclude that FK506 is pharmacokinetically inferior
      to cyclosporin A for continuous i.a. administration to the vascularly isolated
      rabbit forelimb, and hypothesize that this difference is the result of
      differences in the distribution of each drug within whole blood. Our findings
      suggest that, despite its demonstrated efficacy in experimental and clinical
      transplantation, FK506 would not be an appropriate immunosuppressant to deliver
      via the i.a. route for prevention of limb allograft rejection.

PMID- 10336508
TI  - Long-term regulation of locus ceruleus sensitivity to corticotropin-releasing
      factor by swim stress.
AB  - Corticotropin-releasing factor (CRF) acts as a putative neurotransmitter in the
      locus ceruleus (LC) to mediate its activation by certain stressors. In this
      study, we quantified LC sensitivity to CRF 24 h after swim stress, at a time when
      behavioral depression that is sensitive to antidepressants is apparent. Rats were
      placed in a tank with 30 cm (swim stress) or 4 cm water and 24 h later, either
      behavior was monitored in a forced swim test or LC discharge was recorded. Swim
      stress rats were more immobile than control animals in the swim test. LC neurons
      of swim stress rats were sensitized to low doses of CRF (0.1-0.3 microgram
      i.c.v.) that were ineffective in control animals and were desensitized to higher
      doses. Swim stress selectively altered LC sensitivity to CRF because neither LC
      spontaneous discharge nor responses to other agents (e.g., carbachol, vasoactive
      intestinal peptide) were altered. Finally, the mechanism for sensitization was
      localized to the LC because neuronal activation by low doses of CRF was prevented
      by the intracerulear administration of a CRF antagonist. CRF dose-response curves
      were consistent with a two-site model with similar dissociation constants under
      control conditions but divergent dissociation constants after swim stress. The
      results suggest that swim stress (and perhaps other stressors) functionally
      alters CRF receptors that have an impact on LC activity. Stress-induced
      regulation of LC sensitivity to CRF may underlie behavioral aspects of stress
      related psychiatric disorders.

PMID- 10336507
TI  - Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the
      neurotrophic action of FK506.
AB  - The neurotrophic property of the immunosuppressant drug FK506 (tacrolimus) is
      believed to depend on the 12-kDa FK506-binding protein (FKBP-12). Here, we show
      that FK506 maintains its neurotrophic activity in primary hippocampal cell
      cultures from FKBP-12 knockout mice. In human neuroblastoma SH-SY5Y cells, the
      neurotrophic action of FK506 (10 pM to 10 nM) is completely prevented by the
      addition of a monoclonal antibody (50-100 nM) to the immunophilin FKBP-52 (also
      known as FKBP-59 or heat shock protein 56), a component of mature steroid
      receptor complexes. By itself, the FKBP-52 antibody is also neurotrophic. The
      neurotrophic activity of dexamethasone (50 nM) is potentiated by FK506, whereas
      that of beta-estradiol (50 nM) is not altered, suggesting a common mechanisms of
      action. Geldanamycin (which disrupts mature steroid receptor complexes) is also
      neurotrophic (0.1-10 nM), whereas it reduces the neurotrophic activity of FK506
      and steroid hormones (dexamethasone and beta-estradiol). Conversely, 20 mM
      molybdate (which prevents the disruption of mature steroid receptor complexes)
      decreases the neurotrophic activity of FK506, FKBP-52 antibody, dexamethasone,
      and beta-estradiol. In rats, FK506 (10 mg/kg s.c.) augments the regenerative
      response of regenerating motor and sensory neurons to nerve injury as shown by
      its ability to increase the axotomy-induced induction of c-jun expression. A
      model is proposed to account for the neurotrophic action of both
      neuroimmunophilin ligands (FK506) and steroid hormones. Components of steroid
      receptor complexes represent novel targets for the rational design of new
      neurotrophic drugs.

PMID- 10336509
TI  - Pharmacological analysis of the novel mode of interaction between xanomeline and
      the M1 muscarinic acetylcholine receptor.
AB  - Previous findings in our laboratory suggested that the M1 muscarinic
      acetylcholine receptor (mAChR) agonist xanomeline exhibits a novel mode of
      interaction that involves persistent binding to and activation of the M1 mAChR,
      subsequent to extensive washout, as well as a possible insurmountable element. In
      the present study, we examined this interaction in greater detail, using Chinese
      hamster ovary cells transfected with the genes for the M1 mAChR and neuronal
      nitric oxide synthase. Pretreatment of cells with xanomeline, followed by
      extensive washout, resulted in elevated basal levels of neuronal nitric oxide
      synthase activity that were suppressed by the antagonists atropine or pirenzepine
      in a concentration-dependent manner. Analysis of the data yielded estimates of
      Schild slope factors and pKB values for the antagonists that were consistent with
      a model of simple competition between these latter agents and the persistently
      bound form of xanomeline. The ability of the antagonists to produce parallel
      dextral shifts of the concentration-response curves to carbachol and xanomeline
      was also investigated. The interaction between xanomeline and pirenzepine
      appeared to be insurmountable, but this may have been due to an equilibrium
      artifact. In contrast, the interaction between xanomeline and atropine conformed
      to a model of competition, indicating that the mode of interaction of free
      xanomeline at the M1 mAChR is pharmacologically identical with that of the
      persistently bound form. Radioligand binding studies also showed that the
      presence of various concentrations of xanomeline had no significant effect on the
      calculated affinity of atropine or pirenzepine in inhibiting the binding of [3H]N
      methylscopolamine. Overall, these findings suggest that the persistent attachment
      of xanomeline to the M1 mAChR does not prevent this agonist from interacting with
      the classic binding site in a competitive fashion.

PMID- 10336510
TI  - Pharmacological characterization of nicotine's interaction with cocaine and
      cocaine analogs.
AB  - Cocaine and a number of 3beta-phenyltropane cocaine analogs were investigated for
      their potential to block various pharmacological effects of nicotine in animals.
      They blocked the antinociceptive effect of nicotine in the tail-flick test after
      systemic administration in a dose-dependent manner. Similarly, cocaine was also
      able to block nicotine-induced motor impairment in mice. Furthermore, cocaine
      blocked nicotine-induced seizures at a lower potency than for antinociception,
      but failed to block nicotine's effect on body temperature and drug
      discrimination. The antagonistic potencies of the 3beta-phenyltropane cocaine
      analogs were not correlated with their affinity for monoamines transporters.
      Additionally, bupropion, nomifensin, GBR 12909, and nisoxetine, but not
      methylphenidate and fluoxetine, blocked nicotine-induced antinociception;
      however, their antagonistic potencies were unrelated to their affinities for the
      transporters. Taken together, these results suggest that the mechanism of
      cocaine's antagonistic activity is not related to its binding and uptake of
      inhibition on monoamine neurotransporters. The failure of lidocaine and procaine
      to antagonize nicotine's effects in the tail-flick assay rules out local
      anesthetic effects. In addition, cocaine blocked differentially the response of
      nicotine in the oocyte receptor expression system for the alpha4beta2 and
      alpha3beta2 subtypes in a dose-dependent manner. Our results suggest that cocaine
      is a noncompetitive nicotinic antagonist with some selectivity for neuronal
      nicotinic receptor subtypes. Our studies also demonstrate that 3beta
      phenyltropane analogs constitute a new class of nicotinic antagonists.
      Elucidation of the mechanism of action of this new class of antagonists may
      provide an explanation for the effectiveness of agents such as bupropion for the
      treatment of smoking cessation.

PMID- 10336511
TI  - Vasorelaxing action of rutaecarpine: effects of rutaecarpine on calcium channel
      activities in vascular endothelial and smooth muscle cells.
AB  - Rutaecarpine (Rut) has been shown to induce hypotension and vasorelaxation. In
      vitro studies indicated that the vasorelaxant effect of Rut was largely
      endothelium-dependent. We previously reported that Rut increased intracellular
      Ca2+ concentrations ([Ca2+]i) in cultured rat endothelial cells (ECs) and
      decreased [Ca2+]i in cultured rat vascular smooth muscle (VSMCs) cells. The
      present results showed that the hypotensive effect of Rut (10-100 microgram/kg
      i.v.) was significantly blocked by the nitric oxide synthase inhibitor Nomega
      nitro-L-arginine. In aortic rings, Rut (0. 1-3.0 microM)-induced vasorelaxation
      was inhibited by Nomega-nitro-L-arginine and hydroquinone but not by antagonists
      of the various K+ channels, 4-aminopyridine, apamin, charybdotoxin, or
      glibenclamide. Rut (0.1 and 1.0 microM) inhibited the norepinephrine-induced
      contraction generated by Ca2+ influx and at 1.0 microM increased cyclic GMP
      (cGMP) production in endothelium-intact rings and to a lesser extent in
      endothelium-denuded rings. In whole-cell patch-clamp recording, nonvoltage
      dependent Ca2+ channels were recorded in ECs and Rut (0.1, 1.0 microM) elicited
      an opening of such channels. However, in VSMCs, Rut (10.0 microM) inhibited
      significantly the L-type voltage-dependent Ca2+ channels. In ECs cells, Rut (1.0,
      10.0 microM) increased nitric oxide release in a Ca2+-dependent manner. Taken
      together, the results suggested that Rut lowered blood pressure by mainly
      activating the endothelial Ca2+-nitric oxide-cGMP pathway to reduce smooth muscle
      tone. Although the contribution seemed to be minor in nature, inhibition of
      contractile response in VSMCs, as evidenced by inhibition of Ca2+ currents, was
      also involved. Potassium channels, on the other hand, had no apparent roles.

PMID- 10336512
TI  - Improved effects of novel glucocorticosteroids on immune-induced epithelial
      pathophysiology.
AB  - Glucocorticosteroids are a mainstay therapy in inflammatory bowel disease and
      other chronic inflammatory conditions. However, severe systemic side effects are
      associated with their long-term use. The new generation of glucocorticosteroids
      have a high degree of topical activity with reduced systemic effects due to rapid
      metabolism. We previously described an in vitro model of inflammation in which
      monolayers of the human T84 colonic epithelial cell line displayed altered ion
      secretion and increased permeability after coculture with endotoxin-activated
      monocytes/macrophages (MPhi). Here, we tested the effects of budesonide and two
      novel analogs, D5519 and S1316, on MPhi-induced epithelial changes. Filter-grown
      T84 monolayers were cocultured with activated MPhi and single daily doses of drug
      were added to the luminal (physiological) side of the monolayer. Basal and
      stimulated epithelial ion transport [baseline short-circuit current (Isc) and
      DeltaIsc to forskolin, respectively] and barrier (transepithelial resistance)
      parameters were measured 48 h later in Ussing chambers. D5519, S1316, and
      budesonide (10(-7) to 10(-9) M) dose dependently inhibited the MPhi-induced
      epithelial abnormalities, restoring normal resistance, decreasing the elevated
      baseline Isc, and improving the reduced Isc response to forskolin. Of the drugs
      tested, D5519 was consistently the most potent and effective in inhibiting the
      MPhi-induced epithelial irregularities. Coupled with a further improvement in
      their rate of hepatic inactivation, our findings indicate that the novel
      steroids, particularly D5519, will be a valuable addition to current treatment
      strategies for inflammatory bowel disease and other chronic inflammatory
      conditions.

PMID- 10336513
TI  - MEN 11270, A novel selective constrained peptide antagonist with high affinity at
      the human B2 kinin receptor.
AB  - We investigated the pharmacological profile of MEN 11270, or H-D-Arg-Arg-Pro-Hyp
      Gly-Thi-c(Dab-DTic-Oic-Arg)c(7gamma-10 alpha), a conformationally constrained
      derivative of the B2 kinin receptor antagonist Icatibant. MEN 11270 bound with
      high-affinity to the B2 kinin receptor constitutively expressed by WI38 human
      fibroblasts, inhibiting 3H-bradykinin (BK) with a pKi value of 10.3 +/- 0.08 (n =
      5). The rank order of affinity of several peptide and nonpeptide antagonists was
      also assessed: Icatibant (pKi = 10.6) approximately MEN 11270 (pKi = 10.3)
      approximately B9430 (pKi = 10.0) > B9858 (pKi = 8.0) > FR173657 (pKi = 7.6) >
      WIN64338 (pKi = 7.2) > Lys-[des-Arg9, Leu8]-BK (pKi < 6) > [des-Arg9,Leu8]-BK
      (pKi < 5). MEN 11270 showed a low affinity in inhibiting 3H-Lys-[des-Arg9]-BK
      binding at the human B1 kinin receptor constitutively expressed by the same cells
      (pKi 6.0 +/- 0.33; n = 3). MEN 11270 showed no binding affinity (pIC50 < 5.5) at
      29 different receptors and ion channels. In the human umbilical vein contraction
      assay, MEN 11270, shifted the concentration-response curve to BK to the right in
      a concentration-dependent manner (pA2 8.14 +/- 0.22, n = 7). The Schild plot was
      linear (slope 0.95 +/- 0.11), consistent with a competitive antagonism. In the
      same bioassay, MEN 11270 (10 microM) did not affect the concentration-response
      curve to the B1 agonist Lys-[des-Arg9]-BK nor the contractile responses elicited
      by noradrenaline or serotonin. These findings indicate MEN 11270 as an antagonist
      at the human B2 kinin receptor, with potency and selectivity comparable to those
      of the linear peptide antagonist, supporting the hypothesis that a constrained C
      terminal beta-turn conformation preserves a high affinity for the interaction of
      Icatibant with the B2 kinin receptor.

PMID- 10336514
TI  - In vivo assessment of captopril selectivity of angiotensin I-converting enzyme
      inhibition: differential inhibition of acetyl-ser-asp-lys-pro and angiotensin I
      hydrolysis.
AB  - Angiotensin I-converting enzyme (ACE) is a zinc metallopeptidase that plays a
      major role in blood pressure regulation. The demonstration that the
      hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a natural and specific
      substrate of the N-active site of ACE suggests that this enzyme may have a new
      physiological role such as the modulation of hematopoietic stem cells. In vitro
      studies have shown that ACE inhibitors displayed various potencies in inhibiting
      the degradation of different natural or synthetic substrates of ACE, among which
      captopril inhibits AcSDKP hydrolysis more potently than angiotensin I hydrolysis.
      To look for this selectivity in vivo, we investigated the pharmacodynamic effect
      of increasing doses of captopril (0.01-10 mg/kg) during the 90 min after i.v.
      administration to spontaneously hypertensive rats. Plasma and urinary AcSDKP
      levels were measured. The renin-angiotensin system was evaluated by measurements
      of ACE activity in plasma samples, using the synthetic substrate Hip-His-Leu, by
      determinations of plasma renin concentrations and measurements of arterial blood
      pressure. The results showed that captopril (0.01-0.3 mg/kg) selectively
      inhibited AcSDKP hydrolysis, with limited effects on the renin-angiotensin
      system. AcSDKP levels in plasma and urine rose to a plateau 4 times the basal
      level for doses more than 0.3 mg/kg. All of the parameters reflecting the renin
      angiotensin system were significantly affected at doses of 1 and 10 mg/kg. The
      present study therefore confirms that captopril can be used to protect
      hematopoietic stem cells during antitumor chemotherapy while having only a
      limited effect on cardiovascular homeostasis.

PMID- 10336515
TI  - Pharmacological properties of J-104132 (L-753,037), a potent, orally active,
      mixed ETA/ETB endothelin receptor antagonist.
AB  - J-104132 [(+)-(5S,6R, 7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5
      (3, 4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic; also
      referred to as L-753,037] is a potent, selective inhibitor of ETA and ETB
      endothelin (ET) receptors (e.g., Ki: cloned human ETA = 0.034 nM; cloned human
      ETB = 0.104 nM). In both ligand-binding and isolated tissue preparation
      protocols, the inhibition of ET receptors with J-104132 is reversible and
      competitive. In vitro, J-104132 is a potent antagonist of ET-1-induced
      accumulation of [3H]inositol phosphates in Chinese hamster ovary cells stably
      expressing cloned human ETA receptors (IC50 = 0.059 nM), ET-1-induced
      contractions in rabbit iliac artery (pA2 = 9.70) and of BQ-3020-induced
      contractions in pulmonary artery (pA2 = 10.14). J-104132 is selective for ET
      receptors because it had no effect on contractions elicited by norepinephrine or
      KCl in the vascular preparations. The in vivo potency of J-104132 was assessed
      using challenges with exogenous ET-1. In conscious mice, 5 nmol/kg i.v. ET-1
      causes death. Pretreatment with J-104132 prevents the lethal response to ET-1
      when administered i.v. (ED50 = 0.045 mg/kg) or p.o. in fed animals (ED50 = 0.35
      mg/kg). In conscious, normotensive rats, pressor responses to 0.5 nmol/kg i.v. ET
      1 are inhibited by J-104132 after i.v. (0.1 mg/kg) or p.o. (1 mg/kg)
      administration. In anesthetized dogs, ET-1 was administered directly into the
      renal artery or brachial artery to generate dose-response (blood flow) curves,
      and the inhibitory potency of J-104132 (i.v. infusion) was quantified. J-104132
      produced greater than 10-fold shifts in the ET-1 dose-response curves at 0.03
      mg/kg/h (renal) and 0.3 mg/kg/h (brachial). Oral bioavailability of J-104132 in
      rats was approximately 40%. These studies indicate that J-104132 is a selective,
      potent, orally active antagonist of both ETA and ETB receptors and is an
      excellent pharmacological tool to explore the therapeutic use of a mixed ETA/ETB
      receptor antagonist.

PMID- 10336516
TI  - Characterization of antiallodynic actions of ALE-0540, a novel nerve growth
      factor receptor antagonist, in the rat.
AB  - There is growing evidence that nerve growth factor (NGF) may function as a
      mediator of persistent pain states. We have identified a novel nonpeptidic
      molecule, ALE-0540, that inhibits the binding of NGF to tyrosine kinase (Trk) A
      or both p75 and TrkA (IC50 5.88 +/- 1. 87 microM, 3.72 +/- 1.3 microM,
      respectively), as well as signal transduction and biological responses mediated
      by TrkA receptors. ALE-0540 was tested in models of neuropathic pain and
      thermally-induced inflammatory pain, using two routes of administration, a
      systemic i.p. and a spinal intrathecal (i.th.) route. Morphine was also tested
      for comparison in the antiallodynia model using mechanical stimuli. We show that
      either i.p. or i.th. administration of ALE-0540 in rats produced antiallodynia in
      the L5/L6 ligation model of neuropathic pain. The calculated A50 values (and 95%
      confidence intervals) for ALE-0540 administered i.p. and i. th. were 38 (17.5-83)
      mg/kg and 34.6 (17.3-69.4) microgram, respectively. ALE-0540 given i.th., at
      doses of 30 and 60 microgram, also blocked tactile allodynia in the thermal
      sensitization model. Although morphine displayed greater potency [A50 value of
      7.1 (5.6-8. 8) mg/kg] than ALE-0540 in anti-allodynic effect when given i.p. to
      L5/L6-ligated rats, it was not active when administered i.th. These data suggest
      that a blockade of NGF bioactivity using a NGF receptor antagonist is capable of
      blocking neuropathic and inflammatory pain and further support the hypothesis
      that NGF is involved in signaling pathways associated with these pain states. ALE
      0540 represents a nonpeptidic small molecule which can be used to examine
      mechanisms leading to the development of agents for the treatment of pain.

PMID- 10336517
TI  - Identification of a small-molecule, nonpeptide macrophage scavenger receptor
      antagonist.
AB  - Class A scavenger receptor (SR-A) antagonists may prevent the initiation of
      atherosclerosis, because a recent report found that SR-A/apolipoprotein E (apoE)
      double-knockout mice had 60% smaller lesions than apoE single-knockout
      littermates. We transfected human embryonic kidney (HEK) 293 cells with SR-A type
      I or II receptors to find small-molecule antagonists. Uptake of 1,1'-dioctadecyl
      3,3,3', 3'-tetramethylindocarbocyanine perchlorate-labeled acetylated low-density
      lipoprotein (DiI-AcLDL) showed that among common polyanionic ligands, polyinosine
      was the most potent, with an IC50 of 0.74 microgram/ml, whereas the novel
      compound (E)-methyl 4-chloro-alpha-[4-(4-chlorophenyl)-1, 5-dihydro-3-hydroxy-5
      oxo-1-(2-thiazolyl)-2H-pyrrol-2-ylidene]benzene acetate gave an IC50 of 6.1
      microgram/ml (13 microM). The novel antagonist also inhibited DiI-AcLDL uptake in
      cultured human peripheral and rat peritoneal macrophages with IC50 values of 21
      microM and 17 microM, respectively. With [125I]AcLDL as ligand for transfected
      HEK 293 cells, binding/uptake and degradation at 37 degrees C for 5 h was
      saturable and selective. In a comparison of both types of receptor, we found no
      difference between the capacity of SR-AI or SR-AII for either binding or
      degradation. Polyinosine competed both [125I]AcLDL binding and degradation with a
      Ki of 1 microgram/ml, whereas the novel antagonist competed with a Ki of 19
      microgram/ml (40 microM) and 8.6 microgram/ml (18 microM), respectively, for
      binding and degradation. Saturation binding in the presence of the ionophore
      monensin indicated that the novel compound behaved as a noncompetitive antagonist
      and perhaps as an allosteric effector. This is the first report to describe a
      small-molecule macrophage scavenger receptor antagonist. Utilization of this
      permanently transfected HEK 293 cell line will allow the identification of more
      potent macrophage scavenger receptor antagonists, so that their utility as
      therapeutics for atherosclerosis can be determined.

PMID- 10336518
TI  - alpha2C adrenoceptors inhibit adenylyl cyclase in mouse striatum: potential
      activation by dopamine.
AB  - alpha2C adrenoceptors occur in high density in the striatum, but the functional
      role of these receptors is uncertain. Mice with targeted inactivation of the
      alpha2C adrenoceptor gene (Adra2c-/-) and genetically related control mice
      expressing the wild-type alpha2C adrenoceptor (Adra2c+/+) were used to determine
      whether striatal alpha2C adrenoceptors modulate adenylyl cyclase activation. In
      striatal slices from Adra2c+/+ mice, the alpha2 adrenoceptor antagonist RX821002
      facilitated forskolin-stimulated cyclic AMP accumulation in a concentration
      dependent manner. In contrast, RX821002 had no effect on forskolin-stimulated
      cAMP accumulation in striatal slices from Adra2c-/- mice or in striatal slices
      from Adra2c+/+ mice treated with reserpine and alpha-methyl-rho-tyrosine to
      deplete monoamine neurotransmitters. Given the sparse innervation of the striatum
      by noradrenergic neurons, the possibility that dopamine can activate the mouse
      alpha2C adrenoceptor at physiologically relevant concentrations was investigated
      using normal rat kidney (NRK) cells transfected with the mouse alpha2A or alpha2C
      adrenoceptor cDNA (NRK-alpha2A or NRK-alpha2C cells). Inhibition of [3H]RX821002
      binding by agonists in homogenates of transfected cells revealed an affinity of
      dopamine for alpha2C adrenoceptors that was higher than the affinity of
      norepinephrine for its cognate receptor, the alpha2A adrenoceptor. Both
      norepinephrine and dopamine inhibited forskolin-stimulated cAMP accumulation in
      intact NRK-alpha2C cells. In NRK-alpha2A cells, norepinephrine facilitated
      forskolin-stimulated cAMP accumulation, an effect not observed for dopamine.
      Together, these data demonstrate that the alpha2C adrenoceptor is negatively
      coupled to adenylyl cyclase and is tonically activated in mouse striatal slices.
      The endogenous activator of the striatal alpha2C adrenoceptor may be dopamine, as
      well as norepinephrine.

PMID- 10336519
TI  - Ethanol enhances basal and flow-stimulated nitric oxide synthase activity in
      vitro by activating an inhibitory guanine nucleotide binding protein.
AB  - The aim of this study was to determine the effect of ethanol on endothelial
      nitric oxide synthase (eNOS), the enzyme responsible for the production of the
      important vasoactive agent nitric oxide. The effect of ethanol (0.8-160 mM) on
      both basal and flow-stimulated eNOS activity was determined using cultured bovine
      aortic endothelial cells (EC). In "static" EC ethanol dose-dependently increased
      basal eNOS activity with a maximum response (approximately 2.0-fold increase)
      achieved at 40 mM in the absence of any effect on cell viability or nitric oxide
      synthase protein expression. Pertussis toxin (PTX) pretreatment significantly
      inhibited the ethanol-induced increase in basal eNOS activity. EC exposed to
      steady laminar flow exhibited a flow- and time-dependent increase in eNOS
      activity. Ethanol significantly enhanced the laminar flow-induced eNOS response
      from 0.62 +/- 0.1 to 1.06 +/- 0. 06 pmol [14C]citrulline/mg/min, a response that
      was inhibited by PTX. PTX-catalyzed ribosylation of Gialpha substrates, an index
      of G-protein functional activity, was increased in laminar flow-exposed EC
      compared with static controls and was further enhanced by ethanol treatment.
      Likewise, EC exposed to low ( approximately 0.5 dynes/cm2) and high (
      approximately 12 dynes/cm2) pulsatile flow demonstrated increased eNOS activity,
      an effect that was associated with increased PTX-catalyzed ribosylation of
      Gialpha substrates. Ethanol enhanced the low flow response in a PTX-sensitive
      manner. These data demonstrate a stimulatory effect of ethanol on basal and flow
      stimulated eNOS activity, mediated in part by a mechanism involving a PTX
      sensitive G protein.

PMID- 10336520
TI  - Transport of ochratoxin A by renal multispecific organic anion transporter 1.
AB  - In the present study, we investigated the transport of ochratoxin A (OTA) by
      kidney-specific organic anion transporter 1 (OAT1). When expressed in Xenopus
      laevis oocytes, OAT1 mediated sodium-independent uptake of OTA (Km = 2.1 microM).
      Piroxicam, which has been shown to prevent the nephrotoxicity of OTA, inhibited
      OAT1-mediated uptake of OTA. By contrast, another protective compound, aspartame,
      did not. Using a cell line derived from the mouse kidney terminal proximal tubule
      (S3) transfected with OAT1 cDNA, we investigated the transport of OTA and also
      its effect on cell proliferation and cell viability. S3 cells expressing OAT1
      mediated the saturable transport of OTA (Km = 0.57 microM). Cell proliferation
      was suppressed in S3 cells expressing OAT1 when exposed to 2 and 10 microM OTA.
      This suppression was rescued by the coaddition of 1 mM p-aminohippurate in the
      media. The present study indicates that OTA is transported by OAT1 and that the
      accumulation of OTA via OAT1 in proximal tubular cells is the primary event in
      the development of OTA nephrotoxicity.

PMID- 10336521
TI  - Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for
      new protein synthesis, formation of reactive oxygen species, and caspase
      processing.
AB  - Betulinic acid (BA), a pentacyclic triterpene, is an experimental cytotoxic agent
      for malignant melanoma. Here, we show that BA triggers apoptosis in five human
      glioma cell lines. BA-induced apoptosis requires new protein, but not RNA,
      synthesis, is independent of p53, and results in p21 protein accumulation in the
      absence of a cell cycle arrest. BA-induced apoptosis involves the activation of
      caspases that cleave poly(ADP ribose)polymerase. Interactions of death
      ligand/receptor pairs of the CD95/CD95 ligand family do not mediate BA-induced
      caspase activation. BA enhances the levels of BAX and BCL-2 proteins but does not
      alter the levels of BCL-xS or BCL-xL. Ectopic expression of BCL-2 prevents BA
      induced caspase activation, DNA fragmentation, and cell death. Furthermore, BA
      induces the formation of reactive oxygen species that are essential for BA
      triggered cell death. The generation of reactive oxygen species is blocked by BCL
      2 and requires new protein synthesis but is unaffected by caspase inhibitors,
      suggesting that BA toxicity sequentially involves new protein synthesis,
      formation of reactive oxygen species, and activation of crm-A-insensitive
      caspases.

PMID- 10336523
TI  - Measurement of agonist and antagonist ligand-binding parameters at the human
      parathyroid hormone type 1 receptor: evaluation of receptor states and modulation
      by guanine nucleotide.
AB  - Determination of ligand-binding constants for parathyroid hormone (PTH) receptors
      has been hampered by a lack of suitable experimental systems and mechanistic
      models for data analysis. In this study, ligand binding to the cloned human PTH-1
      receptor was measured using membrane-based radioligand-binding assays. Guanosine
      5'-O-(3-thiotriphosphate) (GTPgammaS) (10 microM) reduced binding of agonist
      radioligands [125I]rPTH(1-34) and [125I]PTHrP(1-36) but only to a limited extent
      (by 29 +/- 5 and 42 +/- 3%, respectively). Radiolabeled agonist dissociation was
      described by three and two phases in the absence and presence of GTPgammaS,
      respectively. GTPgammaS treatment removed a pseudoirreversible binding phase.
      Inhibition of radiolabeled antagonist ([125I]bPTH(3-34)) binding was measured
      using a 90-min incubation, which allowed binding of ligands to closely approach
      the asymptotic maximum. Agonist/[125I]bPTH(3-34) displacement curves were fitted
      best by assuming two independent affinity states, both in the presence and
      absence of GTPgammaS. After a 3-h incubation, binding of PTH agonists in the
      presence of GTPgammaS was described by a single affinity state, indicating the
      presence of slow components in the binding reaction. Antagonist binding was
      described by a single affinity state and was not significantly affected by
      GTPgammaS. The data were used to evaluate potential receptor-binding models.
      Although other models could not be excluded, all of the observations could be
      explained by assuming two binding sites on the receptor that recognize two
      corresponding sites on agonist ligands. Using the model, it was possible to
      estimate receptor-ligand-binding constants and to propose a direct method for
      identifying ligands that interact with a putative antagonist binding region of
      the receptor.

PMID- 10336522
TI  - Synergism between neuropeptide Y and norepinephrine highlights sympathetic
      cotransmission: studies in rat arterial mesenteric bed with neuropeptide Y,
      analogs, and BIBP 3226.
AB  - Although abundant literature supports the notion that neuropeptide Y (NPY)
      synergizes in vivo and in vitro, the vasomotor activity elicited by
      norepinephrine (NE), the converse interaction (i.e., the adrenergic modulation of
      the NPY vasomotor response) has been less characterized. To assess whether NE
      synergizes the vasomotor effect of NPY, the rat arterial mesenteric bed was
      chosen as a model experimental system. Mesenteries were precontracted with NE and
      few minutes later were perfused with exogenous NPY. Under these conditions, NPY
      contracted the arterial mesenteric bed with an EC50 value of 0.72 +/- 0.06 nM.
      NPY was unable to contract this vascular territory without an agonist-induced
      precontraction. Other agonists, such as endothelin-1, a synthetic analog of
      prostaglandin F2alpha, or 5-hydroxytryptamine, also were effective primers
      because in their presence, NPY was a potent vasoconstrictor. In contrast,
      mesenteries precontracted with KCl failed to evidence the NPY-induced rise in
      perfusion pressure. Two structural analogs of NPY, PYY and [Leu31, Pro34]NPY,
      mimicked the activity of NPY. The NPY fragment 13-36 did not elicit such a
      response. All NPY analogs exhibited less efficacy and potency relative to NPY.
      The NPY- and related structural analog-induced vasoconstriction was competitively
      and reversibly antagonized by BIBP 3226; the pA2 of the NPY interaction was 7.0.
      The application of 0.1 to 1 microM BIBP 3226 or 0.1 to 10 nM prazosin at the peak
      of the NPY vasomotor response elicited a gradual blockade of the
      vasoconstriction. Although BIBP 3226 blocked the increase in perfusion pressure
      elicited by NPY, leaving unaffected the NE-induced tone, 10 nM prazosin blocked
      the full response, including the NE-induced component. Tissue preincubation with
      200 nM nifedipine abolished the NPY-induced vasoconstriction; likewise, the acute
      application of 10 to 100 nM nifedipine blocked gradually the maximal NPY-induced
      contraction. Removal of the mesenteric endothelial layer increased the potency of
      NPY by 2-fold; it also slightly potentiated the antagonist activity of BIBP 3226.
      The synergism between NPY and NE backs the principle of sympathetic
      cotransmission.

PMID- 10336524
TI  - Effects of verapamil, zatebradine, and E-4031 on the pacemaker location and rate
      in response to sympathetic stimulation in dog hearts.
AB  - To investigate whether slow inward Ca2+ current (ICa), hyperpolarization
      activated inward current (If), and a rapid type of delayed rectifier K+ current
      (IKr) similarly act on the pacemaker location, sinoatrial node region, and
      subsidiary superior and inferior pacemaker regions, we studied the effects of
      verapamil, zatebradine, and E-4031 on the atrial rate and the 3-ms earliest
      activation region (EAR) determined from the isochronal activation sequence map in
      the autonomically decentralized heart of the anesthetized dog. Three blockers
      decreased atrial rate similarly. Verapamil shifted the EAR from the SA node
      region to the inferior pacemaker region. The EAR induced by zatebradine was
      variable, but the EAR induced by E-4031 tended to shift to the inferior pacemaker
      region. Sympathetic nerve stimulation increased atrial rate and shifted the EAR
      to the superior pacemaker region. Verapamil attenuated the increased atrial rate
      by 28%, and it shifted the EAR to the lower pacemaker regions consistently.
      Zatebradine also attenuated the increased rate by 53% and shifted the EAR from
      the anterior to the posterior-superior right atrium. On the other hand, E-4031
      affected neither the rate nor the EAR in response to sympathetic stimulation.
      These results suggest that ICa, If, and IKr inhibitors differentially influence
      the pacemaker activity among three pacemaker regions when sympathetic tone is
      absent or present and that the role of ICa, If, and IKr of the pacemaker cells
      distributed in the atrial pacemaker complex is different in the dog heart in
      situ.

PMID- 10336526
TI  - Assessment of opioid partial agonist activity with a three-choice hydromorphone
      dose-discrimination procedure.
AB  - The discriminative stimulus and subjective effects of opioid mixed agonist
      antagonists were assessed in volunteer nondependent heroin users trained in a
      three-choice drug discrimination procedure to discriminate among the effects of
      i.m. administration of 2 ml of saline, 1 mg of hydromorphone, and 4 mg of
      hydromorphone (a morphine-like mu agonist). Other subjective, behavioral, and
      physiological measures were concurrently collected. The discrimination was
      readily learned by six of the eight subjects. After training, generalization
      curves were determined for the following i.m. drug conditions: hydromorphone
      (0.375-4.0 mg), pentazocine (7.5-60 mg), butorphanol (0.75-6 mg), nalbuphine (3
      24 mg), and buprenorphine (0.075-0.6 mg). All five of the test drugs were
      discriminated significantly or showed trends toward being discriminated as
      hydromorphone 1 mg-like at one or more dose levels. Hydromorphone showed an
      inverted U-shaped dose-effect function on the hydromorphone 1 mg-like
      discrimination. Subjective effect measures produced clearer differentiation among
      the test drugs than did drug discrimination performance. The present results
      differ from those of a previous study that observed a close relationship between
      the results of the discrimination measure and subjective effect measures. The
      previous study used similar methods and test drugs but different training drugs
      (e.g., 3 mg of hydromorphone versus 6 mg of butorphanol versus saline). It
      appears that both the sensitivity of drug discrimination performance to between
      drug differences and the relationship between discriminative and subjective
      effects depends upon the specific discrimination that is trained (e.g., two
      choice or three-choice). The present high dose-low dose-saline discrimination
      procedure appears useful for assessing partial agonist activity. The present data
      are consistent with partial agonist activity for pentazocine, butorphanol,
      nalbuphine, and buprenorphine.

PMID- 10336525
TI  - BIIR 561 CL: a novel combined antagonist of alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid receptors and voltage-dependent sodium channels with
      anticonvulsive and neuroprotective properties.
AB  - Antagonists of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid (AMPA) subtype, as well as of voltage-gated sodium
      channels, exhibit anticonvulsive and neuroprotective properties in vivo. One can
      postulate that a compound that combines both principles might be useful for the
      treatment of disorders of the central nervous system, like focal or global
      ischemia. Here, we present data on the effects of dimethyl-(2-[2-(3-phenyl-[1,2,
      4]oxadiazol-5-yl)-phenoxy]ethyl)-amine hydrochloride (BIIR 561 CL) on neuronal
      AMPA receptors and voltage-dependent sodium channels. BIIR 561 CL inhibited AMPA
      receptor-mediated membrane currents in cultured cortical neurons with an IC50
      value of 8.5 microM. The inhibition was noncompetitive. In a cortical wedge
      preparation, BIIR 561 CL reduced AMPA-induced depolarizations with an IC50 value
      of 10.8 microM. In addition to the effects on the glutamatergic system, BIIR 561
      CL inhibited binding of radiolabeled batrachotoxin to rat brain synaptosomal
      membranes with a Ki value of 1.2 microM. The compound reduced sodium currents in
      voltage-clamped cortical neurons with an IC50 value of 5.2 microM and inhibited
      the veratridine-induced release of glutamate from rat brain slices with an IC50
      value of 2.3 microM. Thus, BIIR 561 CL inhibited AMPA receptors and voltage-gated
      sodium channels in a variety of preparations. BIIR 561 CL suppressed tonic
      seizures in a maximum electroshock model in mice with an ED50 value of 2.8 mg/kg
      after s.c. administration. In a model of focal ischemia in mice, i.p.
      administration of 6 or 60 mg/kg BIIR 561 CL reduced the area of the infarcted
      cortical surface. These data show that BIIR 561 CL is a combined antagonist of
      AMPA receptors and voltage-gated sodium channels with promising anticonvulsive
      and neuroprotective properties.

PMID- 10336527
TI  - Sigma1 recognition sites in rabbit iris-ciliary body: topical sigma1-site
      agonists lower intraocular pressure.
AB  - In this study, we examined the presence of sigma1 and sigma2 sites in the rabbit
      iris-ciliary body by receptor binding and investigated their effects on
      intraocular pressure (IOP) in albino rabbits. The iris-ciliary body has binding
      sites for the sigma1-site agonist [3H](+)-pentazocine (Kd = 4.6 nM; Bmax = 212
      fmol/mg protein) and sigma2 sites labeled with [3H]1,3-di-o-tolylguanidine (DTG)
      (Kd = 8. 2 nM; Bmax = 1120 fmol/mg protein). In competition binding studies, (+)
      pentazocine and the sigma antagonist NE-100 displayed high affinity for sigma1
      sites (Ki = 2.1 and 2.4 nM, respectively), whereas (+)-N-allylnormetazocine
      (NANM) was less potent (Ki = 178 nM). Unilateral topical (+)-pentazocine (0.01
      0.1%) caused a significant dose-related reduction of IOP in ocular normotensive
      rabbits and in the alpha-chymotrypsin model of ocular hypertension. (+)-NANM was
      less potent than (+)-pentazocine. Neither compound altered the IOP of the
      contralateral eye, and their hypotensive activity was blocked by NE-100 that, by
      itself, had no effect on IOP. (-)-Pentazocine, (-)-NANM, and DTG had no effect on
      IOP. DTG prevented the hypotensive effect of (+)-pentazocine, suggesting that it
      acts as a sigma1-site antagonist. sigma-Site ligands did not affect pupil
      diameter or cause ocular inflammation. Topical [3H](+)-pentazocine reaches the
      intraocular tissues within 30 min, and its uptake in the iris-ciliary body and
      retina was significantly reduced by topical pretreatment with NE-100, as expected
      for a receptor-specific agent. Reverse-phase HPLC confirmed the presence of
      intact (+)-pentazocine in iris-ciliary body homogenates. sigma1-Site agonists may
      offer a novel class of agents potentially effective in the control of ocular
      hypertension.

PMID- 10336528
TI  - Sex differences in supraspinal morphine analgesia are dependent on genotype.
AB  - Several variables have been reported to affect the expression of sex differences
      in the analgesic potency of morphine. Although the effect of genetic background
      on morphine analgesia has been well documented, the relevance of genotype to sex
      differences in morphine analgesia has rarely been considered. The present study
      investigated morphine dose-response relationships in male and female mice of 11
      inbred mouse strains on the tail-withdrawal test after i.c.v. administration.
      Large differences in morphine analgesic potency were observed between strains,
      reflecting the important influence of genotype on this trait. We identified three
      strains (AKR/J, C57BL/6J, and SWR/J) in which males displayed approximately 3.5-
      to 7.0-fold greater sensitivities to the analgesic effects of morphine than did
      their female counterparts. In contrast, in the CBA/J strain, females were found
      to be approximately 5-fold more sensitive to morphine than were the males. In all
      other strains, morphine potency estimates between the sexes were not
      statistically different. These data support the importance of genotype, sex, and
      their interaction in the mediation of morphine analgesia and suggest that
      equivocal findings regarding opioid sex differences in the literature may be
      partially accounted for by the use of different subject populations. The fact
      that female mice of the AKR/J and CBA/J strains exhibit 35-fold different
      morphine analgesic potency and that males of these strains are equally sensitive
      should facilitate the mapping and identification of sex-specific genes of
      relevance to morphine analgesia.

PMID- 10336530
TI  - Typical endothelin ETA receptors mediate atypical endothelin-1-induced
      contractions in sheep isolated tracheal smooth muscle.
AB  - Contraction of vascular and nonvascular smooth muscle induced by the
      endothelin/sarafotoxin family of peptides frequently does not readily fit into
      the current classification criteria for ETA and ETB receptors, raising the
      possibility of additional atypical receptors. In the current study, isometric
      tension recording and radioligand binding techniques were used to characterize
      the ETA receptor population in sheep isolated tracheal smooth muscle. Endothelin
      1 and sarafotoxin S6b induced similar concentration-dependent contractions,
      although endothelin-1 was 2.6-fold more potent (P <.05, n = 15-18). The ETA
      receptor-selective antagonists BQ-123 and FR139317 caused concentration-dependent
      inhibition of the contractions induced by endothelin-1 and sarafotoxin S6b, but
      both antagonists were significantly less potent in inhibiting contractions
      induced by endothelin-1 than sarafotoxin S6b. For example, 0.03 microM FR139317
      shifted the endothelin-1 and sarafotoxin S6b concentration-effect curves to the
      right by 1.8- and 8.3-fold, respectively (P <.01, n = 6-8). Although the observed
      agonist dependence of antagonist potency may indicate the presence of atypical
      ETA receptors, competition binding studies using 125I-endothelin-1 and 125-I
      sarafotoxin S6b identified only a single population of BQ-123- and sarafotoxin
      S6b-sensitive ETA receptors. Additional association-, dissociation-, and
      saturation-binding studies revealed that 125I-endothelin-1 binding to these ETA
      receptors was pseudoirreversible, whereas 125I-sarafotoxin S6b binding was
      readily reversible. Thus, marked differences in the kinetic profiles of ETA
      receptor binding to endothelin-1, sarafotoxin S6b, and BQ-123, rather than the
      existence of another ETA receptor subtype, may explain the stark agonist
      dependence of antagonist potency observed in contractile studies.

PMID- 10336529
TI  - alpha1-adrenergic receptor activation of c-fos expression in transfected rat-1
      fibroblasts: role of Ca2+.
AB  - alpha1-Adrenergic receptors mediate mitogenic responses and increase
      intracellular free Ca2+ ([Ca2+]i) in vascular smooth muscle cells. Induction of c
      fos is a critical early event in cell growth; expression of this gene is
      regulated by a number of signaling pathways including Ca2+. We wondered whether
      Ca2+ signaling plays a critical role in the induction of c-fos gene by alpha1
      adrenergic receptors. Using stably transfected rat-1 fibroblasts, we confirmed
      that PE induced c-fos mRNA expression in a time- and dose-dependent manner, and
      also increased [Ca2+]i (measured with Fura-2 AM). These responses were blocked by
      the alpha1-adrenergic receptor antagonist doxazosin. Both intracellular Ca2+
      chelation (using BAPTA/AM) and extracellular Ca2+ depletion (using EGTA)
      significantly inhibited PE-induced c-fos expression by alpha1A and alpha1B
      receptors. Brief (1-min) stimulation of alpha1A and alpha1B receptors with PE did
      not maximally induce c-fos expression, suggesting that a sustained increase in
      [Ca2+]i due to Ca2+ influx is required. The calmodulin (CaM) antagonists, R24571,
      W7, and trifluoperazine, but not the CaM-dependent protein kinases inhibitor KN
      62, significantly inhibited c-fos induction by alpha1A and alpha1B receptors.
      Neither inhibition of protein kinase C nor inhibition of adenylyl cyclase
      modified c-fos induction by PE. These results suggest that alpha1-adrenergic
      receptor-induced c-fos expression in rat-1 cells is dependent on a Ca2+/CaM
      associated pathway.

PMID- 10336532
TI  - Down-regulation of nitric oxide production by ibuprofen in human volunteers.
AB  - Ibuprofen has been shown in vitro to modulate production of nitric oxide (NO), a
      mediator of sepsis-induced hypotension. We sought to determine whether ibuprofen
      alters NO production and, thereby, vascular tone, in normal and endotoxin
      challenged volunteers. Techniques for detecting NO were validated in 17 subjects
      infused with sodium nitroprusside, a NO donor. Then, endotoxin (4 ng/kg) or
      saline (vehicle alone) was administered in a single-blinded, crossover design to
      12 other subjects randomized to receive either ibuprofen (2400 mg p.o.) or a
      placebo. Endotoxin decreased mean arterial pressure (MAP; P =.002) and increased
      alveolar NO flow rates (P =.04) and urinary excretion of nitrite and nitrate (P
      =.07). In both endotoxemic and normal subjects, ibuprofen blunted the small fall
      in MAP associated with bed rest (P =.005) and decreased alveolar NO flow rates (P
      =.03) and urinary excretion of nitrite and nitrate (P =.02). However, ibuprofen
      had no effect on the decrease in MAP caused by endotoxin, although it blocked NO
      production to the point of disrupting the normal relationship between increases
      in exhaled NO flow rate and decreases in MAP (P =.002). These are the first in
      vivo data to demonstrate that ibuprofen down-regulates NO in humans. Ibuprofen
      impaired the NO response to bed rest, producing a small rise in blood pressure.
      Although ibuprofen also interfered with the ability of endotoxin to induce NO
      production, it had no effect on the fall in blood pressure, suggesting that the
      hemodynamic response to endotoxin is not completely dependent on NO under these
      conditions.

PMID- 10336531
TI  - Pharmacological properties of trimebutine and N-monodesmethyltrimebutine.
AB  - Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxybenzoate hydrogen
      maleate (TMB)] has been demonstrated to be active for relieving abdominal pain in
      humans. To better understand its mechanism of action, we have tested TMB; nor
      TMB, its main metabolite in humans; and their respective stereoisomers for their
      affinity toward sodium channels labeled by [3H]batrachotoxin, their effect on
      sodium, potassium, and calcium currents in rat dorsal root ganglia neurons, and
      their effect on veratridine-induced glutamate release from rat spinal cord
      slices. TMB has also been tested in an animal model of local anesthesia. TMB (Ki
      = 2.66 +/- 0.15 microM) and nor-TMB (Ki = 0.73 +/- 0.02 microM) displaced
      [3H]batrachotoxin from its binding site with affinities similar to that of
      bupivacaine (Ki = 7.1 +/- 0.9 microM). nor-TMB was found to block veratridine
      induced glutamate release with an IC50 value of 8.5 microM, which is very similar
      to that of bupivacaine (IC50 = 8.2 microM); the effect of TMB was limited to 50%
      inhibition at 100 microM. TMB and nor-TMB blocked sodium currents in sensory
      neurons from rat dorsal root ganglia (IC50 = 0.83 +/- 0.09 and 1.23 +/- 0.19
      microM, respectively), whereas no effect was observed on calcium currents at the
      same concentrations. A limited effect was observed on potassium currents (IC50 =
      23 +/- 6 at 10 microM) for TMB. In vivo, when tested in the rabbit corneal
      reflex, TMB displayed a local anesthetic activity 17-fold more potent than that
      of lidocaine.

PMID- 10336533
TI  - Sensitization of 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin cytotoxicity
      by 5-bromo-2'-deoxyuridine in human glioma.
AB  - 5-Bromo-2'-deoxyuridine (BrdUrd) was found to increase the cytotoxicity induced
      by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cisplatin in human glioma
      cells. At a fixed concentration of BrdUrd and BCNU, the greatest cell loss was
      observed in exponentially growing cells. As cells approached plateau growth,
      cytotoxicity was reduced as indicated by greater cell viability. Under varying
      growth conditions the percentage of thymine replacement by bromouracil in DNA, as
      determined by gas chromatography/mass spectrometry analysis, declined as cultures
      approached maximum density. These data indicate BrdUrd must be incorporated into
      DNA for the enhanced effect to be observed. In exponentially growing cells,
      sensitization was dependent upon both the concentration of BrdUrd and alkylating
      agent. Using regression analysis (at 95% CL), a relationship between the level of
      bromouracil in DNA and the extent of enhanced cytotoxicity was observed at two
      concentrations of BCNU (r2 = 0.99, 0.96). Although it is known that bifunctional
      alkylating agents exert cytotoxicity by forming cross-links between cDNA strands,
      increased cross-link formation was not observed in BrdUrd substituted DNA as
      determined by alkaline elution. The data suggest that DNA damage induced by
      halogenated pyrimidines may not involve interstrand cross-links and that these
      agents may be useful in the treatment of glioma in combination with alkylating
      agents.

PMID- 10336534
TI  - Comparison of the potassium channel openers, WAY-133537, ZD6169, and celikalim on
      isolated bladder tissue and In vivo bladder instability in rat.
AB  - The effects of the ATP-dependent potassium channel agonists ZD6169, celikalim,
      and WAY-133537 on bladder contractile function were examined in vitro on isolated
      bladder strips and in vivo on spontaneous bladder contractions. All three
      compounds produced a concentration-dependent relaxation of isolated rat detrusor
      strips (IC50 values = 0.93, 0.03, and 0.09 microM, respectively for ZD6169,
      celikalim, and WAY-133537. Contractile inhibition by all three compounds was
      fully reversed by 6 microM glyburide. These compounds also effectively inhibited
      spontaneous bladder contractions in the rat hypertrophied bladder model of
      detrusor instability. We also examined the electrophysiological properties of WAY
      133537 on isolated rat bladder detrusor myocytes. Myocytes had an average resting
      membrane potential of -40 mV. Under patch current-clamp conditions, WAY-133537
      (0.3 and 1.0 microM, n = 4-5) produced a significant hyperpolarization of 21 and
      26 mV, respectively. Hyperpolarization was reversed by the addition of 5 microM
      glyburide. In patch voltage-clamp studies, WAY-133537 (0.3 microM, n = 3)
      significantly increased outward current in response to both voltage step and ramp
      protocols consistent with activation of the ATP-dependent potassium channel. In
      the detrusor instability model, WAY-133537 and celikalim had similar oral
      potencies (ED50 = 0.13 and 0.3 mg/kg, respectively), whereas ZD6169 was less
      potent (ED50 = 2.4 mg/kg). The antihypertensive agent celikalim exerted effects
      on the bladder at doses that significantly reduced systemic blood pressure. In
      contrast, both WAY-133537 and ZD6169 inhibited bladder hyperactivity at doses
      that produced minimal changes in both mean arterial blood pressure and heart
      rate. These data suggest that both WAY-133537 and ZD6169 may be useful in the
      treatment of bladder instability at doses associated with minimal hemodynamic
      side effects.

PMID- 10336535
TI  - Limitations in using peptide drugs to characterize calcitonin gene-related
      peptide receptors.
AB  - Calcitonin gene-related peptide (CGRP) is an endogenous vasodilator peptide that
      produces its effects by activation of CGRP1 and CGRP2 receptor subtypes. These
      receptor subtypes are characterized in functional studies using the agonist
      Cys(Acm)2, 7-human-alpha-calcitonin gene-related peptide (Cys(ACM)2, 7-h-alpha
      CGRP), which activates CGRP2 receptors, and the antagonist h-alphaCGRP(8-37)
      which has a high affinity for CGRP1 receptors and a low affinity for CGRP2
      receptors. Our aim was to identify factors that may limit the use of these drugs
      to characterize CGRP receptor subtypes. We studied CGRP receptors using isolated
      ring segments of pig coronary and basilar arteries studied in vitro. The affinity
      of the antagonist h-alphaCGRP(8-37) for inhibiting h-alphaCGRP-induced relaxation
      of coronary arteries (log10 of the antagonist equilibrium dissociation constant =
      -5.33) was determined from Schild plots that had steep slopes. Therefore, we used
      capsaicin to investigate the role of endogenous CGRP in confounding affinity
      measurements for h-alphaCGRP(8-37). After capsaicin treatment, the slopes of the
      Schild plots were not different from one, and a higher affinity of h-CGRP(8-37)
      in blocking relaxation was obtained (log10 of the antagonist equilibrium
      dissociation constant = -6.01). We also investigated the agonist activity of the
      putative CGRP2 receptor selective agonist Cys(Acm)2,7-h-alphaCGRP. We found that
      maximal relaxation of coronary arteries caused by Cys(Acm)2,7-h-alphaCGRP was
      dependent upon the level of contractile tone induced by KCl. We also determined
      the KA for Cys(Acm)2,7-h-alphaCGRP and found that the KA (817 nM) was not
      significantly different from the EC50 (503 nM) for this drug in causing
      relaxation, indicating that Cys(Acm)2, 7-h-alphaCGRP is a partial agonist.
      Because experimental conditions affect the actions of h-CGRP(8-37) and
      Cys(Acm)2,7-h-alphaCGRP, the conditions must be carefully controlled to reliably
      identify CGRP receptor subtypes.

PMID- 10336537
TI  - Drug discrimination analysis of partial agonists at the benzodiazepine site. I.
      Differential effects of U-78875 across training conditions in baboons and rats.
AB  - The benzodiazepine receptor ligand U-78875 [3-(5-cyclopro pyl-1,2, 4-oxadiazol-3
      yl)-5-(1-methylethyl)imidazol(1, 5-a)quinoxalin-4(5H)-o-ne] was studied in rats
      trained to discriminate i.p. 1.0 mg/kg lorazepam, 1.0 mg/kg diazepam, or 10 mg/kg
      pentobarbital, and baboons trained to discriminate oral 1.8 mg/kg lorazepam or 10
      mg/kg pentobarbital. U-78875 doses were 0.01 to 10 mg/kg i.p. in rats and 0.32 to
      56 mg/kg orally in baboons. U-78875 occasioned drug-appropriate responding in
      pentobarbital-trained (ED50 = 1.8 mg/kg) and diazepam-trained (ED50 = 0.056
      mg/kg) rats, but it occurred in only one pentobarbital-trained baboon and not in
      the majority of lorazepam-trained baboons or rats. In baboons that generalized to
      U-78875, discriminative effects were antagonized by flumazenil. The interaction
      of U-78875 with pentobarbital, diazepam, and lorazepam revealed further
      differences in its behavioral effects. U-78875 potentiated the effects of
      pentobarbital, even in baboons that did not generalize to U-78875, but U-78875
      had little effect in combination with diazepam. In lorazepam-trained animals that
      did not generalize to it, U-78875 antagonized lorazepam's effects, but U-78875
      neither antagonized nor potentiated lorazepam in animals that did generalize to U
      78875. Thus, although U-78875 generally functioned as a benzodiazepine agonist in
      pentobarbital- and diazepam-trained animals, its unique effects in lorazepam
      trained animals appear to reflect its in vitro profile as a partial agonist.

PMID- 10336536
TI  - Synthesis and characterization of potent and selective agonists of the neuronal
      cannabinoid receptor (CB1).
AB  - Two subtypes of the cannabinoid receptor (CB1 and CB2) are expressed in mammalian
      tissues. Although selective antagonists are available for each of the subtypes,
      most of the available cannabinoid agonists bind to both CB1 and CB2 with similar
      affinities. We have synthesized two analogs of N-arachidonylethanolamine (AEA),
      arachidonylcyclopropylamide (ACPA) and arachidonyl-2-chloroethylamide (ACEA),
      that bind to the CB1 receptor with very high affinity (KI values of 2.2 +/- 0.4
      nM and 1.4 +/- 0.3 nM, respectively) and to the CB2 receptor with low affinity
      (KI values of 0.7 +/- 0.01 microM and 3.1 +/- 1.0 microM, respectively). Both
      ACPA and ACEA have the characteristics of agonists at the CB1 receptor; both
      inhibit forskolin-induced accumulation of cAMP in Chinese hamster ovary cells
      expressing the human CB1 receptor, and both analogs increase the binding of
      [35S]GTPgammaS to cerebellar membranes and inhibit electrically evoked
      contractions of the mouse vas deferens. ACPA and ACEA produce hypothermia in
      mice, and this effect is inhibited by coadministration of the CB1 receptor
      antagonist SR141716A. Therefore, ACPA and ACEA are high-affinity agonists of the
      CB1 receptor but do not bind the CB2 receptor, suggesting that structural analogs
      of AEA can be designed with considerable selectivity for the CB1 receptor over
      the CB2 receptor.

PMID- 10336538
TI  - Block by ruthenium red of cloned neuronal voltage-gated calcium channels.
AB  - The dye ruthenium red (RuR) has diverse experimental uses, including block of ion
      channels. RuR is a well described antagonist of one class of intracellular Ca2+
      release channels, the ryanodine receptors, but recently this compound has also
      been identified as a putative blocker of voltage-gated calcium channels of the
      surface membrane involved in neurotransmitter release. Using electrophysiological
      methods, we have studied the action of RuR upon pure populations of neuronal
      voltage-gated ion channels heterologously expressed in Xenopus laevis oocytes.
      All four channel types studied, including class A (P/Q-type), class B (N-type),
      class C (L-type), and class E channels, are sensitive to RuR, with IC50 values
      ranging from 0.7 to 67.1 microM. Block of class C and class E channels most
      likely results from 1:1 binding of ruthenium red at a site in the extracellular
      entrance to the pore, resulting in obstruction of permeant ion flux through these
      channels. The mechanism of block of class A and class B channels is more complex,
      requiring binding of more than one molecule of RuR per channel.

PMID- 10336539
TI  - Subjective, psychomotor, and physiological effects of cumulative doses of opioid
      mu agonists in healthy volunteers.
AB  - The subjective, psychomotor, and physiological effects of three opioid mu
      receptor agonists were studied in healthy volunteers using a cumulative-dosing
      procedure. Sixteen volunteers with no history of drug abuse received i.v.
      injections of saline (SAL), morphine (MOR), hydromorphone (HM), or meperidine
      (MEP) in a randomized double-blind crossover design. Subjects received 1
      injection/h for the first 4 h, and a 3-h recovery period followed. SAL was
      injected first during each session, then SAL or increasing doses of each drug
      were administered every hour for the next 3 h. The absolute doses per injection
      were MOR: 2.5, 5, and 10 mg/70 kg; HM: 0.33, 0.65, and 1.3 mg/70 kg; and MEP:
      17.5, 35, and 70 mg/70 kg. These injections resulted in cumulative doses of MOR:
      2.5, 7.5, and 17.5; HM: 0.33, 0.98, and 2.28; and MEP: 17.5, 52.5, and 122.5
      mg/70 kg. Subjects completed mood forms and psychomotor tests, and physiological
      measures were recorded at various times after each injection and during recovery.
      MEP tended to produce the most intense effects immediately after drug injection,
      which dissipated rapidly. MOR produced the mildest effects but was associated
      with unpleasant side effects during recovery and after the session. HM's effects
      were stronger than MOR's, and the recovery from HM was slower than with MEP. None
      of the opioids produced consistent effects that are typically associated with
      abuse liability. Orderly dose-response functions suggested that our cumulative
      dosing procedure is an efficient way of determining dose-response functions for
      multiple opioids within the same subjects within the same study.

PMID- 10336540
TI  - Tepoxalin enhances the activity of an antioxidant, pyrrolidine dithiocarbamate,
      in attenuating tumor necrosis factor alpha-induced apoptosis in WEHI 164 cells.
AB  - The nuclear transcription factor-kappaB (NF-kappaB) and free radicals are known
      to be involved in apoptosis. We studied the effects of a series of di-aryl
      substituted pyrazole NF-kappaB inhibitors including tepoxalin on tumor necrosis
      factor alpha (TNFalpha)-induced apoptosis in murine fibrosarcoma WEHI 164 cells.
      We found that potent inhibitors of NF-kappaB were also effective in attenuating
      apoptosis. WEHI 164 cells that had been dually treated with tepoxalin and the
      antioxidant pyrrolidine dithiocarbamate (PDTC) were significantly protected from
      TNFalpha-induced killing. To study the role of free radicals in mediating
      TNFalpha-induced apoptosis, stable WEHI 164 cells overexpressing Bcl-2, an
      antioxidant protein, were generated. These cells were protected from TNFalpha
      induced apoptosis and neither tepoxalin nor PDTC provided further significant
      protection. These results suggest that Bcl-2, PDTC, and tepoxalin may attenuate
      apoptosis in this system by affecting the same signaling pathway or converging
      pathways. Because tepoxalin suppresses the release of free radicals, PDTC
      scavenges free radicals and Bcl-2 is an antioxidant protein, free radicals are
      among the key mediators of this TNF-induced killing event. Tepoxalin and
      antioxidants may be useful in developing new therapeutics for treating
      neurodegenerative diseases, autoimmune deficiency syndrome, and ischemia
      reperfusion injuries.

PMID- 10336542
TI  - The protein phosphatase inhibitor cantharidin alters vascular endothelial cell
      permeability.
AB  - In this study, we characterized the effects of the protein phosphatases type 1
      (PP 1) and type 2A (PP 2A) inhibitor cantharidin in endothelial cells. We
      identified catalytic subunits of PP 1alpha, PP 2Aalpha, and PP 2Abeta
      immunologically in bovine aortic endothelial cells. Moreover, we detected mRNAs
      coding for catalytic subunits of PP 1alpha, PP 1beta, and PP 2Aalpha by
      hybridization with specific DNA probes in total RNA from these cells. Okadaic
      acid and cantharidin inhibited the activities of catalytic subunits of PP 1
      (okadaic acid, 0.01-1 microM; cantharidin, 1-100 microM) and PP 2A (okadaic acid,
      0.1 nM to 1 microM; cantharidin, 0.1-100 microM) separated by column
      chromatography in a concentration-dependent manner. Moreover, cantharidin (1
      microM to 1 mM) increased the phosphorylation state of endothelial proteins
      including the regulatory light chains of myosin without affecting cytosolic
      calcium concentrations. Cantharidin (5-100 microM) increased the permeability of
      cultured endothelial cells in a time- and concentration-dependent manner. We
      suggest that inhibition of PP 1 and PP 2A activities by cantharidin increases
      endothelial permeability by enhancing the phosphorylation state of endothelial
      regulatory proteins. Thus, cantharidin might be a useful tool to study the
      function of protein phosphatases in endothelial barrier function.

PMID- 10336541
TI  - Distinctions in the molecular determinants of charged and neutral dihydropyridine
      block of L-type calcium channels.
AB  - We investigated block of the alpha1Cb subunit of L-type calcium channels by
      dihydropyridines (DHPs) in which a permanently charged or neutral head group was
      linked to the active DHP moiety by a spacer chain containing ten methylene (-CH2)
      groups. We compared the sensitivity of channel modulation by the charged (DHPch)
      and neutral (DHPn) forms to specific alpha1Cb mutations in domains IIIS5, IIIS6,
      and IVS6, which had previously been shown to reduce channel modulation by the
      neutral DHP (+)-isradipine. The effects of these mutations were studied on
      channel block recorded from polarized (-80 mV) and depolarized (-40 mV) holding
      potentials (HPs). We found that channel block by DHPn was markedly reduced at
      both HPs by each mutation studied. In contrast, channel block by DHPch was only
      modestly reduced by mutations in IIIS6 and IVS6 for block from either -40 mV or 
      80 mV. Replacement of IIIS5 Thr1061 by Tyr, which abolished block by DHPn in an
      HP-independent manner, had little effect on channel block by DHPch recorded from 
      40 mV. However, this mutation markedly reduced DHPch block of currents recorded
      from a -80 mV HP. Inhibition of current by DHPch was not markedly use-dependent,
      in contrast with block by verapamil, another charged calcium channel blocker.
      These results suggest that the presence of a permanently charged head group
      restricts the access of the attached DHP moiety to a subset of interaction
      residues on the alpha1C subunit in a voltage-dependent manner. Furthermore, these
      restricted interactions confer distinct functional properties upon the charged
      DHP molecules.

PMID- 10336543
TI  - Functional characterization of a human purine-selective, Na+-dependent nucleoside
      transporter (hSPNT1) in a mammalian expression system.
AB  - Nucleosides and nucleoside analogs are actively transported in the human kidney.
      With the recent cloning of a purine-selective, Na+-dependent, nucleoside
      transporter (hSPNT1, also termed hCNT2) from human kidney, it is now possible to
      study the interaction of nucleosides and nucleoside analogs with this transport
      protein and gain a more detailed knowledge of the underlying mechanisms of
      nucleoside transport in the human kidney. In this study we examined the substrate
      selectivity of hSPNT1 for nucleosides and nucleoside analogs. We determined that
      the naturally occurring nucleosides adenosine, inosine, and uridine are
      substrates for this carrier, whereas thymidine is not. The nucleoside analogs
      (0.5 mM) 2', 3'-dideoxyadenosine; 2',3'-dideoxyinosine; and 2-chloro
      2'deoxyadenosine (2CdA), significantly inhibited the uptake of [3H]inosine in
      HeLa cells transiently transfected with hSPNT1. However, there was no significant
      Na+-dependent uptake of [3H]2', 3'-dideoxyinosine or [3H]2CdA in the transfected
      cells, suggesting that these nucleoside analogs are not permeants of hSPNT1.
      Interestingly, 2CdA was considerably less potent in inhibiting [3H]inosine uptake
      in HeLa cells expressing hSPNT1 than in cells expressing the rat homolog rSPNT
      (IC50 = 371 microM versus 13.8 microM), suggesting that there may be notable
      species differences in the kinetic interactions of some nucleoside analogs with
      purine- selective nucleoside transporters.

PMID- 10336544
TI  - SPD 502: a water-soluble and in vivo long-lasting AMPA antagonist with
      neuroprotective activity.
AB  - Accumulating preclinical data suggest that compounds that block the excitatory
      effect of glutamate on excitatory amino acid receptors may have neuroprotective
      effects and utility for the treatment of neurodegeneration after brain ischemia.
      In the present study, the in vitro and in vivo pharmacological properties of the
      novel glutamate antagonist SPD 502 [8-methyl-5(4-(N,N-dimethylsulfamoyl)phenyl)
      6,7, 8,9,-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2, 3-dione-3-O-(4
      hydroxybutyric acid-2-yl)oxime] are described. In binding studies, SPD 502 was
      shown to display selectivity for the [3H]alpha-amino-3-hydroxy-5-methylisoxazole
      4-propionic acid (AMPA)-binding site (IC50 = 0.043 microM) compared with the
      [3H]kainate- (IC50 = 81 microM), [3H]cis-4-phosphonomethyl-2-piperidine
      carboxylic acid-(CGS 19755), and [3H]glycine-binding sites (IC50 > 30 microM) in
      rat cortical membranes. In an in vitro functional assay, SPD 502 blocked the AMPA
      induced release of [3H]gamma-aminobutyric acid from cultured mouse cortical
      neurons in a competitive manner with an IC50 value of 0.23 microM. Furthermore,
      SPD 502 potently and selectively inhibited AMPA-induced currents in cortical
      neurons with an IC50 value of 0.15 microM. In in vivo electrophysiology, SPD 502
      blocked AMPA-evoked spike activity in rat hippocampus after i.v. administration
      with an ED50 value of 6.1 mg/kg and with a duration of action of more than 1 h.
      Furthermore, SPD 502 increased the seizure threshold for electroshock-induced
      tonic seizures in mice at i.v doses of 40 mg/kg and higher. In the two-vessel
      occlusion model of transient forebrain ischemia in gerbils, SPD 502 (10 mg/kg
      bolus injection followed by a 10 mg/kg/h infusion for 2 h) resulted in a highly
      significant protection against the ischemia-induced damage in the hippocampal CA1
      pyramidal neurons.

PMID- 10336545
TI  - Mechanisms of verapamil inhibition of action potential firing in rat intracardiac
      ganglion neurons.
AB  - The effects of verapamil and related phenylalkylamines on neuronal excitability
      were investigated in isolated neurons of rat intracardiac ganglia using whole
      cell perforated patch-clamp recording. Verapamil (>/=10 microM) inhibits tonic
      firing observed in response to depolarizing current pulses at 22 degrees C. The
      inhibition of discharge activity is not due to block of voltage-dependent Ca2+
      channels because firing is not affected by 100 microM Cd2+. The K+ channel
      inhibitors charybdotoxin (100 nM), 4-aminopyridine (0.5 mM), apamin (30-100 nM),
      and tetraethylammonium ions (1 mM) also have no effect on firing behavior at 22
      degrees C. Verapamil does not antagonize the acetylcholine-induced inhibition of
      the muscarine-sensitive K+ current (M-current) in rat intracardiac neurons.
      Verapamil inhibits the delayed outwardly rectifying K+ current with an IC50 value
      of 11 microM, which is approximately 7-fold more potent than its inhibition of
      high voltage-activated Ca2+ channel currents. These data suggest that verapamil
      inhibits tonic firing in rat intracardiac neurons primarily via inhibition of
      delayed outwardly rectifying K+ current. Verapamil inhibition of action potential
      firing in intracardiac neurons may contribute, in part, to verapamil-induced
      tachycardia.

PMID- 10336546
TI  - Characterization of a vertebrate neuromuscular junction that demonstrates
      selective resistance to botulinum toxin.
AB  - Botulinum toxin blocks transmitter release by proceeding through a series of four
      steps: binding to cell surface receptors, penetration of the cell membrane by
      receptor-mediated endocytosis, penetration of the endosome membrane by pH-induced
      translocation, and intracellular proteolysis of substrates that govern
      exocytosis. Each of these steps is essential for toxin action on intact cells.
      Therefore, alterations in cell structure or cell function that impede any of
      these steps should confer resistance to toxin. In the present study, screening
      for susceptibility to four serotypes of botulinum toxin revealed that the
      cutaneous-pectoris nerve-muscle preparation of Rana pipiens is resistant to type
      B botulinum toxin. Resistance was demonstrated both by electrophysiologic
      techniques and by dye-staining techniques. In addition, resistance to serotype B
      was demonstrated at toxin concentrations that were 2 orders of magnitude higher
      than those associated with blockade produced by other serotypes. In experiments
      on broken cell preparations, type B toxin cleaved synaptobrevin from frog brain
      synaptosomes. However, the toxin did not bind to frog nerve membranes. These
      findings suggest that resistance is due to an absence of cell surface receptors
      for botulinum toxin type B. The fact that cutaneous-pectoris preparations were
      sensitive to other botulinum toxin serotypes (A, C, and D), as well as other
      neuromuscular blocking agents (alpha-latrotoxin, beta-bungarotoxin), indicates
      that botulinum toxin type B receptors are distinct.

PMID- 10336548
TI  - A pharmacokinetic/pharmacodynamic model for recombinant human growth hormone
      effects on induction of insulin-like growth factor I in monkeys.
AB  - The pharmacokinetics of recombinant human growth hormone (rhGH) and its effects
      on the induction of insulin-like growth factor I (IGF-I) were studied in juvenile
      rhesus monkeys. Disposition profiles of rhGH from two short-term i.v. infusion
      studies were described by a two-compartment model yielding a clearance of 16.1
      ml/min and T1/2 of 2.0 h. Four rhGH treatment groups were included in this study:
      group A, ProLease rhGH (24 mg), a sustained-release microsphere formulation;
      group B, a single s.c. injection plus an implanted osmotic pump (24.4 mg); group
      C, a single s.c. injection (25.9 mg); group D, daily 0.86-mg s.c. injection for
      28 days. Their rhGH input profiles were analyzed by a numerical deconvolution
      method. ProLease and osmotic pump provided zero-order inputs of rhGH and
      maintained the serum rhGH concentrations around 9 to 13 ng/ml for 16 (group A)
      and 30 days (group B). For s.c. injections, rhGH underwent first-order
      absorption. An indirect response model was applied based on use of a Hill
      function for stimulation of IGF-I production. Parameter values obtained included
      Smax = 2.2, SC50 = 6.5 ng/ml, and gamma (slope coefficient) = 6.8, which were
      applicable to all treatments. The area under effect curve showed group B to be
      most effective for IGF-I induction, whereas group A produced the highest peak
      level in 16 days. Group C had the lowest induction among the four groups, despite
      being given the highest dose. Group D had modest IGF-I induction, but the
      pulsatile rhGH input is less effective than continuous input provided by
      ProLease. Our pharmacokinetic/pharmacodynamic model demonstrates that ProLease
      and osmotic pump delivery were best able to maintain rhGH level above the s.c.50
      value, which provided more effective IGF-I induction compared with the single or
      daily subcutaneous injections in solution.

PMID- 10336547
TI  - Peptidyl inhibitors of shaker-type Kv1 channels elicit twitches in guinea pig
      ileum by blocking kv1.1 at enteric nervous system and enhancing acetylcholine
      release.
AB  - Potent and selective peptidyl blockers of the Shaker-type (Kv1) voltage-gated
      potassium channels were used to determine the role of these channels in
      regulating the spontaneous motility of smooth muscle preparations. Margatoxin
      (MgTX), kaliotoxin, and agitoxin-2 at 1 to 10 nM and agitoxin-1 at 50 to 100 nM
      induce twitches in guinea pig ileum strips. These twitches are abolished by
      tetrodotoxin (TTX, 0.5 microM), atropine (1 microM), hexamethonium (10 microM),
      or nifedipine (0.1 microM). It is proposed that blockade of Kv1 channels by MgTX,
      kaliotoxin, or the agitoxins increases excitability of intramural nerve plexuses
      in the ileum, promoting release of acetylcholine from excitatory motor nerve
      terminals. This, in turn, leads to Ca2+-dependent action potentials and twitching
      of the muscle fibers. MgTX does not induce twitches in several other guinea pig
      and/or rat vascular, genitourinary, or gastrointestinal smooth muscles, although
      small increases in spontaneous myogenic activity may be seen in detrusor muscle
      exposed to >30 nM MgTX. This effect is not reversed by TTX or atropine. The TTX-
      and atropine-sensitive twitches of guinea pig ileum are also induced by nanomolar
      concentrations of alpha-dendrotoxin, a selective blocker of Shaker Kv1.1 and 1.2
      subtypes, or stichodactylatoxin, a peptide isolated from sea anemone that
      displays high affinity for Kv1.1 and 1.3, but not by charybdotoxin, which blocks
      Kv1.2 and 1.3 but not 1.1. The data taken together suggest that high-affinity
      blockade of Kv1.1 underlies the ability of MgTX, kaliotoxin, agitoxin-1, agitoxin
      2, alpha-dendrotoxin, and stichodactylatoxin to elicit TTX-sensitive twitches in
      guinea pig ileum.

PMID- 10336549
TI  - Effects of rolipram and cilostamide on renal functions and cyclic AMP release in
      anesthetized dogs.
AB  - The present study was undertaken to examine whether phosphodiesterases III and IV
      regulate renal cAMP level and whether inhibition of these enzymes influences
      renal functions in anesthetized dogs. The intrarenal arterial infusion of
      rolipram (0.1, 0.3, and 1 microgram/kg/min), a selective phosphodiesterase IV
      inhibitor, increased renal blood flow, glomerular filtration rate, urine flow
      rate, and urinary Na+ excretion with elevating arterial and renal venous plasma
      cAMP concentrations and urinary cAMP excretion. However, cilostamide (0.1, 0.3,
      and 1 microgram/kg/min), a selective phosphodiesterase III inhibitor, did not
      affect the values of these parameters. Indomethacin (3 mg/kg i.v. bolus and 1
      mg/kg/min i.v. infusion), a cyclooxygenase inhibitor, reduced the basal arterial
      and renal venous plasma cAMP concentrations and blunted the rolipram-induced
      elevation of cAMP concentrations and urinary cAMP excretion. The effects of
      rolipram on renal hemodynamics and urine formation were attenuated in the
      presence of indomethacin. These results suggest that in the dog kidney in vivo,
      1) phosphodiesterase IV, but not phosphodiesterase III, participates in
      degradation of cAMP and 2) the inhibition of phosphodiesterase IV enhances
      glomerular filtration and urinary Na+ excretion, the responses of which depend in
      part on indomethacin-susceptible (prostaglandin-mediated, probably) control of
      basal cAMP level.

PMID- 10336550
TI  - The effects of morphine-induced increases in extracellular acetylcholine levels
      in the rostral ventrolateral medulla of rat.
AB  - The present study examined the role of the rostral ventrolateral medulla (RVLM)
      in the modulation of acetylcholine (ACh) release by morphine. We examined the
      effect of morphine on the release of ACh in the RVLM of freely moving rats using
      the in vivo microdialysis method. The basal level of ACh was 303.0 +/- 28.2
      fmol/20 microliter/15 min in the presence of neostigmine (10 microM). Morphine at
      a low dose of 5 mg/kg (i.p.) increased ACh release by the RVLM by 42.4%. A higher
      morphine dose (10 mg/kg i.p.) significantly increased the release of ACh by
      75.4%, with a maximal effect (86.4%) at 75 min. This enhancement following i.p.
      administration of morphine was reversed by naloxone (1 mg/kg i.p.). Addition of
      morphine (10(-4) M) to the perfusion medium increased the ACh release by 85.8% of
      the predrug values. The increased ACh release induced by local application of
      morphine was reversed by pretreatment with naloxone (1 mg/kg i.p.). The
      antinociceptive effect of locally applied morphine into the RVLM was assessed
      using the hot-plate test and tail immersion test in unanesthetized rats. Local
      application of morphine (10(-4) M) via a microdialysis probe induced an increase
      in both tail withdrawal and hot-plate response. These findings suggest that
      morphine seems to exert a direct stimulatory effect on ACh release by the RVLM
      and that morphine-induced nociception is, in part, activated by the release of
      ACh in freely moving rats.

PMID- 10336551
TI  - Increased nicotinic receptors in brains from smokers: membrane binding and
      autoradiography studies.
AB  - Chronic administration of nicotine increases the density of neuronal cholinergic
      nicotinic receptors in cells and in rodent brain, and similar increases have been
      reported in brains from human smokers. To further examine this phenomenon, we
      measured nicotinic receptor binding sites in brain regions from matched
      populations of smokers and nonsmokers. We first measured binding of [3H](+/
      )epibatidine ([3H]EB) and [3H]cytisine in homogenate preparations from samples of
      prefrontal and temporal cerebral cortex. Binding of each radioligand was
      significantly higher (250-300%) in both cortical regions from brains of smokers.
      Frozen sections from each of the cerebral cortical regions and the hippocampus
      were used for autoradiographic analysis of [3H]EB binding. In cerebral cortex,
      binding was most dense in layer VI in the prefrontal cortex and layers IV and VI
      in the temporal cortex. Densitometric analysis of [3H]EB binding sites revealed
      marked increases of 300 to 400% of control in all cortical regions examined from
      smokers' brains. Binding in the hippocampal formation was heterogeneously
      distributed, with dense areas of binding sites seen in the parasubiculum,
      subiculum, and molecular layer of the dentate gyrus, and the lacunosum-moleculare
      layer of the CA1/2. Binding of [3H]EB was significantly higher in all six regions
      of the hippocampus examined from brains of smokers compared with nonsmokers.
      These increases ranged from 160% of control in parasubiculum to 290% in the
      molecular layer of the dentate gyrus. The increase in nicotinic receptors in the
      cerebral cortex and hippocampus of smokers may modify the central nervous system
      effects of nicotine and contribute to an altered response of smokers to nicotine.

PMID- 10336552
TI  - Hepatic artery flow and propranolol metabolism in perfused cirrhotic rat liver.
AB  - The oxygen limitation theory states that capillarization of the sinusoidal
      endothelium in cirrhosis impairs hepatocellular oxygen uptake manifesting as a
      reduction in oxygen-dependent enzyme activity including phase 1 drug metabolism.
      The hepatic artery supplies highly oxygenated blood to the liver. Therefore, we
      tested whether augmentation of hepatic arterial blood flow could improve hepatic
      oxygenation and function in cirrhosis. Rats were treated with carbon
      tetrachloride and phenobarbitone to induce hepatic cirrhosis or fibrosis. We used
      a bivascular rat liver perfusion model to examine the effects of increased
      hepatic artery flow on propranolol clearance and oxygen consumption. Each liver
      was perfused at three hepatic artery flow rates, 1 to 3, 4 to 6, and 7 to 9
      ml/min with a constant portal venous flow of 7 to 9 ml/min. Increasing the
      hepatic artery flow led to improvement in propranolol clearance in control (n =
      7, P <.001), fibrotic (n = 8, P <.001), and cirrhotic (n = 6, P <.001) livers.
      Intrinsic clearance of propranolol increased only in the cirrhotic livers (P
      =.01), indicating an improvement in enzyme activity. Regression analysis
      indicated that this improvement was mediated by change in oxygen delivery alone
      (P =.001). The results confirm that propranolol metabolizing enzyme activity in
      cirrhosis can be improved by increasing oxygen delivery by increasing hepatic
      arterial blood flow. These findings suggest that increasing hepatic arterial
      blood flow may be an important therapeutic strategy for improving global liver
      function in cirrhosis.

PMID- 10336554
TI  - Factors that enhance ethanol inhibition of N-methyl-D-aspartate receptors in
      cerebellar granule cells.
AB  - The objective of this study was to identify factors that influence ethanol (EtOH)
      inhibition of the N-methyl-D-aspartate receptor (NMDAR) in primary cultured
      cerebellar granule cells. Several factors contributing to the inhibitory effects
      of EtOH on NMDAR function were assessed using both whole-cell and perforated
      patch-clamp recordings. The NMDAR subunit composition was examined by Western
      blot analysis using NR2 subunit-specific antibodies and pharmacological
      manipulation with the NR2B-specific antagonist infenprodil. Western blot analysis
      indicated that NMDAR subunit composition changed from a combination of NR2A and
      NR2B containing NMDARs to primarily NR2A with increasing days in vitro (DIV).
      Although the NR2B subunit was detectable until 21 DIV, there was a significant
      decrease in ifenprodil sensitivity after 7 DIV. EtOH sensitivity did not change
      with an increasing DIV. A high concentration of glycine reversed EtOH inhibition
      of steady-state, but not peak, NMDA-induced current during whole-cell recordings.
      Significant glycine reversal of effects of a low concentration of EtOH on peak
      current was observed under perforated patch-clamp conditions. A 30-s EtOH
      pretreatment significantly enhanced EtOH inhibition of NMDA-induced peak current.
      Collectively, these results indicate that EtOH sensitivity of the NMDAR in
      primary cultured cerebellar granule cells is not related to subunit composition
      nor ifenprodil sensitivity, involves a kinetic interaction with glycine, and can
      be enhanced by a slowly developing transduction mechanism that occurs within tens
      of seconds.

PMID- 10336553
TI  - Na+, K+-ATPase inhibitors down-regulate gene expression of the intracellular
      signaling protein 14-3-3 in rat lens.
AB  - To identify genes that are differentially expressed by Na+, K+-ATPase inhibitors,
      we used the differential display technique to compare mRNA expression patterns in
      rat lens. Lenses were treated with 10 microM ouabain, bufalin, or 19-norbufalin
      derivative for 24 h and were compared with control lenses. Differential display
      analysis revealed that one of the down-regulated genes was 14-3-3 theta. Down
      regulation was confirmed by Northern blot and by reverse transcription-polymerase
      chain reaction analysis. Reverse transcription-polymerase chain reaction of
      additional 14-3-3 isoforms revealed that the eta and gamma isoforms of 14-3-3 are
      also down-regulated by ouabain, bufalin, and 19-norbufalin derivative, whereas
      the zeta isoform is down-regulated only by bufalin. Down-regulation of the 14-3-3
      isoforms occurred without a significant change in gamma-crystallin gene
      expression. These results demonstrate that one of the consequences of Na+, K+
      ATPase inhibition by exogenous or endogenous inhibitors is the down-regulation of
      mRNA transcripts encoding several isoforms of 14-3-3. Because the 14-3-3 proteins
      are multifunctional regulatory proteins, the reduction in the abundance of
      various isoforms will have profound effects on cell function.

PMID- 10336555
TI  - In vivo measurement by [3H]Tamsulosin of alpha1 adrenoceptors in rat tissues in
      relation to the pharmacokinetics.
AB  - The present study was undertaken to simultaneously measure alpha1 adrenoceptors
      in rat tissues by [3H]tamsulosin in vivo. In vivo specific [3H]tamsulosin binding
      was observed in the prostate, vas deferens, aorta, submaxillary gland, spleen,
      heart, lung, and kidney after i.v. injection of the ligand but not in the
      cerebral cortex and liver. Specific [3H]tamsulosin binding in the kidney, lung,
      heart, and spleen was greatest at 3 min after i.v. injection and declined rapidly
      with the disappearance of [3H]tamsulosin from the plasma. On the other hand,
      [3H]tamsulosin binding in the prostate and aorta peaked at 10 to 60 min after
      i.v. injection, and a considerable level of specific binding in both tissues
      persisted up to 240 min. The most sustained binding of [3H]tamsulosin occurred in
      the submaxillary gland. In vivo specific [3H]tamsulosin binding in rat tissues
      was effectively inhibited by the coinjection of low doses of unlabeled
      tamsulosin, prazosin, and terazosin with the radioligand but not by relatively
      high doses of yohimbine and propranolol. Based on estimated ID50 values, in vivo
      inhibitory effect of tamsulosin compared with prazosin was 5 to 14 times greater
      in rat tissues except the spleen, which showed 1.6 times less potent than
      prazosin. From ratios of ID50 (spleen) to ID50 (submaxillary gland) or ID50
      (prostate), tamsulosin was 9 and 19 times, respectively, greater than prazosin in
      selectivity of alpha1 adrenoceptors in the submaxillary gland and prostate versus
      the spleen, respectively, suggesting that tamsulosin binds to alpha1A subtype
      with higher affinity than alpha1B subtype in vivo. The present study suggests
      that [3H]tamsulosin is a useful radioligand for in vivo measurement of alpha1
      adrenoceptors in rat tissues.

PMID- 10336556
TI  - Zinc and ifenprodil allosterically inhibit two separate polyamine-sensitive sites
      at N-methyl-D-aspartate receptor complex.
AB  - In this study, we investigated the hypothesis that inhibition of the N-methyl-D
      aspartate (NMDA) receptor complex by zinc involves a polyamine-sensitive
      regulatory site. We found that the specific binding of the open channel ligand
      [3H]MK-801 to rat hippocampal membranes 1) was inhibited by low concentrations of
      Zn2+ (IC50 = 5.5 microM) by 65%. 2) This high-affinity component of inhibition
      was reversed by the polyamine spermine to an extent that could be reconciled with
      competitive interaction between Zn2+ and spermine. 3) Partial inhibition by Zn2+
      was additive with partial inhibition by ifenprodil, an inhibitor of the NMDA
      receptor complex supposed to act at a polyamine-sensitive regulatory site, and 4)
      in membranes prepared from several other brain regions, inhibition of [3H]MK-801
      binding by Zn2+ and by ifenprodil was either less than additive, or
      superadditive. Our observation that ifenprodil, at concentrations saturating its
      high-affinity component of inhibition, prevented spermine from reversing the
      inhibition by Zn2+ indicates that spermine did not increase [3H]MK-801 binding by
      competition with Zn2+ but rather via another polyamine regulatory site not
      sensitive to zinc but sensitive to ifenprodil. We conclude that Zn2+ reduces
      channel opening of the NMDA receptor complex by allosteric inhibition of a
      polyamine-sensitive regulatory site different from that inhibited by ifenprodil
      and that these two allosteric sites influence each other in a manner dependent on
      the brain region investigated. The different proportions of zinc/ifenprodil
      inhibition in different regions could reflect different percentages of various
      NMDA receptor subtypes.

PMID- 10336557
TI  - Use of Ca2+ modulation to evaluate biliary excretion in sandwich-cultured rat
      hepatocytes.
AB  - Previous work in our laboratory has indicated that biliary excretion of a
      substrate in sandwich-cultured hepatocytes can be quantitated by measurement of
      substrate accumulation in the presence and absence of extracellular Ca2+. The
      present study was designed to examine the effects of Ca2+ on taurocholate
      accumulation and tight junction integrity in cultured hepatocytes. Kinetic
      modeling was used to characterize taurocholate disposition in the hepatocyte
      monolayers in the presence and absence of extracellular Ca2+. The accumulation of
      taurocholate in freshly isolated hepatocytes, which lack an intact canalicular
      network, was the same in the presence and absence of extracellular Ca2+. Electron
      microscopy studies showed that Ca2+ depletion increased the permeability of the
      tight junctions to ruthenium red, demonstrating that tight junctions were the
      major diffusional barrier between the canalicular lumen and the extracellular
      space. Cell morphology and substrate accumulation studies in the monolayers
      indicated that Ca2+ depletion disrupted the tight junctions in 1 to 2 min. The
      integrity of the disrupted tight junctions was not re-established completely
      after reincubation in the presence of Ca2+ for 1 h. The accumulation of
      taurocholate was described best by a two-compartment model (cytosol and bile)
      with Michaelis-Menten kinetics for both uptake and biliary excretion. In summary,
      Ca2+ depletion does not alter hepatocyte transport properties of taurocholate.
      Ca2+ modulation may be a useful approach to study biliary excretion of substrates
      in sandwich-cultured hepatocytes.

PMID- 10336558
TI  - Expression of the GLT-1 subtype of Na+-dependent glutamate transporter:
      pharmacological characterization and lack of regulation by protein kinase C.
AB  - Several subtypes of Na+-dependent glutamate transporters have been
      pharmacologically differentiated in brain tissues. Five distinct cDNA clones that
      express Na+-dependent glutamate transport activity have been isolated. One goal
      of the current study was to compare the pharmacological properties of the rat GLT
      1 subtype of transporter to those identified previously using rat brain tissues.
      To accomplish this goal, GLT-1 was stably transfected into two different cell
      lines that express low levels of endogenous transport activity (MCB and L-M (TK
      )). Several clones stably transfected with GLT-1 were isolated. In each cell
      line, Na+-dependent glutamate transport activity was saturable with similar Km
      values (19 and 37 microM). The pharmacological properties of GLT-1-mediated
      transport in these cell lines paralleled those observed for the predominant
      pharmacology observed in cortical crude synaptosomes. These data are consistent
      with other lines of evidence that suggest that GLT-1 may be sufficient to explain
      most of the Na+-dependent glutamate transport activity in cortical synaptosomes.
      Although recent studies using HeLa cells have suggested that GLT-1 can be rapidly
      up-regulated by activation of protein kinase C (PKC), modulation of PKC or
      phosphatase activity had no effect on GLT-1-mediated activity in these
      transfected cell lines. To determine if GLT-1 regulation by PKC is cell-specific,
      HeLa cells, which endogenously express the EAAC1 subtype of transporter, were
      stably transfected with GLT-1. Although EAAC1-mediated activity was increased by
      activation of PKC, we found no evidence for regulation of GLT-1. Despite the
      present findings, GLT-1 activity may be regulated by PKC under certain
      conditions.

PMID- 10336559
TI  - Hypoxia-induced production of 12-hydroxyeicosanoids in the corneal epithelium:
      involvement of a cytochrome P-4504B1 isoform.
AB  - The corneal epithelium metabolizes arachidonic acid by a cytochrome P-450 (CYP)
      mediated activity to 12-hydroxy-5,8,11, 14-eicosatetraenoic acid (12(R)-HETE) and
      12-hydroxy-5,8, 14-eicosatrienoic acid (12(R)-HETrE ). Both metabolites possess
      potent inflammatory properties, with 12(R)-HETrE being a powerful angiogenic
      factor, and they assume the role of inflammatory mediators in hypoxia- and
      chemical-induced injury in the cornea in vivo and in vitro. We used a model of
      corneal organ culture that exhibits hypoxia-induced epithelial CYP-dependent
      12(R)-HETE and 12(R)-HETrE synthesis for isolating, identifying, and
      characterizing the CYP protein responsible for these eicosanoid syntheses.
      Northern analysis revealed the presence of a CYP4A-hybridizable mRNA, the levels
      of which were increased after hypoxia. Reverse transcription-polymerase chain
      reaction analysis with primers specific for the CYP4A family led to the isolation
      of a 671-base pair fragment with a 98.8% sequence homology to the rabbit lung
      CYP4B1 isoform, of which the levels in the corneal epithelium were greatly
      increased under hypoxic conditions. Moreover, phenobarbital, an inducer of
      hepatic CYP4B1 in the rabbit, also induced 12-HETE and 12-HETrE synthesis.
      Antibodies against CYP4B1, but not against CYP4A1, inhibited hypoxia-, clofibrate
      , and phenobarbital-induced 12-HETE and 12-HETrE synthesis. These results suggest
      the involvement of a CYP4B1 isoform in the corneal epithelial synthesis of these
      eicosanoids in response to hypoxia.

PMID- 10336560
TI  - Cannabinoid inhibition of the processing of intact lysozyme by macrophages:
      evidence for CB2 receptor participation.
AB  - Delta9-tetrahydrocannabinol (THC) impairs multiple immunological functions. The
      ability of a macrophage hybridoma to function as an antigen-presenting cell was
      examined by the stimulation of a soluble protein antigen-specific helper T cell
      hybridoma to secrete interleukin-2. THC exposure significantly reduced the T cell
      response to the native form of the antigen after a 24-h pretreatment of the
      macrophages with nanomolar drug concentrations. However, THC did not affect
      interleukin-2 production when the macrophages presented a synthetic peptide of
      the antigen to the T cells, suggesting that the drug may interfere with antigen
      processing, not peptide presentation. Cannabinoid inhibition of the T cell
      response to the native antigen was stereoselective consistent with the
      involvement of a cannabinoid (CB) receptor. Bioactive CP-55,940 diminished T cell
      activation, whereas the inactive stereoisomer CP-56,667 did not. The macrophage
      hybridoma expressed mRNA for the CB2 but not the CB1 receptor whereas the T cells
      expressed an extremely low level of mRNA for the CB2 receptor. The CB1-selective
      antagonist SR141716A did not reverse the suppression caused by THC, demonstrating
      that the CB1 receptor was not responsible for the drug's inhibitory effect. In
      contrast, the CB2-selective antagonist SR144528 completely blocked THC's
      suppression of the T cell response, implicating the participation of the CB2
      receptor. These findings suggest that the CB2 receptor may be involved in CB
      inhibition of antigen processing by macrophages in this system.

PMID- 10336561
TI  - Acute pentylenetetrazol injection reduces rat GABAA receptor mRNA levels and GABA
      stimulation of benzodiazepine binding with No effect on benzodiazepine binding
      site density.
AB  - The effects of a single convulsive dose of pentylenetetrazol (PTZ, 45 mg/kg i.p.)
      on rat brain gamma-aminobutyric acid type A (GABAA) receptors were studied.
      Selected GABAA receptor subunit mRNAs were measured by Northern blot analysis
      (with beta-actin mRNA as a standard). Four hours after PTZ, the GABAA receptor
      gamma2-mRNA was decreased in hippocampus, cerebral cortex, and cerebellum; alpha1
      mRNA was decreased in cerebellum; and beta2 subunit mRNA was decreased in cortex
      and cerebellum. The alpha5 subunit mRNA level was not altered. Those mRNAs that
      had been reduced were increased in some brain regions at the 24-h time point, and
      these changes reverted to control levels by 48 h. PTZ effect on GABAA receptors
      was also studied by autoradiographic binding assay with the benzodiazepine
      agonist [3H]flunitrazepam (FNP), the GABAA agonist [3H]muscimol, and the
      benzodiazepine antagonist [3H]flumazenil. There was an overall decrease in
      [3H]FNP binding 12 but not 24 h after PTZ treatment. In contrast, [3H]muscimol
      binding was minimally affected, and [3H]flumazenil binding was unchanged after
      PTZ treatment. Additional binding studies were performed with well-washed
      cerebral cortical homogenates to minimize the amount of endogenous GABA. There
      was no PTZ effect on specific [3H]FNP binding. However, there was a significant
      reduction in the stimulation of [3H]FNP binding by GABA. The results showed that
      an acute injection of PTZ caused transient changes in GABAA receptor mRNA levels
      without altering receptor number but affected the coupling mechanism between the
      GABA and benzodiazepine sites of the GABAA receptor.

PMID- 10336563
TI  - Effects of self-administered cocaine on plasma adrenocorticotropic hormone and
      cortisol in male rhesus monkeys.
AB  - This study was designed to examine the effects of self-administered cocaine on
      hypothalamic-pituitary-adrenal (HPA) axis activity in rhesus monkeys. Initially,
      basal release of cortisol and adrenocorticotropic hormone (ACTH) was measured in
      singly housed male and female monkeys (n = 9) over a 24-h period using plasma
      samples obtained from indwelling venous catheters. Basal cortisol and ACTH levels
      in both male and female rhesus monkeys demonstrated a circadian pattern of
      release, with peak levels for cortisol (19.60 +/- 2.16 microgram/dl) and ACTH
      (19.63 +/- 2.56 pg/ml) measured at 6:00 AM. The nadir for ACTH (6.27 +/- 0.62
      pg/ml) occurred at 6:00 PM, preceding the cortisol nadir (5.55 +/- 1.21
      microgram/dl) at 9:00 PM. The reinforcing effects of saline, 0.01, 0.03, 0.1, and
      0.3 mg/kg/injection cocaine were then evaluated using a fixed-ratio 30, time-out
      10-min schedule of reinforcement in seven male monkeys. Blood was sampled before,
      during, and after self-administration sessions. Self-administration of cocaine
      produced dose-dependent increases in cortisol and ACTH. One dose of cocaine (0.03
      mg/kg/injection), although reliably self-administered, did not produce a
      significant increase in HPA axis activity. These results indicate that although
      cocaine dose-dependently increases HPA axis activity, the HPA effect is more
      likely a consequence of overall cocaine intake than it is an indicator of cocaine
      doses that are sufficient to maintain self-administration behavior.

PMID- 10336562
TI  - Induction of stromelysin gene expression by tumor necrosis factor alpha is
      inhibited by dexamethasone, salicylate, and N-acetylcysteine in synovial
      fibroblasts.
AB  - Proinflammatory cytokines, altered connective tissue metabolism, and
      overexpression of matrix metalloproteinases (MMPs) such as stromelysin compared
      to tissue inhibitors of metalloproteinases (TIMPs) result in synovial
      inflammation and erosion of arthritic cartilage. Tumor necrosis factor alpha (TNF
      alpha) is a major synovial inflammatory mediator responsible for inhibiting
      extracellular matrix (ECM) synthesis and stimulating degradation of cartilage ECM
      by activated MMPs in arthritic joints. To suppress these effects and to gain
      insight into the mechanism of TNF-alpha action, we identified the inhibitors of
      TNF-alpha stimulation of stromelysin gene expression. In bovine synovial
      fibroblasts, TNF-alpha did not affect a recently identified inhibitor, TIMP-3,
      but induced stromelysin mRNA expression in a dose- and time-dependent fashion (3-
      to 5-fold) which required de novo protein synthesis. Stimulation by TNF-alpha was
      potently inhibited (99-100%) by the synthetic glucocorticoid, dexamethasone.
      Sodium salicylate dose-dependently inhibited (100%) the TNF-alpha action.
      Indomethacin and ibuprofen were partially inhibitory. Free radical scavenger
      antioxidant, N-acetylcysteine (but not other antioxidants) also suppressed the
      TNF-alpha induction (36-100%) of stromelysin suggesting involvement of reactive
      oxygen species in the induction process. TNF-alpha induction of stromelysin gene
      expression can therefore be inhibited at the gene expression level by several
      pharmacological agents which are likely to function via arachidonic acid
      metabolites, free radical scavenging or interference with the activator protein
      1, polyoma virus enhancer A-binding protein 3, and nuclear factor kappaB classes
      of transcription factors. Our results may help to elucidate the mechanism of TNF
      alpha action and explain the beneficial role of these agents in the treatment of
      inflammatory diseases.

PMID- 10336564
TI  - Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human
      brain.
AB  - Cytochrome P-450 2E1 (CYP2E1) is a readily inducible hemoprotein that catalyzes
      the oxidation of endogenous compounds and many low molecular weight xenobiotics.
      As the major component of the microsomal ethanol oxidizing system, it contributes
      significantly to ethanol metabolism and the formation of the highly reactive
      metabolite acetaldehyde. The leaky property of this enzyme results in the
      generation of reactive oxygen species that can induce oxidative stress and
      cytotoxic conditions deleterious to development. To further investigate the
      proposed role of CYP2E1 in the etiology of alcohol teratogenesis, the current
      study focused on the quantification of CYP2E1 in prenatal human brain, a tissue
      that is highly vulnerable to the damaging effects of ethanol throughout
      gestation. In microsomal samples prepared from pools of brain tissues,
      immunoreactive protein was detected by Western blot analysis using enhanced
      chemiluminescence, whereas functional protein was estimated with an enzymatic
      assay using p-nitrophenol and an electrochemical detection system. CYP2E1
      transcript was consistently detected in RNA samples prepared from individual
      brain tissues using the ribonuclease protection assay. Quantitative data were
      collected by scanning densitometry and phosphorimaging technology. There was a
      dramatic increase in human brain CYP2E1 content around gestational day 50 and a
      fairly constant level was maintained throughout the early fetal period, until at
      least day 113. The relatively low levels of the P-450 isoform present in
      conceptal brain may be sufficient to generate reactive intermediates that elicit
      neuroembryotoxicity following maternal alcohol consumption.

PMID- 10336565
TI  - Gi-mediated activation of mitogen-activated protein kinase (MAPK) pathway by
      receptor mimetic basic secretagogues of connective tissue-type mast cells:
      bifurcation of arachidonic acid-induced release upstream of MAPK.
AB  - The family of basic secretagogues of connective tissue mast cells act as receptor
      mimetic agents, which trigger exocytosis by directly activating G proteins. We
      now demonstrate that pertussis toxin (Ptx)-sensitive Gi proteins, activated by
      compound 48/80 (c48/80), a potent member of this family, also activate the
      p42/p44 MAP kinases (MAPKs). This activation was potentiated by the protein
      tyrosine phosphatase inhibitor vanadate, whereas the tyrphostin AG-18, a
      competitive inhibitor of protein tyrosine kinases (PTKs); the protein kinase C
      inhibitors K252a and GF109203X; the phosphatidylinositol-3-kinase (PI-3K)
      inhibitors wortmannin and LY294002; and EGTA have abolished this activation.
      These results suggest that c48/80 activated the p42/p44 MAPKs via a mechanism
      that involves PTKs, protein kinase C, phosphatidylinositol-3-kinase and Ca2+ as
      mediators. Protein tyrosine phosphorylation and activation of the p42/p44 MAPKs
      were closely correlated with stimulation of arachidonic acid (AA) release by
      c48/80 but not with histamine secretion. However, whereas PD98059, the inhibitor
      of the MAPK kinase has abrogated MAPK activation, this inhibitor failed to effect
      release of AA. We therefore conclude that by activating Ptx-sensitive Gi
      protein(s), the basic secretagogues of mast cells stimulate multiple signaling
      pathways, which diverge to regulate the production and release of the different
      inflammatory mediators. Whereas the signaling pathway responsible for triggering
      histamine release is PTK independent, the pathway responsible for the stimulation
      of AA release bifurcates downstream to PTKs but upstream to the activation of
      MAPKs.

PMID- 10336566
TI  - Determinants of the response of human blood vessels to nitric oxide donors in
      vivo.
AB  - The potency of the nitric oxide (NO) donors glyceryltrinitrate (GTN) and 3
      morpholinosydnonimine was compared in human dorsal hand veins, the radial artery,
      and the forearm resistance vessels. NO donors were more potent in veins and the
      radial artery (vessels with minimal basal NO-mediated dilatation) than in the
      resistance vascular bed (where basal NO is a major determinant of vascular tone).
      In contrast, 8-bromoguanosine 3',5'-cyclic monophosphate (a cGMP mimetic) was
      approximately equipotent in resistance arteries and veins and was less potent in
      the radial artery. Inhibition of phosphodiesterase V with dipyridamole did not
      alter the arteriovenous profile of GTN. Increasing the local concentration of NO
      in veins (by infusing sodium nitroprusside) reduced their sensitivity to GTN but
      not to 8-bromoguanosine 3',5'-cyclic monophosphate. Conversely, reducing
      endogenous NO production in the resistance vasculature led to time-dependent
      increases in the response to GTN. These data suggest that soluble guanylate
      cyclase rather than cGMP-dependent protein kinase or phosphodiesterase V is the
      site in the second messenger pathway that determines the arteriovenous profile of
      NO donors. Moreover, the sensitivity of soluble guanylate cyclase to NO donors
      might be regulated by the ambient concentration of NO, with increased local NO
      down-regulating the dilator response to NO donors.

PMID- 10336567
TI  - Adenosine kinase inhibitors as a novel approach to anticonvulsant therapy.
AB  - Adenosine levels increase at seizure foci as part of a postulated endogenous
      negative feedback mechanism that controls seizure activity through activation of
      A1 adenosine receptors. Agents that amplify this site- and event-specific surge
      of adenosine could provide antiseizure activity similar to that of adenosine
      receptor agonists but with fewer dose-limiting side effects. Inhibitors of
      adenosine kinase (AK) were examined because AK is normally the primary route of
      adenosine metabolism. The AK inhibitors 5'-amino-5'-deoxyadenosine, 5
      iodotubercidin, and 5'-deoxy-5-iodotubercidin inhibited maximal electroshock
      (MES) seizures in rats. Several structural classes of novel AK inhibitors were
      identified and shown to exhibit similar activity, including a prototype
      inhibitor, 4-(N-phenylamino)-5-phenyl-7-(5'-deoxyribofuranosyl)pyrrolo[2, 3
      d]pyrimidine (GP683; MES ED50 = 1.1 mg/kg). AK inhibitors also reduced
      epileptiform discharges induced by removal of Mg2+ in a rat neocortical
      preparation. Overall, inhibitors of adenosine deaminase or of adenosine transport
      were less effective. The antiseizure activities of GP683 in the in vivo and in
      vitro preparations were reversed by the adenosine receptor antagonists
      theophylline and 8-(p-sulfophenyl)theophylline. GP683 showed little or no
      hypotension or bradycardia and minimal hypothermic effect at anticonvulsant
      doses. This improved side effect profile contrasts markedly with the profound
      hypotension, bradycardia, and hypothermia and greater inhibition of motor
      function observed with the adenosine receptor agonist N6-cyclopentyladenosine and
      opens the way to clinical evaluation of AK inhibitors as a novel, adenosine-based
      approach to anticonvulsant therapy.

PMID- 10336569
TI  - Effects of specific modifications of several hydroxyls of tetrodotoxin on its
      affinity to rat brain membrane.
AB  - The widely used sodium channel blocker tetrodotoxin (TTX) is a compound that has
      six hydroxyl residues at the C-4, C-6, C-8, C-9, C-10, and C-11 positions in
      addition to a guanidinium group, which is positively charged in biological pH
      range. Thirteen analogs of this toxin with structural modifications involving one
      or more of these hydroxyls were examined on their affinity to a rat brain
      membrane preparation, which is known to contain sodium channels abundantly. The
      equilibrium dissociation constants associated with the binding of TTX and its
      analogs to the sodium channels were estimated, from their ability to inhibit the
      binding of [3H]saxitoxin, as follows (in nM): TTX, 1.8; chiriquitoxin, 1.0; 11
      oxoTTX, 1.5; 11-norTTX-6,6-diol, 1.6; 11-norTTX-6(S)-ol, 23; 11-norTTX-6(R)-ol,
      31; 11-deoxyTTX, 37; 6-epiTTX, 39; 4-epiTTX, 68; 4,9-anhydroTTX, 180; TTX-8-O
      hemisuccinate, >380; TTX-11-carboxylic acid, >2300; tetrodonic acid, >3600;
      5,6,11-trideoxyTTX, >5000. The reduction of the affinity observed with the
      analogs involving reduction or translocation of the hydroxyls at C-6 and C-11 is
      indicative of the contribution of these residues to the binding to sodium
      channels as hydrogen bond donors. The especially large value of the dissociation
      constant for TTX-11-carboxylic acid is consistent with the idea that the C-11
      hydroxyl forms a hydrogen bond with a carboxylic acid residue of the channel
      protein. The markedly low affinity of TTX-8-O-hemisuccinate may possibly be
      ascribable to intramolecular salt-bridge formation, which neutralizes the
      positive charge of the guanidinium group.

PMID- 10336568
TI  - (R,S)-4-phosphonophenylglycine, a potent and selective group III metabotropic
      glutamate receptor agonist, is anticonvulsive and neuroprotective in vivo.
AB  - Group III metabotropic glutamate receptors (mGluRs) are thought to modulate
      neurotoxicity of excitatory amino acids, via mechanisms of presynaptic
      inhibition, such as regulation of neurotransmitter release. Here, we describe
      (R,S)-4-phosphonophenylglycine (PPG) as a novel, potent, and selective agonist
      for group III mGluRs. In recombinant cell lines expressing the human receptors
      hmGluR4a, hmGluR6, hmGluR7b, or hmGluR8a, EC50 values for (R,S)-PPG of 5.2 +/-
      0.7 microM, 4.7 +/- 0.9 microM, 185 +/- 42 microM, and 0.2 +/- 0.1 microM,
      respectively, were measured. The compound showed EC50 and IC50 values of >/=200
      microM at group I and II hmGluRs and was inactive at cloned human N-methyl-D
      aspartate, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate, and kainate
      receptors (>300 microM). On the other hand, it showed micromolar affinity for a
      Ca2+/Cl--dependent L-glutamate binding site in rat brain, similar to other
      phosphono-substituted amino acids like L-2-amino-4-phosphonobutyrate. In cultured
      cortical neurons, (R, S)-PPG provided protection against a toxic pulse of N
      methyl-D-aspartate (EC50 = 12 microM), which was reversed by the group III mGluR
      antagonist (R,S)-alpha-methylserine-O-phosphate but not by the group II
      antagonist (2S)-alpha-ethylglutamate. Moreover, (R,S)-PPG protected against N
      methyl-D-aspartate- and quinolinic acid-induced striatal lesions in rats and was
      anticonvulsive in the maximal electroshock model in mice. In contrast to the
      group III mGluR agonists L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate,
      (R,S)-PPG showed no proconvulsive effects (2200 nmol i.c.v.). These data provide
      novel in vivo evidence for group III mGluRs as attractive targets for
      neuroprotective and anticonvulsive therapy. Also, (R,S)-PPG represents an
      attractive tool to analyze the roles of group III mGluRs in nervous system
      physiology and pathology.

PMID- 10336570
TI  - Why does spironolactone improve mortality over and above an ACE inhibitor in
      chronic heart failure?

PMID- 10336571
TI  - Integrated modelling of the clinical pharmacokinetics of SDZ HTF 919, a novel
      selective 5-HT4 receptor agonist, following oral and intravenous administration.
AB  - AIMS: The purpose of the present study was to assess the pharmacokinetics of the
      novel selective 5-HT4 receptor agonist SDZ HTF 919 (HTF) including food effect,
      absolute bioavailability, interoccasion and intersubject variabilities. METHODS:
      In the randomized, open-label, three treatment, four period crossover study, HTF
      was administered to 12 young healthy male subjects as a 12 mg tablet (twice under
      fasted and once under fed conditions) and a 3 mg intravenous (i.v.) infusion over
      40 min (fasted). Pharmacokinetic parameters were obtained by noncompartmental
      methods. A more comprehensive pharmacokinetic characterization was achieved by
      integrated modelling of oral (p.o.) and i.v. data. To describe the absorption
      phase a Weibull function and a classical first order input function were
      compared. RESULTS: Noncompartmental pharmacokinetic analysis revealed a rapid
      absorption (tmax 1.3 h, fasted), an absolute bioavailability of 11+/-3%, a
      biphasic disposition phase with a terminal half-life of 11+/-5 h, a clearance of
      77+/-15 l h-1, and a volume of distribution at steady state of 368+/-223 l. The
      coefficients of interoccasion and interindividual variability in Cmax and AUC
      ranged between 17 and 28%. Food intake caused a delay (tmax 2.0 h) and decrease
      in absorption with consequently lower systemic exposure ( approximately 5%
      absolute bioavailability). Integrated p.o./i.v. pharmacokinetic modelling with a
      Weibull input function allowed accurate description of individual profiles.
      Modelling of the data from the p.o. dosing improved the description of the
      terminal phase by inclusion of the i. v. data and additionally provided
      quantitative characterization of the absorption phase. CONCLUSIONS: The
      pharmacokinetics of HTF could be well described by an integrated modelling
      approach for both p.o. and i.v. data. The derived model will provide guidance in
      the design of future studies.

PMID- 10336572
TI  - Combination of calcium channel blockers and beta-adrenoceptor blockers for
      patients with exercise-induced angina pectoris: a double-blind parallel-group
      comparison of different classes of calcium channel blockers. Netherlands Working
      Group on Cardiovascular Research (WCN).
AB  - AIMS: The combination of calcium channel blockers and beta-adrenoceptor blockers
      is more effective for the treatment of exercise-induced angina pectoris than beta
      adrenoceptor blocker monotherapy. As ischaemia in exercise-induced angina is
      preceded by increase in heart rate, calcium channel blockers with negative
      chronotropic properties may perform better for this purpose than nonchronotropic
      compounds. METHODS: A 335 patient double-blind parallel-group study comparing 14
      day treatment with amlodipine 5 and 10 mg, with diltiazem 200 and 300 mg, and
      mibefradil 50 and 100 mg added to baseline beta-adrenoceptor blocker treatment
      was performed. Exercise testing (ETT) was performed by bicycle ergometry.
      RESULTS: Although none of the calcium channel blockers improved duration of
      exercise or amount of workload, all significantly delayed onset of 1 mm ST
      segment depression on ETT (P<0.001 for any treatment vs baseline). In addition,
      mibefradil, both low and high dose treatment, produced the longest delays (low
      dose: different from diltiazem and amlodipine by 24.1 and 29.8 s, respectively,
      P<0. 003 and <0.001; high dose: different from diltiazem and amlodipine by 33.7
      and 37.0 s, respectively, P<0.001 and <0.001). These effects were linearly
      correlated with the reduction in rate pressure product (RPP). Serious symptoms of
      dizziness occurred significantly more frequently on mibefradil (P<0.05), and 19
      patients on mibefradil withdrew from trial. CONCLUSIONS: Calcium channel blockers
      with negative chronotropic properties provide greater delay of ischaemia in
      patients with exercise-induced angina, but the concomitant risk of intolerable
      dizziness attenuates this benefit.

PMID- 10336574
TI  - Impaired cholinergic dilator response of resistance arteries isolated from
      patients with Raynaud's disease.
AB  - AIMS: We examined the effect of cooling on the response to the endothelium
      dependent and -independent dilators, acetylcholine (ACh) and sodium nitroprusside
      (SNP), respectively, in human microvessels in vitro, and compared the responses
      between Raynaud's disease (RD) patients and controls, in order to assess the
      pathogenic role of the endothelium in RD. METHODS: Subcutaneous resistance
      arteries were dissected from gluteal fat biopsies taken from patients with RD
      (n=18) and from age-and sex-matched control subjects (n=17). Vessels were
      cannulated in a small vessel arteriograph, in which a pressure of 50 mmHg was
      maintained across the vessel wall. Cumulative concentration-response curves for
      ACh (10-10-10-4 m ) and SNP (10-10-10-3 m ) were generated in vessels at either
      37 degrees C or 24 degrees C, with endothelium intact for ACh and removed for SNP
      (n=6 per group). RESULTS: Neither dilator showed significant differences in
      sensitivity when comparing responses between vessels from RD patients and
      controls, at either temperature, but the maximal relaxation to ACh was depressed
      in vessels from RD patients compared with controls at 37 degrees C (Emax=45+/-13
      in RD vs 89+/-4 in controls; P=0.004). CONCLUSIONS: These results support the
      hypothesis that impaired endothelium-dependent vasodilatation is involved in the
      pathophysiology of RD.

PMID- 10336573
TI  - Nisoldipine improves the impaired erythrocyte deformability correlating with
      elevated intracellular free calcium-ion concentration and poor glycaemic control
      in NIDDM.
AB  - AIMS: To explore the mechanisms underlying the impaired erythrocyte deformability
      (RBC-df) in diabetic patients, the relationship between erythrocyte intracellular
      free calcium-ion concentration ([Ca2+]i) and RBC-df, and the effects of Ca2+
      channel blocker on [Ca2+]i and RBC-df were evaluated. METHODS: Forty-eight
      patients with NIDDM and 24 control subjects were enrolled in this study. [Ca2+]i
      was determined using fura-2, and RBC-df by filtration method expressed as
      Deformability Index (DI). Erythrocytes were treated with nisoldipine to evaluate
      the effects of a Ca2+-channel blocker. RESULTS: [Ca2+]i was significantly higher
      (82.6 (78.0-87.2) vs 76.6 (74.3-81.2) nmol lRBC-1, P<0.001), and DI was
      significantly lower (0. 14 (0.09-0.28) vs 0.22 (0.16-0.28), P<0.01) in NIDDM than
      in controls. There was a significant correlation between HbA1c and [Ca2+]i
      (r=0.38, P<0.01), between HbA1c and DI (r=-0.51, P<0.01), and between [Ca2+]i and
      DI (r=-0.42, P<0.01). Stepwise multiple regression analysis revealed HbA1c and
      [Ca2+]i as independent determinants for the impaired RBC-df. Nisoldipine
      treatment in vitro significantly decreased [Ca2+]i, and significantly improved
      RBC-df. CONCLUSIONS: These data indicate that the impaired RBC-df in NIDDM may at
      least partly be attributed to the elevated [Ca2+]i and poor glycaemic control. In
      addition, favorable effects of a Ca2+-channel blocker on both [Ca2+]i and RBC-df
      have been demonstrated.

PMID- 10336575
TI  - Study of cardiac repolarization in healthy volunteers performed with mizolastine,
      a new H1-receptor antagonist.
AB  - AIMS: The occurrence of serious dysrhythmias, such as torsades de pointes, with
      terfenadine and astemizole had led to a reexamination of the potential effect of
      H1 antihistamines on cardiac repolarization. Mizolastine is a potent, selective,
      nonsedating peripherally acting H1-receptor antagonist which is registered for
      rhinitis and urticaria at a recommended dose of 10 mg once daily. The present
      study was carried out to investigate the effects of therapeutic and
      supratherapeutic doses of mizolastine, on ventricular repolarization in healthy
      volunteers. METHODS: Twenty-four healthy young volunteers participated in a
      double-blind, placebo-controlled, randomised study with three parallel groups.
      Each group consisted of 2 way cross-over 7 day treatment periods where
      mizolastine (10, 20 or 40 mg) and placebo were randomly administered. On day 1
      and day 7, 12-lead ECG recordings were performed prior and 0.5, 1, 2, 3, 4, 6, 8,
      12, 16, and 20 h after dosing and from day 2 to day 6, before dosing and 1, 2, 3,
      and 4 h after. RESULTS: Whatever the analysis used (raw data, changes from
      baseline, incidence of individual out-of-range values) no significant differences
      were observed at any dose level vs placebo, on any of ECG parameters (HR, PR,
      QRS, QT, and QTc). In particular, no effect of mizolastine vs placebo was shown
      on QT and QTc although 95% CIs were wide. The only subject who exhibited a
      QTc>/=450 ms received placebo for 7 days. CONCLUSIONS: This study found no
      evidence of an effect of mizolastine up to 40 mg (four times the therapeutic
      dose) on ventricular repolarization in healthy volunteers.

PMID- 10336576
TI  - Pharmacokinetics and pharmacodynamics of Ro 44-3888 after single ascending oral
      doses of sibrafiban, an oral platelet aggregation inhibitor, in healthy male
      volunteers.
AB  - AIMS: This study constituted the first administration of the oral platelet
      inhibitor, sibrafiban, to humans. The aim was to investigate the pharmacokinetics
      and pharmacodynamics of Ro 44-3888, the active principle of sibrafiban, after
      single ascending oral doses of sibrafiban. Particular emphasis was placed on
      intersubject variability of the pharmacokinetic and pharmacodynamic parameters of
      Ro 44-3888. METHODS: The study consisted of three parts. Part I was an open
      ascending-dose study to determine target effect ranges of sibrafiban. Part II, a
      double-blind, placebo-controlled, parallel-group study, addressed the
      intersubject variability of pharmacokinetic and pharmacodynamic parameters of the
      active principle at a sibrafiban dose achieving an intermediate effect. Part III
      was a double-blind, placebo-controlled, ascending-dose design covering the
      complete plasma concentration vs pharmacodynamic response curve of sibrafiban.
      RESULTS: At sibrafiban doses between 5 mg and 12 mg, the pharmacokinetics of free
      Ro 44-3888 in plasma were linear whereas those of total Ro 44-3888 were non
      linear because of the saturable binding to the glycoprotein IIb-IIIa receptor.
      Saturation of the GP IIb-IIIa receptor was reached at plasma concentrations of
      15.9 ng ml-1. At sibrafiban doses up to 2 mg, ADP-induced platelet aggregation
      was inhibited by 50%, whereas the inhibition of TRAP-induced platelet aggregation
      was about 20-30%. At the higher doses, ADP-induced platelet aggregation was
      almost completely inhibited while a clear dose-response could be observed with
      TRAP-induced inhibition of platelet aggregation at sibrafiban doses of 5 to 12
      mg. Ivy bleeding time increased very steeply with dose with a significant
      prolongation observed at doses of 5 to 7 mg of sibrafiban (5-7 min, >30 min in
      one case). At a sibrafiban dose of 12 mg, the stopping criterion for dose
      escalation (prolongation of the Ivy bleeding time >30 min in three out of four
      subjects per dose group) was reached. The interindividual coefficients of
      variation of the integrated pharmacokinetic and pharmacodynamic parameters (AUC
      and AUE) were below 20%, thus lying well within the pre-set level of acceptance.
      CONCLUSIONS: With a low intersubject variability of its pharmacokinetic and
      pharmacodynamic parameters, linear pharmacokinetics and pharmacodynamic effects
      closely related to its plasma concentrations, Ro 44-3888 has good pharmacological
      prerequisites for a well controllable therapy of secondary prevention of arterial
      thrombosis in patients with acute coronary syndrome.

PMID- 10336577
TI  - Clinical and pharmacokinetic results with a new ultrashort-acting calcium
      antagonist, clevidipine, following gradually increasing intravenous doses to
      healthy volunteers.
AB  - AIMS: To investigate the tolerability and safety of clevidipine in healthy male
      volunteers during intravenous infusion at gradually increasing dose rates and to
      obtain preliminary information on the pharmacokinetics and pharmacodynamic
      effects of the drug. METHODS: Twenty-five subjects were enrolled in the study and
      twenty-one of them were included twice, resulting in a total of forty-six study
      entries encompassing 20 min infusions of clevidipine at target dose rates ranging
      from 0.12 to 48 nmol min-1 kg-1. Haemodynamic variables and adverse events were
      recorded throughout the study. Concentrations of clevidipine and its primary
      metabolite, H 152/81, were followed in whole blood, and the pharmacokinetics were
      evaluated by non-compartmental and compartmental analysis. An Emax model was
      fitted to the effect on mean arterial pressure (MAP) over heart rate (HR) and the
      corresponding blood concentrations of clevidipine. RESULTS: Clevidipine was
      administered up to a target dose rate of 48 nmol min-1 kg-1, where a pre
      determined escape criterion was reached (HR>120 beats min-1 ) and the study was
      stopped. The most common adverse events were flush and headache, which can be
      directly related to the mechanism of action of clevidipine. There was a linear
      relationship between blood concentration and dose rate in the range studied. The
      median clearance value determined by non-compartmental analysis was 0.125 l min-1
      kg-1. Applying the population approach to the sparse data on clevidipine
      concentrations, an open two compartment pharmacokinetic model was found to be the
      best model in describing the disposition of the drug. The population mean
      clearance value determined by this method was 0.121 l min-1 kg-1, and the volume
      of distribution at steady state was 0.56 l kg-1. The initial half-life,
      contributing by more than 80% to the total area under the blood concentration
      time curve following i.v. bolus administration, was 1.8 min, and the terminal
      half-life was 9.5 min. At the highest dose rates, MAP was reduced by
      approximately 10%, and the HR reached the pre-determined escape criterion for
      this study (>120 beats min-1 ). CONCLUSIONS: Clevidipine is well tolerated and
      safe in healthy volunteers at dose rates up to at least 48 nmol min-1 kg-1. The
      pharmacokinetics are linear over a wide dose range. Clevidipine is a high
      clearance drug with extremely short half-lives. The effect of clevidipine on the
      blood pressure was marginal, probably due to a compensatory baroreflex activation
      in this population of healthy volunteers. A simple Emax model adequately
      describes the relationship between the pharmacodynamic response (MAP/HR) and the
      blood concentrations of clevidipine.

PMID- 10336578
TI  - Pharmacokinetic-pharmacodynamic profile of systemic nitric oxide-synthase
      inhibition with L-NMMA in humans.
AB  - AIMS: It has been demonstrated that inhibition of endothelium derived nitric
      oxide with NG-monomethyl-L-arginine (L-NMMA) results in a different cardiac and
      peripheral vascular response. The purpose of this study was to investigate the
      pharmacokinetic-pharmacodynamic profile of L-NMMA and pharmacokinetic
      interactions with L-arginine in healthy subjects. METHODS: Plasma
      pharmacokinetics were analysed from two different studies: In study 1, 3 mg kg-1
      L-NMMA was administered i.v. over 5 min and systemic haemodynamics, cardiac
      output (CO), fundus pulsation amplitude (FPA), and NO-exhalation (exhNO) were
      measured at baseline and 15, 65, 95, 155, and 305 min after start of drug
      administration (n=7). In study 2, 17 mg kg-1 min-1 of the physiologic substrate
      for nitric oxide synthase, L-arginine, was coinfused i.v. over 30 min with a
      primed constant infusion of 50 microg kg-1 min-1 L-NMMA (n=8). RESULTS: Bolus
      infusion of L-NMMA resulted in a maximum plasma concentration of 12. 9+/-3.4
      microg ml-1 (mean+/-s.d.) with elimination half-life of 63. 5+/-14.5 min and
      clearance of 12.2+/-3.5 ml min-1 kg-1 and caused a small hypertensive response,
      decreased CO by 13%, FPA by 26%, exhNO by 46% and increased systemic vascular
      resistance by 16% (P<0.05 each) 15 min after start of drug administration.
      Although only limited data points were available in the L-NMMA plasma
      concentration range between 0 and 4 microg ml-1, drug effects over time were in
      good agreement with an Emax model (r2>0.98 each), which also suggested that
      concentrations producing half-maximum effects were higher for FPA than for CO and
      exhNO. The coinfusion with L-arginine caused a nearly two-fold increase in plasma
      L-NMMA levels, indicating a pharmacokinetic interaction. CONCLUSIONS: In the
      absence of a systemic hypertensive response, L-NMMA significantly decreased CO,
      exhNO, and FPA. The concentration calculated to produce a half maximal effect was
      equivalent for exhNO and CO, but markedly higher for FPA. Furthermore,
      measurement of FPA is susceptible to changes in L-NMMA levels at small plasma
      concentrations.

PMID- 10336579
TI  - Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil
      and norverapamil.
AB  - AIMS: The present study was conducted to evaluate metabolism of the enantiomers
      of verapamil and norverapamil using a broad range of cytochrome P450 isoforms and
      measure the kinetic parameters of these processes. METHODS: Cytochrome P450 cDNA
      expressed cells and microsomes from a P450-expressed lymphoblastoid cell line
      were incubated with 40 microm concentrations of R- or S-verapamil and R- or S
      norverapamil and metabolite formation measured by h.p.l.c. as an initial
      screening. Those isoforms exhibiting substantial activity were then studied over
      a range of substrate concentrations (2.5-450 microm ) to estimate the kinetic
      parameters for metabolite formation. RESULTS: P450s 3A4, 3A5, 2C8 and to a minor
      extent 2E1 were involved in the metabolism of the enantiomers of verapamil.
      Estimated Km values for the production of D-617 and norverapamil by P450 s 3A4
      and 3A5 were similar (range=60-127 microm ) regardless of the enantiomer of
      verapamil studied while the Vmax estimates were also similar (range=4-8 pmol min
      1 pmol-1 P450). Only nominal production of D-620 by these isoforms was noted.
      Interestingly, P450 2C8 readily metabolized both S- and R-verapamil to D-617,
      norverapamil and PR-22 with only slightly higher Km values than noted for P450s
      3A4 and 3A5. However, the Vmax estimates for P450 2C8 metabolism of S- and R
      verapamil were in general greater (range=8-15 pmol min-1 pmol-1 P450) than those
      noted for P450 s 3A4 and 3A5 with preference noted for metabolism of the S
      enantiomer. Similarly, P450 s 3A4, 3A5 and 2C8 also mediated the metabolism of
      the enantiomers of norverapamil with minor contributions by P450 s 2D6 and 2E1.
      P450s 3A4 and 3A5 readily formed the D-620 metabolite with generally a lower Km
      and higher Vmax for S-norverapamil than for the R-enantiomer. In contrast, P450
      2C8 produced both the D-620 and PR-22 metabolites from the enantiomers of
      norverapamil, again with stereoselective preference seen for the S-enantiomer.
      CONCLUSIONS: These results confirm that P450s 3A4, 3A5 and 2C8 play a major role
      in verapamil metabolism and demonstrate that norverapamil can also be further
      metabolized by the P450s.

PMID- 10336580
TI  - The influence of CYP2D6 activity on the kinetics of propafenone enantiomers in
      Chinese subjects.
AB  - AIMS: To determine role of CYP2D6 activity in the pharmacokinetics of propafenone
      (PPF) enantiomers in native Chinese subjects. METHODS: Sixteen extensive
      metabolizers (EMs) and one poor metabolizer (PM), whose phenotype had been
      previously assessed with dextromethorphan metabolic phenotyping, were enrolled.
      Blood samples (0 approximately 15 h) were taken after oral administration of a
      single dose (400 mg) of racemic-propafenone hydrochloride. A reverse-phase
      h.p.l.c. method with pre-column derivatization was employed to quantitate
      enantiomeric concentrations of propafenone in plasma. RESULTS: For the EM
      subjects, S-PPF was less rapidly metabolized and had higher peak plasma
      concentrations than R-PPF (413+/-143 vs 291+/-109 ng ml-1, P<0.001). The AUC was
      markedly higher for S-PPF than for R-PPF (2214+/-776 vs 1639+/-630 microg h l-1,
      P<0.001), whereas the clearance of S-PPF was significantly lower than that of R
      PPF (96.0+/-39.0 vs 138+/-78 l h-1, P<0.01). There were no differences in t1/2,
      and Cmax between the two isomers (P >0.05). In the one PM subject, not only did S
      PPF appear to undergo less rapid metabolism than R-PPF, but the subject also
      showed 2 approximately 3 fold differences in Cmax, CL and AUC compared with EMs.
      The correlation coefficients (rs ) between dextromethorphan metabolic ratio (lg
      MR) and pharmacokinetic parameters (Cmax, CL and AUC) were 0.63, -0.87, 0.87 for
      S-PPF and 0. 57, -0.73, 0.86 for R-PPF, respectively. CONCLUSIONS: Our results
      suggest that CYP2D6 activity contributes to the pharmacokinetic variability of
      propafenone enantiomers in Chinese subjects.

PMID- 10336581
TI  - Retrospective analysis of the frequency and recognition of adverse drug reactions
      by means of automatically recorded laboratory signals.
AB  - AIMS: To estimate the frequency of adverse drug reactions (ADRs) identified
      through the use of automatic signals generated from laboratory data (ALS) in
      hospitalised patients. To determine the frequency of spontaneous recognition of
      these ADRs by the attending physicians and to assess the potential value of ALS
      for detection of ADRs. METHODS: Laboratory results of patients hospitalised in a
      nine bed medical ward were automatically recorded over a period of 17 months.
      Values exceeding defined boundaries were used as ALS. Charts of every third
      patient were analysed retrospectively with regard to adverse drug related
      reactions and causality was evaluated as well as whether the ADR had been
      recognised during the period of hospitalisation. RESULTS: The charts and ALS of
      98 patients were analysed. In 18 cases a drug-related adverse reaction was
      probable. Awareness to the reaction by the treating physicians was evident in 6
      out of these 18 ADRs. Approximately 80% of the ADRs were considered predictable.
      Three ADRs were regarded as serious. CONCLUSIONS: Adverse drug reactions are
      common and often preventable. Only one third of ADRs which could have been
      detected through ALS were recognised by the attending physicians. An increased
      doctor's awareness of the frequency of drug related abnormal laboratory results
      by means of ALS is likely to increase the recognition rate of ADRs and might help
      to prevent them.

PMID- 10336582
TI  - Use of dexfenfluramine, fenfluramine and phentermine and the risk of stroke.
AB  - AIMS: To estimate the incidence of newly diagnosed idiopathic stroke among users
      of fenfluramine, dexfenfluramine and phentermine compared to obese nonusers.
      METHODS: We conducted a cohort study with nested case-control analysis utilizing
      data from the General Practice Research Database in the UK. Eight thousand four
      hundred and twenty-three subjects aged 69 years or less at the start of follow-up
      were exposed to at least one of the three study drugs and 17 225 similarly obese
      subjects were not exposed to any of the study drugs. RESULTS: We identified 45
      incident cases of idiopathic CVA in this cohort of subjects. The incidence of CVA
      among all current users of a diet drug was 1.3/1000 person-years (95% CI 0.5,
      3.5). The incidence for current fenfluramine users (n=2) was 2.6/1000 person
      years (95% CI 0.7, 9.6), for current dexfenfluramine users (n=1) 1.1/1000 person
      years (95% CI 0.3, 3.8), and for current phentermine users 0/1000 person-years
      (95% CI 0.0, 12.9). The incidence in obese nonusers was 0.6/1000 person-years
      (95% CI 0.4, 0. 9). The adjusted matched odds ratio (OR) for thrombotic stroke
      from the case-control analysis comparing current use of a diet drug to nonuse was
      2.4 (95% CI 0.6, 9.1). There was only one exposed subject among seven who had
      haemorrhagic stroke. CONCLUSIONS: The incidence of CVA in generally young obese
      subjects during use of fenfluramine, dexfenfluramine or phentermine is low.
      Although we found an OR of 2. 4 comparing users of any of the anorexiants with
      nonusers, this is based on only three exposed cases and the confidence limits are
      wide. We conclude that our study does not support a substantial increased risk of
      stroke attributable to the use of fenfluramine, dexfenfluramine or phentermine.

PMID- 10336583
TI  - The Cheshire cat's grin--is cat allergy here to stay?

PMID- 10336584
TI  - The use of antibiotics in the first year of life and development of asthma: which
      comes first?

PMID- 10336585
TI  - Early life receipt of antibiotics and atopic disorder.

PMID- 10336586
TI  - Grass pollen: trends and predictions.

PMID- 10336587
TI  - Asthma versus chronic obstructive pulmonary disease--exploring why 'reversibility
      versus irreversibility' is no longer an appropriate approach.

PMID- 10336588
TI  - Penicillins and cephalosporins as allergens--structural aspects of recognition
      and cross-reactions.

PMID- 10336589
TI  - Ten years of the SWORD project. Surveillance of Work-related and Occupational
      Respiratory Disease.

PMID- 10336590
TI  - High prevalence of sensitization to cat allergen among Japanese children with
      asthma, living without cats.
AB  - BACKGROUND: Cat allergy is common among children with asthma. Many cat-allergic
      patients in Japan and elsewhere do not keep cats, but nonetheless become
      sensitized through environmental exposure to cat allergen. OBJECTIVE: To assess
      the frequency of cat allergy and cat-specific immunoglobulin E (IgE) and
      immunoglobulin G (IgG) antibody responses in young Japanese patients with asthma
      in relation to self-reported cat exposure and Fel d 1 levels in dust samples.
      METHODS: Cat dander-specific IgE antibody was measured in sera from asthma
      patients using the CAP system. IgE and IgG antibody to Fel d 1 was measured by
      antigen binding radioimmunoassay and by chimeric enzyme immunoassay. Fel d 1
      levels in dust samples from a subset of patients' homes were measured by
      monoclonal antibody-based enzyme immunoassay. RESULTS: Cat-specific IgE (CAP
      class>/=2) was found in sera from 70% of 44 patients who kept cats and 34% of 394
      patients who had never kept cats. The prevalence of sensitization increased
      progressively to age 6 years (40%: positive), and then increased gradually to age
      16 years (approximately 60%: positive) in patients who had never kept cats. There
      was an excellent correlation between cat CAP values and IgE levels to Fel d 1.
      The absolute amount of IgE antibody to Fel d 1 ranged from 0.01 to 15.6% of total
      IgE. Most patients who did not keep cats were exposed to Fel d 1 levels ranging
      from 0.07-8 microg/g dust. CONCLUSIONS: Sensitization to cat allergen is common
      among young asthmatic patients in Japan, even among patients who do not keep
      cats. Use of CAP and the chimeric enzyme-linked immunosorbent assay allows
      accurate diagnosis of cat allergy and quantification of specific IgE antibody
      levels.

PMID- 10336591
TI  - Sensitization to cat without direct exposure to cats.
AB  - BACKGROUND: Allergy to pets, particularly cats, is one of the most important
      determinants of asthma and asthma-like symptoms in many parts of the world. Cat
      allergen is found in homes and public places without cats. OBJECTIVE: The purpose
      of the study is to investigate the prevalence of sensitization to cat on the
      island of Tristan da Cunha where cats have been eliminated since 1974. METHODS: A
      cross-sectional survey was conducted in 1993 on all residents on the island
      including allergy skin testing. Dust samples were collected from 20 homes on the
      island for measurement of house dust mite and cat allergens. RESULTS: Positive
      skin test reaction to cat was present in 57 (20.1%) of all islanders and in six
      (12.8%) of those born in or after 1975, 1 year after cats had been exterminated.
      Five of these six residents were born within 5 years of extermination of cats;
      two of these had attended school outside the island. A low level of cat allergen
      (Fel d 1) was found in only one out of 20 homes even though house dust mite
      allergens (Der p 1 or Der f 1) were found in all homes. CONCLUSION: Sensitization
      to cat allergen occurs on the island of Tristan da Cunha where there is no direct
      exposure to cats. This is due either to the persistence of the allergen after the
      removal of the animal or to the allergen being brought in on visitors' clothing.

PMID- 10336592
TI  - Antibiotic use in early childhood and the development of asthma.
AB  - BACKGROUND AND OBJECTIVE: Recent investigations have focused on the role of
      infections in infancy in promoting or protecting against the subsequent
      development of asthma. A related hypothesis concerns the possible role of medical
      responses to infections, including the widespread use of antibiotics. We chose
      children at Rudolf Steiner schools to test this latter hypothesis because a
      significant proportion of parents rejects the use of conventional treatments,
      including antibiotics. METHODS: Seventy-five per cent (n = 456) of parents of
      children aged 5-10 years attending Rudolf Steiner schools throughout New Zealand
      completed questionnaires which included questions on the use of antibiotics and a
      history of asthma and wheeze in their children. RESULTS: After controlling for
      potential confounders, antibiotic use was significantly associated with having a
      history of asthma (OR = 2.74, 95% CI: 1.10-6.85) or wheeze (OR = 1. 86, 95% CI:
      1.06-3.26) but not with current wheeze (OR = 1.08, 95% CI: 0.54-2-16). The
      adjusted odds ratio for asthma was 4.05 (95% CI: 1.55-10.59) if antibiotics were
      used in the first year of life and 1. 64 (95% CI: 0.60-4.46) if antibiotics had
      been used only after the first year of life when compared with children who had
      never used antibiotics. The number of courses of antibiotics during the first
      year of life was also associated with increased odds ratios for asthma: 2.27 (95%
      CI: 1.14-4.51) for one to two courses and 4.02 (95% CI: 1.57-10.31) for three or
      more courses when compared with no antibiotic use in the first year of life.
      Although not significant, the association of antibiotics and hay fever (OR = 1.99
      [95% CI: 0. 93-4.26]) was of a similar strength to the association of antibiotics
      with a history of wheeze. Antibiotics were not significantly associated with
      eczema (OR = 1.23 [95% CI: 0.71-2.13]). CONCLUSION: Antibiotic use in infancy may
      be associated with an increased risk of developing asthma. Further study is
      required to determine the reasons for this association.

PMID- 10336593
TI  - Peripheral blood T lymphocytes from asthmatic patients are primed for enhanced
      expression of interleukin (IL)-4 and IL-5 mRNA: associations with lung function
      and serum IgE.
AB  - BACKGROUND: The TH2-like cytokines interleukin (IL)-4 and IL-5 play a pivotal
      role in airway wall inflammation in asthma and these cytokines are increased in
      peripheral blood and bronchoalveolar lavage fluid from asthmatic patients. It is
      unclear why specifically TH2-like cytokines are increased in asthmatic patients.
      A possible explanation may be an impaired adenylyl cyclase activity, which has
      been observed in peripheral blood mononuclear cells of asthmatics. OBJECTIVE: To
      assess interferon (IFN)-gamma, IL-4 and IL-5 mRNA expressions and their control
      by prostaglandin E2 (PGE2), which activates adenylyl cyclases, of peripheral T
      lymphocytes from patients with moderately severe asthma and healthy controls.
      METHODS: Peripheral blood T lymphocytes from asthmatics and healthy controls were
      isolated and stimulated with antibodies against CD3 plus CD28 in the absence and
      presence of increasing concentrations of PGE2. IFN-gamma, IL-4 and IL-5 mRNA
      levels were detected by reverse transcription-polymerase chain reaction. RESULTS:
      In contrast to IFN-gamma mRNA, IL-4 (P = 0.03, n = 8) and IL-5 (P < 0. 05, n = 5)
      mRNAs in the asthma group were significantly higher than in controls (n = 4). In
      addition, IL-5 showed a significant inverse correlation with forced expiratory
      volume (FEV1) (P < 0.04, n = 5), whereas IL-4 positively correlated with
      PC20adenosine-monophosphate (AMP) (P < 0.02, n = 8). Accumulation of mRNA for IFN
      gamma, IL-4 and IL-5 mRNA were significantly diminished by 10-5 m PGE2 in both
      asthmatics and controls. In contrast, 10-6 m PGE2 significantly down-regulated
      IFN-gamma and IL-4 mRNAs (P < 0.05 for both IFN-gamma and IL-4, n = 4) in the
      control group, whereas this was not observed for IL-4 mRNA in the asthma group (n
      = 7). CONCLUSIONS: Activated peripheral blood T lymphocytes from asthma patients
      display higher levels of IL-4 and IL-5 mRNA in vitro, which may be due to a
      diminished activity of adenylyl cyclase. A new observation is that higher IL-4
      mRNA levels are associated with less severe AMP responsiveness, which might be
      due to a negative feedback loop of IL-4 production by mast cells.

PMID- 10336594
TI  - Functional interleukin-5 activity in peripheral blood mononuclear cells from
      adolescents with mite antigen asthma in remission.
AB  - BACKGROUND: Asthma improves in most children during adolescence such that a small
      minority of patients exhibit clinically significant symptoms by the age of 20
      years. OBJECTIVE AND METHODS: To investigate late allergic reactions, including
      eosinophil inflammation, associated with outgrowing mite antigen-induced
      bronchial asthma during adolescence, the relationship between clinical status and
      functional activity of interleukin (IL)-5 produced by Dermatophagoides farinae
      (Df)-stimulated peripheral mononuclear cells (PBMCs) in culture was assessed in
      mouse IL-3-dependent cells transfected with the human IL-5 receptor gene.
      RESULTS: Activity of IL-5 spontaneously produced by PBMCs from either patients
      with mite-sensitive bronchial asthma or nonatopic control subjects was low. The
      activity of IL-5 produced by PBMCs stimulated with concanavalin A was
      significantly higher. Upon challenge with specific allergens, such as Df antigen,
      but not with irrelevant antigens, including ovalbumin, the in vitro activity was
      increased in patients with active disease and decreased in patients in remission.
      CONCLUSION: Results suggest that the antigen-specific up-regulation of functional
      IL-5 activity in late allergic reactions is reduced in patients in remission and
      likely to result in an improvement in clinical status. The Df antigen may
      suppress Df-induced responses in patients with asthma in remission.

PMID- 10336595
TI  - Assessment of eosinophil granule proteins in various body fluids: is there a
      relation to clinical variables in childhood asthma?
AB  - BACKGROUND: The eosinophil plays a central role in the inflammatory process in
      bronchial asthma. Recent studies have indicated that the assessment of eosinophil
      derived proteins in various body fluids could be used for monitoring disease
      activity of childhood asthma. Till now, no study exists which compared the levels
      of eosinophil-derived proteins in various body fluids such as serum, nasal lavage
      fluid (NALF) and urine. OBJECTIVE: To investigate whether eosinophil granule
      proteins in different compartments were correlated and whether there is a
      relationship between disease activity, pulmonary function and bronchial
      hyperreactivity. METHODS: Twenty-eight children with atopic bronchial asthma were
      recruited. Serum, NALF and urine samples were obtained and assessed for
      eosinophil cationic protein (ECP) and eosinophil protein X (EPX). The levels of
      eosinophil proteins were analysed for a relationship with lung function
      variables, bronchial hyperreactivity and disease activity. Eleven healthy control
      subjects were used as controls. RESULTS: Median ECP and EPX concentrations in
      serum (31.4 and 74.8 microg/L vs 15.8 and 24.3 microg/L, respectively), NALF (9.9
      and 44. 9 microg/L vs 0 and 2.5 microg/L, respectively) and urine (49.4 vs 16.5
      microg/mmol creatinine) were significantly raised in children with bronchial
      asthma compared with healthy control subjects. In addition, ECP and EPX levels in
      serum and urine samples were significantly higher in symptomatic patients
      compared with asymptomatic subjects with asthma. Although no relationship between
      eosinophil-derived proteins in serum, NALF or urine and the level of nonspecific
      bronchial hyperreactivity could be detected, the concentrations of EPX in serum
      and urine were correlated with variables of pulmonary function. CONCLUSION: Our
      findings demonstrate increased eosinophil activity in serum, NALF and urine
      derived from children with bronchial asthma. Due to the relationship between
      levels of eosinophil proteins in serum/urine samples and lung function, as well
      as significant concentration differences between symptomatic and asymptomatic
      asthmatic children, the assessment of eosinophil proteins in serum or urine
      samples appear to be more appropriate in monitoring disease activity than
      measurement of ECP or EPX in NALF. Thus, the determination of serum ECP/EPX or
      urinary EPX may be preferentially used in monitoring eosinophilic inflammation in
      childhood asthma.

PMID- 10336596
TI  - Association studies on beta2-adrenoceptor polymorphisms and enhanced IgE
      responsiveness in an atopic population.
AB  - The beta2 adrenergic receptor 2 represents a cell surface receptor responsible
      for the binding of endogenous catecholamines and their exogenously administered
      agonists and antagonists, mediating their effects to the interior of the cell. On
      the basis of these functions, the observed association of two of its
      polymorphisms, Gly16 and Gln27, with nocturnal- and steroid-dependent asthma has
      been discussed. It has recently been suggested that Gln27 contributes to IgE
      variability in families with asthma. The aim of this study was to investigate
      possible influences of the polymorphisms Arg16Gly and Glu27Gln on IgE levels in
      families recruited through an atopic index case without regard to the presence of
      clinical symptoms. We employed linkage analysis in affected sibpairs
      characterized by elevated total IgE concentrations or sensitization to common
      inhalant allergens. Furthermore, we tested 258 children for association of any of
      the polymorphisms with enhanced IgE responsiveness. We could find neither linkage
      at the locus 5q31 nor significant association of the polymorphisms with elevated
      total IgE concentrations or specific sensitization. We conclude from our data
      that the polymorphisms Gln27Glu and Arg16Gly of the beta2-adrenergic receptor do
      not play a significant role in the pathogenesis of enhanced IgE responsiveness in
      an atopic population in general.

PMID- 10336597
TI  - Association between mast cell chymase genotype and atopic eczema: comparison
      between patients with atopic eczema alone and those with atopic eczema and atopic
      respiratory disease.
AB  - BACKGROUND: It has remained unclear whether genetic background of patients with
      atopic eczema (AE) alone is identical to that of patients with both AE and atopic
      respiratory disease. OBJECTIVE: We aimed to assess whether there is a genetic
      difference between these two groups of AE patients. METHOD: We determined the
      genotype with regard to an allelic polymorphism in the gene for mast cell chymase
      (MCC; a serine protease secreted from mast cells) in 169 AE patients. RESULTS:
      MCC genotype was significantly associated with pure AE patients who did not have
      a predisposition to atopic respiratory disease and whose serum IgE concentration
      was < 500 IU/mL. The distribution of MCC genotypes also differed significantly
      between the latter patients and those AE patients with bronchial asthma and a
      serum IgE concentration of > 2000 IU/mL. CONCLUSION: These results suggest that
      pure AE is associated with genetic variants of MCC, and that the genetic basis of
      pure AE differs from that of AE associated with atopic asthma.

PMID- 10336598
TI  - Mast cell tryptase as a mediator of hyperresponsiveness in human isolated
      bronchi.
AB  - BACKGROUND: Although the role of mediators and cytokines produced by mast cells
      is well established in asthmatic bronchial inflammation, the contribution of mast
      cell-derived proteases to the development of hyperresponsiveness remains unclear.
      There have been reports indicating that tryptase alters the mechanical activity
      of animal airway smooth muscle or spontaneously sensitized human isolated
      airways. OBJECTIVE: The aim of this study was to analyse the effect of purified
      mast cell tryptase on non-sensitized human isolated bronchi. METHODS: Both
      central and peripheral bronchi, dissected from lung specimens obtained at
      thoracotomy, were studied in terms of both mechanical activity i.e. isometric
      contraction in response to a variety of agonists and distribution of inflammatory
      cells i.e. immunohistochemistry. RESULTS: In both proximal and distal bronchi,
      the reactivity to histamine was significantly increased by a previous incubation
      in the presence of 1 microg/mL of tryptase (increase in maximal force, DeltaFmax
      was 12.1 +/- 3.8%, and 8.8 +/- 3.1%, respectively). This effect of tryptase on
      histamine-induced contraction was completely abrogated in the presence of the
      protease inhibitor benzamidine (100 micromol/L). Histological examination of
      specimens exposed to tryptase demonstrated an increase in mast cell number within
      the subepithelial tissue whereas mast cell numbers in the epithelial layer
      concomittently decreased. CONCLUSION: These results indicate that human mast cell
      tryptase alters the contractile response of non-sensitized human isolated bronchi
      and that this alteration is accompanied by a change in the mast cell distribution
      within the airway wall.

PMID- 10336599
TI  - Peptidase activities in serum and bronchoalveolar lavage fluid from allergic
      asthmatics--comparison with healthy non-smokers and smokers and effects of
      inhaled glucocorticoids.
AB  - BACKGROUND: Neuropeptides may be involved in the pathogenesis of asthma by
      evoking neurogenic inflammation. Since the effects of neuropeptides are limited
      by peptidases, reduced activity of peptidases may contribute to the inflammatory
      process. OBJECTIVE: We hypothesized that soluble peptidase activities are
      decreased in asthmatics and that inhaled glucocorticoids exert part of their anti
      inflammatory action by increasing soluble peptidase activities. METHODS: Serum
      and bronchoalveolar lavage (BAL) fluid was obtained from non-smoking and smoking
      volunteers and from allergic asthmatics both before and after treatment for 12
      weeks with placebo or inhaled fluticasone propionate. Activities of neutral
      endopeptidase (NEP), aminopeptidase N (APN) and dipeptidyl peptidase IV (DPP IV)
      were determined using colourometric assays. RESULTS: Reduced DPP IV activity in
      serum and reduced NEP activity in BAL fluid were found in healthy smokers
      compared with non-smokers. In contrast, no differences in peptidase activities in
      serum or BAL fluid were observed between allergic asthmatics and healthy non
      smokers. Fluticasone propionate treatment did not affect peptidase activities in
      the asthmatic patients. CONCLUSIONS: We conclude that reduced peptidase
      activities in serum or BAL fluid can be found in healthy smokers, but not in
      allergic asthmatics, and that inhaled glucocorticoids do not affect peptidase
      activities in BAL fluid or serum of asthmatics. Our results do not support the
      hypothesized dysfunction of peptidases in the asthmatic airways.

PMID- 10336600
TI  - Candida albicans mannan- and protein-induced humoral, cellular and cytokine
      responses in atopic dermatitis patients.
AB  - BACKGROUND: The cytokine observed most often in atopic dermatitis (AD) is IL-4,
      but a role for IL-5 and IFN-gamma in the late and delayed phase reactions has
      been suggested. In AD with head, neck and shoulder distribution, hypersensitivity
      to saprophytic yeasts is an important pathogenetic factor. The yeast allergens
      include both the mannan polysaccharides and the proteins. Mannans are major cross
      reacting allergens likely to be involved in the pathogenesis of AD. OBJECTIVE: To
      characterize the humoral, lymphoproliferative and cytokine (IL-2, 4, 5 and IFN
      gamma) responses of peripheral blood mononuclear cells (PBMCs) induced by Candida
      albicans mannan and protein antigens in AD. METHODS: Fifteen AD patients and
      seven healthy controls were included. Ficoll-isolated PBMCs were stimulated by
      PHA and laboratory-generated mannan and protein extracts of C. albicans.
      Lymphocyte proliferation was measured and cytokine production was studied by
      ELISA. The antigen-specific IgG and IgE antibodies were analysed by ELISA and
      nitrocellulose RAST. RESULTS: In AD mannan (P < 0.005) and protein (P < 0.002),
      specific IgE levels were higher than in healthy controls. Both mannan and protein
      specific lymphoproliferations (both: P < 0.02) were higher in AD than in healthy
      controls. Mannan, but not protein, induced long lasting IL-2 and IL-4 productions
      from 24 h lasting up to 66-96 h and IL-5 and IFN-gamma productions with elevated
      levels at 66 and 96 h. The mannan-induced IL-2 (P = 0.015) and IFN-gamma (P <
      0.005) were increased in AD as compared with healthy controls. Significant
      correlations were seen between the protein-induced proliferation responses and
      both serum total IgE (r = 0.59, P < 0.01) and protein-specific IgE (r = 0.65, P <
      0.005). The mannan-induced IL-2 responses correlated with the specific IgE (r =
      0.62, P < 0.01) and proliferation (r = 0.51, P < 0.02) and S-IgE level (r = 0.71,
      P < 0. 002). Mannan-induced IL-4 and IFN-gamma productions also correlated (r =
      0.43, P < 0.05). CONCLUSIONS: C. albicans mannan induced elevated IL-2 and IFN
      gamma responses in AD patients. The correlations of the cytokine responses with
      mannan-induced IgE and proliferation responses suggest that C. albicans mannan
      induced TH1 type cytokine responses are involved in AD.

PMID- 10336601
TI  - Relationship between allergic status and specificity of IgG antibody to inhaled
      allergens: the grass pollen model.
AB  - BACKGROUND: We have previously reported that IgG antibodies from healthy
      individuals and patients suffering from non-seasonal mite allergy bind to
      different sets of epitopes on Der p 1, allowing almost complete discrimination of
      the populations. OBJECTIVES: To confirm this observation in a seasonal allergy
      model where a clear relationship between allergic symptoms and exposure to the
      offending agent is established. To investigate whether the pattern of modified
      specificity is related to the differences in IgG subclass hierarchy usually
      exhibited by nonallergic and allergic populations. METHODS: The capacity of
      individual sera from patients allergic to grass pollen and healthy individuals,
      including grass pollen-sensitized subjects, to prevent the binding of pooled IgG,
      IgG1, and IgG4 fractions from grass pollen-allergic patients and healthy
      individuals to solid-phase bound grass pollen antigen was evaluated in enzyme
      linked immunosorbent assay (ELISA) using streptavidin-biotin technology.
      Specificity controls were performed using sera from patients allergic to cat
      dander and house dust mite. RESULTS: The capacity of sera to prevent the antigen
      binding of allergic IgG averaged 84 +/- 5% for allergic sera and 53 +/- 6% for
      healthy sera (P < 0.001 by one-way anova). Conversely, using the antigen-binding
      capacity of healthy control IgG as reference, percentage inhibitions averaged 46
      +/- 9% in grass pollen-allergic subjects compared with 80 +/- 4%, 82 +/- 2% in
      healthy individuals, and mite- and cat-allergic patients, respectively, resulting
      in two well-separated populations (P < 0.0001 by one-way anova). Similar results
      were found regardless of whether pooled IgG1 or IgG4 were used. CONCLUSION:
      Together with previous data, our results define a new type of humoral signature
      in the immune response to inhaled allergens. Allergic and healthy status differ
      not only in the presence or absence of specific IgE antibody but also in the
      preferential expression of distinct IgG specificities that are better correlated
      with clinical manifestations and are unrelated to subclass distribution.

PMID- 10336602
TI  - Molecular characterization of Dau c 1, the Bet v 1 homologous protein from carrot
      and its cross-reactivity with Bet v 1 and Api g 1.
AB  - BACKGROUND: Up to 70% of patients with birch pollen allergy exhibit the so-called
      oral allergy syndrome, an IgE-mediated food allergy. The most frequent and
      therefore best characterized pollen-fruit syndrome is apple allergy in patients
      suffering from tree pollen-induced pollinosis. The occurrence of adverse
      reactions to proteins present in vegetables such as celery and carrots in
      patients suffering from pollen allergy has also been reported. cDNAs for Bet v 1
      homologous proteins have been cloned from celery, apple and cherry. Objective The
      aim of the study was to identify Bet v 1 homologues from carrot (Daucus carota),
      to isolate the respective cDNA, to compare the IgE-binding capacity of the
      natural protein to the recombinant allergen and determine the cross-reactivity to
      Api g 1 and Bet v 1. METHODS: Molecular characterization of the carrot allergen
      was performed using IgE-immunoblotting, cross-inhibition assays, N-terminal
      sequencing, PCR-based cDNA cloning and expression of the recombinant protein in
      Escherichia coli. RESULTS: A 16-kDa protein from carrot was identified as a major
      IgE-binding component and designated Dau c 1. Sequencing corresponding cDNAs
      revealed three extremely similar sequences (Dau c 1.1, 1.2 and 1.3) with an open
      reading frame of 462 bp coding for 154 amino acid residues. CONCLUSIONS: Purified
      recombinant Dau c 1.2 was tested in immunoblots displaying IgE-binding capacity
      comparable to its natural counterpart. Cross-inhibition assays verified the
      existence of common B-cell epitopes present on Dau c 1, Api g 1 as well as on Bet
      v 1.

PMID- 10336603
TI  - How far can we simplify in vitro diagnostics for Fagales tree pollen allergy? A
      study with three whole pollen extracts and purified natural and recombinant
      allergens.
AB  - BACKGROUND: Current diagnostic tests for Fagales tree pollen allergy are often
      composed of mixtures of pollen of birch, alder and hazel. Their complex
      composition hampers accurate standardization. OBJECTIVE: The aim of this study
      was to investigate whether mixtures of tree pollen extracts can be replaced by a
      single pollen species, and whether a single pollen species can be replaced by a
      limited number of purified natural or recombinant major allergens. METHODS: Sera
      (n = 1725) were selected on ground of a general suspicion for inhalant allergy,
      and tested in a RAST for birch, alder and hazel pollen. Sera with > 0.5 RU/mL for
      any of the three species were tested in a RAST for natural Bet v 1 and Bet v 2 as
      well as for recombinant versions of both allergens. RESULTS: Specific IgE
      antibodies (> 0.3 RU/mL) against birch, alder and hazel were found in 242, 298
      and 292 sera, respectively. All sera with a positive RAST for alder and/or hazel
      and a negative RAST for birch were low-responder sera on alder and hazel, only
      five sera having a RAST value > 1.0 (all < 2.0). For all sera with a RAST > 0.5
      RU/mL (n = 250), the mean of individual ratio's alder/birch and hazel/birch was
      1.02 and 0.54, respectively. Of 223 of these sera, 63.2% had specific IgE against
      natural Bet v 1 and 63.7% against natural Bet v 2. When responses to both
      allergens were combined 93.7% were positive. The mean ratios Bet v 1 + 2/extract
      were 1.00, 1.04 and 2. 11 in case of birch, alder and hazel, respectively. For
      211 sera the same analysis was performed with recombinant Bet v 1 and Bet v 2.
      Only six sera with Bet v 1-specific IgE (all < 0.5 RU/mL) were negative (< 0.3
      RU/mL) on recombinant Bet v 1. For Bet v 2, 77/132 sera with specific IgE to the
      natural allergen did not react to the recombinant version. Twelve false-negatives
      had RAST values > 1.0 RU/mL. The mean of the individual recombinant/natural
      ratios was 0. 98 for Bet v 1 and 0.38 for Bet v 2 (P < 0.001). The mean ratio
      rBet v 1 + 2/birch was 0.75 with 17.5% false-negatives on the combination of
      recombinant allergens. CONCLUSION: Reliable in vitro diagnosis is possible with a
      single tree pollen extract (birch or alder). The same is true for purified
      natural Bet v 1 and Bet v 2. A combination of recombinant molecules is slightly
      less efficient.

PMID- 10336604
TI  - IgE reactivity and cross-reactivity of Japanese monkeys (Macaca fuscata) to
      Japanese cedar (Cryptomeria japonica) and cypress (Chamaecyparis obtusa) pollen
      allergens.
AB  - BACKGROUND: The natural occurrence of Japanese cedar (Cryptomeria japonica, CJ)
      pollinosis has been reported in Japanese monkeys (Macaca fuscata). However, the
      reactivity to Japanese cypress (Chamaecyparis obtusa, CO) pollen allergens in
      these monkeys has not yet been reported. OBJECTIVES: The present study was
      designed to investigate the reactivity to CO pollen allergens in monkeys
      sensitized to CJ pollen allergens. METHODS: Serum samples from 40 monkeys
      naturally sensitized to CJ pollen allergens were collected from four troops. We
      measured the specific IgE to CO pollen allergens and examined the reactivity to
      the allergens by intradermal test. Cross-reactivity between CJ and CO pollen
      allergens was examined by ELISA inhibition method. Furthermore, we examined the
      sensitivity to the allergens by histamine release assay from leucocytes. RESULTS:
      All 40 monkeys had specific IgE to crude and purified major allergens (Cha o 1)
      of CO pollen. The monkeys showed a positive reaction to CO pollen allergens in
      the intradermal test. Allergenic cross-reactivity between Cha o 1 and Cry j 1 (a
      major allergen in CJ pollen) was also observed. Specific histamine release to
      both the major allergens was noted in two monkeys with CJ pollinosis. CONCLUSION:
      Japanese monkeys sensitized to Japanese cedar pollen allergens also demonstrate
      reactivity to Japanese cypress pollen allergens.

PMID- 10336605
TI  - Transcription factors and their genes in higher plants functional domains,
      evolution and regulation.
AB  - A typical plant transcription factor contains, with few exceptions, a DNA-binding
      region, an oligomerization site, a transcription-regulation domain, and a nuclear
      localization signal. Most transcription factors exhibit only one type of DNA
      binding and oligomerization domain, occasionally in multiple copies, but some
      contain two distinct types. DNA-binding regions are normally adjacent to or
      overlap with oligomerization sites, and their combined tertiary structure
      determines critical aspects of transcription factor activity. Pairs of nuclear
      localization signals exist in several transcription factors, and basic amino acid
      residues play essential roles in their function, a property also true for DNA
      binding domains. Multigene families encode transcription factors, with members
      either dispersed in the genome or clustered on the same chromosome. Distribution
      and sequence analyses suggest that transcription factor families evolved via gene
      duplication, exon capture, translocation, and mutation. The expression of
      transcription factor genes in plants is regulated at transcriptional and post
      transcriptional levels, while the activity of their protein products is modulated
      post-translationally. The purpose of this review is to describe the domain
      structure of plant transcription factors, and to relate this information to
      processes that control the synthesis and action of these proteins.

PMID- 10336606
TI  - Structure and expression of the highly repetitive histone H1-related sperm
      chromatin proteins from winter flounder.
AB  - In the late stages of spermatogenesis, winter flounder produce a family of high
      molecular mass (80-200 kDa) basic nuclear proteins (HMrBNPs) that combine with
      the normal complement of histones to produce condensed sperm chromatin with an
      increased nucleosomal repeat length. The HMrBNPs have a biased amino-acid
      composition in which Arg, Ser, Lys and Pro are abundant because of their presence
      in many simple peptide repeats. The organization of these repeats was deduced by
      cDNA cloning. The predominant repeating units are related 26- and 30-amino-acid
      sequences that in turn are linked by 6-amino-acid spacers to form 58- and 62
      amino-acid repeats. Subsets of these repeats are also present, such as a
      dispersed 20-amino-acid repeat and a tandem array of nine heptapeptides at the C
      terminus. The HMrBNPs appear to have evolved from an extreme H1 variant that has
      an N-terminal tail of HMrBNP-like sequence linked to an H1 globular region. Based
      on sequences of the most abundant HMrBNP cDNAs, and the lack of hybridization
      between HMrBNP mRNAs and a DNA probe for the H1 globular region, the latter
      domain appears to have been lost during expansion and amplification of the HMrBNP
      like repeats. Transcripts of the HMrBNP and H1 variant genes are present in
      testis RNAs only during the mid-spermatid stage of spermatogenesis, at the same
      time that HMrBNPs in their highly phosphorylated form first appear in the
      nucleus. Judging by the lack of a lag between HMrBNP mRNA synthesis and
      translation, the mRNAs for these highly basic proteins are not stored for any
      length of time. Instead, the deposition of HMrBNPs onto DNA, which coincides with
      the major reorganization and silencing of the chromatin, may be controlled by
      dephosphorylation.

PMID- 10336607
TI  - Calcium-binding properties and molecular organization of bradykinin A solution 1H
      NMR study.
AB  - The NMR features of bradykinin were investigated in dimethylsulfoxide containing
      1% water. The temperature dependence of chemical shifts and ROESY maps were
      monitored for the major species where all X-Pro bonds are trans. The occurrence
      of a head-to-tail ionic interaction and intramolecular hydrogen bonds stabilizing
      a pseudo cyclic arrangement was inferred, a beta turn at the C-terminus being the
      main feature of the secondary structure. Calcium was shown to bind to the peptide
      with a dissociation constant Kd = 2.8 + 0.2 mm. 2Pro and 3Pro carbonyls, as well
      as the 9Arg carboxyl, were assigned as the metal-binding sites. A molecular model
      of the 1 : 1 metal-complex was obtained. In light of conformational changes
      experienced by the peptide upon interaction with calcium, a role for the metal
      was hypothesized in the process of conformational selection from the free to the
      receptor-bound state of bradykinin.

PMID- 10336608
TI  - A novel isoform of the low molecular weight phosphotyrosine phosphatase, LMPTP-C,
      arising from alternative mRNA splicing.
AB  - The low molecular weight protein tyrosine phosphatase (LMPTP) is an 18-kDa enzyme
      that it distantly related to other protein tyrosine phosphatases. The single gene
      for LMPTP is known to undergo an alternative splicing event in which exon 3 or
      exon 4 is excised, resulting in two isoforms termed A and B; the latter is more
      mobile in SDS/PAGE. In this paper we report the existence of a third isoform,
      which we call C, in which both exons 3 and 4 are lacking. We find the resulting
      mRNA to be ubiquitously expressed at levels that exceed those of the mRNAs for
      isoforms A and B. This mRNA was reverse-transcribed, cloned and sequenced,
      confirming the direct splicing of exon 2 to exon 5. In-vitro transcription and
      translation of the cDNA for the novel isoform resulted in the expected 16 kDa
      protein. This protein was also detected in Jurkat T cells using an antipeptide
      antiserum. LMPTP-C immunoprecipitated from transfected cells, as well as
      bacterially produced recombinant LMPTP-C, lacked phosphatase activity. Unlike
      LMPTP-B, LMPTP-C was not phosphorylated on tyrosine when coexpressed with Lck
      despite the presence of the two acceptor tyrosines. Finally, whereas c-fos
      induction by platelet-derived growth factor was inhibited by LMPTP-B, LMPTP-C
      augmented it. These results suggest that the lack of the 38-amino acid fragment
      encoded by exon 3 or 4 results in a protein product with a different three
      dimensional folding, that lacks a functional catalytic pocket and that may
      function as a natural antagonist of isoforms A and B.

PMID- 10336609
TI  - Antisense-mediated depletion of potato leaf omega3 fatty acid desaturase lowers
      linolenic acid content and reduces gene activation in response to wounding.
AB  - Fatty acid omega3 desaturases act on membrane lipids to catalyse the formation of
      trienoic fatty acids, the most abundant in plant tissues being alpha-linolenic
      acid. This fatty acid is a precursor of jasmonic acid, a plant growth regulator
      involved in the control of wound-induced gene activation in plants and in the
      induction of tuberization in potato. We isolated a potato omega3 desaturase cDNA,
      possibly encoding a plastidial isoform, and used it to investigate its expression
      pattern throughout plant development and in response to wounding. Plastidial
      omega3 desaturase gene transcripts accumulate rapidly upon wounding, preceding
      the jasmonate-dependent induction of the wound-responsive proteinase inhibitor II
      gene. We generated transgenic potato plants constitutively expressing an
      antisense RNA to this plastidial omega3 desaturase. Selected transgenic lines in
      which the cognate omega3 desaturase mRNA is largely depleted show a marked
      reduction, of up to 60%, in trienoic acids in leaves and tubers. In these lines,
      a corresponding reduction in jasmonate content and proteinase inhibitor II
      expression is observed upon wounding. Our results indicate that a reduction in
      omega3 desaturase mRNA levels compromises the wound-induced activation of
      proteinase inhibitor II, suggesting that wound-induced synthesis of linolenic
      acid is required for jasmonic acid production. The antisense-mediated depletion
      of fatty acid omega3 desaturases is a viable alternative for reducing trienoic
      fatty acid content in plant species in which a mutant screening approach is not
      applicable.

PMID- 10336610
TI  - Phospholipase C-delta3 binds with high specificity to phosphatidylinositol 4,5
      bisphosphate and phosphatidic acid in bilayer membranes.
AB  - In order to acquire an understanding of phospholipase C-delta3 (PLC-delta3)
      action on substrate localized in lipid membrane we have studied the binding of
      human recombinant PLC-delta3 to large, unilamellar phospholipid vesicles (LUVs).
      PLC-delta3 bound weakly to vesicles composed of phosphatidylcholine (PtdCho) or
      PtdCho plus phosphatidylethanolamine (PtdEtn) or phosphatidylinositol (PtdIns).
      The enzyme bound strongly to LUVs composed of PtdEtn + PtdCho and
      phosphatidylinositol 4,5-bisphosphate (PtdInsP2). The binding affinity (molar
      partition coefficient) of PLC-delta3 to PtdEtn + PtdCho + PtdInsP2 vesicles was
      7.7 x 105 m-1. High binding of PLC-delta3 was also observed for LUVs composed of
      phosphatidic acid (PA). Binding of PLC-delta3 to phosphatidylserine (PtdSer)
      vesicles was less efficient. Calculated molar partition coefficient for binding
      of PLC-delta3 to PA and PtdSer vesicles was 1.6 x 104 m-1 and 9.4 x 102 m-1,
      respectively. Presence of PA in the LUVs containing PtdInsP2 considerably
      enhanced the binding of PLC-delta3 to the phospholipid membrane. Binding of PLC
      delta3 to phospholipid vesicles was not dependent on Ca2+ presence. In the
      liposome assay PA caused a concentration-dependent increase in activity of PLC
      delta3. The stimulatory effect of PA on PLC-delta3 was calcium-dependent. At Ca2+
      concentrations lower than 1 microm, no effect of PA on the activity of PLC-delta3
      was observed. PA enhanced PLC-delta3 activity by increasing the Vmax and lowering
      Km for PtdInsP2. As the mol fraction of PA increased from 0-40 mol% the enzyme
      Vmax increased 2.3-fold and Km decreased threefold. Based on the results
      presented, we assume that PA supports binding of PLC-delta3 to lipid membranes by
      interaction with the PH domain of the enzyme. The stimulatory effect of PA
      depends on calcium-dependent interaction with the C2 domain of PLC-delta3. We
      propose that binding of PLC-delta3 to PA may serve as a mechanism for dynamic
      membrane association and modulation of PLC-delta3 activity.

PMID- 10336611
TI  - Overexpression, purification and characterization of Mycobacterium bovis BCG
      alcohol dehydrogenase.
AB  - A previous study of the effect of zinc deprivation on Mycobacterium bovis BCG
      pointed out the potential importance of an alcohol dehydrogenase for maintaining
      the hydrophobic character of the cell envelope. In this report, the effect of the
      overexpression of the M. bovis BCG alcohol dehydrogenase (ADH) in Mycobacterium
      smegmatis and M. bovis BCG is described. The purification of the enzyme was
      performed to apparent homogeneity from overexpressing M. bovis BCG cells and its
      kinetic parameters were determined. The enzyme showed a strong preference for
      both aromatic and aliphatic aldehydes while the corresponding alcohols were
      processed 100-1000-fold less efficiently. The best kcat/Km values were found with
      benzaldehyde > 3-methoxybenzaldehyde > octanal > coniferaldehyde. A phylogenetic
      analysis clearly revealed that the M. bovis BCG ADH together with the ADHs from
      Bacillus subtilis and Helicobacter pylori formed a sister group of the class C
      medium-chain alcohol dehydrogenases, the plant cinnamyl alcohol dehydrogenases
      (CADs). Comparison of the kinetic properties of our ADH with some related class C
      enzymes indicated that the mycobacterial enzyme substrate profile resembled that
      of the CADs involved in plant defence rather than those implicated in
      lignification. A possible role for the M. bovis BCG ADH in the biosynthesis of
      the lipids composing the mycobacterial cell envelope is proposed.

PMID- 10336612
TI  - Platelet-activating factor modulates brain sphingomyelin metabolism.
AB  - In the present study the modulatory action of platelet-activating factor (PAF) on
      sphingolipid metabolism in cerebral cortical slices was studied. PAF did not
      alter the basal levels of either sphingomyelin (SM) or ceramide. However, the
      SMase-elicited reciprocal alterations in SM and ceramide levels were partially
      prevented by the PAF treatment. The PAF effect was dose-dependent, with 10-8 m
      being the lowest effective concentration, and receptor-mediated as it was
      abolished by WEB 2086, a PAF receptor antagonist. Neither N-oleoylethanolamine
      (OE, ceramidase inhibitor) or d,l-1-phenyl-2-decanoylamino-3-morpholino-1
      propanol (PDMP, an inhibitor of glucosylceramide synthase and the formation of 1
      O-acyl ceramides) prevented the action of PAF. Therefore, the effect of PAF was
      unlikely to be dependent upon transformation of ceramides into
      glycosphingolipids, 1-O-acyl ceramides or sphingosine. Experiments with different
      labeled compounds ([14C]serine, [14C]arachidonate and phosphatidyl [N-methyl
      3H]choline) were also performed to test whether PAF could affect the resynthesis
      of SM. Data obtained agree with the idea that selective pools of both choline and
      ethanolamine phospholipids were used as precursors for the resynthesis of SM
      elicited by SMase treatment. PAF itself did not evoke any variation in the lipids
      analyzed but always prevented the SMase-evoked alterations. Together the data
      suggest the interesting possibility that PAF increases the overall turnover of
      SM. In summary, the present data demonstrate that PAF is able to regulate the
      cellular ceramide levels in brain by accelerating the SM cycle.

PMID- 10336613
TI  - Identification of subunit g of yeast mitochondrial F1F0-ATP synthase, a protein
      required for maximal activity of cytochrome c oxidase.
AB  - By means of a yeast genome database search, we have identified an open reading
      frame located on chromosome XVI of Saccharomyces cerevisiae that encodes a
      protein with 53% amino acid similarity to the 11.3-kDa subunit g of bovine
      mitochondrial F1F0-ATP synthase. We have designated this ORF ATP20, and its
      product subunit g. A null mutant strain, constructed by insertion of the HIS3
      gene into the coding region of ATP20, retained oxidative phosphorylation
      function. Assembly of F1F0-ATP synthase in the atp20-null strain was not affected
      in the absence of subunit g and levels of oligomycin-sensitive ATP hydrolase
      activity in mitochondria were normal. Immunoprecipitation of F1F0-ATP synthase
      from mitochondrial lysates prepared from atp20-null cells expressing a variant of
      subunit g with a hexahistidine motif indicated that this polypeptide was
      associated with other well-characterized subunits of the yeast complex. Whilst
      mitochondria isolated from the atp20-null strain had the same oxidative
      phosphorylation efficiency (ATP : O) as that of the control strain, the atp20
      null strain displayed approximately a 30% reduction in both respiratory capacity
      and ATP synthetic rate. The absence of subunit g also reduced the activity of
      cytochrome c oxidase, and altered the kinetic control of this complex as
      demonstrated by experiments titrating ATP synthetic activity with cyanide. These
      results indicate that subunit g is associated with F1F0-ATP synthase and is
      required for maximal levels of respiration, ATP synthesis and cytochrome c
      oxidase activity in yeast.

PMID- 10336614
TI  - Activities of human alcohol dehydrogenases in the metabolic pathways of ethanol
      and serotonin.
AB  - Alcohols and aldehydes in the metabolic pathways of ethanol and serotonin are
      substrates for alcohol dehydrogenases (ADH) of class I and II. In addition to the
      reversible alcohol oxidation/aldehyde reduction, these enzymes catalyse aldehyde
      oxidation. Class-I gammagamma ADH catalyses the dismutation of both acetaldehyde
      and 5-hydroxyindole-3-acetaldehyde (5-HIAL) into their corresponding alcohols and
      carboxylic acids. The turnover of acetaldehyde dismutation is high (kcat = 180
      min-1) but saturation is reached first at high concentrations (Km = 30 mm) while
      dismutation of 5-HIAL is saturated at lower concentrations and is thereby more
      efficient (Km = 150 microm; kcat = 40 min-1). In a system where NAD+ is
      regenerated, the oxidation of 5-hydroxytryptophol to 5-hydroxyindole-3-acetic
      acid proceeds with concentration levels of the intermediary 5-HIAL expected for a
      two-step oxidation. Butanal and 5-HIAL oxidation is also observed for class-I ADH
      in the presence of NADH. The class-II enzyme is less efficient in aldehyde
      oxidation, and the ethanol-oxidation activity of this enzyme is competitively
      inhibited by acetate (Ki = 12 mm) and 5-hydroxyindole-3-acetic acid (Ki = 2 mm).
      Reduction of 5-HIAL is efficiently catalysed by class-I gammagamma ADH (kcat =
      400 min-1; Km = 33 microm) in the presence of NADH. This indicates that the
      increased 5-hydroxytryptophol/5-hydroxyindole-3-acetic acid ratio observed after
      ethanol intake may be due to the increased NADH/NAD+ ratio on the class-I ADH.

PMID- 10336615
TI  - Co-operative binding of Ca2+ ions to the regulatory binding sites of gelsolin.
AB  - The rate of association of actin with gelsolin was measured at various Ca2+ and
      ATP concentrations. The fraction of Ca2+-activated gelsolin was determined by
      quantitative evaluation of the association rates thereby assuming that Ca2+
      binding gelsolin associates with actin and Ca2+-free gelsolin does not. A plot of
      the fraction of Ca2+-activated gelsolin vs. the free Ca2+ concentration revealed
      a sigmoidal shape suggesting that co-operative binding of Ca2+ ions is required
      for activation of gelsolin. A good fit of the experimental data by calculated
      binding curves was obtained if two Ca2+ ions were assumed to bind to actin in a
      highly co-operative manner. ATP decreased the rate of association of gelsolin
      with actin and bound to gelsolin at a low affinity (Kd = 32 microm for Ca2+-free
      and Kd = 400 microm for Ca2+-activated gelsolin). In contrast, a 1 : 1 gelsolin
      actin complex was found to be activated for association with actin by a single
      Ca2+ ion in a non-co-operative manner.

PMID- 10336616
TI  - Fluorescence studies of the carboxyl-terminal domain of smooth muscle calponin
      effects of F-actin and salts.
AB  - The fluorescence parameters of the environment-sensitive acrylodan, selectively
      attached to Cys273 in the C-terminal domain of smooth muscle calponin, were
      studied in the presence of F-actin and using varying salt concentrations. The
      formation of the F-actin acrylodan labeled calponin complex at 75 mm NaCl
      resulted in a 21-nm blue shift of the maximum emission wavelength from 496 nm to
      474 nm and a twofold increase of the fluorescent quantum yield at 460 nm. These
      spectral changes were observed at the low ionic strengths (< 110 mm) where the
      calponin : F-actin stoichiometry is 1 : 1 as well as at the high ionic strengths
      (> 110 mm) where the binding stoichiometry is a 1 : 2 ratio of calponin : actin
      monomers. On the basis of previous three-dimensional reconstruction and chemical
      crosslinking of the F-actin-calponin complex, the actin effect is shown to derive
      from the low ionic strength interaction of calponin with the bottom of subdomain
      1 of an upper actin monomer in F-actin and not from its further association with
      the subdomain-1 of the adjacent lower monomer which occurs at the high ionic
      strength. Remarkably, the F-actin-dependent fluorescence change of acrylodan is
      qualitatively but not quantitatively similar to that earlier reported for the
      complexes of calponin and Ca2+-calmodulin or Ca2+-caltropin. As the three
      calponin ligands bind to the same segment of the protein, encompassing residues
      145-182, the acrylodan can be considered as a sensitive probe of the functioning
      of this critical region. A distance of 29 A was measured by fluorescence
      resonance energy transfer between Cys273 of calponin and Cys374 of actin in the 1
      : 1 F-actin-calponin complex suggesting that the F-actin effect was allosteric
      reflecting a global conformational change in the C-terminal domain of calponin.

PMID- 10336617
TI  - Polymorphic forms of human ADP-ribosyltransferase-1 differences in their
      catalytic activities revealed by labeling of membrane-associated substrates.
AB  - Full length cDNA encoding ADP-ribosyltransferase-1 (ART1) was generated from
      human skeletal muscle. A single base variation from the published sequence was
      observed (C770-->T), and was established as a polymorphism by the screening of a
      population of 50 Caucasians. The base variation predicted a nonconservative
      substitution of Leu for Pro at codon 257. Cell lines with stable and doxycycline
      inducible expression of the two polymorphic forms of ART1 were generated from
      Chinese hamster V79 cells, and exploited in studies to compare the activities of
      ART1-Pro257 and ART1-Leu257. The results revealed no differences in the capacity
      of phosphoinositide-specific phospholipase C to cleave the two ART1 isoforms from
      the plasma membrane. Furthermore, the capacities of ART1-Pro257 and ART1-Leu257
      to ADP-ribosylate agmatine or fibroblast growth factor-2 were similar.
      Differences in the catalytic activities of ART1-Pro257 and ART1-Leu257 were
      however, identified when measurements were made of their capacities to ADP
      ribosylate membrane-associated proteins on the surface of V79 cells. Protein(s)
      of molecular mass 80-110 kDa were more extensively ADP-ribosylated by ART1-Pro257
      than ART1-Leu257, in accordance with the Vmax (59.5 +/- 5.5 and 37.0 +/- 3.0) and
      Km values (12.5 +/- 4.5 and 5.0 +/- 1. 9) for ART1-Pro257 and ART1-Leu257,
      respectively.

PMID- 10336618
TI  - Inhibition of an ecto-ATP-diphosphohydrolase by azide.
AB  - Cell surface ATPases (ecto-ATPases or E-ATPases) hydrolyze extracellular ATP and
      other nucleotides. Regulation of extracellular nucleotide concentration is one of
      their major proposed functions. Based on enzymatic characterization, the E
      ATPases have been divided into two subfamilies, ecto-ATPases and ecto-ATP
      diphosphohydrolases (ecto-ATPDases). In the presence of either Mg2+ or Ca2+, ecto
      ATPDases, including proteins closely related to CD39, hydrolyze nucleoside
      diphosphates in addition to nucleoside triphosphates and are inhibited by
      millimolar concentrations of azide, whereas ecto-ATPases appear to lack these two
      properties. This report presents the first systematic kinetic study of a purified
      ecto-ATPDase, the chicken oviduct ecto-ATPDase (Strobel, R.S., Nagy, A.K.,
      Knowles, A.F., Buegel, J. & Rosenberg, M.O. (1996) J. Biol. Chem. 271, 16323
      16331), with respect to ATP and ADP, and azide inhibition. Km values for ATP
      obtained at pH 6.4 and 7.4 are 10-30 times lower than for ADP and the catalytic
      efficiency is greater with ATP as the substrate. The enzyme also exhibits
      complicated behavior toward azide. Variable inhibition by azide is observed
      depending on nucleotide substrate, divalent ion, and pH. Nearly complete
      inhibition by 5 mm azide is obtained when MgADP is the substrate and when assays
      are conducted at pH 6-6.4. Azide inhibition diminishes when ATP is the substrate,
      Ca2+ as the activating ion, and at higher pH. The greater efficacy of azide in
      inhibiting ADP hydrolysis compared to ATP hydrolysis may be related to the
      different modes of inhibition with the two nucleotide substrates. While azide
      decreases both Vmax and Km for ADP, it does not alter the Km for ATP. These
      results suggest that the apparent affinity of azide for the E.ADP complex is
      significantly greater than that for the free enzyme or E.ATP. The response of the
      enzyme to three other inhibitors, fluoride, vanadate, and pyrophosphate, is also
      dependent on substrate and pH. Taken together, these results are indicative of a
      discrimination between ADP and ATP by the enzyme. A mechanism of azide inhibition
      is proposed.

PMID- 10336619
TI  - Investigation on the detergent role in the function of secondary quinone in
      bacterial reaction centers.
AB  - In this paper are reported studies on the detergent role in isolated reaction
      centers (RC) from Rhodobacter sphaeroides, over a large range of
      lauryldimethylamino-N-oxide (LDAO) concentrations, in influencing the
      thermodynamics of the quinone exchange reaction as well as the protein
      aggregation. The occurrence of the quinone exchange reaction between the QB
      binding site (where QB is the second quinone molecule of two in the RC) and the
      ubiquinone 0 dissolved in the different environments (water, LDAO micelles and
      detergent phase of the protein-detergent complex) has also been analyzed.
      Measurements carried out in QB-depleted RC to which exogenous quinone has been
      added show that the relative amplitudes of the slow and fast phase of the
      recombination reaction depend on this parameter. The overall amount of the
      restored QB-functionality is affected by the concentration of the LDAO in
      solution. Interpolation of the titration curves with a quadratic function
      obtained by simple considerations allowed the binding constant of UQ0 to the QB
      binding site to be calculated. From the fitting procedure, the distribution of
      the quinone in the different environments present in solution was evaluated,
      indicating that the exchange reaction can take place only between the QB-site and
      the detergent phase. The dependence of the quinone pool size upon the volume of
      the phase in which the interacting quinone is solubilized is also discussed. The
      increasing difficulty in saturating the QB-pocket above the LDAO critical
      micellar concentration is finally related to the association of protein-detergent
      complexes to form large protein clusters.

PMID- 10336620
TI  - Molecular cloning and tissue expression of an insect farnesyl diphosphate
      synthase.
AB  - The enzyme farnesyl-diphosphate synthase (FPS, EC2.5.1.1/EC2.5.1.10), which has
      been shown to play a key role in isoprenoid biosynthesis, catalyzes the synthesis
      of farnesyl diphosphate from isopentenyl diphosphate and di-methylallyl
      diphosphate. Insects do not synthesize cholesterol de novo, rather farnesyl
      diphosphate leads to the formation of nonsterol isoprenoids, which are essential
      for insect development and reproduction. In this paper, we describe the
      characterization of one FPS from the moth Agrotis ipsilon, the first insect FPS
      to be reported. An homologous probe was obtained through a nested PCR strategy
      using degenerate primers designed from the conserved domains of FPS from other
      organisms. The complete cDNA clone was isolated by PCR screening of a brain cDNA
      library by using homologous primers deduced from the probe. Analysis of the
      nucleotide sequence revealed that the cDNA encodes a polypeptide of 412 amino
      acids (Mr = 47 170), which shares regions similar to the FPS of other organisms,
      but exhibits singularities such as an extra N-terminal extension of approximately
      70 amino acid residues. Using an RNase protection assay, a protected fragment
      corresponding to the region encoding the FPS catalytic site was found in brain,
      ovary, fat body and corpora allata samples, but not in muscle. FPS is
      overexpressed in the corpora allata, the endocrine gland that produces the
      juvenile hormones. These hormones are specific to insects and play a crucial role
      in regulating insect physiology.

PMID- 10336621
TI  - Mechanism of metabolite transfer in coupled two-enzyme reactions involving
      aldolase.
AB  - Transient-state kinetic experiments and analyses have been performed to examine
      the validity of hitherto unchallenged evidence proposed to be indicative of a
      channelled transfer of triose phosphates from aldolase to glyceraldehyde-3
      phosphate dehydrogenase and glycerol-3-phosphate dehydrogenase. The results lend
      no support to such proposals, but show that the kinetic behaviour of the examined
      aldolase-dehydrogenase reactions is fully consistent with a free-diffusion
      mechanism of metabolite transfer.

PMID- 10336622
TI  - Identification and characterization of a tri-partite hydrophobin from Claviceps
      fusiformis. A novel type of class II hydrophobin.
AB  - A new type of hydrophobin is encoded by an abundant mRNA of Claviceps fusiformis.
      The predicted amino-acid sequence of the protein, dubbed CFTH1, shows a putative
      signal sequence for secretion, followed by three class II hydrophobin domains
      each preceded by glycine/asparagine rich regions. SDS/PAGE analysis of 60%
      ethanol extractions of C. fusiformis mycelia from shaken cultures showed CFTH1 at
      the 50-55-kDa position. N-terminal sequencing of both untreated mature CFTH1 and
      of a fragment obtained by trypsin digestion revealed that CFTH1 is not processed
      between the hydrophobin domains. Mass spectroscopy showed a mass of about 36 500
      Da, which is about 1500 Da higher than the mass predicted from the constituent
      amino acids, indicating post-translational modification but not glycosylation.
      Purified CFTH1 self-assembled at hydrophilic/hydrophobic interfaces and, after
      assembly at a water/air interface, it was found to be highly surface active.
      Antibodies raised against CFTH1 localized the protein in a mucilageous coat
      surrounding submerged vegetative hyphae in liquid shaken culture and, as a
      discrete layer of about 10 nm thickness at the surface of aerial hyphae of
      standing cultures, suggesting a role in the formation of aerial hyphae.

PMID- 10336623
TI  - Glyceraldehyde-3-phosphate dehydrogenase from Ehrlich ascites carcinoma cells its
      possible role in the high glycolysis of malignant cells.
AB  - Glyceraldehyde-3-phosphate dehydrogenase has been purified to apparent
      homogeneity from Ehrlich ascites carcinoma (EAC) cells. The enzyme is quite
      active over a pH range of 7.5-9.0 with an optimum pH of 8.4-8.7. The specific
      activity of the enzyme is much higher than that from other normal sources. In
      contrast to enzyme obtained from rabbit muscle, the EAC cell enzyme is not
      significantly inhibited by physiological concentrations of ATP at physiological
      pH. Kinetic studies using different substrates and inhibitors indicate that the
      properties of the EAC cell enzyme are significantly different from those of
      glyceraldehyde-3-phosphate dehydrogenase obtained from other normal sources. The
      striking dissimilarity of the malignant cell glyceraldehyde-3-phosphate
      dehydrogenase compared with this enzyme from other normal sources, particularly
      in respect to the interaction with ATP, may in part explain the high glycolysis
      of malignant cells.

PMID- 10336624
TI  - Phospholipid bound to the flavohemoprotein from Alcaligenes eutrophus.
AB  - The structurally characterized flavohemoprotein from Alcaligenes eutrophus (FHP)
      contains a phospholipid-binding site with 1-16 : 0-2-cyclo-17 : 0-diacyl
      glycerophospho-ethanolamine and 1-16 : 0-2-cyclo-17 : 0-diacyl-glycerophospho
      glycerol as the major occupying compounds. The structure of the phospholipid is
      characterized by its compact form, due to the -sc/beta/-sc conformation of the
      glycerol and the nonlinear arrangement of the sn-1- and sn-2-fatty acid chains.
      The phospholipid-binding site is located adjacent to the heme molecule at the
      bottom of a large cavity. The fatty acid chains form a large number of van der
      Waal's contacts with nonpolar side chains, whereas the glycerophosphate moiety,
      which points towards the entrance of the channel, is linked to the protein matrix
      by polar interactions. The thermodynamically stable globin module of FHP,
      obtained after cleaving off the oxidoreductase module, also contains the
      phospholipid and can therefore be considered as a phospholipid-binding protein.
      Single amino acid exchanges designed to decrease the lipid-binding site revealed
      both the possibility of blocking incorporation of the phospholipid and its
      capability to evade steric barriers. Conformational changes in the phospholipid
      can also be induced by binding heme-ligating compounds. Phospholipid binding is
      not a general feature of flavohemoproteins, because the Escherichia coli and the
      yeast protein exhibit less and no lipid affinity, respectively.

PMID- 10336625
TI  - Purification and characterization of the 16-kDa heat-shock-responsive protein
      from the thermophilic cyanobacterium Synechococcus vulcanus, which is an alpha
      crystallin-related, small heat shock protein.
AB  - A 16-kDa protein, one of the major proteins that accumulates upon heat-shock
      treatment in the thermophilic cyanobacterium Synechococcus vulcanus, was purified
      to apparent homogeneity. The N-terminal and internal amino acid sequences of the
      protein exhibited a homology to the alpha-crystallin-related, small heat shock
      proteins from other organisms. The protein was designated HspA. Size-exclusion
      chromatography and nondenaturing gel electrophoresis demonstrated that HspA
      formed a large homo-oligomer consisting of 24 subunits. It prevented the
      aggregation of porcine malic dehydrogenase at 45 degrees C and 50 degrees C and
      citrate synthase at 50 degrees C. The activity of the malic dehydrogenase,
      however, was not protected under these heat-shock conditions or reactivated after
      a shift in temperature from 45 or 50 degrees C to 21 degrees C. HspA was able to
      enhance the refolding of chemically denatured rabbit muscle lactate dehydrogenase
      in an ATP-independent manner. A homologue to the 16-kDa protein was also found to
      be induced upon heat-shock treatment in the mesophilic cyanobacterium
      Synechocystis sp. PCC 6803.

PMID- 10336626
TI  - Properties and molecular cloning of Ca2+/H+ antiporter in the vacuolar membrane
      of mung bean.
AB  - Kinetic and molecular properties of the Ca2+/H+ antiporter in the vacuolar
      membrane of mung bean hypocotyls were examined and compared with Ca2+-ATPase.
      Ca2+ transport activities of both transporters were assayed separately by the
      filtration method using vacuolar membrane vesicles and 45Ca2+. Ca2+ uptake in the
      presence of ATP and bafilomycin A1, namely Ca2+-ATPase, showed a relatively low
      Vmax (6 nmol.min-1.mg-1 protein) and a low Km for Ca2+. The Ca2+/H+ antiporter
      activity driven by H+-pyrophosphatase showed a high Vmax (25 nmol.min-1.mg-1) and
      a relatively high Km for Ca2+. The cDNA for mung bean Ca2+/H+ antiporter (VCAX1)
      codes for a 444 amino-acid polypeptide. Two peptide-specific antibodies of the
      antiporter clearly reacted with a 42-kDa protein from vacuolar membranes and a
      cell lysate from a Escherichia coli transformant in which VCAX1 was expressed.
      These observations directly demonstrate that a low-affinity, high-capacity
      Ca2+/H+ antiporter and a high-affinity Ca2+-ATPase coexist in the vacuolar
      membrane. It is likely that the Ca2+/H+ antiporter removes excess Ca2+ in the
      cytosol to lower the Ca2+ concentration to micromolar levels after stimuli have
      increased the cytosolic Ca2+ level, the Ca2+-ATPase then acts to lower the
      cytosolic Ca2+ level further.

PMID- 10336627
TI  - Characterization of a chromatin remodelling activity in Xenopus oocytes.
AB  - The yeast SWI2/SNF2 protein is a component of a large protein complex which is
      involved in the remodelling of chromatin during transcriptional activation.
      Several homologous complexes have been found in Drosophila and mammals. We have
      examined the expression of the SWI2/SNF2 homologue BRG1 in Xenopus laevis using
      two antisera originally raised against the C-terminus of the rat and the human
      BRG1 protein. These two antisera cross-reacted with a protein found in both
      Xenopus liver and Xenopus oocytes. The Xenopus BRG1-like protein is expressed
      throughout oogenesis (stages I-VI) and embryogenesis. By injecting an expression
      vector containing the full-length human BRG1 cDNA into Xenopus oocytes, the
      relative molecular weight (Mr) of the Xenopus BRG1-like protein was shown to be
      slightly lower than that of the human BRG1, 190 000 and 200 000, respectively.
      The Xenopus BRG1-like protein elutes at a Mr of approximately 2 000 000 on
      Superose HR6trade mark size-exclusion chromatography, indicating that it is part
      of a larger complex, as are all other known SWI/SNF proteins. Nucleosome
      remodelling activity was co-eluted with the BRG1 immunogenic activity in both ion
      exchange and size-exclusion chromatography.

PMID- 10336628
TI  - Optimized expression and catalytic properties of a wheat obtusifoliol 14alpha
      demethylase (CYP51) expressed in yeast. Complementation of erg11Delta yeast
      mutants by plant CYP51.
AB  - CYP51s form the only family of P450 proteins conserved in evolution from
      prokaryotes to fungi, plants and mammals. In all eukaryotes, CYP51s catalyse
      14alpha-demethylation of sterols. We have recently isolated two CYP51 cDNAs from
      sorghum [Bak, S., Kahn, R.A., Olsen, C. E. & Halkier, B.A. (1997) Plant J. 11,
      191-201] and wheat [Cabello-Hurtado, F., Zimmerlin, A., Rahier, A., Taton, M.,
      DeRose, R., Nedelkina, S., Batard, Y., Durst, F., Pallett, K.E. & Werck
      Reichhart, D. (1997) Biophys. Biochem. Res. Commun. 230, 381-385]. Wheat and
      sorghum CYP51 proteins show a high identity (92%) compared with their identity
      with their fungal and mammalian orthologues (32-39%). Data obtained with plant
      microsomes have previously suggested that differences in primary sequences
      reflect differences in sterol pathways and CYP51 substrate specificities between
      animals, fungi and plants. To investigate more thoroughly the properties of the
      plant CYP51, the wheat enzyme was expressed in yeast strains overexpressing
      different P450 reductases as a fusion with either yeast or plant (sorghum)
      membrane targeting sequences. The endogenous sterol demethylase gene (ERG11) was
      then disrupted. A sorghum-wheat fusion protein expressed with the Arabidopsis
      thaliana reductase ATR1 showed the highest level of expression and activity. The
      expression induced a marked proliferation of microsomal membranes so as to obtain
      70 nmol P450.(L culture)-1, with CYP51 representing 1.5% of microsomal protein.
      Without disruption of the ERG11 gene, the expression level was fivefold reduced.
      CYP51 from wheat complemented the ERG11 disruption, as the modified yeasts did
      not need supplementation with exogenous ergosterol and grew normally under
      aerobic conditions. The fusion plant enzyme catalysed 14alpha-demethylation of
      obtusifoliol very actively (Km,app = 197 microm, kcat = 1.2 min-1) and with very
      strict substrate specificity. No metabolism of lanosterol and eburicol, the
      substrates of the fungal and mammalian CYP51s, nor metabolism of herbicides and
      fatty acids was detected in the recombinant yeast microsomes. Surprisingly
      lanosterol (Ks = 2.2 microM) and eburicol (Ks = 2.5 microm) were found to bind
      the active site of the plant enzyme with affinities higher than that for
      obtusifoliol (Ks = 289 microM), giving typical type-I spectra. The amplitudes of
      these spectra, however, suggested that lanosterol and eburicol were less
      favourably positioned to be metabolized than obtusifoliol. The recombinant enzyme
      was also used to test the relative binding constants of two azole compounds,
      LAB170250F and gamma-ketotriazole, which were previously reported to be potent
      inhibitors of the plant enzyme. The Ks of plant CYP51 for LAB170250F (0.29
      microM) and gamma-ketotriazole (0.40 microM) calculated from the type-II sp2
      nitrogen-binding spectra were in better agreement with their reported effects as
      plant CYP51 inhibitors than values previously determined with plant microsomes.
      This optimized expression system thus provides an excellent tool for detailed
      enzymological and mechanistic studies, and for improving the selectivity of
      inhibitory molecules.

PMID- 10336629
TI  - Roles of key functional groups in omega-conotoxin GVIA synthesis, structure and
      functional assay of selected peptide analogues.
AB  - The contributions of various functional groups to the pharmacophore of the N-type
      calcium-channel blocker, omega-conotoxin GVIA (GVIA), have been investigated
      using structural and in-vitro functional studies of analogues substituted at one
      or two positions with non-native residues. In most cases the structure of the
      analogue was shown to be native-like by 1H NMR spectroscopy. Minor conformational
      changes observed in some cases were characterized by two-dimensional NMR. Three
      functional assays (sympathetic nerve stimulation of rat isolated vas deferens,
      right atrium and mesenteric artery) were employed to monitor N-type calcium
      channel activity. The data provide a more detailed picture of the roles in GVIA
      structure and activity of the crucial Lys2 and Tyr13, as well as all other
      positively charged residues, Tyr22, the hydroxyproline residues and the C
      terminal amido moiety, many of which were identified as being important for
      activity in an alanine scan [Lew et al. (1997) J. Biol. Chem. 272, 12014-12023].
      Substitutions of Lys2 with nonstandard amino acids and arginine quantified the
      roles of the length and charge of the Lys side chain. The orientation of the
      Tyr13 side chain and its hydroxyl moiety was shown to be important by
      substitution with d-Tyr and the d-form and l-form of the constrained analogue 7
      hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [Tic(OH)]. The roles of
      the Hyp10 and Hyp21 hydroxyl groups, investigated by proline substitutions,
      appear to be more structural (as monitored by NMR) than functional, although
      small decreases in potency were observed in some assays. The reversibility of the
      channel blockade was also studied, and several analogues with faster wash-out
      characteristics than native GVIA were identified. Rapid reversibility (as in the
      case of omega-conotoxin MVIIA) may be beneficial for therapeutic applications.
      Disubstituted analogues revealed some interesting cooperative effects, which were
      not predicted from single-residue substitutions. A disubstituted chimera of GVIA
      and omega-conotoxin MVIIA was more potent than either native molecule. The more
      detailed description of the GVIA pharmacophore obtained here provides a better
      basis for the future design of truncated peptide and peptidomimetic analogues.

PMID- 10336630
TI  - Sex-specific transcripts of the Dstpk61 serine/threonine kinase gene in
      Drosophila melanogaster.
AB  - We describe the characterization of several transcripts of the Drosophila
      serine/threonine protein kinase 61 (Dstpk61) gene. Dstpk61 produces at least four
      transcripts, including a 3.0-kb testis-specific transcript, a 4.5-kb female
      specific carcass transcript, a 3.5-kb ovary-specific transcript, and a 4.7-kb non
      sex-specific transcript. Two cDNAs, a 4.5-kb cDNA (cDNAB) and a 3.0-kb cDNA
      (cDNAA), likely to correspond to either the non-specific or the female-specific
      carcass and the testis-specific transcript, respectively, were fully sequenced
      and found to encode a novel OPA-repeat-containing serine/threonine-specific
      protein kinase. cDNAA and cDNAB both contain the entire ORF that encodes this
      predicted protein, but differ in the untranslated regions. The cDNAs contain
      translational control elements which are found in transcripts under male germline
      specific translational control, and doublesex-like 13-nucleotide repeat elements,
      which are required for transformer/transformer-2-mediated splicing of the female
      doublesex transcript. The complex tissue and sex-specific transcripts, differing
      in the untranslated regions which are likely to be crucial in translational
      control, suggest that this kinase may have both general and sex-specific
      functions. The protein is homologous to human 3-phosphoinositide dependent
      protein kinase, which is involved in transduction of insulin signalling.

PMID- 10336631
TI  - Characterization of MB-1. A dimeric helical protein with a compact core.
AB  - MB-1 is a de-novo protein designed to incorporate a large number of the
      nutritionally important amino acids methionine, lysine, leucine and threonine
      into a stable four-helix bundle protein. MB-1 has been expressed and purified
      from Escherichia coli, indicating it was resistant to intracellular proteases
      [Beauregard, M., Dupont, C., Teather, R.M. & Hefford, M.A. (1995) Bio/Technology
      13, 974]. Here we report an analysis of the secondary, tertiary and quaternary
      structures in MB-1 using circular dichroism, fluorospectroscopy and size
      exclusion chromatography. Our data indicate that the MB-1 structure is close to
      the target structure, an alpha-helical bundle, in many respects and is highly
      helical in solution. The single tyrosine incorporated into the designed protein
      as a spectrocopic probe of tertiary structure, is buried in a compact, folded
      core and becomes accessible on protein denaturation, as per design. Furthermore,
      MB-1 was found to be native-like in many respects: (a) protein denaturation
      induced by urea is cooperative and fully reversible; (b) its oligomeric state at
      moderate concentration is well defined; and (c) MB-1 has very low affinity for 8
      anilino-1-naphthalenesulfonic acid (ANSA), leading to enhancement of ANSA
      fluorescence that resembles that of other native proteins. On the other hand, our
      analysis revealed two aspects that command further attention. The folding
      stability of MB-1 as assessed by urea and thermal denaturation is somewhat less
      than that found for natural globular proteins of similar size. Size-exclusion
      chromatography experiments and analysis of MB-1 denaturation indicate that MB-1
      is dimeric, not monomeric as designed. In light of these results, the utility and
      the current limitations of our design approach are discussed.

PMID- 10336632
TI  - Contribution of the carbohydrate moiety to conformational stability of the
      carboxypeptidase Y high pressure study.
AB  - The process of pressure-induced denaturation of carboxypeptidase Y and the role
      of the carbohydrate moiety in its response to pressure and low temperature were
      investigated by measuring in situ the catalytic activity and, the intrinsic and 8
      anilino-1-naphthalene sulfonic acid binding fluorescences. Pressure-induced
      denaturation of carboxypeptidase Y is a process involving at least three
      transitions. Low pressures (below 150 MPa) induced slight conformational changes
      characterized by a slight decrease in the center of the spectral mass of
      intrinsic fluorescence, whereas no changes in 8-anilino-1-naphthalene sulfonic
      acid binding fluorescence were observed and 80% of the catalytic activity
      remained. Higher pressure (150-500 MPa) induced further conformational changes,
      characterized by a large decrease in the center of the spectral mass of intrinsic
      fluorescence, a large increase in the 8-anilino-1-naphthalene sulfonic acid
      binding fluorescence and the loss of all catalytic activity. Thus, this
      intermediate exhibited characteristics of molten globule-like state. A further
      increase, in pressure (above 550 MPa) induced transition from this first molten
      globule-like state to a second molten globule-like state. This two-stage
      denaturation process can be explained by assuming the existence of two
      independent structural domains in the carboxypeptidase molecule. A similar three
      transition process was found for unglycosylated carboxypeptidase Y, but, the
      first two transitions clearly occurred at lower pressures than those for
      glycosylated carboxypeptidase Y. These findings indicate that the carbohydrate
      moiety protects carboxypeptidase Y against pressure-induced denaturation. The
      origin of the protective effects is discussed based on the known crystallographic
      structure of CPY.

PMID- 10336633
TI  - Biosynthesis of the vacuolar H+-ATPase accessory subunit Ac45 in Xenopus
      pituitary.
AB  - Vacuolar H+-ATPases (V-ATPases) mediate the acidification of multiple
      intracellular compartments, including secretory granules in which an acidic
      milieu is necessary for prohormone processing. A search for genes coordinately
      expressed with the prohormone proopiomelanocortin (POMC) in the melanotrope cells
      of Xenopus intermediate pituitary led to the isolation of a cDNA encoding the
      complete amino-acid sequence of the type I transmembrane V-ATPase accessory
      subunit Ac45 (predicted size 48 kDa). Comparison of Xenopus and mammalian Ac45
      sequences revealed conserved regions in the protein that may be of functional
      importance. Western blot analysis showed that immunoreactive Ac45 represents a
      approximately 40-kDa product that is expressed predominantly in neuroendocrine
      tissues; deglycosylation resulted in a approximately 27-kDa immunoreactive Ac45
      product which is smaller than predicted for the intact protein. Biosynthetic
      studies revealed that newly synthesized Xenopus Ac45 is an N-glycosylated protein
      of approximately 60 kDa; the nonglycosylated, newly synthesized form is
      approximately 46 kDa which is similar to the predicted size. Immunocytochemical
      analysis showed that in Xenopus pituitary, Ac45 is highly expressed in the
      biosynthetically active melanotrope cells. We conclude that the regionally
      conserved Xenopus Ac45 protein is synthesized as an N-glycosylated approximately
      60-kDa precursor that is intracellularly cleaved to an approximately 40-kDa
      product and speculate that it may assist in the V-ATPase-mediated acidification
      of neuroendocrine secretory granules.

PMID- 10336634
TI  - Structures and co-regulated expression of the genes encoding mouse cytosolic
      chaperonin CCT subunits.
AB  - The chaperonin-containing TCP-1 (CCT) is a hetero-oligomeric molecular chaperone
      that mediates protein folding in the cytosol of eukaryotes. Eight (or nine in
      testis) subunit species are assembled in the CCT hexadecamer complex. We have
      cloned seven CCT subunit genes, Cctb, Cctd, Ccte, Cctz-1, Cctz-2 (testis
      specific), Ccth and Cctq, from mouse genomic DNA libraries, in addition to the
      Ccta and Cctg genes reported previously, and the entire nucleotide sequences of
      these DNA clones were determined. These genes are approximately 15-20 kb in
      length except for Cctz-2 which is longer than 35 kb, and all the Cct genes
      consist of 11-16 exons. Primer extension analyses of testis RNA indicate one to
      several potential transcription start sites 50-150 bp upstream from the
      translation start codon of each Cct gene. There are several possible Sp1-binding
      sequences, but no obvious TATA box was observed around the potential start sites.
      From 5'-flanking regions to the first introns, the Cct genes are rich in CpG
      dinucleotides. In reporter gene assays using these regions, five of eight Cct
      genes showed strong transcriptional activity comparable with the combination of
      SV40 promoter and enhancer in HeLa cells. We also show, by Western and Northern
      blot analyses, that CCT expression levels vary widely among different tissues but
      the expression patterns are very similar among the eight subunit species. It is
      likely that expression levels of the eight different subunits are tightly co
      regulated to maintain a constant ratio of these subunits which constitute the CCT
      hexadecamer complex with a fixed subunit arrangement.

PMID- 10336635
TI  - Analysis of ectatomin action on cell membranes.
AB  - Ectatomin (m = 7928 Da) is a toxic component from the Ectatomma tuberculatum ant
      venom containing two homologous polypeptide chains (37 and 34 residues) linked to
      each other by a disulfide bond. In aqueous solution it forms a four alpha-helix
      bundle. At concentrations of 0.05-0.1 microm, ectatomin forms channels in
      cellular and artificial bilayer membranes. Immunochemical analysis of the
      intracellular distribution of ectatomin showed that the toxin gets efficiently
      inserted into the plasma membrane at a concentration of 5 x 10-7 m and does not
      penetrate inside the cell. The effect of ectatomin on cardiac L-type calcium
      current was studied. Calcium currents (ICa) in isolated rat cardiac ventricular
      myocytes were measured using the whole-cell perforated patch-clamp technique. It
      was shown that ectatomin at concentrations of 0.01-10 nm inhibited ICa after a
      latency of few seconds. ICa was decreased twofold by 10 nm ectatomin. However,
      the most prominent effect of ectatomin was observed after stimulation of ICa by
      isoproterenol, an agonist of beta-adrenoreceptors, or forskolin, a stimulator of
      adenylate cyclase. At a concentration of 1 nm, ectatomin abolished the
      isoproterenol- and forskolin-sensitive components of ICa. The inhibitory effect
      of ectatomin was partially reversed by subsequent application of 2 microm of
      forskolin, whereas subsequent isoproterenol application did not produce the same
      effect.

PMID- 10336636
TI  - Phenylacetyl-CoA:acceptor oxidoreductase, a membrane-bound molybdenum-iron-sulfur
      enzyme involved in anaerobic metabolism of phenylalanine in the denitrifying
      bacterium Thauera aromatica.
AB  - Phenylacetic acids are common intermediates in the microbial metabolism of
      various aromatic substrates including phenylalanine. In the denitrifying
      bacterium Thauera aromatica phenylacetate is oxidized, under anoxic conditions,
      to the common intermediate benzoyl-CoA via the intermediates phenylacetyl-CoA and
      phenylglyoxylate (benzoylformate). The enzyme that catalyzes the four-electron
      oxidation of phenylacetyl-CoA has been purified from this bacterium and studied.
      The enzyme preparation catalyzes the reaction phenylacetyl-CoA + 2 quinone + 2
      H2O --> phenylglyoxylate + 2 quinone H2 + CoASH. Phenylacetyl-CoA:acceptor
      oxidoreductase is a membrane-bound molybdenum-iron-sulfur protein. The purest
      preparations contained three subunits of 93, 27, and 26 kDa. Ubiquinone is most
      likely to act as the electron acceptor, and the oxygen atom introduced into the
      product is derived from water. The protein preparations contained 0.66 mol Mo, 30
      mol Fe, and 25 mol acid-labile sulfur per mol of native enzyme, assuming a native
      molecular mass of 280 kDa. Phenylglyoxylyl-CoA, but not mandelyl-CoA, was
      observed as a free intermediate. All enzyme preparations also catalyzed the
      subsequent hydrolytic release of coenzyme A from phenylglyoxylyl-CoA but not from
      phenylacetyl-CoA. The enzyme is reversibly inactivated by a low concentration of
      cyanide, but is remarkably stable with respect to oxygen. This new member of the
      molybdoproteins represents the first example of an enzyme which catalyzes the
      alpha-oxidation of a CoA-activated carboxylic acid without utilizing molecular
      oxygen.

PMID- 10336637
TI  - Changing the efficiency and specificity of the esterase activity of human
      carbonic anhydrase II by site-specific mutagenesis.
AB  - Rates of hydrolysis of 4-, 3-, and 2-nitrophenyl acetate and 4-nitrophenyl
      propionate catalyzed by wild-type and mutant forms of human carbonic anhydrase II
      have been measured. The results show that the mutations Tyr7-->Phe and Ala65-
      >Leu lead to activity enhancements with all the investigated substrates, but
      there is no significant effect on the specificity. In contrast, some mutations at
      sequence position 200 have large effects on specificity. For example, while the
      mutation Thr200-->Gly results in a threefold increase of the rate of hydrolysis
      of 4-nitrophenyl acetate, the activity is enhanced 10 times with the meta
      substituted substrate and 380 times with the ortho-substituted substrate. These
      results are interpreted in terms of the removal in the mutant of a steric
      interference between the 2-NO2 group, in particular, and the side chain of
      Thr200. Mutants involving residues lining a hydrophobic pocket near the
      catalytically essential zinc ion have also been investigated. The most pronounced
      effect on specificity was found for the Val143-->Gly mutant. This mutation leads
      to a sixfold decrease of the rate of hydrolysis of 4-nitrophenyl acetate but a 20
      fold increase of the activity with the propionyl ester as substrate. These
      results suggest that the side chain of Val143 interferes sterically with the acyl
      moiety of 4-nitrophenyl propionate. Based on these results, we have constructed a
      hypothetical model of the location of these ester substrates in the enzymic
      active site.

PMID- 10336638
TI  - The interaction of thrombomodulin with Ca2+.
AB  - Thrombomodulin (TM) is a cofactor for protein C activation by thrombin and each
      residue of a consensus Ca2+ site in the sixth epidermal growth factor domain
      (EGF6) is essential for this cofactor activity [Nagashima, M., Lundh, E.,
      Leonard, J.C., Morser, J. & Parkinson, J.F. (1993) J. Biol. Chem. 268, 2888
      2892]. Three soluble analogs of the extracellular domain of TM, solulin (Glu4
      Pro490), TME1-6 (Cys227-Cys462) and TMEi4-6 (Val345-Cys462) were prepared for
      equilibrium dialysis experiments by exhaustive dialysis against Ca2+-depleted
      buffer. However, all three analogs still contained one tightly bound Ca2+ (Kd
      approximately 2 microm), which could only be removed by EDTA. Epitope mapping
      with Ca2+-dependent monoclonal antibodies to EGF6 provided further localization
      of this tight Ca2+ site. Equilibrium dialysis of the soluble TM analogs in
      [45Ca2+] between 10 and 200 microm revealed a second Ca2+ site (Kd = 30 +/- 10
      microm) in both solulin and TME1-6, but not in TMEi4-6. Ca2+ binding to this
      second site was unaffected by bound thrombin and we attribute it to the consensus
      Ca2+ site in EGF3. A 75-fold decrease in the binding affinity of thrombin to TM
      was observed with immobilized solulin treated with EDTA to remove the high
      affinity Ca2+ by measuring kassoc and kdiss rates in a BIAcoretrade mark
      instrument. Ca2+-dependent conformational transitions detected by CD spectroscopy
      in the far UV indicate a more ordered structure upon Ca2+ binding. Bound Ca2+
      stabilized soluble TM against protease digestion at a trypsin-like protease
      sensitive site between Arg456 and His457 in EGF6 compared with protease treatment
      in EDTA. Finally, TM containing EGF domains 4-6, but lacking the interdomain loop
      between EGF3 and 4 (TME4-6), has an identical Ca2+ dependence for the activation
      of protein C as found for TMEi4-6, indicating this interdomain loop is not
      involved in Ca2+ binding.

PMID- 10336639
TI  - Enhanced expression of glucose transporter GLUT3 in tumorigenic HeLa cell hybrids
      associated with tumor suppressor dysfunction.
AB  - Previous studies on human cell hybrids between HeLa and normal human fibroblasts
      have indicated that the tumorigenicy may be controlled by a putative tumor
      suppressor gene on chromosome 11. We previously demonstrated a twofold increase
      in glucose uptake with a reduced Km by tumorigenic HeLa cell hybrids which
      expressed a highly glycosylated GLUT1. In this study, we reported that a
      tumorigenic cell hybrid, CGL4, also expressed a glucose transporter isoform,
      GLUT3, that was undetectable in nontumorigenic CGL1 cells. The expression of
      GLUT3 together with GLUT1 of 70 kDa was also evident in three gamma-ray-induced
      tumorigenic clones isolated from CGL1 cells, while control nontumorigenic
      irradiated cells expressed 50 kDa GLUT1 alone. In accordance with this, GLUT3
      mRNA was specifically expressed in tumorigenic cell hybrids. To examine the role
      of GLUT3, clones which stably overexpress GLUT3 were developed from both CGL1 and
      CGL4 cells. In these transfectants, the affinity for 2-deoxyglucose markedly
      increased, in parallel with the amount of expressed GLUT3 irrespective of its N
      glycosylation state. These results suggest that the enhanced GLUT3 expression in
      HeLa cell hybrids associated with the tumorigenic phenotypes may account for the
      increased affinity for 2-deoxyglucose. Possible roles of the putative tumor
      suppressor in control of gene expression and glucose uptake is discussed.

PMID- 10336640
TI  - C-CAM-mediated adhesion leads to an outside-in dephosphorylation signal.
AB  - The rat cell-cell adhesion molecule C-CAM, a member of the carcinoembryonic
      antigen family, was shown to be expressed in various isoforms, differing in the
      length of the cytoplasmic domain. The long isoform C-CAML inhibits the growth of
      different malignant cells. Several studies suggest that it is involved in the
      mechanism of signal transduction. So far no direct correlation between C-CAM
      function and C-CAM phosphorylation has been reported. In the present study we
      addressed the question of whether C-CAM-mediated adhesion is accompanied by
      changes in phosphorylation of the cytoplasmic domain of C-CAM. It was
      demonstrated that C-CAML is constitutively phosphorylated in adherent growing
      cells as well as in cells growing in suspension. In contrast, C-CAML-mediated
      cell aggregation is accompanied by a 40% reduction in C-CAML phosphorylation
      compared with nonaggregated cells. The same dephosphorylation was achieved by
      antibody-induced clustering of C-CAML in the plasma membrane. Phosphorylation and
      dephosphorylation indicate a C-CAM-mediated outside-in signalling induced by cell
      cell adhesion.

PMID- 10336641
TI  - Biochemical characteristics of Eiseniapore, a pore-forming protein in the
      coelomic fluid of earthworms.
AB  - The cytolytic protein Eiseniapore (38 kDa) from coelomic fluid of the earthworm
      Eisenia fetida functionally requires sphingomyelin as revealed by using mammalian
      erythrocytes and phospholipid vesicles. The effects of ions, glycoproteins and
      phospholipids were investigated for the two-step Eiseniapore action mode, binding
      and pore formation in different assays. Eiseniapore lysis is activated by thiol
      groups but inhibited by metal ions. Eiseniapore binding to target membranes is
      inhibited by Eiseniapore-regulating factor, vitronectin, heparin and
      lysophosphatidylcholine. Ca2+ and Mg2+ were found to be not necessary for
      membrane binding or lytic activity. Sphingomyelin was essential for Eiseniapore
      induced leakage of liposomes. We describe a cytolytic protein/toxin in
      Eiseniapore which differs from the established classification; it can be
      activated by thiol groups and is inhibited by sphingomyelin. Electron microscopy
      of erythrocyte membranes confirmed ring-shaped structures (pores) with a central
      channel with outer (10 nm) and inner (3 nm) diameters as shown previously [Lange,
      S., Nussler, F., Kauschke, E., Lutsch, G., Cooper, E.L. & Herrmann, A. (1997) J.
      Biol. Chem. 272, 20 884-20 892] using artificial membranes. Functional evidence
      of pore formation by Eiseniapore was revealed as protection of lysis by
      carbohydrates occurred at an effective diameter above 3 nm. From these results,
      we suggest a plausible explanation for the mechanism by which components of the
      earthworm's immune system destroy non-self components.

PMID- 10336642
TI  - OP18/stathmin binds near the C-terminus of tubulin and facilitates GTP binding.
AB  - It is has been previously suggested that the protein Op18/stathmin may interact
      with tubulin via the alpha-tubulin subunit [Larsson, N., Marklund, U., Melander
      Gradin, H., Brattsand, G. & Gullberg, M. (1997) Mol. Cell. Biol. 17, 5530-5539].
      In this study we have used limited proteolysis and cross-linking analysis to
      localize further the stathmin-binding site on alpha-tubulin. Our results indicate
      that such a binding site is in a region close to the C-terminus of the molecule
      comprising residues 307 to the subtilisin-cleavage site on the alpha-tubulin
      subunit. Based on a recent model of the structure of tubulin [Nogales, E., Wolf,
      S.G. & Dowing, D.H. (1998) Nature (London) 391, 199-203], we found that this
      region contained the same areas that may be involved in longitudinal contacts of
      alpha-tubulin subunits within the microtubule. We also observed that the binding
      of stathmin to tubulin can modulate the binding of GTP to tubulin, as a
      consequence of a conformational change in the beta-tubulin subunit that occurs
      upon interaction of stathmin with tubulin.

PMID- 10336643
TI  - The noncatalytic site-deficient alpha3beta3gamma subcomplex and FoF1-ATP synthase
      can continuously catalyse ATP hydrolysis when Pi is present.
AB  - We investigated ATP hydrolysis by a mutant (DeltaNC) alpha3beta3gamma subcomplex
      of F0F1-ATP synthase from the thermophilic Bacillus PS3 that is defective in the
      noncatalytic nucleotide binding sites. This mutant subcomplex was activated by
      inorganic phosphate ions (Pi) and did not show continuous ATP hydrolysis activity
      in the absence of Pi. Pi also activated the wild-type alpha3beta3gamma subcomplex
      in a similar manner. Sulphate activated wild-type alpha3beta3gamma but not
      DeltaNC alpha3beta3gamma, indicating that Pi activation did not involve
      noncatalytic sites but that sulphate activation did. Pi also activated ATP
      hydrolysis and coupled proton translocation by the wild-type and DeltaNC F0F1-ATP
      synthases reconstituted into vesicle membranes.

PMID- 10336644
TI  - Hydrolysis by somatic angiotensin-I converting enzyme of basic dipeptides from a
      cholecystokinin/gastrin and a LH-RH peptide extended at the C-terminus with gly
      Arg/Lys-arg, but not from diarginyl insulin.
AB  - Endoproteolytic cleavage of protein prohormones often generates intermediates
      extended at the C-terminus by Arg-Arg or Lys-Arg, the removal of which by a
      carboxypeptidase (CPE) is normally an important step in the maturation of many
      peptide hormones. Recent studies in mice that lack CP activity indicate the
      existence of alternative tissue or plasma enzymes capable of removing C-terminal
      basic residues from prohormone intermediates. Using inhibitors of angiotensin I
      converting enzyme (ACE) and CP, we show that both these enzymes in mouse serum
      can remove the basic amino acids from the C-terminus of CCK5-GRR and LH-RH-GKR,
      but only CP is responsible for converting diarginyl insulin to insulin. ACE
      activity removes C-terminal dipeptides to generate the Gly-extended peptides,
      whereas CP hydrolysis gives rise to CCK5-GR and LH-RH-GK, both of which are
      susceptible to the dipeptidyl carboxypeptidase activity of ACE. Somatic ACE has
      two similar protein domains (the N-domain and the C-domain), each with an active
      site that can display different substrate specificities. CCK5-GRR is a high
      affinity substrate for both the N-domain and C-domain active sites of human sACE
      (Km of 9.4 microm and 9.0 microm, respectively) with the N-domain showing greater
      efficiency (kcat : Km ratio of 2.6 in favour of the N-domain). We conclude that
      somatic forms of ACE should be considered as alternatives to CPs for the removal
      of basic residues from some Arg/Lys-extended peptides.

PMID- 10336646
TI  - 1H-NMR structural studies of a cystine-linked peptide containing residues 71-93
      of transthyretin and effects of a Ser84 substitution implicated in familial
      amyloidotic polyneuropathy.
AB  - The Ile-->Ser84 substitution in the thyroid hormone transport protein
      transthyretin is one of over 50 variations found to be associated with familial
      amyloid polyneuropathy, a hereditary type of lethal amyloidosis. Using a peptide
      analogue of the loop containing residue 84 in transthyretin, we have examined the
      putative local structural effects of this substitution using 1H-NMR spectroscopy.
      The peptide, containing residues 71-93 of transthyretin with its termini linked
      via a disulfide bond, was found to possess the same helix-turn motif as in the
      corresponding region of the crystallographically derived structure of
      transthyretin in 20% trifluoroethanol (TFE) solution. It therefore, represents a
      useful model with which to examine the effects of amyloidogenic substitutions. In
      a peptide analogue containing the Ile84-->Ser substitution it was found that the
      substitution does not greatly disrupt the overall three-dimensional structure,
      but leads to minor local differences at the turn in which residue 84 is involved.
      Coupling constant and NOE measurements indicate that the helix-turn motif is
      still present, but differences in chemical shifts and amide-exchange rates
      reflect a small distortion. This is in keeping with observations that several
      other mutant forms of transthyretin display similar subunit interactions and
      those that have been structurally analysed possess a near native structure. We
      propose that the Ser84 mutation induces only subtle perturbations to the
      transthyretin structure which predisposes the protein to amyloid formation.

PMID- 10336645
TI  - The human calcium-independent phospholipase A2 gene multiple enzymes with
      distinct properties from a single gene.
AB  - Recently, we reported the human 88-kDa calcium-independent phospholipase A2
      (iPLA2) cDNA sequence, as well as extensive alternative splicing of the iPLA2
      mRNA. In this report we identified the gene coding for iPLA2, which was localized
      on chromosome 22q13.1. The gene consists of at least 17 exons spanning > 69 kb.
      Based on the iPLA2 gene organization the splice variants can be explained. The
      putative promotor for the iPLA2 gene lacks a TATA-box and contains a CpG island
      as well as several potential Sp-1-binding sites. Furthermore, the 5'-flanking
      region also contains one medium reiteration frequency repeat (MER53) and an Alu
      repetitive sequence. Northern blot analysis of iPLA2 mRNA in various human
      tissues demonstrated tissue-specific expression of four distinct iPLA2
      transcripts. The native human 3.2-kb iPLA2 transcript was predominantly expressed
      in heart, brain, skeletal muscle, prostate, testis, thyroid and spinal cord, and
      to a lesser extent in peripheral blood leucocytes, stomach, trachea and bone
      marrow. Studies on the subcellular localization of the native iPLA2 protein were
      performed in COS-7 cells overexpressing this enzyme. The cytosolic fraction of
      untransfected and cells overexpressing iPLA2 contained equal amounts of calcium
      independent PLA2 activity. However, the membrane fraction displayed a 5.5-fold
      increased activity in iPLA2 overexpressing cells. This increased calcium
      independent PLA2 activity correlated with the presence of iPLA2 immunoreactive
      protein in the membrane fraction, indicating that this form of iPLA2 protein was
      membrane associated. Studies of iPLA2 in rat vascular smooth muscle cells
      verified the membrane association of this form of iPLA2. The major difference
      between this form of iPLA2 enzyme and the soluble forms of iPLA2 studied
      previously is the presence of 54 additional amino acid residues derived from exon
      9. We suggest that the addition of these 54 amino acids leads to a membrane
      associated protein. In summary, these results demonstrate that alternative
      splicing of the human iPLA2 transcript generates multiple iPLA2 isoforms with
      distinct tissue distribution and cellular localization.

PMID- 10336647
TI  - Changes in the proton-motive force in Escherichia coli in response to external
      oxidoreduction potential.
AB  - The pH homeostasis and proton-motive force (Deltap) of Escherichia coli are
      dependent on the surrounding oxidoreduction potential (ORP). Only the internal pH
      value and, thus, the membrane pH gradient (DeltapH) component of the Deltap is
      modified, while the membrane potential (DeltaPsi) does not change in a
      significant way. Under reducing conditions (Eh < 50 mV at pH 7.0), E. coli
      decreases its Deltap especially in acidic media (21% decrease at pH 7.0 and 48%
      at pH 5.0 for a 850-mV ORP decrease). Measurements of ATPase activity and
      membrane proton conductance (CH+m) depending on ORP and pH have shown that the
      internal pH decrease is due to an increase in membrane proton permeability
      without any modification of ATPase activity. We propose that low ORP values de
      energize E. coli by modifying the thiol : disulfide balance of proteins, which
      leads to an increase in the membrane permeability to protons.

PMID- 10336648
TI  - The A26G replacement in the consensus sequence A-X-X-X-X-G-K-[T,S] of the guanine
      nucleotide binding site activates the intrinsic GTPase of the elongation factor 2
      from the archaeon Sulfolobus solfataricus.
AB  - A recombinant form of the elongation factor 2 from the archaeon Sulfolobus
      solfataricus (SsEF-2), carrying the A26G substitution, has been produced and
      characterized. The amino acid replacement converted the guanine nucleotide
      binding consensus sequences A-X-X-X-X-G-K-[T,S] of the elongation factors EF-G or
      EF-2 into the corresponding G-X-X-X-X-G-K-[T,S] motif which is present in all the
      other GTP-binding proteins. The rate of poly(U)-directed poly(Phe) synthesis and
      the ribosome-dependent GTPase activity of A26GSsEF-2 were decreased compared to
      SsEF-2, thus indicating that the A26G replacement partially affected the function
      of SsEF-2 during translocation. In contrast, the A26G substitution enhanced the
      catalytic efficiency of the intrinsic SsEF-2 GTPase triggered by ethylene glycol
      [Raimo, G., Masullo, M., Scarano, G., & Bocchini, V. (1997) Biochimie 78, 832
      837]. Surprisingly, A26GSsEF-2 was able to hydrolyse GTP even in the absence of
      ethylene glycol; furthermore, the alcohol increased the affinity for GTP without
      modifying the catalytic constant of A26GSsEF-2 GTPase. Compared to SsEF-2, the
      affinity of A26GSsEF-2 for [3H]GDP was significantly reduced. These findings
      suggest that A26 is a regulator of the biochemical functions of SsEF-2. The
      involvement of this alanine residue in the guanine nucleotide-binding pocket of
      EF-2 or EF-G is discussed.

PMID- 10336649
TI  - Interaction of elongation factor eEF-2 with ribosomal P proteins.
AB  - The eukaryotic P1 and P2 ribosomal proteins which constitute, with P0, a pentamer
      forming the lateral stalk of the 60 S ribosomal subunit, exhibit several
      differences from their prokaryotic equivalents L7 and L12; in particular, P1 does
      not have the same primary structure as P2 and both of them are phosphorylated,
      the significance of the latter remaining unclear. Rat liver P1 and P2 were
      overproduced in Escherichia coli cells and their interaction with elongation
      factor eEF-2 was studied. Both recombinant proteins were found to be required for
      the ribosome-dependent GTPase activity of eEF-2, with P2 in the phosphorylated
      form. The surface plasmon resonance technique revealed that, in vitro, both
      proteins interact specifically with eEF-2, with a higher affinity for P1 (Kd =
      3.8 x 10-8 m) than for P2 (Kd = 2.2 x 10-6 m). Phosphorylation resulted in a
      moderate increase (two- to four-fold) in these affinities. The interaction of
      both P1 and P2 (phosphorylated or not) with eEF-2 resulted in a conformational
      change in the factor, revealed by an increase in the accessibility of Glu554 to
      proteinase Glu-C. This increase was observed in both the presence and absence of
      GTP and GDP, which themselves produced marked opposite effects on the
      conformation of eEF-2. Our results suggest that the two proteins P1 and P2 both
      interact with eEF-2 inducing a conformational transition of the factor, but have
      acquired some specific properties during evolution.

PMID- 10336650
TI  - Phlorisovalerophenone synthase, a novel polyketide synthase from hop (Humulus
      lupulus L.) cones.
AB  - Phlorisovalerophenone synthase (VPS), a novel aromatic polyketide synthase, was
      purified to homogeneity from 4.2 mg protein extract obtained from hop (Humulus
      lupulus L.) cone glandular hairs. The enzyme uses isovaleryl-CoA or isobutyryl
      CoA and three molecules of malonyl-CoA to form phlorisovalerophenone or
      phlorisobutyrophenone, intermediates in the biosynthesis of the hop bitter acids
      (alpha- and beta-acids). VPS is an homodimeric enzyme, with subunits of 45 kDa.
      The pI of the enzyme was 6.1. Km values of 4 microm for isovaleryl-CoA, 10 microm
      for isobutyryl-CoA and 33 microm for malonyl-CoA, were found. The amino-acid
      sequences of two peptides, obtained by digestion of VPS, showed that the enzyme
      is highly homologous to plant chalcone synthases. The functional and structural
      relationship between VPS and other aromatic polyketide synthases is discussed.

PMID- 10336651
TI  - A single-chain antibody fragment is functionally expressed in the cytoplasm of
      both Escherichia coli and transgenic plants.
AB  - Despite the well-known crucial role of intradomain disulfide bridges for
      immunoglobulin folding and stability, the single-chain variable fragment of the
      anti-viral antibody F8 is functionally expressed when targeted to the reducing
      environment of the plant cytoplasm. We show here that this antibody fragment is
      also functionally expressed in the cytoplasm of Escherichia coli. A gel shift
      assay revealed that the single-chain variable fragment (scFv) accumulating in the
      plant and bacterial cytoplasm bears free sulfhydryl groups. Guanidinium chloride
      denaturation/renaturation studies indicated that refolding occurs even in a
      reducing environment, producing a functional molecule with the same spectral
      properties of the native scFv(F8). Taken together, these results suggest that
      folding and functionality of this antibody fragment are not prevented in a
      reducing environment. This antibody fragment could therefore represent a suitable
      framework for engineering recombinant antibodies to be targeted to the cytoplasm.

PMID- 10336652
TI  - Involvement of primary afferent C-fibres in touch-evoked pain (allodynia) induced
      by prostaglandin E2.
AB  - Nociceptive primary afferents have the capacity to induce a state of increased
      excitability in dorsal horn neurons of the spinal cord or central sensitization
      causing thermal hyperalgesia and touch-evoked pain (allodynia). It is believed
      that primary afferent C-fibres become hypersensitive and induce hyperalgesia and
      that low-threshold Abeta-fibres are responsible for induction of allodynia, the
      mechanisms of which remain elusive. We previously showed that intrathecal
      administration of prostaglandin E2 (PGE2) and prostaglandin F2alpha (PGF2alpha)
      induce allodynia in conscious mice. Here we demonstrated that selective
      elimination of C-fibres by neonatal capsaicin treatment resulted in the
      disappearance of allodynia induced by PGE2, but not that by PGF2alpha. PGE2
      induced allodynia was not observed in N-methyl-D-aspartate (NMDA) receptor
      epsilon1 subunit knockout mice and was sensitive to morphine. In contrast,
      PGF2alpha-induced allodynia was not observed in NMDA epsilon4 subunit knockout
      mice and was insensitive to morphine. Furthermore, while PGF2alpha showed a
      capsaicin-insensitive feeble facilitatory action on evoked excitatory
      postsynaptic currents in dorsal horn neurons, PGE2 induced a long-lasting
      facilitation of evoked excitatory postsynaptic currents in a capsaicin-sensitive
      manner. Taken together, the present study demonstrates that there are two
      pathways for induction of allodynia and that capsaicin-sensitive C-fibres may
      participate in PGE2-induced allodynia.

PMID- 10336653
TI  - Morphine injected into the paraventricular nucleus of the hypothalamus prevents
      noncontact penile erections and impairs copulation: involvement of nitric oxide.
AB  - Male rats show four to six penile erection episodes when put in the presence of
      an inaccessible receptive female for 80 min. These noncontact erections occur
      concomitantly with an increase in nitric oxide production in the paraventricular
      nucleus of the hypothalamus. This is shown by the increases in the NO2- and NO3-
      concentrations in the paraventricular dialysate obtained from these males by in
      vivo microdialysis. The NO2- concentration increased from 0.75 +/- 0. 10 microm
      to 2.89 +/- 0.39 microm and that of NO3- from 4.13 +/- 0. 58 microm to 9.5 +/-
      1.2 microm. Morphine (0.5, 1 and 5 microg), given unilaterally into the
      paraventricular nucleus 15 min before the introduction of the receptive female,
      prevented the NO2- and NO3- increases, and noncontact erections, dose
      dependently. In contrast, the kappa opioid receptor agonist U-69 593 (5 microg)
      was ineffective. The effects of morphine on NO2- and NO3-, and on noncontact
      erections, were prevented by the opiate receptor antagonist naloxone (10 microg)
      injected into the paraventricular nucleus 15 min before morphine. The NO2- and
      NO3- concentrations were also increased in the paraventricular dialysate of male
      rats during copulation, i.e. when in copula penile erections occurred. As found
      with noncontact erections, morphine, but not U-69 593, injected into the
      paraventricular nucleus prevented the NO2- and NO3- increases and impaired
      copulatory behaviour, and naloxone prevented these responses when given before
      morphine. Although some diffusion of the opiate to surrounding brain areas cannot
      be completely ruled out, the present results suggest that morphine acts through
      mu receptors in the paraventricular nucleus to impair noncontact erections and
      copulation. These effects of morphine are apparently mediated by a prevention of
      the increased nitric oxide production that occurs in the paraventricular nucleus
      of the hypothalamus of male rats during sexual activity.

PMID- 10336654
TI  - In vitro electrophysiological properties of rat dorsal column nuclei neurons.
AB  - The dorsal column nuclei include the gracile and cuneate nuclei, which receive
      somatosensory information from the periphery and project to the ventroposterior
      nucleus of the contralateral thalamus. The aim of this study was to determine the
      electrophysiological and morphological characteristics of the neurons of the
      dorsal column nuclei and to identify synaptic events evoked by electrical
      stimulation of the dorsal column, using an in vitro slice preparation. The
      results show two types of neurons, termed type I and II. A repolarizing sag
      distinguished type I cells during hyperpolarizing current injection, suggesting
      the activation of a Q-current. Moreover, type I cells, but not type II cells,
      were capable of maintaining spontaneous rhythmic activity at 9-15 Hz. Both types
      of cells displayed a delay in their return to the resting membrane potential
      following hyperpolarizing current pulses, indicating the existence of an A
      current. Electrical stimuli applied to the dorsal column elicited brief EPSPs and
      IPSPs in both cell types. EPSPs were abolished by 6-cyano-7-nitroquinoxaline-2,3
      dione, indicating that they were mediated through non-NMDA receptors. IPSPs were
      blocked by picrotoxin, implying the activation of GABAA receptors. Intracellular
      staining with carboxyfluoresceine revealed that type I neurons had elongated
      somas and primary dendrites that extended radially. Type II cells were smaller
      and had round somas with few primary dendrites, most of them emerging from one
      pole of the soma. The axon of many type I neurons was stained and could be
      followed running ventrally and in rostral direction.

PMID- 10336655
TI  - Intrinsic optical signal measurements reveal characteristic features during
      different forms of spontaneous neuronal hyperactivity associated with ECS
      shrinkage in vitro.
AB  - We induced three different forms of spontaneous synchronous hyperactivity in
      adult rat hippocampal-entorhinal cortex slices in order to investigate effects on
      the intrinsic optical signal and associated changes in the extracellular space
      (ECS) volume. Low-Mg2+ artificial cerebrospinal fluid (ACSF) and the addition of
      4-aminopyridine induced synchronous hyperactivity resulting mainly from increased
      synaptic transmission, while low-Ca2+ ACSF induced hyperactivity in the absence
      of evoked synaptic transmission. In the two models of enhanced synaptic
      transmission, spontaneous activity lead to an immediate increase of light
      transmission. In contrast, a decrease of light transmission took place during low
      Ca2+-induced hyperactivity. All three forms of synchronous neuronal hyperactivity
      were associated with a shrinkage of the ECS volume, as revealed by the
      tetraethylammonium signal, measured with ion-sensitive microelectrodes. This
      indicates that the change in the intrinsic optical signal is not simply related
      to a shrinkage in ECS volume. We conclude that different forms of spontaneous
      synchronous neuronal hyperactivity are associated with characteristic optical
      signals and that the direction of the change in intrinsic optical signal does not
      reflect ECS shrinkage alone.

PMID- 10336657
TI  - Social intelligence in the normal and autistic brain: an fMRI study.
AB  - There is increasing support for the existence of 'social intelligence' [Humphrey
      (1984) Consciousness Regained], independent of general intelligence. Brothers et
      al. 1990) J. Cog. Neurosci., 4, 107-118] proposed a network of neural regions
      that comprise the 'social brain': the orbito-frontal cortex (OFC), superior
      temporal gyrus (STG) and amygdala. We tested Brothers' theory by examining both
      normal subjects as well as patients with high-functioning autism or Asperger
      syndrome (AS), who are well known to have deficits in social intelligence, and
      perhaps deficits in amygdala function [Bauman & Kemper (1988) J. Neuropath. Exp.
      Neurol., 47, 369]. We used a test of judging from the expressions of another
      person's eyes what that other person might be thinking or feeling. Using
      functional magnetic resonance imaging (fMRI) we confirmed Brothers' prediction
      that the STG and amygdala show increased activation when using social
      intelligence. Some areas of the prefrontal cortex also showed activation. In
      contrast, patients with autism or AS activated the fronto-temporal regions but
      not the amygdala when making mentalistic inferences from the eyes. These results
      provide support for the social brain theory of normal function, and the amygdala
      theory of autism.

PMID- 10336656
TI  - Functional characteristics of skate connexin35, a member of the gamma subfamily
      of connexins expressed in the vertebrate retina.
AB  - Retinal neurons are coupled by electrical synapses that have been studied
      extensively in situ and in isolated cell pairs. Although many unique gating
      properties have been identified, the connexin composition of retinal gap
      junctions is not well defined. We have functionally characterized connexin35
      (Cx35), a recently cloned connexin belonging to the gamma subgroup expressed in
      the skate retina, and compared its biophysical properties with those obtained
      from electrically coupled retinal cells. Injection of Cx35 RNA into pairs of
      Xenopus oocytes induced intercellular conductances that were voltage-gated at
      transjunctional potentials >/= 60 mV, and that were also closed by intracellular
      acidification. In contrast, Cx35 was unable to functionally interact with rodent
      connexins from the alpha or beta subfamilies. Voltage-activated hemichannel
      currents were also observed in single oocytes expressing Cx35, and superfusing
      these oocytes with medium containing 100 microm quinine resulted in a 1.8-fold
      increase in the magnitude of the outward currents, but did not change the
      threshold of voltage activation (membrane potential = +20 mV). Cx35 intercellular
      channels between paired oocytes were insensitive to quinine treatment. Both
      hemichannel activity and its modulation by quinine were seen previously in
      recordings from isolated skate horizontal cells. Voltage-activated currents of
      Cx46 hemichannels were also enhanced 1. 6-fold following quinine treatment,
      whereas Cx43-injected oocytes showed no hemichannel activity in the presence, or
      absence, of quinine. Although the cellular localization of Cx35 is unknown, the
      functional characteristics of Cx35 in Xenopus oocytes are consistent with the
      hemichannel and intercellular channel properties of skate horizontal cells.

PMID- 10336658
TI  - Limbic P300s in temporal lobe epilepsy with and without Ammon's horn sclerosis.
AB  - Limbic P300 potentials can be recorded within the mesial temporal lobes of
      patients with temporal lobe epilepsy (TLE). To delineate possible mechanisms of
      their generation and pathological alteration, we analysed limbic P300s in 55 TLE
      patients with and 29 without Ammon's horn sclerosis (AHS) and correlated their
      amplitudes with neuronal cell counts in 30 histopathological specimens. Limbic
      P300 amplitudes were reduced on the side of the epileptogenic focus only in
      patients with AHS. Moreover, in AHS patients, limbic P300 latencies were
      prolonged bilaterally; and in patients with left-sided AHS, amplitudes were
      reduced bilaterally. Both findings suggest bilateral functional deficits in TLE
      with unilateral AHS. Limbic P300 areas correlated significantly with neuronal
      densities of dentate gyrus granule cells but not hippocampal pyramidal cells in
      the CA1-4 (cornu ammonis) subfields. This finding points to a potential mechanism
      for the bilateral effects of unilateral AHS as both dentate gyri exhibit strong
      reciprocal contralateral connectivity.

PMID- 10336659
TI  - Amino-terminal region of secreted form of amyloid precursor protein stimulates
      proliferation of neural stem cells.
AB  - Beta-amyloid precursor protein (APP) has been reported to be expressed in the CNS
      from the early stages of development. However, the functional role of APP during
      early development remains unclear. In the present study, we found that the
      secreted form of APP (sAPP) significantly enhanced proliferation of neural stem
      cells. Cells were prepared from 13-day embryonic rat neocortex, which was
      dissected with a Pasteur pipette to make cell clusters. After 12 h of cultivation
      in the medium without serum, cells around the centre of the cluster were still
      nestin-positive proliferative cells, i.e. neural stem cells. To determine whether
      the proliferation of cells was regulated by sAPP, cultures were treated with
      recombinant sAPP695, the secreted form of human APP695 produced by yeast. Both
      DNA synthesis and expression of proliferating cell nuclear antigen markedly
      increased after 5 h of sAPP695 addition. The enhancement of DNA synthesis by
      sAPP695 stimulation was blocked by the 22C11 monoclonal antibody specific for the
      amino-terminal region of sAPP. Then, we examined the effect of the amino-terminal
      fragment of sAPP and the epitope peptide of 22C11 antibody, and found that both
      of them also promoted DNA synthesis, suggesting that the amino-terminal region of
      sAPP is responsible for the biological activity. Our findings indicate the
      possibility that sAPP enhances proliferation of neural stem cells in vivo and
      plays an important role during the early CNS development.

PMID- 10336660
TI  - Heparan sulphates upregulate regeneration of transected sciatic nerves of adult
      guinea-pigs.
AB  - The increased content of soluble glycosaminoglycan-containing forms in sciatic
      nerves during recovery from crush injury [Shum & Chau (1996) J. Neurosci. Res.,
      46, 465] suggests that the glycosaminoglycans modulate the environment for post
      traumatic tissue remodelling and axonal regrowth. To test this, defined amounts
      of soluble heparan sulphates from bovine kidney or guinea-pig nerve were
      introduced into the regenerating environment via silicone conduits that bridged 8
      mm gaps of transected sciatic nerves of adult guinea-pigs. Controls were bridged
      using the phosphate-buffered saline (PBS) vehicle or a chondroition sulphate
      preparation from whale cartilage. After timed periods of recovery, the animals
      were assessed for electromyographic signals at the target gastrocnemius muscle to
      determine the conduction velocity across the bridged nerve. Sections of the
      bridge were also histologically examined for nerve fibres. Transected sciatic
      nerves bridged with heparan sulphates or chondroitin sulphate showed earlier
      stimulated myelination of axons (week 5-6) than PBS-bridged nerves (week 9).
      Initial electromyographic indication of reconnection with the target was at week
      9 post-transection. In the course of 20 weeks, transected sections of the bridge
      indicated similar numbers of unmyelinated axons irrespective of bridge material,
      but distinctly higher numbers of myelinated axons in heparan sulphate-bridged
      nerves than either PBS- or chondroitin sulphate-bridged nerves. At the end of the
      same period, heparan sulphate-bridged nerves resumed normal conduction
      velocities, but both PBS- and chondroitin sulphate-bridged nerves remained at 50%
      of that of the intact contralateral nerves. These results are the first to
      demonstrate that supplementation of soluble heparan sulphate to the fluid
      regenerative neural environment can restore functional, axonal reconnection of
      the severed nerve with the target muscle.

PMID- 10336661
TI  - Real-time imaging of glucocorticoid receptor dynamics in living neurons and glial
      cells in comparison with non-neural cells.
AB  - To investigate the intracellular trafficking of glucocorticoid receptor (GR) in
      response to various conditions in a single living cell, a green fluorescent
      protein (GFP) and rat GR chimera construct (GFP-GR) was prepared. We transiently
      transfected GFP-GR into primary cultured rat hippocampal neurons, cortical glial
      cells, and non-neural cells, e.g. COS-1 cells and CV-1 cells, and compared the
      dynamic changes in subcellular localization of GFP-GR in these cells. When GFP-GR
      was expressed in the cells, GFP-GR efficiently transactivated the mouse mammary
      tumour virus promoter in response to dexamethasone (DEX). The cytoplasm-to
      nuclear translocation of GFP-GR induced with 10(-7) m DEX, a specific agonist of
      GR, at 37 degrees C was completed within 30 min in all cell types used, and the
      rate of nuclear translocation was dependent on the ligand dose. The translocation
      of GFP-GR into the nucleus from the cytoplasm was induced in a ligand-specific
      manner, similar to that of the native GR. The disruption of microtubules by
      colchicine or nocodazole showed no significant effect on the DEX-induced GFP-GR
      translocation from the cytoplasmic region to the nuclear region. The cells were
      not deteriorated during time-lapse imaging analysis for 1 h at 37 degrees C. The
      present findings suggest that the subcellular localization of GFP-GR is
      dynamically changed in response to extracellular and intracellular conditions,
      and that there are no conspicuous variations in the manner of trafficking of GR
      among different types of cells in vitro.

PMID- 10336662
TI  - Transcriptional repression by the zinc finger protein REST is mediated by
      titratable nuclear factors.
AB  - The zinc finger protein REST (RE-1 silencing transcription factor) is a
      transcriptional repressor that inhibits neuronal gene transcription in non
      neuronal tissues. REST may represent a master regulator of neuronal gene
      expression. REST contains two repressor domains located at the N- and C-termini
      of the molecule. To investigate the molecular mechanism of transcriptional
      repression by REST, in vivo competition experiments were performed. Both
      repression domains were expressed in the nucleus as fusion proteins with S.
      japonicum glutathione S-transferase (GST). The ability of these fusion proteins
      to block transcriptional repression mediated by the repressor domains of REST was
      tested. The results show that transcriptional repression by the N-terminal
      repression domain of REST could be overcome by expression of a GST fusion protein
      encoding the N-terminal, but not C-terminal repression domain, and vice versa,
      suggesting that both repression domains have to interact with distinct nuclear
      factors to exhibit biological activity. The GST-REST fusion proteins had no
      effect upon transcriptional repression mediated by the KRAB (Kruppel-associated
      box) domain, a strong mammalian repressor domain, or the repressor domain derived
      from the thyroid hormone receptors alpha. We conclude that REST has to interact
      with at least two distinct nuclear factors to inhibit transcription. These
      factors are distinct from the mammalian corepressor proteins KAP-1/KRIP-1 and N
      CoR that mediate repression by the KRAB domain or the thyroid hormone receptor
      alpha. Thus, mammalian transcriptional repressors utilize different mechanisms to
      inhibit transcription by using different kinds of protein-protein interactions.

PMID- 10336664
TI  - K+-dependence of Na+-Ca2+ exchange in type I vestibular sensory cells of guinea
      pig.
AB  - The properties of the vestibular Na+-Ca2+ exchanger in mammalian type I
      vestibular sensory cells were studied using fura-2 fluorescence and
      immunocytochemical techniques. In the absence of external Na+, the activation of
      Na+-Ca2+ exchange in reverse mode required the presence of external K+ (K+o) and
      depended on K+o concentration. Alkali cations Rb+ and NH4+ but not Li+ or Cs+
      substituted for K+o to activate the exchange. For pressure applications of 10 mm
      K+, the contribution of voltage-sensitive calcium channels to the increase in
      [Ca2+]i was < 15%. The dependence of the exchange on [K+]o was also recorded when
      the membrane potential was clamped using carbonyl cyanide p-trifluoromethoxy
      phenylhydrazone (FCCP) and monensin ionophores. In these conditions, where there
      was no intracellular Na+, the increase in [Ca2+]i was completely blocked. These
      physiological results suggest that in reverse mode, Ca2+ entry is driven by both
      an outward transport of Na+ and an inward transport of K+. The dependence of the
      vestibular Na+-Ca2+ exchanger on K+ is more reminiscent of the properties of the
      retinal type Na+-Ca2+ exchanger than those of the more widely distributed cardiac
      type exchanger. Moreover, the immunocytochemical localization of both types of
      exchange proteins in the vestibular sensory epithelium confirmed the presence in
      the vestibular sensory cells of a Na+-Ca2+ exchanger which is recognized by an
      antibody raised against retinal type and not by an antibody raised against the
      cardiac type.

PMID- 10336663
TI  - Control of neuronal excitability by an ion-sensing receptor (correction of anion
      sensing)
AB  - While most central nervous system (CNS) neurons receive the majority of their
      input through direct synaptic connections, there is evidence suggesting that they
      are in fact susceptible to modulation by changes in extracellular ionic
      composition during both physiological and pathophysiological conditions. In many
      regions of the CNS, there exists an identified extracellular receptor with the
      ability to sense levels of cations, most notably calcium. Here we report that
      activation of this calcium receptor (CaR) in neurons of the subfornical organ
      (SFO), a forebrain circumventricular structure, results in profound effects on
      neuronal excitability through metabotropic actions on a non-selective cation
      channel. Activation of the CaR by NPS R-467, an allosteric agonist of the CaR,
      evoked depolarizing plateau potentials ranging in duration from 5 to 30 s.
      Similarly, 5 mm CaCl2 caused depolarization and increased action potential
      frequency. NPS R-467 was found to activate a non-selective cation channel with a
      reversal potential of -48 +/- 4 mV, and a slope conductance of 2.54 +/- 11 nS.
      This current could also be elicited by spermine, a known agonist of the CaR. CaR
      mediated activation of this channel was dependent upon both G proteins and
      intracellular Ca2+ signalling, as disruption of these pathways through inclusion
      of guanosine 5'-O-(2-thiodiphosphate) (GDP-beta-S) and 1,2-bis(2
      aminophenoxy)ethane-N,N,N ',N '-tetraacetic acid (BAPTA), respectively, in the
      recording pipette prevented activation of the current. Microinjection of CaR
      agonists into the SFO of anaesthetized rats resulted in a significant, site
      specific elevation of blood pressure (mean area under curve, 141 +/- 50 mmHg. s).
      Together, these results indicate that the CaR can play an important role in
      transducing the effects of changes in the extracellular ionic composition, and
      that these effects have implications for the neural control of fluid balance.

PMID- 10336665
TI  - Visualization of local afferent inputs to magnocellular oxytocin neurons in
      vitro.
AB  - We recently showed that oxytocin (OT) neurons in organotypic slice cultures
      obtained from postnatal rat hypothalamus display complex patterns of electrical
      activity, similar to those of adult magnocellular OT neurons in vivo. Here we
      used such cultures to investigate the identity and, in particular, the origin of
      afferent inputs responsible for this activity. Multiple immunostaining with light
      and confocal microscopy showed that the somata and dendrites of oxytocinergic
      neurons were contacted by numerous synapses, visualized by their reaction to the
      synaptic markers, synaptophysin or synapsin. Many were GABAergic, displaying
      immunoreactivities for glutamic acid decarboxylase or gamma-aminobutyric acid
      (GABA); others were enriched in glutamate immunoreactivity. Such afferents
      presumably arose from GABA- or glutamate-immunoreactive neurons, respectively,
      with distinct and characteristic morphologies and topographies. A few
      dopaminergic boutons (tyrosine hydroxylase- or dopamine-immunopositive) impinged
      on OT neurons; they arose from dopamine-positive neurons located along the third
      ventricle. No noradrenergic profiles were detected. Despite the presence of
      choline acetyl-transferase (ChAT)-immunoreactive neurons, there were no
      cholinergic contacts. Lastly, we found oxytocinergic synapses, identified by
      immunoreaction for OT-related neurophysin and synapsin, contacting OT somata and
      dendrites. Our observations thus demonstrate that inhibitory and excitatory
      inputs to OT neurons derive from local intrahypothalamic GABA and glutamate
      neurons, in close proximity to the neurons. They also reveal that OT neurons are
      innervated by hypothalamic dopaminergic neurons. Finally, they confirm the
      existence of homotypic OT synaptic contacts which derive from local OT neurons.

PMID- 10336666
TI  - Muscarinic receptors regulate two different calcium-dependent non-selective
      cation currents in rat prefrontal cortex.
AB  - Pyramidal neurons of layer V in rat prefrontal cortex display a prominent fast
      afterdepolarization (fADP) and a muscarinic-induced slow afterdepolarization
      (sADP). We have shown previously that both of these ADPs are produced by the
      activation of calcium-dependent non-selective cation currents. In the present
      report we examine whether they represent two distinct currents. In most pyramidal
      neurons recorded with caesium gluconate-based intracellular solution, a calcium
      spike is followed by a fast decaying inward aftercurrent (IfADP). The decay of
      IfADP is monoexponential with a time constant (t) of approximately 35 ms.
      Administration of carbachol (10-30 microm) increases the time constant of this
      decay by approximately 80% and induces the appearance of a much slower inward
      aftercurrent (IsADP). IfADP recorded in control conditions and in the presence of
      carbachol increases linearly with membrane hyperpolarization. In contrast, the
      carbachol-induced IsADP decreases with membrane hyperpolarization. When the
      sodium driving force across the cell membrane was reduced, IfADP was found to
      reverse at around -40 mV whereas IsADP remain inward over the same voltage range
      tested. Finally, bath administration of flufenamic acid (100 microm-1 mm)
      selectively blocks the carbachol-induced IsADP without a significant effect on
      the amplitude of IfADP. These differences in the electrical and pharmacological
      properties of IfADP and IsADP suggest that they were mediated by two distinct non
      selective cation currents.

PMID- 10336667
TI  - Perturbation of the synaptic release machinery in hippocampal neurons by
      overexpression of SNAP-25 with the Semliki Forest virus vector.
AB  - We have examined whether the Semliki Forest virus (SFV) expression vector can be
      used to manipulate the exocytotic machinery in cultured hippocampal neurons.
      Autaptic responses were recorded in individually identified neurons which
      overexpressed either a non-synaptic protein, the transferrin receptor, or the
      synaptic SNARE protein SNAP-25 (synaptosomal-associated protein of 25 kDA). In
      neurons overexpressing the transferrin receptor, autaptic responses occurred in a
      similar proportion and had similar amplitudes (12-18 h postinfection) as in
      uninfected control neurons. With increasing time after the infection, an
      increasing proportion of the transferrin receptor-overexpressing neurons showed
      changes in the shape of the cell body, but the autaptic responses appeared normal
      as long as recordings could be performed (up to 30 h postinfection). In contrast,
      in SNAP-25-overexpressing neurons, the proportion of responding cells was reduced
      12-18 h after the infection, and the amplitude of the autaptic current in
      responding neurons was also reduced. The sensitivity to exogenously applied
      glutamate was, however, unchanged. Biochemical analysis showed that 50% of the
      overexpressed SNAP-25 was palmitoylated. The levels of two other SNAREs, syntaxin
      and synaptobrevin (also called vesicle-associated membrane protein), were not
      affected. Our results indicate that the SFV vector can provide an effective tool
      to study the function of proteins participating in neurotransmitter release.

PMID- 10336668
TI  - Mint2/X11-like colocalizes with the Alzheimer's disease amyloid precursor protein
      and is associated with neuritic plaques in Alzheimer's disease.
AB  - Aberrant metabolism of the amyloid precursor protein (APP) is believed to be at
      least part of the pathogenic process in Alzheimer's disease. The carboxy-terminus
      of APP has been shown to interact with the Mint/X11 family of phosphotyrosine
      binding (PTB) domain-bearing proteins. It is via their PTB domains that the
      Mints/X11s bind to APP. Here we report the cloning of full-length mouse Mint2 and
      demonstrate that in primary cortical neurons, Mint2 and APP share highly similar
      distributions. Mint2 also colocalizes with APP in transfected CHO cells. In
      Mint2/APP-cotransfected cells, Mint2 reorganizes the subcellular distribution of
      APP and also increases the steady-state levels of APP. Finally, we demonstrate
      that Mint2 is associated with the neuritic plaques found in Alzheimer's disease
      but not with neurofibrillary tangles. These results are consistent with a role
      for Mint2 in APP metabolism and trafficking, and suggest a possible role for the
      Mints/X11s in the pathogenesis of Alzheimer's disease.

PMID- 10336669
TI  - Raf-1 and B-Raf proteins have similar regional distributions but differential
      subcellular localization in adult rat brain.
AB  - The Raf kinases play an important and specific role in the activation of
      extracellular signal-regulated kinases (ERK) cascade. Beside its role in the
      control of proliferation and differentiation, the ERK cascade has also been
      implicated in neuron-specific functions. In order to gain clues on the function
      of Raf kinases in the adult central nervous system (CNS), we performed a
      comparative analysis of the distribution and subcellular localization of the
      different Raf kinases in rat brain with antibodies specific for the different Raf
      kinases. We show that B-Raf and Raf-1 proteins are present in most brain areas,
      whereas A-Raf is not detected. Interestingly, the two Raf proteins have an
      approximately similar pattern of distribution with a rostro-caudal decreasing
      gradient of expression. These two kinases are colocalized in neurons but they are
      differentially located in subcellular compartments. Raf-1 is localized mainly in
      the cytosolic fraction around the nucleus, whereas B-Raf is widely distributed in
      the cell bodies and in the neuritic processes. In addition, we demonstrated that
      numerous B-Raf isoforms are present in the brain. These isoforms have a
      differential pattern of distribution, some of them being ubiquitously expressed
      whereas others are localized to specific brain areas. These isoforms also have a
      clear differential subcellular localization, specially in Triton-insoluble
      fractions, but also in synaptosomal, membrane and cytosolic compartments.
      Altogether these results suggest that each Raf protein could have a distinct
      signalling regulatory function in the brain with regard to its subcellular
      localization.

PMID- 10336670
TI  - Localization of synapse-associated proteins during postnatal development of the
      rat retina.
AB  - The expression of synapse-associated proteins (SAPs) was monitored throughout
      postnatal development of the rat retina using specific antibodies and
      immunocytochemistry. The distribution of chapsin-110/postsynaptic density protein
      (PSD)-93, SAP90/PSD-95, SAP97 and SAP102 immunoreactivity was characterized. All
      SAPs were found to be expressed in the inner plexiform layer (IPL) from birth on
      or soon after birth. With the exception of SAP97, the IPL labelling changed from
      a diffuse pattern staining the whole developing IPL to the typical adult punctate
      synaptic staining in the second postnatal week. Staining in the outer retina was
      first observed at postnatal day 5 (P5) for all proteins at the onset of outer
      plexiform layer (OPL) development. All SAPs showed a differential cellular and
      temporal distribution being either exclusively pre- or postsynaptically
      localized. Except for SAP90/PSD-95, immunoreactivity was also detected in the
      nerve fibre layer throughout postnatal development. Possible functions of the
      early expression of SAPs well before differentiation and maturation of
      glutamatergic ribbon synapses are discussed.

PMID- 10336671
TI  - Neuroprotective actions of peripherally administered insulin-like growth factor I
      in the injured olivo-cerebellar pathway.
AB  - Exogenous administration of insulin-like growth factor I (IGF-I) restores motor
      function in rats with neurotoxin-induced cerebellar deafferentation. We first
      determined that endogenous IGFs are directly involved in the recovery process
      because infusion of an IGF-I receptor antagonist into the lateral ventricle
      blocks gradual recovery of limb coordination that spontaneously occurs after
      partial deafferentation of the olivo-cerebellar circuitry. We then analysed
      mechanisms whereby exogenous IGF-I restores motor function in rats with complete
      damage of the olivo-cerebellar pathway. Treatment with IGF-I normalized several
      markers of cell function in the cerebellum, including calbindin, glutamate
      receptor 1 (GluR1), gamma-aminobutyric acid (GABA) and glutamate, which are all
      depressed after 3-acetylpyridine (3AP)-induced deafferentation. IGF-I also
      promoted functional reinnervation of the cerebellar cortex by inferior olive (IO)
      axons. In the IO, increased expression of bax in neurons and bcl-X in astrocytes
      after 3AP was significantly reduced by IGF-I treatment. On the contrary, IGF-I
      prevented the decrease in poly-sialic-acid neural cell adhesion molecule (PSA
      NCAM) and GAP-43 expression induced by 3AP in IO cells. IGF-I also significantly
      increased the number of neurons expressing bcl-2 in brainstem areas surrounding
      the IO. Altogether, these results indicate that subcutaneous IGF-I therapy
      promotes functional recovery of the olivo-cerebellar pathway by acting at two
      sites within this circuitry: (i) by modulating death- and plasticity-related
      proteins in IO neurons; and (ii) by impinging on homeostatic mechanisms leading
      to normalization of cell function in the cerebellum. These results provide
      insight into the neuroprotective actions of IGF-I and may be of practical
      consequence in the design of new therapeutic approaches for neurodegenerative
      diseases.

PMID- 10336672
TI  - Differential interaction of the tSXV motifs of the NR1 and NR2A NMDA receptor
      subunits with PSD-95 and SAP97.
AB  - The NR1 and NR2 subunits of the N-methyl-D-aspartate (NMDA) receptor are encoded
      by distinct genes. In the rat brain, four C-terminal variants of the NR1 subunit
      (NR1-1 to NR1-4) are encoded by a single gene, and are generated by alternative
      splicing of the C1 and C2 exon cassettes, while four different genes encode the
      NR2 subunits (NR2 A-D). Functional NMDA receptors result from the
      heteromultimeric assembly of NR1 variants with distinct NR2 subunits. The NR2B
      subunit interacts with post-synaptic density protein 95 (PSD-95), SAP97 and
      members of the membrane-associated guanylate-like kinase (MAGUK) family of
      proteins. This interaction occurs through the binding of the C-terminal tSXV
      intracellular motif of the NR2B subunit to the N-terminal PDZ (PSD-95, discs
      large, ZO-1) domains of the PSD-95 and SAP97 proteins. Both NR1-3 and NR1-4 also
      display a consensus C-terminal tSXV motif. Using the two-hybrid genetic system in
      yeast and site-directed mutagenesis, we compared the binding of the NR2A, NR1-3
      and NR1-4 tSXV motifs with the PDZ domains of PSD-95 and SAP97. The main
      conclusions of the present report are that: (i) while NR2A displays a strong
      interaction with PSD-95 and SAP97, the NR1-3 and NR1-4 NMDA receptor subunits do
      not display any interaction despite the presence of tSXV motifs; (ii) the C
      terminal tSXV motif of the NR2A subunit is mandatory but not sufficient for
      efficient interaction with the PSD-95 and SAP97 proteins; (iii) as yet
      unidentified upstream sequences of the receptor subunits determine whether the
      tSXV motifs will bind to the PSD-95 and SAP97 PDZ domains; (iv) different tSXV
      motifs elicit interactions of variable strengths; and (v) residues in positions 
      3 and -4 modulate the binding affinity of the C-terminal tSXV motifs. Using
      immunohistochemistry, we also compared the distribution of the PSD-95, NR2A and
      SAP97 proteins in adult rat brain, and we show that in the cortex, hippocampus
      and cerebellum, there is evidence for colocalization of these proteins.

PMID- 10336673
TI  - Decision-related activity in the macaque dorsal visual pathway.
AB  - Brain areas at higher levels of cortical organization are thought to be more
      involved in decision processes than are earlier, i.e. lower, sensory areas.
      Hence, neuronal activity correlated with decisions should vary with an area's
      position in the cortical hierarchy. To test this proposal, we investigated
      whether a change in neuronal activity during error trials depends in a systematic
      way on cortical hierarchical position. While macaque monkeys discriminated the
      direction of moving visual stimuli, the activity of direction-selective neurons
      was recorded in four extrastriate visual areas: V3A, the middle temporal area,
      the middle superior temporal area and the posterior part of the superior temporal
      polysensory area. Neuronal activity was significantly reduced in all areas when
      the monkeys made errors in judging the direction of stimuli moving in the
      preferred direction with low and intermediate luminance contrast. The amount of
      activity reduction was approximately 50% in all of the visual areas. Thus, the
      activity on error trials is reduced in early visual processing, independent of
      the hierarchy in the dorsal visual pathway. The activity reduction depended on
      stimulus contrast and the direction of the decision relative to the stimulus
      motion. It was profound and significant in all areas at low stimulus contrast.
      However, it was nonsignificant at high stimulus contrast. Our data suggest that
      activity reduction on error trials is due to lack of attention in association
      with stimulus expectation.

PMID- 10336674
TI  - Stimulation of mu- and delta-opioid receptors enhances phosphoinositide
      metabolism in mouse spinal cord: evidence for subtypes of delta-receptors.
AB  - The accumulation of inositol phosphates (IPs) induced by agonist-activated opioid
      receptors was analysed in mouse spinal cord slices pre-labelled with myo
      [3H]inositol. Agonists showing selectivity to mu-opioid receptors, morphine and
      [D-Ala2,MePhe4, Gly(ol)5]enkephalin (DAMGO), promoted concentration-dependent
      increases in the formation of IPs. The activation of delta-opioid receptors by
      the selective agonists [D-Pen2,5]enkephalin (DPDPE) and [D-Ala2]deltorphin II
      produced similar increases in phosphoinositide (PI) metabolism. Pre-treatment of
      the slices with pertussis toxin (PTX) blocked the effect of opioid agonists on IP
      production. The involvement of Gi/Go-protein (guanine nucleotide-binding protein)
      classes in this opioid effect is therefore suggested. The activity of the opioid
      agonists was reduced by the opioid antagonists naltrexone and naloxone. The
      antagonist at delta1-receptors, 7-benzylidenenaltrexone (BNTX), exhibited greater
      potency than the antagonists at delta2-receptors, naltriben methanesulphonate
      (NTB) or naltrindrole 5'-isothiocyanate (NT II), in reducing the activating
      effect of DPDPE on phosphoinositide metabolism. Conversely, NTB and NT II were
      more potent antagonists of the activity of [D-Ala2]deltorphin II than BNTX. This
      work demonstrates the coupling of spinal mu- and delta-opioid receptors to
      phospholipase C and the generation of IPs. It also provides biochemical evidence
      for pharmacological subtypes of delta-opioid receptors in the activation of this
      signalling pathway.

PMID- 10336675
TI  - Involvement of substance P in the anti-inflammatory effects of the peripherally
      selective kappa-opioid asimadoline and the NK1 antagonist GR205171.
AB  - We have previously shown that kappa-opioids have antiarthritic properties. In
      this study, using two differently acting drugs (the peripherally selective kappa
      agonist, asimadoline, and the NK1-antagonist, GR205171), we have examined
      possible roles of the neuropeptide substance P (SP) in the pathogenesis and
      maintenance of experimental arthritis in rats. The anti-inflammatory actions and
      the time dependence of these drugs were compared, and concentrations of SP
      determined in joint tissue. In untreated animals, SP levels in ankle joint tissue
      increased late in the disease (by day 21) but substantially lagged behind
      development of clinical disease. Prolonged (days 1-21 or days 12-18) but not
      early, short-term (days 1-3) treatment with the NK1-antagonist GR205171 (1
      mg/kg/day i.p.) significantly attenuated joint damage; SP levels showed
      multiphasic dose dependence over the 21-day treatment. The data suggest that
      GR205171 antagonizes the action of SP by presynaptic as well as postsynaptic
      mechanisms. Treatment with asimadoline (5 mg/kg/day i.p. ) produced marked (and
      sustained) attenuation of the disease with all three time regimes. The effect of
      asimadoline on SP levels was time dependent: reduction of SP content after 3 days
      but an increase after 12 or 21 days treatment, paradoxically with clinical
      improvement in each case. Drug-induced changes in SP content could follow from
      changed release or synthesis from either neural or immune cells. The results
      suggest that both drugs have potential therapeutic value at different stages of
      inflammatory joint disease.

PMID- 10336676
TI  - Activation of the extracellular signal-regulated kinase 2 by metabotropic
      glutamate receptors.
AB  - Activation of metabotropic glutamate receptors (mGluRs) leads to modulation of a
      variety of second messenger pathways probably including the mitogen-activated
      protein kinase (MAPK) extracellular signal-regulated protein kinases (ERK). MAPK
      play a key role in the control of cellular responses to changes in the external
      environment by regulating transcriptional activity and the phosphorylation state
      of several cytoplasmic targets. In this study, Chinese hamster ovary (CHO) cells
      permanently transfected with rat mGluR1a, mGluR2 and mGluR4 were employed as a
      model to examine the activation of MAPK by glutamate through mGluRs. All three
      mGluR subtypes rapidly stimulated ERK activation. In particular, mGluR1a and
      mGluR2 preferentially mediated phosphorylation and activation of ERK2 in a
      pertussis toxin (PTX)-sensitive and concentration-dependent manner. The
      activation was blocked completely by pretreatment with the antagonist (rs)-alpha
      methyl-4-carboxyphenylglycine (MCPG) or with the MEK inhibitor PD098059.
      Furthermore, mGluR1a-mediated ERK activation was suppressed by the depletion of
      endogenous protein kinase C (PKC) activity and by the PKC inhibitors
      staurosporine and calphostin C, but not chelerythrine. When cAMP was elevated in
      mGluR2-expressing cells, by forskolin or dibutyryl-cAMP, slight elevation of ERK
      activity was observed. However, glutamate-stimulated ERK activation remained
      unaffected. In these cells, the phosphatidylinositol 3 kinase (PI3K) inhibitor
      wortmannin produced a significant, albeit only partial, inhibition of mGluR2
      mediated ERK activation. These findings raise the possibility of a MAPK cascade
      involvement in glutamate-dependent neuronal plasticity mediated through
      stimulation of mGluRs.

PMID- 10336677
TI  - Regulation of the murine NMDA-receptor-subunit NR2C promoter by Sp1 and fushi
      tarazu factor1 (FTZ-F1) homologues.
AB  - We have cloned the 5'-region of the murine N-methyl-d-aspartate (NMDA) receptor
      channel subunit NR2C (GluRepsilon3) gene and characterized the cis- and trans
      activating regulatory elements responsible for its tissue specific activity. By
      using a native epsilon3-promoter/lacZ-construct & various 5'-deletion constructs,
      we compared beta-galactosidase expression in non-neuronal NIH3T3 cells and in
      neuronal epsilon3-gene-expressing HT-4 cells and show that large parts of the
      epsilon3 promoter are responsible for the repression of the epsilon3 gene in non
      neuronal cells. Deletion of exon 1 sequences led to an enhancement of epsilon3
      transcription, suggesting a role of the 5'-untranslated region in epsilon3 gene
      regulation. Sequence analysis of the promoter region revealed potential binding
      sites for the transcription factor Sp1, the murine fushi tarazu factor1 (FTZ-F1)
      homologues, embryonic LTR binding proteins (ELP1,2,3) and steroidogenic factor
      (SF-1), as well as for the chicken ovalbumin upstream promoter transcription
      factor (COUP-TF). Electrophoretic mobility shift assays confirmed specific
      binding of Sp1, SF-1 and COUP-TFI. Whereas point mutation studies indicate that,
      in neuronal HT-4 cells, Sp1 is apparently not critically involved in basal
      epsilon3 gene transcription, SF1 is a positive regulator. This was evident from a
      selective enhancement of epsilon3-promoter-driven reporter gene expression upon
      cotransfection of an SF1-expression vector, which was reverted by deletion and
      point mutation of the SF1 binding site.

PMID- 10336679
TI  - Positional specificities of retinal growth cones in the mouse superior
      colliculus.
AB  - In the developing retinotectal system, repulsive topographic tectal cues have
      been demonstrated to contribute to the final mapping. Here, we describe a novel
      response of nasal axons to growth-promoting cues expressed by anterior tectal
      cells. In in vitro experiments, contact of fibres from the nasal (but not
      temporal) pole of the mouse retina with anterior (but not posterior) tectal
      membranes leads to their adopting very elongated and filopodial morphologies, and
      to increase their growth rates. As previously demonstrated, fibres from the
      temporal pole of the retina are collapsed by posterior tectal membranes in vitro.
      In addition, a study of retinal growth cone morphologies in vivo, at early stages
      of target invasion, shows that growth cones of nasal fibres have streamlined
      morphologies, usually indicative of active elongation growth modes, in the
      anterior part of the embryonic mouse tectum, and more elaborate morphologies
      posteriorly. Vice versa, temporal fibres have mainly elaborate growth cones
      anteriorly, and collapsed growth cones posteriorly. These experiments demonstrate
      that nasal retinal fibres respond preferentially to permissive or growth
      promoting cues in the embryonic mouse tectal environment, both in vitro and in
      vivo. This phenomenon might contribute to ingrowth of retinal fibres in their
      target area, and to promote the homing of nasal fibres towards the posterior
      aspect of the tectum, which is their normal target region.

PMID- 10336678
TI  - The homeodomain transcription factors Islet 1 and HB9 are expressed in adult
      alpha and gamma motoneurons identified by selective retrograde tracing.
AB  - To study gene expression in differentiated adult motoneuron subtypes, we used
      fluorescent dextrans for both anterograde and retrograde axonal tracing in adult
      rat and mouse. Application of these dyes to the cut distal and proximal ends of
      small extramuscular nerve branches revealed both the peripheral ramifications and
      the cell bodies of subsets of motoneurons. We show that the soleus muscle is
      innervated by two nerve branches, one of which contains gamma motor and sensory
      axons but no alpha motor axons. By retrograde tracing of this branch, we
      selectively labelled gamma motoneurons. In adult rat, the nerves innervating the
      soleus and extensor digitorum longus muscles contain almost exclusively axons
      innervating slow (type I) and fast (type 2) muscle fibres, respectively. We
      selectively labelled slow and fast type motoneurons by retrograde tracing of
      these nerves. With immunocytochemistry we show that adult motoneurons express
      several homeodomain genes that are associated with motoneuron differentiation
      during early embryonic development. Combining selective retrograde labelling with
      immunocytochemistry we compared the expression patterns in alpha and gamma
      motoneurons. The homeodomain transcription factors Islet 1 and HB9 were expressed
      in slow and fast alpha motoneurons and in soleus gamma motoneurons. Motoneurons
      in each population varied in their intensity of the immunostaining, but no factor
      or combination of factors was unique to any one population.

PMID- 10336680
TI  - Spectral sensitivity in hemianopic macaque monkeys.
AB  - We measured the increment threshold sensitivity to 2 degrees, 200-ms targets
      presented at a lateral and radial eccentricity of approximately 20-26 degrees in
      both visual hemifields of three macaque monkeys whose left striate cortex had
      been removed 5 years earlier, and in one normal control. As in patients with
      blindsight, sensitivity of the hemianopic field for blue, green and red stimuli
      was reduced by as little as 0.5 log units. With increasing light adaptation from
      scotopic to mesopic to photopic levels, there was a progressive increase in the
      sensitivity to long wavelengths relative to that for short and medium
      wavelengths. This shift in relative sensitivity ('Purkinje shift') shows that rod
      and cone mechanisms operate in both the normal and hemianopic fields and that the
      sensitivity that remains following removal of striate cortex is not mediated
      exclusively by rods.

PMID- 10336681
TI  - Dystrophin and beta-dystroglycan in photoreceptor terminals from normal and
      mdx3Cv mouse retinae.
AB  - Mutations in the dystrophin gene cause muscular dystrophy as well as cognitive
      impairments, including an abnormal dark-adapted electroretinogram. To investigate
      the basis for the ocular phenotype, we analysed dystrophin and the dystrophin
      associated protein beta-dystroglycan in retinae from mdx3Cv mice. This strain has
      a mutation in the dystrophin gene and abnormalities in the electroretinogram
      which are similar to those of muscular dystrophy patients. Despite an overall
      reduction of all dystrophin isoforms and of beta-dystroglycan in retinal tissue
      from mutant mice, we observed no apparent change in the histotypic layering of
      the retina, or in the ultrastructure of several specific cell types, including
      rods and cones. In retinae from wild type and mdx3Cv mice, dystrophin and beta
      dystroglycan were concentrated in small extensions of rod and cone photoreceptor
      terminals protruding into the outer plexiform layer. Beta-dystroglycan but not
      dystrophin was also clustered around the inner limiting membrane and the
      capillary basal laminae. While the labelling pattern around the basal laminae was
      not altered in the mutant mice, we found that the area as well as the intensity
      of the dystrophin and beta-dystroglycan immunoreactivity associated with the
      terminals of rod photoreceptors were severely reduced. The same parameters were
      much less affected in cone terminals. These results show, that dystrophin and
      beta-dystroglycan are differentially distributed in the retina, and that a severe
      reduction of dystrophin has no gross effect on retinal structure, but could
      influence intraretinal signalling at the level of the photoreceptor terminals.
      Moreover, the mutation in mdx3Cv mice has a selective effect on rods, providing
      an explanation for the altered electroretinogram.

PMID- 10336682
TI  - Effects of noradrenaline on frequency tuning of auditory cortex neurons during
      wakefulness and slow-wave sleep.
AB  - This study shows the effects of noradrenaline (NA) on receptive fields of
      auditory cortex neurons in awake animals; it is the first one to describe the
      effects of NA on neurons in sensory cortex, in different natural states of
      vigilance. The frequency receptive field of 250 auditory cortex neurons was
      determined before, during and after ionophoretic application of NA while
      recording the state of vigilance of unanaesthetized guinea-pigs. When NA
      significantly changed the spontaneous activity (85 out of 250 cells), the
      dominant effect was a decrease (61 out of 85 cells, 72%). When NA significantly
      changed the evoked activity (107 out of 250 cells), the dominant effect was also
      a decrease (84 out of 107 cells, 78%). During and after NA application, the
      signal-to-noise ratio (S/N, i.e. evoked/spontaneous activity) was unchanged, but
      the selectivity for pure-tone frequencies was enhanced. When the effects
      occurring in wakefulness and in slow-wave sleep (SWS) were compared, it appeared
      that the predominantly inhibitory effect of NA on spontaneous and evoked activity
      was present in both states. The S/N ratio was unchanged and the selectivity was
      increased in both states. However, during SWS, the percentage of cells inhibited
      by NA was lower, and the effects on the frequency selectivity were smaller than
      in wakefulness. In contrast, GABA produced similar inhibitory effects on
      spontaneous and on evoked activity during wakefulness and SWS. Comparisons with
      previous data obtained using the same protocol in urethane anaesthetized animals
      (Manunta & Edeline 1997) indicate that the effects of NA were qualitatively the
      same. Based on these results, we suggest that any hypothesis concerning the role
      of NA in cortical plasticity should take into account the fact that the
      predominantly inhibitory effects of NA lead to decrease the size of the receptive
      field.

PMID- 10336683
TI  - Axoaxonic synapses on terminals of group II muscle spindle afferent axons in the
      spinal cord of the cat.
AB  - The purpose of the present study was to determine if terminals of identified
      group II muscle spindle afferents participate in axoaxonic synaptic arrangements
      and, if so, to investigate the transmitter content of presynaptic terminals in
      these arrangements. Group II muscle afferents supplying the gastrocnemius-soleus
      or semitendinosus muscles were identified in adult cats and stained intra
      axonally with horseradish peroxidase. In total, three group II axons were
      labelled and processed for combined light and electron microscopy. Group II axons
      gave rise to collaterals which characteristically descended through the
      superficial dorsal horn and formed relatively sparse terminal arborizations in
      the dorsal horn (laminae IV and V) and more profuse arbors in the intermediate
      grey matter (laminae VI-VII). Forty boutons were examined through series of
      ultrathin sections and all but four were postsynaptic to other axon terminals.
      Occasionally, more than one axon was presynaptic to a single group II terminal.
      Immunogold studies showed that all axons in presynaptic apposition to group II
      boutons contained gamma-aminobutyric acid (GABA) and also that glycine was
      colocalized in the majority of these axons. This evidence suggests that
      transmission from group II muscle afferents is under strong presynaptic
      inhibitory control and that it is mainly the subgroup of GABAergic interneurons
      with colocalized glycine which mediate this inhibition. Seventeen group II
      boutons were components of synaptic triads where the presynaptic axoaxonic bouton
      formed a synapse with the same dendrite as the group II axon. Therefore, a
      proportion of the interneurons which form axoaxonic synapses with group II axons
      are also likely to have postsynaptic inhibitory actions on target neurons of
      group II afferents.

PMID- 10336684
TI  - Dimethylarginine dimethylaminohydrolase (DDAH) as a nerve-injury-associated
      molecule: mRNA localization in the rat brain and its coincident up-regulation
      with neuronal NO synthase (nNOS) in axotomized motoneurons.
AB  - As part of a project to identify genes up-regulated by injury of the motor
      neuron, a clone encoding dimethylarginine dimethylaminohydrolase (DDAH) was
      isolated. This enzyme is known to metabolize methylarginines, which are
      endogenous inhibitors of NOS activity. DDAH may therefore contribute to the
      control of NO synthesis. The present study demonstrated that both DDAH and nNOS
      mRNAs are up-regulated after axotomy in injured hypoglossal motor neurons. The
      profile of DDAH mRNA up-regulation in the injured hypoglossal motor neurons
      paralleled that of NADPH diaphorase staining. While the expression of both DDAH
      and nNOS was upregulated in motor neurons following nerve injury, the normal
      distribution of DDAH and nNOS mRNAs in the noninjured central nervous system were
      distinctly different. We speculate that both genes are involved in the
      upregulation of NO production following nerve transection, although the role of
      NO in the process of nerve regeneration is so far unknown.

PMID- 10336685
TI  - Involvement of the subthalamic nucleus in glutamatergic compensatory mechanisms.
AB  - The purpose of the present study was to investigate whether the subthalamic
      nucleus (STN) was implicated in the glutamatergic compensatory mechanisms which
      have been shown to mask the parkinsonian motor abnormalities at the end of the
      presymptomatic period in experimental parkinsonism. Using multiunit
      electrophysiological recordings, we follow changes of activity occurring in the
      STN and in both the pars externalis and the pars internalis of the globus
      pallidus of monkeys chronically intoxicated with 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP), according to a protocol designed to mimic the gradual
      evolution of dopaminergic neuronal death. STN activity augmented significantly in
      the course of treatment, even before the first appearance of clinical signs (P <
      0.01). This result would indicate that the STN, which increases its level of
      activity even before the end of the presymptomatic period, is principally
      responsible for the instigation of glutamatergic compensatory mechanisms which
      allow the maintenance of the striatal dopaminergic homeostasis.

PMID- 10336686
TI  - Facilitation of GABA release by arachidonic acid in rat hippocampal synaptosomes.
AB  - Arachidonic acid (AA) is proposed to be a facilitatory retrograde messenger in
      hippocampal glutamatergic synapses. In this study, we found that AA (10 microM)
      increased the basal outflow (19 +/- 4%) and the K+-evoked release of [3H]GABA (38
      +/- 3%) from rat hippocampal synaptosomes. This effect is likely to be a direct
      action of AA, as it was not mimicked by arachidic acid (10 microM) and was not
      modified by inhibition of either lipooxygenase with nordihydroguaiaretic acid (50
      microM) or cyclooxygenase with indomethacin (100 microM). Activation of protein
      kinase C may be involved, as chelerythrine (6 microM), a protein kinase C
      inhibitor, attenuated the AA (10 microM)-facilitation of K+-evoked [3H]GABA
      release by 58 +/- 5%. Phospholipase A2 (2 U/mL), an enzyme that releases AA, and
      melittin (1 microM), a phospholipase A2 activator, mimicked the AA-facilitation
      of evoked [3H]GABA release (70 +/- 6% and 76 +/- 7% facilitation, respectively).
      These results show that exogenously added and endogenously produced AA increased
      basal outflow and K+-evoked release of [3H]GABA from rat hippocampal
      synaptosomes. Thus, AA can no longer be considered solely a facilitatory
      neuromodulator in the hippocampus, as this AA-facilitation of the release of the
      main inhibitory neurotransmitter may predominate under certain circumstances.

PMID- 10336687
TI  - Can GABAA conductances explain the fast oscillation frequency of absence seizures
      in rodents?
AB  - Rodent models of absence epilepsy generate spike-and-wave oscillations at
      relatively fast frequency (5-10 Hz) compared with humans ( approximately 3 Hz).
      Possible mechanisms for these oscillations were investigated by computational
      models that included the complex intrinsic firing properties of thalamic and
      cortical neurons, as well as the multiple types of synaptic receptors mediating
      their interactions. The model indicates that oscillations with spike-and-wave
      field potentials can be generated by thalamocortical circuits. The frequency of
      these oscillations critically depended on GABAergic conductances in thalamic
      relay cells, ranging from 2-4 Hz for strong GABAB conductances to 5-10 Hz when
      GABAA conductances were dominant. This model therefore suggests that
      thalamocortical circuits can generate two types of spike-and-wave oscillations,
      whose frequency is determined by the receptor type mediating inhibition in
      thalamic relay cells. Experiments are proposed to test this mechanism.

PMID- 10336688
TI  - Mu- and delta-opioid receptor agonists inhibit DARPP-32 phosphorylation in
      distinct populations of striatal projection neurons.
AB  - In the striatum, DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa)
      is highly expressed by virtually all projection medium-sized spiny neurons. cAMP
      dependent phosphorylation of DARPP-32 is stimulated via activation of dopamine D1
      receptors in striatonigral neurons, and via activation of adenosine A2A receptors
      in striatopallidal neurons. In this study, we have examined the contribution of
      mu-, delta- and kappa-opioid receptors to the regulation of DARPP-32
      phosphorylation, in rat striatal slices. The results show that, at low
      concentrations (100 pm-1 nm), the mu-opioid agonist, Tyr-D-Ala-Gly-N-Me-Phe
      glycinol (DAMGO), inhibits the increase in DARPP-32 phosphorylation induced by
      activation of D1, but not by activation of A2A receptors. Conversely, the delta
      receptor agonist, Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE), inhibits DARPP-32
      phosphorylation induced by activation of A2A, but not by activation of D1
      receptors. The kappa-receptor agonist, U50488, does not affect DARPP-32
      phosphorylation induced by either D1 or A2A agonists. Thus, mu-opioid receptors
      interact with dopamine D1 receptors on striatonigral neurons, whereas delta
      opioid receptors interact with adenosine A2A receptors on striatopallidal
      neurons. These results suggest that regulation of DARPP-32 phosphorylation is
      involved in mediating some of the effects exerted by enkephalin on striatal
      medium-sized spiny neurons.

PMID- 10336690
TI  - The intrinsic specification of gamma-aminobutyric acid type A receptor alpha6
      subunit gene expression in cerebellar granule cells.
AB  - The patterns of gamma-aminobutyric acid type A (GABAA) receptor subunit gene
      expression in the brain are complex. For example, mouse hippocampal dentate
      granule cells express many subunit genes, whereas adult cerebellar granule cells,
      which may share differentiation mechanisms, have a smaller compliment and
      uniquely express the alpha6 subunit gene. To see how the alpha6 expression
      component arises, i.e. if intrinsically or environmentally specified, we used a
      mouse line (Deltaalpha6lacZ) with a beta-galactosidase reporter inserted into the
      alpha6 gene. Precursor cells from postnatal day 1 Deltaalpha6lacZ cerebellum were
      transplanted to the adult hippocampus and cerebellum of wild-type mice; 4 weeks
      after transplantation, Deltaalpha6lacZ cells expressed alpha6-lacZ in the
      hippocampus, amygdala and cerebellum. Thus, different adult environments support
      both the development and maintenance of alpha6 gene expression from cerebellar
      granule cell precursors. Establishing alpha6 gene expression is not likely to
      require specific patterns of neurotransmitter innervation or other factors
      present only in the developing brain; instead, alpha6 expression can be timed and
      maintained autonomously.

PMID- 10336689
TI  - Selective expression of the NOS II isoform during mouse vestibulocochlear
      receptorgenesis.
AB  - Based on in vitro studies, nitric oxide (NO) is reported to be involved in
      initial neuronal differentiation. In order to compare this finding with the
      situation in vivo, we have looked for the expression of the three NO synthase
      isoforms in the developing mouse vestibulocochlear system. From these isoforms
      only the inducible NOS II is expressed during inner ear development. Examination
      of a series of embryonic and early postnatal animals, up to postnatal day 6,
      reveals a maturation-dependent, monophasic expression of this isoform. Initial
      expression is observed by day 10 of gestation in nerve cells of the
      vestibolocochlear ganglion and on their fibres. By day 14 of gestation, these
      afferent fibres penetrate the epithelium of the prospective receptor fields
      making contact with early, differentiating immunoreactive cochlear hair cells and
      receptor cells of the macula and crista ampullaris. This receptor-cell-derived
      immunoreactivity vanished in differentiated sensory hair cells by postnatal day
      6, when both the constitutive isoforms and subsequent activated members of the
      down stream second messenger cascade (guanylate cyclase/cGMP) of the adult mouse
      were not then detectable. The strict phasic expression of NOS-II, independent of
      the second messenger system mentioned above, implies that there is a unique role
      for the inducible NOS isoform in nerve cell differentiation, independent of the
      NO/guanylate cyclase/cGMP pathway.

PMID- 10336691
TI  - Incorporation of Drosophila TAF110 into the yeast TFIID complex does not permit
      the Sp1 glutamine-rich activation domain to function in vivo.
AB  - BACKGROUND: Acidic activation domains function across eukaryotic species, and
      hence stimulate transcription by a conserved molecular mechanism. In contrast,
      glutamine-rich activation domains function in flies, mammals, and fission yeasts
      but not in the budding yeast Saccharomyces cerevisiae. The glutamine-rich
      activation domain of Sp1 interacts with TAF110, and it has been suggested that
      this interaction is important for transcriptional activation. S. cerevisiae does
      not contain a homologue of TAF110, suggesting a potential mechanism to account
      for the failure of glutamine-rich activation domains to stimulate transcription.
      RESULTS: Here, we have artificially recruited Drosophila TAF110 into the yeast
      TFIID complex by fusing it to yeast TBP. The resulting TFIID complex supports
      normal cell growth, but it is unable to mediate Sp1-dependent activation.
      CONCLUSIONS: Thus, the interaction of glutamine-rich activation domains with
      TAF110 is insufficient for transcriptional activation in vivo, indicating that
      other targets within the PolII machinery are necessary.

PMID- 10336692
TI  - Identification of engrailed promoter elements essential for interactions with a
      stripe enhancer in Drosophila embryos.
AB  - BACKGROUND: The structures and functions of promoter sequences of most genes have
      been analysed using in vitro transcription and/or cultured cell systems, neither
      possessing tissue-specific enhancers. Promoter-enhancer interactions in vivo, in
      particular, during ontogeny, are still poorly understood. RESULTS: We have
      established a new method for the assessment of promoter activity in cells that
      participate in fly body formation, using the UAS/GAL4 system. A functional
      analysis was then conducted on the promoter sequence of the engrailed gene in
      Drosophila embryos. A 38-bp-long sequence, terminating with an initiator or RNA
      start site and a downstream promoter element, was found to be capable of
      receiving activation signals from the engrailed stripe enhancer. Transcriptional
      efficiency was improved significantly by the presence of upstream promoting
      elements, most functionally replaceable with synthetic GAGA factor binding sites.
      CONCLUSIONS: We identified the in vivo minimum promoter of engrailed and
      demonstrated that the GAGA factor binding sites serve primarily as quantitative
      elements which augment transcriptional efficiency. Evidence was also obtained
      that indicated that not only enhancer but also promoter sequences were involved
      in the determination of the tissue-specificity of gene expression.

PMID- 10336693
TI  - Impaired extrapyramidal function caused by the targeted disruption of retinoid X
      receptor RXRgamma1 isoform.
AB  - BACKGROUND: Retinoid X receptors RXRalpha, beta and gamma exert multiple
      functions in the genetic regulation of mammalian signalling systems by forming
      heterodimeric complexes with several nuclear ligand receptors. In contrast to the
      widespread expression of RXRalpha and RXRbeta, the expression of RXRgamma is
      restricted to particular tissues in which RXRgamma1 is the major isoform
      expressed in the mouse corpus striatum. RESULTS: To investigate the function of
      this particular isoform RXRgamma1, we generated RXRgamma1 gene-knockout mice by
      homologous recombination in ES cells. Both heterozygous and homozygous mice
      showed severe runting after birth, which often resulted in the early death of
      mice of the 129/C57BL-6 genetic background. Independent of genetic background,
      however, the expression of choline acetyltransferase (ChAT) in the cholinergic
      interneurones in the striatum (caudal putamen) was markedly reduced in the
      RXRgamma1 gene-null mice. Furthermore, the mutant exhibited an altered response
      to the administration of dopamine receptor antagonists, haloperidol and
      chlorpromazine, which normally induce catalepsy in mice. CONCLUSIONS: These
      results strongly suggest that RXRgamma1 plays an important role in either the
      development or activation of cholinergic neurones in nigrostriatal extrapyramidal
      pathways.

PMID- 10336694
TI  - Enhancer and silencer binding proteins involved in the rat cdc2 promoter
      activation at the G1/S boundary.
AB  - BACKGROUND: Expression of the rat cdc2 gene during G1-S phase progression is
      negatively and positively regulated by the silencer and enhancer elements located
      upstream of the basal promoter. The silencer and enhancer sequences resemble each
      other, but the silencer contains extra internal AG residues. RESULTS: The cDNA
      clones encoding the enhancer binding proteins cdc2E1 and cdc2E2 were isolated by
      South-Western blotting. cdc2E1 and cdc2E2 comprise 436 and 256 amino acids and
      have two RNA binding domains which contain an RNP1 octamer and an RNP 2 hexamer.
      Both cdc2E1 and cdc2E2 bind to the double-stranded and single-stranded silencer
      and enhancer sequences, but their binding affinity to the enhancer was stronger
      than that to the silencer. Transfection of quiescent 3Y1 cells with the cdc2
      promoter-luciferase constructs, followed by serum stimulation, showed that the
      promoter activation at the G1-S phase boundary was reduced greatly by base
      substitutions within the enhancer, but not within the silencer. Gel shift assays
      with oligonucleotides containing both the silencer and enhancer showed that
      formation of the large complex was greatly reduced if base-substitutions were
      introduced into the enhancer, but not within the silencer. The complex was
      supershifted completely by anti-cdc2E1 antibody and partially by anti-cdc2E2
      antibody. CONCLUSION: These results suggest that cdc2E1 and cdc2E2 preferentially
      form the multimeric complex at the enhancer site after the late G1 phase for
      activation of the cdc2 promoter.

PMID- 10336696
TI  - Population differentiation in mediterranean plants: insights into colonization
      history and the evolution and conservation of endemic species 
AB  - Colonization and isolation are critical events in the evolutionary dynamics of
      plant populations. In this paper I review how spatial population structure of
      genetic markers provides insights into the evolutionary significance of episodes
      of colonization and isolation in the Mediterranean flora. I use as themes to
      structure my review the following topics: spatial structure induced by historical
      associations among populations of widespread species; population differentiation
      in relation to the evolution of closely related species with disjunct
      distributions; the potential effect of founder events during colonization on
      character evolution; and the conservation implications of spatial population
      structure. My review illustrates that the Mediterranean flora is full of examples
      that provide key insights into such evolutionary and conservation issues.

PMID- 10336695
TI  - Abnormalities of developmental cell death in Dad1-deficient mice.
AB  - BACKGROUND: Dad1, the defender against apoptotic cell death, comprises the
      oligosaccharyltransferase complex and is well conserved among eukaryotes. In
      hamster BHK21-derived tsBN7 cells, loss of Dad1 causes apoptosis which cannot be
      prevented by Bcl-2. RESULTS: To determine the role of Dad1 function in vivo, we
      prepared by gene targeting, mice harbouring a disrupted Dad1 gene. Homozygous
      mutants died shortly after they were implanted with the characteristic features
      of apoptosis. In an in vitro blastocyst culture system, Dad1-null cells displayed
      abnormalities which were comparable to those obtained in vivo. However,
      oligosaccharyltransferase activity was apparently retained even after the Dad1
      null cells were destined to die. Some live-born heterozygous mutants displayed
      soft-tissue syndactyly. Mild thymic hypoplasia was also indicated in
      heterozygotes. CONCLUSION: These results suggest the involvement of the Dad1 gene
      in the acquisition of a common syndactyly phenotype, as well as in the control of
      programmed cell death during development.

PMID- 10336697
TI  - Mating systems of diploid and allotetraploid populations of tragopogon
      (Asteraceae). I. Natural populations 
AB  - Although polyploidy is a significant force in the diversification of plants, the
      evolutionary consequences of polyploidization are not thoroughly understood. One
      possible consequence of polyploidy predicted by most population genetic theories
      is that the newly synthesized polyploid will self-fertilize at a greater rate
      than its diploid progenitors. To test for increased selfing rates in a polyploid,
      the mating systems of the allotetraploid Tragopogon mirus and one of its diploid
      progenitors, T. dubius, were compared. Tragopogon mirus is a recently derived
      species that arose sometime in the last 80 years and thus provides an opportunity
      to probe how quickly a shift in outcrossing rates might occur. Based on analyses
      of variation in maternal plants and their progeny arrays, the two tetraploid
      populations surveyed have higher outcrossing rates than the two diploid
      populations. This result is the opposite of that predicted by population genetic
      theory. This discrepancy between theoretical and empirical results may result
      from bias in the genetic sample, traits in the natural histories of the taxa
      involved or a lack of sufficient time since the formation of the polyploid (80
      years or 40-80 generations) for a shift towards increased selfing to have
      occurred. Alternatively, the partial dominance model of inbreeding depression
      typically applied to polyploids may not be appropriate; the overdominance model
      predicts outcrossing rates in diploids and their tetraploid derivatives that are
      consistent with those observed in T. dubius and T. mirus.

PMID- 10336698
TI  - Mapping morphological genes relative to molecular markers in lettuce (Lactuca
      sativa L.) 
AB  - Two F2 populations were generated by crossing morphologically diverse genetic
      stocks in order to map 10 morphological traits relative to polymerase chain
      reaction-based molecular markers (RAPDs). Using one segregating population
      generated from crossing the experimental line, 'dwarf-2', with the butterhead
      cultivar, 'Saffier', the dwarf phenotype conditioned by the dwf2 locus was mapped
      using bulked segregation analysis to within 38 cM of the Adh3 locus. Using the
      second segregating population generated by crossing two experimental lines, 87-25
      1M x 87-109M, nine traits [white seed (w), brown seed (br), salmon flower colour
      (sa), pale yellow flower colour (pa), virescent juvenile leaf colour (vi), plump
      involucre (pl), yellow seed (y), one of two complementary genes for anthocyanin
      expression (C or G) and anthocyanin spotting (Rs)] were linked to RAPD loci, but
      only six of them could be placed on an existing genetic map of lettuce generated
      by analysis of cv. 'Calmar' x cv. 'Kordaat'. A tenth trait, golden yellow (gy),
      remained unlinked. Approximately a third of the RAPD markers analysed segregated
      in both the 87-25-1M x 87-1090M and 'Calmar' x 'Kordaat' populations. In the
      genomic regions with multiple segregating loci in common, their relative orders
      and distances were mostly conserved. In one instance, linkage detected in the
      present study consolidated two separate groups on the earlier genetic map.

PMID- 10336699
TI  - Properties of AFLP markers in inheritance and genetic diversity studies of pinus
      sylvestris L 
AB  - We analysed the properties of AFLP markers in Pinus sylvestris. Using primers
      with three selective nucleotides, the AFLP protocol produced large numbers of
      amplified bands and could only be used with a restricted number of primer
      combinations. Replacement of the EcoRI +3 primer by an EcoRI +4 primer halved the
      number of bands, facilitating analysis. The inheritance of all but about 8.4% of
      the amplified bands has been confirmed to be Mendelian. We compared band patterns
      among selected P. sylvestris trees from northern Sweden, two Asian species of
      Pinus and one species from the genus Picea. The dendrogram obtained was generally
      concordant with the taxonomic data, although the genetic similarity values
      between trees from different genera did not entirely follow accepted inter- and
      intraspecific relationships. This deviation was less pronounced using primer
      combinations that generated fewer bands. More than 69.1% of the bands that were
      polymorphic in two P. sylvestris trees or 29 of their F1 progeny were in a pseudo
      testcross configuration and thus were useful for the development of a linkage map
      for each parent. These markers have been analysed in four other crosses, and 83%
      of the bands could be mapped in at least one cross. Depending on the level of
      heterozygosity of the parents, the efficiency of such mapping will vary, but the
      AFLP technique appears to be a powerful way to generate, very quickly, large
      numbers of markers that are useful for constructing and comparing linkage maps.

PMID- 10336700
TI  - Evolutionary DNA variation in the genus hypochaeris 
AB  - The genome size and the base composition (GC%) of eight Hypochaeris species were
      determined by flow cytometry in order to establish the pattern of nuclear DNA
      variation within the genus. The species analysed showed an almost fivefold range
      of variation from 1.68 pg in H. cretensis to 8.10 pg in H. uniflora. This
      variation in DNA content is greater between taxonomic sections of Hypochaeris
      species than within a section. There was no correlation between 2C DNA content
      and GC% indicating that neither the GC fraction nor the AT fraction were
      preferentially associated with variation in genome size. Because there is little
      heterochromatin, these results show that it is interspersed repeated sequences
      that are most probably implicated in this variation. From phylogenetic analysis,
      it is likely that genome size has evolved by loss of DNA content in some lineages
      and by gain in one lineage from an ancestral genome which was probably similar to
      genomes of intermediate size in Hypochaeris.

PMID- 10336702
TI  - Female mating behaviour, sexual selection and chromosome I inversion karyotype in
      the seaweed fly, coelopa frigida 
AB  - Previous studies of the seaweed fly, Coelopa frigida, have revealed the operation
      of several different forces of sexual selection. The overall pattern of mate
      choice seen in natural populations is not consistent with the predictions of
      indirect sexual selection as females do not express preferences that maximize the
      fitness of their offspring, even though the benefits from such choice are
      relatively large in this species. Thus, the maintenance of female mate choice for
      large male size must instead either be a result of a direct benefit to the female
      of mating with large males, or a side-effect of the evolution of another
      character, in other words pleiotropy. In order to separate these two alternatives
      the genetical basis of female mating behaviour needs to be studied. Previous
      studies have revealed associations between chromosomal inversion karyotype and
      both general female willingness to mate and mate choice for large male size,
      however these associations were lost after several generations of laboratory
      culture. Here several isokaryotypic lines from wild collections of flies were
      derived. The willingness to mate and mate choice of females from each line were
      determined. Pairs of lines of opposite inversion karyotype that significantly
      differed in either or both willingness to mate and mate choice were crossed. The
      mating behaviour and inversion karyotype of the F2 progeny (all F1 progeny are
      heterokaryotypes) were determined. Clear differences in the general levels of
      female willingness to mate were found between the two inversion homokaryotypes in
      several families, whereas variation in the strength of female choice for large
      male size were not revealed. It is suggested that mate choice in this species
      occurs as a pleiotropic effect of selection acting on female willingness to mate.

PMID- 10336703
TI  - Diversity of sex-determining alleles in bracon hebetor 
AB  - In many hymenopterans, sex is determined at a single polymorphic 'sex locus'.
      Individuals that are heterozygous at this locus develop as females whereas
      homozygotes and hemizygotes develop as diploid and haploid males, respectively.
      Diploid males are developmentally inviable or sterile, and the likelihood of
      diploid male production depends in large part on allelic diversity at the sex
      locus. We assessed sex allele diversity within and among five U.S. populations of
      the parasitoid wasp Bracon hebetor using a series of crosses between isofemale
      lines. The study included two laboratory populations originating in Wisconsin,
      two field populations originating in Kansas and California, and a population
      purchased from a commercial insectary. Given the number of isofemale lines that
      we established, the maximum number of alleles that we could detect per population
      was 10. The number of sex alleles identified within populations ranged between
      three or four (for the two Wisconsin populations) and nine (for the California
      population). Subsampling three or four alleles from each population for between
      population crosses led to identification of 12 alleles. Of these, four were
      unique to the California population, three were unique to one other population
      each, and one was found in only two populations. Extrapolation of the
      relationships between the subsampled lines led to a total estimate of 20 alleles
      within our lines. The relatively high allele diversity in the field and
      commercial insectary populations suggests that the sex determination load is
      relatively low in B. hebetor, and the differences in allele profiles between
      populations suggest that interpopulation dispersal can increase sex allele
      diversity within populations.

PMID- 10336704
TI  - Genetic diversity in the monospecific western australian endemic, geleznowia
      verrucosa turcz. (Rutaceae) 
AB  - Allozyme diversity was surveyed at 16 loci across 16 populations of the
      monospecific, but morphologically diverse, endemic shrub Geleznowia verrucosa
      Turcz. (Rutaceae). Single-locus diversity measures portrayed G. verrucosa as a
      genetically depauperate genus (A, 1.4; P, 29.6%), with total genetic diversity
      (HT, 0.304) partitioned between populations (DST, 0.175), rather than within (HS,
      0.129). Some 58% of the total genetic diversity was attributable to
      interpopulational differences. Although restricted distribution, bottlenecks
      and/or founder effects and small population size have probably contributed to the
      low levels of genetic diversity found within this genus, it is evident from this
      investigation that the genus is not monospecific. The partitioning of genetic
      diversity, and possible differences in reproductive strategy, suggest that the
      small- and large-flowered forms represent distinct taxa. Higher levels of
      divergence between the intermediate-form populations and increased heterozygosity
      at the Lap locus suggest that this form is of hybrid origin and has arisen
      through a series of hybrid events between the small and large forms.

PMID- 10336705
TI  - Host and parasite population structure in a natural plant-pathogen system 
AB  - We investigated the genetic population structure in a metapopulation of the plant
      Silene latifolia (Caryophyllaceae) and its fungal pathogen Microbotryum violaceum
      (Ustilaginales), a pollinator-borne disease. Population structure of the host
      plant was estimated using allozyme markers and that of the fungus by
      microsatellites. Both host and parasite showed significant differentiation, but
      parasite populations were 12 times more strongly differentiated than those of the
      hosts. We found significant isolation by distance for host populations but not
      for parasite populations. Higher population differentiation for the parasite may
      result from small effective population size, high selfing rates, or low migration
      rate. In this system, hosts are obligate outcrossers and they migrate by seeds
      and pollen, whereas parasites can self-fertilize and migrate only on pollinating
      insects. We discuss the effect of limited gene flow in this parasite on its
      coevolutionary interaction with its host, and its potential for local adaptation
      on sympatric host populations.

PMID- 10336706
TI  - Genetic structure of island populations of the anurans rana temporaria and bufo
      bufo 
AB  - Amphibians have traditionally been considered to have low dispersal ability and
      they have become a model for studies on the effects of man-made habitat
      fragmentation on genetic variation and population differentiation. This study
      examined the genetic population structure in the common frog (Rana temporaria)
      and the common toad (Bufo bufo) in an archipelago of the northern Baltic Sea.
      Heterozygosity was not correlated with distance of the island from the mainland
      nor, in R. temporaria, with effective population size based on census estimates.
      Generally, no inbreeding was detected in island populations. The overall
      differentiation among islands was weak, but the FST values were significantly
      larger in R. temporaria (FST = 0.068) than in B. bufo (FST = 0.019). Most of the
      differentiation was a result of differences among groups of islands,
      differentiation within them playing a minor role. Thus, assuming Wright's island
      model of migration, gene flow was rather high among closely located islands, but
      longer distances seemed to form a slight dispersal barrier for R. temporaria.
      Strong gene flow within the study area was confirmed by lack of isolation by
      distance. The estimated effective population sizes in R. temporaria were small,
      the average being 32 breeding females per island. The results indicate that gene
      flow between island populations across the matrix of open, brackish-water sea is
      extensive and suggest that the anurans are well able to disperse in this natural
      metapopulation system.

PMID- 10336707
TI  - Genetic variation of the riparian pioneer tree species populus nigra. II.
      Variation In susceptibility to the foliar rust melampsora larici-populina 
AB  - Partial resistance of Populus nigra L. to three races of the foliar rust
      Melampsora larici-populina Kleb. was studied in a field trial and in laboratory
      tests, using a collection of P. nigra originating from different places
      throughout France. No total resistance was found. The partial resistance was
      split into epidemiological components, which proved to be under genetic control.
      Various patterns of association of epidemiological components values were found.
      Principal components analysis revealed their relationships. Only 24% of the
      variance of the field susceptibility could be explained by the variation of the
      epidemiological components of susceptibility. This variable was significantly
      correlated with susceptibility to the most ancient and widespread race of the
      pathogen, and with the variables related to the size of the lesions of the
      different races. Analysis of variance showed significant differences in
      susceptibility between regions and between stands within one region. Up to 20% of
      variation was between regions, and up to 22% between stands, so that these
      genetic factors appeared to be more differentiated than the neutral diversity (up
      to 3.5% Legionnet & Lefevre, 1996). However, no clear pattern of geographical
      distribution of diversity was detected.

PMID- 10336708
TI  - The inheritance of female colour morphs in the damselfly ceriagrion tenellum
      (Odonata, coenagrionidae) 
AB  - Female-limited polychromatism is found in many species of Odonata. In Ceriagrion
      tenellum (Coenagrionidae) one of the morphs is red-coloured, like the conspecific
      male (androchrome, erythrogastrum morph), whereas most females are red and black
      (typica morph) or black (melanogastrum morph). Virgin females of this species
      were mated in the laboratory and their progeny reared (13 crosses). Results of
      these crosses indicate that colour morphs are controlled by one autosomal locus
      with female-limited expression. A second laboratory generation (two crosses)
      confirmed this inheritance system. This locus has three alleles (one per
      phenotype) and a hierarchy of dominance: typica > melanogastrum > erythrogastrum.
      The dominance relationships of andro/gynochrome alleles in polymorphic
      damselflies so far studied are discussed. The frequencies of female morphs in
      natural populations are highly variable, but in all cases typica females are the
      commonest.

PMID- 10336709
TI  - Change in morph frequency in the snail cepaea nemoralis on the marlborough downs 
AB  - Temporal change in morph frequency has been examined in Cepaea nemoralis (L.)
      from the Marlborough Downs, southern England, first studied by Cain and Currey
      and resurveyed after 25 years by Cowie and Jones. Three methods of estimating
      selective coefficients over a few generations have been applied to data on the
      frequency of brown at the shell colour locus, showing an average selective
      disadvantage of 3-6% per generation. The integration method overestimated
      selection, whereas the ratio method gave values close to those obtained by
      iteration. There is heterogeneity in response between samples, indicating a
      patchy distribution of morph frequency change, and evidence of homogenization of
      frequency over the period of the study. Both tendencies are also seen when banded
      vs. unbanded at the banding locus is examined. Possible reasons are discussed.
      Between-colony migration may be involved, at levels higher than usually assumed
      to prevail.

PMID- 10336710
TI  - Editorial.

PMID- 10336711
TI  - Vegetarianism and dental fluorosis among children in a high fluoride area of
      northern Tanzania.
AB  - OBJECTIVE: The purpose of this study was to compare the prevalence and severity
      of dental fluorosis among vegetarian and nonvegetarian children and adolescents
      living in an area where dental fluorosis is endemic. DESIGN: An analytical cross
      sectional retrospective study. SAMPLE AND METHODS: Children (n = 165) aged 6-18
      years, from five schools in Arusha town were examined. The children had a life
      long exposure to drinking water with 3.6 mg F/litre. The severity of dental
      fluorosis was assessed using the Thylstrup & Fejerskov Index (TFI). RESULTS: In
      the vegetarian group (n = 24), the prevalence of dental fluorosis (TFI score > or
      = 1) was 67%, while 21% had severe fluorosis (TFI score > or = 5). In the
      nonvegetarian group (n = 141) the prevalence of fluorosis and severe fluorosis
      was 95% and 35%, respectively. In bi-variate correlation analyses age,
      vegetarianism and a series of other factors related to childhood nutrition (meals
      per day, the use of home-made porridge, the use of fish, etc.) were significantly
      associated with the tooth prevalence of dental fluorosis (TPF, P < 0.05).
      Stepwise multiple linear regression analyses explained 30% of the variance in
      TPF; age 15% points and vegetarianism 13% points. Multiple logistic regression
      analysis showed that the risk of developing dental fluorosis was seven times
      higher among nonvegetarians than among vegetarians. CONCLUSION: The significantly
      lower prevalence and severity of dental fluorosis among the vegetarian group
      compared to the nonvegetarians would seem to be related to diet.

PMID- 10336712
TI  - Morphology of dental enamel and dentine-enamel junction in osteogenesis
      imperfecta.
AB  - OBJECTIVES: The aim of this study was to examine the morphology of primary and
      permanent human enamel, and the dentine-enamel junction, in individuals with
      osteogenesis imperfecta (OI) type I, III and IV in undecalcified sections using
      polarized light microscopy, microradiography and scanning electron microscopy
      (SEM), and to relate the findings to the type of OI. SAMPLE AND METHODS:
      Extracted or exfoliated teeth from 15 patients representing the OI types I, III
      and IV (12 primary teeth from seven patients, and 11 permanent teeth from eight
      patients). Ten primary and nine permanent teeth from normal healthy patients
      served as controls. The teeth were serially cut longitudinally in a bucco-lingual
      direction and contact microradiographs were made. The sections were examined in
      polarized light. Sections of primary and permanent teeth were examined by means
      of SEM. RESULTS: This study shows that the permanent enamel from patients with OI
      exhibits few structural changes. No relationships were found between enamel
      morphology and the types of OI (I, III, IV). Primary enamel appeared to be
      slightly more irregularly mineralized, especially in cases with the additional
      diagnosis dentinogenesis imperfecta. The major findings were deviations in
      association with the dentine-enamel junction, and locally a lower degree of
      mineralization. CONCLUSIONS: The mesodermal disease OI might also be manifested
      in ectodermal enamel, probably because of suboptimal mesenchymal-ectodermal
      interactions during amelogenesis.

PMID- 10336713
TI  - Oral health behaviour of 12-year-old children in Kuwait.
AB  - OBJECTIVES: The objectives of the study were: (1) to describe the pattern of oral
      health behaviour of 12-year-old children in Kuwait, (2) to analyse this in
      relation to parental education, dental visiting habits and location, and (3) to
      establish a baseline for planning and evaluation of an oral health care programme
      for secondary schoolchildren. DESIGN: Cross-sectional, interviews with children
      in 1995. SAMPLE AND METHODS: The sample included 500 12-year-old schoolchildren
      (250 boys and 250 girls) selected from schools in Kuwait. All the children agreed
      to take part. Interviews with the children were carried out in the schools by
      four trained and calibrated Arabic speaking interviewers. RESULTS: During the
      previous 12 months, 28% of the children had experienced oral health problems-
      toothache (10%), or had felt discomfort (18%) either often or occassionally. The
      children reported that they needed oral hygiene instruction (71%), fillings (32%)
      and tooth extraction (23%). For 53% of the children the reason for the most
      recent visit to a dentist was pain or problems with teeth or gums. At their last
      dental visit 26% of the children had undergone a tooth extraction. The
      consumption of sugary foods and drinks was extremely high. Children who had
      visited a dentist within the last 12 months and children whose parents had higher
      education levels more often claimed frequent toothbrushing than those with no
      previous dental visiting experience and those whose parents had a low level of
      education. CONCLUSIONS: Oral health education and oral health care programmes
      should be established in secondary schools in Kuwait to influence the oral health
      behaviour of the children and to avoid further deterioration in their oral
      health.

PMID- 10336714
TI  - Pharmacists' knowledge, attitudes and practices concerning sugar-free medicines.
AB  - AIMS: To examine the attitudes of pharmacists to sugar in medicine and sugar-free
      preparations and their levels of knowledge concerning sugar-free preparations and
      the implications for dental health. DESIGN: A questionnaire was designed with a
      mixture of closed and open-ended questions. SETTING: Pharmacists practising in
      the Greater Belfast area of Northern Ireland. METHOD: Seventy pharmacists were
      randomly chosen from the list of pharmacists practising in the area and were
      asked to participate in the study. RESULTS: Responses were obtained from 52 of
      the 70 selected pharmacists, representing a response rate of 74%. Seventy-five
      per cent of the pharmacists stated that they had not received formal education
      concerning sugar in medication and it's effect on dental health. Their main
      source of information on the subject was dental health literature. Eighty-seven
      per cent felt that all medication should be available in sugar-free form. Forty
      six per cent stated that sugar in medication was definitely an important cause of
      dental caries in children and 44% felt that it was a possible factor. The major
      factors influencing the provision of sugar-free medicines were parental request,
      health promotion literature, reports and media advertising. Thirty-nine per cent
      of the pharmacists always offered a sugar-free preparation for over-the-counter
      medication (provided that a sugar-free alternative was available), and 56%
      sometimes did so. Fifty per cent always offered a sugar-free form for prescribed
      items wherever possible, the remainder depended on it being specified by the
      prescriber. CONCLUSION: There is a high level of interest in this issue among
      pharmacists, but there is a need for an increased educational input on a
      continuous basis.

PMID- 10336715
TI  - Dentinal dysplasia type I: report of a case.
AB  - A case of dentinal dysplasia type I is presented. This rare hereditary
      disturbance of dentine is characterized by short-rooted teeth with sharp conical
      apical constrictions, aberrant growth of dentine in the pulp chamber leading to
      reduced pulp space in permanent teeth and total pulpal obliteration in the
      primary dentition. Clinical, radiographic and histopathological material from a 7
      year-old boy, showing the typical features of this disorder in which teeth are
      prematurely lost through periapical abscesses, cysts or spontaneous exfoliation,
      is described. A review of the theories of pathogenesis of this condition is
      included. Management of patients with dentinal dysplasia is difficult and a
      discussion of the shortcomings of various treatment strategies, including
      conventional endodontic therapy, periapical curettage and retrograde root
      filling, and a preventive regimen, are discussed. In this case, despite diagnosis
      being made at an early age and the provision of regular dental care, the patient
      is now losing teeth because of spontaneous abscess formation.

PMID- 10336716
TI  - Autotransplantation as a treatment option after loss of a maxillary permanent
      incisor tooth. A case report.
AB  - A case is described of the management of a maxillary left permanent incisor,
      damaged by several traumatic injuries, in a 13-year-old girl. The traumatized
      incisor tooth required extraction and as part of an orthodontic treatment plan, a
      mandibular left second premolar was surgically transplanted to the prepared
      extraction socket at the maxillary anterior alveolus. After splinting, the
      transplanted tooth underwent endodontic treatment, because of pulpal necrosis.
      Orthodontic treatment commenced 3 months post-transplantation. Permanent root
      obturation was provided after orthodontic treatment and a porcelain veneer was
      placed to restore aesthetic appearance. The case emphasizes the importance of
      correct case selection, a multidisciplinary approach to treatment planning, and
      regular follow-up for transplanted teeth.

PMID- 10336717
TI  - Aberrant root development of the mandibular premolars: a case report.
AB  - A rare case of a patient with aberrant root morphology in all the mandibular
      premolars is reported. A thorough review of the dental literature revealed little
      significant data concerning such cases, because much of the literature is
      concerned with variation in root canal morphology rather than variations in root
      morphology. Failure to obtain preoperative radiographs of diagnostic quality
      could result in unexpected complications during endodontic treatment or
      extraction of such variant teeth.

PMID- 10336718
TI  - Endodontic treatment of immature tooth with dens invaginatus: a case report.
AB  - The endodontic treatment of a dens invaginatus in an immature permanent upper
      lateral incisor of a 9-year-old boy is presented. Root canal treatment was
      performed using calcium hydroxide paste as a temporary root canal filling in
      order to achieve apexification. This was replaced after closure of the apex with
      a final root canal filling using gutta-percha and AH 26 as the sealer. The follow
      up radiographic control demonstrated the effectiveness of nonsurgical treatment
      in a case of incomplete root formation in a tooth with dens invaginatus.

PMID- 10336719
TI  - On the pulpal nerve supply in primary human teeth: evidence for the innervation
      of primary dentine.
AB  - The presence of nerves in human tooth pulp has been recognized for over a hundred
      years, and the innervation of dentine for about 40 years. These observations have
      been made in permanent teeth. Very few studies have reported on the innervation
      of the primary pulp and dentine. The purpose of this study was to describe the
      innervation of the primary tooth pulp-dentine complex. Ten mature primary teeth
      (one incisor, six canines and three molars) were used. Immediately following
      extraction they were divided into three sections using a diamond disc and saline
      coolant. They were then immersion fixed in a solution of formaldehyde and picric
      acid dissolved in a phosphate buffer pH 7.4). The teeth were then demineralized
      for 1-3 weeks in formic acid. Following complete demineralization, 30 microns
      sections were cut on a freezing microtome. Neural tissue was stained using a
      specific antibody to calcitonin gene related peptide (CGRP). Sections were
      mounted on glass slides and examined using light microscopy. No individual nerve
      fibres were seen in the control sections, suggesting that the method used was
      specific for CGRP-containing nerve fibres. The primary teeth appeared to be well
      innervated. Myelinated and unmyelinated nerves were seen. There was a dense but
      variable subodontoblastic plexus of nerves (plexus of Raschkow) and nerve fibres
      were seen to leave this to travel towards the odontoblast layer. Most terminated
      here, but a few penetrated the odontoblast layer to enter predentine and the
      dentine tubules. The maximum penetration was 125 microns but most terminated
      within 30 microns of the dentinopulpal junction. The coronal region was more
      densely innervated than the root. Within the crown the cervical third was the
      most densely innervated region, followed by the pulp horn and the middle third.
      In conclusion, this study has demonstrated that mature primary tooth contains a
      pulp which is well innervated and has many nerve endings terminating in or near
      the odontoblast layer, with a small number penetrating into dentine.

PMID- 10336720
TI  - Hyper-reactive hypothalamo-pituitary-adrenocortical axis in rats bred for high
      anxiety-related behaviour.
AB  - Psychiatric patients suffering from anxiety disorders or endogenous depression
      exhibit increased activity in their hypothalamo-pituitary-adrenocortical (HPA)
      axis. Recently, two Wistar rat lines, bred for high (HAB) and low (LAB) anxiety
      related behaviour on the elevated plus-maze, were described as a unique
      psychopathological animal model (1). The present study focused on the HPA axis
      reactivity of HAB and LAB animals to an emotional stressor. Thus, adult male HAB
      and LAB animals, fitted with jugular vein catheters 5 days prior to the
      experiment, were exposed to an open arm of the elevated plus-maze for 5 min.
      Whereas basal levels of ACTH and corticosterone were similar in both lines, HAB
      rats showed higher plasma concentrations at 5 and 15 min following stressor
      exposure (both hormones and both time points: P<0.01 vs LAB). Furthermore,
      increased basal (P<0.05 vs LAB) and stimulated (P<0.01 vs LAB) prolactin
      concentrations in HAB rats were found. In contrast to ACTH, corticosterone and
      prolactin, plasma oxytocin and vasopressin levels did not differ between HAB and
      LAB animals; oxytocin, but not vasopressin, responding to open arm exposure with
      a significant increase in both lines (P<0.05). In conclusion, particularly due to
      the association between inborn anxiety and HPA axis hyper-reactivity, the HAB rat
      represents a promising animal model for further investigation of the relationship
      between emotional disturbance and neuroendocrine activity.

PMID- 10336721
TI  - Radioligand assays for oestradiol and progesterone conjugated to protein reveal
      evidence for a common membrane binding site in the medial preoptic area-anterior
      hypothalamus and differential modulation by cholera toxin and GTPgammaS.
AB  - In this study membrane oestradiol (E) binding sites in the medial preoptic area
      anterior hypothalamus (MPOA-AH) of ovariectomized (OVX) rats were characterized
      using standard radioligand binding techniques employing E conjugated to bovine
      serum albumin (BSA) at position 6 and radiolabeled with 125I (E-6-[125I-BSA]). In
      previous studies binding of a radioactive conjugate of progesterone (P) and BSA
      (P-3-[125I-BSA]) was examined using the same membrane preparation. E-6-[125I-BSA]
      binding was linear across a tissue concentration range of 0.005-0.02 mg
      protein/0.1 ml of membrane suspension. An association T1/2 of 9.5 min and a
      dissociation T1/2 of 52.1 min for E-6-[125I-BSA] were derived from kinetic
      experiments. Competition binding experiments revealed high (Ki=0.63+/-(0.50 nM)
      and low (Ki=161.5(96.5 nM) affinity binding sites for E-6-[125I-BSA],
      demonstrating different binding parameters than shown in our previous work for P
      3-[125I-BSA] binding. Further studies on MPOA-AH membranes treated with cholera
      toxin (CTX) and GTPgammaS suggested that E-6-BSA binding sites are associated
      with G proteins. E-6-[125I-BSA] binding demonstrated both high-and low-affinity
      sites. GTPgammaS added to the assay reduced both E-6-[125I-BSA] and P-3-[125I
      BSA] binding suggesting that G proteins are associated with both binding sites.
      Extensive analysis of both E-6-[125I-BSA] and P-3-[125I-BSA] binding sites
      demonstrated a reciprocal relationship such that high-affinity E-6-[125I-BSA]
      binding sites exhibit low affinity for P-3-[125I-BSA] and low-affinity E-6-[125I
      BSA] binding sites exhibit high affinity for P-3-[125I-BSA]. Preincubating
      membranes with CTX or GTPgammaS reduced high-affinity E-6-[125I-BSA] binding and
      enhanced high-affinity P-3-[125I-BSA] binding. These results suggest that, in the
      MPOA-AH, membrane steroid binding sites exist in two interconvertible
      conformations that preferentially bind either E-6-BSA or P-3-BSA, depending on
      their association with a G protein. Additional studies with free steroids
      revealed that: (1) oestrogens (17beta-oestradiol, diethylstilbestrol) as well as
      synthetic oestrogen antagonists tamoxifen and ICI 182 780 displaced P-3-[125I
      BSA] further suggesting a relationship between membrane binding sites for E and P
      3-[125I-BSA] binding sites; and (2) treatment of OVX rats with E decreased
      displacement by P-3-BSA and increased displacement by ICI 182,780 and tamoxifen
      suggesting these antagonists affect membrane P-3-[125I-BSA] binding sites after
      in-vivo E treatment. The membrane binding sites for E and P demonstrate
      interrelationships not demonstrated by their nuclear receptors.

PMID- 10336722
TI  - Isolation and pharmacological characterization of two functional splice variants
      of corticotropin-releasing factor type 2 receptor from Tupaia belangeri.
AB  - From brain, heart and muscle tissue of the tree shrew (Tupaia belangeri), a
      higher order mammal, cDNA clones were isolated that encoded two functional splice
      variants of the corticotropin-releasing factor (CRF) type 2 receptor (CRF-R2).
      The first, full-length splice variant, amplified from brain and heart tissue,
      encoded a CRF receptor protein that is 410 amino acids in length and
      approximately 96% homologous to human CRF-R2alpha. The second, full-length splice
      variant, derived from skeletal muscle tissue, encoded a 437-amino acid CRF
      receptor protein that is approximately 92% homologous to human CRF-R2beta.
      Semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR)
      amplifications and RNase protection analyses, showed that tree shrew CRF-R2alpha
      (tCRF-R2alpha) and tree shrew CRF-R2beta (tCRF-R2beta) were coexpressed in brain
      tissue but not in heart and skeletal muscle tissue. Finally, human embryonic
      kidney 293 (HEK293) cells stably transfected with tCRF-R2alpha and tCRF-R2beta
      were used to demonstrate that the CRF analogs urocortin and sauvagine bind with
      significantly greater affinity (21- to 140-fold) to these two CRF-R2 splice
      variants than do human/rat and ovine CRF analogs. In keeping with these results
      of our CRF binding studies, EC50 values were substantially lower for urocortin
      and sauvagine-stimulated than for h/rCRF-and oCRF-stimulated cyclic AMP
      accumulation in HEK293 cells stably transfected with tCRF-R2alpha or tCRF-R2beta
      cDNAs. The tree shrew therefore constitutes an important animal model in which to
      investigate the role of CRF receptor subtypes in the stress response.

PMID- 10336723
TI  - Adrenomedullectomy prevents the suppression of pulsatile luteinising hormone
      release during fasting in female rats.
AB  - Fasting inhibits the pulsatile secretion of luteinising hormone (LH) in female
      rats, an effect which is potentiated by the presence of oestradiol (E2). We have
      previously described various pharmacological or surgical treatments that can
      rapidly restore the pulses in a fasting animal. Nevertheless, the central and
      peripheral mechanisms that mediate this suppression of the pulses remain unclear.
      We have recently shown that adrenomedullectomy prevents the suppression of LH
      pulses by insulin-induced hypoglycaemia, a state which activates the
      sympathoadrenal axis. The present study was undertaken to establish whether this
      axis might contribute to the loss of the pulses that occurs in ovariectomised E2
      treated rats that have been fasted for 48 h. Following sham adrenomedullectomy LH
      pulses were observed in animals fed ad libitum; after 48 h of fasting the animals
      that had received this sham procedure showed a significant suppression of LH
      levels and LH pulse frequency. In contrast, adrenomedullectomy prevented the
      inhibition of the pulses by 48 h of fasting; it had no effect on the pulses in
      the absence of fasting. These results suggest that adrenomedullary activity plays
      a significant role in the fasting-induced suppression of LH pulses in rats.

PMID- 10336724
TI  - Characterization of the insulin-like growth factor axis in the human thymus.
AB  - The components of the insulin-like growth factor (IGF) axis have been
      investigated in the normal human thymus. Using ribonuclease protection assays
      (RPA), IGF-II transcripts were detected in the normal human thymus. By reverse
      transcriptase polymerase chain reaction (RT-PCR) analyses, promoters P3 and P4
      were found to be active in the transcription of IGF2 gene within human thymic
      epithelial cells (TEC). No IGF-II mRNA could be detected in human lymphoid Jurkat
      T cells with 30 cycles of RT-PCR. By Northern blot analyses, IGFBP-2 to -6 (but
      not IGFBP-1) were found to be expressed in TEC with a predominance of IGFBP-4.
      Interestingly, Jurkat T cells only express IGFBP-2 but at high levels. The type 1
      IGF receptor was detected in Jurkat T cells but not in human TEC. The
      identification of the components of the IGF axis within separate compartments of
      the human thymus adds further evidence for a role of this axis in the control of
      T-cell development. The precise influence of thymic IGF axis upon T-cell
      differentiation and immunological self-tolerance however needs to be further
      investigated.

PMID- 10336725
TI  - Sex differences in the parental behaviour of adult virgin prairie voles:
      independence from gonadal hormones and vasopressin.
AB  - Sexually and parentally experienced prairie voles display robust biparental care
      of pups that is similar between the sexes. Little is known, however, about
      possible sex differences in the parental behaviours of sexually inexperienced
      prairie voles. Parental behaviour of adult virgin male and female prairie voles
      was examined in sham-operated and gonadectomized subjects treated with vehicle or
      oestradiol. Since arginine-vasopressin (AVP) has been suggested to stimulate
      parental behaviour in sexually inexperienced males, neural AVP immunoreactivity
      (AVP IR) was quantified. Most sham-operated and castrated males displayed high
      levels of parental behaviour (9/9 controls, 6/9 castrates) during a 15-min
      exposure to pups 4 weeks after surgery, and few behavioural differences were seen
      between groups. Conversely, almost all gonadally intact (8/9) and gonadectomized
      (8/9) females attacked pups. Implantation of a 0.1-mg pellet of oestradiol
      immediately after gonadectomy had little effect on males (9/9 parental), whereas
      most (5/9) oestradiol-treated females acted maternally. AVP-immunoreactive (AVP
      ir) fibre density in the lateral septum (LS) and lateral habenula (LHb),
      expressed by the number of pixels that covered AVP-ir fibres during computerized
      optical density analysis, was greater in males than females, was non
      significantly reduced in castrated males, and doubled in the LS of oestradiol
      treated females. In a second experiment, males tested 8 weeks after similar
      manipulations remained highly parental though castrated males had almost no AVP
      ir fibres in the LS and LHb. Levels of AVP IR in males treated with oestradiol
      were similar to those observed in intact males. A dramatic sex difference
      therefore exists in the parental behaviour of adult sexually naive prairie voles
      which cannot be explained by sex differences in gonadal hormones. Because both
      castrated and intact males were highly parental, even though castrates had
      virtually no AVP-ir in the LS or LHb, AVP does not appear to be crucial for their
      responsiveness toward pups.

PMID- 10336726
TI  - Thyrotropin-releasing hormone stimulates nitric oxide release from GH3 cells.
AB  - Constitutive nitric oxide synthase (NOS) is expressed in the rat adenohypophysis
      but the mechanisms regulating its activity at the cellular level remain to be
      elucidated. The effect of TRH on nitric oxide release from GH3 cells was studied
      by means of reverse-phase HPLC to measure NO-2 and NO-3 concentrations in the
      incubation medium, and by polarography using electrodes specific for NO. Medium
      NO-2 concentrations in the incubation medium were dependent on the incubation
      time, and were further increased by sodium nitroprusside (SNP) or high potassium.
      NO-3 was detectable only in the presence of 100 microM SNP. Addition of L
      arginine increased medium NO-2 concentrations. Diamino-hydroxypyrimidine
      decreased medium NO-2 concentrations, which were restored by the addition of (6R)
      5, 6, 7, 8-tetrahydro-L-biopterin (THB). TRH elicited dose-related increases in
      medium NO-2 concentrations and in nitric oxide-specific currents, which were
      abolished by Nomega-nitro-L-arginine methyl ester. TRH failed to increase medium
      NO-2 concentrations in cells loaded with an intracellular Ca2+-chelating agent.
      The findings suggest that mobilization of intracellular Ca2+ by TRH stimulation
      activates Ca2+-dependent NOS in GH3 cells.

PMID- 10336727
TI  - Characterization of 17beta-hydroxysteroid dehydrogenase activity in brain tissue:
      testosterone formation in the human temporal lobe.
AB  - Sex steroids exert important effects on the central nervous system (CNS).
      Although the formation of 17beta-hydroxysteroid dehydrogenase (17beta-HSD)
      metabolites in the CNS was discovered almost 30 years ago, conclusive studies
      concerning 17beta-HSD activity in the human brain are still lacking. Therefore,
      we investigated 17beta-HSD in vitro activity in human temporal lobe biopsies of
      13 women and 13 men using radioactively labelled androstenedione, testosterone,
      oestrone and 17beta-oestradiol and compared it to that in human placenta, liver,
      testis and prostate. We could demonstrate androgenic and oestrogenic 17beta-HSD
      activities in all tissues under investigation. The reduction of androstenedione
      and oestrone in brain was NADPH dependent with a broad pH optimum between 6.5 and
      9.0, whereas the oxidation of testosterone and 17beta-oestradiol was NAD
      dependent with a pH optimum of >/=9.0. Using optimum cofactors sex differences of
      brain 17beta-HSD activities were not observed. Conversion of androstenedione,
      testosterone, oestrone and 17beta-oestradiol was significantly higher in the
      subcortical white matter than in the cerebral cortex. We could demonstrate a
      significant formation of testosterone in the brain tissue of all patients under
      investigation. Substrate specificity and cofactor requirement patterns as well as
      pH optima and kinetic properties suggest the occurrence of 17beta-HSD type 3 and
      type 4 in the human temporal lobe.

PMID- 10336728
TI  - Acute and long-term treatments with the selective serotonin reuptake inhibitor
      citalopram modulate the HPA axis activity at different levels in male rats.
AB  - It is well established that the maximal therapeutic effect of selective serotonin
      reuptake inhibitors (SSRI) are achieved in depressive patients after several
      weeks of treatment, but the adaptive processes leading to the therapeutic effects
      are unclear. It has been shown that hyperactivity in the hypothalamic-pituitary
      adrenal (HPA) axis in depressive patients is affected by long-term antidepressant
      treatment. These changes occur in association with the mood normalising effect,
      suggesting that antidepressants affect the HPA axis and this effect is associated
      with the therapeutic effect. Male Wistar rats were treated with the SSRI,
      citalopram, to investigate time-related changes in components that may be
      involved in the desensitization of the HPA axis. A single injection of citalopram
      (10 mg/kg, s.c.), increased the plasma levels of ACTH and corticosterone in a
      dose-dependent manner and increased the number of c-Fos containing cells in the
      hypothalamic paraventricular nucleus. A daily treatment with the same compound
      (10 mg/kg, s.c.) for 14 days decreased the expression of POMC mRNA (
      approximately 40%). In addition, a blunted response to citalopram was observed in
      animals long-term treated with citalopram. Also CRF-stimulated cAMP accumulation
      in the pituitary was altered. In conclusion, acute citalopram activated the HPA
      axis at the hypothalamic level and long-term citalopram treatment desensitized
      the HPA-axis at the pituitary level. These results support the hypothesis that
      the therapeutic effects of long-term antidepressant treatments reduce HPA axis
      responsiveness.

PMID- 10336730
TI  - Editorial.

PMID- 10336729
TI  - Effects of growth hormone-releasing peptide-6 on the nocturnal secretion of GH,
      ACTH and cortisol and on the sleep EEG in man: role of routes of administration.
AB  - After repeated intravenous (i.v.) boluses of growth hormone-releasing peptide-6
      (GHRP-6) we found recently increases of growth hormone (GH), corticotropin (ACTH)
      and cortisol levels and of the amount of stage 2 sleep. In clinical use, oral
      (p.o.), intranasal (i.n.) and sublingual (s.l.) routes of administration have
      advantages over i.v. administration. We compared the sleep-endocrine effects of
      300 microg/kg of body weight (b.w.) GHRP-6 in enteric-coated capsules given p.o.
      at 21.00 h and of 30 microg/kg GHRP-6 i.n. or 30 microg/kg GHRP-6 sl. given at
      22.45 h in normal young male controls with placebo conditions. After GHRP-6 p.o.
      secretion of GH, ACTH and cortisol remained unchanged. The only effect of GHRP-6
      s.l. was a trend toward an increase in GH in the first half of the night. GHRP-6
      i.n. prompted a significant increase in GH concentration during the total night
      and a trend toward an increase in ACTH secretion during the first half of the
      night, whereas cortisol secretion remained unchanged. Furthermore, after GHRP-6
      i.n., sleep stage 2 increased in the second half of the night by trend, and
      spectral analysis of total night non-rapid eye movement (REM) sleep revealed a
      decrease of delta power by trend. In contrast sleep stage 2 decreased during the
      second half of the night after GHRP-6 p.o. Our data demonstrate that GHRP-6 is
      capable of modulating GH and ACTH secretion as well as sleep. However, the
      effects depend upon dosage, duration and route of administration.

PMID- 10336731
TI  - Spiritual high vs high on spirits: is religiosity related to adolescent alcohol
      and drug abuse?
AB  - This study investigated relationships between alcohol and drug abuse by
      adolescents and frequency of religious service attendance in the south-east
      United States. Data obtained from surveys of 217 adolescents, age 12-19 years,
      was analysed. The adolescents included participants from both clinical and non
      clinical settings. Results from both groups showed that, as attendance at
      religious services increased, alcohol and drug abuse decreased. Spirituality is a
      concept that warrants further study to determine if its inclusion in treatment
      programs could enhance recovery or drastically reduce recidivism.

PMID- 10336732
TI  - The process of constant observation: perspectives of staff and suicidal patients.
AB  - This ethnographic study explores the perceptions of staff regarding the nursing
      activity of constant observation of the suicidal patient in mental health
      settings. Unusually, the paper also addresses the perceptions of the patients
      themselves, and compares the two. Two major categories of nursing interventions,
      Therapeutic and Controlling, were identified by both groups of respondents.
      However, although there was a degree of commonality between the groups'
      descriptions of subcategories, there are also interesting anomalies. Patients did
      not perceive some actions at all, one action was not perceived by staff, and one
      action was perceived to be in different categories by the two groups. Such
      differences are discussed, and implications explored.

PMID- 10336733
TI  - Triumvirate nursing for personality disordered patients: crossing the boundaries
      safely.
AB  - As the issue of the treatment and effective management of personality disordered
      patients comes under close scrutiny in the wake of the Fallon Inquiry, we offer a
      brief overview of the nature of the challenges involved in nursing this difficult
      group of patients. Traditional methods of setting limits and defining boundaries
      are no longer convincing amidst the allegations of multidisciplinary staff being
      culpable, at one level or another, for their contribution in this tragic inquiry.
      In this paper we offer a strategic mechanism of constructing nursing care for
      this difficult group of patients and provide a framework for crossing boundaries
      safely through a multidisciplinary framework. We term this triumvirate nursing.
      Nursing management of those patients considered to have personality disorders is
      traditionally very difficult. This difficulty, in part, stems from the inability
      of nurses to strategically develop therapeutic relationships in a safe manner.
      Crossing boundaries is a necessary part of therapeutic exploration and
      relationship building; triumvirate nursing offers a safe mechanism for
      undertaking this. Creative thinking is a necessary part of the future development
      of the nursing management of these disorders.

PMID- 10336734
TI  - Expert practice: the interventions used by a community mental health nurse with
      carers of dementia sufferers.
AB  - The role of the Community Mental Health Nurse working with carers of dementia
      sufferers is investigated using a case study approach. Ten specific themes
      (socializing, assessing, coping strategies, advice, family dynamics, liaison,
      education, counselling, crisis intervention and loving) are identified and
      discussed. Links are drawn between theory and practice and suggestions for future
      research are made.

PMID- 10336735
TI  - Therapeutic communication strategies used by Hong Kong mental health nurses with
      their Chinese clients.
AB  - Therapeutic communication is central to mental health nursing and through this
      process nurse-client relationships can be enhanced. In Hong Kong, mental health
      nurses are educated in 'western' theories and strategies in using therapeutic
      communication and the field of communication is predominantly Eurocentric.
      However, the majority of people in Hong Kong are Chinese and little research has
      been conducted into how Hong Kong nurses communicate with their Chinese clients.
      This qualitative study focused on identifying the therapeutic communication
      strategies used by mental health nurses with Chinese clients in Hong Kong. Three
      case study vignettes with some of the characteristics of Chinese culture were
      developed to elicit information about the strategies that respondents used in
      therapeutic communication. The purposive sample of 20 comprised 10 admission ward
      nurses and 10 community nurses from two psychiatric hospitals. All participants
      had at least five years post-registration experience. Content analysis revealed
      categories of communication and theme clusters for the nurses' response to the
      vignettes. The result showed a unique cultural influence emerged in communication
      patterns. In view of the scant nature of existing literature and studies in this
      area, this research provided some valuable data for further studies. Implications
      for mental health nursing education and practice in Hong Kong are raised, as are
      implications for nurses working in multicultural countries such as Australia, the
      UK and the USA, where there are significant numbers of Chinese clients who would
      benefit from nurses practising with a deeper understanding of communication
      strategies which are culturally bound.

PMID- 10336736
TI  - Compulsory community treatment: ethical considerations.
AB  - Compulsory community treatment (CCT) of people with serious mental health
      problems is analysed using the bioethical principles of autonomy and beneficence.
      Feminist ethical theory is then used to clarify these principles as they relate
      to community commitment of the severely and persistently mentally ill. Finally, a
      model of practice is proposed as an alternative to CCT in which both autonomy and
      beneficence are better served.

PMID- 10336737
TI  - The development and evaluation of a brief risk screening instrument for the
      psychiatric inpatient setting.
AB  - This paper reports on the development and evaluation of a risk screening
      instrument (RSI) intended for use by nursing staff on general acute psychiatric
      admission wards. The RSI comprised six questions concerning patient status on
      admission (e.g. sex, legal status, employment) and 11 items of judgement
      concerning the presentation of the patient (e.g. threatening behaviour,
      suicidality, family and social support). The interrater reliability of the RSI
      was calculated to be 85% overall. The predictive value of the RSI was not
      confirmed when tested against harmful incidents subsequent to admission. However,
      the mean RSI score of that group of patients involved in harmful incidents tended
      to be higher than that group of patients not involved in such incidents, and all
      such incidents were found to occur within eight days of admission. Analysis of
      other data collected in the course of the study revealed discrete patient groups
      and provided systematic insights into their characteristics, which are
      potentially valuable when considering the nursing skills required on acute
      psychiatric inpatient units. It is concluded that the RSI tested has the
      potential to contribute to the assessment and management of risk within the acute
      psychiatric inpatient setting, by augmenting and guiding clinical judgement.

PMID- 10336738
TI  - Discourses on empowerment.
AB  - The discourse community of British psychiatric and mental health nursing is a
      contested realm. The 'Big Stories' of policy and planning of services are clearly
      articulated in disputes in journals, but the 'Little Stories' of nurses' work and
      patients' or users' experiences may be ignored or under-valued. This paper
      illustrates how the Big Story of a central theme in current policy--empowerment-
      is articulated in the realm of research funding and design, and how it is
      articulated by practitioners. The paper focuses attention on the responsibilities
      faced by researchers, in relating the Little Stories of practice and the Big
      Story of policy. It reports early and tentative findings from a study of
      community psychiatric nurses' empowerment of people with enduring mental
      disorders. The paper suggests ways in which strategies for analysis of
      qualitative data from interviews with CPNs may be informed by ideas drawn from
      the field of discourse analysis; reflexively examining how researchers'
      discourses relate to those of policy makers and mental health nursing
      practitioners. This paper is based on a presentation at the Network for
      Psychiatric Nursing Research Conference, Napier University, Edinburgh, 17
      September 1997.

PMID- 10336739
TI  - Maintaining health: proactive client-oriented community day treatment centres for
      the chronic mentally ill.
AB  - This grounded theory study compared the definition of health by clients of two
      rural mental health day treatment centres, Big Sky Centre and Montana Centre.
      Based on an original grounded theory study of seven chronic mentally ill/disabled
      clients in Big Sky Centre (Yurkovich et al. 1997), the core variable, 'preventing
      loss of control' and related properties, were validated with nine residents of
      Montana Centre. While establishing a 'fit' with previous research findings,
      differences emerged between these two centres. These differences related to the
      staffs' philosophical approaches in providing treatment to the chronic mentally
      ill. Big Sky Centre care providers empowered their clients to learn new
      behaviours from their peers and assume new roles such as newcomer, member and
      leader. They also encouraged a prosocial attitude, and created a sense of
      belonging through valued involvement in their treatment. Montana Centre clients
      were not empowered to try out new behaviours in the treatment environment, or
      seek social support networks among their peers at the centre, which would foster
      a sense of belonging. The result was that clients from Montana Centre relied on
      the formal healthcare system more often than clients from the Big Sky Centre. The
      competing forces in healthcare today--family members, mental health providers,
      and insurance or managed care providers--make it easy to lose sight of or fail to
      gain the client's perspective about their health status and maintenance,
      particularly as it concerns day treatment centres. The importance of the day
      treatment centre as a therapeutic community which requires educational processes,
      innovative nursing practice, and client-centred interventions will be discussed.

PMID- 10336740
TI  - Quality of life for people with severe and enduring mental illness in the
      community: the issue of activity.

PMID- 10336751
TI  - In this issue ellipsis

PMID- 10336752
TI  - Learning by example.

PMID- 10336753
TI  - Motivation for medical school: the relationship to gender and specialty
      preferences in a nationwide sample.
AB  - OBJECTIVES: Motivation for going to medical school and career plans of a 1 year
      cohort of students entering medical school in Norway (n = 420 response rate: 90%,
      54% women, mean age: 22 years) were surveyed by a postal questionnaire the first
      month after they had started. DESIGN: Motives for choosing medicine were
      categorized into three indexes: 'people orientated', 'status/security orientated'
      and 'natural science orientated' motives. SETTING: University of Oslo. SUBJECTS:
      Medical students. RESULTS: Students picked out which they preferred among 53
      specialties. The highest motivational scores were on the 'person orientated'
      index, female students scoring higher than men. Female students were, however,
      nearly as highly motivated by status/security and interests in natural science as
      were men. 'Person orientated' and 'natural science orientated' motives exerted
      the strongest influence on specialty preferences. Those who preferred family
      medicine were more person orientated and less natural science orientated, while
      those who preferred internal medicine were more natural science orientated.
      Father being a physician did not influence the motivational pattern, but
      increased the preference for laboratory and internal medicine. Frequently
      repeated upper secondary school exams for acceptance into medical school were
      negatively related to natural science motivation, and to increased preference for
      becoming a surgeon. CONCLUSIONS: In this first month of the curriculum students
      regarded person oriented motives as the most important for becoming a doctor.

PMID- 10336754
TI  - A prospective analysis of stress and academic performance in the first two years
      of medical school.
AB  - AIM: This study provides prospective, longitudinal data on the relationship
      between stress-related measures and academic performance during the first two
      years of medical school. METHODS: First year medical students (n = 121) were
      surveyed prior to beginning classes (wave 1), and again 8 months later (wave 2).
      Personality variables predisposing to distress (optimism and trait anxiety),
      stress response (depression and state anxiety), and stress management strategies
      were assessed at wave 1 and wave 2. Pre-medical academic scores, and grades at
      the end of five assessment periods over the course of the first 2 years of
      medical school were also obtained. RESULTS AND CONCLUSIONS: As expected, pre
      medical-school academic performance strongly predicted performance in medical
      school. Academic performance before and during medical school was negatively
      related to reported stress levels. On bivariate correlations, there were numerous
      significant relationships between stress reported at waves 1 and 2, and medical
      school academic performance assessed after these measures. In addition there were
      modest negative correlations between self-reported coping strategies of 'humour'
      and 'wishful thinking', and consequent academic performance. However, the
      predictive value of stress and its management on prospective academic performance
      was much decreased once pre-medical-school performance was statistically
      controlled.

PMID- 10336755
TI  - Factors associated with success or failure in radiological interpretation:
      diagnostic thinking approaches.
AB  - RATIONALE AND OBJECTIVES: To identify those radiological diagnostic thinking
      approaches associated with success or failure in film interpretation. METHODS: A
      questionnaire was designed, piloted and tested for validity and reliability prior
      to use. This questionnaire was adapted and modified from the 'diagnostic thinking
      inventory' by Bordage et al. 21 One hundred and eighty students anonymously
      answered the questionnaire prior to their 15-case comprehensive film
      interpretation examination. Oral film-reading sessions were performed on a
      stratified random sample (n = 48) of students with complete transcripts of each
      session recorded. Spearman's correlation coefficient and multiple regression
      analysis statistics were applied to the questionnaire data. The unpaired t-test,
      ANOVA and correlation statistics were used to analyse the oral film-reading
      sessions. RESULTS: The most successful students were those who could easily see
      the integration of radiology with other subjects (P = 0.0042), students who could
      easily link the clinical information to the radiographic signs (P = 0.0354), and
      students who could easily identify the 'key' abnormal radiographic findings (P =
      0.047). Students who used a flexible but complete search pattern performed
      significantly better (P = 0.0235) than students using any other search pattern
      approach. CONCLUSIONS: Radiology is a classic example of clinical problem solving
      and thus should be taught in that format. Those same factors which differentiate
      expert from novice diagnosticians are also evident in more successful vs. less
      successful students in radiology.

PMID- 10336756
TI  - The development and evaluation of a personal learning log for senior house
      officers.
AB  - OBJECT: To develop and evaluate the effect of having a personal learning log on
      Senior House Officers knowledge and confidence. METHODS: A multiple choice paper
      and a confidence checklist for two hospital specialties were developed to assess
      knowledge and confidence. These were administered to a control group and to an
      intervention group who had the learning log. Both groups completed an evaluation
      at the end of the post. SETTING: The study took place in Accident & Emergency and
      Obstetric & Gynaecology posts in Greater Glasgow and Lanarkshire. SUBJECTS: 79
      Senior House Officers in Accident & Emergency and 78 Senior House Officers in
      Obstetrics & Gynaecology. RESULTS: The mean scores in the MCQ and the mode in the
      confidence checklist increased significantly in both specialties during the post,
      but there was no significant difference between the control and intervention
      groups. Forty two learning logs were returned at the end of the study and
      analysis of these revealed that there was great scope for learning but few
      documented the specific learning achieved. Evaluation of the posts revealed that
      some improvements had taken place in teaching and assessment frequency, however,
      there was scope for further improvement. CONCLUSION: While the problems of
      hospital training are well documented, an attempt to improve the situation using
      a learning log did not have a statistically significant impact on SHO knowledge
      or confidence. A six-month hospital post appears to present many opportunities
      for learning but these are not exploited. It is suggested that three things are
      needed. Firstly, active participation by and personalized feedback from a senior
      member of staff, with training where needed. Secondly, protected time for
      tutorials with a planned system of formative assessment, and thirdly, a more
      positive approach to learning by both SHOs and consultants. Once this occurs, a
      learning log may have a more significant impact on training.

PMID- 10336757
TI  - The effect of a 'don't know' option on test scores: number-right and formula
      scoring compared.
AB  - OBJECTIVES: In multiple-choice tests using a 'don't-know' option the number of
      correct minus incorrect answers was used as the test score (formula scoring) in
      order to reduce the measurement error resulting from random guessing. In the
      literature diverging results are reported when comparing formula scoring and
      number-right scoring, the scoring method without the don't-know option. DESIGN:
      To investigate which method was most appropriate, both scoring methods were used
      in true-false tests (block tests) taken at the end of a second- and third-year
      educational module (block). The students were asked to answer each item initially
      by choosing from the response options true, false or don't know, and secondly to
      replace all don't-know answers by a true-false answer. SETTING: Maastricht
      University, The Netherlands. SUBJECTS: Medical students. RESULTS: The correct
      scores for the don't-know answered items were found to be 4.5% and 5.9%,
      respectively, higher than expected with pure random guesswork. This represents a
      source of bias with formula scoring, because students who were less willing to
      guess obtained lower scores. The average difference in the correct minus
      incorrect score for the two scoring methods (2.5%, P < 0.001, and 3.4%, P < 0.
      001, respectively) indicates the size of the bias (compare: the standard
      deviation of the score equals 11%). Test reliability was higher with formula
      scoring (0.72 vs. 0.66 and 0.74 vs. 0.66), but the difference decreased when the
      test was restricted to items which were close to the core content of the block
      (0.81 vs. 0.77, resp. 0. 75 vs. 0.70). CONCLUSIONS: In deciding what scoring
      method to use, less bias (number-right scoring) has to be weighed against higher
      reliability (formula scoring). Apart from these psychometric reasons educational
      factors must be considered.

PMID- 10336758
TI  - Evaluating assessment: the missing link?
AB  - BACKGROUND: Methods chosen for assessment and the manner in which they are
      applied are so intimately associated with how individuals learn that developing
      appropriate assessment strategies is a key part of effective curriculum
      development. THE ASSESSMENT CYCLE: We describe a four-stage assessment cycle
      identifying important steps in assessment. Each step is described in detail,
      stressing its key aspects, including: the need for clear assessment policy and
      strategy, the importance of assessment blueprints in planning assessment, the
      need for effective feedback when presenting results, and the essential, but often
      overlooked, need to evaluate the assessment process itself. EVALUATING
      ASSESSMENT: This final evaluation stage is the most important part of the
      assessment cycle and can be divided into four levels. The first level includes
      evaluating each question in the assessment, the second level is concerned with
      establishing validity and reliability, the third level centres on the assessment
      process and review of assessments by external examiners and the fourth level
      involves evaluation over several assessments. RELATING ASSESSMENT TO THE
      CURRICULUM: This long-term evaluation should examine whether existing assessments
      are congruent with the curriculum and relate to all facets of the students'
      learning experiences. This is particularly important in a curriculum where the
      learning outcomes of student-centred learning are emphasized. Changes in the
      assessment of postgraduate trainees and increasing emphasis on peer review of
      clinicians will raise the profile of these outcomes in undergraduate education.

PMID- 10336759
TI  - Approaches to experiential learning, course delivery and validation in medicine.
      A background document.
AB  - Educational models and approaches change over time in their dominance and use,
      offering a wide selection to educational planners and teachers. This paper
      discusses aspects of experiential learning, distance learning, learning
      contracts, portfolios, reflection, appraisal, assessment and validation of
      education. It offers triggers to further thought and enables the analysis of
      current educational practice.

PMID- 10336760
TI  - Development and integration of CAL: a case study in medicine.
AB  - CONTEXT: The Faculty of Medicine and Medical Sciences at the University of
      Aberdeen viewed the use of Computer Assisted Leaning (CAL) and other IT based
      learning resources as a possible way of coping with an increase in student
      numbers whilst maintaining or increasing the quality of medical teaching.
      OBJECTIVES: Our primary objective was to develop and integrate Computer Assisted
      Learning (CAL) applications into the undergraduate medical curriculum.
      SUBJECTS/MATERIALS: A wide spectrum of CAL applications were developed dealing
      with many topics in the curriculum. METHODS: We formulated a structured approach
      to CAL development by establishing a team of professionals (forming a CAL Unit),
      using existing expertise and by implementing a process to ensure that the CAL had
      a maximum impact upon the curriculum. The CAL included multimedia tutorials,
      learning guides, computer aided assessment (CAA) and Model Patients. RESULTS:
      There are now over 150 IT based learning resources in our curriculum and course
      evaluation has showed that these have been well received by students.
      CONCLUSIONS: We conclude that with the wise use of the many skills and facilities
      usually available within an institution and by promoting collaborative projects
      with others, the production of high quality CAL is possible within most
      institutions.

PMID- 10336762
TI  - In this issueellipsis

PMID- 10336763
TI  - George E miller, MD, 1919-98

PMID- 10336761
TI  - ASME/NACT meeting, 4 december 1998 making career choices - based on evidence.

PMID- 10336764
TI  - Is it time for a community-based medical school in the UK?

PMID- 10336765
TI  - Careers in academic medicine: can they survive structured specialist training?

PMID- 10336766
TI  - Junior doctors' views about careers in academic medicine.
AB  - OBJECTIVE: To investigate junior doctors' views about careers in academic
      medicine. DESIGN: Postal questionnaire survey. SETTING: National Health Service
      in England. SUBJECTS: Doctors in university posts at specialist registrar level,
      Medical Research Council and Wellcome Trust training fellows, and specialist
      registrars in National Health Service posts. RESULTS: Incentives to pursue an
      academic career which respondents rated as strong related to the challenge of
      research and the intellectual environment of research units. The strongest
      disincentives were perceived difficulties in obtaining research grants and
      uncertainty regarding pay parity with National Health Service colleagues. Medical
      Research Council and Wellcome fellows had much more protected research time than
      other academic doctors but were less satisfied with their clinical training.
      Academic doctors who were not fellows reported spending less than half their time
      on research and the great majority agreed that their research suffers when there
      is pressure on the service side. CONCLUSIONS: The job content of academic posts
      should be kept under regular review to ensure that clinical service pressures do
      not inappropriately erode research time while also ensuring that postholders have
      adequate clinical training. Training programmes need flexibility to accommodate
      the needs of clinical academics in their progress through higher specialist
      training.

PMID- 10336767
TI  - Attitudes to recertification measured over time using a validated semantic
      differential scale.
AB  - OBJECTIVES: This study was designed to measure the acceptability of the Royal New
      Zealand College of GPs' Recertification programme to the GPs in the programme.
      DESIGN: Questionnaire study of a stratified random sample of members of the
      RNZCGP. METHOD: A semantic differential attitude scale was developed and
      validated. The scale was administered to 300 GPs before the Recertification
      programme began and repeated with 100 of these GPs 18 months later. After 3 years
      of the programme the questionnaire was administered to the original 300 GPs.
      RESULTS: Baseline data showed reasonable acceptance of the concept of
      recertification but by 18 months there was a significant deterioration in the way
      the programme was perceived and this did not change over 3 years. Many GPs were
      not convinced of the value of the programme.

PMID- 10336768
TI  - Variation in medical students' approaches to diagnosis: a basis for initiating
      conceptual change among teachers and students.
AB  - OBJECTIVES: This study examines Finnish medical students' approaches to diagnosis
      and investigates further how medical teachers can use information about variation
      in their students' approaches to diagnosis to foster teaching in medical school.
      DESIGN: The medical students responded to the Conceptions and Experiences of
      Diagnosis Inventory (CEDI). SETTING: Faculty of Medicine, University of Helsinki.
      SUBJECTS: Ninety medical students in their clinical years and eight clinical
      teachers from the same Faculty of Medicine. RESULTS: The 11 subscales of the CEDI
      formed two contrasting factors: the first reflecting variation in 'non
      virtuously' labelled, and the second in 'virtuously' labelled, aspects of
      diagnosis. CONCLUSIONS: Cluster analyses revealed subgroup characteristics of
      students' diagnostic processes that are of potential benefit to both students and
      teachers. Teacher interviews indicated that, for students, the CEDI may act as a
      self-assessment tool to help develop their diagnostic and metacognitive skills.
      For teachers, the CEDI was seen to offer important information about their
      students' conceptions of diagnosis and diagnostic skills.

PMID- 10336769
TI  - Gender comparisons of medical students' psychosocial profiles.
AB  - OBJECTIVES: This study was designed to compare male and female medical students
      on selected personality attributes that could influence their academic attainment
      and personal success. DESIGN: Participants were 1157 medical students (743 men,
      414 women) who completed a set of psychosocial questionnaires measuring intensity
      and chronicity of loneliness, general anxiety, test anxiety, neuroticism,
      depression, extraversion, self-esteem, locus of control, perceptions of parents,
      general health and appraisals of stressful life events. Data were analysed by
      employing multivariate and univariate analysis of variance and chi-square
      analysis. SETTING: Jefferson Medical College. SUBJECTS: Medical students.
      RESULTS: Men scored significantly higher on the intensity of loneliness, and
      women scored higher on general anxiety, test anxiety and neuroticism scales, but
      the magnitudes of the effect size estimates were not large. No significant gender
      difference was observed on measures of chronicity of loneliness, depression,
      extraversion, self-esteem, external locus of control, perception of general
      health and perceptions of the mother and the father. Women who experienced
      stressful life events, such as death in the family or personal illness, appraised
      these events more negatively than did their male counterparts. CONCLUSIONS:
      Implications of the findings for medical education and practice are discussed.

PMID- 10336770
TI  - Service increment for teaching (SIFT): a review of its origins, development and
      current role in supporting undergraduate medical education in England and Wales.
AB  - OBJECTIVES: To describe the ways in which total resources available for the
      Service Increment for Teaching (SIFT) have been determined and related to numbers
      of undergraduate medical students; and the development and current arrangements
      for allocating SIFT to the providers of service support for teaching. DESIGN: The
      derivation of SIFT from excess costs of teaching hospitals over general hospitals
      is described. The official principles of organizing SIFT to reimburse the service
      costs of teaching undergraduate medical students are explained. The crucial
      development that is examined is the change from SIFT being a global subsidy to
      being related to educational contracts. This development has facilitated both the
      specification of standards and innovative uses of SIFT. These are illustrated
      with examples. SETTING: Hospital and Community Health Services and Primary Care
      in the National Health Service (NHS) in England and Wales. SUBJECTS: Medical
      students. RESULTS: There is often confusion caused by SIFT being intended to
      cover the service costs of teaching but not having been derived in this way. This
      causes problems in deciding what providers should be paid through contracts for
      teaching of different kinds. CONCLUSIONS: The new contractual basis has enabled
      medical schools to use contracts to improve the clinical teaching of
      undergraduate medical students in the NHS. These developments may offer useful
      models for other countries.

PMID- 10336771
TI  - The relation between understanding and practice in problem-based medical
      education.
AB  - The importance of conceptions of the soundness of medical education are
      considered briefly. This leads to the question of misconceptions. A pervasive
      misconception characterized by the separation of understanding from action and
      practice, illustrated by two examples from the literature on medical education,
      is discussed. Questions as to the soundness of medical education are usually
      approached in terms of empirical inquiry; this paper takes a different,
      complementary, approach. Five medical faculties in Australia, Sweden and the UK.
      Problem-based medical course staff and students. The practical effect of the
      separation between action and practice is illustrated in the question of problem
      solving as conceived in transitional semiproblem-based curricula in common with
      traditional curricula, limiting the development of sound professional education.
      The centrality of the misconception generates a widespread approach to the
      curriculum, described as the 'Convenient peg' model. In contrast, the 'Growing
      web' model enables the design of rigorous problem-based curricula which
      acknowledge that action and practice are necessarily related to understanding in
      a way unrecognized in the 'Convenient peg' model. Consequently, rigorous problem
      based curricula embody a thoroughly integrated curriculum enabling improved
      medical education.

PMID- 10336772
TI  - The WISDOM project: training primary care professionals in informatics in a
      collaborative 'virtual classroom'.
AB  - OBJECTIVES: The WISDOM project applies Internet technologies to create a virtual
      classroom in health informatics for primary care professionals. Participants use
      a facilitated E-mail discussion list supported by a web site which provides on
      line resources and an archive of teaching materials. DESIGN: The project took an
      adult-learning model in which participants identify their learning needs,
      emphasized using informatics skills in practice, and focused on skills likely to
      enhance evidence-based practice. The paper describes the project and an
      evaluation of the first programme which ran in 1997 with 28 participants. Pre-
      and post-intervention questionnaires were used to assess perceived skills in
      informatics and evidence-based practice. SETTING: University of Sheffield.
      SUBJECTS: Primary care professionals. RESULTS: Participants reported
      statistically significant increases in eight informatics skills. There were no
      significant changes in evidence-based practice skills. The web-site, seminar
      programme and discussion list were highly rated as useful in delivering
      informatics training. CONCLUSIONS: The WISDOM approach is effective for the
      delivery of informatics training to primary care professionals, and may be used
      more widely for other subjects and professional groups. There is a need for
      further research into facilitating virtual classrooms.

PMID- 10336773
TI  - Does formal approval of educational courses guarantee quality?
AB  - OBJECTIVES: To assess whether organizers of continuing medical education for
      general practitioners used principles of adult learning when designing their
      meetings. DESIGN: A questionnaire study of organizers of approved educational
      meetings for general medical practitioners (GPs). SETTING: South East Scotland.
      SUBJECTS: Organizers of educational meetings. RESULTS: Organizers often failed to
      use principles of adult learning in the construction of their meetings.
      Organizers with prior training in medical education were, however, significantly
      more likely to adopt these principles. CONCLUSIONS: Given concern about the
      quality of educational meetings as assessed by their educational impact, formal
      approval is not an indicator of quality. Postgraduate bodies should use explicit
      criteria both in the development and approval of continuing educational meetings.

PMID- 10336775
TI  - Establishing community-orientated medical schools: key issues and steps in early
      planning.
AB  - OBJECTIVES: To describe briefly the process of early planning and establishment
      of community-based medical schools with highlights of the key issues and
      milestones. DESIGN: After outlining some basic concerns and provisos for the Dean
      and suggested strategies for setting the stage (preparing the ground) for the
      innovation, three phases of early planning and action steps within each are
      listed to serve as a guide and a general checklist. SETTING: University of
      Gezira, Sudan and UAE University, AL-Ain. CONCLUSION: As the curriculum with its
      implications constitutes the driving force for establishing the schools, it has
      been given due emphasis and greater share in planning. The communication is
      concluded with further advice to founding Deans through the proposition of a five
      star Dean.

PMID- 10336774
TI  - Use of learning contracts in an office-based primary care clerkship.
AB  - OBJECTIVES: This paper describes implementation of the learner-centred learning
      goal within the primary care clerkship at a Midwestern, United States medical
      school. DESIGN: The learner-centred learning goal exercise was developed to
      tailor students' educational activities to their personal level of development
      and to enhance their commitment to life-long learning in medicine. In the learner
      centred learning goal exercise, each student records three specific learning
      goals early in the primary care clerkship. Students record the methods by which
      they will pursue and document achievement of each goal. Attainment of the learner
      centred learning goal is evaluated based on an oral presentation at the end of
      the clerkship. We compiled presented learning goals along with the corresponding
      grade. Students' ratings of the learner-centred learning goal exercise were also
      compiled. Evaluations and ratings were made on a 1-5 Likert scale, where 1 is the
      best rating and 5 is worst. SETTING: Department of Medicine, Northwestern
      University Medical School, Chicago, USA. SUBJECTS: One hundred and seventy-seven
      third- and fourth-year medical students who presented learner-centred learning
      goals between 1 July 1995 and 30 June 1996. RESULTS: Students rated pursuing
      their individual learning goals more worthwhile than most clerkship lectures but
      less worthwhile than the office experience. Several learning goals were chosen by
      a disproportionate number of students, potentially indicative of some perceived
      deficiencies elsewhere in the curriculum. Third-year students ranked the learner
      centred learning goal exercise more favourably than fourth-year students (2.14
      vs. 2. 51, P = 0.03). CONCLUSIONS: The learner-centred learning goal exercise is
      a feasible and well-received method within our primary care clerkship. Further
      study is required to determine whether the exercise promotes independent learning
      after formal medical school education is completed.

PMID- 10336776
TI  - Medication discussion groups in the Netherlands: five years of experience.
AB  - INTRODUCTION: Nation-wide implementation of medication discussion (MD) groups in
      the Netherlands was designed as a bottom-up approach and has been in progress for
      five years. This invites a review of what has been achieved in these structured
      discussions between general practitioners and pharmacists. CONTEXT: Early in 1997
      the Dutch Foundation for Effective Use of Medication (DGV) initiated a fact
      finding exercise among general practitioners and pharmacists representing MD
      groups all over the country. OBJECTIVE: Description of the setting up and the
      operation of medical discussion groups. Comparison of the quality of the
      consultations between the start of the project (1992) and 1997. METHODS: Two
      surveys of medical discussion groups in 1992 and 1997, respectively. RESULTS: The
      quality of the consultations was found to have improved in comparison with an
      evaluation shortly after the start of the project. CONCLUSION: The overwhelming
      majority of those interviewed were satisfied with the MD process, which they
      consider a useful effort. But there is also a wish for increased commitment to
      guidelines agreed in MD group consultations.

PMID- 10336777
TI  - Reforming higher specialist training in the UK.

PMID- 10336778
TI  - The English language and Arabic medical students.

PMID- 10336779
TI  - Analysis of CpG C-to-T mutations in neurofibromatosis type 1. Mutations in brief
      no. 129. Online.
AB  - Neurofibromatosis type 1 (NF1) is a dominant disorder caused by mutations in the
      NF1 gene; approximately 100 NF1 gene mutations have been published. The CpG C-to
      T transition is a frequent mutation mechanism in genetic disorders. To estimate
      its frequency in NF1, we employed a PCR-restriction digestion method to examine
      17 CpGs in 65 patients, and also screened for a CpG nonsense transition (R1947X)
      that occurs in 1-2% of patients. The analysis revealed disease-related CpG C-to-T
      transitions (including a nonsense mutation that may be as frequent as R1947X) as
      well as a benign variant and another mutation at a CpG. Four patients showed CpG
      mutations in analysis of 18 sites (17 surveyed by restriction digest, plus the
      R1947X assay), including three C-to-T transitions and one C-to-G transversion.
      These 18 sites represent one-fifth of the 91 CpGs at which a C-to-T transition
      would result in a nonsense or nonconservative missense mutation. Thus, it is
      feasible that the CpG mutation rate at NF1 might be similar to that seen in other
      disorders with a high mutation rate, and that recurrent NF1 mutations may
      frequently reside at CpG sites.

PMID- 10336790
TI  - Flexible vs. Rigid dieting strategies: relationship with adverse behavioral
      outcomes.
AB  - This study was designed to test the hypothesis that different types of dieting
      strategies are associated with different behavioral outcomes by investigating the
      relationship of dieting behaviors with overeating, body mass and mood. A sample
      of 223 adult male and female participants from a large community were studied.
      Only a small proportion of the sample (18%) was seeking weight loss treatment,
      though almost half (49.3%) of the subjects were significantly overweight (body
      mass index, BMI>30). Subjects were administered questionnaires measuring dietary
      restraint, overeating, depression and anxiety. Measurements of height and weight
      were also obtained in order to calculate BMI. Canonical correlation was performed
      to evaluate the relationship of dietary restraint variables with overeating
      variables, body mass, depression and anxiety. The strongest canonical correlation
      (r=0.65) was the relationship between flexible dieting and the absence of
      overeating, lower body mass and lower levels of depression and anxiety. The
      second strongest canonical correlation (r=0.59) associated calorie counting and
      conscious dieting with overeating while alone and increased body mass. The third
      canonical correlation (r=0.57) found a relationship between low dietary restraint
      and binge eating. The results support the hypothesis that overeating and other
      adverse behaviors and moods are associated with the presence or absence of
      certain types of dieting behavior.

PMID- 10336791
TI  - Asymmetry in the disconfirmation of expectations for natural yogurt.
AB  - Effects of expectations conveyed by a product description or an empty package on
      the evaluation of four types of natural yogurt were studied in a laboratory
      setting. Hedonic and perceptual responses for the correctly or incorrectly
      identified products generally showed assimilation: they fell between the
      responses to the unlabelled products and the responses for the expected
      properties evoked by presenting only product descriptions or empty packages.
      Hedonic judgments remained close to the expectation when the product performed
      better than expected, whereas they were relatively close to the evaluation for
      the unlabelled product when the product performed worse than expected. The
      asymmetry was largest for the buying intentions of subjects who received product
      packages. This is in accordance with the theory that positive disconfirmations
      are regarded as "gains" and negative disconfirmations as "losses". The asymmetry
      is likely to be more important in actual buying behaviour than in the
      experimental settings generally studied, as here.

PMID- 10336792
TI  - Food "cravings" and the acute effects of alprazolam on food intake in women with
      premenstrual dysphoric disorder.
AB  - Women with premenstrual dysphoric disorder (PMS) report negative mood
      premenstrually, and increased food cravings and food intake. Although the
      benzodiazepine alprazolam has been used to treat PMS, alprazolam has been shown
      to increase food intake. The present study investigated the acute effects of
      alprazolam (0, 0.25, 0.50, 0.75 mg) on food intake in 19 women with PMS. Each
      dose was tested once during the premenstrual phase and again during the
      postmenstrual phase. Each session, before drug administration, participants
      completed a Food Desirability Questionnaire and selected lunch, which was
      consumed 3.5 h after drug administration. Desire for foods containing fat were
      significantly increased premenstrually compared to postmenstrually, while desires
      for carbohydrate (CHO) alone and beverages did not change as a function of
      menstrual cycle phase. Cognitive Restraint scores predicted the amount of food
      consumed, i. e. restrained eaters consumed less food at lunch. Alprazolam
      significantly increased food intake, specifically fat, premenstrually compared to
      postmenstrually. Restrained eaters consumed 26% more calories premenstrually
      following 0.75 mg alprazolam relative to placebo, whereas unrestrained eaters
      consumed 9% more calories. Thus, women with PMS, particularly restrained eaters,
      are more sensitive to the food-intake increasing effects of alprazolam
      premenstrually.

PMID- 10336793
TI  - Effects of prior exposure to palatable and unpalatable novel foods on children's
      willingness to taste other novel foods.
AB  - In two studies, 7- to 9-year-old and 10- to 12-year-old children received taste
      exposure to four good-tasting familiar, four good-tasting novel or four bad
      tasting novel foods. Following this exposure phase, they saw a series of
      different foods, familiar and novel, and rated their willingness to taste them.
      For older children, exposure to the novel-good foods increased willingness to
      taste novel foods in comparison to the familiar-good control, while exposure to
      the novel-bad foods had no effect. For younger children, exposure to both novel
      good and novel-bad foods decreased willingness to taste novel foods. The studies
      were originally framed in terms of children's schemas about novel foods and how
      exposure to good- and bad-tasting novel foods constituted provision of schema
      inconsistent (novel-good) or schema-consistent (novel-bad) information. While
      such a framework accounted well for the results for the older children, it did
      not account for those for the younger children. The behaviour of the younger
      children was tentatively explained in terms of their attempt to regulate arousal
      produced by the initial exposure to the novel foods.

PMID- 10336794
TI  - Attitudinal moderation of correlation between food liking and consumption.
AB  - This paper focuses on the degree of correlation between food liking and
      consumption and proposes the degree of correspondence between affective and
      cognitive aspects of liking and consumption as moderators of this correlation. In
      a close-response questionnaire, 103 young females (average age of 20) indicated
      their liking for and consumption of 12 non-alcoholic cold beverages. They also
      indicated their level of agreement with affective and cognitive statements
      associated with each beverage as well as the affective or cognitive statement
      that was representative of their attitude toward each beverage. Even though there
      are affective and cognitive bases of both liking and consumption, the affective
      basis dominates liking whereas the cognitive basis dominates consumption for most
      beverage categories. Separate analyses conducted at the level of individual
      subjects and of individual beverage categories both revealed that those cases in
      which the attitude basis for liking and consumption showed the highest
      correspondence, also manifested the highest liking-consumption correlation.
      Results are discussed with regard to health promotion and food marketing
      strategies.

PMID- 10336795
TI  - Individual differences in the use of pleasantness and palatability ratings.
AB  - Previously we have suggested that individual subjects interpret the phrase
      "palatable food" in different ways. To test the consistency of the use of this
      term, 50 male volunteers consumed a simple lunch on two occasions, once with a
      more palatable food and once with a more bland version. Ratings of hunger,
      fullness, pleasantness and palatability were completed at the start and end of
      each meal. Overall, subjects ate slightly more of the palatable food. The
      difference in intake between conditions correlated with differences in
      pleasantness and palatability but not hunger at the start of eating. Rated
      pleasantness of the food declined between the start and end of the meal in most
      subjects, but changes in palatability were more variable, with a significant
      minority showing no change across the meal. Detailed analysis confirmed the
      existence of two populations of responses, one where pleasantness and
      palatability were synonymous, and one where palatability was rated as a constant
      property of a food. The existence of two interpretations of the term palatability
      in common English usage cautions against the use of this term as a reliable means
      of evaluating hedonic responses to foods in appetite studies.

PMID- 10336796
TI  - A figurative measure of subjective hunger sensations.
AB  - In an attempt to better characterize the subjective experience of hunger, we
      assessed the locus and extent of sensations associated with varying degrees of
      hunger. In the first study, 83 subjects indicated by marking on a drawing of a
      human figure where they felt hungry under hypothetical conditions of slight to
      extreme hunger. Approximately 55% of subjects indicated an abdominal locus with
      slight hunger, a proportion which increased somewhat with increasing levels of
      imagined hunger. The proportion of subjects indicating other or additional body
      sites grew significantly with increasing hunger states; for example, those
      identifying the head region increased from about 10-35%. In a second study, 14
      subjects were fasted for 22 h and then refed. Using the drawn figures, they
      outlined body areas where they experienced hunger during and after fasting. The
      size of the abdominal area and the total body area associated with hunger
      sensations expanded with increasing food deprivation and contracted after
      refeeding. The size of the area of hunger sensation did not necessarily correlate
      with the degree of hunger as assessed by standard rating scales. The results
      indicate that the extent and locus of hunger sensations vary with fasting and
      feeding, and suggest that the site and size of the body areas associated with
      hunger sensations may provide qualitative and quantitative measures of the
      subjective experience of hunger not captured by analogue rating scales.

PMID- 10336797
TI  - Restricting access to foods and children's eating.
AB  - This study evaluated maternal restriction of children's access to snack foods as
      a predictor of children's intake of those foods when they were made freely
      available. In addition, child and parent eating-related "risk" factors were used
      to predict maternal reports of restricting access. Participants were 71, 3-to-5
      year-old children (36 boys, 35 girls) and their parents. Children's snack food
      intake was measured immediately following a meal, in a setting offering free
      access to palatable snack foods. Child and maternal reports of restricting
      children's access to those snack foods were obtained. In addition, information on
      child and parent adiposity as well as parents' restrained and disinhibited eating
      was used to examine "risk" factors for restricting access. For girls only, child
      and maternal reports of restricting access predicted girls' snack food intake,
      with higher levels of restriction predicting higher levels of snack food intake.
      Maternal restriction, in turn, was predicted by children's adiposity.
      Additionally, parents' own restrained eating style predicted maternal restriction
      of girls' access to snack foods.

PMID- 10336798
TI  - Intestinal lipid absorption and apolipoprotein A-IV production.

PMID- 10336799
TI  - Does genetic taste sensitivity to PROP influence food preferences and body
      weight?

PMID- 10336801
TI  - Sample size estimation in phase III cancer clinical trials.
AB  - This paper deals with the basic principles involved in sample size calculation of
      phase III cancer clinical trials. It illustrates the concepts and factors
      determining the sample size. Various examples of phase III cancer clinical trials
      are provided and the sample size is calculated taking into account the
      assumptions made. The examples provided include sample sizes for comparing
      proportions and sample sizes for comparing survival times. Several special topics
      are also discussed including choice of endpoint, number of treatment groups,
      factorial designs and equivalence trials.

PMID- 10336800
TI  - The effect of surgical wounding on tumour development.
AB  - For more than a century, a role for wound healing in the outgrowth of tumours has
      been implied based on observations in both experimental and clinical studies.
      Wound healing can be divided into stages of inflammatory, proliferative, repair
      and remodelling processes. Through proper regulation of activation of epithelial,
      endothelial and inflammatory cells, platelets and fibroblasts, and the production
      of growth factors, wounds heal and the various cell types resume their normal
      function. In tumour growth, similar processes of cell activation and growth
      factor production are observed. These processes are, however, differently
      regulated leading to ongoing cellular activation. In recent years, growth factors
      such as EGF, TGF-alpha and TGF-beta, bFGF, IGF I and II, and PDGF have been
      identified to play a role in the different stages of wound healing. In addition,
      some of these factors have now been identified as also being involved in the
      outgrowth of tumours. In this review, cell types involved in wound healing and
      tumour growth, as well as the growth factors and cytokines they produce and the
      role of the extracellular matrix, extensively present in both conditions, are
      being discussed. A better understanding of the time interval during which the
      sequelae of events in wound healing occur in relation to the time interval of
      tumour recurrence may be the basis for defining new therapeutic strategies that
      can interfere with tumour outgrowth without affecting wound healing processes.
      These new therapeutic approaches may be of importance especially after surgery or
      other invasive (diagnostic) procedures in cancer patients.

PMID- 10336803
TI  - Management of primary breast cancer in Hong Kong -- can the guidelines be met?
AB  - AIMS: To assess the quality standards in the management of primary breast cancer
      in Hong Kong and as a result to give recommendations with regard to further
      improving the existing specialist service. METHODS: A prospective, continuous
      audit using quality standards laid down in the Guidelines for Surgeons in the
      Management of Symptomatic Breast Disease in the United Kingdom. RESULTS: Quality
      standards in surgical expertise, radiology and pathology service have reached the
      level required while there is still room for improvement in the diagnostic
      services. CONCLUSIONS: The establishment of an expeditious new referral system
      with combined surgical and radiological expertise should be pursued.

PMID- 10336802
TI  - The National Breast Referral Guidelines have cut down inappropriate referrals in
      the under 50s.
AB  - AIMS: When the National Breast Referral Guidelines were applied to our local GPs
      letters immediately prior to their release in January 1996, it was shown that on
      the basis of the GPs own conclusions that 29% of symptomatic women could have
      been managed initially by their own GP without missing any carcinomas. We
      conducted this study at the Rapid Access Breast Clinic at the University Hospital
      of Wales to determine if the breast referral practices of local GPs have altered
      due to the breast referral guidelines. METHODS: We studied 2332 referrals from
      the inception of the Rapid Access Clinic in May 1995 to the issue of the
      guidelines, and 2421 referrals from May 1996 to the end of the year. Random
      samples of 600 patients were drawn from each year and the referral letters were
      scored as within or outside the guidelines. Family history patients were
      excluded. RESULTS: There was an 11% fall in referrals outside the guidelines in
      the under 50s (chi-squared=<0.001) but the 7% fall in the over 50s was not
      significant. CONCLUSIONS: The Breast Referral Guidelines seem to have been
      effective in reducing the higher level of inappropriate referrals in younger
      patients at less risk of carcinoma.

PMID- 10336804
TI  - Breast cancer: outcome audit of axillary management in 1991.
AB  - AIMS: To audit the outcome of axillary treatment of patients diagnosed with
      invasive breast cancer in 1991, with particular reference to the incidence of
      regional recurrence and lymphoedema after limited axillary dissection. METHODS: A
      review of records of patients identified prospectively. RESULTS: Two per cent
      regional recurrence and 5.7% lymphoedema incidence at 5 years. CONCLUSIONS: There
      is no indication from these results that axillary treatment, for our patient
      population, should be more aggressive.

PMID- 10336805
TI  - Influence of tumour bed assessment on local recurrence following breast
      conserving surgery for breast cancer.
AB  - AIMS: To assess the impact of adopting a policy of tumour bed assessment with
      selective re-excision in patients undergoing breast-conserving surgery for breast
      cancer. METHODS: Tumour bed assessment was introduced in our institution in 1988.
      Patients treated prior to 1988 (125 patients) were compared with patients treated
      post-1988 (239 patients) for clinico-pathological factors, surgical and adjuvant
      therapy. Outcome measures were examined at a fixed 5-year follow-up period for
      each patient. RESULTS: There were a greater number of small, node-negative,
      oestrogen receptor tumours post-1988, probably due to the influence of the
      National Breast Screening Programme. There was also a difference in the
      prescription of adjuvant systemic therapy between the two cohorts. The incidence
      of tumour bed positivity was 30.5%. The re-excision rate was 16.4%. There was a
      significant fall in the incidence of local recurrence from pre-1988 (15.7%) to
      post-1988 (2.5%). CONCLUSION: By adopting a policy of tumour bed assessment with
      selective re-excision, a low local recurrence rate has been achieved. The
      improvement in systemic recurrence and breast cancer-related death rate are
      mainly secondary to other factors.

PMID- 10336806
TI  - Telomerase activity and prognosis in breast cancer.
AB  - AIMS: Telomerase is a ribonucleoprotein enzyme which appears to play an important
      role in carcinogenesis. Its reactivation is associated with the acquisition of
      immortalization and malignancy. The present study aims to examine the association
      between telomerase activity and prognosis in breast cancer. METHODS: Using a PCR
      based assay, we retrospectively examined telomerase activity in 45 frozen human
      breast cancer specimens. Telomerase activity was compared with histopathological
      and clinical data. RESULTS: Telomerase activity was detected in 20 (44%) of 45
      cases and was associated with advanced histopathological grade and tumour type
      (ductal vs. lobular). The association with these histological parameters was
      statistically significant (chi-squared test P<0.05). There was no significant
      difference in the overall survival rate (78 vs. 77%) or disease-free survival (73
      vs. 69%) at 5 years (Kaplan-Meier method, log-rank test P>0.05). CONCLUSIONS: The
      present results indicate that telomerase activity in human breast cancer is not
      associated with nodal status or disease outcome.

PMID- 10336807
TI  - The relationship between findings on pre-treatment mammograms and local
      recurrence after breast-conserving therapy for invasive breast cancer.
AB  - AIMS: This study was planned (a) to determine the correlation between findings on
      the pre-treatment mammogram and local recurrence after breast-conserving therapy
      (BCT), and (b) to analyse the relationship between mammographical features,
      specific pathological characteristics and the need for re-excision. METHOD: The
      size and outline of the lesion, the presence of suspect microcalcifications and
      signs of multifocality on pre-treatment mammograms of 39 patients with local
      recurrence after BCT and 126 randomly selected control patients without local
      recurrence were compared. Tissue slides of the primary tumour were reviewed to
      confirm the histological type and grade, the aspect of the margins, microscopic
      margin involvement, presence of vascular invasion and the presence and extent of
      an intraductal component. RESULTS: Among patients </=50 years of age, the
      proportion with a mammographically occult tumour was 48% of the patients with
      local recurrence and 26% of the control group (P=0.05). In the age group >/=50
      years, 67% of the patients with local recurrence had a non-circumscribed lesion
      compared to 9% of the control group (P<0.001). Suspect microcalcifications on the
      mammogram were associated with the finding of an extensive intraductal component,
      vascular invasion and a higher histological grade by the pathologist. Patients
      with a non-circumscribed density or a scirrhous lesion needed re-excision more
      often (30 and 33%, respectively) than those with a well-circumscribed density
      (9%). CONCLUSIONS: Although the number of patients was small, this study
      indicates that some mammographical features are associated with a higher risk of
      local recurrence after BCT and the need for re-excision. This was supported by
      the findings of the pathological review.

PMID- 10336808
TI  - Does the new TNM classification (1997) improve prognostic stratification in
      gastric cancer submitted to R0 surgery?
AB  - AIMS: To determine the eventual advantage of the new 1997 TNM as prognosis
      predictor for gastric cancer patients submitted to an R0 resection and to compare
      it with two other lymph-node involvement classifications, the 1990 TNM and the
      Okusa system. METHODS: From January 1980 to December 1995, an R0 resection was
      performed as primary therapy in 275 cases of gastric cancer. These operations
      consisted of a total or sub-total gastrectomy and of a D2 type lymph-node
      dissection. Tumour classification was performed according to 1990 and 1997 TNM
      systems, and to the Okusa lymph node classification. The statistical methods used
      to evaluate prognostic value were: Kaplan-Meier survival estimates; the log-rank
      test for univariate analysis; and Cox's model for multivariate analysis. RESULTS:
      The 1990 TNM showed the best stratification power in univariate analysis. In
      multivariate analysis, the Okusa classification was identified as the best
      prognostic index (P<0.01). The 1997 TNM showed worse stratification capability
      than the two other systems. CONCLUSIONS: In the present series, the new TNM
      (1997) did not improve the prognostic stratification of lymph-node involvement.
      An adequate and universal system for lymph-node stratification is necessary and
      further validation of these classifications is needed.

PMID- 10336809
TI  - Long-term results of radical surgery for rectal cancer: multivariate analysis of
      prognostic factors influencing survival and local recurrence.
AB  - AIMS: To evaluate consistent radical surgery performed over a 13-year period for
      rectal cancer in terms of local tumour control and long-term survival. METHODS:
      Radical surgical procedure principally using total mesorectal excision (TME) for
      middle and lower rectal tumours, high ligation of the inferior mesenteric artery
      and sphincter-saving resections (SSR) whenever possible, has been performed
      prospectively since January 1984. RESULTS: Tumour resection was possible in 98.8%
      (636/644), potentially curative resections (UICC/AJCC R0 resection) in 85.7%
      (552/644) and sphincter preservation in 71.7% (462/644). Five- and 10-year
      observed survival rates, surgical mortality not excluded, for all patients were
      49.2% and 37.4%. Tumour-adjusted 5- and 10-year survival rates were 60.5% and
      55.3%. For curatively operated patients (UICC/AJCC R0) 5- and 10-year observed
      survival rates were 56.3% and 42.6% and tumour-adjusted survival rates were 68.6%
      and 62.7%. The 5- and 10-year local recurrence rates for R0 resected patients
      were 12.0% and 12.6%. Post-operative hospital mortality was 3.1%. CONCLUSIONS:
      Multivariate analysis using Cox's model identified increasing pT category and pN
      category, old age and low tumour location as detrimental factors having
      independent influence on survival. For local tumour failure only pT and pN
      category as well as adjuvant radiation therapy were identified in the Cox model
      as having an independent detrimental influence.

PMID- 10336810
TI  - The relationship between prognosis and CEA-dt after hepatic resection in patients
      with colorectal carcinomas.
AB  - AIMS: CEA-doubling time (CEA-dt) was calculated by measuring serum CEA at two
      voluntary points. As CEA-dt is correlated with tumour doubling time the growth
      rate of liver metastasis could be determined. We investigated the relationship
      between CEA-dt and prognosis to determine the indications for resection of liver
      metastasis. METHODS: We examined 334 patients diagnosed with resected liver
      metastasis of colorectal carcinoma. Patients were divided into three categories
      based on CEA-dt; Group A, CEA-dt <30 days; Group B, 30 days </=cCEA-dt <80 days;
      and Group C, CEA-dt >/=s80 days. Clinicopathological parameters, the 3-year or 5
      year survival rate and the rate of recurrence were compared among the three
      groups. RESULTS: In Group A, the survival time after hepatic resection was
      significantly shorter compared to the other groups. Furthermore, multiple liver
      metastasis showed slightly reduced CEA-dt levels compared with solitary
      metastasis, but even in patients with solitary liver metastasis, the rate of
      survival was poor. In 70% of Group A patients, recurrent tumour was recognized
      within 1 year of hepatic resection. CONCLUSION: When surgery for liver metastasis
      of colorectal cancer is considered. Group A patients should be recognized as
      having a poor prognosis and a high rate of recurrence after hepatic resection,
      and CEA-dt should be employed as a prognostic factor.

PMID- 10336811
TI  - p53 expression as a prognostic determinant in resected distal bile duct
      carcinoma.
AB  - AIMS: To determine the incidence and prognostic value of p53 immunopositivity in
      resectable distal bile duct carcinoma (DBDC). METHODS: Forty-seven paraffin
      embedded archival tumour samples of patients with DBDC, who underwent subtotal
      pancreatoduodenectomy from 1985 to 1996, were immunohistochemically examined for
      p53 positivity, using the anti-p53 antibody D07. RESULTS: Nineteen (40%) of the
      47 tumours demonstrated positive (>30%) p53 protein immunostaining. Focally
      positive or negative staining was seen in the remaining 28 (60%) cases. Patients
      in this low p53 category survived significantly longer than those in the high p53
      category, with median survival durations of 29 and 13 months respectively (P=0.
      039). p53 positivity was independent of age, sex, tumour size, radicality of
      resection, histopathological grading, lymph-node status, perineural invasion and
      vasoinvasive growth. CONCLUSIONS: This study indicates that low (0-30%) p53
      expression is a favourable prognostic factor in patients with resected DBDC.

PMID- 10336812
TI  - Results of treatment of 17 patients with heart tumour.
AB  - BACKGROUND: Between 1989 and 1997, 17 patients underwent surgery for excision of
      primary cardiac tumour at the Department for Cardiovascular Surgery in Ljubljana.
      PATIENTS AND METHODS: There were 13 female (76.5%) and four male (23.5%) patients
      with an average age of 49+/-14 years (mean+/-SD). The study was retrospective.
      Special attention was paid to clinical presentation, method of diagnosis, elapsed
      time between the confirmed diagnosis and excision of the tumour, operatively
      determined location of tumour and post-operative course-diuresis in first 48 h,
      levels of CK and CK-MB, on first and on second day after operation and time of
      hospitalization. RESULTS: Thirteen patients (76.5%) had cardiac symptoms at the
      time of presentation (dyspnoea, syncope, vertigo, palpitations) and four (23. 5%)
      had embolic complications. In all the patients diagnosis was made by
      echocardiography. Average elapsed time between the confirmed diagnosis and the
      operation was 26+/-40 (mean+/-SD) days. Histological examination revealed myxoma
      in 15 patients (88.2%), one patient had lipoma and one malignant
      haemangiosarcoma. The most common location of tumour was in the left atrium (12
      patients; 70. 6%). Post-operative complications occurred in four patients
      (23.5%); 76.5% of patients had diuresis in the range between 0.8 and 2.0 ml/h/kg;
      there was no post-operative oligouric renal failure. Average levels of both CK
      and CK-MB were statistically significantly lower on the second day after
      operation, there was no case of peri-operative myocardial infarction and post
      operative death did not occur. One patient with multiple myxoma had two
      recurrences. CONCLUSIONS: Symptoms in patients with heart tumours, especially at
      the beginning of illness, are often uncharacteristic. Due to the non-specific
      presentation of cardiac tumours, a high index of suspicion is needed. The
      diagnostic method of choice is echocardiography. Operative removal of tumour is a
      safe procedure and recurrences in patients with benign tumours are rare.

PMID- 10336813
TI  - Malignancy load on general surgeons: the need to change the general surgical
      training curriculum.
AB  - AIMS: With the advent of newer diagnostic modalities more and more cancer
      patients are being diagnosed each year. The rising detection rate and greater
      public awareness have immensely increased the load on already overburdened and
      increasingly fewer surgical oncology units. As a result a large number of these
      cases are being dealt with by general surgeons. METHODS: We have used a
      retrospective case count from a single surgical unit, based at the University
      Hospital, Varanasi, and data from the Hospital Based Cancer Registry (HBCR),
      Regional Cancer Centre (RCC), Trivandrum, from 1990 to 1994, to define the
      malignancy load on general surgical units and to define the number and sites of
      malignancies commonly encountered by general surgeons. RESULTS: A total of 28,136
      patients were registered at the RCC, the commonest malignancy being oral cavity
      (16.35%), followed by lung (12.7%) and breast (23.8%) among men and women,
      respectively. On the other hand, in the 2123 patients with malignancy who were
      treated at the Medical College (MCH) in Trivandrum, the commonest sites
      encountered were stomach (11.68%), thyroid (10.31%) and colorectal (9.5%). This
      was quite similar to the frequencies observed at Varanasi, where colorectal
      cancer constituted 10.26% and stomach 6.98%. Only 13.6% of the patients reporting
      to RCC were treated by surgery alone or in combination, while this figure was 48.
      1% for MCH. Similarly 2056 (7.3%) patients presenting to RCC had completed
      treatment prior to being referred to RCC; almost all of these patients were
      treated by surgery at referral institutions by general surgeons. CONCLUSIONS: The
      results clearly indicate an increased demand on the surgical oncology units, or
      alternatively an urgent need to redefine the postgraduate curriculum for the
      better training of general surgeons in understanding malignant disease,
      especially in the developing countries. We recommend a minimum of 6 months
      training in surgical oncology for each general surgery postgraduate.

PMID- 10336814
TI  - Part II. Europe and surgery from AD 1500 to 1800; the modern world is shaped.
AB  - 'The farther backward you can look, the farther forward you can see. WINSTON
      CHURCHILL.

PMID- 10336816
TI  - Survival analysis: caveats and pitfalls.
AB  - BACKGROUND: Survival analysis in clinical studies is important to assess the
      effectiveness of a given treatment and to understand the effect of various
      disease characteristics. A number of methods exist to estimate the survival rate
      and its standard error. However, one cannot be certain that these methods have
      been handled appropriately. The widespread use of computers has made it possible
      to carry out survival analysis without expert guidance, but using inappropriate
      methods can give rise to erroneous conclusions. The majority of the biomedical
      journals now recommend that a statistical review of each manuscript should be
      carried out by an experienced bio-statistician, in addition to obtaining expert
      referees' comments on the article. The problem is compounded in papers from third
      world countries where bio-statisticians may not be available in all institutions
      to guide clinicians as to the selection of proper techniques. METHODS: The
      present paper deals with the various techniques of survival analysis and their
      interpretation, using a modal data set of malignant upper-aerodigestive tract
      melanoma patients treated in the Regional Cancer Centre, Trivandrum since 1982.
      RESULTS: The Kaplan-Meier method was found to be the most suitable for survival
      analysis. The median survival time is a better method of summarizing data than
      the mean. Rothman's method of estimation of the confidence limit is better than
      Peto's method as the confidence limit for survival probability tends to go beyond
      the range of 0-1.0 when calculated by Peto's method, especially when the sample
      size is small. CONCLUSION: The results from the present study suggest that
      survival analysis should be carried out by the Kaplan-Meier method. The median
      survival time should be provided wherever possible, rather than relying on mean
      survival. Confidence limits should be calculated as a measure of variability. A
      suitable rank test should be used to compare two or more survival curves, rather
      than a Z-test. Stratified analysis and Cox's model, when stratified analysis
      fails, can be used to define the impact of prognostic factors on survival.

PMID- 10336815
TI  - Late adverse psychological sequelae of breast cancer and its treatment.

PMID- 10336817
TI  - Management of a large pleomorphic adenoma of the parotid gland.
AB  - The surgical management of an extensive pleomorphic adenoma arising within deep
      lobe of the parotid gland is presented.

PMID- 10336818
TI  - Isolated hypoxic perfusion with mitomycin C in patients with advanced pancreatic
      cancer.

PMID- 10336819
TI  - Influence of continuous growth hormone or insulin-like growth factor I
      administration in adult female chickens.
AB  - A series of studies was conducted to determine whether growth hormone (GH) exerts
      effects on adult female chickens. Recombinant chicken GH (rcGH) was administered
      continuously via osmotic minipumps. No consistent effects of rcGH treatment were
      observed on reproductive indices. Hens receiving rcGH treatment for 10 days
      exhibited hepatomegaly and showed a tendency (P < 0.1) for increased spleen and
      thymus weights. Moreover, there were increases in the circulating concentrations
      of insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IGF-BPs) (22
      kDa IGF-BP after 2, 5, and 10 days; 28-kDa IGF-BP after 5 and 10 days; and 36-kDa
      IGF-BP after 10 days) with rcGH treatment. To determine whether the changes in
      IGF-BPs were due directly to GH or indirectly via IGF-I, the effects of the
      continuous administration of rcGH or recombinant human IGF-I (rhIGF-I) were
      compared. While rcGH again elevated the circulating levels of 28- and 36-kDa IGF
      BPs, no such effect was observed with rhIGF-I treatment. However, both treatments
      exerted similar effects in depressing pituitary GH mRNA levels and elevating
      plasma concentrations of IGF-I. It is concluded that GH directly elevates
      circulating concentrations of IGF-I and IGF-BPs, but the negative feedback effect
      on GH synthesis is mediated via IGF-I.

PMID- 10336820
TI  - Plasma calcium and calcitonin levels in eels fed a high calcium solution or
      transferred to seawater.
AB  - To examine the physiological role of calcitonin (CT) in calcium homeostasis of
      teleosts, we compared calcium and CT levels in freshwater eels fed a high calcium
      consomme solution (Ca2+: 1.25 M; 1 ml/100 g body wt) into the stomach (Experiment
      I), and in freshwater eels transferred from freshwater to seawater (Experiment
      II). In experiment I, plasma calcium and CT levels in the high calcium-treated
      eels rapidly increased (calcium: 2.63 mM at 0 h to 8. 50 mM at 3 h; CT: below
      detection level at 0 h to 1118.2 pg/ml at 3 h). Plasma calcium and CT levels in
      the control eels remained below detection level during the 3 h of the experiment.
      In experiment II, the plasma CT levels did not increase, although the plasma
      calcium levels increased from 3.23 mM at 0 h to 4.10 mM at 8 h. Therefore, in
      eels, we demonstrate a correlation between plasma CT and plasma calcium raised by
      dietary calcium in the consomme form, but it does not participate in the initial
      processes of seawater adaptation.

PMID- 10336821
TI  - Developmental and protein kinase-dependent regulation of ovarian connexin mRNA
      and oocyte maturational competence in Atlantic croaker.
AB  - The acquisition of oocyte maturational competence (OMC) in ovarian follicles of
      Atlantic croaker is associated with increased gap junction (GJ) contacts and
      increased levels of ovarian connexin (Cx) 32.2 mRNA. However, the developmental
      control of ovarian Cx gene expression and the mechanisms of OMC acquisition are
      unknown. Ovarian Cx32.2 and Cx32.7 mRNA levels were determined in fish with
      gonadosomatic indices (GSI; gonad weight-to-body weight ratio) ranging from 0.1
      to 13%. The mRNA level for both Cx increased from a low level in previtellogenic
      ovaries (GSI, <1%) to a peak level during the midstage of ovarian growth (GSI, 6
      7%). Levels of Cx32.2 mRNA, but not Cx32.7 mRNA, declined markedly during late
      ovarian vitellogenic growth (GSI, 7-13%), and increased again upon stimulation of
      OMC by human chorionic gonadotropin (hCG). These changes in ovarian Cx32.2 mRNA
      seem to parallel previously reported changes in the incidence of oocyte-granulosa
      cell GJ during follicular growth and early maturation. In vitro treatment with
      hCG and protein kinase A (PKA) activators (dbcAMP and forskolin) induced ovarian
      Cx32.2 mRNA levels and OMC. The effects of hCG were blocked by PKA inhibitors
      (H89, H7). Protein kinase C (PKC) inhibitors (GF 109207X) had little effect on
      hCG-induced Cx32.2 mRNA or OMC, whereas PKC activators (PMA) blocked both events.
      There was no association between changes in Cx32.7 mRNA levels and OMC status in
      these experiments. In conclusion, changes in Cx32.2 gene expression seem to be
      involved in the regulation of oocyte-granulosa cell GJ during growth and
      differentiation of the croaker ovarian follicle. Also, the stimulation of OMC and
      Cx32.2 mRNA levels by hCG is mediated by PKA-dependent pathways and antagonized
      by PKC-dependent mechanisms.

PMID- 10336822
TI  - Noninvasive fecal monitoring of glucocorticoids in spotted hyenas, Crocuta
      crocuta.
AB  - The aim of this study was to validate a method for measuring glucocorticoids
      noninvasively in feces of spotted hyenas (Crocuta crocuta). Three established
      enzyme immunoassays (EIA) for cortisol, corticosterone, and 11-oxoetiocholanolone
      were tested, but proved unsatisfactory. A new EIA using another corticosterone
      antibody was established and was used for all subsequent analyses; this EIA was
      validated by demonstrating parallelism between serial dilutions of spotted hyena
      fecal extracts and dilutions of standard corticosterone and by the recovery of
      corticosterone added to fecal extracts. High-performance liquid chromatography
      (HPLC) fractions analyzed by EIA showed various immunoreactive substances with
      polarities of unconjugated steroids. The physiological relevance of fecal
      glucocorticoid metabolites was further validated by demonstrating that (1)
      injection of exogenous ACTH to four males and two females led to a significant
      increase in fecal glucocorticoid metabolites within 24-50 h, (2) the
      translocation of a male spotted hyena to a new enclosure resulted in a fivefold
      increase compared to baseline concentrations, and (3) agonistic social
      interactions and physical conflict resulted in large increases of fecal
      glucocorticoid metabolites in both protagonists. Fecal steroid assessment is
      therefore of use in monitoring adrenal activity in spotted hyenas.

PMID- 10336823
TI  - Corticotropin releasing factor in the brain of the gymnotiform fish, Apteronotus
      leptorhynchus: immunohistochemical studies combined with neuronal tract tracing.
AB  - The expression of corticotropin-releasing factor (CRF) has been studied by
      immunohistochemistry in the brain of the gymnotiform fish, Apteronotus
      leptorhynchus. Labeled somata were found exclusively in the posterior subdivision
      of the nucleus preopticus periventricularis and in the hypothalamus anterioris,
      where these cells form a continuous cluster of neurons. Combination of anti
      peptide immunohistochemistry with an in vitro tract-tracing technique confirmed
      that at least some of these neurons project to the pituitary. Additional terminal
      fields were present in the following areas of the telencephalon and the
      diencephalon: ventral subdivision of the ventral telencephalon, supracommissural
      subdivision of the ventral telencephalon, anterior subdivision of the nucleus
      preopticus periventricularis, inferior subdivision of the nucleus recessus
      lateralis, central posterior/prepacemaker nucleus, hypothalamus dorsalis and
      lateralis, medial subdivision 2 of the nucleus recessus lateralis, and in the
      region between the dorsal edge of the nucleus tuberis anterior on the one side
      and both the glomerular nucleus and the central nucleus of the inferior lobe on
      the other side. It is likely that the projection of CRF-expressing neurons of the
      posterior subdivision of the nucleus preopticus periventricularis/hypothalamus
      anterioris to the pituitary provides, similarly as in other fishes, the neural
      substrate for the activation of the hypothalamo-pituitary adrenal axis through
      CRF. In addition to this function, CRF may be involved in the regulation of
      several other processes, including neural control of communicatory behavior
      exerted by neurons of the central posterior/prepacemaker nucleus.

PMID- 10336824
TI  - Changes in estrogen receptor expression and cell activity of lactotropes in
      female mink (Mustela vison) pituitary in response to variations in the gonadal
      steroid environment.
AB  - This study was undertaken to get new information on the role played by estrogen
      (E) on the activity of mink lactotropes. Immunocytochemistry for estrogen
      receptor (ER) and prolactin (PRL) was applied to assess modifications in the
      protein production that occur as a result of in vivo changes in the gonadal
      steroid environment. Variations in the functional activity of lactotropes were
      demonstrated from the ultrastructural characteristics and morphometric parameters
      (cellular area, numerical density, and secretory granular size). The present
      study documents the presence of ER in mink lactotropes revealing the ability of E
      to regulate the expression of ER in the mink pituitary. Furthermore, all
      morphological and morphometric parameters of lactotropes activity appeared
      significantly increased in intact females, killed during the mating period,
      compared with castrated females under the same photoperiodic conditions.
      Castration thus blocks the stimulatory effect of photoperiod on metabolic
      activity of mink lactotropes suggesting that E may participate in the
      photoperiodic regulation of PRL.

PMID- 10336825
TI  - Hormonal effects on amino acids and related compounds in plasma, amniotic fluid,
      and allantoic fluid of the chicken embryo.
AB  - So far, more than 40 free amino acids and related compounds have been identified
      in plasma, amniotic fluid, and/or allantoic fluid of the 13-day chicken embryo.
      Concentration differences, and greatly varying behavior of these compounds under
      experimental conditions, revealed the presence of specific barriers among the
      three fluids. We tested the hypotheses that (1) the absence of an innervation of
      amnion and allantois indicates a hormonal control of their barriers, and (2)
      changes in the concentrations of certain amino compounds in the three fluids
      indicate anabolic or catabolic actions of hormones. Insulin, prolactin, and
      stress caused complex changes of the concentrations of amino compounds in all
      three fluids within 30 min. Some of these changes indicated breakdown of
      embryonic tissues, while others must have been due to transfer of amino compounds
      among the three fluid compartments. However, there was no significant effect on
      the glucose concentration in any of the three compartments under any of the
      experimental conditions. This is the first demonstration of hormonal effects on
      the amino compounds in the extraembryonic fluids of nonmammalian amniotes.

PMID- 10336826
TI  - A newly characterized melanotropin in proopiomelanocortin in pituitaries of an
      elasmobranch, Squalus acanthias.
AB  - Proopiomelanocortin (POMC) is a precursor for corticotropin (ACTH), three or
      fewer molecular types of melanotropin (MSH), and beta-endorphin. This protein is
      thought to have evolved by duplication of MSH genomic segments. Here we report
      that the POMC in the dogfish, an elasmobranch, contains a fourth type of MSH in
      addition to classical alpha-, beta-, and gamma-MSH. POMC cDNA was amplified by
      PCR from double-strand cDNA prepared from dogfish pituitary and ligated into
      lambdaZAP II. The POMC cDNA is composed of 1315 bp without a poly(A) tail.
      Northern blot analysis detected a 1.4-kb signal of dogfish POMC mRNA. An open
      reading frame of the POMC cDNA encodes 320 amino acids, including a signal
      peptide of 26 amino acids. The dogfish POMC includes gamma-MSH, ACTH, alpha-MSH,
      beta-MSH, and beta-endorphin at positions 50-61, 115-153, 115-127, 239-256, and
      259-294, respectively. In addition to these classical peptides, a newly
      discovered MSH, which we have termed delta-MSH, is present in dogfish POMC at
      position (184-195). The four dogfish MSHs can be separated into two groups based
      on their sequence identities: one pair consists of alpha-MSH and gamma-MSH, and
      the other consists of beta-MSH and delta-MSH, suggesting that gamma-MSH and delta
      MSH may have been duplicated evolutionarily from alpha-MSH and beta-MSH,
      respectively. gamma-MSH might first have appeared in early gnathostomes because
      it is absent in the most primitive vertebrate group, the agnathans. delta-MSH,
      which at this time is found only in chondrichthians, might have appeared after
      the divergence of chondrichthians from a lineage leading to osteichthyans and
      tetrapods.

PMID- 10336827
TI  - The effect of GH and IGF-I on preadipocytes from Large White and Meishan pigs in
      primary culture.
AB  - Proliferation and differentiation of preadipocytes from 7-day-old Large White
      (LW) and Meishan (MS) pigs were studied in primary culture. The effects of
      porcine GH (pGH) and IGF-I as well as the expression of GH (GHR) and IGF-I (IGF
      IR) receptors mRNA were examined. Preadipocytes were exposed to serum
      supplemented and serum-free medium to determine proliferation and
      differentiation, respectively. Proliferation was higher in MS than in LW pigs.
      Treatment with pGH (2 nM) or IGF-I (10 nM) resulted in a similar decrease in
      proliferation in LW and MS pigs. Parameters assessing differentiation and the
      effects of pGH and IGF-I on differentiation did not differ between the two
      breeds. The percentage of differentiating cells and LPL and ME activities were
      markedly reduced by pGH. IGF-I did not reduce differentiation significantly. Both
      GHR and IGF-IR mRNA were expressed in adipose tissue, adipocytes, preadipocytes,
      and 6-day-cultured cells from LW and MS pigs. The similar action of pGH and IGF-I
      on preadipocyte proliferation and differentiation, associated with the similar
      expression of GHR and IGF-IR mRNA in LW and MS pigs, suggests that the GH/IGF-I
      axis is not impaired in MS pigs. The difference in preadipocyte proliferation
      observed between LW and MS pigs could account for their adiposity difference.

PMID- 10336828
TI  - Effects of insulin on lipid metabolism of larvae and metamorphosing landlocked
      sea lamprey, Petromyzon marinus.
AB  - This study was designed to examine the role of insulin (INS) in regulating
      changes in lipid metabolism of larval and metamorphosing landlocked lamprey,
      Petromyzon marinus. Larvae and stage 6 metamorphosing individuals were injected
      intraperitoneally once per day for 2 days with either saline (0.6%), bovine INS
      (100 ng/g body weight), or alloxan (0.2 mg/g body weight). Insulin administration
      resulted in depressed plasma fatty acid (FA) levels, whereas alloxan injection
      elevated plasma FA levels at both life cycle intervals. In larvae, INS-induced
      hypolipidemia was attended by increased lipid concentration in kidney and muscle,
      reduced rates of lipolysis in kidney, liver, and muscle (as indicated by
      decreased triacylglycerol lipase activity), and, to a lesser extent, by higher
      rates of lipogenesis in kidney and muscle (as evidenced by higher acetyl-CoA
      carboxylase and/or diacylglycerol acyltransferase activities). In general, the
      effects of alloxan were opposite of those of INS. The alloxan-induced increase in
      plasma FA was supported by an enhanced rate of lipolysis in the kidney, a
      relatively lower rate of fatty acid synthesis in kidney, liver, and muscle, and a
      relatively lower renal rate of TG synthesis. In stage 6 metamorphosing lamprey,
      the INS-induced decline in plasma FA was attended by reduced renal and hepatic
      rates of lipolysis and by enhanced lipogenesis, as indicated by increased renal
      and hepatic rates of de novo fatty acid synthesis and hepatic and muscular rates
      of TG synthesis. In contrast, the increase in plasma FA induced by alloxan in
      stage 6 animals was supported by reduced TG synthesis in liver.
      Immunocytochemistry revealed that alloxan was not cytotoxic to pancreatic beta
      cells, suggesting that the effects of alloxan were extrapancreatic in the time
      frame of our study. Because insulin-induced lipogenesis and antilipolysis is
      similar to the pattern of lipid metabolism (phase I) displayed by lamprey during
      their spontaneous metamorphosis, INS may play a role, possibly in concert with
      other factors, in coordinating metamorphosis-associated changes in lipid
      metabolism.

PMID- 10336830
TI  - Time of thyroidectomy variably affects seasonality in female American tree
      sparrows (Spizella arborea).
AB  - Female American tree sparrows (Spizella arborea) were injected with Na131I
      before, at, or after the onset of photostimulation in order to study the effect
      of time of thyroidectomy on three components of seasonality: thyroid-dependent
      photoperiodic ovarian growth, photorefractoriness, and postnuptial (prebasic)
      molt. Thyroidectomy before or at the onset of photostimulation abolished all
      components of seasonality; birds exhibited only minor thyroid-independent
      photoperiodic ovarian growth. Thyroidectomy on day 7 of photostimulation blocked
      the transition from photosensitivity to photorefractoriness; although birds
      showed thyroid-dependent photoperiodic ovarian growth, they neither exhibited
      ovarian regression nor initiated postnuptial molt. Thyroidectomy on day 14, 21,
      or 28 of photostimulation had no remarkable effect on any component of
      seasonality. We conclude that separate mechanisms control photoperiodic ovarian
      growth and photorefractoriness/molt and that, early during photostimulation, the
      thyroid has a codependent role in programming female tree sparrows for vernal as
      well as autumnal seasonal events.

PMID- 10336829
TI  - Characterization of chromatophorotropic neuropeptides from the kuruma prawn
      Penaeus japonicus.
AB  - Three chromatophorotropic neuropeptide hormones were purified from an aqueous
      extract of the sinus glands of the kuruma prawn Penaeus japonicus by two steps of
      reverse-phase HPLC and their amino acid sequences determined. One of them was
      found to show pigment concentrating activity and to have an amino acid sequence
      identical with that of the known red pigment concentrating hormone (RPCH), and
      therefore it was named Pej-RPCH. The other two peptides showed pigment dispersing
      hormone (PDH) activity and were named Pej-PDH-I and -II. They both consisted of
      18 amino acid residues with a free amino-terminus and an amidated carboxyl
      terminus, the sequences of Pej-PDH-I and -II being NSELINSLLGIPKVMTDAamide and
      NSELINSLLGLPKFMIDAamide, respectively. Three amino acid residues at positions 11,
      14, and 16 differed between the two PDHs. Pej-PDH-II was about 5-, 7-, and 10
      fold more potent than Pej-PDH-I for erythrophores, xanthophores, and
      melanophores, respectively. The major reason for the difference in potency
      between the two PDHs was attributed to differences in residues at position 16. In
      addition, they were found to be produced by a single individual. The order of
      sensitivity of the four types of chromatophores to Pej-RPCH and both PDHs was
      found to be erythrophores = xanthophores > melanophores > leukophores.

PMID- 10336831
TI  - Streptozotocin dose-response curve in tilapia, a glucose-responsive teleost fish.
AB  - Streptozotocin (STZ) causes beta cell necrosis and insulin-dependent diabetes in
      many species. The specificity of this beta cell toxin relates to its structure as
      an alkylating agent with an attached glucose moiety. STZ uptake by rodent beta
      cells appears to be via the GLUT-2 glucose transporter. Teleost fish, in general,
      are severely glucose intolerant. The effects of STZ were examined in tilapia, a
      teleost fish with highly glucose-responsive islets. Fasted tilapia were given 0,
      100, 150, 200, 250, 300, or 350 mg/kg STZ iv. Plasma glucose levels were followed
      for 72 h and the fish autopsied. Histological sections of islets were stained by
      immunoperoxidase for tilapia insulin. Severe hyperglycemia was seen in 20, 80,
      and 100% of fish receiving 250, 300, and 350 mg/kg doses; however, sections of
      islets showed only partial degranulation with no evidence of beta cell necrosis.
      Another group of fish receiving the highest dose were followed longer to
      determine whether beta cell necrosis and permanent hyperglycemia ensued. All fish
      died or were killed within 9 days because of severe hepatic failure characterized
      by hepatic necrosis, jaundice, and ascites; islet morphology was relatively
      normal suggesting, even in a glucose-sensitive species, that fish islets either
      do not take up STZ or are highly resistant to its "diabetogenic" effects. Tilapia
      may thus be a useful model to elucidate mechanisms of action of STZ. Furthermore,
      STZ may provide important insights into differences in glucose uptake and
      metabolism by mammalian and piscine beta cells.

PMID- 10336832
TI  - cDNA cloning and developmental alterations in gene expression of the two Pit
      1/GHF-1 transcription factors in the chicken pituitary.
AB  - Pit-1/GHF-1 (Pit-1) transcription factors promote the gene expressions for growth
      hormone (GH), prolactin (PRL), and the beta chain of thyroid-stimulating hormone
      in vertebrate pituitary glands. The present study analyzed the nature of chicken
      Pit-1s (cPit-1s) and their developmental expressions in the pituitary. Chicken
      pituitary expressed two cPit-1 mRNAs encoding cPit-1alpha and cPit-1gamma
      composed of 335 and 327 amino acid residues, respectively. They possessed
      different N-terminal regions and the common C-terminal regions containing a POU
      specific domain and a POU homeodomain. Northern blot analysis revealed the
      pituitary-specific expressions of these Pit-1 mRNAs, and the Pit-1alpha mRNA
      expressions were two to three times higher than those for Pit-1gamma in both
      cephalic and caudal lobes of the pituitary. The cPit-1alpha and gamma mRNA
      expressions simultaneously increased after hatching until 4 weeks and then
      slightly decreased at 5 weeks. Similar gene expression profiles were observed for
      GH and PRL during the posthatch developmental period.

PMID- 10336833
TI  - Development and differentiation of gonadotropin hormone-releasing hormone
      neuronal systems and testes in the Japanese eel (Anguilla japonica).
AB  - In this study we investigated the relationship between the development of the
      olfactory, preoptic, and midbrain gonadotropin-releasing hormone (GnRH) neuronal
      systems and testicular differentiation in eels (Anguilla japonica) from embryonic
      stages through adulthood (5.4-50 cm body length). GnRH-synthesizing neuronal
      populations were first observed in the youngest fish ( approximately 5.0 cm) at
      the rostrobasal and caudalmost olfactory bulbs immunoreactive to a "promiscuous"
      (nonspecific) GnRH antiserum (635.5), and in the preoptic area and midbrain
      tegmentum immunoreactive to chicken GnRH II antiserum. The eel brains lacked
      salmon and seabream GnRH immunoreactivity. The evidence from our study suggests
      that the olfactory, preoptic, and midbrain GnRH populations have origins
      independent from those of proliferative periventricular zones within the brain.
      However, the olfactory GnRH neurons could have migrated out of the olfactory
      placodes during ages earlier than those observed in this study. Although all
      three GnRH neuronal populations contribute to pituitary innervation to some
      degree, the preoptic GnRH innervation was pronounced in the pituitary when
      primordial germ cells (animals approximately 5.0 cm) differentiated into male
      germ cells (animals 14-16 cm) and, therefore, an association can be assumed
      between preoptic GnRH expression and testicular differentiation in the Japanese
      eel.

PMID- 10336834
TI  - Cholecalciferol modulates plasma phosphate but not plasma vitamin D levels and
      intestinal phosphate absorption in rainbow trout (Oncorhynchus mykiss).
AB  - Since the vitamin D endocrine system modulates phosphorus homeostasis and
      regulates inorganic phosphate (Pi) uptake by the small intestine in mammals and
      birds, we determined the effects of dietary cholecalciferol (vitamin D3) on Pi
      uptake by the small intestine, Pi concentrations in the plasma, Pi concentrations
      in the intestinal lumen, intestinal weights, liver weights, and concentrations of
      vitamin D metabolites in the plasma of rainbow trout (Oncorhynchus mykiss) fed
      phosphorus-sufficient (0.6 g/100 g) diets. Five groups of trout initially
      weighing 55.8 +/- 0.6 g were fed purified diets containing 0, 300, 2,500, 10,000,
      and 40,000 IU vitamin D3/kg diet over a 7- to 8-day feeding period. Plasma Pi
      concentration was higher in trout fed 2,500-40,000 IU/kg diet (8.26 +/- 0.27
      mmol/L) than in those fed 0 and 300 IU/kg (6.99 +/- 0.30). Liver weights were 30
      50% greater in fish fed 0 IU/kg than in those fed 300-40,000 IU/kg. There were no
      significant, diet-related differences in plasma levels of 25
      hydroxycholecalciferol [25(OH)D3] and 1,25 dihydroxycholecalciferol
      [1,25(OH)2D3]. Increasing levels of dietary cholecalciferol also did not enhance
      in vitro Pi uptakes by the intestine (range of means: 0.22-0.29 nmol/mg tissue.
      min) and Pi concentrations in the intestinal lumen (8.5-13.5 mmol/L). Pi uptake
      did not differ among tissues incubated in vitamin D3, 25(OH)D3, or 1,25(OH)2D3.
      These results demonstrate that when fish are fed P-sufficient diets, dietary
      cholecalciferol increases plasma Pi concentrations but decreases liver weights,
      alterations which are not accompanied by changes in intestinal weight, Pi uptake
      by the intestine, Pi concentration in the intestinal lumen, and circulating
      metabolites of cholecalciferol.

PMID- 10336835
TI  - Therapeutic strategies to reduce TNF-alpha mediated cardiac contractile
      depression following ischemia and reperfusion.
AB  - Recent evidence has implicated proinflammatory mediators such as TNF- alpha in
      the pathophysiology of ischemia-reperfusion (I/R) injury. Clinically, serum
      levels of TNF-alpha are increased after myocardial infarction and after
      cardiopulmonary bypass. Each of these represent clinically relevant instances of
      cardiac I/R injury. We and others have recently reported that TNF-alpha is
      produced by the heart following experimental I/R in animals and that TNF-alpha
      directly decreases animal and human myocardial contractility in a dose dependent
      fashion. Thus, strategies to reduce or neutralize myocardial TNF- alpha
      production should conceptually decrease myocardial contractile dysfunction
      following I/R. The purposes of this manuscript are: 1) to explore the clinical
      and experimental instances of I/R injury in which TNF-alpha is elevated, 2) to
      review the molecular mechanisms of TNF- alpha induced contractile dysfunction, 3)
      to examine both experimental and clinical strategies of reducing myocardial TNF
      alpha production, and 4) to determine the influence of reducing post-I/R TNF
      alpha on cardiac contractile function in both animals and man.

PMID- 10336836
TI  - Renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes.
AB  - In response to humoral and mechanical stimuli, the myocardium adapts to increased
      work load through hypertrophy of individual muscle cells. Myocardial hypertrophy
      is characterized by an increase in cell size in the absence of cell division and
      is accompanied by changes in gene expression. Angiotensin II (ANG II), the
      effector peptide of the renin-angiotensin system (RAS), regulates volume and
      electrolyte homeostasis and is involved in cardiac and vascular growth in rats.
      In this review, the role of RAS on the myocyte protein synthesis (myocyte
      hypertrophy) and on the induction of gene expression will be discussed in rat
      cardiomyocytes in culture. The traditional RAS can be considered as a system in
      which circulating ANG II is delivered to target tissues or cells. However, a
      local RAS has also been described in cardiac cells and evidence has been
      accumulated for autocrine and/or paracrine pathways by which biological actions
      of ANG II can be mediated. These actions of ANG II are primarily mediated through
      ANG II receptors of the subtype I (AT1-R). When evaluating the effects of ANG II
      in situ, both changes in circulating levels and local production have to be taken
      into account. Discrepant findings on the in vitro effect of ANG II on the protein
      synthesis in cardiac myocytes are described and can be at least partly be
      attributed to methodological problems such as assay of the de novo protein
      synthesis, isolation and the separation procedure of cardiac myocytes. The ANG II
      induced hypertrophic effect also depends on the existence of non-myocytes in a
      cardiocyte culture. In rat cardiocytes ANG II also causes induction of many
      immediately-early genes (c-fos, c-jun, jun-B, Egr-1 and c-myc) and induces also
      late markers of cardiac hypertrophy (skeletal alpha-actin and atrial natriuretic
      peptide expression) and growth factors (TGF-beta1 gene expression). In vivo ANG
      II via AT1-R, causes not only ventricular hypertrophy, independently of blood
      pressure, but also a shift to the fetal phenotype of the myocardium. Angiotensin
      converting enzyme inhibitors and ANG II receptor antagonists of the subtype I not
      only induce the regression, but also prevent the development of cardiac
      hypertrophy in experimental rat models.

PMID- 10336837
TI  - Identification and quantitation of cAMP-dependent protein kinase R subunit
      isoforms in subcellular fractions of failing human myocardium.
AB  - Isoforms of regulatory (R) subunits of cAMP-dependent protein kinase were
      identified immunochemically and quantified in soluble and washed particulate
      fractions of failing human left ventricular myocardium. The predominant isoforms
      in both fractions were RI alpha and RII alpha. Both isoforms were present in
      comparable amounts in these fractions, although RII alpha subunits were somewhat
      more prevalent than RI alpha subunits in washed particulate fractions. The ratio
      of R subunits to catalytic (C) subunits was three-fold higher in soluble than in
      particulate fractions. Identical observations were made in preparations from non
      failing human left ventricular myocardium. Since RI and RII have different
      affinities for cAMP and may direct catalytic activity to different substrates,
      the presence of both subunits in both soluble and particulate fractions provides
      a mechanism whereby the compartment-selective changes in cAMP content that have
      been described in failing human myocardium may affect not only the level but also
      the profile of protein phosphorylation in these compartments. The high R:C
      subunit ratio in soluble fractions suggests that cytosolic kinase activity in
      human myocardium may be less sensitive to changes in cAMP content than membrane
      bound kinase activity, and this may contribute to the different effects of
      increases in soluble and particulate cAMP content on intracellular Ca2+transients
      and contraction and relaxation.

PMID- 10336838
TI  - ATP-sensitive K+ channels mediate the delayed cardioprotective effect of
      adenosine A1 receptor activation.
AB  - Adenosine A1 receptor stimulation increases myocardial resilience to ischaemia
      many hours later but the mechanism of protection is unclear. We hypothesized that
      A1 receptor-induced delayed cardioprotection is mediated by KATP channel opening.
      Rabbits were pretreated with saline or the selective A1 receptor agonist 2-chloro
      N6-cyclopentyladenosine (CCPA), 0.1 mg/kg i.v. After 24 h, they were
      anaesthetized and subjected to 30 min left coronary artery occlusion (CAO) and
      120 min reperfusion. Twenty minutes before CAO, either glibenclamide 0.3 mg/kg,
      sodium 5-hydroxydecanoate (5-HD) 5 mg/kg, or a corresponding volume of vehicle
      solution were given i.v. Infarct size as a percentage of ischaemic risk volume
      (I/R%) was assessed by triphenyltetrazolium. In the absence of either
      glibenclamide or 5-HD, CCPA pretreatment resulted in significant limitation of
      infarction (I/R 23.4+/-3.3%vs 39.6+/-2.6% in saline pretreated animals, P<0.01).
      Administration of glibenclamide before CAO abolished this delayed protective
      effect of CCPA (I/R 37.4+/-4. 7%), as did 5-HD (I/R 48.8+/-3.7%). Neither
      glibenclamide nor 5-HD significantly modified I/R in saline pretreated animals.
      Risk volume was similar in all groups (0.8-1.1 cm3). Systemic haemodynamic
      variables were not markedly different between any of the groups immediately
      before or during the ischaemia-reperfusion protocol. Thus, delayed protection
      following transient A1 receptor activation was abolished by pre-ischaemic
      treatment with either glibenclamide or 5-HD, providing pharmacological evidence
      that KATP channel opening mediates A1 agonist-induced delayed myocardial
      protection. The inhibitory effect of 5-HD suggests specific involvement of
      mitochondrial KATP but the mechanisms of sub-acute regulation of KATP function
      following A1 receptor stimulation remain to be determined.

PMID- 10336839
TI  - Chamber-related differences in connexin expression in the human heart.
AB  - Electrical coupling in the heart is mediated by gap junctions, aggregates of cell
      to-cell channels composed of connexins. The principal cardiac gap-junctional
      connexin, connexin43 (Cx43), is reduced in diseased human myocardium that is
      prone to arrhythmia. Three additional connexin isoforms, Cx40, Cx45 and Cx37, of
      distinctive functional capacities in vitro, are expressed in cardiovascular
      cells, but our knowledge of their expression patterns in the human heart is
      fragmentary. In the present study, we therefore applied Northern blotting,
      Western blotting and immunoconfocal microscopy to analyse and compare the
      expression of Cx43, Cx40, Cx37 and Cx45 mRNA and protein in the human left
      ventricle, right ventricle, left atrium and right atrium of the human heart. Cx43
      was confirmed to be abundantly expressed at similar levels by myocytes in all
      four chambers. Cx40 levels varied between chambers in the order right atrium
      >left atrium >/= right ventricle approximately left ventricle. Cx37 (exclusively
      expressed in the endothelium) was expressed at similar overall levels in all
      chambers (as judged from Northern blots). Cx45 was detectable only at very low
      levels, with a trend toward higher levels in the atria than the ventricles in a
      pattern similar to Cx40. The results indicate that in humans, the ventricles and
      atria have distinctive connexin expression profiles, and that the atrial-type
      connexin profile is more pronounced in the right atrium than the left atrium.
      While the ventricular connexin expression pattern resembles that of other
      mammalian species, atrial connexin expression shows greater species variation.
      These differences contribute to the interpretative framework for examining the
      potential role of altered connexin expression in ventricular and atrial
      arrhythmia in the human heart.

PMID- 10336840
TI  - Appearance and regression of rat pouch tissue.
AB  - Fibrosis, a consequence of tissue repair, can become a final common pathway to
      organ failure, if progressive. Prevention and regression of organ fibrosis
      represent targets of considerable interest. The natural fate of fibrosis differs
      among various tissues being either persistent, progressive or regressive.
      Cellular and molecular responses involving myofibroblasts (myoFb), a
      phenotypically transformed fibroblast-like cell of considerable functional
      diversity, is involved in collagen turnover at sites of repair, where they govern
      the fate of fibrosis. Insights gained from the natural regression of established
      fibrous tissue may offer strategies to remove unwanted fibrosis in failing
      organs. In the present study, we addressed the temporal sequence to various
      components of collagen synthesis and degradation involved in the appearance and
      subsequent regression of pouch tissue induced in the rat by subcutaneous
      injection of air followed by instillation of the phorbol ester croton oil. Pouch
      tissue was collected on day 2, 4, 10, 14, 21, 28 and 35 (n=6 at each time point).
      Activities of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of MMP-1
      (TIMP-1) were determined by zymography and reverse zymography, respectively;
      collagen accumulation by hydroxyproline concentration; gene expression of TIMP-1
      or tissue inhibitor of MMP-1, type I collagen and transforming growth factor
      beta1 (TGF-beta1) by in situ hybridization; TGF-beta1 concentration by sandwich
      enzyme-linked immunosorbant assay (ELISA); and myoFb and its phenotypes by
      immunohistochemistry using antibodies to alpha-smooth muscle actin (alpha-SMA),
      vimentin or desmin. During pouch tissue formation, we found: (1) pouch weight
      increased progressively from day 2 to day 14 and then declined progressively
      thereafter; (2) type I collagen mRNA expression, barely detectable at day 2,
      increased at day 4, together with tissue hydroxyproline concentration (P<0.05)
      reaching a peak on day 10, and gradually decreased thereafter in association with
      declining tissue hydroxyproline concentration; (3) mRNA expression and
      concentration of TGF-beta1, detectable at day 2, significantly (P<0.05) increased
      at day 4, reached a peak at day 10, and gradually declined thereafter; (4) MMP-1
      activity, low at day 2, increased continually over the course of 35 days; (5)
      TIMP-1 mRNA, detectable at day 2 and significantly (P<0.05) increased at day 4,
      gradually decreased thereafter; (6) activity of TIMP-1 increased continuously
      from day 2 to day 14 and then was markedly reduced thereafter; and (7) myoFb were
      first observed in pouch tissue at day 4 and became more extensive thereafter with
      their phenotype changing over time. Early appearing myoFb (day 4, 10, 14, and 21)
      expressed alpha -SMA and vimentin (VA phenotype), while later appearing cells
      (day 28 and 35) additionally expressed desmin (VAD phenotype). Thus, in croton
      oil-induced rat pouch model, the subcutaneous accumulation of pouch tissue
      hydroxyproline over the course of 10 days is initially associated with a VA
      positive myoFb phenotype and its transcription of TGF-beta1, type I collagen and
      TIMP-1. Beyond day 10, a regression of pouch tissue collagen begins in
      association with the appearance of a VAD-positive myoFb phenotype and progressive
      increase in MMP-1 activity as the expression of TIMP-1 and TGF-beta1 are
      withdrawn. Regression of established fibrosis in failing organs may, therefore,
      be attainable through manipulation of myoFb phenotype and/or enhanced collagen
      degradation relative to collagen synthesis.

PMID- 10336841
TI  - Cell death in the endocardial cushions of the developing heart.
AB  - The incidence of apoptotic cells in the hearts of chick embryos between days 4
      and 8 of development was examined using an in situ technique for the detection of
      DNA fragmentation. Using this method it was possible to demonstrate foci of
      apoptotic cells primarily in two locations: the outflow tract cushions and the
      atrioventricular cushions. Both occurred only during narrow time windows: between
      embryonic days 4.5 and 6.5 in the outflow tract, and between embryonic days 5.5
      and 7.5 in the atrioventricular canal. This is a much more restricted
      distribution of dying cells than previously thought, with reproducible cell death
      notably absent from the atrial and ventricular walls. Dying cells were also
      unexpectedly absent from the fusion seam of apposed cushions. In a complementary
      study, cell proliferation in these tissues was examined over the same time period
      using the expression of proliferating cell nuclear antigen as a marker for
      dividing cells. Cell proliferation occurred throughout the region of the cushions
      at these stages, including the myocardium and the fusion points of the apposed
      cushions. It is concluded that cells undergoing programmed cell death at this
      time in the developing chick heart are abundant in, and largely restricted to,
      the cushion tissue, and that cushion morphogenesis is regulated by the co
      ordination of cell transformation, cell proliferation and, during a narrow time
      window, cell death.

PMID- 10336842
TI  - Characterization of a unique genetic variant in the beta1-adrenoceptor gene and
      evaluation of its role in idiopathic dilated cardiomyopathy. CARDIGENE Group.
AB  - The genetic factors that underlie idiopathic dilated cardiomyopathy (IDCM) have
      not yet been elucidated. Since beta1-adrenoceptors are downregulated in patients
      with IDCM, and since beta-blocker therapy is consistently beneficial in this
      setting, we hypothesized that genetic variation in the beta1-adrenoceptor might
      affect susceptibility to and/or severity of IDCM. As no intragenic polymorphism
      was available, a systematic screening of the gene was first performed. The
      organization and sequence of the human beta1-adrenoceptor gene were established
      using polymerase chain reaction, single-strand conformation polymorphism analysis
      and sequencing. The gene comprises 1434 bp and no intron was observed. We found a
      unique and frequent polymorphism (C1165G) which predicts an Arg389Gly
      substitution. The association of this polymorphism with IDCM was then analysed
      using the PCR-restriction fragment length polymorphism method in the CARDIGENE
      population, a clinically well-characterized population of IDCM. Genotypic
      distribution was in agreement with Hardy-Weinberg equilibrium. There were no
      differences in the beta1-adrenoceptor allele frequencies between IDCM (n=426;
      C/G=0.76/0.24) and age- and sex-matched control subjects (n=395; C/G=0.78/0.22).
      Within the patient group, no association was observed with the severity of the
      disease. In conclusion, the genomic organization of beta1-adrenoceptor is
      described here for the first time. We found a unique and frequent polymorphism in
      the coding sequence of the gene. No association was observed between IDCM and the
      genetic variant. Its possible involvement in other cardiac diseases related to
      the beta1-adrenoceptor remains to be analysed.

PMID- 10336843
TI  - Pharmacological characterization of effects of UK-1745, a novel cardiotonic agent
      with beta-adrenoceptor-blocking action, in aequorin-loaded canine right
      ventricular muscle.
AB  - UK-1745, a derivative of furoindolinone, is a novel cardiotonic agent that was
      designed to have both beta-adrenoceptor-blocking and cardiotonic activity. The
      aim of this study was to clarify the mode of action of UK-1745 in the canine and
      rabbit myocardium. UK-1745 elicited a weak but definite concentration-dependent
      positive inotropic effect in association with a decrease in the total duration of
      contraction: in particular, a decrease in the relaxation time in isolated canine
      right ventricular trabeculae. The maximum positive inotropic effect of UK-1745
      was achieved at 3x10(-5)m and amounted to approximately 15% of the maximum
      response to isoproterenol. The EC50 for the positive inotropic effect of UK-1745
      was 3.3x10(-6)m. Carbachol, a muscarinic receptor agonist, at 3x10(-6)m
      completely inhibited the positive inotropic effect of UK-1745. UK-1745 shifted
      the concentration-response curve for isoproterenol to the right with pA2 value of
      5.70. By contrast, UK-1745 at 3x10(-7)to 3x10(-5)m shifted the concentration
      response curve for forskolin to the left. In aequorin-loaded ventricular
      trabeculae, UK-1745 induced a positive inotropic effect that was accompanied by
      an increase in Ca2+ transients. It did not affect the relationship between the
      amplitude of Ca2+ transients and peak force as compared with that associated with
      elevation of the extracellular concentration of Ca2+ ions ([Ca2+]o). The level of
      cyclic AMP in tissue was not significantly increased at 3x10(-5)m UK-1745. The
      present results indicate that UK-1745 exerts a positive inotropic effect mainly
      via a cyclic AMP-dependent mechanism but, in addition, it has beta-adrenoceptor
      blocking activity over the same range of concentrations. A drug with such a
      pharmacological profile might have the potential advantage of avoiding Ca2+
      overload and superfluous oxygen consumption, which may contribute to the
      unfavorable effects of novel cardiotonic agents that act purely by inhibition of
      phosphodiesterase III.

PMID- 10336845
TI  - Inhibition of apoptosis after ischemia-reperfusion in rat myocardium by
      cycloheximide.
AB  - Macromolecular synthesis inhibitors protect cells from apoptosis in many systems.
      To determine whether the protein synthesis inhibitor cycloheximide (CHX) might
      inhibit apoptosis and protect the myocardium during ischemia-reperfusion, we
      subjected isovolumic isolated perfused rat hearts to 25 min of normothermic
      global ischemia followed by reperfusion. We monitored coronary flow, end
      diastolic pressure and rate-pressure product (RPP) throughout and assessed
      apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end
      labeling (TUNEL). Regardless of the treatment regimen (only before ischemia; only
      during reperfusion; or both before ischemia and during reperfusion), CHX
      significantly improved functional recovery during reperfusion. These effects were
      most pronounced when CHX was present during reperfusion. When hearts were treated
      with CHX only during reperfusion the recovery of sinus rhythm was more frequent
      in the CHX-treated hearts than control hearts (80% v 53%) and earlier for CHX
      treated than control hearts: 6.4 +/- 2 v 19.4 +/- 4.7 min of reperfusion. The
      maximal RPP recoveries for the CHX-treated hearts were 45 +/- 4.0% (P=0.005) of
      pre-ischemic values, compared to 26 +/- 3% for controls. In control hearts
      reperfused for 2 h, TUNEL identified 49.5 +/- 10 intact nuclei and 7.5 +/- 2
      fragmented nuclei per 1000 nuclei counted. A significantly lower incidence of
      labeled nuclei with or without fragmentation was observed in CHX treated hearts:
      7.6 +/- 3.4 (P=0.009) intact labeled nuclei and 1.8 +/- 0.7/10(3)fragmented
      labeled nuclei. Our results suggest that CHX-induced inhibition of apoptosis in
      reperfused myocardium is cardioprotective and promotes functional recovery in
      vitro.

PMID- 10336844
TI  - Pyridoxal 5'-phosphate is an ATP-receptor antagonist in freshly isolated rat
      cardiomyocytes.
AB  - Although extracellular ATP is considered to exert a positive inotropic action on
      the myocardium through purinoceptors, very little information is available
      regarding interventions which may modify the actions of ATP on the heart. We
      report here that pyridoxal 5'-phosphate (PLP), an active form of vitamin B6,
      shows antagonism towards ATP-induced positive inotropic effect in isolated
      perfused rat hearts, ATP-induced increase in [Ca2+] in freshly isolated adult
      cardiomyocytes and ATP-binding in cardiac sarcolemma; ED50 for PLP in each of
      these cases varied from 10-15 microM. PLP (5-50 microM) was observed to
      antagonize the positive inotropic effect of ATP but did not modify the action of
      isoproterenol in the isolated perfused heart. Preincubation of cardiomyocytes
      with 1-50 microM PLP prevented the ATP-induced increase in [Ca2+]i in a
      concentration-dependent manner but showed no effect on the KCl-induced increase
      in [Ca2+]i. Creatine phosphate and Na2HPO4 as well as vitamin B6-related
      compounds, such as pyridoxine, pyridoxal, 4-deoxypyridoxine and isonicotinic acid
      hydrazide showed no effect on the ATP-induced increase in [Ca2+]i in
      cardiomyocytes. Furthermore, different concentrations of PLP (1-50 microM) were
      shown to inhibit the specific ATP gamma S binding at both the high and low
      affinity sites in the cardiac sarcolemmal membrane; adrenoceptor and Ca2+-channel
      inhibitors did not affect the ATP-binding. It is concluded that PLP may
      antagonize the actions of ATP on the heart in a selective manner and both
      pyridoxal and phosphate moieties are essential for its action. Furthermore, it is
      suggested that PLP may serve as a valuable tool for monitoring the role of
      purinoceptors in cellular function.

PMID- 10336846
TI  - PKC-dependent preconditioning with norepinephrine protects sarcoplasmic reticulum
      function in rat trabeculae following metabolic inhibition.
AB  - The authors have previously shown that norepinephrine (NE) pretreatment
      attenuates Ca2+ overloading in cardiac rat trabeculae during metabolic
      inhibition, and improves contractile function during a subsequent recovery
      period. The present study investigated: (i) whether protection of sarcoplasmic
      reticulum (SR) function during metabolic inhibition (MI) is involved in the
      preconditioning-like effect of NE-pretreatment, and (ii) whether or not this
      process is PKC-dependent. A 15 min preincubation period was used with 1
      micromol/l exogenous NE to precondition isolated, superfused rat trabeculae
      against contractile dysfunctioning following 40 min of MI in 2 mmol/l NaCN
      containing Tyrode (gassed with 95% O2/5% CO2; pH 7.4, 24 degrees C) without
      glucose at 1-Hz stimulation frequency. Contractile recovery was studied during a
      subsequent 60 min recovery period (RP) in glucose containing Tyrode at 0.2 Hz.
      Force and intracellular free calcium ([Ca2+]ii) were monitored throughout the
      experimental protocol. Pretreatment of trabeculae with NE (group NE)
      substantially diminished the Ca2+ rise from the onset of rigor development during
      MI, compared to preparations which were pretreated with NE, in the presence of
      specific PKC blocker chelerythrine (2 micromol/l; group NE+CHEL). After 40 min of
      MI, resting [Ca2+]i in group NE and NE+CHEL was increased to 0.50+/-0.03 and
      2.08+/-0.20 micromol/l, respectively (P<0.05), whereas total intracellular ATP
      levels were similar in both groups (approximately 0.20 micromol/g dry wt). This
      corresponded with an increase in active force development (119%) and a decrease
      in twitch force relaxation time (77%) during subsequent RP in group NE, compared
      to pre-MI values of the same group. In contrast, a significant decrease in force
      recovery (54%) and an increase in twitch force relaxation time (123%) was
      observed in group NE+CHEL. Values for [Ca2+]i, contractile recovery, and twitch
      force relaxation time in untreated controls as well as CHEL preparations
      corresponded to those measured in the NE+CHEL group. Rapid cooling contractures
      (RCCs), which provide information on both SR-Ca2+ loading and Ca2+ re-uptake
      activity, revealed a 2-fold higher SR Ca2+ content during RP in group NE compared
      to controls and group NE+CHEL. In addition, kinetic analysis of the RCC rewarming
      spike (RWS) showed that this was accompanied by greater than a 28% increase in
      the maximum rate of RWS relaxation (-dF/dt/rws) in group NE compared to group
      NE+CHEL. The change of -dF/dt/rws in the NE group during RP following MI
      persisted after SR Ca2+-release channel blockade by ryanodine treatment (100
      micromol/l), which suggests involvement of NE-induced, PKC-dependent protection
      of SR Ca2+-ATPase activity. The results of the present study point to an inverse
      relationship between the Ca2+ rise during MI and SR functioning, in which PKC
      appears to play a key role. It is concluded that the preconditioning-like effect
      of NE-pretreatment on contractile recovery is at least partly mediated by
      protection of SR function.

PMID- 10336847
TI  - Activation of a beta-adrenergic-sensitive signal transduction pathway by the
      secosteroid hormone 1,25-(OH)2-vitamin D3 in chick heart.
AB  - In recent studies we have established that 1 alpha, 25-dihydroxy-vitamin
      D3[1,25(OH)2D3] rapidly stimulates dihydropyridine-sensitive calcium channel
      mediated Ca2+influx in chick cardiac muscle by a non-genomic action which is
      accompanied by PKA-dependent phosphorylation of a 45 kDa microsomal membrane
      protein. To investigate the signal transduction pathway activated by 1,25(OH)2D3
      in heart, we have compared the effects of the secosteroid hormone with those of
      the beta-adrenergic agonist isoproterenol (IPT) by employing cultured chick
      embryonic cardiac cells (myocytes) and thin-slice preparations of differentiated
      adult heart muscle. The increases in 45Ca2+ uptake and intracellular calcium
      ([Ca2+]i), cyclic AMP accumulation and changes in microsomal protein
      phosphorylation evoked by 1,25(OH)2D3 could be reproduced by IPT. When combined
      treatments with the sterol and the beta-adrenergic agonist were performed, no
      additive stimulation of these parameters was observed, suggesting that a common
      signal transduction pathway mediates the effects of 1,25(OH)2D3 and IPT. The
      participation of a guanine nucleotide binding protein (G protein) in the 1,
      25(OH)2D3-induced changes in heart was investigated. AlF4(-), an activator of G
      proteins, and cholera and pertussis toxins, like 1, 25(OH)2D3 increased 45Ca2+
      uptake by myocytes. AlF4(-) did not further stimulate the effects of 1,25(OH)2D3
      thereby showing that a G protein is involved in the hormone action. Moreover,
      1,25(OH)2D3 potentiated pertussis toxin but was unable to modify choleric toxin
      dependent myocyte Ca2+ influx. Altogether, these results provide evidence
      indicating that the non-genomic action of 1,25(OH)2D3 on cardiac muscle calcium
      influx involves modulation of the beta-adrenergic-sensitive adenylyl
      cyclase/cAMP/PKA pathway coupled to a Gs protein.

PMID- 10336848
TI  - Time course of alterations in phospholipid fatty acids and number of beta
      adrenoceptors in the rat heart during adrenergic stimulation in vivo.
AB  - The purpose of this study was to test the hypothesis that catecholamine induced
      down-regulation of beta-adrenoceptors in cardiac muscle is facilitated by
      modifications of the lipid milieu in cellular membranes. The time course of down
      regulation of beta -adrenoceptors and changes in the fatty acid composition of
      phospholipids was examined in the rat heart during adaptation to repeated
      epinephrine administration. By this we studied a possible relationship between
      modulation of the membrane phospholipids and the properties of beta-adrenoceptors
      during 7 days of epinephrine administration. The fatty acid composition of
      cardiac membrane phosphatidylcholine (PC) and phosphatidylethanolamine (PE) and
      Bmax and Kd of [3H]dihydroalprenolol binding to beta -adrenoceptors were measured
      in rats after 1, 2, 3, 5 and 7 days of epinephrine administration. The in vivo
      adrenergic stimulation led to a significant response of phospholipid fatty acyl
      chains. In both PC and PE the linoleic acid (18:2n-6) level decreased markedly.
      The docosahexanoic acid (22:6n-3) level increased in PE and the arachidonic acid
      (20:4n-6) level increased in PC. These fatty acid changes were all significant
      after 3-5 days of epinephrine administration. During the 7 day epinephrine
      administration, the polyunsaturated fatty acid levels in the phospholipids of
      purified cardiac sarcolemma changed in the same way as in the phospholipids of
      whole ventricular muscle. The number of binding sites of beta -adrenoceptors
      (Bmax) decreased as expected. The decrease in Bmax occurred later than the
      changes in their lipid environment and was only significant after 7 days of
      epinephrine administration. The conclusion is that during adaptation to
      epinephrine administration, the down-regulation of beta-adrenoceptors is preceded
      by alterations in the polyunsaturated fatty acid composition of phospholipids in
      heart muscle. This supports the concept of a regulatory role of membrane lipids
      in the response of beta-adrenoceptors to prolonged stimulation.

PMID- 10336849
TI  - Delayed endothelial protective effects of monophosphoryl lipid A after myocardial
      ischemia and reperfusion in rats.
AB  - Monophosphoryl lipid A (MLA) induces delayed (24 h) myocardial protection in
      various animal models of ischemia/reperfusion injury, and thus mimics the second
      window of preconditioning against cardiac injury. However, the potential
      endothelial protective effects of this drug have not been evaluated. The present
      study was designed to assess whether MLA exerts delayed protective effects
      against reperfusion-induced coronary endothelial dysfunction in rats, as well as
      the protective role of iNOS in this protection. Wistar rats received a single
      i.v. injection of MLA (450 microg/kg) or solvent. Twenty-four hours later, they
      were anesthetized and subjected to 20 min ischemia with 60 min reperfusion, in
      the absence or the presence of the iNOS inhibitor aminoguanidine (300 mg/kg
      i.p.). At the end of reperfusion, 1.5-2 mm coronary segments (average diameter
      250 microm) were removed distal to the site of occlusion and mounted in wire
      myographs. Endothelium-dependent relaxations to acetylcholine were determined in
      arteries pre-contracted by serotonin. Ischemia/reperfusion induced a marked
      decrease in the coronary responses to acetylcholine (maximal relaxations: sham
      64+/-8%, n=8; ischemia/reperfusion: 41+/-9%, n=8 P<0.05). This impaired response
      was partially restored by MLA (55+/-4%, n=10 P<0.05 vs ischemia/reperfusion). The
      effect of MLA was not affected by aminoguanidine (57+/-5%, n=6). Thus, in
      addition to protecting myocytes, MLA induces a delayed protection against
      coronary endothelial dysfunction. However, in contrast to its effects on
      myocytes, the endothelial protective effects do not appear to involve iNOS.

PMID- 10336850
TI  - Quantitation of Na/Ca exchanger function in single ventricular myocytes.
AB  - A Na/Ca exchange current can be elicited in voltage clamped single ventricular
      myocytes by the abrupt removal of extracellular Na+ by means of a rapid switcher
      device. We measured this reverse Na/Ca exchange current in isolated mouse
      ventricular myocytes from wild-type mice, and from transgenic mice with hearts
      overexpressing the Na/Ca exchanger. In mouse ventricular myocytes, the current
      was sensitive to nickel, and was eliminated by removal of intracellular Na+. It
      was not influenced by 3 m m ouabain, and thus not contaminated by Na pump
      currents. The magnitude of the current reached a plateau within 10-15 min after
      obtaining a whole cell patch with the pipettes containing EGTA, to buffer [Ca2+]i
      and in zero extracellular K+ concentration to completely inhibit the Na pump, and
      allow equilibration of pipette Na+ with subsarcolemmal [Na+]. The magnitude of
      the current increased with increases in pipette [Na+]. Comparison of the current
      magnitudes in wild-type and transgenic myocytes showed a 2.5 and 2.7 fold
      increase in the current in transgenic myocytes at pipette [Na+] of 10 and 20 m m.
      The magnitude of this increase in Na/Ca exchanger currents in single transgenic
      myocytes compares well with the reported 2.5 fold increase in Na+-dependent
      45Ca2+ uptake measured in ventricular sarcolemmal vesicles obtained from
      transgenic animals. With this approach, we found variation in exchanger current
      densities in different species, with values for mouse>rat>rabbit>dog>human. This
      technique should also be useful in quantifying changes in Na/Ca exchanger current
      density as a consequence of pathologic processes, and exposure to drugs.

PMID- 10336851
TI  - Olfactory receptors, Golf alpha and adenylyl cyclase mRNA expressions in the rat
      heart during ontogenic development.
AB  - Golf alpha (a G heterotrimeric protein which shares a high homology with Gs
      alpha) expression was studied in the rat heart before birth and until weaning.
      Since Golf alpha in the neuro-olfactory epithelium is coupled to olfactory
      receptors and type III adenylyl cyclase, we looked for the presence of such
      molecules in the heart. Golf alpha mRNA was detected in the rat heart, highest
      levels being found in 21-day old fetuses until 3 days post partum. The protein
      amounts measured by Western blots paralleled the Golf alpha mRNA levels.
      Immunohistochemical studies revealed the presence of Golf alpha in atrial and
      ventricular cardiomyocytes. OL1 and latrophilin mRNAs, G protein-coupled
      olfactory receptors, were expressed at early postnatal stages. Adenylyl cyclase
      mRNAs for type II, type III, type V and type VI were expressed before birth and
      until weaning. Elements for an unexpected signaling pathway involving odorant
      receptors like OL1 and latrophilin, Golf alpha and type III adenylyl cyclase were
      expressed in rat heart, and appeared developmentally regulated.

PMID- 10336852
TI  - Effect of transient ischemia on the expression of glucose transporters GLUT-1 and
      GLUT-4 in rat myocardium.
AB  - A number of observations indicate that myocardial glucose utilization is
      increased late during post-ischemic reperfusion. The present study was designed
      to examine whether transient ischemia elicits altered expression of glucose
      transporters GLUT-1 and GLUT-4. In rats, the left anterior descending coronary
      artery was occluded for 20 min followed by reperfusion for 1, 3 or 7 days.
      Regional myocardial uptake and phosphorylation of glucose was determined based on
      myocardial accumulation of 2-deoxy-D-[2, 6-3H]glucose-6-phosphate. In hearts from
      fasted rats, after 3 days of reperfusion, myocardial uptake and phosphorylation
      of glucose was 48% higher in the reperfused region compared to a remote control
      region. No regional difference in myocardial glucose uptake and phosphorylation
      was detectable in hearts from fed rats. After 1 day of reperfusion, expression of
      myocardial glucose transporter GLUT-1 mRNA was increased to 195+/-24% (mean+/
      SEM) of the value measured in the remote region and the expression of GLUT-4 mRNA
      was decreased to 58+/-7%. After 3 days of reperfusion both mRNA and protein of
      GLUT-1 were higher in the reperfused region, averaging 133+/-23% and 249+/-36%,
      respectively. The corresponding values for GLUT-4 mRNA and protein were 77+/-7%
      and 62+/-6%, respectively. The results indicate that a short period of ischemia
      alters the expression of glucose transporter isoforms GLUT-1 and GLUT-4. Observed
      changes may be involved in the mechanisms underlying late changes of substrate
      metabolism during reperfusion.

PMID- 10336853
TI  - Non-elastic deformation of myocardium in low-flow ischemia and reperfusion:
      ultrastructure-function relations.
AB  - This study tested the hypothesis that regional low-flow ischemia and reperfusion
      alter myocardial material properties by causing non-elastic deformation. Twenty
      two anesthetized, open-chest pigs were studied. Pigs underwent 90 min of regional
      low-flow ischemia (anterior LV subendocardial blood flow 29+/-7% of baseline)
      followed by 90 min reperfusion. LV pressure and regional subendocardial segment
      length were recorded to derive end-diastolic pressure vs segment length (EDP vs
      EDL) and preload-recruitable stroke work (PRSW) relations. In vivo, non-elastic
      myocardial deformation was inferred from increases in minimally loaded myocardial
      dimensions: the EDL at zero EDP (L0) and the EDL at which no regional external
      work was performed (Lw, the PRSW intercept). In 15 pigs, ultrastructural
      confirmation of non-elastic deformation was obtained from sarcomere dimensions
      measured by transmission electron microscopy after in situ perfusion fixation
      under non-ischemic conditions, after 90 min ischemia, or after 90 min ischemia
      plus 90 min reperfusion. Ischemia increased L0 and Lw to 1.17+/-0.05 and 1. 13+/
      0.04 times baseline, respectively. After reperfusion, L0 and Lw remained
      increased to 1.09+/-0.03 and 1.15+/-0.02 times baseline (all P<0.05). After
      reperfusion, PRSW slope was not different from baseline, but regional external
      work remained depressed (0.38+/-0.03 times baseline) due to the persistent
      increase in Lw. Neither L0 nor Lw changed in the posterior (non-ischemic) region.
      In hearts fixed after ischemia or after ischemia plus reperfusion, sarcomere
      length was significantly greater and transverse distance between thick
      myofilaments was significantly smaller in the anterior (ischemic) subendocardium
      than in the posterior (non-ischemic) subendocardium (P<0.01). We conclude that
      regional low-flow ischemia and reperfusion cause non-elastic deformation of
      myocardium, manifest in vivo by increased minimally loaded myocardial dimensions
      (L0 and Lw) and ultrastructurally by increased sarcomere length and decreased
      transverse interfilament distance. Non-elastic deformation of myocardium may
      contribute to contractile dysfunction in low-flow ischemia and reperfusion.

PMID- 10336854
TI  - An Escherichia coli expression vector that allows recovery of proteins with
      native N-termini from purified calmodulin-binding peptide fusions.
AB  - We describe a T7-based Escherichia coli expression vector in which protein coding
      sequence is seamlessly fused to the N-terminal calmodulin-binding peptide (CBP)
      purification tag. We combined the use of the site-specific protease enterokinase
      (EK) and the type IIs restriction enzyme Eam1104 I, which cleave outside their
      respective (amino acid and nucleotide) target sequences, such that any amino acid
      sequence may be fused directly C-terminal to the EK cleavage site without codon
      constraints conferred by the cloning method. PCR products are cloned using
      ligation-dependent or ligation-independent methods with high cloning efficiencies
      (>10(6) cfu/microg vector), allowing production of insert quantities sufficient
      for several cloning experiments with a limited number of PCR cycles, resulting in
      a significant time-savings and reduced likelihood of accumulating PCR-derived
      mutations. CBP fusion proteins are expressed to high levels when the CBP peptide
      is positioned at the N-terminus. CBP binds to calmodulin with nanomolar affinity,
      and fusion proteins are purified to near homogeneity from crude extracts with one
      pass through calmodulin affinity resin using gentle binding and elution
      conditions. We show high efficiency seamless cloning of three inserts into the
      pCAL-n-EK vector, including one encoding the protein c-Jun N-terminal kinase
      (JNK). CBP-EK-JNK fusion protein was synthesized to 10-20 mg/liter culture and
      purified to near homogeneity in one step with calmodulin affinity resin. The
      fusion tag was efficiently removed with EK to yield active JNK with native N
      terminal amino acid sequence.

PMID- 10336855
TI  - Kinetic properties of human dopamine sulfotransferase (SULT1A3) expressed in
      prokaryotic and eukaryotic systems: comparison with the recombinant enzyme
      purified from Escherichia coli.
AB  - Sulfation, catalyzed by members of the sulfotransferase enzyme family, is a major
      metabolic pathway which modulates the biological activity of numerous endogenous
      and xenobiotic chemicals. A number of these enzymes have been expressed in
      prokaryotic and eukaryotic systems to produce protein for biochemical and
      physical characterization. However, the effective use of heterologous expression
      systems to produce recombinant enzymes for such purposes depends upon the
      expressed protein faithfully representing the "native" protein. For human
      sulfotransferases, little attention has been paid to this despite the widespread
      use of recombinant enzymes. Here we have validated a number of heterologous
      expression systems for producing the human dopamine-metabolizing sulfotransferase
      SULT1A3, including Escherichia coli, Saccharomyces cerevisiae, COS-7, and V79
      cells, by comparison of Km values of the recombinant enzyme in cell extracts with
      enzyme present in human platelets and with recombinant enzyme purified to
      homogeneity following E. coli expression. This is the first report of
      heterologous expression of a cytosolic sulfotransferase in yeast. Expression of
      SULT1A3 was achieved in all cell types, and the Km for dopamine under the
      conditions applied was approximately 1 microM in all heterologous systems
      studied, which compared favorably with the value determined with human platelets.
      We also determined the subunit and native molecular weights of the purified
      recombinant enzyme by SDS-PAGE, electrospray ionization mass spectrometry,
      dynamic light scattering, and sedimentation analysis. The enzyme purified
      following expression in E. coli existed as a homodimer with Mr approximately
      68,000 as determined by light scattering and sedimentation analysis. Mass
      spectrometry revealed two species with experimentally determined masses of 34,272
      and 34,348 which correspond to the native protein with either one or two 2
      mercaptoethanol adducts. We conclude that the enzyme expressed in prokaryotic and
      eukaryotic heterologous systems, and also purified from E. coli, equates to that
      which is found in human tissue preparations.

PMID- 10336856
TI  - Soluble expression in Escherichia coli of murine endogenous retroviral
      transmembrane envelope protein having immunosuppressive activity.
AB  - Recently, we cloned a fragment of the endogenous murine leukemia viral envelope
      gene from beta cell line (MIN6N8a) as a new autoantigen gene, whose product was
      reactive with nonobese diabetic (NOD) mice sera. As a result of determination of
      nucleotide sequence, this envelope protein had the CKS-17 peptide sequence having
      immunosuppressive activity. To investigate the role of our cloned transmembrane
      envelope protein in the pathogenesis of autoimmune insulin-dependent diabetes
      mellitus (IDDM) as an autoantigen or immunosuppressive modulator, a high amount
      of transmembrane envelope protein was essentially required. Therefore, the
      expression of our cloned retroviral transmembrane envelope gene was tried in
      Escherichia coli by a pET vector. However, the expression rate was very low (less
      than 2%) and most of the expressed protein was insoluble. To improve solubility,
      the hydrophobic transmembrane anchor domain of our envelope gene was deleted and
      then the expression of the hydrophilic transmembrane envelope protein was carried
      out by using the same pET expression system. The expressed protein was completely
      soluble and the expression yield was dramatically improved by around 25-fold
      increase. The hydrophilic transmembrane envelope protein was purified by one-step
      Ni-NTA affinity chromatography and then the fusion tag consisting of the six
      histidine peptide and S peptide was removed by cleavage with enterokinase. The
      processed hydrophilic retroviral transmembrane envelope protein was still immune
      reactive with NOD sera and also showed immunosuppressive activity by down
      regulating the Th1-type cytokine (interferon-gamma) and up-regulating the Th2
      type cytokine (interleukin 10).

PMID- 10336857
TI  - Site-directed mutagenesis of human dihydrolipoamide dehydrogenase: role of lysine
      54 and glutamate-192 in stabilizing the thiolate-FAD intermediate.
AB  - The roles of lysine-54 (K54) and glutamate-192 (E192) of human dihydrolipoamide
      dehydrogenase (E3) in stabilizing the thiolate-FAD intermediate during electron
      transfer were investigated by site-directed mutagenesis. Recombinant human E3s,
      wild-type, K54E, S53K54-K53S54 (SK-KS), and E192Q, were overexpressed, purified,
      and characterized. Only K54E and SK-KS E3s had about 25% less bound FAD compared
      to wild-type, implicating that K54 is crucial for the protein-FAD interaction.
      The specific activities of all mutant E3s were markedly decreased (<5% wild
      type). In the case of K54E E3, the Km for lipoamide in the reverse reaction was
      increased by about twofold. Surprisingly, for both SK-KS and E192Q E3s, the Kms
      for both dihydrolipoamide (forward reaction) and lipoamide (reverse reaction)
      were markedly reduced. The catalytic rate constants (kcat/Km) for both reactions
      for SK-KS E3 were significantly lower than wild-type, indicating that K54 is
      crucial for the catalytic efficiency of the enzyme. Fluorescence spectral
      analyses showed that the FAD in E3s were reduced by the addition of
      dihydrolipoamide, and that its reoxidation by NAD+ in the mutant E3s was slower
      than wild-type E3. Interestingly, in K54E E3 dihydrolipoamide reduced FAD
      efficiently only when NAD+ was present, indicating that K54 stabilizes the
      thiolate-FAD interaction. The lack of the formation of thiolate-FAD intermediate
      in the absence of NAD+ in K54E E3 was also confirmed by CD spectra. The SK-KS
      mutation demonstrates that the correct sequence of residues is as critical as the
      nature of the amino acid residues. These results suggest that K54 plays an
      important role in stabilizing the thiolate-FAD intermediate during the electron
      transfer in the reaction, and E192 is involved in maintaining correct orientation
      of K54 during catalysis.

PMID- 10336858
TI  - Circular dichroism analysis of insect cell expressed herpes simplex virus type I
      single-stranded DNA-binding protein ICP8.
AB  - We have developed a baculovirus expression system for the rapid and efficient
      production of large quantities (>5 mg/10(8) cells) of ICP8. The recombinant ICP8
      is fully functional and binds to single-stranded DNA. Secondary structure
      calculations from circular dichroism measurements indicate a content of 34.5%
      alpha-helix and 15.4% beta-sheet. This is the first structural report for ICP8
      using CD analysis, which will be very useful for high-throughput assay
      development and mechanistic studies.

PMID- 10336859
TI  - Purification of bovine S100A12 from recombinant Escherichia coli.
AB  - S100A12, a member of the S100 family of EF-hand calcium-binding proteins, was
      purified from Escherichia coli cells expressing the corresponding cDNA. The
      procedure involved washing induced E. coli cells with EDTA-containing hypotonic
      solution, ion-exchange chromatography, and HPLC. Recombinant S100A12 was purified
      to homogeneity with the final yield around 6.7 mg per 20 ml of culture. The
      purified protein was identical to native S100A12 in the N-terminal amino acid
      sequence, lysylendopeptidase peptide mapping, mass spectrum, and Ca2+-dependent
      binding affinity to amlexanox, an antiallergy drug. However, the N-terminal
      methionine residue of the purified protein was not cleaved off as in the native
      protein. The method used in the present study permits the purification of
      recombinant S100A12 in large quantities and may also be applicable to preparation
      of other S100 family proteins.

PMID- 10336861
TI  - pSKAP/S: An expression vector for the production of single-chain Fv alkaline
      phosphatase fusion proteins.
AB  - The vector pSKAP/S was constructed to enable overexpression of single-chain
      variable fragment antibody (scFv)-alkaline phosphatase fusion proteins. In
      pSKAP/S, the scFv were genetically fused to the mutated Escherichia coli PhoA/S
      gene that encodes an alkaline phosphatase with increased specific activity. The
      restriction sites incorporated into pSKAP/S allowed the scFv genes to be easily
      transferred from pUC119-derived phagemid vectors that are used frequently in
      phage display antibody library technology. Strong transcriptional control of
      expression was achieved using the tetracycline promoter, and induction of
      different individual clones with anhydrotetracycline resulted in secretion of
      most of the scFv-alkaline phosphatase fusion proteins into the culture medium.
      Although some of the clones secreted fusion proteins that were retained in the
      periplasm, these proteins could be isolated with a simple extraction procedure.
      Increased amounts of a scFv-alkaline phosphatase fusion protein were obtained
      when expressed in the pSKAP/S vector compared with expression in a vector
      incorporating the lac promoter. Testing for binding of the scFv-alkaline
      phosphatase fusion proteins to antigen was possible in an ELISA without the need
      for additional enzyme-conjugated antibodies. The pSKAP/S vector was successfully
      used to obtain scFv fragments from a preparation of phage-antibody clones after
      subcloning and expression of individual clones as scFv-alkaline phosphatase
      fusions, whereas fewer clones (and clones with different properties) were
      obtained from the same phage-antibody preparations when expressed as soluble scFv
      fragments. Therefore, the pSKAP/S vector was shown to be useful in extending the
      range of scFv obtained from phage display libraries.

PMID- 10336860
TI  - Stable, high-level expression of a type I antifreeze protein in Escherichia coli.
AB  - The type I antifreeze proteins are simple amphipathic helical proteins found in
      abundance in polar fish species, where they act to prevent freezing of internal
      fluids by a mechanism of noncolligative freezing point depression. Large-scale
      production of these proteins for research and biotechnological purposes has been
      hampered by their apparent instability when expressed in heterologous host
      systems. This has necessitated their production as fusion proteins, in polymeric
      form, or as proproteins for secretion, with the concomitant necessity for
      postpurification processing to generate the mature form of the protein. We have
      successfully expressed a recombinant variant of type I antifreeze protein (rAFP)
      in Escherichia coli using the inducible T7 polymerase transcription expression
      system. The rAFP contains five copies of the 11 amino acid ice-binding repeat
      motif found in all type I antifreeze proteins. The protein accumulates to high
      levels intracellularly in the form of inclusion bodies, with no apparent
      degradation by the cellular proteolytic machinery. We have devised a simple and
      rapid purification protocol for this recombinant type I antifreeze protein which
      does not require cellular fractionation, purification of the inclusion bodies, or
      chromatographic steps. This protocol may be of general use for this class of
      protein. The protein displays all three activities common to these proteins:
      recrystallization inhibition, noncolligative freezing point depression, and
      modification of the morphology of single ice crystals in solution.

PMID- 10336862
TI  - Expression of a lipocalin in prokaryote and eukaryote cells: quantification and
      structural characterization of recombinant bovine beta-lactoglobulin.
AB  - In this paper we quantify and characterize the expression of recombinant beta
      lactoglobulin (rBLG) in prokaryote and eukaryote cells. In Escherichia coli we
      used the pET26 vector, which permits the secretion of rBLG in periplasm. We
      studied the expression of rBLG in COS-7 cells and in vivo in mouse tibialis
      muscle. The expression of rBLG was measured by two immunoassays specific,
      respectively, for BLG in its native and denatured conformation. We observed that
      rBLG was essentially expressed in a denatured form in E. coli even in the
      periplasm, whereas rBLG in eukaryote cells was found in its native conformation.

PMID- 10336863
TI  - Purification of active matrix metalloproteinase catalytic domains and its use for
      screening of specific stromelysin-3 inhibitors.
AB  - The matrix metalloproteinase (MMP) stromelysin-3 (ST3) has been shown to be
      involved in malignant tumor progression and therefore represents an attractive
      therapeutical target. In order to screen for ST3 synthetic inhibitors, we have
      produced and purified the catalytic domain of ST3, matrilysin, stromelysin-2, and
      membrane type-1 MMP from inclusion bodies in a bacterial system. Our strategy
      allowed the purification of MMPs directly in the active form, thereby avoiding in
      vitro activation. A total of 140,000 synthetic compounds from the Bristol-Myers
      Pharmaceutical Research Institute chemical deck were tested, using a substrate
      based colorimetric enzymatic assay, in which ST3 activity was evaluated through
      its ability to cleave and inactivate alpha-1 proteinase inhibitor. One ST3
      inhibitor belonging to the cephalosporin family of antibiotics was thereby
      identified.

PMID- 10336865
TI  - The in situ regeneration and extraction of recombinant aequorin from Escherichia
      coli cells and the purification of extracted aequorin.
AB  - Recombinant apoaequorin expressed in the periplasmic space of Escherichia coli
      cells was regenerated into aequorin and extracted from the cells, simultaneously,
      using a buffer that contained coelenterazine. Due to the mild extraction
      conditions, the impurities in the extract were minimal. Thus, the purification of
      extracted aequorin could be accomplished in only two steps, anion-exchange
      chromatography and hydrophobic interaction chromatography, simply by adsorption
      and elution in both steps. The purified recombinant aequorin was pure, based on
      various data, including HPLC analysis and light-emitting activity. The yield of
      purified aequorin was 25-35 mg from 600 ml of culture, which was over 75% of the
      total amount of apoaequorin expressed in E. coli cells.

PMID- 10336864
TI  - Bacterial expression and purification of the Fab fragment of a monoclonal
      antibody specific for the low-density lipoprotein receptor-binding site of human
      apolipoprotein E.
AB  - We report the bacterial expression and the purification of a monoclonal antibody
      (mAb) specific for an epitope that coincides with the LDL receptor (LDLr)-binding
      domain of human apolipoprotein E (apoE). This antibody resembles the LDLr in its
      primary structure and its specificity for apoE variants. The recombinant Fab
      (rFab) fragment of mAb 2E8, consisting of the entire light chain and the Fd
      portion of the heavy chain, was expressed in Escherichia coli and purified to
      homogeneity. Purification was facilitated by including a five-histidine carboxyl
      terminal extension on the Fd chain. A 5- to 10-fold difference in yield of the
      antibody was observed when the plasmid was expressed in two different strains of
      E. coli. Typically 2-6 mg of rFab per liter of culture medium was recovered in
      the periplasm of the TG1 strain and less than 1 mg was recovered in the periplasm
      of the XL1-Blue strain. Culture temperatures above 35 degrees C or inclusion of
      sucrose in the medium reduced rFab yields. The 2E8 rFab was indistinguishable
      from Fab prepared from 2E8 hybridoma-generated IgG with respect to its affinity
      and fine specificity. We are using this system to express a panel of 2E8 variant
      Fabs that will be used as probes to establish the structural features responsible
      for the binding of apoE to the LDLr.

PMID- 10336866
TI  - Cloning, overexpression, and purification of the recombinant His-tagged SSB
      protein of Escherichia coli and use in polymerase chain reaction amplification.
AB  - Polymerase chain reaction (PCR)-derived DNA fragment containing the complete
      structural gene for SSB protein of the Escherichia coli was cloned into an
      expression vector. The clones expressing His-tagged SSB protein were selected.
      The cloned DNA fragments were verified to be authentic by sequencing several
      clones. The recombinant SSB protein (His-tagged SSB) contained a polyhistidine
      tag at the N-terminus (38 additional amino acids) that allowed single-step
      isolation by Ni2+ affinity chromatography. We found that recombinant plasmids are
      unstable and give a low level of expression in E. coli BL21(DE3) strain. However,
      the plasmids were stable in E. coli BL21(DE3) containing the pLysS plasmid, which
      suppresses expression prior to induction, and His-tagged proteins were highly
      expressed upon IPTG addition. The SSB protein was purified by metal-affinity
      chromatography on Ni2+-TED-Sepharose columns. The enzyme was characterized by
      fluorescence titration experiments for single-stranded DNA binding activity. We
      have applied the use of His-tagged SSB protein to increase amplification
      efficiency with a number of diverse templates. The use of SSB protein may prove
      to be generally applicable in improving PCR efficiency.

PMID- 10336867
TI  - Soluble expression of cloned phage K11 RNA polymerase gene in Escherichia coli at
      a low temperature.
AB  - The gene 1 of the Klebsiella phage K11 encoding the phage RNA polymerase was
      amplified using the polymerase chain reaction of the Pfu DNA polymerase, cloned
      and expressed under the control of tac promoter in Escherichia coli. Although the
      gene was efficiently expressed in E. coli BL21 cells at 37 degrees C, most of the
      K11 RNA polymerase produced was insoluble, in contrast to soluble expression of
      the cloned T7 RNA polymerase gene. Coexpression of the bacterial chaperone GroES
      and GroEL genes together did not help solubilize the K11 RNA polymerase. When the
      temperature of cell growth was lowered, however, solubility of the K11 RNA
      polymerase was increased substantially. It was found much more soluble when
      expressed at 25 degrees C than at 30 and 37 degrees C. Thus, the cloned K11 RNA
      polymerase gene was expressed in E. coli mostly to the soluble form at 25 degrees
      C. The protein was purified to homogeneity by chromatography using DEAE-Sephacel
      and Affigel-blue columns and was found to be active in vitro with the K11 genome
      or a K11 promoter. The purified K11 RNA polymerase showed highly stringent
      specificity for the K11 promoter. Low-level cross-reactivity was shown with the
      SP6 and T7 consensus promoters, while no activity shown with the T3 consensus
      promoter at all.

PMID- 10336868
TI  - Application of fed-batch fermentation to the preparation of isotopically labeled
      or selenomethionyl-labeled proteins.
AB  - An increasing demand for isotopically labeled samples for spectroscopic and
      crystallographic studies has led to a corresponding need for effective and
      efficient methods for producing these samples. The present work is based on the
      strategy of using an isotopically labeled compound as the growth-limiting
      nutrient during protein expression in Escherichia coli (DE3) strains. By using
      dissolved O2 and agitation rate data, the cell growth, feeding of the isotopic
      label, induction of protein expression, and the harvest of cells can be
      coordinated in a feedback controlled fermenter in a simple, easily defined
      manner. This approach is demonstrated for the nutrient-limited production of [U
      15N]- and [U-13C, U-15N]-labeled toluene 4-monooxygenase effector protein in E.
      coli BL21(DE3) with isotopic abundance identical to that of the labeled
      precursors. For selective labeling, demonstrated with selenomethionine using
      methionine auxotroph E. coli B834(DE3), approximately 80-85% incorporation was
      obtained from methionine-dependent growth of the auxotroph followed by
      selenomethionine feeding and protein induction upon methionine depletion. This
      selective labeling is accomplished in a single culture, does not require washing
      or resuspension, minimizes costly incorporation of label into host cell mass
      prior to induction, and can be easily adapted to selective labeling with other
      amino acids. Moreover, cell mass yield from these experiments can be readily
      optimized to provide the desired level of protein for a given investigation from
      a single growth and purification. This combination provides an efficient,
      controllable option for isotopic labeling experiments.

PMID- 10336869
TI  - Saccharomyces cerevisiae cells harboring the gene encoding sarcotoxin IA secrete
      a peptide that is toxic to plant pathogenic bacteria.
AB  - Sarcotoxin IA is a cecropin-type antibacterial protein produced by the flesh fly,
      Sarcophaga peregrina. Similar to other bactericidal small proteins produced by
      insects, sarcotoxin IA is released into the hemolymph of larvae and nymphs upon
      mechanical injury or bacterial infection. The gene (sarco) that encodes this
      toxin was introduced into Saccharomyces cerevisiae yeast cells and was expressed
      under a constitutive yeast promoter. The transformed yeast cells were grown in a
      liquid medium, and a peptide with a similar molecular size to that of the mature
      sarcotoxin IA was detected in the medium by Western blot analysis. The secreted
      sarcotoxin-like peptide (SLP) had a potent cytotoxic effect against several
      bacteria, including plant pathogenic bacteria, similar to the toxic effects of
      the authentic sarcotoxin IA. Erwinia carotovora was more susceptible to the toxic
      medium than Pseudomonas solanacearum and Pseudomonas syringae pv. lachrymans.
      Thus, yeast may be used in the production of such proteins for employment against
      various bacterial pathogens.

PMID- 10336870
TI  - Heterologous expression of 5'-methylthioadenosine phosphorylase from the archaeon
      Sulfolobus solfataricus: characterization of the recombinant protein and
      involvement of disulfide bonds in thermophilicity and thermostability.
AB  - The gene for the extremely thermophilic and thermostable 5'-methylthioadenosine
      phosphorylase from the archaeon Sulfolobus solfataricus was expressed at a high
      level in Escherichia coli thus providing a basis for detailed structural and
      functional studies of the enzyme. The recombinant enzyme was purified to
      homogeneity by means of a heat treatment (10 min at 100 degrees C) and by a
      single affinity chromatography step. The appropriate expression vector and host
      strain were selected and the culture conditions were determined that would ensure
      a consistent yield of 6 mg of pure enzyme per liter of culture. The
      heterologously expressed enzyme is identical to the original S. solfataricus 5'
      methylthioadenosine phosphorylase regarding molecular weight, substrate
      specificity, and the presence of intersubunit disulfide bonds. On the other hand,
      the recombinant 5'-methylthioadenosine phosphorylase is less thermophilic and
      thermostable than the S. solfataricus enzyme, since an incorrect positioning of
      disulfide bonds within the molecule generates structures less stable to thermal
      unfolding.

PMID- 10336871
TI  - Expression of human plasminogen in Drosophila Schneider S2 cells.
AB  - The cDNA that encodes full-length human plasminogen (Glu1-hPg) has been expressed
      in Drosophila Schneider S2 cells under the influence of the Drosophila BiP
      protein signal sequence, which allowed the protein to be secreted into the
      medium. A procedure was devised for clonal selection of high-expressing cells,
      which were then used for large-scale expression of 10-15 mg/liter of the protein
      in the culture medium. The protein produced using this system was extensively
      characterized and contained full-length recombinant (r) Glu1-hPg plasminogen. As
      with human plasma Glu1-hPg, the S2-expressed protein underwent the Cl--induced
      transition to the tight conformation, which resulted in a weakly activatable
      zymogen. The addition of the ligand, epsilon-amino caproic acid, induced the
      relaxed conformation of r-Glu1-hPg, which was highly activatable, again in
      agreement with similar data for human plasma Glu1-hPg. The thermal stability of
      the S2-expressed r-Glu1-hPg also correlated well with that of human plasma hPg.
      These studies show that intact r-Glu1-hPg can be produced in high yield in
      Drosophila Schneider S2 cells, which possesses similar properties to its human
      plasma counterpart.

PMID- 10336872
TI  - Recombinant production of the p10CKS1At protein from Arabidopsis thaliana and 13C
      and 15N double-isotopic enrichment for NMR studies.
AB  - The CKS1At gene product, p10CKS1At from Arabidopsis thaliana, is a member of the
      cyclin-dependent kinase subunit (CKS) family of small proteins. These proteins
      bind the cyclin-dependent kinase (CDK)/cyclin complexes and play an essential,
      but still not precisely known role in cell cycle progression. To solve the
      structure of p10CKS1At, a protocol was needed to produce the quantity of protein
      large enough for nuclear magnetic resonance (NMR) spectroscopy. The first attempt
      to express CKS1At in Escherichia coli under the control of the T7 promoter was
      not successful. E. coli BL21(DE3) cotransformed with the CKS1At gene and the E.
      coli argU gene that encoded the arginine acceptor tRNAUCU produced a sufficient
      amount of p10CKS1At to start the structural study by NMR. Replacement of four
      rare codons in the CKS1At gene sequence, including a tandem arginine, by highly
      used codons in E. coli, restored also a high expression of the recombinant
      protein. Double-isotopic enrichment by 13C and 15N is reported that will
      facilitate the NMR study. Isotopically labeled p10CKS1At was purified to yield as
      much as 55 mg from 1 liter of minimal media by a two-step chromatographic
      procedure. Preliminary results of NMR spectroscopy demonstrate that a full
      structural analysis using triple-resonance spectra is feasible for the labeled
      p10CKS1At protein.

PMID- 10336873
TI  - Recombinant expression of a galectin from the sheep gastrointestinal parasite
      Teladorsagia circumcincta: its use in isolating galectin-glycoconjugates.
AB  - Galectins, or beta-galactoside-binding lectins, are a family of proteins that
      have been described in vertebrates and, more recently, invertebrates, including
      nematode parasites. A tandem repeat-type galectin from the sheep gastrointestinal
      parasite, Teladorsagia circumcincta, has previously been isolated and the cDNA
      cloned. This molecule and each of its domains were expressed as fusion proteins
      with glutathione S-transferase (GST). The full-length molecule and the C-terminal
      domain were expressed in soluble form and the purified fusion proteins
      demonstrated a capacity to bind beta-galactoside sugars, with the greatest
      preference for lactose. The full-length fusion protein was used to successfully
      isolate potential galectin-glycoconjugates from within the parasite and from
      sheep serum.

PMID- 10336874
TI  - Folding and purification of a recombinantly expressed interferon regulatory
      factor, IRF-4.
AB  - Interferon regulatory factor 4 (IRF-4), an intracellular, multidomain protein, is
      a member of the interferon regulatory factor family and a lymphoid-specific
      transcription factor that can form a ternary complex with DNA and the
      transcription factor PU.1. Recombinant human IRF-4 was expressed in Escherichia
      coli and purified from the soluble cell extract and the insoluble inclusion
      bodies. The inclusion bodies were solubilized with guanidinium-hydrochloride and
      sequentially buffer exchanged into urea- and then NaCl-containing solutions. This
      two-step process for the removal of the denaturants was the critical step to
      allow for the correct folding of IRF-4. Following purification through
      immobilized metal affinity, hydrophobic interaction, and gel permeation
      chromatographies, the renatured protein was shown to be structurally and
      physically equivalent to a sample of IRF-4 produced in the soluble fraction of E.
      coli cells. This was confirmed by near and far UV circular dichroism analysis,
      including thermal stability analysis. The purified IRF-4 was also shown to be
      capable of binding DNA in a PU.1-dependent manner by electrophoretic mobility
      shift analysis. The protein folding and purification methods are suitable for
      producing large quantities of full-length IRF-4.

PMID- 10336875
TI  - Expression, purification, and characterization of the recombinant calcium-binding
      equine lysozyme secreted by the filamentous fungus Aspergillus niger: comparisons
      with the production of hen and human lysozymes.
AB  - Equine lysozyme (EqL) has been expressed from a synthetic gene and secreted from
      a heterologous host, the filamentous fungus Aspergillus niger. By including 100
      mM Ca2+ in the growth medium, secreted yields of more than 50 mg/liter could be
      achieved using polyvinylpyrrolidone (PVP) complete medium. In a soya medium
      yields of up to 150 mg/liter were achieved. The production of recombinant human
      lysozyme (HuL) from A. niger with yields of over 40 mg/liter was also achieved
      using PVP medium. Addition of Ca2+ to the growth medium reduced the yield of both
      HuL and hen egg white lysozyme (HEWL). Sequence differences between the three
      lysozymes, EqL, HuL, and HEWL, resulted in different susceptibilities to cleavage
      by A. niger proteases. An improved procedure for the purification of EqL and HuL
      from A. niger allowed separation of the proteins from pigments produced by the
      fungus. Detailed spectroscopic analysis, including 2D 1H NMR, for recombinant EqL
      and recombinant HuL confirm that both proteins possess their native structure and
      are purified to homogeneity.

PMID- 10336876
TI  - Renaturation of Escherichia coli-derived recombinant human macrophage colony
      stimulating factor.
AB  - Recombinant human macrophage colony-stimulating factor (rhM-CSF), a homodimeric,
      disulfide bonded protein, was expressed in Escherichia coli in the form of
      inclusion bodies. Reduced and denatured rhM-CSF monomers were refolded in the
      presence of a thiol mixture (reduced and oxidized glutathione) and a low
      concentration of denaturing agent (urea or guanidinium chloride). Refolding was
      monitored by nonreducing gel electrophoresis and recovery of bioactivity. The
      effects of denaturant type and concentration, protein concentration,
      concentration of thiol/disulfide reagents, temperature, and presence of
      impurities on the kinetics of rhM-CSF renaturation were investigated. Low
      denaturant concentrations (<0.5 M urea) and high protein concentrations (>0.4
      mg/ml) in the refolding mixture resulted in increased formation of aggregates,
      although aggregation was never significant even when refolding was carried out at
      room temperature. Higher protein concentration resulted in higher rates but did
      not lead to increased yields, due to the formation of unwanted aggregates.
      Experiments conducted at room temperature resulted in slightly higher rates than
      those conducted at 4 degrees C. Although the initial renaturation rate for
      solubilized inclusion body protein without purification was higher than that of
      the reversed-phase purified reduced denatured rhM-CSF, the final renaturation
      yield was much higher for the purified material. A maximum refolding yield of 95%
      was obtained for the purified material at the following refolding conditions: 0.5
      M urea, 50 mM Tris, 1.25 mM DTT, 2 mM GSH, 2 mM GSSG, 22 degrees C, pH 8,
      [protein] = 0.13 mg/ml.

PMID- 10336877
TI  - High-level expression and purification of the recombinant diphtheria fusion toxin
      DTGM for PHASE I clinical trials.
AB  - A genetically engineered fusion toxin targeted to acute myeloid leukemic (AML)
      blasts was designed with the first 388 amino acid residues of diphtheria toxin
      with an H-M linker fused to human granulocyte-macrophage colony-stimulating
      factor. The cDNA was subcloned in the pRK bacterial expression plasmid and used
      to transform BL21 (DE3) Escherichia coli harboring pUBS500 plasmid. Transformants
      were grown in Superbroth and induced with IPTG. Inclusion bodies were isolated,
      washed, and denatured in guanidine hydrochloride with dithioerythritol.
      Recombinant protein was refolded by diluting 100-fold in cold buffer with
      arginine and oxidized glutathione. After dialysis, purified protein was obtained
      after anion-exchange, size exclusion on FPLC, and polymixin B affinity
      chromatography. The final material was filter sterilized, aseptically vialed, and
      stored at -80 degrees C. Fifty-four 3-liter bacterial culture preparations were
      made and pooled into 27 batches. The final product was characterized by Coomassie
      Plus protein assay, Coomassie-stained SDS-PAGE, limulus amebocyte lysate
      endotoxin assay, human AML HL60 cell cytotoxicity assay, HPLC TSK3000, N-terminal
      sequencing, E. coli DNA contamination, C57BL6 mouse toxicity, and
      immunohistochemistry. Yields were 23 mg/liter bacterial culture of denatured
      fusion toxin. After refolding and chromatography, final yields were 24 +/- 4% or
      5 mg/liter. Vialed product was sterile and 1.7 +/- 0.4 mg/ml in PBS. Purity by
      SDS-PAGE was 99 +/- 1%. Aggregates by HPLC were <1%. Potency revealed a 24-h IC50
      of 2.7 +/- 0.5 pM on HL60 cells. Endotoxin levels were 1 eu/mg. The N-terminal
      sequence was confirmed, and E. coli DNA was <113 pg/mg. The LD10 in mice was 110
      microg/kg/day x5. There was no evidence of loss of solubility, proteolysis,
      aggregation, or loss of potency over 3 months at -80 and -20 degrees C. Further,
      the drug was stable at 4, 25, and 37 degrees C in human serum for 48 h. Drug
      reacted only with human monocytes, granulocytes, and myeloid precursors in frozen
      human tissue sections by immunohistochemistry. The synthesis of this protein drug
      should be useful for production for clinical phase I/II clinical trials and may
      be suitable for other diphtheria fusion toxins indicated for clinical
      development. This is the first report of the scaleup of a recombinant fusion
      toxin for clinical trials.

PMID- 10336879
TI  - Molecular and biological mechanisms of antioxidant action 

PMID- 10336878
TI  - Adenoviral-mediated expression of human insulin-like growth factor-binding
      protein-3.
AB  - Insulin-like growth factors (IGFs) in the circulation are predominantly
      sequestered into ternary complexes comprising IGF, IGF-binding protein-3 (IGFBP
      3), and the acid-labile subunit (ALS). Besides its role in regulating IGF
      bioavailability in the circulation, IGFBP-3 has both IGF-dependent and IGF
      independent actions on cell proliferation. As part of our studies into the
      structure-function relationships of the multifunctional IGFBP-3, we have
      evaluated the efficiency of an adenovirus-mediated expression system for rapid,
      medium-scale production of functional, glycosylated IGFBP-3. Replication
      deficient adenovirus containing human IGFBP-3 cDNA was generated using standard
      techniques. Secreted, recombinant IGFBP-3 (IGFBP-3(Ad)) was purified from the
      culture medium of virus-infected cells by IGF-I affinity chromatography followed
      by reverse-phase HPLC. When analyzed by SDS-PAGE, IGFBP-3(Ad) was similar in size
      (43- to 45-kDa glycoform doublet) to IGFBP-3(Pl) derived from plasma. In
      addition, IGFBP-3(Ad) was detected by immunoblot using an antibody specific for
      human IGFBP-3 and by ligand blot using radiolabeled IGF-I. IGFBP-3(Ad) had
      similar affinities for IGF-I and ALS and an approximately 25% decreased affinity
      for IGF-II compared to IGFBP-3(Pl). IGFBP-3(Ad) showed no significant difference
      in its susceptibility to an IGFBP-3 protease present in medium conditioned by MCF
      7 breast cancer cells compared to IGFBP-3(Pl), but appeared more resistant to the
      IGFBP-3 protease present in pregnancy serum. IGFBP-3(Ad) also exhibited increased
      binding to T47D cells which may be related to the glycosylation state of the
      protein.

PMID- 10336880
TI  - Vitamin E and vascular homeostasis: implications for atherosclerosis.
AB  - Considerable epidemiologic data suggest that dietary consumption of vitamin E
      reduces the incidence of cardiovascular disease. The precise mechanisms are not
      clear, but emerging data indicate that vitamin E has numerous activities that
      may, in part, explain its effect on vascular disease. In particular, vitamin E
      enhances the bioactivity of nitric oxide, inhibits smooth muscle proliferation,
      and limits platelet aggregation. One common mechanism to account for these
      effects of vitamin E is the inhibition of protein kinase C stimulation. In the
      setting of atherosclerosis, inhibition of protein kinase C by vitamin E would be
      expected to maintain normal vascular homeostasis and thus reduce the clinical
      incidence of cardiovascular disease.

PMID- 10336881
TI  - Tocopherol-mediated peroxidation of lipoproteins: implications for vitamin E as a
      potential antiatherogenic supplement.
AB  - The 'oxidation theory' of atherosclerosis proposes that oxidation of low density
      lipoprotein (LDL) contributes to atherogenesis. Although little direct evidence
      for a causative role of 'oxidized LDL' in atherogenesis exists, several studies
      show that, in vitro, oxidized LDL exhibits potentially proatherogenic activities
      and lipoproteins isolated from atherosclerotic lesions are oxidized. As a
      consequence, the molecular mechanisms of LDL oxidation and the actions of alpha
      tocopherol (alpha-TOH, vitamin E), the major lipid-soluble lipoprotein
      antioxidant, have been studied in detail. Based on the known antioxidant action
      of alpha-TOH and epidemiological evidence, vitamin E is generally considered to
      be beneficial in coronary artery disease. However, intervention studies overall
      show a null effect of vitamin E on atherosclerosis. This confounding outcome can
      be rationalized by the recently discovered diverse role for alpha-TOH in
      lipoprotein oxidation; that is, alpha-TOH displays neutral, anti-, or, indeed,
      pro-oxidant activity under various conditions. This review describes the latter,
      novel action of alpha-TOH, termed tocopherol-mediated peroxidation, and discusses
      the benefits of vitamin E supplementation alone or together with other
      antioxidants that work in concert with alpha-TOH in ameliorating lipoprotein
      lipid peroxidation in the artery wall and, hence, atherosclerosis.

PMID- 10336882
TI  - Is ascorbic acid an antioxidant for the plasma membrane?
AB  - Ascorbic acid, or vitamin C, is a primary antioxidant in plasma and within cells,
      but it can also interact with the plasma membrane by donating electrons to the
      alpha-tocopheroxyl radical and a trans-plasma membrane oxidoreductase activity.
      Ascorbate-derived reducing capacity is thus transmitted both into and across the
      plasma membrane. Recycling of alpha-tocopherol by ascorbate helps to protect
      membrane lipids from peroxidation. However, neither the mechanism nor function of
      the ascorbate-dependent oxidoreductase activity is known. This activity has
      typically been studied using extracellular ferricyanide as an electron acceptor.
      Whereas an NADH:ferricyanide reductase activity is evident in open membranes,
      ascorbate is the preferred electron donor within cells. The oxidoreductase may be
      a single membrane-spanning protein or may only partially span the membrane as
      part of a trans-membrane electron transport chain composed of a cytochrome or
      even hydrophobic antioxidants such as alpha-tocopherol or ubiquinol-10. Further
      studies are needed to elucidate the structural components, mechanism, and
      physiological significance of this activity. Proposed functions for the
      oxidoreductase include stimulation of cell growth, reduction of the ascorbate
      free radical outside cells, recycling of alpha-tocopherol, reduction of lipid
      hydroperoxides, and reduction of ferric iron prior to iron uptake by a
      transferrin-independent pathway.

PMID- 10336883
TI  - Does vitamin C act as a pro-oxidant under physiological conditions?
AB  - Vitamin C readily scavenges reactive oxygen and nitrogen species and may thereby
      prevent oxidative damage to important biological macromolecules such as DNA,
      lipids, and proteins. Vitamin C also reduces redox active transition metal ions
      in the active sites of specific biosynthetic enzymes. The interaction of vitamin
      C with 'free', catalytically active metal ions could contribute to oxidative
      damage through the production of hydroxyl and alkoxyl radicals; whether these
      mechanisms occur in vivo, however, is uncertain. To examine this issue, we
      reviewed studies that investigated the role of vitamin C, both in the presence
      and absence of metal ions, in oxidative DNA, lipid, and protein damage. We found
      compelling evidence for antioxidant protection of lipids by vitamin C in
      biological fluids, animals, and humans, both with and without iron
      cosupplementation. Although the data on protein oxidation in humans are sparse
      and inconclusive, the available data in animals consistently show an antioxidant
      role of vitamin C. The data on vitamin C and DNA oxidation in vivo are
      inconsistent and conflicting, but some of the discrepancies can be explained by
      flaws in experimental design and methodology. These and other important issues
      discussed here need to be addressed in future studies of the role of vitamin C in
      oxidative damage.

PMID- 10336884
TI  - Isoprostanes and PGE2 production in human isolated pulmonary artery smooth muscle
      cells: concomitant and differential release.
AB  - The isoprostanes are a group of biologically active arachidonic acid metabolites
      initially thought to be formed under conditions of oxidative stress and
      independently of cyclooxygenase. However, recent studies have demonstrated
      isoprostane production under conditions in which cyclooxygenase is intentionally
      activated/induced. Here we describe for the first time formation of isoprostanes
      by human vascular cells via independent pathways of oxidative stress and
      cyclooxygenase induction. We compared the release of the isoprostane with that of
      the traditional prostaglandin, prostaglandin E2. Cyclooxygenase-2 induction was
      confirmed by Western blot. When cells were stimulated with cytokines, the release
      of isoprostanes was inhibited by the cyclooxygenase-1 and -2 inhibitor
      indomethacin as well by as the cyclooxygenase-2 selective inhibitor L-745,337.
      However, treatment of cells with the superoxide-producing enzyme xanthine oxidase
      also resulted in isoprostane release, which was not affected by cyclooxygenase
      inhibition, unlike PGE2 release under the same condition. Thus, two independent
      pathways relating to oxidative stress and cyclooxygenase-2 induction form
      isoprostanes. These findings may have particular importance in diseases such as
      sepsis and ARDS in which oxidant stress occurs and cyclooxygenase is induced.

PMID- 10336885
TI  - Space travel directly induces skeletal muscle atrophy.
AB  - Space travel causes rapid and pronounced skeletal muscle wasting in humans that
      reduces their long-term flight capabilities. To develop effective
      countermeasures, the basis of this atrophy needs to be better understood. Space
      travel may cause muscle atrophy indirectly by altering circulating levels of
      factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by
      a direct effect on the muscle fibers themselves. To determine whether skeletal
      muscle cells are directly affected by space travel, tissue-cultured avian
      skeletal muscle cells were tissue engineered into bioartificial muscles and flown
      in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System
      (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a
      decrease in protein synthesis rates without alterations in protein degradation.
      Return of the muscle cells to Earth stimulated protein synthesis rates of both
      muscle-specific and extracellular matrix proteins relative to ground controls.
      These results show for the first time that skeletal muscle fibers are directly
      responsive to space travel and should be a target for countermeasure development.

PMID- 10336886
TI  - Vascular endothelial growth factor attenuates leukocyte-endothelium interaction
      during acute endothelial dysfunction: essential role of endothelium-derived
      nitric oxide.
AB  - Vascular endothelial growth factor (VEGF) is an endothelium-specific secreted
      protein that induces vasodilation and increases endothelial release of nitric
      oxide (NO). NO is also reported to modulate leukocyte-endothelium interaction.
      Therefore, we hypothesized that VEGF might inhibit leukocyte-endothelium
      interaction via increased release of NO from the vascular endothelium. We used
      intravital microscopy of the rat mesenteric microcirculation to measure leukocyte
      endothelium interactions 2, 4, and 24 h after systemic administration of VEGF to
      the rat (120 microg/kg, i.v., bolus). Superfusion of the rat mesentery with
      either 0.5 U/ml thrombin or 50 microM L-NAME consistently increased the number of
      rolling, adhering, and transmigrated leukocytes (P<0.01 vs. control mesenteries
      superfused with Krebs-Henseleit buffer). At 4 and 24 h posttreatment, VEGF
      significantly attenuated thrombin-induced and L-NAME-induced leukocyte rolling,
      adherence, and transmigration in rat mesenteric venules. In addition, adherence
      of isolated rat PMNs to thrombin-stimulated mesenteric artery segments in vitro
      was significantly reduced in mesenteric arteries isolated from VEGF-treated rats
      (P<0.001 vs. control rats). Direct measurement of NO demonstrated a threefold
      increase in basal NO release from aortic tissue of rats injected with VEGF, at 4
      and 24 h posttreatment (P<0. 01 vs. aortic tissue from control rats). Finally,
      systemic administration of VEGF to ecNOS-deficient mice failed to inhibit
      leukocyte-endothelium interactions observed in peri-intestinal venules. We
      concluded that VEGF is a potent inhibitor of leukocyte-endothelium interaction,
      and this effect is specifically correlated to augmentation of NO release from the
      vascular endothelium.--Scalia, R., Booth, G., Lefer, D. J. Vascular endothelial
      growth factor attenuates leukocyte-endothelium interaction during acute
      endothelial dysfunction: essential role of endothelium-derived nitric oxide.

PMID- 10336887
TI  - Telomerase activity as a measure for monitoring radiocurability of tumor cells.
AB  - Radiotherapy plays a key role in the treatment of many tumors. It is difficult to
      determine what fraction of tumor cells survives after treatment with ionizing
      radiation. A convenient and sensitive biochemical assay could be efficacious in
      determining the potential success of radiotherapy. Since telomerase activity is
      frequently associated with the malignant phenotype, we sought to determine
      whether a correlation existed between ionizing radiation-induced cell killing and
      telomerase activity. We evaluated telomerase activity in two telomerase-positive
      and one telomerase-negative human cell line exposed to ionizing radiation.
      Telomerase activity was determined using a PCR-based telomeric repeat
      amplification protocol coupled with ELISA. We found ionizing radiation treatment
      to decrease the telomerase activity (in plateau phase cells of RKO, HeLa; and
      growing cells of RKO) in a dose-dependent manner, which correlated with cell
      death in in vitro tests as well as during tumor regression in nude mice. In
      contrast, growing HeLa cells after 24 h postradiation treatment showed an
      increase in telomerase activity, but there was no increase in the levels of mRNA
      of hTERT. To assess the sensitivity of the telomerase activity assay, we
      performed mixing experiments of HeLa and AG1522 cell extracts. These studies
      showed that telomerase activity could be detected in lysate equal to a single
      HeLa cell when mixed with 10,000 AG1522 cells. Our results indicate that even a
      few surviving neoplastic cells can be detected by telomerase activity assay.
      Therefore, detection of telomerase activity may be a useful monitor of
      radiotherapeutic efficacy and an early predictor of outcome.

PMID- 10336888
TI  - Oxidative damage to mitochondrial DNA and glutathione oxidation in apoptosis:
      studies in vivo and in vitro.
AB  - Free radicals may be involved in apoptosis although this is the subject of some
      controversy. Furthermore, the source of free radicals in apoptotic cells is not
      certain. The aim of this study was to elucidate the role of oxidative stress in
      the induction of apoptosis in serum-deprived fibroblast cultures and in weaned
      lactating mammary glands as in vitro and in vivo experimental models,
      respectively. Oxidative damage to mtDNA is higher in apoptotic cells than in
      controls. Oxidized glutathione (GSSG) levels in mitochondria from lactating
      mammary gland are also higher in apoptosis. There is a direct relationship
      between mtDNA damage and the GSSG/reduced glutathione (GSH) ratio. Furthermore,
      whole cell GSH is decreased and GSSG is increased in both models of apoptosis.
      Glutathione oxidation precedes nuclear DNA fragmentation. These signs of
      oxidative stress are caused, at least in part, by an increase in peroxide
      production by mitochondria from apoptotic cells. We report a direct relationship
      between glutathione oxidation and mtDNA damage in apoptosis. Our results support
      the role of mitochondrial oxidative stress in the induction of apoptosis.

PMID- 10336889
TI  - Amphetamines induce apoptosis and regulation of bcl-x splice variants in
      neocortical neurons.
AB  - Amphetamineanalogs have emerged as popular recreational drugs of abuse. The
      number of reports of these substances producing severe acute toxicity and death
      is increasing. In 'Ecstasy' -associated deaths, focal necrosis in the liver and
      individual myocytic necrosis has been reported. Furthermore, serotonergic and
      dopaminergic neuronal cell damage has been observed in experimental amphetamine
      intoxication in laboratory animals. Here we demonstrate that subchronic exposure
      to D-amphetamine, methamphetamine, methylenedioxyamphetamine, and
      methylenedioxymethamphetamine ('Ecstasy') results in significant neurotoxicity in
      rat neocortical neurons in vitro. This neuronal cell death is accompanied by
      endonucleosomal DNA cleavage and differential expression of anti- and
      proapoptotic bcl-xL/S splice variants. In addition, we observed pronounced
      induction of cell stress-associated transcription factor c-jun and translation
      initiation inhibitor p97 after amphetamine treatment. These data support that the
      neurotoxic effects of different amphetamines are extended to rat neocortical
      neurons and that apoptotic pathways are involved in amphetamine-induced
      neurotoxicity.

PMID- 10336890
TI  - The vitamin D receptor binds in a transcriptionally inactive form and without a
      defined polarity on a retinoic acid response element.
AB  - Heterodimers of the vitamin D receptor (VDR) with the retinoid X receptor (RXR)
      bind in a transcriptionally unproductive manner to the retinoic acid response
      element present in the retinoic acid receptor-beta2 promoter. This element is
      composed of a direct repeat (DR) of the sequence PuGTTCA spaced by five
      nucleotides. However, the same sequence separated by three nucleotides (DR3) acts
      as a strong vitamin D response element. Here we show that the polarity of binding
      of the heterodimers to the DR3 was 5'-RXR-VDR-3', whereas on the DR5, both
      heterodimeric partners bind indistinctly to the 5' or 3' hemi-sites. These
      results suggest that the response elements can allosterically regulate the
      conformation of the receptors to determine positive or negative regulation of
      gene expression. Despite the altered polarity, the DR5-bound heterodimer was able
      to recruit the nuclear receptor coactivator ACTR in a vitamin D-dependent
      fashion. Furthermore, binding of the corepressor SMRT (silencing mediator of
      retinoid and thyroid hormone receptors) to the RXR/VDR heterodimer on a DR5 was
      not observed. Binding of RXR/VDR heterodimers to DRs with different
      transcriptional outcomes may generate selectivity and provide a greater
      complexity and flexibility to the vitamin D responses.

PMID- 10336891
TI  - Mitochondrial DNA 4977 bp deletion and OH8dG levels correlate in the brain of
      aged subjects but not Alzheimer's disease patients.
AB  - The levels of mitochondrial DNA 4977 bp deletion (mtDNA4977) and mitochondrial
      DNA 8'-hydroxy-2'-deoxyguanosine (OH8dG) were determined in the same samples from
      two brain areas of healthy subjects and Alzheimer's disease (AD) patients. A
      positive correlation between the age-related increases of mtDNA4977 and of OH8dG
      levels was found in the brain of healthy individuals. On the contrary, in both
      brain areas of AD patients, mtDNA4977 levels were very low in the presence of
      high OH8dG amounts. These results might be explained assuming that the increase
      of OH8dG above a threshold level, as in AD patients, implies consequences for
      mtDNA replication and neuronal cell survival.

PMID- 10336892
TI  - Differentiation lineage-specific expression of human heat shock transcription
      factor 2.
AB  - Differentiation of multipotential hematopoietic cells into lineage-committed
      precursors involves the selection and maintenance of appropriate programs of gene
      expression, regulated by specific transcription factors. Using human K562
      erythroleukemia cells capable of differentiating along erythroid and
      megakaryocytic lineages, we explore the differentiation-related role of heat
      shock transcription factor 2 (HSF2), which belongs to a family of transcription
      factors generally known to regulate heat shock gene expression. We demonstrate
      that enhanced HSF2 expression and the acquisition of HSF2 DNA binding activity
      are strictly specific for erythroid characteristics of K562 cells. Our results
      reveal a multistep regulatory process of HSF2 gene expression. In K562 cells
      undergoing hemin-mediated erythroid differentiation, the increase in HSF2 protein
      levels is preceded by transcriptional induction of the HSF2 gene, accompanied by
      increased HSF2 mRNA stability. In contrast, during megakaryocytic differentiation
      induced by the phorbol ester TPA, expression of HSF2 is rapidly down-regulated,
      leading to a complete loss of the HSF2 protein. These results indicate that the
      determination of HSF2 expression occurs at the early stages of lineage
      commitment. Taken together, our data suggest that HSF2 could function as a
      lineage-restricted transcription factor during differentiation of K562 cells
      along either the erythroid or the megakaryocytic pathway.

PMID- 10336893
TI  - Expression of the Huntington's disease gene is regulated in astrocytes in the
      arcuate nucleus of the hypothalamus of postpartum rats.
AB  - Huntington's disease (HD) is one of a number of neurodegenerative disorders
      caused by expansion of polyglutamine-encoding CAG repeats within specific genes.
      Huntingtin, the protein product of the HD gene, is widely expressed in neural and
      nonneural human and rodent tissue. The function of the wild-type or mutated form
      of huntingtin is currently unknown. We have observed that relative to naive and
      male animals, huntingtin protein was significantly increased in the arcuate
      nucleus of postpartum rats. Using an oligonucleotide probe, in situ and Northern
      blot hybridization confirmed the expression of huntingtin mRNA. Quantification of
      the in situ hybridization signal in the arcuate nucleus revealed an approximate
      sevenfold increase in the expression of huntingtin mRNA in postpartum, lactating
      animals compared with naive female or male animals. Emulsion autoradiography and
      immunohistochemistry revealed that the cells with elevated huntingtin expression
      had a stellate conformation that morphologically resembled astrocytes. Dual label
      immunofluorescence immunohistochemistry demonstrated the colocalization of
      huntingtin and glial fibrillary acidic protein in these cells, confirming that
      they were astrocytes. Astrocytes expressing huntingtin were consistently found in
      close apposition to neuronal soma, suggesting interactions between these cell
      types. During the perinatal and postnatal period, the hypothalamus undergoes
      alterations in metabolic function. Our results support the idea of glia-induced
      metabolic changes in the hypothalamus. These results provide the first
      demonstration of naturally occurring changes in the expression of the
      Huntington's disease gene in the brain and suggest that huntingtin may play an
      important role in the processes that regulate neuroendocrine function.

PMID- 10336894
TI  - Overexpression of DNA polymerase beta: a genomic instability enhancer process.
AB  - DNA polymerase beta (Pol beta) is the most inaccurate of the six DNA polymerases
      found in mammalian cells. In a normal situation, it is expressed at a constant
      low level and its role is believed to be restricted to repair synthesis in the
      base excision repair pathway participating to the genome stability. However,
      excess of Pol beta, found in some human tumors, could confer an increase in
      spontaneous mutagenesis and result in a highly mutagenic tolerance phenotype
      toward bifunctional DNA cross-linking anticancer drugs. Here, we present a
      hypothesis on the mechanisms used by Pol beta to be a genetic instability
      enhancer through its overexpression. We hypothesize that an excess of Pol beta
      perturbs the well-defined specific functions of DNA polymerases developed by the
      cell and propose Pol beta-mediated gap fillings during DNA transactions like
      repair, replication, or recombination pathways as key processes to introduce
      illegitimate deoxyribonucleotides or mutagenic base analogs like those produced
      by intracellular oxidative processes. These mechanisms may predominate during
      cellular nonproliferative phases in the absence of DNA replication.

PMID- 10336907
TI  - Managing waiting lists for cardiac surgery.

PMID- 10336908
TI  - Death on the waiting list for cardiac surgery.

PMID- 10336909
TI  - Management of unstable angina: what role intervention, ask the RITA-3 trialists?
      Randomised intervention treatment of angina.

PMID- 10336910
TI  - Ventricular tachycardia: is it a burning issue?

PMID- 10336911
TI  - Stamps in cardiology. Miniature sheets.

PMID- 10336912
TI  - Mapping and ablation of ventricular tachycardia with the aid of a non-contact
      mapping system.
AB  - OBJECTIVE: Treatment of ventricular tachycardia (VT) in coronary heart disease
      has to date been limited to palliative treatment with drugs or implantable
      defibrillators. The results of curative treatment with catheter ablation have
      proved disappointing because the complexity of the VT mechanism makes
      identification of the substrate using conventional mapping techniques difficult.
      The use of a mapping technology that may address some of these issues, and thus
      make possible a cure for VT with catheter ablation, is reported. PATIENTS AND
      INTERVENTION: The non-contact system, consisting of a multielectrode array
      catheter (MEA) and a computer mapping system, was used to map VT in 24 patients.
      Twenty two patients had structural heart disease, the remainder having "normal"
      left ventricles with either fasicular tachycardia or left ventricular ectopic
      tachycardia. RESULTS: Exit sites were demonstrated in 80 of 81 VT morphologies by
      the non-contact system, and complete VT circuits were traced in 17. In another 37
      morphologies of VT 36 (30)% (mean (SD)) of the diastolic interval was identified.
      Thirty eight VT morphologies were ablated using 154 radiofrequency energy
      applications. Successful ablation was achieved by 77% of radiofrequency within
      diastolic activation identified by the non-contact system and was significantly
      more likely to ablate VT than radiofrequency at the VT exit, or remote from
      diastolic activation. Over a mean follow up of 1.5 years, 14 patients have had no
      recurrence of VT and only two target VTs have recurred. Five patients have had
      recurrence of either slower non-sustained, undocumented or fast non-target VT.
      Five patients have died, one from tamponade from a pre-existing temporary pacing
      wire, and four from causes unrelated to the procedure. CONCLUSION: The non
      contact system can safely be used to map and ablate haemodynamically stable VT
      with low VT recurrence rates. It is yet to be established whether this system may
      be applied with equal success to patients with haemodynamically unstable VT.

PMID- 10336913
TI  - Randomised comparison of electrode positions for cardioversion of atrial
      fibrillation.
AB  - OBJECTIVE: To compare the relative efficacy of anteroanterior v anteroposterior
      electrode pad positions for external cardioversion of atrial fibrillation.
      DESIGN: Prospective randomised trial. SETTING: Tertiary referral cardiology
      centre in the United Kingdom. PATIENTS: 90 patients undergoing elective
      cardioversion for atrial fibrillation. INTERVENTIONS: Cardioversion was attempted
      with self adhesive electrode pads with an area of 106 cm2 placed either in the
      anteroanterior (AA) or anteroposterior (AP) positions. Initial shock was 100 J
      which, if unsuccessful, was followed by 200 J, 300 J, and 360 J if required. Peak
      current and transthoracic impedance were measured. MAIN OUTCOME MEASURES:
      Cardioversion success rate and energy requirements. RESULTS: Cardioversion was
      successful in 81% of the patients (73/90). There was no statistically significant
      difference in the cardioversion success rate (AA 84%, 38/45 patients; AP 78%,
      35/45 patients; p = 0.42) or mean (SD) energy requirement for all patients (AA
      223 (96.1) J; AP 232 (110) J) or for patients who were successfully cardioverted
      (AA 197.9 (82.4) J; AP 195.4 (97.2) J; p = 0.9) between the two pad positions.
      The mean transthoracic impedance (TTI) for the first shock (AA 77.5 (18.4) ohms;
      AP 73.7 (18.7) ohms; p = 0.34) was not significantly different between the two
      groups. TTI correlated significantly with body mass index, percentage body fat,
      and chest AP diameter. There was a progressive decrease in TTI with serial
      shocks. While aetiology and TTI were the two independent significant predictive
      factors for energy requirement, duration of atrial fibrillation was the only
      independent predictor of cardioversion success in a multivariate analysis.
      CONCLUSIONS: Electrode pad position is not a determinant of cardioversion success
      rate or energy requirement.

PMID- 10336914
TI  - Development of sinus node disease in patients with AV block: implications for
      single lead VDD pacing.
AB  - OBJECTIVE: To investigate the incidence of sinus node disease after pacemaker
      implantation for exclusive atrioventricular (AV) block. DESIGN: 441 patients were
      followed after VDD (n = 219) or DDD pacemaker (n = 222) implantation for AV block
      over a mean period of 37 months. Sinus node disease and atrial arrhythmias had
      been excluded by Holter monitoring and treadmill exercise preoperatively in 286
      patients (group A). In 155 patients with complete AV block, a sinus rate above 70
      beats/min was required for inclusion in the study (group B). Holter monitoring
      and treadmill exercise were performed two weeks, three months, and every six
      months after implantation. Sinus bradycardia below 40 beats/min, sinoatrial
      block, sinus arrest, or subnormal increase of heart rate during treadmill
      exercise were defined as sinus node dysfunction. RESULTS: Cumulative incidence of
      sinus node disease was 0.65% per year without differences between groups.
      Clinical indicators of sinus node dysfunction were sinus bradycardia below 40
      beats/min in six patients (1.4%), intermittent sinoatrial block in two (0.5%),
      and chronotropic incompetence in five patients (1.1%). Only one of these patients
      (0.2%) was symptomatic. Cumulative incidence of atrial fibrillation was 2.0% per
      year, independent of the method used for the assessment of sinus node function
      and of the implanted device. CONCLUSIONS: In patients undergoing pacemaker
      implantation for isolated AV block, sinus node syndrome rarely occurs during
      follow up. Thus single lead VDD pacing can safely be performed in these patients.

PMID- 10336915
TI  - Waiting times and prioritization for coronary artery bypass surgery in New
      Zealand.
AB  - OBJECTIVES: To review the New Zealand coronary artery bypass priority score
      instituted in May 1996, and specifically to determine whether it prioritizes
      patients at high risk of cardiac events while waiting. The New Zealand score is
      compared with the Ontario urgency rating score, and waiting times for surgery are
      compared with the maximum times recommended by the Ontario consensus panel.
      DESIGN: Retrospective review of patients accepted for isolated coronary artery
      bypass surgery between 1 January 1993 and 31 January 1996. SETTING: Green Lane
      Hospital, Auckland, New Zealand. MAIN OUTCOME MEASURES: Waiting time, cardiac
      death, myocardial infarction, and cardiac readmission. RESULTS: The median
      waiting times were five days for hospital cases (n = 721) and 146 days for out of
      hospital cases (n = 701). Of the latter group, 28% waited more than a year, 33%
      had their surgery expedited because of worsening symptoms, and 19% failed to meet
      the cut off point set by the New Zealand score for acceptance onto the list.
      Twenty two patients died, 18 on the outpatient waiting list (waiting list
      mortality 2.6%, risk 0.28% per month of waiting), and 132 were readmitted, 12%
      with myocardial infarction and 76% with unstable angina. Risk factors for a
      composite end point of death or myocardial infarction and/or cardiac readmission
      were: previous coronary artery bypass surgery (p = 0. 001), class III or IV
      angina (p = 0.002), and hypertension (p = 0. 005). The New Zealand score did not
      identify those at risk. Excluding hospital cases, 32% had surgery within the time
      recommended by the Ontario consensus panel. CONCLUSIONS: Waiting times for
      coronary artery bypass surgery in New Zealand are considerably longer than those
      in Ontario, Canada. By using a numerical cut off point, implementation of the New
      Zealand priority scoring system has restricted access to coronary surgery on the
      basis of funding constraints rather than clinical appropriateness. The score does
      not add greatly to the clinicians' prioritization in predicting those patients
      who will suffer events while waiting.

PMID- 10336916
TI  - Death on the waiting list for cardiac surgery in The Netherlands in 1994 and
      1995.
AB  - OBJECTIVE: To describe the causes and circumstances of death regarding patients
      who died in 1994 and 1995 while on a waiting list for cardiac surgery in the
      Netherlands. DESIGN: Retrospective multicentre case study. SETTING: 11 Dutch
      cardiac surgery centres. PATIENTS: All patients reported as dying while on the
      waiting list for cardiac surgery in 1994 and 1995. MAIN OUTCOME MEASURES:
      Classification of death by an independent adjudication committee into
      "erroneously reported", "waiting list related" or "not waiting list related".
      Death was judged as "waiting list related" if the clinical course would have been
      substantially different if there had been unrestricted surgical capacity.
      RESULTS: 138 and 129 deaths were reported in 1994 and 1995, respectively. 43
      deaths (16%) were considered as erroneously reported. 181 of the remaining 224
      cases were adjudicated as waiting list related. Median time from acceptance for
      surgery to death was 35 days (interquartile range 14-75 days). 97 of 181 deaths
      occurred within six weeks following addition to the waiting list. The estimated
      incidence of death ranged from 1.33 per 1000 patient-weeks during weeks 2-4 to
      0.68 per 1000 patient-weeks after 12 weeks. CONCLUSIONS: The causes and
      circumstances of death are waiting list related for approximately 100 patients
      per year in the Netherlands. At least half of the deaths may occur within the
      first six weeks. Waiting lists for cardiac surgery engender high risks for the
      patients involved.

PMID- 10336917
TI  - Relevance of clinical trial results in myocardial infarction to medical practice:
      comparison of four year outcome in participants of a thrombolytic trial, patients
      receiving routine thrombolysis, and those deemed ineligible for thrombolysis.
AB  - OBJECTIVE: To assess the medium to long term outcome of patients ineligible for
      thrombolysis compared to those enrolled in a clinical trial of thrombolysis and
      patients receiving non-trial thrombolysis. DESIGN: Cohort study based on the
      Nottingham heart attack register. SETTING: Two district general hospitals serving
      a defined urban/rural population. SUBJECTS: All patients admitted with a
      confirmed acute myocardial infarction during 1992 categorised as either
      participants of a thrombolytic trial (group A, n = 140), receiving non-trial
      thrombolysis (group B, n = 329), or deemed ineligible for lytic treatment (group
      C, n = 431). MAIN OUTCOME MEASURES: Background characteristics, inhospital
      treatment, patterns of follow up, referrals to cardiologists, revascularisation
      rates, and short and long term survival. RESULTS: Clinical trial recruits were
      younger by almost 10 years, were less likely to have a previous history of
      myocardial infarction, and more likely to be in Killip class 1 on admission than
      those ineligible for thrombolysis. Cardiology follow up was mandatory for all
      surviving trial participants but 22% of patients in group B and 31% of patients
      in group C received no follow up, and during four years less than 50% ever saw a
      cardiologist. Revascularisation was performed in 17.2% of patients in group A,
      13.6% of patients in group B, and 7.5% of patients in group C. Cumulative
      mortality at a median of four years was 24.3% in group A, 36.8% in B, and 59.6%
      in group C. Adjusting for age, sex, previous myocardial infarction, type of
      infarction, and Killip class in a logistic regression model the odds ratios (OR)
      of death at four years for groups B and C were 1.60 (95% confidence intervals
      (CI) 0.97 to 2.63, p = 0.065) and 2.64 (95% CI 1.61 to 4. 32, p < 0.001),
      respectively, when compared to group A (OR 1). CONCLUSIONS: Patients enrolled
      into thrombolytic trials are at low risk. Patients deemed ineligible for
      thrombolysis are high risk, receive less surveillance, are less likely to be
      revascularised or receive trial proven treatments, have a poor long term outcome
      not entirely explained by increased age or severity of infarction, and deserve
      further evaluation.

PMID- 10336918
TI  - Comparing two different protocols for tilt table testing: sublingual glyceryl
      trinitrate versus isoprenaline infusion.
AB  - OBJECTIVE: To assess the diagnostic value and safety of sublingual glyceryl
      trinitrate tilt testing compared with isoprenaline infusion in patients with
      unexplained syncope. DESIGN: Glyceryl trinitrate and isoprenaline tilt tests were
      performed in two successive days on a random basis in cases and controls.
      SETTING: Outpatient cases with syncope referred to Shahid Rajaii Heart Hospital.
      SUBJECTS: 65 consecutive patients with unexplained syncope after thorough work
      up; 20 healthy volunteers. RESULTS: Positive responses were observed in 20
      patients during the passive phase. Of the other 45 patients, positive responses
      occurred in 25 cases during the glyceryl trinitrate phase and in 26 cases during
      the isoprenaline phase. In the control group, positive responses during the
      passive, glyceryl trinitrate, and isoprenaline phases occurred in one, one, and
      two cases, respectively. The sensitivity and specificity of the protocols were
      55% and 94.7%, respectively, for glyceryl trinitrate v 58% and 89.4% for
      isoprenaline. Owing to discordant responses in 75% of the cases, the sequential
      use of the tests (if one was negative) would increase the sensitivity to 84%
      while decreasing the specificity slightly (to 84%). Side effects were less
      frequent with glyceryl trinitrate. CONCLUSIONS: Sublingual glyceryl trinitrate
      tilt testing is an effective and safe alternative to the isoprenaline infusion
      test and can be used as a complementary test.

PMID- 10336919
TI  - Does the addition of losartan improve the beneficial effects of ACE inhibitors in
      patients with anterior myocardial infarction? A pilot study.
AB  - OBJECTIVE: To verify the efficacy of the combination of captopril (75 mg day) and
      losartan (25 mg/day) in early postinfarction phases of reperfused anterior acute
      myocardial infarction. DESIGN AND PATIENTS: 99 patients, hospitalised for
      suspected anterior acute myocardial infarction within four hours from the onset
      of symptoms, were randomised into two groups: group A included 50 patients who
      received captopril 75 mg/day and placebo; group B included 49 patients who
      received captopril 75 mg/day within three days of admission plus losartan 12.5
      mg, as a first dose, and 25 mg/day successively. An additional 23 patients with
      anterior acute myocardial infarction received losartan 25 mg alone and acted as
      controls (group C) to check the effects of losartan on plasma angiotensin II
      (AII) concentrations. Noradrenaline (norepinephrine) (NA) and AII plasma
      concentrations were measured on the third and 10th day after admission in 93
      patients (35 from group A, 35 from group B, and 23 from group C). 90 days after
      admission patients underwent echocardiography to determine end systolic volume
      (ESV) and ejection fraction (EF). RESULTS: Patients in groups A and B were
      similar with regard to age, sex, creatine kinase peak, EF, ESV, and risk factors.
      Group B (captopril plus losartan) patients showed a significant reduction in mean
      (SD) systolic blood pressure within the group (basal 128 (10) mm Hg; 10 days
      after admission 105 (9) mm Hg, p < 0.001), and in comparison with group A
      (captopril) patients (basal 127 (11) mm Hg; 10 days after admission 116 (10) mm
      Hg, p < 0. 001). Diastolic blood pressure was also lower in group B patients
      versus group A (66 (11) v 77 (11) mm Hg). Group C (losartan) patients also showed
      a significant reduction in systolic blood pressure (131 (13) mm Hg down to 121
      (12) mm Hg, p < 0.001). Neither NA nor AII plasma concentrations in groups A and
      B differed significantly in basal samples (NA 673 (138) v 675 (141) pg/ml; AII
      12.77 (4.79) v 12.65 (4.71) pg/ml) or 10 days after admission (NA 283 (93) v 277
      (98) pg/ml; AII 5.31 (2.25) v 6.09 (3.31) pg/ml). However, patients in group C
      had higher plasma concentrations of AII (14.79 (5.7) pg/ml on the third day and
      7.98 (4.92) pg/ml on the 10th day) than patients in either group A or B (p =
      0.006). After 90 days following treatment, group B (captopril plus losartan)
      patients had a smaller ESV than patients in group A (captopril) and group C
      (losartan). CONCLUSION: The data suggest that the combination of captopril plus
      losartan is feasible in the early treatment of acute myocardial infarction
      patients, and it appears that this combination has more effect on ESV than
      captopril alone in the short term.

PMID- 10336920
TI  - Correlation of heart rate variability with cardiac functional and metabolic
      variables in cyclists with training induced left ventricular hypertrophy.
AB  - OBJECTIVE: To examine the correlation between heart rate variability and left
      ventricular mass in cyclists with an athlete's heart. METHODS: Left ventricular
      mass and diastolic function were determined at rest and myocardial high energy
      phosphates were quantified at rest and during atropine-dobutamine stress in 12
      male cyclists and 10 control subjects, using magnetic resonance techniques.
      Ambulatory 24 hour ECG recordings were obtained, and time and frequency domain
      heart rate variability indices were computed. RESULTS: In the cyclists, the mean
      of all RR intervals between normal beats (meanNN), the SD of the RR intervals,
      and their coefficient of variation were significantly greater than in control
      subjects (p < 0.01, p < 0.01, and p < 0.05, respectively). For cyclists and
      control subjects, only meanNN correlated with left ventricular mass (r = 0.48, p
      = 0.038). The heart rate variability indices that correlated with functional or
      metabolic variables were: meanNN v E/A peak (the ratio of peak early and peak
      atrial filling rate) (r = 0.48, p = 0.039); the root mean square of successive
      differences in RR intervals among successive normal beats v E/A area (ratio of
      peak early and peak atrial filling volume) (r = 0.48, p = 0.040); percentage of
      successive RR intervals differing by more than 50 ms v the phosphocreatine to ATP
      ratio at rest (r = 0.54, p = 0. 017); and the SD of the average RR intervals
      during all five minute periods v the phosphocreatine to ATP ratio during stress
      (r = 0.60, p = 0.007). CONCLUSIONS: Highly trained cyclists have increased heart
      rate variability indices, reflecting increased cardiac vagal control compared
      with control subjects. Left ventricular mass has no major influence on heart rate
      variability, but heart rate variability is significantly correlated with high
      energy phosphate metabolism and diastolic function.

PMID- 10336921
TI  - Pulmonary function and respiratory muscle strength in chronic heart failure:
      comparison between ischaemic and idiopathic dilated cardiomyopathy.
AB  - OBJECTIVE: To compare pulmonary function and respiratory muscle strength in
      patients with ischaemic and idiopathic dilated cardiomyopathy, well matched for
      indices of heart failure. METHODS: The study involved 30 patients with ischaemic
      cardiomyopathy and 30 with idiopathic dilated cardiomyopathy. The groups were
      well matched for age, weight, and clinical severity of cardiac dysfunction as
      assessed by ejection fraction and the New York Heart Association functional
      class. There were more smokers in the ischaemic group (p < 0.05), but indices of
      pulmonary function were comparable. RESULTS: Mean (SD) maximum static inspiratory
      pressure was lower in dilated cardiomyopathy than in ischaemic cardiomyopathy (73
      (20) v 84 (22) cm H2O, p < 0.05), as was the maximum static expiratory pressure
      (90 (20) v 104 (21) cm H2O, p < 0.05). CONCLUSIONS: For a given degree of cardiac
      dysfunction, the respiratory muscles are weaker in patients with idiopathic
      dilated cardiomyopathy than in those with ischaemic cardiomyopathy.

PMID- 10336922
TI  - Screening of ruptured plaques in patients with coronary artery disease by
      intravascular ultrasound.
AB  - AIM: To visualise the characteristics of ruptured plaques by intravascular
      ultrasound (IVUS) and to correlate plaque characteristics with clinical symptoms
      to establish a quantitative index of plaque vulnerability. METHODS: 144
      consecutive patients with angina were examined using IVUS. Ruptured plaques,
      characterised by a plaque cavity and a tear on the thin fibrous cap, were
      identified in 31 patients (group A), of whom 23 (74%) presented with unstable
      angina. Plaque rupture was confirmed by injecting contrast medium filling the
      plaque cavity during IVUS examination. Of the patients without plaque rupture
      (group B, n = 108), only 19 (18%) had unstable angina. RESULTS: No significant
      differences were found between groups A and B in relation to plaque and vessel
      area (p > 0.05). Mean (SD) per cent stenosis in group A was less than in group B,
      at 56.2 (16.5)% v 67.9 (13.4)%; p < 0.001. Area of the emptied plaque cavity in
      group A (4.1 (3.2) mm2) was larger than the echolucent zone in group B (1.32
      (0.79) mm2) (p < 0.001). The plaque cavity to plaque ratio in group A (38.5
      (17.1)%) was larger than the echolucent area to plaque ratio in group B (11.2
      (8.9)%) (p < 0.001). The thickness of the fibrous cap in group A was less than in
      group B, at 0.47 (0.20) mm v 0.96 (0.94) mm; p < 0.001. CONCLUSIONS: Plaques seem
      to be prone to rupture when the echolucent area is larger than 4.1 (3.2) mm2,
      when the echolucent area to plaque ratio is greater than 38.5 (17.1)%, and when
      the fibrous cap is thinner than 0.7 mm. IVUS can identify plaque rupture and
      vulnerable plaques. This may influence patient management and treatment.

PMID- 10336923
TI  - Validation of minimally invasive measurement of myocardial perfusion using
      electron beam computed tomography and application in human volunteers.
AB  - OBJECTIVES: To measure myocardial perfusion using an estimate of intramyocardial
      vascular volume obtained by electron beam computed tomography (EBCT) in an animal
      model; to assess the feasibility and validity of measuring regional myocardial
      perfusion in human volunteers using the techniques developed and validated in the
      animal studies. METHODS: Measurements of myocardial perfusion with EBCT employing
      intravenous contrast injections were compared with radioactive microsphere
      measurements (flow 57 to 346 ml/100 g/min) in seven closed chest dogs. Fourteen
      human volunteers then underwent EBCT scans using intravenous contrast injections.
      RESULTS: Mean (SEM) global intramyocardial vascular volume by EBCT was 7.6
      (1.1)%. The correlation between global EBCT (y) and microsphere (x) perfusion was
      y = 0.59x + 15.56 (r = 0.86) before, and y = 0.72x + 6. 06 (r = 0.88) after
      correcting for intramyocardial vascular volume. Regional perfusion correlation
      was y = 0.75x + 23.84 (r = 0.82). Corresponding improvements in agreement between
      the two techniques were also seen using Bland-Altman plots. In the human
      subjects, mean resting global myocardial flow was 98 (6) ml/100 g/min, with
      homogeneous flow across all regions. In 10 of these subjects, perfusion was
      studied during coronary vasodilatation using intravenous adenosine. Global flow
      increased from 93 (5) ml/100 g/min at rest to 250 (19) ml/100 g/min during
      adenosine (p < 0.001), with an average perfusion reserve ratio of 2.8 (0.2).
      Similar changes in regional perfusion were observed and were uniform throughout
      all regions, with a mean regional perfusion reserve ratio of 2.8 (0.3).
      CONCLUSIONS: Accounting for intramyocardial vascular volume improves the accuracy
      of EBCT measurements of myocardial perfusion when using intravenous contrast
      injections. The feasibility of providing accurate measurements of global and
      regional myocardial perfusion and perfusion reserve in people using this
      minimally invasive technique has also been demonstrated.

PMID- 10336924
TI  - Evaluation of myocardial, hepatic, and renal perfusion in a variety of clinical
      conditions using an intravenous ultrasound contrast agent (Optison) and second
      harmonic imaging.
AB  - OBJECTIVE: To assess the potential of intravenous Optison, a second generation
      ultrasound contrast agent, and various ultrasound imaging modes to determine
      myocardial, kidney, and liver perfusion in normal subjects and patients with left
      ventricular dysfunction or chronic pulmonary disease together with renal or
      hepatic dysfunction. METHODS: Five normal subjects and 20 patients underwent grey
      scale echocardiographic imaging of myocardium, kidney, and liver during 505
      intravenous injections of Optison. Images were assessed qualitatively by two
      independent observers and quantitatively using video densitometry to determine
      the peak contrast enhancement effect. RESULTS: Qualitative analysis showed that
      intermittent harmonic imaging was superior to either conventional fundamental or
      continuous harmonic imaging for all organs. Quantitative analysis showed that the
      peak change in echocardiographic intensity v baseline during continuous harmonic
      imaging was 11 units for myocardium (p < 0.03), 7 units for kidney (NS), and 14
      units for liver (p < 0.05). During intermittent harmonic imaging the peak change
      was significantly greater, being 33 units for myocardium (p < 0.0001), 24 units
      for kidney (p < 0.0002), and 16 units for liver (p < 0.001). CONCLUSIONS: Organ
      tissue perfusion can be demonstrated following intravenous injection of Optison,
      particularly when used in combination with intermittent harmonic imaging
      techniques. This contrast agent is effective in a variety of clinical conditions.

PMID- 10336925
TI  - Lung perfusion studies after detachable coil occlusion of persistent arterial
      duct.
AB  - OBJECTIVE: To evaluate relative lung perfusion following complete occlusion of
      persistent arterial duct with detachable Cook coils. METHODS: Ductal occlusion
      using detachable coils was performed in 35 patients (median age 3.9 years, range
      0.5 to 16; 32 native ducts, three patients with previous devices). If the duct
      could be crossed with a 0.035 inch guidewire and a 4 F catheter after coil
      implantation, a further coil was implanted. Between one and seven coils were used
      (median two). RESULTS: Complete ductal occlusion was confirmed by
      echocardiography 24 hours after the procedure in all patients. Lung perfusion
      scans were performed three months after the procedure in 33 of 35 patients (two
      older patients with a single coil each did not attend). Decreased perfusion to
      the left lung (defined as < 40% of total lung flow) was observed in only one
      patient, who had previously had a 17 mm Rashkind umbrella implanted. There was no
      correlation between left lung perfusion and peak left pulmonary artery Doppler
      velocities (r = 0.27 and p = 0.125 for the entire group; r = 0.29 and p = 0.124
      after excluding patients with previous devices). CONCLUSIONS: Coil occlusion is
      effective in achieving complete closure of the duct. An aggressive approach using
      multiple coils did not compromise perfusion to the left lung.

PMID- 10336926
TI  - Pattern of pulmonary venous blood flow in the hypoplastic left heart syndrome in
      the fetus.
AB  - OBJECTIVE: To determine whether restriction at the atrial septum in the newborn
      with hypoplastic left heart syndrome can be predicted accurately by examining the
      pattern of pulmonary venous flow in the fetus. A restrictive atrial septum can
      contribute to haemodynamic instability before surgery for this lesion and has
      been associated with an increased mortality. DESIGN: Pulmonary venous pulsed
      Doppler tracings were compared between fetuses with hypoplastic left heart
      syndrome and controls. The size of the atrial septal defect on the postnatal
      echocardiogram was graded according to the degree of restriction. Pulsed Doppler
      tracings of pulmonary venous blood flow were obtained in 18 fetuses with left
      atrial outflow atresia and compared with 77 controls, adjusted for gestational
      age. Postnatal echocardiograms were available for analysis in 13 of 18 neonates.
      SETTING: A tertiary referral centre for fetal cardiology and paediatric cardiac
      surgery. RESULTS: Fetuses with hypoplastic left heart syndrome were different
      from controls in all pulmonary vein indices measured. As assessed from the
      postnatal echocardiogram, there were seven fetuses with a restrictive atrial
      septum. In these fetuses, the systolic flow velocity (p < 0.01), S/D ratio (p <
      0.01), and peak reversal wave (p < 0.001) in the pulmonary vein tracing showed a
      good correlation with the degree of restriction. CONCLUSIONS: The Doppler pattern
      of pulmonary venous flow in the fetus with hypoplastic left heart syndrome
      appears to be a reliable predictor of restriction of the atrial septum in the
      neonate. This may help in the immediate post-delivery management of these infants
      before surgery.

PMID- 10336927
TI  - Accuracy of electrocardiographic and echocardiographic indices in predicting life
      threatening ventricular arrhythmias in patients operated for tetralogy of Fallot.
AB  - OBJECTIVE: To validate the accuracy of the prognostic significance of non
      invasive clinical diagnostic indices as predictors of sustained ventricular
      tachycardia (sVT) or fibrillation (VF) in patients undergoing repair for
      tetralogy of Fallot. METHODS: One way analysis of variance and pairwise
      comparison of the values with the Bonferroni correction, logistic multivariate
      analysis, and ordinal logistic analysis were used to study quantitative
      electrocardiographic and echocardiographic variables in 66 patients who had
      undergone surgery for tetralogy of Fallot by ventriculotomy at a mean (SD) age of
      11.8 (9.5) years. The mean (SD) period of follow up was 16.1 (5.7) years after
      surgery. RESULTS: Four groups of patients were identified by ECG and 24 hour
      Holter monitoring: 19 (28.7%) without ventricular arrhythmias, 34 (51.5%) with
      minor ventricular arrhythmias, seven (10.6%) with non-sustained ventricular
      tachycardia (nsVT), and six (9.0%) with sVT or VF. One way analysis indicated
      significant differences in QT dispersion (QTd) and end diastolic volume of the
      right ventricle (EDVRV) among the groups. Univariate logistic analysis showed
      EDVRV, QTd, and QRS duration to be significantly associated with sVT or VF.
      Stepwise multivariate analysis and ordinal logistic analysis showed QTd to be
      preferable to QRS duration as an indicator, because it was unrelated to EDVRV,
      and was capable of separating different probability curves for nsVT as opposed to
      sVT or VF. CONCLUSIONS: Stratification of patients undergoing corrective surgery
      for tetralogy of Fallot and at risk of life threatening arrhythmias is possible
      by simple and inexpensive means, which provide sensitive and specific indices.

PMID- 10336929
TI  - Images in cardiology. False aneurysm following balloon dilatation of multiple
      right pulmonary artery stenoses.

PMID- 10336928
TI  - Reduced heart rate variability following repair of tetralogy of Fallot.
AB  - OBJECTIVE: To examine autonomic function as assessed by heart rate variability in
      patients 10 or more years after repair of tetralogy of Fallot, and to relate this
      to cardiac structure, function, and electrocardiographic indices. METHODS: Heart
      rate variability was measured by standard time domain techniques on a 24 hour
      Holter ECG in 28 patients, aged 12 to 34 years (mean 19.5), who had undergone
      repair of tetralogy of Fallot at least 10 years previously. Echocardiography was
      performed to assess left ventricular size and function, right ventricular size
      and pressure, and any proximal pulmonary arterial stenosis. Right ventricular
      function was evaluated by radionuclide scan. QRS duration, QT interval, and QT
      dispersion were measured on a standard 12 lead ECG. Measurements of heart rate
      variability were compared with values from 28 age matched healthy controls (mean
      age 19.9 years). Interrelations between variables were assessed using Pearson
      correlation coefficients and stepwise regression analysis. RESULTS: Heart rate
      variability was reduced, compared with values for age matched normal controls, in
      12 of the 28 patients. Reduced heart rate variability was associated with
      increased age, increased right ventricular size and pressure, and widening of the
      QRS complex. CONCLUSIONS: Reduced heart rate variability is a feature following
      repair of tetralogy of Fallot. It is associated with increasing age, impaired
      right ventricular haemodynamics, and widening of the QRS complex. Under these
      circumstances, reduced heart rate variability may be a marker for deteriorating
      right ventricular function. Increased QRS duration has been identified as a risk
      factor for sudden death following repair of tetralogy of Fallot, and impaired
      cardiac autonomic control may be one of the mechanisms involved.

PMID- 10336930
TI  - Prenatal diagnosis of right ventricular outflow tract obstruction with intact
      ventricular septum, and detection of ventriculocoronary connections.
AB  - OBJECTIVES: To determine the accuracy of prenatal diagnosis of pulmonary atresia
      and intact ventricular septum (PAIVS), and pulmonary stenosis, including prenatal
      detection of ventriculocoronary connections, to evaluate heart size during the
      prenatal period, and to evaluate the outcome. DESIGN AND PATIENTS: Medical
      records of 20 cases with prenatally diagnosed PAIVS and pulmonary stenosis were
      reviewed retrospectively. Prenatal and postnatal echocardiography were also
      reviewed and dimensions of the ventricles and vessels were measured
      retrespectively. RESULTS: Of 20 prenatal diagnoses (15 PAIVS and five pulmonary
      stenosis), 16 were confirmed as correct. One critical pulmonary stenosis case had
      been diagnosed as PAIVS prenatally; three had no confirmation. Eight pregnancies
      were terminated, three had no active treatment, and nine were treated; all
      survived. Of 13 assessed with ventriculocoronary connections prenatally, seven
      were diagnosed correctly (four with, three without ventriculocoronary
      connections), but one was falsely positive; five had no confirmation. The more
      prominent hypoplasia of the main pulmonary artery and the tricuspid valve
      annulus, and the sigmoid shape of the ductus arteriosus, seemed to be associated
      with the presence of ventriculocoronary connections. CONCLUSIONS: Current
      prenatal echocardiography can accurately diagnose right ventricular outflow tract
      obstruction and ventriculocoronary connections. Prenatal detection of this
      constellation of abnormalities aids in family counselling and decisions on
      postnatal management.

PMID- 10336931
TI  - Eosinophilic myocarditis associated with dense deposits of eosinophil cationic
      protein (ECP) in endomyocardium with high serum ECP.
AB  - A case of eosinophilic myocarditis following high serum levels of eosinophil
      cationic protein (ECP) is described. A 27 year old woman was admitted with New
      York Heart Association (NYHA) class III congestive heart failure. A
      haematological study showed hypereosinophilia with degranulation and vacuoles;
      the total eosinophil count was 7980/ml and the ECP serum concentration was
      noticeably high at 150 ng/ml. Endomyocardial biopsy from the right ventricle
      showed infiltration of eosinophils and dense deposits of ECP in the endocardium
      as well as the myocardium. Steroid treatment returned the total eosinophil count
      and serum ECP to normal, with satisfactory improvement in clinical features.
      Eosinophilia may cause cardiac damage, and this report confirms that eosinophil
      degranulation is toxic. Thus, serum ECP seems to be a reliable indicator for
      diagnosis and for determining treatment parameters of eosinophilic myocarditis.

PMID- 10336932
TI  - Images in cardiology. Aortic coarctation diagnosed by magnetic resonance
      angiography.

PMID- 10336933
TI  - A novel use of an Amplatzer septal occluder.

PMID- 10336984
TI  - Rat liver contains age-regulated cytosolic 3-deoxy-D-glycero-D-galacto-non-2
      ulopyranosonic acid (Kdn).
AB  - Kdn (3-deoxy-D-glycero-D-galacto-non-2-ulopyranosonic acid), a unique deaminated
      member of the sialic acid family, has emerged as a new building block of
      glycoconjugates from a wide variety of organisms, ranging from bacteria to
      mammals. In particular, the presence of Kdn has been demonstrated in different
      rat organs and tissues, but not in liver. Here we report on the detection and
      quantitation of Kdn in rat liver and on its variations with postnatal development
      and aging. We have previously established the optimal conditions for
      derivatization of Kdn with 1,2-diamino-4, 5-methylene-dioxybenzene (DMB), and
      detection by reverse-phase HPLC. Analysis of whole liver homogenates and
      different subcellular fractions reveals that Kdn is fundamentally present in the
      cytosolic fraction as nucleotide precursor. The expression of Kdn, Neu5Gc, and
      Neu5Ac changes unevenly with age. While the content of Neu5Ac, the major species,
      and Neu5Gc decreases to a different extent from newborn to old animals, Kdn
      content decreases from newborn to trace amounts in adult rats and increases again
      with aging. Thus, expression of Kdn, Neu5Gc, and Neu5Ac appears to be
      independently regulated.

PMID- 10336985
TI  - Purification and biochemical characterization of two soluble alpha-mannosidases
      from Candida albicans.
AB  - Two soluble alpha-mannosidases, E-I and E-II, were purified from C. albicans
      yeast cells by a three-step procedure consisting of size exclusion and ion
      exchange chromatographies in Sepharose CL6B and Mono Q columns, respectively, and
      preparative nondenaturing electrophoresis. E-I and E-II migrated as monomeric
      polypeptides of 54.3 and 93.3 kDa in SDS-PAGE, respectively. Some biochemical
      properties of purified enzymes were investigated by using 4-methylumbelliferyl
      alpha-D-mannopyranoside and p-nitrophenyl-alpha-D-mannopyranoside as substrates.
      Hydrolysis of both substrates by either enzyme was optimum at pH 6.0 with 50 mM
      Mes-Tris buffer and at 42 degrees C. Apparent Kmvalues for hydrolysis of 4
      methylumbelliferyl-alpha-D-mannopyranoside and p-nitrophenyl-alpha-D
      mannopyranoside by E-I were 0.83 microM and 2. 4 mM, respectively. Corresponding
      values for E-II were 0.25 microM and 1.86 mM. Swansonine and deoxymannojirimicin
      strongly inhibited the hydrolysis of 4-methylumbelliferyl-alpha-D-mannopyranoside
      by both enzymes. On the contrary, hydrolysis of p-nitrophenyl-alpha-D
      mannopyranoside by E-I and E-II was slightly stimulated or not affected,
      respectively, by both inhibitors. E-I and E-II did not depend on metal ions
      although activity of the latter was slightly stimulated by Mn2+and Ca2+in the
      range of 0.5-2 mM. At the same concentrations, Mg2+was slightly inhibitory of
      both enzymes. Substrate specificity experiments revealed that both E-I and E-II
      preferentially cleaved alpha-1,6 and alpha-1,3 linkages, respectively.

PMID- 10336986
TI  - Man alpha1-2 Man alpha-OMe-concanavalin A complex reveals a balance of forces
      involved in carbohydrate recognition.
AB  - We have determined the crystal structure of the methyl glycoside of Man alpha1-2
      Man in complex with the carbohydrate binding legume lectin concanavalin A (Con
      A). Man alpha1-2 Man alpha-OMe binds more tightly to concanavalin A than do its
      alpha1-3 and alpha1-6 linked counterparts. There has been much speculation as to
      why this is so, including a suggestion of the presence of multiple binding sites
      for the alpha1-2 linked disaccharide. Crystals of the Man alpha1-2 Man alpha-OMe
      Con A complex form in the space group P2(1)2(1)2(1) with cell dimensions a =
      119.7 A, b = 119.7 A, c = 68.9 A and diffract to 2. 75A. The final model has good
      geometry and an R factor of 19.6% (Rfree= 22.8%). One tetramer is present in the
      asymmetric unit. In three of the four subunits, electron density for the
      disaccharide is visible. In the fourth only a monosaccharide is seen. In one
      subunit the reducing terminal sugar is recognized by the monosaccharide site; the
      nonreducing terminal sugar occupies a new site and the major solution
      conformation of the inter-sugar glycosidic linkage conformation is adopted. In
      contrast, in another subunit the non reducing terminal sugar sits in the so
      called monosaccharide binding site; the reducing terminal sugar adopts a
      different conformation about its inter-sugar glycosidic linkage in order for the
      methyl group to access a hydrophobic pocket. In the third subunit, electron
      density for both binding modes is observed. We demonstrate that an extended
      carbohydrate binding site is capable of binding the disaccharide in two distinct
      ways. These results provide an insight in to the balance of forces controlling
      protein carbohydrate interactions.

PMID- 10336987
TI  - Glycosylation of the overlapping sequons in yeast external invertase: effect of
      amino acid variation on site selectivity in vivo and in vitro.
AB  - Yeast invertase contains 14 sequons, all of which are glycosylated to varying
      degrees except for sequon 5 which is marginally glycosylated, if at all. This
      sequon overlaps with sequon 4 in a sequence consisting of Asn92-Asn93-Thr94
      Ser95(Reddy et al., 1988, J. Biol. Chem., 263, 6978-6985). To determine whether
      glycosylation at Asn93is sterically hindered by the oligosaccharide on Asn92, the
      latter amino acid was converted to a glutamine residue by site-directed
      mutagenesis of the SUC2 gene in a plasmid vector which was expressed in
      Saccharomyces cerevisiae. A glycopeptide encompassing sequons 3 through 6 was
      purified from a tryptic digest of the mutagenized invertase and sequenced by
      Edman degradation, which revealed that Asn93 of sequon 5 contained very little,
      if any, carbohydrate, despite the elimination of sequon 4. When Ser and Thr were
      inverted to yield Asn-Asn-Ser-Thr carbohydrate was associated primarily with the
      second sequon, in agreement with numerous studies indicating that Asn-X-Thr is
      preferred to Asn-X-Ser as an oligosaccharide acceptor. However, when the
      invertase overlapping sequons were converted to Asn-Asn-Ser-Ser, both sequons
      were clearly glycosylated, with the latter sequon predominating. These findings
      rule out steric hindrance as a factor involved in preventing the glycosylation of
      sequon 5 in invertase. Comparable results were obtained using an in vitro system
      with sequon-containing tri- and tetrapeptides acceptors, in addition to larger
      oligosaccharide acceptors.

PMID- 10336988
TI  - Differential sialylation of cell surface glycoconjugates in a human B lymphoma
      cell line regulates susceptibility for CD95 (APO-1/Fas)-mediated apoptosis and
      for infection by a lymphotropic virus.
AB  - Sialic acid, as a terminal saccharide residue on cell surface glycoconjugates,
      plays an important role in a variety of biological processes. In this study, we
      investigated subclones of the human B lymphoma cell line BJA-B for differences in
      the glycosylation of cell surface glycoconjugates, and studied the functional
      implications of such differences. With respect to the expression level of most of
      the tested B cell-associated antigens, as well as the presence of penultimate
      saccharide moieties on oligosaccharide chains, subclones were phenotypically
      indistinguishable. Marked differences among subclones, however, were found in the
      overall level of glycoconjugate sialylation, involving both alpha-2,6 and alpha
      2,3-linked sialic acid residues. Accordingly, subclones were classified as highly
      (group I) or hyposialylated (group II). The function of two sialic acid
      dependent receptor-mediated processes is correlated with the sialylation status
      of BJA-B subclones. Susceptibility to and binding of the B lymphotropic
      papovavirus (LPV) was dependent on a high sialylation status of host cells,
      suggesting that differential sialylation in BJA-B cells can modulate LPV
      infection via its alpha-2,6-sialylated glycoprotein receptor. CD95-mediated
      apoptosis, induced by either the human CD95 ligand or a cytotoxic anti-CD95
      monoclonal antibody, was drastically enhanced in hyposialylated group II cells.
      An increase in endogenous sialylation may be one antiapoptotic mechanism that
      converts tumor cells to a more malignant phenotype. To our knowledge, this is the
      first report demonstrating that differential sialylation in a clonal cell line
      may regulate the function of virus and signal-transducing receptors.

PMID- 10336989
TI  - Expression of the insulin-like growth factor 1 receptor (IGF-1R) in breast cancer
      cells: evidence for a regulatory role of dolichyl phosphate in the transition
      from an intracellular to an extracellular IGF-1 pathway.
AB  - In this study we provide evidence that the low expression of IGF-1R at the cell
      surface of estrogen-independent breast cancer cells is due to a low rate of de
      novo synthesis of dolichyl phosphate. The analyses were performed on the estrogen
      receptor-negative breast cancer cell line MDA231 and, in comparison, the melanoma
      cell line SK-MEL-2, which expresses a high number of plasma membrane-bound IGF
      1R. Whereas the MDA231 cells had little or no surface expression of IGF-1R, they
      expressed functional (i.e., ligand-binding) intracellular receptors. By measuring
      the incorporation of [3H]mevalonate into dolichyl phosphate, we could demonstrate
      that the rate of dolichyl phosphate synthesis was considerably lower in MDA231
      cells than in SK-MEL-2 cells. Furthermore, N-linked glycosylation of the alpha
      subunit of IGF-1R was 8-fold higher in the melanoma cells. Following addition of
      dolichyl phosphate to MDA231 cells, N-linked glycosylation of IGF-1R was
      drastically increased, which in turn was correlated to a substantial
      translocation of IGF-1R to the plasma membrane, as assayed by IGF-1 binding
      analysis and by Western blotting of plasma membrane proteins. The dolichyl
      phosphate-stimulated receptors were proven to be biochemically active since they
      exhibited autophosphorylation. Under normal conditions MDA231 cells, expressing
      very few IGF-1R at the cell surface, were not growth-arrested by an antibody
      (alphaIR-3) blocking the binding of IGF-1 to IGF-1R. However, after treatment
      with dolichyl phosphate, leading to a high cell surface expression of IGF-1R,
      alphaIR-3 efficiently blocked MDA231 cell growth. Taken together with the fact
      that the breast cancer cells produce IGF-1 and exhibit intracellular binding, our
      data suggest that the level of de novo -synthesized dolichyl phosphate may be
      critical for whether the cells will use an intracellular or an extracellular
      autocrine IGF-1 pathway.

PMID- 10336990
TI  - Enzymically inactive members of the trans-sialidase family from Trypanosoma cruzi
      display beta-galactose binding activity.
AB  - trans-sialidase is a unique sialidase in that, instead of hydrolizing sialic
      acid, it preferentially transfers the monosaccharide to a terminal beta-galactose
      in glycoproteins and glycolipids. This enzyme, originally identified in
      Trypanosoma cruzi, belongs to a large family of proteins. Some members of the
      family lack the enzymatic activity. No function has been yet assigned to them. In
      this work, the gene copy number and the possible function of inactive members of
      the trans -sialidase family was studied. It is shown that genes encoding inactive
      members are not a few, but rather, are present in the same copy number (60-80 per
      haploid genome) as those encoding active trans -sialidases. Recombinant inactive
      proteins were purified and assayed for sialic acid and galactose binding activity
      in agglutination tests. The enzymatically inactive trans -sialidases were found
      to agglutinate de-sialylated erythrocytes but not untreated red blood cells.
      Assays made with mouse and rabbit red blood cells suggest that inactive trans 
      sialidases bind to beta, rather than alpha, terminal galactoses, the same
      specificity required by active trans -sialidases. A recombinant molecule that was
      made enzymatically inactive through a mutation in a single amino acid also
      retained the galactose binding activity. The binding was competed by lactose and
      was dependent on conservation of the protein native conformation. Therefore, at
      least some molecules in the trans -sialidase family that have lost their
      enzymatic function still retain their Gal-binding properties and might have a
      function as lectins in the parasite-host interaction.

PMID- 10336991
TI  - Structure of the human gene for lysosomal di-N-acetylchitobiase.
AB  - Chitobiase is a lysosomal glycosidase that acts during the ordered degradation of
      asparagine-linked glycoproteins to cleave the core chitobiose unit at its
      reducing end. Human chitobiase is expressed in significant amounts, while bovine
      chitobiase is produced at extremely low levels. To begin to understand this
      species-dependent expression, we determined the gene structure of human
      chitobiase. The human chitobiase gene ( CTB S) is approximately 20 kb comprising
      seven exons varying from 0.1 to 2.3 kb and six introns of 0.3 to 8 kb. The
      previously characterized partial bovine chitobiase gene structure is similarly
      organized including exon and intron sizes and locations, but the human and bovine
      5'-flanking regions differ significantly. 5'-RACE analysis of human chitobiase
      cDNA revealed only one transcriptional start site 45 bp upstream of the ATG
      translation initiation site. Computer analysis of the human chitobiase gene 5'
      flanking region shows characteristics of a typical housekeeping gene. The
      putative promoter region contains a distal TATA box, and there are several Sp-1
      and AP-2 cis elements. In contrast, bovine chitobiase gene 5'-flanking region
      shows totally different structures and may contain several silencers. A partial
      art-2 segment which is an artiodactyl Alu -like repetitive sequence, is also
      present. These evolutionary differences in the 5'-flanking region of the
      chitobiase genes from human and bovine could account for the widely varied
      expression levels of the hydrolase within these two species.

PMID- 10336992
TI  - cDNA cloning and expression of UDP-glucose dehydrogenase from bovine kidney.
AB  - We have isolated a cDNA encoding UDP-glucose dehydrogenase from a bovine kidney
      cDNA-library, the first mammalian cDNA clone published. [After submission of the
      manuscript, a study appeared describing the molecular cloning and
      characterization of the human and mouse UDP-glucose dehydrogenase genes (Spicer
      et al., 1998).] The enzyme catalyzes the conversion of UDP-glucose to UDP
      glucuronic acid, an essential precursor in glycosaminoglycan biosynthesis. The
      cDNA has an open reading frame of 1482 nucleotides coding for a 55 kDa protein.
      Expression of the enzyme in COS-7 cells showed a 3-fold increase in UDP-glucose
      dehydrogenase activity; also, the C-terminal 23 amino acids was shown not to be
      necessary for enzyme activity. Northern blots from human and mouse tissues reveal
      high expression in liver and low in skeletal muscle. Human tissues have a major
      transcript size of 3.2 kilobases and a minor of 2.6 whereas mouse tissues have a
      single 2.6 kilobase transcript. We have also developed a sensitive and direct
      assay using UDP-[14C]Glc as a substrate for detection of small amounts of UDPGDH
      activity.

PMID- 10336993
TI  - Species-specific distribution of alpha-galactosyl epitopes on the gastric H/K
      ATPase beta-subunit: relevance to the binding of human anti-parietal cell
      autoantibodies.
AB  - The gastric H/K ATPase beta-subunit, an abundant glycoprotein of the secretory
      membranes of gastric parietal cells, is the major autoantigen recognized by human
      parietal cell autoantibodies in gastric autoimmunity. Our previous studies
      demonstrated that the human autoantibodies recognize the H/K ATPase beta-subunit
      from a number of species and that glycosylation of the beta-subunit with complex
      N-glycans is required for autoantibody binding. The N-glycans of the beta-subunit
      contain polylactosamine chains. The lactosamine chains of the rabbit beta-subunit
      are terminated with alpha-linked galactosyl residues (alpha-galactosyl epitope)
      (Tyagarajan et al., Biochemistry, 1996, 35, 3238-3246). Here we have investigated
      the expression of alpha-galactosyl epitopes on the H/K ATPase beta-subunit from a
      number of species. Using the alpha-galactosyl binding lectin, BS1-IB4, and
      naturally occurring anti-alpha-galactosyl antibodies, we have demonstrated that
      the rat H/K ATPase beta-subunit also contains terminal alpha-galactosyl residues,
      but not the beta-subunit from pig, dog, and mouse, indicating species-specific
      differences in the terminal saccharide sequences of the beta-subunit. We also
      investigated the potential contribution of the alpha-galactosyl epitopes to the
      binding by human sera. The reactivity of human pernicious anemia serum with
      gastric parietal cells could not be inhibited with saccharide inhibitors and, in
      addition, no binding was observed with normal human sera. We conclude that the
      H/K ATPase beta-subunit oligosaccharides from rabbit and rat are terminated with
      alpha-galactosyl epitopes, and although the presence of this epitope does not
      contribute to binding by human parietal cell autoantibodies at the concentrations
      routinely used, it is recommended that neither rat or rabbit stomachs be used for
      screening human sera.

PMID- 10336994
TI  - Molecular mechanisms of expression of Lewis b antigen and other type I Lewis
      antigens in human colorectal cancer.
AB  - Lewis b (Leb) antigens are gradiently expressed from the proximal to the distal
      colon, i.e., they are abundantly expressed in the proximal colon, but only
      faintly in the distal colon. In the distal colon, they begin to increase at the
      adenoma stage of cancer development and then increase with cancer progression. We
      aimed to clarify the molecular basis of Leb antigen expression in correlation
      with the expression of other type I Lewis antigens, such as Lewis a (Lea) and
      sialylated Lewis a (sLea), in colon cancer cells. Considering the Se genotype and
      the relative activities of the H and Se enzymes, the amounts of Leb antigens were
      proved to be determined by both the H and Se enzymes in noncancerous and
      cancerous colon tissues. But the Se enzyme made a much greater contribution to
      determining the Lebamounts than the H enzyme. In noncancerous colons, the Se
      enzyme were gradiently expressed in good correlation with the Leb expression,
      while the H enzyme was constantly expressed throughout the whole colon. In distal
      colon cancers, the H and Se enzymes were both significantly upregulated in
      comparison with in adjacent noncancerous tissues. In proximal colon cancers,
      expression of the H enzyme alone was highly augmented. The augmented expression
      of Leb antigens in distal colon cancers is caused mainly by upregulation of the
      Se enzyme and partly by the H enzymes, while it is caused by upregulation of the
      H enzyme alone in proximal colon cancers. The Se gene dosage profoundly
      influences the amounts of the Leb, Lea, and sLea antigens in whole colon tissues,
      regardless of whether they are noncancerous or cancerous tissues. It suggests
      that the Se enzyme competes with alpha2,3 sialyltransferase(s) and the Le enzyme
      for the type I acceptor substrates.

PMID- 10336995
TI  - Ordered assembly of the asymmetrically branched lipid-linked oligosaccharide in
      the endoplasmic reticulum is ensured by the substrate specificity of the
      individual glycosyltransferases.
AB  - The assembly of the lipid-linked core oligosaccharide Glc3Man9GlcNAc2, the
      substrate for N-linked glycosylation of proteins in the endoplasmic reticulum
      (ER), is catalyzed by different glycosyltransferases located at the membrane of
      the ER. We report on the identification and characterization of the ALG12 locus
      encoding a novel mannosyltransferase responsible for the addition of the alpha
      1,6 mannose to dolichol-linked Man7GlcNAc2. The biosynthesis of the highly
      branched oligosaccharide follows an ordered pathway which ensures that only
      completely assembled oligosaccharide is transferred from the lipid anchor to
      proteins. Using the combination of mutant strains affected in the assembly
      pathway of lipid-linked oligosaccharides and overexpression of distinct
      glycosyltransferases, we were able to define the substrate specificities of the
      transferases that are critical for branching. Our results demonstrate that
      branched oligosaccharide structures can be specifically recognized by the ER
      glycosyltransferases. This substrate specificity of the different transferases
      explains the ordered assembly of the complex structure of lipid-linked
      Glc3Man9GlcNAc2 in the endoplasmic reticulum.

PMID- 10336996
TI  - Phosphoglycosylation of a secreted acid phosphatase from Leishmania donovani.
AB  - The secreted acid phosphatase (SAcP) of L.donovani is a heterogeneous
      glycoprotein that displays a wide array of N- and O-linked glycosylations. The O
      linked sugars are of particular interest due to their similarity to the
      phosphoglycan structures of the major lipophosphoglycan surface antigen and
      released phosphoglycan (Turco et al., 1987; Greis et al., 1992). This study
      describes a structural analysis of the SAcP O-linked glycosylations using mass
      spectroscopy, amino acid sequencing, and enzymatic carbohydrate sequencing.
      Analysis of glycan chain lengths and peptide glycosylation site distribution was
      performed, revealing that the average O-linked structure was approximately 32
      repeat units in length. Amino acid sequence analysis of glycosylated peptides
      showed that phosphoglycosylations did not occur randomly but were localized to
      specific serine residues within an array of degenerate serine/threonine-rich
      repeat sequences localized in the C-terminus. No evidence was obtained for
      modification of threonine residues. The observed pattern suggested that a
      consensus sequence may exist for localization of phosphoglycan structures.

PMID- 10336997
TI  - Dose-response relationship between amphibole fiber lung burden and mesothelioma.
AB  - In a mesothelioma case-control study, asbestos and other mineral fibers from lung
      burden were examined as causal factors. Diagnosis was confirmed by a panel of
      pathologists. For 66 cases and 66 controls from hospitals in five German towns,
      lung tissue fiber analysis by transmission electron microscopy was available.
      Control patients were treated by a surgical lung resection mostly because of lung
      cancer. For chrysotile and other mineral fibers a significantly increased odds
      ratio (OR) was not observed. A clear dose-response relationship was demonstrated
      for the concentration CA of amphibole fibers longer than 5 microm. Between 0.025
      and 2.5 fibers/microg dry weight (f/microg) the relationship can be approximated
      as OR = CA/(0. 025 f/microg). Similar but less distinct dose-response
      relationships were found in a Canadian and an Australian study. It is concluded
      that among German mesothelioma patients factors not associated with amphibole
      fiber concentration are not predominating.

PMID- 10336998
TI  - Association of p53, K-ras and proliferating cell nuclear antigen with rat lung
      lesions following exposure to simulated nuclear fuel particles.
AB  - Expression of p53, K-ras, and proliferating cell nuclear antigen (PCNA) and
      mutations of p53 and K-ras genes in lung lesions of Han/Wistar rats were
      investigated by immunohistochemistry and direct DNA sequencing following a long
      term exposure of animals to neutron-activated UO2 particles. The p53 protein was
      overexpressed in all five malignant tumors, in 62% of benign tumors, and in 42%
      of hyperplastic lesions examined. K-ras protein and PCNA levels were only
      slightly elevated in all types of lung lesions. In three malignant tumors a C-->T
      transition was detected in codon 288 (human 290) of the p53 gene, but this
      mutation was not present in seven other tumors analyzed. No mutations were
      detected in codons 12/13 and 61 of the K-ras gene in any of the five tumors
      analyzed. Our findings suggest that K-ras overexpression is a rare alteration,
      whereas p53 protein overexpression (sometimes associated with mutated p53 gene),
      as assessed with the CM5 antibody, is a relatively common phenomenon in hot
      particle-induced preneoplastic and neoplastic rat lung lesions.

PMID- 10336999
TI  - Microsatellite instability and K-ras mutations in gastric adenomas, with
      reference to associated gastric cancers.
AB  - Gastric adenomas are often detected in the stomach resected for gastric cancer.
      Previous investigation have revealed that the prevalence of their malignant
      transformation is generally low, but the frequent coexistence with carcinoma
      suggests that they may share some common processes with gastric cancer in
      tumorigenesis. In contrast to the cumulative information about genetic
      alterations in gastric cancer, inquiries into the genetic changes of adenoma and
      coexisting carcinoma in the same individual's stomach are still few. We
      investigated microsatellite instability (MSI) and K-ras point mutations in codons
      12 and 13 in 50 lesions of gastric adenomas in 43 cases, and 31 lesions of
      gastric cancers that coexisted with these adenomas. In gastric adenomas, we found
      seven lesions (14.0%) to have microsatellite instability (MSI) at one or more
      loci, and most of them (six cases) had MSI at only one locus and were not
      associated with alterations in presumable target molecules. MSI was detected more
      frequently (11/31, 35.5%) and more extensively (five lesions at multiple loci) in
      accompanying gastric carcinomas. The prevalence of MSI in adenomas was more
      frequently found in those with synchronous gastric cancer (6/37, 16.2%, vs. 1/13,
      7.6%) than without, and gastric adenoma accompanied by gastric cancer with
      multiple MSI tended to have MSI more frequently than that accompanied by cancer
      without MSI (4/5, 80%, vs. 1/24, 4.2%; p = 0. 01). In at least some individuals,
      MSI appears to represent one step in the pathway of gastric tumorigenesis, shared
      by adenoma and carcinoma. We found K-ras gene alteration in 8 lesions (16.0%) out
      of 50 gastric flat adenomas and no difference in its prevalence between adenoma
      with or without cancer. Only one gastric cancer, which had adenoma without K-ras
      mutation, had K-ras codon 12 mutation. Adenomas with a higher grade of atypia (p
      < 0.05) more frequently carried K-ras point mutation, which is consistent with
      the situation in colorectal adenoma. We conclude that MSI, not K-ras mutation, is
      a shared genetic alteration in adenoma and carcinoma of the individual stomach.

PMID- 10337000
TI  - The role of cytokines and chemokines on tumor progression: A review.

PMID- 10337001
TI  - Altered release of tumor necrosis factor and its soluble receptor in non
      Hodgkin's lymphoma patients.
AB  - Increased expression and elevated serum levels of tumor necrosis factor-alpha
      (TNF-alpha) have been shown to be associated with the presence of constitutional
      B symptoms and poor prognosis in non-Hodgkin's lymphoma (NHL) patients. Soluble
      TNF receptors (sTNF-R) are suggested to act as biological buffers in inflammatory
      conditions by binding and inactivating increased circulating TNF. Whereas studies
      have shown elevated TNF to be correlated with B symptoms, similar studies showing
      the status of soluble receptor release in these patients have not been conducted.
      Here, we show that there is increased soluble p75 TNF receptor release from
      peripheral blood mononuclear cells (PBMNC) in NHL patients in the early stages of
      the disease but it is severely depressed in patients with advanced disease.
      Decreased release is associated with presence of B symptoms in these patients.
      All NHL patients also show increased TNF secretion and a decreased rate of
      receptor release with time compared with healthy controls. These findings imply
      that decreased sTNF-R receptor release, in addition to increased TNF secretion,
      is also important in predisposing the patients to B symptoms. This opens up the
      possibility of the use of sTNF-Rs as a therapeutic tool to counter increased TNF
      and alleviate systemic symptoms in these patients and also as a marker for the
      progression of the disease.

PMID- 10337002
TI  - Role of estradiol metabolism and CYP1A1 polymorphisms in breast cancer risk.
AB  - The endogenous metabolism of estrogens is primarily oxidative and involves
      hydroxylation of the steroid at either C2 (2-OHE1) or C16 (16-OHE1). While the 2
      OHE1 metabolites are essentially devoid of peripheral biological activity, 16
      OHE1 is an estrogen agonist. There is evidence of an association between the 2
      OHE1/16-OHE1 metabolites ratio and breast cancer risk. The CYP1A1 gene may play a
      role in the 2-hydroxylation (2-OH) of estradiol. African-American women with the
      wild-type CYP1A1 gene showed a significant increase in the 2-OHE1/16-OHE1 ratio,
      from 1.35 +/- 0.56 at baseline to 2.39 +/- 0.98 (p = 0.006) after 5 days of
      treatment with indole-3-carbinol (400 mg/day), a 2-OHE1 inducer. Women with the
      Msp1 polymorphism showed no significant increase, (0.37% +/- 0.17%). In a case
      control study involving 57 women with breast cancer and 312 female controls, the
      frequency of the homozygous Msp1 polymorphism was 4.2% in African-American
      controls and 16% in African-American breast cancer cases. The odds ratio of
      breast cancer with the Msp1 homozygous variant was 8.4 (95% confidence interval:
      1.7-41.7). This association was not observed in Caucasian women. The other CYP1A1
      polymorphisms were not associated with breast cancer. The CYP1A1 Msp1
      polymorphism may be a marker of altered estradiol metabolism and of increased
      susceptibility to estrogen-related breast cancer in African-Americans.

PMID- 10337003
TI  - Estrogen and progesterone receptor concentrations and prevalence of tumor
      hormonal phenotypes in older breast cancer patients.
AB  - We examined the concentrations of estrogen (ER) and progesterone receptors (PR)
      and the distribution of tumor phenotypes as a function of age in breast cancer
      patients. ER and PR concentrations were determined in tissue biopsies from 1739
      patients with primary breast cancer, using ligand binding assays. Tumors were
      classified as estrogen receptor positive (ER+) or negative (ER-) and progesterone
      receptor positive (PR+) or negative (PR-) based on the presence or absence of
      receptor binding activity. Tumors were stratified into four phenotypes: ER+PR+;
      ER+PR-; ER-PR+; and ER-PR-. Significant positive associations were found between
      ER concentration and age (p = 0.0001) and between PR concentration and age (p =
      0.0002). The median ER concentrations were statistically different by age groups,
      with the greatest levels in older versus younger patients. The prevalence of
      ER+PR+ tumor phenotype increased with age. In contrast, the prevalence of ER-PR-
      and ER-PR+ tumor phenotypes decreased with age. The median PR-to-ER ratio
      decreased with age (p = 0.0001), and this trend was attributed to increased ER
      concentration with age. The prevalence of ER-PR- and ER-PR+ tumor phenotypes is
      greater in younger patients suggesting that hormonal regulation of ER gene
      expression may be responsible for the observed age disparity of tumor phenotypes
      in breast cancer.

PMID- 10337004
TI  - Classification of breast tumors by grade and steroid receptor status using
      pattern recognition analysis of infrared spectra.
AB  - Infrared (IR) spectroscopy applied to tissue sections yields complex spectra that
      provide a molecular fingerprint of the tissue. We have studied a cohort of 77
      breast tumors by IR spectroscopy to develop an objective method for the
      assignment of grade of breast tumors. Although the major variations between
      spectra from different tumors were in absorptions arising from triglycerides
      (adipose tissue) and collagen, subtle changes in spectra could be detected that
      were independent of cellularity and tissue composition. Using a specific
      multivariate pattern recognition strategy to associate these changes in spectra
      with different tumor grades, we then were able to accurately reclassify tumors by
      grade (87% accuracy; kappa = 0.835). A similar approach allowed classification of
      steroid receptor status (93% accuracy; kappa = 0.852). We conclude that IR
      spectroscopy may have clinical utility in the objective assignment of breast
      tumor grade.

PMID- 10337005
TI  - A motivational message, external barriers, and mammography utilization.
AB  - Based on a theory of behavior, the interaction of a motivational message and
      external barriers on mammography utilization was tested. Participants (N = 101)
      had not had mammograms annually, and were identified from an urban clinic serving
      a disproportionally high percentage of indigent clients. Fifty-five percent were
      Caucasian; 45% were African-American. In an experimental design, half of the
      sample received a telephone discussion about rationale, feelings, and beliefs
      regarding mammograms, and half did not receive this contact. Four months later,
      nurses assessed women's recent mammography utilization and external barriers
      (e.g., affordability and accessibility). A logistic regression revealed an
      interaction between the intervention and barriers on postintervention mammography
      utilization (odds ratio: 2.12; p < 0.05). As proposed, the intervention was
      associated with a 64% rate of mammography utilization among women without
      barriers, but only a 26% rate among women with barriers. Not only should
      clinicians offer motivational messages about mammography, but also administrators
      should address external barriers to maximize mammography among socioeconomically
      disadvantaged groups.

PMID- 10337006
TI  - Breast cancer screening and family history among rural women in Wisconsin.
AB  - This study examines the relationship between family history of breast cancer and
      current compliance with mammography screening guidelines. A random telephone
      survey of women age 40 or older living in rural Wisconsin (N = 2398) was
      conducted to determine mammography screening knowledge, family history of breast
      cancer, attitudes, intentions, physician recommendation, and compliance with
      screening guidelines. Compared with women without a family history of breast
      cancer, women with a family history were significantly more likely to demonstrate
      correct knowledge (p = 0. 01); express intentions in compliance with recommended
      screening guidelines (p < 0.001); report having been advised by a physician to
      obtain a mammogram (p < 0.001); and be in current compliance with mammography
      screening guidelines (p < 0.001). Results of simultaneous and individual logistic
      regression suggest that the effects of family history on compliance with
      screening guidelines are directly mediated through the combination of women's
      knowledge, women's intentions, and physician recommendation. Thus, programs to
      increase compliance with mammography screening guidelines should address both
      women and providers.

PMID- 10337007
TI  - Passive immunity against human pathogens using bovine antibodies.

PMID- 10337009
TI  - Induction in transgenic mice of HLA-A2.1-restricted cytotoxic T cells specific
      for a peptide sequence from a mutated p21ras protein.
AB  - Cytotoxic T cells (CTL) recognize short peptides that are derived from the
      proteolysis of endogenous cellular proteins and presented on the cell surface as
      a complex with MHC class I molecules. CTL can recognize single amino acid
      substitutions in proteins, including those involved in malignant transformation.
      The mutated sequence of an oncogene may be presented on the cell surface as a
      peptide, and thus represents a potential target antigen for tumour therapy. The
      p21ras gene is mutated in a wide variety of tumours and since the transforming
      mutations result in amino acid substitutions at positions 12, 13 and 61 of the
      protein, a limited number of ras peptides could potentially be used in the
      treatment of a wide variety of malignancies. A common substitution is Val for Gly
      at position 12 of p21ras. In this study, we show that the peptide sequence from
      position 5 to position 14 with Val at position 12-ras p5-14 (Val-12)-has a motif
      which allows it to bind to HLA-A2.1. HLA-A2.1-restricted ras p5-14 (Val-12)
      specific CTL were induced in mice transgenic for both HLA-A2.1 and human beta2
      microglobulin after in vivo priming with the peptide. The murine CTL could
      recognize the ras p5-14 (Val-12) peptide when they were presented on both murine
      and human target cells bearing HLA-A2.1. No cross-reactivity was observed with
      the native peptide ras p5-14 (Gly-12), and this peptide was not immunogenic in
      HLA-A2.1 transgenic mice. This represents an interesting model for the study of
      an HLA-restricted CD8 cytotoxic T cell response to a defined tumour antigen in
      vivo.

PMID- 10337008
TI  - Are anti-neutrophil cytoplasmic antibodies (ANCA) clinically useful in
      inflammatory bowel disease (IBD)?
AB  - Since the first detection of ANCA in IBD, numerous studies have dealt with their
      prevalence, antigenic specificities, clinical significance, pathophysiological
      role, and their induction. This review summarizes the information obtained from
      those studies and shows that ANCA are not directly useful as diagnostic and
      prognostic factors in IBD. ANCA were detected in 50-85% of patients with
      ulcerative colitis (UC) and 10-20% of patients with Crohn's disease (CD).
      Multiple target antigens are recognized by these autoantibodies, including both
      cytoplasmic and nuclear proteins. A pathophysiological role for ANCA in IBD is
      far from clear. On the one hand, it is suggested that ANCA are genetic markers of
      susceptibility for IBD, and on the other hand, the induction of ANCA in those
      diseases may just be an epiphenomenon of chronic inflammation. We discuss recent
      evidence that ANCA may be induced by a break-through of tolerance towards
      bacterial antigens.

PMID- 10337010
TI  - Consumption of C4b-binding protein (C4BP) during in vivo activation of the
      classical complement pathway.
AB  - C4BP has a central role in regulating the classical complement (C') pathway, but
      it is still uncertain whether or not it is consumed during in vivo complement
      activation. Attempts to demonstrate changes in C4BP plasma levels in systemic
      lupus erythematosus and essential mixed cryoglobulinaemia have failed, probably
      due to up-regulation of this protein during the inflammatory reaction. We have
      studied one patient with severe post-transfusion complement-mediated anaphylaxis
      (CMA), and 67 patients with hereditary C1 inhibitor deficiency (hereditary
      angioedema (HAE)). The first of these two conditions is characterized by the
      absence of systemic inflammatory reaction and the second by acute and chronic
      activation of the C' classical pathway. C4BP, C4BP-C4b complex, and soluble
      terminal C' complex (sC5b-9) were measured in the patients' plasmas by ELISA
      techniques and C3a and C4a by radioimmunoassays. In CMA, 15 min after the
      transfusion, there was a massive C' activation, with increases in C4a, C3a, sC5b
      9, C4BP-C4b complexes and decreases in C4, C3 and C4BP. All parameters reverted
      to preinfusion values within 24 h. Depletion of C4 was correlated with that of
      C4BP. In patients with HAE, the median value of C4BP (83% range 54-165) was
      significantly lower (P < 0.0001) than in normal controls (99% range 70-159), with
      no difference between patients in remission or during acute attacks. C4BP-C4b
      complexes could not be detected in HAE patients. The results of this study
      indicate that C4BP is consumed in vivo during acute, and possibly during chronic
      activation of the C' classical pathway, and that this protein, after interaction
      with C4b, not longer circulates in plasma.

PMID- 10337011
TI  - Absence of significant Th2 response in diabetes-prone non-obese diabetic (NOD)
      mice.
AB  - Accumulating evidence suggests that Th1 T cells play a pivotal role in the
      development of autoimmune diabetes. Conversely, promoting a Th2 response inhibits
      disease progression. However, it has not been determined whether Th2 cells are
      regulatory T cells that fail at the time of diabetes development in naive non
      diabetic NOD mice. Therefore, in order to evaluate cytokine secretion by spleen
      and islet infiltrating T cells in NOD mice at different stages of the autoimmune
      process, we developed an ELISPOT assay that detects IL-2, IL-4, and interferon
      gamma (IFN-gamma) secretion in vitro at the single-cell level. We showed that,
      whatever the age considered, IFN-gamma is predominantly secreted, and that no IL
      4-secreting cells are detected in the islets of male and female NOD mice. Spleen
      cells from 8-week-old female NOD mice, which include regulatory suppressor T
      cells, do not secrete IL-4, either upon presentation of islet cell antigens in
      vitro, or after transfer in vivo, but do secrete IFN-gamma. IFN-gamma secretion
      by T cells from diabetic mice results from CD4 but not CD8 T cells in transfer
      experiments into NOD/severe combined immunodeficient (SCID) recipients. These
      results suggest that (i) detection of regulatory CD4 T cells in NOD mice is not
      paralleled by a Th2 response; (ii) beta cell destruction does not depend on a
      switch from a Th2 to a Th1-type response; and (iii) CD8 T cells do not
      participate in induction of diabetes by secreting IFN-gamma.

PMID- 10337012
TI  - Requirement for splenic CD4+ T cells in the immune privilege of the anterior
      chamber of the eye.
AB  - Injection of antigen into the anterior chamber of the eye induces suppression of
      antigen-specific DTH, called anterior chamber-associated immune deviation
      (ACAID). It has been shown that the spleen is required for the induction of ACAID
      and detecting the ACAID-inducing signal from the eye. To examine the in vivo role
      of spleen cells, fractions of spleen cells were adoptively transferred into
      splenectomized mice. The present study showed that DTH was not suppressed in
      splenectomized mice, but was inhibited in splenectomized mice transferred with a
      primed CD4+ T cell-containing fraction of spleen cells. This indicates that the
      splenic CD4+ T cells comprise the regulatory T cells for the DTH response. When
      we examined the cytokine profile of the infiltrating T cells in the eye of primed
      mice by reverse transcriptase-polymerase chain reaction (RT-PCR), we found that
      they expressed IL-4, IL-10 mRNA (Th2 type), but not IL-2 and interferon-gamma
      (IFN-gamma) mRNA (Th1 type). By contrast, T cells which can elicit normal DTH
      response expressed IL-2 and IFN-gamma mRNA. These results suggest that splenic
      CD4+ T cells comprising the regulatory phenotype are required for the induction
      of ACAID, and that a DTH response to the antigen may be prevented by Th2-dominant
      CD4+ T cells.

PMID- 10337013
TI  - Interferon-gamma (IFN-gamma)- and tumour necrosis factor (TNF)-induced nitric
      oxide as toxic effector molecule in chronic dextran sulphate sodium (DSS)-induced
      colitis in mice.
AB  - Excess nitric oxide formation caused by the activity of the inducible nitric
      oxide synthase has been implicated as a toxic effector molecule in the
      pathogenesis of experimental colitis and inflammatory bowel disease. It was
      therefore investigated whether inhibition of this synthase or the cytokines TNF
      and IFN-gamma, inducers of nitric oxide synthase, had effects on chronic colitis
      in mice. Chronic colitis was induced in mice by repeated feeding of DSS.
      Cytokines were neutralized by treatment with MoAbs and nitric oxide synthase was
      inhibited by aminoguanidine. The degree of colonic inflammation was assessed by a
      histological score and colon length. Aminoguanidine treatment reduced nitric
      oxide activity by 60% (P = 0. 0004), the histological score by 31% (P = 0.005)
      and increased colon length by 1.4 cm (P = 0.002). Neutralization of TNF and IFN
      gamma resulted in increased colon length (0.7 cm, P = 0.07 and 0.8 cm, P = 0.03),
      improved histological score (19%, P = 0.045 and 25%, P = 0. 013), and reduced
      nitric oxide activity (31%, P = 0.07 and 54%, P = 0.004) compared with controls.
      The combination of anti-cytokine treatments had additive effects. TNF and IFN
      gamma are involved in perpetuation of chronic DSS-induced colitis, and induction
      of excessive nitric oxide activity could be their common effector mechanism.

PMID- 10337014
TI  - Cytokine-producing cells in peripheral blood of children with coeliac disease
      secrete cytokines with a type 1 profile.
AB  - Coeliac disease (CoD) is a small intestinal disorder characterized by crypt cell
      hyperplasia and villous atrophy, and the production of cytokines from T cells and
      macrophages are of importance for the histological changes seen in CoD. A peroral
      immunization with an antigen, which gives rise to a mucosal immune response, may
      increase the levels of circulating cytokine-producing cells, and we wanted to
      obtain a better picture of an eventual emergence of activated circulating T cells
      in the peripheral blood in children with CoD. The cytokine expression of
      interferon-gamma (IFN-gamma), IL-4, IL-6 and IL-10 was measured at the single
      cell level by an ELISPOT method in 38 children with CoD. The numbers of IFN-gamma
      producing cells in the peripheral blood was increased in children with untreated
      CoD (P < 0.01) and after gluten challenge (P < 0.05) compared with healthy
      controls. Also, the numbers of IL-6-producing cells were increased (P < 0.05)
      after gluten challenge compared with the healthy controls. A paired comparison
      showed that the numbers of IFN-gamma-producing cells increased after gluten
      challenge (P < 0.05), whereas no such change was seen for IL-4- or IL-10
      producing cells. There were no differences in the numbers of IFN-gamma-producing
      cells between the group of children with treated CoD and the groups of untreated
      or challenged CoD children. IL-4 production correlated with serum levels of total
      IgE. These results show that circulating mononuclear cells in children with
      active CoD secrete cytokines compatible with a type 1 response.

PMID- 10337015
TI  - Investigation of the expression of IL-1beta converting enzyme and apoptosis in
      normal and inflammatory bowel disease (IBD) mucosal macrophages.
AB  - Activated mucosal macrophages are derived from circulating monocytes and appear
      to play a major role in the pathogenesis of IBD. We have recently shown that IBD,
      but not normal, mucosal macrophages express the active form of IL-1beta
      converting enzyme (ICE) and are therefore capable of releasing mature IL-1beta.
      ICE expression by other mucosal cell types is unknown. Active ICE expression has
      also been implicated in apoptosis. The aim of this study was to investigate ICE
      expression (using an antibody that recognizes both active and precursor forms) in
      normal and IBD mucosa and to determine whether ICE-expressing macrophages are
      undergoing apoptosis. Normal and active IBD mucosal cells, in tissue sections and
      after isolation, were studied by immunohistochemistry and flow cytometry. In the
      mucosa, macrophages were the predominant ICE-expressing cell type. In contrast to
      normal, most IBD mucosal macrophages expressed ICE. Of IBD colonic macrophages
      11.8 +/- 3.2%, and of normal colonic macrophages 6.6 +/- 0.6% expressed Apo2.7, a
      marker for apoptotic cells. Similar data were obtained when annexin V was used to
      identify cells undergoing apoptosis. DNA fluorescence flow cytometric analysis of
      normal and IBD lamina propria cells showed the presence of only small hypodiploid
      DNA peaks. We conclude that in the human intestinal mucosa, macrophages are the
      predominant ICE-expressing cell type. Expression of the active form of ICE and
      macrophage apoptosis are not interdependent. One mechanism of loss of resident
      macrophages from normal mucosa and of recruited macrophages from IBD mucosa is by
      apoptosis.

PMID- 10337016
TI  - Anti-tissue transglutaminase, anti-endomysium and anti-R1-reticulin
      autoantibodies-the antibody trinity of coeliac disease.
AB  - Anti-tissue transglutaminase has been recently described as the predominant
      autoantigen in coeliac disease. We purified serum anti-tissue transglutaminase
      antibodies from three patients with coeliac disease by column chromatography and
      eluted tissue section-bound R1-anti-reticulin antibodies from sections of rat
      tissue for two of these. Lastly, we generated seven mouse MoAbs to guinea pig
      tissue transglutaminase. Each preparation was examined for anti-tissue
      transglutaminase, anti-endomysium, anti-R1 reticulin and anti-gliadin antibodies.
      Column-purified patient antibodies and 2/7 mouse MoAbs gave characteristic anti
      endomysium/anti-R1 reticulin reactivity on rat, monkey and human tissue. All
      positive sera gave indistinguishable patterns of immunofluorescence on rat liver,
      kidney and stomach, monkey oesophagus, and human umbilical cord. Anti-R1
      reticulin eluted from sections showed anti-tissue transglutaminase reactivity in
      2/2 cases, but 0/2 showed anti-gliadin reactivity. In both, tissue section-eluted
      anti-R1 reticulin gave endomysial staining on monkey oesophagus. None of the
      mouse monoclonals, or any of the purified patient's anti-tissue transglutaminase
      or anti-R1-reticulin antibody showed any reactivity with gliadin. These data
      confirm tissue transglutaminase as the predominant autoantigen in coeliac disease
      and suggest that both anti-endomysium and anti-R1 reticulin reactivities seen in
      coeliac disease arise due to an immune response to tissue transglutaminase.
      Rigorous immunoabsorption was sufficient to abrogate reactivity in the tissue
      transglutaminase ELISA, but failed to completely absorb anti-endomysium and anti
      reticulin activity. The possibility remains that some of the anti-endomysium and
      anti-reticulin activity was directed against antigens other than tissue
      transglutaminase.

PMID- 10337017
TI  - Use of a whole blood assay to evaluate in vitro T cell responses to new leprosy
      skin test antigens in leprosy patients and healthy subjects.
AB  - Development of an immunological tool to detect infection with Mycobacterium
      leprae would greatly benefit leprosy control programmes, as demonstrated by the
      contribution of the tuberculin test to tuberculosis control. In a new approach to
      develop a 'tuberculin-like' reagent for use in leprosy, two new fractions of M.
      leprae depleted of cross-reactive and immunomodulatory lipids- MLSA-LAM (cytosol
      derived) and MLCwA (cell wall-derived)-have been produced in a form suitable for
      use as skin test reagents. T cell responses (interferon-gamma (IFN-gamma) and
      lymphoproliferation) to these two new fractions were evaluated in a leprosy
      endemic area of Nepal using a simple in vitro whole blood test. The two fractions
      were shown to be highly potent T cell antigens in subjects exposed to M. leprae
      paucibacillary leprosy patients and household contacts. Responses to the
      fractions decreased towards the lepromatous pole of leprosy. Endemic control
      subjects also showed high responses to the fractions, indicating high exposure to
      M. leprae, or cross-reactive mycobacterial antigens, in this Nepali population.
      The new fractions, depleted of lipids and lipoarabinomannan (LAM) gave enhanced
      responses compared with a standard M. leprae sonicate. The cell wall fraction
      appeared a more potent antigen than the cytosol fraction, which may be due to the
      predominance of the 65-kD GroEL antigen in the cell wall. The whole blood assay
      proved a robust field tool and a useful way of evaluating such reagents prior to
      clinical trials.

PMID- 10337018
TI  - Nitrotyrosine formation after activation of murine macrophages with mycobacteria
      and mycobacterial lipoarabinomannan.
AB  - Murine peritoneal macrophages, elicited with thioglycollate, were stimulated in
      vitro with lipopolysaccharide (LPS). The production of nitrite, superoxide anion
      (SOA), and the accumulation of nitrotyrosine in the cells increased after
      treatment, and all were inhibitable by the NO synthase inhibitor NG-monomethyl-L
      arginine monoacetate (L-NMMA). This effect suggests a direct correlation between
      the accumulation of those metabolites and NO synthase activity. Lipoarabinomannan
      (LAM) purified from Mycobacterium tuberculosis was added to peritoneal
      macrophages in the presence of interferon-gamma (IFN-gamma); the cells produced
      nitrite and SOA, both inhibitable by L-NMMA. There was, as well, accumulation of
      nitrotyrosine in the macrophage proteins. Strikingly, the amount of nitrotyrosine
      measured after LAM plus IFN-gamma, or LAM plus the low molecular weight adjuvant
      glutamylmuramyl dipeptide (GMDP), increased significantly in the presence of L
      NMMA. These results suggest that murine macrophages, upon LAM stimulation, might
      generate reactive nitrogen metabolites by a route other than NO synthase.
      Nitrotyrosine accumulation after infection of macrophages in vitro, with either
      live bacille Calmette-Guerin (BCG) or live M. tuberculosis, in the presence or
      absence of IFN-gamma, showed no correlation with nitrite production, suggesting a
      low superoxide production.

PMID- 10337019
TI  - Lactobacilli from human gastrointestinal mucosa are strong stimulators of IL-12
      production.
AB  - Interaction of macrophages with bacteria is a stimulus for production of
      cytokines such as IL-10 and IL-12. IL-12 stimulates T cell and natural killer
      (NK) cell cytotoxicity and interferon-gamma (IFN-gamma) production. IL-10 opposes
      the T cell-stimulating action of IL-12, decreases the release of proinflammatory
      cytokines from macrophages, and stimulates B cells. We have studied the capacity
      of human intestinal isolates from the three Lactobacillus species dominating on
      the human gastrointestinal mucosa, L. plantarum, L. rhamnosus and L. paracasei
      ssp. paracasei, to induce production of IL-10 and IL-12 from human blood
      mononuclear cells, or monocytes. Whole killed lactobacilli were potent
      stimulators of IL-12 over a wide range of bacterial concentrations. Lactobacillus
      paracasei gave the highest levels of IL-12 (1.5 ng/ml in response to 5 x 106
      bacteria/ml), roughly 10 times more than obtained by stimulation with L.
      rhamnosus or L. plantarum. Escherichia coli induced on average < 50 pg/ml of IL
      12 regardless of the bacterial concentration used. The secretion of free p40
      subunit IL-12 followed the same pattern as the secretion of p70 (bioactive IL-12)
      with regard to the efficiency of different bacteria as stimulators. Escherichia
      coli was the most efficient trigger of IL-10 production, inducing 0.5 ng/ml IL-10
      after stimulation with 5 x 106 bacteria/ml. Lactobacillus rhamnosus induced the
      highest levels of IL-10 among the lactobacilli (0.5 ng/ml) compared with 0.1
      ng/ml evoked by L. plantarum or L. paracasei, but 10 times more bacteria were
      required for optimal stimulation than with E. coli. When neutralizing anti-IL-10
      antibodies were added to the cultures, the IL-12-inducing capacity of L.
      rhamnosus was increased markedly, while that of E. coli remained low. The results
      show that mucosa-associated lactobacilli can be potent stimulators of IL-12, and
      thus potentially of cell-mediated immunity, if they pass over the gut epithelial
      barrier and interact with cells of the gut immune system.

PMID- 10337020
TI  - Immunomodulatory effects of Lactobacillus plantarum colonizing the intestine of
      gnotobiotic rats.
AB  - We have studied the effect of the probiotic strain Lactobacillus plantarum 299v
      on the immune functions of gnotobiotic rats. One group of germ-free rats was
      colonized with the type 1-fimbriated Escherichia coli O6:K13:H1 and another group
      with the same E. coli strain together with L. plantarum 299v. One and 5 weeks
      after colonization, bacterial numbers were determined in the contents of the
      small intestine, caecum and mesenteric lymph nodes. Small intestinal sections
      were examined for CD8+, CD4+, CD25+ (IL-2R alpha-chain), IgA+ and MHC class II+
      cells and mitogen-induced spleen cell proliferation was determined.
      Immunoglobulin levels and E. coli-specific antibodies were measured in serum.
      Rats given L. plantarum in addition to E. coli showed lower counts of E. coli in
      the small intestine and caecum 1 week after colonization compared with the group
      colonized with E. coli alone, but similar levels after 5 weeks. Rats colonized
      with L. plantarum + E. coli had significantly higher total serum IgA levels and
      marginally higher IgM and IgA antibody levels against E. coli than those
      colonized with E. coli alone. They also showed a significantly increased density
      of CD25+ cells in the lamina propria and displayed a decreased proliferative
      spleen cell response after stimulation with concanavalin A or E. coli 1 week
      after colonization. The results indicate that L. plantarum colonization competes
      with E. coli for intestinal colonization and can influence intestinal and
      systemic immunity.

PMID- 10337021
TI  - Effects of glycyrrhizin, an active component of licorice roots, on Candida
      albicans infection in thermally injured mice.
AB  - Due to the generation of burn-associated CD8+ CD11b+ TCR gamma/delta+ type 2 T
      cells (burn-associated type 2 T cells), the susceptibility of thermally injured
      mice to infection with C. albicans has been shown to be increased by up to 50
      fold when compared with normal mice. Glycyrrhizin (GR), an active component of
      licorice roots, reduced the susceptibility of thermally injured mice to C.
      albicans infection to levels observed in normal mice. Thermally injured mice
      inoculated with CD4+ T cells from GR-treated mice were also resistant to C.
      albicans infection. The following demonstrated that susceptibility to fungal
      infection was similar in thermally injured mice and normal mice inoculated with
      T6S cells (a clone of burn-associated type 2 T cells). This susceptibility of T6S
      mice (normal mice inoculated with T6S cells) was reversible by (i) administration
      of GR, (ii) inoculation of CD4+ T cells from GR-treated mice, and (iii) injection
      of a mixture of MoAbs targeted against type 2 cytokines (IL-4 and IL-10). After
      stimulation with anti-CD3 MoAb, splenic T cells from thermally injured and T6S
      mice, treated with GR or inoculated with CD4+ T cells from GR-treated mice, did
      not have type 2 cytokines in culture supernatants. They were present in splenic T
      cell cultures from thermally injured and T6S mice that were treated with saline
      or inoculated with naive T cells. These results suggest that GR, by inducing CD4+
      T cells which suppress type 2 cytokines produced by burn-associated type 2 T
      cells, improves the resistance of thermally injured mice to C. albicans. An anti
      type 2 T cell action of the CD4+ T cells derived from GR-treated mice was
      previously described.

PMID- 10337022
TI  - Soluble tumour necrosis factor (TNF)-receptor levels in serum as markers of anti
      viral host reactivity.
AB  - The role of soluble receptors for TNF-alpha (sTNF-Rs) as markers of virus-induced
      host responses was studied by the use of murine model infections. A marked
      elevation in serum levels of sTNF-R75, but not sTNF-R55, was found 1 day after
      infection with vesicular stomatitis virus (VSV). In mice infected with
      lymphocytic choriomeningitis virus (LCMV), an early increase was also revealed,
      but peak levels of sTNF-R75 were observed later temporally related to maximal T
      cell-mediated anti-viral activity. Analysing different well characterized
      knockout mice, it was found that elevated release of sTNF-R75 into serum early
      after VSV infection was independent of T cells, whereas interferon (IFN)
      alpha/beta seemed to be a major mediator. In contrast, increased release of sTNF
      R75 into serum 8 days post-LCMV infection was mediated via T cells but
      independently of both CD40 ligand and IFN-gamma. A simple correlation between
      release of sTNF-Rs in vivo and macrophage activation in vitro was not present.
      These findings indicate that sTNF-R75 is indeed a sensitive marker of both innate
      and specific cell-mediated host reactivity during viral infection, but it is not
      correlated to a single immunological parameter.

PMID- 10337024
TI  - Diminished IL-2 responses and alteration of CD2 expression on CD8+ T cells are
      associated with a lack of cytotoxic T cell responses during Theileria annulata
      infection.
AB  - Theileria annulata is a tick-borne protozoan parasite which causes the disease
      bovine tropical theileriosis. In immunized or drug-treated animals, the
      pathogenic macroschizont stage of the parasite is destroyed by MHC class I
      restricted cytotoxic T lymphocytes (CTL). Here we show that although CD8+ T cells
      increase greatly in number and display activation markers during an acute
      infection, they exhibit no killing of infected cells. During the ineffectual
      response, efferent lymph cells' ability to proliferate to IL-2 drops, coinciding
      with loss of MoAb binding to CD2 by CD8+ cells. When animals were treated with
      the anti-parasite drug 'Butalex', IL-2 responses, anti-CD2 antibody binding by
      CD8+ cells and strong CTL activity were restored within 24 h. The initial
      activation of CD4+ T cells by parasite-infected cells altering the IL-2
      production in the draining lymph node is the likely cause of the failure of CTL
      responses.

PMID- 10337023
TI  - Early reduction of the over-expression of CD40L, OX40 and Fas on T cells in HIV-1
      infection during triple anti-retroviral therapy: possible implications for
      lymphocyte traffic and functional recovery.
AB  - Fas, CD40L and OX40 are members of the tumour necrosis factor (TNF) receptor
      superfamily with critical roles in T cell activation and death, B cell function,
      dendritic cell maturation and leucocyte traffic regulation. The aim of this study
      was to evaluate the effects of anti-retroviral therapy (HAART) on CD40L, OX40 and
      Fas expression on freshly isolated peripheral blood T cells by three-colour flow
      cytometry and compare them with lymphoproliferative responses, peripheral blood
      cell counts and viral load. Fourteen asymptomatic HIV-1+ patients treated with
      Lamivudine, Stavudine and Nelfinavir were prospectively investigated sequentially
      for 48 weeks. At baseline, patients exhibited significantly enhanced proportions
      and counts of CD40L+ and OX40+ cells within the CD4 subset which were corrected
      by weeks 8-16 of HAART. Interestingly, in the five patients showing viral load
      rebound during therapy in spite of increasing CD4 counts, the reduction of the
      levels of these costimulatory molecules was similarly maintained. Therapy induced
      a decrease in the over-expression of Fas, particularly in the CD4 subset where
      normal levels were reached at week 8. This reduction occurred in parallel with
      the major recovery of lymphoproliferative responses. Higher basal levels and
      lower reduction of Fas were associated with suboptimal suppression of viraemia.
      In conclusion, this previously undescribed increased expression of CD40L and OX40
      may play a role in the HIV-associated pan-immune activation and represent a
      possible target for immunointervention, as suggested for several immunologically
      mediated diseases. Moreover, HAART induced an early correction of the over
      expression of Fas, CD40L and OX40 in CD4 T cells which could be involved in the
      recovery of the cell traffic disturbances and in the T cell renewal capacity.

PMID- 10337025
TI  - Treatment of idiopathic CD4 T lymphocytopenia with IL-2.
AB  - Idiopathic CD4 T lymphocytopenia (ICL) is an unusual immune defect in which there
      is an unexplained deficit of CD4 T cells, leading to fungal, parasitic or other
      serious opportunistic infections. Current treatment efforts are directed at
      eliminating infections. Here we describe the use of a novel treatment,
      subcutaneous polyethylene glycol (PEG)-IL-2 injections, in a woman with this
      disorder, who had chronic severe mycobacterial disease which led to repeated
      hospitalizations, and advancing respiratory insufficiency. For this patient, PEG
      IL-2, 50 000 U/m2, has been given by weekly subcutaneous injections for 5.5
      years. This treatment has resulted in marked (and still continuing) long-term
      immunological improvement with normalized T cell functions and increased CD4 cell
      numbers. She has had substantial clinical improvement with clearing of
      mycobacterial disease, reducing hospitalizations and improved lung functions. The
      improvement seen in this patient suggests that low-dose IL-2 is a safe and
      practical therapy, which might be useful in other subjects with this potentially
      serious immune defect.

PMID- 10337026
TI  - Lysophosphatidylcholine (LPC) induces proinflammatory cytokines by a platelet
      activating factor (PAF) receptor-dependent mechanism.
AB  - Oxidized low-density lipoprotein (oxLDL) consists of both lipid components and
      apoprotein B100. OxLDL has both proinflammatory and cytotoxic properties. The
      present study was undertaken to investigate the effects of components in the
      lipid moiety of oxLDL on immune activation as determined by cytokine and
      immunoglobulin secretion. LPC induced interferon-gamma (IFN-gamma) secretion in
      peripheral blood mononuclear leucocytes from healthy blood donors. The effect
      varied between individuals, and there were both responders and non-responders.
      Furthermore, LPC induced enhanced antibody production, indicating B cell
      activation. None of eight oxysterols, arachidonic acid (AA), or 15-lipoxygenase
      products of AA tested had immune stimulatory properties. We recently demonstrated
      that PAF and oxLDL induce IFN-gamma secretion by a common mechanism. LPC-induced
      IFN-gamma secretion was inhibited by a specific PAF receptor antagonist, WEB
      2170, indicating that the PAF receptor is involved in LPC-induced immune
      activation. Both oxLDL- and LPC-induced antibody formation was inhibited by WEB
      2170. Furthermore LPC also induced tumour necrosis factor-alpha secretion, and
      this effect was inhibited by WEB 2170. LPC is produced during lipid oxidation (as
      in oxLDL), but also by enzymes such as phospholipase A2. The findings indicate
      that LPC may play an important role in inflammatory reactions, including
      atherosclerosis.

PMID- 10337027
TI  - In situ expression of B7 and CD40 costimulatory molecules by normal human lung
      macrophages and epithelioid cells in tuberculoid granulomas.
AB  - Normal alveolar macrophages (AM) are not efficient in inducing the proliferation
      of resting T lymphocytes, and, rather, tend to inhibit pulmonary immune
      responses. In contrast, epithelioid cells (EC), activated macrophages that play
      an essential role in the course of granulomatous responses, appear to stimulate T
      cell proliferation efficiently. The inability of macrophages to deliver potent
      costimulatory signals through the B7/CD28 and CD40/CD40L pathways could explain
      their weak accessory cell activity. Using MoAbs and immunohistochemical
      techniques, however, we found that essentially all AM in normal human lung tissue
      expressed B7-1, B7-2 and CD40 molecules, and most of these cells were strongly
      positive. Pulmonary macrophages in other compartments also expressed these
      costimulatory molecules; no differences in expression were observed comparing
      macrophages from smokers and non-smokers. Most AM recovered by bronchoalveolar
      lavage from normal lung segments also strongly expressed B7-1, B7-2 and CD40
      molecules. In comparison, resting blood monocytes were B7-1- and only moderately
      positive for B7-2. Activation of monocytes with lipopolysaccharide (LPS) induced
      expression of these costimulatory molecules to levels similar to that of AM from
      the control subjects. EC in granulomatous lesions also expressed easily
      detectable levels of B7-1, B7-2 and CD40. T lymphocytes within and surrounding
      the granulomas expressed CD28, the counter-receptor for B7, and many of these T
      cells also expressed B7-1 and B7-2. These findings suggest that both AM and EC
      can deliver costimulatory signals through B7-1, B7-2 and CD40 molecules, and
      indicate that the impairment in accessory cell activity observed for normal AM
      cannot be attributed to the absence of expression of these costimulatory
      molecules.

PMID- 10337028
TI  - Expression of mucosa-related integrin alphaEbeta7 on alveolar T cells in
      interstitial lung diseases.
AB  - The expression of alphaEbeta7 integrin has been related to the selective
      retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To
      identify potential disease-associated alphaEbeta7 expression patterns on cells
      accounting for lymphocytic alveolitis in interstitial lung disease (ILD), alphaE
      expression on CD4+ and CD8+ T cell subsets was evaluated by dual-colour flow
      cytometry in peripheral blood and bronchoalveolar lavage fluid (BALF) of patients
      with idiopathic pulmonary fibrosis (IPF; n = 18), hypersensitivity pneumonitis
      (HP; n = 20) and sarcoidosis (n = 44) in comparison with healthy controls (n =
      15). In both healthy individuals and all patient groups the proportion of alphaE
      bearing T cells in peripheral blood was < 2%, whereas the vast majority of
      alveolar CD8+ T cells consistently co-expressed alphaE. Absolute alveolar
      CD8+alphaE+ cell numbers/ml were up to 30-fold increased in HP patients.
      Proportions of alphaE-bearing CD4+ cells in BALF were significantly elevated in
      IPF (74.0 +/- 2.7%) and HP (70.0 +/- 2.4%) compared with normals (30.0 +/- 1.8%)
      (mean +/- s.e.m.; P < 0.01). In sarcoidosis, the alphaE expression on BALF CD4+
      cells displayed subgroup dependency: proportions significantly lower than normal
      were noted in chest radiographic stage I (14.3 +/- 1.5%), but increased
      proportions in stages II (50.0 +/- 3.8%) and III (64.0 +/- 4.8%). Correlations
      between common markers of T cell activation or BALF transforming growth factor
      beta (TGF-beta ) bioactivity and alphaE expression were not noted. We conclude
      that the vast majority of alveolar CD8+ T cells consistently express alphaEbeta7
      and that distinct patterns of alphaEbeta7 expression on alveolar CD4+ lymphocytes
      in sarcoidosis are related to the diverse manifestations of the sarcoid
      inflammatory process in the lung.

PMID- 10337030
TI  - The influence of DNA size on the binding of antibodies to DNA in the sera of
      normal human subjects and patients with systemic lupus erythematosus (SLE).
AB  - To elucidate antibody recognition of DNA in normal and aberrant immunity, the
      binding of sera of normal human subjects (NHS) and patients with SLE was tested
      with mammalian and bacterial DNA varying in size. Klebsiella pneumoniae (KP) and
      calf thymus (CT) single-stranded DNA (ssDNA) were investigated as model antigens
      using the restriction enzyme HinfI to generate fragments with the size range of
      800-5000 base pairs. The influence of size on activity was assessed by ELISA by
      both titration of serum as well as coating antigen concentration. In both assay
      formats, SLE sera bound equivalently to intact CT and KP DNA, but had
      dramatically reduced reactivity to fragments of both antigens. In contrast, NHS
      bound similarly to intact KP DNA and its fragments but had low reactivity to CT
      DNA. These results suggest that SLE and NHS anti-DNA react with different
      antigenic determinants on DNA, as shown by cross-reactivity as well as size
      dependency in solid-phase assays.

PMID- 10337029
TI  - Gene expression of 5-lipoxygenase and LTA4 hydrolase in renal tissue of nephrotic
      syndrome patients.
AB  - Leukotrienes (LT) of the 5-lipoxygenase pathway constitute a class of potent
      biological lipid mediators of inflammation implicated in the pathogenesis of
      different models of experimental glomerulonephritis. The key enzyme, 5
      lipoxygenase (5-LO), catalyses oxygenation of arachidonic acid to generate the
      primary leukotriene LTA4. This LT, in turn, serves as a substrate for either LTA4
      hydrolase, to form the potent chemoattractant LTB4, or LTC4 synthase, to produce
      the powerful vasoconstrictor LTC4. To investigate the potential role of LT in the
      pathogenesis of human glomerulonephritis with nephrotic syndrome, we examined the
      gene expression of 5-LO and LTA4 hydrolase in renal tissue of 21 adult patients
      with nephrotic syndrome and 11 controls. The patients consisted of 11 cases of
      membranous nephropathy (MN), seven focal and segmental glomerulosclerosis (FSGS),
      two non-IgA mesangial glomerulonephritis and one minimal change disease. Total
      RNA purified from renal tissue was reverse transcribed into cDNA and amplified
      with specific primers in a polymerase chain reaction (RT-PCR). Eight patients'
      renal tissue, four MN and four FSGS, co-expressed 5-LO and LTA4 hydrolase. In
      situ hybridization analysis revealed 5-LO expression and distribution limited to
      the interstitial cells surrounding the peritubular capillaries. Comparative
      clinical and immunohistological data showed that these eight patients had
      impaired renal function and interstitial changes that significantly correlated
      with 5-LO expression. These findings suggest that leukotrienes may play an
      important role in the pathogenesis of MN and FSGS. These results are also
      relevant to elucidating the pathophysiologic mechanisms which underlie
      progression to renal failure in these diseases.

PMID- 10337031
TI  - Inhibitory effects of anti-rheumatic drugs on vascular endothelial growth factor
      in cultured rheumatoid synovial cells.
AB  - Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis and
      is constitutively expressed in the synovium of rheumatoid arthritis (RA). Over
      expression of VEGF may play an important role in pathogenic vascularization and
      synovial hyperplasia of RA. In the present study, we examined whether disease
      modifying anti-rheumatic drugs (DMARDs), including bucillamine (BUC), gold sodium
      thiomalate (GST), methotrexate (MTX) and salazosulfapiridine (SASP), act by
      inhibiting the production of VEGF by cultured synovial cells of patients with RA.
      Treatment of cultured synoviocytes with lipopolysaccharide (LPS) significantly
      increased VEGF production by cultured synovial cells. BUC significantly inhibited
      LPS-induced VEGF production, while GST tended to inhibit the production of VEGF.
      The inhibitory effects on VEGF production were dose-dependent. In contrast, MTX
      and SASP did not affect VEGF production. Reverse transcriptase-polymerase chain
      reaction (RT-PCR) analysis showed that BUC also inhibited LPS-induced VEGF mRNA
      expression in RA synovial cells. The present study provides the first evidence
      that BUC inhibits VEGF production and the expression of its mRNA in synovial
      cells of RA patients. Our results indicate that the anti-rheumatic effects of BUC
      are mediated by suppression of angiogenesis and synovial proliferation in the RA
      synovium through the inhibition of VEGF production by synovial cells.

PMID- 10337032
TI  - The levels of soluble granzyme A and B are elevated in plasma and synovial fluid
      of patients with rheumatoid arthritis (RA).
AB  - Cytotoxic cells possess specialized granules which contain perforin and a group
      of serine proteinases termed granzymes. Granzyme-positive cells have been
      identified in synovial fluid and tissue of patients with RA, where they may play
      an important role as mediators of granule-mediated apoptosis, extracellular
      proteolysis, and cytokine induction. The aim here was to define further the
      involvement of cytotoxic cells in RA. Plasma and synovial fluid samples from the
      knee joint were obtained from 31 RA patients. The disease controls included 20
      osteoarthritis (OA) patients and 10 reactive arthritis (ReA) patients. A recently
      developed capture ELISA was used to detect soluble granzymes A and B in all
      patients. Compared with OA and ReA disease controls, markedly increased levels of
      soluble granzymes A and B were detected in both plasma and synovial fluid of RA
      patients (P < 0.00001). When values for soluble granzymes A and B in plasma and
      synovial fluid were used simultaneously as independent variables, logistic
      regression analysis indicated that a diagnosis of RA could be predicted correctly
      in 84% of the RA patients and a diagnosis of non-RA in 90% of the controls. The
      markedly elevated levels of soluble granzymes A and B in plasma and synovial
      fluid of RA patients strongly suggest that cytotoxic cells are active
      participants in the pathogenesis of RA. Moreover, the results suggest that
      measurement of granzymes may assist the laboratory evaluation of patients with
      arthritis. Larger studies in patients with early disease may clarify the role of
      this test system in differential diagnosis.

PMID- 10337033
TI  - Chemokine expression by subchondral bone marrow stromal cells isolated from
      osteoarthritis (OA) and rheumatoid arthritis (RA) patients.
AB  - We analysed the spontaneous and cytokine-stimulated production and expression in
      vitro of IL-8, GROalpha, MCP-1, RANTES, MIP-1alpha, MIP-1beta, by subchondral
      bone marrow stromal cells (BMSC) isolated from RA, OA, post-traumatic (PT)
      patients and normal donors (ND). BMSC were cultured in vitro in the presence or
      absence of IL-1beta and tumour necrosis factor-alpha (TNF-alpha), and assessed
      for chemokine production, expression and immunolocalization. BMSC from different
      sources constitutively released MCP-1, GROalpha and IL-8, but not MIP-1alpha or
      MIP-1beta, while BMSC from ND constitutively released only IL-8 and MCP-1. IL-8,
      GROalpha and RANTES production in basal conditions was significantly higher in RA
      patients than in ND. RANTES production was also higher in OA and RA than in PT
      patients. The combination of TNF-alpha and IL-1beta synergistically increased the
      production of all chemokines tested except for RANTES. Reverse transcriptase
      polymerase chain reaction (RT-PCR) demonstrated that all chemokines not
      detectable in the supernatants were expressed at the mRNA level. Chemokine
      immunostaining was localized around the nuclei. This work demonstrates that BMSC
      from subchondral bone produce chemokines and indicates that these cells could
      actively participate in the mechanisms directly or indirectly causing cartilage
      destruction and bone remodelling.

PMID- 10337034
TI  - C3 and C4 allotypes in anti-neutrophil cytoplasmic autoantibody (ANCA)-positive
      vasculitis.
AB  - In ANCA-associated small vessel vasculitis few genetic factors have proven to be
      of importance for disease susceptibility, an exception being deficiency of alpha1
      anti-trypsin, the main inhibitor of proteinase 3 (PR3). Alerted by our finding
      that myeloperoxidase has affinity for C3, and the finding of an increased
      frequency of the C3F allele in systemic vasculitis in a British cohort, we
      examined polymorphism of C3 and C4 in patients with ANCA+ small vessel
      vasculitis. After identification of all patients at our department with a
      positive ANCA test during the period 1991-95 and a diagnosis of small vessel
      vasculitis, blood samples were collected after informed consent. The 67 included
      patients were grouped according to ANCA serology and disease phenotype using the
      Chapel Hill nomenclature. The gene frequency of C3F was found to be increased (0.
      32) compared with controls (0.20; P < 0.05) in the PR3-ANCA+ subgroup. The
      frequency of C4A3 was increased in the group as a whole, but no increase of C4
      null alleles was seen. The findings imply a role for the complement system in the
      pathogenesis of ANCA-associated small vessel vasculitis.

PMID- 10337035
TI  - Adherence to combination antiretroviral therapies in HIV patients of low health
      literacy.
AB  - OBJECTIVE: To test the significance of health literacy relative to other
      predictors of adherence to treatment for HIV and AIDS. PARTICIPANTS: Community
      sample of HIV-seropositive men (n = 138) and women (n = 44) currently taking a
      triple-drug combination of antiretroviral therapies for HIV infection; 60% were
      ethnic minorities, and 73% had been diagnosed with AIDS. MEASUREMENTS: An adapted
      form of the Test of Health Literacy in Adults (TOFHLA), a comprehensive health
      and treatment interview that included 2-day recall of treatment adherence and
      reasons for nonadherence, and measures of substance abuse, social support,
      emotional distress, and attitudes toward primary care providers. MAIN RESULTS:
      Multiple logistic regression showed that education and health literacy were
      significant and independent predictors of 2-day treatment adherence after
      controlling for age, ethnicity, income, HIV symptoms, substance abuse, social
      support, emotional distress, and attitudes toward primary care providers. Persons
      of low literacy were more likely to miss treatment doses because of confusion,
      depression, and desire to cleanse their body than were participants with higher
      health literacy. CONCLUSIONS: Interventions are needed to help persons of low
      literacy adhere to antiretroviral therapies.

PMID- 10337036
TI  - Dual use of VA and non-VA primary care.
AB  - OBJECTIVE: To determine how frequently veterans use non-Department of Veterans
      Affairs (VA) sources of care in addition to primary care provided by the VA and
      to assess the association of this pattern of "dual use" to patient
      characteristics and satisfaction with VA care. DESIGN: Cross-sectional telephone
      survey of randomly selected patients from four VA medical centers. PARTICIPANTS:
      Of 1,240 eligible veterans, 830 (67%) participated in the survey. MEASUREMENTS
      AND MAIN RESULTS: Survey data were used to assess whether a veteran reported
      receiving primary care from both VA and non-VA sources of care, as well as the
      proportion of all primary care visits made to non-VA providers. Of 577 veterans
      who reported VA primary care visits, 159 (28%) also reported non-VA primary care
      visits. Among these dual users the mean proportion of non-VA primary care visits
      was 0.50. Multivariate analysis revealed that the odds of dual use were reduced
      for those without insurance (odds ratio [OR] 0.34; 95% confidence interval [CI]
      0.18, 0.66) and with less education (OR 0.60; 95% CI 0.38, 0.92), while increased
      for those not satisfied with VA care (OR 2.40; 95% CI 1.40, 4.13). Among primary
      care dual users, the proportion of primary care visits made to non-VA providers
      was decreased for patients with heart disease ( p <.05) and patients with alcohol
      or drug dependence ( p <.05). CONCLUSIONS: Primary care dual use was common among
      these veterans. Those with more education, those with any type of insurance, and
      those not satisfied with VA care were more likely to be dual users. Non-VA care
      accounted for approximately half of dual users' total primary care visits.

PMID- 10337037
TI  - Reasons for outpatient referrals from generalists to specialists.
AB  - OBJECTIVE: To determine the relative importance of medical and nonmedical factors
      influencing generalists' decisions to refer, and of the factors that might avert
      unnecessary referrals. DESIGN: Prospective survey of all referrals from
      generalists to subspecialists over a 5-month period. SETTING: University hospital
      outpatient clinics. PARTICIPANTS: Fifty-seven staff physicians in general
      internal medicine, family medicine, dermatology, orthopedics, gastroenterology,
      and rheumatology. MEASUREMENTS AND MAIN RESULTS: For each referral, the
      generalist rated a number of medical and nonmedical reasons for referral, as well
      as factors that may have helped avert the referral; the specialist seeing the
      patient then rated the appropriateness, timeliness, and complexity of the
      referral. Both physicians rated the potential avoidability of the referral by
      telephone consultation. Generalists were influenced by a combination of both
      medical and nonmedical reasons for 76% of the referrals, by only medical reasons
      in 20%, and by only nonmedical reasons in 3%. In 33% of all referrals,
      generalists felt that training in simple procedures or communication with a
      generalist or specialist colleague would have allowed them to avoid referral.
      Specialists felt that the vast majority of referrals were timely (as opposed to
      premature or delayed) and of average complexity. Although specialists rated most
      referrals as appropriate, 30% were rated as possibly appropriate or
      inappropriate. Generalists and specialists failed to agree on the avoidability of
      34% of referrals. CONCLUSIONS: Generalists made most referrals for a combination
      of medical and nonmedical reasons, and many referrals were considered avoidable.
      Increasing procedural training for generalists and enhancing informal channels of
      communication between generalists and subspecialists might result in more
      appropriate referrals at lower cost.

PMID- 10337038
TI  - The influence of gatekeeping and utilization review on patient satisfaction.
AB  - OBJECTIVE: To examine the influence of utilization review and denial of specialty
      referrals on patient satisfaction with overall medical care, willingness to
      recommend one's physician group to a friend, and desire to disenroll from the
      health plan. DESIGN: Two cross-sectional questionnaires: one of physician groups
      and one of patient satisfaction. SETTING: Eighty-eight capitated physician groups
      in California. PARTICIPANTS: Participants were 11,710 patients enrolled in a
      large California network-model HMO in 1993 who received care in one of the 88
      physician groups. MEASUREMENTS AND MAIN RESULTS: Our main measures were how
      groups conducted utilization review for specialty referrals and tests, patient
      reported denial of specialty referrals, and patient satisfaction with overall
      medical care. Patients in groups that required preauthorization for access to
      many types of specialists were significantly (p </=.001) less satisfied than
      patients in groups that had few preauthorization requirements, even after
      adjusting for patient and other group characteristics. Patients who had wanted to
      see a specialist in the previous year but did not see one were significantly less
      satisfied than those who had wanted to see a specialist and actually saw one (p
      <.001). In addition, patients who did not see a specialist when desired were more
      likely to want to disenroll from the health plan than patients who saw the
      specialist (40% vs 18%, p </=.001) and more likely not to recommend their group
      to a friend (38% vs 13%, p </=.001). CONCLUSIONS: Policies that limited direct
      access to specialists, and especially denial of patient-desired referrals, were
      associated with significantly lower patient satisfaction, increased desire to
      disenroll, and lower likelihood of recommending the group to a friend. Health
      plans and physician groups need to take these factors into account when designing
      strategies to reduce specialty care use.

PMID- 10337039
TI  - Primary care physicians' decisions to perform flexible sigmoidoscopy.
AB  - OBJECTIVE: This study was designed to identify factors that influence primary
      care physicians' willingness to perform flexible sigmoidoscopy. MEASUREMENTS:
      Using a mailed questionnaire, we surveyed all 161 primary care physicians
      participating in a large health care system. We obtained information on training,
      current practice patterns, beliefs about screening for colorectal cancer, and the
      influence of various factors on their decision whether or not to perform flexible
      sigmoidoscopy in practice. MAIN RESULTS: Of the 131 physicians included in the
      analysis, 68 (52%) reported training in flexible sigmoidoscopy, of whom 36 (53%)
      were currently performing flexible sigmoidoscopy in practice. Time required to
      perform flexible sigmoidoscopy, availability of adequately trained staff, and
      availability of flexible sigmoidoscopy services provided by other clinicians were
      identified most often as reasons not to perform the procedure in practice. Male
      physicians were more likely than female physicians to report either performing
      flexible sigmoidoscopy or desiring to train to perform flexible sigmoidoscopy
      (odds ratio 2.61; 95% confidence interval 1.10, 6.23). This observed difference
      appears to be mediated through different weighting of decision criteria by male
      and female physicians. CONCLUSIONS: Approximately half of these primary care
      physicians trained in flexible sigmoidoscopy chose not to perform this procedure
      in practice. Self-perceived inefficiency in performing office-based flexible
      sigmoidoscopy deterred many of these physicians from providing this service for
      their patients.

PMID- 10337040
TI  - Do physicians spend more time with non-English-speaking patients?
AB  - OBJECTIVE: To determine whether physicians at a general internal medicine clinic
      spend more time with non-English-speaking patients. DESIGN: A time-motion study
      comparing physician time spent with non-English-speaking patients and time spent
      with English-speaking patients during 5 months of observation. We also tested
      physicians' perceptions of their time use with a questionnaire. SETTING: Primary
      care internal medicine clinic at a county hospital. PATIENTS/PARTICIPANTS: One
      hundred sixty-six established clinic patients, of whom 57 were non-English
      speaking and 109 were English speaking, and 15 attending physicians and 8 third
      year resident physicians. MEASUREMENTS AND MAIN RESULTS: Outcome measures
      included total patient time in clinic, wait for first nurse or physician contact,
      time in contact with the nurse or physician, physician time spent on the visit,
      and physician perceptions of time use with non-English-speaking patients. After
      adjustment for demographic and comorbidity variables, non-English-speaking and
      English-speaking patients did not differ on any time-motion variables, including
      physician time spent on the visit (26.0 vs 25.8 minutes). A significant number of
      clinic physicians believed that they spent more time during a visit with non
      English-speaking patients (85.7%) and needed more time to address important
      issues during a visit (90. 4%), (both p <.01). Physicians did not perceive
      differences in the amount they accomplished during a visit with non-English
      speaking patients. CONCLUSIONS: There were no differences in the time these
      physicians spent providing care to non-English-speaking patients and English
      speaking patients. An important limitation of this study is that we were unable
      to measure quality of care provided or patients' satisfaction with their care.
      Physicians may believe that they are spending more time with non-English-speaking
      patients because of the challenges of language and cultural barriers.

PMID- 10337041
TI  - Nonoccupational risk factors for carpal tunnel syndrome.
AB  - OBJECTIVE: To examine the relation between selected nonoccupational risk factors
      and surgery for carpal tunnel syndrome. DESIGN: Case-control study using an
      administrative database. PARTICIPANTS: Enrollees of New Jersey Medicare or
      Medicaid programs during 1989 to 1991. MEASUREMENTS: The outcome of interest was
      open or endoscopic carpal tunnel release. We examined the relation between carpal
      tunnel release and diabetes mellitus, thyroid disease, inflammatory arthritis,
      hemodialysis, pregnancy, use of corticosteroids, and hormone replacement therapy.
      MAIN RESULTS: In multivariate models, inflammatory arthritis was strongly
      associated with carpal tunnel release (odds ratio [OR] 2.9; 95% confidence
      interval [CI] 2.2, 3.8). However, corticosteroid use also appeared to be
      associated with a greater likelihood of undergoing carpal tunnel release, even in
      the absence of inflammatory arthritis (OR 1.6; 95% CI 1.2, 2.1). Diabetes had a
      weak but significant association with carpal tunnel release (OR 1.4; 95% CI 1.2,
      1.8), as did hypothyroidism (OR 1.7; 95% CI 1.1, 2.8), although patients with
      hyperthyroidism did not have any change in risk. Women who underwent carpal
      tunnel release were almost twice as likely to be users of estrogen replacement
      therapy as controls (OR 1.8; 95% CI 1.0, 3.2). CONCLUSIONS: Although inflammatory
      arthritis is the most important nonoccupational risk factor for carpal tunnel
      release, these data substantiate the increase in risk associated with diabetes
      and untreated hypothyroidism. Further investigation in detailed clinical studies
      will be necessary to confirm whether changes in corticosteroid use and hormone
      replacement therapy offer additional means of risk reduction for this common
      condition.

PMID- 10337042
TI  - Reading between the lines: deciphering the connections between literacy and
      health.

PMID- 10337043
TI  - Does the VA provide "primary" primary care?

PMID- 10337044
TI  - The good (gatekeeper), the bad (gatekeeper), and the ugly (situation)

PMID- 10337045
TI  - Improving the health and health care of non-English-speaking patients.

PMID- 10337046
TI  - [Group for the Advancement of Microsurgery. A little history].

PMID- 10337047
TI  - [Lower limb stump reconstruction with a functional calcaneo-plantar unit free
      flap. A series of 16 cases].
AB  - The main objective of surgery, once amputation is inevitable, is to preserve a
      functional stump. This report describes the immediate reconstruction of 16 leg
      stumps in children by transfer of a functional calcaneo-plantar unit. Of these, 3
      were thigh and 13 were lower leg reconstructions. Amputation was performed for
      tumor in 4 cases, and was due to accidents in the remaining twelve. The main
      technical features of flap preparation are preservation of the calcaneum branch
      and attachment of the heel skin to the greater tuberosity of the calcaneum. One
      case resulted in failure due to vascular thrombosis. The other 15 cases resulted
      in bone consolidation after an average of 45 days, sensitive protection by 70
      days, and very good trophic and protective results. The provision of good distal
      pressure area encourages overall development of the child. There was no morbidity
      at the donor site, and because there is no major muscle mass in the distal
      fragment, the overall risk is very low compared to that of total proximal leg
      replantation. The transfer of functional calcaneo-plantar tissue as a single unit
      is the best strategy for one-step restoration of good distal support area for the
      stump. All surgeons liable to perform leg amputations should be aware of this
      technical approach.

PMID- 10337048
TI  - [Serratus anterior muscle flap: indications and sequelae. 26 cases and review of
      the literature].
AB  - The authors report their experience of the use of the serratus anterior flap.
      Between 1992 and 1997, this flap was used for 14 head and neck and 11 limb and 1
      intra-thoracic reconstructions. Twelve patients were examined for functional
      evaluation of the donor site. When only 2 or 3 slips are raised donor site
      morbidity is limited to moderate winging of the scapula with no functional
      disorders. Because of its thinness, and the length and diameter of the vascular
      pedicle, the serratus anterior flap is our favourite option for small wounds of
      the distal limb or composite and large defects in association with flaps of the
      subscapular system.

PMID- 10337049
TI  - [Dorsal metacarpal flap with an extensive retrograde pedicle. Anatomic study and
      22 clinical cases].
AB  - The dorsal digitometacarpal flap or extended distal pedicled dorsal metacarpal
      flap is a new skin flap, useful in reconstructing large distal defects on the
      dorsal aspect of the digits. It is raised on the dorsum of the hand, over an
      intermetacarpal space. Its vascularisation is provided by proximal dorsal
      cutaneous branches of the digital collateral arteries through the rich,
      anastomotic arterial network of the webspace. This flap is a useful flap compared
      to others flaps harvested from the dorsum of the hand, such as the reverse
      metacarpal flaps. The operative procedure preserves the dorsal interosseous
      muscles aponeurosis, the junctura tendinum and the dorsal metacarpal artery. Its
      vascularisation depends on the webspace arterial network; it is constant contrary
      to the dorsal metacarpal arteries of the ulnar spaces. This flap is indicated to
      cover distal defects on the dorsum of the digits because of its large rotation
      arc. The anatomical basis and operative technique of the flap are described. Two
      out of 22 clinical cases were selected to illustrate the ability of this flap for
      reconstruction of digital defects.

PMID- 10337050
TI  - [Latissimus dorsi free flap with "Y" anastomoses. Technical variant and use in
      leg reconstruction].
AB  - The authors report a new technique for harvesting and anastomosis of the
      latissimus dorsi free flap. The latissimus dorsi free flap is elevated with the
      subscapular and circumflex scapular vessels forming a "Y" pedicle. The recipient
      artery is sectioned and the arterial tree of the flap is anastomosed to the
      recipient vessel by two end-to-end anastomoses. This technique is particularly
      useful in leg reconstructive surgery when only one vessel remains: it simplifies
      transfer (end-to-end anastomosis), anastomoses are easier because more
      superficial.

PMID- 10337051
TI  - [Reconstruction of a complex defect of the upper third of the humerus by pedicle
      transplant of the lateral edge of the scapula. A case report].
AB  - Vascularized bone transfer of the lateral border of the scapula is exceptionally
      used in orthopaedic surgery. The authors report a case of pedicle transfer of the
      lateral border of the scapula designed to reconstruct a nine centimetre bone
      defect of the upper third of the humerus following a gunshot wound. A
      complementary conventional bone graft was performed one month later and
      consolidation was achieved at the fourth month.

PMID- 10337052
TI  - [Necessity of double testing of meat juice samples from pigs using ELISA for the
      determination of Salmonella status in pig farms].
AB  - According to the test protocol of the "meat juice ELISA" for detection of
      salmonella antibodies in pigs, all meat juice samples and serum controls are to
      be tested in duplicate. Results from routine investigations of repeatedly double
      tested meat juice and serum samples have been used to analyze the effect of
      double testing versus single testing with regard to the reliability of the final
      result. In case of an individual animal, testing of samples in duplicate
      increases the reliability of the results significantly, especially, if samples
      are retested at different occasions. In contrast, such a difference between mono
      and double testing of samples is not of importance when a group of animals is
      tested in order to determine the mean antibody rate in a herd. Here, results from
      double testing practically do not contribute to a higher reliability of the final
      result. This observation provides the possibility to reduce the costs for
      investigation programmes drastically.

PMID- 10337053
TI  - Investigations on airborne microorganisms in animal stables. 2. Report: further
      characterization of airborne Clostridium perfringens.
AB  - Toxovars of 97 airborne C. perfringens isolates and 10 C. perfringens isolates
      from fecal samples of a calf stable were determined by an EIA procedure. Most
      airborne and fecal isolates belonged to toxovar A (88.7% and 80.0% respectively).
      Eight point two% of airborne C. perfringens were identified as toxovar C and 3.1%
      as toxovar D. Toxovar B was not found in the airborne state. Twenty% of fecal C.
      perfringens belonged to toxovar D. Toxovar B and C was not isolated from fecal
      samples. In addition, all fecal and air-borne isolates of C. perfringens toxovar
      D strains were analyzed in SDS-PAGE for their polypeptide pattern. All isolates
      from both sources exhibited the same polypeptide pattern after electrophoretic
      analysis in SDS-PAGE. Both results, determination of toxovars as well as
      polypeptide pattern analysis in SDS-PAGE, suggest that a major source of airborne
      C. perfringens in animal stables is animal feces.

PMID- 10337054
TI  - [Detection of pas gene in shiga toxin producing Escherichia coli (STEC)].
AB  - Results of detection of the pas gene in 10 shigatoxin-producing Escherichia coli
      strains (STEC) isolated from foods (raw milk, certified milk, and beef) and in 18
      enterohaemorrhagic Escherichia coli strains (EHEC) isolated from stool samples of
      patients suffering from HUS, diarrhea or from carriers without symptoms are
      given. All isolates showed the eae gene coding for intimin. We could make sure by
      using PCR that all isolates showed the pas gene, too. This gene is a factor
      mainly responsible for proteinsecretion and for the attacing and effacing
      phenomenon. A correlation of pas to other virulence factors was not given. The
      detection of the pas gene makes further characterization of STEC/EHEC-Isolates
      possible.

PMID- 10337055
TI  - [Remarks on the domestic dog as an object of instruction for the education of the
      developing child].
AB  - Based on an intensive analysis of literature, the study summarizes problems
      involved in the significance of domesticated dogs as objects of instruction and
      assistants of the education of children. Several important topics are discussed
      in view of advances for children in families keeping dogs. Such topics are mainly
      related to a general socio-emotional level, the support of cognitive development
      and character formation. Further aspects are the acquisition of a sense of
      responsibility, and the development of self-confidence, a sense of social
      membership and security, as well as important attributes of character such as
      frankness, broad mindedness, and sympathetic understanding. Moreover, knowledge
      about the life cycle and functions of body organs can be conveyed, and the dog
      could, at least in part, substitute for brothers and sisters. Basically, positive
      attitudes towards animals in general, as well as nature and environment are
      supported. All topics are critically commented and considered to be realistic or
      not. The supporting role of parents, in particular, is emphasized. Parental
      commitment should include deep concern with the typical attributes of the dog
      breed desired, and optimal dog keeping conditions to prevent harm to the
      children. The final commentary lays special emphasis on negative features of
      domestication for a pet owner, and cautions against non-biological and
      illusionary ideas about domesticated animals.

PMID- 10337056
TI  - [Botulism--a forgotten disease?].
AB  - The laboratory diagnosis of C. botulinum is described for cattle and horses in
      the years 1995-1998. Out of 122 cases 66 were positive. All types of toxins were
      identified; in cattle mainly types C and D. In 9 cases typing was not conclusive.
      The results of an enquiry of afflicated animal owners showed, that modern
      agricultural technology has an important impact on toxinogenesis in feed stuff.
      Possibilities to prevent the disease and to reduce economic losses are discussed;
      a solution cannot be presented.

PMID- 10337057
TI  - Straussenhaltung in Deutschland / Straussenfleisch aus Namibia--ein Fallbeispiel.
      [Ostrich husbandry in Germany / ostrich meat from Namibia - a case study].
AB  - Within the European Union, academic professions themselves are expected to reach
      a comparable level of professionalism, a fact that veterinary medicine as well
      should not ignore. At present, a working group is developing a concept of a
      teaching module for the Socrates programme "Education in Veterinary Public Health
      (VPH)", enabling the students by "case studies" to be induced to an integrated
      approach of tackling problems. In an attempt to demonstrate the didactic
      procedure, a study of ostrich meat as food for human consumption is presented as
      a concrete example. In the detailed teacher's guide, informations are given about
      ostrich husbandry, slaughter procedure and meat inspection, as well as detailed
      explanations how the health of human consumer can be safeguarded by the
      introduction of the HACCP system.

PMID- 10337058
TI  - Survival of cryopreserved fetal substantia nigra implanted into the rat brain in
      the two forms and estimation of the host brain reaction against graft.
AB  - A fetal, cryopreserved ventral mesencephalic rat tissue was grafted into striatum
      of 143 healthy adult rats, applying two different forms, solid tissue block or
      cell-suspension. The fetal tissue was preserved in liquid nitrogen for 30-80
      days. For transplantation stereotaxic placement technique was employed. The
      controls were subjected to sham transplantation. The survival of transplanted
      dopaminergic cells in rat striatum was evaluated by means of histological and
      immunocytochemical methods (TH-tyrosine hydroxylase) 1, 3, 7, 14 and 21 days
      after transplantation. The host cellular reaction against the graft and sham
      lesion was examined. Glial fibrillary acidic protein (GFAP) was used for the
      visualization of astroglial reaction and ferritin for microglia. The occurrence
      of T-lymphocytes was also assessed using W3/13 antibodies. Electron microscopy
      was utilized as well in the evaluation. It was found that fetal cells of
      cryopreserved rat mesencephalon transplanted into adult rat striatum in two
      different models survive and mature similarly. The host cellular reaction against
      the graft was nonspecific and similar to that found in the control groups. Over a
      posttransplantation period of 21 days no graft rejection was observed in any of
      the experimental groups.

PMID- 10337059
TI  - Immunocytochemical localization of endothelial nitric oxide synthase (e-NOS) and
      inducible nitric oxide synthase (i-NOS) in rat neurohypophysis after transient
      cerebral ischemia.
AB  - The expression pattern of endothelial and inducible forms of nitric oxide
      synthase (e-NOS, i-NOS) in rat neurohypophysis after transient ischemia was
      investigated using post-embedding immunogold method. We demonstrate that ischemia
      induced an early (10 min) expression of e-NOS not only in endothelium but also in
      the mast cells. Expression of i-NOS was almost exclusively confined to glial
      cells (pituicytes) and perivascular macrophages of experimental animals, and
      peaked at 24 h after ischemia. This evidence indicates that NO plays a
      significant role in mechanisms of cerebral ischemia. Taking into account the
      known beneficial role of e-NOS in ischemia it is likely that mast cells protect
      against post-ischemic brain damage by producing vasodilatation via nitric oxide.
      In contrast, cerebral macrophages and pituicytes may mediate neuronal and
      endothelial damage in late period after ischemia in rat neurohypophysis.

PMID- 10337060
TI  - Disorganization of cortical structure and the brain tumors.
AB  - In the course of histopathological investigation of the temporal lobe sections,
      selected from 63 patients treated surgically for intractable epilepsy and finally
      presented with primary temporal tumors, we found 12 cases expressed both
      neoplastic process' and developmental disorders. The temporal mass lesions
      consisting of neuro-glial or pure glial tumors were associated with some
      developmental abnormalities such as cortical dysplasia, neuronal heterotopias and
      additional cortical neoplastic nodules. The possible "dual pathology" concerning
      these lesions are discussed in this paper.

PMID- 10337061
TI  - Primary malignant lymphoma of brain. A review of four cases diagnosed by means of
      CT-guided stereotactic biopsy.
AB  - In a series of 66 CT-guided stereotactic biopsies (SB) of the brain performed in
      1995-1998, four were found to be the primary non-Hodgkin's lymphomas (PCNSL). All
      cases were studied with immunohistochemistry (broad panel of antibodies;
      reactions performed mainly on cytological smears) and with the use of an electron
      microscopy. In an immunophenotyping all cases were positive for leukocyte common
      antigen (LCA) and 3/4 showed B-cell phenotype. Since the PCNSL are typically
      located in central, periventricular region of brain and the surgical removal does
      not bring any benefit, the stereotactic biopsy is a method of choice to make a
      definite diagnosis that opens the chances for implementation of chemo- and
      radiotherapy. The diagnostic difficulties that are derivatives of an extremely
      small amount of the available biopsy material were discussed and the role of the
      immunophenotyping and of the electron microscopy for avoiding the possible
      diagnostic mistakes was stressed. Cytological smears stained with H&E and the
      smears and histological slides with immunohistochemical reaction against glial
      fibrillary acidic protein (GFAP) showing sometimes extremely dense network of
      astrocytes mingled with neoplastic lymphoma cells are especially interesting and
      seem to suggest the involvement of astroglia in the pathogenesis of PCNSL.

PMID- 10337062
TI  - Computerized morphometric analysis of the cerebellum in patients with
      lymphoblastic lymphomas of various survival time.
AB  - Post-mortem neuropathological investigations of the cerebellum were carried out
      in 15 patients deceased due to lymphoblastic lymphoma (LBL). In patients with
      survival time of LBL longer than 20 months, neuronal structures of the cerebellum
      appeared to be significantly rarefied. It was especially observed within granular
      layer, less frequently in Purkinje and dentate nuclei cells. In cases with longer
      survival time shrinkage and deformation of neurons, especially Purkinje and
      dentate nuclei cells were observed. The morphometric analysis suggests that the
      cerebellar neuronal changes might be a consequence of remote effects of LBL on
      nervous tissue. The longer survival time contribute to the nervous system
      exposure on remote effects of neoplasm. The dentate nuclei cells are damaged due
      to remote effect of lymphoma, irrespective of Purkinje cells destruction.

PMID- 10337063
TI  - Central nervous system infection caused by Borrelia burgdorferi. Clinico
      pathological correlation of three post-mortem cases.
AB  - The spirochete Borrelia burgdorferi (B. burgdorferi) may cause severe
      meningoencephalomyelitis as the sole manifestation of Lyme borreliosis. We would
      like to present three such cases, where definite neuroborreliosis was clinically
      diagnosed in two cases and possible neuroborreliosis was recognized in one case.
      Alive spirochetes were isolated and cultured from blood and cerebrospinal fluid
      (CSF) in both definite cases. B. burgdorferi as the causative agent of the
      infection was confirmed in CSF by polymerase chain reaction (PCR) in one definite
      case. In the possible case spirochetes were cultured from blood and CSF. Alive
      spirochetes were not isolated, however anti-B. burgdorferi antibody value in
      serum was significantly elevated. On necropsy gross examination brain edema
      without focal changes was detected in two cases. Cerebral atrophy was seen in
      Case 3. Microscopically, lymphocytic infiltrates, microglial diffuse and nodular
      activation, spongiform changes, diffuse demyelination of the cerebral and
      cerebellar white matter, and diffuse astrocytosis, were characteristic
      pathological features in all presented cases. Multifocal, perivascular
      degenerative changes in the cerebral and cerebellar white matter were observed in
      the first case. Inflammatory changes in the nuclei and roots of cranial nerves
      were present in the third case.

PMID- 10337064
TI  - Electron microscopic and immunohistochemical verification of diagnosis in two
      archival cases recognized as encephalitis necroticans acuta (ENA) on routine
      examinations.
AB  - Two archival cases diagnosed 20 years ago on routine neuropathological methods as
      Encephalitis Necroticans Acuta (ENA) were investigated in EM and by
      immunohistochemical methods. The previous diagnosis was confirmed only in one
      case because Herpes simplex virus was found. In the second case the intracellular
      inclusions visible in ME corresponded to Measles Virus thus previous diagnosis
      was changed to SSPE.

PMID- 10337065
TI  - A Polish pedigree with Alzheimer's disease determined by a novel mutation in exon
      12 of the presenilin 1 gene: clinical and molecular characterization.
AB  - The presenilin 1 (PS-1) gene, recently identified on chromosome 14q24.3, is a
      major gene involved into the autosomal dominant forms of early onset Alzheimer's
      disease (EOAD). Mutations of the PS-1 gene are responsible for the majority of
      familial EOAD. We found a novel mutation in a Polish family with EOAD from the
      Poznan region. The mutation at codon 424 in exon 12 of the PS-1 gene leads to an
      amino acid substitution Leu-Arg in a transmembrane domain VIII of the presenilin
      1 molecule. The change is predicted to have a drastic effect on the protein
      function because it is associated with a very early age of onset (a range of 30
      35 years) and a quick progression (about a 4-5 years duration) of the disease.

PMID- 10337066
TI  - [Obituary to Prof. Witold Michalkiewicz].

PMID- 10337067
TI  - [Determination of newborn feeding in maternity hospital care. Part I: Factors
      associated with breast feeding initiation].
AB  - The data on 11,750 newborns collected in 427 hospitals during the survey of
      maternity words practices in 1995 were used to analyse the factors related to
      breastfeeding initiation while in hospital. The statistical analyses were done
      using percentage of newborn breastfed as well as odds ratio (OR) and population
      attributable risk in percent (PAR%) of artificial feeding. The identified factors
      of artificial feeding were: newborn birth weight < 2500 g (OR = 28.2; PAR = 52%),
      complications in neonatal period (OR = 10.3; PAR = 64%), caesarean section (OR =
      4.3; PAR = 32.2%), mother and newborn separation longer than 1h/24h (OR = 13%;
      PAR = 87.2%), lack of skin-to-skin contact after birth (OR = 8.5; PAR = 60.9%).

PMID- 10337068
TI  - [A clinical analysis of fetoplacental blood flow in prognosis of fetal emergency
      in pregnancies complicated by hypertension].
AB  - DESIGN: The aim of our study was a clinical analysis of fetoplacental blood flow
      in prevision of fetal hypoxia in pregnancy complicated by a hypertension.
      MATERIALS AND METHODS: Between 1995-1997 105 pregnant women delivered in 2nd
      Dept. Of Gynecology and Obstetrics Medical University of Gdansk. They were
      divided into two groups: 53 patients with hypertension and control group of 52
      pregnant women. In all cases a doppler umbilical blood flow was estimated using 5
      MHz Convex sounder. RESULTS: In a group of pregnant women with hypertension
      abnormal results of doppler fetoplacental blood flow were found. Twice more often
      a caesarean section was made because of fetal emergency symptoms. CONCLUSIONS:
      The results of fetoplacental blood flow are one of more important prognostic
      factors in pregnancies complicated by a hypertension.

PMID- 10337070
TI  - [The expression of c-myc gene detected by in situ hybridization in endometrial
      hyperplasia].
AB  - The expression of c-MYC gene has been detected by using the method of in situ
      hybridization. It has been detected mainly in glandular cells but also in stromal
      cells in atypical endometrial hyperplasia in women after menopause regardless of
      their age. A similar expression has been found to occur in nonatypical case of
      hyperplasia in a women of premenopausal age.

PMID- 10337069
TI  - [Prevention of deep vein thrombosis (DVT) with the low molecular weight heparin
      (LMWH) and epidural/spinal anesthesia. The efficacy viewpoint].
AB  - OBJECTIVES: To compare the frequency of DVT and PE (pulmonary embolism) events in
      patients who had undergone gynecological operations under epidural/spinal
      anaesthesia without LMWH prophylaxis with patients receiving LMWH prophylaxis.
      DESIGN: Retrospective, hospital record based study. MATERIALS AND METHODS: The
      majority of patients had undergone vaginal operations. 441 consecutive,
      unselected patients without LMWH prophylaxis vs. 463 ones treated with LMWH. The
      patients were given Fraxiparine a 7,500 ICU s.c. 2 h before operation. The same
      doses were repeated every 24 h during 5-7 days or to the regaining by the patient
      sufficient physical activity. DVT diagnosis was based on the clinical signs and
      ultrasound techniques. PE was stated on clinical symptoms, ECG chest x-ray
      characteristics and gasometric data. RESULTS: Among the patients without LMWH
      prophylaxis 2 cases of PE occurred (0.45%), one of these was fatal. 1 case of
      proximal DVT (0.23%) and 3 distal DVT complications (0.68%) were stated. In the
      LMWH group 1 proximal DVT (0.22%) and 2 distal DVT (0.43%) developed.
      CONCLUSIONS: Perioperative LMWH prevention proved to be efficient. The clinically
      expressed incidence of DVT expressively diminished: 8 cases-(1.66%) vs. 3 cases
      (0.53%). The pulmonary embolism was avoided.

PMID- 10337071
TI  - [Coexistence of ovarian adenocarcinoma with tubal pregnancy and plano-epithelial
      cervical cancer of uterus].
AB  - OBJECTIVES: Ovarian tumors during pregnancy are rare event. Histologic subtypes
      and prognosis do not differ from tumors not associated with pregnancy, it seems
      however, that are more lesions of borderline malignancy and of low grade. An
      extremely rare of ovary adenocarcinoma coexisting with tubal pregnancy and
      planoepithelial cervical cancer of uterus has been discussed. STUDY DESIGN: The
      patient S. D. age 39, was admitted to hospital with a diagnosis of peritonism,
      shock and general condition-hard. The patient was operated half an hour after
      admission to hospital. During laparotomy tubal pregnancy coexisting with ovarian
      carcinoma has been satisfied and total hysterectomy, bilateral salpingo
      oophorectomy, omentectomy, appendectomy and staging was done. RESULTS:
      Histopathological examination of surgical specimen revealed tubal pregnancy
      coexisting with bilateral focal ovarian adenocarcinoma (stage IC) and
      planoepithelial praeinvasive cervical cancer of uterus. Six cycles of PC
      chemotherapy are given. During second look laparotomy complete pathological
      response (pCR) was observed. The Ca-125 value was less then 35 IU/ml. Now the
      patient is followed for disease status every three month. Her health and is good.
      CONCLUSION: On the basis of the follow-up of the patient it seams that the
      coexistence of ovarian carcinoma with cervical cancer and tubal pregnancy neither
      accelerate the development of disease or make worse the prognosis.

PMID- 10337072
TI  - [Endolymphatic stromal myosis corporis in a 50-year-old woman].
AB  - The authors present a rarely-observed case of endolymphatic stromal miosis (ESM)
      in a fifty-year old female patient. ESM is a low malignancy stromal endometrial
      tumor that is usually treated by surgery.

PMID- 10337073
TI  - [True and pseudo-Meigs' syndrome].
AB  - In this paper two cases were reported. The first case concerns the truth Meigs
      syndrome at 70-year old woman, who was admitted into gynaecological clinic
      because of quickly increasing abdominal circumference, metrorrhagia and liquid in
      pleural cavity. In this woman benign ovarian neoplasm-thecoma was detected. The
      second case concerns pseudo Meigs syndrome at 57-year old woman, who was operated
      because of ovarian cancer. In this patient recurrent ascites was observed. In
      this case radical surgery and chemotherapy was performed.

PMID- 10337074
TI  - [Pregnancy in a woman with a prior myocardial infarction: a case report].
AB  - Myocardial infarction during pregnancy is a rare event but is considered to be
      associated with very high mortality of both mother and fetus. We report
      uncomplicated cesarean section in the 3rd pregnancy in woman with a prior
      myocardial infarction that occurred during the first hours after cesarean section
      delivery of the 2nd pregnancy. Intensive cardiological and obstetrical
      supervision are required for correct management of the pregnancy.

PMID- 10337075
TI  - [Antiretroviral therapy in pregnant women with HIV].
AB  - Antiretroviral therapy decreases rates of maternal-infant HIV transmission when
      given ante and intrapartum to the pregnant women and post partum to the infant.
      The use of zidovudine (AZT) in pregnant women and newborn is well tolerated and
      reduces the maternal-infant transmission of HIV even though the complete protocol
      has not been used. Combination therapy leads to a sustained undetectable viral
      load in mother blood and does not have detrimental effects on the newborn. The
      use of combination antiretroviral therapy is now recommended in pregnancy,
      although limited data currently exists on the impact of this regimen on newborns.
      In future, there is a clear need to assemble larger population-based cohorts of
      HIV+ parturients and their offspring to explore the safety of antiviral therapy
      in pregnancy.

PMID- 10337076
TI  - [Discussion with an article in Ginekologia Polska No. 10, 1997, pg. 473 on
      "efficient electroconization in the prevention of cervical cancer: analysis of
      2555 cases].

PMID- 10337077
TI  - Estimating adolescent cigarette consumption in Japan.
AB  - We estimated the cigarette consumption among Japanese adolescents based on the
      data which was obtained from a 1990 nationwide school-based questionnaire survey
      of smoking prevalence among high school students. Cigarette consumption for
      adolescents was estimated using the data on current smokers' rate and cigarette
      consumption per day. Participants were 57,189 high school students (aged 13-18
      years) including 4666 current smokers. The estimated adolescents' consumption was
      calculated at 3.5 to 4.3 billion units in 1990. The proportion of adolescents'
      consumption to the total sales was 1.1% to 1.3%. The corresponding tax amounted
      to between 21 and 25 billion yen in 1990. The difference between the total sales
      and the crude cigarette consumption for adults has increased gradually over 20
      years. Logically, some part of this increase should be attributed to cigarettes
      consumed by adolescents. The increase in this difference seemed to keep pace with
      the increasing number of cigarette vending machines. These results indicate that
      a considerable amount of cigarettes were consumed by adolescents in 1990.

PMID- 10337078
TI  - Cancer mortality among radiological technologists in Japan: updated analysis of
      follow-up data from 1969 to 1993.
AB  - A retrospective cohort study was conducted for 12,195 male radiological
      technologists who received the occupational exposure to low dose radiation over a
      long term. A total of 1,097 deaths including 435 from cancer were ascertained by
      Koseki and death certificates from 1969 to 1993. Cancer mortality among the study
      population was basically compared with that of whole Japanese men. The
      significant low SMRs were obtained for all cancers, stomach and lung cancer
      partly due to Healthy Worker Effect, unlike the results of the early reports with
      some inappropriateness in the methods. Apparent high risks of lymphatic and
      hematopoietic cancers were observed, although none of site-specific cancers
      revealed the statistically significant increase. For these cancers, the SMRs
      among old sub-cohort were somewhat higher than those of young sub-cohort, whereas
      similar SMRs for solid cancer were obtained between the two sub-cohorts. The SMR
      for leukemia reached statistically significant level of 1.75 (95% CI: 1.07-2.71)
      when using whole professional and technical workers as a standard population. The
      study results might suggest that the chronic exposure to low-dose radiation
      enhanced the risk of lymphatic and hematopoietic cancers.

PMID- 10337079
TI  - A pilot study of mammographic density patterns among Japanese women.
AB  - Mammographic density patterns, which refer to the distribution of fat,
      connective, and epithelial tissue in the healthy female breast, have been shown
      to be related to breast cancer risk. We used a quantitative method to assess
      mammographic densities in 41 mammograms from women in Japan without a diagnosis
      of breast cancer. Information about reproductive behavior and family history for
      breast cancer was available from a questionnaire. The statistical analysis
      applied Spearman correlation coefficients and multiple linear regression. The
      breast size as measured on the cranio-caudal view of the mammogram was
      approximately 12% larger, the size of the dense areas was 20% smaller, and the
      mean percent mammographic densities were 30% greater among premenopausal than
      among postmenopausal women. We found a strong relation between age at menarche
      and mammographic densities in premenopausal women and significant associations
      for age, family history of breast cancer, and age at menopause with mammographic
      densities in postmenopausal women. These preliminary data will be used to plan a
      future study that will compare mammographic density patterns and the relative
      importance of dietary, reproductive, and anthropometric factors between women in
      Japan and in the United States.

PMID- 10337080
TI  - Foods contributing to absolute intake and variance in intake of fat, fatty acids
      and cholesterol in middle-aged Japanese.
AB  - On the basis of 351 one-day weighed diet records, we selected foods/recipes
      contributing to nutrients of interest for a data-based food frequency
      questionnaire by contribution analysis and multiple regression analysis. Total
      fat was largely of animal and vegetable origin, irrespective of analytic methods.
      Saturated fatty acid was mostly from animal and vegetable sources according to
      contribution analysis, and that of animal origin was the main contributor by
      multiple regression analysis. Mono-unsaturated fatty acid was substantially
      supplied by animal and vegetable products by either analytic method. Poly
      unsaturated fatty acid, n-6 poly-unsaturated fatty acid and linoleic acid were
      found to be of vegetable origin and chicken egg according to contribution
      analysis; while vegetable oil and mayonnaise were the major contributors to
      variance in intake. Arachidonic acid was, however, mostly provided by animal
      sources including chicken egg and fish, irrespective of analytic methods. N-3
      poly-unsaturated fatty acids and alpha-linolenic acid were of vegetable and
      marine origin. Eicosapentaenoic and docosahexaenoic acids were particularly from
      marine products, irrespective of analytic methods, except for chicken egg in
      docosahexaenoic acid by contribution analysis. Cholesterol was of animal and
      marine origin by either analytic method. Thus, foods contributing to absolute
      intake and variance in intake of fat, fatty acids and cholesterol differed
      considerably.

PMID- 10337081
TI  - Nutrient intakes in relation to style of breakfast and taste preferences.
AB  - Style of breakfast (western- or Japanese-style) and taste preferences were
      associated with various diseases in some epidemiological studies in Japan. To
      evaluate what are measured by asking these dietary behaviors, we administered
      semiquantitative food frequency questionnaire (SFFQ) and asked style of breakfast
      and taste preferences to a subsample of residents in Takayama City, Gifu, Japan.
      Style of breakfast and total diet were studied in a random sample of 346
      residents. There were no statistically significant differences in the nutrient
      intakes estimated from SFFQ between those with western- and Japanese-style of
      breakfast except for crude fiber. Taste preferences were asked to 555 men and
      1,130 women who attended a health check-up program in the community. Salt intakes
      were slightly higher (< 3%) in those who had a favor for salty food than the
      others in both sexes. Fat or carbohydrate intake was similar between those
      stratified by preference for greasy or sweet foods. The data suggest that western
      style of breakfast is not associated with western diet, in general, i.e., high
      calorie and high-fat diet. Intakes of salt, fat, or carbohydrate appear to be
      unrelated to preferences for salty, greasy or sweet foods, respectively.

PMID- 10337082
TI  - Serum uric acid: correlation with biological, clinical and behavioral factors in
      Japanese men.
AB  - Cross-sectional associations between biological, clinical and behavioral factors
      and serum uric acid (SUA) levels were examined in 2,438 Japanese male office
      workers aged 20 to 59 years in Osaka, Japan. Stepwise regression analysis for SUA
      was carried out for all persons and repeated excluding those under medication for
      hypertension, hyperuricemia or diabetes mellitus. The results were essentially
      the same without change in the sequence of the seven most important variables.
      When 150 men under medication were excluded, independent correlates with SUA
      levels were, in order of relative importance, history of gout, log triglyceride,
      creatinine, hemoglobin A1c (negative association), body mass index, total
      protein, alcohol intake, age (negative association), and total cholesterol. 32.7
      percent of total variation in SUA was accounted for by these variables combined.
      Our data suggest that weight and serum lipids control and avoiding excessive
      drinking may be beneficial in the prevention of hyperuricemia.

PMID- 10337083
TI  - Getting a high response rate of sexual behavior survey among the general
      population in Japan: three different methods of survey on sexual behavior.
AB  - The purpose of this study was to specify the most accurate, reliable and valid
      technique for a general sexual behavioral survey in Japan. This pilot study was
      conducted to assure a high response rate and to keep respondents' privacy
      confidential by using an anonymous questionnaire survey technique. The sample
      (360 potential respondents) was selected randomly from basic resident registers
      in two geographically different areas. From the registries, 90 residents, aged 20
      to 49 years old, were randomly selected to represent each sex from each area. The
      subjects were randomly assigned to three groups each having a different procedure
      of requesting the completion of the survey and providing the questionnaires: (1)
      Postal Group, (2) Telephone Group, and (3) Face-to-face Group. The survey was
      carried out from October 1995 to February 1996. Effective response rates for the
      above mentioned three groups were 69.2%, 69.2% and 55.8%, respectively. It is
      difficult to determine the best method when only considering the effective
      response rates. However, judging from our effort and expense, the mail survey is
      the best possible procedure and would be a reasonable method for a national
      sexual behavior survey.

PMID- 10337084
TI  - Trend of HIV incidence rates among drug users in an HIV epicenter in northern
      Thailand (1989-1997).
AB  - OBJECTIVES: To determine trends and associated risk factors of HIV incidence
      (1989-1997) in a drug abuse treatment clinic in northern Thailand where HIV is
      epidemic. DESIGN: Retrospective cohort study. METHODS: Nine-years (1989-1997) of
      data (excluding names) from the logbook of drug abusers seeking treatments in Mae
      Chan Hospital in Chiangrai Thailand, were transcribed and double-entered into
      separate computer files which were later validated against each other. For each
      patient, the dates of the first HIV negative, the last HIV negative, and the
      first HIV positive were determined. A retrospective cohort of drug users who were
      initially HIV-negative and treated for more than once was constructed. HIV
      seroconversion was assumed to follow a uniform distribution between the last
      negative and the first positive HIV tests. The incidence rates and their 95%
      confidence intervals (CI) were calculated. RESULTS: Of the 378 repeat patients,
      16 (4.2%) HIV seroconverted. This is equivalent to 5.11 per 100 person-years of
      observation (PYO) (95% CI = 3.13-8.35). The incidence remained relatively stable
      over the study period while the prevalence was on the decline. The younger, Thai
      lowlanders, drug injectors had higher incidence rates than the older, ethnic
      minorities and drug smokers, respectively. CONCLUSION: Prevalence can give
      illusional results. It is necessary to know baseline HIV incidence to monitor and
      evaluate an HIV intervention program.

PMID- 10337086
TI  - Spray-dried bovine blood: an effective laboratory diet for Ctenocephalides felis
      felis (Siphonaptera: Pulicidae).
AB  - Commercially available spray-dried protein sources were evaluated as replacement
      laboratory cat flea, Ctenocephalides felis felis (Bouche), larval diets for
      slaughterhouse-collected heat-dried blood. Percentage of adult emergence of fleas
      reared on adult flea feces (87.7%) and spray-dried bovine blood (79%) did not
      significantly differ, and yeast supplementation did not significantly increase
      adult emergence for spray-dried diets. However, yeast supplementation of heat
      dried blood increased percentage adult emergence from 0 to 41.7%. Spray-dried
      bovine blood was found to be a satisfactory laboratory diet for cat flea larvae.

PMID- 10337085
TI  - Health consciousness of young people in relation to their personality.
AB  - Personality of targeted individuals can be assumed to influence behavior
      modification by health education. In this study the influence of personality on
      health consciousness was analyzed by a questionnaire for lifestyle, health
      consciousness, and the NEO-FFI personality test. Subjects were 942 new students
      in the Tokyo University of Agriculture who were surveyed in April, 1998.
      Separately performed health examination data were used to verify reliability of
      answers to the questionnaire. Among students, 83.2% of males and 90.4% of females
      felt themselves to be healthy, and more than 80% students desired to improve
      their health more. The rate of having no physical complaints, however, was only
      31.7% in males and 20.4% in females. Distribution of NEO-FFI scores of
      neuroticism (N), extraversion (E), openness (O), agreeableness (A), and
      conscientiousness (C) corresponded well between males and females, except for
      significantly higher scores of O and A in females. Odds ratios (ORs) between high
      and low tertial points of NEO-FFI score for health consciousness were
      significantly elevated in the high scoring groups of E and C (OR = 6.26, 95% CI =
      1.46-26.82, and OR = 6.04, 95% CI = 1.42-25.71, respectively) in males. On the
      contrary, high N and O groups had low health consciousness. Smoking habit was
      associated with high E scores (OR = 2.24, 95% CI = 1.13-4.43). Dietary habits,
      regular eating time, and avoidance of salty foods were associated with high C
      scores in both males and females. The OR of regular eating time was 2.66 (95% CI
      = 1.42-1.98), and 2.20 (95% CI = 1.31-3.71) for males and females, respectively.
      The OR of avoidance of salty foods were 2.09 (95% CI = 1.11-3.91), 1.87 (95% CI =
      1.11-3.16) for males and females, respectively. Significant associations between
      lifestyle and personality require further study for risk association analysis and
      for relationship to interventive practices for prevention of lifestyle associated
      diseases.

PMID- 10337087
TI  - Molecular phylogeny of Chrysomya albiceps and C. rufifacies (Diptera:
      Calliphoridae).
AB  - Mitochondrial DNA was used to infer the phylogeny and genetic divergences of
      Chrysomya albiceps (Wiedemann) and C. rufifacies (Maquart) specimens from widely
      separated localities in the Old and New World. Analyses based on a 2.3-kb region
      including the genes for cytochrome oxidase subunits I and II indicated that the 2
      species were separate monophyletic lineages that have been separated for > 1
      million years. Analysis of DNA, in the form of either sequence or restriction
      fragment-length polymorphism (RFLP) data, will permit the identification of
      problematic specimens.

PMID- 10337088
TI  - Severe reaction in domestic animals following the bite of Ixodes muris (Acari:
      Ixodidae).
AB  - Free tick identification has been offered by our laboratory since 1989, during
      which time > 8,000 specimens have been submitted. We have noted that the bite of
      1 of the less frequently identified ticks, Ixodes muris Bishopp & Smith, may be
      associated with a severe reaction in domestic animals characterized by extreme
      pain and swelling at the site and, with more complete engorgement, lethargy,
      anorexia, and high fever. These symptoms may be confused with other serious
      illness if the tick is not found. This reaction has not been seen following the
      bite of other species of ixodid ticks in Maine. Here we report 43 such cases,
      most involving dogs and cats from which ticks were removed by veterinarians and
      submitted to our laboratory for identification. Although I. muris was initially
      widespread in the United States and eastern Canada, its current range is unclear.
      In view of the potential for severe reaction to the bite of I. muris, the current
      distribution of the tick needs better definition, as does the mechanism of this
      response in animals that are unnatural hosts.

PMID- 10337089
TI  - Importance of Triatoma pallidipennis (Hemiptera: Reduviidae) as a vector of
      Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae) in the state of Morelos,
      Mexico, and possible ecotopes.
AB  - We performed a transversal-type epidemiological study in the state of Morelos,
      Mexico, to determine the presence of triatomines, their ecotopes, and importance
      in transmission of Trypanosoma cruzi Chagas. Sampling sites included domestic,
      peridomestic, and wild areas with collection based on the person per hour
      technique. We determined the entomological indices related to infestation,
      density, overcrowding, colonization, infection, and dispersion, which were used
      to calculate transmission risk. During the study, observations were made on the
      predominant building material, presence of cracks and illumination as factors
      fostering colonization. The most important results were related to infection
      indices, which were higher for domestic type triatomines (29%), whereas it was 4%
      for peridomestic sites, and 20% for sylvatic areas. The actual risk of human
      contact with the vector was of 0.51%, and the predominating ecotopes were stone
      heaps.

PMID- 10337090
TI  - Three species of blowfly (Diptera: Calliphoridae) collected from a human
      stillborn infant in the Rocky Mountains of Colorado.
AB  - In July of 1997, the remains of a human stillborn infant were found at an
      elevation of 2,835 m in Summit County, CO. Larvae recovered from the infant were
      reared to adulthood and identified as Calliphora terraenovae (Macquart),
      Protophormia terraenovae (Robineau-Desvoidy), and Phormia regina (Meigen). These
      represent new county records for high elevation species in Colorado.

PMID- 10337091
TI  - Responses of three species of adult ticks (Acari: Ixodidae) to chemicals in the
      coats of principal and minor hosts.
AB  - In laboratory bioassays, host-seeking adult blacklegged ticks, Ixodes scapularis
      Say, lone star ticks, Amblyomma americanum (L.), and American dog ticks,
      Dermacentor variabilis (Say), were exposed to substances from the pelage of dogs
      and white-tailed deer, Odocoileus virginianus (Zimmermann). Male A. americanum
      exhibited an arrestant response to all samples of deer tarsal gland substances
      tested, whereas female A. americanum, female I. scapularis, and male and female
      D. variabilis responded to samples from certain deer and not others. Female I.
      scapularis, D. variabilis, and A. americanum of both sexes also showed an
      arrestant response to substances rubbed from the dorsal surface of dogs' ears.
      These findings suggest that, although these 3 species of ticks are associated
      with certain host species as adults (A. americanum and I. scapularis with white
      tailed deer, D. variabilis with dogs), their repertoires of host-finding
      behaviors are broad, and use of minor host species may not be purely accidental.

PMID- 10337092
TI  - Abundance of Ixodes scapularis (Acari: Ixodidae) larvae and nymphs in relation to
      host density and habitat on Long Point, Ontario.
AB  - Ixodes scapularis Say populations were evaluated within 4 habitats on Long Point,
      Ontario, from 1990 to 1992 to ascertain whether differences in density of mouse
      populations within and among habitats were correlated with that of immature I.
      scapularis populations. I. scapularis immatures were rarely collected by dragging
      within the cottonwood dune habitat. Significantly more larvae (P < or = 0.05)
      were collected by drag sampling within the maple forest habitat than in the oak
      savannah or white pine habitats for the 1989, 1990, and 1991 cohorts, whereas the
      size of the 1992 larval cohort did not differ significantly among these habitats.
      Significantly more nymphs were collected by dragging within the maple forest than
      in the other 2 habitats for all 4 cohorts. Nymphs from the 1989 and 1990 cohort
      were more abundant within the oak savannah than the white pine habitat, whereas
      the 1991 and 1992 cohorts were similar. With few exceptions, I. scapularis
      immatures were most prevalent on white-footed mice, Peromyscus leucopus
      (Rafinesque), captured within the maple forest > oak savannah > white pine >
      cottonwood dune, although differences were not significant in all years and in
      all habitats. The number of mice captured within the 4 habitats was not
      correlated with the number of I. scapularis larvae or nymphs infesting them.
      Likewise, the minimum number of mice alive was not significantly correlated with
      conversion indices of larvae to nymphs or nymphs to adults. Lack of association
      between mouse availability and relative size of subsequent cohorts of host
      seeking ticks suggests that factors other than the size of the mouse populations
      were responsible for the observed differences in tick abundance among habitats.

PMID- 10337093
TI  - Microclimate and habitat in relation to Ixodes scapularis (Acari: Ixodidae)
      populations on Long Point, Ontario, Canada.
AB  - The impact of microclimate and density of hosts for adult ticks on the density of
      Ixodes scapularis Say was evaluated within 4 habitats on Long Point, Ontario,
      from 1989-1992. During the period from May to September, mean weekly vapor
      pressure deficits were greater within the oak savannah and cottonwood dune
      habitats than at the maple forest and white pine habitats, which were similar.
      Vapor pressure deficit was likely the major factor affecting the survivorship of
      eggs and immature tricks in these habitats. Based on drag sampling, I. scapularis
      adults demonstrated peak activity in April and October of each year. The mean
      number of I. scapularis adults collected by dragging during the fall or in the
      spring did not differ significantly within each habitat. The mean number of
      adults collected also did not differ among tick cohorts within each habitat;
      however, significantly more adults were collected within the maple forest than in
      the white pine habitat. The mean number of I. scapularis adults per white-tailed
      deer, Odocoileus virginianus (Zimmerman), increased from 1989 to 1991 and then
      decreased in 1992. Significantly more adult I. scapularis infested deer were
      observed in 1990 than in 1989. Removal of deer in 1989 and 1990 resulted in a
      calculated decrease of > 100,000 fed female ticks. Although seasonal variation in
      microclimate within habitats was closely linked with tick survival and partly
      explains the differences in abundance of I. scapularis among habitats on Long
      Point, habitat utilization by deer was also a primary factor governing the local
      abundance of I. scapularis populations.

PMID- 10337094
TI  - Patterns of infestation by adult Dermacentor variabilis (Acari: Ixodidae) in a
      mark-recapture study of raccoons (Mammalia: Carnivora) and Virginia opossums
      (Mammalia: Didelphimorphia) in Tennessee.
AB  - A mark-recapture study of raccoons (Procyon lotor L.) and Virginia opossums
      (Didelphis virginiana Kerr) was conducted from February 1991 through April 1994
      to determine host interactions with adult Dermacentor variabilis Say. We captured
      1,293 raccoons and Virginia opossums during the 3-yr study (140 individual
      raccoons and 160 individual Virginia opossums) with 1,895 adult D. variabilis
      collected. Raccoons had a significantly higher mean intensity and higher
      prevalence of adult ticks than Virginia opossums (Mann-Whitney Z = 6.15, chi 2 =
      51.9, P < 0.001). Mean intensity follows Margolis et al. (1982) as being the mean
      number of parasite species per infected host. Prevalence follows Margolis et al.
      (1982) as being the number of individuals of the host species infected with a
      parasite species divided by the number of hosts examined. The time required for a
      higher prevalence and mean intensity of ticks to occur on raccoons than Virginia
      opossums was < 7 d. No significant differences occurred between the mean
      intensity or prevalence of D. variabilis between sexes or among age classes of
      raccoons. Significant differences in prevalence and mean intensity of ticks
      occurred between sexes and among age classes of Virginia opposums. Infestation
      increased by 0.64 ticks per day on Virginia opossums and 1.77/d on raccoons
      during the first 7 d. The base host finding rate (ticks per host per day) of
      adult D. variabilis on Virginia opossums was 0.064 and 0.053 on raccoons. Tick
      interactions with hosts are quantified and may reflect behavioral differences
      between sexes and among age groups intraspecifically, and host preferences of
      adult D. variabilis interspecifically.

PMID- 10337095
TI  - Sugar feeding by Culicoides mississippiensis (Diptera: Ceratopogonidae) on the
      yaupon holly, Ilex vomitoria.
AB  - Adult Culicoides mississippiensis Hoffman were collected from 5 flowering yaupon
      holly plants at sunrise, late morning, early afternoon, and sunset from 5
      flowering yaupon holly plants during the entire flowering season (16 March-15
      April 1995). Individual insects were tested for fructose by using the cold
      anthrone test. Prevalence of fructose in C. mississippiensis was 55.6% (427 of
      768), with positivity for gravid females greater than for males. Fructose
      positive rates decreased in gravid females from morning to evening, whereas male
      rates were constant until evening, when they decreased. Both sugar feeding by
      gravid females and host-seeking by parous females were highest at sunset,
      followed by sunrise.

PMID- 10337096
TI  - Survival of starved Aedes aegypti (Diptera: Culicidae) in Puerto Rico and
      Thailand.
AB  - Survival of adult Aedes aegypti (L.) was studied in Thailand (1995) and Puerto
      Rico (1996) during periods of high and low dengue virus transmission. Resting
      males and females were collected inside houses by aspiration. Females were
      separated into different cages by their degree of engorgement and ovarian
      development. Teneral adults were obtained from pupae collected from natural
      breeding sites. All mosquitoes were given access to water, held at ambient
      temperature in the shade, and their survival monitored daily. We calculated
      median survival for each stage to estimate when mosquitoes had to feed again or
      die. No differences in survival between seasons were observed in Thailand. In
      Puerto Rico, except for wild males, survival was longer in the cool/dry season
      than in the hot/rainy season, indicating that mosquitoes may need to feed more
      frequently during the high than low dengue transmission season. During both study
      periods and at both sites, blood-engorged females survived as long or longer than
      mosquitoes in other gonotrophic or developmental stages. Except in Puerto Rico
      during the cool season, when females had a relatively high probability of
      surviving 3-4 d without feeding, females needed to feed approximately every other
      day to avoid death caused by starvation. Our results indicate that in some
      regions, there are seasonal differences in the length of time female Ae. aegypti
      can survive without feeding, females with a blood meal can survive for a longer
      time than those without blood, and teneral males can live longer without food
      than teneral females.

PMID- 10337097
TI  - Sandflies (Diptera: Psychodidae) associated with epidemic cutaneous leishmaniasis
      in Sanliurfa, Turkey.
AB  - As part of a project to study the possible impact of environmental change on
      health in southeastern Turkey, we evaluated sandfly species diversity, abundance,
      and habitat associations in an urban area where cutaneous leishmaniasis was
      undergoing epidemic re-emergence. Houses and caves in and around the city of
      Sanliurfa, Turkey, were sampled using mechanical aspirators, sticky papers, and
      CDC light traps. Of 1,649 sandflies captured, including 6 Phlebotomus and 1
      Sergentomyia species, nearly all were P. papatasi (Scopoli) (967) or P. sergenti
      Parrot (674). Sandflies were active during June-September (hot dry season), but
      not during January (cool rainy season). Resting phlebotomines were abundant
      inside houses. Houses sampled in 3 neighborhoods with a high cutaneous
      leishmaniasis incidence (9-65 cases per 1,000 population) had > 10 times more
      flies than at a comparison site where few cases (0.2 per 1,000) have been
      reported. Results indicated that P. sergenti or P. papatasi were the probable
      vectors of cutaneous leishmaniasis during this outbreak and that control of these
      sandflies may eliminate transmission.

PMID- 10337098
TI  - Taxonomic study of species formerly identified as Anopheles mediopunctatus and
      resurrection of An. costai (Diptera: Culicidae).
AB  - Anopheles (Anopheles) mediopunctatus (Lutz) and Anopheles (Anopheles) costai
      Fonseca & Ramos are redescribed with illustrations of the male genitalia and
      larval and pupal stages. The pupa of An. costai has paired lateral projections on
      the wing case, a feature also known in members of the Umbrosus Group from
      Southeast Asia. An. costai is resurrected from the synonymy of An. mediopunctatus
      based on features of the male genitalia, larva, and pupa, and An. bonneorum
      Fonseca & Ramos (emended from bonnei) is considered to be a new synonym of An.
      costai. It is noted that the author of An. mediopunctatus is Lutz, not Theobald,
      as cited in most literature references.

PMID- 10337099
TI  - Effect of diet on biting, oviposition, and survival of Aedes aegypti (Diptera:
      Culicidae).
AB  - The effect of adult diet on host biting, sugar probing and water probing
      patterns, oviposition behavior, and survival of Aedes aegypti (L.) from Charters
      Towers, Australia, were tested in the laboratory. The 7 diets were as follows:
      (1) starvation, (2) water, (3) 10% sugar, (4) blood, (5) blood with water
      supplement, (6) blood with 10% sugar supplement, and (7) blood with 3% sugar
      supplement. Biting, probing, oviposition, and survival observations were made
      every 6 h (0600-0800 hours, 1200-1400 hours, 1800-2000 hours, 2400-0200 hours).
      Biting frequency on the blood with 3% sugar diet (0.26 feeds per mosquito per 6
      h) and the blood with 10% sugar diet (0.23 feeds per mosquito per 6 h) was
      significantly less than on blood (0.51 feeds per mosquito per 6 h) and 10% sugar
      (0.40 feeds per mosquito per 6 h) alone. Biting frequency was not significantly
      different between blood with water (0.47 feeds per mosquito per 6 h) and blood
      alone (0.51 feeds per mosquito per 6 h). Biting and oviposition occurred
      throughout the day, peaking between 1800 and 2000 hours and between 2000 and 2400
      hours, respectively. Biting frequency with a 3% sugar supplement decreased after
      the 1st oviposition cycle on day 6 compared with unsupplemented biting. The
      presence of sugar delayed or inhibited oviposition. Females with access to blood
      with water bit and oviposited concurrently on days 4-6, 8-9, and 11, indicating a
      3-d gonotrophic cycle. Survival on blood alone was not significantly lower than
      survival on sugar and water supplemented diets. Behavior of the Charters Towers
      strain proved to be significantly influenced by diet, and biting occurred
      opportunistically without regard for previously observed crepuscular or diurnal
      rhythms. The biting frequencies observed were the highest yet recorded for this
      species, which indicates that the vectorial capacity of the Australian Ae.
      aegypti may be underestimated severely.

PMID- 10337100
TI  - Review of the palearctic desert biting midges Culicoides langeroni group, with a
      description of a new species (Diptera: Ceratopogonidae).
AB  - The biting midges of the Culicoides langeroni group, which consists of 4 species:
      C. langeroni Kieffer, C. judaeae Macfie, C. pseudolangeroni Kremer, Chaker &
      Delecolle, and 1 new species, C. molotovae, are reviewed.

PMID- 10337101
TI  - Role of habitat components on the dynamics of Aedes albopictus (Diptera:
      Culicidae) from New Orleans.
AB  - Monthly sampling of tire pile populations of Aedes albopictus (Skuse) in Orleans
      Parish, New Orleans, LA, was done in 1995 to determine prevalence of
      ascogregarine parasites and changes in wing length. Prevalence of Ascogregarina
      taiwanensis (Lien & Levine) infection was 100% in midsummer and decreased in the
      fall and spring (60-70%). Wing lengths were longest in the spring and fall and
      shortest in midsummer. We evaluated the effect of A. taiwanensis infections under
      high and deficient levels of leaf litter nutrients on mortality, development
      time, wing length, and reproductive potential of a New Orleans strain of Ae.
      albopictus. Parasitism and deficient nutrients caused a 35% increase in the rate
      of larval mortality and significantly extended the development time of females.
      Parasitized adults were 5% smaller and produced 23% fewer eggs than unparasitized
      siblings. In addition, abnormal Malpighian tubule morphology and melanization of
      ascogregarines were seen in adults from nutrient-deficient microcosms. We
      conclude that ascogregarine infections affect the dynamics of Ae. albopictus by
      increasing the mortality of immature stages when nutrients supplies are scarce,
      and by decreasing the reproductive capacity of females under high nutrient
      conditions.

PMID- 10337102
TI  - Dermacentor hunteri (Acari: Ixodidae): an experimental vector of Anaplasma
      marginale and A. ovis (Rickettsiales: Anaplasmataceae) to calves and sheep.
AB  - The experimental vector competence of laboratory-reared Dermacentor hunteri
      Bishopp for Anaplasma marginale Theiler and Anaplasma ovis Lestoquard was
      evaluated by delayed transfer of male ticks from infected to susceptible Holstein
      calves and from infected to susceptible domestic sheep, respectively. After
      feeding for 4 or 5 d on rickettsemic acquisition hosts, the ticks were held off
      the host at 26 degrees C, approximately 93% RH, and a photoperiod of 14:10 (L:D)
      h for 7 or 8 d, then test fed for 5 or 7 d. Additionally, ticks test-fed for 5 d
      on 2 susceptible calves were removed, held off the host for 7 d, and test-fed for
      5 d on a 3rd susceptible calf to test the tick's ability to transmit A. marginale
      by delayed serial transfer. Tick transmission of A. marginale to 3 test calves
      and A. ovis to 3 test sheep was demonstrated by blood smear and indirect
      immunofluorescence serology. These data indicate that males of D. hunteri, a tick
      commonly found on desert bighorn, Ovis canadensis Shaw, in the southwestern
      United States and northern Mexico, may be competent natural vectors of these
      organisms present in desert bighorn populations.

PMID- 10337104
TI  - Life history of Ixodes (Ixodes) jellisoni (Acari: Ixodidae) and its vector
      competence for Borrelia burgdorferi sensu lato.
AB  - Ixodes (Ixodes) jellisoni Cooley & Kohls, a nonhuman biting and little known
      tick, is one of 4 members of the I. ricinus complex in the United States. A
      localized population of I. jellisoni inhabiting a grassland biotope in Mendocino
      County, CA, was studied from 1993 to 1997. Rodent trapping in all seasons
      revealed that the only host of both immature and adult I. jellisoni was the
      heteromyid rodent Dipodomys californicus Merriam. Field investigations suggested
      that I. jellisoni is nidicolous in habit, and laboratory findings demonstrated
      that it reproduces parthenogenetically. Known parthenogenetic females (n = 4)
      produced an average of 530 eggs of which 74% hatched, which was comparable to the
      fecundity and fertility of wild-caught females (n = 8). After the transstadial
      molt, 57 F1 or F2 nymphs derived from 2 wild-caught or 4 laboratory-reared,
      unmated females produced only females. Ixodes jellisoni males were not found on
      112 wild-caught D. californicus individuals that were captured an average of 2
      times. Collectively, these findings suggest that I. jellisoni may be obligatorily
      parthenogenetic. Borrelial isolates were obtained from 85% of 58 D. californicus
      and 33% of 21 I. jellisoni females removed from this rodent. None of the 7
      infected female ticks passed borreliae ovarially to its F1 larval progeny. Eight
      D. californicus and 5 I. jellisoni-derived isolates that were genetically
      characterized belonged to 2 restriction pattern groups of Borrelia burgdorferi
      s.l. Neither restriction pattern group has been assigned to a particular
      genospecies yet. After placement on naturally infected D. californicus,
      noninfected larval ticks acquired and transstadially passed spirochetes as
      efficiently as (group 1 borreliae) or 6 times more efficiently (group 2
      borreliae) than Ixodes pacificus Cooley & Kohls. As few as 1-4 infected I.
      jellisoni nymphs were capable of transmitting group 1 or group 2 borreliae to
      naive D. californicus. We conclude that I. jellisoni is a competent vector of
      both restriction fragment groups when D. californicus is used as the animal
      model.

PMID- 10337103
TI  - Evaluation of injectable abamectin to control natural infestations of Haematobia
      irritans (Diptera: Muscidae) in cattle.
AB  - The effect of 200 micrograms/kg of body weight of injectable 1% abamectin to
      control Hematobia irritans (L.) was evaluated in heifers treated every 45 or 63 d
      versus control heifers. Fly numbers were estimated every 7 d with additional
      counts on days 1, 4, and 10 after treatment. Samples of feces were obtained up to
      28 d after treatment from treated and control heifers to culture H. irritans in
      the laboratory. The H. irritans population reduction for 14 d after treatment
      ranged from 51% (3rd treatment of heifers treated every 45 d) to > 73% in the 1st
      treatments of both groups of heifers and the 2nd treatment of the group treated
      every 63 d. Medication every 45 d did not provide a better control than treatment
      every 63 d. The abamectin arrested the immature stages for 7 d after the 1st
      treatment; this period increased to 28 d after the 3rd treatment but its effect
      on heifer infestation was low, probably because of fly immigration. Abamectin may
      help maintain H. irritans populations below the threshold of economic damage.

PMID- 10337105
TI  - Modulation of murine lymphocyte responsiveness by the saliva of Rhodnius prolixus
      (Hemiptera: Reduviidae).
AB  - Incorporation of 3H-thymidine by splenic lymphocytes was studied in CBA mice that
      were bitten by the triatomine bug Rhodnius prolixus (Stal) 14, 7, 4, and 2 d
      before lymphocyte isolation, respectively. In bitten mice, both spontaneous and
      mitogen-induced proliferative responses were reduced. The most pronounced effect
      was observed 4 d after exposure when lymphocytes were significantly suppressed in
      proliferative response to the mitogens concanavalin A, phytohemagglutinin, and
      bacterial lipopolysaccharide. The maximum inhibition caused an 85% reduction of
      proliferation and was observed in phytohemagglutinin-stimulated cell cultures.
      The immunosuppressive effect was caused neither by stress nor by an nonspecific
      cytotoxic effect of R. prolixus saliva. The described immunosuppressive activity
      of saliva could aid in successful repeated feedings of R. prolixus on the same
      host and possibly could play a role in transmission of Trypanosoma cruzi.

PMID- 10337106
TI  - Anopheles (Anopheles) forattinii: a new species in Series Arribalzagia (Diptera:
      Culicidae).
AB  - Anopheles (Anopheles) forattinii new species, a member of the Series
      Arribalzagia, is described with illustrations of the larval and pupal stages, and
      male and female genitalia. It is contrasted with 2 similar species, An.
      (Anopheles) costai Fonseca & Ramos and An. (Anopheles) mediopunctatus (Lutz).
      This species, and An. costai, occur over much of South America where both have
      been misidentified as An. mediopunctatus, a species presently only known from
      southeastern Brazil.

PMID- 10337107
TI  - Juvenile hormone biosynthesis in diapausing and nondiapausing Culex pipiens
      (Diptera: Culicidae).
AB  - The synthesis of juvenile hormone in vitro by diapausing and nondiapausing Culex
      pipiens L. was measured by radiochemical assay. Paired corpora allata from
      diapausing females synthesized < 18 fmols of juvenile hormone per hour during the
      first 3 wk after emergence. In contrast, juvenile hormone synthesis in
      nondiapausing females increased rapidly reaching a peak of 87.3 +/- 21 (mean +/-
      SE) fmol/h 3 d after emergence. By 3 wk, juvenile hormone synthesis had decreased
      in both groups of females, but corpora allata from nondiapausing mosquitoes still
      were 3 times more active than those from diapausing mosquitoes. By 16 wk after
      diapause induction, females maintained at 8:16 (L:D) h and 15 degrees C produced
      levels of juvenile hormone similar to 3-wk-old nondiapausing females. When
      females were held in diapause conditions for up to 22 wk, follicles gradually
      grew longer and by 15 wk were significantly longer than in the previous 14 wk.
      Blood feeding also increased in older females, indicating that over time,
      juvenile hormone synthesis gradually stimulated blood-feeding behavior. When 21-d
      old diapausing mosquitoes were moved to a long-day photoperiod of 16:8 (L:D) h
      and 26 degrees C, juvenile hormone synthesis increased rapidly and peaked 5 d
      later while the ovarian follicles grew to the resting stage. Allatectomy of young
      diapausing females prevented follicle growth and blood feeding when diapause was
      terminated prematurely, demonstrating that the physiological events associated
      with diapause termination were associated with juvenile hormone biosynthesis.

PMID- 10337108
TI  - Attachment sites of four tick species (Acari: Ixodidae) parasitizing humans in
      Georgia and South Carolina.
AB  - From June 1995 through January 1998, 677 tick specimens were submitted by 521
      humans from 14 states. Analysis was limited to specimens originating in Georgia
      and South Carolina, representing 87.3% of total submissions. Attachment sites
      were specified in 367 specimens (62.3%). The American dog tick, Dermacentor
      variabilis (Say), a vector of the agent of Rocky Mountain spotted fever, favored
      the head and neck in 59% of attached specimens. The lone star tick, Amblyomma
      americanum (L.), a strongly implicated vector of the agent of human monocytic
      ehrlichiosis, favored the lower extremities, buttocks, and groin in 54% of
      specimens. The blacklegged tick, Ixodes scapularis Say, the main eastern vector
      of the Lyme disease spirochete, had widely distributed attachment sites with no
      apparent site preference. The Gulf Coast tick, A. maculatum Koch, parasitized
      humans in too few instances for analysis. In the southeastern United States,
      prevention of tick bites and tickborne illnesses such as Rocky Mountain spotted
      fever, ehrlichiosis, and Lyme disease may be enhanced by personal practices and
      public health measures based on knowledge of preferred attachment sites of
      potentially infectious tick species.

PMID- 10337109
TI  - Palp-splaying behavior and a specific mouthpart site associated with active water
      vapor uptake in Amblyomma americanum (Acari: Ixodidae).
AB  - Ticks actively absorb water vapor from unsaturated air via their mouthparts. A
      wax technique was used to cover select areas of the mouthparts of the lone star
      tick, Amblyomma americanum (L.), to examine whether a specific site is involved
      in uptake. Covering dorsal, ventral, and distal regions failed to inhibit uptake,
      whereas wax applied to the proximal region, specifically the hypostome-cheliceral
      junction, blocked water absorption. A novel occurrence of a palp-splaying
      behavior was observed during hydrating conditions (93% RH), while ticks were
      motionless, compared with those held at desiccating conditions (63% RH), which
      were more active and the palps were not splayed.

PMID- 10337110
TI  - Enzymatic analyses of house dust mite extracts from Dermatophagoides
      pteronyssinus and Dermatophagoides farinae (Acari: Pyroglyphidae) during
      different phases of culture growth.
AB  - The majority of clinically important allergens of Dermatophagoides pteronyssinus
      (Trouessart, 1897) and Dermatophagoides farinae Hughes, 1961 present enzymatic
      activity. The allergenic enzymes described include cysteine proteases in group 1
      allergens, trypsins in group 3, amylases in group 4, and chymotrypsins in group
      6. Apart from these, other possibly allergenic enzymes also have been identified.
      Therefore, enzymatic profiles were studied during the 3 growth periods of the
      mite population--latency phase, exponential growth phase, and death phase. The
      activity of 19 different enzymes was analyzed by means of the Api Zym system, a
      method that has been used to study both mite extracts and other allergenic
      materials. Our study has demonstrated that the extracts contain a large variety
      of enzymes. It has been observed that enzymatic activity is caused exclusively by
      mites because the control carried out on the culture medium was negative for all
      the enzymes studied. Generally, the levels of diverse enzymatic activity
      increased with the growth of the culture, and decreased later, in both species.
      However, proteases are the exception; they maintain a high level of activity
      during the death phase of the cultured mites. The ratio between trypsin and
      chymotrypsin activity can be used as an excellent tool for quality control
      parameters during obtention of allergenic mite extracts.

PMID- 10337111
TI  - Influence of deer abundance on the abundance of questing adult Ixodes scapularis
      (Acari: Ixodidae).
AB  - Nymphal and adult Ixodes scapularis Say were sampled by flagging at 2 sites on a
      barrier island, Fire Island, NY, and at 2 sites on the nearby mainland. Nymphal
      densities did not differ consistently between island and mainland sites, but
      adult densities were consistently lower on the island. We tested whether lower
      adult densities on the island resulted from greater nymphal mortality on the
      island than the mainland, or whether adult ticks on the island were poorly
      sampled by flagging because they had attached abundantly to deer, which were
      common on Fire Island. Differential nymphal mortality on islands versus mainland
      did not explain this difference in adult densities because survival of flat and
      engorged nymphs in enclosures was the same at island and mainland sites. Ticks
      were infected by parasitic wasps on the island and not the mainland, but the
      infection rate (4.3%) was too low to explain the difference in adult tick
      densities. In contrast, exclusion of deer by game fencing on Fire Island resulted
      in markedly increased numbers of adult ticks in flagging samples inside compared
      with samples taken outside the exclosures. Therefore, the scarcity of adult ticks
      in flagging samples on Fire Island resulted, at least in part, from the ticks
      being unavailable to flagging samples because they were on deer hosts.
      Differences in the densities of flagged ticks inside and outside the exclosures
      were used to estimate the percentage of questing adults on Fire Island that found
      deer hosts, excluding those that attached to other host species. Approximately
      56% of these questing adult ticks found deer hosts in 1995 and 50% found deer
      hosts in 1996. Therefore, in areas where vertebrate hosts are highly abundant,
      large proportions of the questing tick population can find hosts. Moreover,
      comparisons of tick densities at different sites by flagging can be potentially
      biased by differences in host densities among sites.

PMID- 10337112
TI  - Rearing stable fly larvae (Diptera: Muscidae) on an egg yolk medium.
AB  - The growth and survival of Stomoxys calcitrans (L.) larvae on egg yolk medium
      inoculated with bacteria isolated from a colony of stable flies was evaluated.
      Five species of bacteria--Acinetobacter sp., Aeromonas sp., Empedobacter breve
      (Holmes & Owen), Flavobacterium odoratum Stutzer, and Serratia marcescens Bizio-
      were identified according to fatty acid profiles using a microbial identification
      system. Larvae failed to develop on uninoculated plates, confirming that bacteria
      are required to complete development. Larvae also failed to complete development
      on plates inoculated with Aeromonas sp. and S. marcescens, and died during the
      1st instar. Larvae completed development on the remaining 3 bacterial species as
      well as on Escherichia coli (Migula). Survival was generally higher when larvae
      were reared on Acinetobacter sp. and F. odoratum compared with E. coli and E.
      breve. Egg density did not influence larval survival, although the variability in
      survival was lowest using 20 and 40 eggs per plate. Larval survival in mixed
      cultures of Acinetobacter and Flavobacterium averaged 22.7% lower than survival
      in the pure cultures, and averaged 21.6% higher in mixed cultures of Empedobacter
      and Flavobacterium compared with pure cultures. Larval survival in mixed cultures
      did not differ significantly from mean survival in pure cultures for combinations
      of Acinetobacter and E. coli, Acinetobacter and Empedobacter, E. coli and
      Empedobacter, and E. coli and Flavobacterium. Larval developmental time was
      faster on all mixed bacterial cultures compared with developmental time on pure
      bacterial cultures. Optimal sample sizes and egg numbers are presented for
      detecting specified differences in larval survival. This rearing procedure will
      be useful for studying insect-microbe interactions and evaluating mortality using
      bacterial agents.

PMID- 10337113
TI  - Resistance to deltamethrin in Culex pipiens pallens (Diptera: Culicidae) from
      Zhejiang, China.
AB  - Resistance to deltamethrin, a pyrethroid insecticide, was found in 7 Culex
      pipiens pallens L. populations collected in Zhejiang (southeast China). Larval
      populations exhibited resistance ratios of 5.9-24.73 at LC50 and of 95.8-294.5 at
      LC95. Mortality ratios between field-collected adults and susceptible laboratory
      adults exposed to the discriminating dosage (0.01%/20 min) were 44.7-87.3.
      Resistance levels varied among populations as follows: Wenzhou > Ningbo >
      Hangzhou > Zhoushan > Jiaxing > Jinhua > Taizhou. Heavy use of pyrethroid
      insecticides for controlling mosquitoes in some areas has increased pyrethroid
      resistance in their regional populations. After selecting larvae from each
      population with deltamethrin for 12-15 generations, the resistance ratio
      increased by 103.3-342.5 at LC50 and by 79.7-203.1 at LC95. These results
      indicated that a large-scale Cx. p. pallens control with pyrethroid insecticides
      would induce a further increase of pyrethroid resistance in Zhejiang.

PMID- 10337114
TI  - Intraguild predation among larval treehole mosquitoes, Aedes albopictus, Ae.
      aegypti, and Ae. triseriatus (Diptera: Culicidae), in laboratory microcosms.
AB  - We compared the tendency for 4th-instar larvae to prey on newly hatched larvae,
      and the vulnerability of those 1st instars to such predation for Aedes
      triseriatus (Say), Ae. aegypti (L.), and Ae. albopictus (Skuse), all container
      breeding mosquitoes. The latter 2 species were introduced to North America and
      are now sympatric with Ae. triseriatus, a native species in eastern North
      America. The experiment also enabled the assessment of species-specific
      influences of food supplements and spatial heterogeneity on predatory behavior.
      Ae. triseriatus was substantially more predatory and less susceptible to attack
      than the other 2 species. These differences were amplified in food-deprived and
      spatially simple conditions, indicating that Ae. triseriatus predatory behavior
      may have important retarding effects on the colonization of occupied treehole
      habitats by Ae. albopictus. Ae. aegypti and Ae. albopictus were similar in
      imposing little (Ae. aegypti) or almost no (Ae. albopictus) predation on 1st
      instars and in being susceptible to predation by Ae. triseriatus. The general
      lack of species-specific differences between Ae. aegypti and Ae. albopictus
      indicates that interspecific predation is not a likely explanation for the rapid
      displacement of Ae. aegypti by Ae. albopictus in domestic containers in the
      southeastern United States.

PMID- 10337115
TI  - Genetic structure of Aedes albifasciatus (Diptera: Culicidae) populations in
      central Argentina determined by random amplified polymorphic DNA-polymerase chain
      reaction markers.
AB  - The floodwater mosquito, Aedes albifasciatus (Macquart), is the main vector of
      western equine encephalomyelitis virus in Argentina. Previous studies on the
      genetic structure of this species using allozymes showed low levels of
      polymorphism, absence of subpopulations at distinct habitats, and moderate
      differentiation among localities separated up to 500 km. To examine gene flow
      using other genetic methods, we analyzed random amplified polymorphic DNA
      polymerase chain reaction (RAPD-PCR) polymorphism in 28 presumptive loci of Ae.
      albifasciatus from 6 populations in central Argentina. Allele frequencies were
      estimated assuming that RAPD products segregate as dominants and that genotype
      frequencies at those loci are in Hardy-Weinberg equilibrium. Expected
      heterozygosity ranged between 0.19 and 0.31, approximately 3 times the value
      obtained on the basis of the 16 allozymic loci studied previously. Four of the
      populations formed a single panmictic unit. Allele frequencies in populations
      occupying different phytogeographic regions gave significant FST values at 5
      loci. Effective migration rates among populations estimated from FST ranged from
      2.3 to 9.0. The results support the existence of a north-south cline.

PMID- 10337116
TI  - Genetics and health care.

PMID- 10337117
TI  - Illness narratives: discursive constructions of self in pediatric oncology.
AB  - Narratives from adolescents in treatment for cancer were examined for the variety
      of ways in which self is constructed in discourse. Narratives were elicited by
      the second author (Bearison) from 75 children ranging in age from 3 to 19 years
      and at various stages of treatment for cancer. The present study examined a
      subset of these data. According to discourse theory, narratives are a means of
      constructing and understanding the self, particularly during unsettling life
      events that perturb the self-system. Adolescents who have cancer strive to make
      sense of the threatening and uncertain consequences of treatment, and their
      narratives reflect this struggle and their attempt to resolve it. The present
      study identified three narrative domains of self (biomedical, social, and
      personal) and considered variations among them according to the following
      features: (1) degree of otherness (i.e., to what extent and in what manner are
      other people, family, peers, and medical staff brought into the discourse), (2)
      expression of self as agent versus object, and (3) a series of linguistic markers
      denoting the narrative voice: understatement, exaggeration, reassurance, passive
      voice, and the use of personal and impersonal pronouns. In addition, expressions
      of denial and control were identified as central issues of self in narrative.
      Findings indicated that there were patterns of co-occurrence of discourse
      features that constituted different narrative styles by which participants gave
      voice to their struggle to redefine the self.

PMID- 10337118
TI  - Skin care of the pediatric patient.
AB  - Several factors influence the chronically ill child's susceptibility for skin
      breakdown. Nurses are an integral part of the care team that has the
      responsibility for identification of these factors, as well as pressure ulcer
      prevention and early intervention. An important aspect of this responsibility is
      identification of individuals at risk. This article provides a guide for
      assessment and early intervention for skin breakdown in chronically ill children.
      A care plan and consultation recommendations are included.

PMID- 10337119
TI  - A comparison of the use of tympanic, axillary, and rectal thermometers in
      infants.
AB  - This study examined the relationship between three instruments used in measuring
      tympanic, axillary, and rectal temperatures in infants less than 1 year of age.
      Temperatures were measured by Oto-temp Pedi Q tympanic thermometers, Becton
      Dickinson axillary thermometer, and rectal thermometers. A convenience sample of
      5 infants less than 90 day and 54 greater than 90 days with fever, as well as 34
      infants less than 90 days and 27 infants greater than 90 days without fever were
      studied. Correlations of infants less than 90 days and greater 90 days of age, as
      well as differences between infant temperature with and without fevers as
      variables, were examined. Results indicated a strong statistical relationship
      between Oto-Temp Pedi Q, Becton Dickinson axillary temperatures, and rectal
      temperatures, but not strong enough to base critical clinical decisions. Age and
      presence or absence of fever significantly affected the relationships between
      thermometers.

PMID- 10337120
TI  - A partnership for community-based nursing experience: Head Start/Harper College.
AB  - In an effort to provide a meaningful community-based nursing experience for the
      students of William Rainey Harper College, a project was developed with the
      Community Economic Development Association of Cook County, Illinois to link
      second-year nursing students and clients in a Head Start program. The goals were
      designed to meet the needs of both the students and the Head Start clients. The
      students provided a portion of the health service plan for the Head Start
      families, and at the same time they received a comprehensive community/family
      learning experience. Throughout the second year of the nursing program the
      students followed their assigned family utilizing a unique integration of
      pediatric and psychiatric nursing concepts. The article will outline the project
      from development to completion of the first year of student involvement. It will
      address successes, failures, and changes made in the second year of the program.

PMID- 10337121
TI  - Comparison of Chinese and Caucasian families caregiving to children with cancer
      at home: Part I.
AB  - This 1-year, longitudinal comparative study of Chinese and Caucasian family
      caregiving for a child with cancer is reported in two parts. Part I describes
      data obtained from the initial interviews at diagnosis with Chinese and Caucasian
      families. Interviews revealed that Chinese families use supplemental care
      methods, Chinese families have fewer resources and are more isolated; Caucasian
      families emphasize emotional care; and family emotional coping patterns differed
      between the two groups. Measures of functional status of the child, the impact of
      the child's illness on the family, the symptomatic responses of the parents to
      the child's illness, and patterns of caregiving were also analyzed over the first
      year after diagnosis. There were no statistical differences between ethnic
      groups. General health was lower for the children with cancer than for
      chronically ill children. Part II reports on the results from the two following
      interviews during the first year after diagnosis.

PMID- 10337122
TI  - Common themes and ethnic differences in family caregiving the first year after
      diagnosis of childhood cancer: Part II.
AB  - Chinese immigrant and North American white family caregiving for a child with
      cancer was compared in a 1-year study. This second of a two-part report describes
      interview results after first remission and at 1-year postdiagnosis. (The first
      part reported results of the initial interview and family function, symptom and
      caregiving inventories administered at diagnosis and at first remission). In
      follow-up interviews, the ill child remained the family priority in both groups,
      with sequelae for siblings and parents. All children were physically well cared
      for, with strict adherence to Western medical protocols. Cultural differences and
      immigrant status contributed to lower verbal expression of distress, more
      isolation, and lower attention to emotional distress for the Chinese. Caregiving
      emphases were dietary for the Chinese; emotional for the Caucasians. Differences
      over time in family caregiving and coping were determined by demands of care and
      evolving expertise. Care inclusive routines were established by most families by
      the second interview, in spite of extent of continued difficulties. Emotional
      care demands, concern for needs of siblings, and marital conflict increased over
      time. At 1 year, all families complained of emotional and physical fatigue and
      the need to adapt to a tentative future with their child.

PMID- 10337123
TI  - Every child deserves Bright Futures.
AB  - Bright Futures is a national program dedicated to promoting and improving the
      health of children in the United States. This article gives a brief historical
      perspective of Bright Futures, its mission, goals, available resources, and
      strategies that pediatric nurses can use in a variety of health care settings
      with children and families.

PMID- 10337124
TI  - S.T.E.P.: students transitioning effectively into practice.

PMID- 10337125
TI  - Parenting stress and mothers of young children with chronic illness: a cross
      cultural study.
AB  - This study examined the sources of parenting stress among mothers from Israel,
      Japan, Jordan, and the United States who had a young child with a chronic
      illness. The results indicated mothers from all four countries experienced high
      levels of child-focused and parent-focused stress that indicated a need for
      nursing intervention.

PMID- 10337126
TI  - Patterns of respite use by aging mothers of adults with mental retardation.
AB  - Use of respite services by 275 aging families of adults with mental retardation
      was examined over a 4.5-year period. Although more than twice as many families
      used respite in 1993 compared to 1988, over half never used respite during this
      period. Most families using respite received in-home services, in moderate
      amounts, and with high levels of satisfaction. In an analysis of predictors of
      respite use, the only significant predictor in 1988 was poorer functional
      abilities of the adult with mental retardation. By 1993, respite use was
      predicted by three characteristics: poorer functional abilities, better health in
      the adult with mental retardation, and greater maternal caregiving burden. These
      findings reflect variability in aging families' needs for support and changing
      respite policies.

PMID- 10337127
TI  - Effectiveness and quality of individual planning in residential settings: an
      analysis of outcomes.
AB  - Individual Habilitation Plan objectives for adults with mental retardation living
      in institutional or community settings were evaluated for effectiveness and
      quality. Effectiveness was assessed by contrasting change in relevant outcomes
      over time for participants with and without individual plan objectives in
      specified content areas. No significant change in outcomes associated with having
      an objective was detected for any of the content areas. Except for functionality,
      ratings of individual plans on all quality domains were poor. Regression analyses
      mostly failed to show any significant relationship between quality domain ratings
      and outcomes, although there was weak but inconsistent evidence for validity of
      the technical adequacy and data-collection quality domains. Findings present a
      challenge to current expectations that presence and quality of IHP objectives are
      associated with improved outcomes.

PMID- 10337128
TI  - Acknowledging barriers in adopting person-centered planning.
AB  - An apparent contradiction in adopting person-centered planning is exemplified by
      the question "If a system adopts person-centered planning, isn't it system
      centered"? Such ambiguities are obvious to employees, who increasingly are being
      asked to consider more personalized ways of assisting people through person
      centered planning. Our premise in this article is that employees' reservations
      are well-founded and should be addressed in order to facilitate understanding and
      eventual reconciliation of unavoidable conflicts that emerge when person-centered
      planning is undertaken by agency employees. Administrators who acknowledge the
      uncertainties accompanying person-centered planning and invite discussion about
      conceptual and practical difficulties inherent in its adoption are modeling a
      collaborative method of discovering ways to help people get what they need.
      Examples of group solutions are presented.

PMID- 10337129
TI  - Cognitive modifiability in adult and older people with mental retardation.
AB  - Activation of change processes in cognitive capacity of 71 institutionalized
      adults with mental retardation in four age groups was investigated. The central
      means of intervention was the Instrumental Enrichment Program. Effects of the
      intervention were examined in reference to logical thinking, predictive thinking,
      and insightful thinking. The test series was administered twice before and twice
      after the intervention. Although all subjects improved significantly, the initial
      and final scores of adults with Down syndrome were lower than those of adults
      with other forms of mental retardation. Subjects with moderate retardation
      achieved greater improvement than did those with mild retardation only in the
      Children Test. Significant changes were obtained in all age groups. For logical
      and predictive thinking, a divergency effect was found. Results support
      structural cognitive modifiability theory.

PMID- 10337130
TI  - Reported medication errors in community residences for individuals with mental
      retardation: a quality review.
AB  - Medication errors have long been a barometer of quality in the health care arena.
      A review of medication errors in community residences for individuals with mental
      retardation managed by one agency was performed. Medication errors were analyzed
      and compared to data in the literature. Although the frequency of medication
      errors in these residential settings was less than medication errors in hospital
      settings, there is concern about how common the medication error experience is:
      85% of residents experienced at least one reported medication error. The number
      of medications administered to residents also doubled in one year. As this
      population ages, experiences more complex health problems, and takes more
      medication, medication administration practices will require systematic
      monitoring.

PMID- 10337131
TI  - Short-changed in the name of socialization? Acquisition of functional skills by
      students with severe disabilities.

PMID- 10337132
TI  - Seeking the functional.

PMID- 10337133
TI  - Aging and developmental disabilities: demographic and policy issues affecting
      American families.

PMID- 10337134
TI  - The Equal Employment Opportunity Commission and people with mental retardation.

PMID- 10337135
TI  - East meets west at Hennepin County Medical Center.

PMID- 10337136
TI  - Herbalism in Minnesota. What should physicians know?

PMID- 10337137
TI  - The hazards of psychotropic herbs.
AB  - The use of medicinal herbs has increased over the past few years, and
      psychotropic herbs are among the most popular on the market. Patients and
      physicians may assume these products are safe; however, dietary supplements are
      not subject to the rigorous testing required for prescription medications.
      Problems that may occur with the use of psychotropic herbs include overuse or
      abuse, side effects, and herb-drug interactions. Ma huang, St. John's wort, and
      kava are examples of readily available herbs with the potential for negative
      effects. Physicians should improve their knowledge of these products so they can
      provide reliable information to their patients.

PMID- 10337138
TI  - Natural options for menopause.

PMID- 10337139
TI  - Safety and quality concerns related to the use of herbal therapies.

PMID- 10337140
TI  - Patient demand for integrative medicine.

PMID- 10337141
TI  - Legal aspects of alternative medicine in Minnesota.

PMID- 10337144
TI  - Medicine online. How useful is it?

PMID- 10337142
TI  - Making computers physician-friendly.

PMID- 10337145
TI  - The e-mail connection.

PMID- 10337147
TI  - Y2K. What u need 2 know.

PMID- 10337146
TI  - A stop at the Oasis. Lessons from the Mayo Clinic's popular Web site.

PMID- 10337148
TI  - Electronic collection of birth and death records.

PMID- 10337149
TI  - Malpractice risks online.

PMID- 10337150
TI  - [Results of nasopharynx cancer treatment: some prognostic factors].
AB  - 42 cases of nasopharynx cancer treated between 1985 and 1995 in ENT and
      Radiotherapeutic Clinic of the Pomeranian Medical Academy were analyzed. In 15
      patients (34.5%) planoepithelial carcinoma was found, in 9 (20.9%)--anaplastic
      carcinoma, in 6 (13.9%)--lymphoepithelial, and in individual cases--spindle
      shaped and mucoepidermal carcinoma solidum. 34 patients were treated by radical
      irradiation (60-70 Gy doses) and 8--by palliative (20-35 Gy). In 7 patients neck
      dissection was carried out. Better results were achieved in older patients (over
      60 years old) than in younger ones. Prognosis in women was better than in men. 5
      years' survival rate for T1-2 group was achieved in 77% of cases. For T3-4 group
      it amounted to 48%; in N0-1--69% and in N2-3 group--52%. 71% patients with
      planoepithelial carcinoma, whereas only 48% with undifferentiated carcinoma
      survived 5 years. The rate of 56% of 5 years' survival time is comparable with
      good results of other authors.

PMID- 10337151
TI  - [Primary orbital tumors treated surgically in ENT department of Silesian Medical
      Academy in Katowice].
AB  - Primary tumours of orbital cavity are a difficult diagnostic and therapeutic
      problem from a borderline of ophthalmology, laryngology and neurosurgery.
      Particular anatomical relations of orbital cavity surrounded by paranasal
      sinuses, cranial cavity cause that it has become an interdisciplinary region and
      the best method of therapy is multispecialistic surgical treatment ("team
      approach"). In this article the classification and general symptomatology of
      orbital cavity primary tumours were presented. 37 patients suffering from primary
      orbital tumours were treated surgically in the ENT Department of Silesian Medical
      Academy in Katowice. The patients were aged from 23 (woman with neurosarcoma) to
      73 (man with melanoma). All patients were treated surgically: 15 of them by
      orbital exenteration, 10 by lateral orbitotomy m. Kronlein-Reese-Berk, and 12 by
      canthotomy. Special attention was paid to possible postoperative complications.

PMID- 10337152
TI  - [Morphometric assessment of the precancerous lesions and laryngeal cancer].
AB  - The authors assessed morphometrically nuclei of the normal mucosa, precancerous
      lesions and laryngeal cancer in the postoperative samples of 12 patients treated
      in the II Laryngology Clinic, Silesian Medical Academy in Zabrze. The results
      indicate significant cariometric differences of the normal mucosa, precancerous
      mucosal lesions and cancer of the larynx.

PMID- 10337153
TI  - [Tumor DNA content as a prognostic indicator in squamous cell carcinoma of the
      larynx].
AB  - Celluar DNA content has been found to be an important prognostic factor in many
      head and neck tumours, yet within the larynx few studies have examined its effect
      on survival. 31 patients with squamous carcinoma of the larynx treated in years
      1983-85 by total laryngectomy were studied. The tumours were classified according
      to the TNM classification 1987 and graded histopathologically according to
      Jaccobson's classification. Quantitative DNA content was determined with the use
      of image cytometry performed by an image analyzer (CAS-200). Quantitative DNA
      analysis correlated with tumor grade and patient outcome within 6 years of follow
      up.

PMID- 10337154
TI  - [On the problem of rhinophyma management].
AB  - On the basis of cases of their own and the literature the authors review the
      etiology, pathophysiology and management of rhinophyma.

PMID- 10337156
TI  - [Hormonal receptors of laryngeal cancer].
AB  - Supported with available literature the authors described the role of hormonal
      receptors in normal and neoplastic larynx tissue. The presence of receptors
      depending on sex, age, organ location and histology of larynx cancer was
      described. The possibility of hormonal treatment of that cancer was emphasized.

PMID- 10337155
TI  - [Second primary neoplasms in laryngeal cancer patients].
AB  - In the period of 1990-1992, 238 patients underwent surgical treatment for
      laryngeal carcinoma in ORL Department of Medical Academy in Bialystok. Until now
      27 cases of second primary malignances (SPM) have been found in this group (11.3%
      of the screened population). Upper aerodigestive tract was the most frequent
      location, i.e. it was observed in 18 cases (66.6%). There was 100% mortality
      among patients with SPM of stomach, oesophagus and lung estabishing 13% deaths in
      the whole group. There was no correlation between the stage and the location of
      primary laryngeal cancer and SPM. Carcinogenic influence of smoking and alcohol
      on primary malignancies and SPM within upper aerodigestive tract development has
      been confirmed.

PMID- 10337157
TI  - [Surgical treatment of partial defects of the nose].
AB  - During the last 15 years (1981-1995) 70 patients (38 male and 32 female) with
      partial defects of the nose were treated in the Department of Plastic Surgery of
      the Medical University of Lodz. In 26 cases there were posttraumatic defects and
      in 44 patients the defects were secondary to removal of a neoplasm. Patients were
      divided into two groups. In the first one there were patients with loss of the
      skin and subcutaneous tissue of a part of the nose; in the second group there
      were full-thickness defects of the alar base and/or alar rim and columella. Type
      of surgical reconstruction of the partial defects of the nose depends on
      location, size and deepness of the defect as well as on the patient's age. The
      goal of a surgeon who performs the reconstruction is to choose the most simple
      method with the lowest risk of complications and the method of the best possible
      esthetic and functional effect. The authors analyze the results of reconstruction
      of partial defects of the nose with the application of different methods. In 25
      patients reconstruction was performed with the use of the pedicled nosolabial
      transposition flaps, while in other 17 cases composite grafts from auricle were
      made. Pedicled flaps from the forehead were used in 18 patients, tubed flaps in 3
      and retroauricular flaps in 2 individuals. In one case replantation of the nose
      tissues was performed.

PMID- 10337158
TI  - [Antigen specific immunoglobulin E to grass and weed pollens in the plasma of
      patients with seasonal allergic rhinitis].
AB  - The study involved 22 patients with seasonal allergic rhinitis between 13 and 53
      years of age. The level of antigen specific IgE (AS IgE) to 5 grass and 3 weed
      pollens was determined with the use of CAP FEIA (Pharmacia, Uppsala, Sweden). The
      control group consisted of 20 persons. All above AS IgE were significantly higher
      in the patients with seasonal allergic rhinithis than in the control group. The
      most commonly present hypersensitivities were to Meadow fescue (Festuca elatior),
      Meadow grass (Poa pratensis), Cocksfoot (Dactylis glomerata), Ribwort (Plantago
      lanceolata) and Mugwort (Artemisia vulgaris) allergens. The authors believe that
      the pathomechanism of the development of seasonal allergic rhinithis is governed
      to a large degree by hypersensitivity to grass and weed pollens and suggest that
      precise determination of AS IgE to these allergens in patients blood sera should
      form the basis of the construction of the vaccine used in their immunotherapy.

PMID- 10337159
TI  - [Treatment of recurrent nose bleeding caused by Rendu-Osler-Weber's disease in
      patients treated at the ENT department of the Regional Hospital in Opole].
AB  - The authors describe a method of surgical treatment of nosebleeds caused by Rendu
      Osler-Weber's disease. Free skin graft of the thigh region was used for closure
      of nasal septal defects. A new dermatoplasty technique allows to cover both sides
      of the nasal septum with a single skin graft. The diseased septal mucosa is
      denuded with a scalpel, but the underlying perichondrium is preserved. Excellent
      exposure of the nasal septum is obtained via a modified external rhinoplasty
      approach. This new dermatoplasty technique described by dr Bridger is a
      modification of traditional Saunders dermatoplasty. In three patients treated by
      this method at our department the transplantation ended successful.

PMID- 10337160
TI  - [Palisade cartilage tympanoplasty in reconstructing almost total defects of
      tympanic membrane: own experience].
AB  - The authors described 8 patients with almost total defects of tympanic membrane.
      The patients were operated on with palisade tympanoplasty technique (m. Heermann)
      with the use of conchal autografts for reconstruction of the tympanic membrane.
      The technique is very useful and gives good results.

PMID- 10337161
TI  - [The surgical treatment of malignant tumors of the maxillo-ethmoid complex].
AB  - Forty-seven patients were treated in the Department of Laryngology, Medical
      Academy in Warsaw between 1980 and 1989. Twenty-seven patients had squamous cell
      carcinoma. All cases were advanced. The patients were treated by combination of
      surgery and postoperative radiotherapy. Nineteen patients (40.4%) survived five
      years.

PMID- 10337162
TI  - [Histiocytosis X (Langerhans cell histiocytosis) of temporal bone. Role of
      scintigraphy in disease progress evaluation].
AB  - The authors present a case report of a 7-year-old girl with Langerhans cell
      histiocytosis of temporal bone. Edema and bone destruction involved zygomatic
      process of temporal bone and temporal fossa without ear occupation. The role of
      picturing diagnosis in evaluation of lesion extent with special importance of
      scintigraphy is discussed. Treatment methods of Langerhans cell histiocytosis
      lesions in temporal bone are presented. In our case locally Depo-Medrol injection
      was given and radiation was left as last resort management.

PMID- 10337163
TI  - [The results of treatment of otitis media with suppuration in children by
      ventilation tubes].
AB  - The authors present the results of surgical treatment of secretory otitis media
      by means of drainage of tympanic cavity. The ventilation tubes used were made of
      Polish plastic Tarflen. The control assessments were carried out from 6 months to
      6 years after the surgery, 58 children were studied, 49 of them had control
      examination. The improvement in hearing was found in 65 per cent of the patients.
      The appearance of tympanic membrane after the surgery was as follows: normal in
      38.8%, retraction pockets in 10.2%, tympanosclerosis in 8.2%, secretory fluid in
      6.1%, perforation of the tympanic membrane in 4.1%.

PMID- 10337164
TI  - [Otitis media in patients with Down's syndrome].
AB  - 61 patients with Down's syndrome were examined. Otitis media was diagnosed in 19
      patients. Conductive hearing impairment after otitis media was observed in pure
      tone audiometry and speech audiometry. It was emphasized that conductive hearing
      loss in children with Down's syndrome is a very important factor in retarded
      speech development. Children with recurrent otitis media were treated by surgery
      (9 adenotomies) and conservative treatment such as insufflation and
      catheterisation of Eustachian tubes, pharmacotherapy. Treatment of otitis media
      was difficult because of anatomical anomalies of facialocranium, atrophic mucous
      membrane of upper respiratory tract, reduced immunity.

PMID- 10337165
TI  - [The application of otoacoustic emissions measurement in the assessment of the
      function of cochlear efferent fibers: the study of normal hearing subjects].
AB  - It has been shown by L. Collet in 1990 that the contralateral noise stimulation
      causes the decrease in the amplitude of otoacoustic emissions in the ipsilateral
      (tested) ear. This effect is linked to the activation of crossed efferent fibres
      in the cochlea. This non-invasive method is becoming a useful tool in assessing
      the function of efferent system in human. In this study the effect of
      contralateral noise stimulation was assessed in 10 young subjects with normal
      hearing. The contralateral stimulation caused the decrease in the amplitude of
      both transient evoked otoacoustic emission (TEOAE) and distortion-product
      otoacoustic emission (DPOAE) in the majority of tested ears. The statistically
      significant effect was observed already at the intensity of noise of 40 dB (A).
      At the lower level of noise (30 dB-A) the small increase in the amplitude of
      otoacoustic emissions in some ears was observed. The suppressive effect of
      contralateral stimulation depended clearly on the intensity of noise; the higher
      intensity of noise, the greater suppressive effect was seen. However, the
      decrease in the otoacoustic emissions was very small (usually in the range from 1
      to 2 dB), which may limit practical application of this method in the assessment
      of the function of efferent system.

PMID- 10337166
TI  - [Electrophysiological examination (ENG, EEG) in Alzheimer's disease].
AB  - The aim of the study was the electronystagmographic and electroencephalographic
      examination in patients with clinical diagnosis of Alzheimer's disease. The
      results showed that visual-oculomotor and vestibulo-oculomotor disturbances have
      had the central origin. ENG and EEG examination showed the lesions of both
      frontal and temporal cortes in these patients.

PMID- 10337167
TI  - [A case of preserved otoacoustic emissions in a child with unilateral idiopathic
      severe sensorineural hearing loss].
AB  - In this study there is presented a case of unilateral, idiopathic, severe
      sensorineural hearing loss in a child. The inner ear pathology has been confirmed
      by tonal and impedance audiometry, and brainstem evoked response audiometry.
      Simultaneously in the same ear normal otoacoustic emission (SOAE, TEOAE, DPOAE)
      has been recorded. MRI did not reveal any pathology in internal ear canal and
      cerebellopontine angle. The presented case suggests that there is a possibility
      of existence of the normal outer hair cell function with simultaneous inner ear
      cell disorder or first neuron pathology. Similar cases of idiopathic
      sensorineural hearing losses with preserved otoacoustic emissions in children
      were described by Katona (1993), Welz-Mueller (1993) and Konradsson (1996).

PMID- 10337168
TI  - [A case of laryngeal mucoepidermoid carcinoma].
AB  - The authors present a very rare case of laryngeal mucoepidermoid cancer. Well
      separated and encysted tumor was totaly removed with Kleinsasser method.

PMID- 10337169
TI  - [Multiple cancer of the external ear].
AB  - Neoplasmatic multifocal tumors develop inside the same tissue or organ. They
      refer to skin, mucosal membrane of gastrointestinal tract or respiratory tract.
      To diagnose them a histopatological confirmation of their malignancy is needed,
      there must be macroscopic border line between tumors, the change can not be a
      metastasis from primary defect. The authors present two cases of external ear
      squamous cell carcinoma a which appeared bilaterally in different periods of
      time.

PMID- 10337171
TI  - [Protein p53 in gastric carcinoma: clinical use of cancer research on neoplasms].
AB  - Mutations of the tumour-suppressor p53 gene are a very frequent event in many
      human cancers. In normal cells and tissue, p53 protein has a very short half-life
      and attains such a low level that is not detectable immunohistochemically. In
      contrast, the altered forms, present in 30 to 80% of different neoplasms, are
      more stable and accumulate to concentration that can be detected by
      immunohistochemistry. Changes in the p53 gene product can be immunogenic. Thus a
      simple procedures as immunohistochemistry or Elisa test which stratifies cancer
      patients into those with and without p53 accumulation or p53 auto- antibodies can
      be analyzed for useful correlations with clinical and histopathological data. The
      p53 studies have demonstrated that in gastric carcinoma the expression of p53
      protein can be properly assessed prior to surgery, using immunohistochemistry on
      a small tissue samples obtained during endoscopy. It has been shown that p53
      assessment in this carcinoma can be helpful in identifying patients at high risk
      for metastatic spread, including regional lymph node involvement, and in the
      discrimination of those patients with especially poor prognosis. Furthermore it
      was demonstrated that in stomach p53 accumulation is a marker of malignancy.
      Thus, when combined with routine procedures, a simple test as p53
      immunohistochemistry might allow better planing of appropriate treatment
      strategies and help in the pre-operative diagnosis of gastric carcinoma. Further
      studies are required to determine the clinical significance of p53 serum
      antibodies in gastric cancer.

PMID- 10337172
TI  - [Sources of infections and genotypes of hepatitis C virus in children].
AB  - The aim of the study was to analyse possible sources of HCV infection as well as
      to study their relation to specific HCV genotype. The study comprised 60 children
      with chronic hepatitis C age from 3 to 15 years. In 36.6% of patients, the
      probable risk factors were surgical interventions or injures; in 60% prior
      hospitalisation in conservative wards. Surgery was a risk factor in 59% of cases
      of infection with genotype 1a and in 41%--with genotype 1b. Hospitalisation
      conservative was the risk factor for the infection in 47% and 50% of cases,
      respectively.

PMID- 10337173
TI  - [Clinical and morphological picture of hepatitis C in children with genotype
      4c4d].
AB  - Actually, HCV genotype 4 is frequent in central Africa and in the Middle East. In
      contrast, in Europe genotype 4 is uncommon (1-4%). In this study we present 12
      children with HCV genotype 4c4d. Clinical picture in this group was asymptomatic,
      morphological was moderate.

PMID- 10337174
TI  - [The differences in liver regenerative rate after partial hepatectomy in rats
      treated wtih selected immunosuppressants].
AB  - The aim of this study was to assess the influence of selected immunosuppressants
      on liver regeneration. In fifty experiments were performed on fifty male Buffalo
      strain rats, 12 weeks old and weighing between 206 and 266 grams. Partial
      hepatectomy (2/3) was carried out under ether anaesthesia. Rats were randomly
      assigned to one of six groups (10 rats per group) and treated orally as follows:
      group 1--without immunosuppressant (control group), group 2--ciclosporin A (CyA)
      10 mg/kg/day, group 3--azathioprine (Aza) 3 mg/kg/day, group 4--tacrolimus (Tac)
      0.1 mg/kg/day and group 5--prednisolone (Pred) 1 mg/kg/day. After 42 days
      observation all rats were killed. Resected liver tissue was weighed at the day of
      operation and also the remnant liver was weighed after sacrification of the
      animal. The regenerative rate was obtained by dividing the wet weight of the
      remaining liver by the estimated preoperative weight of the whole liver and
      multiplying by 100. Regenerative rate of liver tissue was significantly higher in
      rats treated with CyA and Tac and significantly lower in rats treated with Pred.
      There were no significant differences between control group and rats treated with
      Aza. This study has shown that among immunosupressant used in experiment only CyA
      and Tac stimulated liver regeneration after partial hepatectomy. On the other
      hand only Pred inhibited liver regeneration, whereas Aza had no influence on
      liver restoration.

PMID- 10337175
TI  - [Examination of skin microcirculation with laser-Doppler flowmetry in patients
      with essential hypertension].
AB  - The estimation of microcirculatory parameters in patients with essential
      hypertension and in normotensic control group was the aim of this study. The
      study group consisted of 14 patients with essential hypertension confirmed by 24
      hours ABP. 10 healthy patients served as control group. The flow in the skin
      microcirculation was measured by laser-Doppler flowmeter (PF-3, PERIMED) on
      dorsal part of the palm. Microcirculatory indices were registered in resting
      conditions, during one-minute occlusion reaction and during reactive hyperemia.
      The following indices were calculated: resting flow, biological zero, maximal
      flow, time to maximal flow, ratio of maximal to resting flow, ratio of resting
      flow to biological zero and ratio of maximal flow to biological zero. Skin
      microcirculation was highly disturbed in patients with essential hypertension. It
      was expressed by significantly higher biological zero and longer time to maximal
      flow.

PMID- 10337176
TI  - [Effects of L-carnitine on erythropoiesis and blood platelet aggregation in
      patients with chronic renal failure treated with hemodialysis].
AB  - The aim of the work has to assess the effects of L-carnitine therapy on
      erythropoiesis and whole blood platelet aggregation. The studies were performed
      in 28 patients divided into 3 groups: I-group was given erythropoietin, II-group
      was given erythropoietin and L-carnitine, III-group was given L-carnitine. After
      22 month of the therapy a statistically significant rise in hematocrit was
      observed in group III, improvement in muscle strength, a rise in free and total
      carnitine concentration was found in group II and III. There were no significant
      changes in urea concentration, platelet count and iron metabolism. Whole blood
      platelet aggregation induced by ADP, collagen and ristocetin was impaired
      relative to healthy volunteers. After 2 month of L-carnitine treatment of
      significant rise in collagen induced platelet aggregation was observed in group
      II.

PMID- 10337177
TI  - [Markers of endothelial stimulation in hyperthyroidism].
AB  - The aim of the study was to evaluate function of endothelial cells in the
      patients with hyperthyrosis before thyrostatic treatment on the base of known
      markers of endothelial disturbances: von Willebrand factor and tissue plasminogen
      activator. The study was performed in the 36 patients aged 20-60 (means 36.7)
      years suffering from Graves disease and in 17 patients with hyperthyrotic goitre
      aged 30-59 (means 45.8). The control group consisted of 40 healthy volunteers. In
      the blood plasma concentration of tissue plasminogen activator (t-PA) and von
      Willebrand factor (vWF) antigen were determined with enzyme-linked immunoassay
      (ELISA). In patients with hyperthyroidism significantly increased antigen
      concentration of both studied parameters were observed. It seems that increased
      concentration of t-PA and vWF antigen in the blood of hyperthyrotic patients was
      the result of the release of them from injured thyroid gland by disease or of
      stimulating effect of thyroid hormones on the t-PA and vWF synthesis in the
      endothelial cells.

PMID- 10337178
TI  - [Coexistent hepatitis G virus infection and autoimmune hepatitis].
AB  - Report a case of a girl with HGV-RNA in the serum, which was detected during the
      treatment of autoimmune hepatitis. Infection HGV may cause aminotransferases
      abnormalities because they were elevated despite of the 2.5-year
      immunosuppressive therapy.

PMID- 10337179
TI  - [Chylomicronemia syndrome complicating type 1 hyperlipoproteinemia with
      concomitant insulin-dependent diabetes].
AB  - The case of chylomicronaemia syndrome complicating clinical course of type-1
      hyperlipoproteinaemia and insulin-dependent diabetes is described. The patient
      required hypoglycaemic and lipid-lowering therapy.

PMID- 10337180
TI  - [Primary malignant neoplasms of intestine].
AB  - The authors presented 6 cases of malignant neoplasms of intestine. Five of them
      were undergone emergency surgery, while one elective, due to complaints notified
      previously for a longer time. In all cases a segmental resection of intestine was
      done. Two patients were complementarily treated using chemiotherapeutics. Three
      patients survived 2-5 years after the operation. The last three patients are
      under the further follow up.

PMID- 10337181
TI  - [Sarcopenia: definition and clinical implications].
AB  - Age-related decrease in skeletal muscle mass has been referred to as sarcopenia.
      This reduction in muscle mass is a direct cause of the age-related decrease in
      muscle strength and power. Reduced muscle strength and power is a major cause of
      functional dependence in the elderly, contributing also to the increase in the
      prevalence of many age-associated chronic diseases.

PMID- 10337183
TI  - [Watermelon stomach].
AB  - Watermelon stomach is a rare cause of chronic gastroinestinal bleeding. It is
      often associated with some other diseases, as for example the primary billiary
      cirrhosis, autoimmune diseases or connective tissue disorders. Pathogenesis is
      still unclear. The role of chronic prolaps of gastric mucosa, influence of other
      diseases or local neurohormon disturbancies are taken into account. The most
      important in diagnosis is typical endoscopic view and characteristic histology.
      The fundamental thing in management is to stop chronic and massive blood loss,
      requiring multiple transfusions. Farmacotherapy does not bring satisfactory
      results and definite treatment is antrectomy. A very good alternative is
      endoscopic therapy by means of heater probe, bipolar electrocoagulation or laser
      photocoagulation, especially in patients with poor operation risk. Patients who
      cannot undergo endoscopic treatment can be offered sterydotherapy, also quite
      effective method but with its typical side effects.

PMID- 10337182
TI  - [Genetic diagnosis of hepatitis C virus infection].
AB  - Hepatitis C virus, a small enveloped RNA member of Flaviviridae, is the major
      causative agent of non-A, non-B hepatitis. The discovery and genetic
      characterization of HCV is described. Modern genetic procedures and methods
      involved in the studies of HCV biology, genetic heterogenity and diagnostics of
      HCV infections are presented. Interferon-alfa treatment is the only licensed
      therapy for chronic hepatitis C until now, but an efficacy of such treatment is
      highly variable. Viral factors predicting the long-term outcome of interferon
      alfa therapy, such as genotype, baseline viral load, quasispecies or ISDR
      mutations, and current concepts of their predictive values are discussed. Our own
      results are presented and compared with those present in the latest publications.

PMID- 10337184
TI  - [Inflammatory mediators in the acute pancreatitis].
AB  - During the last few years attention has been focused on an important role of
      inflammatory mediators in the pathophysiology and systemic complications of acute
      pancreatitis. The present study deals with those of the mediators which have
      shown demonstrable activity in the course of pancreatitis, e.g. acute-phase
      proteins (among others C-reactive protein and alpha-1-antitrypsin) and neutrophil
      elastase (PMN-elastase) as the marker for granulocyte activity. The activity of
      cytokines IL-6, IL-8 and IL-1, of alpha-cachectin (TNF alpha), as well as of the
      platelet-activating factor (PAF) and the trypsinogen activation peptide (TAP),
      was discussed.

PMID- 10337185
TI  - [Flow cytometry: diagnostic, therapeutic and prognostic usefulness in solid
      tumors].
AB  - Flow cytometry is a new technique measuring several optical parameters of
      particular cells in cell suspension. These parameters are: optical density, light
      scatter and fluorescence emission. Optical assay conjugated with digital data
      processing permit the precise characterisation of chosen cellular subpopulations.
      The optical signs transformed by photomultipliers as analogue signals are
      presented as descriptive cytograms. Digitally converted signals analysed by
      multichannel analyser are stored as histigrams. Flow cytometry is widely used in
      the diagnostics of blood neoplastic diseases and, in a less routine manner, in
      the diagnostics of solid tumours. The latter requires accurate disaggregation of
      tumour tissue to obtain homogenous cell suspension. Different, more or less
      efficient, mechanical or enzymatic disaggregation techniques are used to prepare
      appropriate cell suspensions. Flow cytometry DNA analysis with simultaneous
      determination of several protein proliferation factors are heavily used in
      research and clinical laboratories to follow tumour cell proliferation, efficacy
      of cancer therapy and finally as prognostic factors. Although these assays yield
      promising results in some specific tumours, their value and accuracy seems still
      equivocal.

PMID- 10337186
TI  - [Ehrlichiosis: a tick-born infection].
AB  - Ehrlichiosis is the potentially life-threating infection. It is caused by
      obligate intracellular bacteria. The clinical presentations are fever, headache,
      myalgia, malaise, nausea, vomiting and other nonspecyfic symptoms. Some patients
      develop neurologic symptoms and signs. The are two distinct forms of human
      ehrlichiosis: human monocytic ehrlichiosis /HME/--cased by Ehrlichia chaffeensis
      that infects mononuclear phagocytes and human granulocytic ehrlichiosis /HGE/-
      caused by E. species closely related to E. phagocytophyla and E. equi and infects
      granulocytes. Successful treatment of these infections may depend on proper
      diagnosis. Appropiate diagnostic tests are still not available. This diagnisis
      should be considered in febrile patients with tick bites.

PMID- 10337187
TI  - Habituation and sensitization as phenomena modeling learning processes in two
      groups of children: normally developing and mentally deficient in biofeedback
      research.
AB  - Problems of habituation and sensitization as phenomena which help to control and
      to predict results of the learning speed in the 8-13 olds, depending on the level
      of their intellectual development, expressed by the intelligence quotient, were
      carried out with the use of the biofeedback method. The statistical analysis
      proved that there is relationship between the intelligence quotient and the level
      of the general organismic excitation has been observed in children with the
      intelligence quotient between 62 and 77, whereas the decreased one--at the
      intelligence quotient between 115 and 138. It seems that changes towards either
      the habituation or may a priori indicate the intelligence quotient value and vice
      versa. The correlation value has to be identified by further statistical
      psychological analyses.

PMID- 10337188
TI  - [The dangers of evidence-based medicine].

PMID- 10337189
TI  - [Leon Daudet, Charcot's biographer].

PMID- 10337191
TI  - [Skin carcinogenesis].
AB  - Two main distinct subtypes of epithelial skin cancers can be distinguished, both
      arising from keratinocytes, most frequently at sun-exposed body sites. Basal cell
      carcinomas (BCC) grow slowly, nearly never metastases, whereas squamous
      carcinomas (SCC) are locally more invasive tumors, which have a greater
      metastatic potential. Skin carcinogenesis is a multiple step process, in which UV
      light play a major role. Numerous genetic lesions occur, either inactivating
      tumor suppressor genes (which normally repress cell growth), or activating
      oncogenes (which promote cellular multiplication). The most important tumor
      suppressor gene involved in both skin neoplasms is p53, which is inactivated in
      40-50% of cases, by specific UV induced mutations. Yet, some differences exist
      between these two subtypes, which could explain their difference in invasiveness.

PMID- 10337192
TI  - [Epidermoid carcinoma].
AB  - Squamous-cell carcinomas are the most frequent skin cancer after the basal-cell
      carcinomas. They occur in precursor lesions (dysplasia, actinic keratoses,
      Bowen's disease). They are mainly present in sun-exposed areas (face, hands). It
      is important to detect and treat them early. Surgical treatment is easy at an
      early stage. At a later stage their prognosis is poorer because the squamous cell
      carcinomas tend to invade locoregional tissue and metastase. Their prevention
      remains the most important thing by using a photoprotection and treating actinic
      keratoses.

PMID- 10337193
TI  - [Basal cell carcinoma].
AB  - Basal cell carcinoma is the most frequent of all cancers. Its incidence has risen
      those last decades because of the increase in sun exposure habits. People with
      light skin complexion are particularly at risk. Ionizing radiations, arsenicism,
      various genodermatoses (Gorlin syndrome, xeroderma pigmentosum, nevus sebaceous)
      are other pre-disposing factors. Basal cell carcinoma usually present as small
      lesion with a pearly border and telangiectasias. Other clinical types must also
      be recognized such as the nodular, the infiltrative, the superficial and the
      pigmented forms. They are usually located on the head and trunk. The prognosis of
      basal cell carcinoma is usually good since they can be cured by surgical excision
      and because they usually do not metastasize. However, large, multiple or
      recurrent basal cell carcinomas can be difficult to treat. In these cases,
      cryosurgery, radiotherapy or intralesional interferon-alfa may be needed.

PMID- 10337194
TI  - [Melanocytic nevi].
AB  - Acquired melanocytic naevi are believed to have been developed from epidermal
      melanocytes that completed their migration from the neural crest to the dermo
      epidermal junction in fetal life or to arise from dermal melanocytes that have
      become arrested in the dermis during fetal migration and have never reached their
      normal site. Uncommon in infancy, naevi increase in frequency during childhood
      and adolescence and then more slowly to a plateau in middle age. During old age
      their prevalence falls. Studies on epidemiology suggest that melanocytic naevi
      are commoner when sun exposure is constant and intense and with some individual
      characteristics. Giant congenital melanocytic naevi, a positive family history of
      melanoma are risk factors responsible for the development of melanomas and
      require surveillance. In the great majority of naevi, removal is not required
      except if clinical suspicion.

PMID- 10337195
TI  - [Melanoma].
AB  - Melanoma has the worst pronostic among the cutaneous tumours. Many patients die
      with this tumour. It is the cancer whose incidence increases the most among all
      the tumours (double every 10 years). The pronostic of melanoma is very bad at
      metastatic stage. On the contrary, the excision of tumour at an early stage may
      be associated to a complete remission. So it is important to encourage skin
      cancer detection for an early treatment of melanoma. Finally, it appears crucial
      to increase the diffusion of informations about the photoprotection. Indeed,
      solar exposition probably plays on important role in the increasing incidence fo
      this skin tumour.

PMID- 10337197
TI  - [Kaposi's disease].
AB  - The 4 clinical settings of Kaposi's sarcoma, namely classic, endemic, epidemic
      and post-transplant Kaposi's sarcoma share the same histological features and are
      all associated to a new herpesvirus, human herpesvirus 8. However, they differ
      according to their prognosis and therapeutic considerations.

PMID- 10337196
TI  - [Prevention of skin cancers].
AB  - Skin cancer should be the ideal cancer for prevention. The environmental risk
      factors subject to modification by primary prevention are known for melanoma and
      cutaneous carcinoma. Some precursors have been identified, opening the
      possibility of secondary prevention. In addition, skin cancers are easily
      visualised, facilitating diagnosis.

PMID- 10337198
TI  - [Benign tumors of the skin and its appendages].
AB  - At least, about a hundred of benign specific tumours originating in the
      epithelial and connective structures of the skin are nosologically
      individualized. In this count are not included all the clinicopathological
      variants of these entities and the numerous lesions which only look like tumours
      such viral warts or cheloidal scars. The most frequent benign skin tumours are
      seborrhoic keratoses, nevocytic nevi, dermatofibromas and hemangiomas. In this
      practical review we describe the most common tumours which have some clinical
      hallmarks and can be easily recognized without a histological checking.

PMID- 10337199
TI  - [What's in the bottom of white coat pockets?].

PMID- 10337200
TI  - [Prematurity and retarded growth at birth].

PMID- 10337201
TI  - [Chronic alcoholic pancreatitis].

PMID- 10337202
TI  - [Pulmonary tuberculosis and tuberculous primary infection].

PMID- 10337203
TI  - [Genetic imprints].

PMID- 10337204
TI  - [Nutritional requirements of infants, children, pregnant and breastfeeding women
      and the elderly].

PMID- 10337205
TI  - [Superficial adenopathy].

PMID- 10337206
TI  - [Corticosteroids].

PMID- 10337207
TI  - [Deep vein thromboses of the lower extremities].

PMID- 10337208
TI  - [Caval filters: to insert or not?].

PMID- 10337210
TI  - [The CASS-CHOU study of mesenteric angina. The comparative effects of cassoulet
      and sauerkraut with sausages].
AB  - The goal of study was evaluate in 1,837 consecutive patients the comparative
      effects of French cassoulet (CASS) and international sauerkraut (CHOU). After
      procedures of exclusion classical, 8 patients could be evaluated and received in
      a randomised, doubleblind, crossover protocol an mouth dose of 22.5 g/kg of CASS
      or CHOU. The results show a very significative difference between the 2 products.
      A regular absorption of couscous is therefore recommended.

PMID- 10337211
TI  - [Depression. Introduction. Between hope and disappointment?].

PMID- 10337212
TI  - [Clinical expressions of depression].
AB  - The main clinical manifestations of depression can be described as a decrease of
      the psychic tone resulting in a disturbance of mood prone to sadness and a
      psychomotor retardation with slowness and feeling of fatigue. Anxiety is usually
      associated to these core symptoms as well as somatic signs. Suicidal risk is
      always present and is increased during melancolic states. A great clinical
      polymorphism makes the diagnosis difficult in some cases. If the spontaneous
      course of depression is usually favorable within a year, antidepressant
      treatments are necessary to shorten the duration of the illness and to avoid
      chronicisation and relapse.

PMID- 10337213
TI  - [The neurobiology of depression].
AB  - Neurobiology dominates efforts to understand depression. This psychiatric illness
      is thought to result from dysfunctions in monoaminergic systems affecting
      norepinephrine, serotonin and dopamine. Abnormalities are linked to functional
      deficit of monoamines at several effector sites. Findings include reduced
      cerebrospinal fluid and urinary concentrations of metabolites, decreased plasma
      concentrations of precursors, modifications of receptor density and clinical
      effectiveness of drugs which increase neurotransmission in depressed patients.
      The original hypothesis of affective disorder envisaged a single transmitter
      model, but neuroscientific developments highlight the complexity of the central
      nervous system. Considerable evidence supports the hypothesis of combined
      alterations of monoaminergic functions and other systems like neuropeptides and
      neuroendocrine functions.

PMID- 10337214
TI  - [Depression and manic-depressive disorders].
AB  - The two major subtypes of manic-depressive illness are bipolar disorder and
      recurrent major depressive disorder. Biological data strongly indicate that a
      significant genetic factor is involved in the development of manic-depressive
      illness. But, stressful life events, environmental stress and premorbid
      personality factors may also be involved in other important etiologic factors.
      Some research data indicate that cyclothymic disorder and temperamental disorders
      may be considered as mild forms of bipolar disorders so called "subaffective
      disorders". The identification of clinical or biological features reflecting the
      severity of the major depressive episode is very important in regard of the high
      potential for suicide of the illness.

PMID- 10337215
TI  - [Dysthymic disorders].
AB  - Long lasting, low intensity depressive episodes have been diversely integrated
      according to the classifications types or the psychodynamic points of view. The
      concept of anxious persistent lasting depression, neurotic depressive states,
      neurotic depression ... have been unified into the dysthymic disorder category of
      the DSM classification. This concept unification have been a topic of dispute
      considering that dysthymic disorder was a restrictive, heterogeneous an
      extensively comorbid diagnosis. Nevertheless the definition of this category
      offers the opportunity to place the notions of temperament, personality,
      adjustment disorder. Including dysthymic disorders as a category inside of the
      mood disorders classification suggests the interest of using an antidepressive
      medication in presence of chronic depressive states not included in the major
      depressive disorder category.

PMID- 10337216
TI  - [Atypical depression].
AB  - The principal atypical aspects of depressive disease are: minor and attenued
      aspects, monosymptomatic and atypical aspects (food disorders and sleep
      disorders), masqued aspects (somatoform, anxious, characterial and addict
      disorders), atypical aspects of child (anxious nevrotical disorder), pseudo
      demented and characterial aspects of aged subjects. Facing to these aspects, the
      diagnosis of depression is evoqued on: the recent and fast advent of these
      disorders, their morning predominance, their recurrent character, the state of
      attenued depressive symptoms (anhedonia), the positive responsiveness to
      treatment.

PMID- 10337217
TI  - [Symptomatic and concurrent depressions].
AB  - The symptomatic and concurrent depressions description need to resort to
      comorbidity and symptomatic co-occurrence concepts. Patients with depressive
      symptoms or in a major depressive episode may also be suffering from another
      nonmood psychiatric disorders as alcoholism, anxiety or eating disorders. Many
      general medical conditions which are link with depression are illustrated with
      the examples of cancer, coronary artery disease, endocrinologic diseases,
      dementia, stroke and chronic fatigue syndrome. When depression and another
      psychiatric or medical conditions occur together, it is important to provide to
      the practitioner guidelines for the decision to treat one of the two disorders.
      This paper contains an example of decisional algorithm.

PMID- 10337218
TI  - [Biological treatment of depression].
AB  - Pharmacotherapy remains the main medical means of treating depression, and
      constant progress during recent years has led to the present availability of many
      effective and well tolerated drugs. Some essential conditions should be present
      for optimum therapeutic efficacy. The appropriate indications should be precisely
      defined. The most active and best tolerated product should be chosen for each
      patient. The medical treatment should be associated with psychotherapy. Finally,
      the patient should be followed-up with regard to restoration of his relations
      with his family, social and professional groups. Much progress remains to be
      made. The most important are better knowledge of the mechanisms of action of
      antidepressants and of the pathophysiopsychological mechanisms of depression.
      Some rare cases of very severe depression, either unresponsive to medical
      treatment or when such treatment is contraindicated, still require the use of
      electroconvulsive therapy. Light therapy is used in seasonal affective disorder.

PMID- 10337219
TI  - [Psychotherapy in depression].
AB  - The field of psychotherapies has in general widely evolved for these ten last
      years in France and more in depressive disorders treatment, namely owing to short
      structured therapies development and especially cognitive-behaviour therapies
      well fitted for controlled studies assessment. Pyschoanalytically oriented
      psychotherapies have also changed but not so much and they still remain less
      efficacious in this area. Henceforth the numerous technicals of this kind of
      therapy will be modified in the eclective and integrative approach; they must not
      be compared in opposition one another but used in a collaborative way on the
      basis of scientific data in order to make them more effective. So some very
      exciting prospects are open in the future of that field of research. Practically,
      nowadays the best outcomes are obtained in the association of both antidepressant
      drugs and cognitive-behavior psychotherapy.

PMID- 10337220
TI  - [How to encourage the direction of students?].

PMID- 10337221
TI  - [Liquid effusion of the pleura. Diagnostic guidelines].

PMID- 10337222
TI  - [Acute myeloblastic leukemia. Diagnosis and course].

PMID- 10337223
TI  - [Pancytopenia. Diagnostic guidelines].

PMID- 10337224
TI  - [Congestive heart failure in adults. Etiology, physiopathology, diagnosis,
      course, treatment].

PMID- 10337225
TI  - [Broncho-alveolitis in infants. Diagnosis and treatment].

PMID- 10337226
TI  - [Pyramidal syndrome. Diagnostic guidelines].

PMID- 10337227
TI  - [Cancer of the colon. Epidemiology, pathologic anatomy, Dukes staging,
      physiopathology, diagnosis, course, principles of treatment and prevention].

PMID- 10337228
TI  - Evaluation of techniques for the enumeration of Dicrocoelium eggs in sheep
      faeces.
AB  - To evaluate the accuracy of quantitative techniques for the enumeration of
      Dicrocoelium dendriticum eggs in faeces, eggs were added to fluke free sheep
      faeces to achieve densities of 25, 50, 100, 200, 400 or 800 eggs per gram (epg)
      (5 replicates per density). The faecal egg counts were determined by a modified
      McMaster method (WETZEL, 1951) utilizing solutions of ZnSO4 (sp. g. 1.3 and
      1.45), K2CO3 (sp. g. 1.45) and HgI2/KI (sp. g. 1.44) for flotation or by a
      sedimentation technique (4 sedimentation processes of 45 min each). The influence
      of flotation time on egg counts was assessed by counting the eggs 3-5, 15-20, 30
      35, 45-50 and 60-65 min after loading the McMaster chamber. The results were
      expressed as percentage rate of recovery. Significant best rate of recovery, 91.2
      +/- 9.4%, was achieved using HgI2/KI solution for flotation and there was no
      significant influence of flotation time on the egg count. Utilizing ZnSO4
      solutions and K2CO3 solution for flotation the rates of recovery for Dicrocoelium
      eggs were 9.0 +/- 7.1%, 26.7 +/- 24.9% and 13.0 +/- 11.6%, respectively, and a
      flotation time of more than 3-5 min did significantly increase the number of
      floated eggs. The rate of recovery for Dicrocoelium eggs using the sedimentation
      technique was 41.2 +/- 1.5%.

PMID- 10337229
TI  - Comparison of sedative effects of medetomidine-midazolam, acepromazine
      butorphanol and midazolam-butorphanol in dogs.
AB  - Sedative effects of medetomidine at 20 micrograms/kg and midazolam at 0.3 mg/kg
      (MM), acepromazine at 0.05 mg/kg and butorphanol at 0.2 mg/kg (AB), and midazolam
      at 0.1 mg/kg and butorphanol at 0.2 mg/kg (MB) were compared in dogs. All dogs
      given MM were laterally recumbent within 11 min of the administration of the
      drugs, and this combination also induced deep sedation accompanied by analgesia
      and muscle relaxation, and strongly depressed arousal reactions to external
      stimuli. However, undesirable effects such as bradycardia and decreased
      respiration were also observed in dogs given MM. Six of seven dogs given AB were
      laterally recumbent within 16 min of the administration of the drugs, and this
      combination induced relatively deep sedation but only a mild depression of
      arousal reactions to external stimuli. MB induced mild or moderate sedation with
      relatively large differences in effects among individuals. The recovery from
      sedation in each group was smooth and total recovery times were not significantly
      different.

PMID- 10337230
TI  - Unexpected outcome after two consecutive infusions of disodium EDTA in dairy
      cows.
AB  - Disodium ethylenediaminetetraacetic acid (Na2EDTA) is a cation chelator which is
      used as an anticoagulant in blood samples and as a therapeutic agent in lead
      poisoning. Several experiments have been carried out with EDTA to induce
      hypocalcemia in cows and other animals, and toxic effects have rarely been
      reported. In this study, hypocalcemia was induced by means of a 5% Na2EDTA
      infusion (0.55 mg/kg/min Na2EDTA for 5 h = total dose of 100.6 g). Accidental
      acute toxicity and fatalities occurred after a consecutive second infusion in
      several cows. Researchers designing new experiments should be aware of a
      potential EDTA toxicity at a routinely used dose and rate of administration.

PMID- 10337231
TI  - Digestibility and compatibility of mixed diets and faecal consistency in
      different breeds of dog.
AB  - The digestive capacity of dogs varying in body size was tested. Digestive
      experiments were conducted with 10 different canine breeds (n = 66) with body
      weights ranging from 4.2 to 52.5 kg with 4-9 individuals. The animals were fed a
      canned or a dry commercial diet with a constant dry matter intake of 13 g/kg
      BW/day, except in Irish wolfhounds, which ingested only 10 g dry matter with the
      canned diet. Faecal dry matter was around 14% (absolutely) higher for the dry
      diet compared to the canned food, with a tendency in the larger breeds towards
      higher faecal water contents, less favourable faecal quality and increased
      numbers of defaecations. The Irish wolfhounds, the largest breed tested, had
      faeces with considerably lower water contents compared to Labrador retrievers,
      indicating that body weight is not the only factor to be considered. There were
      only small differences in the apparent digestibility of crude nutrients amongst
      the breeds. Sodium and potassium absorption was higher when the dry diet was fed
      compared to the canned food. In conclusion, breed and individual factors have to
      be taken into account when performing tests with dog food. Test panels for
      evaluating commercial diets should include breeds of larger body size and higher
      sensitivity to dietary disorders.

PMID- 10337232
TI  - Comparison of a conventional reproductive management programme based on rectal
      palpation and uterine treatment of endometritis with a strategic prostaglandin F2
      alpha programme.
AB  - Two reproductive management programmes were implemented on a dairy farm with 780
      cows in milk to compare their effects on reproductive efficiency and
      endometritis. The herd was divided into two groups. All cows in Group 1 received
      0.15 mg of D-cloprostenol (Preloban, Hoechst Roussel Vet, Wiesbaden)
      intramuscularly (i.m.) at 14-day intervals starting at 22-28 days postpartum (pp)
      until breeding. Group 2 was examined by rectal palpation twice during the third
      and fifth weeks pp, respectively. Cows that showed signs of endometritis were
      treated with a uterine infusion of 720 mg polycondensated m-cresolsulphuric acid
      formaldehyd (14:1) in 150 ml of water (Lotagen, 2%, Essex Tierarznei, Munchen).
      For both groups, the voluntary waiting period was set at 50 days pp. Cows were
      bred on observed oestrus. Cows not bred until day 71 pp were examined by rectal
      palpation and treated according to a predefined protocol. Group 1 had a higher
      service rate, and reduced days to first service (P < 0.05) and days open (7.6
      days, P = 0.08). First service conception rate and total conception rate were
      lower than in Group 2 (P < 0.05) and first service conception rate was
      considerably lower than second service conception rate in Group 1 (P < 0.01).
      Days open were 4.5 days higher and conception rates were lower in cows with
      endometritis than in cows without endometritis at post-partum examination (P >
      0.05). Results indicate that reproductive management programmes based on
      strategic use of prostaglandin F2 alpha present an alternative to conventional
      reproductive management programmes based on rectal palpation and uterine
      infusions in large dairy herds.

PMID- 10337233
TI  - Phenotypic analysis of bronchoalveolar lavage fluid lymphocytes in horses with
      chronic pulmonary disease.
AB  - A panel of specific antibodies against CD3, CD4, CD5, CD8, MHC I and II was used
      in single and two colour flow cytometry to define T cell subpopulations in
      bronchoalveolar lavage fluid of horses affected with chronic obstructive
      pulmonary disease and of healthy controls. According to the results of the
      clinical examination including bronchoscopy and cytology of the tracheal aspirate
      the horses were divided into four groups (healthy, subclinically to mildly
      affected; moderately affected, and severely affected). All groups of horses had a
      similar percentage of CD3+ cells in the BALF. Compared to controls, severely
      affected horses had a significantly increased number of CD4+ cells in the BALF,
      but a similar percentage of CD4+ cells whereas mildly and moderately affected
      horses had a decreased percentage. The percentage and number of CD8+ cells and
      the percentage of CD8+/MHCII+ cells in the BALF was found to be higher than
      normal and varied according to the disease state. This novel finding raises the
      possibility that not only the CD4+ cells but also the CD8+ cells are involved in
      the pathogenesis of COPD. The percentage and the number of CD8+ cells in BALF
      might be of diagnostic value to detect subclinical to mild cases of COPD.

PMID- 10337234
TI  - The use of non-immune plasma powder in the prophylaxis of neonatal Escherichia
      coli diarrhoea in calves.
AB  - The protective use of plasma powder from cattle and swine against experimentally
      induced neonatal E. coli diarrhoea in colostrum-deprived calves was examined.
      Diarrhoea was induced with a strain expressing F5+ fimbriae and a strain
      expressing F17+ fimbriae. In all groups supplemented with bovine plasma powder,
      diarrhoea and fever were less severe than in the control groups. For the groups
      infected with the F5+ E. coli strain, a reduction in excretion of the challenge
      strain by 2-4 orders of magnitude and by 1-2 orders of magnitude was seen when
      supplemented with bovine plasma powder at a dose of 25 g/l milk and 10 g/l milk,
      respectively. The bovine plasma powder showed also beneficial effects in the F17+
      infected groups. No mortality, no septicaemia and no severe clinical signs were
      observed. Concerning the excretion of the E. coli F17+ strain in the faeces, no
      significant difference with the control group was found. Swine plasma powder
      showed little beneficial effect on E. coli diarrhoea in calves in this study.

PMID- 10337235
TI  - Clinical and microbiological study of an otitis media outbreak in calves in a
      dairy herd.
AB  - On a dairy farm, otitis media was diagnosed in 64 suckler calves (21.8%) during a
      study period of 2 years, and in 10 calves (3.4%) in the third year. The
      inflammation was unilateral in 63 and bilateral in 11 calves. The affected calves
      were dull, lacked appetite, were pyrexic and displayed drooping ear or ears and
      tilted heads with purulent discharge exuding from the external ear canal. Of the
      affected animals, 56 (87.5%) were aged between 3 and 8 weeks. Morbidity was
      higher during the calving season and during the autumn and winter months (October
      December). Pasteurella haemolytica was isolated from 21 (32.8%), P. multocida
      from 20 (31.2%), Actinomyces pyogenes from 11 (17.2%) and Streptococcus
      pneumoniae from three (4.7%) of the clinically affected calves only during the
      first two study years. The exudate of the acute ear infections contained, in
      addition to Pasteurella spp., various bacteria and yeasts. Most of these bacteria
      were isolated from healthy ears as well, and are likely to be part of the normal
      ear flora. On the other hand most of the yeasts were isolated from otitic calves.
      After a short course of an appropriate treatment infections healed in all cases.
      Possible preventive measures are discussed.

PMID- 10337236
TI  - An evaluation of immunofluorescence and PCR methods for detection of rabies in
      archival Carnoy-fixed, paraffin-embedded brain tissue.
AB  - Direct immunofluorescence and PCR detection methods were compared for sensitivity
      in evaluating the rabies status of archival specimens of Carnoy-fixed, paraffin
      embedded brain tissue. The material consisted of 23 samples obtained during a
      rabies outbreak in Finland in 1988, and one sample isolated from a bat researcher
      who died of rabies in Finland in 1985. These results were compared with the
      original diagnoses performed on the fresh tissues. The immunofluorescence assay
      detected 100% (12/12) of the rabies-positive archival cases. A PCR assay designed
      to detect a 139-bp target near the 5' end of the rabies nucleoprotein gene also
      detected 100% (12/12) of the samples identified as positive in the fresh tissue
      specimens. A PCR assay designed to detect a 304-bp target spanning the 139-bp
      target of the first assay detected only 67% (8/12) of the original cases. No
      false positives were recorded. Both immunofluorescence detection of antigen and
      PCR detection of a short region of the nucleoprotein gene are useful in
      determining the rabies status of fixed, paraffin embedded (archival) material.

PMID- 10337237
TI  - Serological survey of viral antibodies in llamas (Lama glama) in Argentina.
AB  - This study analysed sera from 390 llamas (Lama glama) from nine farms located in
      three different Argentine provinces: Buenos Aires, Cordoba and Jujuy. The samples
      were tested for antibodies against 8 virus known to infect cattle: bovine
      herpesvirus type 1 (BHV-1), bovine viral diarrhea virus (BVDV), bovine adenovirus
      (BAdV III), bovine enterovirus (BEV), bovine rotavirus (BRV), bluetongue virus
      (BTV), bovine leukaemia virus (BLV), and foot-and-mouth virus (FMDV) by
      conventional methods such as seroneutralization, immunoperoxidase staining, and
      agar gel immunodiffusion. The antibody prevalences detected in llamas were: BHV-1
      in 0.77% (3/390), BVDV in 2.05% (8/390), BAdV III in 5.13% (20/390), BEV in 4.10%
      (16/390), BRV in 87.69% (342/390). No antibodies against BTV, BLV and VIAA (FMDV
      infection associated antigen) were detected.

PMID- 10337238
TI  - Biotin-streptavidin enzyme-linked immunosorbent assay for the detection of
      antibodies to Campylobacter jejuni and C. coli in chickens.
AB  - An enzyme-linked immunosorbent assay (ELISA) was developed in a homologous system
      with bacterial ultrasonic-treated proteins as the antigen and antisera from
      chickens infected orally and subcutaneously with the strain Campylobacter jejuni
      serovar 6 (CJ 6). The cut-off level was determined using antisera from non
      infected specific-pathogen-free chickens up to the age of 10 weeks. The
      suitability of the ELISA system was verified using antisera taken from chickens
      orally infected at the age of 4 weeks with CJ 1, 6, 28 or 36 or with
      Campylobacter coli serovar 28 (CC 28). The development of antibodies was
      monitored up to 6 weeks post-infection (p.i.). Sera from chickens infected with
      CJ 1, 6, 36 or CC 28 contained specific antibodies to Campylobacter, whereas in
      those infected with CJ 28 no specific antibodies were found. Distinct cross
      reactions were observed between CJ 6, 28 and CC 28 antigens and their antisera 6
      weeks p.i., while poor cross-reactions were found with antisera to CJ 1 and 28.
      Antibodies to strains of all heterologous serovars were successfully detected
      with an antigen pool comprised of CJ 1, 6 and 36 antigens. In 11 out of the 12
      field sera obtained from 5- and 9-week-old broiler chickens suffering from
      campylobacteriosis, high specific antibody titres to Campylobacter jejuni were
      found.

PMID- 10337239
TI  - Detection and identification of Mycoplasma conjunctivae in infectious
      keratoconjunctivitis by PCR based on the 16S rRNA gene.
AB  - A specific PCR assay based on unique sequences of the rrs genes (16S rRNA) of
      Mycoplasma conjunctivae was developed for direct detection and identification of
      this pathogen from clinical material. DNA from eye swabs was amplified after a
      simple lysis step by either a single PCR with the M. conjunctivae specific primer
      pair McoR1 and McoF1, or by a nested PCR with the Mycoplasma genus specific
      primer pair MOLIGEN1-L and 16UNI-R in the first step and McoR1 and McoF1 in the
      second step. The specificity of the primer pair McoR1 and McoF1 was verified with
      purified DNA from the type strain, from 17 field isolates of M. conjunctivae and
      from several Mollicutes which are phylogenetically related to M. conjunctivae or
      which can be isolated from the same host animals. This method identified
      mycoplasma isolates from goat, sheep, ibex and chamois originating from different
      countries as M. conjunctivae. No cross amplifications with other mycoplasmas
      which are related to M. conjunctivae were observed. Eye swab samples containing
      known numbers of M. conjunctivae cells were analysed after direct lysis of the
      material. The detection level was estimated to be 20 cells per swab when the
      nested PCR procedure was used and 2 x 10(5) by the single PCR method. In an
      experimental infection model of sheep, the nested PCR method for detection of M.
      conjunctivae gave results which were comparable to mycoplasmal culture. These are
      the implications for diagnostic purposes: M. conjunctivae isolates can be
      identified by the one-step PCR method, whereas for detection and identification
      of M. conjunctivae in clinical material the two-step method should be used
      (higher sensitivity).

PMID- 10337240
TI  - Antibodies against Helicobacter felis in sera of cats and dogs.
AB  - Serum samples from 61 dogs and 49 cats were screened for circulating antibodies
      against Helicobacter felis by an enzyme-linked immunosorbent assay (ELISA) using
      sonicated bacteria as an antigen. To improve the specificity of the ELISA, sera
      were absorbed with Campylobacter jejuni subsp. jejuni H. pylori as well as H.
      felis. Sera from 26 dogs (43%) and 19 cats (39%) revealed clear positive
      absorbance readings determined as an optical density (OD) that was statistically
      significant above the OD mean value [P < 0.025 (one-tailed); log10]. The
      absorbance pattern of ELISA-positive sera corresponded to results obtained with
      bovine and human reference sera. Furthermore, a correlation between the immune
      response and results from histopathological examination of gastric specimens from
      22 dogs was demonstrated. It could be shown that antibodies against H. felis in
      sera of cats and dogs can easily be detected using an ELISA. The diagnostic value
      of this test must be evaluated in further investigations.

PMID- 10337241
TI  - Evaluation of culture methods for rapid screening of swine faecal samples for
      Yersinia enterocolitica O:3/biotype 4.
AB  - In two studies, seven different culture protocols were compared to test naturally
      contaminated faecal samples from pigs for isolation of Y. enterocolitica serotype
      O:3/biotype 4 (n = 70 and n = 79). Four of the protocols were based on the Nordic
      Committee on Food Analysis (NMKL, protocols), while three protocols were based on
      a rapid and selective method (here called ITC protocols). The protocols differed
      mainly in time of pre-enrichment (1, 10 and 24 d) and enrichment (2, 10, 24 d)
      and the type of selective enrichment media (ITC vs. MRB). The sensitivity of the
      rapid ITC protocol (24% and 9%) was comparable with the lengthy NMKL-protocols
      (16% and 11%), while the results of direct plating after 3 h (4%) and the
      extended enrichment in ITC-broth (4%) were very low. In addition, there was a
      marked reduction in the number of false positive plates in the short selective
      protocol (62% vs. 12%). The results indicate possibilities of shortening the
      culture methods by replacing most of the biochemical tests with an agglutination
      test based on a monoclonal antibody.

PMID- 10337242
TI  - Comparison of restriction pattern polymorphism of Mycoplasma agalactiae and
      Mycoplasma bovis by pulsed field gel electrophoresis.
AB  - Mycoplasma agalactiae and Mycoplasma bovis are closely related species in
      phylogenetic terms. Pulsed Field Gel Electrophoresis (PFGE) of SmaI, EclXI, Bsi
      WI, MluI, BssHII, SalI, XhoI, NruI and ApaI digested DNAs were used to analyse
      and to compare restriction fragment length polymorphism between M. agalactiae and
      M. bovis and to estimate their genome sizes. SmaI, EclXI and Bsi WI enzymes
      cleaved DNAs of both microrganisms. MluI, BssHII, SalI, XhoI and NruI digested
      only M. agalactiae DNA whereas ApaI cut only M. bovis DNA. The total DNA length
      was established to be 945 +/- 8.4 Kb for M. agalactiae and 961 +/- 18.9 Kb for M.
      bovis.

PMID- 10337244
TI  - How to tell if you're tired of your job.

PMID- 10337243
TI  - Possible causes of diabetes mellitus in cattle infected with bovine viral
      diarrhoea virus.
AB  - In cattle, we encountered insulin-dependent diabetes mellitus (IDDM) associated
      with bovine viral diarrhoea virus (BVDV) infection. To estimate the correlation
      between IDDM and BVDV infection, the distribution of BVDV in the pancreas and
      islet-cell antibody (ICA) were investigated. The distribution of BVDV in the
      pancreas was examined by in situ hybridization using two oligonucleotide probes
      that recognized the gp25- and p14-coding regions of the BVDV gene. ICA was
      examined by indirect fluorescence antibody assay using the sera from affected
      cattle and pancreata from normal cattle. In the pancreata of all BVDV-infected
      cattle, including IDDM-complicated cattle, oligonucleotide probe hybridized
      portions were recognized. In short, BVDV genes were detected not only in IDDM
      complicated cattle but also in uncomplicated cattle. Moreover, there was no
      hybridized portion in the islet cells. In BVDV-infected and IDDM-complicated
      cattle, ICA was frequently detected. On the other hand, ICA was not detected in
      BVDV-infected and IDDM uncomplicated cattle. These results suggest that IDDM
      associated with BVDV infection is not a direct effect of BVDV on islet cells.
      Therefore, as BVDV did not induce IDDM in any cases, it appears that BVDV does
      not induce IDDM directly, but rather may be an autoimmune disease induced by
      autoantibodies against islet cells.

PMID- 10337245
TI  - Technology advances and changes in treatment planning.

PMID- 10337246
TI  - The female soft tissue profile as presented in fashion magazines during the
      1900s: a photographic analysis.
AB  - Numerous studies have emphasized the importance of the facial profile in
      orthodontic treatment planning, with some arguing that the esthetic ideal has
      remained unchanged for thousands of years. To evaluate changes in the white
      female facial profile, we measured 14 soft tissue variables on profile
      photographs presented in fashion magazines during the 1900s. Five time frames
      were studied, with a sample of 25 photographs from each period corrected for size
      and orientation. Between-group differences were examined by use of analysis of
      variance, using a P value corrected for a multivariable analysis. Significant
      between-group differences (P < 0.0001) were found for anteroposterior lip
      position, amount of visible lip tissue, and interlabial angle, with the more
      recent groups displaying fuller and more anteriorly positioned lips. No
      significant differences were found for measurements calculated superior to
      subnasale (frontonasal angle, nasal tip angle, and nasolabial angle) or in the
      relationship of the chin to the upper face (total facial angle). The results of
      this study suggest that standards for the esthetic white female facial profile
      are not static and show a trend in this century toward fuller and more anteriorly
      positioned lips.

PMID- 10337247
TI  - Prediction accuracy of soft tissue profile in orthognathic surgery.
AB  - The purpose of this study was to compare soft tissue prediction accuracy of model
      surgery combined with computer software prediction with that of computer software
      prediction alone and to assess surgical accuracy by comparing the immediate
      postsurgical cephalogram with the planned movement of skeletal hard tissue. The
      predicted and actual soft tissue changes and the corresponding skeletal changes
      of 16 patients were compared using the Quick Ceph Image cephalometric treatment
      simulation software. A custom analysis was created to measure the hard tissue and
      soft tissue changes that occurred as a result of the surgical procedure. On
      average, the predictions were not significantly different from the actual
      postsurgical profile changes. Surgical changes of hard tissues from presurgery to
      postsurgery were accurate as planned except for the position of N-ANS. All lower
      soft tissue points moved significantly during treatment. Quick Ceph Image offers
      a rapid and reliable method of profile prediction that does not require artistic
      skill. If predictions are interpreted with caution and transferred accurately to
      the model surgery, they can provide an excellent visual aid during presurgical
      treatment planning and patient presentation.

PMID- 10337248
TI  - Analysis of soft tissue profile changes associated with mandibular setback and
      double-jaw surgeries.
AB  - The soft tissue profile changes resulting from double-jaw surgery (maxillary
      advancement and mandibular setback) and mandibular setback alone were evaluated.
      The measurements were evaluated on the preoperative and postoperative
      cephalometric radiographs of 24 skeletal Class III patients. The results
      demonstrated significant correlations and suggested that the soft tissue ratios
      seen in double-jaw surgery were similar to those in mandibular setback surgery
      alone, with the exception of the changes in nasal tip projection and the upper
      lip area.

PMID- 10337249
TI  - Semirigid fixation of the mandible in bimaxillary orthognathic surgery: stability
      after 18 months.
AB  - The stability of osteosynthesis with the use of semirigid mandibular fixation was
      evaluated in 15 patients who underwent bimaxillary procedures for correction of
      Class III malocclusion. All patients received rigid fixation (4 miniplates and
      screws) in the maxilla. Cephalometric evaluation was performed before the
      operation, immediately after the operation, and at least 18 months after the
      operation. At the 18-month follow-up, a mean mandibular relapse of 2.2 mm,
      associated with an additional advancement of the maxilla of 0.27 mm, was
      observed. The dental relationship was substantially correct. Stability of
      mandibular fragments in this sample of patients depended on the stability of the
      maxilla. In addition, neither clinical damage to the temporomandibular joint nor
      lesions to the neurovascular bundle were detected.

PMID- 10337250
TI  - Simplified cephalometric lines for the estimation of muscular lines of action.
AB  - In the study of masticatory muscle performance, one of the biomechanical
      variables that can be estimated is the mechanical advantage of the masticatory
      muscles, namely, the ratio between the muscular moment arm and the bite force
      moment arm. In the present study, the position of the estimated line of action of
      the masseter muscle, drawn between gonion and orbitale (Go-Or) relative to dental
      (occlusal plane) and skeletal (Frankfort plane) references was analyzed in 431
      pretreatment lateral cephalograms of orthodontic patients (195 males, 236
      females) aged 6 to 50 years, and in the lateral tracings of the Bolton standards
      (6 to 18 years of age). The following measurements were evaluated: (1)
      skeletocutaneous class (soft tissue equivalent of Wits appraisal, linear distance
      in millimeters between the projections of points A' and B' on the occlusal
      plane); (2) angle between the Go-Or line and the perpendicular to the occlusal
      plane at the molar occlusal point; and (3) angle between the Go-Or line and the
      Frankfort plane. In the patients, the skeletocutaneous class ranged between--14.5
      and 15.5 mm, without any sex- or age-related differences. The angle between the
      Go-Or line and the perpendicular to the occlusal plane was, on average, 39
      degrees (range 15 to 53 degrees), and it decreased with advancing age; while the
      average angle between Go-Or and Frankfort plane was 42 degrees (range 30 to 54
      degrees), and it increased in older patients. No effects of sex were found. The
      two angles were significantly correlated to each other, while no correlations
      were found with the sagittal jaw discrepancy. Similar results were obtained on
      the Bolton tracings. Overall, the present cephalometric analogue could be useful
      in biomechanical simulations.

PMID- 10337251
TI  - Surgical cephalometric prediction tracing for the alteration of the occlusal
      plane by means of rotation of the maxillomandibular complex.
AB  - The surgical cephalometric prediction tracing involving the alteration of the
      occlusal plane differs from the conventional surgical prediction tracing. When
      conventional surgical prediction is developed, the final occlusal plane is
      dictated by the occlusal plane of the mandible, with or without autorotation. The
      mandible (and therefore the mandibular occlusal plane) will rotate around a point
      at or just posterior to the condyle. This principle is not adhered to in
      treatment planning requiring rotation of the maxillomandibular complex and
      consequent alteration of the occlusal plane. The aim of this paper is to present
      a method for developing a surgical cephalometric prediction tracing involving
      rotation of the maxillomandibular complex.

PMID- 10337252
TI  - Assessment of health-related quality of life for patients with severe skeletal
      disharmony: a review of the issues.
AB  - Health-related quality of life (HRQOL) assessments made by patients provide a
      view of dentofacial disharmony and surgical outcome that can inform clinicians in
      important ways. In this paper, HRQOL as it pertains to patients with dentofacial
      disharmony and orthognathic surgery is discussed from three perspectives. First,
      arguments regarding the necessity of studying HRQOL in orthognathic patients are
      presented. Second, a variety of ways of defining HRQOL are reviewed, and
      implications for applications to orthognathic surgery are discussed. Finally,
      various measurement techniques are presented for assessing HRQOL in orthognathic
      patients. Use of dental HRQOL measures, as well as multi-item, multimeasure
      techniques, are discussed. For more reliable and comprehensive HRQOL measurement
      in patients with dentofacial disharmony, multi-item, multimeasurement techniques
      should be employed. While such techniques place greater demands on patients who
      are completing paper-and-pencil measures, the resultant low measurement error and
      comprehensive HRQOL assessment outweighs the risk of subject fatigue.

PMID- 10337254
TI  - The state of technical schools.

PMID- 10337253
TI  - Alternative methods for reduction of blood loss during elective orthognathic
      surgery.
AB  - Bimaxillary orthognathic surgery and genioplasty are frequently performed to
      correct dentoskeletal anomalies in otherwise healthy young patients. Until 1990
      homologous blood transfusions were routinely necessary for these procedures. The
      present study describes a protocol of blood-saving measures that was adopted and
      tested on a continuous sample of 127 patients treated between 1994 and 1997. The
      protocol comprises acute normovolemic hemodilution, controlled moderate
      hypotension, positioning the surgical field above the heart level, cell saving,
      intraoperative homeostasis, preoperative autologous blood donation,
      administration of recombinant erythropoietin, and acceptance of a low hematocrit
      perioperatively. This study shows that homologous blood transfusions may be
      avoided intraoperatively by following the protocol described.

PMID- 10337255
TI  - Spark erosion for precise fitting of implant retained restorations.
AB  - This article describes modern, precise methods of imaging and manufacturing
      implant-retained dental restorations. Scan data, combined with spark erosion
      technology, eliminates many of the problems associated with implant retained
      restorations.

PMID- 10337256
TI  - Are you listening?

PMID- 10337257
TI  - Does your laboratory just say no?

PMID- 10337258
TI  - Achieving natural looking restorations.
AB  - Early in my career, I realized that to achieve lifelike restorations, one needed
      to introduce the same excellence into the laboratory that exists in a high-end
      esthetic dental practice. I discovered that the foundation for excellent
      esthetics begins with good communication between the dental technician and the
      dentist. To establish good communication, one should acquire knowledge of the
      requirements and limitations encountered by both the technician and the dentist.
      Once meaningful communication is established between the two disciplines,
      esthetic excellence will follow.

PMID- 10337259
TI  - The bilateral free-end situation in the maxilla.

PMID- 10337260
TI  - New horizons in military dental laboratory training.
AB  - Dental laboratory training has taken on a new look for the military. As a result
      of numerous cost analyses Air Force, Navy, and Army training has been combined
      under one roof. All three services have molded their courses together to form a
      tri-service training program at Sheppard AFB in Wichita Falls, Texas. Graduation
      of the first class occurred on June 24, 1998. A 6 month basic course, as well as
      several advanced concept courses are offered by the program. Instructors from all
      branches of service are represented on staff to teach. The facility is state of
      the art and was built in 1991 to provide for Air Force Dental Training.
      Downsizing of today's military has resulted in dental training coming together to
      provide one quality course to military individuals qualified to enroll, thus
      ensuring tomorrow's laboratory technicians will be as qualified as those in the
      past.

PMID- 10337261
TI  - Give directions that are understood the first time--Part II.

PMID- 10337262
TI  - Resin bonding to various alloys by means of the Silicoater MD System.
AB  - The aim of this research was to evaluate the effectiveness of the Silicoater MD
      System for bonding resin to four different Brazilian alloys. The alloys included
      the following proprietary materials: Duracast, Durabond II, Palad and Premium.
      Biobond II, a popular nickel-chromium alloy has been used as control. Dentacolor
      served as the veneering agent. All specimens were thermo-cycled for 24 hours
      between 41 degrees and 131 degrees C at a dwell time of one minute per
      temperature. Shear-bond strengths ranged from 1667 to 2842 psi. Scanning electron
      microscopic evaluation demonstrated no gap formations at the resin/metal
      interface for all of the aforementioned systems, the Silicoater MD System
      demonstrated acceptable retention efficiency in five types of metallic alloys.

PMID- 10337263
TI  - Training: leading the way.
AB  - As Dental Laboratory owners, managers, technicians and office staff, we must
      recognize that our number one priority to become and remain successful is
      customer retention. To that end, it's essential that we gain insight into
      customizing the services we offer our clientele. This article will reveal and
      discuss considerations and available actions, specific to the dental laboratory,
      for achieving exemplary customer service. By providing on-going customer service
      training for staff through customized training and role playing optimal
      communication and customer service awareness will result.

PMID- 10337264
TI  - Human hepatitis viruses.
AB  - Dental care workers, including dental laboratory technologists, are at
      occupational risk for the occupational acquisition of hepatitis viruses. Of
      course, personal behaviors, home environments and health histories affect the
      rate of viral infections for all persons. Of greatest concern are hepatitis B, C
      and D. Although highly infectious, there are highly effective vaccines that
      prevent acquisition of hepatitis B. Prevention of hepatitis B infection precludes
      any hepatitis D infection. Hepatitis C viruses are less infectious than hepatitis
      B. However, since no vaccine exists for hepatitis C and the increased chances for
      the development of chronic infection hepatitis C will remain a serious health
      concern. Human blood is an excellent medium for the growth and transmission of
      human hepatitis. This means that new (and possible more virulent forms of
      currently known viruses) hepatitis viruses will likely continue to be identified
      for the foreseeable future.

PMID- 10337265
TI  - How important is it to understand people?

PMID- 10337266
TI  - A milled implant-supported removable partial denture.
AB  - Implant supported prostheses are highly successful restorations. There are
      multitudes of differing designs for these restorations. It is advantageous to
      retain some nervous input from the remaining dentition. The treatment modality
      presented in this paper not only has the support, stability, and retention
      necessary for all restorations, some of the remaining teeth are retained and are
      included in the restoration design.

PMID- 10337267
TI  - Precise, full-arch fixed mandibular implant-retained restorations.
AB  - Many completely edentulous patients would prefer to have their missing teeth
      replaced with fixed, implant-retained restorations that restore normal form and
      function. Unlike natural teeth, implants are rigidly attached to the supporting
      alveolar bone and require unique laboratory procedures.

PMID- 10337268
TI  - Happily ever after...? Study explores how baby boomers envision retirement.

PMID- 10337270
TI  - Developing a marketing strategy for the small laboratory.

PMID- 10337269
TI  - What are your communication goals for 1999?

PMID- 10337271
TI  - Profession of professionalism.

PMID- 10337272
TI  - Let's raise the standard.

PMID- 10337274
TI  - Customer service and your business.

PMID- 10337273
TI  - Empress 2. First year clinical results.
AB  - As the search for perfect dental restorative materials continues, it seems we
      routinely return to ceramics as our standard. Current all-ceramic systems are
      state-of-the-art with regard to esthetics and function, but are limited in use to
      single unit restorations. Recently, an all-ceramic lithium disilicate
      fluorapatite ceramic system was introduced (IPS Empress 2, Ivoclar North America,
      Amherst, NY), that allows multiple unit restorations to be fabricated and
      cemented using adhesive or traditional cementation techniques. This article will
      overview the technical procedures and advantages of this new ceramic system.

PMID- 10337275
TI  - Metal-free, pressable ceramic restorations.

PMID- 10337276
TI  - Cool down. Heated conversations with constructive communication.

PMID- 10337277
TI  - Answering the temptation of higher pay.

PMID- 10337279
TI  - Removable partial dentures: the altered-cast technique.
AB  - The altered-cast technique, also known as the corrected-cast technique, for
      distal extension removable partial dentures (RPD), is not routinely utilized by
      dentists. Although the technique requires an additional step for both the dentist
      and dental technician, it offers several advantages--maximum stability, minimal
      stress on abutment teeth, and more predictable occlusion. The following article
      describes the altered-cast technique, as well as some advantages and
      disadvantages of the technique. A quick and easy procedure for constructing an
      altered-cast is also presented.

PMID- 10337278
TI  - The John Hubbard Ceramic Margin Anchor System.

PMID- 10337280
TI  - Meeting the challenge of the orthodontics specialty exam.

PMID- 10337281
TI  - Education for the dental technician: a unique experience at the health science
      center.

PMID- 10337282
TI  - What I expect from a commercial laboratory.

PMID- 10337283
TI  - What makes dental laboratory software unique?

PMID- 10337284
TI  - Motivating your laboratory.

PMID- 10337286
TI  - Use of a customized rigid clear matrix for fabricating provisional veneers.
AB  - The fabrication of provisional veneers is time consuming, and may be
      unpredictable, especially in cases of multiple veneer preparations; however,
      functional and esthetic provisional veneers, may be used as diagnostic adjuncts
      for the fabrication of the definitive restoration. This article presents, in a
      step-by-step procedure, the use of a customized rigid clear matrix with light
      cured composite resin as a fast alternative for the fabrication of functional and
      esthetic provisional composite resin veneers. CLINICAL SIGNIFICANCE: The use of a
      customized rigid clear matrix for the fabrication of light-cured composite resin
      provisional veneers has the following advantages: the shape and surface texture
      produced in the diagnostic wax-up are accurately transferred to the patient's
      mouth; the provisional restoration is fabricated without violation of the soft
      tissue and the margins of the preparations; use of the matrix can be repeated
      when needed; and esthetic and functional provisional veneers can be fabricated
      relatively quickly.

PMID- 10337285
TI  - Rationalization of esthetic restorative dentistry based on biomimetics.
AB  - The exponential progressivism that characterizes the current decade often comes
      with substantial financial implications. Dental care is not spared by this
      phenomenon. However, new generations of concepts emerging from biomimetics
      provide the operator with the ability to restore the biomechanical, structural,
      and esthetic integrity of teeth. The development of adhesion and the evolution of
      porcelain veneers constitute striking examples of this nascent process.
      Indications for bonding porcelain are extending to more perilous situations
      (crown-fractured incisors, nonvital teeth), resulting in considerable
      improvements, comprising both the medical-biologic aspect (economy of sound
      tissues and maintenance of tooth vitality) and the socioeconomical context
      (decrease of costs compared to traditional and more invasive prosthetic
      treatments). CLINICAL SIGNIFICANCE: In the bonded porcelain veneer and its
      extensions, restorative dentistry has found new solutions for the anterior
      segment that balance the need for functional and esthetic reconstruction. The
      optimal stiffness of porcelain in thin section, the ideal surface
      characteristics, and the biomechanical continuum achieved through high
      performance bonding mean the crown of the tooth as a whole can support incisal or
      masticatory function. By the same token, the conduction of optical effects from
      within the tooth combined with the ideal surface features of the porcelain veneer
      make this restorative approach the ultimate in esthetic satisfaction, for both
      the practitioner and the patient.

PMID- 10337287
TI  - Laboratory evaluation and clinical application of a new one-bottle adhesive.
AB  - PURPOSE: The purposes of this project were to compare the enamel and dentin bond
      strengths of a new nanofilled one-coat adhesive system with its predecessor, an
      unfilled two-coat adhesive system; to analyze the dentin interfacial
      ultramorphology, using scanning and transmission electron microscopy (SEM and
      TEM); and to illustrate the clinical technique associated with the use of the new
      nanofilled one-coat adhesive system. MATERIAL AND METHODS: Twenty flat dentin
      surfaces and 20 flat enamel surfaces were polished on the labial surface of
      bovine incisors mounted in acrylic resin. The specimens were equally and randomly
      assigned to four bonding groups: (1) dentin with Prime & Bond 2.1; (2) dentin
      with Prime & Bond NT; (3) enamel with Prime & Bond 2.1; and (4) enamel with Prime
      & Bond NT. A composite post was then adapted to the treated area and light-cured.
      After thermocycling, shear bond strengths were determined by testing the shear
      strength of the specimens. The data were analyzed using one-way analysis of
      variance (ANOVA) and Student's t-test. For SEM and TEM, six dentin disks were
      obtained from middle dentin of human third molars and assigned equally to each
      adhesive. The adhesives were applied to dentin according to manufacturer's
      directions. The hybrid layer and resin penetration into dentin tubules were
      analyzed at an ultramorphologic level, and the observations were compared.
      RESULTS: Shear bond strengths were as follows: group 1: 17.8 +/- 4.1 MPa; group
      2: 20.5 +/- 3.5 MPa; group 3: 24.7 +/- 6.7 MPa; and group 4; 27.0 +/- 5.4 MPa.
      Electron microscopy showed that both adhesives penetrated the dentin tubules and
      formed a fully infiltrated hybrid layer. The nanofiller included in the new one
      application adhesive penetrated the dentin tubules and infiltrated the
      microspaces between the collagen fibers within the hybrid layer. CLINICAL
      SIGNIFICANCE: The new one-application nanofilled adhesive tested in this study
      resulted in bond strengths and dentin hybridization comparable to those obtained
      with the corresponding two-application system. The clinical sequences presented
      illustrate the ease of use of the newest simplified adhesives.

PMID- 10337288
TI  - Two-year clinical evaluation of tooth whitening using an at-home bleaching
      system.
AB  - PURPOSE: The purpose of this study was to evaluate the 2-year effectiveness of a
      carbamide peroxide at-home bleaching gel used to provide tooth lightening
      treatment. MATERIAL AND METHODS: Twenty-nine patients participated in the
      original study, during which they treated their maxillary teeth with a 10%
      carbamide peroxide gel nightly for 2 weeks. Shades were determined before and
      after treatment by comparison with a Vita shade guide. Twenty-four patients (a
      recall rate of 83%) were recalled for evaluation 2 years after the initial
      bleaching treatment. The shade of the maxillary incisors was evaluated and
      compared with shades before, immediately after, and at 6 months and 2 years after
      initial treatment. Data were analyzed using a repeated-measures analysis of
      variance. RESULTS: At 2 years after bleaching with a 10% carbamide peroxide gel,
      the median shade was D2, a six-increment difference from the baseline median of
      D3. Twenty of 24 patients (83.3%) had a shade change of two or more units, which
      is the threshold value for bleaching efficacy using American Dental Association
      guidelines. The lightening result remained statistically significant (p < .0001)
      at 2 years. CLINICAL SIGNIFICANCE: Although some reversal of the lightening
      effect occurs over time following the original bleaching treatment, loss of the
      lighter color appears to be gradual for most patients. Although the longevity of
      the lightening effect remains to be determined, this clinical trial indicates
      that the majority of patients have a satisfactory result 2 years after treatment.

PMID- 10337289
TI  - Dental and oral discolorations associated with minocycline and other tetracycline
      analogs.
AB  - It has been well acknowledged in recent literature that minocycline, a
      semisynthetic tetracycline derivative, causes discolorations in adult teeth and
      various other collagenous tissues. This article presents the most common patterns
      of minocycline staining in addition to comparing the staining patterns of other
      tetracycline analogs in the permanent dentition. It also reviews the literature's
      most prominent theories describing the process of minocycline discoloration, and
      evaluates their plausibility. It is a goal of this article to make dental
      practitioners aware of the possible effects of minocycline therapy and to
      highlight useful ways to treat or prevent these discolorations. Currently,
      conventional treatments include vital and nonvital bleaching, veneers, or crowns,
      depending on the severity of the discoloration. The literature shows that
      possible preventive efforts revolve around cessation of the drug or the use of
      large doses of vitamin C or other antioxidants in conjunction with minocycline
      therapy to prevent the formation of the pigment responsible for the staining.
      CLINICAL SIGNIFICANCE: Minocycline and other tetracycline analogs are well known
      for causing discoloration of developing teeth in children. However, practitioners
      must be aware of the tooth staining potential of minocycline in adult populations
      as well. Studies suggest that the concomitant use of vitamin C may help prevent
      adult-onset pigmentation caused by minocycline.

PMID- 10337290
TI  - Diversity: a blessing or a curse?

PMID- 10337291
TI  - Mechanical properties of compomer restorative materials.
AB  - The purpose of this study was to measure the compressive strength, flexural
      strength, microhardness, and surface roughness of three compomers (Compoglass,
      Dyract, and Hytac) and compare the values to the ones obtained for a resin
      modified glass-ionomer cement (Vitremer) and a resin composite (Z100). All
      materials were handled according to the manufacturers' instructions. There was a
      significant difference (P < 0.01) among Vitremer, Hytac and Z100 composite with
      regard to yield strength. Vitremer values were lower than for Hytac, which were
      lower than for Z100. The yield strength values for Compoglass and Dyract were
      significantly lower than for Hytac and Z100 composite and significantly higher
      than for Vitremer (P < 0.01). There was no significant difference in the strain
      at yield among Vitremer, Hytac, and Z100, but their values were significantly
      higher than for Compoglass and Dyract (P < 0.01). The flexural strength data
      displayed a significant difference between Vitremer and Hytac (P < 0.05). Z100
      was significantly stronger than the other products tested. The values of strain
      at break for Vitremer, Hytac, and Z100 were significantly lower than for
      Compoglass and Dyract (P < 0.01). The compressive strength results showed
      significantly higher values for Dyract, Compoglass, and Hytac than for Vitremer
      (P < 0.01). Z100 displayed higher values than the other products tested (P <
      0.01). Hytac strength was significantly higher than for Dyract (P < 0.01). The
      microhardness of Compoglass and Dyract was not significantly different (P <
      0.05). Hytac displayed microhardness values higher than for Vitremer, Compoglass,
      and Dyract (P < 0.01). However, all products tested showed values significantly
      lower than for Z100 (P < 0.01). The surface roughness values for Compoglass,
      Dyract, Hytac, and Z100 were not significantly different. Vitremer displayed a
      significantly higher value than Dyract, Hytac, and Z100 (P < 0.05).

PMID- 10337292
TI  - Two-year clinical performance of a resin-modified glass-ionomer restorative
      material.
AB  - This study was a 2-year clinical evaluation of a conventional and a resin
      modified glass-ionomer restorative material. Thirty-four restorations each of
      Ketac-Fil and Photac-Fil were placed without tooth preparation in cervical
      abrasion/abfraction lesions, primarily in premolar teeth. Patients ranged in age
      from 30 to 73 years, with a median age of 45 years. Isolation for the
      restorations was accomplished with cotton rolls. Restorations of both materials
      were retained at the rate of 93%, and both were comparable in appearance,
      receiving Alfa ratings for more than 85% of the restorations. One occurrence of
      secondary caries was observed for each material. No significant difference
      between the materials was observed for any evaluation category (exact binomial
      test, P > 0.05).

PMID- 10337293
TI  - Fluoride release from some dental materials in different solutions.
AB  - Most of the data reported on release of fluoride from dental materials are based
      upon measurements made in deionized water and artificial saliva, which do not
      simulate the dynamics of caries development. So, the purpose of this study was to
      determine the level of fluoride released from different restorative materials in
      storage solutions, considering the caries process (pH-cycling). Six cylindrical
      samples of each material (Chelon-Fil, Dyract, Variglass, Vitremer, and Tetric)
      were prepared and suspended individually in 2.0 mL of each studied solution. The
      studied media were deionized water, artificial saliva, and solutions for pH
      cycling (demineralizing solution--pH 4.3 and remineralizing solution--pH 7.0).
      All solutions were changed daily over 15 days. Fluoride release was determined
      after buffering the solutions with an equal volume of TISAB. The fluoride release
      was higher in pH-cycling than in the other solutions (P < 0.05), and changes of
      the rank order of fluoride release from the studied materials occurred when the
      different media were considered (P < 0.05). The data suggest that the comparison
      of fluoride released from dental materials is dependent on the medium used in the
      evaluation.

PMID- 10337294
TI  - Radiopacity of compomers, flowable and conventional resin composites for
      posterior restorations.
AB  - The objective of this study was to densitometrically determine the relative
      radiopacity (aluminum [Al]-equivalent values) of dentin, enamel, and 20 resin
      composite materials currently used for posterior restorations. Specimens 5 mm in
      diameter and 2 mm thick were fabricated from 20 materials (n = 7) for a total of
      140 specimens. Human molars were longitudinally sectioned 2.0 mm thick to include
      both enamel and dentin. The optical densities of enamel, dentin, restorative
      materials, lead, and aluminum step wedge were obtained from radiographic images,
      using a transmission photodensitometer. The Al equivalent (mm) for each material
      was calculated from the linear regression equation of the log of normalized
      optical density and Al mm thickness obtained from the step wedge. A linear
      regression of the logarithm of normalized optical density and Al mm thickness was
      plotted (r2 = 0.9953), and the relative radiopacities, expressed as equivalent
      thickness of Al, were ranked ordinally. All materials tested, with the exception
      of an unfilled resin adhesive, complied with ISO Standard 4049, being at least as
      radiopaque as a 2.0 mm thickness of 99.6% pure Al. Four of six flowable
      composites had radiopacity values that fell between that of dentin and enamel,
      while two materials were more radiopaque than enamel. The three compomers tested
      had radiopacities greater than enamel. In addition, all traditional light- and
      chemical-cure resin composite materials tested were more radiopaque than enamel.
      All materials tested, with the exception of one adhesive resin, were at least as
      radiopaque as dentin and complied with ISO Standard 4049. Clinicians should be
      able to distinguish these restorative materials radiographically from recurrent
      decay, voids, gaps, or other defects that lead to clinical failure. Utilization
      of materials ranked more radiopaque than enamel would enable clinicians to
      distinguish the restorative material from tooth structure.

PMID- 10337295
TI  - Retention of microfilled and hybrid resin-based composite in noncarious Class 5
      lesions: a double-blind, randomized clinical trial.
AB  - This double-blind clinical trial was undertaken to compare the retention rate of
      restorative materials with contrasting stiffness in noncarious class 5 lesions.
      All restorations were placed using retraction cord and cotton roll isolation to
      more closely mimic the general practice setting. Thirty subjects with at least
      two lesions were recruited to participate in the study. Each subject received one
      restoration using Silux Plus and one using Z100. The assignment of material was
      randomized, and the subjects were unaware of which tooth had received which
      material. All restorations were placed with a fourth-generation adhesive liner,
      Scotchbond Multi-Purpose. Evaluations were performed at baseline, 6, and 12
      months by two independent examiners unaware of the restoration's group identity.
      The restorations were evaluated using criteria developed by Cvar and Ryge in a
      forced-consensus model. Despite the fact that the two materials have widely
      different elastic modulus values, after 12 months no difference between the
      retention rates for the two groups was found, and both groups of restorations
      performed very well.

PMID- 10337296
TI  - Effect of curing-tip diameter on the accuracy of dental radiometers.
AB  - The purpose of this study was to determine the accuracy of four commercially
      available radiometers when curing tips of different diameters were used. A
      visible-light curing unit (Optilux 500) with a new 80-watt quartz-halogen bulb
      (OptiBulb) was used as the light source for all measurements. The unit's
      irradiance value was measured using three hand-held radiometers (Demetron model
      #100, Cure-Rite model #644726, and Coltolux Light Meter) and a built-in visible
      light curing unit radiometer (Optilux 500). Measurements were made with four
      curing tips of diameters 4 mm, 7.5 mm, 10.5 mm, and 12 mm. For each tip, trials
      were made with five radiometers of each model. Student's t-tests at the 0.05
      level of significance were used to compare the mean irradiance measured by each
      model of radiometer, to the irradiance value measured by a laboratory-grade power
      meter. A one-way analysis of variance at the 0.05 level of significance was used
      to compare the irradiance values among the five samples of each commercially
      available radiometer model. Except for the Optilux 500 built-in radiometer with
      the 10.5-mm tip, all the commercially available radiometers exhibited irradiance
      values significantly different from those of the laboratory-grade power meter.
      There were no statistically significant differences among the five samples of
      each commercially available radiometer model.

PMID- 10337297
TI  - Hardening of new resin cements cured through a ceramic inlay.
AB  - This study investigated the degree of hardening achieved through self-curing only
      and through dual-curing a group of eight new resin-based cements. In addition,
      the effect of ceramic inlay thickness on cement hardness was determined. Disk
      specimens measuring 6 mm in diameter and 2.5 mm thick were prepared from eight
      cements: Adherence, Choice, Duolink, Enforce, Lute-It, Nexus, Resinomer, and
      Variolink. Eight specimens were prepared from each material; half were self
      cured, while the remainder were dual-cured. Knoop hardness measurements were then
      made at 1-hour, 1-day, and 1-week intervals. In addition 12 specimens of the same
      dimensions were prepared from each cement and were dual-cured through ceramic
      spacers of varying thickness (1-6 mm). Hardness measurements were made as above.
      ANOVA showed significant differences in hardness of self-cured versus dual-cured
      specimens for all cements (P < 0.0001). Significant differences were also found
      in the hardness of specimens dual-cured through ceramic spacers 2-3 mm in
      thickness or more compared with those that were dual-cured without spacer. It is
      concluded that for some materials self-curing alone was not adequate to achieve
      sufficient hardening; cement hardness was significantly reduced when ceramic
      inlay thickness was 2-3 mm or more.

PMID- 10337298
TI  - Fracture strength of Class 2 amalgams with various cavity-lining materials.
AB  - This in vitro study compared the fracture resistance of class 2 amalgam
      restorations placed over seven materials: three resin-modified glass-ionomer
      cements (Fuji II LC, Vitrebond, and Vitremer), one polyacid-modified composite
      resin (VariGlass VLC), two conventional glass-ionomer cements (Ketac-Bond and
      GlasIonomer Cement), and one calcium-hydroxide material (Dycal). Eighty maxillary
      molars with flattened occlusal surfaces were divided into 14 experimental groups
      and two control (no liner) groups. One standardized class 2 amalgam cavity
      preparation was completed per tooth. Lining materials standardized at a thickness
      of 0.5 mm were placed in the approximal box portion of 10 test specimens per
      experimental group. Spherical amalgam was hand condensed into each cavity
      preparation. At 1 hour and again at 7 days, five samples from each group were
      fractured in compression using an Instron Universal Testing Machine. The force
      was directed at 10 degrees to the long axis of the tooth, 2.0 mm inside the
      approximal portion of the restoration. Results were analyzed using a two-way
      ANOVA for time and material. No statistically significant differences were found
      among the materials and controls at either time interval tested (P > 0.05). A
      statistically significant difference was found (P < 0.05) when comparing 1-hour
      and 7-day strengths. The 7-day specimens were more resistant to fracture than the
      1-hour specimens. CONCLUSION: The fracture resistance of amalgam restorations was
      not affected by the presence of a material 0.5 mm thick placed in the approximal
      box when 3 mm of bulk of amalgam remained over it.

PMID- 10337300
TI  - Periodontal disease among older adults.

PMID- 10337299
TI  - Bond strength of composite to enamel and dentin using Prime & Bond 2.1.
AB  - A laboratory study was conducted to determine the bond strength of composite to
      enamel and dentin using a one-component dental adhesive system (Prime & Bond 2.1)
      with three application regimens ranging from four to seven procedural steps. In
      addition, the effect of acid conditioning of dentin on bond strength was
      evaluated. Enamel bond strengths ranged from 29.2 to 29.8 MPa, and dentin bond
      strengths ranged from 18.6 to 21.3 MPa. Enamel bond strengths were significantly
      higher (P = 0.000) than dentin values. There was no significant difference (P >
      0.05) among the bond strengths in either the enamel or dentin groups using the
      three application regimens. Nor did acid conditioning of dentin increase bond
      strengths (P = 0.683).

PMID- 10337301
TI  - Who are older adults? Demographics and major health problems.
AB  - The care of older patients is a challenging and often rewarding experience.
      Elderly people can be helped to fulfill their needs and realize their goals with
      a sensitive and comprehensive evaluation, a positive and supportive attitude and
      an emphasis on illness rather than disease. Health care providers can contribute
      greatly to improved function and enhanced quality of life through an
      understanding of and respect for the individual qualities and aspirations of
      their older patients.

PMID- 10337302
TI  - Epidemiology of periodontal disease among older adults: a review.
AB  - Although many epidemiological studies have been conducted concerning periodontal
      disease, the majority were not included in this review because of deficiencies in
      the measures used. Although it is increasingly common for studies in this field
      to measure periodontal disease using clinical attachment level, attachment loss
      or bone loss, the evidence pertaining to prevalence, incidence and risk in older
      adult populations is limited. Although it is the best indicator to date,
      characterizing periodontal disease by means of attachment loss has some
      limitations. Prevalence and incidence rates may vary according to the number of
      teeth and sites probed and bias and case misclassification may occur because of
      the healthy survivor effect. Moreover, prevalence data that document lifetime
      disease experience are of little use in planning for periodontal treatment needs.
      Problems with sampling or subject selection and idiosyncratic ways of reporting
      data also limit the quality of the evidence currently available. In order to
      standardize the collection of data on loss of attachment and to measure it as
      accurately as possible, Papapanou (63) recommends that studies use full-mouth
      periodontal examinations and the assessment of clinical attachment level at four
      sites on each remaining tooth. Given the inconsistencies in and problems with the
      methods used in the studies reviewed above, only broad conclusions can be drawn
      concerning periodontal disease in older adults. These confirm the conclusions
      reached in other reviews of the literature. While moderate levels of attachment
      loss are to be found in a high percentage of middle-aged and elderly subjects,
      severe loss is confined to a minority, albeit a substantial one. Severe loss is
      evident in only a few sites and, in general, affects only a small proportion of
      sites examined. Nevertheless, approximately one-fifth of older individuals have
      experienced more generalized severe loss; the rate is much higher in the oldest
      subjects and subjects from minority groups. Although not universal, severe
      disease is common in some older populations and some population subgroups.
      Studies using common approaches are needed to fully elucidate the extent to which
      disease experience varies across different populations. Similar conclusions can
      be drawn from prevalence studies measuring bone loss. These show that a minority
      of subjects accounted for most sites with advanced loss. Studies of incidence
      suggest that 50-75% of older adults experience additional loss of attachment of 2
      or 3 mm or more at a minimum of one site over relatively short periods of time.
      Rates fall dramatically when more stringent case definitions are used. Moreover,
      relatively few sites examined show evidence of additional loss so that, although
      rates are high, extent and severity are low. More detailed analyses of incidence
      data, although few, indicate that new lesions are more common than progressing
      lesions, and the pattern of loss tends to support an episodic model of
      periodontal disease progression.

PMID- 10337303
TI  - Influences on the perceptions of and responses to periodontal disease among older
      adults.

PMID- 10337304
TI  - Aging and the periodontal and peri-implant microbiota.

PMID- 10337305
TI  - Effect of aging on immunocompetent and inflammatory cells.

PMID- 10337306
TI  - Interactions between periodontal disease, medical diseases and immunity in the
      older individual.

PMID- 10337307
TI  - Treatment of periodontal disease in older adults.
AB  - The literature does not indicate that older adults differ from younger
      individuals in their response to periodontal treatment. However, in older adults,
      it is more common to find compromised general conditions that may negatively
      affect the patient's ability to maintain an adequate standard of self-performed
      plaque control. Although this can be compensated for partly by a carefully
      designed program for supportive therapy, the prevention and/or elimination of
      clinical signs of periodontal inflammation may not always be a reachable goal of
      periodontal therapy in older adults, particularly in those who are frail and
      functionally dependent. For many patients, a more realistic goal may be the
      control of disease progression in order to preserve a functional and comfortable
      dentition throughout life and hence, the decision making process regarding
      therapeutic levels for the individual patient must include factors such as the
      amount of remaining periodontal support, the risk for disease progression,
      demands for oral health and life expectancy.

PMID- 10337308
TI  - Implant dentistry.

PMID- 10337309
TI  - Titanium--the material of choice?

PMID- 10337310
TI  - Osseointegration: a reality.

PMID- 10337311
TI  - Surface configurations of dental implants.

PMID- 10337312
TI  - The interface between the mucosa and the implant.

PMID- 10337313
TI  - Risk factors for osseodisintegration.

PMID- 10337314
TI  - The diagnosis and treatment of peri-implantitis.

PMID- 10337315
TI  - Use of radiographs in evaluating success, stability and failure in implant
      dentistry.

PMID- 10337316
TI  - The first two-stage dental implant system and its clinical application.

PMID- 10337317
TI  - A subsequent two-stage dental implant system and its clinical application.

PMID- 10337318
TI  - The original one-stage dental implant system and its clinical application.

PMID- 10337319
TI  - Biomechanical aspects of prosthetic implant-borne reconstructions.

PMID- 10337320
TI  - Longitudinal studies of implant systems.

PMID- 10337321
TI  - Aesthetic implant restorations in partially edentulous patients--a critical
      appraisal.

PMID- 10337322
TI  - Guided bone regeneration at oral implant sites.

PMID- 10337323
TI  - Maxillary sinus floor elevation: a valuable pre-prosthetic procedure.

PMID- 10337324
TI  - Transpositioning and repositioning the inferior alveolar and mental nerves in
      conjunction with endosteal implant reconstruction.
AB  - Without the benefit of the computed tomographic scan with three-dimensional
      reformatted imaging, this procedure would be difficult if not impossible to carry
      out. The end-point results would not be as valid. It is also not indicated to
      place any type of granular allograft and/or any one of the alloplast materials in
      this area, as it could prove to irritate the exposed neurovascular bundle. I have
      also found that, in most instances, the residual bone from the osteotomy site is
      not sufficient to replace at the termination of the procedure. However, if it is
      sufficient, then it would be necessary to thin down the medial aspect of the
      cortical plate in repositioning it, as it would then prevent excessive pressure
      or crushing of the nerve against the surface of the implant(s). Procedures such
      as onlay or saddle grafting can be offered to the patient as an alternative to
      these nerve procedures. However, a second surgical site is then required as well
      as, in some cases, staging of the procedure, thus increasing treatment time and
      the number of procedures for the patient. Lastly, adequate soft tissue coverage
      over the graft is often difficult, if not impossible to achieve.

PMID- 10337325
TI  - Five common retirement planning blunders doctors make.

PMID- 10337326
TI  - Exfoliation of maxillary central incisors due to misapplication of orthodontic
      rubber bands.
AB  - The patient's problem consisted of a large diastema between the central incisors.
      The cost-cutting treatment plan recommended to the patient and his parents by the
      general dentist was to use orthodontic rubber bands to loop the teeth and close
      the diastema.

PMID- 10337327
TI  - How effective is your surface disinfectant.

PMID- 10337328
TI  - NIDR turns 50; gets new name.

PMID- 10337329
TI  - Valley dentists meet indigent care challenge.

PMID- 10337330
TI  - DR plan: a winner with orthodontist's employees.

PMID- 10337331
TI  - TDA watches closely as Texas legislature considers phase II of CHIP.

PMID- 10337332
TI  - Child abuse and neglect: implications for the dental profession.
AB  - Dentists, as a group, have participated in the recognition and reporting of child
      maltreatment to a lesser degree than other health professionals, being either
      unaware of their legal responsibility to report or, when abuse or neglect is
      suspected, reluctant to do so.

PMID- 10337333
TI  - Drug interactions: important new developments for dentistry.

PMID- 10337334
TI  - [Diagnosis of coronary disease: thallium-201 dipyridamole tomoscintigraphy of the
      myocardium].
AB  - OBJECTIVES: Determine the diagnostic performance of thallium-201 myocardial
      scintigraphy using dipyridamole injection for the detection of coronary heart
      disease (myocardial ischemia and/or necrosis). Determine for each coronary artery
      the degree of angiographic stenosis for optimal diagnostic performance. PATIENTS
      AND METHODS: The study included 309 patients who underwent coronarography within
      6 months of the scintigraphy examination. None of the patients experienced a
      coronary event during this interval. Diagnostic performance of the scintigraphic
      exploration was compared with angiographic findings (stenosis 70%) used as the
      gold standard. The degree of angiographic stenosis for optimal scintigraphic
      performance was determined from the receiver operating characteristic (ROC)
      curves. RESULTS: The sensitivity of scintigraphy to detect angiographically
      demonstrated coronary disease was 84% with a specificity of 72%. The positive and
      negative predictive values were 87% and 66% respectively. Test accuracy was 80%.
      Sensitivity was better for detecting lesions of the anterior interventricular
      coronary than for the right coronary or circumflex. In addition, sensitivity
      varied with the number of vessels involved: 76% for single-vessel disease versus
      90% for two- or three-vessel disease. The data analysis also suggested that an
      angiographic stenosis threshold of 50% provided optimal predictive value for
      scintigraphy for each of the three vessel territories. An analysis based on
      maximal stenosis in each patient, notwithstanding the congruency between lesion
      localization and diseased vessel territories, was found to provide less
      diagnostic precision. CONCLUSION: Thallium-201 dipyridamole myocardial
      scintigraphy offers diagnostic performance comparable to that established with
      thallium-201 scintigraphy performed after exercise alone. Scintigraphic detection
      of a perfusion defect generally corresponds to an angiographic stenosis of 50%.

PMID- 10337336
TI  - [Arterial hypertension due to compression of the renal artery, revealing ovarian
      cancer].
AB  - BACKGROUND: The etiologic work-up of hypertension with hyperaldosteronism and
      elevated serum renin includes search for renal artery stenosis. Intrinsic
      stenosis is a common finding, but hypertension secondary to extrinsic compression
      of the renal artery is exceptional. CASE REPORT: A 48-year-old woman with an
      uneventful history was hospitalized for recent onset hypertension. Laboratory
      tests showed hypokaliemia, and elevated aldosterone and renin. Duplex Doppler
      exploration of the renal vessels evidenced extrinsic compression of the left
      renal artery by a tumoral mass found to be a nodal metastasis at surgery.
      Pathology reported cancer of the ovary. Blood pressure, and aldosterone and renin
      levels returned to normal after complete tumor resection. No antihypertensive
      treatment was required. CONCLUSION: This is undoubtedly the first case of
      metastatic cancer of the ovary revealed by hypertension; it can be added to the
      list of 49 other published cases of extrinsic compression of the renal artery by
      various causes leading to hypertension. In most cases, surgical removal of the
      obstacle or nephrectomy provided cure of the hypertension.

PMID- 10337335
TI  - [Heart perforation following transvenous implantation of a cardiac pacemaker].
AB  - OBJECTIVES: We studied the incidence, clinical signs and severity of heart
      perforations occurring after transvenous pacemaker implantation. PATIENTS AND
      METHODS: A series of 16 consecutive cases of heart perforation observed in one
      cardiac pacing unit from 1989 to 1998 were reviewed. RESULTS: Heart perforation
      occurred after implantation in 9 cases; the verall incidence for all lead
      implantation was 0.57%. The ventricle was perforated in 6 cases, the atrium in 1,
      and an undetermined site in 2 cases. Active fixation was involved in 5 cases,
      passive fixation in 4. A bipolar lead was used in 7 cases and a unipolar lead in
      2. Heart perforation occurred after prior external stimulation in 7 cases,
      including one case with tamponnade requiring emergency pericardial drainage after
      implantation. Repositioning the lead in the ventricle was sufficient in 6 cases
      and a thoracotomy for an atrial wound was performed in 1 case. Difficulties in
      right ventricular catheterism due to kyphoscoliosis in elderly subjects was found
      to be a risk factor. CONCLUSION: Heart perforation following transvenous
      pacemaker implantation is an exceptional complication with currently used
      material. Tamponnade is extremely rare. Besides verifying the mechanical
      performance of the leads, prevention requires a rigorous protocol for catheterism
      and wall fixation.

PMID- 10337337
TI  - [Consumption of psychotropic drugs after implantation of a cardiac
      defibrillator].

PMID- 10337338
TI  - [Rapid resolution of acute myocarditis: side effect of a drug or effect of
      hepatitis C virus?].

PMID- 10337339
TI  - [On thyrotoxic heart failure].

PMID- 10337340
TI  - [Nuts, Mediterranian women and coronary arteries].

PMID- 10337342
TI  - [Patients operated on for pheochromocytoma: biological surveillance].

PMID- 10337341
TI  - [Dyslipidemia: prevention of cardiovascular risk].

PMID- 10337343
TI  - [Sixth report of the Joint National Committee on the prevention, detection,
      evaluation and treatment of arterial hypertension].

PMID- 10337344
TI  - [Apropos of the JNC VI (Joint National Committee)].

PMID- 10337345
TI  - [Current development on hypertension].

PMID- 10337346
TI  - [Current aspects of arterial hypertension: hypertension in the aged].
AB  - HIGH PREVALENCE: In France, an estimated 5 million persons aged over 65 years
      have hypertension. Accepting a treatment threshold of systolic pressure 160 mmHg
      whatever the diastolic pressure, more than 3 million require antihypertension
      therapy. PATHOPHYSIOLOGY: During the aging process, the arterial trunks
      progressively loose their elasticity, becoming more and more rigid. Other age
      related modifications of the vascular bed, as well as environmental factors
      (diet, sodium intake) also play a role. USEFUL TREATMENT: Several meta-analyses
      have demonstrated that active antihypertensive therapy can reduce overall
      mortality by 12%, the risk of cerebral vascular events by 36% and cardiac events
      by 25%. The risk of non-fatal cerebral vascular events can be reduced by 35%.
      POSITIVE DIAGNOSIS: Repeated blood pressure measurements are needed. Measurements
      should be made well after meals and take into account possible overestimation
      related to the rigidity of the humeral artery. THERAPEUTIC MODALITIES: Moderate
      salt intake and antihypertension drugs should be prescribed. A single drug
      regimen can be advised for initial treatment, avoiding long-action or high-dose
      regimens. Episodes of hypotension should be suspected if patients complain of
      malaise.

PMID- 10337347
TI  - [Current aspects of arterial hypertension. Prognostic value of self-monitoring
      blood pressure measurements in aged hypertensive patients: a SHEAF study
      protocol].
AB  - HOW TO MEASURE BLOOD PRESSURE: Studies conducted in large series have established
      the prognostic value of blood pressure measured by conventional methods. This
      measurement technique has however a certain number of limitations and alternative
      systems have been proposed, including self-monitoring methods. A preliminary
      study suggested that the prognostic value of self-monitoring blood pressure
      measurements would be superior to those obtained with conventional methods. These
      findings require confirmation. A LARGE SCALE STUDY: The primary objective of the
      SHEAF study is to determine the prognostic value of self-monitoring blood
      pressure measurements in terms of cardiovascular mortality in a population of
      hypertensive elderly subjects living in France. The study protocol projects to
      include 5,000 hypertensive patients, whether treated or not, aged 60 and over.
      Baseline pressures are to be measured by a physician using a mercury
      sphygmomanometer (3 successive measurements at 2 visits) and by the participants
      using a self-monitoring device in their home (3 measurements in the morning and
      evening for 4 consecutive days). The patients will be followed for 3 years and
      all cardiovascular events will be recorded, including: death, myocardial
      infarction, cerebral vascular events, transitory ischemic events, hospitalization
      for angina, episodes of angina, heart failure, angioplasy or coronary bypass. The
      results of this large-scale epidemiology study should be available in 2002.
      METHODOLOGICAL PRECAUTIONS: The SHEAF study will analyze the patient's usual
      blood pressures, whatever the treatment at study inclusion, rather than blood
      pressures observed after treatment withdrawal. Efforts will be made to limit the
      number of drop-outs.

PMID- 10337348
TI  - [Current aspects of arterial hypertension. Doppler echocardiography. Value and
      indications].
AB  - DETECTION OF LEFT VENTRICULAR HYPERTROPHY: High blood pressure can lead to left
      ventricular hypertrophy and is an independent risk factor of cardiovascular
      disease. Echocardiography can be used to measure left ventricular mass based on
      equations established from anatomoclinical studies. Echocardiography can also
      give a precise map of the left ventricle allowing a prognostic classification:
      poor prognosis, concentric remodeling, eccentric hypertrophy, concentric
      hypertrophy. INDICATIONS: Doppler-echocardiographic analysis of left ventricular
      filling provides information on systolic function and is clearly indicated in
      case of symptomatic hypertension, or associated cardiopathies or
      electrocardiographic abnormalities. Indications should be discussed in case of
      moderate hypertension in order to evaluate the cardiovascular risk. LIMITATIONS
      AND PERSPECTIVES: Because of the low reproducibility, Doppler-echocardiography is
      not useful for follow-up of established left ventricular hypertrophy in
      hypertensive patients, all the more so since it has not been established that
      regression is associated with improved cardiovascular prognosis.

PMID- 10337349
TI  - [Hypertensive syndrpomes in pregnancy].

PMID- 10337350
TI  - [Hypertensive syndromes in pregnancy. Physiopathology, definition and
      fetomaternal complications].
AB  - A MAJOR CONCERN: Hypertensive syndromes occur in approximately 10 to 15% of all
      pregnancies and are the cause of 30% of maternal deaths and 20% of fetal and
      neonatal deaths. Syndromes include gestational hypertension also called pregnancy
      induced hypertension, chronic hypertension and preeclampsia. DEFINITION: In
      pregnant women, hypertension is defined as blood pressure levels above 140/90
      mmHg at two successive measurements at a 4-hour interval. The primum movens is
      the development, at about 16 weeks gestation, of secondary placental ischemia due
      to a defect in the second trophoblastic invasion of the spiral arteries of the
      myometrium. This induces endothelial dysfunction leading to pro-coagulation
      activation and inhibited physiological vasodilatation. RISK FACTORS: The risk of
      vasculoplacental disease increases with age, body mass index, primiparity,
      stressful working conditions, and personal history of vascular events during
      pregnancy. MATERNAL RISKS: Maternal complications include preeclampsia-eclampsia,
      retroplacental hematoma, acute renal failure, and HELLP syndrome (hemolysis,
      elevated liver enzymes, low platelet count). FETAL RISKS: Hypotrophy, in utero
      death and prematurity may occur. The development of hypertension during pregnancy
      may also reveal a hypertensive background which could progress to persistent high
      blood pressure. Preeclampsia is an independent risk factor of cardiovascular
      disease requiring regular surveillance after delivery.

PMID- 10337351
TI  - [Hypertensive syndromes in pregnancy. Diagnosis and therapy].
AB  - ACHIEVE PRECISE DIAGNOSIS: Hypertensive syndromes during pregnancy secondary to
      placental ischemia still cause threatening matemofetal complications. A precise
      differential diagnosis between gestational hypertension, chronic hypertension and
      preeclampsia must be achieved as the management protocols are quite different.
      PATIENT MONITORING: Blood tests for urea, creatinine, platelet counts,
      coagulation, and liver enzymes are required. Fetal monitoring, urine protein and
      ambulatory blood pressure measurements are also helpful. Ultrasound-Duplex
      explorations allow an evaluation of the maternal vascular status and fetal
      development. THERAPEUTIC MANAGEMENT: These patients should be managed in
      specialized centers, limiting the minimum the number of hospitalizations. Unlike
      good rules of hygiene and dietetics, antihypertensive therapy has little effect
      on the progression of the pregnancy. An antihypertensive therapy is only
      warranted to avoid cardiovascular complications in the mother. In case of chronic
      hypertension, treatment should be tailored to the measured pressures. Prudent
      antihypertensive therapy may be useful for severe gestational hypertension and
      preeclampsia. Because of their safety profile and pharmacologic properties,
      antihypertension drugs with central action and alph-beta-blockers should be
      preferred over other drug classes. PREVENTIVE TREATMENT: Antiaggregates (aspirin
      50-100 mg/d) starting at 16 weeks gestation should be reserved for high-risk
      pregnancies. Regular follow-up, both pre- and post-natally, is essential,
      especially in light of the large number of women who can be expected to progress
      to established hypertensive states.

PMID- 10337354
TI  - Chronic and paroxysmal atrial fibrillation: course, prognosis, and stroke risk.

PMID- 10337356
TI  - Risk factors for stroke and primary prevention of stroke in atrial fibrillation.

PMID- 10337355
TI  - Physiology and pathophysiology of the atria: its role in atrial fibrillation.

PMID- 10337357
TI  - Idiopathic atrial fibrillation: prevalence, course, treatment, and prognosis.

PMID- 10337358
TI  - Pharmacological control of rate and maintenance of sinus rhythm.

PMID- 10337359
TI  - Surgery for atrial fibrillation.

PMID- 10337360
TI  - Endocavitary treatment of atrial fibrillation.

PMID- 10337361
TI  - Cardioversion in atrial fibrillation: indications, thromboembolic prophylaxis,
      and role of transesophageal echocardiography.

PMID- 10337362
TI  - Secondary stroke prevention in atrial fibrillation: indications, risks, and
      benefits.
AB  - Patients with nonrheumatic atrial fibrillation (NRAF) and a recent transient
      ischemic attack (TIA) or nondisabling ischemic stroke have a high risk of stroke
      recurrence of about 12% per year. Two randomized clinical trials have shown that
      oral anticoagulant therapy reduces the risk by two thirds, very similar to the
      benefit in primary prevention. The optimal intensity is INR 2.0-3.0. In case of a
      containdication to AC, aspirin and ibuprofen are safe, but less effective,
      alternatives. During the first 2 weeks following AF-related major stroke, the
      benefit of subcutaneous heparin is offset by a higher risk of secondary cerebral
      bleeding, and therefore cannot be recommended, at present, during that period.
      The risk of stroke recurrence can be predicted by means of easily available
      clinical information.

PMID- 10337363
TI  - Very low-intensity antithrombotic therapy in atrial fibrillation.

PMID- 10337364
TI  - Transthoracic and transesophageal echocardiography in atrial fibrillation.

PMID- 10337365
TI  - The evolving face of palliative care in cancer medicine.

PMID- 10337366
TI  - Cancer-related fatigue: guidelines for evaluation and management.
AB  - Fatigue is a highly prevalent condition among cancer patients. Although most
      cancer patients report that fatigue is a major obstacle to maintaining normal
      daily activities and quality of life, it is seldom assessed and treated in
      clinical practice. Few studies have explored its epidemiology, possible
      etiologies, or management. Cancer-related fatigue, which recently was accepted as
      a diagnosis in the International Classification of Diseases 10th Revision
      Clinical Modification, reduces physical, psychological, and social functioning
      and results in significant distress for patients and caregivers. Adequate
      evaluation of fatigue must do more than simply assess severity. The assessment
      should clarify other characteristics, determine the degree to which fatigue
      interferes with the activities of daily living, and identify potential causes,
      including the underlying disease, disease treatments, intercurrent systemic
      disorders, psychological disorders, and other conditions. Possible primary
      therapies include modification of the patient's drug regimen, correction of
      metabolic abnormalities, and pharmacologic treatments for anemia (e.g., epoetin
      alfa), depression, or insomnia. Other symptomatic interventions include specific
      drug treatments, exercise, modification of activity and rest patterns, cognitive
      therapies, sleep hygiene approaches, and nutritional support. Pharmacologic
      approaches, which are supported by limited studies and growing clinical
      experience, include psychostimulant drugs, corticosteroids, and possibly other
      therapies. Although additional research is needed to further identify the causes
      and corresponding treatment of fatigue, practitioners should routinely assess and
      treat patients who may benefit from currently identified interventions, because
      fatigue can profoundly undermine the quality of life of patients with cancer.

PMID- 10337367
TI  - Head and neck cancer: altered fractionation schedules.
AB  - Local control is paramount in the treatment of localized advanced head and neck
      cancer. Standard radiotherapy cures a high percentage of early tumors--more than
      80% of the early laryngeal tumors--but fewer of the advanced tumors. Attempts
      have therefore been made to improve the therapeutic ratio by: A)
      hyperfractionation: reducing the dose per fraction to reduce late morbidity; the
      total dose is then elevated in an attempt to improve local tumor control with
      equal morbidity, and B) acceleration: reducing the overall treatment time to
      overcome repopulation during a protracted course of radiotherapy. The total dose
      and dose per fraction have been reduced in the accelerated arm in some trials,
      while in others the total dose has been maintained. Both these strategies have
      been tested in multicenter randomized controlled trials, but neither have become
      part of routine clinical practice. The biological parameters determining local
      tumor control and normal tissue effects are being studied at Mount Vernon by an
      analysis of selected randomized controlled trials, with the aim of designing new
      schedules of radiotherapy for future studies.

PMID- 10337368
TI  - Monotherapy of metastatic breast cancer: a review of newer agents.
AB  - PURPOSE: New agents for the palliative treatment of metastatic breast cancer have
      emerged in the 1990s. This review summarizes the response rates of these agents
      with an emphasis on recent findings, such as presentations from the 1998 Meeting
      of the American Society of Clinical Oncology. METHODS: The English medical
      literature was reviewed to identify clinical trials involving monotherapy for the
      treatment of metastatic breast cancer. Three agents--paclitaxel, vinorelbine, and
      docetaxel--are emphasized because their databases are extensive enough to allow
      interesting comparisons. Liposomal-encapsulated anthracyclines, losoxantrone,
      gemcitabine, oral surrogates of continuous-infusion fluorouracil, raltitrexed, LY
      231514, edatrexate, topoisomerase I inhibitors, and trastuzumab are reviewed
      briefly. RESULTS: Many of the new agents produce response rates approaching or
      even surpassing those achievable with doxorubicin monotherapy. Compared with
      older agents, some new agents have improved or at least different safety
      profiles, and some are easier to administer. DISCUSSION AND CONCLUSIONS: The new
      agents offer useful therapeutic options that make them suitable for combining
      with each other and with older agents, which could result in more effective
      regimens for metastatic disease, and, ultimately, primary disease in the adjuvant
      setting. The chemotherapeutic paradigms governing the management of breast cancer
      for the past three decades are likely to change as we move into the 21st century.

PMID- 10337369
TI  - Rhabdomyosarcoma: an overview.
AB  - Rhabdomyosarcoma (RMS) is a malignant tumor of mesenchymal origin thought to
      arise from cells committed to a skeletal muscle lineage. With approximately 250
      cases diagnosed yearly in the United States, it is the third most common
      extracranial solid tumor of childhood after Wilms' tumor and neuroblastoma.
      Important epidemiologic, biologic, and therapeutic differences have been
      elucidated within the RMS family. Common sites of primary disease include the
      head and neck region, genitourinary tract, and extremities. A site-based tumor
      nodes-metastasis staging system is being incorporated into use for assessing
      prognosis and assigning therapy in conjunction with the traditional
      surgicopathologic clinical grouping system. The development of intensive
      multimodality treatment protocols tested in large-scale international trials has
      resulted in significant improvements in outcome, especially for patients with
      local or locally extensive disease for whom a 60%-70% disease-free survival can
      be expected. Despite aggressive approaches incorporating surgery, dose-intensive
      combination chemotherapy, and radiation therapy, the outcome for patients with
      metastatic disease remains poor. Future challenges include the development of
      less toxic therapy for patients with localized disease and new approaches for
      patients with metastatic disease.

PMID- 10337370
TI  - Long-term survivors of childhood cancer: the late effects of therapy.
AB  - The successful treatment of pediatric malignancy by multimodality therapy has
      improved the outcome for children with cancer. It has been estimated that 0.1% of
      individuals 20 years of age are survivors of childhood cancer. This represents a
      large cohort nationally who, with maturation, may be increasingly beset by the
      medical and social consequences of treatment. The study of long-term effects of
      cancer chemotherapy has grown enormously in the past decade. Any side effect that
      does not resolve after the completion of therapy is a long-term effect of
      therapy. Side effects recognized during the therapeutic period are usually
      addressed by the treating physicians. More problematic are those effects of
      therapy that are subclinical at completion of therapy but manifest years later.
      These are the true late effects of therapy and are the focus of this review. The
      cytotoxic effects on maturing tissues become apparent only with development. Thus
      physical, intellectual and pubertal development as well as reproductive potential
      may be impossible to assess for a decade or more, depending upon the age at the
      time of treatment. Nonetheless, the ability to predict the likelihood of a given
      adverse outcome is enormously helpful to the survivor and may allow for the
      mitigation of severe effects. Organ injury may also be subclinical initially.
      With aging and additional stress, compensatory mechanisms may fail. The
      development of effective screening methodologies may be essential for early
      interventions. Lifestyle changes may reduce exposure to further toxins and
      mutagenic agents such as alcohol and cigarette smoke that may lead to secondary
      malignancy, particularly if compounded in some instances by genetic
      predisposition. Programs for survivors of childhood cancer were developed within
      pediatric oncology. As the children become adults, the likelihood of continued
      care at the initial treating institution decreases. Oncologists and other health
      care professionals who become responsible for the health care of this maturing
      cohort will need to understand the risks engendered by childhood cancer therapy.

PMID- 10337371
TI  - Patient-physician communication: an emerging partnership.

PMID- 10337372
TI  - Alone together. Cancer patients and survivors find treatment--and support-
      online. It can make all the difference.

PMID- 10337373
TI  - One survivor's tale: notes from the edge.

PMID- 10337374
TI  - A staff dialogue on aggressive palliative treatment demanded by a terminally ill
      patient: psychosocial issues faced by patients, their families, and caregivers.
AB  - Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at
      Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at
      MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and
      advancing compassionate health care delivery which provides hope to the patient,
      support to caregivers, and encourages the healing process. The center sponsors
      the Schwartz Center Rounds, a monthly multidisciplinary forum during which
      caregivers discuss a specific cancer patient, reflect on the important
      psychosocial issues faced by patients, their families, and their caregivers, and
      gain insight and support from their fellow staff members. In this article, the
      case presentation and verbatim dialogue from the rounds are discussed with an
      emphasis on staff psychosocial issues. The case presented was of a 32-year-old
      man, who developed small cell osteosarcoma and was treated at MGH. He died after
      undergoing multiple courses of relatively ineffective chemotherapy. The case is
      made all the more poignant because of the pleasures, hopes and stresses of having
      a child late in the course of his illness. Staff identified closely, both with
      him and his family, and their concern for him brought joy and meaning to their
      work, yet this complicated their ability to deal with his impending death. They
      felt that his unwillingness to admit defeat prevented them from saying goodbye to
      someone whom they loved and admired. Despite this, staff recognized that,
      ultimately, the patient's emotional needs and wishes had to be respected as a
      first priority and that constructive closure can be worked toward, if not
      achieved. In such situations, it is vital to have a colleague support system and
      a forum for discussion of such issues in order to defuse distress and reassure
      staff that they are doing all that can be done as professionals and caregivers.

PMID- 10337375
TI  - Hematopoietic stem cell transplantation: a new therapy for autoimmune disease.

PMID- 10337376
TI  - UFT and eniluracil, oral variations of 5-FU, offer lower toxicity, phase II
      results show.

PMID- 10337377
TI  - Coulter, SmithKline agree to develop anti-B1 antibody.

PMID- 10337378
TI  - Extending the platinum-free interval in recurrent ovarian cancer: the role of
      topotecan in second-line chemotherapy.
AB  - Although the combination of platinum and paclitaxel offers effective chemotherapy
      for advanced ovarian cancer, the majority of women will eventually relapse with
      development of drug-resistant disease. Topotecan is the most extensively studied
      agent currently available for management of recurrent ovarian cancer and has been
      approved by the FDA for that particular indication. Early use of topotecan offers
      an effective and tolerable strategy that can prolong the platinum-free interval
      and optimize subsequent retreatment with platinum.

PMID- 10337379
TI  - Surgical management of esophageal carcinoma.
AB  - Surgical management of esophageal carcinoma is reviewed. The anatomy and biology
      are briefly mentioned, since these factors mitigate against the success of
      surgery. Staging, the key to proper treatment allocation and prognosis, is
      discussed, including the use of endoscopic ultrasonography, positron emission
      tomography, and thoracoscopy/laparoscopy. Patient selection and preparation for
      surgery are important considerations. Surgical techniques are then discussed, as
      are the advantages and disadvantages of various approaches, the morbidity of
      surgical resection, survival, and quality-of-life issues. Adjuvant treatment
      strategies (preoperative radiation, induction chemotherapy, induction
      chemoradiotherapy, and postoperative treatment) are summarized.

PMID- 10337380
TI  - Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer.
AB  - BACKGROUND: Neoadjuvant chemotherapy improves survival in patients with locally
      advanced breast cancer (LABC). Usually three to four cycles of conventional-dose
      neoadjuvant chemotherapy are administered prior to local therapy, and another
      three cycles thereafter. In an attempt to improve results, we increased the
      dosages and applied GM-CSF, which, besides being a hematopoietic growth factor,
      has become increasingly known for its immunostimulatory effects, which might
      enhance the antitumor effect. METHODS: Forty-two patients with stage IIIA or IIIB
      breast cancer were treated with doxorubicin (A) (90 mg/m2) and cyclophosphamide
      (C) (1,000 mg/m2) at three-weekly intervals. In the second and fourth cycle a 10%
      dose reduction of both agents was applied. On the second day GM-CSF 250
      micrograms/m2/day was started and given for 10 days. Initially, some patients
      were treated with < or = four cycles, but as the study progressed and toxicity
      appeared tolerable, six cycles were given whenever possible. After the
      chemotherapy, patients underwent surgery and postoperative radiotherapy. RESULTS:
      The response rate for the whole group to AC was 98% (95% confidence interval 94%
      100%), with a clinical complete response rate of 50% (95% confidence interval 35%
      65%). Six patients had a pathological complete response. Median follow-up from
      the start of chemotherapy is 49 months (range 10-100). The disease-free survival
      (DFS) at three years is 57% and the overall survival (OS) at three years is 79%.
      There is a significant trend for improved DFS (p = 0.0000) and OS (p = 0.0002)
      with increasing number of cycles. CONCLUSION: The results of the present study
      with neoadjuvant dose-intensive AC chemotherapy and GM-CSF compare favorably with
      previous studies in patients with LABC. This is most apparent in patients who
      received six cycles of neoadjuvant chemotherapy. We hypothesize that these
      encouraging results are probably related to the prolonged presence of the primary
      tumor, and to the long-term administration of GM-CSF with the primary tumor and
      axillary lymph nodes in situ. Therefore, a randomized study is warranted. We
      already initiated an international randomized trial in patients with LABC in
      order to answer two questions. First, does prolonged neoadjuvant chemotherapy
      result in an improved DFS and OS in comparison with the conventional approach,
      and secondly, what is the effect of GM-CSF in this approach in comparison with G
      CSF?

PMID- 10337381
TI  - Cytoprotection: shelter from the storm.

PMID- 10337382
TI  - A staff dialogue on caring for a cancer patient who commits suicide: psychosocial
      issues faced by patients, their families, and caregivers.
AB  - Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at
      Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at
      MGH. The Schwartz Center is a non-profit organization dedicated to supporting and
      advancing compassionate health care delivery which provides hope to the patient,
      support to caregivers, and encourages the healing process. The Center sponsors
      the Schwartz Center Rounds, a monthly multidisciplinary forum during which
      caregivers discuss a specific cancer patient, reflect on the important
      psychosocial issues faced by patients, their families, and their caregivers, and
      gain insight and support from their fellow staff members. The case presented was
      of a 31-year-old man who developed adenocarcinoma of the lung with painful bone
      metastases. His tumor was unresponsive to treatment and he subsequently committed
      suicide by shooting himself. The verbatim and subsequent discussion raised a
      number of issues. Staff were devastated by the violent way that he ended his
      life. They questioned whether more could have been done to prevent this outcome,
      yet acknowledged that it mirrored the way he had lived, and were able to discuss
      the values by which we live and die. Some, but not all, felt that the patient had
      the right to choose how and when to end his life.

PMID- 10337383
TI  - Lymphocytes.

PMID- 10337384
TI  - The molecular perspective: p53 tumor suppressor.

PMID- 10337385
TI  - Clinical applications of dendritic cell cancer vaccines.

PMID- 10337388
TI  - Cancer prevention: the U.S. Department of Health and Human Services calls for
      warning labels on cigars; says teen use high.

PMID- 10337389
TI  - European Committee signs off on Paxene for Kaposi's sarcoma treatment.

PMID- 10337390
TI  - Clearance given for Panretin gel.

PMID- 10337392
TI  - An aqueous concentration model for riverine spills.
AB  - A numerical model is developed to predict the aqueous concentrations of sparingly
      soluble compounds resulting from oil, fuel, or chemical spills onto rivers. The
      model computes the concentration of compounds both in the slick phase and in the
      aqueous phase by simulating the processes that affect the fate of the spilled
      compound. Processes simulated by the model include spreading and drifting of the
      surface slick, evaporation from the slick, dissolution from the slick into the
      water, volatilization from the water, and longitudinal dispersion in the river.
      The model is used to simulate a hypothetical spill of jet fuel, demonstrating
      that the concentration of a compound in the aqueous phase is strongly linked to
      its concentration in the slick phase. The most soluble and most volatile
      compounds exhibit the highest aqueous concentrations in the early stages of the
      spill, but ultimately the less soluble and less volatile compounds reach the
      highest aqueous concentrations. Streamwise concentration gradients in the slick
      due to the rapid evaporation of the more volatile compounds are shown to have an
      effect on the aqueous concentration.

PMID- 10337391
TI  - Corrosive effects from the deposition of gaseous pollutants on surfaces of
      cultural and artistic value inside museums.
AB  - The objectives of the project were to assess the critical relationships between
      environmental factors and damage of the artifacts and other cultural property
      exposed inside museums, by studying: (a) the outdoor/indoor pollutant
      concentration and their transfer inside the museum; (b) the distribution and
      circulation of pollutants inside the museum influenced by various factors; (c)
      chemical interactions between pollutants in the gas phase leading to removal
      and/or formation of secondary pollutants; (d) the final deposition of the indoor
      pollutants on surfaces of artistic interest and the damage on them, governed by
      strictly defined physicochemical parameters. All the above information, together
      with the main factors influencing each stage, were obtained by applying the
      methodology developed and described in detail here. Measurements of rate
      constants of reactions in the gas phase, of physicochemical deposition parameters
      on artefacts, and the synergistic effects of pollutants on the deposition
      parameters, were conducted. Seven PC programmes for analysing the experimental
      data were written and used. The pollutants, the solid materials and the museums
      chosen in this programme are only examples needed to develop the necessary
      methodology. The numerical results obtained serve the purpose of exemplifying the
      procedures and not enriching the world's bibliography with useless empirical
      information. Two commercially available protectives for marble were investigated
      from the point of view of their reactivity towards SO2 by using a diffusional
      technique. From measurements of SO2 concentration carried out on three types of
      marble, the deposition velocities have been calculated. Indoor monitoring of the
      church of San Luigi dei Francesi and of the Museo della Civilta Romana in Rome
      has shown that indoor production of nitrous acid most likely results from
      heterogeneous reactions indoors, on the walls and the exposed surfaces.

PMID- 10337393
TI  - Processes controlling aqueous concentrations for riverine spills.
AB  - The aqueous concentrations of sparingly soluble compounds resulting from oil,
      fuel, or chemical spills onto rivers predicted by numerical spill models contain
      an inherent degree of uncertainty due to the inaccuracies, or bias, of the user
      supplied rate coefficients. Methods for estimating the values of spreading,
      evaporation, dissolution, volatilization, and longitudinal dispersion
      coefficients for a small sheltered river are reviewed, and the uncertainties
      associated with each coefficient are estimated. The uncertainties in the
      predicted aqueous concentrations are then computed using a concurrently developed
      riverine spill model for a simulated spill of 10,000 kg of jet fuel. The
      resulting aqueous concentrations were found to be most sensitive to the
      saturation concentrations and the dissolution rates, moderately sensitive to the
      evaporation rates and longitudinal dispersion coefficient, and nearly completely
      insensitive to the volatilization coefficient.

PMID- 10337394
TI  - Behaviour of metals under the conditions of roasting MSW incinerator fly ash with
      chlorinating agents.
AB  - A total elemental analysis was performed on a municipal solid waste (MSW) fly ash
      sample, before and after it was treated at 1000 degrees C, to reveal the metal
      distribution between the volatile matter and the ash residue. Metals such as Pb,
      Zn, Cd, and to a lesser degree, Cr, Mn and Ni, were volatilized. Addition of
      chlorinating agents generally increased the volatility of certain elements. More
      acid resistant compounds were formed in the ash residue after the heat treatment
      using CaCl2 as a chlorinating agent. The efficiencies of volatilization of the
      metals, using Cl2 as a chlorinating agent, were generally higher compared with
      using CaCl2. However, CaCl2 was found to be a more selective chlorinating agent
      for volatilizing the heavy metals of concern, i.e., Pb, Cd, Zn and Cu. The
      efficiencies of volatilization of the recovered metals were approximately
      proportional to their standard free-energy changes (delta G(o) for the
      corresponding chlorination reactions.

PMID- 10337395
TI  - Estimation of .OH radical reaction rate constants for phenol and chlorinated
      phenols using UV/H2O2 photo-oxidation.
AB  - A detailed investigation on UV/H2O2 photooxidation has been carried out in order
      to determine the kinetics of the oxidative degradation of phenol and 2- and 4
      chlorophenols in dilute aqueous solutions. Effects of different process
      parameters, such as initial substrate and H2O2 concentrations, substrate to H2O2
      ratio on the degradation kinetics of the phenolic substrates, have been studied.
      Degradation rates of phenol and chlorophenols are insignificantly small with
      ultraviolet radiation only and also with hydrogen peroxide (in the absence of UV
      radiation), but the synergistic effect of UV/H2O2 results in a marked enhancement
      of the rates of degradation. A mechanistic model for UV/H2O2 photooxidation has
      been developed. Room temperature (27 degrees C) rate constants for the reaction
      of .OH radical (formed by absorption of photons) with the substrates have been
      estimated by using the model equation. The calculated rate constants are of the
      same order of magnitude as reported for other similar aromatic compounds.

PMID- 10337396
TI  - Oxygen release kinetics from solid phase oxygen in Arctic Alaska.
AB  - Child's Pad is a gravel construction surface that was contaminated with petroleum
      during oil-field service operations in Deadhorse, Alaska. As part of a remedial
      action plan, a buffer strip of uncontaminated sandy gravel was placed along
      sections of the pad boundary. A magnesium peroxide formulation manufactured by
      Regenesis, and sold as Oxygen Release Compound (ORC), was placed in the buffer
      strips. The ORC was intended to supply oxygen to aerobic microorganisms capable
      of degrading petroleum. Studies were conducted in the laboratory to determine
      initial oxygen release kinetics from ORC in contact with barrier soil. Studies
      quantified the biotic and abiotic catalytic mechanisms for converting hydrogen
      peroxide (a possible MgO2 intermediate) and ORC to oxygen and water, the effects
      of temperature on oxygen release from ORC, and the effect of field exposure on
      ORC viability. Barrier soil exhibited sufficient catalytic activity to convert
      hydrogen peroxide to oxygen faster than the expected biological demand. The
      oxygen evolution rate (OER) from ORC was lower at 7 degrees C than 21 degrees C
      by more than two times. The ORC recovered from Child's Pad after less than 1 year
      retained nearly all of the original available oxygen, although physical bridging
      was evident.

PMID- 10337397
TI  - Bimetallic catalysts for continuous catalytic wet air oxidation of phenol.
AB  - Catalytic wet oxidation has proved to be effective at eliminating hazardous
      organic compounds, such as phenol, from waste waters. However, the lack of active
      long-life oxidation catalysts which can perform in aqueous phase is its main
      drawback. This study explores the ability of bimetallic supported catalysts to
      oxidize aqueous phenol solutions using air as oxidant. Combinations of 2% of CoO,
      Fe2O3, MnO or ZnO with 10% CuO were supported on gamma-alumina by pore filling,
      calcined and later tested. The oxidation was carried out in a packed bed reactor
      operating in trickle flow regime at 140 degrees C and 900 kPa of oxygen partial
      pressure. Lifetime tests were conducted for 8 days. The pH of the feed solution
      was also varied. The results show that all the catalysts tested undergo severe
      deactivation during the first 2 days of operation. Later, the catalysts present
      steady activity until the end of the test. The highest residual phenol conversion
      was obtained for the ZnO-CuO, which was significantly higher than that obtained
      with the 10% CuO catalyst used as reference. The catalyst deactivation is related
      to the dissolution of the metal oxides from the catalyst surface due to the
      acidic reaction conditions. Generally, the performance of the catalysts was
      better when the pH of the feed solution was increased.

PMID- 10337398
TI  - The thermal decomposition of dimethoate.
AB  - The thermal decomposition of dimethoate, an organophosphorus pesticide, has been
      studied with the aim at assessing the reaction kinetics, the energy released
      during the process and the decomposition products. Dimethoate shows a marked
      tendency to undergo thermal decomposition at temperature higher than 369 K. A
      moderate pressure increase has been recorded at the end of all runs. Many
      thiophosphoric compounds have been identified among the decomposition products.

PMID- 10337400
TI  - Photocatalytic decomposition of 4-chlorophenol over oxide catalysts.
AB  - 4-Chlorophenol in the presence of catalysts was decomposed in aqueous solution by
      a 125 W medium pressure mercury lamp in a thermostated quartz batch photoreactor,
      and the organic bound chlorine was catalytically converted into the
      environmentally less harmful inorganic chloride. Differences in the concentration
      of 4-chlorophenol and of the intermediates, such as hydroquinone and quinone, are
      followed by HPLC. The best catalyst among a homolog series for the photo
      decomposition of 4-chlorophenol was selected as finely dispersed platinum oxide
      on a TiO2 semiconductor support, and kinetic parameters of the Langmuir
      Hinshelwood type decomposition reaction were reported for the selected catalyst.
      A simple mechanism of substrate degradation in accord with the chosen kinetic
      model was postulated. The developed process may serve photooxidative removal of
      chlorophenols in wastewater without using costly oxidants.

PMID- 10337399
TI  - Thermogravimetric study of thermal decontamination of soils polluted by
      hexachlorobenzene, 4-chlorobiphenyl, naphthalene, or n-decane.
AB  - To determine decontamination behavior as affected by temperature, shallow beds of
      a clay-rich, a calcerous, and a sedimentary soil, artificially polluted with
      hexachlorobenzene, 4-chlorobiphenyl, naphthalene, or n-decane, were separately
      heated at 5 degrees C min-1 in a thermogravimetric analyzer. Temperatures for
      deep cleaning of the calcerous and the sedimentary soil increased with increasing
      boiling point (bp) of the aromatic contaminants, but removal efficiencies still
      approached 100% well below the bp. Decontamination rates were therefore modelled
      according to a pollutant evaporation-diffusion transport model. For the calcerous
      and sedimentary soils, this model reasonably correlated removal of roughly the
      first 2/3 of the naphthalene, but gave only fair predictions for
      hexachlorobenzene and 4-chlorobiphenyl. It was necessary to heat the clay soil
      above the aromatics bp to achieve high decontamination efficiencies. Weight loss
      data imply that for temperatures from near ambient to as much as 150 degrees C,
      interactions of each aromatic with the clay soil, or its decomposition products,
      result in lower net volatilization of the contaminated vs. neat clay. A similar
      effect was observed in heating calcerous soil polluted with hexachlorobenzene
      from near ambient to about 140 degrees C. Decontamination mechanisms remain to be
      established, although the higher temperatures needed to remove aromatics from the
      clay may reflect a more prominent role for surface desorption than evaporation.
      This would be consistent with our estimates that the clay can accommodate all of
      the initial pollutant loadings within a single surface monolayer, whereas the
      calcerous and sedimentary soils cannot.

PMID- 10337401
TI  - Slow desorption of volatile organic compounds from soil: evidence of desorption
      step limitations.
AB  - Transient adsorption and desorption of 1,2 dichloroethane and toluene on dry Yolo
      silt loam soil were studied by continuously measuring the composition of the
      effluent from a soil-packed chromatography column with a mass spectrometer. After
      obtaining complete breakthrough at approximately 30% relative saturation of one
      chemical in nitrogen, pure nitrogen feed was initiated and maintained for several
      hours. Of the material adsorbed at breakthrough, 9.7% of the 1,2 dichloroethane
      and 14.2% of the toluene were highly resistant to desorption and remained sorbed
      on the soil even after 5 h of nitrogen flow. When a second chemical with a higher
      adsorption affinity was introduced into the soil column (water following toluene
      or toluene following 1,2 dichloroethane), the majority of the first chemical was
      quickly desorbed and began leaving the soil column before breakthrough of the
      second chemical. Conversely, when a second chemical with a smaller adsorption
      affinity was introduced into the soil column, only a small amount of the first
      chemical was displaced and began leaving the soil column after breakthrough of
      the second chemical. The results of this study indicate that the desorption step
      itself may be the rate-limiting step for sorbate which remains after prolonged
      exposure to sorbate-free gas.

PMID- 10337402
TI  - Immobilization of chromium-contaminated soil by means of microwave energy.
AB  - To reduce the amount of hazardous wastes contaminated by heavy metals, a new
      technology to immobilize heavy metal ions is desired. Microwave (MW) technology
      which can be used to vitrify the contaminated soil wastes and immobilize the
      heavy metal ions for this purpose to satisfy the leachate test standard. We found
      that 90%+ of the chromium-contaminated soil went through the glass/ceramic
      transformation and was thus vitrified after being radiated with MW for 60 min.
      The chromium ion (Cr6+) concentration in the leaching test of all the vitrified
      soil samples is less than 1 mg/l, below the USEPA regulatory limit of 5.0 mg/l.
      This technology may become a major treatment method for hazardous wastes if the
      large-scale field test proves to be successful. In this paper, we will present
      the experimental conditions, the results and the future projects.

PMID- 10337403
TI  - Oxidation of dichlorvos with hydrogen peroxide using ferrous ion as catalyst.
AB  - This study examines how Fenton's reagent (Fe2+ and H2O2) decomposed dichlorvos
      insecticide. Results showed that dichlorvos decomposed in a two-stage reaction.
      The first stage is a Fe2+/H2O2 reaction in which dichlorvos swiftly decomposed.
      In the second stage, dichlorvos decomposed somewhat less rapidly, and it is a
      Fe3+/H2O2 reaction. The detection of ferrous ions also supports the theory of the
      two-stage reaction for the dichlorvos oxidation with Fenton's reagent. The
      dissolved oxygen of the solution decreased rapidly in the first stage reaction,
      but it slowly increased in the second stage with a zero-order kinetics. The
      Fenton system decomposed dichlorvos most rapidly when the initial pH in the
      solution is 3-4. In addition, increasing the concentration of hydrogen peroxide
      or ferrous ions can enhance the decomposition of dichlorvos. Consequently, the
      relationship of rate constant (kobs), [H2O2] and [Fe2+] at initial pH 3 is
      determined as kobs = 2.67 x 10(4)[H2O2]0.7[Fe2+]1.2.

PMID- 10337404
TI  - Bioremediation of phenols and polycyclic aromatic hydrocarbons in creosote
      contaminated soil using ex-situ landtreatment.
AB  - Soil from a former creosoting plant containing phenols and polycyclic aromatic
      hydrocarbons, was remediated using an ex-situ landtreatment process. Total 16
      USEPA priority PAH and total phenol were reduced from 290 mg/kg and 40 mg/kg to <
      200 mg/kg and 2 mg/kg, respectively. The bioremediation process involved soil
      mixing, aeration, and slow release fertilizer addition. The indigenous
      populations of PAH and phenol utilizing populations of microorganisms were shown
      to increase during the treatment process, indicating that biostimulation was
      effective. The most extensive degradation was apparent with the 2- and 3-ring
      PAH, with decreases of 97% and 82%, respectively. The higher molecular weight 3-
      and 4-ring PAH were degraded at slower rates, with reductions of 45% and 51%,
      respectively. Six-ring PAH were degraded the least with average reductions of <
      35%. The residual concentrations of PAH and total phenol obtained in the study
      allowed the treated soil to be disposed of as low level contaminated landfill.

PMID- 10337405
TI  - Application of the Seveso Directive in France.
AB  - First, the paper presents a brief summary of the French actual regulation on
      installations registered for the protection of the environment and covered by the
      Seveso I Directive. Then the paper discusses research and development needs for a
      sound implementation of the Directive, and for the new requirements on safety
      reports established by the Seveso II Directive. Further, it discusses issues
      connected with coverage of hazardous activities, learning from accidents,
      technical and organisational measures (safety management systems and emergency
      response) and human factors. The conclusions stress the need for networking and
      dissemination of accident investigations, development of safety management
      systems, and research on cognitive ergonomics and psychology related to the
      decision making and interventions of the operator.

PMID- 10337406
TI  - Precautions against industrial accidents: experience in applying the Seveso II
      Directive in central and eastern European countries.
AB  - Adopted approaches to safety reports and internal emergency plans are described.
      Based on the provisions of the Seveso II Directive and on the achieved state of
      hazard prevention management of the respective enterprises in central and eastern
      European states, reports and plans were prepared. Although these states are no
      members of the European Union, the parties recognised the requirements of the
      Seveso II Directive as a working basis. In detail: Methodical experience in
      preparing safety reports and emergency plans include a methodology in the three
      main steps: Analysis of information on hazardous substances, hazard analysis
      including all plants, more specific hazard analysis for representative plants.
      Basic ways of forming scenarios are given. According to a procedure, various
      types of scenarios were usually taken into account. Based on the assessment of
      effects of a substance release, important conclusions can be drawn regarding the
      extent of danger prevention. In most cases, the structure of the described
      internal accident emergency plan turned out to be helpful. The programmed system
      DISMA (Disaster Management) which is widely used in Germany turned out to be a
      suitable tool for the internal as well as external emergency planning. An example
      of information to the population is described.

PMID- 10337407
TI  - Precursors of dangerous substances formed in the loss of control of chemical
      systems.
AB  - Article 2 of Directive 96/82/EC on the control of major accident hazards caused
      by dangerous substances requires to consider also the hazards due to the
      dangerous substances "which it is believed may be generated during loss of
      control of an industrial chemical process", although no generally accepted
      guidelines are available for the identification of these substances. In the
      present study, the accidents involving the unwanted formation of dangerous
      substances as a consequence of the loss of control of chemical systems were
      investigated. A specifically developed database was used, containing data on more
      than 400 of these accidents and on the substances involved. The hazardous
      substances formed in the accidents and the precursors of these substances were
      identified. The influence of accident characteristics on the substances formed
      was investigated. In the context of the application of Directive 96/82/EC, an
      accident severity index and a hazard rating of the precursors of dangerous
      substances formed in the accidents were proposed. A lumping approach was used in
      order to develop schemes for the preliminary identification of substances that
      may be formed in the loss of control of chemical system. The results of accident
      analysis were used to test the schemes developed.

PMID- 10337408
TI  - The control of major accident hazards: the land-use planning issue.
AB  - Land-Use Planning with respect to major accident hazards constitutes one of the
      new requirements of the 'Seveso II Directive'. The paper discusses the rationale
      and the requirements set by the Directive for the operators of the plants and the
      planning authorities to take into account the major accident hazards in the land
      use planning procedure. Then, the paper focuses on approaches and criteria
      applied in the European Union, and gives information on procedures in other
      countries, wherever available. The approaches analysed are grouped into three
      broad categories, namely, establishing 'generic distances', 'consequence based',
      and 'risk based'. Finally, two illustrative examples facilitate understanding and
      comparison of the analysed approaches.

PMID- 10337409
TI  - A tribute to Helge Nornes.
AB  - This supplement of the Acta Neurochirurgica is dedicated to professor Helge
      Nornes on the occasion of his retirement. Helge Nornes started his neurosurgical
      training in Oslo in 1965. In 1980 he was offered the neurosurgical chair of Bern,
      Switzerland, where he stayed until 1983 when his old university called him back
      to the chair at the National Hospital in Oslo, a position he filled until he
      retired last year. The present paper briefly reviews examples of his
      contributions to neurosurgery and to the understanding of intracranial
      pathophysiology, including the transcranial doppler, the miniature transducer for
      intracranial pressure monitoring, his observations on intracranial pressure and
      internal carotid blood flow during subarachnoid haemorrhage, intracranial
      arterial blood flow in patients undergoing aneurysm surgery, his studies of the
      pathophysiology of arteriovenous malformations, the introduction of
      intraoperative Doppler recordings during surgery for aneurysms and arteriovenous
      malformations, and his methods for evaluating collateral circulation prior to
      internal carotid artery occlusion.

PMID- 10337410
TI  - Intracranial aneurysms and subarachnoid hemorrhage management of the poor grade
      patient.
AB  - Between 20 and 30% of patients who suffer cerebral aneurysm rupture are in poor
      clinical grade when first evaluated. Management of these patients is
      controversial and challenging but can be successful with an aggressive proactive
      approach that begins with in the field resuscitation and continues through
      rehabilitation. In this article we review the epidemiology, pathology and
      pathophysiology, clinical features, evaluation, surgical and endovascular
      management, critical care, cost, and outcome prediction of patients in poor
      clinical grade after subarachnoid hemorrhage.

PMID- 10337411
TI  - Etiology of cerebral vasospasm.
AB  - Cerebral vasospasm is a gradual onset and prolonged constriction of the cerebral
      arteries in the subarachnoid space after subarachnoid hemorrhage. The principal
      cause is the surrounding blood clot. The significance of vasospasm is that flow
      through the constricted arteries may be reduced sufficiently to cause cerebral
      infarction. Subarachnoid blood clot is sufficient to cause vasospasm; it does not
      require additional arterial injury, intracranial hypertension or brain
      infarction, although these elements are often coexistent. The blood released at
      the time of aneurysmal rupture into the alien subarachnoid environment is an
      extraordinarily complex mix of cellular and extracellular elements that evolves
      as clotting occurs; cells disintegrate; local inflammation, phagocytosis and
      repair take place; severe constriction alters the metabolism and structure of the
      arterial wall as well as the balance of vasoconstrictor and dilator substances
      produced by its endothelium, neurogenic network and perhaps smooth muscle cells.

PMID- 10337412
TI  - Hemodynamics of cerebrovascular spasm.
AB  - An understanding of the hemodynamics of cerebrovascular spasm following
      subarachnoid hemorrhage is important for the diagnosis and treatment of this
      potentially dangerous condition. An overview model is presented which includes
      the main elements determining the overall effect of vasospasm. The model included
      realistic pressure-flow-velocity-diameter relationship encountered in a geometry
      resembling that of vasospasm of the middle cerebral artery. Viscosity was
      adjusted to that expected of human blood. Furthermore, a realistic model the
      cerebral autoregulation was included. The effects of induced hypertension as well
      as hypotension were studied. It was found that the friction pressure loss in the
      spastic segment was 3.5 times as high as that predicted by using the Hagen
      Poiseuille formula. The reason for this discrepancy was probably the 'inlet
      length effect' considerably increasing the friction. Furthermore, including the
      Bernoulli kinetic pressure energy, a formula was proposed that accurately
      described the experimental data. From this hemodynamic perspective, strong
      support was found for the present trend to use aggressive hypertensive therapy in
      patients with vasospasm. The results also confirmed that TCD velocity
      measurements in the spastic segment when taken alone may not be a good index of
      the degree and effect of the spasm. These measurements must be combined with
      other techniques such as extracranial Doppler or CBF to assess the degree of
      spasm.

PMID- 10337413
TI  - The role of transcranial Doppler in the management of patients with subarachnoid
      haemorrhage--a review.
AB  - Introduced 15 years ago, transcranial Doppler (TCD) recordings of blood-velocity
      in patients with recent subarachnoid haemorrhage (SAH) have two objectives: to
      detect elevated blood velocities suggesting cerebral vasospasm (VSP) and to
      identify patients at risk for delayed cerebral ischemic deficits (DID). The
      pathophysiological cascade causing DID is complex. Discrepancies between blood
      velocities and DID (presuming that there actually is an "ischemic threshold" for
      blood velocity in absolute terms, which seems most unlikely) have been
      demonstrated, particularly in patients with elevated intracranial pressure (ICP)
      levels. Furthermore, the vessel showing the highest blood velocity is not always
      the one perfusing the area where ischemic symptoms arise, nor does the site of
      the greatest subarachnoid blood clot always relate to the ischemic brain region.
      Moreover, it is probable that the complex haemodynamic changes following SAH and
      the subsequent development of VSP may be underestimated if only considering the
      crude intracranial artery blood velocities. Cerebral blood flow measurements
      combined with TCD to assess both flow and velocity have emphasised this point.
      Despite these findings and ignoring the basic principles of cerebral
      haemodynamics, cerebral vasospasm is still being assessed from the intracranial
      velocity measurement alone. The addition of at least a careful measurement from
      the extracranial internal carotid artery--using the same TCD equipment and taking
      only a few short minutes to perform--allows a much more accurate assessment of
      the degree and the effects of vasospasm. This probably explains why the clinical
      value of TCD is still debated. There is still uncertainty as to the best method
      to prevent and to treat VSP, and the overall outcome after SAH depends on so many
      factors besides VSP. Conclusive evidence may therefore be hard to obtain, and it
      appears sound to conclude that even with advanced investigation technology
      available, proper selection, pre- peri- and postoperative care and timing of
      surgery remain cornerstones in the management of these patients,--equal in
      importance to their treatment in the operating room or in the interventional
      angiography suite.

PMID- 10337414
TI  - Neurointensive care of aneurysmal SAH.
AB  - This paper briefly reviews some basic principles of neurosurgical intensive care
      of patients with aneurysmal subarachnoid hemorrhage. The importance of early
      identification of secondary insults are underlined. Special attention is paid to
      the newly introduced method for neurochemical monitoring by means of
      intracerebral microdialysis. It is concluded that a well functioning
      neurointensive care unit constitutes an important organisational frame for the
      detection, prevention and treatment of secondary insults, after aneurysmal
      subarachnoidal hemorrhage and that improved results can be expected by applying a
      modern neurointensive care strategy also for patients with aneurysmal
      subarachnoid hemorrhage.

PMID- 10337415
TI  - Virtues and drawbacks of titanium alloy aneurysm clips.
AB  - This report describes the imaging characteristics of titanium alloy aneurysm
      clips and our clinical experience with these clips in more than 300 patients.
      Phantom and clinical investigations showed that clip artifacts on CT and MR are
      minor as compared to the cobalt alloy clips used previously. Spiral CT
      angiography (CTA) in combination with titanium alloy clips could be shown to be a
      feasible mode of postoperative control and can be used to determine completeness
      of aneurysm elimination, patency of adjacent arteries as well as vasospasm. In
      contrast, magnetic resonance angiography (MRA) proved to be unfeasible as a
      method of postoperative vascular imaging since the titanium clips still produce a
      shadow in the order of size of the entire aneurysm. Therefore, completeness of
      aneurysm elimination cannot be judged on magnetic resonance angiography. The
      clinical experience in more than 300 cases showed that the titanium alloy clips
      essentially performed well. However, the limits of elastic deformation appear to
      be somewhat inferior to cobalt alloy clips. The standard appliers do not open the
      blades of the titanium clips quite as far as with the comparable cobalt alloy
      clips and the corresponding appliers. Therefore the titanium aneurysm clips are
      not quite as well suited for large broad based aneurysms. Furthermore, the
      increased susceptibility of the new clips with regard to abuse suggests to follow
      the recommendations of the manufacturer not to recycle and re-sterilize clips
      that have been tried but not permanently implanted.

PMID- 10337416
TI  - A combined transorbital-transclinoid and transsylvian approach to carotid
      ophthalmic aneurysms without retraction of the brain.
AB  - A series of 138 patients with 143 carotid-ophthalmic aneurysms (COAs) have been
      treated by direct surgical approach over the past 15 years. In 5 cases the COAs
      were bilateral and in 15 cases either one or more aneurysms were associated with
      a COA. Of the 143 COAs, 87 were small, 41 large and 15 were giant. Seventy-four
      COAs bled, while 69 were diagnosed either incidentally or else manifested
      themselves through neurological deficits resulting from compression of the
      adjacent structures by the aneurysms. Visual deficits were diagnosed in all the
      patients with large/giant COAs and in 27 patients with small COAs. Of the whole
      series of patients operated on for COAs, 2 died after surgery. Two patients had
      endocrinological deficits, 2 had hemiparesis, 36 had the same visual deficits as
      prior to surgery, whereas in 47 patients the visual function improved. Of all the
      138 patients, 96 remained without neurological deficits, and the 36 patients with
      the same visual deficits as preoperatively also showed no neurological deficits
      after surgery and hence they were able to resume their previous way of life.
      Vasospasm did not occur in patients with COA(s) only, but was observed in 6 out
      of 15 patients with multiple aneurysms where subarachnoid hemorrhage (SAH) had
      occurred due to a rupture of an aneurysm other than the COA. There has been a
      major change in the surgical approach to COAs, from the classical pterional
      intradural approach to the transorbital-transclinoid and transsylvian approach
      which is described in this report. The latter approach provides ample space for
      proximal and distal control of the internal carotid artery (ICA) and makes it
      possible to deal with demanding large/giant COAs safely. In the series presented,
      there was no case of premature rupture of the aneurysm. Moreover, since we
      started using the described approach to COAs, retraction of the brain has not
      been necessary, regardless of the size of the aneurysm.

PMID- 10337417
TI  - Extradural approach to intracavernous ICA aneurysms.
AB  - A series of 115 intracavernous internal carotid artery (ICA) aneurysms have been
      treated by a direct surgical approach during the past 15 years. Sixty-eight
      aneurysms were small. Of these 11 were traumatic; nine caused by severe head
      injury and 2 by ICA injury during transsphenoidal surgery. Twenty-six aneurysms
      were large and 21 were giant. Thirty-eight aneurysms were clipped, 46 were
      treated by resection followed by ICA wall reconstruction with interrupted
      sutures, 16 by excision and proximal/distal ICA end-to-end anastomosis and 15 by
      resection/grafting. Postoperative angiography was performed in 107 cases and the
      ICA was found to be patent in 100 of these. Three patients died after surgery,
      two (with traumatic aneurysms) from associated brain injury and 1 from pulmonary
      embolism. Oculomotor palsy was present in the immediate postoperative period in
      104 patients. However, six months after surgery only 7 patients had residual
      palsy. The direct surgical approach to intracavernous ICA aneurysms has
      constantly been changed and improved. The approach in its original version [6]
      was mainly intradural, whereas its contemporary version in most cases is
      extradural [10, 11]. The latter approach provides complete exposure of the entire
      parasellar region, good proximal control of the ICA [13], and good access to the
      cavernous sinus through the individual "corridors" between the cranial nerves
      [7]. In the author's opinion the direct surgical approach provides better results
      than endovascular treatment with regard to patency of the ICA [11].

PMID- 10337418
TI  - Surgical treatment of anterior circulation aneurysms.
AB  - The purpose of this paper is to present the results, assessed by an independent
      observer, of surgical treatment of 428 consecutive patients harbouring aneurysms
      of the anterior circulation, together with a review of relevant anatomy and
      operative strategy. At follow-up (mean 5.6 years) 89.3% lived at home and were
      independent, 5.1% lived at home but needed some kind of assistance, 2.0% lived in
      institution, whereas information was unavailable in 3.6% of living patients. Two
      hundred and fifty-three patients (64.5%) had unchanged employment status, 0.3%
      worked in sheltered environment, whereas 30.9% went out of work due to their
      subarachnoid hemorrhage (SAH). Information about employment status was
      unavailable in 4.3%. For aneurysms of the internal carotid, anterior
      communicating and middle cerebral artery, respectively, mortality was 3.2, 3.9
      and 5.6%, whereas 92.0, 88.1 and 89.0% of surviving patients lived at home and
      were independent and 67.0, 63.6 and 63.0% had unchanged employment status. Three
      months mortality of all causes was 4.2%. In the postoperative period 53 (12.4%)
      patients developed clinical signs of vasospasms, 6 (1.4%) had cardiac infarction,
      4 (0.9%) lung oedema, 4 (0.9%) deep vein thrombosis, and 7 patients (1.6%)
      infection. During the follow-up period shunt-dependent hydrocephalus developed in
      4.2% and 0.2% had a subsequent SAH from the same aneurysm. Forty-three patients
      were on anticonvulsive therapy.

PMID- 10337419
TI  - Posterior circulation aneurysms. Technical strategies based on angiographic
      anatomical findings and the results of 60 recent consecutive cases.
AB  - Ninety-eight patients with aneurysms of the posterior circulation were admitted
      to our department from 1993 to 1997. Sixty of them underwent microsurgical
      treatment, mostly in the acute stage of subarachnoid hemorrhage. Peri- and
      intraoperative management were carried out according to a structured treatment
      strategy. Special aspects of surgical technique included extradural selective
      anterior clinoidectomy for basilar head aneurysms, lateral suboccipital
      craniotomy and partial condylectomy without laminectomy for aneurysms of the
      vertebral artery or posterior inferior cerebellar artery, and a trans-Sylvian
      approach, as used in selective amygdalohippocampectomy, for aneurysms of the
      posterior cerebral artery. A careful angiographic evaluation of the aneurysms in
      relation to the neighboring important arteries and bony structures was essential
      for optimal surgical planning. Forty-nine patients (82%) made a good recovery by
      3 months after surgery. The mortality was 7%.

PMID- 10337420
TI  - Surgical strategies for giant intracranial aneurysms.
AB  - Untreated giant intracranial aneurysms have a dismal natural history as a result
      of hemorrhage, cerebral compression, and thromboembolism. The poor prognosis of
      patients with giant aneurysms therefore warrants aggressive treatment. A surgical
      approach is chosen to maximize the operative exposure of the aneurysm and depends
      mainly on the aneurysm's location. Once exposed, vascular control of the aneurysm
      is required not only to manage an intraoperative rupture, but also to collapse
      the aneurysm, to increase working space, and to improve visualization of the
      anatomy. Hypothermic circulatory arrest may be indicated in select patients with
      complex posterior circulation aneurysms. Direct clipping of giant aneurysms, with
      meticulous preservation of parent and branch arteries, is the preferred method of
      occlusion. Unclippable aneurysms require alternative techniques (e.g., trapping,
      parent artery occlusion, excision, and aneurysmorrhaphy) that compromise parent
      arteries and may require revascularization to restore adequate cerebral blood
      flow. Giant aneurysms are complex lesions that demand thorough surgical planning,
      individualized strategies, and a multidisciplinary effort in specialized
      neurovascular centers.

PMID- 10337422
TI  - Atopic keratoconjunctivitis (AKC).

PMID- 10337421
TI  - Functional outcome after aneurysmal subarachnoid hemorrhage.
AB  - The introduction of the operating microscope, the principle of early surgery,
      specialized intensive care units, the calcium antagonist nimodipine, the
      sophisticated pre- and postoperative management and an aggressive antiischemic
      pharmacological management have substantially reduced morbidity and mortality
      after aneurysmal subarachnoid hemorrhage (SAH). In spite of this progress, many
      patients after rupture and surgical repair of an intracranial aneurysm exhibit
      substantial cognitive deficits and emotional problems although their neurological
      outcome was rated as good according to the Glasgow Outcome Scale (GOS = I).
      Therefore, a comprehensive neuropsychological examination is called for in order
      to evaluate the factual functional outcome after SAH. Neither focal brain damage
      associated with aneurysm location nor surgery but the hemorrhage itself and
      related events can be regarded as the most important causal factors for the late
      result after SAH. In contrast to the mild permanent effects of aneurysm surgery,
      the initial bleeding itself seems to have substantial lasting adverse
      neurobehavioral effects after. In concordance with other authors our own data
      stress the strong predictive power of the bleeding pattern such as the presence
      of intraventricular and/or intracerebral blood on the functional outcome after
      aneurysmal SAH.

PMID- 10337423
TI  - Classification of ocular atopic/allergic disorders and conditions: an unsolved
      problem.
AB  - PURPOSE: To review the different classifications of ocular allergic diseases and
      to define the most suitable one according to the current understanding of the
      pathophysiology and clinical course of these disorders. METHODS: Review of the
      major published ocular allergy classifications. RESULTS: Based on past and
      present classifications, the author proposes the following classification: 1.
      allergic conjunctivitis (acute and chronic); 2. giant papillary conjunctivitis;
      3. vernal keratoconjunctivitis; and 4. atopic keratoconjunctivitis. In addition,
      use of the term "allergic conjunctivitis" as a synonym for all ocular allergic
      disease is discouraged. CONCLUSION: The proposed classification for ocular
      allergic disorders intends to unify the present criteria and to serve as an
      initial forum of discussion. This should enhance a common understanding among and
      between ophthalmologists and other allergy specialists. Constructive criticism of
      this classification system is required for further improvement.

PMID- 10337424
TI  - Vernal keratoconjunctivitis.
AB  - Vernal keratoconjunctivitis therefore, if managed properly, can be controlled.
      Inaccurate diagnosis or staging of the disease, together with inaccurate
      treatment will however, result in changes which can jeopardize sight and may even
      necessitate corneal surgery at a later date.

PMID- 10337425
TI  - Giant papillary conjunctivitis--a review.
AB  - First described in 1974 by an Australian ophthalmologist Dr. Spring, Giant
      Papillary Conjunctivitis (GPC) is one of the external ocular allergic conditions.
      It is most often associated with contact lens wear, but has also been described
      in patients with ocular prostheses and corneal sutures following surgery.
      Diagnosis is usually straightforward. Patients complain of decreasing lens
      tolerance, mucus production, often severe enough to cause blurred vision, and
      some itch. Inspection will reveal conjunctival hyperaemia and enlarged tarsal
      papillae. Management centres around patient education regarding careful lens
      hygiene but in severe cases may require a change to disposable lenses or a
      cessation of lens wear. In some cases, pharmacological agents may be required.
      The histopathology of GPC is very similar to Vernal Keratoconjunctivitis (VKC).
      It is caused by a complex immunological reaction and is not solely IgE-mediated.
      Trauma and foreign body reactions also play a role. The incidence of GPC has
      decreased with the advent of disposable lenses.

PMID- 10337426
TI  - Pathophysiology of allergic conjunctivitis.

PMID- 10337427
TI  - Allergic versus pseudoallergic conjunctivitis.

PMID- 10337428
TI  - Differential diagnosis of allergic ocular disorders.

PMID- 10337429
TI  - Genetics of ocular allergy.

PMID- 10337430
TI  - A current appreciation of sites for pharmacological intervention in allergic
      conjunctivitis: effects of new topical ocular drugs.
AB  - Two important realizations about pathophysiological mechanisms involved in
      allergic conjunctivitis have led to novel drug discovery efforts and new topical
      ocular medications for prevention and treatment of this prevent allergic disease.
      The first of these, interspecies and intraspecies mast cell heterogeneity, was
      established in the mid-1980's by investigators working in the field of asthma. It
      is now appreciated that secretory responses as well as effects of pharmacological
      agents differ depending upon the mast cell population studied. Two types of human
      mast cells, the tryptase containing (T) and the tryptase/chymase containing (TC)
      mast cells, have been characterized in a variety of tissues. Significantly, Irani
      et al. (1) demonstrated by immunohistochemical staining that the mast cells
      present in conjunctival tissues from patients with allergic conjunctivitis were
      100% TC. Functional responses of human conjunctival mast cells to a variety of
      secretagogues (2) were consistent with their classification as TC or connective
      tissue type mast cells. Importantly, the studies by Miller et al. mentioned above
      allowed the harvesting and preparation of human conjunctival mast cells for use
      in drug screening studies. Utilization of these cells has led to the
      identification of Patanol, the most effective human conjunctival mast cell
      stabilizer available for topical use in allergic conjunctivitis (3). These same
      studies demonstrated the lack of mast cell stabilizing activity for cromolyn and
      nedocromil in these connective tissue type, TC containing, human conjunctival
      mast cells. Similar lack of effect was noted with these drugs on human skin mast
      cell degranulation (4). The second important discovery in the area of allergic
      conjunctivitis has been the demonstration that conjunctival epithelial cells may
      contribute to the perpetuation of the allergic response. A report from Gamache et
      al. (5) identified cytokines produced by human conjunctival epithelial cells
      following treatment with a number of stimuli. Significantly, Sharif et al. (6)
      subsequently identified functional histamine H1 receptors on these same cell
      types. Recently, Weimer et al. (7) have shown that exposure of human conjunctival
      epithelial cells to histamine leads to the production of pro-inflammatory
      cytokines IL-6 and IL-8. Importantly, treatment of the epithelial cells with
      drugs that possess histamine H1 antagonist properties prevents cytokine
      production. It is noteworthy that first generation anti-histamines antazoline and
      pheniramine are not potent inhibitors of histamine-stimulated cytokine synthesis
      in intact epithelial cells, while newer anti-histamines Emadine and levocabastine
      are more potent. Surprisingly, Patanol was more potent as an inhibitor of
      histamine-stimulated cytokine production by the epithelial cells than would be
      predicted from its histamine H1 antagonist affinity. These inhibitory effects on
      conjunctival epithelial cell production of pro-inflammatory cytokines may
      contribute to enhanced clinical activity noted with these recently approved
      drugs.

PMID- 10337431
TI  - Comparison of the conjunctival allergen challenge model with the environmental
      model of allergic conjunctivitis.

PMID- 10337432
TI  - Comparison of the topical ocular antiallergic efficacy of emedastine 0.05%
      ophthalmic solution to ketorolac 0.5% ophthalmic solution in a clinical model of
      allergic conjunctivitis.
AB  - PURPOSE: To compare the clinical efficacy of emedastine ophthalmic solution to
      that of ketorolac ophthalmic solution using a conjunctival allergen challenge
      model. METHODS: The conjunctival allergen challenge model was used in this
      randomized, double-masked, single center, crossover study. The titer of allergen
      that elicited a positive allergic reaction was selected. After at least 14 days,
      36 subjects were randomized into two groups of 18 to receive either emedastine in
      one eye and placebo in the contralateral eye, or ketorolac in one eye and placebo
      in the contralateral eye. Ten minutes after drug instillation, subjects were
      challenged with antigen. At 3, 10 and 20 minutes following challenge subjects
      graded ocular itching and were assessed for hyperemia in conjunctival, ciliary,
      and episcleral vessel beds. Approximately 14 days later, subjects received the
      alternate treatment in one eye and placebo in the contralateral eye. They were
      again challenged with allergen and their responses were rated in the same manner.
      Ocular discomfort was assessed by the subjects after administration of each study
      drug. RESULTS: Emedastine significantly (p < 0.05) inhibited ocular itching and
      redness in vascular beds following topical ocular administration. In contrast,
      ketorolac failed to significantly inhibit ocular itching or redness in this
      study. Patient assessment of comfort indicated emedastine was significantly (p <
      0.05) more comfortable than ketorolac upon topical ocular administration.
      CONCLUSION: Emedastine is superior to ketorolac in controlling itching and
      redness, the cardinal symptom and sign of allergic conjunctivitis.

PMID- 10337433
TI  - Comparative evaluation of olopatadine ophthalmic solution (0.1%) versus ketorolac
      ophthalmic solution (0.5%) using the provocative antigen challenge model.
AB  - OBJECTIVE: This study was conducted to compare the efficacy and safety of
      olopatadine ophthalmic solution (0.1%) with ketorolac ophthalmic solution (0.5%)
      in a clinical model of acute allergic conjunctivitis. Olopatadine is a dual
      acting H1 histamine receptor antagonist and a mast cell stabilizer, shown to be
      effective in treating allergic conjunctivitis. Ketorolac is a non-steroidal anti
      inflammatory drug approved in the United States for the relief of ocular itching
      associated with seasonal allergic conjunctivitis. METHODS: The provocative
      antigen challenge model was used in this randomized, double-blind, single-center,
      crossover study. The allergen and concentration that consistently elicited a
      positive allergic reaction was used for challenge. After at least 14 days,
      subjects were randomized to receive either olopatadine in one eye and placebo in
      the contralateral eye, or ketorolac in one eye and placebo in the contralateral
      eye. Twenty-seven minutes after drug instillation subjects were challenged with
      allergen. At 3, 10, and 20 minutes following allergen challenge, subjects graded
      ocular itching and were assessed for hyperemia in conjunctival, ciliary, and
      episcleral vessel beds. Approximately 14 days later, subjects received the
      alternate treatment in one eye and placebo in the contralateral eye. They were
      again challenged with allergen and their responses were rated in the same manner.
      RESULTS: Olopatadine significantly (p < 0.0001) reduced both ocular itching and
      hyperemia in all three vessel beds compared to placebo at all time points tested
      following allergen challenge. Ketorolac did not significantly reduce itching and
      showed a trend of increased hyperemia compared to placebo. Olopatadine was
      significantly (p < 0.001) more effective than ketorolac in reducing hyperemia and
      ocular itching at all time points and was also significantly (p < 0.05) more
      comfortable than ketorolac as reported by subjects immediately following drug
      instillation. CONCLUSION: The study demonstrated that olopatadine is effective
      and safe in preventing and treating ocular itching and hyperemia associated with
      acute allergic conjunctivitis and is more effective and more comfortable than
      ketorolac.

PMID- 10337434
TI  - The added benefit of local Patanol therapy when combined with systemic Claritin
      for the inhibition of ocular itching in the conjunctival antigen challenge model.
AB  - BACKGROUND: Allergic conjunctivitis very often occurs simultaneously with
      rhinitis in seasonal allergy sufferers. While systemic anti-allergic and
      antihistaminic agents are effective against many signs and symptoms of allergy,
      they may not adequately control ocular signs and symptoms in patients with
      multiple target organ hypersensitivity. Patanol (olopatadine hydrochloride 0.1%
      ophthalmic solution, Alcon Laboratories, Inc., Fort Worth, TX), a new effective
      anti-allergic mast cell stabilizer with antihistaminic properties, is approved
      for the prevention of ocular itching due to allergic conjunctivitis. OBJECTIVE:
      To determine whether Patanol in combination with the systemic antihistamine
      Claritin (loratadine, Schering, Kenilworth, NJ) reduces the ocular itching
      associated with allergic conjunctivitis more effectively than Claritin alone. A
      topical ocular antigen challenge induced the allergic conjunctivitis in 15
      subjects. METHODS: This was a randomized, double-masked study in which the
      contralateral eye served as the control. On Visit 1, an allergen dose which
      elicited response scores > 2 for ocular itching was identified. Itching was
      graded by the subject using a 0 to 4 point scale. At Visit 2, the threshold
      allergen concentration was confirmed. At Visit 3, the onset of action challenge,
      in addition to Claritin (10 mg tablet), each subject received Patanol in one eye
      and placebo in the fellow eye in a randomized, double-masked fashion. Allergen
      was instilled one hour after dosing, and ocular itching was graded at 3, 7, 10
      and 20 minutes after challenge. At Visit 4, the duration of action challenge, the
      same drug regimen was followed as in Visit 3. However, allergen challenge was
      performed eight hours after dosing, and itching graded after 3, 7, 10 and 20
      minutes. RESULTS: Patient eyes treated with Patanol were significantly less itchy
      than those treated with systemic Claritin alone at critical time points 3, 7, and
      10 minutes after the onset of action challenge (p < 0.05), and at 3 and 7 minutes
      after the duration of action challenge (p < 0.05). CONCLUSION: The addition of
      topical Patanol to systemic Claritin therapy significantly reduced ocular itching
      associated with allergic conjunctivitis compared to treatment with Claritin
      alone. These findings prove the added benefit of local Patanol therapy in the
      treatment of ocular allergic symptoms in patients receiving systemic
      antihistamines for concomitant systemic allergies.

PMID- 10337435
TI  - Cell culture aging: insights for cell aging in vivo?

PMID- 10337436
TI  - Lack of association of anabolic hormone status and muscle strength with regional
      and whole body bone mineral density in healthy men aged 60-79 years.
AB  - This study investigated the capacity of muscle strength and anabolic hormone
      status to predict regional and whole body bone mineral density (BMD) in older
      men. Fifty-two healthy men aged 60-79 years served as subjects. BMD of the lumbar
      spine, proximal femur, upper and lower limbs, and whole body was assessed by dual
      X-ray absorptiometry. Dynamic muscle strength for several upper and lower body
      muscle groups was determined by the one-repetition maximum and isometric grip
      strength by dynamometry. Anabolic hormone status was assessed by the ratio of
      testosterone (T) to sex hormone binding globulin (SHBG), given as the free
      androgen index (FAI), and the ratio of insulin-like growth factor I (IGF-I) to
      IGF binding protein-3 (IGFBP-3). Age was associated with declines in dynamic
      strength and the log FAI. In stepwise regression analysis, only body mass was an
      independent predictor of whole body and upper limb BMD (R2 = 0.13), and hip
      adductor strength predicted the Ward's triangle (R2 = 0.14). For lumbar spine
      BMD, triceps extensor strength was significantly correlated (r = 0.36, p < 0.01),
      while no strength or hormonal variable was associated with the femoral neck,
      trochanter, or lower limb. The lack of association between muscle strength and
      BMD was generally unaltered after controlling for hormone status and body mass.
      There was no difference in BMD when analyzed by tertiles of log FAI or IGF
      I/IGFBP-3 or by tertiles of muscle strength. These results suggest that in
      healthy community-dwelling men in the seventh and eighth decade, muscle strength
      and hormonal status are not significant contributors to regional or whole body
      BMD.

PMID- 10337437
TI  - Age differences in ratings of medical care among older adults living in the
      community.
AB  - Patients ratings of care serve as an indicator of quality of care, as well as a
      predictor of patient behavior. In spite of the heterogeneity of the older
      population and their disproportionate consumption of health care resources,
      relatively little attention has been paid to assessing the elderly's satisfaction
      with medical care. Using data from the 1991 Medicare Current Beneficiary Survey,
      we compare ratings of medical care and quality of physician care between the
      young-old (65-79 years) and old-old (80+ years) living in the community.
      Multivariate logistic regression analyses are performed to assess the independent
      effect of age on patients' ratings of care. Results show a significant negative
      association between age and highly positive ratings of care in the elderly; the
      old-old are less likely than the young-old to give very favorable opinions (e.g.,
      very satisfied vs other) of the care they received. The relationship remains even
      after controlling for measures of health status and experience and use of health
      care. However, variations were observed when more negative ratings (e.g.,
      satisfied/very satisfied vs dissatisfied/very dissatisfied) were considered.
      Although elderly people as a group usually are found to rate their care more
      positively than younger adults, this study indicates there is heterogeneity in
      the older population regarding views of medical care.

PMID- 10337438
TI  - Cancer mortality trends in two cohorts of elderly people having different life
      styles.
AB  - We analyzed cancer mortality trends in 3282 elderly subjects from two general
      Italian populations with different life-style patterns taking part in the
      Cardiovascular Study in the Elderly (CASTEL). The aim of the study was to
      evaluate which predictors were able to influence cancer mortality. Age, gender,
      tobacco smoking, the presence of respiratory symptoms, increased serum levels of
      ALT and ALP, and the town of residence were powerful predictors. Subjects living
      in Chioggia (low income, rural) had significantly greater lung and liver cancer
      mortality, compared with those living in Castelfranco (industrial). The findings
      suggest that an incongruous life-style (smoking, alcohol consumption, poor
      hygienic conditions) may increase cancer mortality despite the favorable
      environmental conditions typical of rural Mediterranean areas.

PMID- 10337439
TI  - Dehydroepiandrosterone sulfate, diseases and mortality in a general aged
      population.
AB  - Dehydroepiandrosterone sulfate (DHEAS) was measured in a five-year follow-up
      study of random persons of three age cohorts (75-, 80-, and 85-years, N = 571) in
      order to investigate its associations with clinical diseases and their risk
      indicators, as well as its prognostic significance in old age. DHEAS was higher
      in men (3.1 mumol/L) than in women (1.9 mumol/L) in the 75-year age group. It
      decreased in men up 85 years. Compared to healthy men, DHEAS was lower in men
      with a history of or manifest vascular diseases, presence of dementia, diabetes
      mellitus, malignancies and musculoskeletal disorders, but was similar in all
      these disease groups. No differences were found in women. DHEAS did not relate to
      cardioechographic findings, cardiovascular risk factors or predictors of impaired
      survival prognosis. After controlling for age, DHEAS tended to be lower in the
      non-surviving than in the surviving men (2.28 mumol/L vs 2.65 mumol/L, p =
      0.065). After controlling for disease, DHEAS did not predict increased risk of
      all-cause or cardiovascular mortality during the 5-year follow-up. In this study,
      gender differences in DHEAS persisted up to the age of 75 years. Low plasma DHEAS
      appears to be a secondary phenomenon rather than a specific risk indicator of
      common diseases in old age.

PMID- 10337440
TI  - Is age a negative prognostic indicator in HIV infection or AIDS?
AB  - To better understand disease progression in older persons with human
      immunodeficiency virus (HIV infection or acquired immunodeficiency syndrome
      (AIDS), we studied patients aged 50 years and older hospitalized with a diagnosis
      of HIV infection or AIDS between January 1985 and October 1995. Data collected
      included demographics, opportunistic infections, comorbid disease, neurologic
      dysfunction, and antiretroviral therapy. A total of 86 patients with a mean age
      of 54.3 years was identified. Pneumocystis carinii pneumonia was the most
      frequent opportunistic infection (43%). Hypertension was the most common previous
      medical condition (38%). Other comorbid disease was present in less than 15% of
      the subjects. Fifty-seven patients (66%) had neurologic impairment, with 30
      requiring treatment for delirium. In these 30, 23 (77%) had anemia, infection, or
      both. The median length of survival following the diagnosis of AIDS was 18.5
      months, for HIV it was 48 months. The median survival following the diagnosis of
      AIDS in patients who received antiretroviral therapy was 22 months compared with
      11 months for those who did not receive antiretroviral therapy (p < 0.0004).
      Multivariable analysis found that antiretroviral therapy was the only independent
      predictor of survival after the diagnosis of AIDS. In contrast to previous
      studies, the present findings suggest that older age may not necessarily be
      associated with more rapid disease progression and reduced survival times in
      persons with HIV infection or AIDS. In those patients with delirium, many may
      have readily treatable conditions (anemia and/or infection). The absence of
      significant comorbid disease and the access to antiretroviral therapy may be in
      part responsible for the longer survival times obtained in this cohort compared
      to that reported previously.

PMID- 10337441
TI  - Antioxidant systems in rat lens as a function of age: effect of chronic
      administration of vitamin E and ascorbate.
AB  - Oxidative damage occurring in the lenses of patients with senile cataract may be
      due to partially reduced forms of oxygen. We assayed the activities of superoxide
      dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSH
      Red), and glucose-6-phosphate dehydrogenase (G6PD) in rat lenses at different
      ages (1, 4, and 24 months), and also evaluated lens glutathione (GSH) levels and
      the effects of chronic administration of vitamin E and sodium ascorbate. We
      observed a significant age-related decrease in GSH-Px, GSH-Red and G6PD
      activities, but no age-related change in SOD activity. Chronic treatment with
      both vitamin E and sodium ascorbate failed to restore enzymatic activities to the
      levels of younger rats. An age-related reduction in GSH content was also
      observed; however, chronic administration of vitamin E, but not of sodium
      ascorbate, restored GSH levels to those of younger rats.

PMID- 10337442
TI  - Heart fatty acid unsaturation and lipid peroxidation, and aging rate, are lower
      in the canary and the parakeet than in the mouse.
AB  - Despite their high metabolic rates, birds have a much higher maximum longevity
      (MLSP) than mammals of similar body size, and thus represent ideal models for
      identifying longevity characteristics not linked to low metabolic rates. This
      study shows that the fatty acid double bond content of both canary (MLSP = 24
      years) and parakeet (MLSP = 21 years) hearts is intrinsically lower than in mouse
      (MLSP = 3.5 years) heart. This is caused by a redistribution between types of
      unsaturated fatty acids, mainly due to a lower content of the most highly
      unsaturated docosahexaenoic acid (22:6n-3) in the two birds in relation to the
      mammal. The lower double bond content leads to a lower sensitivity to lipid
      peroxidation, and to a lower level of in vivo lipid peroxidation in the heart of
      parakeets and canaries than in that of mice. Similar results have been previously
      found comparing liver mitochondria of rats and pigeons and tissues of different
      mammalian species. All these results taken together suggest that a low degree of
      fatty acid unsaturation is a general characteristic of longevous homeothermic
      vertebrate animals, both when they have low metabolic rates (mammals of large
      body size) or high metabolic rates (the studied birds); this constitutive trait
      protects their tissues and organelles against free radical mediated lipid
      peroxidation, and can contribute to their slow aging rate.

PMID- 10337443
TI  - A survey of hypnotic use in geriatric institutions in Sogn og Fjordane, Norway.
AB  - We investigated the use of hypnotics in nursing homes and old age homes in the
      county of Sogn og Fjordane, Norway. Data on administration of hypnotics on 3
      separate days within a week in August 1995 was obtained from the drug
      administration records in 31 institutions. Twenty-five percent of the 1062
      patients in the institutions used hypnotics, with no difference between patients
      from nursing homes and old age homes. The number of patients treated with
      hypnotics, the doses administered, and the time of administration were similar
      for weekends and workdays. About 100% of the hypnotics were used as scheduled,
      and 29% of the doses administered were higher than the recommended lowest dose
      for elderly patients. Furthermore, about 50% of the hypnotics administered were
      long-acting benzodiazepines. The results indicate a need for a review of the
      prescribing of hypnotics in geriatric institutions.

PMID- 10337444
TI  - Increased medical attention needed for frail elderly initially admitted to the
      emergency department for lack of community support.
AB  - The demographic changes in society with growing numbers of elderly subjects will
      inevitably increase admission rates to acute emergency departments (AMU). Early
      discharge might augment emergency readmissions due to a relapse in medical
      conditions. Our aim was to study precipitating factors in frail elderly patients
      who got the diagnosis "lack of community support" after initial medical
      examination at an AMU, as well as discharge rates and one-year mortality. The
      study population was 380 cases of 18,015 patients attending the AMU at a city
      hospital during one year. Inclusion criteria were age above 65 years, and given
      the diagnosis "lack of community support" by a physician, defined as no other
      etiological or symptom diagnosis after an initial medical examination, and in
      some cases 24 to 48-hours observation. All but three medical records were
      checked. Reduced ability to eat, drink and walk prior to admission were noted
      among 22 to 58% of cases. Two thirds of the patients needed further medical care
      as inpatients, and physical medical causes were identified in 85% of the cases
      (mean number 3 causes); infectious diseases, cardiovascular diseases, dementia
      and trauma were the most prevalent factors. The median hospital stay was 14 days,
      and 10% had been discharged from the hospital the week prior to admission. The
      one-year mortality was 34%. The deceased had more precipitating physical causes,
      and were more often admitted to medical wards, but fewer had been referred to a
      senior consultant at the time of admission than survivors, adjusted for age (14%
      vs 42%, p < 0.05). Multiple medical conditions were noted in the majority of
      patients admitted to an emergency department with reduced abilities to cope with
      basic activities of daily life, even though a preliminary examination stated lack
      of social support as the underlying cause. The need for better medical attention
      seems important, especially for patients discharged directly home from an
      emergency department.

PMID- 10337445
TI  - Bitter taste threshold and its relation to number of circumvallate papillae in
      the elderly.
AB  - The main purpose of this study was to determine the relationship between the
      number of circumvallate papillae and the bitter taste threshold with age. The
      study group consisted of 10 women (age range, 60-80) and 14 men (age range, 60
      85) and the control group of 15 young women (age range, 18-25) and 15 young men
      (age range, 17-20); the total number of subjects was 54. The number of
      circumvallate papillae was counted by direct observation with the naked eye;
      bitter taste thresholds were evaluated by the three drop forced-choice method
      with an ascending series, using quinine sulfate dehydrate as the bitter agent. We
      observed that while the number of circumvallate papillae did not increase with
      age, the bitter taste threshold changed significantly with age.

PMID- 10337446
TI  - Comparison of equivalence between the St. John's wort extract LoHyp-57 and
      fluoxetine.
AB  - In a randomised double-blind comparative trial, the antidepressant efficacy of a
      daily dose of 800 mg of the St. John's wort extract LoHyp-57 (dry extract of St.
      John's wort, drug extrakt ratio 5-7:1, solvent, ethanol 60% [w/w]) was shown to
      be equivalent to that of 20 mg fluoxetine (CAS 54910-89-3) in elderly patients
      with mild or moderate depressive episodes according to ICD 10 (International
      Statistical Classification of Diseases and Related Health Problems). Treatment
      was given for six weeks. 149 out-patients (129 females and 20 males) were
      included in the intention-to-treat analysis. 72 of these patients were assigned
      to the ICD 10 diagnostic criterion F32.0 (mild depressive episode), while 77
      patients were suffering from moderate depressive episodes, corresponding to
      F32.1. The principal target criterion was the patient's global score on the
      HAMILTON Depression Scale (items 1-17). During the six-week course of treatment
      with LoHyp-57, the HAMILTON global score fell from 16.60 points at entry to 7.91
      points, and in the fluoxetine sample it fell from 17.18 to 8.11 points. In the
      group of patients with mild depressive episodes, the score showed a mean fall
      from 14.21 to 6.21 points on LoHyp-57, and from 15.21 to 7.46 points on
      fluoxetine. In patients with moderate depressive episodes, the score showed a
      mean fall from 18.73 to 9.43 points on LoHyp-57 and from 19.10 to 8.75 points on
      fluoxetine. The efficacy of both medications was found to be equivalent both in
      mild and moderate depressive episodes. Both treatment groups showed adverse drug
      reactions (ADRs). Twelve ADRs with a possible relationship to the study
      medication were reported during treatment with LoHyp-57. Six patients were
      prematurely withdrawn from treatment with the study medication for this reason.
      On fluoxetine 17 ADRs occurred with a possible relationship to the study
      medication. These led to abandonment of treatment and therefore premature
      withdrawal from the study in 8 cases.

PMID- 10337447
TI  - Ca2+ sensitization of myocardial force and actomyosin ATPase by (D-Ala2, Met5)
      enkephalinamide.
AB  - The presence of proenkephalin mRNA and proenkephalin peptides in cardiac muscle
      cells suggests the local production of enkephalins in the myocardium. Yet, the
      effects of these peptides on the function of the contractile proteins are
      unknown. The effects of (D-Ala2, Met5) enkephalinamide (DALA) on the activity of
      the actin stimulated Ca, Mg-myosin ATPase in myofibrils and on the contractility
      and the activity of the related actomyosin ATPase of chemically skinned muscle
      fibres from pig myocardium were studied. In this article, it is shown that the
      myofibrillar actomyosin ATPase as well as the contractility and the actomyosin
      ATPase in skinned fibres are sensitized to Ca2+ ions by DALA. 10(-11) -10(-6)
      mol/l DALA decrease the effective concentration of Ca2+ stimulating the
      myofibrillar ATPase activity by 50% (EC50) from 4.0.10(-5) to 1.5.10(-5) mol/l (p
      < 0.05). The magnesium dependent myosin ATPase activity at low Ca2+ concentration
      (10(-9) mol/l) is increased. The EC50 values of Ca2+ for both force development
      and the related actomyosin ATPase activity of skinned fibres are decreased by
      DALA (10(-11) -10(-5) mol/l) from 2.5.10(-6) to 2.0.10(-6) mol/l (contractions; p
      < 0.01) and from 2.0.10(-6) to 1.3.10(-6) mol/l (ATPase activity; p < 0.01). The
      tension cost (ATPase/tension) of the fibres is unchanged by DALA. In conclusion,
      the results demonstrate a Ca2+ sensitization of the contractile proteins by low
      concentrations of DALA, indicating a direct regulatory involvement of enkephalins
      in the regulation of myocardial contractility. These results correspond with the
      positive inotropic effects of enkephalins in isolated heart muscle cells.

PMID- 10337448
TI  - Effects of MS-31-038, a novel Na(+)-H+ exchange inhibitor, on the myocardial
      infarct size in rats after postischemic administration.
AB  - The abilities of 2-(2-methylphenyl)-5,7-dimethoxy-4-quinolyl carbonylguanidine
      dihydrochloride (CAS 181048-29-3, MS-31-050) and 2-phenyl-8-(2-methoxyethoxy)-4
      quinolyl carbonylguanidine bismethanesulfonate (CAS 181048-36-2, MS-31-038) in
      inhibiting Na(+)-H+ exchange, ischemia- and reperfusion-induced injury were
      determined and compared with those of 4-isopropyl-3-methylsulfonylbenzoyl
      guanidine methanesulfonate (CAS 159138-81-5, IMGM), a selective inhibitor of
      Na(+)-H+ exchange. MS-31-050 and IMGM exhibited comparable inhibitory effects on
      Na(+)-dependent pH recovery and antiarrhythmic effects during ischemia in
      anesthetized rats. In rats subjected to ischemia and reperfusion, MS-31-050 (10
      mg/kg i.v.) significantly reduced the infarct size when given prior to the onset
      of ischemia. However, postischemic treatment with either MS-31-050 or IMGM failed
      to protect reperfused hearts. In contrast, MS-31-038 reduced the infarct size
      dramatically from 65.4 +/- 7.4% in control to 29.9 +/- 11.6% at 3 mg/kg and 9.8
      +/- 3.4% at 10 mg/kg even when administered before the onset of reperfusion.
      These results suggest the beneficial effects of Na(+)-H+ exchange inhibitors on
      myocardial ischemia/reperfusion injury.

PMID- 10337449
TI  - Betaxolol versus carvedilol in chronic heart failure (BETACAR study). Rationale
      and design.
AB  - The use of beta-blockers in heart failure for a long time was regarded as contra
      indicated because of their negative inotropic effects. Nevertheless, there is
      growing evidence that beta-blockers slow down the progression of left ventricular
      dilatation that characterizes heart failure. In addition changes in left
      ventricular ejection fraction after several months of beta-blocker treatment
      appears to have predictive value for survival. This beneficial effect of beta
      blockade in chronic heart failure needs to be assessed further. The presumed
      benefit of beta-blockade with betaxolol (CAS 63659-18-7), a highly selective beta
      blocker with long duration of action in chronic heart failure (CHF) will be
      assessed in BETACAR, a comparative study versus carvedilol (CAS 72956-09-3). The
      design of this study is provided in this article.

PMID- 10337450
TI  - Persistent antihypertensive effect of oral nitrite supplied up to one year via
      the drinking water in spontaneously hypertensive rats.
AB  - The hypothesis was studied whether the chronic administration of nitrite lowers
      the blood pressure of spontaneously hypertensive rats (SHR) and prevents
      secondary hypertension-induced organ lesions. For this purpose totally 96 SHR
      received 50 to 75 mmol/l NaNO2 or equimolar amounts of NaHCO3 in their drinking
      water during 4, 8 or 12 months. At each point of time arterial blood pressure,
      determined with the tail cuff method, was significantly lower in the NaNO2-group
      in comparison to the controls indicating that no significant tolerance towards
      nitrite had developed. There was also a tendency towards reduced cardiac
      hypertrophy and renal atrophy in the NaNO2-group, however without reaching the
      level of significance. Drinking water containing 75 mmol NaNO2/l was not well
      tolerated by young rats in contrast to 50 mmol/l. Possible beneficial effects of
      high dietary nitrate/nitrite levels are discussed with respect to the low
      frequency of hypertension observed in vegetarians.

PMID- 10337451
TI  - Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase
      inhibitors on serum coenzyme Q10 in diabetic patients.
AB  - Serum coenzyme Q10 (CoQ10: 2-(3,7,11,15,19,23,27,31,35,39-decamethyl
      2,6,10,14,18,22,26,30,34 ,38 -tetracontadecaenyl)-5,6-dimethoxy-3-methyl-1,4
      benzoquinone, CAS 303-98-0) and cholesterol levels were measured to assess the
      effect of cholesterol-lowering therapy in patients with non-insulin-dependent
      diabetes mellitus (NIDDM). Twenty healthy volunteers, 97 NIDDM patients and 2
      patients with familial hypercholesterolemia were studied. None had overt heart
      failure or any other heart disease. Mean serum CoQ10 concentrations were
      significantly (p < 0.01) lower in diabetic patients with normal serum cholesterol
      concentrations, either with or without administration of 3-hydroxy-3
      methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) including
      simvastatin (normal: 0.91 +/- 0.26 (mean +/- SD) mumol 1(-1); diabetic with HMG
      CoA RI: 0.63 +/- 0.19; diabetic without HMG-CoA RI: 0.66 +/- 0.21). CoQ10
      concentrations were higher (1.37 +/- 0.48, p < 0.001) in diabetic patients with
      hypercholesterolemia. Simvastatin or low density lipoprotein apheresis decreased
      serum CoQ10 concentrations along with decreasing serum cholesterol. Oral CoQ10
      supplementation in diabetic patients receiving HMG-CoA RI significantly (p <
      0.001) increased serum CoQ10 from 0.81 +/- 0.24 to 1.47 +/- 0.44 mumol 1(-1),
      without affecting cholesterol levels. It significantly (p < 0.03) decreased
      cardiothoracic ratios from 51.4 +/- 5.1 to 49.2 +/- 4.7%. In conclusion, serum
      CoQ10 levels in NIDDM patients are decreased and may be associated with
      subclinical diabetic cardiomyopathy reversible by CoQ10 supplementation.

PMID- 10337452
TI  - Effect of oral antidiabetic agents on plasma amylin level in patients with non
      insulin-dependent diabetes mellitus (type 2).
AB  - The purpose of the study was the comparison of the effect of the oral therapy of
      non-insulin-dependent diabetes mellitus (NIDDM) with either a sulphonylurea or
      biguanide derivative on plasma amylin level. In 10 healthy individuals the
      fasting plasma amylin level was 1.56 +/- 0.27 pmol/l (mean +/- SEM) and 6 min
      after i.v. injection of 1 mg glucagon a fourfold increase was observed. In 10
      patients with NIDDM receiving glibenclamide (CAS 10238-21-8) the fasting plasma
      amylin level was twofold higher than in healthy control (2.72 +/- 0.38 pmol/l; p
      < 0.025) but following glucagon administration it increased only twofold. In 15
      patients treated with metformin (CAS 657-24-9) the fasting plasma amylin level
      was similar to that in healthy individuals (1.64 +/- 0.25 pmol/l), but after
      glucagon stimulation the increment of plasma amylin was minimal and the relevant
      mean value was significantly lower when compared with those in healthy
      individuals and with NIDDM patients treated with glibenclamide. In 10 untreated
      obese patients with newly diagnosed NIDDM the administration of glibenclamide (14
      days) resulted in the increase of basal (2.47 +/- 0.23 and 3.16 +/- 0.29 pmol/l;
      p < 0.1), and glucagon stimulated (3.34 +/- 0.39 and 4.56 +/- 0.38; p < 0.05)
      plasma amylin concentrations, whereas other 10 patients receiving metformin
      showed a decrease in fasting plasma level of this peptide before (2.64 +/- 0.59
      and 1.28 +/- 0.38 pmol/l; p < 0.1), and after glucagon injection (5.02 +/- 0.55
      and 2.83 +/- 0.65 pmol/l; p < 0.02). With the respect to the trophic effect of
      amyloid deposits in the pancreatic islets and to a hypothetic effect of amylin
      increasing insulin resistance, the present results emphasize the particular
      usefulness of metformin in the pharmacological treatment of NIDDM. All
      contraindications and side effects of metformin should be taken into account
      before drug administration.

PMID- 10337453
TI  - Studies on the chemical identity and biological functions of pangamic acid.
AB  - Pangamic acid (6-O-(dimethylaminoacetyl)-D-gluconic acid) has been detected 1938
      and described as a natural, universally occurring substance with multiple
      biological and medical functions. In this respect pangamic acid has been
      worldwide on the market since decades as a drug stimulating cellular respiration.
      In addition to the natural pangamic acid, diisopropylammonium dichloroacetate
      (DIPA), a synthetic product not found in biological material, is on the market
      requesting similar biological functions. In commercially available drugs on the
      German market declared as pangamic acid three separate substances can be found by
      chemical identification of pangamic acid, namely: gluconic acid, glycine and
      diisopropylamonium dichloroacetate. As biological functions have been found in
      vitro inhibition of Cu-dependent LDL oxidation by glycine due to chelation of
      Cu2+ ions and deterioration of mitochondrial respiratory control due to an
      increased state IV oxygen consumption rate at high concentrations of DIPA.

PMID- 10337454
TI  - Effects of erdosteine and its metabolites on bacterial adhesiveness.
AB  - Erdosteine (CAS 84611-23-4) is administered as a mucolytic drug in patients with
      pulmonary disorders who suffer from a thickening of bronchial mucus with altered
      physico-chemical characteristics. Erdosteine itself does not have a free thiol
      group but its metabolization produces active metabolites with a -SH group that is
      capable of breaking disulfide bonds of mucins and improving the mucociliary
      clearance of the airways, and thus reproducing the effects of the class of muco
      active drugs having a thiol group. It has also been reported that muco-active
      drugs with this group reduce bacterial adhesiveness to human mucosal cells. The
      aim of this study was to investigate whether erdosteine and its SH-metabolites
      are capable of interfering with bacterial adhesiveness. Metabolite I
      significantly reduces both S. aureus and E. coli adhesiveness to human mucosal
      epithelial cells at concentrations of 2.5, 5 and 10 micrograms/ml. The same
      concentrations of erdosteine, metabolite II, metabolite III and N-acetylcysteine
      (as a control drug) were devoid of such activity, whereas the results of
      hemagglutination and hydrophobicity assays showed that the behaviour of
      metabolite I overlapped that of bacterial adhesiveness, thus indicating that
      interference takes place at a fimbrial level. This is confirmed by the fact that
      the incubation of human buccal cells with drugs does not reduce the adhesiveness
      of untreated bacteria. The presence of this additional activity in a muco-active
      drug is useful because bacteria not only adhere to epithelial cells but also to
      tracheobronchial secretions.

PMID- 10337455
TI  - Efficacy and tolerability of myrtol standardized in long-term treatment of
      chronic bronchitis. A double-blind, placebo-controlled study. Study Group
      Investigators.
AB  - This multicenter, placebo-controlled, double-blind, randomized parallel-group
      trial was conducted to investigate the efficacy and tolerability of myrtol
      standardized (MYS, Gelomyrtol forte, 3 x 300 mg) in the long-term treatment of
      patients with chronic bronchitis during the winter. 246 patients received the
      investigational treatments (MYS: 122, placebo: 124) for at least 1 month; 215
      subjects (110 under MYS and 105 under placebo) were evaluable in terms of
      efficacy (exacerbation rate, the need for antibiotics, symptom scores and general
      well-being) for the protocol-defined 6 months of treatment. Statistically
      significantly (p < 0.01) more patients remained without acute exacerbation in the
      myrtol standardized group (72%) compared to the placebo group (53%). In the
      placebo group, there was an evident peak in the incidence of exacerbations during
      the third month of treatment, which was not observed in the active treatment
      group. In the MYS group, 51.6% of the patients with an acute exacerbation
      required antibiotics vs. 61.2% under placebo. 62.5% of the patients treated with
      antibiotics in the MYS group required them for < or = 7 days, whereas 76.7% of
      the patients in the placebo group treated with antibiotics for exacerbation
      needed antibiotics for > 7 days. Well-being (assessed in terms of general health
      and health impairment by cough and expectoration) was significantly better under
      treatment with MYS. The overall therapeutic efficacy evaluation scored higher for
      MYS. Therefore, it is concluded that long-term treatment with MYS is equally well
      tolerated as placebo but is clearly superior in efficacy in terms of protecting
      against acute exacerbations in patients with chronic bronchitis: it reduces the
      frequency and intensity of acute exacerbations, the need of antibiotics for them
      and the health impairment by cough and expectoration.

PMID- 10337456
TI  - Influence of rebamipide on indometacin-induced gastric hemorrhage in rats under
      restraint stress.
AB  - The effect of rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]
      propionic acid, CAS 11911-87-6) in preventing acute gastritis was examined in
      rats by stomach perfusion. Teprenone (CAS 6809-52-5), cimetidine (CAS 51481-61-9)
      and omeprazole (CAS 73590-58-6) were used as control drugs. Severe gastric
      hemorrhage was observed in conscious restrained rats, 1 h after treatment with
      indometacin (20 mg/kg i.p.). Pretreatment with rebamipide (3, 10 or 30 mg/kg
      s.c.) suppressed the hemorrhage induced by indometacin plus restraint stress,
      being more effective than teprenone or cimetidine. Pretreatment with omeprazole
      (30 mg/kg s.c.) did not suppress the gastric hemorrhage. Superoxide dismutase
      (30,000 U/kg s.c.) significantly decreased the hemorrhage. Anti-rat PMN
      (polymorphonuclear leukocytes), 1 ml/kg i.v., which caused depletion of
      circulating neutrophils, also suppressed the hemorrhage induced by indometacin
      plus restraint stress. Thus reactive oxygen species derived from neutrophils may
      play a role in the occurrence of the hemorrhage during acute gastritis induced by
      indometacin with restraint stress.

PMID- 10337458
TI  - Dimethindene maleate in the treatment of sunburn. A double-blind, placebo
      controlled pilot study.
AB  - The efficacy of topical dimethindene maleate (DMM, CAS 31614-69-5, Fenistil Gel)
      in the treatment of sunburn was evaluated in a placebo-controlled, 1-period
      crossover trial in 24 healthy volunteers. An UV-erythema (sunburn) of a well
      defined intensity and extent was experimentally induced on three different skin
      test-areas by means of UV-A/B irradiation with three times the minimal erythema
      dose (MED). About 24 h after irradiation, one skin test-area was subjected to a 1
      h occlusive treatment with DMM gel, the second test area was subjected to
      treatment with a placebo gel and the third one remained untreated. As objective
      quantitative indicators of tenderness, a key symptom of sunburn, sensory and pain
      thresholds to CO2-Laser stimulation and laser somatosensory evoked potentials
      (SEPs) in Vertex-EEG were assessed about 1.5 h postdose. The reaction times (RTs)
      to painless and painful CO2-laser stimulation (sensory and pain threshold level,
      respectively) on the DMM-treated area were significantly longer than RTs to
      stimulation on the placebo-treated area. Thresholds in terms of laser energy
      showed no differences between the treatments. The SEP N1-amplitude on the DMM
      area was markedly decreased in comparison to placebo. With regard to subjective
      sensations of pain, itching and tenderness assessed by means of visual analogue
      scales (VAS), no clinically relevant differences between treatments were observed
      after sole UV-irradiation. After additional laser stimulation tenderness was-
      objectively but not subjectively--decreased on the DMM-area versus placebo. Both
      gel preparations were well tolerated.

PMID- 10337457
TI  - Study on local inflammatory reactions and other parameters during subcutaneous
      mistletoe application in HIV-positive patients and HIV-negative subjects over a
      period of 18 weeks.
AB  - Subcutaneous injections of fermented and unfermented aqueous extracts of Viscum
      album L. result in a local inflammatory reaction at the injection site. In this
      trial, the symptoms associated with this local reaction were investigated.
      Furthermore the occurrence of local reactions was tried to correlate with an
      increase in CD3/25- and CD8/38-positive lymphocyte counts, with eosinophilic
      granulocyte numbers, and with the formation of mistletoe lectin antibodies.
      Included in the trial were 30 HIV-antibody-positive patients and 17 healthy non
      smokers, aged 24-51 years. The CD4 cell count in the HIV-negative subjects was >
      800/microliter, compared with 200-600/microliter in the HIV-positive patients.
      All study participants had a Karnofsky score > or = 70. The trial subjects were
      observed over a period of 18 weeks. With escalation of the dose of a fermented
      and unfermented extract of Viscum album L. (Iscador Qu Spezial and Viscum album
      QuFrF), there was an increase in local reactions. Erythema at the injection site
      was the most frequently reported symptom. Between the doses and the symptoms
      induration, swelling and pruritus were marked correlations. Effects of the
      application of mistletoe extracts on the immune system were demonstrated by an
      increase in CD3/25-positive lymphocyte counts and antibodies against mistletoe
      lectins. There were no changes in eosinophilic granulocytes or CD8/38-positive
      lymphocyte populations. For evaluation of the therapeutic applications of
      mistletoe extracts in HIV-positive patients it is advisable to assess primarily
      activation of CD3-positive lymphocytes and the patient response on the basis of
      the local reaction. The local inflammatory reaction at the injection site is
      desirable and well tolerated if the reaction is smaller than 5 cm in diameter.

PMID- 10337459
TI  - Combinations of four virostatics applied in rotational sequences induce an
      exponential VL regression curve, the first part of which is rapidly decreasing to
      a PCR-undetectable level, while the last part is insensitive to the model.
      Indications for virostatic and immunotherapeutic reinforcements?
AB  - Between 1992 and 1995, we have had five virostatics available: zidovudine (AZT),
      didanosine (ddI), zalcitabine (ddC) (as retrotranscriptase nucleosidic
      antagonists, RTNA), acriflavine (ACF), and hydroxy-methyl-ellipticine (HEL), as
      respectively a DNA synthesis and structure antagonist, and a topoisomerase II
      inhibitor. Between 1995 and now, we have had ten virostatics the same, plus
      lamivudine (3TC), stavudine (d4T) as RTNA, and indinavir (IDV), ritonavir (RTV)
      and saquinavir (SQV) as protease inhibitors. We first conducted a phase I-like
      study concerning the ratios of the drug numbers in combinations over the numbers
      available. The optimal model for the study was that of four virostatics selected
      out of the ten. The four virostatic combinations were applied in short (3 week)
      sequences, differing each others by drug rotation. The patients were, before
      treatment, nine at the phase of AIDS, one at the A3 stage. They presented a very
      rapid decrease of viral load (VL) which became undetectable at PCR, being first
      below 200 RNA copies/mL, then below 20. We call this condition 'minimum residual
      disease' as HIV1 persistence is revealed by virus rebounds, reversible, and
      probably induced by cofactors. The frequency of the latter selection is due to
      the very frequent (each 3 weeks) VL evaluations. The last part of the VL
      exponential curve which the minimum residual disease represents, is almost
      horizontal and quasi insensitive to the powerful virostatic model described
      above, though no resistance has appeared at the combination or sequence levels.
      Thus we propose to add phases of: a) reinforcements by virostatics, adding two
      more ones to the four of the model; and b) treatment complement by active
      immunotherapy phases: the most adapted immunomodulator is the combination of the
      peptidic cytokine, tuftsine, and of its antipeptidase, bestatine If they are not
      available, another interleukine, able to help restoring the AIDS disturbed
      immunologic system, interleukin 2, could be tried, as it has induced beneficial
      effects at very small doses by subcutaneous injections.

PMID- 10337460
TI  - Antiretroviral therapy: 'the state of the art'.
AB  - The field of antiretroviral therapy is evolving at a very rapid pace. At this
      time, the initiation and optimization of antiretroviral therapy is based on
      serial plasma viral load determinations which aim to suppress viral replication
      to as low as possible for as long as possible, thus preventing disease
      progression. Currently available antiretrovirals require combination therapy with
      at least three agents to achieve this goal. Increasing availability of newer and
      more potent antiretroviral regimens will continue to enhance and simplify the
      number of therapeutic options available in the not too distant future.

PMID- 10337461
TI  - Highly active antiretroviral therapy (HAART) for the treatment of infection with
      human immunodeficiency virus type 1.
AB  - Highly active antiretroviral therapy (HAART) refers to a broad category of
      treatment regimens usually comprised of three or more antiretroviral drugs that,
      in previously untreated HIV-1-infected patients, are expected to reduce plasma
      virus levels below the limits of detection. Most HAART regimens include drugs
      from at least two of the three classes of antiretroviral therapy (nucleoside
      analog reverse transcriptase (RT) inhibitors, non-nucleoside analog RT
      inhibitors, and protease inhibitors). In deciding when to initiate antiretroviral
      therapy, physicians and their patients must balance the virological and
      immunological benefits of early treatment with the costs of drug therapy, the
      risk of drug side effects, and the risk of drug resistance if adherence is
      suboptimal. In previously untreated patients, HIV-1 replication can be suppressed
      indefinitely with certain HAART regimens. In previously treated patients, the
      benefits of HAART are often significantly diminished.

PMID- 10337462
TI  - IFN alpha kinoid vaccine in conjunction with tritherapy, a weapon to combat
      immunopathogenesis in AIDS.
AB  - Antiviral therapy, including antiprotease treatment, suppresses viral
      replication, but it does not restore the HIV-1 induced immunopathogenesis which
      includes IFN alpha overproduction and cellular immunosuppression. To combat HIV-1
      induced immunopathogenesis, anti-IFN alpha kinoid immunization in combination
      with tritherapy may be beneficial to HIV-1 infected immunodeficient patients.

PMID- 10337463
TI  - Anti-IFN alpha immunization raises the IFN alpha-neutralizing capacity of serum-
      an adjuvant to antiretroviral tritherapy.
AB  - HAART (highly active antiretroviral therapy) suppresses but does not eradicate
      HIV-1 infection. However, since the antiretroviral agents used in HAART may also
      be toxic in the long-term, immunotherapies which correct HIV-1 immunosuppression
      or the cytokine dysregulation associated with it may be beneficial. In this
      respect, a double blind multicentric placebo-controlled phase II/III anti-IFN
      alpha vaccine trial has been carried out on 242 HIV-1 patients, the majority of
      whom were undergoing HAART treatment. In vaccinated patients (vaccinees) who
      responded to immunization by increased levels of IFN alpha Abs (whether under
      HAART or not) when compared to placebo or non-responder vaccinees, a strong
      correlation was found between an increased IFN alpha neutralizing capacity and
      the reduction of clinical manifestations.

PMID- 10337464
TI  - HIV disease treatment in the era of HAART.
AB  - In the last three years basic science and clinical research have radically
      changed the therapeutical approach to HIV disease. Recent guidelines suggest that
      treatments to HIV disease should be early and aggressive, with the use of new
      potent antiretroviral drugs. This approach has been defined as HAART (highly
      active antiretroviral therapy). In this review we will discuss the main stages of
      antiretroviral therapy focusing on the acquisitions about results as well as
      problems of triple therapy.

PMID- 10337465
TI  - Extender PCR: a method for the isolation of sequences regulating gene expression
      from genomic DNA.

PMID- 10337466
TI  - Baculovirus-transfer vector for eukaryotic expression and immunoaffinity
      purification of Gal4-fusion proteins.

PMID- 10337467
TI  - Generation of epitope-tagged proteins by inverse PCR mutagenesis.

PMID- 10337468
TI  - Selective PCR amplification of functional immunoglobulin light chain from
      hybridoma containing the aberrant MOPC 21-derived V kappa by PNA-mediated PCR
      clamping.

PMID- 10337469
TI  - The pKNOCK series of broad-host-range mobilizable suicide vectors for gene
      knockout and targeted DNA insertion into the chromosome of gram-negative
      bacteria.

PMID- 10337470
TI  - Amplification of FADD mRNA using RT-PCR results in an artifact.

PMID- 10337471
TI  - Concentration of recombinant baculovirus by cation-exchange chromatography.

PMID- 10337473
TI  - Reverse strand priming: a versatile cDNA radiolabeling method for differential
      hybridization on nucleic acid arrays.

PMID- 10337472
TI  - Improved LM-PCR procedure for in vivo footprinting analysis of GC-rich promoters.

PMID- 10337474
TI  - Nonselective colony-color assays for HIS3, LEU2, LYS2, TRP1 and URA3 in ade2
      yeast strains using media with limiting nutrients.

PMID- 10337475
TI  - Modification of enzyme-conjugated streptavidin-biotin western blot technique to
      avoid detection of endogenous biotin-containing proteins.

PMID- 10337476
TI  - Mapping of nuclear localization signals by simultaneous fusion to green
      fluorescent protein and to beta-galactosidase.

PMID- 10337477
TI  - Induction of cell death by hydrophobic hydrocarbons.

PMID- 10337478
TI  - "Microprep" method for rapidly isolating plasmid DNAs for restriction enzyme
      analysis.

PMID- 10337479
TI  - Simple version of "megaprimer" PCR for site-directed mutagenesis.

PMID- 10337480
TI  - Scripting Wizards for Chime and RasMol.

PMID- 10337481
TI  - Identification and isolation of differentially expressed genes from very small
      tissue samples.
AB  - Identification of differentially expressed genes from tissue samples weighing
      only a few milligrams has remained a major challenge. Here, we describe a novel
      and simple strategy that uses standard molecular biology equipment and
      commercially available kits. The approach combines isolation of total RNA by
      silica-gel binding, reverse transcription using anchored modified, 5' end
      enhancers oligonucleotides, exponential amplification of the single-stranded cDNA
      and hybridization to high-density cDNA filter arrays. The method was tested by
      comparing genes expressed on freshly isolated human trabecular meshwork tissue
      with those expressed in corresponding primary cells at third passage. Validation
      was achieved by using two biological properties: (i) hybridization, to identify
      the differentially expressed genes, and (ii) PCR amplification, to confirm their
      distinct expression. The strategy presented allows the identification of
      differentially expressed genes and/or uncharacterized expressed sequence tags
      (ESTs) in very small tissue samples, including those from clinical specimens.

PMID- 10337482
TI  - Increasing DNA transfer efficiency by temporary inactivation of host restriction.
AB  - E. coli and Salmonella typhimurium are widely used bacterial hosts for genetic
      manipulation of DNA from prokaryotes and eukaryotes. Introduction of foreign DNA
      by electroporation or transduction into E. coli and Salmonella is limited by host
      restriction of incoming DNA by the recipient cells. Here, we describe a simple
      method that temporarily inactivates host restriction, allowing high-frequency DNA
      transfer. This technique might be readily applied to a wide range of bacteria to
      increase DNA transfer between strains and species.

PMID- 10337483
TI  - Microsatellite analysis using a two-step procedure for fluorescence labeling of
      PCR products.
AB  - A method for fluorescent labeling of PCR products has been developed. This method
      consists in a two-step procedure in which a first exponential classical PCR is
      followed by a "linear amplification". This second step relies on incorporation of
      fluorescent dNTP (dUTP or dCTP) in order to label the product on only one strand.
      The products can be applied without prior purification directly to a gel on a
      fluorescence-based automated DNA sequencer, for length and allele determination.
      The reliability of the results equals those of the classical 32P or fluorescent
      primer labeling methods, and the method is definitely less costly. Since the
      interpretation of the results is easier than with the method consisting in a
      fluorescent dNTP uptake in both strands in a single PCR, the present strategy
      should prove useful in mapping projects requiring analysis of a large number of
      microsatellites.

PMID- 10337484
TI  - Internal and flanking sequence from AFLP fragments using ligation-mediated
      suppression PCR.
AB  - Amplification fragment-length polymorphism (AFLP) analysis has proven to be a
      powerful tool for developing a large number of reliable genetic markers across a
      wide variety of organisms. Often it is desirable to further characterize these
      markers by obtaining internal and flanking sequence information. Here, we present
      a systematic approach for obtaining such information from AFLP markers. AFLP
      fragments can be isolated from dried polyacryamide sequencing gels (that have
      been stored for extended periods of time), amplified using PCR and subjected to
      sequence analysis. Outwardly oriented locus-specific primers are designed from
      the internal sequence and used in conjunction with adapter primers to amplify
      unknown regions that flank the internal sequence from up to 22 different
      restriction-ligation (R-L) reactions. This often results in multiple reactions
      yielding products of appropriate size and specificity for direct sequencing
      without the need for a nested PCR, extensive gel purification or subcloning. The
      detailed protocol is presented with PCR results from a variable AFLP fragment
      from Bacillus anthracis.

PMID- 10337485
TI  - Two-color GFP expression system for C. elegans.
AB  - We describe the use of modified versions of the Aequora victoria green
      fluorescent protein (GFP) to simultaneously follow the expression and
      distribution of two different proteins in the nematode, Caenorhabditis elegans. A
      cyan-colored GFP derivative, designated CFP, contains amino acid (aa)
      substitutions Y66W, N146I, M153T and V163A relative to the original GFP sequence
      and is similar to the previously reported "W7" form. A yellow-shifted GFP
      derivative, designated YFP, contains aa substitutions S65G, V68A, S72A and T203Y
      and is similar to the previously described "I0C" variant. Coding regions for CFP
      and YFP were constructed in the context of a high-activity C. elegans expression
      system. Previously characterized promoters and localization signals have been
      used to express CFP and YFP in C. elegans. Filter sets designed to distinguish
      YFP and CFP fluorescence spectra allowed visualization of the two distinct forms
      of GFP in neurons and in muscle cells. A series of expression vectors carrying
      CFP and YFP have been constructed and are being made available to the scientific
      community.

PMID- 10337486
TI  - Use of enhanced green fluorescent protein to optimize and quantitate infection of
      target cells with recombinant retroviruses.
AB  - Recombinant retroviral vectors are useful tools for gene transfer in both gene
      therapy and research applications. An enhanced form of green fluorescent protein
      has been incorporated into recombinant retroviruses as a marker to follow
      infected cells. In this paper, we extended the use of the fluorescent reporter to
      quantify protein expression using such analytical tools as fluorescent
      microscopy, flow cytometry and fluorescent plate reader analysis. These tools
      enabled us to rapidly assess the titer of recombinant retrovirus harvested from
      packaging cells and to optimize parameters for infection of different cell lines.

PMID- 10337487
TI  - Detection of virtually all mutations-SSCP (DOVAM-S): a rapid method for mutation
      scanning with virtually 100% sensitivity.
AB  - Dideoxy fingerprinting (ddF) was used as a tool to search for a generic set of
      conditions with sufficient power to detect virtually all mutations. For each
      condition tested, a very large sample of mutation-containing, single-stranded
      segments (about 1500) were analyzed with ddF. Correlation coefficients identified
      pairs of conditions in which single-strand conformation polymorphism (SSCP)
      mobilities were poorly correlated. The data strongly suggest that tertiary
      structure (e.g., base-sugar and sugar-sugar interactions) rather than secondary
      structure is the predominant determinant of mobility shifts by SSCP. Five
      conditions were selected with sufficient redundancy to detect all the mutations.
      The sensitivity of detection of virtually all mutations-SSCP (DOVAM-S) was
      determined by blinded analyses on samples containing additional mutations
      scattered throughout the eight exons and splice junctions in the factor IX gene.
      The factor IX gene sequence (2.5 kb) was scanned in one lane by 15 PCR-amplified
      segments (125 kb of sequence scanned per gel). All of the 84 single-base
      substitutions were detected in the blinded analyses, the first consisting of 50
      hemizygous mutant and wild-type (WT) samples and the second consisting of 50
      heterozygous mutant and WT samples. DOVAM-S is estimated to be five times faster
      than fluorescent DNA sequencing for the detection of virtually all mutations when
      the five conditions are applied.

PMID- 10337488
TI  - Production of human CNS neurons from embryonal carcinoma cells using a cell
      aggregation method.
AB  - When treated with retinoic acid (RA), a human embryonal carcinoma (EC) cell line,
      NTera2 cl.D/1 (NT2), differentiates into several morphologically distinct cell
      types, which include terminally differentiated postmitotic central nervous system
      (CNS) neurons. Accumulating evidence has demonstrated the significant potential
      of NT2 cells in studies related to cancer therapy and neurodegenerative diseases.
      However, preparation of enriched NT2 neurons often requires a lengthy period (ca.
      five weeks) and depends largely on tedious techniques similar to those used for
      primary neuronal cultures. Here, we report a rapid protocol for the preparation
      of these human CNS neurons. Using the method of cell aggregation, enriched NT2
      neurons can be obtained in approximately two weeks. We also demonstrated that
      cell aggregation reduced the time normally required for the induction of neuronal
      differentiation, as revealed by the early expression of neuronal markers. The
      period of RA treatment could also be reduced if NT2 cells were maintained as
      aggregates for a sufficient period of time. Taken together, our findings
      demonstrated that cell aggregation promoted RA-induced neuronal differentiation
      of NT2 cells and provided a rapid protocol for the efficient production of NT2
      neurons. The ability to produce large quantities of human CNS neurons should
      facilitate future use of these neurons for basic research and applications in
      cell therapy.

PMID- 10337489
TI  - Determination of phage antibody affinities to antigen by a microbalance sensor
      system.
AB  - Over the past decade, phage display has maturated to be a frequently used method
      for the generation of monoclonal antibodies of human origin. The essential step
      of this method is the "biopanning" of phage carrying functional antibody
      fragments on their surface on an immobilized antigen. The screening of large
      combinatorial gene libraries with this method usually leads to a set of diverse
      clones specifically binding to the antigen that need to be characterized further.
      Beside its specificity, the key parameter to be determined is the affinity of the
      recombinant antibody fragment to its antigen. Here, we present a mass sensitive
      microsensor method that allows the estimation of antibody affinity directly from
      the phage supernatant. Binding of phage antibodies to the antigen immobilized on
      a quartz crystal microbalance (QCM) induced a mass dependent decrease in
      frequency. This principle was used to determine the apparent affinity of a single
      chain (sc)Fv antibody against the RNA polymerase of Drosophila melanogaster
      presented on the surface of a filamentous phage (M13) from its association and
      dissociation rates. The apparent affinity obtained is in accordance with the
      affinity of the scFv fragment as determined by conventional equilibrium enzyme
      linked immunosorbent assay (ELISA) and plasmon resonance methods.

PMID- 10337490
TI  - High-performance subtractive hybridization of cDNAs by covalent bonding between
      specific complementary nucleotides.
AB  - We have developed an improved subtractive hybridization method that provides a
      fast, simple and reliable isolation of desired different sequences from two
      compared DNA libraries, one of which contains all unwanted homologues
      (subtracter) and another contains certain desired heterologues (tester). The DNA
      library can be made from either mRNA or genomic DNA. An excess amount of modified
      subtracter DNA from control cells was generated by chemical carboxylation of the
      pyrimidines to provide covalent affinity to the purines of a natural tester DNA.
      Hybridization of the control subtracter and the experimental tester DNA was
      performed with a heat-melting and then cool-reassociation technique. The desired
      different sequences remained in the form of hydrogen-bonded, homologous sequences
      of both libraries covalently bonded to each other, resulting in no separation
      during PCR and cloning. Consequently, the DNA sequences obtained from the
      covalent homology subtraction represent the nucleotide sequences abundant in the
      tester but rare in the subtracter library.

PMID- 10337491
TI  - Automated system for purification of dye-terminator sequencing products
      eliminates up-stream purification of templates.
AB  - The quality of sequencing results is to a large extent determined by the purity
      of the template and the purification of the sequencing products. Fragments that
      can act as unspecific primers and templates are removed before gel analysis, and
      the background of unspecific signals is highly reduced. Purification of the
      sequencing products is needed to remove salts, nucleotides, proteins and template
      DNA that can interfere with the gel separation. We have developed a product,
      DYNAPURE Dye Terminator Removal, that specifically isolates and purifies the
      sequencing products in 10 min. The method is based on biotinylated sequencing
      primers and super-paramagnetic streptavidin beads. A PCR product is sequenced
      using a biotinylated sequencing primer, and the sequencing products are then
      bound to streptavidin beads in a 5-min reaction. The bead-DNA complexes are
      magnetically separated from the rest of the solution, and the remaining buffer
      constituents are washed away with TE buffer or with 70% ethanol. The whole
      procedure can be automated on liquid-handling robots fitted with a magnet
      station. The method eliminates purification of templates before cycle sequencing.

PMID- 10337493
TI  - PALIREL, a computer program for analyzing particle-to-membrane relations, with
      emphasis on electron micrographs of immunocytochemical preparations and gold
      labeled molecules.
AB  - Many vital substances, such as receptors, transporters, and ion channels, in
      cells occur associated with membranes. To an increasing extent their precise
      localization is demonstrated by immunocytochemical methods including labeling
      with gold particles followed by electron microscopy. PALIREL has primarily been
      developed to facilitate such research, enabling rapid analysis of topographic
      relations of particles (gold or others) to neighboring linear interfaces
      (membranes). After digitization of membranes and particles, the program
      particularly allows computation of (1) the particle number and number per unit
      length of membrane, in individual bins (membrane lengths) interactively defined
      along the membrane; (2) the distance of each particle from the membrane; (3) the
      particle number, and the density (number per micron2), in zones defined along
      (over and under) the membrane; and (4) the particle number and density in
      "zonebins" resulting from zones and bins being defined simultaneously. If there
      occurs, somewhere in the membrane, a segment of different nature, such as a
      synapse, the quantitative data may be had separately for that and the adjoining
      parts of the membrane. PALIREL allows interactive redefinition of bins, zones, or
      objects (particle-line files) while other definitions are retained. The results
      can be presented on the screen as tables and histograms and be printed on
      request. A dedicated graphic routine permits inspection on screen of lines,
      particles, zones, and bins. PALIREL is equally applicable to biological
      investigations of other kinds, in which the topographic relations of points
      (structures represented as points) to lines (boundaries) are to be examined.
      PALIREL is available from the authors on a noncommercial basis.

PMID- 10337492
TI  - GelStar nucleic acid gel stain: high sensitivity detection in gels.
AB  - GelStar nucleic acid gel stain can be used for sensitive fluorescent detection of
      both double-stranded (ds) and single-stranded (ss) DNAs, oligonucleotides and RNA
      in gels. The stain can be added to agarose gels at casting for immediate imaging
      after electrophoresis or can be used after electrophoresis with both agarose and
      acrylamide gels. GelStar stain is highly fluorescent only when bound to nucleic
      acids thus giving superior signal-to-noise ratios and obviating the need to
      destain the gel. The detection limits of GelStar strain are 20 pg for dsDNA, 25
      pg for ssDNA and 10 ng for native or glyoxal-treated RNA.

PMID- 10337494
TI  - Implementation of three-dimensional EEG brain mapping.
AB  - The electroencephalogram (EEG) visualization software was developed containing
      two-dimensional (2D) and three-dimensional (3D) brain mapping modules. The input
      to the program is standard clinical individual patient data recorded using
      digital EEG and magnetic resonance imaging (MRI). The software utilizes several
      techniques, such as heuristic triangulation, ray casting, Gouraud shading, and
      image fusion to form multimodal 3D images. The program has been applied to the 3D
      visualization of various EEG signals, "cortical" EEG signals, and potential
      fields generated by a computer model. The developed program appears to operate
      efficiently and intuitively in PC/Windows environment.

PMID- 10337495
TI  - Prediction of blood glucose levels in diabetic patients using a hybrid AI
      technique.
AB  - One of the problems in the management of the diabetic patient is to balance the
      dose of insulin without exactly knowing how the patient's blood glucose
      concentration will respond. Being able to predict the blood glucose level would
      simplify the management. This paper describes an attempt to predict blood glucose
      levels using a hybrid AI technique combining the principal component method and
      neural networks. With this approach, no complicated models or algorithms need be
      considered. The results obtained from this fairly simple model show a correlation
      coefficient of 0.76 between the observed and the predicted values during the
      first 15 days of prediction. By using this technique, all the factors affecting
      this patient's blood glucose level are considered, since they are integrated in
      the data collected during this time period. It must be emphasized that the
      present method results in an individual model, valid for that particular patient
      under a limited period of time. However, the method itself has general validity,
      since the blood glucose variations over time have similar properties in any
      diabetic patient.

PMID- 10337496
TI  - CombiTool--a new computer program for analyzing combination experiments with
      biologically active agents.
AB  - CombiTool is a new computer program for the analysis of combination effects of
      biologically active agents. It performs model calculations and an analysis of
      experimental combination effects for two or three agents according to both the
      Bliss independence and the Loewe additivity criteria. Zero interaction response
      surfaces are calculated from single-agent dose-response relations and compared to
      experimental combination data. The calculation of response surfaces for Loewe
      additivity is based on a new approach which combines the implicit definition
      equation in terms of doses alone with single-agent dose-response relations. The
      simultaneous analysis of experimental data according to both Loewe additivity and
      Bliss independence within one program can hopefully contribute to a better
      understanding of the meaning and limits of the two criteria. CombiTool has a
      built-in graphics facility which allows the direct visualization of the response
      surfaces or the corresponding contour plots and the experimental data.

PMID- 10337497
TI  - An algebraic solution to dead space determination according to Fowler's graphical
      method.
AB  - According to Fowler's method, anatomical dead space (VD) can be determined
      graphically or computer-aided by iteration procedures by which phase III of a
      fraction-volume expirogram F(V) is back-extrapolated by a straight line R(V).
      Whereas Fowler visually partitioned phase II into two equal areas bordered by
      F(V), R(V), and VD, in the present paper the area between F(V) and R(V) is set
      equal to the area of a trapezoid, one side of which is the unknown VD to be
      determined. We obtained two algebraic equations for both possible conditions,
      nonsloping and sloping alveolar plateau, and, as the main result, an even more
      general third equation that includes both Bohr's and Fowler's solution. The
      formulas exactly represent Fowler's graphical method and can be applied to all
      gases which are applicable in dead space determination. The derived equations
      were tested in experimental situations, showing equality between values of dead
      space determined by using the algebraic solution and the graphical method. Their
      major advantage is facilitating and speeding up computer-aided on-line
      determinations of VD.

PMID- 10337498
TI  - Using the Internet to calculate clinical action thresholds.
AB  - Understanding the risks and benefits of available treatments represents an
      essential element of clinical practice. Previous work has demonstrated that
      knowledge of net benefits and net risks can relate to our decisions on whether or
      not to administer a particular treatment or order a diagnostic test. A wider
      application of this model has been difficult because data on net benefits and net
      risks are not directly reported. We used more frequently reported data on
      treatment efficacy (E) and risks (Rrx) to obtain an equation for the treatment
      threshold probability above which treatment should be given and below which it
      should be withheld. The diagnostic test should only be performed if the
      probability of a disease is between the testing threshold and the treatment
      threshold. We first described a theoretical background for these calculations. We
      then used a JavaScript programming language to write a computer program which
      physicians can use to calculate these threshold probabilities effortlessly
      through the Internet. In most clinical situations we do not have to achieve
      maximum diagnostic certainty in order to act. However, we should never treat or
      order a diagnostic test if the risk of the treatment is greater than its
      efficacy. The minimally required E/R ratio of a particular treatment is equal to
      the reciprocal value of the mortality/morbidity of untreated disease. Similarly,
      the lowest number of patients needed to be treated (NNT) for therapy to be worth
      administering is equal to the reciprocal of the treatment risk. We show how
      evidence-based summary measures of therapeutic effects, such as the treatment
      efficacy, harms, and NNT, can successfully be integrated within a decision
      analytic model. This in turn will facilitate wider use of the quantitative
      benefit-risk analysis. Accessing the Internet for direct and immediate approach
      to the formulas described here should make this task even easier in everyday
      clinical decision making.

PMID- 10337499
TI  - Cellular uptake and intraphagocytic activity of the new fluoroquinolone AF 3013
      against Klebsiella pneumoniae.
AB  - The entry of an antibiotic into phagocytes is a prerequisite for its
      intracellular bioactivity against susceptible facultative or obligatory
      intracellular microorganisms. AF 3013 is a new fluoroquinolone, and its uptake
      into and elimination from mouse peritoneal macrophages, together with its effects
      on phagocytic and antimicrobial mechanisms against Klebsiella pneumoniae, were
      investigated. AF 3013 efficiently penetrated into phagocytic cells at all
      concentrations tested. The uptake proceeded rapidly and was energy independent,
      since it was not affected by cell viability, environmental temperature or the
      addition of a metabolic inhibitor. Therefore, a possible passive transmembrane
      diffusion mechanism might be proposed. The elution of AF 3013 from macrophages
      occurred relatively slowly; in fact, 60 min after the removal of extracellular AF
      3013, nearly 40% of the drug still remained in the phagocytes. Exposure to 1 MIC
      of AF 3013 significantly enhanced macrophages phagocytosis and increased
      intracellular bactericidal activity against K. pneumoniae. Following preexposure
      of macrophages to 1 MIC of AF 3013, there was a significant increase in both
      phagocytosis and killing, compared with the controls, indicating the ability of
      AF 3013 to interact with biological membranes and remain active within
      phagocytes. Preexposure of Klebsiella to AF 3013 made the bacteria more
      susceptible to the bactericidal mechanisms of macrophages than untreated
      organisms.

PMID- 10337500
TI  - Antagonistic effects of combination photosensitization by hypericin, meso
      tetrahydroxyphenylchlorin (mTHPC) and photofrin II on Staphylococcus aureus.
AB  - Photodynamic therapy involves the application of a photosensitizer activated by
      visible light to generate cytotoxic reactive oxygen. In addition to clinical
      investigations, in vitro studies concerning photodynamic potency of sensitizers
      as well as quantification of illumination procedures are necessary. In our
      investigation, the objective was to evaluate not only the effects of
      photosensitizer and light on Gram-positive Staphylococcus aureus, but also to
      investigate possible synergistic or antagonistic effects of these sensitizers.
      Therefore, we used hypericin, Photofrin II, porfimer sodium and meso
      tetrahydroxyphenylchlorin (mTHPC) alone, as well as in combination. Log-phase
      cells of S. aureus exhibited a marked sensitivity to white thermal light
      irradiation in the presence of Photofrin II and mTHPC. However, hypericin caused
      a rather stimulated growth expressed in increased optical density (OD) and
      increase of total cell count (TCC) of the culture. Combination sensitization of
      S. aureus by Photofrin II and mTHPC with hypericin likewise caused a stimulation
      of bacterial growth. No synergistic effects were obtained by combination of
      Photofrin II and mTHPC; photoresponse of S. aureus was rather decreased by using
      combined porphyrins. In comparison, TCC and colony-forming units (CFU) were
      suppressed in the presence of mTHPC after an illumination procedure as well as in
      dark reactions. These effects were also obtained in the combination
      photosensitization by mTHPC and Photofrin II. In the presence the of hypericin,
      photodynamic effects of mTHPC and Photofrin II were inhibited. It was finally
      concluded that hypericin in our model is not a proper sensitizer for combination
      photo-sensitization due to antagonistic effects on photodynamic activity of mTHPC
      and Photofrin II.

PMID- 10337501
TI  - Diet only and diet plus simvastatin in the treatment of heterozygous familial
      hypercholesterolemia in childhood.
AB  - This study was a 1-year clinical study on 16 (7 males and 9 females) pediatric
      patients with heterozygous familial hypercholesterolemia treated with
      hypocholesterolemic diet only, or with diet plus drug (simvastatin 10 mg/day).
      According to the study protocol, the children were submitted to a 3-month washout
      (free diet). Then they were given a diet (American Heart Association, step 2) for
      6 months. After 6 months they were divided into two groups matched for sex, age
      and body mass index (BMI). Diet only was given to group A (n = 8); simvastatin
      (10 mg/daily) was given to group B, for 1 year. All patients were examined at
      baseline, and monitored for safety during the study by pediatricians. All
      patients were submitted to noninvasive cardiovascular examinations (exercise
      electrocardiogram, echocardiography). After 12 months of treatment with
      simvastatin, total cholesterol (TC) and low density lipoprotein cholesterol
      (LDLC) showed a statistically significant reduction (group B). The decrease of TC
      and LDLC in patients on diet only was 4% and 3% (all) and 17% and 4% (group A)
      after 6 and 12 months, respectively.

PMID- 10337502
TI  - Effects of propionyl-L-carnitine on peripheral arterial obliterative disease of
      the lower limbs: a double-blind clinical trial.
AB  - The authors evaluated the efficacy of propionyl-l-carnitine, a drug able to
      reduce peripheral resistance and protect the cells against oxidative stress
      damage, in patients affected by peripheral arterial obliterative disease at class
      II of Fontaine. The study was performed on 22 patients according to a double
      blind, randomized design in parallel with placebo. The drug was administered at a
      dosage of 1 g three times a day orally for 90 days. At recruitment and at the end
      of the study all patients underwent physical examination, treadmill test, doppler
      C.W. of the lower limbs, ankle/brachial index, dosage of tissue plasminogen
      activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), hematocrit, hematic
      filtration, and viscosity. In the group treated with propionyl-l-carnitine a
      statistically significant increase of claudication distance, blood flow velocity,
      PAI-1 activity and red blood cell deformity was observed. These data suggest the
      usefulness of propionyl-l-carnitine in the treatment of patients affected by
      peripheral arterial obliterative disease.

PMID- 10337503
TI  - Ambulant photodynamic therapy of superficial malignomas with 5-ALA in combination
      with folic acid and use of noncoherent light.
AB  - This study reports our first results of ambulant photodynamic treatment with 5
      aminolevulinic acid (5-ALA) in combination with folic acid and subsequent
      illumination with a noncoherent light source. The compound was topically applied
      to avoid total body skin sensitivity which occurs in the case of systemic
      administration. If no therapeutic response could be proved, we added folic acid
      to 5-ALA for a further treatment attempt. Illumination was performed by broad
      band red thermic light to also excitate reaction products with absorption bands
      located near to that of the sensitizer. As a result, we observed a response in
      all cases, however, in some cases only after the addition of folic acid.

PMID- 10337504
TI  - An ex vivo biochemical model to study the antioxidant clinical properties of
      cosmetic products in human antiaging skin care.
AB  - It is generally accepted that lipid peroxides play an important role in the
      pathogenesis of free radical-induced cellular injury and that endogenous thiols
      are vital in cellular defense against oxidative stress. The purpose of this study
      was to investigate in cultured human skin fibroblasts the effect of oxidative
      stress on the synthesis of heat shock protein (HSP70) and on the sulfhydryl group
      content in the absence and presence of alpha-tocopherol as an antioxidant
      compound. The interesting observation emerging from this study was a marked
      increase in malonaldehyde and fluorescent peroxide levels associated with a
      significant thiol depletion and induction of HSP70 stress proteins observed in
      primary cultures of normal human skin fibroblasts subjected to heat shock or
      incubated with hydrogen peroxide. These changes were significantly reduced in the
      presence of alpha-tocopherol. Our findings suggest a correlation between the
      mechanisms of oxidative stress, antioxidants and HSP70 induction, which can be
      assessed to evaluate either the perturbation of skin oxidant/antioxidant balance
      or the protection afforded by antioxidant test compounds.

PMID- 10337506
TI  - Structural changes in the rat middle ear mucosa due to endotoxin and eustachian
      tube obstruction.
AB  - The middle ears of 48 rats were used to examine the effects of endotoxin
      injection, eustachian tube obstruction or a combination of eustachian tube
      obstruction and endotoxin injection. Animals were killed after 1, 2, 4, or 12
      weeks and the middle ears processed for light and scanning electron microscopy.
      Compared to the normal middle ear mucosa, the epithelial layer was more
      pseudostratified, cuboidal or cylindrical after endotoxin injection or
      obstruction of the eustachian tube. In the early phase, numerous ciliated cells
      occurred in areas originally almost devoid of these cells. At 3 months,
      degeneration of ciliated cells was observed. The combination of eustachian tube
      obstruction and endotoxin injection also induced a more pseudostratified,
      cuboidal or cylindrical epithelium with an increased number of goblet cells.
      However, an early decrease occurred in the number of ciliated cells in the
      tympanic orifice of the eustachian tube. Furthermore, inflammatory cells, mainly
      PMNs, macrophages and lymphocytes, invaded the subepithelial layer after
      eustachian tube obstruction and endotoxin injection. These structural changes
      resulted in an impairment of the mucociliary transport system for clearance of
      the middle ear cavity. For this reason we believe that both endotoxin and
      eustachian tube obstruction or dysfunction play an important role in inducing
      persistent mucosal changes in the middle ear cavity, thereby prolonging otitis
      media with effusion.

PMID- 10337505
TI  - Anti-labyrinthine antibodies in a patient with relapsing polychondritis.
AB  - Relapsing polychondritis is a rare inflammatory disease that causes destruction
      of cartilaginous tissue in various anatomical regions. We report here about a 55
      year-old female patient with relapsing polychondritis that involved the right
      auricle, both audiovestibular organs and both eyes. The patient presented with
      persisting inflammation of the right auricle, sudden lower-frequency hearing
      loss, acute moderate vertigo with nausea and mild ocular symptoms.
      Immunofluorescence assays were used for the detection of antibodies against the
      cochlea and the vestibular organ and demonstrated the presence of circulating
      antibodies against the audiovestibular organ. No staining for anti-corneal IgG
      was detected. Improvement of clinical disease was achieved by treatment with
      systemic steroids and vasodilator drugs, and long-term medication with low-dose
      corticosteroids.

PMID- 10337507
TI  - Electronystagmographic changes in patients with unilateral vestibular schwannomas
      in relation to tumor progression and central compensation.
AB  - Vestibular function was studied in a group of 121 patients with unilateral
      vestibular schwannomas who were referred to University Hospital Utrecht between
      1986 and 1996. Testing included the caloric test, torsion test, saccade test,
      smooth pursuit test and the registration of spontaneous nystagmus. Each patient's
      symptoms were taken from a chart review. The size of the tumor was expressed as
      the maximum extrameatal diameter in the axial plane parallel to the petrous ridge
      as seen in magnetic resonance imaging or computed tomography. Large tumors were
      significantly more often accompanied by a more severe paresis on caloric testing,
      a smaller gain on torsion testing, spontaneous nystagmus, an abnormal saccade
      test and an abnormal smooth pursuit test. The presence of spontaneous nystagmus
      was significantly more frequently combined with an abnormal smooth pursuit and
      saccade test. There was a significant correlation between the slow component's
      velocity of the spontaneous nystagmus and the size and progression of tumor.
      However, a specific relation between tumor size and central vestibular
      compensation could not be demonstrated.

PMID- 10337508
TI  - The relationship between auditory threshold and evoked otoacoustic emissions.
AB  - The aim of this study was to compare transiently evoked otoacoustic emissions
      (TEOAE) and distortion product otoacoustic emissions (DPOAE) in normal hearing
      ears (n = 44) and ears with cochlear hearing loss (HL) to obtain defined data on
      qualitative and quantitative correlations. In addition, we wanted to determine
      the reliability with which a clinical examiner could predict a typical, idealized
      audiometric configuration from TEOAE measurements. In the hearing-impaired
      subjects (n = 149), a 50% reduction of OAE incidence was caused by a mean HL of
      10.5 dB for TEOAE compared to 27 dB SPL for DPOAE. A 90% incidence reduction was
      found at a mean threshold elevation of 33 dB for TEOAE and 51 dB for DPOAE.
      Correlation between TEOAE amplitudes and HL was in general rather low (r = -0.1
      to -0.5), while DPOAE amplitudes showed a slightly better correlation with HL (r
      = -0.3 to -0.6). In general, efforts to derive an audiogram from evoked OAE have
      been more promising for DPOAE than for TEOAE. However, our studies showed that
      approximately 40% of the ears with HL could be categorized correctly into one of
      five typical audiometric patterns from TEOAE measurements. Additionally, a
      cochlear HL in or near the medium frequency range was much more likely to cause a
      reduction in TEOAE than an isolated low- or high-frequency lesion. Accordingly,
      TEOAE were often preserved in ears with isolated HL in the high or low
      frequencies.

PMID- 10337509
TI  - The diagnostic and prognostic value of eardrum mobility in otitis media with
      effusion.
AB  - Diagnostic and prognostic values of eardrum mobility were determined by pneumatic
      otoscopy in 37 patients (56 ears) having otitis media with effusion (OME).
      Eardrum mobility was impaired or lost in less than half of the ears (46.4%),
      while a tympanogram detected 77.8% of OME. In 27 of the 37 patients (42 of the 56
      ears), aeration of the middle ear space was examined by CT and demonstrated that
      the presence or absence of aeration was significantly correlated with the
      presence or absence of eardrum mobility. In another 38 children (62 ears with
      OME), effect of antibiotics was correlated with eardrum mobility before
      treatment, and the improvement rate was found to be significantly higher in ears
      with positive mobility of eardrum (34.3%) than in ears without eardrum mobility
      (10.0%). These results indicate that eardrum mobility is a good prognostic
      indicator of OME rather than its diagnostic indicator alone.

PMID- 10337510
TI  - Semi-automatic segmentation of computed tomographic images in volumetric
      estimation of nasal airway.
AB  - The objective of this study was to determine nasal cavity volumes and cross
      sectional profiles from segmented coronal high-resolution computed tomography
      (HRCT) images. Pathological mucosal changes and congenital sinonasal variants
      were quantitated and three-dimensional (3D) images for determining sinonasal
      airway diseases evaluated by using the new semiautomatic segmentation software,
      Anatomatic. Anterior to posterior cross-sectional profiles of the sinonasal
      airway were obtained from acoustic rhinometry and segmented coronal HRCT images
      and compared in five patients having complaints of nasal obstruction and chronic
      sinusitis. Results showed that accurate volumes of air spaces in the nasal cavity
      and paranasal sinuses were obtained. When compared, the cross-sectional profiles
      of the nasal cavities obtained from acoustic rhinometry and the segmentation
      technique were similar in the anterior portion, but differed in the posterior
      portion. The results obtained by coronal HRCT and segmentation were more reliable
      than those produced with acoustic rhinometry. 3D images acquired from segmented
      images were found to help make a good pre-operative assessment of the whole
      sinonasal compartment. Segmentation and volumetric analysis using the Anatomatic
      technique also proved to be well suited to the evaluation of the nasal cavity and
      paranasal sinus geometry in patients with sinonasal diseases.

PMID- 10337511
TI  - Myositis ossificans in the neck.
AB  - Myositis ossificans is a non-neoplastic heterotopic bone formation within muscle
      or soft tissues. The most commonly involved muscles are the muscles of the upper
      arm and thigh. Occurrence in the head and neck is rarely encountered clinically.
      A 53-year-old Turkish man (farmer) was operated on for traumatic myositis
      ossificans circumscripta in his neck. During the operation the mass was found to
      originate from the scalenus medius muscle and was readily and completely
      dissected from surrounding tissues. The histologic examination of the specimen
      revealed focal cartilage and mature bone tissue, which was compatible with the
      late stage of myositis ossificans. In 5 years of follow-up, the patient has
      remained asymptomatic and no signs of recurrence have been noted.

PMID- 10337512
TI  - Primary hydatid cyst of the neck.
AB  - Hydatid cysts in the cervicofacial region are rare. We present an unusual case of
      a hydatid cyst found in the nape of a 66-year-old Turkish woman. There was no
      pulmonary or hepatic involvement. Excision of the cystic mass as definitive
      therapy was performed. The location of the lesion, diagnostic tests available and
      therapeutic approach are discussed and the literature reviewed.

PMID- 10337513
TI  - Mandibular neuralgia due to anatomical variations.
AB  - In our large collection of macerated human adult skulls and disarticulated skulls
      of young individuals we found cases with an extremely large lateral lamina of the
      pterygoid process. The medial wall of the infratemporal fossa was defined as its
      formation by the lateral lamina of the pterygoid process and the medial pterygoid
      muscle. The muscular part formed two-thirds and the lateral lamina one-third of
      this wall. In cases of a very large lateral lamina in our specimens nearly the
      whole medial wall was osseous. The third portion of the trigeminal nerve gives
      off the lingual nerve and alveolar mandibular nerve in the region of the
      infratemporal fossa. These two nerves generally passed between the lateral and
      medial pterygoid muscles to their terminal sites. In cases of extremely large
      lateral laminae the nerves had to make a curve in their course, following the
      shape of the enlarged lamina. During contraction of the pterygoid muscles both
      nerves can be compressed. Since the lingual nerve runs between muscular elements,
      tension and compression is probably avoided. In contrast, the mandibular nerve
      fixed between the oval and mandibular foramina cannot avoid tension and
      compression. The result is possible pain, especially during chewing, and may
      finally create a trigeminal neuralgia. Similar symptoms could be provoked by a
      foramen pterygospinale or ovalis canal replacing the foramen ovale.

PMID- 10337515
TI  - Transnasal endoscopic resection of juvenile nasopharyngeal angiofibroma with KTP
      laser.

PMID- 10337514
TI  - Laryngeal symptoms in patients exposed to Japanese cedar pollen: allergic
      reactions and environmental pollution.

PMID- 10337516
TI  - Regulation of inner ear fluid in the guinea pig cochlea after the application of
      saturated NaCl solution to the round window membrane.
AB  - The regulation of K+ and Na+ in the inner ear fluid of the guinea pig was studied
      after the application of saturated NaCl solution to the round window membrane. K+
      and Na+ activities in the scala tympani increased rapidly and then decreased. K+
      activity in the scala media increased immediately, but Na+ activity continued to
      increase during the period of observation. K+ activity in the scala vestibuli
      continued to increase in the observation period. Na+ activity in the scala
      vestibuli increased and then decreased. The endocochlear potential decreased
      immediately to approximately 20% of its initial level. Total activities of K+ and
      Na+ increased immediately and then decreased in both the scala tympani and scala
      media. The total activity of K+ and Na+ increased slowly and showed no regulatory
      decrease in the scala vestibuli. Thus, changing patterns in the total activity of
      K+ and Na+ were similar for the scala tympani and scala media, but not for the
      scala media and the scala vestibuli. Different patterns of K+ and Na+ activities
      among the three scalae indicate that their mechanisms for regulating inner ear
      fluid differ.

PMID- 10337517
TI  - Ramsay-Hunt syndrome in a 4-year-old child.
AB  - The Ramsay-Hunt syndrome mostly affects adults, but a small number of children
      with herpes zoster oticus have been reported. We describe a case of Ramsay Hunt
      syndrome in a healthy 4-year-old boy. He developed varicella at 7 months of age.
      At the age of 4 years, he complained of pain in his right ear, and herpes zoster
      vesicles were noted on his right pinna. Three days later, he developed right
      facial paralysis. He was treated with intravenous acyclovir and
      methylprednisolone. One month later, his facial paralysis had fully resolved.

PMID- 10337518
TI  - Treatment of cholesteatoma in children.
AB  - We studied retrospectively 28 cases of cholesteatoma in children whose ages were
      3 to 13 years old. All had undergone surgery between 1989 and 1995. The intact
      canal wall technique was the predominant method used in the initial operation,
      with long term goals of an anatomically normal and infection-free ear.
      Cholesteatoma was found postoperatively in 15 cases and was considered to be
      residual in 6 cases and recurrent in 9. The residual cholesteatoma was relatively
      uncommon and usually removable in an exploratory second operation. Our findings
      showed that the intact canal wall technique was the best initial operation if two
      stage surgery was planned. Avoidance of a retraction pocket, which tends to
      progress to a recurrent cholesteatoma, is important to successful treatment.

PMID- 10337519
TI  - Congenital malformation of the inner ear associated with recurrent meningitis.
AB  - Congenital deformities of the labyrinth of the inner ear can be associated with
      meningitis and varying degrees of hearing loss or deafness. A recurrence of
      meningitis is due to the development of a fistulous communication between the
      subarachnoid space and the middle ear cavity, and can prove lethal. An
      illustrative case of a 4-year-old Japanese girl with bilateral severe hearing
      loss, recurrent meningitis and malformations of the inner ear and stapes
      footplate is presented. Removal of the stapes during tympanotomy provoked a gush
      of cerebrospinal fluid. The defect was repaired successfully, and there has been
      no further episodes of meningitis to date.

PMID- 10337520
TI  - Cholesteatoma extending into the internal auditory meatus.
AB  - We report our experiences in managing a patient with cholesteatoma complicated by
      meningitis, labyrinthitis and facial nerve palsy. The antero-inferior half of the
      tympanum was aerated but the postero-superior portion of the tympanic membrane
      was tightly adherent to the promontry mucosa. An attic perforation was present at
      the back of the malleolar head. High-resolution computed tomography also
      uncovered a fistula in the lateral semicircular canal. Surgical exploration of
      the middle ear cavity demonstrated that both the vestibule and cochlea were
      filled with cholesteatoma, and the cholesteatoma extended into the internal
      auditory meatus through the lateral semi-circular canal fistula. The
      cholesteatoma was removed by opening the vestibule and cochlea with a
      preservation of the facial nerve. Post-operatively, an incomplete facial palsy
      remained, but has improved slowly. There is no sign of recurrence to date after a
      3-year period of observation.

PMID- 10337521
TI  - Treatment of sudden sensorineural hearing loss with a continuous epidural block.
AB  - The efficacy of a continuous epidural block was evaluated in the treatment of 20
      patients with sudden sensorineural hearing loss (SNHL). Ten patients were treated
      with continuous cervicothoracic epidural block (group A) and the other 10 were
      treated with stellate ganglion block (group B). No significant difference in
      factors affecting prognosis was noted between the groups. In the epidural block
      group 70% achieved substantial hearing improvement, while this occurred in only
      30% of patients undergoing stellate ganglion block. These findings suggest that
      continuous epidural block can be effective in the treatment of sudden SNHL.

PMID- 10337523
TI  - The role of the labyrinth, proprioception and plantar mechanosensors in the
      maintenance of an upright posture.
AB  - The maintenance of an upright posture in man requires information from vision,
      the labyrinth, proprioception and plantar mechanosensors. In order to evaluate
      the role of the labyrinth, proprioception and plantar mechanosensors,
      stabilometry was performed in subjects with closed eyes. Ten patients with
      bilateral severe or complete labyrinthine paresis were studied, as well as 9
      patients with severe proprioceptive disorders and 10 normal healthy persons whose
      plantar mechanosensors were anesthetized by hypothermia. Both the area of sway
      and the total locus length (accumulated shift distance length) were evaluated. On
      closing eyes, in patients with labyrinthine disorders demonstrated that the area
      of sway increased more than length. On the other hand, in patients with
      proprioceptive disorders, length increased more than the area. In plantar
      anesthetized subjects, similar to the labyrinthine disorder cases, the area of
      sway increased more than length. These findings suggest that the labyrinth is a
      main monitor of the area of body sway, while proprioception is a principle
      monitor of the velocity of body movement of sway (or locus length). The plantar
      mechanosensor monitors the area of body sway similar to the labyrinth, but works
      less than the labyrinth. The locus length is the distance per minute and reflects
      the velocity of body sway. Thus, the length per area is a parameter for the
      velocity of body sway per area. Since proprioceptive disorders increase both the
      locus length and the length per area, present findings suggest that if
      proprioception is damaged, the body begins to move faster. Compensated
      labyrinthine disorders have a tendency to increase the length per area,
      indicating that if a labyrinthine disorder is compensated, the body adapts and
      moves faster to maintain an upright posture.

PMID- 10337522
TI  - Effects of the antihistaminergic drugs diphenhydramine and zolantidine on
      vestibular-induced hypothalamic neuronal activity in the guinea pig.
AB  - The mode of action of diphenhydramine in treating motion sickness is unknown.
      Using an electrophysiologic technique, we investigated the effects of intravenous
      diphenhydramine and zolantidine on the changes in neuronal activity produced by
      caloric stimulation in the hypothalamic paraventricular nucleus (PVN) in the
      guinea pig. Changes in neuronal activity were modulated by the administration of
      diphenhydramine in a high percentage of the neurons tested (71%), while
      zolantidine affected only a small number (29%). This finding reinforces the
      involvement of a histaminergic system in vestibular autonomic responses. The
      modulatory effect of diphenhydramine on PVN neuron activity may explain in part
      this drug's efficacy in treating motion sickness.

PMID- 10337524
TI  - Huge hamartoma with inverted papilloma in the nasal cavity.
AB  - We report clinical experience in managing a 46-year-old Japanese man with long
      standing nasal obstruction resulting from a huge left nasal mass. Computed
      tomography, magnetic resonance imaging and biopsy were used to make a provisional
      diagnosis of inverted papilloma. The mass was resected via a frontal approach
      combined with rhinotomy. Histopathologic examination of the resected specimen was
      consistent with a hamartoma that included an inverted papilloma on a portion of
      its surface. In addition to being rare tumors in the nasal cavity, we believe
      that our patient's tumor the largest nasal hamartoma ever reported.

PMID- 10337525
TI  - Effects of cytochalasin D on taste pores of rat fungiform papillae.
AB  - Effects of cytochalasin D on actin filaments in cells encircling taste pores were
      examined to clarify the functional role of actin filaments in the maintenance of
      taste pores in rat fungiform papillae, using a confocal laser microscope and a
      scanning electron microscope. Fluorescence in the taste pore cells was detected
      as a ring shape produced by actin staining with rhodamine-phalloidin. Treatment
      of fungiform papillae with cytochalasin D diminished the positive reactions in
      the taste pore cells and increased the inner diameter of the ring reactions.
      However, deformation of the taste pores in fungiform papillae was not detected
      under a scanning electron microscope after treatment with cytochalasin D. These
      findings suggest that the organization of actin filaments encircling the taste
      pores contributes to regulation of the taste pore's size in rat fungiform
      papillae.

PMID- 10337526
TI  - Magnetic sensory cortical responses evoked by tactile stimulations of the human
      face, oral cavity and flap reconstructions of the tongue.
AB  - Magnetoencephalography (MEG) is a procedure that analyzes the magnetic responses
      of neurons. An MEG system with a 37-channel superconductivity quantum
      interference device (SQUID) was used to record magnetic signals from the human
      brain in response to tactile stimulations of the face and oral cavity. Six normal
      individuals were studied as well as three patients who had undergone
      hemiglossectomies as treatment for carcinoma of the tongue and reconstruction
      with a pectoralis major myocutaneous flap. When the locations of the magnetic
      responses having latencies of 40 ms from onset of tactile stimulation were
      identified, these corresponded to the primary somatosensory cortex. In patients
      whose tongues had been reconstructed with a pectoralis major myocutaneous flap,
      the magnetic response upon stimulation of the flap was recorded in a sensory
      cortical area identical to that corresponding to the tongue. MEG systems such as
      the one described permit functional mapping of the cerebral cortex on stimulating
      the face and oral cavity.

PMID- 10337527
TI  - Transcutaneous PCO2 monitoring in the evaluation of hyperventilation of patients
      with recurrent nerve paralysis.
AB  - Hyperventilation during phonation is one of the causes of fatigue in patients
      with vocal cord disorders. Transcutaneous (TC) PCO2 and PO2 were analyzed during
      phonation in patients with known recurrent nerve paralyses (RNP). There was no
      significant change in TCPCO2 in eight normal subjects. In cases with unilateral
      RNP and incomplete glottic closure, TCPCO2 decreased during phonation. This
      decrease in TCPCO2 resulted from hyperventilation during phonation. The TCPCO2
      did not decrease in one case with RNP and complete glottic closure. In one case
      with incomplete glottic closure, the decrease in TCPCO2 and fatigue disappeared
      after treatment. These results suggest that hyperventilation is one of the causes
      for easy fatiguability during phonation in patients with RNP, Findings also show
      that measurements of TCPCO2 during phonation are useful for evaluating the cause
      of fatigue in patients with vocal disorders.

PMID- 10337528
TI  - Quantitative evaluation of the voice range profile in patients with voice
      disorder.
AB  - In 1953, Calvet first displayed the fundamental frequency (pitch) and sound
      pressure level (intensity) of a voice on a two-dimensional plane and created a
      voice range profile. This profile has been used to evaluate clinically various
      vocal disorders, although such evaluations to date have been subjective without
      quantitative assessment. In the present study, a quantitative system was
      developed to evaluate the voice range profile utilizing a personal computer. The
      area of the voice range profile was defined as the voice volume. This volume was
      analyzed in 137 males and 175 females who were treated for various dysphonias at
      Kyushu University between 1984 and 1990. Ten normal subjects served as controls.
      The voice volume in cases with voice disorders significantly decreased
      irrespective of the disease and sex. Furthermore, cases having better improvement
      after treatment showed a tendency for the voice volume to increase. These
      findings illustrated the voice volume as a useful clinical test for evaluating
      voice control in cases with vocal disorders.

PMID- 10337529
TI  - Overexpression of p53 nuclear protein in premalignant and malignant laryngeal
      lesions.
AB  - To investigate the role of p53 nuclear protein mutations in the initiation and
      progression of laryngeal carcinoma, 111 premalignant and malignant laryngeal
      lesions (19 specimens with hyperkeratosis and 92 with carcinoma) were studied
      immunohistochemically. Over-expression of p53 was observed in 8 cases (42%) of
      laryngeal hyperkeratosis and 44 cases (47%) of laryngeal carcinoma. However, the
      expression of p53 showed no relationship to patients' clinical courses. Our study
      confirms that p53 overexpression can be found in laryngeal carcinogenesis and is
      an early event but not a useful prognostic marker.

PMID- 10337530
TI  - Comparison of survival rates of patients with nasopharyngeal carcinoma treated
      with radiotherapy, 5-fluorouracil and vitamin A ("FAR" therapy) vs FAR therapy
      plus adjunctive cisplatin and peplomycin chemotherapy.
AB  - The overall survival rate (OSR) of 36 patients with nasopharyngeal carcinomas
      (NPC) treated at Kyushu University hospital between 1983 to 1992 was analyzed. As
      primary treatment, 16 patients received a combination therapy of 5-fluorouracil,
      vitamin A, and radiation (FAR therapy); two patients received radiotherapy only;
      18 patients received FAR therapy plus adjunctive systemic chemotherapy consisting
      of cisplatin and peplomycin. The radiation dose to the nasopharynx was 6000 to
      7050 cGy while that to the neck was 4000-6000 cGy. The 5-year OSR of all the
      patients was 49%. Histological type (moderately differentiated squamous cell
      carcinoma) and patient age (> or = 55) were found to be significant prognostic
      factors for a worse OSR. Although survival decreased with increasing T stage, no
      significant difference was observed. The 5-year OSR of the patients treated with
      FAR therapy was 53% and was 51% with FAR therapy plus chemotherapy. Compared to
      FAR therapy alone, adjunctive chemotherapy did not increase OSR of the patients
      with NPC.

PMID- 10337531
TI  - Induction of apoptosis in maxillary sinus cancer cells by 5-fluorouracil, vitamin
      A and radiation (FAR) therapy.
AB  - The triple combination of 5-fluorouracil (5-FU), vitamin A and radiation (FAR
      therapy) has been used since 1972 to treat malignant tumors of the head and neck
      at Kyushu University. Using nick end labeling of tumor specimens, cells of human
      maxillary sinus carcinomas were observed previously to undergo apoptosis in
      response to FAR therapy. The present study evaluated the in vitro effects of FAR
      therapy on a human maxillary sinus cancer (IMC-4) cell line. We further compared
      the effects of FAR therapy on this cell line with those effects seen on tissue
      samples taken from patients with maxillary sinus cancers. DNA electrophoresis and
      electron microscopic examination of the IMC-4 cells after treatment with FAR
      therapy revealed typical apoptotic features. The effects of 50-100 micrograms/ml
      5-FU, 10(-4) M all-trans-retinoic acid and radiation to 6 Gy on IMC-4 cells were
      evaluated by trypan blue dye exclusion and a cell colony formation assay. 5-FU
      and radiation caused direct cell death, while vitamin A mainly inhibited cell
      growth. The combination of these treatment as FAR therapy synergistically
      enhanced cell death and inhibited cell growth. Flow cytometry demonstrated that
      FAR-treated cells were arrested in the G1 phase of the cell cycle before
      undergoing apoptosis. To further investigate possible biological parameters
      influencing a tumor's apoptotic sensitivity, we also examined the expression of
      p53 in human maxillary sinus cancer cells and analyzed the relationship between
      p53 expression and apoptosis. However, no relationship was found between these
      two markers at the time point studied.

PMID- 10337532
TI  - Stomal recurrence invading the cervicothoracic esophagus and upper mediastinum:
      resectability and the creation of a safe anterior mediastinal tracheostoma.
AB  - Surgical salvage for stomal recurrence is a for midable problem for head and neck
      surgeons. The two factors of considerable significance are resectability and
      establishment of a safe anterior mediastinal tracheostoma. A case of stomal
      recurrence invading the cervicothoracic esophagus and upper mediastinum is
      presented. Total esophagectomy and upper mediastinal dissection was performed.
      The esophagus was reconstructed immediately with a pedicled gastric flap. The
      omentum on the gastric pedicle was wrapped around the trachea to reduce the
      likelihood of erosion into the great vessels and to supplement the lateral blood
      supply to the trachea. No serious postoperative complications were observed. We
      believe that the total esophagectomy improved the resectability, and that the
      bulk of the gastric pedicle and the use of the omentum prevented significant
      postoperative complications associated with an anterior mediastinal tracheostoma.

PMID- 10337533
TI  - Three-dimensional ultrasonic imaging of blood flow.

PMID- 10337534
TI  - Hyperhomocysteinaemia, genetics and cardiovascular disease risk.

PMID- 10337535
TI  - Inflammation and outcome in unstable angina.

PMID- 10337536
TI  - Expression of cell-cycle regulators during heart development and failure.

PMID- 10337537
TI  - Cardiologists and their war on platelets.

PMID- 10337538
TI  - Is tissue Doppler echocardiography ready for clinical application?

PMID- 10337539
TI  - Beta-blockers for heart failure: is slowing of heart rate essential?

PMID- 10337540
TI  - International co-operation in world cardiology. The role of the World Heart
      Federation.

PMID- 10337541
TI  - Inflammatory status as a main determinant of outcome in patients with unstable
      angina, independent of coagulation activation and endothelial cell function.
AB  - AIMS: Inflammation, endothelial cell function and the coagulation system have
      been demonstrated to be involved in the onset and course of unstable angina.
      Whether a proinflammatory state independently determines outcome is unknown and
      has not been determined yet in a clinically well defined study population of
      consecutive patients admitted with unstable angina. METHODS AND RESULTS: Markers
      of inflammation, coagulation activation and endothelial cell function were
      determined on admission in blood of 211 consecutive patients with severe unstable
      angina and were related to the in-hospital course. Refractory unstable angina
      occurred in 76 patients (36%) during their hospital stay. In a univariate
      analysis, C-reactive protein (P = 0.03), fibrinogen (P < 0.001) and erythrocyte
      sedimentation rate (P = 0.001) levels were significantly higher in patients with
      refractory unstable angina, when compared with patients who had an uneventful
      clinical course. The odds ratios (95% CI) adjusted for age, sex, body mass index,
      smoking behaviour and cholesterol levels of the occurrence of refractory unstable
      angina for patients in the highest quartile compared with patients in the lowest
      quartile of inflammatory markers were 2.19 (0.94-5.11) for C-reactive protein,
      2.83 (1.13-7.10) for fibrinogen and 4.72 (1.70-13.09) for the erythrocyte
      sedimentation rate. The findings were not affected by the presence or absence of
      myocardial necrosis or the interval between onset of angina and blood collection.
      No association was found between markers of coagulation activation or markers of
      endothelial cell function, and in-hospital outcome. CONCLUSION: We found that in
      a clinically well-defined study population of patients with severe unstable
      angina, a proinflammatory state is an important and independent determinant of
      short-term outcome. The data strengthen the importance of inflammation in this
      syndrome.

PMID- 10337542
TI  - Heart rate dependency of cardiac performance in heart failure patients treated
      with metoprolol.
AB  - AIMS: To investigate whether a low heart rate is necessary to maintain
      improvement in myocardial function after long-term treatment with a beta-blocker
      in patients with heart failure. METHODS AND RESULTS: Forty-eight patients with
      congestive heart failure were investigated: 30 patients with dilated
      cardiomyopathy participating in a placebo-controlled trial (15 on placebo, 15 on
      metoprolol), and 18 patients treated by metoprolol in an open protocol.
      Investigations of spontaneous heart rate and of matched paced heart rates were
      performed at baseline and after 3, 6 and 12 months of follow-up by radionuclide
      angiography. There were significant signs of improvement in systolic indices of
      the spontaneous heart rate in the metoprolol-treated group (peak ejection rate:
      0.98 to 1.32 end-diastolic volume.s-1, P = 0.015) as compared to placebo (1.14 to
      1.19 end-diastolic volume.s-1, not significant). Similar effects were observed
      during the matched paced heart rate (peak ejection rate: metoprolol 0.91 to 1.38
      end-diastolic volume.s-1, P = 0.037; placebo 1.22 to 1.12 end-diastolic volume.s
      1, not significant). No effects were observed in the early peak filling rate.
      Left ventricular volumes decreased during metoprolol treatment, both for the
      spontaneous heart rate and during matched pacing. CONCLUSIONS: These data imply
      that beta-blocker treatment improves the force-frequency relationship of
      myocardial performance. A lower heart rate is not necessary to maintain cardiac
      function on a short-term basis, once myocardial recovery has occurred.

PMID- 10337543
TI  - The TT genotype of the methylenetetrahydrofolate reductase C677T gene
      polymorphism is associated with the extent of coronary atherosclerosis in
      patients at high risk for coronary artery disease.
AB  - BACKGROUND: There are conflicting results on the relationship of N5,N10
      methylenetetrahydrofolate reductase C677T gene variation in coronary artery
      disease and myocardial infarction. METHODS AND RESULTS: We analysed this gene
      variation in 2453 male Caucasians whose coronary anatomy was defined by coronary
      angiography. In the total sample, the C677T gene polymorphism was not associated
      with the presence or the extent of coronary artery disease (defined by the degree
      of vessel disease or by the coronary heart disease score according to Gensini).
      However, after excluding individuals with low risk profiles, an association
      between the C677T TT genotype and the Gensini score was found. This observation
      applies only to individuals (i) with high glucose levels, (ii) with low
      apolipoprotein Al/apolipoprotein B ratios, (iii) with low apolipoprotein
      Al/apolipoprotein B ratios and high lipoprotein (a) levels and (iv) with low
      apolipoprotein Al/apolipoprotein B ratios and high glucose concentrations. In
      patients with high glucose levels, the paraoxonase 191 A/B gene variation
      presupposed whether differences in Gensini scores between C677T C allele carriers
      and TT homozygotes became apparent, since only in paraoxonase 191 AA homoxygotes,
      but not in paraoxonase 191 B allele carriers, did C677T TT homozygotes have
      clearly higher Gensini scores than C allele carriers (two-way interaction; P =
      0.013). The MTHFR C677T gene polymorphism was not associated with non-fatal
      myocardial infarction. CONCLUSION: The present study extends previous
      observations by the finding that carriers of the N5,N10-methylenetetrahydrofolate
      reductase C677T TT genotype with various coronary high risk profiles had clearly
      higher coronary heart disease scores than individuals with at least one C677T C
      allele.

PMID- 10337544
TI  - Quantitative systolic and diastolic transmyocardial velocity gradients assessed
      by M-mode colour Doppler tissue imaging as reliable indicators of regional left
      ventricular function after acute myocardial infarction.
AB  - AIMS: The aim of this study was to determine whether myocardial velocity
      gradients assessed by M-mode colour Doppler tissue imaging could be of clinical
      relevance and represent reliable indicators of regional left ventricular function
      after acute myocardial infarction. METHODS AND RESULTS: Among 64 consecutive
      patients with a first acute myocardial infarction, in 50 who had a marked
      asynergy in the parasternal short-axis view at the mid-papillary muscle level,
      myocardial velocities and velocity gradients were assessed in the anteroseptum
      and posterior wall by M-mode Doppler tissue imaging. Similar measurements were
      obtained in 11 matched healthy volunteers who served as a control group. In
      patients with anterior myocardial infarction, the peak myocardial velocity
      gradient in the anteroseptum was significantly lower when compared with controls
      (mean +/- [SD] 0.0 +/- 0.5 vs 1.1 +/- 0.7 s-1 during systole, P < 0.01; and 0.3
      +/- 0.6 vs 2.0 +/- 0.5 s-1 during diastole, P < 0.01). Conversely, the peak
      systolic myocardial velocity gradient in the posterior wall was significantly
      higher than in controls (2.6 +/- 1.2 vs 1.8 +/- 1.2 s-1, P < 0.05). In patients
      with inferior myocardial infarction, the peak velocity gradient in the posterior
      wall was significantly lower when compared with healthy subjects (0.9 +/- 0.6 vs
      1.8 +/- 1.2 s-1 during systole and 1.4 +/- 1.4 vs 4.9 +/- 1.2 s-1 during
      diastole, both P < 0.01). The peak systolic tissue velocity gradient in the
      anteroseptum was significantly higher than in controls (2.1 +/- 1.0 vs 1.1 +/-
      0.7 s-1, P < 0.01). CONCLUSION: The present study indicates that myocardial
      velocity gradients assessed by M-mode Doppler tissue imaging are of clinical
      relevance for the characterization of ischaemic myocardial dysfunction after
      infarction and may provide quantitative assessment of segmental left ventricular
      function in this clinical setting.

PMID- 10337545
TI  - Cyclin-dependent kinase inhibitor expression in human heart failure. A comparison
      with fetal development.
AB  - AIMS: Terminal differentiation of cardiac myocyte is associated with their
      permanent withdrawal from the cell cycle. In adult end-stage heart failure,
      significant numbers of myocytes express proliferating cell nuclear antigen yet
      fail to progress to cell division. Cyclin dependent kinase inhibitors are
      powerful inhibitors of the cell cycle and may play a direct role both in myocyte
      development and in preventing cell division in the adult. METHODS AND RESULTS:
      The expression of the CIP/KIP cyclin dependent kinase inhibitors p21, p27, p57
      and the retinoblastoma protein was examined in acute (seen in brain dead
      transplant donors) and end-stage heart failure by Western blot analysis and
      compared to that seen in human and rat cardiac development. The expression of p21
      showed a gradual increase during development in both rat and man, becoming
      maximal in adulthood p27. levels showed an initial rise with subsequent continual
      expression throughout life. p57 expression was detectable at only early stages in
      rat but persisted throughout life in man. In both acute and end-stage heart
      failure the levels of p21, p27 and p57 reverted to a pattern similar to that
      observed in human fetal heart: p21 and p27 declined while p57 expression was
      significantly increased. In contrast, retinoblast protein levels declined during
      human heart development but were unaltered in heart failure. CONCLUSIONS: The
      expression of p21, but not p27 or p57, is consistent with a role in the gradual
      withdrawal of cardiac myocytes from cell cycle during development. In adult heart
      failure cyclin dependent kinase inhibitor expression reverts to the fetal pattern
      but is insufficient to initiate cell cycle activation.

PMID- 10337546
TI  - Left atrioventricular plane displacement is related to both systolic and
      diastolic left ventricular performance in patients with chronic heart failure.
AB  - AIMS: Left atrioventricular plane displacement is proposed to reflect left
      ventricular systolic function and is strongly related to prognosis in patients
      with heart failure. Left atrioventricular plane displacement is a different
      measure of left ventricular function compared to ejection fraction, and the
      factors influencing left atrioventricular plane displacement are insufficiently
      characterized. We wanted to assess any relationship between left atrioventricular
      plane displacement and left ventricular diastolic performance. METHODS AND
      RESULTS: Left ventricular diastolic filling, left atrioventricular plane
      displacement, and fractional shortening were assessed by echocardiography/Doppler
      in 54 patients with chronic heart failure (age 64 +/- 7 years). Left
      atrioventricular plane displacement correlated significantly with Doppler
      variables of left ventricular filling, in particular the inverse logarithm of
      early transmitral flow deceleration time; log-1 Edt (r = -0.61, P < 0.0001, n =
      54). Left atrioventricular plane displacement also correlated with fractional
      shortening (r = 0.49, P < 0.001, n = 50). However, fractional shortening did not
      correlate with any Doppler variable. Log-1 Edt, fractional shortening, age, heart
      rate, left ventricular and atrial size, and degree of mitral regurgitation were
      included in a multiple regression analysis. Only log-1 Edt (P = 0.001) and
      fractional shortening (P = 0.03) correlated independently with left
      atrioventricular plane displacement. Among patients with similar fractional
      shortening, those with more compromised diastolic performance had lower left
      atrioventricular plane displacement. CONCLUSION: Left atrioventricular plane
      displacement was related to both systolic and diastolic left ventricular
      performance, which may explain some of the discrepancies between left
      atrioventricular plane displacement and ejection fraction.

PMID- 10337547
TI  - Three-dimensional Doppler. Techniques and clinical applications.
AB  - AIMS: Colour Doppler is the most widely used technique for assessing valve
      disease, but eccentric regurgitant jets cannot be visualized and measured by
      conventional 2D techniques. We have developed a new procedure for three
      dimensional (3D) reconstruction of colour Doppler signals. METHODS AND RESULTS:
      Fifty patients with mitral regurgitation underwent transoesophageal
      echocardiography and 3D acquisition. The severity of mitral regurgitation was
      assessed by angiography and the regurgitant volumes were measured by pulsed
      Doppler. The jet areas were calculated by planimetry from conventional colour
      Doppler; the jet volumes were obtained by 3D Doppler. A higher degree of mitral
      regurgitation was found in the patients with eccentric jets. While jet areas
      showed poor correlation with regurgitant volumes (r = 0.61), jet volumes
      correlated significantly with regurgitant volumes (r = 0.93; P < 0.001). While
      jet areas failed to identify patients with different grades of regurgitation, jet
      volumes could so discriminate. CONCLUSIONS: 3D Doppler revealed new patterns of
      regurgitant flow and allowed a more accurate semiquantitative assessment of
      complex asymmetrical regurgitant jets. Three-dimensional colour Doppler has a
      great potential for becoming a reference method for the assessment of patients
      with heart valve disease.

PMID- 10337548
TI  - Effect of crimping on the contamination of coronary stents.

PMID- 10337549
TI  - [Effective treatment of a large muscle hernia by local botulinum toxin
      administration].
AB  - A 53-year-old patient developed an impairing muscle hernia when a fascia lata
      graft was harvested as a substitute for a cruciate ligament of the knee and
      closure of the defect was not possible. The fascial defect enlarged with time,
      extending along the whole upper leg. The large muscle protrusion and
      incarceration in the distal fascial slit was extremely painful during walking and
      getting up from a chair. Since autologous grafts were disregarded because of the
      high tissue pressure and alloplastic substitutes seemed problematic, the large
      hernia was successfully reduced by local muscle denervation with injections of
      botulinum-A toxin into the protruding vastus lateralis muscle. This procedure
      achieved relief of pain and enabled the patient to walk without complaints. Side
      effects were not observed.

PMID- 10337550
TI  - Isolated capitate fracture diagnosed by computed tomography. Case report.
AB  - Isolated fractures of the capitate, though rare, are probably often missed
      entirely. As in scaphoid fractures, repeated radiographs, tomography, or bone
      scanning are necessary for the diagnosis. Reviewing the literature, we found that
      most capitate fractures reported were transverse or combined with other carpal
      injuries, including the scapho-capitate fracture syndrome. Our patient presented
      an isolated oblique intraarticular fracture of the capitate. An old fracture of
      the styloid process of the ulna was seen at the primary examination. This special
      type of capitate fracture has not been previously described. The fracture was
      missed on standard radiographs, but discovered by computed tomography (CT). The
      different types of fractures of the capitate and their treatment are discussed.

PMID- 10337551
TI  - [Dorsal intra-articular end-phalangeal fractures].
AB  - In a retrospective clinical study, thirty-six patients with a dorsal
      intraarticular fracture of the DIP-joint were examined. The fracture can be
      classified according to the size of the dorsal fragment as a mallet finger or as
      an intraarticular fracture with the tendency for dislocation. Subcutaneous tendon
      ruptures with a small dorsal fragment respond well to conservative treatment.
      Intraarticular fractures should be treated surgically. Anatomical reduction and
      joint stability are the treatment aims. In 21 patients, tension band wiring was
      performed, in eight cases percutaneous treatment with the "Hakendraht" was
      carried out.

PMID- 10337552
TI  - [Lengemann suture versus bone screw osteosynthesis in treatment of ulnar osseous
      collateral ligament rupture of the thumb metacarpophalangeal joint].
AB  - Out of 95 ligamentous lesions of the thumb metacarpophalangeal joint, those with
      an isolated bony rupture of the ulnar collateral ligament were chosen. Of these,
      15 patients treated with Lengemann suture and 16 with screw fixation were
      followed-up on average 27.3 and 26.4 months, respectively, after operative
      treatment. Under only "good" and "very good" clinical results, the statistical
      analysis of the objective and subjective parameters showed no significant
      difference, except for the measurement of the soft-tissue circumference (p <
      0.01) between either procedure. Although both procedures have a low rate of
      complications, screw fixation is preferable since implant removal is not
      necessary.

PMID- 10337553
TI  - [Successful ear replantation without venous anastomosis by using leeches].
AB  - Replantation of the ear is a challenging problem for the reconstructive surgeon.
      Avulsion injury and intima tears of these small vessels often make back cuts and
      venous interposition necessary. Furthermore, identification and differentiation
      of the vessels are difficult. The volume of the ear is large in relation to the
      wound surface and the absence of axial venous outflow makes replantation prone to
      venous congestion. On the basis of a case report we present the problems, the
      specific management and final outcome of a successful ear replantation and we
      discuss the alternative possibilities of reconstruction.

PMID- 10337554
TI  - Experimental use of prosthetic grafts in microvascular surgery.
AB  - Interpositional microvascular grafts are very often required in reconstructive
      surgery for bridging microvascular defects, particularly in association with
      replantation of amputated segments and free tissue transplantation. The present
      experimental study was undertaken to evaluate patency and healing of small
      diameter polytetrafluoroethylene (PTFE) prostheses and to compare them with those
      of microvenous grafts. 10-mm long microarterial PTFE grafts of 1 mm internal
      diameter were implanted into the femoral artery of the rabbit to restore vascular
      continuity. Patency was assessed by Doppler ultrasound up to four weeks
      postoperatively. After harvesting, all grafts were evaluated macroscopically and
      examined by light and transmission electron microscopy. According to our results,
      five of 20 re-explored PTFE grafts (25%) remained patent at four weeks, while all
      microvenous grafts were judged to be patent at the same time. The difference
      between patency rates was found to be statistically significant (p < 0.0001).
      Recent literature on the experimental use of microvascular prostheses is reviewed
      and various factors affecting graft patency are discussed.

PMID- 10337555
TI  - [Techniques for postoperative monitoring of tissue circulation after free
      microvascular tissue transplantation].
AB  - Success rates after free tissue transplantation (FTT) have greatly improved over
      the last 20 years, partly due to improved technical performance of microvascular
      anastomoses with better optical and instrumental aids. However, flap failure is
      still a clinical problem and occurs in 5 to 10%, mainly due to blood vessel
      thrombosis within the first 24 postoperative hours. The clinical results after
      FTT can be optimized by in-time diagnosis of irreversibly compromised tissue
      blood flow and immediate operative reexploration. Therefore, there is a special
      demand for adequate and reliable postoperative monitoring techniques. This
      article reviews all monitoring techniques which have been performed in the
      experimental-clinical setting after FTT thus far.

PMID- 10337556
TI  - [The value of various techniques for esthetic correction of the lower eyelid].
AB  - Blepharoplasties are amongst the most commonly performed aesthetic procedures.
      Various lower blepharoplasty techniques have been described in the literature.
      Often, value and appropriate indication for each individual technique have not
      been sufficiently delineated. The recent renaissance of the transconjunctival
      blepharoplasty allowed the evolution of new and safe procedures for correction of
      the lower lid. Additionally, the technique of resection of the herniated orbital
      fat underwent certain improvements. The aim of this article is to describe the
      currently utilized surgical techniques and to discuss their indications.

PMID- 10337557
TI  - [Experiences with internal thoracic vessels in breast reconstruction with the
      free TRAM flap].
AB  - In breast reconstruction with free TRAM flaps, the thoracodorsal vessels are most
      commonly used as recipient vessels. In case of an irradiated and scarred axillary
      region, the internal thoracic vessels may be an alternative. In the pertinent
      literature it has been pointed out that the veins may be fragile and thin and,
      thus, not suitable for microvascular anastomosis. In a series of 31 breast
      reconstructions with free TRAM flaps, the internal thoracic vessels were
      dissected and evaluated in 24 cases in order to assess the value of this vascular
      system as a recipient site for free flap transplantation. In four cases, the
      veins were too small for anastomosis, and in one case the artery was severed
      during dissection. End-to-end anastomoses were performed in 19 cases (79%). The
      following complications were recorded: One marginal necrosis; one venous
      thrombosis, which was detected and salvaged by revision; one recurrent arterial
      thrombosis, resulting in flap loss; one pleural lesion healed uneventfully.

PMID- 10337558
TI  - [Pedicled versus free TRAM flap for breast reconstruction].
AB  - In breast reconstruction, the free TRAM-flap offers many advantages over the
      pedicled TRAM-flap. Due to its superior perfusion, the free flap rarely develops
      necrosis. Shaping of the flap is easier due to the lack of the thick muscle
      pedicle. Because the rectus muscle is spared, there is minimal donor site
      morbidity. However, the necessary microvascular anastomoses reduced the
      acceptance of the free TRAM-flap. During a 13-months period, 51 breast
      reconstructions were performed in 41 patients, 31 unilateral and ten bilateral.
      45 flaps served for delayed reconstruction and six flaps for immediate
      reconstruction. The operations were performed by two teams working
      simultaneously. The average operating time was 3.9 hours for unilateral and 6.9
      hours for bilateral delayed reconstruction. For immediate reconstruction, 6.2 and
      6.3 hours were required for uni- and bilateral procedures, respectively. In 38
      flaps, the thoracodorsal vessels served as recipient vessels; 13 flaps were
      anastomosed to the internal mammary artery and vein. Postoperative complications
      were observed in 13 patients. Three vessel anastomoses had to be revised. In one
      flap, a partial necrosis occurred; in two flaps hematoma evacuation was
      necessary. Two patients suffered from fat necroses at the abdomen and one
      umbilicus was lost. Skin irritations and seromas at the abdomen occurred in five
      patients. Pulmonary embolism was diagnosed in one patient three weeks
      postoperatively. Abdominal hernias or bulging in the epigastric area were not
      observed up to 15 months after reconstruction. These results reveal a low
      complication rate for breast reconstruction with the free TRAM-flap. The
      advantages of this technique as compared to the pedicled technique are discussed.

PMID- 10337559
TI  - [Standard technique of breast reduction surgery with vertical scar].
AB  - In 1991, we started to use a new surgical technique for breast reduction with a
      single vertical scar incision as developed by Marchac, Lassus, and Lejour. The
      operative procedure wsa changed step-by-step according to the following
      significant modifications: Simultaneous liposuction is carried out only in the
      presence of extensive axillary fatty tissue. The undermining of the glandular
      tissue is limited to the extension of glandular resection. The number of
      glandular sutures is significantly reduced. A central fixating suture to the
      pectoral fascia is performed only in the presence of extreme ptosis. The
      positioning of the nipple-areola complex represents the final step of the
      reduction procedure after the resection of the glandular tissue. Based on our
      experience with more than 800 breast reductions, this technique is considered to
      be a safe standard procedure for nearly all breast sizes.

PMID- 10337560
TI  - [Quality of life after breast reduction-plasty].
AB  - We have investigated the improvement in the quality of life in 384 breast
      reduction patients within a seven-year postoperative follow-up. Through the use
      of a questionnaire (recall of n = 223 patients), we sought to establish the
      patient's most compelling reason for seeking this surgical procedure. In
      addition, the effect of the operation on the patient's quality of life was
      investigated. Preoperatively, the main complaint was pain in the shoulder girdle
      in 77% of the patients, followed by 67% patients suffering from lower and
      thoracic back pain symptoms, whereas 51% defined mastodynia as their primary
      complaint. 95% of the patients noted a remarkable improvement in the quality of
      their professional and social lifes. 94% were able to specify this improvement as
      an increase in the feeling of self-esteem, 53% showed up with amelioration of
      selfconfidence. 95% of the patients felt that the breast reduction had a positive
      influence on their sexual behaviour and personal relationships. Our study reveals
      that breast reduction surgery offers not only an aesthetic improvement but also
      the relief of preoperative pain and discomfort, leading to important improvements
      in the patient's quality of life.

PMID- 10337561
TI  - The past, present, and future of cochlear prostheses.

PMID- 10337562
TI  - Signal-processing techniques for cochlear implants.

PMID- 10337564
TI  - Oscillatory brain theory: a new trend in neuroscience.

PMID- 10337563
TI  - Neuro-electronic interfacing with multielectrode arrays.

PMID- 10337565
TI  - Source analysis of lesional frontal-lobe epilepsy.

PMID- 10337566
TI  - Detecting the onset of epileptic seizures.

PMID- 10337567
TI  - Nonlinear analysis of time series generated by schizophrenic patients.

PMID- 10337568
TI  - Cuff electrodes for long-term recording of natural sensory information.

PMID- 10337569
TI  - Modeling neuronal dynamics-transition during sleep.

PMID- 10337570
TI  - Biomagnetic approaches to studying the brain.

PMID- 10337571
TI  - [Quality. Can the quality management of industry be used in university hospital
      center departments?].

PMID- 10337572
TI  - [Publication of a tool to aid in the implementation of quality measures in
      radiology].

PMID- 10337573
TI  - [Imaging of the cochleo-vestibular system].
AB  - This article will review the main pathologies affecting the vestibulocochlear
      system from the sensorineural organs to the cerebral cortex. MR imaging has
      greatly improved detection of these pathologies. Thin slice MR imaging using
      different pulse sequences now allows improved depiction of anatomical structures.
      Vestibular schwannoma is by far the most common lesion, but MR imaging allows
      detection and characterization of rarer lesions in patients often presenting with
      similar symptoms.

PMID- 10337574
TI  - [Comparison of accreditation procedures, ISO 9000 certification procedures and
      total quality management. Personal experiences and application of quality
      assurance in a department of radiology and medical imaging].
AB  - Management of quality assurance protocols in a radiology department can be done
      by using several tools or models. Some are specific like accreditation manuals
      issued by some organizations, others like the ISO 9000 certification and the
      Total Quality management are more general and already well known by
      manufacturers. In order to implement a process of quality improvement, we have
      reviewed three models of quality assurance: evaluation in total quality based on
      the European model "EFQM", accreditation based on booklets from French cancer
      centers and Canadian radiology centers and, finally, accreditation based on the
      ISO 9002 certification model. Based on results of our comparative study, these
      three tools of quality management are not contradictory and may be complementary.
      However, they can be compared in terms of constraints they impose, of their
      historical background, of the criteria evaluated as well as the role of different
      teams. In conclusion, we suggest that directors of radiology department
      interested in implementing a quality assurance program first evaluate their
      department using the Canadian accreditation model issued in 1993 which is useful
      to become familiar with this new concept of quality. In a second step, a self
      assessment using the EFQM has to be done in collaboration with all members of the
      administration board in order to integrate all parameters and to share this
      protocol with all decision makers. The last step is to consolidate the
      organization of the quality assurance protocols by means of the ISO 9002
      certification.

PMID- 10337575
TI  - [Is ultrasonographic evaluation the the length of the kidney possible in
      children? Apropos of a prospective study in Madagascar children less than 1 year
      of age].
AB  - Renal US was prospectively performed in 124 madagascan children less than 1 year
      of age. Patients were examined in the prone position and maximum kidney length
      was measured in the longitudinal plane. These measurements and the height and
      weight of our patient population were compared to published tables. Kidney length
      and height and weight of our patient population were inferior to the previously
      published reference data and the growth curve of kidneys steeper than normative
      standards (p < 0.001). Because of the important variability in US measurement of
      kidney length it is not possible to definitely conclude that length and growth
      curve of kidneys in madagascan children are statistically different from those of
      the published normative standards.

PMID- 10337576
TI  - [Prognostic aspects of scintigraphy and MRI during the first 6 months of reflex
      sympathetic dystrophy of the distal lower limb: a preliminary prospective study
      of 4 cases].
AB  - PURPOSE: The appearance of scintigraphic and magnetic resonance imaging during
      the evolution of reflex sympathetic dystrophy of the foot is not well known and
      subject to controversies. The purpose of this preliminary study is to compare
      these two types of investigation during the first 6 months of evolution. METHODS:
      4 non-selected patients with a diagnosis of acute reflex sympathetic dystrophy of
      the foot (no more than 2 months of evolution and more than 3 out of 6 clinical
      criteria suggesting a "warm" phase) were studied prospectively. A clinical
      evaluation, scintigraphy and magnetic resonance imaging (MRI) were performed at
      diagnosis and after 3 and 6 months. All available examinations (n = 22) were
      analyzed independently by independent observers. RESULTS: Clinically 3 of 4
      patients developed or previously had another site of sympathetic dystrophy
      confirmed by total body scintigraphy. After 6 months 2 of 4 patients still have a
      "warm" dystrophy. Bone scanning showed localized or diffuse tracer uptake and MRI
      showed bone and soft tissue edema when the sympathetic dystrophy was and/or
      remained clinically "warm". MRI bone edema moved from one location to another in
      3 of 4 patients during the follow-up. There was a good correlation between bone
      scan and MRI images. In "warm" dystrophy, MRI was positive 5 out of 7 times and
      scintigraphy in all cases. Bone edema and tracer uptake faded simultaneously
      although the latter was more diffuse and more persistent than the former.
      CONCLUSION: MRI as well as bone scintigraphy are suitable for the diagnosis of
      warm dystrophy of the foot. Both exams remain positive when the dystrophy is
      still "warm" after 6 months. The radiographic evolution after 6 months still has
      to be evaluated.

PMID- 10337577
TI  - [Snapping scapula: the value of 3D imaging].
AB  - Snapping scapula is a rare and poorly known cause of shoulder pain and is related
      to mechanical impingement between the scapula and the rib cage. We present a case
      in which CT scan was valuable, as a complement to clinical evaluation, for
      demonstrating the bony component of this entity. 3D reconstructions greatly
      facilitated diagnosis.

PMID- 10337578
TI  - [MRI evaluation of placenta accreta treated by embolization. Apropos of a case.
      Review of the literature].
AB  - Placenta accreta results from an abnormal attachment of the placenta to the
      uterine myometrium. The reported incidence in literature is variable, with an
      average of 1/7000 pregnancies. This condition is associated with a significant
      risk of bleeding at the time of delivery, usually requiring hysterectomy.
      Sonography associated with color Doppler is useful for diagnosis, but MRI can be
      used successfully to evaluate the degree of placental tissue invading into the
      myometrium, the serosa, and for follow-up after conservative management. To our
      knowledge, only two cases of placenta accreta evaluated with MR and six cases of
      placenta accreta treated by embolization have been reported in the literature.
      The authors report one case of placenta accreta treated successfully by
      embolization, and followed-up by MRI.

PMID- 10337579
TI  - [Computed tomography imaging of abdominal wall metastases after laparoscopy].
AB  - We report a case of abdominal wall metastases which occurred after diagnostic
      laparoscopy in a 64-year-old man presenting with gallbladder carcinoma and
      peritoneal carcinomatosis. CT showed enhancing masses along the laparoscopic
      tracts, suggesting metastatic seeding at the time of the surgery. This unusual
      complication fuels the current debate regarding indications of laparoscopic
      surgery in patients with malignancy.

PMID- 10337580
TI  - [Congenital aneurysm of the trunk of the pulmonary artery].
AB  - A case of congenital aneurysm of the main pulmonary artery incidentally
      discovered following blunt chest trauma is reported. This anormaly is rare and
      the authors will emphasize the plain radiographic and MRI findings. The etiology
      and evolution of this entity are not well known.

PMID- 10337581
TI  - [What is it? Bourneville tuberous sclerosis associated with an arteriovenous
      malformation, a pituitary adenoma and 2 arachnoid cysts].

PMID- 10337582
TI  - [Angio-MRI of the lower limbs using the moving-bolus technic without subtraction:
      technical note].

PMID- 10337584
TI  - [Non-penetrating deep sclerectomy in the surgical treatment of chronic open-angle
      glaucoma. Mid-term results].
AB  - PURPOSE: Non-penetrating deep sclerectomy has been performed in France since the
      early nineties and appears to be an interesting alternative to Cairn's
      trabeculectomy. The technical characteristics, the ability to use antimitotic
      procedures and postoperative YAG laser goniotomy contribute to make deep
      sclerectomy an attractive surgical method. We evaluated its efficacy and adverse
      effects in a mid-term retrospective series. PATIENTS AND METHODS: Fifty patients
      (all POAG) without usually accepted failure risks for trabeculectomy
      (trabeculoretraction less than 3 months, intraocular anterior or posterior lens,
      aphakia, black or Asian subject, failure of previous surgical procedure, patients
      under 40) underwent this surgical procedure between June 96 and October 97
      performed by several skilled surgeons in our unit. This was the first
      antiglaucoma surgical procedure for all patients. Collagen draining implant was
      not used. Two pressure criteria (21 mmHg and 16 mmHg) were used to assess
      success. Success rate and adverse effects were compared with previously published
      data using the Kaplan-Meier test. RESULTS: Medium follow-up was 14.24 months. The
      success rate was 81% (IOP 21 mmHg) and 50% (IOP 16 mmHg) at maximum follow-up of
      18 months. There was no statistical difference between treated and untreated
      groups for target IOP at 21 mmHg (p = 0.12). These results were comparable to
      those in previous studies and to those obtained with trabeculectomy. The
      complication rate was low (hyphema 0%, choroidal detachment 2%, hypothalamia 2%,
      endocular infection 0%). DISCUSSION: Our success rate and complication rate were
      comparable with previously published series. Choosing a target IOP of 16 mmHg
      allowed a better comparison between daily clinical observations and mid-term
      results, showing a significant difference from the 21 mmHg target. Nevertheless,
      the success rate was comparable to that obtained with trabeculectomy and the
      complication rate was lower, supporting the favorable opinion concerning deep
      sclerectomy. CONCLUSION: Non-penetrating deep sclerectomy appears to be as
      efficient as Cairn's trabeculectomy for surgical treatment of glaucoma and allows
      a lower complication rate. Long-term results, visual field and papilla remain to
      be evaluated. Furthermore, results with a pressure goal of 16 mmHg are
      interesting to evaluate because they reflect the real clinical situation better
      than the target 21 mmHg IOP. This technique should be evaluated in other forms of
      glaucoma.

PMID- 10337585
TI  - [Treatment of unilateral limbal stem cell deficiency syndrome by limbal
      autograft].
AB  - PURPOSE: To evaluate the improvement of the ocular surface after limbal autograft
      in patients with unilateral limbal stem cell deficiency related to chemical
      burns. MATERIALS AND METHODS: Limbal autograft was performed in five patients
      with unilateral limbal stem cell deficiency related to chemical burns.
      Thereafter, four patients underwent penetrating keratoplasty. The limbal graft
      was obtained from the fellow eye, and was secured with interrupted sutures.
      Patient follow-up ranged from 10 to 47 months. Limbus and corneas were studied by
      means of light microscopy. RESULTS: All five patients reported subjective
      improvement. Vascularization decreased in one cornea. Visual acuity improved in
      one eye and did not change in the remaining four eyes. After penetrating
      keratoplasty, graft reepithelialization was achieved after respectively 3, 4, 21,
      and 30 days. Light microscopy showed the presence of goblet cells in the limbal
      epithelium in four cases. After limbal autograft, the corneal epithelium was
      devoid of goblet cells in three out of four cases. CONCLUSION: Limbal autograft
      improves the ocular surface and the prognosis of subsequent penetrating
      keratoplasty in patients with unilateral limbal stem cell deficiency related to
      chemical burn.

PMID- 10337586
TI  - [Central retinal vein occlusion and opto-ciliary shunts. An angiographic
      diagnosis].
AB  - Opto-ciliary shunts are compensatory bypass channels from the retinal venous
      system to the choroidal veins in case of long standing central retinal vein
      occlusion. Indocyanine green angiography with the Scanning Laser Ophtalmoscope
      may be helpful to differentiate acquired optociliary shunts from retinal or
      choroidal arteriovenous malformations.

PMID- 10337587
TI  - [Prognostic factors in malignant melanoma of the conjunctiva. An anatomo-clinical
      study of 56 patients].
AB  - We have reviewed a serie of 56 patients treated in our Institute for malignant
      melanoma of the conjunctiva between 1980 and 1992. We selected cases where
      histology had been reviewed. PATIENTS AND METHOD: The median follow up is 96
      months. The age varies from 13 to 88 years with a mean age of 56 years. There
      were 22 men and 34 females. In 29 cases (51%) the melanoma appeared de novo, ten
      cases (17%) it derived from a naevus and in 14 cases (25%) on a precancerous
      melanosis. The tumour was localized at the limbus and bulbar conjunctiva in 57%
      of cases. The mean diameter was 6.1 mm and the mean thickness was 2.3 mm. The
      treatment consisted in surgical excision of the tumour followed by external beam
      radiotherapy in 49 cases. Histological examination showed invasion of the chorion
      in 44 cases (78%) and of the sclera in 6 cases (1%). RESULTS: 38 patients are
      alive and 29 without disease. 2 with disease, 7 lost follow-up. 18 patients died
      (32%) and among them 14 (25%) died of metastatic disease. 22 patients (39%) have
      presented local recurrence and among them 10 have had multiple recurrences. The
      mean delay for recurrence was 56 months. The overall survival was 77% at 5 years
      and 64% at 10 years. Tumours appeared de novo have a worse prognosis. If we
      consider the localization tumour located at the limbus or on bulbar conjunctiva
      have less metastasis. CONCLUSION: Malignant melanoma of conjunctiva is a tumour
      that can frequently recur. Metastasis are not infrequent and follow up must be
      prolonged.

PMID- 10337589
TI  - [Hydatid orbital cyst: a unique intra-orbital locality. A case report].
AB  - Orbital hydatidosis is uncommon, accounting for 1 to 2% of all localizations. It
      is caused by Echinococcus granulosis, a dog parasite tapeworm. We report an intra
      orbital hydatid cyst observed in a five-year-old boy, presenting the main
      features of this unusual localization. Hydatid cyst should be evoked in case of
      tumorous exophthalmia in young patients, especially in children having lived in
      endemic zones. The preoperative diagnosis is based on clinical findings and
      ultrasonographic, computed tomographic and magnetic resonance imaging findings.
      The fronto-orbital approach is most commonly used for treatment. Infectious and
      functional prognosis depends on early surgery.

PMID- 10337588
TI  - [Myopic anterior chamber intraocular lens implantation: evaluation at 8 years].
AB  - PURPOSE: The aim of this study was to analyse the tolerance of Myopic Anterior
      Chamber IOL's 8 years after surgery. MATERIAL AND METHODS: We have studied 21
      eyes implanted with an anterior chamber phakic IOL between May 1989 and June
      1990. The 21 eyes had a very high myopia (mean pre-operative myopia--13.5
      Dipters). Surgical technique was easy, without peroperative complications.
      RESULTS: Post-operative refractive results were excellent with a mean refraction
      of -0.25 D. Post-operative complications were a pupillary ovalisation in 42% of
      the eyes and glare in 50% of the eyes. Specular microscopy was normal pre
      operatively for all the eyes but at 8 years, 4 (19%) of the eyes have had a
      strong loss of their endothelial cells and have to be explanted. Decreasing of
      endothelial cells is the most severe complication occurring after Phakic anterior
      chamber myopic IOL implantation. CONCLUSION: These 21 Myopic Anterior chamber
      IOL's have given a very good refractive result for all the eyes. 4 (19%) of the
      eyes operated on with these IOL's had a decreasing of their endothelial cells and
      the IOL had to be removed. Rigourous follow-up of the implanted eyes is required.

PMID- 10337590
TI  - [Fluctuations in uncorrected visual acuity after refractive surgery using intra
      stromal corneal rings].
AB  - PURPOSE: Refractive surgery is meant to provide early stable and good uncorrected
      visual acuity. Our main concern in this study was to take special interest in
      fluctuation in uncorrected acuity within the first three months after
      implantation of Schanzlin intracorneal ring segments (ICRS) produced by
      Keravision. PATIENTS AND METHODS: Ten eyes in 6 patients underwent implantation
      of 2 intrastromal corneal segments for myopias ranging from -1.00 to -3.50
      Dipoters. Visual acuity was measured with cytoplegy on day one, on day 8, two
      weeks, 1 month, and 2 months after surgery. The fluctuations of visual acuity
      were noted between observations. RESULTS: Uncorrected visual acuity varied up to
      4 lines without an obvious pattern of progression over time. Fifty percent of the
      eyes had a variation of 2 lines. The best spectacle corrected visual acuity was
      preserved in all patients. DISCUSSION: Corneal topography with measurement of
      keratometry, intraocular pressure, and examination of the anterior chamber must
      be studied to identify the parameter that could condition these fluctuations of
      visual acuity. No parameter was found to predict these variations that may result
      from individual corneal healing factors peculiar to each patient. The
      fluctuations of uncorrected visual acuity were relatively important during the 3
      first postoperative months. In all patients, final uncorrected visual acuity was
      always at least 10/10.

PMID- 10337592
TI  - [Scleral mini-incision without ultrasound in the treatment of congenital
      cataract].
AB  - PURPOSE: Congenital cataract surgery can be performed by pars plana or limbal
      incision. We report our experience with scleral incision without ultrasounds in
      congenital cataract surgery. MATERIAL AND METHODS: Fifteen children with
      congenital cataract underwent surgery of both eyes (30 eyes). The zonular
      ciliaris and the lens anlage were normal in all cases. All procedures were
      performed by the same surgeon. A 3.2 mm scleral tunnel incision was made 2 mm
      from the limbus. Large capsulorhexis or capsulopuncture were performed after
      injection of a viscoelastic substance in the anterior chamber. After
      hydrodissection, the nucleus and cortex were aspirated. The wound was closed by
      apposition suture. RESULTS: The mean age was 70.13 months (range 5 months to 130
      months). Mean induced astimatism calculated with the Cravy method was 0.70
      dipoters. A posterior capsular tear was observed in 1 case. CONCLUSION: Small
      scleral incision without ultrasounds has advantages. No expensive instruments are
      required and astimatism is not induced. The anterior chamber lies deep during the
      operation, protecting the endothelial cells and facilitating aspiration.
      Postoperative inflammation is minimal. The small scleral incision technique is
      useful in selected cases of congenital cataract.

PMID- 10337591
TI  - [Cyclin-dependent kinase inhibitory proteins in normal and transformed choroidal
      melanocytes].
AB  - PURPOSE: Recent studies have demonstrated the close link between oncogenesis and
      cell cycle machinery. Cyclin dependent kinase inhibitory proteins (Ckis) have
      been shown to be implicated in cancer progression. We investigated the levels of
      the different regulatory inhibitory proteins involved in the G1 progression and
      G1/S in choroidal melanomas. METHODS: Immunoblotting, immunoprecipitation and
      immunohistochemistry were performed on human choroidal cell lines and human
      choroidal tumors. RESULTS: Our findings suggested a lack of expression of Cdk
      inhibitor p21 in two of three melanoma cell lines and a striking underexpression
      of p27 in the three transformed cell lines. The p16 level was found to be almost
      the same in both normal and transformed cells, a loss of p16-Cdk4 interaction was
      observed in two of the three melanoma cell lines. In immunohistochemistry,
      nuclear positivity for p16 was observed in six tumors. Nuclear positivity for p21
      was observed in five tumors. All of theses tumors had scleral invasion (p =
      0.003). Nuclear positivity for p27 was observed in only two tumors. CONCLUSION:
      Our results demonstrate that immunoreactivity for p16, p21 and p27 could be
      implicated in progression of melanoma tumors. More cases are required to further
      clarify this issue.

PMID- 10337593
TI  - [Pseudophakia and aptitude of aviation personnel].
AB  - Because of sensorial disruptions, aphakia post-cataract surgery is a cause of
      unfitness for the job of aeronautics flying personnel. Its correction thanks to
      intraocular lenses and a correct functional check-up permit to reconsider the
      fitness through a derogation given by the competent authorities. EQUIPMENT AND
      METHODS: The authors realized a retrospective study on the 5 last years. 27
      flying personnel, 24 to 76 years old, went through a cataract surgery with
      implantation. The check-up includes a chemical exam completed by a morphoscopic,
      coloured and spatial study. RESULTS AND DISCUSSION: The files are more or less
      well-documented according to their origin. The flying personnel have an average
      of 4,010 flying hours. The average post-operative hindsight is 30 months. 3 wear
      intraocular lenses of rear chamber among which 1 is multifocal. 7 were examinated
      at the CPEMPN with satisfying morphoscopic, coloured and luminous sense
      compatible with the fitness. 4 are declared permanent unfit (1 professional pilot
      with bad results, 1 private pilot with other pathologies, 1 inexperienced
      stewardess getting through the admission visit with insufficient post-operative
      hindsight, 1 professional pilot declared unfit for its military activity in the
      reserve). 4 are qualified with restriction. 20 are qualified without restriction.
      CONCLUSION: The correction of aphakia with intraocular lenses permits in most
      cases to obtain good functional results compatible with the flying aptitude.

PMID- 10337594
TI  - [Indications and results of surgical removal of "congenital" epimacular
      membranes].
AB  - INTRODUCTION: Congenital epimacular membranes differ from acquired membranes of
      young adults by their slow evolution and absence of vitreously their cortex
      detachment. CLINICAL CASES: We report five observations. In all these cases of
      unilateral maculopathy, no etiologic factors were found. Surgical removal was
      required in only two of these cases. RESULTS: These membranes were whitish and
      presented extensions along retinal vessals to which they were very adhesive. The
      absence of posterior vitreous detachment was confirmed during vitrectomy and
      histopathologic examination found a predominance of extracellular matrix.
      DISCUSSION: In these idiopathic membranes, clinical and histopathological
      findings evoke a dysembryopathy. Surgery decision must attach great importance to
      the relative amblyopia of these eyes, the low evolutivity and the risks of
      iatrogenic tears during dissection.

PMID- 10337595
TI  - [Congenital hypertrophy of retinal pigment epithelium: a marker in familial
      adenomatous polyposis].
AB  - PURPOSE: Familial adenomatous polyposis (FAP) is an inherited autosomal dominant
      disorder with marked propensity for malignant transformation. The potential for
      congenital hypertrophy of retinal pigment epithelium (CHRPE) as a phenotypic
      marker for this disease is recognized. MATERIAL AND METHODS: We report our
      investigations in 11 families with familial adenomatous polyposis. CHRPE
      characteristics were described and the relations between genotype and phenotype
      and those between CHRPE and severity of FAP are discussed. DISCUSSION: All
      members of the family should undergo retinal examination at the earliest age
      possible. The results give an indication of the severity of the intestinal
      disease and allow an approximate localization of the mutation in the coding
      sequence, leading to a more rapid genetic analysis.

PMID- 10337596
TI  - [Bacillary endophthalmitis. Four case reports].
AB  - PURPOSE: Bacillary endophthalmitis occurring after penetrating ocular trauma with
      an intraocular foreign body is always associated with poor visual outcome.
      Bacilli cause fulminant infection associated with tissue damage in the
      intraocular structures. CASE REPORTS: Our series consisted of four patients with
      penetrating ocular trauma and endophthalmitis caused by B. cereus or B.
      licheniformis. Three eyes ultimately developed phtisis. Only on eye recovered
      good vision (2.5/10 P4). DISCUSSION: Recommended early treatment includes
      topical, subconjunctival, parenteral antibiotics. A review of the literature
      indicates that intravitreal antibiotic infusion is crucial for sufficient
      concentration to control infection. Early vitrectomy is recommended in the
      management of endophthalmitis. Vitreous and intraocular foreign bodies should be
      cultured to identify pathogens and ascertain antibiotic susceptibilities.

PMID- 10337597
TI  - [Non-traumatic orbital diseases in Lausanne from 1965 to 1996].
AB  - PURPOSE: Describe our series of patients with non-traumatic orbital diseases.
      PATIENTS AND METHODS: A series of patients with non-traumatic orbital diseases
      seen in Lausanne from 1965 to 1996. RESULTS: Inflammatory conditions and
      infections were the most frequently observed diseases. Pseudotumors were the most
      representative. Orbital involvement in systemic diseases (for example Graves'
      disease), vascular tumors and malformations, as well as orbital involvement in
      rhinological diseases were also often observed. Orbital cysts, particularly
      dermoid and epidermoid cysts, and orbital diseases of nervous origin were
      exceptional. Finally, diseases of the lacrimal gland, metastases, secondary
      tumors from adjacent structures and diseases of mesenchymal origin were more
      rare. DISCUSSION: This study also reports the proportion of male and female
      patients and the percentage of proptosis.

PMID- 10337598
TI  - [Simplified electroretinography protocol and diagnosis of retinal dystrophies in
      children].
AB  - PURPOSE: To report results of a simplified electroretinogram in children.
      PATIENTS: 124 children under 6 years of age with nystagmus, blindness,
      neurological disease, cone rod dystrophy in the family, or abnormal fundus
      appearance were examined. METHOD: The electroretinogram was recorded by corneal
      electrodes in an awake state without sedation. A light-emitting orange diode
      stimulator was used. Stimulation was performed subsequently after 3 minutes of
      light adaptation and after 8 minutes of darkness. If the electroretinogram was
      abnormal, a second recording was done a few weeks later using the same method. In
      some cases, the children were re-examined, and a ganzfeld stimulation ERG was
      recorded. RESULTS AND DISCUSSION: This method allowed a reliable diagnosis of
      photoreceptor dystrophy: Leber's congenital amaurosis with or without rare
      metabolic diseases, X link pigmentary retinopathy or retinal dystrophy with
      general disease in children. It helped to differentiate isolated retinal pigment
      changes with normal electroretinogram from functional retinal impairment and rod
      cone dystrophy from other retinal dystrophies.

PMID- 10337599
TI  - [Isolated occlusion of a cilioretinal artery].
AB  - PURPOSE: Isolated cilioretinal artery occlusion is uncommon but has
      characteristic features. Based on a case report and a review of the literature,
      we present the clinical findings and angiographic particularities of this
      syndrome and discuss controversial pathophysiological data. CASE REPORT AND
      METHOD: A 56-year-old man had sudden visual loss in the right eye estimated at
      3/10 P10. Fundus examination showed areas of retinal interpapillomacular
      infarction due to cilioretinal artery occlusion. Fluorescein angiography
      demonstrated delayed filling and emptying of this artery. Left fundus examination
      was normal. RESULTS: Systemic examinations revealed severe hypertension (240/130)
      rapidly controlled with a two-drug regimen. The clinical course was good with
      normalization of fundus and angiography, and visual recovery to 8/10 P3 with a
      small absolute paracentral scotoma. DISCUSSION: The few cases described would
      offer an explanation of the low prevalence of cilioretinal arteries and the more
      frequent association with central retina venous obstruction which can mask
      arterial occlusion. A relative reversible occlusion explains the generally good
      prognosis especially if the capillary network is not affected by the occluded
      artery as was observed in our case. CONCLUSION: Although diagnosis of isolated
      cilioretinal artery occlusion is made without difficulty, the underlying
      pathogenic mechanism remains difficult to explain due to the various phenomena
      revealed by the increased arterial pressure.

PMID- 10337600
TI  - [Epidemiology of orbital processes in children. 54 cases].
AB  - PURPOSE: The aim of this work was to study epidemiological aspect of orbital
      processes occurring in childhood. PATIENTS AND METHODS: Fifty-four cases of
      orbital processes treated between January 1990 and January 1997 were
      retrospectively reviewed. RESULTS: Mean patient age was 4.2 years (range 1 to
      15), 36 were males and 18 were females. Proptosis was the first manifestation in
      34 cases, other manifestations were low vision (8 cases), ocular pain (14 cases),
      inflammatory signs (11 cases), ocular palsy (14 cases). The first cause of these
      processes was secondary tumors, especially retinoblastoma (13 cases). Other
      causes were rhabdomyosarcoma (9 cases), orbital hydatic cyst (8 cases),
      inflammatory pseudotumors (7 cases), capillary hemanigoma (4 cases) chloroma (3
      cases), glioma (1 case), lymphangioma (8 cases), and mucocele (1 case).
      DISCUSSION: We emphasize the particular epidemiological aspect of orbital
      processes in Moroccan children where retinoblastoma predominates and compare our
      findings with data in the literature.

PMID- 10337601
TI  - [Anterior chamber and retinal detachment].

PMID- 10337602
TI  - [Ophthalmologic complications of diabetes except for diabetic retinopathy].

PMID- 10337603
TI  - Hazards for nearby residents and cleanup workers of waste sites.
AB  - This study weighs the risks to workers of cleaning up Superfund sites against the
      risks to residents if the sites were not cleaned up. Risks are measured by the
      number of deaths and disabilities due to injuries and diseases, as well as by the
      costs of these deaths and disabilities. We posit three methods to clean up the
      sites: one that is labor-intensive and two that are not. We posit 24 hypothetical
      sites, with varying numbers of residents and levels of cancer death and cancer
      disability rates. Depending on the cleanup method, the number of residents, and
      the rates, we find that the risks to workers frequently outweigh the risks to
      residents. We conclude that risks to workers should be accounted for in
      Environmental Protection Agency judgments regarding which and how Superfund sites
      should be cleaned up.

PMID- 10337605
TI  - Decision model for optimizing respirator protection.
AB  - Respirators are widely used for protection against inhaled toxins. The emphasis
      of research and implementation effort has evolved through several stages: the
      respirator device itself, use situation, respirator program factors under
      employer control, individual worker factors not under employer control, and
      occupational health systems. For this study, a computer-simulation decision
      assistance model was developed to assess the impact of various factors on the
      number of workers receiving adequate protection. Factors include the respirator
      protection factor, identification of sites needing respirator protection,
      selection of proper device, availability when needed, frequency of ever use,
      regularity of use among users, and variability in personal susceptibility or
      other factors. This analysis demonstrates that for both moderate-risk and high
      risk (i.e., IDLH, immediately dangerous to life and health) exposures under
      current circumstances, the actual protection afforded depends upon the
      optimization of program factors and detection of atypical outlier persons and
      worksites. Therefore, programs and research must focus on these areas.
      Occupational medicine specialists should help optimize these areas and, in
      addition, use each case of respiratory protection failure as an index case to
      improve the overall programs.

PMID- 10337604
TI  - Relationship of lead in drinking water to bone lead levels twenty years later in
      Boston men: the Normative Aging Study.
AB  - Tap water in a city like Boston, which has old houses containing lead plumbing,
      is known to be a significant source of potential lead exposure. Bone lead levels
      integrate exposure over many years, and in vivo bone lead measurements have
      recently become possible with the advent of K x-ray fluorescence instruments.
      Thus we examined the relationship between first morning tap-water lead levels
      measured in homes in the 1970s and levels of lead in bone measured in the 1990s
      among middle-aged to elderly men who lived in those homes. We studied 129
      participants in the Normative Aging Study who had lead measured in their homes'
      tap water in 1976 and 1977 by graphite furnace-atomic absorption
      spectrophotometry. From 1991 to 1995, the same subjects had blood lead levels
      measured by graphite furnace-atomic absorption spectroscopy and tibia and patella
      bone lead levels measured by K x-ray fluorescence. We ran multivariate linear
      regression models predicting bone lead levels that adjusted for factors which had
      previously been linked with this outcome in the Normative Aging Study (age, pack
      years of smoking, and educational level). Among subjects who lived in houses with
      > or = 50 micrograms lead/liter of first morning tap water representing water
      that had been standing overnight in the plumbing in 1976 and 1977, those who
      reported medium or high levels of tap-water ingestion (> or = 1 glass/day) had
      progressively higher patella lead levels than did those with low levels of
      ingestion (< 1 glass/day). No such relationship was found among subjects who
      lived in houses with < 50 micrograms lead/liter of first morning tap water in
      1976 and 1977. We conclude that ingestion of lead-contaminated tap water is an
      important predictor of elevated bone lead levels later in life.

PMID- 10337606
TI  - Multiple chemical sensitivity: a test of the olfactory-limbic model.
AB  - Thus far, no neuropsychological study has examined the cognitive profile of
      multiple chemical sensitivity (MCS) within the framework of Bell's Olfactory
      Limbic Model. It predicts that cognitive weaknesses will be associated more with
      limbic (i.e., frontal and/or temporal lobe) than with non-limbic (i.e., posterior
      cortex) brain regions. Matched MCS, asthma, and healthy control groups (n = 63)
      were tested on cognitive measures with localizing value. Between-group
      comparisons found that the MCS group performed as well as controls on all
      cognitive tasks. Within-group comparisons found that both the MCS and asthma
      groups performed significantly more poorly on tasks that were sensitive to
      frontal and temporal regions than to posterior regions. Additional research is
      needed before concluding that the Olfactory-Limbic Model adequately describes the
      cognitive strengths and weaknesses of MCS. Confounding factors such as medication
      use and chronic illness need to be considered.

PMID- 10337607
TI  - Evaluation of pulmonary function in workers exposed to hexamethylene
      diisocyanate.
AB  - Production of hexamethylene diisocyanate (HDI) biuret and trimer from HDI monomer
      was started in 1988 at the plant under study. Pulmonary function tests were
      included as part of the annual evaluation of the workers in that unit. HDI is
      expected to have toxic properties similar to those of toluene diisocyanate. The
      latter has caused accelerated declines in pulmonary function in exposed workers.
      In 1991, an initial longitudinal evaluation of those pulmonary function tests was
      performed, comparing annual declines in forced vital capacity (FVC) and forced
      expiratory volume in 1 second (FEV1). The purpose of the study was to evaluate
      whether or not exposures to HDI at the unit had caused any accelerated decline in
      FVC or FEV1. No significant differences were seen in that evaluation, but it was
      decided that the study be continued in a prospective fashion. The study has been
      continued through 1997. The slope of the annual change in FVC and FEV1 were
      calculated for a group of workers and a matched control group. The average annual
      decline in FVC for the exposed group (cases) was 0.026 L, compared with 0.025 L
      for the control group. For the decline in FEV1, the results were 0.044 L,
      compared with 0.041 L (P = 0.79). These results are virtually identical and
      support a conclusion that exposures within this unit to HDI have not caused an
      accelerated decline in FVC or FEV1. Exposures to HDI were measured during this
      period. The time-weighted average exposure to HDI during work not requiring
      respiratory protection in the unit (approximately 2 hours per day) was 0.5 parts
      per billion. The average daily high peak exposure was 2.9 parts per billion.
      Exposure to these levels appear to pose no risk of accelerated decline in
      pulmonary function.

PMID- 10337608
TI  - Psychological conditions diagnosed among veterans seeking Department of Defense
      Care for Gulf War-related health concerns.
AB  - The Comprehensive Clinical Evaluation Program is a US military program that
      provides a voluntary, clinically oriented evaluation for Gulf War health
      concerns. This article presents administrative data on psychological conditions
      (as coded using the International Classification of Diseases, 9th Revision) from
      the first year of the program. The most commonly diagnosed psychological
      conditions were medically unexplained physical-symptom syndromes; depression and
      anxiety, including post-traumatic stress disorder; and alcohol abuse or
      dependence. Psychological conditions were significantly related to a higher
      number of workdays lost, and the 19% of veterans with a primary diagnosis of a
      psychological condition reported 28% of the lost workdays among veteran who
      participated. Stressful Gulf War experiences were weakly but significantly
      related to psychological conditions. We conclude that among Gulf War veterans
      seeking evaluation for Gulf War-related health concerns, psychological conditions
      are common and are associated with important occupational morbidity.

PMID- 10337609
TI  - Evaluation of the two-step tuberculin skin test in health care workers at an
      inner-city medical center.
AB  - The increased rate of tuberculosis (TB) infection and transmission from patients
      to health care workers (HCWs) has brought awareness of the need for better
      surveillance programs. The two-step purified protein derivative (PPD) skin test
      decreases the misinterpretation of a "boosted reaction" as a recent infection
      with Mycobacterium tuberculosis in HCWs. We reviewed the medical records of 4082
      HCWs at an inner-city medical center who had PPD skin-testing performed as a
      component of the TB medical surveillance program during the years 1994 and 1995.
      Of those HCWs tested, 3896 (95.4%) returned for the PPD skin-test evaluation. Of
      those 3896 HCWs, 3659 (93.9%) had a negative baseline PPD skin test, and 237
      (6.1%) had a positive skin test. Of those HCWs with a negative baseline skin
      test, 252 (6.9%) were eligible for the second PPD skin test. Of the 241 who
      returned for their second PPD skin-test reading, six (2.5%) had positive results.
      All six cases were foreign-born physician residents with a previous history of
      Bacille bilie de Calmette-Guerin (BCG) vaccination. We conclude that the two-step
      PPD skin test method is not indicted for HCWs at this urban medical facility.

PMID- 10337610
TI  - Clinical practices in the management of new-onset, uncomplicated, low back
      workers' compensation disability claims.
AB  - Recent consensus guidelines delineate what appears to be the most successful and
      cost-effective management of low back pain (LBP), and some recent studies have
      suggested that better outcomes occur with the least aggressive forms of medical
      intervention. The purpose of this study was to describe how practitioners manage
      new-onset, uncomplicated low back workers' compensation (WC) disability cases. A
      sample of cases was randomly selected from a large insurance carrier's national
      data source. An effort was made to select only uncomplicated cases, which would
      be expected to have relatively minimal need for medical intervention. There was
      an apparent overuse of diagnostic and treatment modalities. Diagnostic imaging
      was overutilized, not only in terms of the number of studies done (65% had plain
      films, 22% had magnetic resonance imaging scans) but also in the time frame in
      which they were performed (38% had plain films on the first clinic visit). Ninety
      percent received at least one medication, and 38% received more than one
      prescription for opioid analgesics. Expensive non-steroidal anti-inflammatory
      drugs were prescribed more often than acetaminophen (61% versus 6%,
      respectively). Sixty-two percent received physical therapy that often included
      modalities with as yet unproven efficacy. Overutilization of either diagnostic or
      treatment procedures increases the likelihood of iatrogenic complications, is not
      cost-effective, and may adversely impact clinical and occupational outcomes.

PMID- 10337611
TI  - A multi-modality assessment of peripheral nerve function in organophosphate
      pesticide applicators.
AB  - Health effects from chronic, low-level exposure to organophosphate pesticides
      have not been studied extensively and are not well-established. This report
      follows up a study in New York State in which a cohort of 90 male pesticide
      applicators were found to have increased vibration sensitivity thresholds,
      compared with a matched sample drawn from the general population. This
      investigation examined the nature and extent of peripheral nerve abnormalities in
      a small subgroup of the original cohort. Of the nine subjects studied, four had
      clinical evidence of peripheral neuropathic dysfunction, and one who was normal
      physiologically showed electrophysiological abnormalities. The remaining four
      showed no clinical, electrophysiologic, or quantitative signs or other
      abnormalities. This study adds to the growing evidence that organophosphates are
      toxic to the peripheral nervous system at levels of exposure that do not induce
      acute or subacute symptomatology.

PMID- 10337612
TI  - Has perchlorate in drinking water increased the rate of congenital
      hypothyroidism?
AB  - Perchlorate, known to inhibit the human thyroid at doses above 200 mg/day, was
      detected in the drinking-water supplies of seven counties in California and
      Nevada at levels of 4 to 16 micrograms/L in 1997. The data from the neonatal
      screening programs of the state health departments in these two states were
      analyzed for any increased incidence of congenital hypothyroidism in those
      counties. County-specific, ethnicity-specific data for Nevada and California were
      obtained for 1996 and 1997. Within these seven counties, nearly 700,000 newborns
      had been screened. In all, 249 cases were identified, where 243 were expected,
      for an overall risk ratio of 1.0 (95% confidence interval, 0.9 to 1.2). The risk
      ratios for the individual counties ranged between 0.6 and 1.1. These data in this
      ecological analysis do not indicate an increase in the incidence of congenital
      hypothyroidism with the reported perchlorate levels.

PMID- 10337613
TI  - Quantitative trait loci affecting risk for pentobarbital withdrawal map near
      alcohol withdrawal loci on mouse chromosomes 1, 4, and 11.
AB  - Barbiturate dependence is associated with the development of physiological
      dependence (withdrawal), tolerance, or a maladaptive pattern of drug use.
      Analysis of strain and individual differences with animal models for
      physiological dependence liability are useful means to identify potential genetic
      determinants of liability in humans. Behavioral and quantitative trait locus
      (QTL) mapping analyses were conducted with mice that are resistant versus
      sensitive to pentobarbital withdrawal. With a multistage genetic mapping
      strategy, a pentobarbital withdrawal QTL (Pbw1) was mapped to the distal region
      of mouse Chromosome (Chr) 1 and may be identical to an alcohol withdrawal QTL
      mapped to this chromosomal region. Two suggestive QTLs for pentobarbital
      withdrawal, both in proximity to QTLs definitely mapped for alcohol withdrawal,
      were also tentatively identified. These were on Chr 11 in proximity to a gene
      cluster including several members of the GABAA receptor gene family, and on Chr 4
      near a locus associated with beta-carboline-induced seizure severity. These data
      represent the first detection and mapping of loci influencing risk for
      physiological dependence on barbiturates, and suggest the involvement of common
      genes in physiological dependence on pentobarbital and alcohol.

PMID- 10337614
TI  - Sequence-ready physical map of the mouse chromosome 16 region with conserved
      synteny to the human velocardiofacial syndrome region on 22q11.2.
AB  - Proximal mouse Chromosome (Chr) 16 shows conserved synteny with human Chrs 16, 8,
      22, and 3. The mouse Chr 16/human Chr 22 conserved synteny region includes the
      DiGeorge/Velocardiofacial syndrome region of human Chr 22q11.2. A physical map of
      the entire mouse Chr 16/human Chr 22 region of conserved synteny has been
      constructed to provide a substrate for gene discovery, genomic sequencing, and
      animal model development. A YAC contig was constructed that extends ca. 5.4 Mb
      from a region of conserved synteny with human Chr 8 at Prkdc through the region
      conserved with human Chr 3 at DVL3. Sixty-one markers including 37 genes are
      mapped with average marker spacing of 90 kb. Physical distance was determined
      across the 2.6-Mb region from D16Mit74 to Hira with YAC fragmentation. The
      central region from D16Jhu28 to Igl-C1 was converted into BAC and PAC clones,
      further refining the physical map and providing sequence-ready template. The gene
      content and borders of three blocks of conserved linkage between human Chr
      22q11.2 mouse Chr 16 are refined.

PMID- 10337615
TI  - Sequence and genomic organization of the mouse Lim1 gene.
AB  - The sequence and genomic organization of the mouse Lim1 gene were determined. The
      mouse Lim1 gene has five coding exons. The Lim1 transcription initiation start
      site was determined by 5' RACE. indicating that the first exon encodes the
      translation initiation codon and a 1360-bp 5' untranslated region. Sequence
      analysis of the 450-bp upstream of the transcription start site revealed the
      presence of a CATTAA motif at -32 bp and a CAATT box located in reverse
      orientation at -68 bp. HNF3 beta and Pbx1 binding sites were also identified.
      Like most LIM domain encoding genes, the LIM domains of Lim1 are each encoded on
      separate and adjacent exons. Knowledge of the sequence and structure of the mouse
      Lim1 gene provides important information for the genetic manipulation of the Lim1
      locus.

PMID- 10337616
TI  - Mouse male sterility and histoincompatibility (mshi) maps between the
      D10Mit51/168/212 cluster and D10Mit213.
AB  - The recessive male sterility and histoincompatibility (mshi) mutation in the
      mouse generates pleiotropic effects on graft transplantation and male
      reproduction. Previous analysis of backcross mice typed for mshi either by
      testicular morphology or by allograft rejection has located each trait to a 20-cM
      region on proximal mouse Chr 10. Here we present the microsatellite polymorphism
      analysis of a new 276-member intraspecific backcross panel--including a set of
      135 males typed for sterility and histoincompatibility--that places both features
      controlled by mshi within a 1.7-cM interval between markers D10Mit51/168/212 and
      D10Mit213. In addition, this analysis has allowed an explicit test of a two-gene
      model for the mshi locus and has provided a measurement of the penetrance of the
      mshi-generated histogenic phenotype in both male (88.4 +/- 3.9%) and female (91.0
      +/- 3.5%) mutants. The fine-structure map presented should facilitate a
      chromosome walk across this region and, ultimately, the molecular identification
      of the gene or genes affected by this interesting mutation.

PMID- 10337617
TI  - Cloning and characterization of the mouse interleukin enhancer binding factor 3
      (Ilf3) homolog in a screen for RNA binding proteins.
AB  - In a screen for RNA-binding proteins expressed during murine spermatogenesis, we
      have identified a cDNA that encodes a protein of 911 amino acids that contains
      two copies of the double-stranded RNA-binding motif and has 80% identity with
      human Interleukin Enhancer Binding Factor 3 (ILF3). Linkage and cytogenetic
      analyses localized the Ilf3 cDNA to a portion of mouse Chr 9, which shows
      conserved synteny with a region of human Chr 19 where the human ILF3 gene had
      been previously localized, supporting that we had cloned the murine homolog of
      ILF3. Northern analysis indicated the Ilf3 gene is ubiquitously expressed in
      mouse adult tissues with high levels of expression in the brain, thymus, testis,
      and ovary. Polyclonal antibodies detected multiple protein species in a subset of
      the tissues expressing Ilf3 RNA. Immunoreactive species are present at high
      levels in the thymus, testis, ovary, and the spleen to a lesser extent. The high
      degree of sequence similarity between the mouse ILF3 protein and other dsRNA
      binding motif-containing proteins suggests a role in RNA metabolism, while the
      differential expression indicates the mouse ILF3 protein predominantly functions
      in tissues containing developing lymphocyte and germ cells.

PMID- 10337619
TI  - Genomic organization of the rat alpha 2u-globulin gene cluster.
AB  - The alpha 2u-globulin are a group of similar proteins, belonging to the lipocalin
      superfamily of proteins, that are synthesized in a subset of secretory tissues in
      rats. The many alpha 2u-globulin isoforms are encoded by a multigene family that
      exhibits extensive homology. Despite a high degree of sequence identity,
      individual family members show diverse expression patterns involving complex
      hormonal, tissue-specific, and developmental regulation. Analysis suggests that
      there are approximately 20 alpha 2u-globulin genes in the rat genome. We have
      used fluorescence in situ hybridization (FISH) to show that the alpha 2u-globulin
      genes are clustered at a single site on rat Chromosome (Chr) 5 (5q22-24).
      Southern blots of rat genomic DNA separated by pulsed field gel electrophoresis
      indicated that the alpha 2u-globulin genes are contained on two NruI fragments
      with a total size of 880 kbp. Analysis of three P1 clones containing alpha 2u
      globulin genes indicated that the alpha 2u-globulin genes are tandemly arranged
      in a head-to-tail fashion. The organization of the alpha 2u-globulin genes in the
      rat as a tandem array of single genes differs from the homologous major urinary
      protein genes in the mouse, which are organized as tandem arrays of divergently
      oriented gene pairs. The structure of these gene clusters may have consequences
      for the proposed function, as a pheromone transporter, for the protein products
      encoded by these genes.

PMID- 10337618
TI  - Gene-environment interaction: a significant diet-dependent obesity locus
      demonstrated in a congenic segment on mouse chromosome 7.
AB  - We have previously reported suggestive evidence for a locus on Chromosome (Chr) 7
      that affects adiposity in F2 mice from a CAST/Ei x C57BL/6J intercross fed a high
      fat diet. Here we characterize the effect of a high-fat (32.6 Kcal% fat) diet on
      male and female congenic mice with a C57BL/6J background and a CAST/Ei-derived
      segment on Chr 7. Adiposity index (AI) and weights of certain fat pads were
      approximately 50% lower in both male and female congenic mice than in control
      C57BL/6J mice, and carcass fat content was significantly reduced. The reduction
      of fat depot weights was not seen, however, in congenic animals fed a low-fat
      chow diet (12 Kcal% fat). The congenic segment is approximately 25 cM in length,
      extending from D7Mit213 to D7Mit41, and includes the tub, Ucp2 and Ucp3, genes,
      all of which are candidate genes for this effect. Some polymorphisms have been
      found on comparing c-DNA sequences of the Ucp2 gene from C57BL/6J and CAST/Ei
      mice. These results suggest that one or more genes present in the congenic
      segment modulate the susceptibility to fat deposition on feeding a high-fat diet.
      We were unable to show any significant difference between the energy intakes of
      the congenic and the control C57BL/6J mice on the high-fat diet. Also,
      measurements of energy expenditure in male mice at 6 weeks of age, during the
      first 2 weeks of exposure to the high-fat diet, failed to show any differences
      between control and congenic animals.

PMID- 10337620
TI  - A high-resolution radiation hybrid map of the proximal region of rat chromosome
      4.
AB  - Radiation hybrid (RH) mapping has been used to produce genome maps in the human
      and mouse, but as yet the technique has been applied little to other species. We
      describe the use of RH mapping in the rat, using a newly available rat/hamster RH
      panel, to construct an RH map of the proximal part of rat Chromosome (Chr) 4.
      This region is of interest because quantitative trait loci (QTLs) for defective
      insulin and catecholamine action, hypertension, and dyslipidemia map to this
      region. The RH map includes 23 rat genes or microsatellites previously mapped to
      this part of Chr 4, one rat gene not previously mapped in the rat, and markers
      for four new genes, homologs of which map to the syntenic region of the mouse
      genome. The RH map integrates genetic markers previously mapped on several rat
      crosses, increases the resolution of existing maps, and may provide a suitable
      basis for physical map construction and gene identification in this chromosomal
      region. Our results demonstrate the utility of RH mapping in the rat genome and
      show that RH mapping can be used to localize, in the rat genome, the homologs of
      genes from other species such as the mouse. This will facilitate identification
      of candidate genes underlying QTLs on this chromosomal segment.

PMID- 10337621
TI  - MuERVC: a new family of murine retrovirus-related repetitive sequences and its
      relationship to previously known families.
AB  - Characterization of a new murine endogenous retrovirus-related sequence named
      MuERVC-C105 is reported. This sequence was found to be most similar to the murine
      leukemia C-type retroviruses and to murine defective endogenous retrovirus-like
      families MuRRS and MuRVY, although MuERVC-C105 has a novel LTR. MuERVC-C105, like
      MuRRS and MuRVY, represents a family of retrovirus-like sequences characterized
      by many defects in its reading frames. Phylogenetic analyses, in particular
      analysis of nonsynonymous and synonymous nucleotide substitutions in the descent
      of these sequences, revealed that the MuERVC-C105, MuRRS, and MuRVY families were
      each derived from a different nondefective retroviral ancestor, thus justifying
      the new family name MuERVC. These nondefective ancestors cluster together with
      Gibbon Ape Leukemia Virus, but were nearly as distinct from each other as are
      other subgroups of murine leukemia virus (MoMLV, BaEV, GALV). The analysis
      further indicated that, in spite of the high density of defects in these three
      families, most of their divergence from their common ancestor was as nondefective
      retroviruses.

PMID- 10337622
TI  - A comparative linkage and physical map of bovine chromosome 24 with human
      chromosome 18.
AB  - Polymorphic microsatellites have been developed in the vicinity of nine genes on
      bovine chromosome (BTA) 24, all orthologous to genes on human chromosome (HSA)
      18. The microsatellites have been isolated from bacterial and yeast artificial
      chromosome clones containing the genes. A linkage map was developed including
      these polymorphic markers and four anonymous, published microsatellites. Yeast
      artificial chromosomes containing six of these genes have also been mapped using
      fluorescent in situ hybridization (FISH), thereby tying the linkage map together
      with the physical map of BTA24. Comparing gene location on HSA18 and BTA24
      identifies four regions of conserved gene order, each containing at least two
      genes. These genes identify six regions of conserved order between human and
      mouse, two more than in the human-bovine comparison. The breakpoints between
      regions of conserved order for human-bovine are also breakpoints in the human
      mouse comparison. The centromere identifies a fifth conserved region if the BTA24
      centromere is orthologous with the HSA18 centromere.

PMID- 10337623
TI  - New insights into porcine-human synteny conservation.
AB  - Eleven genes were mapped to the porcine genome with the aim of improving the
      human-porcine comparative gene map. Five of these genes were from regions of the
      human genome painted by porcine chromosomal probes; of these, two mapped to
      chromosomes not expected from the painting results. Among the six genes from
      human regions not painted by porcine chromosomal probes, three genes did not map
      where expected by the principle of parsimony. Several of the gene assignments
      indicate the existence of small regions of conserved synteny not detected by
      heterologous chromosome painting, especially in telomeric regions. We have also
      detected new rearrangements in gene order within the regions of correspondence
      between human Chromosome (HSA) 15 and porcine Chromosome (SSC) 1 as well as
      between HSA4 and SSC8.

PMID- 10337624
TI  - The maternal DDK syndrome phenotype is determined by modifier genes that are not
      linked to Om.
AB  - The DDK syndrome is a polar, early embryonic lethal phenotype caused by
      incompatibility between a maternal factor of DDK origin and a paternal gene of
      non-DDK origin. Both maternal factor and paternal gene have been mapped to the Om
      locus on mouse Chromosome (Chr) 11. The paternal contribution to the syndrome has
      been shown to segregate as a single locus. Although the inheritance of the
      maternal contribution has not been characterized in depth, it as been assumed to
      segregate as a single locus. We have now characterized the segregation of the DDK
      fertility phenotype in over 240 females. Our results demonstrate that females
      require at least one DDK allele at Om to manifest the syndrome. However, the DDK
      syndrome inter-strain cross-fertility phenotype of heterozygous females is highly
      variable and spans the gamut from completely infertile to completely fertile. Our
      results indicate that this phenotypic variability has a genetic basis and that
      the modifiers of the DDK syndrome segregate independently of Om.

PMID- 10337625
TI  - Cloning and characterization of murine Aqp5: evidence for a conserved aquaporin
      gene cluster.
AB  - Aquaporin 5 (Aqp5), a member of the aquaporin family of membrane water channels,
      is thought to modulate the osmolality of fluids in the eye, lung, and salivary
      gland. Here, we report the cloning and genomic characterization of murine Aqp5
      and its expression in relevant mouse tissues. This gene, comprised of four exons
      encoding 265 amino acids (121, 55, 28, and 61 amino acids respectively), is
      transcribed into an approximate 1.8-kb mRNA detected in lung, parotid,
      submandibular, sublingual, and lacrimal tissues. Aqp5 encodes a protein that is
      98% identical to rat Aqp5. An Aqp5 antibody detects an approximately 27-kDa
      protein band in mouse lung, and an additional 29 kDa band in salivary gland.
      Cloning and physical mapping genomic fragments contiguous with Aqp5 revealed two
      other members of the aquaporin family: Aqp2 and Aqp6, arrayed head to tail in the
      order Aqp2-Aqp5-Aqp6, and provides evidence of a gene cluster conserved in order
      and orientation in both mice and humans.

PMID- 10337626
TI  - The 5' region of the COX4 gene contains a novel overlapping gene, NOC4.
AB  - We identified a novel human gene, NOC4 (Neighbor Of COX4), located 5' to COX4,
      the gene for cytochrome c oxidase subunit IV, on Chr 16q32-ter. Transcripts from
      this gene were identified among human expressed sequence tags. A full-length,
      1.06-kb human retinal NOC4 cDNA encoded a 24-kDa, 210-amino acid hypothetical
      protein of unknown function. Northern hybridization analysis of human RNAs from
      various tissues detected NOC4 transcripts of 2.2 and 1.4 kb in all tissues
      examined, suggesting that NOC4 expression is ubiquitous. Transcription of both
      the COX4 and NOC4 genes initiates within a 250-bp intergenic promoter and occurs
      in opposite directions. The bidirectional promoter is G + C-rich, lacks TATA and
      CCAAT elements, and contains multiple potential binding sites for Sp1 and NRF
      2/GABP. Two of the NRF-2/GABP sites are located within 14-bp direct repeats, a
      conserved feature of mammalian COX4 promoters. The NOC4 and COX4 genes are also
      linked in the rat, mouse, and bovine genomes. A NOC4-GFP fusion protein is
      located in both the nucleus and the cytoplasm, including the mitochondria.

PMID- 10337627
TI  - Genetic mapping of the whirler mutation.
AB  - The whirler (wi) mutation on mouse Chromosome (Chr) 4 results in an autosomal
      recessive neuroepithelial deafness and vestibular dysfunction exhibited as a
      characteristic shaker-waltzer behavior (deafness, circling, and head-bobbing). We
      have constructed a genetic linkage map across the wi region in both an
      interspecific [(wi/wi x CAST/Ei)F1 x wi/wi] backcross (n = 817) and an
      intraspecific [(wi/wi x CBA/Ca)F1 x wi/wi)] backcross (n = 335). In the
      interspecific backcross, wi was found to be non-recombinant with Orm1, 0.12 cM
      distal of D4Mit87 and Ambp, and 0.12 cM proximal of CD301. In the intraspecific
      backcross, wi was found to be non-recombinant with Orm1 and D4Mit244, 0.3 cM
      distal of Mup1, and 0.6 cM proximal of Tnc. We also report a family from the
      interspecific backcross that shows evidence of multiple recombinations across the
      region of mouse Chr 4 around the wi locus. These rearrangements appear specific
      to both the region and the family.

PMID- 10337628
TI  - Mapping of the otogelin gene (OTGN) to mouse chromosome 7 and human chromosome
      11p14.3: a candidate for human autosomal recessive nonsyndromic deafness DFNB18.

PMID- 10337629
TI  - Genomic organization and chromosomal localization of mouse coronin-1.

PMID- 10337630
TI  - Genetic relationships among hippopotamus, whales, and bovine based on SINE
      insertion analysis.

PMID- 10337631
TI  - Genomic structure of the human retinoic acid receptor-alpha1 gene.

PMID- 10337632
TI  - Conservation of the linkage of the murine Itga2b and Itgb3 loci in mouse
      chromosome 11.

PMID- 10337633
TI  - Global and U.S. tobacco use and proposals for tobacco policies.

PMID- 10337634
TI  - Positive results achieved with new oral chemotherapy agent.

PMID- 10337635
TI  - Central venous catheter maintenance care.

PMID- 10337636
TI  - Management of diarrhea post-colorectal cancer treatment.

PMID- 10337638
TI  - Promoting nursing research in a clinical setting.

PMID- 10337637
TI  - The Multiport manifold tubing system for delivery of i.v. medications.

PMID- 10337639
TI  - Using data to enhance postoperative patient comfort and decrease costs.

PMID- 10337641
TI  - Compliance task force.

PMID- 10337640
TI  - Central venous catheter occlusion.

PMID- 10337642
TI  - Removing rings from swollen fingers.

PMID- 10337643
TI  - Patient teaching forms.

PMID- 10337644
TI  - Staff orientation using a collaborative pathway.

PMID- 10337645
TI  - Posterior approach for female urinary catheterization.

PMID- 10337646
TI  - Using a quick and easy cancer pain assessment tool.

PMID- 10337647
TI  - Breast cancer screening in relation to access to health services.
AB  - PURPOSE/OBJECTIVES: This study examined mammography screening and breast self
      examination (BSE) in relation to perceived access to health services to identify
      persistent barriers to earlier detection. DESIGN: Community-based, cross
      sectional, survey, and interview. SETTING: More than 80 nonhealthcare-related,
      women's group settings in northern California. SAMPLE: Convenience sample of 838
      black/African American, Latina/Hispanic, and Caucasian/Anglo women varying in
      age, annual family income, sexual orientation, and educational history. METHODS:
      Survey and interview (in English or Spanish) by on-site research assistants
      facilitating participation of women with limited reading capability. MAIN
      RESEARCH VARIABLES: Perceived access to services, breast cancer screening
      behaviors, acculturation and spoken language, habits of use, perceived prejudice
      in health delivery, available economic resources, and other social and behavioral
      variables reported elsewhere. FINDINGS: Healthcare habits, the perception of
      prejudicial treatment in health service delivery, spoken language, and three
      different measures of financial capability explained a large degree of perceived
      access to services. Perceptions of a lack of access to services were related to
      decreased mammography screening participation and to decreased BSE behavior.
      CONCLUSIONS: Participation in cancer screening depends on real economic access
      and previous health service delivery experience. BSE behavior may be influenced
      by lack of money to pay for healthcare services, and experienced prejudice in
      healthcare delivery appears to have a lasting influence on mammography screening
      behavior. IMPLICATIONS FOR NURSING PRACTICE: Tolerance and culturally sensitive
      service delivery coupled with economic access to both screening and necessary
      treatment will be vital to eliciting women's complete participation in attaining
      desired earlier detection goals for breast cancer.

PMID- 10337648
TI  - Taste changes experienced by patients receiving chemotherapy.
AB  - PURPOSE/OBJECTIVES: To increase knowledge about the nature, frequency, and
      quality-of-life (QOL) effects associated with taste changes after chemotherapy.
      DESIGN: Cross-sectional, descriptive. SETTING: 11 outpatient urban and suburban
      oncology centers. SAMPLE: 284 adults who had received at least two chemotherapy
      cycles. METHODS: Patients completed a taste change questionnaire and the
      Functional Assessment of Cancer Therapy-General, and nurses collected demographic
      and disease-related information. Descriptive statistics, Spearman correlations,
      chi-square, Mann-Whitney, and Kruskal-Wallis one-way analysis of variance were
      calculated. FINDINGS: Taste changes were frequent and at least moderately severe
      for many patients, who often reported dry mouth, decreased appetite, nausea, and
      vomiting. Cisplatin and doxorubicin were the agents most likely to be related to
      severe taste changes and to have caused greater distress from taste changes,
      which also were associated with decreased QOL. Oncology nurses and physicians
      rarely discussed taste changes with patients, who often tried changing the ways
      they seasoned their food. CONCLUSIONS: Taste changes are a frequent and
      significant problem for patients receiving chemotherapy and have negative effects
      on patients' QOL. Oncology nurses and physicians typically do not offer self
      management suggestions to patients. IMPLICATIONS FOR NURSING RESEARCH AND
      PRACTICE: Repeated-measures research may provide a clearer understanding of
      chemotherapy-associated taste changes over time. Studies to examine strategies
      suggested from this and other research as well as clinical literature may
      determine which self-care interventions are most useful. Nurses should inform
      patients that taste changes may occur following chemotherapy, provide self
      management information, and assess for related problems that could increase
      chemotherapy morbidity.

PMID- 10337649
TI  - Overcoming multidrug resistance: valspodar as a paradigm for nursing care.
AB  - PURPOSE/OBJECTIVES: To review the mechanisms of multidrug resistance (MDR) in
      human cancer and the clinical use of MDR modulators to overcome or reverse P
      glycoprotein (P-gp)-mediated MDR. DATA SOURCES: Current literature, ongoing
      clinical trials, and clinical experience. DATA SYNTHESIS: Agents, such as
      valspodar, that block the activity of P-gp can reverse or overcome MDR caused by
      overexpression of P-gp. The MDR modulator valspodar (PSC 833; Novartis
      Pharmaceuticals Corporation, East Hanover, NJ) is examined as a model for
      establishing nursing guidelines for this new class of therapeutic agents.
      CONCLUSIONS: The dose of some chemotherapy agents must be modified with
      concurrent valspodar administration. Studies examining the safety and efficacy of
      valspodar as a prototype of MDR modulators provide the basis for establishing
      nursing care guidelines. IMPLICATIONS FOR NURSING PRACTICE: Nursing care for the
      administration of valspodar includes understanding patient selection, criteria,
      dosing, and administration; side-effect management; patient monitoring and follow
      up; and patient education.

PMID- 10337650
TI  - Cancer pain and common pain: a comparison of patient-reported intensities.
AB  - PURPOSE/OBJECTIVES: To compare patient reports of present and worst cancer
      related pain intensity to the recalled intensity of several commonly experienced
      types of pain. DESIGN: A secondary analysis on baseline data from patients with
      cancer pain. SETTING: Tertiary-care facilities and patients' homes. Patients were
      enrolled between 1988 and 1995. SAMPLE: Patients who were diagnosed with either
      primary lung cancer or cancer metastatic to bone, able to read and write English,
      over 18 years of age, and able to provide written informed consent. The sample of
      125 patients was 62% male with a mean age of 60 years (SD = 11). METHODS:
      Patients completed the McGill Pain Questionnaire as a baseline measure in a pain
      research study. Investigators conducted comparisons among pain intensity scores
      reported for present pain intensity and worst cancer pain with the worst
      toothache, headache, and stomachache ever experienced using the Stuart test of
      marginal homogeneity. MAIN RESEARCH VARIABLES: Present cancer pain intensity and
      worst toothache, headache, and stomachache pain intensity. FINDINGS: Only 14% of
      the subjects reported that their present pain intensity was distressing,
      horrible, or excruciating, but 83% of them reported that their worst cancer pain
      was at these levels. The subjects reported that they experienced (a)
      significantly more intense pain with their worst toothache than either their
      present pain intensity (p < 0.001) or their worst cancer pain (p < 0.001), (b)
      significantly more intense pain with their worst headache than their present pain
      intensity (p < 0.001), and (c) significantly more intense pain with their worst
      stomachache than their present pain intensity (p < 0.001). In contrast, subjects
      reported that their worst cancer pain was significantly more intense than their
      worst headache (p = 0.047) or stomachache (p = 0.001). CONCLUSIONS: The findings
      suggest that present cancer pain is not only experienced at lower intensity
      levels than common pains, but at lower levels than expected by patients, their
      families, and the public. Consistent with common beliefs though, the worst cancer
      pain is severe and not adequately controlled for 9 out of 10 patients.
      IMPLICATIONS FOR NURSING PRACTICE: Healthcare professionals could use study
      findings to inspire hope in patients with lung cancer or bone metastasis and
      their families that present pain in cancer can be controlled successfully.
      Clinicians should devote greater efforts to relieve the worst cancer pain to
      levels achieved for the present pain experienced by people with cancer.

PMID- 10337652
TI  - Justifying radiation oncology nursing practice--a literature review.
AB  - PURPOSE/OBJECTIVES: To determine the scientific basis for the nursing care given
      to individuals undergoing radiation therapy, identify patient needs, and develop
      recommendations for care delivery based on these findings. DATA SOURCES:
      Scientific literature dating from 1993 to June 1997. Articles of recognized
      importance and those cited repeatedly were included, dating back to 1977. DATA
      SYNTHESIS: Articles included in this review investigated patient-information
      needs, psychosocial reactions, self-care, side effects, and sexual dysfunction.
      The weight of the scientific evidence varies in the included studies.
      CONCLUSIONS: The findings provide a foundation on which future studies can build.
      Additional conceptual work and resolution of methodologic issues are needed for
      research in this area to guide future practice. IMPLICATIONS FOR NURSING
      PRACTICE: Patients receiving radiation therapy often experience side effects and
      complications as a result of treatment. The scientific literature suggests that
      patients need information about their treatment, general emotional support, and
      practical help with side effects. A need exists to substantiate radiation nursing
      care practice using the literature and to create contemporary studies to enhance
      practice.

PMID- 10337651
TI  - The evolution of a breast health program for Plains Indian women.
AB  - PURPOSE/OBJECTIVES: To discuss the development and implementation of a culturally
      sensitive breast cancer outreach program focusing on early detection, screening,
      and education for Plains Indian women living in Montana and northern Wyoming.
      DATA SOURCES: Professional journals, government reports, culturally sensitive
      materials, and field experience. DATA SYNTHESIS: Perceptions about cancer, the
      prevalence of poverty and alcoholism, the traditional role of the Native American
      woman, and rural living influence breast health and breast cancer education for
      Plains Indian women. An outreach program was developed specifically for this
      population and included individualized education, distribution of culturally
      sensitive materials, culturally sensitive professional education, and train-the
      trainer seminars. CONCLUSIONS: After years of working with Native American women,
      the percentages of mammograms and clinical breast examinations increased by more
      than 100%. IMPLICATIONS FOR NURSING PRACTICE: Nurses can bridge the cultural gap
      and work effectively with Native American women by building trust and being
      sensitive to cultural customs and related healthcare behaviors. Furthermore, this
      program provides a model that nurses can use to develop culturally sensitive
      breast health programs.

PMID- 10337653
TI  - Capecitabine: nursing implications of a new oral chemotherapeutic agent.
AB  - PURPOSE/OBJECTIVES: To describe the new oral chemotherapeutic agent capecitabine
      (Xeloda, Roche Laboratories Inc., Nutley, NJ) and key concepts driving its
      development and to delineate the nursing impact of patient-administered, home
      based chemotherapies. DATA SOURCES: Published papers, investigational materials,
      package inserts, and clinical experience. DATA SYNTHESIS: Capecitabine recently
      was approved to treat metastatic breast cancer refractory to paclitaxel and
      anthracycline-containing regimens. Efficacy has been demonstrated. However,
      although the current regimen is well-tolerated, > or = 40% of patients require
      dose modification because of grade 2 or greater toxicity, usually hand-foot
      syndrome or gastrointestinal symptoms. CONCLUSIONS: Capecitabine frees nurses
      from infusion-related workload, allowing and demanding a new type and level of
      patient education. Such education emphasizes compliance with the treatment plan
      and prevention, timely recognition, and management of toxicities. These practice
      changes also challenge nurses to advocate for reimbursement of educational
      practices. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses will play more of a
      central role as use of patient-administered, home-based therapies increases.
      Nurses must enhance their patient-education and telephone symptom-management
      skills and help to secure reimbursement for such activities.

PMID- 10337654
TI  - Anxiety and directed attention in women awaiting breast cancer surgery.
AB  - PURPOSE/OBJECTIVES: To investigate the relationship between anxiety and directed
      attention (the ability to focus and concentrate) in women awaiting breast cancer
      surgery and the potential influence of age and extent of anticipated surgery
      (breast conservation versus mastectomy) on attentional functioning and anxiety.
      DESIGN: Descriptive, cross-sectional. SAMPLE AND SETTING: Convenience sample of
      45 women newly diagnosed with localized breast cancer at a Midwestern university
      medical center. METHODS: Subjects were assessed approximately 11 days before
      surgery using objective measures of attention: Digit Span, the Symbol Digit
      Modalities Test, the Necker Cube Pattern Control Test, the Attentional Function
      Index (a subjective measure of effectiveness of attentional functioning), and the
      Tension-Anxiety subscale of the Profile of Mood States. MAIN RESEARCH VARIABLES:
      Capacity to direct attention, perceived attentional functioning, anxiety level,
      age, and extent of anticipated breast surgery. FINDINGS: Level of anxiety was
      related inversely (r = -0.63, p < 0.01) to perceptions of attentional functioning
      but not to performance on any objective measures of attention in the pretreatment
      period. No differences in anxiety level existed in regard to age or extent of
      anticipated surgery. However, older women (> or = 55 years) showed overall
      significantly lowered (p < 0.001) performance on the attentional measures than
      younger women. CONCLUSIONS: Preoperative anxiety is a clinically significant
      issue in women newly diagnosed with breast cancer regardless of age and extent of
      anticipated surgery. Higher anxiety requires use of attentional resources and
      initially may act to reduce perceptions of effectiveness in attentional
      functioning. Older women who have high anxiety combined with both subjective and
      objective decline in attentional functioning may be at particularly high risk for
      attentional fatigue. IMPLICATIONS FOR NURSING PRACTICE: Women newly diagnosed
      with breast cancer may experience not only increased anxiety and associated
      perceptions of decreased attentional functioning but also a subsequent depletion
      of attentional reserves as a result of the onset of attentional fatigue. Nurses
      can assess anxiety in women during the preoperative period and assist them in
      coping with the psychological and cognitive demands associated with this highly
      stressful period.

PMID- 10337655
TI  - A flowsheet for documenting independent nursing visits after breast surgery.
AB  - PURPOSE/OBJECTIVES: To redesign a postoperative flowsheet already used in
      clinical practice with patients who have undergone breast surgery to reflect
      documentation of assessments and interventions noted on each nursing visit. DATA
      SOURCES: Memorial Sloan-Kettering Cancer Center Standards of Practice for
      Ambulatory Care, clinical experience, and published articles. DATA SYNTHESIS: A
      comprehensive flowsheet was redesigned to provide consistency in documentation
      and reflect current needs of patients who have undergone breast surgery who are
      in ambulatory care. CONCLUSIONS: Implementation of the new flowsheet has
      decreased staff documentation time during busy office practices and accurately
      reflects the nursing care provided to patients after breast surgery. IMPLICATIONS
      FOR NURSING PRACTICE: Consistency in patient care can be maintained and
      efficiency can be increased with use of a comprehensive flowsheet.

PMID- 10337656
TI  - [Fast protection against osteoporotic fractures by using alendronat].

PMID- 10337657
TI  - Effect of total androgen ablation on pathologic stage and resection limit status
      of prostate cancer. Initial results of the Italian PROSIT study.
AB  - The likelihood of finding organ-confined untreated prostate cancer (PCa) by
      pathological examination at the time of radical prostatectomy (RP) is only 50% in
      patients with clinically organ-confined disease. In addition, tumour is present
      at the resection margin in approximately 30% of clinical T2 (clinical stage B)
      cases. The issue of clinical "understaging" and of resection limit positivity
      have led to the development of novel management practices, including
      "neoadjuvant" hormonal therapy (NHT). The optimal duration of NHT is unknown. We
      undertook the present analysis to evaluate the effect of NHT on pathologic stage
      of PCa and resection limit status in patients with prostate cancer and treated
      with total androgen ablation either for three or six months before RP. Between
      January 1996 and February 1998, 259 men with prostate cancer underwent radical
      retropubic prostatectomy and bilateral pelvic node dissection in the 26 centres
      participating in the Italian randomised prospective PROSIT study. Whole mount
      sectioning of the complete RP specimens was adopted in each centre for accurately
      evaluating the pathologic stage and resection limit status. By February 1998,
      haematoxylin and eosin stained sections from 155 RP specimens had been received
      and evaluated by the reviewing pathologist (RM). 64 cases had not been treated
      with total androgen ablation (e.g. NHT) before RP was performed, whereas 58 and
      33 had been treated for three and six months, respectively. 114 patients were
      clinical stage B whereas 41 were clinical stage C. After three months of total
      androgen ablation, pathological stage B was more prevalent among patients with
      clinical B tumours, compared with untreated patients (57% in treated patients vs.
      36% in untreated). The percentage of cancers with negative margins was
      statistically significantly greater in patients treated with neoadjuvant therapy
      than those treated with immediate surgery alone (69% vs. 42%, respectively).
      After six months of NHT therapy the proportion of patients with pathological
      stage B (67% vs. 36%, respectively) and negative margins was greater than after 3
      months (92% vs. 42%, respectively). For clinical C tumours, the prevalence of
      pathological stage B and negative margins in the patients treated for either 3 or
      6 months was not as high as in the clinical B tumours, when compared with the
      untreated group (pathological stage B: 31% and 33% vs. 6% in the clinical C
      cases, respectively. Negative margins: 56% and 67% vs. 31%, respectively). The
      initial results of this study suggest that total androgen ablation before RP is
      beneficial in men with clinical stage B because of the significant pathological
      downstaging and decrease in the number of positive margins in the RP specimens.
      These two effects are more pronounced after six months of NHT than after three
      months of therapy. The same degree of beneficial effects are not observed in
      clinical C tumours.

PMID- 10337658
TI  - Autopsy findings in the acquired immunodeficiency syndrome (AIDS). A report of
      395 cases from the south of France.
AB  - Necropsy findings in 395 adult patients with the acquired immunodeficiency
      syndrome (AIDS) who died in Nice, France, between March 1983 and May 1996 were
      compared retrospectively with antemortem diagnoses, risk factors and number of
      positive T CD4 lymphocytes at the time of death. Special emphasis on bacterial
      infections was made in this study. Lesions observed from 1983 through 1989 and
      from 1990 through 1996 were compared. We assessed the role of organ lesions in
      the immediate cause of death. The organ system distribution of major
      opportunistic infections and neoplasms was similar throughout the years of the
      study. The most common diagnostic disease entities in all organ sites were
      cytomegalovirus infection, toxoplasmosis and candidiasis. Toxoplasmosis was more
      common in the intravenous drug abuser group. Bacterial infections were frequent
      and contributed to the mortality and morbidity of all risk factor groups. Kaposi'
      sarcoma continued to occur more frequently in the homosexual population.
      Cytomegalovirus infection remained one of the most common causes of death from
      1983 to 1996. Mortality from fungal and bacterial infections, and mycobacteriosis
      increased in frequency during the course of this study whereas deaths from
      pneumocystosis declined. The death rate from malignant lymphoma and carcinoma
      increased after 1989. The clinical cause of death concurred with the pathological
      cause in 55% of the cases. Lung was the most frequent organ involved followed by
      the central nervous system the gastrointestinal tract and the heart.

PMID- 10337659
TI  - Standardized in situ AgNOR analysis in breast pathology: diagnostic and cell
      kinetic implications.
AB  - The aim of the present study was to assess the diagnostic value of the recently
      standardized morphometric analysis of silver-stained nucleolar organizer region
      associated proteins (AgNORs) [30] in a variety of 155 routinely processed benign
      and malignant breast lesions. 5 normal breast samples, 21 adenoses, 20 ductal
      hyperplasias, 10 atypical ductal hyperplasias, 20 in situ and 43 invasive ductal
      carcinomas, 10 in situ and 26 invasive lobular carcinomas were investigated. A
      statistically highly significant difference was found between normal/ordinary
      hyperplastic and neoplastic breast lesions with all 4 consensus AgNOR parameters
      (mean area, mean number, CV of area, CV of number) evaluated. AgNOR quantity was
      significantly related to histological grade of both in situ and invasive
      carcinomas. However, variable overlap was found between AgNOR values in different
      diagnostic groups. We conclude that standardized AgNOR analysis is a prerequisite
      for objective and reproductible AgNOR assessment in archival tissues. Despite its
      limited diagnostic utility for individual breast lesions, standardized AgNOR
      analysis bears a significant potential for characterizing cell kinetic and
      metabolical activity of breast lesions. This may give insight into the biological
      background of breast carcinogenesis, differentiation and tumor progression and
      may also underlie the independent prognostic value of AgNORs in breast cancer.

PMID- 10337660
TI  - Mammary hamartomas: an immunohistochemical study of ten cases.
AB  - Ten cases of breast hamartomas were reviewed; the patients' age ranged from 31 to
      55 (mean 40.4, median 39). All cases presented with a palpable, sometimes tender,
      lump. The typical mammographic feature was a well defined, round to lens shaped,
      variable dense mass, occasionally surrounded by a thin radiolucent zone. All
      hamartomas were unilateral (4 in the right and 6 in the left breast,
      respectively) and no recurrence occurred after local excision. The tumor size
      ranged from 5 to 150 mm (mean 54 mm). Histologically all hamartomas were composed
      of a typical fibrous, adipose and glandular tissue combination.
      Immunohistochemically there was a strong positivity for cytokeratin and
      epithelial membrane antigen in the epithelial cells, a positive finding for
      vimentin and muscle-specific actin in stromal and myoepithelial cells, and for S
      100 protein in myoepithelial cells. Vessels endothelial cells were immunoreactive
      for Factor VIII. Immunohistochemical analysis of hormone receptors completed on
      formaldehyde-fixed paraffin-embedded specimens, showed estrogen and progesterone
      receptors positivity in 9 cases and estrogen positive progesterone negative
      receptors in one case. In all cases the receptorial positivity was limited to the
      epithelial elements. These data revealed that 1) breast hamartoma is a benign,
      tumor-like lesion, histologically dissimilar from other lesions such as
      fibroadenoma and pseudoangiomatous hyperplasia; and 2) hamartoma tissue is
      influenced by hormones like the surrounding normal breast parenchyma.

PMID- 10337662
TI  - Decrease of antigastric autoantibodies in Helicobacter pylori gastritis after
      cure of infection.
AB  - H. pylori infection leads to the formation of autoantibodies against canalicular
      structures with human parietal cells in about 30% of all patients. This type of
      autoreactivity is associated with gastric mucosa atrophy. This study aimed to
      analyse the effect of cure of infection on anticanalicular autoantibodies. H.
      pylori infection was cured in 34 patients. Sera of these patients were screened
      for anticanalicular autoantibodies using an immunohistochemical method before, 10
      weeks after and one year after cure of infection. Prevalence of anticanalicular
      autoantibodies significantly decreased from 26% before treatment to 9% after one
      year. The data presented in this study add new information to the possible
      reversibility of gastric mucosa atrophy.

PMID- 10337661
TI  - Establishment and characterization of a serous papillary adenocarcinoma cell line
      of the human ovary in a serum-free culture.
AB  - In order to clarify the biologic characteristics of serous papillary
      adenocarcinoma of the human ovary, we tried to establish a continuous cell line
      using four primary tumor specimens derived from four patients with such tumors.
      We also evaluated c-myc, MYCN and c-erbB2 gene amplification in the cultured
      cells, and the xenografts, as well as in these four primary tissue specimens by a
      Southern blot analysis. One continuous cell line, named as FU-OV-1, was
      established in a serum-free culture system and this line propagated continuously
      for 96 serial passages over a 2-year-period in vitro. FU-OV-1 reproduced and
      still maintained the characteristics of the original tumor. C-myc gene
      amplification was found in the FU-OV-1 cells, and the xenografts, as well as in
      only the primary tumor of FU-OV-1 out of the four primary serous papillary
      adenocarcinomas. However, neither MYCN amplification nor c-erbB2 amplification
      was observed in any tumor specimens including FU-OV-1 cells. In conclusion, FU-OV
      1 is thus considered to be a useful system for studying the biological behavior
      of serous papillary adenocarcinoma in the human ovary. The results of this study
      suggest that c-myc gene amplification might thus be associated with the
      progression of this tumor both in vitro and in vivo.

PMID- 10337663
TI  - Lipomatous pleomorphic adenoma of the parotid gland. Classification of lipomatous
      tissue in salivary glands.
AB  - Lipomatous pleomorphic adenoma is an unusual subtype with a lipomatous stromal
      component of more than 90% of the tumour tissue. This special type of pleomorphic
      adenoma must be distinguished from other types of lipomatous tumours or non
      tumourous lipomatosis of the salivary glands. Until now only two cases of
      lipomatous pleomorphic adenoma have been reported in the literature. We report of
      a 36-year old woman who developed a well circumscribed nodule measuring 3.5 x 2.5
      x 2 cm in the right parotid gland. The cut surface was grey-yellowish.
      Histologically, more than 90% of the tumour tissue was fatty tissue with
      univacuolar adipocytes. The pleomorphic epithelial elements were duct-like cells
      forming small lumina and spindle-shaped myoepithelial cell with surrounding
      mucoid stroma. Components of pleomorphic adenoma were intermingled with mature
      adipose tissue which was more concentrated in the central portion of the adenoma.
      Some compressed epithelial cords in the adipose tissue formed a septa-like
      pattern. The differential diagnosis to other lipomatous tumours (lipoadenoma,
      lipoma) and to non-tumourous interstitial lipomatosis as well as the possible
      pathogenesis as metaplastic change or epithelial-mesenchymal transdifferentiation
      are discussed.

PMID- 10337664
TI  - Intraductal papillary carcinoma of the parotid gland with low malignancy.
AB  - A peculiar case of papillary carcinoma arising in the parotid gland is reported.
      A 68-year-old woman presented with a right, painless, parotid mass, measuring
      approximately 3 cm in greatest diameter. A conservative parotidectomy was
      performed. Histologically, the neoplasm showed exophytic papillary projections
      into a cavity. The cells were focally suggestive of epidermoidal differentiation,
      whereas a transitional differentiation was noted in other portions, as in bladder
      papilloma. Immunohistochemical studies showed strong positivity of the neoplastic
      cells for cytokeratin and weak positivity for PCNA and Mib-1. We classified this
      neoplasm among the papillary tumors with a low-grade of malignancy.

PMID- 10337665
TI  - Myofibroblastoma of the breast with hemangiopericytoma-like pattern and
      pleomorphic lipoma-like areas. Report of a case with diagnostic and histogenetic
      considerations.
AB  - Myofibroblastoma (MFB) of the breast is an uncommon benign spindle cell tumor
      which may exhibit a wide spectrum of histological features. We report an unusual
      case of MFB of the male breast, showing cellular areas with a hemangiopericytoma
      like pattern similar to that observed in solitary fibrous tumor (SFT) and
      extensive fibromyxoid areas containing numerous atypical stromal cells. The
      association of these atypical cells with mature adipocytes and microcystic and/or
      myxoid degenerative changes resembled pleomorphic lipoma-like and myxoid
      liposarcoma-like features, respectively. To our knowledge, these peculiar
      morphological findings have not been previously reported in MFB of the breast.
      They should be recognized to avoid confusion with other mesenchymal tumors,
      especially with hemangiopericytoma, pleomorphic lipoma (PL), spindle-cell lipoma
      (SCL) and myxoid liposarcoma. A case of MFB of the breast showing morphological
      features also commonly seen in SFT and PL/SCL is further morphological evidence
      in support of the speculation that the mesenchymal tumors of the breast, also
      known under the terms benign spindle cell tumors, fibromas, SFTs, SCLs and MFBs,
      are histogenetically related lesions.

PMID- 10337666
TI  - Epithelial inclusion in axillary lymph node associated with a breast carcinoma:
      report of a case with a review of the literature.
AB  - Since epithelial inclusions in axillary lymph nodes are rare, some diagnostic
      problems concerning their nature have arisen. We report a case of a cystic
      squamous epithelial inclusion in an axillary lymph node of a patient affected by
      a high grade breast carcinoma with focal squamous differentiation. Although the
      lesion was histologically benign, the possibility that it represents a well
      differentiated squamous metastasis cannot be completely ruled out. To our
      knowledge, this is the first case of an epithelial lymph node inclusion
      associated with a breast carcinoma showing morphological evidence of squamous
      differentiation. Here, we discuss the diagnostic problems and give a review of
      the literature.

PMID- 10337667
TI  - Cardiac myxoma with glandular component: case report and review of the
      literature.
AB  - A 7 cm diameter tumor of the left atrium is reported in a 78 year-old woman with
      a past history of pT3N1M0 colonic adenocarcinoma. The histological examination of
      the atrial tumor disclosed areas of highly vascularized myxoid stroma with cells
      strongly reactive for vimentin. Multiple mucoid spaces lined by a single layer of
      goblet cells were scattered among those typical areas of myxoma. No nuclear
      atypia was observed. Cytoplasm of the glandular cells was immunoreactive for
      epithelial antisera (keratin, EMA), CEA and CA19.9. Two years later, the patient
      was doing well, with no local recurrence of the cardiac myxoma and no secondary
      location of the colonic adenocarcinoma. The histological characteristics, the
      absence of atypia, the absence of tumoral extension or neoplastic lymphatic
      vascular thrombi in the pedicle or in the interatrial septum, and the finding of
      typical myxomatous areas supported the diagnosis of cardiac myxoma with glandular
      component. To our knowledge, 21 cases of myxoma with glandular mucinous
      component, focal or prominent, have been previously published in the literature.
      These myxoma were generally sporadic cases with the same clinical features and
      prognosis as typical myxoma. Immunoreactivity of these glandular structures was
      constant for epithelial markers. The positive immunostaining by CEA, and by
      CA19.9 in our case, reflects the histogenetic endodermal origin.

PMID- 10337668
TI  - How often are dermatophytes present in apparently normal versus scaly feet of
      children?
AB  - The purpose of this investigation was to find out how often pathogenic
      dermatophytes are found in apparently normal versus scaly feet of children. In
      this prospective protocol, we studied 100 patients, 2 to 12 years of age,
      consulting for plantar and/or interdigital scaling with or without erythema,
      maceration, and pruritus, and 100 controls with apparently healthy feet. Direct
      microscopic examination (KOH) and mycologic culture (Mycosel) of skin scrapings
      were performed from the lesions of patients and from the soles and interdigital
      folds of controls. Mean age of patients and controls was 7 years 7 months (SD = 3
      years 2 months). Scaling was present in 100% of patients with a mean time of
      evolution of 8.9 months (SD = 16.3 months). Shoes fashioned from man-made
      material were significantly more frequently used by patients than by controls
      (chi 2(df = 1) = 9.4; p = 0.002). Pathogenic dermatophytes were present in the
      soles and/or interdigital webs of 21 patients and 7 controls. Not all foot
      scaling in children, pruritic or not, is associated with dermatophytes.
      Dermatophytes may be present on the apparently healthy feet of children.

PMID- 10337669
TI  - Dermatologic findings in anorexia and bulimia nervosa of childhood and
      adolescence.
AB  - The cutaneous signs of anorexia nervosa (AN) and bulimia nervosa (BN) have been
      described previously in adult patients. For the first time, we present here
      dermatologic findings in children and adolescents suffering from eating
      disorders. Thirty consecutive young anorexic and bulimic inpatients (8 to 17
      years of age, mean 15.1 years) underwent a standardized dermatologic examination.
      Patients were checked for abnormalities of the skin including atopic stigmata,
      dermographism, hair, nails, and oral cavity. Serum was obtained for hemoglobin,
      iron, zinc, GPT, thyroid, and sex-hormone levels. In 13 patients, the total serum
      IgE was determined, and a prick test was carried out with defined type I
      allergens. Findings in order of frequency included xerosis of the skin, white
      dermographism, diffuse hypertrichosis, acrocyanosis, scars, diffuse effluvium,
      artifacts, brittle nails, and onychophagia. Significant co-relations were found
      between the presence of hypertrichosis and the existence of amenorrhea or a body
      mass index of less than 16. In 22 patients a low T3 level was found. In summary,
      children and adolescents suffering from AN or BN show dermatologic features
      similar to those reported in older patients. Special findings in this age group
      are extensive lanugo hair and signs of autoaggressive behavior.

PMID- 10337671
TI  - Evidence that AEC syndrome and Bowen--Armstrong syndrome are variable expressions
      of the same disease.
AB  - Several clinical disorders combine ectodermal dysplasia (ED) and cleft lip and/or
      palate (CL/P). These conditions have been recognized as a group of diseases with
      a narrow phenotypic spectrum and multiple points of overlap. We report a patient
      with a clinical diagnosis of AEC syndrome (ankyloblepharon, ectodermal defects,
      and CL/P) who additionally has some features observed in a different ED-CL/P
      disorder, Bowen-Armstrong syndrome. Because of this clinical overlap, we suggest
      that AEC syndrome and Bowen-Armstrong syndrome may be variable manifestations of
      the same pathologic entity.

PMID- 10337670
TI  - Dermatosis in a child with kwashiorkor secondary to food aversion.
AB  - Kwashiorkor is a common affliction of children worldwide. It occurs less often in
      developed countries, but has been reported under a variety of circumstances,
      including poverty, neurologic disease, and malabsorption. Because of its rare
      occurrence in the United States and because the affected child has an edematous
      rather than wasted appearance, physicians often do not consider it as a
      diagnostic entity. This article describes a case of kwashiorkor in a child with
      food aversion that manifested as "flaky paint dermatitis." Our discussion will
      attempt to delineate underlying conditions that may predispose to kwashiorkor. In
      addition, biochemical and cellular etiologic factors that may be linked with
      classical and nonclassical skin findings of kwashiorkor are considered. Finally,
      we present a differential diagnosis for any child with a generalized eczematous
      or desquamative rash. Our aim is to increase the ability of health care providers
      to identify and treat children with kwashiorkor in a timely manner.

PMID- 10337672
TI  - Multiple eruptive milia in a 15-year-old boy.
AB  - We present a 15-year-old boy with periorbital idiopathic multiple eruptive milia.
      He represents the youngest case to date of this unusual dermatosis.

PMID- 10337673
TI  - Acute generalized varicella zoster in the setting of preexisting generalized
      erythema.
AB  - We report a 5-year-old girl who initially had generalized erythema from scarlet
      fever. Four days later she developed sheets of monomorphous vesicles in the areas
      of erythema. A Tzanck smear of a vesicle base showed multinucleated giant cells,
      and viral culture grew varicella zoster virus, confirming a clinical diagnosis of
      varicella. This case illustrates that, with a background of preexisting erythema,
      varicella may present in an atypical manner.

PMID- 10337674
TI  - Wrinkly skin syndrome: ultrastructural alterations of the elastic fibers.
AB  - We report the clinical and pathologic features of a patient with wrinkly skin
      syndrome. The essential clinical features were wrinkly skin with poor elasticity
      over the abdomen and on the dorsum of the hands and feet, increased palmar and
      plantar creases, and a prominent venous pattern over the chest. On light
      microscopy, histopathologic findings included appreciable heterogeneity in the
      structure, amount, and distribution pattern of elastic fibers. Agglutination and
      fragmentation of the microfibrillar component and a remarkable decrease in
      elastin were the major ultrastructural features. The differential diagnosis with
      other connective tissue disorders is discussed.

PMID- 10337675
TI  - Eosinophilic pustular folliculitis in infancy: report of two new cases.
AB  - Eosinophilic pustular folliculitis (EPF) is a cutaneous inflammatory follicular
      disorder of unknown etiology. The diagnosis is made on the basis of clinical and
      histopathologic features. We describe two patients who had recurrent episodes of
      pruritic follicular papular and pustular lesions on the face, extremities, and
      trunk. The eruptions lasted for 1 month with intermittent remissions. Laboratory
      tests disclosed no infectious or parasitic etiology in patient 2. In patient 1 we
      isolated methicillin-resistant Staphylococcus aureus in a blood culture. He had
      sepsis with lung and liver involvement. EPF is a self-limited dermatosis. On
      occasion, skin lesions may become superinfected, resulting in localized pyoderma
      or rarely systemic infection (sepsis). Histologically both of our patients showed
      a moderate mixed inflammatory infiltrate with numerous eosinophils centered
      around hair follicles. Their lesions responded well to topical corticosteroids.

PMID- 10337676
TI  - Pagetoid self-healing Langerhans cell histiocytosis in an infant.
AB  - We report Langerhans cell (LC) histiocytosis in a male infant who developed
      numerous papular lesions on the trunk and posterior scalp soon after birth and
      spontaneously recovered from the disease within 7 months. Histologically S-100
      positive cells were detected in the epidermis and papillary dermis, in some
      lesions mostly in the epidermis. Tumor cells in the epidermis were either
      clustered, forming nests, or scattered singly in pagetoid fashion. Electron
      microscopy confirmed the presence of Birbeck granules in these cells. They
      exhibited many interesting features usually not found in normal LCs, including
      mitosis, frequent apoptosis, Birbeck granules invaginated in the nucleus,
      autophagocytosis of Birbeck granules, and active ingestion of extracellular
      material through Birbeck granules attached to cell membranes. It is suggested
      that either a strong epidermotropism of tumor cells or a proliferation of the
      resident LCs of the epidermis is responsible for this intraepidermal growth
      pattern. Cellular necrosis through very active apoptosis and the superficial
      nature of the growth might have contributed to the self-healing course in this
      patient.

PMID- 10337677
TI  - Linear childhood discoid lupus erythematosus following the lines of Blaschko: a
      case report with review of the linear manifestations of lupus erythematosus.
AB  - Seventeen cases of childhood discoid lupus erythematosus (DLE) have been
      previously reported in the literature. We describe the first reported case of
      childhood linear DLE following the lines of Blaschko. The clinical and histologic
      characteristics of childhood DLE are discussed and a review of the linear
      manifestations of childhood LE is presented.

PMID- 10337678
TI  - Rubinstein--Taybi syndrome and ulerythema ophryogenes in a 9-year-old boy.
AB  - Rubinstein-Taybi syndrome is characterized by the presence of a peculiar facies,
      mental retardation, and broad thumbs and great toes. Several associated cutaneous
      abnormalities have been reported with this syndrome. Ulerythema ophryogenes is a
      form of follicular keratosis associated occasionally with other ectodermal
      defects and congenital anomalies. We describe a 9-year-old child with Rubinstein
      Taybi syndrome and ulerythema ophryogenes. This association has not been
      described previously to our knowledge.

PMID- 10337679
TI  - Atypical erythema toxicum neonatorum of delayed onset in a term infant.
AB  - We describe a 10-day-old term infant who presented to the emergency room with an
      acute pustular eruption. Laboratory tests and clinical outcome confirmed the
      diagnosis of erythema toxicum neonatorum. A full septic workup was performed and
      all cultures were negative. Wright-stained smear of pustular contents showed a
      predominance of neutrophils with 10% eosinophils. The white blood cell count was
      19,000/mm3 with 10% eosinophils. The eruption resolved spontaneously at 15 days
      of age leaving no sequelae. This is the first fully documented case of erythema
      toxicum in a term infant occurring as late as 10 days of age. When erythema
      toxicum presents in an atypical fashion, diagnostic tests are important to
      exclude other causes of pustular dermatoses of the neonate.

PMID- 10337680
TI  - Accessory scrotum: an unusual localization of scrotal skin.
AB  - Accessory scrotum is an extremely rare congenital scrotal anomaly defined as the
      occurrence of scrotal skin outside of its proper location with no testicular
      tissue. We report a preterm twin male infant who had an accessory scrotum located
      on the right inguinal and proximal femoral region.

PMID- 10337681
TI  - Psoriasis associated with human immunodeficiency virus in an infant.
AB  - Psoriasis is commonly reported in association with HIV in adults. A 3-month-old
      girl with HIV presented with a widespread eruption and was diagnosed with
      psoriasis. This is the first infant reported with psoriasis in association with
      HIV infection. The relationship between the two entities is discussed, as is the
      role of treatment with zidovudine.

PMID- 10337682
TI  - Adverse reaction to prednisone in a patient with systemic lupus erythematosus.
AB  - Oral corticosteroids are the main therapeutic choice for systemic lupus
      erythematosus (SLE). Adverse reactions to systemic corticosteroids rarely occur
      and the etiology is unclear in most cases. A 14-year-old girl with newly
      diagnosed SLE developed a pruritic bullous eruption while on prednisone. The
      patient had been treated successfully in the hospital with intravenous
      methylprednisolone. In preparation for discharge, the steroid preparation was
      changed to prednisone to which the patient reacted with a development of new
      crops of bullous lesions. Skin biopsy specimens of lesional areas showed a
      bullous eruption consistent with erythema multiforme. The patient underwent
      immediate and delayed hypersensitivity tests. Intradermal and patch tests to
      liquid prednisone were positive. The patient was discharged on oral
      methylprednisolone and has not had recurrence of the skin lesions. In conclusion,
      a case of prednisone sensitivity in a patient with SLE is presented here. An
      alternative preparation, methylprednisolone, was used to successfully treat her
      underlying condition.

PMID- 10337683
TI  - What syndrome is this? Restrictive dermopathy.

PMID- 10337684
TI  - An asymptomatic abdominal nodule in a 5-year-old boy.

PMID- 10337685
TI  - Tinea pedis: the child and the family.

PMID- 10337686
TI  - Menarche precipitating the onset of atopic dermatitis.

PMID- 10337687
TI  - Juvenile xanthogranuloma: further evidence of a reactive etiology.

PMID- 10337688
TI  - The pattern of inheritance in KID syndrome.

PMID- 10337689
TI  - Atrophoderma vermiculata along Blaschko lines.

PMID- 10337690
TI  - Paracetamol-induced bilateral symmetric, multiple fixed drug eruption (MFDE) in a
      child.

PMID- 10337691
TI  - Linear acantholytic dyskeratotic epidermal nevus of the sole.

PMID- 10337692
TI  - [PACS. Current status and possible applications].

PMID- 10337693
TI  - [Medical picture archiving and communication systems (PACS). Recommendations of
      the Committee of Computer Services of the German Research Society on compliance
      with recommendations of the university building code promotion law].

PMID- 10337694
TI  - [Economic effects of integrated RIS-PACS solution in the university environment].
AB  - PROBLEM: The goal of the current article is to demonstrate how qualitative and
      monetary effects resulting from an integrated RIS/PACS installation can be
      evaluated. METHODS: First of all, the system concept of a RIS/PACS solution for a
      university hospital is defined and described. Based on this example, a generic
      method for the evaluation of qualitative and monetary effects as well as
      associated risks is depicted and demonstrated. To this end, qualitative analyses,
      investment calculations and risk analysis are employed. RESULTS: The sample
      analysis of a RIS/PACS solution specially designed for a university hospital
      demonstrates positive qualitative and monetary effects of the system. Under ideal
      conditions the payoff time of the investments is reached after 4 years of an
      assumed 8 years effective life of the system. Furthermore, under conservative
      assumptions, the risk analysis shows a probability of 0% for realising a negative
      net present value at the end of the payoff time period. CONCLUSION: It should be
      pointed out that the positive result of this sample analysis will not necessarily
      apply to other clinics or hospitals. However, the same methods may be used for
      the individual evaluation of the qualitative and monetary effects of a RIS/PACS
      installation in any clinic.

PMID- 10337695
TI  - [Definition and specification requirements for PAC-systems (picture archiving and
      communication system). A performance index with reference to the standard "IEEE
      Recommended Practice for Software Requirement Specifications"].
AB  - PROBLEM: The formulation of requirements is necessary to control the goals of a
      PACS project. Furthermore, in this way, the scope of functionality necessary to
      support radiological working processes becomes clear. METHOD: Definitions of
      requirements and specification are formulated independently of systems according
      to the IEEE standard "Recommended Practice for Software Requirements
      Specifications". Definitions are given in the Request for Information,
      specifications in the Request for Proposal. Functional and non-functional
      requirements are distinguished. The solutions are rated with respect to scope,
      appropriateness and quality of implementation. RESULTS: A PACS checklist was
      created according to the methods described above. It is published on the homepage
      of the "Arbeitsgemeinschaft Informationstechnologie" (AGIT) within the "Deutsche
      Rontgengesellschaft" (DRG) (http://www.uni-marburg.de/mzr/agit). CONCLUSION: The
      checklist provides a discussion forum which should contribute to an agreement on
      accepted basic PACS functionalities.

PMID- 10337696
TI  - [Filmless magnetic resonance tomography. Advantages and disadvantages in
      comparison with film reports].
AB  - At our hospital, an average MRI examination comprises 170 images. These
      examinations were evaluated exclusively on digital reporting systems with two
      high-resolution monitors for a period of 1 year. A retrospective analysis of this
      reporting method in comparison with films on a conventional viewing wall was
      performed with subjective and objective data. Radiologists and technicians were
      requested to evaluate the system on a subjective scale from 1 to 5 for seven
      topics (image analysis, inspection, time for reporting, handling, comparison with
      previous reports, quality of PC laser prints, training period). Moreover,
      personal interviews were conducted and protocols taken. Patient and image
      frequency, film costs, data transfer time and amount of system failures were
      evaluated as objective data. The most important results were: Two thirds of the
      film checking radiologists prefer the conventional viewing walls over the
      computer monitors. However, 70% of the residents prefer using the computer
      monitor for reporting. Seventy percent of the interviewed radiologists considered
      comparison with former examinations on film very difficult. Digitizing of former
      MRI examinations was not a convincing method; printing on a standard PC laser
      printer was considered to yield insufficient quality. The different acceptance
      between radiologists and residents seems to be related to different experiences.
      The reduction in film costs (48.6%) will improve further with complete PACS
      installation in the whole hospital. Data transfer rates are still poor; further
      improvement of network performance is necessary for convenient work. One whole
      MRI examination and report could be stored on CD-ROM for a cost of less than 2
      euros. This could be a future means of cheap archiving and documentation suitable
      for viewing on any PC with DICOM III viewer. Images and reports could stay with
      the patients as in the past.

PMID- 10337697
TI  - [Use of the DICOM standard in a heterogenous environment. Incompatibility or
      inoperability?].
AB  - PURPOSE: The DICOM standard, introduced in 1993, is now established in many of
      today's image modalities. Experiences with DICOM implementations and requirements
      for future developments are described. METHODS: First a brief summary of the
      development of the DICOM standard is given. Based on general observations,
      different problems with installation, programming and maintenance are outlined.
      RESULTS: The standard consists of mandatory and optional information models and
      functionalities to enable the use and development of a broad spectrum of
      applications. But the available options lead to specific applications not
      compatible with the basic idea of the standard. DISCUSSION: For functional
      communication distinct DICOM services are necessary. This includes DICOM Basic
      Worklist, Storage Commitment and Performed Procedure Step. A constructive way to
      achieve inter-operability through voluntary arrangements between manufactures and
      users will be shown.

PMID- 10337698
TI  - [RIS modality interfaces. From proprietary solutions to DICOM worklist
      management].
AB  - Radiologic information systems (RIS) and picture archiving and communication
      systems (PACS) are becoming increasingly widespread. This leads to new demands on
      the integration of the individual, formerly independent information systems (RIS,
      modalities, PACS). Possible ways of integrating individual systems are
      introduced. Besides the detailed description of different realizations of system
      communication, its role in the PACS at the university hospital in Freiburg is
      explained. The integration of different information systems still requires the
      use of proprietary interfaces. An appropriate integration generally has been
      realized in Freiburg. In the near future DICOM basic worklist management will
      standardize system integration and render an interdepartmental workflow concept
      possible. Even though an available communication standard exists, not all
      problems in the RIS-modality interface are solved. Different data models in the
      various RI systems and modalities demand certain degrees of freedom in the
      standard. Thus a satisfactory workflow cannot be guaranteed even when all
      involved systems conform with the standard.

PMID- 10337699
TI  - [Modern network technologies for data communication in the hospital].
AB  - Modern network technologies provide the basic infrastructure for information and
      communication systems in the hospital today. The goal to build up a universal
      network infrastructure which meets the broadly varied requirements. Analysis of
      data communication in the hospital and the evaluation of established network
      technologies, as well as new developments, leads to the switching concept as the
      suitable solution. Two technologies play the major role in building enterprise
      networks: the Ethernet family, based on frame switching, and ATM, based on cell
      switching. Orientation on established standards is the key to free system choice
      and grants interoperability between systems from different manufacturers.
      However, the network design must meet the application and system architecture of
      the information technology in order to achieve successful mapping of the involved
      communication profiles. This means scaling of the bandwidth as needed, suitable
      segmenting of the network and resilient links. In a further step, policy-based
      networking takes advantages of prioritizing critical applications and therefore
      reduces interdependencies across the network.

PMID- 10337700
TI  - [Uniform access to clinical data in a distributed system. The radiology example].
AB  - PURPOSE: Providing medical reports onwards and ambulatory settings in electronic
      form can improve the quality of health care delivery. Radiology was chosen as an
      example to demonstrate how to implement uniform access to clinical data in a
      hospital. METHOD: Medical professionals at the university hospital in Munich,
      Grosshadern, have access to all radiological reports of their patients. Web
      browsers are used as a front end. A centralized administration of users and
      patients is in place. RESULTS: Centralized access control and patient selection
      guarantee uniform access to all applicable data via intranet and controls access
      rights. The high acceptance of this service is reflected by the high number of
      150 requests per day. DISCUSSION: Access to radiological reports within the
      Grosshadern University Clinics was enabled via web browsers in a short time. The
      high acceptance of the system also proves its easy use. Integration of the system
      in a centralized user and patient identification system supports the unified
      access to clinical data.

PMID- 10337701
TI  - [Wish and reality in installation of a clinic-wide system for image and
      documentation access].
AB  - PROBLEM: This report describes the problems that can occur in the representation
      of the radiological workplace in a digital environment. On one hand the
      radiologist can sometimes access good equipment in "stand-alone" surroundings
      (CT, laser printer, workstations,...); on the other hand, the existing
      insufficient communication between different components is only rarely qualified
      to support the radiological workflow. This unsatisfactory framework handicaps the
      required clinic-wide distribution of radiological information. METHODS: From the
      beginning we defined user groups requiring different radiological data closely
      associated with specific hard- and software: The radiological workstation in the
      department for reporting and image processing. The demonstration workstation in
      wards/outpatient departments for clinicians involved in treatment. Standard PCs
      with access to the digital medical document for clinicians involved in treatment.
      At all workstations the medical as well as the legal unity of digital
      radiological images and the corresponding report is ensured. RESULTS: Only the
      first two user groups have unrestricted access to the RIS database and to the
      PACS archive. We have decided that the RIS should be the master of the RIS/PACS
      System. For an effective master/slave relationship between RIS and PACS archive
      and PACS workstations we suggest to mark images and/or series of images.
      CONCLUSION: The third user group depends on the information exported by the
      radiologist from PACS. After the report is written and signed by the radiologist,
      the digital report is transferred from the RIS to the HIS. The report is
      automatically attached to these images. Authorized personnel at the wards and
      outpatient are able to read the combination of validated report and exported
      radiological images as part of the digital medical record with an intranet
      browser on standard PCs.

PMID- 10337702
TI  - [Aspects of electronic patient records in radiology].
AB  - PURPOSE: The computerized patient record must provide patient- and problem
      oriented access to all relevant patient data for health care professionals. The
      aspects of such systems will be analyzed in the light of the radiologist's needs.
      METHODS: Integration of the computerized patient record in a hospital
      communication network allows automated data exchange with the ancillary systems.
      Accessibility of electronic textbooks supports case-based learning during routine
      work. RESULTS: The computerized patient record not only supports routine clinical
      tasks but also training, education and research. The workflow in a hospital can
      be supported by the computerized patient record. Studying the tasks of a
      radiology department shows that both clinicians and radiologists will benefit
      from such a system. DISCUSSION: Current implementations of clinical computerized
      workstations offer only a fraction of these features. Advances in technology and
      increasing demands at the point of care will promote the development of new
      information systems of this kind.

PMID- 10337703
TI  - [Filmless documentation and image distribution to referring physicians
      exemplified by a radiologic community practice].
AB  - In healthcare, cost effectiveness as well as the quality of examinations and
      procedures are subjected to quickly increasing expectations and demands: we like
      to demonstrate how the resulting challenges and problems can be met with
      implementation of modern information technology. Analysing the respective demands
      (pattern of quantities) and choosing the adequate technical solution/technical
      approach, we found filmless reading and the usage of digital image distribution
      to communicate with referring physicians to be cost effective as well as of
      higher quality. Special attention should be paid to the rigorous maintenance of
      data security and access. Today's information technology allows individual
      adjustment to the respective size and requirements of a radiological department
      or practice for filmless reading and digital image distribution. Working with the
      systems as a matter of routine and using all of the expanding technological
      possibilities, an important improvement of service and quality can be achieved.
      Amortisation will be obtained despite high investments, due to the subsequent
      savings in personal- and enterprise costs.

PMID- 10337704
TI  - [Regional fibrinolysis with rt-PA in hypothenar hammer syndrome].
AB  - The hypothenar hammer syndrome (HHS) is characterized by lesions of the ulnar
      artery secondary to repetitive trauma to the hypothenar eminence. We report the
      case of an orthopedic surgeon with HHS due to his occupational practice.
      Angiography and MRI confirmed an aneurysm of the ulnar artery and embolic
      occlusions of his carpal and digital arteries. Patency was reestablished with
      regional thrombolysis using rt-PA. So far there have been no reports on
      thrombolysis with rt-PA in HHS.

PMID- 10337705
TI  - [Pulmonary, nodular cavernous, calcifying form of amyloidosis].
AB  - We report a rare case of pulmonary nodular amyloidosis featuring all typical
      morphologic alterations associated with this disease; multiple amyloidomas,
      calcification and cavernous transformation were present. Definite diagnosis was
      established histologically with CT-guided biopsy. The different types of
      pulmonary amyloidosis and their radiological appearances are described and
      discussed.

PMID- 10337706
TI  - [Thoracic space-occupying lesion 10 years after mastectomy. Fibrous mesothelioma
      of the pleura].

PMID- 10337707
TI  - [Soft tissue tumors. II].

PMID- 10337708
TI  - [The year 2000 problem in radiology].

PMID- 10337709
TI  - [Larger radiology clinics are superior to smaller facilities].

PMID- 10337710
TI  - ["There is no cost explosion in public health service". Insurance contributions
      are hardly relevant for salary deductions].

PMID- 10337711
TI  - [Standardized image transmission. An important step in the direction of
      teleradiology and telemedicine].

PMID- 10337716
TI  - Chemoprevention of head and neck and lung (pre)cancer.
AB  - Oral cancer is often preceded by precancerous lesions, the most common of which
      is leukoplakia. Several treatment modalities are available: elimination of the
      possible cause, cold knife, laser, or cryosurgery, and topical application of
      bleomycin and 5-fluorouracil. In research, oral leukoplakia is used as a model to
      study the value of chemoprevention as a strategy to prevent cancer, because its
      effect is directly visible and material for analysis is easily obtainable from
      the mouth. In several studies and chemoprevention trials the efficacy of
      retinoids, retinol and/or beta-carotene on oral leukoplakia has been
      demonstrated. Second primary tumors occur in 10-30% of head and neck cancer
      patients and 10% of lung cancer patients. Chemoprevention offers an attractive
      approach to combat this threat to such patients, which is bound to cast a shadow
      over their lives. In the last 10-15 years several chemoprevention studies with
      vitamin A, retinoids or agents working through other mechanisms (antioxidants)
      have been launched. The largest chemoprevention study in curatively treated early
      stage oral cancer, laryngeal cancer and lung cancer (N = 2595) is EUROSCAN, an
      EORTC study initiated in 1988. End-points are second tumors, local/regional
      recurrence and distant metastases, and long-term survival rates. Preminary
      results will be available in 1998.

PMID- 10337715
TI  - Is there a genetic basis for lung cancer susceptibility?
AB  - The major risk factor for lung cancer is exposure to tobacco smoke. Exposure to
      radon, heavy metals used in smelting, and asbestos also greatly increase risks
      for lung cancer. However, only about 11% of tobacco smokers ultimately develop
      lung cancer, suggesting that genetic factors may influence the risk for lung
      cancer among those who are exposed to carcinogens. Further support for this
      hypothesis is provided by several epidemiological studies and also from molecular
      epidemiological studies. Epidemiological studies show approximately 14-fold
      increased risks for lung cancer among average tobacco smokers and approximately
      2.5-fold increased risks attributable to a family history of lung cancer after
      controlling for tobacco smoke. Segregation analyses suggest that a rare autosomal
      dominant gene may explain susceptibility to early-onset lung cancer, but these
      results explain a minority of lung cancer cases, which include a family history.
      Therefore, more common genetic variants or polymorphisms are hypothesized to
      affect lung cancer risk. Environmental carcinogenesis resulting from tobacco
      smoke exposure is a complex process that can involve activation of procarcinogens
      that lead to adduct formation and subsequent failure of DNA repair, which should
      normally remove these adducts. Studies comparing DNA repair capacity among newly
      diagnosed lung cancer patients and age-matched controls indicate significant
      differences between the two groups. On culturing with bleomycin lymphocytes from
      lung cancer patients and age- and ethnicity-matched controls, the lymphocytes
      from lung cancer cases have been consistently observed to show higher levels of
      chromatid breaks than the control lymphocytes. A similar assay has been developed
      using benzo-[alpha]pyrene diol-epoxide (BPDE), a reactive substrate that is
      derived by in vitro processes from benzo[alpha]pyrene, a major carcinogen in
      tobacco smoke. Results from this assay show an even more significantly higher
      level of damaged chromatids in lung cancer patients than in controls. Poor DNA
      repair is independent of tobacco smoking status. The cellular processes involved
      in DNA repair of bleomycin and BPDE have not yet been fully elaborated. However,
      the consistency of findings with these two carcinogens indicates that DNA repair
      capacity influences risk for lung cancer among individuals.

PMID- 10337717
TI  - Rationale and mechanisms of cancer chemoprevention.
AB  - Chronic degenerative diseases, including cancer, have a multifactorial origin. An
      intricate network connects each disease with multiple risk factors and also with
      multiple protective factors. From the point of view of preventive medicine, this
      implies that removal of a single risk factor will have a beneficial impact on the
      epidemiology of several diseases. However, in contrast to the situation in
      infectious diseases, it will never be possible to eradicate any chronic
      degenerative disease in this way, because each of them is associated with other
      risk factors at the same time. Similarly, a single protective factor can decrease
      the risk of contracting different diseases, and the risk of developing a single
      disease can be attenuated by different protective factors, often in a coordinated
      fashion. It is thus evident that cancer can be prevented not only by avoiding
      exposure to recognized risk factors, but also, as a complementary approach
      referred to as chemoprevention, by favouring the intake of protective factors and
      by fortifying the physiological defences of the host organism. Chemoprevention
      can be applied in a primary prevention setting when it is addressed to healthy
      individuals with the goal of inhibiting occurrence of the disease. Conversely, it
      is applied in a secondary prevention setting when it is addressed to individuals
      affected by premalignant tumours, with the goal of reversing the carcinogenesis
      process. A rational use of chemopreventive agents is based not only on the
      assessment of their efficacy and safety but also on understanding of their
      mechanisms of action. A detailed classification is proposed, which covers a
      variety of mechanisms interfering with different phases of mutagenesis and
      carcinogenesis. However, this sequence of events does not fit in with a rigid
      scheme, and several mechanisms, such as inhibition of genotoxic effects,
      antioxidant activity and scavenging of free radicals, inhibition of cell
      proliferation, and signal transduction modulation are reiterated several times
      throughout evolution of these processes. Some of these mechanisms are also
      involved in advanced stages of tumour progression towards malignancy, invasion
      and metastasis, and can therefore conveniently be applied for the tertiary
      prevention of cancer. Most inhibitors work through multiple mechanisms, examples
      of which are given for 18 chemopreventive agents.

PMID- 10337718
TI  - Metabolic targets of cancer chemoprevention: interruption of tumor development by
      inhibitors of arachidonic acid metabolism.
AB  - Tumor promotion is understood as a process that favors the clonal outgrowth of
      single mutated (initiated) cells to premalignant lesions through co-mitogenic and
      anti-apoptotic effects. This process can be evoked by repeated induction of a
      regenerative tissue response as achieved either by irritation and wounding or by
      agents (tumor promoters) that interact with the corresponding pathways of
      cellular signaling. Metabolic processes regulated by such pathways and essential
      for tumor development are potential targets of cancer chemoprevention. Examples
      are provided by the expression of ornithine decarboxylase and the activation of
      eicosanoid formation from arachidonic acid. Arachidonic acid metabolism is a
      particularly attractive and important target of chemopreventive measures. Its
      induction is a characteristic response to tissue damage and irritation and an
      apparently critical event in epithelial tumor promotion. Inhibitors of eicosanoid
      formation, such as nonsteroidal anti-inflammatory drugs, rank among the most
      powerful chemopreventive agents in animal models and have been shown to halve the
      incidence of colorectal cancer in man. Recently, the role of cyclooxygenase-2
      (COX-2)-catalyzed prostaglandin synthesis has been the subject of much attention.
      COX-2 is a typical 'emergency enzyme', since in most tissues it is transiently
      induced only in the course of repair and defense reactions. In epithelial
      neoplasia, i.e. in skin and colorectal tumors, the enzyme is constitutively
      overexpressed along different molecular pathways, and it seems to be critically
      involved in tumor promotion. Consequently, specific COX-2 inhibitors have been
      shown to exhibit considerable cancer chemopreventive potential. The putative role
      of other pathways of arachidonic acid metabolism in tumor promotion and malignant
      progression is presently under investigation.

PMID- 10337719
TI  - Prognostic implications of cancer susceptibility genes: any news?
AB  - Recent advances in our understanding of the genetic basis of several inherited
      predispositions to cancer have raised the possibility that there may be
      differences in prognosis between patients harbouring genetic susceptibilities to
      cancer and persons presenting with sporadic disease. The two best studied models
      of inherited susceptibilities to cancer will be considered, those of colorectal
      cancer and familial breast cancer. Familial colorectal cancer can be subdivided
      into essentially two groups: familial adenomatous polyposis and hereditary non
      polyposis colorectal cancer. Familial breast cancer can be subdivided into three
      groups: those that can be accounted for by mutations in the breast cancer
      susceptibility gene BRCA 1, families harbouring mutations in BRCA 2 and families
      where neither BRCA 1 nor BRCA 2 appear to be involved. In this chapter several
      aspects of these inherited cancer predispositions will be discussed and compared
      with their equivalent sporadic disease counterparts.

PMID- 10337720
TI  - Identification of the woman at risk for breast cancer: problem solved?
AB  - The clinical availability of antiestrogens to reduce breast cancer incidence has
      focused increased attention on the ability to identify women at increased risk
      for breast cancer development. Multiple risk factors, which can be grouped under
      the headings of genetic and familial factors, hormonal factors, benign breast
      disease, and environmental factors have been described. However, of these risk
      factors, only genetic mutations and atypical hyperplasia, lobular carcinoma in
      situ, and ductal carcinoma in situ have a relative risk of four or more. Many of
      the other risk factors, although associated with statistically significant
      increases in risk in large populations, are of little practical significance for
      the individual woman. Lack of knowledge of the interactions among various
      positive and negative risk factors also complicates the evaluation of risk. In
      addition, the impact of some risk factors may not be constant over time, and the
      majority of data on risk come from studies of white women, and little is known
      about the impact of ethnic diversity on these factors. Finally, there is no
      consensus about what level of increase in risk is necessary for a women to be
      labeled "high risk." It is important to recognize that only 50% of breast cancers
      occur in women with identifiable risk factors other than age. Thus, an improved
      ability to define risk status is needed if prevention studies directed at high
      risk women are to have a major impact on breast cancer incidence and mortality.

PMID- 10337721
TI  - Development of a new prevention maintenance therapy for postmenopausal women.
AB  - In spring 1998, breast cancer prevention emerged from being a concept to being a
      reality. The National Surgical Adjuvant Breast and Bowel Project prevention trial
      showed that tamoxifen reduced breast cancer by 45% in high-risk women between the
      ages of 35 and 75. Additionally, an evaluation of 10,550 patients randomized to
      osteoporosis trials of placebo versus raloxifene demonstrated a 50% reduction in
      the incidence of breast cancer in woman taking raloxifene. For the future, a
      Study of Tamoxifen Against Raloxifene (STAR) is ongoing in high-risk
      postmenopausal women. This chapter describes the biological rationale for the
      current clinical advances.

PMID- 10337722
TI  - Chemoprevention of human cancer: a reasonable strategy?
AB  - The field of chemoprevention of cancer in humans is at a teenage level of
      maturity. There is anticipation and energy, and some promising results have come
      in, but it's unclear whether the entire enterprise is worth the effort.
      Reflecting on the status of the organism and where we are in its developmental
      history is therefore an important exercise at this time. Empirical and
      philosophical perspectives are offered for several key questions: Why prevent
      Cancer? What is the preclinical evidence that chemoprevention of cancer in humans
      should work? What is the clinical evidence that chemoprevention agents work? What
      is the clinical evidence that chemoprevention agent don't work? What is the
      status of ongoing randomized phase III/IV chemoprevention trials? The answers to
      each of these questions provide a part of the scaffold for a logical platform for
      the launching of the chemoprevention imperative as an integral part of our
      approach to the overall management of human cancer.

PMID- 10337723
TI  - Chemoprevention of colorectal cancer.
AB  - Epidemiological studies have emphasised the major role of diet in the aetiology
      of large bowel cancer. Attempts to identify causative or protective factors in
      epidemiological and experimental studies have led to some discrepancies. The time
      has come to test the most important hypotheses within the frame-work of
      intervention studies. Among studies specifically devoted to colorectal
      carcinogenesis, eight have been completed and five are ongoing. They evaluate the
      effect of the intervention on adenoma recurrence and, in three studies, on
      adenoma growth. Five intervention trials considering cardiovascular diseases and
      different cancer sites will provide data on the effect of the intervention on
      colorectal cancer incidence. Vitamins and antioxidants, fibre or calcium
      supplementation, aspirin therapy and dietary modifications are evaluated. Most of
      the available data do not support the idea of a protective effect of vitamins and
      antioxidants against colorectal carcinogenesis. It is too early to draw any
      conclusions on the effects of fibre, calcium supplementation, aspirin therapy and
      dietary intervention. The results of ongoing studies will be available within 2
      years. If one of the evaluated interventions proves efficient, the benefits of a
      simple, safe and inexpensive prophylaxis for a very common cancer will be clear.

PMID- 10337724
TI  - [Gonorrhea].

PMID- 10337725
TI  - [Chancroid].

PMID- 10337726
TI  - [Granuloma inguinale (donovanosis)].

PMID- 10337727
TI  - [Bacterial vaginosis].

PMID- 10337728
TI  - [Congenital syphilis].

PMID- 10337729
TI  - [Syphilitic aortitis].

PMID- 10337730
TI  - [Mycoplasmal urethritis].

PMID- 10337731
TI  - [Cervicitis].

PMID- 10337732
TI  - [Inclusion conjunctivitis of the newborn infant].

PMID- 10337733
TI  - [Lymphogranuloma inguinale].

PMID- 10337734
TI  - [Cervicitis].

PMID- 10337735
TI  - [Chlamydia trachomatis proctitis].

PMID- 10337736
TI  - [Pelvic inflammatory disease].

PMID- 10337737
TI  - [Chlamydia genital infection].

PMID- 10337738
TI  - [Perihepatitis (Fitz-Hugh-Curtis syndrome)].

PMID- 10337739
TI  - [Hepatitis viruses].

PMID- 10337740
TI  - [Condyloma acuminatum].

PMID- 10337741
TI  - [Genital herpes].

PMID- 10337742
TI  - [Molluscum contagiosum (genital)].

PMID- 10337743
TI  - [Trichomoniasis].

PMID- 10337744
TI  - [Vulvovaginal candidiasis].

PMID- 10337745
TI  - [TORCH syndrome].

PMID- 10337746
TI  - [Congenital cytomegalovirus infection].

PMID- 10337747
TI  - [Congenital rubella syndrome].

PMID- 10337748
TI  - [Scarlet fever].

PMID- 10337749
TI  - [Rheumatic fever].

PMID- 10337750
TI  - [Kawasaki disease].

PMID- 10337751
TI  - [Yersinia pseudotuberculosis infection].

PMID- 10337752
TI  - [Poliomyelitis and polio-like paralysis].

PMID- 10337753
TI  - [Infant botulism].

PMID- 10337754
TI  - [Reye's syndrome].

PMID- 10337756
TI  - [Pharyngitis].

PMID- 10337755
TI  - [Acute nasopharyngitis (common colds)].

PMID- 10337757
TI  - [Bronchitis, bronchiolitis].

PMID- 10337758
TI  - [Tuberculosis in children].

PMID- 10337759
TI  - [Human calicivirus (SRSV) gastroenteritis].

PMID- 10337760
TI  - [Urinary tract infection].

PMID- 10337761
TI  - [Infectious mononucleosis].

PMID- 10337762
TI  - [Pharyngoconjunctival fever].

PMID- 10337763
TI  - [Herpangina].

PMID- 10337764
TI  - [Mumps (epidemic parotitis)].

PMID- 10337765
TI  - [Erythema infectiosum].

PMID- 10337766
TI  - [Exanthem subitum].

PMID- 10337767
TI  - [Varicella].

PMID- 10337768
TI  - [Rubella and measles].

PMID- 10337769
TI  - [Hand-foot and mouth disease].

PMID- 10337770
TI  - [Neonatal herpetic infection].

PMID- 10337771
TI  - [Eczema herpeticum].

PMID- 10337772
TI  - [Herpetic gingivostomatitis].

PMID- 10337773
TI  - [Ophthalmia neonatorum (neonatal conjunctivitis)].

PMID- 10337774
TI  - [Diarrhea associated with systemic infection].

PMID- 10337775
TI  - [Mastitis puerperalis].

PMID- 10337776
TI  - [Puerperal endometritis and parametritis].

PMID- 10337777
TI  - [Chorioamnionitis].

PMID- 10337778
TI  - [Abscess in Douglas pouch].

PMID- 10337779
TI  - [Bartholinitis, Bartholin's abscess, Bartholin's cyst].

PMID- 10337780
TI  - [Vulvitis].

PMID- 10337781
TI  - [Bacterial vaginitis].

PMID- 10337782
TI  - [Endometritis, myometritis].

PMID- 10337783
TI  - [Adnexitis (salpingitis, oophoritis)].

PMID- 10337784
TI  - [Pelvic abscess].

PMID- 10337785
TI  - [Balanoposthitis].

PMID- 10337786
TI  - [Asymptomatic bacteriuria].

PMID- 10337787
TI  - [Nonbacterial prostatitis].

PMID- 10337788
TI  - [Prostatic abscess].

PMID- 10337789
TI  - [Renal abscess and perinephric abscess, perirenal abscess].

PMID- 10337790
TI  - [Epididymitis].

PMID- 10337791
TI  - [Orchitis].

PMID- 10337792
TI  - [Erysipelas].

PMID- 10337793
TI  - [Mycetoma pedis (nocardiosis)].

PMID- 10337794
TI  - [Cutaneous alternariosis].

PMID- 10337795
TI  - [Skin diseases associated with Malassezia furfur].

PMID- 10337796
TI  - [Verruca vulgaris].

PMID- 10337797
TI  - [Verruca plana juvenilis].

PMID- 10337798
TI  - [Molluscum contagiosum].

PMID- 10337799
TI  - [Osteomyelitis].

PMID- 10337800
TI  - [Infectious arthritis].

PMID- 10337801
TI  - [External otitis].

PMID- 10337802
TI  - [Acute otitis media].

PMID- 10337803
TI  - [Chronic otitis media].

PMID- 10337804
TI  - [Bullous myringitis].

PMID- 10337805
TI  - [Labyrinthitis].

PMID- 10337806
TI  - [Sinusitis].

PMID- 10337807
TI  - [Maxillary sinusitis].

PMID- 10337808
TI  - [Sphenoid sinusitis].

PMID- 10337809
TI  - [Suppurative parotitis].

PMID- 10337810
TI  - [Acute tonsillitis, peritonsillitis, and deep neck infection].

PMID- 10337811
TI  - [Acute mastoiditis].

PMID- 10337812
TI  - [Bacterial conjunctivitis].

PMID- 10337813
TI  - [Viral conjunctivitis].

PMID- 10337814
TI  - [Bacterial keratitis].

PMID- 10337815
TI  - [Viral keratitis].

PMID- 10337816
TI  - [Fungal keratitis].

PMID- 10337817
TI  - [Blepharitis, hordeolum, abscess in the lids].

PMID- 10337818
TI  - [Bacterial endophthalmitis].

PMID- 10337819
TI  - [Viral infectious diseases of the retina].

PMID- 10337820
TI  - [Fungal endophthalmitis].

PMID- 10337821
TI  - [Orbital cellulitis].

PMID- 10337822
TI  - [Canaliculitis, dacryocystitis, dacryoadenitis].

PMID- 10337823
TI  - [Acanthamoeba keratitis].

PMID- 10337824
TI  - [Periodontal disease and periodontal abscess].

PMID- 10337825
TI  - [Osteomyelitis of the jaw].

PMID- 10337826
TI  - [Deep neck infection and cervical necrotizing fasciitis due to odontogenic
      infections].

PMID- 10337827
TI  - [Ludwig's angina].

PMID- 10337829
TI  - [Necrotizing stomatitis].

PMID- 10337828
TI  - [Aphthous stomatitis].

PMID- 10337830
TI  - [Vertical infection].

PMID- 10337831
TI  - [Imported infectious disease].

PMID- 10337832
TI  - [Zoonosis].

PMID- 10337833
TI  - [AIDS-associated infections].

PMID- 10337834
TI  - [Hospital infection].

PMID- 10337835
TI  - [Endogenous infection].

PMID- 10337836
TI  - [Opportunistic infection].

PMID- 10337837
TI  - [Bacterial infection-induced autoimmune disease].

PMID- 10337838
TI  - [Potential mechanism of viral infection in immunological diseases].

PMID- 10337839
TI  - [Bacterial infection and malignancies].

PMID- 10337841
TI  - [Communicable diseases defined in the new 'Infectious Diseases Prevention Law'].

PMID- 10337840
TI  - [Virus-associated malignancies].

PMID- 10337842
TI  - The core of caregiving.

PMID- 10337843
TI  - Caregiving effectiveness in families managing complex technology at home:
      replication of a model.
AB  - BACKGROUND: Original testing of the Caregiving Effectiveness Model, in a randomly
      drawn national sample (n = 111) of family caregivers, explained variance in the
      home care outcomes of patient physical condition, technology side effects, and
      quality of life. The variables in the resulting model reflected the challenges
      specific to family caregivers managing complex home care for the growing
      populations of technology-dependent patients. OBJECTIVE: To seek further
      empirical verification of the relationships among home care outcomes and the
      variables in the original trimmed model. METHOD: Data were collected from family
      caregivers (n = 31) and adult patients (n = 31) requiring lifelong daily total
      parenteral nutrition (TPN) infusion technology for nonmalignant bowel disease.
      Hierarchical regression was used with variables entered in the two stages that
      coincided with the model configuration of Caregiving and Adaptive concepts, with
      a criteria of alpha = .05 at a power of > .80. RESULTS: The model variables
      explained variance in all four outcomes. Specifically, Caregiving and Adaptive
      concept variables contributed to the explained variance in quality of life of
      both caregivers (R2 = .559, F = 4.65, p = .003) and patients (R2 = .464, F =
      5.17, p = .04). Variance in patients' physical condition (R2 = .345, F = 6.37, p
      = .032) and the technological side effects outcomes (R2 = .357, F = 3.60, p =
      .018) were accounted for by variables in the model. CONCLUSIONS: In this sample,
      the Caregiving Effectiveness Model concepts accounted for significant variance in
      home care outcomes (quality in patients' and caregivers' lives, patients'
      physical condition, and technological side effect). Longitudinal study of this
      sample will determine if variables explain variance over time, as in the original
      model testing.

PMID- 10337844
TI  - Distress and growth outcomes in mothers of medically fragile infants.
AB  - BACKGROUND: With recent advances in medical and nursing care, many high-risk
      infants are surviving the neonatal period with severe, life-threatening chronic
      illnesses, resulting in extended hospitalizations and/or frequent
      rehospitalizations and long periods of dependence on technology for survival.
      OBJECTIVE: To describe the factors predicting maternal adjustment in mothers
      caring for medically fragile infants. METHOD: Subjects were mothers (n = 67)
      whose infants had a serious life-threatening illness requiring hospitalization
      and technology for survival. Data for this longitudinal study were collected at
      enrollment and hospital discharge, and at 6, 12, and 16 months after birth.
      Distress was measured as depressive symptoms using the Center for Epidemiologic
      Studies Depression Scale, and growth was assessed using a personal developmental
      impact rating scale. Data about personal characteristics, parental role
      attainment, infant-illness characteristics, and maternal illness distress were
      collected. RESULTS: Mothers of medically fragile infants experience distress and
      growth as a result of their child's illness. Mean scores on the depression scale
      at both time points were moderately high and a high percentage of mothers scored
      at risk for depressive symptoms. Maternal developmental impact ratings at 6
      months were neutral to slightly negative and at 16 months were between neutral
      and positive. While the mean depressive symptom scores and maternal developmental
      ratings were lower at the later time points, these differences were not
      significant. Maternal depressive symptoms and developmental impact ratings were
      moderately but negatively correlated at 6 and 16 months, indicating that higher
      depressive symptoms were related to more negative developmental impact ratings.
      Distress was influenced by maternal characteristics, hospital environmental
      stress, and worry about the child's health. Growth was influenced by
      characteristics of the child's illness, hospital environmental stress, concern
      about the child's health, and level of maternal role attainment. CONCLUSIONS:
      Nurses should consider personal characteristics and level of parental role
      attainment as well as characteristics of the child and illness-related distress
      in their approaches to intervention with mothers of critically ill infants.

PMID- 10337845
TI  - Diagnosis disclosure by family caregivers to children who have perinatally
      acquired HIV disease: when the time comes.
AB  - BACKGROUND: Children with perinatally acquired HIV disease (PAHD) can be
      relatively symptom-free and live to school age and older. These children often
      confront their caregivers with questions about the illness and complex
      treatments; however, caregivers may try to avoid disclosing the diagnosis of PAHD
      to the child. PURPOSE: To generate a substantive theory that describes and
      explains how family caregivers manage diagnosis disclosure to a child who has
      PAHD. METHOD: Using grounded theory, a substantive theory was constructed based
      on the accounts of 18 ethnically diverse families. Eight families had 10 children
      with PAHD who had been told their diagnosis. Ten families had 10 children with
      PAHD who had not been told their diagnosis. RESULTS: The basic social
      psychological problem was identified as caregiver readiness to disclose the
      diagnosis. When the Time Comes was identified as the central phenomenon linked to
      the problem of caregiver readiness. Causal conditions, intervening conditions,
      and strategic responses of caregivers and children were discovered and are
      inextricably linked to the central phenomenon. CONCLUSIONS: The process by which
      family caregivers respond to diagnosis disclosure to children with PAHD is based
      on the perceived self-readiness of the caregiver to disclose the diagnosis and
      illness-related information to their child.

PMID- 10337846
TI  - Mood and blood pressure responses in black female caregivers and noncaregivers.
AB  - BACKGROUND: Substantial interaction between mood and blood pressure, especially
      in the context of caregiving for a dependent elder, could increase the risk in
      the already at-risk population of black women for either higher blood pressure or
      the onset of hypertension. OBJECTIVES: To examine the relationship between mood
      symptoms and daytime ambulatory blood pressures during a 12-hour period in Black
      female caregivers and noncaregivers. METHOD: A prospective cohort design was
      employed to study black females 18 years of age or older identified by randomly
      selected elders as the provider or potential provider of 5 or more hours of care
      per week to the elder. Mood symptoms were measured on visual analogue scales by
      the subjects in a diary attached to a retractable clip key ring worn by the
      subject. Blood pressure responses were measured with automated portable blood
      pressure monitors every 30 minutes. Additional risk and treatment factors were
      considered for descriptive purposes. RESULTS: The two groups were equivalent on
      all hypertension risk and treatment factors except alcohol use (more
      noncaregivers consumed alcohol). Among caregivers, anger and mean diastolic blood
      pressure (DBP) were negatively related (parameter = -0.64, SE = .23, p = .01) and
      the negative relationship between anger and systolic blood pressure approached
      significance (parameter = -0.81, SE = 0.65, p = 0.10). Anxiety and sadness were
      not significant predictors. CONCLUSION: Among black caregivers, elevated anger
      was associated with significant decreases in DBP, while lowered anger was
      associated with significant increases in DBP. Whether lower anger scores reflect
      a low level of perceived anger or suppressed anger among black caregivers should
      be explored in future studies.

PMID- 10337847
TI  - Problem-solving counseling for caregivers of the cognitively impaired: effective
      for whom?
AB  - BACKGROUND: Individualized problem-solving counseling for caregivers of
      cognitively impaired relatives is thought to help caregivers cope with the stress
      and burden of caregiving. Few studies have shown the effectiveness of counseling
      for these caregivers. OBJECTIVES: To determine the effectiveness of
      individualized problem-solving counseling by nurses for caregivers and the
      expenditures of health care utilization. METHOD: Caregivers (n = 77) of the
      cognitively impaired living at home were randomized to receive nurse counseling
      or not. Psychosocial adjustment to their relative's illness, psychological
      distress, burden, coping skills, and expenditures were measured after 6 months
      and 1 year. RESULTS: Although on average, all caregivers receiving nurse
      counseling indicated no improvement in psychosocial adjustment to their
      relative's illness, psychological distress, or caregiver burden, they found
      counseling very helpful and it was effective for a subgroup of caregivers. Those
      with poor logical analysis coping skills at baseline had decreased psychological
      distress (F(1,53) = 9.7, p = .003) and improved psychosocial adjustment (F(1,53)
      = 4.7, p = .035) after 1 year. Caregivers in control and counseling groups whose
      relatives entered a nursing home improved their psychosocial adjustment 23% on
      average whereas those continuing to live in the community decreased by 8%. Almost
      half as many relatives entered nursing homes in the counseling group (n = 9 vs. n
      = 5) but these compared to control group relatives had greater annualized per
      person expenditures for health and social services (Cdn$23,437 vs. Cdn$15,151).
      CONCLUSIONS: Caregivers found nurse counseling most helpful. Those indicating
      infrequent use of logical analysis coping skills showed benefits.

PMID- 10337848
TI  - Cognitive-behavioral intervention for homebound caregivers of persons with
      dementia.
AB  - BACKGROUND: Family caregivers experience considerable stress in their management
      of specific behaviors of persons with dementia. OBJECTIVE: To examine the effects
      of an 8-week cognitive-behavioral (C-B) intervention tailored to the specific
      deficits of persons with dementia (PWDs) on selected outcomes for homebound
      caregivers and the functional status of the PWD. METHOD: The design was a two
      group randomized trial with measures taken at baseline, 4 weeks, 8 weeks, and 12
      weeks. Subjects were 65 caregiver-care recipient dyads. A majority of the 65
      female caregivers were spouses with a mean age of 66.5 years. Thirty-one women
      who received the C-B intervention were compared to 34 who received the attention
      only (A-O) placebo telephone calls. Coping strategies, perceptions of caregiver
      burden and satisfaction, and emotional and physical health were assessed at the
      four points in time. RESULTS: Results indicated a time by group interaction in
      depression, with less depression in the C-B than the A-O group. Both groups
      experienced a significant reduction in anxiety, and a significant consistent
      decrease in satisfaction over time. Both groups also demonstrated decreased use
      of emotion-focused coping strategies. CONCLUSION: The results suggest a plausible
      effectiveness of the C-B intervention in preventing the progression of
      depression. Suggestions for future research are provided.

PMID- 10337849
TI  - Family recruitment issues and strategies: caregiving in rural African Americans.

PMID- 10337850
TI  - Lack of leptin suppression in response to hypersecretion of catecholamines in
      pheochromocytoma patients.
AB  - Leptin is a major regulator of body weight and energy balance and is subject to a
      variety of regulatory inputs. From several previous studies, catecholamines have
      been suggested to exert an inhibitory influence on leptin production in animals.
      In the present study, we analyzed leptin levels in relation to catecholamine
      hypersecretion in 27 human pheochromocytoma patients. A 10-fold increase in
      circulating norepinephrine (P < .0001) did not result in suppression of plasma
      leptin in the patients compared with normal controls (median and interquartile
      range, 4.3 ng/mL [2.4 to 6.8] v 2.2 ng/mL [1.9 to 3.0] in men and 18.6 [12.3 to
      27.0] v 11.4 [10.1 to 15.9] in women). Correlation analysis indicated a
      significant association of leptin with epinephrine in normal subjects (r = -.81,
      P < .0001), but not in pheochromocytoma patients. Leptin was not related to
      norepinephrine in either group. In conclusion, our data suggest that a chronic
      elevation of catecholamines does not cause suppression of leptin secretion in
      patients with pheochromocytoma. This lack of effect may be attributable to the
      development of tolerance of adipose tissue leptin production to catecholamines.

PMID- 10337851
TI  - Effect of resistance training with or without chromium picolinate supplementation
      on glucose metabolism in older men and women.
AB  - The effect of 12 weeks of resistance training (RT) with or without chromium
      picolinate (Cr-pic) supplementation on glucose tolerance was assessed in
      moderately overweight older men and women (age, 62 +/- 4 years; body mass index
      [BMI], 29.1 +/- 2.5 kg/m2). Seventeen men and 15 women were randomized to groups
      that consumed either 17.8 micromol chromium per day (924 microg Cr/d) as Cr-pic
      or a placebo (<0.1 microg Cr/d) while performing RT twice weekly. For all 32
      subjects combined, fasting glucose increased but there were no changes in insulin
      or C-peptide concentrations after 12 weeks of RT. In response to an oral glucose
      challenge, the glucose and C-peptide areas under the curve (AUCs) were unchanged,
      whereas there was a 19% decrease in the insulin AUC (from 68 +/- 53 to 55 +/- 29
      x 10(3) pmol/L/180 min, P = .045). The RT responses for the fasting concentration
      or AUC for glucose, insulin, or C-peptide were not influenced by Cr-pic. The
      decrease in the insulin AUC without any change in insulin secretion, as evidenced
      by a lack of change in the C-peptide AUC, suggests enhanced insulin clearance
      from the circulation with RT. Collectively, these data suggest that RT decreases
      the insulin response following an oral glucose challenge in older moderately
      overweight men and women without affecting glucose tolerance. The data also
      suggest that the decrease in circulating insulin may result from an increase in
      insulin clearance, not a decrease in insulin secretion. High-dose Cr-pic
      supplementation had no effect on any measure of glucose metabolism during RT.

PMID- 10337852
TI  - A study on human umbilical cord endothelial cells: functional modifications
      induced by plasma from insulin-dependent diabetes mellitus patients.
AB  - The aim of the present study was to evaluate the action of plasma from insulin
      dependent diabetic (IDDM) pregnant women on nitric oxide synthase (NOS) activity
      in cultured human umbilical vein endothelial cells (HUVECs). We also studied the
      effect of the plasma on cytosolic calcium and on Na+/K+-adenosine triphosphatase
      (ATPase) activity. Dynamic fluorescence studies of membrane fluidity were
      contemporarily performed to detect a direct effect of plasma on the endothelial
      cell membrane. We observed a significant increase in NOS activity, intracellular
      calcium, and Na+/K+-ATPase activity in cultured HUVECs exposed to IDDM plasma.
      Our dynamic fluorescence study showed a different microenvironmental organization
      of the cellular membrane after incubation with plasma from IDDM pregnant women,
      with a marked decrease in microheterogeneity as evaluated in terms of 1-(4
      trimethylaminophenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) lifetime distribution
      width. The present investigation suggests that plasma from IDDM pregnant women
      can cause a generalized disturbance in the function of endothelial cells cultured
      from healthy subjects. Such a modification might play a central role in the
      pathogenesis of the vascular complications of the disease.

PMID- 10337853
TI  - Influence of streptozotocin-induced diabetes in rats on the lithium content of
      tissue and the effect of dietary lithium supplements on this diabetic condition.
AB  - To study the effects of lithium supplementation on the diabetic condition, we
      measured the lithium concentration in the liver, kidney, and muscle from
      streptozotocin (STZ)-induced diabetic male Sprague-Dawley (SD) rats that were
      either treated or untreated with peroral lithium carbonate (0.3 mg/mL). The data
      showed that the lithium content of the liver and muscle was significantly lower
      in STZ rats than in normal control rats (0.22 +/- 0.05 v 1.30 +/- 0.15, P < .01,
      and 0.79 +/- 0.30 v 2.48 +/- 2.00 microg/g, respectively). After 4 weeks of
      lithium carbonate supplementation, we found that (1) the lithium content of the
      liver and muscle returned to the normal range, (2) the extent of STZ-mediated
      destruction of beta cells in the pancreas decreased, (3) fasting blood glucose
      (FBG) and 2-hour postprandial blood glucose (PBG) decreased (P < .05), (4) among
      the indicators of oxidative stress and antioxidant defenses, blood lipid
      peroxidate (LPO) decreased and erythrocyte superoxide dismutase (RBC-SOD) and
      glutathione (GSH) returned to normal, and (5) hepatic LPO decreased and
      glutathione peroxidase (GSH-Px) increased. These results suggest that the
      restoration of lithium to control levels in the liver and muscle of diabetic
      animals is associated not only with decreased blood glucose but also with reduced
      oxidative stress, and consequently with the protection of insulin-secreting
      pancreatic islet cells.

PMID- 10337854
TI  - Relation of beta3-adrenergic receptor gene mutation to total body fat but not
      percent body fat and insulin levels in Thais.
AB  - A Trp64Arg mutation in the beta3-adrenergic receptor gene has been implicated in
      the pathophysiology of non-insulin-dependent diabetes mellitus and obesity.
      However, the findings have been controversial due to the use of different
      populations and different methods for the estimation of body fat. In the present
      study, the prevalence of Trp64Arg mutation of the beta3-adrenergic receptor gene
      was determined and its relation to body fat as assessed by dual-energy x-ray
      absorptiometry (DEXA) was evaluated in Thai men and women. The effect on insulin
      sensitivity as assessed by the serum insulin to glucose ratio was also examined.
      The subjects were 76 men and 135 women aged 20 to 80 years. Body fat and its
      regional distribution were assessed by DEXA. Mutation in the beta3-adrenergic
      receptor gene was determined by polymerase chain reaction (PCR)-restriction
      fragment length polymorphism. Data are expressed as the mean +/- SEM. Fifty-nine
      subjects (28.0%) had the Trp64Arg mutation in the beta3-adrenergic receptor gene;
      54 (25.6%) were heterozygotes and five (2.4%) were homozygotes. The gene
      frequency of Trp64Arg mutation was 15.2% in these subjects. In women, Trp64Arg
      mutation was not associated with the difference in total body fat (Trp/Arg or
      Arg/Arg, 19.4 +/- 1.0 kg; Trp/Trp, 19.2 +/- 0.6 kg) or percent body fat (Trp/Arg
      or Arg/Arg, 34.6% +/- 1.2%; Trp/Trp, 34.3% +/- 0.6%). In contrast to the findings
      in women, men with Trp64Arg mutation had lower total body fat after controlling
      for age (Trp/Arg or Arg/Arg, 13.2 +/- 1.1 kg; Trp/Trp, 15.8 +/- 0.7 kg; P < .05).
      However, no difference was found in percent body fat (Trp/Arg or Arg/Arg, 20.9%
      +/- 1.3%; Trp/Trp, 23.3% +/- 0.7%). No difference in the fasting insulin
      resistance index (FIRI) was found between subjects with and without Trp64Arg
      mutation. The data suggest that Trp64Arg mutation of the beta3-adrenergic
      receptor is common in Thais and appears to exert effects on total body fat but
      not percent body fat in men. Trp64Arg mutation is not associated with insulin
      resistance as assessed by the FIRI in Thais.

PMID- 10337855
TI  - Insulin counterregulatory hormones are ineffective in neonatal hyperinsulinemic
      hypoglycemia.
AB  - Insulin counterregulatory hormones play a major role in the maintenance of
      glucose homeostasis. To evaluate the hypothesis that the reported imprecise
      control of glucose production by insulin is mirrored by a corresponding lack of
      response to the various insulin counterregulatory hormones, 30 spontaneously
      delivered mixed-breed term lambs weighing 4.9 +/- 0.5 kg (mean +/- SD) were
      studied at 5.0 +/- 0.7 days after birth following administration of 100 microCi D
      [6-(3)H2]glucose in 0.9% NaCl by the primed-constant infusion technique to
      measure glucose kinetics. Infusion of 2.0 mU kg(-1) x min(-1) insulin produced
      hyperinsulinemic hypoglycemia and was combined with 1.0 mg x kg(-1) x min(-1)
      somatostatin (SRIF) to block insulin, glucagon, and growth hormone release.
      Infusion of 2 ng x mg(-1) x min(-1) glucagon or 10 microg x kg(-1) x h(-1) growth
      hormone with SRIF and insulin isolated the glucagon or growth hormone effect,
      respectively. The addition of metyrapone blocked cortisol release. Controls
      received only the isotope. In toto, the data can be interpreted to suggest that
      insulin has a greater effect on glucose uptake than on glucose production, and
      that neither glucagon, growth hormone, nor cortisol appreciably influenced the
      endogenous glucose production rate (Rp) during hyperinsulinemic hypoglycemia. The
      imprecise effect of these insulin counterregulatory hormones on neonatal glucose
      production mirrors the previously documented imprecise control by insulin.

PMID- 10337857
TI  - Screening for variants of the uncoupling protein 2 gene in Japanese patients with
      non-insulin-dependent diabetes mellitus.
AB  - We examined genetic mutations in the coding regions of the uncoupling protein 2
      (UCP2) gene in 100 patients with non-insulin-dependent diabetes mellitus (NIDDM).
      The sequences of each exon-intron boundary were detected by polymerase chain
      reaction (PCR) using specific primer pairs designed in the cDNA sequence of UCP2
      and a cycle-sequence method. Using the specific primer pairs in the intron 5'- or
      3'-untranslated region, each exon with its exon-intron boundaries was amplified
      with the PCR method, and the PCR products were analyzed using a single-strand
      conformation polymorphism (SSCP) method. One nucleotide substitution in exon 4
      was found, which exchanged Ala (gcc) at position 55 of the amino acid sequence
      for Val (gtc), previously reported in Denmark by Urhammer et al in 1997. The
      polymorphism was reanalyzed in all patients and 120 normal subjects using a PCR
      restriction fragment length polymorphism method. There was no difference in the
      genotype distribution between patients and normal subjects, and our genotype
      distribution was similar to the Danish study. Furthermore, there were no clinical
      differences between genotype groups among the patients. No other mutation
      including the exon-intron boundary was found in these patients. Genetic mutations
      of UCP2 may not be commonly associated with obesity or diabetes in Japanese
      subjects.

PMID- 10337856
TI  - Cholesterol reduction by different plant stanol mixtures and with variable fat
      intake.
AB  - Our aim was to investigate (1) whether different campestanol/sitostanol mixtures
      in margarine differ in reducing serum cholesterol, and (2) whether sitostanol
      ester in butter decreases serum cholesterol and alters cholesterol absorption and
      metabolism. Twenty-three postmenopausal women replaced 25 g dietary fat with (1)
      sitostanol ester-rich (campestanol to sitostanol ratio 1:11) and (2) campestanol
      ester-rich (campestanol to sitostanol ratio 1:2) rapeseed oil margarine, (3)
      butter, and (4) sitostanol ester-rich (campestanol to sitostanol ratio 1:13)
      butter. The respective scheduled stanol intake was 3.18, 3.16, and 2.43 g/d. The
      6-week margarine periods and, after an 8-week washout, 5-week butter periods were
      double-blind and in random order. Serum cholesterol precursor sterols (indicators
      of cholesterol synthesis) and plant sterols (indicators of cholesterol
      absorption) were quantified with gas-liquid chromatography (GLC). Low-density
      lipoprotein (LDL) cholesterol was reduced by 8% and 10% with the sitostanol and
      campestanol ester-rich margarines versus baseline (P < .05 for both) and high
      density lipoprotein (HDL) cholesterol was increased by 6% and 5% (P < .05), so
      the LDL/HDL cholesterol ratio was reduced by 15% (P < .05 for both). Sitostanol
      ester-rich butter decreased LDL cholesterol 12% and the LDL/HDL cholesterol ratio
      11% (P < .05 for both) versus the butter period. The serum proportions of plant
      sterols and cholestanol were similarly reduced and those of cholesterol precursor
      sterols were similarly increased during all periods (P < .05 for all). Serum
      proportions of sitostanol and campestanol were slightly increased, indicating
      that their absorption related to their dietary intake. During all stanol
      interventions, serum vitamin D and retinol concentrations and alpha-tocopherol to
      cholesterol ratios were unchanged, whereas those of alpha- and beta-carotenes
      were significantly reduced. We conclude that varying the campestanol to
      sitostanol ratio from 1:13 to 1:2 in margarine and in butter similarly decreased
      cholesterol absorption, LDL cholesterol, and the LDL/HDL cholesterol ratio such
      that the serum lipids became less atherogenic.

PMID- 10337858
TI  - Preservation of growth hormone secretion in response to growth hormone-releasing
      peptide-2 during prednisone therapy.
AB  - Children who require long-term glucocorticoid treatment often demonstrate poor
      growth. Growth hormone (GH) secretion is decreased during glucocorticoid
      treatment, and this decrease may be due to a relative excess of the hypothalamic
      hormone somatostatin (SRIF). GH-releasing peptide-2 (GHRP-2) is a GH secretagogue
      that acts via multiple mechanisms at multiple sites. One of its proposed
      mechanisms is the ability to bypass SRIF blockade of GH secretion. We measured
      the ability of GHRP-2 to release GH before and during prednisone therapy (20 mg
      orally three times daily for 4 days). The degree of preservation of GH secretion
      and the pattern of GH release in response to GHRP-2 were compared with those
      observed in response to arginine, a known SRIF inhibitor. GH release in response
      to GHRP-2 and arginine was measured in the same eight subjects before and during
      prednisone therapy. Before prednisone, peak GH levels in response to arginine and
      GHRP-2 were 8.8 +/- 2.8 and 80.8 +/- 21.2 microg/L. During prednisone therapy,
      the peak GH level in response to arginine and to GHRP-2 was 20.1 +/- 8.3 and 71.3
      +/- 18.4 microg/L, respectively. The difference in peak values before and after
      prednisone was not significant. The time to the peak GH level during prednisone
      therapy occurred sooner for both arginine and GHRP-2. The pattern of GH release
      to arginine and to GHRP-2 was not identical, and the mean area under the curve
      for GH release to GHRP-2 decreased significantly with steroid treatment (P =
      .04), suggesting that GHRP-2 acts by mechanisms additional to the removal of SRIF
      inhibition. GHRP-2 elicited a 10-fold greater GH response than arginine at
      baseline, and the GH response was threefold greater versus arginine even in the
      face of prednisone therapy. GH release occurred earlier for both arginine and
      GHRP-2 during steroid treatment. We propose that this may suggest an increased
      storage phenomenon due to the blockade of GH secretion by glucocorticoids and
      then a sudden release with SRIF inhibition. If GHRP-2 can indeed counteract the
      inhibitory effect of glucocorticoids on GH secretion, then a new form of therapy
      may be available to support growth in children who must receive long-term steroid
      treatment.

PMID- 10337859
TI  - Influence of various modes of androgen substitution on serum lipids and
      lipoproteins in hypogonadal men.
AB  - We investigated whether the androgen type or application mode or testosterone (T)
      serum levels influence serum lipids and lipoprotein levels differentially in 55
      hypogonadal men randomly assigned to the following treatment groups: mesterolone
      100 mg orally daily ([MES] n = 12), testosterone undecanoate 160 mg orally daily
      ([TU] n = 13), testosterone enanthate 250 mg intramuscularly every 21 days ([TE]
      n = 15), or a single subcutaneous implantation of crystalline T 1,200 mg ([TPEL]
      n = 15). The dosages were based on standard treatment regimens. Previous androgen
      substitution was suspended for at least 3 months. Only metabolically healthy men
      with serum T less than 3.6 nmol/L and total cholesterol (TC) and triglyceride
      (TG) less than 200 mg/dL were included. After a screening period of 2 weeks, the
      study medication was taken from days 0 to 189, with follow-up visits on days 246
      and 300. Before substitution, all men were clearly hypogonadal, with mean serum T
      less than 3 nmol/L in all groups. Androgen substitution led to no significant
      increase of serum T in the MES group, subnormal T in the TU group (5.7 +/- 0.3
      nmol/L), normal T in the TE group (13.5 +/- 0.7 nmol/L), and high-normal T in the
      TPEL group (23.2 +/- 1.1 nmol/L). 5 alpha-Dihydrotestosterone significantly
      increased in all treatment groups compared with baseline. Compared with
      presubstitution levels, a significant increase of TC was observed in all
      treatment groups (TU, 14.4% +/- 3.0%; MES, 18.8% +/- 2.5%; TE, 20.4% +/- 3.0%;
      TPEL, 20.2% +/- 2.6%). Low-density lipoprotein cholesterol (LDL-C) also increased
      significantly by 34.3% +/- 5.5% (TU), 46.4% +/- 4.1% (MES), 65.2% +/- 5.7% (TE),
      and 47.5% +/- 4.3% (TPEL). High-density lipoprotein cholesterol (HDL-C) showed a
      significant decrease by -30.9% +/- 2.8% (TU), -34.9% +/- 2.5% (MES), -35.7% +/-
      2.6% (TE), and -32.5% +/- 3.5% (TPEL). Serum TG significantly increased by 37.3%
      +/- 11.3% (TU), 46.4% +/- 10.3% (MES), 29.4% +/- 6.5% (TE), and 22.9% +/- 6.7%
      (TPEL). TU caused a smaller increase of TC than TE and TPEL, whereas the
      parenteral treatment modes showed a lower increase of TG. There was no
      correlation between serum T and lipid concentrations. Despite the return of serum
      T to pretreatment levels, serum lipid and lipoprotein levels did not return to
      baseline during follow-up evaluation. In summary, androgen substitution in
      hypogonadal men increases TC, LDL-C, and TG and decreases HDL-C independently of
      the androgen type and application made and the serum androgen levels achieved.
      Due to the extended washout period for previous androgen medication and the
      exclusion of men with preexisting hyperlipidemia, this investigation demonstrates
      more clearly than previous studies the impact of androgen effects on serum lipids
      and lipoproteins. It is concluded that preexisting low serum androgens induce a
      "male-type" serum lipid profile, and increasing serum androgens further within
      the male normal range does not exert any additional effects. The threshold
      appears to be above the normal female androgen serum levels and far below the
      lower limit of normal serum T levels in adult men. These findings may have
      considerable implications for the use of androgens as a male contraceptive and
      for androgen therapy in elderly men.

PMID- 10337860
TI  - Alcohol and postexercise metabolic responses in type 2 diabetes.
AB  - The objective was to investigate the impact of the combination of exercise and
      alcohol on the metabolic response in nonfasting and fasting type 2 diabetic
      subjects. In part 1, 12 untrained middle-aged type 2 diabetic subjects
      participated on 3 test days. On each day, they ingested a light meal (1,824 kJ)
      containing 48 energy percent (E%) carbohydrate, 38 E% fat, and 14 E% protein. The
      meal was followed by either (A) rest or (B) 30 minutes of exercise (40% of
      maximum O2 consumption [VO2max]) or (C) taken with alcohol (0.4 g/kg body weight)
      followed by 30 minutes of exercise (40% of VO2max). In part 2, 11 untrained
      middle-aged type 2 diabetic subjects participated on 4 test days without a meal.
      The subjects were either (A) resting, (B) drinking alcohol (0.4 g/kg body
      weight), (C) exercising 30 minutes (40% of VO2max), or (D) drinking alcohol (0.4
      g/kg body weight) and exercising 30 minutes (40% of VO2max). On each test day,
      regular blood samples were drawn for 4 hours for analysis of glucose, insulin,
      lactate, triglycerides, nonesterified fatty acid (NEFA), and ethanol. Comparing
      exercise and rest following a light meal (part 1, no change (7%) occurred in the
      plasma glucose response area (642 +/- 119 v 724 +/- 109 mmol x L(-1) x 240 min,
      NS). However, it was significantly reduced (by 27%) in response to exercise and
      alcohol (509 +/- 98 v 724 +/- 109 mmol x L(-1) x 240 min; P = .03). Similar serum
      insulin response areas were obtained. After exercise and alcohol, plasma lactate
      increased compared with the resting state (2.2 +/- 0.2 v 1.6 +/- 0.1 mmol x L(
      1), P = .004) and with exercise alone (2.2 +/- 0.2 v 1.8 +/- 0.2 mmol x L(-1), P
      = .04). Serum NEFAs were significantly reduced by exercise and alcohol compared
      with the resting state (0.50 +/- 0.04 v 0.65 +/- 0.06 mmol x L(-1), P = .008) and
      with exercise alone (0.50 +/- 0.04 v 0.61 +/- 0.05 mmol x L(-1), P = .02).
      Similar serum triglycerides were found. During the fasting state (part 2),
      similar plasma glucose response areas were obtained in the four situations. The
      insulin response area to exercise and alcohol increased significantly compared
      with the resting state (3,325 +/- 744 v 882 +/- 295 pmol x L(-1) x 240 min, P =
      .02) and with exercise alone (3,325 +/- 744 v 1,328 +/- 422 pmol x L(-1) x 240
      min, P = .007). No difference was found compared with alcohol alone. Plasma
      lactate was higher after alcohol intake versus the resting state (1.9 +/- 0.1 v
      1.3 +/- 0.1 mmol x L(-1), P = .003), as well as after exercise and alcohol (1.9
      +/- 0.1 v 1.3 +/- 0.1 mmol x L(-1), P = .01). After exercise and alcohol serum
      NEFAs were significantly reduced compared with the resting state (0.43 +/- 0.02 v
      0.64 +/- 0.02 mmol x L(-1), P < .001), alcohol alone (0.43 +/- 0.02 v 0.51 +/-
      0.02 mmol x L(-1), P < .001), and exercise alone (0.43 +/- 0.02 v 0.64 +/- 0.02
      mmol x L(-1), P < .001). Serum triglycerides were similar in the four situations.
      We conclude that moderate exercise with or without moderate alcohol intake does
      not cause acute hypoglycemia either after a light meal or in the fasting state in
      untrained overweight type 2 diabetic subjects.

PMID- 10337861
TI  - Insulin- and glucagon-independent effects of calcitonin gene-related peptide in
      the conscious dog.
AB  - Calcitonin gene-related peptide (CGRP) causes vasodilation in many vascular beds,
      resulting in hypotension and tachycardia. The current studies were conducted in
      overnight-fasted conscious dogs to determine the effect of different CGRP dosages
      on carbohydrate metabolism and catecholamine release resulting from hemodynamic
      changes. During a pancreatic clamp, dogs received intraportal infusions of CGRP
      at 13, 26, and 52 (n = 3) or 52, 105, and 210 pmol x kg(-1) x min(-1) (n = 4; 60
      minutes at each rate). Blood pressure decreased (P < .05) and the heart rate and
      hepatic blood flow (HBF) increased a maximum of 100% and 30%, respectively (P <
      .05). For the five CGRP infusion rates, arterial plasma epinephrine increased
      approximately 1.3-, 2.4-, 7.4-, 12-fold, and eightfold basal, respectively;
      norepinephrine increased about 2.3-, 3.3-, 4.1-, 4.6-, and 4.8-fold basal,
      respectively; and cortisol increased about twofold, 3.4-fold, fivefold, sixfold,
      and 6.2-fold basal, respectively. At CGRP infusion rates of 52 pmol x kg(-1) x
      min(-1) or higher, increases (P < .05) occurred for plasma glucose, endogenous
      glucose production (EndoRa), and net hepatic uptake of gluconeogenic substrates
      (maximum change, 24 mg/dL, 1.3 mg x kg(-1) x min(-1), and 9.9 micromol x kg(-1) x
      min(-1), respectively). Arterial blood glycerol concentrations increased only a
      maximum of 30%. At the two highest CGRP infusion rates, glycerol returned to
      basal concentrations and arterial plasma nonesterified fatty acids (NEFAs)
      decreased. The increased net hepatic uptake of gluconeogenic substrates during
      CGRP infusion was sufficient to account for 49% to 58% of the increase in EndoRa.
      CGRP has no apparent direct effects on hepatic carbohydrate metabolism, but the
      catecholamines, at levels similar to those observed during CGRP infusion,
      stimulate hepatic glycogenolysis. Therefore, some factor(s) other than CGRP,
      probably an increase in circulating catecholamine concentrations, would appear to
      be responsible for at least 42% to 51% of the increase in EndoRa.

PMID- 10337862
TI  - Differences in the cellular processing of AspB10 human insulin compared with
      human insulin and LysB28ProB29 human insulin.
AB  - Cellular metabolism studies were performed comparing human insulin with two rapid
      acting analogs, LysB28ProB29 insulin (LysPro) and AspB10 insulin (B10-Asp). B10
      Asp bound to isolated hepatocytes at 37 degrees C to a greater extent than LysPro
      or native insulin, which were equivalent. The rate of degradation was similar for
      the three materials, resulting in a significant reduction in the degraded/bound
      ratio for the B10 analog. The processing of membrane-bound material was examined
      by incubating cells with hormone at 4 degrees C, removing unbound insulin, and
      incubating the cells at 37 degrees C. Again, binding was greater for B10-Asp
      versus LysPro or native insulin, with a reduction in the degraded/bound ratio.
      Hormone internalization and processing was examined by an acid wash of cells
      incubated with 125I(A14)-labeled hormone to remove surface-bound materials. The
      processing rate was slower for B10-Asp versus LysPro or native insulin. Cell
      extraction and examination on molecular-sieve chromatography confirmed that B10
      Asp was processed at a slower rate than either LysPro or native insulin. Intact
      B10-Asp was found in the cell after 4 hours, whereas all native insulin and
      LysPro were degraded by 90 to 120 minutes. B10-Asp also caused a greater
      incorporation of thymidine into DNA in cultured cells than LysPro or native
      insulin, which were similar. These data show that the cellular processing of
      LysPro is essentially identical to that of native insulin. However, B10-Asp has
      markedly different properties and is processed much more slowly. The prolonged
      cell residence time of B10-Asp could contribute to its greater effects on cell
      growth and mitogenesis.

PMID- 10337864
TI  - CD36 LIMPII analogous-1, a human homolog of the rodent scavenger receptor B1,
      provides the cholesterol ester for steroidogenesis in adrenocortical cells.
AB  - CD36 and LIMPII analogous-1 (CLA-1), a human homolog of the rodent scavenger
      receptor B1 (SR-B1), binds high-density lipoprotein (HDL) and mediates the
      selective uptake of HDL cholesterol ester (CE) by cultured transfected cells. CLA
      1 is strongly expressed in steroidogenic tissues, including the adrenal gland,
      suggesting that CLA-1 plays a role in providing substrates for steroidogenesis.
      To address this, we established an adrenocortical cell line that highly expresses
      CLA-1. These cells increased CE uptake from HDL to 140.5% of the level in mock
      transfected cells. After incubation of the transfected cells with HDL,
      corticosterone secretion from CLA-1-transfected cells increased to about two
      times the level in mock-transfected cells. These results indicate the possibility
      that CLA-1 (a close structural homolog of SR-B1)-mediated uptake of HDL CE may be
      a significant source of precursor cholesterol for steroidogenesis in humans as it
      is in mice.

PMID- 10337863
TI  - Enhancement of fatty acid and cholesterol synthesis accompanied by enhanced
      biliary but not very-low-density lipoprotein lipid secretion following sustained
      pravastatin blockade of hydroxymethyl glutaryl coenzyme A reductase in rat liver.
AB  - A 3-week treatment of rats with pravastatin (PV) augmented biliary cholesterol
      and phospholipid output 3.6- and 2.2-fold over controls, while bile acid (BA)
      output and kinetics were unchanged. No major changes were detected in hepatic and
      serum cholesterol concentrations despite the PV inhibitory property on
      hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase. To evaluate the mechanisms
      of this adaptive phenomenon, several parameters of hepatic lipid homeostasis were
      assessed. Biliary cholesterol changes could not be attributed to an increased
      influx of lipoprotein cholesterol to the liver and bile. Hepatic low-density
      lipoprotein (LDL) receptor content, as inferred from Western blot analysis, was
      unchanged, as was the biliary excretion of labeled cholesterol derived from
      chylomicron remnants. In vivo 3H2O-incorporation studies showed an 80% increase
      in hepatic cholesterol synthesis, evidence for bypass of the PV block.
      Remarkably, fatty acid synthesis was also stimulated twofold, providing substrate
      for hepatic triglycerides, which were slightly enhanced. However, serum
      triglycerides decreased 52% associated with a 22% decrease in hepatic very-low
      density lipoprotein (VLDL) secretion. Thus, the biochemical adaptation following
      PV treatment produces complex alterations in hepatic lipid metabolism. An
      enhanced supply of newly synthesized cholesterol and fatty acids in association
      with a limited VLDL secretion rate augments the biliary lipid secretion pathway
      in this experimental model.

PMID- 10337865
TI  - Supplementation with vitamin B12 decreases homocysteine and methylmalonic acid
      but also serum folate in patients with end-stage renal disease.
AB  - Hyperhomocysteinemia is frequently found in patients with end-stage renal disease
      (ESRD). Plasma total homocysteine (tHcy) concentrations may be reduced by
      supplementation with folic acid or combinations of folic acid, vitamin B12, and
      vitamin B6. Supplementation studies with vitamin B12 alone in patients with ESRD
      have not yet been published. In this study, we investigated the effects of
      intravenous injection of cyanocobalamin (1 mg/wk for 4 weeks) in ESRD patients (N
      = 14) with low serum cobalamin concentrations (<180 pmol/L). All patients had
      elevated levels of plasma tHcy, methylmalonic acid (MMA), and cystathionine
      before supplementation. After supplementation, plasma tHcy and MMA decreased 35%
      and 48%, respectively; however, cystathionine levels were unchanged. The extent
      of the plasma tHcy reduction tended to be influenced by the C677T polymorphism of
      methylenetetrahydrofolate reductase (MTHFR). Serum cobalamin increased
      significantly upon supplementation, whereas serum folate levels were
      substantially reduced by 47%. In contrast, red blood cell (RBC) folate was
      unchanged. This study shows that vitamin B12 supplementation effectively
      decreases both MMA and plasma tHcy in ESRD patients with low B12 levels.
      Furthermore, it illustrates the close interrelation between vitamin B12 and
      folate metabolism.

PMID- 10337867
TI  - Influence of 4 weeks' intervention by exercise and diet on low-density
      lipoprotein subfractions in obese men with type 2 diabetes.
AB  - Insulin resistance is associated with dyslipoproteinemia characterized by
      increased serum triglycerides, reduced high-density lipoprotein 2 (HDL2)
      cholesterol, and increased small, dense low-density lipoprotein (LDL) subfraction
      particles. Physical activity and weight reduction are known to improve insulin
      resistance and dyslipoproteinemia, but their influence on LDL subfractions in
      diabetic patients is unknown. Therefore, we investigated the effect of a 4-week
      intervention program of exercise (2,200 kcal/wk) and diet (1,000 kcal/d: 50%
      carbohydrate, 25% protein, and 25% fat; polyunsaturated/saturated fat ratio, 1.0)
      on glycemic control and HDL and LDL subfractions in 34 obese patients with non
      insulin-dependent diabetes (age, 49 +/- 9 years; body mass index [BMI], 33.1 +/-
      5.1 kg/m2). Reductions in body weight (P < .001) and improvements in fasting
      blood glucose, insulin, fructosamine (P < .001), and free fatty acids (P < .01)
      by intervention were associated with reductions in serum cholesterol and
      apolipoprotein B (apo B) concentrations in very-low-density lipoprotein (VLDL) (P
      < .01), intermediate-density lipoprotein (IDL), and small, dense (>1.040 g/mL)
      LDL particles (P < .001). These data underlie the positive influence of weight
      reduction induced by exercise and diet on insulin resistance and lipoprotein
      metabolism in obese diabetic patients, particularly showing improvements of the
      LDL subfraction profile with a decrease of small, dense LDL particles. This is of
      particular importance, as these particles have been shown to be associated with
      coronary artery disease.

PMID- 10337866
TI  - Phenotypic characterization of the beta3-adrenergic receptor mutation and the
      uncoupling protein 1 polymorphism in Japanese men.
AB  - The Trp64Arg mutation of the beta3-adrenergic receptor (beta3AR) gene and A to G
      polymorphism of the uncoupling protein 1 (UCP1) gene are reported to be
      associated with weight gain, and both have been shown to have an additive effect
      on weight gain in Caucasians. Racial differences have also been noted in the
      beta3AR mutation; however, the effect of UCP1 polymorphism on body weight is not
      obvious in the Japanese. Thus, we investigated the association of genetic
      variations in beta3AR and UCP1 genes and the additive effects of these two genes
      in 214 Japanese men. The frequency of the Trp64Arg allele was 0.19, and serum
      triglyceride was significantly higher in Arg64 homozygotes versus Trp64
      homozygotes. The frequency of the G allele was 0.51, and the body mass index
      (BMI) was significantly higher in subjects with the G allele (GG homozygotes and
      AG heterozygotes) versus those without it (AA homozygotes). The beta3AR mutation
      and UCP1 polymorphism were not found to have additive effects, and they were not
      related to glucose tolerance patterns and insulin resistance. Our results suggest
      that the beta3AR mutation is associated with hypertriglyceridemia and the UCP1
      polymorphism may be a weak contributing factor to obesity in Japanese men.

PMID- 10337868
TI  - Preservation of the incretin effect after orthotopic pancreas transplantation in
      inbred rats.
AB  - To establish whether the incretin effect is under neural control, insulin, C
      peptide, and glucose-dependent insulinotropic peptide (GIP) responses and hepatic
      insulin clearance were investigated after oral and "isoglycemic" intravenous
      glucose in 12 inbred rats after denervation of the pancreas by orthotopic
      transplantation with portal venous drainage (Tx group) and in 12 laparotomized
      controls (sham group). Effective pancreas denervation was documented by a
      decreased pancreatic polypeptide (PP) response to insulin-induced hypoglycemia
      and by decreased levels of norepinephrine and calcitonin gene-related peptide
      (CGRP) in pancreatic tissue. Basal and incremental arterial plasma glucose
      integrated over 180 minutes did not differ between oral and intravenous glucose,
      but the integrated insulin response (mean +/- SEM) was significantly greater with
      oral versus intravenous glucose (Tx group, 104.9 +/- 22.0 v 31.0 +/- 4.9 nmol x
      L(-1) x min, P < .01; sham group, 79.5 +/- 10.6 v 36.6 +/- 5.8 nmol x L(-1) x
      min, P < .01). The integrated response of C-peptide was similar during both tests
      (Tx group, 105 +/- 14 v 79 +/- 8 pmol x mL(-1) x min; sham group, 112 +/- 10 v
      121 +/- 12 pmol x mL(-1) x min). Hepatic insulin clearance was significantly
      decreased in both groups by oral compared with intravenous glucose administration
      (Tx group, 1.3 +/- 0.2 v 3.3 +/- 0.6 mmol/mmol, P < .01; sham group, 1.6 +/- 0.1
      v 3.9 +/- 0.6 mmol/mmol, P < .02). The incretin effects for insulin (Tx group,
      5.6 +/- 2.7; sham group, 3.0 +/- 0.8) and C-peptide (Tx group, 1.4 +/- 0.2; sham
      group, 1.1 +/- 0.2), calculated as the ratio of the integrated oral response and
      integrated intravenous response, and GIP responses to oral and intravenous
      glucose were not significantly different between the two groups. We conclude that
      there is preservation of the incretin effect in rats with orthotopically
      transplanted and hence extrinsically denervated pancreas, thus ruling out the
      possibility that the autonomic nervous system substantially contributes. Hepatic
      insulin clearance and insulinotropic hormones such as GIP appear to be more
      important.

PMID- 10337869
TI  - Lack of association between genetic variation in the beta3-adrenergic receptor
      gene and insulin resistance in patients with coronary heart disease.
AB  - The beta-adrenergic system plays a critical role in regulating lipolysis and
      thermogenesis. Recent studies have suggested that a missense Trp64Arg mutation in
      the beta3-adrenergic receptor gene is involved in visceral obesity and insulin
      resistance. We investigated the effect of this mutation on insulin resistance in
      patients with angiographically documented coronary heart disease ([CHD]n = 137)
      and normal subjects (n = 188). Plasma glucose and insulin responses to a 75-g
      oral glucose tolerance test and insulin resistance measured by the insulin
      suppression test, were determined in 58 (42%) patients with CHD and 121 (64%)
      controls. The genotype and allele frequency of the beta3-adrenergic receptor did
      not differ between patients with CHD and controls. The blood pressure, body mass
      index (BMI), waist to hip ratio, fasting plasma glucose, insulin, and lipid, and
      plasma glucose and insulin responses to the glucose load were relatively similar
      in subjects with and without the mutation in CHD and normal groups. The degree of
      insulin sensitivity, ie, the steady-state plasma glucose concentration, was not
      significantly different between subjects with and without the mutation in the CHD
      group (11.3 +/- 1.2, n = 11 v 11.9 +/- 0.6 mmol/L, n = 47, P = NS) and control
      group (8.4 +/- 0.7, n = 30 v 8.2 +/- 0.4 mmol/L, n = 91, P = NS). We conclude
      that Trp64Arg polymorphism of the beta3-adrenergic receptor gene does not likely
      play a major role in the development of CHD in the Chinese population. In
      addition, it appears to have no association with the insulin resistance syndrome
      in either CHD or non-CHD subjects.

PMID- 10337870
TI  - Variation of the fatty acid binding protein 2 gene is not associated with obesity
      and insulin resistance in Japanese subjects.
AB  - An alanine to threonine substitution at codon 54 of the fatty acid binding
      protein 2 (FABP2) gene has been associated with insulin resistance in Pima
      Indians and with obesity in aboriginal Canadians. We investigated whether this
      polymorphism contributes to obesity and insulin resistance in 258 Japanese
      subjects. Thirty-six subjects (13.9%) were homozygous for the Thr54 allele, 106
      (41.1%) were heterozygous for the Ala54/Thr54 allele, and 116 (45.0%) were
      homozygous for the Ala54 allele. The frequency of the Thr54 allele was 0.34 and
      did not differ significantly between men and women. The incidence of non-insulin
      dependent diabetes mellitus (NIDDM) was not different among the three genotypes.
      The variation at codon 54 of the FABP2 gene was not associated with obesity,
      hypertension, dyslipidemia, hyperuricemia, or hyperinsulinemia. These results
      suggest that the polymorphism at codon 54 of the FABP2 gene is not a major
      contributing factor to obesity and insulin resistance in Japanese subjects.

PMID- 10337872
TI  - Age-related blunting of growth hormone secretion during exercise may not be soley
      due to increased somatostatin tone.
AB  - Age-related declines in growth hormone (GH) secretion may result from augmented
      somatostatin (SRIH) tone and/or diminished GH-releasing hormone (GHRH) secretion.
      We assessed GH release during exercise without and with pyridostigmine (PYR),
      which indirectly suppresses SRIH. GH levels were measured throughout exercise and
      recovery in 12 young men (mean +/- SEM, 20.8 +/- 0.4 years) and seven old men
      (66.1 +/- 1.9). The area under the GH curve (GH-AUC) was greater in young versus
      old men during a short-term maximal exercise test (12.9 +/- 2.8 v 1.5 +/- 0.2 ng
      x min(-1) x mL(-1), P = .002) and a 1-hour 60% maximal (submaximal, 10.0 +/- 1.5
      v 3.0 +/- 1.0 ng x min(-1) x mL(-1), P = .001) cycle exercise bout. PYR increased
      the GH-AUC in young and old men during maximal (20.9 +/- 5.2 v 4.9 +/- 1.8) and
      submaximal (12.3 +/- 1.6 v 4.7 +/- 1.5) exercise (P < .05). The greater GH
      response to maximal versus submaximal exercise suggests a role for adrenergic
      modulation of GHRH during exercise. However, the failure of PYR to restore the
      responses of the old to those of the young suggests that increased SRIH tone does
      not completely explain the age difference in GH secretion during exercise.

PMID- 10337871
TI  - Comparison of the effects of triphasic oral contraceptives with desogestrel or
      levonorgestrel on apolipoprotein A-I-containing high-density lipoprotein
      particles.
AB  - Recent observations suggest that the risk of coronary artery disease (CAD) is
      associated with both the level and composition of the two major populations of
      apolipoprotein (apo)-defined high-density lipoprotein (HDL) particles: those
      containing both apo A-I and apo A-II [Lp(AI,AII)] and those containing apo A-I
      without apo A-II [Lp(AI)]. While sex hormones are known to affect HDL, their
      influence on these apo-defined HDL particles is not known. We have determined the
      effects of two triphasic oral contraceptive (OC) formulations on these HDL
      particles in healthy normolipidemic women aged 21 to 35 years. The formulations
      contain comparable quantities of ethinyl estradiol (EE) and either desogestrel
      (DG), a minimally androgenic progestin, or levonorgestrel (LN), a more androgenic
      progestin. Lipid and lipoprotein levels were measured during the third week of
      the normal menstrual cycle and the sixth month of OC use. The DG/EE formulation
      significantly increased total cholesterol (C) 15%, triglyceride (TG) 99%,
      phospholipid (PL) 17%, apo A-I 28%, apo A-II 34%, apo B 21%, very-low-density
      lipoprotein cholesterol (VLDL-C) 238%, HDL-C 20%, and HDL3-C 28% (P < .02 to
      .005, n = 11), but not low-density lipoprotein cholesterol (LDL-C). The LN/EE
      formulation also increased total C 15%, TG 33%, apo A-I 15%, HDL3-C 21% (P < .05,
      n = 10), apo B 30% (P < .005), and, additionally, LDL-C 19% (P < .05). Both
      formulations increased Lp(AI,AII) (DG/EE, 34%, P < .005; LN/EE, 24%, P < .01).
      These changes reflected comparable increases of small (7.0 to 8.2 nm) and medium
      (8.2 to 9.2 nm) particles in the LN/EE group and a predominant increase of medium
      sized particles in the DG/EE group. Also, in the LN/EE group but not the DG/EE
      group, there were fewer large (9.2 to 11.2 nm) particles. Lp(AI) increased only
      in the DG/EE group (25%, P = .075) and was due to the presence of more large
      particles. The level of Lp(AI) did not change in the LN/EE group, but the lipid/A
      I ratio of these particles was lower (P = .012) and there were more small
      particles. Thus, triphasic OC formulations with progestins of different
      androgenicity had different effects on VLDL, LDL, and the level and composition
      of HDL particles with and without apo A-II, possibly reflecting
      estrogen/progestin/androgen balance. Estrogen dominance increases both Lp(AI,AII)
      and Lp(AI) and favors large Lp(AI) particles, while progestin/androgen dominance
      increases only Lp(AI,AII) and favors small particles. Because of the importance
      of HDL in the arterial wall physiology, OC formulations with different estrogen
      and progestin content may affect arterial wall health to a different extent.

PMID- 10337873
TI  - Chronic leptin administration increases insulin-stimulated skeletal muscle
      glucose uptake and transport.
AB  - Leptin, the product of the ob gene, has been shown to reduce fat mass, food
      intake, hyperglycemia, and hyperinsulinemia and to increase whole-body glucose
      disposal. However, it is unknown if leptin improves insulin action in skeletal
      muscle. Therefore, the purpose of this investigation was to determine if chronic
      leptin administration increases insulin-stimulated skeletal muscle glucose uptake
      and transport. Sixty-nine female Sprague-Dawley rats (240 to 250 g) were randomly
      assigned to one of three groups: (1) control, (2) pair-fed, and (3) leptin. All
      animals were subcutaneously implanted with miniosmotic pumps that delivered 0.5
      mg leptin/kg/d to the leptin animals and vehicle to the control and pair-fed
      animals for 14 days. Following this 14-day period, all animals were subjected to
      hindlimb perfusion to determine the rates of skeletal muscle glucose uptake and 3
      O-methyl-D-glucose (3-MG) transport under basal, submaximal (500 microU/mL), and
      maximal (10,000 microU/mL) insulin concentrations. Chronic leptin treatment
      significantly increased (P < .05) the rate of glucose uptake across the hindlimb
      by 27%, 32%, and 47% under basal, submaximal, and maximal insulin, respectively,
      compared with the control and pair-fed condition. However, when the submaximal
      rate of glucose uptake was expressed as a percentage of maximal insulin
      stimulated glucose uptake, no differences existed among the groups, indicating
      that leptin treatment does not increase insulin sensitivity. Rates of 3-MG
      transport in the soleus, plantaris, and white and red portions of the
      gastrocnemius (WG and RG) were significantly increased (P < .05) in leptin
      animals under all perfusion conditions. 3-MG transport was not different between
      control and pair-fed animals. Collectively, these findings suggest that
      improvements in insulin-stimulated skeletal muscle glucose uptake and transport
      following chronic leptin treatment result from increased insulin responsiveness.

PMID- 10337874
TI  - Utility of comprehensive toxicologic screens in children.
AB  - This study was undertaken to evaluate the clinical utility and cost-effectiveness
      of the limited component versus the high performance liquid chromatography (HPLC)
      component of comprehensive toxicologic screens in children. A retrospective
      patient series was studied at the emergency department (ED) of Hughes Spalding
      Children's Hospital, an urban, tertiary-care ED, consisting of all patients
      younger than 19 years of age who had a comprehensive toxicologic screen between
      January 1994 and July 1995. The comprehensive test included a broad-spectrum HPLC
      component as well as a limited component that examined serum for ethanol,
      aspirin, and acetaminophen and urine for benzodiazepines, barbiturates,
      amphetamines, cocaine, phencyclidine, and opiates. All toxicologic screens were
      reviewed for the presence of exogenous toxins, followed by a chart review of all
      patients with positive screens and a selection of negative screens. Toxins were
      categorized as (1) iatrogenic or noniatrogenic, (2) clinically or nonclinically
      suspected by history and physical, and (3) clinically or nonclinically
      significant. Comprehensive toxicology screens were performed in 463 cases during
      the study period; 234 (51%) were positive for exogenous toxins. In 227 of 234
      positive screens (97%), toxins were either suspected by history and/or physical,
      were present on the limited portion of the toxicology screen, or were clinically
      insignificant. The remaining 7 of the 234 positive screens (3%) were clinically
      significant and detected solely by the broad-spectrum HPLC portion of the
      comprehensive screen. However, in none of these 7 cases was patient management
      clinically altered as a result of the positive screen. The total additional cost
      for the HPLC component was $16,205 ($35x463), an average distributive charge of
      $2,315 per patient in whom the HPLC portion provided additional clinical
      information ($16,205/7). Although adding significant charges to the evaluation of
      suspected toxic exposures in children, the HPLC component of the comprehensive
      drug screen was of no additional clinical benefit compared with its limited
      component alone.

PMID- 10337875
TI  - Elevation of serum cardiac troponin I in noncardiac and cardiac diseases other
      than acute coronary syndromes.
AB  - This study evaluated the role of serum cardiac troponin I as a biochemical marker
      for the diagnosis of acute coronary syndromes in the presence of noncardiac
      diseases. Diagnostic characteristics were examined in 102 consecutive patients
      who were found to have serum cardiac troponin I levels higher than the upper
      reference limit of 0.6 ng/mL. Of 102 patients with cardiac troponin I levels of
      >0.6 ng/mL, 35 did not have the final diagnoses of acute coronary syndromes
      (myocardial infarction or unstable angina) but had various other final diagnoses,
      including nonischemic dilated cardiomyopathy, muscular disorders, central nervous
      system disorders, HIV disease, chronic renal failure, sepsis, lung diseases, and
      endocrine disorders. The mean value of serum cardiac troponin I in the patients
      with diseases other than acute coronary syndromes was significantly lesser than
      in those with acute coronary syndromes (2.0+/-1.9 [SD] v. 24.7+/-28.2 ng/mL;
      P<.0001). There were significantly fewer histories of chest pain and prior
      myocardial infarction in patients with diseases other than acute coronary
      syndromes than in those with acute coronary syndromes (history of chest pain, 3
      v. 48 patients [P<.001]; history of prior myocardial infarction, 0 v. 30 patients
      [P<.001]). In conclusion, elevated serum levels of cardiac troponin I, especially
      in the lower ranges, should be interpreted with caution, particularly in patients
      suffering from acute illnesses who lack other diagnostic features suggestive of
      acute coronary ischemic events.

PMID- 10337876
TI  - Evaluation of pediatric cervical spine injuries.
AB  - To compare historical features, clinical examination findings, and radiographic
      results among pediatric patients with cervical spine injury (CSI), a
      retrospective review of patients who were diagnosed with CSI was undertaken. Two
      main groups were identified: radiographically evident cervical spine injury
      (RESCI), and spinal cord injury without radiographic abnormality (SCIWORA).
      Demographic, historical, clinical, and radiographic information was obtained from
      patients' charts and analyzed to determine factors associated with CSI and to
      determine the efficacy of the various radiographic views. Seventy-two children,
      ages from 1 month to 15 years (median age, 9 yrs), were included in the study.
      Sports-related injuries were the most common. Forty patients had RESCI and 32 had
      SCIWORA. Forty-nine (80%) of all the patients had abnormal findings on neck
      examination, and six (16%) of the RECSI group had abnormal neurological findings.
      Lateral radiographs had a sensitivity for CSI of 79%; a three-view radiographic
      series had a sensitivity of 94%. All patients with CSI who were clinically
      asymptomatic had both a high-risk injury mechanism and a distracting injury. CSI
      should be suspected in any child with abnormal findings on neck or neurological
      examination. A minimum of three radiographic cervical spine views should be
      obtained in the evaluation of CSI in children. Even in the face of a three-view
      series, CSI should be suspected in patients with an abnormal neck or neurological
      exam, high-risk mechanism of injury, or distracting injury.

PMID- 10337877
TI  - Facial imaging in an urban emergency department.
AB  - To describe the facial imaging practice pattern in our an emergency department
      and to assess the implications of this practice, a retrospective review was
      conducted of patients with blunt facial trauma requiring facial imaging over a 2
      month period. Patients were compared based on their initial imaging study, either
      facial x-rays (primary FXR) or spiral computed tomography (primary FSCT). Of 211
      patients imaged, 148 (70%) received primary FXR and 63 (30%) primary FSCT. A
      greater proportion of primary FSCT patients had at least one fracture detected
      (57% v. 26%; odds ratio 3.9, confidence interval 2.0-7.5). Of patients with a
      fracture on FXR, 29% underwent secondary FSCT. The average facial imaging charges
      per case detected (patient with a fracture) were $978 for primary FXR and $2,048
      for primary FSCT. Physicians made avid use of FSCT. Additional studies are needed
      to determine the appropriateness of this practice and to improve clinical
      selection of patients requiring FSCT.

PMID- 10337878
TI  - Autonomic dysreflexia presenting as a severe headache.
AB  - Hypertension, bradycardia, and severe headache have been associated with
      autonomic dysreflexia. Autonomic dysreflexia affects those with spinal
      transection above the level of T6 after plastic changes of the afferent pathways.
      This restructuring in the presence of noxious stimuli below the level of the
      lesion leads to autonomic dysreflexia. The onset of the first episode of
      autonomic dysreflexia has been documented as soon as 30 days and as late as 13
      years after the injury. This report presents a case study of a paraplegic man 8
      years after injury with autonomic dysreflexia associated with a urinary tract
      infection.

PMID- 10337879
TI  - Acute neonatal scalp abscess and E coli bacteremia in the ED.
AB  - An atypical presentation of newborn scalp abscess is described in a 9-day-old
      infant. The infant appeared nontoxic upon presentation on day 9 after birth with
      a scalp abscess and Escherichia coli bacteremia. The infant had been admitted
      from the emergency department to the newborn intensive care unit on day 4 after
      birth with the same diagnosis; however, she was discharged within hours without
      treatment. This case report demonstrates the subtle clinical features,
      presentation, microbiology, and appropriate emergency department management of
      neonatal scalp abscesses.

PMID- 10337880
TI  - Unrecognized fatal liver injury caused by a bicycle handlebar.
AB  - Patterned injuries often remain unrecognized by emergency department personnel.
      Immediate recognition of a simple, superficial patterned injury may result in
      prompt and possibly life-saving treatment. A fall off a bicycle with a patterned
      abdominal bruise should suggest potentially life-threatening trauma.

PMID- 10337881
TI  - Spontaneous pyopneumopericardium.
AB  - A previously healthy 42-year-old man presented to the emergency department with
      progressive weakness, lightheadedness, nausea, and lower extremity edema.
      Evaluation revealed hypotension, pulsus paradoxus, leukocytosis, hepatic and
      renal dysfunction, and an air-fluid level in the mediastinum. Emergency
      department ultrasound confirmed the presence of a large pericardial fluid
      collection. The patient was admitted to the medical intensive care unit with a
      diagnosis of pyopneumopericardium for emergent pericardiocentesis.

PMID- 10337882
TI  - Complications of transesophageal echocardiography in the ED.
AB  - The complication rate of transesophageal echocardiography (TEE) performed in
      clinical settings outside the emergency department (ED) has been reported to be
      1% to 3%. The rate of complications of performing TEE in the ED has not been
      established. The purpose of this study was to determine the rate of complications
      associated TEE with carried out on ED patients, and to investigate parameters
      that might predict complications. A retrospective chart review was carried out on
      consecutive ED patients undergoing TEE at a major referral center. Complications
      were abstracted. Parameters to predict complications were assessed, including
      age, gender, vital signs, pulse oximetry values, serum bicarbonate level, and
      hematocrit level. A total of 142 patients underwent TEE in the ED during the
      study period; 88 of these were trauma patients. There were 18 (12.6%)
      complications: death (1), respiratory insufficiency/failure (7), hypotension (3),
      emesis (4), agitation (2), and cardiac dysrhythmia (1). None of the tested
      variables predicted a complication. TEE carried out in the ED has a higher
      complication rate than has been reported in other clinical settings.

PMID- 10337883
TI  - Nitrous oxide for the treatment of acute migraine headache.
AB  - The objective of this study was to determine the efficacy of nitrous oxide in the
      therapy of acute migraine symptoms in emergency department (ED) patients. This
      was a prospective, randomized, double blind study of patients presenting to an
      ED. All eligible patients had a prior diagnosis and symptoms consistent with
      migraine headache and a normal neurological examination. Patients were randomized
      to receive either 50% nitrous oxide and 50% oxygen or 100% oxygen over 20
      minutes. All patients completed a visual analog pain scale before and immediately
      after intervention. Initial pain scores and change in pain scores between the two
      groups were compared. There were 22 patients enrolled, 10 in the nitrous oxide
      group and 12 in the oxygen group. The groups were similar in age, gender,
      duration of headache, and initial pain scores. Pain scores decreased
      significantly in the nitrous oxide group (median change, 69 to 21 mm, P = .02).
      The oxygen group did not show significant change in pain scores (median change,
      78.5 to 72, P = .09). Eighty percent of patients receiving nitrous oxide required
      no rescue medication at the completion of the intervention, compared with 17% of
      those receiving 100% oxygen (P = .008). Twenty minutes after termination of
      intervention, 60% of patients who had received nitrous oxide still required no
      rescue medication, compared with 8% of those who had received 100% oxygen (P =
      .02). Nitrous oxide shows efficacy in ED short-term treatment of acute migraine
      headache.

PMID- 10337884
TI  - The effectiveness of ice as a topical anesthetic for the insertion of intravenous
      catheters.
AB  - In a paired clinical trial, the effectiveness of ice in reducing the pain of
      intravenous catheter placement was assessed in 28 adult volunteers. An ice pack
      was placed over one arm for 10 minutes, followed by insertion of an 18-gauge
      angiocatheter in both arms. Patients recorded their pain assessment after each
      venipuncture on a previously validated 100-mm visual analog scale (VAS) and
      identified their preferred method for the procedure (pretreatment with ice or no
      pretreatment). The mean pain score for catheter placement on arms pretreated with
      ice was 27.5+/-15.9 mm; the mean pain score for the control arms was 34.2+/-21.6
      mm (P = .17). Most patients (61%) preferred no pretreatment (P = .014). Although
      most men (75%) preferred no pretreatment, 75% of women preferred pretreatment
      with ice (P = .014). Future studies should examine whether ice is effective at
      reducing pain from other more painful procedures and whether the response to ice
      is gender-related.

PMID- 10337886
TI  - Snowboarding injuries in children and adolescents.
AB  - To study snowboarding injuries in children and adolescents, a 6-year
      retrospective study was conducted of patients 18 years old and younger admitted
      to a pediatric trauma center after snowboarding accidents. The study was designed
      to identify the most severely injured patients. Comparison was made to data from
      a recent comparable study of skiing injuries. Twenty-seven patients were
      identified, all but one male and none under 10 years old. Nineteen were injured
      in a fall, 6 collided with a stationary object, one collided with a skier, and in
      one case the mechanism of injury was unclear. The average pediatric trauma score
      was 10.5, and the average injury severity score 10.2. Most of the 12 head
      injuries were minor. Most extremity fractures were to the upper extremity. There
      were two lumbar vertebral burst fractures, suggesting that the sport may
      predispose to this injury. There were no deaths. When compared with skiing, in
      snowboarding the overall severity of injury is lower, collision is a less common
      mechanism of injury and results in less serious injury, head injuries are less
      severe, the relative frequency of upper extremity fracture is higher, abdominal
      injuries are caused by falls rather than collisions, and facial injuries are less
      common. These differences are predictable on the basis of differences in the
      equipment. However, it is too early to say that snowboarding has less potential
      for life-threatening injury than skiing. Expected changes in the mix of
      participants, with an increase in the average skill level over time, may well
      result in different patterns, mechanisms, and severity of injury.

PMID- 10337885
TI  - Ranitidine-induced acute dystonia.
AB  - Acute dystonia is a dramatic form of extrapyramidal side effects of antipsychotic
      medications. Although extrapyramidal reactions have been noted in related drugs,
      there are no existing reports associated with ranitidine. This report describes a
      case of an acute dystonic reaction secondary to a commonly prescribed, currently
      approved over-the-counter drug, ranitidine.

PMID- 10337888
TI  - Diagnostic role of ED ultrasound in deep venous thrombosis and pulmonary
      embolism.
AB  - Proximal deep venous thrombosis (DVT), which may lead to pulmonary embolism (PE),
      is one of the serious and underrecognized causes of lower extremity pain and
      swelling. The diagnosis of DVT requires a confirmatory objective test because
      clinical signs and symptoms are unreliable. Assessment of thigh vein
      compressibility with real-time ultrasound is an accurate test for DVT that may be
      performed rapidly at the bedside. Although unproven, we propose that wider use of
      this test in the emergency department by emergency physicians might increase the
      diagnosis of DVT, prevent PE, and reduce utilization of other more costly and
      invasive diagnostic tests. Evaluation of DVT by compression ultrasound may also
      be incorporated in the diagnostic workup of suspected PE. In the case of a
      nondiagnostic ventilation/perfusion scan, demonstration of proximal DVT by
      ultrasound represents a likely source of PE and an indication for
      anticoagulation, eliminating the need for pulmonary angiography. In the
      critically ill patient whose presentation is consistent with massive PE, one
      rapid approach to the diagnosis may be to combine transthoracic echocardiography
      with lower extremity ultrasound.

PMID- 10337887
TI  - The etiology of cardiac arrest in children and young adults: special
      considerations for ED management.
AB  - Children and young adults rarely present to the emergency department (ED) in
      cardiac arrest. This review examines published series on nontraumatic, cardiac
      arrest for patients aged 1 to 45 years and discusses the differential diagnosis
      for cardiovascular collapse. Among the most common entities encountered are
      cardiac diseases (hypertrophic cardiomyopathy, myocarditis), airway diseases
      (pneumonia, epiglottitis, and asthma), epilepsy, hemorrhage (gastrointestinal
      bleeding, ectopic pregnancy), and drug toxicity (tricyclic antidepressants,
      cocaine). ED management of children and young adults in cardiac arrest requires
      an understanding of the heterogeneous pathophysiologic mechanisms and etiologies
      leading to cardiopulmonary dysfunction in these patients. The emergency physician
      should give particular focus to airway management for toddlers and
      preadolescents, because respiratory diseases predominate. When treating an
      adolescent or young adult, the resuscitation team should also consider toxic
      causes as well as occult hemorrhage. Management considerations unique to this
      patient population are discussed.

PMID- 10337889
TI  - Helical CT in the evaluation of renal colic.
AB  - This study assessed the clinical effectiveness of unenhanced helical (spiral)
      computed tomography (CT) for evaluation of patients presenting with symptoms of
      renal colic. Two hundred patients with symptoms and signs of renal colic (flank
      or groin pain, hematuria) were imaged. Unenhanced CT was performed using 5-mm
      collimation with a pitch of 1.5 to 1.8. Image reconstruction was performed at 3
      mm intervals. Exam time was approximately 5 minutes. The financial charge at the
      study institution was the same as for an intravenous urogram. Clinical follow-up
      was performed by review of available medical records and patient interviews. The
      sensitivity for detecting clinically relevant ureteral and bladder calculi was
      0.862 (0.95 confidence interval [CI] 0.771 to 0.927), the specificity was 0.914
      (0.95 CI 0.837 to 0.962), and the accuracy was 0.89 (0.95 CI 0.833 to 0.931).
      Helical CT is an effective technique in the evaluation of suspected acute urinary
      tract obstruction.

PMID- 10337891
TI  - Traumatic aortic rupture: delayed presentation with a normal chest radiograph.
AB  - Traumatic aortic injury is a potentially fatal complication of blunt trauma.
      Patients with this entity may have a constellation of signs and symptoms and
      frequently have other significant injuries. The diagnosis is often suspected
      through abnormalities on the presenting chest radiograph. Delay in diagnosis
      results in increased morbidity and mortality. This report details the delayed
      presentation of an ambulatory patient with traumatic aortic rupture and a normal
      chest radiograph.

PMID- 10337890
TI  - Eyelid foreign body mimics an intraocular foreign body on plain orbital
      radiography.
AB  - Localization of a foreign body detected on plain orbital radiography may be
      achieved by comparing radiographs taken with the eyes in upgaze and downgaze.
      Movement of the foreign body with ocular rotation is considered to indicate
      localization either within the globe itself or within the soft tissues of the
      orbit closely related to the globe. A case is reported that demonstrates that
      this radiologic feature may also occur when a foreign body is located within an
      eyelid because the position of the eyelids also changes on vertical eye
      movements. An eyelid foreign body may therefore mimic an intraocular foreign body
      on plain orbital radiography.

PMID- 10337892
TI  - Complications of shoulder dislocation.
AB  - Dislocations of the shoulder are the most common joint dislocations seen in the
      emergency department, and complications of shoulder dislocations are more
      frequent than is generally believed. It is vital that emergency physicians have
      current knowledge of complications associated with shoulder dislocations because
      of their important role in recognition and prevention. Delayed recognition of
      complications can have an impact on the long-term outcome of patients. Prompt
      recognition and follow-up are essential. Most references address reduction
      methods rather than recognition of specific complications. Emergency physicians
      have few opportunities to update their knowledge of complications of shoulder
      dislocations. This article briefly reviews mechanisms of shoulder dislocation and
      discusses complications in light of the mechanisms of injury.

PMID- 10337893
TI  - Persistent ST segment elevation: a new ECG finding in hypertrophic
      cardiomyopathy.
AB  - Hypertrophic cardiomyopathy is a primary disease of myocardium resulting in
      myocardial hypertrophy without any inciting pressure or volume overload. The
      typical triad of symptoms includes exertional angina, syncope, and shortness of
      breath. Sudden cardiac death, the most dreadful complication of this disorder,
      can be the first manifestation of the disease and is more common in young
      patients. Elderly patients, on the other hand, may have a relatively benign
      course with normal or near-normal life span. The electrocardiogram (ECG) and
      echocardiography are the two most useful measures to diagnose hypertrophic
      cardiomyopathy. The electrocardiographic features of hypertrophic cardiomyopathy
      are numerous, including ST segment elevation that may simulate other ST segment
      elevation syndromes, including acute myocardial infarction, variant angina
      pectoria, acute pericarditis, bundle branch blocks, ventricular paced rhythm,
      dyskinetic ventricular segment, ventricular aneurysm, left ventricular
      hypertrophy, Wolff-Parkinson-White syndrome, and early repolarization syndrome.
      This report describes a case of an asymptomatic patient who presented with ST
      segment elevation of acute injury type and, therefore, was admitted to rule out
      silent myocardial infarction. Myocardial infarction was ruled out by cardiac
      enzyme levels, but ST segment elevation remained persistent in all of the
      subsequent ECGs. Echocardiography was performed, which clearly showed
      hypertrophic cardiomyopathy with left ventricular outflow tract obstruction and a
      high intracavity pressure gradient. Subsequently, retrieval of old ECGs showed a
      similar type of ST segment elevation in the patient's previous ECGs.

PMID- 10337894
TI  - Ultrasound-assisted ankle arthrocentesis.
AB  - Difficulty is frequently encountered in performing ankle arthrocentesis. This
      report describes an ultrasound-assisted technique that can be readily learned by
      emergency physicians. It involves using the ultrasound beam to accurately locate
      the tibiotalar joint, thereby increasing the probability of obtaining joint fluid
      on aspiration.

PMID- 10337895
TI  - Blunt trauma-induced bilateral chylothorax.
AB  - This report describes the case of a man who presented in a delayed manner after
      blunt trauma with bilateral chylothoraces, a rare result of trauma. He presented
      with shortness of breath and chest pain. A diagnostic workup resulted in the
      determination of traumatic chylothorax. His course in the hospital identified a
      disruption at a level of the 5th thoracic vertebra. No surgical ligation was
      required because his leak spontaneously sealed after conservative measures. The
      anatomy, physiology, mechanisms, and management of this injury are discussed.

PMID- 10337896
TI  - ED hemodialysis for treatment of renal failure emergencies.
AB  - Patients with chronic renal failure (CRF) are at risk for unique medical
      emergencies, many of which require hemodialysis for their definitive treatment.
      This study describes the use of emergency department (ED) hemodialysis in the
      management of CRF patients. A retrospective chart review was conducted of
      patients who underwent ED hemodialysis at a regional dialysis center between
      April 1994 and September 1996. Data were collected on presenting complaint, ED
      diagnosis, indication for hemodialysis, ED pharmacologic treatment, ED airway
      management, cardiovascular stability, and disposition. Fifty episodes of ED
      hemodialysis were identified in 37 different patients. Presenting complaints
      included: shortness of breath, 38 (69%); weakness, 8 (15%); chest pain, 3 (5%);
      and other, 6 (11%). ED diagnoses included: congestive heart failure, 36 (65%);
      hyperkalemia, 13 (24%); and other, 6 (11%). Indications for hemodialysis
      included: cardiovascular instability, 33 (38%); respiratory distress, 22 (26%);
      cardiac monitoring, 16 (19%), timing, 13 (15%); and other, 2 (2%). Predialysis
      stabilization included: nitroglycerin, 29 (26%); sublingual captopril, 17 (15%);
      calcium chloride, 13 (11%); sodium bicarbonate, 12 (11%); insulin/dextrose, 11
      (10%); none, 12 (11%); and other, 18 (16%). Airway support included: noninvasive
      pressure support ventilation (NPSV), 9 (18%); and endotracheal intubation, 6
      (12%). NPSV was provided with a bilevel positive airway pressure system. Three of
      the endotracheal intubation patients were weaned to NPSV during dialysis, and all
      NPSV patients were weaned from respiratory support during their hemodialysis in
      the ED. Some patients had more than one problem. Sixteen patients (32%) were
      admitted, while 34 (68%) were discharged, including 3 NPSV patients and 22
      initially unstable patients. ED hemodialysis in conjunction with additional
      medical care is a useful emergency medicine technique that can prevent hospital
      admission in patients with acute renal emergencies.

PMID- 10337897
TI  - Acute postoperative neck hematoma.

PMID- 10337898
TI  - Pneumothorax secondary to acupuncture.

PMID- 10337899
TI  - Pneumoperitoneum secondary to fallopian coelomic fistula.

PMID- 10337900
TI  - Ectopic pregnancy after tubal ligation.

PMID- 10337901
TI  - Bedside ultrasound in delayed traumatic pericardial effusion.

PMID- 10337902
TI  - Black widow spider envenomation mimicking cholecystitis.

PMID- 10337903
TI  - Delayed increase in acetaminophen concentration after Tylenol PM overdose.

PMID- 10337904
TI  - Hypertensive crisis from herbal treatment of impotence.

PMID- 10337905
TI  - Hypoglycemia masquerading as acute psychosis and acute cocaine intoxication.

PMID- 10337906
TI  - Acute laryngeal dystonia related to neuroleptic agents.

PMID- 10337907
TI  - Niacin reaction: common vitamin, uncommon ED diagnosis.

PMID- 10337908
TI  - A mnemonic for the Salter-Harris classification.

PMID- 10337910
TI  - Weapon changes over time after initiation of a comprehensive weapon surveillance
      system.

PMID- 10337909
TI  - Sedation of intoxicated, agitated patients requiring CT to evaluate head injury.

PMID- 10337911
TI  - Requirement of peptidergic sensory innervation for disease activity in murine
      models of immune hepatitis and protection by beta-adrenergic stimulation.
AB  - To investigate the interaction between the peripheral nervous and the immune
      system in vivo, we used two mouse models of T cell and TNF-alpha dependent liver
      injury inducible by either concanavalin A or a combination of D-galactosamine and
      staphylococcal enterotoxin B. Mice depleted of peptidergic sensory nerve fibres
      by capsaicin were protected from liver injury. Moreover, TNF-alpha production was
      significantly reduced. Examination of the effect of catecholamines on liver
      injury showed that the beta2-adrenergic agonist salbutamol prevented, whereas
      chemical sympathectomy by 6-hydroxydopamine, deteriorated the disease. Hence,
      strategies reducing the activity of peptidergic sensory nerve fibres or
      stimulating beta2-adrenoreceptors, may be of benefit in immune-mediated liver
      disease.

PMID- 10337912
TI  - CTLA-4-Fc treatment of ongoing EAE improves recovery, but has no effect upon
      relapse rate. Implications for the mechanisms involved in disease perpetuation.
AB  - Several laboratories including ours have shown that T cell co-stimulation
      mediated through B7-1 or B7-2 is critical to the initiation of EAE. The role of T
      cell co-stimulation in ongoing EAE is less clear. In the present study, 32 mice
      with established EAE were randomly assigned to receive treatment with either CTLA
      4-Fc or control Ig. Mice were followed daily by clinical scoring for 2 months
      post-immunization. A significant improvement in the degree of recovery following
      the acute episode and following relapses of EAE was observed in those mice
      randomized to CTLA-4-Fc treatment. Full clinical remission occurred twice as
      often in the CTLA-4-Fc group as in those mice receiving placebo, whereas placebo
      treated mice were more likely to develop a stable prolonged neurologic deficit.
      Serial clinical scoring revealed no effect of CTLA-4-Fc upon relapse rate, with
      greater than 80% of the mice in each group displaying at least one clinical EAE
      relapse. In that the activation of memory T cells is relatively independent of T
      cell co-stimulation, these results indicate that development of chronic disease
      is associated with the activation of naive T cells and the recruitment of the
      latter cells into the disease process. Blocking B7 molecules may be beneficial in
      the treatment of established CNS inflammatory demyelinating diseases such as
      multiple sclerosis.

PMID- 10337913
TI  - Infection with a recombinant vaccinia virus encoding myelin proteolipid protein
      causes suppression of chronic relapsing-remitting experimental allergic
      encephalomyelitis.
AB  - Mice infected with a recombinant vaccinia virus (VVplp) encoding the myelin
      proteolipid protein (PLP) and then challenged with the encephalitogenic peptide,
      PLP139-151, developed a more severe acute attack vs. control mice. Following this
      initial acute attack, vaccinated mice had significantly less clinical disease
      (relapses) than control vaccinated or mock vaccinated mice. Control mice
      developed a relapsing-remitting disease with severe clinical relapses. During the
      remission state in VVplp vaccinated mice, histopathologic changes were markedly
      reduced in the central nervous system (CNS) vs. control vaccinated or
      unvaccinated mice. Inflammation was mainly limited to the meninges with a
      reduction of mononuclear cells in the parenchyma of the spinal cord in VVplp
      vaccinated and PLP139-151 challenged mice vs. control mice where inflammatory
      changes with demyelination was observed. During the remission period an increase
      in IL-4 was seen. In addition, there was significantly less T cell proliferation
      to PLP139-151 that was confirmed by an in vivo measurement of T cell reactivity,
      DTH responses. This suggests that the almost permanent remission state was
      dictated by a decreased responsiveness to PLP139-151 in VVplp vaccinated mice.

PMID- 10337914
TI  - Costimulatory signal blockade in murine relapsing experimental autoimmune
      encephalomyelitis.
AB  - Blockade of the CD28-B7 or CD40L-CD40 T cell costimulatory signals prevents
      induction of experimental autoimmune encephalomyelitis (EAE). However, the effect
      of simultaneous blockade of these signals in EAE is unknown. We show that
      administration of either MR1 (to block CD40L) or CTLA4Ig (to block B7) after
      immunization or after the first attack protects from EAE. Treatment with a
      combination of CTLA4Ig and MR1 provides additive protection, and is associated
      with complete absence of mononuclear cell infiltrates in the central nervous
      system, and marked suppression of proliferation of primed T cells in the
      periphery. Selective B7-1 blockade did not protect from EAE. These observations
      have implications for therapy of autoimmune diseases.

PMID- 10337915
TI  - VIP and PACAP inhibit IL-12 production in LPS-stimulated macrophages. Subsequent
      effect on IFNgamma synthesis by T cells.
AB  - Since IL-12 plays a central role against intracellular pathogens, and contributes
      to the pathogenesis of immune diseases, its regulation is essential. This study
      examines the effect of two neuropeptides, vasoactive intestinal peptide (VIP) and
      pituitary adenylate cyclase activating polypeptide (PACAP), on interleukin-12 (IL
      12) production. VIP/PACAP inhibit IL-12 dose-dependently. Type 1 VIP receptor
      (VPAC1), and to a lesser degree type 2 VIP receptor (VPAC2), mediate the
      inhibition of IL-12, primarily through the cAMP/PKA pathway. VIP/PACAP inhibit
      the production of IL-12, IL-6, tumor necrosis factor alpha (TNFalpha), and
      interferon gamma (IFNgamma) in vivo in endotoxemic mice. The presence of
      VIP/PACAP in the lymphoid organs and the specific effects on cytokine production
      offer a physiological basis for their immunomodulatory role in vivo.

PMID- 10337916
TI  - Dynamic norepinephrine alterations in bone marrow: evidence of functional
      innervation.
AB  - Efferent sympathetic nerve activity has been hypothesized to regulate the
      proliferation and maturation of leukocytes in the bone marrow. Although there is
      histological evidence for bone marrow innervation and documentation of measurable
      neurotransmitter, functional activation of these nerves to external stimulation
      has never been demonstrated. The present study was designed to assess the
      dynamics of norepinephrine (NE) release in bone marrow in response to well
      established protocols known to elevate sympathetic activity. Toward this end,
      norepinephrine turnover was measured using isotopic and non-isotopic methods in
      mice in response to cold exposure and bacterial challenge. Cold exposure
      increased NE turnover rate in bone marrow by 36% from 0.33 to 0.45 ng g(-1) h(
      1), while peritoneal Pseudomonas aeruginosa infection increased bone marrow NE
      turnover rate by 131% from 0.13 to 0.30 ng g(-1) h(-1). These results demonstrate
      that the adrenergic innervation of the bone marrow is functionally dynamic and is
      responsive to generalized stress. Furthermore, these results lend credence to the
      premise that neural mechanisms participate in regulation of lympho- and
      myelopoietic cellular events.

PMID- 10337917
TI  - Superoxide production by primary rat cerebral endothelial cells in response to
      pneumococci.
AB  - Animal studies of experimental bacterial meningitis have provided evidence for an
      involvement of reactive oxygen species (ROS) in the pathophysiology of this
      disease. Using a lucigenin-enhanced chemiluminescence (CL) method, we tested
      whether primary rat cerebral endothelial cells can be induced to release ROS upon
      stimulation with pneumococci. In addition, we determined CSF levels of two
      markers of lipid peroxidation in patients with bacterial meningitis, compared to
      patients with viral meningitis and noninflammatory neurological disorders.
      Malondialdehyde/4-hydroxynonenal concentrations were significantly elevated in
      CSF samples obtained from patients with bacterial meningitis (23.12+/-5.47
      microM), as compared to both control groups (5.43+/-0.18 microM and 7.80+/-0.33
      microM, respectively). Cerebromicrovascular endothelial cells, granulocytes, and
      the macrophage cell line RAW 264.7 (but not astrocytes and neuron-like cells)
      produced an increase in CL intensity after stimulation with pneumococci. The peak
      value produced by endothelial cells (500+/-83 cpm) was significantly lower than
      the maximum CL response in macrophages (1386+/-142 cpm; p<0.05). After addition
      of superoxide dismutase (SOD), the CL signal returned to baseline values. Equal
      to the CL technique, nitroblue tetrazolium (NBT) staining of RAW 264.7 showed SOD
      inhibitable formazan precipitation when stimulated with pneumococci. In
      conclusion, this study suggests an important role of endothelial cells in the
      pathophysiology of bacterial meningitis-namely as a source for ROS production.

PMID- 10337918
TI  - Neuroblastoma cells can express the hematopoietic progenitor cell antigen CD34 as
      detected at surface protein and mRNA level.
AB  - Recently, we have shown the expression of the hematopoietic precursor cell
      antigen CD34 on neuroblastoma cells. Here, we present the CD34 expression on 16
      permanent neuroblastoma cell lines and primary cell lines at the mRNA level and
      the flow cytometric results on neuroblastoma cells grown in the same culture and
      split for flow cytometric analysis and total mRNA extraction. The flow cytometry
      was performed using a panel of anti-CD34 antibodies covering the epitope classes
      I to III. In eight neuroblastoma cell lines, CD34 mRNA expression could be
      detected and corresponded always with the protein surface expression.
      Alternatively, when CD34 mRNA expression was not seen, CD34 antigen expression
      ranged from negative to as high as 78%. Based on these results caution should be
      taken with transplants obtained by CD34+ stem cell selection from neuroblastoma
      patients.

PMID- 10337919
TI  - Characterization of the inflammatory response during acute measles encephalitis
      in NSE-CD46 transgenic mice.
AB  - Expression of the human measles virus receptor, CD46, in the murine central
      nervous system allows infection and replication by wild-type human measles virus
      (MV) strains (Rall, G.F., Manchester, M., Daniels L.R., Callahan, E., Belman, A.,
      Oldstone, M.B.A., 1997. A transgenic mouse model for measles virus infection of
      the brain. Proc. Natl. Acad. Sci. U.S.A. 94, 2243-2248). MV replicates in neurons
      in focal lesions of the cortex, hippocampus and thalamus, leading to death of the
      animals. In MV-infected CD46 transgenic mice, infiltration of CD4+ and CD8+ T
      lymphocytes, B-lymphocytes and macrophages was seen. Upregulation of MHC class I
      and class II molecules was observed, along with reactive astrocytosis and
      microgliosis. Increased chemokine mRNAs, especially RANTES and IP-10, and
      cytokine RNAs IL-6, TNF-alpha, and IL1-beta were observed. Apoptosis of neurons
      also was increased. No MV replication or inflammation was seen in similarly
      inoculated nontransgenic littermates. These results further characterize the MV
      induced encephalitis in CD46 transgenic mice and highlight similarities to MV
      infection of the human CNS.

PMID- 10337921
TI  - Polyclonal immunoglobulins for intravenous use do not influence the behaviour of
      cultured oligodendrocytes.
AB  - Treatment studies in multiple sclerosis and the experimental murine model of
      Theiler's virus encephalomyelitis have suggested that intravenous immunoglobulins
      (IVIg) promote central nervous system remyelination. It is not clear if this
      results from a direct effect on myelinating oligodendroglial cells, or from
      suppression of the immune response permitting better endogenous repair. We
      systematically explored the effects of IVIg on various aspects of oligodendrocyte
      precursor cell (OPC) behaviour in vitro. Neither proliferation, differentiation
      nor migration of OPC was affected by IVIg. These results argue against a direct
      effect of IVIg on remyelination and are in favour of an indirect yet not clearly
      defined mechanism that supports remyelination.

PMID- 10337920
TI  - Site-specific control of T cell traffic in the brain: T cell entry to brainstem
      vs. hippocampus after local injection of IFN-gamma.
AB  - Although it is known that neurotransmitters and neuropeptides can affect immune
      function in vitro, less is understood about how the neural environment affects
      immune function in the brain. Previously, we showed that regulation of
      parenchymal class II MHC after local injection of IFN-gamma is site-specific. In
      this companion study, we defined the effect of local IFN-gamma on the entry of
      class II-restricted T cells to the brain parenchyma. To activate endogenous T
      cells, adult CDF rats were immunized with a normal neural antigen (MBP). Two
      weeks later, the proinflammatory cytokine IFN-gamma (100 to 10,000 U/site) was
      injected stereotaxically into two neurochemically and anatomically distinct
      sites, the hippocampus (area CAI) and brainstem (nucleus of the solitary tract).
      Monoclonal R73 was used to detect T cells on cryostat sections. The greatest
      difference was seen 48 h after 300 U IFN-gamma was injected at each site, when
      there were several-fold more parenchymal T cells in the brainstem than in the
      hippocampus. Most parenchymal T cells were CD4+ /class II-restricted. Thus,
      parenchymal T cell entry and parenchymal class II up-regulation show the same
      hierarchy (brainstem >> hippocampus) after local IFN-gamma injection, although T
      cell entry was more sensitive to the IFN-gamma dose. We suggest that the local
      regulatory environment contributes to site-specific immune regulation, and
      discuss implications for the distribution of MS plaques and other aspects of
      local immune control. Further, in interpreting the many previous studies of
      cytokine-mediated immune changes in the CNS, the possibility of site-specific
      differences should be considered.

PMID- 10337922
TI  - Dopamine D1-like receptor subtypes in human peripheral blood lymphocytes.
AB  - Molecular biology studies have shown that human peripheral blood lymphocytes
      express a dopamine D5 receptor, whereas no information is available on dopamine D
      receptor, the other dopamine D1-like receptor subtype. Radioligand binding assay
      investigations with the nonsubtype selective dopamine D1-like receptor antagonist
      [3H]SCH 23390 as radioligand have suggested the presence of a dopamine D5
      receptor in human peripheral blood lymphocytes. However, so far no evidence was
      provided as whether or not human peripheral blood lymphocytes express a dopamine
      D1 receptor. In this study, we have investigated dopamine D1 and D5 receptor mRNA
      and the influence of antibodies against dopamine D1 and D5 receptors on [3H]SCH
      23390 binding to intact human peripheral blood lymphocytes. The two receptors
      were also analyzed by immunocytochemistry. Dopamine D5 receptor, but not D1 mRNA,
      was detected in human peripheral blood lymphocytes. Anti-dopamine D5 receptor
      antibodies, but not anti-dopamine D1 receptor antibodies, significantly decreased
      [3H]SCH 23390 binding to human peripheral blood lymphocytes. A dark-brown
      immunoreactivity was visualized in cytospin centrifuged human peripheral blood
      lymphocytes exposed to anti-dopamine D5, but not to anti-dopamine D1 receptor
      antibodies. These data collectively indicate that dopamine D5 receptor is the
      only dopamine D1-like receptor subtype expressed by human peripheral blood
      lymphocytes.

PMID- 10337923
TI  - A major influence of the T cell receptor repertoire as compared to antigen
      processing-presentation in the selection of myelin basic protein epitopes in
      multiple sclerosis.
AB  - We selected two multiple sclerosis (MS) patients, compatible for HLA-DR2 subtype,
      and differing for HLA-DM haplotype as well as for the myelin basic protein (MBP)
      epitope recognized by the vast majority of their T cell lines (TCL) (residues 16
      38 and 86-99, respectively). TCL sharing the same restriction element were re
      assayed in the presence of reciprocally mismatched antigen-presenting cells
      (APC). The TCL recognized both the whole MBP and the relevant peptide also in the
      presence of non-autologous APC, (compatibility for processing, despite a
      difference in the DM haplotype). The same protocol, performed in serum-free
      pulsing experiments or in the presence of 'fixed' APC, excluded extracellular
      processing or mutual T cell presentation, and confirmed the need for MBP
      processing in our system. The finding, that only TCL recognizing MBP peptide 16
      38 (a region not previously related to the DR2 haplotype) used a novel Vbeta,
      supports the importance of the TCR repertoire over the processing-presentation
      machinery in the selection of MBP epitopes in MS.

PMID- 10337924
TI  - Subclass distribution and the secretory component of serum IgA anti-ganglioside
      antibodies in Guillain-Barre syndrome after Campylobacter jejuni enteritis.
AB  - Previously, we reported that IgA anti-GM1 antibody is more closely associated
      with preceding Campylobacter jejuni enteritis in Guillain-Barre syndrome (GBS)
      than are IgG and IgM antibodies. However, the mechanism of the induction of IgA
      anti-ganglioside antibodies is not clear. In this study, serum IgA antibodies
      against GM1, GM1b, and GD1a, and GalNAc-GD1a were examined in 152 GBS patients.
      In GBS, antecedent C. jejuni infection is closely associated with IgA antibodies,
      other than GM1, against GM1b. The IgA subclass distribution is completely
      restricted to IgA1, no secretory IgA anti-ganglioside antibody being detected.
      This result does not support the hypothesis that the serum IgA antibodies present
      in GBS after C. jejuni enteritis originate at mucosal sites, such as the gut
      mucosal immune system. Seventeen (85%) of 20 patients with IgA anti-ganglioside
      antibodies had serological evidence of C. jejuni infection and/or a history of
      antecedent diarrhea. Moreover, a motor nerve conduction study showed that
      patients with IgA antibodies frequently had axonal neuropathy, whereas none had
      demyelinating neuropathy. This may support the previous report that IgA isotype
      anti-GM1 antibodies are more closely associated with poor outcome than are the
      IgG or IgM isotypes. The induction mechanism of IgA anti-ganglioside antibodies
      must be clarified by determining whether concentrations of cytokines, which
      increase the IgA class switch, are elevated in patients with GBS after C. jejuni
      enteritis.

PMID- 10337925
TI  - Plaques, T cells and beyond: report on an international meeting on the
      immunological basis of multiple sclerosis held at the University of Chieti,
      Italy.

PMID- 10337926
TI  - Helicobacter heilmannii: a spiral shaped organism other than Helicobacter pylori.

PMID- 10337927
TI  - Colonic side effects of nonsteroidal antiinflammatory drugs.

PMID- 10337928
TI  - An attractive relation of human herpesvirus-8 with multicentric Castleman's
      disease.

PMID- 10337929
TI  - Molecular base of "de novo" DRPLA.

PMID- 10337930
TI  - Cytophagic histiocytic panniculitis--what is the best therapy?

PMID- 10337931
TI  - Takayasu arteritis--beyond pulselessness.

PMID- 10337932
TI  - Gene therapy of arthritis.
AB  - Genes encoding anti-arthritic products can be transferred to intra-or
      extraarticular sites where their expression suppresses various aspects of the
      pathophysiology of arthritis. A variety of viral and non-viral vectors can be
      used for the in vivo or ex vivo delivery of such genes. Promising pre-clinical
      data have resulted from the application of these strategies in several animal
      models of disease. Genes showing efficacy in this way include these encoding
      interleukin (IL) -1Ra, IL-1sR, TNFsR, transforming growth factor beta (TGF-beta),
      IL-13, Fas L, IL- 10 and vIL-10. Two human arthritis gene therapy protocols are
      underway in the USA and Germany. Both studies involve the ex vivo transfer of an
      IL-1Ra cDNA to the metacarpophalangeal joints of patients with rheumatoid
      arthritis. Progress in developing gene treatments for arthritis has been rapid,
      and permits optimism about their ability eventually to improve the treatment of
      this group of diseases.

PMID- 10337933
TI  - Helicobacter heilmannii associated erosive gastritis.
AB  - The spiral bacteria, Helicobacter heilmannii (H. heilmannii), distinct from
      Helicobacter pylori (H. pylori), was found in the gastric mucosa of a 71-year-old
      man without clinical symptoms. The endoscopic examination revealed erosive
      gastritis. Rapid urease test from the antral specimen was positive, but both
      culture and immunohistological staining for H. pylori were negative. Touch smear
      cytology showed tightly spiral bacteria, which were consistent with H.
      heilmannii. At the second endoscopy after medication regimen for eradication of
      H. pylori, inflammation was decreased and the rapid urease test was negative. The
      second cytology showed no evidence of H. heilmannii. Anti-H. pylori therapy may
      be a useful medication for H. heilmannii.

PMID- 10337934
TI  - Primary biliary cirrhosis associated with painless thyroiditis.
AB  - A case of anti-mitochondrial antibody (AMA)-negative primary biliary cirrhosis
      (PBC) associated with painless thyroiditis is reported in a 47-year-old woman who
      diagnosed as PBC based on her elevated serum gamma-glutamyl transpeptidase and
      immunoglobulin M levels, as well as histological findings of destroyed bile ducts
      surrounded by mononuclear infiltrates in the biopsied liver. She was negative for
      AMA and had a depressed level of thyroid-stimulating hormone accompanied by
      increased free thyrosine, thyroxine and triiodothyronine levels and low titers of
      anti-microsomal and anti-thyroid peroxidase antibodies. Her thyroid disorder
      corresponded with painless thyroiditis. An association between PBC and
      hyperthyroidism is rare. Furthermore, an association between AMA-negative PBC and
      hyperthyroidism due to painless thyroiditis has not previously been reported.

PMID- 10337935
TI  - Colonic ulceration caused by administration of loxoprofen sodium.
AB  - A 54-year-old female with chronic headache was admitted to our hospital because
      of hematochezia. She had routinely taken loxoprofen sodium because of severe
      headache. Emergent colonoscopic examination revealed ulceration of the cecum.
      After administration of loxoprofen sodium was discontinued and administration of
      sulfasalazine was initiated, her intestinal bleeding subsided. Two months after
      discontinuation of loxoprofen sodium, the colonoscopic examination revealed scar
      formation at the site of cecal ulceration. In this case, it was conceivable that
      the administration of loxoprofen sodium might have induced colonic ulceration.

PMID- 10337936
TI  - Hypokalemia with syncope caused by habitual drinking of oolong tea.
AB  - A 61-year-old woman developed hypokalemia, atrioventricular block and ventricular
      tachycardia with syncope after habitual drinking 2 to 3 liters of oolong tea per
      day. She had been suffering from rheumatoid arthritis and Sjogren's syndrome and
      her serum albumin was decreased (2.9 g/dl). Oolong tea contains caffeine at
      approximately 20 mg/dl. Great quantities of caffeine can induce hypokalemia. The
      serum protein binding caffeine is albumin. Accordingly, in patients with
      hypoalbuminemia, caffeine is apt to induce hypokalemia. This case suggested that
      great quantities of oolong tea, one of the so-called "healthy" drinks, result in
      serious symptoms for patients with hypoalbuminemia.

PMID- 10337937
TI  - Insulin resistance in patients with depression and its changes in the clinical
      course of depression: a report on three cases using the minimal model analysis.
AB  - It has been reported that depression and diabetes mellitus often occur together,
      and insulin resistance has been observed in patients with depression. For further
      understanding of the relationship of depression to insulin resistance, three
      patients with depression were given the oral glucose tolerance test (OGTT) and
      the frequently sampled intravenous glucose tolerance test (FSIGT) with minimal
      model analysis before and after antidepressant treatment. Depressive patients
      showed decreased glucose tolerance, enhanced insulin secretion, and diminished
      insulin sensitively during OGTT and FSIGT. These abnormalities were resolved
      after their recovery from depression without changes in body weight or diet.

PMID- 10337938
TI  - Primary hypomagnesemia caused by isolated magnesium malabsorption: atypical case
      in adult.
AB  - Isolated magnesium malabsorption is a rare disorder, which bas been described in
      no more than 30 patients worldwide. Patients with this disorder typically present
      with convulsion and diarrhea in early infancy. Hypomagnesemia and hypocalcemia
      were found in a 35-year-old man with muscle cramps, who bad been diagnosed as
      primary hypoparathyroidism. Oral magnesium therapy corrected the low serum
      calcium, magnesium and parathyroid hormone levels. We report an atypical case of
      isolated magnesium malabsorption in an adult.

PMID- 10337939
TI  - Reduction of plasma gonadotropin levels and pituitary tumor size by treatment
      with bromocriptine in a patient with gonadotropinoma.
AB  - A pituitary tumor with suprasellar extension was found by magnetic resonance
      imaging (MRI) in a male with diabetes mellitus. Endocrine examination revealed
      high plasma follicle-stimulating hormone (FSH) and alpha-subunit levels, which
      increased with administration of thyrotropin (TSH)-releasing hormone (TRH).
      Plasma luteinizing hormone (LH) and testosterone levels were low. Pituitary
      gonadotropin producing tumor was diagnosed. Because the patient refused surgery,
      bromocriptine was administered and plasma FSH and alpha-subunit rapidly
      decreased; on MRI the tumor size was gradually reduced. When pituitary operation
      is not feasible, bromocriptine is one choice of treatment.

PMID- 10337940
TI  - Cyclosporin A mono-therapy in nephrotic syndrome with contra-indication of
      steroid therapy.
AB  - We describe three cases of nephrotic syndrome with a contra-indication for
      steroid therapy successfully treated with cyclosporin A (CsA). A 21-year-old man
      with focal segmental glomerulosclerosis (FSGS) complicated by necrosis of the
      femoral head, and a 34-year-old woman and a 48-year-old man with minimal change
      disease (MCD) complicated by psychogenic reaction and diabetes mellitus,
      respectively, were given CsA at initial dosages of 3.8-5.0 mg/kg/day and
      immediately remitted completely. However, two of these patients suffered relapses
      when CsA was tapered. They are currently maintained in complete or partial
      remission on CsA at dosages of 3.2-4.7 mg/kg/day. These findings suggest that CsA
      mono-therapy may be useful in nephrotic syndrome patients contra-indicated for
      steroid therapy.

PMID- 10337941
TI  - Bronchoscopic therapy for mucosa-associated lymphoid tissue lymphoma of the
      trachea.
AB  - The tracheal tumor of a 74-year-old female was detected on bronchoscopy and
      histologically diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma. We
      successfully treated the tumor with endoscopic neodyminum-yttruim-aluminium
      garnet (Nd-YAG) laser photoresection followed by local ethanol injection. This is
      the first case in which tracheal MALT lymphoma was successfully treated with
      bronchoscopy. Bronchoscopic therapy seems to be one of the most valuable
      strategies for treatment of MALT lymphomas of the central airway.

PMID- 10337942
TI  - Kaposi's sarcoma-associated herpesvirus infection in the lung in multicentric
      Castleman's disease.
AB  - A 32-year-old female was admitted for evaluation of multiple infiltrates on a
      chest radiograph. A diagnosis of multicentric Castleman's disease was made on the
      basis of typical clinical manifestations. Transbronchial lung biopsy (TBLB)
      revealed histological findings reported in lymphocytic interstitial pneumonia.
      Both the polymerase chain reaction and in situ hybridization with a probe
      specific for Kaposi's sarcoma-associated herpesvirus (KSHV) sequences
      demonstrated the presence of KSHV in the TBLB sample.

PMID- 10337943
TI  - Acquired factor VIII inhibitor in a non-hemophilic patient with chronic hepatitis
      C viral infection.
AB  - Production of coagulation factor VIII inhibitor is rarely encountered in non
      hemophilic patients. A 63-year-old Japanese male suffered from severe bleeding
      tendency caused by this inhibitor. Although he did not have malignancy or
      collagen disease, he had chronic hepatitis C virus (HCV) infection. Although HCV
      is known to induce production of various autoimmune antibodies, this may be the
      first report of a case with both acquired factor VIII inhibitor and HCV
      infection.

PMID- 10337944
TI  - Genetic analysis of a dentatorubral-pallidoluysian atrophy family: relevance to
      apparent sporadic cases.
AB  - Dentatorubral-pallidoluysian atrophy (DRPLA) is associated with an unstable CAG
      trinucleotide sequence. We describe a DRPLA family whose members have an allele
      containing an expanded CAG repeat, even in an elderly neurologically normal
      individual. The proband developed DRPLA at age 14. She was initially considered a
      sporadic case, but later her sister became symptomatic. Investigation of the
      number of CAG repeat units in her family revealed the 81-year-old father to have
      an expanded CAG repeat of 51 units. To our knowledge, such an advanced aged
      unaffected patient has not been previously documented. The present example may
      explain apparent sporadic cases.

PMID- 10337945
TI  - Syndrome of inappropriate secretion of antidiuretic hormone associated with
      idiopathic normal pressure hydrocephalus.
AB  - A 79-year-old woman suffering from urinary incontinence and unsteady gait was
      diagnosed as having idiopathic normal pressure hydrocephalus (NPH) with
      hyponatremia due to the syndrome of inappropriate secretion of antidiuretic
      hormone (SIADH). The concentration of antidiuretic hormone was high while the
      plasma osmolality was low in the presence of concentrated urine during the
      episodes of hyponatremia. Magnetic resonance imaging (MRI) of the head showed
      enlargement of the third and lateral ventricles. After ventriculoperitoneal shunt
      surgery, the symptoms of NPH and hyponatremia improved. It may be possibly
      explained that mechanical pressure on the hypothalamus from the third ventricle
      is responsible for hyponatremia.

PMID- 10337946
TI  - Pure anomic aphasia caused by a subcortical hemorrhage in the left temporo
      parieto-occipital lobe.
AB  - There have been few case reports of pure anomic aphasia and the underlying
      mechanism remains to be clarified. We report a patient in whom pure anomic
      aphasia was caused by subcortical hemorrhage in the left temporo-parieto
      occipital lobe. Based on magnetic resonance images and cerebral blood flow
      imaging, the structural lesion underlying the pure anomic aphasia was thought to
      be located at the left temporo-occipital junction.

PMID- 10337947
TI  - Cytophagic histiocytic panniculitis improved by combined CHOP and cyclosporin A
      treatment.
AB  - In a 31-year-old Japanese man with cytophagic histiocytic panniculitis (CHP)
      remission was achieved by a combination of combined chemotherapy CHOP and
      cyclosporin A treatment. He was admitted to our hospital in January 1994 with
      recurrent high fever of 40.2 degrees C and tender and violaceous subcutaneous
      nodules on his trunk, arms and legs. He developed pancytopenia, hemorrhagic
      diathesis, liver dysfunction. Histological examination of the biopsied
      subcutaneous nodule revealed a lobular panniculitis with fat necrosis and a
      massive infiltration of histiocytes phagocytosing nuclear debris. He was treated
      initially with 40 mg/day prednisolone. However, following a reduction in
      prednisolone dosage, his symptoms reappeared. CHOP (cyclophosphamide,
      doxorubicin, vincristine and prednisolone) therapy was then initiated. Three
      courses of CHOP treatment alleviated his symptoms and cyclosporin A was used to
      maintain his condition for 15 months. His medication was then discontinued and he
      has been in complete remission for 10 months. Combined treatment of cyclosporin A
      and CHOP combined chemotherapy was shown to be effective for this patient with
      severe CHP.

PMID- 10337948
TI  - A generalized seizure following initiation of nelfinavir in a patient with human
      immunodeficiency virus type 1 infection, suspected due to interaction between
      nelfinavir and phenytoin.
AB  - Nelfinavir, one of human immunodeficiency virus (HIV) specific protease
      inhibitors(PIs), is widely used for the treatment of HIV infection. Nelfinavir,
      which is metabolized with the cytochrome p450 isoforms, elevate the phenytoin
      level theoretically because nelfinavir acts as an inhibitor of phenytoin
      metabolism through the enzyme. However, we encountered a case of seizure
      recurrence caused by a lowered phenytoin level after initiation of nelfinavir. We
      should be aware of the change in the phenytoin level in concomitant use of
      nelfinavir.

PMID- 10337950
TI  - Expression of tissue type and urokinase type plasminogen activators as well as
      plasminogen activator inhibitor type-1 and type-2 in human and rhesus monkey
      placenta.
AB  - The distribution of mRNAs and antigens of tissue type (t) and urokinase type (u)
      plasminogen activators (PA) plus their corresponding inhibitors, type-1 (PAI-1)
      and type-2 (PAI-2) were studied in human and rhesus monkey placentae by in situ
      hybridisation and immunocytochemistry. Specific monkey cRNA and antibodies
      against human tPA, uPA, PAI-1 and PAI-2 were used as probes. The following
      results were obtained. (1) All the molecules tPA, uPA, PAI-1 and PAI-2 and their
      mRNAs were identified in the majority of the extravillous cytotrophoblast cells
      of the decidual layer between Rohr's and Nitabuch's striae and in cytotrophoblast
      cells of the chorionic plate, basal plate, intercotyledonary septae and
      cytotrophoblast cells of the chorionic villous tree. (2) Expression of uPA and
      PAI-2 was noted in villous trophoblast whereas tPA and PAI-1 were mainly
      concentrated where detachment from maternal tissue occurs. (3) No expression of
      tPA, uPA, PAI-1 and PAI-2 was observed in the basal plate endometrial stromal
      cells, chorionic plate connective tissue cells, septal endometrial stromal cells
      or villous core mesenchyme. (4) The distribution of probes observed following in
      situ hybridisation is generally consistent with the immunofluorescence pattern of
      the corresponding antigens and no significant interspecies differences were
      noted. It is possible that both decidual and extravillous trophoblast cells of
      placentae of human and rhesus monkey are capable of producing tPA, uPA, PAI-1 and
      PAI-2 to differing extents. Coordinated expression of these genes in the tissue
      may play an essential role in the maintenance of normal placentation and
      parturition. The differences in distribution we observed are consistent with the
      suggestion that coordinated expression of tPA and its inhibitor PAI-1 may play a
      key role in fibrinolytic activity in the early stages of placentation and
      separation of placenta from maternal tissue at term. On the other hand, uPA with
      its inhibitor PAI-2 appears mainly to play a role in degradation of trophoblast
      cell-associated extracellular matrix, and thus may be of greatest importance
      during early stages of placentation.

PMID- 10337949
TI  - The transitional zone and CNS regeneration.
AB  - Most nerves are attached to the neuraxis by rootlets. The CNS-PNS transitional
      zone (TZ) is that length of rootlet containing both central and peripheral
      nervous tissue. The 2 tissues are separated by a very irregular but clearly
      defined interface, consisting of the surface of the astrocytic tissue comprising
      the central component of the TZ. Central to this, myelin sheaths are formed by
      oligodendrocytes and the supporting tissue is astrocytic. Peripheral to it,
      sheaths are formed by Schwann cells which are enveloped in endoneurium. The
      features of transitional nodes are a composite of those of central and peripheral
      type. The interface is penetrated only by axons. It is absent at first. It is
      formed by growth of processes into the axon bundle from glial cell bodies around
      its perimeter. These form a barrier across the bundle which fully segregates
      prospectively myelinated axons. Rat spinal dorsal root TZs have been used
      extensively to study CNS axon regeneration. The CNS part of the TZ responds to
      primary afferent axon degeneration and to regenerating axons in ways which
      constitute a satisfactory model of the gliotic tissue response which occurs in
      CNS lesions. It undergoes gliosis and the gliotic TZ tissue expands distally
      along the root. In mature animals axons can regenerate satisfactorily through the
      endoneurial tubes of the root but cease growth on reaching the gliotic tissue.
      The general objective of experimental studies is to achieve axon regeneration
      from the PNS through this outgrowth and into the dorsal spinal cord. Since
      immature tissue has a greater capacity for regeneration than that of the adult,
      one approach includes the transplantation of embryonic or fetal dorsal root
      ganglia into the locus of an extirpated adult ganglion. Axons grow centrally from
      the transplanted ganglion cells and some enter the cord. Other approaches include
      alteration of the TZ environment to facilitate axon regeneration, for example, by
      the application of tropic, trophic, or other molecular factors, and also by
      transplantation of cultured olfactory ensheathing cells (OECs) into the TZ
      region. OECs, by association with growing axons, facilitate their extensive
      regeneration into the cord. Unusually, ventral motoneuron axons may undergo some
      degree of unaided CNS regeneration. When interrupted in the spinal cord white
      matter, some grow out to the ventral rootlet TZ and thence distally in the PNS.
      The DRTZ is especially useful for quantitative studies on regeneration. Since the
      tissue is anisometric, individual parameters such as axon numbers, axon size and
      glial ensheathment can be readily measured and compared in the CNS and PNS
      environments, thereby yielding indices of regeneration across the interface for
      different sets of experimental conditions.

PMID- 10337952
TI  - Adaptation in the vertebral column: a comparative study of patterns of metameric
      variation in seven species of small mammals.
AB  - The pattern of variation of certain vertebral measurements along the vertebral
      column is known to differ in man and mouse. This paper investigates changes in
      this pattern in 7 species of small mammals and attempts to correlate them with
      locomotor adaptations and limb dimensions.

PMID- 10337951
TI  - The effects of lithium on vascular development in the chick area vasculosa.
AB  - The effects of lithium on vascular development were examined using the chick
      embryo area vasculosa in shell-less culture as an experimental model. Embryos
      were explanted after 48 h in ovo and LiC1 (50, 100, 150 and 200 microg in 10
      microl water) was applied to the centre of the blastodisc. Controls were
      untreated or given equimolar amounts of NaCl. At 24 h and 48 h after treatment,
      untreated and NaCl controls were identical, having well developed extraembryonic
      vessels. At doses of 100 microg and greater, LiCl significantly inhibited normal
      vascular development and expansion of the area vasculosa in the majority of
      explants. In many specimens blood islands continued to form but their assembly
      into primitive vessels was prevented, indicating that lithium affects the
      mechanism regulating the assembly of vascular endothelium. At the same time the
      embryos were alive but retarded in development compared with controls. When LiCl
      (150 microg) was applied to cultures explanted after 72 h in ovo (when the
      primary vascular network had already formed through vasculogenesis) no adverse
      effects were seen. This suggests that lithium affects vasculogenesis but not
      angiogenesis. Treatment with myo-inositol completely reversed the effects of
      lithium in a time dependent manner indicating that the phosphatidylinositol
      second messenger cycle may be involved in the cellular events of vasculogenesis.
      Finally the results of this study show that the yolk sac vasculature is
      particularly vulnerable to lithium and the consequent effects of this
      interference on embryonic development are discussed.

PMID- 10337953
TI  - Differences in the width of the intercellular spaces in the epithelial basal
      infolding and the renal glomerular filtration site between freeze-substitution
      and conventional fixation.
AB  - After aldehyde prefixation, pretreatment with cryoprotectant and subsequent
      freeze-substitution with OsO4 in acetone (AC-FS), extensive gap junction-like
      close membrane appositions are frequently found in the basal infolding of the
      salivary gland epithelium, although the desmosomal intercellular space had the
      same width as with conventional electron microscopy. The intercellular space
      between podocyte pedicles and endothelial cells at the renal glomerular
      filtration site was narrower by the total width of 2 laminae lucidae following AC
      FS than with conventional electron microscopy and was occupied by a homogeneous
      lamina densa without a lamina lucida, although no marked difference was
      discernable in the thickness of the lamina densa itself between the 2 preparative
      procedures. In addition, a decrease in the thickness of the glycocalyx was
      evident in the intestinal epithelial microvilli following AC-FS. It is thus
      likely that osmication in acetone at freezing temperatures remove the glycocalyx
      and related structures to a variable extent, and that this loss is responsible
      for reducing the intercellular spaces at some of the simple appositions narrower
      to the dimensions of the gap junction. It is also responsible for disappearance
      of the lamina lucida of the basement membrane.

PMID- 10337954
TI  - Acrosome formation during sperm transit through the epididymis in two marsupials,
      the tammar wallaby (Macropus eugenii) and the brushtail possum (Trichosurus
      vulpecula).
AB  - In certain Australian marsupials including the tammar wallaby (Macropus eugenii)
      and the brushtail possum (Trichosurus vulpecula), formation of the acrosome is
      not completed in the testis but during a complex differentiation process as
      spermatozoa pass through the epididymis. Using transmission and scanning electron
      microscopy this paper defined the process of acrosome formation in the
      epididymis, providing temporal and spatial information on the striking
      reorganisation of the acrosomal membranes and matrix and of the overlying sperm
      surface involved. On leaving the testis wallaby and possum spermatozoa had
      elongated 'scoop'-shaped acrosomes projecting from the dorsal surface of the
      head. During passage down the epididymis, this structure condensed into the
      compact button-like organelle found on ejaculated spermatozoa. This condensation
      was achieved by a complex process of infolding and fusion of the lateral
      projections of the 'scoop'. In the head of the epididymis the rims of the lateral
      scoop projections became shorter and thickened and folded inwards, to eventually
      meet midway along the longitudinal axis of the acrosome. As spermatozoa passed
      through the body of the epididymis the lateral projections fused together.
      Evidence of this fusion of the immature outer acrosomal membrane is the presence
      of vesicles within the acrosomal matrix which persist even in ejaculated
      spermatozoa. When spermatozoa have reached the tail of the epididymis the
      acrosome condenses into its mature form, as a small button-like structure
      contained within the depression on the anterior end of the nucleus. During the
      infolding process, the membranes associated with the immature acrosome are either
      engulfed into the acrosomal matrix (outer acrosomal membrane), or eliminated from
      the sperm head as tubular membrane elements (cytoplasmic membrane). Thus the
      surface and organelles of the testicular sperm head are transient structures in
      those marsupials with posttesticular acrosome formation and this must be taken
      into consideration in attempts to dissect the cell and molecular biology of
      fertilisation.

PMID- 10337956
TI  - The porcine bronchial artery: surgical and angiographic anatomy.
AB  - The pig is often used in experimental studies on the significance of bronchial
      artery circulation, but the anatomy of this artery is only poorly described. The
      purpose of this study was to improve the anatomical basis for experimental
      studies on the porcine bronchial artery circulation. The origin of the artery
      from the aorta is described in 32 pigs. Heart-lung blocks were perfused with
      saline and removed in 16 pigs, and the broncho-oesophageal orifice was identified
      and cannulated. In these 16 specimens the intrapulmonary ramification was studied
      by angiography, and the extrapulmonary distribution and supply area by injection
      of Evans Blue. The broncho-oesophageal artery originated from the aorta as a
      single trunk in 91%. Angiography showed that each principal bronchus was
      accompanied by 2 bronchial artery branches far into the lung parenchyma. The
      central branching pattern of the artery between the aorta and the principal
      bronchi was divided into 3 subtypes. Evans Blue showed communication with the
      whole mediastinum. The anatomical relations are described. It is concluded that
      the broncho-oesophageal artery divides to follow each bronchus with 2 bronchial
      branches. A nomenclature for these branches is suggested. The pig anatomy is
      suited for experimental investigations on the bronchial circulation.

PMID- 10337955
TI  - Quantitative analysis of the sympathetic innervation of the rat knee joint.
AB  - Retrograde tracing with Fluoro-Gold (FG) was used to identify the complete
      population of knee joint sympathetic postganglionic efferents in the lumbar
      sympathetic chain of adult female Wistar rats. In 6 rats, the total number and
      distribution of FG-labelled neurons in the lumbar sympathetic chain was
      determined. The rat knee joint is supplied by an average of 187+/-57 sympathetic
      afferents with the majority at the L3 and L4 levels. Immunohistochemistry using
      antibodies specific for tyrosine hydroxylase (TH), somatostatin (SS) or
      vasoactive intestinal polypeptide (VIP) revealed that 33 % of knee joint
      sympathetic afferents contained TH, 42 % contained VIP, and none contained
      somatostatin. Retrograde tracing with FG provided accurate and reproducible
      labelling of the joint-innervating subpopulation of sympathetic efferent neurons.
      This model lends itself to the further study of the molecular responses of this
      neuronal population in the various disorders and conditions affecting joints.

PMID- 10337957
TI  - Shape differences in the cervical and upper thoracic vertebrae in rats (Rattus
      norvegicus) and bats (Pteropus poiocephalus): can we see shape patterns derived
      from position in column and species membership?
AB  - The shapes of cervical (C1-C7) and upper thoracic (T1, T2) vertebrae from the rat
      and the grey-headed flying fox have been analysed by Fourier analysis to
      investigate the types of variation present and to try to isolate bones according
      to position along the vertebral column and species. It was found that the T2
      vertebrae of the rat are very different from all others in the study, that C2 and
      C6 vertebrae are very similar and that the remaining vertebrae split according to
      species.

PMID- 10337958
TI  - Expression of parathyroid hormone-related protein and the parathyroid
      hormone/parathyroid hormone-related protein receptor in rat thymic epithelial
      cells.
AB  - Thymic epithelial cells are an important source of cytokines and other regulatory
      peptides which guide thymocyte proliferation and maturation. Parathyroid hormone
      related protein (PTHrP), a cytokine-like peptide, has been reported to affect the
      proliferation of lymphocytes in vitro. The studies presented here were undertaken
      to test the hypotheses that PTHrP is produced locally within the thymus where it
      could influence thymocyte maturation and, more specifically, that thymic
      epithelial cells (TEC) could be the intrathymic source of PTHrP expression. To
      this end, immunohistochemical studies were performed to localise PTHrP and the
      PTH/PTHrP receptor within the adult rat thymus. Antibodies directed against 2
      different PTHrP epitopes, PTHrP(1-34) and PTHrP(34-53), demonstrated prominent
      specific PTHrP immunoreactivity in both subcapsular and medullary TEC. In
      addition, faint but specific staining for PTHrP was seen in the cortex,
      interdigitating between cortical lymphocytes while sparing epithelial-free
      subcapsular areas, thus suggesting that cortical TEC could also be a source of
      PTHrP immunoreactivity. In contrast, PTH/PTHrP receptor immunoreactivity was only
      seen in medullary and occasional septal TEC; no evidence of cortical or
      lymphocytic PTH/PTHrP receptor immunoreactivity was detected. Immunohistochemical
      studies of cultured cytokeratin-positive rat TEC confirmed the results of these
      in situ studies as cultured TEC were immunoreactive both for PTHrP and the
      PTH/PTHrP receptor. Thus these results demonstrate that PTHrP is produced by the
      epithelial cells of the mature rat thymus. This suggests that PTHrP, a peptide
      with known cytokine, growth factor and neuroendocrine actions, could exert
      important intrathymic effects mediated by direct interactions with TEC, or
      indirect effects on PTH/PTHrP receptor-negative thymocytes.

PMID- 10337959
TI  - Histochemical and immunohistochemical analysis of the mechanism of calcification
      of Meckel's cartilage during mandible development in rodents.
AB  - It is widely accepted that Meckel's cartilage in mammals is uncalcified hyaline
      cartilage that is resorbed and is not involved in bone formation of the mandible.
      We examined the spatial and temporal characteristics of matrix calcification in
      Meckel's cartilage, using histochemical and immunocytochemical methods, electron
      microscopy and an electron probe microanalyser. The intramandibular portion of
      Meckel's cartilage could be divided schematically into anterior and posterior
      portions with respect to the site of initiation of ossification beneath the
      mental foramen. Calcification of the matrix occurred in areas in which alkaline
      phosphatase activity could be detected by light and electron microscopy and by
      immunohistochemical staining. The expression of type X collagen was restricted to
      the hypertrophic cells of intramandibular Meckel's cartilage, and staining with
      alizarin red and von Kossa stain revealed that calcification progressed in both
      posterior and anterior directions from the primary centre of ossification. After
      the active cellular resorption of calcified cartilage matrix, new osseous islands
      were formed by trabecular bone that intruded from the perichondrial bone collar.
      Evidence of such formation of bone was supported by results of double
      immunofluorescence staining specific for type I and type II collagens, in
      addition to results of immunostaining for osteopontin. Calcification of the
      posterior portion resembled that in the anterior portion of intramandibular
      Meckel's cartilage, and our findings indicate that the posterior portion also
      contributes to the bone formation of the mandible by an endochondral-type
      mechanism of calcification.

PMID- 10337960
TI  - Quantitative description of the spatial arrangement of organelles in a polarised
      secretory epithelial cell: the salivary gland acinar cell.
AB  - Previous quantitative descriptions of cellular ultrastructure have focused on
      spatial content (volume, surface area and number of organelles and membrane
      domains). It is possible to complement such descriptions by also quantifying
      spatial arrangements. Hitherto, applications of stereological methods for
      achieving this (notably, estimation of covariance and pair correlation functions)
      have been confined to organ and tissue levels. This study explores 3-dimensional
      subcellular arrangements of key organelles within acinar cells of rabbit parotid
      salivary glands, highly polarised epithelial cells specialised for exocrine
      secretion of alpha-amylase. It focuses on spatial arrangements of secretion
      product stores (zymogen granules), rough endoplasmic reticulum (RER) and
      mitochondria. Systematic random samples of electron microscopical fields of view
      from 3 rabbits were analysed using test grids bearing linear dipole probes of
      different sizes. Unbiased estimates of organelle volume densities were obtained
      by point counting and estimates of covariance and pair correlation functions by
      dipole counting. Plots of pair correlation functions against dipole length
      identified spatial arrangement differences between organelle types. Volumes
      within RER and mitochondrial compartments were positively correlated with
      themselves at distances below 4 microm and 2 microm respectively but were
      essentially randomly arranged at longer distances. In sharp contrast, zymogen
      granules were not randomly arranged. They were clustered at distances below 6-7
      microm and more widely scattered at greater distances. These findings provide
      quantitative confirmation of the polarised arrangement of zymogen granules within
      acinar cells and further support for the relative invariance of biological
      organisation between subjects.

PMID- 10337961
TI  - The timing between skeletal muscle myoblast replication and fusion into myotubes,
      and the stability of regenerated dystrophic myofibres: an autoradiographic study
      in mdx mice.
AB  - In mdx mice, a model for Duchenne muscular dystrophy, the timing between the
      replication of myoblasts and their incorporation into myotubes was determined
      autoradiographically. Thirty-eight mdx mice aged 23 d were injected with
      tritiated thymidine to label myoblasts replicating early in the dystrophic
      process. At intervals from 8 h to 30 d after injection the tibialis anterior
      muscles were removed, processed for autoradiography and analysed for labelled
      central myonuclei (derived from the progeny of myoblasts which had been labelled
      at 23 d). At 8 h after injection there were no labelled central myonuclei,
      showing that the labelled myoblasts had not fused within this time. At 1 d, 2 %
      of central myonuclei were labelled, at 2 d, up to 32% were labelled, at 3 d
      approximately 60% were labelled, and at 4 d the labelling peaked at 74%. In the
      27 mice sampled from 5-30 d after injection, the levels of central myonuclear
      labelling varied enormously: from 1-63%. However, there was a consistent decrease
      in the numbers of labelled central myonuclei with time. This may have been due to
      dilution of the relative numbers of labelled myonuclei due to other, nonlabelled,
      myoblasts replicating after the availability of tritiated thymidine, and fusing.
      It was also possible that labelled myofibres underwent subsequent necrosis and
      were eliminated from the muscle. The proposal that a regenerated myofibre can
      undergo a subsequent cycle of necrosis and regeneration was supported by evidence
      of some necrotic myofibres with labelled and unlabelled central nuclei. These
      results have implications for understanding the cellular biology and pathology of
      dystrophic muscle, particularly in relation to myoblast transfer therapy as a
      potential treatment of Duchenne muscular dystrophy.

PMID- 10337962
TI  - Granulated metrial gland cells and interstitial trophoblast in the uterine wall
      of the bank vole, Clethrionomys glareolus, in early pregnancy.
AB  - The morphology and distribution of granulated metrial gland cells and of
      interstitial trophoblast cells in the uterine wall was studied in the first half
      of pregnancy in the bank vole, Clethrionomys glareolus. The morphology and
      distribution of granulated metrial gland cells was generally similar to that
      found in other members of the Rodentia, although they were absent from the walls
      of the arterial vessels passing through the decidua basalis. Interstitial
      trophoblast invaded the decidualising endometrium mesometrial to, and
      antimesometrial to, the implanted embryos. There was no apparent spatiotemporal
      relationship between the distribution of granulated metrial gland cells and
      interstitial trophoblast cells.

PMID- 10337963
TI  - Anatomical differences in the psoas muscles in young black and white men.
AB  - The anatomy of the psoas major muscle (PMA) in young black and white men was
      studied during routine autopsies. The forensic autopsies included 44 fresh male
      cadavers (21 black, 23 white) with an age span of 14 to 25 y. The range for
      weight was 66-76 kg and for height 169-182 cm. The PMA was initially measured in
      its entire length before measuring the diameter and circumference at each
      segmental level (L1-S1). At each segmental level, the calculated anatomical cross
      sectional area (ACSA) was more than 3 times greater in the black group compared
      with the white (P < 0.001). The psoas minor muscle (PMI) was absent in 91% of the
      black subjects, but only in 13% of the white subjects. These data show that the
      PMA is markedly larger in black than white subjects. The marked race specific
      difference in the size of the PMA may have implications for hip flexor strength,
      spine function and race specific incidence in low back pathology, and warrants
      further investigation.

PMID- 10337964
TI  - The possibility of deep peroneal nerve neurotisation by the superficial peroneal
      nerve: an anatomical approach.
AB  - Neurotisation involves transfer of nerves for the restoration of function
      following injury. A number of nerves have been used in different part of the
      peripheral nervous system. This study was undertaken to develop a practical and
      relatively safe surgical approach to the treatment of L4 root lesion's. We
      examined the effectiveness and safety of neurotisation of the deep peroneal nerve
      and its branches by the superficial peroneal nerve. Twelve legs of dissected
      cadavers provided for teaching purposes in the anatomy laboratory were used to
      display the common peroneal nerve and its branches. Each branch was measured
      using calipers and analysed to investigate the possibility of neurotisation of
      the deep peroneal nerve by the superficial peroneal nerve and its branches. It
      was found that of the measured branches, transposition was possible between those
      to peroneus longus and tibialis anterior on the basis of their diameter and
      length. In recent decades, advances in microsurgical reconstruction and
      understanding of the microanatomy have played major roles in improving the
      results of surgical treatment of nerve injuries. There is a need for further
      experimental studies on the feasibility of this surgical approach.

PMID- 10337966
TI  - Critical judgment.

PMID- 10337965
TI  - Case report: bilateral occurrence of a chondroepitrochlearis muscle.

PMID- 10337967
TI  - News from the National Institute on Deafness and Other Communication Disorders.

PMID- 10337968
TI  - Endoscopy of the middle ear through the eustachian tube: anatomic possibilities
      and limitations.
AB  - HYPOTHESIS: This anatomic study was designed to provide otosurgeons with a
      detailed description of the technique of transtubal middle ear endoscopy and
      anatomic landmarks facilitating orientation. To establish the role of transtubal
      endoscopy, its anatomical potentials and limitations were studied. BACKGROUND:
      Transtubal endoscopy has recently been described as an atraumatic tool for
      exploring the tympanic cavity. From the nasopharynx, a thin, flexible endoscope
      is advanced into the middle ear through the Eustachian tube. After the endoscope
      has been placed, it offers an anteroposterior view of the tympanic structures.
      METHODS: Temporal bone blocks and whole skulls of recently deceased persons were
      examined to define the average range of view obtained by transtubal endoscopy.
      Key structures in each region of the tympanic cavity were chosen for inspection,
      and positive identifications were noted. RESULTS: With a 0.8-mm, flexible,
      steerable scope, most mesotympanic structures (stapes suprastructure,
      incudostapedial joint, tympanic chord, and inner surface of the eardrum) were
      clearly defined. Areas of the posterior wall that were not accessible with the
      otomicroscope (lateral tympanic sinus, tympanic sinus, and facial recess) were
      also seen. Unlike with transtympanic endoscopy, the epitympanum (incudomalleal
      joint and malleus neck) was also evaluable. The stapes footplate was not seen
      well and the round window niche was unable to be inspected in the anteroposterior
      view inherent in the technique. Technical factors (poor illumination and small
      image size) and the unfamiliar anteroposterior view made orientation in the
      middle ear difficult. CONCLUSION: Transtubal middle ear endoscopy is a suitable
      method for exploring the tympanic cavity without traumatizing the eardrum.

PMID- 10337969
TI  - Anterior subannular T-tube for long-term middle ear ventilation during
      tympanoplasty.
AB  - OBJECTIVE: A technique for providing long-term ventilation of the middle ear (ME)
      during tympanoplasty is described, and the results using this technique in 20
      patients with chronic Eustachian tube dysfunction (ETD) are reported. STUDY
      DESIGN: This study was a retrospective, nonrandomized case review. SETTING: This
      study was conducted at an otology clinic in a tertiary referral center. PATIENTS:
      Twenty consecutive patients who underwent tympanoplasty with ETD, adhesive otitis
      media, or chronic otitis media with perforation were included in this study.
      INTERVENTION: All patients had a subannular T-tube placed anteriorly at the time
      of tympanoplasty for long-term ventilation of the ME space. MAIN OUTCOME
      MEASURES: The two main outcome measures were tube position and patency.
      Preoperative and postoperative hearing levels were also tested in most patients,
      and any complications were documented. RESULTS: Twenty patients (20 ears)
      received anterior subannular T-tubes at the time of tympanoplasty. Fourteen
      females and 6 males were evaluated (median age, 36 years; range, 7 to 72 years).
      All patients had ETD; 7 had adhesive otitis media, 10 had chronic otitis media, 8
      had cholesteatoma, and 2 had cleft palate. All patients had conductive hearing
      loss and previous surgery. All patients underwent tympanoplasty; 11 had
      concomitant ossiculoplasty, and 5 had mastoidectomy. Follow-up ranged from 8 to
      22 months (mean, 13.4 months). One patient was lost to follow-up. One tube
      extruded after 16 months. Two patients had persistent mild retraction of the
      tympanic membrane. All other tubes are patent and have not migrated or plugged.
      There has been no evidence of anterior blunting or ingrowth of epithelium around
      the tube. CONCLUSIONS: Anterior subannular T-tube placement is a simple, safe,
      and effective alternative for long-term ME ventilation in patients in whom
      standard transtympanic sites are not available. At their last follow-up visit,
      all but one patient had a patent tube. All MEs were aerated. This technique
      offers the advantage of ease of placement during simultaneous tympanoplasty,
      mastoidectomy, or ossiculoplasty. Longer follow-up is necessary to confirm these
      initial findings.

PMID- 10337970
TI  - Tympanic membrane changes in experimental cholesteatoma in the gerbil.
AB  - HYPOTHESIS: The current study aimed to analyze changes of the acoustic stiffness
      properties and coincident morphologic changes of the tympanic membrane (TM) in
      early stages of cholesteatoma. The results were compared with those obtained in
      previous studies of otitis media with effusion and purulent otitis media.
      BACKGROUND: The pathophysiology of the cholesteatoma development process remains
      unclear. Changes of the physical properties of the TM seem to play an important
      role. In chronic middle ear disease, atrophic regions and retraction pockets of
      the TM are often present. Such changes of the TM may facilitate the development
      of cholesteatoma. METHODS: Early stages of external ear canal cholesteatoma were
      produced in the Mongolian gerbil by closing the external meatus with a suture.
      Acoustic admittance measurements were performed after 1, 2, or 3 months after
      surgery. After completed measurements, the TMs were analyzed morphologically.
      RESULTS: The acoustic stiffness of the TM was significantly increased in all
      cholesteatoma ears compared to normal control ears. A pronounced thickening and
      proliferative activity of the entire TM was observed in the early stage of
      cholesteatoma. The outer keratinizing epithelium showed an increased number of
      cell layers and an increased keratin production. The fibrous layer was thickened
      because of an increased amount of collagen fibers combined with minor edema.
      CONCLUSIONS: The thickness of the fibrous layer was almost doubled, mostly
      because of an increased amount of collagen fibers. The acoustic stiffness was
      significantly increased in all cholesteatoma ears. The results of the acoustic
      admittance measurements are comparable with those obtained in previous studies on
      purulent otitis media and otitis media with effusion.

PMID- 10337971
TI  - The protective effect of brain-derived neurotrophic factor after gentamicin
      ototoxicity.
AB  - HYPOTHESIS: Brain-derived neurotrophic factor (BDNF) influences the process of
      hair cell recovery in the vestibular sensory epithelium of the chinchilla after
      local application of gentamicin (GM). BACKGROUND: Hair cell regeneration in the
      inner ear after GM ototoxicity has been demonstrated. However, the mechanisms
      responsible for this recovery have yet to be completely elucidated. This report
      examines the protective and proliferative effects that BDNF exerts on vestibular
      hair cells in experiments designed to further elucidate the mechanisms of hair
      cell regeneration. METHODS: The inner ears of three separate groups of
      chinchillas were treated with GM only, GM and BDNF simultaneously, and GM
      followed by BDNF 1 week later. The numbers of hair and supporting cells in the
      horizontal cristae of each group were then estimated at 1, 2, 4, and 8 weeks, and
      the data were compared. RESULTS: Type I hair cells after GM treatment completely
      disappeared. After simultaneous BDNF and GM treatment, their numbers decreased to
      23% at 1 week and progressively disappeared by week 8. When BDNF was applied 1
      week after GM administration, type I hair cells recovered to 12% at week 4 and
      28% at week 8. Type II hair cells after GM treatment decreased to 15%, but
      recovered to 83% 4 weeks later. Simultaneous administration of BDNF and GM
      prevented the ototoxic effects of GM alone. When BDNF was administered 1 week
      after GM, type II hair cell recovery was accelerated and was greater than after
      GM alone (81% versus 18%). Supporting cells after GM treatment decreased to 74%
      at 1 week after treatment, recovered to 91% at 2 weeks, and remained at 86% at 4
      weeks and 85% at 8 weeks. With the simultaneous administration of BDNF and GM,
      supporting cells significantly decreased at 2 weeks after treatment (63%), but
      recovered to normal by week 8. CONCLUSIONS: These results suggest that BDNF
      provided simultaneously with GM minimizes the ototoxic effect of GM on type II
      hair cells. The increase in the number of new hair cells when BDNF is provided
      after ototoxic damage is evidence of the proliferative capacity of this
      neurotrophic factor.

PMID- 10337972
TI  - Salt-load electrocochleography.
AB  - OBJECTIVE: To introduce a new protocol for diagnostic electrocochleography using
      a pretest oral salt load to improve test sensitivity in patients with suspected
      inner ear fluid imbalance. STUDY DESIGN: A retrospective review of patients who
      reported vertigo that, by medical history, was suggestive of an inner ear fluid
      imbalance was preformed. The patients received a complete audiovestibular
      evaluation that included a baseline electrocochleogram. Despite the
      incapacitating nature of their vertigo, there were no symptoms or
      electrophysiologic abnormalities that would isolate an etiologic ear. After the
      baseline studies, the patients received 4 g of sodium chloride daily for 3 days
      before repeat electrocochleography. A control group of 13 healthy volunteers with
      normal baseline electrocochleography and pure tone audiometry was tested under
      similar conditions. SETTING: This study was conducted at an ambulatory care
      clinic associated with a tertiary referral medical center. INTERVENTION:
      Electrocochleography was performed using alternating polarity clicks presented at
      a rate of 9.7/sec at 95 dB nHL by an extratympanic TIPtrode electrode and
      recorded with a Nicolet Spirit (Nicolet Instrument Corp., Madison, WI, U.S.A.).
      Responses were averaged for 1000 sweeps using a 10-msec time base with bandpass
      filtering from 5 to 1500 Hz. A summating potential/action potential (SP/AP) ratio
      of 0.37 was considered the upper limit of normal. MAIN OUTCOME MEASURES:
      Enhancement in the SP/AP ratio from a normal baseline value to > 0.37 after oral
      salt loading was indicative of a positive test. RESULTS: None of the ears from
      control subjects had a positive salt load electrocochleogram, and one or both
      ears in 38% of the patients in the study group with normal baseline SP/AP ratios
      and symptoms of inner ear fluid imbalance converted to abnormal. The mean SP/AP
      ratio of the control group for the conditions before and after salt-load was not
      statistically different (p = 0.48), although the difference in the mean SP/AP
      ratio in the study group after salt loading was statistically significant (p =
      1.329 x 10(-5)). CONCLUSIONS: A group of patients who reported vertigo with no
      localizing abnormalities had a statistically significant increase in the mean
      SP/AP ratio after ingestion of a large quantity of sodium chloride. A modest
      percentage had elevation of the SP/AP ratio above the upper limit of normal for
      our audiovestibular lab. The localization of a "salt-senstitive" ear could assist
      the clinician in the management of these difficult problems with long-term
      medical therapy or surgical treatment when alternative measures fail.

PMID- 10337973
TI  - Minimizing wound complications in cochlear implant surgery.
AB  - OBJECTIVE: An extended postauricular incision has replaced the standard C-shaped
      scalp flap for cochlear implant surgery at our institution. The postoperative
      wound complication rates of the two incisions were evaluated. STUDY DESIGN: This
      study was a retrospective case review. SETTING: This study was performed in a
      tertiary referral center. PATIENTS: A total of 256 adult and pediatric patients
      who underwent cochlear implantation during a 10-year period (1986 to 1996) were
      reviewed. MAIN OUTCOME MEASURE: Postoperative wound complications were
      identified. Major complications included flap necrosis, wound dehiscence with or
      without implant exposure, and wound infection requiring hospitalization.
      Hematoma, seroma, or superficial wound infections were considered minor
      complications. RESULTS: There were 6 major and 6 minor complications among 116
      patients with the standard scalp flap (complication rate, 10.3%). There was only
      1 minor complication among 140 implants using the postauricular incision (0.7%).
      CONCLUSION: The extended postauricular incision appears to significantly reduce
      the incidence of wound complications in cochlear implant surgery.

PMID- 10337974
TI  - Cochlear nerve aplasia: its importance in cochlear implantation.
AB  - OBJECTIVE: The objective of this study was to outline the possible implications
      and potentially valuable techniques for managing cases in which the neural
      integrity of the peripheral auditory system is in question. STUDY DESIGN: This
      study was a retrospective case review. SUBJECT AND METHOD: A 3-year-old child
      with a profound blilateral sensorineural hearing loss was assessed for
      suitability of cochlear implantation. Audiologic tests confirmed that the child
      met the audiologic criteria for cochlear implantation. Computed tomographic
      scanning and magnetic resonance imaging were undertaken. RESULTS: Computed
      tomographic scanning showed bilateral narrow internal auditory canals. Magnetic
      resonance imaging showed the absence of the acousticofacial bundle on the left
      side and possible atrophy of the bundle on the right. After detailed discussion,
      the parents elected to proceed with implantation on the right ear using the
      Nucleus mini-22 cochlear implant. Tuning of the device resulted in myogenic
      facial activity with no electrically stimulated auditory sensation. Postoperative
      electrophysiologic testing confirmed the presence of a compound muscle action
      potential only. CONCLUSIONS: Seven months after implantation, the child was
      explanted uneventfully. The electrical auditory nerve action potential and the
      electrically evoked auditory brainstem response, using intracochlear stimulation,
      are potentially valuable measurements to assess neural integrity before the
      decision to proceed with implantation is made.

PMID- 10337975
TI  - Sensorineural hearing loss after occlusion of the enlarged vestibular aqueduct.
AB  - OBJECTIVE: This study aimed to report the hearing results of endolymphatic sac
      occlusion in patients with enlarged vestibular aqueduct syndrome. STUDY DESIGN:
      The study design was a multiinstitutional retrospective case series. SETTING: The
      study was conducted at tertiary otologic referral centers. PATIENTS: The study
      included 10 previously unreported patients with progressive sensorineural hearing
      loss and vestibular aqueducts greater than 1.5 mm in diameter on computerized
      tomography. INTERVENTION: Occlusion of the enlarged vestibular aqueduct was
      performed by means of a transmastoid surgical approach. Either intraluminal
      endolymphatic sac obliteration (five patients) or extraluminal extradural
      endolymphatic sac obliteration (five patients) was accomplished with temporalis
      fascia. MAIN OUTCOME MEASURES: The postoperative pure tone average (PTA) and
      speech discrimination scores were compared with the preoperative levels using
      conventional audiometry. RESULTS: Nine of 10 patients experienced some degree of
      sensorineural hearing loss. The median change in PTA was a loss of 21 decibels
      (dB), and 50% of the patients experienced a sensorineural hearing loss greater
      than 25 dB. Postoperative change in PTA ranged from +10 dB to -59 dB. The median
      change in speech discrimination score was a loss of 27.5%. Only one patient had
      an improvement in both speech discrimination score and pure tone averages after
      surgery. Patients who underwent extraluminal occlusion had a median PTA loss of
      12 dB, and patients who underwent open sac occlusion had a median PTA loss of 34
      dB. These were not statistically different. CONCLUSION: In this series of 10
      patients, 5 had a greater than 25 dB decrease in hearing after occlusion of the
      enlarged vestibular aqueduct. Surgical occlusion of the enlarged vestibular
      aqueduct showed no significant benefit in hearing preservation. The otologic
      surgeon is alerted to the potential for severe sensiorineural hearing loss after
      occlusion of the enlarged vestibular aqueduct.

PMID- 10337976
TI  - Proximal symphalangism and congenital conductive hearing loss: otologic aspects.
AB  - OBJECTIVE: Results of stapedectomy are reported in a Belgian 26-year-old woman
      and two Dutch brothers having the proximal symphalangism syndrome (McKusick
      18580). STUDY DESIGN: Case reports are presented. A review of the results of ear
      surgery for congenital conductive hearing loss in this syndrome is given.
      SETTING: The Belgian patient was treated in a general hospital. The Dutch
      patients were treated in a university hospital, which was a tertiary referral
      center. PATIENTS: Patients were referred to have an evaluation of their hearing
      impairment. INTERVENTION: Based on the syndromal diagnosis and based on routine
      audiometric tests, a congenital ossicular fixation was considered to be the cause
      of the hearing loss. By exploratory tympanotomies, this was confirmed.
      Reconstructive procedures including stapedotomy were performed. MAIN OUTCOME
      MEASURES/RESULTS: Long-term audiometric data are presented to evaluate the
      outcome of the surgical interventions. CONCLUSIONS: Congenital stapes ankylosis
      eventually combined with a congenital fixation of the short process of the incus
      in the fossa incudis, causing the congenital conductive hearing loss. Surgical
      intervention is very successful in most reported cases, but negative side effects
      are incidentally found as well.

PMID- 10337977
TI  - Effect of intratympanic gentamicin on hearing and tinnitus in Meniere's disease.
AB  - OBJECTIVE: The objective of this study was to examine the effect of
      intratympanically applied gentamicin (GM) (30 mg/mL) on hearing and tinnitus in
      patients with intractable Meniere's disease. STUDY DESIGN: A prospective study
      was conducted on 93 subjects treated with intratympanically applied GM. The mean
      pure-tone average (PTA) at speech frequencies was measured before the treatment
      and after 2 weeks, 1 month, 3 months, 6 months, 1 year, and 2 years after
      injections. Tinnitus was surveyed with a questionnaire. The mean duration of
      Meniere's disease was 9.8 years (range, 1-33 years). PATIENTS: The study group
      consisted of 28 men and 65 women. The mean age was 50.9 years (range, 19-74
      years). RESULTS: The mean PTA at speech frequencies for the group worsened from
      60 dB to 68 dB, which was statistically significant. Ten ears were deafened. The
      mean tinnitus handicap score before treatment was 2.92; 2 years after treatment,
      it was 2.26, indicating significant abatement of tinnitus during the course of
      the treatment. CONCLUSIONS: The authors found that the average frequency of
      deafening was 10% and it was dose dependent. GM caused alleviation of tinnitus in
      the majority of the patients.

PMID- 10337978
TI  - Intratympanic gentamicin titration therapy for intractable Meniere's disease.
AB  - OBJECTIVE: This study aimed to assess the efficacy and morbidity of intratympanic
      gentamicin titration therapy on patients with intractable unilateral Meniere's
      disease. STUDY DESIGN: The study design was a retrospective chart review and
      patient interviews. SETTING: The study was conducted at a tertiary referral
      ambulatory dizziness clinic at the London Health Sciences Centre, University
      Campus, from July 1992 to June 1997. INTERVENTION: Eighty-three patients received
      weekly intratympanic gentamicin injections in their diseased ear. Treatments were
      terminated after four injections or sooner if patients met clinical or audiologic
      criteria. Sixty-eight patients were available for detailed follow-up. MAIN
      OUTCOME MEASURES: Vertigo frequency, hearing status, personal disability ratings,
      tinnitus level, and caloric responses before and after gentamicin therapy were
      measured. RESULTS: Eighty-four percent of patients showed complete, and an
      additional 6% showed substantial, vertigo control. At 24 months, 17% of patients
      demonstrated a clinically significant (10-dB) reduction in hearing, but 26%
      showed a significant hearing improvement. Overall, the group showed no combined
      statistically significant changes in any of the hearing parameters. No patients
      had an "extreme" drop in hearing (>30 dB). CONCLUSIONS: Intratympanic gentamicin
      titration therapy provides excellent vertigo control with a low incidence of
      hearing loss.

PMID- 10337979
TI  - Microsurgical removal of a vestibular schwannoma after stereotactic radiosurgery:
      surgical and pathologic findings.
AB  - OBJECTIVE: The objective of this study was to provide objective evidence of the
      enhanced difficulty of preserving the facial nerve in patients who need
      microsurgery after failed stereotactic radiosurgery (SRS) of vestibular
      schwannoma. STUDY DESIGN: This study was a retrospective case review. SETTING: A
      tertiary care referral center was the setting for the study. PATIENTS: The
      authors present a case of a young woman with a vestibular schwannoma that
      enlarged 2 years after treatment with SRS. INTERVENTION: Microsurgery via the
      translabyrinthine approach was used. RESULTS: At surgery, extensive scarring
      between the facial nerve and tumor capsule was seen, and the nerve could not be
      identified at all beyond several millimeters proximal to the porus acusticus.
      Adhesions of the tumor to the ninth and tenth cranial nerves, the brain stem, and
      the anterior inferior cerebellar artery were also markedly increased. Histologic
      examination confirmed fibrotic adhesions surrounding the facial nerve.
      CONCLUSIONS: The unusual degree of fibrosis, scarring, and adhesions of the tumor
      to the surrounding structures after SRS made microsurgical removal of the tumor
      difficult and preservation of the facial nerve impossible.

PMID- 10337980
TI  - Delayed intracranial abscess after acoustic neuroma surgery: a report of two
      cases.
AB  - OBJECTIVE: The use of antibiotics before and after surgery has made infectious
      complications of neurotologic surgery rare. The neurosurgical literature cites a
      rate of postoperative meningitis between 1% and 2% for "clean" cases and 1.5% to
      2.5% for "clean contaminated" cases, such as cerebrospinal fluid contact with the
      middle ear or mastoid. Reports of infections after neurotologic procedures are
      rare in the otologic literature. In this report, two patients with brain abscess
      occurring in a delayed fashion after surgery are described. STUDY DESIGN: The
      study design was a retrospective chart review and case report. SETTING: The study
      was conducted at a tertiary referral center. RESULTS: Patient 1 underwent a
      suboccipital craniotomy for removal of an acoustic neuroma and had an uneventful
      postoperative recovery. Three months after surgery, he reported mild
      unsteadiness. Examination revealed mild ataxia, which led to repeat magnetic
      resonance imaging (MRI) and a diagnosis of cerebellar abscess. Patient 2
      underwent translabyrinthine removal of an acoustic neuroma complicated by
      postoperative Pseudomonas aeruginosa meningitis, which responded promptly to
      intravenous antibiotics. Fifteen months after surgery, he visited a neurologist
      after having a seizure and was treated with anticonvulsants. After a second
      episode of seizure, imaging studies showed a temporal lobe abscess. CONCLUSIONS:
      The signs of intracranial abscess may be subtle and can occur weeks or months
      after surgery, requiring vigilance and a high index of suspicion for diagnosis. A
      change in postoperative symptoms after acoustic neuroma surgery should signal
      further investigation using MRI with gadolinium.

PMID- 10337981
TI  - Extradural temporal lobe retraction in the middle fossa approach to the internal
      auditory canal: biomechanical analysis.
AB  - HYPOTHESIS: The middle fossa (MF) approach is undergoing a marked resurgence in
      vestibular schwannoma surgery as a hearing conservation technique. It is widely
      recognized that the extradural temporal lobe retractors used in this procedure,
      despite their cleverness of design, could be improved. METHODS: To identify the
      characteristics of an ideal MF retractor, a systematic analysis of the safety and
      functionality of four commonly used retractors (House-Urban, Fisch, Garcia
      Ibanez, and UCSF) in a human anatomical model was conducted. Intensity of
      temporal lobe compression, width of exposure, angle of visualization, obstruction
      to instrument access, ergonomic convenience of use, and adaptability to other
      subtemporal procedures (e.g. lesions of Meckel's cave and cavernous sinus) were
      quantified. RESULTS: Because the intracranial portions of the retractors are
      similar, the force transmitted to the brain differed little among the four
      retractors. Numerous differences were noted in the ergonomics of use and
      versatility of the various designs. CONCLUSIONS: The optimal MF retractor would
      incorporate the best features of each of the existing systems: the integral
      suction of the Garcia-Ibanez, the bone contour-following design of the Fisch
      retractor base, the unobtrusiveness and adaptability of the UCSF, and the three
      plane adjustability of the vintage House-Urban. Evolution of an "ideal" MF
      retractor requires further technical refinements and the development of an
      experimental model of extradural brain retraction to assess the optimal strategy
      for obtaining exposure while minimizing the risk for temporal lobe injury.

PMID- 10337982
TI  - Intralabyrinthine schwannomas.
AB  - OBJECTIVE: To describe characteristic features of intralabyrinthine schwannomas
      (ISs) that may be used to distinguish them from other otologic disorders with
      similar symptoms so that appropriate evaluation and management can be instituted.
      STUDY DESIGN: This study was a retrospective case review. SETTING: This study was
      conducted at a university-affiliated urban tertiary care medical center and a
      university medical center in the same city. PATIENTS: Seven patients with ISs
      were included in this study. INTERVENTIONS: Tumor removal versus observation and
      monitoring with periodic magnetic resonance imaging (MRI) scans was investigated.
      MAIN OUTCOME MEASURES: Hearing, vertigo, and tumor growth were measured. RESULTS:
      Four of seven patients with ISs underwent surgical excision with no evidence of
      tumor recurrence. The remaining three patients are being followed-up with repeat
      MRI that has demonstrated minimal or no tumor growth. CONCLUSIONS: ISs can be
      detected in early stages if MRI is performed in patients with unilateral
      sensorineural hearing loss without vertiginous symptoms typical of Meniere's
      disease. Although complete surgical excision can be achieved readily with
      labyrinthectomy, observation and monitoring with rep--MRI is an option for some
      patients.

PMID- 10337983
TI  - Intraoperative corticosteroids in acoustic tumor surgery.
AB  - BACKGROUND: Corticosteroids are frequently used for the prevention and treatment
      of neural edema. Although perioperative steroid therapy has been used in patients
      undergoing acoustic neuroma removal, the efficacy of such therapy has not been
      previously documented. METHODS: A retrospective review of 169 patients who
      underwent acoustic neuroma surgery with (n = 75) or without (n = 94) a single
      dose of intraoperative corticosteroids was performed. Tumor size ranged from 0.4
      cm to 6 cm (mean, 2.1; SD, 1.0) The translabyrinthine approach was used in 85% of
      the patients, and the middle cranial fossa approach was used in 13%. Data were
      analyzed for differences in postoperative facial function and complication rates.
      RESULTS: After controlling for differences in tumor size, no significant effects
      of steroid therapy were found for any of the outcome variables. CONCLUSIONS: This
      retrospective study showed no apparent benefit from intraoperative steroid use in
      acoustic neuroma surgery. A prospective, randomized, placebo-controlled trial
      should be performed to confirm these findings.

PMID- 10337984
TI  - Idiopathic temporal encephalocele: report of two cases.
AB  - BACKGROUND: Idiopathic brain herniation into the middle ear is a rare condition
      that represents diagnostic and therapeutic challenges. OBJECTIVE: The authors
      present here two new cases of idiopathic brain herniation with special clinical
      presentation and emphasis on radiographic studies, particularly computed
      tomographic scan and magnetic resonance imaging, which allowed the authors to
      detect the malformation. RESULTS: The two patients underwent surgical treatment
      with infratemporal approach and recovered perfectly.

PMID- 10337985
TI  - Protuberant fibro-osseous lesions of the temporal bone: a unique
      clinicopathologic diagnosis.
AB  - OBJECTIVE: The objective of the study was to describe the clinical presentation
      and treatment of exophytic fibro-osseous temporal bone lesions, a clinical entity
      never previously reported, and to consider the differential diagnosis. STUDY
      DESIGN: The design of the study was a retrospective case review. SETTING: The
      setting was a tertiary referral center. PATIENTS: Two patients diagnosed with
      exophytic fibro-osseous temporal bone lesions were included in the study.
      INTERVENTION: The intervention used was surgical excision. MAIN OUTCOME MEASURE:
      The main outcome measures were clinical, radiographic, and histopathologic
      examination. RESULTS: There was no evidence of recurrence at 15 and 17 months
      after surgery. CONCLUSION: Although fibro-osseous lesions of the temporal bone
      have been previously reported, there have been no reported cases of an exophytic
      variant.

PMID- 10337986
TI  - From the roots of otology: diseases of the ear and their treatment in Byzantine
      times (324-1453 A.D.).
AB  - HYPOTHESIS: The aim of this study is to present the therapeutic methods and
      surgical techniques in diseases of the ear during Byzantine times (324-1453
      A.D.). BACKGROUND/METHODS: The original Greek language texts of the Byzantine
      medical writers were studied to research early otologic knowledge of
      symptomatology, conservative treatments, and surgical confrontation of diseases
      of the ear. RESULTS: A considerable number of conservative treatments for many
      otologic conditions were identified; these therapies were especially based on
      herbs, animal and mineral substances applied either as eardrops, clysters,
      poultices, or by using special instruments and apparatus. Among these were
      identified otitis, rupture of the eardrum, hemorrhage from the ears, deficiency
      of hearing and deafness, vertigo, tinnitus, and earwax. Furthermore, in these
      early texts, there were also described some surgical techniques in cases of
      atresia of the external auditory canal, of defects in or lack of the pinna, and
      for removal of foreign bodies and fleshy tumors. Some of the earliest hearing
      aids were also mentioned. CONCLUSIONS: From the study of the original works of
      Byzantine writers, it is evident that numerous treatments and surgical techniques
      relating to otology were practiced; these were derived not only from compilation
      of knowledge obtained from the ancient Greek medical sources, a considerable part
      of which are now lost, but also enriched by Byzantine physicians' personal
      experience. This knowledge influenced medieval European medicine and, through it,
      that of the rest of the world.

PMID- 10337987
TI  - Aberrant internal carotid artery.

PMID- 10337988
TI  - Arachnoid granulations of the temporal bone.

PMID- 10337989
TI  - Germline hMSH2 and differential somatic mutations in patients with Turcot's
      syndrome.
AB  - Turcot's syndrome is characterized clinically by the occurrence of primary brain
      tumor and colorectal tumor and has in previous reports been shown to be
      associated with germline mutations in the genes APC, hMLH1, and hPMS2. Here we
      describe three patients with Turcot's syndrome, each having colorectal
      adenocarcinoma and malignant glioma. All the colorectal and brain tumors from
      these patients showed replication errors in most of the microsatellite loci
      investigated. Search for underlying germline mutations in the nucleotide mismatch
      repair genes revealed three different hMSH2 mutations. All colorectal tumors
      showed a frameshift in the A(10) tract in the coding sequence of the transforming
      growth factor beta type II receptor (TGFBRII) gene, but no such change was
      detected in any of the brain tumors. Frameshift mutation in the BAX gene was
      found in one colon carcinoma and mutations in insulin-like growth factor type II
      receptor (IGFIIR) gene in one glioma. Our data have broadened the possible
      mutation spectrum of patients with Turcot's syndrome. The difference in the
      mutation spectrum of TGFBRII, BAX, and IGFIIR between brain and colorectal tumors
      in these individuals suggests that the mutator phenotype may target different
      pathogenic pathways in the oncogenic process of the two organs.

PMID- 10337990
TI  - Chromosome arm 20q gains and other genomic alterations in colorectal cancer
      metastatic to liver, as analyzed by comparative genomic hybridization and
      fluorescence in situ hybridization.
AB  - Comprehensive information about the molecular cytogenetic changes in metastases
      of colorectal cancer is not yet available. To define such changes in metastases,
      we measured relative DNA sequence copy numbers by comparative genomic
      hybridization (CGH). Samples from 27 liver metastases and 6 synchronous primary
      tumors were analyzed. An average of 9.9 aberrations per tumor was found in the
      metastases. Gains of chromosome arms 20q (85%), 13q (48%), 7p (44%), and 8q (44%)
      and losses of chromosome arms 18q (89%), 8p (59%), 1p (56%), and 18p (48%) were
      detected most frequently. Chromosomes 14 and 15 were lost in 26% and 30% of the
      metastases, respectively. No consistent differences were observed between primary
      tumors and synchronous metastases. Fluorescence in situ hybridization (FISH) was
      used for further characterization of gains of chromosome arm 20q. Touch
      preparations of 13 tumors that had demonstrated 20q gain with CGH were examined
      with FISH by use of a set of probes mapping to different parts of 20q. A probe
      for 20p was used as a reference. FISH showed relative gain of at least one 20q
      locus in 12 of the tumors. High-level gains were detected in 38% of the tumors,
      preferentially for probes mapping to band 20q13. Our CGH data indicate that
      colorectal metastases show chromosomal changes similar to those that have been
      reported for primary tumors. Chromosomal losses were seen at higher frequency,
      particularly for chromosomes 14 and 15. By FISH, we identified subregions on
      chromosome arm 20q that are frequently involved in DNA amplifications in
      colorectal cancer and that may harbor candidate proto-oncogenes.

PMID- 10337991
TI  - Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours.
AB  - We screened 81 ovarian tumours (30 BRCA1 associated, 18 BRCA2 associated, and 33
      sporadic) for somatic TP53 mutations using both DNA analysis and immunostaining.
      TP53 mutations were significantly more frequent in tumours with mutations in
      BRCA1 (70% by immunostaining and 60% by DNA analysis) and BRCA2 (67% and 50%)
      compared to sporadic controls (39% and 30%) (P = 0.009). A higher proportion of
      tumours with BRCA1 and BRCA2 mutations were poorly differentiated, and TP53
      mutant tumours in all categories were also more likely to be poorly
      differentiated. The poor differentiation of tumours with BRCA1 and BRCA2
      mutations may be directly related to the role of these genes in DNA repair, and
      the need to overcome cell cycle checkpoints, often through loss of TP53. These
      results are consistent with the model of BRCA-induced tumorigenesis in which loss
      of checkpoint control is necessary for tumour development.

PMID- 10337992
TI  - Fusion of a novel gene, ELKS, to RET due to translocation t(10;12)(q11;p13) in a
      papillary thyroid carcinoma.
AB  - In papillary thyroid carcinomas, the genes for receptor-type tyrosine kinase, RET
      or TRKA, are sometimes rearranged, resulting in fusion of its tyrosine kinase
      domain to 5' portions of several activating genes. In a papillary thyroid
      carcinoma, we identified a novel gene (ELKS), the 5' portion of which is fused to
      the RET gene by gene rearrangement due to the translocation t(10;12)(q11;p13).
      Subsequent cloning of the ELKS cDNA revealed that ELKS encodes a novel 948 amino
      acid peptide and is expressed ubiquitously in human tissues. The presence of
      multiple coiled-coil domains in the ELKS product suggests that the ELKS protein
      forms dimers. Since the tyrosine kinase of RET is activated by dimerization that
      occurs when its ligands bind to the receptor, fusion of RET with the 5'
      dimerization domains of ELKS would activate its cytoplasmic tyrosine kinase
      constitutively in papillary thyroid carcinomas.

PMID- 10337993
TI  - Among numerous DNA copy number changes, losses of chromosome 13 are highly
      recurrent in plasmacytoma.
AB  - Chromosomal imbalances were studied by comparative genomic hybridization (CGH) on
      27 specimens from 24 patients with plasmacytoma. All the specimens exhibited DNA
      copy number changes (mean, 7.7 aberrations/tumor; range, 2-15). The most
      recurrent change involved losses at 13q, found in 19 out of 24 patients. Other
      frequent losses were at 1p (42%), 14q (33%), X (33%), 8p (25%), and 6q (25%).
      Gains were frequent at 19p (58%), 9q (58%), 1q (58%), 7p (42%), 11q (38%), 15
      (33%), 6p (25%), 8q (25%), and 5p (21%). High-level copy number increases were
      found at 1q, 5, 7, 8q, 9q, 11q, 15, and 19. The findings of highly recurrent
      chromosomal imbalances in plasmacytomas confirm the analytical power of CGH to
      detect chromosomal abnormalities in malignancies characterized by low mitotic
      activity. Our most striking finding, the losses in chromosome 13, provides a
      basis to investigate the role of the 13q loss in the tumorigenesis and
      progression of plasmacytoma and to evaluate the prognostic significance of this
      loss.

PMID- 10337994
TI  - Three distinct regions of allelic loss at 13q14, 13q21-22, and 13q33 in prostate
      cancer.
AB  - Chromosome 13 is one of the most frequently altered chromosomes in cancer,
      including carcinoma of the prostate. Two known tumor suppressor genes, RB1 and
      BRCA2, map to chromosome 13; however, recent reports suggest that unknown genes
      on 13q are more likely to be involved in the development of prostate cancer. In
      order more fully to define the genetic changes on chromosome 13 in prostate
      neoplasms, we analyzed 27 polymorphic microsatellite markers spanning the q arm
      for loss of heterozygosity in 40 primary tumors and in metastases from 11 other
      patients who died of prostate cancer. Of the 40 primary tumors, 23 (58%) showed
      LOH for at least one marker. Three distinct regions at q14, q21-22, and q33,
      defined by markers D13S267-->D13S153, D13S166-->D13S1225, and D13S259-->D13S274,
      showed the most frequent LOH, suggesting their involvement in the development of
      prostate cancer. For the 12 patients whose tumors showed LOH at these markers,
      the average age at diagnosis was 58 years, which was younger than that (63 years,
      P < 0.05) for the 28 patients whose tumors lacked LOH. Ten of the 11 (91%)
      metastases showed LOH with one or more markers. Two of the three most frequently
      deleted regions (i.e., q14 and q21-22) in the primary tumors and markers linked
      to the RB1, BRCA2, and EDNRB genes showed high frequencies (56-71%) of LOH in
      metastases. These results demonstrate that allelic loss on chromosome 13 at q14,
      q21-22, and q33 occurs in a subset of primary prostate tumors and is a frequent
      event in metastatic lesions of prostate cancer.

PMID- 10337995
TI  - Chromosomal aberrations in breast cancer: a comparison between cytogenetics and
      comparative genomic hybridization.
AB  - The analysis of chromosomal imbalances in solid tumors using comparative genetic
      hybridization (CGH) has gained much attention. A survey of the literature
      suggests that CGH is more sensitive in detecting copy number aberrations than is
      karyotyping, although careful comparisons between CGH and cytogenetics have not
      been performed. Here, we compared cytogenetics and CGH in 29 invasive breast
      cancers after converting the karyotypes into net copy number gains and losses. We
      found 15 tumors (56%) with a significant agreement between the two methods and 12
      tumors (44%) where the methods were in disagreement (two cases failed CGH
      analysis). Interestingly, in 13 of the 15 tumors where the two methods were
      concordant, there was also a strong correlation between chromosome index and DNA
      index by flow cytometry. In the opposite situation, i.e., when chromosome and DNA
      indices were not matching, there was disagreement between cytogenetics and CGH in
      10 of the 12 tumors. Of the discordant cases, all except one had a "simple"
      abnormal karyotype. Unresolved chromosomal aberrations (marker chromosomes,
      homogeneously staining regions, double minutes) could not completely explain the
      differences between CGH and karyotyping. A likely explanation for the
      discrepancies is that the methods analyzed different cell populations. Gains and
      losses found by CGH represented the predominant (often aneuploid) clone, whereas
      the abnormal, near-diploid karyotypes represented minor cell clone(s), which, for
      unknown reasons, had a growth advantage in vitro.

PMID- 10337996
TI  - Cytogenetic analysis of 363 consecutively ascertained diffuse large B-cell
      lymphomas.
AB  - Cytogenetic analysis was performed on 363 biopsy specimens with histologically
      confirmed diffuse large B-cell lymphoma (DLBCL), consecutively ascertained at the
      Memorial Sloan-Kettering Cancer Center, New York, between 1984 and 1994. Among
      248 samples successfully karyotyped, clonal chromosomal abnormalities were noted
      in 215 (87%). The salient cytogenetic features of DLBCL from this analysis
      comprised the following. Breakpoints clustered, in decreasing frequency, at 10
      recurring sites: 14q32, 18q21, 1q21, 3q27, 1p36, 8q24, 3p21, 6q21, 1p22, and
      22q11. Of these, deletion breaks affecting bands 3p2 and 1p22 and translocation
      breaks affecting bands 14q32, 3q27, and 1q2 were frequent and distinctive for
      this subset of lymphomas. Translocations affecting band 14q32 were noted in 110
      cases (51%) of which 42 (20%) had t(14;18)(q32;q21), 21 (10%) had
      t(8;14)(q24;q32) or t(8;22)(q24;q11), 14 (6.5%) had t(3;14)(q27;q32) or
      t(3;22)(q27;q11), and 33 (15%) had other rearrangements of 14q32. Among 144 new
      translocations detected in the entire group, the breakpoints in 19 were recurrent
      and clustered at three sites: 1q21, 3q27, and 14q32. Regions of common
      cytogenetic deletions were identified at 11 sites, 1p36, 1p33-34, 1p31, 1q32,
      3p25-26, 3p21, 3q21, 6q15, 6q21, 6q23-24, and 7q32, suggesting possible loss of
      candidate tumor suppressor genes associated with DLBCL development. Of these,
      only those at 6q21, 6q23, and 7q32 have previously been described in lymphoid
      neoplasms. The group of DLBCL with translocations affecting band 14q32 showed a
      significantly different pattern of additional cytogenetic changes compared to the
      group lacking such translocation. This new comprehensive cytogenetic
      characterization provides the basis for investigations aimed at identifying
      molecular mechanisms as well as the clinical impact of cytogenetic changes in
      DLBCL.

PMID- 10337997
TI  - Chromosome abnormalities of eighty-one pediatric germ cell tumors: sex-, age-,
      site-, and histopathology-related differences--a Children's Cancer Group study.
AB  - The chromosomes of 81 pediatric germ cell tumors (GCTs) were analyzed as part of
      two clinical treatment trials, INT-0098 and INT-0097, conducted by the Children's
      Cancer Group. The analysis of chromosome results showed differences with respect
      to sex, age, tumor location, and histology. Sixteen of 17 benign teratomas of
      infants and children less than 4 years old and from gonadal and extragonadal
      locations were chromosomally normal. Twenty-three malignant GCTs from gonadal and
      extragonadal locations of the same age group were endodermal sinus tumors and
      varied in their karyotypic findings. The most common abnormalities were gains of
      1q and chromosome 3. Of eight benign ovarian teratomas from older girls, five
      with normal G-banded karyotypes were determined to be homozygous for Q-band
      heteromorphisms, suggesting a meiosis II error. Among the 12 malignant ovarian
      GCTs from older girls, the common abnormalities were loss of 1p/gain of 1q, +3,
      +8, +14, and +21. Four of eight extragonadal tumors from older boys demonstrated
      +21; one had +X. Five of the eight had associated constitutional chromosome
      abnormalities, including one trisomy 21 and three with Klinefelter syndrome. The
      testicular GCTs of adolescents had abnormalities resembling those found in adult
      testicular GCT, including near-triploidy, loss of chromosomes 11, 13, and 18, and
      gain of chromosomes 7, 8, the X chromosome, and an isochromosome 12p. The gain of
      an isochromosome 12p was only frequent in the tumors from adolescent boys.
      Deletion of 1p/gain of 1q and +3 were the most common abnormalities among the
      malignant tumors from both sexes.

PMID- 10337998
TI  - Deletion mapping of the tumor suppressor locus involved in colorectal cancer on
      chromosome band 8p21.
AB  - Several somatic genetic alterations have been described in colorectal carcinoma
      (CRC). Recurrent chromosomal deletions have suggested the presence of tumor
      suppressor genes (TSG) specifically involved in colorectal carcinogenesis. For
      one of them, two non-overlapping regions have been proposed on the short arm of
      chromosome 8, encompassing the LPL and NEFL genes. The short arm of chromosome 8
      has been extensively studied in colorectal cancer and in other cancer types. Both
      regions have been reported as candidate loci for a TSG. In order to delineate a
      reliable region of deletional overlap on chromosome arm 8p in CRC, a series of
      365 CRC samples was selected for the absence of microsatellite instability (RER,
      replication error); tumor and normal matched DNAs were studied for 54
      microsatellite polymorphisms distributed on 8p using multiplex-PCR amplification.
      After purification of tumor nuclei by flow cytometry based on either the abnormal
      DNA index or the presence of a high expression of cytokeratin, complete allelic
      losses on 8p were observed in 48% of cases. Measurement of the DNA index showed
      that 88% of RER tumors were hyperploid. Complete allelic losses of only part of
      the short arm were observed on 26 occasions. These data allowed us to define a 1
      cM interval of common deletion, flanked by the loci D8S1771 and NEFL, where a
      putative TSG may be localized.

PMID- 10337999
TI  - Refined mapping of two regions of loss of heterozygosity on chromosome band 11q23
      in lung cancer.
AB  - 11q23-24 chromosome is a region containing frequent allelic loss (loss of
      heterozygosity; LOH) in human cancers. To examine cancer-related allelic loss in
      the region between D11S940 and APOC3, we used 17 polymorphic markers and
      allotyped 28 lung cancer-derived cell lines and their corresponding matched
      lymphoblastoid cell lines. LOH was found in 71.4% (20/28) of the lung cancer cell
      lines and was localized to two distinct minimal regions of loss. One region is
      bracketed by markers D11S1647 and NCAM2 and contains the gene encoding the beta
      isoform of the A subunit of the human protein phosphatase 2A (PPP2R1B). Recently,
      mutations in this gene were described in lung and colon cancers, suggesting that
      PPP2R1B functions as a tumor-suppressor gene. A second minimal region of loss was
      defined between markers D11S1792 and D11S1885, a region estimated to be less than
      I Mb. Thus, chromosome 11 likely harbors two sites of suppressor oncogene
      activity in lung cancer, one defined by the PPP2R1B gene and the second located
      telomeric to PPP2R1B. This study facilitates the identification and cloning of a
      second critical tumor-suppressor gene involved in lung cancer, and possibly a
      variety of other cancers, on human chromosome band 11q23.

PMID- 10338000
TI  - Molecular cytogenetic fingerprinting of esophageal squamous cell carcinoma by
      comparative genomic hybridization reveals a consistent pattern of chromosomal
      alterations.
AB  - Esophageal cancer is the third most prevalent gastrointestinal malignancy in the
      world. The tumor responds poorly to various therapeutic regimens and the genetic
      events underlying esophageal carcinogenesis are not well understood. To identify
      overall chromosomal aberrations in esophageal squamous cell carcinoma, we
      performed comparative genomic hybridization (CGH). All 17 tumor samples were
      found to exhibit multiple gains and losses involving different chromosomal
      regions. The frequency of chromosomal loss associated with this type of tumor was
      as follows: in 2q (100%), 3p (100%), 13q (100%), Xq (94%), 4 (82%), 5q (82%), 18q
      (76%), 9p (76%), 6q (70%), 12q (70%), 14q (65%), 11q (59%), and 1p (53%).
      Interstitial deletions on 1p, 3p, 5q, 6q, 11q, and 12q were detected also.
      Chromosomal gains were displayed by chromosomes and chromosome areas: 19 (100%),
      20q (94%), 22 (94%), 16p (65%), 17 (59%), 12q (59%), 8q (53%), 9q (53%), and 3q
      (50%). Two sites showing apparent amplification were 11q (70%) and 5p15 (47%). To
      validate the CGH data, we isolated a BAC clone mapping to 18q12.1. This clone was
      used as a probe in interphase fluorescence in situ hybridization of tumor touch
      preparations and allelic loss was clearly revealed. This study represents the
      first whole-genome analysis in esophageal squamous cell carcinoma for associated
      chromosomal aberrations that may be involved in either the genesis or progression
      of this malignancy.

PMID- 10338001
TI  - Chromosomal aberrations in nasopharyngeal carcinoma analyzed by comparative
      genomic hybridization.
AB  - To investigate the genomic imbalances associated with nasopharyngeal carcinoma
      (NPC), we have performed chromosome analysis by comparative genomic hybridization
      (CGH) on 51 tumors, including 25 primary and 26 recurrent tumors. The most common
      copy number increases occurred on chromosome arms 12p (59%), 1q (47%), 17q (47%),
      11q (41%), and 12q (35%). The minimal overlapping regions were at 12p12-13, 1q21
      22, 17q21, 17q25, 11q13, and 12q13. The most frequent losses were from chromosome
      arms 3p (53%), 9p (41%), 13q (41%), 14q (35%), and 11q (29%). The minimal
      overlapping regions were at 3p12-14, 3p25-26, 9p21-23, 13q21-32, 14q12-21, and
      11q14-23. Compared with the primary cancers, no additional chromosomal change was
      found in the recurrent tumors; however, the most frequent gain in the recurrent
      NPCs was at 11q13 (53%) instead of 12p in the primary tumors. An increase of gene
      alterations correlated with clinical stage. Our results provide a first
      comprehensive view of the genomic changes associated with NPC and reveal several
      new sites of genomic imbalance, indicating the possible involvement of novel
      oncogenes/tumor suppressor genes in the carcinogenesis of NPC.

PMID- 10338002
TI  - Mutations of the WT1 gene in childhood nonlymphoid hematological malignancies.
AB  - The Wilms' tumor gene WT1, whose loss of function accounts for the genesis of
      about 10% of Wilms' tumors, is expressed in hematopoietic stem cells and
      leukemia. By analogy with the relationship between the kidney stem cell and
      Wilms' tumor, it is probable that WT1 is mutated in leukemia. WT1 mutations have
      been found in only eight cases of primary leukemia, mainly in acute myeloid
      leukemia (AML) and rarely in acute lymphoblastic leukemia. However, two other
      studies have demonstrated the absence of WT1 mutations in leukemia. To determine
      if WT1 mutations are associated with leukemias, we screened childhood nonlymphoid
      malignancies for WT1 mutation. WT1 mutations were found in 6 of 46 (13%) AMLs,
      but not in other nonlymphoid hematological malignancies. In addition, the
      presence of WT1 mutations in AML caused by chromosomal translocations suggests
      that mutations of WT1 may lead to the progression of leukemia.

PMID- 10338003
TI  - Severe phenotype of neurofibromatosis type 2 in a patient with a 7.4-MB
      constitutional deletion on chromosome 22: possible localization of a
      neurofibromatosis type 2 modifier gene?
AB  - Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder predisposing to
      multiple neoplastic lesions with the hallmark of schwannoma arising at the eighth
      cranial nerve. NF2 shows a distinct clinical variability, with a mild and a
      severe form of the disease. The NF2 gene is mutated in constitutional DNA of
      affected patients from NF2 families and in sporadic cases. Comprehensive mutation
      analyses in patients with severe and mild phenotypes revealed mutations in only
      34%-66%. In the remaining fraction, the genetic mechanism behind the development
      of NF2 is unknown. Analyses of germline mutations do not provide a conclusive
      explanation for the observed clinical heterogeneity of NF2. It can therefore be
      hypothesized that other factors, e.g., modifier gene(s), contribute to the
      development of a more severe NF2 phenotype. We report a mentally retarded patient
      with the severe form of NF2 who displays a 7.4 million base pair deletion on
      chromosome 22. We performed a full genetic characterization of this case using
      heterozygozity analysis of 41 markers from chromosome 22, detailed FISH mapping
      of deletion breakpoints, allelotyping of all other chromosomes, and sequencing of
      the NF2 gene in tumor DNA. Two genomically large deletions similar in size (700
      800 kb), which encompass the entire NF2 gene, have been reported previously in
      mildly affected NF2 patients. The centromeric breakpoints of these deletions were
      similar to the centromeric breakpoint in the present case. However, the deletion
      in our patient extends over a much larger distance toward the telomere of 22q.
      Our results support the existence of NF2 modifier gene(s) and suggest that such a
      putative locus maps to a 6.5-MB interval on 22q, between D22S32 and the MB gene.

PMID- 10338004
TI  - Nuclear receptor co-repressor gene localizes to 17p11.2, a frequently deleted
      band in malignant disorders.
AB  - The t(8;21) between the AML1 and ETO genes is a commonly seen genetic alteration
      in acute myeloid leukemia. Recently, we reported that the fusion partner ETO
      binds to the human nuclear receptor co-repressor (NCOR), a member of the
      NCOR/SIN3/histone deacetylase complex. This complex mediates transcriptional
      repression as a result of chromatin remodeling. Here, we used a combination of
      fluorescence in situ hybridization and hybrid panels to localize the human NCOR
      gene (NCOR) to chromosome band 17p11.2. The position of human NCOR on 17p11
      raises the possibility of deranged transcriptional regulation in malignant
      disorders associated with deletions of 17p.

PMID- 10338005
TI  - Auracyanin A from the thermophilic green gliding photosynthetic bacterium
      Chloroflexus aurantiacus represents an unusual class of small blue copper
      proteins.
AB  - The amino acid sequence of the small copper protein auracyanin A isolated from
      the thermophilic photosynthetic green bacterium Chloroflexus aurantiacus has been
      determined to be a polypeptide of 139 residues. His58, Cys123, His128, and Met132
      are spaced in a way to be expected if they are the evolutionary conserved metal
      ligands as in the known small copper proteins plastocyanin and azurin. Secondary
      structure prediction also indicates that auracyanin has a general beta-barrel
      structure similar to that of azurin from Pseudomonas aeruginosa and plastocyanin
      from poplar leaves. However, auracyanin appears to have sequence characteristics
      of both small copper protein sequence classes. The overall similarity with a
      consensus sequence of azurin is roughly the same as that with a consensus
      sequence of plastocyanin, namely 30.5%. We suggest that auracyanin A, together
      with the B forms, is the first example of a new class of small copper proteins
      that may be descendants of an ancestral sequence to both the azurin proteins
      occurring in prokaryotic nonphotosynthetic bacteria and the plastocyanin proteins
      occurring in both prokaryotic cyanobacteria and eukaryotic algae and plants. The
      N-terminal sequence region 1-18 of auracyanin is remarkably rich in glycine and
      hydroxy amino acids, and required mass spectrometric analysis to be determined.
      The nature of the blocking group X is not yet known, although its mass has been
      determined to be 220 Da. The auracyanins are the first small blue copper proteins
      found and studied in anoxygenic photosynthetic bacteria and are likely to mediate
      electron transfer between the cytochrome bc1 complex and the photosynthetic
      reaction center.

PMID- 10338006
TI  - Energetic analysis of an antigen/antibody interface: alanine scanning mutagenesis
      and double mutant cycles on the HyHEL-10/lysozyme interaction.
AB  - Alanine scanning mutagenesis of the HyHEL-10 paratope of the HyHEL-10/HEWL
      complex demonstrates that the energetically important side chains (hot spots) of
      both partners are in contact. A plot of deltadeltaG(HyHEL-10_mutant) vs.
      deltadeltaG(HEWL_mutant) for the five of six interacting side-chain hydrogen
      bonds is linear (Slope = 1). Only 3 of the 13 residues in the HEWL epitope
      contribute >4 kcal/mol to the free energy of formation of the complex when
      replaced by alanine, but 6 of the 12 HyHEL-10 paratope amino acids do. Double
      mutant cycle analysis of the single crystallographically identified salt bridge,
      D32H/K97, shows that there is a significant energetic penalty when either partner
      is replaced with a neutral side-chain amino acid, but the D32(H)N/K97M complex is
      as stable as the WT. The role of the disproportionately high number of Tyr
      residues in the CDR was evaluated by comparing the deltadeltaG values of the Tyr 
      -> Phe vs. the corresponding Tyr --> Ala mutations. The nonpolar contacts in the
      light chain contribute only about one-half of the total deltadeltaG observed for
      the Tyr --> Ala mutation, while they are significantly more important in the
      heavy chain. Replacement of the N31L/K96 hydrogen bond with a salt bridge,
      N31D(L)/K96, destabilizes the complex by 1.4 kcal/mol. The free energy of
      interaction, deltadeltaG(int), obtained from double mutant cycle analysis showed
      that deltadeltaG(int) for any complex for which the HEWL residue probed is a
      major immunodeterminant is very close to the loss of free energy observed for the
      HyHEL-10 single mutant. Error propagation analysis of double mutant cycles shows
      that data of atypically high precision are required to use this method
      meaningfully, except where large deltadeltaG values are analyzed.

PMID- 10338007
TI  - The variable and conserved interfaces of modeled olfactory receptor proteins.
AB  - The accumulation of hundreds of olfactory receptor (OR) sequences, along with the
      recent availability of detailed models of other G-protein-coupled receptors,
      allows us to analyze the OR amino acid variability patterns in a structural
      context. A Fourier analysis of 197 multiply aligned olfactory receptor sequences
      showed an alpha-helical periodicity in the variability profile. This was
      particularly pronounced in the more variable transmembranal segments 3, 4, and 5.
      Rhodopsin-based homology modeling demonstrated that the inferred variable helical
      faces largely point to the interior of the receptor barrel. We propose that a set
      of 17 hypervariable residues, which point to the barrel interior and are more
      extracellularly disposed, constitute the odorant complementarity determining
      regions. While 12 of these residues coincide with established ligand-binding
      contact positions in other G-protein-coupled receptors, the rest are suggested to
      form an olfactory-unique aspect of the binding pocket. Highly conserved olfactory
      receptor-specific sequence motifs, found in the second and third intracellular
      loops, may comprise the G-protein recognition epitope. The prediction of
      olfactory receptor functional sites provides concrete suggestions of site
      directed mutagenesis experiments for altering ligand and G-protein specificity.

PMID- 10338008
TI  - ChloroP, a neural network-based method for predicting chloroplast transit
      peptides and their cleavage sites.
AB  - We present a neural network based method (ChloroP) for identifying chloroplast
      transit peptides and their cleavage sites. Using cross-validation, 88% of the
      sequences in our homology reduced training set were correctly classified as
      transit peptides or nontransit peptides. This performance level is well above
      that of the publicly available chloroplast localization predictor PSORT. Cleavage
      sites are predicted using a scoring matrix derived by an automatic motif-finding
      algorithm. Approximately 60% of the known cleavage sites in our sequence
      collection were predicted to within +/-2 residues from the cleavage sites given
      in SWISS-PROT. An analysis of 715 Arabidopsis thaliana sequences from SWISS-PROT
      suggests that the ChloroP method should be useful for the identification of
      putative transit peptides in genome-wide sequence data. The ChloroP predictor is
      available as a web-server at http://www.cbs.dtu.dk/services/ChloroP/.

PMID- 10338010
TI  - Analysis of long-range interactions in a model denatured state of staphylococcal
      nuclease based on correlated changes in backbone dynamics.
AB  - An expanded, highly dynamic denatured state of staphylococcal nuclease exhibits a
      native-like topology in the apparent absence of tight packing and fixed hydrogen
      bonds (Gillespie JR, Shortle D, 1997, J Mol Biol 268:158-169, 170-184). To
      address the physical basis of the long-range spatial ordering of this molecule,
      we probe the effects of perturbations of the sequence and solution conditions on
      the local chain dynamics of a denatured 101-residue fragment that is missing the
      first three beta strands. Structural interactions between chain segments are
      inferred from correlated changes in the motional behavior of residues monitored
      by 15N NMR relaxation measurements. Restoration of the sequence corresponding to
      the first three beta strands significantly increases the average order of all
      chain segments that form the five strand beta barrel including loops but has no
      effect on the carboxy terminal 30 residues. Addition of the denaturing salt
      sodium perchlorate enhances ordering over the entire sequence of this fragment.
      Analysis of seven different substitution mutants points to a complex set of
      interactions between the hydrophobic segment corresponding to beta strand 5 and
      the remainder of the chain. General patterns in the data suggest there is a
      hierarchy of native-like interactions that occur transiently in the denatured
      state and are consistent with the overall topology of the denatured state
      ensemble being determined by many coupled local interactions rather than a few
      highly specific long-range interactions.

PMID- 10338009
TI  - Evidence for a copper-coordinated histidine-tyrosine cross-link in the active
      site of cytochrome oxidase.
AB  - Following hints from X-ray data (Ostermeier C et al., 1997, Proc Natl Acad Sci
      USA 94:10547-10553; Yoshikawa S et al., 1998, Science 280: 1723-1729), chemical
      evidence is presented from four distantly related cytochrome-c oxidases for the
      existence of a copperB-coordinated His240-Tyr244) cross-link at the O2-activating
      Heme Fea3-CuB center in the catalytic subunit 1 of the enzyme. The early
      evolutionary invention of this unusual structure may have prevented damaging *OH
      radical release at e(-)-transfer to dioxygen and thus have enabled O2
      respiration.

PMID- 10338011
TI  - Feasibility in the inverse protein folding protocol.
AB  - Methods for protein structure (3D)-sequence (1D) compatibility evaluation
      (threading) have been developed during the past decade. The protocol in which a
      sequence can recognize its compatible structure in the structural library (i.e.,
      the fold recognition or the forward-folding search) is available for the
      structure prediction of new proteins. However, the reverse protocol, in which a
      structure recognizes its homologous sequences among a sequence database, named
      the inverse-folding search, is a more difficult application. In this study, we
      have investigated the feasibility of the latter approach. A structural library,
      composed of about 400 well-resolved structures with mutually dissimilar
      sequences, was prepared, and 163 of them had remote homologs in the library. We
      examined whether they could correctly seek their homologs by both forward- and
      inverse-folding searches. The results showed that the inverse-folding protocol is
      more effective than the forward-folding protocol, once the reference states of
      the compatibility functions are appropriately adjusted. This adjustment only
      slightly affects the ability of the forward-folding search. We noticed that the
      scoring, in which a given sequence is re-mounted onto a structure according to
      the 3D-1D alignment determined by the dynamic programming method, is only
      effective in the forward-folding protocol and not in the inverse-folding
      protocol. Namely, the inverse-folding search works significantly better with the
      score given by the 3D-1D alignment per se, rather than that obtained by the re
      mounting. The implications of these results are discussed.

PMID- 10338012
TI  - Macromolecular docking of a three-body system: the recognition of human growth
      hormone by its receptor.
AB  - Human growth hormone (hGH) binds to its receptor (hGHr) in a three-body
      interaction: one molecule of the hormone and two identical monomers of the
      receptor form a trimer. Curiously, the hormone-receptor interactions in the
      trimer are not equivalent and the formation of the complex occurs in a specific
      kinetic order (Cunningham BC, Ultsch M, De Vos AM, Mulkerrin MG, Clauser KR,
      Wells JA, 1991, Science 254:821-825). In this paper, we model the recognition of
      hGH to the hGHr using shape complementarity of the three-dimensional structures
      and macromolecular docking to explore possible binding modes between the receptor
      and hormone. The method, reported previously (Hendrix DK, Kuntz ID, 1998, Pacific
      symposium on biocomputing 1998, pp 1234-1244), is based upon matching
      complementary-shaped strategic sites on the molecular surface. We modify the
      procedure to examine three-body systems. We find that the order of binding seen
      experimentally is also essential to our model. We explore the use of mutational
      data available for hGH to guide our model. In addition to docking hGH to the
      hGHr, we further test our methodology by successfully reproducing 16
      macromolecular complexes from X-ray crystal structures, including enzyme
      inhibitor, antibody-antigen, protein dimer, and protein-DNA complexes.

PMID- 10338013
TI  - Ternary complex structure of human HGPRTase, PRPP, Mg2+, and the inhibitor HPP
      reveals the involvement of the flexible loop in substrate binding.
AB  - Site-directed mutagenesis was used to replace Lys68 of the human hypoxanthine
      phosphoribosyltransferase (HGPRTase) with alanine to exploit this less reactive
      form of the enzyme to gain additional insights into the structure activity
      relationship of HGPRTase. Although this substitution resulted in only a minimal
      (one- to threefold) increase in the Km values for binding pyrophosphate or
      phosphoribosylpyrophosphate, the catalytic efficiencies (k(cat)/Km) of the
      forward and reverse reactions were more severely reduced (6- to 30-fold), and the
      mutant enzyme showed positive cooperativity in binding of alpha-D-5
      phosphoribosyl-1-pyrophosphate (PRPP) and nucleotide. The K68A form of the human
      HGPRTase was cocrystallized with 7-hydroxy [4,3-d] pyrazolo pyrimidine (HPP) and
      Mg PRPP, and the refined structure reported. The PRPP molecule built into the
      [(Fo - Fc)phi(calc)] electron density shows atomic interactions between the Mg
      PRPP and enzyme residues in the pyrophosphate binding domain as well as in a long
      flexible loop (residues Leu101 to Gly111) that closes over the active site. Loop
      closure reveals the functional roles for the conserved SY dipeptide of the loop
      as well as the molecular basis for one form of gouty arthritis (S103R). In
      addition, the closed loop conformation provides structural information relevant
      to the mechanism of catalysis in human HGPRTase.

PMID- 10338015
TI  - Prediction of the location and type of beta-turns in proteins using neural
      networks.
AB  - A neural network has been used to predict both the location and the type of beta
      turns in a set of 300 nonhomologous protein domains. A substantial improvement in
      prediction accuracy compared with previous methods has been achieved by
      incorporating secondary structure information in the input data. The total
      percentage of residues correctly classified as beta-turn or not-beta-turn is
      around 75% with predicted secondary structure information. More significantly,
      the method gives a Matthews correlation coefficient (MCC) of around 0.35,
      compared with a typical MCC of around 0.20 using other beta-turn prediction
      methods. Our method also distinguishes the two most numerous and well-defined
      types of beta-turn, types I and II, with a significant level of accuracy (MCCs
      0.22 and 0.26, respectively).

PMID- 10338014
TI  - Mass spectrometric characterization of oat phytochrome A: isoforms and
      posttranslational modifications.
AB  - At least four mRNAs for oat phytochrome A (phyA) are present in etiolated oat
      tissue. The complete amino acid sequences of two phyA isoforms (A3 and A4) and
      the N-terminal amino acid sequence of a third isoform (A5) were deduced from cDNA
      sequencing (Hershey et al., 1985). In the present study, heterogeneity of phyA on
      a protein level was studied by tryptic mapping using electrospray ionization mass
      spectrometry (ESIMS). The total tryptic digest of iodoacetamide-modified phyA was
      fractionated by gel filtration chromatography followed by reversed-phase high
      performance liquid chromatography. ESIMS was used to identify peptides. Amino
      acid sequences of the peptides were confirmed or determined by collision-induced
      dissociation mass spectrometry (CID MS), MS/MS, or by subdigestion of the tryptic
      peptides followed by ESIMS analysis. More than 97% of the phyA3 sequence (1,128
      amino acid residues) was determined in the present study. Mass-spectrometric
      analysis of peptides unique to each form showed that phyA purified from etiolated
      oat seedling is represented by three isoforms A5, A3, and A4, with ratio
      3.4:2.3:1.0. Possible light-induced changes in phytochrome in vivo
      phosphorylation site at Ser7 (Lapko VN et al., 1997, Biochemistry 36:10595-10599)
      as well at Ser17 and Ser598 (known as in vitro phosphorylation sites) were also
      analyzed. The extent of phosphorylation at Ser7 appears to be the same for phyA
      isolated from dark-grown and red-light illuminated seedlings. In addition to
      Ser7, Ser598 was identified as an in vivo phosphorylation site in oat phyA.
      Ser598 phosphorylation was found only in phyA from the red light-treated
      seedlings, suggesting that the protein phosphorylation plays a functional role in
      the phytochrome A-mediated light-signal transduction.

PMID- 10338016
TI  - Pressure-induced thermostabilization of glutamate dehydrogenase from the
      hyperthermophile Pyrococcus furiosus.
AB  - In this paper, elevated pressures up to 750 atm (1 atm = 101 kPa) were found to
      have a strong stabilizing effect on two extremely thermophilic glutamate
      dehydrogenases (GDHs): the native enzyme from the hyperthermophile Pyrococcus
      furiosus (Pf), and a recombinant GDH mutant containing an extra tetrapeptide at
      the C-terminus (rGDHt). The presence of the tetrapeptide greatly destabilized the
      recombinant mutant at ambient pressure; however, the destabilizing effect was
      largely reversed by the application of pressure. Electron spin resonance (ESR)
      spectroscopy of a spin-label attached to the terminal cysteine of rGDHt revealed
      a high degree of mobility, suggesting that destabilization is due to weakened
      intersubunit ion-pair interactions induced by thermal fluctuations of the
      tetrapeptide. For both enzymes, the stabilizing effect of pressure increased with
      temperature as well as pressure, reaching 36-fold for rGDHt at 105 degrees C and
      750 atm, the largest pressure-induced thermostabilization of an enzyme reported
      to date. Stabilization of both native GDH and rGDHt was also achieved by adding
      glycerol. Based on the kinetics of thermal inactivation and the known effects of
      glycerol on protein structure, a mechanism of pressure-induced
      thermostabilization is proposed.

PMID- 10338017
TI  - The calorimetric criterion for a two-state process revisited.
AB  - The "calorimetric criterion" is one of the important experimental approaches for
      determining whether protein folding is an "all-or-none" two-state transition
      (i.e., whether intermediates are present at equilibrium). The calorimetric
      criterion states that the equivalence of the "measured" calorimetric enthalpy
      change and the effective two-state van't Hoff enthalpy change demonstrates that
      there is a two-state transition. This paper addresses the essential question of
      whether the calorimetric criterion is a necessary and sufficient condition for a
      two-state process and shows that it is necessary but not sufficient by means of
      specific examples. Analysis of simple models indicates that the heat capacity
      curve, regardless of whether it originates from a two-state process or not, can
      always be decomposed in such a way that the calorimetric criterion is satisfied.
      Exact results for a three-state model and a homopolymer tetramer demonstrate that
      the deviation from the calorimetric criterion is not simply related to the
      population of intermediate states. Analysis of a three-helix bundle protein
      model, which has a two-state folding from a random coil to ordered (molten)
      globule, shows that the calorimetric criterion may not be satisfied if the
      standard linear interpolation of baselines (weighted or unweighted) is employed.
      A specific example also suggests that the more recently introduced deconvolution
      method is not necessarily better than the simple calorimetric criterion for
      distinguishing a two-state transition from a three-state transition. Although the
      calorimetric criterion is not a sufficient condition for a two-state process, it
      is likely to continue to be of practical utility, particularly when its results
      are shown to be consistent with those from other experimental methods.

PMID- 10338018
TI  - Structural bases of lectin-carbohydrate affinities: comparison with protein
      folding energetics.
AB  - We have made a comparative structure based analysis of the thermodynamics of
      lectin-carbohydrate (L-C) binding and protein folding. Examination of the total
      change in accessible surface area in those processes revealed a much larger
      decrease in free energy per unit of area buried in the case of L-C associations.
      According to our analysis, this larger stabilization of L-C interactions arises
      from a more favorable enthalpy of burying a unit of polar surface area, and from
      higher proportions of polar areas. Hydrogen bonds present at 14 L-C interfaces
      were identified, and their overall characteristics were compared to those
      reported before for hydrogen bonds in protein structures. Three major factors
      might explain why polar-polar interactions are stronger in L-C binding than in
      protein folding: (1) higher surface density of hydrogen bonds; (2) better
      hydrogen-bonding geometry; (3) larger proportion of hydrogen bonds involving
      charged groups. Theoretically, the binding entropy can be partitioned into three
      main contributions: entropy changes due to surface desolvation, entropy losses
      arising from freezing rotatable bonds, and entropic effects that result from
      restricting translation and overall rotation motions. These contributions were
      estimated from structural information and added up to give calculated binding
      entropies. Good correlation between experimental and calculated values was
      observed when solvation effects were treated according to a parametrization
      developed by other authors from protein folding studies. Finally, our structural
      parametrization gave calculated free energies that deviate from experimental
      values by 1.1 kcal/mol on the average; this amounts to an uncertainty of one
      order of magnitude in the binding constant.

PMID- 10338019
TI  - Carbocations in the synthesis of prostaglandins by the cyclooxygenase of PGH
      synthase? A radical departure!
AB  - Evidence already available is used to demonstrate that although prostaglandin G/H
      synthase hydroxylates arachidonic acid through radical intermediates, it effects
      cyclizations through a carbocation center at C-10. This is produced following
      migration of H to the initial radical at C-13 and a 1epsilon oxidation. Under
      orbital symmetry control, the cyclizations can give only the ring size and trans
      stereochemistry actually observed. After cyclization, the H-shift reverses to
      take the sequence back into current radical theory for hydroxylation at C-15.
      Thus 10,10-difluoroarachidonic acid cannot be cyclized, although it can be
      hydroxylated. Acetylation of Ser516 in the isoform synthase-2 is considered to
      oppose carbocation formation and/or H-migration and so prevent cyclizations while
      permitting hydroxylations; the associated inversion of chirality at C-15 can then
      readily be accommodated without the change in conformation required by other
      schemes. Suicide inhibition occurs when carbocations form stable bonds upon
      (thermal) contact with adjacent heteroatoms, etc. Because the cyclooxygenase and
      peroxidase functions operate simultaneously through the same heme, phenol acts as
      reducing cosubstrate for the cyclooxygenase, thus enabling it to promote PGG2
      production and protect the enzyme from oxidative destruction.

PMID- 10338020
TI  - Hydrophobic photolabeling as a new method for structural characterization of
      molten globule and related protein folding intermediates.
AB  - Recent advances in attempts to unravel the protein folding mechanism have
      indicated the need to identify the folding intermediates. Despite their transient
      nature, in a number of cases it has been possible to detect and characterize some
      of the equilibrium intermediates, for example, the molten globule (MG) state. The
      key features of the MG state are retention of substantial secondary structure of
      the native state, considerable loss of tertiary structure leading to increased
      hydrophobic exposure, and a compact structure. NMR, circular dichroism, and
      fluorescence spectroscopies have been most useful in characterizing such
      intermediates. We report here a new method for structural characterization of the
      MG state that involves probing the exposed hydrophobic sites with a hydrophobic
      photoactivable reagent--2[3H]diazofluorene. This carbene-based reagent binds to
      hydrophobic sites, and on photolysis covalently attaches itself to the
      neighboring amino acid side chains. The reagent photolabels alpha-lactalbumin as
      a function of pH (3-7.4), the labeling at neutral pH being negligible and maximal
      at pH 3. Chemical and proteolytic fragmentation of the photolabeled protein
      followed by peptide sequencing permitted identification of the labeled residues.
      The results obtained indicate that the sequence corresponding to B (23-34) and C
      (86-98) helix of the native structure are extensively labeled. The small beta
      domain (40-50) is poorly labeled, Val42 being the only residue that is
      significantly labeled. Our data, like NMR data, indicate that in the MG state of
      alpha-lactalbumin, the alpha-domain has a greater degree of persistent structure
      than the beta-domain. However, unlike the NMR method, the photolabeling method is
      not limited by the size of the protein and can provide information on several new
      residues, for example, Leu115. The current method using DAF thus allows
      identification of stable and hydrophobic exposed regions in folding intermediates
      as the reagent binds and on photolysis covalently links to these regions.

PMID- 10338021
TI  - From fold predictions to function predictions: automation of functional site
      conservation analysis for functional genome predictions.
AB  - A database of functional sites for proteins with known structures, SITE, is
      constructed and used in conjunction with a simple pattern matching program
      SiteMatch to evaluate possible function conservation in a recently constructed
      database of fold predictions for Escherichia coli proteins (Rychlewski L et al.,
      1999, Protein Sci 8:614-624). In this and other prediction databases, fold
      predictions are based on algorithms that can recognize weak sequence similarities
      and putatively assign new proteins into already characterized protein families.
      It is not clear whether such sequence similarities arise from distant homologies
      or general similarity of physicochemical features along the sequence. Leaving
      aside the important question of nature of relations within fold superfamilies, it
      is possible to assess possible function conservation by looking at the pattern of
      conservation of crucial functional residues. SITE consists of a multilevel
      function description based on structure annotations and structure analyses. In
      particular, active site residues, ligand binding residues, and patterns of
      hydrophobic residues on the protein surface are used to describe different
      functional features. SiteMatch, a simple pattern matching program, is designed to
      check the conservation of residues involved in protein activity in alignments
      generated by any alignment method. Here, this procedure is used to study
      conservation of functional features in alignments between protein sequences from
      the E. coli genome and their optimal structural templates. The optimal templates
      were identified and alignments taken from the database of genomic structural
      predictions was described in a previous publication (Rychlewski L et al., 1999,
      Protein Sci 8:614-624). An automated assessment of function conservation is used
      to analyze the relation between fold and function similarity for a large number
      of fold predictions. For instance, it is shown that identifying low significance
      predictions with a high level of functional residue conservations can be used to
      extend the prediction sensitivity for fold prediction methods. Over 100 new
      fold/function predictions in this class were obtained in the E. coli genome. At
      the same time, about 30% of our previous fold predictions are not confirmed as
      function predictions, further highlighting the problem of function divergence in
      fold superfamilies.

PMID- 10338022
TI  - A stable intermediate in the equilibrium unfolding of Escherichia coli citrate
      synthase.
AB  - Urea-induced unfolding of Escherichia coli citrate synthase occurs in two phases,
      as monitored by circular dichroism at 222 nm (measuring secondary structure) or
      by tryptophan fluorescence. In this paper we characterize the intermediate state,
      which retains about 40% of the ellipticity of the native state, and is stable
      between 2.5 M and 5.5 M urea, approximately. This intermediate binds significant
      amounts of the probe for hydrophobic surfaces, anilinonaphthalene sulfonate, but
      forms aggregates at least as high as an octamer, as shown by transverse urea
      gradient polyacrylamide electrophoresis. Thermal denaturation of E. coli citrate
      synthase also produces an intermediate at temperatures near 60 degrees C, which
      also retains about 40% of the native ellipticity and forms aggregates, as
      measured by electrospray-ionization/time-of-flight mass spectrometry. We have
      used a collection of "cavity-forming" mutant proteins, in which bulky buried
      hydrophobic residues are replaced by alanines, to explore the nature of the
      intermediate state further. A certain amount of these mutant proteins shows a
      destabilized intermediate, as measured by the urea concentration range in which
      the intermediate is observed. These mutants are found in parts of the citrate
      synthase sequence that, in a native state, form helices G, M, N, Q, R, and S.
      From this and other evidence, it is argued that the intermediate state is an
      aggregated state in which these six helices, or parts of them, remain folded, and
      that formation of this intermediate is also likely to be a key step in the
      folding of E. coli citrate synthase.

PMID- 10338024
TI  - The effect of multiple binding modes on empirical modeling of ligand docking to
      proteins.
AB  - A popular approach to the computational modeling of ligand/receptor interactions
      is to use an empirical free energy like model with adjustable parameters.
      Parameters are learned from one set of complexes, then used to predict another
      set. To improve these empirical methods requires an independent way to study
      their inherent errors. We introduce a toy model of ligand/receptor binding as a
      workbench for testing such errors. We study the errors incurred from the two
      state binding assumption--the assumption that a ligand is either bound in one
      orientation, or unbound. We find that the two state assumption can cause large
      errors in free energy predictions, but it does not affect rank order predictions
      significantly. We show that fitting parameters using data from high affinity
      ligands can reduce two state errors; so can using more physical models that do
      not use the two state assumption. We also find that when using two state models
      to predict free energies, errors are more severe on high affinity ligands than
      low affinity ligands. And we show that two state errors can be diagnosed by
      systematically adding new binding modes when predicting free energies: if
      predictions worsen as the modes are added, then the two state assumption in the
      fitting step may be at fault.

PMID- 10338023
TI  - Enhanced protein fold recognition using secondary structure information from NMR.
AB  - NMR offers the possibility of accurate secondary structure for proteins that
      would be too large for structure determination. In the absence of an X-ray
      crystal structure, this information should be useful as an adjunct to protein
      fold recognition methods based on low resolution force fields. The value of this
      information has been tested by adding varying amounts of artificial secondary
      structure data and threading a sequence through a library of candidate folds.
      Using a literature test set, the threading method alone has only a one-third
      chance of producing a correct answer among the top ten guesses. With realistic
      secondary structure information, one can expect a 60-80% chance of finding a
      homologous structure. The method has then been applied to examples with published
      estimates of secondary structure. This implementation is completely independent
      of sequence homology, and sequences are optimally aligned to candidate structures
      with gaps and insertions allowed. Unlike work using predicted secondary
      structure, we test the effect of differing amounts of relatively reliable data.

PMID- 10338025
TI  - Expression, purification, and crystallography of the conserved methionine-rich
      domain of human signal recognition particle 54 kDa protein.
AB  - Protein SRP54 is an essential component of eukaryotic signal recognition particle
      (SRP). The methionine-rich M-domain (SRP54M or 54M) interacts with the SRP RNA
      and is also involved in the binding to signal peptides of secretory proteins
      during their targeting to cellular membranes. To gain insight into the molecular
      details of SRP-mediated protein targeting, we studied the human 54M polypeptide.
      The recombinant human protein was expressed successfully in Escherichia coli and
      was purified to homogeneity. Our studies determined the sites that were
      susceptible to limited proteolysis, with the goal to design smaller functional
      mutant derivatives that lacked nonessential amino acid residues from both
      termini. Of the four polypeptides produced by V8 protease or chymotrypsin, 54MM-2
      was the shortest (120 residues; Mr = 13,584.8), but still contained the conserved
      amino acids suggested to associate with the signal peptide or the SRP RNA. 54MM-2
      was cloned, expressed, purified to homogeneity, and was shown to bind human SRP
      RNA in the presence of protein SRP19, indicating that it was functional. Highly
      reproducible conditions for the crystallization of 54MM-2 were established.
      Examination of the crystals by X-ray diffraction showed an orthorhombic unit cell
      of dimensions a = 29.127 A, b = 63.693 A, and c = 129.601 A, in space group
      P2(1)2(1)2(1), with reflections extending to at least 2.0 A.

PMID- 10338026
TI  - Amino acid substitutions at the subunit interface of dimeric Escherichia coli
      alkaline phosphatase cause reduced structural stability.
AB  - The consequences of amino acid substitutions at the dimer interface for the
      strength of the interactions between the monomers and for the catalytic function
      of the dimeric enzyme alkaline phosphatase from Escherichia coli have been
      investigated. The altered enzymes R10A, R10K, R24A, R24K, T59A, and R10A/R24A,
      which have amino acid substitutions at the dimer interface, were characterized
      using kinetic assays, ultracentrifugation, and transverse urea gradient gel
      electrophoresis. The kinetic data for the wild-type and altered alkaline
      phosphatases show comparable catalytic behavior with k(cat) values between 51.3
      and 69.5 s(-1) and Km values between 14.8 and 26.3 microM. The
      ultracentrifugation profiles indicate that the wild-type enzyme is more stable
      than all the interface-modified enzymes. The wild-type enzyme is dimeric in the
      pH range of pH 4.0 and above, and disassembled at pH 3.5 and below. All the
      interface-modified enzymes, however, are apparently monomeric at pH 4.0, begin
      assembly at pH 5.0, and are not fully assembled into the dimeric form until pH
      6.0. The results from transverse urea gradient gel electrophoresis show clear and
      reproducible differences both in the position and the shape of the unfolding
      patterns; all these modified enzymes are more sensitive to the denaturant and
      begin to unfold at urea concentrations between 1.0 and 1.5 M; the wild-type
      enzyme remains in the folded high mobility form beyond 2.5 M urea. Alkaline
      phosphatase H370A, modified at the active site and not at the dimer interface,
      resembles the wild-type enzyme both in ultracentrifugation and electrophoresis
      studies. The results obtained suggest that substitution of a single amino acid at
      the interface sacrifices not only the integrity of the assembled dimer, but also
      the stability of the monomer fold, even though the activity of the enzyme at
      optimal pH remains unaffected and does not appear to depend on interface
      stability.

PMID- 10338027
TI  - Estimation of epicardial activation maps from intravascular recordings.
AB  - Multielectrode catheters provide a percutaneous means of recording activation
      near the epicardium but only for a relatively small number of sites that are
      restricted to the major coronary vessels. We have applied a statistical signal
      processing technique to estimate the value of activation time over the entire
      epicardium (490 sites) from leadsets consisting of 4 to 40 sites aligned with
      major branches of the coronary veins. We tested this method using data from high
      resolution epicardial mapping from six dog hearts and 153 activation sequences. A
      study including data from both normal and infarcted dog hearts yielded estimates
      of activation time, with mean correlation coefficients ranging from 0.97 to 0.84
      and achieved localization of earliest site of activation to within 3 to 15 mm,
      depending on training parameters and leadset. These results suggest that with 10
      to 15 catheter-mounted electrodes, it may be possible to reconstruct epicardial
      activation maps from percutaneous recordings.

PMID- 10338028
TI  - On selecting a body surface mapping procedure.
AB  - Throughout the world, various procedures related to body surface mapping have
      evolved. The large differences in these procedures make multicenter studies
      difficult. This paper discusses the problems involved in selecting the number of
      leads, lead placement, and map format. Methods are highlighted that have been
      developed for pooling of the data as obtained by different centers.
      Recommendations are included to newcomers in the field. (The work stems from an
      international study, the Noninvasive Evaluation of the Myocardium, a study group
      sponsored by the European Commission, which has as one of its objectives the
      standardization of body surface mapping procedures.)

PMID- 10338029
TI  - Spherical-harmonic approximation to the forward problem of electrocardiology.
AB  - Forward-problem solutions were approximated using spherical-harmonic series on an
      adult male torso model with heart and lungs. These approximations were found
      using only a knowledge of torso-model geometry and were not based on a prior
      solution for surface potentials. Because these series depend only on polar and
      azimuthal angles, they allow continuous estimation of the forward-problem
      solution over the torso without further knowledge of the torso geometry. Compared
      to the conventional method, potentials estimated from fifth-degree series for
      eight distributed double-layer sources had an average relative error of 0.036.
      Relative errors were similar with and without torso inhomogeneities. The fifth
      degree series solution (36 terms) was found four times faster than the
      conventional method and provided a data reduction factor of about 20 in the 715
      node torso model studied. Spherical-harmonic series transform surface potentials
      into an orthogonal basis set whose spatial-frequency content increases with
      increasing degree. Consequently, these series may provide a structure for the
      systematic study of the effect on forward-problem solutions of both changes in
      torso shape and inclusion of inhomogeneities.

PMID- 10338030
TI  - Simulation of late potentials and arrhythmias by use of a three-dimensional heart
      model: casuality of peri-infarctional slow conduction in ventricular
      fibrillation.
AB  - A three-dimensional heart model was constructed to simulate late potentials and
      ventricular fibrillation (VF). The model consisted of 50,000 discrete elements
      having a 1.5-mm spatial resolution. Each element represented excitable
      ventricular tissue, including a conduction system, and was characterized with
      classical features of the action potential, refractory period, and conduction
      velocity (theta). An infarcted area on the lateral wall was identified as dead
      (inexcitable) cells or scar tissue, and peri-infarctional (PI) cells with slow
      conduction. Body surface potentials were calculated by using the boundary element
      method. When theta of PI cells was reduced below 0.3 m/s, late potentials became
      evident after the J point of simulated electrocardiograms (ECGs), and VF was
      induced by applying four consecutive premature stimuli. However, when Purkinje
      fibers were removed, VF could not be initiated. Late potentials were induced when
      slow conduction was present. The presence of PI slow conduction and Purkinje
      fibers, which were normally contained in the model, was essential for the
      induction of VF.

PMID- 10338031
TI  - QRST integral analysis of body surface electrocardiographic mapping for assessing
      exercise-induced changes in the spatial distribution of local repolarization
      properties in patients with coronary artery disease and in patients with previous
      anterior infarction.
AB  - We studied resting, postexercise, difference (postexercise - rest) QRST
      isointegral maps, and the correlation coefficient between resting and
      postexercise maps. Study I Fifteen controls and 48 patients without previous
      myocardial infarction were studied. In coronary syndrome X group (n = 14), no
      patients showed an abnormally negative area on the postexercise map. In coronary
      ST depression group (n = 26), 12 patients (46%) showed an abnormally negative
      area on the postexercise map, and the correlation coefficient was low. Although
      all control, syndrome X, and coronary ST depression patients showed the global
      downward type of difference map, coronary ST elevation patients (n = 8) showed
      the right-downward and left-upward type, right-upward and left-downward type, or
      reversed saddle type. Coronary ST depression is related to a globally marked
      decrease in local repolarization forces. Coronary ST elevation is associated with
      multidirectional changes in local repolarization forces. Study II Fifty-one
      patients with previous anterior infarction (29 with residual ischemia and 22
      without) were studied. The incidence of the global-positive type of maps was
      increased and that of the saddle-type map was decreased from rest to postexercise
      in both groups. The global-upward type or right-downward and left-upward type of
      difference map was observed in both groups, but the reversed saddle type, right
      upward and left-downward type, or global-downward type was observed in the
      residual ischemia group (34%, 24%, and 14%, respectively). Residual ischemia
      causes multidirectional changes or a global decrease in local repolarization
      forces. In both studies, multidirectional changes in local repolarization forces
      may be related to the vulnerability to ventricular arrhythmias.

PMID- 10338032
TI  - Interindividual variability of multilead electrocardiographic recordings:
      influence of heart position.
AB  - The electrocardiogram (ECG) of normal, healthy subjects shows a large
      interindividual variability. Part of this variability is due to the heart
      position and orientation relative to the electrodes. In this report, the
      interindividual variability is quantified using the relative variability measure,
      computed as the averaged standard deviation in the ECGs, scaled by the average
      root mean square of the ECGs. The relative variability in the QRS complex is
      estimated as 0.52. The heart position and orientation relative to the lead
      positions is documented in 25 normal subjects. The long axis angle varies
      considerably among the subjects (27.1+/-8.8 degrees to the transversal plane and
      38 degrees +/-5 degrees to the frontal plane). Moving the electrodes in the
      frontal plane to a position relative to a common reference point at the base of
      the heart (shift: 0.8+/-0.7 cm leftward and 2.4+/-2.3 cm downward) did not reduce
      the interindividual variability.

PMID- 10338033
TI  - Temporal and positional variability of the ST segment during continuous
      vectorcardiography monitoring in healthy subjects.
AB  - Continuous vectorcardiography ST-segment monitoring (cVST) is a well-established
      method in the diagnosis and risk evaluation of patients with acute myocardial
      ischemia. Previous investigations have demonstrated that electrocardiographic ST
      segment changes are to be expected, during both repeated measurements and changes
      in body position. We prospectively analyzed the influence of spontaneous temporal
      variation (technical and biological noise) and changes in body position on the ST
      segment (ST-vector magnitude [ST-VM]) during cVST of 21 healthy human subjects.
      The 95% expectancy range of the spontaneous intraindividual ST-VM variation was
      found to be +/-8 microV for the error of measurement, and +/-14 and +/-24 microV
      during 24-hour and day-to-day cVST measurements, respectively. Positional ST
      segment changes in the orthogonal leads were frequent, especially in leads X and
      Z, and in the left lateral position. Positional orthogonal ST-segment changes
      resulted in significant ST-VM changes in two of seven subjects. It is concluded
      that the low spontaneous temporal ST-VM variation must be considered as good
      reproducibility. Moreover, the present findings support currently used ST-VM
      ischemia criteria. However, the impact of positional changes on ST-VM seems to be
      of importance (with the possibility of false-positive results) and should be
      taken into account during cVST.

PMID- 10338034
TI  - Defibrillation and the upper limit of vulnerability to fibrillation in a
      transthoracic guinea pig model.
AB  - Recent studies have shown sustained tachyarrhythmias in guinea pigs. We
      hypothesized that guinea pigs could be used as a model of ventricular
      fibrillation, focusing on defibrillation waveform efficacy and the upper limit of
      vulnerability to fibrillation. In 10 male guinea pigs, an esophageal/apical
      pacing electrode configuration was used. The electrocardiogram (ECG) and arterial
      blood pressure were continuously monitored. T-wave and defibrillation shocks were
      applied transthoracically. A modified up-down protocol was used. After up-down
      testing was completed, a tachyarrhythmia was induced without electrical
      termination. All animals died of a sustained tachyarrhythmia. The monophasic
      DFT50 (the 50% successful defibrillation voltage, 496 +/-176 V) was larger than
      the biphasic DFT50 (364+/-94 V, P < .005). The upper limit of vulnerability to
      fibrillation (ULV50) (the 50% successful induction voltage) was correlated with
      the DFT50 for both monophasic (r = .82, P < .005) and biphasic shocks (r = .88, P
      < .005). Its low cost and ease of handling may make the guinea pig a preferred
      model for some fibrillation and defibrillation studies.

PMID- 10338035
TI  - Diurnal variation of autonomic nervous activity in the rat: investigation by
      power spectral analysis of heart rate variability.
AB  - We studied the diurnal variations of autonomic nervous function in rats. For this
      purpose, a long-term electrocardiogram (ECG) was recorded from conscious and
      unrestrained rats using a telemetry system, and the autonomic nervous function
      was investigated by the power spectral analysis of heart rate variability. No
      arrhythmias were observed in the ECG of any of the rats. Nocturnal patterns, in
      which the values of heart rate in the dark phase (2000-0600) were higher than
      those in the light phase (0600-2000), were observed. All normal rats shared a
      characteristic pattern in their power spectrum analysis. Both low-frequency and
      high-frequency power in the light phase were higher than those in the dark phase.
      However, these differences were not statistically significant (P > .05). The low
      frequency to high frequency ratio also showed a nocturnal pattern. The value in
      the dark phase was significantly higher (P < .05) than that in the light phase.
      These results suggest that the sympathetic nervous activity is predominant in the
      dark phase in rats. Therefore, we believe that this information may be useful for
      future biobehavioral studies.

PMID- 10338036
TI  - QT dispersion as a noninvasive predictor of inducible ventricular tachycardia.
AB  - The QT dispersion (QTD) on the surface electrocardiogram is a noninvasive marker
      of heterogeneity of ventricular repolarization. An increased QTD has been
      associated with spontaneous ventricular arrhythmias. We investigated the
      relationship of QTD to inducible reentrant sustained ventricular tachycardia (VT)
      in 66 patients who underwent programmed electrical stimulation. Thirty-three
      patients had inducible VT and 33 had noninducible VT with up to three extra
      stimuli. The QTD was significantly longer in patients with inducible VT (79+/-30
      ms) compared with those in whom VT was noninducible (50+/-20 ms, P < .0001). QTD
      of > or =70 ms had a sensitivity of 67%, a specificity of 94%, a positive
      predictive value of 92%, and a negative predictive value of 74% for inducible VT.
      We conclude that QTD is an easily measurable electrocardiographic index that is
      increased in patients with inducible VT, and a QTD of > or =70 ms is highly
      predictive of VT inducibility.

PMID- 10338037
TI  - Myocardial infarction-induced ventricular aneurysm in the presence of complete
      left bundle branch block: a case report suggesting a new electrocardiographic
      diagnostic criterion.
AB  - A 65-year-old man who had suffered an anterior myocardial infarction (MI) 10
      years ago, complicated by a ventricular aneurysm (VA), and subsequently many
      years later developed complete left bundle branch block (LBBB), is described,
      with main emphasis on the feasibility of the electrocardiographic (ECG) diagnosis
      of VA in the presence of this conduction abnormality. Ventricular aneurysm in our
      patient was repeatedly confirmed by echocardiography over the intervening years.
      During the time the patient maintained normal intraventricular conduction, the
      ECG showed persisting ST-segment elevations in the precordial leads. After the
      development of LBBB, the ECG displayed accentuated ST-segment elevations in the
      precordial leads with predominantly negative QRS complexes, and ST elevation in
      V5, despite its primarily positive QRS complex. The authors extend the findings
      from the previous literature on the diagnosis of acute MI in patients with LBBB
      or right intraventricular pacing, and the concept of primary and secondary
      repolarization changes, to the diagnosis of VA in the presence of LBBB.

PMID- 10338038
TI  - Transient complete atrioventricular block provoked by ventricular pacing in a
      patient with nonsustained ventricular tachycardia.
AB  - A 75-year-old woman with complete left bundle branch block underwent
      electrophysiological study (EPS) to assess the conduction in the His-Purkinje
      conduction system and to further investigate the electrical instability in the
      ventricle, which was suggestive by the findings of nonsustained ventricular
      tachycardia in ambulatory monitoring. Transient complete atrioventricular (AV)
      block was provoked by ventricular pacing, and the intracardiac recordings proved
      that the site of AV block was distal to the His bundle. This phenomenon was not
      related to the rate or the duration of the ventricular pacing. The transient
      impairment of the conduction appeared to be due to the fatigue phenomenon in the
      His-Purkinje system.

PMID- 10338039
TI  - The role of thiotepa in allogeneic bone marrow transplantation for genetic
      diseases.
AB  - Graft-versus-host disease (GVHD), graft rejection, disease recurrence and long
      term toxicity remain significant obstacles to successful allogeneic bone marrow
      transplantation (BMT) in children with genetic diseases. In an attempt to improve
      results, we used a preparative regimen consisting of three alkylating agents,
      busulfan (BU), thiotepa (TTP) and cyclophosphamide (CY), for T cell-depleted
      allogeneic bone marrow transplantation instead of the conventional BU-CY
      protocol. The effect of this intensified regimen was investigated in 26
      consecutive children with genetic diseases who underwent T cell-depleted BMT from
      HLA-identical siblings. Sixteen patients were males and 10 females, of median age
      5 (0.2-14) years. The diseases included beta-thalassemia major, osteopetrosis,
      severe combined immunodeficiency, Wiskott-Aldrich syndrome, familial
      agranulocytosis, congenital idiopathic hemolytic anemia (CIHA), Gaucher's
      disease, Niemann-Pick disease, Hurler's syndrome, and adrenoleukodystrophy. The
      conditioning regimen consisted of BU 4 mg/kg x 4 days (-8 to -5), TTP 5 mg/kg x 2
      days (-4 and -3), and CY 60 mg/kg x 2 days (-2 and -1). Engraftment was as
      expected, with WBC >1.0 x 10(9)/l at day +19 (10-33), ANC >0.5 x 10(9)/l at day
      +22 (10-56) and platelets >25 x 10(9)/l at day +32 (18-131). Transplant-related
      mortality was 19%. Overall survival and disease-free survival (DFS) at 60 months
      follow-up were both 77%. Our results with the BU-TTP-CY regimen followed by T
      cell-depleted BMT in genetic diseases may provide a basis for prospective
      comparison with the standard conditioning regimen of BU-CY in the management of
      children suffering from these conditions.

PMID- 10338040
TI  - Comparison of autologous peripheral blood stem cell dosing by ideal vs actual
      body weight.
AB  - In this retrospective study, we evaluated the predictability of PBSC dose for
      hematopoietic engraftment comparing that calculated by ideal body weight (IBW) vs
      another calculated by actual body weight (ABW) for each patient. Sixty-three
      consecutive patients treated similarly using one transplant protocol were
      analyzed. While all patients had data available on CFU-GM and nucleated cells
      (NC), data on CD34+ enumeration was present only in 34 patients. We found that
      49% of the patients were greater than 25% over their IBW. In addition, least
      squares linear regression was used to assess the strength of the linear
      relationship between the inverse of cell dose/kg of ABW or IBW and time to AGC or
      platelet engraftment and showed no difference in r2 values for platelet
      engraftment, while using dose/kg of IBW greatly improved the ability of NC (r2
      improved from 0.19 for ABW to 0.35 for IBW) and CFU-GM (r2 improved from 0.35 for
      ABW to 0.53 for IBW) to predict time to AGC engraftment, but did not change the
      CD34 r2. Hazard ratios were estimated using Cox proportional hazards regression
      and in all instances were found greater than 1.0 indicating that the probability
      of engraftment increased as cell dose/kg ABW or IBW increased. Finally, our data
      showed that 10 patients (16%) could have had one less apheresis procedure
      performed to obtain their set target stem cell dose calculated per kg IBW rather
      than ABW. In conclusion, PBSC dose per kg IBW is as good or better predictor of
      engraftment of AGC and may lead to cost savings in a certain subset of patients.

PMID- 10338041
TI  - Long-term outcome of adult acute leukemia patients who are alive and well 2 years
      after autologous blood or marrow transplantation.
AB  - We studied the long-term outcome of 87 adults with acute leukemia (age 15-59
      years at transplant, median 27; 44 myeloid, 42 lymphoblastic, one biphenotypic)
      who were alive in continuous remission 2 years after a marrow (n = 74) or blood
      stem cell (n = 13) autograft. Nine relapsed 25-50 months (median 38) after
      transplantation. Five relapses were straightforward with no karyotypic or
      morphologic evolution of the original disease. Four recurrences were unusual,
      with development of myelodysplasia (n = 3) or myeloproliferative disease (n = 1).
      Five patients died of relapsed disease and four are still alive. Two patients
      died of complications related to the transplant, and one of ischemic heart
      disease. Seventy-nine patients (91%) are alive in remission 24-149 months (median
      67) after transplantation (75 in continuous remission and four after further
      therapy) with Karnofsky scores of 80-100% (median 100%). The 8-year probabilities
      of survival, toxic death, and relapse (from the 2-year mark) are 89%, 3% and 12%.
      Eleven (12%) survivors had creatinine levels of >110 micromol/l (one more than
      double), and 14 (16%) had bilirubin levels of >17 mmol/l (one more than double)
      at the last follow-up. None of the following factors was found to be predictive
      for survival, non-relapse death, or relapse from the 2-year mark in multivariate
      analysis: age, sex, type of leukemia, disease stage, diagnosis, conditioning,
      origin of cells, and nucleated cell dose. We conclude that adult patients with
      acute leukemia who are alive and well 2 years following an autograft have a high
      probability of being cured, and the incidence of long-term liver and kidney
      dysfunction measured by serum bilirubin and creatinine is low.

PMID- 10338042
TI  - Extracorporeal photopheresis (ECP) in the treatment of chronic graft-versus-host
      disease (GVHD)
AB  - The aim of our study was to assess the efficacy of extracorporeal photopheresis
      (ECP) in chronic graft-versus-host disease (GVHD). Eleven patients with chronic
      cutaneous GVHD were studied. Four had mucosal involvement and five had pulmonary
      involvement. All had failed to improve on first- and second-line therapy. Three
      patients received ECP alone; the remainder continued to receive steroids and/or
      immunosuppressive therapy. Patients received ECP twice monthly for 4 months and
      then once monthly for 3 months. They were evaluated by serial skin scores,
      mucosal and skin photography, pulmonary function tests, biochemical and
      haematological parameters. Nine patients showed objective evidence of cutaneous
      improvement with a mean reduction in skin score of 48% overall. In the 10th
      patient, skin scores and oral involvement improved on twice monthly ECP but
      deteriorated when reduced to once monthly. The final patient died from renal
      failure secondary to cyclosporin toxicity. Two out of five patients with lung
      involvement showed a mild improvement in pulmonary function tests. Liver function
      tests were abnormal in five patients; they improved in one and deteriorated in
      three. All patients receiving concomitant immunosuppressive/steroid therapy were
      able to reduce drug dosages by trial completion. Our results indicate that ECP
      can benefit patients with cutaneous and mucosal chronic GVHD who have failed on
      first- and second-line therapies. The effect on the systemic manifestations of
      GVHD is less consistent.

PMID- 10338043
TI  - Use of a five-agent GVHD prevention regimen in recipients of unrelated donor
      marrow.
AB  - A five-agent GVHD prophylaxis programme consisting of cyclosporin A,
      methotrexate, anti-thymocyte-globulin, pentaglobin and metronidazol was given to
      48 recipients of unrelated donor marrow with chronic myelogenous leukemia, acute
      leukemia, myelodysplastic syndromes, and familiar lymphocytic hemophagocytosis of
      an average age of 33.5 (0.6-56) years. GVHD grades II-IV occurred in 18 patients
      (39%) and grades III-IV in five patients (11%). Chronic GVHD developed in nine
      patients (23%), three limited and six extensive. Fifteen patients died. Clinical
      relapse was detected in eight patients. Four patients died as a consequence of
      the underlying disease and subsequent treatment, 11 patients died of transplant
      related causes. After a median follow-up of 19 months, the overall and disease
      free survival are 67% and 62%, respectively. Survival by age is as follows: 0-19
      years: 12/13 patients; 20-39 years: 14/25 patients; 40-59 years: 7/10 patients.
      The five-agent GVHD prophylaxis regimen is effective. Matched-unrelated donor
      transplants can be carried out safely in patients younger than 50 years of age.
      The results in patients younger than 20 years of age should encourage matched
      unrelated donor transplants at earlier stages of the disease.

PMID- 10338044
TI  - Flow cytometric DNA quantification in immunophenotyped cells as a sensitive
      method for determination of aneuploid multiple myeloma cells in peripheral blood
      stem cell harvests and bone marrow after therapy.
AB  - The simultaneous measurement of DNA content and myeloma-related antigens (B-B4 or
      CD38) by flow cytometry is proposed as a method for the detection of aneuploid
      plasma cells in peripheral blood stem cell (PBSC) harvests and in bone marrow
      after therapy. In 30 patients with initially detected aneuploid myeloma cells we
      evaluated the bone marrow after therapy and in eight of these patients 23 PBSC
      harvests were analyzed. In 13 of 23 PBSC harvests aneuploid myeloma cells were
      detectable (range: 0.02-0.63%). In the bone marrow of the 30 patients aneuploid
      plasma cells were detectable in all samples after chemotherapy (range: 0.12
      35.70%) and after autologous PBSC transplantation in two of three patients (0.21%
      and 0.03%). Furthermore the relationship between diploid and aneuploid plasma
      cells can be evaluated. In the PBSC harvests the percentage of aneuploid plasma
      cells is significantly lower than that of diploid plasma cells (P=0.006). In
      contrast, in bone marrow the aneuploid plasma cells are predominant in most
      patients even after therapy (24 of 30 patients; P=0.0055). In the case of
      initially detected aneuploid myeloma cells, a contamination with malignant cells
      can be estimated with a simple flow cytometric method in PBSC harvests and in
      bone marrow after therapy.

PMID- 10338045
TI  - Haematopoietic damage persists 1 year after autologous peripheral blood stem cell
      transplantation.
AB  - In the present study we have used cell culture assays in order to assess the
      damage in the haematopoietic system 1 year after peripheral blood stem cell
      transplantation (PBSCT), and to establish at what level, haematopoietic
      progenitor cells (HPC) or stroma, this damage occurs. Thirty-one patients, nine
      breast cancer (BC), 17 non-Hodgkin lymphoma (NHL) and five Hodgkin disease (HD),
      who had received autologous PBSCT were included. Forty-eight normal subjects who
      had given informed consent were used as controls. Results were also compared with
      a matched group of patients (25 cases) prior to PBSCT. Progenitor cells were
      analysed using CFU-GM and plastic adherent delta (Pdelta) assays. Long-term bone
      marrow cultures (LTBMC) in one and two stages were established. One year after
      transplant both the number of committed progenitor cells and the CFU-GM
      production in LTBMC were significantly reduced in the three groups of patients
      when compared with controls (P < 0.05 or P < 0.01). Two-stage LTBMC experiments
      showed that the impairment in CFU-GM production was due to damage in both
      patients' stroma and haematopoietic progenitor cells (HPC). All patients, except
      those with HD, showed a decreased stromal layer confluence (P < 0.05), with
      significant differences in cell composition as compared to normal bone marrow (P
      = 0.001). When all these variables were compared with pretransplant results, we
      observed that stroma formation was significantly lower after PBSCT (P < 0.05),
      while the number of progenitor cells analysed by the Pdelta assay was
      significantly increased (P < 0.05). We can conclude that even 1 year after PBSCT,
      both the committed HPC and BM stroma remain damaged.

PMID- 10338047
TI  - Predictive value of left ventricular ejection fraction in stem cell
      transplantation.
AB  - We evaluated predictive value of left ventricular ejection fraction at rest (REF)
      and its increment with exercise (deltaEF) on autologous and allogeneic stem cell
      transplantation mortality. In a 7 year period, a total of 163 patients evaluated
      for stem cell transplantation were studied. All were followed for at least 3
      months after the transplant. REF was discriminatory for peritransplant mortality
      only in younger (<43 years) patients (n = 66), particularly those who underwent
      autologous transplantation (n = 30). Resting ejection fraction was not a
      discriminator for early death in any other subgroup. Cardiac reserve (deltaEF)
      was significantly lower in patients (n = 35), who died early. The finding was
      most prominent in younger patients who underwent autologous transplantation (n =
      26). Combination of decreased REF and low deltaEF (n = 18) was associated with
      high peritransplant mortality (56%), after both autologous and allogeneic
      transplantation. A low REF with an appropriate deltaEF (n = 43) was associated
      with a 19% peritransplant mortality and no deaths in the autologous group. These
      observations indicate that resting ejection fraction is of only limited value for
      pretransplant evaluation. However, measurement of cardiac reserve during exercise
      can provide important prognostic information before stem cell transplantation.

PMID- 10338046
TI  - Production and culture of HSVtk transduced suicidal lymphocytes induces variable
      changes in the lymphocyte subset composition.
AB  - Allogeneic bone marrow transplant followed by donor lymphocyte infusion (DLI) is
      limited by T cell-mediated graft-versus-host disease (GVHD). A potential solution
      to alleviate uncontrolled GVHD is to create a controllable suicidal lymphocyte
      using retroviral transduction of the herpes simplex virus thymidine kinase gene
      (HSVtk) into the T cell graft. Should GVHD arise, the administration of
      ganciclovir (GCV) should eliminate the causal T cells. The culture conditions and
      expansion protocols required to produce suicidal lymphocytes may affect the
      composition of the T cell product. In this report we describe how T cells from
      individual donor samples respond to the same culture condition in highly varied
      ways. Among five donors, two demonstrated predominant expansion of CD4+ cells
      (with a decrease of CD8+), two donors resulted in predominately CD8+ cells, and
      one donor developed mainly dual positive CD8+/CD56+ cells. We observed a 20-fold
      expansion of T cells during the 14 day protocol. The function of the T cells was
      not affected by the transduction procedures (as tested by 51Cr release assays).
      In contrast to suicidal lymphocytes prepared using entire T cell populations, T
      cells pre-selected into CD3+/CD4+ or CD3+/CD8+ subpopulations prior to culture
      maintained their initial phenotype during the 14 day culture period, with little
      or no drift. Results from clinical trials using suicidal lymphocytes may be
      confounded by variance in lymphocyte subset compositions (LSC) and optimal use of
      suicidal lymphocytes may require separate culture and transduction to control the
      LSC delivered to the patient.

PMID- 10338048
TI  - Biliary obstruction in hematopoietic cell transplant recipients: an uncommon
      diagnosis with specific causes.
AB  - Jaundice is a common problem in marrow transplant recipients. The incidence of
      bile duct obstruction in this setting is unknown. The purpose of this study was
      to determine the incidence of biliary obstruction, the causes, and outcomes
      following marrow transplant. Consecutive cases were reviewed at two major
      transplant centers in the United States from 1969 to 1996 at the Fred Hutchinson
      Cancer Research Center and 1989 to 1996 at the City of Hope National Medical
      Center. Nine cases of biliary obstruction were identified as a cause of jaundice
      in 7412 marrow transplant recipients, an incidence of 0.12%. The presentation was
      bimodal, with seven cases occurring prior to day 100 and two occurring 2 to 4
      years after transplantation. The age distribution was 15 to 50 years and all
      patients had received allogeneic transplants. The causes of obstruction included
      gallbladder sludge (n=1), a duodenal hematoma (n=1), choledocholithiasis with
      biliary pancreatitis (n=1), bile duct infection (n=2), recurrent malignancy
      (n=1), choledocholithiasis associated with a benign stricture (n=1), Epstein-Barr
      virus-related lymphoproliferative disorder (n=1), and a benign stricture of
      unknown etiology (n=1). Biliary obstruction is a rare cause of jaundice in the
      post-transplant period. The presentation was similar to that of other post
      transplant hepatobiliary problems, but with disparate causes.

PMID- 10338049
TI  - Comparison of two doses of intravenous immunoglobulin after allogeneic bone
      marrow transplants.
AB  - Intravenous immunoglobulin has been used after bone marrow transplants to prevent
      infections and acute graft-versus-host disease. However, the minimum dose
      required for protection is unknown. This may have significant economic
      implications. A multicenter randomized clinical trial compared the impact of two
      intravenous immunoglobulin doses on systemic infections and acute graft-versus
      host disease in transplant recipients. Either 250 mg/kg or 500 mg/kg was given
      weekly from day -8 to day +111. Multivariate analysis was used to assess the
      effect of dose and other risk factors on event-free survival, systemic infection,
      and acute graft-versus-host disease. The two-dose cohorts had similar event-free
      survival and infection frequencies. The higher dose was associated with less
      acute graft-versus-host disease (P = 0.03).

PMID- 10338050
TI  - Parenteral nutrition following intensive cytotoxic therapy: an exploratory study
      on the need for parenteral nutrition after various treatment approaches for
      haematological malignancies.
AB  - Patients receiving intensive cytotoxic therapy are traditionally supported with
      parenteral nutrition (PN), although it is unclear whether all patients benefit
      from PN. This study aimed to identify regimen-associated differences in PN
      requirements, to reveal discrepancies between the number of PN indications and
      the frequency with which PN was actually given, and to describe characteristics
      of patients who met nutritional goals without PN. PN indications were defined as:
      (1) severe malnutrition at admission; (2) a prolonged period (7-10 days) of
      minimal oral intake; or (3) clinical weight loss >10%. PN was found to be needed
      in only 35% of consolidation courses, compared with 80% during remission
      induction and 55% during BMT. Significant differences were also seen between BMT
      protocols: PN was required in only 37% of autologous BMT recipients conditioned
      without total body irradiation (for lymphoma) vs 92% of recipients of a
      mismatched graft. A high body mass index was the only significant characteristic
      of patients who could do without PN. In conclusion, PN is not required for all
      patients undergoing intensive cytotoxic therapy. Screening of nutritional status
      at the start of therapy and monitoring oral intake following cytotoxic treatment
      may allow more appropriate identification of patients requiring PN.

PMID- 10338051
TI  - Bone marrow harvesting using EMLA (eutectic mixture of local anaesthetics) cream,
      local anaesthesia and patient-controlled analgesia with alfentanil.
AB  - Bone marrow harvesting (BMH) was performed on 40 consecutive allogeneic or
      autologous donors using EMLA (eutectic mixture of local anaesthetics), local
      anaesthesia (LA) and patient-controlled analgesia with alfentanil (PCA-A). The
      effect of alkalinizing the LA solution on reducing pain during LA infiltration in
      the presence of EMLA was also investigated. EMLA 10 g with occlusive dressing was
      applied to the harvest sites at least 60 min before BMH. The PCA device was
      programmed to deliver an intravenous loading dose of 15 microg/kg alfentanil,
      followed by a background alfentanil infusion of 0.05 microg/kg/min. Demand dose
      was 4 microg/kg and lockout time was 3 min. Donors were randomized to receive
      either alkalinized (n = 19) or non-alkalinized (n=21) LA solution (lignocaine 1%
      with 1:100000 adrenaline). While post-operative nausea and vomiting were the only
      side-effects, all donors in both groups reported satisfactory pain scores during
      LA infiltration and satisfactory overall intra-operative comfort scores. They
      completed BMH using either regimen successfully, found this technique acceptable
      and would recommend this form of anaesthesia to others. Alkalinizing the LA
      solution did not significantly improve the pain scores during LA infiltration in
      the presence of EMLA. In conclusion, BMH can be performed safely using EMLA, LA
      and PCA-A without major complications.

PMID- 10338052
TI  - Analgesic infiltration at the site of bone marrow harvest significantly reduces
      donor morbidity.
AB  - Little information has been published concerning the severity of pain experienced
      by bone marrow donors or the use of local analgesia following bone marrow
      harvesting procedures. The aims of this study were to assess duration and
      severity of pain experienced by bone marrow donors and the effectiveness of
      bupivacaine as a local analgesic agent following bone marrow harvest. During a
      single blinded randomised study of 24 bone marrow donors, 10 ml of 0.5%
      bupivacaine was infiltrated either into the right or left posterior iliac crest
      of the donor immediately following bone marrow harvest. Donors were requested to
      record the level of pain experienced at the right and left harvest sites on a
      pain rating score sheet (0-10) at time intervals of 4, 8, 12, 24, 48 and 72 h
      following harvest. A significant reduction in pain was experienced at the harvest
      site infiltrated with bupivacaine when compared with the control site during the
      first 3 days post-harvest. It is recommended that bupivacaine be infiltrated
      routinely into the harvest sites of all bone marrow donors to reduce the pain
      experienced in the 3 days following harvest.

PMID- 10338053
TI  - CD8+ cytotoxic T cell repertoire implicated in grafts-versus-leukemia effect in a
      murine bone marrow transplantation model.
AB  - In our model of murine BMT, the lethal GVHD which develops against DBA/2 host
      incompatible minor histocompatibility antigens (mHAgs) can be prevented by donor
      preimmunization before grafting. Recipient mice become long survivors (LS mice)
      and tolerant to host mHAgs. However, a GVL effect is preserved and mediated by
      CD8+ CTL able to kill P815 tumor cells in vitro and in vivo. To explain why a GVL
      exists without GVHD, we compared the CTL activity of LS and B10.D2 donor mice
      after immunization with DBA/2 spleen cells or with P815 cells. Experimental
      results indicated that: (1) the level of cytotoxicity for H-2b incompatible cells
      was similar in LS and B10.D2 mice; (2) CTL recognizing host DBA/2 mHAgs, whose
      expression is restricted to the spleen or is shared between spleen and P815
      cells, were partially unresponsive in LS mice; (3) P815 injection into LS mice
      predominantly generated CTL specific for antigens restricted to P815 cells, the
      repertoire of which was not tolerized. Characterization of TCR beta chain showed
      that the diversity of Vbeta and Jbeta usage by CD8+ T cells activated after P815
      injection is considerably restricted in LS mice, compared to B10.D2 donor mice.
      These results indicated that the GVL effect in LS mice involved mainly T cells
      specific for tissue-restricted antigens expressed on P815 cells and not on normal
      DBA/2 spleen cells. In addition, the absence of GVHD may be attributed to the
      unresponsiveness of CD8+ CTL specific for host mHAgs expressed on DBA/2 spleen
      cells.

PMID- 10338054
TI  - Cortical blindness and seizures in a patient receiving FK506 after bone marrow
      transplantation.
AB  - A 54-year-old woman with a myelodysplastic syndrome treated with high-dose
      chemotherapy and an allogenic bone marrow transplant developed acute cortical
      blindness while receiving tacrolimus (FK506). MRI showed white matter
      abnormalities. After discontinuation of FK506, the patient's vision returned
      within 8 days. FK506 neurotoxicity is similar to cyclosporine neurotoxicity and
      can occur in allogenic bone marrow transplant patients treated with FK506.

PMID- 10338055
TI  - Unilateral papilledema after bone marrow transplantation.
AB  - We describe a patient who developed unilateral papilledema after allogeneic BMT.
      This is a rare manifestation of pseudotumor cerebri, which results from elevated
      intracranial pressure caused by cyclosporin A. The papilledema usually involves
      the fundi bilaterally, but unilateral involvement has been described. Congenital
      anomalies, compression and adhesion of the optic nerve sheath are its causes. In
      this patient, the right optic fundus was spared although leukemic infiltration
      was present on this side and high-dose irradiation (72 Gy) was given. Although
      papilledema is a sensitive marker of elevated intracranial pressure, this sign
      may be masked by constriction of the optic sheath in patients who suffer from
      leukemic infiltration of the central nervous system and receive high doses of
      cranial irradiation.

PMID- 10338056
TI  - Rapid reversal of nephrotic syndrome due to primary systemic AL amyloidosis after
      VAD and subsequent high-dose chemotherapy with autologous stem cell support.
AB  - In a patient with nephrotic syndrome, renal biopsy revealed AL amyloid deposits.
      Monoclonal lambda light chains were identified in serum and urine. A low
      percentage of monoclonal plasma cells was detected in the bone marrow. The
      patient received four cycles of VAD and subsequent high-dose chemotherapy (HDCT)
      with melphalan (200 mg/m2) followed by autologous peripheral blood stem cell
      transplantation. Proteinuria rapidly diminished during chemotherapy. Three months
      after HDCT, the patient has no edema, and no signs of plasma cell dyscrasia are
      currently detectable. Using VAD before starting HDCT may improve the condition of
      patients with amyloidosis and reduce transplantation-related morbidity and
      mortality.

PMID- 10338057
TI  - Disseminated retinoblastoma successfully treated with myeloablative chemotherapy-
      implication for molecular detection of minimal residual disease.
AB  - A useful marker for detecting minimal residual disease (MRD) has not been
      established yet in retinoblastoma. We assessed neuroendocrine protein gene
      product 9.5 (PGP9.5) expression, one of the markers for detecting MRD in
      neuroblastoma, in a patient with disseminated retinoblastoma. A 3-year-old boy
      with disseminated retinoblastoma in multiple bones and marrow was referred to our
      hospital. He received intensive treatment and has maintained CR for 48 months
      following myeloablative chemotherapy with hematopoietic stem cell transplantation
      (SCT). PGP9.5 expression was serially assessed by RT-PCR in peripheral blood
      mononuclear cells (PBMC), bone marrow cells (BMC) and mobilized peripheral blood
      stem cells (PBSC). Initially, his BMC consisted of 96% tumor cells which were
      proved to express PGP9.5 by RT-PCR. Moreover, PBMC were found to be positive for
      PGP9.5 indicating the presence of tumor cells in the peripheral blood. After
      intensive chemotherapy, PGP9.5 expression became negative in both PBMC and BMC.
      Prior to SCT, PBSC and BMC transplants were confirmed negative for PGP9.5
      expression. It is suggested that PGP9.5 expression is a useful marker for
      evaluating therapeutic effects as well as detecting MRD in retinoblastoma.

PMID- 10338058
TI  - G-CSF-mobilized PBSCT in children with AML in first complete remission.

PMID- 10338059
TI  - Preterm labor, placental abruption, and premature rupture of membranes in
      relation to maternal violence or verbal abuse.
AB  - OBJECTIVE: The prevalence of preterm labor (PTL) in prenatal populations has been
      estimated to be from 6.9 to 10.0%. It has been suggested that violence during
      pregnancy may be associated with an increase in antenatal complications. The
      hypothesis is that physical violence and verbal abuse in pregnancy lead to
      increased risk of PTL. METHODS: A cohort of 636 women attending the Adult
      Obstetrical Clinic for their first prenatal visit, between December 1989 and
      September 1990, were approached; 567 women enlisted as study participants. Study
      participants were interviewed 3 times during the course of their prenatal care,
      and 401 participants successfully completed their third prenatal interviews.
      Violence data were obtained during the third interview. Obstetrical and neonatal
      outcome data were obtained by abstracting the maternal and neonatal medical
      records. RESULTS: When stratified by levels of violence, women who experienced
      moderate or severe violence had incidences of PTL of 15.4 and 17.2%,
      respectively. Chi-square test for homogeneity revealed a significant difference
      among these groups. CONCLUSIONS: In our cohort of women, serious acts of verbal
      abuse and physical violence occurred with significant frequency. PTL was strongly
      correlated with increasing acts of violence with 4.1 times greater risk of PTL in
      women who experienced severe violence as compared to those who experienced no
      maternal abuse.

PMID- 10338060
TI  - Maternal, but not fetal, administration of corticosteroids restricts fetal
      growth.
AB  - OBJECTIVE: Previous studies have shown that repeated doses of corticosteroids
      given to pregnant sheep improve postnatal lung function, but restrict fetal
      growth. Repeated administration of corticosteroids directly to the fetus also
      enhances postnatal lung function. The purpose of the present study was to
      investigate and characterize the relative effects on growth of repeated maternal
      and fetal treatments by study of body, organ, and placental weights. METHODS:
      Date-bred pregnant sheep were given intramuscular betamethasone or saline to
      either the mother or fetus on three occasions at weekly intervals commencing at
      104 days gestation, followed by cesarean section at 125 days. Twenty-two animals
      which had received three doses of betamethasone were compared with 21 which had
      received a single dose at 104 days and with 12 saline-treated controls. RESULTS:
      Repeated maternal doses of betamethasone resulted in reductions in birthweight
      and weights of the placenta and major organs. Direct fetal injection did not
      affect birthweight, placental weight, placental/ birthweight ratio, or weights of
      the major organs with the exception of the liver. CONCLUSIONS: Administration of
      repeated doses of betamethasone directly to the sheep fetus does not produce the
      growth-restricting effects induced by maternal administration and does not affect
      the placental/birthweight ratio.

PMID- 10338061
TI  - Maternal chorioamnionitis and umbilical vein interleukin-6 levels for identifying
      early neonatal sepsis.
AB  - OBJECTIVE: The purpose of this study was to determine whether elevated levels of
      umbilical vein IL-6 would be a better marker for early neonatal sepsis than the
      clinical signs of maternal chorioamnionitis. METHODS: Patients delivering preterm
      because of spontaneous preterm labor or premature rupture of the membranes were
      evaluated for clinical signs of chorioamnionitis, which was defined as a
      temperature of > or =100.4 degrees F along with > or =2 of the following:
      significant maternal tachycardia (> or = 120 bpm), fetal tachycardia (> or =160
      bpm), purulent discharge, uterine tenderness, and leukocytosis (WBC > or =18,000
      cells/mm3). Umbilical vein blood was assayed for interleukin-6. An elevated
      interleukin-6 level was determined to be 25 pg/mL. Infants were evaluated for
      evidence of early neonatal sepsis. The abilities of clinical chorioamnionitis and
      interleukin-6 levels > or =25 pg/mL to predict early neonatal sepsis were
      compared. RESULTS: There were 28 patients delivering 14 (50%) neonates with
      evidence for early neonatal sepsis. The incidence of suspected neonatal sepsis in
      women with and without clinical chorioamnionitis was 6/10 (60%) vs. 8/18 (44.4%),
      P = 0.43. Using receiver operator characteristic curves, the best cutoff for
      interleukin-6 was found to be 25 pg/mL. The compared sensitivity, specificity,
      and positive and negative predictive values of clinical chorioamnionitis vs.
      interleukin-6 levels > or =25 pg/mL for predicting early neonatal sepsis were
      42.9% vs. 92.9%, 71.4% vs. 92.9%, 60% vs. 92.9%, and 55.6% vs. 92.9%,
      respectively. CONCLUSIONS: Elevated umbilical vein levels of interleukin-6
      predict those preterm infants with early sepsis better than the presence of
      clinical chorioamnionitis.

PMID- 10338062
TI  - Serum calcium and parathormone during normal pregnancy in Malay women.
AB  - OBJECTIVE: To ascertain the calcium status in normal pregnant Malay women.
      METHODS: In a cross-sectional study, serum parathormone (PTH) and calcium
      concentrations, and 24-h urinary calcium excretion were estimated in age-matched
      normotensive pregnant women, over the 3 trimesters. RESULTS: No statistically
      significant differences were evident in serum ionised calcium concentrations
      between the pregnant women in the 3 trimesters. Serum total calcium however, was
      significantly lower in women in the 3rd trimester of pregnancy (2.29+/-0.16,
      2.26+/-0.13, and 2.16+/-0.12 mmol l(-1) in the 1st, 2nd, and 3rd trimesters,
      respectively; P < 0.001). Serum parathyroid hormone concentration was
      significantly higher in the 3rd trimester of pregnancy (3.37+/-3.31, 4.36+/-4.55,
      and 7.17+/-6.6 pg ml(-1) in the 1st, 2nd, and 3rd trimesters, respectively; P <
      0.05). No significant differences were evident in serum sodium and potassium
      concentrations between the 3 groups. Urinary calcium excretion was significantly
      lower in women in the 3rd trimester of pregnancy (3.41+/-1.80, 3.56+/-3.31, and
      2.46+/-1.71 mmol day(-1) in the 1st, 2nd, and in the 3rd trimesters,
      respectively; P < 0.05). No significant differences were evident in urine output,
      creatinine clearance, or in the excretion of sodium and potassium between the 3
      groups. CONCLUSIONS: It appears that a significant fall in serum total calcium
      occurs in the 2nd half of normal human pregnancy when there is also an increased
      fetal demand and perhaps also a relatively insufficient maternal intake and/or
      intestinal absorption. The lower urinary calcium excretion probably occurs
      secondary to this and may suggest a fall in total body calcium and an attempt by
      the body to conserve calcium. While under normal circumstances, this level of
      fall in total calcium may not be significant, the coincidence of occurrence of
      hypertensive disorders of pregnancy during this stage of pregnancy, and the
      evident link between low calcium intake and pregnancy-induced hypertension (PIH)
      and its possible amelioration with calcium supplementation, suggests a need to
      assess calcium status in pregnant women with a view to providing calcium
      supplementation during pregnancy.

PMID- 10338063
TI  - Acute fetal asphyxia and permanent brain injury: a retrospective analysis of
      current indicators.
AB  - OBJECTIVE: To determine whether a term neonate who has had sufficient intrapartum
      asphyxia to produce persistent brain injury will manifest the following four
      criteria: profound acidemia (arterial pH <7.00), an APGAR score < or =3 for 5 min
      or longer, seizures within 24 h of birth, and multiorgan system dysfunction.
      METHODS: Singleton, liveborn, neurologically impaired neonates > or =37 weeks
      gestation who lived at least 6 days and had sufficient documentation of current
      intrapartum asphyxia criteria were retrospectively analyzed. Of these infants,
      solely neonates with acute fetal asphyxia due to a sudden prolonged FHR
      deceleration that lasted until delivery from a catastrophic event, e.g., uterine
      rupture, cord prolapse, were included. Organ system dysfunction was defined by
      separate criteria for each organ system. Dysfunction in one or more was defined
      as multiorgan system dysfunction. RESULTS: Of the 292 eligible infants in the
      registry, 47 satisfied the entry criteria. In these 47 neonates, 10 (21%)
      satisfied all 4 criteria for intrapartum asphyxia. CONCLUSIONS: Our retrospective
      study suggests that currently used indicators to define permanent fetal brain
      injury are not valid.

PMID- 10338064
TI  - Hemodynamic concomitants of glycemia in diabetes mellitus: working hypothesis.
AB  - This report illustrates a working hypothesis that proposes a simple-to-use,
      noninvasive hemodynamic system to provide myocardial contractility and arterial
      compliance patterns that may be clinically useful adjuncts to insulin and
      glycemic measurements in diabetes mellitus. This proposition is based on the
      concept that biochemical cellular milieu may only obliquely predict cellular
      function, whereas in the biophysical domain, it may be more clearly delineated.

PMID- 10338066
TI  - Perinatal outcome of triplet gestation: does prophylactic cerclage make a
      difference?
AB  - OBJECTIVE: To compare the perinatal outcome of triplet gestations with and
      without prophylactic cerclage. METHODS: A retrospective chart review of all
      triplet gestations delivered between January 1988 and June 1997 was performed.
      Only women initiating prenatal care before 15 weeks gestation were included. The
      cerclage group was compared to the no-cerclage group for maternal and perinatal
      outcome variables. Student t-test, Chi-square, and Fisher's exact test were used
      for analysis. RESULTS: Twenty of the 59 (33.8%) sets of triplet gestations had
      prophylactic cerclage. There were no differences between groups when compared for
      maternal age, parity, preterm labor rate, gestational diabetes, anemia, antenatal
      steroid use, histologic chorioamnionitis, and postoperative endometritis. In
      addition, there were no differences in mean birth weight, Apgar scores,
      respiratory distress syndrome (RDS), intraventricular hemorrhage/periventricular
      leucomalacia (IVH/PVL), and neonatal mortality. Although the mean gestational age
      at delivery for the cerclage group (32.8+/-2.4 weeks) was not different from the
      no-cerclage group (31.5+/-3.6 weeks), the proportion of pregnancies delivered at
      31 weeks or more, and at 32 weeks or more, was significantly higher in the
      cerclage group (90 vs. 62%, P = .02; 80 vs. 54%, P = .05), respectively. In
      addition, the incidence of extremely low birth weight (LBW) was significantly
      decreased in the cerclage compared with the no-cerclage group (1.7 vs. 15.4%, P =
      .005). CONCLUSIONS: Prophylactic cerclage decreased significantly the incidence
      of extremely LBW neonates in triplet pregnancies. The proportion of neonates
      delivered at 31 weeks or more, and at 32 weeks or more was higher in the cerclage
      group.

PMID- 10338065
TI  - A double-blind randomized trial of two dose regimens of misoprostol for cervical
      ripening and labor induction.
AB  - OBJECTIVES: The objective of this study was to compare the efficacy and safety of
      two dosing regimens of misoprostol for cervical ripening and labor induction.
      METHODS: Patients who fulfilled the study criteria were randomized to received
      misoprostol 25 microg or 50 microg intravaginally every 3 h for a total of eight
      doses for cervical ripening or until labor was established. Endpoints for
      successful cervical ripening was achievement of Bishop score of nine or greater,
      and for labor induction reaching the active phase of labor in the first 24 h. The
      rates of success, duration of first and second stages of labor, type of delivery,
      significant side effects, and neonatal outcome were measured and compared between
      the two study groups. Two hundred and fifty-one patients were randomized in two
      groups--126 received 50 microg and 125 received 25 microg misoprostol.
      Demographics of the two study groups were similar. RESULTS: Patients in the 50
      microg group had a shorter first stage (848 min vs. 1,122 min, P < 0.007),
      shorter induction-to-vaginal delivery interval (933 min vs. 1,194 min, P <
      0.013), decreased incidence of oxytocin augmentation (53.9% vs. 68%, P < 0.015),
      and decreased total units of oxytocin (2,763 mU vs. 5,236 mU, P < 0.023), but
      there was a higher hyperstimulation rate (19% vs. 7.2%, P < 0.005). CONCLUSIONS:
      Successful induction rate, delivery types, and fetal outcome were similar in both
      groups. Although the rate of vaginal delivery and neonatal outcome were similar
      in both groups, the 50 microg regimen had shorter first and second stages of
      labor, and a higher hyperstimulation rate that was easily manageable, allowing
      for flexibility in using the higher dose in low-risk pregnancies.

PMID- 10338067
TI  - Human and ovine amniotic fluid composition differences: implications for fluid
      dynamics.
AB  - OBJECTIVE: The ovine model is frequently utilized to extrapolate data regarding
      fetal and amniotic fluid dynamics to human pregnancy. The ovine amnion is highly
      vascularized, facilitating intramembranous exchange of water and solutes between
      the amniotic fluid and fetal plasma. In comparison, the relatively avascular
      human amniotic membrane may have a reduced potential for intramembranous
      absorption. In view of these anatomical differences, we hypothesized that
      comparison of human and ovine amniotic fluid composition would provide insight
      into differences in the mechanisms of amniotic fluid exchange. METHODS: Amniotic
      fluid was sampled from 43 patients upon hospital admission, and from 27 ovine
      ewes at five days following amniotic fluid catheter placement. Both human (32 to
      39 weeks' gestation) and ovine pregnancies (125 to 136 days' gestation) were
      sampled during the last 20% of gestation. Samples were analyzed for osmolality
      and sodium, potassium and chloride concentrations. The contribution of
      electrolytes to amniotic fluid osmolality and changes in osmolality and
      electrolyte composition versus gestational age were assessed by regression and
      covariance analysis. RESULTS: Mean (+/-SEM) amniotic fluid sodium concentration
      (134.6+/-1.9 vs. 127.1+/-2.0 mEq/1) was greater and potassium (4.6+/-0.1 vs.
      6.1+/-0.6 mEq/l) and osmolality (263.9+/-3.7 vs. 285.1+/-1.6 mOsm/kg) less in
      human than sheep. The range of amniotic fluid osmolality was greater in human
      (223 to 336 mOsm/kg) than in sheep (274 to 298 mOsm/kg). Human amniotic fluid
      osmolality was highly correlated with amniotic fluid sodium (r = 0.97) and
      chloride (r = 0.96) while ovine amniotic fluid osmolality was only weakly
      correlated with amniotic fluid sodium (r = 0.75) and chloride (r = 0.51). The
      slope of the regression line of amniotic fluid sodium and osmolality was greater
      for human than for sheep amniotic fluid (P < 0.0001). The percent of amniotic
      fluid osmolality accounted for by sodium, chloride and potassium concentrations
      was greater for human (97%) than for sheep (86%; P < 0.0001). CONCLUSIONS: The
      results suggest that human amniotic fluid osmolality is comprised almost entirely
      of the major electrolytes while alternative solutes (e.g., fructose) contribute
      to ovine amniotic fluid osmolality. Extrapolation of fetal and amniotic fluid
      dynamics from ovine models to humans should incorporate differences in amniotic
      fluid osmolality and electrolyte composition.

PMID- 10338068
TI  - Perinatally acquired Chlamydia trachomatis associated morbidity in young infants.
AB  - OBJECTIVE: This study was designed to evaluate the spectrum of morbidity
      associated with perinatally acquired Chlamydia trachomatis in infants < or =12
      weeks of age, and to determine its relationship to maternal Chlamydia trachomatis
      status. METHODS:  DESIGN: Retrospective review of maternal and infant records.
      SETTING: Large inner city teaching hospital. PATIENTS: A cohort of 530
      symptomatic infants < or =12 weeks of age who were tested for Chlamydia
      trachomatis infection in the upper respiratory tract during a 2-year period from
      January 1993 to December 1994. RESULTS: During the study period, 70/530 (13.2%)
      patients tested positive for Chlamydia trachomatis from the conjunctiva and/or
      the nasopharynx. Complete medical records of 66 of these infants were available
      for review. Forty-eight of 66 (73%) infants had conjunctivitis, 13/66 (20%) had
      pneumonia, 5/66 (7%) had both conjunctivitis and pneumonia. Thirteen of 66 (20%)
      infants were hospitalized, 7 for pneumonia and 6 for ophthalmia, accounting for
      68 hospital days. In 55/66 (83%), maternal records were available for review.
      Nineteen of 55 (35%) mothers had documented Chlamydia trachomatis infection at
      delivery or during pregnancy that had not been treated; 16/55 (29%) mothers
      tested negative for Chlamydia trachomatis sometime during pregnancy but were not
      retested at delivery, 8/55 (14%) were treated for Chlamydia trachomatis during
      pregnancy but status at delivery regarding reinfection was not evaluated. In
      12/55 (22%) mothers, no prenatal testing was documented. CONCLUSIONS: This study
      demonstrates significant morbidity in early infancy associated with perinatally
      acquired Chlamydia trachomatis infection. There is need for studies evaluating
      the importance of adequate maternal testing and treatment to reduce perinatal
      transmission.

PMID- 10338069
TI  - Is knowledge of health behavior associated with low birth weight?
AB  - OBJECTIVE: To examine the relationship of patient knowledge concerning seven
      health behaviors identified by the U.S. Public Health Service Expert Panel and
      low birth weight. METHODS: Interviews of 538 women delivering at an inner-city
      hospital in New Orleans were conducted. Information concerning patient
      characteristics, health behavior knowledge, and birth weight was collected. Data
      were analyzed as dichotomous and compared using odds ratios. Logistic regression
      was chosen to calculate adjusted odds ratios, including only factors found to be
      associated with the tested end point, low birth weight. RESULTS: A majority of
      women knew all seven health behavior items. Individual items were known by > or
      =80% of respondents. Knowledge associated with low birth weight included
      avoidance of alcohol and drugs, taking of prenatal vitamins, and following a
      proper diet. Information on all seven was not associated with a reduction in low
      birth weight. Other factors found to be associated with low birth weight included
      inadequate prenatal care, absence of health insurance (primarily Medicaid), and a
      prior low birth weight infant. Logistic regression confirmed both the importance
      of the last three factors, and the lack of association with health knowledge
      about all seven items. CONCLUSIONS: Knowledge concerning health advice behavior
      recommended by the U.S. Public Health Service was more widely known than
      previously thought. While individual components were associated with a reduction
      in low birth weight, overall knowledge was not.

PMID- 10338070
TI  - Pneumocephalus following inadvertent intrathecal puncture during epidural
      anesthesia: a case report and review of the literature.
AB  - Regional anesthesia techniques (epidural and spinal) are preferred anesthetic
      modalities in modern obstetrics, in that both of these modalities enable maternal
      participation in the delivery process and assist in avoiding maternal aspiration
      associated with general anesthesia. We report an unusual and potentially severe
      complication of epidural anesthesia for elective repeat cesarean delivery.
      Following intravenous hydration and lateral uterine displacement, uneventful
      epidural anesthesia was administered. Toward the end of the otherwise uneventful
      cesarean the patient, who had been completely stable, became unresponsive, with
      dilated pupils that did not respond to light. The patient was immediately
      intubated and gradually regained consciousness and was extubated within 1 h.
      Cranial computed tomography disclosed pneumocephalus. Inadvertent pneumocephalus
      is reviewed.

PMID- 10338072
TI  - Determination of estrogen receptor in primary breast cancer using two different
      monoclonal antibodies, and correlation with its mRNA expression.
AB  - Estrogen receptor (ER) protein status was investigated in the MCF-7 cell line and
      70 invasive ductal carcinomas of the breast. This was achieved by
      immunohistochemical assay (IHA) using two different monoclonal antibodies (ER-1D5
      and AER311), which are able to recognize either the amino or carboxyl terminal.
      The staining results were assessed in terms of index score, and compared with the
      ERalpha mRNA expression, which was determined by reverse transcription-polymerase
      chain reaction for the positions of exons 5 and 7. MCF-7 showed similar
      immunoreactions with both antibodies, and expressed the wild-type (WT) ER mRNA
      coexpressing deletions of exons 5 and 7. Although there was a significant
      difference between the ER-1 D5 and AER311 indices in the tissue samples (20.5 +/-
      27.2 and 5.7 +/- 16.4; P < 0.001), in the majority of cases ER mRNA expression
      patterns were similar to that of MCF-7, and WT ER mRNA was expressed in all cases
      that yielded PCR products. It was concluded that a number of palpable breast
      cancers lack the carboxyl terminal of the ER protein, regardless of WT ER mRNA
      expression. These results suggest that the incidence of WT ER mRNA in such
      cancers is lower than that in the MCF-7 cell line, or that WT ER is less stable.

PMID- 10338073
TI  - Obesity affects expression of progesterone receptors and node metastasis of
      mammary carcinomas in postmenopausal women without a family history.
AB  - Possible relationships between risk factors, such as obesity and a family history
      of breast cancer, and prognostic factors of mammary carcinomas were investigated
      by examining the body mass index of patients and the expression of estrogen (ER)
      and progesterone receptors (PgR), c-erbB-2 and p53, grade of histology, size of
      tumors and nodal status of mammary carcinomas. There was no significant
      difference in the body mass index of premenopausal patients either with or
      without a family history. For postmenopausal patients, the body mass index was
      significantly low in patients with a family history compared with patients
      without a family history. In premenopausal patients with or without a family
      history and in postmenopausal patients with a family history, there was no
      significant difference in the body mass index regardless of the mammary carcinoma
      prognostic factor, such as expression of ER, PgR, c-erbB-2 and p53, grade of
      histology, size of tumors and nodal status. However, in postmenopausal patients
      without a family history, body mass index was significantly high for patients
      with mammary carcinomas that had PgR expression and node metastasis. These
      results suggest that obesity may affect the PgR status and nodal status of
      mammary carcinomas in postmenopausal patients without a family history.

PMID- 10338071
TI  - Use of recombinant human erythropoietin (EPO-alfa) in a mother alloimmunized to
      the Js(b) antigen.
AB  - Erythropoietin (EPO) is a glycoprotein hormone and the principal regulator of
      erythropoiesis in the fetus, newborn, and adult. EPO-alfa is erythropoietin
      manufactured by recombinant human DNA technology (rhEPO). After counseling, a
      pregnant woman with anti-Js(b) in her serum was started on rhEPO (600 U/Kg,
      biweekly) to prevent anemia secondary to serial donations of her blood for fetal
      transfusions. After a total of 25 rhEPO infusions and autologous donation of 8
      units of whole blood, maternal hemoglobin prior to the elective cesarean section
      at 37 weeks was 11.3 gm/dL. Serum EPO concentration was determined in paired
      maternal and fetal blood samples, before ultrasound guided intravascular
      transfusions, in this alloimmunized Js(b)-negative and another Rh(D)
      alloimmunized pregnancy to determine possible correlations between maternal and
      fetal serum EPO. rhEPO prevented anemia in a patient who donated 8 units of blood
      from 18-37 weeks of pregnancy without inducing adverse biological effects such as
      hypertension or thrombotic complications in the placenta. Data presented in this
      study suggest that EPO does not cross the human placenta.

PMID- 10338074
TI  - Expression of pepsinogen II with androgen and estrogen receptors in human
      prostate carcinoma.
AB  - The expression of pepsinogen II (PG II), an aspartyl proteinase usually involved
      in the digestion of proteins in the stomach, was immunohistochemically
      investigated in conjunction with androgen (AR) and estrogen receptor (ER) status
      in prostate adenocarcinomas. Of a total of 38 samples obtained from radical
      prostatectomies, 23 tumors (60.5%) were positive for PG II and there was a
      significant positive correlation to the expression of AR but not to ER. Cells
      positive for PG II were localized mainly to the peripheral zones of tumorous
      glands which, in normal prostate, are negative, and in areas also expressing AR.
      In addition, a significant correlation between AR and ER was detected in the
      prostate carcinomas examined, which suggests a hormone-dependent status. On the
      basis of these results, PG II expression might be closely related to hormonal
      alterations associated with the development of prostate tumors.

PMID- 10338075
TI  - Interstitial invasion of well-differentiated hepatocellular carcinoma and
      subsequent tumor growth.
AB  - Pathological processes of interstitial invasion of hepatocellular carcinoma (HCC)
      were investigated in 125 autopsy and seven surgical cases, where selection
      focused on those occurring in well-differentiated HCC. The invasive pattern of
      well-differentiated HCC was characterized by the formation of streaks of tumor
      cell cords running along connective tissue fibers, referred to as a streak
      pattern. These cell cords were unaccompanied by reticulin frameworks and type IV
      collagen, which are consistent components of HCC parenchyma. The typical streak
      pattern was observed only in HCC cases and could be useful in differential
      diagnosis. Following progressive accumulation or proliferation of the tumor cells
      within the interstitium, many capillaries appeared between the cell cords while
      collagen fibers tended to disappear. The tumor cell cords then showed branching
      and were accompanied by reticulin frameworks, type IV collagen and sinusoidal
      blood spaces. In the setting of interstitial invasion of well-differentiated HCC,
      it is suggested that interstitial tissue is converted into HCC parenchyma via the
      aforementioned steps.

PMID- 10338076
TI  - P53 and proliferating cell nuclear antigen (PCNA) expression in non-tumoral liver
      diseases.
AB  - The tumor suppressor gene p53 is known to be involved in the negative regulation
      of cell growth. Proliferating cell nuclear antigen (PCNA), which is a nuclear
      protein and a component of the DNA replication process, is also involved in
      growth regulation. Both have been studied as progression markers in various
      tumors including hepatocellular carcinoma. In the present study, the aberrant p53
      protein and PCNA expressions in non-tumoral liver diseases were investigated.
      Using monoclonal antibodies anti-p53 (D07-DAKO) and anti-PCNA (PC10-DAKO), 149
      samples were stained, including 10 normal and 10 tumoral control liver tissues.
      p53 Overexpression was detected in 52 specimens (35%) whereas PCNA positivity was
      found in 96 (64%). There were 21 different pathological entities but most of the
      positive samples could be grouped into four types of diseases; namely, non
      specific reactive hepatitis, steatohepatitis, chronic hepatitis and cirrhosis.
      Statistical analyses performed on these groups revealed that p53 positivity was
      found to be significantly higher in steatohepatitis (P < 0.05), while PCNA
      positivity did not show any statistical significance. The number of samples
      showing both p53 and PCNA positivity was 42 but their coexistence was not found
      to be significant. Certain cytological alterations like nuclear pleomorphism,
      steatosis and cholestasis, in addition to necroinflammatory activity, were
      evaluated for their possible impact on p53 and/or PCNA positivity.
      Necroinflammatory activity in steatohepatitis and steatosis in chronic hepatitis
      was found to be significant for p53 positivity (P < 0.05). In contrast, nuclear
      pleomorphism in non-specific reactive hepatitis was found to be significant for
      PCNA positivity (P < 0.05).

PMID- 10338077
TI  - Multiple pulmonary leiomyomatous hamartoma with secondary ossification.
AB  - A 31-year-old woman presented with multiple pulmonary leiomyomatous hamartoma
      (MPLH) with secondary ossification. She had a past history of parosteal
      osteosarcoma. The pulmonary lesions were composed of spindle-shaped cells
      arranged in interlacing fascicles, among which glands or duct-like spaces were
      scattered. As some lesions contained bony tissues, it was unclear whether or not
      the pulmonary lesions were metastases of parosteal osteosarcoma. However, the
      majority of spindle-shaped cells were positive for alpha-smooth muscle actin,
      including cells proliferating around the bony tissues. Clonality analysis using a
      target of human androgen receptor (HUMARA) gene disclosed that the pulmonary
      nodules were polyclonal. These findings do not indicate that the lesions were
      metastatic. We would like to emphasize that MPLH can show osseous metaplasia.

PMID- 10338078
TI  - Infantile disseminated visceral giant cell arteritis presenting as sudden infant
      death.
AB  - The rare clinicopathological entity 'disseminated visceral giant cell arteritis'
      (DVGCA) was first described in 1978. It is characterized by widespread small
      vessel giant cell angitis and extravascular granulomas. A normal and healthy 7
      month-old boy who presented unexpectedly with sudden infant death syndrome (SIDS)
      is reported. Histological examination at autopsy revealed giant cell angitis of
      the aorta, common carotid, coronary, pulmonary, celiac, mesenteric and common
      iliac arteries. There were also granulomas in the tracheal wall and liver. To our
      knowledge, this is the first documented case of DVGCA occurring in an infant
      younger than 12 months of age. A review of the literature on DVGCA is presented
      in this report, and the differential diagnosis is discussed.

PMID- 10338079
TI  - Solid-pseudopapillary carcinoma of the pancreas.
AB  - A case of solid-pseudopapillary carcinoma (SPC) of the pancreas in a 34-year-old
      Japanese woman is presented. An abdominal ultrasonography revealed a mass, which
      measured 10 cm in diameter, in the body and tail of the pancreas. The tumor was
      resected and it was originally diagnosed as a non-functioning islet cell tumor.
      One year and five months later, the patient was re-admitted to hospital, and
      liver metastasis was confirmed by ultrasonography. The patient died 6 days after
      the second transcatheter arterial embolization (TAE) required for the metastasis.
      The autopsy showed small foci of liver metastasis. A retrospective examination of
      the tumor suggested the diagnosis of SPC because of its characteristic solid and
      pseudopapillary structures, immunohistochemical findings, and liver metastasis.
      This case suggests that capsular invasion, specifically found at the surgical
      margin of the peritoneal side, may be an important pathological finding that is
      suggestive of malignant potential in solid-pseudopapillary tumor. If there is
      such a finding in a surgical specimen, an intensive follow up should be advised
      to the clinician.

PMID- 10338080
TI  - Renal adenomatosis associated with carcinoma of the lower urinary tract: a case
      report with immunohistochemical study.
AB  - A case of renal adenomatosis of the left kidney associated with a carcinoma of
      the ipsilateral ureter in a 49-year-old man is examined. One hundred and eight
      adenomas, which were smaller than 15 mm in diameter, and a single microcarcinoma,
      which measured 1 mm in diameter, were found in the kidney. Further, there were
      more than 800 hyperplastic lesions which could be classified into three groups:
      (i) 792 of distal origin; (ii) 24 of proximal origin; and 10 of collecting duct
      origin. The serial sections obtained from 19 paraffin blocks were stained using
      Leu M1 as the proximal marker and epithelial membrane antigen (EMA) as the
      distal/collecting marker to assist in determining the origins. Ten of the small
      adenomas (15 lesions), which did not exceed 3 mm in diameter, were predominantly
      positive for EMA and five were predominantly positive for Leu M1. Further,
      hyperplastic lesions of distal and collecting duct origins were diffusely
      positive for EMA and sporadically positive for Leu M1. The lesions of proximal
      origin were predominantly positive for Leu M1 and sporadically positive for EMA.
      These findings suggest that a progression from hyperplasia and a direct
      transition from a single tubule to adenoma occurred multifocally in different
      segments of the nephrons throughout the left kidney.

PMID- 10338081
TI  - A case of natural killer/T cell lymphoma of the subcutis resembling subcutaneous
      panniculitis-like T cell lymphoma.
AB  - A case of nasal type natural killer (NK)/T cell lymphoma of the subcutis showing
      clinical and morphological features that resemble subcutaneous panniculitis-like
      T cell lymphoma (SPTCL) is presented. A 73-year-old man presented with swelling
      of the left arm and was diagnosed with panniculitis by a dermatologist. It was
      concluded from a skin biopsy specimen that the patient had non-Hodgkin's lymphoma
      of the large cell, NK/T cell type because the neoplastic cells showed polyclonal
      CD3 immunoreactivity. Treatment with interferon-gamma was initiated, but the
      patient died of disseminated intravascular coagulation and multiple organ failure
      2 months after the initial symptoms appeared. However, involvement of additional
      organs by the lymphoma was not apparent clinically. An autopsy was not performed.
      A routinely stained section of the biopsy skin specimen revealed massive necrosis
      of the subcutaneous fat, karyorrhexis admixed with reactive histiocytes, and
      large atypical lymphoid cells. Immunoreactivity for polyclonal CD3 was present in
      the perinuclear region, but absent in the neoplastic cell membranes. CD56, CD45RO
      (UCHL-1), CD43 (MT1), CD45 (leukocyte common antigen), and the cytotoxic
      molecules perforin, granzyme B and TIA-1 were positive, but CD20 (L26), CD4, CD8,
      and betaF1 were negative. Epstein-Barr virus (EBV) mRNA was detected in the
      nuclei of neoplastic cells by in situ hybridization. Subcutaneous panniculitis
      like T cell lymphoma is reported to be an EBV-negative, clonal T cell neoplasm.
      Although this case showed clinical and morphological features that resembled
      SPTCL, perinuclear polyclonal CD3 staining and membranous CD56 reactivity seen in
      neoplastic cells were suggestive of NK cells. Furthermore, the neoplastic cells
      were positive for EBV. This case is considered to be a NK/T cell lymphoma of the
      subcutis resembling SPTCL. It is believed that it is important to recognize such
      a tumor because patients may undergo a fulminant clinical course, despite the
      tumor being localized in the subcutaneous adipose tissue.

PMID- 10338082
TI  - Small cell type malignant melanoma which developed in a 16-year-old female with a
      congenital dermal nevus and metastasized 12 years after excision.
AB  - A case of malignant melanoma arising from a congenital dermal nevus on the right
      forehead of a 16-year-old female is presented. In the mole, small pigmented
      nevoid cells gathered around the skin appendages and between the collagen fibers.
      From the age of 17, a verrucous nevoid melanoma consisting of lymphoblast-like
      large nevoid cells, which were positive for HMB-45 and had a high Ki-67 index up
      to 18.7%, gradually increased in size. The melanoma cells vertically invaded the
      dermis to a depth of 3 mm and radially spread in the papillary dermis. Twelve
      years after undergoing a wide local resection and additional chemotherapy,
      metastatic lesions were found in the lung and the anterior mediastinum, which
      gradually increased in size and caused death a few months later. Metastatic
      melanoma cells were positive for HMB-45 and had a high Ki-67 index up to 33.7%.
      Most metastatic melanoma cells were positive for p53 while the primary ones were
      negative. Deteriorating mutations probably accumulated during the latent period.

PMID- 10338083
TI  - Primary liver carcinoma complicating membranous obstruction of the inferior vena
      cava.
AB  - A rare autopsy case of primary liver carcinoma complicating a pre-existing,
      incomplete membranous obstruction of the inferior vena cava (MOVC) is reported.
      The patient, a 67-year-old Japanese male, was admitted to hospital following a 2
      year illness of a left chest wall tumor and a 3 month illness with progressive
      abdominal pain. Computed tomography scans of the abdomen displayed space
      occupying lesions in the third and seventh hepatic segments, respectively. One
      month later, the patient developed edema of the lower extremities and marked
      venous dilatation of the abdominal trunk. At that time, Doppler examination
      revealed the presence of intrahepatic large venovenous collaterals. The patient
      subsequently succumbed 82 days after hospitalization. At subsequent autopsy, the
      inferior vena cava was completely obstructed by tumor thrombus, which was formed
      caudally and cranially to a thin membrane and mimicked the valve, with
      calcification and elastic lamina, at the phrenic portion. Intrahepatic large
      collateral pathways were found between submembranous and supramembranous hepatic
      veins. Anomalous absence of the ostia of the middle hepatic vein was found. In
      addition, the portal venous trunk was occluded by tumor thrombus. Histology of
      hepatic tumors revealed a combined hepatocellular and cholangiocellular carcinoma
      in the non-cirrhotic liver with severe acute centrilobular congestion. In MOVC
      patients such as the case presented, malignancy-induced thrombosis was deemed to
      be an important factor in prognosis.

PMID- 10338084
TI  - Extracranial metastasis of anaplastic ganglioglioma through a
      ventriculoperitoneal shunt: a case report.
AB  - Extracranial metastasis of an intracranial anaplastic ganglioglioma through a
      ventriculoperitoneal shunt is reported. A 53-year-old woman was treated by
      surgery, radiation and chemotherapy and died 2 years later. At autopsy, multiple
      metastatic lesions were found in the spinal cord, and the abdominal and pleural
      cavities. Histologically, all the metastatic lesions were composed of atypical
      cells which resembled primitive glial elements found in intracranial anaplastic
      ganglioglioma, suggesting that anaplastic glial elements have a metastatic
      potential. Extracranial metastasis of ganglioglioma is a rare occurrence;
      however, the spread of glial elements through the shunt further suggests that
      caution is required in therapy and indicates a need for protective filters in the
      shunt system.

PMID- 10338085
TI  - Dipeptidyl peptidase IV (DPP IV/CD26) staining predicts distant metastasis of
      'benign' thyroid tumor.
AB  - Because follicular thyroid carcinoma is extremely difficult to diagnose, several
      cases were encountered which have been rediagnosed as carcinoma due to distant
      metastasis. In the search for a method of correctly diagnosing 'benign' thyroid
      tumor, dipeptidyl peptidase (DPP) IV immunostaining was applied to 10 cases whose
      diagnoses had been corrected to follicular thyroid carcinoma because of distant
      metastases. The positive rate of immunostaining using paraffin sections in the
      rediagnosed follicular thyroid carcinoma group (7/10) was much higher than that
      of the control group (1/29), which consisted of 15 cases of follicular thyroid
      adenoma and 14 cases of nodular hyperplasia. These results suggested that pre- or
      postoperative DPP IV staining is useful for predicting distant metastasis of
      'benign' thyroid tumor.

PMID- 10338086
TI  - A peculiar Factor VIII-related antigen staining of an oxyphilic cell nodule
      within an intrathyroidal parathyroid adenoma.
AB  - A case of intrathyroidal parathyroid adenoma, which was found in the lower
      portion of the right thyroid lobe, is presented. The nodule in this lesion was
      composed of oxyphilic cells. In order to verify a possible vascular invasion,
      immunohistochemical study with Factor VIII-related antigen/von Willebrand factor,
      which is known to be synthesized by the endothelial cells and stored in Weibel
      Palade bodies, and ulex europaeus lectin 1 were applied. It was interesting to
      find positivity for Factor VIII-related antigen and ulex europaeus lectin I
      strictly confined in the nodule of oxyphil cells, which are known to have large
      numbers of mitochondria. This led to investigating similar immunoreactions in
      different lesions of oxyphilic cells with several other markers. The possible
      cross-reaction between Weibel-Palade bodies and mitochondria deserves further
      detailed research.

PMID- 10338087
TI  - Asiatic Center of Pathology as a basis of progress of Asiatic pathology in the
      future.
AB  - Nowadays in the Asian continent the necessary conditions seem ripe for the
      creation of an Asiatic Center for Pathology which could function as a 'brain'
      center and, at the same time, be an office of the Asian continent's pathologists.
      The process of organizing the Asiatic Center for Pathology is proposed in the
      form of brief outlines and considerations for scrutiny and analysis to be
      followed by a thorough discussion. The creation of such an Asiatic Center for
      Pathology, which would have no counterpart in the world's pathoanatomical
      practice, will undoubtedly be a powerful breakthrough in Asiatic pathology.

PMID- 10338088
TI  - Guidelines and recommendations for content, structure, and deployment of mutation
      databases.
AB  - These Guidelines recognize the need for annotated online mutation databases
      documenting allelic variation (both pathogenic and phenotype modifying, and also
      neutral polymorphic); the databases will be both generalized (genomic) and
      specialized (locus specific), and a seamless integration of the two types is
      intended. Each requires a Document (its "biography"). Different mutation
      databases will have different content and structure, but a minimum core of
      content in a shared syntax is a necessity; the core includes: (1) a unique
      identifier of the allele; (2) the source/report of the data; (3) context of the
      allele; and (4) the allele itself (the description). The allele description
      should be validated. There is no single correct way to design a mutation
      database. The uses to which databases are put dictate the design. Software and
      deployment together recognize the different needs of specialized and generalized
      databases, while making them mutually compatible through shared content and the
      appropriate search facilities. A set of eight Recommendations completes these
      Guidelines for Content, Design, and Deployment of Mutation Databases.

PMID- 10338089
TI  - Congenital hyperinsulinism: molecular basis of a heterogeneous disease.
AB  - Congenital hyperinsulinism (CHI) is a disease phenotype characterized by
      increased, usually irregular, insulin secretion leading to hypoglycemia, coma,
      and severe brain damage, left untreated. Hyperinsulinism may be caused by a range
      of biochemical disturbances and molecular defects. In pancreatic beta cells,
      insulin secretion is stimulated by closure of the ATP-dependent potassium channel
      (K(ATP) channel). K(ATP) channel is a complex composed of at least two subunits:
      the sulfonylurea receptor SUR1 and Kir6.2, an inward rectifier K+ channel member.
      Mutations in both subunits have been identified in patients with the autosomal
      recessive form of hyperinsulinism, including 28 different mutations in the SUR1
      gene and two mutations in the Kir6.2 gene. These mutations co-segregated with
      disease phenotype, also known as persistent hyperinsulinemic hypoglycemia of
      infancy (PHHI), and with attenuated K(ATP) channel function. Inadequately high
      insulin secretion in one family with an autosomal dominant mode of inheritance is
      caused by a mutation in the glucokinase gene, resulting in increased affinity of
      the enzyme for glucose. Five different mutations have been identified in the
      glutamate dehydrogenase gene, resulting in overactivity of this enzyme and
      causing a syndrome of hyperinsulinism and hyperammonemia. In 13 cases,
      hyperinsulinism was caused by one or more focal pancreatic lesions with specific
      loss of maternal alleles of the imprinted chromosome region 11p15. In five
      patients, this loss of heterozygosity unmasked a paternally inherited recessive
      SUR1 mutation. The new molecular approaches in PHHI give further insight into the
      mechanism of pancreatic beta cell insulin secretion. The heterogeneous group of
      patients with CHI may now be classified according to their basic defects in the
      four different genes, with potential implications for a more specific treatment.

PMID- 10338090
TI  - Cystathionine beta-synthase mutations in homocystinuria.
AB  - The major cause of homocystinuria is mutation of the gene encoding the enzyme
      cystathionine beta-synthase (CBS). Deficiency of CBS activity results in elevated
      levels of homocysteine as well as methionine in plasma and urine and decreased
      levels of cystathionine and cysteine. Ninety-two different disease-associated
      mutations have been identified in the CBS gene in 310 examined homocystinuric
      alleles in more than a dozen laboratories around the world. Most of these
      mutations are missense, and the vast majority of these are private mutations. The
      two most frequently encountered of these mutations are the pyridoxine-responsive
      I278T and the pyridoxine-nonresponsive G307S. Mutations due to deaminations of
      methylcytosines represent 53% of all point substitutions in the coding region of
      the CBS gene.

PMID- 10338091
TI  - Two novel mutations of the FMO3 gene in a proband with trimethylaminuria.
AB  - The mammalian flavin-containing monooxygenases catalyze the NADPH-dependent N
      oxygenation of nucleophilic nitrogen-, sulfur-, and phosphorus-containing
      chemicals, drugs, and xenobiotics, including trimethylamine. The FMO3 gene
      encodes the dominant catalytically active isoform present in human liver. We have
      identified two missense mutations in the coding region of the gene in a proband
      with trimethylaminuria (TMA): M66I and R492W. Whereas two mutations (P153L,
      E305X) accounted for TMA in our eight unrelated previously documented Australian
      families of British origin, the present report is the first evidence of compound
      heterozygosity for two rare mutations in a proband with this disorder. This
      suggests that other rarer alleles, also causing TMA, will be found in the same
      populations.

PMID- 10338092
TI  - Molecular genetic study of Pompe disease in Chinese patients in Taiwan.
AB  - Pompe disease is caused by mutations in the acid alpha-glucosidase (GAA) gene.
      Multiple kinds of mutations in the GAA gene have been reported worldwide. In
      order to elucidate the molecular basis of the disease in Taiwanese patients of
      Chinese origin, we have recruited 11 unrelated families who had at least one
      member with Pompe disease for study. We used 16 pairs of oligonucleotide primers
      to amplify all the coding regions from exon 2 to 20 in the family members. The
      coding regions were sequenced on both the sense and antisense strands. We
      identified 7 different mutations in 17 alleles but failed to identify the defects
      in the other 5 alleles. The most common defect was D645E (Asp645Glu), accounting
      for 36% (8/22 alleles) of mutations, followed by G615R (Gly615Arg) (3 alleles);
      1411del4 (Glu471-shift) (2 alleles); and one allele each of R600H (Arg600His);
      deltaN675 (deltaAsn675); 2380delC (Arg794-shift) and 2815delGT (Val939-shift).
      The molecular defects of Pompe disease are highly heterogeneous in Chinese.
      Characterization of the molecular defects of the disease is useful for a genotype
      phenotype correlation and for genetic counseling and prenatal diagnosis.

PMID- 10338093
TI  - Genetic diagnosis of 21-hydroxylase deficiency: DGGE-based mutation scanning of
      CYP21.
AB  - Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is caused
      by mutations in the gene CYP21 encoding the enzyme steroid 21-hydroxylase. In
      addition to deletions, approximately 20 different point mutations have been
      reported, and still novel mutations are detected. This makes genetic diagnosis as
      well as carrier detection of 21-hydroxylase deficiency a complicated matter. We
      developed a simple nonradioactive assay based on the polymerase chain reaction
      (PCR) in combination with denaturing gradient gel electrophoresis (DGGE) to
      screen for mutations in the CYP21 gene. DGGE allows a fast scanning of PCR
      amplified segments of genes for the presence or absence of any single base pair
      alterations. We have performed this technique on the coding sequence and intron
      exon junctions of CYP21. Our results emphasize that this procedure constitutes a
      fast and reliable approach when performing diagnosis of 21-hydroxylase
      deficiency.

PMID- 10338094
TI  - Detection of the deltaF508 (F508del) mutation of the cystic fibrosis gene by
      surface plasmon resonance and biosensor technology.
AB  - In the present paper, we applied surface plasmon resonance (SPR) and biosensor
      technologies for biospecific interaction analysis (BIA) to detect deltaF508
      mutation (F508del) of the cystic fibrosis transmembrane regulator (CFTR) gene in
      both homozygous as well as heterozygous human subjects. The proposed method is
      divided into three major steps. The first step is the immobilization on a SA5
      sensor chip of two biotinylated oligonucleotide probes (one normal, N-508, and
      the other mutant, deltaF508) that are able to hybridize to the CFTR gene region
      involved in F508del mutation. The second step consists of the molecular
      hybridization between the oligonucleotide probes immobilized on the sensor chips
      and (1) wild-type or mutant oligonucleotides, as well as (2) single-stranded DNA
      obtained by asymmetric polymerase chain reaction (PCR), performed using genomic
      DNA from normal individuals and from F508del heterozygous and F508del homozygous
      patients. The third, and most important, step consists of the evaluation of
      differential stabilities of DNA/DNA molecular complexes generated after
      hybridization of normal and deltaF508 probes immobilized on the sensor chips. The
      results obtained strongly suggest that the proposed procedure employing SPR
      technology enables a one-step, nonradioactive protocol for the molecular
      diagnosis of F508del mutation of the CFTR gene. This approach could be of
      interest in clinical genetics, as the hybridization step is oftenly required to
      detect microdeletions present within PCR products.

PMID- 10338095
TI  - Six novel beta-galactosidase gene mutations in Brazilian patients with GM1
      gangliosidosis.
AB  - GM1-gangliosidosis is a lysosomal storage disease caused by a deficiency of acid
      beta-galactosidase. Three clinical forms are recognized-infantile, juvenile, and
      adult-based on age of onset and severity of the symptoms. We have performed
      molecular analysis of a large cohort of GM1 patients (19 Brazilian and one
      Uruguayan), using nonradioactive single-strand conformation polymorphism (SSCP)
      and restriction enzyme analysis of genomic DNA. Six novel mutations (R121S,
      V240M, D491N, 638-641insT, 895-896insC, 1622-1627insG) and two previously
      described point mutations (R59H, R208C) were identified. Together they accounted
      for 90% of the disease alleles of the patients. Two mutations, 1622-1627insG and
      R59H, were present in 18 of 20 patients. In addition, four polymorphisms (L10P,
      L12L, R521C, S532G) were identified. All cases reported are infantile GM1
      gangliosidosis. This report constitutes the most comprehensive molecular study to
      date of this disorder in infantile patients. Since GM1-gangliosidosis is the most
      common lysosomal storage disorder in Southern Brazil, molecular diagnosis will be
      important for genetic counseling, carrier detection and prenatal diagnosis in
      index families.

PMID- 10338097
TI  - Three new mutations in the uroporphyrinogen decarboxylase gene in familial
      porphyria cutanea tarda. Mutation in brief no. 237. Online.
AB  - We have characterised three new mutations in the uroporphyrinogen decarboxylase
      gene in familial porphyria cutanea tarda. The first of these was a G to A
      substitution in the 5' splice junction of exon 4 which generated an mRNA that
      lacked exon 4. The second was a nonsense mutation in exon 5 which changed the
      arginine residue at position 142 to a stop codon, and the third mutation, also in
      exon 5, was a triple base substitution from nucleotide position 417 to 419. This
      mutation encompassed two codons but only changed the amino acid predicted from
      the second codon, resulting in the replacement of valine with glutamine at
      position 134. This missense mutation has been described previously by Meguro et
      al. 1994, on one allele in a compound heterozygote with hepatoerythropoietic
      porphyria. This is the third case of an hepatoerythropoietic porphyria mutation
      in an individual diagnosed with familial porphyria cutanea tarda.

PMID- 10338096
TI  - Low frequency of oncogenic mutations in the core promoter region of the RB1 gene.

PMID- 10338099
TI  - Mitochondrial DNA variations in patients with Type 2 (non-insulin dependent)
      diabetes mellitus and a Welsh control population. Mutation in brief no. 239.
      Online.
AB  - Type 2 (non-insulin dependent) diabetes mellitus may be inherited along the
      maternal line and a variety of mitochondrial DNA (mtDNA) variants have been
      implicated in the pathogenesis. We have previously reported mutations in five
      regions of the mitochondrial genome which encompass 11 of the 22 tRNA genes. Now
      we employ the technique of single stranded conformational polymorphism (SSCP)
      analysis to investigate a further 6 regions of the mitochondrial genome, covering
      the remaining 11 tRNA genes in 40 patients with Type 2 diabetes and 30 racially
      matched normal controls. A variety of homoplasmic mutations were detected in
      patients with diabetes and these will be of value in further population
      association studies.

PMID- 10338098
TI  - Rapid screening of the LDL receptor point mutation FH-Genoa/Palermo. Mutation in
      brief no. 238. Online.
AB  - The LDL-receptor gene point mutation FH-Genoa/Palermo is the most frequent
      mutation responsible for Familial Hypercholesterolemia in Sicily. The mutation
      does not introduce or abolish any useful restriction site. We establish a
      GeneComb-based strategy to identify this mutation in a population of Sicilian
      unrelated clinically diagnosed FH probands. The method was very sensitive and
      specific; 12 out of 90 (13.3%) unrelated FH probands were found to carry the FH
      Genoa/Palermo mutation. According to these results, the FH-Genoa/Palermo is the
      more frequent LDL-receptor gene mutation among the Sicilian FH patients. Moreover
      FH-Genoa/Palermo is the mutation cluster to date more represented in Southern
      Italy.

PMID- 10338100
TI  - A single, large deletion accounts for all the beta-globin gene mutations in
      twenty families from Sabah (North Borneo), Malaysia. Mutation in brief no. 240.
      Online.
AB  - Beta-thalassemia major is one of the commonest genetic disorders in South-East
      Asia. The spectrum of beta-thalassemia mutations in the various ethnic sub
      populations on the island of Borneo is unknown. We studied 20 Dusun children from
      the East Malaysian state of Sabah (North Borneo) with a severe beta-thalassemia
      major phenotype, using a combination of Southern analysis, polymerase chain
      reaction analysis and direct sequencing. We found the children to be homozygous
      for a large deletion, which has a 5' breakpoint at position -4279 from the cap
      site of the beta-globin gene (HBB) with the 3' breakpoint located in a L1 family
      of repetitive sequences at an unknown distance from the beta-globin gene. This
      was similar to a recent finding of a large deletion causing beta-thalassemia
      first described in unrelated beta-thalassemia heterozygotes of Filipino descent.
      This report describes the first 20 families with homozygosity of the deletion
      causing a severe phenotype. It provides the first information on the molecular
      epidemiology of beta-thalassemia in Sabah. This finding has implications for the
      population genetics and preventative strategies for beta-thalassemia major for
      nearly 300 million individuals in South-East Asia.

PMID- 10338101
TI  - Screen of 55 Slovenian haemophilia A patients: identification of 2 novel
      mutations (S-1R and IVS23+1G-->A) and discussion of mutation spectrum. Mutation
      in brief no. 241. Online.
AB  - Using polymerase chain reaction, single-stranded conformational polymorphism
      (SSCP), TaqI restriction analysis and direct sequencing, exons 1, 7, 8, 9, 12,
      13, 14, 18, 22, 23, 24, and 26 of the factor VIII gene were screened for point
      mutations in 55 Slovenian haemophilia A patients. In eighteen patients eleven
      different mutations were found; one (in six patients) in exon 26, one (in two
      patients) in exon 24, two in exon 23, one in intron 23, one in exon 18, one in
      exon 12, one in exon 8, two (1 + 1 in two patients) in exon 7 and one in exon 1.
      Of the mutations detected one has recently been reported by us (Q602X), and two
      are novel; S-1R in exon 1 and IVS23+1G-->A in intron 23.

PMID- 10338102
TI  - Piracetam: novelty in a unique mode of action.
AB  - Extensive research of the recent years has demonstrated that piracetam is
      effective in the treatment of cognitive decline in aging and dementia. It is
      usually much more active in situations of impaired brain function. Accordingly,
      its mechanism of action has been associated with neurochemical deficits of the
      aged brain relevant to cognitive dysfunctions. Since many of these neurochemical
      deficits depend on changes of membrane properties, including fluidity, it is of
      special importance that piracetam not only modifies membrane properties by
      interacting with the polar head moieties of the phospholipid bilayer, but also
      that this effect is more pronounced in membranes of aged as opposed to young
      animal and human brains, and that this mechanism also has specific relevance for
      brain membranes of Alzheimer's disease patients. Altering membrane properties
      might also be involved in vascular effects of piracetam such as improved
      erythrocyte deformability and normalization of hyperactive platelet aggregation.
      This novel mechanism of piracetam thus combines a rather non-specific physico
      chemical mode of action with the pharmacological and clinical experience with
      this unique drug - effects are always much more pronounced when function is
      impaired.

PMID- 10338103
TI  - Piracetam improves cognitive performance by restoring neurochemical deficits of
      the aged rat brain.
AB  - In order to test the hypothesis that piracetam improves cognitive functions by
      restoring biochemical deficits of the aging brain, we investigated the effects of
      piracetam treatment (300 mg/kg daily for 6 weeks) on the active avoidance
      performance of young and aged rats. After testing, the rats were killed and
      membrane fluidity and NMDA as well muscarinic cholinergic receptor densities were
      determined in the frontal cortex, the hippocampus, the striatum, as well as the
      cerebellum. Piracetam treatment improved active avoidance learning in the aged
      rats only and elevated membrane fluidity in all brain regions except the
      cerebellum in the aged animals. Moreover, we observed a positive effect of
      piracetam treatment on NMDA receptor density in the hippocampus and on muscarinic
      cholinergic receptor densities in the frontal cortex and the striatum and to a
      lesser extent in the hippocampus. Again, these effects were only observed in aged
      animals. Discrimination analysis indicated that piracetam effects on membrane
      fluidity in the frontal cortex, the hippocampus, and the striatum and its effects
      on NMDA densities in the hippocampus might be involved in its positive effects on
      cognitive performance.

PMID- 10338104
TI  - From neuronal and vascular impairment to dementia.
AB  - This paper reviews aspects of existing knowledge and recent concepts related to
      the development of vascular dementia which, after Alzheimer's disease, is the
      most frequent type of dementia. The disorder may result from cerebrovascular
      disorders, including multi-infarct dementia due to thromboembolic disease, other
      less common vasculopathies and ischemic brain damage secondary to systemic
      hypotension. Characteristic clinical features are stepwise cognitive
      deterioration resulting from repeated strokes and the presence of focal signs and
      symptoms. The clinical distinction between Alzheimer's disease and vascular
      dementia may be difficult and strict criteria (NINDS/ AIREN) have recently been
      adopted as standard guidelines for research studies. Vascular dementia and
      Alzheimer's disease can co-exist, so-called "mixed dementia", and the presence of
      cerebrovascular disease may worsen Alzheimer dementia. Indeed, there is often a
      vascular component in the pathogenesis of dementia. The pathogenesis of vascular
      dementia is complex. Post-stroke patients are at increased risk; some
      predisposing or risk factors are the volume, number and site (whether strategic
      or not) of cerebral injuries, distal field vascular injury with reduced cerebral
      blood flow, white matter ischemia due to small vessel disease, the co-existence
      of vascular disease and Alzheimer's dementia, and the presence of cognitive
      decline prior to stroke. There is increasing evidence of a complex relationship
      between vascular dementia and Alzheimer's disease. When post-stroke dementia is
      progressive this may reflect associated Alzheimer's disease either unrecognized
      or asymptomatic prior to the stroke. The apolipoprotein E4 genotype is a risk
      factor for ischemic stroke, vascular dementia and Alzheimer dementia. Although
      dementia is usually irreversible, it is now accepted that cognitive impairment
      may be delayed, stabilized or sometimes reversed. The treatment of vascular
      dementia consists of two approaches: preventive measures, including attempts to
      control risk factors for stroke and the use of antiplatelet agents and/or
      surgery, and the treatment of cognitive symptoms. Nootropic and vasodilator
      agents have been reported to improve cognitive impairment from various causes.
      Ongoing research is attempting to show their specific benefit in vascular
      dementia.

PMID- 10338106
TI  - The clinical safety of high-dose piracetam--its use in the treatment of acute
      stroke.
AB  - Recent post-marketing surveillance reports have confirmed the benign safety
      profile and lack of organ toxicity shown by piracetam during its 25 years of
      clinical usage. Tolerance has proved equally good with the more recent use of
      larger doses (up to 24 g/day) for the long-term control of cortical myoclonus and
      when given intravenously to patients with acute stroke. This paper provides a
      brief review of these findings and records the safety of piracetam as found in
      the Piracetam in Acute Stroke Study (PASS), a randomized multicenter placebo
      controlled study in 927 patients with acute ischemic stroke. Patients receive one
      intravenous bolus injection of placebo or 12 g piracetam, piracetam 12 g daily
      for 4 weeks and maintenance treatment for 8 weeks. The major results have been
      reported (De Deyn et al., Stroke 28 [1997] 2347-2352). Safety was assessed taking
      into account adverse events including abnormal laboratory test results and
      mortality. Death within 12 weeks occurred more frequently in the piracetam group
      but the difference from placebo was not significant. Of many potential risk,
      prognostic and treatment-related factors examined by logistic regression, 6
      contributed significantly to death of which the most important were initial
      severity of stroke and age. Neither treatment nor any treatment-related factor
      contributed significantly to death. Adverse events were similar in frequency,
      type and severity in piracetam and placebo groups. Events of cerebral, non
      cerebral and uncertain origin likewise occurred with similar frequency. Few
      patients discontinued because of adverse events. There was no difference between
      treatments in the frequency of events associated with bleeding, including
      hemorrhagic transformation of infarction. An important finding was that, of 31
      patients with primary hemorrhagic stroke enrolled, 3 piracetam-treated patients
      died compared with 6 on placebo. The results suggest that piracetam in high
      dosage may be given to patients with acute stroke without significant adverse
      effects.

PMID- 10338105
TI  - Piracetam in the treatment of acute stroke.
AB  - The neuroprotective properties of the nootropic agent piracetam together with
      reported hemorrheologic and antithrombotic effects provided the rationale for the
      evaluation of piracetam in acute stroke. Pilot studies showed an increase in
      compromised regional cerebral blood flow and improvement in motor function,
      aphasia and level of consciousness. Subsequently the Piracetam in Acute Stroke
      Study (PASS) was performed and the chief results have recently been reported
      (Stroke 28 (1997) 2347-2352). This was a multicenter double-blind trial in 927
      patients to determine whether, compared with placebo, piracetam improved outcome
      when given within 12 hours of the onset of acute ischemic stroke, confirmed by
      computed tomography within 24 hours of admission (but not necessarily prior to
      treatment). Patients received an initial iv bolus of placebo or 12g piracetam,
      12g piracetam daily for 4 weeks and maintenance treatment for a further 8 weeks.
      Neurologic status at 4 weeks was the primary end point; secondary outcome
      measures were functional outcome and aphasia at 12 weeks. Results in aphasic
      patients have not previously been reported. Analysis was planned both in all
      patients (n = 927) and an early treatment subgroup (n = 460) treated within 6
      hours of stroke onset. This period was subsequently redefined as 7 hours.
      Intention-to-treat analyses in the total population showed a significant (P =
      0.04) increase compared with placebo in the number of patients recovered from
      aphasia but no significant neurologic or functional improvement. Post hoc
      analysis in the early treatment subgroup showed improved neurologic outcome (P =
      0.07), better function (P = 0.02) and a greater recovery rate from aphasia (P =
      0.02). Additional analysis in this early treatment subgroup confined to 360
      patients with moderate and severe stroke showed significant improvement in all 3
      outcomes. There was no significant difference in mortality between treatment
      groups after 12 weeks. There were fewer deaths in piracetam-treated patients in
      those patients in the intention-to-treat population admitted with primary
      hemorrhagic stroke.

PMID- 10338107
TI  - The role of piracetam in the treatment of acute and chronic aphasia.
AB  - Piracetam has been shown to improve speech in aphasic patients. This paper
      reviews the evidence for this benefit in aphasic patients with acute stroke and,
      in conjunction with language treatment, in post-acute and chronic aphasia. Early
      double-blind, placebo-controlled trials in acute stroke showed improvement in
      several neurologic parameters including aphasia. Subsequently two randomized
      double-blind placebo-controlled studies were performed which utilised the Aachen
      Aphasia Test (AAT), a validated and standardized procedure, to assess language
      function. Patients received placebo or piracetam 4.8g daily for 12 weeks in one
      study and for 6 weeks in the other. In both studies patients received concomitant
      intensive speech therapy; one included patients 6-9 weeks after stroke while in
      the other the duration of aphasia varied between 4 weeks and 3 years. Compared
      with placebo there was improvement in both studies on piracetam in all 5 subtests
      of the AAT and significant overall improvement in aphasia. This indicated that,
      given in conjunction with language therapy, piracetam improved speech in patients
      with post-acute and chronic aphasia. In the Piracetam in Acute Stroke Study
      (PASS), of 927 patients treated within 12 hours of the onset of acute ischemic
      stroke, 373 were aphasic. Treatment consisted of placebo or an intravenous bolus
      of 12g piracetam, 12g piracetam daily for 4 weeks and 4.8 g daily for a further 8
      weeks. After 12 weeks significantly more patients (approximately 10%, P=0.04) had
      recovered from aphasia on piracetam than placebo while in 197 patients treated
      within 7 hours of stroke onset, the difference in favor of piracetam was 16% (P=
      0.02). These studies indicate that piracetam improves aphasia in acute stroke
      and, as an adjuvant to language therapy, in post-acute and chronic aphasia.

PMID- 10338108
TI  - Piracetam and platelets--a review of laboratory and clinical data.
AB  - This paper reviews the effects of piracetam on platelet function and the evidence
      for its antiplatelet effect which is mediated mainly by inhibition of platelet
      aggregation. Piracetam also possesses antithrombotic activity in vivo. It has
      been shown to normalize platelet aggregation in patients with increased platelet
      aggregability in various disorders including acute stroke, transient cerebral
      ischemic attacks and diabetes mellitus. This, together with clinical improvement,
      has also been shown in patients with Raynaud's phenomenon. The results of recent
      studies are presented in which piracetam showed similar efficacy to aspirin in
      the secondary prophylaxis of ischemic stroke.

PMID- 10338109
TI  - Piracetam in the treatment of cortical myoclonus.
AB  - This paper reviews existing publications on the use of piracetam for the
      treatment of cortical myoclonus of various etiologies and includes the personal
      experience of the authors in progressive myoclonus epilepsy. Two double-blind
      comparisons with placebo provided results which allow recommendations for the
      dosage and usage of piracetam in cortical myoclonus. Wide individual variation (7
      24g daily) exists in dosage requirements but responses are dose-related so that
      dosage should be increased until an optimum effect is obtained. Tolerability
      after long-term use of piracetam in high dosage has been very good and without
      toxicity or serious adverse effects. Side effects have been occasional, mild and
      transient. The authors present their experience of 12 patients with progressive
      myoclonus epilepsy in whom the administration of up to 45 g piracetam daily, when
      added to existing anti-epileptic treatment, caused marked and sometimes
      spectacular improvement and was without significant adverse effects. Improvement
      was maintained for up to 7 years. The use of piracetam for disabling cortical
      myoclonus of any etiology, either as an addition to existing antimyoclonic drugs
      or as monotherapy, may bring about profound improvement in disability and quality
      of life. Piracetam should be considered a first-line drug for the treatment of
      cortical myoclonus.

PMID- 10338110
TI  - The effectiveness of piracetam in vertigo.
AB  - Vertigo is a sensation of altered orientation in space and may be defined as an
      illusion of movement. It is a subjective symptom and therefore difficult to
      assess. Examination and diagnosis remain difficult. Although treatment should be
      directed at the underlying cause or disorder, the origin of vertigo is frequently
      unknown or untreatable. Pharmacotherapy is required for symptomatic treatment.
      Piracetam has been shown to be effective in vertigo of both central and
      peripheral origin. It is thought to act on vestibular and oculomotor nuclei in
      the brain stem and thus on the central control of balance enhancing mechanisms of
      compensation and habituation. This review of double-blind trials shows that
      piracetam alleviates vertigo after head injury, vertigo of central origin as, for
      example, in vertebrobasilar insufficiency and in peripheral vestibular disorders,
      especially in middle-aged and elderly subjects. Piracetam decreases the frequency
      but probably not the severity of exacerbations in patients with chronic or
      recurrent vertigo. The usual dosage of piracetam in vertigo is 2.4-4.8 g daily.
      Tolerability of piracetam is good and adverse effects have been mild and
      infrequent.

PMID- 10338111
TI  - The non-enzymatic microbicidal activity of lysozymes.
AB  - T4 lysozyme was thought to destroy bacteria by its muramidase activity. However,
      we demonstrate here that amphipathic helix stretches in the C-terminus of T4
      lysozyme mediate its bactericidal and fungistatic activities. In heat-denatured
      T4 lysozyme, the enzymatic activity is completely abolished but unexpectedly, the
      antimicrobial functions remain preserved. Small synthetic peptides corresponding
      to amphipathic C-terminal domains of T4 lysozyme show a microbicidal activity.
      Its membrane disturbing activity was directly demonstrated for bacterial, fungal
      and plant cells but not in a hemolysis assay. Comparable results were obtained
      with hen egg white lysozyme. This opens up many new opportunities for
      optimization of lysozymes as antimicrobial agents in various applications by
      protein engineering.

PMID- 10338112
TI  - Cysteine 29 is the major palmitoylation site on stomatin.
AB  - The 31 kDa membrane protein stomatin was metabolically labeled with tritiated
      palmitic acid in the human amniotic cell line UAC and immunoprecipitated. We show
      that the incorporated palmitate is sensitive to hydroxylamine, indicating the
      binding to cysteine residues. Stomatin contains three cysteines. By expressing a
      myc-tagged stomatin and substituting the three cysteines by serine, individually
      or in combination, we demonstrate that Cys-29 is the predominant site of
      palmitoylation and that Cys-86 accounts for the remaining palmitate labeling.
      Disruption of Cys-52 alone does not show any detectable reduction of palmitic
      acid incorporation. Given the organization of stomatin into homo-oligomers, the
      presence of multiple palmitate chains is likely to increase greatly the affinity
      of these oligomers for the membrane and perhaps particular lipid domains within
      it.

PMID- 10338113
TI  - A critical comparison of the hemolytic and fungicidal activities of cationic
      antimicrobial peptides.
AB  - The hemolytic and fungicidal activity of a number of cationic antimicrobial
      peptides was investigated. Histatins and magainins were inactive against human
      erythrocytes and Candida albicans cells in phosphate buffered saline, but
      displayed strong activity against both cell types when tested in 1 mM potassium
      phosphate buffer supplemented with 287 mM glucose. The HC50/IC50 ratio,
      indicative of the therapeutic index, was about 30 for all peptides tested. PGLa
      was most hemolytic (HC50 = 0.6 microM) and had the lowest therapeutic index
      (HC50/IC50 = 0.5). Susceptibility to hemolysis was shown to increase with storage
      duration of the erythrocytes and also significant differences were found between
      blood collected from different individuals. In this report, a sensitive assay is
      proposed for the testing of the hemolytic activities of cationic peptides. This
      assay detects subtle differences between peptides and allows the comparison
      between the hemolytic and fungicidal potency of cationic peptides.

PMID- 10338114
TI  - The inhibitory effect of 2-deoxyglucose on insulin receptor autophosphorylation
      does not depend on known serine phosphorylation sites or other conserved serine
      residues of the receptor beta-subunit.
AB  - Hyperglycemia induces insulin resistance in diabetic patients. It is known that
      supraphysiological levels of D-glucose or 2-deoxyglucose inhibit the insulin
      receptor and it is speculated that this effect is mediated by serine
      phosphorylation of the insulin receptor beta-subunit and other proteins of the
      insulin signaling chain. To test this hypothesis we prepared point mutations of
      the human insulin receptor where serine was exchanged to alanine at 16 different
      positions, either at known phosphorylation sites or at positions which are
      conserved in different tyrosine kinase receptors. These receptor constructs were
      expressed in HEK 293 cells and the effect of 2-deoxyglucose (25 mM) on insulin
      (100 nM) induced receptor autophosphorylation was studied. 2-Deoxyglucose
      consistently inhibits insulin stimulated autophosphorylation of all constructs to
      the same degree as observed in wild-type human insulin receptor. The data suggest
      that none of the chosen serine positions are involved in 2-deoxyglucose induced
      receptor inhibition.

PMID- 10338115
TI  - Cooperative interaction of NF-kappaB and C/EBP binding sites is necessary for
      manganese superoxide dismutase gene transcription mediated by lipopolysaccharide
      and interferon-gamma.
AB  - Expression of the manganese superoxide dismutase (Mn-SOD) is induced by pro
      inflammatory cytokines. We investigated the cis-acting elements within a tumor
      necrosis factor-responsive element (TNFRE) which was identified in the second
      intron of the murine Mn-SOD gene. Site-directed mutagenesis, reporter plasmid
      transfection studies and electrophoretic mobility shift assays demonstrated that
      inducible transcription factors enhanced the transcriptional activity of the Mn
      SOD gene through the TNFRE. The cooperation between proteins binding to the newly
      identified NF-kappaB and C/EBP sites led to synergistic gene transcription. This
      report provides the first evidence that cooperation between two distinct cis
      acting elements may be required for induction of Mn-SOD gene expression mediated
      by lipopolysaccharide and interferon-gamma.

PMID- 10338116
TI  - Human growth hormone site 2 lactogenic activity requires a distant tyrosine164.
AB  - Comparison of crystallographic structures of human growth hormone, either bound
      to the prolactin receptor or free of receptors, reveals that human growth hormone
      binding to the prolactin receptor at site 1 is associated with a structural
      change in human growth hormone that influences the organization of residues which
      constitute site 2. We have identified Tyr164 as a residue that is critical for
      the propagation of this structural rearrangement. Tyr164 is a structural epitope
      for site 1 and is distal to site 2. Mutation of Tyr164 to glutamic acid (Y164E)
      does not affect the somatotrophic activity, absorption or fluorescence spectra or
      binding to the human prolactin receptor when compared to wild-type human growth
      hormone, indicating the subtle effects of the mutation. Lactogenic assays using
      extended concentrations of Y164E human growth hormone produce dose-response
      curves that are characterized by a right-shifted agonist phase and an unchanged
      antagonist phase when compared to wild-type human growth hormone. These results
      indicate that Tyr164 is required for the lactogenic activity of human growth
      hormone and that mutation to glutamic acid disrupts the lactogenic function of
      site 2.

PMID- 10338117
TI  - cDNA cloning of an adult male putative lipocalin specific to tergal gland
      aphrodisiac secretion in an insect (Leucophaea maderae).
AB  - Lma-P22 is a cuticular surface protein specific to the tergal gland secretion of
      Leucophaea maderae adult males which is ingested by females just before
      copulation. The complete Lma-P22 cDNA sequence was determined by RT-PCR using
      primers based on Edman degradation fragments. The recombinant protein expressed
      in Escherichia coli was recognized by an anti-Lma-P22 antibody. Northern blot
      analysis indicates that the corresponding mRNA is transcribed only in the
      epidermis of male tergites. Sequence analysis indicated that Lma-P22 deduced
      protein belongs to the lipocalin family. Lipocalins are extracellular proteins
      which carry hydrophobic compounds and some of them can bind sexual pheromone in
      vertebrates. Lma-P22 is the first example of a lipocalin-like protein involved in
      insect sexual behavior.

PMID- 10338119
TI  - Heparin down-regulates the phorbol ester-induced protein kinase C gene expression
      in human endothelial cells: enzyme-mediated autoregulation of protein kinase C
      alpha and -delta genes.
AB  - Overexpression of protein kinase C-alpha and protein kinase C-delta has been
      shown to modulate a number of biological effects, including the cell growth and
      differentiation. We hypothesized that heparin, a potent antimitogenic drug, could
      affect the cell proliferation by inhibiting the expression of specific protein
      kinase C genes. Heparin, markedly but not completely, inhibited the serum
      stimulated protein kinase C-alpha and -delta mRNA expression. Protein kinase C
      inhibition or down-regulation significantly decreased the serum-induced protein
      kinase C isoenzyme gene expression. Heparin failed to inhibit the residual effect
      of serum that was resistant to the above-mentioned treatments. Phorbol 12
      myristate 13-acetate elicited an increase of protein kinase C isoenzyme gene
      expression that was completely prevented by protein kinase C inhibition or down
      regulation. Heparin dose-dependently counteracted and ultimately abolished the
      increase in the protein kinase C isoenzyme gene expression elicited by phorbol 12
      myristate 13-acetate. These results suggest that the inhibition of an
      autoregulatory role wielded by protein kinase C on the protein kinase C-alpha and
      -delta gene expression might represent a possible mechanism by which
      glycosaminoglycans modulate the cell growth.

PMID- 10338118
TI  - Assessment of uncoupling activity of uncoupling protein 3 using a yeast
      heterologous expression system.
AB  - Uncoupling protein 3L, uncoupling protein 1 and the mitochondrial oxoglutarate
      carrier were expressed in Saccharomyces cerevisae. Effects on different
      parameters related to the energy expenditure were studied. Both uncoupling
      protein 3L and uncoupling protein 1 reduced the growth rate by 49% and 32% and
      increased the whole yeast O2 consumption by 31% and 19%, respectively. In
      isolated mitochondria, uncoupling protein 1 increased the state 4 respiration by
      1.8-fold, while uncoupling protein 3L increased the state 4 respiration by 1.2
      fold. Interestingly, mutant uncoupling protein 1 carrying the H145Q and H147N
      mutations, previously shown to markedly decrease the H+ transport activity of
      uncoupling protein 1 when assessed using a proteoliposome system (Bienengraeber
      et al. (1998) Biochem. 37, 3-8), uncoupled the mitochondrial respiration to
      almost the same degree as wild-type uncoupling protein 1. Thus, absence of this
      histidine pair in uncoupling protein 2 and uncoupling protein 3 does not by
      itself rule out the possibility that these carriers have an uncoupling function.
      The oxoglutarate carrier had no effect on any of the studied parameters. In
      summary, a discordance exists between the magnitude of effects of uncoupling
      protein 3L and uncoupling protein 1 in whole yeast versus isolated mitochondria,
      with uncoupling protein 3L having greater effects in whole yeast and a smaller
      effect on the state 4 respiration in isolated mitochondria. These findings
      suggest that uncoupling protein 3L, like uncoupling protein 1, has an uncoupling
      activity. However, the mechanism of action and/or regulation of the activity of
      uncoupling protein 3L is likely to be different.

PMID- 10338120
TI  - Human platelets exclusively bind oxidized low density lipoprotein showing no
      specificity for acetylated low density lipoprotein.
AB  - The widely studied macrophage scavenger receptor system is known to bind both
      acetylated low density lipoprotein and oxidized low density lipoprotein. Although
      only the latter ligand has been shown to occur in vivo, acetylated low density
      lipoprotein is often used to evaluate the contribution of scavenger receptors to
      different (patho)physiologic processes, assuming that all existing subtypes of
      scavenger receptors recognise both lipoproteins. In the present work, we identify
      human platelets as the first natural cell type to bind oxidized low density
      lipoprotein without showing specificity for acetylated low density lipoprotein.
      Consequently, platelets possess exclusive receptor(s) for oxidized low density
      lipoprotein distinct from the 'classical' scavenger receptor AI/AII. From the
      data presented in this work, we conclude that the class B scavenger receptor CD36
      (GPIV) is responsible for this exclusive oxidized low density lipoprotein
      binding.

PMID- 10338121
TI  - Localization and age-dependent expression of the inward rectifier K+ channel
      subunit Kir 5.1 in a mammalian reproductive system.
AB  - Kir 5.1 is a member of the inward rectifier potassium channel superfamily which
      does not form functional channels when expressed by itself in Xenopus laevis
      oocytes. rt-PCR reveals high levels of Kir 5.1 mRNA expression in testis but the
      function of this channel remains unknown. To determine the cell-specific
      expression of this channel in the testis we raised a polyclonal antibody against
      an external epitope of Kir 5.1 and tested its specificity in Xenopus oocytes
      expressing several cloned Kir subunits. Strong immunoreactivity for Kir 5.1 was
      found in seminiferous tubules of rat testis and, particularly, in spermatogonia,
      primary and secondary spermatocytes, spermatids and in the head and body of
      spermatozoa. The intensity of Kir 5.1 immunofluorescence, quantified using laser
      scanning microscopy, increased with age at every stage in the development of
      sperm from spermatogonia and reached a peak in 60-day-old rats. In contrast, the
      immunofluorescence decreased in 90-day-old animals and was detected mostly in
      spermatozoa. The results demonstrate that Kir 5.1 expression in the testis is
      localised to cells involved in spermatogenesis, showing a temporal pattern of
      expression during sexual maturity.

PMID- 10338122
TI  - Engineering a central metabolic pathway: glycolysis with no net phosphorylation
      in an Escherichia coli gap mutant complemented with a plant GapN gene.
AB  - A cDNA fragment containing the Pisum sativum GapN gene, which encodes the non
      phosphorylating glyceraldehyde-3-phosphate dehydrogenase, was cloned in a
      prokaryote expression vector. This construct enabled Escherichia coli strain
      W3CG, a mutant which lacks the glycolytic phosphorylating G3P dehydrogenase, to
      grow aerobically on sugars. The functionally complemented mutant exhibited high
      levels of the catalytically active plant enzyme, which renders 3-phosphoglycerate
      and NADPH, thus bypassing the first substrate level phosphorylation step of the
      glycolysis. As expected if such a glycolytic bypass would be operative in vivo,
      this clone failed to grow anaerobically on sugars in contrast to W3CG clones
      complemented with phosphorylating glyceraldehyde-3-phosphate dehydrogenases.
      According to the irreversible catabolic character of the non-phosphorylating
      reaction, the GapN-complemented clone was unable to grow on gluconeogenic
      substrates. This metabolic engineering approach demonstrates that a pure
      catabolic Embden-Meyerhof pathway with no net energy yield is feasible.

PMID- 10338123
TI  - Constitutive and nitrogen-regulated promoters of the petH gene encoding
      ferredoxin:NADP+ reductase in the heterocyst-forming cyanobacterium Anabaena sp.
AB  - Determination of the putative transcription start points of the petH gene
      encoding ferredoxin:NADP+ reductase in the heterocyst-forming cyanobacteria
      Anabaena sp. PCC 7119 and PCC 7120 showed that this gene is transcribed from two
      promoters, one constitutively used under different conditions of nitrogen
      nutrition and the other one used in cells subjected to nitrogen stepdown and in
      nitrogen-fixing filaments. The latter promoter, whose use was NtcA-dependent but
      HetR-independent, was functional in heterocysts. The N-control transcriptional
      regulator NtcA was observed to bind in vitro to this promoter. For the sake of
      comparison, the transcription start points of the nifHDK operon in strain PCC
      7120 and binding of NtcA to the nifHDK promoter were also examined.

PMID- 10338124
TI  - The energy conserving methyltetrahydromethanopterin:coenzyme M methyltransferase
      complex from methanogenic archaea: function of the subunit MtrH.
AB  - In methanogenic archaea the transfer of the methyl group of N5
      methyltetrahydromethanopterin to coenzyme M is coupled with energy conservation.
      The reaction is catalyzed by a membrane associated multienzyme complex composed
      of eight different subunits MtrA-H. The 23 kDa subunit MtrA harbors a corrinoid
      prosthetic group which is methylated and demethylated in the catalytic cycle. We
      report here that the 34 kDa subunit MtrH catalyzes the methylation reaction. MtrH
      was purified and shown to exhibit methyltetrahydromethanopterin:cob(I)alamin
      methyltransferase activity. Sequence comparison revealed similarity of MtrH with
      MetH from Escherichia coli and AcsE from Clostridium thermoaceticum: both enzymes
      exhibit methyltetrahydrofolate:cob(I)alamin methyltransferase activity.

PMID- 10338125
TI  - Binding of oligopyrimidines to the RNA hairpin responsible for the ribosome gag
      pol frameshift in HIV-1.
AB  - The 12 bp stem of the RNA hairpin responsible for the gag-pol frameshifting of
      the ribosomes during translation of the polycistronic HIV-1 mRNA has a pyrimidine
      rich 5' strand and, consequently, a purine-rich 3' strand. Electrophoretic
      mobility shift assays have shown that DNA oligopyrimidines, 12 and 20 nucleotides
      long (but not oligopurines or G,T-containing oligomers), designed to form
      triplexes actually bind to the double-stranded RNA target. RNase V1 footprinting
      studies have confirmed the interaction between the hairpin stem and the RNA and
      2'-O-methyl oligoribonucleotide analogues of the 12-mer oligodeoxypyrimidine as
      well as 5 propynyl,cytosine, containing the 12-mer oligodeoxypyrimidine, bind
      more strongly to the RNA target than the unmodified parent DNA oligomer. The
      complexes formed by the RNA hairpin and either the 12-mer oligodeoxypyrimidine or
      the 20-mer oligopyrimidine are stable at a neutral pH and in the absence of Mg2+
      but blocked neither the reverse transcription nor cell-free translation of a RNA
      template in which the gag-pol frameshifting hairpin was inserted at the 5' end of
      the luciferase open reading frame.

PMID- 10338126
TI  - Characterization of a soluble class I alpha-mannosidase in human serum.
AB  - Class I alpha-mannosidases are thought to exist exclusively as integral membrane
      proteins that play intracellulary an essential role in the N-glycan biosynthesis.
      Using [3H]Man9GlcNAc2 as a substrate, we were able to identify a soluble alpha
      mannosidase in human serum that trims the substrate Man9GlcNAc2 to Man(5
      8)GlcNAc2 with Man6GlcNAc2 being the major product. This serum mannosidase is
      Ca2+-dependent, sensitive to 1-deoxymannojirimycin but insensitive to the class
      II inhibitor swainsonine and, hence, belongs to class I mannosidases. The
      enzymatic properties of the serum class I mannosidase are similar to that of the
      membrane bound class I mannosidases Golgi-mannosidase IA and IB and Man9
      mannosidase.

PMID- 10338127
TI  - Absorption and metabolism of cyanidin 3-O-beta-D-glucoside in rats.
AB  - We have clarified for the first time how cyanidin 3-O-beta-D-glucoside (C3G),
      which is a potent antioxidant anthocyanin, is absorbed and metabolized in vivo.
      Rats were orally administered C3G (0.9 mmol/kg body weight), and C3G rapidly
      appeared in the plasma. However, the aglycon of C3G (cyanidin; Cy) was not
      detected, although it was present in the jejunum. Protocatechuic acid (PC), which
      may be produced by degradation of Cy, was present in the plasma and the
      concentration was 8-fold higher than that of C3G. These results suggest that
      plasma PC and C3G may contribute to the antioxidant activity of the plasma. In
      the liver and kidney, C3G was metabolized to methylated C3G (methyl-C3G),
      suggesting that C3G and/or methyl-C3G act as antioxidants in the tissues.

PMID- 10338128
TI  - Uptake of N-acetyl-D-mannosamine: an essential intermediate in polysialic acid
      biosynthesis by Escherichia coli K92.
AB  - The N-acetyl-D-mannosamine (ManNAc) transport system of Escherichia coli K92 was
      studied when this bacterium was grown in a chemically defined medium containing
      ManNAc as carbon source. Kinetic measurements were carried out in vivo at 37
      degrees C in 25 mM phosphate buffer, pH 7.5. Under these conditions, the uptake
      rate was linear for at least 15 min and the calculated Km for ManNAc was 280
      microM. The transport system was strongly inhibited by sodium arsenate (97%),
      potassium cyanide (84%) and 2,4-dinitrophenol (88%) added at final concentrations
      of 1 mM (each). Analysis of bacterial ManNAc phosphotransferase activity revealed
      in vitro ManNAc phosphorylation activity only when phosphoenolpyruvate was
      present. These results strongly support the notion that ManNAc uptake depends on
      a specific phosphotransferase system. Study of specificities showed that N
      acetylglucosamine and mannosamine specifically inhibited the transport of ManNAc
      in this bacterium. Analysis of expression revealed that the ManNAc transport
      system was induced by ManNAc, glucosamine, galactosamine, mannosamine and mannose
      but not by N-acetylglucosamine or N-acetylgalactosamine. Moreover, ManNAc
      permease was subject to glucose repression and cAMP stimulation. Full induction
      of the ManNAc transport system required the simultaneous presence of both cAMP
      and ManNAc.

PMID- 10338129
TI  - Comparison of synthesis and antibacterial activity of temporin A.
AB  - Temporin A is a small, basic, highly hydrophobic, antibacterial peptide found in
      the skin of the European red frog, Rana temporaria. It was synthesized twice by
      the FastMoc solid phase method using amino acids protected at the N(alpha)
      position with either 9-fluorenylmethoxycarbonyl or 2-(4
      nitrophenylsulfonyl)ethoxycarbonyl. The syntheses of temporin A demonstrates the
      difference between 2-(4-nitrophenylsulfonyl)ethoxycarbonyl and 9
      fluorenylmethoxycarbonyl amino acids. The purified peptide showed also
      antibacterial activity against clinically important gram-positive bacteria. It
      was found to have a moderately good activity against both methicillin resistant
      and sensitive strains of Staphylococcus aureus, but a weaker activity against
      vancomycin resistant strains of Enterococcus faecium.

PMID- 10338130
TI  - Fourier-transform infrared studies on azide-binding to the binuclear center of
      the Escherichia coli bo-type ubiquinol oxidase.
AB  - Azide-binding to the heme-copper binuclear center of bo-type ubiquinol oxidase
      from Escherichia coli was investigated with Fourier-transform infrared
      spectroscopy. Deconvolution analyses of infrared spectra of the azide (14N3)
      inhibited air-oxidized form showed a major infrared azide antisymmetric
      stretching band at 2041 cm(-1). An additional band developed at 2062.5 cm(-1)
      during a longer incubation. Isotope substitutions with terminally 15N-labelled
      azides did not show a splitting of the major band, indicating that the geometry
      of the bound azide is mainly in a bridging configuration between high-spin heme o
      and CuB. The band at 2062.5 cm(-1) showed clear splittings upon substitution with
      the terminally 15N-labelled azides, indicating the Cu(2+)B-N=N=N structure.
      Partial reduction of the oxidase with beta-NADH in the presence of azide caused
      an appearance of new infrared bands at 2038.5 (major) and 2009 (minor) cm(-1).
      The former band also showed clear splittings in the presence of the terminally
      15N-labelled azides, indicating that reduction of low-spin heme b alters the
      structure of the binuclear center leading to the Fe(3+)o-N=N=N configuration.

PMID- 10338131
TI  - Direct NMR observation of the Cys-14 thiol proton of reduced Escherichia coli
      glutaredoxin-3 supports the presence of an active site thiol-thiolate hydrogen
      bond.
AB  - The active site of Escherichia coli glutaredoxin-3 (Grx3) consists of two redox
      active cysteine residues in the sequence -C11-P-Y-C14-H-. The 1H NMR resonance of
      the cysteine thiol proton of Cys-14 in reduced Grx3 is observed at 7.6 ppm. The
      large downfield shift and NOEs observed with this thiol proton resonance suggest
      the presence of a hydrogen bond with the Cys-11 thiolate, which is shown to have
      an abnormally low pKa value. A hydrogen bond would also agree with activity data
      of Grx3 active site mutants. Furthermore, the activity is reduced in a Grx3 H15V
      mutant, indicating electrostatic contributions to the stabilization of the Cys-11
      thiolate.

PMID- 10338132
TI  - The cleaved presequence is not required for import of subunit 6 of the cytochrome
      bc1 complex into yeast mitochondria or assembly into the complex.
AB  - Subunit 6 of the yeast cytochrome bc1 complex contains a 25 amino acid
      presequence that is not present in the mature form of the protein in the bc1
      complex. The presequence of subunit 6 is atypical of presequences responsible for
      targeting proteins to mitochondria. Whereas mitochondrial targeting sequences
      rarely contain acidic residues and typically contain basic residues that can
      potentially form an amphiphilic structure, the presequence of subunit 6 contains
      only one basic amino acid and is enriched in acidic amino acids. If the 25 amino
      acid presequence is deleted, subunit 6 is imported into mitochondria and
      assembled into the cytochrome bc1 complex and the activity of the bc1 complex is
      identical to that from a wild-type yeast strain. However, if the C-terminal 45
      amino acids are truncated from the protein, subunit 6 is not present in the
      mitochondria and the activity of the bc1 complex is diminished by half, identical
      to that of the bc1 complex from a yeast strain in which the QCR6 gene is deleted.
      These results indicate that the presequence of subunit 6 is not required for
      targeting to mitochondria or assembly of the subunit into the bc1 complex and
      that information necessary for targeting and import into mitochondria may be
      present in the C-terminus of the protein.

PMID- 10338133
TI  - N-acetylserotonin is a better extra- and intracellular antioxidant than
      melatonin.
AB  - Both melatonin and its precursor N-acetylserotonin have been reported to exert
      antioxidant properties both in vitro and in vivo. Since little is known about
      their antioxidant activity in lymphocytes, we investigated their effects on
      spontaneous and on oxidant-induced reactive oxygen species formation in human
      peripheral blood lymphocytes in comparison to the antioxidant trolox, a water
      soluble analogue of alpha-tocopherol. Both melatonin and N-acetylserotonin
      exhibited antioxidant properties against t-butylated hydroperoxide- and diamide
      induced reactive oxygen species formation in peripheral blood lymphocytes. N
      acetylserotonin turned out to be about three times more effective than melatonin.
      In resting cells, the intracellular reactive oxygen species concentration was
      only decreased by N-acetylserotonin and trolox, melatonin had no effect. In t
      butylated hydroperoxide-mediated cell death, N-acetylserotonin was as effective
      as trolox in protecting peripheral blood lymphocytes from cell death and required
      10-fold lower concentrations than melatonin. Furthermore, in an aqueous cell-free
      solution, the capacity of N-acetylserotonin to scavenge peroxyl radicals was much
      higher than that of melatonin. These results clearly indicate N-acetylserotonin
      to be a much better antioxidant than melatonin.

PMID- 10338134
TI  - Heptameric association of light-harvesting complex II trimers in partially
      solubilized photosystem II membranes.
AB  - We report a structural characterization by electron microscopy and image analysis
      of a supramolecular complex consisting of seven trimeric light-harvesting complex
      II proteins. The complex was readily observed in partially-solubilized Tris
      washed photosystem II membranes from spinach but was also found to occur, with a
      low frequency, in oxygen-evolving photosystem II membranes. The structure reveals
      six peripheral trimers with the same rotational orientation and a central trimer
      with the opposite orientation. We conclude that the heptamer represents a
      naturally occurring aggregation state of part of the light-harvesting complex II
      trimers in the thylakoid membranes.

PMID- 10338135
TI  - Mu1B, a novel adaptor medium chain expressed in polarized epithelial cells.
AB  - The apical and basolateral plasma membrane domains of polarized epithelial cells
      contain distinct sets of integral membrane proteins. Biosynthetic targeting of
      proteins to the basolateral plasma membrane is mediated by cytosolic tail
      determinants, many of which resemble signals involved in the rapid endocytosis or
      lysosomal targeting. Since these signals are recognized by adaptor proteins, we
      hypothesized that there could be epithelial-specific adaptors involved in
      polarized sorting. Here, we report the identification of a novel member of the
      adaptor medium chain family, named mu1B, which is closely related to the
      previously described mu1A (79% amino acid sequence identity). Northern blotting
      and in situ hybridization analyses reveal the specific expression of mu1B mRNA in
      a subset of polarized epithelial and exocrine cells. Yeast two-hybrid analyses
      show that mu1B is capable of interacting with generic tyrosine-based sorting
      signals. These observations suggest that mu1B may be involved in protein sorting
      events specific to polarized cells.

PMID- 10338136
TI  - Interactions of an antimicrobial peptide, magainin 2, with lipopolysaccharide
      containing liposomes as a model for outer membranes of gram-negative bacteria.
AB  - F12W-magainin 2 preferentially interacted with lipopolysaccharide-containing
      bilayers, permeabilizing the membranes, compared with lipopolysaccharide-free
      phosphatidylcholine vesicles. Using this system, we demonstrated for the first
      time that the magainin peptide forms a helix upon binding to lipopolysaccharide.
      Incorporation of lipid A into phosphatidylcholine liposomes also enhanced
      interactions with the peptide. The presence of Mg2+, which nullifies the
      peptide's antibacterial activity against gram-negative bacteria, again weakened
      the interactions between the peptide and lipopolysaccharide-doped bilayers. This
      system seems to be useful for investigating the molecular details of peptide
      lipopolysaccharide interactions.

PMID- 10338137
TI  - Phosphorylation of p67phox in the neutrophil occurs in the cytosol and is
      independent of p47phox.
AB  - p67phox and p47phox are phosphorylated in the course of stimulation of the NADPH
      oxidase in neutrophils. Isolated neutrophil cytosol can phosphorylate both of
      these proteins in vitro. Phosphoamino acid analysis showed that isolated
      membranes can tyrosine-phosphorylate p67phox in vitro. Further experiments with
      anti-phosphotyrosine antibodies did not support a role for tyrosine
      phosphorylation of p67phox in the cell. A phosphopeptide analysis showed that the
      phosphorylation of p67phox is unchanged in the absence of p47phox. These results
      further characterise the phosphorylation of p67phox and provide evidence that
      this is a cytosolic event independent of interaction with p47phox and the
      membrane.

PMID- 10338139
TI  - The biological significance of non-enzymatic reaction of menadione with plasma
      thiols: enhancement of menadione-induced cytotoxicity to platelets by the
      presence of blood plasma.
AB  - To test the hypothesis that the non-enzymatic reaction of quinones with thiols in
      plasma can generate reactive oxygens (ROS), thereby leading to potentiated
      cellular toxicity, we have studied the effect of a representative quinone
      compound, menadione, on plasma isolated from rats. The experimental results are
      as follows: (1) menadione generated ROS via non-enzymatic reaction with protein
      thiols in plasma; (2) the presence of plasma increased menadione-induced
      cytotoxicity to platelets; (3) pretreatment of plasma with a thiol-depleting
      agent significantly suppressed menadione-induced ROS and cytotoxicity. These
      results suggest that the non-enzymatic reaction of menadione with plasma thiols
      could be an important process in quinone-induced cellular toxicity.

PMID- 10338138
TI  - Incorporation of N-acetylgalactosamine into consecutive threonine residues in
      MUC2 tandem repeat by recombinant human N-acetyl-D-galactosamine transferase-T1,
      T2 and T3.
AB  - An oligopeptide containing three consecutive Thr residues mimicking the tandem
      repeat portion of MUC2 (PTTTPLK) was investigated for the acceptor specificity to
      UDP-N-acetyl-D-galactosamine:peptide N-acetylgalactosaminyltransferase isozymes,
      UDP-N-acetyl-D-galactosamine:peptide N-acetylgalactosaminyltransferase-T1, T2 and
      T3. The enzymatic reaction products were fractionated by the reversed-phase high
      performance liquid chromatography, then characterized by matrix-assisted laser
      desorption ionization time of flight mass spectrometry and by a peptide
      sequencing analysis. A maximum of two, one or three N-acetyl-D-galactosamine
      residues was transferred by UDP-N-acetyl-D-galactosamine:peptide N
      acetylgalactosaminyltransferase-T1, T2 or T3, respectively. The preferential
      orders of N-acetyl-D-galactosamine incorporation were Thr-2, then Thr-4 for UDP-N
      acetyl-D-galactosamine:peptide N-acetylgalactosaminyltransferase-T1, Thr-2 for
      UDP-N-acetyl-D-galactosamine:peptide N-acetylgalactosaminyltransferase-T2 and
      Thr4, Thr-3, then Thr-2 for UDP-N-acetyl-D-galactosamine:peptide N
      acetylgalactosaminyltransferase-T3.

PMID- 10338140
TI  - Astrocytes enhance radical defence in capillary endothelial cells constituting
      the blood-brain barrier.
AB  - Astrocytes (AC) induce blood-brain barrier (BBB) properties in brain endothelial
      cells (EC). As antioxidative activity (AOA) is assumed to be a BBB
      characteristic, we tested whether AC improve AOA of EC. Monocultivated AC showed
      higher AOA [manganese superoxide dismutase (SOD), catalase (Cat), glutathione
      peroxidase (GPx)] than EC. Cocultivation elevated AOA in EC (MnSOD, CuZnSOD, Cat,
      GPx), and AC (MnSOD, CuZnSOD, GPx). Hypoxia increased radical-induced membrane
      lipid peroxidation in monocultivated, but not in cocultivated EC. Thus, EC/AC
      cocultivation intensifies AOA in both cell types, protects the EC, and therefore,
      the BBB against oxidative stress. The high AOA is regarded as an essential
      property of the BBB, which is induced by AC.

PMID- 10338141
TI  - Thiamine repression and pyruvate decarboxylase autoregulation independently
      control the expression of the Saccharomyces cerevisiae PDC5 gene.
AB  - The Saccharomyces cerevisiae gene PDC5 encodes the minor isoform of pyruvate
      decarboxylase (Pdc). In this work we show that expression of PDC5 but not that of
      PDC1, which encodes the major isoform, is repressed by thiamine. Hence, under
      thiamine limitation both PDC1 and PDC5 are expressed. PDC5 also becomes strongly
      expressed in a pdc1delta mutant. Two-dimensional gel electrophoresis of whole
      protein extracts shows that thiamine limitation stimulates the production of THI
      gene products and of Pdc5p. Deletion of PDC1 only stimulates production of Pdc5p.
      We conclude that the stimulation of PDC5 expression in a pdc1delta mutant is not
      due to a response to thiamine limitation.

PMID- 10338142
TI  - A re-investigation of the ribonuclease sensitivity of a DNA demethylation
      reaction in chicken embryo and G8 mouse myoblasts.
AB  - Recently published results (Nucleic Acids Res. 26, 5573-5580, 1998) suggest that
      the ribonuclease sensitivity of the DNA demethylation reaction may be an
      experimental artifact due to the possible tight binding of the nucleases to the
      methylated DNA substrate. Using an improved protocol we show for two different
      systems that demethylation of hemimethylated DNA is indeed sensitive to
      micrococcal nuclease, requires RNA and is not an experimental artifact. The
      purified 5-MeC-DNA glycosylase from chicken embryos and G8 mouse myoblasts was
      first incubated for 5 min at 37 degrees C with micrococcal nuclease in the
      presence of Ca2+ in the absence of the DNA substrate. Upon blocking the nuclease
      activity by the addition of 25 mM EGTA, the DNA demethylation reaction was
      initiated by adding the labeled hemimethylated DNA substrate to the reaction
      mixture. Under these conditions the DNA demethylation reaction was abolished. In
      parallel controls, where the purified 5-MeC-DNA glycosylase was pre-incubated at
      37 degrees C with the nuclease, Ca2+ and EGTA or with the nuclease and EGTA, RNA
      was not degraded and no inhibition of the demethylation reaction was obtained. As
      has already been shown for chicken embryos, the loss of 5-MeC-DNA glycosylase
      activity from G8 myoblasts following nuclease treatment can also be restored by
      the addition of synthetic RNA complementary to the methylated strand of the
      substrate DNA. No reactivation of 5-MeC-DNA glycosylase is obtained by
      complementation with a random RNA sequence, the RNA sequence complementary to the
      non-methylated strand or DNA, thus ruling out a non-specific competition of the
      RNA for the binding of the nuclease to the labeled DNA substrate.

PMID- 10338143
TI  - Beta-carotene enhances hydrogen peroxide-induced DNA damage in human
      hepatocellular HepG2 cells.
AB  - In this study, the alkaline version of the comet assay has been used to determine
      the effect of beta-carotene supplementation (10 microM) on peroxide-initiated
      free radical-mediated DNA damage in human HepG2 hepatoma cells. In supplemented
      cells, beta-carotene failed to afford any protection against hydrogen peroxide
      induced DNA strand breaks. Indeed, levels of strand breaks in supplemented cells
      were significantly higher than in cells exposed to hydrogen peroxide alone,
      especially after a long incubation period. In contrast, beta-carotene afforded
      significant levels of protection against DNA strand breaks when cells were
      treated with tert-butyl hydroperoxide. In this case, the level of protection
      increased as supplementation continued.

PMID- 10338144
TI  - pADPRT-2: a novel mammalian polymerizing(ADP-ribosyl)transferase gene related to
      truncated pADPRT homologues in plants and Caenorhabditis elegans.
AB  - Until recently, poly(ADP-ribosyl)ation was supposed to be confined only to
      polymerizing(ADP-ribosyl)transferase/(ADP-ribose)polymerase (E.C. 2.4.2.30).
      Here, we present novel polymerizing(ADP-ribosyl)transferase homologues from mouse
      and man that lack all of the N-terminal DNA binding and BRCA1 C-terminus domains
      and will be designated polymerizing(ADP-ribosyl)transferase-2 as distinguished
      from the classical polymerizing(ADP-ribosyl)transferase (polymerizing(ADP
      ribosyl)transferase-1). The murine polymerizing(ADP-ribosyl)transferase-2 gene
      shares three identical intron positions with its Caenorhabditis elegans (EMBL
      nucleotide sequence database Z47075) and one with the Arabidopsis thaliana
      homologue ('APP', GenBank database AF069298). Expression of the murine
      polymerizing(ADP-ribosyl)transferase-2 gene was elevated in spleen, thymus and
      testis and the corresponding poly(ADP-ribosyl)ation activity might account for
      most of the residual poly(ADP-ribosyl)ation observed in polymerizing(ADP
      ribosyl)transferase-1(-/-) mice.

PMID- 10338146
TI  - Bacteriochlorin-protein interactions in native B800-B850, B800 deficient and B800
      Bchla(p)-reconstituted complexes from Rhodopseudomonas acidophila, strain 10050.
AB  - Recently, a method which allows the selective release and removal of the 800 nm
      absorbing bacteriochlorophyll a (B800) molecules from the LH2 complex of
      Rhodopseudomonas acidophila strain 10050 has been described [Fraser, N.J. (1999)
      Ph.D. Thesis, University of Glasgow, UK]. This procedure also allows the
      reconstitution of empty binding sites with the native pigment Bchla(p),
      esterified with phytol. We have investigated the bacteriochlorophylla-protein
      interactions in native, B800 deficient (or B850) and in B8110
      bacteriochlorophylla(p)-reconstituted LH2 complexes by resonance Raman
      spectroscopy. We present the first direct structural evidence which shows that
      the reconstituted pigments are correctly bound within their binding pockets.

PMID- 10338145
TI  - Isolation and characterisation of oxygen evolving thylakoids from the marine
      prokaryote Prochloron didemni.
AB  - The present study describes the first successful attempt to isolate oxygen
      evolving thylakoids and thylakoid fragments from the marine prokaryote Prochloron
      didemni, a member of the recently discovered group of prochlorophytes. Oxygen
      evolving thylakoid membranes and fragments were isolated from seawater suspended
      cells of Prochloron didemni by passage of the cells through a Yeda press and
      subsequent differential centrifugation of the broken material. Three fractions
      were collected at 1000 x g, 5000 x g, and 3000 x g and identified by light
      microscopy as cells (and their fragments), thylakoids and membrane fragments,
      respectively. Pigment content, oxygen evolution rate and 77 K fluorescence
      spectra of these fractions were virtually identical. This finding indicates that
      the membrane fragments obtained are not enriched in photosystem II. The P680+*
      reduction kinetics of thylakoid membrane fragments were determined by monitoring
      flash induced absorption changes at 830 nm and analysing the time course of their
      decay. The multiphasic relaxation kinetics and their modification by NH2OH were
      found to be similar to those observed in cyanobacteria and plants. These findings
      provide an independent line of evidence for the idea of a high conservation of
      the basic structural and functional pattern of the water oxidising complex in all
      organisms that perform oxygenic photosynthesis.

PMID- 10338147
TI  - Endometrial expression of cellular protooncogene c-ski and its regulation by
      estradiol-17beta.
AB  - The expression of the cellular protooncogene c-ski was examined in the rat
      uterus. In situ hybridization revealed that c-ski mRNA was expressed in the
      uterus of the adult rat on the day of estrous and localized mainly in the luminal
      and glandular epithelia. To test the possibility that the expression of c-ski
      mRNA is induced by estrogen, rats were ovariectomized and estradiol-17beta (E2)
      was injected. The expression of c-ski mRNA was upregulated 3 h after E2
      treatment, reaching the highest level at 6 h and this persisted until 24 h; the
      E2-induced expression of c-ski mRNA was restricted to the luminal and glandular
      epithelia. These results suggest that the c-ski gene plays a role in uterine
      epithelial cell proliferation and mediates the proliferative action of E2.

PMID- 10338148
TI  - Real-time observation of acrosomal dispersal from mouse sperm using GFP as a
      marker protein.
AB  - We produced transgenic mouse lines that accumulate mutated green fluorescent
      protein (EGFP) in sperm acrosome, a membrane limited organelle overlying the
      nucleus. The sperm showed normal fertilizing ability and the integrity of their
      acrosome was easily examined in a non-invasive manner by tracing the GFP in
      individual 'live' sperm with fluorescent microscopy. The time required for the
      dispersal of acrosomal contents was demonstrated to be approximately 3 s after
      the onset of acrosome reaction.

PMID- 10338149
TI  - Inhibition of insulin-like growth factor-I mitogenic action by zinc chelation is
      associated with a decreased mitogen-activated protein kinase activation in RAT-1
      fibroblasts.
AB  - The mechanisms responsible for the resistance to the anabolic actions of IGF-I
      induced by zinc deficiency are not understood. We showed that zinc chelation by
      DTPA (diethylenetriaminepenta-acetic acid) inhibits [3H]thymidine incorporation
      stimulated by IGF-I in Rat-1 fibroblasts. This inhibition was specific of zinc
      chelation since it was prevented by the addition of zinc to DTPA. The stimulation
      of MAPK, which is crucial for the [3H]thymidine incorporation induced by IGF-I in
      Rat-1 cells, was partially blunted by DTPA. Therefore, the inhibition of the
      mitogenic action of IGF-I in Rat-1 fibroblasts by DTPA is potentially caused by
      decreased MAPK activation by IGF-I.

PMID- 10338150
TI  - UDP-N-acetylglucosamine:N-acetylmuramoyl-(pentapeptide) pyrophosphoryl
      undecaprenol N-acetylglucosamine transferase from Escherichia coli:
      overproduction, solubilization, and purification.
AB  - Plasmids for the high-level overproduction of wild-type, and C- and N-terminal
      His-tagged MurG N-acetylglucosaminyl transferase from Escherichia coli were
      constructed. In complementation tests the three forms were active in vivo. After
      IPTG induction, growth, spheroplast formation and lysis, overproduced MurG
      proteins were mainly present (90%) in the particulate fraction. Readily
      solubilized by CHAPS, they were purified without any detergent to over 80% purity
      for both His-tagged forms but only up to 20% for the wild-type form. The
      enzymatic activity of each purified MurG protein was determined and found to be
      inhibited to the same extent by ramoplanin.

PMID- 10338151
TI  - Relation of natural killer cell line NK-92-mediated cytolysis (NK-92-lysis) with
      the surface markers of major histocompatibility complex class I antigens,
      adhesion molecules, and Fas of target cells.
AB  - Natural killer (NK) cell line NK-92 has recently been established by Klingemann
      et al. In this study, we compared the NK-92-mediated cytolysis (NK-92-lysis) with
      the killing of healthy volunteers' NK cells and lymphokine-activated killer (LAK)
      cells. The NK-92-lysis was partially different from the NK- and LAK-lysis. 1) The
      NK-92 could kill most of major histocompatibility complex (MHC) class I antigen
      positive tumor cells. 2) The NK cells killed a myeloid leukemia cell line K562,
      but the NK-92 showed low killer activity against it. 3) The LAK cells could not
      kill a CD58-deficient cell line OKM-2T, whereas the NK-92 could kill it
      sufficiently. 4) The NK-92 could not kill CD54-, CD102-deficient cell lines T98G
      and U373MG; however, the LAK cells could kill them. Blocking tests using specific
      antibodies revealed the reason for these differences. The K562 expressed
      relatively low levels of CD54 and CD102. When the K562 was pretreated with anti
      CD54 and anti-CD102, the NK-92 could not kill it at all, whereas the NK cells
      could still kill it, although the killing level decreased. The NK-92 could not
      kill the anti-CD54- and anti-CD102-treated OKM-2T. The LAK cells could not kill
      anti-CD58-treated U373MG and T98G. These findings suggest that NK-92-lysis may
      require the CD54 and CD102 but that NK-lysis does not require them as much,
      whereas the LAK-lysis may be rather in relation with the CD58. The NK-92 has high
      killer activity, and may be applicable for clinical use. However, it should be
      considered that the NK-92 cannnot kill CD54-, CD102-deficient tumor cells.

PMID- 10338152
TI  - Effect of local anesthetic ropivacaine on the energy metabolism of Ehrlich
      ascites tumor cells.
AB  - The effect of local anesthetic ropivacaine on the energy metabolism of Ehrlich
      ascites tumor cells has been investigated. Ropivacaine impaired energy metabolism
      of Ehrlich ascites tumor cells by affecting primarily mitochondrial metabolism.
      Even at low concentrations ropivacaine decreased the rate of oxygen uptake, but
      its effect was remarkably higher on the uncoupled respiration and, in both cases,
      it was strongly enhanced by hydrophobic anion tetraphenylboron (TPB-). The
      decrease of oxygen uptake was ascribed to an impairment of electron transport
      from site 1- and 2-entering substrates to respiratory chain. The inhibition of
      respiration, coupled to a true uncoupling mechanism by an electrophoretic
      mechanism, impaired ADP phosphorylation, decreased ATP content, and collapsed
      mitochondrial membrane potential. Ropivacaine, at all concentrations tested,
      stimulated aerobic lactate production, and this increase, in addition to the
      inhibition of respiration, was also due to an activation of mitochondrial ATPase.

PMID- 10338153
TI  - An alpha2-macroglobulin-serine proteinase complex from human carcinomatous
      ascites and pleural effusion: isolation, monoclonal antibody preparation, and
      immunohistochemical study.
AB  - A protein with the apparent molecular mass of 720 kDa which hydrolyzes anilide
      substrates of p-guanidino-L-phenylalanine was purified from ascites and pleural
      effusion of patients with pulmonary, breast, gastric, and ovarian cancers by
      chromatographic techniques. When this protein was separated on SDS-PAGE on
      nonreducing conditions, two bands corresponding to 720 and 360 kDa were seen to
      have gelatin-digestive activity in zymography assay. Moreover, when it separated
      by SDS-PAGE on reducing conditions, it migrated as several bands up to 180 kDa.
      The N-terminal amino acid sequence and immunoreactivity of anti-alpha2
      macroglobulin polyclonal antibody revealed that the 180-kDa band was intact
      alpha2-macroglobulin. The hydrolytic activity of this complex was completely
      inhibited by diisopropyl fluorophosphate (DFP) and p-amidinophenylmethanesulfonyl
      fluoride. In addition, the 65-kDa protein observed under reducing conditions
      bound 3H-labeled DFP. These results suggest that the purified protein is a
      complex of the plasma proteinase inhibitor alpha2-macroglobulin and a serine
      proteinase. Several monoclonal antibodies were obtained when the purified complex
      was used as an antigen. One of these antibodies, which was immunoreactive to this
      complex but not to alpha2-macroglobulin, gave a positive band corresponding to 65
      kDa on SDS-PAGE under reducing conditions. Use of this antibody in
      immunohistochemical studies revealed immunoreactivities in numerous neoplastic
      tissues with strong activity in advanced gastric cancers (e.g., poorly
      differentiated adenocarcinoma). In addition, strong cross-reactivity was detected
      in glandular cells of the fetus intestine.

PMID- 10338154
TI  - Formation of a major DNA adduct of the mitomycin metabolite 2,7-diaminomitosene
      in EMT6 mouse mammary tumor cells treated with mitomycin C.
AB  - Treatment of EMT6 mouse mammary tumor cells with [3H]mitomycin C (MC) results in
      the formation of six major DNA adducts, as described earlier using an HPLC assay
      of 3H-labeled products of enzymatic hydrolysis of DNA isolated from MC-treated
      cells. Four of these adducts were identified as monofunctional and bifunctional
      guanine-N2 adducts in the minor groove of DNA. In order to establish
      relationships between individual types of MC-DNA adducts and biological responses
      it is necessary to identify all of the adducts formed in cells. To this end we
      have now identified a predominant, previously unknown adduct formed in MC-treated
      EMT6 cells as a derivative not of MC, but of 2,7-diaminomitosene (2,7-DAM), the
      major bioreductive metabolite of MC. Rigorous proof demonstrates that it is a DNA
      major groove, guanine-N7 adduct of 2,7-DAM, linked at C-10 to DNA. The adduct is
      relatively stable at ambient temperature, but is readily depurinated upon
      heating. Its isolation from MC-treated cells indicates that MC is reductively
      metabolized to 2,7-DAM, which then undergoes further reductive activation to
      alkylate DNA, along with the parent MC. Low MC:DNA ratios were identified as a
      critical factor promoting 2,7-DAM adduct formation in an in vitro model calf
      thymus DNA/ MC/reductase model system, as well as in MC-treated EMT6 cells. The
      2,7-DAM-guanine-N7 DNA adduct appears to be relatively noncytotoxic, as indicated
      by the dramatically lower cytotoxicity of 2,7-DAM in comparison with MC in EMT6
      cells. Like MC, 2,7-DAM exhibited slightly greater cytotoxicity to cells treated
      under hypoxic as compared to aerobic conditions. However, 2,7-DAM was markedly
      less cytotoxic than MC under both aerobic and hypoxic conditions. Thus, metabolic
      reduction of MC to 2,7-DAM represents a detoxification process. The differential
      effects of MC-DNA and 2,7-DAM-DNA adducts support the concept that specific
      structural features of the DNA damage may play a critical role in the cytotoxic
      response to a DNA-targeted chemotherapeutic agent.

PMID- 10338155
TI  - Antiproliferative effects of acyclic nucleoside phosphonates on human
      papillomavirus (HPV)-harboring cell lines compared with HPV-negative cell lines.
AB  - Acyclic nucleoside phosphonates (ANPs) possess a broad-spectrum activity against
      DNA viruses and retroviruses. HPMPC (cidofovir) has proved to be effective in the
      treatment of HPV-associated diseases. We have evaluated the effects of various
      ANPs [i.e., 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA)
      and cytosine (HPMPC, cidofovir)]; cyclic HPMPC (cHPMPC); 9-(2
      phosphonylmethoxyethyl) derivatives of adenine (PMEA, adefovir), guanine (PMEG),
      and 2,6-diaminopurine (PMEDAP); and cyclo-propyl PMEDAP (cPr-PMEDAP), several
      other antiviral drugs [i.e., acyclovir (ACV), ganciclovir (GCV), foscarnet (PFA),
      and ribavirin]; the antitumor agents cytarabine (AraC) and 5-fluorouracil (5-FU);
      and the immunosuppressant mycophenolic acid (MPA) on the proliferation of human
      cervical keratinocytes immortalized by HPV-33 (CK-1 cells) and the cervical
      carcinoma cell lines containing HPV-16 (CaSki and SiHa) or HPV-18 (HeLa). In
      vitro incubation of these cell lines with ANPs resulted in a concentration- and
      time-dependent inhibition of cell proliferation. This inhibitory effect was most
      striking for HPMPC. The 50% inhibitory concentration (IC50) of HPMPC decreased
      from 20-50 microg/ml at day 3 to 0.6-2 microg/ml at day 7. When the IC50 values
      of the ANPs for the various HPV-harboring cells were compared with those for
      primary human keratinocytes isolated from normal cervix, HPMPC emerged as the
      most selective ANP, with a selectivity index (SI) in the range of 15-42. When
      IC50 values as a function of time were determined for several tumor cell lines
      (i.e., human melanomas, lung, colon, and breast carcinomas), ANPs again showed an
      antiproliferative effect as a function of time, although of a lower extent (5- to
      25-fold decrease in the IC50 values between days 3 and 7) than for the HPV
      positive cells. Treatment of SV40- and adenovirus-transformed cells with ANPs
      resulted in the inhibition of cell proliferation as a function of time, similar
      to that observed with HPV-positive cells, HPMPC and cHPMPC being the most potent
      antiproliferative agents. These results suggest that the antiproliferative
      activity of ANPs, in particular HPMPC, against HPV-bearing tumor cells may be
      explained, at least in part, by a specific inhibitory effect on rapidly
      proliferating cells, and the presence of the HPV genome might enhance the
      sensitivity of cells to HPMPC due to interactions of the viral-transforming
      proteins with products of the tumor suppressor genes.

PMID- 10338156
TI  - Inhibiting effects of cidofovir (HPMPC) on the growth of the human cervical
      carcinoma (SiHa) xenografts in athymic nude mice.
AB  - At present more than 70 human papillomaviruses (HPV) genotypes have been
      described and each shows a predilection for a cutaneous or mucosal surface. There
      is a strong association between infection with specific genital viruses (i.e.,
      types 16 and 18) and the development of cervical cancer. Thus, intervention with
      the natural history of HPV infection in the genital tract may form the basis for
      an effective anticancer strategy. We have shown that treatment of cell lines
      derived from human cervical carcinomas [i.e., SiHa and CaSki (HPV-16-positive)]
      and HeLa (HPV-18-positive)] with HPMPC (cidofovir) results in a concentration-
      and time-dependent inhibition of cell proliferation. We report here the effects
      of HPMPC on the growth of cervical carcinoma (SiHa) xenografts in athymic nude
      mice. Athymic mice between the age of 6 and 8 weeks were injected SC with 5 to
      10x10(6) cells. Once tumors were established, the mice were injected with PBS
      (placebo), HPMPC, or cytarabine (AraC) at the tumor site. Animals that were
      injected intratumorally with HPMPC at a dose of 5 mg/ml (0.25 mg/injection) or 10
      mg/ml (0.5 mg/injection) three or five times per week, once daily, during 4 weeks
      showed a statistically significant reduction in tumor size compared to the
      placebo group or AraC group. However, when HMPC was administered topically (as a
      cream) or systemically (intraperitoneally), no reduction of tumor growth was
      observed at nontoxic concentrations, suggesting that a high local concentration
      of HPMPC is required to achieve a significant decrease of tumor growth.

PMID- 10338157
TI  - Possible hemolytic uremic syndrome in three cats after renal transplantation and
      cyclosporine therapy.
AB  - OBJECTIVE: To describe the clinical history of 3 cats with possible hemolytic
      uremic syndrome (HUS) after renal transplantation. STUDY DESIGN: This case series
      documents historical findings, physical examination findings, clinical pathologic
      features, necropsy and histopathologic findings of 3 cats with possible HUS.
      RESULTS: Two cats had chronic renal failure; 1 cat had acute renal failure
      secondary to ethylene glycol toxicity. A renal transplant was performed in each
      of the 3 cats without obvious problems. Complications that would support a
      diagnosis of HUS, including anemia, thrombocytopenia, and azotemia occurred
      within 24 hours in 1 cat, within 8 days in a second cat, and 2 months after
      transplantation in the third cat. In 2 cats, HUS was likely secondary to
      cyclosporine immunosuppression. In the third cat, HUS may have been secondary to
      allograft rejection. Renal biopsies from all 3 cats were suggestive of HUS.
      CONCLUSION AND CLINICAL RELEVANCE: In human beings, HUS in transplant recipients
      may occur secondary to immunosuppressive drugs, vascular rejection, or recurrence
      of original disease. Graft loss occurred in all 3 cats in this study and the
      mortality rate was 100%. Clinicians caring for these patients need to be aware of
      this disorder because early recognition and treatment is critical in the
      management of post-transplant HUS.

PMID- 10338158
TI  - Axial pattern flap based on the cutaneous branch of the superficial temporal
      artery in dogs: an experimental study and case report.
AB  - OBJECTIVE: To determine the anatomic guidelines and viability of an axial pattern
      flap based on the cutaneous branch of the superficial temporal artery (STA) in
      dogs. Application of the flap in a clinical patient is reported. STUDY DESIGN:
      Flap viability in control and experimental groups was determined 7 days
      postoperatively. ANIMALS: A total of 14 mature, mesaticephalic dogs; 1 clinical
      patient. METHODS: The cutaneous branch of the STA and vein were incorporated in
      the flaps of the experimental groups (group A, n = 5; group B, n = 4) and were
      ligated in the control group (n = 5). Flap length was extended in experimental
      group B. Seven days postoperatively, the length and area of tissue that remained
      viable in each flap was determined and compared with similar measurements
      performed intraoperatively. Cutaneous fluorescence was also used postoperatively
      to assess flap perfusion. The flap used in the clinical patient had the same
      dimensions as flaps developed in group A. RESULTS: Mean survival length (+/- SD)
      of STA flaps [group A, 9.1 (0.8) cm], was significantly increased (P < .05)
      compared with control flaps [7.0 (0.6) cm]. Percentage flap length survival (+/-
      SD) of STA flaps [group A, 91.8 (8.9)%], was significantly increased (P < .05)
      compared with control flaps [71.6 (7.0)%]. Mean percentage area of survival (+/-
      SD) of STA flaps [group A, 93.1 (7.5)%], was significantly increased (P < .05)
      compared with control flaps [73.5 (7.4)%]. Group B flaps had a mean survival
      length of 10.4 (1.1) cm, percentage flap length survival of 69.5 (4.8)%, and mean
      percentage area of survival of 69.1 (6.5)%. There was no positive correlation
      between the area of flap fluorescence at days 0, 1, and 3, and the area of flap
      survival. Application of the flap in a clinical patient allowed primary wound
      reconstruction with 100% survival. CONCLUSION: A flap based on the cutaneous
      branch of the STA may be a source of skin for reconstructive procedures of the
      maxillofacial region in dogs. CLINICAL RELEVANCE: Knowledge of the anatomic
      landmarks and expected viability of a STA axial pattern flap is essential before
      consideration of its use as a reconstructive surgical technique.

PMID- 10338159
TI  - Biomechanical comparison of two plating techniques for fixation of acetabular
      osteotomies in dogs.
AB  - OBJECTIVE: To compare the failure properties of a 5-hole, 2.7-mm curved
      acetabular plate (AP) to a 5-hole, 3.5-mm reconstruction plate (RP) when applied
      to acetabular osteotomies. STUDY DESIGN: Cadaver study. ANIMALS OR SAMPLE
      POPULATION: Pelves of 8 mature, large-breed dogs. METHODS: A 5-hole, 2.7-mm AP
      and a 5-hole, 3.5-mm RP were contoured and applied to the dorsal acetabulum of
      each pelvis. A central acetabular fracture was simulated after plate application
      by a transverse osteotomy with a fine saw. Each acetabulum was loaded in a weight
      bearing direction. A load-deformation curve was produced for each construct, and
      biomechanical properties of the AP and RP were compared with the Student's paired
      t-test. A P value of < .05 was considered significant. RESULTS: For the AP and RP
      composite respectively, the mean +/- SD maximum load to failure was 2,721 +/- 632
      N and 2,488 +/- 800 N, the stiffness was 4.8 +/- 1.8 N/m and 5.3 +/- 1.9 N/m, and
      the energy absorbed was 15.1 +/- 5.2 Nm and 16.3 +/- 8.3 Nm. None of these
      differences was statistically significant. CONCLUSIONS: Both fixation techniques
      provided comparable strength, stiffness, and energy absorbed under the loading
      conditions of this study. CLINICAL RELEVANCE: Because of the relative ease of
      application, the 2.7-mm curved AP may be the practical choice for acetabular
      fracture repair in large dogs.

PMID- 10338160
TI  - The effect of oral isoxsuprine and pentoxifylline on digital and laminar blood
      flow in healthy horses.
AB  - OBJECTIVE: To quantitate blood flow in the palmar digital artery and dorsal
      laminae of the hoof in standing, unmedicated, nonsedated horses, and in horses
      treated with oral isoxsuprine, oral pentoxifylline, and intravenous
      acetylpromazine as a positive control. STUDY DESIGN: Experimental study;
      treatments administered in a random cross-over design. ANIMALS: A total of 6
      healthy horses selected with at least one nonpigmented forelimb hoof wall and
      determined to be free of laminitis. METHODS: All horses were instrumented with a
      flow probe placed around one palmar digital artery under general anesthesia and a
      laser doppler flow probe placed within a hole in the dorsal hoof wall to measure
      digital blood flow and laminar perfusion respectively. Baseline readings of
      palmar digital blood flow and laminar perfusion were recorded before and between
      treatments. Horses were randomly assigned to one of two groups and treated with
      either isoxsuprine (1.2 mg/kg, orally twice daily for 10 days) or pentoxifylline
      (4.4 mg/kg, orally every 8 hours for 10 days) in a random cross-over design.
      Digital blood flow (DBF) and laminar perfusion (LP) were measured on days 2, 5,
      7, and 10 of treatment. Horses also received acetylpromazine as a positive
      control (0.066 mg/kg, intravenously) during the washout period, and measurements
      were taken every 15 minutes until measurements returned to baseline readings.
      Data were analyzed by using repeated measures ANOVA. RESULTS: Digital blood flow
      (11.2 to 97.7 mL/min) and laminar perfusion (1.0 to 11.1 Capillary Perfusion
      Units) differed between horses. No statistically significant increases in DBF or
      LP were detected over the 10 day treatment period with either isoxsuprine or
      pentoxifylline. Acepromazine resulted in a significant increase (P = .0007) in
      DBF for approximately 75 minutes beginning 15 minutes after treatment. A mild but
      insignificant increase in LP was identified after acetylpromazine treatment.
      CONCLUSION: Neither isoxsuprine nor pentoxifylline increased blood flow to the
      digit or dorsal laminae in healthy horses. Acepromazine caused an increased blood
      flow to the digit. Based on the results of this study acetylpromazine potentially
      would have a greater effect on improving digital blood flow than oral isoxsuprine
      or pentoxifylline when treating ischemic conditions of the foot in horses.

PMID- 10338161
TI  - A biomechanical comparison of screw and wire fixation with and without
      polymethylmethacrylate re-enforcement for acetabular osteotomy stabilization in
      dogs.
AB  - OBJECTIVE: Compare the biomechanical characteristics of screw and wire fixation
      with and without polymethylmethacrylate (PMMA) re-enforcement for acetabular
      osteotomy stabilization in dogs. ANIMALS: Pelves removed from 8 adult mixed breed
      dogs weighing between 25 and 30 kg. PROCEDURE: The pubic symphysis of each pelvis
      was split and a central transverse acetabular osteotomy was performed. One
      hemipelvis from each dog was stabilized with the composite fixation
      (interfragmentary Kirschner wire, two screws and a figure-of-eight orthopedic
      wire with PMMA). The contralateral hemipelves was stabilized with an
      interfragmentary Kirschner wire, two screws, and a figure-of-eight orthopedic
      wire without PMMA. All hemipelves were tested in bending by using a materials
      testing machine at a cross head speed of 5 mm/min. An extensometer was placed on
      the dorsomedial surface of the hemipelves centered over acetabular osteotomy to
      record distraction of the osteotomy during loading. A load/deformation curve and
      a load/distraction curve was produced for each hemipelvis. The slope for the
      initial linear portion of the load/deformation curve and the load/distraction
      curve, yield load and maximum load sustained were compared between repair groups
      using a paired t-test with P < .05 considered significant. RESULTS: The slope of
      the load/deformation curve was significantly greater (P = .001) for hemipelves
      stabilized with the composite fixation (mean +/- SD: 69 +/- 18 N/mm) compared
      with hemipelves stabilized without PMMA (mean +/- SD: 39 +/- 8 N/mm). There was
      no significant difference (P = .593) between repair groups in the slope of the
      load/distraction curves as measured on the extensometer. Yield load was
      significantly greater (P = .0002) for hemipelves stabilized with the composite
      fixation (mean +/- SD: 184 +/- 25 N) compared to hemipelves stabilized without
      PMMA (mean +/- SD: 74 +/- 12 N). Maximum load sustained was also significantly
      greater (P = .013) for hemipelves stabilized with the composite fixation (mean +/
      SD: 396 +/- 71 N) compared to hemipelves stabilized without PMMA (mean +/- SD:
      265 +/- 94 N). Failure of hemipelves stabilized with the composite fixation
      occurred primarily by ventrolateral bending of the cranial and caudal pelvic
      segments at the osteotomy site. Failure of hemipelves stabilized without PMMA
      occurred by ventrolateral bending of the cranial and caudal pelvic segments at
      the osteotomy site with pronounced concurrent ventrolateral rotation of the
      cranial pelvic segment. CONCLUSION: PMMA improves the mechanical characteristics
      of acetabular fracture fixation, at least in part by neutralization of rotational
      forces. The results of this study justify use of PMMA as a component of the
      composite fixation when repairing acetabular fractures.

PMID- 10338162
TI  - Effect of disk fenestration on sagittal kinematics of the canine C5-C6
      intervertebral space.
AB  - OBJECTIVE: To determine the effect that ventral intervertebral disk fenestration
      has on the sagittal range of motion about the C5-C6 intervertebral space. STUDY
      DESIGN: A repeated measures in vitro mechanical study of spinal range of motion
      under controlled loading conditions before and after fenestration. SAMPLE
      POPULATION: A total of 10 canine cervical vertebral specimens (C4-C7) collected
      from clinically normal animals within 12 hours of euthanasia. METHODS: Specimens
      were loaded as cantilever beams fixed at C7. Weights (1 to 5 kg) were
      progressively applied to C4 to produce flexion or extension in the sagittal
      plane. Radiographs were taken at each load, 3 times before and 3 times after
      fenestration of the C5-C6 disk. The positions of radiodense markers embedded in
      the vertebrae were used to calculate flexion and extension angles and range of
      motion. RESULTS: Range of motion (difference between flexion and extension) and
      flexion and extension angles (individually) significantly increased after
      fenestration (P < .0001). CONCLUSION: Ventral fenestration produces sagittal
      instability of the C5-C6 disk space. CLINICAL RELEVANCE: In surgical fusion of
      caudal cervical intervertebral spaces in dogs, radiographically normal disks
      adjacent to the affected space are often fenestrated to facilitate distraction
      before surgical stabilization. This study shows that ventral fenestration
      produces instability of a caudal cervical intervertebral space in the model used.
      Such instability may contribute to the development of the secondary instability
      ("domino lesions") seen in some surgically treated dogs.

PMID- 10338163
TI  - Effect of ischemia and reperfusion on neutrophil accumulation in equine
      microvascular tissue flaps.
AB  - OBJECTIVE: To investigate neutrophil accumulation after ischemia and reperfusion
      (IR) in microvascular tissue flaps in horses. STUDY DESIGN: Randomized controlled
      experiment. SAMPLE POPULATION: A total of 8 horses between 1 and 10 years of age,
      4 of each sex. METHODS: Control and experimental myocutaneous island flaps based
      on the superficial branch of the deep circumflex iliac vessels were dissected on
      each horse. Atraumatic vascular clamps were applied to the pedicle of the
      experimental flap for 90 minutes and then removed to allow reperfusion. Based on
      the assumption that rapid infiltration of neutrophils into affected tissues is a
      hallmark of IR injury, radiolabeled autogenous leukocytes were used to indirectly
      quantify neutrophil accumulation in flap tissues. Labeled leukocytes were
      administered through a jugular catheter 30 minutes before flap reperfusion.
      Biopsies were collected from each flap over a 6 hour postischemia time period; in
      group 1 (n = 4) from 0 to 6 hours postischemia, and in group 2 (n = 4) from 24 to
      30 hours postischemia. Biopsies were examined scintigraphically and
      histologically for evidence of neutrophil infiltration. RESULTS: All control
      flaps survived and 6 of 8 experimental flaps survived. There was no significant
      evidence of acute neutrophil infiltration into flap tissues after reperfusion in
      either group. CONCLUSIONS: The results of this study suggest that equine
      myocutaneous flap tissues can survive a 90-minute ischemic period and
      reperfusion. No significant evidence of the occurrence of IR injury in flap
      tissues was found. CLINICAL RELEVANCE: The reasons for the previously reported
      failures of equine free tissue transfer remain uncertain, but they do not appear
      to be caused by neutrophil mediated injury associated with ischemia and
      reperfusion.

PMID- 10338164
TI  - Closed reduction and lag screw fixation of sacroiliac luxations and fractures.
AB  - OBJECTIVE: To describe a technique for closed reduction and percutaneous
      insertion of a lag screw for fixation of sacroiliac fracture-luxations, and to
      report the success of this technique in stabilizing sacroiliac fracture
      luxations. STUDY DESIGN: A retrospective clinical study. STUDY POPULATION: 13
      consecutive client-owned dogs with sacroiliac fracture-luxations. METHODS:
      Sacroiliac fracture-luxations were stabilized by using a closed reduction and
      percutaneous lag screw fixation technique. Preoperative, postoperative, and last
      re-examination radiographs were used to assess the location and number of pelvic
      injuries, other orthopedic injuries, percent reduction of the sacroiliac joint,
      percent sacral width screw depth, position of the screw, pelvic canal diameter
      ratio, hemipelvic canal width ratio, and complications. Information on
      signalment, weight, weight-bearing status, neurologic status, and complications
      was obtained from the medical record. RESULTS: Mean percent reduction of the
      sacroiliac joint was 92.33%. All screws were placed within the sacral body with a
      mean screw depth/sacral width of 79.03%. No screw loosening occurred. Mean pelvic
      canal diameter ratios were 0.99, 1.20, and 1.14 preoperatively, immediately
      postoperatively, and at the last re-examination, respectively. Nine of 13 dogs
      were willing to walk on the ipsilateral rear leg the day after surgery.
      CONCLUSIONS: Closed reduction and percutaneous insertion of a lag screw for
      stabilization of fracture-luxation of the sacroiliac joint is an acceptable
      method of repair. CLINICAL RELEVANCE: Sacroiliac fracture-luxations can be
      successfully reduced and stabilized using a minimally invasive technique.

PMID- 10338165
TI  - Preferred method of repair of cranial cruciate ligament rupture in dogs: a survey
      of ACVS diplomates specializing in canine orthopedics. American College of
      Veterinary Surgery.

PMID- 10338166
TI  - Detomidine-propofol anesthesia for abdominal surgery in horses.
AB  - OBJECTIVE: To evaluate propofol for induction and maintenance of anesthesia,
      after detomidine premedication, in horses undergoing abdominal surgery for
      creation of an experimental intestinal adhesion model. STUDY DESIGN: Prospective
      study. ANIMALS: Twelve horses (424 +/- 81 kg) from 1 to 20 years of age (5
      females, 7 males). METHODS: Horses were premedicated with detomidine (0.015 mg/kg
      i.v.) 20 to 25 minutes before induction, and a propofol bolus (2 mg/kg i.v.) was
      administered for induction. Propofol infusion (0.2 mg/kg/min i.v.) was used to
      maintain anesthesia. The infusion rate was adjusted to maintain an acceptable
      anesthetic plane as determined by muscle relaxation, occular signs, response to
      surgery, and cardiopulmonary responses. Oxygen (15 L/min) was insufflated through
      an endotracheal tube as necessary to maintain the SpO2 greater than 90%. Systolic
      (SAP), mean (MAP), and diastolic (DAP) arterial pressures, heart rate (HR),
      electrocardiogram (ECG), respiratory rate (RR), SpO2 (via pulse oximetry), and
      nasal temperature were recorded at 15 minute intervals, before premedication and
      after induction of anesthesia. Arterial blood gas samples were collected at the
      same times. Objective data are reported as mean (+/-SD); subjective data are
      reported as medians (range). RESULTS: Propofol (2.0 mg/kg i.v.) induced
      anesthesia (mean bolus time, 85 sec) within 24 sec (+/-22 sec) after the bolus
      was completed. Induction was good in 10 horses; 2 horses showed signs of
      excitement and these two inductions were not smooth. Propofol infusion (0.18
      mg/kg/min +/- 0.04) was used to maintain anesthesia for 61 +/- 19 minutes with
      the horses in dorsal recumbency. Mean SAP, DAP, and MAP increased significantly
      over time from 131 to 148, 89 to 101, and 105 to 121 mm Hg, respectively. Mean HR
      varied over time from 43 to 45 beats/min, whereas mean RR increased significantly
      over anesthesia time from 4 to 6 breaths/min. Mean arterial pH decreased from a
      baseline of 7.41 +/- 0.07 to 7.30 +/- 0.05 at 15 minutes of anesthesia, then
      increased towards baseline values. Mean PaCO2 values increased during anesthesia,
      ranging from 47 to 61 mm Hg whereas PaO2 values decreased from baseline (97 +/-
      20 mm Hg), ranging from 42 to 57 mm Hg. Muscle relaxation was good and no horses
      moved during surgery: Recovery was good in 9 horses and acceptable in 3; mean
      recovery time was 67 +/- 29 minutes with 2.4 +/- 2.4 attempts necessary for the
      horses to stand. CONCLUSIONS: Detomidine-propofol anesthesia in horses in dorsal
      recumbency was associated with little cardiovascular depression, but hypoxemia
      and respiratory depression occurred and some excitement was seen on induction.
      CLINICAL RELEVANCE: Detomidine-propofol anesthesia is not recommended for
      surgical procedures in horses if dorsal recumbency is necessary and supplemental
      oxygen is not available (eg, field anesthesia).

PMID- 10338167
TI  - Percutaneous epidural neuroplasty: cutting edge or potentially harmful pain
      management?

PMID- 10338168
TI  - Percutaneous epidural neuroplasty: prospective evaluation of 0.9% NaCl versus 10%
      NaCl with or without hyaluronidase.
AB  - BACKGROUND AND OBJECTIVES: Percutaneous epidural neuroplasty (epidural
      neurolysis, lysis of epidural adhesions) is an interventional pain management
      technique that has emerged over approximately the last 10 years as part of a
      multidisciplinary approach to treating radiculopathy with low back pain. In
      addition to local anesthetic and corticosteroid, hypertonic saline (10% NaCl) and
      hyaluronidase are used for the technique. The objective of this study was to
      determine if hypertonic saline or hyaluronidase influenced treatment outcomes.
      METHODS: Eighty-three subjects with radiculopathy plus low back pain were
      assigned to one of four epidural neuroplasty treatment groups: (a) hypertonic
      saline plus hyaluronidase, (b) hypertonic saline, (b) isotonic saline (0.9%
      NaCl), or (d) isotonic saline plus hyaluronidase. Subjects in all treatment
      groups received epidural corticosteroid and local anesthetic. RESULTS: Twenty
      four subjects did not complete the study. Most of the other 59 subjects receiving
      any of the four treatments as part of their pain management obtained significant
      relief immediately after treatment. Visual analog scale (VAS) scores for the area
      of maximal pain (VASmax; back or leg) were reduced in 25% or more of subjects in
      all treatment groups at all post-treatment follow-up times (1, 3, 6, 9, and 12
      months). A smaller fraction of subjects treated with hypertonic saline or
      hyaluronidase and hypertonic saline required more additional treatments than did
      subjects receiving the other treatments. CONCLUSIONS: Percutaneous epidural
      neuroplasty, as part of an overall pain management strategy, reduces pain
      (sometimes for over one year) in 25% or more of subjects with radiculopathy plus
      low back pain refractory to conventional therapies. The use of hypertonic saline
      may reduce the number of patients that require additional treatments.

PMID- 10338169
TI  - Preemptive intrathecal ketamine injection produces a long-lasting decrease in
      neuropathic pain behaviors in a rat model.
AB  - BACKGROUND AND OBJECTIVES: Ketamine is an N-Methyl-D-Aspartate (NMDA) receptor
      antagonist, which has been found to effectively treat somatic and neuropathic
      pain. This study examines the effect (on neuropathic pain) of preemptive ketamine
      using different routes of administration (intrathecal versus intraperitoneal).
      METHODS: The Institutional Animal Care and Use Committee approved the study.
      Thirty male Sprague-Dawley rats (250-275 g) were divided into three treatment
      groups [intrathecal saline/intraperitoneal saline or Control (CTL), intrathecal
      ketamine/intraperitoneal saline (ITK), and intrathecal saline/intraperitoneal
      ketamine (IPK)] prior to undergoing surgery to induce neuropathic pain by tight
      ligation of the left L5 and L6 spinal nerves. All drugs were given 15 minutes
      before nerve ligation. The ITK group received intrathecal ketamine (0.5%
      solution, 1 mg/kg), the IPK group received intraperitoneal ketamine (0.5%
      solution, 1 mg/kg), saline was given in equal volume (approximately 0.05 mL).
      Mechanical allodynia, cold allodynia, and ongoing pain behaviors indicative of
      neuropathic pain were assessed on postoperative days 1, 3, 7, and 14 using
      validated methods. RESULTS: Compared with the CTL group, the ITK group showed a
      state of decreased mechanical allodynia, cold allodynia, and ongoing pain as
      revealed by the von Frey hair, acetone, and cold plate testing, respectively.
      Further, this decrease was sustained for at least 2 weeks. The IPK group showed
      intermediate results between the CTL and ITK. CONCLUSIONS: Neuropathic pain
      behaviors were significantly reduced for at least 2 weeks after intrathecal
      ketamine was preemptively administered to animals undergoing surgery to induce
      neuropathic pain. The mechanism of action is thought to be prevention of spinal
      cord sensitization.

PMID- 10338170
TI  - Frequency of hypotension during conventional or asymmetric hyperbaric spinal
      block.
AB  - BACKGROUND AND OBJECTIVES: The purpose of this randomized, double-blind study was
      to evaluate if use of an asymmetric spinal block affects the incidence of
      hypotension during spinal anesthesia. METHODS: With Ethical Committee approval
      and patient consent, 120 patients undergoing lower limb surgery were placed in
      the lateral position with the side to be operated on dependent, and received 8 mg
      0.5% hyperbaric bupivacaine through a 25-gauge Whitacre spinal needle. Patients
      were randomized to one of two groups: (a) local anesthetic was injected with
      barbotage through a cranially directed needle orifice, then patients were
      immediately turned to supine (conventional, n = 60); (b) local anesthetic was
      injected without barbotage with the needle orifice turned toward the dependent
      side, then the lateral position was maintained for 15 minutes (unilateral, n =
      60). A blind observer recorded noninvasive hemodynamic variables, as well as loss
      of cold and pinprick sensation and motor block on both sides. RESULTS: In the
      unilateral group, 31 patients (52%) showed a unilateral loss of cold sensation
      and 48 patients (80%) had no motor block on the nondependent side for the
      duration of the study, whereas all conventional patients had bilateral
      distribution of spinal block (P < .0001). The onset time and two-segment
      regression of sensory block on the dependent side were more rapid in the
      conventional group (18 +/- 7 minutes and 60 +/- 18 minutes) than in the
      unilateral group (22 +/- 8 minutes and 67 +/- 19 minutes) (P < .05 and P < .05,
      respectively). The incidence of hypotension (SAP decrease >30% from baseline) was
      higher in the conventional (22.4%) than unilateral group (5%) (P < .01). The
      maximum percentage changes from baseline values of systolic arterial blood
      pressure and heart rate were greater in conventional group (-28% +/- 16% and -19%
      +/- 10%) than in unilateral group (-8% +/- 16% and -12% +/- 18%) (P < .0001 and P
      < .01, respectively). CONCLUSIONS: Achieving an asymmetric distribution of spinal
      block by injecting a small dose of 0.5% hyperbaric bupivacaine through a Whitacre
      spinal needle into patients placed in the lateral position for 15 min reduces the
      incidence of hypotension during spinal anesthesia.

PMID- 10338171
TI  - Preoperative intra-articular morphine and bupivacaine for pain control after
      outpatient arthroscopic anterior cruciate ligament reconstruction.
AB  - BACKGROUND AND OBJECTIVES: The purpose of this study was to determine whether
      intra-articular injection of bupivacaine, morphine, or a combination prior to
      surgery provided pain control after arthroscopic anterior cruciate ligament (ACL)
      reconstruction. METHODS: These data were collected as a two-stage prospective,
      randomized, blinded observer study. All patients received a standard general
      anesthetic, which included an intra-articular injection 20 minutes prior to
      incision. In phase I, three solutions were assigned randomly in a 60-mL volume.
      Group 1 was saline, group 2 was 0.25% bupivacaine, and group 3 was 0.25%
      bupivacaine with 1 mg morphine sulfate (MS). Phase II was identical to phase I in
      technique and had four groups. Group 1 was 0.25% bupivacaine, group 2 was 1 mg MS
      in saline, group 3 was 0.25% bupivacaine with 1 mg MS, and group 4 was 0.25%
      bupivacaine with 3 mg MS. All groups in phases I and II contained 1:200,000
      epinephrine, freshly added. Pain scores were evaluated at 0, 30, 60, 90, 120, and
      240 minutes postoperative using a visual analog scale. For pain scores of 5 or
      greater, 50 microg fentanyl was administered at 5-minute intervals until pain was
      controlled. After transition from phase I to phase II of the postanesthesia care
      unit (PACU), hydrocodone/acetaminophen tablets were used. RESULTS: Thirty
      patients were entered into phase I of the study. Both treatment groups (2 and 3)
      had significant (P < .05) pain reduction on arrival to the PACU. Group 3 had
      significantly (P < .05) reduced need for fentanyl during the PACU stay. Forty
      nine patients entered phase II of the study. In phase II, group 3 had the lowest
      pain scores on arrival to the PACU. At 120 and 240 minutes, pain scores were
      lower in groups 3 and 4. Fentanyl and hydrocodone uses were significantly lower
      during the PACU stay in groups 3 and 4. CONCLUSIONS: Presurgical injection of a
      solution of 0.25 % bupivacaine, morphine, and epinephrine provided pain control
      and decreased opioid use in the PACU. Increasing the morphine dose did not
      improve the clinical result.

PMID- 10338172
TI  - Postoperative pain following knee arthroscopy: the effects of intra-articular
      ketorolac and/or morphine.
AB  - BACKGROUND AND OBJECTIVES: Morphine and nonsteroidal antiinflammatory drugs
      (NSAID) have been found to be effective in relieving postoperative pain. The goal
      of this study was to determine whether ketorolac alone or in combination with
      morphine provides superior pain relief following arthroscopy performed with local
      anesthesia (LA). METHODS: This was a randomized, double-blind, prospective, study
      in 100 healthy patients from 15 to 60 years of age. Knee arthroscopy was
      performed with LA using 40 mL prilocaine (5 mg/mL) with adrenaline (4 microg/mL).
      At the end of the operation, a catheter was inserted intra-articularly, and one
      of the following solutions diluted to a total volume of 40 mL was injected: group
      P (40 mL normal saline), group M (3 mg morphine), group K30 (30 mg ketorolac),
      group K60 (60 mg ketorolac), and group KM (3 mg morphine + 30 mg ketorolac).
      Visual analog scale (VAS) pain scores (0-100 mm) were measured preoperative and
      at 30, 60, 90, 120 minutes postoperative and thereafter 4, 8, 24, and 48 hours at
      rest and on movement of the knee. The total number of distalgesic tablets (325 mg
      paracetamol + 32.5 mg dextropropoxyphene) consumed during the 48 hours
      postoperative was recorded. RESULTS: Significant differences in VAS pain scores
      were seen between group P and group KM at 4, 8, and 24 hours (P < .05) and
      between group M and group KM at 4, 8, 24, and 48 hours (P < .01) after the
      operation at rest. During mobilization of the knee, a significant difference in
      VAS pain score was found between group P and group KM at 8, 24, and 48 hours (P <
      .05) and between group P and group K60 at 24 and 48 hours (P < .05). The total
      consumption of distalgesic tablets did not differ among the groups. CONCLUSIONS:
      The combination of 3 mg morphine plus 30 mg ketorolac provided significantly
      better analgesia than either placebo alone or morphine alone. This result could
      be a synergistic effect.

PMID- 10338173
TI  - Phrenic nerve block caused by interscalene brachial plexus block: effects of
      digital pressure and a low volume of local anesthetic.
AB  - BACKGROUND AND OBJECTIVES: Interscalene brachial plexus block (ISB) is associated
      with phrenic block and diaphragmatic paralysis when high volumes (40-50 mL) of
      local anesthetic are injected. The goal of our study was to test if a low volume
      of local anesthetic administered while maintaining proximal digital pressure
      might more selectively block the brachial plexus and decrease the frequency of
      phrenic nerve block. METHODS: Twenty healthy patients undergoing ISB for
      orthopedic surgery of the upper extremity were randomly allocated to receive
      either 20 mL 1.5% mepivacaine while proximal digital pressure to the site of
      puncture was performed, or 40 mL 1.5% mepivacaine without digital pressure.
      Spirometry and clinical data were evaluated at baseline, 10, and 90 minutes after
      accomplishing the block and after the motor and sensory block resolved.
      Diaphragmatic excursion during deep inspiration was also evaluated 90 minutes
      after the block was performed, with the patient in the sitting position. RESULTS:
      Interscalene brachial plexus block produced diaphragmatic paralysis in all
      patients included in the study, as demonstrated by the pulmonary function testing
      and the chest radiograph. No significant differences were found in any of the
      parameters studied. At 10 minutes, baseline functional residual capacity had
      diminished by 34 +/- 10% in the 40 mL group and 37 +/- 13% in the 20 mL group.
      Maximum cephalad sensory dermatome level was also similar in both groups, being C
      3 or above in all patients. Ipsilateral hemidiaphragmatic motion was similar in
      both groups (3.2 +/- 2.3 cm in the 40 mL group and 2.6 +/- 1.7 cm in the 20 mL
      group). However, in no case was dyspnea manifested. CONCLUSIONS: Decreasing the
      volume of local anesthetic and applying proximal digital pressure to the site of
      injection is not effective in reducing the cervical block spread and the
      frequency or intensity of diaphragmatic paralysis during interscalene ISB.

PMID- 10338174
TI  - Quantitative sensory changes in humans after intravenous regional block with
      mepivacaine.
AB  - BACKGROUND AND OBJECTIVES: In previous studies we have demonstrated that after
      intravenous regional block (IVRA) with dilute mepivacaine, there is a decrease in
      neurogenic inflammation as well as in post-ischemic hyperemia and steady-state
      flow, the latter for at least 60 minutes. It is unclear whether these vascular
      reactions reflect a uniform depression of nerve function in the treated arms.
      Because the various afferents convey impulses from different types of sensory
      receptors, we used quantitative sensory testing (QST) to define these effects of
      IVRA with mepivacaine. METHODS: In 16 volunteers, bilateral blocks were performed
      by simultaneously injecting mepivacaine in one arm and normal saline in the other
      in a randomized, double-blind manner. Both arms were kept ischemic for 20
      minutes, and the pain was rated on a visual analogue scale. Skin temperature and
      perception threshold values regarding touch (Abeta-fibers), warmth (C-fibers) and
      cold (Adelta-fibers), and heat pain (C-fibers) were determined before and
      repeatedly after the blocks. RESULTS: Ischemic pain did not differ between the
      arms. After reflow, the thresholds for touch, warmth, and heat pain were
      unchanged. In the mepivacaine-treated arm, the sensibility to cold was
      significantly decreased 10 and 30 minutes after the block, though there was a
      slight decrease in skin temperature. CONCLUSIONS: There was no uniform depression
      of nerve function after IVRA. The cold receptors and/or their Adelta-fibers were
      selectively depressed after the block. In conjunction with earlier findings, this
      suggests that IVRA with mepivacaine can differentially decrease neurogenic
      inflammation, with little impairment of sensory function.

PMID- 10338175
TI  - High-performance liquid chromatographic analysis of the 2-chloroprocaine
      metabolite, diethylaminoethanol, in blood and serum.
AB  - BACKGROUND AND OBJECTIVES: 2-Chloroprocaine is rapidly metabolized in the blood
      to yield 2-chloro-para-aminobenzoic acid (an inactive metabolite) and
      diethylaminoethanol (DEAE). DEAE possesses local anesthetic activity. The only
      reported assay for DEAE is a colorimetric method. METHODS: Clinical samples of
      whole blood and serum were obtained from patients receiving stepped intravenous
      infusions of 3% 2-chloroprocaine. A high pH-dependent liquid-liquid extraction
      step with diethyl ether was used to eliminate interfering peaks in high-pressure
      liquid chromatography (HPLC) analysis. Separation and quantitation were performed
      using HPLC on a polymeric-reversed phase column with a mobile phase consisting of
      10% or 20% acetonitrile (for whole blood or serum analysis, respectively) in 50
      mm aqueous sodium phosphate buffer, pH = 11.50. The elution order of DEAE and its
      analogues was tested to interpret the HPLC separation mechanism. RESULTS:
      Extraction recovery of DEAE from whole blood was 67 +/- 13.5%, from serum, 71 +/-
      12.2%, and from water, 75 +/- 2.9%. The high pH value of the mobile phase
      resulted in sharp, well-resolved peaks with run times of approximately 8 minutes
      using 20% acetonitrile. The lower limit of detection was 5 ng/mL of DEAE from a 1
      mL sample. The elution order of DEAE and its analogues indicated that separation
      was based on the hydrophobicity of the analytes rather than polar group
      interactions occurring with silica-based stationary phase. CONCLUSIONS: A new,
      simple and rapid HPLC method for extraction and measurement of DEAE in whole
      blood or serum samples is reported here.

PMID- 10338176
TI  - The peripheral analgesic effect of tramadol in reducing propofol injection pain:
      a comparison with lidocaine.
AB  - BACKGROUND AND OBJECTIVES: Tramadol and metoclopramide have a local anesthetic
      effect similar to lidocaine following intradermal injection. When metoclopramide
      was retained in the venous system for 1 minute, it was found to be as effective
      as lidocaine in reducing propofol injection pain. Using this metoclopramide
      model, the effects of tramadol in reducing pain on propofol injection was
      investigated. METHODS: One hundred five patients were randomly allocated to
      receive 50 mg tramadol (group T), 60 mg lidocaine (group L), or normal saline
      (group NS) as pretreatment to reduce pain on propofol injection. Following venous
      occlusion with a tourniquet (70 mm Hg), one of the drugs was intravenously
      administered. Venous retention of the drug was maintained for 1 minute.
      Immediately after the tourniquet release, intravenous injection of 100 mg
      propofol (10 mL) at a rate of 0.5 mL/s followed. Pain assessment was made after
      each injection. RESULTS: Transient minor injection pain and local skin reactions
      were significantly greater with tramadol than with lidocaine (P < .05). Both
      tramadol and lidocaine significantly reduced the incidence and intensity of
      propofol injection pain when compared with normal saline (P < .05). CONCLUSIONS:
      Using -minute retention in veins, both tramadol and lidocaine significantly
      reduced propofol injection pain. A local anesthetic activity is postulated.

PMID- 10338177
TI  - Neurotrophins.

PMID- 10338178
TI  - Ralph Waters as a regional anesthesiologist.

PMID- 10338179
TI  - Intrathecal lipophilic opioids as adjuncts to surgical spinal anesthesia.
AB  - BACKGROUND AND OBJECTIVES: Lipophilic opioids, especially fentanyl and
      sufentanil, are increasingly being administered intrathecally as adjuncts to
      spinal anesthesia. This review analyzes the efficacy of these opioids for
      subarachnoid anesthesia. METHODS: Medline search of the literature from 1980 to
      the present and a survey of recent meeting abstracts are reviewed. RESULTS: A
      significant number of citations regarding intrathecal lipophilic opioids as
      adjuncts to spinal anesthesia were found: 59 are cited in this review. Most
      clinical experience has been in obstetric surgery, but lipophilic spinal opioid
      administration is being used with greater frequency for other surgical procedures
      as well. The benefits include reduction of minimal alveolar concentration (MAC)
      when general anesthesia is combined with spinal anesthesia and enhancement of the
      quality of spinal anesthesia without prolongation of motor block. Intrathecal
      fentanyl and sufentanil allow clinicians to use smaller doses of spinal local
      anesthetic, yet still provide excellent anesthesia for surgical procedures.
      Furthermore, lipophilic opioid/local anesthetic combination permits more rapid
      motor recovery; short outpatient procedures are therefore more amenable to spinal
      anesthesia. Finally, the side-effect profiles of intrathecal lipophilic opioids
      are now well characterized and appear less troublesome than intrathecal morphine.
      CONCLUSIONS: The anesthesia-enhancing properties and side-effect profile of
      lipophilic opioids administered intrathecally suggest significant roles for these
      agents as adjuncts to spinal anesthesia for obstetric and outpatient procedures.

PMID- 10338180
TI  - Axillary block complicated by hematoma and radial nerve injury.
AB  - BACKGROUND AND OBJECTIVES: Hematoma is typically cited as one mechanism of nerve
      injury following axillary block. However, documented cases of this are lacking.
      METHODS: A healthy 38-year-old man was scheduled for surgical removal of a tumor
      of the hand. A transarterial axillary block was performed with a 22-gauge short
      bevel needle using 40 mL of a mixture of equal volumes of 1.5% lidocaine and 0.5%
      bupivacaine containing 1:200,000 epinephrine. No paresthesias were reported.
      Postoperative, the patient developed a large axillary hematoma accompanied by
      paresthesias and radial nerve weakness. RESULTS: With conservative management,
      nerve recovery was complete in 6 months. CONCLUSIONS: Hematoma complicating
      axillary block may result in nerve dysfunction.

PMID- 10338181
TI  - Excision of spinal tumor in a patient with severe pulmonary dysfunction using
      combined spinal and epidural anesthesia with two epidural catheters.
AB  - BACKGROUND AND OBJECTIVES: Combined spinal and epidural anesthesia (CSEA) has
      become common practice. We performed CSEA using two epidural catheters in a 69
      year-old female with severe pulmonary dysfunction caused by a diaphragmatic
      hernia, who underwent surgical excision of a lumbar spinal tumor. METHODS:
      Combined spinal and epidural anesthesia was performed using two epidural
      catheters to minimize postoperative pulmonary complications. One epidural
      catheter was inserted above the surgical region, at the T11-12 interspace, and
      another one below the surgical region, via the sacral hiatus. Spinal anesthesia
      was produced using the L5-S1 interspace and 3 mL 0.5% bupivacaine. Oxygen, 3
      L/min, was administered through a face mask during surgery. RESULTS: Fifteen
      minutes after spinal anesthesia, analgesic level was confirmed below T7 using the
      pinprick method. The patient complained of pain in the surgical region 10 minutes
      after the dura mater was opened. We injected 5 mL 2% mepivacaine through the
      upper epidural catheter to relieve the pain. We also injected 10 mL 2%
      mepivacaine through the lower catheter when she felt pain in the right leg. The
      perioperative course was uneventful. Oxygen saturation was maintained above 95%.
      CONCLUSIONS: Combined spinal and epidural anesthesia using two epidural catheters
      was used successfully to excise a spinal tumor in a patient with severe pulmonary
      dysfunction.

PMID- 10338182
TI  - Thoracic epidurals: reply to Hough.

PMID- 10338183
TI  - Thoracic epidurals: reply to Hough.

PMID- 10338184
TI  - Safety of epidurals: further comment and response.

PMID- 10338185
TI  - The relative increase in skin temperature after stellate ganglion block is
      predictive of a complete sympathectomy of the hand.

PMID- 10338186
TI  - A case of catheter misplacement.

PMID- 10338187
TI  - Genes that induce immunity--DNA vaccines.

PMID- 10338188
TI  - Characterization of serotypes and outer membrane protein profiles in
      enteroaggregative Escherichia coli strains.
AB  - Twenty-four Escherichia coli strains mainly isolated from children with diarrhea
      in Sao Paulo, and showing characteristics of enteroaggregative E. coli (EAEC),
      were characterized by serotyping and outer membrane protein (OMP) profiles. The
      relationship between these characteristics was evaluated, as well as the
      usefulness of OMP profiles in the clonal analysis of EAEC strains. All strains
      presented aggregative adherence to HeLa cells and were classified in two groups
      based on their interaction with the EAEC DNA probe. A diversity of serotypes and
      OMP profiles was observed in both groups studied. Although no significant
      correlation between serotypes and OMP profiles was observed, unique OMP profiles
      were identified in 80% of the probe-positive strains which were distributed in
      only 4 OMP profiles. This result may indicate the presence of a few clones in the
      probe-positive group. On the other hand, probe-negative strains seem to
      constitute a more diverse group. In general, the observed heterogeneity in
      serotypes and OMP profiles described in the present study suggest a great genetic
      diversity in EAEC isolates of either the same or different serotypes and in
      strains presenting the same EAEC markers identified in our community.

PMID- 10338189
TI  - Abscess forming ability of streptococcus milleri group: synergistic effect with
      Fusobacterium nucleatum.
AB  - The abscess forming abilities of "Streptococcus milleri" strains (Streptococcus
      constellatus, Streptococcus anginiosus, and Streptococcus intermedius) isolated
      from dentoalveolar abscesses and the synergistic effect of Fusobacterium
      nucleatum co-inoculated with the isolates were examined on a mouse subcutaneous
      abscess model. Five days after inoculation, all S. milleri strains formed
      abscesses, which showed less pathological spread to surrounding connective
      tissues than those formed by Staphylococcus aureus 209P strain and were similar
      to those by F. nucleatum ATCC25586. When each S. milleri strain and F. nucleatum
      were co-inoculated, abscess sizes and each bacterial number recovered from
      abscesses increased in comparison to those treated by bacterial mono-inoculation
      of each S. milleri strain or F. nucleatum alone. The strongest synergistic effect
      was observed in the combination of S. constellatus and F. nucleatum. In a time
      course experiment with this combination, the recovery of S. constellatus
      subsequently decreased after the decrement of F. nucleatum, and it appeared that
      the association with F. nucleatum maintained the bacterial number of S.
      constellatus in the abscess. The cell-free supernatant of F. nucleatum had a
      tendency to increase the abscess size caused by S. constellatus in this model.
      When S. constellatus was cultured with F. nucleatum culture supernatant in vitro,
      growth enhancement in the early phase was observed. Furthermore, the phagocytic
      killing of S. constellatus by human polymorphonuclear leukocytes (PMNs) was
      significantly suppressed and the PMN membranes appeared to be injured by addition
      of the F. nucleatum culture supernatant. These results suggest that the
      pathogenicity of S. milleri strains in odontogenic infections may be enhanced by
      the co-existence of F. nucleatum.

PMID- 10338190
TI  - Growth of starved Escherichia coli O157 cells in selective and non-selective
      media.
AB  - Escherichia coli O157 strains starved in sterile deionized water (SDW) and filter
      sterilized natural river water (SRW) were investigated with specific reference to
      their culturability in selective and non-selective media. Growth of the strains
      starved in both SDW and SRW were markedly suppressed with time in selective
      liquid media such as modified trypticase soy broth supplemented with novobiocin
      (mTSB+n) and modified E. coli broth supplemented with novobiocin (mEC+n). This
      suppression was more pronounced when incubated at 42 C than at 37 C, especially
      with mEC+n. By contrast, such growth suppression was seldom observed when
      cultured at 37 C in non-selective liquid media such as trypticase soy broth (TSB)
      and buffered peptone water. In mEC+n at 42 C, the non-starved cells from
      overnight cultures with an initial density of less than 10(3) colony-forming
      units (CFU)/ml grew to the density of over 10(7) CFU/ml after 24 hr incubation,
      whereas those starved for 6 weeks in SRW were only to maintain their initial
      density or died off after 24 hr incubation under the same culturing conditions.
      These results indicated that the isolation of starved cells of E. coli O157 from
      water samples would be most difficult with selective enrichment or direct plating
      on the selective plate media. It is thus highly recommended that a
      "resuscitation" of the cells with non-selective enrichment should be performed as
      a routine practice for maximum recovery of E. coli O157 from water systems.

PMID- 10338191
TI  - Antigenic relationship among the eight prototype and new serotype strains of
      Orientia tsutsugamushi revealed by monoclonal antibodies.
AB  - Orientia tsutsugamushi, the etiologic agent of tsutsugamushi disease, exhibits
      great antigenic variation. Three classical strains (Karp, Gilliam, and Kato) and
      new antigenic types from Thailand (TA686, TA678, TA716, TA763, and TH1817) have
      been used as prototype strains of O. tsutsugamushi in many studies. In this
      study, monoclonal antibodies to the five Thailand strains were produced, and
      their reactivity against prototype strains and newly identified isolates from
      Korea and Japan was tested. With a panel of these monoclonal antibodies, we could
      analyze the antigenic relationship among various strains of O. tsutsugamushi from
      Thailand, Japan, and Korea. Twelve strains of the O. tsutsugamushi tested showed
      various reactivities to monoclonal antibodies, and no distinct pattern of
      reactivity was found according to their location of isolation. Although the
      Boryong and Kuroki strains were similar in reactivities to most monoclonal
      antibodies, several monoclonal antibodies could differentiate the two strains.
      These results indicate that the immunofluorescence antibody test using monoclonal
      antibodies used in this study is valuable for analyzing the antigenic
      relationship and classification of O. tsutsugamushi.

PMID- 10338193
TI  - Serum antibody level against GroEL type heat-shock protein of Campylobacter
      jejuni in patients with Guillain-Barre syndrome.
AB  - Recently there has been an increase in the number of cases reported of Guillain
      Barre syndrome (GBS) developed after Campylobacter jejuni infection. To
      investigate the role of a C.jejuni GroEL-type heat-shock protein (CjHsp60) in the
      infection and induction of GBS, we examined the antibody level against CjHsp60 in
      27 human sera, including GBS and non-GBS patients, by an enzyme-linked
      immunosorbent assay. Sera from patients with C. jejuni infection, despite the
      development of GBS, had a higher titer of anti-CjHsp60 antibody than those of
      patients without the infection and healthy control subjects. The patients with C.
      jejuni infection followed by GBS had slightly higher levels of this antibody than
      did the patients with infection who did not develop GBS, but there was no
      statistical significance. In conclusion, CjHsp60 is found to be one of the major
      immunogenic antigens in actual C. jejuni infection, but no evidence that supports
      the direct relationship between this protein and C. jejuni-associated GBS was
      found in this study.

PMID- 10338192
TI  - Effective inhibition of Candida albicans growth by the combination of murine
      peritoneal neutrophils and activated macrophages.
AB  - The effect of leukocytes on the anti-Candida activity of neutrophils was
      examined. Murine neutrophils which were purified from casein-induced peritoneal
      cells inhibited the mycelial growth of Candida albicans. This anti-Candida
      activity of neutrophils was augmented by the addition of spleen cells prepared
      from mice pretreated with bacterial lipopolysaccharide 3 hr before, but not from
      non-treated mice. The population in the spleen cells, which enhanced the anti
      Candida activity of neutrophils, was plastic-plate adherent, nylon-fiber columns
      adherent and anti-Mac-1 antigen-positive. These immunological profiles suggested
      that the enhancing cells are classified to splenic macrophages. Peritoneal
      exudated macrophages from mice treated with lipopolysaccharide also augmented the
      anti-Candida activity of neutrophils. These results suggest that the anti-Candida
      activity of neutrophils may be upregulated by activated macrophages.

PMID- 10338194
TI  - Recruitment of apoptotic cysteine proteases (caspases) in influenza virus-induced
      cell death.
AB  - Influenza virus infection induces apoptosis in cultured cells with an augmented
      expression of Fas (APO-1/CD95). Caspases, a family of cysteine proteases
      structurally related to interleukin-1-beta-converting enzyme (ICE), play crucial
      roles in apoptosis induced by various stimuli, including Fas. However, activation
      of the caspase-cascade seems to be different in various pathways of apoptotic
      stimuli. We therefore examined the involvement of caspases in influenza virus
      induced apoptosis using caspase inhibitors. We found that z-VAD-fmk and z-IETD
      fmk effectively inhibited virus-induced apoptosis, whereas Ac-DEVD-CHO and Ac
      YVAD-CHO showed partial and little effect on virus-induced cell death,
      respectively. Consistently, caspase-3-like activity, but not caspase-1-like
      activity, was increased in the virus-infected cells. The transfection of plasmids
      encoding viral inhibitors of caspase (v-FLIP or crmA) into HeLa cells inhibited
      apoptosis by virus infection. The peptide inhibitors of caspases used in this
      study did not inhibit viral replication. We conclude that influenza virus
      infection activates some caspases, and that this activation may be downstream of
      viral replication.

PMID- 10338195
TI  - Assessment of mucosal immune response in genitourinary tract using urine.
AB  - A novel method to assess mucosal immune response in the genitourinary mucosa
      after immunization with a mucosal vaccine has been developed. In this method,
      secretory IgA antibody is measured by a highly sensitive enzyme immunoassay
      (immune-complex transfer enzyme immunoassay) using urine as a specimen. The
      urinary IgA antibody response could be detected by the immune-complex transfer
      enzyme immunoassay. In contrast, a conventional enzyme immunoassay (enzyme-linked
      immunosorbent assay (ELISA)) could not detect this response because of its low
      sensitivity. Because urine samples can be collected easily and nontraumatically,
      not only from experimental animals but also from humans, both males and females,
      the present method may be applicable for assessing the protective efficacy of
      candidates for mucosal vaccines against sexually transmitted microorganisms, such
      as human immunodeficiency virus. Furthermore, the usefulness of this method for
      novel mucosal vaccine formulae was shown for a model in which vaccine antigen and
      Bordetella pertussis adjuvant were adsorbed onto CaCO, and enclosed in enteric
      coated capsules.

PMID- 10338196
TI  - Intracellular behavior of rabies virus matrix protein (M) is determined by the
      viral glycoprotein (G).
AB  - To investigate the nature and intracellular behavior of the matrix (M) protein of
      an avirulent strain (HEP-Flury) of rabies virus, we cloned and sequenced the cDNA
      of the protein. Using expression vectors pZIP-NeoSV(X)1 and pCDM8, the cDNA was
      transfected to animal cells (BHK-21 and COS-7) with or without coexpression of
      viral glycoprotein (G). When M protein alone was expressed in the cells, it
      displayed homogeneous distribution in the whole cell including the nucleus. In
      contrast, coexpression with G protein resulted in the abolishment of nuclear
      distribution of M antigen, and both of the antigens displayed a colocalized
      distribution in the cell, especially at the cellular membrane as seen in the
      virus-infected cells, while the distribution of G antigen was not affected by
      coexpressed M antigen. Immunoprecipitation studies revealed that M protein was
      coprecipitated with G protein by anti-G antibody, and vice versa, although cross
      linking with dithiobis(succinimidyl propionate) was necessary for coprecipitation
      because of their easier dissociation in the presence of sodium deoxycholate.
      These results suggest that M protein intimately associates with G protein, which
      may affect or regulate the behavior (e.g., intracellular localization) of M
      protein. Studies with deletion mutants of M protein indicate that an internal
      region around the amino acids from 115 to 151 is essential for the M protein to
      preserve its binding ability to G protein.

PMID- 10338198
TI  - Proinflammatory cytokines secreted by monocytes of filarial patients.
AB  - The levels of interleukin 1, granulocyte macrophage colony stimulating factor (GM
      CSF) and tumour necrosis factor (TNF)-alpha secreted by the monocytes of filarial
      patients, such as asymptomatic microfilaremics (MF), chronic pathology (CP), and
      normal individuals, residing in a Wuchereria bancrofti endemic area (EN) in
      response to whole Brugia malayi antigen (BmA) and Setaria digitata (Sd-cuticular)
      and a recombinant filarial antigen (pRJ51) were studied. Stimulation of
      peripheral blood adherent cells with whole parasite antigen showed marked
      increase in IL-1 levels in MF as compared to CP or EN. The recombinant antigen
      stimulation, however, resulted in similar levels of IL-1 in MF and CP. In
      contrast, stimulation of peripheral blood adherent cells with whole parasite
      antigen produced high levels of GM-CSF and TNF-alpha in CP as opposed to MF or
      EN. Recombinant antigen stimulation, however, produced high levels of GM-CSF in
      EN as compared to MF or CP, while no significant change in the release of TNF
      alpha was observed in these patients. These results suggest that monocytes from
      filarial patients exhibit functional activity similar to that observed by the
      monocytes of endemic normals (control group).

PMID- 10338197
TI  - The distribution of HIV-1 subtypes in Fukuoka, Japan.
AB  - To determine the incidence of human immunodeficiency virus type-1 (HIV-1)
      subtypes in Fukuoka, Japan, viruses from 41 HIV-1 infected individuals were
      subtyped. Subtyping by V3-loop enzyme-linked immunosorbent assay (ELISA) showed
      31 of the 41 subjects as subtype B (MN type), one as subtype A, one as subtype C,
      and eight untypable. The subject infected with subtype C was identified as a
      foreigner; the subtype A subject was Japanese. A phylogenetic analysis of nucleic
      acid sequences from the env C2-V3 region was also conducted. Genetic subtyping
      was successful for 25 samples: 23 samples were determined as subtype B, one
      subtype A and one subtype E. One of the individuals infected with subtype B, as
      well as the subtype A and subtype E subjects, were not Japanese. This study
      indicated that subtype B (USA and European type) is still dominant among HIV-1
      infections in Fukuoka. Further, no Japanese were subtype E positive, which is
      increasing in the Kanto region. It is notable, however, that subtype A and
      subtype C infections, which are rare in Japan, were found in Fukuoka, located far
      from the metropolitan area of Tokyo.

PMID- 10338200
TI  - Genotypic characterization of human and environmental isolates of Salmonella
      choleraesuis subspecies choleraesuis serovar infantis by pulsed-field gel
      electrophoresis.
AB  - To determine the extent of genetic diversity of Salmonella choleraesuis
      subspecies choleraesuis serovar Infantis and whether environmental isolates were
      similar or identical to human isolates, a total of 110 isolates from humans,
      broiler samples, egg production facilities, riverwater, sewage, and chicken meat
      were analyzed epidemiologically by pulsed-field gel electrophoresis. While the
      isolates showed 35 distinct pulsed-field profiles, none had the genotype of the
      human isolates. One pulsed-field profile was shared by 43 (39%) of the 110
      isolates. These results indicate that relatively fewer clonal lines of S. serovar
      Infantis had spread widely while multiple clonal lines, including the strain
      involved in the outbreak, exist in Western Japan.

PMID- 10338199
TI  - A novel negative regulator molecule, Cho-1, is involved in the cytotoxicity by
      human natural killer cells but not in cytotoxic T lymphocytes.
AB  - We previously reported the cytotoxic negative regulatory molecule, Cho-1, that
      was expressed on the cell surface of rat fetal fibroblast cells in the
      cytotoxicity by natural killer (NK) cells. This molecule was IFN-gamma-inducible,
      but appeared to be different from MHC class I. It was expressed on NK-resistant
      cells but not on NK-sensitive murine target cells such as YAC-1. In this paper,
      first we determined whether Cho-1 could also act as the negative regulatory
      molecule in a human NK-resistant HEPM line. Our data strongly suggested that Cho
      1 could act as such a negative regulatory molecule in human NK cytotoxicity. The
      immunoprecipitates made with HEPM cell lysate and anti-MHC class I monoclonal
      antibody (mAb) did not react against anti-Cho-1 mAb, indicating that Cho-I was
      different from MHC class I. Second, an assessment was made as to whether or not
      this molecule is involved in the cytotoxicity of CD8 (+) cytotoxic T lymphocytes
      (CTL) against human autologous tumor cells. The data indicated that although this
      cell surface molecule was expressed on certain tumor lines, it was not involved
      in the cytotoxic mechanism of CTL. Thus, Cho-1 appeared to be the novel
      regulatory molecule in the NK cytotoxic mechanism.

PMID- 10338201
TI  - Molecular cloning and characterization of the oprQ gene coding for outer membrane
      protein OprE3 of Pseudomonas aeruginosa.
AB  - We cloned and characterized the oprQ gene coding for outer membrane protein OprE3
      of Pseudomonas aeruginosa PAO1. The oprQ gene was composed of 1,275 base pairs
      including a sequence encoding for the signal sequence and a mature protein with a
      Mr of 44,602. Computer-aided alignment and hydropathy analyses of the predicted
      amino acid sequences suggested that OprE3 is a transmembrane protein homologous
      to outer membrane proteins of P. aeruginosa such as OprD2 (OprD) porin and OprE1
      (OprE) porin. Susceptibility to several antibiotics of the strains lacking or
      overproducing OprE3 was indistinguishable from that of the wild-type strain,
      suggesting that OprE3 is unlikely involved in the diffusion of carbapenems and
      other beta-lactam antibiotics.

PMID- 10338202
TI  - Disappearance of glyceraldehyde 3-phosphate dehydrogenase from erythrocyte
      membrane by hemolysis with thermostable direct hemolysin of Vibrio
      parahaemolyticus or Vibrio cholerae El Tor hemolysin.
AB  - It is believed that the thermostable direct hemolysin (TDH) of Vibrio
      parahaemolyticus and El Tor hemolysin (ETH) of Vibrio cholerae damage
      erythrocytes and other cells by acting as pore-forming toxins. In this study, we
      found that a protein band with a molecular weight of 37,000 daltons specifically
      disappeared from erythrocyte membrane after hemolysis by TDH and ETH, but not
      after hypotonic hemolysis. The 37 kDa band was identified as glyceraldehyde 3
      phosphate dehydrogenase (G3PD), a glycolytic enzyme, based on N-terminal 14 amino
      acid sequencing. The role of G3PD in hemolysis is discussed.

PMID- 10338203
TI  - Induction of neutralizing antibody against human cytomegalovirus (HCMV) with DNA
      mediated immunization of HCMV glycoprotein B in mice.
AB  - Immunization was accomplished by inoculating pcGB containing human
      cytomegalovirus (HCMV) glycoprotein B (gB) gene into BALB/c mice intramuscularly.
      IgM antibody was detected in all the immunized group. IgG antibody was also found
      in all the tested mice with a mean peak antibody titer of 1:262 in three-times
      immunized groups. IgG antibody appeared at 2 weeks postinoculation, raised peak
      levels at 7 weeks postinoculation and persisted over 6 months. Neutralizing
      antibody was developed, and the percent reduction of input infectivity in 1:100
      diluted sera was 74.5 % in three-times immunized groups. This study suggested
      that DNA vaccine using the gene encoding HCMV gB is a candidate method for
      developing immunity to HCMV.

PMID- 10338204
TI  - Telomeres do D-loop-T-loop.

PMID- 10338205
TI  - Ribosomal mechanics, antibiotics, and GTP hydrolysis.

PMID- 10338206
TI  - Substrate targeting in the ubiquitin system.

PMID- 10338207
TI  - How the cyclin became a cyclin: regulated proteolysis in the cell cycle.

PMID- 10338208
TI  - A coat protein on phagosomes involved in the intracellular survival of
      mycobacteria.
AB  - Mycobacteria are intracellular pathogens that can survive within macrophage
      phagosomes, thereby evading host defense strategies by largely unknown
      mechanisms. We have identified a WD repeat host protein that was recruited to and
      actively retained on phagosomes by living, but not dead, mycobacteria. This
      protein, termed TACO, represents a component of the phagosome coat that is
      normally released prior to phagosome fusion with or maturation into lysosomes. In
      macrophages lacking TACO, mycobacteria were readily transported to lysosomes
      followed by their degradation. Expression of TACO in nonmacrophages prevented
      lysosomal delivery of mycobacteria and prolonged their intracellular survival.
      Active retention of TACO on phagosomes by living mycobacteria thus represents a
      mechanism preventing cargo delivery to lysosomes, allowing mycobacteria to
      survive within macrophages.

PMID- 10338209
TI  - Crystal structure of the tandem phosphatase domains of RPTP LAR.
AB  - Most receptor-like protein tyrosine phosphatases (RPTPs) contain two conserved
      phosphatase domains (D1 and D2) in their intracellular region. The carboxy
      terminal D2 domain has little or no catalytic activity. The crystal structure of
      the tandem D1 and D2 domains of the human RPTP LAR revealed that the tertiary
      structures of the LAR D1 and D2 domains are very similar to each other, with the
      exception of conformational differences at two amino acid positions in the D2
      domain. Site-directed mutational changes at these positions (Leu-1644-to-Tyr and
      Glu-1779-to-Asp) conferred a robust PTPase activity to the D2 domain. The
      catalytic sites of both domains are accessible, in contrast to the dimeric
      blocked orientation model previously suggested. The relative orientation of the
      LAR D1 and D2 domains, constrained by a short linker, is stabilized by extensive
      interdomain interactions, suggesting that this orientation might be favored in
      solution.

PMID- 10338210
TI  - Atomic structure of scallop myosin subfragment S1 complexed with MgADP: a novel
      conformation of the myosin head.
AB  - The crystal structure of a proteolytic subfragment from scallop striated muscle
      myosin, complexed with MgADP, has been solved at 2.5 A resolution and reveals an
      unusual conformation of the myosin head. The converter and the lever arm are in
      very different positions from those in either the pre-power stroke or near-rigor
      state structures; moreover, in contrast to these structures, the SH1 helix is
      seen to be unwound. Here we compare the overall organization of the myosin head
      in these three states and show how the conformation of three flexible "joints"
      produces rearrangements of the four major subdomains in the myosin head with
      different bound nucleotides. We believe that this novel structure represents one
      of the prehydrolysis ("ATP") states of the contractile cycle in which the myosin
      heads stay detached from actin.

PMID- 10338211
TI  - Structure of the enabled/VASP homology 1 domain-peptide complex: a key component
      in the spatial control of actin assembly.
AB  - The Enabled/VASP homology 1 (EVH1; also called WH1) domain is an interaction
      module found in several proteins implicated in actin-based cell motility. EVH1
      domains bind the consensus proline-rich motif FPPPP and are required for
      targeting the actin assembly machinery to sites of cytoskeletal remodeling. The
      crystal structure of the mammalian Enabled (Mena) EVH1 domain complexed with a
      peptide ligand reveals a mechanism of recognition distinct from that used by
      other proline-binding modules. The EVH1 domain fold is unexpectedly similar to
      that of the pleckstrin homology domain, a membrane localization module. This
      finding demonstrates the functional plasticity of the pleckstrin homology fold as
      a binding scaffold and suggests that membrane association may play an auxiliary
      role in EVH1 targeting.

PMID- 10338212
TI  - The highly ordered double-stranded RNA genome of bluetongue virus revealed by
      crystallography.
AB  - The concentration of double-stranded RNA within the bluetongue virus core renders
      the genome segments liquid crystalline. Powder diffraction rings confirm this
      local ordering with a 30 A separation between strands. Determination of the
      structure of the bluetongue virus core serotype 10 and comparison with that of
      serotype 1 reveals most of the genomic double-stranded RNA, packaged as well
      ordered layers surrounding putative transcription complexes at the apices of the
      particle. The outer layer of RNA is sufficiently well ordered by interaction with
      the capsid that a model can be built and extended to the less-ordered inner
      layers, providing a structural framework for understanding the mechanism of this
      complex transcriptional machine. We show that the genome segments maintain local
      order during transcription.

PMID- 10338213
TI  - A detailed view of a ribosomal active site: the structure of the L11-RNA complex.
AB  - We report the crystal structure of a 58 nucleotide fragment of 23S ribosomal RNA
      bound to ribosomal protein L11. This highly conserved ribonucleoprotein domain is
      the target for the thiostrepton family of antibiotics that disrupt elongation
      factor function. The highly compact RNA has both familiar and novel structural
      motifs. While the C-terminal domain of L11 binds RNA tightly, the N-terminal
      domain makes only limited contacts with RNA and is proposed to function as a
      switch that reversibly associates with an adjacent region of RNA. The sites of
      mutations conferring resistance to thiostrepton and micrococcin line a narrow
      cleft between the RNA and the N-terminal domain. These antibiotics are proposed
      to bind in this cleft, locking the putative switch and interfering with the
      function of elongation factors.

PMID- 10338214
TI  - Mammalian telomeres end in a large duplex loop.
AB  - Mammalian telomeres contain a duplex array of telomeric repeats bound to the
      telomeric repeat-binding factors TRF1 and TRF2. Inhibition of TRF2 results in
      immediate deprotection of chromosome ends, manifested by loss of the telomeric 3'
      overhang, activation of p53, and end-to-end chromosome fusions. Electron
      microscopy reported here demonstrated that TRF2 can remodel linear telomeric DNA
      into large duplex loops (t loops) in vitro. Electron microscopy analysis of
      psoralen cross-linked telomeric DNA purified from human and mouse cells revealed
      abundant large t loops with a size distribution consistent with their telomeric
      origin. Binding of TRF1 and single strand binding protein suggested that t loops
      are formed by invasion of the 3' telomeric overhang into the duplex telomeric
      repeat array. T loops may provide a general mechanism for the protection and
      replication of telomeres.

PMID- 10338215
TI  - Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer
      prone mouse.
AB  - Maintenance of telomere length is predicted to be essential for bypass of
      senescence and crisis checkpoints in cancer cells. The impact of telomere
      dysfunction on tumorigenesis was assessed in successive generations of mice
      doubly null for the telomerase RNA (mTR) and the INK4a tumor suppressor genes.
      Significant reductions in tumor formation in vivo and oncogenic potential in
      vitro were observed in late generations of telomerase deficiency, coincident with
      severe telomere shortening and associated dysfunction. Reintroduction of mTR into
      cells significantly restored the oncogenic potential, indicating telomerase
      activation is a cooperating event in the malignant transformation of cells
      containing critically short telomeres. The results described here demonstrate
      that loss of telomere function in a cancer-prone mouse model possessing intact
      DNA damage responses impairs, but does not prevent, tumor formation.

PMID- 10338216
TI  - p53 deficiency rescues the adverse effects of telomere loss and cooperates with
      telomere dysfunction to accelerate carcinogenesis.
AB  - Maintenance of telomere length and function is critical for the efficient
      proliferation of eukaryotic cells. Here, we examine the interactions between
      telomere dysfunction and p53 in cells and organs of telomerase-deficient mice.
      Coincident with severe telomere shortening and associated genomic instability,
      p53 is activated, leading to growth arrest and/or apoptosis. Deletion of p53
      significantly attenuated the adverse cellular and organismal effects of telomere
      dysfunction, but only during the earliest stages of genetic crisis.
      Correspondingly, the loss of telomere function and p53 deficiency cooperated to
      initiate the transformation process. Together, these studies establish a key role
      for p53 in the cellular response to telomere dysfunction in both normal and
      neoplastic cells, question the significance of crisis as a tumor suppressor
      mechanism, and identify a biologically relevant stage of advanced crisis, termed
      genetic catastrophe.

PMID- 10338217
TI  - Oral and parenteral glutamine in bone marrow transplantation: a randomized,
      double-blind study.
AB  - BACKGROUND: Total parenteral nutrition (TPN) supplemented with glutamine (GLN)
      has been reported to be effective for patients with bone marrow transplantation
      (BMT). Our aim was to evaluate enteral and parenteral glutamine in patients
      undergoing BMT. METHODS: For evaluation of GLN in BMT, 66 patients with 43
      hematologic and 23 solid malignancies (21 breast carcinomas), were randomized,
      double-blinded, to either oral GLN (n = 35) or glycine-control (GLY) (n = 31), 10
      g three times daily. When TPN became necessary, patients who received GLN orally
      were given TPN with GLN (0.57 g/kg). Those who received GLY received standard
      TPN, isocaloric and isonitrogenous. Patients with hematologic malignancies
      received high-dose chemotherapy, total body irradiation, and either allogeneic
      (ALLO) BMT (n = 18) or autologous (AUTO) stem cell transplantation (n = 25).
      Patients with solid malignancies (n = 23) received AUTO. RESULTS: There were 14
      in-hospital deaths without relationship to GLN administration. For respective
      comparisons of ALLO and AUTO transplants in the GLN and GLY hematologic groups
      and AUTO in the solid tumor groups, there were no significant differences in
      hospital stay, duration of stay after BMT, TPN days, neutrophil recovery
      >500/mm3, incidence of positive blood cultures, sepsis, mucositis, and diarrhea.
      Acute graft us host disease occurred in 1 of 10 hematologic patients receiving
      GLN and in 3 of 8 patients receiving GLY placebo (p > .05). Possible reduction in
      need for TPN and a suggestion of improved long-term survival were associated with
      GLN. CONCLUSIONS: Oral and parenteral GLN seemed to be of limited benefit for
      patients having AUTO or ALLO BMT for hematologic or solid malignancies. Further
      study of long-term effects of GLN in BMT seems warranted.

PMID- 10338218
TI  - Structured versus long-chain triglycerides: a safety, tolerance, and efficacy
      randomized study in colorectal surgical patients.
AB  - BACKGROUND: After trauma or surgery, researchers have suggested that medium-chain
      triglycerides have metabolic advantages, although they are toxic in large doses.
      To try to reduce this potential toxicity, structured lipids, which provide a
      higher oxidation rate, faster clearance from blood, improved nitrogen balance,
      and less accumulation in the reticuloendothelial system, could be used.
      Therefore, we evaluated, through a blind randomized study, the safety, tolerance,
      and efficacy of structured triglycerides, compared with long-chain triglycerides
      (LCT), in patients undergoing colorectal surgery. METHODS: Nineteen patients were
      randomized to receive long-chain or structured triglycerides as a lipid source.
      They received the same amount of calories (27.2/kg/d), glucose (4 g/kg/d),
      protein (0.2 g/kg/d), and lipids (11.2 kcal/kg/d). Patients were evaluated during
      and after the treatment for clinical and laboratory variables, daily and
      cumulative nitrogen balance, urinary excretion of 3-methyl-histidine, and urinary
      3-methylhistidine/creatinine ratio. RESULTS: No adverse effect that required the
      interruption of the treatment was observed. Triglyceride levels and clinical and
      laboratory variables were similar in the two groups. A predominantly positive
      nitrogen balance was observed from day 2 until day 5 in the LCT group and from
      day 1 until day 4 in the structured triglycerides group. The cumulative nitrogen
      balance (in grams) for days 1 to 3 was 9.7+/-5.2 in the experimental group and
      4.4+/-11.8 in the control group (p = .2). For days 1 to 5 it was 10.7+/-10.5 and
      6.5+/-17.9 (p = .05), respectively. The excretion of 3-methylhistidine was higher
      in the control group but decreased in the following days and was similar to the
      experimental group on day 5. CONCLUSIONS: This study represents the first report
      in which structured triglycerides are administered in postoperative patients to
      evaluate safety, tolerance, and efficacy. It suggests that Fe73403 is safe, well
      tolerated, and efficacious in terms of nitrogen balance when compared with LCT
      emulsion.

PMID- 10338219
TI  - Nutritional, respiratory, and psychological effects of recombinant human growth
      hormone in patients undergoing abdominal aortic aneurysm repair.
AB  - BACKGROUND: Recombinant human growth hormone (rhGH) has been shown to have
      powerful anabolic effects and to reduce or even prevent nitrogen catabolism in
      stressed patients. The effects of rhGH on functional parameters are less clearly
      defined. The aim of this study was to assess the effects of perioperative rhGH on
      nutritional markers, skeletal muscle function, and psychological well-being in
      patients undergoing infrarenal, abdominal aortic aneurysm repair. METHODS: Thirty
      three patients undergoing elective infrarenal abdominal aortic aneurysm repair
      were randomized to one of three groups: (1) control (n = 12): placebo for 6 days
      before and after surgery; (2) preop + postop (n = 10): rhGH (Genotropin;
      Pharmacia Ltd, Uppsala, Sweden) 0.3 IU/kg/d for 6 days before and after surgery;
      and (3) postop (n = 11): placebo for 6 days before and rhGH 0.3 IU/kg/d for 6
      days after surgery. Patients were assessed on days -7 and -1 before surgery and
      days 7, 14, and 60 after surgery. RESULTS: Administration of rhGH resulted in
      increased insulin-like growth factor 1 levels, the increase being significantly
      more marked in the group given rhGH preoperatively. Preoperative and
      postoperative rhGH reduced the postoperative decrease in both serum transferrin
      and grip strength at day 7 by 30% and 70%, respectively. Postoperative
      respiratory function and arterial oxygenation also were improved, with
      significant differences in arterial oxygenation between rhGH-treated and
      untreated groups. No difference in mood was seen between groups after surgery,
      nor was there any difference between subjective assessment of fatigue scores
      between groups. CONCLUSIONS: This pilot study indicates that rhGH administered
      preoperatively has beneficial effects on skeletal muscle and respiratory function
      and may be more useful than postoperative rhGH administration alone.

PMID- 10338220
TI  - Glutamine reduces phorbol-12,13-dibutyrate-induced macromolecular
      hyperpermeability in HT-29Cl.19A intestinal cells.
AB  - BACKGROUND: Loss of mucosal integrity is associated with intestinal
      hyperpermeability, which may be inhibited by glutamine. The nature of this effect
      is unknown. The effect of glutamine on protein kinase C (PKC)-mediated
      hyperpermeability in HT-29Cl.19A intestinal cells was studied. METHODS: Confluent
      monolayers of HT-29C1.19A cells were cultured on permeable filters and mounted in
      Ussing chambers for permeability studies. Apical to basolateral transepithelial
      permeability for intact horseradish peroxidase (HRP) was determined. Phorbol
      12,13-dibutyrate (PDB) was used to activate PKC-mediated hyperpermeability, and
      the effect of glutamine (0.6 mmol/L) was studied. RESULTS: Two hours of PDB
      stimulation increased the HRP flux, reaching five times control values after 4
      hours. Bilateral exposure to glutamine for 4 hours reduced PDB-induced
      hyperpermeability (37%). Preincubation with glutamine 2 hours before PDB
      stimulation showed an earlier and greater effect (3 hours, 43%; 4 hours, 50%).
      This bilateral effect of glutamine was mimicked by separate apical exposure.
      Basolateral exposure alone had no effect. CONCLUSIONS: Glutamine rapidly reduced
      the PKC-mediated hyperpermeability for HRP in HT-29Cl.19A intestinal cells. The
      dependency on apical exposure suggests that glutamine may be more effective when
      delivered by the enteral route.

PMID- 10338222
TI  - Predictive versus measured energy expenditure using limits-of-agreement analysis
      in hospitalized, obese patients.
AB  - BACKGROUND: Accuracy of predictive formulae is crucial for therapeutic planning
      because indirect calorimetry measurement is not always possible or cost
      effective. Energy requirements are more difficult to predict in the acutely ill
      obese patient compared with lean patients because of an increased resting energy
      expenditure per lean body mass and a variable stress response to illness.
      METHODS: A retrospective review of 726 patients identified 57 patients (32
      spontaneous breathing, S; 25 ventilator dependent, V) with body mass indexes of
      30-50 kg/m2. Limits-of-agreement analysis determined bias (the mean difference
      between measured and predicted values) and precision (the standard deviation of
      the bias) to evaluate the accuracy of predictive formulae compared with measured
      resting energy expenditure (MREE) by a Deltatrac Metabolic Monitor. Predictive
      accuracy was determined within+/-10% MREE. The predictive formulae examined were:
      variations of the Harris-Benedict equations using ideal, adjusted weights of 25%
      and 50% and actual weights with stress factors ranging from 1.0 to 1.5; the
      Ireton-Jones equation for obesity; the Ireton-Jones equations for hospitalized
      patients (S and V); and the ratio of 21 kcalories per kilogram actual weight.
      RESULTS: The mean MREE was 21 kcal/kg actual weight. The adjusted Harris-Benedict
      average weight equation was optimal for predicting MREE for the combined S and V
      sets (bias = 182+/-123; 67%+/-10% MREE), as well as the S subset (bias = 159+/
      112; 69%+/-10% MREE). CONCLUSIONS: The Harris-Benedict equations using the
      average of actual and ideal weight and a stress factor of 1.3 most accurately
      predicted MREE in acutely ill, obese patients with BMIs of 30-50 kg/m2.
      Predictive formulae were least accurate for obese, ventilator-dependent patients.

PMID- 10338221
TI  - Glutamine synthetase: a key enzyme for intestinal epithelial differentiation?
AB  - BACKGROUND: We have previously shown that glutamine synthetase protein and mRNA
      are concentrated in the crypt region of the rat small intestine and that the
      activity of this enzyme is highest around the time of weaning. This anatomical
      location and time of peak activity are sites and periods of active enterocyte
      differentiation. This led to our current hypothesis that glutamine synthetase is
      important in the differentiation of enterocytes. METHODS: To test our hypothesis,
      we treated Caco-2 cells with physiologic (0.6 mM) glutamine concentrations in
      cell culture medium. The experimental group was treated with methionine
      sulfoximine, an irreversible glutamine synthetase inhibitor, and the control
      group with phosphate buffered saline. Three standard and well-defined markers of
      intestinal differentiation-sucrase-isomaltase activity, microvillus formation,
      and electrical impedance in transwell plates-were compared between the two
      groups. RESULTS: The methionine-sulfoximine-inhibited group was found to have
      lower sucrase-isomaltase activity, a lower density of microvilli, and lower
      electrical impedance values over time compared with the control group.
      CONCLUSION: The experimental group was found to be less differentiated by all
      three markers of differentiation. Therefore, glutamine synthetase is important
      for Caco-2 cell differentiation.

PMID- 10338223
TI  - Molybdenum requirements in low-birth-weight infants receiving parenteral and
      enteral nutrition.
AB  - BACKGROUND: Molybdenum (Mo) is an essential trace element required by three
      enzymatic systems, yet there are no reports of Mo deficiency in infants. Low
      birth-weight infants (LBW) might be at risk for Mo deficiency because they are
      born before adequate stores for Mo can be acquired, they have rapid growth
      requiring increased intakes, and they frequently receive supplemental parenteral
      nutrition (SPN) and total parenteral nutrition (TPN) unsupplemented with
      molybdenum. METHODS: To investigate Mo requirements of LBW infants (n = 16; birth
      weight, 1336+/-351 g; gestational age, 29.8+/-2.5 weeks; M+/-SD), the authors
      collected all feeds, urine, and feces prior to TPN (baseline, n = 16, collections
      = 16), during TPN (n = 9, collections = 19), during SPN (n = 13, collections =
      17), and after one week of full oral feeds (FOFs) of formula or human milk (FOF,
      n = 16, collections = 16). RESULTS: Infant weights at collection times were:
      1.3+/-0.3 g, 1.27+/-0.4 g, 1.4+/-0.3 g, and 1.7+/-0.5 g, respectively. Mo intake
      was 0.03+/-0.1 microg/d, 0.34+/-0.1 microg/d, 1.25+/-1.7 microg/d, and 6.1+/-2.5
      microg/d. Mo output was 0.64+/-0.6, 0.34+/-0.5, 0.68+/-0.8, and 4.1+/-2.5
      microg/d. Mo balance at these times was -0.60+/-0.5, -0.001+/-0.5, 0.57+/-1.9,
      and 2.0+/-2.9 microg/d. Mo balance increased with time, yet some infants were
      always in negative balance, even though Mo intakes exceeded recommendations.
      CONCLUSIONS: The authors speculate that an intravenous intake of 1 microg/kg/d
      (10 nmol/kg/d) and an oral intake of 4-6 microg/kg/d (40-60 nmol/kg/d) would be
      adequate for the LBW infant.

PMID- 10338224
TI  - The metabolic basis of the increase of the increase in energy expenditure in
      severely burned patients.
AB  - BACKGROUND: Severe burn trauma is characterized by an elevated rate of whole-body
      energy expenditure. APPROACH: In this short review, we have attempted to assess
      the metabolic characteristics of and basis for the persistent increase in energy
      expenditure during the flow phase of the injury. We consider some aspects of
      normal energy metabolism, including the contribution of the major adenosine
      triphosphate (ATP)-consuming reactions to the standard or basal metabolic rate.
      Rate estimates are compiled from the literature for a number of these reactions
      in healthy adults and burned patients, and the values are related to the
      increased rates of whole-body energy expenditure with burn injury. RESULTS: Whole
      body protein synthesis, gluconeogenesis, urea production, and substrate cycles
      (total fatty acid and glycolytic-gluconeogenic) account for approximately 22%,
      11%, 3%, 17%, and 4%, respectively, of the burn-induced increase in total energy
      expenditure. CONCLUSIONS: These ATP-consuming reactions, therefore, seem to
      explain approximately 57% of the increase in energy expenditure. The remainder of
      the increase may be due, in large part, to altered Na(+)-K(+)-ATPase activity and
      increased proton leakage across the mitochondrial membrane.

PMID- 10338225
TI  - Rapid development of severe copper deficiency in a patient with Crohn's disease
      receiving parenteral nutrition.
AB  - A 32-year-old man with active Crohn's disease and recurrent small bowel
      strictures underwent abdominal surgery and was subsequently given total
      parenteral nutrition (TPN). Severe cholestasis developed and copper was removed
      from the TPN. Although serum ceruloplasmin levels were within normal limits, 8
      weeks after copper removal, he developed pancytopenia. Serum copper levels were
      severely depressed. Bone marrow biopsy was consistent with copper deficiency;
      cytoplasmic vacuolization of both myeloid and erythroid precursors, megaloblastic
      erthropoiesis, and marked hypocellularity were observed. IV replacement with
      copper sulfate resulted in improvement in the patient's anemia, neutropenia, and
      thrombocytopenia, but the patient died suddenly from cardiac tamponade.
      Postmortem examination revealed fibrinous and hemorrhagic pericarditis. Despite
      the rare occurrence of overt copper deficiency, this case emphasizes the need to
      recognize copper deficiency as an important etiology of iron-resistant anemia in
      patients receiving TPN. Furthermore, the relative rapidity with which our patient
      developed pancytopenia suggests that, in view of the established recommendation
      that copper be removed from TPN in cholestatic conditions, serum copper levels
      must be measured periodically.

PMID- 10338226
TI  - The human Na+ glucose cotransporter is a molecular water pump.

PMID- 10338227
TI  - Test ordering guidelines can alter ordering patterns in an academic emergency
      department.
AB  - To determine the impact of an educational program designed to modify test
      ordering behavior in an academic Emergency Department (ED), an observational,
      before-and-after study was conducted at a university tertiary referral center and
      Emergency Medicine (EM) residency site. Test ordering standards were developed by
      EM faculty, RNs, and NPs based upon group consensus and published data. The
      standards were given to all ED staff beginning February 1996, and included in the
      evidence-based medicine orientation and educational program for all residents and
      medical students prior to beginning their rotation. No restrictions were placed
      on actual test ordering. The number of laboratory tests (total and individual)
      ordered per 100 patients decreased significantly after the educational program
      began for: total testing, CBC, and liver function test (LFT). In addition,
      declines during individual months for these tests were statistically significant.
      Prothrombin time and blood culture testing showed no significant decreases in
      test ordering frequency. Chemistry test ordering frequency showed statistically
      significant increases. Overall, approximately $50,000 was saved by decreasing
      test ordering. Test ordering behavior can be modified and maintained by an
      educational program and may have significant economic effects.

PMID- 10338228
TI  - Emergency physicians versus laboratory technicians: are the urinalysis and
      microscopy results comparable? A pilot study.
AB  - In the literature to date, there are no studies that directly evaluate
      microscopic urine examination results obtained by a physician compared to those
      of a trained laboratory technician. Our purpose in undertaking this study was to
      determine whether there would be comparable results obtained by these two groups.
      The study took place in an Emergency Medicine Department with 45,000 visits
      annually. Each urine sample obtained on patients presenting to the Emergency
      Department was divided into two lots: one was sent to the laboratory and the
      other was analyzed by the emergency physician. A comparison of both dipstick and
      microscopic results by physician and laboratory staff was then made using
      sensitivity, specificity, and Kappa analysis. Statistical analysis of the data
      revealed close agreement between the emergency physician and laboratory
      technician with respect to the following components of urinalysis: red blood cell
      urinalysis and microscopy, leukocyte esterase, and nitrite testing. Microscopy
      for white cells and bacteria and testing for proteinuria were not in close
      agreement. Urinalysis by emergency physicians is comparable to laboratory
      technicians for a number of the testing components. However, in this limited
      pilot study, emergency physicians were not able to consistently perform
      urinalysis for the laboratory standard.

PMID- 10338229
TI  - Primary care physician and patient factors that result in patients seeking
      emergency care in a hospital setting: the patient's perspective.
AB  - Much has been written about "abuse" and "overutilization" of Emergency
      Departments (EDs). We undertook to study, from the patient's perspective,
      physician and patient factors that influence the patient's decision to seek ED
      care. The study was designed as a convenience cohort, multi-centre survey,
      conducted in 13 hospitals in the Greater Toronto Area. In our study group of 948,
      most ambulatory patients (93%) seeking care in an ED have a primary care
      physician. From the patient's perspective, most (76%) primary care physicians are
      not educating their patients about which situations warrant ED care and up to 54%
      are not informing their patients about which services are offered in the office.
      As many as 55% of patients presented to the ED because it was more convenient.
      Only a minority (23%) of patients felt their acuity of illness warranted an ED
      visit. Primary care physicians need to play a stronger role in educating their
      patients about the utilization of emergency care and the services offered in the
      office setting.

PMID- 10338230
TI  - How do prudent laypeople define an emergency medical condition?
AB  - To determine the public's perception as to the general definition of an emergency
      medical condition (EMC), and to compare opinions between the general public and
      healthcare workers (HCW) on which specific medical conditions require emergency
      department (ED) care, a survey of people at 12 supermarkets and shopping malls in
      Northern California was conducted over a 6-month period in 1997. Individuals over
      age 18 were asked in person to complete a survey sheet. It asked participants to
      choose one of four definitions of "emergency medical condition." In addition,
      people were asked to determine which of 30 chief complaints they thought needed
      care in the ED. Demographic information was also collected. A second set of
      surveys asking the same questions was conducted among nonemergency healthcare
      providers at hospitals. Healthcare worker was defined as an MD, RN, LVN, or PA. A
      total of 1,018 members of the public and 126 healthcare workers completed the
      survey. EMC definitions selected by the public were: 1) an abbreviated federal
      EMTALA definition: a condition that may result in death, permanent disability, or
      severe pain (48.7%); 2) the federal definition plus other conditions preventing
      work (3.0%); 3) the federal definition plus any other conditions outside business
      hours (16.5%); and 4) any condition at any time as determined by the patient
      (31.6%). HCWs selected the following: definition 1 (71%); definitions 2 and 3
      (0%); and definition 4 (27%). Definitions 1 and 3 were statistically different
      when comparisons were made between the public and HCWs. On the question of which
      of the 30 chief complaints needed care in an ED, agreement was seen between the
      public and HCWs for severe abdominal pain (94% vs. 99%, respectively) and severe
      chest pain (96% vs. 99%, respectively). However, the two disagreed on the need
      for ED care for severe headache (58% vs. 91%, respectively); mild chest pain (51%
      vs. 79%, respectively); and difficulty breathing (77% vs. 98%, respectively). No
      significant difference in opinions on the need for ED care was seen for some
      minor conditions: mild headache, sore throat, cough, flu symptoms, minor foot
      problems. No significant differences in answers occurred when age groups,
      occupations, or locations were compared. In conclusion, the public has split
      views concerning the general definition of an emergency medical condition.
      Approximately half uses a conservative federal definition, and half uses patient
      self-determined need as the definition. Data on which specific conditions need ED
      care provide additional insight on agreement between the public and HCWs on most
      problems. Both groups agree that many perceived minor medical complaints do not
      require ED care.

PMID- 10338231
TI  - Utility of a single beta HCG measurement to evaluate for absence of ectopic
      pregnancy.
AB  - The objectives of this study were to determine the optimal cutoff value (CV) and
      utility of a single serum beta human chorionic gonadotropin hormone (HCG) level
      in assessing the likelihood of ectopic pregnancy (ECP). A retrospective chart
      review was performed at an urban county hospital. The optimal CV was determined
      by comparing all available patients diagnosed with ECP and patients diagnosed
      with threatened abortion (TA) in the Emergency Department (ED) who subsequently
      delivered a baby at the same hospital. The utility of the test was assessed in a
      group of all known patients who presented to the ED with lower abdominal or
      pelvic pain or vaginal bleeding between 6 and 13 weeks estimated gestational age
      (EGA). There were 212 ECPs with measured HCGs. Only nine presented after 13 weeks
      EGA. The mean HCG value was 5,378 mIU/mL. There was no significant correlation
      between HCG and EGA. There were 132 TAs with measured HCGs who subsequently
      delivered. Only four TAs presented before 6 weeks EGA. Regarding the TA patients
      who presented between 6 and 13 weeks EGA, there were 81 with a mean HCG of 83,810
      mIU/mL. Between 6 and 13 weeks EGA, HCG was not significantly correlated with
      EGA. The entire ECP group was compared with the TA group with 6-13 week EGA. A
      receiver-operating characteristic curve with nine HCG cutoff values was
      constructed. Clinically, the optimal CV was 40K. At this level, a test for the
      condition "absence of ECP" had a specificity of 99%, and only two of 212 ECPs in
      our group would test false-positive with an HCG value over 40K. When the test was
      applied to a group of 175 women who presented with pain or bleeding between 6 and
      13 weeks EGA, the sensitivity and positive predictive value for an intrauterine
      pregnancy were 24% and 99.9 %, respectively. However, if this test was applied to
      all patients regardless of clinical findings, and then an ultrasound (U/S)
      algorithm was applied to the patients who had an HCG of less than 40K, it would
      predictably increase the rate of ECPs falsely identified as intrauterine
      pregnancies (IUPs) by 1%, regardless of the false-positive rate of the U/S
      algorithm itself. Given the potential morbidity and mortality of undiagnosed
      ectopic pregnancy, ultimately neither this test nor any other that is less than
      100% specific for IUP can be recommended instead of an initial U/S evaluation for
      patients who present at risk for ECP.

PMID- 10338232
TI  - Emergency department airway management before and after an emergency medicine
      residency.
AB  - To determine whether the start of an Emergency Medicine (EM) training program
      affects the appropriateness, timeliness, and safety of Emergency Department (ED)
      intubations, all ED intubations performed 12 months before and after the start of
      an EM residency were reviewed. In addition, all patients intubated within 12 h
      after being admitted through the ED were reviewed. We found that all ED
      intubations before and after the start of a residency program were deemed
      appropriate. Of patients intubated after admission, 13 of 20 (65%) were felt to
      have warranted intubation while in the ED for the pre-residency group, compared
      with 9 of 29 patients (31%) for the post-residency group. There were no
      differences between the complication rates of these groups. We conclude that an
      EM residency program did not increase the number of inappropriate intubations or
      complications, and reduced the number of patients who required but did not
      receive intubation in the ED.

PMID- 10338233
TI  - Use of the Trousseau dilator in cricothyrotomy.
AB  - When performing cricothyrotomy, once the initial incision has been created, the
      scalpel handle may be inserted into the incision and rotated, or a Trousseau
      dilator may be used to widen the opening. During endotracheal (ET) tube passage,
      the Trousseau dilator may be left in place or a tracheal hook may be inserted for
      tracheal stabilization. This experimental crossover trial of cricothyrotomy in a
      cadaver model compared: 1) scalpel handle rotation to the use of a Trousseau
      dilator in widening the initial incision, and 2) the use of a tracheal hook to a
      Trousseau dilator during ET tube passage. Part 1: Cricothyrotomy incisions were
      made in 30 formalin-fixed cadavers using a #11 scalpel blade. The opening was
      initially widened using a Trousseau dilator or a scalpel handle rotated through
      360 degrees. Progressively larger ET tubes were passed using a tracheal hook for
      stabilization at the thyroid cartilage, and the size of the largest ET tube
      passed without significant resistance was recorded. Each opening was then widened
      using the other technique and ET tubes again passed as above. The dimensions of
      the opening after initial dilatation and after final ET tube passage were also
      recorded. Part 2: A tracheal hook inserted cephalad at the thyroid cartilage or a
      Trousseau dilator was used to stabilize the trachea during passage of
      progressively larger ET tubes, and the size of the largest ET tube passed without
      significant resistance was recorded. The insertion techniques were then reversed
      and ET tubes again passed as above. The trachea was inspected for damage and the
      balloon cuff checked for rupture after each attempt. Descriptive statistics were
      applied using a paired t-test and a chi-square analysis. We found no significant
      difference between the two techniques with regard to initial opening dimensions,
      final opening dimensions, or maximal ET tube size. There was no damage to local
      tissue and no balloon cuff ruptures. We found that the average size of the
      largest ET tube passed was significantly greater with the use of a tracheal hook
      (internal diameter mean 7.0 mm, median 7.0 mm) than with a Trousseau dilator
      (internal diameter mean 5.7 mm, median 5.5 mm). There was no damage to local
      tissue and no cuff ruptures. We conclude that the scalpel handle rotation
      technique is equal to the use of the Trousseau dilator with regard to opening
      size and maximal ET tube size but that use of a tracheal hook rather than a
      Trousseau dilator allows for passage of a larger ET tube in a cadaver model of
      cricothyrotomy.

PMID- 10338234
TI  - Acute carpal tunnel syndrome from thrombosed persistent median artery.
AB  - We report a case of acute carpal tunnel syndrome from thrombosis of a persistent
      median artery caused by blunt trauma. The sudden onset of numbness in the median
      nerve distribution with pain in the fingers in a young adult may provide clues to
      the diagnosis.

PMID- 10338235
TI  - Whistler technique used to reduce traumatic dislocation of the hip in the
      emergency department setting.
AB  - The authors appraised the effectiveness of an in-line traction technique
      developed to reduce posteriorly dislocated hips. We had found certain application
      difficulties with the Allis, or modified Allis, technique, and subsequently
      developed a method that was easier to implement for the physician. The dislocated
      hip is relocated using the physician's arm to raise and maneuver the affected leg
      as the physician's shoulder is raised. Patient data for the case series were
      collected from March 1994 to March 1998.

PMID- 10338236
TI  - Pasteurella multocida meningitis and septic arthritis secondary to a cat bite.
AB  - Animal bites are seen almost daily in the emergency department, and the majority
      heal without complication. Pasteurella multocida is frequently the causative
      organism of localized wound infections and cellulitis in this patient population.
      P. multocida infection is usually associated with close contact with pets, such
      as dogs and cats, that harbor this organism as normal oral flora. Meningitis and
      septic arthritis are very rare sequelae of P. multocida infection. This case
      report presents a patient with P. multocida bacteremia, meningitis, and septic
      arthritis developing together as a complication of a cat bite.

PMID- 10338237
TI  - Headache: cortical vein thrombosis and response to anticoagulation.
AB  - Cerebral venous thrombosis (CVT) is being diagnosed more frequently with the use
      of advanced radiologic imaging. The presentation of CVT includes a wide spectrum
      of nonspecific symptoms with headache predominating. We present a case with
      acute, severe headache. The evaluation included a head computed tomography (CT)
      scan that was normal. The presence of opacified sinuses led to treatment for
      sinusitis. The patient returned the following day with a generalized tonic-clonic
      seizure. A magnetic resonance imaging (MRI) study identified an isolated cortical
      venous thrombosis. This patient was treated with anticonvulsant and
      anticoagulation therapy. A CVT is an unusual cause of headache and should be
      considered in patients with atypical presentation or associated seizure, or who
      are refractory to current therapy. Diagnosis may be made with MRI. Resolution and
      complete recovery are possible with appropriate therapy.

PMID- 10338238
TI  - Delayed presentation of splenic rupture after colonoscopy.
AB  - Splenic rupture is a rare but potentially deadly complication of colonoscopy. We
      present the case of a 70-year-old male who presented with abdominal pain,
      initially stable, almost 2 days after colonoscopy. The patient's clinical status
      deteriorated shortly after abdominal CT scan identified splenic rupture.

PMID- 10338239
TI  - Sudden death of a young hockey player: case report of commotio cordis.
AB  - Despite the use of protective gear, a 15-year-old hockey player died when he was
      struck in the chest by a puck. This is the fifth recorded hockey death related to
      so-called commotio cordis, that is, blunt chest injury without myocardial
      structural damage. In light of inadequacies of commercial chest protectors
      currently in use for hockey, the authors hope to educate players and coaches
      about the danger of blocking shots with the chest. Physicians should be aware
      that commotio cordis represents a distinctive pathological condition, in the
      event of which immediate recognition, precordial thump, CPR, and defibrillation
      are potentially lifesaving. Appropriate medical supervision at amateur hockey
      games, 911 telephone access, and on-site automated external defibrillators are
      issues that deserve careful consideration.

PMID- 10338240
TI  - Delayed toxicity following ingestion of enteric-coated divalproex sodium
      (Epival).
AB  - Toxicity occurs rapidly after overdose with regular-release valproic acid, but
      there is less experience with enteric-coated formulations. We report a case of
      delayed onset of toxicity and time to peak levels after ingestion of enteric
      coated divalproex sodium (Epival). The patient was a 24-year-old female who
      ingested an unknown amount of Epival together with ibuprofen, dimenhydrinate, and
      ethanol. Ninety minutes after ingestion, the patient had only mild toxicity, and
      valproic acid was undetectable in her blood. By 13 h post-ingestion, valproate
      levels were 7450 micromol/L (1,075 mg/L), and the patient was comatose and
      required endotracheal intubation and mechanical ventilation. The toxicity and
      pharmacokinetics of valproic acid are discussed in the context of this case, and
      management guidelines are proposed.

PMID- 10338241
TI  - Methamphetamine-related stroke: four cases.
AB  - Amphetamine use in certain parts of the United States has risen dramatically.
      Methamphetamine, the most-common illicitly abused type of amphetamine, can be
      inhaled, injected intravenously, or smoked. It is a potent sympathomimetic that
      may lead to vascular events including myocardial infarction and stroke. Because
      of the demographics of drug use, these potentially devastating events usually
      occur in relatively young patients. The pathophysiology of stroke related to
      amphetamine use is multifactorial. Elevation in blood pressure, vasculitis, or
      other vascular toxicity are postulated as major mechanisms. Four cases of stroke
      associated with the use of methamphetamine, all occurring in patients ranging in
      age from 29-45 years, are described. Methamphetamine use appears to be a risk
      factor for the development of stroke. The rise in methamphetamine use will
      undoubtedly result in increased Emergency Department admissions with clinical
      presentations very similar to those of cocaine intoxication.

PMID- 10338242
TI  - Electrocardiographic manifestations: benign early repolarization.
AB  - Early repolarization, also known as benign early repolarization (BER) or normal
      variant, is noted in approximately 1% of the population and in up to 48% of
      patients seen in the Emergency Department with chest pain. BER represents a
      benign variant of the normal electrocardiogram and is one of several syndromes
      producing electrocardiographic ST segment elevation (STE). The electrocardiogram
      (EKG) findings of BER include diffuse or widespread ST segment elevation, upward
      concavity of the initial portion of the ST segment, notching or slurring of the
      terminal QRS complex, and concordant T waves of large amplitude. This article
      focuses on BER and includes the electrocardiographic findings useful in making
      the diagnosis as well as distinguishing BER from other STE syndromes.

PMID- 10338243
TI  - Permanent cardiac pacemakers: issues relevant to the emergency physician, Part I.
AB  - Many people benefit from the implantation of cardiac pacemakers for management of
      certain cardiac dysrhythmias. These patients are seen regularly in the emergency
      department with a variety of pacemaker complications and malfunctions. The
      presence of a pacemaker may also affect management of unrelated medical problems.
      This two-part series reviews the medical issues related to patients with
      permanent pacemakers. Part I covers pacing modes and terminology, complications
      of the implant procedure, and the approach to a patient with a permanent
      pacemaker. Part II covers the causes, diagnosis and management of pacemaker
      malfunction; the pacemaker syndrome; the pacemaker Twiddler's syndrome; and other
      considerations in the paced patient including diagnosis of acute myocardial
      infarction, ACLS protocols, trauma, and sources of interference. Indications for
      permanent pacemaker implantation and temporary external pacing will not be
      covered.

PMID- 10338244
TI  - Ultrasonographic guidance of transvenous pacemaker insertion in the emergency
      department: a report of three cases.
AB  - We report three cases in which ultrasound was used in the Emergency Department to
      facilitate the placement of a temporary transvenous cardiac pacemaker.

PMID- 10338245
TI  - The management of stab wounds to the back.
AB  - The management of stab wounds to the back is controversial. There are certain
      clear indications for exploratory laparotomy, but most cases require a diagnostic
      workup and a period of observation. In this article, different diagnostic
      modalities are presented, including local wound exploration, diagnostic
      peritoneal lavage, abdominal computed tomography (CT) scan, triple-contrast
      abdominal CT scan, and intravenous pyelography (IVP). Recommendations for
      management are given, with emphasis on abdominal CT scan and observation.

PMID- 10338246
TI  - Cross-sensitivity and the anticonvulsant hypersensitivity syndrome.
AB  - The anticonvulsant hypersensitivity syndrome is a rare complication that occurs
      with the use of antiepileptic medications. Although phenytoin is the most common
      culprit, carbamazepine and phenobarbital are known to cause a similar reaction. A
      familial occurrence has been reported. We present a case of the anticonvulsant
      hypersensitivity syndrome to emphasize the importance of recognizing the multiple
      clinical components of the syndrome and to raise awareness of the cross
      sensitivity among anticonvulsants metabolized via arene oxide metabolites.

PMID- 10338247
TI  - Dyspnea in pregnancy.

PMID- 10338248
TI  - Cavitary Pneumocystis carinii pneumonia.

PMID- 10338249
TI  - Chronic inguinal hernia.

PMID- 10338250
TI  - Atypical air in the abdomen.

PMID- 10338251
TI  - The carpal tunnel syndrome.
AB  - Chronic carpal tunnel syndrome was initially described by James Jackson Putnam in
      1880. A number of medical luminaries have also contributed to our understanding
      of the syndrome, including Paget, Marie, Ramsay Hunt, Phalen. and Osler. Carpal
      tunnel syndrome is the most common peripheral compression neuropathy. Most cases
      are idiopathic, with nonspecific tenosynovitis leading to median nerve
      compression. A number of diseases and other conditions are also associated with
      chronic carpal tunnel. Patients characteristically complain of nocturnal
      paresthesias or burning pain. Motor complaints relate to thenar muscular weakness
      and atrophy. Bedside diagnostic tests include Tinel's and Phalen's signs, and
      application of pressure over the median nerve by inflating a sphygmomanometer
      over the wrist. Tinel's sign is the induction of paresthesias by tapping over the
      site of the median nerve at the wrist. In Phalen's sign, symptoms are reproduced
      by maximum flexion of the wrist for 60 s. The classically described patients are
      middle-aged women. In addition, another distinct population is receiving
      increased attention, the relatively young male and female workers who experience
      symptoms performing repetitive manual labor.

PMID- 10338252
TI  - Ingested foreign bodies of the gastrointestinal tract.

PMID- 10338253
TI  - Mechanical ventilation: past and present.

PMID- 10338255
TI  - A call to arms: the emergency physician, international perspectives on firearm
      injury prevention and the Canadian gun control debate.
AB  - There are more than seven million firearms in Canada and approximately 1400
      firearm-related deaths per year. These figures are far greater than those for
      most European countries, but far less than those for the United States. This
      article will discuss the different classes of firearm deaths and the associated
      costs. Public health issues will be explored, especially as they relate to the
      involvement of the Canadian Association of Emergency Physicians, as well as
      injury control recommendations.

PMID- 10338254
TI  - Acute dystonic reactions that fail to respond to diphenhydramine: think of PCP.

PMID- 10338256
TI  - Coroners and lack of emergency department resources.

PMID- 10338257
TI  - The role of platelets and platelet glycoprotein IIb/IIIa receptor inhibition in
      acute coronary syndromes: an educational supplement. Introduction.

PMID- 10338258
TI  - Overview of the use of glycoprotein IIb/IIIa inhibitors in acute myocardial
      infarction.

PMID- 10338259
TI  - The platelet in acute coronary syndromes: defining the pivotal role of platelet
      glycoprotein IIb/IIIa receptor blockade.

PMID- 10338260
TI  - Treatment of non-ST-segment-elevation acute coronary syndromes with platelet
      glycoprotein IIb/IIIa inhibitors: an emergency department perspective.

PMID- 10338261
TI  - Combination fibrinolytic therapy and platelet glycoprotein IIb/IIIa receptor
      blockade in acute myocardial infarction: an emerging solution for reperfusion.

PMID- 10338262
TI  - The overactive bladder: an overview for primary care health providers.
AB  - The overactive bladder, with symptoms of frequency, urgency and urge
      incontinence, substantially affects the life styles of millions of people
      throughout the world. The symptoms are associated with significant social,
      psychological, occupational, domestic, physical, and sexual problems. Despite the
      considerable impact of the condition on quality of life, sufferers are often
      reluctant to discuss their problem with family members or health care
      professionals. This state of affairs is unfortunate, for much can be done to
      alleviate the symptoms of this distressing condition. It is therefore of utmost
      importance that medical education about symptoms of the overactive bladder and
      other related problems be improved, to help health care professionals identify
      and treat patients who will benefit from therapy. This article reviews current
      thinking regarding definition, epidemiology, quality of life effects, evaluation
      and management. Emphasis is placed on knowledge particularly useful in primary
      care, especially, noninvasive modalities of therapy.

PMID- 10338263
TI  - Micronized progesterone: a new therapeutic option.
AB  - The recent release of micronized progesterone adds a new physiologic alternative
      to the available therapeutic agents for common indications in both pre- and
      postmenopausal women. This compound overcomes problems with absorption through
      the gut associated with exogenous progesterone administration so that it can be
      used orally to achieve required serum and tissue levels of a hormone that is
      structurally identical to endogenous progesterone. Available data suggest that it
      is functionally equivalent to synthetic progestogens for common applications,
      such as secondary amenorrhea, while offering the advantage of a more physiologic
      metabolic profile that could be important for sustained use in applications such
      as postmenopausal hormone replacement therapy.

PMID- 10338264
TI  - Hyperprolactinemia.
AB  - Prolactinomas are the most common pituitary tumors. Hyperprolactinemia is
      characterized by increased production of prolactin, often leading to reproductive
      dysfunction and galactorrhea. Prolactinomas may also cause male-factor
      infertility by producing hypogonadism. In addition, if large, they can produce
      neurologic symptoms by mass effect in the sellar area. The diagnostic evaluation
      first requires exclusion of other causes of hyperprolactinemia, such as
      pregnancy, primary hypothyroidism, numerous medications, and miscellaneous
      causes. The second step in the diagnostic evaluation is to perform a head scan,
      preferably an MRI. This is essential in order to exclude a "pseudoprolactinoma"
      which would require surgery. Following diagnostic evaluation, the next step is to
      determine whether a patient with hyperprolactinemia has an indication for
      therapy, such as a macroprolactinoma (tumor >1 cm), hypogonadism (risk of
      osteoporosis), infertility, significant galactorrhea, acne, hirsutism, or
      headache. The treatment of choice for nearly all patients with hyperprolactinemic
      disorders is medical. In most cases, dopamine agonists (bromocriptine, pergolide,
      cabergoline) are extremely effective in lowering serum prolactin, restoring
      gonadal function, decreasing tumor size, and improving visual fields. The main
      limitation is side effects, particularly nausea or orthostatic dizziness. The
      newest dopamine agonist, cabergoline, can be given just once or twice a week, is
      more effective in normalizing prolactin and restoring menses than bromocriptine,
      and is significantly better tolerated. However, it is not yet recommended as
      first-line therapy for patients seeking fertility, because adequate safety data
      in pregnancy are not available. For the infrequent patient unable to tolerate, or
      resistant to, medical therapy, neurosurgical transsphenoidal resection may be
      necessary, particularly if the patient has a large lesion jeopardizing the optic
      chiasm. Hyperprolactinemia is a rewarding disorder to manage because patients
      typically respond well to medication, with restoration of menses and fertility.

PMID- 10338265
TI  - Oral contraception: safety issues re-examined.
AB  - Oral contraceptives are highly effective contraceptive agents that are used
      throughout the world. However, misperceptions about the safety of oral
      contraceptives as well as a relative lack of information concerning their
      numerous and important noncontraceptive benefits may limit their use and place
      women at increased risk for unintended pregnancy. Safety issues concerning the
      use of oral contraceptives have largely been laid to rest; indeed, except for a
      slight increased risk of venous thromboembolism in combination oral contraceptive
      users, conventional oral contraceptive use is not associated with an increased
      risk for cardiovascular events. In addition, fears regarding breast cancer
      development in OC users have been unsubstantiated by the plethora of available
      data. Clinicians must provide accurate and empathetic counseling concerning the
      safety and applicability of oral contraceptives and other pregnancy prevention
      methods.

PMID- 10338266
TI  - A lifetime of healthy skin: implications for women.
AB  - During her lifetime, a woman faces the possibility of seeking dermatological
      assistance for a myriad of conditions, including acne, rosacea, striae,
      photodamage, and skin cancers. It is important for clinicians and patients to be
      aware of the symptoms of these conditions as well as the most beneficial
      approaches for prevention, diagnosis, treatment, and management. The life
      expectancy of women has increased and predictions for the year 2050 estimate the
      average age at 81 years. This will place women at greater risk for dermatological
      problems, especially photodamage and skin cancer. In addition, various ethnic
      groups may manifest these conditions differently. Although acne is most prevalent
      among teenaged males, most can expect clearing by age 25. Females may continue to
      experience acne into the adult years, sometimes beyond the age of 40. Although it
      is not a life-threatening disease, acne may have psychosocial and quality-of-life
      consequences. Treatments for acne can be topical or systemic, and include
      retinoids, antibiotics, benzoyl peroxide, azelaic acid, and hormonal therapy.
      Rosacea is more common in women (especially during menopause) than in men. It is
      a chronic condition that can cause complications, including telangiectasia,
      conjunctivitis, and blepharitis. Although there is no cure, rosacea can be
      managed and controlled with medication. Topical antibiotics, such as
      metronidazole, and systemic antibiotics, such as tetracycline, clarithromycin,
      and doxycycline, are used to manage rosacea. Striae, or stretch marks, occur most
      frequently in pregnant women, adolescents experiencing growth spurts, weight
      lifters, and the obese. Although not a health threat, they can be psychologically
      distressing. There are not many treatment options for striae, but topical
      tretinoin and the pulsed dye laser offer promising results. Intrinsic, or normal,
      aging of the skin results from the process of chronological aging. Photodamage is
      skin damage caused by chronic exposure to ultraviolet (UV) light. It is the
      leading cause of extrinsic aging, or alterations of the skin due to environmental
      exposure. Estimates indicate that almost half of a person's UV exposure occurs by
      age 18. Photoaging causes numerous histologic, physiologic, and clinical changes;
      it also increases the risk for skin cancer. Photodamage can be prevented through
      the use of sun screens, protective clothing, and avoidance of the sun during peak
      intensity time. The only product approved by the FDA for the treatment of
      photodamage (fine wrinkles, mottled hyperpigmentation, and skin roughness),
      topical tretinoin emollient cream, may help prevent additional photoaging when it
      is used to treat existing photoaging. Other management options for photodamaged
      skin include alpha-hydroxy acids, antioxidants, antiandrogens, moisturizers, and
      exfoliants. In patients with excessive manifestations of photodamage, surgical
      management may be needed, including dermabrasion, chemical peels, soft tissue
      augmentation, laser resurfacing, botulism toxin, and Gortex threads. Clinicians
      must educate their patients about the most appropriate skin care regimen as well
      as approaches for preventing and treating common afflictions. In this way, women
      will have the best opportunity for having and maintaining healthy skin.

PMID- 10338267
TI  - Uses of progesterone in clinical practice.
AB  - Progesterone is the natural progestagen produced by the corpus luteum during the
      luteal phase. It is absorbed when administered orally, but is greater than 90%
      metabolized during the first hepatic pass. This greatly limits the efficacy of
      once-daily administration and also results in unphysiologically high levels of
      progesterone metabolites, particularly those reduced at the 5-a position. These
      metabolites can cause dizziness and drowsiness to the point of preventing the
      operation of a motor vehicle. Synthetic progestins, such as medroxyprogesterone
      acetate and norethindrone acetate (NETA), have been specifically designed to
      resist enzymatic degradation and remain active after oral administration.
      However, these compounds exert undesirable effects on the liver and often cause
      severe psychological side effects. The permeability of the skin does not allow
      for administration of progesterone in the quantities normally produced by the
      corpus luteum, i.e., up to 25 mg/day during the mid-luteal phase. To avoid this
      problem, synthetic progestins such as NETA have been administered transdermally.
      These compounds, though, just like synthetic estrogens administered non-orally,
      retain undesirable hepatic effects even when administered transdermally.
      Transvaginal administration of progesterone is a practical non-oral route
      available for administering progesterone. Early experience was gained with
      vaginal suppositories, which lack manufacturing controls. Recently, a new
      progesterone gel formulation has been designed for vaginal use. The clinical
      acceptability of this product has been enhanced by the bioadhesive
      characteristics of its polycarbophil-based gel, which conveys controlled and
      sustained-released properties. Investigations have shown that because of local
      direct vagina-to-uterus transport, which results in a preferential uterine uptake
      of progesterone, this formulation given in conjunction with physiological amounts
      of estradiol produces endometrial changes similar to those seen in the luteal
      phase, despite plasma progesterone levels that remain subphysiologic. Studies in
      infertility show that vaginal progesterone in this form allows secretory
      transformation of the endometrium and the development of pregnancy despite
      providing low systemic progesterone concentrations. Fewer side effects occur when
      used for hormone replacement than typically encountered with progestins and oral
      progesterone. Uses in patients with infertility and hypoestrogenism and secondary
      amenorrhea are reviewed.

PMID- 10338268
TI  - Fosfomycin tromethamine: single-dose treatment of acute cystitis.
AB  - Fosfomycin tromethamine is an oral antimicrobial indicated for the treatment of
      uncomplicated lower urinary tract infections (UTIs). This agent is active in the
      urine against common uropathogens that are associated with cystitis in women,
      including organisms resistant to other antibiotics. A single dose of fosfomycin
      tromethamine is well absorbed and produces a therapeutic concentration in the
      urine for one to three days. Comparative clinical trials suggest that a single
      3.0-g dose of fosfomycin tromethamine is as clinically effective as 7- to 10-day
      treatment regimens of standard agents such as nitrofurantoin, norfloxacin, and
      trimethoprim/sulfamethoxazole used to treat UTIs. Fosfomycin tromethamine is well
      tolerated and appears safe for use during pregnancy. Quality-of-life advantages,
      such as enhanced compliance and convenience, are also important aspects of
      fosfomycin tromethamine therapy.

PMID- 10338269
TI  - Long-acting hormonal contraception: assessing impact on bone density, weight, and
      mood.
AB  - The decline in unintended pregnancies and abortions in the United States has been
      attributed largely to increased use of two highly effective, hormonal
      contraceptive methods, depot medroxyprogesterone acetate injection (DMPA) and
      levonorgestrel implants (Norplant). Despite the efficacy and increasing
      acceptability of these long-term methods, some clinicians and women are reluctant
      to use them because of concerns regarding reduction in bone density with DMPA,
      and depressive symptoms and body weight issues with both injectables and
      implants. Recent multicenter experience showed no increase in depressive symptoms
      after 1 year's DMPA use and 2 years' Norplant use, even among users with the
      highest mean depressive symptom scores pre-therapy. Observational studies
      indicate that, as with other hormonal contraceptives and hormone replacement,
      DMPA does not cause significant weight gain, even during long-term use.
      Multicenter experience with the new soft-tubing Norplant product found an average
      annual pregnancy rate of <1% and a cumulative 5-year pregnancy rate of 4.2% in
      women weighing 70 kg or more--substantially lower than failure rates cited in the
      product labeling. Trends in bone density seen with DMPA appear similar to those
      during lactation. Subgroups of long-term DMPA users may experience a decrease in
      spinal bone density that appears to be reversible following discontinuation. A
      once-a-month injectable contraceptive combining 25 mg medroxyprogesterone acetate
      and 5 mg estradiol cypionate (Cyclo-Provera, Cyclofem or Lunelle), a 2-rod
      levonorgestrel system, and a single-rod 3-ketodesogestrel implant system may
      become available in the United States. Large-scale trials have established the
      safety, efficacy, and acceptability of Cyclo-Provera. In contrast to DMPA, users
      of Cyclo-Provera experience predictable, regular monthly bleeding, fewer
      discontinue due to bleeding-related problems. Fertility returns rapidly following
      discontinuation. A U.S. multicenter study is currently nearing completion.

PMID- 10338270
TI  - Cell transplantation and neuroscience.

PMID- 10338272
TI  - [3H]CNQX and NMDA-sensitive [3H]glutamate binding sites and AMPA receptor subunit
      RNA transcripts in the striatum of normal and weaver mutant mice and effects of
      ventral mesencephalic grafts.
AB  - Levels of excitatory amino acid receptors were studied in the weaver mouse model
      of DA deficiency after unilateral intrastriatal transplantation of E12+/+
      mesencephalic cell suspensions. Graft integration was verified by turning
      behavior tests and from the topographical levels of the DA transporter, tagged
      autoradiographically with 3 nM [3H]GBR 12935 (average increase in grafted dorsal
      striatum compared to nongrafted side, 60%). Autoradiography of 80 nM [3H]CNQX and
      100 nM NMDA-sensitive [3H]glutamate binding was carried out to visualize the
      topography of non-NMDA and NMDA receptors, respectively, in +/+ mice and in
      recipient weaver mutants 3 months after grafting. Increases of 30% or more were
      found for [3H]CNQX binding in the dorsal nongrafted weaver striatum compared to
      +/+, and a further 6-9% increase in grafted weaver compared to nongrafted side.
      The added increase of non-NMDA receptors in the transplanted striatum might be
      explained by a presence of such receptors on DA presynaptic endings of graft
      origin. A 20% increase in NMDA-sensitive [3H]glutamate binding was measured in
      the dorsal nongrafted weaver striatum compared to +/+. NMDA-sensitive
      [3H]glutamate binding in the transplanted side of weaver mutants tended to be
      slightly higher in all areas of the striatal complex compared to the nongrafted
      side, without reaching conventional levels of statistical significance. Using in
      situ hybridization histochemistry with synthetic 32p labeled oligonucleotide
      probes, we investigated RNA transcripts encoding the four AMPA receptor subunits.
      RNA transcripts in the striatum are seen with a decreasing signal intensity in
      the following order: GluRB > GluRA > GluRC > GluRD. The weaver caudate-putamen
      shows a 12% increase in GluRA subunit mRNA compared to +/+, whereas mesencephalic
      neuron transplantation leads to slight increases (3%) in the levels of GluRB mRNA
      in the nucleus accumbens. The results are placed in the context of the important
      interaction between the converging glutamatergic corticostriatal and the DAergic
      nigrostriatal pathways in controlling the functional output of the basal ganglia
      in Parkinson's disease and in experimental models of DA deficiency.

PMID- 10338273
TI  - GDNF increases the density of cells containing calbindin but not of cells
      containing calretinin in cultured rat and human fetal nigral tissue.
AB  - Among the dopaminergic neurons in substantia nigra pars compacta and in the
      ventral tegmental area, subpopulations express the calcium-binding proteins
      calbindin (CB) and calretinin (CR), and the CB-containing neurons are supposed to
      be less prone to degeneration in Parkinson's disease. Glial cell line-derived
      neurotrophic factor (GDNF) is a potent survival factor for nigrostriatal
      dopaminergic neurons. Using free-floating roller-tube (FFRT) cultures derived
      from fetal rat (E14) ventral mesencephalon we found that GDNF (10 ng/ml)
      significantly increased the number of surviving tyrosine hydroxylase (TH)
      immunoreactive neurons. The possible effects of GDNF treatment on CB
      immunoreactive (CB-ir) and CR-ir neurons in such cultures were examined in the
      present study. The neuronal cell densities were measured by quantifying the
      numbers of CB-ir and CR-ir neurons in areas of sections through the most
      extensive parts of the spherical cultures. In 4-day-old and 8-day-old cultures
      GDNF treatment increased the density of CB-ir neurons by 50% and 59%,
      respectively. Partial co-existence of TH and CB was shown using the method of
      double immunolabeling. The density of CR-containing neurons was unaffected by
      GDNF treatment as confirmed by Western blotting for CR. Parallel effects of GDNF
      treatment were obtained for cultures of human fetal ventral mesencephalon (8
      weeks postconception). In conclusion, our findings identify GDNF as a potent
      factor for fetal rat and human nigral CB-ir neurons able to promote their
      survival in culture. Referring to a suggested neuroprotective role of CB, the
      results may be of relevance in the context of neuronal transplantation of
      patients suffering from severe Parkinson's disease.

PMID- 10338274
TI  - Intranigral transplantation of fetal substantia nigra allograft in the
      hemiparkinsonian rhesus monkey.
AB  - Current clinical protocols for fetal cell transplantation for Parkinson's disease
      (PD) have focused on restoring dopamine in the striatum. However, there are now a
      number of human transplant recipients who have had robust innervation of the
      striatum by dopaminergic grafts (documented by positron emission tomography or by
      autopsy), but only a partial improvement in parkinsonian motor signs. Thus, there
      is a need for improved transplant strategies. In animal models of PD, there is
      recent evidence that restoring dopamine in the substantia nigra, instead of or in
      addition to the striatum, may be important to correct abnormal motor behavior.
      This pilot study examined the morphological features and behavioral effects of
      fetal dopaminergic neuronal allografts placed into the substantia nigra of three
      1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated hemiparkinsonian
      rhesus monkeys. We show that grafts can survive in host substantia nigra.
      Characteristics of the graft-host interface were variable. In one animal,
      reinnervation of host substantia nigra was observed, and this animal showed
      behavioral improvement in a reach-and-retrieval task.

PMID- 10338275
TI  - Biocompatibility of poly (DL-lactide-co-glycolide) microspheres implanted into
      the brain.
AB  - The delivery of therapeutic molecules to the brain has been limited in part due
      to the presence of the blood-brain barrier. One potential solution is the
      implantation of biodegradable polymers with sustained release of drugs. Poly (DL
      lactide-co-glycolide) (PLG) is a bioerodible polymer with a long and successful
      history of use as a suture material. More recently, PLG has been investigated for
      localized and sustained delivery of molecules into both peripheral sites and the
      brain. Despite its well-defined safety profile for parenteral applications,
      little information exists concerning the safety of PLG when implanted into the
      brain. To further characterize the biocompatibility of PLG in the brain, we
      examined the gliotic response following implants of PLG into the brains of rats.
      As a control, each animal received an injection of the suspension medium into the
      contralateral hemisphere. Following implantation, PLG was well tolerated. GFAP
      positive astrocytes were observed throughout the cerebral cortex and striatum on
      both the implanted and control sides, with the reaction being greatest within the
      heavily myelinated fiber tracts of the corpus callosum. Quantitative analyses
      revealed that this reaction occurred within 1 h postsurgery, reached its peak at
      1 week following surgery, and then decreased markedly by 1 month postsurgery. A
      minimal gliotic reaction was still present 1 year postsurgery but was localized
      to the needle tract. No differences in GFAP reactivity were seen between the
      polymer-implanted and control sides at any time point. Histological analysis
      determined that the majority of the PLG disappeared between 1 and 4 weeks. A set
      of parallel studies in which PLG samples were retrieved from the brain at various
      time points corroborated these findings and determined that the majority of PLG
      degraded within 2 weeks following implantation. Together, these results
      demonstrate that PLG is well tolerated following implantation into the CNS and
      that the astrocytic response to PLG is largely a consequence of the mechanical
      trauma that occurs during surgery. The biocompatibility of PLG implanted into the
      CNS provides further support for its use in a wide range of new therapeutic
      applications for sustained and localized drug delivery to the brain.

PMID- 10338276
TI  - Neuron-enriched second trimester human cultures: growth factor response and in
      vivo graft survival.
AB  - Grafts of first trimester fetal tissue show limited survival and integration in
      the adult CNS. Alternative grafting strategies have been sought for treatment of
      neurodegenerative disease. We have developed cultures of human second trimester
      fetal tissues to study neuronal differentiation. Grafted into the SCID mouse
      striatum, aggregates of these cultures formed neuron-rich xenografts for at least
      8 months. We examined the influence of various neurotrophic factors, including
      basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF),
      transforming growth factor-beta 1 (TGF-beta1), and hepatocyte growth factor
      (HGF), on the growth and differentiation of neuronal and glial cell populations.
      BDNF promoted the survival and differentiation of second trimester neurons
      whereas bFGF exhibited a strong proliferative effect on precursors and the
      astroglial population. Our data suggest that second trimester human fetal
      cultures contain neuroprogenitor cells that can be directed to the neuronal
      lineage. This process may be amplified by treatment with BDNF, which we
      hypothesize could improve the long-term in vivo survival of neuron-enriched
      grafts.

PMID- 10338277
TI  - Effects of osteogenic protein-1 (OP-1) treatment on fetal spinal cord transplants
      to the anterior chamber of the eye.
AB  - Spinal cord injury represents a serious medical problem, and leads to chronic
      conditions that cannot be reversed at present. It has been suggested that trophic
      factor treatment may reduce the extent of damage and restore damaged neurons
      following the injury. We have tested the effects of osteogenic protein-1 (OP-1,
      also known as BMP-7), a member of the transforming growth factor-beta superfamily
      of growth factors, on developing spinal cord motor neurons in an intraocular
      transplantation model. Embryonic day 13 or 18 spinal cord tissue was dissected,
      incubated with OP-1 or vehicle, and injected into the anterior chamber of the eye
      of adult rats. Injections of additional doses of OP-1 were performed weekly, and
      the overall growth of the grafted tissue was assessed noninvasively. Four to 6
      weeks postgrafting, animals were sacrificed and the tissue was processed for
      immunohistochemistry using antibodies directed against choline acetyltransferase,
      neurofilament, and the dendritic marker MAP-II. We found that OP-1 treatment
      stimulated overall growth of spinal cord tissue when dissected from embryonic day
      18, but not from embryonic day 13. OP-1 treatment increased cell size and extent
      of cholinergic markers in motor neurons from both embryonic stages. The neurons
      also appeared to have a more extensive dendritic network in OP-1-treated grafts
      compared to controls. These findings indicate that OP-1 treatment may reduce the
      extent of axotomy-induced cell death of motor neurons, at least in the developing
      spinal cord.

PMID- 10338278
TI  - Transplants of neuronal cells bioengineered to synthesize GABA alleviate chronic
      neuropathic pain.
AB  - The use of cell lines utilized as biologic "minipumps" to provide antinociceptive
      molecules, such as GABA, in animal models of pain is a newly developing area in
      transplantation biology. The neuronal cell line, RN33B, derived from E13 brain
      stem raphe and immortalized with the SV40 temperature-sensitive allele of large T
      antigen (tsTag), was transfected with rat GAD67 cDNA (glutamate decarboxylase,
      the synthetic enzyme for GABA), and the GABAergic cell line, 33G10.17, was
      isolated. The 33G10.17 cells transfected with the GAD67 gene expressed GAD67
      protein and synthesized low levels of GABA at permissive temperature (33 degrees
      C), when the cells were proliferating, and increased GAD67 and GABA during
      differentiation at nonpermissive temperature (39 degrees C) in vitro, because
      GAD67 protein expression was upregulated with differentiation. A control cell
      line, 33V1, transfected with the vector alone, contained no GAD67 or GABA at
      either temperature. These cell lines were used as grafts in a model of chronic
      neuropathic pain induced by unilateral chronic constriction injury (CCI) of the
      sciatic nerve. Pain-related behaviors, including cold and tactile allodynia and
      thermal and tactile hyperalgesia, were evaluated after CCI in the affected hind
      paw. When 33G10.17 and 33V1 cells were transplanted in the lumbar subarachnoid
      space of the spinal cord 1 week after CCI, they survived greater than 7 weeks on
      the pia mater around the spinal cord. Furthermore, the tactile and cold allodynia
      and tactile and thermal hyperalgesia induced by CCI was significantly reduced
      during the 2-7-week period after grafts of 33G10.17 cells. The maximal effect on
      chronic pain behaviors with the GABAergic grafts occurred 2-3 weeks after
      transplantation. Transplants of 33V1 control cells had no effect on the allodynia
      and hyperalgesia induced by CCI. These data suggest that a chronically applied,
      low local dose of GABA presumably supplied by transplanted cells near the spinal
      dorsal horn was able to reverse the development of chronic neuropathic pain
      following CCI. The use of neural cell lines that are able to deliver inhibitory
      neurotransmitters, such as GABA, in a model of chronic pain offers a novel
      approach to pain management.

PMID- 10338280
TI  - Pig fetal septal neurons implanted into the hippocampus of aged or cholinergic
      deafferented rats grow axons and form cross-species synapses in appropriate
      target regions.
AB  - The anatomical specificity of axon growth from fetal pig septal xenografts was
      studied by transplanting septal cells from E30-35 pig fetuses into cholinergic
      deafferented (192-IgG-saporin-infused) rats or into aged rats (> 18 months). Cell
      suspensions (100,000 cells/microl) were injected bilaterally into the dorsal and
      ventral hippocampus of immunosuppressed rats (10 mg/kg/day cyclosporine A). To
      assess axonal growth and synapse formation, acetylcholinesterase histochemistry,
      an antibody to choline acetyltransferase (ChAT), and three pig-positive/rat
      negative antibodies: bovine 70kD neurofilament (NF70), human low-affinity NGF
      receptor (hNGFr), and human synaptobrevin (hSB) were used. In rats with surviving
      grafts at 6 months, NF70 axonal labeling was more extensive than either ChAT or
      hNGFr labeling. All three markers demonstrated graft axons extending selectively
      through the hippocampal CA fields and the molecular layer of the dentate gyrus.
      Graft axons did not extend into adjacent entorhinal cortex or neocortex. The
      distribution of pig hSB-positive synapses correlated with AChE-positive fiber
      outgrowth in to the host. Electron microscopic analysis of hSB-immunostained
      hippocampal sections revealed pig presynaptic terminals in contact with normal
      rat postsynaptic structures in the CA fields and the dentate gyrus. These data
      demonstrate target-appropriate growth of pig cholinergic axons and the formation
      of cross-species synapses in the deafferented or aged rat hippocampus.

PMID- 10338279
TI  - Purification of adrenal chromaffin cells increases antinociceptive efficacy of
      xenotransplants without immunosuppression.
AB  - We have found that immunosuppression is necessary for the survival of xenogeneic
      adrenal medullary transplants. Because chromaffin cells are essentially
      nonimmunogenic, it is likely that the highly immunogenic "passenger" cells in the
      transplant preparation bring about rejection. This article describes a procedure
      that produces an essentially pure preparation of chromaffin cells for
      transplantation. Bovine adrenal medullary cells were isolated and differentially
      plated, resulting in a semipurified preparation of chromaffin cells.
      Ferromagnetic beads were added to the cell suspension, some of which were
      phagocytized by endothelial cells, which allowed their removal by exposure to a
      magnet. The remaining cells were then exposed to ferromagnetic beads coated with
      isolectin B4 from Griffonia simplicifolia and once again to a magnetic field. The
      "semipurified" preparation contained approximately 90% chromaffin cells, whereas
      the "highly purified" preparation was > 99.5% chromaffin cells as determined
      immunohistochemically. The immunogenicity of the two cell preparations was
      assessed in vitro by determining their capacity to evoke lymphocyte
      proliferation. Rat spleen lymphocytes were mixed with either a highly purified or
      semipurified population of bovine chromaffin cells. The results of this assay
      demonstrated that the highly purified preparation was a much weaker stimulant of
      lymphocyte proliferation than was the semipurified preparation and may
      demonstrate better graft survival in vivo. Transplantation via intrathecal
      catheter of either 80,000 or 250,000 cells from the highly or partially purified
      preparations onto the lumbar spinal cord of nonimmunosuppressed and non-nicotine
      stimulated rats produced a cell number-dependent antinociception for both
      A(delta) and C fiber-mediated thermonociception at 6 days after transplantation.
      After 6 days and up to 28 days, only the "highly purified" preparation showed
      antinociception. These results suggest that nearly complete purification of
      bovine chromaffin cells minimizes immunorejection of xenogeneic transplants of
      these cells.

PMID- 10338281
TI  - Morris water maze analysis of 192-IgG-saporin-lesioned rats and porcine
      cholinergic transplants to the hippocampus.
AB  - Adults rats were lesioned with 192-IgG-saporin, an immunotoxin that targets
      cholinergic neurons in the basal forebrain expressing the low-affinity nerve
      growth factor receptor (p75). One month later, rats received E30-35 porcine
      cholinergic neurons bilaterally into the hippocampus, and were tested in the
      Morris water maze and the passive avoidance task 4.5-6 months after
      transplantation (in two experiments, rats were retested in the water maze)
      followed by histological and cellular analyses. The 192-IgG-saporin-lesioned
      animals displayed clear cognitive deficits in the Morris water maze. In all
      experiments the lesioned animals had spatial probe deficits on day 5 testing. A
      large variance was found among the transplanted animals, with individual animals
      exhibiting improved performance, but little overall improvement when compared to
      lesion-alone animals as a group. The relationships between behavioral performance
      and graft cholinergic factors were established by histological analyses. Grafted
      animals exhibited an increase in cholinergic innervation of the dentate gyrus
      (DG) region of the dorsal hippocampus when compared to lesion-alone animals.
      There was a significant correlation between the level of cholinergic innervation
      in the dentate gyrus and spatial navigation performance (latency and spatial
      probe) in the Morris water maze task. These data provide evidence of memory and
      spatial deficits following cholinergic denervation, and of target-specific growth
      of xenogeneic cholinergic neurons into the hippocampus. The lack of a clear
      treatment (transplant) effect in the behavioral measures leads us to believe that
      functional restoration of cognitive function would require cholinergic
      reinnervation of both the hippocampus and the neocortex in this 192-IgG-saporin
      animal model.

PMID- 10338282
TI  - Neural transplantation of hNT neurons for Huntington's disease.
AB  - Fetal striatal tissue transplants have been shown to restore motor deficits in
      rat and monkey models of Huntington's disease (HD). In the present study, using
      rats with unilateral striatal lesions, we compared fetal striatal tissue
      transplants to transplants of human NT (hNT) neurons. hNT neurons are terminally
      differentiated cells derived from the human NTera-2 cell line. In vitro, we have
      found that purified hNT neurons have a biochemical phenotype similar to that of
      human fetal striatal tissue. Both hNT neurons and fetal striatal tissue express
      mRNAs for glutamic acid decarboxylase, choline acetyltransferase, and the D1 and
      D2 dopamine receptors. Grafts of either hNT neurons or fetal striatal tissue into
      unilateral quinolinic acid-lesioned rat striatum improved methamphetamine-induced
      circling behavior. Sham controls showed no changes in methamphetamine-induced
      circling behavior. In the staircase test for skilled forelimb use, both
      transplant groups showed partial recovery in skilled use of the paw contralateral
      to the side of lesion, whereas the control animals showed continued deficits.
      These findings suggest that transplantation of hNT neurons may be an alternative
      to transplantation of fetal striatal tissue in the treatment of HD.

PMID- 10338284
TI  - Learning from mistakes.
AB  - We re-examine the commonly held view that learning and memory necessarily require
      potentiation of synapses. A simple neuronal model of self-organized learning with
      no positive reinforcement is presented. The strongest synapses are selected for
      propagation of activity. Active synaptic connections are temporarily "tagged" and
      subsequently depressed if the resulting output turns out to be unsuccessful.
      Thus, all learning occurs by mistakes. The model operates at a highly adaptive
      state with low activity. Previously stored patterns may be swiftly retrieved when
      the environment and the demands of the brain change. The combined process of: (i)
      activity selection by extremal "winner-take-all" dynamics; and (ii) the
      subsequent weeding out of synapses may be viewed as synaptic Darwinism. We argue
      that all the features of the model are biologically plausible and discuss our
      results in light of recent experiments by Fitzsimonds et al. on back-propagation
      of long-term depression, by Xu et al. on facilitation of long-term depression in
      the hippocampus by behavioural stress, and by Frey and Morris on synaptic
      tagging.

PMID- 10338283
TI  - Cyclosporine A-induced hyperactivity in rats: is it mediated by
      immunosuppression, neurotrophism, or both?
AB  - Cyclosporine A (CsA) immunosuppressive treatment has become an adjunctive therapy
      in neural transplantation of dopamine-secreting cells for treatment of
      Parkinson's disease (PD). Recently, CsA and its analogues have been shown to
      promote trophic effects against neurodegenerative disorders, and therefore CsA
      may have direct beneficial effects on dopaminergic neurons and dopamine-mediated
      behaviors. The present study examined the interaction between the reported CsA
      induced hyperactivity and the possible alterations in nigral tyrosine hydroxylase
      (TH)-immunoreactive neurons in rats with damaged blood-brain barrier. CsA was
      administered at a therapeutic dose (10 mg/kg/day, IP, for 9 days) used in neural
      transplantation protocol for PD animal models. CsA-treated animals displayed
      significantly higher general spontaneous locomotor activity than control animals
      at drug injection days 7 and 9. Histological assays at day 9 revealed that there
      was a significant increase in TH-immunoreactive neurons in the nigra of CsA
      treated rats compared to that of the vehicle-treated rats. The nigral TH
      elevation was accompanied by suppressed calcium-phosphotase calcineurin activity,
      indicating an inhibition of host immune response. This is the first report of CsA
      exerting simultaneous immunosuppressive and neurotrophic effects, as well as
      increasing general spontaneous locomotor behavior. These results support the
      utility of CsA as a therapeutic agent for PD and other movement disorders.

PMID- 10338285
TI  - Enhanced gamma (30-150 Hz) frequency in the human medial temporal lobe.
AB  - We performed fast Fourier transformation power spectral analysis of the
      electrocorticogram in human medial temporal lobe during wakeful rest in six
      epileptic subjects. Compared with the electrocorticogram wave in the basal
      temporal lobe, which showed monotonic decline of spectral power across the
      frequency axis, the electrocorticogram wave in the parahippocampal gyrus was
      enhanced (or did not decline) in the gamma frequency range (30-150 Hz) in all
      subjects. Although it has been suggested that electrical oscillations of the
      hippocampus have functional roles in higher brain functions, namely learning and
      memory, the knowledge of hippocampal oscillations is largely limited to animal
      studies. The present results demonstrate that fast frequency oscillation is also
      present in the human medial temporal lobe, which has been reported in animal
      hippocampi. They also demonstrate the importance of recording very fast field
      potentials in human electrocorticograms. This fast oscillation is likely to play
      important functional roles related to learning and memory, possibly to induce
      long-term potentiation in the human medial temporal lobe.

PMID- 10338286
TI  - Mice deficient in endothelial nitric oxide synthase exhibit a selective deficit
      in hippocampal long-term potentiation.
AB  - Long-term potentiation, a persistent increase in synaptic efficacy, may require a
      retrograde signal originating in the postsynaptic cell that induces an increase
      in presynaptic neurotransmitter release. We have constructed a mouse homozygous
      for a targeted null mutation in the endothelial isoform of nitric oxide synthase
      and report that long-term potentiation in the CA1 region of these mice is
      entirely absent under weak stimulation conditions. Application of a membrane
      permeant guanosine-3',5'-cyclic monophosphate analogue during tetanus fails to
      compensate for this deficit, suggesting that nitric oxide produced by endothelial
      nitric oxide synthase may affect long-term potentiation through a cascade that
      does not include guanylyl cyclase. We also report that strong tetanic stimulation
      can induce robust long-term potentiation in these mice which is not blocked by
      pharmacological inhibitors of nitric oxide synthase. Furthermore, mice lacking
      endothelial nitric oxide synthase show no shift in the frequency-response curve
      for the induction of long-term potentiation. Basal synaptic transmission, paired
      pulse facilitation and the electrical properties of CA1 cells in these mice were
      similar to controls. These results support a selective role for endothelial
      nitric oxide synthase in long-term potentiation, but also demonstrate that nitric
      oxide synthase is not involved in this process under all conditions.

PMID- 10338288
TI  - Neurosteroid regulation of inhibitory synaptic transmission in the rat
      hippocampus in vitro.
AB  - The effect of the neurosteroid dehydroepiandrosterone sulfate on inhibitory
      synaptic transmission was studied in area CA1 of the rat hippocampus using an in
      vitro hippocampal slice preparation. Synaptic responses elicited by stimulation
      of Schaffer collateral fibers were recorded extracellularly as population spikes
      in the somatic region and as synaptic field potentials in the dendritic region.
      Bath application of dehydroepiandrosterone sulfate (10 microM) enhanced the
      synaptically evoked somatic population spike with no effect on the dendritic
      synaptic potential. Isolation of the alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionate receptor-mediated component of the synaptic response by
      addition of antagonists of N-methyl-D-aspartate and GABA receptors to the
      perfusion saline demonstrated that dehydroepiandrosterone sulfate had no effect
      on this component of the dendritic synaptic potential. In contrast,
      dehydroepiandrosterone sulfate antagonized GABA receptor-mediated inhibitory
      effects in the somatic region, resulting in an augmentation of the somatic
      population spike amplitude. Paired-pulse facilitation was unaltered by
      dehydroepiandrosterone sulfate, thus arguing against possible presynaptic sites
      of dehydroepiandrosterone sulfate's actions. These results indicate that
      dehydroepiandrosterone sulfate can alter synaptic transmission in the hippocampus
      through selective postsynaptic actions on inhibitory synaptic transmission. A
      synaptic effect of dehydroepiandrosterone sulfate is consistent with a
      neuromodulatory role for this neurosteroid in the central nervous system, and may
      contribute to the reported effects of dehydroepiandrosterone sulfate on cognitive
      processes such as learning and memory.

PMID- 10338287
TI  - Activation of p42 mitogen-activated protein kinase by arachidonic acid and trans
      1-amino-cyclopentyl-1,3- dicarboxylate impacts on long-term potentiation in the
      dentate gyrus in the rat: analysis of age-related changes.
AB  - Maintenance of long-term potentiation in perforant path-granule cell synapses is
      associated with an increase in glutamate release, which we have suggested relies
      on an interaction between arachidonic acid and the metabotropic glutamate
      receptor agonist, trans-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD). Evidence
      suggests that this interaction is dependent on stimulation of tyrosine kinase,
      which phosphorylates and activates phospholipase Cgamma. In this study, we
      demonstrate that arachidonic acid and ACPD stimulate tyrosine phosphorylation of
      a protein of about 40,000 mol. wt and further analysis, using a specific
      antibody, suggested that this may be extracellular signal-regulated kinase, one
      member of the family of mitogen-activated protein kinases. Activity of
      extracellular signal-regulated kinase was increased by arachidonic acid and ACPD
      in vitro, but it was also increased by induction of long-term potentiation in
      perforant path-granule cell synapses. A role for extracellular signal-regulated
      kinase in long-term potentiation was supported by the observation that expression
      of long-term potentiation, as well as the associated increases in endogenous
      glutamate release and extracellular signal-regulated kinase activation, were
      inhibited by pretreatment with the mitogen-activated protein kinase inhibitor,
      PD98059, while PD98059 pretreatment inhibited the interaction between arachidonic
      acid and ACPD on glutamate release. An age-related decrease in extracellular
      signal-regulated kinase activity was observed in the dentate gyrus, and there was
      no evidence of increased extracellular signal-regulated kinase activity or
      endogenous glutamate release in tissue prepared from aged rats in which long-term
      potentiation was compromised. The evidence is consistent with the view that
      increased activation of extracellular signal-regulated kinase plays a role in
      long-term potentiation, and that activation of this kinase relies on the
      interaction between arachidonic acid and ACPD.

PMID- 10338289
TI  - Long-term lack of endogenous glucocorticoids down-regulates glucocorticoid
      receptor levels in the rat forebrain.
AB  - To understand the effect of a chronic lack of endogenous glucocorticoids on
      glucocorticoid receptor levels, the changes of glucocorticoid receptor content in
      the rat forebrain five months after adrenalectomy were investigated. In the long
      term adrenalectomized rats that showed a hormone deficiency and loss of
      glucocorticoid receptor immunoreactivity in the forebrain, an intraperitoneal
      injection of corticosterone was used to elevate the serum hormone levels and
      recover glucocorticoid receptor immunoreactivity in the forebrain. One hour
      later, when the blood corticosterone returned to the normal level, the recovery
      of glucocorticoid receptor immunoreactivity in the forebrain was examined by
      immunohistochemistry. Since the complete restoration of glucocorticoid receptor
      immunoreactivity was shown to depend on the presence of normal levels of both
      serum hormone and intracellular glucocorticoid receptors, the weak reappearance
      of glucocorticoid receptor immunoreactivity in any forebrain area of the long
      term adrenalectomized rats that had normal serum corticosterone might reflect the
      low intracellular glucocorticoid receptor levels there. Our results revealed a
      weak reappearance of glucocorticoid receptor immunoreactivity in some forebrain
      areas of the long-term adrenalectomized rats after corticosterone treatment; the
      hippocampal granule cell layer and cerebral cortex in particular showed very weak
      recovery of glucocorticoid receptor immunoreactivity. Conversely, neurons in the
      CA1/CA2 subfields of the hippocampal pyramidal cell layer, immediately adjacent
      to the granule cell layer on the same brain section, exhibited a strong
      reappearance of glucocorticoid receptor immunoreactivity, to near normal levels.
      These results suggest that, five months after adrenalectomy, the intracellular
      glucocorticoid receptor content decreased in the rat granule cell layer and
      cerebral cortex. Therefore, the long-term lack of endogenous glucocorticoids
      after adrenalectomy might down-regulate but not up-regulate the intracellular
      glucocorticoid receptor level, and the presence of glucocorticoids is important
      for the continued synthesis of glucocorticoid receptors.

PMID- 10338290
TI  - Two electrophysiologically distinct types of granule cells in epileptic human
      hippocampus.
AB  - We investigated the electrophysiology of morphologically identified human granule
      cells with conventional current-clamp recordings. Slices were prepared from 14
      human epileptic sclerotic hippocampi. Granule cells appeared to have a diverse
      electrophysiology. Each cell was distinguished by the shape of the
      afterhyperpolarization following single action potentials. Two types could be
      discerned: type I afterhyperpolarizations were monophasic and brief (typically 10
      40 ms), whilst type II afterhyperpolarizations were biphasic and long (typically
      50-100 ms). The two types also differed in their repetitive firing behaviour and
      action potential morphology: type I cells had significantly weaker spike
      frequency adaptation, lower action potential amplitude and smaller action
      potential upstroke/downstroke ratio. Thus, the firing pattern of type I cells
      resembled that of rodent dentate interneurons. In contrast, the corresponding
      parameters of type II cells were comparable to rodent dentate granule cells.
      Despite the distinct firing patterns, membrane properties were not different. The
      two types of cells also differed in their synaptic responses to stimulation of
      the perforant path. At strong suprathreshold stimulation intensity, type I cells
      always generated multiple action potentials, whereas type II cells usually spiked
      once only. Slow inhibitory postsynaptic potentials were not detected in type I
      neurons, but were easily identified in type II neurons. Extracellular recordings
      of perforant path-evoked field potentials in the cell layer confirmed that the
      majority of granule cells showed multiple discharges even when we recorded
      simultaneously from a type II cell that generated one action potential only. The
      morphology of both types of cells was characteristic of what has been described
      for primate dentate granule cells. Based on comparisons with previous studies on
      rodent and human granule cells, we tentatively hypothesize that: (i) the majority
      of granule cells from sclerotic hippocampus display an hyperexcitable
      epileptogenic electrophysiology; (ii) there is a subset of granule cells whose
      electrophysiology is preserved and is more comparable to granule cells from non
      epileptic hippocampus.

PMID- 10338291
TI  - No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta
      amyloid precursor protein-null mice.
AB  - Aged beta-amyloid precursor protein-null mice were used to investigate the
      relationship between beta-amyloid precursor protein, hippocampal neuron and
      synaptic bouton number, and cognitive function. Learning and memory performance
      of aged beta-amyloid precursor protein-null mice and age-matched controls were
      assessed in the Morris water maze. Beta-amyloid precursor protein-null mice
      demonstrated impaired task acquisition as measured by significantly longer swim
      path lengths, a higher percentage of failed trials, and more frequent thigmotaxis
      behavior than controls. In a subsequent probe trial, beta-amyloid precursor
      protein-null mice spent significantly less time in the old goal quadrant, and
      made fewer crossings over the old platform location than did controls. No
      differences in motor or visual skills were observed which could account for the
      performance differences. In light of these findings and previous evidence for a
      role of beta-amyloid precursor protein in neuronal maintenance and
      synaptogenesis, we pursued the hypothesis that the learning impairment of beta
      amyloid precursor protein-null mice may be a reflection of differences in neuron
      or synaptophysin-positive presynaptic bouton number. Thus, unbiased stereological
      analysis was used to estimate neuron and synaptic bouton number in dentate gyrus
      and hippocampal CA1 of the behaviorally characterized mice. No difference in
      neuron or synaptophysin-positive presynaptic bouton number was found between the
      beta-amyloid precursor protein-null mice and age-matched controls. Our results
      suggest that the learning impairment of beta-amyloid precursor protein-null mice
      is not mediated by a loss of hippocampal neurons or synaptic boutons.

PMID- 10338292
TI  - Apolipoprotein E promotes the binding and uptake of beta-amyloid into Chinese
      hamster ovary cells in an isoform-specific manner.
AB  - The epsilon4 allele of apolipoprotein E gene is a major risk factor for
      Alzheimer's disease. However, the mechanism by which the E4 isoform of
      apolipoprotein E increases the risk of Alzheimer's disease is poorly understood.
      To determine whether the isoform-specific effects of apolipoprotein E may be
      mediated via clearance of bound beta-amyloid, we examined the uptake of beta
      amyloid 1-40 into Chinese hamster ovary cells in the presence or absence of the
      apolipoprotein E isoforms E2, E3 and E4. Apolipoprotein E2 and E3 treatments were
      associated with higher association of beta-amyloid with cells as compared to
      treatment with E4. Heparin blocked the association of beta-amyloid with cells, as
      did an antibody to one of the apolipoprotein E receptors (the low-density
      lipoprotein receptor-related protein). Thus, the apolipoproteins E2 and E3, but
      not E4, may play important roles in the clearance of beta-amyloid from the
      extracellular space via the low-density lipoprotein receptor-related protein.

PMID- 10338293
TI  - Differences in responses to 70 dB clicks of cerebellar units with simple versus
      complex spike activity: (i) in medial and lateral ansiform lobes and flocculus;
      and (ii) before and after conditioning blink conditioned responses with clicks as
      conditioned stimuli.
AB  - Activity was recorded from 554 cerebellar units in eleven conscious cats to
      determine if responses to 70 dB clicks differed in units with simple and complex
      spike discharges. Effects of region of recording and behavioral state (with click
      used as a conditioned stimulus for conditioning) were also assessed. Cells with
      only simple spikes were distinguished from cells that had the following types of
      complex spike events: Type I-simple or initial spike followed > 1 ms by multiple
      spikes with baseline displacement (classical complex spikes), Type II--followed <
      or = 1 ms by spikes with or without baseline displacement (spikes in the absolute
      refractory period should arise from a separate site of initiation), and Type III
      followed by spikes and displacement too close to the baseline noise to
      distinguish as Type I or II. Among the groups mean baseline activity was greatest
      in cells with Type I complex spikes, least in cells with Type III complex spikes,
      and greater in Type II cells than simple cells. Significant increases in activity
      within 32 ms of presenting clicks were found in the groups of Type II cells and
      simple cells. These appear to be the main auditory responsive cells of the
      cerebellar regions studied. Activity of Type II cells best reflected the temporal
      properties of the click; responses of simple cells had slower onsets (except in
      flocculus) and longer durations. Responses to click in Type II and simple cells
      differed in recordings from: (i) lateral ansiform lobe (lateral crus I and
      portions of crus II), (ii) medial ansiform lobe (medial crus I), and (iii)
      flocculus. The largest mean responses above baseline in the first 32 ms after
      click were found in Type II cells of the lateral ansiform lobe with onsets of 8
      16 ms. Magnitudes of response differed before and after conditioning and backward
      conditioning. In the lateral ansiform lobe, the < 32 ms response to click was
      greater in Type II than simple cells in each state, but showed a greater increase
      above baseline after backward conditioning when conditioned responses were not
      produced than after conditioning. The onset of increased activity to click
      conditioned stimuli in Type II cells of the lateral ansiform region preceded the
      onset of the blink conditioned response after conditioning, consisted almost
      entirely of simple spikes, and reflected an increase in magnitude of response as
      opposed to an increased number of responsive units. After conditioning, an
      increased number of units in the flocculus responded to click conditioned stimuli
      in the 16-24 ms post stimulus period. Of the 16 cells with an onset of increased
      activity at this time, eight showed only simple spike activity. Seven of the
      remaining eight cells (all Type II) showed a significant increase in conditioned
      stimulus-evoked complex spiking above the low (usually < 1/s) baseline level of
      complex spike discharges. The findings support the conclusions that cerebellar
      units can respond rapidly enough to acoustic stimuli to play a role in auditory
      as well as motor processing and that the responses to 70 dB clicks differ among
      cells with simple and complex spike discharges. The differences are influenced
      substantially by the region of cerebellar recording and the behavioral state. The
      findings in cells of the flocculus offer the first evidence that complex as well
      as simple spike activity can contribute to an increased probability of discharge
      to click as a conditioned stimulus after conditioning.

PMID- 10338294
TI  - The differentiation of cerebellar interneurons is independent of their mitotic
      history.
AB  - A narrow time window centered around the terminal mitosis of their precursors has
      been recognized to be critical for the determination and/or realization of the
      developmental fate of a variety of neuronal phenotypes. In contrast, individual
      cell lineages in the cerebellum get separated early during embryonic development,
      and at least precursors for granule neurons have been found to be specified while
      still proliferating. We utilized primary dissociated cultures to address the
      issue of whether the faithful development of cerebellar granule cells and
      basket/stellate cells is dependent on their mitotic history and on the completion
      of a fixed number of cell cycles. Neuroblasts derived from embryonic cerebellar
      anlagen and transferred into primary dissociated cultures stopped proliferating
      as assessed by a loss of expression of the cell proliferation marker, Ki-67, and
      a failure to incorporate 5-bromo-2'-deoxyuridine. Although these cells had been
      forced to leave the proliferating cell pool prematurely, they developed into
      granule neurons or basket/stellate cells as judged by their distinct pattern of
      expression of specific molecular markers and the acquisition of a typical
      morphology. This included the cell intrinsic capacity of granule neurons to
      position their afferent synapses specifically to their dendrites. Thus, the
      competence of cerebellar interneurons to differentiate appropriately is
      independent of the precise timing of their final mitosis; however, their
      sensitivity towards extrinsic developmental signals appears to vary in a cell
      cycle-dependent manner, as suggested by the failure to survive of those cells
      that were in S-phase at the time of cultivation.

PMID- 10338295
TI  - The beta2-adrenoceptor agonist clenbuterol modulates Bcl-2, Bcl-xl and Bax
      protein expression following transient forebrain ischemia.
AB  - It is well known that proteins encoded by the Bcl-2 gene family play a major role
      in the regulation of apoptosis. We have demonstrated previously that neuronal
      apoptosis can be induced in the hippocampus and striatum after global ischemia.
      Clenbuterol, a beta2-adrenoceptor agonist, showed considerable activity against
      neuronal apoptosis. In the present study, we attempted to find out whether the
      members of the Bcl-2 family are induced after ischemia, and whether expression of
      these genes could be altered by clenbuterol. Transient forebrain ischemia was
      performed in male Wistar rats by clamping both common carotid arteries and
      reducing the blood pressure to 40 mmHg for 10 min. Clenbuterol (0.5 mg/kg, i.p.)
      or vehicle were injected 3 h before onset of ischemia or in non-ischemic rats.
      The hippocampus and striatum were taken from non-ischemic rats 3, 6 and 24 h
      after injection of clenbuterol, as well as from drug-treated and untreated rats 6
      and 24 h after ischemia. Eighty micrograms/lane total protein were loaded on a
      15% sodium dodecyl sulfate-polyacrylamide gel for western blotting. Bcl-2, Bax
      and Bcl-xl proteins were detectable in the non-ischemic hippocampus and the
      striatum. Clenbuterol up-regulated the expression of Bcl-2 protein at 3, 6 and 24
      h after administration. Enhanced Bcl-xl signals were found in the non-ischemic
      striatum 3, 6 and 24 h after clenbuterol treatment, but no change of Bcl-xl
      expression by clenbuterol was seen in the non-ischemic hippocampus. Bax
      expression was not altered by clenbuterol in the non-ischemic hippocampus and
      striatum. Bcl-2 was up-regulated in both detected regions at 24 h after ischemia,
      while the increase in Bax and Bcl-xl protein expression had appeared already at 6
      h and also 24 h after ischemia. Clenbuterol further increased the expression of
      Bcl-2 at 6 and 24 h after ischemia. In contrast, Bax protein level was down
      regulated by clenbuterol at 6 and 24 h after ischemia. Clenbuterol also increased
      Bcl-xl level in the ischemic striatum. The results suggest that global ischemia
      induces proto-oncogenes which are associated with apoptosis. Clenbuterol not only
      increased Bcl-2 expression in the non-ischemic hippocampus and striatum, but also
      up-regulated Bcl-2 and down-regulated Bax expression in the ischemic hippocampus
      and striatum. The increase in the ratio of Bcl-2 and Bax may contribute to the
      anti-apoptotic effect of clenbuterol. The present study indicates that
      pharmacological modulation of Bcl-2 family member expression could become a new
      strategy to interfere with neuronal damage.

PMID- 10338296
TI  - Selective detection of adenosine A1 receptor-dependent G-protein activity in
      basal and stimulated conditions of rat brain [35S]guanosine 5'-(gamma
      thio)triphosphate autoradiography.
AB  - [35S]Guanosine 5'-(gamma-thio)triphosphate autoradiography is a novel technique
      to detect receptor-dependent activation of G-proteins in brain tissue sections.
      While an increasing number of reports using this approach are beginning to
      appear, little effort has been directed to the identification of factors
      responsible for the heterogeneously distributed [35S]guanosine 5'-(gamma
      thio)triphosphate signal in basal conditions. The present study demonstrates that
      endogenously formed adenosine generates a widespread and prominent adenosine A1
      receptor-dependent signal in basal conditions using this technique. Treatment of
      rat brain tissue sections with the A1-selective antagonist 8-cyclopentyl-1,3
      dipropylxanthine dose-dependently (EC50 < 10 nM) suppressed basal [35S]guanosine
      5'-(gamma-thio)triphosphate binding in a region-specific manner, an effect fully
      mimicked by the adenosine-depleting enzyme adenosine deaminase, and less so by
      the A1 antagonist cirsimarin and by caffeine. That adenosine was continuously
      formed during the incubation is supported by the constant requirements of
      adenosine deaminase in order to suppress basal radioligand binding and further by
      the fact that low micromolar concentrations of adenine nucleotides evoked only
      adenosine-mimicking and fully 8-cyclopentyl-1,3-dipropylxanthine-sensitive
      binding responses. In the presence of adenosine deaminase, all responses to
      adenine nucleotides were abolished, indicating that prior conversion to adenosine
      was required. Upon stimulation, this technique selectively detected A1 receptor
      activated G-proteins, as the non-selective agonists adenosine and 2
      chloroadenosine and the A1-selective agonist N6-p-sulfophenyladenosine all evoked
      only 8-cyclopentyl-1,3-dipropylxanthine-sensitive responses in identical gray
      matter areas, and also in several white matter areas such as the corpus callosum,
      anterior commissure, optic tract and cerebellar white matter. Dose-response
      studies revealed region-specific differences in the magnitude of A1 receptor
      stimulated G-protein activation, with the highest response (nine-fold over basal)
      detectable in the hippocampus. No response to the A2A-selective agonist 2-[(2
      aminoethylamino)carbonylethylphenylethylamino]-5'-N-et hylcarboxamidoadenosine or
      the A3-selective agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N
      methyluronamide was detected in any region. These data reveal that a significant
      amount of noise inherent to [35S]guanosine 5'-(gamma-thio)triphosphate
      autoradiography can be eliminated by removal of the adenosine signal, a step
      likely facilitating detection of responses to other receptors. Furthermore, the
      data establish [35S]guanosine 5-(gamma-thio)triphosphate autoradiography as a
      novel and selective approach to directly assess A1 receptor-G-protein coupling in
      anatomically defined regions of the central nervous system.

PMID- 10338297
TI  - A high-affinity presynaptic kainate-type glutamate receptor facilitates glutamate
      exocytosis from cerebral cortex nerve terminals (synaptosomes).
AB  - Ionotropic glutamate receptor agonists, kainate, alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionate (AMPA) and domoate, all facilitated 4-aminopyridine-evoked
      glutamate release from rat cerebrocortical nerve terminals (synaptosomes). The
      non-selective, non-N-methyl-D-aspartate receptor antagonist 6-cyano-7
      nitroquinoxaline-2,3-dione blocked kainate facilitation of glutamate release.
      AMPA responses were non-desensitizing and insensitive to the AMPA receptor
      desensitization inhibitor, cyclothiazide. The AMPA receptor antagonist GYKI 52466
      failed to block ionotropic glutamate receptor-mediated facilitation, but the
      ionotropic glutamate receptor 6 kainate receptor subunit antagonist NS-102 was a
      potent blocker. Furthermore, kainate and AMPA responses were not additive. Taken
      together, our results indicate that, in the cerebral cortex, both kainate and
      AMPA may be facilitating glutamate release through the activation of a high
      affinity kainate receptor containing glutamate receptor 6 kainate subunits.
      Kainate enhanced 4-aminopyridine-evoked depolarization of the synaptosomal plasma
      membrane potential, indicating that a ligand-gated ion channel that conducts
      cations may underlie the mechanism by which kainate mediates facilitation of
      glutamate release. While the facilitatory effect of kainate on glutamate release
      is consistent with a classical ionotropic action of ionotropic glutamate
      receptors, our observation that kainate inhibits GABA release suggests that
      alternative presynaptic mechanisms may operate in cerebrocortical nerve terminals
      to mediate the ionotropic glutamate receptor modulation of glutamate and GABA
      release. We conclude that high-affinity kainate-type glutamate autoreceptors
      represent a positive feed-forward system for potentiating the release of
      glutamate from cerebrocortical nerve terminals.

PMID- 10338298
TI  - Optical identification of calcium-dependent action potentials transiently
      expressed in the embryonic rat brainstem.
AB  - Using multiple-site optical recording of transmembrane potential changes, we have
      found a new type of calcium-dependent action potential expressed transiently in
      the embryonic rat dorsal motor nucleus of the vagus nerve. Slice preparations
      with vagus nerve fibers attached were dissected from 12- to 16-day-old embryonic
      (E12-E16) rat brainstems, and they were stained with a voltage-sensitive
      merocyanine-rhodanine dye (NK2761). Electrical activities in response to vagal
      stimuli were optically recorded simultaneously from many sites using 1020- or 128
      element photodiode array measuring systems. In brainstem preparations, two types
      of action potential-related optical signals were identified. One was detected
      from the dorsolateral region, and was related to sensory nerve activity (Type I).
      The other was detected from the dorsomedial region, and corresponded to the
      action potential in the dorsal motor nucleus of the vagus nerve (Type II). We
      found a difference in the ionic basis of the Type I vs Type II signals. The Type
      I signal was not altered in Ca2+-free bathing solution and was eliminated by
      tetrodotoxin, suggesting that the sensory nerve activity is mediated by Na+
      currents. The Type II signal at early developmental stages (E12-E13, and some
      preparations in E14) was also independent of Ca2+. However, the Type II signal in
      later developmental stages (E15-E16, and some preparations in E14) did depend
      upon Ca2+: it was eliminated in Ca2+-free Ringer's solution, blocked by Cd2+,
      Ni2+ or Mn2+, and elicited in Sr2+-containing Ringer's solution, where CaCl2 was
      replaced with SrCl2. These results suggest that the cation which dominates the
      motoneuron action potential changes from Na+ to Ca2+ during development, and this
      change occurs around E14. With pharmacological analysis using Ca2+ channel
      blockers, we show that the Ca2+ channel mediating the motoneuron action potential
      is distinct from T-, L-, N-, P- or Q-type channels. Because the vagal action
      potential in adult mammals is mainly mediated by Na+, we suggest that a Ca2+
      action potential mediated by a new type of Ca2+ channel is expressed transiently
      in the rat dorsal motor nucleus of the vagus nerve at particular stages of
      development.

PMID- 10338299
TI  - Ionic mechanisms underlying excitatory effects of serotonin on embryonic rat
      motoneurons in long-term culture.
AB  - The actions of serotonin were investigated on motoneurons isolated from embryonic
      day 14 rat spinal cord and enriched by metrizamide density gradient
      centrifugation. Trophic support was provided by a spinal cord glial monolayer,
      ciliary neurotrophic factor and heat-inactivated serum. Cultures were maintained
      for 17-83 days and investigated using whole-cell patch-clamp recording. Serotonin
      evoked slow depolarizations (6.2+/-0.7 or 9.3+/-1.3 mV in the presence of 6-cyano
      7-nitroquinoxaline-2,3-dione and strychnine, EC50 8.2 nM), which were reversibly
      blocked by 0.1 microM ketanserin. Serotonin generated synaptic potentials in
      motoneurons, lowered the threshold for repetitive firing and changed the slope of
      the current intensity-firing frequency relationship. The inward current evoked by
      serotonin (-147+/-15.2 pA) was ascribed to a complex ionic mechanism, which
      varied amongst neurons in the sampled population. It was due to closure of barium
      sensitive potassium channels, effects on Ih and increase in a separate mixed
      cation current which comprised both transient voltage-sensitive and sustained
      components. We conclude that serotonergic responses develop in motoneurons
      cultured under these conditions in the absence of serotonergic input, sensory
      neurons or many interneurons.

PMID- 10338300
TI  - Mitochondrial permeability transition induced DNA-fragmentation in the rat
      hippocampus following hypoglycemia.
AB  - In the present study the time-course of DNA fragmentation following insulin
      induced hypoglycemia was examined. In situ localization of DNA breaks were
      studied by the terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine
      triphosphate nick-end labelling method, and the temporal profile of DNA
      fragmentation by agarose gel electrophoresis. Cell nuclei displayed terminal
      deoxynucleotidyl transferase-deoxyuridine triphosphate nick-end labelling within
      3 h of recovery following 30 min of a hypoglycemic insult, and DNA from the
      hippocampus displayed oligonucleosomal fragmentation. Ultrastructural examination
      of the dentate granule cells showed mitochondrial swelling during the acute phase
      of the hypoglycemic insult, which preceded the DNA fragmentation seen in the
      recovery phase. Cyclosporin A but not tacrolimus, prevented mitochondrial
      swelling and subsequent DNA fragmentation. We conclude that during severe energy
      deprivation following hypoglycemia, mitochondrial swelling occurs due to
      mitochondrial permeability transition and that factors are released, which upon
      recovery can activate processes leading to DNA fragmentation and cell death.

PMID- 10338301
TI  - Calcium ionophores can induce either apoptosis or necrosis in cultured cortical
      neurons.
AB  - Cultured cortical neurons exposed for 24 h to low concentrations of the Ca2+
      ionophores, ionomycin (250 nM) or A-23187 (100 nM), underwent apoptosis,
      accompanied by early degeneration of neurites, cell body shrinkage, chromatin
      condensation and internucleosomal DNA fragmentation. This death could be blocked
      by protein synthesis inhibitors, as well as by the growth factors brain-derived
      neurotrophic factor or insulin-like growth factor I. If the ionomycin
      concentration was increased to 1-3 microM, then neurons underwent necrosis,
      accompanied by early cell body swelling without DNA laddering, or sensitivity to
      cycloheximide or growth factors. Calcium imaging with Fura-2 suggested a possible
      basis for the differential effects of low and high concentrations of ionomycin.
      At low concentrations, ionomycin induced greater increases in intracellular Ca2+
      concentration in neurites than in neuronal cell bodies, whereas at high
      concentrations, ionomycin produced large increases in intracellular Ca2+
      concentration in both neurites and cell bodies. We hypothesize that the ability
      of low concentrations of Ca2+ ionophores to raise intracellular Ca2+
      concentration preferentially in neurites caused early neurite degeneration,
      leading to loss of growth factor availability to the cell body and consequent
      apoptosis, whereas high concentrations of ionophores produced global cellular
      Ca2+ overload and consequent necrosis.

PMID- 10338302
TI  - Differential regulation of the growth-associated proteins, GAP-43 and SCG-10, in
      response to unilateral cortical ablation in adult rats.
AB  - Synapse replacement after brain injury has been widely documented by anatomical
      studies in various parts of both the developing and adult nervous system.
      However, the molecular events that define the specificity of the empirically
      derived rules of reactive synaptogenesis in different regions of the adult brain
      remain unclear. In this study we examined the differential regulation of the
      lesion-induced response of the two growth-associated proteins, superior cervical
      ganglia-10 and growth-associated protein-43, after unilateral cortex ablation,
      and determined a hierarchical order for the lesion response from remaining
      afferent projection neurons originating from the contralateral cortex,
      ipsilateral thalamus and substantia nigra. We report that in response to
      unilateral cortex ablation both messenger RNA, by northern blot, and protein, by
      western blot, for superior cervical ganglia-10 but not growth-associated protein
      43 was increased in the homologous area of the contralateral cortex but not the
      ipsilateral thalamus or substantia nigra. In addition, the specificity of the
      superior cervical ganglia-10 response, assessed by combined in situ hybridization
      and retrograde FluoroGold labeling of striatal afferent neurons, found that
      superior cervical ganglia-10 messenger RNA was increased prominently in layer V
      pyramidal neurons of the contralateral corticostriatal pathway but was unchanged
      in afferent projection neurons from the thalamus and substantia nigra.
      Furthermore, the increase in both superior cervical ganglia-10 messenger RNA and
      protein seen at three days postlesion in contralateral corticostriatal neurons
      coincides in time with the initiation of neurite outgrowth in the deafferented
      striatum by contralateral corticostriatal axons described in our previous
      ultrastructural study. However, if cortical input to the striatum was removed
      bilaterally the lesion-induced response for superior cervical ganglia-10
      messenger RNA shifted secondarily to thalamostriatal neurons in the ipsilateral
      thalamus. These data provide evidence that superior cervical ganglia-10 and
      growth-associated protein-43 are differentially regulated in neurons of the
      contralateral corticostriatal pathway in response to unilateral cortex ablation
      and suggests that superior cervical ganglia-10 plays a role in the regulation of
      neurite outgrowth in the adult striatum after brain injury. However, the specific
      role that superior cervical ganglia-10 may play in reactive synaptogenesis
      remains unclear. In addition, our data suggest that a hierarchical order exists
      for the reinnervation of deafferented striatal neurons after unilateral cortex
      ablation with preference given to homologous axons from the contralateral cortex.

PMID- 10338303
TI  - Co-expression of TrkB and the N-methyl-D-aspartate receptor subunits NR1-C1, NR2A
      and NR2B in the rat visual cortex.
AB  - In the visual cortex, brain-derived neurotrophic factor expression is modulated
      through glutamate receptors, including the N-methyl-D-aspartate glutamate
      receptor. It has been proposed that the N-methyl-D-aspartate glutamate receptor
      subunit composition itself might be regulated by brain-derived neurotrophic
      factor. Here, we investigated the co-expression of the neurotrophin-4/brain
      derived neurotrophic factor receptor TrkB with the N-methyl-D-aspartate glutamate
      receptor subunits NR1-C1, NR2A and NR2B, on postnatal days 10 and 22 and in the
      adult rat primary visual cortex. At both postnatal days 10 and 22, TrkB is co
      expressed in all cortical layers with the studied N-methyl-D-aspartate glutamate
      receptor subunits. In the adult, in layers IV-V, co-expression is restricted to a
      subpopulation of neurons, while in layers II-III, VI nearly all neurons co
      express TrkB with NR1-C1, NR2A and NR2B. We conclude that in layers IV-V, the co
      expression of TrkB with subunits NR2B and NR2A is developmentally regulated.

PMID- 10338304
TI  - Trigeminovascular nociceptive transmission involves N-methyl-D-aspartate and non
      N-methyl-D-aspartate glutamate receptors.
AB  - Interest in the fundamental mechanisms underlying headache, particularly the
      pathophysiology of migraine and cluster headache, has lead to the study of the
      physiology and pharmacology of the trigeminovascular system and its central
      ramifications. Cats were anaesthetized (60 mg/kg alpha-chloralose, i.p., along
      with halothane for all surgical procedures) and prepared for physiological
      monitoring. The animals were placed in a stereotaxic frame and ventilated. A
      midline craniotomy and C2 laminectomy were performed for access to the superior
      sagittal sinus and C2 dorsal horn, respectively. The sinus was isolated from the
      underlying cortex and stimulated electrically after the animals had been
      paralysed with gallamine (6 mg/kg, i.v.). Units linked to stimulation were
      recorded with a tungsten-in-glass microelectrode placed in the most caudal part
      of the trigeminal nucleus, the trigeminocervical complex. Signals from the
      neurons were amplified, filtered and passed to a microcomputer, where post
      stimulus histograms were constructed on-line to analyse the responses to
      stimulation. Units responded to sagittal sinus stimulation with a typical latency
      of 8-10 ms. All units studied had a probability of firing of 0.6 or greater.
      Intravenous injection of the non-competitive N-methyl-D-aspartate receptor
      antagonist, dizocilpine maleate (4 mg/kg, i.v.), resulted in a substantial and
      prolonged blockade of firing of units in the trigeminocervical complex.
      Similarly, administration of the non-N-methyl-D-aspartate excitatory amino acid
      receptor blocker, GYKI 52466, lead to a dose-dependent inhibition of
      trigeminovascular-evoked responses in the trigeminocervical complex. These data
      demonstrate the participation of both N-methyl-D-aspartate- and non-N-methyl-D
      aspartate-mediated mechanisms in transmission within the trigeminocervical
      complex, and suggest a clear preclinical role of glutamatergic mechanisms in
      primary headache syndromes, such as migraine and cluster headache.

PMID- 10338305
TI  - Responses of primate spinomesencephalic tract cells to intradermal capsaicin.
AB  - The responses of 32 spinomesencephalic tract cells to intradermal capsaicin were
      examined in anesthetized monkeys. Wide dynamic range (n = 20) and nociceptive
      specific (n = 6) cells showed two types of excitatory responses to intradermal
      injection of capsaicin. The first excitatory response shown by the majority of
      wide dynamic range (n = 13) and nociceptive specific (n = 4) cells was consistent
      with their sensitization by capsaicin. The cells showed an acute and prolonged
      increase in ongoing activity with capsaicin injection. Responses to mechanical
      stimuli were substantially increased after capsaicin and an expansion of
      receptive field was often observed. The responses of the same cells to excitatory
      amino acid agonists applied locally by iontophoresis also increased. All cells
      showing sensitization were antidromically activated from periaqueductal gray
      regions dorsal to the sulcus limitans. Electrical stimulation at these sites did
      not affect the ongoing or evoked discharges of these cells. The second excitatory
      response of wide dynamic range (n = 5) and nociceptive specific (n = 1) cells was
      a novel pattern not consistent with sensitization. These cells nevertheless
      showed an acute and prolonged increase in background activity after capsaicin
      injection. Yet, there was no change or a decrease in responses to cutaneous
      stimuli, no evidence for change in receptive field size and no increase in
      responses to locally released excitatory amino acids. These cells projected to
      regions in the periaqueductal gray ventral to the sulcus limitans. Electrical
      stimulation at these sites produced a decrease in spontaneous activity of the
      same cell. Low threshold mesencephalic-projecting neurons (n = 6) showed a single
      inhibitory pattern (n = 4) of responses to capsaicin. The injection produced an
      acute decrease in spontaneous activity that was sustained for at least 30 min
      after injection. The responses to cutaneous stimuli and to excitatory amino acids
      were also substantially reduced. Low threshold cells were found that projected to
      both dorsal-lateral and ventral-lateral regions of the periaqueductal gray. In
      summary, three patterns of responses shown by primate spinomesencephalic tract
      cells to intradermal capsaicin appear dependent on the functional regions of the
      periaqueductal gray to which they project. These results suggest that inputs of
      spinomesencephalic tract neurons to the periaqueductal gray may evoke important
      components of the systemic response to the neurogenic hyperalgesia produced by
      intradermal capsaicin.

PMID- 10338306
TI  - Response properties of hind limb single motor units in normal rats and after
      carrageenan-induced inflammation.
AB  - The properties of single motor units from hind limb muscles and the changes in
      situations of hyperalgesia are not known in detail. We have therefore
      characterized the properties of single motor units in normal Wistar male rats and
      in rats with carrageenan-induced inflammation, under alpha-chloralose
      anaesthesia. Units were studied from three different muscles: peroneus longus,
      tibialis anterior and extensor digitorum longus. The properties of single motor
      units were not homogeneous in the three muscles studied in normal animals,
      showing different sizes of cutaneous receptive fields, thresholds for natural and
      electrical stimulation, and encoding of responses at different intensities of
      stimulation. Intraplantar injections of carrageenan induced a significant
      inflammation of the paw and a change in spontaneous behaviour observed in open
      field experiments. After inflammation, the responses to cutaneous stimulation of
      the single motor units became more homogeneous. The threshold for mechanical
      stimulation was lower for peroneus longus and tibialis anterior but not for
      extensor digitorum longus units when compared to normal animals. The receptive
      fields were larger when mapped with a 500 mN von Frey hair but not when mapped
      using a threshold intensity hair. The threshold for thermal stimulation was lower
      after inflammation than in normal conditions in all cases, whereas the threshold
      for electrical stimulation was lower in tibialis anterior and extensor digitorum
      longus units. An enhancement of responses related to the increase of stimulus
      intensity was seen in normal animals in all muscles for mechanical and electrical
      stimuli (but not for thermal). After inflammation, a relationship between firing
      rate and intensity of stimulation was seen in all cases studied. The firing of
      single motor units showed over 50% adaptation in the normal condition and over
      75% after inflammation when stimulated for 10 s at mechanical threshold
      intensity. After inflammation, the rate of adaptation was significantly lower
      when suprathreshold intensity was used for mechanical stimulation. No differences
      were seen in the adaptation of units to thermal stimulation. We conclude that, in
      situations of hyperalgesia due to inflammation, the threshold, encoding of
      stimulus intensity and adaptation of single motor units from different muscles
      changed, resulting in a narrower range of responses and a more homogeneous
      population of units.

PMID- 10338307
TI  - Evidence of metabotropic glutamate receptor subtypes found on catfish horizontal
      and bipolar retinal neurons.
AB  - We have used electrophysiological, pharmacological and immunological techniques
      to determine which classes of metabotropic glutamate receptors exist on cone
      horizontal cells in the catfish retina. Patch-clamp recordings in acutely
      dissociated cone horizontal cells provide evidence that group I and III
      metabotropic glutamate receptors exist, and are linked to modulation of a voltage
      gated calcium current. Group II metabotropic glutamate receptor agonists did not
      affect the calcium current. Immunocytochemical techniques were used to study the
      localization of metabotropic glutamate receptor subtypes found in the catfish
      retina. Antibodies raised against group I (metabotropic glutamate receptor
      1alpha, metabotropic glutamate receptor 5), group II (metabotropic glutamate
      receptor 2/3) and group III (metabotropic glutamate receptor 6) metabotropic
      glutamate receptor subtypes were used to label acutely dissociated horizontal,
      bipolar and Muller cells. Results from immunostaining provide evidence that cone
      horizontal cells express group I (metabotropic glutamate receptor 1alpha,
      metabotropic glutamate receptor 5) and group III (metabotropic glutamate receptor
      6), but not group II (metabotropic glutamate receptor 2/3) receptor subtypes,
      consistent with our electrophysiological results. Cone horizontal cells exposed
      to anti-metabotropic glutamate receptor 1alpha, 5 or 6 antibodies all
      demonstrated diffuse overall staining, with patches of dark immunostaining found
      on both dendritic processes and cell somata. In catfish bipolar cells, all four
      of the anti-metabotropic glutamate receptor antibodies stained the processes and
      cell bodies of bipolar cells homogeneously. There was no evidence for a group of
      bipolar cells that did not stain with the antimetabotropic glutamate receptor
      antibodies, although the densest immunostaining occurred when bipolar cells were
      incubated with the anti-metabotropic glutamate receptor 6 antibody. Muller cells
      did not show immunostaining against any anti-metabotropic glutamate receptor
      antibody. Our non-immune controls confirmed that immunostaining was specific for
      the antigen, and immunoblots were performed to demonstrate the specificity of the
      antibodies in catfish retina. These results support the hypothesis that group I
      and III metabotropic glutamate receptor subtypes are found on catfish horizontal
      cells, and group I, II and III metabotropic glutamate receptor subtypes are
      expressed on catfish bipolar cells. The metabotropic glutamate receptors on
      catfish cone horizontal cells act to modulate the voltage-gated sustained calcium
      current found on these cells.

PMID- 10338308
TI  - Effects of N-methyl-D-aspartate (dizocilpine) and alpha-amino-3-hydroxy-4
      isoxazolepropionate (LY215490) receptor antagonists on the voiding reflex induced
      by perineal stimulation in the neonatal rat.
AB  - The present study was undertaken to examine the role of alpha-amino-3-hydroxy-5
      methyl-4-isoxazolepropionate and N-methyl-D-aspartate glutamate receptors in the
      regulation of voiding reflexes induced by perineal stimulation in the neonatal
      rat. Four-, six- and 10-day-old awake rats were used in the experiments and
      perineal stimulation was applied using the tip of a 1-ml syringe to evoke
      voiding. Voided volume and residual volume were measured. In 10-day-old rats,
      LY215490 (3-10 mg/kg, i.p.), a competitive alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionate receptor antagonist, significantly inhibited reflex voiding,
      increasing the residual volume 34-53-fold. A 3 mg/kg dose decreased the urine
      release by 55%, whereas 10 mg/kg totally suppressed the voiding reflex induced by
      the perineal stimulation. LY215490 (10 mg/kg, i.p.) produced similar effects in
      four- and six-day-old rats. Dizocilpine (1-3 mg/kg, i.p.), a non-competitive N
      methyl-D-aspartate receptor antagonist, also significantly decreased the urine
      release (62-82%) and increased residual volume (180-230-fold). Combined
      administration of LY215490 (1 mg/kg, i.p.) and dizocilpine (0.3 mg/kg, i.p.) to
      10-day-old rats, in doses that individually had no effect on perineal stimulation
      evoked voiding, depressed voided volume by 65%. These results indicate that, in
      neonatal rats, glutamatergic transmission in the spinal cord has an essential
      role in reflex micturition induced by perineal stimulation, and that facilitatory
      interactions between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and N
      methyl-D-aspartate glutamatergic mechanisms are important for voiding, as noted
      previously in adult rats.

PMID- 10338309
TI  - Selective early induction of synaptosomal-associated protein (molecular weight
      25,000) following systemic administration of kainate at convulsant doses in the
      rat.
AB  - SNAP-25 (synaptosomal-associated protein of mol. wt 25,000) is an essential
      component for neurotransmitter release, and its expression has been related to
      the plastic responses that follow CNS injury. In the present study, transient
      induction of SNAP-25 in selected brain areas is shown by immunohistochemistry at
      short times after a single intraperitoneal injection of kainate at convulsant
      doses. Six hours after kainate injection, SNAP-25 immunoreactivity was noticed in
      the perikarya of certain neurons of the perirhinal and lateral cortices,
      polymorphic layer of the dentate gyrus, CA3 pyramidal area of the hippocampus,
      and thalamus. In the same areas, a strong increase in SNAP-25 immunorectivity was
      detected at 12 and 24 h after kainate injection in cell bodies and fibers. Four
      days after kainate administration, the immunostaining pattern was similar to that
      observed in control animals. Intraperitoneal injection of cycloheximide blocked
      the expression of SNAP-25, thus suggesting de novo SNAP-25 protein synthesis
      following kainate administration. Kainate-dependent induction of SNAP-25a
      messenger RNA synthesis was observed by in situ hybridization in the mentioned
      brain areas. Heat shock protein of mol. wt 72,000 (HSP70/72) is a chaperone whose
      expression is induced early under stress conditions. Its expression and
      distribution were compared to that of SNAP-25 after the excitotoxic insult. Brain
      areas overexpressing SNAP-25 and HSP70/72 overlapped. In addition, partial co
      localization of both antigens was observed by double-labeling
      immunohistochemistry. These results provide evidence of an involvement of SNAP-25
      in the reactive response that follows kainate administration, and support the
      role of this protein in the plastic events that take place after kainate
      excitotoxicity.

PMID- 10338310
TI  - Expression of thymosin beta4 messenger RNA in normal and kainate-treated rat
      forebrain.
AB  - Thymosin beta4 is a major actin-sequestering peptide widely distributed in
      mammalian tissues, including the nervous system. In the present study, we analyse
      the expression of thymosin beta4 in normal and kainate-treated rat forebrain. In
      untreated animals, thymosin beta4 messenger RNA is mainly expressed in neurons of
      the hippocampal formation, neocortex and amygdaloid complex, as well as in
      oligodendrocytes. Other high-expressing areas are the tanycytic ependyma of the
      infundibulum, the substantia nigra pars compacta, and the supraoptic and
      premammillary nuclei. In rats treated with kainate, an excitotoxin that induces
      synaptic activation in the CA1-CA3 pyramidal neurons of the hippocampus, the
      levels of thymosin beta4 were clearly increased in the hippocampus and neocortex
      during the first 2-3 h after injection. In the long term, kainate causes neuronal
      degeneration in the CA1-CA3 regions of the hippocampus and functionally related
      structures, provoking a depletion of thymosin beta4 messenger RNA in these areas;
      however, the levels of this transcript are restored two weeks after kainate
      injection. Moreover, we have found that, in these degenerating zones, gliosis is
      accompanied by an elevation of the levels of thymosin beta4 messenger RNA,
      particularly in the CA1-CA3 region of the hippocampus, the lateral geniculate
      nucleus and the mammillothalamic tract. The present results demonstrate the
      existence of relatively high levels of thymosin beta4 messenger RNA in several
      areas of the rat forebrain, indicating that this peptide plays an important role
      in the regulation of actin polymerization in these regions of the brain.
      Moreover, the elevation of this messenger RNA after kainate treatment suggests a
      function of thymosin beta4 in the production and remodelling of neuronal
      processes. Finally, our findings provide evidence for a participation of this
      actin-sequestering molecule in the reactivity of certain types of glial cell that
      follows kainate lesions.

PMID- 10338311
TI  - Brain-derived neurotrophic factor immunoreactivity in the limbic system of rats
      after acute seizures and during spontaneous convulsions: temporal evolution of
      changes as compared to neuropeptide Y.
AB  - Seizures increase the synthesis of brain-derived neurotrophic factor in forebrain
      areas, suggesting this neurotrophin has biological actions in epileptic tissue.
      The understanding of these actions requires information on the sites and extent
      of brain-derived neurotrophic factor production in areas involved in seizures
      onset and their spread. In this study, we investigated by immunocytochemistry the
      changes in brain-derived neurotrophic factor in the hippocampus, entorhinal and
      perirhinal cortices of rats at increasing times after acute seizures eventually
      leading to spontaneous convulsions. We also tested the hypothesis that seizure
      induced changes in brain-derived neurotrophic factor induce later modifications
      in neuropeptide Y expression by comparing, in each instance, their immunoreactive
      patterns. As early as 100 min after seizure induction, brain-derived neurotrophic
      factor immunoreactivity increased in CA1 pyramidal and granule neurons and in
      cells of layers II-III of the entorhinal cortex. At later times, immunoreactivity
      progressively decreased in somata while increasing in fibres in the hippocampus,
      the subicular complex and in specific layers of the entorhinal and perirhinal
      cortices. Changes in neuropeptide Y immunoreactivity were superimposed upon and
      closely followed those of brain-derived neurotrophic factor. One week after
      seizure induction, brain-derived neurotrophic factor and neuropeptide Y
      immunoreactivities were similar to controls in 50% of rats. In rats experiencing
      spontaneous convulsions, brain-derived neurotrophic factor and neuropeptide Y
      immunoreactivity was strongly enhanced in fibres in the
      hippocampus/parahippocampal gyrus and in the temporal cortex. In the dentate
      gyrus, changes in immunoreactivity depended on sprouting of mossy fibres as
      assessed by growth-associated protein-43-immunoreactivity. These modifications
      were inhibited by repeated anticonvulsant treatment with phenobarbital. The
      dynamic and temporally-linked alterations in brain-derived neurotrophic factor
      and neuropeptide Y in brain regions critically involved in epileptogenesis
      suggest a functional link between these two substances in the regulation of
      network excitability.

PMID- 10338312
TI  - Patterns of expression of the immediate-early gene egr-1 in the accessory
      olfactory bulb of female mice exposed to pheromonal constituents of male urine.
AB  - Male mice excrete large quantities of major urinary proteins that have been
      proposed to have an important pheromonal role either alone or by way of their
      bound ligands. We have found that these major urinary proteins are not only
      likely to mediate the pregnancy blocking effects of male urine, but that they
      also convey the strain recognition signal of the male pheromone. Recent molecular
      biological investigations have characterized two classes of pheromonal receptor
      in the vomeronasal organ that appear to project separately to anterior and
      posterior regions of the accessory olfactory bulb. However, it is not known
      whether these separate pathways handle fundamentally different types of
      pheromonal information. We have attempted to investigate this question using the
      expression of the immediate-early gene egr-1 as a marker for activity of neurons
      in the accessory olfactory bulb of female mice in response to putative pheromonal
      constituents. Exposure to 2,3 dihydro-exo-brevicomin and 2-sec-butyl-4,5-dihydro
      thiazole, the main ligands bound to the major urinary proteins, elicited
      expression of egr-1 in clusters of presumed mitral neurons at the medial and
      lateral margins of the posterior accessory olfactory bulb. Whole male urine and a
      preparation of major urinary proteins that had been stripped of their ligands
      induced egr-1 expression in mitral cells of the anterior half of the accessory
      olfactory bulb in addition to the posterior clusters. This would suggest that the
      anterior and posterior halves of the accessory olfactory bulb are processing
      different aspects of the male pheromone signal with the anterior region, which
      responds preferentially to major urinary proteins, being principally concerned
      with the strain recognition component.

PMID- 10338313
TI  - Developmental sex differences in amino acid neurotransmitter levels in
      hypothalamic and limbic areas of rat brain.
AB  - GABA, glutamate and aspartate are the predominant amino acid neurotransmitters in
      the mammalian brain. We have previously reported a developmental sex difference
      in messenger RNA levels of glutamate decarboxylase, the rate-limiting enzyme in
      GABA synthesis [Davis A. M. et al. (1996) Horm. Behav. 30, 538-552]. Males were
      found to have significantly higher levels of messenger RNA in many steroid
      concentrating regions of the hypothalamus and limbic system on day 1 of life.
      Therefore, in this study, we have examined levels of amino acid neurotransmitters
      during early postnatal development in many of the same or related brain areas. We
      found that levels of all three transmitters change as animals age. While both
      GABA and aspartate concentrations increase, glutamate levels decrease. In
      addition, there are sex differences in neurotransmitter levels in several areas
      examined, including the ventromedial and arcuate nuclei of the hypothalamus, and
      the CA1 region of the hippocampus. Sex differences for GABA occur only on
      postnatal days 1 and 5. However, sex differences in aspartate occur later in
      development (postnatal day 20). The CA1 region of males has a significantly
      greater concentration of GABA, glutamate and aspartate than females on postnatal
      day 1. In addition, treatment of females with testosterone propionate on the day
      of birth results in increased GABA levels, suggesting that these sex differences
      may be the result of hormone exposure during development. We hypothesize that
      these hormonally mediated sex differences in amino acid transmitters early in
      development contribute to the establishment of sexually dimorphic neuronal
      architecture in the adult.

PMID- 10338315
TI  - Glutathione depletion causes an uncoupling effect on retinal horizontal cells
      through oxidative stress.
AB  - To investigate a physiological role of glutathione in the horizontal cells of
      carp retina, the gap junctional intercellular communication between horizontal
      cells was studied using the techniques of intracellular recording of light
      induced responses and coupling of the fluorescence dye Lucifer Yellow.
      Intravitreal injection of 2.5 micromol L-buthionine sulfoximine, an inhibitor of
      glutathione synthesis, induced a dramatic reduction (20% of control) of retinal
      glutathione level two days after treatment. The low level of glutathione
      continued for a further four to five days, and thereafter gradually recovered to
      about 40% (20 days after injection) and 70% (50 days after injection) of the
      control level. The spatial properties of the photopic L-type horizontal cell
      response were examined by enlarging the diameter of the central spot and
      peripheral annulus over the recording point. In normal retinas, the response
      amplitude of horizontal cells was monotonically enhanced as the diameter of the
      spot increased (0.5-4.0 mm) and correspondingly the dye diffusion area was wide,
      as the injected Lucifer Yellow normally diffused to several neighboring cells.
      Treatment with L-buthionine sulfoximine significantly altered the spatial
      properties of horizontal cells by increasing the response amplitude to central
      spots and slightly decreasing that to peripheral annuli, which were observed by
      four days after injection. It also restricted intracellular Lucifer Yellow to one
      or two cells. Accompanying the recovery of the cellular level of glutathione, the
      spatial properties and dye coupling of horizontal cells were restored to normal.
      A time lag (two days) of initiation in retinal glutathione depletion and
      alteration of spatial or dye coupling properties of horizontal cells is
      discussed, together with reactive oxygen species accumulation.

PMID- 10338314
TI  - Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a
      transgenic mouse model of familial amyotrophic lateral sclerosis.
AB  - A subset of familial cases of amyotrophic lateral sclerosis are linked to
      missense mutations in copper/zinc superoxide dismutase type 1. Patients with
      missense mutations in copper/zinc superoxide dismutase type 1 develop a paralytic
      disease indistinguishable from sporadic amyotrophic lateral sclerosis through an
      unknown toxic gain of function. Nitric oxide reacts with the superoxide anion to
      form the strong oxidant, peroxynitrite, which participates in neuronal injury in
      a variety of model systems. Peroxynitrite is an alternate substrate for
      copper/zinc superoxide dismutase type 1, causing catalytic nitration of tyrosine
      residues in other proteins. Mutations in copper/zinc superoxide dismutase type 1
      may disrupt the active site of the enzyme and permit greater access of
      peroxynitrite to copper, leading to increased nitration by peroxynitrite of
      critical cellular targets. To investigate whether neuronal-derived nitric oxide
      plays a role in the pathogenesis of familial amyotrophic lateral sclerosis, we
      examined the effects of three different nitric oxide synthase inhibitors: a non
      selective nitric oxide synthase inhibitor, nitro-L-arginine methyl ester; a
      relatively selective inhibitor of neuronal nitric oxide synthase, 7
      nitroindazole; and a novel highly selective neuronal nitric oxide synthase
      inhibitor, AR-R 17,477, in transgenic mice expressing a familial amyotrophic
      lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1
      (Gly-->Ala at position 93; G93A) containing a high transgene copy number and a
      low transgene copy number. AR-R 17,477, but not nitro-L-arginine methyl ester or
      7-nitroindazole, significantly prolonged survival in both the high and low
      transgene transgenic mice. To determine whether neuronal nitric oxide synthase is
      involved in the pathogenesis resulting from the familial amyotrophic lateral
      sclerosis copper/zinc superoxide dismutase type 1 mutation, we produced mice with
      the copper/zinc superoxide dismutase type 1 mutation which lack the neuronal
      nitric oxide synthase gene. The transgenic mice expressing a familial amyotrophic
      lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 on
      neuronal nitric oxide synthase null background do not live significantly longer
      than transgenic mice expressing a familial amyotrophic lateral sclerosis-linked
      mutant human copper/zinc superoxide dismutase type 1. Western blot analysis
      indicates the presence of two neuronal nitric oxide synthase-like immunoreactive
      bands in spinal cord homogenates of the neuronal nitric oxide synthase null mice,
      and residual neuronal nitric oxide synthase catalytic activity ( > 7%) is
      detected in the spinal cord of the transgenic mice expressing a familial
      amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide
      dismutase type 1 on neuronal nitric oxide synthase null background. This amount
      of residual activity probably does not account for lack of protection afforded by
      the disrupted neuronal nitric oxide synthase gene in the familial amyotrophic
      lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1
      mice. Immunological nitric oxide synthase is not detected in the copper/zinc
      superoxide dismutase type 1 mutant mice at several different ages, thus excluding
      immunological nitric oxide synthase as a contributor to the pathogenesis of
      familial amyotrophic lateral sclerosis. Levels of neuronal nitric oxide synthase
      as well as Ca2+-dependent nitric oxide synthase catalytic activity in the
      copper/zinc superoxide dismutase type 1 mutant mice do not differ from wild type
      mice. Endothelial nitric oxide synthase levels may be decreased in the
      copper/zinc superoxide dismutase type 1 mutant mice. Together, these results do
      not support a significant role for neuronal-derived nitric oxide in the
      pathogenesis of familial amyotrophic lateral sclerosis transgenic mice.

PMID- 10338316
TI  - Transneuronal tracing of neural pathways controlling activity of diaphragm
      motoneurons in the ferret.
AB  - Previous studies have shown that neurons in addition to those in the medullary
      respiratory groups are involved in activating phrenic motoneurons during a number
      of behaviors, including vomiting and reaction to vestibular stimulation. However,
      the location of premotor inspiratory neurons outside of the main medullary
      respiratory groups is largely unknown, particularly in emetic species. In the
      present study, the transneuronal tracer pseudorabies virus was injected into the
      diaphragm of the ferret, and the locations of retrogradely-labeled motoneurons
      and transneuronally-labeled pre-motoneurons in the brainstem and cervical and
      thoracic spinal cord were mapped. Injections of a monosynaptic tracer, cholera
      toxin, were also made in order to verify the location of motoneurons innervating
      the diaphragm. Phrenic motoneurons identified with pseudorabies virus and cholera
      toxin were confined largely to the C5-C7 levels of spinal cord, and often gave
      rise to prominent polarized dendritic arbors that extended across the midline. At
      post-inoculation survival times > or = three days, transneuronally-labeled
      interneurons were located in the cervical and thoracic spinal cord and portions
      of the brainstem, including the midline pontomedullary reticular formation and
      the lateral medullary reticular formation. Double-labeling studies revealed that
      although the infected midline neurons were located in the proximity of
      serotonergic neurons, only a small number of the virus-containing cells were
      positive for serotonin. These findings suggest that neurons in the midline of the
      medulla and pons influence the activity of phrenic motoneurons, perhaps during
      inspiratory behaviors unique to emetic animals (such as vomiting).

PMID- 10338317
TI  - Role of proprioception in the control of lid position during reflex and
      conditioned blink responses in the alert behaving cat.
AB  - The contribution of the orbicularis oculi muscle to the determination of lid
      position, and the putative role of eyelid proprioception in the control of reflex
      and conditioned eye blinks, were studied in alert behaving cats. Upper lid
      movements and the electromyographic activity of the orbicularis oculi muscle were
      recorded during reflexively evoked blinks and during the classical conditioning
      of the eyelid response. Blinks were evoked by air puffs, flashes and electrical
      stimulation of the supraorbitary branch of the trigeminal nerve. Eyelid responses
      were conditioned with a trace classical conditioning paradigm consisting of a
      short, weak air puff, followed 250 ms later by a long, strong air puff.
      Orbicularis oculi muscle activation during reflex blinks was independent of lid
      position and was not modified by the presence of weights acting in the upward or
      downward directions. Local anesthesia of the supraorbital nerve reduced blinks
      evoked by air puffs applied to the lower jaw, but did not affect flash-evoked
      blinks. No relationship was established between initial lid position and the
      first downward component of conditioned eyelid responses. In contrast, initial
      lid position was related to the first upward component of the same conditioned
      response. It is concluded that orbicularis oculi motor units receive no feedback
      proprioceptive signals from the eyelid, other than those coming from cutaneous
      receptors, and that lid position is determined by the activity of the levator
      palpebrae superioris muscle. The lack of sensory information about lid position
      in facial motoneurons probably has some functional implications on the central
      control of cognitive and emotional facial expressions.

PMID- 10338318
TI  - Vascular, glial and neuronal effects of vascular endothelial growth factor in
      mesencephalic explant cultures.
AB  - Vascular endothelial growth factor is a highly conserved, heparin-binding protein
      which mediates a number of critical developmental processes in both vertebrates
      and invertebrates, including angiogenesis, vasculogenesis and hematopoiesis. We
      employed an organotypic rat explant model (produced from embryonic day 17
      fetuses) to assess the effects of vascular endothelial growth factor on brain
      microvasculature in general and the ventral midbrain specifically.
      Immunohistochemistry using antisera to rat endothelial cell antigen and laminin
      demonstrated a robust, dose-dependent effect of vascular endothelial growth
      factor, resulting in increased vessel neogenesis, branching and lumen size by
      three days in vitro. This effect was blocked by addition of an anti-vascular
      endothelial growth factor antibody. At higher doses of vascular endothelial
      growth factor, the effect was attenuated, though a statistically significant
      increase in both astrocyte, and neuronal density was observed using antisera to
      glial and neuronal markers. Tyrosine hydroxylase-immunoreactive (i.e.
      dopaminergic) neurons, particularly, exhibited increased survival in response to
      vascular endothelial growth factor application. Vascular endothelial growth
      factor had a mitogenic effect on endothelial cells and astrocytes, but not
      dopaminergic neurons, as demonstrated by the addition of [3H]thymidine to the
      cultures 2 h after the cultures were established. Similarly, results of a
      radioreceptor assay indicated that specific vascular endothelial growth factor
      binding sites were present on blood vessels and astrocytes, and were up-regulated
      by exposure to vascular endothelial growth factor. We conclude that, in explants
      of the ventral mesencephalon, exogenously applied vascular endothelial growth
      factor is mitogenic for endothelial cells and astrocytes, and promotes
      growth/survival of neurons in general and dopaminergic neurons in particular.

PMID- 10338319
TI  - Gradual development of the ventral funiculus input to lumbar motoneurons in the
      neonatal rat.
AB  - The in vitro brainstem-spinal cord preparation of newborn rats (0 to six-days
      old) was used to investigate the development of pathways descending ventrally
      from the brainstem, which are important for the control of posture and
      locomotion. The ventral funiculus of the spinal cord was stimulated at the
      cervical (C1) level. Responses were recorded at the lumbar level from either
      motoneurons or ventral roots using intracellular microelectrodes or suction
      electrodes, respectively. Responses consisted of a pure excitation lasting 15 ms,
      followed by mixed excitatory/inhibitory responses. The inhibition was, at least
      partly, mediated by glycine. Excitatory amino acid transmission appears to be
      responsible for the excitation. The characteristics of the ventral funiculus
      evoked postsynaptic potentials and ventral root potentials changed significantly
      with age. Their latency decreased whereas the slope and the area, measured over
      the first 15 ms, increased. The increase of the ventral funiculus input to
      motoneurons was slightly more pronounced than that of the monosynaptic dorsal
      root-evoked potentials from day 0 to day 4. These data suggest a gradual arrival
      of ventral descending axons in the lumbar enlargement which may be responsible
      for the gradual acquisition of postural control that takes place during the first
      days after birth. This is a prerequisite for the development of the adult pattern
      of quadrupedal locomotion, with elevated trunk.

PMID- 10338320
TI  - Molecular advances in cardiac and cardiovascular disease.
AB  - Recent advances in the field of molecular biology have led to a better
      understanding of the pathological mechanisms of cardiovascular disease. The
      impact of these findings will shape the future of treatment modalities for
      cardiovascular disorders. Postulated targets and biological rationale of new
      techniques are being developed in a race towards molecular therapies for vascular
      diseases. Whether it is modulation of transmembrane cell receptors or phenotypic
      changes via vectors that mediate gene transfer, there is no doubt that molecular
      strategies will be an integral part of the future. Here we examine past and
      recent perspectives, describe directions and challenges in cardiac and
      cardiovascular areas of research, and discuss relevance to the field of
      cardiovascular perfusion.

PMID- 10338321
TI  - Rabbit model of cardiopulmonary bypass.
AB  - Mainly because of technical problems, the use of rabbits as a cardiopulmonary
      bypass (CPB) animal model with direct cannulation of the ascending aorta is known
      to be extremely difficult. The objectives of this study were the establishment of
      a CPB model in rabbits with direct cannulation of the ascending aorta, and the
      evaluation of the protective effect of steroid on the development of brain edema
      during circulatory arrest (CA) in an established rabbit CPB model. Fifteen New
      Zealand white rabbits were divided into three groups; control CA group, CA with
      Trendelenberg position, and CA with Trendelenberg position and steroid
      administration. After anesthetic induction and tracheostomy, median sternotomy
      was performed. An aortic cannula (3.3 mm) and a venous cannula (14 Fr) were
      inserted into the ascending aorta and the right atrium, respectively. The CPB
      circuit consisted of a roller pump and a bubble oxygenator. With 120-150 ml of
      blood, the priming volume of the circuit was approximately 450 ml, and CPB at a
      flow rate of 80-85 ml/kg/min was initiated. Blood in the priming solution was
      obtained from donor rabbits through cardiac puncture. Ten minutes later, CA with
      cessation of CPB was established for 40 min at 20 degrees C (rectal temperature).
      After CA, CPB was restarted with a 20 min period of rewarming. Ten minutes after
      weaning, the animal was sacrificed. Between 1 and 2 g of the brain was removed
      and the water content was determined and compared between groups. CPB with CA was
      successfully performed in all cases, with a flow rate of 60-100 ml/kg/min
      maintained throughout the CPB procedure. At that time, blood gases were
      reasonably maintained and aortic pressure ranged from 35 to 55 mmHg. After
      weaning from CPB, all hearts resumed beating spontaneously. Among the three
      groups, there were no statistically significant differences in the water content
      of the brain. These results indicate that: (1) if the proper technique is used,
      CPB in rabbits with direct cannulation of the ascending aorta is a reliable
      procedure, and (2) the effect of steroid on the prevention of brain edema related
      to the Trendelenburg position during CA is not established within the scope of
      this study.

PMID- 10338322
TI  - Leucocyte filtration during cardiopulmonary reperfusion in coronary artery bypass
      surgery.
AB  - Postoperative organ dysfunction after cardiac operations has been related to the
      damaging effects of cardiopulmonary bypass (CPB). These complications are
      considered to be mediated partly by complement activation and subsequent
      activation of leucocytes due to the contact between blood and the large
      nonendothelial surfaces in the bypass circuit. Removal of leucocytes by
      filtration during the reperfusion period may potentially reduce the postoperative
      morbidity after CPB. Forty patients undergoing elective, primary coronary artery
      bypass grafting were randomized to initial identical bypass circuits until the
      aortic crossclamp was released. Then, the ordinary arterial line filter was
      closed and either a leucocyte depletion filter (n = 20), or a control filter (n =
      20) was incorporated in the circuits during the reperfusion period of CPB. Blood
      samples were drawn at fixed intervals and analysed for white blood cell and
      platelet counts, plasma concentration of myeloperoxidase, C3-complement
      activation products, the terminal complement complex, and interleukins (IL)-6 and
      -8. The numbers of circulating white blood cells in the leucocyte-depleted group
      decreased during the reperfusion period from 5.5 (4.8-6.8) to 5.3 (4.4-6.2) x
      10(9)/l, and increased in the control group from 6.5 (5.1-8.0) to 7.4 (5.7-9.0) x
      10(9)/l. Two hours postoperatively the total white blood cell count in the
      leucocyte-depleted group was 14.7 (12.1-17.2) x 10(9)/l, and in the control group
      17.6 (14.5-20.7) x 10(9)/l. The differences between the groups were statistical
      significant (p = 0.05). There were no statistically significant differences
      between the groups with regard to other test parameters or clinical data. We
      conclude that the use of leucocyte filters during the reperfusion period in
      elective coronary artery bypass surgery significantly reduced the number of
      circulating leucocytes, whereas no effects were seen for granulocyte activation
      measured as myeloperoxidase release, platelet counts, complement activation, or
      IL-6 and -8 release. The clinical benefit of leucocyte filters in routine or high
      risk patients remains to be demonstrated and is suggested to be dependent on both
      the efficacy and the biocompatibility of the filters.

PMID- 10338323
TI  - Comparison of three oxygenator-coated and one total-circuit-coated extracorporeal
      devices.
AB  - The present study was designed to compare the biocompatibility of three
      cardiopulmonary bypass setups with different surface coatings, and to determine
      if coating of the whole circuit with one of the coatings was more beneficial than
      coating of the oxygenator only. Extracorporeal devices entirely coated with
      synthetic polymers (Avecor, n = 6) were compared to oxygenators coated with
      synthetic polymers (Avecor, n = 6), end-point, covalently attached heparin (CBAS,
      n = 6) or absorbed heparin (Duraflo 2, n = 6) in an in vitro model of a heart
      lung machine. The circuits were primed with fresh human whole blood and Ringer's
      acetate and recirculated at 4 l/min at 30 degrees C for 2 h. Test samples were
      obtained at regular intervals and analysed for myeloperoxidase (MPO), platelet
      counts, beta-thromboglobulin, heparin, prothrombin fragment 1+2, plasmin anti
      plasmin complexes, and complement activation products. The mean MPO
      concentrations increased in the Avecor-coated oxygenator group (AV) from 247 at
      the start to 671 microg/l at the termination of the experiments, in the Avecor
      coated total circuit group (AV-T) from 116 to 288 microg/l, in the Duraflo 2
      coated oxygenator group (DU) from 160 to 332 microg/l, and in the CBAS-coated
      oxygenator (CA) group from 172 to 311 microg/l. The MPO concentrations increased
      significantly in all groups (p < 0.03). The increase in group A was significantly
      higher than in the other three groups (p = 0.007). The mean platelet counts
      decreased in the Avecor-coated total circuit group from 117 at start to 99 x
      10(9)/l at termination of the experiments, in the Avecor-coated oxygenator group
      from 119 to 103 x 10(9)/l, in the Duraflo 2 group from 96 to 86 x 10(9)/l, and in
      the CBAS group from 132 to 123 x 10(9)/l. The platelet counts decreased
      significantly in all groups (p < 0.01), but the intergroup differences were not
      significant (p = 0.15). The mean beta-thromboglobulin concentrations increased in
      the Avecor-coated total circuit group from 193 at the start to 754 ng/ml at the
      termination of the experiments, in the Avecor-coated oxygenator group from 474 to
      1654 ng/l, in the Duraflo 2 group from 496 to 1280 ng/l, and in the CBAS group
      from 418 to 747 ng/l. The beta-thromboglobulin increase was significant in each
      group (p < 0.01), but not between the groups (p = 0.49). The mean heparin
      concentrations in the Duraflo 2 group increased from 2460 at the start to 2897
      IU/l at termination of the experiments, in the CBAS group from 2468 to 2518 IU/l.
      In the Avecor-coated oxygenator group heparin concentrations decreased from 2010
      to 1968 IU/l, and in the Avecor-coated total circuit group from 2002 to 1927
      IU/l. The differences in heparin concentrations were significant between the
      Duraflo 2 group and the other groups (p < 0.05). The mean prothrombin fragment
      1+2 concentrations increased in the CBAS group from 0.4 at the start to 2.1
      nmol/l at the end of the experiments, in the Avecor-coated oxygenator group from
      0.4 to 0.6 nmol/l, in the Avecor-coated total circuit group from 0.3 to 0.4
      nmol/l, and in the Duraflo 2 group from 1.2 to 1.3 nmol/l. The prothrombin
      fragment 1+2 increase was significant in all groups (p < 0.05), but there were no
      significant intergroup differences (p = 0.54). There were no significant
      differences at the termination of the experiments among the four groups regarding
      complement activation as measured by C3 activation products and the terminal
      complement complex. In the present in vitro model of a heart-lung machine, none
      of the three specific setups with different coatings was superior with regard to
      all test parameters. The CBAS group generated the highest levels of prothrombin
      fragment 1+2 formation, but least complement activation. The increasing plasma
      heparin concentrations in the Duraflo 2 group indicated more unstable heparin
      bonding. The Avecor-coated total circuit group were superior to the Avecor-coated
      oxygenator group regarding plasma concentrations of MPO, but not compa

PMID- 10338324
TI  - Customized perfusion circuit for the tiny ascending aorta.
AB  - Cannulating a pediatric patient with an interrupted aortic arch presents many
      challenges. Two cannulas are necessary to allow for proper blood flow to the head
      and to the extremities. This case was made more difficult by the weight of the
      child and the small size of the ascending aorta. The available pediatric cannulas
      were too large. The perfusionist adapted two 14-gauge intravenous (i.v.)
      catheters as arterial cannulas which were incorporated into the 1/4-inch arterial
      line. The 14-gauge i.v. catheters worked successfully. While on cardiopulmonary
      bypass, the patient was both metabolically and hemodynamically stable. The
      patient survived the procedure and was eventually discharged from hospital.

PMID- 10338325
TI  - Investigation of the phenomenon of electrostatic compromise of a plastic fiber
      heat exchanger.
AB  - The use of a new generation of blood oxygenator design using plastic fibers for
      the heat exchange material is growing. The benefits of a plastic heat exchange
      material are improved biocompatibility and performance over some of the
      traditional metals used. During the initial period of clinical use of one of
      these new oxygenators, there were reports of four blood-to-water leaks. No
      patient complications were associated with these leaks, but the product was
      withdrawn from the market. After a thorough evaluation, the cause of the leaks
      was found to be an electrostatic discharge that occurred within the heat
      exchanger during priming of the extracorporeal circuit. It was found that an
      electrostatic potential between the blood path and the water path of the heat
      exchanger is generated as the prime solution is recirculated by a roller pump
      with polyvinyl chloride (PVC) pumphead tubing. The magnitude of the potential
      generated was found to vary with the make and model of the roller pump. If this
      voltage exceeds the dielectric strength of the fiber, a discharge through the
      wall of a single heat exchange fiber will occur and produce a hole. Several
      solutions to this problem of roller pumps generating an electrostatic charge when
      used with PVC pumphead tubing were identified. Centrifugal blood pumps and roller
      pumps using silicone rubber pumphead tubing were found to generate no significant
      electrostatic potential between the blood path and the water path. Another
      solution, a charge equalization line (CEL), was designed to provide a conductive
      path for the charge to equilibrate across the fiber wall. The CEL can be either
      external or internal to the oxygenator. Each of these solutions was validated and
      the product has been reintroduced for clinical use.

PMID- 10338326
TI  - Treatment of primary peritoneal mesothelioma by hyperthemic intraperitoneal
      chemotherapy.
AB  - Perfusion of the peritoneal cavity with chemotherapy agents under hyperthermic
      conditions has been utilized by several investigators in the treatment of intra
      abdominal malignancies. Based on the concept that hyperthermia may potentiate the
      cytotoxic effects of chemotherapeutic agents, we embarked on a clinical trial of
      two-stage peritoneal chemotherapy for patients with primary peritoneal
      mesothelioma, a neoplasm unresponsive to traditional systemic chemotherapeutic
      regimens. In stage I, patients underwent surgical debulking of gross disease and
      placement of an intraperitoneal infusion catheter, through which intraperitoneal
      chemotherapy was administered for four months. Stage II consisted of debulking of
      residual tumor, placement of two transabdominal perfusion cannulae and
      administration of high-dose intraperitoneal chemotherapy at 40 degrees C using a
      simple, disposable perfusion circuit. Flow rates were maintained at 1 l/min, and
      inflow and outflow temperatures maintained at 42 and 40 degrees C, respectively.
      To date, three patients have undergone both phases of the protocol, with no
      perioperative complications related to either hyperthermia or end-organ toxicity.
      One patient died of progressive disease after three months, and two patients are
      alive and well. One patient developed a small bowel anastomotic leak three weeks
      after operation. In summary, intraoperative hyperthermic peritoneal chemotherapy
      may play a role in novel approaches to the treatment of peritoneal malignancies
      previously unresponsive to traditional chemotherapeutic regimens.

PMID- 10338327
TI  - An unusual complication of central venous catheterization during cardiac surgery.

PMID- 10338328
TI  - Death to endothelial cells, death to melanoma?

PMID- 10338329
TI  - The presence of melanin in genomic DNA isolated from pigmented cell lines
      interferes with successful polymerase chain reaction: a solution.
AB  - We have found that polymerase chain reaction (PCR) amplification of genetic
      material is unsuccessful when using template genomic DNA derived from certain
      normal melanocyte and melanoma cell lines. We demonstrated that this phenomenon
      only occurs with pigmented cell lines and appears to be due to the association of
      genomic DNA with remnants of the pigment melanin. We therefore describe a simple
      and rapid technique that rids genomic DNA samples of melanin, resulting in a
      genomic DNA template that allows successful PCR.

PMID- 10338330
TI  - Multiple abnormalities of the p16INK4a-pRb regulatory pathway in cultured
      melanoma cells.
AB  - The retinoblastoma protein (pRb) pathway is critical in regulating the G1 phase
      of the cell cycle and it is frequently disrupted in human cancers. Components of
      the pRb pathway which are often altered in tumour progression include the INK4
      cyclin-dependent kinase (CDK) inhibitors p16INK4a/ CDKN2A and p15INK4b/CDKN2B,
      CDK4, D-type cyclins and pRb. Several of these components were studied in a
      series of cultured melanoma cell lines in order to determine the frequency and
      spectrum of genetic alterations and to define targets for potential gene transfer
      studies. Also studied were the p16INK4a alternate transcript (p14ARF) and the
      p21(waf1) CDK inhibitor. The majority of the melanoma cell lines tested (13 out
      of 17; 76%) carried mutated (two), deleted (nine) or silenced (two) p16(INK4a).
      CDK4 was mutated or overexpressed in two melanoma cell lines with homozygously
      deleted CDKN2A and CDKN2B genes. This suggests that the selective growth
      advantages afforded by CDKN2A inactivation and CDK4 insensitivity are distinct
      and may involve the mediation of other CDK inhibitors or CDKs.

PMID- 10338331
TI  - Melanoma development in relation to non-functional p16/INK4A protein and
      dysplastic naevus syndrome in Swedish melanoma kindreds.
AB  - The CDKN2A gene encodes the cell cycle inhibitor p16/ INK4A, which is involved in
      familial cutaneous melanoma. We have studied five Swedish familial melanoma
      kindreds characterized by germline mutations in CDKN2A and dysplastic naevus
      syndrome (DNS). We found significant correlations between germline CDKN2A
      mutations and melanoma and between DNS phenotype and melanoma, respectively.
      There was also a correlation between mutation status and the presence of DNS. In
      CDKN2A mutation carriers, all cases of early-onset melanoma occurred in DNS
      individuals, and the mean age at melanoma diagnosis was significantly lower in
      individuals with DNS than in those without a confirmed DNS phenotype. In one
      family where the proband had a P48L mutation in CDKN2A exon 1, the DNS phenotype
      was studied in detail. In vitro binding experiments established that the P48L
      mutant protein does not bind to cdk4 or cdk6 and thus is functionally abnormal.
      Furthermore, we demonstrated loss of heterozygosity at markers on chromosome 9p
      flanking the CDKN2A locus in a primary melanoma and a metastasis from the
      proband. Our results are consistent with the hypothesis that germline CDKN2A
      mutations and DNS both contribute to the predisposition to melanoma and may lead
      to the development of early-onset melanoma when present in the same individual.

PMID- 10338332
TI  - Pentoxifylline-induced modulation of melanoma cell growth, adhesion and
      lymphokine activated killer cell-mediated lysis.
AB  - Pentoxifylline (PX) is a phosphodiesterase inhibitor which effectively increases
      overall cAMP levels within the cell. This study analyses the ability of PX to
      alter growth, adhesion and lymphokine activated killer (LAK) cell-mediated lysis
      of the C8161 and Hs294T human melanoma cell lines, and investigates the role of
      intercellular adhesion molecule-1 (ICAM-1) in the tumour/LAK cell interaction. We
      have demonstrated that 4 days' pretreatment with PX (100-250 microg/ml)
      significantly reduces cell numbers in a dose- and time-dependent manner, with
      cell numbers decreasing by 67.5% in the C8161 cell line and by 65.4% in the
      Hs294T cell line with 250 microg/ml PX. Adherence of both cell lines to a range
      of extracellular matrix components is not affected by PX, with the exception of
      the C8161 cells, where 4 days' pretreatment with 250 microg/ml PX causes a 24.2%
      reduction in adherence to fibronectin. Four days' pretreatment of the tumour
      cells with 250 microg/ml PX leads to increased lysis of the C8161 cells and
      decreased lysis of the Hs294T cells. The addition of blocking ICAM-1 antibody (10
      microg/ml) to the C8161 cells at an effector:tumour cell ratio of 40:1 causes a
      2.3-fold reduction in lysis of both control and PX-treated cells. Addition of
      blocking ICAM-1 antibody (5 microg/ml) to Hs294T cells reduces lysis of control
      cells 1.8-fold. In PX-treated Hs294T cells, 10 microg/ml of blocking ICAM-1
      antibody significantly reduces lysis 1.5-fold. The more aggressive C8161 cells
      produce 5-fold greater levels of soluble ICAM-1 (sICAM-1) than the poorly
      metastatic Hs294T cells. PX (10-250 microg/ml) causes a dose-dependent increase
      in sICAM-1 expression in both cell lines, with maximum increases of 4.7-fold and
      4.3-fold in the Hs294T and C8161 cell lines, respectively, following 4 days'
      pretreatment with 250 microg/ml PX. Collectively, these data demonstrate the
      ability of PX to alter tumour cell growth, adhesion and LAK cell-mediated lysis
      and also support a role for the involvement of ICAM-1 in the tumour/LAK cell
      interaction.

PMID- 10338333
TI  - Therapeutic resistance: characterization and inactivation by specific antiserum
      of a putative protein family produced by tumour cells.
AB  - A multitherapy resistance (MTR) factor produced by Cloudman S91 mouse melanoma
      cells rescues a responsive cell line after gamma-irradiation, short wavelength
      ultraviolet light, mitomycin C, vinblastine and actinomycin D. A similar activity
      with respect to ionizing radiation is now shown to be produced by human melanoma
      cells and by both human and mouse breast cancer cells but not by five normal cell
      lines. In these studies, the factor produced in serum-free conditioned medium
      (SFCM) by Cloudman S91/I3 cells is further characterized. Its activity in a
      clonogenic assay using related Cloudman S91/amel cells is destroyed by trypsin
      but not by DNase and is stable for at least 8 days at a variety of temperatures
      including 37 degrees C. Molecules greater than 30 kDa from SFCM collected from
      S91/I3 cells were concentrated and separated by preparative zonal electrophoresis
      (PZE). Bioactivity was present in both the cathode- and the anode-running
      fractions. The active acidic (anode) fractions were analysed by preparative
      isoelectric focusing. Bioactivity was present between pI 3.5 and 4.2. These PZE
      fractions were also used to immunize two rabbits, both of which produced
      antiserum that abrogated the bioactivity of SFCM and of the PZE cathode
      fractions. Antiserum also decreased the survival of irradiated S91/I3 producer
      cells that do not respond to SFCM but nonetheless must require MTR proteins for
      the expression of radiation resistance. These studies present a model for the
      production of rescue factors by non-clonogenic tumour cells that may persist in
      some tumours for considerable periods of time.

PMID- 10338334
TI  - The chemoresistance of human malignant melanoma: an update.
AB  - Malignant melanoma is considered to be a chemotherapy-refractory tumour and the
      commonly used anticancer drugs do not seem to modify the prognosis of metastatic
      disease. The cellular resistance mechanisms involved in melanoma chemoresistance
      have not yet been elucidated. Melanoma-derived cell lines are often markedly
      chemoresistant. Using the in vitro soft agar culture system to predict tumour
      cell sensitivity in well-established human melanoma cell lines, a high degree of
      resistance against all the cytostatic agents studied has been reported,
      suggesting the presence of intrinsic cellular resistance mechanisms. The
      relevance of the well-defined resistance mechanisms mediated by P-glycoprotein,
      multidrug resistance-associated protein (MRP), the glutathione/glutathione S
      transferase system and topoisomerase II enzyme are reviewed. Mutated N-Ras
      oncogene has recently been implicated in melanoma resistance to cisplatin, both
      in vitro and in vivo, and the role of two other oncogenes, Bcl-2 and p53, which
      are already involved in the chemoresistance of haematological and solid
      malignancies, is beginning to be better elucidated. The finding that many
      chemotherapeutic agents can kill susceptible cells through the apoptosis pathway
      provides new molecular insight into chemoresistance mechanisms and suggests that
      apoptosis and/or resistance to apoptosis of melanoma cells should be investigated
      to better clarify the mechanism of melanoma chemoresistance.

PMID- 10338336
TI  - Hypercalcaemia in melanoma patients associated with increased levels of
      parathyroid hormone-related protein.
AB  - We analysed serum levels of calcium and parathyroid hormone-related protein (PTH
      rP) in 59 patients with melanoma by immunoradiometric assay, since only a few
      studies have been conducted on hypercalcaemia and serum levels of PTH-rP in
      patients with melanoma. Hypercalcaemia was found in seven of the 59 patients with
      melanoma. The serum level of PTH-rP was increased in three of the 59 patients and
      two of the three showed hypercalcaemia. All the patients with hypercalcaemia
      and/or an increased level of PTH-rP had stage IV melanoma. These findings suggest
      that hypercalcaemia is much more common than previously reported in patients with
      advanced stage melanoma and that an increased serum level of PTH-rP is one of the
      causative factors in hypercalcaemia in melanoma. Analysis of the serum PTH-rP
      level will contribute to the monitoring of the clinical course of patients with
      advanced stage melanoma.

PMID- 10338335
TI  - Prognostic value of tumour vascularity in metastatic melanoma and association of
      blood vessel density with vascular endothelial growth factor expression.
AB  - Tumour angiogenesis is essential for tumour growth and metastasis. Several lines
      of evidence indicate that vascular endothelial growth factor (VEGF) is a major
      regulator both of physiological and pathological angiogenesis. In this study we
      assessed the blood vessel density and VEGF expression of 94 melanoma metastases
      of 70 patients by immunohistochemistry, utilizing antibodies against human
      platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) and VEGF. The
      number of blood vessels ranged from 4 to 131 vessels/high power field (HPF), with
      a mean value of 32 vessels/HPF (+/-21) and a median of 29 vessels/ HPF. Survival
      since diagnosis of the primary disease and from the start of chemoimmunotherapy,
      as well as the disease-free survival period, was significantly shorter in the
      high vascularity group of patients compared with the low vascularity group (P<
      0.05 and P< 0.01, respectively). A high overall expression of VEGF in the
      metastatic melanoma samples was observed. The degree of VEGF expression appeared
      to have a strong association with the blood vessel density (P= 0.017). This study
      demonstrates the clinical role of tumour vascularity in the prognosis of patients
      with metastatic melanoma. In addition, the strong association between vascularity
      and VEGF expression suggests a crucial role for this growth factor in the
      neovascularization of metastatic melanoma.

PMID- 10338337
TI  - Pharmacokinetics of 10B-p-boronophenylalanine in tumours, skin and blood of
      melanoma patients: a study of boron neutron capture therapy for malignant
      melanoma.
AB  - To optimize the neutron dose for boron neutron capture therapy (BNCT), the boron
      10 (10B) concentration kinetics of 10B-p-boronophenylalanine (BPA) were analysed
      in 22 melanoma patients with primary or metastatic melanomas who received BPA and
      subsequently underwent BNCT or surgery. The blood concentration in nine patients
      receiving 179.7+/-14.9 mg/kg BPA increased with time during intravenous infusion,
      peaked at the end of administration and decreased thereafter. The peak values at
      the end of administration were 9.4 2.6 microg 10B/g blood, and half-lives for the
      initial and second components of the blood clearance were 2.8 and 9.2 h,
      respectively. Skin concentrations in the 10 patients varied from case to case;
      however, skin-to-blood ratios were relatively constant at 1.31+/-0.22 during the
      6 h after the end of administration. Boron concentrations in the tumours resected
      from the seven patients who were operated on decreased in parallel to the blood
      values, the tumour-to-blood ratio being relatively constant at 3.40+/-0.83. The
      present analytical data of BPA pharmacokinetics support our previous approach for
      optimizing the timing of irradiation and setting the neutron flux large enough
      for tumour eradication but still tolerable for normal skin.

PMID- 10338338
TI  - Naevus-associated melanomas: cause or chance?
AB  - Controversies exist regarding the true incidence and significance of the
      histological association between melanocytic naevi and melanomas. The current
      study was undertaken to determine the incidence of melanocytic naevi
      histologically associated with melanomas, to compare the clinicopathological
      profiles of melanomas associated with a naevus (MN+) and melanomas not associated
      with a naevus (MN-), and to verify the interobserver reliability of classifying
      the naevus remnants as congenital or acquired. We evaluated 131 patients with
      invasive melanoma < or = 4 mm in thickness with a Clark's level < V. Histological
      evidence of an associated melanocytic naevus was found in 27 out of 131 melanoma
      cases (20.6%). MN+ were significantly more frequent among males compared with MN
      (P = 0.002) and were predominantly located on the trunk (P =0.001). No
      significant differences between MN+ and MN- were found in the distribution of
      histotype, Clark's level and thickness. Among MN-, the naevus component showed
      acquired features in 14 cases (51.8%), whereas 12 cases (44.5%) had features of
      small superficial congenital naevi; in one case (3.7%) a confident distinction
      between congenital and acquired naevus could not be made. Overall, there was
      concordance among the three observers in the diagnosis of the type of naevus
      remnants in 81.4% of cases (kappa = 0.78; P<0.0001). We conclude that, although
      the majority of cutaneous melanomas arise de novo, in approximately 20% of cases
      an associated melanocytic naevus is found. Our observation that MN+ and MN- have
      different clinicopathological profiles suggests that, at least for some cases, a
      causal relationship between the two lesions may be present. However, when the
      naevus is histopathologically adjacent to the melanoma, the possibility of a
      collision event cannot be ruled out. Finally, we documented a significant
      concordance among examiners in the diagnosis of the congenital versus acquired
      nature of the associated naevus. This suggests that the histopathological
      criteria generally employed to distinguish between congenital and acquired naevi
      have good reproducibility.

PMID- 10338339
TI  - Cutaneous malignant melanoma in Norway: experiences from the Norwegian Melanoma
      Project.
AB  - The Norwegian Melanoma Project was conducted during 1989-1993 as a co-operative
      study by the dermatological, surgical, oncological and pathological departments
      of the five university hospitals in Norway. We present the results from the
      patients diagnosed and treated in our dermatological department at Ullevaal
      Hospital. During the study period 4582 patients received a clinical evaluation of
      pigmented lesions and 1347 patients were included in follow-up analyses, which
      consisted of a complete anamnestical evaluation and a clinical and pathological
      investigation of excised pigmented lesions. In all, 66 cutaneous malignant
      melanomas, 50 superficial spreading melanomas, seven lentigo maligna melanomas,
      eight nodular melanomas and one acral lentiginous melanoma were diagnosed.
      Correlation of the clinical and anamnestical information demonstrated an
      increased risk of developing malignant melanoma in persons with red hair and skin
      type I/II. When the histological thickness of superficial spreading melanomas
      diagnosed before the start of the project was compared with that of those treated
      during the project, there was a significant decrease in thickness in the project
      period.

PMID- 10338341
TI  - Central pain following spinal and supraspinal lesions.

PMID- 10338340
TI  - Rising melanoma incidence in an Italian community from 1986 to 1997.
AB  - We examined the incidence of primary invasive melanoma in the municipality of
      Reggio Emilia, northern Italy, in the period from 1986 to 1997. We identified 169
      cases, five of which were intraocular. After adjustment for confounders, the risk
      of having a thick melanoma (Breslow > or = 1 mm) did not decrease over time,
      except in older females. The age-standardized incidence of cutaneous melanoma
      during the entire study period was 7.57 in males and 11 in females; from 1986
      1991 to 1992-1997, it rose from 5.04 to 10.04 cases/100,000 person-years in males
      and from 8.96 to 13.09 cases/100,000 person-years in females. In males, the
      increase in incidence was almost entirely confined to subjects aged 30 or more,
      suggesting a possible cohort effect. We noted rising age-standardized incidences
      over time both in males with thin tumours (Breslow < 1 mm) (from 2.05 to 4.38
      cases/100,000 person-years) and thick tumours (from 2.73 to 5.51 cases/100,000
      person-years), while in females the increase was limited to thin melanomas (from
      3.14 to 6.93 cases/100,000 person-years), mainly due to an increase in the older
      age groups (50 69 years and > or =70 years). The increase in thick melanomas
      among males and the expected cohort effects suggests antecedent exposure to
      environmental risk factors.

PMID- 10338342
TI  - Management of respiratory problems unique to high tetraplegia.

PMID- 10338343
TI  - Attentional requirements of walking in spinal cord injured patients compared to
      normal subjects.
AB  - STUDY DESIGN: Recent developments in the field of rehabilitation and the increase
      in the number of incomplete spinal cord injured subjects (SCI) emphasize the
      importance of studying the walking behavior of that population. OBJECTIVES:
      Attentional requirements were measured in spinal cord injured subjects during
      sitting, standing and walking and compared to a healthy group for the same tasks
      and walking at a similar speed. METHODS: Auditory stimuli and verbal responses
      were used to measure the attentional demands in the three experimental tasks.
      RESULTS: For both static tasks, SCI subjects were faster than the normal group.
      During walking at preferred speed, the normal group is significantly faster than
      the SCI subjects are. No difference was found between the two groups when the
      normal group walked at a similar speed. However, SCI subjects need to allocate
      significantly more attentional resource to walking than the normal. SCI patients
      also showed slower reaction times when the stimuli were presented during the
      single-support phase of walking. Kinematics analysis revealed that SCI subjects
      produced longer cycle duration than the normal group even when they walked at a
      match speed. Although variability in the cycle duration and the cycle length were
      comparable between the two groups, when the normal group walked at a slower
      speed, they were significantly more variable than the SCI subjects. CONCLUSION:
      Walking for SCI patients is cognitively challenging. Walking speed seems to be an
      important factor associated with attentional demands.

PMID- 10338344
TI  - Surface electrical stimulation of skeletal muscle after spinal cord injury.
AB  - STUDY DESIGN: Survey. OBJECTIVE: Examine muscle contractile activity during
      electrical stimulation (ES) after spinal cord injury (SCI). SETTING: General
      community of Athens, Georgia, USA. METHODS: Eight clinically complete SCI adults
      (C6 to T12) 4+/-1 (mean+/-SE) years post injury and eight able-bodied adults were
      studied. Surface ES was applied to the left m. quadriceps femoris for three sets
      of 10, 1 s isometric actions (50 Hz trains, 400 micros biphasic pulses, 50 micros
      phase delay, 1 s: 1 s duty cycle) with 90 s of rest between sets. Current was set
      to evoke isometric torque that was (1) sufficient to elicit knee extension with
      2.3 kg attached to the ankle (low level ES), and (2) intended to equal 30% (mid
      level ES) or 60% of maximal voluntary torque of able-bodied adults (high level
      ES, able-bodied only). The absolute and relative cross-sectional area (CSA) of m.
      quadriceps femoris that was stimulated as reflected by contrast shift in magnetic
      resonance images and torque were measured. RESULTS: Six+/-2, 20+/-2 and 38+/-4%
      of the average CSA of m. quadriceps was stimulated during low, mid and high level
      ES, respectively, for able-bodied. Corresponding values for SCI for low and mid
      level ES were greater (61+/-12 and 92+/-7%, P = 0.0002). Torque was related to
      the CSA (cm2) of stimulated muscle (Nm = 3.53 x stimulated CSA+13, r2 = 0.68, P =
      0.0010), thus ES of a greater per cent of m. quadriceps femoris in SCI was
      attributed to their smaller muscle (24+/-3 vs 73+/-5 cm2, P = 0.0001). The
      decline in torque ranged from 9+/-l to 15+/-4% within and over sets for low, mid
      or high level ES in able-bodied. SCI showed greater (P = 0.0001) fatigue (19+/-3
      to 47+/-6%). CONCLUSION: The territory of muscle activation by surface electrical
      stimulation varies among SCI patients. Given sufficient current, a large portion
      of the muscle of interest can be stimulated. The resulting torque is modest,
      however, compared to that attainable in able-bodied individuals due to the small
      size and limited fatigue resistance of skeletal muscle years after spinal cord
      injury.

PMID- 10338345
TI  - The usefulness of the somatosensory evoked potentials of the pudendal nerve in
      diagnosis of probable multiple sclerosis.
AB  - STUDY DESIGN: The aim of the study was to evaluate the sensitivity of pSEP in
      patients affected by probable MS. OBJECTIVES: Bladder dysfunction is the
      presenting symptom in 2% of patients affected by multiple sclerosis (MS) and may
      be present in up to 78% of them. Abnormalities of somatosensory evoked potentials
      of the pudendal nerve (pSEP) have been found by many authors in patients affected
      by clinically defined MS, but little is known of diagnostic reliability of pSEP
      in early stage of MS. METHODS: Sixteen patients, eleven females and five males,
      aged between 18 and 45 years old (mean age 28.9), affected by clinically probable
      MS, were studied. Six of them reported retention or urge incontinence. pSEP with
      P1 (P40) scalp wave was analyzed. All patients also underwent visual evoked
      potentials (VEP), SEP of median and tibial nerves (mSEP, tSEP), brainstem
      acoustic evoked potentials (BAEPs), MRI of the brain and cerebrospinal fluid
      (CSF) evaluation. Urodynamic study with simultaneous measurement of intravesical,
      intraurethral and abdominal pressures with external sphincter electromyography
      was performed. RESULTS: Abnormalities of the evoked potentials were found in all
      patients. Abnormalities of the pSEP were observed in all the symptomatic cases
      and in eight of the remaining ten patients; ten showed no responses from the
      scalp and four showed P1 increased latency. Urodynamic abnormalities were found
      in 12 patients and MRI showed demyelinating lesions in 13 patients and
      oligoclonal bands were found in eight of them. CONCLUSION: pSEP can be worthwhile
      as part of the initial diagnostic evaluation in patients affected by MS. It
      provides information of diagnostic relevance and plays a role in screening
      patients for urodynamic testing, which, however, is more specific for detecting
      urethrovesical dysfunctions and preventing urological complications.

PMID- 10338346
TI  - Histochemical changes in muscle of individuals with spinal cord injury following
      functional electrical stimulated exercise training.
AB  - STUDY DESIGN: Longitudinal training. OBJECTIVES: To determine the effects of
      functional electrical stimulated (FES) leg cycle ergometer training on muscle
      histochemical characteristics in individuals with motor-complete spinal cord
      injury (SCI). SETTING: University of Alberta, Edmonton, Alberta, Canada. METHODS:
      Six individuals with motor-complete SCI (age 31-50 years; 3-25 years post-injury)
      trained using FES leg cycle ergometry for 30 min, 3 days per week for 8 weeks.
      Biopsies of the vastus lateralis muscle were obtained pre- and post-training and
      analyzed for fibre composition, fibre size and capillarization. RESULTS: The
      majority of muscle fibres were classified as type 2 pre- and post-training.
      Average fibre area increased 23% (P<0.05) and capillary number increased 39%
      (P<0.05) with training. As a result of these proportional increases,
      capillarization expressed relative to fibre area was unchanged with training.
      CONCLUSIONS: FES leg cycle ergometer training results in proportional increases
      in fibre area and capillary number in individuals with SCI.

PMID- 10338347
TI  - The effect of Lipo prostaglandin E1 on cauda equina blood flow in patients with
      lumbar spinal canal stenosis: myeloscopic observation.
AB  - STUDY DESIGN: Myeloscopic examination was performed to observe the cauda equina
      in patients with lumbar spinal canal stenosis before and after treatment with
      Lipo prostaglandin E1, a strong peripheral vasodilator. OBJECTIVES: The purpose
      of this study was to clarify the effects of Lipo prostaglandin E1 on blood flow
      in the cauda equina in patients with lumbar spinal canal stenosis. SETTING:
      Japan, Kagoshima METHODS: We performed myeloscopic observations of morphological
      changes in blood vessels running along the cauda equina in 11 patients with
      lumbar spinal canal stenosis before and after treatment with Lipo prostaglandin
      E1. RESULTS: In six of these patients, dilation of the running blood vessels was
      observed immediately after administration. In all of the patients who exhibited a
      dilation of vessels on the surface of the cauda equina, intermittent claudication
      and lower extremity pain and/or numbness lessened immediately after examination.
      However, none of the patients who exhibited no morphological changes in the
      vessels along the cauda equina after administration of Lipo prostaglandin E1
      experienced any improvement of symptoms at the time of examination. CONCLUSION:
      Results of this study suggest that Lipo prostaglandin E1 may enhance blood flow
      in the cauda equina and improve clinical symptoms in some patients with lumbar
      spinal stenosis.

PMID- 10338348
TI  - The Chiari/hydrosyringomyelia complex presenting in adults with
      myelomeningocoele: an indication for early intervention.
AB  - OBJECTIVE: To determine how adults with myelomeningocoele who develop the
      Chiari/hydrosyringomyelia complex present, and to determine if surgical
      intervention influences outcome in these patients. METHODS: A chart review of the
      220 patients who attend a clinic for adults with spina bifida and hydrocephalus
      (CASBAH), and follow-up of the five cases with myelomeningocoele who had surgical
      intervention for associated symptomatic Chiari/hydrosyringomyelia complex.
      RESULTS: Bilateral upper limb weakness and wasting were the commonest presenting
      symptoms (four patients). Sensory disturbance (three patients) was also common,
      dysphagia (one) and ataxia (one) occurring less often. The median time to
      surgical intervention was 36 months. Two patients had a shunting procedure
      performed in isolation, two foramen magnum decompression in addition to a
      shunting procedure and one a foramen magnum decompression. Surgical intervention
      did not completely reverse problems attributed to the Chiari/hydrosyringomyelia
      complex in any of the cases. One patient died post-operatively. Of the four who
      survived one had some improvement in function post-operatively, two remained
      static and one had further mild deterioration. CONCLUSION: All adults with
      myelomeningocoele should be questioned about changes in upper limb function for
      early detection of Chiari/hydrosyringomyelia complex. Our results suggest that
      early intervention is needed if further deterioration is to be avoided, and to
      improve the chances of neurological and functional recovery.

PMID- 10338349
TI  - Inhibition of airway hyperreactivity by oxybutynin chloride in subjects with
      cervical spinal cord injury.
AB  - OBJECTIVE: To further investigate mechanisms of airway hyperreactivity among
      subjects with chronic cervical spinal cord injury (SCI), we assessed airway
      responsiveness to aerosolized methacholine and histamine in subjects receiving
      chronic oxybutynin chloride therapy, and compared the findings with those not
      receiving the agent. METHODS: Twenty-five male subjects with cervical SCI
      participated in this study; 12 were maintained on oral oxybutynin chloride and 13
      served as age-matched controls. Six of the 12 subjects receiving oxybutynin were
      challenged with aerosolized methacholine, and six with histamine; seven of the 13
      control subjects were challenged with aerosolized methacholine and the remaining
      six with histamine. RESULTS: All 13 control subjects and all six
      oxybutynin/histamine subjects exhibited a significant bronchoconstrictor response
      (PC20 < 8 mg/ml), whereas mean PC20 values for the oxybutynin/methacholine group
      were > or =25 mg/ml. CONCLUSION: Our finding that the bronchoconstrictor effects
      of methacholine were blocked by oxybutynin chloride while those of histamine were
      not suggests that oxybutynin acts primarily through anticholinergic pathways
      rather than by causing generalized airway smooth muscle relaxation.

PMID- 10338350
TI  - The effect of tidal volumes on the time to wean persons with high tetraplegia
      from ventilators.
AB  - STUDY DESIGN: Retrospective review of patient medical records comparing the
      outcomes of two groups of individuals with high-level (C3-4) tetraplegia- those
      with high-volume and those with low-volume mechanical ventilation. OBJECTIVES: To
      determine if higher volume mechanical ventilation contributes to faster weaning
      from the ventilator with fewer complications in individuals with ventilator
      dependent high-level tetraplegia. SETTING: A Model Spinal Injury Center, located
      in Colorado, USA, which treats patients referred from throughout the Rocky
      Mountain region as well as other states. METHODS: The medical records of 42
      individuals with ventilator dependent C3-4 tetraplegia, admitted consecutively to
      the Rocky Mountain Regional Spinal Injury System between 1983 and 1993, were
      reviewed. All had required full-time mechanical ventilation upon admission, but
      had successfully weaned by discharge. They were divided into two groups that
      differed with respect to the ventilator tidal volumes used during their treatment
      and weaning: a large volume group (> 20 mls/kg of body weight) and a smaller
      volume group (< 20 mls/kg of body weight). RESULTS: Though the two groups were
      equivalent in neurological level and completeness, muscular function, initial
      spontaneous vital capacity, the weaning method used (T-piece), and final
      spontaneous vital capacity, those in the large tidal volume group successfully
      weaned an average of 21 days faster than the lower tidal volume group (37.6 days
      vs 58.7 days, P=0.02). They also had significantly less atelectasis (P=0.01) than
      the lower tidal volume group. CONCLUSION: This research suggests that the use of
      higher ventilator tidal volumes may speed up the weaning process and lessen
      respiratory complications. Because of the potential for this to decrease the
      length and cost of the rehabilitation programs for persons with high-level
      tetraplegia, further large-scale research is needed to verify these single-center
      findings.

PMID- 10338351
TI  - Development of a short-form Quadriplegia Index of Function scale.
AB  - OBJECTIVE: To develop a short-form version of the Quadriplegia Index of Function
      (QIF) that would be more practical to use than the original version. DESIGN:
      Cross-sectional data collected at 6 months post spinal cord injury. SETTING:
      Regional Spinal Cord Injury Center. PATIENTS: Consecutive sample of 95 patients
      with tetraplegia, non-ambulatory at 6 months, admitted to a regional SCI center
      between December 1987 and August 1992. METHODS: A short-form QIF was developed by
      using regression analysis to determine the best six items that would predict the
      sum of the 37 items selected from seven mobility and self-care categories of the
      original scale. This short-form QIF was evaluated for internal consistency and
      discriminant validity. Validity of the short-form QIF was assessed by correlation
      with motor scores and using analysis of variance by motor levels and motor score
      groupings. RESULTS: Regression analysis identified the following items as best
      predictors of the 37-item QIF score: (1) wash/dry hair, (2) turn supine to side
      in bed, (3) put on lower body clothing, (4) open carton/jar (feeding), (5)
      transfer from bed to chair, and (6) lock wheelchair. These items explained 99% of
      the variance in total scores. Short-form QIF scores (simple sum of the six best
      items) ranged from 0 to 24, with a median score of seven, interquartile range 0
      16. Item response patterns were largely dichotomous. Item-total correlations
      ranged from 0.60 to 0.80; Cronbach's alpha was 0.89. Spearman correlation
      coefficient between upper extremity motor score and short-form QIF was 0.82.
      Analysis of variance indicated that the motor score groupings and motor levels
      accounted for 63 and 54% of the variance in short-form QIF scores, respectively.
      Post hoc analyses indicated that motor levels from C5 to T1 had different mean
      QIF scores, except for C7 versus C8. There may be ceiling effects for individuals
      with low level injuries. CONCLUSION: There is significant redundancy in the QIF.
      Six items, selected from five categories, yield results comparable to the 37-item
      QIF. The short-form QIF must next be assessed for sensitivity to change. A brief
      disability measure would improve data quality and completeness, and may permit
      ongoing collection of observational rather than self-report data.

PMID- 10338352
TI  - Intramedullary cervical tuberculoma.

PMID- 10338353
TI  - Urethral epithelial cells on the surface on hydrophilic catheters after
      intermittent catheterization: cross-over study with two catheters.
AB  - AIM: To count the number of cells on the surface of the two commercial
      hydrophilic catheters, Lofric and EasiCath used for intermittent catheterization
      (IC) after 30-60 s in water without the necessity of catheter jelly.
      PARTICIPANTS: Twenty spinal cord lesioned (SCL) individuals. Six were women, and
      14 men. METHODS: IC was performed on average five times a day (range: 4-10). In a
      randomised cross-over design all catheterizations were performed either with
      Lofric or EasiCath in two consecutive 24 h periods. The catheter used for the
      last catheterization in each 24 h period was fixed, and divided into pieces of 5
      cm. From each of these a piece with the length of 5 mm was taken for surface
      microscopy after staining. The total number of cells was counted without
      knowledge of the type of catheter. According to the fractionator principle an
      unbiased estimate of the total number of cells on the surface of the cateter was
      calculated. RESULTS: There was no difference in the number of urethral epithelia
      cells on the catheters. No granulocytes were identified. The number of cells
      identified on the catheters were from 30 to > 10 000. No differences related to
      age, level of SCL, ASIA impairment scale, months since SCL or type of IC were
      found. There was a trend that women had higher cell counts than men. CONCLUSION:
      No difference was found regarding number of urethral epithelial cells on the
      surface of the catheters after catheterization. This indicates no difference in
      urethral trauma between the two catheters.

PMID- 10338354
TI  - Cervical spinal cord injury in sapho syndrome.
AB  - Cervical spinal fracture and pseudarthrosis are previously described causes of
      spinal cord injury (SCI) in patients with spondylarthropathy. SAPHO (Synovitis
      Acne Pustulosis Hyperostosis Osteitis) syndrome is a recently recognized
      rheumatic condition characterized by hyperostosis and arthro-osteitis of the
      upper anterior chest wall, spinal involvement similar to spondylarthropathies and
      skin manifestations including palmoplantar pustulosis and pustular psoriasis. We
      report the first case of SAPHO syndrome disclosed by SCI related to cervical
      spine ankylosis.

PMID- 10338355
TI  - Double spinal cord injury in a patient with ankylosing spondylitis.
AB  - Ankylosing spondylitis patients are more prone to spinal fractures and these
      fractures commonly result in mobile nonunion. We report a patient with a 30-year
      history of ankylosing spondylitis who sustained double spinal cord injuries
      following minor trauma. The first injury occurred at the lumbar level due to
      pseudoarthrosis of an old fracture, and the second at the thoracic level
      following cardiopulmonary arrest and an episode of hypotension. The possible
      mechanisms of the injuries are discussed and maintaining normal blood pressure in
      these patients is emphasized.

PMID- 10338356
TI  - Autonomic dysreflexia during urodynamics. A Giannantoni et al. Spinal Cord 1998;
      36: 756-760.

PMID- 10338357
TI  - Cellular circadian clocks in the pineal.
AB  - Daily rhythms are a fundamental feature of all living organisms; most are
      synchronized by the 24 hr light/dark (LD) cycle. In most species, these rhythms
      are generated by a circadian system, and free run under constant conditions with
      a period close to 24 hr. To function properly the system needs a pacemaker or
      clock, an entrainment pathway to the clock, and one or more output signals. In
      vertebrates, the pineal hormone melatonin is one of these signals which functions
      as an internal time-keeping molecule. Its production is high at night and low
      during day. Evidence indicates that each melatonin producing cell of the pineal
      constitutes a circadian system per se in non-mammalian vertebrates. In addition
      to the melatonin generating system, they contain the clock as well as the
      photoreceptive unit. This is despite the fact that these cells have been
      profoundly modified from fish to birds. Modifications include a regression of the
      photoreceptive capacities, and of the ability to transmit a nervous message to
      the brain. The ultimate stage of this evolutionary process leads to the
      definitive loss of both the direct photosensitivity and the clock, as observed in
      the pineal of mammals. This review focuses on the functional properties of the
      cellular circadian clocks of non-mammalian vertebrates. How functions the clock?
      How is the photoreceptive unit linked to it and how is the clock linked to its
      output signal? These questions are addressed in light of past and recent data
      obtained in vertebrates, as well as invertebrates and unicellulars.

PMID- 10338358
TI  - I-type lectins in the nervous system.
AB  - The number of animal lectins, basically defined upon their interaction with
      specific carbohydrate structures, is growing considerably during the last few
      years. Among these proteins the recently identified subfamily of I-type lectins
      consists of mainly transmembranous glycoproteins belonging to the immunoglobulin
      superfamily. Most of the I-type lectins participate in cell adhesion events, as
      are the different sialoadhesins recognizing sialylated glycan structures, which
      represent the best characterized subgroup. I-type lectins are abundant in the
      nervous system and have been implicated in a number of morphogenetic processes as
      fundamental as axon growth, myelin formation and growth factor signaling. In the
      present review, we summarize the structural and functional properties of I-type
      lectins expressed in neural tissues with a main focus on the sialoadhesin myelin
      associated glycoprotein, the neural cell adhesion molecule and the fibroblast
      growth factor receptors.

PMID- 10338359
TI  - What functions do reflexes serve during human locomotion?
AB  - Studies on the reflex modulation of vertebrate locomotion have been conducted in
      many different laboratories and with many different preparations: for example,
      lamprey swimming, bird flight, quadrupedal walking in cats and bipedal walking in
      humans. Emerging concepts are that reflexes are task-, phase- and context
      dependent. To function usefully in a behaviour such as locomotion wherein initial
      conditions change from step to step, reflexes would have to show modulation.
      Papers are reviewed in which the study of different reflexes have been conducted
      during different behaviours, with an emphasis on experiments in humans. A
      framework is developed in which the modulation and flexibility of reflexes are
      demonstrated. Alterations in cutaneous, and muscle (stretch and load receptor)
      reflexes between sitting, standing and walking are discussed. Studies in which
      both electrical, mechanical and 'natural' receptor activation have been conducted
      during walking are reviewed. Reflexes are shown to have important regulatory
      functions during human locomotion. A framework for discussion of reflex function
      throughout the step cycle is developed. The function of a given reflex pathway
      changes dynamically throughout the locomotor cycle. While all reflexes act in
      concert to a certain extent, generally cutaneous reflexes act to alter swing limb
      trajectory to avoid stumbling and falling. Stretch reflexes act to stabilize limb
      trajectory and assist force production during stance. Load receptor reflexes are
      shown to have an effect on both stance phase body weight support and step cycle
      timing. After neurotrauma or in disease, reflexes no longer function as during
      normal locomotion, but still have the potential to be clinically exploited in
      gait modification regimens.

PMID- 10338360
TI  - Functional evidence for divergent receptor activation mechanisms of luteotrophic
      and luteolytic events in the human corpus luteum.
AB  - Using a dispersed human luteal cell culture model, progesterone synthesis
      following treatment by incremental doses of human chorionic gonadotrophin (HCG)
      and the stable prostaglandin F2alpha (PGF2alpha) analogue cloprostenol, alone or
      in combination, was related to corpora lutea (CL) mRNA transcript abundance
      coding for the luteinizing hormone (LH)/HCG receptor (LH-R) and PGF2alpha
      receptor (FP) by semi-quantitative reverse transcription-polymerase chain
      reaction (RT-PCR) in 33 otherwise healthy women, scheduled for surgery due to
      benign conditions. CL were grouped according to age, based on the occurrence of a
      preovulatory LH surge where post-LH days 2-5 were designated as early luteal
      phase, days 6-10 as mid-luteal phase and days 11-14 as late luteal phase. When
      exposed to HCG, maximal progesterone output was raised 2.2-fold (P = 0.08, n = 5)
      compared with untreated controls in the early CL, while it increased 5.7- and 4.6
      fold in the mid- and late groups respectively (P<0.05, n = 4 mid-luteal phase, n
      = 3 late luteal phase). This stimulation pattern was found to be concordant with
      the value of mRNA coding for LH-R in all groups (n = 6 early luteal phase, n = 5
      mid-luteal phase, n = 6 late luteal phase). The integrated response to HCG and
      cloprostenol showed a dose-dependent 60% inhibition of progesterone production;
      but only in late luteal phase luteal cells (P<0.01, n = 3). FP mRNA values were
      lowest in early luteal phase, and increased with the age of the CL.
      Interestingly, lowest CL tissue concentrations of the natural FP agonist
      PGF2alpha were found during mid-luteal phase while it increased again 1.6-fold
      during late luteal phase (P<0.05, n = 8 versus mid-luteal phase, n = 6).
      Collectively, these data demonstrate that (i) the extrinsic functional control
      (or rescue of CL in the event of pregnancy) occurs when the sensitivity towards
      LH/HCG is maximal; and (ii) the demise of CL function is mediated via an
      acquisition of sensitivity towards the intrinsic luteolytic signal, PGF2alpha in
      the ageing CL.

PMID- 10338361
TI  - Inhibitory effects of nitric oxide on the expression and activity of aromatase in
      human granulosa cells.
AB  - The aim of the present study was to explore the mechanisms by which nitric oxide
      (NO) may inhibit aromatase activity of human granulosa cells. Ovarian granulosa
      luteal cells, obtained from patients undergoing in-vitro fertilization (IVF) were
      cultured in the presence of NO-related substances. After 24 h of culture,
      aromatase activity of the cells was significantly inhibited by treatment with the
      NO donors, SNAP or NOC12 at > or =10(-4) M in a dose-dependent manner. Treatment
      with NO catabolites or a peroxynitrite-releasing compound, SIN1, had no
      significant influence. Treatment with SNAP at 10(-3) M decreased relative
      aromatase mRNA values by 72% (P<0.05) and intracellular cyclic AMP concentrations
      by 53% (P<0.01). However, treatment with H89, an inhibitor of protein kinase A,
      did not inhibit aromatase activity. Since there were no significant effects of NO
      catabolites or peroxinitrite, the inhibitory action of NO donors on aromatase
      must be related to NO release. The action of NO is, in part, attributable to the
      down-regulation of aromatase gene transcription. Although NO decreased
      intracellular cAMP values, down-regulation of aromatase gene transcription may
      not be mediated by protein kinase A-dependent mechanisms.

PMID- 10338362
TI  - Melatonin, its precursors, and synthesizing enzyme activities in the human ovary.
AB  - The presence of melatonin (N-acetyl-5-methoxytryptamine) and its precursors,
      serotonin (5-hydroxytryptamine) and N-acetylserotonin, was demonstrated in
      extracts of human ovary using reverse-phase high-performance liquid
      chromatography coupled with fluorometric detection. In addition, activities of
      two melatonin-synthesizing enzymes, arylalkylamine N-acetyltransferase (NAT) and
      hydroxyindole-O-methyltransferase (HIOMT), were found in human ovary homogenates.
      The apparent Michaelis constants for the substrates of NAT and HIOMT in the human
      ovary were similar to those reported for the pineal glands of humans and other
      mammals. These findings strongly suggest that the human ovary, like the pineal
      gland, may synthesize melatonin from serotonin by the sequential action of NAT
      and HIOMT.

PMID- 10338363
TI  - Oxidative stress markers in preovulatory follicular fluid in humans.
AB  - Intensified peroxidation in the Graafian follicle may be a factor compromising
      the normal development of the oocyte. The aim of this study was to measure
      concentrations of three oxidative stress markers: conjugated dienes, lipid
      hydroperoxides and thiobarbituric acid-reactive substances, in preovulatory
      follicular fluids and sera of 145 women attending an in-vitro fertilization
      programme, and to correlate these concentrations with pregnancy outcome.
      Determinations were conducted either with or without an antioxidant (10 microM
      butylated hydroxytoluene) and an iron chelate (10 microM deferoxamine mesylate)
      to examine peroxidation associated with the methods used. Concentrations of
      conjugated dienes, lipid hydroperoxides and thiobarbituric acid-reactive
      substances in follicular fluid were all significantly lower than those in serum,
      both in the presence or absence of the antioxidant and iron chelate. These
      concentrations did not correlate with pregnancy outcome. In conclusion, the
      intensity of peroxidation in the Graafian follicle is much lower than that in
      serum. This gradient is the result of the lower rate of initiation of
      peroxidation in the follicular fluid, suggestive of the presence of efficient
      antioxidant defence systems in the direct milieu of the oocyte before ovulation.
      The concentrations of investigated oxidative stress markers in follicular fluid
      do not reflect the reproductive potential of oocytes.

PMID- 10338364
TI  - Fragmentation and death (a.k.a. apoptosis) of ovulated oocytes.
AB  - Accumulating evidence indicates that fragmentation of ovulated murine oocytes,
      resulting spontaneously or following exposure to lethal stimuli such as
      anticancer drugs during in-vitro culture, occurs with several hallmark features
      of apoptosis. However, recent work has failed to demonstrate a correlation
      between DNA cleavage, as assessed by DNA 3'-end-labelling, or of
      phosphatidylserine exposure on the outer leaflet of the plasma membrane, as
      measured by annexin V-staining, with fragmentation of ovulated mouse or human
      oocytes maintained in vitro. Consequently, these authors stated that it is
      'premature to conclude that apoptosis occurs in ovulated oocytes or that such a
      mechanism is involved in the elimination or prevention of fertilization of
      oocytes with cytoplasmic or chromosomal defects'. Here, we have re-assessed DNA
      cleavage in normal and fragmented murine oocytes, have provided new evidence of
      an additional biochemical marker of apoptosis in fragmented oocytes (i.e. caspase
      activity), and have re-evaluated published reports regarding oocyte
      fragmentation, in an effort to clarify these discrepant findings. The results and
      discussions presented herein fully support previous conclusions reached by
      ourselves and others that fragmentation of ovulated oocytes is in fact an
      unequivocal example of apoptotic cell death.

PMID- 10338365
TI  - Synthesis, characterization and preclinical formulation of a dual-action phenyl
      phosphate derivative of bromo-methoxy zidovudine (compound WHI-07) with potent
      anti-HIV and spermicidal activities.
AB  - In a systematic effort to develop a microbicide contraceptive capable of
      preventing transmission of human immunodeficiency virus (HIV), as well as
      providing fertility control, we have previously identified novel phenyl phosphate
      derivatives of zidovudine (ZDV) with 5-halo 6-alkoxy substitutions in the thymine
      ring and halo substitution in the phenyl moiety respectively. Here, we describe
      the synthesis, characterization, and successful preclinical formulation of our
      lead compound, 5-bromo-6-methoxy-3'-azidothymidine-5'-(p-bromophenyl)
      methoxyalaninyl phosphate (WHI-07), which exhibits potent anti-HIV and sperm
      immobilizing activities. The anti-HIV activity of WHI-07 was tested by measuring
      viral p24 antigen production and reverse transcriptase activity as markers of
      viral replication in HIV-1 infected human peripheral blood mononuclear cells
      (PBMC). WHI-07 inhibited replication of HIV in a concentration-dependent fashion
      with nanomolar IC50 values. The effects of WHI-07 on human sperm motion
      kinematics were analysed by computer-assisted sperm analysis (CASA), and its
      effects on sperm membrane integrity were examined by confocal laser scanning
      microscopy (CLSM), and high-resolution low-voltage scanning electron microscopy
      (HR-LVSEM). WHI-07 caused cessation of sperm motility in a concentration- and
      time-dependent fashion. The in-vitro cytotoxicities of WHI-07 and nonoxynol-9 (N
      9) were compared using normal human ectocervical and endocervical epithelial
      cells by the MTT cell viability assay. Unlike N-9, WHI-07 had no effect upon
      sperm plasma and acrosomal membrane integrity. N-9 was cytotoxic to normal human
      ectocervical and endocervical cells at spermicidal doses, whereas WHI-07 was
      selectively spermicidal. The in-vivo vaginal absorption and vaginal toxicity of
      2% gel-microemulsion of WHI-07 was studied in the rabbit model. The sperm
      immobilizing activity of WHI-07 was 18-fold more potent than that of N-9. Over a
      10 day period, there was no irritation or local toxicity to the vaginal epithelia
      or systemic absorption of WHI-07. Therefore, as a potent anti-HIV agent with
      spermicidal activity, and lack of mucosal toxicity, WHI-07 may have the clinical
      potential to become the active ingredient of a vaginal contraceptive for women
      who are at high risk for acquiring HIV by heterosexual vaginal transmission.

PMID- 10338366
TI  - Evidence that a functional fertilin-like ADAM plays a role in human sperm
      oolemmal interactions.
AB  - Fertilin is a protein initially identified in guinea pig spermatozoa; it is the
      prototype of a larger family of conserved, proteins designated as a disintegrin
      and a metalloproteinase (ADAM). These heterodimers which consist of alpha and
      beta subunits, containing metalloproteinase-like and disintegrin-like domains,
      appear to play a role in mammalian fertilization. Peptides derived from the
      disintegrin domains of two ADAMs, fertilin and cyritestin, interfere with gamete
      adhesion and sperm-egg membrane fusion in non-human species. It has been
      suggested that fertilin-beta binds to an oolemmal integrin, and it is proposed
      that the tripeptide FEE (Phe-Glu-Glu) is the integrin recognition sequence in
      human fertilin-beta. We evaluated whether fertilin beta plays a role in human
      fertilization by studying the effects of a linear octapeptide containing the FEE
      sequence, SFEECDLP, and a scrambled octapeptide with the same amino acids,
      SFPCEDEL, on the incorporation of human spermatozoa by human zona-free eggs. The
      effects of G4120, a potent RGD-containing (Arg-Gly-Asp) thioether-bridged cyclic
      peptide which blocks both fibronectin and vitronectin receptors, and the
      relationship between FEE- and RGD-receptor interactions on sperm-egg interactions
      were also studied. The FEE-containing peptide, but not the scrampled peptide,
      inhibited sperm adhesion to oocytes and their penetration, over the range 1-5
      microM. The inhibition induced by SFEECDLP was reversible and occurred only in
      the presence of peptide itself. The G4120 peptide exhibited 10-fold less
      inhibitory effects on sperm adhesion and penetration than did SFEECDLP. When
      combined, SFEECDLP and G4120 exhibited strong inhibition of both adhesion and
      penetration at concentrations that individually had been ineffective, suggesting
      co-operation between the two receptor-ligand interactions during fertilization.
      We propose that a fertilin-like molecule is functionally active on human
      spermatozoa and that its interaction with an oolemmal integrin receptor plays a
      role in fertilization in humans.

PMID- 10338367
TI  - Presence and dynamic redistribution of type I inositol 1,4,5-trisphosphate
      receptors in human oocytes and embryos during in-vitro maturation, fertilization
      and early cleavage divisions.
AB  - We studied the presence and distribution of the intracellular calcium channel
      regulating type I inositol 1,4,5-trisphosphate receptors (IP3R) in human immature
      and mature oocytes, pronuclear zygotes and cleaved embryos using a specific
      antibody. Two approaches were used: (i) fluorescence immunocytochemistry using a
      confocal laser scanning microscope (CLSM) and (ii) Western blotting. With
      confocal microscopy, the receptors were found in the oocytes, fertilized zygotes
      as well as cleaved embryos at all stages studied. The pattern and distribution of
      the receptor staining in the oocytes changed gradually from a diffuse granular
      patchy one at the germinal vesicle (GV) stage to a reticular and predominantly
      peripheral one through the metaphase I and metaphase II (MII) stages. After
      fertilization, the distribution changed gradually to both, peripheral and central
      in the zygotes and early 2-4-cell embryos and predominantly perinuclear in the 6
      8-cell embryos. Furthermore, an overall increase in the staining intensity was
      observed from GV to MII stage oocytes and from zygotes to 6-8-cell embryos. We
      also studied the spatial distribution of the receptor in detail by constructing
      three-dimensional images from the serial optical sections obtained on the CLSM.
      Peculiar peripheral aggregates of receptor clusters were noted in the MII stage
      oocytes, zygotes and some blastomeres from early cleaved embryos. Finally,
      Western blots performed on the extracts of 72 in-vitro matured oocytes and 50
      spare cleavage stage embryos showed positive bands at approximately 260 kDa.
      These findings coincide with and thus possibly represent the dynamic changes
      occurring in the cellular Ca2+ release systems through oocyte maturation,
      fertilization and early embryogenesis. Thus, type I IP3R are likely to play a
      role during these stages of early development in the human.

PMID- 10338368
TI  - Expression of mRNA for vascular endothelial growth factor transmembraneous
      receptors Flt1 and KDR, and the soluble receptor sflt in cycling human
      endometrium.
AB  - The aim of this study was to quantify and localize the mRNA expression of the
      vascular endothelial growth factor (VEGF) receptors Flt1, KDR and sflt, in human
      endometrium throughout the menstrual cycle. Since neoangiogenesis is crucial
      during embryonic implantation, we postulate that endometrial receptivity to VEGF
      may be altered during the luteal phase in order to support implantation. Human
      endometrium was collected and specified as early proliferative (n = 3), mid
      proliferative (n = 4), late proliferative (n = 3), early secretory (n = 2), mid
      secretory (n = 4), and late secretory (n = 4). Competitive reverse transcription
      polymerase chain reaction (RT-PCR) was performed to evaluate the mRNA values
      throughout the menstrual cycle. Additionally, four samples were separated into
      epithelial and stromal-enriched cell fractions and competitive RT-PCR was carried
      out to specify the distribution of the mRNA expression. While mRNA for the
      transmembraneous receptors Flt1 and KDR was shown to be present at almost
      constant values throughout the menstrual cycle, the soluble receptor, sflt, had a
      three-fold higher level of transcription during mid-proliferative and late
      proliferative when compared with early proliferative and the entire secretory
      phase. The expression of Flt1, KDR and sflt mRNA was detected in both isolated
      endometrial epithelial and stromal cell fractions. In conclusion, the down
      regulation of sflt, which functions as a soluble antagonist, during the luteal
      phase may act to sensitize the maternal endothelial receptors to angiogenetic
      stimuli secreted by the implanting embryo.

PMID- 10338369
TI  - The expression, activity and regulation of granulocyte macrophage-colony
      stimulating factor in human endometrial epithelial and stromal cells.
AB  - The expression of granulocyte macrophage-stimulating factor (GM-CSF) and GM-CSF
      receptors in the human endometrium suggests an autocrine/paracrine role for GM
      CSF in this tissue. Using primary cultures of isolated endometrial glandular
      epithelial and stromal cells, the present study examined: (i) the cell specific
      expression of GM-CSF and GM-CSF receptor mRNA and protein; (ii) direct action of
      GM-CSF on the rate of DNA synthesis and cell proliferation; and (iii) regulation
      of GM-CSF expression through its interaction with transforming growth factor
      (TGF)-beta1 in these cells. Quantitative reverse transcription-polymerase chain
      reaction (RT-PCR), enzyme-linked immunosorbent assay and immunocytochemistry
      indicates that glandular epithelial and stromal cells express GM-CSF, GM-CSF
      alpha and GM-CSF beta receptor mRNA and protein. The epithelial cells express a
      significantly higher level of GM-CSF mRNA than stromal cells while both types
      produce low concentrations of protein. At 0.01-100 ng/ml GM-CSF did not have a
      significant effect on the rate of [3H]-thymidine incorporation or proliferation
      of epithelial and stromal cells. However, GM-CSF (1 ng/ ml) up-regulates its own
      protein expression, but does not effect TGF-beta1 mRNA protein expression in
      epithelial and stromal cells, and actually inhibits the cell-associated TGF-beta1
      protein in stromal cells (P<0.05). At 1 ng/ ml TGF-beta1 up-regulates its own
      mRNA and protein expression in epithelial and stromal cells (P<0.05), with no
      significant effect on GM-CSF expression. Co-treatment of the cells with GM-CSF +
      TGF-beta1 resulted in an increased production of GM-CSF protein as well as TGF
      beta1 mRNA and protein expression by epithelial and stromal cells, compared with
      untreated controls (P<0,001). In conclusion, the results suggest that GM-CSF is
      not a mitogenic factor for endometrial glandular epithelial and stromal cells,
      however, in an interactive manner with TGF-beta1 it regulates its own and the
      expression of TGF-beta1.

PMID- 10338370
TI  - Nitric oxide synthase distribution during implantation in the mouse.
AB  - The peri-implantation period is a critical time during murine development.
      Although the importance of nitric oxide has been demonstrated during gestation,
      its role in implantation has not been fully defined. The aim of this study was to
      quantify (by Western blotting) two prominent nitric oxide synthase (NOS)
      isoforms, inducible (iNOS) and endothelial (eNOS) and localize all three forms
      [iNOS, eNOS, and neuronal (nNOS)] by immunohistochemistry in uterine tissue from
      days 4 through 8 of pregnancy. By day 6, iNOS values were significantly elevated
      in implantation sites compared with interimplantation regions and continued to
      rise through day 8. Analysis of eNOS was similar, but implantation site values
      peaked by days 6 and 7. Labelled iNOS cells were within the decidua, around
      myometrial vessels, and within the ectoplacental cone. At implantation, eNOS was
      conspicuous, displaying label adjacent to the embryo in vessels of the primary
      decidual zone. nNOS was localized mainly in the mesometrium and myometrium and
      did not appear to change throughout the peri-implantation period. The increased
      iNOS and eNOS values following implantation in the embryonic site may imply roles
      in tissue remodelling, immunosuppression and vasoregulation. Nitric oxide may
      play an important role in the mechanisms of implantation where these factors are
      keys to successful pregnancy.

PMID- 10338371
TI  - Corticotrophin-releasing hormone and platelet-activating factor induce
      transcription of the type-2 cyclo-oxygenase gene in human fetal membranes.
AB  - Corticotrophin-releasing hormone (CRH) and platelet-activating factor (PAF) are
      considered to be involved in the physiological processes of human labour. Both
      may have dual effects, directly regulating myometrial contractility and fetal
      membrane prostaglandin production. During this study, we investigated the
      mechanisms through which CRH and PAF exert their latter effect. CRH and PAF
      increased prostaglandin production from intact fetal membrane discs, with a
      maximum stimulation after 8 h of culture. Reverse transcription-polymerase chain
      reaction (RT-PCR) analyses using primers specific for type-2 cyclo-oxygenase (COX
      2) showed that CRH and PAF increased the transcription of COX-2 mRNA two-fold
      after 8 h culture. These data indicate that the increased fetal membrane
      prostaglandin production in response to CRH or PAF may involve the induction of
      COX-2.

PMID- 10338372
TI  - Progesterone receptor expression in the human placenta.
AB  - The presence of progesterone receptors (PR) in the human placenta has been
      demonstrated using the reverse transcriptase-polymerase chain reaction technique.
      It was observed that the amount of PR in the human placenta is less during late
      gestation. Electrophoretic mobility shift assays with nuclear extract isolated
      from the first trimester and term revealed three complexes when incubated with
      [32P]dCTP-labelled progesterone response element, and, in competition with
      unlabelled progesterone response element, the formation of all three complexes
      was inhibited. When supershift analysis of these complexes was carried out using
      antibodies which cross-react with both the A and B types of the PR or only with
      the B type receptor, only the A-form of PR was detected in the human placenta.

PMID- 10338373
TI  - Expression and functional analysis of endothelial nitric oxide synthase (eNOS) in
      human placenta.
AB  - We have investigated the expression and localization of endothelium-derived
      nitric oxide synthase (eNOS) and the effect of eNOS on placental human chorionic
      gonadotrophin (HCG) release. eNOS mRNA was found to be expressed in all tissues,
      with its expression significantly (P<0.05) increased across gestation. Compared
      to normal term gestation, placentae from term pregnancies with fetal retardation,
      or maternal diabetes, but not with maternal hypertension, displayed significantly
      more (P<0.05) eNOS mRNA. By immunocytochemistry, we found staining for eNOS in
      both the cyto- and syncytiotrophoblasts of first trimester and a loss of
      cytotrophoblast eNOS staining in term placentae, while syncytiotrophoblasts at
      term were strongly eNOS positive. Additional staining was found in endothelium
      surrounding the vascular tree. HCG was found to colocalize with eNOS in
      trophoblasts, but not in endothelia. When placental explants were perifused,
      exposure to the NOS substrate, the NO donor, I-arginine and trinitroglycerol
      evoked a prompt, albeit transient, increase of HCG release. The NOS inhibitor
      delayed, but did not block arginine-induced HCG release. Thus, eNOS is expressed
      in the human placenta at increasing levels during gestation with further
      increases during some pathological conditions. A role for NO in the acute
      endocrine modulation of the placenta is suggested by the colocalization of eNOS
      with HCG in human trophoblasts and the prompt secretion of HCG in response to
      agents which increase NO concentrations.

PMID- 10338374
TI  - The influence of cigarette smoking on cytokine levels in patients with
      inflammatory bowel disease.
AB  - Anecdotal reports suggest that smoking may be beneficial for patients with
      inflammatory bowel disease (IBD) as nicotine may act through inflammatory
      mediators within the colonic mucosa. Furthermore, there is increasing evidence
      that cytokines play a pathologic role in IBD. Our aim was to determine the
      effects of cigarette smoking on cytokine levels in the colonic mucosa of patients
      with and without IBD. Mucosal biopsies were obtained from 10 patients with
      Crohn's disease (CD), 10 with ulcerative colitis (UC), and 10 healthy controls.
      Five of 10 patients in each of the three groups were smokers and five were
      nonsmokers. Concentrations of interleukin (IL)-1beta, IL-2, IL-6, and IL-8 were
      determined using enzyme-linked immunosorbent assay (ELISA). Cytokine levels of
      smokers were compared with nonsmokers in each group and with controls. Results
      were analyzed using the Mann-Whitney test; significance was set at p<0.05. The
      concentration of IL-8 was significantly higher in healthy controls who smoke
      compared with nonsmokers and significantly reduced in smokers with CD compared
      with nonsmokers with CD. Moreover, concentrations of IL-1beta and IL-8 were
      significantly reduced in smokers with UC compared with nonsmokers with UC.
      Smokers had significantly elevated levels of IL-8 in the colonic mucosa. Smokers
      with IBD had a significant reduction in cytokine levels; specifically, IL-1beta
      and IL-8 for patients with UC and IL-8 for patients with CD. Further studies are
      warranted to determine if this reduction in cytokine levels is histologically and
      clinically significant.

PMID- 10338375
TI  - Time trends in the incidence and disease location of Crohn's disease 1980-1995: a
      prospective analysis in an urban population in Germany.
AB  - To determine the incidence and clinical pattern of Crohn's Disease in a defined
      area in Germany, a prospective, population-based study was carried out from 1980
      to 1984 and again from 1991 to 1995. All patients newly diagnosed with Crohn's
      disease within the respective study period who were resident in the study area
      were included in the study. The results from both study periods were then
      compared to detect time trends. Altogether 288 (156 and 132, respectively)
      incident cases were identified yielding an almost unchanged incidence over the
      years (1980-84: 4.9/10(5); 1991-95 5.2/10(5)). While the peak of incidence is
      still in the 15-24-year-old group, 1 out of 5 incident patients is now age 50
      years and older. Median age at onset of symptoms increased to 30 years (20 years
      in the former period). Time from onset of symptoms was reduced from a median of
      20 months in the 1980s to 5 months. Symptoms did not change significantly,
      although there seems to be less complicated disease recently. Distal migration of
      the inflammation in the intestinal tract was observed with significantly more
      involvement of the sigmoid and rectum in the recent period.

PMID- 10338376
TI  - Intestinal permeability and postheparin plasma diamine oxidase activity in the
      prediction of Crohn's disease relapse.
AB  - A method of detecting presymptomatic relapse of Crohn's disease could allow for
      the selective use of maintenance or intensified medical therapy in those with an
      increased risk of relapse. The aim of this study was to evaluate three potential
      laboratory markers of relapse: intestinal and gastroduodenal permeability and
      plasma diamine oxidase activity. Intestinal permeability (lactulose/mannitol
      test), gastroduodenal permeability (urinary sucrose excretion), and postheparin
      plasma diamine oxidase activity were serially measured in 61 adults with Crohn's
      disease in remission (CDAI <150) for at least 30 days. Subjects were followed
      periodically for clinical relapse (CDAI >150 and increased by at least 100 points
      or the need for steroids or surgery). Fourteen patients (23%) relapsed. A cut-off
      of 0.030 for the lactulose/mannitol ratio was defined. Those with ratios above
      the cutoff had a 7.0 times greater risk of relapse (p<0.001). Three subjects who
      went from a normal ratio to an abnormal ratio relapsed, whereas none of 32
      subjects with a repeatedly normal ratio relapsed. Sucrose excretion and plasma
      diamine oxidase activity did not predict relapse. Serial testing of intestinal
      permeability, but not of gastroduodenal permeability or plasma diamine oxidase
      activity, was useful in predicting relapse in asymptomatic patients.

PMID- 10338377
TI  - The importance of ileocaecal integrity in the arthritic complications of Crohn's
      disease.
AB  - Experiments in animal models have suggested a role for bacterial overgrowth in
      the caecum in the pathogenesis of extracolonic inflammation in IBD. The aim of
      this study was to identify patients with Crohn's disease who have undergone
      ileocaecal resection and to compare the incidence of new arthritic complications
      in these patients with those who have never undergone surgery. Patients who had
      undergone surgery were identified by case note review. The date and nature of
      surgery were noted. The occurrence of new joint complications (Type 1 and 2
      peripheral arthropathy and AS) was noted in patients who had undergone ileocaecal
      resection and in patients who had never undergone surgery. In the surgery group
      the timing in relation to surgery was determined. The groups were compared using
      Kaplan-Meier survival curves and the Logrank test. One hundred sixty-four
      patients who had undergone ileocaecal resection and 221 patients who had never
      undergone surgery for Crohn's disease were studied. The rate of development of
      arthritic complications in patients presurgery and in the nonsurgical group was
      identical. However few arthritic complications occurred postoperatively. There
      were highly significant differences between the nonsurgical group and the
      postsurgical group (p = 0.0001) and between patients presurgery and postsurgery
      (p = 0.0006). New arthritic complications are less common in Crohn's disease
      after resection of the ileocaecal area. This would be consistent with the
      hypothesis that luminal bacteria in this region are important in the pathogenesis
      of these complications.

PMID- 10338378
TI  - Concurrent inflammatory bowel disease and myelodysplastic syndromes.
AB  - Myelodysplastic syndromes (MDS) may be associated with inflammatory bowel disease
      (IBD). We characterized the clinical features and outcomes of patients with
      concurrent IBD and MDS. Using a diagnostic index, we identified all patients with
      both IBD and MDS at our center between 1976 and 1997. We also calculated an
      incidence rate of MDS in IBD using population-based data from Olmsted County,
      Minnesota, between 1950 and 1993. Among approximately 15,000 IBD patients seen,
      25 (approximately 0.17%) were diagnosed with MDS. Fourteen had Crohn's disease
      and 11 had ulcerative colitis. The median age at diagnosis of IBD, particularly
      Crohn's disease, was higher than expected. Median age at diagnosis of MDS was
      typical. All but one ulcerative colitis patient was diagnosed before the
      diagnosis of MDS, while one-half of Crohn's disease patients were diagnosed with
      both ailments simultaneously. Five patients who had been diagnosed with IBD first
      were persistently anemic for at least 1 year prior to diagnosis of MDS. Two
      Crohn's disease patients had received purine analogs in the past. Median follow
      up after MDS diagnosis was 1 year. Seven patients died, including two who
      progressed to acute myeloid leukemia. The incidence rate of MDS in IBD based on
      Olmsted County data was 0 cases per 100,000 person-years (95% CI, 0-55.2). The
      seemingly high frequency of myelodysplastic syndromes in a large referral-based
      group of patients with IBD suggests an association; however, an increased risk of
      MDS was not observed in a small regional cohort of IBD patients. Patients with
      MDS are diagnosed with concurrent IBD at an age older than expected. Simultaneous
      diagnoses were made in one-half of Crohn's disease patients. MDS should be
      considered in the differential diagnosis of anemia in IBD patients.

PMID- 10338379
TI  - Perinatal exposure to measles virus is not associated with the development of
      inflammatory bowel disease.
AB  - It has been suggested that early exposure to measles virus, including perinatal
      exposure via maternal infection, may lead to persistent measles virus infection
      and the subsequent development of inflammatory bowel disease (IBD). We sought to
      examine this association in our patient population. Maternal measles infection
      was identified through the Mayo Clinic diagnostic index, and cases were verified
      by chart review. Cases were included if infection occurred between the second
      trimester and 6 months postpartum. The offspring, or a first degree family
      member, were then interviewed regarding a history of IBD or symptoms which might
      suggest IBD. Seven cases of maternal infection were identified out of 67,912
      pregnancies between 1935 and 1985. One offspring was lost to follow-up through
      adoption, and the remaining six have no evidence of Crohn's disease or ulcerative
      colitis after a mean of 38 years of follow-up (range 12-62 years). Evidence for
      an association between perinatal exposure to measles virus via maternal infection
      and the subsequent development of IBD was not found in our patient population.

PMID- 10338380
TI  - Adapter molecules in T cell receptor signaling.

PMID- 10338382
TI  - Patient compliance and outcomes.

PMID- 10338381
TI  - Antitumor necrosis factor therapy for inflammatory bowel disease: a review of
      agents, pharmacology, clinical results, and safety.
AB  - Tumor necrosis factor-alpha (TNFalpha), a proinflammatory cytokine, plays an
      important role in the pathogenesis of inflammatory bowel disease (IBD).
      Biotechnology agents including a chimeric monoclonal anti-TNF antibody
      (infliximab), a humanized monoclonal anti-TNF antibody (CDP571), and a
      recombinant TNF receptor fusion protein (etanercept) have been used to inhibit
      TNFalpha activity. Controlled trials have demonstrated efficacy for infliximab in
      moderately to severely active Crohn's disease (CD) and fistulizing CD sufficient
      to justify recent U.S. Food and Drug Administration (FDA) approval. Additional
      trials have been completed in rheumatoid arthritis (RA). Similarly, preliminary
      controlled trials have suggested efficacy for CDP571 in active CD and RA. Larger
      controlled trials have demonstrated efficacy for etanercept in RA patients who
      have failed disease modifying antirheumatic drug (DMARD) therapy leading to FDA
      approval for RA. Toxicities observed with anti-TNF therapies have included
      formation of human antichimeric antibodies (HACA) with associated acute and
      delayed hypersensitivity infusion reactions, human antihuman antibodies (HAHAs),
      and formation of autoantibodies with rare instances of drug-induced lupus.
      Several cases of non-Hodgkin's lymphoma also has been described. Future studies
      should evaluate optimal timing and duration of anti-TNF therapy, the utility of
      adjuvant medical treatments during anti-TNF therapy, and evaluate long-term
      safety and efficacy of the various anti-TNF agents.

PMID- 10338383
TI  - The Crohn's Disease Activity Index is a useful tool in clinical practice of
      gastroenterology.

PMID- 10338384
TI  - Is the Crohn's Disease Activity Index outdated? Yes. Is it the gold standard that
      clinicians should use? No.

PMID- 10338385
TI  - Clinical pearls from the 1998 FMAC/CMAC meeting.

PMID- 10338386
TI  - Aberrant mucosal cytokines: the key to the pathogenesis of IBD?

PMID- 10338387
TI  - Will the real 5-aminosalicylic acid please stand up?

PMID- 10338388
TI  - Mesalamine: safe at first look.

PMID- 10338389
TI  - Underlying cholangiocarcinoma in a patient with high-grade dysplasia in the
      pelvic pouch.

PMID- 10338390
TI  - Fatality Analysis Reporting System demonstrates association between trauma system
      initiatives and decreasing death rates.
AB  - BACKGROUND: Trauma registries frequently do not include the deaths of patients
      who do not get to trauma centers (TCs). Thus, complementary methods of monitoring
      the impact of trauma system initiatives should be considered. The objective of
      this study is to use National Highway Safety Traffic Administration's Fatality
      Analysis Reporting System (FARS) and New York State Department of Motor Vehicles
      data and to study the impact of state and regional initiatives over a 10-year
      period in the seven-county Hudson Valley New York (HV) region with one regional
      TC in Westchester County (WC) and to assess its face validity. METHODS: FARS data
      for the United States (US), New York State (NY), the HV region, and WC were
      analyzed from 1987 to 1996. Trauma system initiatives included the following.
      Statewide: (1) TC standards (1989), (2) TC designation and funding (1990), (3)
      State Trauma Advisory Committee (1991), (4) BLS triage protocol and trauma
      registry (1993), and (5) quality improvement site surveys (1994). Regional: (1)
      one regional and two area TCs (1990), (2) helicopter services (1992 and 1994),
      (3) two additional area TCs, and (4) E 911 in all three counties (1995). The
      results were presented to the New York State Trauma Advisory Committee. RESULTS:
      Although nationally motor vehicle crash deaths/100,000 persons have plateaued
      since 1991, trauma system initiatives have been temporally associated with death
      rates continuing to diminish in New York, the HV, and WC. From 1987 to 1996, the
      HV death rate dropped from 17.00 to 9.45, a 44% drop; and the WC rate dropped
      from 12.51 to 7.05, a 44% drop compared with United States death rate drop of 16%
      (p < 0.005). The percentage of seriously injured trauma patients going to the
      trauma centers increased from 53% in 1990 to 72% in 1995 (p < 0.001). The STAC
      felt that the data reflected in part effects of New York State trauma system
      initiatives. CONCLUSION: The drops in motor vehicle crash death rates may reflect
      injury prevention as well as trauma system initiatives. Thus, although FARS and
      New York State Department of Motor Vehicles data cannot establish cause and
      effect relationships, it can monitor the aggregated impact of multiple
      initiatives. Taken together with increasing percentages of seriously injured
      trauma patients going to trauma centers and comparisons with national FARS data,
      the association of decreasing deaths with the implementation of a trauma system
      seems to have face validity.

PMID- 10338391
TI  - Time and motion: a study of trauma surgeons' work at the bedside during the first
      24 hours of blunt trauma care.
AB  - BACKGROUND: The current literature defines the costs of trauma care in terms of
      hospital costs and charges. We sought to define the qualitative and quantitative
      labor costs of trauma care by measuring the various components of bedside care
      provided by surgeons at a community hospital. METHODS: We conducted a prospective
      time-and-motion study during the initial 24 hours of blunt trauma patients' stay
      in the hospital at a Level II trauma center. The services provided by two
      surgeons and one nurse practitioner were examined. All patients were resuscitated
      and seen initially by one of the physicians. Ten service elements (SEs) were
      defined, and total time (TT) spent was the sum of time spent on all service
      elements for that patient. We defined labor cost as TT. Data on Injury Severity
      Score (ISS), alcohol intoxication, length of stay, operative procedures, and
      injury mechanism were also collected. Data are in minutes as means +/- SEM.
      Analysis of linear correlation was by Pearson correlation coefficient, and
      intergroup comparison of means was by two-tailed t test. RESULTS: Fifty-eight
      patients were studied. Mean ISS and length of stay were 11.8 +/- 3 and 4.6 +/- 3
      days, respectively. A mean of seven SEs were provided per patient, and the number
      of SEs provided correlated directly with ISS (r = 0.75, p < 0.01). The mean TT
      spent was 171 +/- 9 minutes, and it correlated directly with ISS (r = 0.64, p <
      0.01). For patients undergoing operative procedures by the trauma surgeon, the
      procedures consumed the greatest portion of TT: 73 +/- 6 minutes (24%). For
      patients not undergoing operative procedures, resuscitation and time spent in the
      radiology department consumed the majority of TT: 30 minutes for each SE (40% of
      TT). Serum ethanol was greater than 0.10 in 33 of 58 patients (57%), and these
      patients required significantly more TT (135 vs. 193 minutes; p < 0.05) than
      nonintoxicated patients. CONCLUSION: A significant labor cost (TT) was required
      for the care of blunt trauma patients, and the majority of that cost was not
      spent in the operating room but involved the performance of cognitive services.
      Significant correlation existed between ISS and labor cost. The presence of
      ethanol intoxication significantly increased this commitment. These data might be
      of use in creating provider reimbursement schemes for trauma care. This
      methodology may have applications in the design of hospital systems for trauma
      care.

PMID- 10338392
TI  - Outcome after major trauma: 12-month and 18-month follow-up results from the
      Trauma Recovery Project.
AB  - BACKGROUND: The importance of outcome after major injury has continued to gain
      attention in light of the ongoing development of sophisticated trauma care
      systems in the United States. The Trauma Recovery Project (TRP) is a large
      prospective epidemiologic study designed to examine multiple outcomes after major
      trauma in adults aged 18 years and older, including quality of life, functional
      outcome, and psychologic sequelae such as depression and posttraumatic stress
      disorder (PTSD). Patient outcomes were assessed at discharge and at 6, 12, and 18
      months after discharge. The specific objectives of the present report are to
      describe functional outcomes at the 12-month and 18-month follow-ups in the TRP
      population and to examine the association of putative risk factors with
      functional outcome. METHODS: Between December 1, 1993, and September 1, 1996,
      1,048 eligible trauma patients triaged to four participating trauma center
      hospitals in the San Diego Regionalized Trauma System were enrolled in the TRP
      study. The admission criteria for patients were as follows: (1) age 18 years or
      older; (2) Glasgow Coma Scale score on admission of 12 or greater; and (3) length
      of stay greater than 24 hours. Functional outcome after trauma was measured
      before and after injury using the Quality of Well-Being (QWB) Scale, an index
      sensitive to the well end of the functioning continuum (0 = death, 1.000 =
      optimum functioning). Follow-up at 12 months after discharge was completed for
      806 patients (79%), and follow-up at 18 months was completed for 780 patients
      (74%). Follow-up contact at any of the study time points (6, 12, or 18 months)
      was achieved for 926 (88%) patients. RESULTS: The mean age was 36 +/- 14.8 years,
      and 70% of the patients were male; 52% were white, 30% were Hispanic, and 18%
      were black or other. Less than 40% of study participants were married or living
      together. The mean Injury Severity Score was 13 +/- 8.5, with 85% blunt injuries
      and a mean length of stay of 7 +/- 9.2 days. QWB scores before injury reflected
      the norm for a healthy adult population (mean, 0.810 +/- 0.171). At the 12-month
      follow-up, there were very high levels of functional limitation (QWB mean score,
      0.670 +/- 0.137). Only 18% of patients followed at 12 months had scores above
      0.800, the norm for a healthy population. There was no improvement in functional
      limitation at the 18-month follow-up (QWB mean score, 0.678 +/- 0.130). The
      majority of patients (80%) at the 18-month follow-up continued to have QWB scores
      below the healthy norm of 0.800. Postinjury depression, PTSD, serious extremity
      injury, and intensive care unit days were significant independent predictors of
      12-month and 18-month QWB outcome. CONCLUSION: This study demonstrates a
      prolonged and profound level of functional limitation after major trauma at 12
      month and 18-month follow-up. This is the first report of long-term outcome based
      on the QWB Scale, a standardized quality-of-life measure, and provides new and
      provocative evidence that the magnitude of dysfunction after major injury has
      been underestimated. Postinjury depression, PTSD, serious extremity injury, and
      intensive care unit days are significantly associated with 12-month and 18-month
      QWB outcome.

PMID- 10338393
TI  - Priming, second-hit priming, and apoptosis in leukocytes from trauma patients.
AB  - BACKGROUND: Polymorphonuclear leukocytes (PMNL) play important roles in both host
      defenses and systemic inflammatory responses after insults. The objectives of
      this study are to examine the serial changes in PMNL priming and apoptosis in
      severely injured patients and to evaluate the impact of second hits on primed
      PMNL function and systemic vascular endothelial damage. METHODS: Twenty-four
      severely injured patients (mean Injury Severity Score, 31.1 +/- 9.7) were
      included. Infections were seen as second hits after trauma in seven patients.
      Oxidative activity, phagocytosis, and apoptosis of PMNL from serial blood samples
      were measured by flow cytometry. Oxidative activity with no stimulus and with
      formylmethionyl-leucyl-phenylalanine (FMLP) were analyzed as the priming index
      and FMLP response, respectively. Interleukin (IL)-6, IL-10, PMNL elastase, and
      thrombomodulin concentrations in blood were also measured before and after the
      second hit. RESULTS: The PMNL priming index was elevated from days 2 to 13,
      especially days 2 to 5 after injury. FMLP response was enhanced from days 2 to 21
      after injury. Apoptosis of PMNL was inhibited for as long as 3 weeks after
      injury. Infections as second hits after trauma enhanced both the priming index
      and the FMLP response within 24 hours after diagnosis of infection and increased
      serum IL-6 concentrations. However, serum thrombomodulin levels were not affected
      by second hits. All patients with second hits survived. CONCLUSION: Severe trauma
      stimulated acute-phase priming in PMNL and inhibited apoptosis. Infections after
      trauma induced second-hit priming in PMNL, but the unchanged serum levels of
      thrombomodulin suggest that priming per se may not cause systemic vascular
      endothelial damage.

PMID- 10338394
TI  - Granulocyte colony-stimulating factor inhibits neutrophil apoptosis at the local
      site after severe head and thoracic injury.
AB  - BACKGROUND: Tissue injury from mechanical trauma often leads to secondary organ
      failure. Local accumulation of neutrophils and excessive release of toxic
      metabolites through inhibition of neutrophil apoptosis may be responsible for
      capillary leakage and irreversible damage of resident cells of injured tissues.
      METHODS: The purpose of this study was to examine the presence of apoptosis
      inhibiting factors at the local site of tissue injury. Cerebrospinal fluid (CSF)
      from patients with severe head injury (n = 10; Abbreviated Injury Scale score,
      4.5 +/- 0.2 points) and bronchoalveolar lavage fluid (BALF) from patients with
      serious chest trauma (n = 10; Abbreviated Injury Scale score, 4.1 +/- 0.1 points)
      were collected on days 1 and 3 after injury and compared with CSF (n = 5) and
      BALF (n = 16) obtained from patients undergoing elective orthopedic surgery.
      Neutrophils from healthy humans were incubated with 10% of CSF or BALF for 16
      hours. Neutrophil apoptosis was determined by flow cytometric analysis of
      propidium iodide nuclear staining, terminal deoxynucleotidyl transferase-mediated
      deoxyuridine triphosphate nick-end labeling, and May-Grunwald-Giemsa staining.
      Levels of granulocyte colony-stimulating factor (G-CSF) in CSF and BALF were
      measured with enzyme-linked immunosorbent assay. RESULTS: CSF and BALF from
      injured patients significantly inhibited spontaneous neutrophil apoptosis of
      healthy humans compared with control samples, whereas respiratory burst activity
      was enhanced (p < 0.05). Moreover, CSF and BALF from injured patients contained
      increased (p < 0.05) amounts of G-CSF. Neutralization of G-CSF in CSF and BALF
      from injured patients using monoclonal anti-G-CSF antibody markedly (p < 0.05)
      reduced the apoptosis-inhibiting effect of those body fluids and decreased the
      respiratory burst. CONCLUSION: In patients with severe head or chest injury, G
      CSF acts locally as a strong inhibitor of spontaneous neutrophil apoptosis, which
      may cause an increased destructive potential of neutrophils present in injured
      tissues.

PMID- 10338395
TI  - Hypertonicity prevents lipopolysaccharide-stimulated CD11b/CD18 expression in
      human neutrophils in vitro: role for p38 inhibition.
AB  - BACKGROUND: Neutrophil sequestration in the lungs plays an important role in the
      development of acute respiratory distress syndrome. We previously reported that
      hypertonic saline resuscitation attenuated lung injury after hemorrhagic shock
      and lipopolysaccharide (LPS) by abolishing neutrophil CD11b up-regulation. We
      investigated the mechanism underlying this effect. METHODS: Human neutrophils
      were exposed to LPS in the presence or absence of hypertonicity or SB203580 (p38
      inhibitor). CD11b and CD14 were studied by immunofluorescence and p38
      phosphorylation by immunoblotting. RESULTS: Hypertonicity had no effect on CD11b
      or CD14, caused a weak p38 phosphorylation, and completely prevented the LPS
      induced p38 phosphorylation and CD11b up-regulation. p38 inhibition also
      abrogated CD11b up-regulation by LPS. CONCLUSION: MAPKp38 is important in CD11b
      regulation by LPS. The inhibitory effect of hypertonicity on the LPS-mediated
      effect may contribute to its protective anti-inflammatory effect observed in
      vivo. Transient hypertonicity might minimize organ injury in diseases
      characterized by neutrophil-mediated damage such as ARDS.

PMID- 10338396
TI  - Pulmonary capillary sieving of hetastarch is not altered by LPS-induced sepsis.
AB  - BACKGROUND: Gram-negative lipopolysaccharide (LPS) has been demonstrated to
      increase pulmonary capillary permeability as judged by the increased flow of
      protein-rich lymph from the lungs of sheep infused with LPS. This finding
      suggests that LPS-injured pulmonary capillaries might be less restrictive than
      uninjured capillaries to the filtration of large hetastarch molecules. Hetastarch
      has a broad molecular mass spectrum (35-1,500 kilodaltons (kDa)), and one way to
      test the restrictiveness of pulmonary capillaries is to measure the size of the
      largest hetastarch molecules that cross the microvascular barrier and enter the
      lymph. To evaluate the effects of LPS, we compared hetastarch molecular
      distributions in the lung lymph of normal and LPS-injured sheep. METHODS: Adult
      sheep (38.2 +/- 0.8 kg) were surgically prepared for the collection of lung
      lymph, with study initiation after a 5- to 7-day recovery period. Hetastarch (6%)
      was infused (10 mL/kg) 24 hours before study to allow for stabilization of the
      hetastarch molecular distribution. On the day of study, LPS (Escherichia coli
      lipopolysaccharide, 2 microg/kg; n = 6) was infused, and plasma and lymph samples
      were collected for 12 hours. An additional group of animals not infused with LPS
      (n = 6) served as controls. Hetastarch molecular distributions in plasma and
      lymph were measured by using high performance size exclusion chromatography.
      RESULTS: In control sheep, the largest hetastarch molecules in lymph averaged 861
      +/- 18 kDa (mean +/- SEM) (plasma, 1,065 +/- 18 kDa). In LPS-treated sheep, the
      largest hetastarch molecules in lymph averaged 845 +/- 19 kDa (not significant
      vs. normal) (plasma, 1,025 +/- 14 kDa). Hetastarch concentrations in plasma and
      lung lymph of normal sheep, respectively, were 0.61 +/- 0.05% and 0.34 +/- 0.07%.
      In LPS-treated sheep, hetastarch concentrations in plasma and lymph were 0.56 +/-
      0.08 (not significant vs. normal) and 0.29 +/- 0.07, respectively (p < or =
      0.05). Lymph concentrations were lower after LPS because of increased lymph flows
      (19.9 +/- 5.4 mL/30 min, compared with 3.6 +/- 0.8 mL/30 min in normal sheep).
      CONCLUSION: Our results suggest that LPS does not alter the diameter of the
      largest pores perforating the walls of pulmonary capillaries. Rather, the number
      of these pores in the capillary wall appears to be increased. This increase would
      explain why lymph flows rise after LPS with little change in the lymph protein
      concentration. Our results are also consistent with a filtration model in which
      capillaries are assumed to be perforated by small pores (protein reflection
      coefficient = 1) as well as large pores (protein reflection coefficient = 0).

PMID- 10338397
TI  - Impact on process of trauma care delivery 1 year after the introduction of a
      trauma program in a provincial trauma center.
AB  - BACKGROUND: Trauma care delivery in Canada, even in major trauma centers, usually
      devolves to the most involved service. For patients with multisystem injuries,
      this is not always optimal and aspects of care outside the domain of the primary
      service are apt to be overlooked. Trauma care is necessarily multidisciplinary,
      and to be optimal, appropriate integration of the care process and prioritization
      are required. The purpose of this study was to examine the impact on care in a
      busy provincial trauma center, after the introduction of a trauma program with a
      clinical trauma service, revised trauma protocols, and a dedicated trauma unit.
      METHODS: Data were collected prospectively before and during the introduction of
      the program. Aspects of care studied included trauma patient volume, compliance
      with trauma team activation and trauma consultation protocols, delays to the
      operating room for hypotension or open fractures, delays in disposition to the
      unit, average length of stay, and mortality based on Trauma and Injury Severity
      Score analysis. Data are presented summarized by quarter, one before and four
      after the introduction of the program. Variance tracking was introduced before
      the last quarter. Differences between preprogram and postprogram performance were
      assessed by using analysis of variance (asterisks indicates p < 0.05 compared
      with preprogram performance). RESULTS: Trauma unit average length of stay
      decreased from 10.15 days initially to 9.66 and 9.14* days at 6 and 12 months,
      reducing costs. Improved survival was demonstrated by Trauma and Injury Severity
      Score methodology with z score achieving significance compared with Major Trauma
      Outcome Study outcomes after program implementation. CONCLUSION: Trauma care
      improvement can be achieved by a multidisciplinary team focusing on the process
      of care, developing a dedicated trauma service to manage the more seriously
      injured patients, collecting them onto a single unit, and initiating program
      management.

PMID- 10338398
TI  - Formal swallowing evaluation and therapy after traumatic brain injury improves
      dysphagia outcomes.
AB  - BACKGROUND: The incidence of swallowing dysfunction after brain injury is
      unknown. The efficacy of dysphagia therapy is also unknown. We reviewed our
      experience to define the incidence of swallowing dysfunction and efficacy of
      therapeutic intervention. METHODS: Patients with brain injury sustained between
      January of 1996 and December of 1997 were reviewed. All were screened with trials
      of oral intake. Abnormal findings were confirmed with a videofluoroscopic swallow
      study. Standard therapies included diet, posture, and behavior modifications.
      RESULTS: A total of 47 patients were evaluated. Bedside evaluations were normal
      in 14 patients, 2 patients had overt aspiration and underwent gastrostomy, and 31
      patients were referred for a videofluoroscopic swallow study (66%). The
      videofluoroscopic swallow study was abnormal in 22 of 31 patients (71%). Of
      these, 4 additional patients required gastrostomy, 13 patients had laryngeal
      penetration or minor aspiration responsive to dysphagia therapy and were fed.
      Five other patients had silent aspiration and were fed by means of nasogastric
      tube; these five patients responded to dysphagia therapy and were able to resume
      oral intake. CONCLUSION: Dysphagia is common after severe head injury. With
      formal swallowing service intervention, aspiration is avoided. Therapeutic
      interventions can be used to restore oral intake.

PMID- 10338399
TI  - Prostanoids: early mediators in the secondary injury that develops after
      unilateral pulmonary contusion.
AB  - BACKGROUND: We have previously shown a sequence of events after unilateral
      pulmonary contusion that suggests the release of blood-borne prostanoid mediators
      and that culminates in refractory bilateral pulmonary failure. PURPOSE: To
      determine the role of platelet-derived thromboxane and endothelial-derived
      prostacyclin in the primary and secondary injury after unilateral blunt chest
      trauma, and to determine whether pretreatment with the cyclooxygenase inhibitor
      indomethacin alters the progression of secondary injury. METHODS: Anesthetized,
      ventilated (FIO2 = 0.50) pigs received a unilateral, blunt injury to the right
      thorax (n = 20) or sham injury (n = 5) and were monitored for 24 hours. Either
      indomethacin (5 mg/kg i.v.; n = 10) or its saline vehicle (n = 10) were
      administered 15 minutes before injury. Serial bronchoalveolar lavages of each
      lung were analyzed for protein and neutrophil (polymorphonuclear neutrophil
      (PMN)) content. RESULTS: Contusion caused profound hypoxemia; PaO2 partially
      recovered within 1 hour of injury to 50% of baseline. Thereafter, worsening
      hypoxemia required positive end-expiratory pressure. With indomethacin compared
      with vehicle, PaO2 was higher at any given level of positive end-expiratory
      pressure (p < 0.05). There was an early increase in serial bronchoalveolar lavage
      protein on the injured side (peak at 2 hours), with a delayed pulmonary capillary
      leak on the contralateral side (peak at 6 hours), which correlated with
      increasing PMN infiltration; this was reduced by 40 to 60% with indomethacin (p <
      0.05). Thromboxane peaked within 1 hour after contusion at 800% baseline, then
      fell off rapidly. This peak preceded the maximal increase in permeability and was
      completely blocked by indomethacin. Prostacyclin slowly rose to 300% baseline by
      3 hours and remained elevated; this change was blocked by indomethacin for 18
      hours. CONCLUSIONS: Contusion of the right thorax induced a delayed pulmonary
      capillary leak in the left lung, which reflects a progressive secondary
      inflammatory response. Elevations in thromboxane and prostacyclin preceded
      progressive bilateral PMN infiltration. Indomethacin blocked thromboxane and
      prostacyclin and attenuated, but did not prevent, the progression to pulmonary
      failure. Overall, these data suggest that prostanoids are released soon after
      unilateral contusion and initiate an inflammatory response in both lungs that is
      sustained by PMN infiltration.

PMID- 10338400
TI  - Pulmonary contusions: quantifying the lesions on chest X-ray films and the
      factors affecting prognosis.
AB  - OBJECTIVES: To quantify pulmonary contusions on chest x-ray film and to evaluate
      factors correlating with the size of the pulmonary contusions, changes in the
      first 24 hours, the need for ventilatory assistance, and death. METHODS: The
      medical records and chest x-ray films of 103 patients with blunt chest trauma
      diagnosed as having a pulmonary contusion were reviewed. RESULTS: A pulmonary
      contusion score was developed (3 = one third of a lung; 9 = an entire lung). In
      the emergency department, pulmonary contusions were not present in 11, were mild
      (one ninth to two ninths of a lung) in 15 patients, moderate-severe (three ninths
      to nine ninths of a lung) in 53 patients, and very severe in 24 patients. Within
      24 hours, the pulmonary contusion score increased in 26 patients by 7.9 +/- 5.5
      (SD). The 26 patients with an increasing contusion had a higher mortality rate
      (38% vs. 17%) (p = 0.044) and tended to need ventilatory assistance more
      frequently (73% vs. 49%) (p = 0.061). The 35 patients with very severe pulmonary
      contusions (pulmonary contusion score = 10-18) had the lowest PaO2:FIO2 ratio at
      24 hours (175 +/- 103 mm Hg), longest hospital length of stay (28 +/- 35 days),
      and the highest Injury Severity Score (26 +/- 9). The factors correlating highest
      with a need for ventilatory support (57/103) were the 24 hour or initial
      PaO2/FIO2 ratio < 300, an Injury Severity Score > or = 24, Revised Trauma Score <
      6.4, Glasgow Coma Scale score < or = 12, and shock or need for blood in the first
      24 hours (p < 0.001). Death correlated highly with a need for ventilatory
      assistance, Injury Severity Score > or = 26, Revised Trauma Score < or = 6.3, and
      Glasgow Coma Scale score < or = 11 (p < 0.001). CONCLUSION: Quantifying and
      noting changes in the extent of the pulmonary contusions and PaO2/FIO2 ratio
      during the first 24 hours may be of value in determining the need for ventilatory
      assistance and predicting outcome.

PMID- 10338401
TI  - Early fracture fixation may be "just fine" after head injury: no difference in
      central nervous system outcomes.
AB  - BACKGROUND: Recent reports suggest that early fracture fixation worsens central
      nervous system (CNS) outcomes. We compared discharge Glasgow Coma Scale (GCS)
      scores, CNS complications, and mortality of severely injured adults with head
      injuries and pelvic/lower extremity fractures treated with early versus delayed
      fixation. METHODS: Using trauma registry data, records meeting preselected
      inclusion criteria from the years 1991 to 1995 were examined. We identified 171
      patients aged 14 to 65 years (mean age, 32.7 years) with head injuries and
      fractures who underwent early fixation (< or = 24 hours after admission) (n =
      147) versus delayed fixation (> 24 hours after admission) (n = 24). RESULTS:
      Patients were severely injured, with a mean admission GCS score of 9.1, Revised
      Trauma Score of 6.2, Injury Severity Score of 38, median intensive care unit
      length of stay of 16.5 days, and hospital length of stay of 23 days. No
      differences between groups were found by age, admission GCS score, Injury
      Severity Score, Revised Trauma Score, intensive care unit length of stay,
      hospital length of stay, shock, vasopressors, major nonorthopedic operative
      procedures, total intravenous fluids or blood products, or mortality rates. In
      survivors, no differences in discharge GCS scores or CNS complications were
      found. CONCLUSION: We found no evidence to suggest that early fracture fixation
      negatively influences CNS outcomes or mortality.

PMID- 10338402
TI  - Evaluation of a diagnostic protocol using screening diagnostic peritoneal lavage
      with selective use of abdominal computed tomography in blunt abdominal trauma.
AB  - BACKGROUND: The optimal method of evaluating blunt abdominal trauma remains
      controversial. A combination of a sensitive screening test, diagnostic peritoneal
      lavage (DPL), and a specific test, abdominal computed tomography (CT), may be a
      safe, efficient approach to adult blunt abdominal trauma. METHODS: A prospective
      cohort study compared a protocol using screening DPL followed by selective use of
      abdominal CT (DPL/abdominal CT) and the use of abdominal CT alone in the
      evaluation of hemodynamically stable, adult blunt trauma patients. RESULTS: One
      hundred sixty-seven adult blunt trauma patients were initially evaluated by DPL
      (n = 71) or abdominal CT (n = 96). Emergency department evaluation required less
      time in the DPL/abdominal CT group than in the abdominal CT alone group (41
      minutes vs. 2.5 hours; p < 0.001). There were no missed injuries in the
      DPL/abdominal CT group versus seven missed injuries in the abdominal CT group (p
      = 0.02). There were no nontherapeutic celiotomies in either study group.
      CONCLUSION: Screening DPL, followed by abdominal CT if positive, is a safe,
      efficient method of evaluating adult blunt abdominal trauma that reduces the time
      required to evaluate the abdomen, does not result in increased nontherapeutic
      celiotomies, results in fewer missed injuries, and reduces the overall use of
      abdominal CT.

PMID- 10338403
TI  - Treatment of fractures of femur and tibia with the telescopic locking nail:
      design of a new implant and the first clinical results.
AB  - BACKGROUND: This study was carried out to evaluate the first clinical experiences
      with the telescopic locking nail (TLN). The TLN is a newly developed universal
      locking nail system for both femur and tibia that permits cyclic dynamic loading
      at the fracture site while weightbearing. The nail can also be used for static
      interlocking or for compression of the fracture elements. The nail is strong
      enough to permit immediate weightbearing, and the diameter of 9 mm allows
      unreamed introduction in many cases. MATERIALS: Seventy-one consecutive patients
      were treated with the TLN, 24 patients with femoral and 47 patients with tibial
      fracture or nonunion. RESULTS: Functional outcome, complication rate, and union
      rate were comparable to other interlocking nail systems. CONCLUSION: Its
      distinctive biomechanical properties and its universal application in both femur
      and tibia make the TLN a sophisticated, yet in practice simple, new asset in the
      practice of intramedullary nailing.

PMID- 10338404
TI  - Pulmonary gas exchange during intramedullary fixation of femoral shaft fractures.
AB  - BACKGROUND: This study was undertaken to determine if the alveolar dead space
      fraction (Vd/Vt) or the alveolar-arterial oxygen gradient (A-a DO2) increased
      during intramedullary fixation of femoral shaft fractures. METHODS: Fifty
      hemodynamically stable patients with femur fractures were prospectively enrolled.
      Three serial measurements of Vd/Vt and A-a DO2 were obtained immediately before
      femoral nailing (Pre), 30 minutes after nailing (+30), and 120 minutes after
      nailing (+120). Vd/Vt was determined by simultaneously measuring PaCO2 and the
      steady-state end-tidal CO2 (PetCO2), where Vd/Vt = (1 - PetCO2/PaCO2). RESULTS:
      Vd/Vt before nailing was 0.09 +/- 0.09 (mean +/- SD); at +30 and +120, Vd/Vt was
      0.10 +/- 0.06 and 0.08 +/- 0.07, respectively (p > 0.2; paired t test, both time
      points). A-a DO2 before nailing was 84 +/- 85 mm Hg, and it did not change
      significantly at +30 (89 +/- 69 mm Hg; p = 0.51 vs. Pre; paired t-test) or at
      +120 (51 +/- 45 mm Hg). No difference in data was found with analysis by fracture
      classification or number of reamer passes. Vd/Vt and A-a DO2, however, were both
      significantly increased in patients with lung contusion (n = 6) before nailing,
      but neither measurement increased after nailing. One patient developed fat
      embolism (Vd/Vt of 0.35 at Pre and 0.31 at +120), and another patient experienced
      postoperative pulmonary thromboembolism (Vd/Vt increased from 0.06 at Pre to 0.17
      at +120). CONCLUSION: The process of femoral nailing does not cause enough
      pulmonary embolization to alter pulmonary gas exchange as measured by Vd/Vt and A
      a DO2. If Vd/Vt is increased preoperatively, the likelihood of subsequent
      pulmonary dysfunction secondary to either preoperative lung injury or fat
      embolism is increased.

PMID- 10338405
TI  - Selective type III phosphodiesterase inhibition prevents elevated compartment
      pressure after ischemia/reperfusion injury.
AB  - BACKGROUND: A new synthetic cyclic adenosine monophosphate phosphodiesterase
      inhibitor, cilostazol, has been shown to inhibit platelet aggregation and act
      synergistically with endogenous prostaglandin I2 to enhance smooth-muscle cell
      vasodilitation. The effect of cilostazol in ischemia/reperfusion injury-induced
      compartment syndrome was investigated. METHODS: Sixteen rabbits underwent femoral
      artery occlusion after ligation of branches from the terminal aorta to the
      femoral artery. After 7 hours of ischemia, reperfusion was established with
      heparinized polyethylene shunts. Experimental animals (n = 8) received cilostazol
      (3.0 mg/kg) and control animals (n = 8) received normal saline as an intravenous
      infusion 10 minutes before shunt placement. During reperfusion, anterior
      compartment pressure was continuously monitored in the left lower extremity, and
      femoral artery blood flow was measured by laser Doppler fluorometry. To
      quantitate skeletal muscle oxidative metabolism and viability,
      triphenyltetrazolium chloride (TTC) reduction (micrograms of TTC per milligram of
      protein) of tibialis anterior muscle from the right lower extremity was measured
      at femoral artery occlusion, 7 hours of ischemia, and 2 hours of reperfusion. To
      assess tissue edema, dry/wet weight ratios were also determined at these
      intervals. Data were expressed as means +/- SE. Comparisons within groups were
      performed by analysis of variance, and comparisons between groups with two-tailed
      unpaired t tests. RESULTS: At 2 hours of reperfusion, the difference between
      controls and cilostazol-treated animals was extremely significant (p = 0.0008).
      Preischemia and 2-hour reperfusion TTC and dry/wet weight ratios were not
      significantly different within or between experimental groups, nor was femoral
      artery blood flow during reperfusion. CONCLUSION: Cilostazol inhibits the
      increase in compartment pressure central to the development of the compartment
      syndrome. The mechanism appears to be independent of altered tissue permeability
      or oxidative metabolism.

PMID- 10338406
TI  - Adrenergic antagonists reduce lactic acidosis in response to hemorrhagic shock.
AB  - BACKGROUND: Hemorrhagic shock is associated with lactic acidosis and increased
      plasma catecholamines. Skeletal muscle increases lactate production under aerobic
      conditions in response to epinephrine, and this effect is blocked by ouabain, a
      specific inhibitor of the cell membrane Na+/K+ pump. In this study, we tested
      whether adrenergic antagonists can block lactate production during shock.
      METHODS: Male Sprague-Dawley rats (250-300 g) were pretreated with
      phenoxybenzamine (2 mg/kg, i.v.) and/or propranolol (0.5 mg/kg, i.p.) before
      hemorrhaging to a mean arterial pressure of 40 mm Hg for 1 hour. Skeletal muscle
      perfusion, plasma lactate, and catecholamines were measured at baseline, 55
      minutes after shock, and 1 hour after resuscitation. In a separate study,
      extensor digitorum longus and soleus muscles were incubated in Krebs buffer
      (95:5, O2:CO2) with 10 mmol/L glucose. One of each muscle pair was incubated in
      the absence or presence of epinephrine and of one or both adrenergic blockers.
      Medium lactate concentration was then measured. RESULTS: The combination of alpha
      and beta-blockers significantly reduced plasma lactate levels during hemorrhage.
      In contrast, beta-blockade alone was associated with a significant increase in
      plasma lactate and epinephrine. None of the blockers altered tissue perfusion.
      Epinephrine stimulation of muscle lactate production in vitro was completely
      blocked by propranolol. CONCLUSION: Epinephrine release in response to
      hypotension is a primary stimulus for muscle lactate production in this model of
      hemorrhagic shock. Hypoxia alone does not explain the increased lactate levels
      because tissue perfusion was not altered by the adrenergic antagonists. These
      observations challenge the rationale behind lactate clearance as an end point for
      resuscitation after hemorrhagic shock.

PMID- 10338407
TI  - Transforming growth factor-beta impairs postburn immunoglobulin production by
      limiting B-cell proliferation, but not cellular synthesis.
AB  - BACKGROUND: Transforming growth factor-beta (TGF-beta) has been shown to be an
      inhibitor of immunoglobulin (Ig) synthesis and may contribute to decreased Ig
      synthesis after burn injury. This study investigated the relationship between TGF
      beta and Ig synthesis after burn injury. METHODS: Twenty-four BALB/c mice
      received either a 30% body surface area full-thickness contact burn or no burn.
      Splenocytes were isolated 8 days after burn and were cultured with 0, 0.05 or 0.5
      ng/mL TGF-beta. After culture, total IgG and total IgM were measured by enzyme
      linked immunosorbent assay. The number of IgM-secreting cells per 10(5) cells was
      measured by enzyme-linked immunoabsorbent spot forming assay. Total IgM per IgM
      secreting cell (pg/cell) was calculated. RESULTS: Total IgG, IgM, IgM-secreting
      cells, and B-cell number after culture were decreased by burn injury, and the
      decrease was exacerbated by the presence of TGF-beta. The total IgM per IgM
      secreting cells, however, was significantly increased by TGF-beta at 0.5 ng/mL.
      CONCLUSION: These data demonstrates that TGF-beta does not specifically impair
      IgM secretion by committed IgM B cells but appears to decrease B-cell
      proliferation or clonal expansion.

PMID- 10338408
TI  - Antioxidative resuscitation solution prevents leukocyte adhesion in the liver
      after hemorrhagic shock.
AB  - BACKGROUND: The generation of iron-dependent toxic oxygen radicals during the
      initial resuscitation from hemorrhagic shock was shown to be a relevant factor
      for the initiation of the inflammatory cascade. Therefore, this experimental
      study was designed to evaluate the effects of a deferoxamine-conjugated
      hydroxyethyl-starch solution (HES-DFO) on oxygen radical induced injury and
      microcirculatory alterations in the rat liver compared with resuscitation with
      regular hydroxyethyl-starch, lactated Ringer's solution (RL), or a gelatin-based
      solution. METHODS: After hemorrhage and random assignment to 1 hour of blood-free
      resuscitation with the aforementioned solutions, hepatic microcirculation and
      leukocyte adhesion characteristics were assessed by intravital fluorescence
      microscopy in anesthetized rats. Oxygen radical activity was estimated by
      determination of glutathione levels in liver homogenate and determination of
      thiobarbituric acid-reactive substances in plasma as markers of lipid
      peroxidation. RESULTS: Resuscitation by HES-DFO resulted in restoration of
      hemodynamic parameters compared with gelatin-based solution and HES. The hepatic
      microcirculation was severely altered 1 hour after resuscitation from shock in
      all groups indicated by sinusoidal narrowing and reduced sinusoidal blood flow.
      HES-DFO, however, attenuated leukocyte adhesion and improved velocity index in
      sinusoids as well as sinusoidal perfusion. The shock-associated generation of
      oxygen radicals during resuscitation was prevented by HES-DFO as indicated by
      restored glutathione and reduced thiobarbituric acid-reactive substances.
      CONCLUSION: The results suggest that HES-DFO effectively reduces oxygen radical
      formation during the initial resuscitation period, thus, attenuating
      pathologically enhanced leukocyte adhesion and improving hepatic
      microcirculation.

PMID- 10338409
TI  - Effects of long-term hemofiltration on circulating mediators and superoxide
      production during continuous endotoxin administration.
AB  - BACKGROUND: The purpose of this study was to test whether continuous
      hemofiltration eliminates cytokines and eicosanoids, or stimulates granulocyte
      function. METHODS: Nineteen pigs were divided into a control group (n = 7), a
      hemofiltration group (n = 7), and an extracorporeal circuit only group (n = 5).
      All animals received the same amount of intravenous endotoxin and resuscitation
      fluid. Zero-balanced hemofiltration was started 30 minutes after initiation of
      endotoxemia and continued throughout the experiment. Plasma endotoxin, tumor
      necrosis factor-alpha, eicosanoids, superoxide production, and other physiologic
      parameters were measured before challenge and at scheduled intervals thereafter.
      RESULTS: Eicosanoids were filtered but plasma concentrations were not reduced.
      Tumor necrosis factor-alpha was not filtered or adsorbed. There were no
      significant differences between groups in any measured parameters. CONCLUSION:
      Continuous hemofiltration could not efficiently remove tumor necrosis factor
      alpha or eicosanoids. Also, continuous hemofiltration did not stimulate
      production of the proinflammatory mediators measured, nor improve respiratory
      distress.

PMID- 10338410
TI  - Tumor necrosis factor depresses myocardial contractility in endotoxemic swine.
AB  - BACKGROUND: Depression of myocardial contractility occurs in septic shock.
      METHODS: Fourteen pigs were instrumented to measure cardiopulmonary dynamics
      after a challenge of Escherichia coli endotoxin (lipopolysaccharide endotoxin,
      LPS). A volumetric Swan-Ganz catheter was placed via the jugular vein, and a
      carotid arterial line was placed into the aortic root. Eight pigs received LPS
      alone and six pigs received tumor necrosis factor monoclonal antibody (TNF MAb)
      15 minutes before the administration of LPS. Pulmonary artery and aortic root
      blood were sampled for amounts of TNF. Ninety minutes after LPS administration,
      thoracotomy was performed to biopsy the right and left ventricles for TNF levels.
      Contractility was determined from the end systolic pressure-volume relationships
      of pressure-volume diagrams. RESULTS: Right ventricular end diastolic volume
      index nearly doubled and myocardial contractility decreased by 40% from baseline
      in the pigs receiving only LPS. Pigs that received TNF MAb had no change in
      myocardial contractility or right ventricular end diastolic volume index from
      baseline. There was a higher level of TNF in the aortic sample than in the
      pulmonary samples at 60 minutes. Right ventricular tissue TNF levels were
      significantly higher in the LPS-alone group. There was no such difference in left
      ventricular tissue. CONCLUSION: The left and right ventricles have different
      susceptibilities to TNF MAb. TNF may decrease myocardial contractility in sepsis.
      Blockade of TNF with TNF MAb reverses the depression of myocardial contractility
      and the right ventricular dilatation associated with septic shock.

PMID- 10338411
TI  - Levels of antibodies to endotoxin and cytokine release in patients with severe
      trauma: does posttraumatic dysergy contribute to organ failure?
AB  - BACKGROUND: We conducted a prospective study in patients with multiple injuries
      investigating the time course of trauma-related changes of systemic immunologic
      defense mechanisms. METHODS: Patients with multiple injuries with Injury Severity
      Scores of more than 20 were included if they survived for more than 4 days after
      injury. Further inclusion criteria were no local or systemic infection
      (pneumonia, sepsis, soft-tissue infection, acquired immunodeficiency syndrome,
      tuberculosis, etc.) at the time of injury and no history of liver disease, bowel
      disease, or abdominal surgery. Serum endotoxin levels were measured from
      peripheral venous blood, as were the immunoglobulin G (IgG) and immunoglobulin M
      (IgM) antibodies against lipid A and against the core polysaccharide of endotoxin
      (lipopolysaccharide [LPS]), during the course of intensive care management.
      Serial central venous levels of interleukin-6 were determined as a marker of the
      inflammatory response. RESULTS: The patients were grouped according to their
      survival, with the survivors belonging to group S (48 patients) and the
      nonsurvivors belonging to group N (16 patients). The time of death for the
      nonsurvivors was between days 10 and 32 after the initial trauma. Thirteen of
      these patients (81%) died of multiple organ failure between days 12 and 17, two
      died of head trauma, and one died of sepsis. In patients who died of multiple
      organ failure, a significantly lower production of the IgM and IgG antibodies
      (AB) against lipid A and LPS was found before death (lipid A IgM-AB, day 11:
      group N, 29 +/- 11 U/mL; group S, 106 +/- 16 U/mL; p = 0.008; lipid A IgG-AB, day
      11: group N, 18 +/- 9 U/mL; group S, 57 +/- 18 U/mL; p = 0.007; LPS IgM-AB, day
      11: group N, 36 +/- 14 U/mL; group S, 122 +/- 23 U/mL; p = 0.009; LPS IgG-AB, day
      11: group N, 17 +/- 12 U/mL; group S, 56 +/- 19 U/mL; p = 0.03). Interleukin-6
      levels were significantly increased in the nonsurvivors (day 1: group N, 1,095 +/
      112 pg/mL; group S, 393 +/- 67 U/L; p = 0.008). CONCLUSION: In patients who died
      of severe trauma and in whom the cause of death was multiple organ failure, a
      significantly lower production of antiendotoxin antibodies was measured shortly
      before death. An insufficient immune defense (dysergy) may be involved in the
      pathomechanisms leading to the development of organ dysfunction.

PMID- 10338412
TI  - Decompressive surgery in acute head injuries: where should it be performed?
AB  - BACKGROUND: In Norway, most patients with severe head injuries are transported
      to, and operated in, the neurosurgical unit of the regional university hospital.
      However, some patients are still occasionally operated on in county central
      hospitals by orthopedic or general surgeons who do not have neurosurgical
      expertise. The aim was to analyze this surgical activity outside the
      neurosurgical units. METHODS: Data were collected from two sources: a nation-wide
      survey and the records of all patients with a severe head injury occurring within
      Vestfold county (1987-1996). RESULTS: The Norwegian county central hospitals
      perform each only 2.5 to 3 surgical evacuations of intracranial hematomas per
      year. In Vestfold county, a total of 161 patients were hospitalized alive with an
      acute severe head injury. One third of the patients (54 patients) underwent
      decompressive surgery, mostly evacuations of intracranial hematomas. The patients
      operated on in the central hospital had a significantly worse outcome than the
      patients who were transferred to and operated on in the neurosurgical unit of the
      regional hospital. Only patients with extracerebral hematomas were operated on in
      the central hospital. Patients with an extradural (epidural) hematoma had a
      better outcome than patients with an acute subdural hematoma. Based on the
      surgery records and preoperative and postoperative computed tomographic scans,
      one third of the operations (10 operations) in the central hospital were
      classified retrospectively as inadequate, because the hematoma was not evacuated
      or found or because the surgeons did not achieve control of the perioperative
      bleeding. The overall mortality rate was 29.8%. CONCLUSION: The present study
      indicates that, in Norway and countries with a similar hospital system, it must
      be difficult for general and orthopedic surgeons to achieve and maintain the
      skills required for emergency operations in patients with acute severe head
      injuries. Thus, it is probably to the patients' benefit to improve the general
      hospitals' competency and speed in the detection of candidates for surgical
      decompression, and stress the importance of these patients being transferred
      without unnecessary delay to a neurosurgical unit.

PMID- 10338413
TI  - Small-bowel and mesentery injuries in blunt trauma.
AB  - BACKGROUND: The purpose of this study was to identify factors that would aid in
      the diagnosis of small-bowel and mesentery injuries (SBMI) in blunt trauma
      patients. METHODS: Retrospective review of 15,779 blunt trauma patients admitted
      to a Level I trauma center between January 1991 and December 1996. RESULTS: A
      total of 5,303 patients sustained abdominal injuries, 70 of whom had more than
      111 SBMI. Seventy-nine percent were victims of motor vehicle collisions. Thirty
      patients had isolated SBMI and 40 had associated intra-abdominal injuries. Twelve
      patients arrived with systolic blood pressure < 90 mm Hg, eight of whom died.
      Mean base deficit was -7.3 +/- 6.3 in 52 patients who had arterial blood gases
      determined. Fifty-three of 60 patients had hematuria. Sixty-seven patients
      required laparotomy. Delayed exploration occurred in 15 patients who underwent
      initial computed tomography but had subsequent changes in physical status. Two of
      20 patients had negative diagnostic peritoneal lavage on admission and were
      eventually explored based on abdominal computed tomographic findings and changes
      in physical examination. There were 15 deaths. Delay in diagnosis (>12 hours
      after arrival) occurred in nine patients with no deaths or significant
      morbidities. Mean Injury Severity Score was 29 +/- 16.7: 43 +/- 17 in
      nonsurvivors and 25 +/- 14.3 in survivors (p < 0.05). CONCLUSION: The diagnosis
      of SBMI is often made in the presence of associated intra-abdominal injuries.
      Isolated SBMI are common, however, and special attention to the mechanism of
      injury, abdominal examination, presence of hematuria, and significant base
      deficit should raise suspicion to the possibility of SBMI. Findings on abdominal
      computed tomography that may suggest SBMI and should prompt further evaluation
      include free fluid, thickened bowel, and extraluminal air. Because delay in
      diagnosis does not seem to affect morbidity or mortality, dedication to
      observation and serial physical examinations will aid in the proper
      identification of elusive SBMI. Mortality, however, does appear to be related to
      the presence of hypotension on admission and associated injuries.

PMID- 10338415
TI  - Electrical injuries: a 30-year review.
AB  - INTRODUCTION: Electrical injuries currently remain a world-wide problem. This
      study determines whether electrical injuries at our institution have changed in
      the past 30 years, and identifies electrical burn complications and any high-risk
      groups. METHODS: From 1967 to 1997, 185 children admitted to our institute were
      identified with electrical burns. Fifty-five percent of these electrical burns
      occurred from 1987 to 1997. RESULTS: During the last 10 years of this study, 43%
      of the electrical injuries (n = 44) were from low voltage (120-240 V) and 57% (n
      = 58) from high voltage (>1,000 V). In 17 children, serious low-voltage burns
      were identified as oral commissure burns. These were treated conservatively with
      one to two reconstructive procedures within 2 years. High-voltage injuries were
      mainly identified in male children (age 11 to 18 years). Thirty-three percent of
      high-voltage burns required amputation, 29% had deep muscle involvement, and 24%
      required either escharotomy or fasciotomy. No mortalities were reported.
      CONCLUSION: Although the incidence of low-voltage burns is currently on a steady
      decline, high-voltage injuries remain a problem, particularly in adolescent
      males.

PMID- 10338414
TI  - Combat trauma airway management: endotracheal intubation versus laryngeal mask
      airway versus combitube use by Navy SEAL and Reconnaissance combat corpsmen.
AB  - BACKGROUND: Airway management takes precedence regardless of what type of life
      support is taking place. The gold standard for airway control and ventilation in
      the hands of the experienced paramedic remains unarguably the endotracheal tube.
      Unfortunately, laryngoscopy and endotracheal intubation require a skilled
      provider who performs this procedure on a frequent basis. Special Operations
      corpsmen and medics receive training in the use of the endotracheal tube, but
      they use it infrequently. The use of alternative airways by Navy SEAL and
      Reconnaissance combat corpsmen has not been evaluated. Our objective was to
      compare the ability of Special Operations corpsmen to use the endotracheal tube
      (ETT), laryngeal mask airway (LMA), and esophageal-tracheal combitube (ETC) under
      combat conditions. METHODS: This study used a prospective, randomized, crossover
      design. Twelve Navy SEAL or Reconnaissance combat corpsmen participated in a 2
      week Advanced Battlefield Trauma course. During the first week, instruction
      included the use of ETT, LMA, and ETC, viewing of videotapes for ETC and LMA, and
      mannequin training. The Special Operations corpsmen were required to reliably
      insert each airway within 40 seconds. During the second week, participants dealt
      with a number of active combat trauma scenarios under fire in combat conditions.
      Each SEAL or Reconnaissance corpsman was asked to control his "casualty's" airway
      with a randomized device. All participants were evaluated in the use of each of
      the three airways. RESULTS: Thirty-six airway insertions were evaluated. No
      failures occurred. All incorrect placements were detected and corrected. Mean
      time to place the ETT was 36.5 seconds versus 40.0 seconds for the ETC. The LMA
      insertion time of 22.3 seconds was significantly shorter than the other times (p
      < 0.05). The mean number of attempts per device was similar with all devices: LMA
      (1.17), ETC (1.17), and ETT (1.25). CONCLUSION: The Special Operations corpsmen
      easily learned how to use the ETC and LMA. In this study, they showed the ability
      to appropriately use the ETT as well as the ETC and LMA. For SEAL corpsmen, the
      alternative airways should not replace the ETT; however, on occasion an advanced
      combat casualty care provider may not be able to use the laryngoscope or may be
      unable to place the ETT. The LMA and ETC are useful alternatives in this
      situation. If none of these airways are feasible, cricothyrotomy remains an
      option. Regardless of the airway device, refresher training must take place
      frequently.

PMID- 10338416
TI  - Lightning: the multisystem group injuries.
AB  - In this article, we present our experience of group lightning injury. Individual
      injuries are most common after single strikes. The largest group previously
      reported was 10 patients. In our series, 17 victims were hit by a single strike;
      11 were admitted to the hospital and 6 were discharged from the accident and
      emergency department. Although injured under the same circumstances, these
      patients presented with a wide range of symptoms and signs. We also describe a
      characteristic burn pattern, the "tip-toe sign."

PMID- 10338417
TI  - Use of endoscopic trocar-cannula for chest drain insertion in trauma patients and
      others.
AB  - BACKGROUND: The insertion of a chest drain into the pleural space is a common
      procedure used for treatment in various intrathoracic abnormalities. Recently, a
      new technique for chest-tube insertion for pleural cavity drainage, using the
      disposable endoscopic trocar-cannula, was described for the treatment of some
      pathologic conditions. METHODS: In a prospective study, we used this technique in
      the treatment of patients with chest trauma, spontaneous and iatrogenic
      pneumothorax, and various kinds of pleural effusion. RESULTS: One hundred twelve
      patients were treated by using the endoscopic trocar-cannula for tube insertion
      into the pleural cavity. Among them, 39 patients were treated after blunt and
      penetrating chest trauma. Most cannulae were of 10 to 11 mm in diameter, which
      enabled the insertion of large-bore drain tubes. In five trauma patients, chest
      tube insertion was done successfully without antecedent chest x-ray films. The
      complication rate was 0.89% for intrapulmonary positioning of a chest tube in a
      patient who had previous ipsilateral thoracic surgery. CONCLUSION: The use of
      endoscopic trocar-cannulae for chest-tube insertion is a safe, simple, and
      effective technique for management of trauma and other diverse intrathoracic
      abnormalities. Its use outside the hospital should be further studied.

PMID- 10338418
TI  - Aneurysm-induced intertrochanteric bone loss reconstructed by a vascularized
      iliac graft: case report.

PMID- 10338419
TI  - Posterior elbow dislocation with associated vascular injury after blunt trauma.
AB  - BACKGROUND: Injury of the brachial artery is a rare (5-13%) but serious
      complication after closed elbow dislocation without associated fractures. METHOD:
      Retrospective analysis of long-term results (mean, 4.1 years) in four patients.
      RESULTS: All patients underwent emergency repair of the arterial injury within
      2.5 hours. In three patients, a reversed saphenous vein graft was used; in one
      patient the artery was sutured. This latter patient needed another operation with
      interposition of a reversed saphenous graft, because the primary anastomosis
      occluded. The capsule and the collateral ligaments were immediately reconstructed
      in three patients because of instability. No patient showed claudication of the
      arm. In three patients, a sensory deficiency of median nerve persisted. Average
      range of motion was 128 degrees of flexion (120-135 degrees) and an extension
      deficit of 7.5 degrees (15-0 degrees). CONCLUSION: Primary repair of vascular
      injury after closed elbow dislocation with vein graft and immediate
      reconstruction of ligamentous injuries results in good long-term functional
      outcome.

PMID- 10338420
TI  - Traumatic aortic arch transection with supracarinal tracheoesophageal fistula:
      case report.

PMID- 10338421
TI  - Tension pneumopericardium in chest trauma.

PMID- 10338422
TI  - Hypopharyngeal perforation after blunt neck trauma: case report and review of the
      literature.

PMID- 10338423
TI  - Entrapment and obstruction of the esophagus from thoracic spine hyperextension
      dislocation injury.
AB  - We have reported a unique case of esophageal entrapment and obstruction from a
      thoracic spine hyperextension-dislocation injury after a motor vehicle crash.
      Because the risk for esophageal injury is not typically associated with thoracic
      spine injury, a heightened sensitivity for developing symptoms and signs is at
      least necessary. As with any injury to the gastrointestinal tract, optimal
      therapy requires resuscitation and prompt operative intervention.

PMID- 10338424
TI  - Bronchial disruption after blunt trauma chest.

PMID- 10338425
TI  - Staged operative treatment in a septic patient with an infected, unstable pelvis,
      and a missed bladder rupture.
AB  - This case demonstrates once again the potential and serious complications of
      pelvic fractures, especially when associated urogenital injuries are missed.
      Missing the bladder rupture proved almost fatal to our patient. Second, it was
      confirmed that in very unstable pelvic fractures, external fixation alone does
      not provide enough stability. Local stability is the cornerstone in the treatment
      of (bone) infection, and in these cases, maximal stability is only obtainable
      with internal fixation. The advantages of metal implants in infected areas
      outweigh the disadvantages by far. For the bladder-rupture, we chose a two-stage
      approach. First, we performed a urinary diversion, to avoid surgical closure of
      the infiltrated bladder wall. All cavities, including the open bladder, were
      packed with omentum to fill the dead space with highly vital tissue to offer
      stout resistance to infection. Two years later, with the patient in excellent
      physical condition, urinary undiversion was carried out. Ultimately physical and
      social recovery was complete.

PMID- 10338426
TI  - A case of urothorax that manifested as posttraumatic pleural effusion after a
      motorcycle crash.

PMID- 10338427
TI  - Pancreaticogastrostomy after pancreaticoduodenectomy: a rational approach to
      severe combined pancreaticoduodenal injury.

PMID- 10338428
TI  - Posttraumatic hypertension secondary to adrenal hemorrhage mimicking
      pheochromocytoma: case report.
AB  - We report the case of a 68-year-old man who presented with a mass 3 x 4 cm in
      size located in the right adrenal gland together with extreme hypertension,
      tripled urine levels for normetanephrine, and normal plasmatic levels of
      metanephrines. The patient had suffered a fall from a height of 2.5 meters before
      hospitalization. [123I]MIBG-scan was repeatedly positive in the area of the right
      adrenal gland. At laparotomy under alpha-adrenergic blocking agents, the
      suspected pheochromocytoma was histologically confirmed as hematoma. After
      resection of the adrenal gland, blood pressure returned to normal without drug
      therapy as did metanephrine levels in urine. Although adrenal insufficiency after
      distension of the gland caused by hemorrhage has been reported, there are no data
      available regarding the mimicking of a hormonally active pheochromocytoma. We
      conclude that intra-adrenal pressure rise caused by hematoma may cause partial
      ischemic necrosis to the gland but may also induce reactive hyperplasia with
      periodic excessive secretion of catecholamines. This interpretation is consistent
      with the finding that plasma levels of catecholamines were normal in contrast to
      the urinary normetanephrines in the presented case. It might be worthwhile to
      investigate patients with intra-adrenal hemorrhage immediately after sustaining
      multiple injuries and in the posttraumatic course of several months up to 1 or
      more years together with verification of abnormal urinary excretion of
      metanephrines as a sign of impaired adrenal function.

PMID- 10338429
TI  - Management of an unusual thermal injury to the thigh.

PMID- 10338430
TI  - Delayed surgery and interventional procedures in complex liver injuries.

PMID- 10338431
TI  - Spinal shock--spinal man.

PMID- 10338432
TI  - Critical analysis of two decades of experience with postinjury emergency
      department thoracotomy in a regional trauma center.

PMID- 10338433
TI  - Intracranial monitoring placement by midlevel practitioners.

PMID- 10338434
TI  - The effects of trauma and sepsis on soluble L-selectin and cell surface
      expression on L-selectin and CD11b on leukocytes.

PMID- 10338435
TI  - Female urology/urogynecology.

PMID- 10338436
TI  - Characteristics of detrusor contractility during micturition in diabetics.
AB  - Pressure-flow studies were performed in 26 diabetics without bladder-outlet
      obstruction to objectively quantify detrusor activity and its variance during
      micturition by using the watts factor (WF) and to clarify the factors inducing a
      post-void residual volume (PVR). The WFmax values obtained from the pressure-flow
      studies were low in the majority of diabetics. There was a significant negative
      correlation between WFmax and PVR. A fading contraction strength during voiding
      was also observed that gave rise to an increased volume of residual urine,
      indicating that detrusor activity could not be maintained until the bladder was
      completely emptied in the diabetics. A positive correlation between bladder
      capacity and PVR was also observed. Our results indicate that residual urine in
      diabetics is related to a decrease in the maximum detrusor contraction strength,
      the fading of detrusor contractility during voiding, and an increase in the size
      of the bladder.

PMID- 10338437
TI  - The International Prostate Symptom score in both sexes: a urodynamics-based
      comparison.
AB  - The aim of our study was to determine the urodynamic basis for the observation
      that aging women report comparable benign prostatic hyperplasia (BPH) symptom
      scores as age-matched men. Sixty-seven women (mean age, 60.4 +/- 1.5 years; mean
      +/- standard error of the mean) and 70 age-matched men (mean age, 63.7 +/- 0.9
      years; P > 0.05) entered this prospective study. Men were referred for the
      diagnostic workup of lower urinary tract symptoms (LUTS) due to BPH and women
      predominantly for urinary incontinence. All patients completed the International
      Prostate Symptom score (IPSS) with quality-of-life assessment and underwent a
      detailed clinical and urodynamic evaluation including a multichannel pressure
      flow study. Results of the IPSS, quality-of-life assessment, and irritative and
      obstructive component of the IPSS were correlated with urodynamic findings and
      the respective data were compared in both sexes. The mean IPSS was 15.7 for men
      and 13.0 for women (P = 0.02), quality-of-life score was higher in women (4.2 vs.
      3.4; P = 0.0008). The irritative score was significantly higher in women (8.7 vs.
      6.8; P = 0.003). Incidence of detrusor instability (DI), however, was higher in
      men (women, 38.1%; men, 48.6%; P = 0.015) and bladder capacity was higher in
      women (425 vs. 333 ml; P = 0.0001). There was no correlation between incidence
      and degree of DI with the irritative score in both sexes. The obstructive score
      was significantly higher in men (8.8 vs. 4.4; P = 0.0001). Ninety-one percent
      (64/70) of men had urodynamically documented bladder outlet obstruction (BOO),
      whereas this was the case in only 9% (6/67) of women. In parallel to the
      irritative score, we could not identify a correlation between the degree of
      urodynamically proven BOO and the obstructive score in both sexes. This
      urodynamics-based comparison fails to give an explanation for the observation
      that aging women report similar BPH scores as men. These data suggest that other
      mechanisms, such as changes in diurnal urine production, structural alterations
      of the aging detrusor, endocrine disturbances affecting lower urinary tract
      function, and subtle urodynamic changes are responsible.

PMID- 10338438
TI  - Low reproducibility of maximum urinary flow rate determined by portable
      flowmetry.
AB  - To evaluate the reproducibility in maximum urinary flow rate (Qmax) in men with
      lower urinary tract symptoms (LUTSs) and to determine the number of flows needed
      to obtain a specified reliability in mean Qmax, 212 patients with LUTSs (mean
      age, 62 years) referred to the University Hospital Nijmegen, with various degrees
      of obstruction on pressure-flow studies, used a portable home-based uroflowmeter
      with 12 disposable beakers. Voided volume and maximum flow rate were recorded
      continuously during micturition. Flows with voided volumes of at least 100 ml and
      without possible artifacts were included. All analyses were repeated while
      excluding flows with voided volumes <150 ml. A coefficient of variation (CV) was
      calculated for each patient. The CV represents the standard deviation relative to
      the mean. All individual CVs were subsequently pooled into a population mean CV.
      This parameter was used to estimate the number of flows required to obtain a mean
      Qmax with specified reliability for an individual patient. All analyses were
      repeated, while successively excluding the first, the first two, and the first
      three flows, to assess a possible learning curve. A total of 1,854 flows was
      available for analyses, yielding an average of nine flows per patient. Mean Qmax
      was 13.2 ml/sec; the mean CV was 24%. To allow, for instance, a 10% deviation
      from the true mean Qmax (e.g., 15 ml/s +/- 1.5 ml/s), approximately 25 flows are
      necessary. The actual number of flows needed is in fact even higher due to the
      presence of small and artifactual flows. Using a 150 ml volume cutoff point,
      somewhat fewer flows are required, but the total number of flows needed (that is,
      valid, small, and artifactual flows) increases. There was no evidence of a
      learning curve. The boundaries of a confidence interval around a single Qmax
      measurement that is likely to contain the true mean Qmax, lie approximately 50%
      below or above that single Qmax measurement. To reduce this proportion down to
      10%, approximately 25 flows are needed. Thus, to obtain reliable mean Qmax
      values, considerably more flows are required than are normally performed in
      urologic practice.

PMID- 10338439
TI  - Development of postoperative urinary stress incontinence in clinically continent
      patients undergoing prophylactic Kelly plication during genitourinary prolapse
      repair.
AB  - The present study was undertaken to evaluate the efficacy of Kelly plication in
      preventing postoperative urinary stress incontinence in clinically continent
      patients undergoing surgery for genitourinary prolapse. Thirty clinically
      continent patients with grade-3 genitourinary prolapse were found to have a
      positive stress test with repositioning of the prolapse during preoperative
      urodynamic evaluation. In addition to the genitourinary prolapse repair, these
      patients underwent a Kelly plication as a preventive measure against possible
      development of postoperative urinary stress incontinence. Postoperative follow-up
      included a detailed urogynecologic questionnaire, pelvic examination, urine
      culture, Q-tip cotton swab test, and a full urodynamic evaluation. The mean
      duration of follow-up was 25.5 +/- 14.1 months. Fifteen (50%) patients developed
      subjective and objective postoperative stress incontinence. Eleven (37%) patients
      developed objective postoperative stress incontinence (proven by urodynamic
      evaluation) with no subjective complaints of stress incontinence. Prophylactic
      Kelly plication as performed by the method described does not appear to be
      effective in preventing postoperative urinary stress incontinence in clinically
      continent patients who undergo surgery for genitourinary prolapse.

PMID- 10338440
TI  - Anal incontinence: prevalence among female patients attending a urogynecologic
      clinic.
AB  - The present study prospectively surveyed the prevalence of anal incontinence
      among 283 consecutive female patients attending a urogynecologic outpatient
      clinic in a maternity hospital. Data concerning bowel habits, laxative use,
      previous anorectal surgery, and the presence, severity, and frequency of anal
      incontinence were collected by interviewing the patients. Anal incontinence was
      reported by 83 women, representing 29% of the study population. Of those
      reporting anal incontinence, 30% (9% of the study population) were incontinent to
      solid feces, 22% (6%) to liquid feces, and 48% (14%) to gas. Age distribution
      demonstrates progressive rise and a high prevalence of anal incontinence in
      patients older than 60 years. A significant higher rate of vacuum deliveries was
      found among patients with anal incontinence, compared with continent patients
      (9.6% vs. 2.5%; P = 0.01). Increased prevalence of anal incontinence was also
      found among patients with past history of hemorrhoidectomy and those with
      urodynamic diagnosis of combined genuine stress incontinence and detrusor
      instability/sensory urgency. In conclusion, in patients attending a
      urogynecologic clinic, anal incontinence is a frequent, although rarely
      volunteered, symptom.

PMID- 10338441
TI  - Pressure-flow studies: short-time repeatability.
AB  - The within and between examination variation in selected test parameters and test
      results in repeated pressure-flow studies was determined in a prospective study
      of consecutive pressure-flow examinations in 22 patients. The patients were
      pressure-flow tested twice within a month. Furthermore, it was evaluated whether
      there was a systematic change in the measured parameters during retesting. By
      using the Abrams-Griffiths nomogram, patients were classified as obstructed,
      equivocal, or unobstructed. Within and between examination variations in
      classification were evaluated. We found a systematic variation in P(det.Qmax)
      during testing, which in the absence of statistically significant systematic
      variations in P(det.Close) and Qmax, indicates a physiological effect of repeated
      pressure-flow studies, resulting in a less-obstructed second voiding. Supporting
      this, we found that all patients who changed group of classification of bladder
      outlet obstruction in the first examination shifted to a group of less
      obstruction, as did 66% of the patients who changed group of classification of
      bladder outlet obstruction in the second examination. Still, 80, respectively
      85%, of the patients remained in the same group of classification of bladder
      outlet obstruction during retesting in the first and second examinations,
      respectively. Classifying the degree of bladder outlet obstruction by Qmax,
      P(det.Qmax), and P(det.Close) 85% of the patients reproduced their test results
      accurately in both examinations and taking only the first voiding in both
      examinations into account 95% reproduced their test results.

PMID- 10338442
TI  - Role of ambulatory urodynamic monitoring in clinical urological practice.
AB  - A retrospective review was conducted of 125 ambulatory monitoring (AM) studies
      performed on 111 women and 11 men between 1992 and 1996. All patients had had
      conventional cystometry prior to AM. All tests were interpreted with the aid of
      event markers and urinary diaries. Ambulatory traces were reported using the
      definitions derived from Coolsaet's work. To assess the role of AM in routine
      clinical urological practice, ambulatory diagnoses were compared with those of
      conventional cystometry. A survey of patient management was carried out by postal
      questionnaire or review of hospital notes to determine whether AM had influenced
      patient management. The study showed that 53 of 94 (56.3%) patients with symptoms
      suggestive of detrusor overactivity had detrusor instability diagnosed on AM. Of
      those with symptoms suggestive of stress incontinence, 5 (29%) had genuine stress
      incontinence and 5 (29%) had detrusor instability. The remainder (42%) had normal
      tests. Overall in 79 of 125 tests (63.2%), additional urodynamic findings were
      made that correlated with symptoms. Following the survey of patient management,
      AM was shown to influence management in all but 8.7% patients. In summary, AM was
      felt to have been shown to be a useful additional tool in clinical urological
      practice for those patients where conventional cystometry had failed to explain
      their symptoms.

PMID- 10338444
TI  - Circulation online only : may 25, 1999 

PMID- 10338443
TI  - Pharmacodynamics of anticholinergic agents measured by ambulatory urodynamic
      monitoring: a study of methodology.
AB  - The aim of the study was to establish a methodology whereby ambulatory urodynamic
      monitoring (AUM) may be used in the assessment of the effects of darifenacin on
      urodynamic measures of detrusor function and symptoms associated with detrusor
      instability. Six patients (one man and five women) with detrusor instability (DI)
      on conventional urodynamic monitoring were recruited into this placebo-controlled
      crossover study. The study was divided into two periods of 7 days of treatment
      with either darifenacin 5 mg t.d.s. or placebo with the patient crossing over to
      the alternative treatment after a washout period of 7 days. On the 7th day of
      each treatment, AUM was carried out. Parameters used to quantify detrusor
      activity on AUM were the number, amplitude, and duration of detrusor contractions
      and the total area under the detrusor pressure/time curve. "Events" recorded were
      urge, leakage episodes, voids, and pain. Six comparable hours of AUM for each
      treatment period could be analyzed in four patients and 4 hr in one. In three of
      the five patients, reduction in activity on AUM while on darifenacin was
      apparent. Symptom data closely matched the changes in detrusor activity measured
      on AUM. This is the first study reporting the use of AUM in the development of a
      drug with an effect on detrusor activity. AUM has clear advantages over
      conventional cystometry, which can only measure surrogate urodynamic parameters
      at a single time point. The optimal duration of monitoring in this context
      appears to be 6 hr with prolongation of monitoring time beyond this being
      unlikely to yield additional useful information. Correlation between symptoms and
      findings on AUM is good with changes in parameters recorded on AUM relating
      closely to the improvement in symptoms.

PMID- 10338445
TI  - Progress for circulation 

PMID- 10338446
TI  - Proposed NIH budget increase too small to meet research needs.

PMID- 10338447
TI  - States set to pass laws limiting liability for lay users of automated external
      defibrillators.

PMID- 10338448
TI  - Stenting the ductus arteriosus: A "wanna-be" Blalock-Taussig.

PMID- 10338449
TI  - Risk stratification for the detection of preclinical coronary artery disease.

PMID- 10338450
TI  - Risks of valve replacements in young women.

PMID- 10338451
TI  - Therapeutic angiogenesis: the new electrophysiology?

PMID- 10338452
TI  - Ultrasound enhances reporter gene expression after transfection of vascular cells
      in vitro.
AB  - BACKGROUND: Restenosis after percutaneous coronary intervention remains a serious
      clinical problem. Progress in local gene therapy to prevent restenosis has been
      hindered by concerns over the safety and efficacy of viral vectors and the
      limited efficiency of nonviral techniques. This study investigates the use of
      adjunctive ultrasound to enhance nonviral gene delivery. METHODS AND RESULTS:
      Cultured porcine vascular smooth muscle cells (VSMCs) and endothelial cells (ECs)
      were transfected with naked or liposome-complexed luciferase reporter plasmid for
      3 hours. Ultrasound exposure (USE) for 60 seconds at 1 MHz, 0.4 W/cm2, 30 minutes
      into this transfection period enhanced luciferase activity 48 hours later by 7.5
      fold and 2. 4-fold, respectively. Luciferase activity after lipofection of ECs
      was similarly enhanced 3.3-fold by adjunctive USE. USE had no effect on cell
      viability, although it inhibited VSMC but not EC proliferation. CONCLUSIONS:
      Adjunctive USE was associated with enhanced transgene expression in VSMCs and ECs
      and reduced VSMC but not EC proliferation in vitro, which suggests that
      ultrasound-assisted local gene therapy has potential as an antirestenotic
      therapy.

PMID- 10338453
TI  - Fate of the stented arterial duct.
AB  - BACKGROUND: The technical aspects of ductal stenting have been reported, but
      little is known of the fate of the duct after stent implantation. METHODS AND
      RESULTS: Nineteen patients underwent stent implantation to maintain ductal
      patency. Eight had hypoplastic left heart (HLH) syndrome, 10 had pulmonary
      atresia, and 1 had tricuspid atresia. Median survival with HLH was 57 (12 to 907)
      days. Stent implantation was successful in all cases of HLH, but there were no
      long-term survivors. Two well-palliated infants died at transplantation. Median
      survival with duct-dependent pulmonary flow was 183 (0 to 1687) days, with 3
      patients well at latest follow-up (56, 55, and 9 months, respectively). There
      were 2 operative deaths due to ductal spasm and 4 late deaths, 1 due to duct
      thrombosis, 1 due to chronic lung disease, and 2 of unknown cause. Stent
      implantation failed in 4 of the 11 cases. Assessment of endothelialization was
      possible in 13 cases; the stent was partially covered in 3 and fully
      endothelialized in all 10 cases assessed >8 weeks after implantation. In patients
      stented for inadequate pulmonary flow, ductal intimal hyperplasia occurred by 9
      months in all 3 survivors but responded to repeated dilation. CONCLUSIONS: Ductal
      stenting cannot be recommended. In patients with HLH, it provides only short-term
      palliation even when combined with pulmonary artery banding. With duct-dependent
      pulmonary blood flow, the procedure carries high risk, and duration of palliation
      is poor. In patients with bilateral ducts and absent central pulmonary arteries,
      good palliation may be achieved, but repeated angioplasty is necessary to
      counteract intimal hyperplasia.

PMID- 10338454
TI  - Glycometabolic state at admission: important risk marker of mortality in
      conventionally treated patients with diabetes mellitus and acute myocardial
      infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in
      Acute Myocardial Infarction (DIGAMI) study.
AB  - BACKGROUND: The Diabetes and Insulin-Glucose Infusion in Acute Myocardial
      Infarction (DIGAMI) study addressed prognostic factors and the effects of
      concomitant treatment and glycometabolic control in diabetic patients with
      myocardial infarction (AMI). METHODS AND RESULTS: Of 620 diabetic patients with
      AMI, 306 were randomly assigned to a >/=24-hour insulin-glucose infusion followed
      by multidose subcutaneous insulin. Three hundred fourteen patients were
      randomized as controls, receiving routine antidiabetic therapy. Thrombolysis and
      beta-blockers were administered when possible. Univariate and multivariate
      statistical analyses were applied to study predictors of long-term mortality.
      During an average follow-up of 3.4 years (range, 1.6 to 5.6 years), 102 patients
      (33%) in the intensive insulin group and 138 (44%) in the control group died
      (P=0. 011). Old age, previous heart failure, diabetes duration, admission blood
      glucose, and admission Hb AIc were independent predictors of mortality in the
      total cohort, whereas previous AMI, hypertension, smoking, or female sex did not
      add independent predictive value. Metabolic control, mirrored by blood glucose
      and Hb AIc, improved significantly more in patients on intensive insulin
      treatment than in the control group. beta-Blockers improved survival in control
      subjects, whereas thrombolysis was most efficient in the intensive insulin group.
      CONCLUSIONS: Mortality in diabetic patients with AMI is predicted by age,
      previous heart failure, and severity of the glycometabolic state at admission but
      not by conventional risk factors or sex. Intensive insulin treatment reduced long
      term mortality despite high admission blood glucose and Hb AIc.

PMID- 10338455
TI  - Coronary calcium does not accurately predict near-term future coronary events in
      high-risk adults.
AB  - BACKGROUND: Prognostic risk models have had limited success in predicting
      coronary events in subjects with multiple risk factors. We and others have
      proposed an alternative approach using radiographically detectable coronary
      calcium. We evaluated and compared the predictive value of these 2 approaches for
      determining coronary event risk in asymptomatic adults with multiple coronary
      risk factors. In addition, we assessed the predictive value of a risk model that
      included calcium score and cardiac risk-factor data. METHODS AND RESULTS: We
      recruited 1196 asymptomatic high-coronary-risk subjects who then underwent risk
      factor assessment and cardiac electron-beam CT (EBCT) scanning and were followed
      up for 41 months with a 99% success rate. We applied the Framingham model and our
      data-derived risk model to determine the 3-year likelihood of a coronary event.
      The mean age of our cohort was 66 years, and mean 3-year Framingham risk was
      3.3+/-3.6%. Sixty-eight percent (818 subjects) had detectable coronary calcium.
      There were 17 coronary deaths (1.4%) and 29 nonfatal infarctions (2. 4%). The
      receiver operating characteristic (ROC) curve areas calculated from the
      Framingham model, our data-derived risk model, and the calcium score were 0.69+/
      0.05, 0.68+/-0.05, and 0.64+/-0.05, respectively (P=NS). When calcium score was
      included as a variable in the data-derived model, the ROC area did not change
      significantly (0.68+/-0.05 to 0.71+/-0.04; P=NS). CONCLUSIONS: Neither risk
      factor assessment nor EBCT calcium is an accurate event predictor in high-risk
      asymptomatic adults. EBCT calcium score does not add significant incremental
      information to risk factors, and its use in clinical screening is not justified
      at this time.

PMID- 10338456
TI  - Treatment of acute myocardial infarction by primary coronary angioplasty or
      intravenous thrombolysis in the "real world": one-year results from a nationwide
      French survey.
AB  - BACKGROUND: Recent randomized trials comparing primary coronary angioplasty and
      intravenous thrombolysis at the acute stage of myocardial infarction have shown a
      limited but definite advantage for primary angioplasty. The aim of this study was
      to document 1-year outcome in patients receiving either thrombolysis or primary
      angioplasty for acute myocardial infarction in the "real world." METHODS AND
      RESULTS: We used a nationwide prospective registry of all patients admitted for
      acute myocardial infarction in French intensive care units in November 1995. Of
      the 721 patients who received reperfusion therapy, 152 were treated with primary
      angioplasty and 569 received intravenous thrombolysis. The two groups were
      remarkably similar with respect to all baseline descriptors, except that a higher
      proportion of patients in the angioplasty group had a history of cerebrovascular
      accident (10% versus 2%, P<0.01). In-hospital outcome was not different in the 2
      groups. One-year survival was 85.5% in the angioplasty group and 89. 5% in the
      thrombolysis group (P=0.18). Multivariate analysis showed that older age,
      anterior location of infarction, female sex, and history of heart failure were
      related to 1-year mortality. In patients alive on day 5, the use of primary
      angioplasty and higher Killip class were additional adverse prognostic
      indicators. CONCLUSIONS: The results of this large registry of real-world
      practice indicate no survival benefit for patients treated with primary
      angioplasty compared with those who received thrombolytic therapy.

PMID- 10338457
TI  - Prospective, randomized comparison of effect of long-term treatment with
      metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative
      stress in heart failure.
AB  - BACKGROUND: With beta-blocker use becoming more prevalent in treating chronic
      heart failure (CHF), the choice of drugs raises important theoretical and
      practical questions. Although the second-generation compound metoprolol is beta1
      selective, the third-generation compound carvedilol is beta-nonselective, with
      ancillary pharmacological properties including alpha-blockade and antioxidant
      effects. A prospective comparison of these 2 agents can address the issue of
      optimal adrenergic blockade in selecting agents for therapy in CHF. METHODS AND
      RESULTS: Sixty-seven patients with symptomatic stable heart failure were randomly
      assigned to receive either carvedilol or metoprolol in addition to standard
      therapy for CHF. Measured variables included symptoms, exercise, ejection
      fraction, and thiobarbituric acid-reactive substances (TBARS) as an indirect
      marker of free radical activity. Metoprolol and carvedilol were well tolerated,
      and both patient groups showed beneficial effects of beta-blocker therapy in each
      of the measured parameters, with no between-group differences. Ejection fraction
      increased over 6 months from 18+/-6.3% to 23+/-8.7% (P<0.005) with metoprolol and
      from 19+/-8.5% to 25+/-9.9% (P<0.0005) with carvedilol (P=NS between groups).
      With metoprolol, TBARS values decreased from 4.7+/-0.9 nmol/mL at baseline to
      4.2+/-1.5 nmol/mL at month 4 to 3.9+/-1.0 nmol/mL at month 6 (P<0.0001). With
      carvedilol, there was a parallel decline from 4.7+/-1.4 to 4.2+/-1.3 to 4.1+/-1.2
      nmol/mL over the same time frame (P<0.025), with no between-group difference in
      these changes. CONCLUSIONS: Carvedilol and metoprolol showed parallel beneficial
      effects in the measured parameters over 6 months, with no relevant between-group
      differences in this heart failure population.

PMID- 10338458
TI  - Double-blind, placebo-controlled study to evaluate the effect of organic nitrates
      in patients with chronic heart failure treated with angiotensin-converting enzyme
      inhibition.
AB  - BACKGROUND: Organic nitrates are widely used in the treatment of chronic heart
      failure (CHF). No information, however, is available regarding their effect in
      patients already treated with ACE inhibitors. METHODS AND RESULTS: In a
      randomized, double-blind, crossover design, we studied the effects of high-dose
      (50 to 100 mg) transdermal nitroglycerin (NTG) and placebo given daily for 12
      hours in 29 patients with CHF (NYHA functional classes II to III). Exercise time
      (4 hours after patch application) showed a progressive improvement during NTG
      administration, with an increase of 38+/-35 seconds (9+/-7%) at the end of the
      first month (P=NS), 76+/-28 seconds (16+/-6%) at the end of the second month
      (P=0.01), and 117+/-34 seconds (27+/-6%) at the end of the third month (P=0.003).
      No significant change was seen during placebo administration (12+/-20, 5+/-26,
      and 19+/-28 seconds, all P=NS). Exercise time 8 hours after NTG application
      measured at 3 months was also significantly longer, with a difference of 87+/-28
      seconds (P=0.006), but not with placebo (23+/-36 seconds, P=0.53). Assessment of
      quality of life and need for additional diuretics or hospitalizations for CHF
      failed to demonstrate a significant difference between the 2 treatment periods.
      In contrast, NTG decreased left ventricular end-diastolic (-2.1+/-0.1%, P<0.05)
      and end-systolic (-3.2+/-1.3%, P<0.05) dimensions and augmented LV fractional
      shortening (24.7+/-10.5%, P<0.03). The effect of placebo on these parameters was
      not statistically significant. CONCLUSION: High-dose nitrate therapy
      significantly improves exercise tolerance and left ventricular size and systolic
      function in patients with chronic, mild to moderate CHF already treated with ACE
      inhibitors. These findings support the role of organic nitrates as an adjunctive
      therapy to ACE inhibitors in patients with chronic CHF.

PMID- 10338459
TI  - Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin
      receptor blocker added to angiotensin converting enzyme inhibitor therapy in
      patients with heart failure. Vasodilator Heart Failure Trial (V-HeFT) Study
      Group.
AB  - BACKGROUND: ACE inhibitors may not adequately suppress deleterious levels of
      angiotensin II in patients with heart failure. An angiotensin receptor blocker
      added to an ACE inhibitor may exert additional beneficial effects. METHODS AND
      RESULTS: Eighty-three symptomatic stable patients with chronic heart failure
      receiving long-term ACE inhibitor therapy were randomly assigned to double-blind
      treatment with valsartan 80 mg BID, valsartan 160 mg BID, or placebo while
      receiving their usual ACE inhibitor therapy. Studies were performed before and
      after the first dose of the test drug and again after 4 weeks of therapy. A
      single dose of lisinopril was administered during study days to ensure sustained
      ACE inhibition. Compared with placebo, the first dose of valsartan 160 mg
      resulted in a significantly greater reduction in pulmonary capillary wedge
      pressure at 3, 4, and 8 hours and during the prespecified 4- to 8-hour interval
      after the dose and in systolic blood pressure at 2, 3, 6, 8, and 12 hours and 4
      to 8 hours after the dose. A pressure reduction from valsartan 80 mg did not
      achieve statistical significance. After 4 weeks of therapy, net reductions in 0
      hour trough pulmonary capillary wedge pressure (-4.3 mm Hg; P=0. 16), pulmonary
      artery diastolic pressure (-4.7 mm Hg; P=0.013), and systolic blood pressure (
      6.8 mm Hg; P=0.013) were observed in the valsartan 160 mg group compared with
      placebo. After 4 weeks of therapy, plasma aldosterone was reduced by valsartan 80
      mg BID (-52. 1 pg/mL; P=0.001) and 160 mg BID (-47.8 pg/mL; P<0.001) compared
      with placebo, and there was a trend for a reduction in plasma norepinephrine (-97
      pg/mL; P=0.10). Seventy-four of the 83 patients completed the trial. CONCLUSIONS:
      Physiologically active levels of angiotensin II persist during standard long-term
      ACE inhibitor therapy.

PMID- 10338460
TI  - Exaggerated endothelin release in high-altitude pulmonary edema.
AB  - BACKGROUND: Exaggerated pulmonary hypertension is thought to play an important
      part in the pathogenesis of high-altitude pulmonary edema (HAPE). Endothelin-1 is
      a potent pulmonary vasoconstrictor peptide that also augments microvascular
      permeability. METHODS AND RESULTS: We measured endothelin-1 plasma levels and
      pulmonary artery pressure in 16 mountaineers prone to HAPE and in 16 mountaineers
      resistant to this condition at low (580 m) and high (4559 m) altitudes. At high
      altitude, in mountaineers prone to HAPE, mean (+/-SE) endothelin-1 plasma levels
      were approximately 33% higher than in HAPE-resistant mountaineers (22.2+/-1.1
      versus 16.8+/-1.1 pg/mL, P<0.01). There was a direct relationship between the
      changes from low to high altitude in endothelin-1 plasma levels and systolic
      pulmonary artery pressure (r=0.82, P<0.01) and between endothelin-1 plasma levels
      and pulmonary artery pressure measured at high altitude (r=0.35, P=0.05).
      CONCLUSIONS: These findings suggest that in HAPE-susceptible mountaineers, an
      augmented release of the potent pulmonary vasoconstrictor peptide endothelin-1
      and/or its reduced pulmonary clearance could represent one of the mechanisms
      contributing to exaggerated pulmonary hypertension at high altitude.

PMID- 10338461
TI  - Long-term survival and valve-related complications in young women with cardiac
      valve replacements.
AB  - BACKGROUND: The type of cardiac valve replacement associated with the lowest
      health risks for young women who may undergo pregnancies is unknown. We
      investigated which valve type was associated with greatest patient and valve
      survival and the effect of pregnancy on valve loss. METHODS AND RESULTS: In this
      retrospective study, all women 12 to 35 years old who underwent valve
      replacements between 1972 and 1992 at Greenlane Hospital were identified, and
      follow-up was available in 93%. The 232 women were followed up for 1499 patient
      years. Ten-year survival of women with mechanical (n=178), bioprosthetic (n=73),
      and homograft (n=72) valves was 70% (95% CI, 59% to 83%), 84% (95% CI, 72% to
      99%), and 96% (95% CI, 91% to 100%), P=0.002. After adjustment for confounding
      variables, the relative risk (RR) of death with mechanical compared with
      bioprosthetic valves was 2.17 (95% CI, 0.78 to 5.88). Thromboembolic events
      occurred in 45% of women with mechanical valves within 5 years, compared with 13%
      with bioprosthetic valves, P=0.0001. Valve loss at 10 years was higher in
      bioprosthetic valves [82% (95% CI, 62% to 92%)] than in mechanical [29% (95% CI,
      17% to 39%)] or homograft [28% (95% CI, 12% to 41%)] valves, P=0.0001. Pregnancy
      was not associated with increased bioprosthetic (RR, 0.96; 95% CI, 0.68 to 1.
      35), homograft (RR, 0.65; 95% CI, 0.37 to 1.13), or mechanical (RR, 0.54; 95% CI,
      0.27 to 1.08) valve loss. CONCLUSIONS: Although 10-year valve survival was
      greater with mechanical than bioprosthetic valves, mechanical valves may be
      associated with reduced patient survival in young women. Thromboembolic
      complications, often with long-term sequelae, were common with mechanical valves.
      Pregnancy did not increase structural deterioration or reduce survival of
      bioprosthetic valves.

PMID- 10338462
TI  - Central pulse pressure is a major determinant of ascending aorta dilation in
      Marfan syndrome.
AB  - BACKGROUND: In patients with Marfan syndrome (MFS), brachial pulse pressure (PP)
      has been recognized as a risk factor for aortic dilatation, leading to aortic
      dissection, the main cause of premature death. However, the relationships between
      aortic PP, aortic stiffness, and aortic root dilation have not been investigated.
      Our main objective was to determine whether central PP, which takes into account
      wave reflections and aortic stiffness, is a better determinant of ascending aorta
      diameter than brachial PP in MFS patients. METHODS AND RESULTS: Twenty patients
      with confirmed MFS and 20 age- and sex-matched control subjects were included in
      this cross-sectional, noninvasive study. Elastic properties of the abdominal
      aorta and common carotid, common femoral, and radial arteries were calculated
      from the pulsatile changes in arterial diameter and pressure. The ascending aorta
      diameter, measured with conventional echocardiography, was 37% larger in MFS than
      in control subjects (P<0.001). Arterial distensibility was 38% lower in MFS than
      in control subjects at the site of the abdominal aorta (P<0.01) but not at other
      sites (common carotid, common femoral, and radial arteries). Independently of age
      and body surface area, ascending aorta diameter was positively correlated with
      carotid PP in MFS (P<0. 01) and negatively in control subjects (P<0.01) but was
      not correlated with brachial PP and mean blood pressure. CONCLUSIONS: In patients
      with MFS, local PP, estimated from carotid PP, was a major determinant of
      ascending aorta diameter, whereas brachial PP was not. Increased arterial
      stiffness was confined to the aorta.

PMID- 10338463
TI  - Establishment of a simple and practical procedure applicable to therapeutic
      angiogenesis.
AB  - BACKGROUND: Therapeutic angiogenesis is thought to be beneficial for serious
      ischemic diseases. This investigation was designed to establish a simple and
      practical procedure applicable to therapeutic angiogenesis. METHODS AND RESULTS:
      When cultured skeletal muscle cells were electrically stimulated at a voltage
      that did not cause their contraction, vascular endothelial growth factor (VEGF)
      mRNA was augmented at an optimal-frequency stimulation. This increase of VEGF
      mRNA was derived primarily from transcriptional activation. Electrical
      stimulation increased the secretion of VEGF protein into the medium. This
      conditioned medium then augmented the growth of endothelial cells. The effect of
      electrical stimulation was further confirmed in a rat model of hindlimb ischemia.
      The tibialis anterior muscle in the ischemic limb was electrically stimulated.
      The frequency of stimulation was 50 Hz and strength was 0.1 V, which was far
      below the threshold for muscle contraction. After a 5-day stimulation, there was
      a significant increase in blood flow within the muscle. Immunohistochemical
      analysis revealed that VEGF protein was synthesized and capillary density was
      significantly increased in the stimulated muscle. Rats tolerated this procedure
      very well, and there was no muscle contraction, muscle injury, or restriction in
      movement. CONCLUSIONS: We propose this procedure as a simple and practical method
      of therapeutic angiogenesis.

PMID- 10338464
TI  - Variant estrogen and progesterone receptor messages in human vascular smooth
      muscle.
AB  - BACKGROUND: Estrogens stimulate growth of breast or uterine cells but have the
      opposite effect on vascular smooth muscle cells, in which they protect against
      coronary artery disease with or without concomitant administration of
      progesterone. A possible cause of differences in hormone action is variable
      tissue-specific expression of hormone receptor. Therefore, we analyzed the
      structure of estrogen receptors (ERs) and progesterone receptors (PRs) in human
      vascular smooth muscle. METHODS AND RESULTS: RNA was isolated from human vascular
      smooth muscle, and the functional domains of ER-alpha and PR were characterized
      by reverse transcriptase and polymerase chain reaction. Interestingly, in
      addition to wild-type ER-alpha and PR, 5 variant ER-alpha and 2 variant PR
      transcripts were found. These variants contained precise deletions of exons
      encoding regions of the hormone-binding domain. The PR transcripts lacked exon 4
      (PRDelta4) and exon 6 (PRDelta6). The ER-alpha transcripts were missing exon 4
      (ERDelta4), exon 5 (ERDelta5), exon 6 (ERDelta6), exon 7 (ERDelta7), and exons 6
      and 7, (ERDelta6,7). ER-beta variants were also detected. The PR variants were
      functionally characterized, and PRDelta6 was found to be a dominant-negative
      transcription inhibitor of wild-type receptors. Variant PR was present in
      premenopausal women but absent in postmenopausal women. CONCLUSIONS: Variant PR
      and ER transcripts are extensively expressed in human vascular smooth muscle. The
      complex tissue-specific effects of sex hormones may be mediated by the expression
      of heterogeneous forms of their cognate receptors. The presence of variant ERs
      and PRs may be of importance in altering the physiological effects of estrogens
      or progestins in vascular smooth muscle.

PMID- 10338465
TI  - Activation of cardiac aldosterone production in rat myocardial infarction: effect
      of angiotensin II receptor blockade and role in cardiac fibrosis.
AB  - BACKGROUND: This study analyzed the regulation and the role of the cardiac
      steroidogenic system in myocardial infarction (MI). METHODS AND RESULTS: Seven
      days after MI, rats were randomized to untreated infarcted group or
      spironolactone- (20 and 80 mg x kg-1 x d-1), losartan- (8 mg x kg-1 x d-1),
      spironolactone plus losartan-, and L-NAME- (5 mg x kg-1 x d-1) treated infarcted
      groups for 25 days. Sham-operated rats served as controls. In the noninfarcted
      myocardium of the left ventricle (LV), MI raised aldosterone synthase mRNA (the
      terminal enzyme of aldosterone synthesis) by 2. 0-fold and the aldosterone level
      by 3.7-fold. Conversely, MI decreased 11beta-hydroxylase mRNA (the terminal
      enzyme of corticosterone synthesis) by 2.4-fold and the corticosterone level by
      1.9-fold. MI also induced a 1.9-fold increase in cardiac angiotensin II level.
      Such cardiac regulations were completely prevented by treatment of the infarcted
      heart with losartan. The MI-induced collagen deposition in noninfarcted LV
      myocardium was prevented by 1.6-fold by both low and high doses of spironolactone
      and by 2.5-fold by losartan. In addition, norepinephrine level was unchanged in
      infarcted heart but was attenuated by both losartan and spironolactone
      treatments. CONCLUSIONS: MI is associated with tissue-specific activation of
      myocardial aldosterone synthesis. This increase is mediated primarily by cardiac
      angiotensin II via AT1-subtype receptor and may be involved in post-MI
      ventricular fibrosis and in control of tissue norepinephrine concentration.

PMID- 10338467
TI  - Images in cardiovascular medicine. Left ventricular electromechanical mapping of
      myocardial ischemia.

PMID- 10338466
TI  - Enhanced contractility and decreased beta-adrenergic receptor kinase-1 in mice
      lacking endogenous norepinephrine and epinephrine.
AB  - BACKGROUND: Elevated circulating norepinephrine (NE) has been implicated in
      causing the profound beta-adrenergic receptor (betaAR) downregulation and
      receptor uncoupling that are characteristic of end-stage human dilated
      cardiomyopathy, a process mediated in part by increased levels of beta-adrenergic
      receptor kinase (betaARK1). To explore whether chronic sustained NE stimulation
      is a primary stimulus that promotes deterioration in cardiac signaling, we
      characterized a gene-targeted mouse in which activation of the sympathetic
      nervous system cannot lead to an elevation in plasma NE and epinephrine. METHODS
      AND RESULTS: Gene-targeted mice that lack dopamine beta-hydroxylase (dbh-/-), the
      enzyme needed to convert dopamine to NE, were created by homologous
      recombination. In vivo contractile response to the beta1AR agonist dobutamine,
      measured by a high-fidelity left ventricular micromanometer, was enhanced in mice
      lacking the dbh gene. In unloaded adult myocytes isolated from dbh-/- mice, basal
      contractility was significantly increased compared with control cells.
      Furthermore, the increase in betaAR responsiveness and enhanced cellular
      contractility were associated with a significant reduction in activity and
      protein level of betaARK1 and increased high-affinity agonist binding without
      changes in betaAR density or G-protein levels. CONCLUSIONS: Mice that lack the
      ability to generate NE or epinephrine show increased contractility associated
      primarily with a decrease in the level of betaARK1 protein and kinase activity.
      This animal model will be valuable in testing whether NE is required for the
      pathogenesis of heart failure through mating strategies that cross the dbh-/-
      mouse into genetically engineered models of heart failure.

PMID- 10338468
TI  - Fibroelastoma and embolic stroke.

PMID- 10338469
TI  - Three-dimensional transesophageal echocardiography for secundum atrial septal
      defects with a large eustachian valve.

PMID- 10338470
TI  - Diversity of antibody-mediated immunity at the mucosal barrier.

PMID- 10338471
TI  - Phylogenetic analysis of enteroaggregative and diffusely adherent Escherichia
      coli.
AB  - The phylogenetics of the various pathotypes of diarrheagenic Escherichia coli are
      not completely understood. In this study, we identified several plasmid and
      chromosomal genes in the pathogenic enteroaggregative E. coli (EAEC) prototype
      strain 042 and determined the prevalence of these loci among EAEC and diffusely
      adherent E. coli strains. The distribution of these genes is analyzed within an
      evolutionary framework provided by the characterization of allelic variation in
      housekeeping genes via multilocus enzyme electrophoresis. Our data reveal that
      EAEC strains are heterogeneous with respect to chromosomal and plasmid-borne
      genes but that the majority harbor a member of a conserved family of virulence
      plasmids. Comparison of plasmid and chromosomal relatedness of strains suggests
      clonality of chromosomal markers and a limited transfer model of plasmid
      distribution.

PMID- 10338472
TI  - Molecular characterization of a Brucella species large DNA fragment deleted in
      Brucella abortus strains: evidence for a locus involved in the synthesis of a
      polysaccharide.
AB  - A Brucella melitensis 16M DNA fragment of 17,119 bp, which contains a large
      region deleted in B. abortus strains and DNA flanking one side of the deletion,
      has been characterized. In addition to the previously identified omp31 gene, 14
      hypothetical genes have been identified in the B. melitensis fragment, most of
      them showing homology to genes involved in the synthesis of a polysaccharide.
      Considering that 10 of the 15 genes are missing in B. abortus and that all the
      polysaccharides described in the Brucella genus (lipopolysaccharide, native
      hapten, and polysaccharide B) have been detected in all the species, it seems
      likely that the genes described here might be part of a cluster for the synthesis
      of a novel Brucella polysaccharide. Several polysaccharides have been identified
      as important virulence factors, and the discovery of a novel polysaccharide in
      the brucellae which is probably not synthesized in B. abortus might be
      interesting for a better understanding of the pathogenicity and host preference
      differences observed between the Brucella species. However, the possibility that
      the genes described in this paper no longer encode the synthesis of a
      polysaccharide cannot be excluded. Brucellae belong to the alpha-2 subdivision of
      the class Proteobacteria, which includes other microorganisms living in
      association with eucaryotic cells, some of them synthesizing extracellular
      polysaccharides involved in the interaction with the host cell. The genes
      described in this paper might be a remnant of the common ancestor of the alpha-2
      subdivision of the class Proteobacteria, and the brucellae might have lost such
      extracellular polysaccharide during evolution if it was not necessary for
      survival or for establishment of the infectious process. Nevertheless, further
      studies are necessary to identify the entire DNA fragment missing in B. abortus
      strains and to elucidate the mechanism responsible for such deletion, since only
      9,948 bp of the deletion was present in the sequenced B. melitensis DNA fragment.

PMID- 10338473
TI  - Profiles of Th1 and Th2 cytokines after primary and secondary infection by
      Schistosoma mansoni in the semipermissive rat host.
AB  - In contrast to most mouse strains, rats eliminate the primary schistosome burden
      around 4 weeks postinfection and subsequently develop protective immunity to
      reinfection. In rat schistosomiasis, we have shown predominant expression of a
      Th2-type cytokine response at the mRNA level after primary infection. In the
      present study, we showed a significant increase in interleukin-4 (IL-4) mRNA
      expression in inguinal lymph nodes early after a secondary infection. IL-5 mRNA
      expression showed a significant increase at days 2 and 4 postreinfection in the
      spleen and lymph nodes, respectively. We did not detect any gamma interferon (IFN
      gamma) mRNA after a challenge infection. Analysis of cytokine secretion by
      stimulated spleen cells after a primary infection showed predominant expression
      of IL-4 with maximum production on day 21, accompanied by production of IL-5 from
      day 11 to day 67. A significant increase in IFN-gamma secretion was detected at
      day 21. Analysis of immunoglobulin G2b (IgG2b) and IgG2c (Th1-related isotypes)
      showed undetectable levels of IgG2b, but detectable levels of specific IgG2c
      antibodies were observed from day 42. The analysis of Th2-related isotypes showed
      high specific IgG1 and IgG2a antibody titers from day 29. After a secondary
      infection, only IL-4 and IL-5 secretion was sustained. This is supported by the
      increased production of Th2-related isotypes. These findings showed that S.
      mansoni infection can drive Th2 responses in rats in the absence of egg
      production which is required to induce a Th2 response in mice and are in favor of
      the role of Th2-type cytokines in protective immunity against reinfection.

PMID- 10338474
TI  - Identification and characterization of a novel fibronectin-binding protein on the
      surface of group A streptococci.
AB  - Understanding the role surface proteins play in the interaction of group A
      streptococci with epithelial cells is an important step toward the development of
      new strategies to fight infections. Fibronectin-binding proteins in streptococci
      and staphylococci have been described as important mediators for adherence to
      eukaryotic cells. In the present study we describe a new Streptococcus pyogenes
      fibronectin-binding protein (PFBP). The gene encoding the PFBP protein (pfbp) was
      identified from an M12 strain genomic library. It encodes a protein of 127.4 kDa
      which contains the LPXTGX motif characteristic of cell wall-associated proteins
      in gram-positive organisms and is among the largest surface molecules described
      for group A streptococci. The pfbp gene is transcribed during cell growth and was
      present in several class I and II streptococcal strains tested. The deduced amino
      acid sequence of PFBP exhibits a variable N-terminal region and a conserved C
      terminal region when compared to most fibronectin-binding proteins identified
      from other gram-positive bacteria. The N-terminal region presents a stretch of
      105 amino acids with no homology with N-terminal regions of previously described
      fibronectin-binding molecules, while the C-terminal region contains three repeat
      domains that share significant similarity with the repeat regions of fibronectin
      binding proteins from S. pyogenes, S. dysgalactiae, and S. equisimilis. The PFBP
      repeated region, when expressed on the surface of S. gordonii, a commensal
      organism, binds to soluble and immobilized fibronectin. This study also shows
      that, in addition to pfbp, a second gene homologous with that of protein F1
      (which also codes for a fibronectin-binding protein) is transcribed during cell
      growth in the same S. pyogenes strain.

PMID- 10338475
TI  - Effect of multiple mutations in the hemoglobin- and hemoglobin-haptoglobin
      binding proteins, HgpA, HgpB, and HgpC, of Haemophilus influenzae type b.
AB  - Haemophilus influenzae requires heme for growth and can utilize hemoglobin and
      hemoglobin-haptoglobin as heme sources. We previously identified two hemoglobin-
      and hemoglobin-haptoglobin-binding proteins, HgpA and HgpB, in H. influenzae
      HI689. Insertional mutation of hgpA and hgpB, either singly or together, did not
      abrogate the ability to utilize or bind either hemoglobin or the hemoglobin
      haptoglobin complex. A hemoglobin affinity purification method was used to
      isolate a protein of approximately 120 kDa from the hgpA hgpB double mutant. We
      have cloned and sequenced the gene encoding this third hemoglobin/hemoglobin
      haptoglobin binding protein and designate it hgpC. Insertional mutation of hgpC
      did not affect the ability of the strain to utilize either hemoglobin or
      hemoglobin-haptoglobin. An hgpA hgpB hgpC triple mutant constructed by
      insertional mutagenesis showed a reduced ability to use the hemoglobin
      haptoglobin complex but was unaltered in the ability to use hemoglobin. A second
      class of mutants was constructed in which the entire structural gene of each of
      the three proteins was deleted. The hgpA hgpB hgpC complete-deletion triple
      mutant was unable to utilize the hemoglobin-haptoglobin complex and showed a
      reduced ability to use hemoglobin. We have identified three hemoglobin/hemoglobin
      haptoglobin-binding proteins in Haemophilus influenzae. Any one of the three
      proteins is sufficient to support growth with hemoglobin-haptoglobin as the heme
      source, and expression of at least one of the three is essential for hemoglobin
      haptoglobin utilization. Although the three proteins play a role in hemoglobin
      utilization, an additional hemoglobin acquisition mechanism(s) exists.

PMID- 10338476
TI  - Production of beta-defensin antimicrobial peptides by the oral mucosa and
      salivary glands.
AB  - beta-Defensins are cationic peptides with broad-spectrum antimicrobial activity
      that are produced by epithelia at mucosal surfaces. Two human beta-defensins, HBD
      1 and HBD-2, were discovered in 1995 and 1997, respectively. However, little is
      known about the expression of HBD-1 or HBD-2 in tissues of the oral cavity and
      whether these proteins are secreted. In this study, we characterized the
      expression of HBD-1 and HBD-2 mRNAs within the major salivary glands, tongue,
      gingiva, and buccal mucosa and detected beta-defensin peptides in salivary
      secretions. Defensin mRNA expression was quantitated by RNase protection assays.
      HBD-1 mRNA expression was detected in the gingiva, parotid gland, buccal mucosa,
      and tongue. Expression of HBD-2 mRNA was detected only in the gingival mucosa and
      was most abundant in tissues with associated inflammation. To test whether beta
      defensin expression was inducible, gingival keratinocyte cell cultures were
      treated with interleukin-1beta (IL-1beta) or bacterial lipopolysaccharide (LPS)
      for 24 h. HBD-2 expression increased approximately 16-fold with IL-1beta
      treatment and approximately 5-fold in the presence of LPS. Western
      immunoblotting, liquid chromatography, and mass spectrometry were used to
      identify the HBD-1 and HBD-2 peptides in human saliva. Human beta-defensins are
      expressed in oral tissues, and the proteins are secreted in saliva; HBD-1
      expression was constitutive, while HBD-2 expression was induced by IL-1beta and
      LPS. Human beta-defensins may play an important role in the innate defenses
      against oral microorganisms.

PMID- 10338478
TI  - Suppression of platelet aggregation by Bordetella pertussis adenylate cyclase
      toxin.
AB  - The effect of Bordetella pertussis adenylate cyclase toxin (ACT) on platelet
      aggregation was investigated. This cell-invasive adenylate cyclase completely
      suppressed ADP (10 microM)-induced aggregation of rabbit platelets at 3
      micrograms/ml and strongly suppressed thrombin (0. 2 U/ml)-induced aggregation at
      10 micrograms/ml. The suppression was accompanied by marked increase in platelet
      intracellular cyclic AMP (cAMP) content and was diminished by the anti-ACT
      monoclonal antibody B7E11. A catalytically inactive point mutant of ACT did not
      show the suppressive effect. Since an increase of cAMP content is a known cause
      of platelet dysfunction, these results indicate that the observed platelet
      inactivation was due to the catalytic activity of ACT through increase of
      intracellular cAMP.

PMID- 10338477
TI  - Protection against development of otitis media induced by nontypeable Haemophilus
      influenzae by both active and passive immunization in a chinchilla model of virus
      bacterium superinfection.
AB  - Three separate studies, two involving active-immunization regimens and one
      involving a passive-transfer protocol, were conducted to initially screen and
      ultimately more fully assess several nontypeable Haemophilus influenzae outer
      membrane proteins or their derivatives for their relative protective efficacy in
      chinchilla models of otitis media. Initial screening of these antigens (P5
      fimbrin, lipoprotein D, and P6), delivered singly or in combination with either
      Freund's adjuvant or alum, indicated that augmented bacterial clearance from the
      nasopharynx, the middle ears, or both anatomical sites could be induced by
      parenteral immunization with P5-fimbrin combined with lipoprotein D, lipoprotein
      D alone, or the synthetic chimeric peptide LB1 (derived from P5-fimbrin),
      respectively. Data from a second study, wherein chinchillas were immunized with
      LB1 or lipoprotein D, each delivered with alum, again indicated that clearance of
      nontypeable H. influenzae could be augmented by immunization with either of these
      immunogens; however, when this adjuvant was used, both antibody titers in serum
      and efficacy were reduced. A third study was performed to investigate passive
      delivery of antisera directed against either LB1, lipoprotein D, nonacylated
      lipoprotein D, or a unique recombinant peptide designated LPD-LB1(f)2,1,3. The
      last three antiserum pools were generated by using the combined adjuvant of alum
      plus monophosphoryl lipid A. Passive transfer of sera specific for LB1 or LPD
      LB1(f)2,1,3 to adenovirus-compromised chinchillas, prior to intranasal challenge
      with nontypeable H. influenzae, significantly reduced the severity of signs and
      incidence of otitis media which developed (P </= 0.001). Collectively, these data
      indicate the continued merit of further developing LB1 and LPD-LB1(f)2,1,3 as
      components of vaccines for otitis media.

PMID- 10338479
TI  - Cross-reactivity between the rheumatoid arthritis-associated motif EQKRAA and
      structurally related sequences found in Proteus mirabilis.
AB  - Cross-reactivity or molecular mimicry may be one of the underlying mechanisms
      involved in the etiopathogenesis of rheumatoid arthritis (RA). Antiserum against
      the RA susceptibility sequence EQKRAA was shown to bind to a similar peptide
      ESRRAL present in the hemolysin of the gram-negative bacterium Proteus mirabilis,
      and an anti-ESRRAL serum reacted with EQKRAA. There was no reactivity with either
      anti-EQKRAA or anti-ESRRAL to a peptide containing the EDERAA sequence which is
      present in HLA-DRB1*0402, an allele not associated with RA. Furthermore, the
      EQKRAA and ESRRAL antisera bound to a mouse fibroblast transfectant cell line
      (Dap.3) expressing HLA-DRB1*0401 but not to DRB1*0402. However, peptide sequences
      structurally related to the RA susceptibility motif LEIEKDFTTYGEE (P. mirabilis
      urease), VEIRAEGNRFTY (collagen type II) and DELSPETSPYVKE (collagen type XI) did
      not bind significantly to cell lines expressing HLA-DRB1*0401 or HLA-DRB1*0402
      compared to the control peptide YASGASGASGAS. It is suggested here that molecular
      mimicry between HLA alleles associated with RA and P. mirabilis may be relevant
      in the etiopathogenesis of the disease.

PMID- 10338480
TI  - Molecular characterization of equine isolates of Streptococcus pneumoniae:
      natural disruption of genes encoding the virulence factors pneumolysin and
      autolysin.
AB  - Although often considered a strict human pathogen, Streptococcus pneumoniae has
      been reported to infect and cause pneumonia in horses, although the pathology
      appears restricted compared to that of human infections. Here we report on the
      molecular characterization of a group of S. pneumoniae isolates obtained from
      horses in England and Ireland. Despite being obtained from geographically
      distinct locations, the isolates were found to represent a tight clonal group,
      virtually identical to each other but genetically distinguishable from more than
      120 divergent isolates of human S. pneumoniae. A comprehensive analysis of known
      pneumococcal virulence determinants was undertaken in an attempt to understand
      the pathogenicity of equine pneumococci. Surprisingly, equine isolates appear to
      lack activities associated with both the hemolytic cytotoxin pneumolysin, often
      considered a major virulence factor of pneumococci, and the major autolysin gene
      lytA, also considered an important virulence factor. In support of phenotypic
      data, molecular studies demonstrated a deletion of parts of the coding sequences
      of both lytA and ply genes in equine pneumococci. The implications of these
      findings for the evolution and pathogenicity of equine S. pneumoniae are
      discussed.

PMID- 10338481
TI  - Environmental modulation of oral treponeme virulence in a murine model.
AB  - This investigation examined the effects of environmental alteration on the
      virulence of the oral treponemes Treponema denticola and Treponema pectinovorum.
      The environmental effects were assessed by using a model of localized
      inflammatory abscesses in mice. In vitro growth of T. denticola and T.
      pectinovorum as a function of modification of the cysteine concentration
      significantly enhanced abscess formation and size. In contrast, growth of T.
      denticola or T. pectinovorum under iron-limiting conditions (e.g., dipyridyl
      chelation) had no effect on abscess induction in comparison to that when the
      strains were grown under normal iron conditions. In vivo modulation of the
      microenvironment at the focus of infection with Cytodex beads demonstrated that
      increasing the local inflammation had no effect on lesion induction or size. In
      vivo studies involved the determination of the effects of increased systemic iron
      availability (e.g., iron dextran or phenylhydrazine) on the induction, kinetics,
      and size of lesions. T. denticola induced significantly larger lesions in mice
      with iron pretreatment and demonstrated systemic manifestations of the infectious
      challenge and an accompanying spreading lesion with phenylhydrazine pretreatment
      (e.g., increases in circulating free hemoglobin). In contrast, T. pectinovorum
      virulence was minimally affected by this in vivo treatment to increase iron
      availability. T. denticola virulence, as evaluated by lesion size, was increased
      additively by in vivo iron availability, and cysteine modified growth of the
      microorganism. Additionally, galactosamine sensitized mice to a lethal outcome
      following infection with both T. denticola and T. pectinovorum, suggesting an
      endotoxin-like activity in these treponemes. These findings demonstrated the
      ability to modify the virulence capacity of T. denticola and T. pectinovorum by
      environmental conditions which can be evaluated by using in vivo murine models.

PMID- 10338483
TI  - Infection-associated decline of cape buffalo blood catalase augments serum
      trypanocidal activity.
AB  - Clearance of trypanosomes from the blood of infected Cape buffalo was associated
      with the development of two responses: (i) complement-dependent and clone
      specific lytic activity and (ii) complement-independent trypanocidal activity
      that was not restricted by trypanosome clone or species. This latter activity was
      mediated by H2O2 and required the presence of xanthine oxidase in serum but not
      the addition of purine substrates. Expression of the xanthine oxidase-dependent
      trypanocidal activity in Cape buffalo serum was coincident with, and required, a
      decline in its H2O2 catabolic activity. The H2O2 catabolic activity of Cape
      buffalo serum was due solely to catalase and declined by eightfold around the
      time that trypanosomes were cleared from the blood, accompanied by a fivefold
      drop in erythrocyte-associated catalase activity. The Cape buffalo did not
      develop subsequent parasitemic waves. Clearance of parasitemia in similarly
      infected cattle was also associated with development of trypanosome clone
      specific lytic activity, but not with the acquisition of H2O2-dependent
      trypanocidal activity in serum, and the cattle supported recurring parasitemia.
      The lack of trypanocidal activity in pre- and postinfection cattle sera was due
      to their low content of xanthine oxidase and sustained catalase activity. These
      data strongly suggest that an infection-induced serum oxidative response, the
      efficacy of which is amplified by a decline in blood catalase, contributes to
      suppression of recurring parasitemia in Cape buffalo.

PMID- 10338482
TI  - Lipopolysaccharide (LPS)-binding synthetic peptides derived from serum amyloid P
      component neutralize LPS.
AB  - Lipopolysaccharide (LPS) is the major mediator of gram-negative septic shock.
      Molecules that bind LPS and neutralize its toxic effects could have important
      clinical applications. We showed that serum amyloid P component (SAP) neutralizes
      LPS. A SAP-derived peptide, consisting of amino acids 27 to 39, inhibited LPS
      mediated effects in the presence of human blood. In this study, we used a pepscan
      of overlapping 15-mer peptides and distinguished two additional LPS-binding
      regions within the SAP molecule, identified in the regions spanning amino acids
      61 to 75 and 186 to 200. The corresponding SAP-derived peptides, pep61-75 and
      pep186-200, inhibited the binding of fluorescein isothiocyanate-labeled LPS to
      monocytes as efficiently as a bactericidal/permeability-increasing protein (BPI)
      derived 15-mer peptide comprising amino acids 85 to 99. The same SAP-derived
      peptides very potently inhibited LPS-induced priming of phagocytes in human
      blood. Also, SAP-derived pep186-200 caused a prolonged survival of actinomycin D
      sensitized mice treated with LPS to induce septic shock, indicating a potential
      use of this peptide in the defense against serious gram-negative sepsis in
      humans.

PMID- 10338485
TI  - Platelet-activating factor induces nitric oxide synthesis in Trypanosoma cruzi
      infected macrophages and mediates resistance to parasite infection in mice.
AB  - Trypanosoma cruzi replicates in nucleated cells and is susceptible to being
      killed by gamma interferon-activated macrophages through a mechanism dependent
      upon NO biosynthesis. In the present study, the role of platelet-activating
      factor (PAF) in the induction of NO synthesis and in the activation of the
      trypanocidal activity of macrophages was investigated. In vitro, PAF induced NO
      secretion by T. cruzi-infected macrophages and the secreted NO inhibited
      intracellular parasite growth. The addition of a PAF antagonist, WEB 2170,
      inhibited both NO biosynthesis and trypanocidal activity. The inducible NO
      synthase/L-arginine pathway mediated trypanocidal activity, since it was
      inhibited by treatment with L-N-monomethyl arginine (L-NMMA), an L-arginine
      analog. PAF-mediated NO production in infected macrophages appears to be
      dependent on tumor necrosis alpha (TNF-alpha) production, since the addition of a
      neutralizing anti-TNF-alpha monoclonal antibody mAb inhibited NO synthesis. To
      test the role of PAF in mediating resistance or susceptibility to T. cruzi
      infection, infected mice were treated with WEB 2170, a PAF antagonist. These
      animals had higher parasitemia and earlier mortality than did vehicle-treated
      mice. Taken together, our results suggest that PAF belongs to a group of
      mediators that coordinate the mechanisms of resistance to infections with
      intracellular parasites.

PMID- 10338484
TI  - CD4(+) T cells and the proinflammatory cytokines gamma interferon and interleukin
      6 contribute to alveolar bone loss in mice.
AB  - In this study, we used a mouse model to examine the role of the adaptive immune
      response in alveolar bone loss induced by oral infection with the human gram
      negative anaerobic bacterium Porphyromonas gingivalis. Severe combined
      immunodeficient mice, which lack B and T lymphocytes, exhibited considerably less
      bone loss than did immunocompetent mice after oral infection, suggesting that
      lymphocytes contribute to this process. Bone loss after oral infection was
      decreased in mice deficient in major histocompatibility complex (MHC) class II
      responsive CD4(+) T cells, but no change in bone loss was observed in mice
      deficient in MHC class I-responsive CD8(+) T cells or NK1(+) T cells. Mice
      lacking the cytokine gamma interferon or interleukin-6 also demonstrated
      decreased bone loss. These results suggest that the adaptive immune response, and
      in particular CD4(+) T cells and the proinflammatory cytokines that they secrete,
      are important effectors of bone loss consequent to P. gingivalis oral infection.
      The studies also reinforce the utility of the mouse oral infection model in
      dissecting the pathobiology of periodontal disease.

PMID- 10338486
TI  - Evaluation of Salmonella typhimurium mutants in a model of experimental
      gastroenteritis.
AB  - Salmonella typhimurium strains harboring independent, defined mutations in aroA,
      invA, ssrA, or msbB were assessed for their ability to induce fluid accumulation,
      tissue damage, and local inflammation in rabbit ileal loops. Three wild-type
      strains of S. typhimurium, TML, HWSH, and SL1344, and two mutant strains, S.
      typhimurium SL1344 ssrA and S. typhimurium SL1344 msbB, consistently induced
      fluid accumulation in the lumen of loops and inflammation of loop-associated
      tissues. In contrast, three different S. typhimurium aroA strains and an invA
      mutant of SL1344 did not induce significant fluid accumulation in the rabbit
      ileal loops. However, the S. typhimurium aroA strains did induce an inflammatory
      infiltrate and some local villus-associated damage, but the invA mutant did not.
      Histologically, wild-type S. typhimurium, S. typhimurium SL1344 ssrA, and S.
      typhimurium SL1344 msbB demonstrated more severe effects on villus architecture
      than S. typhimurium aroA strains, whereas S. typhimurium invA-infected loops
      showed no detectable damage. This suggests that villus damage most likely
      contributes to fluid accumulation within the loop.

PMID- 10338487
TI  - Requirement of MrpH for mannose-resistant Proteus-like fimbria-mediated
      hemagglutination by Proteus mirabilis.
AB  - Two new genes, mrpH and mrpJ, were identified downstream of mrpG in the mrp gene
      cluster encoding mannose-resistant Proteus-like (MR/P) fimbriae of uropathogenic
      Proteus mirabilis. Since the predicted MrpH has 30% amino acid sequence identity
      to PapG, the Galalpha(1-4)Gal-binding adhesin of Escherichia coli P fimbriae, we
      hypothesized that mrpH encodes the functional MR/P hemagglutinin. MR/P fimbriae,
      expressed in E. coli DH5alpha, conferred on bacteria both the ability to cause
      mannose-resistant hemagglutination and the ability to aggregate to form pellicles
      on the broth surface. Both a DeltamrpH mutant expressed in E. coli DH5alpha and
      an isogenic mrpH::aphA mutant of P. mirabilis were unable to produce normal MR/P
      fimbriae efficiently, suggesting that MrpH was involved in fimbrial assembly.
      Amino acid residue substitution of the N-terminal cysteine residues (C66S and
      C128S) of MrpH abolished the receptor-binding activity (hemagglutinating ability)
      of MrpH but allowed normal fimbrial assembly, supporting the notion that MrpH was
      the functional MR/P hemagglutinin. Immunogold electron microscopy of P. mirabilis
      HI4320 revealed that MrpH was located at the tip of MR/P fimbriae, also
      consistent with its role in receptor binding. The isogenic mrpH::aphA mutant of
      HI4320 was less able to colonize the urine, bladder, and kidneys in a mouse model
      of ascending urinary tract infection (P < 0.01), and therefore MR/P fimbriae
      contribute significantly to bacterial colonization in mice. While there are
      similarities between P. mirabilis MR/P and E. coli P fimbriae, there are more
      notable differences: (i) synthesis of the MrpH adhesin is required to initiate
      fimbrial assembly, (ii) MR/P fimbriae confer an aggregation phenotype, (iii) site
      directed mutation of specific residues can abolish receptor binding but allows
      fimbrial assembly, and (iv) mutation of the adhesin gene abolishes virulence in a
      mouse model of ascending urinary tract infection.

PMID- 10338488
TI  - Effects of cytokines and endotoxin on the intracellular growth of bacteria.
AB  - Patients with unresolving acute respiratory distress syndrome (ARDS) have
      persistently elevated levels of proinflammatory cytokines in the lungs and
      circulation and increased rates of bacterial infections. Phagocytic cells
      hyperactivated with lipopolysaccharide (LPS), which induces high levels of
      proinflammatory cytokines in monocytic cells, are inefficient in killing ingested
      bacteria despite having intact phagocytic activity. On the other hand, phagocytic
      cells that are activated with an analogue of LPS that does not induce the
      expression of proinflammatory cytokines effectively ingest and kill bacteria. We
      hypothesized that in the presence of high concentrations of proinflammatory
      cytokines, bacteria may adapt and utilize cytokines to their growth advantage. To
      test our hypothesis, we primed a human monocytic cell line (U937) with escalating
      concentrations of the proinflammatory cytokines tumor necrosis factor alpha,
      interleukin-1beta (IL-1beta), and IL-6 and with LPS. These cells were then
      exposed to fresh isolates of three common nosocomial pathogens: Staphylococcus
      aureus, Pseudomonas aeruginosa, and an Acinetobacter sp. In human monocytes
      primed with lower concentrations of proinflammatory cytokines (10 to 250 pg) or
      LPS (1 and 10 ng), intracellular bacterial growth decreased. However, when human
      monocytes were primed with higher concentrations of proinflammatory cytokines (1
      to 10 ng) or LPS (1 to 10 micrograms), intracellular growth of the tested
      bacteria increased significantly (P <0.0001). These results were reproduced with
      peripheral blood monocytes obtained from normal healthy volunteers. The
      specificity of the cytokine activity was demonstrated by neutralizing the
      cytokines with specific antibodies. Our findings provide a possible mechanism to
      explain the frequent development of bacterial infections in patients with an
      intense and protracted inflammatory response.

PMID- 10338489
TI  - Inhibition of osteoblastic cell differentiation by lipopolysaccharide extract
      from Porphyromonas gingivalis.
AB  - Lipopolysaccharide from Porphyromonas gingivalis (P-LPS), an important pathogenic
      bacterium, is closely associated with inflammatory destruction of periodontal
      tissues. P-LPS induces the release of cytokines and local factors from
      inflammatory cells, stimulates osteoclastic-cell differentiation, and causes
      alveolar bone resorption. However, the effect of P-LPS on osteoblastic-cell
      differentiation remains unclear. In this study, we investigated the effect of P
      LPS extract prepared by the hot-phenol-water method, on the differentiation of
      primary fetal rat calvaria (RC) cells, which contain a subpopulation of
      osteoprogenitor cells, into osteoblastic cells. P-LPS extract significantly
      inhibited bone nodule (BN) formation and the activity of alkaline phosphatase
      (ALPase), an osteoblastic marker, in a dose-dependent manner (0 to 100 ng of P
      LPS extract per ml). P-LPS extract (100 ng/ml) significantly decreased BN
      formation to 27% of the control value and inhibited ALPase activity to
      approximately 60% of the control level on days 10 to 21 but did not affect RC
      cell proliferation and viability. P-LPS extract time-dependently suppressed the
      expression of ALPase mRNA, with an inhibitory pattern similar to that of enzyme
      activity. The expression of mRNAs for osteocalcin and osteopontin, matrix
      proteins related to bone metabolism, was markedly suppressed by P-LPS extract.
      Furthermore, P-LPS extract increased the expression of mRNAs for CD14, LPS
      receptor, and interleukin-1beta in RC cells. These results indicate that P-LPS
      inhibits osteoblastic-cell differentiation and suggest that LPS-induced bone
      resorption in periodontal disease may be mediated by effects on osteoblastic as
      well as osteoclastic cells.

PMID- 10338490
TI  - Interruption of multiple cellular processes in HT-29 epithelial cells by
      Pseudomonas aeruginosa exoenzyme S.
AB  - Exoenzyme S (ExoS), an ADP-ribosylating enzyme produced by the opportunistic
      pathogen Pseudomonas aeruginosa, is directly translocated into eukaryotic cells
      by bacterial contact. Within the cell, ExoS ADP-ribosylates the cell signaling
      protein Ras and causes inhibition of DNA synthesis and alterations in
      cytoskeletal structure. To further understand the interrelationship of the
      different cellular effects of ExoS, functional analyses were performed on HT-29
      epithelial cells after exposure to ExoS-producing P. aeruginosa 388 and the non
      ExoS-producing strain 388DeltaS. Two different mechanisms of morphological
      alteration were identified: (i) a more-transient and less-severe cell rounding
      caused by the non-ExoS-producing strain 388DeltaS and (ii) a more-severe, long
      term cell rounding caused by ExoS-producing strain 388. Long-term effects of ExoS
      on cell morphology occurred in conjunction with ExoS-mediated inhibition of DNA
      synthesis and the ADP-ribosylation of Ras. ExoS was also found to cause
      alterations in HT-29 cell function, leading to the loss of cell adhesion and
      microvillus effacement. Nonadherent ExoS-treated cells remained viable but had a
      high proportion of modified Ras. While microvillus effacement was detected in
      both 388- and 388DeltaS-treated cells, effacement was more prevalent and rapid in
      cells exposed to strain 388. We conclude from these studies that ExoS can have
      multiple effects on epithelial cell function, with more severe cellular
      alterations associated with the enzymatic modification of Ras. The finding that
      ExoS had greater effects on cell growth and adherence than on cell viability
      suggests that ExoS may contribute to the P. aeruginosa infectious process by
      rendering cells nonfunctional.

PMID- 10338491
TI  - Antigenic and molecular conservation of the gonococcal NspA protein.
AB  - A low-molecular-weight protein named NspA (neisserial surface protein A) was
      recently identified in the outer membrane of all Neisseria meningitidis strains
      tested. Antibodies directed against this protein were shown to protect mice
      against an experimental meningococcal infection. Hybridization experiments
      clearly demonstrated that the nspA gene was also present in the genomes of the 15
      Neisseria gonorrhoeae strains tested. Cloning and sequencing of the nspA gene of
      N. gonorrhoeae B2 revealed an open reading frame of 525 nucleotides coding for a
      polypeptide of 174 amino acid residues, with a calculated molecular weight of
      18,316 and a pI of 10.21. Comparison of the predicted amino acid sequence of the
      NspA polypeptides from the gonococcal strains B2 and FA1090, together with that
      of the meningococcal strain 608B, revealed an identity of 93%, suggesting that
      the NspA protein is highly conserved among pathogenic Neisseria strains. The
      level of identity rose to 98% when only the two gonococcal predicted NspA
      polypeptides were compared. To evaluate the level of antigenic conservation of
      the gonococcal NspA protein, monoclonal antibodies (MAbs) were generated. Four of
      the seven NspA-specific MAbs described in this report recognized their
      corresponding epitope in 100% of the 51 N. gonorrhoeae strains tested.
      Radioimmunobinding assays clearly indicated that the gonococcal NspA protein is
      exposed at the surface of intact cells.

PMID- 10338492
TI  - Role of Pneumolysin's complement-activating activity during pneumococcal
      bacteremia in cirrhotic rats.
AB  - We investigated the role of pneumolysin's complement-activating activity during
      Streptococcus pneumoniae bacteremia in a hypocomplementemic, cirrhotic host.
      Isogenic mutant pneumococcal strains, in which pneumolysin was expressed from a
      plasmid, were used. These strains included H+C+, expressing wild-type pneumolysin
      with both cytolytic and complement-activating activity; PLY-, carrying the
      plasmid without the pneumolysin gene; and, H+C-, expressing pneumolysin with
      cytolytic activity only. In control rats, intravenous infection with 2.0 x 10(7)
      CFU of H+C+ per ml of blood resulted in a decrease in bacteremia of 3.5 log units
      by 18 h postinfection and 55% mortality. By contrast, cirrhotic rats infected
      similarly with the H+C+ strain demonstrated a 0.2-log-unit increase in bacteremia
      by 18 h postinfection and 100% mortality. Both control and cirrhotic rats cleared
      the PLY- strain more effectively from their bloodstreams by 18 h postinfection
      (6.2 and 5. 6 log unit decreases, respectively). Infection with the PLY- strain
      also resulted in low mortality (0 and 14%, respectively) for control and
      cirrhotic rats. When infected with the H+C- strain (without complement-activating
      activity), both groups cleared the organism from their bloodstreams nearly as
      well as they did the PLY- strain. Furthermore, the mortality rate for control and
      cirrhotic rats was identical after infection with the H+C- strain. These studies
      suggest that pneumolysin production contributes to decreased pneumococcal
      clearance from the bloodstream and higher mortality in both control and cirrhotic
      rats. However, pneumolysin's complement-activating activity may uniquely enhance
      pneumococcal virulence in the hypocomplementemic, cirrhotic host.

PMID- 10338493
TI  - Persistence and protective efficacy of a Mycobacterium tuberculosis auxotroph
      vaccine.
AB  - New vaccines against tuberculosis are urgently required because of the impressive
      incidence of this disease worldwide and the highly variable protective efficacy
      of the current vaccine. The possibility of creating new live vaccines by the
      rational attenuation of strains from the Mycobacterium tuberculosis complex was
      investigated. Two auxotrophic mutants of M. tuberculosis and M. bovis BCG were
      constructed by disruption of one of their purine biosynthetic genes. These
      mutants appeared unable to multiply in vitro within mouse bone-marrow derived
      macrophages. They were also attenuated in vivo in the mouse and guinea pig animal
      models. In guinea pigs, the two mutants induced strong delayed-type
      hypersensitivity response to purified protein derivative. In a preliminary
      experiment, the two mutants were compared to the BCG vaccine for their protective
      efficacy in a challenge against aerosolized virulent M. tuberculosis in the
      guinea pig model. Both mutants conferred some level of protection. These
      experiments demonstrate that the rational attenuation of M. tuberculosis could
      lead to the design of new candidate live vaccines against tuberculosis.

PMID- 10338495
TI  - Antibody responses in the lower respiratory tract and male urogenital tract in
      humans after nasal and oral vaccination with cholera toxin B subunit.
AB  - Nasal vaccine delivery is superior to oral delivery in inducing specific
      immunoglobulin A (IgA) and IgG antibody responses in the upper respiratory tract.
      Although an antibody response in the nasal passages is important in protecting
      against primary colonization with lung pathogens, antibodies in the lungs are
      usually required as well. We immunized 15 male volunteers twice nasally or orally
      with cholera toxin B subunit (CTB) and determined the specific antibody levels in
      serum, bronchoalveolar lavage (BAL) fluid, and urine before and 2 weeks after
      immunization. Nasal immunization induced fivefold increases in the levels of
      specific IgA antibodies in BAL fluid of most volunteers, whereas there were no
      significant specific IgA responses after oral immunization. The specific IgG
      antibody level increased eightfold in BAL fluid in the nasally vaccinated
      subjects, and the major part of IgG had most probably been transferred from
      serum. Since the specific IgG response in serum was lower in the individuals
      vaccinated orally, the IgG response in BAL fluid in this group was also lower and
      not significant. In conclusion, nasal immunization is also preferable to the oral
      route when vaccinating against lower respiratory tract infections, and a systemic
      immune response is considerably more important in the lower than in the upper
      respiratory tract. Moreover, both nasal and oral immunizations were able to
      stimulate 6- to 10-fold specific IgA and IgG responses in urine in about half of
      the individuals, which indicates that distant mucosal vaccination might be used
      to prevent adhesion of pathogens to the urogenital tract.

PMID- 10338494
TI  - Access of antibody or trypsin to an integral outer membrane protein (P66) of
      Borrelia burgdorferi is hindered by Osp lipoproteins.
AB  - The outer membrane of Borrelia burgdorferi, the Lyme disease agent, contains
      lipoproteins anchored by their lipid moieties and integral proteins with membrane
      spanning regions. We used the techniques of in situ proteolysis,
      immunofluorescence, in vitro growth inhibition, and cross-linking with
      formaldehyde to characterize topological relationships between P66, an integral
      membrane protein, and selected Osp lipoproteins of B. burgdorferi. Protease
      treatment of intact spirochetes cleaved P66 and Osp proteins but not the
      periplasmic flagellin or the BmpA protein of the cytoplasmic membrane. P66 of
      cells lacking OspA, OspB, and OspC was more susceptible to trypsin cleavage than
      was P66 of cells with these Osp proteins. A monoclonal antibody against the
      surface loop of P66 bound, agglutinated, and inhibited the growth of viable
      spirochetes lacking OspA, OspB, OspC, and OspD but not of the cells that
      expressed OspA, OspC, and/or OspD. When cells were fixed, the antibody bound to
      cells that express OspD and OspC but still not to cells with OspA. The close
      association of OspA and P66 was confirmed by the crosslinking of the two proteins
      by formaldehyde. These results show that Osp proteins, particularly OspA, limit
      the access of antibody or trypsin to the surface loop region of P66. The
      proximity and possible contact between P66 and OspA (or other Osp proteins) may
      hinder the effectiveness of antibodies to what otherwise would be an appropriate
      vaccine target.

PMID- 10338496
TI  - Characterization of a murine model of melioidosis: comparison of different
      strains of mice.
AB  - Melioidosis is an infectious disease caused by the saprophytic gram-negative rod
      Burkholderia pseudomallei. The aim of this study was to establish and
      characterize a murine model of melioidosis to provide a basis for further
      investigations on the pathogenesis of the disease. After intravenous infection
      with B. pseudomallei, C57BL/6 mice were found to be significantly more resistant
      than BALB/c mice. There was a marked organotropism of B. pseudomallei for the
      spleen and liver in both strains of mice, with the highest bacterial load in the
      spleen. Electron microscopic investigations of the spleen clearly demonstrated
      intracellular replication within membrane-bound phagosomes. Electron micrographs
      of the liver provided evidence that B. pseudomallei-containing phagosomes in
      hepatocytes fuse with lysosomes, leading to degradation of bacteria. In both
      strains of mice, the course of infection was highly dependent on the infective
      dose and the bacterial strain used, ranging from death within a few days to death
      after several weeks. In comparison with BALB/c mice, the bacterial counts in
      C57BL/6 mice were decreased 12 h after infection, which is suggestive of an
      innate immune mechanism against B. pseudomallei in this early phase of infection
      contributing to the lower susceptibility of C57BL/6 mice. BALB/c mice developed a
      more pronounced lymphopenia, granulocytosis, and splenomegaly at a lower
      infective dose compared to C57BL/6 mice. Analysis of the antibody response
      against B. pseudomallei 11 days after infection revealed a significantly higher
      immunoglobulin G2A (IgG2a)/IgG1 ratio in C57BL/6 mice than in BALB/c mice,
      indicating that a T helper type 1 immune response is associated with resistance
      to infection with B. pseudomallei.

PMID- 10338498
TI  - Chlamydia pneumoniae infection of human endothelial cells induces proliferation
      of smooth muscle cells via an endothelial cell-derived soluble factor(s).
AB  - An association of Chlamydia pneumoniae with atherosclerosis and coronary heart
      disease has been determined epidemiologically and by the detection of C.
      pneumoniae organisms in atherosclerotic lesions in both humans and animal models
      of atherosclerosis. Previously, it has been shown that C. pneumoniae is capable
      of replicating in cell types found within atheromatous lesions, viz., endothelial
      cells, smooth muscle cells (SMC), and macrophages, yet the role of C. pneumoniae
      in the pathogenesis of atherosclerosis has not been determined. Since intimal
      thickening is a hallmark of atherosclerosis, we investigated whether C.
      pneumoniae infection of human umbilical vein endothelial cells (HUVEC) could
      induce the expression of a soluble factor(s) with mitogenic potential for SMC by
      using [3H]thymidine incorporation and direct cell counting. Conditioned medium
      harvested from HUVEC infected with C. pneumoniae stimulated SMC replication in a
      time- and dose-dependent fashion. Infection studies using various multiplicities
      of infection (MOIs) ranging from 0.001 to 1 demonstrated a dose-dependent
      production of the soluble factor(s). At an MOI of 1, SMC stimulation indices were
      8.4 (P < 0.01) and 12.2 (P < 0.01) for conditioned media harvested at 24 and 48
      h, respectively. To determine whether viable C. pneumoniae was required for
      production of the soluble factor(s), HUVEC were infected with heat-inactivated C.
      pneumoniae or with viable organisms in the presence of chloramphenicol. Both
      treatments produced stimulation indices similar to those for live C. pneumoniae
      in the absence of chloramphenicol (P > 0.05), indicating that the factor(s) was
      produced by HUVEC and not by C. pneumoniae and that signal transduction events
      following chlamydia endocytosis may be important in the production of a soluble
      factor(s). The ability of C. pneumoniae to elicit an endothelial cell-derived
      soluble factor(s) that stimulates SMC proliferation may be important in the
      pathogenesis of atherosclerosis.

PMID- 10338497
TI  - Identification and molecular analysis of rough-colony-specific outer membrane
      proteins of Actinobacillus actinomycetemcomitans.
AB  - Actinobacillus actinomycetemcomitans, a gram-negative bacterium isolated from the
      human mouth, has been implicated in the pathogenesis of early-onset
      periodontitis. Primary isolates cultured from subgingival plaque exhibit an
      adherent, rough colony phenotype which spontaneously converts to a nonadherent,
      smooth phenotype upon in vitro subculture. The rough colony variant produces
      abundant fimbriae and autoaggregates, while the smooth colony variant is
      planktonic and produces scant fimbriae. To begin to understand the significance
      of colony variation in biofilm formation by A. actinomycetemcomitans, outer
      membrane protein profiles of four isogenic rough and smooth colony variants were
      compared by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two
      proteins with relative molecular masses of 43 and 20 kDa were expressed by the
      rough colony variants exclusively. Expression of these proteins was not found to
      be dependent on growth phase, oxygen tension, or type of complex medium. N
      terminal amino acid sequences of these proteins obtained by Edman degradation
      were compared with sequences from the University of Oklahoma A.
      actinomycetemcomitans genome database. Two contiguous open reading frames (ORFs)
      encoding proteins having sequence homology with these proteins were identified.
      The 43-kDa protein (RcpA [rough colony protein A]) was similar to precursor
      protein D of the general secretion pathway of gram-negative bacilli, while the 20
      kDa protein (RcpB [rough colony protein B]) appeared to be unique. The genes
      encoding these proteins have been cloned from A. actinomycetemcomitans 283 and
      sequenced. A BLASTX (gapped BLAST) search of the surrounding ORFs revealed
      homology with other fimbria-related proteins. These data suggest that the genes
      encoding the 43-kDa (rcpA) and 20-kDa (rcpB) proteins may be functionally related
      to each other and to genes that may encode fimbria-associated proteins.

PMID- 10338500
TI  - Lipopolysaccharide complexes with Pasteurella haemolytica leukotoxin.
AB  - The presence of lipopolysaccharide (LPS) in gram-negative bacterial repeats-in
      toxin (RTX) toxin preparations, as well as the harsh conditions required to
      remove it, suggests that LPS may complex with RTX toxins. Concentrated culture
      supernatant (CCS) preparations of the RTX toxin Pasteurella haemolytica
      leukotoxin (LKT) contained LKT and LPS as the most prominent components, with LKT
      and LPS constituting approximately 30 and 50% of the density of the silver
      stained fraction on sodium dodecyl sulfate-polyacrylamide gel electrophoresis
      (SDS-PAGE), respectively. CCS LKT contained 3.69 +/- 0.46 mg of LPS per mg of
      protein, which was estimated to indicate an LPS/LKT molar ratio of approximately
      60:1. Subjection of the CCS LKT to preparative SDS-PAGE resulted in separation of
      LPS from LKT as detected by silver-stained analytical SDS-PAGE; however, the LKT
      fraction (SDS-PAGE LKT) contained significant endotoxin activity as detected by
      the Limulus amebocyte lysate assay. Subjection of the SDS-PAGE LKT to a second
      preparative SDS-PAGE run resulted in a reduction of the LPS/LKT molar ratio to
      1:20. The target cell specificity of LKT for bovine leukocytic cells was retained
      by the SDS-PAGE LKT, and isolated LPS at comparable concentrations to that in CCS
      LKT exhibited no leukolytic activity. Addition of isolated LPS back to SDS-PAGE
      LKT resulted in reconstitution of an LPS-LKT complex. Immediately following
      reconstitution of the LPS-LKT complex, there was minimal change in leukolytic
      activity of the complex, but following 9.5 h at temperatures from -135 to 37
      degrees C, the LPS-LKT complex exhibited increased leukolytic activity and
      thermal stability compared to SDS-PAGE LKT. Therefore, it appears that LPS
      complexes with LKT, resulting in enhanced and stabilized leukolytic activity.

PMID- 10338499
TI  - Genes influencing resistance to Coccidioides immitis and the interleukin-10
      response map to chromosomes 4 and 6 in mice.
AB  - Coccidioidomycosis is a fungal infection that is endemic in the southwestern
      United States. Infection is more severe in blacks and Filipinos, which suggests
      that there is a genetic basis for susceptibility to this infection in humans. We
      found that there is also a difference in resistance to Coccidioides immitis
      infection among inbred mouse strains: B6 mice are susceptible, while DBA/2 mice
      are resistant (T. N. Kirkland and J. Fierer, Infect. Immun. 40:912-916, 1983). In
      this paper we report the results of our efforts to map the genes responsible for
      resistance to this infection in mice. Mice were infected by intraperitoneal
      inoculation, and 15 days later the numbers of viable fungi in their lungs and
      spleens were enumerated. We also determined the amounts of interleukin-10 mRNA
      made in the infected lungs. These three phenotypes were mapped as quantitative
      traits by using the 26 available lines of recombinant inbred mice derived from a
      cross between B6 and DBA/2 mice. The best associations were those between the
      regions near the Lv locus on chromosome 4 and the Tnfr1 locus on chromosome 6. We
      then infected backcross mice [(B6 x DBA/2) x B6] and confirmed these
      associations; 14 of 16 (87%) mice that were heterozygous at both Lv and Tnfr1
      were resistant to infection, whereas only 4 of 16 (25%) mice that were homozygous
      B6 at both loci were resistant. These are the first genetic loci to be associated
      with susceptibility to C. immitis, but there may be additional genes involved in
      murine resistance to this infection.

PMID- 10338501
TI  - Deletion of porA by recombination between clusters of repetitive extragenic
      palindromic sequences in Neisseria meningitidis.
AB  - PorA is an important component in a vaccine against infection with Neisseria
      meningitidis. However, porA-negative meningococci were isolated from patients,
      thereby potentially limiting the role of PorA-mediated immunity. To analyze the
      mechanism by which the porA deletion occurred, the regions upstream and
      downstream of porA from three meningococcal strains (H44/76, H355, and 860183)
      were sequenced. The porA upstream region in strain 860183 contains a cluster of
      22 repetitive palindromic RS3 core sequences (ATTCCC-N8-GGGAAT) and 10 RS3 core
      sequences (ATTCCC) in direct orientation. The cluster is flanked by neisserial
      repeats, so-called Correia elements, and can be subdivided into three repeats of
      518 bp followed by a truncated repeat. The porA upstream region of the other two
      strains showed deletions, probably caused by a recombination between RS3 core
      sequences. The porA downstream region of H44/76 and H355 contains the IS1106
      element followed by a cluster of 10 palindromic RS3 core sequences, 4 RS3 core
      sequences, and 1 other RS3 core sequence (GGGAAT) and is followed by a Correia
      element. This cluster can be subdivided into four direct repeats of 370 bp.
      Strain 860183 had two such repeats instead of four. Sequence analysis of the porA
      negative variants indicated that the deletion of porA occurred via a
      recombination between two copies of the 116-bp region, containing two palindromic
      RS3 core sequences and a single RS3 core sequence. This region is homologous in
      the upstream and downstream clusters.

PMID- 10338502
TI  - Resistance to Coccidioides immitis in mice after immunization with recombinant
      protein or a DNA vaccine of a proline-rich antigen.
AB  - Two inbred strains of mice (BALB/c and C57BL/6) were vaccinated with either
      recombinant expression protein of a Coccidioides immitis spherule-derived proline
      rich antigen (rPRA) in monophosphoryl lipid A-oil emulsion adjuvant or a DNA
      vaccine based on the same antigen. Four weeks after vaccination, mice were
      infected intraperitoneally with arthroconidia. By 2 weeks, groups of mice
      receiving saline or plasmids with no PRA insert exhibited significant weight
      loss, and quantitative CFUs in the lungs ranged from 5.9 to 6.4 log10. In
      contrast, groups of mice immunized with either rPRA or DNA vaccine had
      significantly smaller pulmonary fungal burdens, ranging from 3.0 to 4.5 log10
      fewer CFUs. In vitro immunologic markers of lymphocyte proliferation and gamma
      interferon (IFN-gamma) release after splenocytes were stimulated with rPRA
      correlated with protection. Also, plasma concentrations of rPRA-specific total
      immunoglobulin G (IgG), IgG1, and IgG2a showed increases in vaccinated mice.
      These studies expand earlier work by demonstrating protection in mice which
      differ in H-2 background, by using an adjuvant that is potentially applicable to
      human use, and by achieving comparable protections with a DNA-based vaccine. Our
      in vitro results substantiate a Th1 response as evidenced by IFN-gamma release
      and increased IgG2a. However, IgG1 was also stimulated, suggesting some Th2
      response as well. PRA is a promising vaccine candidate for prevention of
      coccidioidomycosis and warrants further investigation.

PMID- 10338503
TI  - Molecular characterization and human T-cell responses to a member of a novel
      Mycobacterium tuberculosis mtb39 gene family.
AB  - We have used expression screening of a genomic Mycobacterium tuberculosis library
      with tuberculosis (TB) patient sera to identify novel genes that may be used
      diagnostically or in the development of a TB vaccine. Using this strategy, we
      have cloned a novel gene, termed mtb39a, that encodes a 39-kDa protein. Molecular
      characterization revealed that mtb39a is a member of a family of three highly
      related genes that are conserved among strains of M. tuberculosis and
      Mycobacterium bovis BCG but not in other mycobacterial species tested. Immunoblot
      analysis demonstrated the presence of Mtb39A in M. tuberculosis lysate but not in
      culture filtrate proteins (CFP), indicating that it is not a secreted antigen.
      This conclusion is strengthened by the observation that a human T-cell clone
      specific for purified recombinant Mtb39A protein recognized autologous dendritic
      cells infected with TB or pulsed with purified protein derivative (PPD) but did
      not respond to M. tuberculosis CFP. Purified recombinant Mtb39A elicited strong T
      cell proliferative and gamma interferon responses in peripheral blood mononuclear
      cells from 9 of 12 PPD-positive individuals tested, and overlapping peptides were
      used to identify a minimum of 10 distinct T-cell epitopes. Additionally, mice
      immunized with mtb39a DNA have shown increased protection from M. tuberculosis
      challenge, as indicated by a reduction of bacterial load. The human T-cell
      responses and initial animal studies provide support for further evaluation of
      this antigen as a possible component of a subunit vaccine for M.tuberculosis.

PMID- 10338504
TI  - Lipid extract of Mycoplasma penetrans proteinase K-digested lipid-associated
      membrane proteins rapidly activates NF-kappaB and activator protein 1.
AB  - Lipid-associated membrane proteins (LAMPs) of Mycoplasma penetrans rapidly
      induced macrophages to produce proinflammatory cytokines such as tumor necrosis
      factor alpha (TNF-alpha). Our analysis showed that the macrophage-stimulating
      activity of TNF-alpha production was mainly attributable to a lipid extractable
      component(s) in the LAMP preparation. Since induction of gene expression is
      normally preceded by activation of transcriptional factors that bind to their
      specific recognition elements located in the upstream promoter region, we
      examined the activity of transcriptional factors, namely, NF-kappaB and activator
      protein 1 (AP-1), in thioglycolate exudate peritoneal (TEP) macrophages treated
      with M. penetrans lipid extract of proteinase K (PK)-digested LAMPs. Initially,
      in the nuclei of unstimulated TEP cells, there was only a low basal level of
      active AP-1, and the active form of NF-kappaB could not be detected. M. penetrans
      lipid extract of PK-digested LAMPs activated both NF-kappaB and AP-1 in TEP
      macrophages within 15 min. The markedly increased activities of both factors
      gradually declined and dissipated after 2 h. Parallel to the rapid increase of NF
      kappaB and AP-1, the TNF-alpha transcript also increased significantly 15 min
      after the stimulation. The high-level expression of TNF-alpha persisted over 2 h.
      Dexamethasone blocked the activation of both NF-kappaB and AP-1 and suppressed
      the production of TNF-alpha in TEP macrophages stimulated by M. penetrans lipid
      extract of PK-digested LAMPs. Our study demonstrates that the M. penetrans lipid
      extract of PK-digested LAMP is a potent activator for NF-kappaB and AP-1 in
      murine TEP macrophages. Our results also suggest that high-level expression of
      TNF-alpha in cells induced by M. penetrans lipid extract of PK-digested LAMPs is
      associated with rapid activation of transcriptional factors NF-kappaB and AP-1.

PMID- 10338505
TI  - Disruption of anthrax toxin binding with the use of human antibodies and
      competitive inhibitors.
AB  - The protective antigen (PA83) of Bacillus anthracis is integral to the mechanism
      of anthrax toxicity. We have isolated a human single-chain Fv antibody fragment
      (scFv) that blocks binding of a fluorescently tagged protective antigen (PA)
      moiety to cell surface receptors. Several phage-displayed scFv were isolated from
      a naive library biopanned against PA83. Soluble, monomeric scFv were
      characterized for affinity and screened for their capacity to disrupt receptor
      mediated binding of PA. Four unique scFv bound to PA83, as determined by surface
      plasmon resonance, the tightest binder exhibiting a Kd of 50 nM. Two scFv had
      similar affinities for natural PA83 and a novel, recombinant, 32-kDa carboxy
      terminal PA fragment (PA32). Binding of scFv to green fluorescent protein fused
      to the amino-terminal 32-kDa fragment of B. anthracis edema factor, EGFP-EF32,
      was used to confirm specificity. Fusion of EGFP to PA32 facilitated development
      of a novel flow cytometric assay that showed that one of the scFv disrupted PA
      receptor binding. This method can now be used as a rapid assay for small molecule
      inhibitors of PA binding to cell receptors. The combined data presented suggest
      the potential utility of human scFv as prophylactics against anthrax poisoning.
      Moreover, recombinant PA32 may also be useful as a therapeutic agent to compete
      with anthrax toxins for cellular receptors during active infection.

PMID- 10338506
TI  - Structures in Bacillus subtilis are recognized by CD14 in a lipopolysaccharide
      binding protein-dependent reaction.
AB  - The CD14 molecule expressed on monocytes and macrophages is a high-affinity
      receptor for bacterial lipopolysaccharide (LPS) and hence an important component
      of the innate immune system. LPS binding protein (LBP) is required to facilitate
      the binding of LPS to CD14 in vitro and is necessary for the induction of an
      inflammatory response to LPS in vivo. Here we show that CD14 and LBP can also
      bind to lipoteichoic acid from the gram-positive bacterium Bacillus subtilis.
      Although CD14 does not interact with intact B. subtilis organisms, a brief
      exposure of the bacteria to serum converts them into a form which can bind to
      CD14 in an LBP-dependent reaction. When serum-pretreated B. subtilis organisms
      are incubated with the myelomonocytic cell line U937, which expresses CD14, the
      bacteria are rapidly phagocytosed. The phagocytosis is strictly dependent both on
      LBP and on CD14. These in vitro results suggest that LBP plays a role in the
      innate response not only to gram-negative but also to gram-positive infections.

PMID- 10338507
TI  - Differential induction of colitis and gastritis in HLA-B27 transgenic rats
      selectively colonized with Bacteroides vulgatus or Escherichia coli.
AB  - Resident bacteria play an important role in initiating and perpetuating
      gastrointestinal inflammation. We previously demonstrated that six commensal
      bacteria including Bacteroides vulgatus caused more aggressive colitis and
      gastritis in HLA-B27 transgenic rats than did the other five bacteria without B.
      vulgatus. This study compared the degree of gastrointestinal inflammation in
      gnotobiotic HLA-B27 transgenic rats monoassociated with either B. vulgatus or
      Escherichia coli. Gnotobiotic transgenic rats raised in Trexler isolators were
      selectively colonized with either B. vulgatus or E. coli. Control rats were
      either germfree or colonized with six common commensal bacteria (Streptococcus
      faecium, E. coli, Streptococcus avium, Eubacterium contortum, Peptostreptococcus
      productus, and B. vulgatus [DESEP-B]). After 1 month, all the rats were killed
      and tissues were prepared for histologic and biochemical evaluation. Colitis
      induced by B. vulgatus monoassociation was almost equal to that in DESEP-B
      colonized rats and was significantly more severe than E. coli-induced colitis,
      which was absent by histological testing and mild by colonic myeloperoxidase and
      interleukin-1beta concentration determinations. However, gastritis was detectable
      only in DESEP-B-associated rats. These studies suggest that not all resident
      bacteria have equal proinflammatory capabilities, since B. vulgatus alone is more
      active than E. coli alone in inducing colitis, and that colitis and gastritis
      result from different luminal bacterial stimuli.

PMID- 10338508
TI  - A longitudinal study of human antibody responses to Plasmodium falciparum rhoptry
      associated protein 1 in a region of seasonal and unstable malaria transmission.
AB  - Rhoptry-associated protein 1 (RAP1) of Plasmodium falciparum is a nonpolymorphic
      merozoite antigen that is considered a potential candidate for a malaria vaccine
      against asexual blood stages. In this longitudinal study, recombinant RAP1
      (rRAP1) proteins with antigenicity similar to that of P. falciparum-derived RAP1
      were used to analyze antibody responses to RAP1 over a period of 4 years (1991 to
      1995) of 53 individuals naturally exposed to P. falciparum malaria. In any 1 year
      during the study, between 23 and 39% of individuals who had malaria developed
      immunoglobulin G (IgG) antibodies detectable with at least one rRAP1 protein.
      However, the anti-RAP1 antibody responses were detected only during or shortly
      after clinical malarial infections. RAP1 antibody levels declined rapidly (within
      1 to 2 months) following drug treatment of the infections. No anti-RAP1
      antibodies were usually detected a few months after the end of malaria
      transmission, during the dry season, or by the start of the next malaria season.
      Thus, RAP1 IgG responses were very short-lived. The short duration of RAP1
      antibody response may explain the apparent lack of response in a surprisingly
      high proportion of individuals after clinical malarial infections. For some
      individuals who experienced more than one malarial infection, a higher anti-RAP1
      antibody response to subsequent infections than to earlier infections was
      observed. This suggested secondary responses to RAP1 and thus the development of
      immunological memory for RAP1.

PMID- 10338509
TI  - Modulation of major histocompatibility complex protein expression by human gamma
      interferon mediated by cysteine proteinase-adhesin polyproteins of Porphyromonas
      gingivalis.
AB  - Cysteine proteinases have been emphasized in the virulence of Porphyromonas
      gingivalis in chronic periodontitis. These hydrolases may promote the degradation
      of extracellular matrix proteins and disrupt components of the immune system. In
      this study it was shown that purified Arg-gingipain and Lys-gingipain inhibited
      expression of class II major histocompatibility complex (MHC) proteins in
      response to the stimulation of endothelial cells with human gamma interferon (IFN
      gamma). Treatment with the cysteine proteinases resulted in a rapid shift in the
      apparent molecular size of IFN-gamma from 17 to 15 kDa, as shown by Western blot
      analysis, a response which also occurred in the presence of serum. Further,
      glycosylated natural IFN-gamma from human leukocytes and unglycosylated
      recombinant IFN-gamma from Escherichia coli were both digested by the cysteine
      proteinases. Immunoblot analysis indicated that cleavage within the carboxyl
      terminus of recombinant IFN-gamma correlated with the loss of induction of MHC
      class II expression as monitored by analytical flow cytometry. No hydrolysis of
      MHC class II molecules or human IFN-gamma receptor by these proteinases was
      detected by Western blot analysis. These findings suggest that P. gingivalis
      cysteine proteinases may alter the cytokine network at the point of infection
      through the cleavage of IFN-gamma. Degradation of IFN-gamma could have important
      consequences for the recruitment and activation of leukocytes and therefore may
      contribute significantly to the destruction of the periodontal attachment.

PMID- 10338510
TI  - Construction of a single-chain interleukin-12-expressing retroviral vector and
      its application in cytokine gene therapy against experimental coccidioidomycosis.
AB  - T-cell-mediated immunity is an important determinant in protection against
      primary infection with Coccidioides immitis, a dimorphic fungal pathogen that
      causes the disease coccidioidomycosis. To determine if interleukin-12 (IL-12)
      gene therapy could potentiate host response against C. immitis, we constructed a
      single-chain cDNA encoding the p40 and p35 subunits linked by a polylinker and,
      using a retroviral vector, transfected J774 macrophages with the construct. The
      transduced J774 cells expressed IL-12 in vitro, with a mean concentration of
      28,440 pg from 10(6) cells in 48 h as measured by an IL-12 (p75)-specific enzyme
      linked immunosorbent assay. The secreted IL-12 was biologically active, as judged
      by its ability to induce the production of gamma interferon (IFN-gamma) by spleen
      cells from BALB/c mice. Treatment of the highly susceptible BALB/c mouse strain
      with the IL-12-transduced J774 cells inhibited C. immitis growth in tissues from
      mice challenged by a pulmonary route, as evidenced by 1.37-, 2.59-, and 1.22-log
      reductions in the number of CFU in the lungs, spleens, and livers, respectively,
      compared to the fungal load in mice given vector-transduced J774 cells. The
      protective effect of IL-12 gene therapy was accompanied by increased levels of
      IFN-gamma in the lungs and sera of mice treated with IL-12-transduced J774 cells
      and the constitutive production of IFN-gamma by their spleen cells cultured in
      vitro. These results suggest that IL-12 gene therapy could be used as adjunct
      therapy for coccidioidomycosis.

PMID- 10338511
TI  - Effects of cytotoxic necrotizing factor 1 and lethal toxin on actin cytoskeleton
      and VE-cadherin localization in human endothelial cell monolayers.
AB  - Integrity of the vascular endothelium is largely dependent on endothelial cell
      shape and establishment of intercellular junctions. Certain pathogenic bacterial
      toxins alter the cytoskeletal architecture of intoxicated cells by modulating the
      GTPase activity of p21 Rho family proteins. In the present study we have analyzed
      the effect of Rho-directed toxins on the actin cytoskeleton and monolayer
      integrity of endothelial cells. We report here that Escherichia coli cytotoxic
      necrotizing factor 1 (CNF1) activates Rho in human umbilical vein endothelial
      cells (HUVEC). In confluent monolayers, CNF1 treatment induces prominent stress
      fiber formation without significantly modifying peripheral localization of VE
      cadherin, a specific marker of vascular endothelial cell adherens junctions.
      Further, Rho activation with CNF1 blocks thrombin-induced redistribution of VE
      cadherin staining and gap formation in HUVEC monolayers. Inhibition of Rho by
      prolonged treatment of cells with C3 exoenzyme (Clostridium botulinum) eliminates
      actin stress fibers without disrupting the continuity of VE-cadherin staining,
      indicating that Rho-dependent stress fibers are not required for maintaining this
      adhesion receptor at sites of intercellular contact. Lethal toxin (Clostridium
      sordellii), an inhibitor of Rac as well as Ras and Rap, potently disrupts the
      actin microfilament system and monolayer integrity in HUVEC cultures.

PMID- 10338512
TI  - A Neisseria gonorrhoeae immunoglobulin A1 protease mutant is infectious in the
      human challenge model of urethral infection.
AB  - Many mucosal pathogens, including Neisseria gonorrhoeae, produce proteases that
      cleave immunoglobulin A (IgA), the predominant immunoglobulin class produced at
      mucosal surfaces. While considerable circumstantial evidence suggests that IgA1
      protease contributes to gonococcal virulence, there is no direct evidence that N.
      gonorrhoeae requires IgA1 protease activity to infect a human host. We
      constructed a N. gonorrhoeae iga mutant without introducing new antibiotic
      resistance markers into the final mutant strain and used human experimental
      infection to test the ability of the mutant to colonize the male urethra and to
      cause gonococcal urethritis. Four of the five male volunteers inoculated with the
      Iga- mutant became infected. In every respect-clinical signs and symptoms,
      incubation period between inoculation and infection, and the proportion of
      volunteers infected-the outcome of human experimental infection with FA1090iga
      was indistinguishable from that previously reported for a variant of parent
      strain FA1090 matching the mutant in expression of Opa proteins,
      lipooligosaccharide, and pilin. These results indicate that N. gonorrhoeae does
      not require IgA1 protease production to cause experimental urethritis in males.

PMID- 10338513
TI  - Interleukin 5 (IL-5) is not required for expression of a Th2 response or host
      resistance mechanisms during murine schistosomiasis mansoni but does play a role
      in development of IL-4-producing non-T, non-B cells.
AB  - During schistosomiasis, interleukin-5 (IL-5)-dependent eosinophil responses have
      been implicated in immunopathology, resistance to superinfection, synergistic
      interactions with chemotherapeutic agents, and the inductive phase of the egg
      induced Th2 response. We examined these issues in IL-5-deficient (IL-5(-/-))
      mice. IL-5(-/-) and wild-type (WT) mice were indistinguishable in terms of
      susceptibility to primary infections and the ability to resist secondary
      infections. Moreover, hepatic pathology was similar in both strains apart from a
      relative lack of eosinophils and, during chronic infection, a significantly
      larger mast cell component in the granulomas of IL-5(-/-) mice. Splenocyte
      cytokine production in response to soluble egg antigen (SEA) or anti-CD3 revealed
      no significant differences except for heightened tumor necrosis factor alpha
      production by cells from chronically infected IL-5(-/-) mice compared to WT
      animals. In contrast, ionomycin-stimulated non-B, non-T (NBNT) cells from IL-5(-/
      ) mice produced significantly smaller IL-4 amounts than did NBNT cells from WT
      animals. This difference was not apparent following plate-bound anti
      immunoglobulin E or SEA stimulation. The absence of IL-5 failed to affect the
      induction of Th2 responses in naive mice. Peritoneal exudate cells recovered from
      egg-injected IL-5(-/-) or WT mice produced equivalent levels of IL-4 following
      restimulation with SEA or anti-CD3.

PMID- 10338514
TI  - Prior genital tract infection with a murine or human biovar of Chlamydia
      trachomatis protects mice against heterotypic challenge infection.
AB  - We sought to assess the degree of cross-protective immunity in a mouse model of
      chlamydial genital tract infection. Following resolution of genital infection
      with the mouse pneumonitis (MoPn) biovar of Chlamydia trachomatis, mice were
      challenged intravaginally with either MoPn or human serovar E or L2. The majority
      of animals previously infected with MoPn were solidly immune to challenge with
      either of the two human biovars. Surprisingly, approximately 50% of animals
      became reinfected when homologously challenged with MoPn, although the secondary
      infection yielded significantly lower numbers of the organism isolated over a
      shorter duration than in the primary infection. Primary infection with serovar E
      also protected against challenge with MoPn or serovar L2, although the degree of
      immune protection was lower than that resulting from primary infection with MoPn.
      Blast transformation and assessment of delayed-type hypersensitivity indicated
      that mice previously infected with either human or murine biovars produced
      broadly cross-reactive T cells that recognized epitopes of either murine or human
      biovars of C. trachomatis. Immunoblotting demonstrated that primary MoPn
      infection produced immunoglobulin G (IgG) antibody to antigens of MoPn as well as
      at least three distinct antigenic components of human serovar E, one of which was
      identical in molecular weight to the major outer membrane protein (MOMP). Primary
      infection with serovar E produced IgG antibody reactive against serovar E but not
      MoPn MOMP and against at least one ca. 60-kDa protein of both chlamydial strains.
      Our results indicate that primary genital infection of mice with murine C.
      trachomatis induces immunity against challenge with either of two human biovars.

PMID- 10338517
TI  - Helicobacter pylori-associated gastritis in mice is host and strain specific.
AB  - The vacA and cagA geno- and phenotypes of two mouse-adapted strains of
      Helicobacter pylori, SS1 and SPM326, were determined. The SS1 strain, which had
      the cagA+ and vacA s2-m2 genotype, induced neither vacuole formation in HeLa
      cells nor interleukin-8 (IL-8) production in KATO III cells. In contrast, H.
      pylori SPM326, with the cagA+ and vacA s1b-m1 genotype, induced vacuoles as well
      as IL-8 production in vitro. Furthermore, a spontaneous mutant of SPM326, which
      produced a vacuolating cytotoxin but was not able to induce IL-8 production
      (SPM326/IL-8(-)), was detected. C57Bl/6 and BALB/c mice were infected with these
      three strains to investigate the colonization pattern and the effect on the
      immune response in vivo. The SS1 strain colonized the stomachs of all mice in
      large numbers which remained constant over time. Colonization with the SPM326/IL
      8(+) and SPM326/IL-8(-) strains was lesser, or even absent, and decreased over
      time. At 5 weeks postinoculation all three H. pylori strains induced a mild
      increase of neutrophil count in the gastric corpus of C57Bl/6 mice, which
      disappeared by 12 weeks. At both 5 and 12 weeks postinoculation C57Bl/6 mice
      colonized with SPM326/IL-8(+) showed an increased expression of major
      histocompatibility complex (MHC) class II antigen in the cardia which was
      accompanied by an increased number of T cells. C57Bl/6 mice that were infected
      with SS1 and SPM326/IL-8(-) did not show chronic inflammation. BALB/c mice
      colonized with SS1 and SPM326/IL-8(-) also showed an increase in neutrophil count
      at 5 weeks, which normalized again by 12 weeks postinoculation. At this time
      point SS1-infected mice showed inflammation in the corpus and antrum. At these
      sites an increased expression of MHC class II antigens and an increased number of
      T cells were observed. Although small lymphoid follicles were already observed 5
      weeks after inoculation with SS1, their incidence as well as their number was
      increased at 12 weeks. These results show that inflammation induced by H. pylori
      depends both on the bacterial strain and the host.

PMID- 10338516
TI  - Citrobacter rodentium infection in mice elicits a mucosal Th1 cytokine response
      and lesions similar to those in murine inflammatory bowel disease.
AB  - Citrobacter rodentium is a classically noninvasive pathogen of mice that is
      similar to enteropathogenic Escherichia coli (EPEC) in man. Following oral
      infection of young mice, the organism colonizes the distal colon, and within 1
      week the colonic mucosa doubles in thickness and there is massive epithelial cell
      hyperplasia. Since T-cell responses in mouse models of inflammatory bowel disease
      (IBD) also cause epithelial hyperplasia, we have investigated the possibility
      that C. rodentium promotes similar T-cell responses in the mucosa, thereby
      increasing epithelial shedding, transmission, and replication of the organism.
      Beginning 6 days after infection, bacteria were observed to be in close
      association with the epithelial surface and were also visible scattered
      throughout the lamina propria and in the submucosa. There was a CD3(+)-cell
      infiltrate into the colonic lamina propria and epithelium as well as mucosal
      thickening and crypt hyperplasia. The majority of CD3(+) cells were CD4(+) and
      were not gammadelta+. Reverse transcription-PCR analysis of cytokines also
      revealed a highly polarized Th1 response (interleukin-12, gamma interferon, and
      tumor necrosis factor alpha) in the mucosa and a large increase in the epithelial
      cell mitogen keratinocyte growth factor. None of the changes were seen in mice
      inoculated with bacteria lacking intimin (which is necessary for colonization),
      but they were seen in mice inoculated with C. rodentium complemented with intimin
      from EPEC. This is the first example of a classically noninvasive bacterial
      pathogen which elicits a strong mucosal Th1 response and which produces pathology
      similar to that seen in mouse models of IBD, which is also characterized by a
      strong Th1 response. These results also suggest that the colonic mucosa responds
      in a stereotypic way to Th1 responses.

PMID- 10338518
TI  - Interleukin-12 enhances antifungal activity of human mononuclear phagocytes
      against Aspergillus fumigatus: implications for a gamma interferon-independent
      pathway.
AB  - The potential of recombinant human interleukin-12 (IL-12) to enhance the capacity
      of human monocytes (MNC) to elicit an oxidative burst and damage hyphae of
      Aspergillus fumigatus was investigated. Incubation of peripheral blood
      mononuclear cells (PBMC) from healthy adults with 10 to 100 ng of IL-12/ml at 37
      degrees C for 2 to 3 days enhanced the production of superoxide anion (O2-) in
      response to phorbol myristate acetate (PMA) (P = 0.04) and unopsonized A.
      fumigatus hyphae (P = 0.03) and further enhanced hyphal damage (P = 0.009). Anti
      gamma interferon (anti-IFN-gamma) blocked secretion of IFN-gamma by IL-12-treated
      PBMC but did not inhibit IL-12-induced O2- production by these cells in response
      to PMA. In addition, IL-12-treated elutriated MNC secreted no IFN-gamma or tumor
      necrosis factor alpha but exhibited enhanced O2- production compared to controls
      (P = 0.013). These findings demonstrate that IL-12 augments oxidative antifungal
      activities of MNC via an IFN-gamma-independent route, suggesting a novel pathway
      of IL-12 action in antifungal defense.

PMID- 10338515
TI  - Anthrax toxin entry into polarized epithelial cells.
AB  - We examined the entry of anthrax edema toxin (EdTx) into polarized human T84
      epithelial cells using cyclic AMP-regulated Cl- secretion as an index of toxin
      entry. EdTx is a binary A/B toxin which self assembles at the cell surface from
      anthrax edema factor and protective antigen (PA). PA binds to cell surface
      receptors and delivers EF, an adenylate cyclase, to the cytosol. EdTx elicited a
      strong Cl- secretory response when it was applied to the basolateral surface of
      T84 cells but no response when it was applied to the apical surface. PA alone had
      no effect when it was applied to either surface. T84 cells exposed basolaterally
      bound at least 30-fold-more PA than did T84 cells exposed apically, indicating
      that the PA receptor is largely or completely restricted to the basolateral
      membrane of these cells. The PA receptor did not fractionate with detergent
      insoluble caveola-like membranes as cholera toxin receptors do. These findings
      have implications regarding the nature of the PA receptor and confirm the view
      that EdTx and CT coopt fundamentally different subcellular systems to enter the
      cell and cause disease.

PMID- 10338519
TI  - Levels of gamma interferon and interleukin-4 are inversely related to the levels
      of their corresponding autoantibodies in patients with lower respiratory tract
      infection.
AB  - To study the involvement of cytokines and their corresponding autoantibodies
      (Aabs) in inflammatory mechanisms in patients with lower respiratory tract
      infections, blood samples were taken from patients at the time of admission to
      the hospital and before treatment. Cell-released capturing enzyme-linked
      immunosorbent assay was used to measure the levels of gamma interferon (IFN
      gamma) and interleukin-4 (IL-4) produced spontaneously by peripheral mononuclear
      cells (PMNC). ELISA was used to measure Aabs to these cytokines in sera. The
      levels of both cytokines were inversely related to the levels of their
      corresponding Aabs. While a high level of IFN-gamma was observed together with a
      low level of anti-IFN-gamma Aab, decreased IL-4 levels were observed with
      increased levels of Aabs to IL-4. Immunoglobulins were purified, digested to
      obtain Fab fragments, and tested for specificity and cross-reactivity. The Aabs
      and their Fab fragments were tested in cytokine biological assays and showed
      neutralizing effects. Our data demonstrated increased levels of the
      proinflammatory cytokine IFN-gamma and decreased release of the anti-inflammatory
      cytokine IL-4 during early presentation of lower respiratory tract infection. The
      levels of these cytokines were inversely related to the levels of their
      corresponding Aabs that exhibited regulatory effects on the cytokine biological
      function in vitro.

PMID- 10338520
TI  - Proteasome activity is required for anthrax lethal toxin to kill macrophages.
AB  - Anthrax lethal toxin (LeTx), consisting of protective antigen (PA) and lethal
      factor (LF), rapidly kills primary mouse macrophages and macrophage-like cell
      lines such as RAW 264.7. LF is translocated by PA into the cytosol of target
      cells, where it acts as a metalloprotease to cleave mitogen-activated protein
      kinase kinase 1 (MEK1) and possibly other proteins. In this study, we show that
      proteasome inhibitors such as acetyl-Leu-Leu-norleucinal, MG132, and lactacystin
      efficiently block LeTx cytotoxicity, whereas other protease inhibitors do not.
      The inhibitor concentrations that block LF cytotoxicity are similar to those that
      inhibit the proteasome-dependent IkappaB-alpha degradation induced by
      lipopolysaccharide. The inhibitors did not interfere with the proteolytic
      cleavage of MEK1 in LeTx-treated cells, indicating that they do not directly
      block the proteolytic activity of LF. However, the proteasome inhibitors did
      prevent ATP depletion, an early effect of LeTx. No overall activation of the
      proteasome by LeTx was detected, as shown by the cleavage of fluorogenic
      substrates of the proteasome. All of these results suggest that the proteasome
      mediates a toxic process initiated by LF in the cell cytosol. This process
      probably involves degradation of unidentified molecules that are essential for
      macrophage homeostasis. Moreover, this proteasome-dependent process is an early
      step in LeTx intoxication, but it is downstream of the cleavage by LF of MEK1 or
      other putative substrates.

PMID- 10338521
TI  - Transcriptional activation of mRNA of intercellular adhesion molecule 1 and
      induction of its cell surface expression in normal human gingival fibroblasts by
      Mycoplasma salivarium and Mycoplasma fermentans.
AB  - Lipoproteins in the cell membranes of both Mycoplasma salivarium and Mycoplasma
      fermentans were demonstrated to trigger the transcription of intercellular
      adhesion molecule-1 mRNA in normal fibroblasts isolated from human gingival
      tissue and to induce its cell surface expression by a mechanism distinct from
      that of Escherichia coli lipopolysaccharide. The lipid moiety of the lipoproteins
      was suggested to play a key role in the expression of the activity.

PMID- 10338522
TI  - Acute clinical disease in cats following infection with a pathogenic strain of
      Bartonella henselae (LSU16).
AB  - Bartonella henselae is the causative agent of human cat scratch disease as well
      as several serious sequelae of infections, including bacillary angiomatosis and
      bacillary peliosis. Conflicting reports describe the pathogenesis of B. henselae
      in the cat. In this study, we characterized a strain of B. henselae termed LSU16.
      This strain was isolated on rabbit blood agar from a naturally infected 10-month
      old female cat during a recurrent episode of bacteremia. The bacterial species
      was confirmed by PCR-restriction fragment length polymorphism analysis. Nine cats
      were infected intradermally with 5 x 10(7) CFU of LSU16, and clinical signs,
      antibody responses, and bacteremia were monitored. All nine cats developed
      raised, erythematous areas at the site of inoculation within 72 h
      postinoculation; the swelling peaked at 14 days postinfection and was not
      palpable by 28 days postinfection. Fever developed in all nine cats between 6 and
      16 days postinfection and lasted for 1 to 8 days. Between 6 and 16 days
      postinfection, all nine cats experienced lethargy which persisted 5 to 18 days.
      Seven of nine cats were bacteremic by day 7, and all nine cats had become
      bacteremic by 14 days postinfection. Bacteremia peaked at 14 to 28 days
      postinfection in all cats. In six of the nine infected cats, bacterial numbers
      reached nondetectable levels during the 7th week postinfection; however, a single
      animal maintained bacteremia to 18 weeks postinfection. All nine cats developed
      strong antibody responses to B. henselae, as determined by Western blot analysis
      and enzyme-linked immunosorbent assay. Subsequently, three naive cats were
      injected intradermally with blood from cats infected with LSU16 from a pure
      culture, and five naive cats were injected with feces from fleas which had been
      feeding on cats infected with a pure culture of LSU16. These cats developed signs
      similar to those described in the previous experiment and were euthanized at 5
      weeks postinfection. We conclude that B. henselae LSU16 is a virulent strain of
      B. henselae in cats and propose that the virulence of B. henselae in cats is
      strain dependent.

PMID- 10338524
TI  - Coinfection with influenza B virus does not affect association of Neisseria
      meningitidis with human nasopharyngeal mucosa in organ culture.
AB  - There is an epidemiological association between influenza virus infection and
      meningococcal disease. Proposed mechanisms are the destruction of the normal
      epithelial barrier function of the upper respiratory tract by influenza virus or
      the expression of human or viral surface-exposed proteins that enhance bacterial
      adherence and/or invasion. To test these hypotheses, human nasopharyngeal mucosa
      specimens from a total of 19 individual donors were successfully infected with
      influenza B virus and then inoculated with serogroup B Neisseria meningitidis.
      Subsequent bacterial association with the epithelial surface was measured in
      three separate series of experiments by using transmission electron microscopy (n
      = 6), scanning electron microscopy (n = 6), and counting of viable bacteria
      within homogenates of explants (n = 7). Penetration of the mucosa was estimated
      by measuring the count of viable bacteria recovered from explants after exposure
      to sodium taurocholate. Bacterial association with the surface of explants was
      time dependent over 24 h of superinfection. Influenza virus did not positively or
      negatively influence bacterial attachment to or penetration of explant mucosa
      compared to those of uninfected controls, even when the period of preincubation
      with virus was extended to 7 days. When proteins were purified from mucosal
      epithelium and immobilized on nitrocellulose membranes, N. meningitidis attached
      predominantly to bands corresponding to proteins of 210 and 130 kDa. In the
      presence of influenza virus infection, these proteins were gradually lost over
      the course of 72 h. In conclusion, influenza B virus did not increase association
      of serogroup B N. meningitidis with human nasopharyngeal mucosa.

PMID- 10338523
TI  - Chitinase secretion by encysting Entamoeba invadens and transfected Entamoeba
      histolytica trophozoites: localization of secretory vesicles, endoplasmic
      reticulum, and Golgi apparatus.
AB  - Entamoeba histolytica, the protozoan parasite that phagocytoses bacteria and host
      cells, has a vesicle/vacuole-filled cytosol like that of macrophages. In
      contrast, the infectious cyst form has four nuclei and a chitin wall. Here, anti
      chitinase antibodies identified hundreds of small secretory vesicles in encysting
      E. invadens parasites and in E. histolytica trophozoites overexpressing chitinase
      under an actin gene promoter. Abundant small secretory vesicles were also
      identified with antibodies to the surface antigen Ariel and with a fluorescent
      substrate of cysteine proteinases. Removal of an N-terminal signal sequence
      directed chitinase to the cytosol. Addition of a C-terminal KDEL peptide,
      identified on amebic BiP, retained chitinase in a putative endoplasmic reticulum,
      which was composed of a few vesicles of mixed sizes. A putative Golgi apparatus,
      which was Brefeldin A sensitive and composed of a few large, perinuclear
      vesicles, was identified with antibodies to ADP-ribosylating factor and to
      epsilon-COP. We conclude that the amebic secretory pathway is similar to those of
      other eukaryotic cells, even if its appearance is somewhat different.

PMID- 10338525
TI  - Increased antimycobacterial immunity in interleukin-10-deficient mice.
AB  - Macrophage effector functions are essential for clearing mycobacterial
      infections. Interleukin 10 (IL-10) negatively regulates macrophages and could be
      a factor inhibiting effective antimycobacterial immunity. We previously showed
      that transgenic mice which produce excess IL-10 from T cells are susceptible to
      infection, even though these mice continue to produce gamma interferon (IFN
      gamma) at levels similar to those in controls. Here, we extend our genetic
      analysis of the functions of IL-10 in antimycobacterial immunity by testing the
      hypothesis that IL-10-deficient (IL-10(-/-)) mice should be more resistant to
      mycobacteria than control mice. Mycobacterium bovis bacillus Calmette-Guerin
      infected IL-10(-/-) mice had significantly lower bacterial burdens than control
      mice early in the infection. Contrary to expectations, however, IL-10(-/-) mice
      did not have increased levels of IFN-gamma, either from T cells or in the plasma,
      suggesting that other mechanisms are responsible for the increased resistance.
      However, macrophages from IL-10(-/-) mice produced increased levels of
      inflammatory cytokines, including IFN-gamma, as well as nitric oxide and
      prostaglandins, which could account for increased antimycobacterial immunity. Our
      genetic analysis revealed that IL-10 is an inhibitor of early mycobacterial
      clearance. The data also suggest that IL-10 negatively regulates numerous
      macrophage functions as well as playing a role in down-regulating the general
      inflammatory response, especially in conditions where an infection must be
      controlled through macrophage activity.

PMID- 10338526
TI  - In vitro and in vivo stability of a Cryptococcus neoformans [corrected]
      glucuronoxylomannan epitope that elicits protective antibodies.
AB  - The monoclonal antibody (MAb) 2H1 defines an epitope in Cryptococcus neoformans
      capsular glucuronoxylomannan (GXM) that can elicit protective antibodies. In
      murine models of cryptococcosis, MAb 2H1 administration prolongs survival and
      reduces fungal burden but seldom clears the infection. The mechanism by which C.
      neoformans persists and escape antibody-mediated clearance is not understood. One
      possibility is that variants that do not bind MAb 2H1 emerge in the course of
      infection. Using an agglutination-sedimentation protocol, we recovered a variant
      of strain 24067 that did not agglutinate, could not be serotyped, and had marked
      reduction in GXM O-acetyl groups. Binding of MAb 2H1 to 24067 variant cells
      produced a different immunofluorescence pattern and lower fluorescence intensity
      relative to the parent 24067 cells. Addition of MAb 2H1 to 24067 variant cells
      had no effect on cell charge. Phagocytic assays demonstrated that MAb 2H1 was not
      an effective opsonin for the 24067 variant. The 24067 variant was less virulent
      than the 24067 parent strain in mice, and MAb 2H1 administration did not prolong
      survival in animals infected with the variant strain. To investigate whether
      variants which do not bind MAb 2H1 are selected in experimental infection, three
      C. neoformans strains were serially passaged in mice given either MAb 2H1 or no
      antibody. Analysis of passaged isolates by agglutination assay, flow cytometry,
      and indirect immunofluorescence revealed changes in MAb 2H1 epitope expression
      but no clear trend with regards to gain or loss of MAb 2H1 epitope. C. neoformans
      variants with reduced MAb 2H1 epitope content can be isolated in vitro, but
      persistence of infection in mice given MAb 2H1 does not appear to be a result of
      selection of escape variants that lack the MAb 2H1 epitope.

PMID- 10338527
TI  - Host defense against Mycobacterium avium does not have an absolute requirement
      for major histocompatibility complex class I-restricted T cells.
AB  - The role of CD8(+) T cells was evaluated in a mouse model of disseminated
      Mycobacterium avium infection. C57BL/6J and C57BL/6Jbeta2-/- (beta2-/-) mice were
      infected intravenously, and the number of viable bacteria in each liver and
      spleen was determined. No significant difference between the number of bacteria
      in the two strains of mice was observed at 2, 4, 6, and 8 weeks after infection.
      Histopathological examination of granulomas from C57BL/6J and beta2-/- mice did
      not show any difference either in the number of organisms per granuloma or in the
      size of the granulomas. Investigation of the cytokine profile in the spleen
      demonstrated that the beta2-/- strain of mice produced a significantly lower
      amount of gamma interferon at 8 weeks after infection and significantly increased
      concentrations of tumor necrosis factor alpha compared with that from the wild
      type mouse. Interleukin-12 and transforming growth factor beta1 levels did not
      differ between the two strains of mice at 2, 4, 6, and 8 weeks. Although previous
      work had found that host response against Mycobacterium tuberculosis involves
      major histocompatibility complex class I-restricted T cells, our results indicate
      that chronic deficiency of CD8(+) T cells does not lead to a different expression
      of the disease and that if CD8(+) T cells are involved in the host response,
      their function can be assumed by other immune cells.

PMID- 10338528
TI  - A conventional beagle dog model for acute and chronic infection with Helicobacter
      pylori.
AB  - Helicobacter pylori has been widely recognized as an important human pathogen
      responsible for chronic gastritis, peptic ulcers, gastric cancer, and mucosa
      associated lymphoid tissue (MALT) lymphoma. Little is known about the natural
      history of this infection since patients are usually recognized as having the
      infection only after years or decades of chronic disease. Several animal models
      of H. pylori infection, including those with different species of rodents,
      nonhuman primates, and germ-free animals, have been developed. Here we describe a
      new animal model in which the clinical, pathological, microbiological, and
      immunological aspects of human acute and chronic infection are mimicked and which
      allows us to monitor these aspects of infection within the same individuals.
      Conventional Beagle dogs were infected orally with a mouse-adapted strain of H.
      pylori and monitored for up to 24 weeks. Acute infection caused vomiting and
      diarrhea. The acute phase was followed by polymorphonuclear cell infiltration,
      interleukin 8 induction, mononuclear cell recruitment, and the appearance of a
      specific antibody response against H. pylori. The chronic phase was characterized
      by gastritis, epithelial alterations, superficial erosions, and the appearance of
      the typical macroscopic follicles that in humans are considered possible
      precursors of MALT lymphoma. In conclusion, infection in this model mimics
      closely human infection and allows us to study those phases that cannot be
      studied in humans. This new model can be a unique tool for learning more about
      the disease and for developing strategies for treatment and prevention.

PMID- 10338529
TI  - Porcine epithelial beta-defensin 1 is expressed in the dorsal tongue at
      antimicrobial concentrations.
AB  - Epithelial cells and phagocytes contain antimicrobial polypeptides that
      participate in innate host defense. A recently cloned porcine beta-defensin, PBD
      1, was detected by Northern organ blots exclusively in the tongue epithelium. We
      generated recombinant PBD-1 peptide by using a baculovirus-insect cell expression
      system and obtained two forms (PBD-142 and PBD-138), which differed by N-terminal
      truncation. Only PBD-142 was found in scrapings of the surface of the dorsal
      tongue or the buccal mucosa. Immunohistochemical staining with antibody to PBD
      142 revealed that PBD-1 was highly concentrated in an approximately 0.1-mm-thick
      layer in the cornified tips of the filiform (but not fungiform) papillae of the
      dorsal tongue and in the superficial squamous cell layers of the buccal mucosa.
      By scraping, extraction, and semiquantitative Western blotting, the concentration
      of PBD-1 in the dorsal tongue surface and the buccal mucosa was estimated at 20
      to 100 micrograms/ml. PBD-1 had antibacterial activity against Escherichia coli,
      Salmonella typhimurium, Listeria monocytogenes, and Candida albicans in 10 mM
      sodium phosphate buffer (pH 7.4). Added NaCl progressively inhibited the activity
      of PBD-1 against E. coli and C. albicans. In 10 mM sodium phosphate with 125 mM
      NaCl, the combinations of sublethal concentrations of PBD-1 and the porcine
      neutrophil peptide PG-3, PR-39, or PR-26 showed synergistic activity against E.
      coli or the multidrug-resistant S. typhimurium DT104. At its physiologic
      concentration, PBD-1 has antimicrobial effects under both low- and high-salt
      conditions encountered in the oral cavity and may contribute to the antimicrobial
      barrier properties of the dorsal tongue and oral epithelium.

PMID- 10338530
TI  - Tumor necrosis factor alpha is a key mediator in the regulation of experimental
      Trypanosoma brucei infections.
AB  - In order to evaluate during experimental Trypanosoma brucei infections the
      potential role of tumor necrosis factor alpha (TNF-alpha) in the host-parasite
      interrelationship, C57BL/6 TNF-alpha knockout mice (TNF-alpha-/-) as well as
      C57BL/6 wild-type mice were infected with pleomorphic T. brucei AnTat 1.1 E
      parasites. In the TNF-alpha-/- mice, the peak levels of parasitemia were strongly
      increased compared to the peak levels recorded in wild-type mice. The increased
      parasite burden did not reflect differences in clearance efficacy or in
      production of T. brucei-specific immunoglobulin M (IgM) and IgG antibodies.
      Trypanosome-mediated immunopathological features, such as lymph node-associated
      immunosuppression and lipopolysaccharide hypersensitivity, were found to be
      greatly reduced in infected TNF-alpha-/- mice. These results demonstrate that,
      during trypanosome infections, TNF-alpha is a key mediator involved in both
      parasitemia control and infection-associated pathology.

PMID- 10338531
TI  - Variation in the Bordetella pertussis virulence factors pertussis toxin and
      pertactin in vaccine strains and clinical isolates in Finland.
AB  - There is evidence that pertussis is reemerging in vaccinated populations. We have
      proposed, and provided evidence for, one explanation for this phenomenon in The
      Netherlands: antigenic divergence between vaccine strains and circulating
      strains. Finland has a pertussis vaccination history very similar to that of The
      Netherlands, and yet there is no evidence for an increase in the incidence of
      pertussis to the extent that it was observed in The Netherlands. A comparison of
      the Bordetella pertussis strains circulating in the two countries may shed light
      on the differences in pertussis epidemiology. Here we investigated whether
      temporal changes had occurred in pertussis toxin and pertactin types produced by
      the Finnish B. pertussis population. We show that strains isolated before 1964
      produced the same pertussis toxin and pertactin variants as the vaccine strains.
      However, these vaccine types were replaced in later years, and in the 1990s most
      strains were distinct from the vaccine strains with respect to the two proteins.
      These trends are similar to those found in the Dutch B. pertussis population. An
      interesting difference between the contemporary Finnish and Dutch B. pertussis
      populations was found in the frequencies of pertactin variants, possibly
      explaining the distinct epidemiology of pertussis in the two countries.

PMID- 10338532
TI  - Analysis of vaginal cell populations during experimental vaginal candidiasis.
AB  - Studies with an estrogen-dependent murine model of vaginal candidiasis suggest
      that local cell-mediated immunity (CMI) is more important than systemic CMI for
      protection against vaginitis. The present study, however, showed that, compared
      to uninfected mice, little to no change in the percentage or types of vaginal T
      cells occurred during a primary vaginal infection or during a secondary vaginal
      infection where partial protection was observed. Furthermore, depletion of
      polymorphonuclear leukocytes (PMN) had no effect on infection in the presence or
      absence of pseudoestrus. These results indicate a lack of demonstrable effects by
      systemic CMI or PMN against vaginitis and suggest that if local T cells are
      important, they are functioning without showing significant increases in numbers
      within the vaginal mucosa during infection.

PMID- 10338533
TI  - FbpC is not essential for iron acquisition in Neisseria gonorrhoeae.
AB  - The fbpABC locus of Neisseria gonorrhoeae has been proposed to encode a
      periplasmic protein-dependent iron transport system. Although the function of the
      gonococcal FbpA protein has been well characterized and its role as a periplasmic
      binding protein is well defined, little is known about the function of the FbpB
      and FbpC proteins. To define the function of the gonococcal FbpC protein, an N.
      gonorrhoeae F62 fbpC mutant was constructed by insertional inactivation with the
      kanamycin gene. The N. gonorrhoeae F62 fbpC mutant was observed to grow with
      heme, transferrin, or ferric nitrate as the sole exogenous iron source,
      indicating that the gonococcal FbpC protein is not absolutely required for growth
      with these iron sources. In previous studies we were unable to detect fbpB- or
      fbpC-specific transcripts by Northern analysis. Reverse transcription-PCR
      analysis with RNA obtained from N. gonorrhoeae F62 grown under iron-replete and 
      depleted conditions detected fbpA and fbpAB transcripts but failed to detect fbpC
      or fbpBC transcripts. These results indicate that FbpC does not play a pivotal
      role in iron transport in N. gonorrhoeae and suggest that additional ABC
      transport systems are functional in the gonococcus for the acquisition of iron.

PMID- 10338534
TI  - Stability of erp loci during Borrelia burgdorferi infection: recombination is not
      required for chronic infection of immunocompetent mice.
AB  - Borrelia burgdorferi can persistently infect mammals despite their production of
      antibodies directed against bacterial proteins, including the Erp lipoproteins.
      We sequenced erp loci of bacteria reisolated from laboratory mice after 1 year of
      infection and found them to be identical to those of the inoculant bacteria. We
      conclude that recombination of erp genes is not essential for chronic mammalian
      infection.

PMID- 10338535
TI  - Macrophages and epithelial cells respond differently to the Pseudomonas
      aeruginosa type III secretion system.
AB  - The multiple effects of Pseudomonas aeruginosa type III secretion have largely
      been attributed to variations in cytotoxin expression between strains. Here we
      show that the target cell type is also important. While lung epithelial cells
      showed significant changes in morphology but not viability when infected with P.
      aeruginosa, macrophages were efficiently killed by P. aeruginosa. Both responses
      were dependent on the type III secretion system.

PMID- 10338537
TI  - Genetic characterization of wild-type and mutant fur genes of Bordetella avium.
AB  - For most, if not all, organisms, iron (Fe) is an essential element. In response
      to the nutritional requirement for Fe, bacteria evolved complex systems to
      acquire the element from the environment. The genes encoding these systems are
      often coordinately regulated in response to the Fe concentration. Recent
      investigations revealed that Bordetella avium, a respiratory pathogen of birds,
      expressed a number of Fe-regulated genes (T. D. Connell, A. Dickenson, A. J.
      Martone, K. T. Militello, M. J. Filiatraut, M. L. Hayman, and J. Pitula, Infect.
      Immun. 66:3597-3605, 1998). By using manganese selection on an engineered strain
      of B. avium that carried an Fe-regulated alkaline phosphatase reporter gene, a
      mutant was obtained that was affected in expression of Fe-regulated genes. To
      determine if Fe-dependent regulation in B. avium was mediated by a fur-like gene,
      a fragment of the B. avium chromosome, corresponding to the fur locus of B.
      pertussis, was cloned by PCR. Sequencing revealed that the fragment from B. avium
      encoded a polypeptide with 92% identity to the Fur protein of B. pertussis. In
      vivo experiments showed that the cloned gene complemented H1780, a fur mutant of
      Escherichia coli. Southern hybridizations and PCRs demonstrated that the
      manganese mutant had a deletion of 2 to 3 kbp of nucleotide sequence in the
      region located immediately 5' of the fur open reading frame. A spontaneous PCR
      derived mutant of the B. avium fur gene was isolated that encoded a Fur protein
      in which a histidine was substituted for an arginine at amino acid position 18
      (R18H). Genetic analysis showed that the R18H mutant gene when cloned into a low
      copy-number vector did not complement the fur mutation in H1780. However, the
      R18H mutant gene was able to complement the fur mutation when cloned into a high
      copy-number vector. The cloned wild-type fur gene will be useful as a genetic
      tool to identify Fur-regulated genes in the B. avium chromosome.

PMID- 10338536
TI  - Early gene expression of NK cell-activating chemokines in mice resistant to
      Leishmania major.
AB  - Susceptibility of mice to Leishmania major is associated with an insufficient NK
      cell-mediated innate immune response. We analyzed the expression of NK cell
      activating chemokines in vivo during the first days of infection in resistant and
      susceptible mice. The mRNA expression of gamma interferon-inducible protein 10
      (IP-10), monocyte chemoattractant protein 1 (MCP-1), and lymphotactin was
      upregulated 1 day after infection in the draining lymph nodes of resistant
      C57BL/6 mice but not in those of susceptible BALB/c mice. In vivo local treatment
      of BALB/c mice with recombinant IP-10 shortly after infection resulted in an
      enhanced NK cell activity in the draining lymph node. The data suggest that
      although the recruitment of NK cells is normal in susceptible mice, the lack of
      NK cell-activating chemokines is a factor resulting in a suboptimal NK cell
      mediated defense.

PMID- 10338538
TI  - Immunity in experimental murine filariasis: roles of T and B cells revisited.
AB  - We have reevaluated the contributions of T and B cells in Brugia malayi infection
      by utilizing knockout mice on a uniform background (C57BL/6J). We find that B
      cell-deficient mice are more permissive to infection than T-cell-deficient mice.

PMID- 10338539
TI  - Sequence conservation of glycerophosphodiester phosphodiesterase among Treponema
      pallidum strains.
AB  - Previous investigations have demonstrated that immunization with Treponema
      pallidum subsp. pallidum glycerophosphodiester phosphodiesterase significantly
      protects rabbits from subsequent treponeme challenge. In this report, we show
      that the glycerophosphodiester phosphodiesterase amino acid sequence is conserved
      among 12 strains from a total of five pathogenic treponemes. The invariant nature
      of this immunoprotective antigen makes it an attractive candidate for inclusion
      in a universal subunit vaccine against T. pallidum infection. In addition, these
      studies show a silent nucleotide substitution at position 579 of the gpd open
      reading frame which is consistently observed in the non-T. pallidum subsp.
      pallidum strains. This sequence alteration introduces a PleI restriction site in
      the nonsyphilis strains and thus allows genetic differentiation from T. pallidum
      subsp. pallidum strains.

PMID- 10338540
TI  - Proinflammatory activation of neutrophils and monocytes by Helicobacter pylori in
      patients with different clinical presentations.
AB  - Chronic Helicobacter pylori infection is associated with mucosal inflammation.
      The aim of the present study was to assess human neutrophil and monocyte
      activation by H. pylori strains obtained from patients with different clinical
      presentations. Bacterial sonicates from 12 strains were used to stimulate
      phagocyte upregulation of CD11b/CD18 adherence molecules assessed by fluorescence
      flow cytometry and oxidative burst responses assessed by chemiluminescence. A
      dose-dependent activation of CD11b/CD18 adherence molecules was observed with all
      strains on both neutrophils and monocytes. The activities were similar for
      strains from patients with duodenal ulceration and for strains from asymptomatic
      volunteers irrespective of histopathologic grades of the biopsy specimens from
      the antral mucosa. The neutrophil chemiluminescence response correlated with
      histopathologic severity. We conclude that upregulation of neutrophil and
      monocyte adherence molecules by H. pylori sonicates is not associated with
      clinical presentation of the infection.

PMID- 10338542
TI  - Activin and follistatin: more than FSH regulators 

PMID- 10338541
TI  - Lymphotoxin inhibits Chlamydia pneumoniae growth in HEp-2 cells.
AB  - Cytokines such as gamma interferon and tumor necrosis factor alpha (TNF-alpha)
      inhibit the intracellular replication of Chlamydia pneumoniae or Chlamydia
      trachomatis. In this study, we found that another cytokine, lymphotoxin (TNF
      beta), restricts the growth of C. pneumoniae in HEp-2 cells. When lymphotoxin (10
      U/ml) was added during incubation from 8 to 16 h postinoculation, inclusion body
      formation was severely reduced. In addition, we observed activation of nitric
      oxide production and the nuclear transition of NF-kappaB in HEp-2 cells in
      response to lymphotoxin. These results suggest that inhibition of chlamydial
      growth by lymphotoxin is mediated, at least in part, by nuclear transition of NF
      kappaB, resulting in induction of nitric oxide synthase to produce nitric oxide,
      a potent bacteristatic agent. This is the first report on antichlamydial activity
      of lymphotoxin through induction of nitric oxide.

PMID- 10338544
TI  - Direct antigen presentation and chronic rejection.

PMID- 10338543
TI  - Is atherosclerosis a no NO state?

PMID- 10338545
TI  - Clinical significance of arterial blood gas analysis for detection and/or
      treatment of central sleep apnea in patients with heart failure.

PMID- 10338546
TI  - Walking a fine line.

PMID- 10338547
TI  - My birth changes.

PMID- 10338549
TI  - Accept the challenge to change.

PMID- 10338548
TI  - Do a midwife's beliefs affect the outcomes of births she attends? How (or how
      not)?

PMID- 10338550
TI  - Talking with Robbie Davis-Floyd. Interview by Joel Southern.

PMID- 10338552
TI  - Post-dates pregnancy.

PMID- 10338551
TI  - Toward birth change.

PMID- 10338553
TI  - Preparing for the post-electronic birthing age.

PMID- 10338554
TI  - AIMS: right on target.

PMID- 10338555
TI  - Start with the small circle: an interview with Elizabeth Davis. Interview by Cher
      Mikkola.

PMID- 10338556
TI  - How to use the medical literature for fun and profit.

PMID- 10338557
TI  - Ethics and common sense vs. protocols: a postpartum emergency.

PMID- 10338558
TI  - Traditional Chinese medicine for hemorrhage.

PMID- 10338560
TI  - Prenatal testing: a thoughtful perspective.

PMID- 10338559
TI  - Integrating waterbirth into maternity care: an agent for change.

PMID- 10338561
TI  - More on calcium and preeclampsia.

PMID- 10338562
TI  - A return to normal birth.

PMID- 10338563
TI  - Reclaiming partnership in birth.

PMID- 10338564
TI  - Birth in Honduras: a source of women's self-esteem.

PMID- 10338566
TI  - Bridges of understanding: midwifery in Mexico.

PMID- 10338565
TI  - The midwives of Hadassah, Ein Kerem.

PMID- 10338568
TI  - A rural hospital in Poland.

PMID- 10338567
TI  - Mexico: keeping midwifery alive.

PMID- 10338569
TI  - Birth balls.

PMID- 10338571
TI  - Breastfeeding and HIV transmission.

PMID- 10338570
TI  - Sowing the seeds of change.

PMID- 10338572
TI  - Trust builds a shelter.

PMID- 10338573
TI  - Colonial midwife Anne Hutchinson.

PMID- 10338574
TI  - As a midwife, what do you do to encourage women to trust birth?

PMID- 10338575
TI  - Doing it her way.

PMID- 10338576
TI  - Josephine: grieving a sad birth made worse.

PMID- 10338577
TI  - First, do no harm.

PMID- 10338578
TI  - Sterile water blocks for back pain in labor.

PMID- 10338579
TI  - Slings: rediscovering mother's mobility.

PMID- 10338580
TI  - Trust the babies.
AB  - The recurrent amnesia the American Medical Association (AMA) suffers regarding
      the brilliant process of birth which has been unfolding perfectly for millennium
      can not eradicate this most precious corporeal knowledge. I have witnessed this
      perfect beauty replete with its regal diversity as an apprentice and in-hospital
      labor coach. Still and perhaps always I walk away from a birth calmly blinking at
      the textures of the world through which I move. There are few if any selfish
      moments between which we are pressed at birth. Humanity's desire to capture its
      immortality becomes possibility. Eons of complicated myths, and stories told,
      still echoing within our collective experience become reality: fantasy blooms
      within us. The tiny tattered leaf, utopia's imperiled banner all but dashed by
      avarice, for a split second reveals its glow. Each one of us has pristine moments
      of giddy altruism when the babes come through clearly negotiating their own
      private passages, journeys only they know despite the multi-billion dollar
      displaced efforts the AMA forges in its researching of bio-technological
      advancement. I saw a most remarkable example of this miraculous other-worldly
      journey at an in-hospital vaginal delivery of twin girls.

PMID- 10338581
TI  - A pitocin induction at home.

PMID- 10338582
TI  - Advocating for intersexed babies and their families.

PMID- 10338583
TI  - Low birth I.Q.

PMID- 10338584
TI  - Birth decisions and heuristics.

PMID- 10338585
TI  - Trusting birth.

PMID- 10338586
TI  - The truest trust.

PMID- 10338588
TI  - The Guarani of northern Bolivia.

PMID- 10338587
TI  - Birth in pre-Hispanic Mexico.

PMID- 10338589
TI  - Kangaroo care: why does it work?

PMID- 10338590
TI  - A visit to The Netherlands: Czech midwives look at quality of care.

PMID- 10338591
TI  - Interventions: consequences for breastfeeding.

PMID- 10338592
TI  - Is she a "partera" or a "matrona"?

PMID- 10338593
TI  - Life's breath.

PMID- 10338594
TI  - Becoming a nurse-midwife in Nigeria.

PMID- 10338595
TI  - R-e-s-p-e-c-t.

PMID- 10338596
TI  - Manual cervical dilation.

PMID- 10338597
TI  - Pitocin caution.

PMID- 10338598
TI  - Midwives, doctors and power.

PMID- 10338599
TI  - Conspiracy of silence.

PMID- 10338600
TI  - Band-aid midwifery.

PMID- 10338601
TI  - Nature of the Internet and the future of midwifery.

PMID- 10338602
TI  - Child abuse and its effects on birth. A research.

PMID- 10338603
TI  - Bridging the gap.

PMID- 10338604
TI  - The political midwife.

PMID- 10338605
TI  - A midwife to all.

PMID- 10338606
TI  - Slings: rediscovering mother's mobility (2).

PMID- 10338607
TI  - Can research be politically incorrect?

PMID- 10338608
TI  - Politics of the heart.

PMID- 10338609
TI  - On trial: women healers.

PMID- 10338610
TI  - The influence of culture.

PMID- 10338611
TI  - Women's reproductive health: a global perspective.

PMID- 10338612
TI  - Working to reduce maternal mortality.

PMID- 10338613
TI  - Mama: the Iranian midwife.

PMID- 10338614
TI  - Grandmother was a midwife.

PMID- 10338615
TI  - The politics of birth.

PMID- 10338616
TI  - Witch hunt, Irish style.

PMID- 10338617
TI  - Conferences bring shared visions.

PMID- 10338619
TI  - Evidence-based practice: should this be our goal?

PMID- 10338618
TI  - Open hearts, open minds.

PMID- 10338620
TI  - Prolonged labor: caught in the middle.

PMID- 10338621
TI  - How long was the longest labor you attended? What was the birth like?

PMID- 10338622
TI  - Prolonged labor: past & present.

PMID- 10338623
TI  - Politics of childbirth education.

PMID- 10338624
TI  - Preventing prolonged labor.

PMID- 10338625
TI  - Shoulder dystocia: never easy.

PMID- 10338626
TI  - Prolonged labor in the hospital setting.

PMID- 10338627
TI  - Denial.

PMID- 10338628
TI  - Anencephalic birth.

PMID- 10338629
TI  - Rhogam: do midwives hold the evidence?

PMID- 10338630
TI  - Prolonged labor and normal birth.

PMID- 10338631
TI  - The spoken word.

PMID- 10338632
TI  - Two births.

PMID- 10338634
TI  - What is midwifery?

PMID- 10338633
TI  - Is this midwifery?

PMID- 10338635
TI  - Sink or swim: midwifery in British Columbia, Canada.

PMID- 10338636
TI  - Birth in Greece: small steps toward change.

PMID- 10338637
TI  - Guatemala: the birth of a midwifery career.

PMID- 10338638
TI  - Midwifery on the threshold of life and death.

PMID- 10338639
TI  - Why keep birth normal? What is normal birth?

PMID- 10338640
TI  - Marion's message. What keeps birth normal?

PMID- 10338641
TI  - Question of the quarter. What is normal birth?

PMID- 10338642
TI  - Normal birth: do we believe? Can we remember?

PMID- 10338643
TI  - Just what is normal?

PMID- 10338644
TI  - Variation is the rule.

PMID- 10338645
TI  - Birth as a normal process.

PMID- 10338646
TI  - High religion in labor & delivery. The bonds of normalcy.

PMID- 10338647
TI  - Balancing midwifery with motherhood.

PMID- 10338648
TI  - Middle class beliefs. How they define normal birth.

PMID- 10338649
TI  - Psychological dystocia.

PMID- 10338650
TI  - Maybe Descartes got it wrong.

PMID- 10338651
TI  - What has happened to normal birth?

PMID- 10338653
TI  - $10,000 reward!

PMID- 10338652
TI  - Freedom at forty. A homebirth experience.

PMID- 10338654
TI  - Nurses can make a difference.

PMID- 10338655
TI  - Ocean.

PMID- 10338656
TI  - Great Britain. Widening the circle.

PMID- 10338657
TI  - From Brooklyn to Havana: the midwifery program delegation to Cuba.

PMID- 10338658
TI  - Midwives have always been respected in Norway: a discussion with Halima Taylor.
      Interview by Alice Evans.

PMID- 10338659
TI  - Australia. Changing midwifery.

PMID- 10338660
TI  - The Virgin Islands. Low key and discreet: a discussion with Linda Caiger.
      Interview by Alice Evans.

PMID- 10338661
TI  - Mexico. Making a difference.

PMID- 10338662
TI  - Guatemala. One step at a time.

PMID- 10338663
TI  - Through the eyes of a Swedish midwife-to-be.

PMID- 10338664
TI  - Can a natural process be taught?

PMID- 10338665
TI  - Marion's message. Keeping childbearing normal through nutrition.

PMID- 10338666
TI  - Question of the quarter. What therapies do you use prenatally to prevent
      hemorrhage?

PMID- 10338667
TI  - Some thoughts on postpartum hemorrhage.

PMID- 10338668
TI  - Hemorrhage: stay close and pay attention to your mothers.

PMID- 10338669
TI  - Hemorrhage prevention and early detection.

PMID- 10338670
TI  - Taking the fear out of third stage.

PMID- 10338671
TI  - Three keys to avoiding postpartum hemorrhage.

PMID- 10338672
TI  - Hemorrhage during pregnancy and childbirth.

PMID- 10338673
TI  - Breastfeeding nemesis.

PMID- 10338674
TI  - Meet the practitioner. Introducing Suzanne Colson.

PMID- 10338675
TI  - Breastfeeding.

PMID- 10338676
TI  - Latex allergy: epidemic of the '90s.

PMID- 10338677
TI  - Life with latex allergy.

PMID- 10338678
TI  - Working with the traditional Indian Village dai.

PMID- 10338679
TI  - Workshop curriculum.

PMID- 10338680
TI  - South to Honduras.

PMID- 10338681
TI  - A double blessing.

PMID- 10338682
TI  - New approaches in the pharmacological treatment of obesity.
AB  - Many new substances are currently being investigated for their usefulness in the
      pharmaco-therapy of obesity. Most drugs interfere with monoamine neuro
      transmitter (serotonin, noradrenalin, dopamine and histamine) effects and act as
      an appetite suppressant. Other approaches are to primarily increase thermogenesis
      (e.g. beta 3-adrenoceptor agonists), or to decrease fat absorption by inhibiting
      the pancreatic lipase (orlistat). New promising agents are substances that
      increase the effect of corticotropin releasing factor (CRF) or urocortin in the
      brain (CRF-binding protein ligand inhibitor) and a neuropeptide Y (NPY) Y5
      receptor antagonist. The clinical relevance of leptin in the therapy of obesity
      is probably limited, but can not be fully evaluated at the moment. As obesity has
      a multifactorial basis, all these substances have in common the fact that they
      can not cure obesity. They should only be used as an adjunct to classical
      strategies like diet and exercise in severe obesity. For developing new, perhaps
      even more specific pharmacological agents, further research is needed to
      understand the individually different genetic and physiological basis of obesity.

PMID- 10338683
TI  - Lipolysis, fatness, gender and plasma leptin concentrations in healthy, normal
      weight subjects.
AB  - BACKGROUND: Relationship between plasma leptin and adiposity and gender has been
      reported in adults. Effects of age on plasma leptin is unclear and regulation of
      leptin production by white adipose tissue is still poorly understood. OBJECTIVES:
      To study if age and parameters of lipolysis are related to plasma leptin
      concentrations. METHODS: Seventy-seven healthy, normal-weight subjects (age range
      19-82 y.) had measurements of body composition (18oxygen dilution technique) and
      of fasting plasma levels of leptin, glycerol, and nonesterified fatty acids
      (NEFA). RESULTS: Plasma leptin was correlated to NEFA (r = 0.28) and glycerol (r
      = 0.48) concentrations. The relationship between %fat and plasma leptin was best
      fitted by an exponential (r2 = 0.82). In multiple regression %fat, body mass
      index, glycerol, and gender, but not fat mass, age or NEFA contributed
      independently to the variation in log plasma leptin. Log plasma leptin was higher
      in women than in men for a given glycerol concentration. CONCLUSION: Adiposity,
      lipolysis, and gender are related to plasma leptin in healthy humans.

PMID- 10338684
TI  - Small supplements of N-3 fatty acids change serum low density lipoprotein
      composition by decreasing phospholid and apolipoprotein B concentrations in young
      adult women.
AB  - In order to investigate the effect of a short-term application of marine n-3
      polyunsaturated fatty acids on the composition of serum very low density
      lipoproteins (VLDL), low density lipoproteins (LDL), and high density
      lipoproteins (HDL), nine women aged 29 +/- 4.2 years, following a diet with a
      SFA/MUFA/PUFA profile of 2.4/3/1, received supplements of six capsules daily,
      each capsule containing 0.137 g of n-3 fatty acids (14.5% eicosapentaenoic acid
      (EPA) and 8.9% docosahexaenoic acid (DHA)) for 10 d. Food consumption, assessed
      during two 10-days periods indicates that percentage contribution of SFA, MUFA,
      and PUFA to the daily energy intake did not change through the fish-oil
      supplementation period, but the daily consumption of n-3 fatty acids increased
      2.3 times. N-3 fatty supplementation increased EPA and DHA percentages in serum
      phospholipids, but failed to decrease (p > 0.05) the cholesterol and triglyceride
      concentration in serum LDL and HDL, although it did so in VLDL. In contrast, the
      lipoprotein-phospholipid and lipoprotein-protein concentrations were markedly
      affected, mainly in LDL and HDL (at least p < 0.01). HDL and VLDL compositions
      were not affected but the total mass (lipid + protein in mg/dl) concentration of
      these lipoproteins significantly decreased (p < 0.05), suggesting a lower number
      of these particles in circulating blood after the n-3 treatment. The LDL
      cholesterol/LDL-apolipoprotein B ratio increased (p < 0.01) reflecting a probable
      increase in LDL size. Following fish oil supplementation, LDL particles contained
      a significantly lower amount of phospholipids, which also suggests changes in the
      surface/core ratio of the average LDL. Changes in serum lipoprotein lipids did
      not significantly correlate with any dietary change other than the n-3 fatty acid
      increase. The results indicate that a 10-day application of a small supplement of
      n-3 change the LDL composition leading to less atherogenic LDL particles with
      lower phospholipid and apolipoprotein (Apo) B concentrations.

PMID- 10338685
TI  - Dietary flavonoids protect human colonocyte DNA from oxidative attack in vitro.
AB  - BACKGROUND & AIMS: Epidemiological studies suggest that antioxidant polyphenols
      in the human diet may protect against diseases such as cancer. In this study we
      investigated the cytoprotective potential of the flavonoids, quercetin,
      myricetin, kaempferol and rutin against oxidative DNA damage in human colonocytes
      in vitro. METHODS: Caco-2 cells, which display specialised enterocyte/colonocyte
      cell functions, were used as an in vitro model for human colonocytes. Hydrogen
      peroxide was employed as the oxidant. DNA damage (strand breakage, oxidised
      purines and oxidised pyrimidines) was determined using the alkaline single cell
      gel electrophoresis or comet assay. Cell growth and viability were measured.
      RESULTS: Hydrogen peroxide caused a dose-dependent increase in DNA strand
      breakage in human colonocytes, presumably via oxygen free radical generation.
      Quercetin and myricetin protected Caco-2 cells against oxidative attack. In
      addition, quercetin decreased hydrogen peroxide-mediated inhibition of growth.
      Neither rutin nor kaempferol was effective. However, quercetin, while inhibiting
      DNA strand breakage, did not alter the levels of oxidised bases following
      peroxide treatment. The antifungal agent ketoconazole, prevented quercetin
      cytoprotection in Caco-2 cells, indicating that P450-mediated metabolism may
      alter the efficacy of the flavonoids against oxidative DNA damage. CONCLUSION:
      Flavonoids, particularly quercetin, the most abundant flavonoid in the human
      diet, are likely to be important in defending human colonocytes from oxidative
      attack.

PMID- 10338686
TI  - Plasma concentrations of carotenoids in healthy volunteers after intervention
      with carotenoid-rich foods.
AB  - AIM OF THE STUDY: The present study was conducted to investigate changes in the
      plasma concentration of carotenoids and carotenoid oxidation products, vitamin A,
      alpha- and gamma-tocopherol, and ubiquinone-10 during a dietary intervention
      trial with 23 male healthy volunteers. METHOD: A two week carotenoid depletion
      period was followed by a daily consumption of 330 mL tomato juice (40 mg
      lycopene), then by 330 mL carrot juice (15.7 mg alpha-carotene and 22.3 mg beta
      carotene), and then by a 10 g spinach powder preparation (11.3 mg lutein and 3.1
      mg beta-carotene) served with main meals for two weeks, respectively. Blood
      samples were collected in the morning after an overnight fasting and carotenoids,
      vitamin A, tocopherols, and ubichinone were analyzed by reversed-phase HPLC.
      RESULTS: During the tomato juice intervention, plasma concentrations of trans-
      and cis-lycopene increased 3-fold compared to the depletion period. Lycopene
      oxidation products could be demonstrated in plasma and were significantly
      elevated compared to control (p < 0.001). After two weeks of carrot juice
      consumption, alpha-carotene and beta-carotene concentrations increased 8.6- and
      3.2-fold, respectively. Finally, during the spinach consumption period the lutein
      concentration increased 2-fold, while the beta-carotene concentrations were still
      elevated 2-fold. CONCLUSIONS: The moderate change in dietary habits, e.g., the
      consumption of 330 mL of carotenoid-rich vegetable juices caused significant
      changes in the plasma carotenoid concentrations, indicating a high
      bioavailability of carotenoids from these processed vegetable products. The
      changes in plasma carotenoid concentrations reflected the carotenoid composition
      of the consumed foods. However, particularly during the tomato juice intervention
      period the occurrence of lycopene oxidation products and cis-lycopene isomers in
      plasma was eminent. The formation may be due to antioxidant reactions of lycopene
      in the organism.

PMID- 10338687
TI  - Mediation of differentiating effects of butyrate on the intestinal cell line Caco
      2 by transforming growth factor-beta 1.
AB  - BACKGROUND: Beside their role as the main energy source in the colonic mucosa,
      short chain fatty acids were found to act as potent antiproliferative and
      differentiation agents in various cancer cell lines. It has recently been shown
      that butyrate also induces TGF-beta 1 mRNA in human keratinocytes, suggesting
      that TGF-beta 1 may play a role in butyrate induced cell differentiation. AIM OF
      THE STUDY: The objective of our study was to investigate the possible role of
      exogenous and endogenous TGF-beta on butyrate induced differentiation of
      intestinal epithelium. METHODS: Studies were performed in Caco-2 cells, a cell
      line resembling functionally normal enterocytes. Cells, cultured in standard
      medium were studied over a 15-day period. Sodium butyrate (5 mM), TGF-beta 1 (2
      ng/ml) or butyrate (5 mM) + anti-human TGF-beta 1 antibody (30 micrograms/ml)
      were added to the medium. At day 4, 8, 11 and 15 total protein content, alkaline
      phosphatase activity, lactate dehydrogenase activity and transepithelial
      resistance were measured. RESULTS: Under culture conditions both, butyrate and
      TGF-beta 1 inhibited growth accompanied by an induction of cell differentiation
      approved by increased alkaline phosphatase activity and transepithelial
      resistance. The differentiating effect of butyrate was accompanied by an
      increased endogenous TGF-beta 1, but not TGF-beta 2 expression in Caco-2 cells.
      Co-incubation of butyrate with anti-human TGF-beta 1 antibody suppressed at least
      in part the differentiating effects of butyrate. CONCLUSIONS: Our results
      directly implicate that the TGF-beta isoform TGF-beta 1 is necessary for butyrate
      induced Caco-2 cell differentiation, but other molecular mechanisms may also play
      a role in the differentiation of this cell line.

PMID- 10338688
TI  - Integrity, ambiguity or duplicity? NHS consultation with the public.
AB  - Recent guidance from the Department of Health and National Health Services (NHS)
      Executive has stressed the importance of public involvement in the NHS. This
      paper places this guidance in the historical context of public consultation in
      the NHS and explores, through a detailed case study, the traditional approach to
      consultation that the guidance is seeking to change. The paper concludes with
      some reflections on the challenges that will need to be addressed in order for
      the guidance to be put into practice.

PMID- 10338690
TI  - Negotiating a 'borderland': nursing, gender and management.

PMID- 10338689
TI  - Performance-related pay for health service professionals: the Italian experience.
AB  - Italy has significant experience of performance-related pay (PRP) for health
      service professionals: a system which links part of doctors' remuneration to
      their productivity dates back to 1938. This paper reports on a two-year field
      research, carried out on the Italian National Health Service, which investigates
      the objectives, design and implementation of PRP, as well as its operation and
      effectiveness. First, the evolution of PRP schemes over the latest 25 years is
      reconstructed, and the range of covert and overt objectives underlying the use of
      PRP are unravelled. Then, after having highlighted the main structural and
      cultural factors which negatively affect PRP effectiveness, a critical evaluation
      of PRP is attempted, drawing on the analysis of both hard performance data and
      the subjective perceptions of stakeholders. The conclusion is that PRP led to
      problems and unforeseen consequences in most of the hospitals examined, due to
      both structural factors, mainly some flaws in PRP design, and cultural
      constraints, mainly the values of health professionals. However, the case of a
      Northern Italian hospital proves that, despite the constraining environmental
      setting, there is still scope for managerial intervention in the implementation
      process which is sufficient to guarantee PRP effectiveness. This indicates that
      the implementation process far outweighs the significance of structural and
      cultural constraints, and that PRP is a powerful tool at management disposal to
      increase employees' performance and commitment.

PMID- 10338691
TI  - Waiting for inpatient hospital care: experience at a VA facility.
AB  - Inpatient care from hospitals operated by the Department of Veterans Affairs (VA)
      is offered free of charge to many eligible veterans. Others must make nominal co
      payments. As a result, in contrast to the private sector, money prices do not
      serve as an allocation mechanism for inpatient care. Many VA hospitals must
      therefore rely on waiting lists as implicit allocation devices. This study
      examines the effects of waiting at one large VA facility. Using multivariate
      statistical techniques on survey data from 195 veterans, the influence of factors
      that determine willingness to wait for VA inpatient care is estimated. The
      results suggest that willingness to wait depends on the expected benefits of
      waiting before treatment can be received. The impact of the monetary and non
      monetary costs imposed by waiting is small. As VA waiting lists continue to grow,
      social workers discharge planners and other providers should investigate the
      tolerance for waiting and incorporate this information into plans for service
      provision.

PMID- 10338693
TI  - Evidence-based care in nursing: reforms versus research, rhetoric versus reality.
AB  - The new evidence-based health care culture, together with nurses' demands for
      enhanced professional status, has embedded within its strategy the imperative to
      develop a corpus of nursing-specific research. These apparently compatible aims
      were intended to meet the need for enhanced professional status while at the same
      time enabling clinical nursing practice to be justified on scientific grounds.
      While the dual reform agendas brought with them the resistance that always
      accompanies radical amendments to the status quo, they also seem to have created
      an unanticipated reciprocal antagonism which has impeded the development of
      nursing research. The policy changes that were necessary to meet the
      prerequisites for professional status have had a detrimental effect on the
      potential for generating an adequate body of nursing research. This second paper
      discusses some of the key reforms to nursing that have been implemented over the
      last decade and their impact on nursing's progress towards creating its own
      esoteric research knowledge base that could inform clinical care. It is suggested
      that policy and research may be diametrically opposed, and that nursing, if it is
      committed to professionalization, may have to reconsider its allegiance to the
      scientific research culture in favor of achieving some of the other objectives on
      its agenda.

PMID- 10338692
TI  - Developing a clinical information system: an interpretive case analysis within a
      UK hospital.
AB  - This paper seeks to adopt an interpretive case analysis for the study of the
      development of a clinical information system within a UK hospital. An initial
      literature review is outlined, which draws attention to the distinction between
      formal-rational and interpretive perspectives on information technology impacts.
      A case study is presented where a number of issues are identified which suggest
      that formal systems analysis techniques do not reflect the organizational
      realities within the hospital. The paper concludes with a brief discussion of the
      concerns for systems development, and notes the value of an interpretive
      perspective in this respect.

PMID- 10338694
TI  - An efficient fault-tolerant order entry management information system based on
      special distributed client/server architecture.
AB  - An automatic order entry system is very important for the processing of out
      patient information, not only helping doctors to enter their orders directly but
      also reducing errors of communication. Many hospitals are anxious to set up a
      direct order entry system but are concerned about possible system failures. In
      this paper we report on an effective and efficient fault-tolerant order entry
      management system which satisfies the requirements for out-patient order entry.
      From the results of experiments on a prototype we found that the system was user
      friendly and reduced the time taken. Doctors are able to enter their orders more
      easily, accurately and quickly by selecting from the standardized and
      personalized menus to be found in the system.

PMID- 10338695
TI  - Practice brief. Data resource administration: the road ahead. American Health
      Information Management Association.

PMID- 10338696
TI  - Quality is key. Interview by Jane E. Blumenthal.

PMID- 10338697
TI  - HCFA publishes proposed rule for hospital outpatient services PPS.

PMID- 10338698
TI  - Using benchmarking to support performance improvement efforts.
AB  - Successful benchmarking can create opportunities to improve performance through
      discovering best practices. The author offers an overview of benchmarking and
      best practices and how they apply to HIM--and ways to get started on your own.

PMID- 10338699
TI  - Reducing accounts receivable through benchmarking and best practices
      identification.
AB  - As HIM professionals look for ways to become more competitive and achieve the
      best results, the importance of discovering best practices becomes more apparent.
      Here's how one team used a benchmarking project to provide specific best
      practices that reduced accounts receivable days.

PMID- 10338700
TI  - Monitoring performance improvement using decision support systems.
AB  - The increasing use of clinically integrated decision support systems is creating
      new opportunities for HIM professionals. Here's a look at how such a system was
      used by one team to monitor performance improvement activities.

PMID- 10338701
TI  - Benchmarks as the signposts on the fraud case trail.

PMID- 10338702
TI  - Best practices in human resources.

PMID- 10338703
TI  - Benchmarking professional practice issues: a preview.

PMID- 10338704
TI  - Celebrating a history together ... AHIMA celebrates its 70th anniversary.

PMID- 10338705
TI  - Telemedicine technology in correctional facilities.

PMID- 10338706
TI  - Redesigning the indexed medical record.

PMID- 10338707
TI  - Rheumatoid arthritis.

PMID- 10338708
TI  - Integrated clinical management: a model for clinical integration.
AB  - The article describes a successful model for clinical integration that has
      improved utilization rates, service levels, physician and staff satisfaction, and
      the financial performance of physician groups and health plans. The model for
      clinical integration provides processes of medical management, care management,
      and patient management that are designed to transform a traditionally fragmented
      delivery system into a more cohesive system where everyone is working toward a
      common objective with aligned incentives. Links are established among primary
      care physicians, specialists, and hospitals to create synergistic relationships
      and seamless, accessible care for members.

PMID- 10338709
TI  - Next generation quality, Part 1: Gateway to clinical process excellence.
AB  - The quality movement has gone through three phases in this century. The first,
      quality assurance, emphasized reacting to problems and identifying "bad apples."
      The second, quality improvement, shifted the focus from individuals to processes
      but still retained a reactive problem-solving approach to improving the quality
      of products and services. The third phase, quality management, has gained
      strength in other industries over the years. The article presents a quality
      management, or "next generation quality," model for health care centered on
      clinical pathways as core clinical processes that are continuously improved and
      monitored through an improved version of variance management systems called the
      gateway model.

PMID- 10338710
TI  - Next generation quality, Part 2: Balanced scorecards and organizational
      improvement.
AB  - Part 1 of this two-part series defined a new quality paradigm called the next
      generation quality model. This model applies the principles of the Malcolm
      Baldrige Criteria for Performance Excellence to clinical processes. The model's
      components are clinical pathways, variance management systems, stream-lined
      patient documentation, and continuous improvement. Part 2 extends the next
      generation quality model, describes the principles and applications of integrated
      performance measurement systems, and explains how measurement systems are adapted
      to different levels of an organization to effect change.

PMID- 10338711
TI  - Clinical pathways from conception to outcome.
AB  - A provider must demonstrate superior performance in several areas, such as cost,
      utilization, and clinical outcomes, to obtain designation as a Center of
      Excellence. A comprehensive orthopedic strategy was designed for use by Good
      Samaritan Health Systems to obtain this designation. The strategy included the
      development of clinical pathways and a profiling system. Acute, subacute, home
      care, and patient/family pathways were developed for diagnosis-related group 209:
      total joint replacement. Six months after implementation, a profile was developed
      using the Dartmouth Clinical Value Compass. Dimensions profiled included patient
      satisfaction, clinical variance data, functional status, and cost/utilization
      data. Improvements were identified in patient satisfaction, cost/utilization, and
      patient care.

PMID- 10338712
TI  - Electronic medical records as tools for quality improvement in ambulatory
      practice: theory and a case study.
AB  - Information management is critical in today's health care environment.
      Traditional paper-based medical records are inadequate information management
      tools. Electronic medical records (EMRs) overcome many problems with paper
      records and are ideally suited to help physicians increase productivity and
      improve the quality of care they provide. The Department of Family Medicine at
      the Medical University of South Carolina uses the Practice Partner Patient Record
      EMR system. Department members have developed a quality improvement model based
      on this EMR system. The model has been used to improve care for acute bronchitis,
      diabetes mellitus, tobacco abuse, asthma, and postmenopausal osteoporosis.

PMID- 10338713
TI  - Embodying medical expertise in decision support systems for health care
      management: techniques and benefits.
AB  - Health care providers and payers are faced with ever-increasing pressures to
      lower costs, improve quality, and maximize profits. As medical information
      technology evolves, more medically related data are being collected, stored
      electronically within a data warehouse, and made available for decision support
      in the pursuit of lower costs and higher quality in health care. The article
      describes how medical expertise can be captured and integrated into decision
      support systems to improve awareness and predictability of disease and disease
      associated financial risk within a population of patients, ultimately providing
      patient-centric and provider-centric opportunities to improve health and decrease
      costs. The concept of medical logic engineering is introduced.

PMID- 10338714
TI  - Using case management data to drive organizational decisions.
AB  - Case managers armed with timely, organized, accurate, and meaningful data are
      powerful influencers and key decision makers. Case managers are in a unique
      position to use data to shape health care services, systems, and organizational
      strategy. They know the customers (internally and externally). They know why the
      organization gets and loses business. They know what the organization does well
      and what could use improvement. Most important, they know how well the
      organization is doing in managing the daily flow of financial resources. Case
      managers, coupled with health information support personnel, are exceptionally
      valuable corporate assets.

PMID- 10338715
TI  - Marketing quality and value to the managed care market.
AB  - Quantifying quality and marketing care delivery have been long-term challenges in
      the health care market. Insurers, employers, other purchasers of care, and
      providers face a constant challenge in positioning their organizations in a
      proactive, competitive niche. Tools that measure patient's self-reported
      perception of health care needs and expectations have increased the ability to
      quantify quality of care delivery. When integrated with case management and
      disease management strategies, outcomes reporting and variance analysis tracking
      can be packaged to position a provider in a competitive niche.

PMID- 10338716
TI  - Facilitating care management through computerized clinical pathways.
AB  - The development and implementation of clinical pathways at New York University
      Medical Center and the transition to a computerized multidisciplinary
      documentation system took place between 1995 and 1998. Both the computerized
      system and the pathway program evolved simultaneously over this 3-year period.
      The article describes the process of creating the clinical pathways and the
      automated documentation system to support the clinical pathways. Migration from
      the paper pathway to the automated system required the efforts of an
      interdisciplinary team, which focused on issues such as translation of written
      pathway detail into language that could be loaded into the automated system. The
      advantages, pitfalls, and lessons learned in this integration experience are also
      described.

PMID- 10338717
TI  - Integrating the patient's perspective: patient pathway development across the
      enterprise.
AB  - Two academic medical centers in a newly integrated structure joined to understand
      better their patients' experience with care processes and to promote increased
      patient involvement in the plan of care. Through a team approach, a patient
      pathway was developed using graphic and text elements to illustrate the normal
      sequence of critical activities and care processes for established clinical
      pathways at these medical centers. A focus group was held to achieve a higher
      level of patient input into care coordination issues. Through the integration of
      the patient's voice into the plan of care, priorities for improvement can be
      identified.

PMID- 10338718
TI  - Surviving and thriving with Vision 2006: information technology in the
      curriculum.
AB  - To prepare graduates for the new roles envisioned in the American Health
      Information Management Association's Vision 2006, which places emphasis on
      information technology and the management of health information, a model
      curriculum has been developed for health information administration and health
      information technology programs in which information technology and information
      systems have been strengthened. With these new directions come the expense and
      problems of purchasing and maintaining computer systems necessitated by these
      changes. There can be great resistance on the part of deans and other individuals
      to authorize the procurement of the hardware and software needed to establish a
      computer laboratory. The article describes a cost-effective alternative.

PMID- 10338719
TI  - The health care reform in Italy: transition or turmoil.
AB  - Health care reform in Italy is transforming its centrally planned, vertically
      integrated National Health Service into a market-oriented system in which public
      funders contract directly with individual providers. A model is envisaged in
      which a plurality of public and private care providers compete for contracts with
      capitated health agencies responsible for assuring uniform levels of services for
      geographically defined populations. The ultimate goal of the reform is to
      guarantee universal coverage and secure global spending limits while, at the same
      time, promoting efficiency in the delivery of care and enhancing responsiveness
      to consumers. The emphasis upon incentives for the individual provider which will
      be introduced should, however, be considered against the quest for equity in
      health care which was the central tenet of the 1978 reform and is yet to be
      attained. The fragmentation of the National Health Service into many separate,
      competing delivery units might well damage the ability to plan strategically for
      addressing the substantial inequities in health status, health care utilization,
      and health service availability which still exist across the country. Competition
      between a plurality of providers and fee-for-service payment schemes add
      additional concerns about unnecessary care and supplier-induced demand. It
      creates the need for developing rules to make competition manageable and
      providing sound clinical and financial information that make enforcement
      possible. The poor record scored in managing the contractual relationships
      between the LHUs and the strong private health sector suggests that massive
      investment in promoting managerial skills and developing appropriate clinical and
      financial information systems are required. Careful experimentation in
      implementing the reform and continuous monitoring of its impact on the health
      care system are, therefore, the imperatives of the next two years.

PMID- 10338720
TI  - Universal coverage and cost control: the United Kingdom National Health Service.
AB  - The UK NHS has a number of important strengths. Its costs are relatively low
      compared to the health care systems of other developed countries due in part to
      cash limited central budgeting. It is extremely popular with the electorate and
      surveys show overall satisfaction with the NHS despite some dissatisfaction with
      waiting lists and a public perception of underfunding. The NHS model of general
      medical care provided by independent contractors has been acclaimed as "a British
      success" (General Medical Services Council, 1983). The role of the UK GP combines
      providing primary care and acting as a gatekeeper to secondary care. This
      increases equitable access to care for the population and assists in cost
      containment. As a model, it is currently being emulated in other countries
      including Sweden and US Health Maintenance Organizations but, as in these
      countries, the UK primary care model has been evaluated poorly. There are of
      course continuing weaknesses in the UK health care system. There is insufficient
      knowledge upon which to base health care services and increase efficiency. In the
      future, if a knowledge-based health care service is to be created, a considerable
      amount of research and evaluation is required to identify "what works" in health
      care (i.e., what is effective) and also the cost effective ways of altering
      provider behaviour to maximise the amount of health gain which can be achieved
      using a limited budget. The NHS reforms created a lot of enthusiasm and energy
      but its effects are difficult to disentangle from the simultaneous increases in
      funding. There is little evidence from the UK or elsewhere that competition in
      health care produces efficiency or improvements in resource allocation.
      Evaluation is required to identify which of the reforms are increasing
      efficiency. Competition needs to be used with caution and recognised as a mean
      and not an end in itself. It is remarkable how both clinical practice and health
      policy reform, in the UK and elsewhere, is poorly evaluated. Medical practice
      varies substantially locally, regionally, and internationally, e.g., patients
      with similar age and stage of cancer receive very different levels of
      radiotherapy across Europe. For most interventions, the appropriate level of
      treatment may be asserted but is not based on cost effectiveness knowledge.
      Health policy analysts, like clinicians, make assertions about competition and
      other health care reforms which are value- rather than knowledge-based. Both
      groups of decision-makers should be more cautious, informing their choices with
      research rather than relying on unsubstantiated optimism!

PMID- 10338721
TI  - The Australian health system: continuity and change.
AB  - The health of Australians, with the exception of Aboriginals and Torres Strait
      Islanders, compares favourably with other industrialised nations. Since 1984,
      universal access for citizens to medical and public hospital services has been
      achieved under a national Health Insurance Scheme called Medicare, partially
      funded by a 1.4 percent levy on all taxpayers. Medicare found early widespread
      support from the electorate but continues to be buffeted by a minority coalition
      of some medical associations, private health insurers, and conservative
      "libertarian" politicians. Over the decade since its inception, Medicare has
      provided stability in maintaining total health costs around 8 percent of GDP.
      This has been largely due to capping hospital costs via Commonwealth-State
      agreements. Medicare has failed in the past five years to contain medical costs
      which have increased proportionally with increases in the medical workforce. This
      article examines the structure and performance of Medicare and its role within
      Australia's overall health system. Benefits of a universal access insurance
      program are outlined together with challenges associated with inequities in
      health status, geography, aging of the population, burgeoning technology,
      ideological diversity, and an economic climate requiring cost containment and
      favouring privatisation and the role of the market. It can be concluded that,
      despite these challenges, universal access to health care is here to stay.
      Australia's Medicare program has become popular with the electorate.

PMID- 10338722
TI  - Avoiding fundamental reform: current cost containment strategies in Canada.
AB  - Provincial governments in Canada are trying very hard to contain and possibly
      reduce health care expenditure. The wide ranging effort and frequent
      announcements of yet another cost cutting measure, including deinsurance, stand
      in marked contrast to the complacency of earlier periods. This activist and
      serious effort to reform the system is certainly welcome, yet the reforms are not
      adequate and ignore some fundamental and structural problems of Canada's health
      care system. Health care reform must do one or more of three things, i.e.,
      improve efficiency, effectiveness, and/or equity of the system. Many cost-cutting
      measures in Canada achieve none of these objectives and merely postpone costs to
      a later time or shift the burden on to the sick. Fundamental health reforms
      include the incentive systems influencing physician behavior and choices;
      efficiency gains via manpower substitution; more effective control over the
      supply and distribution of medical manpower; and changes in the organization and
      design of health care delivery systems. But these fundamental reforms are not
      being pursued in Canada even though this is an opportune time for such reforms.
      Also discussed is the potential for and problems associated with managed and/or
      public sector competition. This article is essentially a critical review of
      current cost containment efforts in Canada.

PMID- 10338723
TI  - The Japanese health care system: citizen complaints, citizen possibilities.
AB  - The Japanese health care system is sometimes considered one of the best in the
      world because it appears to have achieved universal coverage, high quality, and a
      comparatively low level of expenditure. But under compulsory national health
      insurance and the uniform fee schedule which has worked well so far, various
      problems have been produced in Japan. A growing number of persons believe some
      reform or readjustment may be required. Following a brief review of the Japanese
      health care system which includes health insurance mechanisms, the relationship
      among physicians, hospitals and clinics, and the impact of these structures on
      access to care are explored. The resulting cost of care and the quality of care
      are then addressed. The lack of consumer information and the nature of the
      physician-patient relationship related to cultural factors are important
      components of this health care system. These latter factors are in the process of
      change and the likely direction of their influence upon the Japanese health care
      system is explored.

PMID- 10338724
TI  - Comparative health systems: a conceptual framework.
AB  - This article presents a review of the conceptual frameworks utilized in comparing
      health care systems among countries. While much of the available literature
      remains descriptive, several structural features are becoming widely recognized
      and offer a basis for empirical study. The structural variables involving
      financing and reimbursement mechanisms are emphasized and the research centers on
      these structural arrangements as methods of cost containment. There are, however,
      more global or comprehensive approaches which offer a broader range of issues to
      be considered. Finally, the authors note the barriers and hindrances in
      attempting to develop and conduct comparative approaches to health care systems.

PMID- 10338725
TI  - Is pain management lacking in your ED? Here's what you need to do.

PMID- 10338726
TI  - Reduce legal risks of chest pain.

PMID- 10338727
TI  - Mentoring your nursing staff helps create future leaders.

PMID- 10338728
TI  - Novel patient complaint management strategies can improve care.

PMID- 10338729
TI  - New technology: continuous-speech voice activated dictation.

PMID- 10338730
TI  - Fee-for-service nursing: an idea ready to be tested.

PMID- 10338731
TI  - Clinic visits and hospital admissions for care of acid-related upper
      gastrointestinal disorders in women using alendronate for osteoporosis.
AB  - CONTEXT: About 1 in 3 women taking alendronate for osteoporosis report
      gastrointestinal symptoms, a rate much higher than that found during clinical
      trials. OBJECTIVE: To establish the frequency of outpatient visits and hospital
      admissions for acid-related upper gastrointestinal disorder (ARD) among women
      taking alendronate and to identify potential risk factors. METHODS: A
      retrospective database analysis identified 812 women with osteoporosis who had
      filled one or more 10-mg alendronate prescriptions from October 1995 through
      October 1996. RESULTS: One hundred (12.3%) of the 812 women received healthcare
      for ARD, a clinical encounter rate of 28.5 per 100 person-years. A reference
      group of 362,109 women from the same health plan had 17.6 ARD encounters per 100
      person-years. Excluding women who had ARDs before receiving alendronate,
      alendronate users were 1.6 (95% CI = 1.2, 2.7) times more likely to have an ARD
      encounter than nonusers. Risk of having ARD increased with age [users aged 70
      years and older had a relative risk of 1.5 (95% confidence interval (CI) 1.0
      2.30) compared with younger women] and with concurrent use of nonsteroidal anti
      inflammatory drugs (NSAIDS) (relative risk 1.7, 95% CI 1.1-2.6). CONCLUSIONS:
      Elderly alendronate users or those concurrently taking NSAIDS should be carefully
      monitored because of their high risk of having ARD. Cost/benefit analyses of
      alendronate treatment for osteoporosis should include costs of treating ARD.

PMID- 10338732
TI  - Attitudes toward cost-containment features of managed care: differences among
      patient subgroups.
AB  - OBJECTIVE: To analyze the extent to which personal characteristics and
      circumstances affect attitudes toward cost-containment aspects of managed care.
      STUDY DESIGN: A national probability sample component of the 1994 Robert Wood
      Johnson Foundation National Access to Care Survey. METHODS: Telephone and in
      person survey follow-up of 3480 persons who completed the 1993 National Health
      Interview Survey. Findings on respondents' attitudes toward three principal cost
      saving features of managed care are reported. These features are choosing
      physicians from insurance company lists (LIST), accessing specialists through
      referrals only (SPECIALIST), and seeing a nurse sometimes instead of a physician
      (NURSE). Data were categorized and analyzed by different population subgroups.
      RESULTS: Respondents were divided almost equally in terms of how much they minded
      healthcare features of managed care, with approximately one third minding a lot,
      one third minding a little, and one third minding not at all. However, slightly
      more people minded LIST (42%) and NURSE (39%) features a lot. The respondent
      subgroups with the lowest proportion "minding a lot" were the uninsured poor and
      those already in managed care. Those groups minding the most were the elderly,
      those in fee-for-service plans, persons in poor health, and those with ischemic
      heart disease. CONCLUSIONS: Acceptance of managed care cost-containment features
      varies by consumer characteristics. Those who have the most to gain financially
      by cost-containment features and the least to lose in terms of their access to
      care mind the managed care features the least. Persons who object most strongly
      are those who are not financially constrained and who are in poor health.

PMID- 10338733
TI  - An investigation of primary care patients receiving extended treatment with
      selective serotonin reuptake inhibitors.
AB  - OBJECTIVE: To determine the psychiatric characteristics of a sample of primary
      care patients receiving extended treatment with selective serotonin reuptake
      inhibitors (SSRIs) as well as to assess the appropriateness of extended
      treatment. STUDY DESIGN: A prospective case series of patients (convenience
      sample) assessed with survey, psychological testing, interview, and medical
      record review. METHODS: Participants (n = 39) were patients in a health
      maintenance organization primary care setting receiving treatment with SSRI-type
      antidepressants for 12 months or longer, with no psychiatric evaluation or
      treatment immediately before commencement of antidepressant therapy. Each
      participant completed measures of self-destructive behavior and personality
      disturbance, underwent a clinical psychiatric interview, and had their medical
      record reviewed to determine psychiatric diagnoses by the primary care physician
      at the initiation of antidepressant treatment. RESULTS: On psychiatric interview,
      64.1% of participants were diagnosed with major depression, the majority
      recurrent (46.2% of the entire sample); 46.2% with dysthymia; and 38.5% with
      panic disorder. Psychiatric morbidity in this sample was reflected by recurrent
      depressive episodes, long-standing depression, comorbid psychiatric diagnoses on
      interview (average of 1.8 diagnoses per participant), self-harm behaviors, and
      personality pathology. Seventy-seven percent of primary care diagnoses gleaned
      from medical records reflected depressive diagnoses. The approximate "match" rate
      for a depression-spectrum diagnosis between psychiatric interviewer and primary
      care physicians was 90%; however, on psychiatric interview, 16.7% of participants
      had bipolar disorder and 38.5% had panic disorder, which were not noted in the
      primary care medical record. CONCLUSIONS: Patients in primary care settings
      receiving extended treatment with SSRIs may have complex psychopathology for
      which long-term antidepressant treatment appears appropriate.

PMID- 10338734
TI  - Where is the financial safety net for managed care physicians?
AB  - OBJECTIVE: Empiric research on mechanisms by which managed care physicians
      attempt to mitigate financial risk is lacking. We assumed the perspective of a
      managed care plan in investigating the relationship between risk sharing and the
      match between a physician's capitation payments and costs of care. DESIGN: The
      study design was a family of payment simulations using 2 years of managed care
      claims data. METHODS: Claims from a cohort of 82,525 managed care patients were
      used, with year 1 data determining a capitation rate for year 2 primary care
      services. The net provider payment in year 2 was examined under scenarios that
      might modify financial outcomes, including stop-loss insurance, age- and gender
      adjustment of capitation, and risk pooling within independent practice
      associations. RESULTS: The size of a provider's patient panel was positively
      correlated with net per capita payment (r = 0.22; P < 0.0001 without risk
      modification strategies). The variance of the ratio of net to total revenue was
      utilized as a proxy for the degree of risk assumed in caring for a panel of
      capitated enrollees. Risk modification strategies reduced this variance measure,
      with risk pooling producing the largest effect, especially for providers of
      panels of fewer than 135 patients. In contrast, age- and gender-adjustment of
      capitation payments had little effect on reimbursement outcomes. CONCLUSIONS:
      Short of increasing the pool of capitated patients, risk modification strategies
      appear limited in their ability to produce more equitable reimbursement to
      providers with small patient panels. With many providers assuming substantial
      risk in pursuing managed care contracts, these dynamics may favor organizational
      forms of medical practice that facilitate large patient panels within a single
      plan.

PMID- 10338735
TI  - Factors affecting patient compliance with antihyperlipidemic medications in an
      HMO population.
AB  - OBJECTIVE: To identify factors that influence compliance in patients taking
      antihyperlipidemic medications. STUDY DESIGN: This was a retrospective cohort
      study in which computerized pharmacy records were used to estimate medication
      compliance in patients in a Health Maintenance Organization from 1993 to 1995.
      PATIENTS AND METHODS: Data on 772 patients on antihyperlipidemic medications were
      obtained from pharmacy and healthcare utilization claims and from a cross
      sectional survey. The medication compliance ratio for each patient was calculated
      from the prescription profile. Patient compliance was modeled as a function of
      four clusters of determinants: patient characteristics, complexity of drug
      regimen, health status, and patient-provider interaction. Correlation between
      specific characteristics and compliance was estimated by logistic regressions.
      RESULTS: Approximately 37% of patients complied with at least 90% or more of
      their antihyperlipidemic medications. The following variables had a significant
      influence on compliance: female gender (odds ratio [OR], 0.64), baseline
      compliance (high: OR, 3.42; medium: OR, 1.86), perceived health status (SF-36
      bodily pain score: OR, 1.02; SF-36 vitality score: OR, 0.97), comorbidity (OR,
      0.90), and number of daily doses of antihyperlipidemic medications (OR, 0.60).
      CONCLUSIONS: The findings suggest that women, patients with comorbidities,
      patients reporting high SF-36 vitality scores, and patients with multiple doses
      of antihyperlipidemic medications are less likely to be compliant. Patients who
      self-report good compliance with previous medications are more likely to comply.
      This information may be used to target interventions at patients who are likely
      to be noncompliant with their medication regimens.

PMID- 10338736
TI  - Empiric investigation on direct costs-of-illness and healthcare utilization of
      Medicaid patients with diabetes mellitus.
AB  - OBJECTIVE: To determine total direct costs-of-illness and to study the influence
      of different factors affecting these costs. In addition, we examined each type of
      service (e.g., hospitalization, outpatient care, prescription drugs, physician
      encounters, and laboratory tests) for diabetic Medicaid patients to provide
      evidence about the relationship between diabetic patients' healthcare utilization
      and their related predictors. PATIENTS AND METHODS: A total of 7931 patients with
      diabetes who were 65 years or younger in the Alabama Medicaid program from 1992
      to 1995 were studied. Using a relational database created from Medicaid claims,
      multiple regression and canonical correlation methods were used to analyze the
      patients' direct costs-of-illness, including the costs associated with each
      healthcare service used by each patient. RESULTS: The costs of hospitalization,
      outpatient care, prescription drugs, and physician encounters were the four
      largest components of the direct costs-of-illness for diabetic Medicaid patients,
      comprising 29.9%, 21.3%, 28.2%, and 14.3%, respectively. After controlling for
      other factors in an empiric model, the direct costs-of-illness for a patient with
      insulin-dependent diabetes mellitus was $5160 higher than for a patient with
      noninsulin-dependent diabetes mellitus during the 3-year study. The cost for a
      patient with renal dysfunction was $59,920 higher than for other diabetic
      patients. Each increase in the number of different prescribing physicians per
      patient was associated with a cost increase of $450. Each additional comorbidity
      increased the cost by $735 per patient. The cost for a male patient was $2140
      higher than that for a female patient, and the cost for a white patient was $1330
      higher than that for a non-white patient. For a patient who relied on diet to
      control diabetes, there were $2750 less in costs compared with other patients
      during the study period. More than 20% of the variability in patients' healthcare
      utilization costs was explained by the set of predictive factors. CONCLUSIONS:
      The direct costs-of-illness and healthcare utilization for Medicaid diabetic
      patients were significantly accounted for by the number of comorbidities, the
      number of different physicians visited, insulin-dependent diabetes mellitus, and
      complications (especially renal dysfunction). Patients who relied on dietary
      therapy and exercise to control their diabetes had lower healthcare costs and
      utilization than other patients. A significant amount of healthcare costs and
      utilization might be controlled or reduced if diabetes disease management can
      successfully be aimed at preventing diabetic complications, controlling
      comorbidities, and minimizing the number of different physicians visited.

PMID- 10338737
TI  - Determining the cost of gastroesophageal reflux disease: a decision analytic
      model.
AB  - OBJECTIVE: To design a decision analytic model to help determine the costs
      associated with various treatment regimens for gastroesophageal reflux disease
      (GERD). STUDY DESIGN: A decision analytic model incorporating Markov processes
      was developed to calculate clinical and direct economic outcomes for patients
      with GERD after 2 years of treatment. PATIENTS AND METHODS: We used retrospective
      data in the Markov model to generate clinical and economic outcomes. The primary
      data sources were the 1993 MarketScan claims database, the 1992 National Hospital
      Discharge Survey, and the clinical literature. RESULTS: Patients with mild GERD
      (17.6% of patients) contributed 37.8% of costs, while those with moderate to
      severe disease (14.4% of patients) contributed 49.9% of costs. The remaining
      12.3% of costs was spent on the 68% of patients with non-GERD diagnoses. The
      class of drugs with the highest acquisition cost--proton pump inhibitors--had the
      lowest total cost per case. The high level of efficacy of these drugs may explain
      this result. Sensitivity testing showed no evidence that our model's results
      depended heavily on any one probability or cost factor. CONCLUSIONS: This model
      showed that patients with moderate to severe GERD were the most expensive cases
      to treat and that proton pump inhibitors resulted in the lowest total cost per
      case. Further testing and manipulation of the model are required to gain a better
      understanding of the trade-offs involved in different options for GERD
      management.

PMID- 10338738
TI  - Influence of an interventional program on resource use and cost in pediatric
      asthma.
AB  - OBJECTIVE: Asthma is the most common chronic condition of childhood, for which
      morbidity, mortality, and cost are increasing. This study was performed to
      determine whether patient education and assignment to a primary care provider
      improve outcomes and cost in the management of pediatric asthma. STUDY DESIGN: A
      prospective pilot study of 61 patients was conducted with a retrospective review.
      Data were obtained from health and pharmacy records. PATIENTS AND METHODS: Sixty
      one unassigned pediatric asthma patients who were noted to be frequent users of
      emergency department services and who had no primary care provider were
      identified. This cohort received asthma education and was assigned a provider
      trained in the national asthma guidelines. Hospital admissions, Emergency
      Department and clinic visits, use of beta 2 agonists and anti-inflammatory drugs,
      number of chest radiographs, and continuity of care were recorded for a mean of
      58.1 months before and 11.2 months after the intervention. A cost analysis was
      done. RESULTS: All measured parameters showed favorable changes after
      intervention, with the decrease in the number of prescriptions of monthly inhaled
      anti-inflammatory drugs and chest radiographs ordered being statistically
      significant (P = 0.007 and P = 0.040, respectively). Monthly admissions,
      Emergency Department visits, and clinic visits declined after intervention when
      evaluated after 22.8 months of follow up. Annual resource savings after
      intervention was estimated to be $4845.29 per patient for this military hospital.
      CONCLUSIONS: A combined intervention consisting of provider and patient education
      and assignment to a primary care provider was associated with improved care and
      economic outcomes in this group.

PMID- 10338739
TI  - How should managed care treat onychomycosis?
AB  - This activity is designed for leaders and managers of managed care organizations
      and for primary care physicians and specialists involved in evaluating, treating,
      and caring for patients with onychomycosis. GOAL: To help health professionals
      care for patients with onychomycosis through a discussion of new treatment
      choices that exist due to recently approved oral antifungal agents for this
      chronic medical condition. OBJECTIVES: 1. Review the anatomy of the nail unit in
      relation to the pathogenesis, epidemiology, and clinical features of
      onychomycosis. 2. Stress the importance of confirming the diagnosis of
      onychomycosis using relatively simple and cost-effective laboratory procedures,
      since there are many other nonfungal conditions that can pathologically involve
      the nail unit. 3. Detail the ways in which onychomycosis can adversely affect a
      patient's quality of life. 4. Analyze the change in treatment patterns brought
      about by newer potentially curative oral antifungal therapy. 5. Identify
      potential problems with onychomycosis oral antifungal therapy, including dosing
      issues, possible adverse events, and drug-drug interactions.

PMID- 10338740
TI  - Development and evaluation of a pharmacist-directed pharmacotherapy center.
AB  - This article is designed for ambulatory pharmacy specialists, pharmacy
      administrators, and managed care pharmacy and/or medical directors interested in
      developing systems for improved drug therapy outcomes. GOAL: To describe an
      alternative method for the effective delivery of pharmaceutical care. OBJECTIVES:
      1. Identify the barriers to delivery of pharmaceutical care in current systems.
      2. Describe the steps to take to implement a referral-based pharmaceutical care
      service. 3. Describe the financial and patient satisfaction outcomes of a
      referral-based pharmacy. 4. Describe the services that can be offered by a
      referral-based pharmacy.

PMID- 10338742
TI  - Stats & facts. Competitive pressures on group purchasing organizations.

PMID- 10338741
TI  - Information technology, best practices, and care management: Part II.
AB  - As we approach the 21st Century, the health care industry will face an increasing
      number of challenges in dealing with managed care, one of which is information
      technology, or the lack thereof. In the conclusion of a two-part article, the
      author explains that these developing technologies will speed the next revolution
      in health care, a revolution that will increasingly recognize how vital care
      management will be to the future of health care delivery.

PMID- 10338743
TI  - Will the year 2000 shut down the Internet?

PMID- 10338744
TI  - Pediatric otitis media.
AB  - The pediatric patients with routine, easiest-to-treat otitis media utilize 2.1
      office visits during the course of a PTE. This patient group also received 0.13
      tests, 0.14 laboratory and pathology services, and 0.05 medical/surgical
      procedures during the course of a PTE. Though 29.2% of these patients did not
      produce a claim for prescription drug therapy, this patient group received at
      least 1.53 prescriptions per PTEs. One prescription drug group was used in 39.8%
      of all PTEs. Of the PTEs treated with a single drug group, at least 56.4% were
      treated with amoxicillin. Two prescription drug groups were used in 18.1% of the
      PTEs. The prescribing patterns of physicians using two drug groups demonstrate a
      wide variety of switching patterns, some of which may have cost-of-care
      implications. Though surgical procedures are seldom utilized in SOI-1,
      approximately one-half of SOI-2 PTEs undergo some type of surgical procedure. The
      most common surgical procedure was myringotomy with the PE-TM tubes, which
      represents 82% of procedures performed on SOI-2 patients. The major cost drivers
      in the treatment of otitis media are clinical visits and antimicrobial drugs.

PMID- 10338745
TI  - ORYX enters the accreditation race.

PMID- 10338746
TI  - Strengthening evaluations of disease state management programs.

PMID- 10338747
TI  - Health plan satisfaction directly related to health plan choices.

PMID- 10338748
TI  - The effectiveness of one-on-one nurse education on the outcomes of high-risk
      adult and pediatric patients with asthma.
AB  - The effects of an asthma self-management program on asthma outcomes were
      evaluated in adult and pediatric patients with asthma who were considered at high
      risk (i.e., those who were not in control of their disease as determined by
      resource utilization, medication use, or lack of use). The program consisted of
      one-on-one nurse-to-patient ("nurse champion") education and subsequent
      assessment of asthma outcomes using the Asthma Quality Assessment System (AQAS)
      questionnaire, which measured asthma severity, patient quality of life, asthma
      awareness and knowledge, confidence in managing asthma, use of peak flow meters,
      asthma symptoms, medication use, lost work or school days, and affect of asthma.
      Over the course of six months, nurse champions educated 201 patients from four
      managed care plans and collected data at baseline and during four follow-up
      sessions. Adult patients and pediatric patient caregivers reported significant
      improvements in quality of life, and clinical and process measures. Significant
      increases in asthma knowledge were observed immediately after patient education,
      including greater than 89% increase in the proportion of patients who reported
      that they know "a lot" about the "things that cause asthma symptoms." Significant
      decreases were also found in work or school days missed, urgent care utilization,
      and hospital admission rates. Appropriate preventive care visits increased by
      more than 40%. These results indicate that the nurse champion program was
      associated with an improvement in asthma outcomes in high-risk adult and
      pediatric patients and warrant further evaluation in controlled studies.
      Incorporating one-on-one education programs into asthma management is an
      effective and rapid means of improving asthma outcomes.

PMID- 10338749
TI  - Fraud and abuse, or honest mistakes?

PMID- 10338751
TI  - Use caution before taking on claims processing.

PMID- 10338750
TI  - Avoiding pharmacy fraud through automation and audit.
AB  - Pharmacy data offer some of the most reliable and evaluative information in
      managed care today. As fraud constitutes up to 10% of our total health care
      expenditures, the author explains how monitoring the pharmacy network for fraud
      and abuse is an easy way of reclaiming some of these losses.

PMID- 10338752
TI  - Home visits by physicians improve care, reduce utilization, cut costs under
      Medicare risk.
AB  - Bringing back the doctor house call: Only 1% to 3% of your seniors are probably
      homebound frail elderly, but they're responsible for exorbitantly high costs.
      Unable to make office visits, they're at high risk for ER visits and
      hospitalization. The answer to improving their care and reigning in their costs
      are regular doctor house calls, say two physicians who practice in-home primary
      care. Here's why, plus details on their innovative program.

PMID- 10338753
TI  - Plan your organization's Medicare risk strategy using enrollment, disenrollment
      data.
AB  - Data File: We've expanded this month's column to feature the details of two
      studies on Medicare enrollment and disenrollment trends--important information
      that can help you fine-tune your Medicare risk strategy. You'll find the top
      counties poised for growth, a report card on how HMOs are retaining or losing
      their members, and tips for spotting plans that could spell trouble because of
      volatile membership.

PMID- 10338754
TI  - Providers find new opportunities as more states require school-based Medicaid
      services.
AB  - Finding a niche under managed Medicaid: Health Start Inc., a traditional Medicaid
      provider in St. Paul, MN, has carved out its own special niche under managed
      Medicaid. See how this provider, which operates primary care clinics in local
      high schools, has held onto its share of Medicaid business and attracted MCOs.

PMID- 10338755
TI  - HIV treatment strategies must shift to DM focus.

PMID- 10338756
TI  - Community health initiative uses casefinding, intervention to boost prevention
      and revenues.
AB  - As part of a casefinding effort, one hospital-based DM initiative found medical
      records to be chock full of clues and warning signs of impending major health
      care problems. Using its newfound data source, the hospital developed a diabetes
      DM plan that has mushroomed into a full-scale disease prevention strategy.

PMID- 10338757
TI  - Aggressive programs improve immunization rates for children of low-income women.
AB  - Two unique programs are boosting immunization rates, improving prenatal care, and
      increasing the rate of well-baby exams for the children of low-income, unmarried
      women. Here's what's working in this hard-to-reach population.

PMID- 10338758
TI  - HRT (hormone replacement therapy): more than just a quick fix for hot flashes.
AB  - Should hormone replacement therapy be part of the mix when it comes to treating
      and managing cardiovascular disease, high cholesterol, osteoporosis, and cancers?
      Get some answers, and some recommendations for boosting awareness of HRT's
      benefits among patients, physicians, and pharmacists.

PMID- 10338759
TI  - Providers reap DM benefits with in-house programs.

PMID- 10338760
TI  - URAC's phone triage standards: a new 'seal of approval' for DM programs?
AB  - All telephone triage and health information programs are not alike, and the best
      ones may soon appear on the public's radar screen. Recently five of these
      programs were named the first to receive an official "seal of approval" in the
      form of a full two-year accreditation from URAC. Should you submit your own
      program to this new accreditation process?

PMID- 10338761
TI  - Get the most from your disease management vendor.
AB  - Disease management vendors are clamoring to obtain contracts with health plans
      and providers, often in the form of shared risk contracts. Find out what to ask
      for in a contract, what to expect and insist on from the vendor, how to build in
      effective checks and balances.

PMID- 10338762
TI  - Lab, pharmacy data spur docs to better compliance with diabetes DM efforts.

PMID- 10338763
TI  - Specialty providers contract for global transplant rates.

PMID- 10338764
TI  - Health status adjustments coming--are you prepared?

PMID- 10338765
TI  - Can your information system deliver the data you need to adjust population risk?
AB  - To adopt complex risk-adjustment methods, providers will need information systems
      that can sort diagnosis-based data so they can construct workable cap rates and
      develop medical management approaches. Here's what the experts recommend.

PMID- 10338766
TI  - Methodology puts science behind capping chiropractic care.
AB  - An Atlanta-based firm is capitalizing on the movement to capitate chiropractic
      care as an alternative to costly specialty services. Other specialty practices
      can learn from their strategy--and get motivated by their results.

PMID- 10338767
TI  - Small hospitals band together to 'practice' capitation in simulated environment.
AB  - A Kansas City, MO-based organization is using a computer simulation to teach
      member hospitals how to apply managed care principles and strategic planning to
      mixed incentive and capitated reimbursement scenarios.

PMID- 10338768
TI  - Telemetry unit moves from worst to best using redesign process.

PMID- 10338769
TI  - Reduce wait time by tracking patient queues.

PMID- 10338770
TI  - Go the extra mile with subacute care pathways.

PMID- 10338771
TI  - Mentoring nursing staff creates future leaders.

PMID- 10338772
TI  - Common problems plague IHI (Institute for Healthcare Improvement) participants.

PMID- 10338773
TI  - MCO-PBM (managed care organization-prescription benefit management) partnerships
      holding down drug trend.

PMID- 10338774
TI  - Outcomes analysis, clinical pathways improve care, cut costs.

PMID- 10338775
TI  - Achieving goals with physician executives requires delicate touch.

PMID- 10338776
TI  - Internet offers direct access, new ways of providing information to customers.

PMID- 10338777
TI  - Premium increases anticipated after years of slow growth in health expenditures.

PMID- 10338778
TI  - Children's insurance attractive market for health plans, hospitals.

PMID- 10338780
TI  - This is it! Planning the architecture for next-generation patient care.

PMID- 10338779
TI  - Delivering healthcare measurements: a turnkey approach to integrating information
      in healthcare.

PMID- 10338781
TI  - Asynchronous transfer mode (ATM): the technical infrastructure for an integrated
      delivery network.

PMID- 10338782
TI  - Charting the information technology direction for an integrated delivery system.
AB  - Automating the healthcare integrated delivery system requires a special set of
      skills, talent, and communication that goes beyond the capability of the i.t.
      manager alone. Bringing together all elements of the integrated delivery system
      and forming a well-integrated information environment will require a level of
      teamwork rarely seen in any industry. Today's IT manager is like an orchestra
      conductor. He or she should look ahead in the musical composition, manage the
      tempo, and bring all the sounds of the eclectic set of instruments together in
      harmony and achievement of the melody. Following the key success factor outlined
      here may not guarantee success in automating the integrated delivery system, but
      following them should keep the process harmonious.

PMID- 10338783
TI  - A crash course in systems analysis.

PMID- 10338784
TI  - Ending the technology paradox: healthcare management technologies for clinical
      decision making.
AB  - As this article has shown, advances are beginning to put an end to the technology
      paradox that has hindered the industry's efforts to manage care better. Whereas
      in the past the management side of the healthcare industry has been slow to adopt
      new technologies, recent years have seen an explosion in the development and use
      of new tools for managing care. Most of these tools have traditionally focused on
      managing the administrative and financial aspects of providing care; however,
      that has also begun to change. Software systems incorporating clinical decision
      support criteria permit healthcare professionals to make clinical decision-making
      part of the care management process conveniently and efficiently. Clinical
      decision support criteria are also helping to change the focus of managed care.
      At the beginning of the managed care era, insurers and managed care companies
      concentrated primarily on reigning in costs, in many cases by restricting the
      types and duration of care provided to their members. Although these restrictions
      succeeded in conserving resources, they also helped foster an uneasy atmosphere
      between payers and providers, many of whom felt that their clinical judgment was
      too often overruled by the "bean counters." At the same time, many healthcare
      consumers grew to distrust both managed care professionals and providers, feeling
      that medical decisions were often made for the wrong reasons. However, as managed
      care companies have acknowledged that the most efficient way to provide care is
      to provide appropriate care, the focus has begun to move toward the clinical side
      of healthcare. Although healthcare organizations are still relying on financial
      management tools, they are also looking for systems that can make the clinical
      decision-making process more efficient and effective. The end result is that the
      healthcare industry is able to assure the best, most appropriate treatment while
      conserving resources. With the constant stream of new technologies into the
      healthcare management arena, healthcare professionals will have access to new
      tools to make the management process even more efficient. The healthcare
      industry's technology paradox will soon be a thing of the past.

PMID- 10338785
TI  - Evolution of technology in the managed care environment.

PMID- 10338786
TI  - Issues in identification and linkage of patient records across an integrated
      delivery system.
AB  - Historically, the health information systems community has viewed linking
      personal records as a mundane task. The oversimplified view that routine database
      manipulation can accurately identify multiple records for a single individual is
      erroneous, an assumption based on a misperception of the quality of the
      underlying data. Such data have been adversely affected by the evolution of
      individual facility patient indexes from multiple systems and the results of
      backload procedures, and the lack of focus on the need for data integrity by
      users of the automated systems. Much of the random, invalid data we identify on a
      daily basis is directly associated with the need for system users to place data
      in the patient record while they face the situation of having no obvious data
      field in which to place them. Combined with an underlying lack of standards for
      the collection of personal identification information, this results in pure chaos
      when reviewing an MPI file containing a million records at the start of a linkage
      evaluation project. We have documented the considerable effort that must
      therefore be made in standardizing the MPI files using stringent analytical
      procedures and applying common edit routines before commencing record linkage.
      This preprocessing effort must then be supplemented with sophisticated matching
      procedures that can handle the dual challenge of minimizing false negatives (the
      failure to identify true linkages) and false positives (the incorrect linking of
      records that do not represent the same person). The identification of pairs of
      linked records does not, however, complete an EPI loading. Because it is fairly
      common for a multiple facility linkage evaluation to identify more than two
      medical record numbers for the same patient, and the primary goal of an EPI is to
      assign a unique identifier for the patient which will link that patient's
      multiple files, it becomes necessary to develop a means of readily associating
      three or more records for the same patient. One approach we have used with great
      success is to assign a common, sequential identification number to all linked
      medical record numbers for the same patient regardless of facility. The
      assignment of linkage identification numbers is computer-intensive and is
      generally accomplished with a highly iterative process. Both system memory and
      hard disk resources are fully tested as the number of good linkages in an overlap
      evaluation reaches the half-million mark or greater. Because the primary linkage
      analysis goal is to develop linkages on pairs of records, with confidence levels
      based on the comparison of information for those two records, thresholds must be
      set to decide which linkages should be accepted as true without any human
      evaluation. If the threshold is set too low, the defined linkage groups may
      incorrectly join the medical record numbers for different persons. But if the
      threshold is set too high, there will be undesired duplication of persons in the
      enterprise system. As in the identification of the underlying linkage pairs, the
      development of a confidence measure greatly facilitates the assignment of the
      unique identification numbers needed in the EPI implementation.

PMID- 10338787
TI  - Catching chameleons: managing patient identification in evolving healthcare
      systems.

PMID- 10338788
TI  - Leveraging an enterprise-wide scheduling system: a case study.

PMID- 10338789
TI  - Which systems are really strategic?

PMID- 10338790
TI  - Linking and integrating enterprise-wide health information management data.

PMID- 10338791
TI  - Streamlining medical group operations through an integrated computer-based
      patient record.

PMID- 10338792
TI  - Reserve cost reports.

PMID- 10338793
TI  - At a glance. U.S. per capita cost (USPCC) for Medicare aged population.

PMID- 10338794
TI  - Has the Medicare cash cow died?

PMID- 10338795
TI  - Payment reform will shift home health agency valuation parameters.
AB  - Changes authorized by the Balanced Budget Act of 1997 have removed many of the
      payment benefits that motivated past home health agency acquisition activity and
      temporarily have slowed the rapid pace of acquisitions of home health agencies.
      The act required that Medicare's cost-based payment system be replaced with a
      prospective payment system (PPS) and established an interim payment system to
      provide a framework for home health agencies to make the transition to the PPS.
      As a consequence, realistic valuations of home health agencies will be determined
      primarily by cash flows, with consideration given to operational factors, such as
      quality of patient care, service territory, and information systems capabilities.
      The limitations imposed by the change in payment mechanism will cause acquisition
      interest to shift away from home health agencies with higher utilization and
      revenue expansion to agencies able to control costs and achieve operating
      leverage.

PMID- 10338796
TI  - Expanding weekend and holiday clinical services: a financial perspective.
AB  - Many payers view weekend and holiday inpatient stays at hospitals that provide
      interventional and therapeutic services only on weekdays as unnecessary, and are
      denying payment for these days. Hospitals not only must absorb the incremental
      costs associated with maintaining patients during these days, but also may lose
      payment for days to which they legitimately are entitled. To reduce both costs
      and denied payments, hospitals should develop a means to identify unnecessary
      days; provide immediate feedback to physicians in a manner that helps reduce
      problematic days; and place a priority, when appropriate, on moving patients to
      lower-level care settings, such as skilled nursing, home health, and custodial
      care facilities.

PMID- 10338797
TI  - Strategic cost accounting helps create a competitive edge.
AB  - The way healthcare cost allocation is conducted has changed radically over the
      past three decades. Although government regulations have required the step-down
      allocation method be used for determining Medicare payments, this method is
      limited in its ability to generate relevant cost data needed for management
      decision making and effective managed care contract rate negotiation. Deriving
      such data depends on using appropriate cost drivers and allocation methods. Of
      the four method, that may be used to allocate the costs of health are
      organization service departments to revenue departments--the direct method, the
      step-down method, the double-apportionment method, and the reciprocal method--the
      reciprocal method is the most sophisticated and may provide the most accurate
      representation of costs.

PMID- 10338798
TI  - The insurance refund request: a legal analysis.
AB  - When an insurance payment is made erroneously to a healthcare provider and no
      contract between the insurer and provider addresses the issue of refunding such
      payments, the law relating to restitution generally applies. Restitution does not
      apply, however, to three exceptions that the courts have used to refuse claims by
      insurers for refunds of overpayments: the innocent third-party creditor
      exception, whereby the healthcare provider cannot be unjustly enriched by the
      overpayment, cannot have induced the mistaken payment, and cannot have known
      beforehand that the insurer was not obligated to pay; the material change in
      position exception, whereby the healthcare provider in good faith accepts an
      overpayment and so does not pursue other means of payment; and the assumption of
      the risk exception, which occurs when the insurer pays a claim without having
      complete information about it.

PMID- 10338799
TI  - New exclusions and penalties complicate compliance programs.
AB  - A new final rule and a proposed rule published September 2, 1998, by the HHS
      Office of Inspector General (OIG) outline regulations that implement enforcement
      provisions of the Health Insurance Portability and Accountability Act of 1996 and
      the Balanced Budget Act of 1997, respectively. The rules give the OIG
      discretionary authority to exclude organizations from participation in state or
      Federal healthcare programs or exact civil monetary penalties for certain types
      of infractions. Healthcare organizations, therefore, need to understand these
      rules and incorporate corresponding changes and processes into their compliance
      programs to avoid violations that could lead to penalties or exclusions.

PMID- 10338800
TI  - New contractual affiliations can salvage unsuccessful practice acquisitions.
AB  - Many healthcare organizations become disillusioned with their acquired medical
      practices within a few years of purchase because of major financial, operational,
      and political problems with their new networks. As postacquisition financial
      losses increase and relationships with physicians under contract decline, many
      healthcare organizations seek an escape from the situation. Three options for
      dealing with a failing acquisitions program are to do nothing until the
      physicians' employment contract expires, give the practice back to the
      physicians, or negotiate a contractual settlement in which the practice is
      returned to the physicians in exchange for a new contractual commitment to the
      healthcare organization. The third option offers the greatest potential for
      salvaging the arrangement and preserving the physician-organization relationship.

PMID- 10338801
TI  - A second court invalidates HCFA outlier thresholds. Alvarado Community Hospital
      v. Shalala.

PMID- 10338802
TI  - Optimizing the EDI claims submission process.

PMID- 10338803
TI  - Finance professionals benefit from mentoring.

PMID- 10338804
TI  - Data trends. Key organizational performance indicators.

PMID- 10338805
TI  - HIV healthcare delivery and managed care: applications and implications from the
      Special Projects of National Significance Program.

PMID- 10338806
TI  - A national program of innovative AIDS care projects and their evaluation.
AB  - As the number of people seeking HIV care in the U.S. has grown, the demand has
      increased not only for medical care, but also for a wide range of supportive
      services. This in turn has increased the need for demonstrated and tested HIV
      care service models that can address a comprehensive set of needs. The Special
      Projects of National Significance (SPNS) Program's HIV Innovative Models of Care
      Initiative funded by the Health Resources and Services Administration (HRSA)
      began on October 1, 1994. This initiative is an effort by 27 HRSA-funded projects
      to jointly establish goals and objectives, develop common evaluation methods, and
      produce comparable and measurable outcomes for innovative models of HIV care. The
      five projects of the SPNS Program Capitated Care Work Group share, as a central
      theme, the study of the health care provided to individuals with HIV disease
      under models where the health care is capitated, or paid on a "flat fee" basis
      per patient per month. These projects differ in the ways that they provide health
      care, ranging from community- and university-based clinics to a home-based
      hospice to a statewide health care system. Each of the projects shares the goals
      of determining costs for providing health care services to AIDS patients under a
      capitated care system and of ensuring that high quality care is provided under
      such a system.

PMID- 10338807
TI  - The transprofessional model: blending intents in terminal care of AIDS.
AB  - Current terminal care services present dying patients and their families with a
      dichotomy in service delivery and the intent care between curative treatments and
      palliative treatments. This arbitrary dichotomy reduces patients' quality of life
      in many cases and robs patients and families of benefiting from the psychosocial
      aspects of treatment until the last few weeks of life. This article presents a
      blended model of care, the Transprofessional Model, in which patients receive
      both curative and palliative service throughout their care process. The blended
      intent model differs from traditional home care in that services are provided by
      a care coordination team composed of nurses and social workers; the traditional
      model of care is often case managed by a single, registered nurse. The
      combination of the multi-disciplinary approach to care coordination and training
      in both curative and palliative services in the Transprofessional Model
      demonstrates that this blended model of care produces a bio-psychosocial focus to
      terminal care as compared to a primary focus on curative services present in the
      traditional model of home care.

PMID- 10338809
TI  - A typology of service patterns in end-stage AIDS care: relationships to the
      transprofessional model.
AB  - OBJECTIVE: To determine the relationship among 11 types of home health care
      services for patients with HIV/AIDS and to develop a terminal-care, service-usage
      profile of persons receiving such services. Services include the number of
      psychiatric nurse visits, Medical Social Work (MSW) visits, evaluation visits,
      physical therapy visits, occupational therapy visits, homemaker visits, home
      health aide visits, public health nurse visits, registered nurse (RN) visits,
      Licensed Vocational Nurse (LVN) visits, and Intravenous (i.v.) nurse visits. DATA
      SOURCES AND STUDY SETTING: Data were collected on 549 AIDS patients admitted for
      medical/surgical home-care services to the Visiting Nurse Association of Los
      Angeles (VNA-LA). The service utilization data were collected from the VNA-LA's
      computerized data system. STUDY DESIGN: The relationship among the service types
      was evaluated with principal component analysis. A service-usage profile was
      developed for patients using cluster analysis. To control for the variability in
      the amount of time that patients were on service, the number of days that
      patients were in the VNA-LA program and were actually receiving services was
      included as a factor that yielded a variable reflecting the number of each type
      of service that a patient received per day. PRINCIPAL FINDINGS: Five components
      were found to best describe the relationships among the service-type variables.
      These were identified as being: the Number of Evaluation Visits, the Number of
      Intensive Nursing Visits, the Number of Physical Therapy Visits, the Number of
      Psychosocial Visits, and the Number of Attendant Visits. Patients were found to
      cluster into 1 of 5 groups based on the type of service utilization profile that
      they received. The variables that appeared to have the most influence on this
      profile were the number of home health aide visits per day that the patient
      received, the number of RN visits that were made, the number of i.v. nurse visits
      that were provided, and the number of LVN visits that were made. CONCLUSIONS:
      Terminally ill AIDS patients receiving home health care services can be
      identified as having a service utilization profile. This profile can be used to
      evaluate more precisely the service areas in which costs for patient services
      differ. Individually assigned to an experimental Transprofessional Model of care
      had a different service utilization profile than those assigned to a Traditional
      Model of care.

PMID- 10338808
TI  - Evaluation of the transprofessional model of home health care for HIV/AIDS.
AB  - OBJECTIVE: To determine if a Transprofessional care-management approach
      (experimental group) produces savings in service delivery dollars when compared
      to a Traditional treatment approach (control group). The care-management approach
      utilizes an interdisciplinary mix of allied health professionals who adhere to a
      service delivery protocol based on active, medical, surgical treatment (curative
      services) as well as on pain, symptoms, and emotional care (palliative services).
      DATA SOURCES AND STUDY SETTING: Data were collected from 549 AIDS patients
      admitted for medical/surgical home-care services to the Visiting Nurse
      Association of Los Angeles (VNA-LA). Demographic and disease-specific data were
      collected from admitting records; service-utilization data were collected from
      the VNA-LA's computerized data system. STUDY DESIGN: Upon admission for home-care
      services, patients were randomly assigned to an experimental (Transprofessional)
      or control (Traditional) treatment group. Service levels were comparable.
      PRINCIPLE FINDINGS: Post-test measures indicate an 8 percent reduction in labor
      delivery costs for an average experimental patient's entire episode of home-care
      versus for an average control patient's. CONCLUSIONS: An integrated model of
      service delivery, which is based on interdiscriplinary, care-management and
      blended modalities of service, provides a cost-effective method in the provision
      of home-care services for terminally ill AIDS patients.

PMID- 10338811
TI  - Suture prices unlikely to drop further.

PMID- 10338810
TI  - Qualitative issues related to the transprofessional model of end-stage AIDS care.

PMID- 10338812
TI  - Hospitals taking another look at Owens & Minor.

PMID- 10338813
TI  - Integration: it's a long road, but worth the savings.

PMID- 10338814
TI  - Here's a laundry list of savings ideas.

PMID- 10338815
TI  - AmeriNet posts inflationary indices.

PMID- 10338816
TI  - An economic theory of cigarette addiction.
AB  - In this paper we present a model in which individuals act in their own best
      interest, to explain many behaviors associated with cigarette addiction. There
      are two key features of the model. First, there is an explicit representation of
      the withdrawal effects experienced when smokers attempt to quit smoking. Second,
      there is explicit recognition that the negative effects of smoking generally
      appear late in an individual's life. Among the things we use the model to explain
      are: (1) how individuals can become trapped in their decision to smoke; (2) the
      conditions under which cold-turkey quitting and gradual quitting may occur; and
      (3) a reason for the existence of quit-smoking treatments.

PMID- 10338817
TI  - A note on validating Wagstaff and van Doorslaer's health measure in the analysis
      of inequalities in health.
AB  - The aim of this note is to validate Wagstaff and van Doorslaer's approach of
      constructing a continuous health measure to be used in the analysis of
      inequalities in health. We calculate health concentration indices for Uppsala
      County in Sweden based on three different health status measures: health measured
      according to the WvD approach based on a self-assessed categorical health
      measure, health measured by the rating scale method, and health measured by the
      time trade-off method. The concentration index does not differ significantly for
      the three health status measures, and our results thus support the validity of
      the WvD method.

PMID- 10338818
TI  - Adjustment costs, withdrawal effects, and cigarette addiction.

PMID- 10338819
TI  - Impact of augmented prenatal care on birth outcomes of Medicaid recipients in New
      York City.
AB  - I examine whether New York State's Prenatal Care Assistance Program (PCAP) is
      associated with greater use of prenatal services and improved birth outcomes.
      PCAP is New York State's augmented prenatal care initiative that became a part of
      the Medicaid program after expansion in income eligibility thresholds in January,
      1990. Data are from the linkage of Medicaid administrative files with New York
      City birth certificates (N = 23,249). For women on cash assistance, I find PCAP
      is associated with a 20% increase in the likelihood of enrollment in WIC, an
      increase in mean birth weight of 35 g and a 1.3 percentage point drop in the rate
      of low birth weight. Associations between PCAP and improved birth outcomes for
      women on medical assistance are similar, but appear contaminated by selection
      bias. Reductions in newborn costs associated with PCAP participation are modest,
      between US$100-300 per recipient, and are insufficient to offset program
      expenditures.

PMID- 10338820
TI  - The changing effects of competition on non-profit and for-profit hospital pricing
      behavior.
AB  - Has the nature of hospital competition changed from a medical arms race in which
      hospitals compete for patients by offering their doctors high quality services to
      a price war for the patients of payors? This paper uses time-series cross
      sectional methods on California hospital discharge data from 1986-1994 to show
      the association of hospital prices with measures of market concentration changed
      steadily over this period, with prices now higher in less competitive areas, even
      for non-profit hospitals. Regression results are used to simulate the price
      impact of hypothetical hospital mergers.

PMID- 10338821
TI  - Competition and pricing by nonprofit hospitals: a reassessment of Lynk's
      analysis.

PMID- 10338823
TI  - Cutting costs--but not patient satisfaction. Top-performing groups reveal their
      secrets.

PMID- 10338822
TI  - Price and profit.

PMID- 10338824
TI  - Flying solo--and still flying high.

PMID- 10338826
TI  - Would solo practice be right for you?

PMID- 10338825
TI  - Solo practice for sale (someday): any takers?

PMID- 10338827
TI  - We did "too much" for this patient. Good for us!

PMID- 10338828
TI  - Turn uneven income into a smooth cash flow.

PMID- 10338829
TI  - Can it be--Pete Stark, the doctor's pal?. Interview by Michael Pretzer.

PMID- 10338830
TI  - Will the year 2000 bring your practice to a standstill?

PMID- 10338831
TI  - Megabuck malpractice awards: how much do doctors really pay?

PMID- 10338832
TI  - Should you charge for telephone advice?

PMID- 10338833
TI  - Don't like your health-plan profile? Challenge it!

PMID- 10338834
TI  - Billing compliance strategies for physician office laboratories.

PMID- 10338835
TI  - A primer on placental blood banking.

PMID- 10338836
TI  - Multidepartmental management. The challenge of the new millennium.

PMID- 10338837
TI  - How collaboration = quality in maintaining POCT (point-of-care testing) and
      phlebotomy programs.

PMID- 10338838
TI  - Bankruptcy bill would protect patients.

PMID- 10338839
TI  - A market of contrasts. While stocks dry up, new financing options emerge for
      assisted living companies.

PMID- 10338840
TI  - Financial services suppliers.

PMID- 10338841
TI  - Tracking employee turnover.

PMID- 10338842
TI  - Altruism or overtime?

PMID- 10338843
TI  - Calculating your PPS per diem rate.

PMID- 10338844
TI  - Managing wound care under PPS.

PMID- 10338845
TI  - Nurses view end-of-life care.

PMID- 10338846
TI  - Employee recruitment and retention.

PMID- 10338847
TI  - Fear of a white hat.

PMID- 10338848
TI  - Initiation by fire ... a little planning and research would have made all the
      difference.

PMID- 10338849
TI  - On mentoring.

PMID- 10338850
TI  - Competency for administrators.

PMID- 10338851
TI  - Time for reckoning ... Wall Street wasn't interested in healthcare because it had
      not yet become big business.

PMID- 10338852
TI  - Real-world scenarios help improve selection of radiology employees.
AB  - Choosing the right candidate through the interview process is critical,
      particularly in light of rapidly changing skills in various technologies. The
      authors have changed the interviewing process at Jeanes Hospital in Philadelphia
      in order to examine and evaluate multiple objectives simultaneously. To do this,
      they created an instrument that elicits impromptu responses to real-world
      radiology situations. Such responses help assess a potential candidate's
      training, emotional strength, technical experience and growth potential. They
      also determine how much additional training the potential candidate will need to
      be effective in the department. Using the instrument helps sharpen the assessment
      of candidate traits such as face-to-face communication skills and response time.
      The impact on hiring is positive. Quality staff, improved patient care and
      improved patient safety are only some of the results. Many of the questions
      included on the instrument come from past problem situations and help the
      interviewers to determine whether a candidate understands underlying issues and
      the seriousness of situations. The goal is to ensure that patient care and
      productivity are not hampered by unusual situations. When a concrete difference
      is detected between a candidate's response and the department's needs, it is
      possible to assess the cost-effectiveness of training for the discrepancy. For
      entry-level candidates, the question is whether the person is trainable.
      Consistently using this interview document forces hiring managers to identify
      specific abilities, traits and experience desirable in the workplace.

PMID- 10338853
TI  - Absenteeism: causes and cures.
AB  - Absenteeism can be categorized as either uncontrollable or controllable.
      Uncontrollable absences include family illness, accidents, jury duty and
      unexpected emergencies. A typical controllable absence may be dissatisfaction
      with the job. No matter which type, absenteeism is disruptive to the
      organization, reduces the quality of patient care and raises operating costs. The
      Bureau of Labor Statistics has established a standard for comparing the rate of
      absenteesim with other departments or organizations. The rate is equal to the
      number of days absent times 100, divided by the number of days worked. Four
      percent or more is considered excessive. Absence policies are often not used for
      the purposes they were intended. Managers may want to take a critical look at
      their policies, rather than accept abuse as routine or over-hiring staff to make
      up for absent staff. If, in fact, it's time to change your policy, you'll want to
      run possible changes by a legal advisor. You may also want to take a look at your
      corporate culture. Is it encouraging absenteeism? One company that paid employees
      who didn't use their sick time had to eliminate this benefit for budgetary
      reason. Its average sick time then increased 60%. You may want to use your
      culture to spread corporate norms. Employees are expected to be at work: those
      who are there on the job are more likely to receive promotions, for example. Paid
      leave banks have been introduced by many companies to allow broader time-off
      flexibility for employees. Such a bank includes holidays, sick and vacation time,
      grouped together for use by the employee. A final word: employees will rise or
      sink to the level of your expectations.

PMID- 10338854
TI  - The ABCs of labor management.
AB  - Today, many healthcare facilities co-exist with unions, a fact that makes
      collective bargaining agreements (CBAs) important. Considered by many employees
      to be their bible, a CBA is a contract written for a certain period of time and
      negotiated with the employer by union representatives and designated company
      employees. CBAs follow existing laws. Guidelines called "due process" must be
      followed in employee discipline situations. Overlooking even one of these
      guidelines can provide a loophole if a legal dispute should arise. An
      organizational chart is a representation of a department's chain of command. It
      presents a clear picture of how the department is run and is useful for employees
      who wish to make use of an open-door policy. An informal hearing is a meeting
      between an employee and the employer to make the employee aware of an existing
      problem. No disciplinary action is taken, but may be at a later date, if the
      problem continues. In a formal grievance discussion, the employee is made aware
      of an existing problem and discussion centers around resolving the issue. Under
      the Weingarten decision, an employee can refuse submit to an investigatory
      interview without union representation, if the employee reasonably believes
      disciplinary action will be taken. "Just cause," considered the basis for
      disciplinary actions, must contain basic elements and the necessary documentation
      to be valid. Without just cause, an attorney for the employee may find a
      technicality or loophhole in any ensuing hearing, civil action or arbitration.
      Managers must know a great deal about labor-related law. Sooner or later, many
      will face an employee situation where knowledge of the due process guidelines
      will be useful.

PMID- 10338855
TI  - Customer service: developing a new mindset for today's instant gratification
      society.
AB  - Today's society expects and demands immediate service, results and access to
      information. Can those of us in leadership positions say that the service we
      provide is equal to or exceeds what our customers expect? How can we redesign our
      services so they are better than those we currently provide? Some people look to
      advances in technology as one means to improve services and access to
      information, but this should not be the only means. If we are to develop a
      philosophy of exceptional service, we must develop a vision of those services. We
      must gain an understanding of our customers, plus a knowledge of products, the
      availability of resources and any industry constraints. In healthcare, we must
      look to leadership to achieve our goals. A goal of exceptional customer service
      must be communicated to all levels of service providers from management. Top-down
      action by management--leadership by example--is critical. Leadership must gain
      the trust of both customers and employees by actively listening to both verbal
      and nonverbal comments at all points of service. Without an understanding of our
      customers' needs, it won't be possible to deliver services at or above their
      expectations.

PMID- 10338856
TI  - Follow the Yellow Brick Road ... most people have the ability within themselves
      to get the results they want or need.

PMID- 10338857
TI  - At a glance. Medicare allowed charge and frequency data.

PMID- 10338858
TI  - Codified principles enhance physician/patient communications.

PMID- 10338859
TI  - Can using emergent technology incur liability?
AB  - There are numerous areas of potential liability for the practicing surgeon
      attempting to upgrade skills and introduce emergent technology into his or her
      practice. The College understands that graduate medical education in a teaching
      institution, continuing medical education at our College-sponsored venues, and
      all other sponsored or co-sponsored educational activities each carry risks and
      benefits. Current College activities are directed toward enhancing translation of
      emergent surgical technology into clinical practice as effectively, productively,
      safely, and as free of risk as possible.

PMID- 10338860
TI  - The National Patient Safety Foundation: what it offers surgeons.

PMID- 10338861
TI  - In their own words. The College and the AMA--one house, separate rooms.

PMID- 10338862
TI  - NCQA and HEDIS.

PMID- 10338863
TI  - Oh no, here we go again. Health-care costs are soaring--and companies are passing
      the increases along to their workers.

PMID- 10338864
TI  - Self-inflicted cyber wound? If the Y2K bug bites us, we'll deserve it. We could
      have prepared in time--and didn't.

PMID- 10338865
TI  - Eying the fetal future. In the shadows, a controversial search for cures.

PMID- 10338866
TI  - Final farewells.

PMID- 10338867
TI  - Calling the undertaker. Reflections on a deadly business.

PMID- 10338868
TI  - Getting a grip on pain. A new drug may revolutionize arthritis care.

PMID- 10338869
TI  - How to beat job lock. Stuck in a bad job because your insurance won't 'carry
      over' without breaking the bank? There's hope.

PMID- 10338871
TI  - Federal employees health benefits program: disenrollment--OPM. Correction.

PMID- 10338870
TI  - Medical devices; investigational device exemptions--FDA. Final rule.
AB  - The Food and Drug Administration (FDA) is amending the Investigational Device
      Exemptions (IDE) regulation. The regulatory changes are intended to reflect
      amendments to the Federal Food, Drug, and Cosmetic Act (the act) by the FDA
      Modernization Act of 1997 (FDAMA). These amendments provide that the sponsor of
      an IDE may modify the device and/or clinical protocol, without approval of a new
      application or supplemental application, if the modifications meet certain
      criteria and if notice is provided to FDA within 5 days of making the change. The
      rule also defines the credible information to be used by sponsors to determine if
      the criteria are met.

PMID- 10338872
TI  - Import for export; reporting and recordkeeping requirements for unapproved or
      violative products imported for further processing or incorporation and
      subsequent export--FDA. Proposed rule.
AB  - The Food and Drug Administration (FDA) is proposing reporting and recordkeeping
      regulations to implement certain sections of the Federal Food, Drug, and Cosmetic
      Act (the act) as amended by the FDA Export Reform and Enhancement Act of 1996.
      The proposed rule would require an importer to report to FDA each time it imports
      an unapproved or otherwise violative article that is to be exported after further
      processing or incorporation into another product in the United States and to keep
      records to ensure that the article is so processed or incorporated and then
      exported, and that any portion of the import that is not exported is destroyed.

PMID- 10338873
TI  - FDA plan for statutory compliance. Notice of availability.
AB  - The Food and Drug Administration (FDA) is announcing the availability of a
      document entitled "FDA Plan for Statutory Compliance" (the plan). This document
      is the agency's response to section 406(b) of the Food and Drug Administration
      Modernization Act of 1997 (FDAMA), which requires the Secretary of the Department
      of Health and Human Services (the Secretary) to develop a plan bringing the
      agency into compliance with the requirements of the Federal Food, Drug, and
      Cosmetic Act (the act).

PMID- 10338874
TI  - Medical devices; establishment registration and device listing for manufacturers
      and distributors of devices; correction--FDA. Direct final rule; correction.
AB  - The Food and Drug Administration (FDA) is correcting a direct final rule that
      appeared in the Federal Register of September 29, 1998 (63 FR 51825). The
      document amended certain regulations governing establishment registration and
      device listing by domestic distributors. The document was published with an
      error. This document corrects that error.

PMID- 10338875
TI  - Medicare program; prospective payment system and consolidated billing for skilled
      nursing facilities; reopening of comment period--HCFA. Notice of reopening of
      comment period for interim final rule.
AB  - We published an interim final rule with comment period in the Federal Register on
      May 12, 1998 (63 FR 26252). That interim final rule implements provisions in
      section 4432 of the Balanced Budget Act of 1997 related to Medicare payment for
      skilled nursing facility services. Those include the implementation of a Medicare
      prospective payment system for skilled nursing facilities, consolidated billing,
      and a number of related changes. A document published on July 13, 1998 extended
      the comment period for the May 12, 1998 interim final rule until September 11,
      1998. This document reopens and extends the comment period for an additional 30
      days after the date of publication of this notice. The document also clarifies
      the explanation of the Federal rates.

PMID- 10338876
TI  - Medical devices; establishment registration and device listing for manufacturers
      and distributors of devices; correction--FDA. Proposed rule; correction.
AB  - The Food and Drug Administration (FDA) is correcting a proposed rule that
      appeared in the Federal Register of September 29, 1998 (63 FR 51874). The
      document proposed to amend certain regulation governing establishment
      registration and device listing by domestic distributors. The document was
      published with an error. This document corrects that error.

PMID- 10338877
TI  - Prescription drug product labeling; medication guide requirements--FDA. Final
      rule.
AB  - The Food and Drug Administration (FDA) is establishing requirements for the
      distribution of patient labeling for selected prescription human drug and
      biological products used primarily on an outpatient basis. The agency is
      requiring the distribution of patient labeling, called Medication Guides, for
      certain products that pose a serious and significant public health concern
      requiring distribution of FDA-approved patient medication information. The intent
      of this action is to improve public health by providing information necessary for
      patients to use their medications safely and effectively. FDA believes that this
      program will result in direct improvements in the safe and effective use of
      prescription medications.

PMID- 10338878
TI  - Comprehensive quality assurance in medical use and a standard of care--NRC.
      Advance notice of proposed rulemaking: withdrawal.
AB  - The Nuclear Regulatory Commission (NRC) is withdrawing an advance notice of
      proposed rulemaking (ANPRM) that requested public comments on questions related
      to comprehensive quality assurance and a standard of care in medical uses of
      byproduct material. The Commission has decided to withdraw this ANPRM because of
      the effective implementation of the "Quality Management Program and
      Misadministrations" rule and the NRC's current efforts in revising the existing
      regulation for medical uses of byproduct material into a more risk-informed and
      performance-based regulation.

PMID- 10338879
TI  - Medicare program; recognition of the American Association for Accreditation of
      Ambulatory Surgery Facilities, Inc. for ambulatory surgical centers program-HCFA.
      Final notice.
AB  - This notice announces the approval of the American Association for the
      Accreditation of Ambulatory Surgery Facilities, Inc. (AAAASF) as an accreditation
      organization acknowledged by the Medicare program. We have found that AAAASF's
      standards for ambulatory surgical centers (ASCs) meet or exceed those established
      by the Medicare program. ASCs accredited by AAAASF will receive deemed status
      under the Medicare program.

PMID- 10338880
TI  - Regulations requiring manufacturers to assess the safety and effectiveness of new
      drugs and biological products in pediatric patients--FDA. Final rule.
AB  - The Food and Drug Administration (FDA) is issuing new regulations requiring
      pediatric studies of certain new and marketed drug and biological products. Most
      drugs and biologics have not been adequately tested in the pediatric
      subpopulation. As a result, product labeling frequently fails to provide
      directions for safe and effective use in pediatric patients. This rule will
      partially address the lack of pediatric use information by requiring that
      manufacturers of certain products provide sufficient data and information to
      support directions for pediatric use for the claimed indications.

PMID- 10338881
TI  - National emission standards for hazardous air pollutants for ethylene oxide
      commercial sterilization and fumigation operations--EPA. Interim final rule.
AB  - Today's action suspends the National Emission Standards for Hazardous Air
      Pollutants for Ethylene Oxide Commercial Sterilization and Fumigation Operations
      (EO NESHAP) requirements for chamber exhaust and aeration room vents. The
      suspension allows affected sources subject to the EO NESHAP to defer compliance
      with the NESHAP requirements for chamber exhaust and aeration room vents for one
      year until December 6, 1999. This suspension does not affect the requirement for
      sources subject to the EO NESHAP to comply with provisions for sterilizer vents
      by December 6, 1998. This action does not change the level of the standards or
      the intent of the NESHAP promulgated in 1994.

PMID- 10338882
TI  - Medical devices; exemptions from premarket notification; surgical lamps--FDA.
      Notice.
AB  - The Food and Drug Administration (FDA) is publishing an order denying a petition
      requesting an exemption from the premarket notification requirements for surgical
      lamps. FDA is publishing this notice in accordance with procedures established by
      the Food and Drug Administration Modernization Act of 1997 (FDAMA).

PMID- 10338883
TI  - Medical devices; reconditioners, rebuilders of medical devices; revocation of
      compliance policy guide; request for comments--FDA. Notice.
AB  - The Food and Drug Administration (FDA) is revoking Compliance Policy Guide (CPG)
      7124.28 because application of current good manufacturing practice (CGMP)
      requirements to "reconditioners/rebuilders" of used medical devices does not
      comport with definitions in the quality system (QS) regulation or guidance in the
      final rule that applies CGMP requirements to "manufacturers" and
      "remanufacturers." Because "reconditioners/rebuilders" are specifically excluded
      from the definition of "manufacturer" or "remanufacturer" in the QS regulation,
      guidance in the CPG on the applicability of registration, listing, and other
      statutory and regulatory requirements to "reconditioners/rebuilders" does not
      represent current agency thinking. In the advance notice of proposed rulemaking
      (ANPRM), published in the December 23, 1997, Federal Register, FDA announced its
      intention to consider identifying the used device market, for regulatory
      purposes, in terms of "refurbishers," "as-is remarketers," and "servicers" whose
      activities do not significantly change the safety, performance, or use of a
      device, and to examine alternative approaches for regulating these firms. Pending
      the issuance of a rule or guidance setting forth FDA's current position, CPG
      7124.28 is being revoked to eliminate obsolete guidance and reduce industry
      burdens.

PMID- 10338884
TI  - Medicare program; recognition of NAIC model standards for regulation of Medicare
      supplemental insurance--HCFA. Notice.
AB  - This notice describes changes made by the Balanced Budget Act of 1997 to section
      1882 of the Social Security Act, which governs Medicare supplemental insurance.
      It also recognizes that the Model Regulation adopted by the National Association
      of Insurance Commissioners (NAIC) on April 29, 1998, as corrected and clarified
      by HCFA, is considered to be the applicable NAIC Model Regulation for purposes of
      section 1882 of the Social Security Act. The changes made by HCFA (1) correct a
      drafting error in section 12.B(2) of the Model that is inconsistent with Federal
      law, and (2) add a clarification that copayments for hospital outpatient
      department services under Part B of Medicare must be covered under the "core
      benefits" of a Medicare supplemental insurance policy in the same manner as
      coinsurance for those services. Finally, this notice prints as an addendum the
      full text of the NAIC Model Regulation, as corrected and clarified by HCFA.

PMID- 10338885
TI  - Establishment registration and listing for manufacturers of human cellular and
      tissue-based products--FDA. Proposed rule; reopening of comment period.
AB  - The Food and Drug Administration (FDA) is reopening the comment period for the
      proposed rule concerning establishment registration and listing for manufacturers
      of human cellular and tissue-based products that was published in the Federal
      Register of May 14, 1998 (63 FR 26744). FDA is taking this action in response to
      a request for an extension and to allow interested parties additional time for
      review and to submit comments.

PMID- 10338886
TI  - Solicitation of new safe harbors and special fraud alerts--OIG, HHS. Notice of
      intent to develop regulations.
AB  - In accordance with section 205 of the Health Insurance Portability and
      Accountability Act (HIPAA) of 1996, this annual notice solicits proposals and
      recommendations for developing new and modifying existing safe harbor provisions
      under the Federal and State health care programs' antikickback statute, as well
      as developing new OIG Special Fraud Alerts.

PMID- 10338887
TI  - Proposed revisions to certain regulations regarding annual reporting and
      disclosure requirements--Pension and Welfare Benefits Administration, DOL. Notice
      of proposed rulemaking.
AB  - This document contains proposed amendments to Department of Labor (Department)
      regulations relating to the annual reporting and disclosure requirements under
      part 1 of Title I of the Employee Retirement Income Security Act of 1974, as
      amended (ERISA or the Act). In part, the amendments contained in this document
      are necessary to conform the regulations to the previously published revisions to
      the annual return/report forms (Form 5500 Series) filed by administrators of
      employee pension and welfare benefit plans under part 1 of Title I of ERISA. The
      regulatory amendments, in conjunction with the revisions to the Form 5500 Series,
      are intended to reduce the annual reporting burdens on employee benefit plans
      while ensuring that the Department has access to the information it needs to
      carry out its administrative and enforcement responsibilities under ERISA and
      that participants and beneficiaries have access to the information they need to
      protect their rights and benefits under ERISA. Other proposed amendments
      contained in this document would modify the reporting requirements for certain
      group insurance arrangements. The remaining amendments are technical in nature
      and are designed to either simplify or clarify the existing reporting
      regulations. If adopted, the amendments will affect the financial and other
      information required to be reported and disclosed by employee benefit plans
      filing From 5500 Series reports under part 1 of Title I of ERISA.

PMID- 10338888
TI  - Comprehensive quality assurance in medical use and a standard of care; correction
      -NRC. Advance notice of proposed rulemaking: withdrawal; correction.
AB  - This document corrects a notice appearing in the Federal Register on December 2,
      1998 (63 FR 66496), that withdraws an advance notice of proposed rulemaking that
      requested public comments on questions related to comprehensive quality assurance
      and a standard of care in medical uses of byproduct material. This action is
      necessary to correct an erroneous telephone number.

PMID- 10338889
TI  - Solos and the art of recognition.

PMID- 10338890
TI  - Bare necessities for pediatric information sources.

PMID- 10338891
TI  - Managing multiple sites.

PMID- 10338893
TI  - International job exchange: from Dayton to Perth.

PMID- 10338892
TI  - Accessing the Internet--tips for hospital librarians. Resources for patients and
      the public.

PMID- 10338894
TI  - OIG to review medical necessity of therapies provided by SNFs; industry worried
      about how results will be used.

PMID- 10338895
TI  - HCFA publishes more details on federal PPS rate, extends comment period.

PMID- 10338896
TI  - HCFA will not publish list of targeted facilities; reports on oversight progress.

PMID- 10338897
TI  - OIG accuses FI (fiscal intermediaries) fraud units of poor performance, urges
      tougher evaluation by HCFA.

PMID- 10338898
TI  - How to translate terminology used by therapists into MDS (minimum data set)
      lingo.

PMID- 10338899
TI  - Quarterly financial results of post acute/subacute companies.

PMID- 10338900
TI  - Discontinuity of care: urgent care utilization within a health maintenance
      organization.
AB  - OBJECTIVE: To determine the demographic characteristics, attitudes, and perceived
      barriers to primary care reported by patients seen in the urgent care department
      of a health maintenance organization (HMO) health center. STUDY DESIGN: Cross
      sectional survey. PATIENTS AND METHODS: Patients aged 18 years or older who
      sought care at the urgent care department of a large, urban health center of a
      staff-model HMO were eligible for the study. Patients were handed a survey as
      they registered in the urgent care department. Demographic and visit diagnoses
      data were obtained through review of the computerized medical record. RESULTS:
      Patients seeking treatment at the urgent care department were significantly
      younger than those seen at a primary care physician's office (mean age, 40 years
      versus 46 years; P < or = 0.0001) but otherwise had similar demographic
      characteristics. Nearly 90% of 421 patients seen in the urgent care department
      reported having a primary care physician. When asked to list the reasons why they
      came to the urgent care department instead of the primary care offices, 64% said
      they needed to be seen immediately, 47% came because the primary care offices
      were closed, 27% cited the constraints of work or childcare, and 25% said they
      were unable to get an appointment with their primary care physician. Almost half
      of patients (47%) said they would have preferred to see their primary care
      physician within a day or two rather than seeking care at the urgent care
      department. CONCLUSIONS: Patients treated in the urgent care department reported
      various barriers to seeing their primary care physician. Improving same-day
      access to primary care providers will help alleviate this problem and may
      increase patient satisfaction.

PMID- 10338901
TI  - Explaining price variations for the inpatient treatment of congestive heart
      failure.
AB  - OBJECTIVE: To identify key factors affecting hospital charge variations in the
      treatment of congestive heart failure. STUDY DESIGN: The determinants of total
      charges and average charges (the latter being a measure of treatment intensity)
      were evaluated using hospital discharge abstract data from 1994. Multivariate
      regression methods were used to help isolate the impact of key predictors of
      charges. In addition to relating a variety of factors (e.g., drug treatment
      regimens, patient comorbidities, demographic characteristics, insurance status,
      treatment course) to hospital charges, the analysis controlled for hospital
      specific fixed effects. The study includes the effects of pharmacologic agents-
      information typically unavailable on inpatient claims-based data. RESULTS: Drug
      treatment regimens, particularly treatment with inotropic agents, were associated
      with substantially higher total charges. Comorbidities also increased the cost of
      treating congestive heart failure, particularly when septicemia, pneumonia, or
      acute myocardial infarction were involved. In contrast, gender, race, and
      insurance status bore little relationship to total charges or average charges.
      CONCLUSION: The fixed-effects estimates revealed that substantial interhospital
      variations in charges persisted, suggesting that there may be significant
      opportunities to control the inpatient costs of treating congestive heart
      failure.

PMID- 10338902
TI  - Consequences of intermittent treatment for hypertension: the case for medication
      compliance and persistence.
AB  - OBJECTIVE: To review patient compliance with once-daily antihypertensive
      medications and the impact of partial compliance on healthcare outcomes. DATA
      SOURCES: A MEDLINE search of the literature using the terms "patient compliance,"
      "antihypertensive medications," and "hypertension" for the period 1976-1996 was
      conducted. In addition, papers cited in reference lists of source articles were
      reviewed. STUDY SELECTION: Articles were selected if they described patterns of
      compliance, including rates for differing dosing regimens. Articles discussing
      once-daily dosing were selected only if they included information on the
      methodology for compliance assessment. Thirteen reports met these criteria. DATA
      SYNTHESIS: Patterns of compliance vary, with only a partial relationship to
      dosing regimens. Overall compliance was 76% for once-daily antihypertensive
      medications, with a wide range found (53% to 85%). These data were comparable to
      the mean 75% compliance found for other medical disorders. CONCLUSIONS:
      Persistence with treatment is necessary for reduction of long-term consequences
      of hypertension. Enhancing compliance with antihypertensive medications could
      thus have a profound impact on health outcomes. Once-daily dosing should be
      coupled with selection of a drug with long duration of action to overcome
      problems of missed doses. Widespread adoption of simple compliance enhancement
      methods could lead to decreased morbidity and mortality from cardiovascular
      disease and stroke.

PMID- 10338903
TI  - The ethical dilemma of population-based medical decision making.
AB  - Over the past several years, there has been a growing interest in population
      based medicine. Some elements in healthcare have used population-based medicine
      as a technique to decrease healthcare expenditures. However, in their daily
      practice of medicine, physicians must grapple with the question of whether they
      incorporate population-based medicine when making decisions for an individual
      patient. They therefore may encounter an ethical dilemma. Physicians must
      remember that the physician-patient relationship is of paramount importance and
      that even well-conducted research may not be applicable to an individual patient.

PMID- 10338904
TI  - Efficacy, safety, and impact on quality of life of salmeterol in patients with
      moderate persistent asthma.
AB  - OBJECTIVE: To evaluate the efficacy, safety, and impact on asthma-specific
      quality of life of salmeterol, a highly selective, long-acting beta 2-agonist,
      compared with that of placebo (i.e., "as-needed" albuterol). STUDY DESIGN:
      Randomized, double-blind, placebo-controlled, parallel-group, multicenter study.
      PATIENTS AND METHODS: Five hundred thirty-eight nonsmoking symptomatic patients
      12 years of age and older meeting American Thoracic Society asthma criteria were
      enrolled at 55 outpatient clinics; 443 patients completed the study. Patients
      were randomly assigned to treatment with either salmeterol aerosol 42 micrograms
      twice daily or placebo (as-needed albuterol) for 12 weeks. We assessed changes in
      quality of life using the Asthma Quality of Life Questionnaire (AQLQ). Efficacy
      measurements included daily peak expiratory flow (PEF) rate, daytime and
      nighttime asthma symptoms, results of pulmonary function tests, and supplemental
      albuterol use. Patients recorded their PEF rate, supplemental albuterol use, and
      asthma-related symptoms daily. Pulmonary function tests and AQLQ assessments were
      performed at baseline and after 4, 8, and 12 weeks of treatment. Safety
      measurements included vital signs, physical examination, and reports of clinical
      adverse events at baseline and after 4, 8, and 12 weeks of treatment. RESULTS:
      Mean changes from baseline in AQLQ global and domain scores were significantly
      greater in the salmeterol group compared with the placebo group (P < 0.001).
      Patients treated with salmeterol also had significant improvements in mean PEF
      rates, supplemental albuterol use, asthma symptom scores, and forced expiratory
      volume in 1 second compared with those given placebo. Both salmeterol and placebo
      were well tolerated and were not associated with any clinically significant
      changes in vital signs or physical examination findings. CONCLUSIONS: Salmeterol
      42 micrograms twice daily resulted in significantly greater improvements in
      asthma-specific quality of life, pulmonary function, and asthma symptoms compared
      with placebo (as-needed albuterol) in patients with moderate persistent asthma.

PMID- 10338905
TI  - Review of the pharmacoeconomic research on gemcitabine in the treatment of
      advanced non-small cell lung cancer.
AB  - BACKGROUND: Gemcitabine is a novel nucleoside analogue with unique activity
      against a range of solid tumors including non-small cell lung cancer (NSCLC) and
      pancreatic cancer. STUDY DESIGN AND METHODOLOGY: This report reviews a series of
      retrospective economic evaluations that have taken place over the past 4 years
      comparing gemcitabine, both as a single agent and in combination therapy, with
      other treatment modalities for NSCLC in the following countries: United States,
      Spain, Germany, Sweden, Belgium, Canada, and Italy. These economic evaluations
      were in the form of simple cost identification, cost minimization, and cost
      effectiveness in order to estimate the economic impact of gemcitabine in NSCLC
      treatment compared with other treatment modalities. RESULTS AND CONCLUSIONS: The
      results of these retrospective economic evaluations suggest that gemcitabine as
      monotherapy or in a combination regimen may be cost saving or perhaps even cost
      effective. This is largely because the chemotherapy can be administered in an
      outpatient setting and because the side-effect and toxicity profile is lower.
      This economic advantage assumes equivalent efficacy of gemcitabine and other
      treatment modalities for treatment of NSCLC.

PMID- 10338906
TI  - Ventricular arrhythmias and the use of antiarrhythmic drugs after cardiovascular
      surgery.

PMID- 10338907
TI  - Methods of evaluation in outcomes research.
AB  - This activity is designed for pharmacists, physicians, physician assistants,
      nurses, and other healthcare team members; payers for health services; and
      healthcare executives. GOAL: To provide basic information on the methods used and
      computer software available for evaluating invariant factorial structures, such
      as those found in health status measurement tools. OBJECTIVES: 1. Discuss why
      comparison of mean scores may not be appropriate when interpreting humanistic
      outcomes results. 2. Identify alternative methods for evaluating data from health
      status measurement tools, such as the SF-36. 3. Define validity, reliability, and
      structure. 4. Understand the value of structural equation modeling when using
      health status measurement tools, such as the SF-36. 5. Describe the statistical
      software used to perform structural equation modeling.

PMID- 10338908
TI  - Celebration Health: nothing Mickey Mouse about this new paradigm.

PMID- 10338909
TI  - Planning Celebration was a chance to build the best.

PMID- 10338910
TI  - Humana CHF program cuts costs, admissions.
AB  - The Buffalo Grove, IL-based Cardiac Solutions congestive heart failure program
      reduced admissions by 57.5%, inpatient costs by 61.1%, hospital days by 58%, and
      emergency department visits by 48.9% in a two-year study of nearly 5,000 Humana
      patients. The program relies heavily on frequent nursing contact in person and by
      telephone with patients to make sure they comply with doctors' orders and know
      how to identify early warning signs. Nurse disease managers provide the sometimes
      missing link between established treatment guidelines and implementation on the
      patient level.

PMID- 10338911
TI  - Nutrition intervention in ICU improves outcomes.
AB  - Enteral feedings within three days can reduce length of time on a ventilator and
      improve outcomes for critically ill patients. Such feedings, which cost only
      about $80 per day, could save Medicare as much as $1.08 billion from 1996 to
      2002, according to a study by Washington, DC-based KPMG Peat Marwick. A concerted
      effort to disseminate these findings led 66% of nurses at a California hospital
      to change their practice regarding early nutrition support.

PMID- 10338912
TI  - Hospitals are hot for collaborative strategies.

PMID- 10338913
TI  - Do you use benchmarks without benchmarking?

PMID- 10338914
TI  - Manage surgical minutes to reap hefty OR savings.

PMID- 10338915
TI  - New admissions guidelines, policy changes result in fewer c-sections, lower
      costs.
AB  - Hospitals can reduce the rate of costly cesarean births by revamping admissions
      policies for women in labor and revisiting other labor-related policies. Lawrence
      (MA) General Hospital overhauled most of its obstetrics department's policies in
      an effort to cut back on c-sections. Tougher admissions guidelines, fewer
      inductions, and encouraging women to get out of bed and walk around more all
      contributed to cutting the hospital's c-section rate to 17% from a high of 26% in
      1993. Learn how your facility can have similar results.

PMID- 10338917
TI  - New software tools ease move to electronic medical records.
AB  - Converting a hospital to electronic medical records can save big bucks, but it's
      easier said than done. Huge savings await hospitals that eliminate the cost of
      storing, filing and retrieving charts. But making that move is more complex than
      simply converting written notes to an automated format. Learn how one California
      hospital is embarking on its journey to a paperless environment with the help of
      some innovative information systems technology that will take some of the pain
      out of the transformation.

PMID- 10338916
TI  - Reengineering survey finds changes vary widely, as do resulting financial
      benefits.
AB  - DATA BENCHMARK: Reengineering study reveals most hospitals are not reporting huge
      financial improvements as a result of their redesign efforts. A survey
      commissioned by the American Hospital Association finds 1995 was the peak year
      for hospitals to launch new redesign programs. Though that practice is not on the
      wane, the survey's author says many hospitals are pursuing redesign efforts
      without engaging in formal programs. The bad news is financial gains have not
      been huge for many of these institutions.

PMID- 10338918
TI  - Incentive strategies reward winners, discourage sinners.

PMID- 10338919
TI  - Health system takes performance-based pay from theory to practice.
AB  - A Cincinnati health system offers a real-world example of an organization that
      has implemented incentive programs designed to reward physicians for managing
      quality and cost.

PMID- 10338920
TI  - Are capitation dollars slipping through your fingers?
AB  - This study by a San Francisco consultant suggests that provider groups can
      recover 10% to 15% of their capitation dollars by conducting financial recoveries
      in areas such as member-capitation reconciliation, claims paid on ineligible
      members, and duplicate claims.

PMID- 10338921
TI  - Tools help pinpoint cap rates, forecast changes in utilization.
AB  - Data Insight: An Internet-based product from an Evanston, IL, information company
      gives payers and providers local utilization data on which to make contracting
      decisions.

PMID- 10338922
TI  - Marketplace. Why drug companies are banking on Web sites to reach customers.

PMID- 10338923
TI  - Perspectives. HMOs' legislative odyssey, Medicare changes, science explosion are
      top stories of 1998--and likely to dominate news again next year.

PMID- 10338924
TI  - Garen Wintemute, M.D., Founding Director, Violence Research Program and Time
      Magazine Hero in Medicine. Interview by James A. Johnson.

PMID- 10338925
TI  - Developing clinical and community health priorities.

PMID- 10338926
TI  - The chronically ill and managed care.

PMID- 10338927
TI  - Physician executives in managed care: characteristics and job involvement across
      two career stages.
AB  - This paper examines characteristics, job involvement, and career stage
      differences among 294 physician executives working in managed care settings. The
      following research questions guide the study: What types of physicians are
      currently in managerial roles in these settings? What role (if any) does medical
      career stage play in physician executives' professional and job-related
      attitudes? What factors are related to physician executives' involvement in their
      management roles? Several observations are made from the findings. First,
      contemporary physician executives see management as an exciting alternative
      career that involves multiple work loyalties, weaker beliefs in traditional
      professional values, and the sacrifice of significant amounts of clinical for
      management work. Second, these trends are more pronounced for physician
      executives at earlier points in their medical careers, although their work
      loyalties to profession and employing organization are weaker than older
      physician executives' loyalties. Younger individuals' involvement in management
      work, more than older individuals' involvement, appears to depend upon the
      surrounding work climate within the organization. Finally, the amount of time
      spent by physician executives as clinicians is inversely related to how
      psychologically attached they are to management, regardless of career stage.

PMID- 10338928
TI  - Gains from public-private collaborations to improve community health.
AB  - In several disciplines there exists theoretical and empirical evidence to show
      that community affects health and behaviors; but to date such evidence has
      remained largely outside the health services field. In this article, the authors
      introduce and contribute to this evidence and then discuss how those in the
      healthcare sector can work to increase public-private collaborations. Telephone
      survey data collected in 1995 from 1,826 randomly selected residents of a
      Northwest urban county were used in multivariate analysis to assess the
      relationship between community quality and health status. Community quality was
      measured by residents' perceptions of community problems. Findings indicate that
      individual ratings of community problems predicted mental health functioning.
      This effect was found overall and for men and women separately. These results
      suggest that health is dependent on how people perceive the quality of their
      community. Leadership and vision can make an enormous difference in the quality
      of a community health system and in the cost-effectiveness of the care provided.
      Healthcare leaders can develop their understanding of their community and the
      impact of community characteristics on health through consultation with experts,
      input from community leaders, and visits to the neighborhoods that surround the
      delivery services. Community networks can be developed with the common focus of
      improving the community's health. Collaborative efforts between the private
      health sector, the public health sector, and community members can enhance social
      relationships and thus promote the health of residents.

PMID- 10338929
TI  - Competitive strategy in turbulent healthcare markets: an analysis of financially
      effective teaching hospitals.
AB  - As the healthcare marketplace, characterized by declining revenues and heavy
      price competition, continues to evolve toward managed care, teaching hospitals
      are being forced to act more like traditional industrial organizations. Profit
      oriented behavior, including emphases on market strategies and competitive
      advantage, is now a necessity if these hospitals are going to survive the
      transition to managed care. To help teaching hospitals evaluate strategic options
      that maximize financial effectiveness, this study examined the financial and
      operating data for 100 major U.S. teaching hospitals to determine relationships
      among competitive strategy, market environment, and financial return on invested
      capital. Results should help major hospitals formulate more effective strategies
      to combat environmental turbulence.

PMID- 10338931
TI  - The 1998 National Caring Awards for Young Adults.

PMID- 10338930
TI  - Strategic positioning: a case study in governance and management.
AB  - This case describes the experience of the Detroit Medical Center (DMC) in
      restructuring its governance and management. It provides a background on the DMC,
      examines the driving forces that led to modification of its structure, identifies
      key principles in guiding the change, and describes the strategies and specific
      steps taken in managing structural change. Finally, the critical lessons learned
      about leadership style, communication, agenda development, and relations with the
      board, medical staff, and management are discussed. This case study will help
      reduce the learning curve for any large, complex organization undertaking board
      and management restructuring to better meet its mission. At the time of DMC's
      restructuring there were no models to guide the effort. This case study attempts
      to reduce the gap in research on the management of structural change.

PMID- 10338932
TI  - Tribute to Dame Cicely Saunders, First Lady of the modern hospice movement.
      Interview by Val J. Halamandaris.

PMID- 10338933
TI  - The 1998 National Caring Awards.

PMID- 10338934
TI  - Strategies for improving health plan member retention.
AB  - Member retention is an increasingly important issue for health plans to address.
      It costs health plans $75 to $200 to acquire a commercial member and $400 to $800
      to acquire a Medicare member. If members leave the plan within the first year or
      so, up to half of this investment is lost. Health plans should implement several
      strategies, therefore, to improve member retention. They should communicate the
      value of retention throughout the organization, use a cross-functional team
      approach to retention, analyze who is disenrolling and why, improve access to
      referral providers, and extend the retention effort until a relationship exists,
      evaluate and strengthen member orientation efforts. Other ways to enhance member
      retention are to improve access to health and service information, improve
      provider-staff interaction and communication skills, implement relationship
      enhancing communication campaigns, manage expectations about treatment, and
      create personal relationships at the plan-purchaser level.

PMID- 10338935
TI  - 1999 HFM resource guide. Your guide to hundreds of companies with products and
      services for the healthcare industry. Vendor listings by category.

PMID- 10338936
TI  - Managed care contracting for specialists.
AB  - Specialty managed care contracting requires specialists to understand their role
      in managing care, as well as carve-out and subcapitation agreements. Specialists
      should know their referral sources, their costs for providing care, and how to
      provide care that meets their referral sources' needs and the payers'
      requirements. Once specialists enter carve-out or subcapitation arrangements,
      they need to determine the best payment calculation method for their practice.
      Three methods to consider are resource-based relative value scale, per-referral
      basis, and a point system. Because each method produces different results,
      providers need to understand each method and the unique concerns of specialty
      managed care contracting to negotiate the best contracts for their situation.

PMID- 10338937
TI  - Florida law foreshadows big change in credentialing for hospitals nationwide.

PMID- 10338938
TI  - Decision support systems may improve quality.

PMID- 10338939
TI  - Look at comparative data with an eye toward quality.

PMID- 10338940
TI  - Beware of human error in CVE (credentials verification entities) reports.

PMID- 10338941
TI  - Federal databases are increasing in number.

PMID- 10338942
TI  - PraPlus screens for risk of repeat admissions.

PMID- 10338943
TI  - Health care spending slows; up 4.8% in 1997.

PMID- 10338944
TI  - 'Perfect' case management setting found in county's 'closed' system.

PMID- 10338946
TI  - Casualties Union. Making a drama out of a crisis.

PMID- 10338945
TI  - Millennium planning. All right on the night.

PMID- 10338947
TI  - Hospital cinemas. Nurse, the screens.

PMID- 10338948
TI  - Primary care groups. Silent majority.

PMID- 10338950
TI  - An experimental test of question framing in health state utility assessment.
AB  - In the standard gamble and time trade-off methods of health state utility
      assessment, a specified health state and an alternative are compared. This
      alternative can be framed in terms of a loss or a gain in reference to the first
      health state. In this paper, we test whether this framing affects the estimated
      health state utilities. The experiment was carried out on a group of pharmacy
      students, randomly divided between the loss or gain version (n = 182). The null
      hypothesis of no difference between the loss and gain versions is rejected for
      the standard gamble method, but not for the time trade-off method.

PMID- 10338949
TI  - General practice care and patients' priorities in Europe: an international
      comparison.
AB  - Insight into patients' priorities with respect to health care should complement
      the views of professionals and policy makers on what is thought to be appropriate
      health care. To determine the strengths and weaknesses of general practice care
      from patients' perspectives written surveys were performed among patients in
      Denmark, Germany, Israel, Netherlands, Norway, Portugal, Sweden and United
      Kingdom (n = 3540). The potential quality problems identified were spread over
      the different countries: the low involvement of general practitioners in out-of
      hours services in Portugal; the low provision of routine screening in Sweden,
      Norway and The Netherlands; the lack of a defined patient population in Germany;
      the lack of a formal gatekeeper role to secondary care in general practice in
      Germany and Sweden; and the low number of home visits in Sweden.

PMID- 10338951
TI  - Possible objectives and resulting entitlements of essential health care packages.
AB  - The notion of a defined 'core package of essential health care services' has
      appeared in many different health reform proposals in the 1990s. This paper
      attempts to explore the possible objectives of the 'core package' component of
      health care reform. Two board applications are apparent: the use of essential
      packages to ration scarce public funds and the incorporation of a minimum benefit
      package into 'managed competition' type reforms, where they constitute a mandated
      minimum level of private insurance cover. Eight possible objectives for an
      essential benefit package are described: To protect against catastrophic illness
      events; to ensure social risk pooling; to improve allocative efficiency in the
      health system; to eliminate 'high burden of disease' conditions; to improve
      equity of access to services; to combat cost-escalation; to encourage competition
      between insurers; and to facilitate public participation and transparency in
      decision making. Closer examination of objectives reveals that they often
      conflict, which suggests that a clear understanding of the purpose of reform is
      essential before it is worthwhile devoting energy to the development of essential
      benefit packages. It is argued that two main clusters of objectives emerge from
      the eight described, representing Rawlsian (risk avoidance) and utilitarian
      (efficiency improvement) social welfare philosophies, respectively. Practical
      experience suggests that priority setting exercises have been unsuccessful in
      meeting efficiency objectives, but that they may well be quite useful in
      fulfilling risk-pooling aims.

PMID- 10338952
TI  - Syringe and needle exchange as HIV/AIDS prevention for injection drug users in
      Puerto Rico.
AB  - This study evaluated the effectiveness of the first needle exchange program (NEP)
      established in Puerto Rico. The data for this study were collected during the
      first months of the NEP from July 1995 to March 1996 in 13 communities of the San
      Juan metropolitan area. Subjects were the participants of two modalities of the
      NEP: a mobile team and a community-based drug treatment program. During the 3
      week evaluation period, 2401 injection drug users (IDUs) were recruited,
      resulting in a total of 19,195 exchange contacts and 146,323 syringes exchanged.
      No significant change in drug injection was observed. However, the program was
      effective in reducing sharing of syringes and cookers. The study suggests that
      the NEP did help in reducing needle sharing in Puerto Rico. However, the HIV
      seropositivity in returned syringes suggests the need to continue aggressive
      prevention programs to arrest the epidemic among IDUs. However, factors related
      to the socio-cultural environment as well as cultural norms and traditions need
      to be considered when planning and expanding NEPs.

PMID- 10338953
TI  - Self-referral in a gatekeeping system: patients' reasons for skipping the general
      practitioner.
AB  - In the Netherlands general practitioners act as the gatekeepers at the primary
      level to the more specialized and more expensive secondary health-care. As a
      rule, patients are required to have a referral from their general practitioners
      to be able to utilize these services. Not all private insurance companies,
      however, require a referral letter from their customers before reimbursing them
      for their costs or do not always exert a control whether such referral indeed had
      taken place. A mail-questionnaire was targeted to a specific group of 2000
      privately insured patients to find out the reasons of self-referral. The findings
      suggest that patients self-refer to a specialist for medical complaints for which
      they expect to end up at the specialist anyway as they consider these problems as
      specific for the specialist. Complaints of patients who first visit their general
      practitioners, however, might be considered as less typical to the specialist.
      Patients who are living in relatively highly urbanized areas, who are better
      educated, and who expect to achieve a better quality of communication at the
      consultation with the specialist, more commonly skip their GPs before visiting a
      specialist.

PMID- 10338955
TI  - Call for core measures issued.

PMID- 10338954
TI  - Joint Commission on Accreditation of Healthcare Organizations. Revised restraint
      standards for non-psychiatric patients.

PMID- 10338956
TI  - Special report on sentinel events. Joint Commission on Accreditation of
      Healthcare Organizations.

PMID- 10338957
TI  - ORYX and organization status changes: two scenarios.

PMID- 10338958
TI  - Special report on sentinel events. Hermann Hospital: using root cause analysis.

PMID- 10338960
TI  - In-hospital resuscitation requirements reinstated for hospitals.

PMID- 10338959
TI  - Revised decision rules for unlicensed practitioners.

PMID- 10338961
TI  - Physician Database approved as equivalent source for credentials verification.

PMID- 10338962
TI  - Random unannounced survey topics for 1999.

PMID- 10338963
TI  - When hospitals take over.... Who wins? Who loses?

PMID- 10338964
TI  - How Monica mania stalled HMO reform.

PMID- 10338965
TI  - Doctor policing--or persecution?

PMID- 10338966
TI  - Wow, what a merger! Whoa, what a nightmare.

PMID- 10338967
TI  - Are there enough patients for that new associate?

PMID- 10338968
TI  - HCFA's Y2K status worries providers.

PMID- 10338969
TI  - Engineering solutions to the Y2K puzzle.

PMID- 10338970
TI  - Weaving a net to ward off the Y2K bug.

PMID- 10338971
TI  - Y2K escalates provider liability.

PMID- 10338972
TI  - Good computer help is hard to find.

PMID- 10338973
TI  - A kindly touch, a helping hand.

PMID- 10338974
TI  - The missing link: resident participation in performance improvement.

PMID- 10338975
TI  - Liability and risk management issues associated with managing residents.

PMID- 10338976
TI  - Allocating costs for hospital medical liability programs.

PMID- 10338977
TI  - Restraints: controlling a symptom or a symptom of control.

PMID- 10338978
TI  - Physical restraint elimination in the acute care setting: ethical considerations.

PMID- 10338979
TI  - Culture and the use of patient restraints.

PMID- 10338980
TI  - Legal aspects of restraint use in hospitals and nursing homes.

PMID- 10338981
TI  - For their own good? A historical examination of restraint use.

PMID- 10338982
TI  - Nursing home issues in restraint use.

PMID- 10338983
TI  - An ethics committee explores restraint use and practices.

PMID- 10338984
TI  - General anesthesia: an extreme form of chemical and physical restraint.

PMID- 10338985
TI  - Annotated bibliography. Physical restraints.

PMID- 10338986
TI  - Case analysis, Part II. The Pediatric Ethics Forum: exploring the ethical
      dimensions of pediatric care.

PMID- 10338988
TI  - New Morriston Hospital pharmacy.

PMID- 10338989
TI  - A new combined heat and power Energy Centre.

PMID- 10338987
TI  - The significance of the Convention on Human Rights and Biomedicine of the Council
      of Europe for healthcare ethics committees.

PMID- 10338990
TI  - Audit helps health & safety management systems development.

PMID- 10338991
TI  - Construction of high technology healthcare buildings NHS--UK.

PMID- 10338992
TI  - Capital project management for hospitals.

PMID- 10338994
TI  - Code of Ethics and bylaws. Bylaws amended, October 1996. Code of Ethics amended,
      1998. American Health Information Management Association.

PMID- 10338993
TI  - Health service estates management policies for the next millennium.

PMID- 10338995
TI  - Practice brief. Release of information laws and regulations. American Health
      Information Management Association.

PMID- 10338996
TI  - HCFA issues Internet security policy, requires authentication and identification
      procedures.

PMID- 10338997
TI  - Practice brief. Patient photography, videotaping, and other imaging (updated).
      American Health Information Management Association.

PMID- 10338998
TI  - Virtual private networks.

PMID- 10338999
TI  - Keys to compliance.

PMID- 10339001
TI  - OIG mobilizes for 1999.

PMID- 10339000
TI  - In pursuit of healthcare fraud.

PMID- 10339002
TI  - Better coding through improved documentation: strategies for the current
      environment.
AB  - Now more than ever, HIM professionals must ensure that documentation of health
      information is thorough, clear, and accurate. Here are some strategies to solve
      problems and improve processes.

PMID- 10339003
TI  - Auditing and monitoring--elements of HIM compliance.
AB  - Auditing and monitoring are two important components of a compliance plan. The
      author answers the most frequently asked questions about audits. In addition,
      find out how to get started--and what to do with the results.

PMID- 10339005
TI  - Managing change.

PMID- 10339004
TI  - Ongoing coding reviews: ways to ensure quality.
AB  - As compliance becomes an increasingly hot topic, how can a facility ensure its
      coding quality? Here are some ways that HIM departments can improve the quality
      of coding on a daily basis.

PMID- 10339006
TI  - 1999 CPT revisions.

PMID- 10339007
TI  - Facing the knife. Could eating potatoes affect your recovery from surgery? Maybe.
      Here's a list of dos and don'ts.

PMID- 10339009
TI  - Medicare woes. Many HMOs are dropping patients over 65. Here's how to make sure
      you stay well covered.

PMID- 10339008
TI  - The age of Ritalin.

PMID- 10339010
TI  - Showdown for Dr. Death.

PMID- 10339011
TI  - Time for the ice floe, Pop.

PMID- 10339012
TI  - Ernest A. Codman Award. Susquehanna Lutheran Village achieves restraint-free
      environment.

PMID- 10339013
TI  - Charting the future of healthcare improvement.
AB  - Healthcare improvement must become a function of systems--hospitals, delivery
      systems and communities--to overcome inequities in care and to make quality as
      much a priority as financial success, according to Don Berwick, MD, CEO of the
      Institute for Healthcare Improvement.

PMID- 10339014
TI  - Integrating clinical work and management in healthcare's future.

PMID- 10339015
TI  - Ernest A. Codman Award. University of Pennsylvania Hospital extends disease
      management system.

PMID- 10339016
TI  - Ernest A. Codman Award. Warm Springs + Baptist Hospital lab staff in patient
      satisfaction spotlight.

PMID- 10339017
TI  - Quality and evidence in nursing.

PMID- 10339018
TI  - Never mind the quality: feel the improvement.

PMID- 10339019
TI  - End stage renal failure and assessment of health related quality of life.

PMID- 10339020
TI  - Effect of clinical guidelines in nursing, midwifery, and the therapies: a
      systematic review of evaluations.
AB  - BACKGROUND: Although nursing, midwifery, and professions allied to medicine are
      increasingly using clinical guidelines to reduce inappropriate variations in
      practice and ensure higher quality care, there have been no rigorous overviews of
      their effectiveness, 18 evaluations of guidelines were identified that meet
      Cochrane criteria for scientific rigor. METHODS: Guideline evaluations conducted
      since 1975 which used a randomised controlled trial, controlled before and after,
      or interrupted time series design were identified through a combination of
      database and hand searching. RESULTS: 18 studies met the inclusion criteria.
      Three studies evaluated guideline dissemination or implementation strategies,
      nine compared use of a guideline with a no guideline state; six studies examined
      skill substitution: performance of nurses operating according to a guideline were
      compared with standard care, generally provided by a physician. Significant
      changes in the process of care were found in six out of eight studies measuring
      process and in which guidelines were expected to have a positive impact on
      performance. In seven of the nine studies measuring outcomes of care, significant
      differences in favour of the intervention group were found. Skill substitution
      studies generally supported the hypothesis of no difference between protocol
      driven by nurses and care by a physician. Only one study included a formal
      economic evaluation, with equivocal findings. CONCLUSIONS: Findings from the
      review provide some evidence that care driven by a guideline can be effective in
      changing the process and outcome of care. However, many studies fell short of the
      criteria of the Cochrane Effective Practice and Organisation of Care Group (EPOC)
      for methodological quality.

PMID- 10339021
TI  - Formal consensus and consultation: a qualitative method for development of a
      guideline for dementia.
AB  - OBJECTIVES: To use a formal consensus method--the nominal group technique--for
      developing a clinical practice guideline to improve the diagnosis, needs
      assessment, and management of dementia at the primary/secondary care interface.
      To assess the usefulness of this method in an area where there is a dearth of
      clinical trials thus precluding an evidence-based approach. DESIGN: A qualitative
      and iterative method was used. The guideline was developed by an expert panel
      using the nominal group technique, incorporating the deliberations of a Primary
      Care Professionals' Task Group, recent reviews in the scientific literature,
      information from semistructured interviews with local specialists, and a local
      questionnaire survey. SETTING: Mainly Bristol but incorporating other parts of
      the United Kingdom especially the south and west. SUBJECTS: Expert panel group
      (including users and non-statutory organisations), local general practitioners
      (GPs), professionals carrying out the health check for people over 75, local
      geriatricians and psychogeriatricians, and primary care professionals with an
      interest in dementia. MAIN MEASURES: Items important in dementia from the nominal
      group in response to three questions on diagnosis, needs assessment, and
      management, ranked into a series of top 10 items for each area and allocated a
      score according to relative importance to each member; summary outputs from the
      questionnaire survey, semistructured interviews, and primary care professionals'
      task group. RESULTS: A clinical practice guideline covering diagnosis, needs
      assessment, and management of dementia in primary care was produced in the form
      of an algorithm and a management sheet. CONCLUSIONS: A formal consensus method
      can be used as an acceptable alternative to the evidence-based approach when
      developing guidelines in situations in which evidence is scarce, in which the
      guideline is intended as an aid in linking different stages of care, and in which
      practical and political considerations--such as the links between agencies--are
      important.

PMID- 10339022
TI  - Introducing a quality improvement programme to primary healthcare teams.
AB  - OBJECTIVES: To evaluate a programme in which quality improvement was facilitated,
      based on principles of total quality management, in primary healthcare teams, and
      to determine its feasibility, acceptability, effectiveness, and the duration of
      its effect. METHOD: Primary healthcare teams in Leicestershire (n = 147) were
      invited to take part in the facilitated programme. The programme comprised seven
      team meetings, led by a researcher, plus up to two facilitated meetings of
      quality improvement subgroups, appointed by each team to consider specific
      quality issues. OUTCOME MEASURES: To assess the effect and feasibility of the
      programme on improving the quality of care provided, the individual quality
      improvement projects undertaken by the teams were documented and opportunities
      for improvement were noted at each session by the facilitator. The programme's
      acceptability was assessed with questionnaires issued in the final session to
      each participant. To assess the long term impact on teams, interviews with team
      members were conducted 3 years after the programme ended. RESULTS: 10 of the 27
      teams that initially expressed interest in the programme agreed to take part, and
      six started the programme. Of these, five completed their quality improvement
      projects and used several different quality tools, and three completed all seven
      sessions of the programme. The programme was assessed as appropriate and
      acceptable by the participants. Three years later, the changes made during the
      programme were still in place in three of the six teams. Four teams had decided
      to undertake the local quality monitoring programme, resourced and supported by
      the Health Authority. CONCLUSIONS: The facilitated programme was feasible,
      acceptable, and effective for a few primary healthcare teams. The outcomes of the
      programme can be sustained. Research is needed on the characteristics of teams
      likely to be successful in the introduction and maintenance of quality
      improvement programmes.

PMID- 10339023
TI  - The SF36 as an outcome measure of services for end stage renal failure.
AB  - OBJECTIVE: To evaluate the use of the short form 36 (SF36) as a measure of health
      related quality of life of patients with end stage renal failure, document the
      results, and investigate factors, including mode of treatment, which may
      influence it. DESIGN: Cross sectional survey of patients with end stage renal
      failure, with the standard United Kingdom version of the SF36 supplemented by
      specific questions for end stage renal failure. SETTING: A teaching hospital
      renal unit. SUBJECTS AND METHODS: 660 patients treated at the Sheffield Kidney
      Institute by haemodialysis, peritoneal dialysis, and transplantation. Internal
      consistency, percentage of maximal or minimal responses, SF36 scores, effect
      sizes, correlations between independent predictor variables and individual
      dimension scores of the SF36. Multiple regression analysis of the SF36 scores for
      the physical functioning, vitality, and mental health dimensions against
      treatment, age, risk (comorbidity) score, and other independent variables.
      RESULTS: A high response rate was achieved. Internal consistency was good. There
      were no floor or ceiling effects other than for the two "role" dimensions.
      Overall health related quality of life was poor compared with the general
      population. Having a functioning transplant was a significant predictor of higher
      score in the three dimensions (physical functioning, vitality, and mental health)
      for which multiple regression models were constructed. Age, sex, comorbidity,
      duration of treatment, level of social and emotional support, household numbers,
      and hospital dialysis were also (variably) significant predictors. CONCLUSIONS:
      The SF36 is a practical and consistent questionnaire in this context, and there
      is evidence to support its construct validity. Overall the health related quality
      of life of these patients is poor, although transplantation is associated with
      higher scores independently of the effect of age and comorbidity. Age,
      comorbidity, and sex are also predictive of the scores attained in the three
      dimensions studied. Further studies are required to ascertain whether altering
      those predictor variables which are under the influence of professional carers is
      associated with changes in health related quality of life, and thus confirm the
      value of this outcome as a measure of quality of care.

PMID- 10339025
TI  - The National Health Service in England considers on the government's plans to
      improve quality of health care.

PMID- 10339024
TI  - Hospital organisation and outcomes.

PMID- 10339026
TI  - Defining appropriateness: the challenge of knowing the difference.

PMID- 10339029
TI  - Organisational change: the key to quality improvement.

PMID- 10339027
TI  - Cholesterol and coronary heart disease: screening and treatment.

PMID- 10339030
TI  - Power and quality improvement in the new NHS: the roles of doctors and managers.

PMID- 10339028
TI  - Preschool hearing, speech, language, and vision screening.

PMID- 10339031
TI  - Assuring high quality and evidence-based health care: a case study from HIV/AIDS
      services.

PMID- 10339032
TI  - Celebrating teamwork.

PMID- 10339033
TI  - Mapping out the patient's journey: experiences of developing pathways of care.

PMID- 10339034
TI  - Clinical governance: a quality duty for health organisations.

PMID- 10339035
TI  - Promoting health care quality: what role performance indicators?

PMID- 10339036
TI  - Can policy drive quality?

PMID- 10339037
TI  - Evolving quality in the new NHS: policy, process, and pragmatic considerations.

PMID- 10339038
TI  - Different countries, different cultures: convergent or divergent evolution for
      healthcare quality?

PMID- 10339039
TI  - Organisational context for quality: lessons from the fields of organisational
      development and change management.

PMID- 10339040
TI  - A framework for collaborative improvement: lessons from the Institute for
      Healthcare Improvement's Breakthrough Series.
AB  - The article describes the Breakthrough Series, a collaborative improvement model
      developed by the Institute for Healthcare Improvement. The model adapts and
      applies existing knowledge to multiple, similar sites to accomplish common aims.
      It has been used to address several of the most pressing issues in health care
      today. The article outlines key elements of the Breakthrough Series to provide a
      framework for future collaborative improvement efforts.

PMID- 10339042
TI  - Breakthrough change for adult cardiac surgery in a community-based cardiovascular
      program.
AB  - This article describes the use of rapid cycle improvement in a community hospital
      adult cardiac surgery program. The hospital participated in the Breakthrough
      Series: collaborative adult cardiac surgery sponsored by the Institute of
      Healthcare Improvement (IHI). As a result of this 1-year project, median length
      of stay for diagnosis-related groups 104 throug 108 was decreased 30 percent from
      8.62 days to 6.0 days; percentage of patients extubated within 6 hours
      postoperatively rose from 5 percent to 75 percent; median cost per case declined
      $19 percent; and pain and anxiety, service, and satisfaction scores all improved.
      There was no adverse impact on the clinical indicators 30-day readmission rate,
      reintubation, return to operating room, and mortality.

PMID- 10339041
TI  - Reducing adverse drug events and medication errors using rapid cycle improvement.
AB  - The article describes Fairview Health System's participation in the Institute for
      Healthcare Improvement Breakthrough Series on adverse drug events and medication
      errors. Fairview commissioned an interdisciplinary team to design, plan, and lead
      activities focused on reducing adverse drug events and medication errors. This
      team managed, facilitated, or led 15 separate projects, each focusing on a
      specific aspect of the medications process. Specific systems improvements were
      identified, leading to reductions in errors or adverse events. As a result of
      this effort, Fairview has committed to a long-term plan to reduce the risk of
      adverse drug events and medication errors to the lowest possible rate.

PMID- 10339043
TI  - Improving efficiencies and reducing costs in adult cardiac surgery: a team
      approach.
AB  - The article reviews a team effort to reduce operating room costs by 25 percent.
      The team achieved this goal by participating in the Institute for Healthcare
      Improvement Breakthrough Series on adult cardiac surgery. The process
      improvements included standardizing practices, reevaluating equipment, and
      reducing operating room cycle time.

PMID- 10339044
TI  - Multidisciplinary achievement: the collaborative approach to rapid cycle ICU and
      hospital change.
AB  - Multidisciplinary teams are different from the traditional team format in that
      representation and participation from various disciplines characterize the
      structure. In April 1996, a multidisciplinary group from Muhlenberg Regional
      Medical Center's intensive care unit learned methodology at the Institute for
      Health Care Improvement (IHI) Breakthrough Series in Adult Intensive Care. With
      the format learned, improvements in diverse areas such as ventilator management,
      intermediate care, clinical laboratory utilization, and others were accomplished.
      Continued support from an expert staff and utilization of on-line communication
      tools characterized this 15-month quality improvement endeavor. The end of the
      breakthrough series spurred the development of a hospital-wide collaborative cost
      containment team.

PMID- 10339045
TI  - Changing the process of diabetes care improves metabolic outcomes and reduces
      hospitalizations.
AB  - We designed and evaluated an ambulatory care intervention aimed at improving
      glycemic control and reducing hospitalizations in patients with insulin-dependent
      diabetes mellitus (IDDM). One hundred seventy-one youth with IDDM, ages 10-15,
      were assigned either to a Care Ambassador intervention (N = 89) or to standard
      care (N = 82). The intervention consisted of scheduling, confirming, and
      documenting medical follow-up for 24 months. During the study, the intervention
      group had more diabetes visits, 7.1 +/- 1.50 (mean +/- SD) Vs. 5.2 +/- 2.57 in
      the standard care group (P = 0.0001). In the at-risk subjects (baseline HbA1c
      8.1%, N = 162), 50% of intervention subjects compared with 29% of standard care
      achieved HbA1c 8.6% while 17% of intervention subjects compared with 32% of
      standard care had values > 9.6% (P = 0.039). During follow-up, severe
      hypoglycemia and hospitalization/ER use occurred at half the rate in the
      intervention group compared with standard care. This specific, low-cost
      intervention aimed at increasing ambulatory medical visits in at-risk patients
      with diabetes improves metabolic outcomes and significantly reduces hospital/ER
      use.

PMID- 10339046
TI  - Administrative practices and procedures; internal review of decisions--FDA. Final
      rule.
AB  - The Food and Drug Administration (FDA) is amending the regulations governing the
      internal review of agency decisions by inserting a statement that sponsors,
      applicants, or manufacturers of drugs (including human drugs, animal drugs, and
      human biologics) or devices may request review of a scientific controversy by an
      appropriate scientific advisory panel, or advisory committee. This amendment
      implements the "Dispute Resolution" provision of the Food and Drug Administration
      Modernization Act (FDAMA). This document is intended to clarify that sponsors,
      applicants, or manufacturers of drugs, or devices may request review of
      scientific controversies by an appropriate scientific advisory panel or advisory
      committee.

PMID- 10339047
TI  - Medical devices: reports of corrections and removals; delay of effective data-
      FDA. Direct final rule; delay of effective date.
AB  - The Food and Drug Administration (FDA) published in the Federal Register of
      August 7, 1998 (63 FR 42229), a direct final rule. The direct final rule notified
      the public of FDA's intention to amend the regulations that govern reports of
      corrections and removals of medical devices to eliminate the requirement for
      distributors to make such reports. This document delays the effective date of the
      direct final rule.

PMID- 10339048
TI  - Demonstration to improve enrollment in state buy-in to Medicare for low-income
      Medicare beneficiaries--SSA. Notice, request for comments and solicitation for
      demonstration participation by states.
AB  - Title IV of Division A, Social Security Administration, of the Omnibus
      Consolidated and Emergency Supplemental Appropriations Act, 1999, Public Law 105
      277, directs the Commissioner of Social Security to expend $6,000,000 for Federal
      State partnerships which will evaluate means to promote the Medicare buy-in
      programs targeted to elderly and disabled individuals under titles XVIII and XIX
      of the Social Security Act (the Act). Administration of the Medicare buy-in
      programs described in titles XVIII and XIX of the Act is the responsibility of
      the Administrator of the Health Care Financing Administration (HCFA) in the
      Department of Health and Human Services. The Commissioner of Social Security is
      responsible for the Social Security and Supplemental Security Income (SSI)
      programs described in titles II and XVI of the Act. The Medicare and Medicaid
      programs are statutorily linked to the programs administered by the Social
      Security Administration (SSA). Because of this linkage, SSA provides certain
      Medicare- and Medicaid-related services to HCFA, the States and to SSA's
      beneficiaries. Among these services are public service information activities
      about the Medicare and Medicaid programs, categorically needy Medicaid
      eligibility determinations in most States and referral activities for certain
      Medicaid benefits in all States. The scope of SSA's involvement in the Medicare
      and Medicaid programs is defined in the Act and in agreements between SSA and
      HCFA and between SSA and the States. The demonstration project specified in
      Public Law 105-227 will assist SSA's low-income disabled beneficiaries and
      beneficiaries age 65 and over who are or could be eligible for Medicaid benefits
      to help pay their Medicare costs. SSA intends to work with HCFA to identify and
      investigate barriers and to foster enrollment of those beneficiaries in the
      Medicare buy-in programs. SSA is requesting public comment about these plans and
      soliciting States to express their interest in participating in this
      demonstration.

PMID- 10339049
TI  - Medicare program; limited additional opportunity to request certain hospital wage
      data revisions for FY 1999--HCFA. Final rule with comment period.
AB  - This final rule with comment period provides hospitals with a limited additional
      opportunity to request certain revisions to their wage data used to calculate the
      FY 1999 hospital wage index. In addition, it explains the criteria that must be
      met to request a revision, the types of revisions that will be considered, the
      procedures for requesting a revision, the implementation of wage index revisions,
      and other related issues. Requests for wage data revisions must be received by
      the date and time specified in the "DATES" section of this preamble. We will
      implement revisions to the hospital wage index in accordance with this final rule
      with comment period on a prospective basis only.

PMID- 10339050
TI  - Medicaid program; inpatient psychiatric services benefit for individuals under
      age 21--HCFA. Final rule.
AB  - This final rule amends the CFR by adding a choice of accreditation organizations
      that a State Medicaid agency may use to fulfill the requirement for Medicaid
      approval of, and payment to, psychiatric facilities other than psychiatric
      hospitals or psychiatric units of acute care hospitals, that provide the
      "inpatient psychiatric services benefit for individuals under age 21". In
      response to comments received on a prior proposed rule, we are retaining the
      requirement for accreditation of psychiatric facilities, but we are offering
      alternatives to accreditation by the Joint Commission on Accreditation of Health
      Care Organizations. Accreditation of psychiatric facilities, other than
      psychiatric hospitals and psychiatric units in acute care hospitals, could be
      performed by the Council on Accreditation of Services for Families and Children,
      the Commission on Accreditation of Rehabilitation Facilities, or any other
      accrediting body with comparable standards that is recognized by the State. This
      change is being made while we continue to develop HCFA standards for psychiatric
      facilities based on our evaluation of the comments that we received on the
      proposed standards that were published in the NPRM. All of the comments on the
      remaining provisions of the proposed rule will be addressed in a second final
      rule to be published at a future date.

PMID- 10339051
TI  - Bioavailability and bioequivalence requirements; abbreviated applications;
      proposed revisions--FDA. Proposed rule.
AB  - The Food and Drug Administration (FDA) is proposing to revise its regulations on
      bioavailability and bioequivalence and on the content and format of an
      abbreviated application to reflect current FDA policy and to correct certain
      typographical and inadvertent errors. This action is intended to improve the
      accuracy and clarity of the regulations.

PMID- 10339052
TI  - Dissemination of information on unapproved/new uses for marketed drugs,
      biologics, and devices--FDA. Final rule.
AB  - The Food and Drug Administration (FDA) is issuing final regulations pertaining to
      the dissemination of information on unapproved uses (also referred to as "new
      uses" and "off-label uses") for marketed drugs, including biologics, and devices.
      The final rule describes the new use information that a manufacturer may
      disseminate and describes the content of and establishes procedures for a
      manufacturer's submission to FDA before it may begin disseminating information on
      the new use. The final rule also describes how manufacturers seeking to
      disseminate information on a new use must agree to submit a supplemental
      application for that use within a specified period of time, unless a supplemental
      application already has been submitted or FDA has exempted the manufacturer from
      the requirement to submit a supplement. The final rule provides for requests to
      extend the time period for submitting a supplemental application for a new use
      and describes how a manufacturer can seek an exemption from the requirement to
      submit a supplemental application for the new use. Additionally, the final rule
      discusses FDA actions in response to manufacturers' submissions, corrective
      actions that FDA may take or require, and recordkeeping and reporting
      requirements. The final rule implements sections 551 through 557 of the Federal
      Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360aaa through 360aaa-6) as
      amended by section 401 of the Food and Drug Administration Modernization Act of
      1997 (FDAMA).

PMID- 10339053
TI  - National Practitioner Data Bank for Adverse Information on Physicians and Other
      Health Care Practitioners: medical malpractice payments reporting requirements-
      HRSA. Notice of proposed rulemaking.
AB  - This Notice of Proposed Rulemaking (NPRM) proposes amendments to the existing
      regulations implementing the Health Care Quality Improvement Act of 1986,
      establishing the National Practitioner Data Bank for Adverse Information on
      Physicians and Other Health Care Practitioners (the Data Bank). The proposed
      regulations would amend the existing reporting requirements regarding payments on
      medical malpractice claims or actions in order to include reports on payments
      made on behalf of those practitioners who provided the medical care that is the
      subject of the claim or action, whether or not they were named as defendants in
      the claim or action. These amendments are designed to prevent the evasion of Data
      Bank medical malpractice payments reporting requirements.

PMID- 10339054
TI  - Medicare and Medicaid programs; recognition of the Commission for Accreditation
      of Rehabilitation Facilities--HCFA. Notice with comment period.
AB  - This notice announces and invites comments on the receipt of an application from
      the Commission for Accreditation of Rehabilitation Facilities for recognition as
      a national accreditation organization with deemed status authority. The Social
      Security Act requires us to publish this notice in which we identify the national
      accreditation body making the application, describe the nature of the request,
      and provide a 30-day public comment period. The intent of this notice is to
      solicit public comment as to the advisability of recognizing the Commission for
      Accreditation of Rehabilitation Facilities as a national accreditation
      organization with deeming authority to survey and accredit comprehensive
      outpatient rehabilitation facilities for participation in the Medicare or
      Medicaid programs.

PMID- 10339055
TI  - Dental devices; effective date of requirement for premarket approval;
      temporomandibular joint prostheses--FDA. Final rule.
AB  - The Food and Drug Administration (FDA) is issuing a final rule to require the
      filing of a premarket approval application (PMA) or a notice of completion of a
      product development protocol (PDP) for certain devices, namely, the total
      temporomandibular joint (TMJ) prosthesis, the glenoid fossa prosthesis, the
      mandibular condyle prosthesis (for permanent reconstruction), and the
      interarticular disc prosthesis. At a later date, FDA will propose reclassifying
      from class III into class II the generic type of temporary mandibular condyle
      prosthesis intended for temporary reconstruction following surgical ablation of
      malignant and benign tumors. This action establishing the effective date of the
      premarket approval requirement for certain devices is being taken under the
      Federal Food, Drug, and Cosmetic Act (the act), as amended by the Medical Device
      Amendments of 1976 (the 1976 amendments), the Safe Medical Devices Act of 1990
      (the SMDA), and the FDA Modernization Act of 1997 (FDAMA).

PMID- 10339056
TI  - Health Care Fraud and Abuse Data Collection Program: reporting of final adverse
      actions--extension of comment period--OIG, HHS. Notice of proposed rulemaking;
      extension of comment period.
AB  - On October 30, 1998, we published a notice of proposed rulemaking designed to set
      forth the policy and procedures for implementing the new Healthcare Integrity and
      Protection Data Banks (HIPDB), in accordance with the statutory requirements of
      section 1128E of the Social Security Act, as added by section 221(a) of the
      Health Insurance Portability and Accountability Act (HIPAA) of 1996 (63 FR
      58341). We are extending the comment period at the request of several
      organizations.

PMID- 10339057
TI  - Privacy Act of 1974; republication of systems of records--Consumer Product Safety
      Commission. Republication and revision of systems of records.
AB  - The Consumer Product Safety Commission is republishing its Privacy Act systems of
      records with certain changes, additions, and deletions.

PMID- 10339058
TI  - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); TRICARE
      claimcheck appeals--DOD. Notice.
AB  - This Notice sets forth the Department's plans for enhancing the appeals process
      available to providers and beneficiaries for claims determinations resulting from
      TRICARE Claimcheck coding logic.

PMID- 10339059
TI  - Now, the hard part. Medicare has long defied attempts to reform it.

PMID- 10339060
TI  - Clinton and tobacco: what now?

PMID- 10339061
TI  - Claiming the clinical--strategies for enhancing the social work role in case
      management.

PMID- 10339062
TI  - Spirituality in medical training: where biography meets biology.

PMID- 10339063
TI  - Care at the end of life: Oregon's Death with Dignity Act.

PMID- 10339064
TI  - The role of the performance appraisal process in pharmacy management today.

PMID- 10339065
TI  - Situational factors as predictors of pharmaceutical care in a community setting:
      an application of the adaptive decision-making model.
AB  - Various situational factors are perceived to affect the level of pharmaceutical
      care (PC) delivery. Despite numerous discussions in the literature stating its
      importance, a literature search showed a lack of studies evaluating this
      relationship. The objective of this study was to determine the affect of the
      presence of situational factors, based on the adaptive decision making (ADM)
      model, on the level of pharmaceutical care delivered by pharmacists in a
      community setting. Pharmacists in a community setting with access to hypertensive
      patients were selected for study participation. An exploratory, cross-sectional
      study was used to acquire pharmacist self-perception of the level of PC delivered
      (dependent variable) in the state of Ohio.

PMID- 10339067
TI  - Formulary management in an integrated health care system.

PMID- 10339066
TI  - A pharmacy plan for the hospital.

PMID- 10339069
TI  - Leveraging high touch human resource management.

PMID- 10339068
TI  - A medication use evaluation of alendronate: compliance with administration
      guidelines.

PMID- 10339070
TI  - "Cyber-health:" top 10 trends for health care information systems and technology.

PMID- 10339071
TI  - The "value question": investing in IS/IT is the bridge to the 21st century.

PMID- 10339072
TI  - Top 10 trends for health care information systems.

PMID- 10339073
TI  - Integration trend gains steam: how to avoid pitfalls when disciplines merge.
AB  - If your hospital hasn't already collapsed social work, utilization review,
      discharge planning, and other disciplines into case management, it's probably
      just a matter of time before it does, experts say. And whether or not the
      integration effort succeeds depends largely on the real motivation behind it.
      Simply mashing case management and utilization review together in an effort to
      cut costs--and corners--is likely to result in tension among all disciplines
      involved and may not be in the best interests of patients. At University Hospital
      in Denver, the case management team has partnered with the Office of Clinical
      Practice to form a unit that preserves the integrity of both case managers and
      quality managers while giving each group a better perspective on how their roles
      interrelate.

PMID- 10339074
TI  - Study says discharge instructions are poor.

PMID- 10339075
TI  - Written process ensures proper materials review.

PMID- 10339076
TI  - CMs, social workers thrive under triad model.
AB  - Faced with a case-mix index they knew was too low for their facility,
      administrators at Vanderbilt University Hospital in Nashville, TN, set about
      formulating a new, integrated case management model stressing that case
      management is a process rather than a role. Under the new model, the hospital's
      old-fashioned utilization review department was brought out of the basement and
      transformed into a team of utilization management/DRG management professionals
      who perform concurrent chart reviews and actively manage DRGs, making sure
      supporting documentation adequately reflects patient severity. The model, based
      on "triads" of case managers, social workers, and UM staff, allows for some
      flexibility when responsibilities overlap, yet each professional maintains a
      separate and distinct focus within the group.

PMID- 10339077
TI  - Renal transplantation path saves $34K per patient.
AB  - A renal transplantation clinical pathway used at the Hospital of the University
      of Pennsylvania in Philadelphia has cut length of stay from 12 days to nine and
      resulted in an overall savings of $33,636 per patient. Given the hospital's
      average annual volume of 125 renal transplant patients, that's a savings of more
      than $4.2 million per year. Team members attribute much of the success of the
      pathway to standardized order sheets. Because the care of renal transplant
      patients is complicated and residents change every month, it was important to
      maintain documents that allowed for continuity of care. The pathway includes a
      sheet that provides an overview of the patient's progress during the acute care
      stay. The overview allows those unfamiliar with the pathway to understand what is
      happening with the patient.

PMID- 10339078
TI  - Diabetes pathway slashes length of stay by 26%.
AB  - The diabetes pathway at Spohn Memorial Hospital in Corpus Christi, TX, developed
      alongside the diabetes program it complements, has cut health care costs for
      diabetic patients by 68% while also cutting readmissions by 33% and length of
      stay by 26%. Based on standards set by the Alexandria, VA-based American Diabetes
      Association, the pathway can be customized to meet the needs of each patient
      based on his or her level of risk of complications. One key to the success of the
      overall diabetes program was the establishment of a specially designed clinic
      that provides all necessary services for patients in a single location.

PMID- 10339079
TI  - Fast-tracking clinical pathway redesign, Part II.

PMID- 10339080
TI  - Heading for the exits? At a time when major and regional health plans are
      abandoning risk contracts ....

PMID- 10339081
TI  - Hill Physicians: staying independent in a tumultuous market.

PMID- 10339082
TI  - The move toward primary care. One specialty care provider seeks integration
      toward primary care. Which customers will accept the shift?
AB  - This study focuses on an OB/GYN's strategic reaction to the ever-changing health
      care environment and its attempt to transform itself from a specialty care to a
      primary care provider. This study focuses on the clinic's search for information
      as to which, if any, of its current OB/GYN clients would be most likely to
      utilize new primary care services. The study found single mothers, frequent users
      of the clinic's current services, and those clients who have personal physicians
      were more likely to try the clinic's new primary care services. Advertising
      seemed to have no effect on the current clients' likelihood of utilizing the
      clinics new services.

PMID- 10339083
TI  - Managing physicians. More doctors are turning to management companies for
      assistance in the changing health care environment.

PMID- 10339084
TI  - Persuasive messages. Development of persuasive messages may help increase
      mothers' compliance of their children's immunization schedule.
AB  - Effective immunization campaigns can be designed by determining which persuasion
      strategy is most effective in attracting the attention of mothers of
      preschoolers. The authors assess the impact of three persuasional strategies:
      fear-arousal, motherhood-arousal, and rational messages, on mothers of
      preschoolers who are late for their immunizations. The fear-arousal message was
      found to be most effective, followed by the motherhood-arousal, and then the
      rational message, in attracting mothers' attention to their child's immunization
      status.

PMID- 10339085
TI  - Increasing consumer satisfaction. One social service and public health initiative
      shows how social marketing can increase consumer satisfaction.
AB  - The key to a successful social marketing approach to health care is continually
      listening to consumers' feedback and being willing to change the health product
      or service according to their needs and preferences. This approach can increase
      the likelihood of consumers being satisfied with, and continuing to utilize or
      provide the particular health service.

PMID- 10339086
TI  - Hospital marketing and the Internet: revisited.
AB  - In 1995 a study was conducted to explore the use of the Internet in hospital
      marketing. Use of the Internet has exploded since that study was published. This
      manuscript replicates the 1995 study and extends it by investigating several
      managerial and operational issues concerning the use of the Internet in hospital
      marketing.

PMID- 10339087
TI  - Total quality commitment and performance in Canadian health care organisations.
AB  - Although many organisations have in recent years installed TQ programs, many have
      been unable to realize significant performance enhancements. Results from a
      diverse sample of Canadian health care organisations suggest that merely having a
      TQ program is insufficient for attaining selected performance improvements.
      Health care organisations which have both a formal TQ program and a deep
      commitment to quality improvement are perceived to perform better on a number of
      valued outcomes.

PMID- 10339089
TI  - Clinical and managerial quality.

PMID- 10339088
TI  - Antimicrobial resistance: the threat to health and health care.
AB  - This article addresses antimicrobial resistance and the threat it poses to an
      individual's health and the health care system. Diseases, such as pneumococcus
      have gained an overabundance of antimicrobial resistance. In addition, previously
      unknown diseases are surging and sounding alarm bells worldwide. The history and
      causes of this surge are examined globally. One such cause is the overuse of
      antibiotics in long-term care facilities. International strategies that have been
      implemented by organizations, such as the World Health Organization, to control
      the spread of infectious diseases, are also reviewed. The prevalence, causes and
      consequences of antibiotic resistant organisms, are found in long-term care
      facilities and hospitals specifically in Canada, are reviewed. Recommendations
      are made.

PMID- 10339091
TI  - Referral to a psychiatric clinic: what do patients expect?
AB  - Examines the knowledge and expectations of patients newly referred to one
      hospital psychiatric clinic. A total of 57 adults completed a structured
      questionnaire before their first outpatient appointment. The casenotes of all 45
      non-anonymous respondents were reviewed six months later, to discover how their
      expectations regarding management compared with reality. Forty-four (77 per cent)
      referrals expected to see a doctor who dealt with mental health and emotional
      problems, 41 (72 per cent) anticipated that their problem was treatable, and 41
      (72 per cent) wanted, primarily, a chance to talk. Thirty-four respondents (61
      per cent) significantly underestimated their actual appointment duration.
      Patients received psychotropic medication or were referred to another mental
      health professional twice as often as they expected. Nevertheless, 25 out of 35
      patients (71 per cent) correctly predicted their broad clinical management.
      Patients are becoming more informed users of mental health care services.
      Addressing their attitudes and expectations directly at the first outpatient
      attendance may help in predicting final clinical outcome, and assist in the
      efficient management of limited resources.

PMID- 10339090
TI  - Determinants of customer satisfaction with hospitals: a managerial model.
AB  - States that rapid changes in the environment have exerted significant pressures
      on hospitals to incorporate patient satisfaction in their strategic stance and
      quest for market share and long-term viability. This study proposes and tests a
      five-factor model that explains considerable variation in customer satisfaction
      with hospitals. These factors include communication with patients, competence of
      the staff, their demeanour, quality of the facilities, and perceived costs; they
      also represent strategic concepts that managers can address in their bid to
      remain competitive. A probability sample was selected and a multiple regression
      model used to test the hypotheses. The results indicate that all five variables
      were significant in the model and explained 62 per cent of the variation in the
      dependent variable. Managerial implications of the proposed model are discussed.

PMID- 10339092
TI  - Physician outcome measurement: review and proposed model.
AB  - As health care moves from a free-for-service environment to a capitated arena,
      outcome measurements must change. ABC Children's Medical Center is challenged
      with developing comprehensive outcome measures for an employed physician group.
      An extensive literature review validates that physician outcomes must move beyond
      revenue production and measure all aspects of care delivery. The proposed
      measurement model for this physician group is a trilogy model. It includes
      measures of cost, quality, and service. While these measures can be examined
      separately, it is imperative to understand their integration in determining an
      organization's competitive advantage. The recommended measurements for the
      physician group must be consistent with the overall organizational goals. The
      long-term impact will be better utilization of resources. This will result in the
      most cost effective, quality care for the health care consumer.

PMID- 10339094
TI  - Quality at the core.

PMID- 10339093
TI  - Risky business: pre-powdered gloves or powder-free gloves in the operating suite?
AB  - Two of the emerging issues for the health-care sector in the 1990s are
      occupational health and safety, and iatrogenic issues. Both of these issues are
      implicated in the use of pre-powdered latex gloves. Hospital health-care workers
      are exposed to latex in many ways: gloves, intravenous sets, ventilator circuits,
      dental products, resuscitation equipment, anaesthetic equipment. Post-operative
      complications, delayed wound healing, scar formation, and the potential for
      misdiagnosis, in the presence of starch powder, have been well documented in the
      literature with the need for through glove rinsing prior to surgery. Another
      route for glove powder to enter wounds is through a barrier breach. For an
      institution to ensure it provides the most durable and effective barrier for
      healthcare worker protection and patient safety, knowledge is needed regarding
      the various factors which lead to glove barrier failure. The primary aim of the
      study was to evaluate the in-use durability of the surgical gloves in current use
      against powder-free gloves. Descriptive statistics were used to analyse the data,
      in addition a cost analysis was calculated. The results of this study
      demonstrated clinically important differences between existing glove products in
      terms of barrier quality.

PMID- 10339095
TI  - Organisational effectiveness within National Health Service (NHS) Trusts.
AB  - In view of the dearth of information relating to organisational effectiveness of
      NHS Trusts in comparison with clinical effectiveness, a complex study was
      undertaken to determine whether overall effectiveness was a result of management
      processes, people, or a combination of both. The study incorporated two phases
      involving the distribution of a comprehensive questionnaire to identify the
      "whats" of organisational effectiveness, and a bench-marking exercise aimed at
      identifying the "hows". In the main, the better performing trusts were found to
      be subscribing to the concepts of "keeping it simple", innovation and attainment
      of highly efficient processes. A number of examples of better/best practices were
      observed which included visible leadership, a commitment towards stakeholder
      involvement and the practice of teamworking. Given the complexity of the study
      area, the findings were deemed valuable to managers practising within all areas
      of healthcare. However, a need for further research was identified in order to
      substantiate the results.

PMID- 10339096
TI  - Quality and cost impacts: prevention of post-operative clean wound infections.
AB  - This paper report the effectiveness of a nursing quality assurance program over
      three years, which demonstrates improvement in the incidence and severity of post
      operative clean wound infections and the associated extended length of hospital
      stay and cost. General surgery categories included cardiovascular, orthopaedic,
      neurosurgery, kidney, abdominal, mammary and other. Cardiovascular categories
      included coronary artery bypass graft (CABG), heart transplant, and atrial valve
      replacement. Hip replacement and total knee replacement procedures were included
      in the orthopaedic category. Additional length of stay and concomitant hospital
      costs were calculated. Results show that early reporting of observations and
      implementation of appropriate treatment will decrease the incidence, severity and
      associated costs of post-operative clean wound infections.

PMID- 10339097
TI  - Measuring risk in a children's unit: developing a local strategy for health,
      safety and risk management at Queen's Medical Centre, Nottingham.
AB  - This article demonstrates the Queen's Medical Centre approach to assessing and
      addressing risk in terms of Health and Safety within a busy children's unit. This
      article focuses on compartmentalising a large clinical area on two floors of a
      busy teaching hospital which become manageable sized subunits; each has a health,
      safety and risk management link person who attends the regular meetings to
      discuss key issues. These link people, with experience and training observe
      clinical areas within the zone, for hazards and potential hazards (risk
      inspection) and then calculate the hazard on a risk score. This is then risk
      assessed and all risk prioritised within the Children's Services Directorate
      Team. The author describes how a proactive approach to health, safety and risk
      management has brought about significant improvements, enhanced quality of care
      and improved morale and motivation of the nursing team.

PMID- 10339098
TI  - Planned and reported implementation of clinical practice guidelines.
AB  - The aim of this project was to compare the intentions with reported action of
      Health Trusts in Scotland to prioritise and implement published SIGN clinical
      guidelines. All health Trusts in Scotland were asked about plans for
      implementation, and resurveyed 15-18 months later for confirmation. Specific
      guideline implementation groups led by medical doctors were the most common
      implementation structure. Implementation usually consisted of baseline audit,
      development of a local version, and reaudit. In one case a successful link
      between acute and primary care through an area level GP audit facilitator was
      thought to increase implementation. More research is required to: find out what
      influences the ability of an organisation to implement guidelines; identify
      particular facilitating factors or barriers; and on factors influencing the
      ability of a health organisation to implement guidelines.

PMID- 10339099
TI  - Trends in costs of percutaneous transluminal coronary angioplasty.
AB  - OBJECTIVE: To evaluate recent trends in the cost of percutaneous transluminal
      coronary angioplasty (PTCA), particularly the impact of newer technology and
      changing patient profile. STUDY DESIGN: Retrospective study with a 6-month follow
      up. PATIENTS AND METHODS: We compared the data on two groups of 100 consecutive
      patients admitted for elective PTCA at Yale-New Haven Hospital in 1995 and 1996.
      Hospital records, cineangiograms, and hospital cost accounting system were
      reviewed, and 6-month clinical outcomes were obtained from telephone interviews
      and medical chart review. RESULTS: Demographic and clinical characteristics did
      not differ between the 1995 and 1996 groups of patients, nor was a difference
      detected in in-hospital and 6-month clinical outcomes between 1995 and 1996.
      Angiographic features of treated lesions were different between the two groups,
      with a significantly higher frequency of type C and totally occluded lesions in
      1996 (p = 0.002 and p = 0.04, respectively). The total hospital costs were higher
      in 1996 compared with 1995 ($11,799 +/- $6189 vs $10,087 +/- $5608; p = 0.04).
      This difference persisted after adjustment for changes in patient population. The
      major factor responsible for escalating costs was a 45% increase in
      catheterization laboratory costs ($8575 +/- $4524 in 1996 vs $5916 +/- $3030 in
      1995; P < 0.0001). In contrast, the noncatheterization costs decreased
      substantially during this period, largely as a result of an approximately 33%
      decrease in length of stay (3.75 +/- 2.66 days in 1995 vs 2.57 +/- 1.99 days in
      1996; P = 0.0005). In a multiple linear regression model, the most important
      determinants of cost were lesion characteristics, stent use, and radiographic
      contrast volume. CONCLUSIONS: Despite cost reduction efforts, the costs of PTCA
      are rising because of increased consumption of resources in the catheterization
      laboratory.

PMID- 10339100
TI  - Anthem Blue Cross and Blue Shield's coronary services network: a managed care
      organization's approach to improving the quality of cardiac care for its members.
AB  - OBJECTIVE: To describe a managed care organization's efforts to improve value for
      its members by forming a coronary services network (CSN). DESIGN: To identify
      high-quality facilities for its CSN, Anthem Blue Cross and Blue Shield reviewed
      claims data and clinical data from hospitals that met its general quality
      standards. An external firm measured and risk-adjusted applicant hospitals'
      mortality rates. Hospitals that demonstrated superior performance were eligible
      to join the CSN. In 1996, 2 years after the CSN was formed, clinical outcomes of
      participants and new applicants were analyzed again by the same external firm.
      PATIENTS AND METHODS: Data on more than 10,000 consecutive (all-payer) inpatients
      discharged after coronary bypass surgery in 1993 were collected from 16 applicant
      hospitals using a uniform format and data definitions. This analysis was expanded
      to 23 participating and applicant hospitals that discharged more than 13,000
      patients who underwent either bypass surgery or coronary revascularization in
      1995. We compared risk-adjusted routine length of stay (a measure of efficiency),
      mortality rates, and adverse outcome rates between CSN and non-CSN facilities.
      RESULTS: From 1993 to 1995, overall length of stay in the network decreased by
      20%, from 12.3 to 9.8 days (P < or = 0.01) and severity-adjusted mortality rates
      decreased by 7.3%, from 2.9% to 2.7%. Initially, facilities outside the network
      had comparable efficiency but much higher mortality. However, they improved so
      much in both measures that their severity-adjusted mortality rate for bypass
      surgery in 1995 was no more than 10% higher than that of CSN hospitals.
      CONCLUSION: The creation of a statewide CSN that emphasized and improved the
      level of performance among providers ultimately benefited the carrier's managed
      care members. The desirability of participation was evidenced by an increase in
      the number of applicant hospitals over the 2 years. This may have stimulated
      quality improvement among competing providers in the region and among CSN
      facilities themselves.

PMID- 10339101
TI  - Relationship of compliance with hormone replacement therapy to short-term
      healthcare utilization in a managed care population.
AB  - OBJECTIVE: To identify healthcare utilization characteristics that distinguish
      female members of a managed care organization (MCO) who remained compliant with
      hormone replacement therapy (HRT) from those who had poor compliance during an 18
      month period and to estimate the cost of HRT to an MCO. STUDY DESIGN: A
      retrospective cohort design in a population of continuously enrolled female
      members of an MCO. METHODS: All female members of the Lovelace Health Plan 40
      years of age or older who began HRT between January 1, 1993, and June 30, 1994 (n
      = 1158). Compliance was determined by calculating an estrogen medication
      possession ratio based on pharmacy fills over 18 months. "High compliers" (n =
      427) were defined as those purchasing at least 80% of their recommended days
      supply, and "low compliers" (n = 269) as those purchasing less than 20%.
      Healthcare encounters and costs of high and low compliers were compared. RESULTS:
      High compliers were younger (P < 0.01), more likely to be non-Hispanic white than
      Hispanic (P < 0.0001), and had higher costs for obstetric/gynecologic care (P <
      0.0001) and non-HRT prescriptions (P < 0.0001). Low compliers had higher point
      estimates of costs and encounters for all other categories of care, but
      differences were statistically significant only for emergency department visits
      (P < 0.001). CONCLUSIONS: The added cost of HRT did not result in higher total
      healthcare utilization and costs, as women who complied well with therapy had
      decreased utilization and costs in other categories of care. Differences in
      subcategories of healthcare utilization suggest that level of HRT compliance
      reflects differences in how women access healthcare.

PMID- 10339103
TI  - Managed care clinical corner: evaluation of anemia.

PMID- 10339102
TI  - Does length of hospital stay during labor and delivery influence patient
      satisfaction? Results from a regional study.
AB  - OBJECTIVE: To examine the relationship between patients' satisfaction with
      hospital obstetric care, length of stay, and patients' perceived appropriateness
      of the length of stay. STUDY DESIGN: A cross-sectional study. PATIENTS AND
      METHODS: We surveyed 27,789 women (a 58% response rate) discharged after labor
      and delivery from 18 hospitals in a large metropolitan region from 1992 through
      1994. Patient satisfaction was assessed using the Patient Judgment System, a
      previously validated instrument. Our analysis focused on four scales evaluating
      specific aspects of care (physician care, nursing care, provision of information,
      and preparation for discharge) and two single-item indicators of satisfaction
      (overall quality and willingness to return to the hospital). RESULTS: Patients
      with shorter lengths of stay were more likely (P < 0.001) to perceive their stays
      as "too short." In addition, the six measures of satisfaction were lower (P <
      0.001) in patients who perceived their stays as too short. However, the
      hypothesized lower satisfaction in patients with shorter stays was not observed;
      differences in satisfaction according to length of stay were small and of
      questionable practical significance. CONCLUSION: The findings suggest that
      patients' satisfaction with obstetric care may not depend on the absolute
      duration of stay but rather on whether patients perceive the length of stay to be
      adequate. The results are timely because of recent legislation that mandates
      minimum hospital stays for labor and delivery.

PMID- 10339104
TI  - The role of clinical practice guidelines in disease management.
AB  - This activity is designed for medical directors, pharmacy directors, quality
      assurance managers, and all members of disease management or quality improvement
      teams. GOAL: To review the guideline literature and help healthcare organizations
      plan guideline development and implementation strategies. OBJECTIVES: 1. Clarify
      the terminology used in practice policy development. 2. Explain how guideline
      implementation is related to disease management. 3. Discuss interventions
      utilized to enhance guideline adoption. 4. Provide a stepwise plan for healthcare
      organizations to follow.

PMID- 10339105
TI  - Pharmacist compensation for ambulatory patient care services.
AB  - This activity is designed for pharmacists practicing in ambulatory, community,
      and managed care environments. GOAL: To discuss issues involved in the transition
      from product-based to patient-care-based reimbursement and compensation systems
      for pharmacists. OBJECTIVES: 1. Differentiate between reimbursement and
      compensation. 2. Describe the limitations of current third-party reimbursement
      and compensation systems. 3. Describe ways in which compensation for seemingly
      identical products and services can vary. 4. Discuss the use of Medicare's
      Resource-Based Value Scale and the relative value unit. 5. Define and
      differentiate between ICD-9-CM codes and E/M CPT codes. 6. List the three key
      components needed to determine an E/M CPT code for a new patient seen in the
      pharmacy. 7. Describe and provide examples of the SOAP method of documentation.
      8. Understand why the referral process is an important step in the compensation
      process. 9. Discuss the importance of Form HCFA-1500 and other documentation in
      the compensation process.

PMID- 10339106
TI  - Barriers to guideline adherence. Based on a presentation by Michael Cabana, MD.
AB  - Successful implementation of the Sixth Report of the Joint National Committee on
      Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI)
      should improve quality of care by decreasing inappropriate variation and by
      disseminating new advances to everyday practice. A key component of this process
      is physician adherence to JNC-VI guidelines. However several reports in the
      literature show a discrepancy between hypertension guidelines and actual
      practice. The factors that influence physician behavior change and optimal use of
      practice guidelines are poorly understood. A combined model that uses the
      Awareness-to-Adherence Model and Social Cognitive Theory identifies five
      sequential steps that lead to adherence to a guideline--awareness, agreement,
      self-efficacy, outcome expectancy, and presence of a cueing mechanism. Barriers
      to implementation may occur at any of these steps and can be identified with this
      model. Programs can then be designed to overcome specific barriers. By
      conceptualizing the underlying issues in physician adherence, the combined model
      should be useful to guideline developers, practice directors, and health services
      researchers.

PMID- 10339107
TI  - Hypertension and managed care. Based on a presentation by Robert P. Jacobs, MD,
      MBA.
AB  - A shift in principles has accompanied the evolution of healthcare delivery from a
      fee-for-service system to managed care. Managed care organizations have to make
      decisions on the allocation of healthcare resources that will enhance the care of
      the entire population. Cost reduction has been a major driver for managed care,
      but this is increasingly being supplanted by other goals such as increasing the
      quality of care and the value of health services and providing accountability. As
      the population ages, management of chronic lifelong illness will pose an
      increasing challenge. Hypertension is a common chronic illness that, if left
      untreated, imposes an enormous economic burden on society. These and other
      aspects of the disease and its management make it eminently suitable for
      intervention in a managed care setting. Challenges and opportunities exist for
      disease management initiatives for hypertension in the managed care environment.
      As health plans enhance their data systems and begin to focus on the long-term
      benefits of chronic disease management, hypertension will certainly be an early
      target for intervention and control.

PMID- 10339108
TI  - Cost effectiveness of intensive treatment of hypertension. Based on presentations
      by Donald S. Shepard, PhD; and Dominic Hodgkin, PhD.
AB  - The Hypertension Optimal Treatment (HOT) study showed that substantial reductions
      in blood pressure and a corresponding lowering of the risk of myocardial
      infarction could be achieved by intensive antihypertensive therapy. A cost
      effectiveness analysis was performed to determine the possible economic
      consequences of three different targets of diastolic blood pressure lowering--<
      or = 90 mm Hg, < or = 85 mm Hg, and < or = 80 mm Hg, and of the coadministration
      of aspirin. The cost of each drug was first estimated at high and low dosage.
      Next, by drawing on data from the HOT trial, the mixture and dosage of drugs for
      each level of blood pressure control were estimated. This allowed computation of
      the annual cost of drugs for each blood pressure target. Because the rate of
      myocardial infarction (MI) was the only endpoint that differed significantly
      among the three target blood pressure groups, the MI risk data were converted
      into years of life gained on the basis of fatalities from MI averted. The cost
      effectiveness ratios, expressed as cost per year of life gained, were most
      favorable for the < or = 90-mm Hg treatment target group ($4262) and for added
      aspirin treatment ($12,710). For moderately aggressive treatment (blood pressure
      < or = 85 mm Hg), the cost-effectiveness ratio escalated incrementally to $86,360
      and with intensive treatment to $658,370 per year of life gained. Thus treatment
      to a target of 90 mm Hg and coadministering aspirin were considered highly cost
      effective, whereas treatments to lower the blood pressure further to 85 mm Hg
      were marginally cost effective; intensive blood pressure lowering down to 80 mm
      Hg was not cost effective.

PMID- 10339109
TI  - New philosophy and concepts of care: the supportive care model.

PMID- 10339110
TI  - Why good people do bad things to the helpless.

PMID- 10339111
TI  - Conscientious objection: a thorny issue for health care providers.

PMID- 10339112
TI  - Pastoral counselling or pastoral care counselling.

PMID- 10339113
TI  - Hospital system creates compelling alternative to GPO.

PMID- 10339114
TI  - Disease management programs help cut costs, improve care.
AB  - So you think a disease management program could improve the cost picture at your
      integrated health network? You're probably right, but finding a good starting
      point may be tougher than many administrators think. Learn how one health plan in
      Georgia made a mistake in its first foray, then finally got a road map that
      showed it the best path to savings.

PMID- 10339115
TI  - Study ranks most efficient hospitals by state, targets 1996 Medicare LOS data.
AB  - DATA BENCHMARK: Study ranks most efficient hospitals by state. National
      consulting firm Milliman & Robertson identifies one or more hospitals in each
      state as efficient providers based on length of stay for Medicare admissions. See
      how your facility measures up by comparing your LOS with LOS at some of the
      country's most efficient hospitals.

PMID- 10339116
TI  - No clear Y2K roadmap can be costly; may create serious liability.
AB  - Hospitals without Year 2000 plans in place could be setting themselves up for
      costly equipment failure. Learn what the experts say about prioritizing to ensure
      patient care isn't disrupted, and find out about testing medical devices and
      equipment for Y2K compliance, and what to consider when setting up a Y2K analysis
      program in your hospital, including how to ensure vendors tell you the truth
      about whether their products are Y2K compliant.

PMID- 10339117
TI  - Medicare plans to measure, report provider performance.

PMID- 10339118
TI  - Hospital-based system uses hands-on education program to improve senior care.
AB  - Want to improve your clinical performance? Learn how to conduct quality
      improvement projects like Henry Ford Health System in Detroit. And see how one
      geriatric nurse changed how her hospital cares for seniors with urinary tract
      infections.

PMID- 10339119
TI  - New risk-adjusted Medicare payment system promises more accurate patient
      profiles.
AB  - Use your knowledge of PIP-DCGs to bolster rate negotiations with your plan. A
      researcher with experience in operating a plan under Medicare's new risk-adjusted
      payment methodology reveals what you need to know about principal inpatient
      diagnostic cost groups.

PMID- 10339120
TI  - High disenrollment rates persist among Medicare risk plans.
AB  - Data File: Would you expect to succeed in Medicare risk if your plan had a 71%
      annual disenrollment rate? The U.S. General Accounting Office conducts another
      study on beneficiary disenrollment from Medicare plans and finds high annual
      disenrollment rates still persist.

PMID- 10339122
TI  - Successful DM programs give physicians the lead role.

PMID- 10339121
TI  - Rate cuts, lack of state action kill Medicaid-only PSO.
AB  - Providers learn from a Medicaid plan that didn't survive. When the University of
      Chicago started its Family First Medicaid plan, that health system thought it
      could retain its Medicaid patients by offering members a good benefit package
      with top-notch customer service, and even attract more patients when the state
      went to mandatory managed care enrollment. But two years later, the provider
      sponsored plan is gone. Find out what went wrong.

PMID- 10339123
TI  - Asthma program targets patient and physician compliance; wins first DM excellence
      award.
AB  - When motivated with financial incentives and aided by office resources and tools,
      PCPs write more appropriate prescriptions and manage the care of asthma patients
      much better, as this award-winning disease management program proved.

PMID- 10339124
TI  - Medicare coverage changes force a DM approach to ESRD.
AB  - The cost of managing patients with chronic renal disease is staggering, and as
      much of the cost of care for ESRD patients shifts to manage care, new disease
      management strategies are proving instrumental.

PMID- 10339125
TI  - Program finds a better way to manage breast cancer.
AB  - Women faced with a breast cancer diagnosis often find that inattention to their
      psychosocial needs is nearly as problematic as the disease itself. Find out how
      this model breast cancer program fills that void.

PMID- 10339126
TI  - Analysis of claims data provides extra punch for disease management efforts.
AB  - Prescription drug costs in managed care plans continue rising rapidly, but this
      disease management vendor is using patient- and practice-specific data analysis
      to show how modifications in drug management can improve the patient's clinical
      outcome and the health plan's bottom line.

PMID- 10339127
TI  - Will at-risk providers finally cover their tails?

PMID- 10339128
TI  - Hospitalists deliver high performance for capitated provider groups.

PMID- 10339129
TI  - Tackle these 'top 10' risk contracting challenges.
AB  - Data Insight: Does the effort to gather credible eligibility data from payers
      leave you dazed? Do skeptical physicians rebuff your attempts to promote
      capitation? You're not alone.

PMID- 10339130
TI  - Adopting guidelines improves quality of care while reducing provider liability.
AB  - A new report suggests that aggressive implementation of clinical guidelines
      reduces costs while enhancing patient safety--data that offer 'broad and sweeping
      implications' for capitated providers.

PMID- 10339131
TI  - Marketplace. How managed care techniques are changing workers' comp practices.

PMID- 10339132
TI  - Perspectives. AHCPR's evidence-based centers: will their findings guide clinical
      practice?

PMID- 10339134
TI  - Perspectives. ACR showdown, mega-reg comments frame crucial payment, compliance,
      quality issues for Medicare+Choice.

PMID- 10339133
TI  - Perspectives. Regulation run amok? Stark II proposal draws cacophony of comment.

PMID- 10339135
TI  - Perspectives. For better or worse, Medicaid shakeout foreshadows aspects of M+C
      exodus.

PMID- 10339136
TI  - Perspectives. Physician organizations struggle over questions of size and
      structure.

PMID- 10339137
TI  - Marketplace. How U.S. hospitals are luring private-pay patients from abroad.

PMID- 10339138
TI  - Perspectives. Premium support: a fluid concept accommodates contrary viewpoints
      as Medicare reformers toil on.

PMID- 10339139
TI  - Teamwork turns around troubled Arizona hospital maternity unit.

PMID- 10339140
TI  - Self-directed teams replace the bosses.

PMID- 10339141
TI  - Get something done when you call a meeting.

PMID- 10339143
TI  - Will our model of care soon become obsolete?

PMID- 10339142
TI  - Decision-making power rejuvenates, inspires staff.

PMID- 10339144
TI  - Griffin is world class in patient-centered care.

PMID- 10339145
TI  - Want to simplify charting? IL hospital knows how.

PMID- 10339146
TI  - Fire that elusive "somebody" in HR by redefining ESS (employee self-service).
AB  - The recent trend to corporate downsizing has affected many human resources
      departments, frequently making it difficult for employees to get correct benefits
      information. Employers may turn to Web-based technology and utilize an employee
      self-service (ESS) system as a way to make accurate and timely benefits
      information accessible to employees when they need it. To be most effective, an
      ESS system should be redefined to promote employee self-sufficiency.

PMID- 10339148
TI  - Buyer's Guide.

PMID- 10339149
TI  - 22nd Annual EMS state & province survey.

PMID- 10339147
TI  - Medicare+Choice: challenges and opportunities.
AB  - Medicare will soon undergo major changes, as Medicare beneficiaries are given a
      complex array of plan options known as Medicare+Choice. These changes are an
      attempt to extend the financial solvency of Medicare, but they also offer
      employees an opportunity to redesign their retiree health plans. It is essential
      that employers are fully informed about the coming changes and communicate with
      retirees about them.

PMID- 10339150
TI  - Directory of government agencies.

PMID- 10339151
TI  - Directory of EMS organizations.

PMID- 10339152
TI  - The home care crisis: time to abandon ship?

PMID- 10339153
TI  - Getting boards on board a major challenge for integrated systems.
AB  - Among the challenges an integrated health care system faces is helping its board
      members make the transition away from a historic community philanthropic board
      toward a board with more of a business approach.

PMID- 10339154
TI  - Positioning against niche competitors to reduce revenue erosion.
AB  - Health care providers around the country face a growing threat from more limited
      service "niche" providers, often sponsored by specialty physicians. Mark Grube,
      vice president of Abendshien+Grube Associates, writes that hospitals and health
      systems may want to consider joint ventures with physicians to counter this
      trend.

PMID- 10339155
TI  - Five crucial steps in launching an effective compliance program.
AB  - Hospitals and health systems throughout the country are launching compliance
      programs. Brent Saunders, president of the national Health Care Compliance
      Association, offers five important first steps that can enhance chances for
      success.

PMID- 10339156
TI  - Colorado plans bold move to create $5 billion health sciences "city".
AB  - The University of Colorado Health Sciences Center has decided to relocate its
      entire campus six miles away and, collaborating with local government and private
      industry, create a futuristic new health sciences "city" from an old, abandoned
      military base.

PMID- 10339157
TI  - KP (Kaiser Permanente) contracts with hospitalists for patients at non-KP
      hospitals.

PMID- 10339158
TI  - More red ink in 1999; better things to come?
AB  - While hospitals, medical group practices and integrated health care delivery
      systems can expect tight profit margins in 1999, Donald E. L. Johnson writes that
      both Medicare and private sector payments may stabilize over the next 12 months
      to bring improved bottom lines.

PMID- 10339159
TI  - At a glance. Percentage of Medicare beneficiaries in traditional Medicare and
      risk HMOs with supplemental health insurance.

PMID- 10339160
TI  - The future of Medicare and other mad predictions.

PMID- 10339161
TI  - How IDSs can make their risk contracts more profitable.
AB  - To understand the causes of financial losses associated with risk arrangements,
      and eliminate those deficits, integrated delivery systems (IDSs) need to be able
      to perform detailed analyses on all aspects of their utilization data.
      Evaluations of utilization should begin with a traditional variance analysis to
      pinpoint areas where costs are higher than anticipated. Then, a series of
      increasingly specific analyses should be performed on utilization data within
      those areas. Often, losses may be attributable to the inability of primary care
      physicians to serve as effective patient care managers. IDSs, therefore, should
      compare the practices of their primary care physicians and share results in a way
      that highlights each physician's performance while ensuring physician anonymity.
      IDSs should take steps to reduce future losses by providing physicians and
      utilization management staff with information that will help them control costs,
      developing a performance-improvement plan for primary care physicians, and
      implementing payment incentives for physicians.

PMID- 10339163
TI  - Rethinking specialist integration strategies.
AB  - To surmount the economic pressures of managed care, specialists are pursuing
      various initiatives designed to increase revenues and market share that may put
      them into competition with healthcare systems. Systems contemplating
      collaboration with specialists to gain their loyalty may first consider employing
      a strategy involving physician gain sharing. It should be understood, however,
      that there are legal hurdles to be overcome in developing gain sharing, that
      there are different gain-sharing models to be used, and that there are
      limitations as well as benefits to such an initiative. These limitations require
      healthcare systems to consider other, more durable specialist integration
      strategies. The balance of power between a healthcare system and specialists will
      affect the success of whatever integration strategy is employed.

PMID- 10339164
TI  - Developing a reliable medical informatics network.
AB  - As medical informatics increasingly places demands on computer resources,
      healthcare organizations need to plan for and develop fully integrated,
      enterprisewide communications networks. Healthcare systems should invest in
      upgradable equipment that is compatible with industry standards and select
      specialized contractors familiar with the infrastructure required for healthcare
      networks. The potential for downtime should be minimized through remote
      diagnostics that assist repair capabilities. The fully integrated network should
      be supported by staff who are provided with ongoing training and overseen by a
      knowledgeable network manager.

PMID- 10339165
TI  - Tailoring a corporate compliance program for an IDS.
AB  - Integrated delivery systems (IDSs) face a particular challenge in implementing a
      corporate compliance program--that of ensuring the program addresses issues of
      compliance with payment rules and regulations consistently across every component
      of the health system. To successfully implement an effective compliance program,
      the various components of the IDS first must understand what such a program is
      intended to accomplish, and any internal resistance to developing the program
      must be overcome. The IDS then can undertake identifying and assessing areas of
      the health system at risk of being in noncompliance, designing and implementing
      the program, auditing claims processing and cost reporting throughout the health
      system to ensure systemwide compliance, and maintaining the program through
      ongoing monitoring and training.

PMID- 10339166
TI  - New security guidelines will foster EDI use.
AB  - Both HCFA and HHS have issued new policies that provide direction to providers
      and payers regarding maintaining confidentiality of the medical data they
      transmit. A HCFA draft policy allows Medicare contractors and others to use the
      internet to transmit Medicare information, marking a reversal of HCFA's previous
      stand on the issue. At the same time, HHS has issued a proposed rule governing
      security and electronic signature standards, which directs all organizations that
      deal with patient information to develop a policy that ensures security of
      patient data.

PMID- 10339167
TI  - EDI streamlines reporting requirements for Medicare managed care.
AB  - Using automated eligibility verification tools for Medicare patients can help
      providers submit clean claims to managed care plans as well as file secondary
      claims efficiently to fiscal intermediaries. Automated eligibility verification
      systems combine EDI tools and data-processing software so providers can access
      databases to secure all the correct information before billing. In addition, an
      insurance eligibility system can automatically post benefit information to
      patient account files.

PMID- 10339162
TI  - Successful contracting depends on optimal retail pricing.
AB  - Retail price structures are a critical part of the managed care contracting
      process because payers use local and national charge norms to compare hospitals
      and to determine negotiating targets. To successfully negotiate managed care
      contracts, and to be able to offer sensible discounts to payers that require
      them, a healthcare organization needs to determine its retail prices relative to
      the marketplace. By measuring their charge structure's variance from those of
      other providers in the same market, healthcare organizations can ensure that
      their retail prices are competitive.

PMID- 10339168
TI  - EDI and imaging automate the business office.
AB  - By implementing electronic remittance posting and imaging in patient accounting,
      New York's Memorial Sloan-Kettering Cancer Center was able to eliminate 22 full
      time equivalent supervisory and staff positions and save $365,000 in physical
      space, microfilm and media costs the first year the new system was operational.
      Memorial Sloan-Kettering currently is participating in a pilot program with its
      Medicare fiscal intermediary to determine how EDI can be used to manage claim
      status information between payer and provider. By combining EDI, fax, and imaging
      technologies, Memorial Sloan-Kettering is making its patient accounting process
      more efficient and providing better service to its patients.

PMID- 10339169
TI  - Measuring productivity using RBRVS cost accounting.
AB  - The use of a resource-based relative value scale (RBRVS) allows procedures and
      costs to be indexed on a common or relative basis, using relative value units
      (RVUs) linked to the amount of resources consumed. Group practice administrators
      using an RBRVS to account for costs associated with providing services and
      relating practice revenue and costs to RVUs rather than to fee schedules may find
      it easier to discuss productivity--and ultimately compensation--with physicians
      and allied providers. The advantage of RBRVS cost accounting is that it provides
      a convenient format for comparing physician performance across specialty lines
      within a group and with external physician groups.

PMID- 10339170
TI  - Organization under the upside-down revenue cycle processing model.

PMID- 10339171
TI  - Year 2000 compliance: one year and counting.

PMID- 10339172
TI  - Data trends. The impact of pricing on profit.

PMID- 10339174
TI  - Break through to 98 percent inventory record integrity in just 120 days.
AB  - Companies have tried to live without inventory integrity, but high performance
      and high profitability depend on high levels of inventory integrity. Good
      decisions require good facts, and inventory is often the most important fact upon
      which business decisions are based. This article explains how to attain an
      inventory integrity level of between 95 and 98 percent or even higher in 120 days
      or less and how to keep it there.

PMID- 10339173
TI  - Inventory accuracy in 60 days.
AB  - This article describes a program for increasing basic inventory record accuracy.
      The program can be implemented in 60 days, and its cost is likely to be free when
      the benefits are taken into account. The hardest part is selling people on the
      need to improve accuracy and keeping them motivated during the implementation.

PMID- 10339175
TI  - Cycle counting: a quality assurance process.
AB  - Accurate inventory records result from careful tracking of in and out
      transactions. Regardless of how these transactions are done--by computer
      (backflush) or manually--they must be done correctly if accurate inventory
      records are to be the result. Cycle counting plays an important role in assuring
      that there is a sufficient inventory-tracking process in place to achieve
      accuracy. The purpose of this article is to explain how to use cycle counting to
      establish an effective process for keeping records accurate and how to ensure
      that it remains in place.

PMID- 10339176
TI  - Managing inventories for maximum benefit.
AB  - In many companies it is not feasible to go to just-in-time (JIT) inventory
      management practices. In these instances, an aggressive inventory-monitoring
      program is a must. This article describes a program that resulted in a 75-percent
      reduction of inventory over a five-year interval. The topics covered will be
      applicable to those companies where JIT is not the answer.

PMID- 10339177
TI  - Mission impossible? The boss wants to double our inventory turns.
AB  - Despite the prolific implementation of manufacturing systems, JIT principles,
      Kaizen events, and cycle time reduction programs over the past few years, high
      inventories still plague many companies. The assumption that implementing these
      principles and techniques will automatically result in inventory levels that
      satisfy management frequently proves to be false. Events like mergers,
      introduction of new competition, and a dropoff in business often trigger edicts
      to cut inventories. The cost of inventories also extends beyond the traditional
      accounting measurements to include hidden operating costs that everyone should
      want to eliminate. This article looks at the reasons for inventories and explores
      strategies for reducing them.

PMID- 10339178
TI  - How to leverage a bad inventory situation.
AB  - Small manufacturing companies have a hard time taking advantage of the price
      breaks that result from large purchase orders. Besides the greater amount of
      money involved, purchasing large quantities of items demands additional space for
      storing the items. This article describes a company that created separate
      inventory management and finance company to provide inventory management services
      to itself and to market these services to other small companies in its area.

PMID- 10339179
TI  - How to get parts out of prison (without paperwork).
AB  - This article describes the business relationship between a manufacturing company
      and a vendor that is a minimum-security correctional facility. In particular, it
      describes a set of revisions in the purchasing and delivery process that reduced
      the amount of paperwork substantially and also reduced the turnaround time.

PMID- 10339180
TI  - Doing more with less: smart stockroom management equals great service.
AB  - As manufacturers compete for a larger share of a shrinking market, cries for a
      better way of doing business can be heard resounding throughout the business
      community. Many companies are now looking toward these principles for help:
      working smarter, doing more with less, and supplying superior service. One area
      in which they can be applied successfully is stockroom management. Their
      implementation can result in positive, cost-effective changes. This article
      describes how a materiel control organization was able to meet the call for
      change and in the process increase accuracy, reduce cycle time, and enhance its
      commitment to providing "great service" to both internal and external customers.

PMID- 10339181
TI  - Purchasing without paper (well, almost no paper).
AB  - This article describes the process by which one company was able to substantially
      reduce the amount of paperwork required for purchasing material. After
      considering all the variables that affected the amount of paperwork, it developed
      three different models to use in ordering materiel, one for materiel delivered by
      the vendor in standard containers, one for materiel delivered by a carrier in
      standard containers, and the last for materiel that is best delivered in variable
      quantities.

PMID- 10339182
TI  - New purchasing measures for stellar performance.
AB  - According to this article, many manufacturing companies evaluate their purchasing
      departments using inappropriate measures. One reason is that the measures chosen
      are easy to use. Another is that the companies tend to favor predictability, and
      they thus prefer numbers that they can try to achieve. But predictability is not
      always a virtue. In fact, an obsession with predictability can prevent the kind
      of flexibility that is often necessary to respond to changes in the market. The
      article suggests that the best measures to use in evaluating purchasing
      departments are behavior measures, not price, delivery, or quality measures.

PMID- 10339184
TI  - Using the Internet to achieve purchasing improvements at General Electric.
AB  - This article presents a case study of how General Electric's Lighting Division
      has used the Internet to dramatically improve purchasing and logistics
      performance. By applying new techniques and technologies, including an Internet
      based "Trading Process Network," GE Lighting has achieved substantial benefits,
      including cycle time reduction, elimination of paper and mail processing,
      improved information sharing with suppliers, quality improvement, and cost
      reduction.

PMID- 10339183
TI  - Why is traditional accounting failing managers?
AB  - This article provides an account of activity-based costing. It presents a general
      overview of this costing method, lists benefits and key concerns, discusses some
      of the impediments to its spread, and predicts its increasing use.

PMID- 10339185
TI  - Rewarding with dignity.
AB  - Job satisfaction affects employee morale, which in turn affects employee
      productivity. Therefore, managers need to learn about contributing factors and
      use the factors within their power to improve job satisfaction. Extrinsic
      rewards, such as a high salary and good work benefits, are important, but studies
      show that how a job makes an employee feel is the greatest determinant of job
      satisfaction. Managers can influence the emotional effect of work on an employee
      through, among other strategies, recognizing the employee's efforts, providing
      opportunities for the employee to participate in decision making, and allowing
      the employee to grow professionally.

PMID- 10339186
TI  - Hospital chief executive officer perceptions of organizational culture and
      performance.

PMID- 10339187
TI  - A model to enhance culturally competent care.

PMID- 10339188
TI  - Problem solving revisited.

PMID- 10339189
TI  - Son of managed care: profile of healthcare in 2008 (and what to do about it).

PMID- 10339190
TI  - Caught in the crossfire: stress in healthcare settings and ways to address it.

PMID- 10339191
TI  - Telemedicine: across the miles and right next door.

PMID- 10339193
TI  - Information management. Key punch.

PMID- 10339194
TI  - Clinical governance. Shift workers.

PMID- 10339192
TI  - Information management. All tangled on the Web.

PMID- 10339195
TI  - Clinical governance. Onus points.
AB  - A survey of lead GPs in total purchasing pilots revealed poor understanding of
      the responsibilities of clinical governance. Many saw it in a negative light and
      were concerned about its administrative costs. Explicit guidance is needed,
      spelling out the clinical governance responsibilities of GPs and others in
      primary care groups.

PMID- 10339196
TI  - Quality improvement. Acting with assurance.

PMID- 10339197
TI  - Career profile. Health promotion. In tune with the times.

PMID- 10339200
TI  - Pre-admission clinics. Smooth operators.
AB  - A nurse-led clinic providing assessments for surgical patients before their
      admission has proved popular with patients and staff. It has reduced the need for
      patients to come in the night before their operation and has cut non-attendance.
      The clinic is being expanded to cover all surgical specialties.

PMID- 10339199
TI  - Primary care groups. Missed: a motivator.

PMID- 10339198
TI  - Public health. Parity begins at home.
AB  - The NHS can make a considerable contribution to reducing social exclusion and
      inequalities. GPs' surgeries should play a greater role in giving information on
      social security benefits. Primary care should be targeted at those most in need.
      The NHS has many employees on low incomes and should provide them with an
      effective occupational health service.

PMID- 10339201
TI  - Staffing. Nightie-knights.

PMID- 10339202
TI  - Recommendations for managing hospital closure.
AB  - An acute care hospital was closed by the British Columbia Ministry of Health in
      1993. A research study was conducted to investigate the ways closure of the
      hospital affected hospital employees and to identify ways to facilitate the
      closure/reorganization process. Unstructured interviews were conducted with 25
      employees around the time of closure and six months after the closure. In the
      category Living with Closure, six themes arose from the qualitative analysis.
      They related to (1) provision of information; (2) effect of closure on the
      working environment and colleagues; (3) perceived stress; (4) recognition of
      one's worth; (5) provision of support services; and (6) the process of having a
      new job. The authors offer recommendations stemming from the analysis, which are
      intended to assist others planning for future hospital reorganizations or
      closures.

PMID- 10339203
TI  - Applying activity-based costing in long-term care.
AB  - As greater numbers of the elderly use health services, and as health care costs
      climb, effective financial tracking is essential. Cost management in health care
      can benefit if costs are linked to the care activities where they are incurred.
      Activity-based costing (ABC) provides a useful approach. The framework aligns
      costs (inputs), through activities (process), to outputs and outcomes. It
      allocates costs based on client care needs rather than management structure. The
      ABC framework was tested in a residential care facility and in supportive housing
      apartments. The results demonstrate the feasibility and advantages of ABC for
      long term care agencies, including community-based care.

PMID- 10339204
TI  - The experience of clients and informal caregivers with community health care
      services.
AB  - Persistent changes in long term care policy reform in Ontario prompted one home
      care program to undertake a multifaceted study to evaluate the effects of those
      changes. This article describes the qualitative component of the study examining
      perceptions of clients (persons with disabilities; adults over 80 and under 80
      years of age) and of informal caregivers concerning their satisfaction with
      services and the impact of service delivery on their quality of life. Responses
      and descriptions of relevant perceptions and experiences varied with category of
      participant. Study findings revealed that satisfaction with services and
      concomitant quality of life depended upon the quality of communication with
      service providers.

PMID- 10339206
TI  - The last critical care bed in Western Canada.
AB  - This Brief Report provides an assessment of various factors contributing to the
      widely publicized emergency department overflow and bed availability crisis that
      occurred last spring in Edmonton area's Capital Health Region. We were able to
      divide the factors contributing to the crisis into those of a general nature,
      those related specifically to health care restructuring, and factors related even
      more specifically to the nature of Capital Health's Integrated Delivery System.
      Strategies that we have developed to deal with each of these factors are
      described.

PMID- 10339205
TI  - And what do I get for my $365?

PMID- 10339208
TI  - Guidelines for career planning in a changing world.

PMID- 10339209
TI  - Treating victims and survivors with respect when downsizing is necessary.
      Interview by Matthew D. Pavelich.

PMID- 10339210
TI  - Jingle all the way? Managers' salaries slightly up in 1998.

PMID- 10339207
TI  - Regional policy and procedure development: a seven-step process.
AB  - In October 1997, Nova Scotia's Eastern Regional Health Board undertook the
      development of regional policies and procedures relating to both its governance
      and management responsibilities. The process that was adopted included delegation
      of tasks to work groups; development of general administrative policies and
      procedures in accordance with accreditation guidelines and present health
      restructuring initiatives; coordination of the development of the policies and
      procedures within a specific framework; and development of standardized clinical
      policies. A steering committee initiated the project, which involved 24
      subgroups.

PMID- 10339211
TI  - Proving ground. You know you're an asset. Does your CEO?

PMID- 10339212
TI  - Paths to the prize. Interview by Thomas J. Stewart 3rd.

PMID- 10339213
TI  - Lethal weapons. Can you handle hazardous materials incidents?

PMID- 10339215
TI  - I.V. prices may creep upward in 1999.

PMID- 10339214
TI  - On point. New safety syringes and the facts about change-outs.

PMID- 10339216
TI  - GPOs rushing to Web faster than hospitals can get online.

PMID- 10339217
TI  - AmeriNet tries to pin down the Y2K bug.

PMID- 10339218
TI  - Let suppliers help plan purchase needs.

PMID- 10339219
TI  - Suppliers continue to needle GPOs over contract policy.

PMID- 10339220
TI  - CHA supports system grassroots advocacy efforts.

PMID- 10339221
TI  - Outreach is critical to children's healthcare coverage.

PMID- 10339222
TI  - Online community strengthens the ministry.

PMID- 10339223
TI  - Do you work with local parishes? Putting patients first response.

PMID- 10339224
TI  - When children's health matters. Saint Anthony Hospital aggressively seeks
      Medicaid-eligible children.

PMID- 10339225
TI  - Earning extra credit. Saint Alphonsus Regional Medical Center extends its mission
      through partnerships with schools.

PMID- 10339226
TI  - Leaders encourage the heart.

PMID- 10339227
TI  - Selecting the cream of the crop (Part III). Search process should stress
      candidate's lived values.

PMID- 10339228
TI  - Legacy leadership: stewardship and courage. Five attributes characterize genuine
      healthcare leaders.
AB  - In organizations with the power to persist through turbulent eras, one finds
      leaders who live as if they were stewards of a legacy-the culture, mission, and
      founding spirit of the organization. These legacy leaders may be physicians,
      administrators, chief executives, or board members, but they all have the ability
      to weave a thread of constancy through times of peril. Five attributes
      characterize legacy leaders: Their work is a vocation, they possess a moral code,
      they are committed to stewardship, they have a bias for building, and they
      instill hope. Legacy leaders stay with one organization a very long time,
      patiently removing obstacles to worthy accomplishments. Because the profession of
      healthcare is at heart a vocation, not a business, we must pay attention to the
      kinds of leaders we place in our healthcare institutions. To carry out their
      responsibility of transforming healthcare delivery, boards of directors must hire
      legacy leaders, manage their business focus, carefully evaluate executives,
      enhance mechanisms for board evaluation, and raise the bar for decision making.

PMID- 10339230
TI  - Justice: leaders' core responsibility. Leaders in Catholic healthcare are called
      to ensure that a concern for justice permeates all organizational relationships.

PMID- 10339229
TI  - Spirituality and leadership. Genuine leaders recognize the sacredness of the
      human presence.
AB  - Functionalism, which is the dominant philosophy of our time, views the world
      externally and mechanically and describes things in terms of how they work. But
      it cannot answer the "why" or (especially) the "who" questions. Leadership,
      however, requires an ability to recognize the sacredness of individuality. Each
      of us lives simultaneously in four different words: system, society, behavior,
      and experience. True leaders know that effecting change is possible only in the
      realm of experience. Change often begins in the human imagination, from which
      true leaders draw five necessary qualities: integrity, a gift for awakening
      others, compassion, spontaneity, and an ability to make use of failure--which is
      of course at the heart of crucifixion, resurrection, and incarnation. Healthcare
      today is caught up in a conversation between mission and market. Catholic
      healthcare leaders, who believe healthcare is a human right, will have to use all
      their powers of memory and imagination to invoke the vision of the ministry's
      founders. In that way, they may reawaken our numbed hearts.

PMID- 10339231
TI  - Four ways people approach ethics. A practical guide to reaching consensus on
      moral problems.
AB  - Most people use four different approaches when making ethical decisions. Some
      people use one approach predominantly; others vary their approaches according to
      circumstances. In either case, the approaches are usually chosen unconsciously.
      The main source of conflict in decision making is the fact that two parties have
      chosen different approaches. The four approaches are: The principle approach, in
      which decisions are made according to a principle such as the Ten Commandments or
      the Golden Rule The consequence approach, in which decisions are made according
      to their likely outcomes The virtue/character approach, in which decisions are
      made according to the decision makers's view of his or her responsibilities The
      moral sentiment approach, in which decisions are made according to the decision
      maker's feelings Conflicts in decision making become easier to resolve once the
      decision makers, first, recognize that they are using different approaches, and,
      second, agree to "change gears" and use the same approach.

PMID- 10339232
TI  - Launching a geriatric unit. A Bronx medical center is prepared for the "graying
      of America".

PMID- 10339234
TI  - Community networks. Healthy Choices Teen Pregnancy Prevention Program, Van Nuys,
      CA.

PMID- 10339233
TI  - Calvary Hospital focuses on ethics. Integrating clinical and organizational
      ethics meets needs of a changing healthcare system.

PMID- 10339235
TI  - Communications partnership benefits Southern California.

PMID- 10339236
TI  - Mission: a light to our path.

PMID- 10339237
TI  - Internet course on total quality management.
AB  - The Internet provides new opportunities to information-based industries such as
      universities. If a vast majority of potential customers of our programs have
      access to the Internet, then it is conceivable that many universities will begin
      teaching Internet courses and that such courses could, in many cases, replace or
      at least augment existing face-to-face classroom activities. This paper is an
      account of one such course at Cleveland State University and the type of policy
      issues raised by the course at this institution.

PMID- 10339239
TI  - Admission to a graduate program in health services administration: the interview
      process.

PMID- 10339240
TI  - A student-developed health information systems conference.

PMID- 10339242
TI  - The Andrew Pattullo Lecture. Can you teach the management technology of health
      administration? A view of the 21st century.

PMID- 10339241
TI  - Use of voice mail in teaching commuting students.

PMID- 10339238
TI  - Turkish hospital management at a crossroads: prospects for the year 2000.
AB  - The Turkish health system has been undergoing a radical reform process since the
      early 1990s. Reform proposals, based on purchaser/provider split, self-governing
      hospitals (ultimately leading to full privatization), compulsory health insurance
      etc., are expected to have a profound effect on hospital management. In such an
      environment, hospital administrators' views on the domains and issues that will
      come to the fore in the year 2000 gain importance. In this paper, results of a
      study undertaken among hospital administrators are presented. The study aimed to
      find the views of hospital administrators on issues likely to gain prominence in
      the year 2000 and the skills, knowledge, and abilities required to tackle these
      issues. It was concluded the autonomous status of hospitals, privatization,
      competition, and health trusts will become the central domains in the year 2000
      in hospital administration. Innovation and following technological developments
      were considered most critical.

PMID- 10339243
TI  - The Baxter Allegiance Foundation Prize for Health Services Research Address.
      Statistics, tears, stories, and policy proposals: addressing the problems of risk
      adjustment.

PMID- 10339244
TI  - Scene work.

PMID- 10339245
TI  - Telemedicine. The key to expanded EMS or an expensive experiment?

PMID- 10339246
TI  - Terrorism. Part II. New weapons of mass effect.

PMID- 10339248
TI  - Physician response to Medicare fee reductions: changes in the volume of coronary
      artery bypass graft (CABG) surgeries in the Medicare and private sectors.
AB  - The demand inducement hypothesis predicts that physicians will respond to
      reductions in their income by increasing the volume of their services when the
      income effect is strong and negative. I test for such inducement in the market
      for coronary artery bypass grafting (CABG), using a longitudinal panel of
      physicians in New York and Washington states. The results show that physicians
      whose incomes were reduced the most by Medicare fee cuts performed higher volumes
      of CABGs, and they did so in both the Medicare and private markets.

PMID- 10339247
TI  - The effects of regulation and competition in the NHS internal market: the case of
      general practice fundholder prices.
AB  - The 1989 reforms of the UK National Health Service introduced competition in
      supply within a tightly regulated framework. The paper examines whether this
      competition affects the prices posted by sellers of medical services. We argue
      that despite regulation market forces may have an impact on price. We test this
      using the posted prices for one of the two types of buyer, General Practice
      Fundholders. We find the regulatory rules are not observed, and some evidence of
      the impact of market forces on price.

PMID- 10339249
TI  - Incentives for cooperation in quality improvement among hospitals--the impact of
      the reimbursement system.
AB  - Up to now, few analytical models have studied the incentives for cooperation in
      quality improvements among hospitals. Only those dealing with reimbursement
      systems have shown that, from the point of view of individual or competing
      hospitals, retrospective reimbursement is more likely to encourage quality
      improvements than prospective financing, while the reverse holds for efficiency
      improvements. This paper studies the incentives to improve the quality of
      hospital care, in an analytical model, taking into account the possibility of
      cooperative agreements, price besides non-price (quality) competition and quality
      improvements that may simultaneously increase demand, increase or reduce costs
      and spill over to rival hospitals. In this setting quality improvement efforts
      rise with the rate of prospective reimbursement, while the impact of the rate of
      retrospective reimbursement is ambiguous, but likely to be negative for quality
      improvements that are highly cost-reducting and create large spillovers.
      Cooperation may lead to more or less quality improvement than non-cooperative
      conduct, depending on the magnitude of spillovers and the degree of product
      market competition, relative to the net effect of quality on profits and the
      share of costs that is reimbursed retrospectively. Finally, the stability of
      cooperative agreements, supported by grim trigger strategies, is shown to depend
      upon exactly the opposite interaction between these factors.

PMID- 10339250
TI  - Determinants of managed care penetration.
AB  - This paper examines factors associated with differences in managed care
      penetration across geographic areas. Two alternative measures of managed care
      penetration are considered: the percentage of revenue physicians received from
      managed care contracts and market survey data on enrollments in managed care
      plans. Results are similar for both types of measures. Our analysis suggests that
      demographics, labor market characteristics and supply side variables including
      the level of concentration in hospital markets, hospital occupancy rates and the
      practice organization patterns of physicians are all important determinants of
      managed care penetration.

PMID- 10339251
TI  - The labour market costs of community care.
AB  - This paper reports an empirical investigation into the influence of informal care
      responsibilities on the labour supply of women. The objective is to examine the
      argument that the UK policy of caring for the chronic sick 'in the community'
      involves a nontrivial opportunity cost in the form of the forgone labour supply
      of the informal carers upon which it relies. We find that informal carers who
      care for less than 20 h per week are, in fact, more likely to participate in the
      labour market, but tend to work for fewer hours per week than otherwise similar
      noncarers. Informal carers who care for 20 h or more a week are less likely to
      participate, but only slightly. However, when they do undertake formal
      employment, they tend to earn less per hour and work for fewer hours per week.

PMID- 10339253
TI  - Answering your question on resolving disputes over sharing and replacing lab
      equipment.

PMID- 10339252
TI  - Cost-benefit analysis and mammographic screening: a travel cost approach.
AB  - This study describes the methodology and presents preliminary results of an
      economic appraisal of a program to use mobile mammographic screening units in
      rural areas of Australia. The benefits of the project are measured using the
      travel cost method. Since mammograms are a 'binary good', conventional welfare
      analysis must be modified and discrete choice models used to estimate the demand
      for screening. The results suggest that the level of welfare benefits depends on
      the distance a town is from the nearest fixed screening unit. In the 10 towns
      studied, the economic benefits of mobile screening outweighed the economic costs
      if a rural town is situated 29 km or more from a fixed mammographic screening
      unit.

PMID- 10339256
TI  - Frontline Healthcare Workers Safety Foundation holds its 4th conference.

PMID- 10339254
TI  - Drawing the plays with self-directed work teams.

PMID- 10339255
TI  - Satellite laboratories. A cost-benefit study.

PMID- 10339257
TI  - Avoiding Y2Kaos.

PMID- 10339258
TI  - How to plan and produce your laboratory test catalog.
AB  - Creating the lab catalog is a multi-disciplinary crash course in laboratory
      science, writing, publishing, marketing, business administration, and graphic
      design. These eight steps will take you from start to finish in completing a
      showcase catalog.

PMID- 10339259
TI  - Making a difference, one child at a time.
AB  - A colleague going on a surgical mission to rural Guatemala asked the author if
      she could obtain a handheld instrument for the trip. She went one better and
      provided the hands to operate it, and in return learned new skills along with
      some unforgettable life lessons.

PMID- 10339260
TI  - Tradition vs. HMOs. HCFA to probe docs' Medicare 'education' campaign.

PMID- 10339261
TI  - Columbia details spinoffs. Two new companies would control 64 hospitals.

PMID- 10339263
TI  - Cancer-care PPMs announce merger.

PMID- 10339262
TI  - Paying for innovation. Failed strategies add to hospitals' reimbursement losses.
AB  - Hospitals across the country are struggling to balance revenue shortfalls and
      cost increases as the lid on government and private-payer payments closes
      tighter. They're also grappling with losses on failed physician and HMO
      investments, the expense of new medical technologies and larger-than-planned
      costs related to "millennium bug" cures. This is the second part of a two-part
      series on financial turmoil in healthcare.

PMID- 10339265
TI  - Award-winning service--Sodexho Marriott Service Excellence Awards.

PMID- 10339264
TI  - Year in review--1998.
AB  - If adversity tests our strength, healthcare got a real workout in 1998. Sore
      spots included HMO losses, bankruptcies, whistleblower lawsuits and failed
      mergers. Here's a look back at the major events that shaped the industry in 1998.

PMID- 10339266
TI  - IRS targets Utah HMO.

PMID- 10339267
TI  - Leaving home. Home health survey looks at an industry in turmoil.

PMID- 10339268
TI  - Getting the whole story. The way medication errors are reported affects the
      results.

PMID- 10339269
TI  - Healthy numbers. Latest data show improvement in industry financials.

PMID- 10339271
TI  - New twist on old law. High court ruling could broadly help whistleblowers.

PMID- 10339270
TI  - Record PPS margins. Hospitals say MedPAC figures distort industry's health.

PMID- 10339273
TI  - Assisted living gets creative. Staffing strategies for attracting and retaining
      direct line workers.

PMID- 10339274
TI  - AHCA 1998 Volunteers of the Year.

PMID- 10339272
TI  - Congress dulls home health reform teeth.

PMID- 10339275
TI  - The elements of style. Clear documentation is key to creating easy-to-follow care
      plans resulting in quality care.

PMID- 10339276
TI  - Reporting sentinel events. Failure to report adverse incidents can lead to loss
      of JCAHO accreditation.

PMID- 10339277
TI  - Personal outcomes drive active treatment.

PMID- 10339279
TI  - An evaluation of reachers for use by older persons with disabilities.
AB  - With the steady growth in numbers of older persons, the number of elders who have
      impairments impacting on functional performance also increases. Many assistive
      devices are available that have the potential to help elders with impairments to
      maintain or regain independence. Reachers offer a good example of an inexpensive
      and useful assistive device for elders. A needs assessment study of the
      University at Buffalo Rehabilitation Engineering Research Center on Aging (RERC
      Aging) found that 22% of elder owners of reachers were dissatisfied with at least
      one of the reachers they owned. This study sought to explore the reasons for this
      dissatisfaction by, first, determining the tasks for which older persons use
      reachers and, second, testing performance in these tasks with three reachers
      selected on their potential to most satisfactorily meet the needs of older
      persons with disabilities. In the first study component, 16 older people were
      selected randomly from the RERC-Aging study sample pool for telephone interviews.
      In the second component, 30 elders were selected randomly for an evaluation of
      reachers. All study participants were 60 years old or older, lived at home, and
      used one or more reachers in their daily tasks. Consumer criteria for evaluating
      reachers included adjustable length, one-hand use, life-time guarantee, lock
      system for grip, forearm support, light weight, and lever action trigger. The
      Winchester reacher was rated highest by consumers who actually tested three
      reachers that best met the consumer criteria.

PMID- 10339280
TI  - Using telerehabilitation to support assistive technology.
AB  - Telerehabilitation--the use of telecommunications technology to provide
      rehabilitation and long-term support to people with disabilities--offers exciting
      possibilities for the delivery and support of assistive technology services. This
      article describes the experiences of a specialty hospital serving persons with
      disabilities in exploring telerehabilitation to support assistive technology use
      in the home. Four case studies are presented to illustrate how telerehabilitation
      may be used in relation to seating evaluation, evaluation of home accessibility,
      setup of computer access systems, and training in use of augmentative
      communication devices.

PMID- 10339278
TI  - Poka-yoke process controller: designed for individuals with cognitive
      impairments.
AB  - Poka-yoke is a Japanese term meaning "error proofing." Poka-yoke techniques were
      developed to achieve zero defects in manufacturing and assembly processes. The
      application of these techniques tends to reduce both the physical and cognitive
      demands of tasks and thereby make them more accessible. Poka-yoke interventions
      create a dialogue between the worker and the process, and this dialogue provides
      the feedback necessary for workers to prevent errors. For individuals with
      cognitive impairments, weighing and counting tasks can be difficult or
      impossible. Interventions that provide sufficient feedback to workers without
      disabilities tend to be too subtle for workers with cognitive impairments; hence,
      the feedback must be enhanced. The Poka-Yoke Controller (PYC) was designed to
      assist individuals with counting and weighing tasks. The PYC interfaces to an
      Ohaus CT6000 digital scale for weighing parts and for counting parts by weight.
      It also interfaces to sensors and switches for object counting tasks. The PYC
      interfaces to a variety of programmable voice output devices so that voice
      feedback or prompting can be provided at specific points in the weighing or
      counting process. The PYC can also be interfaced to conveyor systems, indexed
      turntables, and other material handling systems for coordinated counting and
      material handling operations. In all of our applications to date, we have
      observed improved worker performance, improved process quality, and greater
      worker independence. These observed benefits have also significantly reduced the
      need for staff intervention. The process controller is described and three
      applications are presented: a weighing task and two counting applications.

PMID- 10339282
TI  - An age of reason for assistive technology?

PMID- 10339283
TI  - A survey of persons who use integrated control devices.
AB  - Integrated devices allow users to operate multiple pieces of assistive technology
      items from a single input device. Through this single input device, users with
      severe physical limitations are able to operate several other devices such as a
      wheelchair, telephone, computer, and communication aid. Twenty-four integrated
      control users completed a telephone survey to ascertain consumer satisfaction
      with integrated controls. Eighteen were either satisfied or very satisfied with
      the evaluation for an integrated control, one was neither satisfied nor
      dissatisfied, two were very dissatisfied, and three did not respond to the
      question. Twenty were very satisfied or satisfied and four were either
      dissatisfied or very dissatisfied with the training they received. Twenty-two
      respondents indicated they were either very satisfied or satisfied with their
      integrated control device, one was neither satisfied nor dissatisfied, and one
      was very dissatisfied. In general, respondents were satisfied with their
      integrated control devices. Specifically, respondents were satisfied with the
      increase in independence and the ability to control other equipment such as
      television sets and computers. Simplicity, touch sensitivity, and visual/auditory
      feedback appeared to play important roles in satisfaction.

PMID- 10339281
TI  - The Ability Program: improving statewide access to assistive technology for
      adults with disabilities.
AB  - In 1995, the Kate B. Reynolds Charitable Trust awarded $2.4 million to support
      the Ability Program, a statewide initiative to improve awareness of and access to
      assistive technology for adult North Carolinians with disabilities. This
      coordinated effort resulted in 11 funded projects, each using a different
      approach to deliver assistive technology to persons in rural communities. An
      overall management, technical assistance, and evaluation program ensured
      coordinated use of the Trust's funds. This paper describes the development and
      implementation of the Ability Program in North Carolina, accomplishments of
      program grantees, and results of a comprehensive program evaluation system used
      to document process and outcome measures. After 2 years of operation, the type
      and extent of assistive technology services for adults with disabilities in North
      Carolina increased as a result of the Ability Program.

PMID- 10339284
TI  - Follow-up assessment of standing mobility device users.
AB  - The use of standing devices by spinal cord-injured subjects was investigated
      through a national survey of a sample of individuals who returned their
      manufacturer's warranty card to two companies. We obtained a 32% response rate
      (99/310). The majority of respondents were male (87%) with a median age between
      41 and 50 years. Seventy-seven percent were paraplegic and 21% were quadriplegic.
      Forty percent had between 1 and 5 years experience with their device, and 84% of
      those responding were currently using their standing device. Forty-one percent
      used their standing device one to six times a week; two-thirds stood between 30
      minutes and 1 hour for each use. Less than 10% of subjects experienced any side
      effects, such as nausea or headaches, from standing. Twenty-one percent of
      subjects reported being able to empty their bladder more completely. There was
      also a favorable response by some individuals on the effects of the standing
      devices on bowel regularity, reduction of urinary tract infections, leg
      spasticity, and number of bed sores. Finally, 79% of subjects highly recommended
      use of standing devices to other people with spinal cord injury. The positive
      responses of individuals using standing devices is a strong recommendation for
      the assistive technology community to make these devices more available to
      individuals with spinal cord injury.

PMID- 10339285
TI  - The flexible contour backrest: a new design concept for wheelchairs.
AB  - Studies have shown that the use of a conventional sling backrest in a wheelchair
      may have a negative impact on the posture and health of users. To avoid such
      problems, this backrest is often replaced by a back cushion on a rigid surface.
      However, the use of the latter deprives many wheelchair users of the advantages
      provided by the sling backrest (easy folding, lightweight, low cost, unobtrusive,
      simplicity of design). In an effort to maintain these features while providing
      adequate posture, a new backrest was designed according to specific criteria. The
      "flexible contour backrest" has been developed so that it can be adapted to a
      person's back contour with stays, adjustable straps, and curved back posts.
      Preliminary comparisons done by some experts with commercially available
      backrests showed that design criteria were reached at 62.9% by the back cushion
      on a rigid surface, at 64% by the sling backrest, and at 67.7% by the adjustable
      tension backrest. On the other hand, design criteria were reached at 80% by the
      new flexible contour backrest because its design brings together most of the
      positive features provided by these other backrests (easy to fold, light weight,
      unobtrusive, airy) as well as providing adequate posture and better fit to the
      user's morphology.

PMID- 10339286
TI  - Experimental evaluation of the Medtronic Maxima Forte hollow fiber membrane
      oxygenator.
AB  - A new hollow fiber membrane oxygenator, the Medtronic Maxima Forte, was tested
      for gas transfer, blood path resistance and blood handling characteristics in a
      standardized setting with surviving animals. Three calves (mean body weight: 71
      +/- 9.6 kg) were placed on cardiopulmonary bypass at a mean flow rate of 50
      ml/kg/min for six hours. The circuit included the Maxima Forte oxygenator. The
      animals were weaned from cardiopulmonary bypass and then from the ventilator.
      After seven days, the animals were sacrificed electively. Physiologic blood gas
      values could be maintained throughout perfusion in all animals. Mean pressure
      drop through the oxygenator varied between 49 mmHg and 66 mmHg. The respective
      baseline values for red blood cell count, white blood cell count and platelets
      were 8.90 +/- 1.26 10(6)/mm3, 7.46 +/- 3.17 10(3)/mm3. and 680 +/- 216 10(3)/mm3.
      Red blood cell and platelet counts dropped slightly to 7.26 +/- 1.61 10(6)/mm3
      and 400 +/- 126 10(3)/mm3 at the end of the bypass, whereas the white blood cell
      count increased up to 9.13 +/- 5.25 10(3)/mm3. All three cell lines returned to
      near their baseline values after seven days. Blood trauma evaluated as a function
      of plasma hemoglobin (plasma Hb) and lactate dehydrogenase (LDH) showed stable
      values during all the perfusion time. Both peaked at 24 hours before returning to
      their baseline values at seven days. LDH showed a statistically significant
      variation: 3255 +/- 693 IU at 24 hours versus 2029 +/- 287 IU at baseline (p =
      0.04). The variation of plasma Hb was not statistically significant (93.5 +/- 7.7
      mumol/l at 24 hours versus 77.3 +/- 52.3 mumol/l at baseline) indicating a weak
      effect of the perfusion on blood trauma. The Medtronic Maxima Forte hollow fiber
      membrane oxygenator offered good gas exchange capabilities, a low pressure drop,
      and low blood trauma over a prolonged perfusion time of six hours in this
      evaluation.

PMID- 10339287
TI  - A fax-back oxygenator-perfusionist clinical performance data collection and
      statistical analysis method.
AB  - A method to collect clinical oxygenator performance data daily is described. At
      the end of a bypass procedure, the perfusionist fills in a fax-back form designed
      to automatically input patient-oxygenator performance data into a computer
      spreadsheet. Multiple blood gases, FiO2, gas and blood flow data, venous
      oxygenator blood inlet conditions (hemoglobin, O2 saturation, hematocrit and
      temperature), time on bypass and device manufacturer information are collected at
      the end of each cardiopulmonary bypass procedure at multiple institutions. A
      large sample database is created that allows multi-parametric analyses in regard
      to clinical practice, device performance, manufacturing consistency and patient
      requirements. The database and analyses facilitate institutional, manufacturer,
      and clinician benchmarking. Monthly reports to the clinicians give valuable
      feedback to improve oxygenator use and patient blood gas control. Reports to the
      device manufacturer provide information used to evaluate the clinical
      consequences of small changes in the manufacturing process.

PMID- 10339288
TI  - Delving deeper.

PMID- 10339289
TI  - Workers' comp gets managed.

PMID- 10339291
TI  - Pathways to better care.

PMID- 10339290
TI  - Child's play.

PMID- 10339292
TI  - Fasting insulin and apolipoprotein B levels and low density lipoprotein particle
      size as risk factors for ischemic heart disease.

PMID- 10339293
TI  - Use of MRI in prediction of recovery from persistent vegetative state.

PMID- 10339294
TI  - Long-term prognosis of seizures.

PMID- 10339295
TI  - Mortality after the treatment of hyperthyroidism with radioactive iodine.

PMID- 10339297
TI  - Detecting alcohol abuse: the value of carbohydrate deficient transferrin.

PMID- 10339298
TI  - Organized medicine and the life insurance industry.

PMID- 10339296
TI  - Incidence of hepatitis C and liver function abnormalities in the insurance tested
      population.

PMID- 10339299
TI  - Additional mortality produced by co-existent cerebral and peripheral
      atherosclerosis in a population with coronary artery disease.
AB  - The effect on survival of cerebral and lower extremity atherosclerosis was
      investigated in a cohort of individuals with known coronary artery disease. Those
      with cerebral and lower extremity atherosclerosis each had mortality ratios about
      220% and extra death rates about 27. With the co-existence of both impairments
      the mortality ratio nearly doubled to 410% and the extra death rate increased to
      71. In a group of individuals with known coronary artery disease, cerebral and
      lower extremity atherosclerosis have a major additional mortality impact.

PMID- 10339300
TI  - Long-term survival of patients with infective endocarditis.
AB  - BACKGROUND: Investigators in Lyon, France reported long-term outcome of 330
      patients with infective endocarditis (IE). This article compares experience of
      the cohort to what would be expected in the general population. RESULTS: Excess
      mortality persisted for many years following IE. Average annual mortality ratios
      were highest in the first and second years (4050% and 662%, respectively) and
      decreased gradually thereafter to a low of 219% during duration 10-12 years.
      Morbidity risk following IE would also be increased because of greater likelihood
      of recurrent IE, heart failure, embolism, valve thrombosis, additional valve
      surgery, complications of anticoagulant therapy, and stroke. CONCLUSIONS:
      Morbidity and mortality risk remain elevated for many years following recovery
      from IE.

PMID- 10339301
TI  - Mortality in rheumatoid arthritis: experience in four clinical series compared
      with the experience in the 1983 medical impairment study.
AB  - BACKGROUND: Survival curves and decimal Standardized Mortality Ratios (SMRs) were
      reported in 1994 for four clinical series of patients with Rheumatoid Arthritis
      (RA), with use of a common data processing system. It was felt to be desirable to
      compare the excess mortality observed in clinical patients with the excess
      mortality found in substandard policyholders with RA in the 1983 Medical
      Impairment Study. RESULTS: The weighted mean SMR was 2.25 for the male RA
      patients and 2.42 for the females. Although similar in magnitude to the
      percentage male and female Mortality Ratios (MRs) in the 1983 Medical Impairment
      Study, the derived Excess Death Rate (EDR) was higher for the clinical RA
      patients, despite the lower select mortality versus the population mortality,
      even after adjustment for difference in mean age between the clinical and
      insurance series. CONCLUSION: The higher EDR in four clinical series of RA
      patients probably reflects a higher proportion of more severe cases, who are
      declined for insurance or do not accept a highly rated offer.

PMID- 10339302
TI  - Life expectancy of persons with chronic disabilities.
AB  - The life expectancy is an important summary measure of an individual's prognosis
      for survival. The life table is the preferred method for computing life
      expectancies, but it is not always feasible. We show that for several chronic
      disabilities, the logarithms of the age-specific mortality ratios (relative to
      the general population) decline linearly with age, reaching parity at age 85 or
      older. This, combined with a standard modeling of an individual's current
      mortality rate, yields a set of age-specific mortality rates that can be used to
      produce a "customized" life table. The life expectancy is then immediately
      available. In a series of empirical comparisons the method performed better than
      an assumption of constant excess death rate (EDR), and much better than one of
      constant mortality ratio (MR). The method may be useful for a variety of non
      progressive disabilities, such as cerebral palsy and injuries of the brain or
      spinal cord.

PMID- 10339303
TI  - Exposing managed care's maladies.

PMID- 10339304
TI  - When laboratories go with flow analysis.

PMID- 10339305
TI  - Bit by bit: keeping legacy data alive.

PMID- 10339306
TI  - Disclaimer now needed for analyte-specific reagents.

PMID- 10339307
TI  - Message to LIS vendors: focus on functionality.

PMID- 10339308
TI  - Clinical laboratory information systems.

PMID- 10339309
TI  - Options broaden lab inspection choices.

PMID- 10339310
TI  - For fetal fibronectin test, the time is right.

PMID- 10339311
TI  - HCV infection still bewilders.

PMID- 10339313
TI  - Finding the proper fit for Pap smear devices.

PMID- 10339312
TI  - Lifting the veil on pathology reports.

PMID- 10339314
TI  - Hematology analyzers in review.

PMID- 10339315
TI  - 'Retail revolution' on horizon for laboratories?

PMID- 10339316
TI  - A giant leap for medical terminology.

PMID- 10339317
TI  - Does generic warfarin measure up?

PMID- 10339319
TI  - Coagulation analyzers. Service above all.

PMID- 10339320
TI  - Intranet technology seeping into laboratories.

PMID- 10339318
TI  - Fine-tuning measures to assess diabetes care.

PMID- 10339321
TI  - Meeting the challenge of antimicrobial resistance: the managed care initiative. A
      clinician's perspective.

PMID- 10339322
TI  - Managed care carve-outs: why, when and how to create a successful partnership.

PMID- 10339323
TI  - AMHO PPO industry contracting guidelines.

PMID- 10339324
TI  - Patient data: fueling your disease management program with targeted interventions
      and measurable outcomes.

PMID- 10339326
TI  - Managing vision care for the Medicare population: strategies for success.

PMID- 10339325
TI  - The growth of automobile managed care: new opportunities for providers.

PMID- 10339328
TI  - PPO market report.

PMID- 10339327
TI  - End-stage renal disease: managing quality and cost.

PMID- 10339329
TI  - A review of cost effectiveness research.

PMID- 10339331
TI  - State legislatures still debating telemedicine issues.

PMID- 10339332
TI  - 5th annual program survey--Part 2. Consultation activity in 35 specialties.

PMID- 10339330
TI  - Cost justification of PACS.

PMID- 10339333
TI  - A prescription for telemedicine.

PMID- 10339334
TI  - HCFA regs, Part III. ATSP responds to proposed HCFA regulations on telemedicine
      reimbursement.

PMID- 10339335
TI  - It's portable, it's wearable, it's telemedicine '99.

PMID- 10339336
TI  - Technology forecast for telemedicine systems planners.

PMID- 10339337
TI  - Distance healthcare education. Internet resources.

PMID- 10339338
TI  - Distance healthcare education. Technology overview.

PMID- 10339340
TI  - Profiles in medical videoconferencing.

PMID- 10339339
TI  - Distance healthcare education. Medical center program survey.

PMID- 10339342
TI  - Pacific Rim report: Australia. An interview with Dr. Peter Yellowlees.

PMID- 10339341
TI  - Pacific Rim report: Australia.
AB  - Some of the major barriers to telemedicine adoption relate to the immaturity of
      the industry, the limited telecommunications infrastructure, the lack of
      appropriate dialogue between vendors and buyers about solutions required, and the
      lack of industry partnerships. Remuneration is only one barrier. There are, of
      course, other substantial organizational, financial and attitudinal barriers.
      However, there are many promising aspects of the telemedicine industry in
      Australia that could provide the foundation for future innovation and expansion.

PMID- 10339343
TI  - Pacific Rim report: Hong Kong.

PMID- 10339344
TI  - Pacific Rim report: Dalian, China.

PMID- 10339345
TI  - Pacific Rim report: Malaysia.

PMID- 10339346
TI  - A question in desperate need of an answer: where does a teleconsultation occur?

PMID- 10339347
TI  - Pacific Rim report: Japan.

PMID- 10339348
TI  - PACS/teleradiology. Tattling on teleradiology.

PMID- 10339350
TI  - To push or to pull. That is the question. The subtleties of store-and-forward
      telemedicine.

PMID- 10339349
TI  - Personal telemedicine. PC host processors, Katmai, and telemedicine: what's the
      link?

PMID- 10339351
TI  - Annual survey--teleradiology service providers.

PMID- 10339352
TI  - A teleradiology primer.

PMID- 10339354
TI  - Adsorption Dynamics of alpha-Lactalbumin and beta-Lactoglobulin at Air-Water
      Interfaces.
AB  - Dynamics of adsorption of 14C radiolabeled beta-lactoglobulin and alpha
      lactalbumin at the air-water interface was investigated through the measurement
      of surface pressure (pi) and surface concentration (Gamma) via a radiotracer
      technique. Adsorption was diffusion controlled at short times, the rates of
      increase of pi and Gamma being lower at longer times because of an energy
      barrier. At low concentrations, an apparent time lag was observed in the
      evolution of pi for beta-lactoglobulin but not for alpha-lactalbumin which was
      shown to be due to the nonlinear nature of the pi-Gamma relationship for the
      former. The area per molecule of an adsorbed beta-lactoglobulin during the
      dynamics of adsorption was smaller than that for spread monolayer since beta
      lactoglobulin was not fully unfolded during adsorption. For alpha-lactalbumin,
      however, no such difference in the molecular areas for adsorbed and spread
      monolayer was observed indicating thereby that alpha-lactalbumin unfolded much
      more rapidly than beta-lactoglobulin. Evolution of Gamma for alpha-lactalbumin
      was found to occur in two steps possibly due to the change in the orientation of
      the adsorbed protein from a side-on to an end-on orientation. A previously
      developed mechanistic model (G. Narsimhan and F. Uraizee, Biotechnology Prog. 8,
      187 (1992)) was improved to account for the presence of hydrophobic patches on
      the surface of the protein molecule as well as an adsorbed protein layer at the
      air-water interface. The model predictions agreed quite well with the
      experimental evolution of Gamma for beta-lactoglobulin and alpha-lactalbumin. The
      model calculations seem to indicate that alpha-lactalbumin changes its
      orientation at the air-water interface from side-on to other orientations at
      higher surface concentrations. Copyright 1999 Academic Press.

PMID- 10339353
TI  - Differential expression of angiotensin-converting enzyme and chymase in dogs with
      chronic mitral regurgitation.
AB  - The current study tested the hypothesis that angiotensin-converting enzyme (ACE)
      and chymase expression are subject to different regulatory processes in the
      heart, as well as the lungs and kidneys and, as a result, have an important
      effect on the efficacy of ACE inhibitor treatment in modulating tissue
      angiotensin II (ANG II) levels in heart failure. A total of 18 dogs underwent the
      induction of mitral regurgitation and were followed for 5 months. Eleven dogs
      were untreated and seven received the ACE-inhibitor ramipril at a dose of 10 mg
      PO BID. Seventeen dogs underwent a sham-operation: six of these dogs were treated
      with ramipril for 3 months (10 mg PO BID) and 11 were untreated and followed for
      3 months prior to sacrifice. In mitral regurgitation dogs, ANG II levels were
      increased >2-fold in left ventricle, lungs, and kidney, but were normalized with
      ACE inhibitor-treatment only in the left ventricle. In the left ventricle and
      lungs steady state ACE mRNA levels and ACE activities were increased 2-fold in
      treated and untreated mitral regurgitation dogs compared to shams (P<0.05,
      ANOVA). In contrast, chymase mRNA levels were decreased by >50% and chymase
      activity was increased in left ventricle (LV) of mitral regurgitation dogs
      (P<0.05). Neither chymase mRNA nor chymase activity could be detected in the
      kidney; however, kidney ACE mRNA and ACE activity were significantly upregulated
      in treated and untreated mitral regurgitation dogs (P<0. 05). These results
      suggest that ACE and chymase expression are regulated differentially in the dog
      in response to chronic mitral regurgitation and ACE inhibitor treatment. Further,
      these responses, as well as regulation of ANG II formation, are organ specific.

PMID- 10339355
TI  - Asymmetric Multiblock Copolymers at the Gas-Liquid Interface: Phase Diagram and
      Surface Pressure.
AB  - A theoretical model of copolymers made of N blocks is studied at the air-water
      interface. Each block is made of a sequence A of ZA hydrophobic and of a sequence
      B of ZB hydrophilic monomers. The A and B sequences cannot cross the interface.
      The conformation of an adsorbed polymer is determined as a random walk of N
      elements whose size is the Flory radius of a single sequence. The structure of
      the interfacial layer is determined as a function of alpha = ZA/ZB and of the
      surface concentration using scaling law arguments. Only three different regions
      are found in the phase diagram to describe the change of surface regime as a
      function of the total surface concentration. The energy of flower-like micelles
      of polymers is calculated and compared with the energy of adsorbed macromolecules
      in order to determine the surface concentration at saturation. The surface
      pressure is also calculated as a function of the surface concentration in the
      three different regions of the phase diagram. It is found that these surface
      pressure isotherms are not affected by the solvent quality except when the
      properties of the interfacial layer are dominated by a purely two-dimensional
      behavior (semidiluted regime of the whole polymer or of the A sequences on the
      air side of the interface). Finally the properties of this model are compared
      with experimental data obtained with protein adsorbed layers and encouraging
      agreement is found although proteins are much more complicated polymers than this
      crude model. Copyright 1999 Academic Press.

PMID- 10339356
TI  - Aqueous Wetting Films on Fused Quartz.
AB  - Using an image analyzing interferometer, IAI, the interfacial characteristics of
      an isothermal constrained vapor bubble, CVB, in a quartz cuvette were studied as
      a precursor to heat transfer research. The effects of pH and electrolyte
      concentration on the meniscus properties (curvature and adsorbed film thickness)
      and the stability of the aqueous wetting films were evaluated. The surface
      potential in the electric double layer was a function of the cleaning and
      hydroxylation of the quartz surface. The disjoining pressure isotherm for pure
      water was very close to that predicted by the Langmuir equation. For aqueous
      solutions of moderate electrolyte concentration, the Gouy-Chapman theory provided
      a good representation of the electrostatic effects in the film. The effect of
      temperature on the film properties of aqueous solutions and pure water was also
      evaluated: The meniscus curvature decreased with increasing temperature, while
      Marangoni effects, intermolecular forces, and local evaporation and condensation
      enhanced waves on the adsorbed film layer. Pure water wetting films were
      mechanically metastable, breaking into droplets and very thin films (less than 10
      nm) after a few hours. Aqueous wetting films with pH 12.4 proved to be stable
      during a test of several months, even when subjected to temperature and
      mechanical perturbations. The mechanical stability of wetting films can explain
      the reported differences between the critical heat fluxes of pure water and
      aqueous solutions. The IAI-CVB technique is a simple and versatile experimental
      technique for studying the characteristics of interfacial systems. Copyright 1999
      Academic Press.

PMID- 10339357
TI  - Sedimentation of Strongly and Weakly Charged Colloidal Particles: Prediction of
      Fractional Density Dependence.
AB  - We report on calculations of the reduced sedimentation velocity U/U0 in
      homogenous suspensions of strongly and weakly charged colloidal spheres as a
      function of particle volume fraction &phi;. For dilute suspensions of strongly
      charged spheres at low salinity, U/U0 is well represented by the parametric form
      1 - p&phi;alpha with a fractional exponent alpha = 13 and a parameter p
      approximately 1.8, which is essentially independent from the macroion charge Z.
      This nonlinear volume fraction dependence can be quantitatively understood in
      terms of a model of effective hard spheres with &phi;-dependent diameter. For
      weakly charged spheres in a deionized solvent, we show that the exponent alpha
      can be equal to 12, if an expression for U/U0 given by Petsev and Denkov (1992,
      J. Colloid Interface Sci. 149, 329) is employed. We further show that the range
      of validity of this expression is limited to very small values of &phi; and Z,
      which are probably not accessible in sedimentation experiments. The presented
      results might also hold for other systems such as spherical proteins or ionic
      micelles. Copyright 1999 Academic Press.

PMID- 10339358
TI  - Effects of Secondary Polymer Covalently Attached to Monodisperse, Poly(maleic
      anhydride-styrene)-Modified Colloidal Silica on Dispersibility in Organic
      Solvent.
AB  - Effects of surface-grafted polymer on the dispersibility of polymer-silica
      composite particles in ethyl acetate-methanol cosolvent were investigated. The
      composite particles were prepared by a two-step modification of monodisperse
      colloidal silica (120 nm in diameter). Modifications were carried out by first
      reacting the surface silanol of the colloidal silica with maleic anhydride
      styrene copolymer silane coupling agent to prevent aggregation and then grafting,
      in acetone or tetrahydrofuran, amino group-terminated poly(methyl acrylate),
      poly(methyl methacrylate), or polystyrene to the maleic anhydride moiety on the
      surface. For poly(methyl acrylate) and poly(methyl methacrylate) graftings,
      composite particles with long polymer chains aggregated in methanol-rich
      cosolvent due to insoluble secondary polymer chain interaction among the
      particles. Particles with a small amount of relatively low-molecular-weight
      secondary polymer were dispersible in the methanol content range from 0 to 90
      vol%. Polystyrene-modified particles never aggregated, even in 90 vol% methanol
      solution. An ESR study of the suspension in ethyl acetate-hexane cosolvent
      suggested that the dispersibility of these composite particles in ethyl acetate
      rich solution is attributable to steric repulsion between solvated and expanded
      secondary polymer chains among the particles. The dispersibility of the composite
      particles in methanol-rich solution was controlled by a delicate balance between
      the electrostatic repulsion and the interparticle attraction due to the
      desolvated and insoluble polymer chain interaction among the particles. Copyright
      1999 Academic Press.

PMID- 10339359
TI  - Surface Complexation Modeling of Organic Acid Sorption to Goethite.
AB  - Surface complexation modeling was performed using the Generalized Two-Layer Model
      for a series of low molecular weight organic acids. Sorption of these organic
      acids to goethite was investigated in a previous study to assess the influence of
      particular structural features on sorption. Here, the ability to describe the
      observed sorption behavior for compounds with similar structural features using
      surface complexation modeling was investigated. A set of surface reactions and
      equilibrium constants yielding optimal data fits was obtained for each organic
      acid over a range of total sorbate concentrations. Surface complexation modeling
      successfully described sorption of a number of the simple organic acids, but an
      additional hydrophobic component was needed to describe sorption behavior of some
      compounds with significant hydrophobic character. These compounds exhibited
      sorption behavior that was inconsistent with ligand exchange mechanisms since
      sorption did not decrease with increasing total sorbate concentration and/or
      exceeded surface site saturation. Hydrophobic interactions appeared to be most
      significant for the compound containing a 5-carbon aliphatic chain. Comparison of
      optimized equilibrium constants for similar surface species showed that model
      results were consistent with observed sorption behavior: equilibrium constants
      were highest for compounds having adjacent carboxylic groups, lower for compounds
      with adjacent phenolic groups, and lowest for compounds with phenolic groups in
      the ortho position relative to a carboxylic group. Surface complexation modeling
      was also performed to fit sorption data for Suwannee River fulvic acid. The data
      could be described well using reactions and constants similar to those for
      pyromellitic acid. This four-carboxyl group compound may be useful as a model for
      fulvic acid with respect to sorption. Other simple organic acids having multiple
      carboxylic and phenolic functional groups were identified as potential models for
      humic substances. Copyright 1999 Academic Press.

PMID- 10339360
TI  - The Equations of State for an Interface Involving a Dissociated Additive.
AB  - On the basis of quasiton theory the equations of state were obtained for a two
      component interface separating liquid and gas phases with a surface-active
      additive to the condensed matter. The first equation describes the state of a
      surface layer of a binary liquid, first for a liquid metal. The second equation
      is that of a surface layer of a vapor in contact with the condensate. With the
      help of these equations computations were conducted for the following systems: Fe
      O, Fe-N, Fe-S, Hg-Na, Hg-K, Hg-Cs, 4He-3He. Except in the last case, the
      thickness l1 of the surface layer of liquid is close to the atomic radii of the
      additives, for the most part, but the thickness l2 of the surface layer of the
      gas is sometimes of an order of magnitude greater than l1. Copyright 1999
      Academic Press.

PMID- 10339361
TI  - Electrophoretic Motion of a Prolate Spheroid in Electro-osmotic Flow Developed in
      a Flat Cell.
AB  - Electrophoretic motion is analyzed for a neutrally buoyant, non-Brownian prolate
      spheroid suspended in an electro-osmotic flow developed in a flat
      microelectrophoresis cell. Neglecting the double-layer deformation, the
      trajectory and orientation of the spheroid is computed to assess the significance
      of particle motion in a lateral direction during an electrophoresis experiment.
      The double-layer thickness of the spheroid is arbitrary. In a closed
      microelectrophoresis system the electro-osmosis results in a parabolic flow
      field. During a short period of time (several seconds) the spheroid may deviate
      significantly in a lateral direction from a straight path parallel to the applied
      electric field. During a longer period of time (several minutes) the spheroid
      undergoes a sinuous motion in which it translates periodically back and forth
      across a straight path along the main flow direction. The spheroid may also
      translate along a closed trajectory. In all cases the orientation of the spheroid
      follows the equation for Jeffery orbit. Copyright 1999 Academic Press.

PMID- 10339362
TI  - Directional Converter Arm Method for Surface and Interfacial Tension Measurements
      with a Top-Loading Balance.
AB  - A method is described for utilizing a top-loading balance, with a directional
      converter arm, in vertical-pull surface force measurements. The Padday rod-pull
      technique, the du Nouy ring method, and the Wilhelmy plate method are utilized
      with rods, thin-walled tubes, wire rings, and plates either rigidly attached to
      the converter arm or hanging freely from a hook at the end of the arm. The
      robustness, large weighing capacity, and accuracy of top-loading balances make
      them ideally suited for a variety of types of surface and interfacial tension
      measurements. The converter arm method can be used with a stainless steel rod (3
      7 mm in diameter) in vertical-pull surface tension measurements, with samples
      having volumes of only a few tenths of a milliliter. Measurements on very small
      liquid volumes are feasible because the rod is firmly attached to the converter
      arm rather than hanging freely as in measurements with balances mounted above the
      sample; therefore, the rod cannot swing toward and attach to the wall of small
      sample tubes. Automation of force and height measurements with the converter
      arm/top-loading balance method is straightforward. Copyright 1999 Academic Press.

PMID- 10339363
TI  - Preparation and Characterization of Polymer-Stabilized Ruthenium-Platinum and
      Ruthenium-Palladium Bimetallic Colloids and Their Catalytic Properties for
      Hydrogenation of o-Chloronitrobenzene.
AB  - Colloidal dispersions of poly(N-vinyl-2-pyrrolidone) (PVP)-stabilized ruthenium
      platinum and ruthenium-palladium bimetallic colloids were prepared by NaBH4
      reduction of the corresponding mixed-metal salts at room temperature and
      characterized by TEM, XPS, and XRD. The resulting bimetallic colloids were used
      as catalysts for the selective hydrogenation of o-chloronitrobenzene (o-CNB) in
      methanol at 303 K under 0.1 MPa of hydrogen. It was observed that the catalytic
      performance of PVP-stabilized ruthenium-platinum colloids (PVP-Ru/Pt) and
      ruthenium-palladium colloids (PVP-Ru/Pd) was dependent on their compositions and
      could be remarkably affected by some added metal cations. In the presence of
      cobalt ion, nearly 100% selectivity to o-chloroaniline (o-CAN) was achieved over
      PVP-Ru/Pt colloids at 100% conversion of o-CNB, with an activity two orders of
      magnitude higher than that of monometallic PVP-Ru colloid. Copyright 1999
      Academic Press.

PMID- 10339364
TI  - Growth of Cetyltrimethylammonium Chloride and Acetate Micelles with Counterion
      Concentration.
AB  - Time resolved fluorescence quenching measurements with pyrene as probe are
      employed to determine aggregation numbers for hexadecyltrimethylammonium acetate
      (CTAOAc) and chloride (CTACl) micelles as a function of the concentration of
      detergent and added common-counterion salt. The aggregation numbers, NA, of CTACl
      are roughly twice those of CTAOAc micelles at equivalent concentrations of
      detergent and salt, consistent with the known relative counterion binding
      affinity (chloride >> acetate). For both detergents, the increase of NA with the
      net concentration of counterions in the intermicellar aqueous phase ([Yaq])
      follows the relationship found previously for anionic micelles: log NA = log No +
      gamma log[Yaq], where gamma and No are constants. However, compared to anionic
      micelles, for which gamma = 0.2-0.25, spherical micelles of both CTAOAc and CTACl
      exhibit less pronounced growth, with gamma = 0.1. Copyright 1999 Academic Press.

PMID- 10339365
TI  - The Surface Charge Density Influence on the Electrokinetic Properties of Model
      Colloids: Solvent Composition Effect.
AB  - This paper deals with two problems found in electrokinetics, the anomalous
      behavior exhibited by most polymer colloids and the discrepancy between the zeta
      potentials obtained from different electrokinetic phenomena. Electrophoretic
      mobility for dilute dispersions and streaming current for concentrated
      dispersions are used to determine the zeta-potential. Two systems with different
      features (particle radius and surface charge density) have been studied. The
      influence of varsigma0 on the above-mentioned problems seems to be very
      important. In order to test this hypothesis, different nonaqueous media were
      used, which were significantly different in several liquid media properties (such
      as bulk conductivity, dielectric constant, and viscosity) and particle properties
      (such as surface charge density). Copyright 1999 Academic Press.

PMID- 10339366
TI  - Permeate Flux in Crossflow Ultrafiltration under Intermediate Pressures.
AB  - The intermediate pressure range stands for an important condition for
      ultrafiltration operations where permeate flux falls below that predicted from a
      linear flux-pressure relationship but does not reach the limiting flux. Optimal
      performance of ultrafiltration might be achieved on the upper end of the
      intermediate pressure range because the maximum permeate flux will be obtained at
      the lowest possible pressure. Unlike in the low pressure range or in the high
      pressure range, little has been known about the behavior of permeate flux in the
      intermediate pressure range. A general theory of permeate flux in the
      intermediate pressure range is developed in this study. The theory includes the
      linear-increasing and limiting fluxes as two special cases and, therefore, can be
      used to study the behavior of permeate flux in ultrafiltration in the whole
      pressure range. Copyright 1999 Academic Press.

PMID- 10339367
TI  - Study on Preparation and Morphology of Uniform Artificial Polystyrene-Poly(methyl
      methacrylate) Composite Microspheres by Employing the SPG (Shirasu Porous Glass)
      Membrane Emulsification Technique.
AB  - Fairly uniform polystyrene-poly(methyl methacrylate) (PST-PMMA) composite
      microspheres were prepared by employing the SPG (Shirasu Porous Glass) membrane
      emulsification technique. PST, PMMA, and cosurfactant (lauryl alcohol, LOH)
      dissolved in dichloromethane (DCM) were used as a dispersed phase, and an aqueous
      phase containing poly(vinyl alcohol) and sodium lauryl sulfate was the continuous
      phase. The effects of LOH amount on the critical pressure of emulsification
      (Pcr), size distribution of droplets, and morphologies of final particles were
      investigated. It was found that Pcr decreased with increasing LOH amount because
      of preferential partition of LOH on the surface of the droplets in the initial
      stage of emulsification. When polymer concentration or PMMA/PST ratio was low,
      the size distribution of droplets decreased with increasing LOH amount, whereas
      an inverse trend was observed when both polymer concentration and PMMA/PST ratio
      were high. When polymer concentration was low, PST-PMMA core-shell particles
      always were obtained in the absence of LOH, irrespective of the PMMA/PST ratio.
      In the presence of LOH, however, microdomain, hemisphere, and inverted core-shell
      morphologies were formed as the PMMA/PST ratio decreased from 5/5 to 1/9 (g/g).
      When polymer concentration was high, different morphologies such as multiplet and
      inverted core-core-shell were observed. Theoretical calculations of morphologies
      were carried out, and agreement was obtained between experimental and calculated
      results. Copyright 1999 Academic Press.

PMID- 10339368
TI  - Reversible Agglomeration: A Kinetic Model for the Peptization of Titania
      Nanocolloids.
AB  - We formulate a model for the peptization of titania nanocolloids. The model
      assumes simultaneous agglomeration/deagglomeration with size-independent rate
      constants. It predicts that the evolution of the particle size exhibits first
      order kinetics and that the final particle size scales as R approximately C1/df,
      where C is the mass concentration of the colloid and df is the fractal dimension.
      These predictions are tested experimentally. We find that the model provides a
      quantitative and consistent description of the peptization process over a wide
      range of experimental variables and that it allows the determination of the
      aggregation and deaggregation rate constants from the time evolution of the
      average size. Copyright 1999 Academic Press.

PMID- 10339369
TI  - Thermodynamics of Micellization of n-Alkyl Sulfates in an Alkaline Medium at
      Different Temperatures.
AB  - Critical micelle concentrations (cmc) have been calculated from conductivity
      measurements at 293.15, 298.15, 303.15, 308.15, and 313.15 K for sodium n-decyl
      sulfate (SDES), sodium n-undecyl sulfate (SUNDS), and sodium n-dodecyl sulfate
      (SDS) in a medium of pH 10.0 and ionic strength 0.0312. Thermodynamic parameters
      of micellization, standard Gibbs energies (), standard enthalpies (), and
      standard entropies (), have been obtained by application of the model of Evans
      and Ninham in terms of hydrophobic and surface contributions. Copyright 1999
      Academic Press.

PMID- 10339370
TI  - The Effect of Slight Deformation on Thermocapillary-Driven Droplet Coalescence
      and Growth.
AB  - The collision efficiency of two slightly deformable drops in thermocapillary
      motion at small Reynolds and Marangoni numbers is determined by a trajectory
      analysis involving methodology from matched asymptotic expansions. The outer
      solution for two spherical drops which are nearly touching provides the contact
      force driving the inner solution. Accurate calculation of the contact force and
      near-contact motion is aided by new solutions for the mobility functions parallel
      and normal to the drops' line of centers that are valid at very small
      separations. Governed by a system of integro-differential equations coupling the
      flow inside the drops and that within the small gap, the inner solution allows
      demarcation of the regions of drop coalescence and separation. Apart from the
      driving force, the thin-film equations are unchanged to leading order from the
      buoyancy-driven case, since no additional singularity is introduced into the
      tangential stress by the presence of the finite temperature gradient. The
      interplay of small deformation, as measured by the capillary number (Ca), and
      attractive van der Waals forces controls the apparent contact motion. Results for
      the collision efficiency are mapped out for a range of five dimensionless
      parameters: Ca, size ratio, drop-to-medium viscosity ratio, drop-to-medium
      thermal conductivity ratio (&kcirc;), and a dimensionless Hamaker parameter.
      Since the only effect on the inner solution of an increase in the thermal
      conductivity ratio is an increase in the amount of time the drops spend in close
      approach, it is possible for the collision efficiency of two slightly deformable
      drops with higher &kcirc; to be greater than that for two similar drops with
      lower &kcirc;. This behavior differs from that of spherical drops, where an
      increase in thermal conductivity ratio always leads to a decrease in the
      collision efficiency, as a result of greater hydrodynamic interaction between the
      spherical drops due to the temperature gradient. In addition, collision
      efficiencies are provided for a model system of ethyl salicylate (ES) drops in
      diethylene glycol (DEG). The collision efficiency decreases rapidly with
      increasing drop size above a critical value, due to the increasing role of
      deformation in retarding the drainage of the thin film between two drops in close
      approach. Population dynamics simulations are performed for homogeneous
      suspensions of the ES/DEG system, showing that slight deformation limits droplet
      growth due to coalescence in dilute dispersions. Copyright 1999 Academic Press.

PMID- 10339371
TI  - Chymotrypsin Adsorption on Montmorillonite: Enzymatic Activity and Kinetic FTIR
      Structural Analysis.
AB  - Soils have a large solid surface area and high adsorptive capacities. To
      determine if structural and solvation changes induced by adsorption on clays are
      related to changes in enzyme activity, alpha-chymotrypsin adsorbed on a
      phyllosilicate with an electronegative surface (montmorillonite) has been studied
      by transmission FTIR spectroscopy. A comparison of the pH-dependent structural
      changes for the solution and adsorbed states probes the electrostatic origin of
      the adsorption. In the pD range 4.5-10, adsorption only perturbs some peripheral
      domains of the protein compared to the solution. Secondary structure unfolding
      affects about 15-20 peptide units. Parts of these domains become hydrated and
      others entail some self-association. However, the inactivation of the catalytic
      activity of the adsorbed enzyme in the 5-7 pD range is due less to these
      structural changes than to steric hindrance when three essential imino/amino
      functions, located close to the entrance of the catalytic cavity (His-40 and -57
      residues and Ala-149 end chain residue), are oriented toward the negatively
      charged mineral surface. When these functions lose their positive charge, the
      orientation of the adsorbed enzyme is changed and an activity similar to that in
      solution at equivalent pH is recovered. This result is of fundamental interest in
      all fields of research where enzymatic activity is monitored using reversible
      adsorption procedures. Copyright 1999 Academic Press.

PMID- 10339372
TI  - Points of Zero Charge and Intrinsic Equilibrium Constants of Silica-Magnetite
      Composite Oxides.
AB  - A series of magnetic adsorbents (silica-magnetite composite oxides) containing 0,
      20, 40, 60, 80, and 100 wt% magnetite were prepared via the sol-gel process,
      where 0.1-um-radius magnetite particles were encased in a mesoporous silica
      matrix. The experimental pHpzc for each of the pure oxides and their mixtures was
      tested against two applicable models in the literature; neither model explained
      the observed behavior. One of the models did not account for the heterogeneous
      nature of the two distinct surfaces present in these silica-magnetite composite
      oxides, and neither model accounted for the possibility of the silica locally
      altering the behavior of the magnetite functional groups. The behavior was
      corroborated independently, however, based on an analysis carried out with the
      measured surface acidity constants. This work also showed that the total exchange
      capacity of each of the mixed oxides was dominated by the high surface area of
      the silica, and that the electrolyte species, Na+ or NO-3, did not completely
      complex with the surface of the oxides, as expected for weak binding ions. The
      chemical component of the free energy of adsorption of protons for the acid-base
      reactions also dominated the solvation and coulombic contributions for each of
      the pure oxides and their mixtures. Copyright 1999 Academic Press.

PMID- 10339373
TI  - Binary and Ternary Adsorption of n-Alkane Mixtures on Activated Carbon.
AB  - The adsorption isotherms of the binary n-alkane mixtures n-hexane/n-octane, n
      octane/n-tetradecane, and n-hexane/n-tetradecane on the activated carbon TA 95
      are measured at 298 K and described with mathematical functions. About 40
      experimental values of the adsorption excess of the ternary mixture n-hexane/n
      octane/n-tetradecane on activated carbon TA 95 at 298 K are gas
      chromatographically measured inside the ternary triangle. The ternary data are
      represented in the three-dimensional space with the help of transformation of
      coordinates and by utilization of the conception of the quasi-two-component
      representation of the mole fractions. A consistency test for the specific wetting
      Gibbs energies calculated from the binary data is carried out. The possibilities
      for a mathematical prediction of ternary data from adsorption data for the
      constituent binary mixtures are proved. Copyright 1999 Academic Press.

PMID- 10339374
TI  - TEM Investigation and Electron Diffraction Study on Dispersion of Gold
      Nanoparticles into a Nylon 11 Thin Film during Heat Treatment.
AB  - We have investigated the effect of heat treatment on the changes in the
      microstructure of nylon 11 thin films containing nanosized Au particles by means
      of lateral and cross-sectional transmission electron microscopy. It was observed
      that, on heat treatment, the Au islandlike particles initially deposited on the
      nylon 11 surface penetrated into the polymer layer to form a composite film
      consisting of nanosized spherical Au particles dispersed in a polymer matrix,
      while the initially amorphous nylon 11 matrix crystallized to the alpha
      crystalline form. The surface stress coefficient of the Au particles, calculated
      from the lattice constant determined by the electron diffraction patterns,
      decreased as the Au particles penetrated into the polymer matrix, which can be
      due to both coalescence of the particles to a spherical shape and reduction of
      the surface free energy of the particles by embedding in the matrix. The
      molecular chain motion of the nylon 11 matrix during the crystallization process
      is suggested to be responsible for the dispersion of Au particles into the
      polymer matrix. Copyright 1999 Academic Press.

PMID- 10339375
TI  - On the Anomalous Behavior of Alcohol Adsorption on Polymer-Coated Siliceous
      Materials.
AB  - Adsorption of alcohols on polymer-coated silica materials is considered. The data
      obtained show that the inner structure of the polymer layer determines the
      adsorptive properties of the material. From the presented results it follows that
      the adsorption of polar alcohol molecules from nonpolar solvent occurs in two
      steps of different kinetics. A simple model which explains large discrepancies
      between the adsorption and desorption heats is proposed. It is also demonstrated
      that the model allows us to explain the adsorption behavior of polar solutes from
      polar solvent. Copyright 1999 Academic Press.

PMID- 10339376
TI  - Wettability, Oil Recovery, and Interfacial Tension with an SDBS-Dodecane-Kaolin
      System.
AB  - The wettability of kaolin with SDBS (sodium dodecyl benzene sulfonate) aqueous
      solutions was measured by the Washburn equation expressed as contact angles. The
      contact angle changes for SDBS aqueous solutions on kaolin surface was studied.
      The interfacial tension between the SDBS solutions and n-dodecane was measured
      using both drop volume and spinning drop methods. Then the oil recovery of n
      dodecane on the kaolin surface was tested. It was found that the minimum contact
      angle (the most hydrophilic condition) and the maximum oil recovery occurred near
      the critical micelle concentration (CMC) of SDBS while the interfacial tension
      between the SDBS solution and n-dodecane was far from ultra-low. Copyright 1999
      Academic Press.

PMID- 10339377
TI  - Microcalorimetric Studies of the Interactions of Lysozyme with Immobilized Metal
      Ions: Effects of Ion, pH Value, and Salt Concentration.
AB  - This study extends previous research on the interaction of biomaterials with
      immobilized Cu(II) by isothermal titration calorimetry (ITC) on Fe(III). The
      difference of the binding behavior of protein with that of the immobilized metal
      ions is also discussed. For the immobilized Fe(III), ITC results show that the
      adsorption enthalpy at a constant pH value decreased as the NaCl concentration
      increased and also decreased with the pH values at constant NaCl concentrations.
      The adsorption enthalpy become negative under higher pH values or higher salt
      concentrations indicating the adsorption process is partly driven by the
      enthalpy. The enthalpy of lysozyme with Fe(III) is higher than that with Cu(II)
      implying that the heat required for the dehydration of Cu(II) is lower than for
      the dehydration of Fe(III) and/or that the heat generated from the formation of
      the coordination with Cu(II) is higher than with Fe(III). In addition, the
      comparison of different immobilized metal ions corresponding to the equilibrium
      binding affinity suggests that the binding force of lysozyme with Cu(II) is
      higher than with Fe(III). This study presents the chemical differences between
      the binding affinity and the adsorption enthalpy of lysozyme interacting with the
      immobilized metal ions. The binding and thermodynamic data presented in this
      study elucidate the mechanism and process of lysozyme binding with immobilized
      metal ions. In addition, the thermodynamic characteristic functions provide
      valuable information enabling a more thorough understanding of protein adsorption
      at the immobilized metal ion affinity surface. Copyright 1999 Academic Press.

PMID- 10339378
TI  - Modification of the Kaolinite Hydroxyl Surfaces through the Application of
      Pressure and Temperature, Part III.
AB  - Kaolinite hydroxyl surfaces have been modified by the combined application of
      heat and pressure in the presence of water at 120 degrees C and 2 bars and at 220
      degrees C and 20 bars. X-ray diffraction shows that some of the layers are
      expanded. It is hypothesized that this expansion occurs at the edges of the
      crystals due to the intercalation of water. The X-ray diffraction data is
      supported by diffuse reflectance infrared spectroscopy, with additional hydroxyl
      stretching bands observed around 3550 and 3590 cm-1. These bands are attributed
      to adsorbed water and to edge-intercalated water. Additional bands are observed
      in the hydroxyl deformation region around 895 and 877 cm-1. The position of these
      bands depends on the defect structure of the kaolinite and the conditions under
      which the kaolinite was thermally treated. Additional water bending vibrations
      were observed at 1651 and 1623 cm-1 for the thermally treated high-defect
      kaolinite and at 1682 and 1610 cm-1 for the low-defect kaolinite. The bands at
      1651 and 1682 cm-1 are attributed to the bending modes of water coordinated to
      the kaolinite surface. The role of water in the edge intercalation of water in
      the high- and low-defect kaolinites is apparently different. Copyright 1999
      Academic Press.

PMID- 10339379
TI  - The Effect of Polymer Concentration on the Dynamics of Adsorbed Poly(N
      isopropylacrylamide) at Particle Surfaces in Water.
AB  - Results are presented of a light scattering study of the dynamics of absorbed
      poly(N-isopropylacrylamide) (PNIPAM) chains at the surfaces of poly(N-tert
      butylacrylamide) (PNTBA) latex particles using several different feed weight
      ratios of PNIPAM to latex particles. The adsorbed layer dynamics under the
      present experimental conditions were postulated to include both the extended-to
      loopily adsorbed state transition of tightly adsorbed chains and the diffusion of
      tenuously adsorbed chains. The dynamics were described by a nonexponential rate
      process. The relaxation times calculated were found to increase with increasing
      polymer to latex feed weight ratio. Kinetic constraints were inferred to play a
      crucial role in controlling the overall dynamics. A higher polymer to latex feed
      weight ratio was considered to enhance these kinetic constraints. Copyright 1999
      Academic Press.

PMID- 10339380
TI  - Effects of Anions on Local Structure of Al and Si in Aluminosilicates.
AB  - Three kinds of amorphous aluminosilicates were synthesized by coprecipitation of
      silicic acid with aluminum hydroxide in the presence of different inorganic ions:
      sulfate, chloride, and nitrate. Although the bulk composition of the
      aluminosilicates obtained was not affected by anion species, their DTA spectra
      were significantly different, suggesting that their structures also differ. The
      local structure of Al and Si in the aluminosilicates was studied in detail by
      27Al and 29Si MAS NMR. From the 27Al MAS NMR spectra and comparison between 29Si
      HD- and CP-MAS NMR spectra, it was concluded that the aluminosilicate obtained in
      the presence of sulfate ions has only a montmorillonite-like structure, whereas
      in the cases of chloride and nitrate, the solids are composed of three phases:
      aluminum hydroxide, silica, and the montmorillonite-like aluminosilicate. The
      difference in the local structure of Al and Si in the aluminosilicates was
      explained by the difference in interaction between the anions and aluminum ions.
      Copyright 1999 Academic Press.

PMID- 10339381
TI  - Dodecyl Pyridinium/Alkali Metals Ion Exchange on Muscovite Mica.
AB  - Model muscovite with high cation exchange capacity was prepared, the surface of
      which was saturated with a single species of alkali metal ions. The kinetics and
      thermodynamics of the exchange reaction of the 1-dodecylpyridinium ion (NDP+)
      with alkali metal ions onto that substrate were studied. The exchange rate
      depended on the type of alkali metal ions present on the surface because of their
      different affinities to mica. However, in all cases the reaction was fast at the
      beginning and about 50% of the ions were exchanged within one hour; then the
      reaction rate decreased and equilibrium was only reached after several hours.
      This was attributed to a rate-determining rearrangement step in which the alkyl
      chains rearrange to adopt a dense packing. The reactivity of the alkali metal
      ions was in the order Li+ > Na+ > K+ > Rb+, Cs+, and in the case of K+, Rb+, and
      Cs+, equilibrium was only reached after 72 h. The lithium and sodium ions were
      exchanged almost quantitatively until a saturation value was nearly reached,
      while the K+, Rb+, and Cs+ exchange isotherms were less steep. The equilibrium
      constants (K) as well as the ion exchange capacity (S) were calculated by least
      squares fits. Since K is infinite for quantitative exchange and decreases
      asymptotically upon deviation from this ideal behavior, the high K values (>10)
      of the NDP+/Li+ and Na+ exchange cannot be accurately determined. K ranges
      between 1 and 3 for the NDP+/K+, Rb+, and Cs+ exchange. The affinity of NDP+ to
      muscovite was similar or slightly higher than that of K+, Rb+, and Cs+, but was
      much higher than that of Li+ and Na+. The presence of oxonium ions in water did
      not strongly influence the exchange reaction on delaminated mica, as in the case
      of mica sheets, due to its high CEC. Copyright 1999 Academic Press.

PMID- 10339382
TI  - Effect of Surface Characteristics of Wood-Based Activated Carbons on Adsorption
      of Hydrogen Sulfide.
AB  - Three wood-based commercial activated carbons supplied by Westvaco were studied
      as adsorbents of hydrogen sulfide. The initial materials were characterized using
      sorption of nitrogen, Boehm titration, potentiometric titration, water sorption,
      thermal analysis, and temperature-programmed desorption. The breakthrough tests
      were done at low concentrations of H2S in the input gas to simulate conditions in
      water pollution control plants where carbon beds are used as odor adsorbents. In
      spite of apparent general similarities in the origin of the materials, method of
      activation, surface chemistry, and porosity, significant differences in their
      performance as hydrogen sulfide adsorbents were observed. Results show that the
      combined effect of the presence of pores large enough to accommodate surface
      functional groups and small enough to have the film of water at relatively low
      pressure contributes to oxidation of hydrogen sulfide. Moreover, there are
      features of activated carbon surfaces such as local environment of acidic/basic
      groups along with the presence of alkali metals which are important to the
      oxidation process. Copyright 1999 Academic Press.

PMID- 10339383
TI  - Critical Condensate Saturation in Porous Media.
AB  - The understanding of gas and condensate flow in porous media is critical to the
      optimum exploitation of gas-condensate reservoirs. Critical condensate saturation
      and relative permeabilities are the key parameters for the evaluation of possible
      recovery strategies. This work is aimed at developing a mechanistic network model
      for the critical condensate saturation in which phase trapping and connectivity
      in the pore corners are critically examined. Porous media are modeled by networks
      of pore bodies interconnected by pore throats. Bodies and throats are
      characterized by their connectivity, shapes, and radii distributions. Pore-level
      laws are identified from micromodel experiments with near-critical fluids. A
      nonzero critical condensate saturation can be obtained in the absence of contact
      angle hysteresis due to the converging-diverging nature of the throats. The
      critical saturation at which the condensate flows is found to be a function of
      pore geometry, water saturation, and interfacial tension (or the Bond number).
      The modified sphere-pack model underpredicts the critical condensate saturation
      of typical sandstones. The cubic model adequately predicts the critical
      saturation and its experimentally observed trends. Copyright 1999 Academic Press.

PMID- 10339384
TI  - Mechanisms of Surface Precipitation and Dissolution of Barite: A Morphology
      Approach.
AB  - Barite (BaSO4) was synthesized at normal pressure and room temperature by mixing
      sodium sulfate and barium chloride solutions by gentle flow (0.5 ml/min.). The
      well-formed rectangular and rhombohedral crystals with smooth faces formed from
      solutions with low degrees of supersaturation. Most precipitates became single
      crystals. We employed the scanning electron microscope (SEM) to observe barite
      dissolution by chemical agent diethylenetrinitrilopentaacetic acid. Molecular
      modeling was used to assist the interpretation of the surface reaction. A kinetic
      model for the pit growth (initial dissolution) on the surface was evaluated. With
      SEM microanalysis of barite and kinetic model of pit growth, important surface
      phenomena and mechanisms of dissolution can be hypothesized. Surface phenomena
      and composition are very important in barite dissolution. Experimental results
      suggest that the initial dissolution starts on the two lowest energy surfaces:
      (001) and (210), and that the etch pits are elongated in one direction on the
      (210) surface and formed cavities on the (001) surface. The simulated surface
      structures by molecular modeling can aid the interpretation the pit formation on
      those selected surfaces. Copyright 1999 Academic Press.

PMID- 10339385
TI  - Monitoring Changes in Surface and Structural Properties of Porous Carbons
      Modified by Different Oxidizing Agents.
AB  - A series of active carbons and carbon blacks was oxidized with various oxidizing
      agents such as hydrogen peroxide, perchloric acid, and nitric acid. Their surface
      and structural properties were evaluated by use of nitrogen and water vapor
      adsorption isotherms, as well as high-resolution thermogravimetry. A comparative
      analysis of differential thermogravimetric curves and adsorption isotherms of
      nitrogen and water vapor for the samples studied showed that the surface
      properties of oxidized carbons depend on the type of oxidizing agent as well as
      oxidation conditions. This comparison shows that the modification of carbons with
      concentrated nitric acid caused the most pronounced surface and structural
      changes. These changes were much smaller for the samples modified with perchloric
      acid and hydrogen peroxide. Copyright 1999 Academic Press.

PMID- 10339386
TI  - An Approach of a Nonlinear Dynamic Model for Micellar Effects on Bimolecular
      Reactions.
AB  - The effects of micellar solutions on bimolecular reactions were studied in detail
      using a newly established nonlinear dynamic model with a far-from-equilibrium
      reaction scheme, by which the incorporation of organic substrates with the
      micellar phase was imitated. Through the linear stability analysis of the steady
      state solutions given by the rate equation of the change of substrate
      concentration within a micellar phase with time, it leads to some explicit
      relationships between the incorporated substrate concentration and the relevant
      parameters. Based on this model the micellar effects on the kinetics of the
      alkaline hydrolysis of esters have been interpreted. Copyright 1999 Academic
      Press.

PMID- 10339387
TI  - Fractal Analysis of Mercury Porosimetry Data in the Framework of the
      Thermodynamic Method.
AB  - The thermodynamic method for fractal analysis is applied to mercury intrusion
      data. The results for representative commercial carbon black samples and a series
      of resorcinol-formaldehyde (RF) freeze-dried gels for different values of the
      molar ratio of resorcinol (R) to catalyst (C) are discussed in relation with the
      type of behavior exhibited by the samples during mercury porosimetry
      measurements. The obtained surface fractal dimensions are compared with those
      derived previously from the small-angle X ray scattering (SAXS) and the nitrogen
      adsorption. Copyright 1999 Academic Press.

PMID- 10339388
TI  - Simplified Description of Adsorption Breakthrough Curves of 1,1-Dichloro-1
      fluoroethane (HCFC-141b) on Activated Carbon with Temperature Effect.
AB  - Recovery of HCFC-141b, used as a major alternative solvent and foam-blowing agent
      for CFCs in industrial applications, has received great attention due to its
      gradual phase out. This paper describes an investigation of the adsorption
      breakthrough of HCFC-141b vapor on a commercial activated carbon. A simple
      theoretical model developed by Yoon and Nelson was applied to investigate the
      breakthrough behavior of HCFC-141b on an activated carbon column. The values of
      parameters k' (a rate constant) and tau (the time required for 50% adsorbate
      breakthrough) in the Yoon and Nelson model were determined at four different
      concentration levels (i.e., 399, 734, 1139, and 1954 ppmv) and five temperature
      ranges (i.e., 283, 293, 298, 303, and 313 K), respectively. These values were
      used to calculate the entire (0-100%) breakthrough curve (plot of percentage
      breakthrough versus time) regarding the adsorption of HCFC-141b on activated
      carbon columns. It was found that the calculated theoretical breakthrough curves
      are in high agreement with the corresponding experimental data. Also, the rate
      constant k' can be reasonably represented by the empirical Arrhenius equation.
      The results obtained are applicable for the scale-up design of adsorption columns
      in the HCFC adsorption on activated carbon adsorbent. Copyright 1999 Academic
      Press.

PMID- 10339389
TI  - gamma-Radiation Synthesis of the Nanocrystalline Semiconductors PbS and CuS.
AB  - The nanocrystalline semiconductors PbS and CuS were prepared by gamma-irradiation
      at room temperature in an ethanol system for the first time. Carbon disulfide was
      used as the sulfur source; lead acetate and copper chloride were used as metal
      ion sources. X-ray Powder Diffraction was used to characterize the products and
      Transmission Electron Microscopy to determine their morphology. The purity and
      compositions of the products were examined by X-ray photoelectron spectra. The
      photoluminescence property of as-prepared PbS was studied. A blue shift was
      observed in the PL spectra, indicating the quantum size effect on nanocrystalline
      PbS. Copyright 1999 Academic Press.

PMID- 10339391
TI  - Estimating protein turnover with a [15N,13C]leucine tracer: a study using
      simulated data.
AB  - We explore the use of [15N,13C]leucine tracer to estimate whole-body fractional
      rates of a fast-turning-over protein pool employing synthetic data. The kinetics
      of [15N,13C]leucine tracer are simplified compared with those of traditional
      leucine tracers and benefit from irreversible transamination to [13C]alpha
      ketoisocaproaic acid (KIC) resulting in a simplified model structure. A three
      compartment model of [15N,13C]leucine kinetics was proposed and evaluated using
      data generated by a Reference Model (based on a model by Cobelli et al.). The
      results suggest that fractional turnover rates of a fast-turning-over protein
      pool can be estimated with a low but acceptable precision during a six-hour
      constant intravenous infusion of [15N,13C]leucine with frequent sampling of
      plasma tracer-to-tracee ratio (TTR) of [15N,13C]leucine. We conclude that
      [15N,13C]leucine may be useful for the measurement of protein kinetics and its
      full potential should be explored in clinical studies with compartmental data
      analysis.

PMID- 10339390
TI  - Theoretical considerations of cross-immunity, recombination and the evolution of
      new parasitic strains.
AB  - We explore the dynamics of multiple strains of a parasite in order to assess the
      conditions under which a novel strain, perhaps a mutant or migrant, may invade a
      population that already carries an endemic strain. Multiple strain dynamics can
      be modeled through coinfection or complete cross-immunity. We examine these three
      modes to discuss the relationships among cross-immunity, the basic reproductive
      rates of each strain, and the invasion of the new strain. Superinfection is more
      restrictive than coinfection in the proportion of parameters that allows
      invasion. The coinfection model is extended to allow haploid strains to undergo
      recombination within the host. We investigate the effects of recombination and
      cross-immunity on the invasion of new strains. Interestingly, although
      recombination is understood to generate diversity, it is not always advantageous.

PMID- 10339392
TI  - Are the fusion processes involved in birth, life and death of the cell depending
      on tilted insertion of peptides into membranes?
AB  - Various peptide segments have been modeled as asymmetric amphipathic alpha
      helices. Theoretical calculations have shown that they insert obliquely into
      model membranes. They have been named "tilted peptides". Molecular modeling
      results reported here also evidence the presence of tilted peptides in ADM-1
      protein of Caenorhabditis elegans that may be involved in fusion events, in
      meltrin alpha, a protein implicated in myoblast fusion, in hemagglutinin of
      influenza virus, in the E2 glycoprotein of rubella virus, in the S protein of
      hepatitis B virus, in a subdomain of Ebola virus and in the malaria CS protein.
      Experimental results have indicated that tilted peptide fragments may be involved
      in cellular life events like sperm-egg fecondation, muscle development, protein
      translocation through signal sequences and cellular death caused by viral
      infection or parasite infestation. We speculate that membrane destabilization by
      these tilted peptides may be an important common step in life processes involving
      fusion phenomena.

PMID- 10339393
TI  - Win-stay, lose-shift strategies for repeated games-memory length, aspiration
      levels and noise.
AB  - Win-stay, lose-shift, the principle to retain a successful action is a simple and
      general learning rule that can be applied to all types of repeated decision
      problems. In this paper I consider win-stay, lose-shift strategies with diverse
      memory sizes and strategies that adapt their aspiration levels, i.e. the payoff
      level considered as "success". I study their evolution for the Prisoner's
      Dilemma, as well as in a rapidly changing environment, where a randomly selected
      game is assigned to the players. For win-stay, lose-shift strategies with memory
      one the average payoffs are computed and their evolutionary stability is
      discussed. Using computer simulations I show that the win-stay, lose-shift
      strategies with longer memory are very successful both for the Prisoner's
      Dilemma, where cooperation dominates even for high noise levels, and the randomly
      assigned games, where the players achieve nearly the expected Pareto optimal
      payoffs. I discuss the impact of noise and show that the memory length of the
      players increases with the noise level. These results indicate that the win-stay,
      lose-shift principle is a very successful strategy in repeated games with noise.

PMID- 10339394
TI  - Characterization and comparison of protein structures. Part I-characterization.
AB  - The quantitative criteria characterizing the regularity of Calpha-backbones in
      the protein structures are presented. A technique is based on the Fourier
      remapping of the Cartesian coordinates for the Calpha-chain. The Fourier spectra
      identify the hidden periodicities and symmetries in protein structures, while the
      integral regularity is assessed via the spectral structural entropies. The formal
      unification of digitizing and the similarities in statistics for the random
      counterparts allow study of the direct correlations between the distribution of
      physico-chemical characteristics along the amino acid sequence and the spatial
      conformation of the polypeptide chain. The significant correlations are found for
      both hydrophobicity and side-chain volumes, though, as expected, the effects for
      hydrophobicity turn out essentially stronger. A scheme is illustrated by the set
      of 120 protein structures comprising the representatives from the main
      superfamilies and superfolds.

PMID- 10339395
TI  - Characterization and comparison of protein structures. Part II-comparison.
AB  - The Fourier methods are applied to the pairwise comparison of Calpha-backbones in
      protein structures. The technique allows to assess both the general similarity
      and the main origins of resemblance (coincident periodicities, similarity of
      fragments, or large-scale semblance of folding). The analogous methods can be
      extended to the study of correlations between the structural characteristics for
      the Calpha-backbone of one protein and the distribution of physico-chemical
      parameters along the primary amino acid sequence for the other. Finally, we
      discuss the problem of clusterization of pairwise data into tree-like
      hierarchical system.

PMID- 10339396
TI  - Cytological, genetic and evolutionary functions of chiasmata based on chiasma
      graph analysis.
AB  - The nature of the chiasma as a cytological parameter for analysing cross-over was
      reexamined quantitatively by an improved chiasma graph method. It was reconfirmed
      in Mus platythrix (n =13) that interstitial chiasmata at diakinesis are
      distributed randomly and almost uniformly along bivalents except for the
      centromere and telomere regions. The size of these chiasma blank regions was
      consistently 0.8% of the total length of haploid autosomes in all chromosomes.
      There was a minimum value of chiasma interference distance between two adjacent
      chiasmata, which was constantly 1.8% in all chromosomes. The chiasma frequency at
      diakinesis was 20.1+/-2. 0 by the conventional method including terminal
      chiasmata. However, the primed in situ labeling technique revealed that terminal
      chiasmata were mostly telomere-telomere associations. From these data and also
      from recent molecular data we concluded that the terminal chiasma is
      cytologically functional for ensuring the normal disjunction of bivalents at
      anaphase I, but genetically non-functional for shuffling genes. The chiasma
      frequency excluding terminal chiasmata was 14.6+/-1.8. Reexamination of the
      chiasma frequency of 106 animal species revealed that the chiasma frequency
      increased linearly in proportion to the haploid chromosome number in spite of
      remarkable difference in their genome size. The increase in chiasma frequency
      would be evolution-adaptive, because gene shuffling is expected to be accelerated
      in species with high chromosome numbers.

PMID- 10339397
TI  - Intramitotic and intraclonal variation in proliferative potential of human
      diploid cells: explained by telomere shortening.
AB  - Normal human diploid cells can only divide for a limited number of times (known
      as the Hayflick limit). They manifest two unique features during in vitro
      senescence. The division capability of individual cells in a clone, though all
      derived from a same ancestor, is heterogeneous with a distinct bimodal
      distribution. Two sister cells derived from a same parent cell can have a large
      difference in their doubling potentials. These two unique features have not been
      properly explained by any known physiological process since their observation in
      1980. Here I represent a telomere-shortening model based on recent experimental
      measurement of telomere deletion in human cells. Using computer simulation, I
      show that the model satisfactorily explains the intraclonal and intramitotic
      variation in division capability of human diploid cells. Moreover, the
      simulations predict that human cells may only monitor the shortening of a few,
      most likely two, telomeres to regulate their proliferative potential.

PMID- 10339398
TI  - The effect of slow allosteric transitions in a coupled biochemical oscillator
      model.
AB  - The effect of slowed allosteric transitions in a coupled biochemical oscillator
      model showing complex dynamic behavior is investigated. When the allosteric
      transitions are sufficiently fast one can obtain a low-dimensional asymptotic
      approximation for the dynamics of the species that evolve on a slow time-scale.
      Such low-dimensional models are common in studies of biological control systems
      and little attention has, so far, been given to the dynamic effect of the large
      number of species usually eliminated from more biochemically detailed models.
      Here we investigate the dynamic effect of explicit inclusion of allosteric
      transitions having finite time-scales of equilibration. It is found that slowed
      allosteric transitions suppress complex dynamic modes such a bursting, quasi
      periodicity and chaos. The effect arises as the enzyme of consideration becomes
      trapped in an active state where it is unable to respond to changes in effector
      concentration on the time-scale necessary to support the modes of complex
      dynamics. Slow allosteric transitions may be favourable in biological systems in
      which complex oscillations are not desirable but which, at the same time, may
      benefit from the presence of positive feedbacks. Our findings suggest that slow
      allosteric transitions and finite internal rates in general may contribute
      significantly to the dynamics of biological control mechanisms.

PMID- 10339399
TI  - Mutation rates: does complexity matter?

PMID- 10339400
TI  - Amino acid acceptor identity switch of Escherichia coli tmRNA from alanine to
      histidine in vitro.
AB  - According to a trans -translation model, tmRNA facilitates the resumption of
      translation that has been stalled on the ribosome with the 3' end of a terminator
      less mRNA, to produce a chimera polypeptide of the nascent peptide and the tmRNA
      encoding 11 amino acid-tag. The first alanine residue of the tag-sequence is
      encoded neither by mRNA nor by tmRNA. This alanine is a key molecule for this
      model, in which it is derived from the alanine moiety aminoacylated to tmRNA.
      This is supported only by the observation that a point mutation at the third base
      pair position of the acceptor stem of Escherichia coli tmRNA that deprives it of
      its aminoacylation ability causes abolishment of tag-peptide synthesis in vitro.
      Here, we made an E. coli tmRNA mutant with a completely switched amino acid
      acceptor identity from alanine to histidine by transplanting the upper half of
      the acceptor stem of tRNAHis. This histidine acceptor tmRNA mutant still retained
      an ability of tag-specific amino acid incorporation into the polypeptide in an in
      vitro poly(U)-dependent tag-peptide synthesis system, with an altered amino acid
      composition. Histidine, which is not a constituent of the original tag-peptide,
      was incorporated into the mutant-directed tag. The molar ratio of amino acids
      incorporated is consistent with that in the tag-sequence with the only expected
      change being the first amino acid from alanine to histidine. These results
      indicate that the first alanine residue of the tag-peptide is actually derived
      from that aminoacylated to tmRNA and is substitutable by other amino acids during
      the trans -translation processes.

PMID- 10339402
TI  - Expansion of DNA repeats in Escherichia coli: effects of recombination and
      replication functions.
AB  - Duplication or expansion of directly repeated sequence elements is associated
      with a number of human genetic diseases. To study the mechanisms of repeat
      expansion, we have developed a plasmid assay in Escherichia coli. Our assay
      involves two simple repeats of 787 bp in length; expansion to three or more
      copies of the repeat can be selected by restoration of an intact tetracycline
      resistance gene. Expansions occurred at relatively high rates, >10(-5), in the
      population. Both RecA-dependent recombination and RecA-independent slipped
      misalignments contributed to the observed expansion events. Mutations that impair
      DNA polymerase III (DnaE, DnaQ subunits) or the replication fork helicase, DnaB,
      stimulated both RecA-dependent and RecA-independent expansion events. In these
      respects, the properties of repeat expansion resemble repeat deletion and suggest
      that difficulties in DNA replication may trigger both classes of rearrangements.
      About 20% of the RecA-independent expansion events are accompanied by reciprocal
      sister-chromosome exchange, producing dimeric plasmids carrying one triplicated
      and one deleted locus. These products are explained by a model involving
      misaligned strands across the replication fork. This model predicts that the
      location of a replication stall site may govern the types of resulting
      rearrangements. The specific location of such a stall site can also, in theory,
      account for propensity towards expansion or deletion of repeat arrays. This may
      have relevance to trinucleotide repeat expansion in human genetic disease.

PMID- 10339401
TI  - Cyanelle RNase P: RNA structure analysis and holoenzyme properties of an
      organellar ribonucleoprotein enzyme.
AB  - The cyanelle of the primitive alga Cyanophora paradoxa is the only photosynthetic
      organelle where the ribonucleoprotein nature of ribonuclease P has been
      functionally proven. To increase our knowledge about RNA structure and overall
      composition of this enzyme, we have now determined relevant physical parameters
      and performed RNA accessibility experiments. Buoyant density and relative
      molecular mass of cyanelle RNase P were more similar to the eukaryotic (nuclear
      or mitochondrial) than to the bacterial enzyme type, despite the close
      phylogenetic relationship between plastids and cyanobacteria. Enzymatic and
      chemical probing was used to establish the secondary structure of cyanelle RNase
      P RNA. The results obtained with the naked transcript support the previously
      proposed, phylogenetically derived structure. Probing of the RNA in the
      holoenzyme resulted in reduced sensitivity at a large number of positions,
      indicating that these regions might be located in the interior of the
      ribonucleoprotein. Protection of the RNA in cyanelle RNase P was more extensive
      than reported for the Escherichia coli holoenzyme, but similar to the pattern
      observed in yeast nuclear RNase P. Taken together, these results indicate that
      the protein contribution in cyanelle RNase P is much larger than in the bacterial
      enzymes, and that the overall composition of the holoenzyme resembles that found
      in eukaryotes.

PMID- 10339403
TI  - Alteration of human UDP-glucuronosyltransferase UGT2B17 regio-specificity by a
      single amino acid substitution.
AB  - The glucuronidation of steroid hormones is catalyzed by a family of UDP
      glucuronosyltransferase (UGT) enzymes. Previously, two cDNA clones, UGT2B15 and
      UGT2B17, which encode UGT enzymes capable of glucuronidating C19steroids, were
      isolated and characterized. These proteins are 95% identical in primary
      structure; however, UGT2B17 is capable of conjugating C19steroid molecules at
      both the 3alpha and 17beta-OH positions, whereas UGT2B15 is only active at the
      17beta-OH position. To identify the amino acid residue(s) which may account for
      this difference in substrate specificity, a comprehensive study on the role of 15
      residues which differ between UGT2B15 and UGT2B17 was performed by site-directed
      mutagenesis. The stable expression of UGT2B17 mutant proteins into HK293 cells
      demonstrated that the mutation of isoleucine 125, valine 181 and valine 455 to
      the residues found in UGT2B15 did not alter enzyme activity nor substrate
      specificity. Furthermore, mutation of the variant residues in UGT2B15 (serine
      124, asparagine 125, phenylalanine 165) to the amino acid residues found in
      UGT2B17 did not alter enzyme activity nor substrate specificity. However,
      mutation of the serine residue at position 121 of UGT2B17 to a tyrosine, as found
      in UGT2B15, abolished the ability of UGT2B17 to conjugate androsterone at the
      3alpha position, but still retained activity for dihydrotestosterone and 5alpha
      androstane-3alpha, 17beta-diol, which have an OH-group at the 17beta position.
      Interestingly, mutation of tyrosine 121 in UGT2B15 to a serine abolished activity
      for C19steroids. It is suggested that the serine residue at position 121 in
      UGT2B17 is required for activity towards the 3alpha and not for the 17beta
      position of C19steroids, whereas the tyrosine 121 in UGT2B15 is necessary for UGT
      activity. Despite the high homology between UGT2B15 and UGT2B17, it is apparent
      that different amino acid residues in the two proteins are required to confer
      conjugation of C19steroid molecules.

PMID- 10339404
TI  - Inhibition of cytoplasmic antigen, glucose- 6-phosphate dehydrogenase, by VH-CH1,
      an intracellular Fd fragment antibody derived from a semisynthetic Fd fragment
      phage display library.
AB  - A library of Fd fragment antibody binding proteins was created by random mutation
      of 15 nucleotides within the CDRIII region of the immunoglobulin heavy chain gene
      and displayed as Fd coat protein fusion constructs of M13 phage. The library was
      screened for those VHbinding sites that bound glucose-6-phosphate dehydrogenase
      (G6PD). One isolate (DH27bp) inhibited G6PD activity by 85 %. The DH27bpgene was
      re-engineered, placed in a eukaryotic expression vector having an isopropyl-beta
      delta-thiogalactopyranoside (IPTG) inducible promoter, and transfected and then
      expressed in Chinese hamster V79 cells. G6PD activity was completely inhibited.
      Removal of IPTG reverted the cell to full G6PD activity. The intracellular
      dynamics of the G6PD/DH27bpcomplex showed that when the proteasomes of cells
      expressing DH27bpwere inhibited (N -acetyl-Leu-Leu-norleucinal or lactacystin)
      G6PD activity increased. Metabolic labelling of newly synthesized IPTG-induced
      proteins during/absence of proteasomal inhibitors showed that both G6PD and
      DH27bpare signaled for degradation when the intracellular complex is formed.
      Furthermore, semi-quantitative RT/PCR demonstrated that G6PD mRNA is upregulated
      over the time course of G6PD inactivation by DH27bpFd binding protein. These
      effects were not observed in those cells expressing a non-mutated Fd (UMHC) or in
      IPTG-treated non-transduced V79 cells. Our results demonstrate that an Fd-based
      intracellular binding protein can find and disable the function of a specific
      intracellular target and once the Fd expression is repressed the activity of
      intracellular targeted protein can revert to normal.

PMID- 10339405
TI  - Biophysical analysis of the interaction of human ifnar2 expressed in E. coli with
      IFNalpha2.
AB  - Type I interferons are cytokines which activate an anti-viral response by binding
      to two specific cell surface receptors, ifnar1 and ifnar2. Here, we report
      purification and refolding of the extracellular part of human ifnar2 (ifnar2-EC)
      expressed in Escherichia coli and its characterization with respect to its
      interaction with interferon alpha2 (IFNalpha2). The 25 kDa, non-glycosylated
      ifnar2-EC is a stable, fully active protein, which inhibits antiviral activity of
      IFNalpha2. The stoichiometry of binding IFNalpha2 is 1:1, as determined by gel
      filtration, chemical cross-linking and solid-phase detection. The affinity of
      this interaction is 10 nM, which is similar to the affinity measured for the cell
      surface-bound ifnar2 receptor. No difference in affinity was found throughout
      various assays using optical detection as BIAcore or reflectometric interference
      spectorscopy. However, the binding kinetics as measured in homogeneous phase by
      fluorescence de-quenching was about three times faster than that measured on a
      sensor surface. The rate of complex formation is relatively high compared to
      other cytokine-receptor interactions. The salt dependence of the association
      kinetics suggest a limited but significant contribution of electrostatic forces
      towards the rate of complex formation. The dissociation constant increases with
      decreasing pH according to the protonation of a base with a pKa of 6.7. The
      surface properties of the IFNalpha2 binding surface on ifnar2 were interpreted
      according to the pH and salt dependence of the interaction.

PMID- 10339406
TI  - Genetic and structural characterization of the human mitochondrial inner membrane
      translocase.
AB  - Translocation of nuclear-encoded mitochondrial preproteins is mediated by
      translocases in the outer and inner membranes. In the yeast Saccharomyces
      cerevisiae, translocation of preproteins into the matrix requires the membrane
      proteins Tim23, Tim17 and Tim44, which drive translocation in cooperation with
      mtHsp70 and its co-chaperone Mge1p. We have cloned and functionally analyzed the
      human homologues of Tim17, Tim23 and Tim44. In contrast to yeast, two TIM17 genes
      were found to be expressed in humans. TIM44, TIM23 and TIM17a genes were mapped
      to chromosomes 19p13.2-p13.3, 10q11. 21-q11.23 and 1q32. The TIM17b gene mapped
      to Xp11.23, near the fusion point where an autosomal region was proposed to have
      been added to the "ancient" part of the X chromosome about 80-130 MY ago. The
      primary sequences of the two proteins, hTim17a and hTim17b, are essentially
      identical, significant differences being restricted to their C termini. They are
      ubiquitously expressed in fetal and adult tissues, and both show expression
      levels comparable to that of hTim23. Biochemical characterization of the human
      Tim components revealed that hTim44 is localized in the matrix and, in contrast
      to yeast, only loosely associated with the inner membrane. hTim23 is organized
      into two distinct complexes in the inner membrane, one containing hTim17a and one
      containing hTim17b. Both TIM complexes display a native molecular mass of 110
      kDa. We suggest that the structural organization of TIM23.17 preprotein
      translocases is conserved from low to high eukaryotes.

PMID- 10339407
TI  - Can anomalous signal of sulfur become a tool for solving protein crystal
      structures?
AB  - A general method for solving the phase problem from native crystals of
      macromolecules has long eluded structural biology. For well diffracting crystals
      this goal can now be achieved, as is shown here, thanks to modern data collection
      techniques and new statistical phasing algorithms. Using solely a native crystal
      of tetragonal hen egg-white lysozyme, a protein of 14 kDa molecular mass, it was
      possible to detect the positions of the ten sulfur and seven chlorine atoms from
      their anomalous signal, and proceed from there to obtain an electron-density map
      of very high quality.

PMID- 10339408
TI  - Anomalous signal of solvent bromides used for phasing of lysozyme.
AB  - The anomalous signal of bromide ions, present in the crystal structure of
      tetragonal hen egg-white lysozyme through the substitution of NaCl by NaBr in the
      crystallization medium, was used for phasing of X-ray data collected to 1.7 A
      resolution with a wavelength near the absorption edge of bromine. Phasing of a
      single wavelength data set, based purely on anomalous deltaf " contribution, led
      to easily interpretable electron density, equivalent to the complete
      multiwavelength anonalous dispersion phasing based on four-wavelength data. The
      classic small-structure direct methods program SHELXS run against all anomalous
      differences gave a successful solution of six highest peaks corresponding to six
      bromide ions in the structure with data limited up to a resolution of 3.5 A.
      Interpretable maps were obtained at a resolution up to 3.0 A using programs
      MLPHARE and DM. Bromide ions occupy well ordered positions at the protein
      surface. Phasing based on the single wavelength signal of anomalous scatterers
      introduced into the ordered solvent shell can be proposed as a tool for solving
      structures of well diffracting crystals.

PMID- 10339410
TI  - Solution structure of an EGF module pair from the Plasmodium falciparum merozoite
      surface protein 1.
AB  - The solution structure of the 96-residue C-terminal fragment of the merozoite
      surface protein 1 (MSP-1) from Plasmodium falciparum has been determined using
      nuclear magnetic resonance (NMR) spectroscopic measurements on uniformly13C/15N
      labelled protein, efficiently expressed in the methylotrophic yeast Komagataella
      (Pichia) pastoris. The structure has two domains with epidermal growth factor
      (EGF)-like folds with a novel domain interface for the EGF domain pair
      interactions, formed from a cluster of hydrophobic residues. This gives the
      protein a U-shaped overall structure with the N-terminal proteolytic processing
      site close to the C-terminal glycosyl phosphatidyl inositol (GPI) membrane anchor
      site, which is consistent with the involvement of a membrane-bound proteinase in
      the processing of MSP-1 during erythrocyte invasion. This structure, which is the
      first protozoan EGF example to be determined, contrasts with the elongated
      structures seen for EGF-module pairs having shared Ca2+-ligation sites at their
      interface, as found, for example, in fibrillin-1. Recognition surfaces for
      antibodies that inhibit processing and invasion, and antibodies that block the
      binding of these inhibitory antibodies, have been mapped on the three-dimensional
      structure by considering specific MSP-1 mutants.

PMID- 10339409
TI  - Crystal structure of coagulation factor IX-binding protein from habu snake venom
      at 2.6 A: implication of central loop swapping based on deletion in the linker
      region.
AB  - Coagulation factor IX-binding protein (IX-bp) isolated from the venom of the habu
      snake (Trimeresurus flavoviridis) is a disulfide-linked heterodimer consisting of
      homologous subunits A and B. The structure of IX-bp has been solved by X-ray
      crystallography at 2.6 A resolution to a crystallographic R -value of 0.181. The
      main-chain fold of each subunit is homologous to the carbohydrate-recognition
      domain of C-type lectins (C-type CRDs) except for the extended central loop. The
      structure is almost identical with that of factors IX and X-binding protein (IX/X
      bp) as expected from the high level of amino acid sequence homology. The
      functional difference in ligand recognition from IX/X-bp must reside in the amino
      acid differences. A continuity of different amino acid residues located from the
      C-terminal of the second alpha-helix to the following loop forms the local
      conformational difference in this region between the two proteins. This loop
      participates in the formation of the concave surface between the two subunits,
      the putative binding site for the Gla-domain (gamma-carboxyglutamic acid
      containing domain) of the coagulation factors. Another difference between the two
      proteins is in the relative disposition of subunits A and B. When the B subunits
      are superimposed, about a 6 degrees rotation is required for the superposition of
      the A subunits. A calcium ion links the second alpha-helix region to the C
      terminal tail in each subunit and helps to stabilize the structure for Gla-domain
      binding. The interface created by the central loop swapping in the dimer IX-bp is
      almost identical with that seen within the monomeric C-type CRDs. This dimer
      forms as the result of the amino acid deletion in the linker region of the
      central loop of the original C-type lectins. Such a dimerization disrupts the
      lectin active site and creates a Gla-domain binding site, imparting functional
      diversity.

PMID- 10339411
TI  - Structure of the anchor-domain of myristoylated and non-myristoylated HIV-1 Nef
      protein.
AB  - Negative factor (Nef) is a regulatory myristoylated protein of human
      immunodeficiency virus (HIV) that has a two-domain structure consisting of an
      anchor domain and a core domain separated by a specific cleavage site of the HIV
      proteases. For structural analysis, the HIV-1 Nef anchor domain (residues 2-57)
      was synthesized with a myristoylated and non-myristoylated N terminus. The
      structures of the two peptides were studied by1H NMR spectroscopy and a
      structural model was obtained by restrained molecular dynamic simulations. The
      non-myristoylated peptide does not have a unique, compactly folded structure but
      occurs in a relatively extended conformation. The only rather well-defined
      canonical secondary structure element is a short two-turn alpha-helix (H2)
      between Arg35 and Gly41. A tendency for another helical secondary structure
      element (H1) can be observed for the arginine-rich region (Arg17 to Arg22).
      Myristoylation of the N-terminal glycine residue leads to stabilization of both
      helices, H1 and H2. The first helix in the arginine-rich region is stabilized by
      the myristoylation and now contains residues Pro14 to Arg22. The second helix
      appears to be better defined and to contain more residues (Ala33 to Gly41) than
      in the absence of myristoylation. In addition, the hydrophobic N-terminal
      myristic acid residue interacts closely with the side-chain of Trp5 and thereby
      forms a loop with Gly2, Gly3 and Lys4 in the kink region. This interaction could
      possibly be disturbed by phosphorylation of a nearby serine residue, and modifiy
      the characteristic membrane interactions of the HIV-1 Nef anchor domain.

PMID- 10339412
TI  - The solution structure and dynamics of human neutrophil gelatinase-associated
      lipocalin.
AB  - Human neutrophil gelatinase-associated lipocalin (HNGAL) is a member of the
      lipocalin family of extracellular proteins that function as transporters of
      small, hydrophobic molecules. HNGAL, a component of human blood granulocytes,
      binds bacterially derived formyl peptides that act as chemotactic agents and
      induce leukocyte granule discharge. HNGAL also forms a complex with the proenzyme
      form of matrix metalloproteinase-9 (pro-MMP-9, or progelatinase B) via an
      intermolecular disulphide bridge. This association allows the subsequent
      formation of ternary and quaternary metalloproteinase/inhibitor complexes that
      vary greatly in their metalloproteinase activities. The structure and dynamics of
      apo-HNGAL have been determined by NMR spectroscopy. Simulated annealing
      calculations yielded a set of 20 convergent structures with an average backbone
      RMSD from mean coordinate positions of 0. 79(+/-0.13) A over secondary structure
      elements. The overall rotational correlation time (13.3 ns) derived from15N
      relaxation data is consistent with a monomeric protein of the size of HNGAL (179
      residues) under the experimental conditions (1.4 mM protein, pH 6.0, 24.5 degrees
      C). The structure features an eight-stranded antiparallel beta-barrel, typical of
      the lipocalin family. One end of the barrel is open, providing access to the
      binding site within the barrel cavity, while the other is closed by a short 310
      helix. The free cysteine residue required for association with pro-MMP-9 lies in
      an inter-strand loop at the closed end of the barrel. The structure provides a
      detailed model of the ligand-binding site and has led to the proposal of a site
      for pro-MMP-9 association. Dynamic data correlate well with structural features,
      which has allowed us to investigate a mechanism by which a cell-surface receptor
      might distinguish between apo and holo-HNGAL through conformational changes at
      the open end of the barrel.

PMID- 10339413
TI  - Averaging data derived from images of helical structures with different
      symmetries.
AB  - There are many examples of macromolecules that form helical tubes or crystals,
      which are useful for structure determination by electron microscopy and image
      processing. Helical crystals can be thought of as two-dimensional crystals that
      have been rolled into a cylinder such that two lattice points are superimposed.
      In many real cases, helical crystals of a particular macromolecule derive from an
      identical two-dimensional lattice but have different lattice points superimposed,
      thus producing different helical symmetries which cannot be simply averaged in
      Fourier-space. When confronted with this situation, one can select images
      corresponding to one of the observed symmetries at the expense of reducing the
      number of images that can be used for data collection and averaging, or one can
      calculate separate density maps from each symmetry, then align and average them
      together in real-space. Here, we present a third alternative, which is based on
      averaging of the Fourier-Bessel coefficients, gn,l(r), and which allows the
      inclusion of data from all symmetry groups derived from a common two-dimensional
      lattice. The method is straightforward and simple in practice and is shown,
      through a specific example with real data, to give results comparable to real
      space averaging.

PMID- 10339414
TI  - Effects of varying the local propensity to form secondary structure on the
      stability and folding kinetics of a rapid folding mixed alpha/beta protein:
      characterization of a truncation mutant of the N-terminal domain of the ribosomal
      protein L9.
AB  - The N-terminal domain of the ribosomal protein L9 forms a split betaalphabeta
      structure with a long C-terminal helix. The folding transitions of a 56 residue
      version of this protein have previously been characterized, here we report the
      results of a study of a truncation mutant corresponding to residues 1-51. The 51
      residue protein adopts the same fold as the 56 residue protein as judged by CD
      and two-dimensional NMR, but it is less stable as judged by chemical and thermal
      denaturation experiments. Studies with synthetic peptides demonstrate that the C
      terminal helix of the 51 residue version has very little propensity to fold in
      isolation in contrast to the C-terminal helix of the 56 residue variant. The
      folding rates of the two proteins, as measured by stopped-flow fluorescence, are
      essentially identical, indicating that formation of local structure in the C
      terminal helix is not involved in the rate-limiting step of folding.

PMID- 10339415
TI  - Interscaffolding additivity: binding of P1 variants of bovine pancreatic trypsin
      inhibitor to four serine proteases.
AB  - Different families of protein inhibitors of serine proteases share similar
      conformation of the enzyme-binding loop, while their scaffoldings are completely
      different. In the enzyme-inhibitor complex, the P1position of the loop makes
      numerous contacts within the S1pocket and significantly influences the energy of
      the interaction. Here, we determine the association energies (DeltaGavalues) for
      the interaction of coded P1variants of bovine pancreatic trypsin inhibitor (BPTI)
      with bovine beta-trypsin (BT), anionic salmon trypsin (AST), bovine alpha
      chymotrypsin (BCHYM), and human neutrophil elastase (HNE). The respective
      DeltaGaranges are 15, 13, 9, and 8 kcal mol-1(1 cal=4.18 J). Next, through
      interscaffolding additivity cycles, we compare our set of DeltaGavalues
      determined for BCHYM and HNE with similar data sets available in the literature
      for three other inhibitor families. The analysis of the cycles shows that 27 to
      83 % of cycles fulfil the criteria of additvity. In one particular case
      (comparison of associations of P1variants of BPTI and OMTKY3 with BCHYM) there is
      a structural basis for strongly non-additive behaviour. We argue that the
      interscaffolding additvity depends on sequential and conformational similarities
      of sites where the mutation(s) are introduced and on the particular substitution.
      In the second interscaffolding analysis, we compare binding of the same P1mutants
      to BT and AST. The high correlation coefficient shows that both trypsins
      recognize with comparable strength the non-cognate side-chains. However, the
      cognate Arg and Lys side-chains are recognized significantly more strongly by
      AST.

PMID- 10339416
TI  - Thermodynamics of the unfolding of the cold-shock protein from Thermotoga
      maritima.
AB  - Proteins from (hyper-)thermophiles are known to exhibit high intrinsic
      stabilities. Commonly, their thermodynamic characterization is impeded by
      irreversible side reactions of the thermal analysis or calorimetrical problems.
      Small single-domain proteins are suitable candidates to overcome these obstacles.
      Here, the thermodynamics of the thermal denaturation of the recombinant cold
      shock protein (Csp) from the hyperthermophilic bacterium Thermotoga maritima (Tm)
      was studied by differential scanning calorimetry. The unfolding transition can be
      described over a broad pH range (3.5-8.5) by a reversible two-state process.
      Maximum stability (DeltaG (25 degrees C)=6.5 kcal/mol) was observed at pH 5-6
      where Tm Csp unfolds with a melting temperature at 95 degrees C. The heat
      capacity difference between the native and the denatured states is 1.1(+/-0.1)
      kcal/(mol K). At pH 7, thermal denaturation occurs at 82 degrees C. The
      corresponding free energy profile has its maximum at 30 degrees C with DeltaGN-
      >U=4.8(+/-0.5) kcal/mol. At the optimal growth temperature of T. maritima (80
      degrees C), Tm Csp in the absence of ligands is only marginally stable, with a
      free energy of stabilization not far beyond the thermal energy. With the known
      stabilizing effect of nucleic acids in mind, this suggests a highly dynamical
      interaction of Tm Csp with its target molecules.

PMID- 10339417
TI  - Auditory perception: The near and far of sound localization.
AB  - Most experiments on auditory localization have been concerned with the horizontal
      and vertical positions of sound sources. Recent studies have cast new light on
      the basis for judging the third dimension - source distance.

PMID- 10339418
TI  - Signal transduction: Gyrating protein kinases.
AB  - Recently determined structures have linked histidine kinases with class II
      topoisomerases, the DNA repair enzyme MutL and the molecular chaperone Hsp90.
      This surprising finding may foreshadow a shift in our understanding of energy
      coupling mechanisms in signal transduction networks.

PMID- 10339419
TI  - Evolutionary genetics: The economics of mutation.
AB  - The presence of mutator genotypes in populations of bacteria may be favoured by
      selection because they produce rare beneficial mutations and thereby increase the
      rate of adaptive evolution. Recent work, however, shows that the relationship
      between mutation rates and adaptive evolution is more complicated.

PMID- 10339420
TI  - Limb development: Farewell to arms.
AB  - Forelimbs and hindlimbs are, clearly, quite different, and it has long been
      appreciated that their differences are assigned early in development; the genetic
      basis of these differences has been more mysterious, however. Recent work has now
      shown that the homeobox gene Pitx1 imparts identity to the developing hindlimb
      bud.

PMID- 10339421
TI  - Apoptosis: Silencing the death receptors.
AB  - Spontaneous signaling from death-domain-containing receptors can result in
      inappropriate cell death. An inhibitory protein has recently been identified,
      called silencer of death domains (SODD), that binds to the death domain of tumor
      necrosis factor receptor 1, thereby negatively regulating downstream signaling.

PMID- 10339422
TI  - Eye development: Notch lends a handedness.
AB  - The arrangement of photoreceptors in the ommatidia of the Drosophila compound eye
      is polarized, having a handedness or chirality. Notch signalling helps determine
      this handedness, first by establishing a signalling center at the eye equator,
      and second by mediating a choice between two photoreceptor fates

PMID- 10339423
TI  - Cognitive disorders: A question of misattribution.
AB  - A recent study indicates that schizophrenia patients are prone to auditory
      hallucinations because they have difficulty recognising their 'inner speech' as
      their own, and consequently tend to misattribute it to an external source.

PMID- 10339424
TI  - Shoot meristems: Intercellular signals keep the balance.
AB  - Recent studies have identified a complex intercellular communication network
      which maintains the balance of indeterminate and determinate cells at the plant
      apical meristem. The widespread presence of homologous regulatory genes indicates
      that 'stemness' arose before the evolutionary split between plants and animals.

PMID- 10339425
TI  - Rapamycin-sensitive phosphorylation of PKC on a carboxy-terminal site by an
      atypical PKC complex.
AB  - BACKGROUND: The protein kinase C (PKC) family has been implicated in the control
      of many cellular functions. Although PKC isotypes are characterized by their
      allosteric activation, phosphorylation also plays a key role in controlling
      activity. In classical PKC isotypes, one of the three critical sites is a carboxy
      terminal hydrophobic site also conserved in other AGC kinase subfamily members.
      Although this site is crucial to the control of this class of enzymes, the
      upstream kinase(s) has not been identified. RESULTS: A membrane-associated kinase
      activity that phosphorylates the hydrophobic site in PKCalpha was detected. This
      activity was suppressed when cells were pretreated with the immunosuppresant drug
      rapamycin or the phosphoinositide (Pl) 3-kinase inhibitor LY294002. These
      pretreatments also blocked specifically the serum-induced phosphorylation of the
      hydrophobic site in PKCdelta in vivo. The most highly purified hydrophobic site
      kinase preparations ( approximately 10,000-fold) reacted with antibodies to
      PKCzeta/iota. Consistent with this, rapamycin and LY294002 reduced the recovery
      of PKCzeta from the membrane fraction of transfected cells. An activated mutant
      of PKCzeta, but not wild-type PKCzeta, induced phosphorylation of the PKCdelta
      hydrophobic site in a rapamycin-independent manner, whereas a kinase-dead PKCzeta
      mutant suppressed this serum-induced phosphorylation. The immunopurified,
      activated mutant of PKCzeta could phosphorylate the PKCdelta hydrophobic site in
      vitro, whereas wild-type PKCzeta could not. CONCLUSIONS: PKCzeta is identified as
      a component of the upstream kinase responsible for the phosphorylation of the
      PKCdelta hydrophobic site in vitro and in vivo. PKCzeta can therefore control the
      phosphorylation of this PKCdelta site, antagonizing a rapamycin-sensitive
      pathway.

PMID- 10339426
TI  - PDGF induces an early and a late wave of PI 3-kinase activity, and only the late
      wave is required for progression through G1.
AB  - BACKGROUND: Platelet-derived growth factor (PDGF) triggers cytoskeletal
      rearrangements and chemotaxis within minutes. These events are at least in part
      due to the activation of phosphoinositide (PI) 3-kinase; there is good temporal
      correlation between these events and the accumulation of 3-phosphorylated
      products of the kinase. Prolonged and continuous PDGF exposure results in S-phase
      entry many hours after the initial burst of activity. Although early signals
      appear responsible for the early responses, they may not fully account for later
      responses, such as cell-cycle progression. RESULTS: We assessed when PI 3-kinase
      products accumulate in PDGF-stimulated cells. In addition to the previously
      identified early accumulation of products, we detected a second, prolonged wave
      of accumulation 3-7 hours after stimulation. To determine the relative
      contribution of each phase to PDGF-dependent DNA synthesis, we first developed an
      assay in which synthetic 3-phosphorylated lipids were used to rescue DNA
      synthesis in cells expressing a PDGF-receptor mutant. The lipids rescued DNA
      synthesis only when added 2-6 hours after PDGF. In addition, PI 3-kinase
      inhibitors failed to block PDGF-dependent DNA synthesis if added during the first
      wave of PI 3-kinase activity, but adding them later, in G1 phase, prevented PDGF
      dependent cell-cycle progression. CONCLUSIONS: PDGF induces distinct waves of PI
      3-kinase activity. The second wave is required for PDGF-dependent DNA synthesis,
      whereas the initial wave is not. One of the ways in which cells use PI 3-kinase
      to mediate distinct cellular responses seems to be by regulating when its
      products accumulate.

PMID- 10339428
TI  - Targeted disruption of the tyrosine phosphatase PTPalpha leads to constitutive
      downregulation of the kinases Src and Fyn.
AB  - A role for the receptor-like protein tyrosine phosphatase alpha (PTPalpha) in
      regulating the kinase activity of Src family members has been proposed because
      ectopic expression of PTPalpha enhances the dephosphorylation and activation of
      Src and Fyn [1] [2] [3]. We have generated mice lacking catalytically active
      PTPalpha to address the question of whether PTPalpha is a physiological activator
      of Src and Fyn, and to investigate its other potential functions in the context
      of the whole animal. Mice homozygous for the targeted PTPalpha allele (PTPalpha-/
      ) and lacking detectable PTPalpha protein exhibited no gross phenotypic defects.
      The kinase activities of Src and Fyn were significantly reduced in PTPalpha-/-
      mouse brain and primary embryonic fibroblasts, and this correlated with enhanced
      phosphorylation of the carboxy-terminal regulatory Tyr527 of Src in PTPalpha-/-
      mice. Thus, PTPalpha is a physiological positive regulator of the tyrosine
      kinases Src and Fyn. Increased tyrosine phosphorylation of several unidentified
      proteins was also apparent in PTPalpha-/- mouse brain lysates. These may be
      PTPalpha substrates or downstream signaling proteins. Taken together, the results
      indicate that PTPalpha has a dual function as a positive and negative regulator
      of tyrosine phosphorylation events, increasing phosphotyrosyl proteins through
      activation of Src and Fyn, and directly or indirectly removing tyrosine phosphate
      from other unidentified proteins.

PMID- 10339427
TI  - Receptor protein tyrosine phosphatase alpha activates Src-family kinases and
      controls integrin-mediated responses in fibroblasts.
AB  - BACKGROUND: Fyn and c-Src are two of the most widely expressed Src-family
      kinases. Both are strongly implicated in the control of cytoskeletal organization
      and in the generation of integrin-dependent signalling responses in fibroblasts.
      These proteins are representative of a large family of tyrosine kinases, the
      activity of which is tightly controlled by inhibitory phosphorylation of a
      carboxyterminal tyrosine residue (Tyr527 in chicken c-Src); this phosphorylation
      induces the kinases to form an inactive conformation. Whereas the identity of
      such inhibitory Tyr527 kinases has been well established, no corresponding
      phosphatases have been identified that, under physiological conditions, function
      as positive regulators of c-Src and Fyn in fibroblasts. RESULTS: Receptor protein
      tyrosine phosphatase alpha (RPTPalpha) was inactivated by homologous
      recombination. Fibroblasts derived from these RPTPalpha-/- mice had impaired
      tyrosine kinase activity of both c-Src and Fyn, and this was accompanied by a
      concomitant increase in c-Src Tyr527 phosphorylation. RPTPalpha-/- fibroblasts
      also showed a reduction in the rate of spreading on fibronectin substrates, a
      trait that is a phenocopy of the effect of inactivation of the c-src gene. In
      response to adhesion on a fibronectin substrate, RPTPalpha-/- fibroblasts also
      exhibited characteristic deficiencies in integrin-mediated signalling responses,
      such as decreased tyrosine phosphorylation of the c-Src substrates Fak and p
      130(cas), and reduced activation of extracellular signal regulated (Erk) MAP
      kinases. CONCLUSIONS: These observations demonstrate that RPTPalpha functions as
      a physiological upstream activator of Src-family kinases in fibroblasts and
      establish this tyrosine phosphatase as a newly identified regulator of integrin
      signalling.

PMID- 10339429
TI  - A trans-receptor mechanism for infection of CD4-negative cells by human
      immunodeficiency virus type 1.
AB  - Chemokine receptors, particularly CCR5 and CXCR4, act as essential coreceptors in
      concert with CD4 for cellular entry by human immunodeficiency virus type 1 (HIV
      1; reviewed in [1]). But infection of CD4(-) cells has also been encountered in
      various tissues in vivo, including astrocytes, neurons and microvascular
      endothelial cells of the brain [2] [3] [4] [5] [6], epithelial cells [5] [7],
      CD4(-) lymphocytes and thymocytes [8] [9], and cardiomyocytes [10]. Here, we
      present evidence for the infection of CD4(-) cell lines bearing coreceptors by
      well-known HIV-1 strains when co-cultured with CD4(+) cells. This process
      requires contact between the coreceptor-bearing and CD4(+) cells and supports the
      full viral replication cycle within the coreceptor-bearing target cell.
      Furthermore, CD4 provided in trans facilitates infection of primary human cells,
      such as brain-derived astrocytes. Although the pathobiological significance of
      infection of CD4(-) cells in vivo remains to be elucidated, this trans-receptor
      mechanism may facilitate generation of hidden reservoirs of latent virus that
      confound antiviral therapies and that contribute to specific AIDS-associated
      clinical syndromes.

PMID- 10339430
TI  - The Wiskott-Aldrich syndrome protein directs actin-based motility by stimulating
      actin nucleation with the Arp2/3 complex.
AB  - Actin polymerization at the cell cortex is thought to provide the driving force
      for aspects of cell-shape change and locomotion. To coordinate cellular
      movements, the initiation of actin polymerization is tightly regulated, both
      spatially and temporally. The Wiskott-Aldrich syndrome protein (WASP), encoded by
      the gene that is mutated in the immunodeficiency disorder Wiskott-Aldrich
      syndrome [1], has been implicated in the control of actin polymerization in cells
      [2] [3] [4] [5]. The Arp2/3 complex, an actin-nucleating factor that consists of
      seven polypeptide subunits [6] [7] [8], was recently shown to physically interact
      with WASP [9]. We sought to determine whether WASP is a cellular activator of the
      Arp2/3 complex and found that WASP stimulates the actin nucleation activity of
      the Arp2/3 complex in vitro. Moreover, WASP-coated microspheres polymerized
      actin, formed actin tails and exhibited actin-based motility in cell extracts,
      similar to those behaviors displayed by the pathogenic bacterium Listeria
      monocytogenes. In extracts depleted of the Arp2/3 complex, WASP-coated
      microspheres and L. monocytogenes were non-motile and exhibited only residual
      actin polymerization. These results demonstrate that WASP is sufficient to direct
      actin-based motility in cell extracts and that this function is mediated by the
      Arp2/3 complex. WASP interacts with diverse signaling proteins and may therefore
      function to couple signal transduction pathways to Arp2/3-complex activation and
      actin polymerization.

PMID- 10339431
TI  - Apoptotic nuclear morphological change without DNA fragmentation.
AB  - Apoptosis is characterized morphologically by condensation and fragmentation of
      nuclei and cells and biochemically by fragmentation of chromosomal DNA into
      nucleosomal units [1]. CAD, also known as CPAN or DFF-40, is a DNase that can be
      activated by caspases [2] [3] [4] [5] [6]. CAD is complexed with its inhibitor,
      ICAD, in growing, non-apoptotic cells [2] [7]. Caspases that are activated by
      apoptotic stimuli [8] cleave ICAD. CAD, thus released from ICAD, digests
      chromosomal DNA into nucleosomal units [2] [3]. Here, we examine whether nuclear
      morphological changes induced by apoptotic stimuli are caused by the degradation
      of chromosomal DNA. Human T-cell lymphoma Jurkat cells, as well as their
      transformants expressing caspase-resistant ICAD, were treated with staurosporine.
      The chromosomal DNA in Jurkat cells underwent fragmentation into nucleosomal
      units, which was preceded by large-scale chromatin fragmentation (50-200 kb). The
      chromosomal DNA in cells expressing caspase-resistant ICAD remained intact after
      treatment with staurosporine but their chromatin condensed as found in parental
      Jurkat cells. These results indicate that large-scale chromatin fragmentation and
      nucleosomal DNA fragmentation are caused by an ICAD-inhibitable DNase, most
      probably CAD, whereas chromatin condensation during apoptosis is controlled, at
      least in part, independently from the degradation of chromosomal DNA.

PMID- 10339432
TI  - The BRCT domain of the S. cerevisiae checkpoint protein Rad9 mediates a Rad9-Rad9
      interaction after DNA damage.
AB  - The Saccharomyces cerevisiae checkpoint protein Rad9 is required for transient
      cell-cycle arrest and transcriptional induction of DNA-repair genes in response
      to DNA damage [1]. It contains a carboxyterminal tandem repeat of the BRCT (BRCA1
      carboxyl terminus) motif, a motif that is also found in many proteins involved in
      various aspects of DNA repair, recombination and checkpoint control [2][3]. We
      produced yeast strains expressing Rad9 in which the BRCT domain had been deleted
      or which harboured point mutations in the highly conserved aromatic residue of
      each BRCT motif. Rates of survival and checkpoint delay of the mutants after
      ultraviolet (UV) irradiation were essentially equivalent to those of rad9Delta
      (null) cells, demonstrating that the BRCT domain is required for Rad9 function.
      Rad9 hyperphosphorylation, which occurs after DNA damage [4][5][6], was absent in
      the BRCT mutants, as was Rad9-dependent phosphorylation of the Rad53 protein. A
      two-hybrid approach identified a specific interaction between the Rad9 BRCT
      domain and itself. Biochemical analysis in vitro and in vivo confirmed this
      interaction and, furthermore, demonstrated that the Rad9 BRCT domain
      preferentially interacted with the hyperphosphorylated forms of Rad9. This
      interaction was suppressed by mutations of the BRCT motifs that caused null
      phenotypes in vivo, suggesting that Rad9 oligomerization is required for Rad9
      function after DNA damage.

PMID- 10339433
TI  - Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB.
AB  - The tumor necrosis factor receptor 1 (TNFR1) and the Fas receptor recruit
      complexes formed by the interactions between RIP kinase, TRADD, FADD and RAIDD -
      adaptor proteins that contain death domains - which in turn recruit other
      proteins to initiate signaling [1][2][3][4][5]. To identify proteins associated
      with the TNF signaling pathway, we performed a yeast two-hybrid interaction
      screen using RIP as bait. We isolated a kinase, RIP3, which shares homology with
      the kinase domain of RIP and RIP2 (also known as Rick or CARDIAK). RIP3 could be
      co-immunoprecipitated with RIP, TRAF2 and TNFR1 in mammalian cells. The carboxy
      terminal domain of RIP3, like that of RIP, could activate the transcription
      factor NFkappaB and induce apoptosis when expressed in mammalian cells.
      Interestingly, this region shares no significant sequence homology to the death
      domain of RIP, the caspase-recruiting domain (CARD) of RIP2 [6][7][8] or any
      other apoptosis-inducing domain. As with RIP and RIP2, the kinase domain of RIP3
      was not required for either NFkappaB activation or apoptosis induction.
      Overexpression of a dominant-negative mutant of RIP3 strongly inhibited the
      caspase activation but not the NFkappaB activation induced by TNFalpha.
      Therefore, RIP3 appears to function as an intermediary in TNFalpha-induced
      apoptosis.

PMID- 10339434
TI  - Thermostable uracil-DNA glycosylase from Thermotoga maritima a member of a novel
      class of DNA repair enzymes.
AB  - Uracil-DNA glycosylase (UDG) is a ubiquitous enzyme found in eukaryotes and
      prokaryotes [1][2][3]. This enzyme removes uracil bases that are present in DNA
      as a result of either deamination of cytosine or misincorporation of dUMP instead
      of dTMP [4] [5], and it is the primary activity in the DNA base excision repair
      pathway. Although UDG activities have been shown to be present in several
      thermophiles [6][7][8], no sequences have been found that are complementary to
      the Escherichia coli ung gene, which encodes UDG [9]. Here, we describe a UDG
      from the thermophile Thermotoga maritima. The T. maritima UDG gene has a low
      level of homology to the E. coli G-T/U mismatch-specific DNA glycosylase gene
      (mug). The expressed protein is capable of removing uracil from DNA containing
      either a U-A or a U-G base pair and is heat-stable up to 75 degrees C. The enzyme
      is also active on single-stranded DNA containing uracil. Analogous genes appear
      to be present in several prokaryotic organisms, including thermophilic and
      mesophilic eubacteria as well as archaebacteria, the human-disease pathogens
      Treponema palladium and Rickettsia prowazekii, and the extremely radioresistant
      organism Deinococcus radiodurans. These findings suggest that the T. maritima UDG
      is a member of a new class of DNA repair enzymes.

PMID- 10339435
TI  - Chaperonins.

PMID- 10339436
TI  - Biology in pictures. A sense of colour.

PMID- 10339438
TI  - The seven good byways of science ... Big Pharma.

PMID- 10339437
TI  - Biology in three dimensions.

PMID- 10339439
TI  - Sequence homology between Wingless/Wnt-1 and a lipid-binding domain in secreted
      phospholipase A2.

PMID- 10339440
TI  - Chemical wastes, children's health, and the Superfund Basic Research Program.
AB  - Three to 4 million children and adolescents in the United States live within 1
      mile of a federally designated Superfund hazardous waste disposal site and are at
      risk of exposure to chemical toxicants released from these sites into air,
      groundwater, surface water, and surrounding communities. Because of their
      patterns of exposure and their biological vulnerability, children are uniquely
      susceptible to health injury resulting from exposures to chemical toxicants in
      the environment. The Superfund Basic Research Program, funded by the U.S.
      Environmental Protection Agency and directed by the National Institute of
      Environmental Health Sciences, is extremely well positioned to organize
      multidisciplinary research that will assess patterns of children's exposures to
      hazardous chemicals from hazardous waste disposal sites; quantify children's
      vulnerability to environmental toxicants; assess causal associations between
      environmental exposures and pediatric disease; and elucidate the mechanisms of
      environmental disease in children at the cellular and molecular level.

PMID- 10339441
TI  - Breast Milk Monitoring Programs (BMMPs): world-wide early warning system for
      polyhalogenated POPs and for targeting studies in children's environmental
      health.

PMID- 10339443
TI  - Predicting the outcome of the CaNa2EDTA challenge test in children with
      moderately elevated blood lead levels.
AB  - The Centers for Disease Control and Prevention suggests the challenge test for
      children whose blood lead levels are 1.21-2.12 micromol/L (25-44 microg/dL).
      However, the challenge test is difficult to perform. By identifying children who
      are likely to have a negative challenge test, a medical provider can minimize the
      number of children undergoing this test. The goal of this study was to identify
      common tests that are likely to predict the outcome of the challenge test. It was
      conducted as a clinical descriptive study from a series of patients who underwent
      a CaNa2EDTA challenge test. Results from 178 challenge tests were eligible for
      analysis. The mean age of children undergoing the challenge test was 38.2 months,
      and the mean blood lead level was 1.83 micromol/L (38 microg/dL). Blood lead
      level, age, erythrocyte protoporphyrin level, and RATE (a measure of the rate of
      change of the blood lead level) were either not sensitive or not specific in
      predicting the outcome of a challenge test. However, based on a logistic
      regression model using blood lead level, age, and RATE, we determined criteria
      that would have identified all children who would have had a positive challenge
      test while excluding most children who would have had a negative challenge test.
      Based on this model, we recommend that the challenge test be conducted on
      children >=36 months of age who have a blood lead level between 1.45 and 1.64
      micromol/L (30-34 microg/dL) and on children who have a blood lead level 1.69
      2.12 micromol/L (35-44 microg/dL) regardless of age. This approach would have
      tested all children who subsequently would have had a positive challenge test
      while testing only 39% of children who would have had a negative challenge test.

PMID- 10339442
TI  - Dietary calcium intakes of urban children at risk of lead poisoning.
AB  - Dietary calcium is well known to decrease gastrointestinal lead absorption and
      thereby reduce the risk for lead poisoning. Because children in economically
      deprived urban centers are especially likely to have excessive lead exposure, we
      surveyed dietary calcium intakes of 314 children from the greater Newark, New
      Jersey, area. The areas of Newark and adjacent communities studied had been
      previously identified as containing significant sources of environmental lead by
      geographic information systems technology. An abbreviated National Cancer
      Institute Health Habits and History Questionnaire, modified to focus on foods
      high in calcium, was used to determine dietary calcium. Calcium intakes were then
      compared to the new Dietary Reference Intake (DRI) guidelines. The respondents
      were primarily the parents of African-American and Hispanic children ranging in
      age from 1 to 8 years, with a mean age of 3.5 years. The most recent blood lead
      concentration was 11.4 +/- 0.8 microg/dL (mean +/- standard error), and 48.6% had
      concentrations at or above the current guideline of 10 microg/dL. Quintiles of
      calcium intake were: 221 +/- 13; 488 +/- 9; 720 +/- 6; 885 +/- 6; and 1,389 +/-
      49 mg/day. Fifty-five of 175 (31.4%) children aged 1-3 years had calcium intakes
      below the DRI, as did 82 of 139 (59.0%) children aged 4-8 years. The percentage
      of mothers reporting lactose intolerance in their children was 2.5%. The
      observation that the children in the highest quintile easily exceeded the DRIs
      for calcium suggests that urban parents who include dairy foods in their
      childrens' meals can provide a diet that meets the DRI guidelines. Children in
      the lowest quintiles are at risk of increased absorption of the environmental
      lead to which they are inevitably exposed, as well as other problems associated
      with a low intake of dietary calcium. The data suggest that both lead exposure
      and low dietary calcium continue to pose significant health risks to urban
      minority children.

PMID- 10339444
TI  - Daily intake of copper from drinking water among young children in Sweden.
AB  - Copper is an essential trace element that may cause intoxication if intake
      becomes excessive. Young children are at risk of intoxication because of high
      consumption of drinking water and immature copper metabolism. The aims of this
      prospective study were to estimate concentrations of copper in drinking water,
      volumes of drinking water consumed by children, and children's daily intake of
      copper. Concentrations of copper in unflushed drinking water were analyzed for
      1,178 children living in Uppsala and Malmo, Sweden, and concentrations and
      amounts of copper consumed from drinking water were estimated for 430 of these
      children, 9-21 months of age. The study children were from Swedish families, were
      not enrolled in publicly provided day care, and were not breast-fed more than
      three times a day. In the initial population, the 10th percentile for copper
      concentration in unflushed drinking water was 0.17 mg/L, the median was 0.72
      mg/L, and the 90th percentile was 2.11 mg/L. In the subpopulation of 430
      children, the 10th percentile for daily intake of copper from drinking water was
      0.03 mg/L, the median was 0.32 mg/L, and the 90th percentile was 1.07 mg/L. The
      median daily intake of copper from drinking water was higher in Uppsala, at 0.46
      mg, than in Malmo, at 0.26 mg. For groups of children whose families took part in
      a later prospective diary study, the copper concentration in consumed water
      could, to some extent, be predicted from the concentration of copper in unflushed
      drinking water. The lowest concentrations of copper in drinking water were found
      in households with old water-pipe systems and in those living in detached houses.
      A large proportion of the young children satisfied their daily requirement of
      copper solely from drinking water. About 10% of the children had a copper intake
      above the level recommended by the World Health Organization.

PMID- 10339445
TI  - Organochlorines in breast milk from two cities in Ukraine.
AB  - Reports of environmental problems in the former Soviet Union, including excess
      use of pesticides, have led to concerns about high levels of contamination in
      humans, but little information is available to assess whether these concerns are
      warranted. Samples of breast milk from 197 women from two cities in Ukraine were
      analyzed for p,p'-DDT, p,p'-DDE, endrin, dieldrin, heptachlor epoxide, trans
      nonachlor, oxychlordane, hexachlorobenzene, ss-hexachlorocyclohexane (HCH), and
      18 polychlorinated biphenyl congeners, and results were compared to previous
      reports from Europe. The median ss-HCH concentration was 731 ng/g milk fat, which
      is higher than other reports from Europe but lower than reports from other parts
      of the world. The median DDE concentration was 2,457 ng/g milk fat, which is
      higher than most but not all other reports from Europe. Concentrations of other
      chemicals were comparable to or lower than other reports from Europe.
      Concentrations from the city of Kyiv were generally lower than those from
      Dniprodzerzhinsk, but the magnitudes of these differences were modest.

PMID- 10339446
TI  - Dermal transfer of chlorpyrifos residues from residential surfaces: comparison of
      hand press, hand drag, wipe, and polyurethane foam roller measurements after
      broadcast and aerosol pesticide applications.
AB  - Indoor residential pesticide applications present the potential for human
      exposures, particularly for small children. Personal contact with target and
      nontarget surfaces can result in transfer of pesticides to the skin, but the
      magnitude of such transfer is uncertain. This research compared surface sampling
      techniques [wipe and polyurethane foam (PUF) roller] with the removal ability of
      human skin following broadcast and total aerosol release applications of Dursban
      (Dow Elanco, Midland, MI), a residential formulation containing the insecticide
      chlorpyrifos. Hands were washed immediately after surface contact, following a
      protocol that included a laboratory-generated adjustment factor to account for
      incomplete removal of chlorpyrifos from skin. Chlorpyrifos transfer was similar
      for hand press and hand drag techniques, averaging approximately 1-6 ng/cm2 of
      carpet contacted. These amounts represented < 1% of the amount of chlorpyrifos
      deposited on the surfaces 3.5 hr earlier. Chlorpyrifos transfer from carpet to
      skin was 23-24 times lower than for wipe sampling and 33-36 times lower than for
      PUF roller sampling (p = 0.0007 and p = 0.0006 for broadcast and aerosol
      applications, respectively). Hand press sampling removed approximately 4.5 times
      less chlorpyrifos from nontarget furniture surfaces (12 ng/cm2) than did wipe
      sampling (56 ng/cm2; p = 0.009). Chlorpyrifos residues on carpet were
      substantially higher after broadcast applications than after aerosol
      applications, but residues on such nontarget surfaces as furniture were
      substantially higher for the aerosol application. This study indicates that human
      skin removes substantially less residue from carpets and furniture than either
      conventional wipe or PUF roller sampling methods following residential pest
      control applications of chlorpyrifos. Although this paper focuses on quantifying
      residue transfer from surface to skin using different surface sampling
      techniques, no attempt is made to quantify the amount of chlorpyrifos residue
      that is subsequently absorbed.

PMID- 10339447
TI  - 8-hydroxy-2'-deoxyguanosine, a major mutagenic oxidative DNA lesion, and DNA
      strand breaks in nasal respiratory epithelium of children exposed to urban
      pollution.
AB  - Southwest metropolitan Mexico City children are repeatedly exposed to high levels
      of a complex mixture of air pollutants, including ozone, particulate matter,
      aldehydes, metals, and nitrogen oxides. We explored nasal cell 8-hydroxy-2'
      deoxyguanosine (8-OHdG), a major mutagenic lesion producing G-->T transversion
      mutations, using an immunohistochemical method, and DNA single strand breaks
      (ssb) using the single cell gel electrophoresis assay as biomarkers of oxidant
      exposure. Nasal biopsies from the posterior inferior turbinate were examined in
      children in grades one through five, including 12 controls from a low-polluted
      coastal town and 87 Mexico City children. Each biopsy was divided for the 8-OHdG
      and DNA ssb assays. There was an age-dependent increase in the percentage of
      nasal cells with DNA tails > 10 microm in Mexico City children: 19 +/- 9% for
      control cells, and 43 +/- 4, 50 +/- 16, 56 +/- 17, 60 +/- 17 and 73 +/- 14%,
      respectively, for first through fifth graders (p < 0.05). Nasal ssb were
      significantly higher in fifth graders than in first graders (p < 0.05). Higher
      levels (2.3- to 3-fold) of specific nuclear staining for 8-OHdG were observed in
      exposed children as compared to controls (p < 0.05). These results suggest that
      DNA damage is present in nasal epithelial cells in Mexico City children.
      Persistent oxidative DNA damage may ultimately result in a selective growth of pr
      eneoplastic nasal initiated cells in this population and the potential for nasal
      neoplasms may increase with age. The combination of 8-OHdG and DNA ssb should be
      useful for monitoring oxidative damage in people exposed to polluted atmospheres.

PMID- 10339448
TI  - Fetal growth and maternal exposure to particulate matter during pregnancy.
AB  - Prior studies reported an association between ambient air concentrations of total
      suspended particles and SO2 during pregnancy and adverse pregnancy outcomes. We
      examined the possible impact of particulate matter up to 10 microm (PM10) and up
      to 2.5 microm (PM2. 5) in size on intrauterine growth retardation (IUGR) risk in
      a highly polluted area of Northern Bohemia (Teplice District). The study group
      includes all singleton full-term births of European origin over a 2-year period
      in the Teplice District. Information on reproductive history, health, and
      lifestyle was obtained from maternal questionnaires. The mean concentrations of
      pollutants for each month of gestation were calculated using continuous
      monitoring data. Three intervals (low, medium, and high) were constructed for
      each pollutant (tertiles). Odds ratios (ORs) for IUGR for PM10 and PM2.5 levels
      were generated using logistic regression for each month of gestation after
      adjustment for potential confounding factors. Adjusted ORs for IUGR related to
      ambient PM10 levels in the first gestational month increased along the
      concentration intervals: medium 1.62 [95% confidence interval (CI), 1.07-2.46],
      high 2.64 (CI, 1.48-4.71). ORs for PM2.5 were 1.26 (CI, 0.81-1.95) and 2.11 (CI,
      1. 20-3.70), respectively. No other associations of IUGR risk with particulate
      matter were found. Influence of particles or other associated air pollutants on
      fetal growth in early gestation is one of several possible explanations of these
      results. Timing of this effect is compatible with a current hypothesis of IUGR
      pathogenesis. Seasonal factors, one of the other possible explanations, is less
      probable. More investigation is required to examine these findings and
      alternative explanations.

PMID- 10339449
TI  - Calculating the interindividual geometric standard deviation for use in the
      integrated exposure uptake biokinetic model for lead in children.
AB  - The integrated exposure uptake biokinetic (IEUBK) model, recommended for use by
      the U.S. Environmental Protection Agency at residential Superfund sites to
      predict potential risks to children from lead exposure and to establish lead
      remediation levels, requires an interindividual geometric standard deviation
      (GSDi) as an essential input parameter. The GSDi quantifies the variability of
      blood lead concentrations for children exposed to similar environmental
      concentrations of lead. Estimates of potential risks are directly related to the
      GSDi, and therefore the GSDi directly impacts the scope of remediation at
      Superfund sites. Site-specific GSDi can be calculated for sites where blood lead
      and environmental lead have been measured. This paper uses data from blood and
      environmental lead studies conducted at the Bingham Creek and Sandy, Utah,
      Superfund sites to calculate GSDi using regression modeling, box modeling, and
      structural equation modeling. GSDis were calculated using various methods for
      treating values below the analytical method detection and quantitation limits.
      Treatment of nonquantifiable blood lead concentrations affected the GSDi more
      than the statistical method used to calculate the GSDi. For any given treatment,
      the different statistical methods produced similar GSDis. Because of the
      uncertainties associated with data in the blood lead studies, we recommend that a
      range of GSDis be used when analyzing site-specific risks associated with
      exposure to environmental lead instead of a single estimate. Because the
      different statistical methods produce similar GSDis, we recommend a simple
      procedure to calculate site-specific GSDi from a scientifically sound blood and
      environmental lead study.

PMID- 10339450
TI  - An association between fine particles and asthma emergency department visits for
      children in Seattle.
AB  - Asthma is the most common chronic illness of childhood and its prevalence is
      increasing, causing much concern for identification of risk factors such as air
      pollution. We previously conducted a study showing a relationship between asthma
      visits in all persons < 65 years of age to emergency departments (EDs) and air
      pollution in Seattle, Washington. In that study the most frequent zip codes of
      the visits were in the inner city. The Seattle-King County Department of Public
      Health (Seattle, WA) subsequently published a report which showed that the
      hospitalization rate for children in the inner city was over 600/100,000, whereas
      it was < 100/100,000 for children living in the suburbs. Therefore, we conducted
      the present study to evaluate whether asthma visits to hospital emergency
      departments in the inner city of Seattle were associated with outdoor air
      pollution levels. ED visits to six hospitals for asthma and daily air pollution
      data were obtained for 15 months during 1995 and 1996. The association between
      air pollution and childhood ED visits for asthma from the inner city area with
      high asthma hospitalization rates were compared with those from lower hospital
      utilization areas. Daily ED counts were regressed against fine particulate matter
      (PM), carbon monoxide (CO), sulfur dioxide, and nitrogen dioxide using a
      semiparametric Poisson regression model. Significant associations were found
      between ED visits for asthma in children and fine PM and CO. A change of 11
      microg/m3 in fine PM was associated with a relative rate of 1.15 [95% confidence
      interval (CI), 1.08-1.23]. There was no stronger association between ED visits
      for asthma and air pollution in the higher hospital utilization area than in the
      lower utilization area. These findings were seen when estimated PM2.5
      concentrations were below the newly adopted annual National Ambient Air Quality
      Standard of 15 microg/m3.

PMID- 10339451
TI  - Combined effect of cigarette smoke and mineral fibers on the gene expression of
      cytokine mRNA.
AB  - To investigate which parameters are stimulated by mineral fibers and whether
      cigarette smoke enhanced a fiber-induced response, we examined the level of
      cytokine mRNA from alveolar macrophages (AMs) and lungs of rats exposed to
      mineral fibers and cigarette smoke in vivo. Male Wistar rats were given a single
      intratracheal instillation of 2 mg of Union Internationale Contre le Cancer
      chrysotile or refractory ceramic fiber (RF1). The animals then inhaled a side
      stream of smoke 5 days per week for 4 weeks. The expression of manganese
      superoxide dismutase, inducible nitric oxide synthase (iNOS), basic fibroblast
      growth factor (bFGF), interleukin-1[alpha] (IL-1[alpha]), interleukin-6 (IL-6),
      and tumor necrosis factor-[alpha] (TNF[alpha]) mRNA from lipopolysaccharide
      stimulated AMs and lungs of rats exposed to mineral fibers and/or cigarette smoke
      were assessed using semiquantitative reverse-transcriptase polymerase chain
      reaction. Exposure only to cigarette smoke increased in IL-1[alpha] mRNA levels
      in AMs. Chrysotile stimulated the expression of IL-1[alpha], TNF[alpha], and IL-6
      in AMs, and the expression of bFGF in lungs. RF1 resulted in increased expression
      of IL-1[alpha] and TNF[alpha] in AMs. Cigarette smoke stimulated the gene
      expression of iNOS in AMs and IL-6 and bFGF in lungs treated with chrysotile; IL
      1[alpha] in AMs and bFGF in lungs did the same in lungs with RF1. Among these
      cytokines, message levels of IL-1[alpha], iNOS, and bFGF were increased in rats
      stimulated with mineral fibers, and the stimulating effects of mineral fibers
      were enhanced by cigarette smoke. Therefore, IL-1[alpha], iNOS, and bFGF would be
      the possible parameters of the lung remodeling induced by mineral fibers.

PMID- 10339454
TI  - A research-oriented framework for risk assessment and prevention of Children's
      exposure to environmental toxicants 
AB  - Learning disabilities, intellectual retardation, dyslexia, attention
      deficit/hyperactivity disorder, autism, and propensity to violence affect
      millions of U.S. citizens and are diagnosed in an estimated 3% of all children
      born in the United States. The consequences of these neurological, developmental,
      and behavioral disorders are often tragic; their familial, societal, and economic
      costs are immense, and the resulting disabilities lifelong. Toxic chemicals in
      the environment--lead, polychlorinated biphenyls, mercury, and certain pesticides
      -are now known to cause some fraction of neurodevelopmental disabilities. The
      implications of this discovery for prevention are potentially enormous;
      developmental disorders of toxic origin can, in theory, be prevented through the
      identification, characterization, and elimination of toxic environmental
      exposures. However, serious impediments to prevention exist: too few chemicals
      are tested for toxicity to early brain development, knowledge of infants' and
      children's special vulnerabilities and unique exposures is scant, and paradigms
      for environmental risk assessment have only begun to address the hazards
      confronting infants and children.

PMID- 10339453
TI  - Reactive airways dysfunction and systemic complaints after mass exposure to
      bromine.
AB  - Occasionally children are the victims of mass poisoning from an environmental
      contaminant that occurs due to an unexpected common point source of exposure. In
      many cases the contaminant is a widely used chemical generally considered to be
      safe. In the following case, members of a sports team visiting a community for an
      athletic event were exposed to chemicals while staying at a local motel. Bromine
      based sanitizing agents and other chemicals such as hydrochloric acid, which were
      used in excess in the motel's swimming pool, may have accounted for symptoms
      experienced by the boy reported here and at least 16 other adolescents. Samples
      of pool water contained excess bromine (8.2 microg/mL; ideal pool bromine
      concentration is 2-4 microg/mL). Symptoms and signs attributable to bromine
      toxicity included irritative skin rashes; eye, nose, and throat irritation;
      bronchospasm; reduced exercise tolerance; fatigue; headache; gastrointestinal
      disturbances; and myalgias. While most of the victims recovered within a few
      days, the index case and several other adolescents had persistent or recurrent
      symptoms lasting weeks to months after the exposure.

PMID- 10339452
TI  - Cytogenetic effects from exposure to mixed pesticides and the influence from
      genetic susceptibility.
AB  - Exposure to pesticides remains a major environmental health problem. Health risk
      from such exposure needs to be more precisely understood. We conducted three
      different cytogenetic assays to elucidate the biological effects of exposure to
      mixed pesticides in 20 Costa Rica farmers (all nonsmokers) compared with 20
      matched controls. The farmers were also exposed to dibromochloropropane during
      the early employment years, and most of them experienced sterility/fertility
      problems. Our data show that the farmers had consistently higher frequencies of
      chromosome aberrations, as determined by the standard chromosome aberration
      assay, and significantly abnormal DNA repair responses (p < 0.05), as determined
      by the challenge assay, but no statistically significant differences in the
      tandem-probe fluorescence in situ hybridization (FISH) assay (p > 0.05). Genotype
      analysis indicates that farmers with certain "unfavorable" versions of
      polymorphic metabolizing genes (cytochrome P4502E1, the glutathione S
      transferases mu and theta, and the paraoxonase genes) had significantly more
      biological effects, as determined by all three cytogenetic assays, than both the
      farmers with the "favorable" alleles and the matched controls. A unique
      observation is that, in individuals who had inherited any of the mentioned
      "unfavorable" alleles, farmers were consistently underrepresented. In conclusion,
      the Costa Rican farmers were exposed to genotoxic agents, most likely pesticides,
      which expressed the induction of biological and adverse health effects. The
      farmers who had inherited "unfavorable" metabolizing alleles were more
      susceptible to genotoxic effects than those with "favorable" alleles. Our
      genotype data suggest that the well-recognized "healthy worker effect" may be
      influenced by unrecognized occupational selection pressure against genetically
      susceptible individuals.

PMID- 10339455
TI  - Carcinogen risk assessment guidelines and children.

PMID- 10339456
TI  - An environment for development.

PMID- 10339457
TI  - Poisoning young minds.
AB  - For some neurotoxic chemicals, neurobehavioral effects are now considered to be
      among the most sensitive end points yet detected, particularly if exposures occur
      during critical windows of vulnerability. Chemically induced problems with
      perception and cognitive ability in children can be hard to identify; teasing
      them out of a host of genetic and sociocultural influences is a difficult task.
      Today, most data on environmentally relevant neurobehavioral effects in children
      are concentrated in three chemicals: lead, methylmercury, and polychlorinated
      biphenyls. But mounting evidence of the neurobehavioral effects of chemicals
      along with growing public concern over pediatric mental health problems such as
      attention deficit/hyperactivity disorder dictates that scientists and legislators
      improve test methods, explore mechanisms, and develop appropriate strategies for
      risk assessment and policy making.

PMID- 10339458
TI  - Still moving toward environmental justice.
AB  - Three years in the making, the Institute of Medicine report Toward Environmental
      Justice was funded by a consortium of agencies, including the NIEHS, the Centers
      for Disease Control and Prevention, the U.S. Environmental Protection Agency, and
      the U.S. Department of Energy. The independent review was authored by a 15-member
      committee that represented academia, public interest, medicine, law, and
      industry. The committee met with stakeholders, citizens, public officials, and
      industry representatives around the United States to assess the need for better
      research, education, and health policy related to environmental justice. The
      report investigates the situation of groups of individuals suspected of having
      disproportionately high levels of exposure to environmental stressors such as
      chemicals, biologics, allergenics, toxicants, light, noise, odors, and
      particulate matter. The report calls for more research to help identify and
      verify the environmental etiologies of diseases. It also recommends that citizens
      be recruited to participate in the design and execution of the research, and that
      communication during all phases of the research be open and reciprocal.

PMID- 10339459
TI  - Look, Ma! No pneumococcus!
AB  - Pneumococcal diseases, caused by the bacterium Streptococcus pneumoniae, include
      pneumonia and otitis media, which accounts for some 12 million doctor visits per
      year in the United States alone. Each year around the world, pneumococcus causes
      1.2 million deaths due to pneumonia, 39% of which are in children under the age
      of five. In a three-year Phase III clinical trial involving 38,000 children, in
      which half of the infants received a new pneumococcal vaccine and half received a
      placebo vaccine, the new vaccine demonstrated an efficacy rate of 100% against
      bacterial meningitis and bacteremia, the two most deadly pneumococcal
      afflictions.

PMID- 10339460
TI  - Platelet surface collagen receptor polymorphisms: variable receptor expression
      and thrombotic/hemorrhagic risk.

PMID- 10339461
TI  - Low platelet alpha2beta1 levels in type I von Willebrand disease correlate with
      impaired platelet function in a high shear stress system.
AB  - Platelet adhesion to collagen-coated surfaces in whole blood under flow
      conditions is mediated by both von Willebrand factor (vWF)-dependent recruitment
      of the platelet glycoprotein Ib-IX receptor complex and collagen interaction with
      the integrin alpha2beta1. In type 1 von Willebrand disease (vWD), platelet
      adhesive functions are impaired due to the decrease in vWF levels in plasma and
      platelets. There are at least three alleles of the human alpha2 gene,
      distinguishable by a cluster of silent or noncoding sequence differences within a
      segment of the gene. Two alleles, associated with low receptor density can be
      distinguished by nucleotide 807C, while the third allele associated with high
      receptor density, expresses nucleotide 807T. Gene frequencies of these alleles in
      a normal population (n = 167) are 0.58 for 807C and 0.42 for 807T. We measured
      the frequencies of these alleles in symptomatic patients with five types of vWD
      (type 1, n = 78; type 2A, n = 25, type 2B, n = 14; type 2M, n = 10; and type 3, n
      = 20). Compared with the normal group, no significant difference in allele
      frequencies was observed among individuals with types 2A, 2B, 2M, or 3 vWD.
      However, the frequency of the 807C allele, associated with low collagen receptor
      density, among type 1 vWD patients (807C =.71; 807T =.29) was significantly
      higher than that of the normal population (P =.007). Also, in patients with vWD
      type 1 and borderline to normal ristocetin-cofactor (vWF:RCo) activity values,
      collagen receptor density correlates inversely with closure time in a high shear
      stress system (platelet function analyzer [PFA-100]). We propose that low
      platelet alpha2beta1 density results in less efficient primary platelet adhesion
      and may result in increased tendency to bleed, as evidenced by the high frequency
      of this polymorphism in patients with type 1 vWD compared with normal
      individuals. In addition, this may account for the variability between patients
      with similar levels of vWF antigen, but strikingly different bleeding histories.

PMID- 10339462
TI  - The alpha2 gene coding sequence T807/A873 of the platelet collagen receptor
      integrin alpha2beta1 might be a genetic risk factor for the development of stroke
      in younger patients.
AB  - The polymorphisms C807T and G873A of the platelet integrin alpha2beta1 (collagen
      receptor glycoprotein [GP] Ia-IIa) are linked to the expression density of this
      receptor. The GPIa T807/A873 allele causes a higher receptor expression,
      enhancing platelet binding to collagen. This might present a genetic
      predisposition for the development of thromboembolic complications. In this case
      control study, the genotypes of the GPIa C807T polymorphism and presence of
      conventional risk factors (hypertension, diabetes mellitus, and smoking) were
      compared in stroke patients and patients without cerebrovascular disease (non-CVD
      patients) </=50 years of age (n = 45 and 41, respectively) and in stroke patients
      and non-CVD patients more than 50 years of age (n = 182 and 129, respectively. In
      patients </=50 years of age, the T807 allele was the only overrepresented
      variable (P =.023; odds ratio, 3.02; 95% confidence interval, 1.20 to 7.61) and
      an independent risk factor, whereas the presence of conventional risk factors was
      similar between stroke patients </=50 years of age and non-CVD patients </=50
      years of age. Large epidemiological studies should prove whether the platelet
      collagen receptor GPIa-IIa T807 allele is an independent risk factor for the
      development of stroke in younger patients.

PMID- 10339463
TI  - Biochemical and genetic control of apoptosis: relevance to normal hematopoiesis
      and hematological malignancies.

PMID- 10339465
TI  - Secondary lymphoid-tissue chemokine (SLC) is chemotactic for mature dendritic
      cells.
AB  - Dendritic cells (DC) take up antigen from the periphery and migrate to the
      lymphoid organs where they present the processed antigens to T cells. The
      propensity of DC to migrate changes during DC maturation and is probably
      dependent on alterations in the expression of chemokine receptors on the surface
      of DC. Secondary lymphoid tissue chemokine (SLC), a recently discovered chemokine
      for naive T cells, is primarily expressed in secondary lymphoid organs and may be
      important for colocalizing T cells with other cell types important for T-cell
      activation. We show here that SLC is a potent chemokine for mature DC but does
      not act on immature DC. SLC also induced calcium mobilization specifically in
      mature DC. SLC and Epstein-Barr virus-induced molecule 1 ligand chemokine
      completely cross-desensitized the calcium response of each other, indicating that
      they share similar signaling pathways in DC. The finding that SLC is a potent
      chemokine for DC as well as naive T cells suggests that it plays a role in
      colocalizing these two cell types leading to cognate T-cell activation.

PMID- 10339464
TI  - The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently
      rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid
      tissue lymphomas.
AB  - Marginal zone cell lymphomas of the mucosa-associated lymphoid tissue (MALT) are
      the most common subtype of lymphoma arising at extranodal sites. The
      t(11;18)(q21;q21) appears to be the key genetic lesion and is found in
      approximately 50% of cytogenetically abnormal low-grade MALT lymphomas. We show
      that the API2 gene, encoding an inhibitor of apoptosis also known as c-IAP2,
      HIAP1, and MIHC, and a novel gene on 18q21 characterized by several Ig-like C2
      type domains, named MLT, are recurrently rearranged in the t(11;18). In both MALT
      lymphomas analyzed, the breakpoint in API2 occurred in the intron separating the
      exons coding respectively for the baculovirus IAP repeat domains and the caspase
      recruitment domain. The breakpoints within MLT differed but the open reading
      frame was conserved in both cases. In one case, the translocation was accompanied
      by a cryptic deletion involving the 3' part of API2. As a result, the reciprocal
      transcript was not present, strongly suggesting that the API2-MLT fusion is
      involved in the oncogenesis of MALT lymphoma.

PMID- 10339466
TI  - Myeloid malignancies induced by alkylating agents in Nf1 mice.
AB  - Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML and
      MDS) are severe late complications of treatment with genotoxic chemotherapeutic
      agents. Children with neurofibromatosis type 1 (NF1) are predisposed to malignant
      myeloid disorders that are associated with inactivation of the NF1 tumor
      suppressor gene in the leukemic clone. Recent clinical data suggest that NF1
      might be also associated with an increased risk of t-AML after treatment with
      alkyating agents. To test this hypothesis, we administered cyclophosphamide or
      etoposide to cohorts of wild-type and heterozygous Nf1 knockout mice.
      Cyclophosphamide exposure cooperated strongly with heterozygous inactivation of
      Nf1 in myeloid leukemogenesis, while etoposide did not. Somatic loss of the
      normal Nf1 allele correlated with clinical disease and was more common in 129/Sv
      mice than in 129/Sv x C57BL/6 animals. Leukemic cells showing loss of
      heterozygosity at Nf1 retained a structural allele on each chromosome 11 homolog.
      These studies establish a novel in vivo model of alkylator-induced myeloid
      malignancy that will facilitate mechanistic and translational studies.

PMID- 10339467
TI  - Inhibition of cell adhesion by antibodies to Arg-Gly-Asp (RGD) in normal
      immunoglobulin for therapeutic use (intravenous immunoglobulin, IVIg).
AB  - Intravenous immunoglobulin (IVIg) therapy is associated with a broad range of
      immunomodulatory activities. Several of the postulated mechanisms of IVIg action
      relate to the presence of antibodies to molecules relevant for regulation of the
      immune response. This article reports that IVIg contains antibodies to the Arg
      Gly-Asp (RGD) sequence, and the attachment site of a number of adhesive
      extracellular matrix proteins, including ligands for beta1, beta3, and beta5
      integrins. Anti-RGD antibodies were identified in IVIg by enzyme-linked
      immunosorbent assay and by using the BIAcore (BIAcore, Uppsala, Sweden)
      technology. The affinity of anti-RGD antibodies to a synthetic RGD-containing
      peptide and to fibronectin (Fn) was found to be in the micromolar range. F(ab')2
      fragments specific for RGD were purified from IVIg by affinity chromatography.
      Anti-RGD F(ab')2 antibodies inhibited adenosine diphosphate induced
      alphaIIb/beta3 integrin-mediated platelet aggregation and the adhesion of
      activated alpha4beta1 integrin-expressing B cells to Fn. Adhesion of unstimulated
      platelets to fibrinogen (Fg) involving both the gamma-chain dodecapeptide
      sequence and the RGD sequence was inhibited by anti-RGD antibodies. In addition,
      adhesion of thrombin-stimulated platelets to von Willebrand factor or Fg was
      completely inhibited by affinity-purified anti-RGD antibodies. Our results
      suggest that the presence of natural IgG antibodies to the RGD motif may
      contribute to the immunomodulatory and anti-inflammatory effects of therapeutic
      preparations of normal IgG.

PMID- 10339468
TI  - ASHAP: a regimen for cytoreduction of refractory or recurrent Hodgkin's disease.
AB  - Patients with Hodgkin's disease, which is either refractory or recurs after
      frontline chemotherapy with MOPP (mechlorethamine, vincristine, procarbazine, and
      prednisone), ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or both
      regimens, generally have a poor prognosis. High-dose chemotherapy with autologous
      marrow or stem cell rescue (ABMT) is now a widely used salvage strategy in these
      patients. In this study, our objective was to determine the response rate to
      ASHAP (Adriamycin = doxorubicin, Solumedrol = methylprednisolone, High-dose Ara-C
      = cytosine arabinoside, and Platinum = cisplatinum), in a group of patients with
      Hodgkin's disease with such poor risk characteristics. The treatment was intended
      as a brief tumor reducing program before ABMT. Fifty-six patients with diagnosed
      relapsed or primary refractory Hodgkin's disease underwent this treatment. The
      program consisted of the administration of two cycles of ASHAP chemotherapy
      (doxorubicin 10 mg/m2/d intravenous (IV) continuous infusion (CI) over 24 hours,
      days 1 to 4; methylprednisolone 500 mg/d IV over 15 minutes daily for 5 days;
      cisplatinum 25 mg/m2/d IV CI over 24 hours, days 1 to 4; cytosine arabinoside 1.5
      g/m2/d IV over 2 hours on day 5). After two courses of ASHAP the patients were
      evaluated for response, including a gallium scan test. Patients with progressive
      disease were taken off the study. Those with responding or stable disease
      received a third course of ASHAP, followed by consolidative treatment with ABMT.
      There were 19 complete responses (34% CR), 20 partial responses (36% PR), and 17
      treatment failures, including 8 with minor responses and 9 with disease
      progression. Thus, in total there were 39 responses out of 56 patients (CR + PR =
      70%). Myelosuppression was the main toxicity. There were no deaths due to
      toxicity. At this time, 23 patients are alive. There were 31 deaths due to
      disease progression and 2 due to other causes. The initial response to ASHAP
      before subsequent ABMT consolidation treatment correlated with survival. All 17
      patients in whom ASHAP failed to achieve a response have died. The presence of B
      symptoms at relapse, and a duration of response to the last regimen of </=6
      months, predicted a poor response to ASHAP. A short program of treatment with
      ASHAP is an effective tumor debulking approach in patients previously treated
      with both or either ABVD and MOPP, before ABMT.

PMID- 10339469
TI  - Prognostic factors in primary cutaneous lymphomas other than mycosis fungoides
      and the Sezary syndrome. The French Study Group on Cutaneous Lymphomas.
AB  - Prognostic studies of primary cutaneous lymphomas (PCL) other than mycosis
      fungoides (MF) and the Sezary syndrome (SS; non-MF/SS PCL) have been mainly
      performed on subgroups or on small numbers of patients by using univariate
      analyses. Our aim was to identify independent prognostic factors in a large
      series of patients with non-MF/SS PCL. We evaluated 158 patients who were
      registered in the French Study Group on Cutaneous Lymphomas database from January
      1, 1986 to March 1, 1997. Variables analyzed for prognostic value were: age; sex;
      type of clinical lesions; maximum diameter, location, and number of skin lesions;
      cutaneous distribution (ie, local, regional, or generalized); prognostic group
      according to the European Organization for Research and Treatment of Cancer
      (EORTC) classification for PCL; B- or T-cell phenotype; serum lactate
      dehydrogenase (LDH) level; and B symptoms. Univariate and multivariate analyses
      were performed using a model of relative survival. Forty-nine patients (31%)
      died. The median relative survival time was 81 months. In univariate analysis,
      EORTC prognostic group, serum LDH level, B symptoms, and variables related to
      tumor extension (ie, distribution, maximum diameter, and number of skin lesions)
      were significantly associated with survival. When these variables were considered
      together in a multivariate analysis, EORTC prognostic group and distribution of
      skin lesions remained statistically significant, independent prognostic factors.
      This study confirms the good predictive value of the EORTC classification for PCL
      and shows that the distribution of skin lesions at initial evaluation is an
      important prognostic indicator.

PMID- 10339470
TI  - Human herpesvirus 8 infection in patients with POEMS syndrome-associated
      multicentric Castleman's disease.
AB  - The polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS)
      syndrome is a rare multisystemic disorder associated with osteosclerotic myeloma
      and multicentric Castleman's disease (MCD). Human herpesvirus type 8 (HHV-8) DNA
      sequences have been detected in lymph nodes of about 40% of human
      immunodeficiency virus (HIV)-negative patients with MCD, and in bone marrow
      stromal cells of patients with multiple myeloma. Considering these data, we
      investigated the presence of HHV-8 in 18 patients with POEMS syndrome (9 with
      MCD), by nested polymerase chain reaction (N-PCR) to detect DNA sequenses in
      various cells and tissues obtained by biopsy or at autopsy (13 patients, of whom
      7 had MCD), and by an immunofluorescence assay to detect anti-HHV-8 IgG
      antibodies in blood (18 patients, of whom 9 had MCD). Detection of HHV-8 DNA was
      performed using three different N-PCR, targeting nonoverlapping regions in open
      reading frame (ORF) 25 and ORF26. Seven of 13 (54%) POEMS patients had HHV-8 DNA
      sequences in their tissues, as assessed by all three N-PCR, and 9 of 18 (50%) had
      circulating anti-HHV-8 antibodies. HHV-8 was mainly detected in the subset of
      POEMS patients with MCD (6 of 7 [85%] for DNA sequences; 7 of 9 [78%] for
      antibodies). The percentage of positive N-PCR was higher in lymph nodes than in
      bone marrow samples (P <.02). Sequencing of amplicons showed a homogeneous
      restricted variability in the ORF26 region, characteristic of the minority
      subgroup B defined by Zong, and responsible for isoleucine and glycine
      substitutions at amino acid positions 134 and 167. These findings strongly
      suggest an association of HHV-8 infection with POEMS syndrome-associated MCD.

PMID- 10339471
TI  - Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus
      infections during prolonged neutropenia: results of a prospective randomized
      multicenter trial.
AB  - We performed a prospective, randomized, multicenter trial to evaluate the
      effectiveness of prophylactic inhalations with aerosolized amphotericin B
      (aeroAmB) to reduce the incidence of invasive aspergillus (IA) infections in
      patients after chemotherapy or autologous bone marrow transplantation and an
      expected duration of neutropenia of at least 10 days. From March 1993 until April
      1996, 382 patients with leukemias, relapsed high-grade non-Hodgkin lymphomas, or
      solid tumors were randomized with a 13:10 ratio to receive either prophylactic
      aeroAmB inhalations at a dose of 10 mg twice daily or no inhalation prophylaxis
      in an unblinded fashion. The incidence of proven, probable, or possible IA
      infections was 10 of 227 (4%) in patients who received prophylactic aeroAmB. This
      did not differ significantly from the 11 of 155 (7%) incidence in patients who
      received no inhalation prophylaxis (P =.37). Moreover, no differences in the
      overall mortality (13% v 10%; P =.37) or in the infection-related mortality (8% v
      7%; P =.79) were found. In contrast to other nonrandomized trials, we observed no
      benefit from prophylactic aeroAmB inhalations, but the overall incidence of IA
      infections was low.

PMID- 10339472
TI  - Factors associated with outcome after cord blood transplantation in children with
      acute leukemia. Eurocord-Cord Blood Transplant Group.
AB  - We have analyzed factors influencing the outcome of 102 children with acute
      leukemia given a cord blood transplantation (CBT) and reported to the Eurocord
      Registry. Seventy patients with acute lymphoblastic and 32 with acute myeloid
      leukemia were given either a related (n = 42) or an unrelated (n = 60) CBT.
      Children given CBT during first or second complete remission were considered as
      belonging to the good-risk group (n = 66), whereas those who received a
      transplant in a more advanced stage of disease were assigned to the poor-risk
      group (n = 36). In the related group (RCBT), 12 of 42 patients received
      transplantation from an HLA-disparate donor, whereas in the unrelated group
      (UCBT) 54 of 60 received an HLA mismatched CBT. Kaplan-Meier estimates for
      neutrophil recovery at day 60 were 84% +/- 7% in RCBT and 79 +/- 6% in UCBT (P
      =.16). In multivariate analysis, the most important factor influencing neutrophil
      engraftment in UCBT was a nucleated cell dose infused greater than 3.7 x 10(7)/kg
      (P =.05, relative risk [RR] of 1.85, 95% confidence interval [CI]: 0.98-3.4). The
      incidence of grade II through IV acute graft-versus-host disease was 41% +/- 8%
      in the RCBT group and 37% +/- 6% in the UCBT group (P =.59). Kaplan-Meier
      estimates of 2-year event-free survival (EFS) after RCBT or UCBT were 39% +/- 8%
      and 30% +/- 7%, respectively (P =.19). In multivariate analysis, the most
      important factor influencing EFS was disease status at time of transplantation:
      good-risk patients had a 2-year EFS of 49% +/- 7% as compared to 8% +/- 5% in
      patients with more advanced disease (P =.0003, RR: 0.40, 95% CI: 0.24 to 0. 65).
      This was a consequence of both an increased 1-year transplant related mortality
      and a higher 2-year relapse rate in the poor-risk group (65% +/- 9% and 77% +/-
      14%, respectively), as compared with good risk patients (34% +/- 6% and 31% +/-
      9%, respectively). These data confirm that allogeneic CBT from either a related
      or an unrelated donor is a feasible procedure able to cure a significant
      proportion of children with acute leukemia, especially if transplanted in a
      favorable phase of disease.

PMID- 10339473
TI  - Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral
      load, and severity of liver disease.
AB  - The natural history of chronic hepatitis C (HCV) infections in long-term leukemia
      survivors has not been well characterized. We studied the prevalence of HCV
      infections, measured HCV RNA levels, and evaluated the severity of liver disease
      in patients with leukemia who achieved long-term remissions after intensive
      chemotherapy or bone marrow transplantation (BMT). HCV antibody tests were
      performed by the enzyme-linked immunosorbent assay (ELISA) and positive tests
      confirmed by the recombinant immunoblot assay (RIBA). HCV RNA levels were
      measured by the branched DNA (bDNA) assay. Seventy-five leukemia survivors with
      25 or more blood donor exposures were identified. Nine (12%) were anti-HCV
      positive. All were infected before 1992 when second generation HCV screening
      tests were implemented. Mean HCV RNA levels were 10.3 x10(6) eq/mL versus 3.2 x
      10(6) eq/mL (P =.056) in a control group of 20 anti-HCV positive immunocompetent
      individuals of comparable age who were infected twice as long (17.8 +/- 6.5 years
      v 9.0 +/- 4.4 years in leukemia survivors, P =.001). Liver biopsies were
      performed on six of the nine anti-HCV positive leukemia survivors. All showed at
      least moderate portal inflammation and half had evidence of bridging fibrosis. We
      conclude that viral loads in anti-HCV positive leukemia survivors are markedly
      higher than in immunocompetent controls. Our results suggest that long-term
      leukemia survivors with chronic HCV may have more rapidly progressive liver
      disease than has been previously recognized.

PMID- 10339474
TI  - Selective ablation of acute myeloid leukemia using antibody-targeted
      chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate.
AB  - Leukemic blast cells express the CD33 antigen in most patients with acute myeloid
      leukemia (AML), but this antigen is not expressed by hematopoietic stem cells. We
      conducted a study to determine whether normal hematopoiesis could be restored in
      patients with AML by selective ablation of cells expressing the CD33 antigen. In
      a dose escalation study, 40 patients with relapsed or refractory CD33(+) AML were
      treated with an immunoconjugate (CMA-676) consisting of humanized anti-CD33
      antibody linked to the potent antitumor antibiotic calicheamicin. The capacity of
      leukemic cells to efflux 3, 3'-diethyloxacarbocyanine iodide (DiOC2) was used to
      estimate pretreatment functional drug resistance. Leukemia was eliminated from
      the blood and marrow of 8 (20%) of the 40 patients; blood counts returned to
      normal in three (8%) patients. A high rate of clinical response was observed in
      leukemias characterized by low dye efflux in vitro. Infusions of CMA-676 were
      generally well tolerated, and a postinfusion syndrome of fever and chills was the
      most common toxic effect. Two patients who were treated at the highest dose level
      (9 mg/m2) were neutropenic >5 weeks after the last dose of CMA-676. These results
      show that an immunoconjugate targeted to CD33 can selectively ablate malignant
      hematopoiesis in some patients with AML.

PMID- 10339476
TI  - Interleukin-4 synergizes with Raf-1 to promote long-term proliferation and
      activation of c-jun N-terminal kinase.
AB  - This report shows that interleukin-4 (IL-4), which plays a key role in regulating
      immune responses, fails to support cellular growth. We investigated whether this
      failure of IL-4 to promote growth was because of its unique inability to activate
      the Ras/Raf/Erk pathway. Consistent with other reports, expression in Ba/F3, a
      factor-dependent hematopoietic cell line, of either activated Q61KN-Ras or a
      hormone-inducible activated Raf-1, resulted in suppression of apoptosis but not
      in long-term growth. However, in the presence of IL-4, Ba/F3 cells that expressed
      either Q61KN-Ras or activated Raf-1 grew continuously at a rate comparable with
      that stimulated by IL-3. Investigation of the biochemical events associated with
      the stimulation of long-term growth showed that, as expected, the presence of
      activated Raf-1 resulted in an increased activity of extracellular signal
      regulated kinase (ERK) mitogen-activated protein kinase (MAPK) but not of c-jun N
      terminal kinase/stress-activated protein kinase (JNK). However, surprisingly, if
      IL-4 was present, cells expressing active Raf-1 exhibited increases in JNK
      activity. These observations point to a novel mechanism for JNK activation
      involving synergy between Raf-1 and pathways activated by IL-4 and suggest that
      in hematopoietic cells proliferation is correlated not only with "mitogen
      activated" ERK activity, but also with JNK activity.

PMID- 10339475
TI  - Monocyte arrest and transmigration on inflamed endothelium in shear flow is
      inhibited by adenovirus-mediated gene transfer of IkappaB-alpha.
AB  - Mobilization of nuclear factor-kappaB (NF-kappaB) activates transcription of
      genes encoding endothelial adhesion molecules and chemokines that contribute to
      monocyte infiltration critical in atherogenesis. Inhibition of NF-kappaB has been
      achieved by pharmacological and genetic approaches; however, monocyte
      interactions with activated endothelium in shear flow following gene transfer of
      the NF-kappaB inhibitor IkappaB-alpha have not been studied. We found that
      overexpression of IkappaB-alpha in endothelial cells using a recombinant
      adenovirus prevented tumor necrosis factor-alpha (TNF-alpha)-induced degradation
      of IkappaB-alpha and suppressed the upregulation of vascular cell adhesion
      molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin
      mRNA and surface protein expression and the upregulation of transcripts for the
      chemokines monocyte chemoattractant protein 1 (MCP-1) and growth-related activity
      alpha (GRO-alpha) by TNF-alpha. This was associated with a reduction in
      endothelial MCP-1 secretion and GRO-alpha immobilization. Adhesion assays under
      physiological shear flow conditions showed that firm arrest, spreading, and
      transmigration of monocytes on TNF-alpha-activated endothelium was markedly
      inhibited by IkappaB-alpha overexpression. Inhibition with monoclonal antibodies
      and peptide antagonists inferred that this was due to reduced expression of Ig
      integrin ligand as well as of chemokines specifically involved in these events.
      In contrast, rolling of monocytes was increased by IkappaB-alpha transfer and was
      partly mediated by P-selectin; however, it appeared to be unaffected by the
      inhibition of E-selectin induction. Thus, our data provide novel evidence that
      selective modulation of NF-kappaB by adenoviral transfer of IkappaB-alpha impairs
      the expression of multiple endothelial gene products required for subsequent
      monocyte arrest and emigration in shear flow and thus for monocyte infiltration
      in atherosclerotic plaques.

PMID- 10339477
TI  - Thrombopoietin augments stem cell factor-dependent growth of human mast cells
      from bone marrow multipotential hematopoietic progenitors.
AB  - The effects of thrombopoietin (TPO) and/or stem cell factor (SCF) on the
      development of human mast cells from CD34(+) bone marrow (BM) cells were
      investigated using a serum-deprived liquid culture system. Mast cells were
      identified by measurement of intracellular histamine content, immunocytochemical
      staining, and flow cytometric analysis. Whereas SCF alone generated only a small
      number of tryptase+ cells, the addition of TPO to the culture containing SCF
      resulted in an apparent production of mast cells from 3 weeks until at least 15
      weeks. Some of the cells reacted with an antichymase monoclonal antibody as well.
      Based on the effects of growth factor(s) on a later phase of the mast cell
      growth, TPO may stimulate an early stage of mast cell development in combination
      with SCF, whereas subsequent growth seems to be supported by SCF alone. Single
      cell culture studies indicated that the CD34(+)CD38(-)c-kit+ cells and
      CD34(+)CD38(+)c-kit+ cells were responsible for the SCF + TPO-dependent mast cell
      production. Two-step culture assays clearly showed that mast cells originated
      from multilineage colony-forming cells that had potential to differentiate into
      neutrophil/mast cell lineages, neutrophil/macrophage/mast cell lineages, or
      neutrophil/macrophage/mast cell/erythroid lineages. These results suggest that
      TPO plays an important role in the development of human mast cells from CD34(+)
      BM cells in concert with SCF, and provide direct evidence of the differentiation
      into the mast cell lineage of human multipotential BM-derived progenitors.

PMID- 10339478
TI  - CrkL activates integrin-mediated hematopoietic cell adhesion through the guanine
      nucleotide exchange factor C3G.
AB  - CrkL is a member of the Crk family of adapter proteins consisting mostly of SH2
      and SH3 domains. CrkL is most abundantly expressed in hematopoietic cells and has
      been implicated in pathogenesis of chronic myelogenous leukemia. However, its
      function has not been precisely defined. Here, we show that overexpression of
      CrkL enhances the adhesion of hematopoietic 32D cells to fibronectin. The CrkL
      induced increase in cell adhesion was blocked by antibodies against VLA-4
      (alpha4beta1) and VLA-5 (alpha5beta1) but was observed without changes in surface
      expression levels of these integrins. Studies using CrkL mutants demonstrated
      that the SH2 domain is partially required for enhancing cell adhesion, whereas
      the C-terminal SH3 domain as well as the tyrosine phosphorylation site (Y207) is
      dispensable. In contrast, the N-terminal SH3 domain, involved in binding C3G and
      other signaling molecules, was showed to play a crucial role, because a mutant
      defective of this domain showed an inhibitory effect on the cell adhesion to
      fibronectin. Furthermore, overexpression of C3G also increased the adhesion of
      hematopoietic cells to fibronectin, whereas a C3G mutant lacking the guanine
      nucleotide exchange domain abrogated the CrkL-induced increase in cell adhesion.
      On the other hand, a dominant negative mutant of H-Ras or that of Raf-1 enhanced
      the basal and CrkL-induced cell adhesion and that of R-Ras modestly decreased the
      adhesion. Taken together, these results indicate that the CrkL-C3G complex
      activates VLA-4 and VLA-5 in hematopoietic cells, possibly by activating the
      small GTP binding proteins, including R-Ras, through the guanine nucleotide
      exchange activity of C3G.

PMID- 10339479
TI  - A common signaling pathway via Syk and Lyn tyrosine kinases generated from
      capping of the sialomucins CD34 and CD43 in immature hematopoietic cells.
AB  - The sialomucin CD34 is a useful marker for hematopoietic stem/progenitor cells.
      However, the role of CD34 remains poorly understood. Here we investigate the
      functions of CD34 and another sialomucin CD43 coexpressed on hematopoietic
      stem/progenitor cells. Stimulation of undifferentiated hematopoietic KG1a cells
      with anti-CD34 or anti-CD43 induced homotypic cytoadhesion, accompanied by
      formation of a long-lived cap of CD34 and CD43 respectively, which colocalized
      with F-actin. Stimulation with either antibody specifically increased tyrosine
      phosphorylation of the identical set of proteins of Lyn, Syk, pp60, pp69, and
      pp77 at the capping site. These events were similar to those observed in
      monocytic U937 cells ectopically expressing CD34. After stimulation of KG1a
      cells, coimmunoprecipitation of Lyn with pp69 and pp77 and of Syk with pp37 was
      detected in the membrane fraction. Blockade of antibody-induced cap formation by
      treatment with cytochalasin D leads to inhibition of tyrosine phosphorylation of
      Syk and pp77 and homotypic cytoadhesion. Moreover, normal human CD34(+) bone
      marrow cells showed cap formation of CD34 or CD43 after stimulation. These
      results suggest that crosslinking of either CD34 or CD43 activates the same
      signaling pathway for cytoadhesion through Lyn, Syk, and the novel tyrosine
      phosphorylated proteins within hematopoiesis.

PMID- 10339480
TI  - Engraftment in nonobese diabetic severe combined immunodeficient mice of human
      CD34(+) cord blood cells after ex vivo expansion: evidence for the amplification
      and self-renewal of repopulating stem cells.
AB  - Understanding the repopulating characteristics of human hematopoietic
      stem/progenitor cells is crucial for predicting their performance after
      transplant into patients receiving high-dose radiochemotherapy. We have
      previously reported that CD34(+) cord blood (CB) cells can be expanded in vitro
      for several months in serum containing culture conditions. The use of
      combinations of recombinant early acting growth factors and the absence of stroma
      was essential in determining this phenomenon. However, the effect of these
      manipulations on in vivo repopulating hematopoietic cells is not known. Recently,
      a new approach has been developed to establish an in vivo model for human
      primitive hematopoietic precursors by transplanting human hematopoietic cells
      into sublethally irradiated nonobese diabetic severe combined immunodeficient
      (NOD/SCID) mice. We have examined here the expansion of cells, CD34(+) and
      CD34(+)38(-) subpopulations, colony-forming cells (CFC), long-term culture
      initiating cells (LTC-IC) and the maintenance or the expansion of SCID
      repopulating cells (SRC) during stroma-free suspension cultures of human CD34(+)
      CB cells for up to 12 weeks. Groups of sublethally irradiated NOD/SCID mice were
      injected with either 35,000, 20,000, and 10,000 unmanipulated CD34(+) CB cells,
      which were cryopreserved at the start of cultures, or the cryopreserved cells
      expanded from 35,000, 20,000, or 10,000 CD34(+) cells for 4, 8, and 12 weeks in
      the presence of a combination of early acting recombinant growth factors (flt
      3/flk2 ligand [FL] + megakaryocyte growth and development factor [MGDF] +/- stem
      cell factor [SCF] +/- interleukin-6 [IL-6]). Mice that had been injected with
      >/=20,000 fresh or cryopreserved uncultured CD34(+) cells did not show any sign
      or showed little engraftment in a limited number of animals. Conversely, cells
      that had been generated by the same number of initial CD34(+) CB cells in 4 to 10
      weeks of expansion cultures engrafted the vast majority of NOD/SCID mice. The
      level of engraftment, well above that usually observed when the same numbers of
      uncultured cells were injected in the same recipients (even in the presence of
      irradiated CD34(-) cells) suggested that primitive hematopoietic cells were
      maintained for up to 10 weeks of cultures. In addition, dilution experiments
      suggest that SRC are expanded more than 70-fold after 9 to 10 weeks of expansion.
      These results support and extend our previous findings that CD34(+) CB stem cells
      (identified as LTC-IC) could indeed be grown and expanded in vitro for an
      extremely long period of time. Such information may be essential to design
      efficient stem cell expansion procedures for clinical use.

PMID- 10339481
TI  - The myeloid-lymphoid initiating cell (ML-IC) assay assesses the fate of
      multipotent human progenitors in vitro.
AB  - Hematopoietic stem cells (HSC) are cells with self-renewing multilineage
      differentiation potential. Although engraftment in xenogeneic recipients can be
      used to measure human HSC, these assays do not allow assessment of individual
      progenitors. We developed an in vitro assay that allows the identification of a
      single human bone marrow progenitor closely related to HSC, which we termed
      "Myeloid-Lymphoid Initiating Cell," or ML-IC, because it is capable of generating
      multiple secondary progenitors that can reinitiate long-term myeloid and lymphoid
      hematopoiesis in vitro. The assay is done in contact with murine AFT024 fetal
      liver stromal cells and with Flt3-Ligand, stem cell factor, and interleukin-7. In
      this assay, 0.2% to 1.7% of Lin -/34(+)/DRdim cells could generate 1 to 3 long
      term culture initiating cells (LTC-IC) as well as 1 to 4 NK-IC after 4 to 6
      weeks. In addition, this assay measures contribution of net-progenitor
      conservation and net-progenitor proliferation over time, providing insight in the
      fate of individual LTC-IC and NK-IC. This assay will prove useful to enumerate
      the number of very primitive human progenitors with multilineage differentiation
      potential, as well as to evaluate future ex vivo culture conditions.

PMID- 10339482
TI  - Protein kinase B (c-Akt), phosphatidylinositol 3-kinase, and STAT5 are activated
      by erythropoietin (EPO) in HCD57 erythroid cells but are constitutively active in
      an EPO-independent, apoptosis-resistant subclone (HCD57-SREI cells).
AB  - We found that erythropoietin (EPO) and stem cell factor (SCF) activated protein
      kinase B (PKB/Akt) in EPO-dependent HCD57 erythroid cells. To better understand
      signals controlling proliferation and viability, erythroid cells that resist
      apoptosis in the absence of EPO were subcloned and characterized (HCD57-SREI
      cells). Constitutive activations of PKB/Akt, STAT5a, and STAT5b were noted in
      these EPO-independent cells. PI3-kinase activity was an upstream activator of
      PKB/Akt because the PI3-kinase inhibitor LY294002 blocked both constitutive
      PKB/Akt and factor-dependent PKB/Akt activity. The LY294002 study showed that
      proliferation and viability of both HCD57-SREI and HCD57 cells correlated with
      the activity of PKB/Akt; however, PKB/Akt activity alone did not protect these
      cells from apoptosis. Treatment of HCD57 cells with SCF also activated PKB/Akt,
      but did not protect from apoptosis. This result suggested that PKB/PI3-kinase
      activity is necessary but not sufficient to promote viability and/or
      proliferation. Constitutive STAT5 activity, activated through an unknown pathway
      not including JAK2 or EPOR, may act in concert with the constitutive PI3
      kinase/PKB/Akt pathway to protect the EPO-independent HCD57-SREI cells from
      apoptosis and promote limited proliferation.

PMID- 10339483
TI  - Functional differentiation signals mediated by distinct regions of the
      cytoplasmic domain of the granulocyte colony-stimulating factor receptor.
AB  - Granulocyte colony-stimulating factor receptor (G-CSFR) regulates the
      proliferation and differentiation of neutrophilic progenitor cells through
      interaction with its cytokine. Exposure of WEHI-3B D+ myelomonocytic leukemia and
      myeloid LGM-1 cells overexpressing the G-CSFR to G-CSF resulted in induction of
      differentiation as measured by (1) the ability to reduce nitroblue tetrazolium
      (NBT), (2) the expression of Mac-I antigen, and (3) the expression of
      FcgammaII/III receptor. Mutational analyses indicated that distinct regions of
      the cytoplasmic domain were critical for efficient induction of each functional
      marker. The membrane proximal region containing homology sequences of boxes 1 and
      2 was important for the activation of all three functional markers of mature
      neutrophils. Induction of the capacities to express Mac-I antigen or
      FcgammaII/III receptor also required additional sequences in the membrane
      proximal region between amino acids 70 and 100 and may be dependent on the
      phosphorylation of Tyr703. The findings suggest that distinct sequences within
      the amino-terminal region of the cytoplasmic domain of the receptor are
      sufficient to induce these functional markers of differentiation, and receptor
      tyrosine phosphorylation may be necessary.

PMID- 10339484
TI  - Noninflammatory expression of E-selectin is regulated by cell growth.
AB  - E-selectin, an endothelial-specific adhesion molecule best known for its role in
      leukocyte adhesion, is not detected in quiescent endothelial cells, but is
      induced by inflammatory stimuli. However, E-selectin is also expressed in
      proliferating endothelial cells under noninflammatory conditions in vivo and in
      vitro, suggesting that E-selectin is also regulated by growth signals. To
      investigate E-selectin expression in lipopolysaccharide-stimulated versus
      nonstimulated proliferating cells, we analyzed the distribution of E-selectin
      positive human microvascular endothelial cells in G0/G1, S, and G2/M phases of
      the cell cycle under both conditions. Lipopolysaccharide treatment resulted in
      uniformly increased E-selectin expression in cells in G0/G1, S, and G2/M. In
      contrast, levels of E-selectin in nonstimulated proliferating cells showed a
      linear correlation with the percentage of cells in G2/M. E-selectin in
      proliferating endothelial cells was not reduced by addition of soluble tumor
      necrosis factor-alpha-receptor or soluble interleukin-1-receptor indicating that
      its expression was not due to endogenous production of either cytokine. In
      addition, E-selectin was increased in cells stimulated with basic fibroblast
      growth factor, a well-known mitogen for endothelial cells. E-selectin in
      proliferating endothelial cells is functional, as shown by E-selectin-dependent
      adhesion of the promyelocytic leukemia cell line HL-60 to subconfluent human
      microvascular endothelial cells. In summary, these studies indicate that E
      selectin can be regulated by a non-inflammatory pathway that is related to the
      proliferative state of the endothelium.

PMID- 10339485
TI  - Activated protein C resistance: effect of platelet activation, platelet-derived
      microparticles, and atherogenic lipoproteins.
AB  - Plasma and platelet factor Va represent different substrates for activated
      protein C (APC). In this study, we have measured platelet-dependent APC
      resistance and the effect of aspirin and a platelet glycoprotein IIbIIIa
      antagonist (GR144053F) on this phenomenon. In platelet rich plasma (PRP),
      progressive APC resistance was observed with increasing platelet activation. APC
      sensitivity ratios of 1.8, 1.7, and 1.4 were observed after platelet activation
      with thrombin receptor activating peptide (TRAP), collagen, and A23187,
      respectively. Ultracentrifugation at 77,000g for 1 hour abolished APC resistance
      indicating that the phenotype is associated exclusively with the platelet
      membrane. APC resistance was not observed in the presence of phosphatidylcholine
      phosphatidylserine (PCPS) vesicles or purified human plasma lipoproteins. APC
      resistance was observed in the presence of platelet-derived microparticles, but
      to a lesser degree than that in the presence of activated platelets. The platelet
      dependent APC resistance phenotype was also observed when endogenous APC was
      generated by Protac (American Diagnostica, Inc, Greenwich, CT). In vitro
      inhibition of platelet activation with aspirin had no effect, but the fibrinogen
      receptor antagonist, GR144053F, inhibited platelet-dependent APC resistance.
      These results indicate that platelet activation results in an APC-resistant
      phenotype comparable to that observed in the plasma of patients with factor V
      gene mutations affecting critical APC cleavage sites. This suggests that platelet
      activation at the site of endothelial damage downregulates a critical natural
      anticoagulant mechanism. The antithrombotic effect of aspirin may be due to an
      indirect effect on platelet-dependent APC resistance with reduced platelet
      retention within a developing thrombus. The more potent antithrombotic effect of
      glycoprotein IIbIIIa antagonists may in addition be the result of reduced
      platelet factor Va expression and modulation of the platelet-dependent APC
      resistance phenotype.

PMID- 10339486
TI  - von Willebrand factor proteolysis is deficient in classic, but not in bone marrow
      transplantation-associated, thrombotic thrombocytopenic purpura.
AB  - Thrombotic thrombocytopenic purpura (TTP) after bone marrow transplantation (BMT)
      differs from classic TTP in its clinical course and therapy. A characteristic of
      classic TTP is the inhibition of a plasma protease that specifically cleaves von
      Willebrand factor (vWF), thus reducing its multimeric size. We investigated
      whether this protease was also inhibited in BMT-associated TTP. Plasma from
      patients with classic or BMT-associated TTP was incubated with recombinant vWF
      R834Q, a vWF mutant with enhanced sensitivity to the protease. The proteolysis of
      vWF multimers was analyzed and quantified on Western blot. Metalloprotease
      activity was strongly inhibited in the classic TTP patient group. However,
      metalloprotease activity was normal in the BMT-associated TTP patient group. The
      difference in activity between the two patient groups was highly significant (P
      =.0016). The results indicate that the etiologies of classic and BMT-associated
      TTP are indeed different and provide an explanation for the lack of success of
      plasma exchange in BMT-associated TTP.

PMID- 10339487
TI  - Overexpression of A1, an NF-kappaB-inducible anti-apoptotic bcl gene, inhibits
      endothelial cell activation.
AB  - A1 is an anti-apoptotic bcl gene that is expressed in endothelial cells (EC) in
      response to pro-inflammatory stimuli. We show that in addition to protecting EC
      from apoptosis, A1 inhibits EC activation and its associated expression of pro
      inflammatory proteins by inhibiting the transcription factor nuclear factor (NF)
      kappaB. This new anti-inflammatory function gives a broader dimension to the
      protective role of A1 in EC. We also show that activation of NF-kappaB is
      essential for the expression of A1. Taken together, our data suggest that A1
      downregulates not only the pro-apoptotic and pro-inflammatory response, but also
      its own expression, thus restoring a quiescent phenotype to EC.

PMID- 10339488
TI  - Vascular endothelial cell growth factor-induced tissue factor expression in
      endothelial cells is mediated by EGR-1.
AB  - Vascular endothelial cell growth factor (VEGF) is a major regulator of
      angiogenesis. We report here that treatment of endothelial cells with VEGF leads
      to upregulation of tissue factor mRNA and protein expression on the cell surface.
      Reporter gene studies show that transcriptional activation of the tissue factor
      gene by VEGF is mediated by a GC-rich promoter element containing overlapping
      binding sites for Sp1 and EGR-1. As shown by immunofluorescence and
      electrophoretic mobility shift assays, upon VEGF treatment EGR-1 rapidly
      accumulates in the nucleus and binds to its respective recognition site in the
      tissue factor promoter. Sp1 occupies this element in unstimulated cells and seems
      to be partially displaced by increasing amounts of EGR-1. Transfection of
      endothelial cells with an EGR-1 expression plasmid mimics the upregulation of
      tissue factor transcription observed after VEGF treatment. In contrast, NFkappaB,
      the major transcription factor involved in tissue factor upregulation by
      inflammatory stimuli, is not activated by VEGF. These data show that VEGF induces
      a response in endothelial cells largely distinct from inflammatory stimuli, and
      suggest that EGR-1 is a major mediator of the activation of the tissue factor and
      possibly other VEGF-responsive genes.

PMID- 10339490
TI  - Endothelial cells undergoing apoptosis become proadhesive for nonactivated
      platelets.
AB  - Under normal conditions, platelets do not adhere to endothelium. However, when
      platelets or endothelial cells are stimulated by thrombin or cytokines,
      respectively, platelets bind avidly to endothelium. Because there is accumulating
      evidence that endothelial cells may become apoptotic under certain
      proinflammatory or prothrombotic conditions, we investigated whether endothelial
      cells undergoing apoptosis may become proadhesive for nonactivated platelets.
      Human umbilical vein endothelial cells (HUVEC) were induced to undergo apoptosis
      by staurosporine, a nonspecific protein kinase inhibitor, or by culture in
      suspension with serum-deprivation. After treatment of HUVEC or platelets with
      different receptor antagonists, nonactivated, washed human platelets were allowed
      to adhere to HUVEC for 20 minutes. To exclude matrix involvement, platelet
      binding was measured in suspension by using flow cytometry. Independent of the
      method of apoptosis induction, there was a marked increase in platelet binding to
      apoptotic HUVEC. Although HUVEC exhibited maximal adhesiveness for platelets
      after 2 to 4 hours, complete DNA fragmentation of HUVEC occurred only several
      hours later. Adhesion assays after blockade of different platelet receptors
      showed only involvement of beta1-integrins. Platelet binding to apoptotic HUVEC
      was inhibited by more than 70% when platelets were treated with blocking anti
      beta1 antibodies. Treatment of apoptotic HUVEC with blocking antibodies to
      different potential platelet receptors, including known ligands for beta1
      integrins, did not affect platelet binding. As assessed by determination of beta
      thromboglobulin and platelet factor 4 in the supernatants, platelets bound to
      apoptotic HUVEC became slightly activated. However, significant expression of
      platelet P-selectin (CD62P) was not found. These data provide further evidence
      that endothelial cells undergoing apoptosis may contribute to thrombotic events.

PMID- 10339489
TI  - Sickle cell anemia as a possible state of enhanced anti-apoptotic tone: survival
      effect of vascular endothelial growth factor on circulating and unanchored
      endothelial cells.
AB  - The biologic processes of apoptosis and angiogenesis are linked in endothelial
      biology because some endothelial cell growth factors also exert anti-apoptotic
      effects. We studied whether apoptosis is occurring in circulating endothelial
      cells (CEC) that have lost the survival signals derived from anchorage to
      extracellular matrix. Consistent with this expectation, 64% +/- 16% of CEC from
      normal donors showed evidence of apoptosis (by morphology and TdT-mediated dUTP
      nick end labeling [TUNEL] assay). However, only 30% +/- 15% (P <.001 v normal) of
      CEC from donors with sickle cell anemia were apoptotic. Vascular endothelial
      growth factor (VEGF) levels were significantly (P =.001) higher in plasma of
      sickle donors (120.1 +/- 81.4 pg/mL) than that of normal donors (37.6 +/- 34.6
      pg/mL), and there was an inverse correlation between VEGF and CEC apoptosis (r =.
      612, P =.001). Consistent with stimulation by VEGF, CEC from sickle donors
      exhibited increased expression of alphavbeta3. In vitro experiments showed that
      VEGF inhibits apoptosis for cultured endothelial cells that are kept unanchored
      and not allowed to re-establish attachment to extracellular matrix, thus
      demonstrating that VEGF provides survival signals independent of its ability to
      promote matrix reattachment. These data suggest the hypothesis that sickle cell
      anemia is a state of enhanced anti-apoptotic tone for endothelial cells. If true,
      this has implications for disease pathobiology, particularly the development of
      neovascularizing retinopathy.

PMID- 10339491
TI  - Characterization of cell-associated plasminogen activation catalyzed by urokinase
      type plasminogen activator, but independent of urokinase receptor (uPAR, CD87).
AB  - The 55-kD urokinase (uPA) receptor (uPAR, CD87) is capable of binding uPA and may
      be involved in regulating cell-associated plasminogen activation and pericellular
      proteolysis. While investigating the relationship between uPAR levels and plasmin
      generation, we found that uPA-catalyzed plasminogen activation is stimulated by
      cells which do not express uPAR. This uPAR-independent mechanism appears to be at
      least as effective in vitro as uPAR-dependent stimulation, such that stimulation
      on the order of 30-fold was observed, resulting from improvements in both
      apparent kcat and apparent Km. The mechanism depends on simultaneous binding of
      both uPA and plasminogen to the cell and requires the presence of the amino
      terminal fragment (ATF), available in single chain and two chain high-molecular
      weight uPA, but not low-molecular-weight uPA. Stimulation was observed in all
      leukemic cell lines investigated at similar optimum concentrations of 10(6) to
      10(7) cells/mL and may be more general. A mechanism is proposed whereby uPA can
      associate with binding sites on the cell surface of lower affinity, but higher
      capacity than uPAR, but these are sufficient to stimulate plasmin generation even
      at subphysiologic uPA concentrations. This mechanism is likely to operate under
      conditions commonly used for in vitro studies and may have some significance in
      vivo.

PMID- 10339492
TI  - Collagen mediates changes in intracellular calcium in primary mouse
      megakaryocytes through syk-dependent and -independent pathways.
AB  - We have characterized changes in [Ca2+]i in primary mouse megakaryocytes in
      response to fibrillar collagen and in response to cross-linking of the collagen
      receptor, the integrin alpha2beta1. The response to collagen was markedly
      different from that seen to a triple helical collagen-related peptide (CRP),
      which signals via the tyrosine kinases p59(fyn) and p72(syk). This peptide binds
      to the collagen receptor glycoprotein VI (GPVI), but not to the integrin
      alpha2beta1. Collagen elicited a sustained increase in [Ca2+]i composed primarily
      of influx of extracellular Ca2+ with some Ca2+ release from internal stores. In
      contrast to CRP, this response was only partially (approximately 30%) inhibited
      by the src-family kinase inhibitor PP1 (10 micromol/L) or by microinjection of
      the tandem SH2 domains of p72(syk). Collagen also caused an increase in [Ca2+]i
      in megakaryocytes deficient in either p59(fyn) or p72(syk), although the response
      was reduced by approximately 40% in both cases: Cross-linking of the alpha2
      integrin increased [Ca2+]i in these cells exclusively via Ca2+ influx. This
      response was reduced by approximately 50% after PP1 pretreatment, but was
      significantly increased in fyn-deficient megakaryocytes. Collagen therefore
      increases [Ca2+]i in mouse megakaryocytes via multiple receptors, including GPVI,
      which causes Ca2+ mobilization, and alpha2beta1, which stimulates a substantial
      influx of extracellular Ca2+.

PMID- 10339493
TI  - In vivo T-lymphocyte tolerance in the absence of thymic clonal deletion mediated
      by hematopoietic cells.
AB  - Thymic negative selection renders the developing T-cell repertoire tolerant to
      self-major histocompatability complex (MHC)/peptide ligands. The major mechanism
      of induction of self-tolerance is thought to be thymic clonal deletion, ie, the
      induction of apoptotic cell death in thymocytes expressing a self-reactive T-cell
      receptor. Consistent with this hypothesis, in mice deficient in thymic clonal
      deletion mediated by cells of hematopoietic origin, a twofold to threefold
      increased generation of mature thymocytes has been observed. Here we describe the
      analysis of the specificity of T lymphocytes developing in the absence of clonal
      deletion mediated by hematopoietic cells. In vitro, targets expressing syngeneic
      MHC were readily lysed by activated CD8(+) T cells from deletion-deficient mice.
      However, proliferative responses of T cells from these mice on activation with
      syngeneic antigen presenting cells were rather poor. In vivo, deletion-deficient
      T cells were incapable of induction of lethal graft-versus-host disease in
      syngeneic hosts. These data indicate that in the absence of thymic deletion
      mediated by hematopoietic cells functional T-cell tolerance can be induced by
      nonhematopoietic cells in the thymus. Moreover, our results emphasize the
      redundancy in thymic negative selection mechanisms.

PMID- 10339494
TI  - HLA-B8 and HLA-A3 coexpressed with HLA-B8 are associated with a reduced risk of
      the development of chronic myeloid leukemia. The Chronic Leukemia Working Party
      of the EBMT.
AB  - Chronic myeloid leukemia (CML) is characterized by the chromosomal translocation
      t(9;22) resulting in the chimeric bcr-abl oncogene that encodes the P210 fusion
      protein, which contains a unique amino acid sequence. If peptides derived from
      the leukemia-specific part of P210 are expressed in HLA molecules on the cell
      membrane of leukemic cells, an immunological response may occur. Recent studies
      using synthetic peptides identical to the bcr-abl fusion region showed that some
      peptides are capable of binding to HLA-A3, -A11, and -B8 molecules. Cytotoxic T
      cell responses have been induced against bcr-abl-derived synthetic peptides bound
      to HLA-A3 and -B8. We hypothesized that if antigen processing of the P210 fusion
      protein leads to presentation of peptides from the fusion region by major
      histocompatibility complex (MHC) molecules in vivo, this may be reflected in a
      diminished incidence of CML in individuals expressing HLA-A3, -A11, or -B8.
      Consequently, lower frequencies of these antigens would be expected in patients
      with CML compared with unaffected individuals. A case-control study and a meta
      analysis were performed to test this hypothesis. The multicenter case-control
      study compared patients with CML from the data base of the European Group for
      Blood and Marrow Transplantation (EBMT) with unaffected individuals from the
      registry of Bone Marrow Donors Worldwide. Patients and controls were matched per
      country. The meta-analysis consisted of five studies reported in the literature.
      The multicenter case-control study consisting of 1,899 patients and 512, 363 bone
      marrow donors as controls yielded odds ratios (ORs) of 0.90 (95% confidence
      interval [CI], 0.80 to 1.00) for HLA-A3, 1.16 (95% CI, 1.02 to 1.33) for HLA-A11,
      and an OR of 0.73 (95% CI, 0.65 to 0. 82) for HLA-B8. Coexpression of HLA-A3 and
      HLA-B8 gave an OR of 0.51 (95% CI, 0.40 to 0.67). This can be translated in a
      protective effect of 27% for HLA-B8, 10% for HLA-A3, and 49% protection for the
      combination of HLA-A3 and HLA-B8. The meta-analysis comprising 463 CML patients
      and 4,912 controls showed a 29% risk reduction for individuals expressing HLA-B8
      (OR of 0.71; 95% CI, 0.52 to 0.97), but an OR of 1.19 (95% CI, 0.90 to 1.56) for
      HLA-A3 and an OR of 1. 09 (95% CI, 0.80 to 1.50) for HLA-A11. In conclusion,
      these results indicate that HLA-B8 expression, in particular when HLA-A3 is
      coexpressed, is associated with a diminished incidence of CML. A biological
      mechanism may be that presentation of bcr-abl breakpoint peptides in these HLA
      molecules can induce a protective immune response.

PMID- 10339495
TI  - The susceptibility to X4 and R5 human immunodeficiency virus-1 strains of
      dendritic cells derived in vitro from CD34(+) hematopoietic progenitor cells is
      primarily determined by their maturation stage.
AB  - Dendritic cells (DC) were sorted on day 8 from cultures of CD34(+) cells with
      stem cell factor/Flt-3 ligand/ granulocyte-macrophage colony-stimulating factor
      (GM-CSF)/tumor necrosis factor-alpha (TNF-alpha)/interleukin-4 (IL-4). Exposing
      immature CCR5(+)CXCR4(lo/-) DC to CCR5-dependent human immunodeficiency virus
      (HIV)-1Ba-L led to productive and cytopathic infection, whereas only low virus
      production occurred in CXCR4-dependent HIV-1LAI-exposed DC. PCR analysis of the
      DC 48 hours postinfection showed efficient entry of HIV-1Ba-L but not of HIV
      1LAI. CD40 ligand- or monocyte-conditioned medium-induced maturation of HIV-1Ba-L
      infected DC reduced virus production by about 1 Log, while cells became CCR5(-).
      However, HIV-1Ba-L-exposed mature DC harbored 15-fold more viral DNA than their
      immature counterparts, ruling out inhibition of virus entry. Simultaneously,
      CXCR4 upregulation by mature DC coincided with highly efficient entry of HIV-1LAI
      which, nonetheless, replicated at the same low level in mature as in immature DC.
      In line with these findings, coculture of HIV-1Ba-L-infected immature DC with CD3
      monoclonal antibody-activated autologous CD4(+) T lymphocytes in the presence of
      AZT decreased virus production by the DC. Finally, whether they originated from
      CD1a+CD14(-) or CD1a-CD14(+) precursors, DC did not differ as regards
      permissivity to HIV, although CD1a+CD14(-) precursor-derived immature DC could
      produce higher HIV-1Ba-L amounts than their CD1a-CD14(+) counterparts. Thus, both
      DC permissivity to, and capacity to support replication of, HIV is primarily
      determined by their maturation stage.

PMID- 10339496
TI  - Interleukin-2-activated rat natural killer cells express inducible nitric oxide
      synthase that contributes to cytotoxic function and interferon-gamma production.
AB  - Natural killer (NK) cells are large granular lymphocytes capable of destroying
      cells infected by virus or bacteria and susceptible tumor cells without prior
      sensitization and restriction by major histocompatability complex (MHC) antigens.
      Their cytotoxic activity could be strongly enhanced by interleukin-2 (IL-2).
      Previous findings, even if obtained with indirect experimental approaches, have
      suggested a possible involvement of the inducible nitric oxide (iNOS) pathway in
      the NK-mediated target cell killing. The aim of the present study was first to
      directly examine the induction of iNOS in IL-2-activated rat NK cells isolated
      from peripheral blood (PB-NK) or spleen (S-NK), and second to investigate the
      involvement of the iNOS-derived NO in the cytotoxic function of these cells. Our
      findings clearly indicate the induction of iNOS expression in IL-2-activated PB
      NK and S-NK cells, as evaluated either at mRNA and protein levels. Accordingly,
      significantly high levels of iNOS activity were shown, as detected by the L
      arginine to L-citrulline conversion in appropriate assay conditions. The
      consequent NO generation appears to partially account for NK cell-mediated DNA
      fragmentation and lysis of sensitive tumor target cells. In fact, functional
      inhibition of iNOS through specific inhibitors, as well as the almost complete
      abrogation of its expression through a specific iNOS mRNA oligodeoxynucleotide
      antisense, significantly reduced the lytic activity of IL-2-activated NK cells.
      Moreover, IL-2-induced interferon-gamma production appears also to be dependent,
      at least in part, on iNOS induction.

PMID- 10339497
TI  - T20/DP178, an ectodomain peptide of human immunodeficiency virus type 1 gp41, is
      an activator of human phagocyte N-formyl peptide receptor.
AB  - Human immunodeficiency virus type 1 (HIV-1) envelope protein gp41 mediates viral
      fusion with human host cells. The peptide segment T20/DP178, located in the C
      terminus of the ectodomain of gp41, interacts with the N-terminal leucine zipper
      like domain on gp41 to establish the fusogenic conformation of the virus.
      Synthetic T20/DP178 peptide is highly efficacious in inhibiting HIV-1 infection
      in vitro by disrupting the transformation of fusogenic status of viral gp41;
      thus, it has been proposed for clinical trial. We report that synthetic T20/DP178
      is a chemoattractant and activator of human peripheral blood phagocytes but not
      of T lymphocytes. We further demonstrate that T20/DP178 specifically activates a
      seven-transmembrane, G-protein-coupled phagocyte receptor for N-formylated
      chemotactic peptides, formyl peptide receptor (FPR). Moreover, synthetic
      T20/DP178 analogs lacking N-terminal amino acids acted as FPR antagonists. Our
      results suggest that gp41 peptides regulate phagocyte function via FPR and
      identify a novel mechanism by which HIV-1 may modulate innate immunity.

PMID- 10339498
TI  - Constitutive activation of extracellular signal-regulated kinase in human acute
      leukemias: combined role of activation of MEK, hyperexpression of extracellular
      signal-regulated kinase, and downregulation of a phosphatase, PAC1.
AB  - Extracellular signal-regulated kinase (ERK) is an important intermediate in
      signal transduction pathways that are initiated by many types of cell surface
      receptors. It is thought to play a pivotal role in integrating and transmitting
      transmembrane signals required for growth and differentiation. Constitutive
      activation of ERK in fibroblasts elicits oncogenic transformation, and recently,
      constitutive activation of ERK has been observed in some human malignancies,
      including acute leukemia. However, mechanisms underlying constitutive activation
      of ERK have not been well characterized. In this study, we examined the
      activation of ERK in 79 human acute leukemia samples and attempted to find
      factors contributing to constitutive ERK activation. First, we showed that ERK
      and MEK were constitutively activated in acute leukemias by in vitro kinase assay
      and immunoblot analysis. However, in only one half of the studied samples, the
      pattern of ERK activation was similar to that of MEK activation. Next, by
      semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and
      immunoblot analysis, we showed hyperexpression of ERK in a majority of acute
      leukemias. In 17 of 26 cases (65.4%) analyzed by immunoblot, the pattern of ERK
      expression was similar to that of ERK activation. The fact of constitutive
      activation of ERK in acute leukemias suggested to us the possibility of an
      abnormal downregulation mechanism of ERK. Therefore, we examined PAC1, a specific
      ERK phosphatase predominantly expressed in hematopoietic tissue and known to be
      upregulated at the transcription level in response to ERK activation.
      Interestingly, in our study, PAC1 gene expression in acute leukemias showing
      constitutive ERK activation was significantly lower than that in unstimulated,
      normal bone marrow (BM) samples showing minimal or no ERK activation (P =.002).
      Also, a significant correlation was observed between PAC1 downregulation and
      phosphorylation of ERK in acute leukemias (P =.002). Finally, by further analysis
      of 26 cases, we showed that a complementary role of MEK activation, ERK
      hyperexpression, and PAC1 downregulation could contribute to determining the
      constitutive activation of ERK in acute leukemia. Our results suggest that ERK is
      constitutively activated in a majority of acute leukemias, and in addition to the
      activation of MEK, the hyperexpression of ERK and downregulation of PAC1 also
      contribute to constitutive ERK activation in acute leukemias.

PMID- 10339499
TI  - Posttranslational regulation of Myc function in response to phorbol
      ester/interferon-gamma-induced differentiation of v-Myc-transformed U-937
      monoblasts.
AB  - The transcription factors of the Myc/Max/Mad network are important regulators of
      cell growth, differentiation, and apoptosis and are frequently involved in tumor
      development. Constitutive expression of v-Myc blocks phorbol ester (TPA)-induced
      differentiation of human U-937 monoblasts. However, costimulation with interferon
      gamma (IFN-gamma) and TPA restores terminal differentiation and G1 cell-cycle
      arrest despite continuous expression of v-Myc. The mechanism by which TPA + IFN
      gamma counteract v-Myc activity has not been unravelled. Our results show that
      TPA + IFN-gamma treatment led to an inhibition of v-Myc- and c-Myc-dependent
      transcription, and a specific reduction of v-Myc:Max complexes and associated DNA
      binding activity, whereas the steady state level of the v-Myc protein was only
      marginally affected. In contrast, TPA + IFN-gamma costimulation neither increased
      the expression of Mad1 or other mad/mnt family genes nor altered
      heterodimerization or DNA-binding activity of Mad1. The reduced amount of v
      Myc:Max heterodimers in response to treatment was accompanied by partial
      dephosphorylation of v-Myc and c-Myc. Phosphatase treatment of Myc:Max complexes
      lead to their dissociation, thus mimicking the effect of TPA + IFN-gamma. In
      addition to modulation of the expression of Myc/Max/Mad network proteins,
      posttranslational negative regulation of Myc by external signals may, therefore,
      be an alternative biologically important level of control with potential
      therapeutic relevance for hematopoietic and other tumors with deregulated Myc
      expression.

PMID- 10339500
TI  - Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in
      adults with anaplastic large cell lymphoma.
AB  - Anaplastic large cell lymphoma (ALCL) is an aggressive lymphoma that is
      frequently associated with the t(2;5)(p23;q35), resulting in expression of a
      fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which can be
      detected by either monoclonal or polyclonal antibodies to the ALK protein. The
      clinical features of adults with ALCL are incompletely described, and the
      prognostic factors that are useful for predicting survival remain unclear. This
      report describes the clinical and laboratory findings in 70 adults with systemic
      ALCL who were treated with curative intent. We attempted to identify the clinical
      and pathological factors of prognostic importance, including the International
      Prognostic Index (IPI), immunophenotype, and expression of the ALK protein. The
      median age of the patients was 49 years (range, 15 to 75). There were 26 women
      and 44 men with a median follow-up of 50 months for living patients. Advanced
      stage was present in 56% and B symptoms were noted in 70% of the patients.
      Immunostains showed that 46% of the cases had a T-cell phenotype, 36% a null
      phenotype, and 18% a B-cell phenotype. The expression of ALK protein was found in
      51% of the cases. The IPI factors were evenly distributed between the ALK+ and
      ALK- groups, except that the ALK+ patients were younger (median age, 30 v 61
      years; P <.002). The ALK+ cohort included cases with null (44%), T-cell (42%),
      and B-cell (14%) phenotypes. All 10 cases with cytogenetic or molecular evidence
      of a t(2;5) were ALK+. The 5-year overall survival (OS) of the entire cohort was
      65%. The 5-year OS of the ALK+ and ALK- cases was 79% and 46%, respectively (P
      <.0003). Analysis of only the T-cell/null cases (n = 57) showed a 5-year OS of
      93% for the ALK+ cases and only 37% for the ALK- cases (P <.00001). Univariate
      analysis of the clinical features showed that age </=60 years (P <.007), a normal
      serum lactate dehydrogenase (LDH) (P <.00001), a good performance status (Eastern
      Cooperative Oncology Group [ECOG] <2) (P <.03), </=1 extranodal site of disease
      (P <.012), and an IPI score </=3 (P <.00001) were associated with improved OS.
      Although a younger age correlated with ALK positivity, multivariate analysis
      showed that only a normal serum LDH (P <. 00001), an IPI score of </=3 (P
      <.0005), and ALK protein expression (P <.005) predicted independently for an
      improved OS. We conclude that ALCL is a heterogeneous disorder. However, ALK
      protein expression is an independent predictor of survival and serves as a useful
      biologic marker of a specific disease entity within the spectrum of ALCL.

PMID- 10339501
TI  - Humanized anti-HM1.24 antibody mediates myeloma cell cytotoxicity that is
      enhanced by cytokine stimulation of effector cells.
AB  - To develop a new immunotherapy for multiple myeloma, we have generated a
      monoclonal antibody (MoAb) that detects a human plasma cell-specific antigen,
      HM1.24. Our previous study has shown that mouse anti-HM1.24 MoAb inhibits the
      proliferation of human myeloma cells implanted into severe combined
      immunodeficiency mice. In this report, we evaluated the antitumor activity of the
      humanized anti-HM1.24 MoAb (IgG1kappa), which was constructed by grafting the
      complementarity-determining regions. In contrast to the parent mouse MoAb,
      humanized anti-HM1.24 MoAb mediated antibody-dependent cellular cytotoxicity
      (ADCC) against both myeloma cell lines and myeloma cells from patients in the
      presence of human peripheral blood mononuclear cells (PBMCs). The PBMCs from
      untreated myeloma patients exhibited ADCC activity as efficiently as those of
      healthy donors. Although decreased ADCC activity of PBMCs was observed in
      patients who responded poorly to conventional chemotherapy, it could be
      significantly augmented by the stimulation with interleukin-2 (IL-2), IL-12, or
      IL-15. There was a strong correlation between the percentage of CD16(+) cells and
      ADCC activity in the PBMCs of myeloma patients. Moreover, peripheral blood stem
      cell collections from myeloma patients contained higher numbers of CD16(+) cells
      than PBMCs and exhibited ADCC activity that was enhanced by IL-2. These results
      indicate that humanized anti-HM1.24 MoAb has potential as a new therapeutic
      strategy in multiple myeloma and that treatment of effector cells with
      immunomodulating cytokines can restore the effect of humanized anti-HM1.24 MoAb
      in patients with diminished ADCC activity.

PMID- 10339502
TI  - Value of immunophenotype in intensively treated adult acute lymphoblastic
      leukemia: cancer and leukemia Group B study 8364.
AB  - The prognostic value of immunophenotype in adult acute lymphoblastic leukemia
      (ALL) has varied based on the methods used, surface markers studied, and therapy
      administered. From April 1991 to September 1996, samples of leukemic marrow or
      blood from 259 eligible and evaluable adult ALL patients entering dose-intensive
      Cancer and Leukemia Group B (CALGB) front-line treatment protocols were
      prospectively studied for immunophenotypic classification by multiparameter flow
      cytometry (MFC) in a central laboratory. A B-lineage (B-LIN) phenotype was
      expressed in 79% of cases, with one third coexpressing myeloid antigens. A T
      lineage (T-LIN) phenotype was expressed in 17% of cases, with one quarter
      coexpressing myeloid antigens. Since the advent of more intensive CALGB therapy
      which incorporated cyclophosphamide and the early use of L-asparaginase into the
      backbone of daunorubicin, vincristine and prednisone, together with central
      nervous system prophylaxis for adult ALL, no significant differences in response
      rates, remission duration, or survival have been seen in those patients
      coexpressing myeloid antigens. The T-LIN phenotype was associated with younger
      age (P =.01), a higher male to female ratio (P =.01), higher white blood cell
      count (P =.001) and hemoglobin (P <.001) levels, presence of a mediastinal mass
      (P <. 001), and longer survival (P =.01) and disease-free survival (DFS) (P =.01)
      when compared to patients with a B-LIN phenotype. The 3-year probability of
      survival and DFS (95% confidence interval [CI]) of T-LIN adult ALL was 0.62 (0.46
      to 0.76) and 0.62 (0.44 to 0. 77), respectively. Comparatively, the 3-year
      probability of survival and DFS (95% CI) of B-LIN adult ALL was 0.42 (0.35 to
      0.50) and 0.39 (0.31 to 0.47), respectively. The number of T markers expressed in
      T-LIN ALL cases was shown to have prognostic significance. In particular,
      patients expressing six or more markers compared with patients expressing three
      or fewer markers had longer DFS (P =.003) and survival (P =.004). The presence of
      the Philadelphia chromosome was significantly associated with B-LIN ALL cases
      which coexpressed CD19(+), CD34(+), and CD10(+) (49%; P =.003), whereas the
      majority of t(4;11) cases were CD19(+), CD34(+) but CD10(-). The knowledge gained
      from this study of MFC of a large number of patients will permit a reduction in
      the number of antigens to be evaluated in future studies. Overall, this should
      lead to cost savings without loss of valuable information. A rational approach
      for future studies would be to use four-color flow cytometry (instead of the
      current three-color) to help further streamline the study of immunophenotype of
      adult ALL by MFC.

PMID- 10339503
TI  - Expression and functional characterization of the beta-isoform of the folate
      receptor on CD34(+) cells.
AB  - We have investigated the expression and functional competence of folate receptor
      (FR) isoforms on human hematopoietic cells. Using immunofluorescence and reverse
      transcriptase-polymerase chain reaction (RT-PCR) methodology, we find that a
      substantial fraction of low-density mononuclear and CD34(+) cells express both
      the beta and gamma isoforms of FR. The alpha isoform of FR (the form most
      commonly found on cancer cells) was surprisingly absent from all hematopoietic
      cells examined. Compared with KB cells (a human cell line known for its elevated
      expression of FR-alpha), the abundance of FR-beta on CD34(+) cell surfaces was
      relatively low (approximately 8% of KB cell levels). Because many antifolates and
      folic acid-linked chemotherapeutic agents enter malignant cells at least
      partially via FR endocytosis, it was important to evaluate the ability of FR on
      CD34(+) cells to bind folic acid (FA). Based on three FR binding assays, freshly
      isolated CD34(+) cells were found to display no affinity for FA. Thus, regardless
      of whether steps were taken to remove endogenous folates before receptor binding
      assays, FR on primitive hematopoietic cells failed to bind 3H-FA, fluorescein
      isothiocyanate (FITC)-linked FA, or FA-derivatized liposomes. In contrast,
      analogous studies on KB cells showed high levels of receptor binding for all
      three FR probes. These studies show that although multipotent hematopoietic
      progenitor cells express FR, the receptor does not transport significant amounts
      of FA. Consequently, antifolates and FA-linked chemotherapeutic agents that can
      be engineered to enter malignant cells exclusively through the FR should not harm
      progenitor/stem cell function.

PMID- 10339504
TI  - Direct Epstein-Barr virus (EBV) typing on peripheral blood mononuclear cells: no
      association between EBV type 2 infection or superinfection and the development of
      acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma.
AB  - In the literature, a correlation has been suggested between the occurrence of
      acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (NHL)
      and Epstein-Barr virus (EBV) type 2 infection. To further investigate a possible
      role for EBV type 2 infection in the development of AIDS-NHL, we developed a
      sensitive and type-specific nested polymerase chain reaction (PCR) assay and
      analyzed EBV types directly on peripheral blood mononuclear cells (PBMC) in three
      subgroups of human immunodeficiency virus (HIV)-1 infected individuals: 30 AIDS
      NHL patients, 42 individuals progressing to AIDS without lymphoma (PROG), either
      developing opportunistic infections (AIDS-OI) or Kaposi's sarcoma (AIDS-KS), and
      18 long-term asymptomatic individuals (LTA). Furthermore, EBV type analysis was
      performed on PBMC samples obtained from AIDS-NHL patients in the course of HIV-1
      infection. The results showed that: (1) direct analysis of PBMC is superior to
      analysis of B-lymphoblastoid cell lines (B-LCL) grown from the same PBMC samples;
      (2) in HIV-1 infected individuals, there is a high prevalence of EBV type 2
      infection (50% in LTA, 62% in progressors, and 53% in AIDS-NHL) and
      superinfection with both type 1 and 2 (24% in LTA, 40% in progressors, and 47% in
      AIDS-NHL); (3) EBV type 2 (super)infection is not associated with an increased
      risk for development of AIDS-NHL; (4) type 2 infection can be found early in HIV
      1 infection, and neither type 2 infection nor superinfection correlates with a
      failing immune system.

PMID- 10339505
TI  - Horizontal transfer of DNA by the uptake of apoptotic bodies.
AB  - In this study we have raised the question of whether DNA can be transferred from
      one cell to another by phagocytosis of apoptotic bodies. We have used integrated
      copies of the Epstein-Barr virus (EBV) as a marker to follow the fate and
      expression pattern of apoptotic DNA in the phagocytotic host. Apoptosis was
      induced in EBV-carrying cell lines by irradiation before cultivation with either
      human fibroblasts, macrophages, or bovine aortic endothelial cells. Analysis of
      the expression pattern of EBV-encoded genes was performed by immunofluorescent
      staining as well as in situ hybridization. Cocultivation of apoptotic bodies from
      lymphoid cell lines containing integrated but not episomal copies of EBV resulted
      in expression of the EBV-encoded genes EBER and EBNA1 in the recipient cells at a
      high frequency. Fluorescence in situ hybridization analysis showed uptake of
      human chromatin as well as integrated EBV-DNA into the nuclei of bovine aortic
      endothelial cells. These data show that DNA may be rescued and reused from
      apoptotic bodies by somatic cells. In addition, our findings suggest that
      apoptotic bodies derived from EBV-carrying B lymphocytes may serve as the source
      of viral transfer to cells that lack receptors for the EBV virus in vivo.

PMID- 10339506
TI  - Somatic mutations within the untranslated regions of rearranged Ig genes in a
      case of classical Hodgkin's disease as a potential cause for the absence of Ig in
      the lymphoma cells.
AB  - Hodgkin-Reed-Sternberg (H-RS) cells are clonal B cells carrying Ig gene
      rearrangements. However, in situ hybridization methods failed to demonstrate Ig
      gene expression in H-RS cells of classical Hodgkin's disease (HD). Because
      somatic mutations rendering potentially functional Ig gene rearrangements
      nonfunctional were detected in some cases of the disease, it was speculated that
      H-RS cells in classical HD may have lost the ability to express antigen receptor
      as a rule. Recently, we established a novel cell line (L1236) from H-RS cells of
      a patient with mixed cellularity subtype of HD. L1236 cells harbor a potentially
      functional VH1 and a potentially functional Vkappa3 gene rearrangement. However,
      no antibody expression was detected. To show potential reasons for this lack of
      Ig expression, we analyzed the genomic organization of the Ig genes and their
      transcription in the primary and cultivated H-RS cells of this patient. The H-RS
      cells were found to have switched their isotype to IgG4, confirming their mature
      B-cell nature. By amplifying cDNA from L1236 cells as well as from frozen biopsy
      material transcripts of the Vkappa3 and the VH1 gene rearrangement were detected
      for both sources of cDNA. However, Northern blot hybridization of L1236 RNA
      failed to demonstrate VH1 and Vkappa3 transcripts, indicating only a low level of
      transcription. Sequence analysis of the promoter and leader regions of the VH1
      gene rearrangement from L1236 cells as well as from lymphoma-affected tissue
      showed a somatic mutation in the conserved octamer motif of the promoter region.
      Somatic mutations were also detected within the 3' splice site of the leader
      intron and adjacent nucleotides in the rearranged Vkappa light chain gene,
      leading to aberrant splicing. These mutations might prevent the generation of
      adequate amounts of functional Ig gene transcripts as template for translation
      into protein. Thus, mutations in H-RS cells that prevent Ig gene expression might
      also be located outside the coding region of the Ig genes.

PMID- 10339507
TI  - Effects of the tyrosine kinase inhibitor AG957 and an Anti-Fas receptor antibody
      on CD34(+) chronic myelogenous leukemia progenitor cells.
AB  - The hallmark of chronic myelogenous leukemia (CML) is the Philadelphia (Ph)
      chromosome that fuses genetic sequences of the BCR gene on chromosome 22 with c
      ABL sequences translocated from chromosome 9. BCR/ABL fusion proteins have a
      dysregulated protein tyrosine kinase (PTK) activity exerting a key role in
      malignant transformation. Targeting the tyrosine kinase activity of BCR/ABL or
      using agents capable of triggering apoptosis might represent attractive
      therapeutic approaches for ex vivo purging. AG957, a member of the tyrphostin
      compounds, exerts a selective inhibition of p210(BCR/ABL) tyrosine
      phosphorylation. We report here that preincubation of CML or normal CD34(+) cells
      with graded concentration of AG957 (1 to 100 micromol/L) resulted in a
      statistically significant, dose-dependent suppression of colony growth from
      multipotent, erythroid, and granulocyte-macrophage progenitors as well as the
      more primitive long-term culture-initiating cells (LTC-IC). However, AG957 doses
      causing 50% inhibition (ID50) of CML and normal progenitors were significantly
      different for multilineage colony-forming units (CFU-Mix; 12 v 64 micromol/L; P
      =.008), burst-forming unit-erythroid (BFU-E; 29 v 89 micromol/L; P =.004), colony
      forming unit-granulocyte-macrophage (CFU-GM; 34 v 85 micromol/L; P =.004), and
      LTC-IC (43 v 181 micromol/L; P =.004). In 5 of 10 patients, analysis of BCR/ABL
      mRNA on single progenitors by reverse transcription-polymerase chain reaction
      showed that AG957 at 50 micromol/L significantly reduced the mean (+/-SD)
      percentage of BCR/ABL-positive progenitors (92% +/- 10% v 33 +/- 5%; P =.001).
      Because AG957 treatment resulted in significantly higher percentages of apoptotic
      cells (30% v 9%) in the BCR/ABL-transfected 32DLG7 cells as compared with 32D
      T2/93 cells (BCR/ABL-negative), we investigated the combined effects of AG957
      with the anti-Fas receptor (Fas-R) monoclonal antibody CH11 that triggers
      apoptosis. As compared with AG957 alone, the sequential treatment of CML CD34(+)
      cells with AG957 (1 micromol/L) and CH11 (1 microgram/mL) increased CFU-Mix, BFU
      E, and CFU-GM growth inhibition by 1.6-fold, 3-fold, and 4-fold, respectively. In
      contrast, the treatment of normal CD34(+) cells with AG957 and CH11 failed to
      enhance AG957-induced colony growth inhibition. We conclude that (1) AG957
      inhibits in a dose-dependent manner CML CD34-derived colony formation by both
      primitive LTC-IC as well as committed CFU-Mix, BFU-E, and CFU-GM; (2) this growth
      inhibition is associated with the selection of a substantial amount of BCR/ABL
      negative progenitors; and (3) the antiproliferative effect of AG957 is
      dramatically increased by combining this compound with the anti-Fas-R antibody
      CH11. These data may have significant therapeutic applications.

PMID- 10339509
TI  - Alteration of actin organization by jaspamide inhibits ruffling, but not
      phagocytosis or oxidative burst, in HL-60 cells and human monocytes.
AB  - Jaspamide, a naturally occurring cyclic peptide isolated from the marine sponge
      Hemiastrella minor, has fungicidal and growth-inhibiting activities. Exposure of
      promyelocytic HL-60 cells and human monocytes to jaspamide induces a dramatic
      reorganization of actin from a typical fibrous network to focal aggregates. HL-60
      cells exposed to 5 x 10(-8) mol/L or 10(-7) mol/L jaspamide exhibited a reduced
      proliferation rate. In addition, 10(-7) mol/L jaspamide induced maturation of HL
      60 cells as indicated by the appearance of a lobulated nucleus in 55% +/- 5% of
      the cells and immunophenotypic maturation of the leukemia cells (upregulation of
      CD16 and CD14 B antigens). Further characterization has shown that F-actin is
      aggregated both in HL-60 cells and in human monocytes exposed to 10(-7) mol/L
      jaspamide. Well-spread cultured human monocytes contracted and adopted round
      shapes after treatment with jaspamide. Moreover, a dose-dependent increase in
      both total actin and de novo synthesized portions of the soluble actin was
      observed in jaspamide-treated HL-60 cells. Jaspamide treatment inhibits ruffling
      and intracellular movement in HL-60 cells and monocytes, but does not affect
      phagocytic activity or respiratory burst activity. The consequential effects of
      jaspamide-induced actin reorganization on ruffling, versus its negligible effect
      on phagocytosis and oxidative burst, may shed light on molecular mechanisms of
      actin involvement in these processes. Jaspamide disrupts the actin cytoskeleton
      of normal and malignant mammalian cells with no significant effect on phagocytic
      activity and may, therefore, be considered as a novel therapeutic agent.

PMID- 10339510
TI  - Red blood cells inhibit apoptosis of human neutrophils.
AB  - Oxidative stress has been implicated in the triggering of apoptosis in
      neutrophils. Because red blood cells (RBCs) are well known to scavenge oxidants
      including H2O2, we tested the hypothesis that RBCs inhibit apoptosis of
      neutrophils by reducing intracellular oxidative stress. Apoptosis of neutrophils
      was evaluated by light microscopy and DNA gel electrophoresis. We found that
      coculture with RBCs protected against neutrophil apoptosis. Neither physical
      contact between RBCs and neutrophils nor the cellular integrity of RBCs was
      required to protect against neutrophil apoptosis. Neutrophil apoptosis was
      promoted by exogenous H2O2 but suppressed by catalase, indicating a role for H2O2
      as a mediator of apoptosis. The protective effect of RBCs against apoptosis was
      due to catalase and glutathione metabolism because blocking of these antioxidant
      systems in RBCs attenuated the protective effect of RBCs. These results suggest
      that neutrophils are protected against apoptosis in the circulation.

PMID- 10339508
TI  - Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer
      and leukemia Group B experience.
AB  - The Cancer and Leukemia Group B (CALGB) has been conducting a prospective
      cytogenetic companion study (CALGB 8461) to all CALGB treatment protocols for
      newly diagnosed adults with acute lymphoblastic leukemia (ALL). These protocols
      underwent a significant change in 1988 when a new intensive chemotherapy program
      was introduced (CALGB 8811). We asked whether karyotype continued to represent a
      significant prognostic factor in adult ALL patients after the change. A total of
      256 patients had adequate pretreatment cytogenetic analyses: 67 before 1988 and
      189 subsequently. The complete remission (CR) rate for the whole group was 80%.
      Patients with t(9;22), t(4;11), -7, or +8 had significantly lower probabilities
      of continuous CR and survival at 5 years (.11 and.12) than patients with a normal
      karyotype (.38 and.37) and patients with miscellaneous cytogenetic abnormalities
      (.52 and.49; P <.001 for each comparison). When analyzed by treatment period, the
      CR rate before CALGB 8811 was 63%; subsequently, it was 86% (P <.001). Patients
      with cytogenetic abnormalities other than t(9;22), t(4;11), -7, or +8 had better
      CR rates, disease-free survival (DFS), and survivals (P =.001, P =.04, and P
      =.004, respectively) after the change to the more intensive chemotherapy
      regimens. Patients with normal cytogenetics had improved CR rate but no improved
      DFS or survival, whereas no significant benefit for patients with t(9;22),
      t(4;11), -7, or +8 was seen. In a multivariate analysis, karyotype retained its
      prognostic significance for DFS but not for survival; it remained the most
      important factor for DFS. We conclude that cytogenetic analysis at diagnosis
      should be used to guide treatment decisions in adults with ALL.

PMID- 10339511
TI  - Lipopolysaccharide regulates macrophage fluid phase pinocytosis via CD14
      dependent and CD14-independent pathways.
AB  - Lipopolysaccharide (LPS) is a mediator of inflammation and septic shock during
      bacterial infection. Although monocytes and macrophages are highly responsive to
      LPS, the biological effects of LPS in these cell types are only partially
      understood. We decided, therefore, to investigate the influence of LPS on
      macrophage pinocytosis and Fc receptor-mediated endocytosis, two prominent and
      related macrophage effector functions. We observed that LPS did not greatly
      influence endocytosis in either macrophages or monocytes, but did exert a dual
      action on pinocytosis: at lower concentrations (0.1 to 100 ng/mL), LPS caused a
      decrease in pinocytosis in both macrophages and monocytes, whereas at higher LPS
      concentrations, enhanced pinocytosis in macrophages was observed. Detoxified LPS
      was two orders of magnitude less potent in producing these effects. After
      inhibition of the LPS receptor CD14, the LPS-induced decrease in pinocytosis was
      absent, and stimulation of pinocytosis at lower LPS concentrations was unmasked.
      We conclude that LPS can influence pinocytosis via CD14-dependent and CD14
      independent signaling pathways. Furthermore, as addition of LPS to macrophages
      effected pinocytosis but not Fc receptor-mediated endocytosis, these two
      processes are independently regulated in macrophages.

PMID- 10339512
TI  - Bacterial cell division: a moveable feast.

PMID- 10339513
TI  - DNA demethylation.

PMID- 10339515
TI  - Novel phenomena in dilute electron systems in two dimensions.
AB  - For the past two decades, all two-dimensional systems of electrons were believed
      to be insulating in the limit of zero temperature. Recent experiments provide
      evidence for an unexpected transition to a conducting phase at very low electron
      densities. The nature of this phase is not understood and is currently the focus
      of intense theoretical and experimental attention.

PMID- 10339514
TI  - Searching for "downhill scenarios" in protein folding.

PMID- 10339516
TI  - Plants and population: is there time?

PMID- 10339517
TI  - World food and agriculture: outlook for the medium and longer term.
AB  - The world has been making progress in improving food security, as measured by the
      per person availability of food for direct human consumption. However, progress
      has been very uneven, and many developing countries have failed to participate in
      such progress. In some countries, the food security situation is today worse than
      20 years ago. The persistence of food insecurity does not reflect so much a lack
      of capacity of the world as a whole to increase food production to whatever level
      would be required for everyone to have consumption levels assuring satisfactory
      nutrition. The world already produces sufficient food. The undernourished and the
      food-insecure persons are in these conditions because they are poor in terms of
      income with which to purchase food or in terms of access to agricultural
      resources, education, technology, infrastructure, credit, etc., to produce their
      own food. Economic development failures account for the persistence of poverty
      and food insecurity. In the majority of countries with severe food-security
      problems, the greatest part of the poor and food-insecure population depend
      greatly on local agriculture for a living. In such cases, development failures
      are often tantamount to failures of agricultural development. Development of
      agriculture is seen as the first crucial step toward broader development,
      reduction of poverty and food insecurity, and eventually freedom from excessive
      economic dependence on poor agricultural resources. Projections indicate that
      progress would continue, but at a pace and pattern that would be insufficient for
      the incidence of undernutrition to be reduced significantly in the medium-term
      future. As in the past, world agricultural production is likely to keep up with,
      and perhaps tend to exceed, the growth of the effective demand for food. The
      problem will continue to be one of persistence of poverty, leading to growth of
      the effective demand for food on the part of the poor that would fall short of
      that required for them to attain levels of consumption compatible with freedom
      from undernutrition.

PMID- 10339518
TI  - The growth of demand will limit output growth for food over the next quarter
      century.
AB  - The rate of growth of world food demand will be much slower for 1990-2010 than it
      was for the prior three decades. The major factor determining the increase in
      food demand is population growth. Income growth has a much smaller effect. From
      1960 to 1990, population growth accounted for approximately three fourths of the
      growth in demand or use of grain. For 1990-2010, it is anticipated that
      population growth will account for nearly all of the increase in world demand for
      grain. The rate of population growth from 1990 to 2020 is projected to be at an
      annual rate of 1.3% compared with 1.9% for 1960 to 1990-a decline of more than
      30%. World per capita use of grain will increase very little-perhaps by 4%. The
      increase in grain use is projected to be 40% less than in 1960-1990. It is
      anticipated that real grain prices will decline during the period, although not
      nearly as much as the 40% decline in the previous three decades. Concern has been
      expressed concerning the deterioration of the quality and productivity of the
      world's farmland. A study for China and Indonesia indicates that there has been
      no significant change in the productive capacity of the land over the past 50
      years. Contrary to numerous claims, the depth of the topsoil has not changed,
      indicating that erosion has had little or no impact.

PMID- 10339519
TI  - Global and local implications of biotechnology and climate change for future food
      supplies.
AB  - The development of improved technology for agricultural production and its
      diffusion to farmers is a process requiring investment and time. A large number
      of studies of this process have been undertaken. The findings of these studies
      have been incorporated into a quantitative policy model projecting supplies of
      commodities (in terms of area and crop yields), equilibrium prices, and
      international trade volumes to the year 2020. These projections show that a
      "global food crisis," as would be manifested in high commodity prices, is
      unlikely to occur. The same projections show, however, that in many countries,
      "local food crisis," as manifested in low agricultural incomes and associated low
      food consumption in the presence of low food prices, will occur. Simulations show
      that delays in the diffusion of modern biotechnology research capabilities to
      developing countries will exacerbate local food crises. Similarly, global climate
      change will also exacerbate these crises, accentuating the importance of bringing
      strengthened research capabilities to developing countries.

PMID- 10339520
TI  - World food trends and prospects to 2025.
AB  - This paper reviews food (especially cereal) production trends and prospects for
      the world and its main regions. Despite fears to the contrary, in recent years we
      have seen continued progress toward better methods of feeding humanity. Sub
      Saharan Africa is the sole major exception. Looking to the future, this paper
      argues that the continuation of recent cereal yield trends should be sufficient
      to cope with most of the demographically driven expansion of cereal demand that
      will occur until the year 2025. However, because of an increasing degree of
      mismatch between the expansion of regional demand and the potential for supply,
      there will be a major expansion of world cereal (and noncereal food) trade. Other
      consequences for global agriculture arising from demographic growth include the
      need to use water much more efficiently and an even greater dependence on
      nitrogen fertilizers (e.g., South Asia). Farming everywhere will depend more on
      information-intensive agricultural management procedures. Moreover, despite
      continued general progress, there still will be a significant number of
      undernourished people in 2025. Signs of heightened harvest variability,
      especially in North America, are of serious concern. Thus, although future
      general food trends are likely to be positive, in some respects we also could be
      entering a more volatile world.

PMID- 10339521
TI  - Plant genetic resources: what can they contribute toward increased crop
      productivity?
AB  - To feed a world population growing by up to 160 people per minute, with >90% of
      them in developing countries, will require an astonishing increase in food
      production. Forecasts call for wheat to become the most important cereal in the
      world, with maize close behind; together, these crops will account for
      approximately 80% of developing countries' cereal import requirements. Access to
      a range of genetic diversity is critical to the success of breeding programs. The
      global effort to assemble, document, and utilize these resources is enormous, and
      the genetic diversity in the collections is critical to the world's fight against
      hunger. The introgression of genes that reduced plant height and increased
      disease and viral resistance in wheat provided the foundation for the "Green
      Revolution" and demonstrated the tremendous impact that genetic resources can
      have on production. Wheat hybrids and synthetics may provide the yield increases
      needed in the future. A wild relative of maize, Tripsacum, represents an untapped
      genetic resource for abiotic and biotic stress resistance and for apomixis, a
      trait that could provide developing world farmers access to hybrid technology.
      Ownership of genetic resources and genes must be resolved to ensure global access
      to these critical resources. The application of molecular and genetic engineering
      technologies enhances the use of genetic resources. The effective and
      complementary use of all of our technological tools and resources will be
      required for meeting the challenge posed by the world's expanding demand for
      food.

PMID- 10339522
TI  - Ecological approaches and the development of "truly integrated" pest management.
AB  - Recent predictions of growth in human populations and food supply suggest that
      there will be a need to substantially increase food production in the near
      future. One possible approach to meeting this demand, at least in part, is the
      control of pests and diseases, which currently cause a 30-40% loss in available
      crop production. In recent years, strategies for controlling pests and diseases
      have tended to focus on short-term, single-technology interventions, particularly
      chemical pesticides. This model frequently applies even where so-called
      integrated pest management strategies are used because in reality, these often
      are dominated by single technologies (e.g., biocontrol, host plant resistance, or
      biopesticides) that are used as replacements for chemicals. Very little attention
      is given to the interaction or compatibility of the different technologies used.
      Unfortunately, evidence suggests that such approaches rarely yield satisfactory
      results and are unlikely to provide sustainable pest control solutions for the
      future. Drawing on two case histories, this paper demonstrates that by increasing
      our basic understanding of how individual pest control technologies act and
      interact, new opportunities for improving pest control can be revealed. This
      approach stresses the need to break away from the existing single-technology,
      pesticide-dominated paradigm and to adopt a more ecological approach built around
      a fundamental understanding of population biology at the local farm level and the
      true integration of renewable technologies such as host plant resistance and
      natural biological control, which are available to even the most resource-poor
      farmers.

PMID- 10339523
TI  - Ecological intensification of cereal production systems: yield potential, soil
      quality, and precision agriculture.
AB  - Wheat (Triticum aestivum L.), rice (Oryza sativa L.), and maize (Zea mays L.)
      provide about two-thirds of all energy in human diets, and four major cropping
      systems in which these cereals are grown represent the foundation of human food
      supply. Yield per unit time and land has increased markedly during the past 30
      years in these systems, a result of intensified crop management involving
      improved germplasm, greater inputs of fertilizer, production of two or more crops
      per year on the same piece of land, and irrigation. Meeting future food demand
      while minimizing expansion of cultivated area primarily will depend on continued
      intensification of these same four systems. The manner in which further
      intensification is achieved, however, will differ markedly from the past because
      the exploitable gap between average farm yields and genetic yield potential is
      closing. At present, the rate of increase in yield potential is much less than
      the expected increase in demand. Hence, average farm yields must reach 70-80% of
      the yield potential ceiling within 30 years in each of these major cereal
      systems. Achieving consistent production at these high levels without causing
      environmental damage requires improvements in soil quality and precise management
      of all production factors in time and space. The scope of the scientific
      challenge related to these objectives is discussed. It is concluded that major
      scientific breakthroughs must occur in basic plant physiology, ecophysiology,
      agroecology, and soil science to achieve the ecological intensification that is
      needed to meet the expected increase in food demand.

PMID- 10339524
TI  - The transition to agricultural sustainability.
AB  - The transition to sustainable growth in agricultural production during the 21st
      century will take place within the context of a transition to a stable population
      and a possible transition to a stable level of material consumption. If the world
      fails to successfully navigate a transition to sustainable growth in agricultural
      production, the failure will be due more to a failure in the area of
      institutional innovation than to resource and environmental constraints.

PMID- 10339525
TI  - Biotechnology: enhancing human nutrition in developing and developed worlds.
AB  - While the last 50 years of agriculture have focused on meeting the food, feed,
      and fiber needs of humans, the challenges for the next 50 years go far beyond
      simply addressing the needs of an ever-growing global population. In addition to
      producing more food, agriculture will have to deal with declining resources like
      water and arable land, need to enhance nutrient density of crops, and achieve
      these and other goals in a way that does not degrade the environment.
      Biotechnology and other emerging life sciences technologies offer valuable tools
      to help meet these multidimensional challenges. This paper explores the
      possibilities afforded through biotechnology in providing improved agronomic
      "input" traits, differentiated crops that impart more desirable "output" traits,
      and using plants as green factories to fortify foods with valuable nutrients
      naturally rather than externally during food processing. The concept of
      leveraging agriculture as green factories is expected to have tremendous positive
      implications for harnessing solar energy to meet fiber and fuel needs as well.
      Widespread adaptation of biotech-derived products of agriculture should lay the
      foundation for transformation of our society from a production-driven system to a
      quality and utility-enhanced system.

PMID- 10339526
TI  - Use of plant roots for phytoremediation and molecular farming.
AB  - Alternative agriculture, which expands the uses of plants well beyond food and
      fiber, is beginning to change plant biology. Two plant-based biotechnologies were
      recently developed that take advantage of the ability of plant roots to absorb or
      secrete various substances. They are (i) phytoextraction, the use of plants to
      remove pollutants from the environment and (ii) rhizosecretion, a subset of
      molecular farming, designed to produce and secrete valuable natural products and
      recombinant proteins from roots. Here we discuss recent advances in these
      technologies and assess their potential in soil remediation, drug discovery, and
      molecular farming.

PMID- 10339527
TI  - Transgenic plants for tropical regions: some considerations about their
      development and their transfer to the small farmer.
AB  - Biotechnological applications, especially transgenic plants, probably hold the
      most promise in augmenting agricultural production in the first decades of the
      next millennium. However, the application of these technologies to the
      agriculture of tropical regions where the largest areas of low productivity are
      located, and where they are most needed, remains a major challenge. In this
      paper, some of the important issues that need to be considered to ensure that
      plant biotechnology is effectively transferred to the developing world are
      discussed.

PMID- 10339528
TI  - From pre-hispanic to future conservation alternatives: lessons from Mexico.
AB  - In this paper, we review some past and present trends in biodiversity
      conservation in Mexico and explore possible explanations of why, in spite of this
      long history of depredation and ineffective conservation policies, the ecosystems
      have been able to cope with and retain most of their biological components. We
      suggest a hypothesis based on the persistence of a complex mosaic of past and
      present traditional land uses as a possible explanation for this resilience. We
      propose an agenda for the scope of future conservation research and policy,
      particularly the need to take the socioeconomic context of environmental
      degradation into account. We put forth a series of questions that we think need
      to be investigated if the conservation research community is to participate in
      developing solutions for the future welfare of the human species and of
      biodiversity on earth.

PMID- 10339529
TI  - Gardenification of tropical conserved wildlands: multitasking, multicropping, and
      multiusers.
AB  - Tropical wildlands and their biodiversity will survive in perpetuity only through
      their integration into human society. One protocol for integration is to
      explicitly recognize conserved tropical wildlands as wildland gardens. A major
      way to facilitate the generation of goods and services by a wildland garden is to
      generate a public-domain Yellow Pages for its organisms. Such a Yellow Pages is
      part and parcel of high-quality search-and-delivery from wildland gardens. And,
      as they and their organisms become better understood, they become higher quality
      biodiversity storage devices than are large freezers. One obstacle to wildland
      garden survival is that specific goods and services, such as biodiversity
      prospecting, lack development protocols that automatically shunt the profits back
      to the source. Other obstacles are that environmental services contracts have the
      unappealing trait of asking for the payment of environmental credit card bills
      and implying delegation of centralized governmental authority to decentralized
      social structures. Many of the potential conflicts associated with wildland
      gardens may be reduced by recognizing two sets of social rules for perpetuating
      biodiversity and ecosystems, one set for the wildland garden and one set for the
      agroscape. In the former, maintaining wildland biodiversity and ecosystem
      survival in perpetuity through minimally damaging use is paramount, while in the
      agroscape, wild biodiversity and ecosystems are tools for a healthy and
      productive agroecosystem, and the loss of much of the original is acceptable.

PMID- 10339530
TI  - Global environmental impacts of agricultural expansion: the need for sustainable
      and efficient practices.
AB  - The recent intensification of agriculture, and the prospects of future
      intensification, will have major detrimental impacts on the nonagricultural
      terrestrial and aquatic ecosystems of the world. The doubling of agricultural
      food production during the past 35 years was associated with a 6.87-fold increase
      in nitrogen fertilization, a 3.48-fold increase in phosphorus fertilization, a
      1.68-fold increase in the amount of irrigated cropland, and a 1.1-fold increase
      in land in cultivation. Based on a simple linear extension of past trends, the
      anticipated next doubling of global food production would be associated with
      approximately 3-fold increases in nitrogen and phosphorus fertilization rates, a
      doubling of the irrigated land area, and an 18% increase in cropland. These
      projected changes would have dramatic impacts on the diversity, composition, and
      functioning of the remaining natural ecosystems of the world, and on their
      ability to provide society with a variety of essential ecosystem services. The
      largest impacts would be on freshwater and marine ecosystems, which would be
      greatly eutrophied by high rates of nitrogen and phosphorus release from
      agricultural fields. Aquatic nutrient eutrophication can lead to loss of
      biodiversity, outbreaks of nuisance species, shifts in the structure of food
      chains, and impairment of fisheries. Because of aerial redistribution of various
      forms of nitrogen, agricultural intensification also would eutrophy many natural
      terrestrial ecosystems and contribute to atmospheric accumulation of greenhouse
      gases. These detrimental environmental impacts of agriculture can be minimized
      only if there is much more efficient use and recycling of nitrogen and phosphorus
      in agroecosystems.

PMID- 10339531
TI  - Nitrogen management and the future of food: lessons from the management of energy
      and carbon.
AB  - The food system dominates anthropogenic disruption of the nitrogen cycle by
      generating excess fixed nitrogen. Excess fixed nitrogen, in various guises,
      augments the greenhouse effect, diminishes stratospheric ozone, promotes smog,
      contaminates drinking water, acidifies rain, eutrophies bays and estuaries, and
      stresses ecosystems. Yet, to date, regulatory efforts to limit these disruptions
      largely ignore the food system. There are many parallels between food and energy.
      Food is to nitrogen as energy is to carbon. Nitrogen fertilizer is analogous to
      fossil fuel. Organic agriculture and agricultural biotechnology play roles
      analogous to renewable energy and nuclear power in political discourse. Nutrition
      research resembles energy end-use analysis. Meat is the electricity of food. As
      the agriculture and food system evolves to contain its impacts on the nitrogen
      cycle, several lessons can be extracted from energy and carbon: (i) set the goal
      of ecosystem stabilization; (ii) search the entire production and consumption
      system (grain, livestock, food distribution, and diet) for opportunities to
      improve efficiency; (iii) implement cap-and-trade systems for fixed nitrogen;
      (iv) expand research at the intersection of agriculture and ecology, and (v)
      focus on the food choices of the prosperous. There are important nitrogen-carbon
      links. The global increase in fixed nitrogen may be fertilizing the Earth,
      transferring significant amounts of carbon from the atmosphere to the biosphere,
      and mitigating global warming. A modern biofuels industry someday may produce
      biofuels from crop residues or dedicated energy crops, reducing the rate of
      fossil fuel use, while losses of nitrogen and other nutrients are minimized.

PMID- 10339532
TI  - An equilibrium statistical model for the spreading phase of open-ocean
      convection.
AB  - A "most probable state" equilibrium statistical theory for random distributions
      of hetons in a closed basin is developed here in the context of two-layer
      quasigeostrophic models for the spreading phase of open-ocean convection. The
      theory depends only on bulk conserved quantities such as energy, circulation, and
      the range of values of potential vorticity in each layer. The simplest theory is
      formulated for a uniform cooling event over the entire basin that triggers a
      homogeneous random distribution of convective towers. For a small Rossby
      deformation radius typical for open-ocean convection sites, the most probable
      states that arise from this theory strongly resemble the saturated baroclinic
      states of the spreading phase of convection, with a stabilizing barotropic rim
      current and localized temperature anomaly.

PMID- 10339533
TI  - Femtosecond dynamics of DNA-mediated electron transfer.
AB  - Diverse biophysical and biochemical studies have sought to understand electron
      transfer (ET) in DNA in part because of its importance to DNA damage and its
      repair. However, the dynamics and mechanisms of the elementary processes of ET in
      this medium are not fully understood and have been heavily debated. Two
      fundamental issues are the distance over which charge is transported and the time
      scale on which the transport through the pi-stack of the DNA base pairs may
      occur. With femtosecond resolution, we report direct observation in DNA of
      ultrafast ET, initiated by excitation of tethered ethidium (E), the intercalated
      electron acceptor (A); the electron donor (D) is 7-deazaguanine (Z), a modified
      base, placed at different, fixed distances from A. The ultrafast ET between these
      reactants in DNA has been observed with time constants of 5 ps and 75 ps and was
      found to be essentially independent of the D-A separation (10-17 A). However, the
      ET efficiency does depend on the D-A distance. The 5-ps decay corresponds to
      direct ET observed from 7-deazaguanine but not guanine to E. From measurements of
      orientation anisotropies, we conclude that the slower 75-ps process requires the
      reorientation of E before ET, similar to E/nucleotide complexes in water. These
      results reveal the nature of ultrafast ET and its mechanism: in DNA, ET cannot be
      described as in proteins simply by a phenomenological parameter, beta. Instead,
      the involvement of the base pairs controls the time scale and the degree of
      coherent transport.

PMID- 10339534
TI  - Chemistry for the analysis of protein-protein interactions: rapid and efficient
      cross-linking triggered by long wavelength light.
AB  - Chemical cross-linking is a potentially useful technique for probing the
      architecture of multiprotein complexes. However, analyses using typical
      bifunctional cross-linkers often suffer from poor yields, and large-scale
      modification of nucleophilic side chains can result in artifactual results
      attributable to structural destabilization. We report here the de novo design and
      development of a type of protein cross-linking reaction that uses a
      photogenerated oxidant to mediate rapid and efficient cross-linking of associated
      proteins. The process involves brief photolysis of tris-bipyridylruthenium(II)
      dication with visible light in the presence of the electron acceptor ammonium
      persulfate and the proteins of interest. Very high yields of cross-linked
      products can be obtained with irradiation times of <1 second. This chemistry
      obviates many of the problems associated with standard cross-linking reagents.

PMID- 10339537
TI  - Solutions of a Lagrangian system on 2.
AB  - A Lagrangian system on 2 that has been studied earlier under a geometrical
      condition and found to possess a pair of solutions, H+/-, homoclinic to periodic
      solutions, v+/-, of a given homotopy type, is considered further. It is shown
      with the aid of H+/- and variational arguments that, in fact, there is a much
      richer structure of homoclinics and heteroclinics to v+/-. Indeed, the system
      admits chaotic solutions.

PMID- 10339535
TI  - Making artificial antibodies: a format for phage display of combinatorial
      heterodimeric arrays.
AB  - The gene VII protein (pVII) and gene IX protein (pIX) are associated closely on
      the surface of filamentous bacteriophage that is opposite of the end harboring
      the widely exploited pIII protein. We developed a phagemid format wherein
      antibody heavy- and light-chain variable regions were fused to the amino termini
      of pVII and pIX, respectively. Significantly, the fusion proteins interacted to
      form a functional Fv-binding domain on the phage surface. Our approach will be
      applicable to the display of generic peptide and protein libraries that can form
      combinatorial heterodimeric arrays. Consequently, it represents a first step
      toward artificial antibodies and the selection of novel biological activities.

PMID- 10339536
TI  - Observation of strange kinetics in protein folding.
AB  - Highly nonexponential folding kinetics in aqueous solution have been observed
      during temperature jump-induced refolding of two proteins, yeast phosphoglycerate
      kinase and a ubiquitin mutant. The observations are most easily interpreted in
      terms of downhill folding, which posits a heterogeneous ensemble of structures en
      route to the folded state. The data are also reconciled with exponential kinetics
      measured under different experimental conditions and with titration experiments
      indicating cooperative folding.

PMID- 10339538
TI  - Field theory in superfluid 3He: what are the lessons for particle physics,
      gravity, and high-temperature superconductivity?
AB  - There are several classes of homogeneous Fermi systems that are characterized by
      the topology of the energy spectrum of fermionic quasiparticles: (i) gapless
      systems with a Fermi surface, (ii) systems with a gap in their spectrum, (iii)
      gapless systems with topologically stable point nodes (Fermi points), and (iv)
      gapless systems with topologically unstable lines of nodes (Fermi lines).
      Superfluid 3He-A and electroweak vacuum belong to the universality class 3. The
      fermionic quasiparticles (particles) in this class are chiral: they are left
      handed or right-handed. The collective bosonic modes of systems of class 3 are
      the effective gauge and gravitational fields. The great advantage of superfluid
      3He-A is that we can perform experiments by using this condensed matter and
      thereby simulate many phenomena in high energy physics, including axial anomaly,
      baryoproduction, and magnetogenesis. 3He-A textures induce a nontrivial effective
      metrics of the space, where the free quasiparticles move along geodesics. With
      3He-A one can simulate event horizons, Hawking radiation, rotating vacuum, etc.
      High-temperature superconductors are believed to belong to class 4. They have
      gapless fermionic quasiparticles with a "relativistic" spectrum close to gap
      nodes, which allows application of ideas developed for superfluid 3He-A.

PMID- 10339539
TI  - Long RNA hairpins that contain inosine are present in Caenorhabditis elegans
      poly(A)+ RNA.
AB  - Adenosine deaminases that act on RNA (ADARs) are RNA-editing enzymes that convert
      adenosine to inosine within double-stranded RNA. In the 12 years since the
      discovery of ADARs only a few natural substrates have been identified. These
      substrates were found by chance, when genomically encoded adenosines were
      identified as guanosines in cDNAs. To advance our understanding of the biological
      roles of ADARs, we developed a method for systematically identifying ADAR
      substrates. In our first application of the method, we identified five additional
      substrates in Caenorhabditis elegans. Four of those substrates are mRNAs edited
      in untranslated regions, and one is a noncoding RNA edited throughout its length.
      The edited regions are predicted to form long hairpin structures, and one of the
      RNAs encodes POP-1, a protein involved in cell fate decisions.

PMID- 10339540
TI  - Ubiquitination of RNA polymerase II large subunit signaled by phosphorylation of
      carboxyl-terminal domain.
AB  - A sensitive assay using biotinylated ubiquitin revealed extensive ubiquitination
      of the large subunit of RNA polymerase II during incubations of transcription
      reactions in vitro. Phosphorylation of the repetitive carboxyl-terminal domain of
      the large subunit was a signal for ubiquitination. Specific inhibitors of cyclin
      dependent kinase (cdk)-type kinases suppress the ubiquitination reaction. These
      kinases are components of transcription factors and have been shown to
      phosphorylate the carboxyl-terminal domain. In both regulation of transcription
      and DNA repair, phosphorylation of the repetitive carboxyl-terminal domain by
      kinases might signal degradation of the polymerase.

PMID- 10339541
TI  - Fire-diffuse-fire model of dynamics of intracellular calcium waves.
AB  - When Ca2+ is released from internal stores in living cells, the resulting wave of
      increased concentration can travel without deformation (continuous propagation)
      or with burst-like behavior (saltatory propagation). We analyze the "fire-diffuse
      fire" model in order to illuminate the differences between these two modes of
      propagation. We show that the Ca2+ release wave in immature Xenopus oocytes and
      cardiac myocytes is saltatory, whereas the fertilization wave in the mature
      oocyte is continuous.

PMID- 10339542
TI  - Substrate sequestration by a proteolytically inactive Lon mutant.
AB  - Lon protein of Escherichia coli is an ATP-dependent protease responsible for the
      rapid turnover of both abnormal and naturally unstable proteins, including SulA,
      a cell division inhibitor made after DNA damage, and RcsA, a positive regulator
      of transcription. Lon is a multimer of identical 94-kDa subunits, each containing
      a consensus ATPase motif and a serine active site. We found that overexpressing
      Lon, which is mutated for the serine active site (LonS679A) and is therefore
      devoid of proteolytic activity, unexpectedly led to complementation of the UV
      sensitivity and capsule overproduction of a lon deletion mutant. SulA was not
      degraded by LonS679A, but rather was completely protected by the Lon mutant from
      degradation by other cellular proteases. We interpret these results to mean that
      the mutant LonS679A binds but does not degrade Lon substrates, resulting in
      sequestration of the substrate proteins and interference with their activities,
      resulting in apparent complementation. Lon that carried a mutation in the
      consensus ATPase site, either with or without the active site serine, was no
      longer able to complement a Deltalon mutant. These in vivo results suggest that
      the pathway of degradation by Lon couples ATP-dependent unfolding with movement
      of the substrate into protected chambers within Lon, where it is held until
      degradation proceeds. In the absence of degradation the substrate remains
      sequestered. Comparison of our results with those from a number of other systems
      suggest that proteins related to the regulatory portions of energy-dependent
      proteases act as energy-dependent sequestration proteins.

PMID- 10339543
TI  - A role for the light-dependent phosphorylation of visual arrestin.
AB  - Arrestins are regulatory proteins that participate in the termination of G
      protein-mediated signal transduction. The major arrestin in the Drosophila visual
      system, Arrestin 2 (Arr2), is phosphorylated in a light-dependent manner by a
      Ca2+/calmodulin-dependent protein kinase and has been shown to be essential for
      the termination of the visual signaling cascade in vivo. Here, we report the
      isolation of nine alleles of the Drosophila photoreceptor cell-specific arr2
      gene. Flies carrying each of these alleles underwent light-dependent retinal
      degeneration and displayed electrophysiological defects typical of previously
      identified arrestin mutants, including an allele encoding a protein that lacks
      the major Ca2+/calmodulin-dependent protein kinase site. The phosphorylation
      mutant had very low levels of phosphorylation and lacked the light-dependent
      phosphorylation observed with wild-type Arr2. Interestingly, we found that the
      Arr2 phosphorylation mutant was still capable of binding to rhodopsin; however,
      it was unable to release from membranes once rhodopsin had converted back to its
      inactive form. This finding suggests that phosphorylation of arrestin is
      necessary for the release of arrestin from rhodopsin. We propose that the
      sequestering of arrestin to membranes is a possible mechanism for retinal disease
      associated with previously identified rhodopsin alleles in humans.

PMID- 10339544
TI  - Structural characterization of an engineered tandem repeat contrasts the
      importance of context and sequence in protein folding.
AB  - To test a different approach to understanding the relationship between the
      sequence of part of a protein and its conformation in the overall folded
      structure, the amino acid sequence corresponding to an alpha-helix of T4 lysozyme
      was duplicated in tandem. The presence of such a sequence repeat provides the
      protein with "choices" during folding. The mutant protein folds with almost wild
      type stability, is active, and crystallizes in two different space groups, one
      isomorphous with wild type and the other with two molecules in the asymmetric
      unit. The fold of the mutant is essentially the same in all cases, showing that
      the inserted segment has a well-defined structure. More than half of the inserted
      residues are themselves helical and extend the helix present in the wild-type
      protein. Participation of additional duplicated residues in this helix would have
      required major disruption of the parent structure. The results clearly show that
      the residues within the duplicated sequence tend to maintain a helical
      conformation even though the packing interactions with the remainder of the
      protein are different from those of the original helix. It supports the
      hypothesis that the structures of individual alpha-helices are determined
      predominantly by the nature of the amino acids within the helix, rather than the
      structural environment provided by the rest of the protein.

PMID- 10339545
TI  - Atrial natriuretic peptide-stimulated Ca2+ reabsorption in rabbit kidney requires
      membrane-targeted, cGMP-dependent protein kinase type II.
AB  - Atrial natriuretic peptide (ANP) and nitric oxide (NO) are key regulators of ion
      and water transport in the kidney. Here, we report that these cGMP-elevating
      hormones stimulate Ca2+ reabsorption via a novel mechanism specifically involving
      type II cGMP-dependent protein kinase (cGK II). ANP and the NO donor, sodium
      nitroprusside (SNP), markedly increased Ca2+ uptake in freshly immunodissected
      rabbit connecting tubules (CNT) and cortical collecting ducts (CCD). Although
      readily increasing cGMP, ANP and SNP did not affect Ca2+ and Na+ reabsorption in
      primary cultures of these segments. Immunoblot analysis demonstrated that cGK II,
      and not cGK I, was present in freshly isolated CNT and CCD but underwent a
      complete down-regulation during the primary cell culture. However, upon
      adenoviral reexpression of cGK II in primary cultures, ANP, SNP, and 8-Br-cGMP
      readily increased Ca2+ reabsorption. In contrast, no cGMP-dependent effect on
      electrogenic Na+ transport was observed. The membrane localization of cGK II
      proved to be crucial for its action, because a nonmyristoylated cGK II mutant
      that was shown to be localized in the cytosol failed to mediate ANP-stimulated
      Ca2+ transport. The Ca2+-regulatory function of cGK II appeared isotype-specific
      because no cGMP-mediated increase in Ca2+ transport was observed after expression
      of the cytosolic cGK Ibeta or a membrane-bound cGK II/Ibeta chimer. These results
      demonstrate that ANP- and NO-stimulated Ca2+ reabsorption requires membrane
      targeted cGK II.

PMID- 10339546
TI  - Recognition of nonhybridizing base pairs during nucleotide excision repair of
      DNA.
AB  - Nondistorting C4' backbone adducts serve as molecular tools to analyze the
      strategy by which a limited number of human nucleotide excision repair (NER)
      factors recognize an infinite variety of DNA lesions. We have constructed
      composite DNA substrates containing a noncomplementary site adjacent to a
      nondistorting C4' adduct to show that the loss of hydrogen bonding contacts
      between partner strands is an essential signal for the recruitment of NER
      enzymes. This specific conformational requirement for excision is mediated by the
      affinity of xeroderma pigmentosum group A (XPA) protein for nonhybridizing sites
      in duplex DNA. XPA recognizes defective Watson-Crick base pair conformations even
      in the absence of DNA adducts or other covalent modifications, apparently through
      detection of hydrophobic base components that are abnormally exposed to the
      double helical surface. This recognition function of XPA is enhanced by
      replication protein A (RPA) such that, in combination, XPA and RPA constitute a
      potent molecular sensor of denatured base pairs. Our results indicate that the
      XPA-RPA complex may promote damage recognition by monitoring Watson-Crick base
      pair integrity, thereby recruiting the human NER system preferentially to sites
      where hybridization between complementary strands is weakened or entirely
      disrupted.

PMID- 10339547
TI  - Cell cycle-dependent regulation of RNA polymerase I transcription: the nucleolar
      transcription factor UBF is inactive in mitosis and early G1.
AB  - Transcription of ribosomal RNA genes by RNA polymerase (pol) I oscillates during
      the cell cycle, being maximal in S and G2 phase, repressed during mitosis, and
      gradually recovering during G1 progression. We have shown that transcription
      initiation factor (TIF)-IB/SL1 is inactivated during mitosis by cdc2/cyclin B
      directed phosphorylation of TAFI110. In this study, we have monitored
      reactivation of transcription after exit from mitosis. We demonstrate that the
      pol I factor UBF is also inactivated by phosphorylation but recovers with
      different kinetics than TIF-IB/SL1. Whereas TIF-IB/SL1 activity is rapidly
      regained on entry into G1, UBF is reactivated later in G1, concomitant with the
      onset of pol I transcription. Repression of pol I transcription in mitosis and
      early G1 can be reproduced with either extracts from cells synchronized in M or
      G1 phase or with purified TIF-IB/SL1 and UBF isolated in the presence of
      phosphatase inhibitors. The results suggest that two basal transcription factors,
      e.g., TIF-IB/SL1 and UBF, are inactivated at mitosis and reactivated by
      dephosphorylation at the exit from mitosis and during G1 progression,
      respectively.

PMID- 10339548
TI  - A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte
      differentiation.
AB  - The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone
      receptors that regulate glucose and lipid homeostasis. The PPARgamma subtype
      plays a central role in the regulation of adipogenesis and is the molecular
      target for the 2, 4-thiazolidinedione class of antidiabetic drugs. Structural
      studies have revealed that agonist ligands activate the PPARs through direct
      interactions with the C-terminal region of the ligand-binding domain, which
      includes the activation function 2 helix. GW0072 was identified as a high
      affinity PPARgamma ligand that was a weak partial agonist of PPARgamma
      transactivation. X-ray crystallography revealed that GW0072 occupied the ligand
      binding pocket by using different epitopes than the known PPAR agonists and did
      not interact with the activation function 2 helix. In cell culture, GW0072 was a
      potent antagonist of adipocyte differentiation. These results establish an
      approach to the design of PPAR ligands with modified biological activities.

PMID- 10339550
TI  - A quantitative method for evaluating the stabilities of nucleic acids.
AB  - We report a general method for screening, in solution, the impact of deviations
      from canonical Watson-Crick composition on the thermodynamic stability of nucleic
      acid duplexes. We demonstrate how fluorescence resonance energy transfer (FRET)
      can be used to detect directly free energy differences between an initially
      formed "reference" duplex (usually a Watson-Crick duplex) and a related "test"
      duplex containing a lesion/alteration of interest (e.g., a mismatch, a modified,
      a deleted, or a bulged base, etc.). In one application, one titrates into a
      solution containing a fluorescently labeled, FRET-active, reference duplex, an
      unlabeled, single-stranded nucleic acid (test strand), which may or may not
      compete successfully to form a new duplex. When a new duplex forms by strand
      displacement, it will not exhibit FRET. The resultant titration curve (normalized
      fluorescence intensity vs. logarithm of test strand concentration) yields a value
      for the difference in stability (free energy) between the newly formed, test
      strand-containing duplex and the initial reference duplex. The use of competitive
      equilibria in this assay allows the measurement of equilibrium association
      constants that far exceed the magnitudes accessible by conventional titrimetric
      techniques. Additionally, because of the sensitivity of fluorescence, the method
      requires several orders of magnitude less material than most other solution
      methods. We discuss the advantages of this method for detecting and
      characterizing any modification that alters duplex stability, including, but not
      limited to, mutagenic lesions. We underscore the wide range of accessible free
      energy values that can be defined by this method, the applicability of the method
      in probing for a myriad of nucleic acid variations, such as single nucleotide
      polymorphisms, and the potential of the method for high throughput screening.

PMID- 10339549
TI  - DNA methylation is a reversible biological signal.
AB  - The pattern of DNA methylation plays an important role in regulating different
      genome functions. To test the hypothesis that DNA methylation is a reversible
      biochemical process, we purified a DNA demethylase from human cells that
      catalyzes the cleavage of a methyl residue from 5-methyl cytosine and its release
      as methanol. We show that similar to DNA methyltransferase, DNA demethylase shows
      CpG dinucleotide specificity, can demethylate mdCpdG sites in different sequence
      contexts, and demethylates both fully methylated and hemimethylated DNA. Thus,
      contrary to the commonly accepted model, DNA methylation is a reversible signal,
      similar to other physiological biochemical modifications.

PMID- 10339551
TI  - Solution structure and peptide binding studies of the C-terminal src homology 3
      like domain of the diphtheria toxin repressor protein.
AB  - The diphtheria toxin repressor (DtxR) is the best-characterized member of a
      family of homologous proteins that regulate iron uptake and virulence gene
      expression in the Gram-positive bacteria. DtxR contains two domains that are
      separated by a short, unstructured linker. The N-terminal domain is structurally
      well-defined and is responsible for Fe2+ binding, dimerization, and DNA binding.
      The C-terminal domain adopts a fold similar to eukaryotic Src homology 3 domains,
      but the functional role of the C-terminal domain in repressor activity is
      unknown. The solution structure of the C-terminal domain, consisting of residues
      N130-L226 plus a 13-residue N-terminal extension, has been determined by using
      NMR spectroscopy. Residues before A147 are highly mobile and adopt a random coil
      conformation, but residues A147-L226 form a single structured domain consisting
      of five beta-strands and three helices arranged into a partially orthogonal, two
      sheet beta-barrel, similar to the structure observed in the crystalline Co2+
      complex of full-length DtxR. Chemical shift perturbation studies demonstrate that
      a proline-rich peptide corresponding to residues R125-G139 of intact DtxR binds
      to the C-terminal domain in a pocket formed by residues in beta-strands 2, 3, and
      5, and helix 3. Binding of the proline-rich peptide by the C-terminal domain of
      DtxR presents an example of peptide binding by a prokaryotic Src homology 3-like
      protein. The results of this study, combined with previous x-ray studies of
      intact DtxR, provide insights into a possible biological function of the C
      terminal domain in regulating repressor activity.

PMID- 10339552
TI  - The SRm160/300 splicing coactivator is required for exon-enhancer function.
AB  - Exonic splicing enhancer (ESE) sequences are important for the recognition of
      splice sites in pre-mRNA. These sequences are bound by specific serine-arginine
      (SR) repeat proteins that promote the assembly of splicing complexes at adjacent
      splice sites. We have recently identified a splicing "coactivator," SRm160/300,
      which contains SRm160 (the SR nuclear matrix protein of 160 kDa) and a 300-kDa
      nuclear matrix antigen. In the present study, we show that SRm160/300 is required
      for a purine-rich ESE to promote the splicing of a pre-mRNA derived from the
      Drosophila doublesex gene. The association of SRm160/300 and U2 small nuclear
      ribonucleoprotein particle (snRNP) with this pre-mRNA requires both U1 snRNP and
      factors bound to the ESE. Independently of pre-mRNA, SRm160/300 specifically
      interacts with U2 snRNP and with a human homolog of the Drosophila alternative
      splicing regulator Transformer 2, which binds to purine-rich ESEs. The results
      suggest a model for ESE function in which the SRm160/300 splicing coactivator
      promotes critical interactions between ESE-bound "activators" and the snRNP
      machinery of the spliceosome.

PMID- 10339553
TI  - Laser-mediated, site-specific inactivation of RNA transcripts.
AB  - The biological function of specific gene products often is determined
      experimentally by blocking their expression in an organism and observing the
      resulting phenotype. Chromophore-assisted laser inactivation using malachite
      green (MG)-tagged antibodies makes it possible to inactivate target proteins in a
      highly restricted manner, probing their temporally and spatially resolved
      functions. In this report, we describe the isolation and in vitro
      characterization of a MG-binding RNA motif that may enable the same high
      resolution analysis of gene function specifically at the RNA level (RNA
      chromophore-assisted laser inactivation). A well-defined asymmetric internal
      bulge within an RNA duplex allows high affinity and high specificity binding by
      MG. Laser irradiation in the presence of low concentrations of MG induces
      destruction of the MG-binding RNA but not of coincubated control RNA. Laser
      induced hydrolysis of the MG-binding RNA is restricted predominantly to a single
      nucleotide within the bulge. By appropriately incorporating this motif into a
      target gene, transcripts generated by the gene may be effectively tagged for
      laser-mediated destruction.

PMID- 10339554
TI  - Mutation R120G in alphaB-crystallin, which is linked to a desmin-related
      myopathy, results in an irregular structure and defective chaperone-like
      function.
AB  - alphaB-crystallin, a member of the small heat shock protein family, possesses
      chaperone-like function. Recently, it has been shown that a missense mutation in
      alphaB-crystallin, R120G, is genetically linked to a desmin-related myopathy as
      well as to cataracts [Vicart, P., Caron, A., Guicheney, P., Li, A., Prevost, M.
      C., Faure, A., Chateau, D., Chapon, F., Tome, F., Dupret, J.-M., et al. (1998)
      Nat. Genet. 20, 92-95]. By using alpha-lactalbumin, alcohol dehydrogenase, and
      insulin as target proteins, in vitro assays indicated that R120G alphaB
      crystallin had reduced or completely lost chaperone-like function. The addition
      of R120G alphaB-crystallin to unfolding alpha-lactalbumin enhanced the kinetics
      and extent of its aggregation. R120G alphaB-crystallin became entangled with
      unfolding alpha-lactalbumin and was a major portion of the resulting insoluble
      pellet. Similarly, incubation of R120G alphaB-crystallin with alcohol
      dehydrogenase and insulin also resulted in the presence of R120G alphaB
      crystallin in the insoluble pellets. Far and near UV CD indicate that R120G
      alphaB-crystallin has decreased beta-sheet secondary structure and an altered
      aromatic residue environment compared with wild-type alphaB-crystallin. The
      apparent molecular mass of R120G alphaB-crystallin, as determined by gel
      filtration chromatography, is 1.4 MDa, which is more than twice the molecular
      mass of wild-type alphaB-crystallin (650 kDa). Images obtained from cryoelectron
      microscopy indicate that R120G alphaB-crystallin possesses an irregular
      quaternary structure with an absence of a clear central cavity. The results of
      this study show, through biochemical analysis, that an altered structure and
      defective chaperone-like function of alphaB-crystallin are associated with a
      point mutation that leads to a desmin-related myopathy and cataracts.

PMID- 10339555
TI  - Comparison of the 5' nuclease activities of taq DNA polymerase and its isolated
      nuclease domain.
AB  - Many eubacterial DNA polymerases are bifunctional molecules having both
      polymerization (P) and 5' nuclease (N) activities, which are contained in
      separable domains. We previously showed that the DNA polymerase I of Thermus
      aquaticus (TaqNP) endonucleolytically cleaves DNA substrates, releasing unpaired
      5' arms of bifurcated duplexes. Here, we compare the substrate specificities of
      TaqNP and the isolated 5' nuclease domain of this enzyme, TaqN. Both enzymes are
      significantly activated by primer oligonucleotides that are hybridized to the 3'
      arm of the bifurcation; optimal stimulation requires overlap of the 3' terminal
      nucleotide of the primer with the terminal base pair of the duplex, but the
      terminal nucleotide need not hybridize to the complementary strand in the
      substrate. In the presence of Mn2+ ions, TaqN can cleave both RNA and circular
      DNA at structural bifurcations. Certain anti-TaqNP mAbs block cleavage by one or
      both enzymes, whereas others can stimulate cleavage of nonoptimal substrates.

PMID- 10339556
TI  - Magnesium-dependent folding of self-splicing RNA: exploring the link between
      cooperativity, thermodynamics, and kinetics.
AB  - Folding of the Tetrahymena self-splicing RNA into its active conformation
      involves a set of discrete intermediate states. The Mg2+-dependent equilibrium
      transition from the intermediates to the native structure is more cooperative
      than the formation of the intermediates from the unfolded states. We show that
      the degree of cooperativity is linked to the free energy of each transition and
      that the rate of the slow transition from the intermediates to the native state
      decreases exponentially with increasing Mg2+ concentration. Monovalent salts,
      which stabilize the folded RNA nonspecifically, induce states that fold in less
      than 30 s after Mg2+ is added to the RNA. A simple model is proposed that
      predicts the folding kinetics from the Mg2+-dependent change in the relative
      stabilities of the intermediate and native states.

PMID- 10339557
TI  - Inhibition of RNase P RNA cleavage by aminoglycosides.
AB  - A number of aminoglycosides have been reported to interact and interfere with the
      function of various RNA molecules. Among these are 16S rRNA, the group I intron,
      and the hammerhead ribozymes. In this report we show that cleavage by RNase P RNA
      in the absence as well as in the presence of the RNase P protein is inhibited by
      several aminoglycosides. Among the ones we tested, neomycin B was found to be the
      strongest inhibitor with a Ki value in the micromolar range (35 microM). Studies
      of lead(II)-induced cleavage of RNase P RNA suggested that binding of neomycin B
      interfered with the binding of divalent metal ions to the RNA. Taken together,
      our findings suggest that aminoglycosides compete with Mg2+ ions for functionally
      important divalent metal ion binding sites. Thus, RNase P, which is an essential
      enzyme, is indeed a potential drug target that can be used to develop new drugs
      by using various aminoglycosides as lead compounds.

PMID- 10339558
TI  - Regulation of the OxyR transcription factor by hydrogen peroxide and the cellular
      thiol-disulfide status.
AB  - The Escherichia coli transcription factor OxyR is activated by the formation of
      an intramolecular disulfide bond and subsequently is deactivated by enzymatic
      reduction of the disulfide bond. Here we show that OxyR can be activated by two
      possible pathways. In mutants defective in the cellular disulfide-reducing
      systems, OxyR is constitutively activated by a change in the thiol-disulfide
      redox status in the absence of added oxidants. In wild-type cells, OxyR is
      activated by hydrogen peroxide. By monitoring the presence of the OxyR disulfide
      bond after exposure to hydrogen peroxide in vivo and in vitro, we also show that
      the kinetics of OxyR oxidation by low concentrations of hydrogen peroxide is
      significantly faster than the kinetics of OxyR reduction, allowing for transient
      activation in an overall reducing environment. We propose that the activity of
      OxyR in vivo is determined by the balance between hydrogen peroxide levels and
      the cellular redox environment.

PMID- 10339559
TI  - Stretching single-domain proteins: phase diagram and kinetics of force-induced
      unfolding.
AB  - Single-molecule force spectroscopy reveals unfolding of domains in titin on
      stretching. We provide a theoretical framework for these experiments by computing
      the phase diagrams for force-induced unfolding of single-domain proteins using
      lattice models. The results show that two-state folders (at zero force) unravel
      cooperatively, whereas stretching of non-two-state folders occurs through
      intermediates. The stretching rates of individual molecules show great variations
      reflecting the heterogeneity of force-induced unfolding pathways. The approach to
      the stretched state occurs in a stepwise "quantized" manner. Unfolding dynamics
      and forces required to stretch proteins depend sensitively on topology. The
      unfolding rates increase exponentially with force f till an optimum value, which
      is determined by the barrier to unfolding when f = 0. A mapping of these results
      to proteins shows qualitative agreement with force-induced unfolding of Ig-like
      domains in titin. We show that single-molecule force spectroscopy can be used to
      map the folding free energy landscape of proteins in the absence of denaturants.

PMID- 10339560
TI  - Thermodynamic basis of the enhanced specificity of structured DNA probes.
AB  - Molecular beacons are DNA probes that form a stem-and-loop structure and possess
      an internally quenched fluorophore. When they bind to complementary nucleic
      acids, they undergo a conformational transition that switches on their
      fluorescence. These probes recognize their targets with higher specificity than
      probes that cannot form a hairpin stem, and they easily discriminate targets that
      differ from one another by only a single nucleotide. Our results show that
      molecular beacons can exist in three different states: bound to a target, free in
      the form of a hairpin structure, and free in the form of a random coil.
      Thermodynamic analysis of the transitions between these states reveals that
      enhanced specificity is a general feature of conformationally constrained probes.

PMID- 10339561
TI  - Shedding light on the dark and weakly fluorescent states of green fluorescent
      proteins.
AB  - Recent experiments on various similar green fluorescent protein (GFP) mutants at
      the single-molecule level and in solution provide evidence of previously unknown
      short- and long-lived "dark" states and of related excited-state decay channels.
      Here, we present quantum chemical calculations on cis-trans photoisomerization
      paths of neutral, anionic, and zwitterionic GFP chromophores in their ground and
      first singlet excited states that explain the observed behaviors from a common
      perspective. The results suggest that favorable radiationless decay channels can
      exist for the different protonation states along these isomerizations, which
      apparently proceed via conical intersections. These channels are suggested to
      rationalize the observed dramatic reduction of fluorescence in solution. The
      observed single-molecule fast blinking is attributed to conversions between the
      fluorescent anionic and the dark zwitterionic forms whereas slow switching is
      attributed to conversions between the anionic and the neutral forms. The
      predicted nonadiabatic crossings are seen to rationalize the origins of a variety
      of experimental observations on a common basis and may have broad implications
      for photobiophysical mechanisms in GFP.

PMID- 10339562
TI  - Identification of the proton pathway in bacterial reaction centers: inhibition of
      proton transfer by binding of Zn2+ or Cd2+.
AB  - The reaction center (RC) from Rhodobacter sphaeroides converts light into
      chemical energy through the light induced two-electron, two-proton reduction of a
      bound quinone molecule QB (the secondary quinone acceptor). A unique pathway for
      proton transfer to the QB site had so far not been determined. To study the
      molecular basis for proton transfer, we investigated the effects of exogenous
      metal ion binding on the kinetics of the proton-assisted electron transfer kAB(2)
      (QA-*QB-* + H+ --> QA(QBH)-, where QA is the primary quinone acceptor). Zn2+ and
      Cd2+ bound stoichiometrically to the RC (KD </= 0.5 microM) and reduced the
      observed value of kAB(2) 10-fold and 20-fold (pH 8.0), respectively. The bound
      metal changed the mechanism of the kAB(2) reaction. In native RCs, kAB(2) was
      previously shown to be rate-limited by electron transfer based on the dependence
      of kAB(2) on the driving force for electron transfer. Upon addition of Zn2+ or
      Cd2+, kAB(2) became approximately independent of the electron driving force,
      implying that the rate of proton transfer was reduced (>/= 10(2)-fold) and has
      become the rate-limiting step. The lack of an effect of the metal binding on the
      charge recombination reaction D+*QAQB-* --> DQAQB suggests that the binding site
      is located far (>10 A) from QB. This hypothesis is confirmed by preliminary x-ray
      structure analysis. The large change in the rate of proton transfer caused by the
      stoichiometric binding of the metal ion shows that there is one dominant site of
      proton entry into the RC from which proton transfer to QB-* occurs.

PMID- 10339563
TI  - How vertebrate and invertebrate visual pigments differ in their mechanism of
      photoactivation.
AB  - In vertebrate visual pigments, a glutamic acid serves as a negative counterion to
      the positively charged chromophore, a protonated Schiff base of retinal. When
      photoisomerization leads to the Schiff base deprotonating, the anionic glutamic
      acid becomes protonated, forming a neutral species that activates the visual
      cascade. We show that in octopus rhodopsin, the glutamic acid has no anionic
      counterpart. Thus, the "counterion" is already neutral, so no protonated form of
      an initially anionic group needs to be created to activate. This helps to explain
      another observation-that the active photoproduct of octopus rhodopsin can be
      formed without its Schiff base deprotonating. In this sense, the mechanism of
      light activation of octopus rhodopsin is simpler than for vertebrates, because it
      eliminates one of the steps required for vertebrate rhodopsins to achieve their
      activating state.

PMID- 10339564
TI  - Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6.
AB  - We have characterized HsCdc6, a human protein homologous to the budding yeast
      Cdc6p that is essential for DNA replication. We show that, unlike Cdc6p, the
      levels of HsCdc6 protein remain constant throughout the cell cycle in human
      cells. However, phosphorylation of HsCdc6 is regulated during the cell cycle.
      HsCdc6 is an excellent substrate for Cdk2 in vitro and is phosphorylated in vivo
      at three sites (Ser-54, Ser-74, and Ser-106) that are phosphorylated by Cdk2 in
      vitro, strongly suggesting that HsCdc6 is an in vivo Cdk substrate. HsCdc6 is
      nuclear in G1, but translocates to the cytoplasm at the start of S phase via Crm1
      dependent export. An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6,
      is exclusively nuclear, and its expression inhibits initiation of DNA
      replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is
      exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix
      fraction. Based on these results, we propose that phosphorylation of HsCdc6 by
      Cdks regulates DNA replication of at least two steps: first, by promoting
      initiation of DNA replication and, second, through nuclear exclusion preventing
      DNA rereplication.

PMID- 10339565
TI  - PTEN modulates cell cycle progression and cell survival by regulating
      phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling
      pathway.
AB  - To investigate the molecular basis of PTEN-mediated tumor suppression, we
      introduced a null mutation into the mouse Pten gene by homologous recombination
      in embryonic stem (ES) cells. Pten-/- ES cells exhibited an increased growth rate
      and proliferated even in the absence of serum. ES cells lacking PTEN function
      also displayed advanced entry into S phase. This accelerated G1/S transition was
      accompanied by down-regulation of p27(KIP1), a major inhibitor for G1 cyclin
      dependent kinases. Inactivation of PTEN in ES cells and in embryonic fibroblasts
      resulted in elevated levels of phosphatidylinositol 3,4,5,-trisphosphate, a
      product of phosphatidylinositol 3 kinase. Consequently, PTEN deficiency led to
      dosage-dependent increases in phosphorylation and activation of Akt/protein
      kinase B, a well-characterized target of the phosphatidylinositol 3 kinase
      signaling pathway. Akt activation increased Bad phosphorylation and promoted Pten
      /- cell survival. Our studies suggest that PTEN regulates the
      phosphatidylinositol 3,4, 5,-trisphosphate and Akt signaling pathway and
      consequently modulates two critical cellular processes: cell cycle progression
      and cell survival.

PMID- 10339566
TI  - Spc29p is a component of the Spc110p subcomplex and is essential for spindle pole
      body duplication.
AB  - In yeast, microtubules are organized by the spindle pole body (SPB). The SPB is a
      disk-like multilayered structure that is embedded in the nuclear envelope via its
      central plaque, whereas the outer and inner plaques are exposed to the cytoplasm
      and nucleoplasm, respectively. How the SPB assembles is poorly understood. We
      show that the inner/central plaque is composed of a stable SPB subcomplex,
      containing the gamma-tubulin complex-binding protein Spc110p, calmodulin, Spc42p,
      and Spc29p. Spc29p acts as a linker between the central plaque component Spc42p
      and the inner plaque protein Spc110p. Evidence is provided that the calmodulin
      binding site of Spc110p influences the binding of Spc29p to Spc110p. Spc42p also
      was identified as a component of a cytoplasmic SPB subcomplex containing
      Spc94p/Nud1p, Cnm67p, and Spc42p. Spc29p and Spc42p may be part of a critical
      interface of nucleoplasmic and cytoplasmic assembled SPB subcomplexes that form
      during SPB duplication. In agreement with this, overexpressed Spc29p was found to
      be a nuclear protein, whereas Spc42p is cytoplasmic. In addition, an essential
      function of SPC29 during SPB assembly is indicated by the SPB duplication defect
      of conditional lethal spc29(ts) cells and by the genetic interaction of SPC29
      with CDC31 and KAR1, two genes that are involved in SPB duplication.

PMID- 10339567
TI  - CMS: an adapter molecule involved in cytoskeletal rearrangements.
AB  - Cas ligand with multiple Src homology (SH) 3 domains (CMS) is an ubiquitously
      expressed signal transduction molecule that interacts with the focal adhesion
      protein p130(Cas). CMS contains three SH3 in its NH2 terminus and proline-rich
      sequences in its center region. The latter sequences mediate the binding to the
      SH3 domains of p130(Cas), Src-family kinases, p85 subunit of phosphatidylinositol
      3-kinase, and Grb2. The COOH-terminal region contains putative actin binding
      sites and a coiled-coil domain that mediates homodimerization of CMS. CMS is a
      cytoplasmic protein that colocalizes with F-actin and p130(Cas) to membrane
      ruffles and leading edges of cells. Ectopic expression of CMS in COS-7 cells
      resulted in alteration in arrangement of the actin cytoskeleton. We observed a
      diffuse distribution of actin in small dots and less actin fiber formation.
      Altogether, these features suggest that CMS functions as a scaffolding molecule
      with a specialized role in regulation of the actin cytoskeleton.

PMID- 10339568
TI  - Mechanism of Ca2+-dependent nuclear accumulation of calmodulin.
AB  - The intracellular Ca2+ receptor calmodulin (CaM) coordinates responses to
      extracellular stimuli by modulating the activities of its various binding
      proteins. Recent reports suggest that, in addition to its familiar functions in
      the cytoplasm, CaM may be directly involved in rapid signaling between cytoplasm
      and nucleus. Here we show that Ca2+-dependent nuclear accumulation of CaM can be
      reconstituted in permeabilized cells. Accumulation was blocked by M13, a CaM
      antagonist peptide, but did not require cytosolic factors or an ATP regenerating
      system. Ca2+-dependent influx of CaM into nuclei was not blocked by inhibitors of
      nuclear localization signal-mediated nuclear import in either permeabilized or
      intact cells. Fluorescence recovery after photobleaching studies of CaM in intact
      cells showed that influx is a first-order process with a rate constant similar to
      that of a freely diffusible control molecule (20-kDa dextran). Studies of CaM
      efflux from preloaded nuclei in permeablized cells revealed the existence of
      three classes of nuclear binding sites that are distinguished by their Ca2+
      dependence and affinity. At high [Ca2+], efflux was enhanced by addition of a
      high affinity CaM-binding protein outside the nucleus. These data suggest that
      CaM diffuses freely through nuclear pores and that CaM-binding proteins in the
      nucleus act as a sink for Ca2+-CaM, resulting in accumulation of CaM in the
      nucleus on elevation of intracellular free Ca2+.

PMID- 10339569
TI  - Poly-ADP ribose polymerase activates nuclear proteasome to degrade oxidatively
      damaged histones.
AB  - The 20S proteasome has been shown to be largely responsible for the degradation
      of oxidatively modified proteins in the cytoplasm. Nuclear proteins are also
      subject to oxidation, and the nucleus of mammalian cells contains proteasome. In
      human beings, tumor cells frequently are subjected to oxidation as a consequence
      of antitumor chemotherapy, and K562 human myelogenous leukemia cells have a
      higher nuclear proteasome activity than do nonmalignant cells. Adaptation to
      oxidative stress appears to be one element in the development of long-term
      resistance to many chemotherapeutic drugs and the mechanisms of inducible tumor
      resistance to oxidation are of obvious importance. After hydrogen peroxide
      treatment of K562 cells, degradation of the model proteasome peptide substrate
      suc-LLVY-MCA and degradation of oxidized histones in nuclei increases
      significantly within minutes. Both increased proteolytic susceptibility of the
      histone substrates (caused by modification by oxidation) and activation of the
      proteasome enzyme complex occur independently during oxidative stress. This rapid
      up-regulation of 20S proteasome activity is accompanied by, and depends on, poly
      ADP ribosylation of the proteasome, as shown by inhibitor experiments, 14C-ADP
      ribose incorporation assays, immunoblotting, in vitro reconstitution experiments,
      and immunoprecipitation of (activated) proteasome with anti-poly-ADP ribose
      polymerase antibodies. The poly-ADP ribosylation-mediated activated nuclear 20S
      proteasome is able to remove oxidatively damaged histones more efficiently and
      therefore is proposed as an oxidant-stimulatable defense or repair system of the
      nucleus in K562 leukemia cells.

PMID- 10339570
TI  - Evidence for specific nucleocytoplasmic transport pathways used by leucine-rich
      nuclear export signals.
AB  - Various proteins with different biological activities have been observed to be
      translocated from the nucleus to the cytoplasm in an energy- and signal-dependent
      manner in eukaryotic cells. This nuclear export is directed by nuclear export
      signals (NESs), typically characterized by hydrophobic, primarily leucine, amino
      acid residues. Moreover, it has been shown that CRM1/exportin 1 is an export
      receptor for leucine-rich NESs. However, additional NES-interacting proteins have
      been described. In particular, eukaryotic initiation factor 5A (eIF-5A) has been
      shown to be a critical cellular cofactor for the nuclear export of the HIV type 1
      (HIV-1) Rev trans-activator protein. In this study we compared the nuclear export
      activity of NESs of different origin. Microinjection of export substrates into
      the nucleus of somatic cells in combination with specific inhibitors indicated
      that specific nuclear export pathways exist for different NES-containing
      proteins. In particular, inhibition of eIF-5A blocked the nuclear export of NESs
      derived from the HIV-1 Rev and human T cell leukemia virus type I Rex trans
      activators, whereas nucleocytoplasmic translocation of the protein kinase
      inhibitor-NES was unaffected. In contrast, however, inhibition of CRM1/exportin 1
      blocked the nuclear export of all NES-containing proteins investigated. Our data
      confirm that CRM1/exportin 1 is a general export receptor for leucine-rich NESs
      and suggest that eIF-5A acts either upstream of CRM1/exportin 1 or forms a
      complex with the NES and CRM1/exportin 1 in the nucleocytoplasmic translocation
      of the HIV-1 Rev and human T cell leukemia virus type I Rex RNA export factors.

PMID- 10339571
TI  - Metalloprotease-mediated ligand release regulates autocrine signaling through the
      epidermal growth factor receptor.
AB  - Ligands that activate the epidermal growth factor receptor (EGFR) are synthesized
      as membrane-anchored precursors that appear to be proteolytically released by
      members of the ADAM family of metalloproteases. Because membrane-anchored EGFR
      ligands are thought to be biologically active, the role of ligand release in the
      regulation of EGFR signaling is unclear. To investigate this question, we used
      metalloprotease inhibitors to block EGFR ligand release from human mammary
      epithelial cells. These cells express both transforming growth factor alpha and
      amphiregulin and require autocrine signaling through the EGFR for proliferation
      and migration. We found that metalloprotease inhibitors reduced cell
      proliferation in direct proportion to their effect on transforming growth factor
      alpha release. Metalloprotease inhibitors also reduced growth of EGF-responsive
      tumorigenic cell lines and were synergistic with the inhibitory effects of
      antagonistic EGFR antibodies. Blocking release of EGFR ligands also strongly
      inhibited autocrine activation of the EGFR and reduced both the rate and
      persistence of cell migration. The effects of metalloprotease inhibitors could be
      reversed by either adding exogenous EGF or by expressing an artificial gene for
      EGF that lacked a membrane-anchoring domain. Our results indicate that soluble
      rather than membrane-anchored forms of the ligands mediate most of the biological
      effects of EGFR ligands. Metalloprotease inhibitors have shown promise in
      preventing spread of metastatic disease. Many of their antimetastatic effects
      could be the result of their ability to inhibit autocrine signaling through the
      EGFR.

PMID- 10339572
TI  - VIP17/MAL, a lipid raft-associated protein, is involved in apical transport in
      MDCK cells.
AB  - Apical proteins are sorted and delivered from the trans-Golgi network to the
      plasma membrane by a mechanism involving sphingolipid-cholesterol rafts. In this
      paper, we report the effects of changing the levels of VIP17/MAL, a tetraspan
      membrane protein localized to post-Golgi transport containers and the apical cell
      surface in MDCK cells. Overexpression of VIP17/MAL disturbed the morphology of
      the MDCK cell layers by increasing apical delivery and seemingly expanding the
      apical cell surface domains. On the other hand, expression of antisense RNA
      directed against VIP17/MAL caused accumulation in the Golgi and/or impaired
      apical transport of different apical protein markers, i.e., influenza virus
      hemagglutinin, the secretory protein clusterin (gp80), the transmembrane protein
      gp114, and a glycosylphosphatidylinositol-anchored protein. However, antisense
      RNA expression did not affect the distribution of E-cadherin to the basolateral
      surface. Because VIP17/MAL associates with sphingolipid-cholesterol rafts, these
      data provide functional evidence that this protein is involved in apical
      transport and might be a component of the machinery clustering lipid rafts with
      apical cargo to form apical transport carriers.

PMID- 10339573
TI  - E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface
      epithelium.
AB  - Ovarian carcinomas are thought to arise in the ovarian surface epithelium (OSE).
      Although this tissue forms a simple epithelial covering on the ovarian surface,
      OSE cells exhibit some mesenchymal characteristics and contain little or no E
      cadherin. However, E-cadherin is present in metaplastic OSE cells that resemble
      the more complex epithelia of the oviduct, endometrium and endocervix, and in
      primary epithelial ovarian carcinomas. To determine whether E-cadherin was a
      cause or consequence of OSE metaplasia, we expressed this cell-adhesion molecule
      in simian virus 40-immortalized OSE cells. In these cells the exogenous E
      cadherin, all three catenins, and F-actin localized at sites of cell-cell
      contact, indicating the formation of functional adherens junctions. Unlike the
      parent OSE cell line, which had undergone a typical mesenchymal transformation in
      culture, E-cadherin-expressing cells contained cytokeratins and the tight
      junction protein occludin. They also formed cobblestone monolayers in two
      dimensional culture and simple epithelia in three-dimensional culture that
      produced CA125 and shed it into the culture medium. CA125 is a normal epithelial
      differentiation product of the oviduct, endometrium, and endocervix, but not of
      normal OSE. It is also a tumor antigen that is produced by ovarian neoplasms and
      by metaplastic OSE. Thus, E-cadherin restored some normal characteristics of OSE,
      such as keratin, and it also induced epithelial-differentiation markers
      associated with weakly preneoplastic, metaplastic OSE and OSE-derived primary
      carcinomas. The results suggest an unexpected role for E-cadherin in ovarian
      neoplastic progression.

PMID- 10339574
TI  - Activation of flavin-containing oxidases underlies light-induced production of
      H2O2 in mammalian cells.
AB  - Violet-blue light is toxic to mammalian cells, and this toxicity has been linked
      with cellular production of H2O2. In this report, we show that violet-blue light,
      as well as UVA, stimulated H2O2 production in cultured mouse, monkey, and human
      cells. We found that H2O2 originated in peroxisomes and mitochondria, and it was
      enhanced in cells overexpressing flavin-containing oxidases. These results
      support the hypothesis that photoreduction of flavoproteins underlies light
      induced production of H2O2 in cells. Because H2O2 and its metabolite, hydroxyl
      radicals, can cause cellular damage, these reactive oxygen species may contribute
      to pathologies associated with exposure to UVA, violet, and blue light. They may
      also contribute to phototoxicity often encountered during light microscopy.
      Because multiphoton excitation imaging with 1,047-nm wavelength prevented light
      induced H2O2 production in cells, possibly by minimizing photoreduction of
      flavoproteins, this technique may be useful for decreasing phototoxicity during
      fluorescence microscopy.

PMID- 10339575
TI  - Converting enzyme-independent release of tumor necrosis factor alpha and IL-1beta
      from a stimulated human monocytic cell line in the presence of activated
      neutrophils or purified proteinase 3.
AB  - Two important cytokines mediating inflammation are tumor necrosis factor alpha
      (TNFalpha) and IL-1beta, both of which require conversion to soluble forms by
      converting enzymes. The importance of TNFalpha-converting enzyme and IL-1beta
      converting enzyme in the production of circulating TNFalpha and IL-1beta in
      response to systemic challenges has been demonstrated by the use of specific
      converting enzyme inhibitors. Many inflammatory responses, however, are not
      systemic but instead are localized. In these situations release and/or activation
      of cytokines may be different from that seen in response to a systemic stimulus,
      particularly because associations of various cell populations in these foci
      allows for the exposure of procytokines to the proteolytic enzymes produced by
      activated neutrophils, neutrophil elastase (NE), proteinase 3 (PR3), and
      cathepsin G (Cat G). To investigate the possibility of alternative processing of
      TNFalpha and/or IL-1beta by neutrophil-derived proteinases, immunoreactive
      TNFalpha and IL-1beta release from lipopolysaccharide-stimulated THP-1 cells was
      measured in the presence of activated human neutrophils. Under these conditions,
      TNFalpha and IL-1beta release was augmented 2- to 5-fold. In the presence of a
      specific inhibitor of NE and PR3, enhanced release of both cytokines was largely
      abolished; however, in the presence of a NE and Cat G selective inhibitor,
      secretory leucocyte proteinase inhibitor, reduction of the enhanced release was
      minimal. This finding suggested that the augmented release was attributable to
      PR3 but not NE nor Cat G. Use of purified enzymes confirmed this conclusion.
      These results indicate that there may be alternative pathways for the production
      of these two proinflammatory cytokines, particularly in the context of local
      inflammatory processes.

PMID- 10339576
TI  - Signaling through fibroblast growth factor receptor 2b plays a key role in the
      development of the exocrine pancreas.
AB  - The development of the pancreas depends on epithelial-mesenchymal interactions.
      Fibroblast growth factors (FGFs) and their receptors (FGFRs 1-4) have been
      identified as mediators of epithelial-mesenchymal interactions in different
      organs. We show here that FGFR-2 IIIb and its ligands FGF-1, FGF-7, and FGF-10
      are expressed throughout pancreatic development. We also show that in mesenchyme
      free cultures of embryonic pancreatic epithelium FGF-1, FGF-7, and FGF-10
      stimulate the growth, morphogenesis, and cytodifferentiation of the exocrine
      cells of the pancreas. The role of FGFs signaling through FGFR-2 IIIb was further
      investigated by inhibiting FGFR-2 IIIb signaling in organocultures of pancreatic
      explants (epithelium + mesenchyme) by using either antisense FGFR-2 IIIb
      oligonucleotides or a soluble recombinant FGFR-2 IIIb protein. Abrogation of FGFR
      2 IIIb signaling resulted in a considerable reduction in the size of the explants
      and in a 2-fold reduction of the development of the exocrine cells. These results
      demonstrate that FGFs signaling through FGFR-2 IIIb play an important role in the
      development of the exocrine pancreas.

PMID- 10339578
TI  - Adaptive evolution of color vision of the Comoran coelacanth (Latimeria
      chalumnae).
AB  - The coelacanth, a "living fossil," lives near the coast of the Comoros
      archipelago in the Indian Ocean. Living at a depth of about 200 m, the Comoran
      coelacanth receives only a narrow range of light, at about 480 nm. To detect the
      entire range of "color" at this depth, the coelacanth appears to use only two
      closely related paralogous RH1 and RH2 visual pigments with the optimum light
      sensitivities (lambdamax) at 478 nm and 485 nm, respectively. The lambdamax
      values are shifted about 20 nm toward blue compared with those of the
      corresponding orthologous pigments. Mutagenesis experiments show that each of
      these coadapted changes is fully explained by two amino acid replacements.

PMID- 10339577
TI  - beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus
      axis formation.
AB  - Regulation of beta-catenin stability is essential for Wnt signal transduction
      during development and tumorigenesis. It is well known that serine
      phosphorylation of beta-catenin by the Axin-glycogen synthase kinase (GSK)-3beta
      complex targets beta-catenin for ubiquitination-degradation, and mutations at
      critical phosphoserine residues stabilize beta-catenin and cause human cancers.
      How beta-catenin phosphorylation results in its degradation is undefined. Here we
      show that phosphorylated beta-catenin is specifically recognized by beta-Trcp, an
      F-box/WD40-repeat protein that also associates with Skp1, an essential component
      of the ubiquitination apparatus. beta-catenin harboring mutations at the critical
      phosphoserine residues escapes recognition by beta-Trcp, thus providing a
      molecular explanation for why these mutations cause beta-catenin accumulation
      that leads to cancer. Inhibition of endogenous beta-Trcp function by a dominant
      negative mutant stabilizes beta-catenin, activates Wnt/beta-catenin signaling,
      and induces axis formation in Xenopus embryos. Therefore, beta-Trcp plays a
      central role in recruiting phosphorylated beta-catenin for degradation and in
      dorsoventral patterning of the Xenopus embryo.

PMID- 10339580
TI  - A normal beta-globin allele as a modifier gene ameliorating the severity of alpha
      thalassemia in mice.
AB  - Thalassemia is a heritable human anemia caused by a variety of mutations that
      affect expression of the alpha- or the beta-chain of hemoglobin. The expressivity
      of the phenotype is likely to be influenced by unlinked modifying genes. Indeed,
      by using a mouse model of alpha-thalassemia, we find that its phenotype is
      strongly influenced by the genetic background in which the alpha-thalassemia
      mutation resides [129(sv/ev)/129(sv/ev) (severe) or 129(sv/ev)/C57BL/6 (mild)].
      Linkage mapping indicates that the modifying gene is very tightly linked to the
      beta-globin locus (Lod score = 13.3). Furthermore, the severity of the phenotype
      correlates with the size of beta-chain-containing inclusion bodies that
      accumulate in red blood cells and likely accelerate their destruction. The beta
      major globin chains encoded by the two strains differ by three amino acids, one
      of which is a glycine-to-cysteine substitution at position 13. The Cys-13 should
      be available for interchain disulfide bridging and consequent aggregation between
      excess beta-chains. This normal polymorphic variation between murine beta-globin
      chains could account for the modifying action of the unlinked beta-globin locus.
      Here, the variation in severity of the phenotype would not depend on a change in
      the ratio between alpha- and beta-chains but on the chemical nature of the normal
      beta-chain, which is in excess. This work also indicates that modifying genes can
      be normal variants that-absent an apparent physiologic rationale-may be difficult
      to identify on the basis of structure alone.

PMID- 10339579
TI  - Convergent evolution of Trichomonas vaginalis lactate dehydrogenase from malate
      dehydrogenase.
AB  - Lactate dehydrogenase (LDH) is present in the amitochondriate parasitic protist
      Trichomonas vaginalis and some but not all other trichomonad species. The derived
      amino acid sequence of T. vaginalis LDH (TvLDH) was found to be more closely
      related to the cytosolic malate dehydrogenase (MDH) of the same species than to
      any other LDH. A key difference between the two T. vaginalis sequences was that
      Arg91 of MDH, known to be important in coordinating the C-4 carboxyl of
      oxalacetate/malate, was replaced by Leu91 in LDH. The change Leu91Arg by site
      directed mutagenesis converted TvLDH into an MDH. The reverse single amino acid
      change Arg91Leu in TvMDH, however, gave a product with no measurable LDH
      activity. Phylogenetic reconstructions indicate that TvLDH arose from an MDH
      relatively recently.

PMID- 10339581
TI  - Mutations in HYAL1, a member of a tandemly distributed multigene family encoding
      disparate hyaluronidase activities, cause a newly described lysosomal disorder,
      mucopolysaccharidosis IX.
AB  - Hyaluronan (HA), a large glycosaminoglycan abundant in the extracellular matrix,
      is important in cell migration during embryonic development, cellular
      proliferation, and differentiation and has a structural role in connective
      tissues. The turnover of HA requires endoglycosidic breakdown by lysosomal
      hyaluronidase, and a congenital deficiency of hyaluronidase has been thought to
      be incompatible with life. However, a patient with a deficiency of serum
      hyaluronidase, now designated as mucopolysaccharidosis IX, was recently
      described. This patient had a surprisingly mild clinical phenotype, including
      notable periarticular soft tissue masses, mild short stature, an absence of
      neurological or visceral involvement, and histological and ultrastructural
      evidence of a lysosomal storage disease. To determine the molecular basis of
      mucopolysaccharidosis IX, we analyzed two candidate genes tandemly distributed on
      human chromosome 3p21.3 and encoding proteins with homology to a sperm protein
      with hyaluronidase activity. These genes, HYAL1 and HYAL2, encode two distinct
      lysosomal hyaluronidases with different substrate specificities. We identified
      two mutations in the HYAL1 alleles of the patient, a 1412G --> A mutation that
      introduces a nonconservative amino acid substitution (Glu268Lys) in a putative
      active site residue and a complex intragenic rearrangement, 1361del37ins14, that
      results in a premature termination codon. We further show that these two
      hyaluronidase genes, as well as a third recently discovered adjacent
      hyaluronidase gene, HYAL3, have markedly different tissue expression patterns,
      consistent with differing roles in HA metabolism. These data provide an
      explanation for the unexpectedly mild phenotype in mucopolysaccharidosis IX and
      predict the existence of other hyaluronidase deficiency disorders.

PMID- 10339582
TI  - Direct genetic analysis by matrix-assisted laser desorption/ionization mass
      spectrometry.
AB  - An approach to analyzing single-nucleotide polymorphisms (SNPs) found in the
      human genome has been developed that couples a recently developed invasive
      cleavage assay for nucleic acids with detection by matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The
      invasive cleavage assay is a signal amplification method that enables the
      analysis of SNPs by MALDI-TOF MS directly from human genomic DNA without the need
      for initial target amplification by PCR. The results presented here show the
      successful genotyping by this approach of twelve SNPs located randomly throughout
      the human genome. Conventional Sanger sequencing of these SNP positions confirmed
      the accuracy of the MALDI-TOF MS analysis results. The ability to unambiguously
      detect both homozygous and heterozygous genotypes is clearly demonstrated. The
      elimination of the need for target amplification by PCR, combined with the
      inherently rapid and accurate nature of detection by MALDI-TOF MS, gives this
      approach unique and significant advantages in the high-throughput genotyping of
      large numbers of SNPs, useful for locating, identifying, and characterizing the
      function of specific genes.

PMID- 10339583
TI  - A single nucleotide in the SMN gene regulates splicing and is responsible for
      spinal muscular atrophy.
AB  - SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical
      question is why only the homozygous loss of SMN1, and not SMN2, results in spinal
      muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a
      new SMN1 mutation showed a direct relationship between presence of disease and
      exon 7 skipping. We have reported previously that the exon-skipped product
      SMNDelta7 is partially defective for self-association and SMN self
      oligomerization correlated with clinical severity. To evaluate systematically
      which of the five nucleotides that differ between SMN1 and SMN2 effect
      alternative splicing of exon 7, a series of SMN minigenes was engineered and
      transfected into cultured cells, and their transcripts were characterized. Of
      these nucleotide differences, the exon 7 C-to-T transition at codon 280, a
      translationally silent variance, was necessary and sufficient to dictate exon 7
      alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and
      protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity
      of an exonic enhancer. These findings demonstrate the molecular genetic basis for
      the nature and pathogenesis of SMA and illustrate a novel disease mechanism.
      Because individuals with SMA retain the SMN2 allele, therapy targeted at
      preventing exon 7 skipping could modify clinical outcome.

PMID- 10339584
TI  - Microsatellites provide evidence for Y chromosome diversity among the founders of
      the New World.
AB  - Recently, Y chromosome markers have begun to be used to study Native American
      origins. Available data have been interpreted as indicating that the colonizers
      of the New World carried a single founder haplotype. However, these early studies
      have been based on a few, mostly complex polymorphisms of insufficient resolution
      to determine whether observed diversity stems from admixture or diversity among
      the colonizers. Because the interpretation of Y chromosomal variation in the New
      World depends on founding diversity, it is important to develop marker systems
      with finer resolution. Here we evaluate the hypothesis of a single-founder Y
      haplotype for Amerinds by using 11 Y-specific markers in five Colombian Amerind
      populations. Two of these markers (DYS271, DYS287) are reliable indicators of
      admixture and detected three non-Amerind chromosomes in our sample. Two other
      markers (DYS199, M19) are single-nucleotide polymorphisms mostly restricted to
      Native Americans. The relatedness of chromosomes defined by these two markers was
      evaluated by constructing haplotypes with seven microsatellite loci (DYS388 to
      394). The microsatellite backgrounds found on the two haplogroups defined by
      marker DYS199 demonstrate the existence of at least two Amerind founder
      haplotypes, one of them (carrying allele DYS199 T) largely restricted to Native
      Americans. The estimated age and distribution of these haplogroups places them
      among the founders of the New World.

PMID- 10339585
TI  - Distinct leukemia phenotypes in transgenic mice and different corepressor
      interactions generated by promyelocytic leukemia variant fusion genes PLZF
      RARalpha and NPM-RARalpha.
AB  - Acute promyelocytic leukemia (APL) is characterized by a specific chromosome
      translocation involving RARalpha and one of four fusion partners: PML, PLZF, NPM,
      and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo,
      we generated transgenic mice with PLZF-RARalpha and NPM-RARalpha. PLZF-RARalpha
      transgenic animals developed chronic myeloid leukemia-like phenotypes at an early
      stage of life (within 3 months in five of six mice), whereas three NPM-RARalpha
      transgenic mice showed a spectrum of phenotypes from typical APL to chronic
      myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to
      bone marrow cells from PLZF-RARalpha transgenic mice, those from NPM-RARalpha
      transgenic mice could be induced to differentiate by all-trans-retinoic acid
      (ATRA). We also studied RARE binding properties and interactions between nuclear
      corepressor SMRT and various fusion proteins in response to ATRA. Dissociation of
      SMRT from different receptors was observed at ATRA concentrations of 0.01 microM,
      0.1 microM, and 1.0 microM for RARalpha-RXRalpha, NPM-RARalpha, and PML-RARalpha,
      respectively, but not observed for PLZF-RARalpha even in the presence of 10
      microM ATRA. We also determined the expression of the tissue factor gene in
      transgenic mice, which was detected only in bone marrow cells of mice expressing
      the fusion genes. These data clearly establish the leukemogenic role of PLZF
      RARalpha and NPM-RARalpha and the importance of fusion receptor/corepressor
      interactions in the pathogenesis as well as in determining different clinical
      phenotypes of APL.

PMID- 10339586
TI  - Calcineurin and vacuolar-type H+-ATPase modulate macrophage effector functions.
AB  - While effector molecules produced by activated macrophages (including nitric
      oxide, tumor necrosis factor alpha, interleukin 1, etc.) help to eliminate
      pathogens, high levels of these molecules can be deleterious to the host itself.
      Despite their importance, the mechanisms modulating macrophage effector functions
      are poorly understood. This work introduces two key negative regulators that
      control the levels and duration of macrophage cytokine production. Vacuolar-type
      H+-ATPase (V-ATPase) and calcineurin (Cn) constitutively act in normal
      macrophages to suppress expression of inflammatory cytokines in the absence of
      specific activation and to inhibit macrophage cytokine responses induced by
      bacterial lipopolysaccharide (V-ATPase), interferon gamma (V-ATPase and Cn), and
      calcium (Ca2+) flux (Cn). Cn and V-ATPase modulate effector gene expression at
      the mRNA level by inhibiting transcription factor NF-kappaB. This negative
      regulation by Cn is opposite to its crucial positive role in T cells, where it
      activates NFAT transcription factor(s) leading to expression of interleukin 2,
      tumor necrosis factor alpha, and other cytokine genes. The negative effects of V
      ATPase and Cn on NF-kappaB-dependent gene expression are not limited to the
      macrophage lineage, as similar effects have been seen with a murine fibroblast
      cell line and with primary astrocytes.

PMID- 10339587
TI  - The natural killer gene complex genetic locus Chok encodes Ly-49D, a target
      recognition receptor that activates natural killing.
AB  - Previously, we established that natural killer (NK) cells from C57BL/6 (B6), but
      not BALB/c, mice lysed Chinese hamster ovary (CHO) cells, and we mapped the locus
      that determines this differential CHO-killing capacity to the NK gene complex on
      chromosome 6. The localization of Chok in the NK gene complex suggested that it
      may encode either an activating or an inhibitory receptor. Here, results from a
      lectin-facilitated lysis assay predicted that Chok is an activating B6 NK
      receptor. Therefore, we immunized BALB/c mice with NK cells from BALB.B6-Cmv1(r)
      congenic mice and generated a mAb, designated 4E4, that blocked B6-mediated CHO
      lysis. mAb 4E4 also redirected lysis of Daudi targets, indicating its reactivity
      with an activating NK cell receptor. Furthermore, only the 4E4(+) B6 NK cell
      subset mediated CHO killing, and this lysis was abrogated by preincubation with
      mAb 4E4. Flow cytometric analysis indicated that mAb 4E4 specifically reacts with
      Ly-49D but not Ly-49A, B, C, E, G, H, or I transfectants. Finally, gene transfer
      of Ly-49DB6 into BALB/c NK cells conferred cytotoxic capacity against CHO cells,
      thus establishing that the Ly-49D receptor is sufficient to activate NK cells to
      lyse this target. Hence, Ly-49D is the Chok gene product and is a mouse NK cell
      receptor capable of directly triggering natural killing.

PMID- 10339588
TI  - Requirement for membrane lymphotoxin in natural killer cell development.
AB  - Development of natural killer (NK) cells is thought to depend on interactions
      between NK progenitors and the bone marrow (BM) microenvironment; however, little
      is known about the molecular signals involved. Here we show that lymphotoxin (LT)
      provides an important signal for the development of both NK cells and NK/T cells.
      LTalpha-/- mice show marked reduction in splenic and BM NK and NK/T cell numbers
      and dramatically impaired NK and NK/T cell function. Mice deficient in either
      tumor necrosis factor receptor (TNFR)-I or TNFR-II have normal numbers of NK and
      NK/T cells, implying that neither of the TNFRs nor soluble LTalpha3 is required
      for development of these cell types. Reciprocal BM transfers between LTalpha-/-
      and wild-type mice suggest that close interactions between membrane LT-expressing
      NK cell precursors and LT-responsive radioresistant stromal cells are necessary
      for NK cell development. When LT-deficient BM cells are incubated with IL-15, NK
      cells are formed. In addition, LT-deficient BM cells produce IL-15 after
      activation. Thus, membrane LT appears to deliver a signal for NK cell development
      that is either independent of IL-15 or upstream in the IL-15 pathway. These
      results reveal a novel function for membrane LT in NK and NK/T cell development.
      They also support a cellular and molecular mechanism by which NK cell precursors
      themselves deliver essential signals, through the membrane ligand, that induce
      the microenvironment to promote further NK cell and NK/T cell development.

PMID- 10339589
TI  - Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3
      domain-binding protein.
AB  - Bruton's tyrosine kinase (Btk) is a cytoplasmic tyrosine kinase that is crucial
      for human and murine B cell development, and its deficiency causes human X-linked
      agammaglobulinemia and murine X-linked immunodeficiency. In this report, we
      describe the function of the Btk-binding protein Sab (SH3-domain binding protein
      that preferentially associates with Btk), which we reported previously as a newly
      identified Src homology 3 domain-binding protein. Sab was shown to inhibit the
      auto- and transphosphorylation activity of Btk, which prompted us to propose that
      Sab functions as a transregulator of Btk. Forced overexpression of Sab in B cells
      led to the reduction of B cell antigen receptor-induced tyrosine phosphorylation
      of Btk and significantly reduced both early and late B cell antigen receptor
      mediated events, including calcium mobilization, inositol 1, 4,5-trisphosphate
      production, and apoptotic cell death, where the involvement of Btk activity has
      been demonstrated previously. Together, these results indicate the negative
      regulatory role of Sab in the B cell cytoplasmic tyrosine kinase pathway.

PMID- 10339590
TI  - Receptors for oxidized low-density lipoprotein on elicited mouse peritoneal
      macrophages can recognize both the modified lipid moieties and the modified
      protein moieties: implications with respect to macrophage recognition of
      apoptotic cells.
AB  - It has been shown previously that the binding of oxidized low-density lipoprotein
      (OxLDL) to resident mouse peritoneal macrophages can be inhibited (up to 70%) by
      the apoprotein B (apoB) isolated from OxLDL, suggesting that macrophage
      recognition of OxLDL is primarily dependent on its modified protein moiety.
      However, recent experiments have demonstrated that the lipids isolated from OxLDL
      and reconstituted into a microemulsion can also strongly inhibit uptake of OxLDL
      (up to 80%). The present studies show that lipid microemulsions prepared from
      OxLDL bind to thioglycollate-elicited macrophages at 4 degrees C in a saturable
      fashion and inhibit the binding of intact OxLDL and also of the apoB from OxLDL.
      Reciprocally, the binding of the OxLDL-lipid microemulsions was strongly
      inhibited by intact OxLDL. A conjugate of synthetic 1-palmitoyl 2(5-oxovaleroyl)
      phosphatidylcholine (an oxidation product of 1-palmitoyl 2-arachidonoyl
      phosphatidylcholine) with serum albumin, shown previously to inhibit macrophage
      binding of intact OxLDL, also inhibited the binding of both the apoprotein and
      the lipid microemulsions prepared from OxLDL. Finally, a monoclonal antibody
      against oxidized phospholipids, one that inhibits binding of intact OxLDL to
      macrophages, also inhibited the binding of both the resolubilized apoB and the
      lipid microemulsions prepared from OxLDL. These studies support the conclusions
      that: (i) at least some of the macrophage receptors for oxidized LDL can
      recognize both the lipid and the protein moieties; and (ii) oxidized
      phospholipids, in the lipid phase of the lipoprotein and/or covalently linked to
      the apoB of OxLDL, likely play a role in that recognition.

PMID- 10339591
TI  - Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic
      cells and inhibit their phagocytosis by elicited macrophages: evidence that
      oxidation-specific epitopes mediate macrophage recognition.
AB  - Apoptosis is recognized as important for normal cellular homeostasis in
      multicellular organisms. Although there have been great advances in our knowledge
      of the molecular events regulating apoptosis, much less is known about the
      receptors on phagocytes responsible for apoptotic cell recognition and
      phagocytosis or the ligands on apoptotic cells mediating such recognition. The
      observations that apoptotic cells are under increased oxidative stress and that
      oxidized low-density lipoprotein (OxLDL) competes with apoptotic cells for
      macrophage binding suggested the hypothesis that both OxLDL and apoptotic cells
      share oxidatively modified moieties on their surfaces that serve as ligands for
      macrophage recognition. To test this hypothesis, we used murine monoclonal
      autoantibodies that bind to oxidation-specific epitopes on OxLDL. In particular,
      antibodies EO6 and EO3 recognize oxidized phospholipids, including 1-palmitoyl 2
      (5-oxovaleroyl) phosphatidylcholine (POVPC), and antibodies EO12 and EO14
      recognize malondialdehyde-lysine, as in malondialdehyde-LDL. Using FACS analysis,
      we demonstrated that each of these EO antibodies bound to apoptotic cells but not
      to normal cells, whereas control IgM antibodies did not. Confocal microscopy
      demonstrated cell-surface expression of the oxidation-specific epitopes on
      apoptotic cells. Furthermore, each of these antibodies inhibited the phagocytosis
      of apoptotic cells by elicited peritoneal macrophages, as did OxLDL. In addition,
      an adduct of POVPC with BSA also effectively prevented phagocytosis. These data
      demonstrate that apoptotic cells express oxidation-specific epitopes-including
      oxidized phospholipids-on their cell surface, and that these serve as ligands for
      recognition and phagocytosis by elicited macrophages.

PMID- 10339592
TI  - Stable exposure of the coreceptor-binding site in a CD4-independent HIV-1
      envelope protein.
AB  - We recently derived a CD4-independent virus from HIV-1/IIIB, termed IIIBx, which
      interacts directly with the chemokine receptor CXCR4 to infect cells. To address
      the underlying mechanism, a cloned Env from the IIIBx swarm (8x) was used to
      produce soluble gp120. 8x gp120 bound directly to cells expressing only CXCR4,
      whereas binding of IIIB gp120 required soluble CD4. Using an optical biosensor,
      we found that CD4-induced (CD4i) epitopes recognized by mAbs 17b and 48d were
      more exposed on 8x than on IIIB gp120. The ability of 8x gp120 to bind directly
      to CXCR4 and to react with mAbs 17b and 48d in the absence of CD4 indicated that
      this gp120 exists in a partially triggered but stable state in which the
      conserved coreceptor-binding site in gp120, which overlaps with the 17b epitope,
      is exposed. Substitution of the 8x V3 loop with that from the R5 virus strain BaL
      resulted in an Env (8x-V3BaL) that mediated CD4-independent CCR5-dependent virus
      infection and a gp120 that bound to CCR5 in the absence of CD4. Thus, in a
      partially triggered Env protein, the V3 loop can change the specificity of
      coreceptor use but does not alter CD4 independence, indicating that these
      properties are dissociable. Finally, IIIBx was more sensitive to neutralization
      by HIV-positive human sera, a variety of anti-IIIB gp120 rabbit sera, and CD4i
      mAbs than was IIIB. The sensitivity of this virus to neutralization and the
      stable exposure of a highly conserved region of gp120 suggest new strategies for
      the development of antibodies and small molecule inhibitors to this functionally
      important domain.

PMID- 10339593
TI  - Microtubule dysfunction by posttranslational nitrotyrosination of alpha-tubulin:
      a nitric oxide-dependent mechanism of cellular injury.
AB  - NO2Tyr (3-Nitrotyrosine) is a modified amino acid that is formed by nitric oxide
      derived species and has been implicated in the pathology of diverse human
      diseases. Nitration of active-site tyrosine residues is known to compromise
      protein structure and function. Although free NO2Tyr is produced in abundant
      concentrations under pathological conditions, its capacity to alter protein
      structure and function at the translational or posttranslational level is
      unknown. Here, we report that free NO2Tyr is transported into mammalian cells and
      selectively incorporated into the extreme carboxyl terminus of alpha-tubulin via
      a posttranslational mechanism catalyzed by the enzyme tubulin-tyrosine ligase. In
      contrast to the enzymatically regulated carboxyl-terminal
      tyrosination/detyrosination cycle of alpha-tubulin, incorporation of NO2Tyr shows
      apparent irreversibility. Nitrotyrosination of alpha-tubulin induces alterations
      in cell morphology, changes in microtubule organization, loss of epithelial
      barrier function, and intracellular redistribution of the motor protein
      cytoplasmic dynein. These observations imply that posttranslational
      nitrotyrosination of alpha-tubulin invokes conformational changes, either
      directly or via allosteric interactions, in the surface-exposed carboxyl terminus
      of alpha-tubulin that compromises the function of this critical domain in
      regulating microtubule organization and binding of motor- and microtubule
      associated proteins. Collectively, these observations illustrate a mechanism
      whereby free NO2Tyr can impact deleteriously on cell function under pathological
      conditions encompassing reactive nitrogen species production. The data also yield
      further insight into the role that the alpha-tubulin tyrosination/detyrosination
      cycle plays in microtubule function.

PMID- 10339594
TI  - Interaction between RGS7 and polycystin.
AB  - Regulators of G protein signaling (RGS) proteins accelerate the intrinsic GTPase
      activity of certain Galpha subunits and thereby modulate a number of G protein
      dependent signaling cascades. Currently, little is known about the regulation of
      RGS proteins themselves. We identified a short-lived RGS protein, RGS7, that is
      rapidly degraded through the proteasome pathway. The degradation of RGS7 is
      inhibited by interaction with a C-terminal domain of polycystin, the protein
      encoded by PKD1, a gene involved in autosomal-dominant polycystic kidney disease.
      Furthermore, membranous expression of C-terminal polycystin relocalized RGS7. Our
      results indicate that rapid degradation and interaction with integral membrane
      proteins are potential means of regulating RGS proteins.

PMID- 10339595
TI  - Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte
      accumulation by an adenosine-dependent mechanism that is independent of
      inhibition of prostaglandin synthesis and p105 of NFkappaB.
AB  - The antiinflammatory action of aspirin generally has been attributed to direct
      inhibition of cyclooxygenases (COX-1 and COX-2), but additional mechanisms are
      likely at work. These include aspirin's inhibition of NFkappaB translocation to
      the nucleus as well as the capacity of salicylates to uncouple oxidative
      phosphorylation (i.e., deplete ATP). At clinically relevant doses, salicylates
      cause cells to release micromolar concentrations of adenosine, which serves as an
      endogenous ligand for at least four different types of well-characterized
      receptors. Previously, we have shown that adenosine mediates the antiinflammatory
      effects of other potent and widely used antiinflammatory agents, methotrexate and
      sulfasalazine, both in vitro and in vivo. To determine in vivo whether clinically
      relevant levels of salicylate act via adenosine, via NFkappaB, or via the
      "inflammatory" cyclooxygenase COX-2, we studied acute inflammation in the generic
      murine air-pouch model by using wild-type mice and mice rendered deficient in
      either COX-2 or p105, the precursor of p50, one of the components of the
      multimeric transcription factor NFkappaB. Here, we show that the antiinflammatory
      effects of aspirin and sodium salicylate, but not glucocorticoids, are largely
      mediated by the antiinflammatory autacoid adenosine independently of inhibition
      of prostaglandin synthesis by COX-1 or COX-2 or of the presence of p105. Indeed,
      both inflammation and the antiinflammatory effects of aspirin and sodium
      salicylate were independent of the levels of prostaglandins at the inflammatory
      site. These experiments also provide in vivo confirmation that the
      antiinflammatory effects of glucocorticoids depend, in part, on the p105
      component of NFkappaB.

PMID- 10339596
TI  - p27 and Rb are on overlapping pathways suppressing tumorigenesis in mice.
AB  - The commitment of cells to replicate and divide correlates with the activation of
      cyclin-dependent kinases and the inactivation of Rb, the product of the
      retinoblastoma tumor suppressor gene. Rb is a target of the cyclin-dependent
      kinases and, when phosphorylated, is inactivated. Biochemical studies exploring
      the nature of the relationship between cyclin-dependent kinase inhibitors and Rb
      have supported the hypothesis that these proteins are on a linear pathway
      regulating commitment. We have been able to study this relationship by genetic
      means by examining the phenotype of Rb+/-p27-/- mice. Tumors arise from the
      intermediate lobe cells of the pituitary gland in p27-/- mice, as well as in Rb+/
      mice after loss of the remaining wild-type allele of Rb. Using these mouse
      models, we examined the genetic interaction between Rb and p27. We found that the
      development of pituitary tumors in Rb+/- mice correlated with a reduction in p27
      mRNA and protein expression. To determine whether the loss of p27 was an indirect
      consequence of tumor formation or a contributing factor to the development of
      this tumor, we analyzed the phenotype of Rb+/-p27-/- mice. We found that these
      mice developed pituitary adenocarcinoma with loss of the remaining wild-type
      allele of Rb and a high-grade thyroid C cell carcinoma that was more aggressive
      than the disease in either Rb+/- or p27-/- mice. Importantly, we detected both
      pituitary and thyroid tumors earlier in the Rb+/-p27-/- mice. We therefore
      propose that Rb and p27 cooperate to suppress tumor development by integrating
      different regulatory signals.

PMID- 10339597
TI  - Delayed symptom onset and increased life expectancy in Sandhoff disease mice
      treated with N-butyldeoxynojirimycin.
AB  - Sandhoff disease is a neurodegenerative disorder resulting from the autosomal
      recessive inheritance of mutations in the HEXB gene, which encodes the beta
      subunit of beta-hexosaminidase. GM2 ganglioside fails to be degraded and
      accumulates within lysosomes in cells of the periphery and the central nervous
      system (CNS). There are currently no therapies for the glycosphingolipid
      lysosomal storage diseases that involve CNS pathology, including the GM2
      gangliosidoses. One strategy for treating this and related diseases is substrate
      deprivation. This would utilize an inhibitor of glycosphingolipid biosynthesis to
      balance synthesis with the impaired rate of catabolism, thus preventing storage.
      One such inhibitor is N-butyldeoxynojirimycin, which currently is in clinical
      trials for the potential treatment of type 1 Gaucher disease, a related disease
      that involves glycosphingolipid storage in peripheral tissues, but not in the
      CNS. In this study, we have evaluated whether this drug also could be applied to
      the treatment of diseases with CNS storage and pathology. We therefore have
      treated a mouse model of Sandhoff disease with the inhibitor N
      butyldeoxynojirimycin. The treated mice have delayed symptom onset, reduced
      storage in the brain and peripheral tissues, and increased life expectancy.
      Substrate deprivation therefore offers a potentially general therapy for this
      family of lysosomal storage diseases, including those with CNS disease.

PMID- 10339598
TI  - Multiplex detection of four pathogenic retroviruses using molecular beacons.
AB  - We describe a multiplex nucleic acid assay that identifies and determines the
      abundance of four different pathogenic retroviruses (HIV-1, HIV-2, and human T
      lymphotrophic virus types I and II). Retroviral DNA sequences are amplified in a
      single, sealed tube by simultaneous PCR assays, and the resulting amplicons are
      detected in real time by the hybridization of four differently colored, amplicon
      specific molecular beacons. The color of the fluorescence generated in the course
      of amplification identifies which retroviruses are present, and the number of
      thermal cycles required for the intensity of each color to rise significantly
      above background provides an accurate measure of the number of copies of each
      retroviral sequence that were present originally in the sample. Fewer than 10
      retroviral genomes can be detected. Moreover, 10 copies of a rare retrovirus can
      be detected in the presence of 100, 000 copies of an abundant retrovirus. Ninety
      six samples can be analyzed in 3 hr on a single plate, and the use of a closed
      tube format eliminates crossover contamination. Utilizing previously well
      characterized clinical samples, we demonstrate that each of the pathogenic
      retroviruses can be identified correctly and no false positives occur. This assay
      enables the rapid and reliable screening of donated blood and transplantable
      tissues.

PMID- 10339599
TI  - Low- and high-level transgenic expression of beta2-adrenergic receptors
      differentially affect cardiac hypertrophy and function in Galphaq-overexpressing
      mice.
AB  - Transgenic overexpression of Galphaq in the heart triggers events leading to a
      phenotype of eccentric hypertrophy, depressed ventricular function, marked
      expression of hypertrophy-associated genes, and depressed beta-adrenergic
      receptor (betaAR) function. The role of betaAR dysfunction in the development of
      this failure phenotype was delineated by transgenic coexpression of the carboxyl
      terminus of the betaAR kinase (betaARK), which acts to inhibit the kinase, or
      concomitant overexpression of the beta2AR at low (approximately 30-fold,
      Galphaq/beta2ARL), moderate (approximately 140-fold, Galphaq/beta2ARM), and high
      (approximately 1,000-fold, Galphaq/beta2ARH) levels above background betaAR
      density. Expression of the betaARK inhibitor had no effect on the phenotype,
      consistent with the lack of increased betaARK levels in Galphaq mice. In marked
      contrast, Galphaq/beta2ARL mice displayed rescue of hypertrophy and resting
      ventricular function and decreased cardiac expression of atrial natriuretic
      factor and alpha-skeletal actin mRNA. These effects occurred in the absence of
      any improvement in basal or agonist-stimulated adenylyl cyclase (AC) activities
      in crude cardiac membranes, although restoration of a compartmentalized
      beta2AR/AC signal cannot be excluded. Higher expression of receptors in
      Galphaq/beta2ARM mice resulted in salvage of AC activity, but hypertrophy,
      ventricular function, and expression of fetal genes were unaffected or worsened.
      With approximately 1,000-fold overexpression, the majority of Galphaq/beta2ARH
      mice died with cardiomegaly at 5 weeks. Thus, although it appears that excessive,
      uncontrolled, or generalized augmentation of betaAR signaling is deleterious in
      heart failure, selective enhancement by overexpressing the beta2AR subtype to
      limited levels restores not only ventricular function but also reverses cardiac
      hypertrophy.

PMID- 10339600
TI  - Synthesis and in vivo murine evaluation of Na4[1-(1'-B10H9)-6-SHB10H8] as a
      potential agent for boron neutron capture therapy.
AB  - Reaction of the normal isomer of [B20H18]2- and the protected thiol anion,
      [SC(O)OC(CH3)3]-, produces an unexpected isomer of [B20H17SC(O)OC(CH3)3]4-
      directly and in good yield. The isomer produced under mild conditions is
      characterized by an apical-apical boron atom intercage connection as well as the
      location of the thiol substituent on an equatorial belt adjacent to the terminal
      boron apex. Although the formation of this isomer from nucleophilic attack of the
      normal isomer of [B20H18]2- has not been reported previously, the isomeric
      assignment has been unambiguously confirmed by one-dimensional and two
      dimensional 11B NMR spectroscopy. Deprotection of the thiol substituent under
      acidic conditions produces a protonated intermediate, [B20H18SH]3-, which can be
      deprotonated with a suitable base to yield the desired product, [B20H17SH]4-. The
      sodium salt of the resulting [B20H17SH]4- ion has been encapsulated in small,
      unilamellar liposomes, which are capable of delivering their contents selectively
      to tumors in vivo, and investigated as a potential agent for boron neutron
      capture therapy. The biodistribution of boron was determined after intravenous
      injection of the liposomal suspension into BALB/c mice bearing EMT6 mammary
      adenocarcinoma. At low injected doses, the tumor boron concentration increased
      throughout the time-course experiment, resulting in a maximum observed boron
      concentration of 46.7 micrograms of B per g of tumor at 48 h and a tumor to blood
      boron ratio of 7.7. The boron concentration obtained in the tumor corresponds to
      22.2% injected dose (i.d.) per g of tissue, a value analogous to the most
      promising polyhedral borane anions investigated for liposomal delivery and
      subsequent application in boron neutron capture therapy.

PMID- 10339601
TI  - Pressure-mediated oligonucleotide transfection of rat and human cardiovascular
      tissues.
AB  - The application of gene therapy to human disease is currently restricted by the
      relatively low efficiency and potential hazards of methods of oligonucleotide or
      gene delivery. Antisense or transcription factor decoy oligonucleotides have been
      shown to be effective at altering gene expression in cell culture expreriments,
      but their in vivo application is limited by the efficiency of cellular delivery,
      the intracellular stability of the compounds, and their duration of activity. We
      report herein the development of a highly efficient method for naked
      oligodeoxynucleotide (ODN) transfection into cardiovascular tissues by using
      controlled, nondistending pressure without the use of viral vectors, lipid
      formulations, or exposure to other adjunctive, potentially hazardous substances.
      In this study, we have documented the ability of ex vivo, pressure-mediated
      transfection to achieve nuclear localization of fluorescent (FITC)-labeled ODN in
      approximately 90% and 50% of cells in intact human saphenous vein and rat
      myocardium, respectively. We have further documented that pressure-mediated
      delivery of antisense ODN can functionally inhibit target gene expression in both
      of these tissues in a sequence-specific manner at the mRNA and protein levels.
      This oligonucleotide transfection system may represent a safe means of achieving
      the intraoperative genetic engineering of failure-resistant human bypass grafts
      and may provide an avenue for the genetic manipultation of cardiac allograft
      rejection, allograft vasculopathy, or other transplant diseases.

PMID- 10339602
TI  - Efficient and regulated erythropoietin production by naked DNA injection and
      muscle electroporation.
AB  - We show that an electric treatment in the form of high-frequency, low-voltage
      electric pulses can increase more than 100-fold the production and secretion of a
      recombinant protein from mouse skeletal muscle. Therapeutical erythopoietin (EPO)
      levels were achieved in mice with a single injection of as little as 1 microgram
      of plasmid DNA, and the increase in hematocrit after EPO production was stable
      and long-lasting. Pharmacological regulation through a tetracycline-inducible
      promoter allowed regulation of serum EPO and hematocrit levels. Tissue damage
      after stimulation was transient. The method described thus provides a potentially
      safe and low-cost treatment for serum protein deficiencies.

PMID- 10339603
TI  - Aging accentuates and bone marrow transplantation ameliorates metabolic defects
      in Fabry disease mice.
AB  - Fabry disease is an X-linked metabolic disorder caused by a deficiency of alpha
      galactosidase A (alpha-Gal A). The enzyme defect leads to the systemic
      accumulation of glycosphingolipids with alpha-galactosyl moieties consisting
      predominantly of globotriaosylceramide (Gb3). In patients with this disorder,
      glycolipid deposition in endothelial cells leads to renal failure and cardiac and
      cerebrovascular disease. Recently, we generated alpha-Gal A gene knockout mouse
      lines and described the phenotype of 10-week-old mice. In the present study, we
      characterize the progression of the disease with aging and explore the effects of
      bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of
      alpha-Gal A -/0 mice revealed subclinical lesions in the Kupffer cells in the
      liver and macrophages in the skin with no gross lesions in the endothelial cells.
      Gb3 accumulation and pathological lesions in the affected organs increased with
      age. Treatment with BMT from the wild-type mice resulted in the clearance of
      accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of
      alpha-Gal A activity. These findings suggest that BMT may have a potential role
      in the management of patients with Fabry disease.

PMID- 10339604
TI  - MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related
      acute myeloid leukemia with a t(11;17)(q23;q25).
AB  - MLL (ALL1, Htrx, HRX), which is located on chromosome band 11q23, frequently is
      rearranged in patients with therapy-related acute myeloid leukemia who previously
      were treated with DNA topoisomerase II inhibitors. In this study, we have
      identified a fusion partner of MLL in a 10-year-old female who developed therapy
      related acute myeloid leukemia 17 months after treatment for Hodgkin's disease.
      Leukemia cells of this patient had a t(11;17)(q23;q25), which involved MLL as
      demonstrated by Southern blot analysis. The partner gene was cloned from cDNA of
      the leukemia cells by use of a combination of adapter reverse transcriptase-PCR,
      rapid amplification of 5' cDNA ends, and BLAST database analysis to identify
      expressed sequence tags. The full-length cDNA of 2.8 kb was found to be an
      additional member of the septin family, therefore it was named MSF (MLL septin
      like fusion). Members of the septin family conserve the GTP binding domain,
      localize in the cytoplasm, and interact with cytoskeletal filaments. A major 4-kb
      transcript of MSF was expressed ubiquitously; a 1.7-kb transcript was found in
      most tissues. An additional 3-kb transcript was found only in hematopoietic
      tissues. By amplification with MLL exon 5 forward primer and reverse primers in
      MSF, the appropriately sized products were obtained. MSF is highly homologous to
      hCDCrel-1, which is a partner gene of MLL in leukemias with a
      t(11;22)(q23;q11.2). Further analysis of MSF may help to delineate the function
      of MLL partner genes in leukemia, particularly in therapy-related leukemia.

PMID- 10339605
TI  - Induction of the Tat-binding protein 1 gene accompanies the disabling of
      oncogenic erbB receptor tyrosine kinases.
AB  - Conversion of a malignant phenotype into a more normal one can be accomplished
      either by down-regulation of erbB family surface receptors or by creating
      inactive erbB heterodimers on the cell surface. In this report, we report the
      identification and cloning of differentially expressed genes from antibody
      treated vs. untreated fibroblasts transformed by oncogenic p185(neu). We
      repeatedly isolated a 325-bp cDNA fragment that, as determined by Northern
      analysis, was expressed at higher levels in anti-p185(neu)-treated tumor cells
      but not in cells expressing internalization defective p185(neu) receptors. This
      cDNA fragment was identical in amino acid sequence to the recently cloned mouse
      Tat binding protein-1 (mTBP1), which has 98.4% homology to the HIV tat-binding
      protein-1 (TBP1). TBP1 mRNA levels were found to be elevated on inhibition of the
      oncogenic phenotype of transformed cells expressing erbB family receptors. TBP1
      overexpression diminished cell proliferation, reduced the ability of the parental
      cells to form colonies in vitro, and almost completely inhibited transforming
      efficiency in athymic mice when stably expressed in human tumor cells containing
      erbB family receptors. Collectively, these results suggest that the attenuation
      of erbB receptor signaling seems to be associated with activation/induction or
      recovery of a functional tumor suppressor-like gene, TBP1. Disabling erbB
      tyrosine kinases by antibodies or by trans-inhibition represents an initial step
      in triggering a TBP1 pathway.

PMID- 10339606
TI  - Regulation of RpoS proteolysis in Escherichia coli: the response regulator RssB
      is a recognition factor that interacts with the turnover element in RpoS.
AB  - The degradation of the RpoS (sigmaS) subunit of RNA polymerase in Escherichia
      coli is a prime example of regulated proteolysis in prokaryotes. RpoS turnover
      depends on ClpXP protease, the response regulator RssB, and a hitherto
      uncharacterized "turnover element" within RpoS itself. Here we localize the
      turnover element to a small element (around the crucial amino acid lysine-173)
      directly downstream of the promoter-recognizing region 2.4 in RpoS. Its sequence
      as well as its location identify the turnover element as a unique proteolysis
      promoting motif. This element is shown to be a site of interaction with RssB.
      Thus, RssB is functionally unique among response regulators as a direct
      recognition factor in ClpXP-dependent RpoS proteolysis. Binding of RssB to RpoS
      is stimulated by phosphorylation of the RssB receiver domain, suggesting that
      environmental stress affects RpoS proteolysis by modulating RssB affinity for
      RpoS. Initial evidence indicates that lysine-173 in RpoS, besides being essential
      of RpoS proteolysis, may play a role in promoter recognition. Thus the same
      region in RpoS is crucial for proteolysis as well as for activity as a
      transcription factor.

PMID- 10339607
TI  - Plasmodium falciparum subtilisin-like protease 2, a merozoite candidate for the
      merozoite surface protein 1-42 maturase.
AB  - The process of human erythrocyte invasion by Plasmodium falciparum parasites
      involves a calcium-dependent serine protease with properties consistent with a
      subtilisin-like activity. This enzyme achieves the last crucial maturation step
      of merozoite surface protein 1 (MSP1) necessary for parasite entry into the host
      erythrocyte. In eukaryotic cells, such processing steps are performed by
      subtilisin-like maturases, known as proprotein convertases. In an attempt to
      characterize the MSP1 maturase, we have identified a gene that encodes a P.
      falciparum subtilisin-like protease (PfSUB2) whose deduced active site sequence
      resembles more bacterial subtilisins. Therefore, we propose that PfSUB2 belongs
      to a subclass of eukaryotic subtilisins different from proprotein convertases.
      Pfsub2 is expressed during merozoite differentiation and encodes an integral
      membrane protein localized in the merozoite dense granules, a secretory organelle
      whose contents are believed to participate in a late step of the erythrocyte
      invasion. PfSUB2's subcellular localization, together with its predicted
      enzymatic properties, leads us to propose that PfSUB2 could be responsible for
      the late MSP1 maturation step and thus is an attractive target for the
      development of new antimalarial drugs.

PMID- 10339608
TI  - Toward functional genomics in bacteria: analysis of gene expression in
      Escherichia coli from a bacterial artificial chromosome library of Bacillus
      cereus.
AB  - As the study of microbes moves into the era of functional genomics, there is an
      increasing need for molecular tools for analysis of a wide diversity of
      microorganisms. Currently, biological study of many prokaryotes of agricultural,
      medical, and fundamental scientific interest is limited by the lack of adequate
      genetic tools. We report the application of the bacterial artificial chromosome
      (BAC) vector to prokaryotic biology as a powerful approach to address this need.
      We constructed a BAC library in Escherichia coli from genomic DNA of the Gram
      positive bacterium Bacillus cereus. This library provides 5.75-fold coverage of
      the B. cereus genome, with an average insert size of 98 kb. To determine the
      extent of heterologous expression of B. cereus genes in the library, we screened
      it for expression of several B. cereus activities in the E. coli host. Clones
      expressing 6 of 10 activities tested were identified in the library, namely,
      ampicillin resistance, zwittermicin A resistance, esculin hydrolysis, hemolysis,
      orange pigment production, and lecithinase activity. We analyzed selected BAC
      clones genetically to identify rapidly specific B. cereus loci. These results
      suggest that BAC libraries will provide a powerful approach for studying gene
      expression from diverse prokaryotes.

PMID- 10339609
TI  - A new pathway for the secretion of virulence factors by bacteria: the flagellar
      export apparatus functions as a protein-secretion system.
AB  - Biogenesis of the flagellum, a motive organelle of many bacterial species, is
      best understood for members of the Enterobacteriaceae. The flagellum is a
      heterooligomeric structure that protrudes from the surface of the cell. Its
      assembly initially involves the synthesis of a dedicated protein export apparatus
      that subsequently transports other flagellar proteins by a type III mechanism
      from the cytoplasm to the outer surface of the cell, where oligomerization
      occurs. In this study, the flagellum export apparatus was shown to function also
      as a secretion system for the transport of several extracellular proteins in the
      pathogenic bacterium Yersinia enterocolitica. One of the proteins exported by the
      flagellar secretion system was the virulence-associated phospholipase, YplA.
      These results suggest type III protein secretion by the flagellar system may be a
      general mechanism for the transport of proteins that influence bacterial-host
      interactions.

PMID- 10339610
TI  - Heme transfer to the heme chaperone CcmE during cytochrome c maturation requires
      the CcmC protein, which may function independently of the ABC-transporter CcmAB.
AB  - Cytochrome c maturation in Escherichia coli requires the ccm operon, which
      encodes eight membrane proteins (CcmABCDEFGH). CcmE is a periplasmic heme
      chaperone that binds heme covalently and transfers it onto apocytochrome c in the
      presence of CcmF, CcmG, and CcmH. In this work we addressed the functions of the
      ccmABCD gene products with respect to holo-CcmE formation and the subsequent
      ligation of heme to apocytochrome c. In the absence of the ccmABCD genes, heme is
      not bound to CcmE. We report that CcmC is functionally uncoupled from the ABC
      transporter subunits CcmA and CcmB, because it is the only Ccm protein that is
      strictly required for heme transfer and attachment to CcmE. Site-directed
      mutagenesis of conserved histidines inactivates the CcmC protein, which is in
      agreement with the hypothesis that this protein interacts directly with heme. We
      also present evidence that questions the role of CcmAB as a heme exporter; yet,
      the transported substrate remains unknown. CcmD was found to be involved in
      stabilizing the heme chaperone CcmE in the membrane. We propose a heme
      trafficking pathway as part of a substantially revised model for cytochrome c
      maturation in E. coli.

PMID- 10339611
TI  - Agrin in Alzheimer's disease: altered solubility and abnormal distribution within
      microvasculature and brain parenchyma.
AB  - Agrin is a heparan sulfate proteoglycan that is widely expressed in neurons and
      microvascular basal lamina in the rodent and avian central nervous system. Agrin
      induces the differentiation of nerve-muscle synapses, but its function in either
      normal or diseased brains is not known. Alzheimer's disease (AD) is characterized
      by loss of synapses, changes in microvascular architecture, and formation of
      neurofibrillary tangles and senile plaques. Here we have asked whether AD causes
      changes in the distribution and biochemical properties of agrin. Immunostaining
      of normal, aged human central nervous system revealed that agrin is expressed in
      neurons in multiple brain areas. Robust agrin immunoreactivity was observed
      uniformly in the microvascular basal lamina. In AD brains, agrin is highly
      concentrated in both diffuse and neuritic plaques as well as neurofibrillary
      tangles; neuronal expression of agrin also was observed. Furthermore, patients
      with AD had microvascular alterations characterized by thinning and fragmentation
      of the basal lamina. Detergent extraction and Western blotting showed that
      virtually all the agrin in normal brain is soluble in 1% SDS. In contrast, a
      large fraction of the agrin in AD brains is insoluble under these conditions,
      suggesting that it is tightly associated with beta-amyloid. Together, these data
      indicate that the agrin abnormalities observed in AD are closely linked to beta
      amyloid deposition. These observations suggest that altered agrin expression in
      the microvasculature and the brain parenchyma contribute to the pathogenesis of
      AD.

PMID- 10339612
TI  - Cholecystokinin-8 protects central cholinergic neurons against fimbria-fornix
      lesion through the up-regulation of nerve growth factor synthesis.
AB  - In this study, we demonstrate that cholecystokinin-8 (CCK-8) induces an increase
      in both nerve growth factor (NGF) protein and NGF mRNA in mouse cortex and
      hippocampus when i.p. injected at physiological doses. By using fimbria-fornix
      lesioned mice, we have also demonstrated that repeated CCK-8 i.p. injections
      result in recovery of lesion-induced NGF deficit in septum and restore the
      baseline NGF levels in hippocampus and cortex. Parallel to the effects on NGF,
      CCK-8 increases choline acetyltransferase (Chat) activity in forebrain when
      injected in unlesioned mice and counteract the septo-hippocampal Chat alterations
      in fimbria-fornix-lesioned mice. To assess the NGF involvement in the mechanism
      by which CCK-8 induces brain Chat, NGF antibody was administrated intracerebrally
      to saline- and CCK-8-injected mice. We observe that pretreatment with NGF
      antibody causes a marked reduction of NGF and Chat activity in septum and
      hippocampus of both saline- and CCK-8-injected mice. This evidence indicates that
      the CCK-8 effects on cholinergic cells are mediated through the synthesis and
      release of NGF. Taken together, our results suggest that peripheral
      administration of CCK-8 may represent a potential experimental model for
      investigating the effects of endogenous NGF up-regulation on diseases associated
      with altered brain cholinergic functions.

PMID- 10339613
TI  - Reversible inactivation of the nucleus basalis magnocellularis induces disruption
      of cortical acetylcholine release and acquisition, but not retrieval, of aversive
      memories.
AB  - The basal forebrain complex, which includes the nucleus basalis magnocellularis
      (NBM), provides widespread cholinergic and gamma-aminobutyric acid-containing
      projections throughout the brain, including the insular and pyriform cortices. A
      number of studies have implicated the cholinergic neurons in the mediation of
      learning and memory processes. However, the role of basal forebrain activity in
      information retrieval mechanisms is less known. The aim of the present study is
      to evaluate the effects of reversible inactivation of the NBM by tetrodotoxin
      (TTX, a voltage-sensitive sodium channel blocker) during the acquisition and
      retrieval of conditioned taste aversion (CTA) and to measure acetylcholine (ACh)
      release during TTX inactivation in the insular cortex, by means of the
      microdialysis technique in free-moving rats. Bilateral infusion of TTX in the NBM
      was performed 30 min before the presentation of gustative stimuli, in either the
      CTA acquisition trial or retrieval trial. At the same time, levels of
      extracellular ACh release were measured in the insular cortex. The behavioral
      results showed significant impairment in CTA acquisition when the TTX was infused
      in the NBM, whereas retrieval was not affected when the treatment was given
      during the test trial. Biochemical results showed that TTX infusion into the NBM
      produced a marked decrease in cortical ACh release as compared with the controls
      during consumption of saccharin in the acquisition trial. Depleted ACh levels
      were found during the test trial in all groups except in the group that received
      TTX during acquisition. These results suggest a cholinergic-dependent process
      during acquisition, but not during memory retrieval, and that NBM-mediated
      cholinergic cortical release may play an important role in early stages of
      learning, but not during recall of aversive memories.

PMID- 10339614
TI  - Cortical auditory signal processing in poor readers.
AB  - Magnetoencephalographic responses recorded from auditory cortex evoked by brief
      and rapidly successive stimuli differed between adults with poor vs. good reading
      abilities in four important ways. First, the response amplitude evoked by short
      duration acoustic stimuli was stronger in the post-stimulus time range of 150-200
      ms in poor readers than in normal readers. Second, response amplitude to rapidly
      successive and brief stimuli that were identical or that differed significantly
      in frequency were substantially weaker in poor readers compared with controls,
      for interstimulus intervals of 100 or 200 ms, but not for an interstimulus
      interval of 500 ms. Third, this neurological deficit closely paralleled subjects'
      ability to distinguish between and to reconstruct the order of presentation of
      those stimulus sequences. Fourth, the average distributed response coherence
      evoked by rapidly successive stimuli was significantly weaker in the beta- and
      gamma-band frequency ranges (20-60 Hz) in poor readers, compared with controls.
      These results provide direct electrophysiological evidence supporting the
      hypothesis that reading disabilities are correlated with the abnormal neural
      representation of brief and rapidly successive sensory inputs, manifested in this
      study at the entry level of the cortical auditory/aural speech representational
      system(s).

PMID- 10339615
TI  - Fidelity of G protein beta-subunit association by the G protein gamma-subunit
      like domains of RGS6, RGS7, and RGS11.
AB  - Several regulators of G protein signaling (RGS) proteins contain a G protein
      gamma-subunit-like (GGL) domain, which, as we have shown, binds to Gbeta5
      subunits. Here, we extend our original findings by describing another GGL-domain
      containing RGS, human RGS6. When RGS6 is coexpressed with different Gbeta
      subunits, only RGS6 and Gbeta5 interact. The expression of mRNA for RGS6 and
      Gbeta5 in human tissues overlaps. Predictions of alpha-helical and coiled-coil
      character within GGL domains, coupled with measurements of Gbeta binding by GGL
      domain mutants, support the contention that Ggamma-like regions within RGS
      proteins interact with Gbeta5 subunits in a fashion comparable to conventional
      Gbeta/Ggamma pairings. Mutation of the highly conserved Phe-61 residue of Ggamma2
      to tryptophan, the residue present in all GGL domains, increases the stability of
      the Gbeta5/Ggamma2 heterodimer, highlighting the importance of this residue to
      GGL/Gbeta5 association.

PMID- 10339616
TI  - Formation of heteromeric gap junction channels by connexins 40 and 43 in vascular
      smooth muscle cells.
AB  - Connexin (Cx) 43 and Cx40 are coexpressed in several tissues, including cardiac
      atrial and ventricular myocytes and vascular smooth muscle. It has been shown
      that these Cxs form homomeric/homotypic channels with distinct permeability and
      gating properties but do not form functional homomeric/heterotypic channels. If
      these Cxs were to form heteromeric channels, they could display functional
      properties not well predicted by the homomeric forms. We assessed this
      possibility by using A7r5 cells, an embryonic rat aortic smooth muscle cell line
      that coexpresses Cxs 43 and 40. Connexons (hemichannels), which were isolated
      from these cells by density centrifugation and immunoprecipitated with antibody
      against Cx43, contained Cx40. Similarly, antibody against Cx40
      coimmunoprecipitated Cx43 from the same connexon fraction but only Cx40 from Cx
      (monomer) fractions. These results indicate that heteromeric connexons are formed
      by these Cxs in the A7r5 cells. The gap junction channels formed in the A7r5
      cells display many unitary conductances distinct from homomeric/homotypic Cx43 or
      Cx40 channels. Voltage-dependent gating parameters in the A7r5 cells are also
      quite variable compared with cells that express only Cx40 or Cx43. These data
      indicate that Cxs 43 and 40 form functional heteromeric channels with unique
      gating and conductance properties.

PMID- 10339617
TI  - Heterothermal acclimation: an experimental paradigm for studying the control of
      thermal acclimation in crabs.
AB  - A method for the study of the control of the attainment of thermal acclimation
      has been applied to the crabs, Cancer pagurus and Carcinus maenas. Crabs were
      heterothermally acclimated by using an anterior-posterior partition between two
      compartments, one at 8 degrees C and the other at 22 degrees C. One compartment
      held a three-quarter section of the crab including the central nervous system
      (CNS), eye stalks, and ipsilateral legs; the other held a quarter section
      including the contralateral legs. Criteria used to assess the acclimation
      responses were comparisons of muscle plasma membrane fatty acid composition and
      "fluidity." In both species, the major fatty acids of phosphatidylcholine were
      16:0, 18:1, 20:5, and 22:6, whereas phosphatidylethanolamine contained
      significantly less 16:0 but more 18:0; these fatty acids comprised 80% of the
      total. Differences in fatty acid composition were demonstrated between fractions
      obtained from the ipsilateral and contralateral legs from the same
      heterothermally acclimated individual. In all acclimation states (except 22CNS,
      phosphatidylcholine fraction), membrane lipid saturation was significantly
      increased with acclimation at 22 degrees as compared with 8 degrees C. Membrane
      fluidity was determined by using 1,3-diphenyl-1,3,5 hexatriene (DPH) fluorescence
      polarization. In both species, membranes from legs held at 8 degrees were more
      fluid than from legs held at 22 degrees C irrespective of the acclimation
      temperature of the CNS. Heterothermal acclimation demonstrated that leg muscle
      membrane composition and fluidity respond primarily to local temperature and were
      not predominately under central direction. The responses between 8 degrees C- and
      22 degrees C-acclimated legs were more pronounced when the CNS was cold
      acclimated, so a central influence cannot be excluded.

PMID- 10339618
TI  - Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking
      the subtype-2 (AT2) angiotensin receptor.
AB  - The vast majority of the known biological effects of the renin-angiotensin system
      are mediated by the type-1 (AT1) receptor, and the functions of the type-2 (AT2)
      receptor are largely unknown. We investigated the role of the AT2 receptor in the
      vascular and renal responses to physiological increases in angiotensin II (ANG
      II) in mice with targeted deletion of the AT2 receptor gene. Mice lacking the AT2
      receptor (AT2-null mice) had slightly elevated systolic blood pressure (SBP)
      compared with that of wild-type (WT) control mice (P < 0.0001). In AT2-null mice,
      infusion of ANG II (4 pmol/kg/min) for 7 days produced a marked and sustained
      increase in SBP [from 116 +/- 0.5 to 208 +/- 1 mmHg (P < 0.0001) (1 mmHg = 133
      Pa)] and reduction in urinary sodium excretion (UNaV) [from 0.6 +/- 0.01 to 0.05
      +/- 0.002 mM/day (P < 0.0001)] whereas neither SBP nor UNaV changed in WT mice.
      AT2-null mice had low basal levels of renal interstitial fluid bradykinin (BK),
      and cyclic guanosine 3', 5'-monophosphate, an index of nitric oxide production,
      compared with WT mice. In WT mice, dietary sodium restriction or ANG II infusion
      increased renal interstitial fluid BK, and cyclic guanosine 3', 5'-monophosphate
      by approximately 4-fold (P < 0.0001) whereas no changes were observed in AT2-null
      mice. These results demonstrate that the AT2 receptor is necessary for normal
      physiological responses of BK and nitric oxide to ANG II. Absence of the AT2
      receptor leads to vascular and renal hypersensitivity to ANG II, including
      sustained antinatriuresis and hypertension. These results strongly suggest that
      the AT2 receptor plays a counterregulatory protective role mediated via BK and
      nitric oxide against the antinatriuretic and pressor actions of ANG II.

PMID- 10339619
TI  - Stretch-activated single K+ channels account for whole-cell currents elicited by
      swelling.
AB  - Functionally significant stretch-activated ion channels have been clearly
      identified in excitable cells. Although single-channel studies suggest their
      expression in other cell types, their activity in the whole-cell configuration
      has not been shown. This discrepancy makes their physiological significance
      doubtful and suggests that their mechanical activation is artifactual. Possible
      roles for these molecules in nonexcitable cells are acute cell-volume regulation
      and, in epithelial cells, the complex adjustment of ion fluxes across individual
      cell membranes when the rate of transepithelial transport changes. We report the
      results of experiments on isolated epithelial cells expressing in the basolateral
      membrane stretch-activated K+ channels demonstrable by the cell-attached patch
      clamp technique. In these cells, reversible whole-cell currents were elicited by
      both isosmotic and hyposmotic cell swelling. Cation selectivity and block by
      inorganic agents were the same for single-channel and whole-cell currents,
      indicating that the same entity underlies single-channel and whole-cell currents
      and that the single-channel events are not artifactual. In these cells, when the
      rate of apical-membrane NaCl entry increases, the cell Na+ content and volume
      also increase, stimulating the Na+,K+-ATPase at the basolateral membrane, i.e.,
      both Na+ extrusion and K+ uptake increase. We speculate that, under these
      conditions, the parallel activation of basolateral K+ channels (by the swelling)
      elevates conductive K+ loss, tending to maintain the cell K+ content constant
      ("pump-leak parallelism"). This study describes a physiologically relevant
      stretch-activated channel, at both the single-channel and whole-cell levels, in a
      nonneural cell type.

PMID- 10339620
TI  - Factors affecting counteraction by methylamines of urea effects on aldose
      reductase.
AB  - The concentration of urea in renal medullary cells is high enough to affect
      enzymes seriously by reducing Vmax or raising Km, yet the cells survive and
      function. The usual explanation is that the methylamines found in the renal
      medulla, namely glycerophosphocholine and betaine, have actions opposite to those
      of urea and thus counteract its effects. However, urea and methylamines have the
      similar (not counteracting) effects of reducing both the Km and Vmax of aldose
      reductase (EC 1.1.1.21), an enzyme whose function is important in renal medullas.
      Therefore, we examined factors that might determine whether counteraction occurs,
      namely different combinations of assay conditions (pH and salt concentration),
      methylamines (glycerophosphocholine, betaine, and trimethylamine N-oxide),
      substrates (DL-glyceraldehyde and D-xylose), and a mutation in recombinant aldose
      reductase protein (C298A). We find that Vmax of both wild-type and C298A mutant
      generally is reduced by urea and/or the methylamines. However, the effects on Km
      are much more complex, varying widely with the combination of conditions. At one
      extreme, we find a reduction of Km of wild-type enzyme by urea and/or
      methylamines that is partially additive, whereas at the other extreme we find
      that urea raises Km for D-xylose of the C298A mutant, betaine lowers the Km, and
      the two counteract in a classical fashion so that at a 2:1 molar ratio of betaine
      to urea there is no net effect. We conclude that counteraction of urea effects on
      enzymes by methylamines can depend on ion concentration, pH, the specific
      methylamine and substrate, and identity of even a single amino acid in the
      enzyme.

PMID- 10339621
TI  - Interaction of NPR1 with basic leucine zipper protein transcription factors that
      bind sequences required for salicylic acid induction of the PR-1 gene.
AB  - The Arabidopsis thaliana NPR1 has been shown to be a key regulator of gene
      expression during the onset of a plant disease-resistance response known as
      systemic acquired resistance. The npr1 mutant plants fail to respond to systemic
      acquired resistance-inducing signals such as salicylic acid (SA), or express SA
      induced pathogenesis-related (PR) genes. Using NPR1 as bait in a yeast two-hybrid
      screen, we identified a subclass of transcription factors in the basic leucine
      zipper protein family (AHBP-1b and TGA6) and showed that they interact
      specifically in yeast and in vitro with NPR1. Point mutations that abolish the
      NPR1 function in A. thaliana also impair the interactions between NPR1 and the
      transcription factors in the yeast two-hybrid assay. Furthermore, a gel mobility
      shift assay showed that the purified transcription factor protein, AHBP-1b, binds
      specifically to an SA-responsive promoter element of the A. thaliana PR-1 gene.
      These data suggest that NPR1 may regulate PR-1 gene expression by interacting
      with a subclass of basic leucine zipper protein transcription factors.

PMID- 10339622
TI  - Dual pathways for regulation of root branching by nitrate.
AB  - Root development is extremely sensitive to variations in nutrient supply, but the
      mechanisms are poorly understood. We have investigated the processes by which
      nitrate (NO3-), depending on its availability and distribution, can have both
      positive and negative effects on the development and growth of lateral roots.
      When Arabidopsis roots were exposed to a locally concentrated supply of NO3-
      there was no increase in lateral root numbers within the NO3--rich zone, but
      there was a localized 2-fold increase in the mean rate of lateral root
      elongation, which was attributable to a corresponding increase in the rate of
      cell production in the lateral root meristem. Localized applications of other N
      sources did not stimulate lateral root elongation, consistent with previous
      evidence that the NO3- ion is acting as a signal rather than a nutrient. The axr4
      auxin-resistant mutant was insensitive to the stimulatory effect of NO3-,
      suggesting an overlap between the NO3- and auxin response pathways. High rates of
      NO3- supply to the roots had a systemic inhibitory effect on lateral root
      development that acted specifically at the stage when the laterals had just
      emerged from the primary root, apparently delaying final activation of the
      lateral root meristem. A nitrate reductase-deficient mutant showed increased
      sensitivity to this systemic inhibitory effect, suggesting that tissue NO3-
      levels may play a role in generating the inhibitory signal. We present a model in
      which root branching is modulated by opposing signals from the plant's internal N
      status and the external supply of NO3-.

PMID- 10339623
TI  - Complementation of plant mutants with large genomic DNA fragments by a
      transformation-competent artificial chromosome vector accelerates positional
      cloning.
AB  - To accelerate gene isolation from plants by positional cloning, vector systems
      suitable for both chromosome walking and genetic complementation are highly
      desirable. Therefore, we developed a transformation-competent artificial
      chromosome (TAC) vector, pYLTAC7, that can accept and maintain large genomic DNA
      fragments stably in both Escherichia coli and Agrobacterium tumefaciens.
      Furthermore, it has the cis sequences required for Agrobacterium-mediated gene
      transfer into plants. We cloned large genomic DNA fragments of Arabidopsis
      thaliana into the vector and showed that most of the DNA fragments were
      maintained stably. Several TAC clones carrying 40- to 80-kb genomic DNA fragments
      were transferred back into Arabidopsis with high efficiency and shown to be
      inherited faithfully among the progeny. Furthermore, we demonstrated the
      practical utility of this vector system for positional cloning in Arabidopsis. A
      TAC contig was constructed in the region of the SGR1 locus, and individual clones
      with ca. 80-kb inserts were tested for their ability to complement the
      gravitropic defects of a homozygous mutant line. Successful complementation
      enabled the physical location of SGR1 to be delimited with high precision and
      confidence.

PMID- 10339624
TI  - The Arabidopsis thaliana HY1 locus, required for phytochrome-chromophore
      biosynthesis, encodes a protein related to heme oxygenases.
AB  - The hy1 mutants of Arabidopsis thaliana fail to make the phytochrome-chromophore
      phytochromobilin and therefore are deficient in a wide range of phytochrome
      mediated responses. Because this defect can be rescued by feeding seedlings
      biliverdin IXalpha, it is likely that the mutations affect an enzyme that
      converts heme to this phytochromobilin intermediate. By a combination of
      positional cloning and candidate-gene isolation, we have identified the HY1 gene
      and found it to be related to cyanobacterial, algal, and animal heme oxygenases.
      Three independent alleles of hy1 contain DNA lesions within the HY1 coding
      region, and a genomic sequence spanning the HY1 locus complements the hy1-1
      mutation. HY1 is a member of a gene family and is expressed in a variety of A.
      thaliana tissues. Based on its homology, we propose that HY1 encodes a higher
      plant heme oxygenase, designated AtHO1, responsible for catalyzing the reaction
      that opens the tetrapyrrole ring of heme to generate biliverdin IXalpha.

PMID- 10339625
TI  - GTP bound to chloroplast thylakoid membranes is required for light-induced,
      multienzyme degradation of the photosystem II D1 protein.
AB  - Even though light is the driving force in photosynthesis, it also can be harmful
      to plants. The water-splitting photosystem II is the main target for this light
      stress, leading to inactivation of photosynthetic electron transport and
      photooxidative damage to its reaction center. The plant survives through an
      intricate repair mechanism involving proteolytic degradation and replacement of
      the photodamaged reaction center D1 protein. Based on experiments with isolated
      chloroplast thylakoid membranes and photosystem II core complexes, we report
      several aspects concerning the rapid turnover of the D1 protein. (i) The primary
      cleavage step is a GTP-dependent process, leading to accumulation of a 23-kDa N
      terminal fragment. (ii) Proteolysis of the D1 protein is inhibited below basal
      levels by nonhydrolyzable GTP analogues and apyrase treatment, indicating the
      existence of endogenous GTP tightly bound to the thylakoid membrane. This
      possibility was corroborated by binding studies. (iii) The proteolysis of the 23
      kDa primary degradation fragment (but not of the D1 protein) is an ATP- and zinc
      dependent process. (iv) D1 protein degradation is a multienzyme event involving a
      strategic (primary) protease and a cleaning-up (secondary) protease. (v) The
      chloroplast FtsH protease is likely to be involved in the secondary degradation
      steps. Apart from its significance for understanding the repair of
      photoinhibition, the discovery of tightly bound GTP should have general
      implications for other regulatory reactions and signal transduction pathways
      associated with the photosynthetic membrane.

PMID- 10339626
TI  - Hydrogen peroxide is generated systemically in plant leaves by wounding and
      systemin via the octadecanoid pathway.
AB  - Hydrogen peroxide (H2O2) generated in response to wounding can be detected at
      wound sites and in distal leaf veins within 1 hr after wounding. The response is
      systemic and maximizes at about 4-6 hr in both wounded and unwounded leaves, and
      then declines. The timing of the response corresponds with an increase in wound
      inducible polygalacturonase (PG) mRNA and enzyme activity previously reported,
      suggesting that oligogalacturonic acid (OGA) fragments produced by PG are
      triggering the H2O2 response. Systemin, OGA, chitosan, and methyl jasmonate (MJ)
      all induce the accumulation of H2O2 in leaves. Tomato plants transformed with an
      antisense prosystemin gene produce neither PG activity or H2O2 in leaves in
      response to wounding, implicating systemin as a primary wound signal. The
      antisense plants do produce both PG activity and H2O2 when supplied with
      systemin, OGA, chitosan, or MJ. A mutant tomato line compromised in the
      octadecanoid pathway does not exhibit PG activity or H2O2 in response to
      wounding, systemin, OGA, or chitosan, but does respond to MJ, indicating that the
      generation of H2O2 requires a functional octadecanoid signaling pathway. Among 18
      plant species from six families that were assayed for wound-inducible PG activity
      and H2O2 generation, 14 species exhibited both wound-inducible PG activity and
      the generation of H2O2. Four species, all from the Fabaceae family, exhibited
      little or no wound-inducible PG activity and did not generate H2O2. The time
      course of wound-inducible PG activity and H2O2 in Arabidopsis thaliana leaves was
      similar to that found in tomato. The cumulative data suggest that systemic wound
      signals that induce PG activity and H2O2 are widespread in the plant kingdom and
      that the response may be associated with the defense of plants against both
      herbivores and pathogens.

PMID- 10339627
TI  - The roles of prefrontal brain regions in components of working memory: effects of
      memory load and individual differences.
AB  - Using an event-related functional MRI design, we explored the relative roles of
      dorsal and ventral prefrontal cortex (PFC) regions during specific components
      (Encoding, Delay, Response) of a working memory task under different memory-load
      conditions. In a group analysis, effects of increased memory load were observed
      only in dorsal PFC in the encoding period. Activity was lateralized to the right
      hemisphere in the high but not the low memory-load condition. Individual analyses
      revealed variability in activation patterns across subjects. Regression analyses
      indicated that one source of variability was subjects' memory retrieval rate. It
      was observed that dorsal PFC plays a differentially greater role in information
      retrieval for slower subjects, possibly because of inefficient retrieval
      processes or a reduced quality of mnemonic representations. This study supports
      the idea that dorsal and ventral PFC play different roles in component processes
      of working memory.

PMID- 10339628
TI  - Fish and mammals in the economy of an ancient Peruvian kingdom.
AB  - Fish and mammal bones from the coastal site of Cerro Azul, Peru shed light on
      economic specialization just before the Inca conquest of A. D. 1470. The site
      devoted itself to procuring anchovies and sardines in quantity for shipment to
      agricultural communities. These small fish were dried, stored, and eventually
      transported inland via caravans of pack llamas. Cerro Azul itself did not raise
      llamas but obtained charqui (or dried meat) as well as occasional whole adult
      animals from the caravans. Guinea pigs were locally raised. Some 20 species of
      larger fish were caught by using nets; the more prestigious varieties of these
      show up mainly in residential compounds occupied by elite families.

PMID- 10339629
TI  - An overview of diabetes mellitus in older persons.
AB  - Diabetes mellitus is very common in older persons. Changes in exercise habits,
      body habitus, leptin, amylin, tumor necrosis factor alpha, and nitric oxide all
      play a role in the pathogenesis of age-related insulin resistance. In older
      persons elevated glucose levels not only produce retinopathy, neuropathy, and
      nephropathy but also decrease quality of life, pain tolerance, cognition, and
      functional status and increase injurious falls, nocturia, incontinence, pressure
      ulcers, and orthostatic hypotension. The availability of multiple new therapies
      has enhanced the ability of physicians to improve glycemic control in older
      persons without unacceptable levels of hypoglycemia. Caregivers play an important
      role in the management of older diabetics. Depression increases mortality rate
      and hospital admissions in older diabetics. In many nursing homes the quality of
      diabetic care is marginal. A new causative theory of the metabolic syndrome
      involving cytokines and nitric oxide-the NO cytokine theory-is proposed.

PMID- 10339630
TI  - Diabetes in the elderly: A perspective from the United Kingdom.
AB  - Within some parts of the United Kingdom major deficiencies in diabetes care for
      older adults exist; these include lack of screening for the disorder, failure to
      evaluate complications, lack of individual management plans, and failure to
      appreciate the role of informal caregivers. The prevalence of diabetes in the
      elderly varies from 3% to 9% among the indigenous population, which, although
      considerably lower than in other European countries, may be a tremendous health
      care burden in the next century. Several community surveys testify to the high
      level of macrovascular and microvascular complications present in the older
      patient with diabetes, but the impact on patients' lives (and their caregivers'
      lives) often is underestimated, especially as a result of unrecognized
      disability. Premature death in aging diabetics also requires highlighting.
      Identifying the most suitable care model for managing the elderly diabetic is the
      subject of interest in the United Kingdom, with momentum growing to facilitate
      shared care between the family practitioner and the hospital specialist
      (diabetologist or geriatrician).

PMID- 10339631
TI  - Pathophysiology of type 2 diabetes in the elderly.
AB  - Diabetes is common in the elderly. Recently, investigators have begun to
      systematically study the pathogenesis of this illness in the aged. These studies
      suggest that although there are many similarities between diabetes in middle-aged
      and elderly subjects, there are several ways in which diabetes in the elderly is
      unique. These differences may have important therapeutic relevance to this
      patient population.

PMID- 10339632
TI  - Glucotoxicity: potential mechanisms.
AB  - Plasma concentration of glucose is found within a relatively narrow range of
      values for most animal species, yet it has little correlation with maximum
      lifespan; however, hyperglycemia in most animals is associated with premature
      death. This article presents evidence for hyperglycemia-induced tissue toxicity
      and discusses potential mechanisms of glucotoxicity and implications for the
      aging organism.

PMID- 10339633
TI  - Diabetes mellitus among ethnic seniors: contrasts with diabetes in whites.
AB  - Diabetes mellitus is one of the most common chronic diseases affecting older
      persons in the United States. It occurs in 18% of persons between 65 and 75 years
      of age and in as many as 40% of persons over 80 years of age. The prevalence of
      diabetes mellitus varies considerably by ethnic group and is higher among most
      minority groups in the United States than among non-Hispanic white persons.
      Published data also show increased complications and mortality rate from diabetes
      in the minority groups. In this article, we review the current literature on the
      prevalence, complications, and mortality-rate effects of diabetes mellitus and
      the results of interventions in three major minority groups in the United States,
      namely African Americans, Hispanic Americans, and Native Americans. Recent
      studies of diabetes mellitus in Mexican seniors also are described. Our review
      focuses primarily on patients with non-insulin-dependent diabetes mellitus,
      because by far this is the most prevalent type in older persons.

PMID- 10339634
TI  - Ocular disease in the diabetic elderly.
AB  - Diabetic retinopathy is a significant complication for the older diabetic
      patient. Visual loss often can be prevented, ameliorated, or delayed, but timely
      referral is key. Even those who cannot be helped medically or surgically can be
      assisted in making use of remaining visual function and other remaining senses.
      Many patients are not screened or referred according to American College of
      Physicians/American Academy of Ophthalmology guidelines and thus are not
      receiving the best possible care.

PMID- 10339635
TI  - Diagnosis and management of diabetic neuropathy.
AB  - Estimates of the prevalence of diabetic neuropathy range from 10% to 90% of the
      diabetic population, depending on the criteria used to define neuropathy.
      Diabetic neuropathy encompasses a wide range of abnormalities affecting both the
      peripheral and autonomic nervous systems and causes considerable injury and
      death. Neurologic complications occur equally in type 1 and type 2 diabetes
      mellitus, as well as various forms of acquired diabetes. In this overview, we
      present and discuss the most recent approaches to the treatment of the common
      forms of diabetic neuropathy, including distal symmetric, proximal motor, and
      autonomic neuropathy. We also provide the reader with algorithms for recognition
      and management of common pain and entrapment syndromes, and a global approach to
      recognition of syndromes requiring specialized treatments based upon our improved
      understanding of their causes.

PMID- 10339636
TI  - Gastric emptying in diabetes mellitus: relationship to blood-glucose control.
AB  - The application of novel investigative techniques has established that disordered
      gastric motility is a frequent complication of diabetes mellitus. Thus, gastric
      emptying of solid or nutrient liquid meals is abnormal in 30% to 50% of randomly
      selected outpatients with long-standing type 1 or type 2 diabetes. Delayed
      gastric emptying occurs more frequently than rapid emptying. There is increasing
      evidence that disordered gastric motility has a major impact on the management of
      patients with diabetes mellitus by leading to gastrointestinal symptoms and poor
      glycemic control. Although both gastroparesis and upper gastrointestinal symptoms
      have been attributed to irreversible autonomic damage, it is now clear that acute
      changes in the blood-glucose concentration have a major effect on both
      gastrointestinal motor function and the perception of sensations arising in the
      gut. For example, there is an inverse relationship between the rate of gastric
      emptying and the blood-glucose concentration, so that gastric emptying is slower
      during hyperglycemia and accelerated during hypoglycemia. This article reviews
      some issues in the etiology, diagnosis, and management of problems associated
      with gastric emptying in elderly persons with diabetes mellitus.

PMID- 10339637
TI  - Oral health and the older diabetic.
AB  - Older diabetics are at high risk for developing certain oral complications.
      Conversely, these oral health problems can complicate overall diabetic
      management, potentially undermining good blood-glucose control and impairing
      mastication of nutritionally appropriate foods. This article reviews the oral
      complications associated with diabetes. Additionally, special considerations in
      dental treatment of the older diabetic patient are discussed, including
      management of diabetic emergencies.

PMID- 10339638
TI  - Foot-ulcer prevention in the elderly diabetic patient.
AB  - Diabetic foot ulceration is frequently the result of repetitive trauma, foot
      deformity, malfunction, or ill-fitting footwear. The failure of such ulcers to
      heal is most often a consequence of the failure to provide protection from
      continuing trauma. Risk evaluation of the diabetic patient, with appropriate
      correction or accommodation of deformity or mechanical pressure, can be expected
      to reduce the incidence of serious infection secondary to ulceration.

PMID- 10339639
TI  - Nutrition and the older diabetic.
AB  - Abnormal glucose tolerance occurs in more than 60% of adults older than 60 years
      of age because of a decrease in glucose tolerance as a result of decreased
      insulin sensitivity and impairment of pancreatic beta-cell function. Because the
      population of the United States is aging, the incidence of diabetes mellitus
      continues to increase. Therefore, the role of dietary treatment for diabetes in
      the older individual is becoming more important to understand. Diet
      recommendations for patients with diabetes mellitus mainly focus on young and
      middle-aged individuals-few definitive studies have been done in the older
      person. This article reviews the contributions of various nutritional elements to
      the health status of older people.

PMID- 10339640
TI  - Obesity and aging.
AB  - This review focuses on studies that pertain to obesity and aging. The prevalence
      of obesity in the elderly is discussed, with an emphasis on body-fat distribution
      as it relates to morbidity and mortality rates. Treatment options, such as
      physical activity, growth hormones, and drug therapy, are briefly mentioned. A
      section that covers some of the most recent issues pertaining to the
      neuroregulation of feeding and energy expenditure is included. Finally, we
      briefly discuss anorexia in the aged.

PMID- 10339641
TI  - Care of the nursing-home resident with diabetes.
AB  - Diabetes is a common and costly illness among elderly nursing-home residents.
      People with diabetes more often require skilled care, experience more frequent
      health problems and hospitalizations, and have longer nursing-home stays. This
      article provides information about recommendations for diabetes care in nursing
      homes, the current level of care, and strategies to improve the quality of care
      for residents with diabetes.

PMID- 10339642
TI  - Index 

PMID- 10339643
TI  - The new lung cancer staging system: what does it mean?
AB  - Staging now provides the basis for any cancer treatment, determining prognosis
      and treatment and allowing for comparison of clinical outcomes. Changes in the
      lung cancer staging system have been implemented to represent our evolving
      knowledge and expanding diagnostic and therapeutic modalities. Current changes
      are designed to be minimally disruptive to historical staging systems, but new
      methods of treatment and better understanding of tumor biology may revolutionize
      our current staging classification in the future.

PMID- 10339644
TI  - Surgical strategies for metastatic lung cancer.
AB  - The role of surgery in the management of synchronous and metachronous metastatic
      lung cancer is examined. The approach to lung cancer metastatic to the brain is
      summarized and the literature on the surgical management of solitary adrenal
      metastasis from lung cancer is reviewed.

PMID- 10339645
TI  - Making sense of multimodality therapy for esophageal cancer.
AB  - The results of single modality treatment for esophageal cancer have been poor
      because of a high rate of local recurrence and distant metastasis. This is
      probably caused by the prevalence of advanced esophageal cancer at the time of
      diagnosis; only 3% of patients have Stage I disease, and most of them (80%) are
      Stage III or IV when they become symptomatic. The most frequently involved
      metastasis sites are lymph nodes (73%), lung (52%), and liver (47%). Neoadjuvant
      preoperative chemotherapy, radiotherapy, and combined chemoradiation have been
      added to the treatment of this disease to enhance local control, increase
      resectability rate, and improve disease-free survival. The results of recent
      trials are discussed.

PMID- 10339646
TI  - Standard resection for cancer of the esophagus and cardia.
AB  - Standard techniques of esophagectomy are the most common operations currently
      performed for cancer of the esophagus and cardia. A review of the recent
      literature discloses a wide difference in findings and postoperative results. A
      review of the findings and results in 505 operations for cancer of the esophagus
      on one surgical service from January 1, 1970 to January 1, 1997 reveals a
      resectability rate of 90%, a hospital mortality rate of 3.3%, a postoperative
      complication rate of 33.9%, and an adjusted actuarial 5-year survival rate of 24.
      7%. As yet, neither the use of neoadjuvant therapy nor extended techniques or
      resection, even when applied only in patients with low-grade lesions, have
      provided convincing evidence of their superiority over standard resection
      techniques.

PMID- 10339647
TI  - The rationale for radical resection.
AB  - Radical esophagectomy results in survival rates exceeding those obtained by
      standard techniques and comparable with or possibly better than survival rates
      following combined modality therapy. The benefits of radical resection include
      improved surgical staging, superior local control, and a higher probability of
      achieving an R0 resection.

PMID- 10339648
TI  - Primary tracheal tumor management.
AB  - Adenoidcystic carcinoma and squamous carcinoma are the most common tracheal
      tumors. Resection and postoperative radiation therapy are the treatment of
      choice. Complete resection is the desired goal and demands knowledge of the
      principles of tracheal surgery. Benign tumors are best treated by resection and
      cure can be expected.

PMID- 10339649
TI  - Current management of thymoma.
AB  - Patients with thymoma present rarely even on active thoracic surgery services.
      These patients may suffer from many associated conditions but the most common is
      myasthenia gravis. Aggressive surgical resection is the mainstay of initial
      therapy. Radiation therapy has a role in patients who are left with retained
      neoplasm after surgical resection. Recurrence may occur at prolonged intervals
      but should be treated aggressively.

PMID- 10339650
TI  - Surgical treatment of pulmonary metastases.
AB  - Pulmonary metastatectomy has been widely adopted for the treatment of
      malignancies spread to the lungs. This article reviews the historical development
      of the procedure, pertinent anatomical background information, means of
      postoperative evaluation, and the conduct and results of surgery.

PMID- 10339651
TI  - Follow-up of patients with thoracic malignancies.
AB  - The optimal approach to the post-treatment management of patients with thoracic
      malignancies is a controversial topic. This is primarily because of the lack of
      widely accepted practice guidelines. Several guidelines have been promulgated for
      the follow-up of thoracic malignancies, but none have been tested in randomized
      controlled trials. The problem is an especially interesting one because little is
      known about how outcomes vary when the follow-up strategy is altered.

PMID- 10339652
TI  - Lung cancer screening and the surgical oncologist: the controversy.
AB  - Although screening for lung cancer is not currently recommended, randomized
      trials consistently demonstrate that chest x-ray screening is associated with
      significant advantages in stage distribution, resectability, and long-term
      survival. Because these advantages have not been accompanied by a reduction in
      lung cancer mortalities a because an excess number of lung cancers were detected
      in experimental populations in two studies, it has been suggested that screening
      leads to the detection of clinically unimportant lung cancers. This hypothesis,
      known as overdiagnosis, is the only obstacle to the conclusion that chest x-ray
      screening saves lives. However, abundant evidence convincingly demonstrates that
      the overdiagnosis hypothesis is myth with regard to chest x-ray screening for
      lung cancer. With more than one million deaths from lung cancer on a worldwide
      basis every year, public policy regarding screening for lung cancer is in urgent
      need of reconsideration.

PMID- 10339653
TI  - Prognostic value of plasma HER-2/neu in African American and Hispanic women with
      breast cancer.
AB  - We examined the significance of plasma HER-2/neu as a clinical or biological
      marker for assessing the progression of breast cancer in African American and
      Hispanic women with similar socioeconomic status, similar health insurance, and
      similar access to health care delivery. Base line studies show the following:
      average age of our breast cancer patients was 48 for Hispanic and 53 for African
      American women. Most of our patients presented invasive ductal carcinoma, and
      there was no ethnic difference. A larger number of Hispanic women had stage
      III/IV disease at the time of diagnosis. There was no significant difference in
      the number of African American or Hispanic patients with ER positive or negative
      receptors. However, a larger number of Hispanic women had PR positive tumors, and
      a larger number of African American women had PR negative tumors. In general,
      there was no difference in the levels of HER-2/neu between the two ethnic groups.
      Patients with tumors >5 cm had elevated plasma HER-2/neu. However, there was no
      ethnic difference between tumor size and HER-2/neu levels. In addition, regional
      node status had no impact on plasma HER-2/neu. Patients with stage III/IV tumors
      had elevated plasma HER-2/neu. No ethnic difference was observed at either stage
      I/II or III/IV. ER positive or negative status had no significant impact on
      plasma HER-2/neu in either ethnic group. In contrast, PR positive patients showed
      elevated plasma HER-2/neu. Plasma HER-2/neu (>60 U/ml) was the strongest
      predictor of overall survival, visceral site metastasis, and local recurrence.

PMID- 10339654
TI  - Non-metastatic Ewing's sarcoma: twenty years of experience suggests that surgery
      is a prime factor for successful multimodality therapy.
AB  - Eighty-five patients (37 female, 48 male; median age 14 years) with non
      metastatic Ewing's sarcoma received definitive treatment at the University of
      Texas M.D. Anderson Cancer Center between 1969 and 1988. Multidisciplinary
      therapy was administered as follows: combination chemotherapy (CC) and local
      radiotherapy (XRT): 65 patients; CC, XRT and surgery, 19 patients; and XRT and
      surgery, 1 patient. This permitted a 10-20 year follow-up for 75% of our
      patients. The overall survival at 5 and 10-20 years was 46.1%, and 37.2%,
      respectively. At 5 years, 80.5% of live patients had control of local disease.
      The influence of sex, age, ethnicity, primary site, size, lactic dehydrogenase
      (LDH) level, presence or absence of systemic symptoms, and XRT dose (<60 Gy and
      </=60 Gy) was analyzed and was not found to be of prognostic significance in
      survival. The presence of a soft tissue mass at diagnosis was found to be a
      significant unfavorable prognostic variable. Nine of 11 patient who underwent
      resection after CC and/or XRT had residual tumor in the surgical specimen.
      Patients who received surgery as part of the planned treatment of their primary
      tumor had significantly better local control and disease-free survival than those
      who did not undergo resection. Complications in long-term survivors are
      described.

PMID- 10339655
TI  - Protein synthesis inhibitor-mediated stability of adenomatous polyposis coli mRNA
      levels in HCT-116 colon cancer cells.
AB  - We examined the effect of a protein synthesis inhibitor, cycloheximide (CHX) on
      the adenomatous polyposis coli (APC) mRNA levels in HCT-116 colon cancer cell
      line. The HCT-116 cells were treated with different concentrations of CHX for 15
      h. APC, p53 and beta-actin mRNA levels were determined by Northern blotting.
      Results showed that APC and beta-actin mRNA levels were significantly increased
      in a dose-dependent manner after CHX treatment. The p53 mRNA levels were
      moderately increased. The increase in APC mRNA levels after CHX treatment was due
      to increase in its stability instead of transcription. These results provide a
      model for CHX-induced APC mRNA stabilization and its implication in cell cycle
      arrest and cell survival studies.

PMID- 10339656
TI  - Expression of TGF-beta related Smad proteins in human epithelial skin tumors.
AB  - Members of the transforming growth factor (TGF)-beta family regulate cell growth
      and differentiation activating intracellular Smad proteins. Their role in skin
      and skin tumorigenesis is not well understood. Therefore we investigated the
      expression of TGF-beta type I receptor (TbetaR-I) and Smad-proteins involved in
      the TGF-beta-pathway, e.g. Smad2, Smad3, Smad4, Smad6 and Smad7. We examined the
      effects of TGF-beta1, -beta2, BMP2, BMP7 on five epithelial cell lines in vitro.
      TGF-beta1-mediated growth inhibition of HaCaT and HSC4 were observed with half
      maximal effects at approximately 7 pg ml-1 and 20 pg ml-1, respectively. However,
      malignant HSC2 and A431 cells were unresponsive to TGF-beta1. A differentiation
      was seen after 5 days in HaCaT and HSC4 cells only. We compared the reactivity
      with specific antisera against TbetaR-I and Smad proteins among the different
      skin tumors: seborrheic keratoses (SK), actinic keratoses (AK), basal cell
      carcinoma (BCC) and squamous cell carcinoma (SCC). There were statistically
      significant differences of the ratio between the expression in tumor and that in
      non-tumorous epithelial cells in each tissue specimen. There was a tendency for
      the lower level of TbetaR-I expression of SCC compared with SK (p=0.08). This was
      accompanied by the decreased expression of the TbetaR-I. We found a markedly
      decreased expression of all antigens in BCC. conversion of normal keratinocytes
      to tumorigenic cells may in part be due to an acquisition of resistance to TGF
      beta and loss of expression of intracellular signalling Smad proteins.

PMID- 10339657
TI  - Clinicopathological and genetic characteristics of mucinous carcinomas in the
      colorectum.
AB  - We investigated the clinicopathological and genetic characteristics including
      patients' gender, age, tumour location, growth pattern, Dukes' stage, DNA ploidy,
      S-phase fraction, PCNA, apoptosis, c-erbB-2, bcl-2, K-ras, p53, DCC and heat
      shock protein in 32 mucinous carcinomas versus 261 non-mucinous carcinomas in the
      colorectum. Sixty percent of mucinous carcinomas were located in the right colon,
      13% in the left colon and 27% in the rectum (p=0.01). More mucinous carcinomas
      grew in expanding pattern than non-mucinous carcinomas (66% vs 39%, p=0.005).
      Compared with non-mucinous carcinoma, mucinous carcinoma had more K-ras mutations
      (50% vs 25%, p=0.02), but less p53 expression (72% vs 49%, p=0.02) and less
      apoptotic activity (19% vs 51%, p=0.01). We further confirm that the mucinous
      carcinoma in the colorectum represents a distinct clinicopathologic and genetic
      features as compared to non-mucinous tumour, and may have a different biological
      behaviour.

PMID- 10339658
TI  - Temporal and spatial expressions of transforming growth factor-betas and their
      receptors in epiphyseal growth plate.
AB  - The activities of TGF-beta and its receptors in enchondral ossification have not
      yet been fully elucidated. The temporal and spatial expressions of TGF-beta and
      its receptors were examined immunohistochemically in epiphyseal growth plate of
      rats, in order to clarify the roles of TGF-beta and receptors in cartilage cells
      during enchondral ossification. TGF-beta1 and TGF-beta3 were expressed from 6 to
      24 weeks in resting, proliferating, and maturing zone. TGF-beta2 was expressed at
      6 week, but decreased during growth. The expression of TGF-betas in hypertrophic
      chondrocytes was weak. TbetaR-I was co-expressed with the ligand in resting,
      proliferating, and maturing zone throughout the development. The expressions of
      TbetaR-II was recognized at 6 weeks but decreased after that. This study suggests
      that TGF-betas play a major role in modulating endochondral ossification during
      growth in epiphyseal growth plate.

PMID- 10339659
TI  - Frequent expression of inducible nitric oxide synthase in esophageal squamous
      cell carcinomas.
AB  - Nitric oxide (NO) plays important biological roles in cardiovascular, nervous and
      immune systems, and is synthesized by nitric oxide synthase (NOS). Intracellular
      NO is known to cause DNA damage as a mutagen. We examined the expression of
      cytokine-inducible NOS (iNOS) in human esophageal squamous cell carcinomas. Weak
      iNOS immunoreactivity was seen in the basal and parabasal layers of non
      neoplastic esophageal stratified squamous epithelium. iNOS expression was
      detected in 50 (87.7%) of the 57 esophageal squamous cell carcinomas, regardless
      of the depth of tumor invasion, histological differentiation and lymph node
      status. Early-stage cancers, i.e. mucosal squamous cell carcinomas, also showed
      significant iNOS expression. We speculate that increased iNOS expression is
      associated with the carcinogenesis of human esophageal cancer.

PMID- 10339660
TI  - Activation of RB tumor suppressor protein and growth suppression of small cell
      lung carcinoma cells by reintroduction of p16INK4A gene.
AB  - The p16INK4A tumor suppressor gene is frequently inactivated in non-small cell
      lung carcinoma (NSCLC) and is less frequently inactivated in small cell lung
      carcinoma (SCLC) by mutation, deletion or DNA methylation. There are several
      reports that the reintroduction of the p16INK4A gene into p16(-) NSCLC cells
      results in significant growth suppression. However, there have been no reports of
      reintroduction of the p16INK4A gene into SCLC cells. To assess the biological
      significance of p16INK4A inactivation in the development of SCLC, full-length
      p16INK4A cDNA was introduced into an SCLC cell line, Ms-13, in which the p16INK4A
      protein was not detected. SCLC cells stably transfected with the p16INK4A
      expression vector formed only 2-16% of the number of neomycin-resistant colonies
      formed by cells transfected with a control vector, and no expression of exogenous
      p16INK4A protein was detected in any of 16 expanded clones. Transient
      transfection of the p16INK4A gene into SCLC cells resulted in exogeneous p16INK4A
      protein expression and dephosphorylation of endogenous retinoblastoma (RB)
      protein. These results suggest that the restoration of the p16INK4A function
      suppresses the growth of SCLC cells by dephosphorylation of the RB protein.
      Therefore, inactivation of p16INK4A may play an important role in the enhancement
      of growth of p16INK4A(-) RB(+) SCLC tumors in vivo.

PMID- 10339661
TI  - Expression of wild-type p53 gene confers increased sensitivity to radiation and
      chemotherapeutic agents in human esophageal carcinoma cells.
AB  - The status of the p53 gene of tumor cells can modify the sensitivity of the
      tumors to radiation and anti-cancer agents. Human esophageal cancer cells (T.Tn)
      bearing mutated p53 gene were retrovirally transduced with wild-type p53 gene.
      The transduced cells (T.Tn/p53) which stably expressed wild-type p53 proliferated
      at the same rate as parental cells. However, the sensitivity to radiation was
      significantly improved by the transduction and T.Tn/p53 cells became markedly
      susceptible to cisplatin and etoposide compared with parental cells.
      Administration of cisplatin noticeably suppressed the growth of T.Tn/p53 tumors
      but not T.Tn tumors inoculated in nude mice. Forced expression of wild-type p53
      gene thereby can increase the sensitivity to DNA damage in esophageal cells.

PMID- 10339662
TI  - Serum vascular endothelial growth factor in the course of transcatheter arterial
      embolization of hepatocellular carcinoma.
AB  - We previously reported that in vitro hypoxic condition enhanced VEGF level and
      its receptor expression in hepatic cancer cell line, HepG2. Transcatheter hepatic
      arterial embolization (TAE) therapy is one of the vasculo-occlusive and hypoxic
      challenges to hepatocellular carcinoma (HCC). Therefore, we examined the level of
      VEGF in sera of patients with HCC who underwent TAE during the course of the
      treatment. Thirty-eight patients with HCC and hepatitis C virus-positive
      cirrhosis were studied. Peripheral blood samples were taken before and 1, 3 and 7
      days after TAE with informed consent. The serum levels of VEGF as well as
      hepatocyte growth factor (HGF), another hepatic remodeling factor, were measured.
      The molar ratio (BTR) of serum branched chain amino acid (BCAA) to tyrosine
      (Tyr), the serum levels of AST, ALT and LDH were also examined. Although the
      level of AST, ALT and LDH reached the peak value within 1 day after TAE, VEGF
      level increased significantly 7 days later. On the other hand, there were no
      significant alterations in the levels of HGF and BTR during the course of TAE.
      Although the level of HGF was significantly correlated with the level of VEGF
      before TAE, this correlation was no more observed after TAE. These data
      collectively suggest that VEGF may be secreted in response to clinical hypoxic
      intervention, TAE, independent of HGF or altered amino acid metabolism. VEGF may
      play a role as a sensitive marker for tumor ischemia.

PMID- 10339664
TI  - Tailoring treatment for classical Kaposi's sarcoma: comprehensive clinical
      guidelines.
AB  - Classical Kaposi's sarcoma (CKS) is a rare indolent proliferative disease which
      is particularly prevalent among Jews of Ashkenazi and Mediterranean origin. To
      define guidelines for its comprehensive management, we conducted a retrospective
      analysis of 123 patients, focusing mainly on treatment modalities. The CKS
      related mortality was 4% (5 patients). Of the 39 patients for whom observation
      only was the primary approach, 15 (38%) remained progression-free for 1-83 months
      (median, 4 months). Twenty-nine of the 52 (56%) patients who underwent surgery as
      the primary approach remained recurrence-free for 1-162 months (median, 15
      months). Radiotherapy achieved an objective response in 74 courses (85%),
      including 50 (58%) complete responses. Symptomatic relief was reported in 95% of
      the patients. Vinblastine (27 series) achieved an objective response in 73% of
      series, including 22% complete responses. Multivariate analysis of time to
      progression with observation alone identified immunosuppression as the only
      significant independent factor that predicted disease progression. Our study
      suggests that observation alone may be sufficient for immunocompetent
      asymptomatic patients; symptomatic resectable lesions are suitable for simple
      excision; and more advanced disease or unresectable lesions require radiotherapy.
      If disease is extensive or the other approaches fail, chemotherapy is
      appropriate. Tailoring the treatment for CKS is an integrative process, requiring
      good understanding of the role of each available modality in the different
      clinical disease settings.

PMID- 10339663
TI  - Retroviruses prepared from human DAF expressing murine packaging cells acquire
      resistance against human serum.
AB  - The complement system of the human body inactivates the infectious ability of
      retroviruses injected as an artificial gene transfer vector. We established new
      murine leukemia virus (MuLV) packaging cell lines; D2SS and D7S which express
      decay-accelerating factor (DAF) on their surface. Both D2SS and D7S were
      resistant against incubation with fresh human serum. Moreover, the retroviruses
      produced from these packaging cell lines were also resistant to serum treatment.
      This resistance can be inhibited by DAF neutralizing antibody 1C6. These data
      demostrate that DAF induces a partial protection of MuLV infection from the human
      complement system.

PMID- 10339665
TI  - Prognostic impact of second cancer on the survival of early breast cancer
      patients.
AB  - Although numerous reports have been published on the incidence of second cancers
      after adjuvant therapy for early breast cancer, there have been few studies on
      the effect of the development of second cancer on overall survival (OS) of the
      patients. 1857 female patients younger than 80 years of age with operable breast
      cancer with UICC Stages I, II, and III who entered 3 trials of adjuvant therapy
      were studied for the detection of recurrence and second cancer. The median follow
      up period for surviving patients was 12 years (range, 5-25 years). 384 of
      recurrence and 119 of second cancers occurred. 465 deaths were recorded, the
      causes of which were designated to be due to recurrence of breast cancer in 326
      patients, second cancers in 57, and due to other causes in 82. Many background
      factors that were significantly related to recurrence did not influence the
      incidence of and death by second cancers after mastectomy: age and menopausal
      status alone were related. The difference in the Kaplan-Meier curves between the
      event (recurrence and second cancers)-free and relapse-free survivals indicates
      the incidence of second cancers is a significant event in post-operation course
      of early breast cancer patients (P=0.0001). The survival curve of patients who
      were free from recurrence- and second cancer-death is shown to be significantly
      lower than that of those free from breast cancer-specific death (P=0.0355),
      suggesting that death by second cancers is significantly influential to the
      overall survival. According to the Cox regression model using a recurrence or
      second cancers as time-dependent variables, the diagnosis of a recurrence or
      second cancer is shown to be highly significant to OS of the patients (hazard
      ratio: 49.3, and 6.3, respectively). Second cancers are shown to be not
      statistically significantly influential to the breast cancer specific survival
      (P=0.0637), nor a recurrence to second cancer specific survival (P=0.2285). In
      spite of heterogeneous distribution of sites of second primary cancers and their
      different natural histories, the incidence of second cancer has a significant
      effect on the postoperative survival of early breast cancer patients. In the
      survival analysis of early breast cancer patients, we have to estimate the
      contribution of second cancers to properly evaluate the effect of treatment.

PMID- 10339666
TI  - Analysis of cyclin dependent kinase inhibitors in malignant astrocytomas.
AB  - The cyclin-dependent kinase inhibitors p16, p21, and p27 in human brain, and
      brain tumors were examined to explore clinicopathologic correlations. Western
      analysis and immunohistochemistry was performed and correlated retrospectively
      with the patients clinical characteristics. A trend was found between increased
      progression-free survival and p27 expression. There was no correlation between
      p27 expression and age or gender. The expression of p27 in malignant gliomas may
      have prognostic value. In addition, an investigation of the therapeutic benefit
      of overexpression of this cyclin-dependent kinase inhibitor is warranted given
      reports of diminished malignant potential of tumors expressing p27.

PMID- 10339667
TI  - Expression of G1 phase regulators in MG-63 osteosarcoma cell line.
AB  - Cyclins and cyclin-dependent kinases (cdks) form complexes that govern
      transitions during cell cycle phases. In this study we characterized a human
      osteosarcoma cell line, MG-63, for the expression level of cyclin D1, cyclin E,
      cdk4, cdk2, and cell cycle inhibitors pRb and p21. To investigate the role of
      these proteins we treated MG-63 cells with tumor necrosis factor-alpha (TNF
      alpha) and interleukin-6 (IL-6). Cell proliferation analysis demonstrated an
      increased proliferation of MG-63 cells with IL-6, while TNF-alpha acted as an
      anti-proliferative agent. Immunoblotting revealed an increased expression of p21
      with TNF-alpha and its complex with cdk2. TNF-alpha reduced the expression of the
      cyclin E-cdk2 complex. TNF-alpha did not affect the amount of cyclin D1, cyclin
      E, cdk4, cdk2, and of cyclin D1-cdk4 complex. IL-6 decreased p21 expression and
      its complex with cdk2, while it increased the cyclin E-cdk2 complex. Cyclin D1
      and cdk4 expression and their complex did not change after IL-6 treatment, nor
      did cyclin E and cdk2 protein expression. Hyperphosphorylated/dephosphorylated Rb
      protein ratio was reduced with TNF-alpha whereas it increased with IL-6. These
      results may suggest an important role of p21 and of cyclin E-cdk2 complex in the
      G1 phase regulation through pRb phosphorylation in MG-63 cells.

PMID- 10339668
TI  - Detection of basic fibroblast growth factor mRNA in urinary bladder cancer:
      correlation with local relapses.
AB  - Natural history of bladder cancer is characterized by high risk of disease
      progression even for patients with a clinical diagnosis of superficial disease;
      in these tumors, the occurrence of local relapse is known to be dependent on the
      angiogenesis rate. Basic fibroblast growth factor (bFGF), has been described to
      be elevated in urine and serum of patients with bladder cancer. We investigated
      the expression of bFGF at mRNA level in a panel of 32 transitional cell tumors of
      the urinary bladder and in normal bladder tissues used as controls. Expression of
      bFGF was found elevated in most tumors of high stage, where its presence was
      found correlated with the occurrence of early local relapses. Furthermore, bFGF
      was found highly expressed in the majority of tumors showing a high bcl-2
      expression rate. Our data suggest that bFGF expression could contribute to the
      progression of disease; it may provide a prognostic indicator in the
      identification of patients with high risk for occurrence of local relapses.

PMID- 10339670
TI  - Gene therapy of chondrosarcoma using retrovirus vectors encoding the herpes
      simplex virus thymidine kinase gene.
AB  - Human chondrosarcoma cells (HCS-TG) were transduced with the gene for a herpes
      simplex virus thymidine kinase (HSV-tk) or Escherichia coli beta-galactosidase
      (lacZ). We investigated the cytotoxicity of human chondrosarcoma bearing an HSV
      tk gene after treatment with ganciclovir. Chondrosarcoma cells bearing an HSV-tk
      gene were more sensitive than non-transduced cells. Coculturing with
      chondrosarcoma cells bearing both an HSV-tk gene (HCS-TG-tk) and lacZ gene (HCS
      TG-Z) in various ratios showed a bystander effect. Chondrosarcoma implanted in
      nude mice were injected with HCS-TG-tk cells. After 4 weeks, the growth of tumors
      was significantly prevented.

PMID- 10339669
TI  - Cholecystokinin regulates the invasiveness of human pancreatic cancer cell lines
      via protein kinase C pathway.
AB  - We have previously reported that cholecystokinin (CCK) plays an important role in
      the invasiveness and the production of matrix metalloproteinase-9 (MMP-9) in two
      human pancreatic cancer cell lines. In this study we investigated the pathway of
      the invasiveness associated with MMP-9 of those lines regulated by CCK. Two human
      pancreatic cancer cell lines were treated with CCK-8 alone, CCK-8 and
      staurosporine, or CCK-8 and indomethacine. The invasiveness and the production of
      MMP-9 were decreased with staurosporine but not indomethacine. These results
      suggest that CCK may regulate the invasiveness and the production of MMP-9 via
      protein kinase C in human pancreatic cancer cell lines.

PMID- 10339671
TI  - Enhancement of 5-fluorouracil cytotoxicity on human colon cancer cells by
      retrovirus-mediated interferon-alpha gene transfer.
AB  - Gene therapy has advantages in the treatment of a variety of disorders due to its
      selective expression within specific mammalian cells. Several reports documented
      the clinical effects of interferon-alpha (IFN-alpha) in management of patients
      with advanced colorectal carcinoma. We report for the first time, the successful
      transduction of human IFN-alpha gene into colon cancer cells, COLO 201 using a
      replication-defective retroviral vector. Retrovirus-containing supernatant from
      PA 317 packaging cells was used to infect colon cancer cells, COLO 201 and NIH
      3T3 cells. Transient infection showed that cell proliferation and cell viability
      were significantly suppressed in colon cancer cells transduced with IFN-alpha
      gene. Moreover, IFN-alpha-transduced cells acquired less resistance to 5-FU
      induced apoptosis. These data demonstrate that IFN-alpha gene transfer may have a
      clinical application and can be combined with chemotherapy for treatment of
      advanced colorectal cancer.

PMID- 10339672
TI  - Detection of hepatitis B virus X-region DNA in liver tissue from patients with
      hepatitis C virus-associated cirrhosis who subsequently developed hepatocellular
      carcinoma.
AB  - The risk of hepatocellular carcinoma (HCC) in patients chronically infected by
      hepatitis C virus (HCV) is relatively higher in Japan than in Western countries.
      The presence of hepatitis B virus X (HBX)-DNA in the liver tissue samples
      obtained on enrollment from 69 patients with HCV-associated cirrhosis who were
      subsequently followed in our hospital was analyzed by polymerase chain reaction
      (PCR). During the follow-up period of 5.7+/-3.2 years (mean +/- SD), 52 (75%) of
      69 patients developed HCC. The PCR analysis indicated that the HBX-DNA sequence
      was detected in 25 (48%) of 52 patients who developed HCC during follow-up, but
      in only 3 (18%) of 17 patients who did not (P<0.05). These results suggest that
      HBX, a hepatitis B viral product relevant to hepatocarcinogenesis, is involved in
      development of HCC in some patients chronically infected by HCV in Japan.

PMID- 10339673
TI  - Comparative genomic hybridization defines frequent loss on 16p in human
      anaplastic thyroid carcinoma.
AB  - Anaplastic thyroid cancer (ATC) is one of the malignant tumors with the poor
      prognosis that is thought to arise from well-differentiated thyroid cancer (DTC).
      To investigate the molecular mechanism of ATC, we studied genomic alterations of
      eight ATC cell lines and three DTC cell lines by means of the comparative genomic
      hybridization (CGH) method. Loss of 16p was observed in five of eight ATC cell
      lines (62. 5%), but none of the three DTC cell lines showed loss of this
      chromosome arm. It is notable that loss of 18q [7/8 of ATC (87.5%), 2/3 of DTC
      (67%)] and gain of 20q [5/8 of ATC (62.5%), 3/3 of DTC (100%)] were frequently
      seen in both histologic types. Our results suggest that there is a gene in 16p
      that is closely associated with transformation from well-differentiated thyroid
      cancer to anaplastic cancer.

PMID- 10339675
TI  - ErbB receptor expression and growth response to heregulin beta 1 in five ovarian
      carcinoma lines.
AB  - SKOV-3, NIH:OVCAR-3, NIH:OVCAR-8, Ovca 429 and Ovca 433 ovarian carcinoma cell
      lines were examined to correlate biological behavior (growth in monolayer and
      soft agar) with erbB family receptor expression levels and response to
      recombinant Heregulin beta1 (Hrg). While all lines expressed variable amounts of
      each receptor, erbB-3 and to a lesser extent erbB-2 were constitutively tyrosine
      phosphorylated in all lines. Hrg beta1 treatment enhanced only erbB-3 tyrosine
      phosphorylation; however, the addition of Hrg in low serum did not stimulate
      ovarian cell growth, unlike all three breast cancer cell lines examined. In
      addition, all five of the ovarian carcinoma cell lines expressed Hrg mRNA by RT
      PCR, unlike two of the three breast cancer cell lines. These results suggest the
      apparent importance of erbB-3 and endogenous Hrg in ovarian carcinoma cell growth
      in vitro.

PMID- 10339674
TI  - Insulin-like growth factor binding protein-3 does not mediate the interferon
      dependent suppression of human ectocervical epithelial cell proliferation.
AB  - Interferon is a potential therapeutic agent for the treatment of cervical cancer.
      In the present study we examine the role of IFNgamma as a regulator of
      proliferation and production of IGFBP-3 expression in ectocervical epithelial
      cells. ECE16-1 cells are a model for studying early human papillomavirus
      dependent cervical disease. IFNgamma produces a concentration-dependent
      inhibition of ECE16-1 cell proliferation that is associated with an increase in
      insulin-like growth factor binding protein-3 level. Growth suppression and IGFBP
      3 increase is maximal at concentrations of IFNgamma >/=0.75 ng/ml. The increased
      IGFBP-3 expression is mediated via an increase in IGFBP-3 encoding mRNA. In
      contrast, IFNgamma inhibits proliferation of CaSki and SiHa cells, but IGFBP-3 is
      barely detectable and levels are not regulated by IFNgamma. These results suggest
      that the IFNgamma-dependent suppression of CaSki and SiHa cell proliferation is
      not mediated by secreted IGFBP-3. This result was confirmed when vector-mediated
      overexpression of immunoreactive IGFBP-3 in SiHa and CaSki cells did not
      consistently result in reduced cell proliferation rate.

PMID- 10339677
TI  - Growth of HPV-18 immortalized human prostatic intraepithelial neoplasia cell
      lines. Influence of IL-10, follistatin, activin-A, and DHT.
AB  - Cultures from high grade prostatic intraepithelial neoplasia (HGPIN) have been
      established and immortalized by HPV-18 infection. The cultures were identified as
      PIN by Western blotting with anti-cytokeratin (34betaE12) and prostate specific
      antigen (PSA) antibodies. We examined the growth capabilities of the cultures in
      the presence of TGF-beta1, activin-A, follistatin (FS), androgens (DHEA, DHT) and
      several cytokines (IL-10, IL-2, IL-4). IL-10, FS, and DHT stimulated cell
      proliferation and colony forming ability, while the other cytokines and growth
      factors had no discernable effect. In addition, DHT and to a lesser extent IL-10
      both stimulated PSA production. Activin-A blocked IL-10, FS, and DHT stimulated
      growth and PSA production. We interpret the data to mean that IL-10 induction of
      FS secretion (and FS binding of activin A) restores the normal growth
      capabilities of HGPIN cultures.

PMID- 10339676
TI  - Differentiation between Spitz nevi and malignant melanomas by interphase
      fluorescence in situ hybridization.
AB  - Spitz nevi are benign melanocytic neoplasias which have distinct pathological
      features that make the pathological differential diagnosis from malignant
      melanomas extremely difficult. The Spitz nevi may be misdiagnosed as malignant
      melanoma and vice versa. Therefore, interphase fluorescence in situ hybridization
      (I-FISH) was used for a possible discrimination between Spitz nevi and malignant
      melanomas on the basis of numerical aberrations of the chromosome complement in
      interphase nuclei of thin sections. Previous studies had shown changes in
      malignant melanomas which were not found at the same level in normal tissue or
      benign tumors. Thin sections of archival paraffin material from 42 Spitz nevi
      with different histological type and grade of anomaly were subjected to FISH
      analyses using commercially available biotinylated and/or digoxigenated alphoid
      DNA probes of chromosomes 1, 6, 7, 9, 17 and 18, which were applied in
      combinations in a two- or three-color-FISH. Unaffected epithelial areas from the
      same sections served as. The obtained data were compared with those collected
      previously from thin sections of malignant melanomas prepared in the same way.
      Due to the sometimes limited nevus area investigated, the number of evaluable
      nuclei was lower than expected from previous experiences with malignant
      melanomas. Therefore, only 20 nevi could be reliably evaluated. The comparison of
      the group of Spitz nevi with the group of controls did not show any significant
      difference regarding chromosomes 1, 6, 7, 9 and 17 (Wilcoxon test). The method
      used to detect chromosomal loss or gain in the individual Spitz nevi demonstrated
      only two nevi (one of the spindle cell type with a low to middle grade of
      anomaly, the other of the epitheloid cell type with a middle grade of anomaly)
      with a gain of chromosome 7 and chromosome 17, respectively. So, with respect to
      the histological type and grade of anomaly, no numerical aberrations could be
      detected in Spitz nevi. The comparison of the group of Spitz nevi with subgroups
      of malignant melanomas (metastatic, non-metastatic, melanomas with a thickness
      <1.5 mm and melanomas with a thickness >2. 0 mm) and with the whole group of
      malignant melanomas showed significant differences concerning chromosome 9 (Mann
      Whitney U test), signal indices, which were higher in the melanomas than in the
      Spitz nevi. Regarding chromosomes 6, 7 and 17 no significant differences could be
      shown, although a trend of gain in melanomas and of loss in Spitz nevi was
      observed of these chromosomes.

PMID- 10339678
TI  - Myocardial perfusion imaging with technetium-99m sestamibi in patients with
      cocaine-associated chest pain.
AB  - STUDY OBJECTIVE: To describe the characteristics and outcome in patients
      presenting to the emergency department with chest pain associated with cocaine
      use, the majority of whom underwent early rest perfusion imaging. METHODS: From
      January 1994 to June 1996, 218 patients had 241 ED visits for evaluation of
      symptoms consistent with myocardial ischemia after cocaine use. High-risk
      patients (N=25) were admitted directly to the CCU for exclusion of myocardial
      infarction (MI). Moderate- to low-risk patients (N=216) were promptly injected
      with technetium-99m sestamibi in the ED and underwent gated myocardial perfusion
      imaging 60 to 90 minutes later. Moderate-risk patients were observed in the CCU,
      whereas low-risk patients with negative perfusion imaging results were discharged
      home directly from the ED. RESULTS: A diagnosis of MI was made in 6 patients, 4
      of whom had ECG findings consistent with MI. Of the 216 patients who underwent
      perfusion imaging, 5 had positive study results, including 2 with MI. None of the
      38 patients with negative results after perfusion imaging who were admitted to
      the CCU had a diagnosis of MI. Only 6 of the 67 patients undergoing stress
      perfusion imaging had reversible perfusion defects. At 30-day follow-up, there
      were no cardiac events in patients with negative results after rest perfusion
      imaging. CONCLUSION: Acute MI is infrequent in patients presenting with cocaine
      associated chest pain. Positive results after rest perfusion imaging are
      uncommon, suggesting that myocardial ischemia is infrequently the cause of
      cocaine-associated chest pain. Early perfusion imaging may offer an effective
      alternative to routine CCU admission of patients with cocaine-related cardiac
      symptoms.

PMID- 10339679
TI  - Fibrinolytic therapy in young women with acute myocardial infarction.
AB  - STUDY OBJECTIVE: Previous studies found that women with acute myocardial
      infarction (AMI) receive less aggressive therapy compared with men. We sought to
      determine the percentage of young women (</=50 years) with an AMI eligible for
      fibrinolytic therapy who received it and explore factors resulting in the
      ineligibility of women for fibrinolytic therapy. METHODS: A retrospective chart
      review was conducted for women 50 years of age or younger who were discharged
      from a tertiary cardiac care hospital with a diagnosis of AMI during the period
      1990 to 1995. Women were included if they met the World Health Organization
      criteria for AMI. RESULTS: There were 126 women meeting inclusion criteria with
      54 (43%) receiving fibrinolytic therapy. Sufficient information to determine
      eligibility for fibrinolytic therapy was available for 118 (94%) of the women.
      Forty-one (91%) of the 45 women who met eligibility criteria received
      fibrinolytic therapy. Of the 73 women who were ineligible for fibrinolytic
      therapy, 52 (71%) had a nondiagnostic ECG, 28 (38%) presented 12 hours after
      symptom onset, and 19 (26%) had an absolute or relative contraindication to
      fibrinolytic therapy. Of the women not meeting eligibility requirements, 15%
      nonetheless received fibrinolytic therapy. CONCLUSION: In this study, most young
      women with AMI who were eligible for fibrinolytic therapy received it.
      Nondiagnostic ECG and late presentation to the emergency department (>12 hours
      after symptom onset) were the most common reasons for ineligibility.

PMID- 10339680
TI  - Comparison of patient and practitioner assessments of pain from commonly
      performed emergency department procedures.
AB  - STUDY OBJECTIVE: To compare patient and practitioner assessments of pain
      associated with commonly performed emergency department procedures and use of
      anesthetics before these procedures. METHODS: This was a prospective,
      observational, cross-sectional study conducted at a university-based ED with a
      convenience sample of ED patients. Research assistants recorded the procedure
      performed and historical and demographic information on standardized data
      collection instruments. After each procedure, both the patient and practitioner
      independently recorded assessments of patient pain on a 100-mm visual analog
      scale (VAS). Use of preprocedure anesthetics and patient preferences regarding
      their use were also identified. Categorical variables were analyzed by chi(2)
      tests. Patient and practitioner VAS scores were compared using a paired t test;
      alpha was preset at .05. Correlation coefficients were calculated to assess
      correlation between patient and practitioner pain scores. RESULTS: A total of
      1,171 procedures were evaluated for the 15 most common procedures performed. The
      mean patient age was 42.8+/-18.7 years and 46.1% were male. Overall, the mean
      patient VAS was 20.8 mm+/-25.1 mm; the mean practitioner VAS was 23.5 mm+/-20.3
      mm. The mean difference between groups was 3.0 mm (95% confidence interval [CI],
      1.3 to 4.1). Correlation between patient and practitioner pain scores for
      individual procedures was poor to fair (r=.26 to.68). The most painful procedures
      according to patients in descending order were nasogastric intubation, abscess
      drainage, fracture reduction, and urethral catheterization. Local anesthetics
      were administered in 12.8% of procedures yet would be requested before similar
      future procedures by 17.1% of patients. Patients who would choose local
      anesthetics in the future gave higher pain scores than those who would not (43.3
      mm versus 16.3 mm; mean difference=27.0 mm, 95% CI, 22.2 to 31.8 mm). CONCLUSION:
      The most painful procedures for ED patients were nasogastric intubation, incision
      and drainage of abscesses, fracture reduction, and urethral catheterization.
      Although practitioners also identified these procedures as most painful, the
      correlation between patient and practitioner pain assessments in individual
      patients was highly variable. Overall use of anesthetics before these procedures
      was low. Practitioners should be attentive to their patients' individual
      anesthetic needs before performing painful procedures.

PMID- 10339681
TI  - Fatal nontraffic injuries involving alcohol: A metaanalysis.
AB  - STUDY OBJECTIVE: Estimates of alcohol involvement in fatal injuries vary widely.
      For injuries other than those involving motor vehicles, no national data exist
      and the quality of regional data is limited. This study synthesizes US medical
      examiner studies of nontraffic fatalities for the purpose of estimating alcohol
      involvement by injury mechanism and intent. METHODS: We reviewed 331 medical
      examiner studies published between 1975 and 1995 that reported nontraffic injury
      fatalities. These studies were identified from computerized bibliographic
      databases and by hand searching of reference lists from 26 review publications
      and the subject indices of 7 prominent journals. A final total of 65 articles
      (19.6%) met our inclusion criteria for analysis. National data on motor vehicle
      fatalities were used for comparison. RESULTS: A total of 7,459 unintentional
      injury deaths, 28,696 homicide cases, and 19,347 suicide cases were aggregated.
      The aggregate percentage tested for blood alcohol concentration (BAC) was highest
      among homicide cases (88.2%), followed by unintentional injury deaths (84.0%) and
      suicide cases (81.7%). The aggregate percentage determined to be intoxicated
      (BAC, >/=100 mg/dL) was highest among homicide cases (31.5%), followed by
      unintentional injury deaths (31.0%) and suicide cases (22.7%). Mean and median
      comparisons produced comparable findings. Fewer than one quarter of the 65
      articles reported gender- and age-specific rates. Inconsistent reporting of
      gender and age-specific rates in fatal nontraffic injuries prevented their
      analysis by cause of death. Fatally injured motor vehicle drivers, however,
      demonstrated distinct variation in alcohol involvement by age and gender.
      CONCLUSION: This metaanalysis is the first systematic attempt to estimate alcohol
      involvement in fatal nontraffic injuries at the national level. It demonstrates
      that alcohol is an important factor in many fatal injuries and that its
      importance varies by cause of injury.

PMID- 10339682
TI  - Universal screening for intimate partner violence in the emergency department:
      importance of patient and provider factors.
AB  - STUDY OBJECTIVE: Screening for intimate partner violence has been widely
      advocated in the health care setting, but efforts to assess effectiveness and
      ensure adequacy of universal screening are largely untested. We sought to
      identify barriers to screening of female emergency department patients for
      intimate partner violence during the first year of implementation of a screening
      protocol. METHODS: A retrospective, structured medical chart review of 1,638
      randomly identified visits included demographic factors of age, race, marital
      status, employment status, insurance status, arrival mode, mechanism of
      presenting complaint, severity of condition, presentation time, and nurse gender.
      The study was conducted an an inner-city Level I trauma center with 43,000 annual
      ED visits and universal procedures for screening for intimate partner violence in
      place since February 1994. The participants were a cohort of 1,509 female
      patients, 18 years of age or older, who were discharged from the ED between July
      1994 and June 1995. The main outcome measure was the odds of being screened as a
      function of patient and provider variables. Statistical analyses involved
      univariate and multivariate logistic regression on screening rates (Yes/No) as
      derived from universal screening instrument variables. RESULTS: Of 1,638 records
      reviewed, 483 patients (29.5%) were screened for intimate partner violence.
      Univariate analyses revealed that women presenting with nonpsychiatric, less
      acute complaints and those who presented during daylight hours were more likely
      to be screened than women who presented with psychiatric or more acute
      complaints, or during the night shift. Male and female nurse providers were
      equally likely to screen for intimate partner violence. Step-down multivariate
      analyses agreed with these findings. CONCLUSION: In this random sample of female
      patients, screening rates varied by severity of the patient's condition, type of
      presenting complaint, and presentation time.

PMID- 10339683
TI  - Effect of a security system on violent incidents and hidden weapons in the
      emergency department.
AB  - STUDY OBJECTIVE: To determine the number of weapons confiscated and assaults
      reported in an urban county emergency department before and after the
      implementation of a security system. METHODS: This is a retrospective review of
      security records for a 54-month period from 1992 to 1996. We determined the
      number of weapons and assaults before and after the implementation of a security
      system consisting of metal detectors, cameras, limited access, and a manned
      security booth at the ED entrance. We calculated the rates of weapons confiscated
      and assaults per 10,000 ED patients treated. RESULTS: Twenty-four weapons were
      confiscated before the implementation of the security system, and 40 were
      confiscated after the implementation ( P<. 001). The percentage of weapons
      confiscated in the patient care area decreased from 92% to 42% after the security
      system was installed (P<.001). Seven of the 17 weapons (41%) found in the patient
      care area after implementation were brought in by ambulance patients who bypassed
      the security booth and metal detector. The reported assaults per 10,000 patients,
      however, did not change significantly. CONCLUSION: The implementation of an ED
      security system increased the number and percentage of weapons confiscated before
      patients were placed in patient care areas, but did not decrease the number of
      assaults. This emphasizes the importance of continued training of ED personnel in
      the management of violent patients and potentially violent situations.

PMID- 10339684
TI  - Lyme disease and related tick-borne illnesses.
AB  - Our knowledge of Lyme disease, currently the most common vector-borne illness in
      North America, has expanded over the past decade. The causative spirochete,
      Borrelia burgdorferi, is transmitted by the bite of an infected Ixodes tick.
      Infection usually results in erythema migrans and can spread hematogenously to
      skin, heart, nervous system, joints, and other organs. Prompt recognition and
      treatment with antibiotics usually leads to rapid improvement and markedly
      reduces subsequent manifestation. Unrecognized and untreated Lyme disease can
      cause late arthritic and neurologic syndromes that are more difficult to treat
      and that may not respond to antibiotics. Other tick-borne illnesses can be fatal
      if not treated.

PMID- 10339685
TI  - Devices for difficult airway management in academic emergency departments:
      results of a national survey.
AB  - STUDY OBJECTIVE: We conducted a national survey of emergency medicine residency
      program directors to determine which alternative devices were available in their
      emergency departments for difficult airway management. We also assessed the
      residency directors' experience in use of these devices. METHODS: After approval
      was received from the institutional review board at our institution, residency
      directors were contacted by mail, fax, or phone in October 1997. Alternative
      intubation devices were defined as devices that do not involve use of a
      laryngoscope and direct visualization for tracheal tube placement. Alternative
      ventilation devices were defined as those that do not use a face mask for
      ventilation. We asked whether the following alternative intubation devices were
      stocked in their department: a flexible fiberoptic bronchoscope, a rigid
      fiberoptic device (ie, Bullard, Wu-Scope), a lighted stylet, or a retrograde
      intubation kit. We also asked about the following alternative ventilation
      devices: a transtracheal jet ventilation system with a 50-psi oxygen source and
      control valve, the esophageal tracheal twin-lumen airway device (Combitube), or
      the laryngeal mask airway. Residency directors were also questioned about their
      duration of practice, intubation experience, and use of these devices. RESULTS:
      We obtained information from 95 of 118 (81%) programs. Of 95 programs, 61 (64%)
      had a fiberoptic bronchoscope, 43 (45%) a retrograde intubation kit, 33 (35%) a
      lighted stylet, and 6 (.06%) a rigid fiberoptic device. Forty-seven (49%) of the
      programs reported 2 or more devices, and 20 (21%) reported having no alternative
      intubation devices. Of 95 programs, 64 (67%) had a transtracheal jet ventilation
      system, 25 (26%) had the Combitube, and 25 (26%) had the laryngeal mask airway.
      Thirty-one (33%) programs had at least 2 alternative ventilation devices, and 20
      (21%) had none. Ten (11%) programs had no alternative intubating or ventilation
      devices. Additional information on duration of practice, intubation experience,
      and actual use of alternative devices was obtained from 83 of the 95 (87%)
      emergency medicine residency directors contacted. Forty-one (49%) reported never
      having used an alternative device for intubation. The most commonly used
      alternative intubation device was the flexible fiberoptic bronchoscope (37%), and
      the mean number of times any alternative device was used was 7. CONCLUSION: The
      availability of devices for difficult airway management varies tremendously
      across emergency medicine residency programs. Only half of residency program
      directors had any experience with these devices, and among those that reported
      any experience, they are used rarely.

PMID- 10339686
TI  - Alcohol-related injuries: Do we really need more proof?

PMID- 10339687
TI  - Accident and emergency medicine in the United Kingdom.
AB  - This article describes the history and current status of the practice of hospital
      based accident and emergency (A&E) medicine in the United Kingdom of Great
      Britain and Northern Ireland. Included are comments on training and
      certification, the operations of the typical A&E department, and developments in
      research and academics. Also included are the authors' thoughts on issues of
      future importance to A&E medicine. As transatlantic links at all levels become
      increasingly common in this dynamic specialty, we clarify unfamiliar terminology
      and practices for international readers.

PMID- 10339688
TI  - Inhaled nitric oxide in a patient with severe pulmonary embolism.
AB  - We describe a 66-year-old woman with right-sided heart failure and cardiogenic
      shock resulting from severe pulmonary embolism. Her hemodynamic status improved
      dramatically with the use of inhaled nitric oxide. A proposed mechanism of action
      and a review of the literature are presented.

PMID- 10339690
TI  - Sky king 

PMID- 10339689
TI  - Anticholinergic toxicity associated with lupine seeds as a home remedy for
      diabetes mellitus.
AB  - We describe a case of sparteine intoxication associated with using a preparation
      from lupine seeds. A female patient of Portuguese origin presented to the
      emergency department with classic anticholinergic signs after ingestion of a
      lupine seed extract. She took the preparation with the belief it represented a
      cure for her recently diagnosed diabetes. Analysis of the patient's lupine bean
      extract identified the preponderant compound as oxo-sparteine by gas
      chromatography/mass spectrometry. Intoxication by lupine seeds rarely occurs in
      human beings. To our knowledge, no medical or toxicologic evidence supports a
      belief that lupine extract could lower serum glucose levels. This case highlights
      the need for emergency care providers to be aware of the health hazards that can
      be associated with the use of such home remedies.

PMID- 10339691
TI  - NHTSA's new crash test dummy "Family" 

PMID- 10339692
TI  - Commentary: the new safer family of dummies 

PMID- 10339693
TI  - TCA overdose.

PMID- 10339694
TI  - TCA overdose 

PMID- 10339695
TI  - Depression in the elderly 

PMID- 10339696
TI  - Massive crystalluria in a patient taking primidone.

PMID- 10339697
TI  - Cervical spine radiography in blunt trauma.

PMID- 10339698
TI  - Clinical policy for the initial approach to patients presenting with acute toxic
      ingestion or dermal or inhalation exposure 

PMID- 10339699
TI  - Multiple sclerosis.

PMID- 10339700
TI  - Neurosciences - A neurosurgeon's perspective.
AB  - The advancements in the field of science in the past fifty years have highlighted
      the need to integrate all fields of human endeavours and have emphasised
      interdependency of various disciplines. The separation of humanities, therefore,
      from neurosciences is a preposterous practical joke on all thinking men. With the
      human genome project on the anvil, biotechnology is making significant headway
      holding out promise for organ regeneration. Macro evolution is over, but micro
      evolution continues in the brain. Neural Darwinism thus, continues to evolve as
      long as individual remains conscious and has memory. In the milieu of widely
      varying internal physiological mechanisms and external stimuli, an alternative
      theory to preprogrammed directionalism is proposed by three mechanisms namely
      developmental variation and selection, experiential selections and reentrant
      signalling. Reentrant signalling reorients and correlates the external inputs
      leading to psychic development preceding the development of consciousness. The
      cholinergic and aminergic neuro-modelling systems are well suited to serve as
      value systems. The main achievement of consciousness is to bring together the
      many categorizations involved in perceptions into a SCENE. Another part of
      evolution involved capacity of reentrant signalling to be guided by a value
      system where it is provided with a lot of choices. With 10(13) neurons and 10(16)
      connections, freedom of choice may manifest into a 'Buddha' or a 'Hitler'. As
      part of the evolutionary process, it was interesting how capacity to categorize
      the need to worship by referring to environment outside evolved into a search
      within our minds. As the next stage of evolution, neuroscience may, thus, serve
      as the next gateway to understanding the mind and soul.

PMID- 10339701
TI  - Multiple sclerosis: experience in neuroimaging era from western India.
AB  - 31 patients of multiple sclerosis (MS) diagnosed in the last six years in a large
      teaching hospital were reviewed. The hospital incidence of 0.85% of total
      admissions in neurology unit in western India is comparable to the series from
      other parts of India. The mean age at onset was slightly lower compared to other
      series. The female preponderence was noted in addition to higher incidence of
      Devic's syndrome. Visual loss (47%) and motor weakness (27%) were the commonest
      presenting symptoms. The clinical pattern was more similar to Asian series of MS
      than the western series. All patients underwent magnetic resonance imaging (MRI)
      scan. 24 out of 25 MRI of Brain and 15 out of 16 MRI of spine were abnormal. CSF
      immuno-globulins were raised in 80% of patients who underwent CSF study. The data
      has been compared with other Indian, Asian and Western series.

PMID- 10339702
TI  - Clinical profile of multiple sclerosis in north-west India.
AB  - A total of 100 patients were enrolled in this study with the clinical diagnosis
      of multiple sclerosis (MS). This included prospective analysis of 35 patients and
      retrospective analysis of 65 patients from their medical records spanning a
      period from January 1986 to March 1998. They were divided into 3 groups (i)
      overall group (ii) MRI group (where MRI was available) (iii) No MRI group (where
      MRI was not available). Data in terms of clinical features and laboratory
      investigations were compared in the three groups. MS was found to constitute
      2.54% of neurology admission between January 1993 to December 1997. It was higher
      as compared to previous data from our institute (1.58%). Cerebellar symptoms were
      higher in the MRI group as compared to the non MRI group. The clinical spectrum
      of MS in the MRI group was comparable to that in the west. Obviously the MRI
      helps in early diagnosis of milder and atypical cases. Oligoclonal bands were
      found in 30.5% of cases only.

PMID- 10339703
TI  - Clinical profile of multiple sclerosis in Bengal.
AB  - Forty five patients of multiple sclerosis diagnosed on the basis of Poser's
      criteria from West Bengal were studied. The male-female ratio was 1:1.5, mean age
      of onset 31.83 years in male and 29.11 years in females. The maximum cases were
      between the 3rd and 4th decade. Definite MS comprised of 60%, while remaining 40%
      were probable. Visual impairment (53.33%), weakness of limbs (31.11%) and sensory
      paraesthesia (20%) were the common presenting symptoms whereas pyramidal tract
      involvement (93.33%) with absent abdominal reflexes (90%) and optic pallor
      (64.44%) were common signs. Posterior column and spinothalamic sensations were
      involved in 55% and 51% of cases respectively. Inter-nuclear ophthalmoplegia was
      present in 6.66% of cases. Pattern of involvement commonly showed three or more
      sites of lesion. Optico-spinal affection was present in 22.2% of cases. Relapsing
      and remitting course was found in 48. 91%, relapsing and progressive course in
      33.33% and chronic progressive in 17.8%. MRI of brain showed positive results in
      16 out of 23 cases. CSF study showed increased positivity in estimation of
      immunoglobulin level than oligoclonal band. Findings revalidate the disease
      pattern as being similar to that in other parts of India as well as Asia.

PMID- 10339704
TI  - Extreme lateral transcondylar approach to the skull base.
AB  - In this study, the authors present their experience of using extreme later
      transcondylar approach (ELTC) for treating 7 patients with lesions in the
      anterolateral foramen magnum, upper cervical spine and cerebellopontine angle
      reaching upto jugular foramen. The tumours included meningiomas, neurofibromas (2
      cases each), chondrosarcoma, epidermoid and aneurysmal bone cyst (one case each).
      The approach was used alone, in combination with retrolabyrinthine presigmoid
      approach in a patient with lower cranial nerve neurofibroma extending
      extracranially through the jugular foramen, or in combination with partial C1-C3
      laminectomy in two patients with meningiomas situated anterolateral to the cord
      from the foramen magnum to C3. In two patients with extradural vertebral artery
      (VA) entrapment by a chondrosarcoma and aneurysmal bone cyst respectively, the
      vertebral artery was ligated distal to the tumour. The tumours were totally
      excised in five cases and partially in two. There was no preoperative mortality.
      The major complications included cerebrospinal fluid leak from the wound (3
      cases) and increase in lower cranial nerve paresis (2 cases). At follow up,
      ranging from 6 months to 2 years, 5 patients showed no tumour recurrence. There
      was improvement in neurological status. One patient, with a partially excised
      aneurysmal bone cyst, showed no added deficits or increase in the tumour size.
      However, there was a massive regrowth in the patient with chondrosarcoma after 6
      months. This technique provided a wide surgical exposure with direct
      visualization of the tumour-anterior cord interface, early proximal control of
      the VA and preservation of lower cranial nerves.

PMID- 10339705
TI  - Remediation of attention deficits in head injury.
AB  - Head injury is associated with psychological sequelae which impair the patient's
      psychosocial functioning. Information processing, attention and memory deficits
      are seen in head injuries of all severity. We attempted to improve deficits of
      focused, sustained and divided attention. The principle of overlapping sources of
      attention resource pools was utilised in devising the remediation programme.
      Tasks used simple inexpensive materials. Four head injured young adult males with
      post concussion syndrome underwent the retraining program for one month. The
      patients had deficits of focused, sustained and divided attention parallel
      processing, serial processing, visual scanning, verbal learning and memory and
      working memory. After the retraining programme the deficits of attention improved
      in the four patients. Serial processing improved in two patients. Parallel
      processing and neuropsychological deficits did not improve in any patient. The
      symptom intensity reduced markedly and behavioural functioning improved in three
      of the four patients. The results supported an association between improving
      attention and reduction of symptom intensity. Attention remediation shows promise
      as a cost effective, time efficient and simple technique to improve the
      psychological and psychosocial functioning of the head injured patient.

PMID- 10339706
TI  - Movement disorders caused by brain tumours.
AB  - Movement disorders are uncommon presenting features of brain tumours. Early
      recognition of such lesions is important to arrest further deficit. We treated
      seven patients with movement disorders secondary to brain tumours over a period
      of seven years. Only two of these were intrinsic thalamic tumours (astrocytomas)
      while the rest were extrinsic tumours. The intrinsic tumours were accompanied by
      hemichorea. Among the extrinsic tumours, there was one pituitary macroadenoma
      with hemiballismus and four meningiomas with parkinsonism. Symptoms were
      unilateral in all patients except one with anterior third falcine meningioma who
      had bilateral rest tremors. There was relief in movement disorders observed after
      surgery. Imaging by computed tomography or magnetic resonance imaging is
      mandatory in the evaluation of movement disorders, especially if the presentation
      is atypical, unilateral and/or accompanied by long tract signs.

PMID- 10339707
TI  - Puerperal cerebral venous thrombosis: therapeutic benefit of low dose heparin.
AB  - Advances in imageology have improved the diagnostic yield of cerebral
      venous/sinus thrombosis (CVT). However, its management remains a challenge. The
      present study was carried out to study the role of heparin in CVT. Therapeutic
      outcome of 150 patients of puerperal CVT manifesting within one month of delivery
      or abortion, was analyzed. The diagnosis was supported by cranial computed
      tomography and/or angiography whenever required. Seventy three patients, 46 with
      non-haemorrhagic infarction and 27 with haemorrhagic infarction, received 2500
      units of subcutaneous heparin, three times a day within 24 hours of
      hospitalization till 30th post partum day or symptomatic relief. Seventy seven
      patients during the same period, 50 with non-haemorrhagic infarction and 27 with
      haemorrhagic infarction, who did not receive heparin formed the control group.
      Repeat CT scans were done when indicated. Among the heparin group, 34 patients
      made full recovery. There were eight deaths, all among the patients with
      haemorrhagic lesion. In control group, only 14 patients recovered completely
      (P=<0.001) and 18 died (P=<0.001). There were no adverse effects of heparin. Low
      dose heparin is safe and efficacious in puerperal CVT, even in patients with
      haemorrhagic infarction.

PMID- 10339708
TI  - Reappearing CT lesions: 4 cases.
AB  - An overwhelming majority of disappearing CT lesions in India have been
      aetiologically linked to cysticercosis. We report 4 patients with disappearing CT
      lesions in whom the lesion later reappeared at the same (3 patients) or different
      site (1 patient). One patient was a Taenia carrier. Serial MRI evaluation in one
      patient revealed a persisting lesion in the interval period. The contribution of
      these observations towards the understanding of the aetiology of disappearing CT
      lesions is discussed.

PMID- 10339709
TI  - Non-traumatic acute rhabdomyolysis.
AB  - A boy developed sudden severe generalized muscle stiffness, bulbar weakness and
      passed dark coloured urine. Laboratory tests revealed marked elevation of
      creatinine kinase(CK) levels and myoglobinuria. Histopathology of quadriceps
      muscle showed features of acute rhabdomyolysis. Patient made complete clinical
      recovery over a period of three weeks and CK returned to normal level. The
      possible aetiologies of non-traumatic rhabdomyolysis are discussed and the
      relevant literature reviewed.

PMID- 10339710
TI  - Medullomyoblastoma: A case report.
AB  - Medullomyoblastoma is a rare tumour seen in childhood. We report a
      medullomyoblastoma occurring in the cerebellar vermis of a 4 year old boy. The
      light microscopic features, immunohistochemistry and histogenesis are described.

PMID- 10339711
TI  - Systemic brucellosis with chronic meningitis: A case report.
AB  - A young adult presenting with 11 months history of fever, headache, vomiting was
      found to have CSF lymphocytic pleocytosis with increased protein. His serum
      tested strongly positive for Brucella (standard tube agglutination titre 1: 320)
      whereas CSF was weakly positive. He became asymptomatic on treatment with
      tetracycline, rifampicin and streptomycin with significant CSF response. This
      case is reported because of its rarity.

PMID- 10339712
TI  - Sacral nerve root cysts: A review on pathophysiology.
AB  - Nerve root cysts of the sacral region are generally asymptomatic but are known to
      cause neurogenic claudication. In this paper we present an elderly lady who
      presented with claudication, whose MR imaging showed a sacral cyst. She underwent
      lumbo-sacral laminectomy, partial excision of the cyst wall with plication. A
      review of the possible pathophysiology of such a lesion is discussed.

PMID- 10339714
TI  - Huntington's disease and alcohol abuse.
AB  - The dopamine, glutamate and GABA systems are known to mediate the effects of
      alcohol on the movement disorders, though their exact roles are not clear. Thus,
      use of alcohol has implications for pathogenesis as well as management of the
      movement disorders. These implications are discussed citing a patient who had a
      strong family history of Huntington's disease and in whom movement disorder and
      behavioral problems were manifest under alcohol use and withdrawal, but not while
      being abstinent.

PMID- 10339713
TI  - CSF orbitorrhoea with tension pneumocephalus.
AB  - A seventy eight year old man sustained penetrating injury to right orbit about 15
      years ago. Later he developed right orbital infection leading to phthisis bulbi.
      Two months before admission he developed CSF leak from the right orbit, tension
      pneumocephalous and meningitis. A rare case of CSF orbitorrhoea is reported here
      along with the discussion on mechanisms and management.

PMID- 10339715
TI  - Choroid plexus papilloma of cerebellopontine angle with extension to foramen
      magnum.
AB  - A case of choroid plexus papilloma resembling meningioma of cerebellopontine (CP)
      angle with its extension to foramen magnum is presented. Occurrence of this
      tumour in CP angle is very rare. Its extension towards foramen magnum is further
      rare. It was a real diagnostic enigma preoperatively as the tumour was resembling
      meningioma upto some extent on radiological study. Retromastoid craniectomy with
      microsurgical excision of tumour and its extension was achieved in toto. Tumour
      was attached to few rootlets of lower cranial nerves which were preserved.
      Attachment of the tumour with lower cranial nerves again caused diagnostic
      confusion with neurofibroma intraoperatively.

PMID- 10339716
TI  - Neuroimage: Congenital toxoplasmosis.

PMID- 10339717
TI  - A case of 27 year old male with recurrent neurological deficit.

PMID- 10339718
TI  - Fibromuscular dysplasia of internal carotid artery.

PMID- 10339719
TI  - Myasthenia gravis with chronic inflammatory demyelinating polyneuropathy - A case
      report.

PMID- 10339720
TI  - Cervical intradural extramedullary bronchiogenic cyst.

PMID- 10339721
TI  - What's in a name? 

PMID- 10339722
TI  - Depression in the elderly.

PMID- 10339723
TI  - Rural health care delivery.

PMID- 10339724
TI  - Cervical spine radiography in blunt trauma 

PMID- 10339725
TI  - Video-assisted thoracic surgery: a renaissance in surgical therapy.
AB  - Within a few years, video-assisted thoracic surgery (VATS) has become the
      accepted or preferred approach over a wide range of thoracic procedures. The
      authors review the development of this technique, the basic operative strategies
      and the current surgical indications. Technical pitfalls and future developments
      are also discussed.

PMID- 10339726
TI  - Thoracoscopic procedures for intrathoracic diseases: the present status.
AB  - Thoracoscopic operations, alternatively termed as video-assisted thoracic surgery
      (VATS), are replacing the variety of surgical procedures which have been
      otherwise performed by open thoracotomy. The minimally invasive nature of the
      procedure, reduced postoperative pain, shortened hospital stay, and reduced cost,
      are the potential advantages of VATS. While these merits are being proven, the
      limits to this technique are also getting clearer. In fact, VATS has already
      become a standard treatment of choice in several diseases, such as bullectomy for
      spontaneous pneumothorax and biopsy for indeterminate nodule and diffuse
      interstitial lung disease, while others, such as major video-assisted lung
      resection for lung carcinoma and resection of metastatic lung tumour, await
      further evaluation of their roles in terms of oncological and technical aspects.
      Three issues that currently need to be addressed as the present role of
      thoracoscopy evolves are instrumentation, economics, indication, and end results
      in certain procedures.

PMID- 10339727
TI  - Thoracoscopic procedures for intrathoracic and pulmonary diseases.
AB  - Since Jacobaeus performed the first thoracoscopy to explore pleural space and
      mechanically broke pleural adhesions to facilitate the collapse therapy for
      pulmonary tuberculosis in 1910, numerous thoracic surgeons have been attempting
      this technique as a means of accomplishing many intrathoracic procedures
      previously done through open thoracotomy. As the refinement of video technology
      has advanced, thoracoscopic surgery has played a very important role in thoracic
      surgery especially since the early 1990s. Because the advantages of video
      assisted thoracoscopic surgery for patients include low post-thoracotomy-related
      morbidity, cosmetic considerations, low pain, earlier post-operative
      mobilization, and a shorter operation time in some indications, surgeons have
      been demonstrating its increasing utility in the diagnosis and treatment of the
      pleura, lung, mediastinum, great vessels, pericardium, and oesophagus. The most
      common application of the thoracoscopic approach still remains in the management
      of pleuropulmonary disease. The indications for the thoracoscopic technique are
      very broad, but its role in the management of primary lung and oesophageal cancer
      has yet to be confirmed. Thus, the surgeon who uses the technique in these
      cancerous diseases should be prudent. In conclusion, these thoracoscopic
      procedures will play more important roles in the practice of thoracic surgery in
      the future.

PMID- 10339729
TI  - Detection of nocturnal wheezing in bronchial asthma using intermittent sleep
      tracheal sounds recording.
AB  - Common clinical features of bronchial asthma include bronchoconstriction during
      the night, particularly while asleep. Although bronchoconstriction reduces the
      quality of life and can cause life-threatening events, a clinical technique for
      evaluating bronchoconstriction during sleep has not been widely applied. In this
      study, we measured nocturnal wheezing by intermittent sleep tracheal sounds
      recording (ISTSR) to detect bronchoconstriction during the hours of sleep. Using
      ISTSR, we studied the number and duration of nocturnal wheezing episodes in 27
      adult patients with bronchial asthma. Nocturnal wheezing was detected in 36 of 39
      recordings. Although the pattern of hourly nocturnal wheezing count (hourly NWC
      pattern) varied among subjects, there appeared to be a reproducible pattern
      within individuals. When wheezing alternated between long and short duration,
      bronchoconstriction tended to be more severe. The NWC in 1 h (NWC/H) was
      positively correlated with subjective symptoms and inversely correlated with the
      morning per cent peak expiratory flow. The hourly NWC was significantly greater
      at 05:00 than that at midnight. Intermittent sleep tracheal sounds recording has
      potential to be a non-invasive clinical tool for detecting nocturnal
      bronchoconstriction during hours of sleep in patients with asthma.

PMID- 10339728
TI  - Pulmonary actinomycosis in Korea.
AB  - Pulmonary actinomycosis is a chronic pulmonary infection caused by Actinomyces, a
      Gram-positive, microaerophilic bacterium. Pulmonary involvement, other than
      cervicofacially or abdominopelvically, is uncommon and often leads to a
      misdiagnosis of pulmonary tuberculosis or lung cancer. In order to investigate
      the clinical, radiological, diagnostic and therapeutic characteristics of
      pulmonary actinomycosis, we reviewed a total of 25 cases reported in Korea.
      Thirteen were diagnosed at our hospital between 1985 and 1997 and 12 were
      reported in Korean publications. The condition occurred most frequently in middle
      aged males, the most common symptom being haemoptysis, followed by cough and
      sputum. The main radiological features were peripherally located mass or nodule
      and consolidation, with central low attenuation. Complications such as empyema,
      sinus fistula or mediastinitis did not occur. Diagnosis was confirmed by
      percutaneous needle aspiration (n = 8), bronchoscopic biopsy (n = 3) or
      thoracotomy (n = 13). Eleven of 25 cases were treated medically and in nine
      others, surgical resection was followed by treatment with antibiotics. In
      conclusion, when a middle-aged male patient presents with haemoptysis and cough,
      together with radiologic findings of a peripheral mass or nodule with/without
      central low attenuation, pulmonary actinomycosis should be suspected.

PMID- 10339730
TI  - Duration of tachyphylaxis in response to methacholine in healthy non-asthmatic
      subjects.
AB  - It is well recognized that bronchial responsiveness to methacholine is reduced
      after methacholine-induced bronchoconstriction in non-asthmatic subjects, but not
      in asthmatic subjects. However, it is unknown how long the methacholine
      tachyphylaxis lasts. The present study was conducted to elucidate duration of the
      methacholine tachyphylaxis in healthy non-asthmatic subjects. Measurements of
      methacholine responsiveness were repeated six times at intervals of 1 h and 1, 2,
      3 and 7 days in eight healthy non-asthmatic young female subjects in whom
      methacholine concentrations causing a 20% fall in forced expiratory volume in 1
      sec (FEV1; PC20-Meth) were 40 mg/mL or less. Geometric mean value (GSEM) of PC20
      Meth was 10.6 (1.44) mg/mL at the first challenge, 63.4 (1.85) at the 1-h
      interval, 50.2 (1.67) at the 1-day interval, 49.7 (1.68) at the 2-day interval,
      17.3 (1.51) at the 3-day interval and 13.1 (1.44) mg/mL at the 7-day interval.
      The values at intervals of 1 h to 3 days were significantly greater than the
      initial value. These results indicate that measurements of methacholine
      responsiveness should be separated by at least 7 days to avoid the tachyphylaxis
      when the tests are repeated in non-asthmatic subjects.

PMID- 10339731
TI  - A diary form quality of life questionnaire for Japanese patients with lung cancer
      and summarization techniques for longitudinal assessment.
AB  - The aim of this study was to confirm the validity and reliability of a new diary
      type quality of life (QOL) self-rating questionnaire tailored for use by Japanese
      inpatients with lung cancer receiving chemotherapy. Two kinds of summary
      statistics were tested in QOL analysis. The questionnaire has a four-scale
      structure; physical, psychological, daily activity and global scales. Fifty-three
      patients were enrolled to test the reliability and validity. Summary statistics
      were assessed using indices of the area under the curve (AUC) and the maximum
      fluctuations of QOL scores (Dif max) in patients receiving cisplatin or
      carboplatin. The questionnaire had satisfactory reliability and validity. The
      physical, psychological and global scales scores changed to the worst levels
      after treatment, continuing for 1 week in the cisplatin group, whereas those of
      the carboplatin group began to worsen from day 3, but returned to prechemotherapy
      levels by day 9. The cisplatin group showed significant decrease of QOL compared
      with the carboplatin group in the AUC of psychological and two global scales, in
      the Dif max of psychological and linear analogue global scales. These results
      suggested that this questionnaire reflects differences in the influence of
      chemotherapy, and that AUC and Dif max may be useful indices for the analysis of
      QOL as measures to assess multidimensional QOL.

PMID- 10339732
TI  - Effects of inhaled corticosteroid on bone turnover in children with bronchial
      asthma.
AB  - Long-term usage of systemic steroids is associated with multiple side effects.
      One of the major morbidities is due to its effect on bone metabolism leading to
      bone loss and resulting in skeletal fractures. This study was conducted to
      determine the effects of inhaled steroids on bone mineral density (BMD) and
      biochemical bone markers. Twenty-four children with frequent episodic or mild
      persistent asthma who satisfied the clinical criteria for starting on inhaled
      corticosteroids (ICS) were enrolled into the study. The BMD scan was done using
      dual energy X-ray absorptiometry, prior to starting ICS therapy and 6 months
      later. Biochemical markers of bone metabolism, (i) serum osteocalcin as a bone
      formation marker, and (ii) urinary deoxypyridinoline (Upd) as a bone resorption
      marker, were taken prior to ICS treatment and at 2 monthly intervals. The
      biochemical markers were all taken in the morning. Twenty-four, age- and sex
      matched children with mild episodic asthma, not requiring ICS, were used as
      controls for the BMD measurements. The BMD scan was done upon enrollment into the
      study and 6 months later. Twenty-four children on ICS and 24 controls completed
      the study. The subjects were on a mean dose of beclomethasone dipropionate (BDP)
      0.4 mg/day. One subject needed a short course of Prednisolone in the early
      treatment period. None of the controls needed oral steroid therapy. One child in
      the control group sustained a greenstick fracture after an accidental fall. The
      mean rate of change of BMD was 1.8% +/- 12.3 in the subjects on BDP. This was
      lower than the 6.1% +/- 10.6 among the control subjects. However, this difference
      did not reach statistical significance (P = 0.16). There was a significant
      increase in serum osteocalcin level after 6 months of BDP treatment from 66.83 +/
      22.71 ng/mL to 81.61 +/- 24.66 ng/mL (P < 0.005). There was a decline in Upd
      from 36.2 +/- 47.1 nmol/mmol creatinine to 21.4 +/- 6.92 nmol/mmol creatinine.
      However, this did not reach statistical significance. There was no difference in
      the statural gain between the subjects on ICS and their controls. This study
      showed that 6 months of ICS therapy (mean dose 0.4 mg/day) had no significant
      adverse effect on bone metabolism in asthmatic children.

PMID- 10339733
TI  - Volume-pressure properties of the upper airway in normal subjects and patients
      with obstructive sleep apnoea.
AB  - The aim of this study was to examine the volume-pressure (V-P) characteristics of
      isolated upper airways in normal subjects and patients with obstructive sleep
      apnoea (OSA) and to ascertain whether an increase in upper airway muscle activity
      affects these characteristics. We studied upper airway pressure changes during
      volume changes by inflation and deflation of air volumes of 5, 10, 15 and 20 mL
      without and with submental electrical stimulation, during voluntary closing of
      the glottis, in seven normal subjects and 13 OSA patients. Volume-pressure
      properties of the upper airway were assessed by elastance (Euaw) which was
      obtained from the slope of the regression line of the V-P relationships. Euaw in
      OSA patients was 0.52 +/- 0.08 cmH2O/mL, which was greater than in normal
      subjects (0.26 +/- 0.06 cmH2O/mL). Submental stimulation increased Euaw in both
      OSA patients and normal subjects (0.70 +/- 0.11 cmH2O/mL and 0.41 +/- 0.11
      cmH2O/mL, respectively). These results suggest that upper airways of OSA patients
      during wakefulness are less collapsible than those of normal subjects, and that,
      in both groups, submental stimulation may stiffen the upper airway.

PMID- 10339734
TI  - Addition of inhaled salmeterol to inhaled corticosteroids in patients with poorly
      controlled nocturnal asthma.
AB  - The effect of adding inhaled salmeterol to inhaled corticosteroids was studied in
      patients with poorly controlled nocturnal asthma. In a double-blind, cross-over
      study, 20 patients were randomized to receive either salmeterol 50 micrograms
      twice daily or placebo via a Diskhaler after a 1-week run-in period. After 4
      weeks of treatment, patients were subsequently crossed over to receive the other
      treatment for a further 4 weeks with a 2-week wash-out period in between. The
      response to treatment was assessed by peak expiratory flow rates (PEF) measured
      in the morning and evening, symptom scores of asthma, number of bronchodilators
      used, forced expiratory volume in one second (FEV1) and forced vital capacity
      (FVC) at regular intervals. Patients' preference for the Diskhaler or metered
      dose inhaler was assessed at the last visit. The results showed that morning PEF
      was significantly higher while on salmeterol than on placebo (296.9 +/- 70.2 vs
      274.6 +/- 77.4 L/min). Evening PEF showed a trend towards a higher value while on
      salmeterol than on placebo (321.1 +/- 73.4 vs 288.7 +/- 79.4 L/min), but the
      difference was not significant. There was no statistically significant
      improvement in symptom scores, number of rescue bronchodilators used and FEV1 or
      FVC between the two treatment groups. The occurrence of side effects in terms of
      tremors and palpitations between treatment and placebo were similar. There were
      more patients who preferred Diskhaler to metered-dose inhaler (70% vs 30%). We
      conclude that salmeterol 50 micrograms twice daily produces significant
      improvement in morning PEF and is well tolerated in patients with nocturnal
      asthma. Diskhaler is a device which is easy to use and preferred to a metered
      dose inhaler.

PMID- 10339735
TI  - Effects of nasal continuous positive airway pressure on pulmonary haemodynamics
      and tissue oxygenation in patients with obstructive sleep apnoea.
AB  - We investigated the acute effects of nasal continuous positive airway pressure
      (CPAP) on pulmonary haemodynamics and tissue oxygenation in eight men with
      obstructive sleep apnoea (OSA) by means of right heart catheterization. They were
      tested at four dosage levels of nasal CPAP: 0, 5, 10, and 15 cmH2O. Nasal CPAP
      significantly reduced the cardiac index at the 10 and 15 cmH2O doses. The mean
      pulmonary artery pressure was significantly elevated with 10 and 15 cmH2O, and
      pulmonary capillary wedge pressure was significantly increased with 15 cmH2O of
      nasal CPAP. Pulmonary vascular resistance was significantly increased with 10
      cmH2O of nasal CPAP. The 5 cmH2O dose of nasal CPAP did not affect significantly
      these parameters. Mixed venous oxygen tension was unchanged at any pressure. We
      conclude that tissue oxygenation was maintained in the OSA patients during
      administration of nasal CPAP, even though a high CPAP clearly affected pulmonary
      haemodynamics.

PMID- 10339736
TI  - Endobronchial metastasis from stomach cancer.
AB  - A young woman presented with a dry cough present during the previous 4 weeks. A
      chest radiograph demonstrated diffuse interstitial infiltration in both lower
      lung fields. Fibreoptic bronchoscopic examination revealed multiple 2-3 mm
      elevated nodules on the bronchial surface and a mucosal biopsy showed extensive
      subepithelial infiltration of poorly differentiated adenocarcinoma without
      definite precancerous alteration in the overlying epithelium. Studies for the
      evaluation of primary tumour focus were performed. Oesophagogastroduodenoscopy
      showed advanced gastric cancer of Borrmann type III, and mucosal biopsy of the
      stomach showed poorly differentiated adenocarcinoma. The patient was treated
      three times with systemic chemotherapy, but her condition deteriorated. Three
      months after diagnosis, she died of complicated pneumonia. This is a rare case of
      endobronchial metastasis from stomach cancer. The stomach is an unusual site of
      endobronchial metastasis from extrathoracic primary malignancy.

PMID- 10339737
TI  - Progressive bronchial obstruction associated with toxic epidermal necrolysis.
AB  - Toxic epidermal necrolysis (TEN) is an acute life-threatening condition,
      characterized by erosion of the mucous membranes, extensive detachment of the
      epidermis, and severe constitutional symptoms. Pulmonary complications of TEN are
      reported as rare, but are one of the most common causes of death. Our report
      focuses on an unusual case of toxic epidermal necrolysis which showed multiple
      bronchial obliteration during the chronic phase of the disease. Biopsied tissue
      of the obliterated bronchi demonstrated non-specific granulation. To improve the
      obliterated ventilatory function, we tried to reopen the bronchial obliteration
      using a balloon catheter under the guidance of fibreoptic bronchoscopy, however
      rapid restenosis of the bronchi ensued.

PMID- 10339738
TI  - Acute myopathy after status asthmaticus: steroids, myorelaxants or carbon
      dioxide?
AB  - Acute myopathy complicating treatment of status asthmaticus has been increasingly
      recognized since its original description in 1977. We report a case of an 11-year
      old boy with severe asthma requiring mechanical ventilation. He was given high
      doses of parenteral steroids and neuromuscular blockade with non-depolarizing
      agents in order to achieve controlled hypoventilation with an ensuing
      hypercapnoea. He developed rhabdomyolysis with elevated creatinine kinase and
      renal impairment secondary to myoglobinuria. Electrophysiological studies
      revealed myopathic abnormalities. The aetiology for this myopathy appears to be
      related to therapy with parenteral steroids, muscle-relaxant agents and
      respiratory acidosis. Patients treated with steroids and neuromuscular blocking
      agents should be regularly monitored for development of myopathy.

PMID- 10339739
TI  - Kinship and genomic imprinting.

PMID- 10339740
TI  - Genomic imprinting in plants.

PMID- 10339741
TI  - Imprinting and paternal genome elimination in insects.

PMID- 10339742
TI  - Imprinting and X-chromosome inactivation.

PMID- 10339743
TI  - The mechanisms of genomic imprinting.

PMID- 10339744
TI  - Human diseases and genomic imprinting.
AB  - In summary, there are a number of conditions where genomic imprinting effects are
      recognized to be associated clinical disorders of importance in humans. There may
      be many more. Genomic imprinting should be suspected in any disorder with
      overgrowth, undergrowth, or behavior abnormalities. Disorders with unusual
      pattern of inheritance should be studied for the possibility that genomically
      imprinted gene(s) are involved. Understanding the mechanisms of genomic
      imprinting has major ramifications in terms of recurrence risk, prediction of
      whether offspring will be affected, and risk of malignancy. Of particular concern
      is the potential for uniparental disomy when trisomy is found during prenatal
      diagnosis.

PMID- 10339745
TI  - Genomic imprinting and cancer.

PMID- 10339746
TI  - Mechanisms of transcriptional regulation.

PMID- 10339747
TI  - Epigenetic control of gene expression.

PMID- 10339748
TI  - Polycomb silencing and the maintenance of stable chromatin states.

PMID- 10339749
TI  - Domains and boundaries in chromosomes.

PMID- 10339750
TI  - A role for modifier genes in genome imprinting.

PMID- 10339751
TI  - Allelic trans-sensing and imprinting.

PMID- 10339752
TI  - Nuclear architecture.

PMID- 10339753
TI  - Appendix: imprinted genes and regions in mouse and human.

PMID- 10339754
TI  - [Radiation exposure and thoracic tomography].

PMID- 10339755
TI  - [A difficult baptism. Where does the syndrome of upper airway resistance exist?].

PMID- 10339756
TI  - [Radiation exposure and computed tomography].
AB  - Computed Tomography (CT) is recognized as a relatively high-dose diagnostic
      procedure. There is some obscurity in the literature about the doses due to
      conventional CT, spiral CT and High Resolution Computed Tomography (HRCT) of the
      chest. Conventional chest CT results in a radiation dose approximately 100 times
      that of a standard chest film and 10 times that of a mammography; on the other
      hand, conventional chest CT is safe for the lens and the pelvis (ovaries, testes
      and uterus). Radiation dose associated with helical CT is potentially lower than
      the dose associated with conventional CT. HRCT, consisting of 1- to 2- mm thick
      sections performed at 10 mm intervals, has an effective radiation dose lower than
      that of conventional CT, even with high-dose techniques (400 mAs). HRCT scans
      obtained at reduced milliamperage (40-80 mAs), the so-called "low-dose HRCT
      technique", may provide satisfactory visualization of lung parenchyma in the
      majority of cases and is recommended in patients in whom radiation dose is a
      major concern (pediatric population or young women in order to minimize breast
      irradiation). The awareness of radiation dose will become increasingly important
      for both referring physicians and radiologists when determining indications and
      deciding which types of imaging procedures and specific protocols should be used.

PMID- 10339757
TI  - [Are the ATS (American Thoracic Society) and the ERS (European Respiratory
      Society) correct in not recommending routine tumor marker assays foeening,
      staging, or evaluation of non-small cell lung cancer?].
AB  - The American Thoracic Society (ATS) and the European Respiratory Society (ERS) do
      not recommend routine tumor marker assay for screening, staging or evaluation of
      non-small-cell lung cancer (NSCLC). In contrast to this position, the statement
      of the French society of pneumology (Societe de Pneumologie de Langue Francaise,
      SPLF) suggests such assays may be useful for prognostic evaluation of NSCLC (and
      certainly so before treatment) and that the usefulness of serum CEA (carcino
      embryonic antigen) measurements before and after treatment is not clearly
      excluded. Our own review of the literature indicates that other routine tests
      less expensive than tumor markers such as LDH, prothrombin time, calcium, blood
      cell counts and even serum proteins might, alone or in combination, have a
      prognostic significance similar to, or even higher than, tumor markers. Since
      routine clinical laboratories have to set priorities for useful analyses, a clear
      reading of the biomedical literature suggests that it is not currently necessary
      to routinely measure serum tumor markers (including Cyfra 21-1) for the
      prognostic evaluation of NSCLC patients.

PMID- 10339758
TI  - [Pathogenesis of adult pulmonary Langerhans-cell histiocytosis].
AB  - Pulmonary Langerhans cell histiocytosis (LCH) is an uncommon disorder occurring
      most often in young smokers. Histologically, the disease is characterized by
      granulomatous lesions containing LC that destroy distal bronchioles. The etiology
      of the disease remains unknown, but progress has been made in understanding its
      pathogenesis. Modifications in the bronchiolar epithelium induced by smoking,
      such as the increased secretion of GM-CSF by these cells, are probably
      responsible for the initial accumulation of large numbers of LC. However, given
      the rarity of pulmonary LCH compared with the frequency of smoking, an as yet
      unidentified genetic predisposition may also be necessary for the development of
      the disease. Although LC in LCH granulomas may be clonal in origin, several
      observations argue against the idea that the disease, which can regress
      spontaneously, is a malignant process. Cells of dendritic cell lineage (including
      LC), are potent antigen presenting cells, suggesting that pulmonary LCH results
      from an uncontrolled immune response initiated by LC. Consistent with this idea,
      LC and T-cells are the predominant cell populations found in the early lesions of
      pulmonary LCH, and unlike LC in the normal bronchial mucosa and those
      accumulating in other pathologic situations, LC in pulmonary LCH granulomas
      express surface molecules important for the activation of T-lymphocytes. A number
      of mediators are produced in the microenvironment of granulomas that probably
      influence the outcome of the local immune and inflammatory reaction. Ultimately,
      precise knowledge of the pathogenesis of this disorder should permit the
      development of specific treatment. In the interim, therapies aimed at modifying
      the state of activation of LC in the granulomatous lesions may prove useful.

PMID- 10339760
TI  - [High (or abnormal) upper airway resistance].

PMID- 10339759
TI  - [Sleep-related cardiac insufficiency and respiratory disorders. Prevalence,
      physiopathology, and treatment].
AB  - Cheyne-Stokes respiration occurs during sleep in 40-45% of patients with NYHA
      class III and IV heart failure. Such patients experience repeated episodes of
      progressively diminishing ventilation associated with desaturation followed by
      periods of increasing-amplitude ventilation. The mechanism appears to be related
      to hyperventilation leading to hypocapnia which occurs near a critical threshold
      of apnea during sleep stages I and stage II and interrupts central ventilatory
      control. The total duration of the periodic respiration cycle would depend on the
      increased circulation time subsequent to lowered cardiac output. Brief periods of
      waking provoked by Cheyne-Stokes respiration, accentuating sympathetic nervous
      system activity, are an unfavorable prognostic factor in heart failure.
      Activation of the sympathetic system may be corrected by CPAP although the long
      term effect on heart failure remains controversial. Other treatments, such as
      oxygen therapy or theophylline, combined with optimized treatment of heart
      failure, have been proposed.

PMID- 10339761
TI  - [Non-invasive ventilation in acute or chronic respiratory failure: a comparison
      of volumetric ventilation].
AB  - BACKGROUND: Although experience acquired with non-invasive ventilation is recent,
      it is often proposed in selected patients with acute respiratory failure
      occurring in a background of chronic airflow obstruction. Barometric or
      volumetric techniques can be used. PATIENTS AND METHODS: We compared tolerance
      and efficacy of inspiration assist (IA) using a preset pressure and volume
      controlled ventilation (VC). Twelve patients with chronic airflow obstruction
      were randomized to IA (n = 7) or VC (n = 9) mode and ventilated with the
      appropriate mask. RESULTS: Tolerance was equivalent for the two groups although
      hypercapnia fell more in the IA group, particularly after 24 h ventilation (p <
      0.03), after three days (p < 0.05), and at complete weaning (p < 0.03).
      Correction of pH was significantly more rapid in the IA group than in the VC
      group (p < 0.05 at 24 h). There was no difference in the number of days of
      ventilation, total ventilation time, or length of hospital stay. Success of non
      invasive ventilation, defined as the control of acute respiratory failure without
      recourse to endotracheal ventilation, was similar in the two groups (86% in group
      IA and 60% in group VC). Two of the 5 patients in the VC group and one of the 7
      in the IA group required intubation.

PMID- 10339762
TI  - [Contribution of high-resolution volume computed tomography (HRVCT) for the
      exploration of diffuse pulmonary infiltrative disorders].
AB  - AIM: To assess high-resolution volume computed tomography (HRVCT) for the
      investigation of diffuse pulmonary infiltrative disorders. PATIENTS AND METHODS:
      Thirty patients with diffuse interstitial disease (idiopathic fibrosis n = 7,
      silicosis n = 4, asbestosis n = 5, sarcoidosis n = 7, histiocytosis n = 2,
      lymphangitis carcinomatosa n = 2, tuberculosis n = 1, bronchiolitis obliterans n
      = 1) were explored using high-resolution computed tomography (HRCT) and HRVCT.
      All diagnoses were proven by fiberscopy, bronchoalveolar lavage and respiratory
      function tests and/or lung biopsy. The HRVCT protocol consisted of spiral
      tomography using 10 mm slices. Data were processed with a Windows Advantage
      workstation (GE Milwaukee). Two readers compared multiprojection volume
      reconstruction (MPVR) using maximal intensity projection (MIP) and minimal
      intensity projection (MINIP) displays with millimetric HRCT slices acquired at
      the same volume. RESULTS: Micronodules were detected better with HRVCT than with
      HRCT. MIP mode enabled better distinction between nodules and vessels. MINIP mode
      enabled better detection of cysts in the pulmonary parenchyma than HRCT. The
      honeycomb aspect of pulmonary fibrosis was differentiated better than super
      infected central-lobar emphysema. MINIP mode enabled detection of ground glass
      opacities which were not visible on HRCT. Certain anomalies were however detected
      only on HRCT. HRVCT was very sensitive to movement effects which altered image
      quality, particularly in the MINIP mode. CONCLUSION: HRVCT is a new and promising
      approach for investigating diffuse pulmonary infiltrative disorders.

PMID- 10339763
TI  - [Occupational asthma in a Senegalese car sprayer. Diagnostic and medico-legal
      problems].
AB  - The industrial development policy adopted by African countries since their
      independence has contrasted with the relative rarity of occupational asthma in
      workers exposed to different situations and substances known to generate
      occupational asthma. Asthma occurring in a Senegalese car sprayer had persisted
      for twenty years before the its work-related nature was recognized. This
      observation demonstrates the need for: 1. Education to make health care
      personnel, as well as workers and employers, more aware of the clinical aspects
      of asthma. Educational programs should include diagnostic and preventive measures
      for respiratory occupational diseases including occupational asthma. 2. A
      registration system for occupational diseases so the occupational nature of
      diseases can acquire legal recognition. 3. Cooperative efforts between general
      practitioners, occupational physicians, physiologists and lung specialists in
      order to create reference laboratories where tests can be performed to confirm
      the diagnosis of occupational asthma, a disease which has not yet been included
      on the list of occupational diseases.

PMID- 10339764
TI  - [Long-term survival of a patient with melanoma with late recurrence of pulmonary
      metastasis treated by repeat surgery].
AB  - We report the case of a young woman initially treated with surgery, radiotherapy,
      chemotherapy and BCG therapy for stage II malignant melanoma involving the limbs.
      Considering that the risk of metastasis is usually maximal between 2 and 5 years
      after initial treatment, metastatic dissemination of this melanoma was rather
      unusual. Metastases were observed locally, regionally, and in the lungs 8, 10 and
      12 years respectively after the primary diagnosis. Repeat surgery was performed
      to resect pulmonary nodules. Such surgery is possible in less than 10% of the
      cases of metastatic melanoma. Our patient has survived without relapse for 21
      years after the initial diagnosis and 8 years after the last tumor excision.
      Recurrent pulmonary metastasis without extrapulmonary dissemination would suggest
      the tumor cell population was composed of a particular metastatic phenotype.

PMID- 10339765
TI  - [Diagnosis of an opacity at the lung base: intrathoracic kidney].
AB  - A 72-year-old patient was admitted for exploration of an opacity of the left base
      discovered fortuitously on a routine chest x-ray. Initial blood tests were
      normal. Fiberoptic bronchoscopy was normal. Computed tomography (CT) led to the
      diagnosis of a left kidney which had risen into a retro-cardiac position.
      Magnetic resonance imaging established the sub-diaphragmatic position of the
      kidney. Renal excretion was normal on intravenous urography. An ectopic kidney in
      an intrathoracic position is very uncommon and may raise a major challenge when
      visualized as a mediastinal or pulmonary opacity. Computed tomography or
      intravenous urography can provide the diagnosis and magnetic resonance imaging
      demonstrates its precise sub-diaphragmatic or supra-diaphragmatic position.

PMID- 10339766
TI  - [Mediastinal leiomyosarcoma].
AB  - Leiomyosarcomas are extremely rare tumors which develop from smooth muscle,
      usually in the esophagus and large vessels (inferior vena cava, pulmonary artery,
      and superior vena cava). In very rare cases, leiomyosarcomas develop from small
      vessels in the soft tissue of the mediastinum. Clinical expression of mediastinal
      leiomyosarcomas (dysphagia, dysphonia) is related to their large size and the
      subsequent compression of mediastinal structures. At pathology examination, the
      gross aspect is one of a single cell tumor. Microscopically, the tumor may be
      highly undifferentiated making it necessary to use specific immune markers (actin
      and desmin) or ultra-structural analysis to establish the diagnosis. Treatment of
      localized tumors is based on surgical excision, either alone or in combination
      with radiotherapy of the mediastinum. Chemotherapy, generally dexorubicin, is
      indicated in case of metastatic dissemination, but outcome remains uncertain. As
      for all soft tissue sarcomas, the prognosis of mediastinal leiomyosarcoma depends
      on the size of the tumor, its histological structure and its resectability.

PMID- 10339767
TI  - [Percutaneous vertebroplasty complicated by pulmonary embolus of acrylic cement].
AB  - Although venous escape of cement has been frequently noted during percutaneous
      vertebroplasty, no case of pulmonary embolus directly linked to this manoeuvre
      has been described in the literature. We report a case of pulmonary embolus of
      acrylic cement occurring immediately after the procedure. Outcome was favorable
      following anticoagulant therapy despite the persistence of some vascular
      obstruction suggesting the association of residual fibrinous matter in the
      pulmonary artery.

PMID- 10339768
TI  - [Diagnosis of unusual bilateral lung opacities].

PMID- 10339769
TI  - [An uncommon endotracheal finding].

PMID- 10339770
TI  - [Management of community-acquired lower respiratory tract infection in the adult.
      Recommendations by the French Language Society of Pneumology with collaboration
      of the French Language Society of Infectious Pathology, from the recommendations
      of the European Respiratory Society].

PMID- 10339771
TI  - [Beriberi: a common disease in Reunion].

PMID- 10339772
TI  - [Climate therapy for children with respiratory allergy].
AB  - Climate therapy is often proposed for children with severe allergic asthma which
      remains uncontrolled in spite of adapted treatment. The beneficial effects of
      climate therapy are related to the reduced allergenic load and to the fact that
      mites do not survive at high altitudes. Less exposure to allergens leads to
      improved respiratory function, decreased bronchial hyperreactivity and lower
      levels of total and specific IgE as well as markers of inflammation. These
      different actions combine to produce a lower prevalence of asthma at higher
      altitudes. Other advantages of climate therapy is related to better management of
      care by a multidisciplinary team. This in turn enables: a combined medial and
      paramedical approach to stablize the asthma with minimal effective doses of drug
      therapy; the development of a specific educational program aimed at improving
      therapeutic compliance; and an individualized education adapted to the learning
      problems which are often important in these children. The problems of the child
      being separated from his/her parents and the risk of recurrence after returning
      home must also be addressed and can generally be prevented by simple precautions.

PMID- 10339773
TI  - TNF-alpha-targeted therapy in rheumatoid arthritis.

PMID- 10339774
TI  - Idiopathic carpal tunnel syndrome. Clinical, electrodiagnostic, and magnetic
      resonance imaging correlations.
AB  - BACKGROUND: Although carpal tunnel syndrome is diagnosed primarily on clinical
      grounds, a number of investigations can be helpful in confirming the diagnosis
      and providing therapeutic orientation. Electrodiagnostic testing is the most
      widely used method in everyday practice but can be inconclusive or inconsistent
      with the clinical findings. Magnetic resonance imaging is useful in such cases.
      OBJECTIVES: To compare the diagnostic usefulness of electrodiagnostic testing and
      magnetic resonance imaging in patients with carpal tunnel syndrome. PATIENTS AND
      METHODS: Thirty-three cases of clinically-defined carpal tunnel syndrome in 20
      patients were investigated by electrodiagnostic testing and magnetic resonance
      imaging. The nerve entrapment was categorized as mild, moderate, or severe based
      on clinical and electrodiagnostic findings. Structures evaluated on magnetic
      resonance imaging scans were the median nerve, the flexor retinaculum, the flexor
      tendons, the fat lying deep to the tendons, the thenar compartment, and the
      carpal bones. RESULTS: Bowing of the transverse carpal ligament, high signal from
      the median nerve on T2 images, and median nerve enlargement were found in 70%,
      57%, and 55% of cases, respectively. Bowing of the transverse carpal ligament is
      a cause of mechanical compression, whereas the other two signs reflect injury to
      the median nerve. High signal from the median nerve was associated with more
      severe clinical and/or electrodiagnostic abnormalities. CONCLUSION: When
      electrodiagnostic abnormalities suggest more severe disease than expected or are
      otherwise discordant with clinical findings, demonstration by magnetic resonance
      imaging of high median nerve signal and/or median nerve enlargement may help to
      select those patients most likely to benefit from surgical treatment.

PMID- 10339775
TI  - Magnetic resonance imaging findings in idiopathic adhesive capsulitis of the
      shoulder.
AB  - OBJECTIVES: To describe magnetic resonance imaging findings in idiopathic
      adhesive capsulitis of the shoulder. PATIENTS AND METHODS: Twenty patients with
      idiopathic adhesive capsulitis of the shoulder underwent magnetic resonance
      imaging involving two spin-echo T2-weighted sequences with fat saturation and two
      spin-echo T1-weighted postgadolinium sequences; for all sequences, sections were
      obtained in the oblique coronal and transverse axial planes. Findings were
      compared to those obtained using the same imaging protocol in 15 patients with
      clinical manifestations of rotator cuff tear. RESULTS: Postgadolinium enhancement
      of the joint capsule and synovial membrane was seen in the rotator interval in
      all 25 adhesive capsulitis patients and in the axillary recess in 22 of the 25.
      Only one of the 15 rotator cuff tear patients had this finding. In both groups,
      postgadolinium enhancement occurred in the subacromial bursa, in the rotator cuff
      tendons, and in the acromioclavicular joint. No significant rotator cuff tears
      were found in any of the adhesive capsulitis patients. CONCLUSION: In difficult
      cases, magnetic resonance imaging with gadolinium injection can contribute to the
      diagnosis of idiopathic adhesive capsulitis of the shoulder.

PMID- 10339776
TI  - Is it possible to predict the efficacy at discharge of inhospital rheumatology
      department management of disk-related sciatica? A study in 150 patients.
AB  - OBJECTIVES: To identify criteria for predicting the outcome at discharge in
      patients scheduled for inhospital treatment of disk-related sciatica. PATIENTS
      AND METHODS: We studied 150 rheumatology department patients admitted for disk
      related sciatica with a mean duration of 88 +/- 127 days to determine the impact
      on treatment outcomes of 50 parameters. RESULTS: After complete bed and 2.2 +/-
      1.1 epidural glucocorticoid injections during a mean hospital stay of 9.9 +/- 4.3
      days, 80% of patients reported either complete or partial pain relief (19% and
      61%, respectively). The remaining 20% reported little (9%) or no (11%) change.
      Surgery was performed in 13% of cases. A tighter straight-leg raising test angle
      was correlated with treatment failure (P = 0.01). Complete bed rest duration
      prior to admission was shorter in the 80% of responders (P = 0.036) than in the
      20% of nonresponders; in the overall population, patients spent on average 64% +/
      33% of daytime hours in bed. Patient predictions about their own outcomes were
      unreliable (P = 0.926). Patients who believed strongly that sciatica requires
      surgical treatment were more likely to be nonresponders (P = 0.06), as were
      patients with a family history of surgically-treated sciatica (P = 0.055).
      Outcomes were not correlated with any of the other parameters studied, including
      sciatica duration (P = 0.13), bedrest duration prior to admission (P = 0.52; mean
      duration, 18 +/- 29 days), the specialty of the physicians seen, investigations
      done prior to admission, or a history of sciatica (noted in 65% of cases and
      treated surgically in 16%). CONCLUSIONS: Eighty percent of patients benefited
      from their hospital stay. Patient opinions on the merits of nonsurgical and
      surgical treatments in their own case were not correlated with their own
      outcomes. A tight straight leg-raising test angle was correlated with a poorer
      outcome. Neither sciatica duration nor rest duration prior to admission had an
      influence on outcome. Absence of complete bed rest prior to admission was
      correlated with a greater likelihood of a therapeutic benefit from the hospital
      stay.

PMID- 10339777
TI  - Evaluation of the efficacy of etidronate therapy in preventing glucocorticoid
      induced bone loss in patients with inflammatory rheumatic diseases. A randomized
      study.
AB  - The prevention and treatment of glucocorticoid-induced osteoporosis is a major
      concern for rheumatologists since inflammatory joint disease is among the most
      common reasons for long-term glucocorticoid therapy. We used a randomized placebo
      controlled design to evaluate the efficacy of one-year cyclical etidronate
      therapy in preventing bone loss in 83 glucocorticoid-treated patients with
      rheumatoid arthritis, polymyalgia rheumatica, or giant cell arteritis.
      Glucocorticoid treatment duration was shorter than three months, and the starting
      dose was greater than 7.5 mg of prednisone-equivalent per day. Etidronate was
      given according to the standard cyclical schedule, i.e. 400 mg/d for periods of
      14 days separated by 76-day intervals during which patients took 500 mg of
      supplemental calcium per day. The primary evaluation criterion was the change in
      lumbar spine bone mineral density after one year of etidronate therapy. Bone
      mineral density decreased by 1.94 +/- 0.61% in the placebo group and increased by
      0.86 +/- 0.6% in the etidronate group, yielding a between-group difference of 2.8
      +/- 0.86% (P = 0.002). The difference was largest in postmenopausal women (3.38
      +/- 1.11%; P = 0.004). At the femoral neck, there was a smaller bone mineral
      density decrease in the etidronate than in the placebo group, but the difference
      (1.11 +/- 1.13%) was not statistically significant. The most common side effects
      were gastrointestinal symptoms and showed no difference between the two groups.
      Four fractures (including one vertebral fracture) occurred in the placebo group
      versus two (including one vertebral) in the etidronate group. Etidronate prevents
      glucocorticoid-induced lumbar spine bone loss in patients with rheumatoid
      arthritis, polymyalgia rheumatica, or giant cell arteritis.

PMID- 10339778
TI  - Shoulder pain in patients with Parkinson's disease.

PMID- 10339779
TI  - Is combination second-line therapy in rheumatoid arthritis more aggressive than
      helpful?

PMID- 10339780
TI  - Polyradiculoneuropathy revealing a solitary plasmacytoma of the ilium. A new case
      report.
AB  - Neurological manifestations are uncommon in myeloma patients, and subacute
      polyradiculoneuropathy as the inaugural manifestations of solitary plasmacytoma
      of bone is exceedingly rare. We report the case of a 52-year-old man who was
      evaluated for a three-month history of flaccid tetraplegia with a gradually
      ascending onset and for a deterioration in general health. Electromyography
      findings were consistent with polyradiculoneuropathy. Laboratory tests showed a
      moderate amount of a monoclonal IgG-lambda antibody. Findings were normal from a
      radiographic bone survey and a radionuclide bone scan. Computed tomography of the
      pelvis disclosed a solitary osteolytic lesion in the right iliac crest, which was
      found upon biopsy to be a malignant plasmacytoma. Radiation therapy and
      chemotherapy were given. Subacute or chronic polyradiculoneuropathy as the
      inaugural manifestation of solitary plasmacytoma is exceedingly rare and should
      be distinguished from the sensorimotor polyneuropathy produced by plasma cell
      infiltration in some multiple myeloma patients. The polyradiculoneuropathy of
      solitary plasmacytoma can be likened to the neuropathies seen in some forms of
      multiple myeloma (sclerotic myeloma and POEMS syndrome). The pathophysiology of
      these neuropathies remains obscure. The case reported here suggests that patients
      with unexplained lasting polyradiculoneuropathy should be investigated for a
      plasma cell proliferation even if they have no serum monoclonal component.
      Because plasmacytomas are painless, imaging studies are needed for their
      diagnosis. The management of the neuropathy consists in treatment of the tumor.

PMID- 10339781
TI  - A leptomeningeal metastasis revealed by sciatica.
AB  - Meningeal metastatic disease usually occurs as a complication of a brain tumor
      and is exceptionally isolated in patients with solid tumors. We report the case
      of a 74-year-old woman admitted for mechanical S1 sciatica refractory to drug
      therapy. She had been treated for breast cancer three years earlier. Physical
      findings were pain upon hyperextension of the lumbar spine and absence of the
      ankle jerks. Analysis of cerebrospinal fluid sampled during an intrathecal
      glucocorticoid injection showed 1 g/L of protein and 11 normal cells per mm3.
      Grade 3 L5-S1 spondylolisthesis was seen on plain radiographs, computed
      tomography scans, and magnetic resonance imaging scans. At that point, the
      patient developed sphincter dysfunction and motor loss in the left lower limb in
      the distribution of several nerve roots. Findings were normal from a myelogram
      and a magnetic resonance imaging study of the brain. A repeat cerebrospinal fluid
      analysis showed 1.1 g/L of protein and 5 cells/mm3. Because of the discrepancy
      between the clinical and imaging study findings, the patient was transferred to a
      neurology department. A third cerebrospinal fluid study showed numerous
      adenocarcinoma cells, and a repeat magnetic resonance imaging demonstrated a mass
      in the dural sac opposite L2. A program of monthly intrathecal methotrexate
      injections was started. A fatal meningeal relapse occurred eight months later.
      CONCLUSION: This case shows that a leptomeningeal metastasis can cause isolated
      nerve root pain, and demonstrates the diagnostic value of magnetic resonance
      imaging and cerebrospinal fluid cytology in patients with atypical symptoms,
      particularly when there is a history of malignant disease.

PMID- 10339782
TI  - Two new cases of glucocorticoid-induced pancreatitis.

PMID- 10339783
TI  - Late-onset McArdle's disease mimicking treatment-resistant polymyositis. Report
      of a case and review of the literature.

PMID- 10339784
TI  - Multiple rib fractures caused by coughing in a young woman without bone loss.

PMID- 10339785
TI  - Tiopronin-induced myasthenia.

PMID- 10339786
TI  - Cutaneous vasculitis is not always benign.

PMID- 10339787
TI  - [Multiple sclerosis and pregnancy: clinical issues].
AB  - Multiple sclerosis (MS) is the most common chronic disabling neurological disease
      affecting young women. Paradoxically, our knowledge of the relationship between
      pregnancy and MS is limited. However, several conclusions emerge from the
      literature: 1) The rate of relapse in MS decreases during pregnancy, and it rises
      significantly during the first three months post partum before coming back to its
      level prior to pregnancy. 2) Although pregnancy and delivery cause changes of the
      relapse rate, they have no influence on mid and long term residual disability. 3)
      Breast-feeding and epidural analgesia do not seem to have any deleterious effect
      on the disease. 4) Lastly, MS does not seem to influence pregnancy, delivery or
      the child's health. The studies available to date suffer from methodological
      limitations. They need to be confirmed by prospective studies. This is the
      purpose of the study entitled "Pregnancy in multiple sclerosis, PRIMS", which has
      been carried out since 1992 at the European level.

PMID- 10339788
TI  - [Epilepsies. Did you say 'epilepsy'?].
AB  - Epileptic disorders have been neglected for a long time by neurologists and
      practically ignored by pediatricians, satisfied with a diagnosis of infantile
      convulsions. Results of animal experimentation, huge progress in ancillary tests,
      potent antiepileptic drugs and efficacious neurosurgical procedures have
      considerably improved the condition of epileptic patients. However, much remains
      to be done. Even if numerous and varied, data given to physicians and patients
      are still insufficient. Stigma linked to the word epilepsy is present in many
      cases. It adds a supplementary burden to people who are not lacking in problems.
      Too often, epilepsy remains a word used in the singular, but epileptic seizure is
      not synonymous with epilepsy. The outcome and hence the consequences of
      epilepsies are quite various. A diagnosis of seizure may be difficult, and its
      classification not easy in all the cases. To place it in context, that is to find
      its causes and consequences is even more difficult. A good knowledge of epileptic
      disorders and efforts to use it are necessary, but one of them, or both, can be
      absent. This is unfortunate, because of the frequency and duration of conditions
      in which seizures are a symptom, and also because their outcome mostly depends on
      therapeutic choices. Only clinical, pragmatic aspects of the issue are considered
      here.

PMID- 10339789
TI  - [Superficial siderosis of the central nervous system].
AB  - We report five cases of superficial siderosis of the central nervous system. All
      patients developed progressive deafness and cerebellar ataxia associated with
      pyramidal tract signs or mental deterioration. The cerebrospinal fluid
      examinations usually revealed an elevated protein level, without other
      abnormalities. Magnetic resonance imaging typically showed a hypointense rim
      around the cerebral and cerebellar hemispheres, the brainstem and the spinal cord
      on T2-weighted images. A definite source of bleeding was only found in two
      patients. The literature on superficial siderosis is reviewed. The etiologies and
      the pathogenesis are discussed.

PMID- 10339790
TI  - [Ataxic hemiparesis due to lacunar infarct].
AB  - Ataxic hemiparesis is a syndrome in which pyramidal and cerebellar signs occur on
      the same side. Few authors have suggested that signs or symptoms can orientate
      toward a supratentorial or toward an infratentorial lesion. We have studied the
      risk factors and the clinical symptoms of 61 patients consecutively admitted for
      an ataxic hemiparesis due to a lacunar infarct diagnosed with MRI. The MRI was
      normal in 2 cases. A tandem lacunar infarct was found in 9 cases (pons and
      internal capsule in 5 cases, pons and corona radiata in 4 cases) and a clinico
      radiological correlation was performed in 50 cases. The comparison of risk
      factors did not show any difference between the infratentorial (n = 10) and the
      supratentorial groups (n = 40) excepting for the history of coronary disease. The
      history of coronary disease was statistically more frequent in the infratentorial
      group. No difference was found for clinical findings between the 2 groups.

PMID- 10339791
TI  - [Neurological manifestations indicative of brucellosis].
AB  - Eight patients presented neurological signs secondary to Brucella infection. The
      clinical presentation was a meningoencephalitis in three cases, a
      meningoencephalomyelitis in one case, an epiduritis with spinal cord compression
      in one case, an acute polyradiculoneuritis in two cases and a chronic
      polyradiculoneuritis in one case. Acoustic nerve was impaired in seven cases.
      Cerebrospinal fluid (CSF) analysis revealed a lymphocytic meningitis and a high
      protein concentration in all cases. The agglutination test titers were elevated
      in the serum and in the CSF of seven patients (> or = 1/80) and two patients
      respectively. Brucella melitensis culture was disclosed in the blood of one
      patient and in the CSF of two patients. Three patients were treated by the
      association cycline and rifampicin whereas a tritherapy including cycline,
      rifampicin and TMP-SMZ was used in the other cases. Outcome was favorable in
      seven cases. This study outlines the polymorphism of neurological manifestations
      due to brucellosis, even in familial cases and this diagnostic must be especially
      done in Middle East and South Mediterranean countries.

PMID- 10339792
TI  - [Should folic acid be given to women treated with valproic acid and/or
      carbamazepine? Folic acid and pregnancy in epilepsy].
AB  - Fetal exposure to valproic acid or carbamazepine increases the risk of neural
      tube defect (NTD). The risk of a mother having a baby with spina bifida has been
      estimated at 1-2 p. 100, close to the rate of risk of recurrent cases. No study
      has evaluated the effect of folic acid in neonates of women treated with valproic
      acid or carbamazepine although the protective effect against NTD has been proven
      in other populations. Periconceptional folic acid supplementation, 0.4 to 1
      mg/day, for at least one month prior to conception and until the date of the
      second missed menstrual period or later decreases the incidence of a first
      occurrence of neural tube defect. Periconceptional folic acid supplementation, 4
      mg/day, decreases the recurrence of NTD in women who had previously had a child
      with NTD. It seems pertinent to recommend periconceptional folic acid
      supplementation in women treated with carbamazepine or valporic acid. There are
      very few data in women on which to base a decision to advise taking 4 mg/day (as
      used in recurrence prevention) or low doses of 0.4 mg/day (used in primary
      prevention).

PMID- 10339793
TI  - [Facial myositis: a localized form of generalized myositis?].
AB  - We report a case of myositis presenting as an apparently unique progressive
      facial weakness. The only biological abnormality after an 8-year follow-up was an
      immunocytoma. Molecular analyses excluded facioscapulohumeral muscular dystrophy.
      Based on this single case and a review of the literature, we suggest a continuum
      between focal myositis and generalized myositis.

PMID- 10339794
TI  - [Steinert disease associated with Klinefelter's syndrome].
AB  - Hypogonadism is common in Steinert disease but may also suggest other diagnoses.
      We report the case of a patient with Steinert's disease who also had Klinefelter
      syndrome disclosed at 62 years of age by an osteoporotic fracture. Both clinical
      diagnoses were confirmed by karyotype and genetic analysis. The hypogonadism
      assigned to the Klinefelter syndrome for this patient may have influenced the
      clinical expression of the muscular pathology.

PMID- 10339795
TI  - [Cerebral miliary granulomatosis with Histoplasma capsulatum in an HIV
      seronegative patient].
AB  - A 51 year old patient who worked in Africa for eight years, presented twelve
      years later a progressive ataxia associated with headaches. Neuroimaging studies
      done after a partial complex seizure demonstrated multiple supra and sub
      tentorial cortical ring enhancing lesions. Histoplasma capsulatum histoplasmosis
      was found on histological examination of brain biopsy and confirmed by isolation
      of the fungus. Medical treatment with intravenous amphotericin B followed by oral
      itraconazole (400 mg per day) improved both clinical and radiological status.
      This observation of cerebral histoplasmosis is rather unusual for a seronegative
      HIV patient in a non endemic area.

PMID- 10339796
TI  - [Transcutaneous neurostimulation].

PMID- 10339797
TI  - [A case of Wernicke's encephalopathy caused by an extremely unbalanced diet].

PMID- 10339798
TI  - [Remaining solvents in dry cleaned over clothes].
AB  - We examined remaining solvents in dry cleaned trousers to estimate the magnitude
      of environmental pollution. A cleaning solvent of petroleum hydrocarbon was
      analyzed by means of capillary column mass spectrum gas chromatography. Principal
      ingredients were identified to be nonane, decane and undecane. The same main
      components were detected in dry cleaned trousers. Total amounts of evaporated
      vapor from a pair of trousers (480 g) in 5 days after dry cleaning were nonane
      (0.73 mg), decane (1.53 mg) and undecane (1.09 mg). The levels on the fifth day
      were 5%(nonane), 18%(decane) and 32%(undecane) of the first day's concentration,
      respectively. The half times of the remaining solvents were 1.0 day (nonane), 1.7
      days (decane) and 2.7 days (undecane), respectively.

PMID- 10339799
TI  - [Evaluation of erythrocyte concentrate prescription in a university hospital
      center].
AB  - This prospective study, based on declaratory data, evaluates the appropriateness
      of red blood cell transfusion prescriptions in a university hospital. Local
      recommendations written after data collection and the analysis of prescriptions
      using a blinded method limited the bias related to the declaratory data. The
      results show that the rate of unjustified prescriptions is 4.2% (95% CI: 2.2%;
      6.2%). This rate is statistically (P = 0.032) lower in the department of surgery
      (1.3%) than in the department of medicine (5.7%). This rate tends to decrease
      according to the experience of the prescriber (P = 0.06) and varies significantly
      according to the hemoglobin levels (P = 0.03). The logistic regression,
      integrating these three parameters, confirms that only the hemoglobin level is
      significantly related (P < 0.003) to the appropriateness of RBC transfusions.
      This study also highlights problems not linked to prescriptions, and the hospital
      created a quality assurance program as a result.

PMID- 10339800
TI  - [Comparison of two techniques for detection of anti-Plasmodium falciparum
      antibodies: Falciparum-spot IF (Biomerieux) and Malaria IgG Celisa (BMD).
      Preliminary results].
AB  - We compared a new Elisa assay to detect malaria antibodies: Malaria IgG Celisa
      (BMD) with the IFAT technique Falciparum-spot IF (Biomerieux): sensitivity,
      specificity, predictive positive and negative values were 81%, 99%, 95%, 95%,
      respectively. Eight patients had positive thick blood smear out of 23 performed.
      For these eight confirmed acute malaria cases, the Elisa assay was negative in
      five instances. For two recent malaria attacks both Elisa and IFI were negative.
      With blood donors, two sera were IFAT positive and Elisa negative; 16 were IFAT
      doubtful and Elisa negative. Doubtful results rose up to 13.5% by IFAT against
      1.5% by Elisa assay. We preferred kappa coefficient instead of chi 2 test for
      data analysis, which measures the concordance degree between the two techniques.
      Here concordance is moderate. Choosing an Elisa assay to detect the transmission
      of malaria for at-risk blood donors collides with the method sensitivity compared
      with IFAT as reference.

PMID- 10339801
TI  - [Diagnostic difficulties of transfusion incidents due to bacterial contamination:
      report of two cases].
AB  - The French hemovigilance system has recently underlined the relative frequency of
      transfusion-associated bacterial sepsis and the necessity to remain constantly
      aware of this eventuality. We describe the experience of a hematology unit over a
      18-month period: 189 acute transfusion reactions were registered and bacterial
      cultures of the implicated cellular blood products realized in 82 of them. A
      positive result was obtained in two cases. For both cases, clinical symptoms of
      transfusion reaction were limited to a lasting fever, and a skin rash occurred in
      aplastic patients with preexisting signs of sepsis. The causal relationship
      between this contamination and the transfusion reaction is difficult to
      establish. Clinical manifestations justifying a bacterial inquiry must therefore
      be more precisely defined, particularly in multitransfused patients.

PMID- 10339802
TI  - [Quality in training].
AB  - Knowledge has become an essential resource in developed societies, and hence the
      role of training has become ever more important. Training is the basis of
      professional proficiency. This is of particular interest in a public service such
      as blood transfusion, which is rapidly developing. To remain competent, a
      professional must regularly update his (her) basic knowledge. This requires an
      efficient training support. To implement a quality assurance system in a training
      center, several factors must be considered: the choice of a reference system; the
      evaluation of the customer's needs; the control and the assessment procedures.

PMID- 10339803
TI  - [Continuous improvement of quality and implementation of a system for
      notification of noncompliance].
AB  - Building the organization for the detection and the management of defects or non
      conformities is a main step in the implementation of a quality system. This
      article describes some ways of doing this in a blood bank. It explains its role
      and its relations with other actions in the process of quality improvement.

PMID- 10339804
TI  - [Inspection of blood transfusion establishments].
AB  - Required by the law, the medico-technical inspection of blood banks is a
      centralized, specialized and pluridisciplinary inspection in order to check that
      blood transfusion centers abide by the official regulations implemented to assure
      the quality of products and transfusion safety.

PMID- 10339805
TI  - [Erythrocyte transfusion practices after allogeneic hematopoietic stem cell
      transplantation].
AB  - Allogeneic peripheral blood hematopoietic stem cell transplantation is being
      evaluated in a randomized French study comparing the use of peripheral blood stem
      cells vs. bone marrow graft stem cells. In order to standardize
      immunohematological (IH) assessment and transfusion practices within our
      protocol, we made suggestions to 25 allo-transplantation French centers on the
      following elements: pre-inclusion IH assessment, IH exclusion criteria,
      transfusion rules, post-transplantation IH surveillance and treatment of
      hemolysis. The analysis of their responses to our suggestions led us to elaborate
      recommendations which were approved and implemented by the French Bone Marrow
      Transplantation Society (SFGM). These recommendations concern the transfusion
      practice in the general framework of allogeneic hematopoietic stem cell
      transplantation and can therefore be considered as referential.

PMID- 10339806
TI  - Anaerobic degradation of 3-halobenzoates by a denitrifying bacterium.
AB  - A denitrifying bacterium was isolated from a river sediment after enrichment on 3
      chlorobenzoate under anoxic, denitrifying conditions. The bacterium, designated
      strain 3CB-1, degraded 3-chlorobenzoate, 3-bromobenzoate, and 3-iodobenzoate with
      stoichiometric release of halide under conditions supporting anaerobic growth by
      denitrification. The 3-halobenzoates and 3-hydroxybenzoate were used as growth
      substrates with nitrate as the terminal electron acceptor. The doubling time when
      growing on 3-halobenzoates ranged from 18 to 25 h. On agar plates with 1 mM 3
      chlorobenzoate as the sole carbon source and 30 mM nitrate as the electron
      acceptor, strain 3CB-1 formed small colonies (1-2 mm in diameter) in 2 to 3
      weeks. Anaerobic degradation of both 3-chlorobenzoate and 3-hydroxybenzoate was
      dependent on nitrate as an electron acceptor and resulted in nitrate reduction
      corresponding to the stoichiometric values for complete oxidation of the
      substrate to CO2. 3-Chlorobenzoate was not degraded in the presence of oxygen. 3
      Bromobenzoate and 3-iodobenzoate were also degraded under denitrifying conditions
      with stoichiometric release of halide, but 3-fluorobenzoate was not utilized by
      the bacterium. Utilization of 3-chlorobenzoate was inducible, while synthesis of
      enzymes for 3-hydroxybenzoate degradation was constitutively low, but inducible.
      Degradation was specific to the positive of the halogen substituent, and strain
      3CB-1 did not utilize 2- or 4-chlorobenzoate.

PMID- 10339807
TI  - Molecular cloning and characterization of Ct-PKAR, a gene encoding the regulatory
      subunit of cAMP-dependent protein kinase in Colletotrichum trifolii.
AB  - Colletotrichum trifolii is a plant pathogenic fungus causing alfalfa anthracnose.
      Prepenetration development, including conidial germination and appressorial
      formation, are requisite for successful infection. Pharmacological data from our
      laboratory indicated a role for a cAMP-dependent protein kinase (PKA) pathway
      during these early morphogenic transitions. Thus, the cloning and
      characterization of the genes for PKA catalytic and regulatory subunits were
      undertaken to more precisely determine the function of PKA during C. trifolii
      pathogenic growth and development. In this report, the cloning, sequencing, and
      partial characterization of the gene encoding the regulatory subunit of cAMP
      dependent protein kinase (Ct-PKAR) is described. An open reading frame of 1,212
      bp containing 404 predicted amino acid residues was identified. Database analysis
      revealed that the deduced amino acid sequence of Ct-PKAR shares considerable
      similarity with that of PKA regulatory subunits in other organisms, particularly
      in the conserved regions. Furthermore, the Ct-PKAR protein is classified as a
      type II regulatory subunit based on the presence of the hall-mark
      autophosphorylation site. Southern blot analysis indicated that Ct-PKAR is a
      single-copy gene. Northern blot analysis showed that the expression of Ct-PKAR is
      developmentally regulated. Ct-PKAR was shown to be a functional regulatory
      subunit of PKA by complementating the Neurospora crassa mcb mutant, which has a
      temperature-sensitive mutation in the regulatory subunit of PKA.

PMID- 10339808
TI  - Specific detection of green sulfur bacteria by in situ hybridization with a
      fluorescently labeled oligonucleotide probe.
AB  - An oligodeoxynucleotide probe (GSB-532) specific for green sulfur bacteria was
      developed. Highly stringent hybridization conditions were established using whole
      cells of Chlorobium limicola DSM249 immobilized on glass slides. At a formamide
      concentration of 10%, the optimum specificity was reached at 47 degrees C. When a
      conventional fixation procedure was used, a conspicuous autofluorescence
      developed within the cells. This autofluorescence was due to the liberation of
      bacteriochlorophyll by the detergent Triton X-100 and a subsequent conversion to
      bacteriophenophytin and related compounds. The signal-to-noise ratio could be
      increased by a final dehydration of the samples with methanol. Finally, the
      method was adapted to the hybridization of natural samples collected on
      polycarbonate membrane filters. In situ hybridization of pure cultures, various
      enrichments, and natural samples from the chemocline of a freshwater lake
      confirmed that probe GSB-532 hybridized exclusively to cells of green sulfur
      bacteria. Our protocol allows the highly specific detection of green sulfur
      bacteria in water samples and a rapid screening of natural bacterial communities.
      Employing probe GSB-532, the phylogenetic affiliation of the epibionts in
      "Chlorochromatium aggregatum" and "Pelochromatium roseum" could be demonstrated
      for the first time.

PMID- 10339809
TI  - Comparative effects of Saccharomyces cerevisiae cultivation under copper stress
      on the activity and kinetic parameters of plasma-membrane-bound H(+)-ATPases PMA1
      and PMA2.
AB  - The major yeast plasma membrane H(+)-ATPase is encoded by the essential PMA1
      gene. The PMA2 gene encodes an H(+)-ATPase that is functionally interchangeable
      with the one encoded by PMA1, but it is expressed at a much lower level than the
      PMA1 gene and it is not essential. Using genetically manipulated strains of
      Saccharomyces cerevisiae that exclusively synthesize PMA1 ATPase or PMA2 ATPase
      under control of the PMA1 promoter, we found that yeast cultivation under mild
      copper stress leads to a similar activation of PMA2 and PMA1 isoforms. At high
      inhibitory copper concentrations (close to the maximum that allowed growth),
      ATPase activity was reduced from maximal levels; this decrease in activity was
      less important for PMA2 ATPase than for PMA1 ATPase. The higher tolerance to high
      copper stress of the artificial strain synthesizing PMA2 ATPase exclusively, as
      compared to that synthesizing solely PMA1 ATPase, correlated both with the lower
      sensitivity of PMA2 ATPase to the deleterious effects of copper in vivo and with
      its higher apparent affinity for MgATP, and suggests that plasma membrane H(+)
      ATPase activity plays a role in yeast tolerance to copper.

PMID- 10339810
TI  - Pathogenesis of Vibrio vulnificus.
AB  - This review describes the factors which are currently recognized as being central
      to the virulence of the human pathogen, Vibrio vulnificus. This estuarine/marine
      bacterium occurs in high numbers in molluscan shellfish, primarily oysters, and
      its ingestion in raw oysters results in a ca. 60% mortality in those persons who
      are susceptible to this bacterium. The organism is also able to produce life
      threatening wound infections. We describe here the nature of both the wound and
      primary septicemia infections, the virulence factors known or believed to be
      involved in these infections, possible immunotherapy, and some thoughts on the
      possibility that not all strains of this pathogen are virulent.

PMID- 10339811
TI  - Cloning and characterization of the esp region from a dog attaching and effacing
      Escherichia coli strain 4221 and detection of EspB protein-binding to HEp-2
      cells.
AB  - The espA, espB and espD genes from enteropathogenic Escherichia coli were
      previously shown to be essential for triggering the signal transduction in
      infected host cells. We have cloned and determined the nucleotide sequences of
      the espA, espB and espD homologues from an E. coli strain (4221) isolated from a
      dog which manifested the attaching and effacing lesions in the small intestine.
      This strain is designated as a dog enteropathogenic E. coli. When comparing
      predicted amino acid sequences to those of the corresponding proteins from
      enteropathogenic E. coli O127, enterohemorrhagic E. coli serotype O26,
      enterohemorrhagic E. coli O157 and rabbit enteropathogenic E. coli, the EspADEPEC
      protein showed the same level of similarity (75% identity) with EspA of
      enteropathogenic E. coli O127 and rabbit enteropathogenic E. coli. The EspBDEPEC
      protein showed the highest similarity with the EspB of enteropathogenic E. coli
      O127 (99% identity). The EspDDEPEC protein showed 88% identity with the EspDEPEC.
      We constructed and purified a maltose-binding fusion protein containing the
      product of the entire espBDEPEC gene of the dog enteropathogenic E. coli strain
      4221. Purified maltose-binding protein-EspBDEPEC fusion protein was shown to bind
      efficiently to HEp-2 cells in a localized fashion as shown by immunofluorescence
      microscopy. In addition, when the dog enteropathogenic E. coli strain 4221 was
      grown in tissue culture medium (DMEM) supplemented with serum, a secreted 36-kDa
      protein was identified by immunoblot analysis using a polyclonal antiserum
      against the maltose-binding protein-EspBDEPEC fusion protein.

PMID- 10339812
TI  - Early colonization of the rat upper respiratory tract by temperature modulated
      Bordetella bronchiseptica.
AB  - The ability of nonmodulated Bvg+ phase cultures, temperature modulated Bvg- phase
      cultures, and a Bvg- phase-locked mutant of Bordetella bronchiseptica to colonize
      the rat upper respiratory tract was investigated. Initially, greater numbers of
      the temperature modulated Bvg- phase bacteria adhered to the nasal cavity of the
      rats. The temperature modulated Bvg- phase bacteria appeared to be quickly
      cleared to levels lower than the Bvg+ phase bacteria by 4 h after inoculation and
      stayed lower until 48 h after inoculation when colonization levels were equal to
      the Bvg+ phase bacteria. The level of colonization with the Bvg- phase-locked
      mutant of B. bronchiseptica was lower than both the nonmodulated Bvg+ phase and
      temperature modulated Bvg- phase cultures and declined over time during the
      experiment. These findings suggest that there may be increased adherence from an
      environmental phase to ensure bacteria survive initial clearance mechanisms until
      the switch to the Bvg+ phase occurs.

PMID- 10339813
TI  - Cloning and molecular characterization of the citrate utilization citMCDEFGRP
      cluster of Leuconostoc paramesenteroides.
AB  - The citMCDEFGRP cluster from Leuconostoc paramesenteroides involved in citrate
      utilization was cloned and its nucleotide sequence determined. Homology of the
      inferred gene products with characterized enzymes reveals that citP encodes the
      citrate permease P, citC the citrate ligase and citDEF the subunits of the
      citrate lyase of Leuconostoc. Moreover, it suggests that citM encodes a
      Leuconostoc malic enzyme. Analysis of citrate consumption by and citrate lyase
      activity of Lc. paramesenteroides J1[pCITJ1] showed that its citrate permease and
      its citrate lyase are induced by the presence of citrate in the growth medium.
      Southern blot analysis demonstrated that the citMCDEFGRP cluster is located in a
      plasmid.

PMID- 10339814
TI  - The molybdenum cofactor biosynthesis protein MobA from Rhodobacter capsulatus is
      required for the activity of molybdenum enzymes containing MGD, but not for
      xanthine dehydrogenase harboring the MPT cofactor.
AB  - The requirement of MobA for molybdoenzymes with different molybdenum cofactors
      was analyzed in Rhodobacter capsulatus. MobA is essential for DMSO reductase and
      nitrate reductase activity, both enzymes containing the molybdopterin guanine
      dinucleotide cofactor (MGD), but not for active xanthine dehydrogenase, harboring
      the molybdopterin cofactor. In contrast to the mob locus of Escherichia coli and
      R. sphaeroides, the mobB gene is not located downstream of mobA in R. capsulatus.
      The mobA gene is expressed constitutively at low levels and no increase in mobA
      expression could be observed even under conditions of high MGD demand.

PMID- 10339815
TI  - BLAST 2 Sequences, a new tool for comparing protein and nucleotide sequences.
AB  - 'BLAST 2 Sequences', a new BLAST-based tool for aligning two protein or
      nucleotide sequences, is described. While the standard BLAST program is widely
      used to search for homologous sequences in nucleotide and protein databases, one
      often needs to compare only two sequences that are already known to be
      homologous, coming from related species or, e.g. different isolates of the same
      virus. In such cases searching the entire database would be unnecessarily time
      consuming. 'BLAST 2 Sequences' utilizes the BLAST algorithm for pairwise DNA-DNA
      or protein-protein sequence comparison. A World Wide Web version of the program
      can be used interactively at the NCBI WWW site
      (http://www.ncbi.nlm.nih.gov/gorf/bl2.++ +html). The resulting alignments are
      presented in both graphical and text form. The variants of the program for PC
      (Windows), Mac and several UNIX-based platforms can be downloaded from the NCBI
      FTP site (ftp://ncbi.nlm.nih.gov).

PMID- 10339816
TI  - FramePlot: a new implementation of the frame analysis for predicting protein
      coding regions in bacterial DNA with a high G + C content.
AB  - FramePlot is a web-based tool for predicting protein-coding regions in bacterial
      DNA with a high G + C content, such as Streptomyces. The graphical output
      provides for easy distinction of protein-coding regions from non-coding regions.
      The plot is a clickable map. Clicking on an ORF provides not only the nucleotide
      sequence but also its deduced amino acid sequence. These sequences can then be
      compared to the NCBI sequence database over the Internet. The program is freely
      available for academic purposes at http://www.nih.go.jp/jun/cgi-bin/frameplot.pl.

PMID- 10339817
TI  - Electron beam fragmentation of bacterial polysaccharides as a method of producing
      oligosaccharides for the preparation of conjugate vaccines.
AB  - End-group mediated conjugation of bacterial polysaccharides (PSs) to carrier
      proteins containing T-helper cell epitopes renders such polysaccharides
      immunogenic also in young infants. Optimal construction of such conjugate
      vaccines requires fragmentation of the PS prior to the coupling reaction. In the
      present study a general simple and inexpensive method for the fragmentation of
      PSs is presented. It is based on the irradiation of isolated PSs in an electron
      beam accelerator. Exposure of isolated pneumococcal capsular polysaccharides
      (PnPSs) to ionizing radiation resulted in their partial depolymerization in a
      radiation dose-dependent manner. Radiation, unlike sonication, generated PnPS
      fragments of molecular size lower than 50 kDa and as small as 1.5 kDa when high
      radiation doses were used. These PnPS fragments have terminal reducing groups
      that can be easily used for chemical activation and subsequent coupling to any
      chosen carrier protein. The radiation-produced PnPS fragments retained their
      antigenic epitopes, when compared to native, full-size PnPSs as determined by
      enzyme-linked immunoassay.

PMID- 10339818
TI  - Identification of a new locus in Listeria monocytogenes involved in cellobiose
      dependent repression of hly expression.
AB  - Expression of the PrfA-controlled virulence gene hly (encoding the pore-forming
      cytolysin listeriolysin) is down-regulated by readily metabolized carbon sources
      in Listeria monocytogenes. We isolated a Tn917-insertional mutant of L.
      monocytogenes (strain LO28), which expressed a hemolytic phenotype in the
      presence of cellobiose. Using hly fusions to luxAluxB genes, we show that hly
      expression was derepressed in the presence of cellobiose at the transcriptional
      level. Surprisingly, hly expression was still repressed by glucose, as observed
      for the parental strain. Genetic analysis of the Tn917-flanking regions indicated
      that the transposon had inserted in a non-coding region located between two genes
      in opposite orientations. These two newly identified genes were designated orfA
      and mdrL. The insertion occurred immediately upstream of orfA, likely into its
      promoter region. Transcriptional analysis of orfA and mdrL revealed that Tn917
      had abolished orfA expression whereas it had activated expression of mdrL. orfA
      encodes a putative protein of 176 amino acids homologous to YfiO of Bacillus
      subtilis (28% identity), a protein of unknown function. mdrL codes for a putative
      protein of 398 amino acids homologous to Bmr and Blt of B. subtilis (21-24%
      identity), two members of the multidrug resistance efflux pump family. Our
      results indicate that we have identified a new locus which plays a crucial role
      in the cellobiose-dependent repression of hly expression.

PMID- 10339819
TI  - Lux-biosensor assessment of pH effects on microbial sorption and toxicity of
      chlorophenols.
AB  - Lux-marked bacterial biosensors and a commercial toxicity testing bacterial
      strain (Microtox) were exposed to 2,4-dichlorophenol (DCP) and the light output
      response measured. Increasing DCP concentrations caused a decrease in light
      output in all three biosensors with an order of sensitivity (in terms of
      luminescence decrease over the DCP concentration range) of Pseudomonas
      fluorescens < Escherichia coli < Microtox. Adsorption of DCP to E. coli was
      measured using uniformly ring labelled [14C]DCP and found to be very rapid. The
      effect of pH on toxicity and adsorption was also investigated. Low pH values
      increased the amount of DCP adsorbed to the cell and increased the toxicity of
      DCP.

PMID- 10339820
TI  - Electropulsation as an alternative method for protein extraction from yeast.
AB  - The application of series of high intensity electric pulses to a yeast suspension
      provoked a considerable release of some cytoplasmic proteins, glutathione
      reductase, 3-phosphoglycerate kinase and alcohol dehydrogenase. A maximal yield
      was achieved 3-8 h after pulsation. The electro-induced protein efflux was
      accelerated by pretreatment with the reducing agent dithiothreitol and showed a
      strong dependence on the growth phase and the presence of monovalent ions in the
      post-pulse incubation medium. The results obtained for two strains of
      Saccharomyces cerevisiae, PV3 (diploid) and Y47 (wild haploid), showed that
      electropulsation can be used for the effective extraction of cytoplasmic proteins
      with a preserved functional activity.

PMID- 10339821
TI  - Molecular characterisation of a 5.75-kb cryptic plasmid from Bifidobacterium
      breve NCFB 2258 and determination of mode of replication.
AB  - A small cryptic plasmid originating from Bifidobacterium breve NCFB 2258 was
      cloned and its complete nucleotide sequence determined. pCIBb1 is a circular DNA
      molecule, 5750 bp in size with a GC composition of 57%. Computer-assisted
      analysis identified 10 possible open reading frames (ORFs), seven of which could
      be assigned no function from homology searches. One ORF, rep (380 amino acids),
      was postulated to encode a replication protein similar to known replication
      proteins of rolling circle replicons, particularly those of the pC194 family.
      Demonstration of single-stranded forms of the plasmid in cell lysates that could
      be specifically degraded by S1 nuclease provided experimental evidence to
      substantiate a replication mechanism via single-stranded intermediates. Two other
      ORFs, par (199 amino acids) and an ftsK-like gene (286 amino acids), were
      assigned putative functions based on the presence of conserved motifs in their
      deduced proteins.

PMID- 10339822
TI  - Metabolism of L(-)-carnitine by Enterobacteriaceae under aerobic conditions.
AB  - Different Enterobacteriaceae, such as Escherichia coli, Proteus vulgaris and
      Proteus mirabilis, are able to convert L(-)-carnitine, via crotonobetaine, into
      gamma-butyrobetaine in the presence of carbon and nitrogen sources under aerobic
      conditions. Intermediates of L(-)-carnitine metabolism (crotonobetaine, gamma
      butyrobetaine) could be detected by thin-layer chromatography. In parallel, L(-)
      carnitine dehydratase, carnitine racemasing system and crotonobetaine reductase
      activities were determined enzymatically. Monoclonal antibodies against purified
      CaiB and CaiA from E. coli O44K74 were used to screen cell-free extracts of
      different Enterobacteriaceae (E. coli ATCC 25922, P. vulgaris, P. mirabilis,
      Citrobacter freundii, Enterobacter cloacae and Klebsiella pneumoniae) grown under
      aerobic conditions in the presence of L(-)-carnitine.

PMID- 10339823
TI  - Distribution of a family of Haemophilus influenzae genes containing CCAA
      nucleotide repeating units.
AB  - A family of genes containing lengths of CCAA nucleotide repeating units directly
      following the sequence encoding the leader peptide has been identified in
      Haemophilus influenzae. The length of the CCAA repeats ranges from 6 to 43 and
      all of the identified genes encode proteins or predicted proteins with a
      significant homology to bacterial iron- or heme-related outer membrane proteins.
      We have previously shown that two of these gene products, HgpA and HgpB, bind
      hemoglobin and the hemoglobin-haptoglobin complex. Studies were performed to
      define the species distribution of the five identified genes and the CCAA
      repeats. We show that both the CCAA motif and the structural genes for hemoglobin
      and hemoglobin-haptoglobin binding are widely distributed among H. influenzae
      strains.

PMID- 10339824
TI  - Cloning and characterization of mdc genes encoding malonate decarboxylase from
      Pseudomonas putida.
AB  - The DNA fragment encoding malonate decarboxylase, involved in malonate
      assimilation, was cloned from Pseudomonas putida. The 11-kb DNA fragment
      contained nine open reading frames, which were designated mdcABCDEGHLM in the
      given order. N-terminal protein sequencing established that the mdcA, mdcC, mdcD,
      mdcE and mdcH genes encoded subunits alpha, delta, beta, gamma and epsilon of the
      malonate decarboxylase, respectively. Malonate decarboxylase was functionally
      expressed in Escherichia coli from plasmid harboring the entire gene cluster or
      the mdc genes lacking the mdcL and mdcM genes. The mdcL and mdcM genes encode
      membrane proteins and disruption of the genes of P. putida by the insertion of a
      kanamycin resistance cassette reduced the malonate uptake activity of the
      organism. Thus, we conclude that MdcLM is a malonate transporter.

PMID- 10339825
TI  - Mycoplasma cavipharyngis and Mycoplasma fastidiosum, the closest relatives to
      Eperythrozoon spp. and Haemobartonella spp.
AB  - The 16S rRNA gene sequences of Mycoplasma cavipharyngis and Mycoplasma
      fastidiosum have been determined. Phylogenetic analysis showed that these species
      formed a new cluster within the so-called pneumoniae group of the mollicutes
      (class Mollicutes). This cluster will be referred to as the M. fastidiosum
      cluster. Interestingly, the M. fastidiosum cluster formed a sister lineage to the
      haemotrophic bacteria. Eperythrozoon spp. and Haemobartonella spp. The two latter
      genera, formerly classified as rickettsias, formed a stable phylogenetic entity
      in the tree as judged from branch lengths, bootstrap values and sequence
      signatures. Thus, the members of the M. fastidiosum cluster are the closest known
      relatives to the haemotrophic bacteria. Our data strongly support that the
      haemotrophic bacteria should be reclassified to reflect their actual phylogenetic
      affiliation.

PMID- 10339826
TI  - A new chloramphenicol and florfenicol resistance gene flanked by two integron
      structures in Salmonella typhimurium DT104.
AB  - A new chloramphenicol resistance gene from Salmonella typhimurium DT104,
      designated floR, also conferring resistance to florfenicol, was characterized.
      Sequence analysis of the deduced FloR protein suggested that it belongs to the 12
      TMS (transmembrane segments) multidrug efflux pumps family. The floR gene, and
      the downstream sequenced tetR and tetA tetracycline resistance genes, were
      surrounded by two class 1 integrons. The first one contained the resistance gene
      aadA2 and a deleted sulI resistance gene. The second one contained the beta
      lactamase gene pse1 and a complete sulI gene. Thus, the floR gene is included in
      a multiresistance locus of at least 12.5 kb. Its particular organization and
      chromosomal location could be involved in the antibioresistance pattern stability
      of the DT104 Salmonella typhimurium strains.

PMID- 10339827
TI  - Structure and function of a conserved DNA region coding for tartrate utilization
      in Agrobacterium vitis.
AB  - Three tartrate utilization regions from Agrobacterium vitis strains involved in
      host specificity have been compared, to clearly define the borders of these
      regions and eventually identify specific sequences that could provide a mechanism
      of duplication of this region. A 10.8-kb conserved DNA fragment called the TAR
      element, found in different genetic contexts, was defined. A comparison of the
      two tartrate dehydrogenase genes (ttuC and ttuC') in each of the three TAR
      elements suggests that these genes co-evolve.

PMID- 10339828
TI  - Effects of hydrogen peroxide on growth and selected properties of Porphyromonas
      gingivalis.
AB  - In this study we first evaluated the effects of hydrogen peroxide (H2O2) on
      growth and selected properties of Porphyromonas gingivalis, and compared them
      with those obtained by a reducing agent (cysteine). The growth of P. gingivalis
      was only moderately affected when H2O2 was added at concentrations up to 30 mM in
      a complex culture medium. However, when a defined basal medium was used, H2O2 at
      a concentration of 3 mM completely inhibited growth of P. gingivalis.
      Incorporation of cysteine at concentrations up to 30 mM in both media had no
      effect on growth. The effects of H2O2 and cysteine on cell-associated
      hemagglutinating and Arg-gingipain activities were evaluated using bacteria grown
      in the complex culture medium. Both activities were strongly decreased when H2O2
      was added in the assay mixtures. This inhibitory effect of H2O2 was reversible.
      On the other hand, including cysteine in the assay mixtures increased both
      activities. H2O2 and cysteine had no effect on the expression of heat shock
      protein (HSP)-68 and HSP-75 by P. gingivalis, as determined by SDS-PAGE and
      Western immunoblotting analysis. In the second part of the study, we tested
      whether growth of selected oral bacterial species may modify the oxidation
      reduction potential (Eh) of the environment. It was found that certain species
      were able to either decrease (P. gingivalis, Fusobacterium nucleatum,
      Peptostreptococcus micros, Streptococcus mutans) or increase (Streptococcus
      sanguis) the Eh of the medium. Our study provides evidence that an oxidizing
      agent such as H2O2 may affect the biology of P. gingivalis. Moreover, growth of
      some members of the oral microflora can generate oxidizing and reducing
      conditions, and thus potentially influence the ecology of subgingival sites by
      affecting strictly anaerobic bacteria such as P. gingivalis.

PMID- 10339829
TI  - Monitoring of chromosomal insertions of the IncJ elements R391 and R997 in
      Escherichia coli K-12.
AB  - The integration site(s) of the IncJ element, R391, was localised to a specific
      region of the Escherichia coli chromosome, between the uxuA and serB loci (98.0
      99.5 min), using classical Hfr mapping techniques. F-prime plasmid hosts, diploid
      for regions spanning the E. coli chromosome, were used as recipients in R391 and
      R997 conjugal transfer assays. Analysis of transconjugants revealed the
      integration of R391 and R997 into specific F-primes that contain the uxuA to serB
      region, but not F-primes that contain other regions of the chromosome. A
      comparison of the electrophoretic mobility of the original F-primes with those
      containing inserts demonstrated the integration of large elements, in excess of
      85 kb. Linear integration of the IncJ elements into chromosomal DNA was
      demonstrated in recombination-deficient (recA) backgrounds in the absence of
      detectable autonomous stages. These observations account for the inability to
      isolate plasmid DNA from IncJ hosts, and suggests that the elements exhibit a
      conjugative transposon-like biology in E. coli.

PMID- 10339830
TI  - Emergence of a laccase-positive variant of Azospirillum lipoferum occurs via a
      two-step phenotypic switching process.
AB  - Two variants have been isolated from the wild-type Azospirillum lipoferum strain
      4B. The first variant, 4V(I), spontaneously emerged from the wild-type at
      frequencies in the order of 10(-4) to 10(-3) per cell generation. Compared to the
      wild-type, the 4V(I) variant gained (production of a carotenoid-like pigment,
      assimilation of certain carbohydrates) and lost (swimming motility, reduction of
      triphenyl tetrazolium chloride, acid production from certain sugars) apparently
      unrelated phenotypic characteristics. Only from the 4V(I) variant, a second
      atypical stable form, variant 4V(II), which acquired laccase activity and ability
      to produce melanin, appeared under very specific conditions, namely growth at
      extremely low oxygen concentrations. Neither of the variants was able to revert
      to the parental phenotype. The results suggest that atypical non-motile laccase
      positive isolates of A. lipoferum that are found in the rice rhizosphere
      originate from wild-type (motile, laccase-negative) cells via a two-step
      phenotypic switching event, a non-motile laccase-negative variant being an
      intermediate phase.

PMID- 10339831
TI  - Characterization of the antiseptic-resistance gene qacE delta 1 isolated from
      clinical and environmental isolates of Vibrio parahaemolyticus and Vibrio
      cholerae non-O1.
AB  - The nucleotide sequence and mechanism of action were examined on the antiseptic
      resistance gene qacE delta 1 that had been isolated from Pseudomonas aeruginosa,
      Vibrio parahaemolyticus and Vibrio cholerae non-O1. The nucleotide sequences of
      qacE delta 1 genes isolated from environmental isolates of V. cholerae non-O1 and
      V. parahaemolyticus differed by one base from that of the gene from P.
      aeruginosa. Escherichia coli C600 that harbored qacE delta 1 genes from several
      strains of Vibrio spp. exhibited low-level resistance to intercalating dyes. The
      resistance of E. coli cells with these genes to intercalating dyes, such as
      ethidium bromide, was mediated by an efflux system. Moreover, the activity of
      QacE delta 1 was inhibited in the presence of calcium channel blockers but not of
      calmodulin inhibitors. These results indicate that the qacE delta 1 gene can be
      function in E. coli and that the gene mediates resistance in a similar manner to
      the antiseptic-resistance gene smr.

PMID- 10339832
TI  - Characterization of gram-positive tellurite resistance encoded by the
      Streptococcus pneumoniae tehB gene.
AB  - Streptococcus pneumoniae is a Gram-positive bacterium which is naturally
      resistant to tellurite. In this study, we cloned and sequenced a homologue of the
      Escherichia coli tellurite resistance gene tehB from S. pneumoniae. It encoded a
      protein of 284 amino acids which is 86 residues longer than E. coli TehB, but
      similar in size to Haemophilus influenzae TehB and Eikenella corrodens
      hemagglutinin (Hag1) as well as homologues from Actinobacillus
      actinomycetemcomitans, Neisseria gonorrhoeae and Neisseria meningitidis. The S.
      pneumoniae TehB displayed 46-58% identity (52-68% similarity) to these proteins.
      The results in this study showed that the S. pneumoniae tehB alone not only
      conferred on E. coli high level resistance to tellurite, but also caused
      filamentous morphology in E. coli.

PMID- 10339833
TI  - Team leadership: network differences in women's and men's instrumental and
      expressive relations.
AB  - Recent studies have emphasised differences in leadership styles between women and
      men. Women have an "interactive" leadership style while men are more "directive"
      and "authoritative." Social network analysis is used to examine differences in
      eight mental health case management teams, half formally supervised by women and
      half by men. The techniques used are graphical displays and measures of
      centrality. Results show male leaders as the most central team member for both
      instrumental and expressive relations. Female leaders, however, do not adhere to
      a single leadership style. Team centralisation also differs with gender
      composition of teams influencing leadership differences.

PMID- 10339834
TI  - Shifts in case mix and locus of mental health care for Washington State adults
      with severe mental illness.
AB  - The author describes outcomes of interventions that were aimed at decreasing high
      use of state hospitals. Research focused on changes in state hospital case mix
      and dynamics of use by individuals identified as "high utilizers" before and
      after the Washington State Mental Health Division (MHD) implemented a series of
      interventions designed to reduce use. A set of recommendations are offered for
      policymakers who plan interventions that shift the locus of care for severely and
      persistently mentally ill adults.

PMID- 10339835
TI  - Follow-up contact bias in evaluation of substance abuse treatment programs.
AB  - This study examined the problem of follow-up contact bias in evaluation of
      substance abuse treatment programs using administrative data sets. Completed
      discharges in Iowa were compared to clients contacted 6 months after treatment.
      The percent of clients reporting no substance use doubled between admission to
      treatment and follow-up. Unemployment, arrests, and number of days of work or
      school missed declined. However, clients included in the follow-up sample were
      significantly different in terms of risk factors for adverse outcomes. The
      authors conclude that improvements in social functioning 6 months after discharge
      cannot be generalized to the entire population of clients treated, since those
      not found have a different combination of risk factors.

PMID- 10339836
TI  - Factors influencing managers' adherence to the Americans with Disabilities Act.

PMID- 10339837
TI  - Privatization and the rise and fall of the public mental health safety net.

PMID- 10339838
TI  - [When a headache has to be investigated?].

PMID- 10339839
TI  - [Recent-onset headache is a risk factor of intracranial lesion. A prospective
      study of 299 patients].
AB  - BACKGROUND: There is some controversy in the medical literature concerning the
      need to perform neuroimaging studies in neurologically normal patients
      complaining of headaches. The objective of the study is to determine the
      detection rate of intracranial abnormalities by computed tomography in patients
      with different headache durations. METHOD: Consecutive patients with the chief
      complaint of headache referred for neurological evaluation from January 1996 to
      April 1997 were studied both clinically and by computed tomography scanning.
      Brain magnetic resonance imaging was performed in 15 patients. Cerebrospinal
      fluid and/or blood analyses were performed when clinically indicated to rule out
      subarachnoid hemorrhage, meningitis or temporal arteritis. RESULTS: 15 (5%) out
      of the 299 patients available for study had significant intracranial lesion. 3
      (1%) out of the 266 patients with headaches lasting for more than 1 month had
      computed tomography findings considered clinically significant and neurological
      examination was normal in 2 (0.7%) patients with abnormal scans. Patients with a
      headache duration of 1 month or less had the following case-finding rate: an
      overall significant intracranial abnormality of 36% (12/33) and significant
      intracranial abnormality in neurologically normal patients of 15% (5/33).
      CONCLUSION: Patients with headache of recent onset (duration of 1 month or less),
      even with normal neurological examination, are at greater risk of significant
      intracranial abnormality than patients with long-lasting headaches. These
      patients at risk should be studied by cranial computed tomography and lumbar
      puncture if the computed tomography scan is normal and the cause of the headaches
      cannot be clinically determined.

PMID- 10339840
TI  - [Left-sided endocarditis in patients with HIV infection].
AB  - BACKGROUND: Left-sided endocarditis in HIV-infected patients has an special
      clinical, epidemiological and microbiological characteristics and its
      relationship with drug addicts subjects is unknown. PATIENTS AND METHODS: Since
      1986 up to 1996 we have been diagnosed 214 episodes of infective endocarditis in
      190 HIV-infected patients. In 34 cases (15%) there was left-sided endocarditis.
      These patients are described. RESULTS: Mean age was 30 years and 28 were male
      (82%). Thirty patients had been intravenous drug addicts (IVDA) but only 18 were
      active-IVDA. In three cases the endocarditis was nosocomial. Mean CD4+ lymphocyte
      count was 176 per mm3 and 59% were AIDS-patients. Tuberculosis was the most
      frequent opportunistic infection (14 cases). The presentation was subacute in 70%
      and the most important symptom was fever. Only 3 (9%) had septic emboli in chest
      X-ray. The affected valve was mitral in 31 patients (91%). The blood culture was
      negative in 21 episodes (62%) and only in 6, Staphylococcus aureus was isolated.
      The mortality was 18% and 68% were outcome without any problem. CONCLUSIONS: Left
      sided endocarditis in patients with HIV infection is a very serious problem. It
      seems to affect to patients with severe immunosuppression and the culture blood
      may be negative. Its diagnosis is difficult and the mortality is elevated.

PMID- 10339841
TI  - [Incidence of primary gastric lymphoma and H. pylori infection in the central
      zone of Asturias].
AB  - OBJECTIVE: We review our experience with primary gastric lymphomas type B of low
      (MALT) and high grade in a population of 366,635 people during 4 years and after
      performing 9,268 gastroscopies. RESULTS: The incidence of these lymphomas in our
      medium is similar to that found in the world population. Possible disagreements
      among the biopsy histology and that of the subsequent gastrectomy samples is
      pointed out. CONCLUSIONS: The frequency of H. pylori involvement in our primary
      gastric lymphomas is similar to that reported in the literature for the age of
      our patients, for the MALT lymphomas an well as for the type B high grade.

PMID- 10339842
TI  - [Adenocarcinoma in Barrett's esophagus. A retrospective study of 46 patients
      followed during 3.5 years].
AB  - OBJECTIVE: To determine the incidence of adenocarcinoma in patients with
      Barrett's esophagus and to study the characteristics in these patients. METHODS:
      Between January 1988 and June 1997 was diagnosed 46 patients with Barrett's
      esophagus. In all tem was analyzed the age, the follow-up period, the chief
      presenting symptoms leading to endoscopy, endoscopy esophagitis and complications
      of Barrett's esophagus. RESULTS: The mean age at the time of Barrett's diagnosis
      was 58 years. The mean follow-up period was 43 months. Presenting symptoms were
      heartburn in 35 (76%) patients, dysphagia in 3 (6.5%), thoracic pain 3 (6.5%),
      hemorrhage 2 (4.5%) and others in 3 (6.5%). Endoscopic esophagitis was present in
      24 (52%) patients during the follow-up. Complications developed was stricture,
      ulceration or haemorrhage in 14 (30.4%) patients, two (4.3%) have adenocarcinoma
      and one dysplasia. Incidence of adenocarcinoma was 1/82 patient-years of follow
      up. All three patients with adenocarcinoma or dysplasia was males. Two of the
      three presented with heartburn and the mean follow-up until development of
      dysplasia or cancer was 63 months. CONCLUSIONS: Heartburn and endoscopic
      esophagitis is frequent in these patients. The risk of development of and
      adenocarcinoma or others complications is high.

PMID- 10339843
TI  - [Vascular risk factors in non-insulin-dependent diabetes mellitus. Correlation
      between albuminuria and glycosylated hemoglobin].
AB  - OBJECTIVE: This study compared 23 patients with non-insulin-dependent diabetes
      mellitus (NIDDM) and 28 non-diabetic control subjects, seeking for associations
      between NIDDM and other cardiovascular risk factors. The relationship of the
      glycemic control with the risk factor profile was also assessed. RESULTS: The
      most outstanding results were: The diabetic group showed higher values in the
      proportion of subjects with diabetes family history (P < 0.01) and the levels of
      systolic blood pressure (P < 0.05), total cholesterol (P < 0.05), triglyceridemia
      (P < 0.001), and total cholesterol to HDL cholesterol ratio (P < 0.01). Within
      the diabetic group, a positive correlation (r = 0.68, P < 0.001) was found
      between the percent of glycosylated haemoglobin (HbA1c) and the 24-hour urinary
      albumin excretion rate (UAER). CONCLUSION: We conclude that NIDDM associates to
      other cardiovascular risk factors. The correlation of HbA1c with UAER suggests a
      possible relationship between poor diabetic control and some of the secondary
      diabetic complications.

PMID- 10339844
TI  - [Non-Hodgkin's disease of the skull in a patient with AIDS].
AB  - The involvement of bone in non-Hodgkin's lymphoma (NHL) is rare and usually
      occurs in the late stages of the disease. The involvement of the cranial vault is
      exceptional and we have found only eleven cases previously reported in the
      revised literature, none of them in an AIDS patient. We report a case of a 38
      years old man, intravenous drug abuser with AIDS diagnosed who presented with
      coma. Computed tomography scan showed a left frontal intra-parenchymatous
      haematoma and multiple osteolytic lesions in the whole of the cranial vault, that
      involved outertable, diploe and innertable. Intra-parenchymatous haematoma was
      removed and a biopsy of the osteolytic lesions was performed. Histology showed
      features of a large B-cell NHL. Patient died of infectious pulmonary
      complications. The incidence of NHL in patients with congenital or acquired
      immunodeficiencies is increasing and Epstein-Barr virus and other factors have
      been involved in its pathogenesis. That's the first AIDS patient reported to have
      a NHL involving the cranial vault. Tumour was limited to the cranial vault
      without involvement of soft-tissue. An intra-parenchymatous haematoma was
      associated without an explained cause.

PMID- 10339845
TI  - [Acute myocardial infarction related to cocaine use].
AB  - Cocaine is a drug capable of potentiating the response to catecholamines. Acute
      myocardial infarction is the most frequently reported cardiac consequence of
      cocaine abuse, usually in those patients who had used cocaine in a habitual
      basis. We report a 30-year-old man, first-time cocaine user, that suffered an
      acute myocardial infarction.

PMID- 10339847
TI  - [Intermittent obstructive jaundice as a form of presentation of duodenal
      diverticulum].
AB  - We report the case of a previously well 89-years-old-healthy man who presented at
      least four episodes of intermittent obstructive jaundice during the eight months
      prior to admission in our Hospital. Studies revealed a duodenal diverticulum
      arising near of the ampulla of Vater. We believed the diverticulum was
      responsible for the intermittent obstructive jaundice and we performed a
      choledochoduodenostomy. He had no postoperative complications and was discharged
      from the hospital asymptomatic. This case documents an uncommon presentation of
      this disease generally asymptomatic with intermittent obstructive jaundice
      episodes.

PMID- 10339846
TI  - [Intravascular infection caused by Salmonella enteritidis].
AB  - We report one case of salmonellosis aortitis in a 70 years old man after an
      episode of gastroenteritis due to Salmonella enteritidis successfully resolved
      with extraanatomic by-pass and prolonged antibiotic administration.

PMID- 10339848
TI  - [Intra-abdominal tumor in a young man].
AB  - Desmoid tumor is a rare neoplasm with extra-abdominal location and female
      predilection. Anatomopatological analysis is necessary to establish the diagnosis
      unequivocally, but Magnetic Resonance is the no aggressive method with the best
      sensitivity and specificity. Surgical resection is the elective treatment yet,
      and prognosis is not so good as it could be expected in a benign tumor. We report
      a young male case without polyposis coli antecedents. When he was attended, he
      related only an abdominal bulk with no other symptom. An intra-abdominal mass 32
      cm length per 25 cm width consistent with desmoid tumor was finally resected.

PMID- 10339849
TI  - [Body composition and constitution: a constitutional syndrome (1st of 2 parts)].
AB  - Constitutional syndrome alters body constitution modifying (usually decreasing)
      two of its dimensions--weight and perimeters--by changing the composition of one,
      several or every body levels. Apart of the cause, the basic physiopathological
      process that characterizes this new syndrome is the amino acid mobilization from
      the muscle (proteolysis). As soon as fat loss has no consequence to the organism,
      proteolysis reduces the muscle mass and life is in danger. Actually, there is no
      effective treatment to improve the nitrogen balance by medication or hormones in
      speed catabolic states but it can also approach us to more proper therapeutics
      for these so frequent processes in clinic.

PMID- 10339851
TI  - [Neutrocytic ascites and Corynebacterium striatum].

PMID- 10339850
TI  - [Adrenal insufficiency: an update].

PMID- 10339852
TI  - [Patients' rights to privacy in publications].

PMID- 10339853
TI  - [Kikuchi's disease].

PMID- 10339854
TI  - [Iron-deficiency anemia and adult celiac disease].

PMID- 10339855
TI  - [Pneumonitis associated with primary infection by varicella-zoster virus: apropos
      of 11 cases].

PMID- 10339856
TI  - [Thrombotic thrombocytopenic purpura associated with HIV infection].

PMID- 10339857
TI  - [The social problem in hospital emergency services].

PMID- 10339858
TI  - [Heparin-associated autoimmune thrombopenia].

PMID- 10339859
TI  - [Mortality in an Internal Medicine Department in a third-level hospital].

PMID- 10339860
TI  - [Analysis of the drainage fluid after cephalic duodenopancreatectomy: a reliable
      clinical criterion].
AB  - The authors have retrospectively analysed the drainage fluid of 39 patients
      undergoing Whipple's operation over a 18-year period. The aim of the study was to
      assess whether the volume and amylase concentration of the drainage fluid were
      good criteria of healing of the pancreatico-jejunal anastomosis. The patients
      have been divided into two groups: Group I (30 patients) with no complications at
      the pancreatico-jejunostomy--Group II (9 patients) with a pancreatic leak. The
      analysis of the volume, amylase concentration and amylase index (Log of the
      amylase concentration x volume) showed that the groups had clearly different
      profiles: in group I all three criteria were rapidly decreasing, while they
      remained abnormally high in group II. Those criteria may help the clinician in
      the monitoring of individual patients; they also may prove useful in prospective
      studies evaluating new means of prevention of this anastomosis.

PMID- 10339862
TI  - [Surgical treatment of pulmonary metastases of osteosarcoma. Apropos of 206
      operated cases].
AB  - Two hundred and six patients were operated for lung metastases from osteosarcoma
      over a period of 7 years. The operative mortality was 0.3%. The actuarial
      survival for the overall population was 78% at one year. 50% at two years, 40% at
      three years and 34% at five years. The most significant prognostic factors (p <
      0.01) were the number of metastases, the duration of the free interval and the
      degree of differentiation. Sex, age, site and type of resection of osteosarcoma
      or the metastases did not have any influence on prognosis. Surgical resection of
      lung metastases currently constitutes an essential part of the multidisciplinary
      management of osteosarcoma.

PMID- 10339861
TI  - [Vaginal hysterectomy in fibroma. Apropos of 453 cases. Retrospective comparison
      with 509 cases of abdominal hysterectomy].
AB  - The authors present a series of 962 hysterectomies for fibroma carried out
      between January 1981 and December 1995 in the Department of Gynecology and
      Obstetrics of CHU Toulouse-La Grave. They carried out 453 vaginal hysterectomies
      and 509 abdominal hysterectomies. They compared the largest series reported in
      the literature, between vaginal and abdominal technique. The vaginal route has
      the obvious advantages of speed of operation, less operative trauma, lower risk
      of thrombo-embolic disease and the hospital stay is shorter. Laparoscopic
      assistance allows to extend indications of vaginal route.

PMID- 10339863
TI  - [Pleural fibromas: a review based on 12 cases].
AB  - The authors report 12 cases of pleural fibroma, which is a rare benign tumor,
      usually discovered incidentally. However, these tumors are sometimes associated
      with a paraneoplastic syndrome, or may lead to compressive symptoms related to
      their large size. Radical resection is mandatory because recurrence may occur,
      sometimes several years later with a malignant behavior. Long-term follow-up is
      therefore necessary to detect any recurrence, particularly when certain
      prognostic factors are initially present.

PMID- 10339864
TI  - [Caustic burns of the esophagus in children: experience at the National Hospital
      and University Center of Cotonou].
AB  - Fifty-two children (mean age = 4.1 years) were admitted from 1992 to 1997 for an
      caustic burn of the oesophagus. Caustic ingestions were accidental in children
      less than 10 years old and mainly suicidal in older children. Burns were due to
      alkaline (82%), acids (14%), ou insecticide (4%). The ingested product was
      decanted from its original packing in 88% of cases. Thirty-six patients had an
      exclusive medical treatment, including a naso-gastric tube in 3. Endoscopic
      treatment included naso-gastric tube (n = 4) and bouginage (n = 5). An
      oesophagoplasty using a colonic transplant was performed in 8 children (15%),
      always after a previous feeding gastrostomy to improve the nutritional status.
      There was no operative mortality. These results conform with the main points of
      the literature. They underline the difficulties in the management of patients
      with caustic burns of the oesophagus and allow to determine preventive measures
      of this disease in children of Benin.

PMID- 10339865
TI  - [Value of human colonic cancer models by surgical cecal implantation in nude
      mice].
AB  - A better understanding of the nature and treatment of colon cancer, and of by
      metastatic dissemination should be achieved by the use and study of appropriate
      animal models. Such models can be created by grafting human cancer cells or
      tumour fragments orthotopically into the colon or caecum of nude mice. This
      review examines the rationale behind these models and the principal results of
      orthotopic transplantation. Despite the fact that they require surgical expertise
      and are time-consuming, they provide valuable information on the mechanism of
      metastasis and the efficacy of novel treatments.

PMID- 10339866
TI  - [Multinodular goiter: natural history].
AB  - Despite its high prevalence, at least in areas with even mild iodine deficiency,
      the aetiopathogenesis of multinodular goitre is poorly understood. The
      combination of genetic and environmental factors, the likely involvement of
      endocrine para and autocrine goitrogenic agents and the remarkable heterogenicity
      of thyroid tissue complicate elucidation of the mechanisms involved. Multinodular
      goitre follows an initial phase of hyperplastic goitre or results from the
      generation of several individual nodules. Alterations of the stromal and vascular
      tissues as well as the occurrence of somatic mutations are contributing factors.
      In many instances, multinodular goitres become autonomous in the long term.

PMID- 10339867
TI  - [Molecular basis of tumors arising in thyroid follicular cells].
AB  - Tumours arising from the thyroid follicular cell have proven to be a very useful
      model for studying the molecular genetics of tumour development. This review
      summarises our current knowledge of the principal abnormalities of oncogenes and
      tumour suppressor genes associated with the major sub-types of thyroid tumour.
      The pattern which emerges demonstrates well how successive genetic abnormalities
      drive clonal progression. In addition, comparison of follicular and papillary sub
      types provides a fascinating example of how the nature of the underlying genetic
      abnormality may determine the clinico-pathological behaviour of the resulting
      tumour. The potential impact of this molecular data on clinical management is
      also discussed.

PMID- 10339868
TI  - [Treatment of stage III and IV hemorrhoids by the Longo technique].

PMID- 10339869
TI  - [Idiopathic portal thrombosis in an adult patient with healthy liver].

PMID- 10339871
TI  - [Modifications of the Deloyers procedure in order to perform a cecal-rectal
      anastomosis without torsion of the vascular pedicle].

PMID- 10339870
TI  - [Bile duct amputation neuroma: a possible cause of postoperative stenosis].

PMID- 10339872
TI  - [Scintigraphic exploration of the adrenal glands using I-131-6 beta iodomethyl-19
      norcholesterol. A practical guide].

PMID- 10339888
TI  - Reminiscences. Presented to the Robert U. Massey History of Medicine Society on
      14 October 1998.

PMID- 10339889
TI  - Robert U. Massey, M.D. Biographical continuation.

PMID- 10339893
TI  - Some historical and philosophical reflections on the myofibroblast concept.

PMID- 10339894
TI  - Transcriptional regulation of the desmin and SM22 genes in vascular smooth muscle
      cells.

PMID- 10339895
TI  - Modulation of myofibroblast and smooth-muscle phenotypes in the lung.
AB  - Considerable progress has been made in defining the phenotype of contractile
      cells of the lung during development, in the adult and during the remodeling
      process. The high degree of phenotypic heterogeneity of subgroups of these cells,
      such as SMCs, is appreciated. Recent studies also have explored the relationship
      between phenotype and cell function, though this remains an important area for
      research in the coming years. Similarly, though our understanding of the
      regulation of cell phenotype is expanding rapidly, much remains to be done,
      particularly at the level of gene regulation. New transgenic models, coupled with
      gene-promotor analyses in transgenic animals and in cultured cells should allow
      rapid progress. Studies of the regulation of specific contractile and
      cytoskeletal proteins at the gene level by specific cytokines and extracellular
      matrix elements will be particularly important.

PMID- 10339896
TI  - Role of platelet-derived growth factors in angiogenesis and alveogenesis.

PMID- 10339897
TI  - Transforming growth factor-beta gene transfer to the lung induces myofibroblast
      presence and pulmonary fibrosis.

PMID- 10339898
TI  - Transforming growth factor-beta induction of alpha-smooth muscle actin is
      dependent on the deformability of the collagen matrix.

PMID- 10339899
TI  - Signal transduction pathways activated during fibroblast contraction of collagen
      matrices.

PMID- 10339900
TI  - Extracellular matrix, integrins and focal adhesions.

PMID- 10339901
TI  - What is new in mechanical properties of tissue-engineered organs.

PMID- 10339902
TI  - Fibroblast-cytokine-extracellular matrix interactions in wound repair.

PMID- 10339903
TI  - Myofibroblastic differentiation and extracellular matrix deposition in early
      stages of cholestatic fibrosis in rat liver.

PMID- 10339904
TI  - Gene therapy of wounds with growth factors.

PMID- 10339905
TI  - What's new in human wound-healing myofibroblasts?

PMID- 10339906
TI  - The myofibroblast in neoplasia.

PMID- 10339907
TI  - The concept of organizing pneumonia.

PMID- 10339908
TI  - Endothelial repair in atherogenesis.

PMID- 10339909
TI  - Glomerulosclerosis: the role of interstitial myofibroblasts in its progression.

PMID- 10339910
TI  - The myofibroblast as an inflammatory cell in pulmonary fibrosis.

PMID- 10339911
TI  - Cell-cell and cell-matrix interactions during breast cancer progression.

PMID- 10339912
TI  - Hepatocyte growth factor secreted by human liver myofibroblasts increases
      invasiveness of hepatocellular carcinoma cells.

PMID- 10339913
TI  - Interplay of matrix and myofibroblasts during hepatic fibrogenesis.

PMID- 10339914
TI  - [New ethics for physicians?].

PMID- 10339915
TI  - [Facts and targets in analgesic therapy. Levels in delivery of care-- advanced
      training--the Swedish National Program].

PMID- 10339916
TI  - [Sexually transmitted infections: to be diagnosed in time!].

PMID- 10339917
TI  - [Viral sexually transmitted urogenital infections. Increased importance of viral
      STD in industrial countries].
AB  - Sexually transmitted urogenital virus infections have shown in recent decades a
      growing prevalence worldwide. In the industrial nations, human papilloma virus
      and herpes simplex virus infections occur more frequently than the typical
      venereal diseases (syphilis, gonorrhoea and ulcus molle). Molluscum caused by
      molluscum contagiosum virus (MCV), while frequently found in HIV-infected and
      AIDS patients (13%), are generally diagnosed decidedly less often than the
      previously mentioned virus infections. Considering the pathogenetic relationship
      of several HPV-subtypes with precancerosis and carcinomas in both genders,
      increasingly greater demands are placed upon the physician today regarding the
      diagnoses and treatment of virus-associated urogenital STDs. Discussed in this
      survey are the epidemiology, clinical symptoms, diagnostic and treatment of the
      three referred to virus infections.

PMID- 10339918
TI  - [Bacterial sexually transmitted diseases (STD). 1. Gonorrhea, syphilis, ulcus
      molle].

PMID- 10339919
TI  - [Hepatitis B and HIV: the role of the family physician].

PMID- 10339920
TI  - [Hypertension induced by sleep apnea--diagnosis and therapy].

PMID- 10339921
TI  - [Microangiopathy in hypertensive heart disease. Angina pectoris with negative
      coronary angiogram].

PMID- 10339922
TI  - [Advantages of insulin Lispro (short-acting) in terminal kidney failure].
AB  - Diabetic management of dialysis patients with end-stage renal failure is often
      problematic. Renal failure interferes with the metabolism of glucose and insulin.
      Many of these diabetics have wide fluctuations in their daily blood glucose
      profile. The kinetics of regular insulin may be appreciably prolonged in
      consequence of the failure of renal insulin degradation, making the dose-effect
      profile of the insulin difficult to control, and hypoglycemia more likely.
      Intensified conventional insulin treatment (ICT) using the short-acting insulin,
      Lispro, facilitates the calculation of insulin requirements and helps to avoid
      large fluctuations in blood glucose levels. The present case report illustrates
      these difficulties in a patient on dialysis, and shows how ICT with Lispro can
      improve the quality of life of diabetics with renal failure.

PMID- 10339923
TI  - [Spondylarthritis. 3. Diagnosis and differential diagnosis of various forms of
      spondylarthritis].

PMID- 10339924
TI  - ["Perversions are like babushka figures". Series: Sex Medicine no.7: cases from
      psychotherapy praxis].

PMID- 10339925
TI  - [Abscess formation after intra-gluteal injection. Series: legal cases from praxis
      no 5: defective injections].

PMID- 10339926
TI  - [Do not let down the aged!].

PMID- 10339927
TI  - Inhibitory effects of combined treatment with vitamin K and D on bone loss of
      ovariectomized rats: a microradiographic study.
AB  - This study was designed to assess the effect of vitamin K and D supplementation
      on ovariectomy-induced bone loss. Female Sprague-Dawley rats aged 8-9 months were
      ovariectomized (OVX) or sham operated and divided into five experimental groups:
      (1) sham operation, (2) ovariectomy (OVX), (3) OVX plus vitamin K
      supplementation, (4) OVX plus vitamin D supplementation, (5) OVX plus vitamin K
      and vitamin D supplementation. The trabecular bone area was estimated by bone
      histomorphometry by microradiography and histological examination. Bone loss in
      OVX plus vitamin K and vitamin D group was significantly reduced at both 7 and 14
      weeks compared with the OVX group. No significant bone loss in OVX plus vitamin K
      or OVX plus vitamin D groups was found. Similar effect of vitamin K and D
      supplementation on ovariectomy-induced bone loss was recognized in histological
      examination. Our findings indicate that vitamin K and D may have synergistic
      effects on reducing bone loss. This is a valuable information for the treatment
      of bone loss in postmenopausal women with osteoporosis.

PMID- 10339928
TI  - [Generation and analyses of transgenic mice containing mutant p53 transgene].
AB  - p53 is known to be a suppressor oncogene product regulating the cell cycle as a
      check point protein. Loss of function mutations were frequently observed in
      various human cancers. To investigate the role of mutant form of p53 in the
      presence of wild-type p53 in vivo, we generated two types of transgenic mice
      carrying p53 transgenes with mutation at the codon 248 from Arg to Trp or at the
      codon 249 from Arg to Ser. We obtained seven transgenic mouse lines with Trp
      mutant type and eight lines from Ser-mutant type which express mutant p53
      transgenes. These transgenic mice were observed for tumor formation over a period
      of one year. However, no tumors were developed within the monitoring period. To
      test whether the mutant p53 has a dominant negative effect on the wild type p53
      or not, transgenic mice were crossed with p53 knockout mice which were
      heterozygous for the endogenous wild type p53 gene. Lymphocytes of these mice
      were cultured after gamma irradiation to induce apoptosis. Viability of
      lymphocytes as well as fragmentation of DNAs were measured. Apoptosis of
      lymphocytes from p53 +/- mutant transgenic mice was not suppressed compared with
      lymphocytes from p53 +/- mice. From these results, the mutant p53 with point
      mutation at the codon 248 from Arg to Trp or at the codon 249 from Arg to Ser,
      has a loss of function mutation, but not a dominant negative mutation over the
      wild type p53.

PMID- 10339929
TI  - [Tissue specific rescue of lymphomas arose various types of tumors with p53
      deficiency].
AB  - p53 deficient mice have been found to be highly prone to develop tumors
      spontaneously. In particular, the thymic lymphoma was observed predominantly,
      which is not the case for p53-related tumorigenesis in human. To elucidate this
      differences, I tried to rescue the p53 deficient mice from lymphoma originated in
      thymus by allowing the p53 expression in their lymphocytes by using transgenic
      technique. They survived longer than the p53 deficient littermates. In addition,
      they developed various types of tumors including glioma, medulloblastoma and
      breast cancer, which have not been observed in p53 deficient mice.

PMID- 10339930
TI  - [A new universal gene replacement method for generating a desired mutant mouse].
AB  - Site-directed gene replacement has been accomplished using two steps of gene
      targeting, which is called universal gene replacement. The previously described
      universal gene replacement method with the "neo-tk" cassette exhibited a very low
      efficiency in the second "replacement" step. The neo-tk tagged allele obtained
      from the first step was never transmitted to offspring through the germ cells of
      chimeric mice. We therefore developed a new system using the Eco-gpt gene instead
      of the HSV-tk gene. With this system, gene replacement for the p53 gene was thus
      consistently accomplished and generated mutant mouse lines with site-directed
      mutations. Further, all manipulated alleles, including the neo-gpt tagged one,
      were successfully transmitted to offspring.

PMID- 10339931
TI  - [Effects of pentobarbital on coronary and cerebral circulation and metabolism in
      dogs subjected to hemorrhage].
AB  - Mongrel dogs were divided into a neuroleptanesthesia group (n = 10) and a
      pentobarbital group (neuroleptanesthesia plus pentobarbital; n = 10). The dogs
      were subjected to stepwise hemorrhage increasing from 30 to 40 and 50 ml.kg-1. In
      the neuroleptanesthesia group, mean arterial pressure, and cerebral and coronary
      blood flow decreased. Furthermore the oxygen and hydrogen ion balance in both the
      brain and the myocardium was aggravated, even at 30 ml.kg-1 of hemorrhage.
      Compared to the neuroleptanesthesia group, mean arterial pressure, and cerebral
      and coronary blood flow showed a greater decrease, cerebral oxygen consumption
      was lower, and the brain and myocardial metabolism worsened similarly at
      equivalent hemorrhage in the pentobarbital group. These results suggest that
      pentobarbital in combination with neuroleptanesthesia reduces cerebral oxygen
      consumption, but does not improve cerebral metabolism in the state of acute
      hemorrhage due to simultaneous induction of severe circulatory depression.

PMID- 10339932
TI  - [The effect of calories of preoperative oral intake on the glucose metabolic
      response in children].
AB  - We performed prospective study to determine whether the increase of calories with
      preoperative oral intake will prevent ketosis due to preoperative starvation in
      children receiving afternoon surgery. Twenty five children (aged 3 to 9 years)
      for elective minor surgery under general anesthesia with sevoflurane and nitrous
      oxide were divided into morning surgery group and afternoon surgery group, and
      the latter was divided into 2 groups according to calories contained in the clear
      fluid. The calorie of the clear fluid in the afternoon group P was 0.24 kcal.ml
      1, and that in the afternoon group A was 0.48 kcal.ml-1. The calorie of the clear
      fluid in the morning group was 0.48 kcal. ml-1. The levels of blood glucose,
      blood ketone body, plasma free fatty acids (NEFA), insulin, glucagon and cortisol
      were measured before and during intravenous infusion in three groups. The urinary
      catecholamine excretion was measured in the urine collected from 18:00 on the day
      before operation day until the start of anesthesia. There were no significant
      differences in the levels of blood glucose, NEFA, insulin, glucagon, cortisol and
      urinary catecholamine excretion. But the level of blood ketone body only in the
      afternoon group P was significantly higher than that in the morning group. But
      the levels of NEFA before infusion were higher than average in 40-60 percent of
      patients of each group. These data suggest that the increasing preoperative
      calories with oral intake will prevent ketosis due to preoperative starvation in
      the afternoon group as well as in the morning group. But the short duration of
      starvation only can not prevent lipolysis completely.

PMID- 10339933
TI  - [Optimal length of nasopharyngeal airway and its correlation with height and body
      weight].
AB  - We studied 26 patients (11 males and 15 females) undergoing elective surgery
      under general anesthesia. The purpose of this study was to decide how long the
      length of nasopharyngeal airway should be by measuring distance A (permitting
      airway obstruction to be released), distance B (giving the most effective
      ventilation), and distance C (between nostril and arytenoid). The values of
      distance A in male group and female group were 12.73 +/- 0.85 cm and 11.70 +/-
      0.75 cm, respectively. The values of distance B were 14.55 +/- 0.96 cm in male
      group and 13.93 +/- 1.12 cm in female group. The values of distance C were 18.84
      +/- 0.90 cm in male group and 17.40 +/- 0.97 cm in female group. This showed that
      it is necessary to advance the nasopharyngeal airway about 2 cm from the distance
      A to give the most effective ventilation to the patients with airway obstruction.
      Therefore, most of standard nasopharyngeal airways commercially available are too
      short. In addition, the distance B has no correlation with height and body weight
      and it is difficult to predict the optimal length of the airway.

PMID- 10339934
TI  - [Anesthetic management of an infant with pulmonary atresia and ventricular septal
      defect accompanied by excess pulmonary blood flow for systemic-pulmonary shunt
      operation].
AB  - A 6-month-old infant had pulmonary atresia with ventricular septal defect (PA +
      VSD) accompanied by excess pulmonary artery flow via major aortopulmonary
      collateral artery, underwent aortopulmonary shunt with artificial graft under
      midazolam-fentanyl anesthesia. After the administration of protamine, arterial
      oxygen saturation gradually decreased. We suspected that hypotension and decrease
      in cardiac output induced by protamine caused the decrease in pulmonary blood
      flow via central shunt. It is suggested that pulmonary blood flow should be
      maintained by using an inotropic agent and a selective pulmonary arterial dilator
      such as prostaglandin E1 in a patient with PA + VSD after the institution of
      aorto-pulmonary shunt, because the patient with excess pulmonary flow has been
      reported to have high pulmonary resistance due to pulmonary abnormalities such as
      stenosis and thrombosis.

PMID- 10339935
TI  - [Prolonged isoflurane inhalation in a patient with bronchospasm associated with
      lung edema].
AB  - An 80-year-old female with bronchospasm associated with lung edema, who had been
      resistive to conventional medical treatment, was mechanically ventilated with
      isoflurane in oxygen for 386 hours. A total amount of isoflurane given was 277.6
      MAC-hours. A serum inorganic fluoride concentration increased after isoflurane
      inhalation and it was 26.8 microM when serum urea nitrogen and creatinine were
      elevated. On the day after discontinuation of isoflurane inhalation, a peak serum
      inorganic fluoride concentration was 38.9 microM. After discontinuation of
      isoflurane inhalation, serum urea nitrogen and creatinine decreased and no
      clinical renal dysfunction was observed. We conclude that this subclinical renal
      dysfunction was due to antibiotics, advanced age, dehydration and prolonged
      elevation of serum inorganic fluoride concentration.

PMID- 10339936
TI  - [Anesthesia experience of three patients with partial intramural coronary
      artery].
AB  - We experienced three patients with partial intramural coronary artery diagnosed
      preoperatively. We gave balanced anesthesia using narcotics and non-narcotic
      analgesics for non-cardiac surgery, administering phenylephrine against
      hypotension. The anesthetic course was relatively stable. According to the
      special pathophysiology of this disease, tachycardia and hypotension associated
      with anesthesia should be avoided, and special caution is needed when
      nitroglycerine is used due to its adverse effect on systolic narrowing of the
      coronary artery.

PMID- 10339937
TI  - [The anesthetic management of tracheal T-tube exchange using Patil-Syracuse
      mask].
AB  - We exchanged the tracheal T-tube inserted to a 17-year-old female, who wanted to
      be able to enunciate again, with relapsing polychondritis and difficulty in
      enunciation which the proximal end of tracheal T-tube above the false vocal cords
      was causing. The procedure was performed using Patil-Syracuse mask, without
      tracheal intubation, under-general anesthesia. This method will ensure precise
      length adjustment and correct placement of the T-tube under fiberoptic
      bronchoscope.

PMID- 10339938
TI  - [The use of noninvasive positive pressure ventilation in the early postoperative
      period after cardiovascular surgery].
AB  - We used noninvasive positive pressure ventilation (NPPV) in 7 ICU patients after
      cardiovascular surgery. In 6 patients, we measured the variables of hemodynamics
      and arterial oxygenation by application of this nasal respiratory support
      (Companion 320 I/E, Puritan Bennett). Ventilator settings of expiratory positive
      airway pressure (EPAP) 3 cmH2O and inspiratory positive airway pressure (IPAP) 10
      cmH2O were used and continued for 30 minutes. There were no significant changes
      in any hemodynamic variables during NPPV. Arterial oxygenation also remained
      unchanged at 30 min after discontinuation of NPPV. To conclude the efficacy of
      NPPV after cardiovascular surgery, higher level of IPAP and the combination with
      postural drainage should be studied further.

PMID- 10339939
TI  - [Anesthetic management of left ventricular reduction surgery (Batista
      procedure)].
AB  - We experienced anesthetic management of left ventricular reduction surgery
      (Batista procedure) which is a newly developed procedure for treating end-stage
      dilated cardiomyopathy. The patient was a 41-year-old man who had been suffering
      from cardiac failure and refractory ventricular tachycardia. The anesthesia was
      induced and maintained with meticulous administration of fentanyl. After
      resection of the left ventricular free-wall, the left ventricular diastolic
      diameter decreased to 46 mm, from 79 mm of preoperative measurement. Weaning from
      cardiopulmonary bypass was successful with the use of catecholamines and intra
      aortic balloon pumping. Administration of both vasodilators and phosphodiesterase
      inhibitors such as milrinone also contributed to reducing afterload and
      maintaining cardiac output. In addition to standard hemodynamic monitoring,
      transesophageal echocardiography provided invaluable information on determining
      cardiac dimensions and evaluating left ventricular wall motion.

PMID- 10339940
TI  - [Endoscopic resection of the thoracic sympathetic trunk for the treatment of
      frequent syncopal attack of idiopathic long QT syndrome].
AB  - A 22 year old man was diagnosed as having Jervell and Lange-Nielsen syndrome
      (JLNS), which includes a prolonged QTc, congenital neural deafness, and syncopal
      attacks or sudden death. In spite of medication with beta blocker, syncopal
      attack increased in frequency since his sister suddenly had died of JLNS. Because
      left stellate ganglion block improved the QTc dispersion, left cardiac
      sympathectomy was scheduled under the video-assisted thoracic surgery. After the
      premedication with midazolam, anesthesia was induced with thiamylal, and
      maintained with nitrous oxide, sevoflurane, and fentanyl. Serious arrhythmias
      were not observed throughout the perioperative period. Sympathetic trunk was
      successfully resected from the top of 1st ganglion to the bottom of 4th ganglion
      of left thoracic sympathetic trunk. Horner's sign did not appear after the
      surgery. Although the shortening of QTc was not significant, QTc dispersion
      during exercise was improved, and syncopal attack was not observed until 6 months
      after the surgery.

PMID- 10339941
TI  - [Management under anesthesia of a patient with renal cell carcinoma extending
      into the retrohepatic inferior vena cava with the aid of partial cardiopulmonary
      bypass].
AB  - A 70-year-old male with renal cell carcinoma extending into the retrohepatic
      inferior vena cava was scheduled for radical nephrectomy with vena caval
      resection under general anesthesia. He had received partial gastrectomy for
      gastric cancer twelve years before. Computed tomography and inferior vena
      cavography confirmed that the vena cava was almost completely occluded and that a
      collateral venous network was well established. It was considered that the
      surgical approach to the retrohepatic cavals area was technically very difficult,
      and that there was a high possibility of a pulmonary embolus during the surgical
      manipulation. To prevent a pulmonary embolus and get good control of the vena
      cava above the tumor and below the hepatic vein, we decided to use a partial
      cardiopulmonary bypass (CPB) until the vena cava was clamping above the tumor.
      Anesthesia was induced with propofol and fentanyl, and maintained with fentanyl
      and isoflurane-N2O-O2. In the partial CPB blood from the hepatic vein was drained
      from the inferior vena cava cannula through right atrium, oxygenated by
      microporus membrane oxygenator, and returned to the left femoral artery.
      Cannulation to drain the venous circulation entering the vena cava below the
      tumor was abandoned because the extensive collateral venous network ultimately
      drains into the superior vena cava. The partial CPB time was 90 min, and the
      bladder temperature during the CPB was 35-36 degrees C. During the 7.3 hr
      procedure, the pulmonary embolus did not occur and the total blood loss was 5515
      ml. The patient made an uncomplicated recovery and was discharged 30 days after
      the operation. This newly reported partial-CPB method may be safe and effective
      for the management under anesthesia of other patients.

PMID- 10339942
TI  - [Severe hypoxia due to persistent left supra vena cava draining to the left
      atrium after weaning from cardiopulmonary bypass in a patient with endocardial
      cushion defect].
AB  - We report a case of severe hypoxia after weaning from cardiopulmonary bypass in a
      ten-month-old patient with endocardial cushion defect. The severe hypoxia was
      improved abruptly when the persistent left supra vena cava (PLSVC) was ligated.
      The hypoxia, therefore, was considered to be caused by venous blood which was
      directly drained into the left atrium through the PLSVC. In cases with large
      right-to-left shunt which is difficult to explain only by intracardiac shunt,
      attention must be paid to existence of PLSVC directly draining into the left
      atrium.

PMID- 10339943
TI  - [Pulmonary tumor mass aberration into the bronchus of the intact right lung
      during total left lung resection].
AB  - A 77-year-old male with lung cancer underwent a total left lung resection. During
      surgery, there was no ventilatory trouble such as hypoventilation or hypoxia.
      However, a mass was found in the right main bronchus by endobronchial fiberscopy
      before extubation. Because the mass could not be aspirated through the
      endobronchial fiberscope, we extracted it using basket-foreceps. We speculated
      that surgical procedures may have caused the tumor mass to move to the bronchus
      of the contralateral intact lung. Accordingly, fiberscopic examination of the
      airway before extubation should be mandatory, even if there is no ventilatory
      trouble during lung resection.

PMID- 10339944
TI  - [A case of pulmonary fat embolism and cardiac arrest after prosthetic replacement
      of the femoral stem].
AB  - We experienced a case of cardiac arrest which occurred after prosthetic
      replacement of the femoral stem. The patient died three hours and fifty minutes
      after the end of operation, following hypouresis, pulmonary edema and hypoxia.
      According to the autopsy, extensive and severe fat embolism was documented in the
      lung and kidney, and this is considered to be the cause of the death. When
      prosthetic replacement of the femoral head is performed, we have to keep in mind
      the danger of fat embolism.

PMID- 10339945
TI  - [Use of the intubating laryngeal mask for tracheal intubation in three patients
      with difficult airways].
AB  - The intubating laryngeal mask has a potential role for tracheal intubation in
      patients with difficult airways, but there have been only reports of the
      techniques of blind tracheal intubation through the intubating laryngeal mask.
      The success rate of blind intubation at the first attempt may be merely 50-60%
      even in patients with normal airways. We report the use of the intubating
      laryngeal mask for tracheal intubation in three patients with difficult airways,
      in whom a tube was easily inserted through the laryngeal mask into the trachea
      either blindly, using a fiberoptic bronchoscope or using a lighted stylet.

PMID- 10339946
TI  - [Recurrent transient increases in liver enzymes specifically after isoflurane
      anesthesia].
AB  - A 69 y-old female underwent orthopedic surgery 12 times in our hospital. A
      variety of agents were used for anesthesia. She developed episodes of transient
      increase in liver enzymes only after each of three isoflurane anesthesia (GOT :
      311, 292, 328 IU.l-1, GPT: 341, 264, 274 IU.l-1). We suspected drug-induced liver
      dysfunction, but results of a lymphocyte stimulation test were negative. We
      conclude that her liver dysfunction was not severe enough to cause clinical
      symptoms. In such susceptible patients we should be careful of our choice of
      anesthetic drugs.

PMID- 10339947
TI  - [Prolonged effects of vecuronium in a patient with Crow-Fukase syndrome].
AB  - We gave anesthesia to a patient with the Crow-Fukase syndrome. A patient with
      this syndrome shows polyneuropathy, endocrinological symptoms, skin change,
      hypertrichosis, organomegaly and osteosclerotic change. We monitored the effects
      of vecuronium using a neuromuscular blockade monitor. The patient with this
      syndrome was hypersensitive to vecuronium and its effects lasted longer than
      usual. It is important to monitor neuromuscular blockade carefully in patients
      with this syndrome.

PMID- 10339948
TI  - [A case of difficult intubation with tracheobronchial anomaly].
AB  - We experienced a case of difficult intubation with tracheobronchial anomaly. A 66
      year-old male was scheduled for subtotal esophagectomy. We used a univent
      bronchial blocker tube (UBT) to separate the lungs because of difficulty with
      tracheal intubation using a 37 F double lumen tube (DLT). Intraoperatively, we
      could not separate the lungs due to tracheobronchial anomaly in the right lung,
      and attempted to change the tube. We could insert a 35 F DLT to the trachea and
      separate the lungs. In the case of difficult or impossible conventional direct
      vision intubation, the use of DLT is a relative contraindication. However, in
      this case, the separation of the lungs with UBT was difficult because of
      tracheobronchial anomaly.

PMID- 10339949
TI  - [The effect of propofol as an anticonvulsant].
AB  - We observed that propofol was very effective for the refractory general
      convulsion after surgical operation of cerebral aneurysmal clipping in two
      patients. The first patient had suffered from asthma. Standard regimens except
      for thiopental were ineffective for the refractory general convulsion after the
      operation. So, we administered propofol to the patient, at the dosage of 1 mg.kg
      1 intravenously and then, 1 mg.kg-1.hr-1 continuously i.v. Propofol suppressed
      the general convulsions completely. On the EEG, there were no convulsive spikes.
      Furthermore, patient's consciousness became clearer during the administration of
      propofol. The convulsion in the second patient not suffering from asthma, was
      intractable, too and diazepam, phenytoin, and phenobalbital were not effective.
      Then, we tried propofol in the same way, and good effect was obtained. Propofol
      may be an effective medicine for the refractory general convulsion.

PMID- 10339950
TI  - [Anesthetic management of a patient with Bartter's syndrome].
AB  - A 48-year-old woman with Bartter's syndrome underwent right mastectomy under
      general anesthesia. Her operative course was uneventful. She was preoperatively
      complicated with severe hypokalemia but had no signs and symptoms of hypokalemia.
      In anesthetic care of patients with Bartter's syndrome, even when they have no
      symptoms of hypokalemia, the meticulous intravenous administration of potassium
      chloride is required in order to maintain the preoperative level of the serum
      potassium during anesthesia. In addition, attention should be paid to factors
      causing an additional reduction in the serum potassium concentration, such as
      alkalosis, elevated beta 2-adrenergic activity, increased availability of insulin
      and hypothermia.

PMID- 10339951
TI  - [Use of personal computers by diplomats of anesthesiology in Japan].
AB  - Use of personal computers by diplomats of the Japanese Board of Anesthesiology
      working in Japanese university hospitals was investigated. Unsigned
      questionnaires were returned from 232 diplomats of 18 anesthesia departments. The
      age of responders ranged from twenties to sixties. Personal computer systems are
      used by 223 diplomats (96.1%), while nine (3.9%) do not use them. The computer
      systems used are: Apple Macintosh 77%, IBM compatible PC 21% and UNIX 2%.
      Although 197 diplomats have e-mail addresses, only 162 of them actually send and
      receive e-mails. Diplomats in fifties use e-mail most actively and those in
      sixties come second.

PMID- 10339952
TI  - [Man-made vitreous fibers: current state of knowledge].
AB  - Artificial vitreous fibres have been used as thermal insulation since the 1930's.
      Experimental studies on possible pathogenic, fibrogenic or carcinogenic effects
      did not produce any clear results until the 1970's, when Stanton demonstrated the
      carcinogenic effect of these and numerous other fibrous materials after direct
      inoculation in the pleural cavity. In subsequent years epidemiological and
      experimental studies multiplied: the epidemiological investigations did not show
      any evident pathogenic effects on very large cohorts of workers, and
      experimentally the carcinogenic effect was confirmed only by inoculation of high
      doses of fibres, while negative results were reported in inhalatory experiments.
      In view of the considerably long time that has elapsed since these materials were
      first used, the low biopersistence of the fibres and the now consolidated results
      of a large amount of reliable research, it is today possible to affirm that
      artificial vitreous fibres are not a hazard for the workers who produce and use
      them. Since current production in Europe involves mostly large diameter, non
      respirable fibres or fibres with extremely low biopersistence, in accordance with
      precise European Union recommendations, we may look to the future without undue
      concern.

PMID- 10339953
TI  - [Chemical and physical characteristics and toxicology of man-made mineral
      fibers].
AB  - The evidence for the adverse health effects following exposure to asbestos (i.e.
      fibrogenic and carcinogenic effect) has prompted widespread removal of asbestos
      containing materials and led to banning of asbestos internationally (in Italy,
      DPR 257/1992), resulting in the increased use of substitutes composed of both
      naturally occurring and synthetic materials, including man made mineral fibres
      (MMMFs) and man made organic fibres (MMOF). MMMFs represent a family of
      synthetic, inorganic vitreous substances derived primarily from glass, rock,
      slag, or clay. MMMFs are further divided into two categories: 1) man made
      vitreous fibres (MMVFs), further divided as follows: a) fibrous glass, including
      mainly continuous filament, special purpose fibres; and microfibres. The
      materials are typically composed of oxides of silicon, calcium, sodium,
      potassium, aluminum, and boron. b) Mineral wool, including glass wool, rock wool
      (derived from magma rock) and slag wool (made from molten slag produced in
      metallurgical processes such as the production of iron, steel, or copper). The
      main components of rock wool and slag wool are oxides of silicon, calcium,
      magnesium, aluminum, and iron. 2) Refractory/ceramic fibres, amorphous or
      partially crystalline materials made from kaolin clay or oxides of aluminum,
      silicon or other metal oxides (i.e. oxides of zirconium and yttrium). Less
      commonly, refractory fibres are also made from non-oxide refractory materials
      such as silicon carbide, silicon nitride, or boron nitride. Industrial production
      of MMVFs began in the second half of the 19th century, while ceramic fibres
      production began more recently, in the early 1970s. Major uses of MMMFs include
      thermal, acoustic and aerospace insulation, fire proofing, reinforcing material
      in plastics, cement and textile, optic fibres, air and liquid filtration,
      friction products, refractory coatings. Serious questions have been raised about
      health implications of MMMFs. Suspicion about the possible occurrence of adverse
      effects following exposure to MMMFs arises mainly from some similarities of MMMFs
      with asbestos (fibrous aspects, inhalability, chemical composition, free radical
      formation). The fibre characteristics that have been identified as crucial in
      influencing the pathogenesis of fibre-related adverse respiratory effects can be
      mainly divided into two groups: fibre dimension, and chemical composition and
      structure. Fibre dimension plays a determining role in conditioning penetration
      in the lung. In a broad sense, the term "respirable" means "capable of being
      carried by breath into the respiratory system". For regulatory purposes,
      "respirable fibres" (i.e. RFP) are defined in most countries following WHO
      criteria: length > 5 microns, diameter < 3 microns, length/diameter > 3. MMMFs
      are generally produced as fibres of diameter higher than asbestos, and too large
      in diameter to be respirable. Moreover, due to the production process, they are
      structurally amorphous. Since MMMFs have no crystalline domains, they also have
      no clearly defined structural faults and they fracture transversely, and
      randomly. Fragments that are too large to be taken up by macrophages can be
      resolved in the lung by a leaching--or dissolution--process which leads to a
      progressive reduction of particle length. In contrast, when abraded, asbestos
      tends to split longitudinally into new, fine, straight fibres: these fibrils are
      of much smaller diameter, more respirable, and consequently more hazardous than
      parent fibres. Fibre chemical composition plays a determining role in
      conditioning the higher or lower biological activity, durability, biopersistence,
      and biodegradability. The term "biological activity" means reactivity or ability
      to interact (possibly due to formation of active oxygen species, identified as a
      crucial step in the mechanism of action) with biological structures and tissues.
      Fibre "durability" is strictly related to its solubility. It can be defined as
      the ability to resist

PMID- 10339954
TI  - [Respiratory disease caused by MMVF fibers and yarn].
AB  - The non-carcinogenic effects of vitreous fibres on the human respiratory
      apparatus have been the subjects of numerous studies on large exposed
      populations. No evidence seems to have been produced of the existence of a
      fibrogenic effect. However, no definite and agreed opinion has yet been expressed
      by the main Agencies and Institutions working in the field of prevention. As a
      contribution to the discussion, the paper presents the experience of the Clinica
      del Lavoro of Milano involving 1000 subjects who underwent broncho-alveolar
      lavage during assessment and checking for suspected occupational respiratory
      disease. A group of 23 cases was selected who were exposed to vitreous fibres
      without other significant exposures to factors considered hazardous for the
      respiratory apparatus, especially asbestos. We observed 7 cases of alveolitis; 6
      cases with pleural thickening; 2 cases of interstitial disease. On the basis of
      the nature of exposure (duration, latency from beginning and from the end of
      hazardous occupation), of the data obtained from the examination of the bronchial
      lavage liquid (presence of vitreous fibres, siderocytes, cellularity), and of the
      clinical and laboratory data (X-ray, PFR), the view expressed is tendentially
      reassuring concerning the possible effects of vitreous fibres on the respiratory
      apparatus. Although the existence of an irritative type of lesion that manifests
      in the form of alveolitis and localised pleural thickening seems possible, albeit
      in a limited number of cases, it does however appear much more difficult to admit
      the existence of a fibrogenic effect.

PMID- 10339955
TI  - [IARC multicenter study on neoplastic disease caused by man-made vitreous mineral
      fibers (MMVF)].
AB  - Man-made vitreous fibres (MMVF) showed carcinogenic potential in experimental
      animals. Epidemiological data suggested an increased mortality from lung cancer
      among production workers, but the interpretation is still a matter of
      controversy. A European study encompassing 13 plants in 7 countries pointed
      towards a moderate excess of lung cancer among workers employed longer than 1
      year in the production of rock/slag wool (SMR = 1.34, 95% CI = 1.08-1.63) and
      glass wool (SMR = 1.27, 95% CI = 1.07-1.50); the latter increase was not
      confirmed after applying local rates to calculate expected deaths. The elevated
      risk among rock/slag wool producers was present even in comparison with local
      rates, and was associated with increasing time from first exposure, and duration
      of exposure. Glass wool results exhibited a less definite pattern. Smoking was
      excluded, although indirectly, as a sufficient alternative explanation of the
      increased lung cancer risk. In a few plants, exposure to asbestos had occurred in
      limited periods for some workers, and might have contributed to the findings.
      Case-control studies are under way to thoroughly investigate the relative and
      possibly combined role of the different exposures, either occupational or not.
      Cohort studies in the USA produced results closely consistent with those of the
      European study.

PMID- 10339956
TI  - [Environmental and occupational exposure to vitreous fibers: the initiatives of
      the European Commission].
AB  - The recent classification of a certain number of glass fibres by the European
      Commission within the framework of the Council Directive 67/548/CEE has reopened
      the debate on the carcinogenicity of these fibres at the level of the European
      Union. There is the risk of a law suit being field before the Court of Justice in
      Luxembourg against Germany, "guilty" of not having observed Community
      regulations. As regards worker protection, the recent Council Directive on
      chemical agents reviews the legal aspects concerning both preventive measures and
      the setting of limit values of occupational exposure.

PMID- 10339957
TI  - Functional requirements for a HIS-RIS-PACS-interface design, including
      integration of "old" modalities.
AB  - Radiology, Information Systems (RIS) and Picture Archiving Systems (PACS), have
      the potential for immense rationalization of operations in radiology and hence
      for the improvement of health care, as well as the return of investments. These
      systems must, however, be carefully designed such that they support routine work
      rather than being an additional burden to radiology staff. Analyses show that
      comprehensive communication of patient demographic and clinical data between RIS,
      PACS and Hospital Information Systems (HIS) are necessary prerequisites to
      achieve cost effectiveness. Based on analyses of radiology operations in a large
      university primary care hospital, functional requirements and data structures for
      designing HIS/RIS/PACS interfaces are presented. These concern communication of
      past examinations, associated written reports and images, appointment scheduling,
      requests of new examinations, digitizing old analog X-ray films, access from
      RIS/PACS to other clinical data, and transfer of new radiology reports and
      relevant images. Consistency of all redundant data stored in the three systems is
      essential. A pragmatic, safe and inexpensive method of electronically integrating
      "old" modalities not fully "PACS capable" in the HIS/RIS/PACS world is presented.

PMID- 10339958
TI  - Stepwise evaluation of information systems in an university hospital.
AB  - A prospective intervention study with historical control has been performed at
      Giessen University Hospital, Germany, to investigate the influence of electronic
      data processing systems on nurses' working environment. Two wards of the medical
      department were selected for this study, using the combined approach of work
      sampling methods and questionnaires. In the first intervention a central
      information system with restricted functions was introduced. For the second
      intervention an additional nursing information system was installed. The
      distribution of nurses' worktime into the fields of general nursing care,
      specific nursing care and administrative activities was not influenced by
      electronic data processing. No time saving could be measured. Results of the
      questionnaires did, however, indicate a positive influence of the hospital
      information system on nurses' working environment.

PMID- 10339959
TI  - ArchiMed: a medical information and retrieval system.
AB  - ArchiMed is a highly flexible medical data storage and retrieval system which
      adds sophisticated clinical research support to a standard hospital information
      system (HIS). Currently, the HIS of Vienna General Hospital-University Hospital
      (2000 beds) stores the clinical data of over 2 million patients. While this
      system supports patient care (e.g., ADT, clinical chemistry, diagnosis,
      procedures), it has no features to facilitate research, such as the management of
      clinical studies. ArchiMed is designed to support clinical research. It includes
      an independent database, which mirrors virtually all the information held in the
      HIS while also allowing new data to be collected independently and to be added to
      the database. Flexible retrieval and analysis of data contained in the database
      are then possible. Thus, existing patient data can be smoothly incorporated into
      a study together with data collected specifically for research purposes. The
      system has already been successfully installed in the departments of surgery and
      soon in other departments as well.

PMID- 10339960
TI  - A computer-assisted drug prescription system: the model and its implementation in
      the ATM knowledge base.
AB  - Informatisation of drug prescription is an important topic in medical
      informatics. For several years now, computerized drug databases have been
      implemented. Usually only a small part of the prescriptions can be stored in
      prescription systems because of the format of the included information;
      prescriptions contain essentially free text without any structure and homogeneity
      of the used vocabulary. In this article a model is presented for knowledge
      representation in a computerized drug prescription system. The model should be
      applicable to clinical practice and be didactic for medical students. The problem
      of standardization of terminology had to be solved. A computer-assisted drug
      prescription program has been developed. The next step is its validation by
      clinicians. The program can also be used in a consultation mode.

PMID- 10339962
TI  - Development of a Bayesian Network for the prognosis of head injuries using
      graphical model selection techniques.
AB  - The assessment of a head-injured patient's prognosis is a task that involves the
      evaluation of diverse sources of information. In this study we propose an
      analytical approach, using a Bayesian Network (BN), of combining the available
      evidence. The BN's structure and parameters are derived by learning techniques
      applied to a database (600 records) of seven clinical and laboratory findings.
      The BN produces quantitative estimations of the prognosis after 24 hours for head
      injured patients in the outpatients department. Alternative models are compared
      and their performance is tested against the success rate of an expert
      neurosurgeon.

PMID- 10339961
TI  - A rational request behavior: the development of prediction instruments regarding
      thyroid function tests in primary care.
AB  - A prospective study was performed to encourage a rational thyroid-stimulating
      hormone (TSH) test request behavior of physicians, using prediction instruments.
      The latter give direct feedback about request adequacy on the basis of pretest
      probabilities of hyperthyroidism using patients' signs and symptoms. For
      instrument design, stepwise logistic regression was used on diagnostic data
      acquired through questionnaires, answered by 80 physicians and 668 patients for
      whom physicians requested a TSH test. Instruments were designed for clinical and
      subclinical hyperthyroidism and for clinical hyperthyroidism alone. Use of the
      instrument for clinical or subclinical hyperthyroidism on the selected group, at
      a 5% probability threshold, can result in a 37% reduction of unnecessary TSH test
      requests. With the instrument for clinical hyperthyroidism at a 5% probability
      threshold, the number of unnecessary test requests can be reduced by 57%.
      Therefore, it can be concluded that the instruments can determine TSH test
      request adequacy and encourage a rational TSH test request behavior of physicians
      at low pretest probability thresholds.

PMID- 10339963
TI  - Computer-supported diagnosis of melanoma in profilometry.
AB  - Laser profilometry offers new possibilities to improve non-invasive tumor
      diagnostics in dermatology. In this paper, a new approach to computer-supported
      analysis and interpretation of high-resolution skin-surface profiles of melanomas
      and nevocellular nevi is presented. Image analysis methods are used to describe
      the profile's structures by texture parameters based on co-occurrence matrices,
      features extracted from the Fourier power spectrum, and fractal features.
      Different feature selection strategies, including genetic algorithms, are applied
      to determine the best possible subsets of features for the classification task.
      Several architectures of multilayer perceptrons with error back-propagation as
      learning paradigm are trained for the automatic recognition of melanomas and
      nevi. Furthermore, network-pruning algorithms are applied to optimize the network
      topology. In the study, the best neural classifier showed an error rate of 4.5%
      and was obtained after network pruning. The smallest error rate in all, of 2.3%,
      was achieved with nearest neighbor classification.

PMID- 10339964
TI  - Optimizing diagnostic test sequences: the probability modifying plot.
AB  - The problem of deciding the optimal sequence of diagnostic tests can be
      structured in decision trees, but unmanageable bushy decision trees result when
      the sequence of two or more tests is investigated. Most modelling techniques
      include tests on the basis of gain in certainty. The aim of this study was to
      explore a model for optimizing the sequence of diagnostic tests based on
      efficiency criteria. The probability modifying plot shows, when in a specific
      test sequence further testing is redundant and which costs are involved. In this
      way different sequences can be compared. The model is illustrated with data on
      urinary tract infection. The sequence of diagnostic tests was optimized on the
      basis of efficiency, which was either defined as the test sequence with the least
      number of tests or the least total cost for testing. Further research on the
      model is needed to handle current limitations.

PMID- 10339965
TI  - A CORBA-based object framework with patient identification translation and
      dynamic linking. Methods for exchanging patient data.
AB  - Exchanging and integration of patient data across heterogeneous databases and
      institutional boundaries offers many problems. We focused on two issues: (1) how
      to identify identical patients between different systems and institutions while
      lacking universal patient identifiers; and (2) how to link patient data across
      heterogeneous databases and institutional boundaries. To solve these problems, we
      created a patient identification (ID) translation model and a dynamic linking
      method in the Common Object Request Broker Architecture (CORBA) environment. The
      algorithm for the patient ID translation is based on patient attribute matching
      plus computer-based human checking; the method for dynamic linking is temporal
      mapping. By implementing these methods into computer systems with help of the
      distributed object computing technology, we built a prototype of a CORBA-based
      object framework in which the patient ID translation and dynamic linking methods
      were embedded. Our experiments with a Web-based user interface using the object
      framework and dynamic linking-through the object framework were successful. These
      methods are important for exchanging and integrating patient data across
      heterogeneous databases and institutional boundaries.

PMID- 10339966
TI  - The medical software quality deployment method.
AB  - The objective of this study was to develop a Quality Function Deployment (QFD)
      model for design of information systems in health-care environments. Consecutive
      blocked-subject case studies were conducted, based on action research methods.
      RESULTS: Starting with a QFD model for software development, a model for
      information system design, the Medical Software Quality Deployment (MSQD) model,
      was developed. The MSQD model was divided into the pre-study phase, in which the
      customer categories and their power to influence the design are determined; the
      data collection phase, in which the voice of customers (VoC) is identified by
      observations and interviews and quantified by Critical. Incident questionnaires;
      the need specification phase, where the VoC is specified into ranked customer
      needs; and the design phase where the customer needs are transformed stepwise to
      technical requirements and design attributes. QFD showed to be useful for
      integrating the values of different customer categories in software development
      for health-care settings. In the later design phases, other quality methods
      should be used for software implementation and testing.

PMID- 10339967
TI  - Methods for correcting risk estimates.

PMID- 10339968
TI  - Calculation and display of confidence bounds for receiver operator
      characteristics.

PMID- 10339969
TI  - [Etiopathogenesis of Vogt Koyanagi-Harada's disease].

PMID- 10339970
TI  - [Expression of brain-derived neurotrophic factor gene in retina following
      vitreous tap].
AB  - PURPOSE: Mechanical injuries to the retina following vitreous tap are reported to
      protect photoreceptor cells in a rat model of the retinal degeneration and
      enhance the survival rate of retinal ganglion cells in the optic nerve
      transection. Neurotrophic factors are presumably involved in the protective
      mechanisms. In order to see whether neurotrophic factors are synthesized in the
      retina, we studied the expression of neurotrophic factors in the retina following
      vitreous tap in rats. MATERIALS AND METHODS: One eye each of 20 mature rats
      received transscleral vitreous taps at three points of entry and retinal injury.
      The retinas were removed and examined at day 0 to 14 of treatment. RESULTS:
      Following injury, the retina showed increased expression of glial fibrillary
      acidic protein (GFAP) mRNA and brain-derived neurotrophic factor (BDNF) mRNA.
      There was no enhancement of neurotrophin-3 (NT-3) mRNA when examined by reverse
      transcription-polymerase chain reaction (RT-PCR). CONCLUSIONS: Activated retinal
      glial cells may produce BDNF which prevents retinal neuronal cell damage
      following injury.

PMID- 10339971
TI  - [Effect of mitomycin C dissolved in a reversible thermosetting gel on outcome of
      filtering surgery in the rabbit].
AB  - PURPOSE: Based on our previous report that showed enhanced transfer of mitomycin
      C to the sclera and the conjunctiva by dissolving the antiproliferative in a
      reversible thermo-setting gel, we conducted a study to investigate the efficacy
      of the mitomycin C-gel in the rabbit. METHODS: We subconjunctivally injected 0.1
      ml of the mitomycin C-gel solution containing several amounts of the drug.
      Trephination was performed in the injected region 24 hours later. Intraocular
      pressure measurement, and photography and ultrasound biomicroscopic examination
      of the filtering bleb were done 1, 2, and 4 weeks postoperatively. RESULTS: The
      gel containing 3.0 micrograms or more mitomycin C significantly enhanced bleb
      formation in addition to reducing the intraocular pressure. CONCLUSION: The
      reversible thermo-setting gel seems to facilitate filtration following glaucoma
      filtering surgery in the rabbit and deserves further investigation as a new
      method of mitomycin C application.

PMID- 10339972
TI  - [Macular morphologic reconstruction and visual recovery in patients following
      macular hole surgery].
AB  - PURPOSE: To examine the characteristics of retinal reconstruction at the macula
      following macular hole surgery and to assess the impact of postoperative macular
      morphological changes on the visual outcome. METHODS: A prototype of the scanning
      retinal thickness analyzer (RTA) was used to obtain optical section images at the
      macula in 53 eyes of 52 patients who underwent macular hole surgery between April
      1994 and July 1997. The mean age of participants was 64.7 years. At the time of
      RTA examination, macular hole was biomicroscopically closed in 49 eyes (91%) and
      unclosed in 5 eyes (9%). RESULTS: There were 5 types of cross-sectional images of
      postoperative maculae: normal foveal depression [19 eyes (36%)], crater-like
      fovea formation [12 eyes (22%)], flattened fovea [8 eyes (15%)], fovea with
      abraded retinal pigment epithelium [9 eyes (17%)], and persistant macular hole [5
      eyes (9%)]. Central macular thickness measured by RTA was 165 +/- 39 (mean +/-
      standard dereation) microns in the normal foveal depression group, 210 +/- 67
      microns in the crater-like fovea formation group, and 300 +/- 50 microns in the
      flatened fovea group. There were statistically significant differences (p < 0.01)
      between groups. Postoperative visual acuity was significantly different (p <
      0.01) between these three groups, and central macular thickness was highly
      correlated with postoperative visual acuity (R = 0.70). CONCLUSION: Visual
      recovery following macular hole surgery is closely associated with the retinal
      reconstruction at the macula.

PMID- 10339973
TI  - [High inducibility of Epstein-Barr virus replication in B lymphocytes in Vogt
      Koyanagi-Harada disease].
AB  - PURPOSE: The role of Epstein-Barr virus (EBV) reactivation in the pathogenesis of
      Vogt-Koyanagi-Harada (VKH) disease was examined. MATERIAL AND METHODS: Using B
      lymphocytes obtained from 8 patients with VKH disease and 10 patients with other
      types of uveitis, immortarized lymphoblast lines were established and infected
      with EBV. The degree of EBV activation in each lymphoblast line, in the presence
      and absence of various stimuli, was assessed by measuring the expression of 3
      different antigens involved in replication by immunofluorescent staining and
      western blot analysis. Quantification of EBV DNA in cell culture supernatants was
      done by polymerase chain reaction. RESULT: Cell lines established from VKH
      patients expressed more viral antigens that those established from patients with
      other types of uveitis. There were greater amounts of EBV DNA in the VKH cell
      lines. CONCLUSION: B lymphocytes from VKH patients may be more susceptible to EBV
      activation, and the reactivation of EBV may be involved in the pathogenesis of
      VKH.

PMID- 10339974
TI  - [Observation of physiological change in the human ciliary body using an
      ultrasound biomicroscope during accommodation].
AB  - PURPOSE: To evaluate changes in the ciliary body during accommodation using an
      ultrasound biomicroscope (UBM). SUBJECTS AND METHODS: Eleven healthy persons,
      aged from 24 to 33 years, served as subjects. They were asked to lie in the
      supine position and to fixate a target placed on the ceiling 2 m above with the
      left eye. A concave lens with the power of -6 to -8 diopters was then placed
      before the fixating left eye. The thickness of the ciliary body in the right eye
      was measured by UBM in the nonaccommodative and accommodative states. FINDINGS:
      The anterior chamber in the right eye became significantly shallow during
      accommodation. The thickness of the ciliary body significantly increased during
      accommodation at 0.5 mm and 1.0 mm posterior to the scleral spur. It
      significantly decreased at 2.0 mm, 2.5 mm and 3.0 mm posterior to the scleral
      spur. CONCLUSION: During induced accommodation in the left eye, the anterior
      portion of the ciliary body in the right eye increased and the posterior portion
      decreased in thickness. The findings imply that the circular ciliary muscles are
      mainly involved in accommodation and not the longitudinal muscles.

PMID- 10339975
TI  - [Vitrectomy for proliferative diabetic retinopathy associated with iris
      rubeosis].
AB  - OBJECT: To compare the results of vitrectomy for phakic cases and those of
      aphakic cases with proliferative diabetic retinopathy (PDR) accompanied by
      rubeosis iridis. MATERIALS & METHODS: We reviewed 34 eyes of 24 cases that
      underwent vitrectomy for proliferative diabetic retinopathy with rubeosis iridis.
      RESULT: Phakic eyes needed significantly more reoperations (p < 0.001) than
      aphakic eyes. Aphakic eyes had significantly more successful visual results (p <
      0.05) and better control of intraocular pressure (p < 0.005) than phakic eyes.
      CONCLUSION: This study showed the possibility that phakic eyes had more ischemic
      retina producing more angiogenic factors than aphakic eyes which had the same
      grade of rubeosis iridis. Phakic eyes with pre-operative rubeosis iridis need
      thorough clearance of ocular ischemia by panretinal photocoagulation.

PMID- 10339976
TI  - [Long-term outcome of topical cyclosporine treatment following penetrating
      keratoplasty].
AB  - PURPOSE: To evaluate the long-term outcome of 2% topical cyclosporine A (CsA)
      treatment as an adjunct to topical corticosteroid in 86 eyes after penetrating
      keratoplasty (PK). MATERIAL AND METHODS: The subjects were 86 eyes of 83 patients
      who had undergone PK and received topical CsA treatments. Ninety-seven eyes of 95
      patients who had undergone PK and received similar postoperative treatments
      except for topical CsA treatments served as control: The clinical outcome of PK
      was evaluated by rates of graft survival and rejection-free graft survival using
      Kaplan-Meier's method and compared with the log-rank test. The patients were
      subdivided into high-risk and low-risk groups. The high-risk patients were those
      who had corneal vascularization in 2 or more quadrants of the cornea
      preoperatively or who received regrafting. All other patients were assigned to
      the low-risk group. Thirty-six eyes of the CsA group and 50 eyes of the control
      group were high-risk cases. RESULTS: In the high-risk patients, the rejection
      free graft survival rate was 69.7% in the CsA group and 45.4% in the control
      group (p = 0.030). However, there was no significant difference in the graft
      survival rate between the two groups. In the low-risk patients, there was no
      significant difference in the rates of rejection-free graft survival and graft
      survival between the CsA and the control group. CONCLUSION: 2% topical
      cyclosporine is effective in reducing the risk of allograft rejection in high
      risk recipients.

PMID- 10339978
TI  - [Predicted versus actual postoperative refractive error after simultaneous
      vitrectomy and cataract surgery].
AB  - PURPOSE: We compared the spread between predicted and postoperative actual
      refractive errors after simultaneous vitrectomy, phacoemulsification, aspiration,
      and acryl lens insertion and after cataract surgery alone. METHODS: Cataract
      surgery and vitrectomy (combined surgery group) were performed in 185 eyes, and
      cataract surgery only (cataract surgery group) in 63 eyes. Vitrectomy was needed
      for diabetic retinopathy in 104 eyes, macular hole in 26 eyes, rhegmatogenous
      retinal detachment in 25 eyes, and other conditions in 30 eyes. RESULTS: The
      spread between predicted and actual refractive errors were +0.19 +/- 1.24 D (mean
      +/- standard deviation) in the combined surgery group and +0.91 +/- 1.40 D in the
      cataract surgery group. Gas tamponade in the combined surgery group increased the
      myopic change more than anything else. CONCLUSION: Actual refractive errors in
      the combined surgery group were found to shift to myopia more than in the
      cataract surgery group. Gas tamponade was considered to press the intraocular
      lens forward in the combined surgery group.

PMID- 10339977
TI  - [Photostimulation that induces flattening of photopic electroretinograms--first
      report. An apparatus for slope photostimulation].
AB  - PURPOSE: We developed a new photostimulation system for electroretinograms
      (ERGs). This apparatus is capable of varying the transients during stimulus on
      and off (up-slope and down-slope times, respectively) as well as the stimulus and
      background intensities. We applied this system to evaluate the photopic ERG in
      human eyes. CASES AND METHODS: Seven normal volunteers and a 43-year-old patient
      with pre-proliferative diabetic retinopathy served as test subjects. We recorded
      ERGs with relatively long intervals of up-slope and down-slope times for
      photostimulation. RESULTS: As the up-slope and down-slope times were increased,
      the amplitude was reduced and the peak latency was prolonged for both the on and
      off responses. When the normal subjects' retinas were stimulated with a 341-msec
      up-slope time and a 34.1-msec down-slope time, the ERG waves showed complete
      flattening in both on and off responses. The ERGs of a patient with pre
      proliferative diabetic retinopathy showed much longer peak latency than that of
      the normal volunteers as the up-slope time was prolonged. When the patient's
      retina was stimulated for a prolonged up-slope time, the average of the amplitude
      of ERG waves was similar to that of the normal volunteers. CONCLUSION: These
      results suggest that this new type of photostimulation might potentially uncover
      some novel aspect of clinical ERGs and might be useful for testing retinal
      functions of patients with diabetic retinopathy.

PMID- 10339979
TI  - [A case of keratitis, ichthyosis, and deafness syndrome with Hutchinson's triad
      like symptoms].
AB  - BACKGROUND: Association of keratitis, ichthyosis, and deafness is known as KID
      syndrome. Only four cases have been reported in Japan by dermatologists. CASE: A
      male infant manifested absence of hair and generalized keratosis of the skin
      since birth. He had been diagnosed as having chronic mucocutaneous candidiasis
      (CMCC). FINDINGS: The patient manifested punctuate superficial keratopathy in the
      right eye and corneal opacity with peripheral neovascularization in the eye when
      initially seen at the age of 1 year and 4 months. The corneal lesion later
      developed into stromal keratitis with neovascularization in the stroma.
      Abnormalities simulating Hutchinson teeth were detected at the age of 4 years.
      Neurosensory deafness in the high-frequency region was detected at the age of 6
      years. Serous tests for syphilis were consistently negative. CONCLUSION: This
      child is the first reported case in Japan manifesting KID syndrome with
      Hutchinson teeth. The associated CMCC was interpreted as due to liability to
      infection in patients with KID syndrome.

PMID- 10339980
TI  - [A case of bilateral continuous central retinal artery occlusion].
AB  - BACKGROUND: We report a case of bilateral simultaneous central retinal artery
      occlusion (CRAO). The time lag was 21 hours. CASE: The patient was a 78-year-old
      woman. She had hypertension, arteriosclerosis, and bilateral thrombosis of the
      legs. Both eyes could only distinguish light and dark at the first medical
      examination. RESULTS: We started steroid and urokinase therapy and used a
      vasodilator of peripheral vessels. When the patient left the hospital, visual
      acuity had improved to the ability of counting fingers (0.01 leftward 30 cm on
      the left). CONCLUSIONS: Both visual field and color vision had improved slightly.
      We think this bilateral CRAO resulted from thrombosis of both central retinal
      arteries at almost the same time.

PMID- 10339981
TI  - [Utility of thin-section/high-pitch helical CT for the assessment of small lung
      nodules].
AB  - To determine the utility of thin-section/high-pitch CT for the assessment of
      small lung nodules, a lung phantom was scanned on 1 mm width collimation at
      variable pitches of 1.0, 1.5, 2.0, 2.5 and 3.0. Images obtained at pitch 3.0 were
      degraded visually. Secondly a bead phantom was scanned on 1 mm width collimation
      at pitches of 1.0, 1.5, 2.0 and 3.0. Focus size was determined with a variable
      setting of small and large. We obtained maximum and full width at half maximum
      (FWHM) scans and performed a clinical study of small lung nodules on 1 mm width
      at pitch 2.0 on small focus. Thirdly, we estimated the image quality of 1 mm/2 mm
      helical scans in comparison with 1 mm/1 mm helical scans. Comparison was made
      using axial, MPR and 3D-CT (MIP) images. The axial and MIP images were almost
      equal qualitatively, whereas MPR images were degraded, especially in the near
      region of the heart and great vessels, due to motion artifacts. We emphasize the
      utility of 1 mm/2 mm helical CT in scanning a much larger volume with the same
      breath holding.

PMID- 10339982
TI  - [CT findings of nasal non-Hodgkin's lymphomas associated with prognosis].
AB  - X-ray CT images of the head obtained from thirteen patients (9 men and 4 women)
      among 33 patients (19 men and 14 women) with nasal non-Hodgkin's lymphoma (NHL)
      who had been seen at Kitasato University Hospital during the period from April
      1975 to March 1995 were retrospectively reviewed to search for useful prognostic
      image factors for nasal NHL. Extracavitary subcutaneous tumor extension into the
      nasal wing or cheek, and tumor penetration through the nasal septum revealed on X
      ray CT images seemed to be likely indicators of a poor prognosis for patients
      with nasal NHL.

PMID- 10339983
TI  - [A gastrointestinal radiographic study of 18 patients with esophageal
      adenocarcinoma arising from Barrett's epithelium].
AB  - Gastrointestinal radiographs were reviewed with pathological correlation in 18
      patients with histologically proven esophageal adenocarcinoma arising from
      Barrett's epithelium. Comparison was also made with postoperative radiographs of
      resected esophageal specimens from 3 of the patients. Esophageal carcinoma could
      be observed in the gastrointestinal radiographs in 17 of the 18 patients. In 14
      of the 17, the classification based on the gastrointestinal radiographs was
      consistent with the gross classification. In 10 of the 18 patients, rough mucosa
      was seen on gastrointestinal radiographs in the same area in which Barrett's
      epithelium was observed in the histopathological specimens. Sliding esophageal
      hiatus hernia was present in 12 of the 18 patients, a relatively high incidence.
      Regular granular or reticular shadows were observed on the mucosal surface of the
      esophagus on the postoperative radiographs of 3 patients. It is believed that a
      diagnosis of Barrett's epithelium can be made from gastrointestinal radiographs
      if these mucosal patterns are present. Although a definitive diagnosis of
      Barrett's epithelium based on upper gastrointestinal radiographs is considered
      difficult, the presence of rough mucosa in the esophagus around the carcinoma in
      combination with esophageal hiatus hernia are suggestive of esophageal
      adenocarcinoma arising from Barrett's epithelium.

PMID- 10339984
TI  - Multi-institutional survey of radiotherapy for octogenarian squamous cell
      carcinoma of the thoracic esophagus: comparison with the results of surgery
      reported in Japan.

PMID- 10339985
TI  - [Application of MR-guided intravascular procedures by passive tracking utilizing
      the magnetic susceptibility effect: a preliminary report].
AB  - In MR-guided intravascular procedures, the position of catheters must be
      confirmed on near-real-time MR images. One way of monitoring this is by passive
      tracking utilizing the magnetic susceptibility effect. A catheter with a
      stainless steel braid had suitable visibility when tracked by magnetic
      susceptibility on fast GRE images, although the direction of the static magnetic
      field affected the apparent width of the catheter. Passive tracking with a 1.5T
      MRI unit was performed in a patient at one image/2 seconds with fast GRE. The
      catheter could be introduced to the SMA and celiac artery from the aorta with
      passive tracking.

PMID- 10339986
TI  - [Application of a new MR microscope using an independent console system (MRMICS)
      for biological tissues in vitro].
AB  - We studied microscopic MR images of the normal appendix in vitro using a new MR
      microscope system: MR Microscope using an Independent Console System (MRMICS).
      The MRMICS was placed in the clinical MR room, and the probe box was fixed on the
      bed of the 1.5 T clinical MR machine. T1-, T2-, and proton density-weighted
      images were obtained using spin echo sequences with an in-plane pixel size of 100
      x 100 microns. Zonal structures of the appendix were clearly demonstrated with
      different contrast by different sequences. Therefore, the MRMICS is a useful add
      on system for investigating microscopic MR images of biological tissues in vitro.

PMID- 10339987
TI  - [Olfactory origin of luteinizing hormone-releasing hormone (LHRH) neurons].

PMID- 10339988
TI  - Chromosome 8 copy numbers and the c-myc gene amplification in non-small cell lung
      cancer. Analysis by interphase cytogenetics.
AB  - Amplification of the c-myc gene has been reported in non-small cell lung cancer
      (NSCLC). We performed dual color fluorescence in situ hybridization (FISH) to
      detect amplifications of the c-myc gene on chromosome 8 to evaluate the
      relationship between these possible abnormalities and pathological stage. Tumor
      tissue samples were obtained from 29 patients of NSCLC in Stage I (n = 15) and
      III (n = 14) who underwent lobectomy at Saitama Cancer Center. Samples were
      analyzed for chromosome 8 centromere and c-myc gene by dual color FISH. The
      numerical aberration rate of chromosome 8 was 36.8 +/- 20.3% in Stage I and 40.6
      +/- 24.8% in Stage III. The amplification rate of c-myc gene was 48.3 +/- 15.2%
      in Stage I and 57.4 +/- 17.0% in Stage III. There was a significnat difference in
      the numerical aberration rate of chromosome 8 between patients who survived for 5
      years or more (28.8 +/- 17.5%) and those who survived less than 5 years (44.7 +/-
      23.1%). The amplification rate of c-myc gene was not different between patients
      who survived more and less than 5 years survival, and who survived more and less
      than 3 years. The 5 year-survival rate in patients who showed 40% or more of
      chromosome 8 aberrations (n = 13) was 15.4%, which revealed significantly less
      than that of patients who showed less than 40% of aberrations (n = 16) (56.3%).
      There was no difference between the 5 year-survival rate in patients whose
      amplification rates of c-myc gene were equal or more than 50% (n = 16) and less
      than 50% (n = 13) (25.0% and 53.9%). The rate of chromosome 8 aberrations and the
      c-myc gene amplification rate were not correlated with pathological stage.
      However, the rate of chromosome 8 aberration showed correlation in terms of
      longevity of survival rate, therefore we considered the rate of chromosome 8
      aberration to be an additional prognostic factor of patient with NSCLC.

PMID- 10339989
TI  - [Examination of non-transmitter effects of catecholamines on clonal cells derived
      from Drosophila CNS].
AB  - The effects of catecholamines (CAs) other than their transmitter action were
      investigated using clonal neuronal cells, ML-DmBG2-c2, derived from Drosophila in
      the larval central nervous system (CNS). All catecholamines tested, adrenaline
      (AD), dopamine (DA), noradrenaline (NA) and isoproterenol (ISO), prevented any
      increase in the number of cells during 2- to 7-day culture. alpha-, beta
      adrenergic and dopaminergic antagonists did not block the effects of CAs on the
      number of cells. Adrenochrome, a product of the oxidative degradation of AD, also
      prevented any increase in the number of cells, as AD did. The effect of AD was
      partially blocked by an antioxidant, dithiothreitol (DTT). These results suggest
      that the inhibition of the increase in cell numbers by CA might be mediated by
      CAs themselves and/or oxidative products in the CA metabolic process. It is
      concluded that CAs inhibit cell proliferation but do not induce cell death in the
      Drosophila clonal cells.

PMID- 10339990
TI  - [Possible contribution of alpha-adrenergic abnormalities to cerebral ischemia in
      the patients with sinus bradycardia. Analysis by pharmacologic autonomic nervous
      test].
AB  - BACKGROUND: Syncope of patients with bradyarrhythmia is perceived as severe sign
      of low cardiac output caused by bradycardia and as a major criteria for pacemaker
      implantation (PMI). However, it has been reported that PMI can not always prevent
      syncope; it has been suggested that not bradycardia but an abnormality of the
      autonomic nervous system plays a part in syncope. PURPOSE: To investigate the
      relation between autonomic nervous dysfunction and syncope in cases of sinus
      bradycardia (SB). SUBJECTS: Thirty-nine patients with SB were divided into two
      groups according to the presence (group S, n = 16, 46.9 +/- 20.0 years) or
      absence (group N, n = 23, 40.4 +/- 17.6 years) of syncope or presyncope. METHODS:
      Corrected sinus node recovery time (CSNRT) was measured by electrophysiologic
      study. Pharmacologic autonomic nervous tests were performed as follows in a quiet
      room. Increased HR by application of 0.04 mg/kg atropine (para-tone), and by
      0.004 microgram/kg/min isoproterenol divided by 0.004 (beta-sens) were evaluated,
      beta-tone was obtained by subtracting HR after application of propranolol (0.2
      mg/kg) from that of atropine. Basal beta-sympathetic activity was evaluated by
      beta-sec that was obtained by beta-tone/beta-sens. Increased SBP by application
      of 0.4 microgram/kg/min phenylephrine divided by 0.4 (alpha-sens) was evaluated.
      alpha-tone was obtained by subtracting minimum SBP after 0.2 mg/kg phentolamine
      from SBP after application of propranolol. Basal alpha-sympathetic activity was
      evaluated by alpha-sec, that was obtained by alpha-tone/alpha-sens. RESULT: There
      were no significant differences in basal clinical characteristics (age, sex,
      cardiac function) between the groups. The parameters of the functions of
      parasympathetic and beta-sympathetic receptors (para-tone, beta-sens, beta-tone,
      beta-sec) showed no significant differences between the groups, alpha-sens was
      attenuated (P < 0.01) and alpha-sec was augmented (P < 0.0001) significantly in
      group S. CONCLUSION: It was suggested that syncope or presyncope in SB patients
      could be attributed to failure of vasoconstriction mediated by alpha-sympathetic
      receptor but to severity of sinus node dysfunction.

PMID- 10339991
TI  - Evidence for norepinephrine-activated Ca2+ permeable channels in guinea-pig
      hepatocytes using a patch clamp technique.
AB  - To determine whether the hepatocyte plasma membrane possesses a Ca2+ channel. we
      applied a patch clamp technique to isolated guinea-pig hepatocytes. In a cell
      attached configuration, using an internal pipette solution of 110 mM BaCl2 or
      CaCl2, we observed sporadic inward single channel currents (Po = 0.004 +/- 0.002,
      n = 6) at various membrane potentials. The unit amplitude was 0.60 +/- 0.15 pA (n
      = 6) at resting membrane potential. The single channel conductance was 20.4 +/-
      4.6 pS (n = 6) and this channel showed no rectification and no voltage
      dependence. Bay K 8644, a dihydropyridine Ca2+ channel activator, did not affect
      this channel activity. Although norepinephrine in the pipette solution did not
      activate this channel, its external application increased channel activity. These
      observations suggest that guinea-pig hepatocytes possess Ca2+ permeable channels
      that differ from the voltage-operated Ca2+ channels found in excitable cells and
      that such channels are responsible for the agonist-stimulated Ca2+ entry in
      hepatocytes.

PMID- 10339992
TI  - [Analysis of ovarian tumors treated at Nippon Medical School Hospital in a 5-year
      period. Problems in a frozen section diagnosis].

PMID- 10339993
TI  - [Diabetes in the elderly: diagnosis and therapy].

PMID- 10339994
TI  - [Case record from Nippon Medical School. Seatbelt injury].

PMID- 10339995
TI  - [The healing process following gynecologic laparoscopy: data on the significance
      of psychological factors].
AB  - It is known that patients undergoing laparoscopic surgery can be discharged from
      hospital sooner and their reconvalescence is achieved faster than after
      laparotomy. Beside the medical judgement of the healing process it is also
      important to assess the length of time needed for the patients to feel themselves
      completely cured and be free of complaints. The data on the subjective judgement
      of the healing process provided by 335 patients who underwent laparoscopic
      surgery are analyzed retrospectively here. The aim of the study was to assess how
      anxiety as a personality trait might influence the healing process and also if
      there is any connection between anxiety, clinical diagnosis and laparoscopic
      findings. Anxiety was measured by Spielberger's State-Trait Anxiety Inventory
      (STAI). The estimated average healing time is 29.8 days (appr. 4 weeks), but
      patients with diagnostic and/or operative laparoscopy felt themselves free of
      complaints after 18.9 days (appr. 3 weeks) on the average. The duration of the
      healing process is independent of the laparoscopic findings and the type of
      procedure. There is a strong correlation between the anxiety level and the
      healing process. The average level of anxiety trait was 47.99 +/- 9.50. Anxiety
      level was the highest in the group of patients operated on for pelvic pain (mean
      = 51.21). There was no serious organic alteration in the small pelvis in 37% of
      the cases. One year after the operation 11.3% of the patients did not feel
      themselves cured and 17.6% had complaints. These data emphasize the role of
      anxiety and that of psychological factors in the etiopathogenesis and treatment
      of gynecologic diseases, especially in chronic pelvic pain and infertility or
      sterility.

PMID- 10339996
TI  - [Occurrence of Helicobacter pylori in patients with gastroesophageal tumors].
AB  - Authors examined the occurrence of H. p. retrospectively in bioptic material for
      three years. Fifty-one oesophageal and gastric tumorous patients were examined
      and as a control fourty-seven non tumorous patients with chronic gastritis chosen
      at random. The demonstration of H. p. was performed by modified Giemsa stain.
      Different types of chronic gastritis, forms and localisation of the tumours as
      well as their relation with sex and age were investigated. The occurrence of H.
      p. was higher in chronic gastritis than in tumorous processes. Seventy-one % H.
      p. positivity was found in the control group against 17.6% in the tumorous
      patients.

PMID- 10339997
TI  - [Caudal epidural injection in the management of lumbosacral nerve pain
      syndromes].
AB  - The effect of epidural steroid injections was assessed in 39 patients with lumbar
      nerve root compression syndromes in a double-blind controlled trial, the patients
      were allocated at random to 3 groups. In group A (n = 13) the patients received a
      caudal epidural injection of 1 ml (7 mg) bethametason (Diprophos) in 10 ml normal
      saline and 20 ml local anesthetic (Lignocaine 1%). The second group B (n = 13)
      received a caudal epidural injection of 20 ml local anaesthetic (Lignocaine 1%)
      and 10 ml normal saline. The third group C (n = 13) received a superficial
      injection of 1 ml (7 mg) bethametason around of the sacral hiatus. All injections
      were performed by the same experienced anaesthesiologist. An independent
      physician, who was not aware which type of injection had been given, carried out
      the clinical measurements and the evaluation. Taking of analgesic drug Tramadol
      was permitted. The symptoms were assessed by visual analogue scale (VAS 100 mm),
      lumbar flexion (Schober and finger-floor distance), the angle of raised leg sign
      (RLS degrees), and by complete neurological examination, the investigation was
      made 5 times (1 hour, 24 hours, 48 hours, 1 week, and 4 weeks after epidural
      injections). The results between 0-1 week and 0-4 week were statistically
      analysed by Student-, Wilcoxon-, and Mann-Whitney test and analysis of variance
      (ANOVA). The mean VAS values decreased in time in all patient groups. There was
      no difference between the three treatment groups either after one or after 4
      weeks by ANOVA. The mobility of the lumbar spine improved in all patient groups,
      but there was no significant difference between the three treatment groups. The
      raised led sign--values improved in all patient groups. There was a significant
      difference between the three treatment groups by ANOVA after one week, due to the
      difference between group A and C. After four weeks there was no significant
      difference. No major complications or side effects were seen in our trial. The
      raised leg sign due to epidural steroid injection showed better results in
      comparison to steroid injection around of the sacral hiatus were seen.

PMID- 10339998
TI  - [Sweet syndrome following therapeutic use of granulocyte colony stimulating
      factor].
AB  - Sweet's syndrome is an acute febrile neutrophilic dermatosis. Classical form
      occurs after infection of the gastrointestinal or respiratory tract. This
      syndrome is often associated with myeloproliferative disorders and solid tumors.
      Some cases are reported in the literature in which usage of granulocyte colony
      stimulating factor induced the symptoms of Sweet's syndrome. We report the case
      of an 53-year-old woman with hyperthyreosis. She wasn't euthyreoid in spite of
      medicaments since 1994, so her doctors planned operation. In the preoperative
      period her peripheral blood revealed agranulcytosis and she has got fever. 2 days
      after administration of granulocyte colony-stimulating factor erythematous
      plaques appeared on her face, neck and extremities. Biopsy from these plaques
      showed dermal neutrophilia, so a diagnosis of neutrophilic dermatosis was made.
      After the administration of corticosteroids, immunglobulin and antibiotics the
      skin lesions were resolved. She was examined because of suspicion of autoimmune
      diseases but we couldn't find any of them. Retrospectively, appearance of Sweet's
      syndrome was associated with granulocyte colony-stimulating factor. The case of
      this woman is important because usage of colony-stimulating factors is widespread
      and the Sweet's syndrome could be occurs as side effect of these drugs.

PMID- 10339999
TI  - [Diagnostic and therapeutic protocol of angiologic diseases. Recommended by the
      Angiologic Committee of the College of Internal Medicine].

PMID- 10340000
TI  - [How does the laboratory medicine correspond to the medical big bang?].

PMID- 10340001
TI  - [Current and future laboratory operations for medical administration--based on
      JAMT].
AB  - The Ministry of Health and Welfare and the Liberal Democratic Party announced a
      preliminary medical insurance system reform plan in July and August 1997,
      respectively. The main goal is to reduce medical expenses in both plans.
      Presently, medical facilities have financial difficulties which influence
      laboratory testing practices. Further cost containment is a major source of
      anxiety in hospital laboratories. Japan Association of Medical Technologists has
      been working to improve the position and capabilities of medical technologists
      and to recognize that some countermeasures to deal with the economic pressures
      should be taken. JAMT would like to work together with other related associations
      and organizations to find solutions to this issue.

PMID- 10340002
TI  - [Work expansion and teamwork in the clinical examination department].
AB  - Changes in hospital management and examination rooms are needed along with
      revisions of medical laws and medical fees. Clinical examination engineers should
      improve hospital management by implementing user service, cost performance and
      effective use of skills to ensure proper treatment.

PMID- 10340003
TI  - [A consideration for the situation of the commercial laboratories and their
      connection with the medical administration in Japan].
AB  - The commercial laboratories in Japan have been serving all physicians to be able
      to use all laboratory tests even if they are newly developed. Though the
      commercial laboratories have functioned very well for clinically, for
      economically they have made a great margin between the official price which is
      decided by medical insurance and the business price which is dealt with
      hospitals. The margin and the margin from drugs have caused excess clinical
      testing and drug prescription, subsequent increase of total medical cost in
      Japan. We are going to revise our medical insurance system to improve various
      inconvenience in the present and future status. For the Japan Registered Clinical
      Laboratories Association which is the representative of the commercial
      laboratories, it's a time to cooperate with the other clinical laboratory tests
      related organizations (ex. Japan Association of Medical Technologists, Japan
      Association of Clinical Laboratory Physicians, etc.) and to built new acceptable
      circumstances of the clinical testing corresponding to medical administration.

PMID- 10340004
TI  - [Trend of health policy and hospital laboratory service--view from hospital
      management].
AB  - As a necessary consequence of deregulation which allows private enterprises to
      participate in hospital management, hospitals (non-profit-organization) are
      forced to become financially stable and to continuously improve the quality and
      standardize health care as well as to promote EBM which is scientifically
      justified. What is required of the laboratory department of hospital under such
      circumstance is described in this paper.

PMID- 10340005
TI  - [Advances in interleukin-6 therapy].
AB  - Interleukin-6 (IL-6) exhibits multiple biologic activities such as regulation of
      immunological responses and hematopoiesis, promotion of acute inflammation, and
      stimulation of some malignant and non-malignant cell growth. The IL-6 receptor
      system consists of an IL-6 specific binding molecule, IL-6R and a signal
      transducer, gp130. Following gp130 dimerization, IL-6 activates multiple
      signaling pathways (Ras dependent MAPk cascade, STAT1-STAT3 heterodimer pathway,
      and STAT3 homodimer pathway). Several other cytokines including oncostatin M, IL
      11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and
      cardiotropin-1 (CT-1) use gp130 as a common signal transducing molecule and
      therefore have similar biological activities. Two major in vivo functions of IL-6
      are reported. Firstly, IL-6 acts as a growth factor of some malignant and non
      malignant cells such as malignant plasma cells in multiple myeloma, mesangial
      cells in the kidney, and keratinocytes. Secondly, IL-6 mediates inflammatory and
      immune responses in rheumatoid arthritis, Castleman disease, psoriasis, cardiac
      myxoma, cachexia, and other inflammatory conditions. Recently, a humanized anti
      IL-6 receptor antibody was developed. Neutralization of IL-6 activity by the
      humanized anti-IL-6 receptor antibody may be a new therapeutic approach for IL-6
      related diseases such as multiple myeloma, Castleman disease and rheumatoid
      arthritis.

PMID- 10340006
TI  - [Clinical evaluation of serum cytokine from patients with collagen diseases].
AB  - PURPOSE: Systemic autoimmune diseases such as systemic lupus erythematosus (SLE)
      and Sjogren's syndrome (SS) are characterized by an imbalance of cytokine
      production. To clarify the relationship between the profile of cytokines and the
      pathophysiology of systemic autoimmune diseases, we estimated the cytokine levels
      in sera from patients with several systemic autoimmune diseases. METHOD: Serum
      cytokine levels in patients with unclassified connective tissue diseases were
      measured using ultrasensitive specific enzyme-linked immunosorbent assay (ELISA).
      RESULT: These patients were diagnosed using the established category by further
      examinations within a 2-year period. Sera from patients with SLE contained higher
      titers of IL-10, and equal levels of IFN gamma and TNF alpha compared with those
      of normal controls. Patients with progressive systemic sclerosis (PSS) showed
      lower titers of IL-10 and higher titers of IFN gamma and TNF alpha in their sera
      than those of healthy controls. Seronegative rheumatoid arthritis (snRA) patients
      had a higher amount of IL-10 and TNF alpha, equivalent level of IFN gamma in
      their sera compared to those of controls. Moreover, patients with Sjogren's
      syndrome (SS) showed higher titers of IL-10 and TNF alpha, and an equivalent
      level of IFN gamma in their sera compared to healthy volunteers. CONCLUSION:
      Based on these findings, for the differential diagnosis of patients with systemic
      autoimmune diseases such as SLE, PSS, snRA and SS, it may be useful to measure
      the levels of cytokines such as IL-10, IFN gamma, and TNF alpha in their sera.

PMID- 10340007
TI  - [Organ-specific autoimmune diseases and cytokines].
AB  - Changes in serum levels of cytokines in organ-specific autoimmune diseases were
      reviewed. Serum levels of IL-12, critical for the development of Th1 cells, were
      increased in thyrotoxic patients with Hashimoto's thyroiditis and Graves'
      disease. Serum levels of IL-5, secreted from Th2 cells, were increased in
      thyrotoxic patients with Graves' disease, but not in thyrotoxic patients with
      Hashimoto's thyroiditis. In patients with IDDM, serum levels of Th1 cytokines
      (IFN-gamma and IL-2) were increased but serum levels of Th2 cytokines (IL-4 and
      IL-10) were not increased. These findings suggest that measuring the serum
      concentration of various cytokines is useful to analyze Th1/Th2 balance in
      autoimmune diseases.

PMID- 10340008
TI  - [Accuracy, precision and clinically acceptable level of complete blood cell count
      by an automated multichannel hematology analyzer].
AB  - Measurement of complete blood cell count (CBC) is one of the essential laboratory
      tests. In this study, the accuracy of CBC was high, when measured by six
      different automated blood cell counters, including SE-9000/RAM-1, CELL-DYN 4000,
      ADVIA 120, VEGA RETIC-LC141 or GEN*S. The correlations of CBC counts among these
      instruments were also good. In contrast, the accuracy in abnormal samples
      depended on matching the instrument and type of clinical conditions. Internal
      quality control of automated multichannel hematology analyzers was recommended by
      the NCCLS H26-A in 1996. However, actual external quality control of the CBC
      count was poorly understood. We surveyed three samples from healthy volunteers
      for CBC values in 1997. Among six different instruments, the inter-assay of the
      red blood cell count (RBC), hemoglobin, hematocrit and MCV was fairly good, shown
      as < 4.2%, < 3.0%, < 4.4% and < 3.4%, respectively. In contrast, the inter-assay
      of the white blood cell count (WBC) and platelet (PLT) was not good, shown as <
      11.4% and < 9.6%, respectively. The clinically acceptable levels for the blood
      cell count were reported to be 4% for RBC, 3% for hemoglobin, 4% for MCV, 5% for
      WBC and 7% for PLT, by JCCLS in 1994. The clinically acceptable CBC by
      hematologists at Keio University resembled those by councilors of The Japanese
      Society of Clinical Hematology, whereas, residents at Keio University and general
      physicians required more precise clinical CBC counts. These results indicate that
      a larger study is needed to clarify the accuracy, clinically acceptable level,
      and performance of different automated blood cell counters.

PMID- 10340009
TI  - [Precision and accuracy of white blood cell differentiation by an automated blood
      cell analyzer].
AB  - Precision and accuracy are important to assure the quality of clinical laboratory
      tests. We investigated the precision and accuracy of white blood cell (WBC)
      differentiation by automated blood cell analyzers. The coefficients of variation
      (CVs) of neutrophil, lymphocyte, monocyte, eosinophil and basophil
      differentiation by GEN.S (Coulter), based on a flow system and VCS technology,
      were 1.1%, 1.5%, 4.6%, 2.1%, and 33.3%, respectively. Between-run precision for
      neutrophil, lymphocyte, monocyte, eosinophil and basophil differentiation by
      GEN.S using cell control, 5C in 26 serial days was 2.0%, 2.8%, 6.5%, 9.2%, and
      29.5%, respectively. The precision of WBC differentiation by blood cell analyzers
      based on the flow system was excellent except for basophil. We studied the
      accuracy of WBC differentiation by blood cell analyzers based on the flow system
      in contrast with eye-count. The correlations between neutrophil, lymphocyte,
      monocyte, eosinophil, and basophil percentages counted by GEN.S and by eye-count
      were r = 0.968, 0.971, 0.902, 0.940, and 0.391, respectively. The agreement rate
      between WBC differentiation by Microx, a blood cell analyzer based on pattern
      recognition, and eye-count cell by cell was good except for basophils. The
      accuracy of WBC differentiation by blood cell analyzers was also excellent
      excluding basophils.

PMID- 10340011
TI  - [Patients with cardiomyopathy screened by an annual health check].
AB  - We identified 12 new cases of hypertrophic cardiomyopathy (HCM) and 3 new cases
      of dilated cardiomyopathy (DCM with echocardiography) in 72980 (aged 18-85 years,
      43.1 +/- 14.1) industrial workers during an annual health check from April to
      October in 1996. Two of 3 patients with DCM were males, 21 and 25 years of age.
      No patients had symptoms. ST-T abnormalities by electrocardiography were found in
      87% (13/15) of patients with cardiomyopathy and left ventricular hypertrophy
      (LVH) in 53% (8/15). Our findings suggest that echocardiography is important in
      mass screening for early detection of asymptomatic cardiomyopathy in middle-aged
      as well as young patients with ST-T abnormalities.

PMID- 10340010
TI  - [Plasma macrophage colony-stimulating factor level and changes of monocyte
      subpopulations in chronic renal failure patients treated with hemodialysis].
AB  - This study was carried out on 52 hemodialysis (HD) patients. The concentrations
      of macrophage colony-stimulating factor (M-CSF) in plasma and dialysate were
      measured by ELISA. Plasma M-CSF level increased in HD patients. M-CSF levels of
      dialysate were under the detection limit. The monocyte subpopulations were
      studied using double staining of CD14 and CD16 by flow cytometry. The percentage
      and absolute number of CD14+/CD16+ cells were much higher in HD patients (p <
      0.001, respectively, Mann-Whitney U-test). A new subpopulation of blood monocyte,
      CD14+/CD16+, has been identified which possesses the features of tissue
      macrophage. The elevations of this subpopulation were also reported under some
      pathological conditions, and in subject treated with recombinant M-CSF. HD is the
      pathological condition which induces the increase in plasma M-CSF as well as
      change of monocyte subpopulation.

PMID- 10340012
TI  - [Changes in nitric oxide-related compounds in endotoxemic rats].
AB  - NO-related compounds in the blood of septic rats were examined by
      chemiluminescence method. Rats were treated with 5 mg/kg or 10 mg/kg
      lipopolysaccharides (LPS) and followed for 30 h. We have determined and evaluated
      the concentrations of the total NO-related compounds in whole blood (Total-NO),
      those in plasma (Plasma-NO) and membrane bound-NO (Membranous-NO) in erythrocytes
      from the LPS-challenged rats. 1) Levels of Plasma-NO after 3 h and Membranous-NO
      after 7 h in the rats were significantly increased, peaked at 14 h, and then
      restored to control levels at 30 h. 2) At 7 h in the rats, latter NO levels were
      exhibited within 10 nM/mg protein. 3) The existence of Membranous-NO can be
      confirmed by the in vitro experiments of rat erythrocytes incubating with
      different NO-donors, NOC-3 or SIN-1. 4) Taken together, the determination of
      Membranous-NO may be an additional marker for pathophysiological states of septic
      stress.

PMID- 10340013
TI  - [80th anniversary of the State Institute of Occupational Medicine].

PMID- 10340014
TI  - [Historical contribution of the State Institute of Occupational Medicine in years
      1945-1997].

PMID- 10340015
TI  - [State Institute of Occupational Medicine and public health].

PMID- 10340016
TI  - [Statute of the State Institute of Occupational Medicine].

PMID- 10340017
TI  - [Public health advocate. Interview of Hanna Lewandowska with Prof. Janusz
      Jeljaszewicz].

PMID- 10340018
TI  - The implications of affiliations between Catholic and non-Catholic health care
      organizations for availability of reproductive health services.
AB  - Four case studies of successfully negotiated affiliations between Catholic and
      non-Catholic organizations reveal the strategies employed to address a range of
      reproductive health services.

PMID- 10340019
TI  - Assessing physical activity among minority women: focus group results.
AB  - Focus group findings indicate a need to develop physical activity surveys that
      are more relevant for women, that include well-defined, inoffensive terminology,
      and that improve recall of unstructured and intermittent physical activities.

PMID- 10340021
TI  - Effects of an intensive diet and exercise program on lipids in postmenopausal
      women.
AB  - An intensive diet and exercise program resulted in significant reductions in
      serum lipids and reduced the susceptibility of low-density lipoprotein to
      oxidation in postmenopausal women.

PMID- 10340022
TI  - Penn Health for Women: the evolution of a women's health program in an academic
      setting.
AB  - Penn Health for Women is an interdisciplinary model for women's health care
      created and implemented in an academic setting to provide comprehensive,
      integrated care to women of all ages and to establish a leadership position in
      women's health within the surrounding communities.

PMID- 10340020
TI  - Medical versus surgical abortion: a survey of knowledge and attitudes among
      abortion clinic patients.
AB  - A survey of 405 abortion clinic patients identified confusion regarding the
      purpose of RU 486 and lack of commitment to required follow-up visits, suggesting
      a need for widespread educational efforts.

PMID- 10340024
TI  - Appropriateness of international heat stress standards for use in tropical
      agricultural environments.
AB  - Where a danger to health from heat stress is identified, standards allow
      decisions for implementing measures to reduce the heat stress to be made. These
      standards, specifically ISO 7243 (Wet Bulb Globe Temperature Index, WBGT) and ISO
      7933 (Sweat Required, SWreq) were designed with European and American subjects,
      primarily for use in those countries. While the scope of the standards is
      international, little consideration has been made about how valid and usable they
      are in industrially developing countries. This investigation evaluated ISO 7933
      and ISO 7243 in terms of validity and usability. A tropical agricultural task was
      simulated; 16 subjects plucking tea leaves for 2 h, (ta = tr = 37.18 degrees C;
      va = 0.16 m/s; rh = 70.17%). While ISO 7243 was valid (if slightly over
      protective) and usable, ISO 7933 was over protective and underestimated sweat and
      evaporation rates in its predictions. The discrepancies between predicted and
      observed results were attributed primarily to the calculations related to
      clothing in the standard. Furthermore, ISO 7933 was unusable without a computer;
      in regions where access to such technology may be limited, a simpler method of
      presentation is required.

PMID- 10340023
TI  - Association of gender with symptoms and complications in type II diabetes
      mellitus.
AB  - Females with Type II diabetes appear more likely than males to experience
      symptoms and vascular complications related to their disease.

PMID- 10340025
TI  - Task effects on fatigue symptoms in overnight driving.
AB  - This study examined the effects of task and time-on-task on fatigue symptoms in
      overnight driving. Four participants drove an instrumented car 1200 km overnight
      and completed the same trip as passengers on another night. Subjective ratings of
      drowsiness, eye blink frequency and duration, microsleeps, and steering-wheel
      inputs were analysed as a function of time-on-task, and for separate samples when
      meeting oncoming heavy vehicles. Four video cameras were used to monitor the road
      view and the face of both the driver and passenger. In terms of eye closure
      duration, the reported microsleeps were shorter while driving (mean = 0.7 s, SD =
      0.2 s) than as a passenger (mean = 2.6 s, SD = 2.0 s). Blink frequency increased
      with time-on-task as expected, indicating tiredness, and decreased when
      approaching an oncoming heavy vehicle, indicating attentive response to a
      potential critical situation. No consistent effect of time-on-task on high
      frequency steering-wheel inputs when meeting oncoming heavy vehicles was found.
      The results raise the important question of what makes a driver wake from a
      microsleep earlier than a passenger and, given proper monitoring of long eyelid
      closures, what the proper intervention should be.

PMID- 10340026
TI  - The effect of mental workload on the visual field size and shape.
AB  - Mental workload is known to reduce the area of one's visual field, but little is
      known about its effects on the shape of the visual field. Considering this, the
      visual fields of 13 subjects were measured concurrently under three levels of
      mental workload using a Goldmann visual perimeter. Tone counting tasks were
      employed to induce mental workload, avoiding interference with visual
      performance. Various methods of shape measurement and analysis were used to
      investigate the variation of the shape of the visual field as a function of
      mental load. As expected, the mean area of visual fields reduced to 92.2% in the
      medium workload condition and to 86.41% under heavy workload, compared to light
      load condition. This tunnelling effect was not uniform, but resulted in
      statistically significant shape distortion as well, as measured by the majority
      of the 12 shape indices used here. These results have visual performance
      implications in many tasks that are susceptible to changes in visual fields and
      peripheral vision. Knowledge of the dynamics of the visual field as a function of
      mental workload can offer significant advantages also in mathematical modelling
      of visual search.

PMID- 10340027
TI  - Assessment of an EMG-based method for continuous estimates of low back
      compression during asymmetrical occupational tasks.
AB  - Variables, such as peak and accumulated moments and spine compression forces,
      have been shown to be risk factors for occupational low back pain. Estimates of
      these forces during prolonged, dynamic, asymmetric tasks using biomechanical
      models is complex and time-consuming. A simple technique for continuous
      measurement of these variables over a prolonged period is needed to measure the
      distribution of spinal loading during both sagittal plane lifts and complex
      asymmetrical jobs. The aim of this study was to determine whether a linear
      normalization of erector spinae EMG to spine compression force, called
      compression normalized EMG (CNEMG), could be used to estimate spinal loading for
      simulations of asymmetrical occupational tasks. The estimates of spine
      compression force obtained using the normalized EMG are presented in the form of
      an amplitude probability distribution function and are compared with estimates of
      a three-dimensional biomechanical model. The per cent time a worker spends above
      particular levels of spinal loading of interest, such as the NIOSH action limit
      for compression, are displayed. Five males performed simulated occupational
      tasks. The exposure time at a specific level of spine compression force for a
      combination of three tasks, estimated by CNEMG, was, on average, within 6.5% of
      the time calculated by the biomechanical model. However, if the task combination
      was dominated by an axial twisting moment, then the difference was, on average,
      13.4%. The difference in magnitude of spine compression at a specific probability
      was, on average, 14.9% and when axial trunk twist dominated, 30.7%. It is
      concluded that CNEMG can estimate probability at a specific level of spine
      compression force when the task combination is characterized by a predominant
      extensor moment in the sagittal plane. Estimates of spine compression at a
      specific probability, and estimates obtained during task combinations dominated
      by an axial twisting moment, are poor.

PMID- 10340028
TI  - Human hand-transmitted vibration measurements on pedestrian controlled tractor
      operators by a laser scanning vibrometer.
AB  - A first application of a new measurement technique to detect vibration
      transmitted to the human body in working conditions is presented. The technique
      is based on the use of a laser scanning vibrometer. It was previously developed,
      analysed and tested using laboratory test benches with electrodynamical exciters,
      and comparisons with traditional measurement techniques based on accelerometers
      were made. First, results of tests performed using a real machine generating
      vibration are illustrated. The machine used is a pedestrian-controlled tractor
      working in a fixed position. Reference measurements by using the accelerometer
      have been simultaneously performed while scanning the hand surface by the laser
      based measurement system. Results achieved by means of both measurement
      techniques have been processed, analysed, compared and used to calculate
      transmissibility maps of the hands of three subjects.

PMID- 10340029
TI  - 59th Annual scientific sessions of the American Diabetes Association. San Diego,
      California, USA. June 19-22, 1999. Abstracts.

PMID- 10340030
TI  - Master index, volumes 421-441 (1998).

PMID- 10340031
TI  - 44th Annual meeting of the Health Physics Society. Philadelphia, Pennsylvania,
      USA. 27 June-1 July, 1999. Abstracts.

PMID- 10340032
TI  - Episodic chest pain in a young woman with hypertension.

PMID- 10340033
TI  - An unusual manifestation of diabetes mellitus.
AB  - MEDICAL HISTORY: Type 2 diabetes mellitus for five years; unexplained 35-lb
      weight loss three years ago; Bell's palsy on right side many years ago.
      MEDICATIONS: Glipizide, 10 mg/day. FAMILY HISTORY: Father died of leukemia at age
      65; mother has kidney stones; no diabetes or neuromuscular disease. SOCIAL
      HISTORY: Insurance salesman; heterosexual, promiscuous, uses condoms; smokes (25
      pack years); does not drink. PHYSICAL EXAMINATION: Well-nourished, well
      developed, not in acute distress; had difficulty rising from a sitting position
      because of right lower extremity weakness. Blood pressure, 154/74; pulse, 88;
      temperature, 36.6 degrees C; respiratory rate, 16. Head, eyes, ears, nose, and
      throat: normal. Neck: normal. Heart: S4. Lungs: clear. Abdomen: mildly obese.
      Extremities: no cyanosis, clubbing, or edema; atrophy and weakness of right thigh
      and both calves; wide-based gait; able to walk on toes but not heels. Neurologic
      responses: cranial nerves intact; deep tendon reflexes, 1 + symmetrically;
      plantar reflexes, flexor bilaterally. Skin: macular rash in sun-exposed areas.
      LABORATORY FINDINGS: Hemoglobin, 13.2 gm/dL; mean corpuscular volume, 80 micron
      3; white blood cell count, 7,200/mm3 (normal differential); platelet count,
      137,000/mm3. Serum: electrolytes, normal; blood urea nitrogen, 18 mg/dL;
      creatinine, 0.8 mg/dL; glucose, 308 mg/dL; total protein, albumin, liver enzymes,
      and creatine kinase, normal. Urine: 1 + glucose. Venereal disease test:
      nonreactive; HIV test: negative. DIFFERENTIAL DIAGNOSIS: Dermatomyositis; heavy
      metal poisoning; diabetic amyotrophy. HOSPITAL COURSE: The patient was given 50
      mg/day of oral amitriptyline to alleviate the painful paresthesias and was
      switched to 20 U/day of subcutaneously injected neutral protamine Hagedorn (NPH)
      insulin to normalize the blood glucose level. Histologic studies of skin and
      muscle showed sun damage and neuropathic changes, respectively. There was no
      evidence of vasculitis. Screening for heavy-metal toxins produced negative
      results.

PMID- 10340034
TI  - Recognizing thyrotoxicosis.
AB  - Clinical manifestations of thyrotoxicosis range from silent to florid and can
      mimic those of other conditions occurring in pregnancy and old age. The diagnosis
      may be particularly vexing in elderly patients with apparent dementia. Once
      clinical suspicion has been aroused, the workup to confirm the diagnosis and
      establish the cause is easily accomplished.

PMID- 10340035
TI  - A practical approach to atrial fibrillation.
AB  - Management of atrial fibrillation is still an individualized proposition,
      requiring considerable clinical judgment to select the most effective means of
      controlling cardiac rate and rhythm and preventing thromboembolism and stroke.
      The advantages and disadvantages of electric shock cardioversion, catheter
      ablation, and several medicinal and mechanical agents are discussed.

PMID- 10340036
TI  - Bisphosphonates as cancer drugs.
AB  - Bone appears to act like fertilizer for many tumors, including myeloma and
      metastatic breast cancer. The explanation must lie in interactions between tumor
      cells and the bone-tissue microenvironment. At this level, too, must lie the
      explanation of how bisphosphonates address not only cancer osteolysis but also
      the tumor burden. By inhibiting osteoclasts, the drugs may block a cancer-related
      vicious cycle.

PMID- 10340037
TI  - Antibiotic troubleshooting in primary care.
AB  - Allergic reactions, adverse effects, and drug interactions are an inevitable part
      of antimicrobial prescribing. A working knowledge of these issues remains
      paramount, especially when administering such agents to patients who are
      pregnant, infected with HIV, or who have renal insufficiency. The discussion also
      includes antibiotic-OTC drug interactions and antibiotic hypersensitivity.

PMID- 10340038
TI  - Androgen abuse: the price of growth and performance.

PMID- 10340039
TI  - A pruritic skin rash followed by chronic diarrhea.

PMID- 10340040
TI  - Importance of organizing surgical trials in oncology.

PMID- 10340042
TI  - Risk factors for severe radiation pneumonitis in lung cancer.
AB  - BACKGROUND: Risk factors for severe radiation pneumonitis, which often spreads
      beyond treatment portals and may even be bilateral, have not been fully
      investigated. The purpose of this study was to identify important factors
      associated with severe radiation pneumonitis. METHODS: 111 cases of primary lung
      cancer, treated with radiotherapy or chemoradiotherapy, were retrospectively
      analyzed. RESULTS: Severe radiation pneumonitis occurred in 17 cases (15.3%). The
      ratio of interstitial change in lungs before radiotherapy and radiotherapy to the
      contralateral mediastinum with > 40 Gy in the radiation pneumonitis group (RP
      group) was significantly higher than in patients without radiation pneumonitis
      (control group) (47.1% vs 5.3%; P < 0.001 and 58.8% vs 27.7%; P = 0.037,
      respectively). Using logistic regression analysis, interstitial changes before
      radiotherapy and radiotherapy to the contralateral mediastinum of > 40 Gy were
      significant risk factors associated with severe radiation pneumonitis.
      CONCLUSIONS: These data suggest that pre-existing interstitial changes detected
      by chest radiography or computed tomography and radiotherapy to the contralateral
      mediastinum (> 40 Gy) may predict the development of severe radiation
      pneumonitis.

PMID- 10340041
TI  - Immunohistochemical analysis of PAI-2 (plasminogen activator inhibitor type 2)
      and p53 protein in early gastric cancer patients with recurrence: a preliminary
      report.
AB  - BACKGROUND: High levels of urokinase-type plasminogen activator (u-PA) were
      demonstrated in gastric carcinomas along with inhibitors of plasminogen
      activators (PAI-1 and PAI-2). They may influence the ability to invade and
      metastasize and therefore be of importance to the risk of recurrence of stomach
      neoplasms after curative operation. This also appears to be the case for p53
      mutations and p53 protein overexpression. METHODS: Six patients, all
      differentiated cancer cases who developed recurrent disease 5-10 years after
      curative operations for early gastric cancers (recurrence group), were studied in
      comparison with 49 patients who had no recurrence more than 10 years after
      similar surgery (control group). The expression of u-PA, PAI-1, PAI-2 and p53 was
      compared immunohistochemically in the recurrence and control groups. RESULTS: The
      expression of PAI-2 was significantly more frequent in the recurrence group,
      being found in five (83.3%) patients vs eight (16.3%) in the control group. p53
      was expressed in five (83.3%) patients in the recurrence group and in 15 (30.6%)
      in the control group; the rate was again significantly higher in the former.
      CONCLUSION: The results suggest that PAI-2 and p53 expressed in differentiated
      early gastric cancers are possible indices of the risk of recurrence.

PMID- 10340043
TI  - Alveolar architecture of clear cell renal carcinomas (< or = 5.0 cm) show high
      attenuation on dynamic CT scanning.
AB  - BACKGROUND: To establish the correlation between tumor appearance on CT and tumor
      histology in renal cell carcinomas. METHODS: The density and attenuation patterns
      of 96 renal cell carcinomas, each < or = 5 cm in greatest diameter, were studied
      by non-enhanced CT and early and late after bolus injection of contrast medium
      using dynamic CT. The density and attenuation patterns and pathological maps of
      each tumor were individually correlated. RESULTS: High attenuated areas were
      present in 72 of the 96 tumors on early enhanced dynamic CT scanning. All 72 high
      attenuated areas were of the clear cell renal cell carcinoma and had alveolar
      architecture. The remaining 24 tumors that did not demonstrate high attenuated
      foci on early enhanced scanning included three clear cell, nine granular cell,
      six papillary, five chromophobe and one collecting duct type. With respect to
      tumor architecture, all clear cell tumors of alveolar architecture demonstrated
      high attenuation on early enhanced scanning. CONCLUSION: Clear cell renal cell
      carcinomas of alveolar architecture show high attenuation on early enhanced
      dynamic CT scanning. A larger number of patients are indispensable to obtaining
      clear results. However, these findings seem to be an important clue to the
      diagnosis of renal cell carcinomas as having an alveolar structure.

PMID- 10340044
TI  - Long-term follow-up results of a Pilot Phase II study of multidrug chemotherapy
      (MVP-CAB) in patients with advanced urothelial cancer.
AB  - BACKGROUND: To determine the long-term effects and toxicity of multidrug
      chemotherapy for advanced urothelial cancer. METHODS: Forty patients with
      metastatic urothelial cancer were treated with a new combination chemotherapy,
      MVP-CAB (methotrexate, doxorubicin, vincristine, cyclophosphamide, bleomycin and
      cisplatin every 28 days). Of the 40 patients, 26 had not undergone prior
      chemotherapy or radiotherapy; the remaining 14 patients had undergone prior
      cisplatin-based chemotherapy. RESULTS: The clinical response rate to MVP-CAB
      therapy for all 40 patients was 63% [complete response (CR), six patients;
      partial response (PR), 19 patients]. The median duration of the effects was 22
      and 13 months in the patients with CR and PR, respectively. The clinical response
      rate for the 26 patients without prior chemotherapy was 77% (CR, four patients;
      PR, 16 patients). The rate for the 14 patients with prior chemotherapy was 36%
      (CR, two patients; PR, three patients). The response rate according to metastatic
      site was highest for the liver (80%), followed by the lymph nodes (74%) and lungs
      (67%). The effect on bone metastasis was poor (22%). There was good compliance
      with the MVP-CAB chemotherapy regimen and toxicity was tolerable. The 1-, 3- and
      5-year overall survival rates were 42.5, 10 and 5%, respectively. CONCLUSIONS:
      MVP-CAB combination chemotherapy was found to be effective for the treatment of
      advanced urothelial cancer, especially for liver metastasis.

PMID- 10340045
TI  - National average for the process of radiation therapy in Japan by Patterns of
      Care Study.
AB  - BACKGROUND: A nationwide effort is in progress to establish the actual state of
      radiotherapy and its quality assurance (QA) in Japan by using the Patterns of
      Care Study (PCS). In this study, national averages are calculated with a limited
      number of patients. A calculation program for national averages was prepared and
      applied to the radiotherapeutic processes used for esophageal cancer patients
      entered in the PCS. METHODS: The calculation program for national averages, which
      were revised on the basis of differences between individual facilities and
      institutional strata, was developed in accordance with Sedransk's equation for
      the original PCS in the USA. National averages for several aspects concerning the
      sampled patients who had esophageal cancer between 1992 and 1994 were calculated
      with these procedures. Data for facilities and stratification of institution were
      simulated from a national structure survey of radiation oncology in 1990.
      RESULTS: Values of the national average by Sedransk's equation were different
      from those of the simple sample average. There were significant differences in
      radiotherapeutic processes among stratification of institutions. For esophageal
      cancer, national averages were 0.129 for applications of endoscopic ultrasound,
      0.599 for 'all fields treated each day' and 0.088 for application of
      brachytherapy. CONCLUSION: National averages for radiotherapy could be
      calculated. The values obtained in this PCS will be a useful measure for future
      QA in radiation oncology and in other specialties in Japan.

PMID- 10340046
TI  - Isolated recurrence of granulocytic sarcoma of the brain: successful treatment
      with surgical resection, intrathecal injection, irradiation and prophylactic
      systemic chemotherapy.
AB  - We describe a 40-year-old male who developed an isolated recurrence of
      granulocytic sarcoma (GS) of the brain 2 years following successful treatment of
      acute myeloblastic leukemia (AML; M2). Computed tomography (CT) scans and
      magnetic resonance (MR) images demonstrated a homogeneously enhanced tumor mass
      in the left temporal lobe and massive peritumoral edema. There was no evidence of
      relapse in the bone marrow. The patient underwent an emergency surgical resection
      of the tumor. Five courses of injection with cytarabine and prednisolone through
      an Ommaya reservoir and whole brain irradiation (total 40 Gy) were performed.
      Furthermore, prophylactic systemic chemotherapy with cytarabine and etoposide was
      added. He has been in complete remission for 21 months. Our results, together
      with other reported cases, indicate that a favorable outcome could be obtained by
      intensive and combined treatment for an isolated recurrence of GS of the brain if
      the bone marrow remained in complete remission.

PMID- 10340047
TI  - A case of synchronous double primary lung cancer with neuroendocrine features.
AB  - We report a case of unique double primary lung cancers with neuroendocrine
      features in a 63-year-old male smoker. The mass in the left lower lobe (LLL) was
      a small cell/large cell carcinoma with spindle cell sarcomatous areas and
      organoid structure. The mass in the left upper lobe (LUL) was a tubular
      adenocarcinoma with neuroendocrine features including organoid nests showing
      occasional rosette formation, nuclear palisading in the periphery of the nests
      and positive immunoreaction for CD56, chromogranin A and synaptophysin. The
      difference in histological structures between the two masses led us to diagnose
      double primary lung cancer. The combination of small cell lung carcinoma and
      spindle cell carcinoma is very uncommon. The relationship between LLL and LUL
      tumors remains unclear. Multiple lung cancers with neuroendocrine features have
      only rarely been reported in the literature. The patient in our case died of
      widespread cancer 2 years and 4 months after the surgery without adjuvant
      chemotherapy, a longer postoperative survival time than in cases of ordinary
      extensive small cell lung cancer. Multiple lung cancers with neuroendocrine
      features are extremely rare and similar cases have not been reported in the
      literature. Neuroendocrine differentiation has attracted widespread attention
      and, therefore, examining neuroendocrine features in lung cancers is important.

PMID- 10340048
TI  - Second lung adenocarcinoma after combination chemotherapy in two patients with
      primary non-Hodgkin's lymphoma.
AB  - We report a rare complication of a secondary malignant solid tumor in two
      patients with non-Hodgkin's malignant lymphoma who developed lung adenocarcinoma
      after treatments with combination chemotherapies. The first was a case of primary
      malignant lymphoma of the cervical spinal cord which had been previously treated
      with radiation to the spinal lesion and combination chemotherapies and entered
      complete remission. The patient was further treated for relapse with autologous
      bone marrow transplantation preconditioned with high-dose chemotherapy. Lung
      adenocarcinoma developed 5.5 years after the initial diagnosis. The second case
      of malignant lymphoma of lymph nodes did not respond to conventional combination
      chemotherapies and did not enter remission. Lung adenocarcinoma developed 1 year
      after the initial diagnosis. The two patients died of lung carcinoma. The
      clinical profiles of these cases are presented and the causal relationship of
      primary malignant neoplasms to the second malignant neoplasms is discussed.

PMID- 10340050
TI  - Introduction of a German genetic counseling program for hereditary breast and
      ovarian cancer.

PMID- 10340049
TI  - External beam radiotherapy for pelvic node recurrence after curative resection of
      colon cancer: report of a case.
AB  - The role of radiotherapy in locally advanced or recurrent colon cancer has not
      yet been determined. A 59-year-old man undergoing curative resection for advanced
      descending colon cancer had pelvic lymph node metastasis detected by computed
      tomography 5 months postoperatively. Intravenous chemotherapy using 5
      fluorouracil and CDDP was repeated bimonthly for 7 months; however, his condition
      deteriorated progressively. External beam radiotherapy (50 Gy) was started
      thereafter. His serum carcinoembryonic antigen level decreased promptly and
      abdominal computed tomography showed apparent shrinkage of the metastatic pelvic
      node with calcification. The patient maintained a partial response for at least
      12 months. Radiotherapy has a more crucial role in the treatment of a subgroup of
      recurrent colorectal tumors.

PMID- 10340051
TI  - Report of the International Workshop on the Health Effects of Ultraviolet
      Radiation.

PMID- 10340053
TI  - NCI overhauls clinical trials system.

PMID- 10340052
TI  - New research subjects in Grant-in-Aid for Cancer Research 1999-2000 from the
      Ministry of Health and Welfare, Japan.

PMID- 10340054
TI  - Cancer vaccine competition wide open as agents move rapidly into clinical arena.

PMID- 10340055
TI  - Dental education at the crossroads: the crisis within.

PMID- 10340056
TI  - Population-based primary care and dental education: a new role for dental
      schools.

PMID- 10340057
TI  - Faculty attitudes and perceptions about the Institute of Medicine report.

PMID- 10340058
TI  - Analysis of oral biology teaching: content versus assessment.

PMID- 10340059
TI  - A survey of statistical methods used in dental literature.

PMID- 10340061
TI  - Accord reached over specialty designations.

PMID- 10340060
TI  - Career choice and occupational perception in accelerated option and traditional
      dental students.

PMID- 10340062
TI  - California acts on reciprocity issue.

PMID- 10340063
TI  - Guidelines help cats age in good health.

PMID- 10340064
TI  - DEA may classify ketamine as schedule III.

PMID- 10340065
TI  - FDA bans firms from importing and distributing contaminated animal drugs.

PMID- 10340066
TI  - New egg safety recommendations added to FDA Food Code.

PMID- 10340067
TI  - Veterinarians help cattle producers beef up quality.

PMID- 10340068
TI  - Suggests biopsy to diagnose causes of high WBC count.

PMID- 10340069
TI  - Disagrees with position on rBST.

PMID- 10340070
TI  - Feline urologic syndrome, feline lower urinary tract disease, feline interstitial
      cystitis: what's in a name?

PMID- 10340071
TI  - What is your diagnosis? A tubular soft-tissue opacity dorsal to the spleen:
      intestinal carcinoma in a dog.

PMID- 10340072
TI  - Theriogenology question of the month. Priapism or paraphimosis.

PMID- 10340073
TI  - Variable compensation and the veterinary profession.

PMID- 10340074
TI  - 1997 income of US veterinarians.

PMID- 10340075
TI  - Evaluation of a low-dose synthetic adrenocorticotropic hormone stimulation test
      in clinically normal dogs and dogs with naturally developing
      hyperadrenocorticism.
AB  - OBJECTIVE: To determine whether low doses of synthetic ACTH could induce a
      maximal cortisol response in clinically normal dogs and to compare a low-dose
      ACTH stimulation protocol to a standard high-dose ACTH stimulation protocol in
      dogs with hyperadrenocorticism. DESIGN: Cohort study. ANIMALS: 6 clinically
      normal dogs and 7 dogs with hyperadrenocorticism. PROCEDURE: Each clinically
      normal dog was given 1 of 3 doses of cosyntropin (1, 5, or 10 micrograms/kg
      [0.45, 2.3, or 4.5 micrograms/lb] of body weight, i.v.) in random order at 2-week
      intervals. Samples for determination of plasma cortisol and ACTH concentrations
      were obtained before and 30, 60, 90, and 120 minutes after ACTH administration.
      Each dog with hyperadrenocorticism was given 2 doses of cosyntropin (5
      micrograms/kg or 250 micrograms/dog) in random order at 2-week intervals. In
      these dogs, samples for determination of plasma cortisol concentrations were
      obtained before and 60 minutes after ACTH administration. RESULTS: In the
      clinically normal dogs, peak cortisol concentration and area under the plasma
      cortisol response curve did not differ significantly among the 3 doses. However,
      mean plasma cortisol concentration in dogs given 1 microgram/kg peaked at 60
      minutes, whereas dogs given doses of 5 or 10 micrograms/kg had peak cortisol
      values at 90 minutes. In dogs with hyperadrenocorticism, significant differences
      were not detected between cortisol concentrations after administration of the low
      or high dose of cosyntropin. CLINICAL IMPLICATIONS: Administration of cosyntropin
      at a rate of 5 micrograms/kg resulted in maximal stimulation of the adrenal
      cortex in clinically normal dogs and dogs with hyperadrenocorticism.

PMID- 10340076
TI  - Copper associated acute hepatic failure in a dog.
AB  - A 1.5-year-old Dalmatian was examined because of vomiting, weight loss, and high
      serum activities of alanine aminotransferase and aspartate aminotransferase.
      Abdominal ultrasonography revealed normal appearing hepatic structure with
      echogenicity, but histologic examination of hepatic biopsy specimens revealed
      extensive necrosis of hepatocytes involving the centrilobular areas. Macrophages
      and remaining hepatocytes contained pigments that were positive for copper by
      rubeanic acid-staining and hepatic copper concentration was high. The dog was
      treated with crystalloid fluids, antibiotics, and a low copper diet; its
      condition deteriorated, and the dog was euthanatized. Primary copper storage
      disease was suspected on the basis of histologic findings and high copper
      concentration in the liver.

PMID- 10340077
TI  - Comparison of a continuous suture pattern with a simple interrupted pattern for
      enteric closure in dogs and cats: 83 cases (1991-1997).
AB  - OBJECTIVE: To describe and compare a simple continuous suture pattern with a
      simple interrupted pattern for enterotomy closure or end-to-end intestinal
      anastomosis. DESIGN: Retrospective study. ANIMALS: 58 dogs and 25 cats that
      underwent enterotomy or intestinal resection and anastomosis. PROCEDURE:
      Signalment, surgical procedure, suture pattern, suture material, confirmation of
      dehiscence, and follow-up were reviewed. Groups were compared by procedure
      (anastomosis or enterotomy) and by suture pattern. RESULTS: 57 animals underwent
      continuous closure; 26 had interrupted closure. Only polydioxanone or
      polypropylene suture materials were used. Overall, 81 (98%) animals had no signs
      of intestinal dehiscence and survived > 2 weeks. Two animals had confirmed
      dehiscence after foreign body removal, 1 of 57 (2%) after continuous closure, and
      1 of 26 (4%) after interrupted closure. CLINICAL IMPLICATIONS: The simple
      continuous closure pattern is an acceptable alternative to simple interrupted
      closure for small intestinal anastomosis or enterotomy closure.

PMID- 10340078
TI  - Risk factors for nosocomial Salmonella infection among hospitalized horses.
AB  - OBJECTIVE: To identify risk factors for nosocomial Salmonella infections among
      hospitalized horses. DESIGN: Longitudinal study. ANIMALS: 1,583 horses
      hospitalized in an intensive care unit between January 1992 and June 1996.
      PROCEDURE: Survivor functions were used to estimate time to shedding salmonellae
      for various Salmonella serotypes. Survival analysis was then used to determine
      how variables associated with patient management, environmental conditions,
      hospital conditions, and other disease processes affected the risk of nosocomial
      Salmonella infection. RESULTS: 78 horses shed Salmonella organisms: 35 shed
      Salmonella krefeld, 26 shed S typhimurium, and 17 shed other Salmonella
      serotypes. Mean time from admission to shedding was significantly longer for
      horses shedding S krefeld or S typhimurium than for horses shedding other
      Salmonella serotypes. Therefore, infection with S krefeld or S typhimurium was
      considered nosocomial. Seven variables were found to be significantly associated
      with risk of nosocomial Salmonella infection: mean number of horses in the
      hospital shedding S krefeld during the 4 days prior to and the day of admission,
      mean number of horses shedding S typhimurium during this period, a diagnosis of
      large colon impaction, withholding feed, number of days fed bran mash, duration
      of treatment with potassium penicillin G, and mean daily ambient temperature.
      CLINICAL IMPLICATIONS: Results suggest that risk of nosocomial Salmonella
      infections is greater for horses with large colon impactions. In addition to
      implementing hospital protocols that minimize cross contamination between
      patients, strategies to reduce the risk of nosocomial Salmonella infection should
      include minimizing use of potassium penicillin G and regulation of environmental
      temperature in the hospital.

PMID- 10340079
TI  - Surgical repair of a diaphragmatic hernia in a racehorse.
AB  - A 9-year-old Thoroughbred was evaluated for clinical signs of acute abdominal
      pain. During laparotomy, a rent in the diaphragm and herniation of the small
      intestine into the thoracic cavity were detected. Because edges of the rent were
      smooth and fibrous, which suggested the defect was chronic, the abdomen was
      closed without repairing the rent. After recurrence of clinical signs, a second
      laparotomy was performed, during which the intestines were found to have
      reherniated. The diaphragmatic rent was repaired, using a polypropylene mesh
      secured with stainless steel staples. The horse recovered and subsequently
      returned to racing and jumping. A diaphragmatic hernia should be suspected in
      horses that have moderate to severe signs of abdominal pain for which a
      definitive cause can not be identified. Thoracic ultrasonography or radiography
      can be used to confirm the hernia. Diaphragmatic hernias in horses can be
      successfully repaired using mesh implants secured with staples.

PMID- 10340080
TI  - Presumed clostridial and aerobic bacterial infections of the cornea in two
      horses.
AB  - Microscopic examination of Gram-stained tissue specimens collected from severe
      corneal ulcers in 2 horses revealed large gram-positive rods suggestive of
      Clostridium spp. Clostridium perfringens was isolated from specimens collected
      from horse 1; anaerobic organisms were not detected in specimens from horse 2.
      Aerobic bacterial culture revealed Aeromonas hydrophila and Enterobacter cloacae
      in specimens collected from horses 1 and 2, respectively. An insect exoskeleton
      was presumed to be the underlying cause of ulceration in horse 1. Cause of
      ulceration in horse 2 was not determined. Antibiotics used to treat the corneal
      infections included ticarcillin disodium-clavulanic acid injected one time
      subconjunctivally and chloramphenicol applied topically at frequent intervals.
      Horse 2 also received penicillin or trimethoprim-sulfadiazine. Small leukomas
      were the only lesion remaining between 2 and 7 months after initial evaluation.
      Chloramphenicol applied topically appears to be an effective treatment against
      clostridial corneal infections in horses.

PMID- 10340081
TI  - Use of a temporary indwelling ureteral stent catheter in a mare with a traumatic
      ureteral tear.
AB  - A 4-year-old primiparous Thoroughbred mare was referred for treatment of
      uroperitoneum subsequent to dystocia. Hematologic and serum biochemical analyses
      revealed values consistent with those reported for foals with uroperitoneum.
      Exploratory celiotomy revealed the source of the uroperitoneum to be a rent in
      the right ureter proximal to the trigone of the bladder. Substantial accumulation
      of urine in the tissues surrounding the ureter prevented accurate identification
      and repair of the defect, so a temporary indwelling ureteral stent catheter was
      inserted. Three weeks later, the stent catheter was removed, and the mare made a
      complete recovery with restoration of continuity of the urinary tract and
      preservation of function of the affected kidney. Use of this procedure offers a
      practical alternative to unilateral nephrectomy or ureteronephrectomy for
      traumatic ureteral injuries of horses.

PMID- 10340082
TI  - Inflammatory bowel disease in horses: 11 cases (1988-1998).
AB  - OBJECTIVE: To determine clinical and surgical abnormalities in, and long-term
      outcome of, horses that undergo surgery because of colic secondary to
      inflammatory bowel disease (IBD). DESIGN: Retrospective study. ANIMALS: 11
      horses. PROCEDURE: Medical records of horses that had undergone abdominal surgery
      and in which IBD had been diagnosed on the basis of histologic examination of
      intestinal biopsy specimens were reviewed. RESULTS: 5 horses were examined
      because of acute colic and 6 were examined because of chronic colic. At surgery,
      all 11 horses had edematous or hemorrhagic bowel segments suggestive of IBD. In
      addition, 6 horses had circumferential mural bands (CMB) causing constriction of
      the small (4 horses) or large (2) intestine. Intestinal resections were performed
      in 7 horses. All 11 horses survived surgery and were discharged from the
      hospital; 10 horses were still alive at the time of follow-up (1.5 to 7 years
      after surgery). CLINICAL IMPLICATIONS: Results suggest that IBD is an uncommon
      cause of colic in horses. Surgical resection of segments of intestine with
      constrictive CMB may relieve clinical signs of colic. Horses with IBD that had
      surgery had a good prognosis for long-term survival.

PMID- 10340083
TI  - Prevalence of severe welfare problems in horses that arrive at slaughter plants.
AB  - OBJECTIVE: To assess the prevalence of severe welfare problems in horses that
      arrive at slaughter plants and to identify horses that were unfit for travel.
      DESIGN: Prevalence survey. ANIMALS: 1,008 horses. PROCEDURE: Horses arriving at 2
      slaughter plants were observed. The following were rated severe welfare problems
      in horses: body condition scores of 1 or 2 (emaciated) of 9; recumbency (down) or
      the inability to walk; fractured limbs or other foot or limb problems that
      extremely impaired mobility; severe wounds, such as deep cuts, extensive
      lacerations, abrasions on the head or back, eye injuries, neglected purulent
      lesions, and numerous bite and kick marks over extensive areas of the body; and
      dead on arrival. Bruises on carcasses were tabulated to further assess injuries.
      Horses that had been loaded with a fractured limb, arrived nonambulatory, had
      severe lameness that interfered with mobility, were weak and emaciated, or were
      dead on arrival or died shortly after arrival were considered unfit for travel.
      RESULTS: Ninety-two percent (930/1,008) of the horses arrived in good condition,
      and 7.7% (78) had a condition that was rated a serious welfare problem. Thirty
      horses (3%) had a body condition score of 1 or 2, 12 (1.0%) had foot and limb
      problems (other than fractures), 4 (0.4%) had fractured limbs, 18 (2.0%) had deep
      cuts, lacerations, or injuries from bites, 8 (0.8%) were nonambulatory or dead on
      arrival, 2 (0.2%) had deformities, 3 (0.3%) had extensive purulent lesions, and 1
      (0.1%) had a behavior problem. Characteristic patterns of 51% of carcass bruises
      indicated that they were caused by bites or kicks. Fighting was the major cause
      of injuries that occurred during transport and marketing. Fifteen (1.5%) horses
      were unfit for travel. Abuse or neglect by owners was the cause of 77% of the
      severe welfare problems observed. CLINICAL IMPLICATIONS: To decrease the number
      of injuries that result from fighting when transporting horses to slaughter
      plants, aggressive mares and geldings that continually attack other horses must
      be segregated.

PMID- 10340084
TI  - 2nd Forum for Pharmacists and Physicians: Clinical Nutrition in Focus and
      Discussion. 16 September 1998.

PMID- 10340085
TI  - XXXIII Angiology meeting of the French Languages. Paris, France. 10-12 March
      1999. Abstracts.

PMID- 10340086
TI  - [The 99th annual meeting of the Japan Surgical Society. Fukuoka, Japan. March 24
      26, 1999. Abstracts].

PMID- 10340087
TI  - VII International Congress on Schizophrenia Research. Santa Fe, New Mexico, USA.
      April 17-21, 1999. Abstracts.

PMID- 10340088
TI  - Erroneous statements in veterinary medical ethics' columns.

PMID- 10340089
TI  - An ethicist's commentary on the case of the veterinary technician who lies in
      order to have a dog euthanized.

PMID- 10340090
TI  - Apropos telemedicine.

PMID- 10340091
TI  - The R.G. Thomson Lecture. Partnerships: an academic imperative.

PMID- 10340092
TI  - Update on revaccination protocols.

PMID- 10340093
TI  - Dose effect and benefits of glycopyrrolate in the treatment of bradycardia in
      anesthetized dogs.
AB  - This study evaluated the effectiveness of glycopyrrolate (0.005 or 0.01 mg/kg
      body weight (BW)) in anesthetized dogs (n = 40) for reversal of bradycardia (< 65
      beats/min). Following random intravenous (i.v.) treatment, heart rate was
      determined at 5 min and, if it was < or = 70 beats/min, the lower dose was
      repeated. A 2-way analysis of variance considered dose and animal size (< or = 10
      kg, > 10 kg) effects (P < 0.05). Glycopyrrolate produced a significant increase
      in heart rate and infrequent tachycardia (< or = 150 beats/min), which was not
      dose-related. The size of the dog produced a significant effect on baseline heart
      rate (higher in small), rate following the first dose (lower in small), and
      requirement for retreatment (47% in small, 13% in large). In a separate group of
      anesthetized dogs (n = 20), the blood pressure effect of glycopyrrolate (0.01
      mg/kg BW, i.v.) treatment of bradycardia (65-85 beats/min, weight-adjusted) was
      studied. A significant increase in systolic, diastolic, and mean blood pressure
      was produced. In conclusion, the effective dose of glycopyrrolate treatment is
      size-related and produces a beneficial effect on blood pressure.

PMID- 10340095
TI  - A survey of helminth parasites of cats from Saskatoon.
AB  - In a survey of 52 cats from the Saskatoon area, Ollulanus tricuspis were found in
      2 animals with burdens of 2308 and 533, respectively. Small burdens of the
      following helminths were also found: Physaloptera spp., Toxocara cati, Taenia
      spp., Dipylidium caninum, and Ancylostoma sp.

PMID- 10340094
TI  - The prevalence of verotoxins, Escherichia coli O157:H7, and Salmonella in the
      feces and rumen of cattle at processing.
AB  - Fecal samples collected from cattle at processing during a 1-year period were
      tested for verotoxins (VT1, VT2), Escherichia coli O157:H7, and Salmonella.
      Verotoxins were detected in 42.6% (95% CI, 39.8% to 45.4%), E. coli O157:H7 in
      7.5% (95% CI, 6.1% to 9.1%), and Salmonella in 0.08% (95% CI, 0.004% to 0.5%) of
      the fecal samples. In yearling cattle, the median within-lot prevalence
      (percentage of positive samples within a lot) was 40% (range, 0% to 100%) for
      verotoxins and 0% for E. coli O157:H7 (range, 0% to 100%) and Salmonella (range,
      0% to 17%). One or more fecal samples were positive for verotoxins in 80.4% (95%
      CI, 72.8% to 86.4%) of the lots of yearling cattle, whereas E. coli O157:H7 were
      detected in 33.6% (95% CI, 26.0% to 42.0%) of the lots. In cull cows, the median
      within-lot prevalence was 50% (range, 0% to 100%) for verotoxins and 0% (range,
      0% to 100%) for E. coli O157:H7 and Salmonella (range, 0% to 0%). Verotoxins were
      detected in one or more fecal samples from 78.0% (95% CI, 70.4% to 84.2%) of the
      lots of cull cows, whereas E. coli O157:H7 were detected in only 6.0% (95% CI,
      3.0% to 11.4%) of the lots of cull cows. The prevalence of verotoxins in fecal
      samples was lower in yearling cattle than in cull cows, whereas the prevalence of
      E. coli O157:H7 in fecal samples was higher in yearling cattle than in cull cows.
      The prevalence of E. coli O157:H7 in fecal samples was highest in the summer
      months. Rumen fill, body condition score, sex, type of cattle (dairy, beef), and
      distance travelled to the plant were not associated with the fecal prevalence of
      verotoxins or E. coli O157:H7. The prevalence of verotoxins in fecal samples of
      cull cows was associated with the source of the cattle. It was highest in cows
      from the auction market (52%) and farm/ranch (47%) and lowest in cows from the
      feedlot (31%). In rumen samples, the prevalence of verotoxins was 6.4% (95% CI,
      4.2% to 9.4%), and it was 0.8% (95% CI, 0.2% to 2.3%) for E. coli O157:H7, and
      0.3% (95% CI, 0.007% to 1.5%) for Salmonella.

PMID- 10340096
TI  - Hypercalcemia and parathyroid hormone-related protein in a dog with
      undifferentiated nasal carcinoma.
AB  - Hypercalcemia was discovered in a 7-year-old, castrated male basset hound with a
      suspected nasal tumor. The dog died the day after admission and nasal carcinoma
      and disseminated intravascular coagulation were diagnosed on postmortem.
      Detectable levels of serum PTHrP support a diagnosis of hypercalcemia of
      malignancy.

PMID- 10340097
TI  - Pancreatic insulin-secreting neoplasm (insulinoma) in a West Highland white
      terrier.
AB  - A West Highland white terrier was evaluated because of persistent hypoglycemia
      and an acute episode of collapse. A pancreatic insulin-secreting neoplasm
      (insulinoma) was diagnosed on the basis of clinical signs, serum glucose levels,
      serum insulin levels, abdominal ultrasonography, and exploratory laparotomy with
      histologic evaluation of neoplastic tissue.

PMID- 10340098
TI  - Salt poisoning in beef cattle on coastal pasture on Prince Edward Island.

PMID- 10340099
TI  - Ornithobacterium rhinotracheale infection in a turkey flock in Ontario.

PMID- 10340100
TI  - Equine abortions in eastern Ontario due to leptospirosis.

PMID- 10340101
TI  - Infectious salmon anemia in Atlantic salmon.

PMID- 10340102
TI  - Quantitation of nucleolar organizer regions by image analysis in glottic squamous
      cell carcinoma.
AB  - OBJECTIVE: To apply computer image analysis as a quantitative method for
      analyzing interphase nucleolar organizer regions (NORs) to determine whether this
      proliferative marker provides useful prognostic information in glottic squamous
      cell carcinoma. DESIGN: Retrospective testing of biopsy samples and resected
      tissue. SETTING: Nova Scotia Regional Cancer Centre and regional hospitals in
      Nova Scotia and Prince Edward Island, Canada. PATIENTS: Patients with primary
      glottic cancer presenting to the cancer centre between 1984 and 1991.
      INTERVENTIONS: Semiautomated image analysis was used to measure the nuclear area
      and the NOR area in formalin-fixed paraffin-embedded tumour samples. OUTCOME
      MEASURES: Mean nuclear area, mean NOR area and NOR percentage of nuclear area,
      calculated as the mean NOR area divided by the mean nuclear area, expressed as a
      percentage. RESULTS: Of 154 cases, 90 samples were received; however, 8 paraffin
      blocks were exhausted and 29 samples stained poorly due to extent of fixation.
      Analysis of the remaining 53 cases, all primary squamous cell carcinomas, showed
      no statistically significant association between, on one hand, mean NOR area or
      NOR percentage of nuclear area and, on the other hand, tumour grade, tumour
      stage, tumour recurrence or disease-related death. CONCLUSIONS: This study does
      not demonstrate a prognostic value of NOR measurement as a proliferative marker
      in primary glottic squamous carcinoma. However, given the small number of cases
      in this study, further research should be conducted using a larger number of
      cases from one centre and comparing NOR measures with other markers of cell
      proliferation.

PMID- 10340103
TI  - Prealbumin measurement as a screening tool for protein calorie malnutrition in
      emergency hospital admissions: a pilot study.
AB  - OBJECTIVE: To examine the effectiveness of prealbumin measurement as a routine
      diagnostic test for protein calorie malnutrition (PCM) in emergency admissions.
      DESIGN: Cohort study. SETTING: Canadian tertiary care hospital. PATIENTS: A total
      of 147 consecutive patients admitted through the emergency department, excluding
      psychiatric admissions, for whom a serum sample was sent to the chemistry
      laboratory. OUTCOME MEASURES: (1) Albumin and prealbumin levels to diagnose PCM;
      (2) length of stay (LOS), in-hospital mortality, and nutritional supplementation
      in patients with PCM; and (3) cost analysis of using prealbumin level as an
      admission screening test for PCM. RESULTS: Twenty-four per cent of the patients
      had at least mild PCM (prealbumin level < 160 mg/L). Albumin level (< 35 g/L) had
      a sensitivity of 50% and specificity of 95% in identifying PCM. The mean LOS in
      the patients with PCM was 16 (standard deviation 18) days, compared with 8 (SD
      12) days in the patients without PCM (p < 0.0002). The in-hospital mortality rate
      was 17% in patients with PCM compared with 4% in patients without PCM (p < 0.02).
      Only 42% of patients with PCM received nutritional supplementation. Cost analysis
      of screening with prealbumin level projected a saving of $414 per patient
      screened. CONCLUSIONS: PCM is underdiagnosed in current clinical practice and is
      associated with an increased LOS and mortality rate. Prealbumin is a biochemical
      marker that could be used as a cost-effective screening test to identify patients
      with PCM who may benefit from nutritional supplementation.

PMID- 10340104
TI  - Pharmacological manipulation of height: qualitative review of study populations
      and designs.
AB  - OBJECTIVE: Various substances that can have an important effect on height are
      increasingly available. However, research into pharmacological manipulation of
      height in children has been criticized. There are concerns about diagnostic
      criteria; about the medical, ethical, and economic ramifications of modulating
      growth in children with no endocrinological abnormalities; and about biased
      results due to weak study designs. The authors reviewed articles published since
      Jan. 1, 1995, to characterize recent research into this area. METHODS: 70 peer
      reviewed articles published in 18 journals in 1995 describing effects of hormonal
      interventions to affect height were reviewed. Study population, intervention,
      main purpose (safety, physiology, or therapeutic effect), and methodology were
      examined. The search was expanded after 1995 to list randomized controlled trials
      (RCTs) investigating pharmacological manipulation in children and its effect on
      ultimate height in adults. RESULTS: The inexpensive and brief androgen therapy
      for pubertal delay has been examined in RCTs, but expensive, long-term treatments
      to alter final adult height in children have rarely been subjected to RCTs. Some
      outcome reports pooled subjects with different causes of short stature.
      Documentation of growth hormone deficiency is problematic. CONCLUSIONS: There is
      a lack of RCTs in which target populations and growth outcomes are explicitly
      defined. Further research into overcoming barriers to relevant RCT studies is
      needed.

PMID- 10340105
TI  - Growth hormone therapy in children in Canada: what have we learned in the past
      decade from an unlimited supply of growth hormone?

PMID- 10340106
TI  - National Meeting of the American College of Rheumatology. November 8-12, 1998,
      San Diego, California.

PMID- 10340107
TI  - [Apropos of a text of Antoine Laurent de Lavoisier].

PMID- 10340108
TI  - [Short-term dynamics of intertidal microphytobenthos biomass. Mathematical
      model].
AB  - We formulate a deterministic mathematical model to describe the dynamics of the
      microphytobenthos of intertidal mudflats. It is 'minimal' because it only takes
      into account the essential processes governing the functioning of the system: the
      autotrophic production, the active upward and downward migrations of epipelic
      microalgae, the saturation of the mud surface by a biofilm of diatoms and the
      global net loss rates of biomass. According to the photic environment of the
      benthic diatoms inhabiting intertidal mudflats, and to their migration rhythm,
      the model is composed of two sub-systems of ordinary differential equations; they
      describe the simultaneous evolution of the biomass 'S' concentrated in the mud
      surface biofilm--the photic layer--and of the biomass 'F' diluted in the topmost
      centimetre of the mud--the aphotic layer. Qualitatively, the model solutions
      agree fairly well with the in situ observed dynamics of the S + F biomass. The
      study of the mathematical properties of the model, under some simplifying
      assumptions, shows the convergence of solutions to a stable cyclic equilibrium,
      whatever the frequencies of the physical synchronizers of the production. The
      sensitivity analysis reveals the necessity of a better knowledge of the processes
      of biomass losses, which so far are uncertain, and may further vary in space and
      time.

PMID- 10340109
TI  - Cryptic speciation suspected by morphometry within Lutzomyia runoides.
AB  - Clear-cut variation in the length of genital filaments amongst Bolivian specimens
      of Lutzomyia runoides (Fairchild & Hertig, 1953), of the species group aragaoi,
      allowed us to recognise two different, non-overlapping populations living in
      sympatry. The additional observation of their mutually exclusive colonisation of
      isolated trees strongly suggested the existence of cryptic speciation.
      Multivariate, size-in and size-free analyses bearing on characters other than
      genital filaments could separate the two putative cryptic species of L. runoides,
      and showed that they were different from L. inflata, previously regarded as
      conspecific.

PMID- 10340112
TI  - [Morphological modifications od the upper femoral metaphysis on man stricken by
      osteoporotic disease].
AB  - A study of cancellous bone in the femoral upper metaphysis was performed using a
      micro-camera. In osteoporotic disease, a qualitative disorganization of bone and
      vessels occurs. Bone lamellae break off or fracture. Lacunae fine down some bone
      plates. Connective tissue replaces part or the totality of the hard structure.
      Some vessels are functional, some are not. Some walls disappear and flux runs out
      of their lumen, producing hematomae. Quantitative bone loss results in cavities.
      Adipocyte cells fill in the gaps. Browish deposits settle on the lamellae. It is
      suggested that these are either settling stem pigments from the breakdown of
      hemoglobin or micro-thrombuses.

PMID- 10340116
TI  - Current status of calcium channel blockers in patients with cardiovascular
      disease.

PMID- 10340117
TI  - [The characteristics of the neuropsychotropic activity of bromantane in
      laboratory animals].
AB  - Bromantan [N-2-(para-(bromphenyl)-N-2-(aminoadamantan)] possesses
      psychostimulating activity in experiments on animals. With LD50 8100 mg/kg (mice,
      intraperitoneal injection) activates simple and complicated forms of behavior,
      induces EEG effects typical of psychostimulators, is an antagonist of substances
      with a deprivationg neuropsychotropic effect. Bromantan is characterized by a
      positive effect on mnemonic processes and on obtaining the results of complex
      operant activity in rats.

PMID- 10340118
TI  - [The role of acetylcholine in the pathogenesis of seizure states of different
      etiologies].
AB  - Experiments were performed on rats to study the dynamics of changes in some
      parameters characterizing the state of the cholinergic part of the nervous system
      during the development of convulsions induced by various convulsants. It is
      concluded that, depending on its concentration in the synaptic space,
      acetylcholine may contribute to the development of convulsions or to their
      arrest. These effects of the mediator are probably due to its interaction with
      muscarine receptors of various localization and type.

PMID- 10340119
TI  - [The distant effects of acetylcholine--links in the pathogenesis of poisoning by
      cholinesterase inhibitors].
AB  - Scanning electron microscopy showed that the capillary endothelial cells of rats
      poisoned by O,O-dimethyl-O(2,2-dichlorvinyl) phosphate swell and become wrinkled,
      while some of the cells acquire fenestrae. In 24 h. these changes become weaker.
      Mass deformity of erythrocytes was seen at the same time and lasted less than 24
      h. Since the capillary endothelium and the erythrocytes are devoid of cholinergic
      innervation but possess cholinoreceptors, the occurring effects may be explained
      by the distant action of acetylcholine accumulating in the blood in poisoning by
      cholinestarase inhibitors.

PMID- 10340120
TI  - [The effect of clofelin on the transudation of plasma proteins into the dura
      mater induced by stimulation of the trigeminal ganglion].
AB  - Intravenous administration of clofelin blocks transudation of 131I-albumin into
      the dura mater of rats in electrical stimulation of the trigeminal ganglion.
      Preliminary injection of the alpha-adrenoblocker yohimbine and the antagonist of
      serotonin receptors 5-NT1 mianserin completely removes the blocking effect of
      clofelin. Naloxon and the alpha 1-adrenoblocker prazosin had no effect on the
      degree of expression of albumin transudation and the clophelin effect. The role
      of the adrenergic system, the presynaptic alpha 2-adrenoceptors in particular, in
      functioning of the trigeminovascular system and the development of neurogenic
      inflammation in the dura mater is discussed.

PMID- 10340122
TI  - [The cardioprotective action of 18-dehydroglycyrrhetic acid in experimental
      myocardial damage].
AB  - Experiments on rats with isadrine damage to the myocardium showed that when used
      for preventive-therapeutic purposes 18-dehydroglycyrrhizic acid (glyderinine
      preparation) causes statistically significant prevention of a rise in the serum
      level of marker enzymes (creatine phosphokinase, lactate dehydrogenase, aspartate
      aminotranspherase), prevents activation of lipid peroxidation, decrease of blood
      serum antioxidation activity and pathological changes in the content of glycogen
      and total lipids in the heart, it also improves the electrocardiographic
      parameters, reduces myocardial inflammatory edema. The results of the study show
      that glyderinine possesses a marked cardioprotective effect.

PMID- 10340124
TI  - [The effect of Cardil (diltiazem) in chronic hypoxia on the cationic balance in
      the cardiovascular system and on blood viscosity in rats].
AB  - Experiments on albino rats showed that injection of cardil (diltiazem) (10.5
      mg/kg) daily for 7 days in chronic pressure-chamber hypoxia promoted the
      correction of hypoxia-induced changes in blood viscosity and cation balance in
      the erythrocytes, blood plasma, tissues of the abdominal aorta and heart (except
      for the myocardial Ca2+ content) in decrease of the passive and active Na+ and K+
      transport through the erythrocyte membrane, increase of free energy (dFi > 0) of
      the erythrocyte--plasma--vascular wall system which was reduced in rats kept for
      14 days under conditions of hypoxia in a pressure chamber. Chronic hypoxia
      reduced the anticalcium effect of of cardil (diltiazem) in the myocardial cells
      and its influence on the increase of the transparietal potential difference in
      the abdominal aorta.

PMID- 10340121
TI  - [The cardioprotective effect of perindopril in rats with experimental
      cardiosclerosis].
AB  - Rats with experimental cardiosclerosis detected 21 days after embolization of the
      coronary arteries were subjected to early chronic perindopril administration (per
      os, 2 mg/kg once a day on days 2-20 after immobilization. As a result, the number
      of scars reduced, focal cardiosclerosis, dystrophy and hypertrophy of the
      cardiomyocytes were less pronounced, and the content of cellular glycogen
      increased. The cardioprotective effect was attended with a normalizing influence
      on the renin-angiotensin system parameters which were significantly changed after
      experimental damage to the myocardium: perindopril restored angiotensin I
      clearance and the level of angiotensin II production in the lungs.

PMID- 10340123
TI  - [The anti-arrhythmia activity of amino acid-containing trimecaine derivatives on
      models of early occlusive and reperfusion arrhythmias in cats].
AB  - Experiments were conducted on models of early occlusion and reperfusion
      arrhythmias in cats to study the antiarrhythmic activity of trimecain, its
      morpholine analogue (MPT), and MPT derivatives containing glycine, magnesium salt
      of aspartic acid, and N-acetylglutaminic acid. All the compounds were injected in
      doses of 5% of LD50. A 22.5 mg/kg dose of trimecain prevented cardiac rhythm
      disorders after occlusion of the coronary arteries as well as after restoration
      of the coronary blood flow. Replacement of the diethyl group in the structure of
      trimecain by the morpholine ring led to diminution of antiarrhythmic activity,
      and MPT in a dose of 28.0 mg/kg, in distinction from the former, had no effect on
      the frequency of the occurrence of early occlusion arrhythmias and the duration
      of reperfusion arrhythmias. Introduction of amino acids as an anion into the MPT
      structure raised the antiarrhythmic activity of the last named.

PMID- 10340125
TI  - [The joint use of prednisolone and phospholipid-containing hepatoprotectors in
      experimental chronic hepatitis].
AB  - In chronic CCl4-hepatitis in rats phospholipid-containing hepatoprotectors,
      essentiale and eplir differ in their influence on the therapeutic effect of
      prednisolone; essentiale does not change the antiproliferative effect of the
      glucocorticoid and weakens its membrane-stabilizing effect, eplir increases these
      therapeutic effects of prednisolone. Besides, eplir, in distinction from
      essentiale, reduces lipid accumulation in the liver and hypoproteinemia which are
      induced by prednisolone.

PMID- 10340126
TI  - [The immunomodulator ximedon lowers the level of induced DNA damages in bone
      marrow and peripheral blood cells: the possibilities for immunogenetic
      correction].
AB  - It was established in experiments on albino unbred mice and during treatment of
      patients with osteomyelitis that 30 mg/kg of ximidon suppresses the formation of
      micronuclear polychromatophilic erythrocytes found in the bone marrow of mice and
      peripheral blood of patients with chronic osteomyelitis. The interrelationship of
      the results obtained with the modulating effect of ximidon on the mitochondrial,
      thiol, and adenylate cyclase-dependent mechanisms of cell regulation is
      discussed.

PMID- 10340127
TI  - [The effect of aqueous extracts of hepatotropic medicinal plants on free-radical
      oxidation processes].
AB  - The authors studied the effect of decoctions and infusions of medicinal plants
      (common barberry, sandy immortelle, common maize, spotted milk thistle) on free
      radical oxidation (FRO) in model systems in vitro and in experiments in vivo on
      nonbred albino mice. In various model systems (in which active forms of oxygen
      are generated and lipid peroxidation takes place) the plants under study
      suppressed as well as intensified the processes of lipid peroxidation, depending
      on the concentration of the phytopreparation and the type of the model systems.
      In in vivo experiments the drugs of plant origin suppressed lipid peroxidation,
      reducing the parameters induced by iron and chemoluminescence and the malonic
      dialdehyde level in the liver.

PMID- 10340128
TI  - [The metabolic effects of isradipine, ramipril, Ednit and beta-adrenoblockers in
      patients with non-insulin-dependent diabetes mellitus and arterial hypertension].
AB  - The effect of isradepin, ramipril, ednyt, and beta-adrenoblockers on carbohydrate
      and lipid metabolism and free-radical oxidation in patients with insulin
      independent diabetes mellitus was studied. Isradepin caused an increase in high
      density lipoproteins (HDLP) in the blood serum and the content of esterified
      cholesterol in HDLP, and reduced the arterogenicity coefficient. Rampiril reduced
      the basal level of glycemia and insulin. Treatment with ednyt lead to increase in
      the content of HDLP and the content of free cholesterol in them. In the course of
      treatment isradepin normalized chemoluminescence of the serum and urine, rampiril
      that of serum, and beta-adrenoblockers the chemoluminescence of the blood. The
      favorable changes induced by the drugs under study allow them to be recommended
      for the treatment of arterial hypertension in patients with insulin-independent
      diabetes mellitus.

PMID- 10340129
TI  - [The polyclonal nature of the immune response to xenobiotics and endobiotics].
AB  - The results of many experiments and clinical observations showed that each
      chemical agent and its metabolites introduced into or mobilized in the organism
      act, along with others, on the lymphoid cells obligatorily inducing a polyclonal
      immune response directed at restoration of the chemism of the internal medium.
      The specificity of the response is attested by the absence of intensification of
      the immune rosette formation phenomenon in administration of a chemical agent of
      a different structure into the animal, as well as when erythrocytes, sensibilized
      by some other chemical agent not introduced or freed in the organism is used in
      the reaction. That an excess of the agent saturates the receptors of cells only
      specific of its clone testifies to the monospecificity of each of the lymphocyte
      clones. Our data are in agreement in this respect with one of the main postulates
      of immunology on the narrow specialization and strict manner of clone formation
      of the lymphocyte B-pool. Our data may possibly set the way for understanding the
      phenomenon of the polyclonal character of the immune response to various antigens
      and effects. We studied intensified immune responses specific of endobiotics, in
      exposure of the lymphocytes of animal organs to the effect fo PGA, tuberculin,
      antiglobulin sera, foreign protein, genetically foreign cells (sheep
      erythrocytes), microbial antigens and toxins. This, possibly, underlies the well
      known phenomenon of synthesis of nonspecific immunoglobulins in the organism in
      response to the effect of an antigen, the mechanism of which is still not clear.

PMID- 10340130
TI  - [The effect of anti-asthmatic preparations on the proliferation of human
      peripheral mononuclear cells].
AB  - The authors studied the effect of some antiasthmatic drugs (theophylline,
      budesonide, sodium cromalyne) and beta-carotene in vitro on spontaneous and PHA
      induced proliferation of human peripheral blood mononuclears (PBMN). It was found
      that the drugs had no effect on spontaneous cell proliferation. But budesonide
      caused a 4-fold and beta-carotene a 6-fold decrease of the index of PHA
      stimulated PBMN proliferation. It is concluded that beta-carotene may be used in
      clinical practice as an anti-inflammatory agent for bronchial asthma treatment.

PMID- 10340131
TI  - [The influence of verapamil on the clastogenic effect of cyclophosphane in
      somatic cells from BALB/c and C57Bl/6 mice].
AB  - The method of chromosome aberration count in the bone marrow cells of male BALB/c
      and C57Bl/6 mice was used to study the influence of intraperitoneal injection of
      verapamil in doses of 0.1-10 mg/kg and its administration into the stomach in
      doses of 2.5-10 mg/kg on the clastogenic effect of cyclophosphamide (10 mg/kg
      intraperitoneally) in a single and repeated (5 times at intervals of 24 h)
      administration. In repeated administration in all the doses used, verapamil
      significantly intensified the mutagenic activity of cyclophosphamide in C57Bl/6
      mice and in doses 10 mg/kg in BALB/c mice. A single intraperitoneal verapamil
      injection (0.1-0.4 mg/kg) caused a statistically increase in the clastogenic
      effect of cyclophosphan in mice of both strains. The same effect was encountered
      in intraperitoneal injection (2.5 mg/kg) and administration into the stomach (5
      mg/kg) of the calcium antagonist in BALB/c mice. Thus, the effect of verapamil on
      cyclophosphamide clastogenic activity depends on the dose, method, and schedule
      of administration of the calcium antagonist.

PMID- 10340132
TI  - [The effect of orthofen (diclofenac) on the embryogenesis of laboratory mice].
AB  - The effect of ortophen on the embryogenesis of laboratory mice of two inbred
      lines BALB/c and C57B1/6 and of outbred stock NMR was studied. The drug was
      injected intraperitoneally on days 1-6, 6-16, and 16-18 of pregnancy in a
      therapeutic dose (1 mg/g) and 10-fold doses. General development of the fetuses
      was delayed and the condition of the pregnant females of both lines and the stock
      deteriorated on injection of the drug in a 10-fold dose on days 16-18 of
      pregnancy. BALB/c mice proved to be most sensitive to the unfavorable effects of
      sodium diclophenac.

PMID- 10340133
TI  - [Melatonin lowers the threshold of light sensitivity of the human retina].
AB  - After chronic use of melatonin (3 mg before night-time for 14 days) campimetry
      showed a significant decrease of the threshold of brilliance sensitiveness of the
      retina in the absence of authentic changes of the sensorimotor response latency
      in individuals of the older age group. A connection between the eye light
      sensitivity and the direct effect of the hormone on the photoreceptors is
      suggested.

PMID- 10340134
TI  - [The metabolic effects of the neurotropic action of actovegin during hypoxia].
AB  - Recent data on the mechanisms of the effect of aktovegin on the brain in hypoxia
      are systematized. It is shown that the drug improves the transport and
      utilization of oxygen and glucose, activates the aerobic routes of energy
      metabolism and, as a result, improves the functional state of the central nervous
      system cells.

PMID- 10340135
TI  - [Natural antioxidants as hepatoprotectors].

PMID- 10340136
TI  - [Agonists of the imidazoline receptors].

PMID- 10340137
TI  - Scientific research in biology, and the freedom of the researchers.

PMID- 10340138
TI  - Proliferating cell nuclear antigen (PCNA) and apoptosis in hyperacute and acute
      myocardial infarction.
AB  - The aim of this study was to determine whether cell proliferation and/or
      apoptotic cell death occur in hyperacute and acute infarction. Proliferating cell
      nuclear antigen (PCNA) and apoptosis were investigated in ten autoptic hearts
      within a few hours of infarction and in three normal hearts as controls. The PCNA
      Labeling Index (PCNA-LI) ranged from 0 to 3.1 in hyperacute infarction (mean
      1.38), from 0.3 to 4 in acute infarction (mean 2.04) and from 0 to 1.2 in
      controls (mean 0.7). Although the results were not statistically significant,
      PCNA-LI was higher in acute than in hyperacute myocardial infarctions; and it was
      higher in hyperacute infarctions than in controls. Regarding apoptosis, the
      Apoptotic Index (AI) in hyperacute infarctions ranged from 0.7 to 3 (mean 1.78),
      in acute infarctions from 0.9 to 5 (mean 3.24) and in controls from 0 to 0.4
      (mean 0.1). The AI was significantly higher in hyperacute and acute infarctions
      than in controls (p < 0.05).

PMID- 10340140
TI  - Distribution of GAP-43-immunoreactive structures in the human fetal amygdala.
AB  - The growth-associated protein GAP-43 is a developmentally regulated protein which
      is involved in the formation of neuronal contacts. In immunohistochemical
      studies, GAP-43 is detected within axons during their elongation; thus a fibrous
      immunoreactivity is visible. After axonal growth is completed there is a shift
      from a fibrous to a punctate immunoreactivity. The latter has been shown to
      correlate with synaptogenesis. In the amygdala of the 5th gestational month, a
      fibrous GAP-43-immunoreactivity is seen in the basolateral nuclei, whereas the
      corticomedial nuclei exclusively show a punctate immunoreactivity. In the 7th
      month, all amygdaloid nuclei display immunoreactive puncta, but no fibers. In the
      9th month GAP-43-immunoreactivity is no longer visible within the amygdala. The
      results demonstrate the differential distribution of GAP-43-immunoreactive
      structures in the amygdaloid nuclei. The nuclear specific immunostaining and its
      changes may indicate the sequential appearance of the monoaminergic innervation
      of the amygdala, as GAP-43 is known to occur in monoaminergic systems. Nuclei
      involved in high levels of the cortical processing hierarchy such as the lateral
      or basal nucleus display a late occurrence of GAP-43-immunoreactivity. In
      general, anti-GAP-43 has been shown to be an appropriate tool to investigate
      axonal growth and synaptogenesis in the developing human brain.

PMID- 10340141
TI  - Hyaluronate receptor CD44 is expressed by astrocytes in the adult chicken and in
      astrocyte cell precursors in early development of the chick spinal cord.
AB  - The role of the hyaluronate receptor, CD44, is well known in adult mammal
      astrocytes where it modulates neuron-glia interactions. However, no data exist
      regarding its expression in other vertebrates during their development. In order
      to detect the expression of CD44 in the chicken and its possible involvement in
      glial precursor migratory patterns during spinal cord development, a monoclonal
      antibody (MoAb) against the mammalian standard isoform, CD44-H, was used in
      immunohistochemical and immunoblot assays. With these methods, CD44 hyaluronate
      receptors were found on mature astrocyte membranes of adult chicken spinal cord.
      Astrocytes were identified using a MoAb against GFAP. During development, small
      clusters of CD44 labelled cells were seen lining the central canal starting from
      embryonic stage E10. These labelled cells were dispersed in the dorsal, lateral
      and ventral funiculi of the spinal cord in the subsequent stages. After stage
      E15, the CD44 labelled cells were identified as astrocytes because of their GFAP
      immunoreactivity. We conclude that CD44 receptors on immature astrocyte
      precursors should be considered as early astrocyte markers which have a possible
      role during cell migratory dispersal.

PMID- 10340139
TI  - Defective apoptosis as potential mechanism in the tumorogenesis of myelolipoma.
AB  - Apoptosis is considered an important mechanism of selective deletion that occurs
      during hematopoiesis. Myelolipoma is a rare benign tumor composed of adipose
      tissue and hematopoietic cells. The pathogenesis of this benign tumor is still
      unclear. Analysing the structural levels and apoptosis of normal human bone
      marrow (NHBM) and human myelolipoma (HM), the apoptotic events resulted
      abundantly present in NHBM compared to HM, which showed a small number of
      apoptotic cells. By contrast, Fas expression was strongly present both in NHBM
      and HM. These findings suggest that an altered function of Fas in myelolipoma is
      not able to trigger the apoptotic machinery. In conclusion, we hypothesize that
      drastic reduction of apoptosis in myelolipoma can be considered one of the growth
      regulatory mechanisms.

PMID- 10340142
TI  - Distribution of immune cells expressing CD3a, CD21 and S-100 protein markers in
      the porcine gut-associated lymphoid tissues.
AB  - The distribution of immune cells within the gut-associated lymphoid tissues
      (GALT) of swine is highly organized. The appearance of such cells could not be
      separated from the effects of age, weaning and exposure to environment. Here, we
      have examined the distribution patterns of a subset of CD3a+ T and CD21+ B cells
      as well as S-100 protein+ cells and secretory (s) IgA+ cells within GALT
      compartments (such as jejunal lamina propria = JLP, ileal Peyeris patches = IPP,
      and mesenteric lymph node = MLN) of juvenile 8-week-old conventionally reared
      pigs using either two monoclonal antibodies (mAbs) or polyclonal antibodies
      (pAbs) in the immunohistochemical staining techniques with avidin-biotin complex
      (ABC) or peroxidase-antiperoxidase complex (PAP), respectively. The most potent
      porcine T-cell marker--CD3 surface antigen--is expressed as CD3a epitope on ileal
      intraepithelial lymphocytes, and numerous lymphocytes in the extrafollicular
      areas of MLN and dome region of IPP. Conversely, the cells expressing CD21
      surface molecules were only demonstrable in the interfollicular areas of MLN and
      in the germinal centers of IPP. A strong reaction to sIgA was displayed by the
      plasma cells in the lumen of crypts and those residing the lamina propria of
      jejunum and ileum. The S-100 protein+ cells were numerous in JLP around the
      crypts and in IPP of weaned pigs. Both applied mAbs proved to be useful reagents
      for phenotypic and functional analyses of porcine lymphoid cell subsets by the
      ABC technique. However, further investigation of the S-100 protein marker is
      needed to determine which (if any) subset of porcine CD3+ CD4- CD8+ T cells could
      be designated as orthologue of human CD8+ CD11b+ suppressor T cells.

PMID- 10340143
TI  - Lectin histochemistry and identification of O-acetylated sialoderivatives in the
      horse sublingual gland.
AB  - This study was aimed at characterizing the glycoconjugates produced by the horse
      sublingual gland and, in particular, at discriminating between the
      sialoderivatives by means of differential oxidation and saponification combined
      with lectin histochemistry and enzymatic degradation. The results showed a
      predominance of sialoglycoconjugates with beta-galactose as acceptor sugar in the
      salivary mucins produced by the sublingual gland. Besides being the most
      represented terminal residue, sialic acid was also expressed in a great variety
      of derivatives distinguishable on the basis of acceptor sugars to the penultimate
      beta-galactose as well as linkage and acetylation degree of the pyranose ring and
      the polyhydroxyl side chain. A role in the protection of mucous membranes from
      physical, chemical and pathogenic agents can be hypothesized for the horse
      sublingual mucins.

PMID- 10340144
TI  - Comparison of K(+)-p-nitrophenyl phosphatase activity in the urinary bladder of
      the frog Rana esculenta during hibernation and active life.
AB  - We have studied effects of hibernation on the frog urinary bladder, an organ
      involved in water and ion transepithelial transport and taking part in
      osmoregulation. We have demonstrated K(+)-p-nitrophenyl phosphatase activity (an
      enzyme involved in ion and water transport) both in active and hibernating frogs.
      Most of the reaction product deposition was found on basolateral membranes of
      granular cells of the urinary bladder epithelium during all seasons. Therefore,
      it seems likely that this organ, unlike organs studied previously (skin, kidney
      and lung), maintains its function in the osmoregulatory process during
      hibernation.

PMID- 10340145
TI  - Distribution and localization of immunoreactive FMRFamide-like peptides in the
      lancelet.
AB  - Immunofluorescence was used to study the distribution of FMRFamide (Phe-Met-Arg
      Phe-NH2) in premetamorphic larvae and adults of the lancelet, Branchiostoma
      lanceolatum. In the larvae, FMR-Famide-containing presumably neuronal perikarya
      and fibers were limited to the anterior third of the dorsal nerve cord.
      Throughout this region, most of the immunoreactive perikarya and fibers were
      located ventrolaterally and ventrally within the nerve cord; in addition, in the
      caudal part of the cerebral vesicle, some of the immunofluorescent cells
      projected cytoplasmic extensions across the slot-like neural canal. In adult
      lancelets, immunofluorescence was detected in cells of the Hatschek's pit (a
      probable homologue of the anterior hypophysis of vertebrates); however, no
      immunofluorescence was detected in the larval preoral pit, which is the
      ontogenetic precursor of Hatschek's pit. Moreover, the FMR-Famide-containing
      elements do not show immunoreactivity to other peptides of the FaRPs family such
      as pancreatic polypeptide (PP). The results suggest that FMRF-amide may be
      involved in neuroendocrine functions of lancelets.

PMID- 10340146
TI  - Relative distribution of myosin, actin, and alpha-actinin in adherent monocytes.
AB  - The characteristic amoeboid movement of human leucocytes uses mechanical energy
      derived from the hydrolysis of adenosine triphosphate through a mechanochemical
      system of the contractile proteins myosin, actin, and the actin-associated
      protein alpha-actinin. We observed the relative distribution of myosin, actin,
      and alpha-actinin in adherent monocytes during movement by a double-fluorescence
      staining procedure. The results indicate that myosin and alpha-actinin are
      closely associated with the actin cable network, and that alpha-actinin is in
      close association with the plasma membrane and anchors filamentous actin (F
      actin) beneath the plasma membrane; F-actin and alpha-actinin play an important
      role at the leading edge during the formation of lamellipodia. These findings
      should be helpful in clarifying the mechanism of leucocyte movement from a
      morphologic standpoint.

PMID- 10340147
TI  - Comparative studies of calretinin expression by WiDr cell line in vivo in
      xenografts in nude mice and in vitro.
AB  - WiDr cells from a human colon adenocarcinoma cultivated in vitro express the
      calcium binding protein calretinin. The immunoreactivity is present in some
      interphasic cells and decreases after seven days in culture together with the
      augmentation of the cell number. Calretinin expression is maintained in the
      undifferentiated cells of the tumoral mass developed in nude mice and in
      recultivated isolated tumour cells from the xenograft. From the experiments here
      described, the protein expression is quantitatively influenced in vitro by the
      addition of drugs, such as colchicine and taxol, which intervene in cytoskeleton
      organisation. The percentage of the calretinin immunoreactive cells increases
      after the addition of colchicine to the medium while the immunoblot analysis
      shows a higher calretinin content in the cells treated with taxol.

PMID- 10340148
TI  - PNA lectin as marker of Py1a cell cycle.

PMID- 10340149
TI  - Benzodiazepine receptor function in the chick social separation-stress procedure.
AB  - The role of benzodiazepine (BZ) receptors in modulating social separation-induced
      distress vocalizations (DVocs) and stress-induced analgesia (SIA) were examined
      in 8-day-old cockerels (Gallus gallus). In Experiment 1, the BZ agonist
      chlordiazepoxide (CDP; 5.0 mg/kg) reversed both DVocs and SIA in isolated chicks.
      Coadministration of the BZ antagonist flumazenil (0.01, 0.03, or 0.10 mg/kg)
      reversed CDP anxiolytic effects. In Experiment 2, the BZ agonists alprazolam
      (ALP; 0.065, 0.125, 0.25, or 1.50 mg/kg) and lorazepam (LOR; 0.125, 0.25, 0.50,
      or 1.0 mg/kg) dose dependently reversed social separation-induced DVocs and SIA.
      The ED50s for ALP and LOR in attenuating DVocs were 0.19 and 0.34 mg/kg,
      respectively. These data strongly support the theory that CDP anxiolytic effects
      are mediated by BZ receptor activity in the chick social separation procedure
      (Experiment 1) and that this model is sensitive to BZ agonists of different
      potencies (Experiment 2).

PMID- 10340150
TI  - The effects of cadmium contamination on the discriminative stimulus properties of
      cocaine and related drugs.
AB  - Rats were exposed to a diet containing 100 ppm cadmium chloride or a control
      diet. At 52 days of exposure, rats were trained to discriminate between saline
      and 5 mg/kg cocaine injections. After acquisition training, successive
      substitution tests were conducted using cocaine, the indirect dopamine agonist d
      amphetamine, the mixed D1-D2 agonist apomorphine, SKF 38393 and SKF 82958 (both
      preferential D1 agonists), quinpirole (a preferential D2 agonist), GBR 12909 (a
      dopamine reuptake inhibitor), procaine (a local anesthetic), and morphine (an
      opiate). The results showed that cadmium-exposed rats were slower to acquire the
      saline-cocaine discrimination than controls. Moreover, cadmium contamination
      reduced substitution when apomorphine, SKF 82958, and GBR 12909 were presented
      during generalization testing. Also, cadmium exposure blocked tolerance to
      cocaine that was evident in control rats following 14 days of exposure to 60
      mg/kg/day cocaine.

PMID- 10340151
TI  - Potential associations among genetic markers in the serotonergic system and the
      antisocial alcoholism subtype.
AB  - Alcoholism is transmitted in families. The complexity and heterogeneity of this
      disorder has made it difficult to identify specific genetic correlates. One
      design with the potential to do so is the family-based association study, in
      which the frequencies of genetic polymorphisms are compared between affected and
      nonaffected members. Reduced central serotonin neurotransmission is associated
      with features of an antisocial subtype of alcoholism, although a primary deficit
      has not been traced to a particular component. Genetic markers related to the
      sertonergic system have been identified, located, and cloned. If associations can
      be discovered, the development process for pharmacotherapy could be facilitated.
      In this review, the evidence for the involvement of the serotonergic system in
      antisocial alcoholism is examined, and the potential for family-based association
      studies to identify specific components that may be involved is discussed.

PMID- 10340152
TI  - Cloninger's constructs related to substance use level and problems in late
      adolescence: a mediational model based on self-control and coping motives.
AB  - Predictions concerning mediating processes for the effects of C. R. Cloninger's
      (1987a) constructs were tested; criterion variables were substance use level and
      substance use problems. Participants were 1,225 adolescents (M age: 15.5 years).
      Structural modeling indicated indirect effects for novelty seeking, harm
      avoidance, and task reward dependence, mediated through self-control; harm
      avoidance also had an inverse direct path to substance use level, and social
      reward dependence had a positive direct path to coping motives for substance use.
      Good self-control had inverse paths to life events and deviant peer affiliations;
      poor self-control had positive paths to life events and coping motives; and risk
      taking had positive paths to coping motives and peer affiliations. Coping motives
      had a path to level and a direct path to problems; peer affiliations had a path
      only to substance use level.

PMID- 10340153
TI  - Gender differences in response to nicotine replacement therapy: objective and
      subjective indexes of tobacco withdrawal.
AB  - K. A. Perkins (1996) recently proposed that nicotine reinforcement controls
      smoking to a greater degree among men than women and that consequently, nicotine
      replacement therapy (NRT) during smoking cessation should benefit men more than
      women. The authors tested this hypothesis. Polysomnographic measures of sleep and
      self-report indexes of tobacco withdrawal were collected pre- and postcessation
      from an active nicotine patch group and a placebo patch group in a randomized,
      double-blind clinical trial (N = 34). Objective sleep parameters supported
      Perkins's hypothesis and indicated that among women, NRT may be less effective at
      suppressing certain withdrawal responses compared with men and may produce some
      iatrogenic effects. Valid and reliable self-report measures of withdrawal did not
      reveal gender differences in response to NRT.

PMID- 10340154
TI  - Sleepiness and the reinforcing and subjective effects of methylphenidate.
AB  - On 4 days, 6 volunteers received 10 mg methylphenidate or placebo at 0900 after 4
      or 8 hr time in bed (TIB) and then on 4 days after 4 or 8 hr TIB chose their
      preferred capsule. On sampling days, 4 hr TIB increased multiple sleep latency
      test (MSLT) scores and Fatigue scale scores on the Profile of Mood States (POMS).
      In both TIBs, the drug increased the MSLT and POMS Vigor and Tension scale
      scores. It reduced POMS Fatigue scores and improved divided attention performance
      to a greater extent after 4 versus 8 hr. Drug was chosen on 88% of days after 4
      hr, but only 29% of days after 8 hr. Preference for the drug depends on
      sleepiness and is mediated by performance-enhancing and fatigue-altering effects.

PMID- 10340155
TI  - Effects of olfactory stimuli on urge reduction in smokers.
AB  - This study examined the possibility that exposure to olfactory stimuli can reduce
      self-reported urge to smoke. After an initial assessment of self-reported urge,
      nicotine-deprived smokers evaluated the pleasantness of a series of 8 odors.
      Facial expressions during odor presentations were coded with P. Ekman and W. V.
      Friesen's (1978a) Facial Action Coding System. After odor administration,
      participants were exposed to smoking cues. Next, participants were administered
      their most pleasant, least pleasant, or a control odor (water) and reported their
      urge to smoke. Results indicated that sniffing either a pleasant or unpleasant
      odor reduced reported urge to smoke relative to the control odor. Reported
      pleasantness of the odors did not differentially affect urge reduction. Odors
      eliciting negative-affect-related expressions, however, were less effective than
      odors that did not elicit negative-affect-related expressions in reducing
      reported urge. Results of this preliminary investigation provide support for the
      consideration of odor stimuli as an approach to craving reduction.

PMID- 10340156
TI  - Adolescent drug use and adult drug problems in women: direct, interactive, and
      mediational effects.
AB  - The authors studied effects of variables assessed in adolescence on problems from
      drug use in adulthood in a community sample of women. One focus of this 13-year
      longitudinal study was moderators, which were hypothesized to exacerbate, or
      attenuate, the effects of early drug consumption on later drug problems.
      Potential moderators were sensation seeking, social conformity, academic
      orientation, parental support, depression, and drug problems in parents. Direct
      and mediating effects of these variables, as well as of drug consumption, were
      also evaluated. Results showed that most of the significant effects involved
      sensation seeking and social conformity. In addition, adolescent drug use
      significantly predicted adult polydrug problems. The effects of sensation seeking
      are consistent with the view that this variable reflects a sensitivity to drug
      use, which makes it more likely that drug use gets translated into drug abuse.

PMID- 10340158
TI  - Including "mental" in health & social work.

PMID- 10340157
TI  - Effects of monetary contingencies on smoking relapse: influences of trait
      depression, personality, and habitual nicotine intake.
AB  - Of 56 male smokers, 34 were randomly assigned (by 60% random odds) to quit
      smoking immediately, whereas the remaining 22 were assigned to quit after an
      additional 31 days. Compensation ($300) was contingent on abstinence for a
      minimum of 31 or 2 days (depending on random assignment) and completion of all
      experimental sessions. Contingencies for the immediate-quit group required 31
      days of abstinence; those for the delayed-quit group required only 2 days of
      abstinence. Contingency duration (31 vs. 2 days) predicted days to relapse. All
      but 4 of the 31-day contingency participants maintained abstinence for at least
      31 days, whereas only 3 of the 2-day contingency group abstained for 31+ days.
      However, 31-day contingencies did not result in longer postcontingency time to
      relapse. Higher trait neuroticism, depression, and psychopathic deviate scores
      predicted decreased time to relapse. Prequit cotinine concentrations and
      Fagerstrom Tolerance Questionnaire scores failed to predict time to relapse.

PMID- 10340159
TI  - Analysis of postdischarge change in a dual diagnosis population.
AB  - Many individuals with serious mental illnesses have co-occurring drug and alcohol
      problems. The research reported in this article examined an integrated inpatient
      mental illness-chemical dependency program and compared it with standard
      inpatient psychiatric treatment for two groups: those demonstrating high change
      from baseline to two-months postdischarge and those with negative or no change.
      Univariate analyses revealed significant differences in the change groups on
      baseline personal-clinical characteristics and on aspects of their social and
      physical environments. The results have implications for improving mental health
      practice by better predicting patients who will optimally benefit from inpatient
      treatment.

PMID- 10340160
TI  - Managed care, meet community support: ten reasons to include direct support
      services in every behavioral health plan.
AB  - In this article, the performance of community support programs over three decades
      is assessed through a review of the professional literature, with emphasis on
      clinical outcomes, cost-effectiveness, and consumer satisfaction. The author
      argues that for managed behavioral health organizations to serve disabled
      customers adequately, community support is required. Ten field-tested reasons to
      include community support services in every behavioral health plan are presented.
      The author concludes that social workers are uniquely qualified to adapt proven
      interventions from model community support programs to the mission of managed
      behavioral health organizations, with the potential to remedy problems of access,
      continuity, and accountability in providing treatment for serious and persistent
      mental illness.

PMID- 10340161
TI  - The impact of clients' mental illness on social workers' job satisfaction and
      burnout.
AB  - The study discussed in this article examined the relationship between the degree
      of involvement with clients with severe mental illness and social workers' job
      satisfaction and burnout. A total of 128 social workers were administered a
      questionnaire that included three scales: an involvement scale, a job
      satisfaction measure, and the Maslach Burnout Inventory. Greater involvement was
      related significantly to higher levels of emotional exhaustion and
      depersonalization. Overall, results suggest that social workers are affected
      negatively by this type of work. The implications for the social work profession
      are discussed as well as the importance of social support systems at the work
      setting that will help social workers cope more effectively with stressful work
      situations.

PMID- 10340162
TI  - Empowerment evaluation as a social work strategy.
AB  - This article explores the application of empowerment strategies to program
      evaluation within a community health setting and presents a case study to examine
      the policy, direct practice, and research issues associated with the plan to
      evaluate a community-based HIV-prevention program. Empowerment evaluation
      strategies were used to develop an innovative street outreach intervention that
      can be measured and evaluated, to transfer evaluation knowledge from the
      researcher-expert to the program stakeholders, and to help overcome evaluation
      implementation obstacles. The article addresses the benefits and risks inherent
      in an empowerment approach to the evaluative research process.

PMID- 10340163
TI  - What families know about funeral-related costs: implications for social work
      practice.
AB  - Social workers provide essential services in the area of end-of-life care to
      individuals who are dying and their families. Results reported here suggest that
      social work's role be expanded to provide basic information about local final
      arrangement (funeral and burial) options and costs. This study was undertaken to
      determine the knowledge and experience level of people responsible for funeral
      and cemetery arrangements and to investigate factors affecting familiarity with
      final costs. Survey responses from 163 survivors of older adults in Kansas City
      showed that adult children play an important role in the final arrangements of a
      parent and that half the survivors responsible for final arrangements had no idea
      what to expect in terms of costs.

PMID- 10340164
TI  - The role of perceived stress on prenatal care utilization: implications for
      social work practice.
AB  - Data from the National Institute of Child Health and Human Development/Missouri
      Maternal and Infant Health Survey on about 2,828 mothers were used to examine the
      relationship between perceived stress and prenatal care utilization. Major life
      events that contribute to stress also were examined in relation to adequacy of
      prenatal care. Women who received inadequate prenatal care were more likely to
      have reported that they almost always felt stress during pregnancy. Odds ratios
      were statistically significant for women who were not black and Medicaid
      recipients but not for black women and women who were not covered by Medicaid.
      Social work intervention for stress reduction on behalf of pregnant women has the
      potential to contribute to improved prenatal care utilization, but further
      analysis of the kinds of stress women experience will enhance social work's
      ability to target specific interventions.

PMID- 10340166
TI  - The role of government in "a society for all ages".

PMID- 10340165
TI  - Risky sex behavior and substance use among young adults.
AB  - Many young adults, despite widespread prevention and education efforts that
      target this age group, engage in behaviors that place them at risk of HIV
      infection. These behaviors include frequent experimentation with alcohol and
      other drugs before sex, sexual activity with different partners, and inconsistent
      safe-sex practices. The combination of these risky behaviors causes increased
      concern about the spread of HIV among this age group. The study discussed in this
      article examined the relationship between substance use during adolescence and
      HIV risk behavior among young adults ages 19 to 21 with and without a college
      education. Results indicated that increased use of alcohol and marijuana at
      younger ages is related to riskier sexual activity and increased use of alcohol
      and marijuana as young adults. Recommendations for interventions are made.

PMID- 10340167
TI  - Clinical trials for severe sepsis. Past failures, and future hopes.
AB  - Recent clinical trials with experimental immunotherapeutic agents for severe
      sepsis and septic shock have been largely unsuccessful despite seemingly
      convincing preclinical evidence of significant benefit of these antisepsis
      therapies. This article reviews basic therapeutic rationale, preclinical
      evaluation, and clinical trial design of past clinical trials of innovative
      sepsis treatments. Lessons learned from past failures should provide insights
      into the design and implementation of successful clinical trials for new anti
      sepsis agents in the future.

PMID- 10340168
TI  - The epidemiology of bacterial sepsis.
AB  - As a result of better understanding of pathogenesis, new definitions of sepsis
      have been proposed, and the complexity of this syndrome is clearer. Population
      based studies of bloodstream infections--what now is called sepsis--have helped
      us to understand the natural history of this very frequent problem. The mortality
      and morbidity of each of the systemic inflammatory response syndrome stages have
      been described; our ability to better understand and predict these stages will
      help us to make better therapeutic decisions.

PMID- 10340169
TI  - Structure-function relationships of bacterial endotoxins. Contribution to
      microbial sepsis.
AB  - A substantial body of knowledge has emerged over the past several decades
      concerning the primary and tertiary, and quaternary structure of endotoxic LPS
      and their contribution to the pathogenesis of gram-negative sepsis; however,
      important questions remain. Among them are the precise three-dimensional
      configuration of the LPS macromolecule and the contribution of the quaternary
      structure to the ability of these potent microbial factors to interact with host
      humoral and cellular inflammatory mediator systems. Also remaining to be
      sufficiently addressed is the relative contribution of endotoxin interactions
      with the host to the overall manifestation of disease and conditions under which
      such contributions serve as the pivotal event in determining outcome. The answers
      to these questions can be expected to provide valuable insights into potential
      novel therapeutic intervention strategies and approaches that will ultimately
      reduce both morbidity and mortality in infection from gram-negative microbes.

PMID- 10340170
TI  - Lipopolysaccharide recognition, CD14, and lipopolysaccharide receptors.
AB  - The ability of a host to sense invasion by a pathogenic organism, and to respond
      appropriately to control infection, is paramount to survival. To that end, an
      array of receptors and binding proteins has evolved as part of the innate immune
      system to detect Gram-negative bacteria. This article reviews the role of CD14,
      other LPS binding proteins, and the Toll family of receptors in the innate
      recognition of bacterial lipopolysaccharide.

PMID- 10340171
TI  - Vaccines and antibodies in the prevention and treatment of sepsis.
AB  - Antibodies to various core glycolipid antigens have been shown to correlate with
      survival from Gram-negative sepsis. Recent preclinical data also support efficacy
      of the anti-core glycolipid antibodies in the treatment of sepsis. Failure of
      some of the previous clinical trials with anti-core glycolipid antibody was
      probably due to inadequate levels of antibody in those preparations. Future
      clinical trials must ensure that sufficient amounts of anti-core glycolipid
      antibodies are present in the circulation of patients with sepsis.

PMID- 10340172
TI  - Antiendotoxin strategies.
AB  - Endotoxin is a potent stimulator of the inflammatory response and is believed to
      initiate the pathology in Gram-negative sepsis. Agents are being developed that
      bind and neutralize or block the effects of endotoxin, with the goal of improving
      outcome in the treatment of sepsis. Strategies discussed in this article include
      anti-LPS antibodies, LPS binding proteins and lipoproteins, polymyxin B
      conjugates, lipid A analogues, and extracorporeal techniques for endotoxin
      removal.

PMID- 10340173
TI  - Structure and function of streptococcal and staphylococcal superantigens in
      septic shock.
AB  - The pyrogenic exotoxins of Group A Streptococci and enterotoxins of
      Staphylococcus aureus constitute a family of related toxins that acts as
      "superantigens" because of their ability to stimulate large numbers of T-cell
      subsets. These toxins have been implicated in gastrointestinal food poisoning,
      toxic shock syndromes, Gram-positive sepsis, and, possibly, septic shock. There
      is increasing evidence that Gram-positive infections frequently coexist in septic
      shock and that bacterial superantigens play a major role.

PMID- 10340174
TI  - Gram-positive sepsis. Mechanisms and differences from gram-negative sepsis.
AB  - This article has reviewed the mechanisms by which gram-positive bacteria lead to
      septic shock, with regard to bacterial structure and toxicology and the host
      responses elicited both in animal models and in the clinical setting. Gram
      positive organisms are better suited to invade host tissues and elicit, in
      general, a brisker phagocytic response than gram-negative organisms. The lack of
      endotoxin in the outer cell wall is compensated for by the presence of exposed
      peptidoglycan and a range of other toxic secreted products. It appears that cell
      wall components of gram-positive bacteria may signal via the same receptor as
      gram-negative endotoxin, although the type of signal and coreceptor may differ.
      Both animal and clinical data suggest that, unlike endotoxin-mediated shock, gram
      positive infection produces a modest TNF response only and does not respond well
      to anti-TNF therapies. This leads one to conclude that the mechanisms leading to
      shock in gram-positive infection may be multifactorial and perhaps more difficult
      to treat. A thorough review of gram-positive mechanisms of sepsis is hampered by
      a lack of basic research in this field. Understanding of gram-negative bacterial
      structure and the regulation of virulence genes is at an advanced stage, yet the
      molecular tools to analyse virulence factors in the gram-positive genome have
      only recently become available. There is a paucity of good animal models of gram
      positive infection and a lack of microbiologic data from some of the major trials
      in sepsis that might have given greater insight into the mechanisms leading to
      shock in various infections.

PMID- 10340175
TI  - Cytokines and anticytokines in the pathogenesis of sepsis.
AB  - Clinical trials with anti-inflammatory agents in patients with sepsis are based
      on the assumption that excessive proinflammatory activity of the cytokine network
      negatively influences the outcome of severe bacterial infections. The failure of
      these trials to show clinical benefit, in conjunction with recent experimental
      data, raises doubt about the validity of this assumption. This article
      reevaluates the role of cytokines in the pathogenesis of sepsis and severe
      bacterial infections. The cytokine network is discussed as consisting of
      proinflammatory cytokines, antiinflammatory cytokines, and soluble inhibitors of
      proinflammatory cytokines.

PMID- 10340176
TI  - Neutrophil and endothelial cell interactions in sepsis. The role of adhesion
      molecules.
AB  - Although adhesion molecules present on circulating neutrophils and endothelial
      cells are essential for normal host defense, generalized activation of these
      molecules has been implicated in the inflammatory tissue injury occurring during
      sepsis and septic shock. A review of both preclinical and clinical studies
      suggests, however, that although these molecules mediate tissue injury related to
      a variety of microbial and host inflammatory mediators, their predominant role
      during sepsis with infection is a protective one.

PMID- 10340177
TI  - Nitric oxide in the pathogenesis of sepsis.
AB  - In sepsis and septic shock, inflammatory mediators result in the production of
      increased concentrations of nitric oxide (NO) from the enzymatic breakdown of the
      amino acid L-arginine. The increased amounts of NO are responsible for changes in
      vasomotor tone, decreased vasopressor responsiveness, and decreased myocardial
      function, characteristic of septic insult. Therapeutic strategies designed to
      reduce the concentration of NO by inhibiting the action of the nitric oxide
      synthase enzyme, or by scavenging the excess NO, offer the potential to treat
      directly the vasomotor abnormalities and myocardial depression seen in sepsis and
      other inflammatory states. This article reviews the biology of NO in sepsis and
      discusses strategies for neutralization of the increased NO production, in the
      setting of severe sepsis and septic shock.

PMID- 10340178
TI  - The gut's role in metabolism, mucosal barrier function, and gut immunology.
AB  - The gastrointestinal tract functions not only to absorb nutrients, it also plays
      an important immunologic role during health and critical illness. Under
      experimental and certain clinical conditions, stimulating the gut attentuates the
      stress response and avoids mucosal atrophy and increases permeability. Gut
      stimulation prevents atrophy of the gut-associated lymphoid tissue, the body's
      major defender of moist mucosal surfaces. A better understanding of gut function
      and improved nutrient delivery has clinical implications in the treatment of
      critically ill patients.

PMID- 10340179
TI  - Rapid diagnostic methods in the detection of sepsis.
AB  - Any delay in the management of infection is deleterious, especially in patients
      whose illness is severe. It is of paramount importance to shorten this delay.
      This article emphasizes the different ways to reach this goal, including the use
      of new biologic markers, such as cytokines or procalcitonin.

PMID- 10340180
TI  - Current therapy for sepsis.
AB  - The treatment of severe sepsis and septic shock remains a challenge as we
      approach the next millennium. Although more attention is being given to
      guidelines and care pathways for sepsis, these are unfortunately based primarily
      on consensus opinion. Additional research into supportive interventions in this
      potentially devastating disease is needed. Priorities in the management of sepsis
      include rapid reversal of hypotension and hypoperfusion, followed by empiric
      antibiotic therapy and definitive localization and treatment of infection nidus.
      A wide variety of adrenergic agents may be useful in sepsis. Initial therapy for
      hypoperfusion, however, should be targeted toward establishing adequate
      intravascular volume and left ventricular preload. Adjunctive therapy to prevent
      complications during the intensive care unit stay is important.

PMID- 10340181
TI  - Anti-dementia drugs.

PMID- 10340182
TI  - Initiating and monitoring cholinesterase inhibitor treatment for Alzheimer's
      disease.
AB  - The availability of acetylcholinesterase inhibitors for the treatment of
      Alzheimer's disease raises a number of clinical and ethical questions. Many of
      the guidelines published in an attempt to tackle these questions lack either
      clinical or scientific validity. Against this background a model is proposed
      whereby specialist monitoring using formal tests is neither appropriate nor
      necessary to determine whether an individual patient should continue or stop
      treatment. Instead the primary care physician should refer potentially suitable
      patients for specialist assessment to confirm the diagnosis/He/she should then
      initiate, monitor, and discontinue treatment based on the establishment of
      realistic treatment goals agreed with the patient/carer at the outset.

PMID- 10340183
TI  - A review and commentary on a sample of 15 UK guidelines for the drug treatment of
      Alzheimer's disease.
AB  - BACKGROUND: There has been widespread development of clinical guidelines for the
      treatment of Alzheimer's disease since the introduction of donepezil in the UK in
      1997. These have been developed nationally, regionally, locally and by
      independent groups. An independent review of guidelines available in the public
      domain was commissioned to provide an overview of the range and variability in
      the recommendations being made. METHODS: Fifteen sets of guidelines obtained from
      a variety of sources were reviewed in a standardized way to extract the
      recommendations being made in the following areas: diagnosis; investigations; the
      evidence base of the recommendations: initiation of drug treatment; monitoring
      and dose adjustment; and decision-making on maintenance or discontinuation of
      treatment. RESULTS: None of the documents fulfilled criteria for high-quality
      evidence-based guidelines. Substantial variability was evident in all areas of
      recommendation. All of the guidelines appeared to be based upon consensus
      opinion. Only one incorporated a statement of potential conflicts of interest
      affecting the working group who developed the guideline. CONCLUSIONS: The lack of
      consistency found in this sample of guidelines would inevitably lead to
      inequalities in the health care delivered in different areas. A national
      initiative is needed to encourage true evidence-based guideline development, not
      only on drug treatment but also on the wider issues raised such as diagnosis,
      investigations and the best treatment setting for delivering drug and other
      therapies.

PMID- 10340184
TI  - New drugs for dementia: a commissioning nightmare?

PMID- 10340185
TI  - Clinical involvement in anti-dementia drug trials--why bother?

PMID- 10340186
TI  - Life review of an older adult with memory difficulties.
AB  - The natural life review process involves emotional processing of events from the
      individual's past. Life review therapy (LRT) addresses issues regarding
      unresolved conflicts, guilt and resentment which the client has particular
      difficulty in reviewing independently. People with memory problems may have
      difficulty mentally manipulating a number of pieces of information at the same
      time. Since LRT involves recollection of past experiences (events, emotions and
      relationships) which need to be processed and integrated with the person's
      current understanding, individuals with memory problems may find this process
      difficult, though not impossible. This article is written in order to demonstrate
      that LRT can be useful for people with memory difficulties, provided that
      individual sessions are tailored to their particular cognitive abilities. A case
      is presented of an older adult, with above-average intellectual abilities, who
      became distressed when recollecting her childhood. LRT was conducted in a manner
      that took account of the memory difficulties and utilized a variety of
      therapeutic techniques. LRT was beneficial for this client despite her memory
      difficulties, since, following therapy, she was no longer distressed when
      thinking about her childhood.

PMID- 10340187
TI  - Dementia in the hospitalized elderly--a study of 100 consecutive cases in
      Singapore.
AB  - AIM: This survey aims to study the medical, functional and social aspects of
      hospitalized elderly patients with dementia. METHODS: The case records of 100
      patients with dementia admitted consecutively to our department were
      systematically reviewed to extract the patients' demographic data, presenting
      features, underlying cause(s) of dementia, functional disabilities and carers'
      difficulties. RESULTS: Eighty per cent of the patients were 75 years of age and
      above and 44% were males. In this cohort 55% had vascular dementia, with
      Alzheimer's disease being the next most common (40%). The overwhelming majority
      had marked cognitive impairment as assessed by the Abbreviated Mental Test and
      worsening degrees of dementia were significantly associated with increasing
      disabilities in both mobility and activities of daily living (ADL). Fifty-seven
      families reported coping difficulties and this group had significant correlations
      with the respective patients' bladder and bowel incontinence as well as worsening
      states of ambulatory and ADL function. CONCLUSION: Patients with dementia present
      with complex problems and management requires attention not only to patients'
      medical problems and rehabilitation strategies but also to education, emotional
      support and help for their frequently stressed out carers.

PMID- 10340188
TI  - Wandering behaviour in community-residing persons with dementia.
AB  - OBJECTIVES: To examine wandering behaviour in elderly demented persons in the
      community setting with respect to dementia characteristics and other factors that
      might influence wandering behaviour; to generate a statistical model to assess
      the relative importance of these various factors in predicting wandering
      behaviour. DESIGN: Cross-sectional, case-control investigation. SETTING:
      University-affiliated outpatient neuropsychiatric assessment center.
      PARTICIPANTS: Six hundred and thirty-eight consecutive community-residing new
      patients with dementia referred for evaluation. MEASUREMENTS: Comprehensive
      neuropsychiatric evaluation, including rating with Mini-Mental State Examination;
      General Medical Health Rating; Comell Scale of Depression in Dementia and
      caregiver interview. RESULTS: Wandering behaviour occurred in 17.4% of
      participants. It was significantly more prevalent in patients with Alzheimer
      Dementia (AD), patients with dementia of longer duration, and patients with more
      severe dementia. Wandering behaviour was associated with moderate to severe
      depression, delusions, hallucinations, and sleep disorder. Other significant
      associations of wandering behaviour included use of neuroleptic medication and
      male gender. After statistical adjustment for other variables, duration of
      dementia, severity of dementia and presence of sleep disorder retained
      significant statistical association with wandering behaviour. CONCLUSIONS:
      Wandering behaviour among community-residing elderly dementia patients is
      associated with a number of factors, some of which may be subject to
      modification. It is possible that management of coexistent psychopathology,
      particularly of sleep disorder, and of the underlying disease process of AD would
      help to ameliorate this problematic behavioural disorder. Further investigation
      is warranted into the relationship between neuroleptic medication and wandering
      behaviour and into possible alternative measures to control agitation in elderly
      dementia patients.

PMID- 10340189
TI  - Benzodiazepine use among the elderly in the community.
AB  - Benzodiazepines are the most commonly prescribed psychotropic drug in the
      elderly. Benzodiazepines with a long duration of action can produce marked
      sedation and psychomotor impairment in older people, and are associated with an
      increased risk of hip fracture and of motor vehicle crash. One thousand seven
      hundred and one individuals of 65 years and over, identified from General
      Practitioner lists, were interviewed using the Geriatric Mental State-AGECAT
      package and current psychotropic drug use was recorded. Benzodiazepines were
      classified as having a short or long elimination half-life. Two hundred and
      ninety-five (17.3%) individuals were taking a benzodiazepine, with use in females
      being twice that in males. Of the 295, 152 (51.5%) were taking a long acting
      benzodiazepine and the use of long acting anxiolytic type benzodiazepines was
      particularly common. Fifty-two (17.6%) benzodiazepine users were taking one or
      more other psychotropic drugs. A benzodiazepine was used by eight of 18 (44.4%)
      subjects with an anxiety disorder, 62 of 180 (34.4%) individuals with depression,
      and seven of 71 (9.9%) people with dementia. Four-fifths of older people on a
      psychotropic drug were taking a benzodiazepine, highlighting the importance of
      this class of drug in the elderly population. The choice of a benzodiazepine with
      a long duration of action, which have been shown to be associated with serious
      adverse events in the elderly in over one half of benzodiazepine users, is of
      concern. The potential for adverse effects was further accentuated by
      polypharmacy practices. The choice of benzodiazepine for an older person has
      important consequences and should be addressed in greater detail with primary
      care.

PMID- 10340190
TI  - Treatment of vocally disruptive behaviour of multifactorial aetiology.
AB  - OBJECTIVE: To describe the treatment of vocally disruptive behaviour (VDB) of
      multifactorial aetiology. METHOD: Three case reports were used to illustrate the
      treatment of multifactorial VDB. RESULTS: A biopsychosocial assessment is
      required to identify the different aetiologies involved and the way they
      interact. Acute medical and psychiatric factors may demand that interventions are
      introduced simultaneously rather than in succession. CONCLUSION: Successful
      interventions require the combination of biopsychosocial strategies tailored to
      the individual case with realistic goals that include the acceptance of a
      residual level of VDB as a reasonable outcome.

PMID- 10340191
TI  - Memory complaints in young and elderly subjects.
AB  - OBJECTIVE: To compare the quantitative and qualitative aspects of memory
      complaints in cognitively normal subjects aged under and above 50 years. SETTING:
      A memory clinic located in a general hospital in a suburb of Paris offering
      direct access to subjects. DESIGN: Retrospective review of the files of
      consecutive patients who attended the clinic during one year. PARTICIPANTS:
      Subjects were included if (a) they presented with memory complaints, (b) they had
      normal general cognitive functioning according to age and educational level, (c)
      they were devoid of present or past history of neurologic or psychiatric
      disorders. METHODS: Subjects rated the severity of memory complaints as major or
      minor and filled in a 8-item questionnaire assessing various memory difficulties
      in everyday life. Relationship between severity of memory complaints and
      demographic data, memory performance and affective status was compared in 183 non
      depressed, non-cognitively impaired healthy adults aged 50 years and over, and in
      77 younger adults. RESULTS: Semiologic aspects and correlates of memory
      complaints were similar in younger and older adults. No close relationship was
      found between severity of memory complaints and memory performance. In both age
      groups, memory complaints were strongly related to affective status, mainly to
      the severity of anxious symptomatology. Memory complaints were related to gender
      in younger subjects, and to subjective assessment of well-being in older.
      CONCLUSION: Memory complaints of elderly do not appear basically different from
      memory complaints of younger subjects. They constitute a complex psychological
      symptom unlikely to be explained by a few variables and cannot be reduced to the
      subjective counterpart of memory performance decline associated with age.

PMID- 10340192
TI  - Dementia carer education and patient behaviour disturbance.
AB  - OBJECTIVE: To evaluate the impact of a dementia Carer Education Programme on
      carer quality of life (QoL), burden, and well-being. DESIGN: Single group before
      after intervention study. The group was subdivided by perceived status post
      programme for intragroup analysis. SETTING: Hospital memory clinic. PARTICIPANTS:
      Convenience sample of 32 dementia carers. INTERVENTION: Eight weekly 2 h
      education and support sessions run by a psychogeriatric clinical team. MEASURES:
      Pre-programme and 6 months post-programme data were obtained. Measures included
      individually perceived QoL, burden, well-being, managing problem behaviour,
      appraisal of social support, knowledge of dementia, and perception of the
      programme. Patients were characterized in terms of cognition, behaviour
      disturbance and functional status. RESULTS: Twelve carers reported their
      situation post-programme as 'better', 12 as 'worse', and four as 'no change'.
      There were no significant baseline differences. For 'better/no change' carers the
      only significant change over time was increased knowledge about dementia. For
      'worse' carers knowledge also increased, but there was evidence of poorer QoL,
      increased burden, a poorer appraisal of social support, and increased patient
      behaviour disturbance. Only patient behaviour disturbance significantly
      discriminated 'no change/better' from 'worse' carers (F = 4.08, p = 0.055).
      CONCLUSIONS: The programme increased carers' knowledge about dementia, but had no
      significant impact on QoL, burden, or well-being. Increased patient behaviour
      disturbance appeared to be a major factor when the carer's situation worsened
      over time. Despite high carer satisfaction the efficacy of a group-based
      education approach to the management of behaviour disturbance in dementia appears
      limited. More intensive or individually tailored interventions may be necessary
      alternatives.

PMID- 10340193
TI  - The impact of behavioral impairment of functional ability in Alzheimer's disease.
AB  - This study sought to determine the relationship between behavioral disturbance
      and functional status in a longitudinally studied sample of patients with
      Alzheimer's disease (AD). One hundred and forty-nine patients meeting NINCDS
      ADRDA criteria for probable AD were followed for an average of 37.3 months, with
      follow-up assessments every 6 months. Subjects were seen at the Alzheimer's
      Disease Research Center clinics at the Mt Sinai Medical Center, New York, and the
      Veterans Affairs Medical Center, Bronx, New York. Measures included the Physical
      and Self-Maintenance Scale (PSMS) and Instrumental Activities of Daily Living
      Scale (IADLS) of Lawton and Brody and the cognitive and non-cognitive subscales
      of the Alzheimer's Disease Assessment Scale (ADAS). For each patient the
      assessment at which they had their most severe non-cognitive symptoms as measured
      by the non-cognitive part of the ADAS (ADAS-NC) was determined. ADAS-NC scores at
      that assessment were correlated with IADLS and PSMS scores at the same assessment
      and at the next assessment 6 months later. While there was some modest
      association of ADAS-NC scores with functional impairment using pairwise
      correlation coefficients, none of the correlations remained significant when the
      severity of cognitive impairment was controlled statistically. Findings were not
      significantly changed when drug status was controlled. These results suggest that
      behavioral disturbance, while very troubling to caregivers and patients, does not
      substantially worsen functional ability beyond the contribution of cognitive
      impairment in AD. Together with previous results indicating that non-cognitive
      symptoms in AD are episodic and fluctuating rather than progressive, the present
      data suggest that interventions for non-cognitive disturbances in AD should be
      viewed as ways to increase patient comfort, safety and ease of care and not as
      ways to improve functional autonomy. The latter can be achieved only by improving
      the progressive cognitive deficits of AD.

PMID- 10340194
TI  - HIV prevention and the positive population.
AB  - Efforts to prevent the spread of HIV have, to an overwhelming degree, addressed
      themselves to the HIV-negative rather than to the positive population. But it
      makes sense to direct more preventive work towards positive individuals, for 3
      reasons. First, because changes in the behaviour of positive people have a
      disproportionately greater effect on the spread of the epidemic--so positive
      targeted interventions are potentially more cost-effective, and in many cases
      enormously so. Second, positive individuals already show a degree of preventive
      altruism that generally outweighs the self-protective efforts of those who are
      negative. And third, there is reason to believe that this preventive altruism can
      be strengthened by appropriate interventions. Some of the practical implications
      of a shift to greater positive targeting, involving both novel interventions and
      modified familiar ones, can be sketched out.

PMID- 10340195
TI  - Neurological manifestations of cytomegalovirus infection in the acquired
      immunodeficiency syndrome.
AB  - Cytomegalovirus (CMV) infection is one of the most important opportunistic
      infections in AIDS. The most common manifestation of neurological CMV disease in
      HIV infection is retinitis followed by encephalitis, polyradiculopathy, and
      multifocal neuropathy. Untreated necrotizing retinitis proceeds to blindness but
      can readily be diagnosed by ophthalmological examination. CMV polyradiculopathy
      presents as subacute leg weakness, paraesthesia, and urinary retention. Untreated
      patients develop ascending paralysis and die within weeks. Multifocal neuropathy
      commonly affects the radial, ulnar, and peroneal nerves but cranial nerves may
      also be involved. Confusion, cranial nerve palsies, and hyperreflexia are signs
      of ventriculoencephalitis, whereas the presentation of diffuse micronodular
      encephalitis is often asymptomatic. The diagnostic approach relies on the
      detection of CMV DNA in the cerebrospinal fluid for polyradiculopathy,
      encephalitis, and neuropathy. Neuroimaging can exclude other causes of
      encephalitis and polyradiculopathy. Ganciclovir, foscarnet, and cidofovir
      monotherapy are current medical treatment options. Intraocular administration can
      be used for refractory retinitis, but additional systemic prophylaxis is required
      to suppress extraocular disease. Ganciclovir and foscarnet have improved the
      prognosis of multifocal neuropathy and polyradiculopathy, but response rates for
      encephalitis are low. However, despite therapy survival of central nervous CMV
      disease is still limited to months. Recently highly active antiretroviral therapy
      (HAART) has decreased the overall incidence of CMV disease in AIDS. Furthermore
      (HAART) has become a mainstay for CMV therapy by improving the patient's
      immunocompetence against CMV.

PMID- 10340196
TI  - Acceptability of female condom use among women exchanging street sex in New York
      City.
AB  - Greater access to alternative female-initiated barrier methods, such as the
      female condom, is needed among women exchanging street sex. This study describes
      knowledge of and experience with the female condom among 101 women exchanging sex
      for money and drugs on the streets of New York City, and examines the
      acceptability of female condom use as an alternative barrier method for HIV/STD
      prevention among this population. Female condom use among this sample of sex
      workers was found to be related to having a regular sexual partner, living with
      someone who is a drug or alcohol abuser, not being homeless, using alcohol or
      intravenous heroin, having heard of the device, and having discussed the device
      with other women or with a regular sexual partner. Despite decreased
      acceptability post-use, most sex workers indicated an intention for future female
      condom use.

PMID- 10340197
TI  - Characterization of an outbreak of tetM-containing Neisseria gonorrhoeae in
      Argentina.
AB  - Phenotypic and molecular characterization of an outbreak of 9 Neisseria
      gonorrhoeae (NG) isolates exhibiting high-level plasmid mediated resistance to
      penicillin and tetracycline (PP-TRNG) that took place in Tandil, Argentina
      between February and April 1995. Comparison with the patterns of the 3 PP-TRNG
      strains previously isolated were made. We determined the following markers for
      each strain: antimicrobial susceptibility, serogroup, auxotype, plasmid profile,
      presence of tetM determinant and restriction pattern of the tetM-containing
      plasmid. Antimicrobial tests values were: tetracycline disk diameter 12-14 mm,
      minimum inhibitory concentration (MIC) 32 micrograms/ml; penicillin disk diameter
      6 mm, MIC 32 micrograms/ml and sensitive by both methods to spectinomycin,
      cefuroxime, ceftriaxone and ciprofloxacin. All isolates were of the same
      serogroup (WI). Ten of the strains, including the 9 from Tandil outbreak, were
      arginine-requiring, while the other 2 were methionine and arginine-requiring. All
      of them demonstrate the same plasmid profile (2.6, 3.2, 25.2 MDa). They were
      positive for the tetM determinant and the restriction analysis identified it is a
      Dutch-type plasmid. In spite of the temporal and geographical dispersion, PP-TRNG
      strains in Argentina seem to be highly homogeneous in terms of antimicrobial
      susceptibility, serogroup, plasmid profiles and even auxotype.

PMID- 10340198
TI  - Brief behavioural skills building intervention for female controlled methods of
      STD-HIV prevention: outcomes of a randomized clinical field trial.
AB  - The need for female controlled methods for preventing HIV infection is well
      recognized and women have been found to accept the female condom for these
      purposes. Women (n = 105) were randomly assigned to receive either (a) a 3-h
      behavioural skills building intervention that concentrated on educating women
      about the female condom, motivating female condom use, and building behavioural
      skills relevant to using the female condom, or (b) a time-matched broadly defined
      women's health education intervention. Women who received the female controlled
      skills building intervention used the female condom to a greater extent than did
      women in the health education condition. Importantly, the effects of the
      behavioural skills intervention were most pronounced for women who reported only
      one male sex partner in the previous 6 months compared to women with multiple sex
      partners. However, female condom use was modest, with only one in 5 vaginal
      intercourse acts being protected by female condoms among women with one partner
      who received skills training. Interventions are needed to further enhance use of
      the female condom and new female controlled methods are needed for the majority
      of women at risk who did not adopt the female condom.

PMID- 10340199
TI  - Network structural dynamics and infectious disease propagation.
AB  - We aimed to relate dynamic changes in risk-network (sex and/or injecting drug)
      structure to observe STD/HIV transmission. We analysed macro- and micro
      structural elements in 2 heterosexual networks, augmented by ethnographic
      observations. In a Colorado cohort of injecting drug users (n = 595), measures of
      subgroup formation and of density of activity show decrease of network cohesion
      over time; only one HIV transmission was observed in 3 years. In a group of
      adolescent heterosexuals in Georgia (n = 99), the reverse process (increase in
      structural cohesion) was associated with efficient syphilis transmission: 10
      cases were observed. Changes in personal risk behaviours over time were modest.
      STD/HIV transmission patterns were associated with intensification or diminution
      of network cohesion. Network and ethnographic data suggest that enhanced
      connectivity facilitates transmission while segmentation impedes it, suggesting
      opportunities for interventions. These data also emphasize the need to re
      evaluate purely behavioural explanations of STD/HIV transmission.

PMID- 10340200
TI  - Behavioural risk factors for HIV/AIDS in a low-HIV prevalence Muslim nation:
      Bangladesh.
AB  - A review of published and unpublished data indicates the prevalence of high-risk
      behaviours for HIV transmission in segments of the Bangladeshi population. These
      include casual unprotected sex, heterosexual as well as between males, prior to
      and after marriage. Intravenous drug use (IVDU) exists though illicit drugs are
      more commonly inhaled. There is a fear, however, that inhalers may turn to
      injecting drugs, as is common in neighbouring countries. The lack of public
      awareness of HIV/AIDS, and misconceptions about the disease, may contribute to
      continued high-risk behaviours by segments of the population and, thus, to the
      spread of HIV. Bangladesh's proximity to India and Myanmar (countries with high
      HIV endemicity and a rapidly growing number of cases) increases fears of an
      epidemic in Bangladesh. This proximity will only be a risk factor, however, if
      high-risk contacts occur between nationals of these countries.

PMID- 10340201
TI  - The relationship between educational background and decline to death in a sample
      of Louisiana male AIDS cases.
AB  - The purpose of this study was to determine the relationship between educational
      level and time of decline to AIDS mortality. A total of 1578 death certificates
      were matched and processed with reported Louisiana male AIDS cases to assess the
      relation between decline to AIDS mortality with educational background, age,
      race, and transmission group. A 2 (race) x 4 (age group) x 2 (transmission group)
      x 3 (educational background) ANOVA was performed. In addition, descriptive
      statistics were utilized to show patterns of the association. A significant (P <
      0.05) main effect of educational background on decline to death was found.
      However, inconsistent educational level effect on mortality was found across
      different subgroups regarding race and AIDS transmission group. Those with higher
      educational levels demonstrated least severity of decline to death. Furthermore,
      a significant 3-way interaction in the well-educated black intravenous drug user
      (IDU) population suggests a call to expand current models of counselling for this
      clientele.

PMID- 10340202
TI  - Evaluation of 2 techniques of HIV pre-test counselling for pregnant women in west
      Africa. DITRAME Study Group.
AB  - This study compares the effect of group and individual pre-test counselling on
      uptake of HIV voluntary counselling and testing (VCT) by African pregnant women
      and knowledge about HIV/AIDS in 2 antenatal clinics of Bobo-Dioulasso, Burkina
      Faso. Pre-test counselling was offered to 3958 pregnant women, 927 by group
      counselling and 3031 by individual counselling. Acceptance of the test improved
      with individual counselling, which was already high with group counselling (93.3%
      versus 89.4%). The return rate for results was independent of the pre-test
      counselling technique. At post-test session, knowledge about HIV/AIDS was better
      after group than individual counselling, except for reporting the existence of an
      asymptomatic stage of HIV infection. At a public health level, group pre-test
      counselling can be easily integrated into existing sessions of antenatal care
      counselling, routinely performed by the current clinic staff. Our findings may
      help programme managers in the field of maternal and child health to choose
      optimal options of pre-test counselling adapted to local circumstances in
      resource-poor settings.

PMID- 10340203
TI  - Recurrent bacterial vaginosis and Netherton's syndrome.

PMID- 10340204
TI  - Many hands make light work.
AB  - As part of an ongoing minute of the Association of Genito-Urinary Medicine
      (AGUM's) national body, this committee's non consultant career grade (NCCG)
      representative has added another reflective chapter about this heterogeneous
      group of doctors working in genitourinary medicine (GUM) throughout the British
      Isles. Here, current progress is briefly explained and some of the revelations
      unmasked by the compilation of a national database for NCCG are enumerated along
      with a few personal suggestions for improving the mutual benefits of NCCG
      contribution within GUM in the UK.

PMID- 10340205
TI  - Management of erectile dysfunction.

PMID- 10340206
TI  - Sexually transmitted organisms in children and child sexual abuse--what do we
      mean by children?

PMID- 10340207
TI  - Financial incentives for ambulatory care performance improvement.
AB  - BACKGROUND: Measuring and improving the quality of care while curtailing costs
      are essential objectives in capitated care. As patient care moves from the
      hospital to outpatient settings, quality management resources must be shifted to
      ambulatory care process improvement. The Quality Improvement and Efficiency
      Financial Incentives Program at Stanford University Medical Center was adopted to
      increase quality improvement efforts and contain costs. THE INCENTIVE PROGRAM:
      Each department's budget for care of capitated patients was reduced by 5% from
      the previous year. Return of a reserve fund (10% of payments for specialty care)
      required completion of substantive quality improvement projects and containing
      costs. Successful departments were also eligible for bonus funds. Implementation
      strategies included endorsement by clinical leaders, physician education, use of
      administrative data to identify project topics and support measurement of quality
      and cost variables, project templates and time lines, and the availability of
      clinical quality managers with special expertise in clinical process improvement.
      RESULTS: Eight of 13 clinical departments developed and implemented 19 ambulatory
      quality improvement projects to varying degrees. Success in the program was
      roughly correlated with the potential impact of the incentive on revenues and the
      status of the lead person selected by the department to spearhead their efforts.
      Only 5 departments achieved their cost containment goals. DISCUSSION: Financial
      incentives are one method of encouraging physicians to use clinical process
      improvement methods. Endorsement by clinical leaders and selection of realistic
      beginning projects enhance chances for success. The capitated population has
      attributes that make it an attractive focus for initial quality improvement
      efforts.

PMID- 10340208
TI  - Using a quality scorecard to measure and improve medical groups' performance.
AB  - BACKGROUND: Blue Cross of California (BCC) uses an annual Quality Scorecard to
      measure performance of participating medical groups (PMGs) and independent
      practice associations (IPAs). The scorecard provides information to the PMGs/IPAs
      on their performance in several domains relative to the average network score.
      BCC pays annual bonuses to PMGs/IPAs with superior quality performance. A
      structured intervention was designed to improve the performance of PMGs/IPAs that
      performed poorly on the scorecard. METHODS: A cohort study was conducted in a
      large health maintenance organization in California in 1997. All PMGs/IPAs
      received a detailed summary of the components of the annual quality scorecard.
      Scorecard components include an annual audit of quality, utilization management,
      credentialing, and members' rights and responsibilities, grievance rates, member
      transfer for quality reasons, a satisfaction survey, and a preventive health
      review. Twenty-two of 124 PMGs/IPAs with more than 1,000 BCC members during 1996
      that had scored lower than 1 standard deviation below the mean were targeted.
      These 22 outlier PMGs/IPAs received additional information indicating that their
      performance was below average. A BCC quality team subsequently visited the
      outlier PMGs/IPAs to provide supplementary information on the deficient areas and
      provide assistance in making improvements. RESULTS: The outlier groups showed
      significant improvements in the annual audit of quality score, member
      satisfaction with access, member satisfaction with last visit, overall member
      satisfaction with PMGs/IPAs, mammography screening, and the total score.
      CONCLUSIONS: A structured quality improvement intervention in poorly performing
      PMGs/IPAs was followed by improvements in specific performance measures.

PMID- 10340209
TI  - A longitudinal study of performance of physicians' office practices: data from
      the Peer Assessment Program in Ontario, Canada.
AB  - BACKGROUND: The College of Physicians and Surgeons of Ontario has conducted a
      Peer Assessment Program since 1980. All physicians who turn 70 years of age in a
      given year are automatically selected for assessment, and the program assesses a
      random selection of physicians within specific practice and specialty areas. Each
      assessor--a physician who practices in the same area of medicine as the physician
      undergoing assessment--reviews the physical facilities, the system of record
      keeping and the content of approximately 20-30 medical records, and the quality
      of care provided, as determined by the medical record content and discussions
      with the physician. The assessed physician is then assigned a grade. In 1998,
      program records for 109 nonspecialist physicians who had undergone two
      assessments more than 10 years apart (first assessment, 1981 to 1987; second,
      1991 to 1997) were examined to determine possible changes in performance.
      RESULTS: The mean time between assessments was 12.2 years. Seventy (64.2%) of the
      109 physicians showed a decline in grade, whereas 35 (32.1%) received the same
      grade, and only 4 (3.7%) had an improvement in grade. CONCLUSIONS: This report is
      consistent with previous observations that performance changes with age. In
      contrast to previous studies, this report is based on longitudinal rather than
      cross-sectional data.

PMID- 10340210
TI  - Making the case for quality: an interview with David Nash. Interview by Gary
      Rosenthal.

PMID- 10340211
TI  - Alginate encapsulated bioadhesive chitosan microspheres for intestinal drug
      delivery.
AB  - Sustained intestinal delivery of drugs such as 5-fluorouracil (choice for colon
      carcinomas) and insulin (for diabetes mellitus) seems to be a feasible
      alternative to injection therapy. For successful therapy, the drug should be
      delivered at proper sites (here, the intestine) for long duration, for producing
      maximum pharmacological activity. We have attempted to develop a formulation that
      can bypass the acidity of the stomach and release the loaded drug for long
      periods into the intestine by using the bioadhesiveness of polyacrylic acid,
      alginate, and chitosan. Bromothymol blue was taken as a model drug. The
      formulation exhibited bioadhesive property and released the drug for an eight-day
      period in vitro.

PMID- 10340212
TI  - End-stage renal disease (ESRD) and vascular access grafting: a critical review.
AB  - End-Stage Renal Disease (ESRD) is a major disease state, costing the U.S. $9.5
      billion in 1992, and increasing 10% yearly. The growth in the number of ESRD
      patients can be attributed principally to demographic trends: the aging of the
      general population and the improved treatment and increased survival rate of
      patients with diabetes, hypertension, and other illnesses that lead to ESRD.
      Moreover, improved dialysis technology has enabled older patients and those who
      previously could not tolerate dialysis due to other illnesses to benefit from
      this treatment. Three modalities exist for the treatment of ESRD: hemodialysis,
      peritoneal dialysis, and kidney transplant. This article reviews the medical
      treatments and the synthetic polymers used in the manufacture of vascular access
      grafts. We report on the development of a new, polyurethane-based microporous
      vascular graft, which displays self-sealing and improved compliance
      characteristics for use in vascular access grafting.

PMID- 10340213
TI  - Assessment of pericardium in cardiac bioprostheses. A review.
AB  - Cardiac valve bioprostheses are assessed in terms of their present and future
      clinical utility. The problems concerning durability basically involve early
      failure due to tears in the valve leaflets and late failure mainly associated
      with calcification of the biological tissue. New strategies for selection and
      chemical treatment of the biomaterials employed are analyzed, and the available
      knowledge regarding their mechanical behavior is reviewed. It is concluded that
      the durability of these devices, and thus their successful use in the future,
      depends on the knowledge of the interactions among the different biomaterials of
      which they are composed, the development of new materials, and the engineering
      design applied in their construction.

PMID- 10340214
TI  - Calcium alginate microparticles for oral administration: I: Effect of sodium
      alginate type on drug release and drug entrapment efficiency.
AB  - The natural polymers alginate and chitosan were used for the preparation of
      controlled release nicardipine HCl gel microparticles. The effect of the
      mannuronic/guluronic acid content and the alginate viscosity on the prolonged
      action of the microparticles, which were prepared with different types of
      alginates, were investigated. The mean particle sizes and the swelling ratios of
      the microparticles were also determined. The in vitro release studies were
      carried out with a flow-through cell apparatus in different media (pH 1.2, 2.5,
      4.5, 7 and 7.5 buffer solutions). The release of nicardipine was extended with
      the alginate gel microparticles prepared with guluronic acid rich alginate. After
      the determination of the most appropriate alginate type, the effect of alginate
      chitosan complex formation was studied on the release pattern of drug
      incorporated. It was observed that the alginate-chitosan complex formation
      reduced the erosion of the alginate-chitosan matrix at pH 7-7.5. The release of
      drug from the chitosan-alginate gel microparticles took place by both diffusion
      through the swollen matrix and relaxation of the polymer at pH 1.2-4.5.

PMID- 10340215
TI  - Calcium alginate microparticles for oral administration: II. Effect of
      formulation factors on drug release and drug entrapment efficiency.
AB  - The release rate of nicardipine HCl from various alginate microparticles was
      investigated. Manugel A7B618 which has a high guluronic acid content of 70% and a
      low polymerization degree of 60-400 was used as alginate. A 2(3) factorial design
      was utilized for the preparation of the alginate microparticles. The effect of
      drug:polymer weight ratio, CaCl2 concentration and curing time on parameters such
      as the time for 50% of the drug to be released (t50%) and the drug entrapment
      efficiency were evaluated with analysis of variance. The mean particle sizes and
      the swelling ratios of the microparticles were determined. The in vitro release
      studies were carried out with a flow-through cell apparatus at different media
      (pH 1.2, 2.5, 4.5, 7, 7.5 buffer solutions). Drug:polymer weight ratio and the
      concentration of the crosslinking agent were the influential factors on the
      release of NC from the alginate microparticles. The release of nicardipine was
      extended with alginate microparticles prepared in a ratio of 1:1 (drug:polymer
      weight ratio). The release of drug from alginate microparticles took place by
      both diffusion through the swollen matrix and relaxation of the polymer at pH:
      1.2-4.5. However, the release was due to diffusion and erosion mechanisms at pH 7
      7.5.

PMID- 10340216
TI  - Calcium pectinate gel beads for controlled release drug delivery: II. Effect of
      formulation and processing variables on drug release.
AB  - The effect of four formulation and processing variables, calcium concentration,
      drying condition, concentration of hardening agent and hardening time on the bead
      properties and the release characteristics of a model drug from calcium pectinate
      gel (CPG) beads were studied. A poorly soluble compound, indomethacin, was used
      as the model drug. The investigated variables affected the bead size, the
      entrapment efficiency and the release of indomethacin from CPG beads. Drug
      release was found to be a function of the formulation and processing variables.
      The slower drug release was achieved from the formulations with higher calcium
      concentration, higher concentration of hardening agent and longer hardening time.
      The drying condition, however, did not influence the drug release. The mechanism
      of indomethacin release from CPG beads followed the diffusion controlled model
      for an inert porous matrix. All drug release data fitted well to the Higuchi
      square root time expression.

PMID- 10340217
TI  - Preparation of spray-dried microspheres of indomethacin and examination of the
      effects of coating on dissolution rates.
AB  - In this study, microspheres were prepared by the spray drying technique using
      suspensions of indomethacin (IM) as active substance and coated by three
      different polymers in order to increase the dissolution rate of IM. Water
      solutions (0.1, 0.2 and 0.5%) of hydroxypropylmethyl cellulose (HPMC), polyvinyl
      alcohol (PVA) and hydroxypropyl cellulose (HPC) were used as coating materials.
      Polyethylene glycol 400 (PEG 400) was added to all formulations as plasticizer.
      Changes of particles size and surface characteristics of the coated products were
      examined using optical microscopy and scanning electron microscopy (SEM),
      respectively. The effects of coatings on the dissolution rates of IM were
      examined using USP XXIII Method II in water and phosphate buffer pH 7.4. It was
      observed that coating the IM particles with HPMC, PVA and HPC polymers using the
      Spray-Drying Technique increased the dissolution rate of IM significantly.

PMID- 10340218
TI  - Ultrasonic atomization for spray drying: a versatile technique for the
      preparation of protein loaded biodegradable microspheres.
AB  - Bovine serum albumin (BDA) loaded microspheres with a spherical shape and smooth
      surface structure were successfully prepared from poly(lactide-co-glycolide)
      using an ultrasonic nozzle installed in a Niro laboratory spray dryer. Process
      and formulation parameters were investigated with respect to their influence on
      microsphere characteristics, such as particle size, loading capacity, and release
      properties. Preparation of microspheres in yields of more than 50% was achieved
      using an ultrasonic atomizer connected to a stream of carrier air. Microsphere
      characteristics could be modified by changing several technological parameters.
      An increased polymer concentration of the feed generated larger particles with a
      significantly reduced initial release of the protein. Moreover, microspheres with
      a smooth surface structure were obtained from the organic polymer solution with
      the highest viscosity. Microparticles with a low BSA loading showed a large
      central cavity surrounded by a thin polymer layer in scanning electron
      microspheres. A high protein loading led to an enlargement of the shell layer, or
      even to dense particles without any cavities. A continuous in vitro release
      pattern of BSA was obtained from the particles with low protein loading. Glass
      transition temperatures (Tg) of the microspheres before and after lyophilization
      did not differ from those of the BSA loaded particles prepared by spray drying
      with a rotary atomizer. Analysis of the polymer by gel permeation chromatography
      indicated that ultrasonication had no effect on polymer molecular weight.
      Molecular weight and polydispersity of the pure polymer, placebo microspheres
      prepared by spray drying, and placebo microspheres prepared using the ultrasonic
      nozzle were in the same range. In conclusion, ultrasonic atomization represents a
      versatile and reliable technique for the production of protein loaded
      biodegradable microspheres without inducing a degradation of the polymer matrix.
      Particle characteristics can be modified by adjusting formulation parameters and
      atomization conditions in a simple manner.

PMID- 10340219
TI  - Sustained release chitosan microspheres prepared by novel spray drying methods.
AB  - Modified spray drying methods, especially a novel w/o/w emulsion-spray drying
      method, were developed to prepare chitosan microspheres with a sustained drug
      release pattern. Release of the model drugs cimetidine and famotidine, from the
      microspheres prepared by the emulsion-spray drying methods, was greatly retarded
      with release lasting for several hours, compared with drug loaded microspheres
      prepared by conventional-spray drying or emulsion methods where drug release was
      almost instant. The slow release of drug was partly due to the poor wetting
      ability of the microspheres which floated on the surface of the dissolution
      medium. The addition of a wetting agent increased the release rate significantly.
      The coating of the microspheres with gelatin decreased the rate of release of
      drug in the presence of wetting agents.

PMID- 10340220
TI  - Encapsulation and stability of clofazimine liposomes.
AB  - The entrapment of clofazimine (CLO) in a liposomal delivery system for topical
      application can protect it from absorption into the blood circulation and
      increase its residence time within the skin. This may reduce the very long mean
      period of leprosy treatment, as well as the side effects due to the long term
      administration of large doses of the drug. This investigation deals with critical
      parameters controlling the formulation and stabilization of liposomes with
      encapsulated CLO. The entrapment efficiency of CLO in liposomes was increased by
      altering the proportion of phosphatidyl choline (PC) and cholesterol (CHOL) in
      liposomes. The stability of liposomal suspensions and the liposomal gels (HPMC
      K4M) in terms of retention of CLO was measured at refrigeration temperature (2-8
      degrees C), room temperature (25 +/- 2 degrees C) and body temperature (37
      degrees C) for a period of 3 months. The results show that entrapment of CLO in
      liposomes can be increased by increasing the proportion of PC. However, the
      optimum encapsulation and retention of CLO was achieved only with a specific
      PC:CHOL molar ratio (5.13:1.00). An almost identical value of the entrapment
      efficiency was obtained when gel filtration and ultracentrifugation methods were
      used to separate the CLO-carrying liposomes from free drug. The effect of
      vortexing and sonication on the entrapment efficiency gave similar results,
      although the mean particle size was different. CLO liposomal gels were found to
      be stable at room temperature for up to 3 months.

PMID- 10340221
TI  - Modulation of rifampicin release from spray-dried microspheres using combinations
      of poly-(DL-lactide).
AB  - Microspheres containing 20% w/w rifampicin (RIF) with smooth morphology have been
      readily prepared from combinations of low, R104 (Mw, 2000) and moderate, R202H
      (Mw, 9000), molecular weight poly(D,L-lactide) (PDLLA) as a means to modulate
      drug release from either polymer when used alone. These have been characterized
      with respect to their drug loading, granulometry, in vitro drug release and
      thermal behaviour. Particle size distributions were Gaussian, whereby mean
      microsphere diameter was found to increase from 2.11 to 2.98 microns as the
      proportion of more viscous R202H increased, whilst > 95% of particles were < 10
      microns, irrespective of the polymer blend used. Use of a reduced inlet
      temperature for spray-drying gave uncharacteristically high production yields in
      the range of 55.8-80.7% for the process. Encapsulation efficiencies were
      quantitative with the weight proportion of drug co-dissolved (p < 0.05), yielding
      microspheres of high and predictable RIF loading. In vitro drug release revealed
      a dramatic shift in release profile between 40 and 60% R104. Closer examination
      in this range showed the predicted pattern of increased release rate as the
      fraction of more hydrophilic R104 increased. However, disproportionate
      differences were evident between 44 and 48% R104. From the apparent temperature
      dependent drug release, the criticality of matrix composition was attributed to
      the coincidence of matrix softening with the dissolution medium temperature and
      consequent hydration, which, at a finite composition, resulted in a controlled
      auto-hydration mechanism. Dramatic dependence of release rate with dissolution
      methodology was accountable to the fact that drug release was considerably
      quicker where microspheres remained suspended and individualized with the USP
      paddle method as opposed to aggregated with the shaking bath methodology. In
      conclusion, the utility of blending racemic PDLLA to modulate drug release and
      the convenience of spray-drying as a technique to produce microspheres of
      predictable character have been demonstrated. The temperature-dependent release
      exhibited may have application in the site-specific delivery of drugs where local
      increased biochemical activity promotes drug release in response to an increased
      pharmacological need.

PMID- 10340222
TI  - Determination of encapsulated menthol flavour using thermal desorption gas
      chromatography.
AB  - The analysis of menthol in encapsulated products is challenging due to the nature
      of the encapsulating matrices and the volatility of the analyte. Normal
      sampling/extraction procedures cannot be applied to the different types of
      menthol encapsulated products, due to variable extraction efficiencies of the
      analyte. This paper details the extraction and analysis of menthol flavour using
      a two stage thermal desorption GC process. This two stage thermal desorption
      system, using a Tenax TR packed cold trap, enables a narrow band of the extracted
      menthol to be focused onto the GC column. The method showed linearity in the
      range of 0.2-0.8 mg of menthol with a correlation coefficient greater than 0.999.
      Average instrumental precision of 3% RSD was determined and method precision was
      in the range of 2.1-9.4% RSD. This method was specific to menthol showing no
      interfering peaks. All the menthol was extracted in one extraction step. The
      specific analysis of menthol in encapsulated products allowed comparison of the
      efficiency of encapsulating processes, by comparing menthol loading values. RSD
      values for the different microparticles also indicate the relative homogeneity of
      the systems.

PMID- 10340224
TI  - Diagnosing depression in primary care.

PMID- 10340223
TI  - Male suicides increase.

PMID- 10340225
TI  - Giving up the car: older women's losses and experiences.
AB  - Numerous activities, often life-long patterns, are based on driving and access to
      a car. When driving ceases, the challenge to change and develop new behavior
      patterns occurs. Women in this study had many losses and challenges to usual ways
      of doing things. Various coping strategies were described, including types,
      benefits, and potential challenges of both informal and formal helpers.
      Implications for health care providers include empathic awareness of the nature
      and extent of loss initiated by giving up driving and determining how best to
      support older adults in coping. More work needs to be done to develop strategies
      that support optimal function and ease this difficult transition for older
      adults.

PMID- 10340226
TI  - Effectiveness of intervention into substance abuse disorders in women with
      comorbid depression.
AB  - Victimization was supported by the occurrence of various forms of abuse--sexual,
      physical, and emotional--and the difficulty in establishing healthy intimate
      relationships. Because relapse is common, nurses must be alert for faulty
      negative thinking, behaviors, and feelings that might lead to relapse.

PMID- 10340227
TI  - Social networks for women with serious mental illness.
AB  - Assessment of ways to work with situations as they exist, and capitalizing on
      positive factors or strengths within the client's life context, may enhance the
      nurse-client relationship, and the likelihood of positive outcomes. It is
      important to identify "natural helpers" and "natural community resources," such
      as churches and adult centers within the community and to assess the actual and
      potential contributions and needs of these resources.

PMID- 10340228
TI  - The difficulties of women living with HIV infection.
AB  - Eighty women described the most difficult aspects of living with HIV infection.
      Content analysis revealed four themes: fear, limitation, symptoms, and emotions.
      Fears related to disclosure and stigma were more frequently described than fears
      of dying. Limitations were financial, sexual/reproductive, and physical. The
      physical limitations were related to the presence of symptoms leading to a wide
      range of emotions.

PMID- 10340229
TI  - The pitfalls of the Golden Rule in caregiving.

PMID- 10340230
TI  - Objective and subjective conceptualizations of social support.

PMID- 10340231
TI  - Transsexualism: a review of etiology, diagnosis and treatment.
AB  - Transsexualism is considered to be the extreme end of the spectrum of gender
      identity disorders characterized by, among other things, a pursuit of sex
      reassignment surgery (SRS). The origins of transsexualism are still largely
      unclear. A first indication of anatomic brain differences between transsexuals
      and nontranssexuals has been found. Also, certain parental (rearing) factors seem
      to be associated with transsexualism. Some contradictory findings regarding
      etiology, psychopathology and success of SRS seem to be related to the fact that
      certain subtypes of transsexuals follow different developmental routes. The
      observations that psychotherapy is not helpful in altering a crystallized cross
      gender identity and that certain transsexuals do not show severe psychopathology
      has led clinicians to adopt sex reassignment as a treatment option. In many
      countries, transsexuals are now treated according to the Standards of Care of the
      Harry Benjamin International Gender Dysphoria Association, a professional
      organization in the field of transsexualism. Research on postoperative
      functioning of transsexuals does not allow for unequivocal conclusions, but there
      is little doubt that sex reassignment substantially alleviates the suffering of
      transsexuals. However, SRS is no panacea. Psychotherapy may be needed to help
      transsexuals in adapting to the new situation or in dealing with issues that
      could not be addressed before treatment.

PMID- 10340232
TI  - The Illness Attitude Scales in chest pain patients: a study of psychometric
      properties.
AB  - The main aim of the study was to assess the factorial structure of the Illness
      Attitude Scales (IAS). The study population comprised 199 patients referred to
      cardiological out-patient investigation because of chest pain. The factor
      analysis revealed three factors of the IAS. Accordingly, we found three
      subscales, interpreted as health anxiety (HA), illness behavior (IB), and health
      habits (HH). The internal consistency of the subscales, measured by Cronbach's
      alpha coefficient, were 0.92, 0.80, and 0.49, respectively. The HA and IB scores
      were significantly intercorrelated (r = 0.39, p < 0.001), but HH was not
      significantly correlated with either HA or IB. The HA and IB subscales
      discriminated between patients with and without panic disorder. The results
      support previous findings, namely that the IAS comprise two subscales with
      psychometrically sound properties. Correlational analysis indicated validity of
      the two subscales. Further studies are needed to confirm the validity.

PMID- 10340234
TI  - Presentation, management and course of angina and suspected angina in primary
      care.
AB  - Previous surveys may have underestimated both prevalence and incidence of
      ischemic heart disease in general practice. Case identification is difficult, as
      many patients presenting with chest pain turn out not to have ischemic heart
      disease, although their outcome is unclear otherwise. In this work we aimed to:
      (1) estimate prevalence and incidence of angina in one Oxford general practice;
      (2) describe the processes of assessment, investigation, and management of
      suspected angina; and (3) describe the 2-year symptomatic and functional outcome
      of angina patients, compared with patients whose provisional diagnosis of
      suspected ischemic heart disease (IHD) was not subsequently sustained (NCCP). A
      retrospective survey of patients was undertaken (aged 45-74 years) by hand
      searching paper and electronic medical records to find, as of 1 January 1992, all
      patients in the practice with continuing treatment of angina diagnosed before
      1989, or those having a new diagnosis of angina being assessed (suspected angina)
      in the 3 year 1989-1991. Two years later, a postal questionnaire survey compared
      the symptomatic and functional outcome of confirmed IHD and NCCP. On 1 January
      1992, the diagnosis of angina was recorded in the notes of 11.1% of patients aged
      45-74 years, and the diagnosis was considered correct in 7.4%. Over a 3-year
      period, 129 people was suspected of suffering from angina, but in 71 (55%) the
      diagnosis was not confirmed; 76 (59%) were either referred to a specialist out
      patient clinic or had an emergency admission. A 2-year follow-up found that
      similar proportions of patients with angina and noncardiac chest pain had a poor
      outcome in terms of symptoms, mental state, quality of everyday life, and
      continuing consultation. The clinical burden of ischemic heart disease in general
      practice has been underestimated by earlier methodological approaches using less
      complete ascertainment strategies. The adequacy of current diagnostic and
      management arrangements for patients with suspected angina merits review, at both
      the primary and secondary care levels.

PMID- 10340233
TI  - The concept of "sense of coherence" and the development of posttraumatic stress
      disorder in traffic accident victims.
AB  - According to the "sense of coherence" concept, those subjects who can give
      meaning to a traumatic event can comprehend what has happened and have a sense of
      manageability of the sequelae, are able to cope better with the traumatic event
      itself. In the present study, this concept was applied to traffic accident
      victims. Severely injured traffic accident victims were assessed a few days after
      the accident and at 6-month follow-up. At follow-up, patients filled in the 29
      item version of the Sense of Coherence (SOC) self-rating scale. The results show
      that the SOC total score correlated negatively with the development of: (i)
      posttraumatic psychopathology; (ii) psychological disorders (i.e., posttraumatic
      stress disorder after the accident); and (iii) anxious cognitions. The
      personality trait of neuroticism correlated negatively and extraversion and
      frustration tolerance correlated positively with SOC total score. Previous
      hypotheses are supported by our findings.

PMID- 10340235
TI  - Psychiatric and social outcome following liver transplantation for alcoholic
      liver disease: a controlled study.
AB  - Psychiatric outcome, quality of life, and alcohol consumption were compared
      between patients transplanted for alcoholic liver disease and those transplanted
      for other chronic liver diseases. Instruments used included the Clinical
      Interview Schedule, the 28-item General Health Questionnaire, the Hospital
      Anxiety and Depression Scale, and the Nottingham Health Profile. There was no
      difference between the two groups with regard to median scores or "caseness" on
      these instruments, except for physical mobility on the Nottingham Health Profile,
      where the alcoholic group was more likely to experience difficulties (p = 0.03).
      The majority of those transplanted for alcoholic liver disease remained
      abstinent, although 7 of the 31 in the alcoholic group (23%) were drinking above
      recommended safe limits. Psychosocial outcome is similar for individuals
      transplanted for alcoholic liver disease and those transplanted for other chronic
      liver diseases. Patients should not be excluded from transplantation on grounds
      of their drinking history.

PMID- 10340236
TI  - Symptomatic myocardial ischemia and everyday life: implications for clinical use
      of interactive monitoring.
AB  - In coronary heart disease (CHD), pathological myocardial ischemic changes do not
      always occur with the symptom of heart pain. Methodological problems make it
      difficult to examine the factors that influence silent and symptomatic myocardial
      ischemia in everyday life. This study uses a computer-assisted monitoring system
      with an interactive Holter ECG, an actometer, and an electronic diary. Self
      report measurements indicate that symptomatic patients tend toward increased
      neuroticism, whereas asymptomatic patients engage in beneficial and active coping
      skills more frequently. The results of the monitoring study demonstrate the same
      degree of ischemia in silent and symptomatic episodes. However, these episodes
      show differences in certain psychological context variables. Symptomatic episodes
      are linked to high subjective strain and severe tension. Because angina pectoris
      is not a reliable warning signal of myocardial ischemia, the use of the
      interactive monitoring system is recommended for educating CHD patients on how to
      cope with excessive strain in everyday life.

PMID- 10340237
TI  - Coping with amputation and phantom limb pain.
AB  - Phantom limb pain is a common, distressing phenomenon that can occur after the
      amputation or denervation of a part of the body. No conclusive etiological models
      or theories have emerged, although the problem was identified some time ago. This
      empirical-diagnostic study deals with correlations between coping with limb loss,
      body image, and the occurrence of phantom limb pain. It is based on Melzack's
      concept of a neuromatrix. Coping strategies were evaluated using semistructured
      interviews and analysis of patients' drawings of their body images. The results
      of the study, based on 43 amputees, show a significant association between coping
      strategies and pain. Patients who cope better with the loss suffer less from
      phantom limb pain. A difference can also be noted in subjective representation of
      the body image: patients suffering from phantom limb pain tend to have an image
      of their bodies as a complete and undamaged entity.

PMID- 10340239
TI  - Early postnatal depressive mood: associations with obstetric and psychosocial
      factors.
AB  - The central purpose of this investigation was to detect incidence and influencing
      factors on early postnatal depressive mood in a large hospital sample. By means
      of an interview we acquired information on sociodemographic data, physical and
      psychiatric anamnesis, and obstetric and psychologic variables. The Edinburgh
      Postnatal Depression Scale (EPDS) served to determine the depressive mood of our
      patients. The interview was carried out on 1250 women at two postnatal wards 5
      days after delivery. According to the results of the German validation of the
      EPDS, where a cutoff of 9/10 indicates at least mild depressive disorder, the
      whole sample was divided into group A (EPDS score < or = 9; n = 996, 79.7%) and
      group B (EPDS score > or = 10; n = 254, 20.3%). Early postnatal depressive mood,
      as assessed by the EPDS, appeared with 20% of all women taking part in our
      investigation on the fifth postnatal day. Subjective measurements such as high
      childbirth burden, elevated trait anxiety, low life satisfaction and lower social
      class, and low birth weight of the infant seem to be of predominant relevance for
      early postnatal depressive mood.

PMID- 10340238
TI  - Serum cholesterol decline and depression in the postpartum period.
AB  - We examined the relation between total serum cholesterol decline and depression
      in the postpartum period in a prospective study of 266 Dutch women, who were
      followed until 34 weeks after delivery. The decline in serum cholesterol between
      week 32 of pregnancy and week 10 postpartum was similar for women who became
      depressed (n = 63) in the subsequent period and women who did not (difference,
      0.10 mmol/l; 95% confidence interval [CI] -0.16 to 0.37). Adjusting for age,
      multiparity, education level, smoking status, concurrent illness, and social
      support, the odds ratio of depression was 1.4 (95% CI, 0.64 to 2.9) for women in
      the highest tertile of serum cholesterol decline and 0.61 (95% CI, 0.28 to 1.3)
      for women in the intermediate tertile, as compared with women in the lowest
      tertile. Our results do not support the hypothesis that rapid serum cholesterol
      decline increases risk of depression in the postpartum period.

PMID- 10340240
TI  - Personality dimensions in chronic fatigue syndrome and depression.
AB  - Chronic fatigue syndrome (CFS) is a poorly understood condition. Possible
      etiological factors include infectious agents, psychiatric disorders, and
      personality characteristics. We examined personality dimensions in 30
      nondepressed patients with CFS, 20 patients with major depressive disorder (MDD),
      and 15 healthy controls. On the NEO-FFI, patients with CFS scored significantly
      lower than healthy controls on the extroversion subscale. On the neuroticism
      dimension of the Eysenck Personality Questionnaire (EPQ), patients with MDD
      scored higher than those with CFS, who in turn scored significantly higher than
      the healthy controls. CFS patients rated themselves as higher on neuroticism and
      less extroverted when ill than when they were well. Our results suggest that high
      scores on neuroticism and low scores on extroversion in CFS could be a reaction
      to chronic illness.

PMID- 10340241
TI  - INTERMED: a tool for controlling for confounding variables and designing
      multimodal treatment.

PMID- 10340242
TI  - What is your diagnosis? Post-rabies-vaccination alopecia.

PMID- 10340243
TI  - Is it possible to diagnose canine hypothyroidism?
AB  - A definitive diagnosis of hypothyroidism can be difficult because of the many
      clinical abnormalities associated with thyroid hormone deficiency, and the lack
      of readily available diagnostic tests with high sensitivity and specificity.
      Thyroid function tests should be performed only in dogs with clinical findings
      consistent with hypothyroidism. Measurement of serum total thyroxine (T4)
      concentration is a useful initial screening test since most hypothyroid dogs have
      values below the reference range. Serum free T4 concentration measured by
      equilibrium dialysis is a more sensitive and specific test of thyroid function
      than total T4 and is particularly useful in dogs with non-thyroidal illness or
      atypical clinical signs. Measurement of serum endogenous thyroid-stimulating
      hormone concentration is also helpful, but many hypothyroid dogs have normal
      results. The gold standard for diagnosis of hypothyroidism remains the thyroid
      stimulating hormone response test. It should be used to confirm hypothyroidism
      when other tests do not agree with the clinical impression or if atypical signs
      or non-thyroidal illness exist or there has been administration of drugs known to
      alter thyroid function tests. Ultimately, a positive response to treatment is
      expected in hypothyroid dogs treated appropriately with levothyroxine.

PMID- 10340244
TI  - Compliance with short-term oral antibacterial drug treatment in dogs.
AB  - Compliance with a 10-day course of oral antibacterial drugs in dogs being treated
      as outpatients at a veterinary clinic was assessed by use of pill count data
      obtained by telephone interview. The association between compliance and several
      possible determinants of compliance was investigated. Ninety-five animal owners
      were included in the study, with 44 per cent reporting 100 per cent compliance
      with the treatment regimen and as many as 88 per cent reporting a compliance
      level of 80 per cent or more. The compliance level was significantly higher (P <
      0.002) when the animal owners felt that the veterinarians spent enough time on
      the consultation. Moreover, compliance was significantly higher (P < 0.05) for
      dogs being treated for gastrointestinal infections compared with those being
      treated for other diseases.

PMID- 10340245
TI  - Miconazole/chlorhexidine shampoo as an adjunct to systemic therapy in controlling
      dermatophytosis in cats.
AB  - A 2 per cent miconazole/2 per cent chlorhexidine shampoo was used in two groups
      of Persian cats infected with Microsporum canis. In the first group, the cats
      were treated with griseofulvin alone while, in the second, griseofulvin was used
      with the shampoo. The clinical signs of the cats were scored on a scale of 1 to 4
      for seborrhoea, ease of epilation of hair and the extent of primary lesions, to
      try to give an overall impression of hair coat condition. The speed of resolution
      of the infection was assessed in terms of time to mycological cure. Samples were
      taken from the environment of both groups to assess the degree of environmental
      contamination at the end of treatment. No statistically significant difference
      was found between the two groups for time to mycological cure, although the
      lesion scores in the second group decreased significantly more quickly than those
      of the first group. Additionally, no dermatophytes were cultured from the
      environment in the second group at the end of the study.

PMID- 10340246
TI  - Transitional lumbosacral vertebral anomaly in the dog: a radiographic study.
AB  - Transitional lumbosacral vertebral anomalies have for some time been suggested as
      a possible cause of cauda equina syndrome (especially in the German shepherd dog
      [GSD]), a condition recently thought to be inherited. The frequency of this
      condition within a large clinical population and the radiographic features used
      in its detection are reported. In a group of 143 patients, the sexes were
      similarly represented and the GSD was greatly overrepresented. The anomaly is
      characterised by separation of the first sacral segment that was identified on
      the lateral view by the presence of a radiolucent disc space between what are
      normally the first and second sacral segments. On the ventrodorsal view, the
      anomaly was characterised by separation of the spinous processes between what are
      normally the first and second sacral segments. In the presence of the
      transitional segment, the nature of the sacroiliac joint at the level of the
      anomalous segment varies from a strong ilial attachment, with the presence of a
      wing-like lateral process, to a weakened ilial attachment because of the presence
      of a lateral process, shaped as that seen on a lumbar segment. These patterns
      were present unilaterally or bilaterally and result in symmetrical or
      asymmetrical patterns. The effect of the weakening of the sacroiliac attachment
      was thought to result in premature disc degeneration, which, together with spinal
      canal stenosis, resulted in potential compression of the overlying spinal nerves
      and creation of a cauda equina syndrome. The condition is thought to have
      clinical significance and should be selected against in breeding, especially in
      the GSD.

PMID- 10340247
TI  - Subdural injection of contrast medium as a complication of myelography.
AB  - In a retrospective evaluation of 654 canine and feline myelograms, 58 were found
      to have been complicated by injection of the contrast medium into the subdural
      space. The medium was present predominantly dorsal to the spinal cord, with a
      sharp dorsal border and an undulating ventral border. Confirmation that this
      myelographic appearance was due to subdural localisation was achieved using fresh
      cadavers injected with contrast medium labelled with Indian ink. It was further
      showed that the dorsal accumulation of contrast medium was due to the denticulate
      ligaments which restricted the ventral extension of the contrast medium.

PMID- 10340249
TI  - Vaginal position and length in the bitch: relationship to spaying and urinary
      incontinence.
AB  - A study was undertaken to determine if the vagina might be a suitable site for
      the measurement of intra-abdominal pressure during cystometry in the bitch. The
      position of the cranial vagina and vaginal length were measured radiographically
      and the effects of spaying and urinary incontinence on these variables were
      evaluated in 30 continent and 30 incontinent bitches. The study used retrograde
      vaginourethrograms which had been obtained from animals used in a previous study.
      The cranial vagina was intra-abdominal on 36 of the vaginourethrograms, being
      least commonly intra-abdominal in incontinent bitches (11/30). Vaginal position
      was related linearly to vaginal length and continence status (P < 0.01), while
      its length was related to bodyweight (P < 0.01). Allowing for bodyweight,
      neutered animals had significantly shorter vaginas than entire bitches (P <
      0.01). Measurement of intra-abdominal pressure with concomitant measurement of
      intravesical pressure is essential if accurate assessment of detrusor pressure is
      to be determined during cystometry. The vagina is unlikely to be a useful
      location from which to measure intra-abdominal pressure since any pressure
      measuring catheter inserted into it may fall outside the abdominal pressure zone.
      This is particularly true of neutered and/or incontinent bitches, the groups in
      which urodynamic investigations of urinary incontinence are most frequently
      indicated.

PMID- 10340248
TI  - Effect of body position on ultrasonographic estimations of bladder volume.
AB  - A study was undertaken to determine the effect of body position on
      ultrasonographic bladder measurements and volume estimations. Of the 42 dogs
      studied, 15 were fresh canine cadavers without urological disease and the
      remaining 27 were undergoing investigations for disorders of the lower urinary
      tract. Bladder volume was estimated using a formula described previously.
      Irrespective of whether all dogs were considered together or only live animals
      were included, measurements made in dorsal recumbency tended to underestimate
      bladder volume while those made in right lateral recumbency resulted in
      overestimation. This was due to significant differences in all linear
      measurements, apart from width, between body positions. Measurements in right
      lateral recumbency were higher than those in dorsal recumbency. In all animals
      and in living dogs alone, bladder measurements in dorsal recumbency appeared to
      give a more accurate estimation of actual bladder volume.

PMID- 10340250
TI  - Idiopathic pulmonary fibrosis in a Staffordshire bull terrier with
      hypothyroidism.
AB  - Radiographic evidence of chronic interstitial lung changes, usually believed to
      be attributable to lung fibrosis, is readily recognised in canine practice.
      Furthermore, there is a body of anecdotal evidence suggesting that a specific
      clinical entity consistent with chronic lung fibrosis occurs in specific breeds
      of terrier dogs. However, there is little pathological data to confirm these
      radiographic and clinical findings and, therefore, chronic interstitial lung
      disease of dogs is poorly characterised. In this report, a case of chronic
      pulmonary fibrosis is described in which histopathological confirmation was
      possible, and suggested that the condition might be analogous to idiopathic
      pulmonary fibrosis (cryptogenic fibrosing alveolitis) in humans.

PMID- 10340251
TI  - Canine idiopathic epilepsy.

PMID- 10340252
TI  - The 'dalmatian dilemma': white coat colour and deafness.

PMID- 10340253
TI  - Appropriate or inappropriate: is there a need for clinical ethics committees?

PMID- 10340255
TI  - Improving geriatric services.

PMID- 10340254
TI  - The diagnosis of dying.

PMID- 10340256
TI  - Commitment to complementary medicine: politically correct lip service or co
      ordinated strategy?

PMID- 10340257
TI  - The modern treatment of ventricular arrhythmias: drugs or defibrillators.

PMID- 10340258
TI  - Impact of molecular genetics on clinical cardiology.

PMID- 10340259
TI  - Acute myocardial infarction. Extended review.

PMID- 10340260
TI  - Time for sharing responsibility in caring.

PMID- 10340261
TI  - A Black look at the independent inquiry into inequalities in health.

PMID- 10340262
TI  - Evidence-based medicine and the district general physician.

PMID- 10340263
TI  - Improving geriatric services: sources of help. Advice from the Royal College of
      Physicians Committee on Geriatrics.

PMID- 10340264
TI  - Hospital readmission among older medical patients in Hong Kong.
AB  - OBJECTIVE: To study the risk factors for hospital readmission among older medical
      patients in Hong Kong. DESIGN: Cohort study. SUBJECTS: 1,204 consecutive hospital
      medical patients aged 70 years and over in Hong Kong. PROCEDURES: Subjects were
      interviewed by a research nurse on discharge, and were followed up for six
      months. OUTCOME: Unplanned hospital readmissions were identified and classified
      as avoidable or unavoidable. The risk factors for early (within 28 days),
      recurrent (three or more) and avoidable readmissions were studied by multiple
      logistic regression. RESULTS: Four hundred and fifty-five patients (37.7%) had at
      least one readmission in six months; 18%, 6.4%, and 2.9% of subjects had early,
      recurrent and avoidable readmissions respectively. Recent hospital stay predicted
      all types of readmissions. Early readmission was predicted by length of stay,
      Barthel index (assessment of physical and mental function) and unresolved medical
      problems. Recurrence readmission was predicted by poor family support, residence
      in a home for the elderly and unresolved medical problems. CONCLUSIONS: Hospital
      readmission may be prevented by ensuring adequate length of stay, so that medical
      problems are resolved before discharge.

PMID- 10340265
TI  - Coronary stenting in routine interventional practice.
AB  - BACKGROUND: Coronary stents have revolutionised interventional cardiology,
      providing a 'bail-out' option when angioplasty results are unsatisfactory, and
      reducing the risk of restenosis. However, despite the results of randomised
      trials, concerns have been expressed about whether stent insertion is cost
      effective in routine clinical practice. METHODS: The notes of 356 patients who
      underwent stent insertion in Oxford between January 1996 and March 1997 were
      examined. Long-term follow-up information was obtained from questionnaires sent
      to general practitioners and patients. RESULTS: The procedure was successful in
      327 (92%) cases. Eighteen (5.1%) patients suffered a serious coronary
      complication, and 13 (3.7%) a bleeding complication. Over the year following
      stent insertion, 238 (83%) of the 286 patients followed-up had suffered no
      coronary event, and 88% were in Canadian Cardiovascular Society (CCS) angina
      class II or below (slight limitation of normal daily activity at worst).
      CONCLUSION: Whilst the initial cost of stent insertion is considerably greater
      than that of angioplasty alone, it reduces the need for high risk emergency
      bypass surgery or redo percutaneous intervention. Stent insertion thus represents
      a clear advantage for patients who have unsatisfactory angioplasties and may be a
      more cost-effective option.

PMID- 10340266
TI  - A cyberclinic in rheumatology.
AB  - OBJECTIVE: To evaluate the feasibility of a rheumatology consultation and
      advisory service using internet and e-mail. METHODS: We placed a detailed
      rheumatology proforma on our website for general practitioners to complete and e
      mail to our outpatients clinic. To study its feasibility, two junior doctors
      interviewed and completed the proforma for 207 new patients. Based on this
      information, the consultant provided provisional diagnoses, work up & management
      plans, which were then compared with those drawn up following face-to-face
      assessment of the same patients in the outpatients clinic. RESULTS: In most
      instances the pre- and post-examination diagnoses, work up & management plans
      were similar. Diagnostic concurrence was noted in 178 (86%) patients; no changes
      were required in x-rays and other tests requested in 129 (62%) patients; and the
      suggested treatment (including corticosteroid injections) remained the same in
      153 (74%) patients. CONCLUSION: Our results suggest that it is feasible to offer
      an e-mail or internet based outpatients consultation and advisory service in
      rheumatology and possibly other disciplines.

PMID- 10340267
TI  - A training course for the UEB examination. The case for retaining an examination
      for overseas doctors excluded from practising in the UK.
AB  - BACKGROUND: Some overseas medical graduates choose to take the United Examining
      Board (UEB) examination to achieve UK registration; others have no other option.
      We have devised a course for overseas doctors who wish to re-qualify via this
      route. THE COURSE: Eighteen doctors enrolled during 1995-1997; all passed the UEB
      examination. Regular formative assessment allowed us to identify students
      adequately prepared to pass the examination. The main predictor of examination
      outcome was performance in a mock examination. Gender, residential status and
      interval since original qualification were not predictive. The eight doctors
      whose primary medical course was conducted in a language other than English did
      not seem to be disadvantaged. OUTCOME: Successful examinees obtained pre
      registration house officer posts without delay; one has since passed the full
      MRCP (UK) and another MRCP Part I. All but one of the intend to pursue their
      medical careers in the UK. SUMMARY: After a structured course (average 9.5
      months) at this medical school, selected overseas doctors can reach a standard
      appropriate to a UK primary qualifying examination. These findings have
      implications for overseas doctors living here and not practising, as well as for
      those concerned with expanding the UK medical workforce.

PMID- 10340268
TI  - Rough guide to organising the MRCP examination.

PMID- 10340269
TI  - Alcohol and the young. What problem? Whose problem?

PMID- 10340270
TI  - The challenge of HIV/AIDS in Sub-Saharan Africa.
AB  - At the end of 1998, an estimated 67% of people living with HIV/AIDS in the world
      were in Sub-Saharan Africa--some 22.5 million people. The challenges posed by the
      HIV/AIDS epidemic in this resource--poor region are enormous. The most important
      is to reduce the number of new infections: simple interventions such as barrier
      methods of contraception and better treatment of sexually transmitted diseases
      must be implemented now whilst waiting for an effective vaccine. There is also a
      need to understand more comprehensively the clinical spectrum and natural history
      of the disease in the region. However, with an ever-growing demand for care
      caused by HIV/AIDS, probably the most compelling yet insoluble challenge is how
      to provide wider access to very costly specialist services, including
      antiretroviral therapy.

PMID- 10340271
TI  - Developing countries need general physicians.

PMID- 10340272
TI  - Sleep apnoea.

PMID- 10340273
TI  - Cardiac risk for non-cardiac surgery.

PMID- 10340274
TI  - Cardiac risk for non-cardiac surgery.

PMID- 10340275
TI  - Setting health priorities.

PMID- 10340276
TI  - Cardiopulmonary resuscitation training.

PMID- 10340277
TI  - No harm done?

PMID- 10340278
TI  - Alzheimer's disease.
AB  - This article reviews the clinical and neuropathological features of Alzheimer's
      disease, its known genetic and non-genetic risk factors, procedures used to make
      the diagnosis and rule out other reversible and non-reversible forms of dementia,
      and the treatment strategies used to help patients and their families cope with
      the problem. In addition, it considers how neuroimaging techniques promise to
      characterize the brain changes which precede the onset of cognitive impairment in
      persons at risk for Alzheimer's disease and identify treatments to prevent the
      onset of dementia.

PMID- 10340279
TI  - Hormone replacement therapy and Alzheimer's disease.
AB  - There is ample evidence to show the beneficial effect of estrogen on the risk and
      course of Alzheimer's disease (AD). Estrogen may play a role in the
      pathophysiology of AD through improvement of cerebral blood flow, stimulation of
      the neuron or gliacyte and interaction with genetic factors. Most etiological
      studies of estrogen replacement therapy and AD have been retrospective studies.
      In these studies, the history of estrogen use was obtained from an informant,
      limiting the validity of the findings. Of the three follow-up studies conducted
      to date, one has failed to show a protective effect. There is some evidence for a
      synergistic effect between estrogen and the genetic factors involved in AD.
      However, up until now, studies of estrogen replacement therapy have generally
      been too small and of low validity. Large scale, long-term population studies may
      clarify the role of estrogen replacement therapy in the prevention and therapy of
      AD.

PMID- 10340280
TI  - The Danish Osteoporosis Prevention Study (DOPS): project design and inclusion of
      2000 normal perimenopausal women.
AB  - OBJECTIVE: In 1990 we initiated a 20 year, partly randomised study (Danish
      Osteoporosis Prevention Study, DOPS) in order to (a) evaluate clinical,
      biochemical and osteodensitometric variables as predictors of low bone mass and
      future osteoporotic fractures, and (b) test the hypothesis, that hormone
      replacement therapy (HRT) initiated shortly after menopause reduces the risk of
      later osteoporotic fractures. This report describes study design and baseline
      characteristics of the DOPS-cohort. METHODS: The study design is pragmatic,
      attempting to mimic the normal clinical situation. Several HRT alternatives are
      available according to clinical need. It was considered futile, impractical and
      unethical to use placebo for 20 years. Instead the study focus on hard endpoints
      (fractures) confirmed by independent persons (peripheral fractures) or by methods
      which allow investigator blinding (spinal X-rays). Statistical evaluation will
      focus on intention to treat analyses evaluating the decision of HRT and it's
      feasibility. With a compliance of 60% we will have sufficient statistical power
      (88%) to detect a fracture reduction of 40% in the treatments group. Clinical
      risk factors, current daily intakes of macronutrients, vitamins and minerals,
      anthropometric variables, biochemical variables (including bone markers and 25
      hydroxyvitamin D), regional bone mineral density (BMD) and total body composition
      were assessed in all participants at entry and at various follow up intervals.
      RESULTS: 2016 study participants were recruited by direct mailing to a random
      sample of 45-58 years old women. In the randomised arm 501 were allocated to HRT
      and 505 to no treatment. In the non-randomised arm 219 preferred HRT and 791
      preferred no treatment. Post-randomisation analysis revealed a slight but
      significant difference in age (50.01 versus 50.44 years) but no difference in
      menopausal age, prevalence of hysterectomy, educational level, BMI, serum bone
      alkaline phosphatase, serum osteocalcin, urine hydroxyproline or serum 25
      hydroxyvitamin D. In the non-randomised arm women preferring HRT were closer to
      menopause, had a higher prevalence of hysterectomy, were better educated, were
      leaner, and had lower bone turnover than the women, who refused HRT. CONCLUSION:
      It is possible to include a sufficient number of perimenopausal women in a
      randomised 20 year study on the antifracture effect of HRT.

PMID- 10340281
TI  - Stiffness index identifies patients with osteoporotic fractures better than
      ultrasound velocity or attenuation alone.
AB  - OBJECTIVES: To compare a composite ultrasonometry variable, the stiffness index
      (SI), with its two component variables of speed of sound (SOS) and broadband
      ultrasound attenuation (BUA), in identifying post-menopausal women with low bone
      mineral density (BMD) and/or osteoporotic fracture. METHODS: A cross sectional
      sample of 1217 women (mean (S.D.) age 53.9 (9.7) years) was studied. Risk factors
      for osteoporosis were assessed by detailed questionnaire and women with diseases,
      or those taking treatments known to affect bone metabolism were excluded. Women
      were allocated to one of four groups: pre-menopausal women (n = 476), healthy
      post-menopausal women (n = 583), post-menopausal women with low BMD (n = 101),
      and post-menopausal women with osteoporotic fracture (n = 57). An Achilles
      ultrasonometer was used to perform quantitative ultrasonometry (QUS) at the os
      calcis. The SI. calculated mathematically from SOS and BUA, was computed.
      RESULTS: Analysis of receiver operating curves (ROC) between healthy post
      menopausal women and post-menopausal women with low BMD but no fracture, showed
      that the area under the curve (AUC) for SI was significantly greater than that
      for BUA (P < 0.001) or SOS (P < 0.05). For healthy post-menopausal women compared
      to women with fracture, the area AUC for SI was significantly greater than that
      for BUA (P < 0.05) or SOS (P < 0.001). No significant difference was found for
      AUC between BUA and SOS. CONCLUSION: QUS variables discriminated women with low
      density or fracture from healthy postmenopausal controls. The SI was a
      significantly better indicator than BUA or SOS in this retrospective study.

PMID- 10340282
TI  - Quality of life in endometrial cancer survivors.
AB  - OBJECTIVE: The aim of this study was to evaluate the health-related quality of
      life in survivors of endometrial cancer (EC); and to identify common problems
      that they may encounter, in the hope of paving the way to improving their quality
      of life. STUDY DESIGN: We investigated and compared the health conditions and
      quality of life between EC survivors and the general population as a control
      group. There were 61 EC patients who were at clinical stage I-III and survived
      for 5-7 years after the primary treatments. The control group was composed of 527
      healthy postmenopausal women. All of them completed a self-evaluated
      questionnaire pertaining to personal conditions, medical surveillance, individual
      well-being and quality of life. RESULTS: The EC survivors were divided into two
      groups: an older group (n = 34) and a younger group (n = 27). The latter was
      compared with the controls. In general, most of the EC survivors were old, low
      educated women. The majority of them were in a poor condition. They were
      inactive, received medical surveillance and had regular medication. The
      distribution of various complications was higher in the older EC group while the
      climacteric symptoms were more common in the younger EC group. In both EC groups,
      the quality of life was lower than in the controls. The prevalence of somatic
      symptoms was higher in the older EC survivors and psychological problems were a
      common complaint of the younger EC survivors. CONCLUSION: The quality of life was
      poor in the EC survivors. To improve their life quality, earlier psychological
      counseling should be offered to EC survivors, in particular to younger and single
      women, and hormone replacement therapy (HRT) should be recommended, but on a
      selective basis, to those patients at low risk of cancer recurrence.

PMID- 10340283
TI  - Endometrial cancer after combined hormone replacement therapy.
AB  - OBJECTIVE: It has been suggested that exposure to relatively high levels of
      unopposed estrogen is a risk factor for endometrial cancer. Combined therapy of
      estrogen with cyclic progestagen was therefore highly recommended for menopausal
      women with an intact uterus. METHODS: The cases of two postmenopausal women who
      developed endometrial cancer after taking continuous sequential HRT for 15 months
      are reported. Both were without bleeding for more than 2 years and presented with
      a normal vaginal ultrasound. They had severe menopausal symptoms and asked for
      HRT. RESULTS: After 15 months irregular bleeding occurred and a hysterectomy was
      performed. The pathohistological finding in both cases was endometrial cancer. As
      we measured the serum estradiol levels 4 h after tablet ingestion
      supraphysiologic values ranging between 418 and 442 pg/ml were found. CONCLUSION:
      Our report strengthens the evidence that supraphysiologic estradiol levels
      despite combination with cyclic progestagen therapy, increase the risk of
      endometrial cancer.

PMID- 10340284
TI  - Finnish physicians' opinions of vaginal estriol in self-care.
AB  - OBJECTIVE: In Finland vaginal estriol drugs became available without prescription
      in 1992, resulting in widespread advertising of these drugs to lay women and in
      an increase in sales. The purpose of this study was to find out what Finnish
      physicians think about the fact that vaginal estriol does not require a
      prescription, and if they have found any problems resulting from this. METHODS: A
      questionnaire survey was sent to gynecologists and general practitioners (n =
      341, 77% response rate) in Finland in 1996. RESULTS: 60% of the physicians
      considered vaginal estriol to be suitable for over-the-counter (OTC) status, and
      to be much more suitable than the other estrogen containing drugs (contraceptive
      pill and drugs for emergency contraception) we asked about in our study. Opinions
      varied by specialty, work experience and reported problems relating to OTC
      status. The most common reasons given for suitability referred to increased
      access, and those given for unsuitability referred to general dangers of self
      care. Of all physicians 12%, and of private gynecologists (n = 33) 49% reported
      having observed problems with the OTC status, mostly in care-seeking and
      indications; some gynecologists mentioned adverse effects of the drug itself. 39%
      of the physicians thought that the best person to provide information about
      vaginal estriol is a physician. CONCLUSIONS: Pharmacological literature and
      physicians' opinions suggest a re-evaluation of the role of physician
      surveillance of vaginal estriol drugs.

PMID- 10340286
TI  - Is there a role for leukocyte and CRP measurements in the diagnosis of acute
      appendicitis in the elderly?
AB  - OBJECTIVES: The diagnosis of acute appendicitis is still difficult and the
      results are unsatisfactory in three particular patient groups: in children, in
      fertile-age women and in elderly patients. As our population ages, the challenge
      for expedient diagnosis and intervention in older age groups will become more and
      more significant. The present study aimed at clarifying the role of leukocyte
      count and C-reactive protein (CRP) measurements in the diagnosis of acute
      appendicitis in the elderly. In particular, are there patients with acute
      appendicitis but unelevated leukocyte count and CRP? METHODS: Eighty-three
      consecutive elderly patients underwent appendectomy for suspected acute
      appendicitis. The mean leukocyte count and CRP value were calculated in patients
      with an uninflamed appendix (group A) and in those with acute appendicitis (group
      B). The percentages of patients with: (1) both values unelevated; (2) only
      leukocyte count elevated; (3) only CRP value elevated; (4) both values elevated
      were calculated within the groups A and B. RESULTS: There was no statistically
      significant difference in leukocyte counts or CRP values between patients with an
      uninflamed appendix (group A) and those with acute appendicitis (group B). When
      the patients were divided into the four subgroups, the most conspicuous finding
      was that group B (acute appendicitis, n = 73) contained no patients with both
      values unelevated. CONCLUSIONS: Although elevated leukocyte count and CRP value
      cannot effectively establish the diagnosis of acute appendicitis in the elderly,
      unelevated values exclude it. Accordingly, appendectomy is not recommended to be
      performed in an elderly patient with unelevated leukocyte count and CRP value,
      although clinical symptoms and signs indicate acute appendicitis.

PMID- 10340285
TI  - Estrogen replacement therapy decreases platelet-activating factor-acetylhydrolase
      activity in post-menopausal women.
AB  - OBJECTIVE: To examine the effects of estrogen replacement therapy on plasma
      platelet-activating factor-acetylhydrolase (PAF-AH) activity and the lipoprotein
      profile in post-menopausal women. METHOD: Eight post-menopausal women received
      conjugated equine estrogen (0.625 mg/day) orally for a period of 10 weeks. PAF-AH
      activity and lipid levels were measured in plasma samples obtained from each
      subject prior to treatment and after 2, 6, and 10 weeks of estrogen therapy.
      RESULTS: Within 2 weeks of initiating estrogen treatment, a significant reduction
      in PAF-AH activity (-26%) was observed. Estrogen also caused significant
      decreases in total cholesterol (-8%), low-density lipoprotein-cholesterol (-24%),
      and the ratio of apolipoprotein B to A-II (-19%). On the other hand, levels of
      both high-density lipoprotein-cholesterol (18%) and triglyceride (31%) were
      elevated. CONCLUSION: Estrogen exerts a favorable effect on the lipoprotein
      profile, but decreased plasma PAF-AH activity may facilitate platelet aggregation
      thereby opposing protective effect of estrogen-replacement therapy with respect
      to thrombotic complications.

PMID- 10340287
TI  - A proposal for the locus of metformin's clinical action: potentiation of the
      activation of pyruvate kinase by fructose-1,6-diphosphate.
AB  - Reduction of hepatic glucose output has been shown to be the chief basis for
      metformin's clinical benefit in diabetes, and the balance of the evidence
      suggests that this reflects inhibition of gluconeogenesis. Recent research with
      hepatocyte cell cultures demonstrates increased flux through pyruvate kinase in
      metformin-treated cells. An analysis of the conditions under which clinically
      relevant concentrations of metformin inhibit gluconeogenesis in hepatocyte
      cultures prompts the hypothesis that metformin potentiates the allosteric
      activation of pyruvate kinase by fructose-1,6-diphosphate. This model
      rationalizes several salient features of metformin's clinical activity: its
      ability to reduce hepatic triglyceride synthesis, its appetite-suppressant
      effect, and its failure to induce hypoglycemia.

PMID- 10340288
TI  - Evolutionary bottlenecks in the agents of tuberculosis, leprosy, and
      paratuberculosis.
AB  - Parasitic mycobacteria cause important human and animal diseases including
      tuberculosis, leprosy, and paratuberculosis. Several methods demonstrate a high
      degree of sequence conservation in three parasitic mycobacterial species
      (Mycobacterium tuberculosis, M. leprae, and M. avium subspecies
      paratuberculosis). Each of these species has completely conserved
      deoxyribonucleic acid (DNA) sequence in an internal transcribed spacer. In
      contrast, several species of environmental mycobacteria (M. intracellulare, M.
      kansasii, M. gordonae, and M. scrofulaceum) have substantial strain-to-strain
      variation in this region. These data suggest that each of the parasitic species
      has gone through a recent evolutionary bottleneck. Comparisons of tandem-repeat
      DNA from ancient and modern mycobacterial strains may allow this hypothesis to be
      tested directly.

PMID- 10340289
TI  - Smoking, nicotine and psychiatric disorders: evidence for therapeutic role,
      controversies and implications for future research.
AB  - Researchers interested in investigating the possible therapeutic effects and the
      mechanisms of action of nicotine in neuropsychiatric disorders face a social
      scientific-ethical dilemma. This dilemma comprises three components: (1) the
      known addictive potential of nicotine makes careful evaluation of the therapeutic
      potential of this compound socially unattractive; (2) the potential misuse of
      scientifically determined data by the tobacco 'lobby' creates ethical concerns;
      and (3) the possible confusion between the differential effects of nicotine in
      human smokers versus non-smokers creates difficulties in study designs in
      voluntary human subjects. Therefore, it is imperative that, at the onset of this
      review, the authors stress that they do not advocate cigarette-smoking as a route
      of nicotine intake under any circumstances on the basis that controlled dosing of
      nicotine may be of potential benefit in some neuropsychiatric disorders. In this
      article, we review the psychopharmacology of nicotine and its effects in a
      variety of neuropsychiatric disorders including schizophrenia, depression,
      anxiety and Tourette's syndrome. Possible mechanisms of action of nicotine
      directly or indirectly via its interaction with other neurotransmitter systems
      (i.e. serotonin, dopamine and noradrenaline) in relation to its potential role in
      these disorders are discussed. It is postulated that new drugs may need to be
      developed that selectively interact with nicotinic receptors without addiction
      potential.

PMID- 10340290
TI  - Does the impairment of the hypothalamic-pituitary-gonadal axis in anorexia
      nervosa depend on increased sensitivity to endogenous melatonin?
AB  - The authors hypothesize that the impairment of hypothalamic-pituitary-gonadal
      axis in patients suffering from anorexia nervosa depends (at least in part) on
      the increased sensitivity to endogenous melatonin. The hypothesis is based mainly
      on the following facts: (1) melatonin is well known to exert an inhibitory effect
      on gonadotropin secretion; (2) melatonin binding is increased in brains of fasted
      rats; (3) undernutrition dramatically increases the inhibitory effect of
      exogenous melatonin on gonadotropin-releasing hormone-induced gonadotropin
      secretion in female rats; (4) the administration of propranolol in girls
      suffering from anorexia nervosa diminishes the nocturnal peak of melatonin and,
      in parallel, restores the gonadotropin response to gonadotropin-releasing
      hormone.

PMID- 10340291
TI  - Mechanism of behavioral adaptation: analyses by a simple model.
AB  - This paper outlines a model describing how animals adapt to a particular
      circumstance. This model is based on observations that animals learn behaviors
      that best fit a circumstance, and that the adapted animals then select the most
      suitable behavior that minimizes their psychological energy usage. The model
      consists of behavioral memory units and their network connections. By using the
      model, various animal disadaptations can be analyzed and the antibody-production
      system can be clearly explained as an adaptation. Finally, it is proposed that
      simulation of the model can be performed on a computer.

PMID- 10340292
TI  - Delusions, superstitious conditioning and chaotic dopamine neurodynamics.
AB  - Excessive mesolimbic dopaminergic neurotransmission is closely related to the
      psychotic symptoms of schizophrenia. A mathematical model of dopamine neuron
      firing rates, developed by King and others, suggests a mechanism by which
      excessive dopaminergic transmission could produce psychotic symptoms, especially
      delusions. In this model, firing rates varied chaotically when the efficacy of
      dopaminergic transmission was enhanced. Such non-contingent changes in firing
      rates in mesolimbic reward pathways could produce delusions by distorting
      thinking in the same way that non-contingent reinforcement produces superstitious
      conditioning. Though difficult to test in humans, the hypothesis is testable as
      an explanation for a common animal model of psychosis--amphetamine stereotypy in
      rats. The hypothesis predicts that: (1) amphetamine will cause chaotic firing
      rates in mesolimbic dopamine neurons; (2) non-contingent brain stimulation reward
      will produce stereotypy; (3) non-contingent microdialysis of dopamine into reward
      areas will produce stereotypy; and (4) dopamine antagonists will block all three
      effects.

PMID- 10340293
TI  - The selenium link: the missing link in our understanding of biochemical trigger
      reactions?
AB  - 'Inorganic' selenium (Se), e.g. selenite and selenate, is assumed to be
      transformed into selenide and to be incorporated into selenoproteins, but this
      has never been proved. There is evidence, however, that vitamin C reduces
      selenite to elemental Se. Elemental sulphur (S) and Se bind easily to sulphides
      and selenides, forming links containing two or more S or Se atoms. Such links
      exist in natural minerals and have been found in proteins in living organisms.
      There are many indications that selenocysteine in special proteins combines with
      elemental Se to form Se links that transfer electrons from redoxable agents to
      oxygen (O2). This implies a reduction to hydrogen peroxide (H2O2) or H2O, while
      gaining energy and achieving trigger effects. H2O2 supplies anaerobic reactions
      with energy eventually via adenosine 5'-triphosphate (ATP) or guanosine 5'
      triphosphate (GTP). Without Se links, redoxable agents can be oxidized by oxygen,
      which leads to the formation of oxygen products and inhibition of further
      electron transference. Nitrous oxide (NO) is one product of oxidation that,
      firmly binding to heme structures, may result in a system of protection. NO can
      prevent O2 from binding to them and thereby stop destroying oxidations.

PMID- 10340294
TI  - HIV pathogenesis: gp120-antibody complexes bind CD4 and kill T4 cells-
      immunotoxin therapy should prevent the progression of HIV to AIDS.
AB  - Current models of the role of human immunodeficiency virus (HIV) in the
      pathogenesis of acquired immune deficiency syndrome (AIDS) are inadequate and
      inconsistent with the literature. This article reviews a wide range of AIDS
      research and proposes the first model of HIV pathogenesis that is entirely
      consistent with the literature. This model is based on antibody-gp120 complex
      crosslinking of CD4 on the T4 cells. Previously unexplained observations embraced
      by this model include early qualitative defects in the immune system, changes in
      cytokine expression, 'bystander' T4 cell death, and the apparent discrepancy
      between the low rate of T4 cell infection and the near-complete elimination of T4
      cells in AIDS. A new class of drugs based on this model is detailed. These drugs
      should disrupt the pathway leading to AIDS and leave an HIV infection
      indefinitely asymptomatic. These drugs are designed to be readily modified, so
      the treatment is immune to HIV's notorious mutation-based drug resistance.

PMID- 10340295
TI  - Front and rear: the pelvic floor is an integrated functional structure.
AB  - The pelvic floor is a muscular structure, pierced by the urologic, genital and
      distal intestinal tract. This structure is not a frozen but a functional unit.
      Normal function can thus be replaced by dysfunctions of several kinds,
      overlapping voiding, sexual, genital and defecatory behaviour. For instance,
      vaginismus is akin to anismus and vesicourethral dyssynergia. Recent recognition
      of the medicosurgical consequences of sexual abuse has shown that many urologic,
      genital and digestive dysfunctions are sort of a body signature of the trauma,
      which must be dealt with if the symptom is to disappear. If the pelvic floor is
      integrated, unsuspected pathology will lie outside of the spectrum of activities
      of a given specialty, and thus urologists, gynecologists, gastroenterologists and
      colorectal surgeons should not only exchange, but should also be aware of the
      pathologies of neighbouring specialties. This paper elaborates on a more holistic
      vision of pelvic floor function including sexuality. Out of this, a number of
      different hypotheses are elaborated in the different spheres of activities, about
      different pathologies, their basic cause, and how they could be dealt with.

PMID- 10340296
TI  - Tumor necrosis factor-alpha: is there a continuum of liability between stress,
      anxiety states and anorexia nervosa?
AB  - Since the time of Freud, psychiatry has embraced the proposition that
      physiological and/or psychological stress precipitates various psychiatric
      disorders. To this effect, we propose that a continuum of liability obtains
      between stress, anxiety states and anorexia nervosa--a continuum which is
      grounded on a cytokine profile common to each of these conditions. For example,
      the biological response to stress, anxiety states and anorexia nervosa includes
      the elevation of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha
      (TNF-alpha), and downregulation of interferon-gamma (IFN-gamma). Sustained
      elevation of IL-1 beta and TNF-alpha dysregulates both somatostatin and insulin
      secretion, the latter of which influences regional cerebral blood flow (rCBF) and
      brain energy metabolism. In addition, IL-1 beta and TNF-alpha influence the
      expression of certain crucial neuropeptides, which are known to be associated
      with anxiety states and anorexia nervosa. These neuropeptides include: beta
      endorphin, cholecystokinin (CCK), neuropeptide Y (NPY) and vasoactive intestinal
      peptide (VIP). beta-endorphin effects glucose metabolism in the limbic system,
      CCK increases the release of beta-endorphin from the anterior pituitary, NPY is a
      powerful anxiolytic that regulates beta-endorphin and insulin, while VIP
      indirectly regulates the expression of TNF-alpha through the inhibition of
      interleukin-4 (IL-4).

PMID- 10340297
TI  - The somatic component of schizophrenia: a dissociation of the goals of visual
      attention and bifoveal fixation?
AB  - The presence of disorders of eye movements is today regarded as 'the strongest
      candidate for a genetically transmitted biological trait marker of schizophrenic
      disorders' (1). The present study is based on the experience, rather than the
      behaviour, of one patient in a search for a method of objectifying his visual
      problems. This method was found to be a simple test, which demonstrates a
      disturbance of fixation: while one eye accommodated on the figure without
      vergence, the other, vergent, eye fused with the image of the related background.
      The disorder had been misdiagnosed as 'exophoria' in conventional
      ophthalmological examinations, because prevailing ophthalmological theory accepts
      only one mode of vision; according to the most recent researches, however, it is
      necessary to distinguish two complementary modes of vision--one for panorama and
      one for detail--which differ in their coordination of vergence and accommodation.
      This new bimodal theory of vision--presented here for the first time--made it
      possible to understand the cause of the disorder as a substitution of sighting
      for fixation, due either to a disinhibition of panorama vision during fixation
      vision, or to an interchange of ipsilateral temporal and contralateral nasal
      projections from the retina, both associated with a fixation disparity. After
      correction of the patient's fixation disparity according to an unusual method,
      the dissociation of the visual goals was remedied and the mental disturbances of
      the patient vanished.

PMID- 10340298
TI  - Vitamin C supplementation and common cold symptoms: factors affecting the
      magnitude of the benefit.
AB  - Placebo-controlled trials have shown that vitamin C supplementation decreases the
      duration and severity of common cold infections. However, the magnitude of the
      benefit has substantially varied, hampering conclusions about the clinical
      significance of the vitamin. In this paper, 23 studies with regular vitamin C
      supplementation (> or = 1 g/day) were analyzed to find out factors that may
      explain some part of the variation in the results. It was found that on average,
      vitamin C produces greater benefit for children than for adults. The dose may
      also affect the magnitude of the benefit, there being on average greater benefit
      from > or = 2 g/day compared to 1 g/day of the vitamin. In five studies with
      adults administered 1 g/day of vitamin C, the median decrease in cold duration
      was only 6%, whereas in two studies with children administered 2 g/day the median
      decrease was four times higher, 26%. The trials analyzed in this work used
      regular vitamin C supplementation, but it is conceivable that therapeutic
      supplementation starting early at the onset of the cold episode could produce
      comparable benefits. Since few trials have examined the effects of therapeutic
      supplementation and their results have been variable, further therapeutic trials
      are required to examine the role of vitamin C in the treatment of colds.

PMID- 10340300
TI  - NMDA NR1 subunit mRNA and glutamate NMDA-sensitive binding are differentially
      affected in the striatum and pre-frontal cortex of Parkinson's disease patients.
AB  - Changes in the levels of mRNA for the NR1 subunit of the glutamate NMDA receptor
      and in NMDA-sensitive glutamate binding were investigated in consecutive sections
      of the prefrontal cortex and striatum of control and Parkinson's disease (PD)
      post-mortem brain using in-situ hybridisation and receptor autoradiography. Both
      markers of NMDA receptors were found to be relatively unaffected when measured by
      microdensitometry in the prefrontal cortex of control and PD brains. At a
      cellular level, a subpopulation of small and medium neurons in the superficial
      layers of the prefrontal cortex of the PD group showed a decreased expression of
      NMDA NR1 mRNA, with the maximal decrease in cortical layer IV. In the striatum,
      levels of glutamate binding to the NMDA receptor detected by receptor
      autoradiodgraphy were significantly reduced in the PD group, while no change
      could be detected at a macroscopical level in NMDA NR1 mRNA expression.
      Consequently, we suggest that the important decrease in agonist binding to the
      NMDA receptor observed in this study in the caudate and putamen of PD brains, in
      the absence of any major change in NMDA NR1 mRNA levels might reflect the
      degeneration of pre-synaptic NMDA receptors located on nigro-striatal projections
      particularly affected by the disease. Small changes observed at a cellular level
      in subsets of neurons of both prefrontal cortex and striatum will be discussed at
      the light of neurochemical changes characteristics of PD.

PMID- 10340301
TI  - The protein kinase C alpha binding protein PICK1 interacts with short but not
      long form alternative splice variants of AMPA receptor subunits.
AB  - Here we report an interaction between AMPA receptor subunits and a single PDZ
      domain-containing protein called PICK1 which is known to bind protein kinase C
      alpha (PKC alpha). The interaction occurs within the last ten amino acid residues
      containing a novel PDZ binding motif (E S V/I K I) of the short C-terminal
      alternative splice variants of AMPA receptor subunits. No interaction occurs with
      the corresponding long splice variants which do not contain the E S V/I K I
      motif. The PDZ domain of PICK1 is required for the interaction and the mutation
      of a single amino acid in this region (Lys-27 to Glu) prevents interaction
      between PICK1 and GluR2 in the yeast two-hybrid assay. A similar mutation has
      been reported to prevent the binding of PICK1 to PKC alpha indicating that the
      same domain of PICK1 binds both PKC alpha and GluRs. Flag-tagged PICK1 is
      retained by a glutathione S-transferase (GST) fusion of the C-terminal of GluR2
      (GST-ct-GluR2; short splice variant) but not by GST-ct-GluR1 (long splice
      variant). Recombinant full length GluR2 is coimmunoprecipitated with flag-PICK1
      using an anti-flag antibody and flag-PICK1 is coimmunoprecipitated with an N
      terminal directed anti-GluR2 antibody. Transient expression of both proteins in
      COS cells reveals colocalization and an altered pattern of distribution for each
      protein from when they are expressed individually. This novel interaction
      provides a possible regulatory mechanism to specifically modulate distinct splice
      variants and may be involved in targeting the phosphorylation of short form GluRs
      by PKC alpha.

PMID- 10340299
TI  - Selective NMDA NR2B antagonists induce antinociception without motor dysfunction:
      correlation with restricted localisation of NR2B subunit in dorsal horn.
AB  - The present study investigated the regional distribution of the N-methyl-D
      aspartate (NMDA) receptor containing the NR2B subunit protein in rat lumbar
      spinal cord and examined whether selective NR2B antagonists would exhibit
      antinociception with reduced side-effect liability than subtype non-selective
      NMDA antagonists and anticonvulsants. Immunocytochemical studies showed the NR2B
      subunit had a restricted distribution, with moderate labelling of fibres in
      laminas I and II of the dorsal horn suggesting a presynaptic location on primary
      afferent fibers and possible involvement in pain transmission. In the in vivo
      studies, the NMDA/glycine antagonists (MK-801, 0.02-1 mg/kg i.p., L-687,414 10
      300 mg/kg i.p., and L-701,324 1-10 mg/kg i.p.) and the anticonvulsant, gabapentin
      (10-500 mg/kg p.o.), induced rotarod deficits at antinociceptive doses. In
      contrast, the selective NR2B antagonists, (+/-)-CP-101,606 (1-100 mg/kg p.o.) and
      (+/-)-Ro 25-6981 (3-100 mg/kg i.p.) showed a significant dose window. (+/-)-CP
      101,606 caused no motor impairment or stimulation in rats at doses up to 100
      mg/kg p.o., which is far in excess of those inhibiting allodynia in neuropathic
      rats (ID50 4.1 mg/kg, p.o.). (+/-)-Ro 25-6981 also showed a significant
      separation (ID50 allodynia 3.8 mg/kg, i.p.), however, some disruption of rotarod
      performance was observed at 100 mg/kg. The anticonvulsant lamotrigine (3-500
      mg/kg p.o.) also showed a good dose window. These findings demonstrate that NR2B
      antagonists may have clinical utility for the treatment of neuropathic and other
      pain conditions in man with a reduced side-effect profile than existing NMDA
      antagonists.

PMID- 10340302
TI  - Activation of metabotropic glutamate receptors enhances synaptic transmission at
      the Drosophila neuromuscular junction.
AB  - We examined the effects of activation of metabotropic glutamate receptors
      (mGluRs) on glutamatergic synaptic transmission at the neuromuscular junction of
      newly hatched Drosophila larvae. In nominally Ca(2+)-free solutions puff
      application of low concentrations of glutamate evoked a transient frequency
      increase of miniature synaptic currents (mSCs). The mean amplitude of mSCs was
      unaffected, suggesting that this effect was presynaptic. Similar alterations of
      the mSC frequency were obtained using the mGluR agonists, (S)-4C3HPG, DCG-IV, or
      (1S,3S)-ACPD, but not when using agonists for ionotropic glutamate receptors,
      NMDA, AMPA or kainate. An mGluR antagonist, MCCG-I, blocked the effect of
      agonists on the mSC frequency. An adenylate cyclase activator, forskolin, and a
      cAMP analog, CPT-cAMP, mimicked the effects of mGluR activation. Meanwhile, an
      adenylate cyclase inhibitor, SQ22,536, blocked the mGluR agonist-induced effects,
      and in rutabaga, an adenylate-cyclase-defective mutant, the effect of the agonist
      was greatly reduced. In the presence of external Ca2+, (S)-4C3HPG decreased the
      failure rate and increased the mean amplitude of stimulus-evoked SCs, while MCCG
      I decreased the amplitudes. We suggest that at the larval Drosophila
      neuromuscular junction endogenous glutamate released at the terminal potentiates
      synaptic transmission via a process involving cAMP.

PMID- 10340303
TI  - Functional properties of ionotropic glutamate receptor channels in rat sacral
      dorsal commissural neurons.
AB  - Nystatin perforated patch and conventional whole-cell recording configurations
      were used to characterize the properties of ionotropic glutamate receptor (GluR)
      channels in neurons freshly dissociated from the rat sacral dorsal commissural
      nucleus (SDCN). L-Glutamate (Glu), N-methyl-D-aspartate (NMDA), quisqualate (QA),
      alpha-amino-3-hydroxy-5-methyl-4-isoxazoleprop ionate (AMPA) and kainate (KA)
      applied via a Y-tube produced inward currents at -44 mV which increased in a
      concentration-dependent manner; they desensitized when induced at higher
      concentrations except for the KA-induced current (IKA). (1S-3R)1-amino
      cyclopentane-1,3-dicarboxylate (1S-3R-ACPD) evoked no response. The EC50 and Hill
      coefficient (nH) values of the GluR responses were 3.3 x 10(-5) M, 0.74 for Glu;
      9.0 x 10(-5) M, 0.83 for NMDA; 6.4 x 10(-7) M, 1.30 for QA; 1.3 x 10(-4) M, 1.10
      for AMPA and 9.6 x 10(-5) M, 1.30 for KA, respectively. The reversal potentials
      of the GluR responses were all near 0 mV. The 6-Cyano-7-nitroquinoxaline-2-3
      dione (CNQX) and D-2-amino-5-phosphonovalerate (D-APV) suppressed the non-NMDA
      and NMDA responses in a concentration-dependent manner, respectively.
      Cyclothiazide strongly potentiated both KA- and AMPA-induced responses while
      concanavalin A potentiated both the responses to a much lesser degree. NS-102
      produced no significant effect on either KA- or AMPA-activated currents, while
      GYKI 52466 reversibly blocked both the currents. The Ca2+ permeabilities
      (PCa/PCs) of the NMDA and AMPA receptor channels were 8.33 and 1.23,
      respectively. In addition, the current-voltage (I-V) relationship of IKA showed
      little rectification. There was a poor correlation between the Ca2+ permeability
      and the shape of the I-V curves of IKA. These results suggest that rat SDCN
      neurons possess NMDA and non-NMDA receptor channels, and express AMPA type
      receptors with unique properties (slow desensitization to AMPA, high Ca2+
      permeability but lack of inward rectification). These ionotropic receptor
      channels may play important roles in mediating and regulating pelvic visceral
      information including nociception.

PMID- 10340304
TI  - In vitro and in vivo protective effect of orphenadrine on glutamate
      neurotoxicity.
AB  - The anticholinergic drug orphenadrine is used in the treatment of Parkinson's
      disease. In this study we evaluate the neuroprotective effects of orphenadrine on
      excitotoxicity in vivo and in vitro. Orphenadrine prevented the mitochondrial and
      the cytoplasmic membrane potential decrease evoked by NMDA (100 microM) in rat
      dissociated cerebellar granule cells showing an IC50 value of 11.6 +/- 4.7 microM
      (mean +/- SEM, n = 5) and 13.5 +/- 2.3 microM (n = 3), respectively. Orphenadrine
      was able to protect cerebellar granule cell cultures from glutamate-induced
      neurotoxicity. Kainic acid (KA, 10 mg/kg)-induced excitotoxicity was evaluated in
      vivo using the microglial marker peripheral-type benzodiazepine receptor (PBR)
      and heat shock protein 72 (HSP72) expression in the hippocampus. The Bmax of PBR
      for control tissues was 589.1 +/- 40.0 fmol/mg protein (n = 4), increasing to
      1692.5 +/- 51.6 fmol/mg protein (n = 5) after the KA treatment. Pretreatment with
      orphenadrine (10 mg/kg) blocked the KA-induced increase in PBR density. As
      expected, KA-administration induced the expression of HSP72 that was blocked in
      the orphenadrine + KA-treated rats. We demonstrate that orphenadrine, interacting
      at the NMDA receptor, is able to prevent the neurotoxicity mediated by activation
      at glutamate ionotropic receptors.

PMID- 10340305
TI  - Characterisation of the binding of [3H]methyllycaconitine: a new radioligand for
      labelling alpha 7-type neuronal nicotinic acetylcholine receptors.
AB  - Methyllycaconitine (MLA), a norditerpenoid alkaloid isolated from Delphinium
      seeds, is one of the most potent non-proteinacious ligands that is selective for
      alpha bungarotoxin-sensitive neuronal nicotinic acetylcholine receptors (nAChR).
      [3H]MLA bound to rat brain membranes with high affinity (Kd = 1.86 +/- 0.31 nM)
      with a good ratio of specific to non-specific binding. The binding of [3H]MLA was
      characterised by rapid association (t 1/2 = 2.3 min) and dissociation (t 1/2 =
      12.6 min) kinetics. The radioligand binding displayed nicotinic pharmacology,
      consistent with an interaction with alpha bungarotoxin-sensitive nAChR. The snake
      alpha-toxins, alpha bungarotoxin and alpha cobratoxin, displaced [3H]MLA with
      high affinity (Ki = 1.8 +/- 0.5 and 5.5 +/- 0.9 nM, respectively), whereas
      nicotine was less potent (Ki = 6.1 +/- 1.1 microM). The distribution of [3H]MLA
      binding sites in crudely dissected rat brain regions was identical to that of
      [125I] alpha bungarotoxin binding sites, with a high binding site density in
      hippocampus and hypothalamus, but low density in striatum and cerebellum. [3H]MLA
      also labelled a sub-population of binding sites which are not sensitive to the
      snake alpha toxins, but which did not differ significantly from the major
      population with respect to their other pharmacological properties or regional
      distribution. [3H]MLA, therefore, is a novel radiolabel for characterising alpha
      7-type nAChR. A good signal to noise ratio and rapid binding kinetics provide
      advantages over the use of radiolabelled alpha bungarotoxin for rapid and
      accurate equilibrium binding assays.

PMID- 10340306
TI  - Phenylmethylsulfonyl fluoride inhibitory effects on acetylcholinesterase of brain
      and muscle.
AB  - Differential inhibition of brain versus peripheral acetylcholinesterase (AChE) by
      phenylmethylsulfonyl fluoride (PMSF) suggested that PMSF might preferentially
      inhibit different AChE molecular forms. AChE inhibition was examined after
      systemic and in vitro PMSF treatment. Systemic administration resulted in no
      overt behavioral changes but produced a 71% reduction in brain AChE;
      hemidiaphragm, extensor digitorum longus and soleus muscles showed 65, 50 and 41%
      reductions. Muscle asymmetric AChE was reduced to the greatest extent (50-80%).
      The tetrameric form was inhibited in brain and hemidiaphragm (60-76%) but spared
      in other muscles (18-22%). Monomeric AChE was spared in all tissues. When PMSF
      was added to a muscle homogenate all forms were inhibited equally. Purified
      monomer and tetramer forms were inhibited equally in vitro. These results suggest
      that PMSF inhibition of AChE is a consequence of a selective inhibition of
      membrane-associated forms and that the apparent brain selectivity is related to
      the greater fraction of membrane-associated AChE in brain.

PMID- 10340307
TI  - P2X2 characteristics of the ATP receptor coupled to [Ca2+]i increases in cultured
      Purkinje neurons from neonatal rat cerebellum.
AB  - P2X receptors present in cerebellar Purkinje cells have been studied by recording
      ATP-elicited [Ca2+]i signals from immuno-identified (calbindin+) cells in culture
      using fura-2 microfluorescence. The [Ca2+]i increases evoked by ATP were mimicked
      by 2MeSATP but not by alpha, beta-meATP and other purinoceptor agonists. The
      selective P2X1 antagonist diinosine pentaphosphate failed to inhibit ATP-elicited
      [Ca2+]i transients, but suramin and PPADS rapidly and reversibly blocked the
      [Ca2+]i responses to ATP and 2MeSATP. The IC50 values for suramin and PPADS
      inhibition were 48.7 +/- 4.4 and 5.9 +/- 0.3 microM, respectively. Both
      antagonists blocked completely the signal elicited by ATP, revealing that there
      was not a separate antagonist-insensitive P2X receptor population in Purkinje
      cells. The effect of ATP was potentiated by Zn2+ and H+ ions. A one unit
      acidification from pH 7.4 to 6.4 enhanced by 172% the [Ca2+]i transient elicited
      by an intermediate concentration of ATP. Conversely, alkalinization of the medium
      to pH 8.4 reduced the ATP response by 88%. This combination of pharmacological
      and modulatory properties indicates that endogenous P2X receptors present in
      Purkinje neurons are formed by P2X2 subunits, rather than the more abundantly
      expressed P2X4 purinoceptor subunits.

PMID- 10340308
TI  - Interaction between purinoceptor subtypes on hippocampal serotonergic
      transmission using in vivo microdialysis.
AB  - The effects of purinoceptor subtypes on hippocampal extracellular serotonin
      levels were determined by using in vivo microdialysis. Perfusion with adenosine
      5'-triphosphate (ATP) for 20 min produced concentration-dependent changes in
      hippocampal extracellular serotonin levels, which consisted of an initial rise
      phase, with levels increasing to 309% of control with 100 microM ATP, followed by
      a later rebound reduction phase, with levels decreasing to 6% of control. The
      P2X1-7 active P2 purinoceptor agonist, 2-methylthioATP (2-MeSATP: 100 microM)
      increased the extracellular serotonin level drastically (638%), while the P2X1,3
      active P2 purinoceptor agonist, alpha, beta-methylene-L-ATP (alpha, beta-meATP:
      100 microM) produced a small increase (132%) in the serotonin level. The
      P2X1,2,3,5,7 active P2 purinoceptor antagonist, suramin (100 microM), reduced the
      basal serotonin level (86%) and the ATP-evoked initial rise phase (from 309 to
      254%) without affecting the late reduction phase. The adenosine A1 receptor
      antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT: 50 microM) potentiated the
      rising phase (167%) and abolished the subsequent ATP-evoked reduction phase.
      Perfusion with CPT and an adenosine A2 receptor antagonist, 3,7-dimethyl-1
      propargylxanthine (DMPX: 10 microM), reduced the ATP-evoked initial rise (to
      181%) and abolished the late reduction phases of serotonin release. These results
      indicate that ATP-evoked hippocampal serotonin release is composed of an initial
      rise phase and a later reduction phase. The ATP-evoked initial rise phase might
      be produced by an activation of P2X purinoceptor function, whereas the late
      reduction phase was modulated by the activation of adenosine A1 receptor function
      by adenosine, metabolized from ATP in the synaptic cleft.

PMID- 10340309
TI  - Characterization of quinolone antibacterial-induced convulsions and increases in
      nuclear AP-1 DNA- and CRE-binding activities in mouse brain.
AB  - The quinolone antibacterials enoxacin and norfloxacin (2.5 mg/kg, i.v.) provoked
      clonic convulsions in mice treated concomitantly with biphenylacetic acid (BPAA,
      100 mg/kg, i.p.), a major metabolite of the nonsteroidal anti-inflammatory drug
      fenbufen. Gel-shift assays showed that enoxacin-induced convulsions resulted in
      increases in nuclear activator protein 1 (AP-1) DNA- and cyclic AMP responsive
      element (CRE)-binding activities in the cerebral cortex and hippocampus, but not
      in other regions, such as the cerebellum and thalamus. In contrast, ofloxacin and
      levofloxacin, at the same doses, in the presence of BPAA did not evoke
      convulsions or increase these DNA-binding activities. Administration of these
      quinolones and BPAA alone elicited neither convulsions nor increases in these DNA
      binding activities. These results suggest that the increased nuclear AP-1 DNA-
      and CRE-binding activities in the cerebral cortex and hippocampus induced by
      quinolones with BPAA correlated with seizure activities and that these brain
      regions play pivotal roles in quinolone-induced convulsions.

PMID- 10340310
TI  - The endozepine ODN stimulates [3H]thymidine incorporation in cultured rat
      astrocytes.
AB  - High concentrations of diazepam-binding inhibitor (DBI) mRNA have been detected
      in astrocytoma, suggesting that DBI-derived peptides may play a role in glial
      cell proliferation. In the present study, we have investigated the effect of a
      processing product of DBI, the octadecaneuropeptide ODN, on DNA synthesis in
      cultured rat astrocytes. At very low concentrations (10(-14) to 10(-11) M), ODN
      caused a dose-dependent increase of [3H]thymidine incorporation. At higher doses
      (10(-10) to 10(-5) M), the effect of ODN gradually declined. The central-type
      benzodiazepine receptor antagonist flumazenil (10(-6) M) completely suppressed
      the stimulatory action of ODN whereas the peripheral-type benzodiazepine receptor
      ligand, PK11195 (10(-6) M) had no effect. The ODN-induced stimulation of
      [3H]thymidine incorporation was mimicked by methyl 6,7-dimethoxy-4-ethyl-beta
      carboline-3-carboxylate (DMCM). The GABAA receptor antagonist bicuculline (10(-4)
      M) suppressed the effect of both ODN and DMCM on DNA synthesis. Exposure of
      cultured astrocytes to the specific GABAA agonist 3APS (10(-10) to 10(-4) M) also
      induced a dose-related increase of [3H]thymidine incorporation. The present study
      indicates that ODN, acting through central-type benzodiazepine receptors
      associated with the GABAA receptor complex, stimulates DNA synthesis in rat glial
      cells. These data provide evidence for an autocrine role of endozepines in the
      control of glial cell proliferation.

PMID- 10340311
TI  - The temporal order judgment paradigm: subcortical attentional contribution under
      exogenous and endogenous cueing conditions.
AB  - The role of subcortical attentional processing was investigated under exogenous
      and endogenous cueing conditions. As retinotectal projections arise predominantly
      from the nasal retina i.e., temporal hemifield, subcortical attention should be
      distributed asymmetrically under monocular viewing conditions with a temporal
      hemifield advantage. We compared the results of monocular and binocular viewing
      conditions using a temporal order judgment (TOJ) paradigm. Subjects fixated a
      centrally located cross and two stimuli were presented with a variable onset
      asynchrony. Three experiments were conducted: no cue, exogenous cue and
      endogenous cue. Subjects reported which stimulus seemed to appear first. An
      effect consistent with subcortical processing was found under exogenous cueing
      conditions. No such effect was found under endogenous cueing conditions. We
      believe that subcortical attentional processing in response to an exogenous cue
      facilitates rapid shifts in attention towards environmental stimuli. We found no
      evidence for subcortical processing in voluntary directed attention and believe
      this process to be cortical in nature.

PMID- 10340312
TI  - Dyslexia, gender, and brain imaging.
AB  - Future brain imaging studies of dyslexia should have a sufficient number of males
      and females to detect possible gender differences in the neurological
      underpinning of this disorder. Detailed knowledge about such differences may
      clarify our understanding of the structural and functional impairments which lead
      to the phonological deficits that characterize dyslexia. Functional brain imaging
      studies have shown that males and females exhibit different patterns of brain
      activation during phonological processing. Further differences between the brains
      of males and females have been suggested by studies of normal brain development,
      morphology, and functional activation during reading. Animal studies have shown
      that lesions, similar to those seen in postmortem studies of dyslexia, affect
      rapid auditory processing in males, but not in females. The large body of
      research on gender differences in brain development, functional organization, and
      activation during reading tasks urges separation of males and females in dyslexia
      research in order to minimize variance and to detect subtle, but functionally
      relevant, differences. Well-controlled studies, with large numbers of male and
      female dyslexics, may produce more sensitive and accurate identification of the
      neurological substrates of dyslexia.

PMID- 10340313
TI  - Repetitive transcranial magnetic stimulation of the dominant hemisphere can
      disrupt visual naming in temporal lobe epilepsy patients.
AB  - We used repetitive transcranial magnetic stimulation (rTMS) to study visual
      naming in 14 patients with temporal lobe epilepsy. Ten had left hemisphere
      language by Wada testing and all experienced speech arrest with rTMS of the motor
      speech area in the left frontal lobe. One left-hander had speech arrest with
      stimulation of sites on both sides. Subjects were asked to name pictures or read
      words presented on a computer monitor. rTMS was delivered on half of the trials.
      Stimulation sites were the motor speech area in the left frontal lobe, the mirror
      site on the right, and the left and right mid superior and posterior temporal
      lobes. rTMS at left hemisphere sites caused more naming errors than did right
      hemisphere rTMS. All individual subjects, except two who had temporal lobe
      resections and the one with bilateral speech arrest, produced more naming errors
      with rTMS of left hemisphere sites. There was no significant effect on word
      reading. rTMS at the left hemisphere and right frontal sites produced reductions
      in reaction time for picture naming, but not for word reading. This was observed
      for both correct and incorrect responses. This study shows that left hemisphere
      rTMS can disrupt visual naming selectively.

PMID- 10340314
TI  - Language organization in patients with early and late left-hemisphere lesion: a
      PET study.
AB  - Functional neuroimaging studies have shown enhanced right-hemisphere language
      activations in adults with left-hemisphere damage. We hypothesized that this
      effect would be stronger in patients with lesion occurring early in development.
      Using [15O]-water PET, we studied eight normal adults and 23 patients with
      unilateral left lesion during rest, listening to sentences, and sentence
      repetition. Thirteen patients had lesions with early onset (< 5 years) and ten
      had lesions with late onset (> 20 years). For listening to sentences,
      frontotemporal blood flow increases were significantly stronger in the left than
      in the right hemisphere in normal adults. This normal asymmetry was reduced in
      patients with late lesion and reversed in those with early lesion. For sentence
      repetition, analogous group differences were significant for the basal ganglia,
      but failed to reach significance for the (pre)motor and insular regions. We
      conclude that left lesion leads to alterations in the asymmetry of language
      activations (in and beyond the perisylvian areas). In addition, rightward shifts
      of language activation tend to be stronger as a consequence of early (as compared
      to late) lesion. Finally, postlesional reorganization appears to reflect a
      coexistence of 'additive' and 'subtractive' effects, i.e., activation in some
      regions that are not normally involved in language processing and lack of
      activation in other (undamaged) regions that are normally activated by language
      tasks.

PMID- 10340315
TI  - Matching and imitation of hand and finger postures in patients with damage in the
      left or right hemispheres.
AB  - To disentangle perceptual, conceptual and motor aspects of imitation of gestures,
      reproduction of meaningless postures of either the hand or the fingers was
      examined in two conditions. In the matching test a target gesture had to be
      identified among an array of four gestures performed by different persons and
      seen under different angles of views. For imitation, the same gestures had to be
      imitated. Thirty-five patients with LBD, 21 patients with RBD, and 17 healthy
      controls were examined. LBD patients had more difficulties with imitation than
      with matching while RBD patients had more difficulties with matching than with
      imitation. Regardless of whether imitation or matching was tested, LBD patients
      made more errors with hand than with finger postures whereas RBD patients made
      more errors with finger than with hand postures. This constellation of results is
      compatible with the assumption that errors are caused by faulty visuoperceptual
      processing in RBD, and by defective conceptual mediation in LBD. Defective motor
      execution does not appear to be a significant source of imitation errors in
      either group.

PMID- 10340316
TI  - Dynamic changes in the functional anatomy of the human brain during recall of
      abstract designs related to practice.
AB  - In the present PET study we explore some functional aspects of the interaction
      between attentional/control processes and learning/memory processes. The network
      of brain regions supporting recall of abstract designs were studied in a less
      practiced and in a well practiced state. The results indicate that automaticity,
      i.e., a decreased dependence on attentional and working memory resources,
      develops as a consequence of practice. This corresponds to the practice related
      decreases of activity in the prefrontal, anterior cingulate, and posterior
      parietal regions. In addition, the activity of the medial temporal regions
      decreased as a function of practice. This indicates an inverse relation between
      the strength of encoding and the activation of the MTL during retrieval.
      Furthermore, the pattern of practice related increases in the auditory, posterior
      insular-opercular extending into perisylvian supramarginal region, and the right
      mid occipito-temporal region, may reflect a lower degree of inhibitory
      attentional modulation of task irrelevant processing and more fully developed
      representations of the abstract designs, respectively. We also suggest that free
      recall is dependent on bilateral prefrontal processing, in particular non
      automatic free recall. The present results confirm previous functional
      neuroimaging studies of memory retrieval indicating that recall is subserved by a
      network of interacting brain regions. Furthermore, the results indicate that some
      components of the neural network subserving free recall may have a dynamic role
      and that there is a functional restructuring of the information processing
      networks during the learning process.

PMID- 10340317
TI  - Neglect-associated constructional disorders: a paradoxical phenomenon?
AB  - Five neglect patients without diffuse cognitive impairment or overt
      constructional disabilities were asked to bisect lines and rectangles and to copy
      rectangles bisected in their midplane. As a group, patients showed the usual
      rightward bias in bisecting lines and a milder deviation in bisecting
      horizontally-aligned rectangles, but showed a leftward deviation of the
      subjective midline in the copying task. This was due to drawing the left half
      shorter with respect to normal controls but three patients also drew the right
      half longer (the total length was the same as that of controls). A possible
      interpretation of rectangle copying results in these three patients is that they
      could create a representation of the stimulus to be copied accurately enough to
      reproduce its total length correctly but the subjective distribution of right and
      left space within that representation was unbalanced. However, specific
      experimental work is needed to verify why our patients with mild to moderate
      unilateral spatial neglect overrepresented the left side in a line bisection task
      and underrepresented it in a copying task.

PMID- 10340318
TI  - Selective visual attention in patients with frontal lobe lesions or Parkinson's
      disease.
AB  - Visual selective attention and response competition were tested in patients with
      frontal lobe lesions or with Parkinson's disease, and matched normal controls.
      The target stimuli were presented with flanking distractors that were either
      compatible, incompatible, or neutral to the target stimulus. The distance between
      the target and distractors was systematically varied. A control condition without
      distractors was also included. Subjects' response times to target stimuli and
      accuracy were measured. Both patient groups responded significantly slower and
      less accurately than their respective matched normal controls across all
      interference conditions and spatial distances. However, they did not show
      significantly greater interference or facilitation effects. Thus, the data
      suggest that the cognitive processes underlying selective attention are, in
      general, spared in patients with frontal lobe lesions or basal ganglia
      dysfunction.

PMID- 10340319
TI  - Mechanisms underlying attentional set-shifting in Parkinson's disease.
AB  - Patients with Parkinson's disease (PD) show impairments on tasks that require
      them to switch attention between two perceptual dimensions (extradimensional (ED)
      shifting). It has been suggested that ED shifting deficits can be caused by two
      separate mechanisms, 'learned irrelevance' and 'perseveration'. This study set
      out to test the hypothesis that enhanced learned irrelevance is present in
      medicated patients with PD. An enhancement of learned irrelevance in PD patients
      should result in increased errors on a 'deficit' shift relative to controls and
      decreased errors on an 'improvement' shift. A similar pair of deficit and
      improvement shifts were used to detect possible enhanced perseveration in
      patients. Instead of showing the predicted patterns of deficit and improvement,
      patients displayed a consistent deficit on those shifts that required that they
      switch their attention to a different dimension (ED shifts). In contrast,
      patients were not impaired on shifts that required no such shift of attention
      (intradimensional shifts). Although there was an increase in errors at the
      learned irrelevance deficit shift, a similar increase at the learned irrelevance
      improvement shift shows that enhanced learned irrelevance is not responsible for
      either of these results. Patients were no more distractible than controls, but
      displayed increased 'loss of set' as measured by errors generated after a rule
      was learned. These results point to the existence of exaggerated, rigid selective
      attention in patients with PD rather than a breakdown in the ability to
      selectively attend. There was no evidence for the existence of enhanced learned
      irrelevance in the patients.

PMID- 10340320
TI  - Hemispheric facilitation as a result of threatening and nonthreatening words:
      blocked vs mixed presentation effects and order effects.
AB  - Sixteen right-handed participants (eight male and eight female students) were
      administered a tachistoscopic unilateral letter-naming task. The design contained
      three valance conditions and two types of presentation. In baseline conditions no
      concurrent task was given. In threat and nonthreat conditions, each unilateral
      stimulus was preceded by a threatening or nonthreatening word in central vision.
      Participants were instructed to recall this word after reporting the unilateral
      letter string. With blocked presentations, a series of trials had the same
      emotional valence (threatening or nonthreatening), whereas with mixed
      presentations the valences were alternating within a series. Analysis of order
      effects for the blocked presentations revealed sustained effects of the initial
      block valence on visual field asymmetries. The sustained effect of the initial
      threatening block was a reduction of the right visual-field advantage. Mixed
      presentations resulted in a enhanced right visual-field advantage following the
      presentation of threatening information and an enhanced left visual-field
      advantage following the presentation of nonthreatening information. The research
      suggests that tonic and phasic reactions to emotional stimuli may affect visual
      field asymmetry in different ways.

PMID- 10340321
TI  - In vivo development of Theileria annulata: major changes in efferent lymph
      following infection with sporozoites or allogeneic schizont-infected mononuclear
      cells.
AB  - The object of these experiments was to study the pathogenesis and kinetics of
      Theileria annulata infection in the efferent lymph of the draining lymph nodes of
      calves. Efferent lymphatics of calves were cannulated prior to infection with T.
      annulata sporozoite or an allogeneic schizont cell line. Potentially lethal
      sporozoite challenge induced cell shut-down from days 4-6 and then a massive
      increase in output of blasting cells (both infected and non-infected) in the
      efferent lymph. The rate of lymph flow and total cell output increased to 5 to 10
      fold from day 6 onwards. Sporozoites were never isolated from the efferent lymph.
      However, large numbers of parasite-infected cells were seen in efferent lymph
      from the sixth day of infection. The animals inoculated with an allogeneic T.
      annulata-infected cell line exhibited only a small increase in flow rate and cell
      output. Parasite-infected cells of recipient origin were seen in efferent lymph
      from day 11 onwards. However, cells of donor origin were never isolated either
      from efferent lymph or peripheral blood. Thus the parasite transferred from the
      inoculated donor cell line to the cells of the recipient before schizonts
      appeared in efferent lymph.

PMID- 10340322
TI  - Plasmodium berghei development in irradiated sporozoite-immunized C57BL6 mice.
AB  - The C57BL6 strain of mice is highly susceptible to Plasmodium berghei sporozoite
      infections and consequently requires repeated immunizations with irradiated
      sporozoites to obtain protective immunity. After a live sporozoite challenge in
      the immunized hosts, hepatic-stage parasites found in the liver after 48 h are of
      different sizes--small schizonts corresponding to blocked forms (derived from
      irradiated sporozoites), and schizonts of intermediate size (derived from live
      sporozoites). Large schizonts corresponding to mature hepatic forms are found
      only in unimmunized but challenged C57BL6 mice. Using monoclonal and polyclonal
      antibodies directed to liver-stage parasites, different patterns of binding
      reactivity to the above forms are observed. More than 20% of the irradiated
      sporozoites transform into blocked forms after immunization and persist in the
      liver. Upon sporozoite challenge in such immunized animals the rate of
      transformation of sporozoites into hepatic parasites is less than 2%. These
      observations shed light on the fate of live sporozoite development in irradiated
      sporozoite-immunized C57BL6 mice.

PMID- 10340323
TI  - Chloroquine increases Plasmodium falciparum gametocytogenesis in vitro.
AB  - Malaria parasites are capable of modulating the diversion of resources from
      asexual growth to the production of stages infective to mosquitoes (gametocytes).
      Increased rates of gametocytogenesis appear to be a general response to stress,
      both naturally encountered and novel. We have previously reported earlier and
      greater gametocytogenesis in response to subcurative antimalarial chemotherapy in
      the rodent malaria, Plasmodium chabaudi, in vivo. Using an immunofluorescent
      assay to detect parasites that had invaded red blood cell monolayers, we
      demonstrate a 5-fold increase in gametocytogenesis in the human malaria, P.
      falciparum, in vitro, in response to treatment with the antimalarial drug
      chloroquine. In all clones used, gametocytogenesis increased with increasing
      inhibition of asexual growth by chloroquine. Furthermore, there were clone
      differences in the relationship between stress and gametocyte production,
      implying the response was genetically variable. This was not, however, associated
      with chloroquine resistance. The epidemiological significance of these results is
      discussed.

PMID- 10340324
TI  - A clonal Plasmodium falciparum population in an isolated outbreak of malaria in
      the Republic of Cabo Verde.
AB  - We present the first parasitological, molecular and longitudinal analysis of an
      isolated outbreak of malaria. This outbreak occurred on Santiago Island (Republic
      of Cabo Verde), a region where malaria is hypoendemic and controlled, and thus
      the population is considered non-immune. Blood samples were collected from the
      inhabitants over 1 month and during cross-sectional surveys in the following
      year. The presence and nature of the parasites was determined by PCR. Plasmodium
      falciparum was the only species detected. Genetic analysis revealed that the
      circulating parasites were genetically homogeneous, and probably clonal.
      Gametocytes were found throughout this period. Our data suggest that this
      represented a focal outbreak, resulting in the infection of at least 40% of the
      villagers with a clonal parasite line. Thus, P. falciparum infections can persist
      for at least 1 year in a substantial proportion (10%) of the hosts. Implications
      for malaria control and the interpretation of epidemiological data are discussed.

PMID- 10340325
TI  - The genus Hammondia is paraphyletic.
AB  - The phylogenetic relationships amongst Hammondia, Neospora and Toxoplasma were
      investigated by DNA sequence comparisons of the D2/D3 domain of the large subunit
      ribosomal DNA and the internal transcribed spacer 1. The results obtained allow
      us to reject the hypothesis that N. caninum and H. heydorni are the same species
      and show that Hammondia hammondi is probably the sister taxon to Toxoplasma
      gondii.

PMID- 10340326
TI  - Comparison of the biological characteristics of two isolates of Neospora caninum.
AB  - This study compared the biological and genetic properties of a bovine (NC-SweB1)
      and a canine (NC-Liverpool) isolate of Neospora caninum. A mouse model for CNS
      infection demonstrated marked differences in pathogenicity between the isolates.
      NC-Liverpool induced severe clinical signs of neosporosis in 57/58 mice including
      discoordinated movement, hindlimb paralysis and coat ruffling with severe weight
      loss. In contrast NC-SweB1 induced similar but less severe symptoms in a much
      smaller proportion of mice over the same time-period. Statistically significant
      differences were observed between the isolates in the response (mean weight loss)
      of mice through time to the different doses inoculated. Histopathological effects
      on brain tissue reflected the isolate-based differences described above. NC
      Liverpool infection resulted in intense inflammatory infiltrates and highly
      necrotic lesions whereas NC-SweB1 induced a milder meningoencephalitis. Passage
      in cell-culture over a period of 14 months did not affect the pathogenicity of NC
      Liverpool. Immunoblots showed that antibodies to N. caninum appeared earlier in
      mice inoculated with NC-Liverpool than with NC-SweB1. Finally, RAPD-PCR analysis
      of NC-Liverpool DNA generated profiles distinct from that observed with DNA from
      NC-SweB1 or Toxoplasma gondii. In summary this study provides evidence for
      significant biological and genetic differences between 2 isolates of N. caninum.

PMID- 10340327
TI  - Kinetoplast minicircle DNA from Leishmania (Viannia) lainsoni.
AB  - To investigate the phenomenon that PCR of Leishmania (V.) lainsoni minicircles
      using primers B1 and B2 gives anomalous small-sized products, unlike all other
      members of the Leishmania Viannia subgenus, cloned kDNA minicircles from L.
      (Viannia) lainsoni were sequenced using fluorescent dye terminator reactions. The
      sequence of L. (V.) lainsoni where the primer B2 would be expected to bind, was
      different from the other members of the L. Viannia subgenus, matching in only 7
      out of 19 bases with the sequence of L. (V.) braziliensis at this position. The
      sequence obtained from the cloned minicircles enabled the design of a new primer
      which, when combined with B1, allowed the amplification of full sized minicircles
      in L. (V.) lainsoni, but not other members of the L. Viannia subgenus. Comparison
      of the sequence obtained for Leishmania (V.) lainsoni with other Leishmania
      minicircle DNA confirms that Leishmania (V.) lainsoni is more similar to members
      of the L. Viannia subgenus than to other Leishmania, but is distinctly different.

PMID- 10340328
TI  - Mini-exon gene sequence polymorphism among Trypanosoma rangeli strains isolated
      from distinct geographical regions.
AB  - Trypanosoma rangeli can infect humans and the same domestic and wild animals and
      triatomine vectors infected by T. cruzi in Central and South America. This
      overlapping distribution complicates the epidemiology of Chagas disease because
      of the cross-reactivity between T. rangeli and T. cruzi antigens. We have studied
      T. rangeli strains isolated from different geographical regions using the mini
      exon gene as a genetic marker. Two pairs of oligonucleotides directed to this
      gene were designed in order to detect specifically T. rangeli DNA by PCR assays.
      This assay was highly sensitive, able to amplify the target sequence using the
      equivalent DNA content of a single parasite as template, and demonstrated no
      cross-reactivity with T. cruzi DNA. T. rangeli SC-58 strain, isolated in southern
      Brazil, showed a distinct electrophoretic pattern from the other T. rangeli
      strains tested. Low stringency single specific primer-PCR (LSSP) assays were able
      to detect sequence polymorphisms at the mini-exon gene among T. rangeli strains.
      Sequence comparisons of this gene revealed that the SC-58 strain was genetically
      distinct from strains isolated in Central America and northern South America. In
      addition to insertion/deletion events, the presence of microsatellite repeats in
      the non-transcribed region of the gene contribute to the intra-species
      variability.

PMID- 10340329
TI  - The influence of temperature on the survival and infectivity of the cercariae of
      Echinoparyphium recurvatum (Digenea: Echinostomatidae).
AB  - Survival and infectivity characteristics are described for cercariae of the
      echinostome Echinoparyphium recurvatum at 10, 15, 20, 25 and 30 degrees C.
      Cercarial survival was markedly age- and temperature-dependent, maximum survival
      time being reduced from 68 h at 10 degrees C to 12 h at 30 degrees C, 50%
      survival times falling from 47.9 h at 10 degrees C to 8.4 h at 30 degrees C. The
      mean instantaneous per capita death rate of cercariae increased exponentially
      with temperature. Cercarial infectivity was also temperature dependent, the main
      effect of temperature being upon the rate at which infectivity diminished with
      increasing age of cercariae. Infectivity increased from zero at 10 degrees C to a
      maximum at 25 degrees C after which it declined to a low level at 30 degrees C.
      Overall transmission efficiency of cercariae at each experimental temperature was
      calculated as the ratio of the mean instantaneous per capita death rate (mu) to
      the mean instantaneous per capita rate of infection (beta). Transmission
      efficiency of cercariae was found to be maximal at 20 degrees C and at a
      relatively high level between 10 and 25 degrees C. Transmission efficiency was
      zero at 10 degrees C and at a very low level at 30 degrees C. These results
      suggest that the cercariae of E. recurvatum show transmission optima at water
      temperatures likely to be encountered in natural habitats in Britain and Europe.

PMID- 10340330
TI  - Identification of a developmentally regulated Schistosoma mansoni serine protease
      homologous to mouse plasma kallikrein and human factor I.
AB  - The isolation of 2 genomic clones has allowed us to further characterize a
      Schistosoma mansoni serine protease designated SmSP1. The deduced amino acid
      sequence (248aa) considered as a 'light chain' encoding the active site, presents
      significant homologies with mouse plasma kallikrein and human factor I light
      chain. The secondary structure of SmSP1 'light chain' is correctly predicted and
      may be sufficient by itself to constitute an active enzyme. The biological
      function of SmSP1 is unknown, however, the homology with 2 serine proteases
      suggests that SmSP1 may play a role in the evasion of the host immune response.
      This is supported by the presence of the native protein corresponding to SmSP1
      particularly in schistosomula released products (SRP) and in male dorsal spines.
      The expression of this enzyme is differentially regulated throughout the parasite
      life-cycle. However, infected animals with S. mansoni did not produce specific
      antibodies to recombinant SmSP1. The lack of such response could be advantageous
      to the parasite by protecting itself from host effector mechanisms.

PMID- 10340331
TI  - Identification and characterization of excreted-secreted products and surface
      coat antigens of animal and plant-parasitic nematodes.
AB  - Nematode surface coat (SC) proteins and excreted-secreted products (E-S) are
      likely to play important roles in the host-parasite interaction and considerable
      similarities can be found in SC proteins and E-S products from certain plant and
      animal parasitic nematodes. Monoclonal antibodies raised to E-S products of plant
      parasitic nematodes were shown to cross-react with E-S products and the surface
      coats of the animal parasites Trichinella spiralis and Haemonchus contortus. Most
      of the antibodies recognized carbohydrate epitopes but the activity of 2 MAbs
      (IACR-CCNj.2a.15 and IACR-Misec.8D.3) which recognized proteic epitopes in these
      nematodes were further characterized. Antibody 2a.15 recognized the SC and oral
      exudate of Meloidogyne incognita, T. spiralis and H. contortus. This antigen was
      also immunolocalized in the lining of the oesophagus and gut and in the exudate
      present during ecdysis of H. contortus L3. Antibody 8D.3 reacted with the SC of
      these nematodes on cryosections but on live nematodes the immunofluorescence was
      very patchy and was shed from the nematode SC.

PMID- 10340332
TI  - Epidemiology of an intestinal parasite (Spirometra spp.) in two populations of
      African lions (Panthera leo).
AB  - Infection with the cestode Spirometra spp. was studied in 2 populations of lions
      in the Serengeti and the Ngorongoro Crater in Tanzania, East Africa. These 2 lion
      populations lived in different habitats and were known to differ genetically:
      lions in the Serengeti were outbred, whereas lions in the Ngorongoro Crater were
      inbred. Faecal samples were collected from 112 individually known lions between
      March 1991 and November 1992. Over 60% of lions were infected and the median
      intensity of infection was 975 eggs per g of faeces. The distribution of egg
      counts was overdispersed. There was variability through time, though this was
      unrelated to seasons delimited by rainfall. There were no significant differences
      in levels of infection between age classes; cubs less than 9 months were already
      heavily infected. Sex and reproductive status did not have a significant effect.
      However, there were significant differences in intensities of infection between
      the Crater and the Serengeti populations--Spirometra spp. showed a higher level
      of infection intensity in the Crater population--with some variation between
      prides within these populations. Allozyme heterozygosity scores were available
      for a subset of 28 lions but were unrelated to levels of Spirometra infection. It
      was not possible to ascribe differences in levels of parasite infection to
      genetic rather than ecological factors.

PMID- 10340333
TI  - Regulation of nematode fecundity in the ring-necked pheasant (Phasianus
      colchicus): not just density dependence.
AB  - Patterns of nematode fecundity were investigated for infections of the caecal
      worm Heterakis gallinarum in the ring-necked pheasant (Phasianus colchicus). Worm
      length was a good predictor of parasite fecundity. After controlling for worm
      length no other factors, including parasite intensity, were related to worm
      fecundity. Density dependence in worm size was detected in natural infections at
      parasite intensities above a threshold of 96 worms (worm size decreased with
      increasing parasite intensity). However, below this threshold, worm size actually
      decreased with decreasing parasite intensity (inverse density dependence). The
      interaction between density dependence and inverse density dependence in
      regulating the development and subsequent fecundity of H. gallinarum worms in
      ring-necked pheasants was demonstrated in an infection experiment. Density
      dependence was observed in the stunted growth of worms in heavily infected hosts,
      relative to worms in lightly infected hosts. Inverse density dependence in worm
      size was the common pattern across hosts by the end of the experiment, when
      parasite intensities were below the density dependence threshold. This is the
      first study to document both density dependence and inverse density dependence in
      parasite fecundity in the same host-helminth system.

PMID- 10340335
TI  - The opercular bond in the egg-shell of the monogenean Entobdella soleae, a
      platyhelminth skin parasite of the common sole (Solea solea).
AB  - The monogenean (platyhelminth) skin parasite Entobdella soleae from the common
      sole (Solea solea) lays tetrahedral eggs. One of the 4 corners of the tetrahedron
      is a detachable operculum which is bonded to the rest of the egg-shell by cement.
      Most of this cement layer, beginning at the inner surface of the shell and
      running through almost to the outer surface (a distance of about 2 microns), is
      more or less uniform in thickness (30-38 nm), or tapers slightly. About 345 nm
      from the outer surface the cement layer narrows abruptly to about 10 nm. The
      cement is exposed on the inner surface of the shell, but in most eggs a layer of
      shell about 10 nm thick covers the narrow outer region of the cement layer. When
      experimentally perforated eggs were incubated with trypsin, the wide inner layer
      of cement was digested, but the narrow outer region initially remained intact.
      These observations are discussed in relation to the following (1) survival of the
      eggs during embryonic development, (2) hatching, (3) the 'hinge' often connecting
      the operculum to the empty egg-shell, (4) the rapid hatching that occurs in some
      other monogeneans.

PMID- 10340334
TI  - Epidemiology and genetic variability of two species of nematodes (Heligmosomoides
      polygyrus and Syphacia stroma) of Apodemus spp.
AB  - The epidemiology and genetic variability of 2 parasitic nematodes Heligmosomoides
      polygyrus and Syphacia stroma of Apodemus spp. were investigated. Both are
      parasites of the same host, exhibit a direct life-cycle and are dioecious.
      However, H. polygyrus has a diploid and S. stroma a haplodiploid mode of
      reproduction. Haplodiploidy may lead to a more female biased sex ratio and
      reduced genetic variability. Levels of genetic diversity were analysed using both
      isoenzyme electrophoresis and RAPDs (random amplified polymorphic DNA). Both
      parasites showed a female biased sex ratio with a stronger bias for the
      haplodiploid parasite. Results showed significantly fewer genetic polymorphisms
      as measured by RAPDs for the haplodiploid parasite S. stroma in comparison with
      H. polygyrus. Despite the observed female biased sex ratio this could not be
      explained by a significant amount of inbreeding. Heterozygote deficiency for
      individual allozyme loci--which could indicate inbreeding--was not found in
      either parasite species. Other features of the particular life-history of these
      species are likely to have an impact on the sex ratio and genetic variability
      too.

PMID- 10340336
TI  - [The 72nd general meeting of Japanese Leprosy Association. Tokyo, Japan. April 14
      16, 1999. Abstracts].

PMID- 10340338
TI  - Annual meeting of the Irish medical societies. 1995, 1996, 1997. Abstracts.

PMID- 10340337
TI  - [11th spring meeting of the Japanese Society of Allergology. Osaka, Japan. May 13
      15, 1999. Abstracts].

PMID- 10340339
TI  - [Regional meeting of the Japanese Association for Thoracic Surgery. Japan. 1997
      1998. Abstracts].

PMID- 10340340
TI  - American Federation for Medical Research at Experimental Biology '99. Washington
      DC, USA. April 16-21, 1999. Abstracts.

PMID- 10340341
TI  - [74th annual meeting of the Japanese Society for Tuberculosis. Utsunomia City,
      Japan. April 14-16, 1999. Abstracts].

PMID- 10340342
TI  - [The 103rd annual meeting of the Japanese Ophthalmological Society. Chiba City,
      Japan. April 21-24, 1999. Abstracts].

PMID- 10340343
TI  - A piece of my mind. Saying good-bye.

PMID- 10340344
TI  - The arts of healing.

PMID- 10340345
TI  - AAMC analyzes 1997 Balanced Budget Act. Association of American Medical Colleges.

PMID- 10340346
TI  - Drug doings Down Under.

PMID- 10340347
TI  - From the Centers for Disease Control and Prevention. Outbreaks of Shigella sonnei
      infection associated with eating fresh parsley--United States and Canada, July
      August 1998.

PMID- 10340348
TI  - From the Centers for Disease Control and Prevention. Outbreak of Hendra-like
      virus--Malaysia and Singapore, 1998-1999.

PMID- 10340349
TI  - The firing of Dr Lundberg.

PMID- 10340350
TI  - The firing of Dr Lundberg.

PMID- 10340351
TI  - The firing of Dr Lundberg.

PMID- 10340352
TI  - The firing of Dr Lundberg.

PMID- 10340353
TI  - The firing of Dr Lundberg.

PMID- 10340354
TI  - The firing of Dr Lundberg.

PMID- 10340355
TI  - The firing of Dr Lundberg.

PMID- 10340356
TI  - The firing of Dr Lundberg.

PMID- 10340357
TI  - The firing of Dr Lundberg.

PMID- 10340358
TI  - The firing of Dr Lundberg.

PMID- 10340359
TI  - The firing of Dr Lundberg.

PMID- 10340360
TI  - The firing of Dr Lundberg.

PMID- 10340361
TI  - Editorial independence and THE JOURNAL.

PMID- 10340362
TI  - High-altitude cerebral edema.

PMID- 10340363
TI  - High-altitude cerebral edema.

PMID- 10340364
TI  - High-altitude cerebral edema.

PMID- 10340365
TI  - Informing patients about urinary incontinence.

PMID- 10340366
TI  - Efficacy of tremacamra, a soluble intercellular adhesion molecule 1, for
      experimental rhinovirus infection: a randomized clinical trial.
AB  - CONTEXT: Attachment of most rhinovirus subtypes to cells depends on a cellular
      receptor, the intercellular adhesion molecule 1 (ICAM-1). A recombinant soluble
      ICAM-1 (tremacamra, formerly BIRR 4) has shown possible efficacy in early
      studies. OBJECTIVE: To determine the efficacy and safety of intranasal
      administration of tremacamra in experimental rhinovirus colds in humans. DESIGN:
      Four randomized, double-blind, placebo-controlled trials conducted in January to
      March 1996. SETTING AND SUBJECTS: Volunteers between the ages of 18 and 60 years
      who had an antibody titer of 1:4 or less to the challenge virus. Subjects were
      isolated in a hotel room during study days 0 to 8; symptoms were recorded through
      day 14. A total of 198 subjects were randomized, of whom 196 received drug or
      placebo and were included in the safety analysis. A total of 177 subjects were
      included in the efficacy analysis. INTERVENTIONS: Tremacamra or placebo was given
      beginning 7 hours before inoculation with rhinovirus type 39 (preinoculation
      studies) or 12 hours after (postinoculation studies). Tremacamra as an inhaled
      solution or as a powder (each given preinoculation and postinoculation for a
      total of 4 studies) and placebo were given in 6 doses at 3-hour intervals daily
      during days 1 through 7. Recipients of active treatment received 367 microg of
      tremacamra per nostril per dose for a total of 4.4 mg/d. MAIN OUTCOME MEASURES:
      Effect of tremacamra on infection, as determined by virus isolation and
      seroconversion, and on illness, as determined by symptom scores, clinical colds,
      and nasal mucus weights. Treatment-by-study interaction was not significant, so
      results were pooled for the main analysis. RESULTS: A total of 88 (92%) of the 96
      subjects in the placebo groups and 69 (85%) of the 81 subjects in the active
      treatment groups were infected (P=.19). For placebo vs tremacamra, respectively,
      the total symptom score (+/- 95% confidence interval [CI]) was 17.6 (+/- 2.7) vs
      9.6 (+/- 2.9), the proportion of clinical colds was 64/96 (67% +/- 9%) vs 36/81
      (44% +/- 11%), and the nasal mucus weight was 32.9 (+/- 8.8) g vs 14.5 (+/- 9.4)
      g (P<.001 for all comparisons). Tremacamra was not associated with adverse
      effects or evidence of absorption through the nasal mucosa and did not interfere
      with development of neutralizing antibody. CONCLUSION: Tremacamra reduced the
      severity of experimental rhinovirus colds. Whether tremacamra will be useful
      clinically will require further study.

PMID- 10340367
TI  - Two outbreaks of multidrug-resistant Salmonella serotype typhimurium DT104
      infections linked to raw-milk cheese in Northern California.
AB  - CONTEXT: Salmonella serotype Typhimurium definitive type 104 (DT104), with
      resistance to 5 drugs (ampicillin, chloramphenicol, streptomycin, sulfonamides,
      and tetracycline), has emerged as the most common multidrug-resistant Salmonella
      strain in the United States. However, illnesses resulting from this strain have
      not been associated definitively with a source in this country. OBJECTIVE: To
      determine the source of 2 outbreaks of Salmonella Typhimurium DT104. DESIGN:
      Matched case-control study conducted between March 24 and April 5, 1997 (outbreak
      1), enhanced surveillance for new cases dating from February 1, 1997 (outbreak
      2), and environmental and laboratory investigations. SETTING AND PARTICIPANTS:
      The case-control study included residents of 2 adjacent counties in northern
      California infected with the outbreak strain of Salmonella Typhimurium var
      Copenhagen and age-matched controls. For enhanced surveillance, a case was
      defined as Salmonella Typhimurium infection in a person exposed to fresh Mexican
      style cheese. MAIN OUTCOME MEASURES: Risk factors for infection and source of
      implicated food. RESULTS: Outbreak 1 peaked in February 1997; 31 patients were
      confirmed by culture as having Salmonella Typhimurium var Copenhagen infection,
      isolates of which showed indistinguishable pulsed-field gel electrophoresis
      (PFGE) patterns. The outbreak strain was phage type DT104 with the 5-drug
      resistance pattern. Sixteen cases and 25 controls were enrolled in the case
      control study; 15 of 16 Salmonella Typhimurium var Copenhagen cases compared with
      14 of 24 matched controls reported eating unpasteurized Mexican-style cheese,
      (matched odds ratio, 7.9; 95% confidence interval, 1.1-354.9). Enhanced
      surveillance uncovered outbreak 2, which peaked in April 1997 and was caused by a
      non-Copenhagen variant of Salmonella Typhimurium. During outbreak 2, Salmonella
      Typhimurium was isolated from 79 persons who ate fresh Mexican-style cheese from
      street vendors and from cheese samples and raw milk. The PFGE pattern of the milk
      isolate matched 1 of the 3 patterns recovered from patients; all strains were
      phage type DT104b with the 5-drug resistance pattern. CONCLUSION: Raw-milk
      products pose a risk for multidrug-resistant Salmonella Typhimurium DT104
      infections.

PMID- 10340368
TI  - Investigation of multidrug-resistant Salmonella serotype typhimurium DT104
      infections linked to raw-milk cheese in Washington State.
AB  - CONTEXT: Multidrug-resistant Salmonella Typhimurium DT104 has recently emerged as
      a cause of human and animal illness in Europe and North America. In early 1997,
      health officials in Yakima County, Washington, noted a 5-fold increase in
      salmonellosis among the county's Hispanic population. OBJECTIVES: To characterize
      bacterial strains and identify risk factors for infection with Salmonella
      Typhimurium in Yakima County. DESIGN: Laboratory, case-control, and environmental
      investigations. SETTING AND PARTICIPANTS: Patients with culture-confirmed
      Salmonella Typhimurium infection living in Yakima County and age- and
      neighborhood-matched control subjects. MAIN OUTCOME MEASURES: Food vehicle
      implication based on case-control study and outbreak control. RESULTS: Between
      January 1 and May 5, 1997, 54 culture-confirmed cases of Salmonella Typhimurium
      were reported. The median age of patients was 4 years and 91% were Hispanic.
      Patients reported diarrhea (100%), abdominal cramps (93%), fever (93%), bloody
      stools (72%), and vomiting (53%); 5 patients (9%) were hospitalized. Twenty-two
      patients and 61 control subjects were enrolled in the case-control study.
      Seventeen case patients (77%) reported eating unpasteurized Mexican-style soft
      cheese in the 7 days before onset of illness compared with 17 control subjects
      (28%) (matched odds ratio, 32.3; 95% confidence interval, 3.0-874.6). All case
      patient isolates were phage definitive type 104 (DT104) (n = 10) or DT104b (n =
      12), and 20 (91%) were resistant to ampicillin, chloramphenicol, streptomycin,
      sulfamethoxazole, and tetracycline. The cheese produced and eaten by 2 unrelated
      patients was made with raw milk traced to the same local farm. Milk samples from
      nearby dairies yielded Salmonella Typhimurium DT104. The incidence of Salmonella
      Typhimurium infections in Yakima County returned to pre-1992 levels following
      interventions based on these findings. CONCLUSIONS: Multidrug-resistant
      Salmonella Typhimurium DT104 emerged as a cause of salmonellosis in Yakima
      County, and Mexican-style soft cheese made with unpasteurized milk is an
      important vehicle for Salmonella Typhimurium DT104 transmission. We postulate
      that recent increases in human salmonellosis reflect the emergence of Salmonella
      Typhimurium DT104 among dairy cows in the region. Continued efforts are needed to
      discourage consumption of raw milk products, promote healthier alternatives, and
      study the ecology of multidrug-resistant Salmonella Typhimurium.

PMID- 10340370
TI  - The clinical effectiveness and cost-effectiveness of screening for anal squamous
      intraepithelial lesions in homosexual and bisexual HIV-positive men.
AB  - CONTEXT: Homosexual and bisexual men infected with human immunodeficiency virus
      (HIV) are at increased risk for human papillomavirus-related anal neoplasia and
      anal squamous cell carcinoma (SCC). OBJECTIVE: To estimate the clinical benefits
      and cost-effectiveness of screening HIV-positive homosexual and bisexual men
      foranal squamous intraepithelial lesions (ASIL) and anal SCC. DESIGN: Cost
      effectiveness analysis performed from a societal perspective that used reference
      case recommendations from the Panel on Cost-Effectiveness in Health and Medicine.
      A state-transition Markov model was developed to calculate lifetime costs, life
      expectancy, and quality-adjusted life expectancy for no screening vs several
      screening strategies for ASIL and anal SCC using anal Papanicolaou (Pap) testing
      at different intervals. Values for incidence, progression, and regression of anal
      neoplasia; efficacy of screening and treatment; natural history of HIV; health
      related quality of life; and costs were obtained from the literature. SETTING AND
      PARTICIPANTS: Hypothetical cohort of homosexual and bisexual HIV-positive men
      living in the United States. MAIN OUTCOME MEASURES: Life expectancy, quality
      adjusted life expectancy, quality-adjusted years of life saved, lifetime costs,
      and incremental cost-effectiveness ratio. RESULTS: Screening for ASIL increased
      quality-adjusted life expectancy at all stages of HIV disease. Screening with
      anal Pap tests every 2 years, beginning in early HIV disease (CD4 cell count
      >0.50 x 10(9)/L), resulted in a 2.7-month gain in quality-adjusted life
      expectancy for an incremental cost-effectiveness ratio of $13,000 per quality
      adjusted life year saved. Screening with anal Pap tests yearly provided
      additional benefit at an incremental cost of $16,600 per quality-adjusted life
      year saved. If screening was not initiated until later in the course of HIV
      disease (CD4 cell count <0.50 x 10(9)/L), then yearly Pap test screening was
      preferred due to the greater amount of prevalent anal disease (cost-effectiveness
      ratio of less than $25,000 per quality-adjusted life year saved compared with no
      screening). Screening every 6 months provided little additional benefit over that
      of yearly screening. Results were most sensitive to the rate of progression of
      ASIL to anal SCC and the effectiveness of treatment of precancerous lesions.
      CONCLUSIONS: Screening HIV-positive homosexual and bisexual men for ASIL and anal
      SCC with anal Pap tests offers quality-adjusted life expectancy benefits at a
      cost comparable with other accepted clinical preventive interventions.

PMID- 10340369
TI  - Homocysteine and risk of cardiovascular disease among postmenopausal women.
AB  - CONTEXT: Individuals with elevated levels of homocysteine tend to have higher
      prevalence of cardiovascular disease. However, prospective studies of
      homocysteine are inconsistent and data among women are limited. OBJECTIVE: To
      determine whether elevated homocysteine levels in healthy postmenopausal women
      predict risk of developing cardiovascular disease. DESIGN: Prospective, nested
      case-control study with a mean 3-year follow-up. SETTING: The Women's Health
      Study, an ongoing US primary prevention trial initiated in 1993. PARTICIPANTS:
      From a total cohort of 28,263 postmenopausal women with no history of
      cardiovascular disease or cancer at baseline, 122 women who subsequently
      experienced cardiovascular events were defined as cases, and 244 age- and smoking
      status-matched women who remained free of disease during follow-up were defined
      as controls. MAIN OUTCOME MEASURES: Incidence of death due to cardiovascular
      disease, nonfatal myocardial infarction (MI), stroke, percutaneous transluminal
      coronary angioplasty, or coronary artery bypass graft by baseline homocysteine
      level. RESULTS: Of the 122 cases, there were 85 events of MI or stroke and 37
      coronary revascularizations. Case subjects had significantly higher baseline
      homocysteine levels than controls (14.1 vs 12.4 micromol/L; P = .02). Subjects
      with homocysteine levels in the highest quartile had a 2-fold increase in risk of
      any cardiovascular event (relative risk [RR], 2.0; 95% confidence interval [CI],
      1.1-3.8). This effect was largely due to an excess of cases with high levels of
      homocysteine; the RR for those with homocysteine levels at or higher than the
      95th percentile (20.7 micromol/L) was 2.6 (95% CI, 1.1-5.7). Risk estimates were
      independent of traditional risk factors and were greatest for the end points of
      MI and stroke (RR for those with baseline homocysteine levels in the top
      quartile, 2.2; 95% CI, 1.1-4.6). Self-reported multivitamin supplement use at
      study entry was associated with significantly reduced levels of homocysteine
      (P<.001). However, the association between increasing quartile of homocysteine
      level and risk of MI or stroke remained significant in analyses controlling for
      baseline multivitamin supplement use (P = .003 for trend), and subgroup analyses
      limited to women who were (P = .02 for trend) or were not (P = .04 for trend)
      taking multivitamin supplements. CONCLUSIONS: Among healthy postmenopausal US
      women, elevated levels of homocysteine moderately increased the risk of future
      cardiovascular disease. Whether lowering the homocysteine level reduces risk of
      cardiovascular events requires testing in randomized controlled trials.

PMID- 10340372
TI  - Users' guides to the medical literature: XVI. How to use a treatment
      recommendation. Evidence-Based Medicine Working Group and the Cochrane
      Applicability Methods Working Group.
AB  - Clinicians can often find treatment recommendations in traditional narrative
      reviews and the discussion sections of original articles and meta-analyses.
      Making a treatment recommendation involves framing a question, identifying
      management options and outcomes, collecting and summarizing evidence, and
      applying value judgments or preferences to arrive at an optimal course of action.
      Each step in this process can be conducted systematically (thus protecting
      against bias) or unsystematically (leaving the process open to bias). Clinicians
      faced with a plethora of recommendations may wish to attend to those that are
      less likely to be biased. Therefore, we propose a hierarchy of rigor of
      recommendations to guide clinicians when judging the usefulness of particular
      recommendations. Recommendations with the highest rigor consider all relevant
      options and outcomes, include a comprehensive collection of the methodologically
      highest quality data with an explicit strategy for summarizing the data (that is,
      a systematic review), and make an explicit statement of the values or preferences
      involved in moving from evidence to action. High rigor recommendations come from
      systematically developed, evidence-based practice guidelines or rigorously
      conducted decision analyses. Systematic reviews, which typically do not consider
      all relevant options and outcomes or make the preferences underlying
      recommendations explicit, offer intermediate rigor recommendations. Traditional
      approaches in which the collection and assessment of evidence remains
      unsystematic, all relevant options and outcomes may not be considered, and values
      remain implicit, provide recommendations of weak rigor. In an era in which
      clinicians are barraged by recommendations as to how to manage their patients,
      this hierarchy provides a potentially useful set of guides.

PMID- 10340371
TI  - Preventing stroke in patients with atrial fibrillation.
AB  - CONTEXT: Atrial fibrillation, a common disorder that affects nearly one sixth of
      the population aged 75 years and older, is a major risk factor for stroke.
      OBJECTIVES: To review and evaluate the evidence supporting the use of warfarin
      and/or aspirin for stroke prevention in patients with atrial fibrillation. DATA
      SOURCES: Prospective, randomized trials of patients with atrial fibrillation
      evaluating either warfarin or aspirin or both, from MEDLINE from January 1, 1966,
      to February 23, 1999. STUDY SELECTION: Five primary prevention placebo-controlled
      studies, which had been formally pooled, 1 study evaluating secondary prevention
      of stroke, 1 study comparing warfarin with aspirin, and 3 studies of warfarin in
      combination with aspirin were identified. DATA SYNTHESIS: The risk of developing
      stroke is heterogeneous and increases with each decade above 65 years; history of
      high blood pressure, diabetes mellitus, previous transient ischemic attack, or
      stroke; poor ventricular function; and in women older than 75 years. For patients
      younger than 65 years, without risk factors, and not receiving antithrombotic
      therapy, the risk of stroke is 1%/y; those without risk factors between the ages
      of 65 and 75 years have a risk of 1.1%/y if taking warfarin and 1.4%/y if taking
      aspirin. For all other patients, stroke risk is reduced from an untreated rate of
      between 4.3%/y and more than 12%/y to a rate of 1.2%/y to 4%/y with warfarin use.
      CONCLUSION: The protection afforded by warfarin is most pronounced in patients at
      the highest risk for stroke, while aspirin treatment seems adequate in low-risk
      populations.

PMID- 10340373
TI  - Closer to a cure for the common cold?

PMID- 10340374
TI  - Lessons from investigations of foodborne disease outbreaks.

PMID- 10340375
TI  - International aspects of US government tobacco bills.

PMID- 10340376
TI  - JAMA Patient Page: food-borne illnesses.

PMID- 10340378
TI  - Re-engineering the target specificity of the insulin receptor by modification of
      a PTB domain binding site.
AB  - Shc and IRS-1 (and their relatives) are cytoplasmic docking proteins that possess
      phosphotyrosine-binding (PTB) domains, through which they bind specific activated
      receptor tyrosine kinases (RTK). The subsequent phosphorylation of Shc or IRS-1
      creates binding sites for the SH2 domains of multiple signaling proteins, leading
      to the activation of intracellular biochemical pathways. The PTB domains of Shc
      and IRS-1 both recognize autophosphorylation sites in RTKs with the consensus
      sequence NPXpY, but show distinct abilities to bind stably to RTKs such as the
      TrkA nerve growth factor receptor and the insulin receptor. In vitro analysis has
      suggested that residues N-terminal to the NPXpY motif may determine the affinity
      with which phosphopeptide ligands are recognized by the Shc and IRS-1 PTB
      domains. Unlike IRS-1, the Shc PTB domain binds poorly to the insulin-receptor
      (IR) beta subunit in vitro, owing to its low affinity for the NPXpY
      autophosphorylation site at Tyr 960 of the IR. As a consequence, Shc does not
      bind stably to the activated IR in cells. We show that substitution of Ser 955,
      five residues N-terminal to the Tyr 960 autophosphorylation site (the -5
      position), with Ile alters the target specificity of the IR such that it stably
      associates with Shc in insulin-stimulated cells. A triple substitution of the -5,
      -8 and -9 residues relative to Tyr 960 of the IR to the corresponding amino acids
      found in the Shc PTB domain binding site of TrkA results in even stronger binding
      of the IR to Shc in vivo. The variant IRs with enhanced ability to bind Shc
      showed an increased ability to activate the MAPK pathway in response to insulin
      stimulation. These results demonstrate that subtle differences in residues N
      terminal to NPXpY autophosphorylation sites determine the ability of RTKs to bind
      specific PTB domain proteins in vivo, and thus modify the signaling properties of
      activated receptors.

PMID- 10340377
TI  - Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role
      for IkappaBalpha.
AB  - The NF-kappaB/Rel family of transcription factors regulates a wide variety of
      genes whose products play a fundamental role in inflammatory and immune
      responses. The implication of NF-kappaB/Rel proteins and their IkappaB regulatory
      subunits in the control of cellular growth and oncogenesis, was suggested by the
      induction of fatal lymphomas in birds by the v-rel oncoprotein, and the
      rearrangement and amplification of several genes encoding the NF
      kappaB/Rel/IkappaB signal transduction factors in human malignancies, primarily
      of lymphoid origin. Hodgkin's disease (HD) is a lymphoma characterized by a low
      frequency of malignant Hodgkin and Reed-Sternberg (H/RS) cells in a reactive
      background of non-neoplastic cells. The peculiar activated phenotype of Hodgkin
      and Reed-Sternberg cells and their pattern of cytokine secretion are believed to
      be a consequence of constitutive activation of the NF-kappaB transcription
      factor. Here, we report the detection of mutations of the IkBa gene, in two HD
      derived cell lines and in two out of eight biopsy samples from patients with
      relapsed Hodgkin's disease. The presence of defective IkappaBalpha is thus likely
      to explain the constitutive activation of NF-kappaB in these cells and suggests
      that IkappaBalpha is a tumour suppressor controlling the oncogenic activation of
      NF-kappaB in Hodgkin and Reed-Sternberg cells.

PMID- 10340379
TI  - Cell specific transformation by c-fms activating loop mutations is attributable
      to constitutive receptor degradation.
AB  - Expression of a receptor for human macrophage-colony stimulating factor (M-CSF or
      CSF-1), containing a point mutation which changes an aspartate to a valine at
      position 802 of the activating loop of the kinase domain, potently transforms the
      haemopoietic cell line FDC-P1 yet prevents Rat-2 fibroblast transformation. In
      order to understand this apparent paradox, aspartate 802 was changed by cassette
      mutagenesis to each of the other 19 amino acids. All hydrophobic amino acid
      substitutions were transforming when tested in FDC-P1 cells yet inactivating when
      tested in Rat-2 fibroblasts. These same amino acid substitutions also activated
      receptor degradation, strongly suggesting a causal relationship between receptor
      degradation and inactivation in fibroblasts. Point mutations or small deletions
      of Y708 within the kinase insert region of the mutant D802V receptor partly
      inhibited receptor degradation. The more stable D802V receptor derivatives were
      able to transform both FDC-P1 cells and Rat-2 fibroblasts, so establishing that
      the cell specific effect of the c-fmsD802V activating loop mutation is
      attributable to receptor degradation which accompanies kinase activation and
      prevents the transformation of Rat-2 but not of FDC-P1 cells.

PMID- 10340380
TI  - Sustained MAP kinase activation is required for the expression of cyclin D1,
      p21Cip1 and a subset of AP-1 proteins in CCL39 cells.
AB  - In CCL39 cells thrombin is a potent growth factor which requires sustained
      activation of mitogen activated protein kinases (MAPKs) to promote DNA synthesis.
      Some of the effects of thrombin can be mimicked by peptides based on the new
      amino terminus of the cleaved receptor; however, these thrombin receptor peptides
      (TRPs) fail to induce sustained activation of MAPK or DNA synthesis. We have used
      thrombin, TRP-7 and other agonists which elicit sustained or transient MAPK
      activation to identify immediate-early and delayed-early genes which are only
      expressed under conditions of sustained MAPK activation focusing on cyclin D1,
      p21CiP1 and the AP-1 transcription factor. Of the stimuli tested only FBS and
      thrombin were able to stimulate a sustained activation of MAPK, expression of
      cyclin D1, p21Cip1 and cell cycle re-entry. The expression of cyclin D1 was
      strongly, though not completely, inhibited by the MEK1 inhibitor PD098059.
      Thrombin stimulated a rapid but transient accumulation of c-Fos whereas the
      expression of Fra-1, Fra-2, c-Jun and JunB was sustained throughout the G1 phase
      of the cell cycle. We focussed our analysis on c-Fos (typical of AP-1 genes which
      are expressed rapidly and transiently) and Fra-1 and JunB (typical of AP-1 genes
      expressed after a delay but in a sustained manner). The expression of c-Fos, Fra
      1 and JunB was dependent upon the activation of MAPK since these responses were
      inhibited by PD098059. However, a comparison of responses to FBS, thrombin, TRPs,
      LPA and EGF revealed that Fra-1 and JunB expression required sustained activation
      of MAPK whereas c-Fos expression was strongly induced even by non-mitogenic
      stimuli which elicited only transient MAPK activation. The expression of c-Fos
      (in response to thrombin, TRP or LPA) or Fra-1, JunB and cyclin D1 (thrombin
      only) was also inhibited by pertussis toxin. This suggests that both early and
      late AP-1 gene expression is regulated by the same Gi-mediated, MEK-dependent
      MAPK signalling pathway but that expression of late AP-1 genes and cyclin D1
      requires that this pathway be persistently activated. The results suggest that
      the duration of receptor signalling and therefore MAPK activation is a key
      determinant of qualitative changes in gene expression during cell cycle re-entry.

PMID- 10340381
TI  - Higher frequency of Smad4 gene mutation in human colorectal cancer with distant
      metastasis.
AB  - We have previously detected an increased frequency of loss of heterozygosity
      (LOH) on chromosome 18q during progression of colorectal carcinomas. To clarify
      the target of 18qLOH, mutation of Smad4 and Smad2 genes was analysed in 176
      colorectal tumors with different stages, including liver metastasis, from 111
      sporadic, 52 familial adenomatous polyposis (FAP) and nine hereditary
      nonpolyposis colorectal cancer (HNPCC) patients. Mutation of other Smad gene
      families in the TGF-beta signaling pathway was also examined. Twenty-one Smad4
      mutations and one Smad2 mutation were detected, whereas mutation of Smad3, 6 and
      7 genes was not detected. Smad4 mutations included seven frameshift, one inframe
      deletion, four nonsense and nine missense mutations, 95% of which resulted in
      alteration of Smad4 protein regions included in homo-oligomer and hetero-oligomer
      formation. Frequencies of tumors with Smad4 mutation were 0/40 (0%) in adenoma,
      4/39 (10%) in intramucosal carcinoma, 3/44 (7%) in primary invasive carcinoma
      without distant metastasis, 6/17 (35%) in primary invasive carcinoma with distant
      metastasis, and 11/36 (31%) in distant metastasis (metastatic/non-metastatic:
      P=0.006 approximately 0.01). Loss of the other allele was observed in 19 of 20
      (95%) invasive and metastasized carcinomas with Smad4 mutations. In four cases
      both primary and metastasized carcinomas in the same patients showed the same
      mutations. The present results suggest that Smad4 gene is one of true targets of
      18qLOH, and that its inactivation is involved in advanced stages, such as distant
      metastasis, in human colorectal carcinogenesis.

PMID- 10340382
TI  - Disabled-2 inactivation is an early step in ovarian tumorigenicity.
AB  - Disabled-2 (Dab2) functions in mitogenic signal transduction pathway, and is
      frequently activated by homozygous gene deletion in tumors, suggesting that Dab2
      is a candidate tumor suppressor. Here, we surveyed the expression of Dab2, and
      report that Dab2 is expressed in a variety of tissues, and the level of
      expression is particularly high in ovary and breast. Dab2 expression was also
      detected in immortalized breast and ovarian epithelial cells. However, in more
      than a dozen established tumor cell lines derived from breast and ovarian
      epithelial tumors examined by Western blotting, Dab2 expression was undetectable
      in 90% of these cell lines. Histological staining of human ovarian tissues with
      specific anti-Dab2 antibodies indicated that Dab2 is highly expressed in the
      surface epithelial layer. In an immunohistological study of 26 ovarian
      carcinomas, 22 (85%) of the tumors were found to lose the expression of Dab2 in
      the tumor cells, which are epithelial origin. Loss of Dab2 expression is not
      correlated with tumor grade, suggesting that Dab2 is lost in an early stage of
      tumorigenicity. Indeed, loss of Dab2 correlates closely with morphological
      transformation of the surface epithelial cells. Additionally, loss of Dab2
      protein occurs in hyperproliferative, but histological benign ovarian epithelium,
      suggesting that loss of Dab2 occurs in pre-malignant lesions. Thus, this study
      indicates that the loss of Dab2 expression is correlated with tumorigenicity of
      the cells disregarding the grade of the tumors, and loss of Dab2 expression is an
      early event in ovarian malignancies.

PMID- 10340383
TI  - DNA-PK, the DNA-activated protein kinase, is differentially expressed in normal
      and malignant human tissues.
AB  - DNA-PK is a nuclear, serine/threonine protein kinase required for repairing DNA
      double-strand breaks and for V(D)J recombination. To determine the distribution
      of DNA-PK in human tissues, we assayed paraffin-embedded sections of normal and
      cancerous tissues for DNA-PKcs and Ku80 by immunohistochemistry. We also assayed
      for Brca2, a human tumor suppressor gene that is implicated in the repair of DNA
      strand-breaks. Brca2 was strongly expressed in epithelial cells of the breast,
      endometrium, and thymus, in tingible body macrophages of follicular germinal
      centers of lymphoid tissue, and in reticuloendothelial cells in the spleen. DNA
      PKcs and Ku80 expression was usually parallel, but both were expressed in a
      highly cell- and tissue-specific manner. The highest levels were observed in
      spermatogenic cells (but not in spermatozoa), and in neurons and glial cells of
      the central and autonomic nervous system. Neither protein was consistently
      expressed in liver nor in resting mammary epithelium, but lactating breast
      epithelium was strongly positive for DNA-PKcs and Ku80. In contrast to
      established human cell cultures, expression between cells in the same tissue was
      highly selective in the epidermis, exocrine pancreas, renal glomeruli, the red
      pulp of the spleen, and within cellular compartments of tonsils, lymph nodes, and
      thymus. Most cancerous tissues were consistently positive for DNA-PKcs and Ku80,
      except invasive carcinoma of the breast. DNA-PKcs, Ku80, and Ku70 mRNAs were
      expressed in all normal tissues with relatively little variation in levels. Our
      results suggest that the apparent absence of DNA-PKcs and Ku80 from some cells or
      tissues is a consequence of post-transcriptional mechanisms that regulate protein
      levels.

PMID- 10340384
TI  - Identification of three distinct regions of allelic deletions on the short arm of
      chromosome 8 in hepatocellular carcinoma.
AB  - The chromosome 8p is associated with a large number of allelic imbalances in
      epithelial tumors including hepatocellular carcinoma (HCC). However, no tumor
      suppressor gene has been identified so far in this particular region of the
      genome. To further clarify the pattern of allelic deletions on chromosome 8p in
      HCC, we have undertaken high-density polymorphic marker analysis of 109 paired
      normal and primary tumor samples using 40 microsatellites positioned every 2 cm
      in average throughout 8p. We found that 60% of the tumors exhibited loss of
      heterozygosity (LOH) at one or more loci at 8p with three distinct minimal
      deleted areas: a 13 cm region in the distal part of 8p21, a 9 cm area in the more
      proximal portion of 8p22 and a 5 cm area in 8p23. These data strongly suggest the
      presence of at least three novel tumor suppressor loci on 8p in hepatocellular
      carcinoma.

PMID- 10340385
TI  - P53-dependent effects of RAS oncogene on chromosome stability and cell cycle
      checkpoints.
AB  - Mutations activating the function of ras proto-oncogenes are often observed in
      human tumors. Their oncogenic potential is mainly due to permanent stimulation of
      cellular proliferation and dramatic changes in morphogenic reactions of the cell.
      To learn more on the role of ras activation in cancerogenesis we studied its
      effects on chromosome stability and cell cycle checkpoints. Since the ability of
      ras oncogenes to cause cell transformation may be dependent on activity of the
      p53 tumor-suppressor the cells with different p53 state were analysed. Ectopic
      expression of N-ras(asp12) caused in p53-deficient MDAH041 cell line an
      augmentation in the number of chromosome breaks in mitogenic cells, significant
      increase in the frequency of metaphases showing chromosome endoreduplication and
      accumulation of polyploid cells. Similar effects were induced by different
      exogenous ras genes (N-ras(asp12), H-ras(leu12), N-ras proto-oncogene) in Rat1
      and Rat2 cells which have a defect in p53-upstream pathways. In contrast, in
      REF52 and human LIM1215 cells showing ras-induced p53 up-regulation, ras
      expression caused only slight increase in the number of chromosome breaks and did
      not enhance the frequency of endoreduplication and polyploidy. Inactivation in
      these cells of p53 function by transduction of dominant-negative C-terminal p53
      fragment (genetic suppressor element #22, GSE22) or mutant p53s significantly
      increased the frequency of both spontaneous and ras-induced karyotypic changes.
      In concordance with these observations we have found that expression of ras
      oncogene caused in p53-defective cells further mitigation of ethyl
      metansulphonate-induced G1 and G2 cell cycle arrest, but did not abrogate G1 and
      G2 cell cycle checkpoints in cells with normal p53 function. These data indicate
      that along with stimulation of cell proliferation and morphological
      transformation ras activation can contribute to cancerogenesis by increasing
      genetic instability.

PMID- 10340387
TI  - DPC4/SMAD4 mediated tumor suppression of colon carcinoma cells is associated with
      reduced urokinase expression.
AB  - We recently identified DPC4/Smad4 as a candidate tumor suppressor gene mutated or
      lost in one half of pancreatic carcinomas and in a subset of colon and biliary
      tract carcinomas. DPC4 plays a key role in signal transduction of the TGF-beta
      superfamily of molecules and inactivation of TGF-beta mediated growth inhibition
      is supposed to be the driving force for DPC4 inactivation in human tumors.
      However, DPC4 mediated tumor suppression by reconstitution of defective cells has
      not yet been reported. Here we show suppression of tumorigenicity in nude mice by
      stable reexpression of DPC4 in SW480 colon carcinoma cells. In vitro growth of
      DPC4-transfected cells was not affected and resistance towards TGF-beta mediated
      growth inhibition was retained. Instead, cells exhibited morphological
      alterations and adhesion and spreading were accelerated. These phenotypic changes
      were associated with reduced expression levels of the endogenous urokinase-type
      plasminogen activator (uPA) and plasminogen-activator-inhibitor-1 (PAI-1) genes,
      the products of which are implicated in the control of cell adhesion and
      invasion. In patients, high expression levels of uPA and PAI-1 correlate with
      poor prognosis. Thus, reduced expression of uPA and PAI-1 is consistent with
      suppression of tumorigenicity in DPC4 reconstituted cells. These results
      demonstrate DPC4's tumor suppressive function and suggest a potential role for
      DPC4 as a modulator of cell adhesion and invasion.

PMID- 10340386
TI  - The Wilms' tumor gene product represses the transcription of thrombospondin 1 in
      response to overexpression of c-Jun.
AB  - Thrombospondin 1 (TSP1) is known for its significant anti-angiogenic properties.
      In a previous study, we have shown that transient or stable overexpression of the
      transcription factor c-Jun, in rat fibroblasts, leads to repression of TSP1. We
      now demonstrate that the c-Jun-induced repression of TSP1 does not occur directly
      and does not require binding of c-Jun to the TSP1 promoter. Instead, repression
      involves a factor secreted by c-Jun-overexpressing cells. This secreted factor
      triggers a signal transduction pathway from the membrane to the nucleus, and
      these signals lead to the binding of the product of the Wilms' tumor suppressor
      gene, WT1, to the -210 region of the TSP1 promoter. This region binds WT1 and
      SP1, but not EGR1, although its sequence fits the consensus binding site for this
      transcription factor. WT1 overexpression in transfected cells inhibits endogenous
      TSP1 gene expression and TSP1 transcription in experiments using TSP1 promoter
      reporter constructs. The WT1 - KTS isoform is more active in repressing TSP1
      transcription than WT1 + KTS, while EGR1 is inactive. Enhancement of WT1 binding
      to DNA in response to c-Jun does not require de novo protein synthesis. The above
      mechanism for TSP1 repression could apply to other genes, thus coordinating their
      regulation in the vicinity of a c-Jun-overexpressing cell. We conclude that WT1,
      which was discovered as a result of its tumor suppressor properties, may also
      possess oncogenic characteristics in the c-Jun transformation process, and thus
      repress the anti-angiogenic protein, TSP1.

PMID- 10340388
TI  - Restriction landmark genome scanning for aberrant methylation in primary
      refractory and relapsed acute myeloid leukemia; involvement of the WIT-1 gene.
AB  - There is substantial evidence to suggest that aberrant DNA methylation in the
      regulatory regions of expressed genes may play a role in hematologic malignancy.
      In the current report, the Restriction Landmark Genomic Scanning (RLGS) method
      was used to detect aberrant DNA methylation (M) in acute myeloid leukemia (AML).
      RLGS-M profiles were initially performed using DNA from diagnostic, remission,
      and relapse samples from a patient with AML. Rp18, one of the eight spots found
      that was absent in the relapse sample, was cloned. Sequence analysis showed that
      the spot represented a portion of the WIT-1 gene on human chromosome 11p13. Rp18
      was missing in the relapse sample due to a distinct DNA methylation pattern of
      the WIT-1 gene. Twenty-seven AML patients that entered CR after therapy (i.e.,
      chemosensitive) were studied and only 10 (37%) of the diagnostic bone marrow (BM)
      samples showed methylation of WIT-1. However, seven of eight (87.5%) diagnostic
      BM samples from primary refractory AML (chemosensitive) showed methylation of WIT
      1. The incidence of WIT-1 methylation in primary refractory AML was significantly
      higher than that noted in chemosensitive AML (P=0.018). Together, these results
      indicate that RLGS-M can be used to find novel epigenetic alterations in human
      cancer that are undetectable by standard methods. In addition, these results
      underline the potential importance of WIT-1 methylation in chemoresistant AML.

PMID- 10340389
TI  - Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein.
AB  - Breast cancer is the most common cancer among American women, whereas Asian
      women, who consume a traditional diet high in soy products, have a relatively low
      incidence. Genistein is a prominent isoflavonoid in soy products and has been
      proposed as the agent responsible for lowering the rate of breast cancer in Asian
      women. We investigated the effects of genistein on cell growth and apoptosis
      related gene expression in breast cancer cells MDA-MB-231. We found up-regulation
      of Bax and p21WAF1 expressions and down-regulation of Bcl-2 and p53 expression in
      genistein-treated cells. Furthermore, DNA ladder formation, CPP32 activation, and
      PARP cleavage were observed after treatment with genistein, indicating apoptotic
      cell deaths. Flow cytometry with 7-amino actinomycin D staining showed that the
      number of apoptotic cells increased with longer treatment of genistein. From
      these results, we conclude that genistein inhibits the growth of MDA-MB-231
      breast cancer cells, regulates the expression of apoptosis-related genes, and
      induces apoptosis through a p53-independent pathway. The up-regulation of Bax and
      p21WAF1 may be the molecular mechanisms by which genistein induces apoptosis,
      however, further definitive studies are needed. These results suggest that
      genistein may be a potentially effective chemopreventive or therapeutic agent
      against breast cancer.

PMID- 10340390
TI  - Functional localization of a melanoma tumor suppressor gene to a small (< or = 2
      Mb) region on 11q23.
AB  - We have previously demonstrated the existence of a melanoma tumor suppressor
      gene(s) on the long arm of chromosome 11 through suppression of tumorigenicity
      assays. Although loss of heterozygosity studies also support this finding, only a
      large critical region (44 cM) has been identified to date on 11q22-25. To further
      localize a tumor suppressor gene(s) within this region, we have now generated and
      characterized nine melanoma microcell hybrids, each retaining an introduced
      fragment of 11q. Of the nine hybrids, four were suppressed for tumor formation in
      nude mice, while five formed tumors at the same rate as the parental melanoma
      cell line (UACC 903). Molecular analysis of the hybrids with 118 microsatellite
      markers narrowed the location of a putative suppressor gene to a small (< or =2
      Mb) candidate region on 11q23 between the markers D11S1786 and D11S2077 and
      within the larger region frequently deleted in melanoma tumors and cell lines.
      While multiple tumor suppressor genes are likely to reside on 11q22-25, the
      presence of this region in all four suppressed hybrids supports the simplest
      model that a single locus is responsible for the suppressed phenotype observed in
      UACC 903.

PMID- 10340391
TI  - PTEN/MMAC1 mutations in hepatocellular carcinomas.
AB  - Mutations in the PTEN/MMAC1 gene have been identified in several types of human
      cancers and cancer cell lines, including brain, endometrial, prostate, breast,
      thyroid, and melanoma. In this study, we screened a total of 96 hepatocellular
      carcinoma (HCC) samples from Taiwan, where HCC is the leading cancer in males and
      third leading cancer in females, for mutations in the PTEN/MMAC1 gene. Complete
      sequence analysis of these samples demonstrated a missense mutation in exon 5
      (K144I) and exon 7 (V255A) from HCC samples B6-21 and B6-2, respectively. A
      putative splice site mutation was also detected in intron 3 from sample B6-2.
      Both B6-21 and B6-2 were previously shown to contain missense mutations in the
      coding sequences of the p53 gene. Functional studies with the two missense
      mutations demonstrated that while mutation V255A in exon 7 resulted in a loss of
      phosphatase activity, mutation K144I in exon 5 retained its phosphatase activity.
      Additionally, we identified a silent mutation (P96P) in exon 5 of the PTEN/MMAC1
      gene from HCC sample B6-22. These data provide the first evidence that the
      PTEN/MMAC1 gene is mutated in a subset of HCC samples.

PMID- 10340392
TI  - Development of the hematopoietic system in the mouse.

PMID- 10340393
TI  - Functional activity of murine CD34+ and CD34- hematopoietic stem cell
      populations.
AB  - The transmembrane glycoprotein CD34 is expressed on human hematopoietic stem
      cells and committed progenitors in the bone marrow, and CD34-positive selection
      currently is used to isolate bone marrow repopulating cells in clinical
      transplantation protocols. Recently, CD34- hematopoietic stem cells were
      described in both humans and mice, and it was suggested that CD34+ murine bone
      marrow cells may lack long-term reconstituting ability. In this study, the long
      term repopulating ability of CD34+Lin- vs CD34-Lin- cells was compared directly
      using syngeneic murine bone marrow transplantation. Highly purified populations
      of CD34+Lin- and CD34-Lin- cells each are able to reconstitute bone marrow,
      confirming that both populations contain hematopoietic stem cells; however, the
      number of hematopoietic stem cells in the CD34+Lin- fraction is approximately 100
      fold greater than the number in the CD34-Lin- fraction. In competitive
      repopulation experiments, CD34+ stem cells are better able to engraft the bone
      marrow than are CD34- cells. CD34+Lin- cells provide both short- and long-term
      engraftment, but the CD34-Lin- cells are capable of only long-term engraftment.
      Ex vivo, the CD34+Lin- stem cells expand over 3 days in culture and maintain the
      ability to durably engraft animals in a serial transplant model. In contrast,
      when CD34-Lin- cells are cultured using the same conditions ex vivo, the cell
      number decreases, and the cells do not retain the ability to repopulate the bone
      marrow. Thus, the CD34+Lin- and CD34-Lin- cells constitute two functionally
      distinct populations that are capable of long-term bone marrow reconstitution.

PMID- 10340395
TI  - Erythropoietin production in anemia associated with experimental cancer.
AB  - Serum erythropoietin (EPO) concentrations reportedly are depressed in patients
      with chronic disorders such as cancer, rheumatoid arthritis, and acquired
      immunodeficiency syndrome. We evaluated serum EPO levels in mice with tumors and
      found that the EPO response was appropriate for the associated anemia during the
      major part of the disease process. The levels of the hormone increased as the
      anemia worsened in association with progression of the disease. The increased EPO
      levels were comparable to those of controls with a similar degree of
      experimentally induced anemia. Only during the terminal stages of cancer, when
      the animals were severely cachectic, were serum EPO concentrations lower than in
      controls with a similar degree of anemia. These findings suggest that a blunted
      EPO response in experimental cancer occurs only in association with advanced
      disease.

PMID- 10340394
TI  - Colony-stimulating factor-1 impairs both proliferation and differentiation
      signals of erythropoietin during the commitment of bipotential NFS-60 cell line
      to the monocytic lineage.
AB  - The interleukin-3 (IL-3) dependent cell line NFS-60 contains bipotential
      progenitors that exhibit both erythroid and myelomonocytic potentials. In order
      to study their commitment to the monocytic lineage, NFS-60 cells were
      retrovirally transduced with mouse c-fms cDNA, which encodes the colony
      stimulating factor-1 receptor (CSF-1R), resulting in the N-Fms cell line. N-Fms
      cells proliferated in response to CSF-1 with a growth rate similar to that
      obtained in response to IL-3 and progressively differentiated from myeloid blasts
      to monocytic cells within 3 days of culture. When maintained in IL-3, about 3% of
      N-Fms cells formed large hemoglobinized colonies in semisolid cultures
      supplemented with erythropoietin (EPO). However, this property was lost after a
      24-hour cultivation in the presence of CSF-1 or, interestingly, both CSF-1 and IL
      3. This loss of response to EPO was reverted following a brief passage (24 hours)
      in IL-3, but the rescued colonies did not undergo terminal erythrocytic
      differentiation. Furthermore, CSF-1 also affected proliferative response to EPO
      of N-Fms cells constitutively expressing EPO receptors. Our data strongly suggest
      that CSF-1 can suppress erythroid potential in bipotential N-Fms cells by
      altering proliferative and differentiation signal of EPO.

PMID- 10340396
TI  - Prolactin exerts hematopoietic growth-promoting effects in vivo and partially
      counteracts myelosuppression by azidothymidine.
AB  - Prolactin (PRL) is a neuroendocrine hormone that influences immune and
      hematopoietic development. The mechanism of action of this hormone in vivo
      remains unclear; therefore, we assessed the effects of PRL on hematopoiesis in
      vivo and in vitro. Normal resting mice were treated with 0, 1, 10, or 100 microg
      of recombinant human prolactin (rhPRL) for 4 consecutive days and euthanized on
      the fifth day for analysis of myeloid and erythroid progenitors in the bone
      marrow and spleen. Both frequencies and absolute numbers of splenic colony
      forming unit granulocyte-macrophage (CFU-GM) and burst-forming unit-erythroid
      (BFU-e) were significantly increased in mice receiving rhPRL compared to the
      controls that had received saline only. Bone marrow cellularities were not
      significantly affected by any dose of rhPRL, but the absolute numbers and
      frequencies of bone marrow CFU-GM and BFU-e were augmented by rhPRL. These
      results suggest that rhPRL can promote hematopoiesis in vivo. Because rhPRL
      augments myeloid development in vivo, we examined the potential of the hormone to
      reverse the anemia and myelosuppression induced by azidothymidine (AZT). Mice
      were given rhPRL injections concurrent with 2.5 mg/mL AZT in drinking water.
      rhPRL partially restored hematocrits in the animals after 2 weeks of treatment
      and increased CFU-GM and BFU-e in both spleens and bone marrow. The experiments
      with AZT and rhPRL support the conclusion that the hormone increases myeloid and
      erythroid progenitor numbers in vivo, and they suggest that the hormone is
      clinically useful in reversing myelosuppression induced by AZT or other
      myeloablative therapies.

PMID- 10340397
TI  - Optimization of retroviral-mediated gene transfer to human NOD/SCID mouse
      repopulating cord blood cells through a systematic analysis of protocol
      variables.
AB  - Retroviral transduction of human hematopoietic stem cells is still limited by
      lack of information about conditions that will maximize stem cell self-renewal
      divisions in vitro. To address this, we first compared the kinetics of entry into
      division of single human CD34+CD38- cord blood (CB) cells exposed in vitro to
      three different flt3-ligand (FL)-containing cytokine combinations. Of the three
      combinations tested, FL + hyperinterleukin 6 (HIL-6) yielded the least clones and
      these developed at a slow rate. With either FL + Steel factor (SF) + HIL-6 +
      thrombopoietin (TPO) or FL + SF + interleukin 3 (IL-3) + IL-6 + granulocyte
      colony-stimulating factor (G-CSF), >90% of the cells that formed clones within 6
      days undertook their first division within 4 days, although not until after 24
      hours. These latter two, more stimulatory, cytokine combinations then were used
      to assess the effect of duration of cytokine exposure on the efficiency of
      transducing primitive CB cells with a gibbon ape leukemia virus-pseudotyped
      murine retroviral vector containing the enhanced green fluorescent protein (GFP)
      cDNA and the neomycin resistance gene. Fresh lin- CB cells exposed once to medium
      containing this virus plus cytokines on fibronectin-coated dishes yielded 23%
      GFP+ CD34+ cells and 52-57% G418-resistant CFC when assessed after 2 days.
      Prestimulation of the target cells (before exposing them to virus) with either
      the four or five cytokine combination increased their susceptibility. In both
      cases, the effect of prestimulation assessed using the same infection protocol
      was maximal with 2 days of prestimulation and resulted in 47-54% GFP+ CD34+ cells
      and 67-69% G418-resistant CFC. Repeated daily addition of new virus (up to three
      times), with assessment of the cells 2 days after the last addition of fresh
      virus, gave only a marginal improvement in the proportion of transduced CD34+
      cells and CFC, but greatly increased the proportion of transduced LTC-IC (from
      40% to >99%). Transplantation of lin- CB cells transduced using this latter 6-day
      protocol into NOD/SCID mice yielded readily detectable GFP+ cells in 10 of 11
      mice that were engrafted with human cells. The proportion of the regenerated
      human cells that were GFP+ ranged from 0.2-72% in individual mice and included
      both human lymphoid and myeloid cells in all cases. High-level reconstitution
      with transduced human cells was confirmed by Southern blot analysis. These
      findings demonstrate that transplantable hematopoietic stem cells in human CB can
      be reproducibly transduced at high efficiency using a 6-day period of culture in
      a retrovirus-containing medium with either FL + SF + HIL-6 + TPO or FL + SF + IL
      3 + IL-6 + G-CSF in which virus is added on the third, fourth, and fifth day.

PMID- 10340398
TI  - Lineage switch in childhood leukemia with monosomy 7 and reverse of lineage
      switch in severe combined immunodeficient mice.
AB  - Morphophenotypic lineage switches occur in a small percentage of those with acute
      leukemia, and the underlying mechanisms are not clear. In this study, we
      attempted to induce a lineage switch in acute myelocytic leukemia (AML) with
      monosomy 7, whose lineage had switched from acute T-lymphocytic leukemia (T-ALL)
      during chemotherapy, in severe combined immunodeficient (SCID) mice. Although the
      transplanted myeloid cells were engrafted in SCID mice without cytokine
      administration, T-ALL developed in SCID mice treated with recombinant human
      granulocyte-macrophage colony-stimulating factor or recombinant human interleukin
      3. Analysis of the nucleotide sequences of the rearranged T-cell receptor gamma
      chain (TCR-gamma) gene revealed that this lineage switch resulted from the
      selection of the T-lineage subclone in SCID mice, which had expanded at onset. In
      addition, we found that the T-lineage and myeloid cells belonged to the distinct
      subclones, which were different in TCR-gamma gene rearrangements, but were
      derived from a common clone with an identical N-ras gene mutation for both
      subclones. In in vitro cultures, only the myeloid subclone grew; the T-lineage
      subclone failed to grow even in the presence of recombinant human granulocyte
      macrophage colony-stimulating factor or recombinant human interleukin 3. These
      results suggested that the initial diagnostic T-lymphoid subclone, whose growth
      was dependent on these cytokines and the hematopoietic microenvironment, emerged
      from a bipotential T-lymphoid/myeloid leukemic stem cell, and further genetic
      event(s) induced the myeloid subclone, which grew independently of these
      cytokines and the microenvironment.

PMID- 10340399
TI  - Adhesion molecules involved in the interactions between early T cells and
      mesenchymal bone marrow stromal cells.
AB  - We previously reported that among the various thymic lymphocyte subpopulations,
      the immature T cells preferentially adhere to mesenchymal bone marrow stroma. In
      the present study we examined the interactions between phenotypically defined
      populations of early T cells and stromal cell lines. The immature T cells
      segregated into two subpopulations according to their adhesive capacity. Whereas
      the majority of the adherent CD4-CD8- T cells were devoid of CD3/TCRalphabeta,
      most of the nonadherent CD4-CD8- T cells expressed this receptor complex. The
      adhesion of T cells to bone marrow stroma almost entirely was accounted for by
      CD49d and CD90, whereas that of adherent CD4-CD8- cells also was dependent on
      CD44, CD62L, and CD117 receptor. Blocking antibody combinations failed to reduce
      the adherence of these early T cells to less than 50% that of the control. On the
      other hand, the adhesion of unselected thymocytes to the stroma was reduced by
      80%, using the same blocking antibodies. Therefore, the participation of
      additional molecules in the adhesion of early T cells to mesenchymal stroma is
      implicated. Comparison between the interaction of T cells with bone marrow
      mesenchymal or with thymus-derived epithelial stroma indicated that T cells
      utilize a selected set of adhesion molecules under each situation. Although CD49d
      and CD90 participated in both cases, CD11a, CD18, and CD2 receptors played a
      dominant role in the adhesion of T cells to thymic epithelium only. This study
      may point to a role of mesenchymal stroma in the regulation of early T-cell
      lymphopoiesis in the bone marrow.

PMID- 10340400
TI  - Effect of arsenic trioxide on viability, proliferation, and apoptosis in human
      megakaryocytic leukemia cell lines.
AB  - Arsenic trioxide (As2O3) has been demonstrated to be effective for the treatment
      of acute promyelocytic leukemia (APL) and to inhibit proliferation and produce
      apoptosis in the APL cell line NB4. To determine if As2O3 might be useful for the
      treatment of other lineages, we investigated the effects of As2O3 on viability,
      proliferation, and induction of apoptosis in the megakaryocytic leukemia cell
      lines HEL, Meg-01, UT7, and M07e. Our results showed that As2O3, at
      concentrations of 0.1-2.0 microM, causes a dose- and time-dependent inhibition of
      survival and growth in all four megakaryocytic leukemia cell lines studied. In
      contrast, As2O3 at similar concentrations had no effects on either viability or
      growth of the nonmegakaryocytic leukemia cell line HL60 and two human breast
      cancer cell lines, ZR75 and MCF7. In situ end-labeling of DNA fragments (TUNEL
      assay) indicated that As2O3, at concentrations of 0.5-2 microM, could
      significantly induce apoptosis in the aforementioned four megakaryocytic leukemia
      cell lines, but not in the nonmegakaryocytic HL60, ZR75, and MCF7 cell lines.
      These results were confirmed using conventional morphologic assessment and the
      DNA ladder assay. Induction of apoptosis in arsenic-treated Meg-01 and UT7 cells
      was accompanied by a dose-response decrease of Bcl-2 protein, whereas As2O3 had
      no effect on this measurement in HL60, ZR75, and MCF7 cell lines. Pertinently,
      these concentrations of As2O3 produced identical changes in the characteristics
      of the APL cell line NB4. Collectively, these data demonstrate that As2O3 can
      selectively inhibit growth and induce apoptosis in megakaryocytic leukemia cell
      lines. The use of As2O3 for the treatment of malignant megakaryocytic disorders
      should be considered.

PMID- 10340401
TI  - CD9 molecule expressed on stromal cells is involved in osteoclastogenesis.
AB  - Osteoclasts are derived from hematopoietic stem cells and their development is
      dependent on the products of stromal cells. CD9, a member of the tetraspan
      transmembrane-superfamily, is expressed on both hematopoietic cells and stromal
      cells. Addition of antagonistic rat anti-mouse CD9 antibody (KMC8.8) to cultures
      inhibited osteoclastogenesis on established stromal cell layers. When rat bone
      marrow cells depleted of adherent stromal cells were cultured on mouse stromal
      cells, numerous tartrate-resistant acid phosphatase-positive multinuclear cells
      were observed, and KMC8.8, which recognizes mouse but not rat CD9, completely
      prevented the generation of osteoclasts, suggesting that the CD9 expressed on the
      stromal cell is essential for osteoclastogenesis. Possibly for the same reason,
      KMC8.8 pretreatment of the mouse macrophage-like cell line C7, which is able to
      differentiate into mature osteoclasts, did not inhibit subsequent C7 cell
      differentiation, whereas the addition of KMC8.8 to cocultures of C7 cells with
      stromal cells inhibited the differentiation of C7 cells into osteoclasts.
      Moreover, we found that blockage of a signal via CD9 on stromal cells reduced
      transcription of the osteoclast differentiation factor (Odf) gene, which,
      together with macrophage colony-stimulating factor, is essential for
      osteoclastogenesis. These results revealed that CD9 molecules on stromal cells
      play a critical role in osteoclast development, possibly by modulating the
      expression of Odf.

PMID- 10340402
TI  - T-cell depletion of allogeneic bone marrow using anti-alphabetaTCR monoclonal
      antibody: prevention of graft-versus-host disease without affecting engraftment
      potential in rats.
AB  - Bone marrow chimerism may solve two major limitations in the transplantation of
      solid organs and cellular grafts: (1) the requirement for life-long
      immunosuppressive therapy, and (2) acute and chronic rejection. When untreated
      bone marrow is transplanted into major histocompatibility complex (MHC)-disparate
      rats, lethal graft-vs-host disease (GVHD) occurs in the majority of recipients. T
      cell depletion using anti-CD3 and anti-CD5 monoclonal antibody (mAb) to avoid
      GVHD led to an increased occurrence of failure of engraftment. We previously
      identified a cellular population in mouse bone marrow that facilitates
      engraftment of highly purified hematopoietic stem cells (HSC) across complete MHC
      barriers. In light of the fact that facilitating cells have a CD8+/CD3+/TCR-
      phenotype and mostly coexpress CD5, we evaluated in this study whether T-cell
      depletion of rat bone marrow using anti-alphabetaTCR mAb would retain engraftment
      potential yet avoid GVHD. T-cell depletion of bone marrow was performed using
      anti-alphabetaTCR mAb and immunomagnetic beads. Recipients were conditioned with
      1100 or 1000 cGy of total body irradiation and reconstituted with 100 x 10(6) T
      cell depleted (TCD) MHC- and minor antigen-disparate bone marrow cells. Animals
      were monitored clinically and histologically for GVHD. Chimerism was assessed by
      flow cytometry. Immunomagnetic bead depletion resulted in a reduction of T cells
      from 1.92%+/-0.21% to 0.10%+/-0.04% of total bone marrow. T-cell depletion did
      not remove facilitating cells (CD8+/alphabetaTCR-/gammadeltaTCR-/NK3.2.3-) from
      bone marrow. Further, the engraftment potential of TCD bone marrow was not
      affected, as 100% of animals engrafted and high levels of donor chimerism were
      detectable. Animals reconstituted with TCD bone marrow showed no clinical
      evidence of GVHD and histology revealed none to minimal changes, whereas
      recipients transplanted with untreated bone marrow succumbed to severe lethal
      GVHD. T-cell depletion using antialphabetaTCR mAb and immunomagnetic beads
      selectively removes T cells from the bone marrow graft while sparing facilitating
      cells that are required for engraftment of allogeneic bone marrow across MHC
      barriers. Moreover, the cells required for engraftment of HSC do not produce
      GVHD.

PMID- 10340403
TI  - Defective apoptosis due to a point mutation in the death domain of CD95
      associated with autoimmune lymphoproliferative syndrome, T-cell lymphoma, and
      Hodgkin's disease.
AB  - Apoptosis via CD95 and its ligand is an important mechanism that prevents
      uncontrolled proliferation of activated lymphocytes and regulates lymphocyte
      homeostasis. The apoptosis receptor CD95 is a transmembrane protein with an
      intracellular domain well conserved between CD95 and tumor necrosis factor
      receptor I, another apoptosis-inducing protein. Because of its functional
      importance, this domain was designated the death domain. We describe the
      molecular analysis of the CD95 death domain in a family with autoimmune
      lymphoproliferative syndrome (Canale-Smith syndrome), T-cell lymphoma, and
      Hodgkin's disease. A functional defect in apoptosis was detected in cells from
      the index patient, a 5-year-old girl suffering from Canale-Smith syndrome and a T
      cell lymphoma, as well as in her father, who had a history of splenomegaly and
      mild hemolysis, and her paternal uncle who had been cured of Hodgkin's disease
      (HD). Expansion of double-negative T cells (CD4-CD8-) was only seen in the index
      patient. All family members with a functional defect in apoptosis were
      heterozygous for a point mutation in the death domain of CD95 (A1009G, E256G). We
      conclude that, within the same family, a defect in apoptosis due to a mutation in
      the CD95 death domain can be associated with diverse clinical phenotypes,
      including mild, reversible symptoms and different malignancies.

PMID- 10340404
TI  - Structural requirements of Syk kinase for Fcgamma receptor-mediated phagocytosis.
AB  - The tyrosine kinase Syk plays a critical role in the phagocytic pathway mediated
      by Fcgamma receptors (FcgammaR). In transfected COS1 cells co-expression of Syk
      enhances FcgammaR mediated phagocytosis. The other member of the Syk kinase
      family, the highly homologous tyrosine kinase Zap70, also plays a role in
      signaling by immunoglobulin gene family receptors, but does not increase the
      phagocytic efficiency of FcgammaRs. The homologous tandem SH2 and kinase domains
      of Syk and Zap70 are separated by a nonhomologous region referred to as the
      unique domain. Zap70's inability to enhance phagocytosis was not due to unique
      domain tyrosine 292, previously implicated in negative regulation of Zap70
      function. We determined the regions of Syk important for its interaction with the
      phagocytic pathway. An intact kinase domain was required for Syk's effect on
      phagocytosis. Furthermore, the Syk variant SykB, lacking 23 amino acids in the
      unique region, signaled for phagocytosis as efficiently as did Syk. We then
      constructed exchange chimeras between Syk and Zap70 and determined the
      contributions of the SH2, unique and kinase domains to phagocytic signaling. Our
      data suggest that the Syk kinase domain, which has high intrinsic kinase
      activity, is important for facilitating phagocytic signaling by FcgammaRI and
      FcgammaRIIIA.

PMID- 10340405
TI  - Expression of granulocyte colony-stimulating factor- and granulocyte-macrophage
      colony-stimulating factor-associated signal transduction proteins of the JAK/STAT
      pathway in normal granulopoiesis and in blast cells of acute myelogenous
      leukemia.
AB  - Acute myelogenous leukemia (AML) is characterized by the malignant transformation
      of hematopoietic stem cells leading to dysregulated growth and differentiation of
      myeloid cells. Normally, proliferation and differentiation of myeloid cells are
      regulated by cytokines such as granulocyte colony-stimulating factor (G-CSF) or
      granulocyte-macrophage colony-stimulating factor (GM-CSF). Abnormal signaling of
      the signal transduction pathway from the cytokine receptors via Janus kinases
      (JAKs) and signal transducers and activators of transcription (STATs) might be
      involved in the pathogenesis of AML. We examined whether an abnormal expression
      of one of the four JAKs, STAT1, STAT3, STAT5, or the tyrosine phosphatase SHP-1,
      a negative regulator of this pathway, is associated with malignant transformation
      in AML. Analysis of the expression of proteins of the JAK/STAT pathway in normal
      myeloid cells at three stages of maturation revealed a strong expression of all
      proteins in CD34+ cells, whereas the level of the proteins was significantly
      lower in granulocytic precursors and mature neutrophils. Furthermore, during
      maturation the relation of the isoforms of STAT1 and STAT3 changed from
      predominantly alpha to predominantly beta. Leukemic blast cells from 25 patients
      and 12 cell lines showed a high level of STAT proteins and SHP-1, whereas a
      deficiency of at least one of the four JAKs was found in 10 of 25 patients. In
      primary AML blast cells a deficiency of three JAKs was more common in patients
      with an abnormal karyotype. In addition, a lack of JAK2 and Tyk2 protein was
      strongly associated with the FAB M2 phenotype. The proliferation rate in response
      to GM-CSF available in a small number of patients appears to be related to the
      JAK2 expression. Our data suggest that the degree of expression of G-CSF/GM-CSF
      receptor-associated proteins of the JAK/STAT pathway in normal myeloid cells is
      related with their clonogenic potential. STAT3 appears to be involved in early
      differentiation. Similar to CD34+ cells, it is likely that the high levels of
      STATs and SHP-1 found in leukemic cells reflects their proliferative activity,
      whereas a lack of members of the JAK family might lead to an inability to
      proliferate in response to G-CSF/GM-CSF described in a considerable percentage of
      AML blasts.

PMID- 10340406
TI  - Expression of interferon-gamma by stromal cells inhibits murine long-term
      repopulating hematopoietic stem cell activity.
AB  - Several lines of evidence suggest that overexpression of interferon gamma (IFN
      gamma) in the marrow microenvironment may play a role in the pathogenesis of
      marrow suppression in aplastic anemia. We previously showed that overexpression
      of IFN-gamma by marrow stromal cells inhibits human long-term culture initiating
      cell activity assayed in vitro to a much greater degree than the addition of
      soluble IFN-gamma. The effect of IFN-gamma on true repopulating stem cells
      assayed in vivo has not been studied previously. We compared the effect of co
      culture of murine marrow cells in the presence of stromal cells transduced with a
      retroviral vector expressing murine IFN-gamma vs stromal cells transduced with a
      control neo vector. Using a murine congenic competitive repopulation assay, there
      was significantly less long-term repopulating stem cell activity remaining after
      culture on mIFN-gamma-expressing stroma as compared to control stroma. We also
      investigated the effect of directly transducing murine bone marrow cells with the
      mIFN-gamma or control vector. Marrow cells transduced with either vector were
      transplanted into W/Wv recipient mice. The percentage of vector-containing cells
      in the mIFN-gamma mice was significantly lower than in the control mice,
      suggesting that mIFN-gamma-transduced primitive cells may not have survived
      culture, or that mIFN-gamma directly decreases gene transfer into repopulating
      cells. Despite no significant differences in white or red blood cells in the mice
      transplanted with the mIFN-gamma-transduced cells, the number of bone marrow
      colony-forming unit-C 16 weeks after transplantation was significantly lower in
      the IFN-gamma group. These data indicate that ectopic or overexpression of mIFN
      gamma, especially by marrow microenvironmental elements, may have a marked effect
      on primitive hematopoiesis as assayed in vivo.

PMID- 10340407
TI  - Rapid ex vivo expansion of human umbilical cord hematopoietic progenitors using a
      novel culture system.
AB  - Cell numbers limit the widespread clinical use of cord blood (CB) for gene
      therapy and marrow replacement in adults; a simple and effective method for ex
      vivo expansion of CB primitive progenitor cells (PPC) is required. Recently, the
      combination of thrombopoietin (TPO) and Flk-2/Flt-3 ligand (FL-2) was reported to
      support slow proliferation of CB-PPC in stroma-free liquid culture. We
      established a novel culture system in which the murine stromal cell line HESS-5
      dramatically supports the rapid expansion of cryopreserved CB-PPC in synergy with
      TPO/FL-2. Furthermore, while HESS-5 cells directly adhered to human progenitors
      during culture, the cultured human cells could easily be harvested without
      contamination by HESS-5 cells. Within 7 days of culture, a 100-fold increase in
      CD34bright/CD38dim cells was obtained in serum-containing culture. When HESS-5
      cells were physically separated from human progenitor cells in the presence of
      TPO/FL-2, synergy was blocked, suggesting that HESS-5 cells support proliferation
      of PPC by direct cell-to-cell interaction. The hematopoietic-supportive effects
      of this xenogeneic coculture system were then assessed in a very short-term (5
      days) serum-free culture. Expansion was further enhanced by addition of stem cell
      factor (SCF) or interleukin-3 (IL-3). As a result, a 50- to 100-fold increase in
      CD34bright/CD38dim cells was noted. Colony-forming units in culture (CFU-C) and
      mixed colonies (CFU-GEMM) were enhanced by 10- to 30-fold and 10- to 20-fold,
      respectively. Moreover, generation of long-term-culture-initiating cells (LTC-IC)
      from CD34bright/CD38dim cells was amplified by 25-fold. The severe-combined
      immunodeficient (SCID) mouse-repopulating cell (SRC) assay confirmed extensive
      ability of the expanded cells to reconstitute long-term hematopoiesis. These
      results indicate that this xenogeneic coculture system, in combination with human
      cytokines, can rapidly generate PPC from cryopreserved CB.

PMID- 10340409
TI  - Development and aging of primitive hematopoietic stem cells in BALB/cBy mice.
AB  - Evaluating the function of an individual hematopoietic stem cell (HSC) is a
      difficult and important problem. The functional ability per HSC, as well as the
      HSC concentration, was measured with minimal disruption to the cells in vivo
      using the new competitive dilution assay. Distribution of HSC into recipients was
      modeled based on Poisson probabilities. Predictions of donor contributions from
      models assuming different levels of donor HSC functional ability and
      concentration were compared to actual observations. The model with the least
      difference between predictions and observations was accepted. In BALB/ cBy (BALB)
      mice, models assuming equal functional ability of HSC from the same donor fit
      extremely well with actual observations, suggesting that all HSC are functionally
      homogeneous at any particular time point during development or aging. Relative
      HSC functional ability per cell declined during development, so that a fetal HSC
      had 1.6 to 3.0 times the functional ability of a young adult HSC. The decline
      continued with age, so that a young adult HSC had 1.6 to 2.0 times the functional
      ability of an old HSC. Concentrations of HSC that engrafted and functioned were
      similar among 16-day fetal liver cells and bone marrow cells (BMC) from 3-month
      and 25 to 28-month-old adult mice. They were either 10 or 4 HSC per million cells
      when tested in BALB or CByB6F1 recipients, respectively. All HSC were pluripotent
      and produced lymphoid and myeloid descendants proportionally (r = 0.80 to 0.98, p
      < 0.01). Fetal and young HSC in both types of recipients maintained clonal
      stability long term so that percentages of donor cells at 6 and 9 months were
      strongly correlated (r = 0.72 to 0.93, p < 0.01). Although HSC from aged donors
      in BALB recipients maintained clonal stability, HSC from the same aged donors
      failed to show clonal stability in CByB6F1 recipients, perhaps due to the less
      suitable host environment. All HSC from BALB mice seemed to have equal functional
      levels at a given stage of life and were gradually exhausted simultaneously
      through development and aging.

PMID- 10340408
TI  - Expression of Flt3 and c-kit during growth and maturation of human CD34+CD38-
      cells.
AB  - Studies of murine stem cells suggest that the cytokine receptors Flt3 and c-kit
      are expressed differentially on the earliest reconstitutional cells, such that
      Flt3 is not expressed until after stem cell activation. Much less is known about
      the expression of Flt3 and c-kit on primitive human cells, especially those
      mobilized into circulation for transplantation. In this study, early circulating
      precursors were analyzed for expression of Flt3 at the gene and protein levels.
      Flow cytometric studies showed that >90% of CD34+CD38- cells expressed Flt3
      antigen (CD135). The proportion of fresh CD34+ cells expressing Flt3 decreased as
      CD38 staining increased. These results were confirmed by reverse transcriptase
      polymerase chain reaction (RT-PCR) analyses, which showed that Flt3 gene
      expression generally was limited to the CD34+CD38- population. Because Flt3
      ligand (FL) enhances the growth and/or maintenance of primitive cells, it was
      important to know how long early cells retain Flt3 receptor expression in
      expansion culture. Both RT-PCR analyses and functional tests demonstrated that
      primitive cells are capable of expressing Flt3 for as long as 2 weeks in liquid
      medium. During the first week of culture, FL enhanced the generation of cells and
      progenitors without causing a loss of primitive CD34+CD38-Flt3+ cells. Flt3
      expression in cell cultures was limited to precursors retaining a CD34+CD38(-/lo)
      phenotype. Because the most primitive human precursors are believed to express c
      kit at a low level, we examined the FL responsiveness of CD34+CD38-c-kit(-/lo)
      cells and CD34+CD38-c-kit+ cells. CD34+CD38-c-kit(-/lo), cells constituted a
      small fraction (12%) of the CD34+CD38- population. Whereas both c-kit(-/lo) and c
      kit+ subsets were stimulated by FL, cell expansion (p < 0.01) and colony
      formation (p < 0.01) were greater and maintained longer with CD34+CD38-c-kit(
      /lo) cells. Furthermore, the rapid response to FL suggests that primitive
      CD34+CD38-c-kit(-/lo) cells express Flt3 at the time of isolation or shortly
      thereafter. These results demonstrate the presence of Flt3 on CD34+CD38 blood
      cells and suggests that Flt3 also may be present on a c-kit(-/lo) subset, among
      the most primitive in circulation. Flt3 is lost during maturation to committed
      (CD34+CD38+) lineages. Addition of FL to primitive cell cultures stimulates cell
      expansion while maintaining early CD34+CD38-Flt3+ precursors for at least 7 days.
      The possible existence of a more primitive CD34+CD38-c-kit(-/lo) Flt3(-/lo)
      precursor remains to be determined.

PMID- 10340410
TI  - Identification of a peptide directed against the anti-CD34 antibody, 9C5, by
      phage display and its use in hematopoietic stem cell selection.
AB  - A peptide sequence was identified by phage display technology that could be used
      as an alternative to chymopapain for the release of hematopoietic progenitor
      cells captured by anti-CD34 monoclonal antibodies. This was achieved by affinity
      selection screening (biopanning) of a random hexapeptide sequence phage display
      library. Four rounds of biopanning were performed to enrich for phage clones with
      specific affinity for anti-CD34 monoclonal antibody, 9C5. DNA sequence analyses
      of these phage clones revealed an enrichment of two predominant sequences, QQGWFP
      and TQGSFW. These two clones also shared a consensus sequence motif, QGxF, that
      exhibited 50% and 67% homology with a region spanning amino acids 14-19 of the
      mature CD34 antigen. Based on these data, synthetic peptides were generated and
      assessed for their ability to release 9C5 from CD34+ cells. Using a flow
      cytometric assay, it was found that the synthetic peptide, 9069N, effectively
      released 9C5 from the CD34-expressing cell line, KG1a, in a concentration
      dependent manner (77% and 99% release of 9C5 at 0.14 and 0.70 mM peptide
      concentrations, respectively). In the Isolex 300i immunomagnetic selection
      system, this peptide was shown to be effective at releasing 9C5 sensitized CD34+
      hematopoietic progenitors from sheep anti-mouse IgG Dynabeads. Thus, a synthetic
      peptide, which specifically and efficiently released immunomagnetically selected
      hematopoietic progenitor cells from paramagnetic beads, was identified. This
      reagent is a significant advance in the selection of hematopoietic progenitors in
      that it does not alter cell surface antigens. As such, further phenotypic
      characterization or immunoselection can be performed.

PMID- 10340411
TI  - Marrow engraftment of hematopoietic stem and progenitor cells is independent of
      Galphai-coupled chemokine receptors.
AB  - The mechanism of hematopoietic stem and progenitor cell (HSPC) homing to
      hematopoietic organs after transplantation is still poorly understood. There is
      evidence that HSPC homing is a multistep process involving integrins and other
      adhesion molecules as well as stimulation of cytokine and chemokine receptors,
      similar to the process of lymphocyte recirculation and leukocyte emigration. This
      study examined the effect of pertussis toxin (PT), an inhibitor of signaling by
      many Galphai protein-coupled chemokine receptors, on engraftment of HSPC. An in
      vitro incubation of total bone marrow cells in PT-supplemented media prior to
      transplantation into lethally irradiated syngeneic mice resulted in an increase
      in marrow repopulation and a parallel decrease of colony-forming unit-spleen (CFU
      S) on day 13. PT treatment of Rh(low)Lineage(neg)Sca-1pos cells prior to
      transplant resulted in delayed spleen cell engraftment, but no observable
      difference in the bone marrow cellularity compared to animals transplanted with
      untreated cells. FACS analysis of hematopoietic organs revealed that myeloid cell
      recovery in the bone marrow was unaffected by PT treatment of HSPC. However, a
      reduced myeloid cell recovery in the spleen and an increased B lymphoid recovery
      in both the spleen and the bone marrow were observed in recipients of PT-treated
      grafts relative to untreated grafts. To test the hypothesis that PT inhibits
      proliferation rather than engraftment of HSPC in the spleen, the effect of PT on
      cytokine-stimulated proliferation of HSPC was tested. Although an inhibition of
      the growth of microcolonies in response to interleukin 6 as a single cytokine
      could be observed after PT treatment, colony growth of HSPC after steel factor or
      steel factor + interleukin 6 stimulation was unaffected by PT. This study
      demonstrates that bone marrow, but not splenic, recovery after HSPC
      transplantation is independent of PT-sensitive mechanisms. It is likely that PT
      inhibits spleen cell recovery by disrupting a Galphai-coupled homing receptor
      expressed by HSPC. These studies support the hypothesis that distinct mechanisms
      regulate splenic vs bone marrow engraftment of HSPC, and that B lymphocyte
      progenitors and HSPC can utilize a PT-resistant homing mechanism to localize in
      hematopoietic tissues after transplantation.

PMID- 10340412
TI  - How many myeloid post-progenitor cells have to be transplanted to completely
      abrogate neutropenia after peripheral blood progenitor cell transplantation?
      Results of a computer simulation.
AB  - Although hematopoietic recovery following high-dose chemotherapy (HD-CT) and
      peripheral blood progenitor cell (PBPC) transplantation is rapid, there is still
      a 5- to 7-day period of severe neutropenia which, theoretically, might be
      abrogated by an additional transplantation of more differentiated myeloid post
      progenitor cells (MPPC). However, both the number of MPPC required to abrogate
      neutropenia as well as the optimum scheduling of MPPC infusions are currently
      unknown. Therefore, these questions were addressed by applying a computer model
      of human granulopoiesis. First, model calculations simulating varying levels of
      chemotherapy dose intensity were performed and compared with typical clinical
      neutrophil recovery curves. Using this approach, the data for HD-CT without PBPC
      transplantation could be reproduced by assuming a reduction of stem cells,
      committed granulopoietic progenitors and proliferating precursors to about 0.001%
      of normal. PBPC-supported HD-CT was reproduced by increasing the starting values
      to at least 0.1%, which corresponded to about 1 to 2 x 10(5)/kg transplanted CFU
      GM. Interestingly, reproduction of PBPC-supported HD-CT data could be observed
      for a wide range of starting values (0.1%-10% of normal), thus confirming the
      clinical observation that hematopoietic recovery after PBPCT cannot be improved
      by increasing the dose of transplanted cells over a certain threshold. Using the
      same simulation model, we then studied the effects of an additional MPPC
      transplantation. The results showed, that at least 5.7 X 10(8) MPPC/kg have to be
      provided in addition to the normal PBPC graft to avoid neutropenia <100/microL,
      and that MPPC are best transplanted on days 0 and 6 after HD-CT. Assuming a 100-
      to 120-fold cellular ex-vivo expansion rate and MPPC representing about 70% of
      total expanded cells, 5.7 X 10(8) MPPC/kg could be generated starting from 1 to 2
      leukapheresis preparations with about 7 to 8 x 10(6) CD34+ PBPC/kg. Considering
      furthermore, that only a fraction of ex-vivo generated cells will seed and
      effectively produce neutrophils in-vivo, the required number of MPPC is most
      likely even higher and, therefore, might be difficult to be achieved clinically.
      However, the validity of the model results remains to be proven in appropriate
      clinical studies.

PMID- 10340413
TI  - Multiple high cell dose injections of normal marrow into newborn jaundiced mice
      dramatically prolong life despite transient repopulation.
AB  - Jaundiced (ja/ja) mice have a severe hemolytic anemia caused by deficiency of the
      erythroid cytoskeletal protein beta-spectrin. Unless they are transfused, 99% of
      the mutant mice die after birth. Here, we test a new therapy involving multiple,
      high cell dose marrow injections into newborn non-ablated recipients. The ja/ja
      and normal newborn mice were injected intravenously with a total of 8.7 x 10(6)
      genetically marked +/+ marrow cells/g body weight. Donor and host red blood cells
      were quantified and the status of the recipients monitored. The jaundiced but not
      the normal recipients had up to 57% replacement with donor red cells by 9 weeks.
      The treatment significantly increased red cell counts and extended the average
      lifespan to 5 months beyond that previously reported for ja/ja mice transfused at
      birth. Replacement was limited to red cells. The donor cells disappeared in three
      of five mutant mice alive beyond 27 weeks. Marrow from a 48-month-old ja/ja
      recipient no longer positive for donor cells was injected into a secondary host.
      The recipient acquired the blood phenotype of the primary ja/ja host. The
      possibility that the marker was not well tolerated following multiple cell
      injections was investigated in normal adult mice injected with a total of 5.3 x
      10(6) marrow cells/g body weight. Recipients became chimeric (>38% donor red and
      white cells) long-term (>12 months). The results indicate donor stem cells (a)
      prolong life in the jaundiced mice, but (b) do not survive long-term when
      injected into newborn mice. We conclude that destructive mechanisms may not be
      limited to ja/ja red cells.

PMID- 10340414
TI  - Electromyography--high tech--now what?

PMID- 10340415
TI  - Bone mineral density of metatarsus in hemiplegic subjects.
AB  - The cortical bone mineral density (BMD) of the first metatarsus was measured
      using computed x-ray densitometry in 84 hemiplegic subjects (35 men and 49
      postmenopausal women) and 49 healthy age-matched controls (23 men and 26
      postmenopausal women), and the determinants of paralysis-induced cortical
      osteopenia were investigated. In the hemiplegia group, ages were 63.9 +/- 9.8 yr
      (mean +/- standard deviation) for men and 66.6 +/- 11.0 yr for women. The
      duration of hemiplegia was 25.3 +/- 19.8 mo for men and 26.0 +/- 26.3 mo for
      women. The Brunnstrom stage (lower limb) was 4.0 +/- 1.1 for men and 3.8 +/- 1.4
      for women. The walking ability, evaluated by walking score, was 3.6 +/- 1.3
      (range, 1-5) for men and 3.2 +/- 1.5 (range, 1-5) for women. The time since
      menopause was 14.8 +/- 10.0 yr. The age and time since menopause were similar in
      the hemiplegia and control groups. On the paralyzed side, the BMD of men and
      women in the hemiplegia group was significantly lower than that of the control
      group on the nondominant side (by 6.1% and 11.6%, respectively). In hemiplegic
      men, Brunnstrom stage and walking score showed a significant positive correlation
      to the BMD (r = 0.418 and r = 0.349, respectively). In hemiplegic women, on the
      other hand, age, duration of hemiplegia, and years since menopause showed a
      significant negative correlation to the BMD (r = -0.260, r = -0.478, and r = 
      0.506, respectively), and Brunnstrom stage and walking score showed a significant
      positive correlation to the BMD (r = 0.526 and r = 0.406, respectively). These
      findings suggest that the determinant of metatarsal cortical BMD loss on the
      paralyzed side of the hemiplegic subject might be different according to gender.
      That is, although the degree of paralysis and walking ability could be a
      determinant of metatarsal cortical BMD loss on the paralyzed side of hemiplegic
      men, additional factors such as age, duration of hemiplegia, and years since
      menopause could play an important role in the determination of metatarsal
      cortical BMD loss in postmenopausal hemiplegic women.

PMID- 10340416
TI  - ADL structure for nondisabled Japanese children based on the Functional
      Independence Measure for Children (WeeFIM).
AB  - The Functional Independence Measure for Children (WeeFIM) instrument was
      developed, based on the FIM instrument, to assess disability in children aged 6
      mo to 7 yr. Normative data are reported for American and Japanese children, and
      it is increasingly used for the disabled. Our purpose was to confirm scale
      quality and to determine the difficulty pattern of the WeeFIM in Japan. The
      WeeFIM was measured in 225 children (113 girls and 112 boys) aged 6 mo to 7 yr
      without developmental delays. The scores were converted to an interval scale by
      Rasch analysis, which assumes unidimensionality of the measurement items,
      determines the degree of the fit to the assumption, and decides item difficulty.
      When the WeeFIM items were divided into two groups of motor and cognitive items
      to minimize misfit, the degree of misfit was acceptable, except for eating,
      bladder management, tub/shower transfer, and comprehension. For the motor items,
      grooming, bathing, and bladder control were more difficult, and stairs, bed/chair
      transfer, and walk or wheelchair were easier. Concerning the cognitive items,
      expression and comprehension were easier, and problem-solving was most difficult.
      When we compared item difficulty patterns in the four age groups (6-21 mo, 22-45
      mo, 46-62 mo, and 63-100 mo), we found no differences, except in toilet transfer.
      It was more difficult for younger children, possibly because of its different
      pattern of chronological change, which shows rapid changes from dependent to
      independent levels over a short period of time. Our study confirmed the scale
      quality of the WeeFIM instrument with Rasch analysis and demonstrated the
      difficulty pattern of the WeeFIM in nondisabled Japanese children.

PMID- 10340417
TI  - Sensory and mixed nerve action potential temporal dispersion in median neuropathy
      at the wrist.
AB  - This retrospective pilot study was undertaken to help determine the usefulness of
      measuring sensory nerve action potential and mixed nerve action potential
      temporal dispersion in median neuropathy at the wrist (MNW; i.e., carpal tunnel
      syndrome). The records were reviewed for 34 patients who were referred to an
      electrodiagnostic medicine laboratory with normal antidromic median sensory nerve
      action potential (recording from the index finger), median transcarpal mixed
      nerve action potential, and ulnar transcarpal mixed nerve action potential peak
      distal latencies (NO group) and 29 patients with prolongation (>2.2 ms) of the
      left median transcarpal mixed nerve action potential peak distal latency or
      relative prolongation of this response (>0.4 ms) compared with the ipsilateral
      normal ulnar transcarpal mixed nerve action potential peak distal latency (MNW
      group). By using the time difference between onset and negative peak as a measure
      of waveform temporal dispersion, mean +/- standard deviation of the median
      transcarpal mixed nerve action potential time difference for the MNW group (0.57
      +/- 0.15 ms) was found to be greater than the NO group (0.44 +/- 0.09 ms; P <
      0.01). No statistically significant differences were found for the median sensory
      nerve action potential time difference between the two groups or between the
      subgroup of MNW patients with concurrent prolongation of the median sensory nerve
      action potential peak distal latency and the NO group. These findings suggest
      that increased median transcarpal mixed nerve action potential temporal
      dispersion may occur in association with median transcarpal mixed nerve action
      potential peak distal latency prolongation in MNW. The small magnitude of this
      increase, however, makes the clinical usefulness of this observation unclear.

PMID- 10340418
TI  - Coefficient of variation in maximal and feigned static and dynamic grip efforts.
AB  - The purpose of this study was to investigate the validity of the coefficient of
      variation as an identifier of feigned grip effort. Seventeen healthy female aged
      20 to 25 yr participated in the study. Maximal and feigned efforts were measured
      isometrically and isokinetically (concentric and eccentric) using the Jamar and
      KinCom dynamometers, respectively. Findings indicated that, in all situations,
      the coefficient of variation derived from the maximal effort was significantly (P
      < 0.0001) lower than that derived from the feigned effort. However, the extent of
      overlapping between the two was sufficiently large to render the test
      sensitivities very low. Consequently, regardless of the measurement method, the
      coefficient of variation is not a valid tool for identifying feigned grip effort
      in healthy subjects.

PMID- 10340419
TI  - Detection of a "faked" strength task effort in volunteers using a computerized
      exercise testing system.
AB  - The objective of this study was to develop an experimental method to separate a
      "faked" strength effort from a "best" effort in volunteers. Thirty-four pain-free
      volunteers (18 males, 16 females) performed a shoulder press and pull-down on an
      isokinetic computerized exercise testing system (CETS), giving a best effort
      followed by a faked effort. Two months later, a randomly selected subgroup (6
      males) repeated the experiment to test the predictive validity of the derived
      variables. In the statistical analysis, best efforts were first compared with
      fake efforts by paired ttest for 80 CETS variables for males and females
      separately. Variables showing a strong difference between the best and faked
      effort were then selected for further analysis. In the second step of the
      analysis, the method of multiple correlations (r2 method) was used to reduce the
      number of redundant CETS variables to five in both the male and female groups. In
      the third step, a stepwise discriminant analysis was used to select predictor
      variables for the male and female groups. For the variables selected by the
      discriminant analysis for both males and females, sensitivities and specificities
      were calculated. Finally, the developed discriminant formula was used in the
      predictive validity part of the study to determine the sensitivities and
      specificities of the developed method. The discriminant analysis selected the
      following CETS variables for male and female groups, respectively: duty cycle
      down, work weight/down, peak value up (males); and average power up, 40%
      repetition down, duty cycle up (females). For males, using their three variables,
      the discriminant function classified 77.14% of the efforts correctly with 88.9%
      sensitivity and 64.7% specificity. For females, using their three variables, the
      discriminant function classified 90.63% of the efforts correctly with 100%
      sensitivity and 81.3% specificity. In the predictive validity group, the
      discriminant function classified 75% of the efforts correctly with 83.3%
      sensitivity and 66.7% specificity. This pilot study indicates that the method
      developed here may be useful in the experimental study for the discrimination
      between faked and best efforts on this isokinetic CETS machine. Future studies
      using this method will need to involve a larger number of volunteers.

PMID- 10340420
TI  - Evidence-based medicine in physiatry: the experience of one department's faculty
      and trainees.
AB  - Evidence-based medicine is regarded by many as the new paradigm in medical
      practice. Sixty-seven medical school faculty and trainees in a physical medicine
      and rehabilitation department were surveyed with regard to training and
      competence in the use of evidence-based medicine techniques. The majority of
      subjects in the present study supported the use of evidence-based medicine
      techniques, although a number of the respondents indicated that they lacked
      adequate training or competence in their use. It is suggested that medical
      schools and physiatry residency programs provide a greater emphasis on training
      in evidence-based medicine. Recommendations are provided that individuals can use
      to develop a systematic strategy to keep up with the rapidly expanding medical
      literature.

PMID- 10340421
TI  - Short form of the Dizziness Handicap Inventory: construction and validation
      through Rasch analysis.
AB  - A new item response scale is presented, which measures the severity of self
      reported balance deficits. The scale, DHIsf, is a short form of the Dizziness
      Handicap Inventory. The scale was constructed and validated by Rasch analysis.
      Rasch analysis was applied to rescore or remove any items misfitting, redundant,
      or off-target, until an optimal instrument was obtained. The 25-item, 3-level
      Dizziness Handicap Inventory was, thus, reduced to the 13-item, 2-level DHIsf.
      The retained items explore the domains of eye/head movements, full body
      activities, and mood alterations. Data were collected from 55 outpatients (63 +/-
      13 yr; 43 females) attending otoneurological rehabilitation referral at a general
      hospital because of complaints of dizziness or imbalance. They were fully
      independent in ambulation and showed no evidence of major neurological or
      orthopedic diseases. Objective tests included brain computed tomography,
      sovraaorctic Doppler sonography, craniocorpography, static posturography, and
      nystagmography. The findings were categorized as pathologic, borderline, or
      normal. At least one examination was borderline or abnormal in 42 patients. The
      DHIsf was well targeted on this sample, with a mean score of 5.7/13 (standard
      deviation, 2.8; median, 5; range, 1-13). The Rasch statistics showed that the 13
      items evenly fitted a hierarchy of difficulty within a homogeneous construct. A
      moderate but significant variance explanation of DHIsf measures was provided by a
      two-way analysis of variance model, with craniocorpography and nystagmography as
      independent categorical variables (r2 = 0.15; P = 0.018). When the clinical tests
      were individually taken into account, their outcome (dichotomized as abnormal v
      borderline or normal) could not be predicted by either of the DHIsf measures or
      raw scores (logistic regression). The DHIsf compares favorably with the original
      Dizziness Handicap Inventory, shows some consistency with the instrumental
      findings, and provides original information on the severity of imbalance
      syndromes, as it is seen from the patient's perspective.

PMID- 10340422
TI  - Identification of kinetic differences between fallers and nonfallers in the
      elderly.
AB  - Falls are a major cause of decreased mobility and disability in the elderly.
      Multiple factors are believed to contribute to falling. Among these, gait
      abnormalities have drawn attention as a possible risk factor. Although previous
      studies have revealed few differences in gait parameters compared with similar
      aged controls, it was hypothesized that because of intrinsic differences in
      balance and motor control, we would observe differences in joint kinetics. In
      this study, 15 subjects (mean age, 77 +/- 9 yr), who had at least 2 mo of
      repeated falls from an unclear cause, were evaluated in a gait laboratory and
      were compared with a control group of 15 subjects (mean age, 75 +/- 5 yr) with no
      history of falls. Analysis of data demonstrated a significantly greater peak
      torque in the falls group for the following: hip flexion, hip adduction, knee
      extension, knee varum, ankle dorsiflexion, and ankle eversion (P < 0.003 in each
      comparison). Also, ankle plantarflexion torque was significantly decreased in the
      falls group (P = 0.001). Joint powers showed different absorption at the knee and
      ankle in the falls group. The discovery of these kinetic differences may provide
      further insight into the mechanism of falls in the elderly and, more importantly,
      lead to identifiable markers to detect those who may be susceptible to falls.

PMID- 10340423
TI  - Continuously infused intrathecal baclofen for spastic/dystonic hemiplegia: a
      preliminary report.
AB  - The objective of this study was to determine whether the continuous intrathecal
      delivery of baclofen will control spastic hypertonia associated with long
      standing hemiplegia from acquired brain injury. Six hemiparetic patients (average
      age, 50 (range, 42-66) yr) with more than 6 mo of disabling lower limb spastic
      hypertonia on one side caused by either a unilateral traumatic brain injury or a
      stroke were recruited in a consecutive manner. The setting was a tertiary care
      outpatient and inpatient rehabilitation center directly attached to a university
      hospital. Patients were screened via a randomized, double-blind, placebo
      controlled, crossover design to receive either an intrathecally administered
      bolus injection of normal saline or 50 microg of baclofen. Data for Ashworth
      rigidity scores, spasm scores, and deep tendon reflex scores were collected on
      the affected upper limb and lower limb side. Those who dropped an average of two
      points on their affected lower limb side Ashworth scores were then offered
      computer-controlled pump implantation for continuous intrathecal administration
      of baclofen. Differences over time were assessed via descriptive statistics and
      Wilcoxon's signed-rank test. After 3 mo of treatment, the average lower limb
      Ashworth score on the affected side decreased from 3.7 +/- 1.0 to 1.9 +/- 0.6
      standard deviation (SD) (P < 0.0001), the reflex score from 1.8 +/- 1.3 to 0.5 +/
      0.8 SD (P = 0.0208), and the spasm score from 1.3 +/- 1.2 to 0.8 +/- 1.3 SD (P >
      0.05). The average upper limb Ashworth score on the affected side decreased from
      3.4 +/- 0.9 to 2.1 +/- 0.9 SD (P = 0.0002), the reflex score from 2.3 +/- 0.5 to
      1.7 +/- 0.5 SD (P > 0.050, and the spasm score from 0.8 +/- 1.3 to 0 +/- 0 SD (P
      > 0.05). The average intrathecally administered dose of baclofen that was
      required to attain these effects was 205.3 microg, which was continuously infused
      for 24 h. Continuous intrathecal infusion of baclofen is capable of maintaining a
      reduction in the dystonia on the hemiparetic side without significantly affecting
      motor strength on the normal side.

PMID- 10340424
TI  - Current therapy in the management of heterotopic ossification of the elbow: a
      review with case studies.
AB  - Heterotopic ossification, or the appearance of ectopic bone in para-articular
      soft tissues after surgery, immobilization, or trauma, complicates the surgical
      and physiatric management of injured joints. The chief symptoms of heterotopic
      ossification are joint and muscle pain and a compromised range of motion. Current
      therapies for prevention or treatment of heterotopic ossification include
      surgery, physical therapy, radiation therapy, and medical management. Unlike
      heterotopic ossification of the hip, heterotopic ossification of the elbow has
      not been extensively investigated, leaving its optimal management ill-defined. To
      remedy this deficiency, we review risk factors, clinical anatomy, physical
      findings, proposed mechanisms, and current practice for treatment and prevention
      of heterotopic ossification. We then consider and draw conclusions from four
      cases of elbow injury treated at our institutions (three complicated by
      heterotopic ossification) in which treatment included surgery, radiation therapy,
      physical therapy, and medical therapy. We summarize our institutional practices
      and conclude with a call for a randomized clinical trial to better define optimal
      management of heterotopic ossification of the elbow.

PMID- 10340425
TI  - Symptoms of recurrent intrathecal baclofen withdrawal resulting from drug
      delivery failure: a case report.
AB  - A 24-yr-old, completely (T8) paraplegic male patient presenting with severe
      spasticity had a drug administration device implanted in April 1991 for
      continuous intrathecal administration of baclofen. After a period of remarkable
      improvement in both the spasticity level and his quality of life, the patient
      experienced several short-lasting episodes of increased spasticity, with severe
      spasms. Among the possible causes of these deleterious episodes were
      microcrystalluria, obstipation, a decubitus ulcer, a foreign body in the
      buttocks, drug tolerance to baclofen, electromagnetic interference, and erroneous
      filling and programing of the pump. The catheter was the most common source of
      intrathecal baclofen withdrawal symptoms and had to be changed four times in 5
      yr. Intrathecal baclofen administered through an implantable drug administration
      device is a highly effective but complex and expensive procedure that requires
      careful patient selection and close monitoring by highly qualified and well
      trained health professional. Withdrawal symptoms may be related to noncompliance
      on the part of the patient, erroneous filling or programing of the pump,
      depletion of the battery, random component failure, concomitant illness, drug
      tolerance, or advancement of the disease itself. When failure of the device is
      suspected, substitution with oral baclofen is recommended until a full work-up is
      performed to determine the defect.

PMID- 10340427
TI  - Electrodiagnostic examination of the supinator--a more dorsal approach: a brief
      report.
AB  - Examination of the supinator muscle of the forearm may be useful in suspected
      lesions of the 5th and 6th cervical nerve roots, the upper trunk of the brachial
      plexus, or the radial nerve. It is critical in localizing the level of
      involvement in a patient with possible posterior interosseous nerve injury. The
      traditional techniques in the electrodiagnostic examination of this muscle have
      approached the muscle from the volar aspect, just radial to the insertion of the
      biceps tendon, medial to the brachioradialis, through the extensor carpi radialis
      longus/brevis, between the radial wrist extensors and extensor digitorum
      communis, or through the extensor digitorum communis. These approaches have the
      inherent risk of piercing vessels and/or nerves. After reviewing the pertinent
      anatomy in standard textbooks, magnetic resonance imaging, and a cadaver, we
      developed a more dorsal approach in the examination of the supinator. Examination
      of 20 patients by staff, fellows, and residents at our institution resulted in
      consistent, accurate needle placement, with no complications. We describe a more
      dorsal approach in the examination of the supinator muscle in the forearm.

PMID- 10340426
TI  - Gait analysis in rehabilitation medicine: a brief report.
AB  - Gait analysis can be a powerful tool for rehabilitation research and clinical
      practice. However, there has been little coordinated effort to set goals for the
      application of gait analysis in rehabilitation. Therefore, a priority setting
      process was engaged to obtain the opinions of a diverse pool of experts related
      to human motion analysis. The primary goal of this process was to develop
      priorities for future research, development, and standardization in gait
      analysis. A multistep approach was used that included expert testimony, group
      discussions, individually developed priorities, and a ranking process. Several
      important priorities emerged from this activity. The highest priority was
      assigned to research on the efficacy, outcomes, and cost-effectiveness of gait
      analysis.

PMID- 10340428
TI  - Plantar fat pad atrophy after corticosteroid injection for an interdigital
      neuroma: a case report.
AB  - A case of bilateral interdigital (Morton's) neuroma treated with steroid
      injection therapy developed plantar fat pad atrophy, shown on magnetic resonance
      imaging. Some pathologic changes at the site of injection (such as subcutaneous
      fat atrophy, depigmentation of the skin, and telangiectasias) are well known
      disadvantages of local steroid injection for the treatment of the Morton's
      neuroma. Scientific literature reports these problems (mainly as an aesthetic
      problem) in the dorsal aspect of the foot. In this work, the authors describe a
      case in which the steroid injection therapy has caused some changes in the
      plantar aspect of the feet, with serious functional problems. Fat pad atrophy is
      a serious problem in the foot and can cause a painful metatarsal syndrome with
      some important effects on the gait.

PMID- 10340429
TI  - Measuring quality of life: methodological issues.
AB  - Quality of life is a term used in a number of disciplines, and definitions and
      conceptualizations vary from utility of health states to life satisfaction and
      from possession of socially desirable characteristics to positive affect. This
      article offers a taxonomy of measures of quality of life based on measurement
      characteristics, which are shown to closely parallel definitions and their
      underlying assumptions. The fact that basic philosophical issues and ethical
      assumptions underlie quality of life measurement is stressed. Clinimetric
      characteristics of quality of life measures (validity, reliability,
      responsiveness, sensitivity, practicality, face validity, interpretability) are
      reviewed. This article concludes with a discussion of a number of additional
      methodological issues, including the following: measurement of change in the
      quality of life; generic v disease-specific measures; the use of self-reports by
      persons with mental health or cognitive-communicative problems; and the use of
      proxy reporters of quality of life.

PMID- 10340430
TI  - Quantitative determination of cholesterol in lipoprotein fractions by
      electrophoresis.
AB  - The Helena REP cholesterol profile system (Helena Laboratories, Beaumont, TX)
      separates VLDL, LDL, HDL and Lp(a) by agarose gel electrophoresis, and
      quantitates cholesterol by enzymatic staining and densitometry. We compared
      results by electrophoresis to combined ultracentrifugation/precipitation (beta
      quantification, BQ) for VLDL, LDL, and HDL cholesterol and to immunonephelometry
      for Lp(a) mass (Behring Diagnostics, Westwood, MA) in serum from 64 patients with
      a variety of lipid disorders. There was good agreement between methods, with a
      mean bias of -0.19 (-7.3), 0.09 (3.5), and 0.09 (3.4) mmol/l (mg/dl) for VLDL,
      HDL, and LDL cholesterol for electrophoresis vs. BQ. These differences were
      significant for HDL and VLDL cholesterol (P < 0.001), but not for LDL cholesterol
      measurement (P > 0.05). There was also good correlation between methods with
      coefficients of 0.83, 0.92, 0.91, and 0.97 for VLDL, HDL, Lp(a), and LDL,
      respectively. Our data indicate that this method can accurately and precisely
      measure LDL cholesterol directly in fresh serum from patients with a wide range
      of triglyceride values. However, HDL cholesterol measurement did not meet NCEP
      guidelines for precision and accuracy. Also, the poor resolution of VLDL and LDL
      in some specimens is a concern.

PMID- 10340431
TI  - Estimating the linear analytic range.
AB  - Although many methods have been proposed to verify assay linearity, or to test
      for nonlinearity, there are few, if any, statistically sound methods to establish
      an assay's linear range. In this article, we propose a simple and statistically
      sound method for initially establishing an assay's linear range as a paradigm for
      standardization of manufacturers' claims of assay linearity. Simulations verify
      that the method outperforms using (Pearson's) coefficient of determination (r2)
      to estimate the linear range, consistently yielding estimates for the linear
      range which are more accurate. In addition, the method permits the addition of
      tolerance limits when a certain amount of nonlinearity is acceptable clinically.

PMID- 10340432
TI  - Oligosaccharides released by hydrazinolysis from Tamm-Horsfall protein of various
      human donors contain similar high-mannose glycans.
AB  - As pathophysiological functions claimed for Tamm-Horsfall protein (THP) are
      related to its sugar moiety, we examined influence of pregnancy and various
      diseases on high-mannose chains. Hydrazinolysis was used to liberate
      oligosaccharides from THP polypeptide backbone. After HPLC separation of
      fluorescently labelled glycans similar profiles of neutral oligosaccharides were
      observed in THP of healthy subjects, pregnant women, patients with Bartter's
      syndrome, patients with acute lymphoblastic leukemia and a patient with
      carbohydrate deficient glycoprotein syndrome. THP contains Man-5, Man-6 and Man-7
      glycans, with the preponderant amount of Man-6 glycan (about 7% of total THP
      oligosaccharides). No statistically significant differences were found in THP
      high-mannose glycans profiles between control subjects and pregnant women or
      patients. It is likely that neither pregnancy nor the pathological conditions
      examined affect high-mannose chains. In our opinion hydrazinolysis as a method of
      oligosaccharides liberation, in contrast to enzymatic deglycosylation, is more
      appropriate for analysis of the sugar moiety of THP.

PMID- 10340433
TI  - Studies on coproporphyrin isomers in urine and feces in the porphyrias.
AB  - The urinary and fecal distribution and the relative proportions of the four
      coproporphyrin (copro) isomers I-IV were analysed in 20 healthy subjects and in
      patients suffering from one of the seven common types of hepatic or
      erythropoietic hereditary porphyrias. The ratios of copro isomers I-IV were
      analyzed by ion-pair high-performance liquid chromatography (HPLC). Observations
      showed significantly increased proportions of fecal copro isomer I and decreased
      proportions of copro isomers III, II and IV in erythropoietic porphyrias. In
      acute hepatic porphyrias the excretion of fecal copro isomer III is dominant
      (isomer III = 58.4+/-24.0%; x+/-S.D.) and significantly higher (P < 0.001) than
      in erythropoietic porphyrias (isomer III = 15.3+/-7.7%; x+/-S.D.) and chronic
      hepatic porphyrias (isomer III = 25.8+/-7.6%; x+/-S.D.). The increased
      proportions of fecal copro isomer III proved to be important for the diagnosis of
      hereditary coproporphyria and porphyria variegata independent of the clinical
      phase existing. These last two acute hepatic porphyrias also showed markedly
      elevated percentages of the fecal atypical isomers II and IV. In urine
      significantly decreased proportions of copro isomer I in acute hepatic porphyrias
      (isomer I = 12.3+/-6.0%; x+/-S.D.) could be observed as compared with non-acute
      porphyrias (isomer I = 53.7+/-15.2%; x+/-S.D.). Conversely, the proportion of
      urinary copro isomer III was significantly higher in acute hepatic porphyrias
      (isomer III= 81.4+/-6.4%; x+/-S.D.). As expected, the greatest amounts of urinary
      copro isomer I were found in congenital erythropoietic porphyria (isomer I
      =92.0+/-3.3; x+/-S.D.) and protoporphyria with hepatobiliary complications
      (isomer I = 81.3+/-10.7; x+/-S.D.). The atypical urinary copro isomers I1 and IV
      were detected in all types of porphyrias ranging from 0.1 to 11.5%. The combined
      amounts of copro isomers II and IV show a significantly decreased percentage in
      congenital erythropoietic porphyria as compared with all other types of
      hereditary porphyrias. In conclusion, we demonstrate that the characteristic
      pattern of the copro isomer constellations I-IV in the various types of
      porphyrias are of differential diagnostic importance. The inversion of the I to
      III ratio in feces in hereditary coproporphyria and porphyria variegata allows
      the recognition of gene carriers.

PMID- 10340434
TI  - Stability of apolipoprotein(a) isoform phenotype to postmortem conditions.
AB  - Studies, such as the one entitled Pathobiological Determinants of Atherosclerosis
      in Youth or PDAY, have investigated the relationship of atherosclerotic lesions
      with lipid and lipoprotein risk factors. However, it is possible that proteolytic
      hydrolysis during the postmortem period could alter protein components of
      lipoproteins. Apo(a) is the defining protein of Lp(a), a lipoprotein associated
      with risk of cardiovascular disease. Apo(a) proteins are highly polymorphic for
      size and we simulated, using baboon tissues, the postmortem conditions for the
      PDAY study in order to determine their effects on apo(a) phenotypes. The bulk of
      the postmortem samples (93%) were correctly phenotyped and showed little or no
      evidence of degradation. Thus, apo(a) isoform size phenotypes can be determined
      in postmortem samples, although with caution.

PMID- 10340435
TI  - A simple and sensitive colorimetric assay of zinc in serum using cationic
      porphyrin.
AB  - A direct colorimetric method is presented for simple and sensitive determination
      of serum zinc in 0.05-ml samples, using a cationic porphyrin,
      alpha,beta,gamma,delta-tetrakis(4-N-trimethylaminophenyl) porphine
      tetratoluenesulfonate salt (ttmapp, epsilon = 41.5 x 10(4) l/mol per cm at 421
      nm). 7-Iodo-8-hydroxyquinoline-5-sulfonic acid (Ferron) as an accelerator for the
      incorporation of zinc into ttmapp was most effective. Interference of iron,
      copper and conjugated bilirubin in serum can be eliminated in the presence of
      proteins such as albumin in serum. Within-run and between-run coefficients of
      variation (CV) were in the ranges of 0.76-3.59 and 2.08-5.20%. A good correlation
      was observed between this method and atomic absorption spectrometry (AAS).

PMID- 10340436
TI  - Occurrence of heavy chain of 7S IgM half-molecule whose NH2-terminal sequence is
      identical with that of kappa light chain sequence in patients with Waldenstrom
      macroglobulinemia.
AB  - We report a rare case of a half molecule 7S IgM (HM 7SIgM) consisting of a unique
      mu heavy chain and kappa light chain found in blood and urine samples from a
      patient with primary Waldenstrom macroglobulinemia. A 64kDa abnormal
      immunoglobulin was detected in serum and urine by immunoblot method, and purified
      by a two-dimensional SDS-PAGE after separation from IgG and albumin fractions on
      gel filtration. NH2-terminal amino acid sequence analysis of the heavy chain
      revealed that residues 1-20 were identical to those of the NH2-terminal region of
      kappa light chain derived from the same patient. This sequence was then followed
      by a sequence that could not be identified by a computer homology search on the
      protein database. Using polypeptide segments obtained from the unique mu chain by
      digestion with endopeptidase, we identified a sequence spanning from residue 127
      in the variable region of the known mu chain to residue 19 in the known CH1
      domain and a sequence spanning from residues 67-82 in the heavy chain variable
      region class II. From these results, we concluded that the 64 kDa protein was an
      abnormal half molecule 7S IgM consisting of a kappa light chain and a unique mu
      heavy chain of 35 kDa polypeptide in which the NH2-terminal 20 amino acids were
      replaced by 20 amino acids derived from the sequence of kappa light chain in the
      NH2-terminal region.

PMID- 10340438
TI  - Simultaneous analysis of tyrosinase mRNA and markers of tyrosinase activity in
      the blood of patients with metastatic melanoma.
AB  - Determination of blood tyrosinase mRNA by RT-PCR and markers of tyrosinase
      activity (L-DOPA/L-tyrosine ratio) by HPLC have been proposed as biological tools
      for the detection of metastases in melanoma patients. We prospectively evaluated
      their significance and clinical value in a group of 30 stage III (n = 10) and IV
      (n = 20) melanoma patients and one with melanosis of Dubreuilh. L-DOPA/L-tyrosine
      ratio was elevated in 30% of stage III, 41% of stage IV patients (range: 7.5
      261.0 x 10(5)) and in melanosis of Dubreuilh (184.8) (reference values: 6-16 X
      10(5)). One stage III and four stage IV melanoma patients were positive for
      tyrosinase mRNA. In stage IV patients, tyrosinase mRNA positivity was associated
      with disease progression (P<0.01). The presence of tyrosinase mRNA in blood is
      more related to clinical status than level of melanin precursors, which probably
      reflects tumor burden.

PMID- 10340437
TI  - Effect of water extracts of Rhizopus delemar on the stimulus coupled responses of
      neutrophils and their modulation by various protein kinase inhibitors.
AB  - Human peripheral blood polymorphonuclear leukocytes were preincubated with water
      extracts from Rhizopus delemar. The water extracts significantly inhibited
      arachidonic acid induced superoxide generation, whereas enhanced superoxide
      generation induced by phorbol 12-myristate 13-acetate but not those induced by N
      formyl-methionyl-leucyl-phenylalanine. Superoxide generation induced by water
      extracts was inhibited by staurosporine, an inhibitor of protein kinase C, and
      was enhanced by genistein, an inhibitor of tyrosine kinase. The water extracts
      incubated with phorbol 12-myristate 13-acetate markedly increased phosphorylation
      of serine residue of 28.5 kDa protein with time and the phosphorylation depended
      on the concentration of the water extracts, whereas the water extracts incubated
      with arachidonic acid decreased the phosphorylation of serine residue of 38 and
      42 kDa proteins. The phosphorylation of 28.5 kDa protein induced by the water
      extracts was inhibited by staurosporine, an inhibitor of protein kinase C, but
      was not inhibited by genistein, an inhibitor of tyrosine kinase.

PMID- 10340439
TI  - Association between insulin resistance, body mass and neopterin concentrations.
AB  - Obesity is frequently associated with insulin resistance. Recently an important
      role of the cytokine tumor necrosis factor-alpha in mediating insulin resistance
      of obesity through its overexpression in fat tissue has been reported. In order
      to examine the relation of insulin resistance to obesity and to serum neopterin,
      as a parameter of immune activation, we studied 1234 otherwise healthy
      outpatients, who visited the physician's office for a medical health check-up. 7%
      showed elevated glucose concentrations, 34% elevated body mass indices. There
      were significant correlations between glucose concentrations and body mass
      indices and of the latter with serum neopterin concentrations. Neopterin
      concentrations were significantly higher in patients with elevated body mass
      indices (Mann-Whitney test, U = 131 358, p = 0.0003) and elevated glucose
      concentrations (Mann-Whitney test, U = 35 350 p =0.02). The data may indicate
      that moderate immune stimulation plays a role in the development of insulin
      resistance, and an influence of tumor necrosis factor-alpha seems to be probable.

PMID- 10340440
TI  - The melanocyte stimulating hormone receptor polymorphism: association of the V92M
      and A294H alleles with basal cell carcinoma.
AB  - Allelic variants in the melanocyte stimulating hormone receptor (MC1R) gene are
      susceptibility/outcome candidates for cutaneous basal cell carcinoma (BCC). We
      identified the val92met (V92M) and asp294his (A294H) alleles in 311 cases and 190
      controls. The cases included four homo- and 53 heterozygotes for V92M and 12
      heterozygotes for A294H and two compound heterozygotes (V92M/A294H). Allele
      frequencies were similar in controls. In the cases, we found no association
      between the alleles and skin type though A294H was more common in those with red
      hair (4/19) than with other hair colours (6/163) (P = 0.012). V92M was not
      associated with BCC numbers. Cases with A294H had fewer BCC in comparison with
      those without the allele though the difference was not significant. After
      inclusion of red hair in the model, A294H was significantly associated with fewer
      tumours. While MCIR alleles are attractive candidates for BCC, the variants
      studied did not influence susceptibility. The association with outcome was
      relatively weak. The large number of MC1R alleles and their low frequency, make
      assessment of the importance of this gene in the pathogenesis of skin cancers
      difficult.

PMID- 10340441
TI  - An inhibitor-free assay of acetylcholinesterase and butyrylcholinesterase in the
      cerebrospinal fluid.
AB  - An inhibitor-free assay for the simultaneous determination of
      acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the cerebrospinal
      fluid (CSF) is described. It is based on our finding that the individual activity
      ratios of BChE on both its substrates acetylthiocholine (ACh) and
      butyrylthiocholine (BCh) in the CSF and in the parallel serum are identical under
      conditions of at least 5 mmol/l substrate concentration (Q(BChE)SE = Q(BChe)CSF).
      Considering that AChE only reacts with ACh as substrate and occurs with
      negligible activities in the serum, the measured individual activity ratio of
      BChE in the serum (Q(BChE)SE) and the total hydrolysis rate of ACh and BCh in the
      CSF do allow a precise calculation of the AChE activity in the cerebrospinal
      fluid. The derivation of the corresponding formula is demonstrated in detail. The
      inhibitor-free assay was compared with procedures using cholinesterase inhibitors
      (BW284c51 for AChE and/or iso-OMPA for BChE). Achieving widely identical results
      in particular between the procedure using the AChE inhibitor and the inhibitor
      free test, the latter has decisive advantages: (1) it avoids the use of highly
      toxic inhibitors, (2) it minimizes the test volume needed, (3) it characterizes
      additionally the status of the blood-CSF barrier by means of the BChE activity
      ratio in the CSF and in the parallel serum.

PMID- 10340442
TI  - Apolipoprotein E gene polymorphism frequencies in a sample of healthy Hungarians.
AB  - Apolipoprotein E (apo E) has been found to play an important role in lipid
      metabolism and has been associated with cardiovascular and neurodegenerative
      conditions. Hungarians have some of the highest rates of cardiovascular morbidity
      and mortality in the world. This study examines the distribution of apo E alleles
      and genotypes in a population of healthy ethnic Hungarian blood donors (n = 302).
      Male (n = 152) and female (n = 150) subjects ranging from 18 to 62 years of age
      (mean 37.0) were involved. To determine the frequency of apo E alleles,
      polymerase chain reaction followed by restriction length polymorphism was
      applied. The analyses of data showed that apo E allele epsilon3 had the greatest
      frequency in this group (0.807), followed by apo epsilon2 (0.104) and apo
      epsilon4 (0.087). The highest genotype frequency was found to be epsilon3/3 at
      65.2% (n = 197) followed by genotype epsilon3/4 at 15.9% (n = 48), genotype
      epsilon2/3 at 15.2% (n = 46), genotype epsilon2/2 at 2.3% (n = 7), genotype
      epsilon2/4 at 1.0% (n = 3) and genotype epsilon4/4 at 0.4% (n = 1). The apo E
      frequencies found in this study appear to differ from an earlier study of blood
      donors, where the results are based on apo E phenotyping.

PMID- 10340443
TI  - Increased urinary excretion of LTB4 and omega-carboxy-LTB4 in patients with
      Zellweger syndrome.
AB  - The metabolic inactivation of leukotrienes proceeds by beta-oxidation from the
      omega-end. We investigated the importance of peroxisomes and mitochondria in LTB4
      oxidation in vivo. LTB4 and its oxidation products were analysed after high
      performance liquid chromatography separation by immunoassays and gas
      chromatography-mass spectrometry in the urine of patients with Zellweger
      syndrome, patients with long-chain acyl CoA dehydrogenase deficiency, and healthy
      controls. LTB4 (median 97; range 35-238 nmol/mol creatinine) and its omega
      oxidation product omega-carboxy-LTB4 (median 898; range 267-4583 nmol/mol
      creatinine) were present and significantly increased in the urine of all patients
      with Zellweger syndrome compared to the controls (P <0.01). In contrast, LTB4 and
      omega-carboxy-LTB4 were below the detection limit (< 5 nmol/ mol creatinine) in
      patients with long-chain acyl CoA dehydrogenase deficiency and healthy controls.
      The beta-oxidation product omega-carboxy-tetranor-LTB3 was neither detectable in
      the urine of patients with Zellweger syndrome, patients with long-chain acyl CoA
      dehydrogenase deficiency nor in the controls (< 5 nmol/mol creatinine). Analysis
      of urinary leukotrienes represents an additional diagnostic tool in peroxisome
      deficiency disorders. Furthermore, these results clearly underline the essential
      role of peroxisomes in the oxidation of LTB4 in humans.

PMID- 10340444
TI  - Homocysteine and B-group vitamins in renal transplant patients.
AB  - Increased plasma homocysteine is an independent risk factor for cardiovascular
      disease. We have investigated homocysteine and B-group vitamin levels in renal
      transplant patients. Fasting blood was collected from 55 renal transplant
      recipients with good renal function and 32 age/sex matched control subjects.
      Total homocysteine was increased in transplant recipients in comparison to
      controls (10.9+/-1.5 vs. 6.7+/-1.3 micromol/l, P < 0.001). There was no
      difference in homocysteine between patients receiving cyclosporin (n = 39,
      homocysteine 11.0+/-1.5 micromol/l) and patients receiving prednisolone +
      azathioprine (n = 16, 10.8+/-1.6 micromol/l, mean+/-S.D.), although there was a
      significant correlation between homocysteine and serum cyclosporin concentration
      in the sub-group of patients receiving that immunosuppressive regimen (r = 0.42,
      P < 0.05). Levels of B-group vitamins were similar in patients and controls.
      Plasma homocysteine is increased in renal transplant recipients even in the
      presence of minor degrees of renal impairment and normal levels of B-group
      vitamins.

PMID- 10340445
TI  - Relationship of serum N-acetyl-beta-glucosaminidase activity to oxidative stress
      in diabetes mellitus.
AB  - Serum N-acetyl-beta-glucosaminidase activity was evaluated in 40 Type 1 and 40
      Type 2 diabetic patients and compared with parameters of diabetes control and
      oxidative stress. Significantly increased mean serum N-acetyl-beta
      glucosaminidase activity was found in both groups of diabetic patients as
      compared with the corresponding group of healthy persons (p < 0.01). Oxidative
      stress measured by plasma malondialdehyde concentration was significantly higher
      in Type 2 than in Type 1 diabetic patients (p < 0.01) but in comparison with
      control subjects it was higher only in Type 2 diabetes. Plasma malondialdehyde
      concentration positively correlated with body mass index (r=0.77, p<0.001) and
      with serum N-acetyl-beta-glucosaminidase activities (r=0.57, p <0.001). Treatment
      of 10 Type 2 diabetic patients with antioxidant alpha-tocopherol caused a
      significant decrease in malondialdehyde concentration (p < 0.001) which was
      accompanied by a decrease of N-acetyl-beta-glucosaminidase activity (p < 0.01).
      We conclude that serum N-acetyl-beta-glucosaminidase activity may be influenced
      by oxidative stress which is more pronounced in Type 2 than in Type 1 diabetic
      patients.

PMID- 10340446
TI  - Likelihood ratios and Fagan's nomogram: valuable but underrated tools for in
      vitro latex sensitization assessment.
AB  - The relevance of latex allergy has greatly increased in the last decade
      especially in health workers and in children with spina bifida. Serological
      testing has been proposed in the diagnosis since history can be inconclusive and
      skin and provocative testing can induce severe adverse reactions. We evaluated
      positive likelihood ratios (LRpos) and the Fagan's nomogram in the diagnosis of
      latex allergy. Thirty patients with positive clinical history, who showed
      positive results in the skin prick test and in glove-exposure test were compared
      to 36 blood donors with negative clinical history, who showed negative results in
      the skin prick test and in glove-exposure test. LRpos was calculated at four
      different cutoff concentrations of IgE specific to latex measured with a totally
      automated analyzer. LRs appear better compared to the traditional classes in the
      reporting of IgE and, coupled with the Fagan's nomogram which allows the
      calculation of post-test probability, could improve laboratory testing in latex
      allergy.

PMID- 10340447
TI  - Quantification of glutaric acid by isotope dilution mass spectrometry for
      patients with glutaric acidemia type I: selected ion monitoring vs. selected ion
      storage.
AB  - An isotope dilution mass spectrometric assay for the quantification of glutaric
      acid in urine and serum samples was developed. The performance of a quadrupole
      mass filter (QMF) gas chromatography-mass spectrometry (GC-MS) instrument,
      operated in the selected ion monitoring mode, and a quadrupole ion trap (QIT)
      GC/MS instrument, operated in the selected ion storage mode, was compared. Both
      instruments gave linear standard curves with glutaric acid concentrations between
      0.19 and 3.8 microM. The average coefficients of correlation were 0.9998 and
      0.9993 for the QMF and the QIT system, respectively. There was good agreement
      between the glutaric acid concentrations measured with the two instruments. The
      run-to-run precision was between 1.2 and 3.7% and between 6.2 and 8.6%, the
      average recovery of glutaric acid in urine and serum samples was 96 and 103% with
      the QMF and QIT instrument, respectively. We conclude that although the QMF has a
      slightly better performance, both instruments can be used to reliably measure
      glutaric acid concentrations from urine and serum patient samples.

PMID- 10340448
TI  - Recovery from acute cholestasis associated with erythropoietic protoporphyria
      treated by antibiotics.

PMID- 10340449
TI  - Effects of pH and urea on the determination of urinary myoglobin concentration by
      an enzyme immunoassay.

PMID- 10340450
TI  - Circadian characteristics of cathepsins B, H, L, and stefins A and B, potential
      markers for disease, in normal sera.

PMID- 10340451
TI  - Correlation between tissue transglutaminase antibodies and endomysium antibodies
      as diagnostic markers of coeliac disease.

PMID- 10340452
TI  - Measurement of serum sodium and potassium with direct ion-selective electrode
      systems.

PMID- 10340453
TI  - Level of termination of the spinal cord and the dural sac: a magnetic resonance
      study.
AB  - Previous studies concerning the level of termination of the human spinal cord
      have been carried out in unselected cadavers. We have used magnetic resonance
      imaging to determine this level of termination, and that of the dural sac, in
      normal living subjects. We found a wider range of the level of termination of
      both the spinal cord and dural sac and a higher median level of termination of
      each than is commonly described. These anatomical findings are of clinical
      relevance to clinicians practicing regional anesthesia.

PMID- 10340454
TI  - Dual anterior interventricular arteries.
AB  - A patient with dual left anterior descending (R. interventricularis anterior of
      the left coronary artery) coronary artery is presented. A normally arising left
      anterior descending was hypoplastic, and an anomalous left anterior descending,
      which arose from the right sinus aorticus had a normal caliber. The anomalous
      left anterior descending artery traversed between the aorta and the pulmonary
      artery supplying most of the anterior myocardial wall of the left ventricle. This
      rare coronary anomaly can potentially have implications on percutaneous coronary
      interventions or on surgical revascularization procedures.

PMID- 10340456
TI  - Phrenoesophageal ligament re-visited.
AB  - The phrenoesophageal ligament, attaching the esophagus to the diaphragm, has been
      given little emphasis in anatomy teaching. This study was undertaken to examine
      the macroscopic and microscopic structure of the phrenoesophageal ligament. The
      results indicate that the ligament is a distinct structure bridging the space
      between the esophageal wall and the margins of the esophageal hiatus. This
      ligament appears to arise from both the endothoracic fascia and the transversalis
      fascia and is composed of abundant collagen and elastic lamellae. Toward the wall
      of the esophagus, the ligament divides into a prominent upper leaf and an ill
      defined lower leaf before inserting into the wall of the esophagus. Histological
      study reveals that the ligament has a substantial and deep insertion into the
      wall of the esophagus. It appears that the ligament plays an important role in
      anchoring the lower esophagus and maintaining gastroesophageal competence.

PMID- 10340455
TI  - Arterial supply of the gracilis muscle and its relevance for the dynamic
      graciloplasty.
AB  - The various methods of transposition of the gracilis muscle in order to serve as
      an anal neo-sphincter have progressed in recent years. Tetanic contraction can be
      achieved by converting Type II muscle fibers into Type I by use of chronic, low
      frequency electrical stimulation. In order to guarantee a good function the
      muscle's vascularization has to have at least one nutritive vessel. In our
      investigation we worked out the various forms of the muscle's arterial blood
      supply. Dissecting 66 specimens we detected four with only one nutritive vessel,
      23 with a double-supply and, as the most common constellation, in 34 cases three
      supplying arteries. A small group of five individuals showed more than three
      arterial vessels. Because of the fact that the obturator nerve is not running
      with the incoming arteries, an angle was measured between the length axis of the
      muscle and the first perforating artery. This information should help the surgeon
      to preserve the nerve.

PMID- 10340457
TI  - Lumbosacral anterolateral spinal arteries and brief review of "accessory"
      longitudinal arteries of the spinal cord.
AB  - The lumbosacral anterolateral spinal arteries (LALSA) were studied in 14 injected
      lumbosacral spinal cords. Contrary to many previously published opinions, which
      claimed that virtually all of the formerly described "accessory" longitudinal
      arteries of the vasa corona, were too inconstant to be of significance, the LALSA
      in this series were reliably present bilaterally and averaged a length of 8.4 cm.
      They ran in the acute angles formed by the emergence of the fascicles of the
      lumbosacral anterior spinal nerve roots and in this position, served as the
      origin for most of the proximal radicular arteries that supply the cranial half
      of the motor roots of the cauda equina. A review of the literature and analysis
      of other accessory longitudinal spinal arteries revealed that two other pairs of
      accessory spinal vessels, the lateral cervical spinal arteries (LCSA) and the
      lateral spinal arterial axes (LSA), have a demonstrable functional role and were
      sufficiently constant, along with the LALSA, to warrant inclusion in detailed
      descriptions of human spinal cord vasculature.

PMID- 10340458
TI  - Anatomical and safety considerations in establishing portals used for wrist
      arthroscopy.
AB  - Eight portals are used for wrist arthroscopy, five for the radiocarpal joint and
      three for the midcarpal space. These portals pass between important vessels and
      cutaneous nerves and the extensor tendons underlying the extensor retinaculum and
      permit access to the common pathologies of the wrist joints. The portals can be
      safely established making precise use of the external landmarks and are
      associated with little soft tissue damage and few complications when performed
      gently and through the dorsal side of the wrist.

PMID- 10340459
TI  - Concepts of variation and normality in morphology: important issues at risk of
      neglect in modern undergraduate medical courses.
AB  - In anatomy, normality embraces a range of morphologies and includes those that
      are most common and others called variations which are less frequent but not
      considered abnormal. Variations ranging from subtle to remarkable affect every
      part of the human body. They may have important influences on predisposition to
      illness, symptomatology, clinical examination and investigation, and patient
      management including operative surgery. Recognition of variations enables
      clinicians to distinguish features which merit further investigation or treatment
      from those which do not. We believe the concepts of normality and variation
      should be introduced early in the medical course and that the dissecting
      laboratory is the ideal venue. Students who are able to examine several specimens
      or are privileged to dissect soon realize that each cadaver is unique. Knowledge
      of variations should be reinforced in several components of the medical course
      where physical examination, imaging investigations, surgical procedures, and
      autopsies are studied. Appreciation of the range of normality including
      variations matures as experience is gained over several years. Current trends in
      undergraduate courses--including reduced exposure to dissection and dissected
      specimens, increased use of plastic bones, models and computer-generated images,
      loss of experienced teachers, especially those who are medically qualified, and
      loss of morphological approach-- all conspire to defer the stage when students
      encounter variation. We are concerned that these trends will compromise the
      knowledge and understanding of variation required to start practicing medicine
      safely and competently.

PMID- 10340460
TI  - Implementing and integrating computer-based activities into a problem-based gross
      anatomy curriculum.
AB  - A problem-based learning curriculum in gross anatomy was begun for a limited
      number of students to address unsuccessful methodology inherent in a traditional
      instructional approach. To eliminate some concerns associated with the laboratory
      component, computer-based instruction and other computer- related activities were
      actively integrated into the total instructional process. Prosections,
      directions, quizzes, images, and grades were provided in lab at table-side
      computer workstations, in the library, and on the web. Results were assessed
      through questionnaires in which students rated their learning experience
      according to a Likert-type scale. Success was measured by quantitative
      improvements in student perception. In this three-year study, observations and
      measurements have suggested increasingly positive student attitudes toward
      educational technology, for networks as a faster and more effective method of
      student/faculty communication, and in the utilization of computer-based
      instruction for greater flexibility and efficiency in learning. This allowed a
      rethinking of the structure and content of the curriculum by the faculty, which
      permitted reduced laboratory time, more small-group activity, and less reliance
      on staff.

PMID- 10340461
TI  - Missteps and masquerade in American medical academe: clinical anatomists call for
      action.

PMID- 10340462
TI  - Research-based clinical anatomists: response to "AACA: purpose, vitality and
      pride". American Association of Clinical Anatomists.

PMID- 10340463
TI  - Bacterial chemoreceptors: recent progress in structure and function.
AB  - The behavior of a bacterial cell is determined by the interplay between
      transmembrane receptor molecules and a cytoplasmic kinase that is linked to the
      flagellar apparatus. In the absence of external stimulus, a balance exists
      between stresses in the periplasmic region of receptor molecules, and
      compensating cytoplasmic forces. A response, positive or negative, is due to a
      temporary disturbance in this balance, with corresponding alterations in kinase
      activity, and ultimately, of swimming behavior. Methylation acts to restore the
      balance by changing the properties of the receptor. Because methylation is slow,
      a response will continue for a period of time following stimulation. The
      mechanisms by which these processes occur are now being elucidated at the
      molecular level, and should soon make bacterial chemotaxis the first available
      picture of a complete sensory system.

PMID- 10340465
TI  - Identification of a full-size hobo element and deletion-derivatives in Korean
      populations of Drosophila melanogaster.
AB  - We have isolated and characterized several members of the hobo transposable
      element family from Korean populations of Drosophila melanogaster. All of the
      Korean lines tested appeared to have 3.0 kb hobo elements and a high copy number
      of smaller derivatives of the element. To determine whether a 3.0 kb hobo element
      of these populations is consistent with the role of an autonomous hobo element,
      we cloned and sequenced this hobo element. Based on the result of the entire DNA
      sequence, a cloned 3.0 kb element called HKN96, it was found to be the same as a
      fully-functional 2959 bp HFL1-type sequence. Each small element appeared to have
      arisen from the HFL1 element by a different internal deletion. A specific 1.7 kb
      Kh hobo element, which is the most abundant in the Korean lines tested, seems to
      have originated from the HFL1 hobo element by an internal deletion of 1253 bp by
      the removal of nucleotides between positions 939 and 2191. The sequences of the
      Th1 and Th2 elements appeared to be identical to that of the HFL1 with the
      exception of internal deletions of 1442 bp and 1455 bp removing nucleotides 940
      2381 and 923-2377, respectively. Based on the number of TPE repeats, all of the
      members of the hobo element family in Korean lines tested have three perfect S
      repeats. The widespread presence of identical copies of the Kh deletion
      derivative suggests that it might have a role in the regulation of hobo-induced
      hybrid dysgenesis.

PMID- 10340464
TI  - Modulation of gelatinase activity correlates with the dedifferentiation profile
      of regenerating salamander limbs.
AB  - Remodeling of extracellular matrix (ECM) is one of the key events in many
      developmental processes. In the present study, a temporal profile of gelatinase
      activities in regenerating salamander limbs was examined zymographically. In
      addition, the effect of retinoic acid (RA) on these enzyme activities was
      examined to relate the pattern-duplicating effect of RA in limb regenerates with
      gelatinase activities. During regeneration, various types of gelatinase
      activities were detected, and these activities were at their maximum levels at
      the dedifferentiation stage. Upon treatment with chelating agents EDTA and 1,10
      phenanthroline, the enzyme activities were inhibited indicating that those
      enzymes are likely matrix metalloproteinases (MMPs). Considering the molecular
      sizes and the decrease of molecular sizes by treatment with p-aminophenylmercuric
      acetate, an artificial activator of proMMP, some of the gelatinases expressed
      during limb regeneration are presumed to be MMP-2 and MMP-9. In RA-treated
      regenerates, overall gelatinase activities increased, especially the MMP-2-like
      gelatinase activity which increased markedly. These results suggest that MMP-2
      like and MMP-9-like gelatinases play a role in ECM remodeling during
      regeneration, and that gelatinases are involved in the excessive
      dedifferentiation after RA treatment.

PMID- 10340466
TI  - Carcinoembryonic antigen gene and carcinoembryonic antigen expression in the
      liver metastasis of colorectal carcinoma.
AB  - The presence of the carcinoembryonic antigen (CEA) gene and CEA expression in the
      liver was tested to identify their possible roles in the liver metastasis of
      colorectal carcinoma. The CEA gene in the liver was identified by amplifying the
      CEA-specific N-terminal domain exon with digoxigenin-dUTP labeling in 16
      colorectal carcinomas with liver metastases. Next, CEA expression was tested by
      immunostaining using the anti-CEA monoclonal antibody (T84.66, ATCC). Liver
      tissues from 13 stomach cancer patients and 12 colorectal cancer patients without
      liver metastasis were also tested as control groups. Three grades (<25%, 25-50%,
      and 50%< or =) were given according to the proportion of positive cells. The CEA
      gene was amplified in the metastatic tumor cells of the liver (2.6 +/- 0.2, mean
      grade +/- SEM) and their surrounding hepatocytes (1.5 +/- 0.2) in all cases. CEA
      expression was found in all metastatic tumor cells and 14 cases of the
      surrounding hepatocytes. Among the control groups, the CEA gene of the
      hepatocytes was found in 9 cases each of the colorectal and the stomach cancers
      that did not exhibit CEA expression. The level of serum CEA was related with the
      numbers and volume of liver metastases, but not with CEA expression in tumor
      cells and surrounding hepatocytes. The CEA gene in the metastatic tumor cells,
      not in the hepatocytes, was closely associated with CEA expression in the
      surrounding hepatocytes (p<0.01). Although the precise mechanism of CEA gene
      regulation in hepatocytes remains to be proven, the CEA gene in the metastatic
      tumor of the liver seems to affect CEA expression in the surrounding hepatocytes
      facilitating liver metastasis in colorectal carcinoma.

PMID- 10340467
TI  - Overexpressed alpha3beta1 and constitutively activated extracellular signal
      regulated kinase modulate the angiogenic properties of ECV304 cells.
AB  - ECV304, a spontaneously transformed cell line derived from the human umbilical
      vein endothelial cell (HUVEC) (Takahashi et al., 1990), has been developed as an
      in vitro angiogenesis model. In the present study, we further characterized the
      angiogenic properties of this cell line. Compared to HUVEC, ECV304 cells showed
      distinct features including a higher activity of cellular adhesion, slower but
      reproducible progression of angiogenesis on Matrigel, and resistance to
      apoptosis. Thus, the expression of integrin and activation of extracellular
      signal regulated kinase 1/2 (Erk1/2), a downstream effector of the integrin
      pathway, were examined. Flow cytometry revealed that alpha3beta1 integrin was
      markedly upregulated in ECV304 cells, while alpha(v)beta1 and alpha5beta1
      integrins were slightly downregulated. Consistent with this, the binding activity
      to collagen type IV and laminin, major extracellular matrices of Matrigel, was
      increased 1.4- and 1.9-fold in ECV304 cells, respectively. This tight binding may
      retard the initial stage of sprouting and migration in the angiogenesis of ECV304
      cells. It has been further demonstrated that Erk1/2 is constitutively active in
      ECV304 cells, rendering them resistent to the inhibitory effect of PD98059 on
      proliferation. However, migration of both HUVEC and ECV304 cells was inhibited to
      a similar extent by PD98059 in a dose-dependent manner. Up to 50 microM of
      PD98059, no significant changes in cell binding and tubulogenesis on Matrigel was
      observed in ECV304 cells. In contrast, the tubulogenesis of HUVEC was severely
      impaired by PD98059. Elevated Erk1/2 activity in ECV304 cells was suppressed by
      dominant negative H-Ras, but not by cytochalasin D. These results suggest that
      the overexpression of alpha3beta1 integrin and the constitutive activation of
      Erk1/2 play a key role in the alteration of the angiogenic properties of ECV304
      cells.

PMID- 10340468
TI  - Regulation of basal expression of catecholamine-synthesizing enzyme genes by
      PACAP.
AB  - We have previously reported that the cAMP/protein kinase A (PKA) pathway is
      important in the gene regulation of both induction and basal expressions of the
      catecholamine synthesizing enzymes tyrosine hydroxylase (TH) and dopamine beta
      hydroxylase (DBH). The neuropeptide pituitary adenylate cyclase activating
      polypeptide (PACAP) has been shown to activate the intracellular cAMP/PKA
      pathway. In the present study, using primary cultured bovine adrenal medullary
      cells, we determined whether the basal activity of the PACAP receptor might play
      a role in the maintenance of the basal expression of these enzyme genes via the
      cAMP/PKA pathway. The potent PACAP receptor antagonist PACAP (6-38) caused a
      reduction of TH and DBH mRNA levels in a dose dependent manner as well as their
      enzyme activities and TH protein level. The effects of PACAP (6-38) and the PKA
      inhibitor H-89 exhibited generally similar trends, and were not additive in the
      reduction of TH and DBH gene expression and activities, suggesting that they take
      a common intracellular signaling pathway. The antagonist also caused decreases in
      the intracellular norepinephrine and epinephrine levels similar to the effect of
      H-89. Taken together, the data suggests that PACAP is involved in the regulation
      of maintenance of the catecholamine synthesizing enzymes TH and DBH by utilizing
      the cAMP/PKA pathway.

PMID- 10340470
TI  - Study on genetic variation and DNA polymorphism for alpha-amylase gene of D.
      melanogaster in Korea.
AB  - The restriction maps of the 20 kb Amy region of Drosophila melanogaster in Korean
      populations were surveyed from 27 isogenic second chromosome lines. A subset of
      these populations were also scored for isozyme type and adult enzyme activity of
      alpha-amylase. Among 34 kinds of restriction site variations that were observed
      in the 20 kb region surrounding the two transcriptional units of the duplicated
      Amy locus, nine were polymorphic (26.5%). The low frequencies at which each of
      the large insertions was found are consistent with earlier reports of variation
      in other loci. Restriction site variation in Korean populations provided an
      estimated heterozygosity per nucleotide pair of 0.007. Three pairwise comparisons
      showed relatively high levels of linkage disequilibria. The enzyme activity of
      the Chounan population showed no significant difference compared with that of the
      Pusan population, and the activity of heterozygotes was higher than that of Amy1.
      Lines bearing insertion/deletion exhibited relatively low enzyme activities. All
      lines examined showed the duplication of Amy transcriptional units that were
      highly conserved, and the manner of concerted evolution.

PMID- 10340469
TI  - Regulation of nitrite reductase by light and nitrate in the cotyledons of hot
      pepper (Capsicum annuum L.).
AB  - Light and nitrate are the major factors regulating the nitrite reductase (NiR)
      amongst various environmental and metabolic cues in plants. Hot pepper was used
      to investigate this regulatory mechanism of the NiR gene expression and its
      dependency on light and nitrate. The major results from this study are: (I) the
      nir partial clone (581 bp) obtained from hot pepper genomic DNA by degenerative
      polymerase chain reaction exhibited an amino acid sequence that is highly
      homologous with other plants. (II) Genomic DNA blot analysis and the NiR
      electrophoretic assay revealed that a small multigene family encodes NiR, which
      exists at least in two isoforms. (III) The light-mediated increase of NiR
      activity is correlated with the nitrate concentration, showing saturation
      kinetics above 50 mM of nitrate. (IV) Exogenous nitrate was required for the
      appearance of nir transcripts, but not for the enzyme activity. These results
      suggest that the gene expression of NiR in hot pepper is determined by the
      presence of nitrate at the transcriptional level. Furthermore, light has a
      synergistic effect on the action of nitrate on NiR levels.

PMID- 10340471
TI  - Induction of ascorbate peroxidase by ethylene and hydrogen peroxide during growth
      of cultured soybean cells.
AB  - In cultured soybean cells, a transient ethylene burst in the pre-stationary phase
      was followed by an induction of ascorbate peroxidase (AsPOX) in the stationary
      phase. Treatment of cells with the ethylene antagonist, silver thiosulfate (STS),
      resulted in the suppression of enzyme activity. Application of the ethylene
      releasing agent 2-chloroethylphosphonic acid (CEPA) in the medium led to an
      increased enzyme activity when treated in the pre-stationary phase. On the
      contrary, a remarkable inhibitory effect on enzyme activity was elicited by 1,3
      dimethyl-2-thiourea (DMTU), trapping the hydrogen peroxide generated when treated
      in the stationary phase. Likewise, a steady level of AsPOX transcript was reduced
      by STS treatment. Furthermore, its effect appeared to be more rapid and prominent
      during the pre-stationary phase. It is suggested that the induction of AsPOX in
      cultured soybean cells during the stationary phase could result, at least in
      part, by the hydrogen peroxide generated as a result of preceding ethylene
      production.

PMID- 10340472
TI  - Aromatic hydrocarbon nuclear translocator as a common component for the hypoxia-
      and dioxin-induced gene expression.
AB  - Aromatic hydrocarbon nuclear translocator (Arnt) is an ubiquitously expressed
      protein that contains basic helix-loop-helix (bHLH) and Per-AhR-Arnt-Sim (PAS)
      motifs. Other bHLH-PAS proteins, hypoxia-inducible factor-1alpha (HIF-1alpha) and
      aromatic hydrocarbon receptor (AhR) mediate hypoxia- and dioxin-signal pathway,
      respectively. Arnt has been identified as a heterodimerization partner for AhR.
      AhR/Arnt heterodimer binds the regulatory region of xenobiotic-induced genes and
      activates their transcription. Here, in vivo results provide evidence that Arnt
      is involved in not only xenobiotic- but also hypoxia-induced transcriptional
      activation. In hypoxic condition, Arnt dimerizes with HIF-1alpha to make HIF
      1alpha/Arnt heterodimer which is able to bind hypoxia-responsive DNA elements.
      The HIF-1alpha/Arnt heterodimer functions as a transactivator for hypoxia
      inducible genes. Given that the expression of Arnt is limited, HIF-1alpha may
      compete with AhR for recruiting Arnt as a heteromeric partner. Consistent with
      this idea, the results indicate that the hypoxic activation of HIF-1alpha reduces
      dioxin-induced AhR's function on the dioxin-responsive reporter gene and the
      endogenous gene.

PMID- 10340473
TI  - Differential expression of mouse Disabled 2 gene in retinoic acid-treated F9
      embryonal carcinoma cells and early mouse embryos.
AB  - Using a differential display PCR, we identified a differentially expressed cDNA
      fragment which was detectable in retinoic acid (RA) treated F9 embryonal
      carcinoma (EC) cells but not in untreated F9 cells. A homology search of the Gene
      Bank indicated that the cDNA fragment is part of the mouse homolog of the
      Drosophila Disabled (mDab2) gene. Aggregate cultures of F9 EC cells grown in the
      presence of the RA differentiated into nonmalignant cells resembling the visceral
      endoderm of the mouse embryo. Upon induction of endodermal differentiation with
      10(-7) M RA, the gene expression of mDab2 was increased gradually during the
      first 96 h. Neither undifferentiated F9 cells, nor the undifferentiated aggregate
      cells without RA expressed mDab2. Whole-mount in situ hybridization and
      quantitative RT-PCR also showed that the temporal expression pattern of the mDab2
      gene coincides with the initiation pattern of RA synthesis that occurs during
      mouse embryogenesis. Also, two alternative splicing messages of mDab2 were
      detected in a tissue specific manner. All the data indicate that mDab2 may play
      an important role in RA-induced signal transduction during mouse development.

PMID- 10340475
TI  - Putative secondary structures of unusually long strepsipteran SSU rRNAs and its
      phylogenetic implications.
AB  - We constructed the putative secondary structures of the small subunit rRNAs (SSU
      rRNA) from three strepsipteran insects. The primary sequences of the
      strepsipteran SSU rRNAs are unusually long due to unique and long insertions. In
      spite of these insertions, the basic shapes of their secondary structures are
      well maintained as shown in those of other eukaryotes, because these insertions
      appear mainly in the variable regions. The secondary structures for the V1, V3,
      V5, V8, and V9 regions are well conserved, even though the primary structures of
      V1, V5, and V8 regions are quite variable. However, the predicted secondary
      structures for the V2, V4, and V7 regions are quite different from those of other
      insects. In the V4 and V7 regions, helices specific to the Strepsiptera exist.
      These helices have not been reported in other organisms so far. Similarly, four
      eukaryotic specific helices (E8-1, E10-2, E23-4 and E45-1) not reported in
      insects exist in the V2, V4, and V8 regions. These helices are formed by the
      inserted sequences. The secondary structures of the expanded segments of the
      strepsipteran SSU rRNA were applied to infer the phylogenetic position of
      Strepsiptera, one of the most enigmatic problems in insect phylogeny. Only the
      secondary structure of the V7 region showed the weak Strepsiptera/Diptera sister
      group relationship.

PMID- 10340474
TI  - Functional studies on the interaction between human replication protein A and
      Xeroderma pigmentosum group A complementing protein (XPA).
AB  - The human replication protein A (RPA; also known as human single-stranded DNA
      binding protein, HSSB) is a multisubunit complex (70, 34 and 11 kDa subunits)
      involved in the three processes of DNA metabolism; replication, repair,
      recombination. We found that both 34 and 70 kDa subunits (p34 and p70,
      respectively), of RPA interacts with the Xeroderma pigmentosum group A
      complementing protein (XPA), a protein that specifically recognizes UV-damaged
      DNA. Our mutational analysis indicated that no particular domains of RPA p70 were
      essential for its interaction with XPA. We also examined the effect of this XPA
      RPA interaction on in vitro simian virus 40 (SV40) DNA replication catalyzed by
      the crude extract and monopolymerase system. XPA inhibited SV40 DNA replication
      in vitro through its interaction with RPA. Taken together, these results suggest
      that there is a role for RPA in the regulation of DNA metabolism through its
      ability to modulate the interactions of proteins involved in the processes of DNA
      metabolism.

PMID- 10340476
TI  - Suppression of ceramide-mediated apoptosis by HSP70.
AB  - Ceramide has been known as an important second messenger in programmed cell death
      (apoptosis) which is induced by various stimuli such as the tumor necrosis factor
      alpha (TNF-alpha), Fas ligand, and environmental stresses such as UV-irradiation
      and heat shock. Although the precise molecular mechanism of apoptosis is not
      fully understood, ceramide generated by sphingomyelinase (SMase) mediates the
      activation of several downstream molecules that are implicated in the regulation
      of apoptosis. Here, we show that stress-inducible heat shock protein 70 (Hsp70)
      prevents apoptosis induced by increased level of intracellular ceramide. In T
      cell hybridoma DO11.10, we examined the effect of Hsp70 on apoptosis mediated by
      TNF-alpha, Fas ligation, SMase, and C2-ceramide, all of which elevate
      intracellular ceramide levels. Hsp70 not only markedly reduced internucleosomal
      DNA fragmentation, but also enhanced cell viability measured by the Trypan blue
      dye exclusion test. Similarly, the ceramide-induced c-jun amino-terminal kinase
      (JNK/SAPK) activation is impaired in cells overexpressing Hsp70. These data
      strongly suggest that hsp70 functions as a regulator of apoptosis downstream of
      ceramide.

PMID- 10340477
TI  - Isolation of developmentally regulated novel genes based on sequence identity and
      gene expression pattern.
AB  - Based on the surmise that a variety of genes might play important roles in
      embryonic development and tissue differentiation, and that some of them are
      likely to be expressed in undifferentiated ES cells, we attempted to identify new
      genes from the ES cell cDNA library. The modified method of expressed sequence
      tags (ESTs) and the examination of the expression patterns in adult tissues and
      in vitro differentiated ES cells were utilized in this study. We have isolated
      and identified several novel cDNA clones with interesting developmental
      expression pattern. Among the 83 clones randomly chosen, 23 clones (27.7%) have
      no homology to any sequences in public databases. The rest contain limited or
      complete sequence homology to the previously reported mammalian genes or ESTs,
      yet some clones have not been previously identified in the mouse. To examine the
      expression profile of clones during development and differentiation, sets of slot
      blots were hybridized with developmental stage specific or tissue specific
      probes. Out of 40 novel clones tested (21 totally unknown clones and 19
      unidentified clones in mouse), most of them were up- or down-regulated as
      differentiation proceeded, and some clones showed differentiation-stage specific
      expression profiles. Surprisingly, a majority of genes were also expressed in
      adult tissues, and some clones even revealed tissue specific expression. These
      results demonstrate that not only was the strategy we employed in this study
      quite efficient for screening novel genes, but that the information gained by
      such studies would also be a useful guide for further analysis of these genes. It
      also suggests the feasibility of this approach to explore the genomewide network
      of gene expression during complicated biological processes, such as embryonic
      development and tissue differentiation.

PMID- 10340478
TI  - Identification of the polyamine induced proteins in Escherichia coli.
AB  - The polyamine (PA)-induced proteins were identified by SDS-PAGE, and by two
      dimensional gel analysis in Escherichia coli strains. A large number of the PA
      induced proteins were acidic. The molecular weights of the most highly induced
      proteins were 40 and 82 kDa proteins in the wild type and PA-auxotrophic mutant,
      respectively. Although a part of the PA-induced proteins were induced both in the
      wild type and PA auxotrophic mutant, most of them seem to be induced either in
      the wild type or mutant. These features may provide a foundation for evaluating
      the role of the PA-induced proteins relative to the physiology and environmental
      stress of Escherichia coli.

PMID- 10340479
TI  - Cloning and sequencing of the fcbB gene encoding 4-chlorobenzoate-coenzyme A
      dehalogenase from Pseudomonas sp. DJ-12.
AB  - Pseudomonas sp. DJ-12 degrades 4-chlorobenzoate through hydrolytic dechlorination
      to produce 4-hydroxybenzoate and a chloride ion. The fcbB gene encoding the 4
      chlorobenzoate-coenzyme A (4CBA-CoA) dehalogenase which catalyzes the
      nucleophilic substitution reaction to convert 4CBA-CoA to 4-hydroxybenzoate
      coenzyme A (4HBA-CoA) in the consecutive steps of dechlorination was cloned from
      the chromosome of the organism. A nucleotide sequence analysis of the gene showed
      an open reading frame consisting of 810 nucleotides, which can encode for a
      polypeptide of molecular mass 30 kDa, containing 269 amino acid residues. A
      promoter-like sequence (-35 and -10 region) and a putative ribosome-binding
      sequence were identified. A deduced amino acid sequence of the 4CBA-CoA
      dehalogenase showed 86%, 50%, and 50% identity with those of corresponding
      enzymes in the Pseudomonas sp. CBS3, Arthrobacter sp. SU, and Arthrobacter sp.
      TM1, respectively.

PMID- 10340480
TI  - Analysis of calsequestrin gene expression using green fluorescent protein in
      Caenorhabditis elegans.
AB  - The calsequestrin gene of Caenorhabditis elegans is expressed in body-wall muscle
      cells during muscle development. In order to study the body-wall muscle specific
      regulation of the calsequestrin gene expression, approximately 2 kb upstream
      sequences of the calsequestrin gene were analyzed. Transcriptional fusion
      constructs utilizing green fluorescent protein as a reporter gene were made and
      microinjected to produce germ-line transformed transgenic C. elegans. The
      expression of green fluorescent protein was observed in the body-wall muscles of
      live transgenic animals under fluorescence microscopy. Deletion analyses of
      upstream sequences have revealed a putative promoter sequence and a regulatory
      element which appeared to enhance reporter gene expression. Both sequence
      elements are juxtaposed to constitute a 260 bp regulatory region approximately
      260 bp upstream from the putative translational initiation codon. Several
      possible binding sites for transcription factors were identified including the
      sites for YY1 and NF-W2, a muscle specific zinc finger transcription factor, and
      an ubiquitous enhancer binding protein, respectively. Interestingly, this region
      also contains a 20 bp sequence element identical to those found in the mouse
      dystrophin gene, which suggests a possible role of this regulatory region in
      muscle specific gene regulation.

PMID- 10340481
TI  - Ancylostoma secreted protein 2: cloning and characterization of a second member
      of a family of nematode secreted proteins from Ancylostoma caninum.
AB  - Invading infective third-stage larvae (L3) of parasitic nematodes execute a
      series of programmed developmental events in response to a host-specific signal
      encountered during infection. One of these early events is the release of
      excretory/secretory products. Using an in vitro feeding assay that mimics these
      early events of infection, a protein released by in vitro activated larvae of the
      hookworm Ancylostoma caninum was identified. This protein, Ac-ASP-2, was
      partially sequenced, and the cDNA encoding it isolated by PCR and screening of an
      A. caninum L3 cDNA library. The Ac-asp-2 cDNA encodes a protein of 219 amino
      acids that is related to a previously identified protein, Ac-ASP-1, from
      hookworms. Both molecules are members of an evolutionarily diverse family of
      molecules that include the venom allergens of the Hymenoptera, and the testes
      specific proteins/sperm-coating glycoproteins of mammals. Homologues are present
      in nearly all nematodes tested, as demonstrated by PCR-hybridization and database
      searching. The Ac-asp-2 mRNA is synthesized in all life history stages, but the
      gene product is released only by L3 activated to feed in vitro. The wide
      distribution of the Ac-asp-2 in nematodes and its release in response to host
      specific signals suggests that Ac-ASP-2 serves an important function in nematode
      physiology and development, and possibly in the infective process of parasitic
      species.

PMID- 10340482
TI  - Characterization of protein Ser/Thr phosphatases of the malaria parasite,
      Plasmodium falciparum: inhibition of the parasitic calcineurin by cyclophilin
      cyclosporin complex.
AB  - Two major protein phosphatase (PP) activities were purified from cytosolic
      extracts of the erythrocytic stage of the malaria parasite, Plasmodium
      falciparum. Both enzymes were specific for phosphoserine and phosphothreonine
      residues with very little activity against phosphotyrosine residues. The
      biochemical properties of the enzymes suggested their strong similarity with
      eukaryotic PP2A and PP2B protein phosphatases. Both enzymes preferentially
      dephosphorylated the alpha subunit of phosphorylase kinase, and were resistant to
      inhibitor-1. The PP2A-like enzyme required Mn2+ for activity and was inhibited by
      nanomolar concentrations of okadaic acid (OA). The cDNA sequence of the PP2A-like
      enzyme was identified through a match of its predicted amino acid sequence with
      the N-terminal sequence of the catalytic subunit. The PP2B-like (calcineurin)
      enzyme was stimulated by calmodulin and Ca2+ or Ni2+, but was resistant to OA.
      Malarial calcineurin was strongly and specifically inhibited by cyclosporin A
      (CsA) only in the presence of wild type P. falciparum cyclophilin but not a
      mutant cyclophilin. The inhibition was noncompetitive, and provides a potential
      explanation for the cyclosporin-sensitivity of the parasite. There was no
      significant quantitative difference in the total protein Ser/Thr phosphatase
      activity among the ring, trophozoite, and schizont stages.

PMID- 10340483
TI  - Chromosomal organisation of a gene family encoding rhoptry proteins in Plasmodium
      yoelii.
AB  - The genomic organisation of the genes coding for a group of high molecular mass
      rhoptry proteins of the rodent malaria parasite Plasmodium yoelii YM was
      investigated using blotting, two dimensional gel electrophoresis and restriction
      fragment length analysis. The genes were found on chromosomes 1, 5, 6 and 10,
      with the possibility that related genes were also present on chromosomes 3 and 4.
      On chromosome 1 the genes were located close to one end, whereas they were
      present at both ends of chromosome 5, 6 and 10. Two genes, e3 and e8, that had
      been partially characterised previously were present on chromosomes 5 and 1,
      respectively. Based on an analysis of the 3' end of the genes, three subfamilies
      present on chromosomes 1, 5 and 6, and 10, respectively, were identified.

PMID- 10340484
TI  - Identification of the transcription initiation site of the asexually expressed
      rRNA genes of the malaria parasite Plasmodium berghei.
AB  - The start site of the A-type ribosomal RNA transcription units of the rodent
      malaria parasite, Plasmodium berghei, has been identified. The two A-type units
      cannot be distinguished within the transcription unit, yet exist as single copies
      on different chromosomes. Gene transcription initiates 820 bp upstream of the A
      type small subunit (SSU) ribosomal gene and two major processing sites were
      mapped 610 and 611 nucleotides upstream of the SSU in the external transcribed
      spacer region. Surprisingly the nucleotide sequence of the DNA region containing
      the putative ribosomal promoter lacked repetitive DNA sequences typical of
      ribosomal promoters. This region was further analysed by computer using programs
      designed to reveal sequence-dependent structural features. Comparison of DNA
      curvature, duplex stability and pattern of twist angle variation revealed a
      striking degree of conservation between the ribosomal promoters from Plasmodium
      and other eukaryotes.

PMID- 10340485
TI  - Partial kinetoplast-mitochondrial gene organization and expression in the
      respiratory deficient plant trypanosomatid Phytomonas serpens.
AB  - In plant-dwelling trypanosomatids from the genus Phytomonas, mitochondrial
      functions, such as cytochrome mediated respiration, ATP production and Krebs
      cycle, are missing, and cell energetics is based on the glycolysis. Using Blue
      Native/Tricine-SDS two-dimensional gel electrophoretic analysis, we observed that
      mitochondrial respiratory Complexes III (cytochrome bc1) and IV (cytochrome c
      oxidase) were absent in Phytomonas serpens; however, Complex V (ATPase) was
      present. A deletion of the genes for cytochrome c oxidase subunit III (COIII) and
      apocytochrome b (Cyb) was identified within the 6234 bp sequenced region of the
      31 kb maxicircle kinetoplast DNA. Genes, found in this region, include 12S and 9S
      ribosomal RNAs, subunits 7, 8 and 9 of NADH dehydrogenase (ND7, ND8 and ND9) and
      subunit 6 of ATPase (A6 or MURF4), as well as the genes (MURF1, MURF5 and G3)
      with unknown function. Most genes are actively transcribed and some mRNAs are
      edited. Fully edited mRNAs for A6 and G3 were abundant, while edited ND7
      transcripts were rare, and only partially edited and pre-edited transcripts for
      ND8 were detected. The data show that the mitochondrial genome of P. serpens is
      functional, although its functions may be limited to expressing the ATPase and,
      possibly, NADH dehydrogenase complexes.

PMID- 10340486
TI  - Isolation and characterization of a subtractive library enriched for
      developmentally regulated transcripts expressed during encystation of Toxoplasma
      gondii.
AB  - To survive within infected hosts, Toxoplasma gondii undergoes profound metabolic
      and morphological changes by differentiating into a cyst characterized by its
      resistance to the immune system and chemotherapy. The stimulus that triggers
      Toxoplasma encystation and the molecular mechanisms regulating the bradyzoite
      phenotype are still unknown. Here, we developed a differentiation method in
      conjunction with a selective and subtracted cDNA strategy devised to identify
      developmentally regulated transcripts. We isolated and analyzed 65 cDNA clones.
      In addition to bradyzoite specific cDNAs previously reported, we demonstrate that
      twelve genes are exclusively or preferentially transcribed in the encysted
      bradyzoite forms of T. gondii using semi-quantitative RT-PCR. Among cDNAs
      identified, are those encoding predicted homologues of chaperones (mitochondrial
      heat shock protein 60, T-complex protein 1), DNA-damage repair protein,
      phosphatidylinositol synthase, glucose-6-phosphate isomerase and enolase. The
      identification of these genes opens the way for further study of molecular
      mechanisms controlling gene expression during T. gondii encystation.

PMID- 10340488
TI  - Molecular cloning of an acetylcholinesterase gene from the plant parasitic
      nematodes, Meloidogyne incognita and Meloidogyne javanica.
AB  - A gene encoding a protein with strong homology with Caenorhabditis elegans and C.
      briggsae acetylcholinesterase ACE-1 was cloned from Meloidogyne incognita and M.
      javanica pre-parasitic juveniles. Both cDNAs have an ORF of 1968 bp for a deduced
      translation product of 656 amino acid residues. The key residues essential to
      acetylcholinesterase (AChE) structure and function are conserved in both
      sequences. M. incognita and M. javanica AChE share a homology of 98.8% at the
      amino acid level and 97% at the nucleotide level. Phylogenetic analysis showed
      that Meloidogyne and Caenorhabditis AChE form a cluster among AChE of
      triploblastic organisms. This Meloidogyne AChE is expressed in eggs, pre
      parasitic juveniles and males and AChE activity was detected in situ in amphids
      of pre-parasitic juveniles. The opportunity of using AChE as a target in new
      strategies of nematode control is discussed.

PMID- 10340487
TI  - Pantropic retroviral vectors mediate gene transfer and expression in Entamoeba
      histolytica.
AB  - Transformation of Entamoeba histolytica has been previously reported, but the
      foreign genes have all been replicated episomally. Pantropic retroviral vectors
      based on the Moloney murine leukemia virus with the envelope glycoprotein of
      vesicular stomatitis virus (VSV-G) have an extremely broad host range and can be
      concentrated to high titer. To investigate whether these pseudotyped, pantropic
      vectors can mediate gene transfer and expression in E. histolytica, we
      constructed a retroviral vector, in which a hygromycin phosphotransferase is
      expressed from the E. histolytica actin promoter. Data confirm the infection,
      integration, and expression of a foreign gene mediated by the provirus. To our
      knowledge, this is the most evolutionarily distant example of successful
      integration and expression of a mammalian retrovirus. Pantropic retroviral
      vectors may thus facilitate genetic analysis in species lacking transformation
      systems.

PMID- 10340489
TI  - Diagnostic glycoproteins of Taenia solium cysts share homologous 14- and 18-kDa
      subunits.

PMID- 10340490
TI  - Molecular characterization of FKBP13 from filarial parasites.

PMID- 10340491
TI  - Assay of Schistosoma mansoni calcineurin phosphatase activity and assessment of
      its role in parasite survival.

PMID- 10340492
TI  - Trichomonas vaginalis possesses a gene encoding the essential spliceosomal
      component, PRP8.

PMID- 10340493
TI  - Identification of novel genes of non-pathogenic Entamoeba dispar by expressed
      sequence tag analysis.

PMID- 10340494
TI  - Cloning and expression of an aquaporin-like gene from a parasitic nematode.

PMID- 10340495
TI  - Cloning and functional expression of the calmodulin gene from Toxoplasma gondii.

PMID- 10340496
TI  - Expression pattern and functional significance of a divergent nematode
      cyclophilin in Caenorhabditis elegans.

PMID- 10340497
TI  - Newly formed excitatory pathways provide a substrate for hyperexcitability in
      experimental temporal lobe epilepsy.
AB  - Temporal lobe epilepsy (TLE) in humans and animals is associated with axonal
      sprouting of glutamatergic neurons and neosynaptogenesis in the hippocampal
      formation. We examined whether this plasticity of excitatory pathways contributes
      to an increased level of glutamatergic excitation in the CA1 region of rats
      experiencing chronic spontaneous limbic seizures following kainic acid or
      pilocarpine treatment. In chronic cases, we report an extensive axonal sprouting
      of CA1 pyramidal neurons, with many axonal branches entering the pyramidal cell
      layer and stratum radiatum, regions that are not innervated by axonal collaterals
      of CA1 pyramidal neurons in control animals. Concurrently with this anatomical
      reorganization, a large increase of the spontaneous glutamatergic drive is
      observed in the dendrites and somata of CA1 pyramidal cells. Furthermore,
      electrical activation of the reorganized CA1 associational pathway evokes
      epileptiform bursts in CA1 pyramidal cells. These findings suggest that reactive
      plasticity could contribute to the hyperexcitability of CA1 pyramidal neurons and
      to the propagation of seizures in these two models of TLE.

PMID- 10340498
TI  - Distinguishing excitotoxic from apoptotic neurodegeneration in the developing rat
      brain.
AB  - Much confusion has arisen recently over the question of whether excitotoxic
      neuronal degeneration can be considered an apoptotic phenomenon. Here, we
      addressed this question by using ultrastructural methods and DNA fragmentation
      analysis to compare a prototypic apoptotic in vivo central nervous system cell
      death process (physiologic cell death in the developing rat brain) with several
      central nervous system cell death processes in the in vivo infant rat brain that
      are generally considered excitotoxic (degeneration of hypothalamic neurons after
      subcutaneous administration of glutamate and acute neurodegeneration induced by
      hypoxia/ischemia or by concussive head trauma). We found by ultrastructural
      analysis that glutamate induces neurodegenerative changes in the hypothalamus
      that are identical to acute changes induced in the infant rat brain by either
      hypoxia/ischemia or head trauma, and that these changes are fundamentally
      different both in type and sequence from those associated with physiologic cell
      death (apoptosis). In addition, we show by ultrastructural analysis that
      concussive head trauma induces both excitotoxic and apoptotic neurodegeneration,
      the excitotoxic degeneration being very acute and localized to the impact site,
      and the apoptotic degeneration being delayed and occurring in regions distant
      from the impact site. Thus, in the head trauma model, excitotoxic and apoptotic
      degeneration can be distinguished not only by ultrastructural criteria but by
      their temporal and spatial patterns of expression. Whereas ultrastructural
      analysis provided an unambiguous means of distinguishing between excitotoxic and
      apoptotic neurodegeneration in each example analysed in this study, DNA
      fragmentation analysis (TUNEL staining or gel electrophoresis) was of no value
      because these tests were positive for both processes.

PMID- 10340499
TI  - Distribution and local differentiation of mast cells in the parenchyma of the
      forebrain.
AB  - Mast cells are found in the brain of many species. Although a considerable body
      of information is available concerning the development and differentiation of
      peripheral mast cells, little is known about brain mast cells. In the present
      study, the ontogeny of mast cells in the dove brain was followed by using three
      markers: acidic toluidine blue, alcian blue/safranin, and an antiserum to
      gonadotropin-releasing hormone (GnRH). Mast cells first appear in the pia on
      embryonic day (E)13-14 in ovo, then along blood vessels extending from the pia
      into the telencephalon on posthatch day 4-5, and in the medial habenula at week
      3. Medial habenular mast cell numbers increase during development, peaking in
      peripubertal birds, and declining thereafter. Several measures indicate that mast
      cells mature within the medial habenula: there is an increase in the intensity of
      metachromasia, a switch from alcian blue granules in young animals to mixed
      alcian blue and safranin granules in older animals, and an increase in GnRH-like
      immunoreactivity. These results were extended by using electron microscopy. The
      architecture of mast cell granules evolved from electron lucent with small
      electron dense deposits at E15 to more electron dense granules with complex
      patterns of internal structure by 2 months. Ultrastructural immunocytochemistry
      for the GnRH-like peptide at 1 month revealed both immunopositive and negative
      cells, suggesting that the acquisition of this phenotype is not simultaneous
      across the population. Thus, immature mast cells infiltrate the central nervous
      system and undergo in situ differentiation within the neuropil.

PMID- 10340500
TI  - Barrels and septa: separate circuits in rat barrels field cortex.
AB  - The neural circuitry within sensory cortex determines its functional properties,
      and different solutions have evolved for integrating the activity that arises
      from an array of sensory inputs to cortex. In rodent, circumscribed receptors,
      such as whiskers, are represented in somatic sensory (S-I) cortex in islands of
      cells in layer IV called "barrels" surrounded by narrow channels that separate
      barrels called "septa." These two cortical domains were previously shown to
      receive sensory inputs through parallel subcortical pathways. Here, by using
      small biocytin injections, we demonstrate that distinct intrinsic and
      corticocortical circuitries arise from barrel and septal columns. The
      intracortical S-I projections originating from barrel columns are rather short
      ranged, terminating for the most part within the far boundaries of the most
      immediate neighboring barrel columns, whereas corticocortical projections reach
      the second somatosensory (S-II) cortex. In contrast, the intrinsic projections
      arising from septal columns extend two to three barrels' distance along the row
      of whisker representation, producing terminals preferentially in other septal
      columns. Septal corticocortical projections terminate in the dysgranular cortex
      anterior to E-row barrels and in the posteromedial parietal cortex in addition to
      S-II. Whereas layer IV barrels are largely isolated from lateral connections,
      septa are the main conduits of intracortical projections arising from neighboring
      barrel and septal columns. These results indicate that the two subcortical
      pathways from whiskers to cortex continue as two distinct partially segregated
      pathways in cortex.

PMID- 10340501
TI  - Dissociation between sensitization and learning-related neuromodulation in an
      aplysiid species.
AB  - Previous phylogenetic analyses of learning and memory in an opisthobranch lineage
      uncovered a correlation between two learning-related neuromodulatory traits and
      their associated behavioral phenotypes. In particular, serotonin-induced
      increases in sensory neuron spike duration and excitability, which are thought to
      underlie several facilitatory forms of learning in Aplysia, appear to have been
      lost over the course of evolution in a distantly related aplysiid, Dolabrifera
      dolabrifera. This deficit is paralleled by a behavioral deficit: individuals of
      Dolabrifera do not express generalized sensitization (reflex enhancement of an
      unhabituated response after a noxious stimulus is applied outside of the reflex
      receptive field) or dishabituation (reflex enhancement of a habituated reflex).
      The goal of the present study was to confirm and extend this correlation by
      testing for the neuromodulatory traits and generalized sensitization in an
      additional species, Phyllaplysia taylori, which is closely related to
      Dolabrifera. Instead, our results indicated a lack of correlation between the
      neuromodulatory and behavioral phenotypes. In particular, sensory neuron
      homologues in Phyllaplysia showed the ancestral neuromodulatory phenotype
      typified by Aplysia. Bath-applied 10 microM serotonin significantly increased
      homologue spike duration and excitability. However, when trained with the
      identical apparatus and protocols that produced generalized sensitization in
      Aplysia, individuals of Phyllaplysia showed no evidence of sensitization. Thus,
      this species expresses the neuromodulatory phenotype of its ancestors while
      appearing to express the behavioral phenotype of its near relative. These results
      suggests that generalized sensitization can be lost during the course of
      evolution in the absence of a deficit in these two neuromodulatory traits, and
      raises the possibility that the two traits may support some other form of
      behavioral plasticity in Phyllaplysia. The results also raise the question of the
      mechanistic basis of the behavioral deficit in Phyllaplysia.

PMID- 10340502
TI  - Glycine immunoreactivity of multipolar neurons in the ventral cochlear nucleus
      which project to the dorsal cochlear nucleus.
AB  - Certain distinct populations of neurons in the dorsal cochlear nucleus are
      inhibited by a neural source that is responsive to a wide range of acoustic
      frequencies. In this study, we examined the glycine immunoreactivity of two types
      of ventral cochlear nucleus neurons (planar and radiate) in the rat which project
      to the dorsal cochlear nucleus (DCN) and thus, might be responsible for this
      inhibition. Previously, we proposed that planar neurons provided a tonotopic and
      narrowly tuned input to the DCN, whereas radiate neurons provided a broadly tuned
      input and thus, were strong candidates as the source of broadband inhibition
      (Doucet and Ryugo [1997] J. Comp. Neurol. 385:245-264). We tested this idea by
      combining retrograde labeling and glycine immunohistochemical protocols. Planar
      and radiate neurons were first retrogradely labeled by injecting biotinylated
      dextran amine into a restricted region of the dorsal cochlear nucleus. The
      labeled cells were visualized using streptavidin conjugated to indocarbocyanine
      (Cy3), a fluorescent marker. Sections that contained planar or radiate neurons
      were then processed for glycine immunocytochemistry using diaminobenzidine as the
      chromogen. Immunostaining of planar neurons was light, comparable to that of
      excitatory neurons (pyramidal neurons in the DCN), whereas immunostaining of
      radiate neurons was dark, comparable to that of glycinergic neurons (cartwheel
      cells in the dorsal cochlear nucleus and principal cells in the medial nucleus of
      the trapezoid body). These results are consistent with the hypothesis that
      radiate neurons in the ventral cochlear nucleus subserve the wideband inhibition
      observed in the dorsal cochlear nucleus.

PMID- 10340503
TI  - Intrinsic and efferent connections of the endopiriform nucleus in rat.
AB  - The endopiriform nucleus is a large group of multipolar cells located deep to the
      piriform cortex. The function of this nucleus is unknown, but studies with animal
      models suggest that it plays an important role in temporal lobe epileptogenesis.
      To address questions concerning mechanisms of epileptogenesis and to gain
      insights into its normal function, efferent axons from the endopiriform nucleus
      were labeled by anterograde transport from small extracellular injections of
      Phaseolus vulgaris leucoagglutinin. Several principles of organization were
      derived: (1) heavy local and long intrinsic connections are present throughout
      the endopiriform nucleus; (2) endopiriform efferents target cortical rather than
      nuclear structures; (3) extensive projections from the endopiriform nucleus
      extend to most basal forebrain areas including the piriform cortex, entorhinal
      cortex, insular cortex, orbital cortex, and all cortical amygdaloid areas. The
      perirhinal cortex, olfactory tubercle, and most subdivisions of the hippocampal
      formation receive light projections; (4) projections are highly distributed
      spatially within all target areas; (5) efferent axons from the endopiriform
      nucleus are unmyelinated and give rise to boutons along their entire course
      rather than arborizing locally; and (6) the endopiriform nucleus and piriform
      cortex share target areas, but efferents from the endopiriform nucleus lack the
      precise laminar order of those from the piriform cortex, and provide a heavy
      caudal to rostral pathway that is lacking in the cortex. The significance of
      these findings for the triggering of generalized seizures from the deep piriform
      region are discussed. An hypothesis for a role of the endopiriform nucleus in
      memory storage is presented.

PMID- 10340504
TI  - Frequent colocalization of mu opioid and NMDA-type glutamate receptors at
      postsynaptic sites in periaqueductal gray neurons.
AB  - In the ventrolateral periaqueductal gray (PAG), endogenous pathways which dampen
      pain transmission can be activated by either opioids or excitatory amino acids
      such as N-methyl D-aspartate (NMDA). The effects of these ligands may converge,
      because morphine-produced analgesia in the PAG can be blocked by NMDA receptor
      antagonists. To determine the relationship between the subcellular sites where
      opioid ligands of the mu opioid receptor (MOR) and NMDA receptor ligands may act,
      we studied the ultrastructural distribution of immunolabeling for MOR and the R1
      subunit of the NMDA receptor (NR1) in the ventrolateral PAG. MOR labeling was
      most commonly distributed along extrasynaptic regions of the plasma membrane of
      neuronal dendrites (80% or 245/306). In addition, MOR labeling was found
      presynaptically in axon terminals (13% or 39/306) which preferentially formed
      symmetric (inhibitory-type) synapses. NR1 immunoreactivity was also prevalent in
      dendrites (72% or 242/335), but in contrast to MOR, was usually associated with a
      subset of postsynaptic densities. Axon terminals (5%, 17/335) and glial processes
      (18%, 61/335) comprised the remainder of NR1-labeled profiles. There was a
      striking colocalization of MOR and NR1 labeling within dendrites. The majority of
      NR1-labeled dendrites contained MOR labeling (72%, 176/242) and likewise, the
      majority of MOR-labeled dendrites contained NR1 labeling (72%, 176/245). Thus, mu
      opioid and NMDA receptor ligands may act at several overlapping subcellular sites
      to modulate behaviors subserved by the ventrolateral PAG, such as
      antinociception.

PMID- 10340505
TI  - Stereological estimation of the total number of neurons in the murine hippocampus
      using the optical disector.
AB  - Using a stereological method, the optical disector, we examined three inbred
      strains of mice (NZB/BINJ, DBA/2, and C57BL/6J) for morphological differences in
      volume, neuronal number, and density of the pyramidal cell and dentate gyrus
      granule cell layers of the hippocampus. We found significant differences in
      volume and neuronal number for both regions between the three strains at 9 weeks
      of age, but only modest differences in neuronal density. The left dentate volume
      was 90% larger in the NZB strain and 70% greater in the DBA strain (P<0.0001),
      and the left pyramidal cell layer was 144% larger in the NZB strain and 150%
      larger in the DBA strain, than in the B6 strain (P<0.0001). Neuron number in the
      left dentate was 81% greater in NZB and 37% greater in DBA (P<0.001), and in the
      left pyramidal cell layer 118% greater in the NZB and 92% greater in the DBA
      (P<0.01). Differences in neuronal density of the left dentate were not
      significant (P = 0.060, ns). For the left pyramidal cell layer, neuronal density
      was 14% greater in B6 and 34% greater in NZB than the DBA strain (P = 0.016). No
      significant differences were found in left-right laterality, or according to sex.
      We found that strain accounted for 60% of the variance in hippocampal volume and
      44% of neuron number. These differences thus mainly reflect genetic variation in
      hippocampal volume and may have important implications for brain evolution,
      behaviour, and human diseases where hippocampal degeneration is involved.

PMID- 10340506
TI  - Immunohistochemical localization of delta opioid receptors in peripheral tissues.
AB  - The distribution of delta opioid receptor (DOR) immunoreactivity (ir) was
      examined in various peripheral tissues of Sprague-Dawley rats and macaque
      monkeys, including glabrous and hairy skin, corneas, eyelids, and the lip. DOR-ir
      was observed in all tissues examined. In addition to the presence of DOR
      immunoreactive fibers in subcutaneous nerve bundles and the papillary dermis, we
      report the existence of positively labeled fibers and terminals in close
      association with peripheral structures not traditionally assigned a primarily
      nociceptive function, such as hair follicles, glandular apparatus, and blood
      vessels. In every case, staining was restricted to small-diameter axons that
      appeared to terminate as free nerve endings. To further classify DOR
      immunoreactive fibers, we examined the extent of colocalization between DOR and
      three commonly used neuronal subtype markers; tyrosine hydroxylase (TH),
      calcitonin gene-related peptide (CGRP), and RT-97, a monoclonal antibody which
      preferentially labels neurons with myelinated axons. Additional double-labeling
      experiments using the nonspecific neuronal marker Protein Gene Product 9.5 were
      performed in glabrous skin to determine the percentage of total fiber count that
      displayed DOR-ir. No colocalization was observed between DOR and RT-97,
      indicating that DOR-ir is localized to unmyelinated axons. In addition, DOR
      colocalized with CGRP, but did not colocalize with TH. Taken together, these data
      support the hypothesis that delta opioid receptors in peripheral tissues are
      associated with sensory fibers, but not with the terminals of postganglionic
      sympathetic neurons.

PMID- 10340507
TI  - Ascending granule cell axon: an important component of cerebellar cortical
      circuitry.
AB  - Physiologic evidence suggests that local activation of the cerebellar granule
      cell layer produces a much more restricted spatial activation of overlying
      Purkinje cells than would be expected from the parallel fiber system. These
      results have led to the suggestion that synapses associated with the ascending
      granule cell axon may provide a large, direct, excitatory input to Purkinje
      cells, whereas parallel fiber synapses may be more modulatory in nature. In the
      current experiments, serial electron microscopy was used to reconstruct synapses
      associated with these two segments of the granule cell axons in the cerebellar
      cortex of albino rats. The results indicate that there are significantly more
      presynaptic vesicles in ascending segment synapses than in parallel fiber
      synapses. Furthermore, a first-order linear regression analysis revealed positive
      correlations between all measures of pre- and postsynaptic morphology for
      parallel fibers, but not for ascending segment synapses. Perhaps most
      surprisingly, serial reconstructions of postsynaptic spines and their associated
      dendrites demonstrated that spines contacted by ascending segment synapses are
      located exclusively on the smallest diameter distal regions of the Purkinje cell
      dendrites, whereas parallel fiber synapses are found exclusively on intermediate-
      and large-diameter regions of the spiny branchlets. Based on two independent
      calculations, we estimate that 20% of the granule cell synapses onto a Purkinje
      cell are actually made by the ascending segment. By using computer simulations of
      a single Purkinje cell dendrite, we have also demonstrated that synchronous
      activation of these distal ascending segment inputs could produce a substantial
      somatic response. Taken together, these results suggest that the two different
      regions of granule cell axons may play very different physiologic roles in
      cerebellar cortex.

PMID- 10340508
TI  - Ultrastructural observations on the expression of axonin-1: implications for the
      fasciculation of sensory axons during axonal outgrowth into the chick hindlimb.
AB  - To help understand how axons interact as they grow into the developing chick
      hindlimb, we used electron microscopy in conjunction with immunoperoxidase
      staining for the cell adhesion molecule axonin-1 to label sensory axons. The
      results showed that sensory axons travel together in bundles, tightly apposed to
      one another. In contrast, motoneuron axons are more widely spaced, although
      motoneuron axons situated at the perimeter of sensory axon bundles are found in
      close contact with neighboring sensory axons. Sensory growth cones and
      lamellipodia tend to be located centrally within the bundles, with several
      lamellipodia typically being found stacked together. Strikingly, regions of close
      axonal apposition are accompanied by axonin-1 expression, suggesting that such
      contacts are indeed adhesive. Taken together, these observations suggest that
      groups of sensory axons of a similar age grow together, with some of the older
      sensory axons fasciculating along motoneuron axons and younger sensory axons
      later fasciculating along older sensory axons. Axons situated at the periphery of
      sensory bundles are typically partly labelled, such that axonin-1 is expressed on
      membranes apposing other labelled axons but not on those facing unlabelled axons
      or unlabelled Schwann cells. Thus, axonin-1 appears to become redistributed
      within the membranes of axons growing into the limb, as it does on cultured
      neurons. In contrast, the neuron-glia cell adhesion molecule (NgCAM), which binds
      heterophilically to axonin-1, appears uniformly distributed on even those axons
      that would have an asymmetric distribution of axonin-1. Thus, the localization of
      axonin-1 strongly suggests that it plays an important role in sensory axon
      fasciculation, but the relative contributions of its interactions with various
      potential ligands are unclear. Finally, we found that some sensory growth cones
      have lamellipodia that are spread over considerable expanses. This suggests that
      although fasciculation is important in sensory axon guidance, sensory axons may
      also explore the local environment.

PMID- 10340509
TI  - Sequential developmental acquisition of cotransmitters in identified sensory
      neurons of the stomatogastric nervous system of the lobsters, Homarus americanus
      and Homarus gammarus.
AB  - We studied the developmental acquisition of three of the cotransmitters found in
      the gastropyloric receptor (GPR) neurons of the stomatogastric nervous systems of
      the lobsters Homarus americanus and Homarus gammarus. By using wholemount
      immunocytochemistry and confocal microscopy, we examined the distribution of
      serotonin-like, allatostatin-like, and FLRF(NH2)-like immunoreactivities within
      the stomatogastric nervous system of embryonic, larval, juvenile, and adult
      animals. The GPR neurons are peripheral sensory neurons that send proprioceptive
      information to the stomatogastric and commissural ganglia. In H. americanus, GPR
      neurons of the adult contain serotonin-like, allatostatin-like, and Phe-Leu-Arg
      Phe-amide (FLRF(NH2))-like immunoreactivities. In the stomatogastric ganglion
      (STG) of the adult H. americanus and H. gammarus, all of the serotonin-like and
      allatostatin-like immunoreactivity colocalizes in neuropil processes that are
      derived exclusively from ramifications of the GPR neurons. In both species,
      FLRF(NH2)-like immunoreactivity was detected in the STG neuropil by 50% of
      embryonic development (E50). Allatostatin-like immunoreactivity was visible first
      in the STG at approximately E70-E80. In contrast, serotonin staining was not
      clearly visible until larval stage I (LI) in H. gammarus and until LII or LIII in
      H. americanus. These data indicate that there is a sequential acquisition of the
      cotransmitters of the GPR neurons.

PMID- 10340510
TI  - Sequential developmental acquisition of neuromodulatory inputs to a central
      pattern-generating network.
AB  - The activity of the adult stomatogastric ganglion (STG) depends on a large number
      of aminergic and peptidergic modulatory inputs. Our aim is to understand the role
      of these modulatory inputs in the development of the central pattern-generating
      networks of the STG. Therefore, we analyze the developmental and adult
      expressions of three neuropeptides in the stomatogastric nervous system of the
      lobsters Homarus americanus and Homarus gammarus by using wholemount
      immunocytochemistry and confocal microscopy. In adults, red pigment-concentrating
      hormone (RPCH)-like, proctolin-like, and a tachykinin-like immunoreactivity are
      present in axonal projections to the STG. At 50% of embryonic development (E50),
      all three peptides stain the commissural ganglia and brain, but only RPCH- and
      proctolin-like immunoreactivities stain axonal arbors in the STG. Tachykinin-like
      immunoreactivity is not apparent in the STG until larval stage II (LII). The RPCH
      immunoreactive projection to the STG consists of two pairs of fibers. One pair
      stains for RPCH immunoreactivity at E50; the second RPCH-immunoreactive pair does
      not stain until about LII. One pair of the RPCH fibers double labels for
      tachykinin-like immunoreactivity. The adult complement of neuromodulatory inputs
      is not fully expressed until close to the developmental time at which major
      changes in the STG motor patterns occur, suggesting that neuromodulators play a
      role in the tuning of the central pattern generators during development.

PMID- 10340511
TI  - Divergence of smooth muscle target and sympathetic pathway cell phenotypes in the
      orbit of the developing rat.
AB  - The periorbital sheath serves as a major pathway for sympathetic nerves traveling
      to distal orbital targets in the rat. This tissue accommodates sympathetic fiber
      sprouting in the neonate but becomes impassable by postnatal day 30 (PND 30). In
      contrast, smooth muscle target remains receptive to sympathetic ingrowth. To
      determine the attributes of receptive and nonreceptive tissues, we compared
      periorbital pathway and target tissue phenotypes prior to (PND 5 and PND 15) and
      after (PND 30 and PND 60) the period when pathway receptivity is lost. Both
      pathway cells and superior tarsal smooth muscle cells expressed alpha-smooth
      muscle actin and smooth muscle myosin heavy chain throughout development. At PND
      5-15, both tissues also expressed vimentin, collagen IV, laminin 1 and laminin
      beta2, whereas fibronectin was detected only in pathway tissue. At PND 30,
      vimentin, collagen IV, and fibronectin were absent in tarsal muscle but were
      robust in pathway tissue. Laminin 1 and laminin beta2 expression was maintained
      in muscle; however, in pathway cells, laminin 1 declined modestly, and laminin
      beta2 decreased precipitously to barely detectable levels. Quantitative
      competitive polymerase chain reaction showed that nerve growth factor mRNA was
      present in the pathway throughout development at levels that were greater than
      both surrounding connective tissue and tarsal muscle. We conclude that the loss
      of pathway receptivity to sympathetic nerve ingrowth is associated with a
      transition from a phenotype similar to fetal smooth muscle cells to one that is
      more consistent with myofibroblast-like cells.

PMID- 10340512
TI  - Autoradiographic and in situ hybridization localization of corticotropin
      releasing factor 1 and 2 receptors in nonhuman primate brain.
AB  - Two different corticotropin-releasing factor (CRF) receptors, CRF1 and CRF2, have
      been identified in rat and human brain. Although the two receptor subtypes show a
      markedly different distribution in the rat brain, their distribution in the
      primate brain has not been described previously. In this study, the neuroanatomic
      distribution of CRF1 and CRF2 receptor binding sites in rhesus monkey (Macaca
      mulatta) was assessed by using iodine 125 ([125I)-Tyr0]-sauvagine with or without
      the selective CRF1 receptor antagonist CP-154,526-1. Radiolabeled human cRNA
      probes were used to map the distribution of the two receptor mRNAs with in situ
      hybridization. Both CRF1 and CRF2 receptors were found in the pituitary and
      throughout the neocortex (especially, in prefrontal, cingulate, striate, and
      insular cortices), amygdala, and hippocampal formation of the monkey brain. This
      is in contrast to the distribution of these receptors reported in the rat brain,
      in which generally only the CRF1 receptor is found in the pituitary and
      neocortex. These results suggest that, in primates, both CRF1 and CRF2 receptors
      may be involved in mediating the effects of CRF on cognition, behavior, and
      pituitary-adrenal function. The presence of CRF1 (but not CRF2) receptors within
      the locus coeruleus, cerebellar cortex, nucleus of the solitary tract, thalamus,
      and striatum and of CRF2 (but not CRF1) receptors in the choroid plexus, certain
      hypothalamic nuclei, the nucleus prepositus, and the nucleus of the stria
      terminalis suggests that each receptor subtype also may have distinct functional
      roles within the primate central nervous system.

PMID- 10340513
TI  - Quantitative evaluation of neurotrophin and trk mRNA expression in visual and
      limbic areas along the occipito-temporo-hippocampal pathway in adult macaque
      monkeys.
AB  - The neurotrophins have been implicated in shaping and remodeling the connectivity
      of neural circuits. To explore the role of neurotrophins and their receptors,
      Trks, in cortical neural circuits of adult macaque monkeys, we determined mRNA
      expression levels of neurotrophins and Trk receptors in various visual and limbic
      areas along the occipito-temporo-hippocampal pathway by using a quantitative
      reverse-transcription polymerase chain reaction technique. The expression level
      of brain-derived neurotrophic factor (BDNF) mRNA was lowest in the primary visual
      cortex (V1), moderate in the temporal visual association area, and highest in the
      hippocampus. The expression levels of trkB mRNA isoforms, the full-length form
      that encodes a receptor tyrosine kinase and the truncated form that encodes a
      noncatalytic receptor, were also low in V1, moderate in the visual association
      area, and high in the entorhinal cortex. However, in contrast to their ligand
      BDNF, the expression levels of both trkB isoforms in the hippocampus were
      significantly lower than those in the entorhinal cortex. NT-3 mRNA was detectable
      only in the hippocampus and the entorhinal cortex, whereas both the full-length
      and the truncated forms of trkC mRNA were widely distributed throughout the
      neocortex and the limbic cortex. The expression levels of NGF and trkA mRNAs in
      these cortical areas were too low to determine quantitatively. The present
      findings suggest that, among neurotrophin/Trk signaling systems, the BDNF/TrkB
      mediated signal most likely contributes to stabilization, remodeling, or both, of
      neural circuits in cortical areas along the occipito-temporo-hippocampal pathway
      in the adult macaque monkey.

PMID- 10340514
TI  - Late axonal sprouting of injured Purkinje cells and its temporal correlation with
      permissive changes in the glial scar.
AB  - Purkinje cells can survive axotomy for as long as 18 months without retracting
      their severed axons. During this period of time, the fate of the terminal bulbs
      of axotomized Purkinje cell axons and their relationship with the glial scar were
      determined. Terminal axonal sprouting begins three months after the lesion and
      continuously increases up to 18 months (the longest survival time studied), when
      the sprouts establish synaptic contacts, mainly on granule cell dendrites at the
      glomeruli. Cellular changes in the glial scar were analyzed to determine whether
      the late onset and continuous increase of axonal sprouting could be correlated
      with an increase of permissive factors and/or a decrease of inhibitory factors
      for axonal growth. Activated macrophages disappeared much earlier than did the
      initiation of sprouting. Myelin and its associated neurite growth inhibitory
      molecules began to decrease from three months after the lesion. This decrease was
      uneven and not correlated spatially with the sprouting. Reactive astrogliosis was
      heterogeneous: only some of the reactive astrocytes expressed PSA-NCAM, the
      embryonic form of the neural cell adhesion molecule, a permissive substratum for
      neurite outgrowth. The expression of PSA-NCAM occurred concurrently with
      sprouting in the area of gliosis containing Purkinje cell sprouts. Moreover, the
      ultrastructural study showed that the majority of sprouts (75%) were totally
      ensheathed by astrocytic processes. Thus, long-term glial scars are permissive to
      axonal sprouting, suggesting that reactive astrocytes, either through the
      expression of permissive molecules or by preventing direct contact between axonal
      elements and myelin inhibitory molecules, regulate the sprouting.

PMID- 10340515
TI  - Brainstem projections to the ventromedial medulla in cat: retrograde transport
      horseradish peroxidase and immunohistochemical studies.
AB  - Stimulation of the nucleus magnocellularis (NMC) of the medulla produces changes
      in locomotion, muscle tone, heart rate, and blood pressure. Glutamatergic input
      has been found to modulate muscle tone, whereas cholinergic input has been found
      to mediate cardiovascular changes produced by stimulation of the NMC. The current
      study was designed to identify the brainstem afferents to NMC by using retrograde
      transport of wheat germ agglutinin and horseradish peroxidase (WGA-HRP) combined
      with glutamate and choline acetyltransferase (ChAT) immunohistochemical and
      nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemical
      techniques. Fifty nanoliters of 2.5% WGA-HRP were microinjected into the NMC in
      the cat. A heavy density of WGA-HRP-labeled neurons was found in the ipsilateral
      mesencephalic reticular formation (MRF), periaqueductal gray, Kolliker-Fuse
      nucleus, and pontis centralis caudalis (PoC), in the contralateral pontis
      centralis oralis (PoO), and bilaterally in the nucleus paragigantocellularis
      lateralis. A moderate density of retrogradely labeled neurons was found in the
      ipsilateral side of the nuclei parvocellularis, retrorubral (RRN), PoO, and
      vestibular complex, in the contralateral PoC and nucleus gigantocellularis, and
      bilaterally in the inferior vestibular nucleus. Retrograde HRP/glutamate-positive
      cells could be found throughout the brainstem, with a high percentage in RRN,
      PoO, PoC, and MRF. Double-labeled WGA-HRP/ChAT neurons were found in the
      pedunculopontine nucleus. Double-labeled WGA-HRP/NADPH-d-positive neurons could
      be seen in many nuclei of the brainstem, although the number of labeled neurons
      was small. The dense glutamatergic projections to the NMC support the hypothesis
      that rostral brainstem glutamatergic mechanisms regulate muscle activity and
      locomotor coordination via the NMC, whereas the pontine cholinergic projections
      to the NMC participate in cardiovascular regulation.

PMID- 10340517
TI  - Tolerance to morphine-induced antinociception is decreased by chronic sucrose or
      polycose intake.
AB  - Chronic intake of palatable fluids alters morphine-induced antinociception. Two
      experiments were conducted to evaluate how long-term access to palatable fluids
      alters the development of tolerance to morphine-induced antinociception. In
      Experiment 1, 40 adult male Long-Evans rats were used. In addition to ad lib chow
      and water, 10 rats were given a 0.15% saccharin solution, 10 were given a 32%
      sucrose solution, and 10 were given a 32% Polycose solution to drink for 3 weeks.
      Ten rats were given chow and water alone, and served as dietary controls.
      Morphine-induced antinociception was assessed using the radiant-heat tail-flick
      method (TF). Half of the animals in each dietary condition were given preexposure
      to 7.5 mg/kg morphine; the other half received saline. All rats were given a TF
      30-min postinjection. To determine whether tolerance developed, a cumulative dose
      paradigm (0.625, 1.25, 2.5, 5.0, 10.0 mg/kg) was employed 1 week after initial
      morphine injections, and was repeated at weekly intervals for 3 weeks.
      Antinociception was significantly lower in rats preexposed to morphine relative
      to rats preexposed to saline. Although all rats displayed decreased
      antinociception relative to the first morphine injection, rats that drank
      saccharin showed greater reductions in morphine-induced antinociception relative
      to rats that drank sucrose or Polycose. Experiment 2 was conducted to determine
      whether initial pairing of the TF with morphine preexposure produced differences
      in the development of opioid tolerance. All conditions and procedures were
      identical to Experiment 1, except that the initial morphine and saline injections
      were not followed by TF. As in Experiment 1, rats that drank saccharin showed
      less antinociception than rats that drank sucrose or Polycose. The present
      results suggest that long-term intake of palatable nutritive solutions curbs
      tolerance to morphine-induced antinociception, whereas long-term intake of a
      nonnutritive, sweet saccharin solution does not.

PMID- 10340516
TI  - Presynaptic cytomatrix protein bassoon is localized at both excitatory and
      inhibitory synapses of rat brain.
AB  - Bassoon is a 420-kDa protein specifically localized at the active zone of
      presynaptic nerve terminals. It is thought to be involved in the structural
      organization of the neurotransmitter release site. We studied the distribution of
      Bassoon transcripts and protein in rat brain and assessed which types of
      presynaptic terminals contain the protein. As shown by in situ hybridization,
      Bassoon transcripts are widely distributed in the brain and occur primarily in
      excitatory neurons. In addition, examples of gamma-aminobutyric acid (GABA)-ergic
      neurons expressing Bassoon are detected. At the light microscopic level, Bassoon
      immunoreactivity is found in synaptic neuropil regions throughout the brain, with
      the strongest expression in the hippocampus, the cerebellar cortex, and the
      olfactory bulb. Immunoelectron microscopy showed that Bassoon immunoreactivity is
      found in both asymmetric type 1 and symmetric type 2 synapses. Immunopositive
      asymmetric synapses include mossy fiber boutons and various spine and shaft
      synapses in the hippocampus and mossy fiber terminals and parallel fiber
      terminals in the cerebellum. Bassoon-containing symmetric synapses are observed,
      e.g., between basket and granule cells in the hippocampus, between Golgi cells
      and granule cells, and between basket cells and Purkinje cells in the cerebellum.
      Within synaptic terminals, Bassoon appears highly concentrated at sites opposite
      to postsynaptic densities. In cultured hippocampal neurons, Bassoon was found to
      colocalize with GABA(A) and glutamate (GluR1) receptors. These data indicate that
      Bassoon is a component of the presynaptic apparatus of both excitatory
      glutamatergic and inhibitory GABAergic synapses.

PMID- 10340518
TI  - Chronic treatment with desipramine induces an estrous cycle-dependent anxiolytic
      like action in the burying behavior, but not in the elevated plus-maze test.
AB  - The effect of chronic desipramine (DMI, 2.5 mg/kg x 21-26 days) treatment in
      female rats in two anxiety paradigms was assessed: the burying behavior (BB) and
      the elevated plus-maze (EPM) tests. In the BB test DMI produced a significant
      decrease in burying in ovariectomized rats, an effect considered as anxiolytic
      like. In cycling females, DMI also reduced the cumulative BB most notably in
      proestrus rats. However, in diestrus rats no anxiolytic-like actions were
      observed. In addition, DMI increased BB latencies in proestrus and estrus rats.
      In the EPM test, DMI produced anxiolytic-like actions only in ovariectomized
      rats, while no significant actions were found in cycling females. Finally, the
      chronic treatment with DMI produced a general reduction in the ambulatory
      behavior of rats in all estrous cycle phases. Results are discussed on the basis
      of the differences between both anxiety paradigms and the probable relationship
      between the steroids secreted during proestrus and chronic DMI treatment.

PMID- 10340519
TI  - Pharmacologic and behavioral responses of inbred C57BL/6J and strain 129/SvJ
      mouse lines.
AB  - Gene-targeting technology is creating an explosion in the number of animals
      available with single gene mutations that affect the function of the central
      nervous system. Most gene-targeted mice are produced on a mixed genetic
      background of C57BL/6J and substrains of Strain 129. Understanding the behavioral
      characteristics and responses to various drugs of these parental strains is vital
      to interpreting data from gene-targeted mice. We directly compared C57BL/6J and
      Strain 129/SvJ mouse lines on several behavioral paradigms and in response to
      several hypnotic and anesthetic drugs. Compared to Strain 129/SvJ mice, C57BL/6J
      animals are more sensitive to the hypnotic effects of midazolam, zolpidem, and
      propofol, less sensitive to etomidate and ethanol, and do not differ in
      sensitivity to Ro15-4513 or pentobarbital. These strains do not differ in their
      sensitivity to the motor ataxic effects of the volatile anesthetics enflurane or
      halothane. However, Strain 129/SvJs are more sensitive to the immobilizing
      effects of halothane but not enflurane. Motor coordination differs initially, but
      with repeated testing strain differences are no longer apparent. Strain 129/SvJ
      mice are more anxious on the elevated plus maze and open-field activity assays.
      Thus, these mouse strains harbor polymorphisms that influence some, but not all,
      traits of interest to behavioral neuroscientists.

PMID- 10340520
TI  - Discriminative stimulus (DS) properties of nicotine in the C57BL/6 mouse.
AB  - Previous research conducted in this and other laboratories has examined the role
      of genetic factors in determining sensitivity to (-)-nicotine in a variety of
      behavioral and physiological measures in the rat. More recent research further
      indicates that genetic factors can also influence the level of sensitivity to (-)
      nicotine when serving as a discriminative stimulus (DS) in different rat strains.
      However, there has been little work examining the influence of genotype on the
      discriminative stimulus (DS) properties of (-)-nicotine in mice, a species that
      has played a major role in understanding the relationship between genetics and (
      )-nicotine pharmacological effects. To further our understanding of the role of
      genetics and the ability of (-)-nicotine to exert DS control of behavior in the
      mouse, a group of C57BL/6 mice was trained to discriminate 0.4 mg/kg (-)-nicotine
      from saline using a two-lever operant procedure. (-)-Nicotine's discriminative
      stimulus in C57BL/6 mice appears to be similar to that generated in the rat.
      Results from behavioral tests with other drugs indicated that d-amphetamine
      exhibited a partial generalization, while (+)-nicotine fully generalized with
      nicotine. Tests of antagonism with mecamylamine and scopolamine further showed
      the cholinergic specificity of the (-)-nicotine DS in the mouse; mecamylamine but
      not scopolamine completely antagonized the (-)-nicotine DS. This work lays the
      groundwork for future comparisons of different mouse strain's sensitivities to (
      )-nicotine's discriminative stimulus as well as using this behavioral model to
      search for new nicotinic receptor agonists and antagonists.

PMID- 10340521
TI  - Diurnal changes in paraventricular hypothalamic alpha1 and alpha2-adrenoceptors
      and food intake in rats.
AB  - The prominent feeding rhythm evident in rats may reflect circadian variation in
      activity of feeding-relevant adrenoceptors within the hypothalamic
      paraventricular nucleus (PVN). In the present study, separate groups of rats were
      sacrificed at six time points (ZT0, ZT4, ZT8, ZT12, ZT16, ZT20) over a diurnal
      cycle. Food intakes were recorded during the 4-h period prior to sacrifice in
      each group. Brain sections were incubated with either an alpha1-adrenoceptor
      ligand (3H)-prazosin [(3H)-PRZ] or an alpha2-adrenoceptor ligand (3H) para
      aminoclonidine [(3H)-PAC] prior to autoradiography analyses. Binding of (3H)-PRZ
      within the PVN varied as a function of the diurnal cycle, with significantly
      greater binding evident during the light phase of ZT0 (first 4 h of the light
      phase) and at ZT4, compared to nadir binding during the dark phase at ZT16 (first
      4 h of the dark phase). Binding of (3H)-PAC within the PVN also varied as a
      function of the diurnal cycle, with significantly greater binding evident during
      the first 8 h of the dark phase (ZT16 and ZT20) than during the light phase. Food
      intake and alpha1-adrenergic binding were inversely related across the diurnal
      cycle. These results support the hypothesis that PVN adrenergic systems may be
      organized in an antagonistic fashion so as to modulate feeding in the rat.

PMID- 10340522
TI  - Evaluation of hypothermia-induced analgesia and influence of opioid antagonists
      in leopard frogs (Rana pipiens).
AB  - Hypothermia results in diminished voluntary muscle activity, and is frequently
      used as a means of providing deep anesthesia to ectotherms and some mammals. In
      ectotherms, however, it is unclear if hypothermia produces true pain insensation.
      A needle-probe thermometer was used to demonstrate in frogs (Rana pipiens) that
      local hypothermia (9 degrees C) could be induced by placement of a tourniqueted
      leg into ice water (6 degrees C) for 10 min in contrast to the contralateral
      nontourniqueted leg (21.8 degrees C) kept out of ice water. Analgesia was tested
      by placement of dilutions of acetic acid on the rear leg. Further tests using
      groups of 10 frogs demonstrated that frogs with local hypothermia tolerated
      greater concentrations of acetic acid (mean acetic acid test score = 11) than
      morphine (10 mg/kg)-treated (9.6) or nontreated (5.8) frogs. Additional studies
      showed that morphine analgesia was blocked with naloxone doses as low as 0.01
      mg/kg and hypothermia-induced analgesia at 10 mg/kg. Naltrexone blocked morphine
      analgesia at dosages as low as 0.01 mg/kg and hypothermia-induced analgesia at
      0.10 mg/kg. In summary, this study demonstrates that hypothermia induces
      significant analgesia in an amphibian, and that this analgesia is partially
      blocked by naloxone and naltrexone, suggesting that the effect is mediated at
      least partially by opioid receptors.

PMID- 10340523
TI  - Inhibition of nitric oxide synthesis with L-NAME suppresses isolation-induced
      ultrasounds in rat pups.
AB  - The present experiments examined the impact of manipulating the NO system on
      production of isolation-induced ultrasonic vocalizations (USVs) in 10- and 11-day
      old rat pups. Pups were tested under both high- and low-baseline USV emission;
      the latter was accomplished by pretest administration of cocaine, a drug known to
      suppress USVs. Treatment with 10, 50, or 100 mg/kg (but not 1 mg/kg) of the
      nitric oxide synthase (NOS) inhibitor L-nitro-arginine methyl ester (L-NAME)
      significantly attenuated USV production, as did injection of 10 mg/kg cocaine;
      combined treatment with both drugs did not result in greater suppression, perhaps
      due to a floor effect. Although cocaine increased locomotor activity, treatment
      with L- or D-NAME alone did not alter activity levels. Exposure to L-NAME induced
      some hypothermia, although these alterations in body temperature were not
      systematically related to the drug-induced suppression of USVs. Alterations in
      USV production by L-NAME were not evident after pretreatment with the less active
      isomer D-NAME, evidence supporting the importance of NO synthesis inhibition per
      se in the marked L-NAME-induced suppression of USVs in isolated infant rats.

PMID- 10340524
TI  - Dopamine antagonists in the orbital prefrontal cortex reduce prepulse inhibition
      of the acoustic startle reflex in the rat.
AB  - Schizophrenia is characterized by, among other things, (a) information processing
      deficits that have been indexed by a number of measures, including deficits in
      prepulse inhibition (PPI) of the acoustic startle reflex; and (b) pathophysiology
      of the frontal lobe. Recent studies have implicated the prefrontal cortex (PFC)
      in the modulation of PPI in rats. These studies suggest that dopamine (DA)
      ablation of the PFC (using 6-OHDA) leads to disruption of PPI. To better
      understand the role of DA type 1 (D1) and type 2 (D2) receptors in the modulation
      of PPI, we investigated the effects of two pharmacologically distinct DA
      antagonists on the modulation of PPI. Microinjection of SCH23390 (a D1
      antagonist) into the orbital PFC markedly decreased PPI (at 0.1, 0.5, and 1.5
      microg), whereas raclopride (a D2 antagonist) decreased PPI at some doses (0.1
      and 0.5 mg/ml) but not at others (5.0 microg). We conclude that both D1 and D2
      receptors mediate the cortical modulation of PPI.

PMID- 10340525
TI  - Measuring emotional memory in the elevated T-maze using a training-to-criterion
      procedure.
AB  - The elevated T-maze, an ethologically based test, has been used to investigate
      the effects of anxiolytic drugs on memory and the relationships between neural
      systems involved in such modulation. This test allows the measurement in the same
      rat of two kinds of aversively motivated behaviors--inhibitory avoidance and one
      way escape. The apparatus consists of three arms of equal dimensions, elevated 50
      cm from the floor. One arm is enclosed by walls and stands perpendicular to the
      two open arms. Placing the rat at the end of the enclosed arm and recording the
      time to withdraw from this arm during three consecutive trials assesses
      inhibitory avoidance. Soon afterwards, the rat is placed at the end of one of the
      open arms and the time to leave this arm recorded as escape response. Three days
      later memory is assessed by reexposing the rats to the maze. One critical
      question raised by these studies is whether the anterograde amnesia induced by
      anxiolytic drugs could be due to insufficient learning during training or to
      amnesia. The present work investigated whether the introduction of a multitrial
      training-to-criterion procedure could overcome this question. For this purpose,
      rats were tested as many times as needed to stay in the enclosed arm continuously
      for 300 s (avoidance learning to criterion). Results from Experiment 1 showed
      that rats trained to a learning criterion shows significantly better retention
      performance. Experiment 2 evaluated the effects of pretraining diazepam (DZP)
      treatment on this training-to-criterion protocol. The results indicate that DZP
      did not affect acquisition performance but induced a dose-dependent impairment of
      the inhibitory avoidance in the memory test. One-way escape (latency to enter the
      enclosed compartment from the open arms) was not affected by DZP. These results
      rule out the possibility that the impairment of inhibitory avoidance memory in
      the elevated T-maze could be due to lack of learning during training, and support
      the hypothesis that the disruptive effects of DZP are on processes involved in
      long-term storage of information.

PMID- 10340526
TI  - The behavior of spontaneously hypertensive and Wistar Kyoto rats under a paced
      fixed consecutive number schedule of reinforcement.
AB  - Spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY) were trained under
      paced FCN schedules of reinforcement to complete a minimum number of consecutive
      responses on one lever, before responding on a second. The levers were retracted
      from the test chamber for a short period after each response to control the speed
      at which the rats could complete the sequence (paced FCN). Changes in the average
      chain length may reflect the influence of impulsivity on the execution of
      behavioral patterns. Although they quickly learned to press the levers, SHR rats
      performed poorly compared to the WKY rats when the chain length requirement was
      increased to FCN 6 and FCN 8. Eventually stable performance was obtained under
      paced FCN 6, although the SHR rats continued to have a consistently lower average
      chain length. Both strains of rats were treated with imipramine (10 mg/kg),
      chlordiazepoxide (3 and 10 mg/kg), d-amphetamine (0.4 and 0.8 mg/kg), haloperidol
      (0.05 and 0.1 mg/kg), 8-OH-DPAT (0.1 mg/kg), WAY-100635 (0.1 mg/kg), and DOI (0.3
      and 1.0 mg/kg). The SHR rats were less sensitive to the effects of d-amphetamine,
      chlordiazepoxide, and DOI and slightly more sensitive to the effects of
      haloperidol. All of these drugs reduced the average chain length. There was no
      difference in the response of the two strains to imipramine and 8-OH-DPAT, both
      of which increased the average chain length. These results support the suggestion
      that SHR rats may more impulsive than WKY rats. The data with d-amphetamine and
      haloperidol support biochemical findings that these rats have a deficit in
      dopaminergic function, and the strain differences in response to chlordiazepoxide
      and DOI suggest that that there may be differences in GABAergic and 5-HT2
      mediated neurotransmission relevant to regulating impulse control in the rat.

PMID- 10340527
TI  - Characterization of the effects of adenosine kinase inhibitors on acute thermal
      nociception in mice.
AB  - Adenosine (ADO) is an inhibitory neuromodulator that can increase the nociceptive
      threshold in animals exposed to a variety of noxious stimuli. Inhibition of the
      ADO-metabolizing enzyme, ADO kinase (AK), provides a means of locally enhancing
      extracellular ADO concentrations. In the present study, the AK inhibitors 5'
      amino,5'-deoxy-ADO (NH2dADO), 5-iodotubercidin (5-IT), and 5'-deoxy,5
      iodotubercidin (5'd-5IT) were examined for their analgesic efficacy in the hot
      plate model of acute somatic nociception. Control and drug-treated adult male
      mice were placed on a 55 degrees C hot plate and the latency to the 10th jump was
      recorded via a computer driven infrared-beam photosensor. All three AK inhibitors
      were found to significantly increase jump latencies in a dose-dependent fashion.
      5'd-5IT was the most potent AK inhibitor (approx. ED50 value = 1 micromol/kg,
      IP), followed by 5-IT (ED50 value = 10 micromol/kg, IP), and NH2dADO (ED50 value
      = 100 micromol/kg, IP). 5'd-5IT was found to be more potent and equally
      efficacious to morphine (ED50 value = 5.2 micromol/kg, IP) in this assay. In a
      model of persistent chemical pain, the phenyl-p-quinone-induced abdominal
      constriction assay, 5'd-5IT (ED50 value = 1.5 micromol/kg, SC) and morphine (ED50
      value = 3.0 micromol/kg, SC) dose dependently reduced nociception. Pretreatment
      of mice with either the nonselective ADO receptor antagonist, theophylline (56
      micromol/kg, IP), but not the peripherally acting antagonist, 8-(p-sulfophenyl)
      theophylline (8-PST, 200 micromol/kg, IP) significantly attenuated the
      antinociceptive effects of 5'd-5IT in the hot-plate assay. Furthermore, the
      antinociceptive effects of 5'd-5IT were completely blocked by an ADO A1 receptor
      selective antagonist, DPCPX, while an ADO A2A receptor selective antagonist, ZM
      241385, showed markedly less antagonist activity. The analgesic effects of 5'd
      5IT were not blocked by the opioid receptor antagonist naloxone; however, 5'd-5IT
      could produce additive analgesic effects with morphine when both compounds were
      administered in combination. The apparent efficacy of 2.5 micromol/kg, IP, of 5'd
      5IT was not significantly altered following the repeated administration of this
      dose twice daily for 4 days. The present data provide evidence for an
      antinociceptive action of AK inhibitors in the hot-plate test, which, at least
      for 5'd-5IT, is mediated by an enhancement of ADO's actions at the ADO A1
      receptor subtype, is nonopioid in nature, and which does not exhibit tolerance
      following repeated administration.

PMID- 10340528
TI  - Increased Ro15-4513-induced seizures following multiple ethanol withdrawals.
AB  - Clinical research into the etiology of ethanol withdrawal seizures has shown an
      increase in the number and severity of seizures with increasing numbers of
      withdrawal episodes. The aim of the present study was to determine the effects of
      multiple ethanol withdrawals on the seizure sensitivity to the GABA(A) receptor
      inverse agonist Ro15-4513. In this study, three groups of laboratory rats
      received varying amounts of either continuous or intermittent ethanol exposure. A
      fourth group (Naive) received no ethanol exposure. Eight hours following the last
      withdrawal from chronic ethanol exposure, animals were tested for sensitivity to
      Ro15-4513-induced motor convulsions. Seizure sensitivity was significantly
      increased in all ethanol-treated groups compared to ethanol-naive controls, which
      did not exhibit any convulsive responses to this dose of Ro15-4513. Furthermore,
      rats exposed to multiple ethanol withdrawals exhibited significantly higher
      sensitivity to drug-induced seizures than did animals experiencing only a single
      ethanol withdrawal. Although the specific mechanism of this enhanced convulsant
      effect of Ro15-4513 following multiple ethanol withdrawals remains to be
      determined, these results suggest an involvement of GABA(A)-benzodiazepine
      receptors in this multiple withdrawal phenomenon.

PMID- 10340529
TI  - Effect of the dopaminergic neurotoxin MPTP on cocaine-induced locomotor
      sensitization.
AB  - The blockade of dopamine (DA) uptake via the dopamine transporter (DAT) in the
      nucleus accumbens (NAC) and striatum by cocaine has a major role in the
      reinforcing and psychomotor stimulating effects of the drug. Here we investigated
      the effect of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP) on the expression and induction of sensitization to the
      locomotor stimulating effect of cocaine. MPTP (20 mg/kg x 4) caused 72 and 76%
      depletion of DAT sites in the NAC and striatum, respectively, in C57BL/6 mice.
      The magnitude of this depletion 3 and 19 days after MPTP administration was the
      same. To determine the effect of MPTP on the expression of the sensitized
      response to cocaine, cocaine-experienced mice (20 mg/kg for 5 days) received MPTP
      3 days before a challenge cocaine injection was given on day 15. Cocaine/MPTP
      mice were significantly more sensitive to the challenge cocaine injection than
      the cocaine/saline-pretreated mice. To determine whether depletion of NAC and
      striatal DAT affects the induction of sensitization to cocaine, mice were
      pretreated with MPTP 3 days before the administration of cocaine (20 mg/kg for 5
      days). The magnitude of the sensitized response of MPTP/cocaine-pretreated mice
      to cocaine challenge was the same as the sensitized response of mice treated with
      saline/cocaine, while the number of DAT binding sites in the MPTP/cocaine group
      was significantly lower than the saline/cocaine group. The present study
      indicates that MPTP exacerbates the expression of locomotor sensitization to
      cocaine, but it had no effect on the induction of sensitization. We conclude that
      the expression, but not the induction, of locomotor sensitization to cocaine may
      be dependent on the level of DAT binding sites.

PMID- 10340530
TI  - Two related forms of long-term habituation in the crab Chasmagnathus are
      differentially affected by scopolamine.
AB  - An opaque screen moving overhead elicits an escape response in the crab
      Chasmagnathus, which, after a few presentations, habituates for a long period
      (long-term habituation, LTH). Previous results distinguished two types of LTH:
      the (context-signal)-LTH yielded by spaced training, determined by an association
      between context and habituating stimulus, and cycloheximide sensitive: and the
      (signal)-LTH produced by massed training, context independent, and cycloheximide
      insensitive. Present experiments were aimed at studying the possible involvement
      of cholinergic mechanisms in one or both types of LTH, using the muscarinic
      antagonist, scopolamine (SCP). Results indicate that LTH acquired by spaced
      training (30 trials separated by 85 s) is blocked in a dose-dependent manner by
      posttraining SCP. Amnesia is shown with 100 ng SCP/g injected immediately before
      or after spaced training but not delayed 1-h posttraining. No effect of SCP on
      LTH acquired by massed training (300 trials separated by 4 s) is detected.
      Pretraining SCP induces a decrease in the response level at the initial trials of
      either a spaced or a massed training. It is concluded that the storage of
      (context-signal)-LTH may be selectively regulated by a muscarinic-cholinergic
      mechanism. However, the possibility that other cholinergic receptors would be
      involved in the consolidation of the (signal)-LTH is discussed.

PMID- 10340531
TI  - Effects of ephedrine enantiomers on conditioned taste aversion and kaolin intake
      in rats.
AB  - The ephedrine (EPH) enantiomers, (-)-EPH and (+)-EPH, have different biological
      activity in the rat, with the (-)-EPH enantiomer exerting a greater impact on
      suppression of feeding, induction of locomotion, and activation of brown adipose
      tissue thermogenesis. Recent studies document that (-)-EPH treatment produces an
      alteration of extracellular dopamine in the brain, an effect that is consistent
      with the locomotor-stimulating and reinforcing effects of this drug. Whether the
      EPH enantiomers exert aversive actions in the rat is unknown. Experiment 1
      examined the impact of systemically administered (+)-EPH (0, 5, 10, or 20 mg/kg)
      or (-)-EPH (0, 5, 10, or 20 mg/kg) on conditioned taste aversion (CTA) in adult
      male rats relative to the effect of 32 mg/kg lithium chloride (LiCl). No dose of
      either enantiomer produced CTA, whereas strong CTA was evident for LiCl. In
      Experiment 2, consumption of kaolin (a nonnutritive clay) over a 24-h period was
      used to assess drug toxicity. Rats treated with either 0, 5, 10, 20, or 40 mg/kg
      (+)-EPH or 0, 5, 10, 20, or 40 mg/kg (-)-EPH did not exhibit alteration of kaolin
      intake. In contrast, systematic increases in kaolin intake were observed in rats
      after systemic administration of LiCl (0, 16, 32, 64, and 96 mg/kg). These
      findings suggest that the enantiomers of EPH do not exert aversive effects at
      behaviorally relevant doses.

PMID- 10340532
TI  - Modulatory effects of ascorbate, alone or with haloperidol, on a lever-release
      conditioned avoidance response task.
AB  - Pretreatment with ascorbate, a modulator of dopamine transmission in the
      striatum, enhances the ability of haloperidol, a dopamine antagonist, to induce
      catalepsy and block the motor-activating effects of amphetamine. The present
      study extended this line of work to a lever-release version of the conditioned
      avoidance response (CAR) task, which is highly sensitive to changes in striatal
      dopamine. Adult male rats were trained to avoid footshock by releasing a lever
      within 500 ms of tone onset. Ascorbate (100 and 1000 mg/kg, IP) or vehicle was
      tested either alone or in conjunction with haloperidol (0.01 and 0.05 mg/kg, SC).
      Compared to vehicle pretreatment, 1000 mg/kg ascorbate alone or in combination
      with haloperidol impaired CAR performance by increasing avoidance latency.
      Latency to escape footshock was not impaired, ruling out a generalized motor
      deficit. In contrast, 100 mg/kg ascorbate alone or in combination with
      haloperidol had no consistent effects on CAR performance, even at a haloperidol
      dose (0.005 mg/kg, SC) known to potentiate dopamine transmission by
      preferentially blocking autoreceptors. Collectively, these results support an
      antidopaminergic action of ascorbate on striatal function, but suggest that this
      effect requires relatively high systemic doses.

PMID- 10340533
TI  - Individual differences in novelty seeking on the playground maze predict
      amphetamine conditioned place preference.
AB  - Previous research has shown that a rat's level of activity in a novel environment
      can predict the strength of amphetamine-induced locomotor behavior and self
      administration, but not amphetamine-conditioned place preference. The increase in
      activity observed when a rat is exposed to an inescapable novel environment may
      reflect escape behavior due to stress. To assess approach to novelty in a free
      choice test, we examined the ability of a new test, the playground maze, to
      predict individual differences in response to amphetamine (1 or 3 mg/kg). Using
      the playground maze to categorize rats as either high or low novelty seekers, it
      was found that individual differences in novelty seeking did not predict
      amphetamine-induced changes in locomotor activity following either a single or
      repeated injections. However, high novelty seekers showed greater amphetamine
      conditioned place preference than low novelty seekers. These results provide
      support for the hypothesis that novelty seeking and drug reward are
      neuropharmacologically related.

PMID- 10340534
TI  - Responses to oral delta9-tetrahydrocannabinol in frequent and infrequent
      marijuana users.
AB  - It is known that an individual's drug use history affects the quality of
      subjective effects experienced following administration of several clinically
      used psychoactive drugs such as barbiturates, diazepam, and morphine. However, it
      is not known whether drug use history also affects responses to therapeutic
      cannabinoids such as delta9-THC. The current experiment compared the subjective
      and behavioral effects of oral delta9-THC in two groups of volunteers: frequent
      users (FREQ; n = 11), who reported using marijuana at least 100 times, and
      infrequent users (INF; n = 10) who reported using marijuana 10 or fewer times.
      Subjects participated in three sessions during which they received delta9-THC
      (7.5 and 15 mg) and placebo. They completed subjective effects questionnaires for
      5 h following administration. In the FREQ group, the lower dose (7.5 mg)
      increased ratings of "feel drug," relative to placebo, whereas it had no effect
      in the INF group. In contrast, at the higher dose (15 mg), ratings of "feel drug"
      were lower in the FREQ group than in the INF group, suggestive of tolerance. In
      addition, the INF group reported greater sedative effects than the FREQ group
      following the higher dose of delta9-THC, again suggesting tolerance to delta9
      THC's sedative effects. These findings demonstrate that marijuana use history may
      affect the subjective effects of oral delta9-THC, but that the influence of drug
      use history depends on the dose of drug administered. These findings may have
      implications for the clinical use of delta9-THC and other cannabinoids.

PMID- 10340535
TI  - Different levels of Fos immunoreactivity after repeated handling and injection
      stress in two inbred strains of mice.
AB  - Expression of Fos and Fos-related antigens was immunohistochemically analyzed in
      DBA/2J and C57BL/6J inbred mice in response to acute or repeated handling and
      injection stress. Both strains showed a strong induction of Fos and Fos-related
      antigens in discrete areas of hypothalamus, amygdala, neocortex, septum, and
      thalamus 2 h after an acute intraperitoneal injection of normal saline. To
      habituate animals to this procedure, mice were subjected to repeated handling and
      injections during 2 weeks preceding the experiment. This procedure led to
      complete habituation of the immediate early gene response to injection stress in
      stress-responsive brain areas of C57BL/6J mice, such that no significant
      difference was found between expression of these proteins in brains of saline
      injected animals after repeated stress vs. control animals. In contrast, many
      brain areas of saline-injected DBA/2J mice still showed elevated Fos and Fos
      related antigen expression after repeated injections. These results indicate that
      identical habituation procedures do not necessarily lead to identical levels of
      gene expression in brains of inbred strains of mice. In turn, they suggest that
      genetic components for some behavioral and pharmacological traits identified
      using inbred strains could be related to different rates of habituation to
      experimental procedures.

PMID- 10340536
TI  - Effects of suramin on hippocampal apyrase activity and inhibitory avoidance
      learning of rats.
AB  - The action of suramin on apyrase activity in hippocampal synaptosomes and its
      effects on retention of inhibitory avoidance learning were evaluated. Suramin, a
      P2-purinoceptor antagonist, significantly inhibited in a noncompetitive manner
      the ATP and ADP hydrolysis promoted by apyrase in hippocampal synaptosomes of
      adult rats. The Ki values obtained were 72.8 and 109 microM for ATP and ADP
      hydrolysis, respectively. Intrahippocampal infusion of suramin (0.01, 0.1, 1, and
      10 microg) immediately posttraining, in a dose-dependent effect, significantly
      reduced the response latency during the retention test applied 24 h after the
      rats received step-down inhibitory avoidance training. The amnesic effects
      promoted by suramin probably occur by its antagonist action on hippocampal P2
      purinoceptors and NMDA receptors. In view of the fact that ATP-metabolizing
      enzymes and P2-purinoceptors have similar binding domains, these results suggest
      that suramin can either alter ATP degradation and/or block purinergic
      neurotransmission.

PMID- 10340537
TI  - The effects of microinjection of d-amphetamine into the n. accumbens during the
      late maintenance phase of an ethanol consumption bout.
AB  - The microinjection of d-amphetamine into the n. accumbens of rats, prior to the
      start of an operant ethanol self-administration session, increases operant
      behavior and the amounts of ethanol presented as the reinforcer. Although this
      effect could result by blocking termination processes regulating a consummatory
      bout, it could also be a result of enhancing the stimulus control regulating the
      maintenance of a drinking bout. To explore this issue, rats were trained to self
      administer 10% ethanol in an operant situation. Following establishment of stable
      behavior, they were surgically instrumented so that the n. accumbens could be
      microinjected with d-amphetamine during a drinking bout, without having to handle
      the animal. The microinjection of d-amphetamine in the rats self-administering
      ethanol at the late phase of the drinking bout resulted in a prolonged bout and
      increased self-administration. During extinction testing, a reinstatement of
      responding was found following the amphetamine microinjection. The data suggest
      the most likely action of the amphetamine microinjection was to alter stimulus
      control factors, which normally regulate the maintenance of drinking, thereby
      prolonging the bout and increasing intake.

PMID- 10340538
TI  - Effect of filter vent blocking on carbon monoxide exposure from selected lower
      tar cigarette brands.
AB  - Two studies were conducted to determine the effect of blocking filter vents on
      carbon monoxide (CO) exposure under ad lib smoking conditions. In Study 1, 12
      daily cigarette smokers smoked cigarettes from the brands Now (1 mg tar by the
      FTC Method) and Marlboro Lights (10 mg tar) under each of two vent-blocking
      conditions (unblocked and finger blocked). Blocking filter vents with fingers led
      to an 85% increase in CO for the brand Now, but had no added effect on CO
      exposure from the Marlboro Lights. In Study 2, another 12 daily cigarette smokers
      smoked cigarettes from each of four additional brands: Carlton (1 mg tar), Now (2
      mg tar), Virginia Slims Ultra-lights (5 mg tar), and Virginia Slims Lights (8 mg
      tar). Blocking filter vents with the lips caused all four brands to produce equal
      CO exposures. Blocking vents increased smokers' exposure to CO by 239% when
      smoking Carltons and by 44% when smoking Nows. No significant increases in CO
      with blocking were found for either of the Virginia Slims brands. These results
      suggest that the degree to which a brand is ventilated determines whether that
      brand is susceptible to increased CO yields as a result of vent blocking.

PMID- 10340539
TI  - The effects of intravenous naltrindole and naltrindole 5'-isothiocyanate on
      sufentanil-induced respiratory depression and antinociception in rats.
AB  - Although the interactions between the mu- and the delta-opiate receptor subtypes
      are well documented with regard to supraspinal analgesia, less is known about the
      mutual interactions on respiratory depression. To clarify the functional
      interactions between both opiate receptor subtypes with regard to antinociception
      and respiratory depression, male Wistar rats were intravenously injected with 2.5
      microg/kg of the mu-opiate agonist sufentanil and subsequently intravenously
      challenged with the delta antagonist naltrindole (NTI) or naltrindole 5'
      isothiocyanate (5'-NTII), a delta-2 antagonist. Antinociception was measured by
      means of the tail-flick latency, and respiratory depression was evaluated by
      means of analysis of PaCO2, PaO2, and oxygen saturation. To quantify the
      antagonistic properties of NTI and 5'-NTII, mean areas under the curve were
      calculated for groups treated with sufentanil, control vehicle, and sufentanil
      plus a dose of the antagonists. NTI, but not 5'-NTII, antagonized the sufentanil
      induced antinociception at 10 mg/kg NTI. Below this dose the effects were
      inconsistent. The sufentanil-induced hypercapnia and hypoxia were diminished with
      10 mg/kg NTI or 5'-NTII. These data indicate that NTI antagonizes the sufentanil
      induced antinociception and respiratory depression in rats. A dissociation
      between the antinociception and respiratory depression following intravenous
      sufentanil could be obtained with 10 mg/kg 5'-NTII pointing to different
      regulatory effects of opiate delta receptor subtypes on mu-opiate agonist-induced
      behavioral effects.

PMID- 10340540
TI  - Behavioral effects of family-selective inhibitors of cyclic nucleotide
      phosphodiesterases.
AB  - The effects of family selective inhibitors of phosphodiesterase (PDEI, PDE2,
      PDE3, PDE4, and PDE5) on the behavior of rats under either a differential
      reinforcement-of-low-rate (DRL) 72-s schedule or a variable-interval (VI) 30-s
      schedule were determined; previous work has shown that antidepressant drugs
      increase reinforcement rate under long DRL schedules. The PDE4-selective
      inhibitor rolipram (0.03-0.1 mg/kg) reduced response rate and increased
      reinforcement rate under the DRL schedule in a dose-dependent manner; similar
      effects were observed with the tricyclic antidepressant drug desipramine (3-10
      mg/kg). Both of these drugs produced biphasic effects on behavior maintained
      under the VI schedule, increasing response rate at the lower doses tested
      (rolipram: 0.003 mg/kg; desipramine: 0.03 mg/kg) and decreasing response rate at
      higher doses (rolipram: 0.1 mg/kg; desipramine: 0.3-18 mg/kg). Of the other PDE
      inhibitors tested, only the PDE5-selective inhibitor zaprinast (10 mg/kg)
      produced an antidepressant-like effect on DRL behavior. However, in contrast to
      the biphasic effects of rolipram and desipramine on VI behavior, zaprinast
      produced monotonic decreases in response rate (10-30 mg/kg). The PDE2-selective
      inhibitor trequinsin produced biphasic effects on response rate under the VI
      schedule, increasing rates at low doses (3-5.6 mg/kg) and decreasing rates at
      higher doses (18-30 mg/kg). Trequinsin also reduced response rate under the DRL
      schedule (30 mg/kg); however, the reduction in response rate was not accompanied
      by increased reinforcement rate. The PDE3-selective inhibitor milrinone (1-10
      mg/kg) tended to increase response rates under both schedules while the PDE1
      selective inhibitor vinpocetine did not affect behavior at the dose range tested
      (1-30 mg/kg). These findings suggest that inhibition of PDE4 results in a rather
      unique pattern of behavioral effects, most notably an antidepressant-like effect
      on DRL behavior. It remains to be determined if a similar effect produced by
      zaprinast also implicates PDE5 in the mediation of antidepressant activity or
      represents an effect of this drug on PDE4 activity at high doses.

PMID- 10340541
TI  - A novel soluble chimera for the treatment of familial hypercholesterolemia.

PMID- 10340542
TI  - Anti-tumor immunity elicited by a recombinant vaccinia virus expressing CD70
      (CD27L).
AB  - CD70, a ligand of the T cell costimulatory receptor CD27, is expressed mainly on
      activated B cells and has been shown to increase cytotoxic activity and
      proliferation of preferentially unprimed T cells. Reported herein is the
      construction of a recombinant vaccinia virus encoding CD70 (designated rV-CD70)
      and a demonstration of its biological effect on naive T cells in vitro and in
      vivo. In a whole tumor cell vaccine model, the growth of CD70-negative murine
      colon adenocarcinoma (MC38) tumor cells infected with rV-CD70 (multiplicity of
      infection [MOI] of 0.1) and transplanted into syngeneic C57BL/6 mice was
      inhibited completely while control tumors infected with wild-type vaccinia grew
      rapidly and killed mice within 3-5 weeks. Tumor-free mice previously immunized
      with rV-CD70-infected tumors were partially protected against rechallenge with
      wild-type tumors, demonstrating the induction of systemic anti-tumor immunity. In
      addition, immunization of C57BL/6 mice with rV-CD70 admixed with vaccinia virus
      encoding carcinoembryonic antigen (rV-CEA) was superior to treatment with rV-CEA
      alone in inducing CEA-specific lymphoproliferative T cell responses and reducing
      growth of murine colon carcinomas transduced with CEA. These studies demonstrate
      for the first time the potential utility of a recombinant vaccinia virus
      expressing CD70 to enhance T cell responses and mediate anti-tumor immunity.

PMID- 10340543
TI  - Percutaneous adenoviral gene transfer into porcine coronary arteries: is catheter
      based gene delivery adapted to coronary circulation?
AB  - Recombinant adenoviral (Ad) vectors represent an efficient gene transfer system
      for targeting the cardiovascular system. Phenotypic modulation of coronary
      vascular cells in vivo is, however, critically dependent on the efficacy of local
      delivery devices. Four local drug delivery catheters were tested for
      intracoronary gene transfer efficiency: the Infiltrator (INF, n = 10), the
      Crescendo (CRE, n = 10), the Infusasleeve (SLE, n = 8), and the Remedy balloon
      (channel balloon [CHA], n = 8). After balloon injury of the LAD, Ad vector
      containing the firefly luciferase cDNA (AdCMVluc, 1.5 x 10(10) plaque-forming
      units) was administered at the site of injury. On day 4, tissue samples from
      different regions in the heart and from the liver were assayed for luciferase
      activity to evaluate local and systemic gene transfer. INF, CRE, and SLE
      catheters showed higher transduction levels of the target LAD segment than did
      the CHA catheter (median luciferase activity = 4.2 x 10(6), 11 x 10(6), and 1.3 x
      10(6) light units [LU]/vessel versus 0.09 x 10(6) LU/vessel, respectively, p <
      0.05). Luciferase activity was occasionally observed in nontarget tissues (right
      and left ventricular free wall, distal LAD, and liver) and was not significantly
      different between groups. The viral circulatory half-life was similar for the
      four groups (<1 min). Gene transfer efficiency was positively correlated with the
      degree of injury for the intralumenal catheters (CRE, SLE, and CHA) but was
      independent of the vessel wall injury for the intramural INF. Local drug delivery
      catheters enable efficient vascular gene transfer in balloon-injured coronary
      arteries, a prerequisite for further development of intracoronary gene therapy
      for restenosis.

PMID- 10340544
TI  - Antiangiogenic gene therapy in a rat glioma model using a dominant-negative
      vascular endothelial growth factor receptor 2.
AB  - Malignant gliomas are a prominent target for cancer gene therapy approaches
      because of their poor prognosis despite all currently available therapies. Gene
      therapy strategies developed to interfere with the normal function of vascular
      endothelial growth factor receptors have been successfully used in different
      experimental models to block tumor angiogenesis and to inhibit tumor growth. In
      this study we examined whether retroviruses encoding a mutant VEGF receptor 2
      (VEGFR-2) could suppress tumor angiogenesis and thereby prolong the survival of
      rats bearing syngeneic intracerebral glioma tumors. Survival time of rats with
      intracerebral tumors was significantly prolonged in a dose-dependent manner when
      retroviruses carrying a VEGFR-2 mutant were cotransplanted with tumor cells. No
      effect on survival was observed in rats that received virus-producing cells or
      virus supernatant intracerebrally after 5 days of tumor injection. In established
      subcutaneous tumors treatment with multiple injections of virus-producing cells
      also inhibited tumor growth in a dose-dependent manner. After implantation of
      tumor cells stably transfected with a truncated form of VEGFR-2, rats exhibited a
      rate of survival similar to that of animals treated with high numbers of virus
      producing cells encoding the truncated form of VEGFR-2. Morphologically, tumors
      showed signs of impaired angiogenesis, such as extensive necrosis and reduced
      tumor vascular density. These results suggest a dual mode of function of
      truncated VEGFR-2, namely dominant-negative inhibition of VEGFR-2 function and
      VEGF depletion by receptor binding. We further explored the safety of retrovirus
      mediated gene transfer. Although virus sequences were found in different tissues
      after intracerebral injection of virus-producing cells, no morphological changes
      were observed in any tissue after a follow-up time of 6 months. Our results
      indicate that VEGFR-2 inhibition is useful for the treatment of malignant
      gliomas.

PMID- 10340545
TI  - Retroviral vectors for the expression of two genes in human multipotent neural
      precursors and their differentiated neuronal and glial progeny.
AB  - Retroviral vectors allow stable integration of exogenous DNA into genomic DNA and
      therefore gene transmission to progeny. Multipotent neural precursors and
      immortal cell lines prepared from them have been demonstrated to integrate into
      either adult or developing brain in a nontumorigenic, functional manner, without
      interfering with normal neurobiological processes. These cells thus appear to
      provide a Trojan horse ideally adapted to directing the expression of transgenes
      appropriately in a host brain. Here we investigated and optimized the
      transduction capacity of MuLV-based retroviral vectors in which internal
      ribosomal entry segments (IRESs) drive coexpression of two heterologous gene
      products from a single bicistronic mRNA in a human multipotent neural precursor
      cell line, "Dev," which was prepared from a medulloblastoma. For this, two
      vectors containing two different combinations of three viral IRESs were used and
      the capacity of different pseudotyped vectors to permit an efficient and stable
      transduction of Dev cells was compared. Our data show that (1) the best
      recombinant vectors for Dev cell transduction are those pseudotyped with the 10A1
      MuLV envelope (40% of transduction) and (2) the initial coexpression of neo and
      plap, observed in transduced undifferentiated Dev cells, is maintained in
      differentiated Dev cells with a neuronal or glial phenotype. Therefore, these
      double-IRES vectors may provide an efficient means of transducing the
      coexpression of two proteins in undifferentiated human neural precursors that is
      maintained in their differentiated progeny. These data suggest that the double
      IRES strategy is well adapted to potential therapeutic situations when
      coexpression of two different transgenes may be required in the same cell.

PMID- 10340546
TI  - Feasibility of adenovirus-mediated nonsurgical synovectomy in collagen-induced
      arthritis-affected rhesus monkeys.
AB  - Gene transfer to synovial tissue by adenoviral vectors (Ad) was studied in vitro
      in cultured human synoviocytes and in vivo in seven primates with arthritis.
      Hyperplastic synovium was efficiently transduced with Ad.lacZ in vitro and in
      vivo in rhesus monkeys with collagen-induced arthritis, whereas chondrocytes were
      not transduced. Intraarticular injection of recombinant Ad harboring the
      luciferase gene showed the presence of reporter gene products only in Ad-injected
      joints. In addition, the feasibility of synovectomy by Ad harboring the herpes
      simplex virus thymidine kinase gene (tk) was studied. In vitro infection of
      synovium from rheumatoid arthritis patients with Ad.TK, followed by
      administration of ganciclovir, resulted in death of >90% of the synoviocytes. By
      mixing Ad.TK-infected with noninfected cells, it appeared that the presence of
      10% infected synoviocytes resulted in the killing of more than 85% of the
      synoviocytes, demonstrating a substantial bystander effect. Intraarticular
      injection of Ad.TK in the knees of rhesus monkeys with arthritis, followed by
      treatment with ganciclovir for 14 days, resulted in increased apoptotic cell
      death in the synovium of Ad.TK-injected as compared with noninjected joints and
      ablation of the synovial lining layer. The procedure revealed no toxic side
      effects. These data suggest that nonsurgical synovectomy by tK gene therapy is
      feasible.

PMID- 10340547
TI  - Enhanced therapeutic efficacy of tumor RNA-pulsed dendritic cells after genetic
      modification with lymphotactin.
AB  - Pulsing dendritic cells (DCs) with tumor cell-derived mRNA is regarded as an
      attractive alternative in the development of DC-based tumor vaccines. Our aim is
      to improve the therapeutic efficacy of DC-based tumor RNA vaccines by augmenting
      the preferential chemotaxis of DCs to T cells. Mouse bone marrow-derived DCs were
      genetically modified with lymphotactin (Lptn) by adenovirus vector, which
      conferred on DCs preferential chemotaxis to CD4+ and CD8+ T cells (Cao et al.,
      1998). Lptn gene-modified DCs (Lptn-DCs) were pulsed with tumor mRNA and used for
      vaccination in the tumor models of 3LL lung carcinoma and B16 melanoma. In both
      tumor models, immunization with 4 X 10(4) tumor RNA-pulsed Lptn-DCs induced more
      potent CTL activity, compared with their counterparts, specifically against tumor
      cells and Mut1 or tyrosinase-related protein 2 (TRP-2) peptide-pulsed RMA-S
      cells, and rendered the immunized mice resistant to tumor challenge much more
      effectively. CD8+ T cells were necessary and sufficient to generate the
      protection of Lptn-DC-based RNA tumor vaccines, and CD4+ T cells were required
      for the induction of tumor rejection. In the preestablished 3LL and B16 tumor
      models, vaccination with DC-based or LacZ-DC-based tumor RNA vaccines (2 X 10(5)
      cells) could reduce pulmonary metastasis and extend survival of tumor-bearing
      mice, but was less effective than the Lptn-DC counterpart (with 60-80% mice
      surviving). When the immunizing dose was decreased to 4 X 10(4) cells, Lptn-DC
      based tumor vaccines rather than their counterparts were still significantly
      effective. Our studies provide a potential strategy to improve the efficacy of DC
      based vaccines, and a new approach to immunological intervention by chemokines.

PMID- 10340548
TI  - High-efficiency transduction and long-term gene expression with a murine stem
      cell retroviral vector encoding the green fluorescent protein in human marrow
      stromal cells.
AB  - Bone marrow stromal cells (MSCs) are unique mesenchymal cells that have been
      utilized as vehicles for the delivery of therapeutic proteins in gene therapy
      protocols. However, there are several unresolved issues regarding their potential
      therapeutic applications. These include low transduction efficiency, attenuation
      of transgene expression, and the technical problems associated with drug-based
      selection markers. To address these issues, we have developed a transduction
      protocol that yields high-level gene transfer into human MSCs, employing a murine
      stem cell virus-based bicistronic vector containing the green fluorescent protein
      (GFP) gene as a selectable marker. Transduction of MSCs plated at low density for
      6 hr per day for 3 days with high-titer viral supernatant resulted in a gene
      transfer efficiency of 80+/-6% (n = 10) as measured by GFP fluorescence. Neither
      centrifugation nor phosphate depletion increased transduction efficiency.
      Assessment of amphotropic receptor (Pit-2) expression by RT-PCR demonstrated that
      all MSCs expressing the receptor were successfully transduced. Cell cycle
      distribution profiles measured by propidium iodide staining showed no correlation
      with the susceptibility of MSCs to transduction by the retroviral vector. Human
      MSCs sequentially transduced with an adenoviral vector encoding the ecotropic
      receptor and ecotropic retroviral vector encoding GFP demonstrated that all MSCs
      are susceptible to retroviral transduction. We further showed that both genes of
      bicistronic vector are expressed for at least 6 months in vitro and that
      transgene expression did not affect the growth or osteogenic differentiation
      potential of MSCs. Future studies will be directed toward the development of gene
      therapy protocols employing this strategy.

PMID- 10340549
TI  - Adenovirus-mediated transgene expression in nonhuman primate brain.
AB  - Transgene expression in the brain of St. Kitts green monkey, Cercopithecus
      aethiops sabeus, was studied following injection of a serotype 5 adenoviral
      vector deleted in E1 and E3. The vector harbored the transgene for Escherichia
      coli beta-galactosidase (beta-Gal) with the simian virus 40 (SV40) nuclear
      localization signal under control of the Rous sarcoma viral (RSV) long terminal
      repeat. Several titers ranging from 5 x 10(7) to 2 x 10(9) plaque-forming units
      (PFU) in volumes ranging from 5 to 250 microl were injected into the caudate
      nuclei of 18 monkeys. Monkeys were treated with dexamethasone for 9 days,
      beginning the day prior to surgery, and were sacrificed at 1 week or at 1, 2, or
      3 months. At 1 week, beta-Gal was expressed in thousands of cells, including both
      neurons and astrocytes. In addition, some dopaminergic neurons in the substantia
      nigra expressed transgene, suggesting retrograde transport of the vector. At 1
      month 162,000+/-68,000 (SEM) or 65,000+/-29,000 beta-Gal-expressing cells
      persisted in striatum injected with 6 x 10(8) PFU in 30 microl or 5 x 10(7) PFU
      in 5 microl, respectively. Transgene expression was also observed in one of two
      monkeys sacrificed at 2 months and in a single monkey sacrificed at 3 months. No
      transgene expression was observed at 1 month in striatum injected with a higher
      titer (2 x 10(9) PFU in 100 microl) or more dilute vector (5 x 10(7) PFU in 30
      microl). Staining for the major histocompatibility complex II (MHC II) subtype DR
      showed intense staining in sites injected with a higher vector titer, in which no
      transgene persisted at 1 month, whereas low to moderate staining was present in
      sites with high transgene expression. These observations suggest that there is an
      optimal range of vector titers for obtaining persistent transgene expression from
      E1E3-deleted adenovirus in primate brain, above which host responses limit
      transgene stability.

PMID- 10340550
TI  - Retrovirus-mediated transfer of anti-MDR1 ribozymes fully restores
      chemosensitivity of P-glycoprotein-expressing human lymphoma cells.
AB  - Development of multidrug resistance (MDR) is the major obstacle to successful
      cancer chemotherapy. We have developed Daudi human lymphoma cells that are 20
      fold more resistant than the parent cell line to vincristine (VCR) by infecting
      cells with pHaMDR1/A retroviral vector (Daudi/MDR20). Three DNA sequences of anti
      MDR1 hammerhead ribozymes (Rzs), one cleaving codon 196 of MDR1 mRNA (196MDR1
      Rz), the second a stem II base-modified (U9-->Gg, U13-->A13, G14-->A14, A18-
      >C18) Rz against codon 196 (196MDR1-sRz), and the third a stem II base-modified
      Rz directed against the -6 approximately -4 GUC sequence of the translation
      initiation site of the MDR1 mRNA (iMDR1-sRz), were synthesized and cloned into
      the retroviral vector N2A+tRNAiMet downstream of the RNA polymerase III promoter
      and adjacent to a tRNA gene sequence, forming the constructs N2A+tRNAiMet-196MDR1
      Rz, N2A+tRNAiMet-196MDR1-sRz, and N2A+tRNAiMet-iMDR1-sRz. The three constructs
      were transfected into GP+envAM 12 cells for packaging the retroviral vectors. The
      supernatants containing the packaged retrovirus in high titers (1.1-2.5 X 10(5)
      CFU/ml as determined by infection of NIH 3T3 cells) were used to infect
      Daudi/MDR20 cells. The iMDR1-sRz- and 196MDR1-sRz-transduced Daudi/MDR20 cells
      completely restored chemosensitivity to VCR and doxorubicin, and were accompanied
      by blocked expression of MDR1 mRNA and P-glycoprotein as well as overexpression
      of anti-MDR1 Rz. In a cell-free system, the chimeric tRNA-sRz molecules were more
      stable and had more efficient catalytic activities than the corresponding naked
      Rz molecules. The stem II base-modified Rz were also more stable and efficient in
      catalytic activities than the unmodified Rz molecules. The base modification in
      the Rz stem II structure and the development of chimeric tRNA-Rz molecules were
      identified to enhance the cleavage efficacy. The combination of these two
      factors, together with the use of a retroviral vector, appear to have contributed
      to the complete reversal of MDR.

PMID- 10340551
TI  - Production of minigene-containing retroviral vectors using an
      alphavirus/retrovirus hybrid vector system.
AB  - In an attempt to increase the synthesis of human clotting factors VIII and IX in
      transduced cells, optimized expression cassettes containing genomic genelike
      elements (minigenes) were assembled. Plasmid DNA containing factor VIII or factor
      IX minigenes and driven by three human cellular promoters (albumin, factor IX,
      PGK) or the strong viral promoter RSV-LTR were electroporated into TE671 and
      HepG2 cell lines, and clotting factor levels were determined by ELISA. In
      comparison with a parallel transfection of MLV-LTR-promoted retroviral vector
      plasmid DNAs, the PGK- and RSV-LTR-promoted minigene constructs produced equal or
      greater amounts of clotting factor proteins. A factor IX minigene cassette was
      cloned into the retrovirus-based gene transfer vector LN (in both forward and
      reverse orientations) and the minigene vector was introduced into the Phoenix
      retroviral packaging cell line. Analysis of neo(r) cells demonstrated that
      insertion of a factor IX minigene into the retroviral vector LN resulted in
      rearrangement of the factor IX sequence and loss of factor IX expression in the
      Phoenix packaging cell line. The same factor IX minigene was then inserted into
      an alphavirus/retrovirus hybrid vector that facilitates the synthesis of
      retroviral vector RNA in the cytoplasm of cells. Alphavirus/retrovirus virions
      were produced and used to transduce the Phoenix retroviral vector packaging cell
      line. The cytoplasmically produced factor IX minigene-containing retroviral
      vectors were collected and used to transduce TE671 cells. Analysis of transduced
      cells demonstrated stable transfer of the minigene and expression of factor IX.

PMID- 10340552
TI  - Insulin production by engineered muscle cells.
AB  - Type 1 diabetic patients depend dramatically on insulin replacement therapy,
      which involves the administration of intermediate- or long-acting insulin,
      together with short-acting insulin to mimic physiological insulin profiles.
      However, the delayed-action preparations available are not generally able to
      produce smooth background levels of insulin. Muscle cells were tested for long
      term delivery of active human insulin as an approach to achieve a constant basal
      level of insulin. Thus, C2C12 mouse myoblast cells were stably transfected with a
      chimeric gene obtained by linking the myosin-light chain 1 (MLC1) promoter to the
      human proinsulin gene, containing genetically engineered furin endoprotease
      cleavage sites (MLC1/Insm). When differentiated, C2C12Insm myotube cells
      expressed high levels of insulin mRNA and protein, whereas no insulin was
      detected in myoblast cells. HPLC fractionation of culture medium and cell
      extracts from differentiated C2C12Insm cells revealed that about 90% of the
      proinsulin was processed to mature insulin. In addition, these cells released
      significant levels (about 100 microU/10(6) cells/hr) of mature insulin to the
      medium. The hormone was biologically active since it increased glucose
      consumption and utilization by the differentiated C2C12Insm cells and was able to
      block the expression of the endogenous phosphoenolpyruvate carboxykinase (PEPCK)
      gene in FTO-2B rat hepatoma cells. Furthermore, when C2C12Insm myoblast cells
      were transplanted into diabetic mice an increase in insulinemia and a decrease in
      hyperglycemia were observed. Thus, our results suggest that the use of engineered
      myotube cells continuously secreting a defined level of insulin might be a useful
      approach to improve the efficacy of insulin injection treatment.

PMID- 10340553
TI  - Construction and in vitro functional evaluation of a low-density lipoprotein
      receptor/transferrin fusion protein as a therapeutic tool for familial
      hypercholesterolemia.
AB  - A cDNA sequence encoding a soluble form of the human low-density lipoprotein
      receptor (LDL-R) was produced by RT-PCR amplification. This form of the receptor
      contains the N-terminal cysteine-rich domain, the EGF homology domain, and the
      serine/threonine-rich domain, but lacks the membrane anchor as well as the
      cytoplasmic domain. By the same technical approach a cDNA sequence encoding
      rabbit transferrin was generated. In-frame fusion of the two cDNAs produced a
      sequence encoding a chimeric protein potentially capable of binding LDL on the N
      terminal side and the transferrin receptor on the C-terminal side. It was
      expected that LDL bound to the chimeric protein could be internalized, targeted
      to an acidic compartment, and processed through the pathway of the transferrin
      receptor. Cells transfected with the LDL-R/transferrin cDNA translate,
      glycosylate, and secrete the corresponding protein in the culture medium. The
      secreted protein binds LDL in a ligand-blotting experiment. Finally, the chimeric
      protein mediates the binding and internalization of LDL in mutant cells lacking
      the LDL receptor. In fact, Watanabe rabbit fibroblasts, incubated with the
      chimeric protein show a fourfold increase in LDL binding, a fivefold increase in
      LDL internalization, and a sixfold increase in LDL degradation, with respect to
      unincubated fibroblasts.

PMID- 10340554
TI  - Influence of sequence and size of DNA on packaging efficiency of parvovirus MVM
      based vectors.
AB  - We have derived a vector from the autonomous parvovirus MVM(p), which expresses
      human IL-2 specifically in transformed cells (Russell et al., J. Virol
      1992;66:2821-2828). Testing the therapeutic potential of these vectors in vivo
      requires high-titer stocks. Stocks with a titer of 10(9) can be obtained after
      concentration and purification (Avalosse et al., J. Virol. Methods 1996;62:179
      183), but this method requires large culture volumes and cannot easily be scaled
      up. We wanted to increase the production of recombinant virus at the initial
      transfection step. Poor vector titers could be due to inadequate genome
      amplification or to inefficient packaging. Here we show that intracellular
      amplification of MVM vector genomes is not the limiting factor for vector
      production. Several vector genomes of different size and/or structure were
      amplified to an equal extent. Their amplification was also equivalent to that of
      a cotransfected wild-type genome. We did not observe any interference between
      vector and wild-type genomes at the level of DNA amplification. Despite
      equivalent genome amplification, vector titers varied greatly between the
      different genomes, presumably owing to differences in packaging efficiency.
      Genomes with a size close to 100% that of wild type were packaged most
      efficiently with loss of efficiency at lower and higher sizes. However, certain
      genomes of identical size showed different packaging efficiencies, illustrating
      the importance of the DNA sequence, and probably its structure.

PMID- 10340555
TI  - In situ gene therapy for adenocarcinoma of the prostate: a phase I clinical
      trial.
AB  - For patients with local recurrence of prostate cancer after definitive
      irradiation therapy there is no treatment widely considered safe and effective.
      After extensive preclinical testing of prodrug gene therapy in vitro and in vivo,
      we conducted a phase I dose escalation clinical trial of intraprostatic injection
      of a replication-deficient adenovirus (ADV) containing the herpes simplex virus
      thymidine kinase gene (HSV-tk) injected directly into the prostate, followed by
      intravenous administration of the prodrug ganciclovir (GCV). Our goal was to
      determine safe dose levels of the vector for future trials of efficacy. Patients
      with a rising serum prostate-specific antigen (PSA) level and biopsy confirmation
      of local recurrence of prostate cancer without evidence of metastases one or more
      years after definitive irradiation therapy were eligible for the trial. After
      giving informed consent, patients received injections of increasing
      concentrations of ADV/HSA-tk in 1 ml into the prostate under ultrasound guidance.
      Ganciclovir was then given intravenously for 14 days (5 mg/kg every 12 hr).
      Patients were monitored closely for evidence of toxicity and for response to
      therapy. Eighteen patients were treated at 4 escalating doses: group 1 (n = 4)
      received 1 x 10(8) infectious units (IU); group 2 (n = 5) received 1 x 10(9) IU;
      group 3 (n = 4) received 1 x 10(10) IU; group 4 (n = 5) received 1 x 10(11) IU.
      Vector was detected by PCR of urine samples after treatment, increasing in
      frequency and duration (up to 32 days) as the dose increased. All cultures of
      blood and urine specimens were negative for growth of adenovirus. Minimal
      toxicity (grade 1-2) was encountered in four patients. One patient at the highest
      dose level developed spontaneously reversible grade 4 thrombocytopenia and grade
      3 hepatotoxicity. Three patients achieved an objective response, one each at the
      three highest dose levels, documented by a fall in serum PSA levels by 50% or
      more, sustained for 6 weeks to 1 year. This study is the first to demonstrate the
      safety of ADV/HSV-tk plus GCV gene therapy in human prostate cancer and the first
      to demonstrate anticancer activity of gene therapy in patients with prostate
      cancer. Further trials are underway to identify the optimal distribution of
      vector within the prostate and to explore the safety of repeat courses of gene
      therapy.

PMID- 10340556
TI  - A paracrine paradigm for in vivo gene therapy in the central nervous system:
      treatment of chronic pain.
AB  - A limitation of current gene therapy efforts aimed at central nervous system
      disorders concerns distribution of vectors on direct injection into neural
      tissue. Here we have circumvented this problem by transferring genes to the
      meninges surrounding the spinal cord, achieving an in vivo gene transfer paradigm
      for treating chronic pain. The therapeutic vector consisted of a recombinant
      adenovirus encoding a secreted form of the potent endogenous opioid beta
      endorphin. In an inflammation model of persistent pain, administration of the
      vector into the cerebrospinal fluid (CSF) surrounding the spinal cord transduced
      meningeal pia mater cells. The resulting increase in beta-endorphin secretion
      attenuated inflammatory hyperalgesia, yet had no effect on basal nociceptive
      responses. This demonstration of a gene transfer approach to pain treatment can
      be generalized to neurodegenerative disorders in which broad spatial distribution
      of therapeutic effect is critical.

PMID- 10340557
TI  - Vasculitic peripheral ulcerative keratitis.
AB  - The onset of peripheral ulcerative keratitis in the course of a connective tissue
      disorder, such as rheumatoid arthritis, relapsing polychondritis, or systemic
      lupus erythematosus, may reflect the presence of potentially lethal systemic
      vasculitis. Moreover, peripheral ulcerative keratitis may be the first sign of
      systemic necrotizing vasculitis in patients with Wegener's granulomatosis,
      polyarteritis nodosa, microscopic polyangiitis, or Churg-Strauss syndrome.
      Although the exact pathogenesis of this severe corneal inflammation and
      destruction is not well understood, evidence points to a dysfunction in
      immunoregulation with immune complexes formed in response to autoantigens or to
      some unknown microbial antigen depositing in scleral and limbal vessels. These
      events lead to changes that are mainly responsible for the resulting tissue
      damage. In pauci-immune vasculitides positive for antineutrophil cytoplasmic
      antibodies, cell-mediated cytotoxicity may play an important role in the
      pathogenesis of peripheral ulcerative keratitis. Untreated systemic conditions
      such as those mentioned above may carry a grave prognosis for the eye and may
      also be life-threatening. Immunosuppressive therapy with corticosteroids and
      cytotoxic agents is, we believe, mandatory in the treatment of these multisystem
      disorders associated with vasculitic peripheral ulcerative keratitis.

PMID- 10340558
TI  - Management of retained intravitreal lens fragments after cataract surgery.
AB  - With the rise of popularity of phacoemulsification as the preferred surgical
      method for cataract extraction, there has been an increased incidence of
      posterior dislocation of lens fragments. The appropriate management of this
      complication both during and after cataract extraction is discussed in this
      review. It is suggested that vigorous attempts by the cataract surgeon to
      retrieve intravitreal lens fragments should be avoided. Timely referral to a
      posterior segment surgeon for pars plana vitrectomy and removal of lens fragments
      can result in good visual outcome. Complications, such as glaucoma and retinal
      detachment, may develop in some cases. The importance of careful clinical follow
      up is emphasized.

PMID- 10340560
TI  - Ethmoid sinus osteoma presenting as epiphora and orbital cellulitis: case report
      and literature review.
AB  - Paranasal sinus osteoma is a slow-growing, benign, encapsulated bony tumor that
      may be commonly asymptomatic, being detected incidentally in 1% of plain sinus
      radiographs or in 3% of sinus computerized tomographic scans. In a patient
      presenting with orbital cellulitis and epiphora, computed tomography disclosed a
      large osteoma of the ethmoid sinus. Excision of the osteoma allowed recovery of
      vision, return of extraocular muscle function, and resolution of choroidal folds.
      Proptosis, diplopia, and visual loss are other frequent presenting signs of
      paranasal osteomas. Epidemiology, diagnosis, treatment, and pathologic findings
      in paranasal sinus osteoma are reviewed.

PMID- 10340559
TI  - Lung cancer, proptosis, and decreased vision.
AB  - A 48-year-old man presented to the emergency department with a 3-day history of
      decreased vision in a painful proptotic right eye. The patient was being treated
      with chemotherapy and radiation for non-small cell lung carcinoma. Examination
      showed visual acuity of hand motions, decreased motility, and an afferent
      pupillary defect on the right, consistent with an orbital apex syndrome.
      Neuroimaging revealed "dirty" orbital fat and no paranasal sinus disease. Orbital
      biopsy initially showed only fibrosis; however, on subsequent biopsies,
      nonseptate hyphae later identified as mucormycosis was recovered. The patient
      survived with exenteration and systemic amphotericin B.

PMID- 10340561
TI  - Management of hereditary retinal degenerations: present status and future
      directions.
AB  - Research on hereditary retinal degenerations has considerably improved our
      understanding of these disorders, although much remains to be learned about the
      exact mechanism involved in the pathogenesis. The advent of recombinant DNA
      technology will refine diagnostic capabilities, which have so far been based on
      the manifestations of the disease to localization of the molecular defects. The
      correlation of the molecular defects with the phenotype of the disease will
      result in better prognostic counseling for patients. In certain forms of
      retinitis pigmentosa, such as Refsum disease, gyrate atrophy of the choroid and
      retina, and abetalipoproteinemia, exact biochemical defects have been identified
      and specific treatments have been applied with some success. In other forms of
      retinitis pigmentosa, various investigations have suggested the possibilities of
      arresting the progress of degeneration by means such as the use of growth factors
      and controlling apoptosis. Efforts to alter the expression of the mutated gene or
      to introduce a normal gene into the genome are in their infancy, but results are
      encouraging. Vitamin A has been tried in patients with retinitis pigmentosa, and
      the results demonstrate statistically significant beneficial effects of this
      vitamin, suggesting that the course of the disease can be decelerated to some
      extent. Another interesting research area with potential for therapeutic
      application is the replacement of the retinal pigment epithelium or the
      degenerated neural retina by transplantation of the respective cell types.
      Clinical trials are being conducted both with retinal pigment epithelium and
      neuroretinal transplants.

PMID- 10340562
TI  - A survey of vision screening policy of preschool children in the United States.
AB  - A state-by-state survey regarding preschool vision screening guidelines,
      policies, and procedures was conducted. Currently 34 states provide vision
      screening guidelines and 15 states require vision screening of at least some of
      their preschool-aged children. The Department of Public Health administers the
      programs in 26 states, the Department of Education in 13. A wide range of
      professional and lay personnel conduct preschool vision screenings, and nurses
      participate in the screening process in 22 states. Visual acuity is assessed in
      30 states, eye alignment in 24 states, refractive error in eight states, and
      color vision in 10 states. A combination of screening tests is recommended in 24
      states. Currently, 45 states do not require screening of all preschool children.
      Thus, although laws, guidelines, and recommendations exist in most states, many
      preschool-age children do not have access to vision screening programs.

PMID- 10340563
TI  - Should I testify for a patient?
AB  - Many physicians are reluctant to serve in the role of expert witness in a suit
      whose defendant is a physician. However, by fulfilling this role in an objective,
      professional manner, the physician-witness can act in the best interest of both
      patients and the medical community.

PMID- 10340564
TI  - Latanoprost-induced uveitis.

PMID- 10340565
TI  - Bilamellar tarsal rotation is the preferred treatment for trachomatous
      trichiasis.

PMID- 10340567
TI  - Influence of management system on litter size, lamb growth, and carcass
      characteristics in sheep.
AB  - Three management systems (winter, spring, and late summer) distinguished by
      season of lambing and management practices were compared for litter size born and
      weaned and growth and carcass characteristics of lambs. Three sire breeds
      (Cheviot, Rambouillet, and Suffolk) and three dam breeds (Florida Native, Native
      X, and Synthetic-X) were used in 698 matings over a 3-yr period. System affected
      (P < .01) litter size born. Spring lambing yielded more lambs (1.62) than winter
      (1.49) and late summer (1.12). The winter-born lambs were lighter but fatter (P <
      .05), and spring-born lambs were leaner with higher leg conformation and carcass
      quality scores. The late summer-born lambs were not different from spring-born
      lambs. Wethers had higher (P < .01) weights off test than ewe lambs (43.9 vs 42
      kg) but had lower (P < .01) leg conformation scores, percentage kidney and pelvic
      fat, yield grade, and dressing percentages. Dam breed effects were significant (P
      < .05) for average preweaning daily gains with 249+/-5, 201+/-9, and 191+/-9 g
      for progeny of Native-X, Florida Native, and Synthetic-X, respectively. Single
      born lambs had higher daily gains (P < .05) than twins in a preweaning period in
      all management systems and higher postweaning and lifetime daily gains for winter
      and spring management systems.

PMID- 10340566
TI  - Effects of bovine somatotropin and ruminally undegraded protein on feed intake,
      live weight gain, and mohair production by yearling Angora wethers.
AB  - Yearling Angora wethers (n = 24; 24+/-1.0 kg BW) were used in an experiment with
      a 2 x 2 factorial arrangement of treatments to investigate effects of bovine
      somatotropin (bST) treatment and dietary level of ruminally undegraded protein on
      DMI, ADG, and mohair production. Untreated casein (UC) or casein treated with
      formaldehyde (TC) was included at 7% DM of a diet containing 11% CP and 46%
      concentrate. A slow-release bST form was administered weekly to deliver 0
      (Control) or 100 microg/ (kg BW.d) of bST. Plasma concentrations of bST and IGF-I
      were increased (P < .05) during the 7-d period following bST injection. Ruminal
      fluid ammonia N concentration was lower (P < .01) for TC than for UC before
      feeding (6.6 vs 7.5 mg/dL) and 4 h later (8.2 vs 12.2 mg/dL), and total VFA
      concentration was lower (P < .01) for TC than for UC. Treatment with bST
      decreased (P = .08) DMI with UC (1.15 vs .91 kg/d) and increased (P = .08) DMI
      with TC (.95 vs 1.06 kg/d). Formaldehyde treatment of casein increased ADG (65,
      74, 55, and 91 g/d; P = .03) and clean fleece production (P < .01; 14.1, 17.3,
      15.0, and 18.4 g/d for UC-Control, TC-Control, UC-bST, and TC-bST, respectively),
      with no effect of bST during the 8-wk period of treatment or for the 8 wk
      thereafter (P > .10). In conclusion, with yearling Angora wethers, bST does not
      seem useful to enhance mohair production and may not alter effects of dietary
      level of ruminally undegradable protein on mohair production.

PMID- 10340568
TI  - Effects of time of suckling during the solar day on duration of the postpartum
      anovulatory interval in Brahman x Hereford (F1) cows.
AB  - Previously published reports have indicated that postpartum anovulatory intervals
      can be markedly reduced and rebreeding performance enhanced in Bos taurus cows by
      eliminating nighttime suckling. We sought to confirm this hypothesis by examining
      the effects of day, nighttime, and ad libitum suckling on suckling behavior of
      calves, duration of the postpartum anovulatory interval, and pregnancy rates in
      45 fall-calving Brahman x Hereford (F1) cows. Beginning on d 9 to 12 postpartum,
      calves were removed from lactating cows from 0700 to 1900 (Night-Suckled, n = 15)
      or from 1900 to 0700 (Day-Suckled, n = 15), or remained with their dams
      continuously (Ad Libitum-Suckled, n = 15). Cows in each group were maintained
      with fertile Angus bulls from d 10 postpartum until the first normal luteal phase
      or 100 d postpartum, whichever occurred first. Cows were observed for estrous
      behavior twice daily, and jugular blood samples were collected twice weekly for
      the determination of serum progesterone concentration. Mean number of suckling
      episodes per 24 h was greater (P < .0001) for the Ad Libitum-Suckled group than
      either Night- or Day-Suckled groups (5.9+/-.42 vs 3.8+/-.14, and 3.9+/-.32,
      respectively). Hourly analysis of suckling episodes in the Ad Libitum group
      indicated that they were not skewed toward a particular period, with suckling
      occurring at a periodicity of 4 to 6 h. Intervals to the first rise in
      progesterone > or = 1 ng/mL (32+/-2.5, 32+/-4.5, and 31+/-1.7 d, respectively),
      first normal luteal phase (38+/-3.1, 38+/-3.8, and 37+/-2.5 d, respectively), and
      first estrus (43+/-3.5, 40+/-3.9, and 36+/-1.1 d, respectively) did not differ (P
      > .05) among the three groups. Similarly, cumulative pregnancy rates within 100 d
      after calving did not differ (P > .05). These results in Bos indicus x Bos taurus
      (F1) cattle do not support the previous conclusions in Bos taurus that
      eliminating nighttime suckling reduces the postpartum anovulatory interval.

PMID- 10340569
TI  - Influence of prepartum body condition score change on reproduction in multiparous
      beef cows calving in moderate body condition.
AB  - Multiparous, spring-calving beef cows (n = 250) were used to determine whether
      large changes in body energy reserves during mid- to late gestation influenced
      subsequent reproductive performance of cows calving in moderate body condition.
      In three states, cows were blocked by BW and body condition score (BCS; 1 =
      emaciated to 9 = obese) then allotted to receive either a high or low plane of
      nutrition from late summer to early winter over a 3-yr period. This generated an
      array of BCS by the beginning of the last trimester of pregnancy when cows were
      grouped by BCS as follows: Group 1, BCS < or = 4; Group 2, BCS of 5 or 6; and
      Group 3, BCS > or = 7. Each group was managed so that individual cows would calve
      with a BCS of 5 to 6. At the time of group assignment, mean BW and BCS differed
      (P < .01) among groups and were 480 kg and 3.6, 541 kg and 5.5, and 594 kg and
      7.1 for Groups 1 to 3, respectively. Within 28 d before calving, BW and BCS were
      similar (P > .20) among groups averaging 555 kg and 5.1. Prepartum BCS changes
      averaged 1.4, -.4, and -2.0 units for Groups 1 to 3, respectively (P < .01). Cows
      were managed as a single group after calving in each state. Location effect was
      significant for the prepartum and postpartum BW and BCS changes but not for
      postpartum reproductive performance. Significant location x BCS group
      interactions were found for the 90-d prepartum BW, BCS at calving, and prepartum
      changes in BW, but were caused by differences in magnitude among locations. The
      percentage of cows with luteal activity at the start of a subsequent breeding
      season was not affected (P > .20) by either location or BCS group, and averaged
      66%. Mean pregnancy rates at 20, 40, and 60 d of a subsequent breeding season
      were 55, 76, and 89% for Group 1; 51, 67, and 82% for Group 2; and 64, 79, and
      89% for Group 3 (P > .30). Mean days to conception were 89, 87, and 85 for Groups
      1 to 3, respectively (P = .70). Neither calf birth weight (x = 38.6 kg) nor
      adjusted 205-d weight (x = 223.6 kg) were affected by prepartum BW and BCS
      changes. We conclude that reproductive performance of cows calving in moderate
      body condition is not influenced by large changes in body energy reserves during
      the last trimester of pregnancy.

PMID- 10340570
TI  - Flake density of steam-processed sorghum grain alters performance and sites of
      digestibility by growing-finishing steers.
AB  - The effect of several flake densities (FD) of steam-processed sorghum grain on
      performance, and site and extent of nutrient digestibilities by steers fed
      growing and finishing diets was determined. The effectiveness of common
      laboratory methods of starch availability (enzymatic hydrolysis or
      gelatinization) to provide target specifications for quality control of steam
      flaked grains was also measured. In vitro starch availability of the processed
      grains increased (P < .05) linearly in response to decreased FD. Flake density
      was more highly correlated with enzymatic measures than with percentage
      gelatinization (R2 = .87 to .93 vs .36). Using 140 crossbred beef steers (181 kg
      initial weight), feedlot performance was determined for 112 d with a growing diet
      (50% grain), followed by 119 d with a finishing diet (78% grain). Each FD
      treatment (412, 360, 309, and 257 g/L or 32, 28, 24, and 20 lb/bu) was randomly
      assigned to five pens of seven steers each. Intake of DM by steers decreased
      linearly (P < .05) as FD decreased (7 and 13%, respectively, for growing and
      finishing diets). Decreasing FD reduced linearly (P < .05) ADG in the finishing
      phase and for the entire 231-d trial. With the growing diet only, feed efficiency
      and estimated diet NEm and NEg responses to decreasing FD were curvilinear (P <
      .05), with the 360 g/L (28 lb/bu) flake being most efficient. Electrical energy
      requirements for processing increased linearly (P < .05) as FD decreased. Using
      four multi-cannulated crossbred steers (275 kg), starch digestibility increased
      linearly (P < .05) in the rumen (82 to 91%) and total tract (98.2 to 99.2%) as FD
      decreased. Digestibilities within the small (74%) and large intestines (62%) were
      not altered by FD. Decreasing FD increased (P < .05) total CP digestibility, but
      did not consistently alter fiber digestibility or DE content of the diets. In
      conclusion, enzymatic laboratory methods to evaluate starch availability in
      processed grains can be used satisfactorily to establish FD criteria for quality
      control of the steam-flaking process. The greatest improvements in efficiency,
      estimated diet NE, and starch and protein digestibilities usually occurred when
      FD was decreased from 412 to 360 g/L (32 to 28 lb/bu). Based on these measures
      and processing costs, the optimal FD was 360 g/L (28 lb/bu).

PMID- 10340571
TI  - Sorghum grain flake density and source of roughage in feedlot cattle diets.
AB  - Feedlot performance was studied in a 262-d trial using 126 crossbred beef steers
      (182 kg initial BW) to determine whether source of dietary roughage influences
      performance and carcass characteristics by steers fed growing (112 d) and
      finishing (150 d) diets with various flake densities (FD) of steam-processed
      sorghum grain. A 3 x 3 arrangement of treatments (two pens of seven steers each)
      was used, with dietary roughages being chopped alfalfa hay or 50:50 mixtures
      (equal NDF basis) of cotton-seed hulls or chopped wheat straw with alfalfa hay;
      sorghum grain was steam-flaked to densities of 386, 322, and 257 g/L (SF30, SF25,
      and SF20, reflecting bushel weight in pounds). The effects of these same FD on
      nutrient digestibilities were determined in three experiments with 24 crossbred
      steers fed finishing diets containing each of the roughage sources. No
      interactions between FD and roughage type were detected in any performance or
      carcass measurements (P > .10). Intake of DM decreased linearly (P < .05) in
      response to decreased FD. Daily rate and efficiency of gain were not altered (P
      >.10) by FD. Decreasing FD decreased linearly (P < .05) dressing percentage and
      fat thickness, but not other carcass measurements. Dietary roughage did not
      affect (P >.10) daily gains or carcass measurements, but DM intake was lower and
      feed efficiencies were superior (P < .05) when alfalfa hay was the sole source of
      roughage. Cottonseed hulls and wheat straw were relatively less valuable in the
      low roughage finishing diets than in higher roughage growing diets.
      Digestibilities of starch increased linearly as FD was decreased (P = .02) when
      steers were fed diets containing wheat straw, but not for alfalfa hay or
      cottonseed hull diets. Digestibilities of DM did not vary with changes in FD;
      however, changes in CP, NDF, and ADF digestibilities due to FD seemed to differ
      among experiments. In conclusion, performance and carcass measurement responses
      by growing-finishing steers to differences in sorghum grain FD were not related
      to source of dietary roughage, but diets with alfalfa hay as the only source of
      roughage were most efficient. Decreasing FD of sorghum grain below 386 g/L (30
      lb/bu) was not advantageous in improving performance or carcass merit by growing
      finishing steers.

PMID- 10340572
TI  - Effect of reconstituting field-dried and early-harvested sorghum grain on the
      ensiling characteristics of the grain and on growth performance and carcass merit
      of feedlot heifers.
AB  - The objective of this study was to determine whether reconstituting field-dried
      and early-harvested sorghum grain affected the fermentation characteristics and
      feed value of the ensiled grain when fed to feedlot heifers. In Trial 1, sorghum
      grain was harvested at 14% moisture, rolled, and reconstituted to 25, 30, or 35%
      moisture, then ensiled in laboratory-scale silos. Lactic acid concentration
      increased (d 5 to 90) and pH decreased more rapidly (d 3 to 90) as moisture level
      increased (P < .05). Acetic acid concentration increased (P < .05) with moisture
      and day postfilling. Concentration of ethanol was highest (P < .05) in the 30 and
      35% moisture grains from d 1 to 5, but by d 90 the ethanol concentration in the
      25% moisture grain exceeded (P < .05) that of the two higher-moisture grains.
      Ammonia N concentration was lowest (P < .05) in the 25% moisture grain at all
      sampling times postfilling. In Trial 2, 288 heifers (BW = 286+/-83 kg) were used
      to compare the feeding value of rolled, ensiled sorghum grain harvested at 25%
      moisture to the same grain reconstituted to 30 or 35% moisture. A steam-flaked
      corn (SFC) diet served as the control. Final live weight; ADG; hot carcass
      weight; backfat depth; marbling score; kidney, pelvic, and heart fat; and liver
      abscess score were not affected by grain treatment (P > .10). Dry matter intake
      was highest (P < .10) for heifers fed the 25 or 30% moisture sorghum grain diets
      and lowest for those fed the SFC diet; DMI for heifers fed the 35% moisture
      sorghum grain diet was intermediate. Feeding 35% moisture sorghum grain improved
      gain efficiency (P < .10) compared with feeding 25 or 30% moisture sorghum grain
      by 9.0 and 5.7%, respectively. We conclude that reconstituting sorghum grain
      beyond the typical moisture levels of 25 to 30% would enhance the fermentation
      characteristics of the ensiled grain and improve gain efficiency in feedlot
      heifers.

PMID- 10340573
TI  - The effect of forage source and particle size on finishing yearling steer
      performance and ruminal metabolism.
AB  - Two finishing trials and a metabolism trial were conducted to evaluate the effect
      of forage source and particle size in dry-rolled corn finishing diets. In Exp. 1,
      224 crossbred yearling steers (BW = 342+/-11 kg) were used in a randomized
      complete block design consisting of seven treatments. Treatments were an all
      concentrate diet or diets containing equal NDF levels provided by alfalfa hay or
      wheat straw (three treatments each) with each forage source ground to pass
      through a .95-, 7.6-, or 12.7-cm screen. Steers fed diets containing forage had
      greater (P < .05) DMI than steers fed an all-concentrate diet. Steers fed alfalfa
      diets gained faster (P < .05) with a greater (P < .05) concentrate efficiency
      than steers fed either all-concentrate or straw diets. In Exp. 2, 120 crossbred
      yearling steers (BW = 307+/-2 kg) were used in a completely randomized design and
      fed dry-rolled corn diets containing 10% alfalfa ground to pass through either a
      .95- or 7.6-cm screen. Alfalfa particle size had no effect on performance or
      carcass measurements. In Exp. 3, six ruminally fistulated steers (BW = 508+/-34
      kg) were used in a 6 x 6 Latin square design and fed an all-concentrate diet or
      diets containing equal NDF levels provided by alfalfa hay, wheat straw, or ground
      corncobs with alfalfa and straw ground to pass through either a 2.54- or 12.7-cm
      screen. Steers fed straw diets spent more time (P < .10) chewing than those
      receiving the other diets. In conclusion, forage particle size had no effect on
      finishing cattle performance or ruminal metabolism data. However, cattle
      consuming different forage sources in dry-rolled corn finishing diets may not
      respond similarly in animal performance.

PMID- 10340574
TI  - Effects of imposed feed intake variation on acidosis and performance of finishing
      steers.
AB  - Four metabolism and two finishing trials were conducted to determine the effects
      of imposed feed intake variation on acidosis and performance of finishing steers.
      In Metabolism Trial 1, four ruminally fistulated steers were limit-fed and
      subjected to either a constant amount of feed per day (C) or low intake variation
      of .7 kg/d (LV). No treatment differences were found for intake or measures of
      acidosis. Metabolism Trial 2 was conducted similarly to Metabolism Trial 1 with
      treatments of C and high intake variation of 1.4 kg/d (HV). Treatment HV
      increased (P < .05) acidosis, as indicated by the area of ruminal pH below 5.6.
      In Metabolism Trial 3, four steers were fed at ad libitum levels of intake and
      subjected to three levels of intake variation: ad libitum intake with no imposed
      intake variation (AL), LV of .7 kg/d, and HV of 1.4 kg/d. No treatment
      differences were found. In Metabolism Trial 4, six ruminally fistulated steers
      were fed at ad libitum levels and subjected to three levels of intake variation:
      AL, LV of .9 kg/d, and HV of 1.8 kg/d. Average ruminal pH increased (P < .05) and
      area of ruminal pH below 5.6 decreased (P < .05) as level of intake variation was
      increased. In Finishing Trial 1, 75 steers were assigned to eight pens and two
      treatments: AL or HV of 1.8 kg/d. Dry matter intake increased (P < .05) from AL
      to HV. Daily gain and gain/feed were not affected by treatment. In Finishing
      Trial 2, 94 steers were assigned to 12 pens and two treatments: AL or HV of 1.8
      kg/d. No treatment differences were noted in DMI, daily gain, or gain/ feed.
      Therefore, results of these trials indicate that intake variation of up to 1.8
      kg/d does not increase acidosis or decrease performance of finishing steers fed
      at ad libitum levels of intake.

PMID- 10340575
TI  - Effect of anabolic implants on beef intramuscular lipid content.
AB  - Sixty ribeye steaks were used to determine the effects of anabolic implants on
      i.m. lipid composition of beef steers. Steaks were obtained from carcasses (346
      kg) of steers assigned to four treatment groups (C = nonimplanted control; ET =
      28 mg of estradiol benzoate plus 200 mg of trenbolone acetate on d 0; ET/ET = ET
      on d 0 and d 61; and S/ET = 20 mg of estradiol benzoate plus 200 mg of
      progesterone on d 0 and ET on d 61) and fed a high-concentrate diet for 127 d.
      Total fatty acid content of the longissimus was less (P < .05) for implanted
      steers. Implanting increased (P < .05) stearic and linolenic acid percentages and
      reduced (P < .05) oleic acid percentage but did not alter (P > .05) percentages
      of other fatty acids. These changes translated into increased (P < .05)
      percentages of saturated fatty acids and reduced (P < .05) monounsaturated fatty
      acids in the longissimus of implanted steers. However, on a per-steak weight
      basis, implanting did not alter (P > .05) the amounts of any of the individual
      fatty acids, but it increased (P < .05) the total cholesterol amount. Implanting
      with an estrogenic compound first reduced (P < .05) the percentage and total
      amounts of linoleic and polyunsaturated fatty acids. On a percentage basis,
      implanting alters fatty acid amounts; however, when the increase in ribeye size
      with implanting is accounted for and fatty acids are evaluated on a per-steak
      basis, these differences are not significant.

PMID- 10340576
TI  - Feeding and watering behavior of healthy and morbid steers in a commercial
      feedlot.
AB  - Our objective was to determine whether there were differences in feeding and
      watering behavior of newly received healthy and morbid feedlot steers. Two
      separate 32-d feeding trials were conducted in Wellton, Arizona, in July and
      November 1996. Radio frequency technology was used to record individual animal
      behaviors from 108 (average weight 139 kg) and 143 (average weight 160 kg) steers
      in each respective trial. Steers that were subsequently identified as morbid were
      present at the feed bunk in greater percentages than reported in previous
      studies. In Trial 1, healthy steers spent more (P < .001) time at the feed bunk
      and had more (P < .009) feeding bouts than morbid steers. In Trial 2, healthy
      steers did not spend more time at the feed bunk, but they had more (P < .02)
      daily feeding bouts than morbid steers. There were no differences in daily time
      spent at the water trough by healthy or morbid steers in either trial. The
      greatest proportion of feeding and watering behavior occurred during the daylight
      hours in response to feed delivery. The pattern of time spent at the feed bunk
      throughout the 32-d feeding period was similar for healthy and subsequently
      morbid steers, but healthy steers had more feeding bouts per day.

PMID- 10340577
TI  - Physiological changes and digestive capabilities of newly received feedlot
      cattle.
AB  - Newly arrived feedlot calves undergo numerous stressors that result in 1)
      transient endocrine responses, 2) altered products of energy and protein
      metabolism, 3) changes in appetite and growth rate, 4) possible limited
      compromise of digestive and rumen function, and 5) a challenged immune system.
      The most consistent endocrine and metabolic responses to marketing, transport,
      and feedlot adaptation are seen with cortisol and epinephrine. In contrast to
      earlier work done with indirect in vitro gas production measurements, recent
      research has shown that the ruminal microbial population is able to effectively
      digest available substrate immediately following a calfs weaning, trucking, and
      24 h of feed and water deprivation. Additionally, a period of feed and water
      deprivation up to 72 h coupled with 8 h of trucking does not reduce the
      concentration or total numbers of either the viable cellulolytic or total
      bacteria present in the rumen of newly weaned or feedlot-adapted calves. However,
      ruminal volume, DM, total weight of ruminal contents, and total protozoal numbers
      decrease as duration of feed deprivation increases. To compensate for the reduced
      DMI that occurs in the first 2 wk after arrival at the feedlot, increased
      nutrient density is needed to meet an animal's requirements for nutrients.
      Limited data suggest that newly arrived calves prefer a diet that is similar in
      moisture and texture to feeds with which they are familiar. Additionally,
      modification of the stress-associated behavior using trainer animals may improve
      the feed intake of newly received calves and may reduce calf morbidity.

PMID- 10340578
TI  - Interaction of cattle health/immunity and nutrition.
AB  - The usual means of assessing the health of newly received beef cattle susceptible
      to bovine respiratory disease (BRD) are subjective, typically involving visual
      evaluation aided by minimal clinical measurements. Recent evidence based on the
      occurrence of pneumonic lung lesions at slaughter indicates a need for more
      accurate methods of diagnosing BRD. Inadequate passive immune transfer at birth
      may be an important risk factor in susceptibility to BRD, suggesting the need for
      management to improve passive transfer success rates. Preweaning management and
      vaccination practices offer opportunities for beef cattle producers to improve
      the immune status of newly weaned calves and decrease postweaning BRD. Feeding
      diets with higher levels of concentrate typically improves performance by newly
      weaned or received cattle, as does feeding diets supplemented with protein;
      however, limited data suggest that increasing concentrate and protein in
      receiving diets increases the rate and severity of subjectively determined BRD
      morbidity. Research with receiving diet concentrate/protein level relative to
      humoral and cell-mediated immune function coupled with indicators of health and
      performance is needed. Supplemental B vitamins are sometimes useful in receiving
      diets, but the effects have been variable, presumably reflecting differences in
      stress and associated feed intake responses. Vitamin E added to receiving diets
      to supply > or = 400 IU/animal daily seems beneficial for increasing gain and
      decreasing BRD morbidity; however, further dose titration experiments are needed.
      Supplemental Zn, Cu, Se, and Cr can alter immune function of newly received
      calves, and some field trials have shown decreases in BRD morbidity rate with
      supplementation; however, several experiments have shown no performance or
      health/immune benefits from supplementation of these trace minerals. Formulation
      of receiving diets should take into account decreased feed intake by highly
      stressed, newly received beef cattle and known nutrient deficiencies, but
      fortification of such diets with trace minerals beyond the levels needed to
      compensate for these effects is difficult to justify from present data.

PMID- 10340579
TI  - Effects of production circumstances on expected responses for growth and carcass
      traits to selection of bulls in Japan.
AB  - Economic values of growth and carcass traits in Japanese beef cattle for
      production systems with various types of integration of levels/ stages (cow-calf
      and feedlot segments and the integrated system) and production circumstances
      (including 20% higher genetic levels of the traits, management, and economic
      alternatives) were used to examine responses to selection. Discounted economic
      values with interest rates of 0, 4.2 (Japanese average), and 8.4% were obtained
      to investigate the effect of discounting on selection efficiency. Traits
      considered were daily gain in the feedlot, marbling score, birth weight, weaning
      weight, and mature weight. The effects of discounting were small. Correlated
      responses to selection were not always economically favorable for all situations.
      Selecting bulls for the base situation (i.e., the typical biological and economic
      conditions for the production of Japanese Black cattle) resulted in negative
      genetic changes in weaning weight and mature weight in the feedlot segment.
      Higher genetic levels of daily gain and weaning weight affected efficiency of
      selection. Although effects of management and economic alternatives on responses
      to selection were generally small, lighter market weight influenced responses to
      selection. The results indicate that predicted correlated responses to selection
      are sensitive to production systems and some production circumstances.

PMID- 10340580
TI  - Inheritance of the "rat-tail" syndrome and its effect on calf performance.
AB  - A form of congenital hypotrichosis, commonly know as the "rat-tail syndrome,"
      occurs in a small percentage of calves produced by crossing some Continental
      cattle breeds with cattle that are black in color. These calves are characterized
      by short, curly, malformed, sometimes sparse hair and a lack of normal tail
      switch development. In our first study, performance of 43 rat-tail calves was
      compared with that of 570 non-rat-tail calves of the same breeding and
      contemporary groups. All rat-tail calves were sired by Simmental bulls and were
      from cows with various percentages of Angus breeding. The rat-tail condition had
      no effect on birth weight, weaning weight, or gain from birth to weaning.
      However, rat-tail calves had significantly lower rates of gain during the winter
      months from weaning to yearling than non-rat-tail calves, resulting in a 19 kg
      lighter yearling weight. Gains of steers from yearling to slaughter were not
      significantly different, but rat-tail steers were 36 kg lighter (P = .01) and 13
      d older (P = .15) at slaughter than the non-rat-tail steers. In a second study,
      Angus-Simmental F1 males and females with the rat-tail condition were mated to
      produce 64 F2 offspring that were used to determine the mode of inheritance of
      this syndrome. Analysis showed that the rat-tail syndrome is controlled by
      interacting genes at two loci. Cattle that express the syndrome must have at
      least one dominant gene for black color and be heterozygous at the other locus
      involved.

PMID- 10340581
TI  - Components of growth in mice hemizygous for a MT/bGH transgene.
AB  - The objective of this study was to determine the effects of a
      metallothionein/bovine GH transgene on duration and rate of growth of lean and
      fat in mice. Mice were produced by mating hemizygous transgenic males to
      nontransgenic females. Ten weights and six measurements of total body electrical
      conductivity to estimate body composition were taken on 147 progeny between birth
      and 84 d of age. Growth traits for fat-free mass (FFM) and body fat mass (FM)
      were obtained by fitting FFM and FM to a logistic curve y = A/(1 + exp(k(b -
      t))), where y is FFM or FM, A is asymptotic mass, k and b are curve parameters,
      and t is time in days. The function and its first, second, and third derivatives
      for FFM and FM were used to model growth. A mixed model was used with animal and
      litter as random effects and trans-genotype, sex, and transgenotype x sex as
      fixed effects in analyses of growth traits. Estimates of transgeno-type and
      transgenotype x sex interaction were tested by using their corresponding standard
      errors. Males had greater response to the transgene than females in final FFM and
      growth rate during the entire growth period. Transgenic males and females had
      greater duration of lean growth than nontransgenics. Transgenic males began to
      accumulate fat later, but they eventually gained more fat than transgenic
      females.

PMID- 10340582
TI  - Genetic relationships among direct and maternal components of milk yield and
      maternal weaning gain in a multibreed beef herd.
AB  - Data spanning 1980 to 1993 from a multibreed beef herd including primarily eight
      breeds (Angus, Charolais, Gelbvieh, Hereford, Maine-Anjou, Pinzgauer, Simmental,
      and Tarentaise) were used to obtain 2,207 records on 200-d weaning gain (WG) and
      1,826 records on 200-d milk yield (MY), obtained by machine milking after
      oxytocin injection. Estimates of (co)variances for the two traits (WG and MY)
      were obtained with REML with breed of calf, breed of cow, and heterotic effects
      modeled for the two traits. Animal effects of calf (CalfWG, CalfMY) and cow
      (CowWG, CowMY) contributions to each trait were modeled including 2,926 animals.
      The permanent environmental effect of the cow was modeled for MY, with 693
      levels. Estimates of breed differences were generally similar to literature
      estimates. Simmental, Charolais, and Maine-Anjou were highest for CalfWG, and
      Tarentaise, Simmental, Gelbvieh, and Maine-Anjou were highest for CowMY.
      Heterosis was estimated at 8.00, 2.58, 4.05, and 5.50% of the mean for CalfWG,
      CowWG, CalfMY, and CowMy, respectively. Variance attributable to repeated records
      on CowMy represented 9% of phenotypic variance. Heritabilities estimated were .22
      and .24 for CalfWG and CowWG and .04 and .35 for CalfMY and CowMY. Genetic
      correlations estimated between CalfWG and CowWG and between CalfMY and CowMY were
      -.35 and -.64, respectively. A genetic correlation between CowWG and CowMY of .76
      indicates that maternal weaning gain evaluations are a good predictor of a cow's
      potential for milk yield.

PMID- 10340583
TI  - Conservation of nitrogen in cattle feedlot waste with urease inhibitors.
AB  - Feedlot cattle normally retain less than 20% of their dietary nitrogen intake.
      Sixty to 80% of the nitrogen excreted is normally lost through volatilization of
      ammonia, which is primarily generated from urea. This loss of ammonia nitrogen
      pollutes the environment and creates an unfavorable ratio of nitrogen to
      phosphorous (N:P) in the waste for crop growth. Two urease inhibitors,
      cyclohexylphosphoric triamide (CHPT) and N-(n-butyl) thiophosphoric triamide
      (NBPT) were evaluated for their ability to reduce the rate of urea hydrolysis in
      beef cattle feedlot pens. Initially, a total of six pens were used, two pens per
      treatment, with approximately 70 cattle per pen, and a single topical application
      of CHPT or NBPT at 20 mg/kg of manure. Essentially no urea was found in untreated
      pens. However, with CHPT treatment, 2 g of urea/kg of dry manure accumulated by d
      4, and all gradually disappeared by d 11; NBPT conserved 3 and 3.5 g of urea/kg
      by d 4 and 9, respectively, and it had disappeared by d 14 (treatment [trt] x
      day, P = .003). A second study involved application of NBPT weekly for 6 wk. This
      caused urea to accumulate to a peak concentration of 17 g/kg of manure by d 30
      (trt x day2, P = .001). Once the treatment was stopped the urea concentration
      began to decrease. When the NBPT was applied weekly, the concentration of ammonia
      in the waste was less for the treated pens (trt x day, P = .01), the total
      nitrogen was greater (trt x day, P = .04), pH tended to be lower (trt x day, P =
      .10), and the total volatile acids were not different (trt x day, P = .51) from
      untreated pens. We concluded that urease inhibitors could be used to control
      ammonia emissions from animal wastes, prevent environmental damage, and produce a
      more balanced (N:P) fertilizer from manure.

PMID- 10340584
TI  - Comparative protein and amino acid digestibilities in growing pigs and sows.
AB  - An experiment was conducted to compare apparent total tract protein
      digestibilities and apparent ileal digestibilities of protein and amino acids in
      growing pigs and adult pregnant and lactating sows. Twelve growing pigs and 12
      sows were used and surgically fitted with simple T-cannulas at the distal ileum.
      Six experimental diets based on corn, barley, wheat, soybean meal, canola meal,
      or meat and bone meal were formulated, and each diet was fed to growing pigs,
      gestating sows, and lactating sows for 7 d. Chromium oxide was included in all
      diets as an indigestible marker (.25%) for calculating nutrient digestibilities.
      Fecal material was collected on d 5 of each feeding period by grab sampling, and
      ileal samples were collected for 12 h/d during the last 2 d of each feeding
      period. Apparent fecal protein digestibilities for all feed ingredients were
      higher (P < .05) in gestating and lactating sows compared to growing pigs, but no
      differences between the two groups of sows were observed (P > .05). At the distal
      ileum, no differences (P > .05) in protein digestibilities were detected between
      sows and growing pigs regardless of feed ingredient. For all feed ingredients
      tested, lactating sows had apparent ileal digestibilities of most amino acids
      that were two to six percentage units higher than those obtained in growing pigs,
      but not all of the differences were significant. Gestating sows had
      digestibilities of most amino acids that were intermediate between those of
      growing pigs and lactating sows. The combined results from the six feed
      ingredients showed that lactating sows had higher (P < .05) digestibilities of
      all indispensable amino acids except arginine, and gestating sows had higher (P <
      .05) digestibilities of five of the indispensable amino acids than did growing
      pigs. The results of this experiment indicate that apparent fecal protein and
      apparent ileal amino acid digestibilities obtained in growing pigs are not always
      representative of digestibilities in either gestating or lactating sows.

PMID- 10340585
TI  - The effect of feeding level and physiological status on total flow and amino acid
      composition of endogenous protein at the distal ileum in swine.
AB  - An experiment was conducted to investigate the effects of BW, feed intake, and
      the physiological condition of the animal on the loss and amino acid composition
      of endogenous protein in swine. Ten growing barrows and five multiparous sows
      were equipped with a T-cannula in the distal ileum for digesta collection. A
      protein-free diet was fed to all animals. The barrows were given free access to
      the experimental diet. The sows also were allowed to consume the diet on an ad
      libitum basis, and digesta were collected during lactation and in the following
      gestation period. In addition, digesta from the gravid sows were collected after
      restricting the sows to 2 kg of feed per day. For each animal group, the
      endogenous losses of protein and amino acids were calculated in relation to DMI,
      and the amino acid composition of endogenous protein was calculated. The total
      endogenous gut protein loss at the distal ileum of growing pigs, lactating sows,
      and gestating sows, given free access to feed, was 12.4, 9.4, and 11.2 g/kg DMI,
      respectively. These values were not different (P > .10). However, when gestating
      sows were fed only 2 kg/d, 17.8 g of endogenous protein was lost per kilogram of
      DMI, which was higher (P < .05) than for any of the other groups. This difference
      was mainly caused by higher (P < .05) losses of glycine, proline, and serine.
      There were no differences (P > .05) in amino acid composition of endogenous
      protein between growing pigs, lactating sows, and gestating sows given free
      access to feed, but restricted-fed gestating sows had an amino acid composition
      of endogenous protein that was significantly different from that of the other
      groups. The results from the experiment showed that age, BW, and the
      physiological condition of the animal have little or no effect on the amount of
      endogenous protein and amino acids lost at the distal ileum of hogs if calculated
      in relation to DMI. Likewise, the amino acid composition was not affected by the
      BW or physiological condition of the animal. However, DMI had a significant
      effect on endogenous protein losses in sows as well as on amino acid composition
      of endogenous protein.

PMID- 10340586
TI  - Efficacy of chromium picolinate on performance and tissue accretion in pigs with
      different lean gain potential.
AB  - We conducted two experiments to determine whether the efficacy of chromium
      picolinate (CrP) on growth performance, carcass composition, and tissue accretion
      rates is dependent on the lean gain potential of the pigs. In Exp. 1, 40 barrows
      (20 from each of two genetic backgrounds; two pigs per pen, five pens per
      treatment) were fed a fortified, corn-soybean meal basal diet (.95% lysine from
      19 to 55 kg BW; .80% lysine from 55 to 109 kg BW) without or with 200 microg/kg
      of Cr from CrP. The addition of Cr had no effect on performance, carcass
      measurements, or accretion rates of carcass protein or lipid, regardless of the
      lean gain potential of the pigs. In Exp. 2, 60 group-penned pigs (three pigs per
      pen; five pens per treatment) were fed a fortified, corn-soybean meal basal diet
      without or with 200 microg/kg of Cr from CrP from 21 to 104 kg BW. Within the
      dietary Cr treatments, half of the pigs received daily injections of 3 mg of
      porcine somatotropin (pST) from 54 to 104 kg BW. The pST administration resulted
      in faster growth rates (P < .007), improved feed efficiency (P < .001), increased
      longissimus area (P < .001), and decreased 10th-rib backfat (P < .001).
      Administration of pST also increased the percentage and accretion rate of carcass
      protein (P < .001) and decreased the percentage and accretion rate of carcass
      lipid (P < .001). The addition of CrP to the diet had no effect on any variable
      measured in either the untreated or pST-treated pigs. In these studies, Cr was
      ineffective at altering the composition of the carcass and its effects were not
      dependent on the pig's potential for lean gain.

PMID- 10340587
TI  - Early- and traditionally weaned nursery pigs benefit from phase-feeding
      pharmacological concentrations of zinc oxide: effect on metallothionein and
      mineral concentrations.
AB  - Benefits of feeding pharmacological concentrations of zinc (Zn) provided by Zn
      oxide (ZnO) to 21-d conventionally weaned pigs in the nursery have been
      documented; however, several management questions remain. We conducted two
      experiments to evaluate the effect on growth from feeding 3,000 ppm Zn as ZnO
      during different weeks of the nursery period. In Exp. 1 (n = 138, 11.5 d of age,
      3.8 kg BW) and Exp. 2 (n = 246, 24.5 d of age, 7.2 kg BW), pigs were fed either
      basal diets containing 100 ppm supplemental Zn (adequate) or the same diet with
      an additional 3,000 ppm Zn (high) supplied as ZnO. Pigs were fed four or two
      dietary phases in Exp. 1 and 2, respectively, that changed in dietary ingredients
      and nutrient content (lysine and crude protein) to meet the changing
      physiological needs of the pigs for the 28-d nursery period. Dietary Zn
      treatments were 1) adequate Zn fed wk 1 to 4, 2) high Zn fed wk 1, 3) high Zn fed
      wk 2, 4) high Zn fed wk 1 and 2, 5) high Zn fed wk 2 and 3, and 6) high Zn fed wk
      1 to 4. In Exp. 1 and 2, pigs fed high Zn for wk 1 and 2 or the entire 28-d
      nursery period had the greatest (P < .05) ADG. During any week, pigs fed high Zn
      had greater concentrations of hepatic metallothionein and Zn in plasma, liver,
      and kidney than those pigs fed adequate Zn (P < .05). In summary, both early- and
      traditionally weaned pigs need to be fed pharmacological concentrations of Zn
      provided as ZnO for a minimum of 2 wk immediately after weaning to enhance
      growth.

PMID- 10340588
TI  - Metabolic utilization of energy and maintenance requirements in growing pigs:
      effects of sex and genotype.
AB  - An experiment was conducted in which the metabolic utilization of energy was
      measured in individually penned pigs from seven groups that differed in genotype
      and(or) sex and ranged in body weight between 20 and 107 kg. The animals were fed
      a diet containing, on a DM basis, 14.7 MJ ME and at least 21% CP. Heat production
      was measured in an open-circuit calorimeter, and energy, nitrogen, and fat
      balances were determined at regular intervals over the growing period; a total of
      177 measurements were performed. Body composition of the animals was measured by
      serial slaughter, and these data were used for estimating the body composition of
      an animal at a given weight through allometric regression. A factorial analysis
      procedure was used to estimate the utilization of ME by regressing the ME intake
      on the observed protein and lipid deposition rates. The intercept of this
      equation is the maintenance energy requirement (MEm) and was represented either
      as a function of body weight with group-specific parameters (MEm = a(i) BWb) or
      as a function of the muscle and visceral mass with an additional additive group
      effect (MEm = aM muscle(b) + a(v) viscera(b) + G(i)). With BW as dependent
      variable, the exponent b was close to .60 and differed significantly from .75.
      The regression coefficient (a(i)) averaged 1.02 MJ ME/kg.60 but it was different
      for most groups, indicating that different groups of animals have different
      maintenance requirements. Fixing the exponent to .75 consistently underestimated
      the maintenance requirement. When the exponent b was not fixed to .75 but
      estimated, the partial efficiencies for protein and lipid deposition were .62 and
      .84, respectively. Body muscle and visceral mass could explain a large part of
      the variation in MEm. Viscera contributed three times more to MEm (per kilogram
      of mass raised to the .70 power) than did muscle. Even though the muscle mass
      exceeds to a large extent the visceral mass in animals, the contribution of
      muscle to MEm was lower than that of viscera for most groups.

PMID- 10340589
TI  - Metabolism and excretion of ochratoxin A fed to sheep.
AB  - Hydrolysis of the mycotoxin ochratoxin A (OA) to ochratoxin alpha (Oalpha) by
      microorganisms within the gastrointestinal tract leads to the excretion of OA as
      the nontoxic alpha form. The Oalpha form is the principal means for the
      detoxification of OA. In the current experiment, three groups of four sheep were
      fed diets consisting of 70% concentrates and 30% hay (dry matter basis, energy to
      supply 1.1 times the requirement for maintenance) for 4 wk with three dietary
      concentrations of OA (0, 2, or 5 mg/kg of concentrate feed). The OA content did
      not affect feed intake or nutrient digestibility. In a preliminary experiment, an
      OA dose of 20 mg/kg of concentrate feed greatly reduced feed intake. After 1, 2,
      3, and 4 wk of the trial, significant concentrations of OA were detected in the
      serum of the animals fed 2 or 5 mg of OA/kg feed. This suggested that even at a
      dosage of 2 mg of OA/kg of concentrate feed, considerable amounts of OA were not
      degraded by ruminal and intestinal microorganisms. The analysis of the feces and
      urine samples reflected these findings; OA and Oalpha were found in significant
      concentrations, escaping fermentation in the rumen and in the hindgut. The
      current experiment demonstrates that OA hydrolysis in the gastrointestinal tract
      of sheep is substantially less than previously described, especially if OA is
      ingested in combination with concentrate-rich diets.

PMID- 10340590
TI  - Effects of mimosine and 2,3-dihydroxypyridine on fiber shedding in Angora goats.
AB  - The effects of intravenous infusion of mimosine or 2,3-dihydroxypyridine (2,3
      DHP) and the effects of oral dose level of mimosine on fiber shedding in Angora
      goats were determined. In one experiment, 20 mature Angora wethers (36+/-1.9 kg
      BW) were infused for 2 d with 79, 102, or 135 mg/(kg BW.d) of mimosine, 90 mg/(kg
      BW.d) of 2,3-DHP, or saline. At 7 d after infusion began, fiber shedding was
      observed in all goats receiving mimosine but not in any goats infused with 2,3
      DHP or saline. Fiber shedding varied among goats; in some goats, fiber shedding
      was complete and occurred without hand-plucking, whereas in others fiber was
      retained by nonshed fibers but could be removed by hand-plucking. Nonshed fibers
      were larger in diameter and more likely to be medullated (P < .05) compared with
      hand-plucked fibers. Mean plasma mimosine concentration at 24 and 48 h after
      infusion began was 79 and 98 micromol/L (P < .05), respectively, and greater (P <
      .05) for mimosine infused at 135 than at 102 mg/(kg BW.d) (89, 68, and 108
      micromol/L for mimosine infused at 79, 102, and 135 mg/[kg BW.d], respectively;
      SE 9.5). In another experiment, oral dosing of eight Angora bucks (23+/-.5 kg BW)
      with 400 or 600 mg/kg BW of mimosine rapidly increased plasma mimosine
      concentration, which reached approximately 100 and 160 micromol/L at 5 h after
      dosing; however, periods of time during which plasma mimosine concentrations were
      comparable to those in the first experiment were considerably shorter. Oral
      mimosine dosing did not induce fiber shedding in 7 d. After 31 d, fiber was
      retained by nonshed fibers but could be removed by hand-plucking or could only be
      partially removed with difficulty by hand-plucking. There were no toxic effects
      of mimosine or 2,3-DHP administration; only minor, short-term inhibitions of feed
      intake by mimosine were noted in some goats. In conclusion, mimosine holds
      promise as a safe means to remove fiber of Angora goats; further research is
      necessary to characterize the seasonality of follicle activity and to develop
      convenient means of mimosine delivery.

PMID- 10340591
TI  - Association of cytochrome b5 with 16-androstene steroid synthesis in the testis
      and accumulation in the fat of male pigs.
AB  - The 16-androstene steroids, one of the principal causes of boar taint, are
      synthesized in the testis by the andien-beta synthase enzyme system. This system
      has been shown in vitro to involve both cytochrome P450c17 and cytochrome b5. The
      objective of this work was to investigate the relationship between the levels of
      cytochrome b5 in the testis, in vitro steroidogenesis, and the accumulation of 16
      androstene steroids in the fat of pubertal boars. We found that the in vitro rate
      of 16-androstene steroidogenesis in testis microsomes was correlated with 16
      androstene steroid concentrations in fat (r = .66, P < .01). Western blots were
      used to determine the amounts of cytochrome b5 and cytochrome P450c17 protein in
      testis, and two immunoreactive cytochrome b5 proteins of approximately 12 and 16
      kDa were found. Levels of cytochrome P450c17 or the high molecular weight
      cytochrome b5 in testis were not significantly correlated to levels of 16
      androstene steroids in fat. However, levels of total cytochrome b5 immunoreactive
      protein and levels of the low molecular weight immunoreactive cytochrome b5 were
      correlated to fat 16-androstene steroid concentrations (r = .59, P < .001; r =
      .72, P = .0001, respectively). Levels of the low molecular weight immunoreactive
      cytochrome b5 were also correlated to 16-androstene steroid synthesis rates in
      vitro (r = .62, P < .05). These results indicate that increased levels of a low
      molecular weight immunoreactive cytochrome b5 protein, and not of cytochrome
      P450c17, are related to increased testicular 16-androstene steroid production and
      accumulation in fat. These results support the hypothesis that selection for
      reduced levels of this low molecular weight immunoreactive cytochrome b5 protein
      in the testis may result in decreased levels of 16-androstene steroids in fat and
      reduced boar taint in uncastrated male pigs.

PMID- 10340592
TI  - A radioimmunoassay for porcine intrauterine folate binding protein.
AB  - A RIA was developed for porcine intrauterine folate binding protein (FBP).
      Displacement of [125I]FBP caused by increasing dilutions of uterine flushings
      collected from either d-15 pregnant or nonpregnant gilts or media from culture of
      endometrial tissue from d-15 pregnant or nonpregnant gilts was parallel to the
      displacement caused by the standard curve. Addition of known amounts of purified
      allantoic fluid FBP to dilutions of either intrauterine flushings or endometrial
      culture medium were measured accurately with the RIA. To test specificity, 2-mL
      samples of uterine flushings collected from d-15 pregnant and nonpregnant gilts
      were preincubated with 10 microCi of [3H]folic acid and then chromatographed
      using Sephadex G-100 (Sigma Chemical Co., St. Louis, MO). The fractions were
      subsequently assayed for radioactivity by liquid scintillation spectrophotometry
      and for FBP by RIA. The [3H]folic acid and FBP peaks coincided, indicating that
      the RIA is specific for FBP. Uterine flushings were collected on d 10, 11, 12,
      13, 14, and 15 of the cycle or pregnancy from 1) White crossbred, 2) progesterone
      treated White crossbred (200 mg of progesterone at 48 and 72 h after estrus), and
      3) Meishan gilts and assayed for FBP. Total FBP increased 140-fold from d 10 to
      15, and the pattern of change across day did not differ between pregnant and
      nonpregnant gilts. Progesterone treatment increased intrauterine FBP content on d
      10 and 11. No difference in FBP concentrations was detected between White
      crossbred and Meishan gilts. These results indicate that the RIA for FBP is
      valid, allowing measurement of this protein in uterine flushings and endometrial
      culture medium. The onset of FBP secretion by the uterus between d 10 and 15 of
      the cycle or pregnancy is influenced by the timing of onset of progesterone
      influence in a manner similar to the endometrial proteins uteroferrin and retinol
      binding protein. In contrast to these endometrial proteins, FBP concentrations
      are similar in Meishan and White crossbred gilts.

PMID- 10340593
TI  - Metabolic effects of amylin in lactating goats.
AB  - The objective of this study was to investigate the role of amylin (a pancreatic
      hormone) in regulating metabolism in support of lactation. Rat amylin was infused
      (320 pmol.kg LW(-1).h(-1)) for 6 h via an external pudic (mammary) artery into
      six lactating goats. This dose of amylin led to a sixfold increase in plasma
      concentrations of amylin relative to baseline. Amylin infusion increased plasma
      concentrations (jugular) of glucose and NEFA up to 16 and 168%, respectively,
      relative to saline infusion. In contrast, plasma concentrations of Ca and PO4
      during amylin infusion were reduced by 18 and 30%, respectively, relative to
      saline infusion. Plasma concentrations of IGF-I, insulin, and Mg were not
      different between the two treatments, although IGF-I concentrations in the amylin
      infused group, 1 and 6 h postinfusion, were significantly higher than those in
      the saline-infused group. Similarly, amylin infusion failed to affect milk yield
      and major constituents of milk except protein; milk protein content decreased
      progressively until the end of amylin infusion and remained low thereafter.
      Amylin also had no effect on minerals in milk (Ca, PO4, Mg, Fe, Sr, S, K, or Na)
      except Zn, which was significantly decreased from 56.8+/-5.8 micromol/L at 0 h to
      44.5+/-2.4 micromol/L at 6 h postinfusion. Mammary blood flow (measured with a
      transit-time blood flow probe) increased up to 26% during amylin infusion,
      although this effect lasted only for the first 3 h. In conclusion, amylin
      increased plasma concentrations of glucose and NEFA, and mammary blood flow,
      while decreasing plasma concentrations of Ca and PO4. Despite these metabolic
      changes, amylin infusion did not increase milk yield of lactating goats.

PMID- 10340594
TI  - The brain-pituitary-adipocyte axis: role of leptin in modulating neuroendocrine
      function.
AB  - The recently discovered protein leptin has a molecular mass of 16 kDa, consists
      of 146 amino acids, and is synthesized and secreted by adipose tissue. Leptin
      affects feed intake, the neuroendocrine-axis, and immunological processes. The
      protein was first identified as the gene product that is deficient in the obese
      ob/ob mouse. Leptin serves as a circulating signal of nutritional status and
      plays a pivotal role in regulation of body weight, energy expenditure, growth,
      and reproduction.

PMID- 10340595
TI  - Heat energy for growing goats and sheep grazing different pastures in the summer.
AB  - Angora goat, Spanish goat, and Suffolk x Rambouillet sheep wethers (20 of each
      type; 30.4+/-.57, 31.3+/-.93, and 32.4+/-1.08 kg BW for Angora goats, Spanish
      goats, and sheep, respectively) were used to investigate influences of animal
      type and two grass-based pasture treatments on heat energy during summer grazing
      (mid-August through September in Oklahoma). The improved pasture treatment
      consisted of .7-ha paddocks primarily of Old World bluestem and johnsongrass,
      whereas the native pasture treatment entailed 10.8-ha paddocks dominated by big
      and little bluestems and indiangrass. Grasses were 95 to 100% of diets for the
      improved pasture treatment and 71 to 95% for the native pasture treatment; forbs
      were 2 to 25%, and shrubs were less than 4% of diets for the native pasture
      treatment. Metabolizable energy intake was similar (P > . 10) between pasture
      treatments but differed (P <.01) among animal types: 79, 99, and 113
      kcal/(kg(.75) BW.d) for Angora goats, Spanish goats, and sheep, respectively; SE
      7.1. Heat energy estimated via CO2 entry rate was affected by pasture treatment (
      P = .08) and animal type (P < .001): improved pasture treatment 109, 132, and 151
      kcal/(kg(.75) BW.d); native pasture treatment 126, 138, and 163 kcal/(kg(.75)
      BW.d) for Angora goats, Spanish goats, and sheep, respectively. Likewise,
      daylight grazing time was greater (P = .04) for the native than for the improved
      pasture treatment and differed (P < .01) among animal types: improved pasture
      treatment 5.3, 4.7, and 6.7 h; native pasture treatment 6.0, 5.7, and 8.1 h for
      Angora goats, Spanish goats, and sheep, respectively. In conclusion, heat energy
      during summer grazing of grass-based paddocks was less for goats than for sheep,
      and animal type can affect the increase in heat energy as energy intake and
      grazing time increase.

PMID- 10340596
TI  - Influence of supplemental alfalfa quality on the intake, use, and subsequent
      performance of beef cattle consuming low-quality roughages.
AB  - Three experiments were conducted to evaluate influences of supplemental alfalfa
      quality on intake and use of low-quality meadow grass roughages (MG) by beef
      cattle. In Exp. 1, 15 steers (250 kg) were assigned to three treatments: 1) MG
      (5.2% CP), no supplement; 2) MG plus high-quality alfalfa (18.8% CP); and 3) MG
      plus low-quality alfalfa (15.2% CP). High- and low-quality alfalfa supplements
      were fed at .45 and .55% BW, respectively. Total DMI was greater (P < .01) for
      alfalfa-supplemented steers than for MG. Likewise, intake of digestible DM, DM
      digestibility (DMD), and ruminal ammonia level were greater (P < .01) for
      supplemented steers. In Exp. 2, 96 pregnant Hereford x Simmental cows (537 kg;
      body condition [BC] score 4.86) were assigned to the same treatments as in Exp.
      1. For d 0 to 42, cows grazed on 19.1 ha of stockpiled MG (4,539 kg/ha; 6.8% CP),
      whereas, on d 43 to 84, cows received MG hay (5.2% CP). Supplemented cows gained
      more BW (P < .01), BC score (P < .01), and had heavier calf birth weight (P <
      .01) than nonsupplemented cows. However, there were no treatment effects (P >
      .10) on cow cyclicity, pregnancy rate, or calving interval. In Exp. 3, 90
      pregnant Angus x Hereford cows (475 kg; BC score 4.59) were assigned to three
      treatments: 16.1%, 17.8% or 20.0% CP alfalfa supplement, with levels of .63, .55,
      and .50% of BW, respectively. Weight gain and BC score for the 84-d study
      displayed a quadratic response (P < .10), yet represented only 7 kg BW and .2
      units of BC score. In conclusion, alfalfa hay supplementation was effective in
      increasing DMI and digestibility. However, alfalfa hay quality did not
      dramatically affect BW, BC score, and(or) calf birth weight, when fed on an
      isonitrogenous basis.

PMID- 10340597
TI  - Tissue distribution of a peptide transporter mRNA in sheep, dairy cows, pigs, and
      chickens.
AB  - A 446-bp cDNA fragment encoding a peptide transport protein was cloned from sheep
      omasum and used as a probe to study the distribution of the peptide transport
      protein mRNA in various tissues of sheep, dairy cows, pigs, and chickens. Because
      the predicted amino acid sequence of this fragment was 85.8, 90.5, and 90.5%
      identical to rabbit, human, and rat intestinal peptide transporter (PepT1),
      respectively, it is believed that this cloned fragment represents PepT1 from
      sheep. In sheep (n = 5) and lactating Holstein cows (n = 3), hybridization was
      observed with mRNA from the omasum, rumen, duodenum, jejunum, and ileum. The
      estimated size of mRNA was 2.8 kb. No hybridization was observed with mRNA from
      the abomasum, cecum, colon, liver, kidney, and semitendinosus and longissimus
      muscles of either species or the mammary gland of the dairy cows. In pigs (n =
      6), the probe hybridized with mRNA from the duodenum, jejunum, and ileum. There
      was no hybridization with mRNA from the stomach, large intestine, liver, kidney,
      and semitendinosus and longissimus muscles. Two bands, 3.5 and 2.9 kb, were
      observed with northern blot analysis, indicating two RNA transcripts that may
      result from alternative mRNA processing. In White Leghorns (n = 15) and broilers
      (n = 20), the strongest hybridization was found in the duodenum, but the jejunum
      and ileum showed faint bands. The size of mRNA in chickens was 1.9 kb. Other
      tissues, including the crop, proventriculus, gizzard, ceca, liver, kidney, and
      muscles showed no hybridization to the probe. In conclusion, mRNA for PepT1 is
      present in the small intestine of all animals examined and the omasal and ruminal
      epithelium of sheep and dairy cows. The size of the mRNA varied among species.

PMID- 10340598
TI  - Dietary protein and chromium tripicolinate in Suffolk wether lambs: effects on
      production characteristics, metabolic and hormonal responses, and immune status.
AB  - Thirty-two Suffolk wether lambs were fed for 84 d in a 2 x 2 factorial experiment
      using two levels of dietary protein (9.0 to 12.1% CP, low protein, LP; or 12.8 to
      14.4% CP, high protein, HP) and supplemental Cr (none, C; or 400 ppb Cr as
      chromium tripicolinate, Cr). At 14- to 21-d intervals, lambs were weighed, and
      jugular blood samples were collected. Mean ADG and carcass weight (P > .10) did
      not differ. In lambs fed HP, Cr reduced liver weight and increased kidney weight
      (P < .01). Lambs fed HP had elevated plasma urea N (PUN; P < .01) and albumin (P
      < .04). During an i.v. epinephrine challenge on d 43, plasma cortisol declined in
      lambs fed Cr (Cr x time, P < .03) and in lambs fed LP (CP x time, P < .001). An
      i.v. glucose tolerance test conducted 3 h later showed that supplemental Cr
      decreased glucose clearance rate in lambs fed HP (CP x Cr, P < .10) but not in
      lambs fed LP. On d 62, PUN was increased in lambs fed HP (P < .001) between 0 and
      3 h postprandial, and there was a Cr x CP interaction (P < .04). Postprandial
      plasma NEFA declined with Cr vs C (Cr x time, P < .07) and with HP vs LP (CP x
      time, P < .10). By d 66, lambs fed Cr had an elevated (P < .03) blood platelet
      and fibrinogen content. Chromium increased erythrocyte count in lambs fed HP (Cr
      x CP, P < .08), and isolated peripheral lymphocytes had greater blastogenic
      response to 4 microg/mL of phytohemagglutinin (Cr x CP, P < .001). The lymphocyte
      response to pokeweed mitogen (.2 microg/mL) was reduced in lambs fed Cr (P <
      .10). In the present experiment, Cr supplementation had minimal and inconsistent
      effects on production and metabolic criteria of lambs.

PMID- 10340599
TI  - Effects of increasing ruminally degraded nitrogen and abomasal casein infusion on
      net portal flux of nutrients in yearling heifers consuming a high-grain diet.
AB  - Seven Meat Animal Research Center (MARC) III heifers (410+/-25 kg) fitted with
      hepatic portal, mesenteric venous, carotid catheters, and an abomasal cannula
      were used in a 7 x 5 incomplete Latin square design experiment. The objective was
      to evaluate the effects of increasing levels of ruminally degradable N (RDN) with
      or without the addition of abomasally infused casein on portal-drained visceral
      (PDV) flux of nutrients. Treatments consisted of dietary CP percentage levels of
      9.5 (control), control plus .72% dietary urea (11.5U), control plus 1.44% dietary
      urea (13.5U), control plus abomasally infused casein (250 g/d; 11.5C), or control
      plus .72% dietary urea and abomasally infused casein (250 g/d; 13.5UC). All diets
      contained (DM basis) 80% ground corn, 15% corn silage, and 5% dry supplement and
      were provided for ad libitum consumption. Nitrogen intake increased (linear, P <
      .001) as CP increased from 9.5 to 13.5%. Portal-drained visceral release of
      ammonia N increased (linear, P < .10) as RDN increased, and was greater (P < .05)
      when protein was fed compared with heifers fed control (P < .10). Urea N removal
      by PDV was not affected ( P > . 10) by level of RDN but was greatest when 11.5C
      was fed and least when 13.5UC was fed. Net alpha-amino N (AAN) release by PDV was
      greatest when 13.5UC was fed (309 mmol/h), least when 9.5% CP was fed (112
      mmol/h), and intermediate for the other groups (205 to 252 mmol/h). These data
      suggest that removal of N by the PDV may promote microbial protein synthesis when
      dietary RDN is low. When RDN needs have been met and amino acids are deficient
      for the host, escape protein should be fed to increase amino acid absorption.

PMID- 10340600
TI  - Use of Internet-based resources to support an introductory animal and poultry
      science course.
AB  - This article describes the development and implementation of a World Wide Web
      page to support a team-taught introductory animal and poultry science course. The
      objectives were to examine the capabilities of this type of instructional
      resource, determine students' willingness to use this type of resource, create
      opportunities for interactive learning, and improve students' enthusiasm for the
      subject area. A variety of course materials were made available through the
      Internet, including the class syllabus, lecture notes, and practice questions to
      support and augment class lectures. Additional on-line resources included a
      bulletin board for instructor announcements, a list-serve for student discussions
      concerning administrative and educational issues arising during the semester, a
      class E-mail list, and a page with links to other sites of agricultural interest.
      Materials were accessible from a variety of computer resources, including campus
      computing laboratories, dial-up access, and access via other Internet service
      providers. Use of the materials was evaluated by analysis of log files from the
      server. Effectiveness of the resources was determined from surveys of students
      conducted before and after implementation of the on-line resource. Students
      indicated that the most useful components of the Web page were the class notes
      and practice/review questions. Effectiveness of the site was related to the
      amount of material available through the site, the level of interaction, whether
      the task was required, and the ease of access to computers and the Web site.
      Student evaluations indicated that this form of instructional supplement is a
      viable method for enhancing the learning experience in the introductory animal
      sciences.

PMID- 10340601
TI  - Design and semisynthesis of spermine-sensitive Ribonuclease S'.
AB  - Spermine-sensitive stabilization of semisynthetic Ribonuclease S' was
      successfully carried out by sequence specific incorporation of a poly-anion
      domain into alpha-helix region of S-peptide.

PMID- 10340602
TI  - Synthesis and biological activities of topoisomerase I inhibitors, 6-N-amino
      analogues of NB-506.
AB  - 6-N-Amino analogues of NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13
      (beta-D-glucopyranosyl) -5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione]
      (3b) were synthesized and tested with respect to topoisomerase inhibition,
      cytotoxicity and anticancer effects. Among them, a 1,3-dihydroxypropane analogue
      (J-109,404, 5t) showed more than ten times more potent anticancer activity in MKN
      45 human stomach cancer cells implanted in mice than NB-506.

PMID- 10340603
TI  - Dienyl diketones as anticancer agents: synthesis and biological evaluation of
      some aromatic derivatives.
AB  - Aiming to develop anticancer agents, synthesis and in vitro evaluation of
      aromatic dienyl diketone derivatives were carried out. All the aromatic (Z.E)
      dienyl diketones synthesized exhibit strong in vitro inhibition of tumor cell
      growth against Colon cell line.

PMID- 10340604
TI  - Solution-phase and solid-phase synthesis of novel transition state inhibitors of
      coagulation enzymes incorporating a piperidinyl moiety.
AB  - 2-Amino-3-piperidin-4-yl-propionic acid containing peptidomimetics are potent
      protease inhibitors when combined with an appropriate keto-thiazole or keto
      carboxylic acid moiety. A novel P1 residue in factor Xa and thrombin inhibitors
      has been found resulting in IC50 values as low as 0.048 microM, a factor of ten
      more potent than Argatroban. Starting with non-chiral synthetic routes, a new
      stereospecific route was developed as well as a new solid-phase method.

PMID- 10340605
TI  - Synthesis and evaluation of geldanamycin-estradiol hybrids.
AB  - Geldanamycin (GDM) binds to the Hsp90 chaperone protein and causes the
      degradation of several important signalling proteins. A series of novel estradiol
      geldanamycin hybrids has been synthesized and evaluated for their ability to
      induce the selective degradation of the estrogen receptor (ER). The hybrid
      compounds are active and more selective than the parent causing degradation of ER
      and HER2, but not other GDM targets.

PMID- 10340606
TI  - A new solid-phase support for oligonucleotide synthesis.
AB  - An alternative solid support for oligonucleotide synthesis was developed by
      coupling a polymer colloid to a modified polyethylene filter disc. The functions
      on the polymer colloid not used for attachment to the surface were derivatized
      with a Jeffamine diamine and loaded with appropriate deoxynucleoside succinates.
      The performance of this support system was evaluated and compared to existing
      resins.

PMID- 10340607
TI  - Anabaenopeptins G and H, potent carboxypeptidase A inhibitors from the
      cyanobacterium Oscillatoria agardhii (NIES-595).
AB  - Anahaenopeptins G (1) and H (2) were isolated from the cultured cyanobacterium
      Oscillatoria agardhii (NIES-595) as potent carboxypeptidase A (CPA) inhibitors.
      The gross structure of 1 and 2 were established by spectroscopic analysis
      including the 2D NMR technique and the absolute configurations of 1 and 2 were
      determined by the spectral and chemical methods. 1 and 2 inhibited CPA with
      IC50's of 0.0018 and 3.4 microg/mL, respectively.

PMID- 10340608
TI  - Synthesis of diether-linked cationic lipids for gene delivery.
AB  - Quaternary ammonium lipids 1b-d, with diether linkages between hydrocarbon chains
      and butane or hexane backbone, were synthesized for cationic liposome-mediated
      gene delivery. The synthetic strategy of using C-4 or C-6 synthon permits the
      achievement of the variation of the hydrophobic domain as well as changes of
      space between the quaternary ammonium head and the hydrophobic domain in the
      diether-linked cationic lipids.

PMID- 10340609
TI  - L-770,644: a potent and selective human beta3 adrenergic receptor agonist with
      improved oral bioavailability.
AB  - L-770,644 (9c) is a potent and selective agonist of the human beta3 adrenergic
      receptor (EC50 = 13 nM). It shows good oral bioavailability in both dogs and rats
      (%F = 27), and is a full agonist for glycerolemia in the rhesus monkey (ED50 =
      0.21 mg/kg). Based on its desirable in vitro and in vivo properties, L-770,644
      was chosen for further preclinical evaluation.

PMID- 10340610
TI  - Isotope edited NMR studies of glycosidases: design and synthesis of a novel
      glycosidase inhibitor.
AB  - N-13C-methyl-deoxynojirimycin was synthesized and used in isotope-edited NMR
      studies to probe the binding site of an alpha-glucosidase. Results from this
      analysis led to the design and preparation of a novel alpha-glucosidase
      inhibitor, N-glycyl deoxynojirimycin.

PMID- 10340612
TI  - Bioreductively-activated prodrugs for targeting hypoxic tissues: elimination of
      aspirin from 2-nitroimidazole derivatives.
AB  - 2-Nitroimidazoles were synthesised substituted with aspirin or salicylic acid, as
      leaving groups linked through the (imidazol-5-yl)methyl position. Activation of
      aqueous solutions by CO2*- (a model one-electron reductant) resulted in release
      of aspirin or salicylate, probably via the 2-hydroxyaminoimidazole. The analogous
      2-nitroimidazole with bromide as leaving group eliminated bromide in < 1 ms via
      the radical-anion.

PMID- 10340611
TI  - Synthesis and biological activities of spiroheterocyclic growth hormone
      secretagogues.
AB  - The synthesis and biological activities of a series of spiroheterocyclic growth
      hormone secretagogues are reported. Modification of the spiroindane part
      structure of the prototypal secretagogue L-162,752 revealed that the spiroindane
      could be replaced with spirobenzodihydrothiophen derivatives to enhance not only
      in vitro potency but also oral activity. In this study non-aromatic D-2-amino-4
      cyclohexylbutanoic analogs (8a-8d) were also identified to be active
      secretagogues.

PMID- 10340613
TI  - Inhibition of human telomerase by PNA-cationic peptide conjugates.
AB  - The inhibition of human telomerase has been explored using peptide conjugated
      derivatives of a PNA pentamer directed at the RNA template of telomerase. It is
      demonstrated that the presence of cationic peptides at the N-terminus of the PNA
      results in enhanced inhibition of telomerase activity. Furthermore, inhibition
      depended on the specificity of PNA recognition.

PMID- 10340614
TI  - Macrocyclic hydroxamate inhibitors of matrix metalloproteinases and TNF-alpha
      production.
AB  - Several macrocyclic, hydroxamate derivatives were synthesized and evaluated as
      inhibitors of matrix metalloproteinases (MMPs) and tumour necrosis factor-alpha
      (TNF-alpha) production. These macrocycles are anti-succinate based inhibitors
      linked from P1 to P2'. A variety of functionality was installed at the P1-P2'
      linkage, which gave inhibitors that displayed excellent MMP inhibition and good
      TNF-alpha suppression.

PMID- 10340616
TI  - Synthesis and in vitro and in vivo evaluation of the 2-(6'methoxy-3',4'-dihydro
      1'-naphtyl)-4H-3,1-benzoxazin-4- one as a new potent substrate inhibitor of human
      leukocyte elastase.
AB  - The title 2-vinyl-4H-3,1-benzoxazin-4-one has been synthesised and tested for
      inhibitory activity against human leukocyte elastase. The compound has shown
      activity both in vitro towards human sputum elastase and in vivo in an
      hemorrhagic assay.

PMID- 10340615
TI  - 4-N-linked-heterocyclic piperidine derivatives with high affinity and selectivity
      for human dopamine D4 receptors.
AB  - The syntheses of a number of different N-linked heterocyclic pyrazole
      replacements based on the structure 1 are described (compounds 3-12) as hD4
      ligands. After further optimisation the best compound identified was 13 which has
      high affinity for hD4 (5.2 nM) and >300-fold selectivity for hD4 receptors over
      hD2 and hD3 receptors.

PMID- 10340617
TI  - New growth hormone secretagogues: C-terminal modified sulfonamide-analogues of
      NN703.
AB  - The C-terminal the orally active growth hormone secretagogue NN703 was changed to
      prepare analogues with inverse sulfonamides and inverse amides. The compounds
      showed high activity in a in vitro rat pituitary model.

PMID- 10340618
TI  - Novel bisbenzamidines and bisbenzimidazolines as noncompetitive NMDA receptor
      antagonists.
AB  - A series of novel bisbenzamidines and bisbenzimidazolines with different linkers
      connecting the aromatic groups was tested in vitro for NMDA receptor antagonist
      activity. IC50 values for these compounds ranged from 1.2 to >200 microM. The
      bisbenzamidine with a homopiperazine ring as the central linker was found to be
      the most potent NMDA receptor antagonist among all the pentamidine analogues
      tested so far.

PMID- 10340619
TI  - New technique for high-throughput synthesis.
AB  - A new technique for high throughput solid phase synthesis using the centrifuge
      based liquid removal from readily available standard microtiterplates is
      described. This technique eliminates the filtration step and is therefore
      applicable to simultaneous processing of an unlimited number of reaction
      compartments. Its application is illustrated on the synthesis of an array of 380
      tetrahydroisoquinolinones.

PMID- 10340620
TI  - Nonpeptide oxytocin antagonists: analogs of L-371,257 with improved potency.
AB  - Structure-activity studies on the oxytocin antagonist 1 (L-371,257; Ki = 9.3 nM)
      have led to the identification of a related series of compounds containing an
      ortho-trifluoroethoxyphenylacetyl core which are orally bioavailable and have
      significantly improved potency in vitro and in vivo, e.g., compound 8 (L-374,943;
      Ki = 1.4 nM).

PMID- 10340621
TI  - Optimisation of the P2 pharmacophore in a series of thrombin inhibitors: ion
      dipole interactions with lysine 60G.
AB  - The optimisation of the P2 pharmacophore in a series of thrombin inhibitors is
      described. The interaction of a number of piperidine P2 functionalities with
      lysine 60G of thrombin is explored with reference to the crystal structure of
      inhibitor enzyme complexes. A primary ion-dipole interaction between the terminal
      P2 side chain group and lysine 60G is evoked to explain the SAR in this series.

PMID- 10340622
TI  - Synthesis of novel analogues of the delta opioid ligand SNC-80 using REM resin.
AB  - Focused libraries of delta opioid ligands were synthesised using REM resin
      methodology. Several high affinity compounds were identified with good
      selectivity over the mu opioid receptor. Automated REM resin recycling was used
      to synthesise larger amounts of ligand for in vivo studies.

PMID- 10340623
TI  - Synthesis of novel analogues of the delta opioid ligand SNC-80 using AlCl3
      promoted aminolysis.
AB  - Two focused libraries of delta opioid ligands were synthesised using AlCl3
      facilitated aminolysis. Several compounds were identified with DOR binding
      affinities higher or similar to SNC-80. A novel acyclic derivative of SNC-80
      produced antinociception in the acetic acid abdominal constriction test, which is
      at least partially mediated via the delta-opioid receptor.

PMID- 10340624
TI  - 4-Alkyl- and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinolines: potent,
      nonsteroidal androgen receptor agonists.
AB  - A series of human androgen receptor (hAR) agonists based on 4-alkyl-; 4,4-dialkyl
      ; and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinoline was synthesized
      and evaluated in competitive receptor binding assays and an androgen receptor
      cotransfection assay in a mammalian cell background. A number of compounds in
      this series demonstrated activity equal to or better than dihydrotestosterone in
      both assays and represent a novel class of compounds for use in androgen
      replacement therapy.

PMID- 10340625
TI  - Neuroprotective effects of riluzole: an electrophysiological and histological
      analysis in an in vitro model of ischemia.
AB  - The protective effects of riluzole against the neuronal damage caused by O2 and
      glucose deprivation (ischemia) was investigated in rat cortical slices by
      recording electrophysiologically the cortico-cortical field potential and by
      evaluating histologically the severity of neuronal death. Five minutes of
      ischemia determined an irreversible depression of the amplitude of the field
      potential. In addition, this insult caused a clear enhancement of the number of
      death cells that were specifically colored with trypan blue (a vital colorant
      which stains altered cells). We found that riluzole, which by itself depressed
      the synaptic transmission, neuroprotected when perfused 15-20 min before and
      during ischemia. In fact, due to the treatment with riluzole, the ischemia
      induced irreversible depression of the field potential recovered and less cells
      were stained with trypan blue. These findings demonstrate that riluzole prevents
      neuronal death in an in vitro model of ischemia and suggest a therapeutic use of
      this drug in order to reduce the pathophysiological outcomes of stroke.

PMID- 10340626
TI  - Neurotensin receptors and dopamine transporters: effects of MPTP lesioning and
      chronic dopaminergic treatments in monkeys.
AB  - The effect of denervation with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
      (MPTP) of the dopamine (DA) nigrostriatal pathway on neurotensin (NT) receptor
      and DA transporter (DAT) in basal ganglia of monkeys (Macaca fascicularis) was
      investigated. The MPTP lesion induced a marked depletion of DA (90% or more vs.
      control) in the caudate nucleus and putamen. The densities of NT agonist binding
      sites labeled with [125I]NT and the NT antagonist binding sites labeled with
      [3H]SR142948A decreased by half in the caudate-putamen of MPTP-monkeys. In
      addition, the densities of [125I]NT and [3H]SR142948A binding sites markedly
      decreased (-77 and -63%, respectively) in the substantia nigra of MPTP-monkeys.
      Levocabastine did not compete with high affinity for [125I]NT binding in the
      monkey cingulate cortex, suggesting that only one class of NT receptors was
      labelled in the monkey brain. An extensive decrease of [3H]GBR12935 DAT binding
      sites (-92% vs. Control) was observed in the striatum of MPTP-monkeys and an
      important loss of DAT mRNA(-86% vs. Control) was observed in substantia nigra.
      Treatments for 1 month with either the D1 agonist SKF-82958 (3 mg/kg/day) or the
      D2 agonist cabergoline (0.25 mg/kg/day) had no effect on the lesion-induced
      decrease in NT and DAT binding sites or DAT mRNA levels. The decrease of striatal
      NT binding sites was less than expected from the decrease of DA content in this
      nucleus, suggesting only partial localization of NT receptors on nigrostriatal
      DAergic projections. These data also suggest that under severe DA denervation,
      treatment with D1 or D2 DA agonists does not modulate NT receptors and DAT
      density.

PMID- 10340627
TI  - GABA(A) and GABA(B) antagonists differentially affect the firing pattern of
      substantia nigra dopaminergic neurons in vivo.
AB  - The effects of local pressure application of the selective GABA(A) antagonists,
      bicuculline, gabazine, and picrotoxin, and the selective GABA(B) antagonists, 2
      OH-saclofen and CGP-55845A, on the spontaneous activity of electrophysiologically
      identified substantia nigra dopaminergic neurons were recorded in vivo in
      urethane anesthetized rats. Blockade of GABA(A) inputs by bicuculline powerfully
      and reversibly induced burst firing in dopaminergic neurons along with a modest
      (25%) increase in firing rate, but the increase in burst firing was not
      correlated with the increase in firing rate. Picrotoxin and gabazine also
      produced an increase in burst firing without an increase in firing rate. In
      contrast, local application of GABA(B) antagonists did not produce bursting but
      rather caused a modest shift to a more regular firing pattern in 50% of the
      cases. These data demonstrate that dopaminergic neurons in vivo are under tonic
      GABAergic inhibition mediated by GABA(A) receptors and suggest that GABAergic
      afferents to substantia nigra comprise a major pathway by which the firing
      pattern of dopaminergic neurons is controlled in vivo.

PMID- 10340629
TI  - Engagement in a non-escape (displacement) behavior elicits a selective and
      lateralized suppression of frontal cortical dopaminergic utilization in stress.
AB  - Although the preferential activation of the prefrontal cortical (PFC)
      dopaminergic system is generally observed in stress, limited exceptions to this
      have been observed. Certain non-escape behaviors have been demonstrated to
      attenuate physiological indices of stress (e.g., coping or displacement
      responses). One well-characterized non-escape behavior observed in stress is
      chewing, or gnawing, of inedible objects. Engagement in this behavior attenuates
      stress-related activation of the hypothalamopituitary-adrenal axis, in a variety
      of species. We examined the degree to which engagement in this non-escape
      behavior modulates stressor-induced activation of the PFC dopamine (DA) system.
      Rats and mice were exposed to a brightly lit novel environment (novelty stress)
      in the presence or absence of inedible objects. Following novelty exposure,
      various dopaminergic terminal fields were collected and dopamine and its major
      catabolite, DOPAC, were measured using HPLC with electrochemical detection.
      DOPAC/DA ratios were calculated as an index of DA utilization. In some cases
      serotonin (5-HT) and its major catabolite, 5-HIAA, were also measured. In animals
      that did not chew, novelty exposure elicited significant increases in DOPAC/DA
      levels within PFC, nucleus accumbens (shell and core subdivisions), and striatum
      (relative to quiet-controls). DOPAC/DA responses were greater in the right PFC
      than in the left PFC. Animals that chewed displayed significantly lower DOPAC/DA
      responses in PFC, but not other dopaminergic terminal fields. This effect of
      chewing was always observed in the right PFC and less consistently in the left
      PFC. Chewing did not alter novelty-induced increases in PFC 5-HIAA/5-HT
      responses. Thus, engagement in this non-escape behavior elicits a
      neuroanatomically and neurochemically specific attenuation of the PFC DA response
      in stress. Given the pivotal role of the PFC in certain cognitive and affective
      processes, behavioral regulation of PFC DA utilization may modulate cognitive
      and/or affective function in stress.

PMID- 10340628
TI  - Origin of the serotonergic innervation to the rat dorsolateral hypothalamus:
      retrograde transport of cholera toxin and upregulation of tryptophan hydroxylase
      mRNA expression following selective nerve terminals lesion.
AB  - The regulation of serotonin synthesis was investigated in the serotonergic
      neurons, which provide afferents to the dorsolateral hypothalamus (DLH). The
      origin of the DLH projection neurons within the raphe nucleus was identified by
      retrograde transport of Cholera toxin (CTb) and their serotonergic nature
      confirmed by tryptophan hydroxylase (TPH) immunocytochemistry. Disruption of
      serotonin synthesis steady-state was induced unilaterally by a selective and
      local destruction of serotonergic nerve terminals with 5,7-dihydroxytryptamine
      (5,7-DHT), stereotaxically injected in the right DLH. The results show that most
      of the serotonergic dorsal raphe neurons projecting to the DLH have an
      ipsilateral localization within the lateral aspects of the nucleus. In rats with
      unilateral DLH lesion, a population of serotonergic cells within the raphe
      nucleus exhibited a clear increase in TPH mRNA. These cells were about five times
      more numerous in the ipsilateral as compared to the contralateral dorsal raphe
      nucleus and they had, for the most part, a lateral localization within the raphe
      nucleus. Sham-operated rats did not exhibit any upregulation of TPH mRNA.
      Together, the present results provide the first demonstration that a discreet and
      selective destruction of serotonergic terminals induces a circumscribed and
      striking increase in TPH mRNA expression in a subset of brainstem serotonergic
      neurons projecting to and/or passing through the DLH. On the basis of these
      results and previous in vivo measurements of TPH activity (e.g., 5-HT synthesis),
      we suggest that this upregulation in TPH mRNA expression results from the loss of
      pre-synaptic and/or post-synaptic regulation of serotonin synthesis. These new
      findings raise important issues related to the repercussions of a local
      disruption in serotonergic neurotransmission on brain areas remote from the site
      of injury.

PMID- 10340630
TI  - Venlafaxine: discrepancy between in vivo 5-HT and NE reuptake blockade and
      affinity for reuptake sites.
AB  - Using an in vivo electrophysiological paradigm, venlafaxine and paroxetine
      displayed similar potency for suppressing the firing activity of dorsal raphe 5
      HT neurons (ED50: 233 and 211 microg/kg i.v., respectively), while venlafaxine
      was three times less potent than desipramine (ED50: 727 and 241 microg/kg i.v.,
      respectively) to suppress the firing activity of locus coeruleus NE neurons. The
      selective 5-HT1A receptor antagonist WAY 100635 (100 microg/kg, i.v.) reversed
      the suppressant effect of venlafaxine and paroxetine on the firing activity of 5
      HT neurons and the alpha2-adrenoceptor antagonist piperoxane (1 mg/kg, i.v.)
      reversed those of venlafaxine and desipramine on the firing activity of NE
      neurons. The ED50 of venlafaxine on the firing activity of 5-HT neurons was not
      altered (ED50: 264 microg/kg) in noradrenergic-lesioned rats, while the
      suppressant effect of venlafaxine on the firing activity of NE neurons was
      greater in serotonergic-lesioned rats (ED50: 285 microg/kg). Taken together,
      these results suggest that, in vivo, venlafaxine blocks both reuptake processes,
      its potency to block the 5-HT reuptake process being greater than that for NE.
      Since the affinities of venlafaxine for the 5-HT and NE reuptake carriers are not
      in keeping with its potencies for suppressing the firing activity of 5-HT and NE
      neurons, the suppressant effect of venlafaxine on the firing activity of 5-HT and
      NE neurons observed in vivo may not be mediated solely by its action on the
      [3H]cyanoimipramine and [3H]nisoxetine binding sites. In an attempt to unravel
      the mechanism responsible for this peculiarity, in vitro superfusion experiments
      were carried out in rat brain slices to assess a putative monoamine releasing
      property for venlafaxine. (+/-)Fenfluramine and tyramine substantially increased
      the spontaneous outflow of [3H]5-HT and [3H]NE, respectively, while venlafaxine
      was devoid of such releasing properties.

PMID- 10340631
TI  - MK-801 interaction with the 5-HT transporter: a real-time study in brain slices
      using fast cyclic voltammetry.
AB  - The effects of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist
      dizocilpine ((+)-MK-801) and a competitive NMDA antagonist, (+/-)-3-2
      carboxypiperazin-4-yl-propyl-1-phosphonic acid (CPP) were compared in
      electrically evoked 5-HT release in the brain slices incorporating the substantia
      nigra pars reticulata (SNr) or the dorsal raphe nucleus (DRN) using fast cyclic
      voltammetry (FCV). Electrical stimulation of either the SNr or the DRN with 50
      pulses at frequencies greater than 10 Hz generated signals that were
      indistinguishable from 5-HT. In the SNr, 0.6-60 microM MK-801 concentration
      dependently potentiated stimulated 5-HT release. CPP 20 microM or NMDA 100 microM
      had no effect on 5-HT release evoked by electrical stimulation. In the SNr, 1
      microM fluvoxamine or 0.6-60 microM MK-801 potentiated electrically evoked
      release of 5-HT. Pre-exposure to 20 microM MK-801 inhibited the enhancing effects
      of 1 microM fluvoxamine on electrically evoked 5-HT release in the SNr. In the
      DRN, the presence of 1 microM fluvoxamine or 20 microM MK-801 weakly potentiated
      5-HT release. In the presence of 1 microM methiothepin (a nonselective 5-HT1-2
      antagonist), 1 microM fluvoxamine or 20 microM MK-801 were equipotent in
      potentiating the concentration of 5-HT released in response to electrical
      stimulation. The T1/2 values for 5-HT release following MK-801 or fluvoxamine
      administration were significantly increased. Potentiation of 5-HT release by MK
      801 in the SNr and the DRN and lack of effect of either CPP or NMDA on 5-HT
      release or uptake argues against a role for NMDA receptors in modulation of 5-HT
      release. Inhibition of fluvoxamine induced potentiation of 5-HT signal in the
      presence of MK-801 suggests that MK-801 and fluvoxamine may interact at the level
      of the 5-HT transporter.

PMID- 10340632
TI  - Cocaine-induced alterations in the density of monoaminergic receptors in the
      embryonic guinea pig cerebral wall.
AB  - Quantitative receptor autoradiography was used to examine the effect of chronic
      cocaine exposure on the density of alpha1-, alpha2- and beta-adrenergic, 5-HT1A-
      and 5-HT2-serotonergic, and D1- and D2-dopaminergic receptors in the fetal guinea
      pig cerebral wall which contained forming motor area of the cerebral cortex. The
      pregnant guinea pig received two daily subcutaneous injections of 20 mg/kg
      cocaine beginning on the 20th day of pregnancy (E20). The control animals
      received injections of equivalent volume of saline. The receptor densities were
      examined between days 5-30 of the treatment, which corresponds to E25-E50. By the
      fifth day of treatment (E25), cocaine produced downregulation of all receptors
      studied throughout the entire depth of the fetal cerebral wall. More extended
      treatment, however, resulted in recovery of receptor levels. Finally, from days
      20-30 of treatment (E40-E50) there was a significant upregulation of
      noradrenergic and dopaminergic receptor sites. These findings demonstrate that
      exposure to cocaine in utero can influence adrenergic, serotonergic, and
      dopaminergic receptors in the embryonic cerebral wall, which may lead to
      alteration in corticogenesis. Furthermore, the present study reveals that, in the
      course of chronic treatment, cocaine may completely reverse its receptor
      regulatory activity in the fetal brain.

PMID- 10340634
TI  - Osteoporosis: current approaches and future prospects in diagnosis, pathogenesis,
      and management.
AB  - This review summarizes some of the major advances in our understanding and
      management of osteoporosis. Bone densitometry is the key to diagnosis but has
      limitations. Ultrasound and peripheral densitometry may provide new, rapid
      screening tools. Biochemical markers may provide an assessment of fracture risk
      as well as the response to therapy. Studies of the genetics of ostoporosis may
      also provide new approaches to diagnosis. The interactions between local and
      systemic factors, particularly between estrogen, cytokines, and prostaglandins,
      have suggested a mechanism for bone loss in rodent models. Nutritional deficits
      of calcium, vitamin D, and vitamin K may play a role in pathogenesis. Therapy is
      largely based on fracture prevention with calcium, vitamin D, and exercise
      programs, coupled with antiresorptive therapy. New approaches involving anabolic
      agents are under development. Our goal must be to increase our understanding of
      pathogenesis and to develop new cost-effective therapeutic agents as rapidly as
      possible so as to prevent an epidemic of osteoporotic fractures throughout the
      world in the next millennium.

PMID- 10340633
TI  - Differential effect of immobilization stress on in vivo synthesis rate of
      monoamines in medial prefrontal cortex and nucleus accumbens of conscious rats.
AB  - We have used microdialysis to measure the in vivo hydroxylation level of tyrosine
      and tryptophan in the medial prefrontal cortex and nucleus accumbens of conscious
      rats that were subjected to immobilization. The brain was perfused with an
      inhibitor of aromatic L-amino acid decarboxylase, 3-hydroxybenzylhydrazine, and
      the amount of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP)
      accumulating in the dialysate was measured as an index of the in vivo
      hydroxylation rate of tyrosine and tryptophan. One hour of immobilization caused
      a significant increase in extracellular DOPAin the medial prefrontal cortex but
      not nucleus accumbens. The same manipulation produced a significant and more
      prolonged elevation in extracellular 5-HTP in the nucleus accumbens as well as
      medial prefrontal cortex. The observed profile of stress-induced 5-HTP response
      was comparable in two brain regions. The results suggest that in vivo
      catecholamine synthesis is heterogenous, whereas in vivo serotonin synthesis is
      homogenous, with respect to responsiveness to stress in the medial prefrontal
      cortex and nucleus accumbens.

PMID- 10340635
TI  - Why do bone strength and "mass" in aging adults become unresponsive to vigorous
      exercise? Insights of the Utah paradigm.
AB  - Trauma excepted, muscle forces cause the largest loads on bones and the largest
      bone strains. In children, steadily increasing muscle strength increases bone
      loads and strains above a modeling threshold, which allows modeling to increase
      bone strength and "mass" and conservation-mode remodeling to retain existing
      bone. As a result, bone strength and "mass" both increase. In young adults,
      muscle strength plateaus, so bone strength can increase enough to reduce strains
      below the modeling threshold, turn modeling off, and also plateau. Those strains
      still exceed the lower remodeling threshold, so conservation-mode remodeling
      retains existing bone. Most aging adults lose momentary muscle strength, so their
      bone strains fall toward the remodeling threshold. That drop leaves modeling off
      and switches remodeling to its disuse mode to begin removing bone next to marrow,
      contributing to the well-known age-related loss of bone. Although "vigorous"
      exercise by aging adults can raise strains above the remodeling threshold to turn
      conservation-mode remodeling back on and reduce or stop further bone losses,
      causing the much larger strains needed to reach or exceed the modeling threshold
      would require larger increases in momentary muscle strength and muscle mass than
      most such adults could achieve. Thus, exercises that can readily increase bone
      strength and "mass" in children and adolescents (in whom modeling is already
      turned on) only seem to reduce bone loss in aging adults. This difference makes
      their bones seem partly unresponsive to physical exercise. This effect would
      occur in addition to possible nonbiomechanical explanations that others have
      suggested for the phenomenon.

PMID- 10340636
TI  - Reversibility of alendronate-induced contraction in human osteoclast-like cells
      formed from bone marrow cells in culture.
AB  - Alendronate is a powerful therapeutic agent for the treatment of hypercalcemia in
      malignancy and osteoporosis and has recently been developed as a treatment for
      hypercalcemia of malignancy. In this study, time-lapse cinemicrography was used
      to investigate the effects of this agent on the morphology and the motility of
      human osteoclast-like multinucleated cells (MNCs) from human bone marrow.
      Alendronate at 10(-5)M induced contraction of the cells starting 7.5 h after its
      addition. Contraction was markedly induced immediately after alendronate removal.
      However, contraction almost disappeared 18h after removal, and osteoclast-like
      MNCs recovered their original sizes and shape. There was only partial recovery
      from contraction after alendronate treatment at 10(-4)M. In contrast, untreated
      control cells did not change their morphology after washing with culture medium.
      Motility analysis showed that osteoclast-like MNCs treated with 10(-5)M
      alendronate moved actively after washing, but at 10(-4)M the motility locus was
      very narrow. At 10(-4)M, the actin ring in the cells began to break down,
      beginning 6h after addition. The effects of alendronate on human osteoclast-like
      MNCs morphology and motility were reversible at 10(-5)M, suggesting that
      alendronate dose not cause any cellular damages in human osteoclasts up to 10(
      5)M, which is an effective dose for bone resorption.

PMID- 10340637
TI  - Fracture simulation of the femoral bone using the finite-element method: how a
      fracture initiates and proceeds.
AB  - Structural analysis of bones is now actively studied by many researchers using
      the finite-element method (FEM) to better understand the mechanism of bone
      fractures. Most previous studies, however, only obtained distribution patterns of
      stress or strain, and did not show how a fracture initiates and proceeds or how a
      fracture line grows. The purpose of this study was to simulate a fracture
      procedure using FEM and to assess its usefulness. Correlation of the strain value
      of the simulation and of the experiment was satisfactory (r = .81). The simulated
      fracture process and the consequent fracture lines were quite compatible with the
      experimental fracture. Quantitatively, however, there was a difference of yield
      load between the simulation and the experiment, i.e., 2000N and 8400N,
      respectively, likely caused by inaccuracies of material properties of the
      elements of the finite-element model.

PMID- 10340639
TI  - The change of bone mineral density in secondary osteoporosis and vertebral
      fracture incidence.
AB  - Causes of secondary osteoporosis are diverse, and bone changes in this condition
      have been elucidated less than those in primary osteoporosis. In this study, bone
      mineral density (BMD) was measured in the lumbar spine, distal and proximal sites
      of the radius, and calcaneus in representative disorders that cause secondary
      osteoporosis to evaluate its changes. Also, the incidence of nontraumatic
      vertebral fracture was examined. The subjects were 80 patients with rheumatoid
      arthritis, 50 patients undergoing glucocorticoid (steroid) therapy, 20 patients
      with chronic hepatitis, 24 patients with liver cirrhosis, 14 patients with
      primary biliary cirrhosis (PBC), 26 patients with diabetes mellitus, and 20
      postgastrectomy patients; all were ambulatory female outpatients. Two hundred
      females with primary osteoporosis were examined as a control group. The
      reproducibility of the measurement of the BMD was satisfactory at about 3% by all
      methods of measurement employed. Concerning changes in BMD, periarticular
      trabecular bone density was most markedly reduced in the rheumatoid arthritis
      group. The patients receiving steroid therapy showed the greatest decreases in
      the trabecular bone mineral density at the distal 4% of the radius and lumbar
      spinal BMD. In addition, the threshold of vertebral fracture was higher in those
      undergoing steroid therapy than in those with primary osteoporosis. The patients
      with PBC showed the greatest decreases in BMD among patients with chronic liver
      disorders, and no decrease in BMD was noted in the chronic hepatitis group. BMD
      was reduced only in the radius in the patients with diabetic mellitus, and it was
      generally reduced in the postgastrectomy patients. BMD of the calcaneus was not
      reduced in any group.

PMID- 10340638
TI  - Urinary pyridinoline and deoxypyridinoline as bone metabolic markers in
      predicting therapeutic effects of estrogen and alfacalcidol in women with
      osteoporosis.
AB  - The purpose of the present study was to evaluate the clinical usefulness of
      urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr) in predicting therapeutic
      effects of estrogen and alfacalcidol (1alpha-D3) in patients with postmenopausal
      osteoporosis. We measured urinary excretion of Pyr and Dpyr, and determined bone
      mineral density (BMD) using a dual-energy x-ray absorptiometry in 48 women with
      osteoporosis (average age, 55.9+/-8.4 years). Patients were treated with estrogen
      (HRT, n = 13), 1alpha-D3 (n = 20), or calcium alone (n = 15). Baseline mean
      levels of urinary Pyr and Dpyr were significantly higher in the 48 patients
      compared to those in the age-matched postmenopausal women. The levels of urinary
      Pyr and Dpyr were inversely correlated with BMD. After treatment with estrogen or
      1alpha-D3, a significant decrease of urinary Pyr and Dpyr was observed, and
      elevated urinary Pyr and Dpyr were reduced to the level in premenopausal women. A
      significant inverse correlation was found in Pyr and Dpyr at 6 months and in
      lumbar BMD after 24 months of treatment (r = -0.43 to -0.52; P < 0.01). We
      concluded that urinary Pyr and Dpyr have clinical utility for predicting response
      to estrogen and 1alpha-D3 therapy of osteoporosis patients.

PMID- 10340640
TI  - Clinical usefulness of serum tartrate-resistant fluoride-sensitive acid
      phosphatase activity in evaluating bone turnover.
AB  - This study was carried out to evaluate the clinical validity and usefulness of
      serum tartrate-resistant fluoride-sensitive acid phosphatase (TrFsACP) activity
      using 2,6-dichloro-4-acetylphenyl phosphate as substrate at pH 6.2 in metabolic
      bone diseases. The mean Z-scores of TrFsACP activity in patients on hemodialysis
      were higher than in healthy subjects (male: 2.04+/-1.98, n = 49, P < .05; female:
      1.49+/-2.43, n = 39, P < .05) and increased with duration of hemodialysis (r =
      .516, P < .01). Bone alkaline phosphatase also was found to be significantly
      higher in hemodialysis patients (male: 0.93+/-1.49, P < .05; female: 1.66+/-2.42,
      P < .05) compared with normal subjects: but had lower correlation with duration
      of hemodialysis than TrFsACP (r = .277, P < .05). Ulcerative colitis (1.37+/
      2.21, n = 15) in males showed a significantly higher Z-score of TrFsACP compared
      with control subjects (P < .05). The relationship of TrFsACP activity and
      ultrasound findings (stiffness; speed of sound [SOS]; broadband ultra sound
      attenuation [BUA]) in healthy women aged 30-75 years (n = 95) were inversely and
      significantly correlated with stiffness (r = -.465, P < .01 ), SOS (r = -.484, P
      < .01), and BUA (r = -.366, P < .01), but were age dependent. TrFsACP activity
      significantly correlated with stiffness (r = -.521, P < .05) and SOS (r = -.527,
      P < .05) only in the age group of 46-55 years. BUA (r = -.313, P > .05) did not
      correlate significantly in any subject in the present study. We conclude that
      serum TrFsACP activity is useful in the diagnosis and monitoring of bone
      turnover.

PMID- 10340641
TI  - Fall of blood ionized calcium on watching a provocative TV program and its
      prevention by active absorbable algal calcium (AAA Ca).
AB  - In December 1997, more than 680 children developed convulsive seizures while
      watching a notorious audiovisually provocative TV program, "Pocket Monster."
      Emotional stimulation via hyperventilation may cause respiratory alkalosis, fall
      of blood ionized calcium (Ca), and sensitization of the nervous system to
      excessive emotional stress. A study was therefore undertaken to follow the
      changes of blood ionized Ca in eight healthy volunteers after watching the
      "Pocket Monster" and also a quiet program, "Classical Music," as a control for
      20min from 4 P.M. Although neither marked hyperventilation nor convulsions
      developed in any of these adult volunteers, blood ionized Ca showed a
      significantly more pronounced fall during and after watching "Pocket Monster,"
      and their plasma intact parathyroid hormone (iPTH) was significantly higher
      120min after the beginning of "Pocket Monster" than the "Classical Music"
      program. Plasma total Ca, pH, and albumin were free of detectable changes.
      Ingestion of 600mg Ca as active absorbable algal Ca (AAA Ca) with high
      bioavailability completely prevented the fall of ionized Ca and suppressed iPTH.
      Plama osteocalcin was also significantly suppressed after ingestion of AAA Ca. It
      may be worthwhile to ingest AAA Ca before anticipated emotional stress such as
      watching a provocative TV program to prevent possible neuromuscular instability.

PMID- 10340643
TI  - Robin sequences and complexes: causal heterogeneity and pathogenetic/phenotypic
      variability.
AB  - Robin sequence has been the subject of numerous general papers and has also been
      cited in specific syndrome articles. Evidence is provided that the condition is
      not only causally heterogeneous but also pathogenetically and phenotypically
      variable, necessitating the use of the terms "Robin sequences" and "Robin
      complexes."

PMID- 10340642
TI  - Growth and bone mineral density in a child with X-linked hypophosphatemic
      rickets: early response to treatment.

PMID- 10340644
TI  - Female predominance (low sex ratio) in 47,+21 mosaics.
AB  - Data from the New York State Chromosome Registry on over 10,000 cases of Down
      syndrome reported from 1977 to 1996 confirm findings in the England and Wales
      Cytogenetic Register that in mosaic 46/47,+21 cases of Down syndrome the
      male/female ratio (as inferred from XY and XY karyotypes respectively) is less
      than 1.0 as opposed to the ratio in nonmosaic 47,+21 cases in which the ratio is
      close to 1.2, or in the general background population with ratio of about 1.05.
      These results may reflect in part differential pairing in 47,+21 somatic cells of
      X and Y chromosomes with a 21 chromosome and/or in in-utero selection.

PMID- 10340645
TI  - New brittle bone disorder: report of a family with six affected individuals.
AB  - We report on a family in which four females and two males in three generations
      had a previously undescribed brittle bone disorder that was dominantly
      transmitted through a maternal line. The cardinal manifestations of the disorder
      comprised dolichocephaly with frontal bossing, hypoplasia of the midface,
      postpubertal prognathism, micromelic short stature, coarse trabeculae of the
      entire skeleton, and bone fragility of variable degrees. Mild spondylar
      modification and iliac hypoplasia were other hallmarks that were recognized in
      childhood. The proband, a 19-year-old male, was most severely affected with
      multiple wormian bones in the calvaria, repetitive fractures, intractable bowing
      of the legs and forearms, and pseudofractures of the long bones with metaphyseal
      narrowing. His male cousin was next severely affected with angular deformity
      restricted to the forearm. The four females were much less affected without
      angular deformity. The mode of inheritance was thus consistent with either an
      autosomal dominant trait with sex-influence or an X-linked semidominant trait.
      Histological bone examination in the proband showed atrophy and fibrous
      degeneration of the lamellar trabeculae and disorganized chondro-osseous
      junction, which implied that the disorder involved both intramembranous and
      enchondral ossifications.

PMID- 10340646
TI  - Syndrome of microcephaly, microphthalmia, cataracts, and intracranial
      calcification.
AB  - We present two sisters with microcephaly, developmental delay, marked
      microphthalmia, congenital cataracts, cerebral and cerebellar hypoplasia, and
      intracranial calcification. No evidence of intrauterine infection was found.
      There have been previous reports of microcephaly, intracranial calcification, and
      an intrauterine infection-like autosomal recessive condition, but the sibs in
      this report appear to represent a more severe form of such a condition or a
      previously undescribed entity.

PMID- 10340647
TI  - Type 1 Gaucher disease presenting with extensive mandibular lytic lesions:
      identification and expression of a novel acid beta-glucosidase mutation.
AB  - The finding of extensive lytic lesions in the mandible of a 19-year-old Ashkenazi
      Jewish woman led to the diagnosis of Type 1 Gaucher disease. She had extensive
      skeletal involvement, marked hepatosplenomegaly, and deficient acid beta
      glucosidase activity. Mutation analysis identified heteroallelism for acid beta
      glucosidase mutations N370S and P401L, the latter being a novel missense mutation
      in exon 9. Expression of the P401L allele resulted in an enzyme with a reduced
      catalytic activity (specific activity based on cross-reacting immunological
      material approximately 0.21), which was similar to that of the mild N370S mutant
      enzyme. The expression studies predicted a mild phenotype for the proposita's
      N370S/P401L genotype which was inconsistent with her severe diffuse skeletal
      disease and organ involvement. Since lytic mandibular lesions may be complicated
      by osteomyelitis, pathologic fracture, and tooth loss, regular dental assessments
      in Type 1 Gaucher patients should be performed.

PMID- 10340648
TI  - Recent trends in the prevalence of Down syndrome in Japan, 1980-1997.
AB  - The aims of the present study were to determine recent trends in the prevalence
      of Down syndrome (DS) in Japan, and to determine whether recent changes in
      demographic and social habits and access to prenatal diagnosis have influenced
      the livebirth rates of DS. Livebirth statistics indicate that the birth rate in
      Japan has decreased for women in their 20s and has increased for those in their
      30s and 40s. During an 18-year period between 1980 and 1997, 1,299 consecutive DS
      infants were born among a total of 2,232,694 births, a rate corresponding to
      approximately 10% of all births in Japan over the same period. The increasing
      risk of DS with advancing maternal age was confirmed. The overall prevalence was
      5.82 DS births per 10,000 livebirths (8.3-9.7 per 10,000 after correction
      according to the estimated ascertainment ratio: 60-70%). The prevalence rate by
      year of child birth represents a statistically significant increase (P = 0.001).
      In conclusion, recent trends in the prevalence of DS in Japan from 1980 to 1997
      failed to show a consistent tendency to decrease, probably because of the
      concomitant increase in pregnancy in advanced maternal age.

PMID- 10340649
TI  - Novel 23-base-pair duplication mutation in TSC1 exon 15 in an infant presenting
      with cardiac rhabdomyomas.
AB  - Tuberous sclerosis (TSC) is a dominantly inherited disorder due to mutations at
      two gene loci, the TSC1 locus on chromosome 9q34 and the TSC2 locus on chromosome
      16p13.3. The TSC2 and the TSC1 genes have now been cloned, enabling mutation
      analysis. We report results of mutation analysis in a sporadic case of TSC first
      identified in intra-uterine life on the basis of the presence of cardiac
      rhabdomyomas. Postnatally this infant was also found to have subependymal nodules
      on brain computed tomographic scan. Hypomelanotic macules were not detected
      neonatally or at 12 months of age. The specific TSC1 exon 15 mutation found in
      our patient has not previously been reported in cases of TSC. This mutation
      involves duplication of a 23-bp segment of DNA between two 9-bp repeated sequence
      elements within exon 15. These repeat elements are located between nucleotides
      1892-1900 and between nucleotides 1915-1923 within the TSC1 gene sequence. It is
      likely that the presence of these two repeated elements predisposes to
      misalignment of DNA strands and unequal crossing over. The mechanism of origin of
      rhabdomyomas in TSC is reviewed. Loss of heterozygosity in the TSC gene regions
      has been reported in cardiac rhabdomyomas; however, these lesions are self
      limiting in their growth. The basis for this self limiting proliferation is not
      clear. One interesting postulation is that cardiac rhabdomyomas may be due to
      delay or failure of apoptosis which occurs as part of the normal remodeling
      process in the heart.

PMID- 10340650
TI  - Cardiac malformations in patients with oral-facial-skeletal syndromes: clinical
      similarities with heterotaxia.
AB  - Oral-facial-skeletal (OFS) syndromes include short rib-polydactyly (SRP) and oral
      facial-digital (OFD) syndromes. Congenital heart defect (CHD), mainly
      atrioventricular canal defect (AVCD), is a cardinal finding in the Ellis-van
      Creveld (EVC) syndrome, but it occurs only occasionally in other SRP and OFD
      syndromes. The cardiac characteristics of all patients with OFS syndromes
      evaluated at our hospital from January 1986 to April 1997 were analyzed and
      compared with published reports. Ten patients with EVC syndrome, one with
      McKusick-Kaufman syndrome, and one with OFD syndrome type II had AVCD. Eight
      patients (67%) had a common atrium, eight (67%) a persistent left superior vena
      cava (LSVC) draining into the left atrium because of an unroofed coronary sinus
      in five (42%), and left-sided obstructive lesions in three (25%). One patient
      with EVC syndrome had AVCD, common atrium, double outlet right ventricle,
      persistent LSVC associated with "asplenia syndrome," visceral heterotaxia, and
      right isomerism. The combination of CHDs found in the personal series of OFS
      syndromes suggests pathogenetic similarity with heterotaxia syndromes. Published
      results also corroborate the association between OFS syndromes and CHDs usually
      occurring in heterotaxia. Molecular studies could shed light on the genetic
      mechanisms implicated in the cause of the OFS and heterotaxia syndromes.

PMID- 10340651
TI  - Guidelines for buccal smear collection in breast-fed infants.
AB  - Buccal smear analysis is a noninvasive, fast, and relatively inexpensive
      diagnostic method. It is used commonly where rapid gender identification is
      necessary or, more recently, for detection of aneusomy, microdeletion syndromes,
      and a variety of polymerase chain reaction-based molecular genetic tests.
      Previously we have shown that maternal cells can contaminate buccal smears taken
      from breast-fed infants, resulting in difficulty with test interpretation. The
      aim of this study was to determine optimal timing and technique for buccal smear
      collection in breast-fed infants in order to avoid diagnostic errors. We analyzed
      prospectively 50 breast-fed male infants for presence of cells with XX signal
      pattern from buccal mucosa scrapings at different times after breast feeding. The
      efficiency of mucosal cleaning on elimination of maternal cells was evaluated by
      comparing the proportion of XX cells before and after wiping of buccal mucosa
      with a cotton swab. Maternal cells were present in 23 of 48 (47.9%) samples
      collected within 5 min of feeding. The proportion of XX signal pattern was
      significantly (P = 0.001) reduced in samples collected at 30 min (8/48, P =
      0.001) and > or =60 min (2/29, P = 0.0002) after feeding. Mucosal cleaning prior
      to smear collection significantly decreased the number of XX positive samples
      from 23 of 48 to 10 of 48 (P = 0.002). Buccal smears should not be obtained in
      nursing neonates until at least 60 min after breast feeding. In addition, prior
      to sample collection, buccal mucosa should be cleaned thoroughly with a cotton
      swab applicator. The same guidelines are applicable to older nursing infants.

PMID- 10340652
TI  - Agenesis of tibia with ectrodactyly/Gollop-Wolfgang complex associated with
      congenital heart malformations and additional skeletal abnormalities.
AB  - We report on a child with bifid femur, absent tibiae, hypoplastic hallux,
      bilateral club feet, congenital heart defects, and segmentation anomalies of the
      spine and ribs. Parents are consanguineous, from a region where other
      consanguineous families with similarly affected individuals have been reported.
      Clinical and genetic controversies of the tibial aplasia-ectrodactyly
      syndrome/Gollop-Wolfgang complex are discussed.

PMID- 10340653
TI  - Analysis of deformations in 26,810 consecutive infants with congenital defects.
AB  - Here we present the analysis of deformations observed in a series of 26,810
      consecutive infants with congenital defects. We observed that 3.88% of these
      infants had deformations, for a prevalence figure of 0.07% live-born infants.
      From the present study we can conclude that there are three different types of
      deformation sequences: one with polyhydramnios, thin skin without dermal ridges,
      hypotonia, and multiple deformations (hypokinesia sequence), which is most often
      due to intrinsic problems; another with oligohydramnios, redundant thick skin,
      and multiple deformations, which can be produced by intrinsic or extrinsic
      factors; and the third, with normal amniotic fluid volume, which is due to
      compression of different causes. Deformations of extrinsic cause are more
      frequently isolated defects and have a better prognosis, while deformations of
      intrinsic origin are more frequently associated with other congenital anomalies
      and, generally, have a poor prognosis.

PMID- 10340654
TI  - Maternally inherited nonsyndromic hearing loss.
AB  - In this study we characterized clinically and evaluated molecularly a large
      family with maternally inherited hearing impairment. Relatives were evaluated
      audiologically and clinically, the most likely pattern of inheritance was
      deduced, and molecular DNA analysis for the known mitochondrial mutations
      associated with hearing impairment was performed. Clinical examination of several
      relatives showed a normal general state of health, but in 14 of the members
      tested variable degrees of sensorineural hearing loss were noted. The pedigree
      was established and demonstrated a clear pattern of maternal inheritance, with 34
      of 38 offspring of deaf mothers being hearing impaired, but none of 22 offspring
      of deaf fathers having any hearing impairment. Since by far the most likely
      explanation of such a maternal inheritance pattern is a mitochondrial mutation,
      molecular testing for the three known mitochondrial mutations, A1555G, A7445G,
      and Cins7472, was performed on 27 of the relatives. All of the individuals tested
      had the normal sequence at the sites tested. This family with nonsyndromic
      sensorineural hearing loss has an inheritance pattern strongly suggestive of a
      mitochondrial mutation. However, molecular testing for the three known
      mitochondrial mutations associated with nonsyndromic hearing impairment was
      negative, implying that additional molecular defects can lead to the same
      phenotype. The search for this novel molecular defect is underway.

PMID- 10340655
TI  - Heterotaxy-neural tube defect and holoprosencephaly occuring independently in two
      sib fetuses.
AB  - We report on two sib fetuses, products of a consanguineous union, who had
      multiple and apparently unrelated malformations. The first fetus, a female, had
      trilobed lungs, a single cardiac ventricle, asplenia, situs ambiguus of the
      liver, and a lumbosacral meningomyelocele. The brain of this fetus was normal.
      The second fetus, a male, had bilobed lungs, a single cardiac ventricle, situs
      solitus of the abdominal organs and spleen, and a semilobar holoprosencephaly.
      The occurrence of these malformations in sibs of different sexes and the parental
      consanguinity suggest a recessive mutation in a gene responsible for both
      heterotaxy and midline defects, including holoprosencephaly.

PMID- 10340656
TI  - FISH characterization of two supernumerary r(1) associated with distinct clinical
      phenotypes.
AB  - Only a few reports on supernumerary r(1) chromosomes associated with a clinical
      phenotype have been published. We describe two unrelated patients with congenital
      malformations and developmental delay who were found to have a de novo
      supernumerary r(1) in 50% (Case 1) and 80% (Case 2) of the examined cells.
      Conventional cytogenetic techniques (QFQ, CBG, and DA-DAPI), complemented by
      fluorescence in situ hybridization studies using alpha satellite probes, showed
      that both small marker chromosomes (SMCs) primarily consisted of the centromere
      and heterochromatin of chromosome 1, a conclusion that was also supported by
      chromosome 1 painting. In an attempt to establish phenotype-genotype
      correlations, a further investigation was performed using YACs mapped to the
      chromosome 1 pericentromeric region. A fluorescent signal was evident after
      hybridization with Y934G9 (1q21) in Case 1 and Y959C4 (1p11.1-12) in Case 2.
      Partial trisomy of unique sequences flanking pericentromeric sequences is shown
      to underlie the clinical phenotype in both patients. This evidence should be
      taken into account when SMCs are ascertained, particularly in prenatal diagnosis.

PMID- 10340657
TI  - Supernumerary ring chromosome 5 identified by FISH.

PMID- 10340658
TI  - Gastrointestinal tract anomalies in velocardiofacial syndrome.

PMID- 10340659
TI  - Female carriers of Xp22.3 deletion including MRX locus.

PMID- 10340660
TI  - Development of a rapid response biosensor for detection of Salmonella
      typhimurium.
AB  - An integrated optic interferometer for detecting foodborne pathogens was
      developed. The interferometer is a planar waveguide with two thin antibody-coated
      channels of immunochemically selective agents that interact with antigen
      molecules. One channel is coated with antibody to Salmonella as a sample, and the
      other is coated with human immunoglobulin G as a reference channel by using
      reductive amination. Salmonella was introduced onto the sensing channels through
      the flow cell on the channels. Phase shift (pi) generated by refractive index
      variation, as determined by interfering the perturbed sample channel with an
      unperturbed reference channel and observing the fringe shift, was used for
      detection. Salmonella Typhimurium (heat-treated or boiled) was detected by
      binding to antibody against Salmonella common structural antigen immobilized on a
      silane-derived sensor surface at concentrations in the range of 1x10(5) to
      1x10(7) CFU/ml. Salmonella (1x10(7) CFU/ml) mixed with Escherichia coli (1x10(7)
      CFU/ml) were readily detected without any decrease in sensitivity by the direct
      assay. Application of a sandwich assay with a second antibody or a gold
      conjugated antibody increased the detection limit to 1x10(5) CFU/ml within a 10
      min reaction time. Various methods for the immobilization of the capture antibody
      to the biosensor channels were compared. The greatest binding response was
      observed in a direct reductive amination method with a long reaction period and
      increased the detection limit of direct binding of Salmonella antigen to 1x10(4)
      CFU/ml. The biosensor was able to detect Salmonella Typhimurium in chicken
      carcass wash fluid originally inoculated at a level of 20 CFU/ml after 12 h of
      nonselective enrichment. The planar optic biosensor shows promise as a fast,
      sensitive, reliable, and economical means of detecting food pathogens in the
      future.

PMID- 10340662
TI  - Contamination of intact apples after immersion in an aqueous environment
      containing Escherichia coli O157:H7.
AB  - The extent and location of Escherichia coli O157:H7 contamination after intact
      apples were immersed in cold (2 degrees C) 1% peptone water containing
      approximately 3x10(7) CFU/ml was assessed using four apple varieties, Golden
      Delicious, McIntosh, Red Delicious, and Braeburn. Room temperature and
      refrigerated apples were used to determine the effect of temperature differential
      on E. coli infiltration. The highest levels of E. coli were associated with the
      outer core region of the apple, followed by the skin. Apples were subsequently
      treated by immersing them for 1 min in 2,000 mg/liter sodium hypochlorite,
      followed by a 1-min tapwater rinse. This treatment reduced pathogen levels by 1-
      to 3-log cycles but did not eliminate the microorganism, particularly from the
      outer core region. While E. coli was not detected in the inner core of most
      apples, warm fruit immersed in cold peptone water occasionally internalized the
      pathogen. The frequency and extent of internalization of the pathogen was less
      when cold apples were immersed in cold peptone water. Subsequent dye uptake
      studies with Golden Delicious apples indicated that approximately 6% of warm
      apples immersed into a cold dye solution accumulated dye via open channels
      leading from the blossom end into the core region. However, dye uptake did not
      occur when the dye solution was warmer than the apple.

PMID- 10340661
TI  - Development of digoxigenin-labeled PCR amplicon probes for use in the detection
      and identification of enteropathogenic Yersinia and Shiga toxin-producing
      Escherichia coli from foods.
AB  - By including digoxigenin-11-dUTP in a polymerase chain reaction (PCR),
      amplification products were produced that contained nonisotopic markers for use
      as DNA hybridization probes. Because these labeled amplicons encode pathogenic
      traits for specific foodborne bacteria, they can be used to detect the presence
      of potentially virulent organisms that may be present in foods. This technology
      allows the synthesis of a variety of shelf-stable probe reagents for detecting a
      number of foodborne microbes of public health concern. We used this technology to
      detect four genes in two potential pathogens: virF and yadA in enteropathogenic
      Yersinia and stx1 and stx2 in Shiga-like toxin-producing Escherichia coli.
      Results of DNA hybridizations of dot blots of 68 Yersinia strains and 24 of 25 E.
      coli strains were consistent with results of equivalent PCR analyses. DNA colony
      hybridization with nonisotopic virF probes of colonies arising on spread plates
      from artificially contaminated food homogenates was able to detect potentially
      pathogenic Y. enterocolitica. When compared with oligonucleotide probes, amplicon
      probes are much less sensitive to changes in hybridization and wash temperatures,
      allowing greater reproducibility. Labeled probe preparations were reused more
      than five times and have been stored at -20 degrees C for more than 8 months.
      This method conveniently generates probes that are safe, stable, inexpensive,
      reusable, and reliable.

PMID- 10340663
TI  - Behavior of acid-adapted and unadapted Escherichia coli O157:H7 when exposed to
      reduced pH achieved with various organic acids.
AB  - A study was done to determine if various organic acids differ in their inhibitory
      or lethal activity against acid-adapted and unadapted Escherichia coli O157:H7
      cells. E. coli O157:H7 strain EO139, isolated from venison jerky, was grown in
      tryptic soy broth (TSB) and in TSB supplemented with 1% glucose (TSBG) for 18 h
      at 37 degrees C, then plated on tryptic soy agar (TSA) acidified with malic,
      citric, lactic, or acetic acid at pH 5.4, 5.1, 4.8, 4.5, 4.2, and 3.9. Regardless
      of whether cells were grown in TSB or TSBG, visible colonies were not formed when
      plated on TSA acidified with acetic, lactic, malic, or citric acids at pH values
      of < or =5.4, < or =4.5, < or =4.2, or < or =4.2, respectively. Cells not adapted
      to reduced pH did not form colonies on TSA acidified with lactic acid (pH 3.9) or
      acetic acid (pH 3.9 and 4.2); however, a portion of acid-adapted cells remained
      viable on TSA containing lactic acid (pH 3.9) or acetic acid (pH 4.2) and could
      be recovered in TSB. Inactivation of acid-adapted cells was less than that of
      unadapted cells in TSB acidified at pH 3.9 with citric, lactic, or acetic acid
      and at pH 3.4 with malic acid. Significantly (P< or =0.05) higher numbers of acid
      adapted cells, compared with unadapted cells, were detected 12 h after
      inoculation of TSB acidified with acetic acid at pH 3.9; in TSB containing lactic
      acid (pH 3.9), the number of acid-adapted cells was higher than the number of
      unadapted cells after 5 h. In TSB acidified at pH 3.9 with citric acid or pH 3.4
      with malic acid, significantly higher numbers of acid-adapted cells survived.
      This study shows that organic acids differ in their inhibitory or lethal activity
      against acid-adapted and unadapted E. coli O157:H7 cells, and acid-adapted cells
      are more tolerant than unadapted cells when subsequently exposed to reduced pH
      caused by these acids.

PMID- 10340664
TI  - Development of a new medium for the isolation of Arcobacter spp.
AB  - Arcobacter, the newly reclassified Campylobacter species, has been shown to cause
      diarrhea in both humans and animals. Few studies have been conducted regarding
      its occurrence in foods because of the lack of effective isolation and
      identification methods. The purpose of this study was to develop a plating medium
      that would be selective for the three most commonly found Arcobacter species. The
      effect of common components used in media intended for the isolation of
      Campylobacter, Helicobacter, and other gram-negative rods was examined. These
      components were divided into five distinct groups: (1) basic growth nutrients,
      (2) reducing and growth-promoting agents, (3) detoxifying agents, (4)
      antibiotics, and (5) color-enhancing compounds. Components from each of these
      groups were tested for their ability to recover Arcobacter on a solid medium when
      incubated aerobically at 30 degrees C for up to 72 h. Growth was evaluated by the
      ecometric technique, colony size, and differential colony morphology after
      incubation. After initial evaluations, five formulas showing the best results
      were selected and tested in detail and compared with brucella agar. A medium
      containing a basal nutrient mix along with 0.05% thioglycolic acid, 0.05% sodium
      pyruvate, and 5% sheep's blood (pH 6.9+/-0.2) was found to be the most effective
      for the growth of A. butzleri, A. cryaerophilus, and A. nitrofigilis. In addition
      to superior growth characteristics, a deep red color around the colonies also was
      observed with this formulation.

PMID- 10340665
TI  - Enumeration and confirmation of Aeromonas hydrophila, Aeromonas caviae, and
      Aeromonas sobria isolated from raw milk and other milk products in Northern
      Greece.
AB  - A total of 138 raw cow's and 57 raw ewe's milk samples; 80 pasteurized cow's milk
      samples; 39 Anthotyros cheese, 36 Manouri cheese, and 23 Feta cheese samples; and
      15 rice pudding samples were examined for the presence and any countable
      population of Aeromonas species. Twenty-two (15.9%) of the 138 cow's milk samples
      analyzed were contaminated with A. hydrophila. In 13 of these samples,
      populations of 3.0x10(2) to 5.0x10(3) CFU/ml were counted in starch ampicillin
      agar (SAA). Eighteen cow's milk samples (13.0%) were contaminated with A. caviae,
      and in eight of these samples, populations of 2.0x10(2) to 3.0x10(3) CFU/ml were
      counted in SAA. Five cow's milk samples (3.6%) were contaminated with A. sobria,
      and in two of these samples, populations of 2.5x10(3) and 5.0x10(3) CFU/ml were
      counted in SAA. Eleven cow's milk samples (7.9%) were contaminated with other
      Aeromonas spp. not classified. Eight (14.0%) of the 57 ewe's milk samples
      analyzed were contaminated with A. hydrophila. In these samples, populations of
      5.0x10(2) to 5.0x10(3) CFU/ml were counted in SAA. Six ewe's milk samples (10.5%)
      were contaminated with A. caviae, and populations of 1.5x10(2) to 1.0x10(3) CFU/
      ml were counted in SAA. Two ewe's milk samples (3.5%) were contaminated with A.
      sobria, and populations counted in SAA were 5.0x10(2) and 1.0x10(3) CFU/ml. Four
      samples (7.0%) were contaminated with other Aeromonas spp. not classified. A.
      hydrophila was recovered in 4 (10.2%) and 3 (8.3%) of the Anthotyros and Manouri
      cheese samples analyzed, respectively, but no countable populations were noted in
      SAA. None of the pasteurized milk, Feta cheese, and rice pudding samples yielded
      Aeromonas spp. The results of this work indicate that motile Aeromonas are common
      in raw milk in Greece. Also, the presence of A. hydrophila in the whey cheeses
      Anthotyros and Manouri indicates that postprocessing contaminations of these
      products with motile Aeromonas may occur during production.

PMID- 10340666
TI  - Incidence of Salmonella on beef carcasses relating to the U.S. meat and poultry
      inspection regulations.
AB  - This article is part of a major study designed to collect baseline contamination
      data by sampling beef carcasses in seven slaughtering plants (four steer-heifer
      and three cow-bull plants) during both a dry season (November to January) and a
      wet season (May to June). Samples (n = 30) were excised from each of three
      carcass anatomical sites (brisket, flank, and rump) at each of three points in
      the slaughtering chain (pre-evisceration, following final carcass washing, after
      24-h carcass chilling). A total of 3,780 samples (100 cm2 each) were analyzed for
      presence of Salmonella; aerobic plate counts, total coliform counts, and
      Escherichia coli counts were also made. After 24-h chilling, average incidence
      (expressed as a percentage) of Salmonella in the brisket, flank, and rump
      samples, respectively, for steer-heifer carcasses was 0.8+/-1.7, 0, and 2.5+/-5.0
      for the wet season and 0.8+/-1.7, 0, and 0 for the dry season; the corresponding
      percentages for cowbull carcasses were 4.4+/-2.0, 2.2+/-3.9, and 1.1+/-1.9 for
      the wet season and 2.2+/-3.9, 1.1+/-1.9, and 0 for the dry season. Depending on
      plant and season, ranges of probabilities of chilled steer-heifer carcasses
      passing the U.S. regulatory requirements for Salmonella contamination were 0.24
      to 1.0 for the brisket, 1.0 for the flank, and 0.002 to 1.0 for the rump; the
      corresponding ranges for the chilled cow-bull carcasses were 0.25 to 1.0, 0.25 to
      1.0, and 0.70 to 1.0. When the number of positive brisket, flank, and rump
      samples were combined, the probabilities of passing the regulatory requirements
      were 0.242 to 1.0 and 0.772 to 1.0 for the wet and dry seasons, respectively, in
      steer-heifer plants and 0.368 to 0.974 and 0.865 to 1.0 in cow-bull plants.
      Correlation coefficients of aerobic plate counts, total coliform counts, and E.
      coli counts with Salmonella incidence were higher (P< or =0.05) for cow-bull
      samples that had increased incidence of the pathogen when compared to steer
      heifer samples.

PMID- 10340668
TI  - Application of high hydrostatic pressure to eliminate Listeria monocytogenes from
      fresh pork sausage.
AB  - Ground pork patties were inoculated separately with 10(9) CFU/g each of three
      strains of Listeria monocytogenes obtained from the National Animal Disease
      Center (NADC). Inoculated patties were packaged under vacuum and treated at 414
      megapascals (60,000 lb/in2) for up to 60 min by high hydrostatic pressure (HHP).
      Survivors were determined by surface plating onto modified Oxford agar and
      trypticase soy agar with yeast extract, as well as by the most probable number
      method using Listeria enrichment broth. Average D values ranged from 1.89 to 4.17
      min, depending on the strain, with the most virulent strain (reported by the
      NADC) having the highest D value. We tested the usefulness of applying a mild
      heat treatment at 50 degrees C, simultaneously with HHP, to lower these values.
      Average D values ranged from 0.37 to 0.63 min, depending on the strain. Thus, a
      10-log10 reduction could be achieved even in the most pressure-resistant strain
      of L. monocytogenes by a 6-min application of heat and HHP. Shelf life studies
      were also conducted, with spoilage levels reached after 5 days of storage at 4
      degrees C for controls versus 28 days for treated samples. Sensory evaluation of
      uninoculated grilled patties showed that panelists could not distinguish between
      those treated by heat and HHP and untreated controls (P<0.05). Thus, treatment by
      HHP in combination with mild heating can be used successfully to produce safer,
      longer-lasting fresh pork without affecting quality.

PMID- 10340667
TI  - The effectiveness of triclosan-incorporated plastic against bacteria on beef
      surfaces.
AB  - Triclosan is a nonionic, broad-spectrum, antimicrobial agent that has been
      incorporated into a variety of personal hygiene products, including hand soaps,
      deodorants, shower gels, mouthwashes, and toothpastes. In this study, plastic
      containing 1,500 ppm of triclosan was evaluated in plate overlay assays and meat
      experiments as a means of reducing populations of bacteria. Plate overlay assays
      indicated that the triclosan-incorporated plastic (TIP) inhibited the following
      organisms: Brochothrix thermosphacta ATCC 11509, Salmonella Typhimurium ATCC
      14028, Staphylococcus aureus ATCC 12598, Bacillus subtilis ATCC 6051, Shigella
      flexneri ATCC 12022, Escherichia coli ATCC 25922, and several strains of E. coli
      O157:H7. In meat experiment 1, irradiated, lean beef surfaces inoculated with B.
      thermosphacta, Salmonella Typhimurium, E. coli O157:H7, or B. subtilis were
      covered with TIP, vacuum packaged, and stored for 24 h at 4 degrees C. Of the
      organisms tested, only populations of B. thermosphacta were slightly reduced. In
      meat experiment 2, prerigor beef surfaces were inoculated with E. coli O157: H7,
      Salmonella Typhimurium, or B. thermosphacta incubated at 4 degrees C for 24 h,
      wrapped in TIP or control plastic, vacuum packaged, and stored at 4 degrees C for
      up to 14 days. There was a slight reduction in the population of the organisms
      after initial application with TIP. However, bacterial populations following long
      term, refrigerated (4 degrees C), vacuum-packaged storage up to 14 days were not
      statistically (P< or =0.05) or numerically different than controls. In meat
      experiment 3, even TIP-wrapped, vacuum-packaged beef samples that were
      temperature abused at 12 degrees C did not exhibit significant (P< or =0.05) or
      sustainable reductions after 14 days of 4 degrees C storage. Another study
      indicated that populations of E. coli O157:H7 or B. thermosphacta added directly
      to TIP were not affected after 2 h of refrigerated storage or that the
      antimicrobial activity could be extracted from the plastic. Additional
      experiments suggest that presence of fatty acids or adipose may diminish the
      antimicrobial activity of TIP on meat surfaces. This study demonstrates that
      while antimicrobial activity is detected against bacterial cultures in
      antimicrobial plate assays, plastic containing 1,500 ppm of triclosan does not
      effectively reduce bacterial populations on refrigerated, vacuum-packaged meat
      surfaces.

PMID- 10340669
TI  - Thermal resistance of bacterial spores in milk-based beverages supplemented with
      nisin.
AB  - The effect of nisin, added in the form of Nisaplin, on the thermal resistance of
      bacterial spores and the effects of medium composition, exposure time, and pH on
      nisin enhancement of heat sensitivity were evaluated. Nisin apparently required
      specific nutrients to sensitize spores to heat. For example, D130 degrees C
      values of approximately 10 s were observed in sodium phosphate buffer with and
      without 6% sucrose with no significant (P> or =0.05) differences detected as a
      result of increased nisin concentration. In a nutrient-rich chocolate milk model
      system (CMMS), increasing either the time of exposure to nisin (5, 15, or 24 h)
      before heating or nisin concentration (0, 2,000, or 4,000 IU/ml) increased the
      sensitivity of Bacillus stearothermophilus spores to heat. In the CMMS with 10 to
      12% fat cocoa powder, increasing nisin concentration (at 5 h of exposure)
      significantly (P< or =0.05) reduced D130 degrees C values; D130 degrees C values
      were 21.7, 17.2, and 17.8 s, respectively, for the 0-, 2,000-, and 4,000-IU/ ml
      nisin treatments. Fifteen and 24 h of exposure further reduced D130 degrees C
      values in the nisin-containing treatments compared to the control (0 IU of nisin
      per ml). A lower-fat CMMS (0 to 1% fat cocoa powder) had lower D130 degrees C
      values (19.3, 15.8, and 14.7 s for the 0-, 2,000-, and 4,000-IU/ml nisin
      treatments, respectively). Nisin activity was enhanced by lowering pH in the CMMS
      (10 to 12% fat cocoa powder), with reductions in D130 degrees C values across all
      pH values (ranging from 18.0% at pH 6.4 to 41.9% at pH 5.0). zD values were 9.6,
      9.0, and 8.4 degrees C for the 0-, 2,000-, and 4,000-IU/ml nisin treatments,
      respectively. Spores of B. licheniformis yielded results similar to those
      obtained with B. stearothermophilus. For example, decreasing CMMS (10 to 12% fat
      cocoa powder) pH values from 6.4 to 5.0 produced D100 degrees C values of 3.3,
      2.8, and 2.8 min (pH 6.4) and 1.0, 0.8, and 0.8 min (pH 5.0) for the 0-, 2,000-,
      and 4,000-IU/ml nisin treatments. This study clearly verified that the addition
      of Nisaplin to dairy-based beverages, such as a chocolate milk drink, or other
      foods intended to be heated reduces the thermal resistance of selected bacterial
      spores. Increased spore sensitivity to heat may provide food processors with an
      opportunity to reduce their thermal processes and expenses while maintaining
      product quality, functionality, and shelf stability.

PMID- 10340670
TI  - Nisin in milk sensitizes Bacillus spores to heat and prevents recovery of
      survivors.
AB  - Decimal reduction times (D values) were determined for Bacillus cereus T spores
      and B. stearothermophilus ATCC 12980 spores in skim milk supplemented with
      various concentrations (0, 2,000, and 4,000 IU/ml) of the bacteriocin nisin by
      using an immersed, sealed capillary tube procedure. For both organisms, the
      addition of nisin lowered the apparent D values. For B. cereus, the addition of
      2,000 IU of nisin per ml to skim milk before heating significantly (P< or =0.05)
      lowered the apparent D value compared to the control treatment. The D values at
      97 degrees C were 7.0, 4.8, and 4.7 min for the control and 2,000- and 4,000
      IU/ml nisin treatments, respectively. At 103 degrees C, the D values were 1.5,
      0.85, and 0.88 min for the control and 2,000-and 4,000-IU/ml nisin treatments.
      When calculated across both nisin treatments, the mean reductions in apparent D
      values at 97, 100, and 103 degrees C due to addition of nisin in comparison to
      the controls were 32, 20, and 42%, respectively. The zD values for B. cereus
      ranged from 8.0 to 8.9 degrees C. With B. stearothermophilus, the apparent D
      values at 130 degrees C were reduced by 13 and 21% respectively, because of the
      presence of 2,000 or 4,000 IU of nisin per ml. The D values were 16.0, 13.8, and
      12.5 s for the control and 2,000- and 4,000-IU/ml nisin treatments, respectively.
      There was a significant (P< or =0.05) decrease in the apparent D value between
      the control and 4,000-IU/ml treatment. Overall, log populations of survivors for
      B. stearothermophilus compared to the control were lower at any given sampling
      time due to the presence of nisin. The results of these studies suggest that
      spore control is likely due to enhanced sensitivity of spores to heat and the
      presence of residual nisin in the recovery medium that could prevent outgrowth of
      survivors.

PMID- 10340671
TI  - Microbiological quality and production of botulinal toxin in film-packaged
      broccoli, carrots, and green beans.
AB  - The production of toxin by a 10-strain mixture of proteolytic Clostridium
      botulinum in fresh produce packaged in polyethylene films with different oxygen
      permeability was determined. Broccoli florets, shredded carrots, and green beans
      inoculated with approximately 10(2) C. botulinum spores per g were placed in bags
      (1.4 kg per bag) composed of four films with different oxygen transmission rates
      (OTRs). Broccoli was packaged in bags with OTRs of 3 (7,000 cm3/m2/24 h) and 4
      (16,000 cm3/m2/24 h), and green beans were packaged in bags with OTRs of 2 (6,000
      cm3/m2/24 h) and 4. Broccoli and green beans in bags were compressed and heat
      sealed. Shredded carrots were packaged in bags with OTRs of 1 (3,000 cm3/m2/24 h)
      and 3 and vacuum-sealed. Produce was stored at 4, 13, and 21 degrees C for up to
      27 (broccoli) or 28 (carrots and green bean) days and analyzed periodically. At
      each sampling time, gas composition within the bags, pH of the produce microbial
      population (total aerobic and anaerobic microorganisms, lactic acid bacteria,
      psychrotrophic bacteria, yeasts, and molds), and the presence or absence of
      botulinal toxin were determined. Packaging material affected the quality of
      vegetables, especially broccoli stored at 4 and 13 degrees C. For example,
      broccoli was scored as "good" after 22 days at 4 degrees C when it was packaged
      in film with higher gas permeability (OTR of 4), whereas broccoli appeared to be
      in "poor" condition when packaged in film with lower gas permeability (OTR of 3).
      With the exception of lactic acid bacteria, packaging material did not noticeably
      influence the growth of microorganisms. Lactic acid bacteria grew better in
      broccoli packaged in bags with an OTR of 3 than in those with an OTR of 4 at all
      temperatures. Botulinal toxin was detected in broccoli packaged in bags with an
      OTR of 3 and stored at 13 degrees C for 21 days and in those with an OTR of 4 and
      3 and stored at 21 degrees C for 10 days. All toxic samples were visibly spoiled.
      Toxin was not detected in produce packaged under any other test conditions.

PMID- 10340672
TI  - Halotolerant and halophilic histamine-forming bacteria isolated during the
      ripening of salted anchovies (Engraulis encrasicholus).
AB  - This study was performed to investigate halotolerant and halophilic histamine
      producing bacteria isolated during the ripening of salted anchovies. Of the
      isolates obtained during the ripening of anchovies, 1.37% showed histamine
      forming activity, most of them (70%) belonging to the Staphylococcus genus. S.
      epidermidis showed a powerful histamine-forming activity, producing more than
      1,000 microg/ml in the presence of 3% and 10% NaCl. Another powerful histamine
      producing bacterium isolated during the ripening of salted anchovies was S.
      capitis. It was able to produce about 400 microg/ml of histamine in 10% NaCl
      under experimental conditions. Most of these species might be expected to be
      found as a result of contamination of fish during capture and subsequent
      unhygienic handling. However, no increase in histamine content was found in any
      batches through the ripening process. Histamine content always was acceptable in
      accordance with the maximum allowable levels of histamine fixed by the Spanish
      and European Union regulations.

PMID- 10340673
TI  - Canning process that diminishes paralytic shellfish poison in naturally
      contaminated mussels (Mytilus galloprovincialis).
AB  - Changes in toxin profile and total toxicity levels of paralytic shellfish poison
      (PSP)-containing mussels were monitored during the standard canning process of
      pickled mussels and mussels in brine using mouse bioassays and high-performance
      liquid chromatography. Detoxification percentages for canned mussel meat exceeded
      50% of initial toxicity. Total toxicity reduction did not fully correspond to
      toxin destruction, which was due to the loss of PSP to cooking water and packing
      media of the canned product. Significant differences in detoxification
      percentages were due to changes in toxin profile during heat treatment in packing
      media. Toxin conversion phenomena should be determined to validate detoxification
      procedures in the canning industry.

PMID- 10340674
TI  - Reliability of an ordinal rating system for assessing the amount of mud and feces
      (tag) on cattle hides at slaughter.
AB  - A study was conducted to provide a quantitative description of the amount of tag
      (mud, soil, and bedding) adhered to the hides of feedlot beef cattle and to
      appraise the statistical reliability of a subjective rating system for assessing
      this trait. Initially, a single rater obtained baseline data by assessing 2,417
      cattle for 1 month at an Ontario beef processing plant. Analysis revealed that
      there was a strong tendency for animals within sale-lots to have a similar total
      tag score (intralot correlation = 0.42). Baseline data were summarized by fitting
      a linear model describing an individual's total tag score as the sum of their lot
      mean tag score (LMTS) plus an amount representing normal variation within the
      lot. LMTSs predicted by the linear model were adequately described by a beta
      distribution with parameters nu = 3.12 and omega = 5.82 scaled to fit on the 0-to
      9 interval. Five raters, trained in use of the tag scoring system, made 1,334 tag
      score observations in a commercial abattoir, allowing reliability to be assessed
      at the individual level and at the lot level. High values for reliability were
      obtained for individual total tag score (0.84) and lot total tag score (0.83);
      these values suggest that the tag scoring system could be used in the marketing
      and slaughter of Ontario beef cattle to improve the cleanliness of animals
      presented for slaughter in an effort to control the entry of microbial
      contamination into abattoirs. Implications for the use of the tag scoring system
      in research are discussed.

PMID- 10340675
TI  - Microbial, physical, and chemical quality of packaged ice in Florida.
AB  - In a statewide survey, ice samples purchased at retail were evaluated for
      labeling information and microbiological, chemical, and physical quality. Only
      11% of bags from on-premises manual facilities, compared to 79% for off-premises
      mechanical facilities, had appropriate label information. One ice sample exceeded
      the state regulatory limit for aerobic plate count (APC) (<500 CFU/ml). Yeasts
      and molds were detected in 12% of the samples. No Listeria monocytogenes were
      found in any of the samples. Coliform counts exceeding the state regulatory limit
      (<1/100 ml) were observed in 13.5% of manual, on-premises facilities compared to
      3.6% of samples from mechanical, off-premises facilities. No significant
      differences were detected between samples from on- and off-premises facilities
      with regard to chemical composition (e.g., aluminum, ammonium, boron, barium,
      calcium, cadmium, chloride, copper, iron, lead, magnesium, manganese, nickel,
      nitrate, phosphorus, potassium, sodium, silicon, and zinc), electrical
      conductivity, or pH. All samples analyzed were in compliance with appropriate
      Environmental Protection Agency drinking water standards. In general, all ice
      samples were acceptable in terms of water hardness values. Approximately 33% of
      samples from off-premises facilities and 62% of the on-premises samples had
      detectable particulate matter. None of the off-premises samples, compared to 8%
      of the on-premises samples, had particulate matter in the "pronounced" category.

PMID- 10340676
TI  - Combined secondary enrichment of primary enrichment broths increases Listeria
      detection.
AB  - The efficacy of combining dual primary enrichment cultures into a single
      secondary broth was evaluated for detecting Listeria in naturally contaminated
      meats and environmental samples obtained from dairy processing plants. A total of
      336 samples were tested using University of Vermont modified Listeria enrichment
      broth (UVM) and Listeria repair broth containing selective agents (LRBS) as
      primary enrichment media. Eighty samples (23.8%) yielded Listeria by at least one
      method. Neither primary enrichment broth was significantly better (P>0.05) than
      the other in identifying Listeria-positive samples. UVM media, when used as a
      primary enrichment broth, identified 66 Listeria-positive samples, while the use
      of LRBS as a primary enrichment broth identified 65 Listeria-positive samples.
      Listeria detection improved significantly (P<0.01) when two primary enrichment
      media were used for sample analysis. It is not clear whether this improvement was
      due to simply replicating the primary enrichment or to the particular pair of
      primary enrichment media used. The use of a dual secondary enrichment procedure
      was better (P<0.05) than the use of either individual primary enrichment medium
      alone. The overall rate of recovery increased from 81.3 to 82.5% for single
      secondary enrichment to 93.8% using a dual secondary enrichment technique.
      Analysis of results obtained when combining two independent isolation methods
      versus combining two primary enrichment media into one single secondary
      enrichment broth indicated that there was no significant difference (P>0.05) in
      either procedure. Inoculum size (0.1 ml versus 0.2 ml) did not have an effect on
      the overall rate of recovery. The procedure developed increased the sensitivity
      of testing while decreasing the potential workload associated with an increase in
      enrichment procedures.

PMID- 10340677
TI  - Acid-adapted Listeria monocytogenes displays enhanced tolerance against the
      lantibiotics nisin and lacticin 3147.
AB  - Log-phase Listeria monocytogenes cells become tolerant to a variety of
      environmental stresses following acid adaptation at pH 5.5. We demonstrated that
      adapted cells also exhibit increased tolerance to nisin and, to a lesser extent,
      lacticin 3147. At nisin concentrations of 100 and 200 IU/ml the survival of acid
      adapted cells was approximately 10-fold greater than nonadapted cells. However,
      acid adaptation had only a moderate effect on the tolerance of L. monocytogenes
      to lacticin 3147, a phenomenon that possibly reflects the distinct mode of action
      of this bacteriocin. Analysis of the fatty acid composition of the bacterial
      membrane indicated that straight-chain fatty acids C14:0 and C16:0 were
      significantly increased in acid-adapted cells while levels of C18:0 decreased.
      The results indicate that stress mechanisms that are induced in mildly acidic
      conditions provide protection against the antimicrobial action of bacteriocins.
      This increased resistance of acid-adapted L. monocytogenes could cause increased
      survival of this pathogen in food products in which nisin or other bacteriocins
      are used as preservatives.

PMID- 10340678
TI  - Individual and combined effects of vanillin and potassium sorbate on Penicillium
      digitatum, Penicillium glabrum, and Penicillium italicum growth.
AB  - The individual and combined effects of potassium sorbate and vanillin
      concentrations on the growth of Penicillium digitatum, P. glabrum, and P.
      italicum in potato dextrose agar adjusted to water activity 0.98 and pH 3.5 were
      evaluated. Inhibitory concentrations of potassium sorbate varied from 150 ppm for
      P. digitatum to 700 ppm for P. glabrum, and for vanillin from 1,100 ppm for P.
      digitatum and P. italicum and 1,300 ppm for P. glabrum. Fractional inhibitory
      concentration (FIC) isobolograms show curves deviated to the left of the additive
      line. Calculated FIC index varied from 0.60 to 0.84. FIC index as well as FIC
      isobolograms show synergistic effects on mold inhibition when vanillin and
      potassium sorbate are applied in combination.

PMID- 10340679
TI  - Purification and characterization of three extracellular proteinases produced by
      Pseudomonas fluorescens INIA 745, an isolate from ewe's milk.
AB  - Three proteinases were isolated from culture medium of Pseudomonas fluorescens
      INIA 745 and purified to homogeneity by a combination of Phenyl-Sepharose, DEAE
      Sepharose, and Sephadex G-100 chromatography. Optimal temperature for enzymatic
      activity was 45 degrees C for all three proteinases. The pH optimum of
      proteinases I and II was found to be 7.0, while that of proteinase III was 8.0.
      Divalent metal ions like Cu2+, Co2+, Zn2+, Fe2+, and Hg2+ were inhibitory to
      proteinase activity while Ca2+, Mg2+, and Mn2+ had little or no inhibitory
      effect. The three enzymes were strongly inhibited by EDTA and 1,10-phenantroline
      and partially by cysteine. The three enzymes are metalloproteinases since they
      were inhibited by chelators and reactivated by Co2+, Mn2+, Cu2+, and Zn2+. The Km
      values of proteinases I, II, and III for casein were calculated to be 3.2, 2.6,
      and 5.2 mg/ml, respectively. Proteinases II and III rapidly degraded beta-casein,
      with preference to alphas1-casein, whereas proteinase I hydrolyzed both casein
      fractions at a slow rate.

PMID- 10340680
TI  - Stability of tetracycline antibiotics in raw milk under laboratory storage
      conditions.
AB  - Raw milk samples collected from bulk milk tankers may be screened for the
      presence of tetracycline antibiotics using rapid screening tests. If tetracycline
      residues are detected, the milk may be shipped to a laboratory for high-pressure
      liquid chromatography (HPLC) analysis. Because the milk may be shipped on ice
      blocks, it is important to know whether tetracycline residues are stable at that
      temperature and for how long. Control raw milk samples fortified with 50 ppb each
      chlortetracycline, demeclocycline, methacycline hydrochloride, minocycline,
      oxytetracycline, and tetracycline were incubated at 4 degrees C or 25 degrees C,
      then analyzed using a metal chelate affinity chromatography extraction and HPLC.
      No loss of tetracycline was observed after 48 h of storage at 4 degrees C or 24 h
      at 25 degrees C. Losses ranging from 4 to 13% and 0 to 18% were noted after 72 h
      at 4 degrees C and 48 h at 25 degrees C, respectively.

PMID- 10340681
TI  - Introduction: What makes an antipsychotic atypical?

PMID- 10340682
TI  - Receptor pharmacology of neuroleptics: relation to clinical effects.
AB  - This article reviews the receptor pharmacology of neuroleptics, with a focus on
      newer drugs (e.g., risperidone, olanzapine, sertindole, quetiapine, and
      ziprasidone) in contrast to older compounds. All these newer compounds are
      considered to be atypical neuroleptics based upon certain criteria, which are
      reviewed. Several hypotheses about the molecular mechanisms that explain
      atypicality are considered. Finally, the in vitro receptor binding data presented
      for these compounds are related to the therapeutic and adverse effects of these
      drugs.

PMID- 10340683
TI  - D2 and 5-HT2 receptor effects of antipsychotics: bridging basic and clinical
      findings using PET.
AB  - The advent of a number of new antipsychotics has been paralleled by efforts to
      better delineate their mechanisms of action and, in doing so, further our
      understanding of schizophrenia and its pathophysiology. Technological advances,
      such as positron emission tomography (PET), have proven to be powerful tools in
      this process, allowing us to evaluate in vivo models based primarily on in vitro
      evidence. Combined serotonin-2/dopamine-2 (5-HT2/D2) antagonism represents one
      such model, and we now have PET evidence available that can be extrapolated to
      our understanding and clinical use of both conventional and novel antipsychotics.

PMID- 10340684
TI  - Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic.
AB  - Recent advances in our understanding of schizophrenia along with neuroscience
      insights into antipsychotic medication mechanisms of action have led to a
      renaissance in new drug development, including an expanded therapeutic spectrum
      encompassing more of the symptoms encountered in schizophrenia. Atypical
      antipsychotics, or new generation therapies, also demonstrate greater selectivity
      for therapeutic actions than for extrapyramidal symptoms (EPS). Our modern
      armamentarium of drugs spans a wide range of pharmacologies, and it is more
      accurate to envision shades of gray rather than a black-and-white description for
      typical versus atypical properties of medications. As our paradigms for
      antipsychotic efficacy have shifted, a reexploration of the "older" neuroleptics
      is warranted to determine if they possess pharmacologic attributes that might
      have been overlooked during the era of high-dose neuroleptic therapy. Loxapine
      appears to be in the center of this spectrum, somewhere between haloperidol and
      risperidone. Dosing implications for drugs with a more even serotonin-2A (5-HT2A)
      receptor and dopamine-2 (D2) receptor blocking effect are discussed. Loxapine
      might have a window of partial atypicality at doses < or = 50 mg/day. These lower
      doses might have potential as both monotherapy in responsive patients with
      persistent psychotic disorders and as an adjunctive treatment in partially
      responding patients on concurrent atypical antipsychotic treatments. The
      pharmacologic properties of loxapine within its usable dosage range are quite
      complex and are the net sum of the parent's plus metabolites' contributions
      (demethylation and hydroxylation by cytochrome P450 enzymes). These pharmacologic
      effects include alpha-adrenergic blockade, inhibition of the noradrenergic
      transporter protein (reuptake inhibition), and antimuscarinic effects. Drug
      interactions and cigarette smoking might alter the parent-to-metabolite
      concentration ratios, affecting the relative atypicality of this antipsychotic
      therapy. Moreover, with the intramuscular formulation, which does not undergo
      first-pass metabolism, the parent compound of loxapine, i.e., not its
      metabolites, is predominantly detected in the plasma of patients, reducing the
      likelihood for EPS during emergency interventions in patients with positive
      symptoms. Further study is warranted to determine loxapine's place in our
      treatment of schizophrenia.

PMID- 10340685
TI  - Selecting an atypical antipsychotic by combining clinical experience with
      guidelines from clinical trials.
AB  - Three atypical antipsychotics are currently considered to be first-line therapies
      for schizophrenia, namely risperidone, olanzapine, and quetiapine. Deciding which
      one of these agents to choose for any given patient can be a daunting task
      because head-to-head comparisons of these 3 agents are just beginning, and most
      published trials are comparisons with typical antipsychotics, not with another
      atypical antipsychotic. Furthermore, results from clinical trials often do not
      match findings from clinical practice. Thus, guidelines for selection and use of
      the atypical antipsychotics are evolving from controlled studies as well as from
      clinical judgment based on the practical use of these agents once they have
      entered clinical practice. The atypical properties of first-line atypical
      antipsychotics as well as clozapine are reviewed here, with clinical pearls and
      dosing tips for each based upon a consensus of information from both clinical
      trials and clinical practice. The conventional antipsychotic loxapine is also
      reviewed and proposed as a potentially valuable agent to augment atypical
      antipsychotics when patients do not experience an acceptable treatment response
      from monotherapy with an atypical antipsychotic. By integrating information from
      clinical trials and clinical practice, the prescriber can be in a better position
      to choose which atypical antipsychotic to select for any given patient.

PMID- 10340686
TI  - Does loxapine have "atypical" properties? Clinical evidence.
AB  - Given findings at a pharmacologic level that loxapine has a ratio of serotonin (5
      HT2) and dopamine (D2) binding affinity similar to that of the atypical
      antipsychotics, 1 review data at a clinical level to see if this agent has
      correlating effects on symptoms and behaviors. I conclude that there is reason to
      infer that loxapine may be more beneficial for negative symptoms and refractory
      states than other typical antipsychotic agents. However, because of the
      limitations within these older studies, controlled fixed-dose designs employing
      current outcome methodologies are needed before concluding that loxapine is an
      atypical antipsychotic agent.

PMID- 10340687
TI  - Low-dose loxapine in the treatment of schizophrenia: is it more effective and
      more "atypical" than standard-dose loxapine?
AB  - Loxapine is chemically related to clozapine and shares with it and other atypical
      antipsychotic drugs relatively greater affinity for serotonin (5-HT)2A than for
      dopamine D2 receptors. However, as is the case for risperidone, the occupancy of
      5-HT2A and D2 receptors can range from partial to full, depending upon the dose.
      It was, therefore, of interest to determine whether loxapine at low doses (< 50
      mg/day) might be at least as or more effective and more tolerable than usual
      clinical doses (> or = 60 mg/day). We retrospectively examined data from 75
      patients treated with loxapine and found psychopathology data from 10 and 12
      patients treated with low-dose or standard-dose loxapine, respectively. No data
      were available on the other 53 patients, 28 of whom were initially treated with
      low-dose and 25 with standard-dose loxapine. For those treated for at least 6
      weeks, there was evidence of equivalent efficacy for both low- and standard-dose
      loxapine with regard to improvement in Brief Psychiatric Rating Scale (BPRS) and
      Global Assessment Scale scores. There were 6 patients with a history of
      neuroleptic resistance among the 22 completers. Four of the low-dose group (40%)
      and 8 of the standard-dose group (67%) had at least a 20% decrease in BPRS total
      scores. Further study of the dose-response curve for loxapine and its usefulness
      in treating neuroleptic-resistant schizophrenia is indicated.

PMID- 10340688
TI  - The role of typical and atypical antipsychotic medications in the management of
      agitation and aggression.
AB  - The management of agitation and aggression in psychiatric inpatients is a
      significant clinical dilemma. Establishing a clear diagnosis and distinguishing
      whether aggression is an acute manifestation or a long-standing or repetitive
      problem are fundamental antecedents of medication treatment. For acute
      aggression, either benzodiazepines or antipsychotic medications (typical and
      atypical) are recommended choices. Currently, on the basis of efficacy, ease of
      use, and availability in multiple (tablet, liquid, intramuscular) preparations,
      typical antipsychotics such as loxapine should be considered as first choice for
      acute aggression (in psychosis). On the other hand, atypical antipsychotics,
      particularly clozapine, should be considered when aggression in psychosis
      persists and/or is repetitive. Typical antipsychotics are indicated for
      persistent aggression in psychosis when medication noncompliance is the obstacle
      to effective treatment.

PMID- 10340689
TI  - Should there be a breast cancer risk chart for New Zealand women?

PMID- 10340690
TI  - Hydatid disease in New Zealand. What remains and how should we treat it?
AB  - AIM: The incidence of hydatid disease in New Zealand has steadily declined since
      the introduction of control measures in the early 1960s. However, patients
      continue to present for management of newly recognised, disseminated or recurrent
      disease. It is desirable that doctors in New Zealand have some knowledge of
      current patterns of presentation and management of the disease. METHODS: Twenty
      five patients with hydatid disease have been seen and managed over a ten-year
      period by one hepato-biliary surgeon. Their presentation and management is
      outlined and discussed. Surgery, after pre-treatment with albendazole, was
      undertaken in 15 patients where eradication seemed possible and desirable and in
      three others presenting with complications (infection, rupture, fistulation).
      Albendazole treatment alone was used in six patients (five with uncomplicated
      recurrent or disseminated disease) and one patient has simply been observed.
      RESULTS: There were no deaths in 18 patients who underwent surgery and no
      recurrent disease has been found. Major morbidity was confined to those having
      surgery for complications. All six patients who received albenzadole alone had a
      good clinical and radiological response, though they required follow-up.
      CONCLUSIONS: It is suggested that surgery (with albendazole pre-treatment) should
      be reserved for those with either curable disease or complications and that all
      others should be managed, in the first instance, by albendazole alone. Providing
      treatment is instituted before complications develop it should be associated with
      minimal morbidity.

PMID- 10340691
TI  - Meningococcal disease and meningitis: a review of deaths proceeding to coroner
      directed autopsy in Auckland.
AB  - AIMS: To assist the early diagnosis of meningitis, by finding trends and patient
      profiles, where delay or other factors may have lead to a fatal outcome. METHODS:
      All deaths from meningitis and meningococcal disease, confirmed at autopsy were
      reviewed. The study involved the Auckland area, in the period January 1988
      November 1997. RESULTS: Cases were divided into those caused by N meningitidis
      and other meningitides. Death due to N meningitidis is often within 12-24 hours
      of the first symptomatology. Symptoms are often vague and may be
      indistinguishable from any other infection, often leading to fatal patient or
      doctor delay. A diagnosis of meningococcal disease cannot be excluded on: no rash
      (44%), no "meningitis" symptoms as sepsis without meningitis occurs (44%), age
      (50% were over 15 years old) or the presence of other abnormalities, eg
      bronchopneumonia or hydrocephalus. Non-N meningitidis menigitis is a disease of
      the very young or old, its time course is also swift with 30% suffering similar
      vague symptoms for less than 24 hours before death. CONCLUSIONS: For both
      categories, treat immediately and treat on suspicion, otherwise conformation of
      the diagnosis might be postmortem.

PMID- 10340692
TI  - Stingray injuries: a lesson in debridement.

PMID- 10340693
TI  - New classification and criteria for diagnosis of diabetes mellitus. The
      Australasian Working Party on Diagnostic Criteria for Diabetes Mellitus.
AB  - Diagnosis of diabetes is not in doubt when there are classical symptoms of thirst
      and polyuria and a random venous plasma glucose level > or =11.1 mmol/L. The
      Australasian Working Party on Diagnostic Criteria for Diabetes Mellitus
      recommends: Immediate adoption of the new criterion for diagnosis of diabetes as
      proposed by the American Diabetes Association (ADA) and the World Health
      Organization (WHO) - fasting venous plasma glucose level > or =7.0 mmol/L;
      Immediate adoption of the new classification for diabetes mellitus proposed by
      the ADA and WHO, which comprises four aetiological types - type 1, type 2, other
      specific types and gestational diabetes - with impaired glucose tolerance and
      impaired fasting glycaemia as stages in the natural history of disordered
      carbohydrate metabolism; Awareness that some cases of diabetes will be missed
      unless an oral glucose tolerance test (OGTT) is performed. If there is any
      suspicion or other risk factor suggesting glucose intolerance, the OGTT should
      continue to be used pending the final WHO recommendation.

PMID- 10340694
TI  - Diabetes complication screening in general practice: a two pass audit with
      benchmarking.
AB  - AIM: To determine whether a two pass audit cycle of diabetes complication
      screening improves screening rates. METHODS: General practitioners in North
      Canterbury were invited to participate in a diabetes complications screening
      audit. Key complication screening tasks and maximum screening intervals were
      agreed. Patients with diabetes were identified in the primary care setting.
      General practitioners were given the option of participating in group feedback
      sessions between the first and second passes of the audit cycle. RESULTS: 106
      general practitioners and 2234 patients participated in the first pass. Ninety
      three of these 106 general practitioners and 2169 patients participated in the
      second pass. Screening rates either improved or remained unchanged and a small
      improvement was seen in the study population's risk factor profile (i.e. total
      cholesterol and glycated haemoglobin). The group feedback sessions facilitated
      discussion on interpretation of results from the benchmarking exercise, the
      optimal time interval between screening procedures and the development of general
      practice diabetes data sets. CONCLUSION: This two pass primary care audit of
      diabetes complications screening resulted in improved screening rates for
      diabetes complications and a small improvement in the study population's risk
      factor profile.

PMID- 10340695
TI  - Development and evaluation of the Rural Trauma and Emergency Care Roadshow.
AB  - AIMS: To validate the Rural Trauma and Emergency Care (RTEC) Roadshow, an
      educational programme comprised of 14 skills-based, educational modules in trauma
      care designed for rural general practitioners and taught as a travelling roadshow
      in isolated rural areas. METHOD: The first 31 rural general practitioners to
      participate in the course completed an extensive participant satisfaction rating
      form. They also underwent pre-and post-testing of knowledge using a written
      true/false test, of skills using an OSCE examination and of stress related to
      being on call using a self-assessment, Likert scale. RESULTS: Participant
      satisfaction was high with a mean rating of 4.7 (maximum of 5) for overall course
      quality and relevance of content. There was a significant increase in skills
      (from 46 to 73% mean OSCE scores), in knowledge (from 58 to 69% mean true-false
      test scores) and in confidence in handling major trauma (from 3.9 to 5.3 on a ten
      point scale) as a result of the course. CONCLUSION: The RTEC course is effective
      in increasing the skills and knowledge of general practitioners in trauma care.

PMID- 10340696
TI  - Education in occupational medicine.

PMID- 10340697
TI  - A comparison of the antistaphylococcal activity of gentamicin and netilmicin.

PMID- 10340698
TI  - Microtubule severing.
AB  - The regulation of microtubule stability by severing of the polymer along its
      length is a newly appreciated and potentially important mechanism for controlling
      microtubule function. Microtubule severing occurs in living cells, but direct
      observation of this event is infrequent. The paucity of direct observations leave
      open to question the significance of regulated microtubule severing in the
      control of microtubule organization. Nevertheless, several lines of evidence
      suggest that microtubule severing is an important cellular activity. First, the
      ATP-dependent microtubule-severing activity of katanin is well documented.
      Katanin is found in most cell types and is enriched at MTOCs. Although it is
      possible that katanin does not sever microtubules in vivo, this seems unlikely.
      Second, a physiological event, deflagellation, has been shown to depend on
      microtubule severing. The deflagellation system of Chlamydomonas has provided a
      genetic approach to the problem of microtubule severing. The FA genes are
      essential for the regulated severing of axonemal microtubules during
      deflagellation, but whether these genes define new severing proteins or whether
      they are important for katanin activity remains to be determined. Microtubule
      severing is a relatively new area of investigation and there are still many more
      questions than answers. It is anticipated that the recent cloning of katanin and
      the introduction of a genetic model system will soon lead to significant
      breakthroughs in this problem.

PMID- 10340700
TI  - Exertion of tractional force requires the coordinated up-regulation of cell
      contractility and adhesion.
AB  - Although it is understood that cells exert mechanical forces on the extracellular
      matrix to promote structural organization, the exact mechanism of force
      transduction is not clearly understood. Using an in vitro force measurement
      assay, we evaluated two opposing conditions that inhibit or promote matrix
      organization by fibroblasts: serum deprivation and lysophosphatidic acid
      stimulation. Under serum deprivation, in spite of significant cell spreading and
      pseudopodial motility, rabbit corneal fibroblasts generated little or no force on
      the matrix within 2 h of observation. Lysophosphatidic acid stimulation of serum
      starved cells caused dramatic cell contraction (within 2 min), which correlated
      temporally with a rapid increase in the tractional force generation on the matrix
      (0.52 x 10(-7) - 1.9 x 10(-7) N; n = 7 experiments). No cell translocation was
      observed during the period of force generation in response to lysophosphatidic
      acid-stimulation. These findings, taken together with a concomitant up-regulation
      of stress fibers in lysophosphatidic acid stimulated fibroblasts, indicate that
      contractility of non-motile cells involved in forming stress fibers and strong
      cell-matrix adhesion is the principal force-generating mechanism involved in
      matrix organization.

PMID- 10340699
TI  - Erythrocyte membrane fractions contain free barbed filament ends despite
      sufficient concentrations of retained capper(s) to prevent barbed end growth.
AB  - Many cellular functions depend on rapid cytoskeletal rearrangements localized to
      specific cytoplasmic domains. Tight regulation of the submembranous microfilament
      network is accomplished in large part in erythrocytes and granulocytes by actin
      binding proteins that cap the fast-growing barbed filament ends. Study of this
      dynamic system is necessarily hampered by the confounding perturbations of cell
      lysis and dilution. In this paper, we characterize the functional properties of
      the membrane-associated spectrin-actin complex from human erythrocytes as it
      exists after hypotonic lysis. Purified spectrin-actin "seeds" extracted from
      erythrocyte membranes effectively nucleated actin elongation from their barbed
      ends. However, polymerization from spectrin-actin complexes associated with the
      membrane fraction prematurely slowed despite the presence of G-actin in great
      excess of the critical monomer concentration. The addition of cytochalasin B
      decreased (rather than augmented) the slowing of elongation attributable to the
      membrane fraction, indicating that capping of barbed filament ends (not monomer
      sequestration) was the major mechanism underlying this effect. The paradoxical
      implication of our findings is that, despite the presence of excess capper(s) in
      the membrane fraction, the membrane-associated spectrin-actin seeds were not
      capped until after dilution into physiological ionic strength buffer containing
      monomeric actin. Furthermore, by comparing the degrees of contamination of the
      extracted and membrane-associated spectrin-actin preparations, it appeared that
      recognized capping proteins (including gelsolin and capping protein beta2) were
      not the predominant cappers found in the membrane pellet after hypotonic lysis.
      We hypothesize that the barbed ends of membrane-associated spectrin-actin
      complexes, while not excluding actin monomers, may be selectively inaccessible to
      certain cappers (perhaps simply as the result of steric hindrance). Growth from
      such complexes in vivo could be limited by the availability of polymerization
      competent G-actin.

PMID- 10340701
TI  - Estrogen induces cytokeratin aggregation in primary cultures of Armenian hamster
      hepatocytes.
AB  - The effect of estrogen administration to cultured Armenian hamster was studied.
      Isolated Armenian hamster hepatocytes were cultured in RPMI medium supplemented
      with beta-estradiol (E2). Beta-estradiol treatment for 24-48 hr induced
      cytoplasmic inclusion bodies which by immunocytochemistry were positive for
      cytokeratin (CK) 8, CK 18, and ubiquitin but negative for CK 7 and CK 19. These
      inclusion bodies appeared as filamentous tangles or amorphous aggregates when
      observed by electron microscopy. F-actin, tubulin, and desmosomes were not
      influenced by the presence of the inclusion bodies. Addition of ethanol to
      culture medium increased the incidence of the inclusion formation. In combination
      with 0.5% ethanol 1 microM of E2 induced five to six times more inclusion bodies,
      while the number of inclusion bodies decreased when epidermal growth factor (EGF)
      was added to the medium in combination with E2. This reduction effect was
      nullified by treatment with anti-EGF receptor antibody. These findings suggest
      that E2 treatment to Armenian hamster hepatocytes in vitro induces Mallory body
      like inclusions whose incidence can be influenced by addition of ethanol or EGF
      to the culture medium.

PMID- 10340702
TI  - Quantitative measurement of the catastrophe rate of dynamic microtubules.
AB  - Previous work has shown that catastrophe frequency is the predominant dynamic
      parameter of microtubules that changes dramatically during the cell cycle. As an
      alternative to videomicroscopy assays, we have developed a biochemical assay to
      measure directly the average catastrophe rate of a population of microtubules. In
      this assay, the growing plus end of the microtubules, polymerized off seeds, are
      labeled with a brief pulse of alpha-32P-GTP, followed by a cold GTP chase. The
      rate of loss of 32P label in microtubules measured by this method is equal to the
      catastrophe frequency at microtubule plus ends measured by videomicroscopy of
      individual microtubules. Addition of mitotic extract from Xenopus eggs increases
      the catastrophe rate of purified tubulin by almost 100-fold, while interphase
      extract alters the catastrophe rate by about 20-fold as compared to pure tubulin.
      Most of the catastrophe-promoting activities in both mitotic and interphase
      extracts is found in particulate fractions. High-speed centrifugation of extracts
      appears to eliminate the components required for increasing microtubule
      catastrophe, but does not eliminate the cell cycle difference in microtubule
      dynamics. This assay provides a new approach to quantitate microtubule
      catastrophe rates. It will be of particular interest to search for catastrophe
      factors associated with intracellular membranes or other insoluble components.

PMID- 10340703
TI  - Characterization of the mammalian septin H5: distinct patterns of cytoskeletal
      and membrane association from other septin proteins.
AB  - The mechanisms controlling cytokinesis during yeast budding and animal cell
      fission appear quite different, yet both require members of the septin protein
      family. Mammalian homologs of this novel family of GTPases have been identified
      but little is known about their properties or functions. Using an antibody
      specific for the mammalian septin H5, we show that this protein is expressed at
      distinct levels in a variety of tissues. Tissue expression levels in different
      tissues did not coincide with those of the only previously characterized
      mammalian septin Nedd5. H5, like Nedd5, localizes to the cleavage furrow in
      mitotic fibroblast cells but in non-mitotic cells these proteins associate with
      actin filaments in different ways. Nedd5 predominantly localizes with stress
      fibers, but only associates with central portions of the microfilament bundles.
      In contrast, H5 associates with the entire length of the stress fibers and the
      cortical actin network. Conditions that disrupt the actin cytoskeleton also
      disrupt the filamentous patterns of both Nedd5 and H5, resulting in a punctate
      cytoplasmic pattern. Cell fractionation revealed that H5 co-fractionated with
      actin, while Nedd5 was predominantly restricted to the membrane fraction. Co
      immunoprecipitation experiments revealed that although H5 will co-precipitate
      with Nedd5, the precipitation is not quantitative. Taken together, these results
      not only show that H5 behaves like a septin, but also demonstrate that individual
      septin proteins have distinct properties, suggesting that they may play different
      roles in cytokinesis and in other stages of the cell cycle.

PMID- 10340704
TI  - Preparation and properties of pure tubulin S.
AB  - Limited proteolysis of the tubulin dimer (alphabeta) by subtilisin occurs more
      rapidly with beta than with alpha tubulin. This leads to the formation of an
      intermediate hybrid dimer, alphabeta(s), before both C termini are cleaved to
      form tubulin S(alpha(s)beta(s)). The three forms of tubulin usually coexist in
      subtilisin-treated preparations and such cross-contamination can be reliably
      detected only by running SDS-polyacrylamide gels well beyond expulsion of the dye
      front. Previously published preparations have not ruled out such contamination or
      have formed poorly reversible polymers. Because ion exchange separation incurred
      substantial protein losses, we have developed a new protocol for rapid
      preparation of tubulin S (alpha(s)beta(s), free of alphabeta or alphabeta(s))
      that is based on proteolysis at low ionic strength. This increases the relative
      rate of C terminal cleavage of beta tubulin. The product forms sheets, bundles,
      or rings that are depolymerized by cold, salt, and podophyllotoxin, partially
      depolymerized by Ca2+, and has a decreased critical concentration for
      polymerization that can be further decreased by taxol. We have also found a
      method for forming nearly pure alphabeta(s) dimers by using methods that retard
      proteolysis of the C terminus of alpha tubulin.

PMID- 10340705
TI  - Centrin-like filaments in the cytopharyngeal apparatus of the ciliates Nassula
      and Furgasonia: evidence for a relationship with microtubular structures.
AB  - The cytopharyngeal apparatus in the Nassulinid ciliates Nassula and Furgasonia is
      a highly specialized microtubular/filamentous organelle designed for ingestion of
      organisms such as filamentous bacteria. From studies on living cells, it was
      previously shown that this organelle, also called "feeding basket," guides the
      filamentous bacteria and manipulates them to some extent during the early steps
      of ingestion. This results in a complex sequence of movements where the basket is
      successively dilated and constricted in its upper part. Whereas some of these
      movements (dilation) seem to be intrinsic to the microtubular components of the
      basket, others (constriction) are believed to be mediated by contractile
      filamentous structures [Tucker, 1968: J. Cell Sci. 3:493-514]. In this study, we
      have used antibodies raised against ciliate centrins to demonstrate these
      proteins by Western blot and immunocytochemical methods in Nassula and
      Furgasonia. In both ciliates, a 20-kDa centrin immunoanalog was localized in the
      upper (contractile) part of the cytopharyngeal apparatus. Immunoelectron
      microscopy revealed that cytopharyngeal centrin is engaged in filamentous
      material, forming a sphincter-like structure possibly involved in the movements
      of contraction. Interestingly, physical links were noted between filaments
      labeled for centrin and cytopharyngeal microtubules. The mechanistic implications
      of these findings are discussed.

PMID- 10340706
TI  - Live virulent Rhodococcus equi, rather than killed or avirulent, elicits
      protective immunity to R. equi infection in mice.
AB  - Mice inoculated intravenously with a sublethal dose of live virulent Rhodococcus
      equi ATCC 33701 that contained an 85-kb virulence plasmid were immune to a lethal
      intravenous challenge of ATCC 33701. This immunity depended upon the dose of
      immunization and developed rapidly: mice primed with 10(5) live ATCC 33701
      eliminated the challenged bacteria more rapidly than mice primed with doses
      ranging from 10(2) to 10(4) bacteria, and mice given 10(5) live ATCC 33701
      intravenously withstood the lethal challenge as early as 5 days after the initial
      inoculation. However, this protective immunity did not develop in mice immunized
      with doses of heat-killed ATCC 33701 ranging from 10(6) to 10(8), or in mice
      immunized with doses of live ATCC 33701P-, a plasmid-cured derivative
      (avirulent), in doses ranging from 10(5) to 10(7). These mice had positive
      antibody titers against R. equi at the challenge (14 days after priming).
      Adoptive transfer of resistance to virulent R equi was obtained with spleen cells
      from mice immunized with live ATCC 33701, but not monoclonal antibody to 15- to
      17-kDa virulence-associated antigens. These results revealed that live ATCC
      33701P-, a plasmid-cured derivative of virulent R equi, could not elicit
      protective immunity, and are consistent with previous observations that
      protective immunity was induced by live virulent, but not killed organisms.

PMID- 10340707
TI  - A new rapid and simple method for large-scale purification of mycobacterial
      lipoarabinomannan.
AB  - Lipoarabinomannan (LAM) is a major and structurally important outer cell wall
      component of all mycobacteria. LAM is also generally regarded as an important
      immunomodulating substance affecting several immunologic networks and hence
      important in the pathogenesis of mycobacterial infections. We here describe a new
      method for large-scale purification of mycobacterial LAM. A crude cell wall
      preparation was prepared from batch-grown Mycobacterium tuberculosis H37Rv. From
      this cell wall preparation LAM was purified by sequential extractions and
      chromatographic steps. From 20 g dry weight cell wall preparation 313 mg of
      highly purified (> 98%) LAM was obtained in only 3 days. The LAM content of the
      final purification step was quantified by ELISA using reference LAM as standard.
      The identity and purity of the LAM preparation was further confirmed by
      comparison with reference LAM preparation from M. tuberculosis strain Erdman in
      polyacrylamide gel electrophoresis and Western blots, using reference anti-LAM
      monoclonals CS-35 and CS-40.

PMID- 10340708
TI  - The effect of dietary lipid manipulation on murine splenic lymphocytes apoptosis
      and heat shock protein over expression.
AB  - In this study, we kept BALB/c mice on a hyperlipidic diet for 120 days and then
      assessed the predisposition to apoptosis and the appearance of heat shock protein
      (Hsp) on splenic lymphocytes. By immunoblot analysis, bands corresponding to Hsp
      60 and Hsp 70 in cells from mice kept on a saturated fatty acid diet showed a
      greater expression already after 1 month while two other bands, which correspond
      to Hsp 25 and Hsp 27, were slightly present after 1 month of treatment. In cells
      from mice kept on a diet rich in unsaturated fatty acid, there was a marked
      expression of Hsp 25 and Hsp 27 after only 30 days of treatment, which was
      maintained constant for up to 4 months; while for bands corresponding to Hsp 60
      and Hsp 70, a significant minor signal was only detectable after 2-4 months from
      the beginning of the treatment. Splenic lymphocytes from animals kept on a
      lipidic diet containing saturated fatty acids were more susceptible to death by
      apoptosis, while cells of animals treated with unsaturated fatty acid were shown
      to be more resistant.

PMID- 10340709
TI  - Phenotypic changes of Helicobacter pylori components during an experimental
      infection in mice.
AB  - The bacterial pathogen Helicobacter pylori is highly adapted to the human stomach
      and the clinical isolates show a high diversity which could be due to adaptative
      changes of the strains passing from one host to another. In order to study these
      variations, experimental infection of mice was developed and provided three out
      of the eleven tested strains able to infect C57BL/6 mice: the Sydney strain which
      is known to be well adapted to mice and two freshly isolated strains from
      infected patients. Mice were orally infected with one of these three strains
      (infecting strains) and were killed 45 days later. H. pylori strains were
      isolated from the stomachs of mice (emerging strains). The three infecting
      strains were compared to the three emerging strains for protein and
      lipopolysaccharide profiles, antigenic profiles revealed by Western blot with
      monospecific sera and genetic status by testing for the cagA gene and the vacA
      genotype. During the 45 days of infection, H. pylori underwent phenotypic
      variations which may be attributed to the adaptation from a human to a mouse
      environment or from an in vitro to a mouse environment. Those variations
      consisted of an over-expression at the cell surface of a 180-kDa protein and of a
      decreased expression of proteins of 260 and 120 kDa. Moreover, antigenic
      variations were shown for the two freshly isolated strains from human: the CagA
      and VacA antigens were in the saline extracts of the infecting strains only while
      the UreA, UreB, HspA and HspB were in the saline extracts of both the infecting
      and the emerging strains. These variations may contribute to the adaptation of
      the strains to the mouse environment.

PMID- 10340710
TI  - Evaluation of immunomodulatory effects of nisin-containing diets on mice.
AB  - The effect of nisin on the immune response of mice was studied. Nisin (in the
      form of the commercial preparation Nisaplin) was incorporated in the diet of
      experimental mice which were fed for 30, 75 or 100 days. Short-term
      administration of diets containing Nisaplin induced an increase of both CD4 and
      CD8 T-lymphocyte cell counts and also a decrease of B-lymphocyte counts. After
      prolonged diet administration, T-cell counts returned to control levels. Normal
      levels of B-lymphocytes were also reached after prolonged administration of the
      lower (but not the higher) Nisaplin concentration. The macrophage/monocyte
      fraction isolated from peripheral blood became significantly increased after long
      term administration (100 days) of Nisaplin-containing diets in a concentration
      dependent way. Although the number of peritoneal cells was not affected by the
      diets, the phagocytic activity of peritoneal cells decreased after prolonged
      administration of low (but not high) Nisaplin doses.

PMID- 10340711
TI  - Bacillus thuringiensis serotype H34 isolated from human and insecticidal strains
      serotypes 3a3b and H14 can lead to death of immunocompetent mice after pulmonary
      infection.
AB  - In 1995, we isolated a strain of Bacillus thuringiensis serotype H34 from severe
      human tissue necrosis. This bacterium was able to induce myonecrosis in
      immunosuppressed mice after cutaneous infection. Its potential pathogenicity for
      immunocompetent hosts was investigated in a mouse model of pulmonary infection.
      Mice infected intranasally by a suspension containing 10(8) spores died within 8
      h in a clinical toxic-shock syndrome. In the same conditions, infection with a
      mutant without crystalline toxin, with the supernatant from a culture containing
      10(8) bacteria ml(-1) and by the insecticidal strain serotypes 3a3b or H14 led to
      identical results. Lower inocula simply induced a local inflammatory reaction
      with bacterial persistence observed during the course of 10 days.

PMID- 10340712
TI  - Spontaneous apoptosis in peripheral blood mononuclear cells of leprosy patients:
      role of cytokines.
AB  - Peripheral blood mononuclear cells from leprosy patients underwent spontaneous
      apoptosis upon culture for 24 h. The apoptosis was inhibited by anti-TNFalpha
      antibodies and to a certain extent by anti-IL-1alpha and IL-6, thus showing that
      T(H)2-type cytokines (mainly TNFalpha) are responsible for inducing apoptosis.
      This cytokine-mediated apoptosis could be inhibited by ionomycin and zinc,
      thereby suggesting that these metal ions can be used to decrease the levels of
      these inflammatory cytokines in various diseases.

PMID- 10340713
TI  - The lipopolysaccharide core type of Escherichia coli O157:H7 and other non-O157
      verotoxin-producing E. coli.
AB  - A mouse monoclonal antibody specific for the R3 lipopolysaccharide core type of
      Escherichia coli was used to determine the core type of E. coli O157:H7 and other
      non-O157 verotoxin-producing E. coli strains. Lipopolysaccharide extracts from 28
      clinical isolates were examined by sodium dodecylsulfate-polyacrylamide gel
      electrophoresis and immunoblotting and all were found to have the R3 core. None
      of the core lipopolysaccharide from the strains tested reacted with the control
      R1 and R2 specific monoclonal antibodies. A common core type between all the
      verotoxin-producing E. coli strains tested may be significant when considering
      the immune response to these bacteria, and to the receptor for the VT
      bacteriophage.

PMID- 10340714
TI  - Non-typical lipopolysaccharide core regions of some Hafnia alvei strains:
      structural and serological studies.
AB  - The lipopolysaccharides of Hafnia alvei strains 23, 1222 and 39 were found to
      have non-typical core region. On the basis of sugar and methylation analyses, 1H
      nuclear magnetic resonance spectra and matrix-assisted laser-desorption
      ionization-time of flight mass spectrometry, it was concluded that the core
      oligosaccharide of strains 23 and 1222 has the same structure as Escherichia coli
      R4 core region, and the core oligosaccharide of strain 39 has the structure of
      Salmonella Ra core. Using the serological methods (passive hemagglutination,
      enzyme-linked immunosorbent assay and immunoblotting) and the anti-conjugate sera
      directed against E. coli R4 and Salmonella Ra core oligosaccharides we have
      confirmed the structural results presented above.

PMID- 10340715
TI  - Detection of IgG and IgM to meningococcal outer membrane proteins in relation to
      carriage of Neisseria meningitidis or Neisseria lactamica.
AB  - Carriage of non-serogroupable Neisseria meningitidis or Neisseria lactamica
      induces antibodies protective against meningococcal disease. Antibodies directed
      against outer membrane proteins are bactericidal and the serotype and subtype
      outer membrane protein antigens are being examined for their value as vaccine
      candidates for serogroup B disease. The aim of this study was to examine the
      effect of carriage of these two Neisseria species among children and young adults
      on induction of antibodies to outer membrane components from strains causing
      disease in Greece. Among 53 patients with meningococcal disease, IgG or IgM
      antibodies were detected by ELISA in 9 of 13 (69%) from whom the bacteria were
      isolated and 27 of 40 (67%) who were culture-negative. For military recruits (n =
      604), the proportion of carriers of meningococci with IgM or IgG to outer
      membrane proteins was higher than non-carriers, P < 0.05 and P = 0.000000,
      respectively. Among school children (n = 319), the proportion with IgM or IgG to
      outer membrane proteins for carriers of meningococci was higher compared with non
      carriers, P = 0.000000 and P = 0000043, respectively. Carriage of N. lactamica
      was not associated with the presence of either IgM or IgG to the outer membrane
      proteins in the children. The higher proportion of children (50%) with IgM to
      outer membrane proteins compared with recruits (10%) might reflect more recent
      exposure and primary immune responses to the bacteria. The lack of association
      between antibodies to outer membrane proteins and carriage of N. lactamica could
      reflect observations that the majority of N. lactamica isolates from Greece and
      other countries do not react with monoclonal typing reagents. Bactericidal
      antibodies to meningococci associated with high levels of IgG to N. lactamica
      were found in a previous study; these are thought to be directed to antigens
      other than outer membrane proteins or capsules and imply antigens such as lipo
      oligosaccharide are involved in induction of antibodies cross-reactive with
      meningococci.

PMID- 10340717
TI  - Modulation of lectinophagocytosis of Escherichia coli by variation of pH and
      temperature.
AB  - The effect of variation of pH and temperature on the lectinophagocytosis of
      enteropathogenic Escherichia coli by polymorphonuclear leukocytes and macrophages
      elicited by thioglycolate medium was evaluated. The phagocytosis of
      enteropathogenic E. coli is dependent on pH, being maximal at pH 7.0 and reduced
      at pH 5.5 or 6.0. Mannan and mannose (as representative sugars that bind to
      phagocyte lectin receptors), are recognized by mannose receptors and reduced the
      phagocytic index at pH 7.0 (from 41.6 +/- 8.5 to 17.0 +/- 6.1) and at pH 6.0
      (from 24.1 +/- 5.1 to 14.5 +/- 5.0), suggesting that mannose receptors, despite
      their reduced affinity for ligand at pH 6.0, also participate in phagocytosis of
      enteropathogenic E. coli. The inhibition of phagocytosis by anti-substance A
      antibody was also examined at pH 7.0 and at pH 6.0, decreasing (from 41.6 +/- 8.5
      to 21.1 +/- 3.4) and (from 24.1 +/- 5.1 to 12.0 +/- 3.5), respectively. This
      antibody reduced the phagocytosis of enteropathogenic E. coli in phagocytic
      assays at 37 or 41 degrees C. These results suggest that the acidic pH decreased
      the affinity of mannose receptors to ligands on the surface of E. coli and also
      affected the binding of lectin from E. coli to N-acetylgalactosamine on
      phagocytes.

PMID- 10340716
TI  - Lack of a relationship between Lewis antigen expression and cagA, CagA, vacA and
      VacA status of Irish Helicobacter pylori isolates.
AB  - The cagA gene, vacA gene, CagA (cytotoxin-associated gene A product) and VacA
      (vacuolating cytotoxin) status of a collection of Helicobacter pylori isolates
      from the geographically distinct Irish population was determined, the potential
      association of these traits with Lewis (Le) antigen expression was assessed, and
      the relationship between these bacterial properties and the pathology associated
      with H. pylori infection was evaluated. Of the 57 isolates, a higher proportion
      from ulcer than from non-ulcer patients expressed VacA (71% vs. 53%). H. pylori
      isolates which were cagA-positive were no more significantly associated with
      peptic ulcers than non-ulcer disease (71% vs. 67%, P = 0.775), nor were CagA
      positive isolates (57% vs. 50%, P = 0.783), but 80% of the isolates from duodenal
      ulcer patients were cagA-positive. Thirty-seven of the 57 isolates were tested
      for Le antigen expression. No statistically significant relationship (P > 0.05)
      was found between the occurrence and level of expression of Le(x) or Le(y) and
      cagA, vacA, or VacA status. This lack of an association in the Irish H. pylori
      isolates contrasts with that previously reported for predominantly North American
      isolates, and may be attributable to the adaptation of H. pylori strains with
      differing attributes to different human populations.

PMID- 10340718
TI  - Role of interleukin-2 receptor expression on macrophages from Salmonella-infected
      mice.
AB  - In this study, it was found that macrophages from Salmonella-infected mice
      expressed the interleukin-2 receptor (IL-2R). The IL-2R induced by the infection
      consisted mainly of both beta and gamma chains, and the expression of IL-2Ralpha
      was very low. Furthermore, similar expression of IL-2Rbeta and gamma chains was
      observed in interferon-gamma-treated macrophages. The effect of recombinant
      interleukin-2 on the intracellular killing activity of macrophages which
      expressed IL-2Rbeta and gamma was then studied. Our results demonstrated that
      interleukin-2 acted synergistically with interferon-gamma through the IL-2R in
      the induction of macrophage intracellular killing activity and established a new
      role of IL-2R on bactericidal activity of macrophages.

PMID- 10340719
TI  - Tissue culture adherence and haemagglutination characteristics of Moraxella
      (Branhamella) catarrhalis.
AB  - The haemagglutination and tissue culture adherence properties of 20 isolates of
      Moraxella catarrhalis obtained from the sputum of elderly patients with lower
      respiratory tract infections were compared with those of 20 isolates of M.
      catarrhalis obtained from the nasopharynx of elderly persons colonised by the
      organism. Eighty percent of isolates from the infected group as opposed to 5% of
      isolates from the colonised group haemagglutinated human erythrocytes (P <
      0.001), indicating that the haemagglutinin might be a marker of pathogenicity for
      M. catarrhalis. There was a significant difference in the adherence to HEp-2
      cells of isolates from the infected group in comparison to isolates from the
      colonised group (P = 0.03). Haemagglutination and tissue culture adherence
      properties were unrelated, indicating that separate adhesin systems are involved.
      The adherence of M. catarrhalis to HEp-2 cells was unaffected following pronase
      and trypsin treatment, however, sodium periodate pre-treatment of the bacteria
      significantly reduced the tissue culture adherence index, indicating that the
      adhesin by which the bacteria bind to HEp-2 cells may have a carbohydrate moiety.
      Transmission electron microscopy studies revealed that adherence of M.
      catarrhalis to HEp-2 cells was mediated by trypsin-resistant 'tack-/spicule-like'
      structures protruding from the surface of the bacteria.

PMID- 10340720
TI  - Pathological effect of synthetic cereulide, an emetic toxin of Bacillus cereus,
      is reversible in mice.
AB  - Cereulide is the causative toxin of the emetic type of food-borne illness caused
      by Bacillus cereus. This toxin was previously shown to be associated with
      fulminant liver failure in a human case. Mice were injected i.p. with synthetic
      cereulide and the development of histopathological changes was examined.
      Hepatocytes showed mitochondrial swelling with loss of cristae, and dose
      dependent increase of small fatty droplets. These microsteatotic hepatocytes were
      distributed mainly in the pericentral area. At higher cereulide doses, massive
      degeneration of hepatocytes occurred. The serum values of hepatic enzymes were
      highest on days 2-3 after the inoculation of cereulide, and rapidly decreased
      thereafter. General recovery from the pathological changes and regeneration of
      hepatocytes was observed after 4 weeks.

PMID- 10340721
TI  - Day/night variation of tryptophan hydroxylase and serotonin N-acetyltransferase
      mRNA levels in the ovine pineal gland and retina.
AB  - In mammals, the photoperiodic information, received by the retina, is transmitted
      to the pineal gland. In both organs, melatonin is produced and functions as a
      neurohormone giving temporal information to the organism. A four-step enzymatic
      pathway, involving in particular the tryptophan hydroxylase (TPOH), the rate
      limiting enzyme in serotonin synthesis, and the serotonin N-acetyltransferase
      (NAT) that converts serotonin to N-acetylserotonin, allows the synthesis of
      melatonin. Many studies on melatonin synthesis modulation have focused on the
      enzyme NAT, but the regulation of TPOH is less well understood. We report here a
      quantitative study, using a reverse transcription polymerase chain reaction (RT
      PCR) analysis, of the nycthemeral expression of TPOH and NAT mRNAs in the ovine
      retina and pineal gland. In both organs, we show a nocturnal increase in mRNA
      levels of the two enzymes. suggesting a role of transcriptional mechanisms in the
      regulation of melatonin synthesis. However, the amplitude of the observed
      increase in TPOH and NAT mRNAs expression can not entirely explain the 7-fold
      nocturnal increase in the plasma melatonin level. Our results suggest that, in
      the sheep, post-transcriptional mechanisms might also be involved in the
      day/night modulation of melatonin production.

PMID- 10340722
TI  - Zinc accumulation in adriamycin-induced cardiomyopathy in rats: effects of
      melatonin, a cardioprotective antioxidant.
AB  - We have recently reported that melatonin protects against adriamycin-induced
      cardiomyopathy whose pathogenesis may involve free radicals and lipid
      peroxidation. Melatonin has also been shown to affect zinc turnover. Since zinc
      may act as an antioxidant, we investigated the role of zinc in the pathogenesis
      of adriamycin-induced cardiomyopathy as well as in the treatment of melatonin
      against this disorder. Sprague-Dawley rats were given adriamycin (cumulative
      dose, 15 mg/kg); melatonin (cumulative dose, 84 mg/kg); adriamycin plus
      melatonin; adriamycin plus probucol, another antioxidant (cumulative dose, 90
      mg/kg); or vehicle alone, according to previously-used regimens. Cardioprotective
      effects of both antioxidants (melatonin and probucol) were confirmed by the
      parameters of fractional shortening, heart weight, heart/body weight ratio,
      ascites volume, and mortality. Adriamycin increased both the myocardial and
      plasma levels of thiobarbituric acid reactive substances (TBARS) and myocardial
      zinc levels, and decreased plasma zinc levels. The significant negative
      correlation observed between the myocardial and plasma zinc levels (r = 0.73, P <
      0.01) among the samples of adriamycin-treated and control rats suggested an
      internal redistribution of zinc. Melatonin and probucol were equally effective in
      inhibiting the increase in myocardial TBARS as well as zinc levels, suggesting
      that myocardial zinc accumulation might be a protective response against
      adriamycin-induced oxidative stress. Melatonin also inhibited the adriamycin
      induced decrease in plasma zinc levels; probucol was not as effective in doing
      so. In addition to melatonin's antioxidative effect, it may have the effect of
      maintaining the plasma zinc levels.

PMID- 10340723
TI  - Melatonin receptors in PC3 human prostate tumor cells.
AB  - Melatonin, secreted nocturnally by the pineal gland, can bind to human benign
      prostate epithelial cells and attenuate their growth and viability. In the
      present study, melatonin binding and responses were explored in the human steroid
      independent PC3 prostatic tumor cells. PC3 cells bound 125I-melatonin with low
      affinity (Kd ca. 0.9 nM) at high as well as low cell density. Melatonin enhanced
      cGMP and 3H-thymidine incorporation at low, but attenuated them at high cell
      density. In addition, melatonin inhibited cAMP at low, but augmented it at high
      cell density. These effects were associated with an increase in cell count at low
      but not high-density cultures. Pertussis toxin treatment suppressed 125I
      melatonin binding and ablated all the effects of melatonin on 3H-thymidine
      incorporation, cAMP, and cGMP at both cell densities. Cholera toxin treatment
      failed to block the effects of melatonin on 3H-thymidine incorporation, but
      prevented the modulation by melatonin of cAMP at low and cGMP at high cell
      density. The cGMP analog 8-Br-cGMP, inhibited melatonin's effects on 3H-thymidine
      incorporation at both cell densities. H89, a protein kinase A inhibitor,
      prevented melatonin's effects on 3H-thymidine incorporation at low but not high
      cell density. These results provide the first demonstration of direct interaction
      of melatonin with hormone-insensitive prostate tumor cells. The melatonin
      receptors in the PC3 cells are coupled to pertussis toxin-sensitive G proteins to
      induce cell density-dependent changes in cGMP, cAMP, and cell growth.

PMID- 10340724
TI  - The pineal and extra-pineal origins of 5-sulphatoxy N-acetyl-serotonin in humans.
AB  - In humans 6-sulphatoxy melatonin (SaMT) is the principal metabolite of endogenous
      and exogenous melatonin. 5-sulphatoxy N-acetyl-serotonin (SNAS) is a minor
      metabolite of exogenous melatonin, but it has not been established whether the
      levels of endogenous SNAS in plasma derives principally from endogenous
      melatonin. We have developed the first radioimmunoassay (RIA) for SNAS and used
      it (together with RIAs for melatonin and SaMT) to determine whether endogenous
      SNAS derives from endogenous melatonin or from platelet serotonin. Our results
      show a) the values of endogenous SNAS, unlike endogenous SaMT, increased with
      blood collection procedures that increased the values of serotonin, b) the values
      of endogenous SNAS in urine or in platelet-poor plasma were approximately the
      same as those of endogenous SaMT, but, unlike SaMT, did not show a diurnal
      rhythm, and c) we confirmed that SNAS was a minor metabolite of orally ingested
      melatonin. Thus, our conclusion is that SNAS is a minor metabolite of exogenous
      melatonin, but is not a significant metabolite of endogenous melatonin. In all
      probability, endogenous SNAS is principally the metabolite of platelet serotonin.

PMID- 10340725
TI  - The pineal secretory product melatonin reduces hydrogen peroxide-induced DNA
      damage in U-937 cells.
AB  - Melatonin, the chief secretory product of the pineal gland, is a potent and
      efficient endogenous radical scavenger. Thus, melatonin was shown to protect
      different biomolecules, such as DNA, membrane lipids, and cytosolic proteins,
      from oxidative damage induced by oxygen-derived free radicals. In order to study
      the protective role of melatonin in hydrogen peroxide (H2O2)-induced DNA damage,
      U-937 cells were treated with different concentrations of H2O2, either in the
      presence or absence of melatonin, and DNA damage was assessed using the
      cytokinesis-block micronucleus technique. Melatonin diminished H2O2-induced
      micronuclei production both in short and long treatments. Additionally, melatonin
      concentrations higher than 1 microM were capable of protecting cells from
      spontaneous micronuclei production. These data suggest that melatonin, an
      endogenous antioxidant and nontoxic compound, may have an important role in
      protecting cells from genetic damage due to free radicals, supporting the idea of
      this hormone as a possible therapeutic agent in preventing aging and age-related
      diseases.

PMID- 10340726
TI  - Pharmacological aspects of N-acetyl-5-methoxytryptamine (melatonin) and 6-methoxy
      1,2,3,4-tetrahydro-beta-carboline (pinoline) as antioxidants: reduction of
      oxidative damage in brain region homogenates.
AB  - Oxygen consumption is a necessity for all aerobic organisms, but oxygen is also a
      toxic molecule that leads to the generation of free radicals. The brain consumes
      a high percentage of the oxygen inhaled (18.5%), and it contains large amounts of
      unsaturated fatty acids, which makes it highly susceptible to lipid peroxidation.
      Melatonin (N-acetyl-5-methoxytryptamine), the main secretory product of the
      pineal gland, is a free radical scavenger that was found to protect against lipid
      peroxidation in many experimental models. Another compound found in the pineal
      gland is pinoline (6-methoxy-1,2,3,4-tetrahydro-beta-carboline). Pinoline is
      structurally related to melatonin. Evidence suggests that pinoline may have an
      antioxidant capacity similar to that of melatonin. In this study, the ability of
      pinoline to protect against H2O2-induced lipid peroxidation of different rat
      brain homogenates (frontal cortex, striatum, cerebellum, hippocampus, and
      hypothalamus) was investigated. The degree of lipid peroxidation was assessed by
      estimating the levels of thiobarbituric acid reactive substances, malondialdehyde
      (MDA) and 4-hydroxyalkenals (4-HDA). Pinoline's antioxidant capacity was compared
      with that of melatonin. Both melatonin and pinoline reduced the level of MDA and
      4-HDA in a dose-dependent manner in all brain regions tested. To compare the
      antioxidant capacities, percent-inhibition curves were created, and the IC50
      values were calculated. The IC50 values for melatonin were higher in all brain
      regions than were those for pinoline. The IC50 values for melatonin in the five
      different brain regions ranged from 0.16 mM-0.66 mM, and for pinoline, they
      ranged from 0.04 mM-0.13 mM. The possibility of synergistic interactions between
      melatonin and pinoline were also determined using the method of Berenbaum. Little
      evidence for either synergistic, additive, or antagonistic interactions between
      melatonin and pinoline was found.

PMID- 10340727
TI  - Inappropriate calls to an emergency medical despatch centre via cellular
      telephones--no impact of a once-only multimedia coverage.
AB  - Due to fusions of emergency despatch centres, implementation of computer-aided
      localization and medical regulation, the despatcher's workload is increasing. We
      report about one more phenomenon which is needlessly disorganizing alarm centres.
      Moreover, the unintentional activation of the '100' ('112') alarm centre
      continued to increase even after a once-only media campaign.

PMID- 10340728
TI  - Patients with recurrent injuries--psychosocial characteristics and injury
      panorama.
AB  - Accidents are often considered to be a direct function of exposure to risk, but
      this study implies that there are subgroups of patients that expose themselves to
      more risks than others. Based on a consecutive series of moderately injured
      patients this study aimed to compare patients with repeated trauma episodes with
      patients with single trauma. The study showed that the former had experienced
      more violence during their lives, had a less favourable psychosocial situation
      and more often reported psychiatric problems and alcohol abuse compared with the
      latter, confirming the clinical knowledge that injury recurrence is associated
      with risk factors such as alcohol abuse, pre-existing psychopathology and a
      propensity towards violence.

PMID- 10340729
TI  - Relevance in the emergency department of a decisional algorithm for outpatient
      care of women with acute pyelonephritis.
AB  - The outcome of three types of management for patients with acute pyelonephritis,
      in an emergency department is assessed. This was carried out by a prospective
      enrolment of patients with acute pyelonephritis. Through a decisional algorithm,
      doctors were encouraged to discharge female patients under 60 years with acute
      uncomplicated pyelonephritis, either directly from the emergency ward or after a
      short stay in the observation unit. All received a single intravenous dose of
      pefloxacin, after urine and blood cultures were obtained; before discharge a
      normal ultrasonography of the abdomen and the pelvis was required. Conversely,
      hospitalization was advised for patients who did not fit the criteria of
      uncomplicated pyelonephritis. Only females with positive urine cultures
      qualified. Of 83 patients enrolled, 70 were females with positive urine cultures,
      60 of whom had uncomplicated pyelonephritis. At 3 weeks, two of 70 patients were
      lost to follow-up. In the remaining 68, favourable outcome was observed in 98% of
      48 patients discharged from the observation unit (95% CI: [94%; 100%]), 90% of 10
      discharged from the emergency ward (95% CI: [73%; 100%]) and 70% of 10
      hospitalized (95% CI: [50%; 93%]). A decisional algorithm was useful in
      determining that over 85% of women who present to our emergency department with
      pyelonephritis have an uncomplicated form and may be safely treated as
      outpatients, if necessary after a brief stay in the observation unit. Prospective
      controlled trials are needed to determine duration of antimicrobial therapy,
      length of follow-up and finally, to compare tolerance and cost-effectiveness of
      outpatient vs. inpatient care of acute uncomplicated pyelonephritis.

PMID- 10340730
TI  - Foreign body aspiration in childhood: management algorithm.
AB  - Foreign body inhalation is still a major cause of morbidity and even mortality in
      the under-fives. To reduce its frequency, more severe preventative measures must
      be imposed and to allow for early diagnosis, a low threshold for bronchoscopy is
      necessary. This retrospective study is based on 33 children referred to us for
      suspicion of inhaled foreign body. Symptomatology, clinical and paraclinical data
      are reviewed. Based on our practice and on the experience gained from the
      literature, we propose a management algorithm which will need to be further
      assessed by a prospective study.

PMID- 10340731
TI  - Electrocardiographic abnormalities in acute pancreatitis.
AB  - It has been reported that electrocardiographic abnormalities may be associated
      with acute pancreatitis. However, the data are lacking or sketchy. The aim of
      this study was to assess the frequency and type of electrocardiographic
      abnormalities present in patients with acute pancreatitis. Fifty-six consecutive
      patients with acute pancreatitis and without previous history of heart disease
      were studied. Eleven patients had arterial hypertension. Forty-one patients had
      mild pancreatitis and 15 had the severe form of the disease. On admission, all
      patients underwent a standard 12-leads electrocardiogram and a serum electrolyte
      determination. Nineteen healthy subjects were also studied as controls. Twenty
      seven patients (48.2%) (10 with severe pancreatitis and 17 with mild
      pancreatitis) had a normal electrocardiogram. In the remaining 29 patients
      (51.8%), one patient with severe pancreatitis had atrial extrasystoles and eight
      had bradycardia (less than 60 beats/minute) (two with severe pancreatitis and six
      with mild pancreatitis); 14 patients had changes of the T-wave and/or the ST
      segment (two with severe pancreatitis and 12 with mild pancreatitis); seven
      patients showed disturbances of the intraventricular conduction (one with severe
      pancreatitis and six with mild pancreatitis): four had left anterior hemiblock,
      two had complete left bundle branch block and one had left anterior hemiblock and
      incomplete right bundle branch block; one patient with mild pancreatitis had
      atrioventricular block (first degree). No differences in heart rate, RR interval,
      PR interval and QT interval were found when patients with acute pancreatitis were
      compared with healthy subjects, nor when patients with severe pancreatitis were
      compared with those having the mild form of the disease. Seventeen of the 29
      patients with electrocardiographic abnormalities (52.6%) also had serum
      electrolyte alterations. More than 50% of the patients with acute pancreatitis
      had electrocardiographic abnormalities and electrolyte alterations were also
      present in about one-half of these.

PMID- 10340732
TI  - Malaria in inner London.
AB  - This retrospective analysis was performed to describe the malarial cases treated
      in an inner London hospital during a single year (1996). A total of 44 case
      records were available for review, 40 (90.9%) were due to Plasmodium falciparum.
      Thirty-seven patients were admitted to hospital, there were no deaths. Only two
      (4.5%) patients had taken adequate malarial prophylaxis. A total of 119 inpatient
      bed-days were utilized in the treatment of malaria in 1 year. In 75 (63%) of
      these bed-days, observation was the only reason for continued inpatient
      treatment. The commonest laboratory findings are mild elevation of serum
      bilirubin to a mean of 28 micromol/l, and a low platelet count to a mean of
      124x10(12)/l. A bilirubin greater than 20 micromol/l was found in 72.9% of
      patients (95% CI; 58.7-87.3%). The platelet count was less than 150x10(12)/l in
      77.3% of patients (95%, CI; 64.9-89.7%). We found that malaria is not uncommon in
      inner London. Whilst most cases are admitted few complications are usually seen.
      Many cases may well be able to be treated with a brief hospital admission,
      possibly to an accident and emergency observation ward.

PMID- 10340733
TI  - Equestrian injuries in the paediatric age group: a two centre study.
AB  - This study's objective was to examine the nature, cause and frequency of injury
      resulting from equestrian sport in paediatric patients attending two accident and
      emergency departments. We recorded the attendances of patients aged less than 16
      years with equestrian-related trauma in 1 year. Demographic details, injury,
      mechanism of injury, rider experience and use of protective equipment were noted.
      There were 41 attendances (39 female, two male, median age 12 years). Thirty-one
      were injured while mounted, 10 while dismounted. The commonest group of injuries
      were soft tissue injuries of the lower limb (13 cases), soft tissue injuries of
      the upper limb (12 cases), fractures of the upper limb (nine cases), and minor
      head injury (seven cases). There was one case of severe head injury. Two patients
      required admission to hospital. The commonest mechanism of injury in the mounted
      group was a fall or throw (23 cases), in the dismounted group injuries were most
      commonly the result of being trodden on or being kicked (seven cases). The
      majority of equestrian-related trauma was minor in this study. The possibility of
      severe trauma exists. Emergency physicians working in areas where equestrian
      sport is popular should be aware of the likely injuries and their treatment.

PMID- 10340734
TI  - Comparison of four drugs for local treatment of burn wounds.
AB  - Effective local treatment is very important in preventing wound infection and its
      generalization and ensuring successful skin grafting. The aim of our study is to
      compare the activity of four topical agents [deflamol (20 patients), polyvidone
      iodine (21 patients), flammazine (silver sulphadiazine--SSD) (28 patients) and
      flammacerium (SSD with cerium nitrate) (five patients)] for treatment of patients
      with burns by confirming our clinical observations of their efficacy with
      comparative bacteriological investigations. The final estimation of our results
      showed the undoubted priority of flammazine and flammacerium over deflamol and
      polyvidone-iodine, as the treatment of all the patients with these two drugs gave
      very good and good results, respectively. In contrast, the results in 70% of the
      patients from the deflamol group and in 52.4% of those from the polyvidone-iodine
      group were unsatisfactory. At this stage we cannot find any significant
      differences in the antibacterial activity between flammazine and flammacerium.
      However, the excision of the firm eschars formed by flammacerium is easier and it
      gives the opportunity to postpone operation for a month or more. In conclusion we
      found suitable indications for preference of each of the topical agents included
      in our study.

PMID- 10340735
TI  - Evaluation of the value of an observation ward in an emergency department.
AB  - A prospective study was undertaken to describe the pattern of utilization of an
      observation ward in an emergency department (ED). During a 1-month study period,
      the following data were collected for all patients admitted to the observation
      ward: (1) patient demographics, (2) purpose of observation, (3) interventions at
      the observation ward, (4) disposal destinations, (5) disposal diagnosis, (6)
      outcome categories, and (7) duration of stay. A total of 12188 patients attended
      our ED and 1042 (8.51%) patients were admitted into the observation ward. An
      average of 34 patients was admitted into the observation ward each day. The age
      of the patients ranged from neonates to 94 years (mean age of 45.7 years, +/-25.7
      SD). Sex distribution was almost equal. The diagnostic evaluation group was the
      largest (58%) followed by short-term therapy (38%) and psychosocial problems
      (3.5%). Of the 554 patients with a disposal diagnosis, 350 (59%) had their
      diagnosis clarified after the observation period. The percentage of patients
      admitted to the hospital was 23%. There were 42 chest pain and 46 trauma
      patients. The impact of an observation ward on the service in ED was discussed.

PMID- 10340736
TI  - Analysis of 1930 bedridden patients in the internal medical sector of the
      emergency department of a large city hospital: appropriate and non-appropriate
      admission.
AB  - This paper discusses criterion for the appropriateness of admission to the
      hospitalization ward in the internal medical sector of the emergency department,
      and analyses the bedridden patients in the emergency department of the major
      hospital in the city of Genoa. The analysis covers 1930 patients, for which
      considerations are made, globally and separately in two different age groups, as
      to the appropriateness of admission to the hospitalization ward of the emergency
      department, the occurrence of subjective urgencies and objective instabilities,
      and progression subsequent to hospitalization (discharge, transfer into other
      hospital wards, decease). The most significant results of the analysis were the
      following: (1) no significant difference was found between younger and older
      patients regarding appropriateness of admission; (2) in cases of appropriate
      admission subjective urgency was clearly prevalent in relation to objective
      instability, the latter being much more frequent in the older age group; (3) a
      lack of self-sufficiency and the absence of adequate family support were
      important factors regarding inappropriate admission of older patients; (4) the
      greater frequency of objective instability in the older patients-as well as a
      lack of self-sufficiency-was the major factor in their greater length of stay in
      the emergency department. These results challenge the misconceived but diffused
      conviction that there is widespread mishandling of the elderly regarding
      admission to the emergency department, while at the same time stresses the need
      for alternative services and structures concerning hospital admission of older
      patients.

PMID- 10340737
TI  - Stroke--a medical emergency.
AB  - Acute ischaemic stroke as an urgent-to-treat condition has gained a more
      prominent role in the consciousness of emergency physicians and neurologists over
      the past decade. This is mainly due to an increasing insight into the
      pathophysiological mechanism of ischaemia, the definition of therapeutical goals,
      such as reperfusion or neuroprotection, and the recent application of respective
      treatment strategies in large multicentre studies. This review article will focus
      on the emergency assessment of stroke patients, on general treatment strategies,
      and particularly on specific measures of intensive care therapy of stroke
      including thrombolysis, decompressive surgery, hypothermia and treatment of brain
      oedema.

PMID- 10340738
TI  - Fracture of the sternum--an unusual case.
AB  - Stress fracture of the sternum is a rare injury and can occur in young athletes
      due to repeated stress and in elderly with osteoporotic bones or other
      pathological conditions under normal stress. A case of a 14-year-old boy is
      reported who sustained fracture of the sternum without any history of significant
      trauma when he simply tried to lift his whole body over his arms and felt pain in
      front of the chest.

PMID- 10340739
TI  - Intussusception in infants: an emergency in diagnosis and treatment.
AB  - Intussusception is an important cause of intestinal obstruction and bowel
      necrosis in infants under 2 years. Most frequently the ileocaecal junction is
      involved. Various aetiologic factors, such as Meckel's diverticulum and lymphoid
      hyperplasia have been identified. Hydrostatic reduction of the intussusception
      should be attempted, but delay in diagnosis frequently leads to surgical
      intervention, because of failing reduction. We report a case of a 4-month-old boy
      whose ileocaecal junction was intussuscepted into the rectum, and therefore could
      be palpated by rectal examination. Unsuccessful hydrostatic reduction and bowel
      necrosis because of delay in diagnosis, made surgical intervention necessary. A
      terminal ileostomy was performed. A second case report considers a 10-month-old
      boy whose ileocaecal junction was intussuscepted into the colon sigmoideum.
      Because there was no delay in diagnosis, this intussusception could be reduced
      hydrostatically. The procedure however was difficult because of a
      dolichosigmoideum. Recent literature is also reviewed.

PMID- 10340740
TI  - Oral clonidine to control hypertension after head injury.
AB  - Clonidine, an alpha2 agonist, was administered through a nasogastric tube for the
      treatment of hypertension in a head-injury patient with elevated plasma
      catecholamines. Haemodynamic parameters were stabilized with a reduction in
      sympathetic nervous activity. The plasma clonidine concentration, measured by
      radioimmunoassay, rapidly increased following the administration. After cessation
      of oral administration of clonidine, mean arterial blood pressure gradually
      increased. So clonidine was again administered orally and good blood pressure
      control was achieved and no change in consciousness level was observed. Oral
      clonidine was useful and effective for hypertension in this head injury patient.

PMID- 10340741
TI  - Regulation of fibronectin alternative splicing during peripheral nerve repair.
AB  - Wallerian degeneration following peripheral nerve injury is associated with
      increased production of fibronectin and other extracellular matrix molecules that
      are thought to enhance repair. We have shown previously that alternative splicing
      of the mRNA for fibronectin also changes following sciatic nerve lesions so as to
      reexpress forms of mRNA seen during embryogenesis. In the present study, we have
      examined the role of the regenerating axons in the regulation of this splicing.
      We have compared the patterns of fibronectin mRNA splicing seen in sciatic nerve
      development with that seen in cut nerves (that do not regenerate), crushed nerves
      (that regenerate successfully), and Schwann cells cultured in forskolin so as to
      mimic axonal signals. By using a reverse transcriptase polymerase chain reaction
      assay to examine all three regions of fibronectin mRNA splicing in a quantitative
      manner, we found that embryonic patterns of fibronectin mRNA splicing appear
      rapidly following injury and are not then altered by reestablishment of axons in
      the nerve. In addition, we found that forskolin has no effect on fibronectin mRNA
      splicing in cultured cells. We conclude that axonal signals do not regulate the
      pattern of fibronectin alternative splicing in peripheral nerve repair.

PMID- 10340742
TI  - Schwann cell development in embryonic mouse nerves.
AB  - Previously we proposed that Schwann cell development from the neural crest is a
      two-step process that involves the generation of one main intermediate cell type,
      the Schwann cell precursor. Until now Schwann cell precursors have only been
      identified in the rat, and much remains to be learned about these cells and how
      they generate Schwann cells. Here we identify this cell in the mouse and analyze
      its transition to form Schwann cells in terms of timing, molecular expression,
      and extracellular signals and intracellular pathways involved in survival,
      proliferation, and differentiation. In the mouse, the transition from precursors
      to Schwann cells takes place 2 days earlier than in the rat, i.e., between embryo
      days 12/13 and 15/16, and is accompanied by the appearance of the 04 antigen and
      the establishment of an autocrine survival circuit. Beta neuregulins block
      precursor apoptosis and support Schwann cell generation in vitro, a process that
      is accelerated by basic fibroblast growth factor 2. The development of Schwann
      cells from precursors also involves a change in the intracellular survival
      signals utilized by neuregulins: To block precursor death neuregulins need to
      signal through both the mitogen-activated protein kinase and the phosphoinositide
      3-kinase pathways although neuregulins support Schwann cell survival by signaling
      through the phosphoinositide-3-kinase pathway alone. Last, we describe the
      generation of precursor cultures from single 12-day-old embryos, a prerequisite
      for culture studies of genetically altered precursors when embryos are non
      identical with respect to the transgene in question.

PMID- 10340743
TI  - Progesterone derivatives are able to influence peripheral myelin protein 22 and
      P0 gene expression: possible mechanisms of action.
AB  - The present study has analyzed the effect of progesterone and its derivatives
      (dihydroprogesterone and tetrahydroprogesterone) on the gene expression of the
      peripheral myelin protein 22 utilizing in vivo and in vitro models. The data
      obtained indicate that tetrahydroprogesterone is able to stimulate the gene
      expression of peripheral myelin protein 22 both in vivo (in adult but not in old
      animals) and in Schwann cell cultures. An effect of this steroid, which is known
      to interact with the GABA(A) receptor, would not be surprising, since in the
      present study we show the presence in Schwann cells and in the sciatic nerve of
      the messengers for several subunits (alpha2, alpha3, beta1, beta2, and beta3) of
      the GABA(A) receptor. An effect of tetrahydroprogesterone is also evident on the
      gene expression of another myelin protein, the peripheral myelin protein zero.
      However, in this case also dihydroprogesterone, which is able to bind the
      progesterone receptor, is involved, both in old and adult animals, in the
      stimulation of messengers levels of this myelin protein. In conclusion, the
      present data show that the gene expression of two important peripheral myelin
      proteins can be influenced by progesterone derivatives. The hypothesis has been
      put forward that part of their effects might occur not through the classical
      progesterone receptor, but rather via an interaction with the GABA(A) receptor.

PMID- 10340744
TI  - Increases in [Ca2+]i and changes in intracellular pH during chemical anoxia in
      mouse neocortical neurons in primary culture.
AB  - The effect of chemical anoxia (azide) in the presence of glucose on the free
      intracellular Ca2+ concentration ([Ca2+]i) and intracellular pH (pHi) in mouse
      neocortical neurons was investigated using Fura-2 and BCECF. Anoxia induced a
      reversible increase in [Ca2+]i which was significantly inhibited in nominally
      Ca2+-free medium. A change in pHo (8.2 or 6.6), or addition of NMDA and non-NMDA
      receptor antagonists (D-AP5 and CNQX) in combination, significantly reduced the
      increase in [Ca2+]i, pointing to a protective effect of extracellular alkalosis
      or acidosis, and involvement of excitatory amino acids. An initial anoxia-induced
      acidification was observed under all experimental conditions. In the control
      situation, this acidification was followed by a recovery/alkalinization of pHi in
      about 50% of the cells, a few cells showed no recovery, and some showed further
      acidification. EIPA, an inhibitor of Na+/H+ exchangers, prevented alkalinization,
      pointing towards anoxia-induced activation of a Na+/H+ exchanger. In a nominally
      Ca2+-free medium, the initial acidification was followed by a significant
      alkalinization. At pHo 8.2, the alkalinization was significantly increased, while
      at pHo 6.2, the initial acidification was followed by further acidification in
      about 50% of the cells, and by no further change in the remaining cells.

PMID- 10340745
TI  - Proximal promoter of the rat brain creatine kinase gene lacks a consensus CRE
      element but is essential for the cAMP-mediated increased transcription in
      glioblastoma cells.
AB  - Our previous studies have shown that transcription of brain creatine kinase (CKB)
      mRNA in U87-MG glioblastoma cells is stimulated by a forskolin-mediated increase
      in cyclic AMP (cAMP) via a pathway involving protein kinase A (PKA) and the
      activation of Galphas proteins. In this report, we have employed transient
      transfection to investigate the rat CKB gene elements essential for the cAMP
      mediated induction of rat CKB transcription in human U87 cells and have mapped
      the transcription start site of the induced CKB transcripts. We found that the
      level of induced transcription from the transfected genomic rat CKB gene was the
      same whether transcription was driven by 2.9 kb of CKB promoter plus 5' flanking
      sequence or the 0.2 kb CKB promoter, suggesting that the proximal CKB promoter
      was essential. Also, the level of induced transcription of the chloramphenicol
      acetyl transferase (CAT) reporter gene driven by the 2.9 kb CKB promoter was the
      same as with the 0.2 kb CKB promoter. Analyses of a series of 5' deletions of the
      0.2 kb proximal CKB promoter showed that the sequences between -80 bp and +1 bp
      were essential for the cAMP-mediated induction of CKB transcription, despite the
      absence of a consensus cAMP response element (CRE) sequence in that region. In
      agreement, gel mobility shift assays showed that nuclear extracts from U87 cells
      contained a protein(s) which bound specifically to a [32P]CKB DNA probe
      containing the -60 bp to +1 bp sequence. Mapping the 5' end of the CKB
      transcripts showed that the initiation of the cAMP-induced transcription occurred
      almost exclusively from the downstream transcription start site, apparently under
      the initiation direction of the nonconsensus (-28) TTAA element and not the
      consensus (-60) TATAAATA element. The results are discussed with regard to
      nuclear protein factors which may be involved, and the possible cAMP-mediated
      increase in CKB transcription during myelinogenesis, since the differentiation of
      oligodendrocytes has previously been shown to be accelerated by increased
      intracellular cAMP.

PMID- 10340747
TI  - Postnatal development of dopamine D1 receptor immunoreactivity in the rat retina.
AB  - Dopamine, an important neuromodulator in the retina, controls the balance of rod
      cone photoreceptor activity and influences the activity of several interneurons.
      The postnatal development of dopaminergic neurons, visualized
      immunocytochemically, was compared to the development of dopamine D1 receptor
      immunoreactivity. Expression of D1 receptors was monitored throughout the
      postnatal development of the rat retina using a subtype-specific monoclonal
      antibody. D1 receptors are expressed in the inner plexiform layer beginning at
      birth. Labeling of the inner plexiform layer changed from a diffuse pattern,
      staining the entire layer, to the typical adult punctate staining, that was
      organized in layered bands and occurred in the second postnatal week. The
      staining did not co-localize with dopaminergic cells; instead, it colocalized
      with cells in the inner nuclear layer or the ganglion cell layer. Within these
      cells, D1 receptors were most heavily expressed in processes stratifying in the
      inner plexiform layer. Staining in the outer plexiform layer and in horizontal
      cells was found beginning in the second postnatal week. Clustering of the D1
      receptor within plexiform layers, a process typical for the well-described
      function of dopamine modulation in the adult, occurred late in postnatal
      development. A possible function of D1 receptors in neuronal development is
      discussed.

PMID- 10340746
TI  - Identification of a potent neurotrophic substance for ciliary ganglionic neurons
      in fetal calf serum as insulin-like growth factor II.
AB  - When fetal calf serum (FCS) alone is used as a trophic support for cultured
      chicken parasympathetic ciliary ganglionic (cCG) neurons, it does not show any
      survival-promoting effects on these neurons. When FCS is applied to heparin
      affinity chromatography, however, potent survival-promoting activity is obtained
      in the fraction eluted with 0.5 M NaCl. Using cCG neurons as a bioassay system,
      this neurotrophic activity was purified by a combination of heparin-affinity
      chromatography, gel filtration chromatography, and Sep-Pak C18 cartridge. The 40
      50-kDa fractions from the gel filtration column with strong survival-promoting
      activity were shown to contain insulin-like growth factor II (IGF-II) by
      immunoblot analysis. By acidification, the survival-promoting activity and IGF-II
      were translocated together from the 40-50-kDa to the 7-10-kDa fractions, and the
      survival-promoting activity in the 7-10-kDa fractions was blocked by an anti-IGF
      II neutralizing monoclonal antibody. These results indicate that the neurotrophic
      substance in 0.5 M NaCl-eluate from heparin-affinity chromatography is IGF-II and
      that mechanisms may exist in vivo for the activation of latent IGF-II, whose
      biological effects may be blocked by its specific binding proteins.

PMID- 10340748
TI  - Analysis of presenilin 1 and presenilin 2 expression and processing by newly
      developed monoclonal antibodies.
AB  - Because distinct mutations in presenilin 1 and presenilin 2 are a major cause of
      early-onset familial Alzheimer's disease, we generated four monoclonal antibodies
      for the identification, localization, and investigation of presenilins in various
      cell lines and tissues from patients and controls. We show that these antibodies
      are specific for the N- and C-terminal domains of human presenilin 1 and
      presenilin 2. They recognize presenilin full-length proteins and their
      approximately 28-35 kDa N-terminal fragments and approximately 18-20 kDa C
      terminal fragments. None of the antibodies showed cross-reaction in their
      specific detection ability. We demonstrated that presenilin 1 and presenilin 2
      are proteolytically processed in human glioma cell lines, transfected and
      untransfected human neuroblastoma SH-SY5Y cells, COS-7 cells, rat cerebellar
      neuronal ST15 cells, mouse and human brain. Remarkably, we observed that
      presenilin 2 is alternatively cleaved during apoptosis, producing smaller C
      terminal fragments. By analyzing the subcellular distribution of presenilins, we
      found reticular and fine vesicular staining throughout the cell bodies. In
      addition, staining of Golgi compartments and the perinuclear envelope was
      observed. Alzheimer's disease brain showed strong immunoreactivity of presenilin
      1 in reactive astrocytes and senile plaques. This high expression of presenilin 1
      may explain the increased production and accumulation of the amyloid-beta peptide
      in patients with sporadic Alzheimer's disease in the absence of familial
      presenilin mutation.

PMID- 10340749
TI  - Radical scavenging compound J 811 inhibits hydrogen peroxide-induced death of
      cerebellar granule cells.
AB  - Oxidative stress is considered to be an important pathophysiological condition to
      promote cell death in a broad variety of disorders, such as cardiovascular and
      neurodegenerative diseases. Scavestrogens, structurally derived from estradiol,
      are potent radical scavengers and inhibitors of iron-induced cell damage in
      vitro. In this study the potential cytoprotective effects of the so-called
      scavestrogen estra-1,3,5(10),8-tetraene-3,17alpha-diol, J 811, was tested using
      rat cerebellar granule cells (CGCs) exposed to 25 or 50 microM hydrogen peroxide
      (H2O2). H2O2-induced apoptotic cell death was detected by the appearance of high
      molecular weight DNA fragments and nuclear condensation. The addition of J 811
      before or shortly after the exposure to H2O2 prevented CGC apoptosis in a dose
      dependent manner. The estrogen receptor antagonist ICI 182.780 failed to prevent
      the protective effect of J 811, suggesting that the latter is not dependent on
      estrogen receptor activation. The lack of protection against apoptosis caused by
      colchicine suggests that J 811 is neither interfering with the activation of
      caspase-3, nor acting downstream of caspase-3. Therefore, the protective effect
      observed against H2O2 seems to be upstream caspases activation, pointing to a
      scavenging action of J 811. Thus the scavestrogen J 811 is a powerful antioxidant
      able to interfere with radical-mediated cell death and is potentially useful in
      diseases where reactive oxygen species are involved.

PMID- 10340750
TI  - p53 expression and regulation by NMDA receptors in the developing rat brain.
AB  - The p53 tumor suppressor gene, which is considered the guardian of the genome,
      encodes a phosphoprotein, which is a sequence-specific transcriptional activator
      or repressor of target genes. The role of p53 in developmental processes has not
      been studied extensively, although its expression appears to undergo temporal and
      spatial changes during prenatal and postnatal development. In the present study,
      we assessed the levels of p53 mRNA and protein in the developing rat brain and
      its relation to developmental cell death. Furthermore, we investigated the
      potential role of n-methyl-d-aspartate (NMDA) receptors in regulating p53
      expression, since these receptors are involved in the control of cell death. We
      found that p53 mRNA and protein were detectable in the rat brain throughout
      perinatal development. In embryos, p53 immunoreactivity was mainly localized in
      the nuclei of neuroepithelial cells, with a maximum in staining at embryonic day
      (E)12. In the neuroepithelium, we also found significant numbers of TdT-mediated
      dUTP nick end labeling (TUNEL)-positive cells, both in dividing periventricular
      cells and in migrating neurons. In neonates, immediately after birth there was a
      reduction in the number of apoptotic cells, which then increased to reach a
      maximum at postnatal day (P)5. Postnatally, apoptotic as well as p53-positive
      cells were detected in most brain areas. P53 immunoreactivity was also highest on
      P5. In most cells, p53 immunoreactivity and the TUNEL signal colocalized. P53
      immunoreactivity as well as the number of TUNEL- positive cells were dramatically
      decreased in the brains of newborns treated with MK-801, an NMDA receptor
      antagonist. Our results show that p53 is involved in the control of developmental
      cell death, and that NMDA receptors play a regulatory role in the expression of
      the p53 gene, and thus in apoptosis occurring in the developing rat brain.

PMID- 10340751
TI  - Impaired learning and memory and altered hippocampal neurodevelopment resulting
      from interleukin-2 gene deletion.
AB  - Interleukin-2 (IL-2), the protypical T cell growth factor and immunoregulatory
      cytokine produced by lymphocytes, has been implicated as a brain neurotrophic
      factor and neuromodulator. The consequences of the absence of endogenous IL-2 on
      brain development and function were unknown. Brain IL-2 receptors are enriched in
      the hippocampal formation, an area critical for the acquisition and consolidation
      of spatial learning and memory. Thus, we tested the hypothesis that mice lacking
      IL-2 would exhibit alterations in hippocampal-dependent learning and
      neurodevelopment. Compared with C57BL/6-IL-2+/+ wild-type mice, we observed that
      C57BL/6-IL-2-/- gene knockout mice had markedly impaired spatial learning and
      memory in the Morris water maze. No significant deficits in parameters of
      learning and memory performance were found in severe combined immunodeficient
      (SCID) mice (C57BL/6scid), however, suggesting that the impaired spatial learning
      and memory exhibited by IL-2 knockout mice is not attributable to generalized
      immunodeficiency resulting from the absence of endogenous IL-2. Examination of
      other domains of behavioral performance showed that the IL-2 knockout and
      wildtype mice did not differ in measures of fearfulness or locomotor activity in
      an elevated plus maze, or in reflexive startle responses to auditory stimuli-
      although prepulse inhibition of acoustic startle (PPI) was increased
      significantly in IL-2 knockout mice. The spatial learning and memory impairment
      in IL-2 knockout mice was accompanied by reductions in hippocampal infrapyramidal
      mossy neuronal fiber length, a factor shown previously to correlate positively
      with spatial learning ability. These findings indicate that, in addition to being
      a pivotal cytokine in immune regulation, IL-2 may play a role in the development
      and regulation of brain neurons involved in spatial learning and memory.

PMID- 10340752
TI  - What guides early embryonic blood vessel formation?
AB  - Survival of vertebrate embryos depends on their ability to assemble a correctly
      patterned, integrated network of blood vessels to supply oxygen and nutrients to
      developing tissues. The arrangement of larger caliber intraembryonic vessels,
      specification of arterial-venous identity, and proper placement of major branch
      points and arterial-venous connections are all precisely determined. A number of
      recent studies in both mammalian and nonmammalian vertebrate species, reviewed
      here, have now begun to reveal the major role played by genetically predetermined
      extrinsic cues in guiding the formation of early embryonic blood vessels and
      determining the global pattern of the vasculature.

PMID- 10340753
TI  - Localization of VEGF-B in the mouse embryo suggests a paracrine role of the
      growth factor in the developing vasculature.
AB  - Vascular endothelial growth factor B (VEGF-B) is structurally closely related to
      VEGF and binds one of its receptors, VEGFR-1. In situ hybridization and
      immunohistochemistry were used to localize VEGF-B mRNA and protein in embryonic
      mouse tissues. In 8.5-17.5 day embryos, VEGF-B was most prominently expressed in
      the developing myocardium, but not in the cardiac cushion tissue. The strong
      expression in the heart persisted at later developmental stages, while weaker
      signals were obtained from several other tissues, including developing muscle,
      bone, pancreas, adrenal gland, and from the smooth muscle cell layer of several
      larger vessels, but not from endothelial cells. VEGF-B is likely to act in a
      paracrine fashion, as its receptor is almost exclusively present in endothelial
      cells. VEGF-B may have a role in vascularization of the heart, skeletal muscles
      and developing bones, and in paracrine interactions between endothelial and
      surrounding muscle cells.

PMID- 10340754
TI  - Anosmin-1 is a regionally restricted component of basement membranes and
      interstitial matrices during organogenesis: implications for the developmental
      anomalies of X chromosome-linked Kallmann syndrome.
AB  - Kallmann syndrome is a developmental disease characterized by gonadotropin
      releasing hormone (GnRH) deficiency and olfactory bulb hypoplasia. The gene
      underlying the X chromosome-linked form, KAL-1, has been identified for several
      years, yet the pathogenesis of the disease is not understood. By
      immunohistofluorescence and immunoelectron microscopy, we establish that the KAL
      1 encoded protein, anosmin-1, is a transient and regionally restricted component
      of extracellular matrices during organogenesis in man. Anosmin-1 was detected in
      the basement membranes and/or interstitial matrices of various structures
      including bronchial tubes, mesonephric tubules and duct, branches of the ureteric
      bud, muscular walls of the digestive tract and larger blood vessels,
      precartilaginous models of skeletal pieces, muscle tendons, head mesenchymes,
      inner ear, and forebrain subregions. Our results suggest that this protein acts
      as a local, rather than a long-range, cue during organogenesis. In the olfactory
      system, anosmin-1 was detected from week 5 onward. The protein was restricted to
      the olfactory bulb presumptive region and later, to the primitive olfactory
      bulbs. We therefore suggest that the genetic defect underlying X-linked Kallmann
      syndrome disrupts the terminal navigation of the early olfactory axons or
      directly affects the initial steps of olfactory bulb differentiation. The
      mechanism of the GnRH deficiency is also discussed, relying on the evidence that
      anosmin-1 is present in the medial walls of the primitive cerebral hemispheres,
      along the rostro-caudal migratory pathway of the GnRH-synthesizing neurons, at 6
      weeks. Finally, the present results strongly suggest that the renal aplasia
      observed in about one third of the affected individuals results from primary
      failure of the collecting duct system.

PMID- 10340755
TI  - Msx1 is required for the induction of Patched by Sonic hedgehog in the mammalian
      tooth germ.
AB  - We have used the mouse developing tooth germ as a model system to explore the
      transmission of Sonic hedgehog (Shh) signal in the induction of Patched (Ptc). In
      the early developing molar tooth germ, Shh is expressed in the dental epithelium,
      and the transcripts of Shh downstream target genes Ptc and Gli1 are expressed in
      dental epithelium as well as adjacent mesenchymal tissue. The homeobox gene Msx1
      is also expressed in the dental mesenchyme of the molar tooth germ at this time.
      We show here that the expression of Ptc, but not Gli1, was downregulated in the
      dental mesenchyme of Msx1 mutants. In wild-type E11.0 molar tooth mesenchyme SHH
      soaked beads induced the expression of Ptc and Gli1. However, in Msx1 mutant
      dental mesenchyme SHH-soaked beads were able to induce Gli1 but failed to induce
      Ptc expression, indicating a requirement for Msx1 in the induction of Ptc by SHH.
      Moreover, we show that another signaling molecule, BMP4, was able to induce Ptc
      expression in wild-type dental mesenchyme, but induced a distinct expression
      pattern of Ptc in the Msx1 mutant molar mesenchyme. We conclude that in the
      context of the tooth germ Msx1 is a component of the Shh signaling pathway that
      leads to Ptc induction. Our results also suggest that the precise pattern of Ptc
      expression in the prospective tooth-forming region is controlled and coordinated
      by at least two inductive signaling pathways.

PMID- 10340756
TI  - Vascular endothelial growth factor expression coincides with coronary
      vasculogenesis and angiogenesis.
AB  - Vascular endothelial growth factor (VEGF) plays an important role in early
      embryonic vasculogenesis. To establish its temporal expression and localization
      in the heart during development, we studied rat hearts from the first embryonic
      day (E) of myocardial vascular tube formation through the early postnatal period.
      Ventricular VEGF immunoreactivity was noted in the epicardium and the thin
      underlying myocardium in E10 ventricles. During the earliest stages of
      vascularization (E13-E16) immunoreactivity was highest in the compact myocardium
      nearest the epicardium, and subsequently (E18 and thereafter) became more evenly
      distributed transmurally. By birth (E22) immunoreactivity was most intense around
      microvessels. Similarly, VEGF mRNA localization, demonstrated by in situ
      hybridization, was initially highest near the epicardium and then became more
      evenly distributed transmurally by late gestation. Within the interventricular
      septum, the highest expression occurred in the middle of the wall where it
      correlated with the greatest vascularization. Northern blot analysis showed that
      from E12 through the first 10 days of postnatal life, VEGF was two to three times
      higher than in the adult. Western blot analysis showed that VEGF tended to be
      higher in the atria than the ventricles, and negligible in the outflow tract. Our
      data indicate that VEGF localization and expression 1) correspond to the pattern
      of vascularization in the embryonic/fetal heart, and 2) remain high during the
      early postnatal period when capillary proliferation is high. Because VEGF is
      stimulated by hypoxia, its preferential mRNA expression near the epicardium, that
      is, farthest from the ventricular lumen and the O2 source, fits with the
      hypothesis that a hypoxic gradient is a driving force in the transmural
      vascularization process.

PMID- 10340757
TI  - An ascidian T-box gene As-T2 is related to the Tbx6 subfamily and is associated
      with embryonic muscle cell differentiation.
AB  - The T-box genes, including Brachyury, encode a novel family of transcription
      factors that play critical roles in various processes of development, in
      particular, mesoderm formation in chordate embryos. In the case of the ascidian
      Halocynthia roretzi, the Brachyury (As-T) is expressed exclusively in notochord
      cells, whereas another T-box gene (As-T2) is expressed in the muscle cells and in
      the tip of the tail of tailbud embryos. In a previous study, we suggested that
      the combined pattern of the spatial expressions of As-T and As-T2 appears to
      correspond to that of a single vertebrate Brachyury gene (Yasuo et al., Dev Biol
      1996;180:773-779). The present molecular phylogenetic analysis suggested that As
      T2 is a divergent member of the T-box family with a similarity to the Tbx6
      subfamily. Vertebrate members of this subfamily are expressed in the posterior
      paraxial mesoderm, and the mouse Tbx6 is essential for the specification of
      posterior somite. To investigate the function of As-T2, we examined an ectopic-
      and/or overexpression of this gene by injecting synthetic mRNA into fertilized
      eggs. The results showed that the injection of As-T2 mRNA induced an ectopic
      expression of muscle-specific myosin heavy-chain gene and actin gene, especially
      in presumptive epidermal cells. This ectopic muscle-specific expression was
      accompanied by the partial suppression of an epidermis-specific gene expression.
      The overexpression of As-T2, however, rarely affected the expression of As-T
      (Brachyury) and genes that are expressed in the tailbud.

PMID- 10340758
TI  - Regulation and role of Sox9 in cartilage formation.
AB  - The HMG-domain transcription factor Sox9 is a known regulator of the type II
      collagen gene, a major developmentally regulated protein of cartilage. In order
      to place Sox9 function in skeletogenesis we have investigated the regulation and
      misexpression of Sox9 in avian embryos. Application of exogenous BMP2 to chick
      limbs resulted in upregulation of Sox9, concomitant with induction of ectopic
      cartilage. Ectopic expression of the BMP antagonist Noggin in the limb resulted
      in loss of Sox9 expression from the developing digits, indicating that Sox9
      expression during chondrogenesis is BMP dependent. Misexpression of Sox9 in vivo
      resulted in ectopic cartilage formation in limbs and in vitro was able to change
      the aggregation properties of limb mesenchymal cells, suggesting that Sox9
      functions at the level of mesenchymal cell condensation. Misexpression of Sox9 in
      dermomyotomal cells, which normally give rise to the axial musculature and
      dermis, can result in the diversion of these cells from their normal fates
      towards the cartilage differentiation programme. These cells not only express
      type II collagen, but also Pax1, a marker of ventral fate in the developing
      somite. This suggests that the cell fate decision to follow the cartilage
      differentiation pathway is regulated at an early stage by Sox9.

PMID- 10340759
TI  - Antibodies directed against the chicken type II TGFbeta receptor identify
      endothelial cells in the developing chicken and quail.
AB  - Due to the availability of the endothelial cell marker QH1, experiments using
      quail embryos have traditionally been used to trace the endothelial cell lineage
      and describe the morphologic events of vessel formation. A comparable marker in
      the chicken has not been available. Here we report that antibodies raised against
      the extracellular domain of the chicken type II TGFbeta receptor (TBRII)
      preferentially identify endothelial cells in the chick. Endothelial cells can
      first be identified in the 6-somite chick embryo by TBRII expression. TBRII
      expression in 12- and 22-somite chick and quail embryos was found to directly
      correlate with the endothelial QH1 staining pattern in quail. This preferential
      labeling of endothelial cells persists until at least embryonic day 10 in the
      chick. These data indicate that antibodies to TBRII are an effective marker of
      endothelial cells in chick and provide useful reagents for the evaluation of
      vascular patterning.

PMID- 10340760
TI  - Role of interleukin-6 and soluble IL-6 receptor in region-specific induction of
      astrocytic differentiation and neurotrophin expression.
AB  - Increasing evidence supports an essential role for interleukin-6 (IL-6) in the
      development, differentiation, as well as de- and re-generation of neurons in the
      central nervous system (CNS). Both IL-6 and its specific receptor (IL-6R) are
      expressed on neurons and glial cells including astrocytes. In this study, we have
      analyzed the responses of primary rat astrocytes of various brain regions to IL-6
      with respect to morphological changes and neurotrophin expression. Since IL-6
      alone failed to initiate effects on astrocytes, we have examined whether the
      soluble IL-6R (sIL-6R) can modulate the responsiveness of to IL-6 in these cells.
      For this purpose, we used a highly active fusion protein of IL-6 and sIL-6R,
      which is designated Hyper-IL-6 (H-IL-6). We show that treatment of cultured
      astrocytes with Hyper-IL-6 promotes region-specific morphological changes of GFAP
      positive astrocytes from typical stellate- to fibrous-like cells. In addition, we
      find that Hyper-IL-6 induces expression of neurotrophins (NTs) of the nerve
      growth factor (NGF)-family in a dose-dependent manner. Interestingly, astrocytes
      of various brain regions show differing patterns of cytokine-induced NT
      expression: NGF is maximally induced in cortex and hippocampus, NT-3 in
      hippocampus, and NT-4/5 in cortex and cerebellum. In summary, our results
      indicate that IL-6 in conjunction with sIL-6R regulates specific neurotrophin
      expression in astrocytes in a brain region dependent manner. Thus, the IL-6
      system provides a local supply of neurotrophins that participate in diverse CNS
      functions such as protection of neurons from insults, neuronal survival, and
      neuro-immune responses.

PMID- 10340762
TI  - Role of IkappaBalpha and IkappaBbeta in the biphasic nuclear translocation of NF
      kappaB in TNFalpha-stimulated astrocytes and in neuroblastoma cells.
AB  - In infectious diseases of the central nervous system astrocytes respond to
      inflammatory cytokines like tumor necrosis factor alpha (TNFalpha) by activation
      of the transcription factor NF-kappaB, mediated by the proteolysis of its
      inhibitors IkappaBalpha and IkappaBbeta. We studied the kinetics of NF-kappaB
      induction by TNFalpha in primary astrocytes, and in the neuroblastoma cell line
      Neuro2A, and compared it to fibroblasts. In the latter, NF-kappaB DNA binding
      activity was induced at 30 min and remained constant up to 4 h. In contrast, in
      astrocytes and in Neuro2A cells NF-kappaB DNA binding activity followed a
      biphasic pattern: it was induced after 30 min (early phase), declined after 1 h,
      and increased again at 2 to 4 h (late phase). The early phase was due to rapid
      degradation of IkappaBalpha. After 1 h IkappaBalpha was resynthesized to levels
      exceeding the amounts present in unstimulated cells. This paralleled the low
      levels of nuclear NF-kappaB binding activity. The decrease was not observed when
      IkappaBalpha resynthesis was inhibited by cycloheximide. Degradation of both
      IkappaBalpha and IkappaBbeta contributed to the late phase of induction. However,
      the second peak occurred also in the absence of IkappaBbeta proteolysis,
      demonstrating the importance of IkappaBalpha in the formation of the biphasic
      nuclear translocation of NF-kappaB.

PMID- 10340761
TI  - Receptor for the C3a anaphylatoxin is expressed by neurons and glial cells.
AB  - Little is known about the expression of the receptor for complement anaphylatoxin
      C3a (C3aR) in the central nervous system (CNS). In this study, we provide the
      first evidence that neurons are the predominant cell type expressing C3aR in the
      normal CNS. By using in situ hybridization (ISH) and immunohistochemistry, we
      found that C3aR is constitutively expressed at high levels in cortical and
      hippocampal neurons as well as in Purkinje cells. Moreover, we showed that
      primary culture of human astrocytes and microglia express the C3aR mRNA as
      assessed by RT-PCR. In situ hybridization performed on rat primary astrocytes
      confirmed the RT-PCR result demonstrating C3aR expression by astrocytes. In
      experimental allergic encephalitis (EAE), C3aR expression was elevated on
      microglia, infiltrating monocyte-macrophage cells and a few astrocytes, whereas
      neuronal expression remained unchanged during the course of the disease. These
      data demonstrate that the C3aR is expressed primarily by neurons in the normal
      CNS and that its neuronal expression is not dramatically upregulated under
      inflammation. This is in contrast to the increased neuronal expression of the
      C5aR in several inflammatory CNS conditions. The high constitutive expression of
      the C3aR by neurons suggests this receptor may play an important role in normal
      physiological conditions in the CNS.

PMID- 10340763
TI  - Voltage-gated sodium and potassium channels in radial glial cells of trout optic
      tectum studied by patch clamp analysis and single cell RT-PCR.
AB  - Radial glial cells in the visual center of trout were analyzed
      immunocytochemically and with the whole cell mode of the patch-clamp technique in
      combination with RT-PCR. By immunostaining with anti-GFAP antibodies radially
      oriented cell processes spanning the entire width of the tectum were brightly
      labeled, while with anti-S-100 antiserum the cell bodies residing in a discrete
      layer close to the ventricular border became most clearly visible. Virtually all
      radial glial cells examined in brain slices exhibited voltage-gated sodium inward
      currents that were activated above -40 mV, blocked by micromolar concentrations
      of TTX and totally eliminated if sodium was substituted for Tris in the bath
      solution. In contrast with adjacent nerve cells of the same slices radial glial
      cells did not exhibit spontaneous electrical activity and could not be stimulated
      to generate action potentials by depolarizing current injections. Two types of
      voltage-gated potassium outward currents were elicited by depolarizing voltage
      steps: a sustained current with delayed rectifier properties and a superimposed
      transient "A"-type current, both being activated at a threshold potential of -40
      mV. In cultured radial glial cells subtle differences were noticed regarding
      current density, inactivation kinetics, and TEA-sensitivity of the potassium
      currents. Inwardly rectifying potassium currents activating at hyperpolarized
      voltages were not observed. By single cell RT-PCR the transcripts of two shaker
      related potassium channel genes (termed tsha1-a fish homologue to Kv1.2- and
      tsha3) were amplified, while transcripts for tsha 2 and tsha 4 were not detected.

PMID- 10340764
TI  - A plethora of presynaptic proteins associated with ATP-storing organelles in
      cultured astrocytes.
AB  - Cultured astrocytes can release a variety of messenger substances via receptor
      mediated mechanisms, implicating their potential for regulated exocytosis and the
      participation of proteins of the SNARE complex. Here we demonstrate the
      astrocytic expression and organellar association of a large variety of synaptic
      proteins (synaptobrevin II, synaptotagmin I, synaptophysin, rab3a, synapsin I,
      SNAP-25, and syntaxin I) and also of the ubiquitous cellubrevin. As revealed by
      immunoblotting the expression of synaptic proteins was highest within the first
      few days after plating. Synaptophysin and SNAP-25 showed the most significant
      decline with prolonged culture time. Rab3a and synaptobrevin II were retained at
      a high level and synaptotagmin I, synapsin I, and syntaxin I at a lower level
      until 20 DIV. The immunoreaction for cellubrevin was low at the beginning and
      increased with prolonged culture time. As revealed by light microscopical
      immunocytochemistry the proteins are expressed by GFAP-positive astrocytes and
      associated with organelles of varying size. Immunoelectron microscopical analysis
      allocates synaptobrevin II and synaptophysin to the membranes of vesicular
      organelles. Double labeling experiments for pairs of synaptic proteins reveal
      that individual synaptic proteins can be entirely colocalized or partly reside on
      different organelles. Subcellular fractionation of astrocyte cultures by sucrose
      density gradient centrifugation after 2, 6, 13, and 20 DIV showed that the
      proteins sediment with ATP containing organelles of a broad density range. Our
      data suggest that messenger substances may be released from cultured astrocytes
      via receptor-mediated, Ca2+-dependent exocytosis.

PMID- 10340765
TI  - Disruption of actin-myosin interactions results in the inhibition of focal
      adhesion assembly in Xenopus XR1 glial cells.
AB  - In the present study we have investigated the role of actin-myosin interactions
      in regulating focal adhesion assembly in Xenopus XR1 glial cells. Actin-myosin
      interactions, stress fiber formation, and focal adhesion assembly are thought to
      allow cells to exert tension in the surrounding extracellular matrix, a process
      essential during morphogenesis and wound healing. Immunocytochemical analysis has
      revealed that myosin heavy chain-A (MHC-A), the predominant isoform in XR1 cells,
      was distributed in a filamentous pattern in the central region but was more
      diffuse towards the cell periphery. Myosin heavy chain-A-like immunoreactivity
      (IR) partially colocalized with phalloidin stained F-actin microfilaments in XR1
      cells but not with microtubules. Furthermore, MHC-A-IR colocalized with
      immunoreactivity for beta1 integrin receptors and vinculin at focal adhesions
      located more centrally along the ventral surface of the cells. The partial
      colocalization of MHC-A with the F-actin cytoskeleton, as well as at focal
      adhesions, provides evidence that actin-myosin interactions may be involved in
      regulating focal adhesion assembly and stabilization. To examine this
      possibility, we have used drugs shown to inhibit cell contractility: the kinase
      inhibitors H7 and HA100, and 2,3-butanedione 2-monoxime (BDM), which inhibits
      muscle and nonmuscle ATPase activity. Compared to control cultures, those treated
      with the inhibitors exhibited a dose-dependent decrease in the percentage of
      cells that displayed focal adhesions. In addition, these cells also displayed
      disrupted actin cytoskeletons and a similar disruption in myosin filaments. Taken
      together, these results provide evidence for an important role of actin-myosin
      generated forces during focal adhesion assembly in glial cells.

PMID- 10340766
TI  - Localization of estrogen receptor beta-immunoreactivity in astrocytes of the
      adult rat brain.
AB  - Estrogen receptors are direct regulators of transcription that function by
      binding to specific DNA sequences in promoters of target genes. The two cloned
      forms of estrogen receptors, alpha and beta, are expressed in the central nervous
      system by different neuronal populations. Astrocytes in vitro are also reported
      to express estrogen receptor alpha; however, this expression has not been
      confirmed in the rat brain in vivo. The apparent absence of estrogen receptors in
      glia in vivo contrasts with the well-known effects of this hormone on astrocytes
      of different brain areas, including the hippocampal formation. In this study, the
      expression of estrogen receptors in the hippocampal formation of adult male rats
      has been assessed by confocal microscopy. Estrogen receptor alpha
      immunoreactivity was localized in neuronal nuclei in the pyramidal cell layer of
      CA1-CA3 fields. Estrogen receptor beta-immunoreactivity was observed in the
      perikarya, apical dendrites, and cell nuclei of pyramidal neurons in CA1 and CA2.
      Furthermore, estrogen receptor beta-immunoreactive glia were observed in CA1,
      CA2, CA3, and in the hilus of the dentate gyrus of male and female rats. Estrogen
      receptor beta-immunoreactivity was localized in glial processes and perikarya
      and, in some cases, in glial cell nuclei. Double immunocytochemical labeling of
      estrogen receptor beta and the specific astroglial marker glial fibrillary acidic
      protein revealed that estrogen receptor beta-immunoreactive glial cells were
      astrocytes. Estrogen receptor alpha was not co-localized with glial fibrillary
      acidic protein. The presence of estrogen receptor beta in astrocytes of adult
      male and female rats demonstrates a possible mechanism by which estrogen can
      directly modulate gene expression in these cells.

PMID- 10340767
TI  - BQ788, an endothelin ET(B) receptor antagonist, attenuates stab wound injury
      induced reactive astrocytes in rat brain.
AB  - Endothelins (ETs) are suggested to be involved in pathological or
      pathophysiological responses on brain injuries. In the present study, an
      involvement of ETs on activation of astrocytes in vivo was examined by using
      selective endothelin receptor antagonists. A stab wound injury on rat cerebral
      cortex increased immunoreactive ET-1 at the injured site. GFAP-positive [GFAP(+)]
      and vimentin-positive [Vim(+)] cells appeared at the injured site in 1 day to 2
      weeks after the injury. A continuous infusion of BQ788, a selective ETB receptor
      antagonist, into cerebral ventricle (23 nmole/day) attenuated increase in the
      numbers of GFAP(+) and Vim(+) cells after the injury. FR139317, a selective ETA
      antagonist (23 nmole/day), slightly decreased the number of Vim(+) cells but not
      that of GFAP(+) cells. Increase in the number of microglia/macrophages by a stab
      wound injury, which was determined by Griffonia simplicifolia isolectin B4
      staining, was not affected by BQ788 and FR139317. These results suggest that
      activation of glial ETB receptors is one of the signal cascades leading to
      reactive astrocytes on brain injuries.

PMID- 10340768
TI  - Survey of vitamin and mineral supplementation after gastric bypass and
      biliopancreatic diversion for morbid obesity.
AB  - BACKGROUND: The authors investigated whether practice patterns of bariatric
      surgeons correlate with published data regarding metabolic deficiencies after
      Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion (BPD). METHODS: 109
      surgeons completed a questionnaire to determine use of supplements and frequency
      of lab tests. RESULTS: Regarding supplements routinely prescribed after RYGB, 96%
      of surgeons gave multivitamins, 63% gave iron, and 49% gave vitamin B12. After
      BPD, 96% of surgeons gave multivitamins, 67% gave iron, 42% gave vitamin B12, 97%
      gave calcium, 63% gave fat-soluble vitamins, and 21% gave protein supplements.
      Regarding laboratory tests obtained routinely after RYGB, 95% of surgeons do
      complete blood counts, 56% do iron determinations, 66% do vitamin B12
      determinations, 58% do folate determinations, 76% do electrolyte determinations,
      and 8% test for proteins. After BPD, 96% of surgeons do complete blood counts,
      80% do iron determinations, 67% do vitamin B12 determinations, 71% do folate
      determinations, 88% do electrolyte determinations, 84% do protein determinations,
      and 46% test for fat-soluble vitamins. Regarding frequency of blood tests, after
      RYGB, 22% of surgeons obtain them after 3 months, 33% after 6 months, and 41%
      after 12 months; 4% do not routinely obtain postoperative laboratory tests. After
      BPD, 46% of surgeons obtain them after 3 months, 33% after 6 months, and 16%
      after 12 months; one does not obtain laboratory tests. Surgeons estimated these
      deficiencies after RYGB: 16% iron, 12% vitamin B12, 14% anemia, 5% protein, and
      3% calcium. They estimated these deficiencies after BPD: 26% iron, 11% vitamin
      B12, 21% anemia, 18% protein, 16% calcium, and 6% fat-soluble vitamins. The
      estimated incidence of deficiencies after RYGB was considerably lower than the
      published incidence. Unnecessary tests were commonly performed (electrolytes
      after RYGB). CONCLUSION: Despite wide variations in the performance of laboratory
      tests and the use of supplements, the practice patterns of most surgeons protect
      patients from developing severe metabolic deficiencies after RYGB and BPD.

PMID- 10340769
TI  - A preliminary comparison of the psychological impact of laparoscopic gastric
      banding and gastric bypass surgery for morbid obesity.
AB  - BACKGROUND: Laparoscopic gastric banding has introduced a new element into weight
      reduction surgery. The authors compared subjects who had undergone a laparoscopic
      gastric banding (lap-band) procedure with those who had undergone a gastric
      bypass operation on relevant psychological and behavioral parameters. METHODS: A
      self-report questionnaire developed by the researchers was used. It included
      questions about aspects of food and eating as well as attitudinal items relating
      to the outcome of the surgery. RESULTS: There were significant differences
      between the lap-band group and the gastric bypass group in their distance from
      their desired weight, their eating, and their attitudes. CONCLUSION: 9 months
      after surgery, gastric bypass surgery appears to be the superior procedure on
      several parameters. The surgery induction process may be critical. Evaluation at
      later stages is vital.

PMID- 10340770
TI  - Biliopancreatic diversion for treatment of morbid obesity: experience in 180
      consecutive cases.
AB  - BACKGROUND: Biliopancreatic diversion (BPD) by Scopinaro's method is used by many
      as a surgical treatment for morbid obesity. The authors present their results in
      180 consecutive cases. METHOD: Between June 1995 and May 1998, the authors
      performed BPD by Scopinaro's method on 180 patients (36 men) with morbid obesity,
      mean age 35.8 years (range 18-58 years), mean body mass index (BMI) 48.8 kg/m2
      (range 35-66 kg/m2). RESULTS: In all cases, a gradual decrease in weight was
      obtained: the mean BMI at 1 month was 40.3 kg/m2, at 6 months 34 kg/m2, at 1
      years 32 kg/m2, at 18 months 30.2 kg/m2, and at 36 months 28.8 kg/m2. At the same
      time a significant improvement in the pathologic conditions associated with
      morbid obesity was observed. Postoperative complications were two duodenum
      blowout syndromes requiring prolonged intensive care, and an 18% rate of
      incisional hernias. Conversion to normal small bowel continuity was necessary in
      three cases. Protein malnutrition developed in 2 patients (1.1%), in 1 patient
      coinciding with addiction to cocaine. One patient could not psychologically
      accept the physical changes and requested conversion. Anastomotic ulceration was
      seen in 11% of the patients. Operation for late obstruction occurred in 2
      patients. There was no mortality. CONCLUSIONS: Although BPD by Scopinaro's method
      is technically complex, it is safe and effective.

PMID- 10340771
TI  - Technical alternatives in laparoscopic distal gastric bypass for morbid obesity
      in a porcine model.
AB  - BACKGROUND: Laparoscopic gastric bypass and vertical banded gastroplasty are two
      procedures used in the treatment of morbid obesity. The authors describe
      alternative techniques of laparoscopic distal gastric bypass as a modification of
      the Scopinaro procedure, which were used experimentally in a porcine model.
      METHODS: Five pigs were used. The laparoscopic procedure was performed with the
      pigs under general anesthesia after pneumoperitoneum had been achieved. Five or
      six trocars were used. One port was converted from 12 to 33 mm, and all the other
      ports were 10-11 mm. The initial surgical technique was similar to that used by
      others for laparoscopic gastrectomy, except that atraumatic ultracision was used
      for all the dissection. The stomach was stapled with a linear cutter stapler
      (Endopath, 31 mm) to create a 50-ml pouch. The ileum was divided with a linear
      cutter-stapler (Endopath, 31 mm) or ultracision cautery. A long length of ileum
      was positioned between the stomach pouch and the jejunoileostomy. Only 50-70 cm
      of terminal ileum was preserved as a common channel. In three animals, the
      circular stapler (ILS, 21 mm) was used to produce an end-to-side anastomosis. In
      one animal, two purse-string sutures were handsewn in the ileum and jejunum
      stumps, and in another two animals, two endoloops were used for the anvil. In two
      animals, the linear stapler was used to form a side-to-side pouch stomach-ileum
      and jejunoileostomy anastomosis. In other animals, the two types of anastomosis
      have been combined. All animals were killed after surgery so that the anastomoses
      could be evaluated for size and integrity. RESULTS: In all animals, with the
      circular and linear stapler, both 21 and 13-15 mm anastomoses were intact.
      CONCLUSION: Distal gastric bypass is feasible laparoscopically, with intact
      anastomoses.

PMID- 10340772
TI  - Swedish adjustable gastric band (SAGB)-distal gastric bypass: a new variant of an
      old technique in the treatment of superobesity and failed band restriction.
AB  - BACKGROUND: Dissatisfied with vertical banded gastroplasty in superobese
      patients, the authors adopted Salmon's gastroplasty/distal gastric bypass (DGBP)
      in 1995. When the Swedish adjustable gastric band (SAGB) became available in
      Switzerland, the authors started using that device instead of the gastroplasty
      because implanting a SAGB is much easier and gastric restriction with a SAGB is
      adjustable to the patients' individual demands. METHODS: The authors evaluated 40
      consecutive patients with SAGB-DGBP (27 primary and 13 secondary operations) for
      weight loss and complications, and compared weight loss with that obtained by
      SAGB alone. The mean initial body weight was 156.6 kg in women and 188.1 kg in
      men for primary and 108.2 kg/147.0 kg for secondary indications, respectively.
      The band was placed in a high position without tunneling sutures, and DGBP was
      done with a 50- to 60-cm common channel and a 60- to 80-cm biliopancreatic limb.
      RESULTS: Weight loss at 1 year was 33.3% of initial body weight for primary
      operations. Weight loss was significantly more than with SAGB-alone cases.
      Complications were as follows: no death, no slipping or pouch dilatation; one
      marginal ulcer, one splenectomy, four cholecystectomies, one Roux-en-O
      reconstruction, two band leaks, eight port-related reoperations. Iron or vitamin
      deficiencies occurred in 75% of patients, with one case of transient protein
      malnutrition and one of intermittent diarrhea. CONCLUSIONS: The SAGB as gastric
      restriction in combination with DGBP can be implanted easily. The new-generation
      SAGB is safe, but longer follow-up is necessary. SAGB-DGBP is more efficient than
      SAGB alone for weight reduction. It is too early to recommend banded DGBP as a
      primary procedure. However, in cases of insufficient weight loss after placement
      of an adjustable band, adding a DGBP without removing the band is an option.
      Follow-up by a specialized team is mandatory.

PMID- 10340773
TI  - Divided vertical banded gastroplasty either for correction or as a first-choice
      operation.
AB  - BACKGROUND: Staple-line disruption may occur after vertical banded gastroplasty
      (VBG). METHODS: Since May 1996, the authors have performed the gastric
      restrictive procedure divided VBG, as described by MacLean, as a first-choice
      operation and not only as correction for staple-line breakdown. Divided VBG was
      done in 111 patients, 32 as correction after staple-line disruption and 79 as a
      first choice, 29 of them by hand-assisted laparoscopy with the dexterity
      pneumosleeve. RESULTS: Weight loss and nutritional status have been very
      satisfactory. Operating time for the standardized operation has been no longer
      than 60 minutes. CONCLUSION: Divided VBG, especially if done by hand-assisted
      laparoscopy using the dexterity pneumosleeve, is a valid restrictive procedure.

PMID- 10340774
TI  - Anesthesia with sevoflurane in bariatric surgery.
AB  - BACKGROUND: Sevoflurane is a good halogen agent for bariatric surgery anesthesia
      because of its physical and chemical characteristics and its repartition
      coefficient (blood/gas = 0.65). METHOD: From November 1997 to April 1998, 98
      bariatric surgery procedures with sevoflurane anesthesia were done: 17
      lipectomies, 71 vertical gastroplasties, and 10 biliopancreatic diversions in 71
      women and 27 men, average age 30.3+/-8.3 years, with body mass index 43.9+/-5.7.
      The average operating time was 50+/-15 minutes for vertical gastroplasty, 160+/
      20 minutes for biliopancreatic diversion, and 80+/-12 minutes for lipectomy. The
      technique of anesthesia was as follows: preanesthesia with atropine sulfate 0.01
      mg/kg (dosage refers to ideal weight), ranitidine 50 mg, fentanyl 0.1 mg,
      ketorolac 60 mg; induction with propofol 0.5-1 mg/kg, succinylcholine 1 mg/kg;
      orotracheal intubation; maintenance with O2-N2O 50%, sevoflurane 1% to 1.5%,
      actracurium 0.5 mg/kg (dosage refers to ideal weight); awakening and
      decurarization with atropine sulfate 1 mg and prostigmine 2 mg. RESULTS: This
      method permitted correct control of the anesthesia, a quick awakening with a low
      incidence of nausea and vomiting, a prompt regain of physical and psychological
      functioning, an early discharge from the hospital, and a larger turnover of
      patients with lower costs. CONCLUSION: Sevoflurane balanced anesthesia seems to
      be the best anesthesiologic method for bariatric surgery.

PMID- 10340775
TI  - Laparoscopic adjustable gastric banding: a prospective 4-year follow-up study.
AB  - BACKGROUND: A body mass index of > or =40 kg/m2 represents clinically severe
      obesity and warrants operative treatment if requested. The adjustable silicone
      gastric band and the Swedish adjustable gastric band are recently produced
      laparoscopic gastric restrictive devices. The aim of this study was to assess all
      complications linked to both the available gastric bands in a long-term follow
      up. METHODS: In a prospective study, the effects, complications, and outcomes of
      this procedure were analyzed. The complications found were divided into early and
      general complications, and complications correlated to the bands. The technique
      of laparoscopic adjustable gastric banding is described. Follow-up was performed
      by the operating team. RESULTS: Between July 1994 and August 1998, the authors
      operated on 158 patients and performed 102 adjustable silicone gastric bandings
      and 54 Swedish adjustable gastric bandings. The mean age at surgery was 36 years
      (range 17-72). The mean preoperative weight was 136 kg (89-230). Of 158 patients
      who underwent laparoscopic procedures, 156 (98%) could be followed up (mean 28
      months; duration of follow-up, 6 weeks to 46 months). In early postoperative
      complications that required operation, one trocar wound hematoma (0.6%) and one
      wound infection of the port site (0.6%) were observed. The late complications
      that required reoperation were two pouch dilatations (1.3%), three band leakages
      (2%), one band migration (0.6%), and one late infection of the port (0.6%). A
      debanding operation was necessary in one patient because of esophageal
      dysmotility disorder. No early or late postoperative mortality was registered.
      The overall reoperation rate is currently about 7%. CONCLUSION: The operation is
      safe and effective. Moreover, adjustable gastric banding is fully reversible and
      is adjustable to the patient's needs. This study verifies the importance of
      correct operating technique. The authors' study and experience clearly indicate
      that laparoscopic adjustable gastric banding is an attractive alternative in the
      surgical treatment of morbid obesity.

PMID- 10340776
TI  - Results and complications of laparoscopic adjustable gastric banding: an early
      and intermediate experience.
AB  - BACKGROUND: Laparoscopic adjustable silicone gastric banding (LASGB) has been
      performed as the initial procedure for weight reduction in the authors'
      institution for the past 22 months. The efficacy and safety of the procedure were
      studied. METHODS: Patients were followed up prospectively during the
      perioperative and long-term course and for complications. RESULTS: 391 patients,
      aged 16-72 years, with a mean body mass index (BMI) of 43.1 (range 33-66) were
      operated on. The laparoscopic procedure was completed in all but four. The mean
      operative time was 78 min (range 36-165), and the mean postoperative hospital
      stay was 1.2 days (range 1-8). There were four (1%) intraoperative complications:
      pneumothorax in one patient, bleeding in two patients, and injury to the stomach
      in one. Early postoperative complications were subphrenic abscess in two patients
      and band malposition in five. Of the patients operated on, 356 (91%) were
      available for follow-up. Over an average follow-up period of 13 months (range 1
      22), band slippage occurred in 16 patients (4.1%), resistant port infection in 1,
      and longstanding pain in the port area in 9. There were 2 cases of port
      migration. A total of 26 (6.4%) reoperations were performed: early band
      repositioning (5), bleeding port site (1), late band repositioning (13), band
      removal (5), and local relocation of the port (2). All abdominal operations were
      performed laparoscopically. During the 18-month follow-up, the average BMI
      dropped from 43.1 to 29.8. CONCLUSION: LASGB is a safe procedure, with low early
      complication rates. Most reoperations may be performed laparoscopically, with
      subsequent low morbidity and short hospitalizations. On intermediate-term follow
      up itseems to be an effective bariatric procedure.

PMID- 10340777
TI  - Adjustable silicone gastric banding and band erosion: personal experience and
      hypotheses.
AB  - BACKGROUND: Adjustable silicone gastric banding (ASGB) has been advocated as a
      minimally invasive procedure that is completely reversible for the surgical
      treatment of morbid obesity. Band erosion (BE) is one of the possible
      complications of ASGB. The authors report their experience with BE and discuss
      its possible causes. METHODS: Between February 1993 and February 1998, the
      authors performed 122 ASGB: 51 open and 71 laparoscopic procedures. RESULTS: Two
      cases of BE occurred (1.6%). CONCLUSION: Band erosion is a possible complication
      of ASGB that is often not diagnosed immediately. Prevention is essential and
      consists primarily in correct placement of the band. There appears to be only one
      solution to BE: removal of the band. Placement of a new band after removal is
      possible; the minimum interval is not known.

PMID- 10340778
TI  - Treatment of morbid obesity with adjustable gastric band: preliminary report.
AB  - BACKGROUND: The goal of surgery for morbid obesity is to achieve a good and
      durable loss of weight and improve health. Previous studies have demonstrated a
      significant weight loss for the Swedish adjustable gastric band (SAGB). PATIENTS
      AND METHODS: Between November 1996 and April 1998, 18 morbidly obese patients
      underwent SAGB laparoscopically. Their mean age at surgery was 35 years. The mean
      preoperative weight was 128 kg (range 89-163), and the mean body mass index was
      50.4+/-9. Comorbidity was present in 13 patients. RESULTS: One gastric
      perforation occurred, and in one patient it was not possible to create the
      pneumoperitoneum. Regarding late morbidity, one intragastric migration and one
      slippage of the band occurred. There was no mortality. CONCLUSION: The low
      morbidity, the good results with weight loss, and the improvement in comorbidity
      lead the authors to believe that Swedish adjustable gastric banding for the
      treatment of morbidly obese patients is a successful means of losing weight and
      improving general health.

PMID- 10340779
TI  - Laparoscopic adjustable gastric band: first experience in Slovakia.
AB  - BACKGROUND: Until recently, surgery for obesity was not done in Slovakia. After
      preparation in workshops, the authors began to perform laparoscopic adjustable
      gastric banding. Their laparoscopic work is based on a 7-year experience in
      laparoscopy. METHODS: From December 1997 to May 1998, 14 procedures were done.
      The laparoscopic adjustable gastric band was used in all procedures. The group
      consisted of 8 women and 6 men. Their ages ranged from 30 to 53 years (mean 43),
      the body mass index was 37-56 (average 46.2), the hospital stay was 3-7 days
      (4.8), and the operating time was 75-285 minutes (145.3). A five-trocar technique
      was used. RESULTS: Weight loss in the first month ranged from 9 to 15 kg. In
      follow-up, the weight loss averaged 3-4 kg monthly. Up to the time of writing, no
      band had been adjusted. Intraoperative hemorrhage occurred in two patients. No
      conversion was done. One patient underwent reoperation and removal of the band
      because of obstruction of the stoma caused by profuse vomiting after enormous
      intake of food. CONCLUSIONS: Despite a small early series, the procedure seems to
      be safe and well tolerated by patients, with sufficient early weight loss.

PMID- 10340780
TI  - A new surgical technique for the silicone gastric band in the presence of a large
      hiatus hernia.
AB  - BACKGROUND: The purpose of this study was to establish the efficacy of a new
      surgical technique for the placement of the silicone gastric band (LAP-Band) in
      the presence of a large (>5 cm) hiatus hernia. METHOD: Hiatus hernias >5 cm were
      identified by endoscopy and barium meal in 6 patients. Each patient underwent
      hiatal hernia repair and attempted gastrodesis with laparoscopic placement of a
      gastric band. RESULTS: At 6 months, there were no complications. Mean weight loss
      was 16 kg. CONCLUSION: Repair of hiatus hernia with hiatal repair and gastrodesis
      of the posterior aspect of the stomach may allow some patients to undergo a
      procedure previously considered contraindicated.

PMID- 10340781
TI  - The world's first obesity surgery performed by a surgeon at a distance.
AB  - BACKGROUND: In recent years, laparoscopic procedures have gained popularity. The
      laparoscopic technique is, however, more difficult than the conventional
      approach, especially in obese patients. The purpose of this article is to
      demonstrate a solution to these difficulties. METHOD: On September 16, 1998, a
      laparoscopic gastric banding procedure was performed by a surgeon while he was
      actually sitting at a distance from his patient. The surgeon's assistant was
      scrubbed and gowned and stood at the patient's side. The surgeon manipulated
      handles that were connected to a computer in command of robotic arms mounted on
      the operating table near the patient. The robotic arms contained surgical tools
      with articulated tips, well inside the abdominal cavity. The system constituted a
      master-slave construction called Mona (Intuitive Surgical, Mountain View, CA).
      The entire procedure (adjustable silicone gastric banding) was performed solely
      by this system without any other intervention. RESULTS: The entire procedure
      lasted 90 minutes. The blood loss was 25 mL. The patient left the hospital on the
      second postoperative day. CONCLUSION: This procedure demonstrates that
      telesurgical procedures are feasible, can be performed safely even in obese
      patients, and improve the surgeon's comfort by restoring ergonomically acceptable
      conditions, by increasing the number of degrees of freedom, and by recreating the
      eye-hand connection lost in videoendoscopic procedures.

PMID- 10340782
TI  - A plea for professionalism.

PMID- 10340783
TI  - First bariatric operations.

PMID- 10340784
TI  - Traditional pharmacology and medicine in Africa. Ethnopharmacological themes in
      sub-Saharan art objects and utensils.
AB  - Drawing from the general description that ethnopharmacology studies the human use
      of crude drugs and poisons in a traditional context, ethnopharmacological themes
      in native art can be defined as themes visualizing different features of
      traditional medicines and poisons, such as natural sources, methods of
      preparation, containers, usage and implements, target diseases and effects. This
      review documents that native African art objects and utensils are a goldmine of
      such ethnopharmacological themes by focusing on the following subjects: (a)
      objects related to the use of medicines (sources as well as tools for their
      collection, preparation and keeping); (b) objects related to the use of poisons
      (e.g. for ordeals, hunting and fishing); (c) objects related to the use of
      psychotropic agents (e.g. alcoholic beverages, kola nuts, smoking and snuffing
      materials); (d) pathological representations (e.g. treponematoses, leprosy,
      smallpox, swollen abdomen, scrotal enlargement, goiter and distorted faces); and
      (e) portrayals of certain types of treatment (e.g. topical instillations,
      perinatal care, and surgery). To avoid the impression that ethnopharmacology has
      little else to offer than armchair amusement, an epilogue outlines the medical
      relevance of this interdisciplinary science for Western and African societies.

PMID- 10340785
TI  - Lectin cytochemistry of the lacrimal sac epithelium in experimental
      dacryocystitis.
AB  - PURPOSE: To study the glycoconjugates in the lacrimal sac epithelium of Japanese
      white rabbits with experimentally induced chronic dacryocystitis. METHODS:
      Chronic dacryocystitis was induced by a subcutaneous injection of albumin
      followed by an injection of Staphylococcus aureus into the lacrimal sac. The
      histological appearance of the lacrimal sac was studied using the alcian blue
      periodic acid-Schiff sequence. In addition, the specific binding to the lacrimal
      sac epithelium of Ulex europaeus agglutinin 1, Ricinus communis agglutinin 1,
      peanut agglutinin, and soybean agglutinin was also studied. RESULTS: Staining
      with alcian blue-periodic acid-Schiff sequence showed hyperplasia of the goblet
      cells in the inflamed lacrimal sac epithelium. Lectin cytochemistry revealed
      specific binding of Ulex europaeus agglutinin 1, Ricinus communis agglutinin 1,
      peanut agglutinin, and soybean agglutinin to the lacrimal sac epithelium.
      CONCLUSIONS: These results indicated that the composition of glycoconjugates in
      the lacrimal sac epithelium is markedly changed in dacryocystitis. There seems to
      be a fundamental abnormality in glycoconjugate synthesis in the chronically
      inflamed lacrimal sac epithelium.

PMID- 10340786
TI  - Mast cells in pterygium: number and phenotype.
AB  - PURPOSE: To investigate the pathogenesis of pterygium. METHODS: The number and
      phenotype of mast cells were examined in excised tissue from 35 pterygia patients
      and compared with those in normal conjunctival specimens obtained during cataract
      or other intraocular surgery. RESULTS: Toluidine blue staining showed that the
      mean number of mast cells in the pterygia specimens was twice as high as that in
      the normal conjunctival tissues. Immunohistochemistry with a primary antibody to
      tryptase, specific for mast cells, also revealed a twofold increase in the mast
      cell number in the pterygia specimens compared with the normal conjunctival
      tissues. In the pterygia, more than 94% of the tryptase-positive mast cells were
      found to express chymase and c-kit. Almost all mast cells in the pterygia were
      tryptase-positive, chymase-positive mast cells (MC(TC)S). There was no phenotypic
      difference between the mast cells in the pterygia and those in the normal
      conjunctival tissues. CONCLUSIONS: The MC(TC)S appear not to be immune system
      related and to have functions in angiogenesis and tissue remodeling. The increase
      in the number of mast cells caused by nonallergic stimulation may contribute to
      the pathogenesis of pterygium.

PMID- 10340787
TI  - Clinical phenotype of a Japanese family with primary open angle glaucoma caused
      by a Pro370Leu mutation in the MYOC/TIGR gene.
AB  - PURPOSE: To present the phenotype of two patients with primary open angle
      glaucoma (POAG) caused by a mutation of the myocilin/trabecular meshwork
      inducible glucocorticoid response (MYOC/TIGR) gene. METHODS: Complete ocular
      examinations were performed on the 13-year-old proband, her father, mother, and
      sister. DNA analysis was performed to detect the mutant gene. RESULTS: The
      proband and her father were found to have a mutation of the MYOC/TIGR gene. Both
      patients carried a heterozygous mutation in the 1,109th nucleotide, which
      corresponds to the 370th amino acid residue of the MYOC/TIGR gene. The clinical
      characteristics of both patients were: (1) development of POAG at an early age,
      (2) high peaks of intraocular pressure. and (3) poor response to medical
      treatment. CONCLUSIONS: The phenotype of these patients with a mutation of the
      MYOC/TIGR gene agreed with reports of other patients with mutations at other loci
      in this gene. The discovery of the MYOC/TIGR gene not only makes early detection
      of glaucoma possible, but also presents a new direction for investigating the
      pathogenesis of glaucoma.

PMID- 10340788
TI  - Detection of a new TIGR gene mutation in a Japanese family with primary open
      angle glaucoma.
AB  - PURPOSE: To describe a new mutation of the trabecular meshwork-inducible
      glucocorticoid response protein (TIGR) gene in a Japanese patient with familial
      primary open angle glaucoma (POAG). METHODS: Standard ocular examinations were
      performed on the 44-year-old patient, his sister, and mother. DNA sequencing was
      used to identify the mutation. We also developed a DNA diagnostic method for
      detecting this missense mutation by polymerase chain reaction-induced mutation
      restriction analysis (PCR-IMRA). RESULTS: The patient, father, and sister had
      been diagnosed as having POAG. The patient and his sister had a Thr448Pro
      mutation (C-->A transition at the nucleotide number 1419) in exon 3. This
      mutation has not been reported before. CONCLUSIONS: Gene analysis is promising
      for an early diagnosis among the family members of familial POAG patients and
      will contribute to early therapy before an occurrence of irreversible visual
      impairment.

PMID- 10340789
TI  - Expression of stress-response protein 60 in lens epithelial cells in atopic
      cataract.
AB  - PURPOSE: To clarify the pathogenesis of atopic cataract, especially to determine
      if there is any relationship between autoimmunity and atopic cataract. METHODS:
      We investigated the lens epithelia obtained at surgery from 12 patients (12 eyes)
      with atopic cataract: from 8 patients (8 eyes) with nonatopic cataract (5 with
      senile cataract, 2 with juvenile cataract, and one with secondary cataract due to
      anterior uveitis); and from 4 autopsy eyes as controls. RESULTS:
      Histopathological findings in the lens epithelial cells from atopic and nonatopic
      cataract patients were essentially the same: atrophy of the cells, presence of
      the superimposed cells, migration of cells into the lens cortex, cytoplasmic
      vacuolation, and loss of cells. In an immunohistochemical study, the expression
      of stress-response protein 60 (srp 60), srp 27, and srp 72 was examined in the
      lens epithelial cells. In atopic cataract specimens, 71%-87% of the lens
      epithelial cells were stained with the antibody against srp 60, but the cells in
      nonatopic cataract and control specimens were not stained. CONCLUSIONS: Srp 27
      and srp 72 were not expressed in any observed epithelial cells. The expression of
      srp 60 may reflect a protective mechanism of the epithelial cells against injury
      triggered by immunorelated agents. These findings suggest that the pathogenesis
      of degeneration of the lens epithelial cells in patients with atopic cataract may
      be related to autoimmunity.

PMID- 10340790
TI  - Immunogenetics of uveitis in leprosy.
AB  - PURPOSE: To identify any possible determinants in the development of uveitis in
      leprosy patients. METHODS: Human leukocyte antigen (HLA) class I and II antigen,
      and HLA class II genotypings were analyzed among Japanese leprosy patients.
      Ninety-three unrelated Japanese leprosy patients (46 patients with a history of
      uveitis and 47 patients without uveitis) and 114 healthy control subjects were
      investigated. RESULTS: The occurrence of HLA-DR2 was significantly higher in
      patients with uveitis (78.3%) than in those without uveitis (57.4%; odds ratio =
      2.7, P<.05) and in the controls (33.3%; odds ratio = 7.2, P<.0000005, Pc<.00005).
      The occurrence of HLA-DR4 was significantly lower in patients with uveitis
      (15.2%) than in those without it (38.3%; odds ratio = 0.29, P<.05) and in the
      controls (46.5%; odds ratio = 0.21, P<.0005, Pc<.05). Furthermore, the
      frequencies of DR2-positive and DR4-negative genotypes were significantly higher
      in patients with uveitis (69.6%) than in those without it (38.3%; odds ratio =
      3.7, P<.005) and in the controls (21.9%; odds ratio = 8.1, P<.00000005). At the
      genomic level, the occurrence of HLA-DQB1*0302 was significantly lower in the
      patients with uveitis (8.7%) than in those without it (25.5%; odds ratio = 0.28,
      P<.05). The distribution of HLA-DRB1 and DQA1 alleles was not significantly
      different between the patients with and those without uveitis. However, the
      frequencies of DRB1*1501-positive, as well as DRB1*0405- and DQB1*0302-negative
      genotypes were significantly higher in the patients with uveitis (47.8%) than in
      those without it (25.5%; odds ratio = 2.7, P<.05) and in the controls (8.8%; odds
      ratio = 9.5, P<.00000005). CONCLUSIONS: Our results suggest that HLA Class II
      genes confer susceptibility to or protection from leprous uveitis.

PMID- 10340791
TI  - Processes of blue light-induced damage to retinal pigment epithelial cells
      lacking phagosomes.
AB  - PURPOSE: To experimentally clarify the processes of the changes induced by blue
      light directly on the retinal pigment epithelium (RPE) before the formation of
      phagosomes or the accumulation of lipofuscin. METHODS: We developed a new
      experimental method in which primary cultured cells of very young pigmented rats
      were exposed to several intensities and durations of blue light (wavelength =
      440+/-10 nm). RESULTS: At 1.0 mW/cm2, the damage was limited to mitochondria. At
      2.0 mW/cm2, the cytoplasm exhibited large whorls of membrane or whorled
      inclusions, which were consistent with autophagic vacuoles. At 4.0 mW/cm2, the
      RPE cells showed lysis of the cytoplasm and a nucleus that was consistent with
      necrosis. CONCLUSIONS: Our results suggested that damage induced by blue light to
      cultured RPE cells may originate in the mitochondria and end in necrosis. The
      type of cell death induced in the RPE by blue light seems to be determined mainly
      by the intensity of the light, but is also related to the duration of exposure.

PMID- 10340792
TI  - Chronic dacryoadenitis misdiagnosed as eyelid edema and allergic conjunctivitis.
AB  - PURPOSE: To report the case of a 53-year-old woman with a 2-year history of
      episodic upper eyelid swelling and nonspecific complaints, who was diagnosed as
      having allergic conjunctivitis. METHODS: A complete ocular examination, orbital
      computerized tomographic (CT) scans followed by complete physical and systemic
      examinations. RESULTS: The results of physical and systemic examinations were
      unremarkable for systemic lymphoma and a primary focus of cancer. The results of
      the ocular examination were normal. CT scans demonstrated well-defined lesions
      bilaterally with a homogeneous internal structure in the lacrimal gland fossa,
      which suggested a diagnosis of chronic dacryoadenitis. The differential diagnosis
      included lymphoma and orbital metastases. The patient refused a biopsy and was
      started on a tapering dose of 60 mg oral prednisolone daily. The follow-up CT
      scans 1 month after cessation of 6-week oral corticosteroid treatment showed near
      complete resolution of the orbital lesions. CONCLUSION: This case demonstrates
      that orbital inflammation can be misdiagnosed as refractory allergic
      conjunctivitis.

PMID- 10340793
TI  - Extensive chorioretinal atrophy in Vogt-Koyanagi-Harada disease.
AB  - PURPOSE: To report extensive chorioretinal atrophy during the long-term course of
      Vogt-Koyanagi-Harada (VKH) disease not treated properly in the initial phase.
      CASES: Four patients with VKH disease were examined more than 10 years after
      onset of the disease. OBSERVATIONS: They presented initially with classic
      features of VKH disease, except 1 patient who had developed bilateral, acute
      angle-closure glaucoma as the initial sign. Two patients received systemic
      corticosteroid therapy at the acute phase of the disease. During the follow-up of
      13-34 years subsequent to onset, these patients had chronic recurrent anterior
      uveitis with apparently stable depigmented fundus. Eventually, they developed
      diffuse, extensive chorioretinal atrophy that resulted in severe visual loss. One
      patient had an unusual familial occurrence of the disease. CONCLUSIONS: Failure
      to prescribe proper corticosteroid therapy in the initial phase of VKH disease
      may lead to chronic recurrent uveitis. Long-standing uveitic reactions may
      eventually result in severe visual loss due to extensive chorioretinal
      degeneration.

PMID- 10340794
TI  - Survey of surgical indications and results of primary pars plana vitrectomy for
      rhegmatogenous retinal detachments.
AB  - BACKGROUND: Several surgical techniques to repair rhegmatogenous retinal
      detachment have been developed. Recently, both the method of reattaching the
      retina and of obtaining an early visual recovery are considered important factors
      when determining which surgical techniques to perform to treat retinal
      detachment. CASES: The surgical outcome in a series of 63 consecutive patients,
      who were treated at Osaka Rosai Hospital between 1993 and 1996, was reviewed
      retrospectively to evaluate the efficacy of primary vitrectomy to treat
      uncomplicated rhegmatogenous retinal detachment associated with posterior hyaloid
      separation. The criteria for vitrectomy included the presence of not only
      posterior retinal breaks, but also of multiple peripheral retinal breaks.
      OBSERVATIONS: The reattachment rate after the first surgery was 92.1% (58 eyes),
      and by the final examination it increased to 100%. Of the 46 eyes with macular
      detachment, good visual rehabilitation and a visual acuity improvement of 5 or
      more lines was obtained in 33 eyes (71.7%) by 1 month postoperatively. No
      statistically significant difference in the reattachment rate was found when eyes
      that underwent an encircling procedure were compared with those that did not. In
      eyes with lens opacity, cataract surgery was also performed and intraocular
      lenses were implanted uneventfully in all but one case with myopia. There was a
      high incidence (53.8%) of cataract progression in phakic eyes. However, no other
      serious complications, such as proliferative vitreoretinopathy, were found
      throughout the follow-up period. CONCLUSIONS: The results indicate that
      vitrectomy performed to alleviate peripheral vitreoretinal traction is an
      effective surgical technique to treat primary rhegmatogenous retinal detachment.
      Vitrectomy combined with cataract surgery may also be a valuable surgical option
      in selected cases to maintain long-standing visual rehabilitation.

PMID- 10340795
TI  - Baseline features of idiopathic optic neuritis as determined by a multicenter
      treatment trial in Japan. Optic Neuritis Treatment Trial Multicenter Cooperative
      Research Group (ONMRG).
AB  - BACKGROUND: An optic neuritis treatment trial was conducted at 30 clinical
      centers in Japan using the same protocol. Patient participation was based on: age
      range of 14-55 years; acute symptoms indicative of unilateral optic neuritis of
      unknown or demyelinating origin; visual symptoms of 14-day duration or less;
      relative afferent pupillary defect in affected eye; and normal or swollen optic
      disc of affected eye. CASES: Initially, 102 patients qualified for participation;
      baseline data were obtained for analysis from 70 of these patients. Demographic
      characteristics of Japanese patients with optic neuritis were clarified and
      compared with those in a US study. OBSERVATIONS: The incidence of ocular or
      periocular pain and the presence of periventricular plaques were noted to be
      lower, and the incidence of disc swelling higher, in the Japanese patients,
      suggesting racial differences in the characteristics of the disease. Such
      differences may possibly be related to the lower incidence of multiple sclerosis
      in Japanese patients. The results of visual function tests were virtually the
      same in both studies. The nonaffected eyes of more than half the patients showed
      abnormal mean deviation in Humphrey field analysis, as also noted in the US
      study. CONCLUSIONS: The baseline clinical features of optic neuritis in the
      Japanese patients have been defined. Some racial differences in the
      characteristics of the disease may exist.

PMID- 10340796
TI  - Multicenter clinical trial for evaluating methylprednisolone pulse treatment of
      idiopathic optic neuritis in Japan. Optic Neuritis Treatment Trial Multicenter
      Cooperative Research Group (ONMRG).
AB  - BACKGROUND: A randomized, controlled clinical trial was conducted in 1991 to
      compare an intravenous megadose of methylprednisolone with a control drug
      (mecobalamin) for treating acute idiopathic optic neuritis. CASES: Sixty-six
      cases from 22 clinical centers throughout Japan were examined to evaluate the
      treatment on visual function parameters, such as visual acuity, visual field,
      color vision, contrast sensitivity, and critical flicker frequency. OBSERVATIONS:
      The methylprednisolone pulse treatment group showed faster recovery of visual
      function, particularly the visual acuity at 1 week (P<.05), Humphrey field
      analyzer mean deviation at 3 weeks (P<.05), and color vision at 1 week (P<.05).
      Recovery of contrast sensitivity at several different spatial frequencies was
      significant in the pulse treatment group at 1 (P<.01), 2 (P<.05), and 4 weeks
      (P<.05) after the start of treatment. Visual function test results at 12 weeks
      and 1 year were essentially the same in the two treatment groups. Side effects
      appeared more frequently in the pulse treatment group than in the control
      (P<.05). CONCLUSIONS: Pulse treatment does not appear effective for idiopathic
      optic neuritis even though visual function in the pulse treatment group of this
      trial recovered more quickly during the initial phase compared to the controls.
      More effective and specific treatment should be established for optic neuritis.

PMID- 10340797
TI  - Current trends in cataract and refractive surgery in Japan: 1997 survey.
AB  - PURPOSE: A sixth annual survey was carried out by mail in January 1998, to
      investigate the current trends in cataract and refractive surgery in Japan.
      RESPONDENTS: Questionnaires were sent to 816 ophthalmologist members of the
      Japanese Society of Cataract and Refractive Surgery. Data received from 409
      (50.1%) of the recipients were cross-analyzed and compared with those from the
      previous surveys. RESULTS AND CONCLUSION: In cataract surgery, there have been
      trends toward more surgical procedures performed by a surgeon, shorter period of
      hospitalization, and increased number of outpatient surgery. Ninety-two percent
      of respondents preferred phacoemulsification, 54% used the self-sealing wound
      closure technique, and 19% used topical anesthesia for phacoemulsification. As
      for refractive surgery, surgeons remained rather conservative; with 28% and 7% of
      surgeons doing astigmatic keratotomy and refractive keratotomy, respectively.
      Photorefractive keratectomy, laser in situ keratomileusis, and phakic intraocular
      lens were judged to be useful refractive surgical procedures by 56.6%, 43.3%, and
      25.1% of the respondents, respectively.

PMID- 10340798
TI  - Risks and consequences of childhood and adolescent obesity.
AB  - This report reviews the risks and consequences associated with childhood and
      adolescent obesity. Although no consensus definition of childhood obesity exists,
      the various measures encountered in the literature are moderately well
      correlated. The paper is organized in three parts. The first section reviews
      childhood obesity sequelae that occur during childhood. These short-term risks,
      for orthopedic, neurological, pulmonary, gasteroenterological, and endocrine
      conditions, although largely limited to severely overweight children, are
      becoming more common as the prevalence of severe overweight rises. The social
      burden of pediatric obesity, especially during middle childhood and adolescence,
      may have lasting effects on self-esteem, body image and economic mobility. The
      second section examines the intermediate consequences, such as the development of
      cardiovascular risk factors and persistence of obesity into adulthood. These mid
      range effects of early obesity presage later adult disease and premature
      mortality. In the final section, the small body of research on the long-term
      morbidity and mortality associated with childhood obesity is reviewed. These
      studies suggest that risk of cardiovascular disease and all-cause mortality is
      elevated among those who were overweight during childhood. The high prevalence
      and dramatic secular trend toward increasing childhood obesity suggest that
      without aggressive approaches to prevention and treatment, the attendant health
      and social consequences will be both substantial and long-lasting.

PMID- 10340799
TI  - How physically active are American children and what can we do about it?
AB  - Any discussion of obesity in youth must consider physical activity level or
      energy output. Many suggest that increasing levels of obesity among children is
      the direct result of declining levels of physical activity. There is accumulating
      evidence that physical activity among youth has declined over the past several
      decades. Less time is spent on physical education classes in school and many
      popular activities among youth such as television and computer games, involve
      minimal physical exertion. These observations are confirmed by studies of
      physical fitness and endurance. These measures have also declined among youth.
      Much has been learned about the factors associated with physical activity among
      youth. These factors were used to develop several innovative school-based
      programs which demonstrate increased physical activity and performance.
      Recommendations are made for increasing physical activity both in the school
      curriculum and outside the school day. Potential health benefits and likely
      effects on obesity are substantial.

PMID- 10340800
TI  - Agreement among anthropometric indicators identifying the fattest adolescents.
AB  - Agreement was sought among six indicators used to classify youth as obese in 625
      white youth, aged 12.0-18.0 y, who participated in the Third National Health and
      Nutrition Examination Survey. Indicators included body mass index (BMI), triceps
      and subscapular skinfolds, the sum of four skinfolds, waist circumference and
      percentage body fat determined by bioelectric impedance analysis (BIA). The
      fattest youth in each age and gender group were considered those > 80th centile
      for the indicator. Agreement was determined by kappa coefficients, which provide
      the chance-adjusted proportion of agreement in the upper quintiles to identify
      the same youth as the fattest. Kappas among indicators range from 0.57-0.85 for
      males and from 0.56-0.79 for females. Categorical agreement with the fattest
      youth by percentage body fat, changes considerably with age for most indicators,
      suggesting that relationships among indicators change during adolescence.
      Different indicators may identify different subpopulations as the fattest,
      arguing for caution in use and interpretation of results from different
      indicators, and in favour of standardized definitions for obesity in youth.

PMID- 10340801
TI  - Overweight prevalence among youth in the United States: why so many different
      numbers?
AB  - Several recent publications have presented different estimates for the prevalence
      of overweight among youth in the United States. Prevalence estimates range from
      11-24%, despite describing the same results from the third National Health and
      Nutrition Examination Survey (NHANES III). This paper discusses the variety and
      evolution of different overweight prevalence estimates. Issues of definition,
      measurements, criteria selection and comparison groups are considered and
      implications for estimates of the prevalence of overweight among youth are
      explored. Reference percentiles for body mass index (BMI) from several
      publications are compared. The differences in published estimates from NHANES III
      are noted and explained.

PMID- 10340802
TI  - Prevalence of overweight and obesity in American Indian School children and
      adolescents in the Aberdeen area: a population study.
AB  - OBJECTIVES: This study estimated the prevalences of overweight and obesity in
      American Indian children and adolescents attending schools in the Aberdeen area
      Indian Health Service (including SD, ND, IA, NE). METHODS: Stature and weight
      were measured for 12559 children aged 5-17y and prevalences of overweight and
      obesity were determined relative to gender and age-specific national reference
      data for the body mass index (BMI). Those with BMI > 85th percentile were
      considered overweight and those with BMI > 95th percentile were considered obese.
      RESULTS: Age-adjusted prevalences of overweight were 39.1% and 38.0% for males
      and females, respectively, and corresponding age-adjusted prevalences for obesity
      were 22.0% and 18.0%, respectively. There were few regular changes in prevalences
      of overweight across ages for either gender, or for obesity in females.
      Prevalences of obesity in males increased systematically with age and exceed
      prevalences in females at many ages. CONCLUSIONS: Overweight and obesity based on
      elevated BMI are highly prevalent among American Indian youth. Even at the
      youngest school ages, overweight is more than twice as likely as national
      patterns and obesity is more than three times as prevalent. Primary prevention
      must begin very early among these children.

PMID- 10340803
TI  - The weight dilemma: a range of philosophical perspectives.
AB  - The aim of this paper is to present a wide range of professional and lay
      viewpoints on obesity. Different perspectives surrounding how obesity is viewed,
      primary etiological factors contributing to obesity and intervention aims are
      brought together for review and discussion. Factors which may contribute to
      different perspectives include: familiarity with the scientific data showing the
      health risks associated with obesity, personal experience with weight and weight
      control, experiences encountered in working with clients in weight management,
      and professional training. In addition to describing and comparing the different
      approaches, possibilities for reconciling their differences and drawing from each
      of their strengths, are explored. The predominant viewpoint among health
      professionals regarding the etiology of obesity is that multiple factors
      contribute to its onset and progression. However, viewpoints tend to differ with
      regard to the main contributing factors and range from those in which the major
      focus is on genetic factors, to those which focus more on familial and/or
      individual choices regarding behavioural implementation. Although the predominant
      viewpoint on obesity in western societies is not a positive one, there is a
      growing size acceptance movement which has had a significant impact on both the
      fashion industry and on the health field. Aims of treatment may vary in
      accordance with beliefs about key etiological factors leading to obesity (for
      example, primarily genetic vs primarily behavioural) and with opinions regarding
      potential consequences and benefits of obesity. Aims of treatment may include
      weight loss, healthy eating and exercise, weight maintenance, improved self
      esteem, fat accepTance and/or advocacy for decreased weight discrimination. An
      increased awareness, understanding and openness towards different philosophical
      perspectives surrounding weight issues may be the first step towards working with
      colleagues and clients whose viewpoints on weight-related issues differ from our
      own.

PMID- 10340804
TI  - Systems approach to childhood and adolescent obesity prevention and treatment in
      a managed care organization.
AB  - OBJECTIVE: To outline an intervention approach to childhood and adolescent
      obesity prevention and treatment, that will systematically facilitate effective
      communication, provide long-term social support and access to resources, that may
      be accessed proactively or on demand. Furthermore, this approach operates in an
      environment that involves all critical parties: child/adolescent, family-unit,
      physician and allied health professionals. SYSTEMS THINKING APPROACH: The
      objective is to bring together all key stakeholders and consider the
      interrelationships among them as a common process. In a managed care setting,
      this may be accomplished by optimizing the contributions of care delivery, health
      promotion and information systems. SETTING: A not-for-profit, community governed
      Managed Care Organization (MCO) in the Midwestern United States. Telephone-based,
      centralized services facilitate a process of access, communication, documentation
      and intervention implementation. CASE STUDIES: Two case studies are presented as
      examples of how access is obtained, the intervention is tailored to individual
      needs, communication is established, documentation is organized and long-term
      support is facilitated. CONCLUSIONS: A systems thinking approach to obesity
      prevention and treatment in youth has great potential. In a MCO setting, such an
      approach may be implemented, since integrated health care delivery systems may
      allow a common process to be established that can bring together all key
      stakeholders.

PMID- 10340805
TI  - School-based approaches for preventing and treating obesity.
AB  - Schools have the potential to make valuable contributions to both the prevention
      and treatment of childhood obesity. This article reviews the research on school
      based interventions to prevent and treat obesity. A literature search from 1965
      to the present on school-based treatment of obesity, identified 11 controlled
      experimental studies. The results show positive, though modest short-term
      results. Relatively few primary prevention research studies, targeted
      specifically to preventing obesity, have been conducted. Therefore, efficacy has
      not been established. Both primary and secondary obesity interventions have a
      role in schools. A comprehensive, integrated model for school-based obesity
      prevention is presented. This model, building upon the comprehensive school
      health program model, consists of eight interacting components: health
      instruction; health services; school environment; food service; school-site
      health promotion for faculty and staff; social support services; physical
      education classes; and integrated and linked family and community health
      promotion efforts. While multi-faceted community-wide efforts are needed to
      address the growing problem of obesity, schools are in a unique position to play
      a pivotal role in promoting healthy lifestyles and helping to prevent obesity.

PMID- 10340806
TI  - Behavioural treatment of childhood and adolescent obesity.
AB  - Current state-of-the-art behavioural treatments for childhood and adolescent
      obesity, produce long-term weight control in up to one-third of participants. A
      review of the most effective treatments suggests structural and organizational
      components and treatment content that are most likely to be successful. These
      include a group format with individualized behavioural counseling; parent
      participation; frequent sessions; a long treatment duration; a simple and
      explicit diet that produces a calorie deficit; a physical activity program
      emphasizing choice and reinforcing reduced sedentary behaviours; making changes
      in the home and family environment to help reduce cues and opportunities
      associated with calorie intake and inactivity, and to increase cues and
      opportunities for physical activity; self-monitoring; goal setting and
      contracting; parenting skills training; skills for managing high-risk situations;
      and skills for maintenance and relapse prevention. Still, there are many
      unanswered questions about the implementation of all the components of treatment.
      Further research, to identify treatment approaches that promote long-term
      maintenance of weight control, is greatly needed.

PMID- 10340807
TI  - A biopsychosocial model for youth obesity: consideration of an ecosystemic
      collaboration.
AB  - Youth obesity is a difficult problem for health care professionals, the patients'
      themselves, and their families. This complex issue requires new theoretical and
      clinical models for intervention, which accommodates interdisciplinary
      collaboration. The Family-Collaborative Ecosystemic Model (FEM) is a view of
      obesity grounded in family systems theory, ecosystems theory and biopsychosocial
      theory, integrated with Eastern and Western philosophical views of health. The
      Ecosystemic Biopsychosocial Grid (EBG) is presented as a clinical application to
      evaluate the clinical picture and organize delivery of interventions. The EBG can
      be used to assess resources and obstacles in ten domains or levels of patients'
      daily experience of obesity. Using a strengths perspective, it utilizes the
      experience of the patient and family, in partnership with the expertise of health
      care professionals, to meet patient and family-centered goals of health.

PMID- 10340808
TI  - Visceral adipose tissue: a critical review of intervention strategies.
AB  - OBJECTIVE: To review the published literature regarding the effect of caloric
      restriction, pharmacologic intervention, and exercise to promote the loss of
      visceral adipose tissue (VAT) DESIGN: A review was conducted of published studies
      which measured VAT using computed tomography or magnetic resonance imaging before
      and after caloric restriction, pharmacologic therapy, or exercise. STUDIES
      REVIEWED: 23 separate studies were reviewed. Men represented 38% and women 63% of
      the 599 volunteers. There were 17 black volunteers and 30 patients with NIDDM
      included in these studies. MEASUREMENTS: Data regarding the baseline and change
      in VAT, body fat, and body weight were collected. RESULTS: Most interventions
      demonstrated a preferential loss of VAT regardless of the intervention applied.
      When expressed as percent change in VAT/percent change in body fat, a ratio can
      be calculated which we call the Selectivity Index (SI). When this index is
      applied to the literature reviewed, two observations can be made. First, the
      Selectivity Index is higher when baseline body fat is higher. Second, there is a
      direct relationship between the Selectivity Index and the baseline visceral fat
      ratio. These two observations suggest that individuals with greater visceral fat
      mass, either through an increase in the body weight or the propensity to store
      fat in the visceral depot, lose more visceral fat when adjusted to the loss of
      body fat. CONCLUSION: In conclusion, the Selectivity Index is useful to compare
      the ability of an intervention to specifically target the loss of AT. This simple
      index can serve as a benchmark for comparing intervention studies to each other.

PMID- 10340809
TI  - Evidence for a local renin angiotensin system in primary cultured human
      preadipocytes.
AB  - OBJECTIVE: To investigate whether human preadipocytes possess a complete
      functional renin angiotensin system. MEASUREMENTS: Gene expression of
      angiotensinogen, renin, renin binding protein, angiotensin converting enzyme
      (ACE) and angiotensin II (ang II) receptor type 1 in human preadipocytes; ACE
      protein and ang II production of human adipose tissue stromal cells
      differentiated or not in primary culture. RESULTS: All genes mentioned above were
      found to be expressed in human preadipocytes. ACE was translated into protein as
      detected by western blot. Ang II was secreted both by undifferentiated
      preadipocytes and immature adipocytes, and its production was significantly
      elevated in differentiated cells. CONCLUSIONS: Preadipocytes from human adipose
      tissue express a functional renin angiotensin system (RAS).

PMID- 10340810
TI  - Determinants of geographical variations in body mass index (BMI) and obesity in
      Spain.
AB  - OBJECTIVE: To identify the factors associated with geographic variations in Body
      Mass Index (BMI) and obesity in Spain. DESIGN: Cross-sectional, ecological
      analysis using data on illiteracy rate (per 1000 population), energy intake
      (kcal/person/d), sedentary population (%), smoking population (%), alcohol
      consumption (g/person/d), and percentage of population aged 65 y or over, for
      Spain's 50 provinces. SUBJECTS: Non-institutionalized population aged 16y or
      over. MEASUREMENTS: Median BMI and percentage of population with obesity, defined
      as BMI > 30 kg/m2. RESULTS: There was a clear geographical pattern, with some
      areas in the south and north-west of the country registering the highest BMI and
      prevalence of obesity and a north-south pattern on illiteracy per 1000
      population. Multivariate regression analysis showed that illiteracy, sedentary
      lifestyle and energy intake explain 35% and 14% of the variation in BMI and
      obesity, respectively. Illiteracy proved to be the variable most associated with
      both BMI (regression coefficient (beta = 0.01; P = 0.005) and obesity (beta =
      0.05; P = 0.013). Sedentary lifestyle showed a statistically significant
      relationship with BMI (beta = 0.01; P = 0.03), but not with obesity (beta = 0.03;
      P = 0.581). Energy intake exhibited a relationship with BMI (beta < 0.01 P =
      0.03) that lost statistical significance when adjusted for age. CONCLUSION:
      Geographical variations in BMI in Spain are partly explained by illiteracy,
      sedentary lifestyle and, to a lesser extent, energy intake, whereas regional
      variations in obesity are related only to the educational level of the
      population.

PMID- 10340811
TI  - Predicting BMI in young adults from childhood data using two approaches to
      modelling adiposity rebound.
AB  - OBJECTIVE: To identify the age of adiposity rebound and the value of its
      associated BMI and examine their association with BMI at ages 18 and 21 y for
      males and females. DESIGN: A longitudinal study of a large cohort of people born
      in Dunedin, New Zealand between 1972-1973. SUBJECTS: Four hundred and seventy
      four males and 448 females aged between birth and 21 y. MEASUREMENTS: BMI was
      derived from measurements of weight and height made when the participants were
      born and at intervals from age 3-21 y. RESULTS: When a random coefficients model
      was fitted to the data for those who had five or more measures of BMI between age
      3 and age 18y, adiposity rebound occurred at 6.0 y of age for boys and 5.6y for
      girls. The values of BMI associated with these were 15.7 kg/m2 for boys and 15.5
      kg/m2 for girls. The correlations between age at adiposity rebound and BMI at
      ages 18 and 21 y were between -0.72 and -0.65 for boys and -0.59 and -0.47 for
      girls. These were higher than those derived from fitting individual curves or
      from deriving the adiposity rebound from data collected up to age 11 y. The
      correlation between BMI at age 7y and BMI at ages 18 and 21 y were 0.70 and 0.61
      for boys and 0.56 and 0.52 for girls. The correlations between measures of
      skeletal maturity at age 7y and adiposity rebound were statistically significant
      for boys but not for girls. CONCLUSIONS: BMI in early adulthood was associated
      with both age of adiposity rebound and BMI at that age. As the correlations
      between BMI at age 7 y and BMI at ages 18 and 21 y were similar in magnitude, BMI
      at age 7 y may be a more practical way of predicting BMI in early adulthood.

PMID- 10340812
TI  - Relationship between plasma leptin levels and the tumor necrosis factor-alpha
      system in obese subjects.
AB  - OBJECTIVE: To evaluate the relationship between plasma leptin and the tumor
      necrosis factor-alpha (TNFalpha), TNF receptor p60 (TNF-R1) and TNF receptor p80
      (TNF-R2) concentrations in obese subjects. DESIGN: Case-control study. SETTING:
      Outpatient's Service for Prevention and Treatment of Obesity at the University
      Hospital. MEASUREMENTS: Body mass index (BMI), waist circumference, hip
      circumference, waist-to-hip ratio (WHR), fasting plasma glucose, fasting plasma
      insulin, homeostasis model assessment of insulin resistance (HOMA IR), plasma
      leptin, TNFalpha, TNF-R1 and TNF-R2 concentrations were evaluated in obese
      subjects (n = 42) and in age- and gender-matched, lean healthy controls (n = 16).
      RESULTS: In obese subjects, fasting plasma glucose and insulin, HOMA IR, plasma
      leptin, TNFalpha, TNF-R1 and TNF-R2 concentrations were significantly higher than
      in controls. Furthermore, females showed higher leptin, TNF-R1 and TNF-R2 plasma
      concentrations compared to males, in both control and obese subjects. In control
      subjects, plasma leptin concentrations showed a direct correlation with BMI
      (r=0.74, P<0.001), hip circumference (r=0.94, P<0.001), TNF-R1 (r=0.79, P<0.001)
      and TNF-R2 (r=0.64, P<0.01), and a negative correlation with WHR (r=-0.58,
      P<0.05). In obese subjects, we found a direct correlation between plasma leptin
      concentrations and BMI (r=0.67, P<0.001), hip circumference (r=0.66, P<0.001),
      fasting glucose (r=0.37, P<0.05), fasting insulin (r=0.31, P<0.05), HOMA IR
      (r=0.38, P<0.05), TNF-R1 (r=0.71, P<0.001) and TNR-R2 (r=0.66, P<0.001), while a
      negative correlation was found between circulating leptin and WHR (r=-0.44,
      P<0.01). In multivariate analysis, plasma leptin concentrations were
      significantly associated with BMI (P=0.015) and gender (P=0.047) in the control
      group, while in obese subjects, plasma leptin showed a significant association
      with BMI (P=0.019) and TNF-R1 (P=0.012). CONCLUSIONS: Our results are consistent
      with the hypothesis that the TNFalpha system could be involved in the regulation
      of plasma leptin concentrations in obese subjects.

PMID- 10340813
TI  - Reduced bone mineral density after surgical treatment for obesity.
AB  - OBJECTIVE: To investigate whether osteoporosis occurs after surgical treatment
      for obesity. DESIGN: A cross-sectional study of five groups of subjects who had
      undergone surgical treatment for obesity: five pre-menopausal women; 13 post
      menopausal women; seven post-menopausal women taking oestrogen replacement (HRT);
      five men; and six women who had undergone surgical reversal (mean time 7 y).
      SUBJECTS: Thirty-six Caucasian subjects who had undergone jejunoileal or
      pancreaticobiliary bypass surgery at St George's Hospital between 1971 and 1992.
      Their mean age was 50.8 y (range 32-69 y) and the median time since the operation
      was 14.8y (range 4-23 y). MEASUREMENTS: A clinical questionnaire was used to
      exclude possible factors, which might influence bone mineral density. A single
      blood sample was collected for measurement of calcium, phosphate, alkaline
      phosphatase, albumin, magnesium, zinc, creatinine, thyroxine, 25-hydroxy-vitamin
      D, sex steroids, gonadotrophins and IGF-1 and 24 h urine calcium excretion was
      measured. Bone mineral density (BMD) was measured in the lumbar (L2-L4) spine
      (LS) and femoral neck (FN) by dual energy X-ray absorptiometry (DEXA). RESULTS:
      There was no difference in serum calcium, alkaline phosphatase, IGF-1, 25-hydroxy
      vitamin D (25-OH vitamin D), magnesium or zinc concentrations between the five
      groups. The LS-BMD T score was lower (P < 0.05) in male subjects ( -2.08 +/- 1.04
      mean 1.0 +/- s.d) and post-menopausal women not taking HRT ( -1.21 +/- 1.33)
      compared to the surgically reversed group (0.87 +/- 2.36). The male group was
      most severely affected, despite normal serum testosterone concentrations. Two of
      the five men studied, had a LS-BMD T score < -2.5 and two had a LS-BMD T score
      between -1.0 and -2.5. In contrast, six of the seven post-menopausal women on HRT
      had an LS BMD T score > - 1.0. There was no difference in the FN-BMD between the
      five groups. The presence of low BMD was not related to age, duration of bypass,
      or degree of postoperative weight loss. Iliac crest bone biopsies in three
      subjects with low BMD, confirmed the presence of osteoporosis. CONCLUSIONS:
      Reduced bone mineral density is a complication of jejunoileal bypass surgery.

PMID- 10340814
TI  - Oleoyl-estrone treatment affects the ponderostat setting differently in lean and
      obese Zucker rats.
AB  - OBJECTIVE: To determine whether the slimming effects of treatment with oleoyl
      estrone (OE) in liposomes of normal and obese rats are permanent, or disappear as
      soon as the treatment with the drug ceased. This study was devised to gain
      further knowledge on the postulated role of OE as a ponderostat signal,
      evaluating whether (in addition) it can lower the ponderostat setting of the rat.
      DESIGN: The rats were infused for 14d (using osmotic minipumps) with oleoyl
      estrone in liposomes at a dose of 3.5 micromol/kg x d, and were studied up to one
      month after the treatment ceased. SUBJECTS: Young adult lean controls (CL) or
      treated (TL) and obese controls (CO) or treated (TO) Zucker rats. MEASUREMENTS:
      Energy balance, blood glucose, liver glycogen, plasma insulin, leptin
      corticosterone, ACTH and estrone (free and total) concentrations, and expression
      of the OB gene in white adipose tissue (WAT). RESULTS: The loss of body weight
      caused by OE was recovered quickly in the TO, which gained weight at the same
      rate as the CO. TL rats, however remained at the low weight attained for one
      month after the treatment ceased. However, no differences were observed in
      calculated energy expenditure (EE) between the TL and TC rats once treatment had
      stopped. In TL and TO rats, liver glycogen concentrations decreased to normal
      shortly after treatment ceased, and leptin expression and concentrations remained
      normal and unchanged after the end of OE treatment. In TO rats, plasma glucose,
      insulin and leptin were lower than in the CO. Total estrone concentrations
      decreased rapidly in TL rats and more slowly in the TO, and free estrone followed
      a similar pattern. CONCLUSION: Continuous infusion of liposomes loaded with OE
      resulted in a decreased energy intake (EI), maintenance of EE and the utilization
      of body fat reserves in lean and obese rats alike. This process ended in obese
      rats as soon as the infusion ceased, so that even when the levels of free and
      total estrone in plasma remained high, there was a marked (and relatively fast)
      shift toward the basal situation, which translated into an increase in EI,
      maintenance of estimated EE and a marked buildup of energy stores. In lean rats,
      the effects of OE on leptin concentrations and OB gene expression persisted after
      infusion ended.

PMID- 10340815
TI  - Endurance training increases the beta-adrenergic lipolytic response in
      subcutaneous adipose tissue in obese subjects.
AB  - OBJECTIVE: The aim of this study was to assess, by longitudinal follow-up, the
      influence of aerobic training on the in vivo lipolytic activity of adipose tissue
      in obese male subjects. SUBJECTS: Eleven obese non-diabetic males, aged 41.5+/
      5.77 (range 27-49 y) with body mass index (BMI) 36.5+/-4.5 kg/m2 (range 29.4-47.1
      kg/m2) participated in the study. DESIGN: Subjects took part in a 12-week aerobic
      training program. Before and after training, microdialysis of abdominal
      subcutaneous adipose tissue (SCAT) was carried out, using perfusion with graded
      doses of the beta-adrenergic agonist isoprenaline and a single dose of the
      phosphodiesterase inhibitor theophylline. In addition, the response of plasma
      glycerol and free fatty acids (FFAs) to intravenous infusion of graded doses of
      isoprenaline was tested. RESULTS: The training did not induce significant weight
      loss and promoted an increase in maximum aerobic capacity (P<0.05). The increase
      of extracellular glycerol in SCAT in response to isoprenaline perfusion was
      enhanced after the training (P<0.05), while no change in the response of
      interstitial glycerol to theophylline action was observed. The training did not
      elicit a change in the isoprenaline-induced changes of blood flow in adipose
      tissue. The increases of plasma FFAs and glycerol in response to intravenous
      isoprenaline infusion, were significantly enhanced after training. CONCLUSION:
      The present study shows that aerobic training induced an increase in the response
      of plasma and subcutaneous adipose tissue concentration of glycerol to beta
      adrenergic stimulation. The effect of an agent acting at the post-receptor level
      (theophylline) in SCAT was not modified by training.

PMID- 10340816
TI  - Nutritional consequences of modified vertical gastroplasty in obese subjects.
AB  - BACKGROUND: Gastroplasty results in a considerable reduction in food intake and
      dramatic weight loss. This is likely to have a nutritional impact, although it is
      expected that this may be minimised by good advice and supplement use. METHODS:
      Twenty six obese subjects were studied in detail before and after modified long
      vertical gastroplasty (MLVG), in a setting where comprehensive nutritional advice
      on symptom avoidance was readily available and multivitamin supplements advised.
      Nutritional intake and anthropometry were measured preoperatively and at 2, 5 (n
      = 22) and 12 months (n = 11) postoperatively. RESULTS: Mean weight loss was 13%,
      22% and 31% of initial body weight at the respective time points. Energy intake
      (EI) was significantly reduced postoperatively, with the mean protein intake
      being only 40 g/d. At 2 months, mean intakes of iron, calcium and zinc from food
      were 40%, 71% and 39%, respectively, of the Australian recommended dietary intake
      (RDI), and iron and zinc intake remained below half the RDI at 5 months. Only
      regular adherence to the vitamin/mineral supplement, brought iron and calcium
      intakes close to RDI, but zinc remained low. Haemoglobin and serum ferritin
      concentrations did not alter significantly and remained within the reference
      range, but serum folate fell significantly between 5 months and 12 months. By 5
      months, 60% of subjects never regurgitated or regurgitated less than once a week.
      Fresh bread was the least tolerated food. Frequency of regurgitation was not
      correlated with adequacy of nutrient intake. CONCLUSIONS: The results emphasise
      the need for regular follow-up of MLVG patients, and nutritional advice which
      includes diet quality as well as symptom management, and regular intake of the
      vitamin/mineral supplement for at least a year postoperatively. Low protein
      intakes, however, remain of potential long-term concern.

PMID- 10340817
TI  - Trends in the prevalence of obesity in the French adult population between 1980
      and 1991.
AB  - OBJECTIVE: To determine changes in the prevalences of overweight and obesity
      between 1980 and 1991 in French adults. DESIGN: Two cross-sectional studies were
      performed in 1980 and 1991 by the French National Institute of Statistics and
      Economics Studies in representative samples of the non-institutionalized French
      population using a similar random sampling of households from the last available
      national population census. Overweight and obesity were defined, based on
      reported height and weight, by a body mass index (BMI)> or = 25 kg/m2 and > or =
      30 kg/m2, respectively. As age and socio-economic class (SEC) distributions
      changed between 1980 and 1991, results were compared before and after a direct
      age class and SEC standardization of the 1991 data, according to the 1980
      population distribution. SUBJECTS: 6792 men and 7150 women in 1980, 7250 men and
      7856 women in 1991, aged at least 20y, about 1/2500th of the French non
      institutionalized adult population. RESULTS: In women, between 1980 and 1991,
      there were slight increases in the prevalences of obesity (from 6.3% to 7.0%,
      P<0.08) and of overweight (26.8% and 27.5%, not statistically significant NS).
      These increases were most pronounced in women aged 20-29y (obesity: 1.4-2.1%,
      P<0.15; overweight: 8.0-11.5%, P<0.01). In men, the corresponding prevalences
      were 6.4% and 6.5%, (NS), and 39.4% and 40.8% (NS). After standardization, the
      increases in the prevalences of obesity and overweight were even higher between
      1980 and 1991 in women (the standardized prevalences in 1991 were respectively:
      7.8% and 28.9%), but were unchanged in men. CONCLUSIONS: There were slight
      overall increases in the prevalences of overweight and obesity between 1980 and
      1991 in both genders, which were most pronounced among young women. Changes in
      the age and SEC distribution in the French population have limited the increase
      in the prevalences of overweight and obesity in women. These results, based on
      reported data, may underestimate the prevalences of overweight and obesity and
      their increase. Nevertheless, the prevalences of reported obesity are similar to
      those of other European countries, such as Sweden and The Netherlands, and lower
      than in the UK, USA and Canada.

PMID- 10340818
TI  - The association of body weight and anthropometry with mortality in elderly men:
      the Honolulu Heart Program.
AB  - OBJECTIVES: To assess the relationship of body weight and anthropometry to all
      cause mortality in older men. DESIGN: A prospective cohort study of 3741 elderly
      Japanese-American men, enrolled in the Honolulu Heart Program. For this report,
      the follow-up began at baseline examinations (1991-1993), when the men were aged
      71-93 y. MEASUREMENTS: Variables of interest were body mass index (BMI), waist-to
      hip ratio (WHR), and the sum of the subscapular and triceps skinfold thickness.
      Possible confounders included age, education, physical activity index, smoking,
      alcohol consumption, systolic and diastolic blood pressure, cholesterol, glucose
      and insulin concentrations. RESULTS: After an average of 4.5 y of follow-up, 766
      men (21%) had died. Higher BMI was associated with lower adjusted mortality risks
      (relative risk (RR)) highest vs lowest quintile-based category = 0.5, 95%
      confidence interval (CI): 0.4-0.6, P-trend < 0.001). Results were independent of
      WHR, and did not change after excluding current and former smokers or those who
      died within one year of follow-up. The relation between WHR and mortality
      appeared to be U-shaped, but after adjustment for BMI, a higher WHR steadily
      increased the risk of dying (RR highest vs lowest category = 1.5, 95%CI: 1.1-2.0,
      P-trend=0.004). Especially in subjects with a high BMI, there was a positive
      association between WHR and mortality. The results for skinfold thickness were
      similar to the results for BMI, but less strong. CONCLUSIONS: In older men, BMI
      and skinfold thickness showed a consistent inverse association with mortality,
      even after accounting for early mortality. The WHR, on the other hand, was
      positively related to mortality, especially when BMI was high. Thus, excess
      abdominal fat mass (FM) warrants closer concern than being overweight, in terms
      of affecting mortality in the elderly.

PMID- 10340819
TI  - Sensory and hedonic associations with macronutrient and energy intakes of lean
      and obese consumers.
AB  - OBJECTIVE: To establish differences between lean and obese subjects in subjective
      reports of predominant taste and texture attributes of 'foods as eaten', and the
      relationships of these qualities to hedonic preference and objective measures of
      dietary intake and composition. DESIGN: Free-living subjects received instruction
      in a laboratory and kept diaries of foods eaten at home. SUBJECTS: 41 lean (body
      mass index (BMI) 20-25 kg/m2) and 35 obese (BMI > or = 30 kg/m2), non-dieting
      healthy adults. MEASUREMENTS: Subjects kept four-day weighed dietary intake
      records, simultaneously assigning ratings for perceived pleasantness and
      predominant sensory attributes (taste and texture) of food eaten, and completed
      the Dutch Eating Behaviour questionnaire (DEBQ). Anthropometric measures included
      body composition assessed by bioelectrical impedance. RESULTS: By all
      anthropometric measures (except height) the obese group was significantly larger
      than the lean group, but no significant differences were found for DEBQ scores.
      There were no significant group differences between pleasantness scores overall,
      nor for foods classified by predominant taste. Whilst macronutrient intakes did
      not differ, the obese group's mean dietary energy density was significantly
      higher, and they reported significantly greater dietary energy from 'salty'
      foods. For the obese group, the percentage of 'salty' foods eaten correlated
      strongly with energy density. A strong positive association was found between
      'liking extremely' and 'sweet' foods for the lean group, but no clear
      associations were found for any particular taste and hedonic rating for the obese
      group. Whilst both groups used similar texture descriptors, there were not clear
      or unambiguous differences in their assignment or association with other
      measures. CONCLUSIONS: The results suggest that obese and lean subjects do not
      self-select diets with markedly different perceived sensory or hedonic
      attributes. However obese subjects appear to consume a diet higher in energy
      density, which is particularly associated with intakes of salty/savoury (rather
      than sweet) food items.

PMID- 10340820
TI  - Substrate utilization and thermogenic responses to beta-adrenergic stimulation in
      obese subjects with NIDDM.
AB  - OBJECTIVE: This study intended to investigate disturbances in beta-adrenergically
      mediated substrate utilization and thermogenesis in obese subjects with mild non
      insulin-dependent diabetes mellitus (NIDDM). DESIGN: Following a baseline period
      of 30 min, the beta-agonist isoproterenol (ISO) was administered in increasing
      doses of 6, 12, and 24 ng/kgFFM x min, each dose for 30 min. SUBJECTS: Nine
      healthy lean males (CON, 50.6+/-2.4 y, % body fat: 16.0+/-1.8) and 10 obese
      subjects with NIDDM (51.8+/-2.4 y, % body fat 34.1+/-1.9). RESULTS: Basal non
      esterified fatty acid concentrations (NEFA) and basal fat oxidation (absolute or
      expressed per unit fat free mass, FFM) were significantly higher in NIDDM as
      compared to CON, whereas basal carbohydrate (CHO) oxidation was significantly
      lower. The ISO-induced increase in NEFA-concentrations was blunted in NIDDM
      (delta at 24 ng/kgFFM x min: CON: 717+/-59 micromol/l vs NIDDM: 358+/-97
      micromol/l, P< 0.01). The non-protein respiratory exchange ratio (RER) did not
      change in NIDDM and significantly decreased in CON during ISO-infusion (P <
      0.05), reflecting the tendency towards a blunted increase in fat oxidation in
      NIDDM (delta fat ox at 24 ng; CON: 0.025+/-0.005 g/min vs NIDDM 0.016+/-0.007
      g/min). The ISO-induced thermogenic response was comparable in NIDDM and CON (at
      24 ng %increase above baseline: CON: 16.8+/-2.2% vs NIDDM: 14.7+/-0.9%). At all
      time points, there were no significant differences in circulating ISO and
      noradrenaline concentrations. Basal adrenaline (A) concentrations and A
      concentrations during ISO-infusion were significantly lower in NIDDM (basal A;
      CON: 64+/-15 pg/ml vs NIDDM: 25+/-2 pg/ml, P < 0.001). CONCLUSION: There appear
      to be deviations in beta-adrenoceptor mediated fat utilization and adrenal
      medulla function in obesity-associated NIDDM. The impairments in sympathetically
      mediated fat utilization have previously been observed in 'simple' obese
      subjects, indicating that these disturbances are confined to the obese state per
      se.

PMID- 10340821
TI  - ACTH and cortisol response to combined corticotropin releasing hormone-arginine
      vasopressin stimulation in obese males and its relationship to body weight, fat
      distribution and parameters of the metabolic syndrome.
AB  - OBJECTIVES: To investigate the activity of the hypothalamic-pituitary-adrenal
      (HPA) axis in male obesity and its relationship with several prominent parameters
      of the metabolic syndrome. DESIGN: A cross-sectional clinical study of the
      activity of the HPA axis in groups of obese males and normal-weight controls.
      SUBJECTS: Seventeen obese non-diabetic males with a body mass index (BMI) >28 and
      eight normal-weight controls were examined. MEASUREMENTS: Fat free mass (FFM) and
      fat mass (FM) were measured by bioelectrical impedance, and the waist-to-hip
      circumference ratio (WHR) was calculated in all subjects. Baseline samples were
      taken for sex hormone and lipid determination, and an oral glucose tolerance test
      (OGTT) was performed for glucose and insulin determination. The activity of the
      HPA axis was determined by the combined administration of human corticotropin
      releasing hormone (CRH) (100 microg) and arginine vasopressin (AVP) (0.3 IU).
      RESULTS: As expected, FFM and FM and the WHR were higher in obese men than in
      controls, as were fasting insulin and stimulated (as area under the curve (AUC))
      glucose and insulin concentrations. Baseline adrenocorticotropin (ACTH) and
      cortisol concentrations were similar in both groups, but stimulated (as AUC),
      ACTH was higher (P < 0.05) in obese subjects than in controls, whereas no
      significant difference in cortisolAUC was present. Since the main differences
      between obese subjects and controls were present during the early 30 min of the
      test, the correlation coefficients between total and incremental ACTH(AUC 0-30
      min) and CortisolAUC 0-30 min and all other variables were analyzed. A
      significant correlation coefficient was present between them and all
      anthropometric parameters, fasting insulin and insulinAUC, but not with androgens
      and gonadotrophins. In addition, a significant correlation was present between
      total and incremental ACTH(AUC 0-30 min) and triglyceride concentrations.
      However, after adjusting for BMI or FM values, all correlation coefficients
      became non-significant, except the one between incremental ACTH(AUC 0-30 min) and
      insulinAUC (P < 0.05). CONCLUSION: These findings indicate that obese men may
      also have an altered pituitary response to combined CRH/AVP stimulation, which
      appears to be predominantly related to body size and total body fat. ACTH
      hyperresponsiveness after CRH/AVP stimulation also appears to be related to
      hyperinsulinaemia, but underlying mechanisms of this relationship remain to be
      elucidated.

PMID- 10340822
TI  - Biochemical mechanisms responsible for the attenuation of diabetic and obese
      conditions in ob/ob mice treated with dopaminergic agonists.
AB  - OBJECTIVE: We previously reported that a two week treatment with SKF 38393 (SKF,
      a dopamine D1 receptor agonist), plus bromocriptine (BC, a dopamine D2 receptor
      agonist) acted synergistically to normalize hyperphagia, body fat, hyperglycaemia
      and hyperlipidaemia in ob/ob mice. The present study further investigates the
      biochemical mechanisms triggered by this drug treatment. DESIGN: Six week old
      female C57BL/6J ob/ob mice were divided into three groups and treated for two
      weeks with either BC and SKF, vehicle (control), or vehicle and pair fed to match
      the drug-treated group's daily food intake. RESULTS: BC/SKF treatment reduced
      food consumption by 55%, and treated mice weighed less than either pair fed or ad
      libitum fed controls after two weeks of treatment. Moreover, oxygen consumption
      was increased by 2.4-fold and the respiratory quotient (RQ) decreased from 1.23
      to 0.96 (indicating a reduction in de novo lipogenesis) by drug treatment
      relative to ad libitum fed controls, but these parameters were unaffected by pair
      feeding control mice. The treatment also reduced blood glucose and free fatty
      acids (FFA) relative to pair fed and ad libitum fed controls. BC/SKF treatment
      (but not pair feeding) concurrently reduced lipolysis, lipogenic enzyme
      activities and hepatic gluconeogenic enzyme activities. Treatment also increased
      hepatic concentrations of glycogen and xylulose-5-phosphate (X-5-P), a key
      stimulator of glycolysis. Finally, BC/SKF, but not pair feeding, reduced the
      circulating concentrations of thyroxine and corticosterone, two hormones known to
      increase lipolysis, lipogenesis and hyperglycaemia. Drug treatment also increased
      serum dehydroepiandrosterone (DHEA) sulfate concentrations, an inhibitor of body
      fat store accumulation. CONCLUSION: These findings demonstrate that BC/SKF
      treatment not only normalizes hyperphagia of ob/ob mice, but also redirects
      several metabolic and endocrine activities, independent of its effects on feeding
      to improve the obese-diabetic syndrome in ob/ob mice.

PMID- 10340824
TI  - Television viewing, physical inactivity and obesity.
AB  - This study examined the relationship between TV viewing and three year change in
      BMI among a community-based sample of 176 men, 428 high-income women and 277 low
      income women who were aged 20-45 years at baseline. Cross-sectionally, TV viewing
      was positively associated with BMI among women, but not among men. This
      relationship was strongest among low-income women, with only a marginal
      relationship among high-income women. There were no significant relationships
      between change in BMI and number of hours of TV viewing at baseline, average
      number of hours of TV viewing over the three year follow-up, or change in number
      of hours of TV viewing from baseline to three years. These findings suggest the
      link between obesity and TV viewing is complex, and that TV viewing may not be
      the simple marker of sedentariness we may have hoped.

PMID- 10340823
TI  - Excess abdominal adiposity remains correlated with altered lipid concentrations
      in healthy older women.
AB  - OBJECTIVE: To determine associations between overall adiposity, absolute and
      relative abdominal adiposity, and lipid concentrations in healthy older women.
      DESIGN: Cross-sectional analysis of baseline data. SUBJECTS: Subjects were 21
      healthy, untrained older women (71 +/- 1 y) entering a randomized, controlled
      aerobic training program. MEASUREMENTS: Overall adiposity was assessed by
      anthropometry and the body mass index (BMI=kg/m2). Absolute and relative
      abdominal adiposity was determined by computed tomography (CT) and circumference
      measures. Fasting serum lipid concentrations of total-, high density lipoprotein
      (HDL)-, and low density lipoprotein (LDL)-cholesterol (C) and triglycerides (TGs)
      were determined by standard enzymatic procedures. RESULTS: Compared to the
      measures of overall adiposity, we observed much stronger correlations between
      measures more specific to absolute or relative abdominal adiposity and lipid
      concentrations. Visceral fat area was the strongest correlate of HDL-C (r = 
      0.75; P < 0.001) and the total-/HDL-C ratio (r = 0.86; P < 0.001). The abdomen-to
      hip circumference ratio (AHR) was strongly correlated with TGs (r = 0.54; P <
      0.01), HDL-C (r= -0.69; P < 0.001), and the total-/HDL-C ratio (r = 0.75; P <
      0.001). CONCLUSION: Excess abdominal adiposity remains an important correlate of
      lipid metabolism, even in healthy older women of normal weight. Thus, overall
      obesity is not a necessary condition for the correlation between excess abdominal
      fat and metabolic risk among postmenopausal women.

PMID- 10340825
TI  - The sugar:fat relationship revisited.

PMID- 10340826
TI  - Biochemistry of hemlock (Conium maculatum L.) alkaloids and their acute and
      chronic toxicity in livestock. A review.
AB  - The literature on Conium maculatum biochemistry and toxicology, dispersed in a
      large number of scientific publications, has been put together in this review. C.
      maculatum is a weed known almost worldwide by its toxicity to many domestic
      animals and to human beings. It is an Umbelliferae, characterized by long, hollow
      stems, reaching up to 2 m height at maturity, producing a large amount of lush
      foliage during its vegetative growth. Its flowers are white, grouped in umbels
      formed by numerous umbellules. It produces a large number of seeds that allow the
      plant to form thick stands in modified soils, sometimes encroaching on cultivated
      fields, to the extent of impeding the growth of any other vegetation inside the
      C. maculatum area of growth. Eight piperidinic alkaloids have been identified in
      this species. Two of them, gamma-coniceine and coniine are generally the most
      abundant and they account for most of the plant acute and chronic toxicity. These
      alkaloids are synthesized by the plant from eight acetate units from the
      metabolic pool, forming a polyketoacid which cyclises through an aminotransferase
      and forms gamma-coniceine as the parent alkaloid via reduction by a NADPH
      dependent reductase. The acute toxicity is observed when animals ingest C.
      maculatum vegetative and flowering plants and seeds. In a short time the
      alkaloids produce a neuromuscular blockage conducive to death when the
      respiratory muscles are affected. The chronic toxicity affects only pregnant
      animals. When they are poisoned by C. maculatum during the fetuses organ
      formation period, the offspring is born with malformations, mainly palatoschisis
      and multiple congenital contractures (MCC; frequently described as
      arthrogryposis). Acute toxicity, if not lethal, may resolve in the spontaneous
      recovery of the affected animals provided further exposure to C. maculatum is
      avoided. It has been observed that poisoned animals tend to return to feed on
      this plant. Chronic toxicity is irreversible and although MCC can be surgically
      corrected in some cases, most of the malformed animals are lost. Since no
      specific antidote is available, prevention is the only way to deal with the
      production loses caused by this weed. Control with herbicides and grazing with
      less susceptible animals (such as sheep) have been suggested. C. maculatum
      alkaloids can be transferred to milk and to fowl muscle tissue through which the
      former can reach the human food chain. The losses produced by C. maculatum
      chronic toxicity may be largely underestimated, at least in some regions, because
      of the difficulty in associate malformations in offspring with the much earlier
      maternal poisoning.

PMID- 10340827
TI  - Antibodies against Tityus discrepans venom do not abolish the effect of Tityus
      serrulatus venom on the rat sodium and potassium channels.
AB  - Anti-(Tityus serrulatus + Tityus bahiensis) and anti-Tityus discrepans venom
      polyclonal antisera were used to investigate whether antigenic differences exist
      between the venoms of the Brazilian T. serrulatus and the Venezuelan T.
      discrepans scorpions. Both antisera recognised the toxin-containing
      electrophoretic fractions of their cognate venoms and also those from Tityus
      zulianus and Tityus trinitatis venoms on Western blots. The anti-T. discrepans
      antiserum reacted only weakly with T. serrulatus toxic polypeptides. The effect
      of T. serrulatus alpha- or beta-toxins on rat skeletal muscle Na+ channels
      expressed in Xenopus laevis oocytes was abolished by pre-incubating the venom
      with anti-(T. serrulatus + T. bahiensis) serum but not with anti-T. discrepans
      serum. Nor did the Brazilian or the Venezuelan sera prevent the reduction in K+
      currents by T. serrulatus venom in X. laevis oocytes expressing the rat brain
      delayed rectifying Shaker K+ channel (Kv1.2). These results indicate that toxins
      from T. serrulatus and T. discrepans venoms, which primarily target mammalian Na+
      channels, are antigenically distinct, although they probably share common
      epitopes. Our results also suggest that Na+ channel-active toxins are the
      immunodominant antigens of the T. serrulatus venom.

PMID- 10340828
TI  - The effects of selected cotton-leaf volatiles on growth, development and
      aflatoxin production of Aspergillus parasiticus.
AB  - The fungi Aspergillus flavus and Aspergillus parasiticus produce the
      hepatocarcinogenic, secondary metabolites, aflatoxins, in cottonseed, corn,
      peanuts and treenuts. Results have shown that aflatoxigenic strains of A. flavus
      and A. parasiticus grown in the presence of specific cotton-leaf volatiles
      exhibit alterations in aflatoxin production accompanied by variations in growth
      of the fungi. In this study, two alcohols (3-methyl-1-butanol (3-MB) and nonanol)
      and two terpenes (camphene and limonene) were chosen as representative cotton
      leaf volatiles based on the effects they had on fungal growth and/ or aflatoxin
      production in previous investigations. The morphological effects of volatile
      exposure were examined in correlation with fungal growth and aflatoxin
      production. 3-MB-treated samples exhibited a decrease in fungal radial growth
      which was directly proportional to the volatile dosage. Additionally, 3-MB
      treatment resulted in loss of mycelial pigmentation and a decrease in
      sporulation. Limonene and camphene-treated samples yielded negligible differences
      in radial growth and morphology when compared to unexposed controls. In addition
      to radial growth inhibition, samples grown in the presence of nonanol
      demonstrated uniquely aerial hyphae. In comparison to an unexposed control,
      aflatoxin production increased in cultures exposed to 3-MB but decreased when
      exposed to the other three volatiles studied.

PMID- 10340829
TI  - A randomized blinded clinical trial of two antivenoms, prepared by caprylic acid
      or ammonium sulphate fractionation of IgG, in Bothrops and Porthidium snake bites
      in Colombia: correlation between safety and biochemical characteristics of
      antivenoms.
AB  - A randomized blinded clinical trial was performed in 53 patients bitten by
      Bothrops sp. and Porthidium sp. in Antioquia and Choco, Colombia, in order to
      compare the efficacy and safety of two antivenoms made of whole IgG obtained by
      either ammonium sulphate (monovalent anti-B. atrox) or caprylic acid (polyvalent)
      fractionation. Additionally, antivenoms were compared by electrophoretic and
      chromatographic analyses and anticomplementary activity in vitro. With a protocol
      of 2, 4 and 6 antivenom vials for the treatment of mild, moderate and severe
      envenomings, respectively, both antivenoms were equally efficient to neutralize
      the most relevant signs of envenoming and to clear serum venom levels in patients
      from the first hour and later on. Three patients with severe envenoming and
      initially treated with less than six vials on admission had persistent or
      recurrent venom antigenemia within 12-48 h. Monovalent antivenom fractionated by
      ammonium sulphate precipitation had higher amounts of protein aggregates and
      nonimmunoglobulin proteins than polyvalent antivenom fractionated by caprylic
      acid precipitation. Both antivenoms presented anticomplementary activity in
      vitro, being higher in the monovalent product. In agreement, monovalent antivenom
      induced a significantly higher incidence of early antivenom reactions (52%) than
      polyvalent antivenom (25%).

PMID- 10340830
TI  - Evaluation of the fluorometric protein phosphatase inhibition assay in the
      determination of okadaic acid in mussels.
AB  - The protein phosphatase inhibition assay for okadaic acid, the major DSP toxin,
      modified to use the fluorescence substrates methylumbelliferyl phosphate (MUP)
      and fluorescein diphosphate (FDP), was compared to the assay using p
      nitrophenylphosphate (p-NPP) and the bioluminescence assay using luciferin
      phosphate (L-P). Under the standard assay conditions used okadaic acid inhibited
      the enzyme activity dose-dependently with IC50 values of 1.5 nM (MUP) and 1.2 nM
      (FDP). This compares to IC50 values of 0.9 and 6 nM using L-P and p-NPP
      respectively. CDP-star, a chemiluminescence substrate, was not hydrolysed by the
      enzyme. Decreasing the enzyme concentration lowered the IC50 for the colorimetric
      method (IC50=2 nM [p-NPP], 0.75 nM enzyme) but no shift was observed with
      fluorimetry. However at enzyme concentrations < 1.5 nM (standard assay) the error
      margin was too great for routine analysis. The method using fluorimetry allowed
      detection of okadaic acid concentrations to levels < or = 1 microg/100 g of
      mussel tissue which is well below the limit of 20 microg/100 g (mouse bioassay)
      set by some regulatory agencies. Determination of the toxin content in naturally
      contaminated mussels in three separate experiments gave coefficients of variance
      ranging from 16 to 29% (MUP) and from 8 to78% (p-NPP). Multicomparison studies
      showed that concentrations of okadaic acid in naturally contaminated mussel
      samples determined by fluorescence generally agreed with those obtained using
      ELISA and LC-MS procedures, and with the mouse bioassay. However using the mouse
      bioassay as the standard, values determined by the ELISA, PP-2A and LC-MS all
      scored false negative results compared to those for the mouse bioassay in the
      range 20-40 microg/100 g mussel, and at the limit of the mouse bioassay the
      values by the other three methods were substantially less. With few exceptions
      the methods scored okadaic acid with highest to lowest values in the following
      order: mouse bioassay > ELISA > PP-2A > LC-MS. The fluorimetric assay was both
      more sensitive and accurate than the colorimetric assay (the latter showed a
      propensity towards false positives in the region 20 microg/100 g), and the
      moderate increase in equipment cost appears to be outweighed by the performance
      of the method.

PMID- 10340831
TI  - Interference by plastics additives in the HPLC determination of microcystin-LR
      and -YR.
AB  - Plastics devices used for the field collection of water samples may contain
      plastics additives which will interfere with the HPLC determination of the
      cyanobacterial toxins microcystins. The presence of the additives resorcinol
      monobenzoate or 2,4-dihydroxybenzophenone can interfere with the determination of
      microcystin-LR. The presence of bisphenol A in plastics can interfere with the
      determination of microcystin-YR.

PMID- 10340832
TI  - Efficacy of digoxin specific Fab fragments (Digibind) in the treatment of toad
      venom poisoning.
AB  - Chan Su, a traditional Chinese medication, and Love Stone, a topical aphrodisiac,
      are both made from dried venom of the toad bufo bufo gargarizans and contain
      bufalin, cinobufotalin, cinobufagin, and other cardioactive steroids of the
      bufadienolide class. Deaths have occurred following ingestion of these products
      and the clinical course resembles digoxin toxicity. The purpose of this study was
      to determine the efficacy of digoxin specific Fab fragments in treating Chan Su
      poisoning. An ethanolic extract was prepared from Chan Su. Digoxin specific Fab
      fragments were reconstituted in normal saline to a concentration of 80 mg/ml. An
      approximate LD90 dose was determined in preliminary experiments. Mice were then
      randomly divided into a treatment group of 15 mice and a control group of 30
      mice. The treatment group was pretreated with 20 ml/kg of digoxin specific Fab
      fragment solution by intraperitoneal injection at t = 0, followed by 10 ml/kg of
      digoxin specific Fab fragments intraperitoneal at t = 30 min. The control group
      was pretreated with equal volumes of intraperitoneal normal saline at the same
      times. Immediately following the 30 min injection, both groups were given the
      estimated LD90 dose of Chan Su extract by subcutaneous injection. An endpoint of
      survival at 6 h was chosen after preliminary results showed that all deaths
      occurred in the first 4 h. All 30 of the control mice had seizures followed by
      death compared to 11 seizures and 7deaths in the 15 treatment mice. These results
      were statistically significant by Fisher's exact test (p = 0.00003 for mortality
      and p = 0.009 for seizures). Digoxin specific Fab fragments are effective in the
      treatment of Chan Su poisoning in mice and may be effective for poisoning by
      other cardioactive steroids of the bufadienolide class.

PMID- 10340833
TI  - Bites by the colubrid snake Philodryas olfersii: a clinical and epidemiological
      study of 43 cases.
AB  - Less than 10 cases of bites by Philodryas olfersii (Colubridae) have been
      reported in the literature. In this study, 43 patients admitted to the Instituto
      Butantan, Sao Paulo, Brazil, with the diagnosis of P. olfersii bite from 1982 to
      1990 were reviewed. The 32 male (74.4%) and 11 female (25.6%) patients presented
      mainly from November to February (65%). The most common clinical features were
      local pain (37.2%), swelling (34.9%), erythema (18.6%) and ecchymosis (9.3%). The
      20 minute whole blood clotting test was performed in 11 patients and in all of
      them the blood was coagulable. Most of the accidents occurred during the hottest
      months and during daylight hours. The most common bite site was the hands. Severe
      envenoming is not frequent in these accidents.

PMID- 10340834
TI  - The antihemorrhagic factor of the Mexican ground squirrel, (Spermophilus
      mexicanus).
AB  - The Mexican ground squirrel (Spermophilus mexicanus) has a natural resistance to
      western diamondback rattlesnake venom (Crotalus atrox). The LD50 for the Mexican
      ground squirrel is 53 mg/kg body weight, which is 13 times higher than that of
      BALB/c mice. An antihemorrhagic factor from serum of the Mexican ground squirrel
      was isolated using Sephadex G-200 gel filtration, ion exchange A-50, G-75 gel
      filtration and HPLC DEAE 5PW ion exchange chromatography. The purified factor
      neutralized proteolytic and hemorrhagic activity of crude C. atrox venom. The
      results of this research suggest that the antihemorrhagic factor in the serum of
      the Mexican ground squirrel is not an antibody and neutralizes hemorrhagic
      activity of C. atrox venom.

PMID- 10340835
TI  - Bibliography of toxinology.

PMID- 10340837
TI  - A call to action for more aggressive treatment of hypertension.
AB  - During the past three decades, tremendous progress has been made in the USA and
      many other nations in detecting and controlling hypertension. Health education
      efforts increased public knowledge of the benefits of treating hypertension, and
      rates of blood pressure control improved. Despite improvements in the past,
      however, more recent information has shown some disturbing trends; we are not as
      healthy a nation as we could be. Hypertension control rates are no longer
      improving, and are likely to fall short of the US Healthy People 2000 goal of
      blood pressure control in 50% of all hypertensive patients. Overwhelming data
      from clinical trials underscore the need to control hypertension, especially in
      the elderly, for whom hypertension control rates are lower than they are for the
      total US population. Data from the Framingham Study indicate that the incidence
      of heart failure increases with age and is greater in hypertensive patients than
      in normotensive patients. Hypertension precedes heart failure in 90% of all
      cases, and the prevalence of heart failure, greater today than it was a decade
      ago, is now the largest component of the Medicare budget (Medicare is the US
      health insurance and standards for medical participation program for those aged
      65 years and older). Hypertension is also associated with an increase in the
      incidence of end-stage renal disease, and stroke and coronary heart disease may
      be increasing again. Such alarming trends are a call to action for the public,
      patients, and health professionals. Strong evidence supports the need for better
      blood pressure control, with an emphasis on the elderly and other difficult-to
      treat populations.

PMID- 10340838
TI  - The Hypertension Optimal Treatment study and the importance of lowering blood
      pressure.
AB  - OBJECTIVES: The Hypertension Optimal Treatment (HOT) Study had two objectives:
      (1) to define the optimal target blood pressure when treating hypertensive
      patients (i.e. the level of blood pressure associated with the lowest incidence
      of major cardiovascular events such as fatal and non-fatal stroke and myocardial
      infarction and other cardiovascular mortality); and (2) to assess the effect of a
      low dose of acetylsalicylic acid (aspirin) compared with placebo on major
      cardiovascular events. METHODS: The HOT study recruited 18 790 hypertensive
      subjects aged 50 to 80 years with diastolic blood pressure (DBP) between 100 and
      115 mmHg (mean DBP 105 mmHg). Subjects were randomly assigned to be treated with
      the goal of reaching one of three target DBPs: < or = 90 mmHg (n = 6264), < or =
      85 mmHg (n = 6264), or < or = 80 mmHg (n = 6262) using felodipine as initial
      therapy with the addition of other agents according to a 5-step regimen. In
      addition, subjects were randomly assigned to receive either 75 mg/day aspirin (n
      = 9399) or placebo (n = 9391). RESULTS: DBP was reduced by 20.3, 22.3, and 24.3
      mmHg in the < or = 90, < or = 85, and < or = 80 mmHg target groups, respectively.
      The incidence of all major cardiovascular events (fatal and non-fatal stroke,
      myocardial infarction, and other cardiovascular mortality) decreased, although
      not significantly, in relation to the randomized target blood pressure. There
      were 84, 64, and 61 fatal and non-fatal myocardial infarctions in the < or = 90
      mmHg, < or = 85 mmHg, and < or = 80 mmHg groups, respectively (P = 0.05). The
      overall effect of aspirin on cardiovascular events was positive, most noticeably
      on fatal and non-fatal myocardial infarctions; aspirin reduced events by 36%.
      There were seven fatal episodes of bleeding (two cerebral) in the aspirin group
      compared with eight (three cerebral) in the placebo group, and 129 versus 70 non
      fatal major episodes of bleeding in the two groups, respectively. The lowest
      incidence of all major cardiovascular events combined was found at an achieved
      DBP of 82.6 mmHg and at an achieved systolic blood pressure (SBP) of 138.5 mmHg.
      In the subgroup with diabetes mellitus at baseline (n = 1501), the effect of
      intensive lowering of blood pressure was especially noticeable. CONCLUSIONS: Most
      cardiovascular end-points showed a declining frequency in relation to target
      blood pressure. The optimal protection against combined major cardiovascular end
      points was observed in the range 80-85 mmHg for DBP and in the range 130-140 mmHg
      for SBP. It is worth noting that 92% of all subjects reached a DBP of < or = 90
      mmHg and that side-effects gradually declined from 16.9% at 3 months to 2.2% at
      the end of the study. A substudy showed that quality of life was linked to the
      level of blood pressure obtained: the lower the blood pressure, the better the
      quality of life.

PMID- 10340839
TI  - The role of systolic blood pressure in determining risk for cardiovascular
      disease.
AB  - Hypertension increases in prevalence with advancing age and is a leading cause of
      morbidity and mortality from cardiovascular disease. Patients with hypertension
      are at increased risk for the development of myocardial infarction, stroke, and
      congestive heart failure compared with their normotensive counterparts. Early
      hypertension intervention trials in patients with diastolic hypertension
      documented the benefits of blood pressure control in reducing the risk for
      cardiovascular disease events. In recent years, several trials have demonstrated
      the benefits of treating older patients with isolated systolic hypertension.
      Consequently, hypertension guidelines have evolved to reflect the important role
      of systolic blood pressure in determining hypertension status and have devoted
      much attention to isolated systolic hypertension as a distinct blood pressure
      category. These data have important implications for the elderly, in whom
      isolated systolic hypertension is the most common form of high blood pressure; in
      addition, the absolute risk of cardiovascular disease is higher in older than in
      younger persons. Since the number of older persons in developed countries is
      increasing, hypertension has become a growing public health concern.

PMID- 10340840
TI  - Difficult-to-treat hypertensive populations: focus on African-Americans and
      people with type 2 diabetes.
AB  - The awareness, treatment, and control of hypertension has risen steadily over the
      past three decades, until the early 1990s. However, blood pressure control to <
      140/90 mmHg is attained in fewer than 25% of all hypertensive patients and fewer
      than 50% of drug-treated hypertensive patients, except for white women. Two
      special populations, African-Americans and diabetics, share several important
      attributes. First, they both have a high prevalence of hypertension, including
      stage 3 hypertension (as defined by the Joint National Committee on Prevention,
      Detection, Evaluation, and Treatment of Hypertension VI: > or =180/110 mmHg),
      relative to other subgroups. African-Americans have an approximate 8% prevalence
      of stage 3 hypertension, and elevated systolic blood pressure is highly prevalent
      among diabetic people, particularly older African-American women. Second, both
      groups have high levels of blood-pressure-related target-organ damage, which
      contributes to their inordinately high absolute risk for cardiovascular disease
      complications (i.e. stroke, congestive heart failure, renal failure) at a given
      level of blood pressure. Moreover, the reduced natriuretic capacity common to
      each group contributes to the attenuated efficacy of antihypertensive drug
      monotherapy, particularly for drug classes other than diuretics and calcium
      antagonists. These two special populations are also typically salt-sensitive, an
      intermediate blood pressure phenotype that raises blood pressure medication
      requirements. This phenomenon has been associated with an attenuation in the
      normal nocturnal fall in blood pressure. The high absolute risk for
      cardiovascular disease among diabetics led to the formulation of more aggressive
      treatment recommendations for antihypertensive drug therapy. In diabetics, blood
      pressure therapy is initiated at blood pressures > or = 130/85 mmHg, and
      treatment goals are at least to this level, unless proteinuria is > or = 1g/day
      (in which case the goals are < 125/75 mmHg). The more aggressive treatment
      targets for diabetics will not be reached with most currently available single
      antihypertensive agents in many African-Americans. While at best only 50-60% of
      hypertensive patients can be controlled with single drug therapy, that percentage
      falls dramatically in persons with stage 3 hypertension and renal insufficiency,
      thereby necessitating the use of combination drug therapy. Treatment alone is not
      enough; treatment to goal blood pressure is an essential first step towards
      optimal target-organ protection. While circulating levels of renin are
      suppressed, in general, in these special populations, each group manifests an
      inordinate burden of blood-pressure-related target-organ damage that has been
      linked to excessive levels of angiotensin II or a reduced bradykinin and nitric
      oxide tissue effect. The renin-angiotensin-aldo-sterone-kinin system is therefore
      an attractive therapeutic target that might conceivably provide target-organ
      protection over and above that attributable solely to lowering the blood
      pressure.

PMID- 10340841
TI  - A rationale for treatment of endothelial dysfunction in hypertension.
AB  - Strategically located between the circulating blood and the vascular smooth
      muscle, endothelial cells release numerous vasoactive substances that regulate
      the function of vascular smooth muscle and circulating blood cells. Important
      endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide (NO)
      and, independent of the former, endothelium-derived hyperpolarizing factor. In
      particular, NO inhibits cellular growth and migration. In concert with
      prostacyclin, NO exerts potent antiatherogenic and thromboresistant properties by
      preventing platelet aggregation and cell adhesion. These effects are
      counterbalanced by vasoconstrictors, angiotensin II and endothelin-1, both of
      which exert prothrombotic and growth-promoting properties. In hypertension,
      elevated blood pressure transmits into cardiovascular disease by causing
      endothelial dysfunction. Hence, modern therapeutic strategies in human
      hypertension focus on preserving or restoring endothelial integrity. Calcium
      antagonists counteract angiotensin II and endothelin-1 at the level of vascular
      smooth muscle by reducing the inflow of Ca2+ and facilitating the vasodilator
      effects of NO. Besides inhibiting the renin-angiotensin system, angiotensin
      converting enzyme inhibitors diminish the inactivation of bradykinin, leading to
      an augmented release of NO. Newly developed vasopeptidase inhibitors induce
      potent antihypertensive effects in low-, normal-, and high-renin models of
      hypertension, not only because of the decreased breakdown of natriuretic
      peptides, but also because of the inhibition of endothelin-1 generation.
      Furthermore, experimental studies suggest that endothelin antagonists effectively
      lower blood pressure and prevent target-organ damage in salt-sensitive forms of
      hypertension. Further clinical studies are already underway to examine whether
      restoring endothelial dysfunction results in a clinical benefit in hypertension.

PMID- 10340842
TI  - Vasopeptidase inhibition: a new concept in blood pressure management.
AB  - Vasopeptidase inhibition is a new concept in cardiovascular therapy. It involves
      simultaneous inhibition with a single molecule of two key enzymes involved in the
      regulation of cardiovascular function, neutral endopeptidase (EC 24.11; NEP) and
      angiotensin-converting enzyme (ACE). Simultaneous inhibition of NEP and ACE
      increases natriuretic and vasodilatory peptides (including atrial natriuretic
      peptide [ANP], brain natriuretic peptide [BNP] of myocardial cell origin, and C
      type natriuretic peptide [CNP] of endothelial cell origin) and increases the half
      life of other vasodilator peptides including bradykinin and adrenomedullin. By
      simultaneously inhibiting the renin-angiotensin-aldosterone system and
      potentiating the natriuretic peptide system, vasopeptidase inhibitors (VPIs)
      reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular
      tone and lowering blood pressure. Omapatrilat, a heterocyclic dipeptide mimetic,
      is a novel vasopeptidase inhibitor and a single molecule that simultaneously
      inhibits NEP and ACE with similar inhibition constants. Unlike ACE inhibitors,
      omapatrilat demonstrates antihypertensive efficacy in low-, normal-, and high
      renin animal models. Unlike NEP inhibitors, omapatrilat provides a potent and
      sustained antihypertensive effect in spontaneously hypertensive rats (SHR), a
      model of human essential hypertension. In animal models of heart failure,
      omapatrilat is more effective than ACE inhibition in improving cardiac
      performance and ventricular remodeling and prolonging survival. Omapatrilat
      effectively reduces blood pressure, provides target-organ protection, and reduces
      morbidity and mortality from cardiovascular events in animal models. Omapatrilat
      is the first VPI to enter advanced USA clinical trials. Omapatrilat appears to be
      a safe, well-tolerated and effective antihypertensive in humans. Vasopeptidase
      inhibition is a novel and efficacious strategy for treating cardiovascular
      disorders, including hypertension and heart failure, that may offer advantages
      over currently available therapies.

PMID- 10340843
TI  - Introduction: V-ATPases 1992-1998.

PMID- 10340844
TI  - Structure and function of vacuolar Na+-translocating ATPase in Enterococcus
      hirae.
AB  - A Na+-translocating ATPase was discovered in a gram-positive bacterium
      Enterococcus hirae. Our biochemical and molecular biological studies revealed
      that this Na+-ATPase belongs to the vacuolar-type enzyme. Purified Na+-ATPase
      consisted of nine subunits: NtpA, B, C, D, E, F, G, I, and K; reconstituted
      proteoliposomes showed ATP-driven electrogenic Na+ translocation. All these
      subunits were encoded by the ntp operon: ntpFIKECGABDHJ. The deduced amino acid
      sequences of the major subunits, A, B, and K (16 kDa proteolipid), were highly
      similar to those of A, B, and proteolipid subunits of vacuolar ATPases, although
      the similarities of other subunits were moderate. The ntpJ gene encoded a K+
      transporter independent of the Na+-ATPase. Expression of this operon, encoding
      two transport systems for Na+ and K+ ions, was regulated at transcriptional level
      by intracellular Na+ as the signal. Two related cation pumps, vacuolar Na+-ATPase
      and F0F1, H+-ATPase, coexist in this bacterium.

PMID- 10340845
TI  - Structure and function of the A1A0-ATPases from methanogenic Archaea.
AB  - Recent molecular studies revealed nine to ten gene products involved in
      function/assembly of the methanoarchaeal ATPase and unravel a close relationship
      of the A1A0-ATPase and the V1V0-ATPase with respect to subunit composition and
      the structure of individual subunits. Most interestingly, there is an astonishing
      variability in the size of the proteolipids in methanoarchaeal A1A0-ATPases with
      six, four, or two transmembrane helices and a variable number of conserved
      protonizable groups per monomer. Despite the structural similarities the A1A0
      ATPase differs fundamentally from the V1V0-ATPase by its ability to synthesize
      ATP, a feature shared with F1F0-ATPases. The discovery of duplicated and
      triplicated versions of the proteolipid in A1A0-ATP synthases questions older
      views of the structural requirements for ATP synthases versus ATP hydrolases and
      sheds new light on the evolution of these secondary energy converters.

PMID- 10340846
TI  - The structure of the vacuolar ATPase in Neurospora crassa.
AB  - The filamentous fungus Neurospora crassa contains many small vacuoles. These
      organelles contain high concentrations of polyphosphates and basic amino acids,
      such as arginine and ornithine. Because of their size and density, the vacuoles
      can be separated from other organelles in the cell. The ATP-driven proton pump in
      the vacuolar membrane is a typical V-type ATPase. We examined the size and
      structure of this enzyme using radiation inactivation and electron microscopy.
      The vacuolar ATPase is a large and complex enzyme, which appears to contain at
      least thirteen different types of subunits. We have characterized the genes that
      encode eleven of these subunits. In this review, we discuss the possible function
      and structure of these subunits.

PMID- 10340847
TI  - Assembly of the yeast vacuolar proton-translocating ATPase.
AB  - The yeast vacuolar proton-translocating ATPase (V-ATPase) is the best
      characterized member of the V-ATPase family. Biochemical and genetic screens led
      to the identification of a large number of genes in yeast, designated VMA,
      encoding proteins required to assemble a functional V-ATPase. A total of thirteen
      genes encode subunits of the final enzyme complex. In addition to subunit
      encoding genes, we have identified three genes that code for proteins that are
      not part of the final V-ATPase complex yet required for its assembly. We refer to
      these nonsubunit Vma proteins as assembly factors, since their function is
      dedicated to assembling the V-ATPase. The assembly factors, Vma12p, Vma21p, and
      Vma22p are localized to the endoplasmic reticulum (ER) and aid the assembly of
      newly synthesized V-ATPase subunits that are translocated into the ER membrane.
      At least two of these proteins, Vma12p and Vma22p, function together in an
      assembly complex and interact directly with nascent V-ATPase subunits.

PMID- 10340848
TI  - Biosynthesis and regulation of the yeast vacuolar H+-ATPase.
AB  - The yeast V-ATPase is highly similar to V-ATPases of higher organisms and has
      proved to be a biochemically and genetically accessible model for many aspects of
      V-ATPase function. Like other V-ATPases, the yeast enzyme consists of a complex
      of peripheral membrane proteins, the V1 sector, attached to a complex of integral
      membrane subunits, the V0 sector. Multiple pathways for biosynthetic assembly of
      the enzyme appear to be available to cells containing a full complement of
      subunits and enzyme activity may be further controlled during biosynthesis by a
      protease activity localized to the late Golgi apparatus. Surprisingly, the
      assembled V-ATPase is not a static structure. Instead, fully assembled V1V0
      complexes appear to exist in a dynamic equilibrium with inactive cytosolic V1 and
      membrane-bound V0 complexes and this equilibrium can be rapidly shifted in
      response to changes in carbon source. The reversible disassembly of the yeast V
      ATPase may be a novel regulatory mechanism, common to V-ATPases, that works in
      vivo in coordination with many other regulatory mechanisms.

PMID- 10340849
TI  - Structure and properties of the clathrin-coated vesicle and yeast vacuolar V
      ATPases.
AB  - The V-ATPases are a family of ATP-dependent proton pumps responsible for
      acidification of intracellular compartments in eukaryotic cells. This review
      focuses on the the V-ATPases from clathrin-coated vesicles and yeast vacuoles.
      The V-ATPase of clathrin-coated vesicles is a precursor to that found in
      endosomes and synaptic vesicles, which function in receptor recycling,
      intracellular membrane traffic, and neurotransmitter uptake. The yeast vacuolar
      ATPase functions to acidify the central vacuole and to drive various coupled
      transport processes across the vacuolar membrane. The V-ATPases are composed of
      two functional domains. The V1 domain is a 570-kDa peripheral complex composed of
      eight subunits of molecular weight 70-14 kDa (subunits A-H) that is responsible
      for ATP hydrolysis. The V0 domain is a 260-kDa integral complex composed of five
      subunits of molecular weight 100-17 kDa (subunits a, d, c, c' and c") that is
      responsible for proton translocation. Using chemical modification and site
      directed mutagenesis, we have begun to identify residues that play a role in ATP
      hydrolysis and proton transport by the V-ATPases. A central question in the V
      ATPase field is the mechanism by which cells regulate vacuolar acidification.
      Several mechanisms are described that may play a role in controlling vacuolar
      acidification in vivo. One mechanism involves disulfide bond formation between
      cysteine residues located at the catalytic nucleotide binding site on the 70-kDa
      A subunit, leading to reversible inhibition of V-ATPase activity. Other
      mechanisms include reversible assembly and dissociation of V1 and V0 domains,
      changes in coupling efficiency of proton transport and ATP hydrolysis, and
      regulation of the activity of intracellular chloride channels required for
      vacuolar acidification.

PMID- 10340850
TI  - The plasma membrane H+-V-ATPase from tobacco hornworm midgut.
AB  - The midgut plasma membrane V-ATPase from larval Manduca sexta, the tobacco
      hornworm, is the sole energizer of any epithelial ion transport in this tissue
      and is responsible for the alkalinization of the gut lumen up to a pH of more
      than 11. This mini-review deals with those topics of research on this enzyme
      which may have contributed or are expected to contribute novel and general
      aspects to the field of V-ATPases. Topics dealt with include novel subunits or
      the quaternary structure of the V1 complex, as well as the regulation of the
      enzyme's function by reversible dissociation of the V1 from the V0 complexes and
      by genetic control on the transcriptional and posttranscriptional level.

PMID- 10340851
TI  - The multifunctional Drosophila melanogaster V-ATPase is encoded by a multigene
      family.
AB  - In animals, V-ATPases are believed to play roles in the plasma membrane, as well
      as endomembrane. To understand these different functions, it is necessary to
      adopt a genetic approach in a physiologically tractable model organism. For this
      purpose, Drosophila melanogaster is ideal, because of the powerful genetics
      associated with the organism and because of the unusually informative epithelial
      phenotype provided by the Malpighian tubule. Recently, the first animal
      "knockouts" of a V-ATPase were described in Drosophila. The resulting phenotypes
      have general utility for our understanding of V-ATPase function and suggest a
      screen for novel subunits and associated proteins. Genome project resources have
      accelerated our knowledge of the V-ATPase gene family size and the new Drosophila
      genes vhaSFD, vha100-1, vha100-2, vha100-3, vha16-2, vha16-3, vha16-4, vhaPPA1,
      vhaPPA2, vhaM9.7.1, and vhaM9.7.2 are described. The Drosophila V-ATPase model is
      thus well-suited to both forward and reverse genetic analysis of this complex
      multifunctional enzyme.

PMID- 10340852
TI  - The pinwheel technique: an adjunct to the periareolar approach in gynecomastia
      resection.
AB  - The most common surgical approach to gynecomastia is through Webster's intra
      areolar incision. The authors have modified the excisional phase of the operation
      to facilitate the delivery of a large mass of breast tissue through a relatively
      small incision. The essential features of this procedure are (1) delineation of
      the perimeter of the breast on the pectoral fascia; (2) elevation of the anterior
      chest wall skin and subcutaneous tissues over the entire breast mass; (3) serial
      application of Kocher clamps at the perimeter of the breast and, with gentle
      traction, sequential lysis of the peripheral and posterior attachments of the
      breast mass; and (4) delivery of the the mass simultaneously through the
      periareolar incision, as the dissection proceeds, until the entire specimen is
      exteriorized. The specimen then consists of the entire breast mass encircled by a
      pinwheel-like arrangement of Kocher clamps. Thirty-one patients (61 gynecomastic
      breasts) were operated using this method. En bloc tissue specimens weighing as
      much as 285 g were removed without the need for dividing the specimen or
      extending the single incision. The authors recommend this technique, which is
      straightforward and efficacious with minimal blood loss and good postoperative
      cosmesis.

PMID- 10340853
TI  - Angiogenesis during mandibular distraction osteogenesis.
AB  - Recruitment of a blood supply is critical for successful bone induction and
      fracture healing. Despite the clinical success of distraction osteogenesis (DO),
      an analysis of angiogenesis during membranous bone DO has not been performed. The
      purpose of this study was to evaluate the temporal and spatial pattern of
      angiogenesis during mandibular DO. The right hemimandible of adult male rats was
      osteotomized, and a customized distraction device was applied. Following a 3-day
      latency period, distraction was begun at a rate of 0.25 mm twice daily for 6 days
      (3.0 mm total; 12% increase in mandibular length). Three animals each were
      sacrificed on days 2, 4, and 6 of distraction (D1, D2, and D3 respectively), or
      after 1, 2, or 4 weeks of consolidation (C1, C2, and C3 respectively). Two
      experienced pathologists reviewed the regenerate histology, and angiogenesis was
      assessed by counting the number of blood vessels per intermediate-power field
      (IPF). Statistical analysis was performed using analysis of variance, with p < or
      = 0.05 considered significant. Results demonstrate that mandibular DO was
      associated with an intense vascular response during the early stages of
      distraction (D1). On average, 31.5+/-7.9 vessels were noted in each IPF examined
      during this time point. The number of blood vessels in the distraction regenerate
      decreased significantly during the later distraction time points, with
      approximately 14.0+/-2.0 and 14.7+/-3.5 blood vessels per IPF in sections
      obtained after days 4 and 6 of distraction (D2, D3) respectively. However, blood
      vessels at these time points took on a more mature histological pattern. During
      the consolidation period, the number of blood vessels noted in the regenerate
      decreased with 8.0+/-2.6, 9.3+/-2.1, and 4.0+/-2.0 vessels per IPF in sections
      obtained after 1, 2, or 4 weeks of consolidation (C1, C2, C3) respectively (p <
      0.05 compared with vessel counts during the earliest distraction time point).
      This study demonstrates for the first time that an intense vascular response
      associated with mandibular DO occurs primarily during the early stages of
      distraction. The authors hypothesize that as distraction continues, newly formed
      vessels likely undergo consolidation, thus forming more mature vessels capable of
      withstanding distraction forces. Future studies will assess the effects of
      therapeutic interventions designed to increase angiogenesis during DO on bony
      regenerate formation.

PMID- 10340854
TI  - A comparison of gradual distraction techniques for modification of the midface in
      growing sheep.
AB  - The authors carried out experiments to advance the midface in growing sheep using
      a distraction force across the zygomaticomaxillary sutures. They wished to assess
      the possibility of performing distraction osteogenesis across intact sutures as
      well as distraction after Le Fort osteotomies. Their results demonstrate that the
      technique of gradual distraction after osteotomy is successful in the growing
      animal. Bilateral distraction across intact sutures did not advance the midface
      or change the dental relationship. Unilateral distraction was successful in
      angulating the midface away from the distracting force in the intact growing
      animal. Alternating unilateral distraction or "waltzing" was surprisingly
      effective in advancing the midface in one of the animals studied and may become
      applicable in some craniofacial deformities. In all intact animals there was some
      expansion of the zygomaticomaxillary suture as well as a substantial migration of
      the distraction devices through the bone.

PMID- 10340855
TI  - Gene expression of insulin-like growth factors I and II in rat membranous
      osteotomy healing.
AB  - Poorly healing mandibular osteotomies can be a difficult problem in
      reconstructive surgery. Many therapies have been attempted to augment the healing
      of mandibular fractures, defects, or osteotomies, but these methods have
      substantial drawbacks or have been ineffective. The difficulty in treating poorly
      healing bony defects has led to the exploration of gene therapy as a possible
      approach to supplement or accelerate mandibular fracture healing. To understand
      at what point the introduction of a suitable gene candidate might be of benefit
      in mandibular healing, it is imperative to examine the temporal expression of
      bone growth factors in a model of membranous bone healing. Insulinlike growth
      factors (IGFs) I and II are two such bone growth factor candidates because of
      their known potent in vitro as well as in vivo effects on bone formation. In this
      study the authors demonstrate the temporal pattern of IGF I and IGF II gene
      expression during mandibular osteotomy healing using a rat model. Their data
      reveal that IGF I and IGF II were elevated 7 days after a mandibular osteotomy
      that was held in external fixation. The upregulation of IGF I and IGF II during
      mandibular bone healing underscores the importance of these growth factors in
      bone repair. Gene therapy utilizing recombinant viral constructs containing IGFs
      I and II may be of benefit during mandibular bone healing in an effort to augment
      clinical scenarios of poor or retarded bony repair.

PMID- 10340856
TI  - Gene-enhanced tissue engineering: applications for bone healing using cultured
      periosteal cells transduced retrovirally with the BMP-7 gene.
AB  - Periosteum has cell populations, including osteoprogenitor and chondroprogenitor
      cells, that can be grown in cell culture and form both bone and cartilage under
      appropriate conditions. The authors have shown previously that cultured
      periosteal cells can be used in the tissue engineering of bone, and they
      demonstrated substantial bone formation in a rabbit cranial defect model. In the
      current study, principles of tissue engineering were combined with principles of
      gene therapy to produce cultured periosteal cells transduced retrovirally with
      the bone morphogenetic protein 7 (BMP-7) gene to be used in the treatment of bone
      defects. Human BMP-7 complementary deoxyribonucleic acid was generated from a
      cell line using reverse transcription polymerase chain reaction and cloned into a
      retroviral vector plasmid. Retroviral vector particles were then used to
      transduce New Zealand White rabbit periosteal cells. Transduced periosteal cells
      demonstrated substantial production of both BMP-7 messenger ribonucleic acid by
      Northern blot analysis and BMP-7 protein by enzyme-linked immunosorbent assay.
      These cells were then seeded into polyglycolic acid (PGA) matrices and used to
      repair critical-size rabbit cranial defects. At 12 weeks, defect sites repaired
      with BMP-7-transduced periosteal cells/PGA had significantly increased
      radiographic and histological evidence of bone repair compared with those defect
      sites repaired with negative control-transduced cells/PGA, nontransduced
      cells/PGA, PGA alone, or unrepaired defects. Thus, this study demonstrates
      successfully a tissue engineering approach to bone repair using genetically
      modified cells.

PMID- 10340857
TI  - Analysis of TGF-beta production by fusing and nonfusing mouse cranial sutures in
      vitro.
AB  - The role of transforming growth factor beta (TGF-beta) in the regulation of
      cranial suture fusion has been studied by various qualitative techniques such as
      in situ hybridization and immunohistochemistry. Although the relative expression
      of TGF-beta isoforms has been assessed in these studies, increased expression of
      TGF-beta has not been demonstrated in a quantitative fashion. Therefore, the
      purpose of this study was to quantify TGF-beta production by fusing
      (posterofrontal [PF]) and nonfusing (sagittal) mouse sutures using two different
      quantitative TGF-beta assays. The PF and sagittal sutures of 25-day-old mice were
      harvested and cultured separately in vitro. Culture media conditioned for 48
      hours were collected after 3, 6, 9, 12, 15, 18, 21, 24, 27, and 30 days of
      culture, and total TGF-beta production was assessed using a TGF-beta bioassay.
      For a quantitative TGF-beta1 immunoassay, media conditioned for 48 hours were
      collected after 3, 5, 7, 9, 14, 22, and 28 days of culture. The TGF-beta bioassay
      revealed large amounts of total TGF-beta activity in both PF and sagittal sutures
      during the first week of culture, with decreasing amounts thereafter. Absolute
      TGF-beta activity in conditioned media collected from PF sutures at several early
      time points was higher than those obtained from sagittal sutures; however, these
      differences were not statistically significant. The results of the TGF-beta1
      immunoassay (enzyme-linked immunosorbent assay) were similar to the bioassay in
      that the highest TGF-beta1 levels were noted during the first week of culture
      period and decreased thereafter. Analysis of variance of these samples, however,
      revealed significantly more TGF-beta1 protein in samples collected from the PF
      suture compared with the sagittal suture on days 3 and 5 of culture (p < 0.05).
      TGF-beta1 levels in the conditioned media obtained from PF sutures remained
      elevated compared with the sagittal suture on days 7 and 9; however, these
      differences were not statistically significant. Increased production of TGF-beta
      in the conditioned media of fusing PF sutures is the first such quantitative
      demonstration of growth factor upregulation during suture fusion and supports the
      hypothesis that TGF-beta expression may be important in cranial suture fusion.

PMID- 10340858
TI  - Expression of high-affinity receptors for TGF-beta during rat cranial suture
      fusion.
AB  - The etiology of craniosynostosis is unknown. The elucidation of the biological
      pathways responsible for this disorder has been hampered by an inability to
      evaluate cranial sutures before, during, and after cranial suture fusion. The
      programmed fusion of the rat posterofrontal (PF) suture postnatally provides an
      excellent model to study the molecular events that occur during cranial suture
      fusion. Previous experiments have implicated transforming growth factor beta (TGF
      beta) growth factors in the regulation of PF suture fusion. The purpose of these
      experiments was to localize the expression of high-affinity receptors for these
      growth factors during cranial suture fusion. Four rats were sacrificed on
      postnatal days 8, 12, 17, and 40 (N = 16). The PF and sagittal sutures were
      harvested and prepared for immunohistochemical localization of TGF-beta receptor
      1 and receptor 2 (Tbeta-RI, Tbeta-RII) protein. Results indicate that
      immunostaining for Tbeta-RI and Tbeta-RII is markedly increased in the dura mater
      and osteoblasts of the sutural margin of the PF suture during active suture
      fusion (on postnatal days 12, 17, and 40) compared with the osteoblasts and dura
      mater underlying the patent sagittal suture. These results, in combination with
      the authors' previous findings as well as studies supporting a role for TGF-beta
      molecules in the regulation of osteogenesis, implicate TGF-beta signaling in the
      regulation of suture fusion. The possible mechanisms of ligand-receptor
      interaction are discussed.

PMID- 10340859
TI  - Human cartilage engineering: chondrocyte extraction, proliferation, and
      characterization for construct development.
AB  - To date, many efforts to engineer cartilage have focused on matrix construction
      with the goal of producing a durable construct as cartilage replaces the
      resorbing matrix. However, the importance of matrix construction is at least
      matched by the challenge of efficient chondrocyte extraction, culture expansion,
      and prevention of dedifferentiation. This challenge is underscored by the large
      number of chondrocytes needed for a clinically significant construct such as an
      ear. Because human rib provides a large, readily available source of hyaline
      cartilage, the authors evaluated human rib chondrocyte extraction and found that
      maximum viable cell yield occurred after a 6-hour digestion. They also evaluated
      human microtic auricular remnant chondrocyte extraction and identified fibroblast
      contamination as a shortcoming of this potential source of chondrocytes.
      Initially, rib chondrocytes proliferated in vitro with a doubling time of
      approximately 1 week. As the cells were passaged, proliferation decreased such
      that the cells stopped proliferating and adopted a large, spindle-shaped
      morphology by passage 6. Interestingly, no increase in proliferation was noted
      when rib chondrocytes were stimulated with transforming growth factor beta 1,
      bone morphogenetic protein 2, and basic fibroblast growth factor. The major
      obstacles to the use of autologous rib chondrocytes in matrix construction are
      the low cell yield from a small piece of rib and the limited proliferation that
      these cells will undergo in vitro. Further investigation of culture systems and
      mitogenic cytokines may help resolve these limitations.

PMID- 10340860
TI  - Hypoxia upregulates VEGF production in keloid fibroblasts.
AB  - The etiology of keloid formation is diverse. They are characterized grossly as
      thick scar tissue that extends beyond the boundaries of the original wound.
      Histologically, keloids are composed of excessive collagen with an abnormally
      large number of partially or totally occluded microvessels. This occlusion of
      keloid microvessels has been hypothesized to contribute to a hypoxic
      microenvironment within these pathological scars. Vascular endothelial growth
      factor (VEGF), a potent endothelial cell mitogen, and proangiogenic cytokine have
      been implicated in normal and pathological wound healing. The purpose of this
      study was to evaluate the amount of VEGF protein production by fibroblast cell
      lines derived from keloids and normal human dermal skin in hypoxic compared with
      normoxic culture conditions. By enzyme-linked immunosorbent protein assay, VEGF
      was increased in both keloid and normal human dermal fibroblasts in hypoxia over
      normoxic controls. There was not, however, a significant difference between
      upregulation of VEGF protein when comparing the keloid and normal fibroblast
      groups. As the result of the data, alternative hypotheses for hypoxia-induced
      keloid formation were explored: (1) downstream modulation or signal transduction
      of VEGF, (2) VEGF production from cells other than fibroblasts, (3) the
      importance of matrix accumulation stimulated by hypoxia, or (4) increased
      migration of cells (other than fibroblasts) specific to keloid biology. These
      hypotheses may help explain the possible role of hypoxia in the pathogenesis of
      keloid formation. Future studies involving in situ hybridization or
      immunohistochemical analysis may offer greater insight into the mechanisms
      underlying keloid formation. Ultimately, our therapeutic goal is the utilization
      of biomolecular approaches for the suppression of keloid formation.

PMID- 10340861
TI  - Salvage of free flaps after secondary venous ischemia by local delivery of
      heparin.
AB  - Recent studies have demonstrated that heparin may protect against reperfusion
      injury through a direct effect on the microvascular endothelium that is
      independent of its effect on systemic coagulation. The purpose of this study was
      to determine whether local delivery of low-dose heparin has a role in the salvage
      of musculocutaneous flaps after secondary venous ischemia and revascularization.
      Cutaneous maximus musculocutaneous flaps were transplanted to the contralateral
      groin in adult Sprague-Dawley rats. All flaps were subjected to 2 hours of
      primary arteriovenous ischemia followed by 20 hours of reperfusion. The flaps
      were then subjected to a 6-hour secondary venous ischemic insult followed by
      anastomotic revision and reperfusion. Animals in group I received no adjunctive
      treatment. Those in group II were treated with low-dose heparin (5-6 U per
      kilogram per hour) infused systemically via the inferior epigastric vein. Those
      in group III received the same dose of heparin infused locally into the flap via
      the inferior epigastric artery. The dose of heparin used in groups II and III was
      insufficient to prolong the activated partial thromboplastin time above normal
      values. At 7 days, mean flap necrosis was 60.8% in group I and 62.1 in group II.
      Local heparin delivery (group III) resulted in complete survival of all flaps.
      Histological examination after 48 hours of reperfusion demonstrated improved
      microvascular patency and reduced neutrophilic infiltration in the flaps of group
      III animals. Thus, local infusion of low-dose heparin resulted in significantly
      improved flap salvage through a mechanism independent of its effect on systemic
      coagulation.

PMID- 10340862
TI  - Effects of topical nitroglycerin and flurbiprofen in the rat comb burn model.
AB  - Burn injury is known to cause thrombosis and occlusion of dermal vessels that
      come in direct contact with thermal energy. Progressive ischemia secondary to
      diminished blood flow may compromise dermal tissues immediately surrounding the
      primary burn site. A standardized brass bar was used to create uniform full
      thickness "comb" burns on 10 rat backs. Topical petrolatum (N = 2), 2%
      nitroglycerin (N = 4), and 5% flurbiprofen (N = 4) was applied to the burns at 2
      and 4 hours postinjury. The vascular patency of dermal vessels was visualized
      directly by latex vascular casts made 24 hours after the burn injury. The
      vascular casts showed an absence of patent vessels within the direct burn sites
      in all treatment groups, and within the burn interspaces of the petrolatum
      treated rats. Interspacial dermal vessel patency was seen in the 2% nitroglycerin
      and 5% flurbiprofen-treated rats. Topical 2% nitroglycerin and 5% flurbiprofen
      applied 2 and 4 hours postinjury effectively prevented interspacial dermal vessel
      thrombosis at 24 hours postinjury.

PMID- 10340863
TI  - The efficacy of single-stage surgical management of multiple pressure sores in
      spinal cord-injured patients.
AB  - The practice of multiple-stage management in the treatment of patients with
      multiple pressure ulcers has long represented the standard of care in many
      specialty centers. The authors have observed that an aggressive surgical approach
      has proved necessary for control of this devastating problem in these patients.
      Their experience with one-stage reconstruction of multiple pressure sores over a
      10-year period (between 1986 and 1996) in 120 spinal cord-injured patients has
      revealed certain advantages of this comprehensive method of surgical management.
      Although cumulative operating time and intraoperative blood loss were somewhat
      increased, the number of anesthetic episodes and the hospital stay were less than
      that seen in patients managed in multiple stages. Accordingly, rehabilitation and
      societal reintegration can be initiated earlier, and overall hospital cost may be
      better contained.

PMID- 10340864
TI  - Use of reverse triangular V-Y flaps to create a web space in syndactyly.
AB  - The authors describe a new technique for division in syndactyly. The web space is
      reconstructed using two reverse V-Y island triangular flaps. The flaps are raised
      both on the dorsal and the palmar aspect of the hand. This technique does not
      require the use of a skin graft. Fourteen syndactylies in 9 children-three
      incomplete (two congenital and one secondary to burn) and six complete-were
      treated using this technique. The results after a maximum 4-month follow-up and
      the advantages of the technique are discussed.

PMID- 10340865
TI  - Modified bilateral advancement flap: the slide-in flap.
AB  - The bilateral V-Y advancement flaps are used commonly in the closure of circular
      skin defects. We modified the standard bilateral V-Y advancement flap technique
      to reduce the tension along the closure, and used it in 10 patients between 1995
      and 1997. In the presence of a circular defect, bilateral V-Y advancement flaps
      were marked on the skin, with the height of the V flaps measuring 1.5 to 2 times
      the diameter of the defect. The limbs of the V were not drawn as straight lines,
      but were curved outward slightly, making the flap and its two extensions broader
      than the standard V-Y flap. The broad extensions of the V flaps encircled the
      defect from above and below. Skin incisions were made vertically down to the
      muscle fascia. Additional undermining was carried out to elevate the upper and
      lower extensions of the V flaps for a distance that equaled the radius of the
      defect. The upper and lower extensions of the V flap on one side were transposed
      into the defect and sutured to the concave base of the opposing flap V flap at
      its midpoint. These extensions were then sutured to each other. The extensions of
      the opposing V flap were then transposed into the defect; the upper being
      superior and the lower being inferior to the extensions of the first flap. The
      rest of the operation was completed by advancement of the V flaps and closure in
      a Y configuration. The efficient redistribution of available tissue by the
      combined use of transposition and advancement principles resulted in the repair
      of relatively large skin defects with reduced tension along the closure.
      Satisfactory results were obtained in all patients in this series without any
      surgical complication.

PMID- 10340866
TI  - Pharyngeal flap for velopharyngeal incompetence in patients with myotonic
      dystrophy.
AB  - Velopharyngeal incompetence (VPI) has been associated with neuromuscular
      disorders. Only 4 patients with myotonic dystrophy (MD) who underwent pharyngeal
      flap elevation for VPI have been reported in the literature. In 3 patients,
      surgery preceded the diagnosis of MD. Cardiorespiratory complications
      characterized the postoperative period of 3 patients. The authors present 3
      patients with VPI and an established diagnosis of MD (by molecular genetics) who
      underwent pharyngeal flap elevation. The operation resulted in a major
      improvement in speech in all patients, although some relapse was noted later in 1
      patient. Contrary to previous reports, none had peri- or postoperative
      cardiorespiratory complications. MD, although an uncommon etiology, should be
      considered in cases of late-onset VPI. Owing to differences between the authors'
      findings and previous reports, additional studies are needed before final
      conclusions can be reached regarding the benefit and safety of pharyngeal flap
      surgery in MD patients. At present, MD should not be considered a
      contraindication for this procedure, although close perioperative monitoring is
      indicated.

PMID- 10340867
TI  - Thrombospondin 1 and its specific cysteine-serine-valine-threonine-cysteine
      clycine receptor in fetal wounds.
AB  - Thrombospondin 1 (TSP-1), an adhesive glycoprotein, plays an important role in
      platelet adhesion, inflammation, cell-cell interaction, and angiogenesis. TSP-1
      is expressed by endothelial cells, fibroblasts, and macrophages. The unique
      cysteine-serinevaline-threonine-cysteine-glycine (CSVTCG) binding domain of TSP-1
      also plays an important role in cell binding and modulation of cellular
      processes. The purpose of this study was to evaluate histologically and
      quantitatively TSP-1 and its CSVTCG receptor in fetal skin wounds over time.
      Pregnant ewes underwent laparotomy and hysterotomy. At 65 days gestation (term,
      145 days), incisional and excisional wounds were created on the fetal back in a
      similar position on each animal. The uterus and laparotomy were closed. The
      wounds were harvested on days 1, 3, 7, 21, and 28. Expression of TSP-1 and its
      CSVTCG receptor was evaluated immunohistochemically and quantitated by computer
      image analysis in units of absorbance. Immunoglobulin G (negative) controls were
      performed and subtracted from the TSP-1 sample to eliminate background absorbance
      readings. Serum (negative) control was used for the CSVTCG receptor. Platelet
      concentrates were used as the positive control: TSP-1, 63.43; CSVTCG, 58.72.
      Results are expressed as absorbance+/-SEM. Results of TSP-1 are as follows: day
      1, 33.02+/-0.26; day 3, 22.21+/-0.14; day 7, 20.56+/-1.07; day 21, 7.76+/-0.40;
      and day 28, 5.99+/-0.03. TSP-1 displays an early peak during fetal skin repair,
      followed by a steep decrease over the viewed time period. Results of CSVTCG
      receptor are as follows: day 1, 26.19+/-2.43; day 3, 30.20+/-0.64; day 7, 24.56+/
      0.80; day 21, 24.70+/-0.40; and day 28, 21.65+/-1.39. Thus, CSVTCG receptor
      displays a slowed decrease in expression over time during fetal repair. No
      significant differences were noted between incisional and excisional samples.
      Temporal and histological differences exist in the localization and expression of
      TSP-1 and its CSVTCG receptor during fetal wound repair. TSP-1 is upregulated in
      tissues early. This corresponds with the known role of TSP-1 in cell-cell
      interaction, including potentiation of growth factor activity. TSP-1 also
      modulates matrix, allowing scar-free provisional matrix in the earlier stages of
      repair deposited by platelets. The potentiation of cell-associated protease
      activity by TSP-1 can support tissue and matrix turnover. This activity of TSP-1
      may contribute to the formation of a scarless wound. TSP-1 destabilizes
      extracellular matrix contacts, and facilitates mitosis and migration. The action
      of TSP-1 as an adhesive protein allows numerous different cells to adhere to the
      extracellular membrane. CSVTCG receptor expression decreases during fetal repair
      as the cells migrate to the epithelial surface, suggesting a significant role of
      the CSVTCG receptor in keratinocytic maturation, differentiation, and
      epithelization.

PMID- 10340868
TI  - False-positive radiographic diagnosis of breast implant rupture because of breast
      abscess.
AB  - A case of a periprosthetic abscess simulating breast implant rupture is
      presented. Both clinical findings and film-screen mammography suggested
      extravasation of a radiodense material adjacent to an implant. Ultrasonography
      was thought to confirm the extraluminal silicone. However, at surgery the mass
      was found to be a breast abscess that had herniated through the capsule. The
      double-lumen implant outer saline-filled chamber had deflated, but the silicone
      containing inner chamber was intact. Magnetic resonance imaging would have
      distinguished between abscess and silicone.

PMID- 10340870
TI  - Drilling for profits.

PMID- 10340869
TI  - A rare case of atypical eccrine acrospiroma of the scalp and a literature review.
AB  - Acrospiromas are rare cutaneous lesions of eccrine sweat gland origin that are
      found most commonly on the extremities. The authors present a rare case of an
      atypical eccrine acrospiroma arising in the scalp, and a review of the
      literature.

PMID- 10340871
TI  - Re: The life span of silicone gel breast implants.

PMID- 10340872
TI  - Re: Eccentric skin resection and purse-string closure for skin reduction with
      mastectomy for gynecomastia.

PMID- 10340873
TI  - A gigantic epidermal cyst.

PMID- 10340874
TI  - Postabdominoplasty hypertension: augmentation in the pressure systems?

PMID- 10340875
TI  - Silicone sheet usage in preventing adhesion in the neck region.

PMID- 10340876
TI  - Establishment of Bioskin bank: how we do it in our hospitals.

PMID- 10340877
TI  - Molecular staging of melanoma.

PMID- 10340878
TI  - Breast cancer treatment in Black women.

PMID- 10340879
TI  - Current treatment options for inflammatory breast cancer.

PMID- 10340880
TI  - Melanoma patients with iliac nodal metastases can be cured.

PMID- 10340881
TI  - Detection of tyrosinase mRNA by reverse transcription-polymerase chain reaction
      in melanoma sentinel nodes.
AB  - BACKGROUND: Sentinel lymph node (SLN) biopsy is an alternative to elective
      dissection or observation for management of lymph node basins in patients with
      cutaneous melanomas. The detection of tyrosinase mRNA in melanoma SLN specimens
      by reverse transcription-polymerase chain reaction (RT-PCR) has been reported to
      be a more sensitive method to detect subclinical metastases, compared with
      histological analysis. The aims of this study were to (1) define the yield of RT
      PCR in assessing SLNs, compared with histological analysis, (2) identify the
      incidence of false-positive results in SLNs, and (3) report the rate of actin PCR
      negativity (i.e., samples with degraded RNA) in SLNs. METHODS: Twenty-eight
      patients with 1.2-9.6-mm cutaneous melanomas underwent SLN biopsy (between
      October 1996 and March 1997). One half of each SLN was analyzed by nested RT-PCR
      for tyrosinase mRNA. The other half of the SLN was examined by routine
      microscopy. Twenty-one lymph nodes from patients without melanoma were evaluated
      as controls. RESULTS: Two of the 28 patients with melanoma were excluded because
      of RNA degradation, as indicated by actin negativity. Six of the remaining 26
      patients exhibited melanoma metastases in routine histological examinations. All
      histologically positive lymph nodes were RT-PCR-positive. Thirteen of the 20
      (65%) histologically negative cases were RT-PCR-positive. Of 21 control lymph
      nodes, 3 were actin-negative and were not assessable for tyrosinase mRNA. Two of
      the remaining 18 (11%) negative-control nodes were RT-PCR-positive. CONCLUSIONS:
      Among patients undergoing SLN biopsy, tyrosinase mRNA was detectable in 73% of
      SLNs from patients at risk for regional nodal metastases, including all of those
      with histologically positive SLNs. There is a definable false-positive rate for
      tyrosinase mRNA detection in the lymph nodes of patients who do not have
      melanoma. Actin verification of RNA integrity is necessary to ensure the accuracy
      of this test in detecting tyrosinase mRNA. Ongoing follow-up monitoring will
      define the prognostic value of this assay.

PMID- 10340882
TI  - Local recurrence and survival among black women with early-stage breast cancer
      treated with breast-conservation therapy or mastectomy.
AB  - BACKGROUND: Black women with breast cancer have significantly worse survival
      rates and receive diagnoses at relatively younger ages, compared with white
      patients with breast cancer, in the United States. Young age at diagnosis has
      been associated with increased risk for local recurrence (LR) after breast
      conservation therapy (BCT). The goal of this study was to evaluate the impact of
      age and BCT on LR and survival rates among black patients with breast cancer.
      METHODS: The records for 363 black women treated for breast cancer (excluding
      stage IV disease) at a comprehensive cancer center were reviewed. RESULTS: Fifty
      eight percent of patients (n = 211) had tumors < or = 5 cm in diameter. Forty-two
      of these patients (19.9%) received BCT; the LR rate for this group was 9.8%. A
      total of 168 patients (79.6%) underwent mastectomy; the LR rate for this group
      was 8.9%. Data on the primary operation were unavailable for one patient. Five
      year disease-free survival rates were similar for patients treated with BCT and
      those treated with mastectomy (88% and 73%, respectively). LR was associated with
      significant decreases in 5-year overall survival rates for both the BCT group
      (67% vs. 95%, P < .01) and the mastectomy group (43% vs. 76%, P < .01). LR and 5
      year disease-specific survival rates were similar for patients <50 years of age
      and patients > or = 50 years of age, regardless of treatment. CONCLUSIONS: LR and
      survival rates are not compromised by the use of BCT among black American
      patients. LR is associated with an increased risk of breast cancer death,
      regardless of treatment type. Younger age at diagnosis was not associated with an
      increased rate of LR after BCT in this series.

PMID- 10340883
TI  - Beyond palliative mastectomy in inflammatory breast cancer--a reassessment of
      margin status.
AB  - BACKGROUND: Inflammatory breast cancer is a locally advanced tumor with an
      aggressive local and systemic course. Treatment of this disease has been evolving
      over the last several decades. The aim of this study was to assess whether
      current therapies, both surgical and chemotherapeutic, are providing better local
      control (LC) and overall survival (OS). We also attempted to identify clinical
      and pathologic factors that may be associated with improved OS, disease-free
      survival (DFS), and LC. METHODS: A 25-year retrospective review performed at the
      City of Hope National Medical Center identified 90 patients with the diagnosis of
      inflammatory breast cancer. RESULTS: Of the 90 patients identified with
      inflammatory breast cancer, 33 received neoadjuvant therapy (NEO) consisting of
      chemotherapy followed by surgery with radiation (n = 26) and without radiation (n
      = 7). Fifty-seven patients received other therapies (nonNEO). Treatments received
      by the nonNEO group consisted of chemotherapy, radiation, mastectomy,
      adrenalectomy, and oophorectomy, alone or in combination. The median follow-up
      was 28.9 months for the NEO group and 17.6 months for the nonNEO group.
      Borderline significant differences in the OS distributions between the two groups
      were found (P = .10), with 3- and 5-year OS for the NEO group of 40.0% and 29.9%
      and for the nonNEO group of 24.7% and 16.5%, respectively. DFS and LC were
      comparable in the two groups. Lower stage was associated with an improved OS (P <
      .05). The 5-year OS for stage IIIB was 30.9%, compared to 7.8% for stage IV. In
      those patients with stage III disease who were treated with mastectomy and
      rendered free of disease, margin status was identified by univariate analysis to
      be a prognostic indicator for OS (P < .05). The 3-year OS, DFS, and LC for
      patients with negative margins were 47.4%, 37.5%, and 60.3%, respectively,
      compared to 0%, 16.7%, and 31.3% in patients with positive margins. CONCLUSIONS:
      This study suggests that in patients with inflammatory breast cancer and
      nonmetastatic disease, an aggressive surgical approach may be justified with the
      goal of a negative surgical margin. Achievement of this local control is
      associated with a better overall outcome for this subset of patients. The ability
      to obtain negative margins may further identify a group of patients with a less
      aggressive tumor biology that may be more responsive to other modalities of
      therapy.

PMID- 10340884
TI  - Positive iliac and obturator nodes in melanoma: survival and prognostic factors.
AB  - BACKGROUND: The need for deep groin dissection when superficial nodes contain
      metastatic melanoma is controversial. METHODS: A review of 362 therapeutic groin
      dissections performed at our tertiary referral center between 1961 and 1995
      revealed 71 patients (20%) with positive iliac and/or obturator nodes. This group
      was analyzed for survival rates, prognostic factors for survival, regional tumor
      control, and morbidity. RESULTS: Patients with involved deep nodes exhibited
      overall 5-year and 10-year survival rates of 24% (SE, 5%) and 20% (SE, 5%),
      respectively. Independent prognostic factors for survival were the number of
      positive iliac nodes (P = .0011), the Breslow thickness (P = .0069), and the site
      of the primary tumor (P = .0075). Patients with an unknown primary tumor seemed
      to have better prognoses. Seven patients (10%) experienced recurrence in the
      surgically treated groin. The short- and long-term morbidity rates (infection,
      17%; skin flap necrosis, 15%; seroma, 17%; mild/ moderate lymphedema, 19%; severe
      lymphedema, 6%) compared well with those of other series studying inguinal as
      well as ilioinguinal dissections. CONCLUSIONS: From the present study it can be
      concluded that removal of deep lymph node metastases is worthwhile, because one
      of every five such patients survives for 10 years. Prognostic factors for
      survival are the number of involved iliac nodes, the Breslow thickness, and the
      site of the primary tumor. Long-term regional tumor control can be obtained for
      90% of the patients. The morbidity of an additional deep lymph node dissection is
      acceptable.

PMID- 10340885
TI  - Does the extent of operation influence the prognosis in patients with melanoma
      metastatic to inguinal nodes?
AB  - BACKGROUND: The role of pelvic lymphadenectomy in melanoma metastatic to the
      superficial inguinal region remains controversial. Some researchers advocate
      aggressive surgical management, whereas others feel that outcome depends more on
      extent of disease rather than extent of treatment. We reviewed our recent
      experience to investigate possible therapeutic effects of extended surgery.
      METHODS: We performed a retrospective clinical and pathological review of 227
      consecutive patients having superficial (SLND) or combined inguinal
      lymphadenectomy (CLND) for cutaneous melanoma. RESULTS: A total of 174 SLNDs and
      53 CLNDs were performed. Overall 5-year survival for node-positive patients was
      39%. Survival for patients with positive superficial nodes was 40%; for those
      with positive deep nodes it was 35% (P = ns). In node-positive patients, number
      and size of involved lymph nodes and the presence of extranodal spread, failure
      to receive adjuvant therapy, and tumor ulceration were associated with poorer
      prognosis. Extent of surgery was not associated with differential survival,
      although CLND patients had worse pathological features. Subgroup analysis showed
      no significant survival difference between SLND and CLND. CONCLUSIONS: Some
      patients with deep nodal involvement apparently are cured by CLND. However, it is
      the biology of the disease and not the extent of surgery that primarily governs
      outcome. Patients with clinical or radiological evidence of pelvic nodal disease
      without evidence of systemic disease should have a CLND, but we find no evidence
      to support CLND if the pelvic nodes are clinically and radiologically negative.

PMID- 10340886
TI  - Adoptive immunotherapy with tumor-infiltrating lymphocytes and subcutaneous
      recombinant interleukin-2 plus interferon alfa-2a for melanoma patients with
      nonresectable distant disease: a phase I/II pilot trial. Melanoma Istituto
      Scientifico Tumori Group.
AB  - BACKGROUND: On the basis of our previous experience, we designed this study to
      determine the activity and toxicity of outpatient treatment with autologous tumor
      infiltrating lymphocytes (TIL) together with intermediate-dose recombinant
      interleukin-2 (rIL-2) and low-dose recombinant interferon alfa-2a (rIFN-alpha2a),
      for patients with metastatic melanoma. METHODS: Between April 1992 and October
      1994, we processed 38 melanoma samples derived from 36 patients with metastases.
      Proliferative cultures of expanded lymphocytes (TIL) were infused only once into
      patients with metastatic melanoma. rIL-2 was administered subcutaneously for 1
      month, starting on the day of TIL infusion, at an escalating dose of 6-18 x 10(6)
      IU/m2/day for the first week and at the maximum-tolerated dose for the subsequent
      3 weeks and then, after a 15-day interval, for 1 week/month for 3 months. rIFN
      alpha2a was administered subcutaneously at 3 X 10(6) IU three times each week
      until progression. RESULTS: Of 38 melanoma samples, 19 (50%) resulted in
      proliferative cultures and were infused. The median number of expanded
      lymphocytes was 18 x 10(9) (range, 1-43 x 10(9)), and the median period of
      culture was 52 days (range, 45-60). rIL-2 was administered at doses ranging
      between 6 and 18 x 10(6) IU/m2/day. Toxicity was mild or moderate, and no life
      threatening side effects were encountered. Two of 19 treated patients experienced
      complete responses of their metastatic sites (soft tissue), 10 had stable
      disease, and 7 showed progressive disease. The response rate was 11% (95%
      confidence interval, 2-35%). CONCLUSIONS: Outpatient treatment with TIL plus rIL
      2 and rIFN-alpha2a is feasible, although, within the context of the small sample
      size, the activity of the combination was no different from the reported activity
      of any of the components used alone.

PMID- 10340887
TI  - Gemcitabine-induced programmed cell death (apoptosis) of human pancreatic
      carcinoma is determined by Bcl-2 content.
AB  - BACKGROUND: Gemcitabine is a new nucleoside analogue that produces a clinical
      response in 30% of patients with unresectable pancreatic carcinoma. The cytotoxic
      effects of many chemotherapeutic agents occur through induction of programmed
      cell death (apoptosis), which is controlled by the bcl-2 gene family. We
      determined whether induction of apoptosis by gemcitabine in pancreatic carcinoma
      is associated with cellular Bcl-2 content. METHODS: Four pancreatic carcinoma
      cell lines (MIA-PaCa-2, AsPC-1, Panc-1, and Panc-48) were screened by Western
      blotting for Bcl-2 protein expression. Dose-response relationships for the
      cytotoxic effects of gemcitabine were determined using methylthiotetrazole
      assays, and induction of apoptosis was confirmed by fluorescence-activated cell
      sorting analysis. MIA-PaCa-2 cells transfected with human bcl-2 were also
      analyzed for gemcitabine-induced apoptosis. RESULTS: Pancreatic cancer cell lines
      expressed varying amounts of Bcl-2, and the 50% lethal dose for gemcitabine
      induced apoptosis was correlated with Bcl-2 content. Furthermore, Bcl-2
      overexpression was associated with a significant increase in the 50% lethal dose
      for gemcitabine-induced apoptosis. CONCLUSIONS: Cellular Bcl-2 content was
      directly correlated with the cytotoxicity of gemcitabine in pancreatic carcinoma.
      Therefore, routine immunohistochemical analyses may be useful in predicting
      gemcitabine efficacy, and patients who would likely not benefit could be spared
      gemcitabine administration. Furthermore, the effectiveness of gemcitabine and
      other chemotherapeutic agents may be increased by gene therapy-mediated
      alteration of bcl-2 gene family members.

PMID- 10340888
TI  - Carcinomatous lymphatic invasion in early gastric cancer invading into the
      submucosa.
AB  - BACKGROUND: Lymphatic invasion is a risk factor for lymph node metastases in
      patients with gastric cancer. No studies have been reported, however, on the
      correlation between lymphatic invasion and lymph node metastasis in early gastric
      cancer invading into the submucosa. METHODS: We performed a retrospective
      analysis of lymphatic invasion in 170 patients with early gastric cancer invading
      into the submucosa. RESULTS: Lymphatic invasion was found in 76 patients.
      Lymphatic invasion correlated significantly with the presence of lymph node
      metastasis and vascular invasion (P < .05) and with the degree of cancerous
      submucosal involvement (P < .05). The presence of lymph node metastasis also
      correlated with the grade of submucosal invasion and lymphatic invasion. The 5
      year survival of patients with lymphatic invasion was poorer than that of
      patients without lymphatic invasion (P < .05). Node-negative patients had similar
      survival, regardless of the presence of lymphatic invasion. All patients with
      severe lymphatic invasion had sm3 invasion and lymph node metastases. CONCLUSION:
      Although lymphatic invasion is the first stage of lymph node metastasis,
      lymphatic invasion in itself does not have clinical importance except for severe
      invasion in early gastric cancer. It is possible to predict lymph node metastases
      from the combined evaluation of degree of lymphatic invasion and submucosal
      involvement of the tumor in patients with early gastric cancer invading into the
      submucosa.

PMID- 10340889
TI  - Prognostic value of Lauren classification and c-erbB-2 oncogene overexpression in
      adenocarcinoma of the esophagus and gastroesophageal junction.
AB  - BACKGROUND: The prognostic value of the Lauren classification and of c-erbB-2
      oncogene overexpression has been described for gastric cancer. The aim of this
      study was to investigate the clinical significance of these factors in
      adenocarcinoma of the esophagus and/or gastroesophageal junction (GEJ). METHODS:
      Forty-one adenocarcinomas of the esophagus and/or GEJ were reviewed for tumor
      stage, lymph node status, Lauren classification, and c-erbB-2 overexpression, as
      assessed by immunohistochemical analysis. RESULTS: According to the Lauren
      classification, tumors were classified as intestinal-, mixed-, or diffuse-type
      (54%, 32%, and 15%, respectively). Diffuse-type tumors were associated with a
      significantly worse prognosis than were intestinal-type tumors (P = .018; log
      rank test). The prognostic value of the Lauren classification was independent of
      stage (P = .048; Cox regression model). Overexpression of c-erbB-2 was detected
      in 24% of the tumors and was present exclusively in intestinal-type tumors and in
      intestinal-type areas of mixed-type tumors. Ten of the 30 stage III/IV tumors
      (33%) were c-erbB-2-positive, whereas none of the 11 stage I/II tumors (0%)
      overexpressed the oncogene product (P = .04; Fisher exact test). The prognostic
      value of c-erbB-2 overexpression was not independent of stage (P = .7; Cox
      regression model). CONCLUSIONS: (1) The Lauren classification is an independent
      prognostic factor in adenocarcinoma of the esophagus and GEJ. (2) c-erbB-2
      overexpression is limited to (areas of) intestinal-type tumors, indicating that
      intestinal- and diffuse-type tumors differ oncogenetically. (3) c-erbB-2
      overexpression is associated with the stage of disease, indicating that it is a
      late event during tumor progression.

PMID- 10340890
TI  - Significance of Fas and retinoblastoma protein expression during the progression
      of Barrett's metaplasia to adenocarcinoma.
AB  - BACKGROUND: Barrett's esophagus (BE) is a premalignant lesion characterized by
      replacement of normal squamous epithelium with columnar epithelium. This lesion
      can progress to dysplasia and adenocarcinoma. Recently, the Fas receptor and
      retinoblastoma (Rb) protein have been described as important mediators of
      apoptosis and tumor suppression, respectively. This study was undertaken to
      examine their expression during the progression of metaplasia to adenocarcinoma
      in BE. METHODS: In a review of 56 adenocarcinomas arising in BE, the specimen
      blocks were examined using the immunohistochemical avidin-biotin-peroxidase
      complex technique. For each specimen, areas of normal epithelium were compared
      with areas of metaplasia, dysplasia, or carcinoma (when present). Monoclonal
      mouse anti-human antibodies were used to identify Rb protein (Rb-Ab5, 1/50
      dilution; Oncogene Science) and the 40-50-kDa cell membrane Fas protein (APO
      1/Fas, 1/5 dilution; DAKO Corp.). RESULTS: Loss of Rb staining was observed as
      the metaplasia progressed to dysplasia and carcinoma, indicating accumulation of
      unstainable aberrant protein. Conversely, Fas protein staining was undetectable
      or weak in normal or metaplastic epithelium, increasing in the areas of high
      grade dysplasia and carcinoma. These differences were statistically significant
      (P < .001). CONCLUSIONS: The accumulation of abnormal Rb protein during the
      progression of Barrett's metaplasia to carcinoma leads to unsuppressed tumor
      growth. Fas overexpression may represent a cellular attempt to balance the
      uncontrolled tumor proliferation by promoting apoptosis.

PMID- 10340891
TI  - Intraoperative pleural lavage in esophageal carcinoma.
AB  - BACKGROUND: Cytological examination of intraoperative pleural or peritoneal
      lavage specimens is useful for predicting outcomes for patients with various
      carcinomas. There have been few reports regarding cytological examination of
      pleural lavage fluid in esophageal carcinoma. METHODS: Intraoperative pleural
      lavage fluid was collected before and after esophagectomy and was examined by
      Papanicolaou and Giemsa staining for 78 patients with esophageal carcinoma.
      RESULTS: Although epithelial cells were found for 29 patients, only blood cells
      were detected for 48. The remaining one patient exhibited no cells in the
      specimen. For 4 of 78 (5.2%) patients, tumor cells were detected in the pleural
      lavage fluid after esophagectomy. Three of these four patients had T4 tumors.
      CONCLUSIONS: Positive cytological findings for pleural lavage fluid, using
      Papanicolaou and Giemsa staining, is correlated with regrowth of residual tumor
      and poor prognosis in esophageal carcinoma.

PMID- 10340892
TI  - Intraoperative ultrasound localization of nonpalpable breast lesions.
AB  - BACKGROUND: The use of preoperative wire localization (PWL) for excision of
      nonpalpable breast lesions has several disadvantages. The purpose of this study
      was to evaluate the use of intraoperative ultrasound localization (IUL) and to
      compare it with PWL. METHODS: Twenty-nine patients (22 with cancer) underwent IUL
      in a solo surgical practice over a 21-month period. They were compared to 22
      patients with cancer in the same practice who underwent PWL in a similar time
      period. Parameters analyzed included accuracy of lesion removal, margin
      involvement, extent of disease-free margin, and the amount of tissue removed.
      RESULTS: The targeted lesions were accurately removed 100% of the time, and
      disease-free margins were obtained at the first operation in 82% of patients in
      both groups. An equivalent amount of disease-free margin (IUL, 6.6 mm; PWL, 6.7
      mm) was obtained with IUL while removing a smaller (IUL, 62.6 cm3; PWL, 81.1 cm3)
      mean volume of tissue. CONCLUSIONS: IUL is an accurate method of localizing most
      nonpalpable mass lesions identified on mammography. Equivalent margin status can
      be achieved while removing no more tissue than with PWL. The trauma of wire
      localization in an awake patient is avoided.

PMID- 10340893
TI  - Are locoregional cutaneous metastases in melanoma predictable?
AB  - BACKGROUND: In-transit metastases and satellite lesions are manifestations of
      locoregional cutaneous recurrence that are characteristic of malignant melanoma.
      They are the result of tumor cell emboli entrapped in the dermal lymphatics
      between the primary tumor and the regional lymph node basin. Histopathological
      features of lymphatic invasion were investigated to determine the possibility of
      predicting locoregional cutaneous metastases in melanoma patients. METHODS: In a
      prospective study, 258 patients with clinical stage I melanoma underwent wide
      local excision and sentinel node biopsy. Nodal metastases were found in 53 (21%)
      patients. Of 29 patients (11.2%) who had developed recurrences to date, 17 (6.6%)
      had locoregional cutaneous metastases. All surgical specimens were examined with
      particular attention to histopathological signs of lymphatic vascular invasion or
      microscopic satellites. RESULTS: Unequivocal signs of lymphatic invasion were
      observed in 14 of 258 patients (5.4%), and 13 (93%) of these patients
      subsequently developed in-transit metastases, after a median interval of 10
      months. The primary melanoma was located on the extremities in seven patients.
      The median Breslow thickness was 2.5 mm, and 5 showed ulceration. In 244 of 258
      patients (94.6%), there were no signs of lymphatic invasion. To date, only four
      patients (1.6%) have had a locoregional cutaneous recurrence, occurring after a
      median interval of 29 months. All four of these patients had ulcerative melanomas
      on an extremity, with a median thickness of 4.0 mm. The presence of lymphatic
      invasion was significantly related to early locoregional cutaneous relapse (P <
      .0001). CONCLUSIONS: Locoregional cutaneous recurrence appears to be highly
      predictable in the presence of histopathological signs of lymphatic invasion.
      Lymphatic invasion is an important prognostic parameter and should be included as
      a stratification criterion when selecting patients for adjuvant (locoregional)
      therapy.

PMID- 10340894
TI  - Long-term survival in patients with ovarian metastases from colorectal carcinoma.

PMID- 10340895
TI  - Does size matter? Association between number of patients treated and patient
      outcome in metastatic testicular cancer.

PMID- 10340896
TI  - Cancer patient care in clinical trials sponsored by the National Cancer
      Institute: what does it cost?

PMID- 10340897
TI  - Angiogenesis research is on fast forward.

PMID- 10340898
TI  - Americans With Disabilities Act: do cancer patients qualify as disabled?

PMID- 10340899
TI  - Exercise and breast cancer risk: lacking consensus.

PMID- 10340900
TI  - New structure for Irish cancer research, NCI agreement planned.

PMID- 10340901
TI  - In utero gene therapy is still a distant promise.

PMID- 10340902
TI  - A tangled web: factors likely to affect the efficacy of screening mammography.

PMID- 10340903
TI  - Impact of the treating institution on survival of patients with "poor-prognosis"
      metastatic nonseminoma. European Organization for Research and Treatment of
      Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research
      Council Testicular Cancer Working Party.
AB  - BACKGROUND: Because metastatic nonseminomatous germ cell cancer is a rare but
      treatable cancer, we have explored whether there is an association between the
      experience of the treating institution with this disease and the long-term
      clinical outcome of the patients, particularly patients with a poor prognosis.
      METHODS: We analyzed data on 380 patients treated in one of 49 institutions
      participating in the European Organization for Research and Treatment of Cancer/
      Medical Research Council randomized trial of four cycles of bleomycin-etoposide
      cisplatin followed by two cycles of etoposide-cisplatin versus three cycles of
      bleomycin-vincristine-cisplatin followed by three cycles of etoposide-ifosfamide
      cisplatin-bleomycin, both treatment regimens given with or without filgrastim
      (granulocyte colony-stimulating factor). Institutions were divided into four
      groups based on the total number of patients entered in the trial. The groups
      were compared by use of the Cox proportional hazards model stratified for
      treatment with filgrastim and for patient prognosis as defined by the
      International Germ Cell Consensus Classification Group. With the use of this
      classification, only 65 % of the patients had a poor prognosis. RESULTS: Patients
      treated in the 26 institutions that entered fewer than five patients into the
      trial had an overall survival that was statistically significantly worse (two
      sided P = .010; hazard ratio = 1.85; 95% confidence interval = 1.16-3.03) than
      that of patients treated in the 23 institutions that entered five patients or
      more. Overall survival and failure-free survival were similar among institutions
      that entered at least five patients. The observed effect may be related to
      differences in adherence to the chemotherapy protocol and in the frequency and
      extent of surgery for residual masses, although only the differences in dose
      intensity achieved statistical significance. CONCLUSIONS: Patients treated in
      institutions that entered fewer than five patients into the trial appeared to
      have poorer survival than those treated in institutions that entered a larger
      number of patients with "poor-prognosis" nonseminoma.

PMID- 10340904
TI  - Incremental costs of enrolling cancer patients in clinical trials: a population
      based study.
AB  - BACKGROUND: Payment for care provided as part of clinical research has become
      less predictable as a result of managed care. Because little is known at present
      about how entry into cancer trials affects the cost of care for cancer patients,
      we conducted a matched case-control comparison of the incremental medical costs
      attributable to participation in cancer treatment trials. METHODS: Case patients
      were residents of Olmsted County, MN, who entered phase II or phase III cancer
      treatment trials at the Mayo Clinic from 1988 through 1994. Control patients were
      patients who did not enter trials but who were eligible on the basis of tumor
      registry matching and medical record review. Sixty-one matched pairs were
      followed for up to 5 years after the date of trial entry for case patients or
      from an equivalent date for control patients. Hospital, physician, and ancillary
      service costs were estimated from a population-based cost database developed at
      the Mayo Clinic. RESULTS: Trial enrollees incurred modestly (no more than 10%)
      higher costs over various follow-up periods. The mean cumulative 5-year cost in
      1995 inflation-adjusted U.S. dollars among trial enrollees after adjustment for
      censoring was $46424 compared with $44 133 for control patients. After 1 year,
      trial enrollee costs were $24645 compared with $23 964 for control patients.
      CONCLUSIONS: This study suggests that cancer chemotherapy trials may not imply
      budget-breaking costs. Cancer itself is a high-cost illness. Clinical protocols
      may add relatively little to that cost.

PMID- 10340905
TI  - Trichloroethylene exposure and specific somatic mutations in patients with renal
      cell carcinoma.
AB  - BACKGROUND: The development of renal cell carcinoma (RCC) has been associated
      with both genetic and environmental factors-with mutations in the von Hippel
      Lindau (VHL) tumor suppressor gene for clear-cell RCC specifically and with long
      term exposure to high doses of trichloroethylene (TRI), an industrially important
      solvent, for RCC generally. We investigated whether TRI exposure produces RCC
      through a specific mutational effect on the VHL gene by analyzing VHL sequences
      in the RCCs of patients exposed to high, cumulative doses of TRI. METHODS: The
      level of exposure for each of 44 patients with RCC who had known industrial
      exposure to TRI was classified according to the duration, frequency, and mode of
      exposure. Samples of normal and cancerous tissues were microdissected from
      paraffin-embedded tissue. DNA was isolated from these samples, and somatic VHL
      mutations were identified by polymerase chain reaction analysis, single-strand
      conformation polymorphism analysis, DNA sequencing, and restriction enzyme
      digestion. Control samples included RCC DNA from 107 patients without known TRI
      exposure and lymphocyte DNA from 97 healthy subjects. RESULTS: RCCs of TRI
      exposed patients showed somatic VHL mutations in 33 (75%) of 44 cases. The
      mutations were frequently multiple and accompanied by loss of heterozygosity, and
      there was an association between the number of mutations and the severity of TRI
      exposure. We observed a specific mutational hot spot at VHL nucleotide 454 in the
      RCCs of 13 (39%) of the patients, and this mutation was present in adjacent non
      neoplastic kidney parenchyma in four of these patients. The nucleotide 454
      mutation was neither detected in any of the RCCs from patients without TRI
      exposure nor in any of the healthy subjects. CONCLUSION: Our results suggest that
      RCC in patients with high, cumulative TRI exposure is associated with a unique
      mutation pattern in the VHL gene.

PMID- 10340906
TI  - Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the
      randomized trials. CLL Trialists' Collaborative Group.
AB  - BACKGROUND: The randomized trials that evaluate the timing and intensity of
      initial chemotherapy for chronic lymphocytic leukemia (CLL) have, in general,
      been too small to provide separately reliable results. We compared the effects on
      survival of the following: a) immediate versus deferred chemotherapy for early
      stage CLL and b) combination chemotherapy (e.g., cyclophosphamide and vincristine
      plus prednisone/prednisolone [COP] or COP plus doxorubicin [CHOP]) versus single
      agent chlorambucil as first-line treatment for more advanced disease. METHODS:
      All relevant randomized trials, whether published or not, were sought for a
      collaborative meta-analysis involving centralized review of the data for each
      patient. RESULTS: There were 2048 patients with early disease in six trials of
      immediate versus deferred chemotherapy (chlorambucil or chlorambucil plus
      prednisone/prednisolone). The 10-year survival was slightly worse (but not
      statistically significantly so) with immediate chemotherapy (44% versus 47%
      survival; difference = -3%; 95% confidence interval [CI] = -10% to 4%). There
      were another 2022 patients in 10 trials of combination chemotherapy versus
      chlorambucil, with or without prednisone/prednisolone. The 5-year survival was 48
      % in both cases (difference = 0%; 95% CI = -6% to 5%). A subgroup of six of these
      10 trials involved an anthracycline-containing regimen but again overall survival
      appeared no better than with chlorambucil (anthracycline-based regimen: 325
      deaths among 627 patients; chlorambucil: 306 deaths among 636 patients; death
      rate ratio = 1.07; 95% CI = 0.91-1.25; not statistically significant).
      CONCLUSIONS: In terms of survival, these trials support a conservative treatment
      strategy for CLL, i.e., no chemotherapy for most patients with early-stage
      disease, and single-agent chlorambucil as the first line of treatment for most
      patients with advanced disease, with no evidence of benefit from early inclusion
      of an anthracycline. This strategy will, however, need to be reconsidered as
      mature results become available from trials of other agents.

PMID- 10340907
TI  - Plasma urokinase receptor levels in patients with colorectal cancer: relationship
      to prognosis.
AB  - BACKGROUND: The proteolytic enzyme plasmin, which is generated from the precursor
      plasminogen by the action of urokinase plasminogen activator, is thought to play
      a role in tumor cell invasion and metastasis. Urokinase plasminogen activator
      receptor (uPAR) is functionally involved in the cell surface activation (i.e.,
      cleavage) of plasminogen. Increased tumor tissue levels of uPAR are associated
      with poor prognosis in several types of cancer. This retrospective study was
      undertaken to test the relationship between preoperative plasma levels of soluble
      uPAR (suPAR) and survival in patients with colorectal cancer. METHODS: suPAR
      levels in preoperative plasma from 591 patients with colorectal cancer were
      determined by use of a kinetic enzyme-linked immunosorbent assay and analyzed
      with respect to associations with postoperative survival, Dukes' stage, age, and
      serum carcinoembryonic antigen level. Plasma suPAR measurements were log
      transformed for survival analysis, which employed the Kaplan-Meier method and the
      Cox proportional hazards model. All P values reported are two-sided. RESULTS:
      Univariate analysis, using the log-transformed suPAR concentrations, demonstrated
      that there was an increasing risk of mortality with increasing plasma suPAR level
      (P<.0001). An arbitrary cut point, the median for all patients (1.37 ng/mL),
      divided patients with Dukes' stage B, C, or D disease into statistically
      different prognostic groups. In multivariate Cox analysis including Dukes' stage,
      age, and carcinoembryonic antigen level, the suPAR concentration independently
      predicted survival (P<.0001). CONCLUSIONS: The preoperative plasma suPAR level
      independently predicted survival of patients with colorectal cancer. Further
      studies of plasma suPAR in patients with cancer are needed to evaluate the
      utility of plasma suPAR measurements and cut points in identifying high-risk
      patients among those with early stage disease.

PMID- 10340909
TI  - Prevalence of mutations in the BRCA1 gene among Chinese patients with breast
      cancer.

PMID- 10340908
TI  - Prognostic significance of transcription factor E2F-1 in bladder cancer:
      genotypic and phenotypic characterization.
AB  - BACKGROUND: We sought to identify and characterize potential alterations in E2F
      1, a transcription factor that binds to the retinoblastoma protein (pRB), in
      bladder neoplasms and to elucidate a possible role for E2F-1 as an oncogene or a
      tumor suppressor gene. METHODS: Tumor samples from 133 evaluable patients with
      bladder cancer were analyzed for E2F-1 gene mutations by use of polymerase chain
      reaction-single-strand conformational polymorphism (PCR-SSCP) analysis and DNA
      sequencing. In addition, tumors were studied for E2F-1 and pRB protein expression
      by use of immunohistochemistry. Results from the above analyses were correlated
      with clinicopathologic parameters and outcome. All P values are two-sided.
      RESULTS: A polymorphism, consisting of a nucleotide change at amino acid codon
      393 in exon 7 (GGC-->AGC [Gly-->Ser]), was identified in seven of 133 case
      patients, being present in both tumor and corresponding normal tissues. No
      bandshifts were identified in the nuclear-localization or DNA-binding domains on
      PCR-SSCP analysis. On immunohistochemical analysis, E2F-1 nuclear reactivity was
      observed in less than 5% of the cells from 53 tumors and in 5%-75% of the cells
      from the remaining 80 tumors. The pattern of E2F-1 protein expression was not
      altered in relation to the identified polymorphism. pRB nuclear reactivity
      greater than 20% (of tumor cells stained) was present in 66% of the samples. E2F
      1 nuclear reactivity correlated inversely with the percentage of cells showing
      pRB reactivity (Kendall tau(b) = -0.18; P = .019). On multivariate analysis,
      patients with lower E2F-1 reactivity had statistically significantly increased
      risks of progression to metastases (P = .001) and death (P = .02). CONCLUSIONS:
      E2F-1 alterations occur at the phenotypic level, rather than at the genotypic
      level, in bladder cancer. The adverse outcome for patients whose tumors exhibit
      low E2F-1 nuclear expression suggests a possible tumor suppressor role for E2F-1
      in bladder cancer.

PMID- 10340910
TI  - Re: Characterization of MOAT-C and MOAT-D, new members of the MRP/cMOAT subfamily
      of transporter proteins.

PMID- 10340911
TI  - Investigation of terbinafine as a CYP2D6 inhibitor in vivo.
AB  - BACKGROUND: Terbinafine is an orally active antifungal used in the treatment of
      dermatophytoses. To date, studies evaluating the effect of terbinafine on the
      cytochromes P450 have failed to show any significant interactions. This
      prospective open-label study was designed to confirm our previous finding that
      terbinafine may inhibit CYP2D6. METHODS: Nine healthy volunteers were enrolled in
      this study-6 genotypically consistent with an extensive metabolizer phenotype and
      3 genotypic poor metabolizers for CYP2D6. The change in CYP2D6 enzyme activity
      before (x 3) and after (monthly x 6 months) administration of terbinafine (250 mg
      once daily x 14 days) was evaluated with the dextromethorphan to dextrorphan
      urinary metabolite ratios. On each study day a predose urine sample was
      collected, 0.3 mg/kg dextromethorphan was administered, and urine was collected
      for 24 hours. Dextromethorphan and its metabolites were quantified from urine by
      HPLC. RESULTS: Baseline phenotype values were concordant with individual
      genotype. In all extensive metabolizers, the administration of terbinafine
      resulted in a dramatic increase in the dextromethorphan/dextrorphan ratio,
      converting 4 of the 6 extensive metabolizers into phenotypic poor metabolizers.
      On average, a 97-fold increase in ratio (range, 35 to 265) was observed for
      extensive metabolizers after the administration of terbinafine. No significant
      change was observed in the metabolite ratios of poor metabolizers during the
      course of the study. CONCLUSIONS: Terbinafine inhibits CYP2D6 sufficiently to
      produce a discordance between genotype and phenotype for the enzyme. The
      dextromethorphan/dextrorphan metabolite ratios increased in all individuals, with
      otherwise functional CYP2D6 activity. The disposition of CYP2D6 substrates
      coadministered with terbinafine may be significantly altered in extensive
      metabolizers for this cytochrome P450 isoform, who comprise approximately 93% of
      the population.

PMID- 10340912
TI  - Pharmacokinetics and pharmacodynamics of SB 209670, an endothelin receptor
      antagonist: effects on the regulation of renal vascular tone.
AB  - OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of an infusion
      of SB 209670, a non-peptide endothelin-A/endothelin-B receptor antagonist.
      METHODS: The study was conducted in 2 parts. Part 1 was a placebo-controlled,
      single-blind, rising-dose crossover evaluation of the pharmacokinetics and safety
      of SB 209670 infused at doses that ranged from 0.2 to 1.5 mirog kg(-1) for
      approximately 8 hours in 17 healthy male volunteers. In part 2, renal hemodynamic
      effects of a 4-hour infusion of SB 209670 were assessed in 10 healthy male
      volunteers in a 2-period, period-balanced, single-blind, randomized, placebo
      controlled crossover study. RESULTS: SB 209670 appeared to display linear
      kinetics over the dose range from 0.2 to 1.5 microg kg(-1) min(-1). The half-life
      was approximately 4 to 5 hours. Plasma immunoreactive endothelin-1 increased in
      an apparent dose-dependent manner. Mean renal hemodynamic responses (para
      aminohippurate clearance) increased by approximately 15% relative to placebo (P =
      .007). Renal sodium excretion was similar during SB 209670 and placebo infusion.
      CONCLUSION: The pharmacokinetics of intravenous SB 209670 appeared to be linear,
      and infusion resulted in dose-related increases in immunoreactive endothelin-1.
      The lack of anti-natriuretic effect and the renal vasodilator response observed
      in this study indicate that SB 209670 does not possess any partial agonist
      activity. Further, the renal hemodynamic response supported a potential
      physiologic role for endogenous endothelin in the maintenance of renal vascular
      tone in humans.

PMID- 10340913
TI  - Thalidomide does not alter estrogen-progesterone hormone single dose
      pharmacokinetics.
AB  - OBJECTIVES: To determine the single- and multiple-dose pharmacokinetics of oral
      thalidomide (200 mg/day, administered for 21 days) and to assess the effects of
      steady-state plasma concentrations of thalidomide on the single-dose
      pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone
      (INN, norethisterone). METHODS: A randomized, 2-period crossover study was
      performed in 10 healthy premenopausal female volunteers. The pharmacokinetic
      profiles of plasma concentrations of thalidomide were evaluated with both
      noncompartmental and compartmental methods, whereas those of ethinyl estradiol
      and norethindrone were calculated with noncompartmental methods. The effects of
      steady-state plasma thalidomide concentrations on the pharmacokinetics of ethinyl
      estradiol and norethindrone were determined with use of an ANOVA model that
      included treatment sequence, subject within sequence, period, and treatment as
      factors. RESULTS: Thalidomide plasma concentrations were best predicted by a 1
      compartment model with first-order absorption and elimination and an absorption
      time-lag. There were no significant differences between pharmacokinetic
      parameters for thalidomide after 1 dose and those after 18 consecutive doses.
      Except for a minor decrease of the elimination rate constant (k(e)) for ethinyl
      estradiol, coadministration of thalidomide had no significant effects on the
      pharmacokinetic profiles for either ethinyl estradiol or norethindrone. The
      change in k(e) for ethinyl estradiol during thalidomide administration was not
      associated with any alteration in the clearance or elimination half-life for this
      hormone. CONCLUSIONS: Multiple-dose pharmacokinetics of thalidomide is similar to
      the single-dose profile. This study did not investigate the efficacy of the 21
      day fixed ethinyl estradiol-norethindrone regimen, but the results suggest that
      thalidomide is unlikely to affect the pharmacokinetics of orally administered
      hormonal contraceptives.

PMID- 10340914
TI  - Clinical pharmacokinetics of encapsulated oral 9-aminocamptothecin in plasma and
      saliva.
AB  - OBJECTIVE: To study the pharmacokinetics and pharmacodynamics of the novel
      topoisomerase I inhibitor and antitumor agent 9-amino-20(S)-camptothecin in
      patients with solid tumors after repeated oral administration. METHODS: Thirty
      two patients with cancer received oral 9-aminocamptothecin formulated in capsules
      with polyethylene glycol-1000 as excipient at doses that ranged from 0.25 to 1.5
      mg/m2/day. Serial plasma and saliva samples were obtained on days 1 and 6 or days
      1 and 8 of the first cycle and analyzed for the lactone and carboxylate forms of
      9-aminocamptothecin by HPLC. RESULTS: 9-Aminocamptothecin showed linear and dose
      independent pharmacokinetics, with extremely small intrapatient kinetic
      variability (coefficient of variation: <10%). However, interpatient variability
      in plasma pharmacokinetics was large (coefficient of variation: 99%). The
      relative extent of lactone to carboxylate interconversion was large (>90%) and
      predictable from individual pretreatment serum albumin values (P = .0099). The 9
      aminocamptothecin concentration ratio in plasma and saliva was strongly patient
      dependent, and highly variable around a mean value of <0.8, suggesting that
      saliva is an unreliable matrix for kinetic monitoring. The area under the curve
      of the lactone form of 9-aminocamptothecin was significantly correlated with the
      dose-limiting hematologic toxicity (P < .001). CONCLUSION: Our data indicate that
      the large interindividual pharmacodynamic variability in response to 9
      aminocamptothecin is caused mainly by a variability in kinetic characteristics,
      suggesting that a kinetic-dynamic guided study design is warranted in future
      clinical investigations.

PMID- 10340915
TI  - Quinine disposition in globally malnourished children with cerebral malaria.
AB  - BACKGROUND: Both malnutrition and malaria affect drug disposition and are
      frequent among children in the tropics. We assessed their respective influence on
      quinine distribution. METHODS: Forty children were divided into 4 groups:
      children with normal nutritional status without (group 1) or with (group 2)
      cerebral malaria, and malnourished children without (group 3) or with (group 4)
      cerebral malaria. All children received an infusion of 8 mg/kg of a combination
      solution of cinchona alkaloids that contained 96.1% quinine, 2.5% quinidine,
      0.68% cinchonine, and 0.67% cinchonidine (corresponding to 4.7 mg/kg quinine
      base). The children with malaria then received repeated infusions every 8 hours
      for 3 days. Pharmacokinetic profiles of plasma and erythrocyte quinine were
      determined during the first 8 hours, together with quinine protein binding.
      Additional measurements of plasma quinine concentrations were used to simulate
      quinine concentrations profiles in children with malaria with and without
      malnutrition. Clinical recovery and parasitemia clearance times were determined
      in the children with malaria. RESULTS: Compared with control children, malaria
      and malnutrition increased plasma concentrations of quinine and reduced both the
      volume of distribution and the total plasma clearance. Simultaneously,
      alglycoprotein plasma concentrations and protein-bound fraction of the drug were
      increased. Erythrocyte quinine concentrations correlated strongly with free
      plasma quinine but not with the extent of parasitemia. Similar effective and
      nontoxic quinine concentration profiles were obtained in malaria with and without
      malnutrition. CONCLUSIONS: Severe global malnutrition and cerebral malaria have a
      similar effect on quinine pharmacokinetics in children. Moderate malnutrition
      does not potentiate cerebral malaria-mediated modifications of quinine
      disposition. These results suggest that current parenteral quinine regimens can
      be used, unmodified, to treat children with both malaria and malnutrition.

PMID- 10340916
TI  - Influence of arteriovenous sampling on remifentanil pharmacokinetics and
      pharmacodynamics.
AB  - INTRODUCTION: Remifentanil is a new, short-acting, rapidly metabolized opioid.
      Because remifentanil is metabolized in blood and tissues by nonspecific
      esterases, there is a substantial difference between arterial and venous
      remifentanil concentrations. This difference may greatly affect the estimation of
      pharmacokinetic and pharmacodynamic parameters. OBJECTIVES: To assess the effects
      of sampling site on the pharmacokinetic and pharmacodynamic characteristics of
      remifentanil. METHODS: Ten healthy female subjects received intravenous
      remifentanil at an infusion rate of 3 microg/kg/min for 10 minutes. Serial blood
      samples were collected during and after drug administration from the radial
      artery and antecubital vein. A spectral edge measure was derived from the
      processed electroencephalographic and used as a measure of opioid effect.
      RESULTS: Venous concentrations were lower than arterial concentrations during the
      infusion of remifentanil. Pharmacokinetic parameters estimated from venous and
      arterial data differed significantly. When arterial concentrations were plotted
      against electroencephalographic effect, a classic counterclockwise hysteresis
      loop was observed, indicating a time-lag between changes in concentration and
      changes in effect. However, concentrations from venous blood produced a clockwise
      hysteresis loop that would classically suggest the development of acute
      tolerance. CONCLUSIONS: If this study had been conducted with venous samples
      alone, inappropriate conclusions such as acute tolerance could have been
      inferred. When designing studies to measure the acute time course (ie, non-steady
      state) of concentration and effect, the potential effects of sampling site on
      pharmacokinetic and pharmacodynamic characteristics must be carefully considered,
      particularly when the arteriovenous drug concentration difference is large.

PMID- 10340918
TI  - The cytotoxicity of clozapine metabolites: implications for predicting clozapine
      induced agranulocytosis.
AB  - BACKGROUND: Therapy of schizophrenia with clozapine is associated with the
      unpredictable development of severe neutropenia and agranulocytosis in 1% to 2%
      of patients. The mechanism of this effect is unknown but may involve reactive
      products of clozapine generated by either hepatic metabolism or oxidation by the
      peroxidase-peroxide system of activated neutrophils. METHODS: Involvement of
      reactive metabolites was tested with in vitro cytotoxicity assays with use of
      peripheral blood mononuclear cells isolated from 3 groups of subjects: normal
      control subjects, patients with schizophrenia who tolerated clozapine therapy
      (control patients), and patients with schizophrenia in whom agranulocytosis
      developed while taking clozapine (patients with agranulocytosis). Cell viability
      was determined after incubations with clozapine and rat liver microsomes or
      clozapine and horseradish peroxidase-peroxide (HRP-H2O2). RESULTS: In microsomal
      incubations, clozapine significantly increased the cell death in all groups:
      control subjects (8.8%+/-1.6%), control patients (7.4%+/-0.4%), and patients with
      agranulocytosis (9.1%+/-1.5%). However, differences between mean values were not
      statistically significant. In similar incubations with HRP-H2O2, clozapine
      significantly increased toxicity (P < .05) in cells from patients with
      agranulocytosis (22%+/-4.6%) compared with those from normal control subjects
      (7.7%+/-4.1%) or control patients (6.5%+/-4.4%). CONCLUSIONS: These results
      suggest that both generating systems metabolized clozapine to toxic products.
      Some products may play a role in clozapine-induced agranulocytosis. Of diagnostic
      relevance is the observation the HRP-H2O2 produces significantly greater toxicity
      in cells from patients with agranulocytosis than in cells from control patients.
      Although the exact mechanism(s) of drug activation in vivo remains unclear, the
      bioactivation of clozapine by HRP-H2O2 may be a useful in vitro tool for
      predicting which patients are at risk for agranulocytosis before initiation of
      therapy.

PMID- 10340917
TI  - Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol
      bronchodilator pharmacodynamics.
AB  - OBJECTIVE: To determine whether genetic polymorphisms of the beta2-adrenergic
      receptor gene affect the relationship between albuterol (INN, salbutamol) plasma
      concentrations and the forced expiratory volume in 1 second (FEV1) in subjects
      with moderate asthma. METHODS: Sixteen clinically stable patients with moderate
      asthma who participated in a pharmacokinetic-pharmacodynamic study of albuterol
      volunteered to provide a blood sample for determination of beta2-adrenergic
      receptor genotype. FEV1 and plasma concentrations of albuterol were determined at
      various times after administration of an oral solution that contained 8 mg
      albuterol. Patients withheld inhaled beta2-agonist and corticosteroid therapy 12
      and 24 hours, respectively, before the study. beta2-Adrenergic receptor genotype
      was determined by polymerase chain reaction with allele-specific oligonucleotide
      hybridization. RESULTS: Albuterol-evoked FEV1 was higher and the response was
      more rapid in Arg16 homozygotes compared with the cohort of carriers of the Gly16
      variant: Maximal percentage increase in FEV1 (%deltaFEV1), 18% versus 4.9% (P <
      .03); area under FEV1 albuterol concentration curve, 194%.mL/ng versus 30%.mL/ng
      (P < .05); initial slope (dE/dC), 1.43%.mL/ng versus 0.55%.mL/ng (P < .003).
      CONCLUSIONS: The beta2-adrenergic receptor gene polymorphism is a major
      determinant of bronchodilator response to albuterol. Future pharmacodynamic
      studies of beta2-agonists should include determination of 02-adrenergic receptor
      genotype.

PMID- 10340919
TI  - Comparison of inhibitory effects of meloxicam and diclofenac on human thromboxane
      biosynthesis after single doses and at steady state.
AB  - OBJECTIVE: To evaluate the extent of human cyclooxygenase-1 (COX-1) inhibition by
      meloxicam, which has been reported to preferentially inhibit cyclooxygenase-2
      (COX-2). The effects of meloxicam were compared with those of diclofenac, a
      nonselective COX inhibitor. METHODS: COX-1 inhibition was determined by measuring
      thromboxane B2 (TXB2)-generation from clotting whole blood ex vivo after single
      oral doses of 7.5 and 15 mg meloxicam and 75 mg diclofenac and at steady state
      (15 mg meloxicam daily and 150 mg diclofenac daily). The effect was expressed as
      percentage inhibition of serum TXB2 generation and was directly related to the
      serum drug concentration with use of a standard sigmoidal E(max) model. RESULTS:
      In terms of inhibition of TXB2 generation, diclofenac was about 1 order of
      magnitude more potent than meloxicam, indicated by a diclofenac EC50
      (concentration of drug required to cause 50% of maximum effect) that was about 10
      times lower than that of meloxicam (EC50 diclofenac single doses: 37.50+/-29.64;
      EC50 meloxicam single doses: 677.50+/-189.08). However, serum concentrations of
      meloxicam after administration of 15 mg were approximately 10-fold higher than
      those of diclofenac. Therefore there was no statistically significant difference
      in the area under the effect time curve (P = .115) and the mean effect (P = .424)
      between meloxicam and diclofenac. The EC50 of both drugs was significantly higher
      at steady state (diclofenac steady state: 87.07+/-55.24 ng/mL; meloxicam steady
      state: 1850.12+/-829.93 ng/mL) than after a single dose (P < .001). CONCLUSION:
      These data show that meloxicam inhibits TXB2 generation at clinically relevant
      doses, although less potently than diclofenac. Thus our data suggest that the COX
      2 preference of meloxicam observed in vitro may not result in clinical advantages
      when the higher dose of 15 mg is needed. Because of the increase in EC50 at
      steady state, COX-1 is relatively spared when the lower dose of 7.5 mg is
      administered.

PMID- 10340920
TI  - G-protein-coupled receptor kinase expression in hypertension.
AB  - In human hypertension we have recently identified an increase in lymphocyte G
      protein receptor kinase-2 (GRK-2) protein expression, the key protein regulating
      the interaction between G-protein-coupled receptors and activation of adenylyl
      cyclase. However, it was not known whether this increase in GRK-2 protein
      expression was attributable to regulation at the level of translation.
      Furthermore, the relationship between extent of GRK-2 expression, receptor
      activation of adenylyl cyclase, and blood pressure was unclear. We therefore
      studied lymphocytes from 7 young subjects with borderline hypertension and 14
      young normotensive subjects. Immunodetectable GRK-2 protein expression in
      lymphocytes from subjects with hypertension was increased (155%+/-7% of
      normotensive subjects; P < .05). In addition, GRK-2 protein expression was
      positively correlated with blood pressure (r = 0.53; P = .013) and inversely
      correlated with beta-adrenergic-mediated adenylyl cyclase activity (r = -0.54, P
      = .012). However, lymphocyte GRK-2 messenger ribonucleic acid (mRNA) content was
      not altered (110%+/-13% of that observed in normotensive control subjects).
      Increased GRK-2 protein expression may be an important factor in the impairment
      of beta-adrenergic-mediated vasodilation, characteristic of the hypertensive
      state.

PMID- 10340921
TI  - CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans.
AB  - OBJECTIVE: Omeprazole is metabolized by genetically determined S-mephenytoin 4'
      hydroxylase (CYP2C19) in the liver. This study aimed to determine whether the
      effect of omeprazole on intragastric pH depends on CYP2C19 genotype status.
      METHODS: CYP2C19 genotype status for 2 mutations associated with the poor
      metabolizer phenotype was determined by a polymerase chain reaction-restriction
      fragment length polymorphism method in 16 healthy volunteers. Helicobacterpylori
      status was determined by serology and the [13C]urea breath test. After a single
      oral administration of 20 mg omeprazole or a placebo, intragastric pH values were
      recorded for 24 hours. Plasma levels of omeprazole and its 2 metabolites and
      gastrin were measured before and 1, 2, 3, 5, 7, 10, and 24 hours after
      administration. RESULTS: Fifteen of the 16 subjects were H pylori negative. Five
      of the 15 subjects were homozygous extensive metabolizers, 4 were heterozygous
      extensive metabolizers, and 6 were poor metabolizers. After omeprazole
      administration, significant differences in mean intragastric pH values and plasma
      levels of gastrin, omeprazole and its metabolites were observed among the 3
      groups, whereas no significant differences in these parameters were observed with
      the placebo administration. CONCLUSIONS: The effect of omeprazole on intragastric
      pH significantly depends on CYP2C19 genotype status. The genotyping test of
      CYP2C19 may be useful for an optimal prescription of omeprazole.

PMID- 10340922
TI  - Relationship between acetylation polymorphism and risk of atopic diseases.
AB  - It has been shown that slow acetylation rate may be a factor that influences the
      development of allergic diseases. The influence of NAT2 genetic polymorphism on
      the risk of development of atopic diseases was evaluated among the white Polish
      population of 85 patients with atopy (62 children and 23 parents) and 181 healthy
      individuals (127 children and 54 adults). The NAT2 alleles (*4, *5, *6, and *7)
      were identified by polymerase chain reaction-restriction fragment length
      polymorphism methods with DNA extracted from peripheral blood. A significant
      predominance of homozygous slow acetylators (85%) among patients with atopic
      diseases was observed. There were no homozygous fast acetylators within this
      group of individuals. Comparison of the frequency of slow acetylators between the
      above group of patients and healthy subjects (54%) showed that the significant
      predominance of slow acetylators was observed in the first group (P < .001). The
      risk of development of atopic diseases was 5-fold greater for homozygous slow
      acetylators (odds ratio, 4.69; 95% confidence interval, 2.33-9.59) compared with
      healthy subjects. We therefore concluded that slow acetylation genotype may be an
      important factor of individual susceptibility to atopic diseases.

PMID- 10340923
TI  - Analysis of the CYP2D6 gene in relation to dextromethorphan O-demethylation
      capacity in a Japanese population.
AB  - OBJECTIVE: To analyze the CYP2D6 allele frequencies in a Japanese population and
      to evaluate the effects of CYP2D6 variants on in vivo CYP2D6 activity as measured
      by the dextromethorphan metabolic ratio (MR). METHODS: Ninety-eight unrelated,
      healthy Japanese men were phenotyped with dextromethorphan and genotyped by the
      polymerase chain reaction amplification method for 7 CYP2D6 alleles. RESULTS: The
      CYP2D6*1, CYP2D6*10, CYP2D6*2, CYP2D6*5, CYP2D6*4, and CYP2D6*21 allele
      frequencies in our Japanese subjects were 0.423, 0.408, 0.092, 0.061, 0.020, and
      0.010, respectively. Thirty-three subjects (33.7%) were heterozygous for *10/*1,
      and 18 (18.4%) and 17 (17.3%) subjects were homozygous for *1 and *10,
      respectively. Subjects who were homozygous for *10 showed the highest
      dextromethorphan MR among these 3 genotypes. Eighteen subjects (18.3%) were
      heterozygous for *2, but their dextromethorphan MR values were not greater than
      the MR values of subjects who were homozygous for *1. One subject was a poor
      metabolizer phenotypically, and he was homozygous for *5. CONCLUSIONS: The CYP2D6
      allele frequencies in our Japanese subjects differed from those determined in
      previous studies of white subjects or mainland Chinese subjects. Individuals
      homozygous for *10 who have relatively low in vivo CYP2D6 activity represent
      almost 20% of the Japanese population. In addition, we did not identify any
      subjects with amplified *2 among our 98 Japanese men.

PMID- 10340924
TI  - Phenotype-genotype correlation of in vitro SN-38 (active metabolite of
      irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1
      promoter polymorphism.
AB  - BACKGROUND: Hepatic uridine diphosphate glucuronosyltransferase (UGT) isoform 1A1
      (UGT1A1) is primarily responsible for the glucuronidation of SN-38 (7-ethyl-10
      hydroxycamptothecin), the active metabolite of the anticancer agent irinotecan.
      UGT1A1, also catalyzing the glucuronidation of bilirubin, has been shown to have
      reduced activity in Gilbert's syndrome. The presence of an additional TA repeat
      [(TA)7TAA] in the TATA sequence of UGT1A1 has been associated with Gilbert's
      syndrome. OBJECTIVE: To evaluate the relationship between UGT1A1 phenotypic
      activity and UGT1A1 promoter polymorphism. METHODS: Phenotypic measurements
      included in vitro SN-38 and bilirubin glucuronidation in human liver microsomes
      (n = 44). A recently developed genotyping test was used to determine TATA
      sequence polymorphisms in UGT1A1. Genotypes were assigned as follows: 7/7,
      homozygous for the (TA)7TAA allele; 6/6, homozygous for the (TA)6TAA allele; and
      6/7, heterozygous with 1 of each allele. RESULTS: Nine percent of screened liver
      samples were found to be homozygous for allele 7 (7/7), 43% were homozygous for
      allele 6 (6/6), and 48% were heterozygous (6/7). Frequencies of (TA)7TAA and
      (TA)6TAA alleles were 0.33 and 0.67, respectively. A significant trend toward a
      decrease in SN-38 and bilirubin glucuronidation rates was found as the number of
      TA repeats increased (6/6 > 6/7 > 7/7). Glucuronidation rates of both substrates
      were significantly lower in the 7/7 and 6/7 groups compared with the 6/6 group.
      CONCLUSIONS: The results indicate a significant association of UGT1A1 phenotype
      and genotype based on in vitro phenotypic measurements. The clinical significance
      of our finding remains to be established.

PMID- 10340925
TI  - Calcium channel blocker-simvastatin interaction.

PMID- 10340926
TI  - Mechanisms of lung injury after bone marrow transplantation.

PMID- 10340927
TI  - Matrix metalloproteinases. Matrix degradation and more.

PMID- 10340928
TI  - Engineering viral vectors to subvert the airway defense response.

PMID- 10340929
TI  - Restoration of cyclic adenosine monophosphate-stimulated chloride channel
      activity in human cystic fibrosis tracheobronchial submucosal gland cells by
      adenovirus-mediated and cationic lipid-mediated gene transfer.
AB  - In human airways, the cystic fibrosis (CF) transmembrane conductance regulator
      (CFTR) is predominantly expressed in serous cells of the tracheobronchial glands.
      Despite considerable evidence that submucosal glands are important contributors
      to the pathophysiology of CF lung disease, most attempts at CFTR gene transfer
      have primarily targeted airway surface epithelial cells. In this study, we
      systematically evaluated CFTR gene transfer into cultures of immortalized CF
      human tracheobronchial submucosal gland (6CFSMEO) cells using adenovirus and
      cationic lipid vectors. We found that the efficiency of adenovirus-mediated gene
      transfer was comparable in 6CFSMEO and CFT1 cells (a surface airway epithelial
      cell line isolated from a subject with CF). So was the ranking order of
      adenovirus vectors containing different enhancers/promoters (CMV >> E1a
      approximately phosphoglycerokinase), as determined by both X-Gal staining and
      quantitative measurement of beta-galactosidase activity. Further, we provide the
      first demonstration that cationic lipids mediate efficient gene transfer into
      6CFSMEO cells in vitro. The transfection efficiency at optimal conditions was
      higher in 6CFSMEO than in CFT1 cells. Finally, either infection with adenoviral
      vectors or transfection with cationic lipid:plasmid DNA complexes encoding CFTR
      significantly increased chloride (Cl-) permeability, as assessed using the 6
      methoxy-N-(3-sulfopropyl)-quinolinium (SPQ) fluorescence assay, indicating
      restoration of functional CFTR Cl- channel activity. These data show that
      although the mechanisms of transfection may be different between the two cell
      types, 6CFSMEO cells are as susceptible as CFT1 cells to transfection by
      adenoviral and cationic-lipid gene transfer vectors.

PMID- 10340930
TI  - Idiopathic pneumonia syndrome after allogeneic bone marrow transplantation in
      mice. Role of pretransplant radiation conditioning.
AB  - Idiopathic pneumonia syndrome (IPS) is a significant clinical problem encountered
      among patients treated with bone marrow transplantation (BMT). IPS is identified
      as an inflammatory lung disease characterized by diffuse interstitial pneumonitis
      and alveolitis leading to interstitial fibrosis in the absence of an identifiable
      infectious agent. In an earlier study we characterized a murine model of IPS
      following allogeneic BMT that exhibits several features of human IPS. In this
      report we show that the lung represents a unique target of post-BMT disease in
      this model. The kinetics of developing lung disease were found to be markedly
      different from the kinetics of graft-versus-host disease in other tissues such as
      liver, colon, ear, skin, and tongue. Mice transplanted by our standard protocol
      with T-cell-depleted semiallogeneic donor bone marrow plus donor spleen cells in
      the absence of pretransplant radiation conditioning did not develop lung
      inflammation or fibrosis characteristic of IPS. Pretransplant radiation
      conditioning in the absence of BMT also failed to cause IPS, demonstrating an
      important role for radiation conditioning in the development of BMT-related IPS.
      The occurrence of lung disease post-BMT was found to be dependent on radiation
      conditioning in a dose-dependent manner. Finally, thoracic irradiation alone was
      demonstrated to be sufficient in causing IPS in mice transplanted with bone
      marrow plus spleen cells, albeit with reduced severity. Based on these findings,
      we conclude that pretransplant radiation conditioning plays an important role in
      the development of IPS following allogeneic BMT.

PMID- 10340931
TI  - High levels of peroxynitrite are generated in the lungs of irradiated mice given
      cyclophosphamide and allogeneic T cells. A potential mechanism of injury after
      marrow transplantation.
AB  - In a murine bone-marrow transplant (BMT) model designed to determine risk factors
      for lung dysfunction in irradiated mice, we reported that cyclophosphamide (Cy)
      induced injury and lethality depended on the infusion of donor spleen T cells. In
      the study reported here, we hypothesized that alveolar macrophage (AM)-derived
      reactive oxygen/nitrogen species are associated with lung dysfunction caused by
      allogeneic T cells, which stimulate nitric oxide (.NO) production, and by Cy,
      which stimulates superoxide production.NO reacts with superoxide to form
      peroxynitrite, a tissue-damaging oxidant. On Day 7 after allogeneic BMT,
      bronchoalveolar lavage fluid (BALF) obtained from mice injected with T cells
      contained increased levels of nitrite, which was associated with increased
      lactate dehydrogenase and protein levels, both of which are indices of lung
      injury. The injury was most severe in mice receiving both T cells and Cy.
      Messenger RNA (mRNA) for inducible nitric oxide synthase was detected only in
      murine lungs injected with T cells +/- Cy. AMs obtained on Day 7 after BMT from
      mice receiving T cells +/- Cy spontaneously generated between 20 and 40 microM
      nitrite in culture, versus < 2 microM generated by macrophages obtained from mice
      undergoing BMT but not receiving T cells. The level of 3-nitrotyrosine, the
      stable byproduct of the reaction of peroxynitrite with tyrosine residues, was
      increased in the BALF proteins of mice injected with both T cells and Cy. We
      conclude that allogeneic T cells stimulate macrophage-derived.NO, and that the
      addition of Cy favors peroxynitrite formation. Peroxynitrite generation clarifies
      the dependence of Cy-induced lung injury and lethality on the presence of
      allogeneic T cells.

PMID- 10340932
TI  - Characterization of matrix metalloproteinases produced by rat alveolar
      macrophages.
AB  - Evidence presented in the accompanying article (Gibbs, D. F., T. P. Shanley, R.
      L. Warner, H. S. Murphy, J. Varani, and K. J. Johnson. 1999. Role of matrix
      metalloproteinases in models of macrophage-dependent acute lung injury: evidence
      for alveolar macrophage as source of proteinases. Am. J. Respir. Cell Mol. Biol.
      20:1145-1154) implicates alveolar macrophage matrix metalloproteinases (MMPs) in
      two models of acute lung inflammation in the rat. As a prerequisite to
      understanding which specific MMPs might be involved in the injury and how they
      might function, it was necessary to know the spectrum of enzymes present. To this
      end, alveolar macrophages were obtained from normal rat lungs by bronchoalveolar
      lavage, placed in culture with and without various agonists, and assessed by a
      variety of techniques for MMPs. The identification process involved
      characterization by gelatin, beta-casein, and kappa-elastin zymography, with
      confirmation of identity by Western blot/immunoprecipitation. Message levels of
      detected MMPs were assessed by Northern blot. Rat alveolar macrophages were found
      to produce a low constitutive level of MMP-2 (72-kD gelatinase A) that was only
      modestly upregulated following stimulation with phorbol myristate acetate,
      bacterial lipopolysaccharide, or immunoglobulin A-containing immune complexes.
      Although control cells were found to produce little or no MMP-9 (92-kD gelatinase
      B) or MMP-12 (metalloelastase), both enzymes were markedly upregulated upon
      stimulation. In the same stimulated macrophages there was little activity against
      type I collagen (associated with MMP-13 [collagenase-3] on the basis of Western
      blotting), no activity suggestive of stromelysin or matrilysin, and no measurable
      secretion of the serine proteinases, elastase and cathepsin G. These data
      demonstrate the ability of rat alveolar macrophages to elaborate certain MMPs
      under proinflammatory conditions, consistent with their possible involvement in
      the progression of acute inflammation.

PMID- 10340933
TI  - Role of matrix metalloproteinases in models of macrophage-dependent acute lung
      injury. Evidence for alveolar macrophage as source of proteinases.
AB  - Matrix metalloproteinases (MMPs) have been implicated in the tissue injury seen
      in neutrophil-dependent models of acute lung injury. However, the role of MMPs in
      macrophage-dependent models of lung injury is unknown. To address this issue, the
      macrophage-dependent immunoglobulin A immune complex-induced lung injury model
      and the macrophage-dependent portion of the lipopolysaccharide-induced acute lung
      injury model in the rat were assessed for MMP involvement and for the source of
      these activities. In both models, injury was inhibited by the recombinant human
      tissue inhibitor of metalloproteinases-2. Bronchoalveolar lavage fluids (BALFs)
      from injured animals in both models showed increased levels of MMPs.
      Characterization of MMP production by isolated lung fibroblasts, endothelial
      cells, type II epithelial cells, and alveolar macrophages revealed that only the
      macrophage had the same spectrum of MMP activity as seen in the BALF. Further,
      isolated alveolar macrophages from injured lungs showed evidence of in vivo
      activation with the release of the same spectrum of MMP activities. Together
      these studies show that MMPs are produced during macrophage-dependent lung
      injury, that these MMPs play a role in the development of the lung injury, and
      that the alveolar macrophage is the likely source of these MMPs.

PMID- 10340934
TI  - Early-onset inflammatory responses in vivo to adenoviral vectors in the presence
      or absence of lipopolysaccharide-induced inflammation.
AB  - Adenoviral vectors (Ad) have potential for use in pulmonary gene transfer for
      treating cystic fibrosis (CF). However, Ad may induce inflammation even in the
      absence of gene expression. Endotoxin from gram-negative bacteria in the airways
      of CF patients may also induce inflammation, and may further inhibit vector
      delivery and gene transfer. We used a mouse model to study the time course of Ad
      induced lung inflammation and to assess additivity with lipopolysaccharide (LPS)
      induced inflammatory responses. C3H/HeJ endotoxin-resistant (RES) mice
      hyporesponsive to inflammatory stimuli and normoresponsive C3HeB/FeJ endotoxin
      sensitive (SEN) mice were studied to characterize inflammatory responses that
      follow intratracheal instillation of inactivated Ad, with or without simultaneous
      inhalation exposure to LPS. Instillation of 10(10) Ad particles dramatically
      increased bronchoalveolar lavage fluid (BALF) concentrations of tumor necrosis
      factor (TNF)-alpha and interleukin (IL)-6 at 3 to 6 h and induced profound
      neutrophilia, maximal at 12 to 24 h. SEN mice had tenfold greater responses than
      did RES mice at 6, 12, and 24 h. Mice exposed to Ad alone, LPS alone, or Ad + LPS
      had significant inflammation at the 3-h time point as demonstrated by BALF
      neutrophils, TNF-alpha, and IL-6. With all three treatments, SEN mice had a five-
      to 300-fold greater response than did RES mice. Importantly, Ad + LPS yielded no
      greater inflammatory response than LPS without Ad. These data demonstrate that
      replication-deficient Ad induce early inflammation and LPS-induced inflammation
      is not augmented by concurrent treatment with Ad.

PMID- 10340935
TI  - Allergen-induced changes in bone-marrow progenitor and airway dendritic cells in
      sensitized rats.
AB  - Eosinophilic airway inflammation is orchestrated by T-helper (Th)-2 lymphocytes.
      We have previously demonstrated that dendritic cells (DC) are essential for the
      presentation of antigen to these Th2 cells leading to airway inflammation. Here,
      we have examined the presence of DC in the lungs, the kinetics of appearance, and
      the possible involvement of the bone-marrow progenitor for DC in a rat model of
      ovalbumin (OVA)-induced airway inflammation. Sensitized rats were exposed to 0,
      1, 3, or 7 consecutive daily OVA aerosols. Control rats were sham sensitized
      and/or exposed to phosphate-buffered saline (PBS), and bronchoalveolar lavage
      (BAL) was performed 24 h after the last challenge. DC were identified in BAL
      fluid as low-density, low-autofluorescence, CD3(-), CD45RA-, OX62(+), OX6(+)
      cells that had long surface extensions and strong costimulatory activity. Low but
      detectable amounts of BAL DC were seen in sensitized, unexposed animals. After
      three OVA exposures, the inflammatory infiltrate consisted of CD4(+)-activated T
      cells, eosinophils, and monocytes. The number of BAL DC was significantly
      increased in OVA-sensitized/OVA-exposed animals compared with sham-sensitized or
      PBS-exposed animals. The kinetics of DC increase closely parallelled those in
      other inflammatory cells. Bone-marrow cells taken from the OVA-sensitized and 
      exposed group were grown in the DC growth factor granulocyte macrophage colony
      stimulating factor for 6 d and the yield of OX62(+)OX6(+) DC was 60% higher
      compared with PBS-exposed or sham-sensitized animals. We conclude that allergen
      exposition in sensitized rats increases the number of DC in the airways and the
      production of progenitors for DC in the bone marrow.

PMID- 10340936
TI  - Expression of serotonin receptor 2c in rat type II pneumocytes.
AB  - Serotonin (5-hydroxytryptamine [5-HT]) is a multifunctional amine with wide
      occurrence in both neural and non-neural tissues, including the lung. The diverse
      responses to 5-HT are elicited through activation of different 5-HT receptor
      subtypes. We report the expression and localization of 5-HT receptor 2c subtype
      (5-HT2c-R) in rat lungs using reverse transcriptase-polymerase chain reaction,
      nonisotopic in situ hybridization (NISH), and immunohistochemistry. At the
      messenger RNA (mRNA) level, signal corresponding to approximately 430 base pairs
      was detected in whole-lung tissue extracts as well as in cultures of isolated
      alveolar type II cells from fetal and adult rat lung. Using antisense RNA probe
      for 5-HT2c-R, NISH showed strong positive signal in type II cells. The expression
      of mRNA signal differed between fetal and adult rat type II cells, with weak,
      predominantly perinuclear localization in the former and strong cytoplasmic
      localization in the latter. Immunohistochemistry, using specific monoclonal
      antibody against 5-HT2c-R, showed perinuclear localization in fetal type II
      cells; whereas in adult type II cells 5-HT2c-R immunoreactivity was confined
      mostly to the plasma membrane, as demonstrated by laser confocal microscopy.
      Identification of 5-HT2c-R expression in alveolar type II cells suggests an
      important role for this amine in modulating the function of these cells. The
      differences in cell domain localization between fetal and adult type II cells
      could indicate developmental regulation of 5-HT2c-R expression in the lung.

PMID- 10340937
TI  - Murine submucosal glands are clonally derived and show a cystic fibrosis gene
      dependent distribution pattern.
AB  - Submucosal glands (SMGs) are the major site of expression of the cystic fibrosis
      (CF) transmembrane conductance regulator gene (CFTR) in the human lung. As such,
      SMGs may be a critical component of CF lung disease pathogenesis and an important
      target for gene therapy. Gene-targeted mouse models exist for CF and these are
      used to validate gene therapy or other interventions and to dissect CF
      phenotypes. It is important, therefore, to compare human and mouse SMGs. We show
      that SMGs in the mouse are similar in structure, cell types, and Cftr expression
      to those in the human. Murine SMGs were found to be present in the proximal
      regions of the trachea at the same density as in humans but, unlike in humans,
      did not extend below the trachea. Upon investigation of homozygous Cftr tm1HGU
      and Cftr tm1G551D mutant mice, SMGs were found to extend more distally than those
      in wild-type control mice (P < 0.05). To investigate the development of SMGs we
      generated aggregation chimeric mice. Chimeric offspring contained a contribution
      of transgenic cells that were detectable either by DNA in situ hybridization
      (reiterated beta-globin transgene TgN[Hbb-bl]83Clo) or beta-galactosidase
      histochemistry (Lac Z reporter gene TgR[ROSA26]- 26Sor). Analysis of the
      distribution of transgenic cells in chimeric SMGs suggests that SMGs are clonally
      derived.

PMID- 10340938
TI  - Relaxation of contracted rabbit tracheal and human bronchial smooth muscle by Y
      27632 through inhibition of Ca2+ sensitization.
AB  - The mechanism of Ca2+ sensitization of contraction has not been elucidated in
      airway smooth muscle (SM). To determine the role of a small G protein, rhoA p21,
      and its target protein, rho-associated coiled coil-forming protein kinase (ROCK),
      in receptor-coupled Ca2+ sensitization of airway SM, we studied the effect of (+)
      (R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexane carboxamide dihydrochloride,
      monohydrate (Y-27632), a ROCK inhibitor, on isometric contractions in rabbit
      tracheal and human bronchial SM. Y-27632 completely reversed 1 microM carbachol
      (CCh)-induced contraction of intact trachea with a concentration producing half
      maximum inhibition of effect (IC50) of 1.29 +/- 0.2 microM (n = 5). Although
      4beta-phorbol 12,13-dibutyrate (1 microM)-induced Ca2+ sensitization was
      relatively resistant to Y-27632 in alpha-toxin-permeabilized trachea, CCh (100
      microM) plus guanosine triphosphate (GTP) (3 microM)- and guanosine 5'-O-(3'
      thiotriphosphate) (10 microM)-induced contractions were relaxed completely by Y
      27632 with IC50 of 1.44 +/- 0.3 (n = 6) and 1.15 +/- 0.3 microM (n = 6).
      Endothelin-1 (1 microM) plus GTP (3 microM)- developed force was also reversed by
      Y-27632 with IC50 of 4. 10 +/- 1.1 microM (n = 6) in the alpha-toxin
      permeabilized bronchus. Both the rabbit and human SM expressed rhoA p21, ROCK I,
      and its isoform ROCK II. Collectively, rho/ROCK-mediated Ca2+ sensitization plays
      a central role in the sustained phase of airway SM contraction, and selective
      inhibition of this pathway may become a new strategy to resolve airflow
      limitation in asthma.

PMID- 10340939
TI  - Molecular cloning and expression of rat lung carboxylesterase and its potential
      role in the detoxification of organophosphorus compounds.
AB  - The 1,839-base pair complementary DNA (cDNA) for rat lung carboxylesterase was
      cloned by reverse transcriptase polymerase chain reaction from total rat lung RNA
      using specific primers derived from the 5' and 3' untranslated regions of rat
      hepatic cholesteryl ester hydrolase (CEH). The unique cDNA was sequenced and
      found to be similar to hepatic CEH, pI 6.1 esterase, and hydrolase A. In Northern
      blot analysis, the cDNA hybridized with a single band from lung messenger RNA
      (mRNA). The 1.7-kb coding sequence, predicting a 62-kD protein, was transfected
      into COS-7 cells and Chinese hamster ovary (CHO) cells. Expression in COS-7 and
      CHO cells was accompanied by 4- and 3.2-fold increases in carboxylesterase
      activity (hydrolysis of p-nitrophenyl acetate), respectively. Unlike the hepatic
      CEH, the expressed lung carboxylesterase described here did not hydrolyze
      cholesterol esters. In situ hybridization experiments localized the lung
      carboxylesterase mRNA to the airway epithelium. The organophosphorus compound
      phosphoric acid diethyl 4-nitrophenyl ester, paraoxon, completely inhibited this
      lung carboxylesterase, placing it in the family of B esterases by this criterion.

PMID- 10340940
TI  - Migration of neutrophils across human pulmonary endothelial cells is not blocked
      by matrix metalloproteinase or serine protease inhibitors.
AB  - It has long been speculated that neutrophils deploy proteases to digest
      subendothelial matrix as they migrate from the bloodstream. Direct evidence for
      the involvement of proteases in neutrophil transendothelial migration is,
      however, lacking. To address this issue we used transmission electron microscopy
      to verify the presence of continuous basal lamina beneath pulmonary endothelial
      cells grown on microporous filters, and then examined the effects of protease
      inhibitors on neutrophil migration through the endothelial cells and their
      associated subcellular matrix. Inhibitors of the two major matrix-degrading
      protease groups present in neutrophils, the matrix metalloproteinases (MMPs) and
      serine proteases, were assessed for their ability to modulate neutrophil
      transendothelial migration in response to the chemoattractant n-formylmethionyl
      leucylphenylalanine (FMLP). Neither the naturally occurring MMP inhibitor, tissue
      inhibitor of metalloproteinase-1, nor the hydroxamic acid-based inhibitors GM
      6001, BB-3103, or Ro 31-9790 had any significant effect on FMLP-stimulated
      neutrophil migration across endothelial cells and associated basal lamina, with
      >/= 80% of neutrophils migrating through the system, even in the presence of
      inhibitors, at concentrations that totally inhibited all the gelatinase B (MMP-9)
      released upon stimulation with FMLP. Similarly, with serine protease inhibitors
      no significant inhibition of neutrophil migration was observed with a naturally
      occurring inhibitor, secretory leukocyte protease inhibitor, or a low molecular
      weight synthetic inhibitor, Pefabloc SC. These results indicate that neither MMP
      nor serine protease digestion of sub-endothelial matrix is required for
      successful neutrophil transendothelial migration.

PMID- 10340941
TI  - Rhinovirus replication causes RANTES production in primary bronchial epithelial
      cells.
AB  - The mechanisms by which rhinovirus (RV) infections produce lower airway symptoms
      in asthmatic individuals are not fully established. To determine effects of RV
      infection on lung epithelial cells, primary human bronchial epithelial (BE) cells
      were infected with either RV16 or RV49, and viral replication, cell viability,
      and cell activation were measured. Both viral serotypes replicated in BE cells at
      33 degrees C (DeltaTCID50 / ml = 2 to 2.5 log units) and at 37 degrees C
      (DeltaTCID50 /ml = 1.6 log units), but only high doses of RV49 (10(6) TCID50 /ml)
      caused cytopathic effects and reduced cell viability. In addition, regulated on
      activation, normal T cells expressed and secreted (RANTES) secretion was
      increased in epithelial cells infected with RV16 or RV49 (243 and 398 pg/ml
      versus 13 pg/ml uninfected control cells), and a similar pattern was seen for
      RANTES messenger RNA. RV infection also caused increased secretion of interleukin
      8 and granulocyte macrophage colony-stimulating factor, but did not alter
      expression of either intercellular adhesion molecule-1 or human leukocyte
      associated antigen-DR. These observations suggest that RVs can replicate in lower
      airway cells in vivo, and support epidemiologic studies that link RV with lower
      respiratory illnesses. Further, RV-induced secretion of RANTES and other
      cytokines could trigger antiviral immune responses in vivo, but these effects
      could also contribute to the pathogenesis of respiratory symptoms in subjects
      with asthma.

PMID- 10340942
TI  - Elevation in pulmonary neutrophils and prolonged production of pulmonary
      macrophage inflammatory protein-2 after burn injury with prior alcohol exposure.
AB  - Various studies have shown that alcohol exposure before thermal injury leads to
      increased morbidity and mortality. Pulmonary failure is a major complication seen
      in these patients. This study examines the effects of prior alcohol exposure on
      lung pathology after burn injury. There is a marked increase in neutrophil
      recruitment in the lung after thermal injury, and herein we show that this
      appears to be significantly elevated in animals given alcohol before burn injury.
      Consequently, we chose to determine whether there is a difference in pulmonary
      production of macrophage inflammatory protein (MIP)-2, a potent neutrophil
      chemoattractant, in mice subjected to a 15% total body surface area scald (or
      sham) injury with or without prior ethanol treatment. Lung tissue was obtained at
      various time points after injury and homogenates were assayed for MIP-2 by enzyme
      linked immunosorbent assay. At 2 h after injury, peak levels of the chemokine
      were produced in both burn and burn + alcohol-treated mice. This represents a 7
      fold increase above baseline. In mice exposed to burn injury alone, the level of
      MIP-2 returned to baseline within 8 h. In contrast, mice given alcohol before
      burn injury continued to show elevated levels of the chemokine at 8 h, after
      which MIP-2 decreased. This study may provide a basis for understanding the
      mechanism responsible for the increased neutrophil presence in the lung after
      thermal injury in individuals who have consumed alcohol. Subsequently, this may
      lead to the enhanced neutrophil-mediated pulmonary damage observed in these
      patients.

PMID- 10340943
TI  - Cigarette smoke potentiates house dust mite allergen-induced increase in the
      permeability of human bronchial epithelial cells in vitro.
AB  - Although studies have suggested that exposure to cigarette smoke (CS) may be
      associated with the development of atopy, the mechanisms underlying this are not
      clearly understood. It has been suggested that CS impairs the barrier function of
      the airway epithelium, leading to increased access of allergens such as those of
      the house dust mite (HDM) Dermatophagoides pteronyssinus (Der p) to antigen
      presenting cells, with subsequent allergic sensitization. In order to test this
      hypothesis, we established primary explant cultures of human bronchial epithelial
      cells (HBEC) in cell culture inserts, and exposed these for 20 min, 1 h, 3 h, and
      6 h to CS or air in the absence or presence of 300 ng/ml Der p, and then further
      incubated the cultures over a period of 24 h. The HBEC cultures were assessed for
      changes in permeability as measured by changes in: (1) electrical resistance
      (ER); and (2) passage of 14C-labeled bovine serum albumin (14C-BSA) and Der p
      allergens across the HBEC cultures. We also assessed the effects of protease
      inhibitors and the antioxidant glutathione (GSH) in this experimental system.
      Damage to HBEC cultures was assessed by the release of [51Cr]sodium chromate from
      prelabeled cells, and by release of lactate dehydrogenase (LDH). Twenty minutes
      of exposure to CS as compared with exposure to air did not significantly alter
      either the ER or passage of 14C-BSA across the HBEC cultures. In contrast,
      incubation with Der p led to a significant increase in the permeability of HBEC
      cultures, an effect that was enhanced by exposure to CS but was abrogated by the
      specific protease inhibitors and GSH. Passage of Der p was also increased by
      exposure to CS. Exposure of HBEC cultures to CS led to a significant release of
      51Cr and LDH from these cells as compared with cells exposed to air. This effect
      was augmented further when HBEC cultures were incubated with Der p. Exposure of
      HBEC cultures for 1 h, 3 h, and 6 h to CS led to a markedly significant dose- and
      time-dependent increase in the permeability of these cells. These results suggest
      that exposure to CS significantly enhances Der p-induced decreases in electrical
      resistance and the increased passage across HBEC cultures of 14C-BSA and of the
      Der p allergen itself.

PMID- 10340944
TI  - Characterization of the integrin and activation steps mediating human eosinophil
      and neutrophil adhesion to chronically inflamed airway endothelium.
AB  - We have used the Stamper-Woodruff frozen-section assay (FSA) to characterize the
      integrin and activation steps involved in adhesion of peripheral blood
      eosinophils and neutrophils to nasal polyp endothelium (NPE). Eosinophil and
      neutrophil adhesion was significantly inhibited by monoclonal antibodies (mAbs)
      against CD18 (beta2) and CD11a-c. Eosinophil adhesion was also inhibited to a
      lesser extent by mAbs against CD29 (beta1), CD49d (alpha4), and vascular cell
      adhesion molecule-1. The involvement of integrins raised the possibility of an
      activation step being involved in the adhesion process. Although stimulation of
      the cells with granulocyte macrophage colony-stimulating factor (GM-CSF) before
      the assay failed to modulate adhesion, binding was inhibited by up to 50% by
      treatment of the leukocytes with azide. In addition, neutrophil adhesion was
      completely abrogated by pertussis toxin (PT) and inhibited by about 50% by the
      platelet-activating factor antagonist WEB 2086 and antibodies against interleukin
      (IL)-8 and the two IL-8 receptors IL8RA and IL8RB (C-X-CR1 and -CR2). In
      contrast, eosinophil adhesion was unaffected by PT, WEB 2086, or anti-IL8R mAbs.
      mAbs against CCR-3, IL-3, IL-5, and GM-CSF also had no effect. This study
      demonstrates that eosinophil and neutrophil adhesion to NPE in the FSA conforms
      to the multistep paradigm for leukocyte adhesion and can be used to model the
      molecular basis for adhesion to endothelium in the context of chronic
      inflammatory disease. Using this assay, we have observed significant differences
      in integrin usage between eosinophils and neutrophils and a striking difference
      in the mechanism of integrin activation. These differences could explain, in
      part, the preferential accumulation of eosinophils in diseases such as asthma.

PMID- 10340945
TI  - Ovalbumin (OVA) and Mycobacterium tuberculosis bacilli cooperatively polarize
      anti-OVA T-helper (Th) cells toward a Th1-dominant phenotype and ameliorate
      murine tracheal eosinophilia.
AB  - A recent increase in allergic disorders has coincided with a decrease in
      infections, including tuberculosis. Although an inverse association between
      tuberculin responses and atopic disorders was reported, it was not known how T
      helper (Th)1-biased immune responses to Mycobacterium tuberculosis influenced Th2
      dominant responses to allergens. We examined whether M. tuberculosis could
      modulate ovalbumin (OVA)-induced eosinophilic inflammation in the murine trachea
      in a manner that transcended the barrier of antigen specificity. We found that
      CD4(+) T cells primed with OVA in complete Freund's adjuvant (CFA) inhibited OVA
      induced tracheal eosinophilia through interferon (IFN)-gamma secretion.
      Immunization with an irrelevant antigen in CFA or with OVA in incomplete Freund's
      adjuvant failed to induce suppressor cells. In vitro experiments confirmed that
      both M. tuberculosis and OVA (as opposed to either one alone) were necessary to
      evoke polarized development toward a Th1-like phenotype through interleukin-12
      secretion. These results indicate that exposure to an allergen along with M.
      tuberculosis switches development of allergen-specific T cells toward a Th1
      phenotype, which, in turn, downregulates allergic manifestations in an antigen
      specific manner. The possible implications of these results are discussed in the
      context of the causal relationship between a decrease in tuberculosis and an
      increase in allergic disorders.

PMID- 10340946
TI  - Calcitonin gene-related peptide-immunoreactive nerves and neuroendocrine cells
      after lung transplantation in the rat.
AB  - Bronchial innervation is interrupted at lung transplantation. Nerve fibers with
      cell bodies above the section, such as sensory C fibers, should degenerate. Using
      histofluorescence, we evaluated calcitonin gene-related peptide (CGRP)
      immunoreactivity in syngeneic Lewis rats 1 and 5 mo after unilateral lung
      transplantation and in controls. CGRP-immunoreactive (IR) neuroendocrine cells
      were located within the epithelium of large and small bronchi. At 1 mo after
      transplantation, their number had significantly increased in large bronchi and
      had normalized 5 mo after transplantation. The density of CGRP-IR fibers in
      control lungs gradually decreased from large (0. 35 +/- 0.02 micron/micron basal
      lamina) to small (0.23 +/- 0.02) and peripheral bronchi (0.12 +/- 0.01). At 1 mo
      after lung transplantation, few CGRP-IR fibers were observed in large bronchi
      (0.17 +/- 0.02), fewer in small bronchi (0.04 +/- 0.01) (P < 0.01), and none in
      peripheral bronchi. At 5 mo after lung transplantation, transplanted lungs still
      had fewer CGRP-IR fibers in large (0.22 +/- 0.02) and small (0.11 +/- 0.02)
      bronchi (P < 0.02) than did controls, but there were, nonetheless, more in the
      small bronchi than at 1 mo after transplantation (P < 0.01). Additionally, few
      CGRP fibers were present in the peripheral bronchi (0.03 +/- 0.01) (P < 0.01).
      These results clearly demonstrate the occurrence of denervation followed by
      partial reinnervation with CGRP-IR fibers after transplantation in rat lung.

PMID- 10340947
TI  - In vitro culture of microdissected rat nasal airway tissues.
AB  - The surface epithelium lining the nasal airways is a potential target for inhaled
      contaminants such as ozone, endotoxin, formaldehyde, tobacco smoke, and organic
      dusts. The epithelial response to injury may depend on the toxicant, the type of
      epithelium, the severity of the injury, and the presence of inflammatory cells
      and their secreted products. To study mechanisms of toxicant-induced epithelial
      injury and repair, in the absence of cellular inflammation or other systemic
      effects, we have developed a culture system to maintain morphologically distinct
      nasal airway epithelium in vitro. Microdissected maxilloturbinates and proximal
      nasal septa of male F344/N rats were cultured at an air-liquid interface for up
      to 14 d in supplemented serum-free medium. Maxilloturbinates are lined by
      nonciliated cuboidal nasal transitional epithelium (NTE) with few or no mucous
      cells. The proximal nasal septum is lined by a mucociliary respiratory epithelium
      (RE) that normally contains numerous mucous cells. Preservation of the normal RE
      and NTE phenotype in culture was assessed by light and electron microscopy, and
      analysis of an airway mucin gene (rMuc-5AC) messenger RNA (mRNA). Both RE and NTE
      retained normal cell morphology for 14 d in culture (DIC). After 14 DIC there
      were 20% fewer RE cells in the septa (equal loss of ciliated and mucous cells)
      and 25% more NTE cells in the maxilloturbinates (increased number of basal
      cells). Compared with the RE, the NTE expressed consistently low levels of rMuc
      5AC mRNA and had little to no histochemically detectable intraepithelial
      mucosubstances (IM) after 0, 3, 7, or 14 DIC. The amount of stored IM and the
      steady-state levels of rMuc-5AC mRNA in the RE decreased with time in culture. In
      summary, this culture system can maintain fully differentiated secretory and
      nonsecretory rat airway epithelia in vitro for up to 14 d. This study was an
      essential first step in developing a system to study the pathogenesis of toxicant
      induced airway epithelial injury and mechanisms of cellular repair and adaptation
      in the absence of cellular inflammation and other systemic influences.

PMID- 10340948
TI  - Oxidative stress produced by marijuana smoke. An adverse effect enhanced by
      cannabinoids.
AB  - Marijuana (MJ) smoking produces inflammation, edema, and cell injury in the
      tracheobronchial mucosa of smokers and may be a risk factor for lung cancer.
      Because oxidative stress may mediate some of these effects, this study was
      designed to test the hypothesis that cannabinoids in MJ smoke contribute to
      cellular oxidative stress. Oxidative stress was evaluated in an endothelial cell
      line (ECV 304) following exposure to smoke produced from MJ cigarettes containing
      either 0, 1.77, or 3.95% Delta9-tetrahydrocannabinol (Delta9-THC). Brief exposure
      to smoke from 3.95% MJ cigarettes stimulated the formation of reactive oxygen
      species (ROS) by 80% over control levels and lowered intracellular glutathione
      levels by 81%. Smoke-induced ROS generation increased in a dose- and time
      dependent manner. In contrast, exposure to smoke from MJ containing 0% Delta9-THC
      produced no increase in ROS despite a 70% decline in glutathione levels. Smoke
      from MJ containing 1.77% Delta9-THC stimulated intermediate levels of ROS. A
      brief, 30-min exposure to MJ smoke, regardless of the Delta9-THC content, also
      induced necrotic cell death that increased steadily up to 48 h of observation. MJ
      smoke passed through a Cambridge filter that removed particulate matter was 3.4
      fold more active in ROS production compared with unfiltered smoke, suggesting
      that most of the oxidative effects are produced by the gaseous phase. Alveolar
      macrophages obtained from habitual MJ smokers displayed low levels of glutathione
      compared with macrophages from nonsmokers. We conclude that MJ smoke containing
      Delta9-THC is a potent source of cellular oxidative stress that could contribute
      significantly to cell injury and dysfunction in the lungs of smokers.

PMID- 10340949
TI  - Platelet-derived growth factor stimulation of mitogen-activated protein kinases
      and cyclin D1 promoter activity in cultured airway smooth-muscle cells. Role of
      Ras.
AB  - We hypothesized that in bovine tracheal myocytes, growth factor treatment induces
      transcription from the cyclin D1 promoter that is dependent on the activation of
      both Ras and extracellular signal-related kinase (ERK). We found that platelet
      derived growth factor (PDGF) treatment induced substantial activation of ERK2
      that was blocked by expression of a dominant-negative Ha-Ras. Further, expression
      of a constitutively active Ha-Ras induced substantial ERK2 activity, consistent
      with the notion that Ras is required and sufficient for ERK activation. PDGF
      treatment induced only modest activation of the Jun amino terminal kinase-1
      (JNK1) and p38 mitogen-activated protein kinases (MAPKs). Active Ras induced
      similar responses, implying that complete activation of the JNK and p38 pathways
      requires additional or alternative upstream signaling intermediates besides Ras.
      In contrast, expression of a constitutively active Rac1, an alternative guanosine
      triphosphatase involved in intracellular signaling, produced a high level of JNK1
      activation, suggesting that Rac1 is an important upstream activator of JNK in
      this system. Active Ras and MAPK/ ERK kinase-1 (MEK1) (the upstream activator of
      ERK) each induced cyclin D1 promoter activity, whereas active stress-activated
      protein kinase/ERK kinase-1 (SEK1), an upstream activator of JNK, did not.
      Finally, the synthetic MEK inhibitor PD98059 blocked Ras-induced cyclin D1
      promoter activity. Together, these data suggest that in bovine tracheal myocytes:
      (1) activation of MAPK by PDGF is dependent on Ras; (2) active Ras is sufficient
      for ERK activation but is insufficient for maximal activation of JNK or p38; (3)
      activation of Rac1 is sufficient for maximal JNK activation; and (4) Ras, MEK,
      and ERK constitute a distinct pathway to cyclin D1 transcriptional activation.

PMID- 10340950
TI  - Neutrophil emigration in the lungs, peritoneum, and skin does not require
      gelatinase B.
AB  - Polymorphonuclear leukocytes (PMN) release gelatinase B in response to variable
      stimuli. Gelatinase B degrades basement membrane components in vitro, and
      inhibition of matrix metalloproteinase activity blunts PMN migration through a
      prototype basement membrane (Matrigel) and amnionic membranes. Accordingly, it
      has been speculated that gelatinase B is necessary for PMN emigration. To test
      this hypothesis we induced acute inflammation in the lungs, peritoneum, and skin
      in mice with a null mutation of the gelatinase B gene (gelatinase B-/-) and
      littermate controls (gelatinase B+/+). At 3, 6, 12, and 24 h after intratracheal
      instillation of LPS, the emigration of PMN in the lung, as determined by PMN in
      bronchoalveolar lavage fluid, was similar in gelatinase B-/- and gelatinase B+/+
      mice. The number of PMN in the peritoneal cavity 4 h after thioglycollate-induced
      peritonitis was also comparable in gelatinase B-/- and gelatinase B+/+ mice. At 4
      h after an intradermal injection of interleukin-8, numerous PMN were present
      extravascularly in the dermis in both gelatinase B-/- and gelatinase B+/+ mice
      and the myeloperoxidase activities of the skin at the injection sites were
      indistinguishable between the two types of mice. PMN from gelatinase B-/- mice
      migrated through Matrigel in response to zymosan-activated serum with the same
      efficiency as did PMN from gelatinase B+/+ mice. In vitro, gelatinase B-/- PMN
      killed Staphylococcus aureus and Klebsiella pneumoniae as effectively as did PMN
      from gelatinase B+/+ mice. These findings indicate that gelatinase B is not
      required for PMN emigration, and suggest that the antibacterial function of PMN
      is preserved despite gelatinase B deficiency.

PMID- 10340951
TI  - 1,1-Dichloroethylene-induced Clara cell damage is associated with in situ
      formation of the reactive epoxide. Immunohistochemical detection of its
      glutathione conjugate.
AB  - Pulmonary Clara cells are selectively damaged in mice given 1, 1-dichloroethylene
      (DCE), a chemical used in the plastics industry. The cytotoxicity is attributed
      to formation of a reactive metabolite believed to be the DCE-epoxide, which was
      detected in vitro. We have undertaken in vivo studies to test the hypothesis that
      in situ formation of the DCE-epoxide within Clara cells mediates the cell
      specific injury manifested after DCE exposure. Formation of the epoxide was
      estimated by trapping of the metabolite with glutathione (GSH) and identifying
      the conjugated products as 2-(S-glutathionyl) acetyl glutathione ([B]) and 2-S
      glutathionyl acetate ([C]). High-pressure liquid chromatographic analyses showed
      that conjugates [B] and [C] were both detected in lung cytosol isolated from mice
      treated in vivo with [14C]DCE. Epoxide levels in the cytosol, as estimated by the
      total amount of conjugates formed, were dose-dependent at DCE doses ranging from
      25 to 225 mg/kg. Pretreatment of mice with buthionine sulfoximine (BSO) decreased
      sulfhydryl levels and significantly inhibited the formation of the GSH
      conjugates. Epoxide levels were also reduced by pretreatment with diallyl sulfone
      (DASO2), an inhibitor of the P450 isozyme CYP2E1. A polyclonal antibody was
      developed that is specific for conjugate [C] and that recognizes an antigen
      consisting of the conjugate epoxide-GSH-glutaraldehyde-bovine serum albumin.
      Immunohistochemical studies with this antibody revealed staining in Clara cells
      of mice treated with DCE. Staining was also present in Clara cells of mice
      treated with both BSO and DCE, but at slightly reduced levels. Reduction of this
      staining was more pronounced in Clara cells of mice treated with both DASO2 and
      DCE. These results show that the DCE-epoxide is formed in vivo, is localized in
      Clara cells, and correlates with the cytotoxicity manifested in this cell type.

PMID- 10340952
TI  - Expression of nerve growth factor-induced clone B subfamily and pro
      opiomelanocortin gene in lung cancer cell lines.
AB  - Nerve growth factor-induced clone B (NGFI-B), Nur-related factor 1, and neuron
      derived orphan receptor-1 have structural features of ligand-activated
      transcriptional regulators and constitute the NGFI-B subfamily within the nuclear
      receptor superfamily. The NGFI-B subfamily is highly expressed in neuroendocrine
      organs and regulates the pro-opiomelanocortin (POMC) gene. Small-cell lung cancer
      (SCLC) is considered to be a neuroendocrine tumor that produces large numbers of
      polypeptide hormones. In this study we measured the NGFI-B subfamily and POMC
      messenger RNA (mRNA) levels in various lung-cancer cell lines by means of the
      quantitative reverse transcription-polymerase chain reaction, and evaluated the
      correlations between expression of these genes and polypeptide hormone
      productions. We also examined the effect of antisense oligonucleotide to NGFI-B
      mRNA on the expression of POMC mRNA. The NGFI-B subfamily and POMC mRNAs were
      highly expressed in SCLC cell lines. In addition, there were strong correlations
      between the NGFI-B, POMC genes, and the adrenocorticotropin hormone (ACTH) level.
      Further, the antisense oligonucleotide significantly suppressed POMC gene
      expression. We conclude that the NGFI-B subfamily was a significant molecule in
      SCLC and that the NGFI-B was a positive transcriptional factor for ACTH
      production.

PMID- 10340953
TI  - Dissociation of airway hyperresponsiveness from immunoglobulin E and airway
      eosinophilia in a murine model of allergic asthma.
AB  - Nonspecific airway hyperresponsiveness (AHR) is a hallmark of human asthma. Both
      airway eosinophilia and high serum levels of total and antigen-specific
      immunoglobulin E (IgE) are associated with AHR. It is unclear, however, whether
      either eosinophilia or increased IgE levels contribute directly to, or predict,
      the development of AHR. Investigations conducted with various murine models of
      asthma and different mouse strains have resulted in conflicting evidence about
      the roles that IgE and airway eosinophilia play in the manifestation of AHR. We
      show that systemic priming with ovalbumin (OVA) in alum, followed by a single day
      of OVA aerosol challenge, is sufficient to induce AHR, as measured by increased
      pulmonary resistance in response to intravenously delivered methacholine in
      BALB/c, but not C57BL/6 or B6D2F1, mice. This was observed despite the fact that
      OVA-challenged BALB/c mice had less airway eosinophilia and smaller increases in
      total IgE than either C57BL/6 or B6D2F1 mice, and had less pulmonary inflammation
      and OVA-specific IgE than B6D2F1 mice. We conclude that airway eosinophilia,
      pulmonary inflammation, and high serum levels of total or OVA-specific IgE are
      all insufficient to induce AHR in C57BL/6 and B6D2F1 mice, whereas BALB/c mice
      demonstrate AHR in the absence of airway eosinophilia. These data confirm that
      the development of AHR is genetically determined, not only in naive mice, but
      also in actively immunized ones, and cannot be predicted by levels of airway
      eosinophilia, pulmonary inflammation, total IgE, or antigen-specific IgE.

PMID- 10340955
TI  - An unusual cause of back pain in osteoporosis: lessons from a spinal lesion.

PMID- 10340954
TI  - How should we manage fibromyalgia?

PMID- 10340956
TI  - Getting to the heart of the matter.

PMID- 10340957
TI  - Biopsy proven and biopsy negative temporal arteritis: differences in clinical
      spectrum at the onset of the disease. Groupe de Recherche sur l'Arterite a
      Cellules Geantes.
AB  - OBJECTIVES: To assess the clinical features of biopsy proven and negative biopsy
      temporal arteritis at the time of diagnosis and during a three year follow up.
      METHODS: Newly diagnosed cases of giant cell arteritis were included in a
      prospective, multicentre study. Initial clinical and biological features, season
      of diagnosis, and cardiovascular events occurring during the follow up were
      recorded. Biopsy proven and negative biopsy cases were compared. RESULTS: Two
      hundred and seven biopsy proven, and 85 negative biopsy cases were included from
      1991 to 1997. Fifty eight per cent of the biopsy proven cases, compared with
      39.29% of the negative biopsy cases, were diagnosed during the autumn or winter
      (p = 0.003). Visual problems (31.5%, v 19.1%, p = 0.031), blindness (9.7% v
      2.38%, p = 0.033), jaw claudication (40.8%, v 28.243%, p = 0.044), and temporal
      artery palpation abnormalities (61.3% v 29.5%, p = 7.10(-7)) were more frequent
      in the biopsy proven than in the negative biopsy group. Less specific symptoms,
      such as headache (82.5% v 92. 9%, p = 0.021), or associated polymyalgia
      rheumatica (40.1% v 65.9%, p = 9 x 10(-5)) were more prevalent in the negative
      biopsy cases. Biological markers of inflammation were significantly more
      increased in the biopsy proven group. All cases of blindness occurring after
      treatment belonged to the biopsy proven group. CONCLUSION: Biopsy proven cases
      seem to be more severe than biopsy negative cases at the time of diagnosis and
      during follow up. Seasonal difference at diagnosis may suggest a different
      aetiological pattern.

PMID- 10340958
TI  - Intra-articular primatised anti-CD4: efficacy in resistant rheumatoid knees. A
      study of combined arthroscopy, magnetic resonance imaging, and histology.
AB  - OBJECTIVES: CD4+ T cells sustain the chronic synovial inflammatory response in
      rheumatoid arthritis (RA). SB-210396/CE 9.1 is an anti-CD4 monoclonal antibody
      that has documented efficacy in RA when given intravenously. This study aimed to
      establish the safety and efficacy of the intra-articular administration of SB
      210396/CE 9.1 compared with placebo, examining its mode of action using a
      combined imaging approach of arthroscopy, magnetic resonance imaging (MRI), and
      histology. METHODS: Thirteen RA patients with active, resistant knee synovitis,
      were randomised to intra-articular injection of placebo (n=3), 0.4 mg (n=3) or 40
      mg (n=7) of anti-CD4 after sequential dynamic gadolinium enhanced MRI, followed
      by same day arthroscopy and synovial membrane biopsy. Imaging and arthroscopic
      synovial membrane sampling were repeated at six weeks. This study used a unique
      region of interest (ROI) analysis mapping the MRI area analysed to the specific
      biopsy site identified arthroscopically, thus providing data for all three
      modalities at the same synovial membrane site. RESULTS: 12 patients completed the
      study (one placebo treated patient refused further MRI). Arthroscopic improvement
      was observed in 0 of 2 placebo patients but in 10 of 10 patients receiving active
      drug (>20% in 6 of 10). Improvement in MRI was consistently observed in all
      patients of the 40 mg group but not in the other two groups. A reduction in SM
      CD4+ score was noted in the 40 mg group and in the 0.4 mg group. Strong
      correlations both before and after treatment, were identified between the three
      imaging modalities. Intra-articular delivery of SB-210396/CE 9.1 was well
      tolerated. CONCLUSIONS: SB-210396/CE 9.1 is safe when administered by intra
      articular injection. A trend toward efficacy was found by coordinated MRI,
      arthroscopic, and histological imaging, not seen in the placebo group. The value
      of ROI analysis was demonstrated.

PMID- 10340959
TI  - Increased vulnerability of postarthritic cartilage to a second arthritic insult:
      accelerated MMP activity in a flare up of arthritis.
AB  - OBJECTIVE: Murine antigen induced arthritis (AIA) is a chronic, smouldering
      inflammation. Flares of arthritis can be induced by antigen rechallenge or
      exposure to inflammatory mediators like interleukin 1 (IL1). These flares are
      characterised by a fast and marked proteoglycan (PG) depletion if compared with
      the initial arthritis. This study investigated the involvement of
      metalloproteinases in both the initial and the flare phase of arthritis. METHODS:
      Murine AIA was induced and a flare up of arthritis was induced by injection of 10
      ng of IL1beta. Messenger RNA levels of MMP-1 and -3 were studied by RT-PCR. MMP
      activity in cartilage, during both primary AIA as well as the flare up of
      arthritis, was studied by immunodetection of MMP specific neoepitopes in aggrecan
      (VDIPEN). Cartilage just before flare induction was analysed for presence of MMPs
      at the mRNA level as well as at the protein level by zymography. RESULTS: At the
      onset of AIA, a fast upregulation of mRNA for stromelysin and collagenase was
      noted. However, no VDIPEN epitopes were detected during this early phase of
      arthritis. They appeared when PG depletion was severe at day 7 of arthritis and
      disappeared when cartilage was repaired. IL1 injection into a knee joint at week
      4 of AIA caused a flare up of arthritis, coinciding with a fast and marked PG
      degradation. This degradation was characterised by accelerated expression of
      VDIPEN epitopes if compared with the expression in primary AIA. Analysis of
      cartilage at week 4 of AIA showed still increased mRNA levels of MMP-1 and -3.
      Moreover, increased levels of latent MMPs were present as well, as APMA
      activation induced profound VDIPEN epitope. In vitro exposure to IL1 did show
      increased PG breakdown but no VDIPEN expression, suggesting that factors in
      addition to IL1 are needed to cause the in vivo VDIPEN expression. CONCLUSIONS:
      The fast and marked PG depletion seen in a flare up of AIA coincides with
      accelarated expression of MMP induced neoepitopes compared with expression during
      primary AIA. This accelerated expression is probably linked to increased levels
      of latent enzyme, which were found to be present in the cartilage before
      induction of a flare up.

PMID- 10340960
TI  - In situ zymographic localisation of type II collagen degrading activity in
      osteoarthritic human articular cartilage.
AB  - OBJECTIVES: Chondrocytic matrix metalloproteinases (MMPs) are believed to be
      important in osteoarthritic cartilage degradation. The cartilage lesion of
      osteoarthritis (OA) is focal and often progressive. During its development
      chondrocytes differentially up and down regulate production of mRNA for
      individual MMPs. This observation has potential implications for understanding
      the disease processes that lead to progressive cartilage loss in OA and designing
      appropriate targeted treatment. The complex regulation of MMP mediated effects
      means there is a pressing need to establish whether visualisation of MMP mRNA or
      protein equates to enzyme activity. The technique of in situ zymography (ISZ)
      offers a way of examining diseased human tissue for in vivo production of an
      excess of degrading enzyme over inhibitor. The primary objective of this study
      was to assess, and if positive follow, collagen II degrading activity in
      cartilage during development of the OA lesion. A secondary objective was to
      assess whether there was any correlation between sites of collagen II degrading
      activity and expression of the collagenase (MMP-13), recently implicated in type
      II collagen degredation in this lesion. METHODS: Biopsied human normal and
      osteoarthritic cartilage, showing various degrees of damage, was examined by in
      situ zymography, with and without enzyme inhibitors, to establish sites of type
      II collagenase activity. Paired samples were probed for MMP-13 mRNA using 35S
      labelled oligonucleotide probes. Comparative analyses were performed. RESULTS: In
      situ zymography showed collagen II degrading activity over chondrocytes only in
      osteoarthritic cartilage. Distribution and amount varied with the extent of
      cartilage damage and position of chondrocytes, being greatest in deep cartilage
      and in cartilage lesions where fissuring was occurring. The enzyme causing the
      degradation behaved as a matrix metalloproteinase. MMP-13 mRNA expression
      codistributed with the type II collagenase activity. CONCLUSION: In OA,
      chondrocytes can degrade type II collagen. The type II collagen degrading
      activity varies in site and amount as the cartilage lesion progresses and
      throughout codistributes with MMP-13 mRNA expression.

PMID- 10340961
TI  - Effects of anti-rheumatic herbal medicines on cellular adhesion molecules.
AB  - OBJECTIVE: To test the hypothesis whether herbal medicines ameliorate
      inflammatory diseases via the modulation of cellular adhesion molecules (CAMs).
      METHODS: Human neutrophils, synovial fibroblasts, and endothelial cells were
      incubated with different concentrations of Tripterygium Wilfordii Hook-f (TWH-f)
      or Tetrandrine in the presence or absence of interleukin 1 (IL1). The amount of
      soluble E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular
      cellular adhesion molecule-1 (VCAM-1) secreted by cells were determined by ELISA.
      The cell surface expression of these three CAMs was detected by flow cytometry.
      RESULTS: TWH-f at high concentration (50 ng/ml) has a significant (p<0.05)
      inhibitory effect on both the secretion and the expression of the cellular
      adhesion molecules. However, Tetrandrine did not demonstrate the same effects.
      CONCLUSIONS: The cellular adhesion molecules of the endothelium and leucocytes
      may constitute excellent targets for the development of new anti-inflammation
      medicines. These results indicate that TWH could be a potential therapeutic agent
      in the treatment of inflammatory diseases.

PMID- 10340962
TI  - Autocrine control of vitamin D metabolism in synovial cells from arthritic
      patients.
AB  - OBJECTIVE: This study was designed to investigate whether 1, 25-dihydroxyvitamin
      D3 (1,25-(OH)2D3), produced by activated synovial fluid macrophages, promotes its
      own catabolism by upregulating vitamin D-24-hydroxylase (24-OHase) in synovial
      fibroblasts through a vitamin D receptor (VDR) mediated mechanism. METHODS:
      Synovial macrophages and fibroblasts were derived from patients with rheumatoid
      arthritis. Expression of VDR and 24-OHase mRNAs was determined using in situ
      hybridisation. Vitamin D hydroxylase activity was determined by incubating cells
      with [3H]-25-(OH)D3, or [3H]-1,25-(OH)2D3, and metabolite synthesis quantified
      using high performance liquid chromatography. RESULTS: 1, 25-(OH)2D3 increased
      expression of mRNA for both VDR and 24-OHase in fibroblasts by approximately
      threefold over 24 hours. 1,25-(OH)2D3 increased fibroblast 24-OHase activity,
      yielding 24-hydroxylated, and more polar, metabolites. In co-culture, fibroblasts
      were able to catabolise macrophage derived 1,25-(OH)2D3. CONCLUSIONS: 1, 25
      (OH)2D3 is produced by macrophages in vitro at biologically relevant
      concentrations and can increase its own catabolism by synovial fibroblasts; this
      effect is probably mediated via upregulation of both synovial fibroblast VDR and
      24-OHase.

PMID- 10340963
TI  - Factors associated with fatigue in patients with systemic lupus erythematosus.
AB  - OBJECTIVE: To examine the relation between fatigue, disease activity, damage, and
      quality of life measures in patients with systemic lupus erythematosus (SLE).
      METHODS: Consecutive patients attending the University of Toronto Lupus Clinic
      were studied. Disease activity was assessed using the SLEDAI and SLAM-R and
      damage using the SLICC/ACR Damage index. Fatigue was measured by the Fatigue
      Severity Score (FSS) and health status by the SF-36 questionnaire. In all cases a
      tender point count was also performed. RESULTS: 81 patients were studied. Their
      mean (SD) age and disease duration were 43 (12.5) years and 12.7 (8.0) years
      respectively. The FSS did not correlate with the SLEDAI nor with the SLAM-R.
      There was no correlation with the SLICC damage index. Fatigue severity correlated
      with the tender point count (SCC r=0.46, p<0.001), and negatively with all
      domains of the SF36 (r values -0.50 to -0.82). Disease activity and damage
      accounted for only 4.8% and 4% respectively of the variance in fatigue severity
      reported by patients. CONCLUSION: In an outpatient population of SLE patients,
      fatigue severity correlates with poor health status and a higher tender point
      count. In patients with SLE, factors associated with quality of life and
      fibromyalgia seem to have a greater influence on the severity of reported fatigue
      than does the level of current disease activity.

PMID- 10340964
TI  - Expression of mitogen activated protein kinases in labial salivary glands of
      patients with Sjogren's syndrome.
AB  - OBJECTIVE: The expression of CD40 and CD40 ligand (CD40L) in mononuclear cells
      (MNCs) infiltrating the salivary glands of patients with Sjogren's syndrome (SS)
      has recently been reported. This study determined the expression of mitogen
      activated protein kinase (MAP kinase) superfamilies, which act as downstream
      effector molecules of CD40, in MNCs infiltrating labial salivary tissues in SS
      patients. METHODS: Six HTLV-I seronegative SS patients and 10 HTLV-I seropositive
      patients including five HTLV-I associated myelopathy (HAM) patients were
      examined. The expression of MAP kinase superfamilies in labial salivary glands
      was examined by immunohistochemistry containing the mirror section technique.
      RESULTS: Both active forms of c-Jun N-terminal kinase (JNK) and p38 were found in
      salivary infiltrating MNCs of SS patients. Only minimal expression of the active
      form of extracellular signal regulated kinase (ERK) was observed in these
      tissues, however, co-expression of active JNK and active p38 was confirmed by the
      mirror section technique. Furthermore, these protein kinases were co-expressed in
      CD40(+) MNCs. No difference in expression levels of active JNK and p38 was found
      in patients who were positive or negative for anti-HTLV-I antibody. CONCLUSION:
      These results indicate that JNK and p38, but not ERK, function as downstream
      effector molecules of CD40 in salivary infiltrating MNCs in SS patients, and
      suggest that these molecules may be involved in the pathological process of
      chronic sialadenitis in SS.

PMID- 10340965
TI  - Bias: adding to the uncertainty.

PMID- 10340966
TI  - Science! Why should the clinician care?

PMID- 10340967
TI  - Posterior capsular opacification prevention: IOL design and material.

PMID- 10340968
TI  - Bias due to incomplete follow up in a cohort study.
AB  - AIM: To investigate the bias introduced by incomplete follow up in a cohort study
      of ocular outcome after premature birth. METHODS: A geographically defined cohort
      of children born before 32 weeks' gestation was prospectively recruited at birth
      to study the ocular outcome at 2 years. On the basis of attendance at 2 years,
      the children's families were allocated to one of three groups: group 1 attended
      for follow up, group 2 were difficult to trace, and group 3 were very reluctant
      for assessment. All children were examined by a single ophthalmologist, masked to
      these groupings. RESULTS: 558 children (98.8% of study group) were examined, of
      whom 505 were in group 1, 20 in group 2, and 33 in group 3. The groups which were
      more difficult to study (groups 2 and 3) showed a significantly higher prevalence
      of ocular abnormalities, including strabismus (p=0. 02) and cicatricial
      retinopathy of prematurity (p=0.002) compared with those attending for follow up.
      Further, not all of these cases could have been identified by review of the
      children's previous records. Ocular abnormalities would be underestimated by 16%
      (11.3% in group 1 compared with 13.4% in the total cohort, p=0.77). CONCLUSIONS:
      This study suggests that the prevalence of abnormalities would be underestimated
      by incomplete follow up, as those subjects who were most difficult to obtain for
      study had a significantly higher prevalence of abnormalities.

PMID- 10340969
TI  - Radiotherapy for isolated occult subfoveal neovascularisation in age related
      macular degeneration: a pilot study.
AB  - BACKGROUND/AIMS: Teletherapy has been proposed as a possible treatment for
      choroidal neovascular membranes (CNV), secondary to age related macular
      degeneration (AMD) not amenable to laser photocoagulation. The aim of this
      prospective study has been to investigate the effect of teletherapy on isolated
      occult choroidal neovascular membranes of subfoveal location. METHODS: 28 AMD
      patients presenting with retrofoveal isolated occult CNV demonstrated by
      fluorescein angiography were treated by external beam radiation. A complete
      ophthalmological examination, fluorescein angiography, and indocyanine green
      angiography (ICG) were performed within 15 days before treatment and repeated at
      follow up. A total dose of 16 Gy was applied in four sessions of 4 Gy using a 4
      MeV photon beam. Follow up ranged from 6 to 9 months (mean follow up 6.4 months).
      RESULTS: Visual acuity was found to be stable in 68% of the cases. The decrease
      in visual acuity was of 3-6 lines in 18% and of more than 6 lines in 10% of the
      eyes at last examination. On fluorescein angiography the size of the lesion area
      was found to be stable in 67%, decreased in 13%, and increased in 20% of the
      cases. On ICG angiography the size of the CNV was stable in 93% and increased in
      7% of the cases. All the eyes experiencing a visual acuity decrease showed either
      no change or an increase in size of the membrane on fluorescein angiography
      and/or on ICG. CONCLUSION: According to this study with strict inclusion
      criteria, external beam radiotherapy seems to have a beneficial effect on the
      evolution of isolated occult subfoveal CNV.

PMID- 10340970
TI  - Cytomegalovirus retinitis after the initiation of highly active antiretroviral
      therapy: a 2 year prospective study.
AB  - BACKGROUND/AIMS: There have been several recent reports suggesting that the
      natural history of cytomegalovirus retinitis (CMVR) has been significantly
      modified with the development of highly active antiretroviral therapy (HAART).
      This 2 year prospective cohort study assesses the effect of HAART on the
      incidence and progression of CMV retinitis in patients with CD4 cell counts below
      50 cells x10(6)/l. METHODS: 63 patients, with CD4 cell counts below 50 cells
      x10(6)/l, who were recruited to a 2 year prospective cohort study at the
      commencement of combination antiretroviral therapy including the use of the
      proteinase inhibitor, indinavir, were reported. The response to HAART was
      assessed in terms of a rise in the CD4 cell count and fall in HIV viral load. An
      experienced ophthalmologist performed dilated funduscopy at the time of
      recruitment and thereafter at 2 weekly intervals and retinal photography was
      performed at monthly intervals in patients with CMVR. The activity and
      progression of CMV retinitis was assessed on the basis of the characteristic
      clinical and photographic findings. RESULTS: 34 patients achieved at least 50 CD4
      cells x10(6)/l at 3 months after initiation of therapy. New diagnoses of CMVR
      were seen only in the non-responder group (p=0. 085). Overall, the relative risk
      of a new retinitis event in this group was 3.52 (95% CI 1.16, 10.68) at 3 months
      compared with those patients who were responsive to HAART. 12 of the 63 patients
      had previous CMVR. Disease progression was associated with non-response to
      therapy (p=0.182 exact). In patients with CMVR the median time to first
      progression was 18 days (95% CI 8, 91) in non-responders and 121 days (95% CI
      0.59, 3.65) in responders. By the end of the 2 year follow up period all
      surviving patients had >50 CD4 cells x10(6)/l. No CMV events were seen after 8
      months of therapy in either group of patients. CONCLUSIONS: These findings
      suggest that significant clinical immunorestoration to CMV occurs in response to
      HAART in patients with CMVR after a lag time of 3-8 months. Initially, a rise in
      CD4 count is predictive of CMVR response but after the lag period all survivors
      appear to have developed a clinical immunorestoration to CMV. If HAART is
      commenced in at risk patients before the development of CMVR the incidence of new
      disease falls significantly.

PMID- 10340971
TI  - Image quality in polypseudophakia for extremely short eyes.
AB  - AIM: To evaluate the image quality produced by polypseudophakia used for strongly
      hypermetropic and nanophthalmic eyes. METHODS: Primary aberration theory and ray
      tracing analysis were used to calculate the optimum lens shapes and power
      distribution between the two intraocular lenses for two example eyes: one a
      strongly hypermetropic eye, the other a nanophthalmic eye. Spherical aberration
      and oblique astigmatism were considered. Modulation transfer function (MTF)
      curves were computed using commercial optical design software (Sigma 2100, Kidger
      Optics Ltd) to assess axial image quality, and the sagittal and tangential image
      surfaces were computed to study image quality across the field. RESULTS: A
      significant improvement in the axial MTF was found for the eyes with double
      implants. However, results indicate that this may be realised as a better
      contrast sensitivity in the low to mid spatial frequency range rather than as a
      better Snellen acuity. The optimum lens shapes for minimum spherical aberration
      (best axial image quality) were approximately convex-plano for both lenses with
      the convex surface facing the cornea. Conversely, the optimum lens shapes for
      zero oblique astigmatism were strongly meniscus with the anterior surface
      concave. Correction of oblique astigmatism was only achieved with a loss in axial
      performance. CONCLUSIONS: Optimum estimated visual acuity exceeds 6/5 in both the
      hypermetropic and the nanophthalmic eyes studied (pupil size of 4 mm) with
      polypseudophakic correction. These results can be attained using convex-plano or
      biconvex lenses with the most convex surface facing the cornea. If the posterior
      surface of the posterior intraocular lens is convex, as is commonly used to help
      prevent migration of lens epithelial cells causing posterior capsular
      opacification (PCO), then it is still possible to achieve 6/4.5 in the
      hypermetropic eye and 6/5.3 in the nanophthalmic eye provided the anterior
      intraocular lens has an approximately convex-plano shape with the convex surface
      anterior. It was therefore concluded that consideration of optical image quality
      does not demand that additional intraocular lens shapes need to be manufactured
      for polypseudophakic correction of extremely short eyes and that implanting the
      posterior intraocular lens in the conventional orientation to help prevent PCO
      does not necessarily limit estimated visual acuity.

PMID- 10340972
TI  - Inter- and intraobserver variation in the analysis of optic disc images:
      comparison of the Heidelberg retina tomograph and computer assisted planimetry.
AB  - AIMS: The development of imaging and measurement techniques has brought the
      prospect of greater objectivity in the measurement of optic disc features, and
      therefore better agreement between observers. The purpose of this study was to
      quantify and compare the variation between observers using two measurement
      devices. METHODS: Optic disc photographs and images from the Heidelberg retina
      tomograph (HRT) of 30 eyes of 30 subjects were presented to six observers for
      analysis, and to one observer on five separate occasions. Agreement between
      observers was studied by comparing the analysis of each observer with the median
      result of the other five, and expressed as the mean difference and standard
      deviation of differences between the observer and the median. Inter- and
      intraobserver variation was calculated as a coefficient of variation (mean
      SD/mean x 100). RESULTS: For planimetry, agreement between observers was
      dependent on observer experience, for the HRT it was independent. Agreement
      between observers (SD of differences as a percentage of the median) for optic
      disc area was 4.0% to 7.2% (planimetry) and 3.3% to 6.0% (HRT), for neuroretinal
      rim area it was 10.8% to 21.0% (planimetry) and 5.2% to 9.6% (HRT). The mean
      interobserver coefficient of variation for optic disc area was 8.1% (planimetry)
      and 4.4% (HRT), for neuroretinal rim area it was 16.3% (planimetry) and 8.1%
      (HRT), and (HRT only) for rim volume was 16.3%, and reference height 9.1%. HRT
      variability was greater for the software version 1.11 reference plane than for
      version 1.10. The intraobserver coefficient of variation for optic disc area was
      1.5% (planimetry) and 2.4% (HRT), for neuroretinal rim area it was 4.0%
      (planimetry) and 4.5% (HRT). CONCLUSIONS: Variation between observers is greatly
      reduced by the HRT when compared with planimetry. However, levels of variation,
      which may be clinically significant, remain for variables that depend on the
      subjective drawing of the disc margin.

PMID- 10340974
TI  - Preschool vision screening: negative predictive value for amblyopia.
AB  - BACKGROUND/AIMS: Single optotype tests of visual acuity are widely used for
      preschool vision screening in order to optimise cooperation with testing. These
      tests may, however, underestimate the visual acuity deficit in amblyopia because
      they lack visual crowding. This study assessed the resultant negative predictive
      value (NPV) for amblyopia. METHODS: Cohort study of 936 children in the Cambridge
      Health District selected by date of birth. The presence of amblyopia among
      children who had passed preschool vision screening was determined using Snellen
      line acuity as the reference test. Preschool vision screening was conducted at
      3.5 years of age by community orthoptists. The screening assessment comprised
      Sheridan-Gardiner single optotype test of visual acuity (referral criterion 6/9
      or worse in either eye), cover test, ocular movements, 20(Delta) prism test, and
      TNO stereotest. RESULTS: The overall NPV of preschool vision screening for
      amblyopia was 100% (95% CI 99.4% to 100%). Most children with amblyopia were
      detected by the Sheridan-Gardiner single optotype test of visual acuity, but the
      other screening tests were necessary to prevent any false negatives. In
      isolation, the Sheridan-Gardiner single optotype test of visual acuity has a NPV
      for amblyopia of only 99.6% (95% CI 98.7% to 99.9%). CONCLUSION: Preschool vision
      screening using a single optotype test of visual acuity does achieve a high NPV
      for amblyopia, but only under certain conditions. These comprise a low threshold
      for referral (6/9 or worse in either eye) and the inclusion of a cover test and
      tests of binocular function in the screening assessment.

PMID- 10340973
TI  - Chronic cortical visual impairment in children: aetiology, prognosis, and
      associated neurological deficits.
AB  - BACKGROUND/AIMS: To evaluate prevalence, aetiology, prognosis, and associated
      neurological and ophthalmological problems in children with cortical visual
      impairment (CVI). METHODS: The records of 7200 outpatients seen in the paediatric
      ophthalmology practice over the past 15 years were reviewed in order to compile
      data concerning CVI. In addition, the authors devised and applied a system for
      grading visual recovery in order to assess prognosis. RESULTS: CVI occurred in
      2.4% of all patients examined. The four most common causes of CVI were perinatal
      hypoxia (22%), cerebral vascular accident (14%), meningitis (12%), and acquired
      hypoxia (10%). Most children with CVI had associated neurological abnormalities.
      The most common were seizures (53%), cerebral palsy (26%) hemiparesis (12%), and
      hypotonia (5%). Associated ophthalmological problems were esotropia (19%),
      exotropia (18%), optic nerve atrophy (16%), ocular motor apraxia (15%), nystagmus
      (11%), and retinal disease (3%). On average, CVI patients improved by two levels
      as measured by the authors' scale. CONCLUSION: The majority of children with CVI
      showed at least some recovery. In this group of children, CVI is often
      accompanied by additional ophthalmological problems and is nearly always
      associated with other, serious neurological abnormalities.

PMID- 10340975
TI  - Ocular ochronosis in alkaptonuria patients carrying mutations in the
      homogentisate 1,2-dioxygenase gene.
AB  - AIMS: To assess the involvement of the recently identified human homogentisate
      1,2-dioxygenase gene (HGO) in alkaptonuria (AKU) in two unrelated patients with
      ochronosis of the conjunctiva, sclera, and cornea. METHODS: A mutation screen of
      the entire coding region of the HGO gene was performed using single stranded
      conformational analysis after polymerase chain reaction with oligonucleotide
      primers flanking all 14 exons of the HGO gene. Fragments showing aberrant
      mobility were directly sequenced. RESULTS: Two homozygous missense mutations,
      L25P and M368V, were identified, each of which leads to the replacement of a
      highly conserved amino acid in the HGO protein. CONCLUSIONS: The authors describe
      a novel mutation, L25P, in the German population and bring to 18 the total number
      of known HGO mutations.

PMID- 10340976
TI  - Decreased tear lactoferrin concentration in patients with chronic hepatitis C.
AB  - BACKGROUND/AIMS: Decreased tear volume in patients with chronic hepatitis C has
      been reported in the literature. Lactoferrin is abundantly present in human
      tears, the main source of which is the acini of the lacrimal glands. In this
      study tear lactoferrin levels were measured to investigate the dry eye condition
      of patients with chronic hepatitis C. METHODS: Lactoferrin in tears/fluid was
      measured by a radial immunodiffusion assay in 42 patients with chronic hepatitis
      C. The rate of lacrimal secretion was determined by the cotton thread test. Rose
      bengal staining of the ocular surface was also performed. RESULTS: Only three
      patients out of 42 complained of dry eye sensation and, in 31 patients, six
      showed positive results on the rose bengal staining test of the ocular surface.
      The lactoferrin concentration of tear fluid in the chronic hepatitis C group
      (1.42 (SD 0.56) mg/ml) was significantly lower than in the control group (1.90
      (0.62) mg/ml; p <0.00048). The cotton thread test results in the chronic
      hepatitis C group (12.9 (5. 5) mm) were significantly lower than in the control
      group (17.9 (5. 3) mm; p<0.00048). Also, in the chronic hepatitis C group, tear
      lactoferrin concentration correlated with the results of the cotton thread test
      (r = 0.35, p<0.05). CONCLUSION: Chronic hepatitis C patients showed both
      decreased tear volume, and decreased tear lactoferrin concentration. These
      findings suggest that there may be dysfunction of the lacrimal glands in patients
      with chronic hepatitis C, which may account for the mild dry eye.

PMID- 10340978
TI  - Treatment of obstructive epiphora in adults by balloon dacryocystoplasty.
AB  - AIMS: To determine the efficacy of dacryocystoplasty with balloon dilatation in
      the treatment of complete and partial obstruction of the lacrimal drainage
      system. METHODS: The procedure was performed on 26 patients with epiphora due to
      complete (n=16) or partial (n=10) obstruction of the lacrimal drainage system. A
      flexible tipped guide wire was introduced through the superior canaliculus into
      the inferior meatus and manipulated out of the nasal cavity. A 3 mm balloon was
      then introduced in a retrograde direction over the guide wire and dilated at the
      obstruction site. RESULTS: The procedure was technically successful in all
      patients with partial obstruction, but unsuccessful in four of 16 cases with
      complete obstruction. Reobstruction occurred in eight of 12 patients with
      complete obstruction, and in five of 10 patients with partial obstruction. The
      overall success rate was 25% for complete and 50% for partial obstructions. The
      mean follow up was 14 months (8-37 months). CONCLUSION: Although the balloon
      dacryocystoplasty is a simple and minimally invasive technique, the outcome from
      our study indicates that it is not advisable for treatment of complete
      obstruction of the lacrimal drainage system. Balloon dilatation may prove
      suitable for the treatment of patients with partial obstruction below the level
      of the lacrimal sac, especially in those who are poor candidates for surgery, or
      who do not wish to undertake dacryocystorhinostomy. Even in the partial
      obstruction group the success rate was only 50%, so that further modification to
      the technique and controlled studies are likely to be required before it could be
      recommended for general use.

PMID- 10340977
TI  - Ocular signs and symptoms and vitamin A status in patients with cystic fibrosis
      treated with daily vitamin A supplements.
AB  - BACKGROUND/AIMS: Patients with cystic fibrosis (CF) may have low plasma vitamin A
      levels from malabsorption, zinc deficiency, liver disease, or poor compliance
      with prescribed supplements. In view of the increasing number of adults with CF,
      many of whom drive cars, it is important to assess vitamin A status. In our
      centre an attempt has been made to achieve normal levels of fat soluble vitamins
      by annual estimation of plasma levels and appropriate oral supplementation. This
      study aimed to determine if this approach prevents vitamin A deficiency and the
      consequent problems with dark adaptation. METHODS: The study was conducted at the
      regional adult and paediatric cystic fibrosis unit and the patients were
      recruited from there. Dark adaptation studies were conducted at the department of
      ophthalmology, St James's University Hospital. All patients are regularly seen in
      the outpatient department by a CF specialist dietitian and have a comprehensive
      annual dietary assessment. 28 patients had the following investigations: serum
      retinol, plasma zinc, serum retinol binding protein, liver function tests, dark
      adaptation, contrast sensitivity, and anterior ocular surface status. 25 age and
      sex matched controls without CF or ocular pathology were also recruited for the
      dark adaptation study. RESULTS: None of the patients had vitamin A deficiency,
      the median value of serum retinol being 48 microg/dl, range 31-80 microg/dl
      (normal range 30-80 microg/dl). Dark adaptation was normal in all cases compared
      with the control group where the mean value was 3.4 log units of threshold
      luminance (95% confidence interval 2.4-4.0). None of the test group had a value
      of threshold luminance 2 SD above the mean value for the control group. Eight
      patients had reduced contrast sensitivity. The median value for serum zinc was
      14.2 micromol/ l, range 13-81 micromol/l (normal range 8-23 micromol/l) and the
      median value for retinol binding protein was 36 mg/l, range 13-81 mg/l (normal
      range 35-58 mg/l). There was no correlation between dark adaptation and serum
      retinol, zinc, or retinol binding protein. Two patients had clinical evidence of
      dry eye. CONCLUSION: Regular estimates of plasma vitamin A together with
      appropriate supplementation and expert dietetic review can maintain normal dark
      adaptation in patients with cystic fibrosis. The occurrence of reduced contrast
      sensitivity function is well documented but remains an unexplained phenomenon and
      deserves further study.

PMID- 10340979
TI  - Confocal microscopy in the iridocorneal endothelial syndrome.
AB  - AIMS: To report the appearances of iridocorneal endothelial (ICE) syndrome from
      real time, white light confocal microscopy. METHODS: Three consecutive patients,
      each with ICE syndrome, were examined prospectively. Corneal specular and
      confocal microscopic examinations were performed in all three patients. In the
      first patient, a penetrating keratoplasty was performed and the cornea was
      examined by light and scanning electron microscopy. No surgery was performed in
      the remaining two patients. RESULTS: In the first patient corneal oedema
      prevented endothelial specular microscopy. Confocal microscopy performed before
      penetrating keratoplasty successfully revealed abnormal epithelial-like
      endothelial cells. Histological examinations of the cornea following penetrating
      keratoplasty revealed the presence of multilayered endothelial cells with
      epithelial features (microvilli). In the remaining two patients, specular
      microscopy showed the presence of ICE cells with typical dark/light reversal.
      Confocal microscopy demonstrated groups of endothelial cells with epitheloid
      appearances. In all three patients, the contralateral endothelial appearance was
      normal by specular and confocal microscopy, except for moderate endothelial
      polymegathism in one patient. Epithelial-like endothelial cells were
      characterised by prominent nuclei on confocal microscopy. CONCLUSIONS: The
      application of confocal microscopy indicates that the ICE syndrome is
      characterised by epitheloid changes in the endothelium. Confocal microscopy may
      be used to diagnose the ICE syndrome by demonstrating epithelial-like endothelial
      cells with hyperreflective nuclei. This technique is especially of value in cases
      of corneal oedema, since specular microscopy may fail to image the endothelium in
      such cases.

PMID- 10340980
TI  - Iris crystals in chronic uveitis.
AB  - AIMS: To analyse the unusual physical sign of iris crystals occurring in patients
      with uveitis. METHODS: Demographic details and clinical features were documented
      in 24 patients with chronic uveitis and iris crystals. Plasma immunoglobulin
      subclasses were measured, and a histopathological review of iridectomy specimens
      from 33 patients with chronic uveitis was also undertaken. RESULTS: The mean age
      of patients was 38 years, with a slight preponderance of females. 17 patients had
      Fuchs' heterochromic cyclitis although a number of other uveitis entities were
      represented. There was no correlation between severity of clinical signs and
      presence of iris crystals. Over a mean follow up period of 15 months no
      significant change in the number, size, or position of the crystals was seen
      except in four patients who underwent intraocular surgery. Only three patients
      had raised plasma IgG1. The review of the histology of iridectomy specimens
      failed to show evidence of Russell body formation in any patient. CONCLUSIONS:
      Iris crystals appear to be rare but may be underreported as they are small and
      can easily be missed. They are likely to be associated with disease processes in
      which there is active immunoglobulin production within the anterior chamber, such
      as Fuchs' heterochromic cyclitis.

PMID- 10340982
TI  - Effect of diode laser trans-scleral cyclophotocoagulation in the management of
      glaucoma after intravitreal silicone oil injection for complicated retinal
      detachments.
AB  - AIMS: To evaluate the effect of trans scleral cyclophotocoagulation (TSCPC) on
      intraocular pressure (IOP) in the eyes retaining intravitreal silicone oil with
      medically uncontrolled secondary glaucoma following intravitreal silicone oil
      injection. METHODS: Medical records of 11 eyes of 11 patients who underwent TSCPC
      for medically uncontrolled glaucoma without pupillary block following
      intravitreal silicone oil injection for complicated retinal detachment were
      reviewed retrospectively. In all cases, intravitreal silicone oil was not removed
      for fear of retinal redetachment. Diode laser contact TSCPC was performed at a
      power of 1.5-2.5 W, for a duration of 2 seconds, and with 20-27 applications.
      IOP, number of glaucoma medications, and success rate were evaluated. RESULTS:
      After a mean follow up period of 52.5 (SD 8.2) (range 42-68) weeks, the mean
      pretreatment level of IOP, 43.0 (14.4) (26-67) mmHg, had fallen to 14.5 (4.3) (7
      20) mm Hg (p=0.003). The number of glaucoma medications was reduced from 2.6
      (0.8) to 0.6 (1.0) (p= 0.005). Qualified success was achieved in nine eyes
      (81.8%) and complete success in six (54.5%). After TSCPC, patients' retinal
      status had not changed. CONCLUSION: Patients with medically uncontrolled glaucoma
      secondary to intravitreal silicone oil injection can be treated with TSCPC in
      spite of the retained intravitreal silicone oil.

PMID- 10340981
TI  - The Bristol Shared Care Glaucoma Study: reliability of community optometric and
      hospital eye service test measures.
AB  - BACKGROUND/AIMS: Primary open angle glaucoma patients and glaucoma suspects make
      up a considerable proportion of outpatient ophthalmological attendances and
      require lifelong review. Community optometrists can be suitably trained for
      assessment of glaucoma. This randomised controlled trial aims to assess the
      ability of community optometrists in the monitoring of this group of patients.
      METHODS: Measures of cup to disc ratio, visual field score, and intraocular
      pressure were taken by community optometrists, the hospital eye service and a
      research clinic reference "gold" standard in 405 stable glaucoma patients and
      ocular hypertensives. Agreement between and within the three centres was assessed
      using mean differences and intraclass correlation coefficients. Tolerance limits
      for a change in status at the level of individual pairs of measurements were also
      calculated. RESULTS: Compared with a research clinic reference standard,
      measurements made by community optometrists and those made in the routine
      hospital eye service were similar. Mean measurement differences and variability
      were similar across all three groups compared for each of the test variables
      (IOP, cup to disc ratio, and visual field). Overall, the visual field was found
      to be the most reliable measurement and the cup to disc ratio the least.
      CONCLUSIONS: Trained community optometrists are able to make reliable
      measurements of the factors important in the assessment of glaucoma patients and
      glaucoma suspects. This clinical ability should allow those optometrists with
      appropriate training to play a role in the monitoring of suitable patients.

PMID- 10340983
TI  - Selective laser trabeculoplasty v argon laser trabeculoplasty: a prospective
      randomised clinical trial.
AB  - AIMS: To compare the effectiveness of selective laser trabeculoplasty (SLT, a 532
      nm Nd:YAG laser) with argon laser trabeculoplasty (ALT) in lowering the
      intraocular pressure (IOP) in patients with medically uncontrolled open angle
      glaucoma. METHODS: A prospective randomised clinical trial was designed. Patients
      were randomised to treatment with either SLT or ALT and were evaluated at 1 hour,
      1 week, 1, 3, and 6 months post-laser. RESULTS: There were 18 eyes in each group.
      Baseline characteristics were similar in both groups. In the SLT group the mean
      IOP at baseline, 1, 3, and 6 months was 22.8 (SD 3.0), 20.1 (4.6), 19.3 (6.0),
      and 17.8 (4.8) mm Hg, respectively. In the ALT group, the mean IOP at baseline,
      1, 3, and 6 months was 22.5 (3.6), 19.5 (4.7), 19.6 (5.6), and 17.7 (3.3) mm Hg,
      respectively. There was a greater anterior chamber reaction, 1 hour after SLT v
      ALT (p< 0.01). Patients with previous failed ALT had a better reduction in IOP
      with SLT than with repeat ALT (6.8 (2. 4) v 3.6 (1.8) mm Hg; p = 0.01).
      CONCLUSION: SLT appears to be equivalent to ALT in lowering IOP during the first
      6 months after treatment. There is a slightly greater anterior chamber reaction 1
      hour after SLT. Patients with previous failed ALT had a significantly greater
      drop in IOP when treated with SLT v ALT. These results need to be confirmed with
      a larger sample size.

PMID- 10340984
TI  - PAX6 expression in the developing human eye.
AB  - AIMS: To investigate the changes in PAX6 expression in the developing human eye.
      METHODS: Six developing human eyes from 6 to 22 weeks' gestation were evaluated.
      Frozen sections were immunohistochemically stained with monoclonal antibody to
      chick Pax6 (amino acids 1-223). To verify antibody specificity, western blot
      analysis was carried out using cell lysates from P19 cells transfected with the
      human PAX6 gene. RESULTS: Western blot analysis demonstrated that the antibody
      reacted to human PAX6 protein. Positive immunostainings for PAX6 were seen in the
      surface ectoderm, lens vesicle, inner and outer layers of the optic cup, and
      optic stalk at 6 weeks, and in the corneal epithelia and conjunctiva, lens, and
      non-pigmented ciliary epithelia from 8 to 22 weeks. In the retina, positive cells
      were seen in the entire retina from 8 to 10 weeks, and were restricted to the
      ganglion cell layer and the inner and outer portions of the inner nuclear layer
      after 21 weeks. CONCLUSIONS: PAX6 is expressed on the surface and neuroectoderms
      at an early stage, then in the differentiating cells in the cornea, lens, ciliary
      body, and retina through development. PAX6 may play a role in determining cell
      fate in the morphogenesis of various human ocular tissue.

PMID- 10340985
TI  - Growth factor staining patterns in the pig retina following retinal laser
      photocoagulation.
AB  - AIM: To identify changes in growth factor expression in miniature pig retinas
      following retinal laser photocoagulation. METHODS: Pigs were sacrificed at
      different times (15 minutes to 42 days) post-laser and the retinas were
      immunolabelled for basic fibroblast growth factor, insulin-like growth factor I,
      transforming growth factor beta, epidermal growth factor, transforming growth
      factor alpha, platelet derived growth factor, vascular endothelial growth factor,
      and epidermal growth factor receptor. Total mRNA levels were also determined.
      RESULTS: With the exception of vascular endothelial growth factor,
      immunoreactivity for all other growth factors studied and epidermal growth factor
      receptor was observed throughout normal non-lasered control retina, generally
      being high in the retinal pigment epithelium and low in the neural retina.
      Changes in growth factor expression following laser photocoagulation were
      observed only in burn areas and changes were mainly confined to the retinal
      pigment epithelium and outer nuclear layer. The immunoreactivity within retinal
      pigment epithelial cells in burn areas was either absent or decreased following
      laser treatment but returned to normal by 21 days. The immunoreactivity was
      increased within the outer nuclear layer of burn areas during the healing process
      but returned to normal by 42 days. Vascular endothelial growth factor
      immunoreactivity was weak/absent in the normal retina and remained unchanged
      following laser photocoagulation. Change of total mRNA levels in burn areas
      during time post-laser was confined to retinal pigment epithelial cells, being
      low immediately following photocoagulation and returning to normal by 42 days.
      CONCLUSIONS: These results demonstrate a temporal alteration in growth factor
      expression and transcriptional activity in the retina following laser
      photocoagulation.

PMID- 10340986
TI  - Antimicrobial defensin peptides of the human ocular surface.
AB  - BACKGROUND/AIMS: The antimicrobial activity of the tear film exceeds the activity
      of its known constituents. The authors postulate that this excess activity is the
      result of antimicrobial peptides called defensins, and they aimed to look for
      defensins in the human eye. METHODS: Evidence of defensin production was sought
      by reverse transcriptase polymerase chain reaction (RT-PCR). Intron spanning
      primers were designed for beta defensins 1 and 2, and alpha defensins 5 and 6. RT
      PCR was performed on cornea, conjunctiva, and lacrimal gland samples, and
      reaction products were size fractionated and sequenced to confirm their identity.
      A monoclonal antibody was utilised for the detection of alpha defensins 1, 2, and
      3 in tissue sections and in immunoblots of tears. RESULTS: RT-PCR revealed beta
      defensin 1 message in samples of conjunctiva, cornea, and lacrimal gland. beta
      Defensin 2 message was detected in the conjunctiva and cornea but was absent from
      the lacrimal gland. alpha Defensin 5 and 6 message was absent in these tissues
      but alpha defensins 1, 2, and 3 were detected in normal tears, lacrimal gland,
      and inflamed conjunctiva by immunochemistry. CONCLUSION: The data suggest the
      human eye innately produces a spectrum of antimicrobial defensin peptides.
      Defensins hold therapeutic potential in ocular infections as they have a broad
      spectrum of antimicrobial activity (bacteria fungi and viruses ) and accelerate
      epithelial healing.

PMID- 10340987
TI  - Ocular adnexal lymphoma-comparison of MALT lymphoma with other histological
      types.
AB  - AIMS: To correlate histological features of ocular adnexal lymphoma using the
      revised European American lymphoma classification (REAL), with stage of disease
      at presentation, treatment modalities, and patient outcome. MALT lymphoma defines
      an extranodal marginal zone B cell lymphoma as outlined in the REAL
      classification. Comparison groups of patients included those with primary ocular
      adnexal MALT lymphoma versus primary ocular adnexal lymphomas of other types,
      MALT lymphoma versus non-MALT lymphomas (primary and secondary), and primary
      ocular adnexal lymphoma (MALT lymphomas and other types) versus secondary ocular
      adnexal lymphomas. METHODS: A retrospective review of the National Ophthalmic
      Pathology Laboratory records identified 20 cases of ocular adnexal lymphoma over
      a 10 year period which were reclassified using appropriate immunohistochemical
      stains. Patients' medical records were examined for data including stage of the
      disease at presentation, mode of treatment, and patient outcome. RESULTS: Among
      the 20 cases identified 14 had primary ocular adnexal lymphomas. 10 of the
      primary lymphomas had histological features of MALT lymphoma. One case was a
      primary ocular adnexal T cell lymphoma, one a follicular centre, follicular B
      cell lymphoma, and two were large cell B cell lymphomas. Six cases had systemic
      disease, four large B cell, one follicular centre, follicular B cell, and one
      mantle cell. A significantly higher proportion of patients with MALT lymphomas
      had early disease (p = 0.005), initially required local treatment (p = 0.005) and
      were alive at last follow up (p = 0.001) than those without. Two patients with
      MALT lymphoma had recurrence of lymphoma which responded to further treatment.
      CONCLUSIONS: Patients with primary ocular adnexal MALT lymphomas present with
      localised disease requiring local treatment and have a better outcome compared
      with patients with other types. As a small percentage of these tumours recur,
      patients should be followed up indefinitely.

PMID- 10340989
TI  - A new substrain of the non-obese diabetic mouse which develops cataracts
      (NOD/Ba/Lop19)

PMID- 10340988
TI  - Amniotic membrane transplantation.

PMID- 10340990
TI  - Cortically visually impaired children.

PMID- 10340992
TI  - Viscoelastic.

PMID- 10340991
TI  - Automated perimetry by optometrists in patients at low risk of glaucoma.

PMID- 10340993
TI  - Ida and the Eye-a Woman in British Ophthalmology.

PMID- 10340994
TI  - Existence of human DAZLA protein in the cytoplasm of human oocytes.
AB  - The human deleted in azoospermia-like autosomal (DAZLA) gene is thought to be a
      candidate gene for azoospermia. cDNA encoding the C-terminal 94 amino acid
      residues of human DAZLA was used to express a bacterial fusion protein which was
      then used to raise polyclonal antibodies in rabbits. Immunohistochemical analyses
      with the human DAZLA antiserum showed that the DAZLA protein is expressed at a
      cytoplasmic location in female germ cells. Available evidence suggests that the
      DAZLA gene is a participant in human oogenesis.

PMID- 10340995
TI  - The neoglycoprotein mannose-bovine serum albumin, but not progesterone, activates
      T-type calcium channels in human spermatozoa.
AB  - The neoglycoproteins alpha-D-mannose-bovine serum albumin (mannose-BSA) and N
      acetyl-alpha-D-glucosamine-BSA (glucNAc-BSA) were shown to rapidly increase
      intracellular free calcium ([Ca2+]i) in human spermatozoa. The increase in
      [Ca2+]i induced by these neoglycoproteins accounts for the known ability of these
      compounds to induce the acrosome reaction in human spermatozoa. Our data support
      the hypothesis that mannose-BSA, but not progesterone, activates T-type Ca2+
      channels in human spermatozoa for the following reasons: (i) the capacity of
      mannose-BSA to increase [Ca2+]i was inhibited by the specific T-type Ca2+ channel
      blocker mibefradil (IC50 = 10(-6) mol/l) while progesterone was not inhibited by
      10(-5) M mibefradil; (ii) the effect of mannose-BSA to elevate [Ca2+]i was
      inhibited more potently by Ni2+ (IC50 = 0.1 mmol/l) than Cd2+ (IC50 = 0.5
      mmol/l), whereas the effect of progesterone to elevate [Ca2+]i was inhibited
      equally by Ni2+ and Cd2+ (IC50 = 0.25 mmol/l); (iii) the effects of mannose-BSA
      and progesterone to increase [Ca2+]i were greater than additive. These data
      support the idea that mannose-BSA and progesterone were activating distinct Ca2+
      channels, one of which was a T-type Ca2+ channel activated by mannose-BSA whereas
      the Ca2+ channel that was activated by progesterone has yet to be defined at the
      molecular level.

PMID- 10340996
TI  - Progesterone promotes the acrosome reaction in capacitated human spermatozoa as
      judged by flow cytometry and CD46 staining.
AB  - The acrosome reaction is a necessary prerequisite for spermatozoa to acquire
      fertilizing ability. Several different moieties appear to promote the acrosome
      reaction through different pathways, including solubilized zona pellucidae,
      recombinant zona protein ZP3, follicular fluid, calcium ionophores, and
      mannosylated bovine serum albumin (BSA). Although many investigators have
      presented evidence that progesterone also promotes the acrosome reaction through
      the mediation of a non-genomic cell membrane receptor, this concept has been
      challenged. Other workers have suggested that progesterone does not promote an
      acrosome reaction in human spermatozoa, as judged by the detection of CD46, a
      complement regulatory protein present on the inner acrosome membrane, through
      flow cytometric analysis of large numbers of spermatozoa. Prior investigations
      were criticized by the limited numbers of spermatozoa enumerated visually, the
      use of non-specific staining techniques, and the failure to eliminate dead
      spermatozoa during the scoring of the acrosome reaction. We have repeated these
      experiments, using both a supravital dye to eliminate dead spermatozoa from flow
      cytometric analysis, and anti-CD46 monoclonal antibody to score acrosome-reacted
      spermatozoa. Care was taken to validate the adequacy of capacitation conditions,
      which were proven by the ability of spermatozoa to acrosome react in response to
      mannosylated BSA and to penetrate zona-free hamster eggs. Confocal microscopy was
      used to confirm that CD46 immunostaining was limited to the acrosomal region of
      the spermatozoon head. Our results indicate that progesterone does promote an
      acrosome reaction within capacitated spermatozoa.

PMID- 10340997
TI  - Functionally inactive protein C inhibitor in seminal plasma may be associated
      with infertility.
AB  - Protein C inhibitor (PCI) has been found in seminal plasma and is considered to
      protect intact surrounding cells and seminal plasma proteins from possible
      proteolytic damage. In the present study, we showed that although the antigenic
      levels of PCI in two seminal plasma samples from patients with infertility were
      normal or slightly elevated, their inhibitory activities toward urokinase
      plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) were
      absent. In contrast, uPA and tPA proteolytic activities in these two samples were
      20-60-fold higher than that from normal volunteers. A time-course analysis of PCI
      uPA complex formation showed that >80% of the complex had been formed within 15
      min in normal seminal plasma in the presence of heparin, compared with the total
      complex formed after 150 min incubation, whereas no response to heparin
      stimulation was observed in the assays with the two patient samples. Similarly,
      >90% of PCI-tPA complex was formed after 30 min of heparin stimulation in normal
      seminal plasma but no response was observed in the two patient samples. Kinetic
      assays of PCI inhibitory function in the presence of activated protein C (APC)
      showed that PCI inhibitory activity in the two patient samples was absent and not
      stimulated by heparin. Western blotting also showed that most of the intact PCI
      molecules, in normal samples, formed complexes with either uPA or tPA but there
      was no complex formed in one of the two patient samples and very little complex
      was observed in the other, suggesting that PCI in the two patient samples is
      inactive. These results suggest that the presence of functionally inactive PCI in
      seminal plasma may be associated with infertility.

PMID- 10340998
TI  - Calpain-calpastatin: a novel, complete calcium-dependent protease system in human
      spermatozoa.
AB  - Calpain, a calcium (Ca2+)-activated cysteine protease presents in several somatic
      mammalian cells, has been demonstrated to mediate specific Ca2+-dependent
      reactions including cell fusion. Because spermatozoa cells have an absolute Ca2+
      requirement for penetration of oocytes, we have postulated that calpain would
      also be found in mammalian spermatozoa. Here we show that whole sperm homogenate
      and cell fractions prepared from ejaculated human spermatozoa contain calpain
      activity. Specific calpain inhibitors impaired this proteolytic activity. Unlike
      the enzyme described in somatic cells, sperm calpain was mostly particulate in
      nature and its activity was maximal at pH 9.0. Presence of sperm calpain was
      confirmed by immunoblot analysis using specific anti-calpain I and anti-calpain
      II antibodies. A 67 kDa calpain II protein and a 75 kDa calpain I protein were
      detected. Also spermatozoa contain the endogenous calpain inhibitor, calpastatin.
      We detected 158.8 +/- 24.5 (mean +/- SD) fmol calpastatin/mg sperm protein.
      Immunoblot analysis using specific antibodies showed a 68 kDa calpastatin protein
      located in the cytosolic fraction. This is the first demonstration that a
      complete calpain-calpastatin system exists in mammalian spermatozoa. Because
      calpain is a unique effector system for calcium-dependent processes, our data
      reveals a novel mechanism by which calcium exerts its regulatory functions in
      spermatozoa.

PMID- 10340999
TI  - Male accessory sex gland secretions affect oocyte Ca2+ oscillations during in
      vitro fertilization in golden hamsters.
AB  - To evaluate the effect of male accessory sex gland secretions on Ca2+
      oscillations of oocytes, epididymal or ejaculated spermatozoa recovered from
      uteri were used to inseminate oocytes. Ca2+ oscillations were measured by Fura 2
      fluorescence imaging (F340/F380). We showed that although Ca2+ oscillations
      induced by ejaculated spermatozoa had a pattern similar to those induced by
      epididymal spermatozoa, the amplitude of the first Ca2+ transient in the former
      group was significantly higher (P < 0.05) and the duration was significantly
      longer (P < 0.01). Oocytes inseminated with ejaculated spermatozoa recovered from
      uteri from males had ampullary glands or ventral prostates removed showed
      significantly lower Ca2+ oscillations compared to the controls (P < 0.05, P <
      0.01 respectively). Moreover, the relative area of the first Ca2+ transient in
      treatment groups was significantly smaller than the control. In addition, a
      significantly higher percentage of oocytes (52%) inseminated by spermatozoa from
      males with all accessory sex glands removed showed non-oscillatory Ca2+
      transients, compared to the controls (5%, P < 0.05). These results indicate that
      accessory sex gland secretions can affect Ca2+ oscillations. The differences
      between Ca2+ oscillations induced by epididymal and uterine spermatozoa from
      males with all accessory sex glands removed suggest that uterine factors may also
      influence this process.

PMID- 10341000
TI  - Characterization of human zona pellucida glycoproteins.
AB  - The human egg may only be fertilized by one spermatozoon to prevent polyploidy.
      In most mammals, the primary block to polyspermy occurs at the zona pellucida
      (ZP). Little is known of the human ZP and the changes occurring following
      fertilization to prevent polyploidy. Using antibodies directed against synthetic
      peptides predicted from the human ZP2 and ZP3 cDNA, we identified ZP3 as a 53-60
      kDa glycoprotein and ZP2 as a 90-110 kDa glycoprotein in prophase-I oocytes.
      Characterization of the ZP from metaphase II arrested eggs (inseminated
      unfertilized and fertilized-uncleaved), shows no visible modification of ZP3, but
      demonstrates that ZP2 undergoes limited proteolysis in the amino terminal domain,
      to a 60-73 kDa species, denoted ZP2p, which remains linked to the proteolysed
      fragments by intramolecular disulphide bonds. A lack of ZP2 proteolytic activity
      in acrosomal supernatants is consistent with an oocyte origin for the protease.
      The ZP2-specific protease may be released during cortical granule exocytosis
      which occurs during meiotic maturation and following sperm-egg fusion as part of
      the block to polyspermy. Since mouse ZP2 acts as a secondary sperm receptor, it
      is possible that intact ZP2 binds a secondary egg binding protein, whereas
      cleaved ZP2 does not, suggesting a possible mechanism for the block to
      polyspermy.

PMID- 10341001
TI  - Search for a human homologue of the mouse Ped gene.
AB  - The Ped gene influences the rate of cleavage division of preimplantation mouse
      embryos and subsequent embryonic survival. The mouse Ped gene product is a major
      histocompatibility complex (MHC) class Ib protein called Qa-2. Studies from many
      human in-vitro fertilization (IVF) clinics suggest that the mouse Ped gene has a
      human homologue because embryos fertilized at the same time have different
      cleavage rates, and those embryos that cleave at a faster rate are more likely to
      result in a viable pregnancy. Candidates for the human homologue of the mouse Ped
      gene include the MHC class Ib genes HLA-E, HLA-F, and HLA-G. The presence of mRNA
      for these three genes was tested in 108 spare day 3 human preimplantation embryos
      from 25 couples by using reverse transcription-polymerase chain reaction (RT
      PCR). Of the 86 embryos tested for HLA-E mRNA, 72 were positive (84%), and of the
      88 embryos tested for HLA-G mRNA, 39 were positive (44%). None of the 17 embryos
      tested for HLA-F mRNA were positive (0%). Studies of expression of HLA-G protein
      were undertaken to ascertain whether HLA-G was attached to the cell membrane via
      a glycosylphosphatidylinositol (GPI) linkage similar to that found in Qa-2
      protein. Treatment of JEG-3 cells, an HLA-G expressing cell line, with
      phospholipase C did not result in removal of HLA-G showing that HLA-G, unlike Qa
      2, is not GPI linked to the cell surface. The pros and cons of HLA-E, HLA-F, and
      HLA-G as candidates for the human Ped gene are discussed.

PMID- 10341002
TI  - Platelet-activating factor stimulates cytokine production by human endometrial
      stromal cells.
AB  - Although preimplantation embryo and decidual cells secrete significant amounts of
      platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF);
      its precise function in early pregnancy has yet to be established. To investigate
      the effect of PAF on cytokine synthesis, we measured the cytokine concentration
      in the culture media of two human cell lines: normal endometrial stromal cells
      (ESC) and endometrial stromal sarcoma cells (MaMi), following stimulation with a
      non-metabolized PAF analogue, carbamyl-PAF (C-PAF). Enzyme-linked immunosorbent
      assays were used to measure five cytokines: interleukin (IL)-6, IL-8, macrophage
      colony-stimulating factor (M-CSF), macrophage inflammatory protein-1alpha (MIP
      1alpha) and tumour necrosis factor-alpha (TNF-alpha). We also evaluated the mRNA
      expression for IL-6 and IL-8 in ESC after C-PAF stimulation using Northern blot
      analysis. Non-stimulated ESC and MaMi cells both secreted IL-6, IL-8, and M-CSF,
      but not MIP-1alpha or TNF-alpha. The concentrations of IL-6, IL-8, M-CSF, MIP
      1alpha, and TNF-alpha in the culture media of both cell lines increased in
      parallel with increasing amounts of C-PAF. C-PAF stimulated IL-6 and IL-8
      transcription in ESC. These results suggest that PAF secretion by decidual
      tissues and developing embryos may induce cytokine synthesis by the ESC, as part
      of the cytokine network in the feto-maternal unit. An increase in the local
      cytokine concentration may be an important factor in the maintenance of early
      stages of gestation.

PMID- 10341003
TI  - Rapid down-regulation of CD63 transcription by progesterone in human endometrial
      stromal cells.
AB  - Differentiation of endometrial stromal cells (decidualization) plays a crucial
      role in embryo implantation and maintenance of pregnancy. While progesterone is a
      key factor in regulating endometrial cell decidualization, the molecular
      mechanisms remain unclear. In the present study, we investigated the effect of
      gene transcription in human endometrial stromal cells (ESC) by progesterone,
      oestrogen or vehicle using the polymerase chain reaction-based differential
      display methodology. A transcript which is down-regulated by progesterone, but
      not by vehicle and oestrogen, was identified from a differential display band and
      the progesterone sensitivity of its expression was verified in Northern blot
      analysis. The level of the gene expression in progesterone-treated ESC was
      approximately 60% of that in the vehicle- and oestrogen-treated ESC. This cDNA
      was revealed to be human CD63 antigen, a recently identified member of the
      transmembrane 4 superfamily. The inhibitory effect of progesterone is observed
      within 30 min after hormone treatment. In human endometrium, CD63 mRNA levels
      were significantly decreased (P < 0.05) during the secretory phase compared with
      levels during the proliferative phase. This down-regulation of CD63 in vivo
      elevated levels of progesterone in the secretory phase. These results suggest
      that CD63 transcription is down-regulated by progesterone in human endometrium.

PMID- 10341004
TI  - Oestrogen receptor alpha and beta mRNA expression in human endometrium throughout
      the menstrual cycle.
AB  - We examined the localization of oestrogen receptor (ER) beta mRNA in the human
      endometrium throughout the menstrual cycle using non-radioactive in-situ
      hybridization with Brigati-tailed oligonucleotides. The findings were compared
      with those of ERalpha in order to examine the possible biological significance of
      ERbeta in the human endometrium. Both ERalpha and ERbeta mRNA expression were
      detected in all major human uterine cell types, including glandular epithelial
      cells, stromal cells and smooth muscle cells of the uterine wall, at every
      menstrual cycle stage. However, ERalpha mRNA expression was more prominent than
      that of ERbeta in all cell types throughout the menstrual cycle. In proliferative
      phase endometrium, ERalpha mRNA was expressed in both glandular epithelial and
      stromal cells, while ERbeta mRNA was expressed predominantly in glandular
      epithelial cells. Although the same pattern was observed in the secretory phase,
      both the ERalpha and ERbeta mRNA expression was relatively weaker. These results
      suggest that oestrogenic effects occur predominantly through ERalpha, but that
      ERbeta may also play a role in the modulation of oestrogenic action, especially
      on glandular epithelial cells in the human endometrium throughout the menstrual
      cycle.

PMID- 10341005
TI  - Opioid peptides inhibit the action of oestradiol on human myometrial cells in
      culture.
AB  - The effect of opioid peptides on cultured, oestradiol-stimulated human myometrial
      cells was examined. Oestradiol increased cell densities in mixed-cell (smooth
      muscle cells + stromal fibroblasts) cultures by 40%. This oestradiol-induced
      stimulation of cell proliferation was decreased to control values by D-met2-pro5
      enkephalinamide. The half-effective inhibitory concentration of enkephalinamide
      was 0.3 nmol/l. The opioid-induced inhibition of cell proliferation was blocked
      completely by the specific opiate receptor antagonist naloxone, while naloxone
      did not have any effect on its own. This opioid effect was mediated dominantly by
      the mu opiate receptor. The optimal concentration for oestradiol to stimulate
      uterine cell proliferation was 2.2 nM. The basal rate of cell proliferation was
      not affected by enkephalinamide. In saturation experiments, the parameters of
      specific [3H]-naloxone binding were: dissociation constant = 1.02 nM, maximal
      binding capacity = 2910 binding sites/cell, Hill coefficient = 1.029. In human
      myometrial pure smooth muscle cell cultures, oestradiol decreased the
      proliferation of cells. Progesterone potentiated these oestradiol effects, but
      had no effect on its own. Enkephalinamide was also able to block the effects of
      oestradiol, but naloxone did not antagonize it. In summary, here we present a
      novel inhibitory role of endogenous opioid peptides in the regulation of cell
      growth and proliferation in the human uterus.

PMID- 10341006
TI  - Cyclic AMP- and differentiation-dependent regulation of the proximal alphaHCG
      gene promoter in term villous trophoblasts.
AB  - Although the regulatory mechanisms controlling alpha and beta human chorionic
      gonadotrophin (HCG) expression have been investigated in choriocarcinoma cell
      model systems, little is known about the regulation of HCG subunit synthesis in
      non-tumourigenic trophoblasts. We therefore investigated alphaHCG mRNA
      transcription in villous cytotrophoblasts isolated from term placentae and have
      shown for the first time that the proximal alphaHCG gene promoter is functional
      in these cells. By establishing conditions which allow efficient transient
      transfection of immunopurified cells, we have demonstrated that a 363 bp sequence
      in the proximal 5' flanking region of the alphaHCG gene is sufficient to direct
      trophoblast-specific expression of a luciferase reporter. After 12-60 h
      cultivation, an increase in endogenous alphaHCG mRNA expression could be
      detected, indicating that aggregated villous trophoblasts undergo biochemical
      differentiation. Concomitantly, we observed induction of alphaHCG promoter-driven
      luciferase activity, suggesting that the 363 bp sequence of the proximal 5'
      flanking region is sufficient to direct differentiation-dependent increase of
      alphaHCG mRNA. Continuous luciferase expression required functional cAMP-response
      elements (CREs), since deletion of both recognition sequences eliminated
      differentiation-dependent transcription of the reporter. Elevation of cAMP values
      increased transcription of the wild-type construct; however, it did not affect
      promoter activity of the mutant plasmid. Moreover, we have demonstrated that
      during in-vitro differentiation, CREs interacted with increasing amounts of
      phosphorylated activating transcription factor/cyclic AMP response element
      binding protein (ATF-1/CREB-1) suggesting that these cAMP-dependent DNA-binding
      factors are major determinants in regulating alphaHCG gene expression in villous
      trophoblasts.

PMID- 10341007
TI  - Leukaemia inhibitory factor gene mutations in infertile women.
AB  - The glycoprotein leukaemia inhibitory factor (LIF) is produced by the endometrium
      and is involved in the control of implantation. In women with unexplained
      infertility reduced uterine concentrations of LIF have been reported. Studies
      with mice lacking a functional LIF gene have shown that the LIF protein is
      essential for implantation of the embryo. We have developed a method for
      screening of gene mutations in the coding region and critical regulatory regions
      of the LIF gene. Thus we could screen nulligravid infertile women (n = 74),
      fertile controls (n = 75) and as a second unrelated control group, neurological
      patients (n = 131) for LIF gene mutations. In infertile women, three heterozygous
      point mutations have been identified: one in close proximity to the start codon
      of exon 1 and two mutations in exon 3. These correspond to regions of the LIF
      protein which are thought to be highly important for interaction with the LIF
      receptor and thus lead to reduced biological activity of the LIF protein. Only
      one point mutation/polymorphism in the non-coding region between exon 2 and 3 was
      found in the control groups. Our results suggest that heterozygosity for a LIF
      gene mutation could give rise to decreased availability or biological activity of
      LIF in the uterus and cause implantation failure. Thus the mutations identified
      in our study could be responsible for infertility in a subgroup of nulligravid
      women.

PMID- 10341008
TI  - Screening for cystic fibrosis transmembrane conductance regulator gene mutations
      in men included in an intracytoplasmic sperm injection programme.
AB  - The present study was undertaken to evaluate the frequency and nature of
      mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
      in infertile patients undergoing intracytoplasmic sperm injection. A total of 90
      patients were screened for a panel of 10 mutations in the CFTR gene frequently
      involved in congenital absence of the vas deferens (CAVD); the patients included
      14 with azoospermia and CAVD, 39 patients with azoospermia without CAVD (n = 39)
      and 37 patients with severe oligozoospermia. The length of the polymorphic
      polypyrimidine tract (allele 5T, 7T and 9T) in the intron 8/exon 9 splice
      acceptor site was also determined. In 10 out of 14 patients with CAVD, CFTR
      mutations were found; nine patients had one DeltaISOdiaDeltaF508 mutation and one
      patient had two CFTR mutations (N1303K/R117H). Allele 5T was present in eight of
      these patients. In six patients, 5T was the non-DeltaISOdiaDeltaF508 allele and
      in two patients there was no known CFTR mutation. None of the CFTR mutations were
      observed in patients with azoospermia without CAVD or with severe oligozoospermia
      and the frequency of allele 5T was 3.6% (three out of 78 alleles) and 1.35% (one
      out of 74 alleles) respectively. Our observation suggests that the CFTR gene is
      not involved in either spermatogenesis or in the pathology of the genital tract,
      except for CAVD.

PMID- 10341010
TI  - Application and Quantitative Validation of Computer-Automated Three-Dimensional
      Counting of Cell Nuclei.
AB  - : This study provides a quantitative validation of qualitative automated three
      dimensional (3-D) analysis methods reported earlier. It demonstrates the
      applicability and quantitative accuracy of our method to detect, characterize,
      and count Feulgen stained cell nuclei in two tissues (hippocampus and testes).
      These methods can provide important insights into the interpretation of
      biological, pharmacological, pathological, and toxicological events. A laser
      scanned confocal light microscope was used to record 3-D images in which our
      algorithms automatically identified individual nuclei from the optical sections
      given an estimate of minimum nuclear size. The hippocampal data sets were also
      manually counted independently by five trained observers using the STERECON 3-D
      image reconstruction system. The automated and manual counts were compared. The
      computer counts were lower ( approximately 14%) than the manual counts, mainly
      because the algorithms counted a nucleus only if it was present in five
      consecutive optical sections but the human counters included nuclei that were in
      fewer optical sections. A nucleus-by-nucleus comparison of the manual and
      automated counts verified that the automated analysis was accurate and
      reproducible, and permitted additional quantitative analyses not available from
      manual methods. The algorithms also identified subpopulations of nuclei within
      the hippocampal samples, and haploid and diploid nuclei in the testes. Our
      methods were shown to be repeatable, accurate, and more consistent than manual
      counting. Nuclei in regions of high (hippocampal pyramidal layer) and low
      (extrapyramidal layer) density were distinguished with equal ease. Haploid and
      diploid nuclei were distinguished in the testes, demonstrating that our automated
      method may be useful for ploidy analysis. The results presented here on
      hippocampus and testis are consistent with other qualitative results from the
      liver and from immunohistochemically labeled substantia nigra, demonstrating the
      applicability of our software across tissues and preparation methods.

PMID- 10341009
TI  - Corrosion Casting in the Reproduction of the Microsurface Topography of Fibrillar
      Collagen.
AB  - : We have used a two-step casting procedure to create replicas of fibrillar
      collagen. A negative replica or mold is first created using either Mercox casting
      resin or a prepolymerized methacrylate resin that was originally described by
      Murakami. In the second step, a positive replica is made from the first using a
      solution of polystyrene or polyurethane to coat the methacrylate cast. The
      resulting replica is removed from the methacrylate cast. Results indicate the
      highest level of spatial resolution is obtained using a modified Murakami resin
      for the negative cast and polystyrene for the positive replica. The 29-nm-wide
      repeat banding structure present on collagen fibrils could be clearly identified
      in both the methacrylate cast and in the polystyrene positive replica of the
      methacrylate cast. Thus high-resolution replicas can be obtained. Such replicas
      may be useful to imprint inplantable devices with biologically relevant textures
      to improve tissue integration or for the development of textured surfaces for the
      in vitro expansion of cultured cells.

PMID- 10341011
TI  - Improved Count Rate and Resolution Performance of a Thermoelectrically Cooled
      Si(Li) X-ray Detector.
AB  - : A new energy-dispersive spectrometer Si(Li) detector for microanalysis
      applications, cooled by a thermoelectric (Peltier) refrigerator, was
      significantly improved with regard to the resolution and high count-rate
      performance. This new detector was mounted on a JEOL 6400 scanning electron
      microscope, and several application tests were run to analyze its performance.
      The common resolution test using an Fe55 radioactive source was performed, and it
      was compared with the conventional liquid nitrogen (LN) detector. The resolution
      at low and high count-rate was found to be slightly less than the LN detector's
      performance; however, these differences are minor and most application
      requirements were easily met. The thermoelectric cooling mechanism was found to
      be stable and reliable with no degradation in its performance recorded during
      several years of use. The collected data show improved performance by the new
      thermoelectrically cooled (TEC) detector compared with the old TEC design and
      underscore performance very close to the LN product. For most microanalysis
      applications, the new TEC X-ray detector can easily replace the LN detector and
      avoid the maintenance associated with LN filling.

PMID- 10341012
TI  - Plasma Cleaning and Its Applications for Electron Microscopy.
AB  - : The effectiveness of applying a high-frequency, low-energy, reactive gas plasma
      for the removal of hydrocarbon contamination from specimens and components for
      electron microscopy has been investigated with a variety of analytical
      techniques. Transmission electron microscopy (TEM) analysis of specimens that
      have been plasma cleaned shows an elimination of the carbonaceous contamination
      from the specimen. With extended cleaning times the removal of existing carbon
      contamination debris due to previously conducted microanalysis is shown.
      Following plasma cleaning, specimens may be examined in the electron microscope
      for several hours without exhibiting evidence of recontamination. The
      effectiveness of plasma cleaning is not limited to applications for TEM
      specimens. Scanning electron microscopy (SEM) specimens that have been plasma
      cleaned likewise show an elimination of carbonaceous contamination. Furthermore,
      other electron microscopy parts and accessories, such as aperture strips,
      specimen clamping rings, and Wehnelts, among others, can benefit from plasma
      cleaning.

PMID- 10341013
TI  - Edge Sharpening for Unbiased Edge Detection in Field Emission Scanning Electron
      Microscope Images.
AB  - : We report here a specific type of edge strength anisotropy observed in field
      emission scanning electron microscope (FESEM) images. The images show weaker edge
      gradients in the scanning direction and hence these edges frequently go
      undetected. Direct application of edge detection algorithms to images with
      nondistinct edges, such as powder particles, show strong bias to edges
      perpendicular to the scanning direction. Edge orientation polarograms obtained
      from these images always show strong fictitious particle orientation in the
      scanning direction. In this work, we discuss an edge-sharpening algorithm that
      corrects for this bias and results in relatively more accurate and consistent
      edge orientation information.

PMID- 10341014
TI  - News and Commentary.

PMID- 10341015
TI  - Evidence for plasma membrane-mediated effects of estrogen.

PMID- 10341016
TI  - An open-label extension study of alendronate treatment in elderly women with
      osteoporosis.
AB  - We have recently reported the results of a 24-month, double-blind, placebo
      controlled study in 359 elderly osteoporotic women who were treated with daily
      oral alendronate (ALN) 1, 2.5, or 5 mg or placebo (PBO). We report the results of
      a 12-month, open-label, extension study during which 246 patients from the
      original study were treated with ALN 10 mg/day. Significant increases in lumbar
      spine bone mineral density (BMD) were observed in patients who had previously
      received PBO or ALN 1 and 2.5 mg/day for 24 months. Significant gains in
      trochanter BMD were seen in all treatment groups. Small changes were observed in
      femoral neck, total body, and forearm BMD during the course of this extension
      study. In general, the greatest increases in BMD during the open-label extension
      year occurred in patients who received either PBO or the lower doses of ALN
      during the previous 2-year blinded study. The frequencies of all categories of
      upper gastrointestinal adverse experiences (AEs) were less during months 25-36
      (open-label extension) than during months 0-24 (original study). In conclusion,
      treatment with ALN 10 mg/day for 12 months in elderly women with osteoporosis who
      were previously treated for 24 months with PBO or ALN 1, 2.5, or 5 mg/day
      increased or maintained BMD of the spine, trochanter, and forearm, and was
      generally safe and well tolerated, especially in the upper gastrointestinal
      tract.

PMID- 10341017
TI  - The role of collagen abnormalities in ultrasound and densitometry assessment: In
      vivo evidence.
AB  - There is little information concerning how the mutation of collagen affects bone
      mineralization and the assessment of bone properties. To estimate these
      influences, we performed ultrasonic assessments of the calcaneus and bone mineral
      density (BMD) measurements of the hip and lumbar spine. Females with diseases
      related to the mutation of collagen [Ehlers-Danlos syndrome (EDS) type III and
      systemic sclerosis (SSc)] participated in this study. We compared the broadband
      ultrasound attenuation (BUA and UBI-4), the average transit time through the heel
      (TTH), and a multiple factor index (UBI-4T) with control subjects matched on age,
      race, and menstrual status. Both groups of patients had BMD of the spine (L2-L4)
      within the normal range for their age and sex (for EDS: n = 23, 1.14 +/- 0. 14
      g/cm2 and z-score = 0.37; for SSc: n = 15, 0.98 +/- 0.15 g/cm2 and z-score =
      0.20). EDS and SSc subjects had lower BMD of the femoral neck (FN) compared with
      controls (for EDS: 0.91 +/- 0.13 g/cm2, z-score = -0.41, P = 0.025; for SSc 0.67
      +/- 0.13 g/cm2, z-score = -0.92, P = 0.006). Subjects with EDS and SSc also had
      lower BUA values (P = 0.051-0.001) compared with controls. After adjusting for
      body weight, height, and the level of physical activity, the difference in FN BMD
      between EDS or SSc and controls became marginal (EDS: P = 0.072; SSc: P = 0.086).
      However, the significant difference for BUA between subjects and controls
      remained for EDS (P = 0.008), and disappeared for SSc (0.70) after adjusting for
      weight, height, level of physical activity, and BMD. These results suggest that
      the abnormalities of collagen may impact on bone mass measurements differently
      depending on skeletal site, modality of the assessment, and the source and nature
      of collagen defects. To determine whether collagen properties influence QUS,
      proper models in vivo and in vitro should be used.

PMID- 10341018
TI  - Relationships between static histomorphometry and ultrasound in the human
      calcaneus.
AB  - The aim of this study was to explore the relationship(s) between
      histomorphometric measurements of cancellous bone structure and ultrasound.
      Ultrasonic measurements were made using a CUBA research system consisting of a
      pair of 1 Mhz unfocused transducers. Speed of sound (SOS) and broadband
      ultrasonic attenuation (BUA) were determined in 15 human cadaveric heels, with
      mean precision for all measurements coefficients of variation (CV) = 0.6% and
      12%, respectively. The calcaneus was dissected and a 7.5 mm transcortical
      cylinder was removed from the path of ultrasound (US) transmission. The cortices
      were removed and the remaining cancellous core was sectioned into approximately 5
      mm blocks, numbered from 1 to 6 (medial-lateral). Histomorphometric measurements
      were performed on decalcified, 5 microm-thick sections from blocks 1-6 using an
      automatic color image analysis system. There were significant differences between
      blocks 1 and 3-6 for BS/TV, BV/TV, Tb.N, and Tb. Sp (all P < 0.001), all
      decreasing in a medial-lateral direction (except Tb.Sp), implying that the medial
      portion of the calcaneus had more trabeculae with less spacing between them than
      the lateral portion. Furthermore, Tb.Th and BS/BV variables were uniform across
      the calcaneus, suggesting that individual trabeculae were of similar dimension.
      We found no significant correlations between US and histomorphometric parameters
      either averaged over all blocks or by using each block region separately. In
      conclusion, this study does not support the notion that US measurements of SOS
      and BUA through the heel reflect calcaneal cancellous bone structure, however,
      further studies using larger sample sizes may be warranted.

PMID- 10341019
TI  - Bone mineral density of patients with thalassemia major: four-year follow-up.
AB  - The purpose of this study was to evaluate the bone mineral density (BMD) of 50
      patients aged 9-28 years, with thalassemia major and to assess the alterations of
      bone density in a 4-year follow-up study. They were measured with a DPX
      densitometer at the lumbar spine and femur area and divided into three groups:
      preadolescents, adolescents, and adults. All patients received calcium and
      vitamin D supplements, and 8 of the 50 received hormone replacement therapy
      (HRT). All patients had a significantly lower BMD compared with healthy subjects.
      Mean values of lumbar BMD of the three groups were 1.3, 2, and 3 standard
      deviations (SDs) lower than those of healthy subjects of the same age. All
      adolescent patients with normal gonadal function and those who received HRT
      showed an increase in BMD during the period of the study. Adult patients also
      showed an increase in bone density as long as the treatment lasted. However,
      adolescent and adult patients who had hypogonadotropic hypogonadism but could not
      get therapy showed a decrease in bone density. BMD of patients with thalassemia
      major shows a good index of bone status which should be evaluated, especially for
      the determination and follow-up of therapy.

PMID- 10341020
TI  - Immobility as a major cause of bone remodeling in residents of a long-stay
      geriatric ward.
AB  - Residents of a long-stay geriatric ward at the University Hospital Basel were
      included in a study to investigate the effects of hypovitaminosis D and
      immobility. All 91 women (mean age 82.5 years) and 92 men (mean age 78.7 years)
      were enrolled in the study. Measurements included bone resorption, as measured by
      urinary deoxypyridinoline (dpd), serum 25-hydroxyvitamin D (25OHD), serum intact
      parathyroid hormone (iPTH), and their correlations with a four grade mobility
      score. Mobility score reflected the degree of weight bearing, ranging from
      walking independently to primarily bed bound. In 86% of all residents, serum
      25OHD levels were below the normal limit of 12 ng/ml. Secondary
      hyperparathyroidism (HPT) was detected in 24% of all patients, using 55 pg/ml as
      the upper limit for serum iPTH. No significant correlation was found between
      urinary dpd and serum 25OHD or serum iPTH. Mobility index and both urinary dpd
      (f: P = 0.001, r = 0.37; m: P < 0.0001, r = 0.47) and serum calcium (female: P =
      0.007, r = 0.28; male: P = 0.02, r = 0.24) were positively related. In
      institutionalized elderly people with a high prevalence of vitamin D deficiency
      serum intact PTH levels did not correlate with bone resorption as measured by
      urinary deoxypyridinolin. However, more immobile subjects had significantly
      higher excretion rates for urinary dpd and higher serum calcium levels. Our
      results suggest that in elderly people immobility may contribute to bone loss
      that might preempt the development of secondary HPT through elevation of serum
      calcium.

PMID- 10341021
TI  - A comparison of bone mineral density and muscle strength in young male adults
      with different exercise level.
AB  - The aim of this study was to investigate any differences in bone mass at
      different sites between young adults subjected to a high physical activity and a
      group of young adults with a low level of physical activity. In addition, we
      compared the relationship among bone mass, muscle strength, and body constitution
      in these two groups. The reference group consisted of 20 men, age 24.6 +/- 2.3
      years, not training for more than 3 hours per week. The ice hockey players
      consisted of 20 players, age 23.4 +/- 4.9 years, from an ice hockey team in the
      second highest national Swedish league, training for about 10 hours per week. The
      groups were matched according to age, height, and weight. Areal bone mineral
      density (BMD) was measured in total body, head, humerus, spine, pelvis, femur,
      femoral neck, Ward's triangle, trochanter, femur diaphysis, proximal tibia, and
      tibia diaphysis using dual energy X-ray absorptiometry. BMD was significantly
      higher in the total body (8.1%), humerus (11.4%), spine (12.7%), pelvis (12.4%),
      femoral neck (10.3%), femur (7.4%), proximal tibia (9.8%), and tibia diaphysis
      (7.5%) in the high activity group. Fat mass was significantly lower in the high
      activity group (18.7%). The high activity group also had a significantly higher
      lean body mass (5.4%) and a significantly higher isokinetic muscle strength of
      the quadriceps muscle compared with the reference group. In the reference group,
      there was a general strong independent relationship between muscle strength of
      the thigh and all BMD sites, except for the head, tibia diaphysis, and proximal
      tibia. Furthermore, in the same group, body mass index (BMI) independently
      predicted pelvis BMD. On the contrary, in the high activity group, muscle
      strength did not predict any BMD site at all. In the same group, body
      constitutional parameters (weight, height, and fat mass) independently predicted
      pelvis BMD, and BMI was shown to be an independent predictor of humerus BMD. The
      differences in BMD between the groups seem to be site-specific and may be
      associated with the type and magnitude of loading during off season training and
      preferentially during ice hockey. High physical activity seems to weaken the
      relationship between BMD and muscle strength. Hence, impact forces may be of
      greater importance in regulating bone mass than muscle strength in itself in
      highly trained athletes.

PMID- 10341022
TI  - Effects of roughness, fibronectin and vitronectin on attachment, spreading, and
      proliferation of human osteoblast-like cells (Saos-2) on titanium surfaces.
AB  - The influence of surface roughness and the presence of adhesion molecules in the
      culture medium were studied regarding cell adhesion, shape, and proliferation of
      osteoblast-like cells grown on two types of titanium disk. Type I disks were acid
      etched and type II disks were sandblasted and acid etched. Surface roughness was
      determined by contact profilometry and scanning electron microscopy. Chemical
      composition and oxide thickness of the superficial titanium layer were
      established with energy dispersive X-ray spectrometry, electron spectroscopy for
      chemical analysis and auger electron spectroscopy. Titanium release in the
      culture medium was assessed by inductively coupled plasma-optical emission
      spectrometry. Osteoblast-like cells (Saos-2) were cultured on both types of
      titanium disks (1) in standard conditions (DMEM culture medium supplemented with
      fetal calf serum), (FCS), (2) with the culture medium alone (DMEM alone), (3) in
      the presence of fibronectin or vitronectin (DMEM supplemented with fibronectin or
      vitronectin). Cultures were also performed in the presence of monoclonal anti
      integrin (beta1, alphav) to test the cell adhesion molecules involved in the cell
      binding to the titanium surface. We found that sandblasting does not modify the
      chemical surface composition and that titanium represents only 5-6% (in the atom
      percentage) of surface elements. Release of titanium in the culture medium was
      found to increase from 24 to 72 hours. In the absence of FCS, fibronectin, or
      vitronectin, cells appeared scanty and packed in clusters. On the contrary, cells
      cultured in the presence of FCS, fibronectin, or vitronectin were flattened with
      large and thin cytoplasmic expansions. The addition of anti beta1 or alphav
      integrin subunit monoclonal antibody in the culture medium decreased adhesion and
      spreading of cells, particularly in the presence of fibronectin. Cell
      proliferation was significantly higher on culture plastic than on both types of
      disks, but was increased on rough but not on smooth surfaces. These results
      indicate that a high surface roughness and presence of fibronectin or vitronectin
      are critical elements for adhesion, spreading, and proliferation of cells on
      titanium surfaces.

PMID- 10341024
TI  - Protein electrostatic surface distribution can determine whether calcium oxalate
      crystal growth is promoted or inhibited.
AB  - Acidic proteins found in mineralized tissues act as nature's crystal engineers,
      where they play a key role in promoting or inhibiting the growth of minerals such
      as hydroxyapatite and calcium oxalate. Despite their importance in such
      fundamental physiological processes as bone and tooth formation, however, there
      is remarkably little known of the protein structure-function relationships that
      govern crystal recognition. We have taken a model system approach to elucidate
      some of the relationships between protein surface chemistry and secondary crystal
      growth of biological minerals. We show here that the distribution of
      electrostatic surface charge on our model protein, Protein G, determined whether
      the secondary growth of calcium oxalate, the principal mineral phase of kidney
      stones, was promoted or inhibited when the proteins were preadsorbed at low and
      equivalent surface coverages of <10%. The native Protein G, which contains 10
      surface carboxylates, increased the rate of calcium oxalate growth from aqueous
      solution under constant composition conditions up to 97%, whereas a site-directed
      mutant with six of the surface charges removed inhibited the growth rate by 60%.
      The adsorption isotherms of both proteins were determined and suggested that the
      differences in electrostatic surface properties also lead to differences in
      protein orientation on the crystal surface. These results demonstrate that
      differences in electrostatic surface potential of proteins can directly determine
      whether secondary calcium oxalate growth is promoted or inhibited, and a model is
      proposed that suggests the distribution of carboxylate residues determines the
      interrelated binding orientation and exposed surface chemistry of the adsorbed
      Protein G.

PMID- 10341023
TI  - Meltrin-alpha, a fusion protein involved in multinucleated giant cell and
      osteoclast formation.
AB  - The formation of multinucleated cells such as myotubes, macrophage-derived giant
      cells (MGC), and osteoclasts is the result of cell-cell fusion of mononuclear
      precursors. Meltrin-alpha, -beta, and -gamma are members of a recently discovered
      family of proteins that contain disintegrin and metalloprotease domains and are
      related to fertilin, a protein involved in egg-sperm fusion. Based on this and
      evidence implicating meltrin-alpha in myoblast formation, we have investigated
      the possibility that meltrins may also play a role in the formation of MGC and
      osteoclasts. Using in situ RT-PCR, we have determined that murine mononuclear
      alveolar macrophages cultured under basal conditions express the transcript for
      meltrin-beta, but not for meltrin-alpha. However, meltrin-alpha mRNA appeared in
      mononuclear cells before cell fusion after treatment with 1,25-dihydroxyvitamin
      D3 [1,25(OH)2D3], a potent inducer of giant cell and osteoclast formation.
      Moreover, addition of meltrin-alpha antisense oligonucleotides to the cultures
      caused a 50% inhibition of giant cell formation. Similarly, meltrin-alpha
      antisense oligonucleotides inhibited by 70% the formation of multinucleated
      osteoclast-like cells expressing tartrate-resistant acid phosphatase (TRAP) in co
      cultures of bone marrow cells and osteoblastic cells (2107) in the presence of
      1,25(OH)2D3. Mononucleated TRAP-positive cells, induced by 1,25(OH)2D3 in the co
      cultures, also expressed meltrin-alpha mRNA, but their number was not changed in
      the presence of meltrin-alpha antisense oligonucleotide. In contrast to
      mononuclear macrophages and osteoclast-like cells, murine bone marrow stroma and
      calvaria derived-cell lines (+/+ LDA.11 and 2107), primary cultures of calvaria
      cells, and primary cultures of bone marrow cells expressed both meltrin-alpha and
      -beta mRNA under basal conditions; whereas embryonic fibroblasts (NIH3T3)
      expressed only the meltrin-beta transcript. Upregulation of meltrin-alpha protein
      expression during cell fusion in alveolar macrophages and expression in
      osteoblastic cell lines were confirmed by Western blot analysis. These
      observations demonstrate that meltrins play a role in MGC and osteoclast
      formation from mononuclear precursors, as in the case with myotubes.

PMID- 10341025
TI  - Transforming growth factor-beta2 mRNA level in unloaded bone analyzed by
      quantitative in situ hybridization.
AB  - The effects of tail suspension hypokinesia on the gene expression for TGF-beta2
      at different sites within bone were evaluated. TGF-beta2 mRNA signal levels were
      determined quantitatively by an image analysis system. The osteopenia induced by
      tail suspension was verified by histomorphometry. In the periosteum of
      nonsuspended control rats, TGF-beta2 mRNA was highly expressed in the
      preosteoblasts and osteoblast-rich cambial layers; very little signal was present
      within the middle and outer fibroblastic layers. Gene expression was
      significantly reduced in suspended rats, and this was evident both in terms of
      the number of silver grains in unit area or length of tissue and in each
      osteoblast and preosteoblast. Hypokinesia also reduced the expression of TGF
      beta2 mRNA level in cortical and trabecular bone osteocytes, but did not
      adversely affect the mRNA level in chondrocytes in growth plate. The results
      affirm the site-specific response of TGF-beta2 gene expression in rats, and
      suggest that the cortical and trabecular bone osteopenia associated with
      hypokinesia in rats may be associated with a deficit in osteoblastic and
      osteocytic TGF-beta2 level.

PMID- 10341026
TI  - Carnitine and dehydroepiandrosterone sulfate induce protein synthesis in porcine
      primary osteoblast-like cells.
AB  - Age-related bone loss eventually leads to osteopenia in men and women. The
      etiology of age-related bone loss is currently unknown; however, decreased
      osteoblast activity contributes to this phenomenon. In turn, osteoblast
      proliferation and function is dependent on energy production, thus the loss of
      energy production that occurs with age may account for the deficient osteoblast
      activity. Carnitine and dehydroepiandrosterone-sulfate (DHEAS), both of which
      decline with age, promote energy production through fatty acid metabolism. Thus,
      we hypothesized that carnitine and DHEAS would increase osteoblast activity in
      vitro. Accordingly, we measured the effect of carnitine and DHEAS on palmitic
      acid oxidation as a measure of energy production, and alkaline phosphatase (ALP)
      activity and collagen type I (COL) as indices of osteoblast function in primary
      porcine osteoblast-like cell cultures. Carnitine (10(-3) and 10(-1) M) but not
      DHEAS (10(-9), 10(-8), and 10(-7) M) increased carnitine levels within the cells.
      Carnitine alone and in combination with DHEAS increased palmitic acid oxidation.
      Both carnitine and DHEAS alone and in an additive fashion increased ALP activity
      and COL levels. These results demonstrate that in osteoblast-like cells in vitro,
      energy production can be increased by carnitine and osteoblast protein production
      can be increased by both carnitine and DHEAS. These data suggest that carnitine
      and DHEAS supplementation in the elderly may stimulate osteoblast activity and
      decrease age-related bone loss.

PMID- 10341028
TI  - Stimulation of bone formation by recombinant fibroblast growth factor-2 in
      callotasis bone lengthening of rabbits.
AB  - Bone lengthening by callotasis is one of the most useful methods not only for the
      treatment of short extremities but also for extensive bone defects; however, the
      procedure takes a long time especially for the consolidation of the distracted
      callus. In this study, effects of a single local injection of recombinant human
      fibroblast growth factor-2 (FGF-2 or basic FGF) on callotasis bone lengthening
      were examined in rabbits. Ten days after the osteotomy at the middle of the tibia
      and the installment of an external fixator, the osteotomized site was distracted
      at a rate of 1.4 mm/day for 7 days, resulting in 9.8 mm lengthening. On the final
      day of distraction, 200 microg of FGF-2 in 150 microl of saline solution or
      vehicle alone was injected into the center of the distracted callus. Injection of
      FGF-2 increased bone formation at the distracted callus radiologically and
      histologically. A significant effect on bone mineral content (BMC) at the callus
      was observed as early as 2 weeks, and FGF-2 increased the BMC about twofold at 5
      weeks after a normal remodeling process. We conclude that the callotasis method
      in combination with FGF-2 injection at the consolidation step could be clinically
      beneficial to shorten the bone lengthening period.

PMID- 10341027
TI  - Aluminum-induced osteogenesis in osteopenic rats with normal renal function.
AB  - Previous studies have shown a different effect of aluminum (Al) on bone
      metabolism in animals with chronic renal failure and conversely, positive
      osteogenic effects in animals with normal renal function. The aim of this study
      was to evaluate the effect of aluminum on bone metabolism in osteopenic rats. We
      studied male Wistar rats with severe osteopenia induced by adding NH4Cl (2%) to
      the drinking water over a 6-month period. The rats were divided into two groups
      and followed for 4 months. The Aluminum group (G1) received AlC13
      intraperitoneally (10 mg/kg/5 days/week) (n = 8); the Control group (G2) did not
      receive any treatment after stopping the administration of NH4Cl (n = 5). In all
      animals we measured biochemical markers (serum Ca, P, Cr, Al, osteocalcin,
      hydroxyproline) as well as bone mineral density and bone histomorphometry (BV/TV,
      CTh, ObS/BS, OTh, and NOc/TV). Bone aluminum content, measured by atomic
      absorption spectrometry, was 101.6 +/- 13 microg/g in the Al overloaded group and
      1.31 +/- 0.14 in controls. Bone mineral density, evaluated by dual X-ray
      absorptiometry (DXA) at the proximal extremity of the tibia was significantly
      higher in G1 (0.292 +/- 0.01 g/cm2 versus 0. 267 +/- 0.02 g/cm2). No significant
      differences were found between the biochemical markers. In the histomorphometric
      parameters we observed significant differences in G1 compared with G2: an
      increase in BV/TV (18.59 +/- 5.6 versus 7.69 +/- 3.08%) and in CTh (0.52 +/- 0.06
      versus 0.36 +/- 0.07 mm) with a moderate increment of the osteoid thickness
      (14.05 +/- 4.72 versus 5.25 +/- 0.9 microm) (P < 0. 05). Changes in others
      parameters and the relationship between biochemical parameters of bone
      remodeling, Al, and histology were analyzed. These findings indicate that in rats
      with normal renal function, Al is able to induce bone formation even when
      osteopenia is present.

PMID- 10341029
TI  - Septins: a highly conserved family of membrane-associated GTPases with functions
      in cell division and beyond.

PMID- 10341030
TI  - Involvement of methionine residues in the fast inactivation mechanism of the
      sodium current from toad skeletal muscle fibers.
AB  - The role of methionine residues on the fast inactivation of the sodium channel
      from toad skeletal muscle fibers was studied with the mild oxidant chloramine-T
      (CT). Isolated segments of fibers were voltage clamped in a triple Vaseline gap
      chamber. Sodium current was isolated by replacing potassium ions by
      tetramethylammonium ions in the external and internal solutions. Externally
      applied chloramine-CT was found to render noninactivating a large fraction of
      sodium channels and to slow down the fast inactivation mechanism of the remainder
      fraction of inactivatable channels. The action of CT appeared to proceed first by
      slowing and then removing the fast inactivation mechanism. The voltage dependence
      of the steady-state inactivation of the inactivatable CT-treated currents was
      shifted +10 mV. CT also had a blocking effect on the sodium current, but was
      without effect on the activation mechanism. The effects of CT were time and
      concentration dependent and irreversible. The use of high CT concentrations
      and/or long exposure times was found to be deleterious to the fiber. This side
      effect precluded the complete removal of fast inactivation. The effects of CT on
      the fast inactivation of the sodium current can be explained assuming that at
      least two methionine residues are critically involved in the mechanism underlying
      this process.

PMID- 10341031
TI  - Quantitative determination of gap junctional permeability in the lens cortex.
AB  - We have developed a simple dye transfer method, which allows the gap junction
      permeability of lens fiber cells to be quantified. Two fixable fluorescent dyes
      (Lucifer yellow and rhodamine-dextran) were introduced into peripheral lens fiber
      cells via mechanical damage induced by removing the lens capsule. After a defined
      incubation period, lenses were fixed, sectioned, and the distribution of the dye
      recorded using confocal microscopy. Rhodamine-dextran and Lucifer yellow both
      labeled the extracellular space between fiber cells and the cytoplasm of fiber
      cells that had been damaged by capsule removal. For the gap junctional permeable
      dye Lucifer yellow, however, labeling was not confined to the damaged cells and
      exhibited intercellular diffusion away from the damaged cells. The extent of dye
      diffusion was quantified by collecting radial dye intensity profiles from the
      confocal images. Effective diffusion coefficients (D eff) for Lucifer yellow were
      then calculated by fitting the profiles to a series of model equations, which
      describe radial diffusion in a sphere. D eff is the combination of dye diffusion
      through the cytoplasm and through gap junction channels. To calculate the gap
      junctional permeability (Pj) an estimate of the cytoplasmic diffusion coefficient
      (Dcyt = 0.7 x 10(-6) cm2/sec) was obtained by observing the time course of dye
      diffusion in isolated elongated fiber cells loaded with Lucifer yellow via a
      patch pipette. Using this approach, we have obtained a value for Pj of 31 x 10(
      5) cm/sec for fiber-fiber gap junctions. This value is significantly larger than
      the value of Pj of 4.4 x 10(-6) cm/sec reported by Rae and coworkers for
      epithelial-fiber junctions (Rae et al., 1996. J. Membrane Biol. 150:89-103), and
      most likely reflects the high abundance of gap junctions between lens fiber
      cells.

PMID- 10341032
TI  - Electric field pulses can induce apoptosis.
AB  - Injection of electric field pulses of high intensity (kV/cm) and short duration
      (microsecond range) into a cell suspension results in a temporary increase of the
      membrane permeability due to a reversible electric breakdown of the cell
      membrane. Here we demonstrate that application of supercritical field pulses
      between 4. 5 and 8.1 kV/cm strength and 40 microsec duration induce typical
      features of apoptosis in Jurkat T-lymphoblasts and in HL-60 cells including DNA
      fragmentation and cleavage of the poly(ADP ribose) polymerase. Apoptosis
      induction did not depend on the presence of any particular electrolyte in the
      extracellular medium. However, no apoptosis was observed in solutions without a
      minimum amount of salt. Apoptotic DNA fragmentation was prevented by the caspase
      inhibitor zVAD.

PMID- 10341033
TI  - Surface pH at the basolateral membrane of the caecal mucosa of guinea pig.
AB  - Since the major mechanisms responsible for regulation of intracellular pH of
      enterocytes are located in the basolateral membrane, respective effects may be
      expected on pH in the compartment near the basolateral membrane. A method was
      established to estimate the pH at the basolateral membrane (pHb) of isolated
      caecal epithelia of guinea pig using pH-sensitive fluorescein attached to lectin
      (lens culinaris). In the presence of bicarbonate and a perfusion solution-pH of
      7.4, pHb was 7.70 +/- 0.15. In the absence of bicarbonate or chloride as well as
      by inhibition of the basolateral Cl--HCO-3 exchange with H2-DIDS, pHb was reduced
      near to solution-pH. Inhibition of the basolateral Na+-H+ exchanger by adding a
      sodium- and bicarbonate-free, low-buffered solution increased pHb. Decrease of pH
      of serosal perfusion solution to 6.4 provoked a similar decrease of pHb to
      solution pH. Short-chain fatty acids (SCFA) added to the mucosal solution caused
      a slight decrease of pHb. SCFA added to the serosal side alkalized pHb. However,
      in the presence of bicarbonate pHb returned quickly to the initial pHb, and after
      removal of SCFA a transient acidification of pHb was seen. These responses could
      not be inhibited by MIA or H2-DIDS. We conclude that no constant pH-microclimate
      exists at the basolateral side. The regulation of the intracellular pH of
      enterocytes reflects pHb. The slightly alkaline pHb is due to the bicarbonate
      efflux. Data support the presence of an SCFA--HCO-3 exchange.

PMID- 10341034
TI  - Functional expression and characterization of G-protein-gated inwardly rectifying
      K+ channels containing GIRK3.
AB  - The G-protein-gated inwardly rectifying K+(GIRK) family of ion channels form
      functional Gbetagamma-sensitive channels as heteromultimers of GIRK1 and either
      the GIRK2 or GIRK4 subunits. However, the homologous mouse brain GIRK3 clone
      failed to express in the earliest reported functional experiments in Xenopus
      oocytes. We recloned the GIRK3 subunit from mouse brain and found that the new
      clone differed significantly from that originally reported. The functional
      aspects of GIRK3 were reinvestigated by expression in CHO cells. The single
      channel properties of GIRK1/GIRK3 were characterized and compared to those of the
      GIRK1/GIRK2 and GIRK1/GIRK4 channels. All three GIRK1/GIRKx combinations produced
      channels with nearly indistinguishable conductances and kinetics. The response of
      GIRK1/GIRK3 to Gbetagamma in the 1-47 nm range was examined and found to be
      indistinguishable from that of GIRK1/GIRK4 channels. We conclude that GIRK1, with
      either GIRK2, 3, or 4, gives rise to heteromultimeric channels with virtually
      identical conductances, kinetics, and Gbetagamma sensitivities.

PMID- 10341036
TI  - Determination of warfarin in waters and human plasma by solid-phase room
      temperature transmitted phosphorescence.
AB  - A new method for the determination of warfarin in waters and human plasma using
      solid-phase room-temperature phosphorescence is proposed. The sample was spotted
      on Whatman No. 4 filter paper, together with iodide and NaOH solutions, after
      which it was dried and its transmitted phosphorescence intensity measured at 467
      nm using two quartz plates to avoid the quenching effect produced by oxygen. The
      applicable concentration range went from 0.3 to 4.0 mg. L-1, and the detection
      and quantification limits were 0.08 and 0.28 mg. L-1 respectively. The precision
      of the method, as a relative standard deviation, was 2.3%. The method was applied
      in the determination of warfarin in human plasma and different types of water.
      The interferences produced by the albumin of the human plasma were eliminated by
      the addition of Na2SO4 saturated solution. Recoveries ranging between 93.0 and
      109.0% in the case of water samples, and between 95.0 and 103.0% in the case of
      human plasma, were obtained. These results were compared with the results
      obtained by other methods.

PMID- 10341035
TI  - Effect of trace levels of nigericin on intracellular pH and acid-base transport
      in rat renal mesangial cells.
AB  - Nigericin is an ionophore commonly used at the end of experiments to calibrate
      intracellularly trapped pH-sensitive dyes. In the present study, we explore the
      possibility that residual nigericin from dye calibration in one experiment might
      interfere with intracellular pH (pHi) changes in the next. Using the pH-sensitive
      fluorescent dye 2', 7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF), we
      measured pHi in cultured rat renal mesangial cells. Nigericin contamination
      caused: (i) an increase in acid loading during the pHi decrease elicited by
      removing extracellular Na+, (ii) an increase in acid extrusion during the pHi
      increase caused by elevating extracellular [K+], and (iii) an acid shift in the
      pHi dependence of the background intracellular acid loading unmasked by
      inhibiting Na-H exchange with ethylisopropylamiloride (EIPA). However,
      contamination had no effect on the pHi dependence of Na-H exchange, computed by
      adding the pHi dependencies of total acid extrusion and background acid loading.
      Nigericin contamination can be conveniently minimized by using a separate line to
      deliver nigericin to the cells, and by briefly washing the tubing with ethanol
      and water after each experiment.

PMID- 10341037
TI  - Distribution of trace elements in streambed sediment associated with mining
      activities in the upper colorado river basin, colorado, USA, 1995-96 
AB  - Streambed-sediment samples were collected in the Southern Rocky Mountains
      physiographic province in the Upper Colorado River Basin in Colorado to
      characterize the occurrence and distribution of trace elements in mined and
      nonmined areas of the basin. During October 1995 and September 1996, streambed
      sediment was collected at 37 sites, and the samples were analyzed for trace
      elements. The ranges in concentrations of As, Cd, Cu, Pb, and Zn at mining sites
      generally were orders of magnitude higher than the ranges of concentrations at
      nonmining sites. Sampling sites located in two predominant rock types in mining
      areas were not significantly different (p > 0.05) for concentrations of As, Cd,
      Pb, and Zn. Cu was significantly different (p < 0.05) between sites in the two
      predominant rock types. Concentrations of As, Cd, Cu, Pb, and Zn were not
      significantly different (p > 0.05) between main-stem sites and tributary sites.
      Concentrations of As, Cd, Cu, Pb, and Zn exceeded established guidelines for
      adverse effects on aquatic biota at some sites in the study area. The patterns in
      concentrations of Cd and Zn, Cd and Pb, and Pb and Zn were highly correlated to
      one another in this study. Concentrations of trace elements in the <63-&mgr;m
      fraction were higher than in the total particle-size fraction analysis.
      Comparison of reference sites to sites affected by a mine source indicated that
      trace-element concentrations initially increased downstream of the source and
      then gradually decreased in concentration with distance from the
      source.http://link. springer-ny.com/link/service/journals/00244/bibs/37n1p7.html

PMID- 10341038
TI  - Translocation of microbenthic algal assemblages used for In situ analysis of
      metal pollution in rivers 
AB  - Effects of metal pollution from a zinc factory on microbenthic algal communities
      were assessed in three neighboring streams on the Dutch-Belgian border. Diatom
      species composition was experimentally related to water quality by transferring
      racks with colonized glass discs from a polluted stream to a reference stream and
      vice versa. The succession of species and the changes in biomass and metal
      accumulation were measured during experiments in spring, autumn, and winter.
      Metal concentrations and dry weight in translocated biofilms tended to conform
      with those in local biofilms within an incubation time of 14 to 18 days. Bray
      Curtis similarity values from the different communities indicated that diatom
      communities responded more completely to the metal-polluted conditions than to
      the reference water quality. Cymbella minuta, Diatoma vulgare var. ehrenbergii,
      Navicula sp., and Melosira varians had a lower percentage in assemblages placed
      in the metal-polluted streams. In contrast, Pinnularia sp. and Neidium ampliatum
      decreased in assemblages from the polluted streams that were transferred to the
      reference stream. Achnanthes minutissima and Navicula seminulum (N. atomus)
      proliferated on any translocation, possibly reflecting an opportunistic strategy
      and a high tolerance for Zn and Cd. The behavior of the species in relation to
      metal pollution generally accorded with observations in the literature. However,
      it seems that metal tolerance is not the only selective factor, and other
      ecological variables may also influence the composition of microphytobenthic
      communities.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n1p19.html

PMID- 10341039
TI  - Toxicity of formulated glycol deicers and ethylene and propylene glycol to
      lactuca sativa, lolium perenne, selenastrum capricornutum, and lemna minor 
AB  - Laboratory studies were conducted to determine the toxicity of ethylene glycol
      (EG) and propylene glycol (PG) as well as two formulated glycol aircraft
      deicing/anti-icing fluids (ADAFs) to lettuce (Lactuca sativa), perennial ryegrass
      (Lolium perenne), a green alga (Selenastrum capricornutum), and duckweed (Lemna
      minor). Seedling emergence, root length, and shoot length were measured in
      lettuce and ryegrass; cell growth of the alga and frond growth, chlorophyll a,
      and pheophytin a of the duckweed were measured. While both the ADAFs and pure
      glycols were toxic to the test species, there were substantial differences in how
      the organisms responded to the test materials. ADAFs affected emergence in
      ryegrass more than in lettuce. However, when considering the sublethal endpoints
      of root and shoot length, the ADAFs were significantly more toxic to lettuce. The
      root length 120-h IC25s for lettuce were 2,710 and 21, 270 mg EG/L for the ADAF
      and pure EG compound, respectively; the root length 120-h IC25s for ryegrass were
      4,150 and 3,620 mg EG/L for the ADAF and pure EG compound, respectively. EG and
      PG ADAFs were more toxic than pure EG or PG to L. minor. To S. capricornutum, EG
      ADAF toxicity was similar to EG toxicity, however, PG ADAF was substantially more
      toxic to the alga than pure PG. The greater toxicity of ADAFs is reflective of
      other studies using animals and suggests that although glycols no doubt
      contribute to toxicity in deicer formulations, other compounds in the mixtures
      also contribute to the toxicity of the deicers. However, differences in responses
      between the four plant species suggest differences in modes of action and/or how
      the plants metabolize the compounds.http://link. springer
      ny.com/link/service/journals/00244/bibs/37n1p29.html

PMID- 10341040
TI  - Effect of atrazine on growth, photosynthesis, and between-strain variability in
      scenedesmus subspicatus (Chlorophyceae) 
AB  - The magnitude of between-strain differences in the sensitivity of algal species
      to toxicants is not well known. Yet, informations obtained with a single strain
      are used for ecotoxicological assessment and for interspecific comparisons. Using
      12 strains, we determined whether intraspecific variability occurs in the green
      alga Scenedesmus subspicatus. We examined growth, photosynthetic activity, and
      short-term sensitivity thereof to the herbicide atrazine (500 &mgr;g. L-1) as
      well as how these responses are affected by chronic exposure to low atrazine
      concentrations (0, 1, 5, and 20 &mgr;g. L-1). Independent of chronic exposure to
      atrazine, the strains differed in growth rate and photosynthesis rate. Yet the
      short-term sensitivity to atrazine was affected by the chronic treatments. All
      but one strain became more tolerant, their short-term sensitivity being inversely
      related to the applied atrazine concentration and dependent on the duration of
      exposure. Differences in response to increments in atrazine concentration
      resulted in differences in rank order of sensitivity of strains. Moreover,
      between-strain variability was markedly higher in the atrazine treatments than in
      the controls. These results can be explained by the significant role of genotype
      versus environment interactions in determining intraspecific differences in
      adaptive physiological responses of S. subspicatus to chronic exposure to
      atrazine.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n1p36.html

PMID- 10341041
TI  - Body residues and responses of the midge chironomus riparius to sediment
      associated 2,4,5-trichlorophenol in subchronic and chronic exposures 
AB  - Subchronic and chronic toxicity of sediment-associated 2,4, 5-trichlorophenol to
      the midge Chironomus riparius was determined by conducting a 10-day growth and a
      50-day emergence tests with spiked lake sediment (nominal initial TCP
      concentrations were 25, 51, 101, 203, 304 and 405 &mgr;mol kg-1 dry weight in the
      growth test and 25, 76, 152 and 304 &mgr;mol kg-1 dry weight the emergence test).
      In addition, we measured the residue of chlorophenol in larval tissue and made an
      attempt to relate it with the observed adverse biological responses. The larvae
      were exposed individually to avoid density-dependent effects of mortality on food
      ration and growth of the surviving larvae. In the growth test, mortality was low
      at sediment concentrations </=193 &mgr;mol TCP kg-1, but it increased sharply at
      the higher concentrations being 37 and 94% at 334 and 441 &mgr;mol kg-1 DW,
      respectively. The effect of sediment TCP concentration on larval mortality was
      highly significant (10-day LC50 337 &mgr;mol TCP kg-1 dry sediment) in the growth
      test. In the emergence test, however, mortality was low (3-13%) at all
      concentrations. TCP did not affect larval growth at the concentrations used. The
      concentration of TCP in the whole larvae after the 10-day exposure was
      proportional to sediment concentration, being at highest 160 &mgr;mol kg-1 fresh
      weight. When the average body residues of TCP were below 80 &mgr;mol kg-1,
      mortality was low, but it increased when the body residue approached 100 &mgr;mol
      kg-1. After the 10-day exposure, the body residue, at which 50% of the larvae
      survived (CBR50) was 113 &mgr;mol g-1. TCP exposure accelerated larval
      development and the midges exposed to 171 and 324 &mgr;mol TCP kg-1 emerged
      earlier than those in the other concentrations or in the control sediment. In
      natural environments, sediment-associated chlorophenolics are probably not a
      major environmental problem to benthic fauna because concentrations similar to
      that which we observed to cause adverse effects to C. riparius (>60 mg kg-1 dry
      sediment) are rare.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n1p42.html

PMID- 10341042
TI  - Distribution and specific bioaccumulation of butyltin compounds in a marine
      ecosystem 
AB  - Butyltin compounds (BTs), including tributyltin (TBT) and its breakdown products,
      di- (DBT) and monobutyltin (MBT), were determined in sea water, sediment, and
      biota at various trophic levels in the food chain collected from Otsuchi Bay,
      Japan, for understanding distribution and bioaccumulation of BTs in natural
      marine ecosystems. BT residues were detected in all the compartments analyzed,
      although their concentrations appeared to be less than those in polluted areas.
      Concentrations of BTs in sea water were higher in locations near Otsuchi Port,
      indicating that maritime activities in the harbor has been a major source of BTs
      in this bay. A specific peak in BT residue levels was found in sediment cores at
      an estimated depth that dated to be from the 1980s. Lack of significant variation
      in the composition of BTs at different depths of cores suggests slow degradation
      rate of these compounds in sediments. BTs were accumulated in plankton and other
      organisms up to approximately 70,000 times higher than in sea water. However, no
      considerable biomagnification was observed for BTs through the food chain.
      Relatively high concentrations were found in caprellids and smaller fish, such as
      gunnels. These organisms accumulated TBT as the predominant compound among BT
      derivatives and showed higher bioconcentration factors for TBT than in other
      species reported so far. Our results suggest that certain organisms in the food
      chain may have a less capacity to degrade TBT, and therefore may accumulate BTs
      at elevated levels.http://link.springer-ny.
      com/link/service/journals/00244/bibs/37n1p50.html

PMID- 10341043
TI  - An enzyme-linked immunosorbent assay for estrogenicity using primary hepatocyte
      cultures from the channel catfish (Ictalurus punctatus).
AB  - An in vitro assay has been developed to screen for estrogenic activity of single
      chemicals or complex mixtures. This method combines primary hepatocyte cultures
      from the channel catfish (Ictalurus punctatus) with an enzyme-linked
      immunosorbant assay (ELISA) to detect and quantify the production of vitellogenin
      (VTG), a liver-derived, estrogen-induced lipoprotein. A variety of
      environmentally relevant chemicals and chemical mixtures were tested, including
      the polyaromatic hydrocarbon benzo(a)pyrene (BaP), the alkylphenolic surfactants
      4-tert-octylphenol (OP) and p-nonylphenol (NP), the chlorinated insecticide o,p'
      DDT, the plant derivative stigmastanol, and a number of waste waters from pulp
      and paper mills. In addition, the effects of estradiol (E2), the synthetic
      estrogen diethylstilbestrol (DES) and the antiestrogens trans-1-(4-beta
      dimethylamino-ethoxyphenyl)-1,2-diphenylbut-1-ene (tamoxifen) and 7alpha-[9
      (4,4,5,5, 5-pentafluoro-pentylsulfinyl)nonyl]estra-3,17beta-diol (ICI-182,780)
      were also examined. The following compounds were observed to be estrogenic: DES >
      E2 >> OP > o,p'-DDT > NP. Tests with BaP, stigmastanol, tamoxifen, ICI-182,780,
      and four paper mill effluents exhibited no detectable estrogenic activity.
      Furthermore, both tamoxifen and ICI-182,780 significantly reduced VTG synthesis
      by cells incubated with E2 or DES. Stigmastanol and the mill effluents were also
      tested for anti-estrogenic activity in cells incubated in media containing both
      DES and stigmastanol or effluent. Compared to DES alone, none of these treatments
      caused a significant reduction in the media concentrations of VTG. The detection
      limit for this assay was typically 15-25 ng VTG/ml medium. Screening results and
      performance characteristics such as inter- and intra-assay variability were
      similar to those reported for VTG assays for other teleost species. Thus, the
      present work provides a sensitive, rapid means for screening the estrogenic
      potency of environmentally relevant chemicals and chemical mixtures in vitro.

PMID- 10341044
TI  - Alteration of leopard frog (Rana pipiens) metamorphosis by the herbicide
      acetochlor.
AB  - Based on the geographic correlation between the use of the pre-emergent herbicide
      acetochlor [2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl) acetamide] and
      the natural range of Northern leopard frogs (Rana pipiens), we investigated the
      effects of acetochlor (ACETO) on frog metamorphosis. We specifically examined the
      interaction of ACETO with thyroid hormone (T3) and corticosterone (CORT),
      hormones that regulate natural metamorphosis. ACETO, T3, and CORT were
      administered via immersion. Growth, developmental stage, and onset of metamorphic
      climax (forelimb emergence, FLE) were measured. We examined three hypotheses: (1)
      ACETO may alter metamorphosis. Premetamorphic tadpoles with low endogenous T3
      were exposed to ACETO +/- 10(-9) M T3 for 7 days. 67% of tadpoles exposed to
      ACETO + T3 attained FLE, while 0% of T3 treated animals did. (2) ACETO mimics T3
      action at the thyroid receptor (TR). Tadpoles were pretreated with T3 for 3 days
      to induce TR expression, then treated for 7 days with vehicle (DMSO), T3, or
      ACETO +/- T3. ACETO treatment after T3 priming did not accelerate FLE, suggesting
      that ACETO does not interact directly with the TR. Cotreatment with ACETO + T3
      after T3 priming accelerated FLE relative to tadpoles primed with T3, then
      treated with T3. Because the ACETO + T3 acceleration of FLE appeared similar to
      the effect of CORT, we examined a third hypothesis: (3) ACETO may interact with
      CORT to accelerate FLE. Premetamorphic tadpoles were exposed to various doses of
      ACETO +/- T3 in the presence or absence of 10(-7) M CORT. CORT inhibited growth
      and hindlimb development and delayed FLE. ACETO never inhibited growth or
      hindlimb development, but ACETO did counteract the effects of CORT when T3 was
      present. ACETO consistently accelerated T3-induced metamorphosis, apparently
      interacting with T3 via a non-TR-mediated mechanism.

PMID- 10341045
TI  - Induction of hsp70 by the herbicide oxyfluorfen (Goal) in the Egyptian Nile fish,
      Oreochromis niloticus.
AB  - This paper deals with the expression of the biomarker hsp70 in the liver and
      kidney of the freshwater fish Oreochromis niloticus following exposure to the
      herbicide oxyfluorfen (Goal). Fishes were exposed to three concentrations, the 96
      h LC50 (3 mg/L), the 96-h (1/2)LC50 (1.5 mg/L), and the 96-h (1/4)LC50 (0.75
      mg/L) of oxyfluorfen for 6, 15, and 24 days, respectively, and samples were taken
      at three different time periods for each concentration. The livers responded to
      the herbicide by an induction of the expression of both the constitutive (hsp75;
      Mr 75 kDa) and the inducible (hsp73; Mr 73 kDa) hsp70 proteins. In kidney, the
      herbicide induced a time-dependent increase in the expression of the constitutive
      hsp70 (hsp75) as well, but the inducible hsp70 (hsp73) required much longer
      incubation periods to reach maximal levels (15 and 24 days). Our results suggest
      that expression of hsp70 in fish is a sensitive indicator of cellular responses
      to herbicide exposure in the aquatic environment.

PMID- 10341046
TI  - Toxicity of 4-chloroaniline in early life stages of zebrafish (Danio rerio): II.
      Cytopathology and regeneration of liver and gills after prolonged exposure to
      waterborne 4-chloroaniline.
AB  - Ultrastructural alterations in liver and gills of embryonic and larval zebrafish
      (Danio rerio) following prolonged exposure to waterborne 0.05, 0.5, and 5 mg/L 4
      chloroaniline for up to 31 days as well as after a 14-day regeneration period
      were investigated by means of light and electron microscopy. Acute toxicity was
      also tested at 25 and 50 mg/L. Survival of zebrafish embryos and larvae was only
      impaired from 25 mg/L 4-chloroaniline, but-after a transient stimulation
      following exposure to 0.5 mg/L-4-chloroaniline hatching was retarded after
      exposure to >/=5 mg/L, and fish displayed increasing rates of abnormal
      development and pigmentation. In contrast, hepatocytes displayed a time- and dose
      dependent response from 0.05 mg/L 4-chloroaniline, including changes in nuclei,
      mitochondria, peroxisomes, endoplasmic reticulum, Golgi fields, lysosomes, and
      hepatic glycogen and lipid stores, as well as invasion of macrophages. In gills,
      dose-dependent effects were evident from 0.5 mg/L 4-chloroaniline and included
      deformation of secondary lamellae due to vacuolization and desquamation of
      respiratory epithelial cells in conjunction with dilation of intercellular
      spaces. Respiratory epithelial cells displayed progressive mitochondrial changes,
      induction of cytoplasmic myelinated structures, augmentation of lysosomes, and
      modifications of Golgi fields. Erythrocytes were severely deformed. A 14-day
      regeneration period was sufficient for almost complete recovery of pathological
      symptoms in both liver and gills. Only minor volumetric changes in hepatocellular
      organelles and a limited number of myelinated bodies, lysosomes, and cytoplasmic
      vacuoles were reminiscent of prior 4-chloroaniline exposure. In both qualitative
      and quantitative terms, most effects in hepatocytes after exposure of embryonic
      and larval zebrafish to waterborne 4-chloroaniline are comparable to the reaction
      of hepatocytes in adult zebrafish liver after prolonged sublethal exposure as
      well as in larval zebrafish after microinjection. Morphological changes in
      erythrocytes indicate disturbance of respiration as an additional mode of action
      of 4-chloroaniline.

PMID- 10341047
TI  - Uptake of mercury by fish in an experimental boreal reservoir.
AB  - We studied the uptake of mercury (Hg) by finescale dace (Phoxinus neogaeus) in an
      experimental boreal reservoir for 2 years prior to flooding and 3 years after
      flooding, and in a natural wetland pond over the same 5-year period. Hg uptake
      was much higher after flooding as compared to uptake before flooding and in the
      natural pond. After flooding, Hg concentrations in late summer were usually 2-3x
      higher than concentrations observed prior to flooding. Net uptake of Hg by fish
      over the summer in the experimental reservoir was 0.25 and -0.07 microg per fish
      in the 2 years before flooding as compared to 0.63, 0.64, and 0.42 microg per
      fish in the 3 years after flooding. Thus, Hg uptake by fish responded quickly to
      flooding and was highest in the first 2 years following impoundment. Uptake in
      the reference pond ranged from 0.10 to 0.28 microg of Hg per fish over the same 5
      year period. Calculated fluxes of Hg on an areal basis ranged from 0.04-0.09
      microg m-2 year-1 in the reference pond, were 0.08 and -0.02 microg m-2 year-1 in
      the experimental reservoir prior to flooding, and ranged from 0.14-0.22 microg m
      2 year-1 in the experimental reservoir after flooding. These fluxes were much
      smaller than fluxes of methyl mercury (MeHg) through the zooplankton and emerging
      insect communities. Most (71-89%) of the mercury measured in the muscle of
      finescale dace was MeHg, and the proportion that was MeHg decreased over the
      summer period prior to flooding, but increased over the summer after flooding.
      Growth of fish was not significantly affected by flooding. Fish ate predominantly
      benthic invertebrates (64-84% of food items found in stomachs), with lesser
      proportions of crustacean zooplankton (16-31% of items found in stomachs) and
      feeding was similar after as compared to before flooding. Therefore, differences
      in Hg uptake did not appear to be the result of changes in diet.

PMID- 10341048
TI  - Sex-related levels of selenium, heavy metals, and organochlorine compounds in
      American white pelicans (Pelecanus erythrorhyncos).
AB  - Liver tissue from male and female adult American white pelicans (Pelecanus
      erythrorhyncos) were individually analyzed for organochlorine compounds and trace
      elements. Levels of most organochlorines, specifically SigmaDDT, SigmaPCB,
      Sigmachlordane, Sigmamirex, dieldrin, and SigmaCBz, were significantly higher in
      male pelicans compared to females. Only concentrations of SigmaHCH were not
      significantly different between sexes. Male livers also contained higher
      concentrations of mercury, cadmium, and arsenic compared to females. Selenium
      concentrations were not different between sexes, and lead was not detected in any
      of the samples. Differences in residue levels between sexes were probably due to
      the female's ability to excrete organochlorines and some trace elements into the
      egg prior to laying. In addition, differences in contaminant concentrations in
      prey available to these birds on their breeding grounds and their wintering areas
      may be influencing sex-related differences.

PMID- 10341049
TI  - Effects of food restriction on food avoidance and risk of acute poisoning of
      captive feral pigeons from fonofos-treated seeds 
AB  - Fonofos is a highly toxic insecticide to birds that, when used as a cereal seed
      treatment, has caused mortality of free-living feral pigeons (Columba livia).
      Pigeons kept individually under ad libitum feeding conditions in the laboratory
      do not suffer lethal poisoning because they develop a strong avoidance response
      to fonofos-treated seed, which restricts consumption to below lethal levels. Two
      laboratory experiments were conducted to assess the role of avoidance in reducing
      the risk of acute poisoning of captive birds under food stress. In the first
      experiment, pigeons acclimatized to feed on untreated wheat seeds for 6 h/day
      were presented with fonofos-treated seeds for 6 h on a testing day, following
      normal food surplus in one experimental group (eight birds) and 6 days of
      deprivation in another (eight birds). In the second experiment, different pigeons
      were acclimatized to a feeding regime of 2 h/day and treated seeds were offered
      without previous restriction (eight birds) or after 6 days of food restriction in
      which birds were given 15% of normal intake (eight birds). In the second
      experiment, six birds in each experimental group were videotaped to study their
      feeding behavior. Survivors at the end of the testing day were killed, and all
      birds were dissected and analyzed to determine carcass and pectoral muscle
      composition. Food-stressed birds lost approximately 11% of their initial body
      weight during 6 days of total or partial food restriction, but they still had
      visible fat deposits and a high body fat content, indicating that they were in
      good body condition in terms of energy reserves. Consumption of treated seeds on
      the testing day was reduced in comparison with normal intake of untreated seed in
      all birds, but there were differences between experimental groups. In ad libitum
      fed birds, consumption of treated seed in each experiment averaged 12% and 19% of
      normal levels, exposure to fonofos was below lethal levels, and no bird died. In
      food-stressed birds, consumption was higher (34% or 56% of normal levels for the
      first and second experiments, respectively) and led to the ingestion of seed
      containing lethal doses of pesticide. Two birds in the first experiment and three
      in the second died of acute poisoning within around 2 h of initial exposure. The
      avoidance response developed quickly in both ad libitum-fed and food-stressed
      birds. Feeding took place in most birds almost exclusively in the first 9 min of
      the testing day. Within this interval, birds of the two experimental groups
      stopped ingesting treated seeds around 6 min after the onset of feeding. The
      differences between experimental groups in consumption of treated seed were due
      to the higher feeding rate and effective feeding time in food-stressed birds. It
      is concluded that although feral pigeons under severe food stress develop an
      early and strong conditioned food aversion to fonofos-treated seeds, avoidance
      does not always prevent mortality. The need for including hunger stress as a
      factor in avian dietary toxicity tests to make testing conditions more
      representative of those experienced by wild birds is discussed.
      http://link.springer-ny. com/link/service/journals/00244/bibs/37n1p115.html

PMID- 10341050
TI  - Organochlorines in stranded pilot whales (Globicephala melaena) from the coast of
      Massachusetts.
AB  - Pilot whales strand periodically along the U.S. coast, and these strandings offer
      an opportunity for the collection of tissues for biomonitoring of contaminant
      exposure in cetaceans, as well as for specimen archiving. Concentrations of
      organochlorine (OC) contaminants (e.g., PCB congeners, pesticides, DDTs) were
      measured in tissue samples from pilot whales that stranded in 1986 and 1990 along
      the Massachusetts coast. Adult and fetal samples of blubber, liver, brain, and
      kidney were collected, as well as ovaries from mature female whales. Many of the
      OCs found in maternal tissues were detected in corresponding fetal tissues
      indicating maternal transfer of OCs to the fetus. The concentrations of
      individual OCs in tissues varied considerably among the animals. Statistically
      significant differences were found between females and males for the
      concentrations of certain analytes (e.g., SigmaPCBs, p,p'-DDE) and these
      differences may be partially due to contaminants being transferred by the female
      whales during gestation and lactation. The concentrations of OCs in different
      tissues were similar when based on total lipid weight, except for the brain,
      which contained the lowest lipid-normalized OC concentrations. The low
      concentrations in brain may be related to the disparate lipid compositions in
      this tissue as well as the presence of the blood-brain barrier. The availability
      of data on these archived and biomonitoring samples provides a baseline for
      future retrospective studies.

PMID- 10341052
TI  - Phylogenetic Composition, Spatial Structure, and Dynamics of Lotic Bacterial
      Biofilms Investigated by Fluorescent in Situ Hybridization and Confocal Laser
      Scanning Microscopy.
AB  - > Abstract The phylogenetic composition, three-dimensional structure and dynamics
      of bacterial communities in river biofilms generated in a rotating annular
      reactor system were studied by fluorescent in situ hybridization (FISH) and
      confocal laser scanning microscopy (CLSM). Biofilms grew on independently
      removable polycarbonate slides exposed in the reactor system with natural river
      water as inoculum and sole nutrient and carbon source. The microbial biofilm
      community developed from attached single cells and distinct microcolonies via a
      more confluent structure characterized by various filamentous bacteria to a
      mature biofilm rich in polymeric material with fewer cells on a per-area basis
      after 56 days. During the different stages of biofilm development, characteristic
      microcolonies and cell morphotypes could be identified as typical features of the
      investigated lotic biofilms. In situ analysis using a comprehensive suite of rRNA
      targeted probes visualized individual cells within the alpha-, beta-, and gamma
      Proteobacteria as well as the Cytophaga-Flavobacterium group as major parts of
      the attached community. The relative abundance of these major groups was
      determined by using digital image analysis to measure specific cell numbers as
      well as specific cell area after in situ probing. Within the lotic biofilm
      community, 87% of the whole bacterial cell area and 79% of the total cell counts
      hybridized with a Bacteria specific probe. During initial biofilm development,
      beta-Proteobacteria dominated the bacterial population. This was followed by a
      rapid increase of alpha-Proteobacteria and bacteria affiliated to the Cytophaga
      Flavobacterium group. In mature biofilms, alpha-Proteobacteria and Cytophaga
      Flavobacteria continued to be the prevalent bacterial groups. Beta-Proteobacteria
      constituted the morphologically most diverse group within the biofilm
      communities, and more narrow phylogenetic staining revealed the importance of
      distinct phylotypes within the beta1-Proteobacteria for the composition of the
      microbial community. The presence of sulfate-reducing bacteria affiliated to the
      Desulfovibrionaceae and Desulfobacteriaceae confirmed the range of metabolic
      potential within the lotic biofilms.http://link.springer
      ny.com/link/service/journals/00248/bibs/37n4p225.html

PMID- 10341051
TI  - Tissue distribution of methylsulfonyl metabolites derived from 2,2',4,5,5'-penta-
      and 2,2',3,4',5',6-hexachlorobiphenyls in rats.
AB  - The time courses of fecal excretion and tissue distribution of metabolites
      derived from 2,2',4,5,5'-pentachlorobiphenyl (CB101) and 2,2',3,4',5',6
      hexachlorobiphenyl (CB149) were investigated in male Wistar rats. The metabolism
      of both congeners involved primarily hydroxylation at the 3-position, and
      methylthiolation at the 4-position. Metabolites distributed in tissue were
      dominated by different ratios of 3- and 4-methylsulfonyl (MeSO2) metabolites. The
      3-/4-MeSO2 metabolite ratios in liver and adipose tissue for both congeners were
      0.41-0.61 at day 4, and then increased to 0.85-1.00 for up to day 42. In
      contrast, the ratios in lung were 0.03-0.04, and then decreased to 0.01. Compared
      to the unchanged PCBs at day 42, the distribution ratios of 3-MeSO2 metabolites
      were greater in the order of liver (0.46 for CB101 and 0.21 for CB149) > kidney >
      blood > lung > adipose tissue, whereas those of 4-MeSO2 metabolites were in the
      order of lung (9.50 for CB101 and 4.00 for CB149) > kidney > blood > liver >
      adipose tissue, indicating the different binding affinity of 3-MeSO2 metabolites
      in liver from that of 4-MeSO2 metabolites in lungs of rats. Furthermore, the
      structure-tissue affinity relationship for 3-MeSO2 metabolites was investigated,
      following the administration of 11 3-MeSO2-PCB congeners to rats. The results
      indicated that the retention potential of 3-MeSO2 metabolites in the liver
      largely depends on the ortho-chlorine substitution in the biphenyl ring rather
      than the degree of chlorination.

PMID- 10341053
TI  - Phylogenetic Diversity and Population Densities of Culturable Cellulolytic Soil
      Bacteria across an Agricultural Encatchment.
AB  - > Abstract A typical, small encatchment (catena Bolkendorf) in the moraine,
      northeast German agricultural landscape Schorfheide-Chorin was studied with
      respect to summit, midslope, and foot-slope positions at northern and southern
      slope exposure, respectively, including a central noncultivated kettle hole
      position (pot hole). Across the sequence of seven distinct sampling positions,
      soil organic carbon and total nitrogen contents, soil gravimetric water content,
      and soil microbial biomass displayed maxima at the kettle hole position. Soil pH
      revealed a decreasing trend at the northern exposed slope and a minimum at the
      kettle hole position. Against this background, the population density of total
      culturable bacteria clearly displayed a minimum at the kettle hole position,
      whereas the population density of carboxymethylcellulose decomposing bacteria was
      not clearly differentiated in relation to sampling positions. To study the
      phylogenetic diversity of culturable cellulolytic bacteria, 311 isolates were
      obtained from the sampling positions across the entire encatchment and examined
      by restriction analysis of PCR-amplified 16S rDNA. Using the restriction enzyme
      ScrFI, isolates were classified into 31 pattern groups. Although the ratio of
      actinomycetes within total isolates ranged from 0.73 to 0.94, only 16 pattern
      groups originated from actinomycetes, but 15 from other bacteria. At all sampling
      positions, a dominant pattern group was identified, containing 38 to 65% of total
      isolates. Two site-specific pattern groups could be identified, representing
      significant parts of the total population, which were highly specific for the
      kettle hole (19% of total isolates) and for foot- and midslope positions (15-18%
      of total isolates), respectively. In general, the composition of cellulolytic
      isolates across the encatchment displayed differences with respect to slope
      positions, but was not significantly affected by soil properties. Based on 16S
      rDNA sequence analysis, isolates of the dominant as well as the specific pattern
      groups could be assigned to the genus Streptomyces. Furthermore, sequencing of
      16S rDNA of isolates of another three pattern groups revealed a high phylogenetic
      diversity among these isolates, including cellulomonads and
      bacilli.http://link.springer
      ny.com/link/service/journals/00248/bibs/37n4p238.html

PMID- 10341054
TI  - Effects of Pseudomonas fluorescens F113 on Ecological Functions in the Pea
      Rhizosphere Are Dependent on pH.
AB  - > Abstract The aim of this microcosm study was to determine influence of the
      antibiotic 2,4-diacetylphloroglucinol (DAPG) on the effect of wild-type and
      functionally modified Pseudomonas fluorescens F113 strains in a sandy loam soil
      of pH 5.4 planted with pea (Pisum sativum var Montana). The functional
      modification of strain F113 was a repressed production of DAPG, useful in plant
      disease control, creating the DAPG negative strain F113 G22; both were marked
      with a lacZY gene cassette. Lowering the soil pH to 4.4 significantly reduced the
      plant shoot and root weights and the root length, whereas the bacterial inocula
      had no significant effect. Both inocula significantly reduced the shoot/root
      ratio at pH 5.4, but this effect was not evident at the lowered or elevated (6.4)
      pH levels. The decrease in pH significantly increased the fungal and yeast colony
      forming units from the rhizosphere (root extract), but did not affect the total
      bacterial c.f.u.'s. Inoculatioin with strain F113 in the pH 4.4 soil resulted in
      a significantly greater total bacterial population. The fungal and yeast c.f.u.'s
      were not significantly affected by the inocula at any pH studied. Increasing the
      pH significantly increased the indigenous Pseudomonas population in comparison to
      the reduced pH treatment and significantly increased both the introduced and
      total Pseudomonas populations. The antibiotic producing strain significantly
      reduced the total bacterial population and the NAGase activity (related to fungal
      activity) at pH 6.4 where the inocula population was the greatest. Alkaline
      phosphatase, phosphodiesterase, aryl sulfatase, beta-glucosidase, alkaline beta
      galactosidase, and NAGase activities significantly increased with increasing in
      pH. The F113 inocula reduced the acid phosphatase activity at pH 5.4 and
      increased the acid beta-galactosidase activity over all the pH treatments. The
      results presented illustrate the variation in impact with soil pH, with
      implications for variability in efficacy of Pseudomonas fluorescens biocontrol
      agents with soil pH.http://link.springer
      ny.com/link/service/journals/00248/bibs/37n4p248.html

PMID- 10341055
TI  - Interspecific Interactions among Tropical and Subtropical Freshwater Fungi.
AB  - > Abstract Twenty-seven species of tropical and subtropical fungi isolated from
      freshwater were examined for evidence of interspecific interactions, which are
      important in determining the ecological roles of fungi. Evidence for
      interspecific interactions was examined by inoculating paired fungi 25 mm apart
      on the surface of agar plates. The antagonistic activities were different among
      different isolates and even between isolates of the same species, for example,
      Ophioceras dolichostomum isolated from different origins. Pseudohalonectria
      longirostrum and Kirschsteiniothelia elaterascus, which produced pigment in
      culture, were strongly inhibitory species. Several aquatic hyphomycetes seems to
      be less competitive and less likely to produce antagonistic substances.
      Competitive abilities were also influenced by the range of enzymes that a fungus
      produced. For example, Verticillium sp. and Diaporthe sp., which produced only
      one or two kinds of enzyme, were found to exhibit weak competitive abilities and
      were easily replaced. The results of competition experiments also showed that
      slow-extending fungi (e.g., Pseudohalonectria longirostrum and
      Kirschsteiniothelia elaterascus) were more competitive than early fast-extending
      fungi (e.g., Ophioceras dolichostomum and Nectria
      haematococca).http://link.springer
      ny.com/link/service/journals/00248/bibs/37n4p257.html

PMID- 10341056
TI  - Distribution of Microbial Physiologic Types in an Aquifer Contaminated by Crude
      Oil.
AB  - > Abstract We conducted a plume-scale study of the microbial ecology in the
      anaerobic portion of an aquifer contaminated by crude-oil compounds. The data
      provide insight into the patterns of ecological succession, microbial nutrient
      demands, and the relative importance of free-living versus attached microbial
      populations. The most probable number (MPN) method was used to characterize the
      spatial distribution of six physiologic types: aerobes, denitrifiers, iron
      reducers, heterotrophic fermenters, sulfate-reducers, and methanogens. Both free
      living and attached numbers were determined over a broad cross-section of the
      aquifer extending horizontally from the source of the plume at a nonaqueous oil
      body to 66 m downgradient, and vertically from above the water table to the base
      of the plume below the water table. Point samples from widely spaced locations
      were combined with three closely spaced vertical profiles to create a map of
      physiologic zones for a cross-section of the plume. Although some estimates
      suggest that less than 1% of the subsurface microbial population can be grown in
      laboratory cultures, the MPN results presented here provide a comprehensive
      qualitative picture of the microbial ecology at the plume scale. Areas in the
      plume that are evolving from iron-reducing to methanogenic conditions are clearly
      delineated and generally occupy 25-50% of the plume thickness. Lower microbial
      numbers below the water table compared to the unsaturated zone suggest that
      nutrient limitations may be important in limiting growth in the saturated zone.
      Finally, the data indicate that an average of 15% of the total population is
      suspended.http://link.springer
      ny.com/link/service/journals/00248/bibs/37n4p263.html

PMID- 10341057
TI  - Particulate and Dissolved Organic Carbon Production by the Heterotrophic
      Nanoflagellate Pteridomonas danica Patterson and Fenchel.
AB  - > Abstract We established a budget of organic carbon utilization of a starved
      heterotrophic nanoflagellate, Pteridomonas danica, incubated in batch cultures
      with Escherichia coli as model prey. The cultures were sampled periodically for
      biomass determinations and total organic carbon dynamics: total organic carbon,
      total organic carbon <1 um, and dissolved organic carbon (DOC, <0.2 um). During
      the 22 h incubation period, P. danica underwent biovolume variations of 3.2-fold.
      Gross growth efficiency was 22% and net growth efficiency 40%. P. danica respired
      33% and egested 44% of the ingested E. coli carbon during lag and exponential
      growth phases. The form of the organic carbon egested varied. Of the total
      ingested carbon, 9% was egested in the form of DOC and occurred mainly during the
      exponential growth phase; 35% was egested in the form of particulate organic
      carbon (POC), ranging in size from 0.2 to 1 um, and took place during the lag
      phase. P. danica could have reingested as much of 58% of this previously produced
      POC during the exponential growth phase as food scarcity increased. We concluded
      that POC egestion by flagellates could represent a significant source of
      submicrometric particles and colloidal organic matter. In addition, flagellate
      reingestion of egested POC could play a nonnegligible role in the microbial food
      web. Finally, the methodology reported in this study has proved to be a useful
      tool in the study of carbon metabolism in aquatic
      microorganisms.http://link.springer
      ny.com/link/service/journals/00248/bibs/37n4p276.html

PMID- 10341058
TI  - FORUM: Bioregional Conflict Resolution: Rebuilding Community in Watershed
      Planning and Organizing.
AB  - / Watershed-based planning has been held as a vanguard for integrated ecosystem
      management based on a collaborative process. Watershed managers, however, must
      contend with conflicts that run much deeper than interests for economic
      development versus sustaining ecosystem health. With data from a survey of
      members of watershed organizations, we characterize the valued-based conflicts
      that watershed managers are likely to face in planning. We propose that utilizing
      collaborative decision-making strategies is important, but successful long-term
      watershed planning requires rebuilding a community-based infrastructure that can
      support important social and bioregional networks and partnerships.KEY WORDS:
      Conflict resolution; Watershed planninghttp://link.springer
      ny.com/link/service/journals/00267/bibs/24n1p1.html

PMID- 10341059
TI  - PROFILE: Environmental Impact Assessment Under the National Environmental Policy
      Act and the Protocol on Environmental Protection to the Antarctic Treaty.
AB  - / Antarctica has been set aside by the international community for protection as
      a natural reserve and a place for scientific research. Through the Antarctic
      Treaty of 1961, the signing nations agreed to cooperate in protecting the
      antarctic environment, in conducting scientific studies, and in abstaining from
      the exercise of territorial claims. The 1991 signing of the Protocol on
      Environmental Protection to the Antarctic Treaty (Protocol) by representatives of
      the 26 nations comprising the Antarctic Treaty Consultative Parties (Parties)
      significantly strengthened environmental protection measures for the continent.
      The Protocol required ratification by each of the governments individually prior
      to official implementation. The US government ratified the Protocol by passage of
      the Antarctic Science, Tourism, and Conservation Act of 1997. Japan completed the
      process by ratifying the Protocol on December 15, 1997. US government actions
      undertaken in Antarctica are subject to the requirements of both the Protocol and
      the US National Environmental Policy Act (NEPA). There are differences in the
      scope and intent of the Protocol and NEPA; however, both require environmental
      impact assessment (EIA) as part of the planning process for proposed actions that
      have the potential for environmental impacts. In this paper we describe the two
      instruments and highlight key similarities and differences with particular
      attention to EIA. Through this comparison of the EIA requirements of NEPA and the
      Protocol, we show how the requirements of each can be used in concert to provide
      enhanced environmental protection for the antarctic environment. NEPA applies
      only to actions of the US government; therefore, because NEPA includes certain
      desirable attributes that have been refined and clarified through numerous court
      cases, and because the Protocol is just entering implementation internationally,
      some recommendations are made for strengthening the procedural requirements of
      the Protocol for activities undertaken by all Parties in Antarctica. The Protocol
      gives clear and strong guidance for protection of specific, valued antarctic
      environmental resources including intrinsic wilderness and aesthetic values, and
      the value of Antarctica as an area for scientific research. That guidance
      requires a higher standard of environmental protection for Antarctica than is
      required in other parts of the world. This paper shows that taken together NEPA
      and the Protocol call for closer examination of proposed actions and a more
      rigorous consideration of environmental impacts than either would alone. Three
      areas are identified where the EIA provisions of the Protocol could be
      strengthened to improve its effectiveness. First, the thresholds defined by the
      Protocol need to be clarified. Specifically, the meanings of the terms "minor"
      and "transitory" are not clear in the context of the Protocol. The use of "or" in
      the phrase "minor or transitory" further confuses the meaning. Second, cumulative
      impact assessment is called for by the Protocol but is not defined. A clear
      definition could reduce the chance that cumulative impacts would be given
      inadequate consideration. Finally, the public has limited opportunities to
      comment on or influence the preparation of initial or comprehensive environmental
      evaluations. Experience has shown that public input to environmental documents
      has a considerable influence on agency decision making and the quality of EIA
      that agencies perform.KEY WORDS: Environment; Impact assessment; Antarctica;
      NEPA; Protocol; Antarctic Treatyhttp://link.springer
      ny.com/link/service/journals/00267/bibs/24n1p13.html

PMID- 10341060
TI  - Restoration of a Canadian Prairie Wetland with Agricultural and Municipal
      Wastewater.
AB  - / A rapid development and approval process was employed by Ducks Unlimited Canada
      and other stakeholders to restore a 1246-ha (3079-acre) northern prairie wetland
      in southern Alberta, Canada, with 3640 m3/day (800,000 US gallons) of municipal
      wastewater and beef processing wastewater. A large nongovernmental organization
      hastened restoration with a development process that outlined restoration goals
      and management objectives to satisfy a dual mandate of wastewater treatment and
      wildlife habitat creation. In 1995, after five years of wastewater additions, the
      basins had been refilled and the surrounding uplands had been acquired and
      restored. The Frank Lake Conservation Area currently provides high-quality
      habitat for a variety of wildlife in a region where many of the native plants and
      animals species have been lost due to habitat loss and fragmentation. The success
      of upland and water management strategies is reflected in the increase of target
      species' abundance and richness: 50 shorebird species, 44 waterfowl species, 15
      raptor species, and 28 other new bird species have returned to the marsh since
      restoration. As well, significant N and P reduction occurs as waters flow through
      the first basin of the marsh. The management strategies of this project that
      satisfied a dual mandate serve as a model to guide managers of other large-scale
      wetland restoration projects.KEY WORDS: Frank Lake; Wetland restoration; Adaptive
      management; Prairie; Wastewaterhttp://link.springer
      ny.com/link/service/journals/00267/bibs/24n1p25.html

PMID- 10341061
TI  - Sustaining Ecosystem Services in Human-Dominated Watersheds: Biohydrology and
      Ecosystem Processes in the South Platte River Basin.
AB  - / Sustaining ecosystem services important to humans while providing a dependable
      water supply for agriculture and urban needs is a major challenge faced by
      managers of human-dominated watersheds. Modification of natural flow regimes
      alters the abundance and composition of native plant and animal communities,
      affecting ecosystem services such as water storage and nutrient cycling that
      depend on particular species or functional groups. Because complete restoration
      of natural hydrology is generally not an option in human-dominated watersheds,
      there is a need to determine which specific flow manipulations are necessary to
      restore species-dependent ecosystem services in particular systems. Here we
      propose a framework for predicting ecological consequences of flow manipulations
      that is based on the role of hydrology in linking population, community, and
      ecosystem processes. We use a case-study approach to examine how interactions
      among the flow regime and species' functional traits help organize local biotic
      communities and generate alternate states of ecosystem functioning. Results
      indicate the importance of integrating hydrology and biology to predict
      ecological consequences of flow regime manipulations and the need to apply
      general flow-restoration principles on a case-by-case basis.KEY WORDS:
      Biohydrology; Aquatic ecosystems; Community assembly; Ecological integrity;
      Watershed restoration; Ecosystem serviceshttp://link.springer
      ny.com/link/service/journals/00267/bibs/24n1p39.html

PMID- 10341062
TI  - Defining Reference Conditions for Restoration of Riparian Plant Communities:
      Examples from California, USA.
AB  - / Currently, there is an emphasis on restoration of riparian vegetation in the
      western United States. Deciding on what and where to restore requires an
      understanding of relationships between riparian plant communities and their
      environments along with establishment of targets, or reference conditions, for
      restoration. Several methods, including off-site data and historical analysis
      have been used for establishing restoration reference conditions. In this paper,
      criteria are proposed for interpreting reference community composition and
      structure from the results of multivariate cluster analysis. The approach is
      illustrated with data from streams in the California Sierra Nevada, Central
      Valley, and southern coastal region to derive descriptions of reference
      communities for stream reaches and floodplain landforms. Cluster analysis results
      can be used to quantify the areas of both degraded and reference communities
      within a floodplain, thereby facilitating restoration cost estimation.KEY WORDS:
      Riparian vegetation; Watershed planning; Riparian restoration; Cluster
      analysishttp://link.springer-ny.com/link/service/journals/00267/bibs/24n1p55.html

PMID- 10341063
TI  - RESEARCH: Prospects for Preservation and Restoration of Riparian Forests in the
      Sacramento Valley, California, USA.
AB  - / This GIS-based study analyzes the distribution and management of woody riparian
      vegetation in California's Sacramento Valley and discusses the prospects for its
      conservation. Although forests were the predominant floodplain vegetation prior
      to extensive settlement, only 3.3% of floodplain was covered by forest in the
      late 1980s. This remaining forest was fragmented into 2607 patches with an
      average area of 3.1 ha. Only 180 patches were >10 ha, with three patches >100 ha.
      Despite over two decades of conservation efforts, these forests are essentially
      unpreserved: Only 14.5% of extant forests are in public ownership or on land
      managed primarily for biological conservation. Some privately owned forests
      represent opportunities for preservation, but owing to their small size and
      scattered distribution, reforestation would be necessary to obtain a high cover
      of forest over large areas. Additionally, high property values, existing land
      uses, and regulated hydrology constrain conservation efforts. As a consequence of
      these constraints, and current distribution and ownership patterns, preservation
      or restoration of substantial areas of riparian forest would be extremely
      expensive and would divert conservation resources from other habitats in this
      rapidly developing state. Therefore, efforts to conserve these forests should
      satisfy two criteria: (1) that the specific goals are attainable with available
      funding and existing human uses, and (2) funding the effort will result in more
      effective regional conservation than would funding the conservation of other
      habitats.KEY WORDS: Central Valley; Conservation; Floodplains; Geographic
      information systems; Riparian vegetationhttp://link.springer
      ny.com/link/service/journals/00267/bibs/24n1p65.html

PMID- 10341064
TI  - A Simple Model for Estimating Mean Monthly Stream Temperatures After Riparian
      Canopy Removal.
AB  - / The removal of riparian vegetation along small streams affects the thermal
      regime of the stream and consequently the biota within it. A simple regression
      model for mean monthly temperature after riparian canopy removal, based on
      conditions prior to removal, is presented. The model is determined to have an
      accuracy of +/-2 degrees C 95% of the time over the temperature range 0.7-17
      degrees C. The regression also predicts a switching point at 3 degrees C, below
      which postharvesting temperatures are colder than prior to harvest. The ability
      to predict postharvest stream temperatures based on preharvest air temperatures
      is also evaluated. Management implications of thermal effects due to riparian
      removal are discussed.KEY WORDS: Stream temperature; Temperature model;
      Prediction; Air temperature; Thermal change; Riparian canopy
      removalhttp://link.springer-ny.com/link/service/journals/00267/bibs/24n1p77.html

PMID- 10341065
TI  - Planning for Water Management in the Daqinghe River Basin, Northern China.
AB  - / In a river basin where existing land and water resources are virtually fully
      exploited, planning for water management in the future becomes a challenging
      task. A scenario-consequence analysis, based on economic growth forecasts, was
      applied to assess alternatives for water management. Comparison of the impacts
      resulting from three growth scenarios provided the local government with a vision
      of the consequences of selection of each of the scenarios. It was concluded that
      a water deficit would result from each scenario. To balance the expectations of
      the population for better employment and living standards and environmental
      degradation and to remedy the water deficit situation, a water management plan
      comprising changes in water policies and institutional arrangements, introduction
      to water conservation and demand management, pollution control, and importation
      of water from other river basins was proposed. The sustainability of the water
      management plan was also discussed.KEY WORDS: Water management; Sustainability;
      Scenario-consequence analysis; Economic growth; Northern
      Chinahttp://link.springer-ny.com/link/service/journals/00267/bibs/24n1p85.html

PMID- 10341066
TI  - Incorporating Geological Effects in Modeling of Revegetation Strategies for Salt
      Affected Landscapes.
AB  - / This paper synthesizes results of research into the impact that major faults
      have on dryland salinity and the development of revegetation treatments in the
      wheatbelt of Western Australia. Currently, landscape planning does not routinely
      incorporate geology, but this research shows that faults can have a dramatic
      impact on land and stream salinization and on the effectiveness of revegetation
      treatments, and evidence exists that other geological features can have a similar
      influence. This research shows that faults can be identified from airborne
      magnetic data, they can be assigned a characteristic hydraulic conductivity based
      on simple borehole tests, and four other geological features that are expected to
      affect land and stream salinity could be identified in airborne geophysical data.
      A geological theme map could then be created to which characteristic hydraulic
      conductivities could be assigned for use in computer groundwater models to
      improve prediction of the effectiveness of revegetation treatments and thus
      enhance the landscape planning process. The work highlights the difficulties of
      using standard sampling and statistical techniques to investigate regional
      phenomena and presents an integrated approach combining small-scale sampling with
      broad-scale observations to provide input into a modeling exercise. It is
      suggested that such approaches are vital if landscape- and regional-scale
      processes are to be understood and managed. The way in which the problem is
      perceived (holistically or piecemeal) affects the way treatments are designed and
      their effectiveness: past approaches have failed to integrate the various scales
      and processes involved. Effective solutions require an integrated holistic
      response.KEY WORDS: Dryland salinity; Geology; Landscape; Revegetation
      integrationhttp://link.springer
      ny.com/link/service/journals/00267/bibs/24n1p99.html

PMID- 10341067
TI  - Salt Marsh Diking and Restoration: Biogeochemical Implications of Altered Wetland
      Hydrology.
AB  - / In salt marshes, most biomass plus large reserves of biologically important N,
      P, Fe, and S are sequestered below ground under saline, waterlogged, and
      anaerobic conditions. Thus, hydrologic alterations such as diking and ditch
      drainage that reduce salinity and increase peat aeration can cause radical
      changes in the composition of salt marsh soils.Experimental short-term
      desalination and drainage of salt marsh cores in greenhouse microcosms caused
      Spartina production to increase after one growing season, reflecting decreased
      salt stress and sulfide toxicity. However, production thereafter declined, likely
      due to pyrite oxidation and acidification in drained treatments and sulfide
      accumulation in waterlogged treatments.A survey of longer-term (decadal) effects
      of diking on peat composition of Cape Cod, Massachusetts, USA, marshes revealed
      acidification, Fe(II) mobilization, and decreased organic content in drained
      sites. Despite the aerobic decomposition of organic matter, abundant nutrients
      remained as sorbed NH4 and mineral-bound PO4. In diked, seasonally waterlogged
      sites, porewater alkalinity, sulfide, ammonium and orthophosphate were much
      lower, and organic solids higher, than in adjacent natural marsh.Seawater was
      added to cores from diked marshes to study the effects of tidal restoration.
      Salination of the drained peat increased porewater pH, alkalinity, ammonium,
      orthophosphate, Fe, and Al; copious ammonium N, and Fe(II) for sulfide
      precipitation favored Spartina growth. Salination of diked-waterlogged peat
      increased sulfate reduction and caused 6-8 cm of sediment subsidence. The
      resulting increase in porewater sulfides and waterlogging decreased vigor of
      transplanted Spartina alterniflora. Results indicate that seawater restoration
      should proceed cautiously to avoid nutrient loading of surface waters in drained
      sites or sulfide toxicity in diked-waterlogged marshes.KEY WORDS: Salt marsh;
      Diking; Biogeochemical cycling; Restoration; Massachusettshttp://link.springer
      ny.com/link/service/journals/00267/bibs/24n1p111.html

PMID- 10341068
TI  - Fitness Landscapes and the Precautionary Principle: The Geometry of Environmental
      Risk.
AB  - / A generalized mathematical model for exploring the implications of the
      Precautionary Principle is developed. This model draws on recent developments in
      the field of complex adaptive systems theory. The existence and importance of the
      Precautionary Principle in the field of environmental law is taken as given and
      used as justification for the development of models for exploring the principle's
      implications.The Precautionary Principle is a legal mechanism for managing the
      environmental risk arising from incomplete scientific knowledge of a proposal's
      impacts. The Precautionary Principle is applied to actions that carry with them
      the potential for serious or irreversible environmental change. The model
      proposed in this paper draws on methods used in a range of disciplines for
      modeling (potentially highly nonlinear) interactions between multiple parts of a
      complex system. These methods have been drawn together under the common
      mathematical umbrella of Fitness Landscape Theory. It is argued that the model,
      called "Environmental Impact Fitness Landscapes," allows statements about the
      sensitivity of the gross effect from a set of impacts to be made when the number
      of impacts in the set, and/or their degree of interaction, is varied. It is
      argued that this can be achieved through identification of "meta" or "emergent"
      properties of the set itself, without reference to the specific causal chains
      determining behavior in specific instances. While such properties are very
      general, they may at least allow for the parameterization of the effects of sets
      of impacts where interactions are highly uncertain and empirical data severely
      limited, i.e., situations that would typically invoke the Precautionary
      Principle.KEY WORDS: Fitness landscapes; Precautionary Principle; Nonlinear
      interactions; Graph theoryhttp://link.springer
      ny.com/link/service/journals/00267/bibs/24n1p121.html

PMID- 10341069
TI  - ENVIRONMENTAL AUDITING: Change in Fish Fauna as Indication of Aquatic Ecosystem
      Condition in Rio Grande de Morelia-Lago de Cuitzeo Basin, Mexico.
AB  - / The Rio Grande de Morelia-Lago de Cuitzeo basin in west central Mexico has
      experienced major increases in water pollution from a rapidly growing human
      population. We examined changes in the long-term distribution of fishes in
      relation to water quality and quantity in order to assess the condition and
      health of aquatic ecosystems inthe basin. Sampling between 1985 and 1993 revealed
      that five (26%) of the 19 native fish species known from the basin had been
      extirpated. Two of these were endemics, Chirostoma charari and C. compressum, and
      they are presumed extinct. Twelve (63%) of the remaining species had declines in
      distribution. Sixteen (80%) of the 20 localities sampled had lost species. The
      greatest declines occurred in Lago de Cuitzeo proper and in the lower portion of
      the Rio Grande de Morelia watershed. Species losses from the lake were
      attributable to drying and hypereutrophication of the lake because of substantial
      reductions in the amount and quality of tributary inputs, whereas losses from the
      Rio Grande de Morelia watershed were the result of pollution from agricultural,
      municipal, and industrial sources, especially in the region around the city of
      Morelia. Three localities in the upper portion of the Rio Grande de Morelia
      watershed-Cointzio reservoir, La Mintzita spring, and Insurgente Morelos stream
      contained most of the remaining fish species diversity in the basin and deserve
      additional protection. Fish faunal changes indicated major declines in the health
      of aquatic ecosystems in the Morelia-Cuitzeo basin.KEY WORDS: Fish distribution;
      Rio Lerma; Ecosystem health; Water quality; Chirostoma; Threatened and endangered
      specieshttp://link.springer-ny.com/link/service/journals/00267/bibs/24n1p133.html

PMID- 10341070
TI  - DNA extraction from activated sludges.
AB  - To optimize the cell lysis step for DNA extraction from activated sludge samples,
      two floc dispersion methods (sonication versus stirring with a cation exchange
      resin), and three cell lysis treatments (lysozyme + SDS, sonication in a water
      bath, and thermal shock) were tested. For dispersion, stirring with cation
      exchange resin was more efficient than sonication. The cell lysis procedures were
      applied in two sequences, and DNA was quantified after each cell lysis treatment.
      Lysozyme + SDS was the most effective step in the cell lysis procedures. The cell
      lysis treatment sequences giving the highest DNA yields were not the same for all
      the sludges. The differences in sludge microbial compositions and floc structures
      required specifically adapted cell lysis protocols. The proposed protocols were
      highly efficient for DNA extraction, yielding about 50 mg DNA g-1 volatile
      suspended solids, and allowed PCR amplification of 16S rDNA.

PMID- 10341071
TI  - A gene (tmpA) for an efflux protein of the transporter family III from
      Brevibacterium linens OC2, an antibacterial substance-producing strain.
AB  - A gene (tmpA) encoding a putative transmembrane protein has been cloned from B.
      linens OC2, an antibacterial substance-producing strain. The deduced TmpA protein
      sequence shares similarities to members of the transporter family III exploiting
      the transmembrane proton gradient to provide export of toxic compounds such as
      antiseptics or antibiotics. Northern blot analysis indicated that tmpA gene is
      expressed. Length of RNA messenger and overlapping of ORFs upstream tmpA gene
      suggested that it might belong to an operon. The tmpA gene is unusual among B.
      linens species since it was not detected among eight B. linens collection strains
      and 40 B. linens industrial strains.

PMID- 10341072
TI  - Detection and transcription of toxin DNA in a nontoxigenic strain of Clostridium
      difficile.
AB  - Genomic DNA from three Clostridium difficile strains was analyzed by PCR for DNA
      sequences encoding toxin A (tcdA) and toxin B (tcdB). Toxigenic control strain
      VPI 10463 possessed tcdA, tcdB, and an open reading frame (tcdE) between these
      two genes, whereas nontoxigenic control strain 85 lacked each of these genetic
      determinants. However, strain M90, also a nontoxigenic strain, was found to
      possess tcdA, tcdB, and tcdE. Normally the presence of toxin genes is associated
      with toxigenicity. Analysis of tcdA and tcdB mRNA revealed toxin gene
      transcription in strains VPI 10463, 23 (a mildly toxigenic strain), and M90, but
      not in strain 85. However, for strain M90, tcdA and tcdB mRNA was at the lower
      limit of detection, whereas mRNAs encoding tcdA and tcdB were easily detected in
      strains VPI 10463 and 23. Low levels of toxin gene transcription is the probable
      cause of M90's lack of toxigenicity.

PMID- 10341073
TI  - Cellular envelopes and tolerance to acid pH in Mesorhizobium loti.
AB  - Changes in the cell envelopes in response to acidity were studied in two strains
      of Mesorhizobium loti differing in their tolerance to pH. When the less acid
      tolerant strain LL22 was grown at pH 5.5, membrane phosphatidylglycerol decreased
      and phosphatidylcholine increased, compared with cells grown at pH 7.0. On the
      other hand, when the more acid-tolerant strain LL56 was grown at pH 5.5,
      phosphatidylglycerol, phosphatidylethanolamine, and lysophospholipid decreased
      25%, 39%, and 51% respectively, while phosphatidyl-N-methylethanolamine and
      cardiolipin increased 26% and 65% respectively compared with cells grown at pH
      7.0. The longest-chain fatty acids (19:0 cy and 20:0) increased in both strains
      at pH 5.5, while in LL56 these fatty acids increased still further at pH 4.0.
      Variations in other wall and membrane properties such as cell hydrophobicity,
      lypopolysaccharides, and protein composition of the outer membrane in relation to
      acid pH are also discussed.

PMID- 10341074
TI  - Expression of human growth hormone by the eukaryotic alga, Chlorella.
AB  - A method to use Chlorella to express a recombinant heterologous protein that can
      be recovered from the extracellular medium has been developed. Plasmids are
      constructed with an extracellular secretion signal sequence inserted between a
      promoter region and a gene for human growth hormone (hGH). The plasmids also
      contain a Kanr region which confers resistance to the antibiotic G418.
      Protoplasts are prepared by enzymatic treatment, and the plasmid is introduced by
      incubation of the protoplasts with polyethylene glycol and dimethyl sulfoxide.
      Cells are then grown in the presence of G418, and the medium is collected from 6
      days after transfection. hGH is measured by immunoassay, and values for expressed
      hGH of about 200-600 ng/ml are obtained.

PMID- 10341075
TI  - Superiority of 11,12 carbonate macrolide antibiotics as inhibitors of translation
      and 50S ribosomal subunit formation in Staphylococcus aureus cells.
AB  - Three pairs of related macrolide antibiotics, differing at the 11,12 position of
      the macrolactone ring, were compared for effects on growth rate, cell viability,
      protein synthesis, and 50S ribosomal subunit formation in Staphylococcus aureus
      cells. For each parameter measured, the 11,12 carbonate-derivatized compound was
      more inhibitory compared with the corresponding 11,12-hydroxy antibiotic.
      Substitution at the 3-position of the ring was also important in the relative
      inhibition observed. The degree of inhibition found in two different growth media
      was proportional to the generation time of the cells. Inhibition of both protein
      synthesis and 50S subunit formation by each drug correlated well with the
      inhibition of cell viability. The results indicate that closure of the 11,12
      hydroxyl groups in macrolide antibiotics with a carbonate substitution generates
      a more effective antimicrobial agent.

PMID- 10341076
TI  - The effects of a tsetse DNA virus infection on the functions of the male
      accessory reproductive gland in the host fly Glossina morsitans centralis
      (Diptera; Glossinidae).
AB  - Freshly deposited third instar Glossina morsitans centralis larvae were infected
      with the tsetse DNA virus by microinjection, and at emergence adult males were
      separated from the females and fed on rabbit blood every second day for 8 days. A
      control group treated with sterile saline were handled similarly. They were
      dissected, and comparative observations made on the appearance and size of the
      accessory reproductive glands (ARG) in infected and control males. Regularly fed
      8-day-old males from infected and control groups were mated to 2-day-old normal
      females obtained from the insectay. After separation from copula, the females
      were dissected and the uteri examined for the presence and quality of the
      spermatophore. The spermathecae were also examined for insemination. ARG tissues
      from the control and virus infected regularly fed 8-day-old male flies were fixed
      and processed for electron microscopic studies. The ARGs from control flies were
      found to be milky in appearance, whereas those from virus-infected flies were
      transparent in most parts. The ARGs from virus-infected males were significantly
      smaller in diameters (F = 42.26, p < 0.0001) and shorter (F = 200.4, p < 0. 0001)
      than those of the controls. Most of the virus-infected males failed to form a
      complete spermatophore, whereas almost all the controls formed complete
      spermatophore as observed in the uteri of the female mates (Chi2 = 111.661, p <
      0.0001). The infected males that formed partial spermatophores and those that did
      not form any at all failed to inseminate their female mates. Histological studies
      of the ARGs revealed some lesions in the epithelial cells characterized by
      degeneration of cytoplasmic organelles and detachment of the muscle layer from
      the basal plasma membrane. However, no virus particles were observed in the
      affected cells.

PMID- 10341078
TI  - Utilization of xylose for growth by the eukaryotic alga, Chlorella.
AB  - A green alga, Chlorella, was found to be capable of utilizing xylose or other
      pentose sugars (xylitol, arabinose) for enhanced growth rates when grown in the
      light, but not when grown heterotrophically in the dark. With selection for
      growth in xylose-containing medium, it was possible to improve dramatically the
      ability of selected Chlorella strains to grow on xylose mixotrophically. Growth
      on arabinose or xylitol was not changed in the xylose-selected strains.

PMID- 10341077
TI  - Primary structure of the DNA polymerase I gene of an alpha-proteobacterium,
      Rhizobium leguminosarum, and comparison with other family A DNA polymerases.
AB  - The structural gene for DNA polymerase I of Rhizobium leguminosarum was
      determined. The rhizobium DNA polymerase I consists of 1016 amino acid residues
      with a calculated molecular weight of 111,491 Dalton. The amino acid sequence
      comparison with E. coli DNA polymerase I, Thermus aquaticus DNA polymerase I, and
      Rickettsia prowazekii DNA polymerase I showed that, although 5'-nuclease and DNA
      polymerase domains are highly conserved, 3' to 5' exonuclease domains are much
      less conserved. While both R. leguminosarum and R. prowazekii belong to the alpha
      subdivision of the Proteobacteria on the basis of 16S ribosomal RNA phylogeny,
      the primary structure of the DNA polymerase I is quite different; the rhizobium
      DNA polymerase I has 3' to 5' proofreading exonuclease, but the rickettsia DNA
      polymerase I does not.

PMID- 10341079
TI  - Chemical analysis of the lamella walls of Agaricus bisporus fruit bodies.
AB  - Purified lamella wall fragments of Agaricus bisporus fruit bodies were analyzed
      and shown to consist of neutral sugars (46.5%), hexosamines (31.7%), proteins
      (9.5%), some lipid material (10.0%), and ash (1.4%). The cell walls were
      fractionated on the basis of their polysaccharide solubility in water and
      alkaline solutions. The isolated fractions, using methylation analysis, exhibited
      striking chemical structural differences compared with the same fractions
      obtained from the corresponding vegetative cells and fruit bodies (stipe and
      pileus) walls. The structural differences detected in the wall seem to correspond
      to the ultimate differentiation of the mycelium inside the fruit body of A.
      bisporus.

PMID- 10341081
TI  - Microsatellite DNA variants among the FVB/NJ, C58/J, and I/LnJ mouse strains.

PMID- 10341080
TI  - Genomic structure, mapping, and expression analysis of the mammalian Lunatic,
      Manic, and Radical fringe genes.
AB  - The three members of the mammalian fringe gene family, Manic fringe (Mfng),
      Radical fringe (Rfng), and Lunatic fringe (Lfng), were identified on the basis of
      their similarity to Drosophila fringe (fng) and their participation in the
      evolutionarily conserved Notch receptor signaling pathway. Fringe genes encode
      pioneer secretory proteins with weak similarity to glycosyltransferases. Both
      expression patterns and functional studies support an important role for Fringe
      genes in patterning during embryonic development and an association with cellular
      transformation. We have now further characterized the expression and determined
      the chromosomal localization and genomic structure of the mouse Mfng, Rfng, and
      Lfng genes; the genomic structure and conceptual open reading frame of the human
      RFNG gene; and the refined chromosomal localization of the three human fringe
      genes. The mouse Fringe genes are expressed in the embryo and in adult tissues.
      The mouse and human Fringe family members map to three different chromosomes in
      regions of conserved synteny: Mfng maps to mouse Chr 15, and MFNG maps to human
      Chr 22q13.1 in the region of two cancer-associated loci; Lfng maps to mouse Chr
      5, and LFNG maps to human Chr 7p22; Rfng maps to mouse Chr 11, and RFNG maps to
      human Chr 17q25 in the minimal region for a familial psoriasis susceptibility
      locus. Characterization of the genomic loci of the Fringe gene family members
      reveals a conserved genomic organization of 8 exons. Comparative analysis of
      mammalian Fringe genomic organization suggests that the first exon is
      evolutionarily labile and that the Fringe genes have a genomic structure distinct
      from those of previously characterized glycosyltransferases.

PMID- 10341082
TI  - High-resolution mapping of tlt, a mouse mutant lacking otoconia.
AB  - The ability to sense gravity is enhanced by an extracellular structure that
      overlies the macular sensory epithelium. This complex consists of high density
      particles, otoconia, embedded within a gelatinous membrane. The tilted mouse
      specifically lacks otoconia, yet has no other detectable anatomic lesions.
      Furthermore, the penetrance of the tilted phenotype is nearly 100%. This mouse
      provides a model to identify genes that are involved in the development and
      function of vestibular otoconia. Using SSLP markers, we have mapped the tilted
      (tlt) gene on mouse Chromosome (Chr) 5 between D5Mit421 and
      D5Mit353/D5Mit128/D5Mit266/D5Mit267 by analysis of the progeny of an
      intersubspecific F2 intercross. We also mapped the fibroblast growth factor
      receptor 3 (Fgfr3) gene, a potential candidate for tlt, and the Huntington's
      disease homolog (Hdh) gene to D5Mit268, approximately 4.3 centiMorgans (cM) from
      the tilted locus. This study excludes both Fgfr3 and Hdh as candidate genes for
      tlt and identifies closely linked microsatellite markers that will be useful for
      the positional cloning of tlt.

PMID- 10341083
TI  - Analysis of murine Snrpn and human SNRPN gene imprinting in transgenic mice.
AB  - The SNRPN gene is known to be expressed exclusively from the paternal allele and
      to map to the critical region for the neurobehavioral disorder, Prader-Willi
      syndrome (PWS). As a means to investigate the mechanism of imprinting for the
      SNRPN gene, we have sought to recapitulate the imprinted expression of the
      endogenous gene. Using an 85-kb murine Snrpn clone, containing 33 kb of 5' and 30
      kb of 3' flanking DNA, we obtained two intact transgenic lines. One line,
      containing two copies of the Snrpn transgene, recapitulated the imprinted
      expression pattern of the endogenous locus, whereas the other transgenic line,
      containing a single copy, was expressed upon both maternal and paternal
      inheritance. This suggests that a 6.6-kb region of maternal-specific DNA
      methylation that we have identified may be sufficient to confer imprinted
      expression, but not in a copy-number independent manner. Finally, we produced
      five lines of transgenic mice using a 76-kb human SNRPN clone containing 45 kb
      and 7 kb of 5' and 3' flanking DNA, respectively. We found all the lines were
      expressed upon both maternal and paternal inheritance, regardless of copy number,
      suggesting that the imprinting machinery in mouse and human may have diverged.

PMID- 10341085
TI  - Isolation, sequencing and relative quantitation by fluorescent-ratio PCR of
      feline beta-lactoglobulin I, II, and III cDNAs.
AB  - Beta-lactoglobulin (betaLG) is a whey protein found in the milk of most mammals,
      except those of humans and rodents. In ruminants, only one type of betaLG is
      expressed in milk, although the presence of pseudogenes has been reported. The
      milk of other mammals (dog, horse, dolphins) contains two types of betaLG: type I
      is related to ruminant betaLG, while type II has a strong similarity to the
      ruminant pseudogenes. The presence of three types of betaLG has been described
      only in cat milk. For the first time, we have cloned, sequenced, and
      characterized the three types of feline betaLG cDNAs from a mammary gland sample
      of a lactating cat. Since no specific probe could be easily used to differentiate
      them by Northern Blotting, we developed a new technique named Fluorescent-Ratio
      PCR (FR-PCR) in order to assess their level of expression during lactation. The
      relative amounts of each feline betaLG cDNA was quantified in two cats by
      capillary electrophoresis of the restricted RT-PCR product, labeled with
      fluorescent primers. We observed the same percentage of expression of the three
      betaLG genes in two cats. The differences of expression could be due to changes
      in the promoter and 3' non-coding region affecting the level of transcription and
      the mRNA stability. The FR-PCR technique was shown to be reproducible and
      accurate even for small percentage differences, being very useful when a small
      amount of sample is available.

PMID- 10341084
TI  - The fit-1 common integration locus in human and mouse is closely linked to MYB.
AB  - The fit-1 locus was originally identified as a common insertion site for feline
      leukemia virus (FeLV) in thymic lymphosarcomas induced by FeLV-myc recombinant
      viruses, suggesting that it harbors a gene that cooperates with Myc in T-cell
      leukemogenesis. We have previously mapped the fit-1 locus to feline Chromosome
      (Chr) B2. We have now identified conserved sequences that allow the mapping of
      the murine homolog using the European Interspecific Backcross (EUCIB). This shows
      that fit-1 is located on mouse Chr 10, 1cM proximal to Ahi-1, a murine retroviral
      integration locus that is closely linked to Myb. Moreover, the physical linkage
      to MYB is maintained in the human genome, as shown by cloning of the human
      homolog of fit-1 from a Chr 6 cosmid library and a series of overlapping PAC
      clones. Generation of a contig map around the human homolog of fit-1 reveals that
      it is approximately 100-kb upstream of MYB. In addition to fit-1 and Ahi-1, two
      other common insertion sites, Mis-2 and Mml-1, have also been mapped adjacent to
      Myb on mouse Chr 10. Previous analysis of tumors carrying insertions at fit-1,
      Mml-1, Mis-2 and Ahi-1 showed no obvious abnormalities in Myb expression.
      However, the cluster of viral insertion loci in this region suggests either the
      presence of a closely linked activation target or that subtle effects on Myb have
      been overlooked.

PMID- 10341086
TI  - A radiation hybrid map of the RN region in pigs demonstrates conserved gene order
      compared with the human and mouse genomes.
AB  - We recently constructed a 7000-rad porcine whole-genome radiation hybrid (RH)
      panel with the primary objective of integrating linkage maps of microsatellites
      with evolutionary conserved genes into one ordered map. In order to evaluate the
      resolution of this RH panel, we have now constructed a radiation hybrid map of
      the Chromosome (Chr) 15q2.3-q2.6 region containing the RN gene. This gene has
      large effects on glycogen content in muscle and meat quality. Ten microsatellites
      covering a region of 55 centiMorgans and eight genes (AE3, FN1, IGFBP5, INHA,
      IRS1, PAX3, TNP1, and VIL1) were placed on the Sscr15 RH map. All the genes,
      except IRS1, were mapped on the RH map between microsatellites located in 15q2.5.
      The relative order of AE3 and INHA was inverted on the porcine physical map in
      comparison with the mouse linkage map. The order of other genes already mapped in
      the mouse (FN1, IGFBP5, TNP1, VIL1, INHA/AE3, and PAX3) was identical in pigs. We
      found no clear difference between the gene order on pig Chr 15 and human Chr 2q.

PMID- 10341087
TI  - Construction and characterization of a porcine P1-derived artificial chromosome
      (PAC) library covering 3.2 genome equivalents and cytogenetical assignment of six
      type I and type II loci.
AB  - A porcine P1-derived artificial chromosome (PAC) library of a male German
      Landrace pig was constructed in pCYPAC2. In total 90,240 clones were generated
      and individually transferred into microtiter plates. An average insert size of
      119.1 kb was determined by analyzing 150 randomly selected PAC clones by pulsed
      field electrophoresis, yielding approximately 3.2 genome equivalents. The
      stability of nine clones was followed through 110 generations showing no
      reduction of the insert size. The probability of identifying a specific
      chromosomal region within the library was tested by screening for the presence of
      seven type I and five type II loci. The analysis showed that most loci (10/12)
      were present in the library at least twice. To determine the percentage of
      chimerism, six clones were analyzed by fluorescence in situ hybridization (FISH)
      on metaphase chromosomes. We assign one type I locus (Triadin) and three type II
      loci (SW855, S0300, SW1129).

PMID- 10341088
TI  - A genomic scan of porcine reproductive traits reveals possible quantitative trait
      loci (QTLs) for number of corpora lutea.
AB  - Reproductive traits have low heritabilities, are expressed in only one sex, and
      are not measurable until sexual maturity (Avalos and Smith, Anim Prod 44:153,
      1987). Using traditional methods, selection for reproductive traits is relatively
      less effective than selecting for growth or carcass traits. Traits most affected
      by a small number of genes with major effects rather than many genes with small
      effects are most amenable to MAS. As part of our porcine genome scan to identify
      quantitative trait loci (QTLs) of economic importance in marker-assisted
      selective (MAS) breeding programs, we examined 8 reproductive and farrowing
      traits in the University of Illinois (UI) Meishan x Yorkshire Resource Family.
      Gilts were genotyped with 119 microsatellite markers (MS) with intervals
      averaging 24 cM over all 18 porcine autosomes. F-ratios supporting QTL location
      were calculated by the least squares regression method. Results suggestive of
      linkage at the 5% genome-wide level were observed for the number of stillborn
      piglets on Chromosome (Chr) 4 (SSC4) (p-value = 0.0001), corpora lutea on SSC8 (p
      value = 0.00027), and gestation length on SSC9 (p-value = 0.00019). Results for
      additional loci relevant to litter size, number of corpora lutea on SSC15 and 7
      (p-value = 0.0029 and 0.0028 at 107 and 150 cM, respectively), gestation length
      on SSC15 and 1 (p-value = 0.0017 and 0.0069 at 96 and 166 cM, respectively),
      uterine length on SSC7 and 5 (p-value = 0.0044 and 0.0075 at 148 and 1 cM,
      respectively) and piglets born per litter on SSC6 (p-value = 0.0075 at 102 cM),
      were not statistically significant at the 5% genome-wide level. Thus, the use of
      a linked marker to facilitate selection for reproductive traits has considerable
      potential. By using linked markers, selection can be applied to both sexes before
      sexual maturity, making genetic selection considerably more efficient and less
      costly.

PMID- 10341089
TI  - Characterization of a swine chromosome-specific centromeric higher-order repeat.
AB  - The centromeric region of swine chromosomes is comprised of tandemly repeated,
      divergent DNA monomer units. Here we report that these divergent DNA monomer
      sequences are organized into higher-order repeats, analogous to the hierarchical
      organization of alpha-satellite monomers in human centromeres. In this study, a
      centromeric cosmid clone was shown to be comprised entirely of a 3.3-kb higher
      order repeat, with independent copies of this higher-order repeat more than 99%
      identical to each other. This higher-order repeat is composed of ten divergent
      monomer units of approximately 340 bp. The ten monomers are on average 79%
      identical, and all ten monomers are arranged in the same 5' to 3' orientation. In
      FISH analysis, a cloned 3.3-kb higher-order repeat hybridized to the centromere
      of Chromosome (Chr) 9 in metaphase spreads and detected two discrete foci in
      interphase nuclei, demonstrating that this swine higher-order repeat is
      chromosome-specific. The Chr 9 centromeric array spanned approximately 2.2 Mb as
      determined by pulsed-field gel electrophoresis. Moreover, the swine Chr 9
      centromere is highly polymorphic, because an EcoRI restriction site polymorphism
      was detected. Thus, the assembly of divergent satellite sequences into chromosome
      specific higher-order repeats appears to be a common organizational feature of
      both the human and swine centromere and suggests that the evolutionary
      mechanism(s) that create and maintain higher-order repeats is conserved between
      their genomes.

PMID- 10341090
TI  - Construction and characterization of a sheep BAC library of three genome
      equivalents.
AB  - A sheep BAC library of over three genome equivalents was constructed and arrayed
      in superpools and row, column, and plate pools. The library contains 90,000
      clones distributed in 39 superpools. The average insert size was estimated at 123
      kb. The library was screened by PCR with 77 primer pairs corresponding to ovine
      microsatellites distributed throughout the genome. The probability of finding a
      random sequence in the library could be estimated at 0.96.

PMID- 10341091
TI  - Genomic imprinting of the insulin-like growth factor 2 gene in sheep.
AB  - A number of genes in the human and mouse genomes are subject to genomic
      imprinting, with selective inactivation of one allele of a gene in a parent-of
      origin specific manner. One of the first imprinted genes identified was the
      Insulin-like Growth Factor 2 gene (IGF2), which promotes growth of the fetus and
      is expressed from only the paternal allele in most tissues in both the mouse and
      human. The aim of this study was to establish the imprinting status of IGF2 in
      sheep (Ovis aries). Sheep provide an interesting model to study imprinting, owing
      to differences in their placental development and the fact that they have been
      subject to strong artificial selection for various production traits. We report
      the identification of a length polymorphism in the transcribed 3'-untranslated
      region of the ovine IGF2 gene. This polymorphism was used to map IGF2 to sheep
      Chromosome (Chr) 21 and demonstrate that IGF2 is indeed imprinted in sheep, being
      expressed from the paternal allele. We also report that the developmental switch
      from imprinted IGF2 expression in the fetal liver to biallelic IGF2 expression in
      the adult liver, which occurs in the human but not mouse, also occurs in sheep.
      Differences in male- and female-specific recombination values reported around the
      IGF2 locus in the human were also observed around the ovine IGF2 locus. The
      techniques developed in this study will enable the imprinting status of IGF2 to
      be assessed in a variety of tissues and stages of development in normal sheep.

PMID- 10341092
TI  - Isolation, genomic organization, and expression analysis of Men1, the murine
      homolog of the MEN1 gene.
AB  - The mouse homolog of the human MEN1 gene, which is defective in a dominant
      familial cancer syndrome, multiple endocrine neoplasia type 1 (MEN1), has been
      identified and characterized. The mouse Men1 transcript contains an open reading
      frame encoding a protein of 611 amino acids which has 97% identity and 98%
      similarity to human menin. Sequence of the entire Men1 gene (9.3 kb) was
      assembled, revealing 10 exons, with exon 1 being non-coding; a polymorphic
      tetranucleotide repeat was located in the 5'- flanking region. The exon-intron
      organization and the size of the coding exons 2-9 were well conserved between the
      human and mouse genes. Fluorescence in situ hybridization localized the Men1 gene
      to mouse Chromosome (Chr) 19, a region known to be syntenic to human Chr 11q13,
      the locus for the MEN1 gene. Northern analysis indicated two messages-2.7 kb and
      3.1 kb-expressed in all stages of the embryo analyzed and in all eight adult
      tissues tested. The larger transcript differs from the smaller by the inclusion
      of an unspliced intron 1. Whole-mount in situ hybridization of 10.5-day and 11.5
      day embryos showed ubiquitous expression of Men1 RNA. Western analysis with
      antibodies raised against a conserved C-terminal peptide identified an
      approximately 67-kDa protein in the lysates of adult mouse brain, kidney, liver,
      pancreas, and spleen tissues, consistent with the size of human menin. The levels
      of mouse menin do not appear to fluctuate during the cell cycle.

PMID- 10341093
TI  - Localization of a locus responsible for the bovine chondrodysplastic dwarfism
      (bcd) on chromosome 6.
AB  - A hereditary chondrodysplastic dwarfism caused by an autosomal recessive gene has
      been reported in a population of Japanese Brown cattle. Affected calves show an
      insufficiency of endochondral ossification at the long bones of the limbs. In the
      present study, we mapped the locus responsible for the disease (bcd) by linkage
      analysis, using microsatellite markers and a single paternal half-sib pedigree
      obtained from commercial herds. Linkage analysis revealed a significant linkage
      between the bcd locus and marker loci on the distal region of bovine Chromosome
      (Chr) 6. The bcd locus was mapped in the interval between microsatellite markers
      BM9257 and BP7 or BMS511 with a recombination fraction of 0.05 and 0.06, and a
      lod score of 8.6 and 10.1, respectively. A comparison of genetic maps between
      bovine Chr 6 and human Chr 4 or mouse Chr 5 indicates possible candidate genes
      including FGFR3 and BMP3 genes, which are responsible for human chondrodysplasias
      and associated with bone morphogenesis, respectively.

PMID- 10341094
TI  - Murine phospholipid hydroperoxide glutathione peroxidase: cDNA sequence, tissue
      expression, and mapping.
AB  - Phospholipid hydroperoxide glutathione peroxidase (PHGPx), also known as
      glutathione peroxidase 4 (GPX4), is a 19-kDa, monomeric enzyme that protects
      cells from lipid peroxide-mediated damage by catalyzing the reduction of lipid
      peroxides. PHGPx is synthesized in two forms, as a 194-amino acid peptide that
      predominates in gonadal tissue and localizes to mitochondria, and as a 170-amino
      acid protein that predominates in most somatic tissues and localizes to the
      cytoplasm. With the rapid amplification of cDNA ends (RACE) procedure, an 876-bp
      PHGPx cDNA was amplified from mouse testis, and a 767-bp PHGPx cDNA was amplified
      from mouse heart. The cDNA sequences were identical except that the testis cDNA
      contained an additional 109 bp at its 5' end. With a partial cDNA with complete
      homology to both the testis and myocardial PHGPx cDNAs, the murine tissue
      distribution of PHGPx mRNA expression was determined by Northern blotting.
      Highest level of PHGPx expression was found in the testis, followed by the
      kidney, heart and skeletal muscle, liver, brain, lung, and spleen. Northern
      blotting performed with a cDNA specific for the longer PHGPx transcript
      demonstrated that this longer PHGPx transcript was present only in the testis. A
      1.4-kb PHGPx genomic fragment was amplified from murine kidney DNA and used to
      map the PHGPx gene by linkage analysis of restriction fragment length variants
      (RFLVs). The murine PHGPx gene (Gpx4) was mapped to a region of murine Chromosome
      (Chr) 10, located 43 cM from the centromere, that is syntenic with the human
      locus, which is located at the terminus of the short arm of human Chr 19. This
      information may be valuable in characterizing the role of PHGPx in modulating
      susceptibility to lipid peroxide-mediated injury in inbred murine strains and for
      targeted disruption of the gene.

PMID- 10341095
TI  - Compact chromatin packaging of inactive X chromosome involves the actively
      transcribed Xist gene.
AB  - The Xist gene responsible for X inactivation may take a unique chromatin
      structure because of exceptional expression from inactive X Chromosome, (Chr). We
      have examined differential chromatin packaging of the Xist gene region between
      active and inactive X Chr with a novel method consisting of the chromatin
      fractionation and allele-specific detection. Analysis of F1 heterozygous female
      mice from T(X;16)16H x MSM crosses and two cell clones derived from inter
      subspecific F1 female mice demonstrated that the packaging level of the
      transcribed Xist region on inactive X Chr was as tight as that of the repressed
      Pgk-1 allele on the same chromosome. On the other hand, restriction endonuclease
      sensitivity assay of chromatin showed that the promoter region, but not
      transcribed regions, of the transcribed Xist allele retained accessibility to
      nucleases. These results may suggest a cis-element(s) in a regulatory region of
      the Xist gene to prevent the transcriptionally inhibitory effect of the chromatin
      packaging.

PMID- 10341096
TI  - Application of the RLGS image analysis tool (RAT) to the construction of a
      genetic linkage map of recombinant inbred strain SMXA.
AB  - The construction of a genetic linkage map is the first, fundamental step to
      analyze the genetic properties of any organism. For this purpose, the restriction
      landmark genome scanning method (RLGS) can be used and has been shown to have
      high productivity in various genetic analyses. However, construction of a genetic
      linkage map by the RLGS method is laborious, because hundreds of spots must be
      scored, usually by visual observation. In order to reduce human involvement in
      the data processing, we developed an image analysis software, RAT (RLGS Analysis
      Tool). We evaluated its accuracy and feasibility by comparing the parental
      distribution patterns of RLGS spots obtained by RAT and by human observation,
      using Syrian hamster strain backcross progeny. We then used RAT to construct a
      genetic linkage map of the recombinant inbred strain SMXA. We were able to obtain
      121 progenitor strain-specific spots that were assigned to a specific chromosome.

PMID- 10341097
TI  - The major brain isoform of kif1b lacks the putative mitochondria-binding domain.
AB  - Kinesin and kinesin superfamily proteins are molecular motors involved in
      important intracellular functions such as organelle transport and cell division.
      They are microtubule-activated ATPases composed of a motor domain that binds to
      microtubules and a cargo-binding domain that binds to specific organelles. While
      searching for the slow Wallerian degeneration mutation (WldS) on distal mouse
      Chromosome (Chr) 4, we have identified a member of the kinesin superfamily whose
      predicted gene product has the N-terminal motor domain of Kif1b and a novel C
      terminal cargo-binding domain homologous to Kif1a. Kif1b is responsible for the
      movement of mitochondria along the axon, but the novel isoform containing the
      alternative C-terminal domain is likely to have a different cargo-binding
      specificity. cDNA library screening and Northern blot analysis indicate that the
      alternatively spliced form of Kif1b containing the novel 3'end accounts for the
      most part of Kif1b expression. We also found more alternatively spliced exons
      that can give rise to heterogeneous transcripts. Therefore, alternative splicing,
      as well as multiple genes, may contribute to the selective movement of diverse
      organelles by anterograde axonal transport. Kif1b maps on distal mouse Chr 4,
      within the Wld genetic candidate interval, but outside the recently identified
      triplication. There is, however, no evidence that Kif1b is the Wld gene.

PMID- 10341098
TI  - Tli1, a resistance locus for carcinogen-induced T-lymphoma.
AB  - Within 180 days after injection with N-methyl-N-nitrosourea (MNU), 83.5% of AKR/J
      mice and 37.5% of BALB/cJ mice developed T-lymphoma. The high tumor incidence was
      a dominant trait, as 93% of MNU-injected F1 mice developed T-lymphoma. A genome
      screen of 285 MNU-injected F2 mice identified a locus, designated T-lymphoma
      Induced 1 or Tli1, in a approximately 10-cM interval on central Chr 1 between
      D1Mit87 and D1Mit423 with significant linkage to the incidence of MNU-induced T
      lymphoma (P = 0.0004). Injection of BALB/cJ.AKR/J-Tli1 congenic mice with MNU
      confirmed the presence of Tli1 on central Chr 1. Mice homozygous for the BALB/cJ
      allele (Tli1bb) were over-represented in the tumor-free F2 mice, while the
      inheritance of parental alleles of Tli1 in tumor-bearing mice was close to
      expected. This suggests that the Tli1b allele is recessive and suppresses MNU
      induced T-lymphoma development in BALB/cJ mice and in Tli1bb F2 mice.
      Furthermore, the kinetics of lymphoma development in BALB/cJ and the Tli1
      congenic mice suggests that Tli1b acts to suppress lymphomas developing late
      after injection with MNU. Two known genes that map in the identified genomic
      interval on central Chr 1 are candidates for Tli1:IL10, encoding the lymphokine
      IL10, and Cmkar4, encoding the chemokine receptor CXCR4.

PMID- 10341099
TI  - PCR in situ followed by microdissection allows whole chromosome painting probes
      to be made from single microdissected chromosomes.
AB  - Whole-chromosome painting probes (WCPs) and chromosome-arm painting probes (CAPs)
      are an integral part of the cytogenetic analysis of chromosome abnormalities.
      While these are routinely made by chromosome microdissection, multiple copies of
      the dissected region have been necessary to achieve a library sufficiently
      complex to provide adequate painting. Performing multiple dissections of
      chromosomes or chromosome regions is time consuming and occasionally impossible,
      such as when working with species whose banded karyotype is not well defined. We
      have developed a method whereby chromosome paints can be reliably generated by
      dissecting single chromosomes. The technique consists of performing degenerate
      oligonucleotide-primed polymerase chain reaction (DOP-PCR) in situ on the
      chromosomes, prior to dissection. Enough amplification occurs to enable a single
      dissected chromosome to be used to create a painting probe sufficiently complex
      for use in fluorescence in situ hybridization (FISH). The amplification products
      remain localized on the chromosomes; this allows region-specific chromosome
      paints to be made. We detail this novel technique and show whole-chromosome, arm
      specific, and contiguous region-specific probes for human and rat, each created
      from single dissected fragments of chromatin.

PMID- 10341100
TI  - Genomic structure and chromosomal mapping of the mouse transcription factor TEF-5
      (Tead3) gene.

PMID- 10341101
TI  - High level of single-nucleotide polymorphism in the rat cyclin B1 gene.

PMID- 10341102
TI  - Complete nucleotide sequence, genomic organization, and promoter analysis of the
      murine survival motor neuron gene (Smn).

PMID- 10341103
TI  - Isolation and characterization of the human SCP2 cDNA and chromosomal
      localization of the gene.

PMID- 10341104
TI  - Inbred lines of mice derived from long-term divergent selection on fat content
      and body weight.

PMID- 10341106
TI  - Electronic data submissions to MGD from 5/26/98 to 1/13/99 

PMID- 10341105
TI  - A YAC contig encompassing the 11q14.3 breakpoint of a translocation associated
      with schizophrenia, and including the tyrosinase gene.

PMID- 10341107
TI  - Note to the community 

PMID- 10341108
TI  - Temporal and durational patterns associating respiration and swallowing.
AB  - This study obtained initial normative data on the temporal coordination of
      respiration and swallowing events in 12 young adults using a first-generation
      Respirodeglutometer. In addition, direction of airflow before and after deglutive
      apnea was obtained. Three swallows of two viscosities of bolus material were
      performed by each subject, yielding a total of 72 swallows. Qualitative and
      quanitative analyses were performed. Time of onset of submental surface
      electromyography and time of laryngeal movement were found to differ between
      males and females. Males began submental muscle contraction before females and
      laryngeal movement after females. Duration of deglutition apnea for all swallows
      was 0.75 +/- 0.14 sec. Expiration occurred before the deglutition apnea 93% of
      the time and after the deglutition apnea 100% of the time. A modal pattern of
      events obtained with the Respirodeglutometer was present in 42% of the swallows,
      and an additional 47% had only one event differ from that order.

PMID- 10341109
TI  - The Dysphagia Outcome and Severity Scale.
AB  - The Dysphagia Outcome and Severity Scale (DOSS) is a simple, easy-to-use, 7-point
      scale developed to systematically rate the functional severity of dysphagia based
      on objective assessment and make recommendations for diet level, independence
      level, and type of nutrition. Intra- and interjudge reliabilities of the DOSS was
      established by four clinicians on 135 consecutive patients who underwent a
      modified barium swallow procedure at a large teaching hospital. Patients were
      assigned a severity level, independence level, and nutritional level based on
      three areas most associated with final recommendations: oral stage bolus
      transfer, pharyngeal stage retention, and airway protection. Results indicate
      high interrater (90%) and intrarater (93%) agreement with this scale.
      Implications are suggested for use of the DOSS in documenting functional outcomes
      of swallowing and diet status based on objective assessment.

PMID- 10341110
TI  - Simultaneous videofluoroscopic swallow study and modified Evans blue dye
      procedure: An evaluation of blue dye visualization in cases of known aspiration.
AB  - The reliability of the modified Evans blue dye (MEBD) test for the detection of
      aspirated materials in patients with tracheostomy has been questioned. The
      videofluoroscopic swallow study (VFSS) has been the standard procedure used to
      detect aspiration, but there are known risks and the VFSS is not always an
      available evaluation option for aspiration detection. The purpose of the present
      study was to investigate the visualization of blue tracheal secretions in cases
      of known aspiration as documented by the VFSS. Twenty consecutive simultaneous
      MEBD study and VFSS were completed on patients with tracheostomies at an acute
      rehabilitation hospital. Overall, the MEBD showed a 50% false-negative error
      rate. The MEBD identified aspiration in 100% of patients who aspirated more than
      trace amounts but failed to identify aspiration of trace amounts (0%).

PMID- 10341111
TI  - The use of simultaneous videofluoroscopic swallow study and modified Evans blue
      dye procedure: An evaluation of blue dye visualization in cases of known
      aspiration.

PMID- 10341112
TI  - Assessment of dysphagia with the use of pulse oximetry.
AB  - Recent anecdotal literature has shown a relation between arterial oxygen
      saturation (SpO2), as measured by pulse oximetry, and aspiration during eating.
      The present study was designed to determine whether bedside pulse oximetry has a
      role in the assessment of pharyngeal phase dysphagia. Forty-six adult patients
      with clinically suspected swallowing abnormalities underwent modified barium
      swallow to evaluate dysphagia. After determining baseline oxygen saturation by
      pulse oximetry, different consistencies of barium were sequentially ingested.
      Patients were monitored for radiographic evidence of penetration or aspiration,
      which was correlated with continuous SpO2 recording. Patients who exhibited
      aspiration or penetration without clearing had a significant decline in SpO2
      compared with those patients who penetrated but cleared or in whom no penetration
      was observed. These relations were not associated with age, gender, or diagnosis.
      These preliminary data indicate that bedside pulse oximetry may be a useful tool
      in the evaluation of patients with dysphagia.

PMID- 10341113
TI  - Effects of nasogastric tubes on the young, normal swallowing mechanism.
AB  - The present study aimed to investigate the effects of different-sized nasogastric
      tubes on swallowing speed and function in 10 young normal volunteers. Using X-ray
      visualization, liquid barium swallows were recorded on video (videofluoroscopy)
      under three experimental conditions: no nasogastric tube, fine-bore nasogastric
      tube, and wide-bore nasogastric tube. Nasogastric tubes slowed swallowing but did
      not alter swallowing function, namely bolus transit and clearance, and airway
      protection. The presence of a wide-bore nasogastric tube caused significant
      duration changes in several swallowing measures, namely duration of stage
      transition, duration of pharyngeal response, duration of pharyngeal transit, and
      duration of upper esophageal sphincter opening. Similar trends were seen for the
      fine-bore tube. The implications for nonoral feeding of patients with swallowing
      disorders are discussed.

PMID- 10341114
TI  - Rehabilitation of neurogenic dysphagia with percutaneous endoscopic gastrostomy.
AB  - Neurogenic oropharyngeal dysphagia is common in nursing home populations, and the
      risk of aspiration is sufficient to indicate the need for percutaneous endoscopid
      gastrostomy (PEG) feedings. Although intake provided through the PEG may meet the
      nutritional and hydration requirements for this group of patients, the risk of
      complication, e.g., aspiration of reflux, skin breakdown at the site of
      insertion, potential for infection, digestive difficulties, higher risk of
      rehospitalization, pneumonia, prolonged nursing home stay, and greater morbidity
      than for those without PEG tubes, may compromise the gains accrued from the ease
      of feeding. In an attempt to reduce these complications and return individuals to
      per orum (PO) diets, a program was developed to treat the dysphagia. Sixteen male
      nursing home patients were enrolled in a treatment program based on
      videofluoroscopic examination. Interventions included combinations of dietary
      consistency modifications, compensatory techniques, and direct swallow
      retraining. Results indicated such an approach reintroduced successful oral
      feeding in all patients, improved dietary consistency, resulted in a mean weight
      gain of 5.1 pounds, yielded a mean albumin increase of 0.5 g/dl, and allowed PEG
      tubes to be removed in 10 of the 16 patients. As a result of intervention, these
      findings suggest significant benefits in both quality of life issues and health
      care savings for this neurogenically based population.

PMID- 10341115
TI  - Effects of physostigmine on swallowing and oral motor functions in patients with
      progressive supranuclear palsy: A pilot study.
AB  - The purpose of this pilot study was to investigate whether cholinergic
      stimulation reduces swallowing and oral motor disturbances in patients with
      progressive supranuclear palsy (PSP). A controlled, double-blind crossover trial
      of physostigmine, a centrally active cholinesterase inhibitor, and placebo was
      conducted. Patients were randomized to a 10-day crossover placebo-controlled
      double-blind trial of physostigmine at their previously determined best dose
      administered orally every 2 hr, six times per day. Patients were evaluated with
      ultrasound imaging of the oropharynx and an oral motor examination at baseline
      and during the third or fourth days of each study phase (placebo and drug). Under
      the double-blind placebo-controlled conditions, patients showed no statistically
      significant improvement in oral motor functions or swallow durations. Because
      patients with PSP have increased sensitivity to cholinergic blockade compared
      with control subjects, studies with newer, more potent cholinergic stimulating
      agents need further exploration. Suggestions for future research include the
      evaluation of newer direct cholinergic agonists in the treatment of the less
      impaired PSP patients who may have a greater number of cholinergic neurons
      preserved and the evaluation of combined therapies.

PMID- 10341116
TI  - Preliminary investigation of voice onset time production in persons with
      dysphagia.
AB  - The purpose of this study was to determine whether voice onset time (VOT) values
      of persons with dysphagia differed from those of a person with normal swallow
      function. Five male subjects with dysphagia (average age = 80.6 years) and a
      control subject (age = 79 years) read 18 consonant-vowel-consonant words in quasi
      random order. These syllables began with the voiced and voiceless cognates from
      the three stop places of articulation (i.e., bilabial, alveolar, and velar).
      These consonants were followed by the vowels /i/, /a/, and /u/. Digital audio
      tape recordings were performed and speech was digitized onto disk. Measurements
      were completed using BLISS software (Mertus J: BLISS User's Manual. Providence:
      Department of Cognitive and Linguistic Sciences, Brown University, 1989)
      implemented on a 486 microcomputer. Averages and standard deviations of the VOT
      measures for the six stop consonants were compared between the two experimental
      groups. For the dysphagic speakers, average VOT values for voiceless stops were
      shorter, and there were larger negative VOT values for voiced stops. Standard
      deviations for the VOT productions pf the dysphagic subjects were smaller.
      Statistical comparisons showed significant differences between individual
      dysphagic speakers and the normal control for three of the five subjects. These
      preliminary data suggest that dysphagia affects the fine motor control required
      for accurate VOT production in speech.

PMID- 10341117
TI  - Free jejunal grafts of the pharynx: surgical methods, complications, and
      radiographic evaluation.
AB  - Free jejunal grafts have been used in the surgical treatment of patients with
      carcinoma of the pharynx and upper esophagus. Post-operative complications,
      including swallowing difficulty, are frequent and radiographic assessment may be
      required. In this pictorial paper, we describe the surgical technique of free
      jejunal grafting of the pharyngoesophagus, and the radiographic appearances and
      clinical importance of early and delayed complications following the procedure.
      Dysphagia after placement of a jejunal graft is a common occurrence which is
      often multifactorial, and may be related to functional, anatomic, or a
      combination of factors.

PMID- 10341120
TI  - Dysphagia research society 1998 

PMID- 10341119
TI  - Bolus aggregation in the otopharynx does not depend on gravity.

PMID- 10341118
TI  - A comment on "Incidence and patient characteristics associated with silent
      aspiration in the acute care setting" (Dysphagia 14:1-7, 1999)

PMID- 10341121
TI  - Call for abstracts 

PMID- 10341122
TI  - Three-dimensional 13C shift/1H-15N coupling/15N shift solid-state NMR correlation
      spectroscopy.
AB  - Triple-resonance experiments capable of correlating directly bonded and proximate
      carbon and nitrogen backbone sites of uniformly 13C- and 15N-labeled peptides in
      stationary oriented samples are described. The pulse sequences integrate cross
      polarization from 1H to 13C and from 13C to 15N with flip-flop (phase and
      frequency switched) Lee-Goldburg irradiation for both 13C homonuclear decoupling
      and 1H-15N spin exchange at the magic angle. Because heteronuclear decoupling is
      applied throughout, the three-dimensional pulse sequence yields 13C shift/1H-15N
      coupling/15N shift correlation spectra with single-line resonances in all three
      frequency dimensions. Not only do the three-dimensional spectra correlate 13C and
      15N resonances, they are well resolved due to the three independent frequency
      dimensions, and they can provide up to four orientationally dependent frequencies
      as input for structure determination. These experiments have the potential to
      make sequential backbone resonance assignments in uniformly 13C- and 15N-labeled
      proteins.

PMID- 10341123
TI  - Linewidth analysis of spin labels in liquids. I. Theory and data analysis.
AB  - We present a method of simulating the EPR spectra of spin labels in liquids using
      direct convolution of hyperfine splitting with Lorentzian linewidths. The aim is
      to simulate the experimental lineshape by considering all spectrometer
      characteristics as well as inhomogeneous and homogeneous linewidth effects. A
      major advance in this method is the correction for the broadening produced by
      Zeeman modulation commonly used to obtain EPR signals; this allows experimenters
      much more freedom to optimize their experimental conditions for the best signal
      to-noise ratio. Microwave power broadening (saturation) effects on the EPR lines
      are significant even at very low observer levels. Successful simulation requires
      that all contributions from unresolved hyperfine splittings be explicitly
      included. Inhomogeneous broadening is dealt with by including all spins that
      interact with the electron (as a set of superhyperfine interactions); there is no
      "effective Gaussian" to substitute for the correct superhyperfine interactions.
      The effects of spin exchange on the linewidth and lineshape can be observed and
      must be taken into account in order to extract the fundamental linewidths.

PMID- 10341125
TI  - Magic echo solid-state NMR imaging without a rapidly switchable field gradient 
AB  - To relax the high-speed requirement imposed on the gradient system used in solid
      state proton imaging, we propose two simple modifications of the magic echo
      imaging sequence, TREV-16TS. In the first modification, the applied gradient is
      inverted in the middle of the RF irradiation; the second modification utilizes a
      sinusoidal gradient synchronized with the RF sequence. It is estimated by
      experiments that as long as the RF amplitude is at least about 10 times stronger
      than the resonance offset induced by the gradient, the spatial resolution is not
      degraded significantly by the line narrowing deterioration due to the gradient
      applied during the on-resonance RF irradiation. The modifications allow
      commercially available standard gradients to be used for the magic echo imaging
      of solids. Copyright 1999 Academic Press.

PMID- 10341124
TI  - Linewidth analysis of spin labels in liquids. II. Experimental.
AB  - This work demonstrates that homogeneous linewidths can be extracted from
      continuous wave electron paramagnetic resonance spectra and that they
      quantitatively agree with the predictions of existing relaxation theory. We
      suggest that relaxation theory can be used to predict experimental lineshapes
      provided that the simulations properly include sources of broadening. We have
      found that the rotational correlation times for spin labels in different
      percentages of glycerol/water mixtures are best modeled by a power law treatment
      for the viscosity, similar to that for translational diffusion. The translational
      diffusion coefficients themselves also have a power law dependence on the
      viscosity for glycerol/water mixtures. The linewidths were linearly dependent
      upon both the oxygen and the spin label concentration. The hyperfine splittings
      of all nuclei were observed to decrease linearly with increasing spin label
      concentration, completely at odds with existing theory which predicts a quadratic
      dependence upon concentration. The linear dependence was independent of hyperfine
      splitting until the magnitude of the hyperfine splitting was less than the
      homogeneous linewidth.

PMID- 10341126
TI  - A near-resonance solution to the bloch equations and its application to RF pulse
      design 
AB  - A near-resonance expansion of the solution to the Bloch equations in the presence
      of a radiofrequency (RF) pulse is presented in this paper. The first-order
      approximation explicitly demonstrates the nonlinear nature of the Bloch equations
      and precisely relates the excitation profile with the RF pulse when the flip
      angle is less than pi/2. As an application of this solution, we present a
      procedure for designing RF pulses to generate symmetric excitation profiles with
      arbitrary shapes for new encoding approaches such as wavelet encoding. Copyright
      1999 Academic Press.

PMID- 10341128
TI  - Superslow backbone protein dynamics as studied by 1D solid-state MAS exchange NMR
      spectroscopy.
AB  - Superslow backbone dynamics of the protein barstar and the polypeptide
      polyglycine was studied by means of a solid-state MAS 1D exchange NMR method
      (time-reverse ODESSA) that can detect reorientation of nuclei carrying
      anisotropic chemical shift tensors. Experiments were performed on carbonyl 13C in
      polyglycine (natural abundance) and backbone 15N nuclei in uniformly 15N-enriched
      barstar within a wide range of temperatures in dry and wet powders for both
      samples. Two exchange processes were observed in the experiments: molecular
      reorientation and spin diffusion. Experimental conditions that are necessary to
      separate these two processes are discussed on a quantitative level. It was
      revealed that the wet protein undergoes molecular motion in the millisecond range
      of correlation times, whereas in dry protein and polyglycine molecular
      reorientations could not be detected. The correlation time of the motion in the
      wet barstar at room temperature is 50-100 ms; the activation energy is about 80
      kJ/mol. Previously, protein motions with such a long correlation time could be
      observed only by methods detecting chemical exchange in solution (e.g., hydrogen
      exchange). The application of solid-state MAS exchange spectroscopy provides new
      opportunities in studying slow biomolecular dynamics that is important for the
      biological function of proteins.

PMID- 10341127
TI  - Pulsed electron-nuclear double resonance (ENDOR) at 140 GHz.
AB  - We describe a spectrometer for pulsed ENDOR at 140 GHz, which is based on
      microwave IMPATT diode amplifiers and a probe consisting of a TE011 cavity with a
      high-quality resonance circuit for variable radiofrequency irradiation. For
      pulsed EPR we obtain an absolute sensitivity of 3x10(9) spins/Gauss at 20 K. The
      performance of the spectrometer is demonstrated with pulsed ENDOR spectra of a
      standard bis-diphenylene-phenyl-allyl (BDPA) doped into polystyrene and of the
      tyrosyl radical from E. coli ribonucleotide reductase (RNR). The EPR spectrum of
      the RNR tyrosyl radical displays substantial g-anisotropy at 5 T and is used to
      demonstrate orientation-selective Davies-ENDOR.

PMID- 10341129
TI  - Fluorine-19 solid-state NMR magic-angle-turning experiments using multiple-pulse
      homonuclear decoupling 
AB  - For compounds giving "crowded" 1-dimensional magic-angle-spinning spectra,
      information about the local atomic environment in the form of the chemical shift
      anisotropy (CSA) is sacrificed for high resolution of the less informative
      isotropic chemical shift. Magic-angle-turning (MAT) NMR pulse sequences preserve
      the CSA information by correlating it to the isotropic chemical shift in a 2
      dimensional experiment. For low natural abundance nuclei such as 13C and 15N and
      under 1H heteronuclear dipolar decoupling conditions, the dominant NMR
      interaction is the chemical shift. For abundant nuclei such as 1H, 19F, and 31P,
      the homonuclear dipolar interaction becomes a significant contribution to the
      observed linewidth in both F1 and F2 dimensions. We incorporate MREV8 homonuclear
      multiple-pulse decoupling sequences into the MAT experiment to give a multiple
      pulse MAT (MP-MAT) experiment in which the homonuclear dipolar interaction is
      suppressed while maintaining the chemical shift information. Extensive use of
      computer simulation using GAMMA has guided the pulse sequence development. In
      particular, we show how the MREV8 pulses can be incorporated into a quadrature
      detected sequence such as MAT. The MP-MAT technique is demonstrated for a model
      two-site system containing a mixture of silver trifluoroacetate and calcium
      difluoride. The resolution in the isotropic evolution dimension is improved by
      faster sample spinning, shorter MREV8 cycle times in the evolution dimension, and
      modifications of the MAT component of the pulse sequence. Copyright 1999 Academic
      Press.

PMID- 10341131
TI  - A low frequency 1H-NMR external unit for the analysis of large foodstuff samples.
AB  - An inexpensive external unit that allows the use of a commercial high-resolution
      NMR spectrometer as a very low frequency instrument is described. The external
      unit is phase coherent, the pulse timing being given by the parent spectrometer.
      With the exception of the probe, the external unit does not contain any tuned
      elements. This permits easy change of frequency in the range 100 kHz-1 MHz. The
      external unit may be appropriately employed in food science where, in several
      cases, low frequency is desirable. An application to hen shell eggs at the
      frequency of 700 kHz is described.

PMID- 10341130
TI  - Selective injection of magnetization by slow chemical exchange in NMR.
AB  - In a system in slow dynamic equilibrium two NMR methods are shown to be suitable
      for injecting magnetization from one resonance to another by means of slow
      chemical exchange. The combined outputs of the methods may be employed to measure
      the value of the off-rate constant kappa(off) in the complex. The methods are
      implemented experimentally using the complex of molecules composed of the enzyme
      Escherichia coli dihydrofolate reductase (DHFR) and the ligand folate. In an
      equilibrium solution with DHFR, folate is known to undergo chemical exchange
      between a free state and a bound state. The modified synchronous nutation method
      is applied to a spin of the folate molecule in the free and bound states;
      magnetization transfer occurs between the two sites due to the underlying
      exchange process. As a preliminary step for the application of the synchronous
      nutation method, a new one-dimensional 1H NMR technique is proposed which
      facilitates the assignment of the resonance of a spin in the bound state,
      provided the resonance of its exchange partner in the free state is known. This
      experiment is also used to obtain quantitative estimates of the transverse
      relaxation rate constant of the bound resonance. The numerical procedure
      necessary to analyze the experimental results of the synchronous nutation
      experiment is presented.

PMID- 10341132
TI  - "BEST" homonuclear adiabatic decoupling for 13C- and 15N-double-labeled proteins.
AB  - The cyclic irradiation sidebands appearing in homonuclear adiabatic decoupling
      are calculated in detail, which reveals the origin of the antisymmetric
      sidebands. The sidebands can be inverted by inserting an initial decoupling with
      a different period, but the same f1rms as the main decoupling that is required
      for Bloch-Siegert shift compensation. The sidebands can be eliminated in a broad
      decoupling range by adding spectra of opposite sidebands. Based on this scheme,
      an offset-independent double-adiabatic decoupling, named Bloch-Siegert Shift
      Eliminated and Cyclic Sideband Trimmed Double-Adiabatic Decoupling, or "BEST"
      decoupling for short, is constructed, which not only compensates the Bloch
      Siegert shift as shown earlier by Zhang and Gorenstein (1998) but also eliminates
      residual sidebands effectively.

PMID- 10341133
TI  - Simulation of magnetic resonance static powder lineshapes: A quantitative
      assessment of spherical codes 
AB  - Simulation of magnetic resonance static powder spectra is performed by a
      (possibly weighted) summation of single-crystal spectra computed for different
      orientations of the external field with respect to the principal axes of the
      magnetic interactions. The many available methods differ in the choice of the
      integration points (i. e., orientations) and weights, the set of which is called
      spherical code. There is continuing interest in minimizing the number of
      integration points necessary to a good simulation. Neglecting the possible
      interpolation of transition frequencies and intensities between integration
      points, we turn our attention to the efficiency of spherical codes themselves. To
      this end, an unbiased quantitative procedure to assess their efficiency in
      simulating magnetic resonance static powder spectra is proposed. To achieve an
      impartial judgement, the procedure has been designed by carefully taking into
      consideration the following points: choice of exact reference spectra; accurate
      definition of the merit figures; extended range of number of integration points;
      orientation dependence of the efficiency. The proposed procedure has been applied
      to an inclusive set of 23 spherical codes. It was found that most codes perform
      rather similarly. SPIRAL is the most efficient code, whereas Monte Carlo and
      "repulsive" codes show the best rotational invariance of the simulated lineshape
      with respect to the orientation of the spherical code. Copyright 1999 Academic
      Press.

PMID- 10341134
TI  - Quadrupolar and chemical shift tensors characterized by 2D multiple-quantum NMR
      spectroscopy 
AB  - The present work discusses a new 2D NMR method for characterizing the principal
      values and relative orientations of the electric field gradient and the chemical
      shift tensors of half-integer quadrupolar sites. The technique exploits the
      different contributions that quadrupolar and shielding interactions impart on the
      evolution of multiple-quantum and of single-quantum coherences, in order to
      obtain 2D powder lineshapes that are highly sensitive to these nuclear spin
      coupling parameters. Different spinning variants of this experiment were assayed,
      but it was concluded that a static version can yield the highest sensitivity to
      the values of the principal components and to the relative geometries of the
      local coupling tensors. It was found that correlating the central transition
      evolution with the highest available order of the spin coherence was also helpful
      for maximizing this spectral information. Good agreement between data obtained on
      87Rb (S = 32) and 59Co (S = 72) samples and ideal theoretical lineshape
      predictions of this experiment was obtained, provided that heterogeneities in the
      multiple-quantum excitation and conversion processes were suitably accounted by
      procedures similar to those described in the spin-(1/2) multiple-quantum NMR
      literature. Copyright 1999 Academic Press.

PMID- 10341135
TI  - NMR imaging of thermally polarized helium-3 gas.
AB  - It is shown that thermally polarized 3He gas can be used to measure important
      physical parameters and to design, test, and tune imaging sequences. The bulk
      values of T1, T2, and the diffusion coefficient were measured in a glass cell
      containing a mixture of helium-3 (0.8 bar) and oxygen (0.2 bar). They were found
      to be T1 = 7 s, T2 = 2.4 s, and D = 1.6 cm2 s(-1). The relaxation times T2* and
      T1 and the apparent diffusion coefficient of thermally polarized helium-3 gas
      were measured in the rat lung, and these parameters were used to design a helium
      3 optimized multi-spin-echo sequence which was shown to increase the signal-to
      noise ratio sufficiently to obtain the first NMR-images of thermally polarized
      helium-3 in the rat lung.

PMID- 10341136
TI  - Low field (10 mT) pulsed dynamic nuclear polarization.
AB  - EPR irradiation by a train of inverting pulses has potential advantages over
      continuous-wave EPR irradiation in DNP applications; however, it has previously
      been used only at high field (5 T). This paper presents the design and testing of
      an apparatus for performing pulsed DNP experiments at 10 mT with large samples
      (17 ml). Experimental results using pulsed DNP with an aqueous solution of a
      narrow-linewidth paramagnetic probe are presented. A maximum DNP enhancement of
      about -36 with a train of inverting pulses (width 500 ns, repetition time 4
      micros) was measured. A preliminary comparison showed that, when the same
      enhancement value is considered, the pulsed DNP technique requires an average
      power that is about three times higher than that required with the CW
      irradiation. However, for in vivo DNP applications it is very important to
      minimize the average power deposited in the sample. From the experimental results
      reported in this work, when considering the maximum enhancement, the pulsed
      technique requires only 2% of the average power necessary with the CW DNP
      technique. We believe that this reduction in the average power can be important
      for future DNP studies with large biological samples.

PMID- 10341137
TI  - Multiple-rotor-cycle QPASS pulse sequences: separation of quadrupolar spinning
      sidebands with an application to 139La NMR 
AB  - The quadrupolar phase-adjusted spinning sidebands (QPASS) pulse sequence has been
      recently demonstrated as a useful method for obtaining quadrupolar parameters
      with magic-angle spinning NMR. The sequence separates spinning sidebands by order
      in a two-dimensional experiment. A sheared projection of the 2D spectrum
      effectively yields the infinite spinning rate second-order quadrupolar powder
      pattern, which can be analyzed to determine quadrupolar coupling constants and
      asymmetry parameters. The RF power and spinning speed requirements of the
      original QPASS sequence make it an experimentally demanding technique. A new
      version of the sequence is demonstrated here and is shown to alleviate many
      problems associated with the original sequence. New solutions to the determining
      equations, based on the use of multiple rotor cycles in the QPASS sequence, lead
      to longer delays between the nine pi pulses, provide less chance of pulse
      overlap, and allow for use of weaker RF field strengths that excite only the
      central quadrupolar transition. A three-rotor-cycle version of the new experiment
      is demonstrated on the 139La nucleus. Copyright 1999 Academic Press.

PMID- 10341138
TI  - Tilt angle dependence of cross-relaxation in off-resonance ROESY.
AB  - We present an efficient experimental method to evaluate whether the effective
      cross-relaxation rate between a pair of spins vanishes when applying an off
      resonance spin-lock field. It is shown that the cross-relaxation rate can be made
      to vanish even when the two spins concerned resonate at different offsets and
      experience significantly different tilt angles of their respective spin-lock
      fields. This is verified experimentally using a sample of 15N-labeled human
      ubiquitin, through selective excitation of chosen amide protons. The results are
      relevant for the quantitative interpretation of off-resonance ROESY experiments.

PMID- 10341139
TI  - Identification of spin diffusion pathways in isotopically labeled biomolecules.
AB  - One-dimensional NOE experiments applicable to labeled macromolecules are
      presented which allow the manipulation of specific spin diffusion pathways and
      thus unambiguously identify clandestine spins through which the direct NOE is
      mediated. A treatment of spin diffusion using average Liouvillian theory is shown
      to describe adequately these phenomena. Experiments are carried out on an 15N
      labeled sample of human ubiquitin.

PMID- 10341140
TI  - Order matrix analysis of residual dipolar couplings using singular value
      decomposition.
AB  - The measurement of anisotropic spin interactions, such as residual dipolar
      couplings, in partially ordered solutions can provide valuable information on
      biomolecular structure. While the information can be used to refine local
      structure, it can make a unique contribution in determining the relative
      orientation of remote parts of molecules, which are locally well structured, but
      poorly connected based on NOE data. Analysis of dipolar couplings in terms of
      Saupe order matrices provides a concise description of both orientation and
      motional properties of locally structured fragments in these cases. This paper
      demonstrates that by using singular value decomposition as a method for
      calculating the order matrices, principal frames and order parameters can be
      determined efficiently, even when a very limited set of experimental data is
      available. Analysis of 1H-15N dipolar couplings, measured in a two-domain
      fragment of the barley lectin protein, is used to illustrate the computational
      method.

PMID- 10341141
TI  - Need for improved science in standard setting for hexavalent chromium.

PMID- 10341142
TI  - Overestimation bias and other pitfalls associated with the estimated 99.9th
      percentile in acute dietary exposure assessments.

PMID- 10341143
TI  - A physiologically based pharmacokinetic model of inorganic arsenic.
AB  - This study presents a physiologically based pharmacokinetic model of inorganic
      arsenic disposition in humans. The model focuses on short-term exposures by the
      oral route. The model considers the four circulating species (AsIII, AsV, and two
      metabolites, i.e., monomethylarsenic (MMA) and dimethylarsenic (DMA)) in tissue
      groups. The model also provides for the reduction of AsV to AsIII via chemical
      reaction with tissue glutathione and the subsequent transformation of AsIII into
      two metabolites (MMA and DMA) based on the experimental observations. Effort on
      the development of the model is directed toward the prediction of the kinetic
      behavior of inorganic arsenic in the body, following environmental exposure at
      ambient water concentrations, including tissue and blood concentrations, and
      especially urinary excretion of arsenic and its methylated metabolites. While it
      is difficult to estimate some of parameters used in the model at this time, the
      current model assumptions and predictions seem to be consistent with the
      experimental observations found in the literature. Therefore, the current model,
      when more fully developed, is expected to provide insight into the behavior of
      inorganic arsenic and its methylated metabolites within the body and may help
      increase the understanding of risk assessment issues associated with inorganic
      arsenic in drinking water.

PMID- 10341144
TI  - Cardiac dysfunction induced by low and high diet antioxidant levels comparing
      selenium and vitamin E in rats.
AB  - The present study was designed to investigate and compare the effects of dietary
      antioxidants on the mechanical characteristics of the rat heart. Both sex
      weanling rats were fed for 12 to 14 weeks a standardized selenium (Se)- and
      vitamin E-deficient diet, a Se-excess diet, or a control diet. Deficiency or
      toxicity of Se was verified by direct (tissue Se analysis and histopathological
      investigations) methods. The hearts of both experimental groups revealed some
      alterations in contractile performance with increased heart rate and coronary
      perfusion pressure. The average peak contractile force of the electrically
      stimulated papillary muscle measured in both experimental groups was not
      significantly different from the control values. When expressed as a percentage,
      the maximal increase in the peak contractile force of papillary muscle (PCF) that
      was obtained with 100 nM isoproterenol, respectively, was less in both
      experimental groups (26% in PCF of deficient group; 34% in PCF of rich group)
      than in the control group (80% in PCF). A decreased stimulation of contractile
      force of papillary muscle strips by a beta-adrenergic agonist seems to be in
      agreement with possible alterations in the response to inotropic agents due to a
      modification of the receptor function.

PMID- 10341145
TI  - A unified approach to risk assessment for cancer and noncancer endpoints based on
      benchmark doses and uncertainty/safety factors.
AB  - A fundamental goal of toxicology is to determine safe levels of human exposure to
      toxic substances. In the absence of information to establish dose-response
      relationships at low exposure levels generally experienced by humans, high-dose
      to low-dose linear extrapolation is generally used for estimating carcinogenic
      risks and the no-observed-adverse-effect-level divided by uncertainty (safety)
      factors is widely used for establishing human exposure guidelines for noncancer
      effects. The basis and impact of this dichotomy is examined and questioned. It is
      proposed that a unified approach be adopted for establishing human exposure
      guidelines for both cancer and noncancer endpoints. It is suggested that a lower
      confidence limit on the dose estimated to produce an excess incidence of adverse
      health effects in 10% of the individuals in a human study or 10% of the animals
      in laboratory experiments be used as a point-of-departure. This dose would be
      divided by appropriate uncertainty factors to establish human exposure
      guidelines. For severe irreversible adverse health effects we suggest a total
      default uncertainty factor (divisor) for animal data on the order of 10,000,
      which is comparable to current guidelines. For reversible biological effects a
      smaller default uncertainty factor on the order of 1000 may be employed. This is
      comparable to the divisor often used currently when the point-of-departure is the
      lowest-observed-adverse-effect-level. It is asserted that the toxicological
      information generally available does not warrant numerical estimates of risk at
      low levels of human exposure. Rather, we support a unified approach for all
      adverse health effects of dividing a benchmark dose by appropriate uncertainty
      factors to establish guidelines for human exposures to toxic substances.

PMID- 10341146
TI  - Biological factors which may influence an older child's or adolescent's responses
      to toxic chemicals.
AB  - Currently, there is considerable interest in scientific and regulatory issues
      relating to protection of children's health. Attention to date has largely been
      focused on establishing the efficacy and safety of drugs in children and on
      assessing potential risks of pesticides and similar agents to infants and young
      children. Older children and adolescents, however, have received little attention
      as special subgroups at risk from exposure to toxic and carcinogenic chemicals.
      Adolescence is the second most rapid period of growth and development, after
      infancy. Several organ systems experience substantial structural and functional
      changes during puberty. Attention is focused in this review on the more important
      organ systems that are undergoing maturation and therefore may be the most likely
      to exhibit aberrant responses to toxicants. Attention is also paid to age-related
      changes in processes which govern the disposition and metabolism of chemicals in
      the body.

PMID- 10341147
TI  - Toxicant-inflicted injury and stimulated tissue repair are opposing toxicodynamic
      forces in predictive toxicology.
AB  - These studies were designed to investigate the dose response for liver injury and
      tissue repair induced by exposure to four structurally and mechanistically
      dissimilar hepatotoxicants, individually and as mixtures. The objective was to
      illuminate the impact of the extent and timeliness of tissue repair on the
      ultimate outcome of toxicity. Dose-response relationships for trichloroethylene
      (TCE), allyl alcohol (AA), thioacetamide (TA), and chloroform alone or as
      mixtures were studied. Male Sprague-Dawley rats (200-250 g) received a single
      intraperitoneal injection of individual toxicants as well as mixtures of these
      toxicants. Liver injury was monitored by plasma enzyme (ALT and SDH) levels and
      histopathology. Tissue regeneration was measured by [3H]thymidine incorporation
      into hepatic nuclear DNA. Individually, TCE, TA, and AA administration, over a 10
      to 12-fold dose range, revealed a dose-related increase in injury as well as
      tissue repair up to a threshold dose. Beyond this threshold, tissue repair was
      delayed and attenuated, and liver injury progressed. Mixtures of the four
      chemicals at the higher doses used in individual dose-response studies resulted
      in 100% mortality. Hence, mixtures at the lower two doses were selected for
      further study. Additional lower doses were also included to better understand the
      dose-response relationship of mixtures. Results of these studies support the
      observations of individual chemicals. Higher and sustained repair was observed at
      low dose levels. These studies show that the extent of injury at early time
      points correlates well with the maximal stimulation of the opposing response of
      tissue repair. It appears that the toxicity of the mixture employed in these
      studies is roughly additive and correlates well with tissue repair response.
      These initial studies suggest that a biologically based mathematical model can be
      constructed and tested to extrapolate the outcome of toxicity from a given dose
      of individual compounds as well as their mixtures, where the responses measured
      are injury on the one hand and compensatory tissue repair on the other.

PMID- 10341148
TI  - Current status of sport fish consumption advisories for PCBs in the Great Lakes.
AB  - During the past two decades, there have been a number of efforts to harmonize the
      advice given by different jurisdictions to consumers of sport-caught fish from
      the Great Lakes. Five years ago, an eight-state task force arrived at consensus
      recommendations with respect to fish consumption advisories for PCB-contaminated
      fish from these bodies of water. This report will examine the impacts of these
      efforts on advisories in these eight states and also how these state advisories
      compare to that of the Province of Ontario which shares some of these Great
      Lakes. Careful analyses of the differences among jurisdictions in recommendations
      and in the bases for these recommendations will illustrate the difficulties in
      achieving complete consensus. It will be shown that there are a large number of
      choices that must be made in developing an advisory and that these choices depend
      largely on policy considerations rather than science. Examples of these policy
      choices include whether to adjust measured fish concentrations for PCB losses due
      to preparation and cooking and whether to adjust PCB concentrations to account
      for nonfish sources of PCBs. Considering the variations among jurisdictions with
      respect to managing the risks from contaminants in various environmental media,
      it appears unlikely that uniformity can be achieved unless a regional rather than
      a state by state approach is taken. Whether a regional or a state by state
      approach is taken, the information in this report can be used to structure the
      fish consumption advisory decision-making process.

PMID- 10341149
TI  - Alternative and traditional models for the safety evaluation of food ingredients:
      summary report.

PMID- 10341150
TI  - Comparative activities of p-nonylphenol and diethylstilbestrol in noble rat
      mammary gland and uterotrophic assays.
AB  - Colerangle and Roy (1996, Endocrine 4, 115-122) have described the apparent
      ability of both diethylstilbestrol (DES) and p-nonylphenol (NP) to cause
      extensive cell proliferation and lobular development in the mammary glands of
      young adult Noble rats. The chemicals were administered over 11 days via
      subcutaneously implanted minipumps. The dose level of DES used (0.076 mg/kg/day)
      was about 70 times higher than its minimum detection level in rodent uterotrophic
      and reproductive toxicology studies. In contrast, the lowest active dose level of
      NP (0.073 mg/kg/day) in the Noble rat mammary gland study was about 600 times
      lower than its minimum detection level in rat uterotrophic and multigeneration
      studies. The apparent enhanced sensitivity of the Noble rat mammary gland to the
      estrogenic activity of NP was considered worthy of further study. Ovariectomized
      Noble rat uterotrophic assays with NP (minimum detection level approximately 40
      mg/kg/day, 3 or 11 days, oral gavage) revealed similar assay sensitivity to that
      observed for earlier immature and ovariectomized Alderley Park (AP) rat
      uterotrophic assays of this chemical. The response of the ovariectomized Noble
      rat uterotrophic assay to DES and estradiol was also as expected from earlier
      immature AP rat assays. It is concluded that the general sensitivity to estrogens
      of the Noble rat and the AP rat is similar. A repeat of the Noble rat mammary
      gland study with DES (11 x 0.076 mg/kg/day) and NP (11 x either 0.073 or 53.2
      mg/kg/day), as originally reported by Colerangle and Roy (1996), revealed a
      strong positive response to DES and no response to NP. It is concluded that the
      minimum detection level of NP as a weakly estrogenic material in the rat should
      be based on the results of rat uterotrophic and multigeneration studies and
      therefore be set at approximately 40 mg/kg/day. It is also concluded that induced
      S-phase in the rodent mammary gland is best monitored using BRDU, as opposed to
      PCNA staining, and that use of subcutaneously implanted minipumps/pellets is
      inappropriate for risk/hazard assessment studies of chemicals already established
      as estrogenic in vitro and in vivo, as are NP and DES.

PMID- 10341151
TI  - Two-generation reproductive toxicity study of plant stanol esters in rats.
AB  - Plant stanol esters are intended for use as an ingredient in food to reduce the
      absorption of cholesterol from the gastrointestinal tract. Consumption of plant
      stanol esters has a demonstrated diet-derived public health benefit, as shown by
      numerous clinical studies. Plant stanol esters are ring-saturated analogs of
      common dietary sterols that are transesterified with fatty acids from vegetable
      oils such as canola oil. The reproductive and developmental toxicity of plant
      stanol esters was investigated in male and female Wistar rats during F0 and F1
      generations using dietary concentrations of 1.75, 4.38, and 8.76% stanol esters
      (equivalent to 1, 2.5, and 5% total stanols). No adverse treatment-related
      effects were noted on reproductive performance of male or female rats in any dose
      group. Increased food consumption was observed in high-dose F0 generation males
      throughout the entire premating period and in F1 males at specific time periods
      during the premating period. This increase in food consumption was also observed
      in F0 generation females (mid- and high-dose groups) and F1 generation females
      (low-, mid-, and high-dose groups) at specific time periods throughout the 10
      week premating period. At different intervals throughout the gestation and
      lactation periods, increased food consumption was observed in F0 generation
      females of the mid- and high-dose groups, while increased food consumption was
      noted in F1 generation females of the mid- and high-dose groups during gestation,
      but not during lactation. Such increases in food consumption are expected as a
      result of the animals' attempt to compensate for the reduced caloric value of the
      test diet compared to controls. No adverse developmental effects were noted in F1
      or F2 pups of the low- and mid-dose groups based on evaluation of the following
      parameters: litter size, pup mortality, pups weights, and sex ratio. However, a
      treatment-related effect on body weight and body weight change was observed in
      both F1 and F2 male and female pups of the high-dose group, particularly during
      the latter stages of lactation (postnatal days 14 and 21) in F1 pups, and during
      the majority of the lactation period (postnatal days 4-21). Lower body weight in
      the high-dose pups is attributed to a reduction in the caloric value of the test
      diet compared to control. The pups, unlike adult animals, are particularly
      sensitive to reductions in caloric value of feed since they are in a rapid growth
      phase of their development. It is likely that they could not increase their food
      consumption enough to adequately meet their caloric and nutritional needs. In
      conclusion, dietary concentrations of up to 4.38% plant stanol esters (equivalent
      to 2.5% total stanols in the diet) are not associated with adverse effects on
      reproduction, pup mortality, pup body weight, or pup body weight change.

PMID- 10341152
TI  - Genotoxicity evaluation of wood-derived and vegetable oil-derived stanol esters.
AB  - Plant stanol esters from wood and vegetable oil sources were tested for
      genotoxicity in bacterial (Salmonella typhimurium) and mammalian cell (L5178Y)
      gene mutation assays and in a mammalian cell chromosome aberration assay (CHO
      cells). The two stanol ester formulations were tested separately at doses up to
      the limit of solubility, with and without the addition of an Aroclor-induced rat
      liver microsome metabolic activation system (S9 mix). All tests were performed in
      duplicate and gave negative results for both wood and vegetable oil stanol ester
      formulations. Thus, plant stanol esters are not genotoxic under the conditions of
      exposure tested.

PMID- 10341153
TI  - Short-term tests of estrogenic potential of plant stanols and plant stanol
      esters.
AB  - To test for potential estrogenic activity of plant stanols and plant stanol
      esters, two short-term tests were performed. These were the E-screen test, which
      measures a substance's ability to induce proliferation of estrogen-responsive
      human breast adenocarcinoma (MCF-7) cells in culture, and an in vivo test, which
      measures uterotrophic activity in immature female rats fed the test substance.
      Four samples of vegetable oil-derived stanols (containing 88-99% stanols) were
      tested in the E-screen test, and one sample of wood-derived and one of vegetable
      oil-derived stanol fatty acid esters were tested in the in vivo test. In the E
      screen test, the positive control substance, 17beta-estradiol, at 100 pM,
      produced a statistically significant, 11.6-fold increase in cell proliferation,
      as measured by sulforhodamine B staining. None of the stanol preparations
      produced any increase in cell proliferation when tested at 1, 10, and 100 microM.
      The highest dose of each stanol sample was associated with microscopic evidence
      of cytotoxicity and crystalline precipitation in the culture dishes. In the in
      vivo test, the positive control compound, diethylstilbestrol, produced a
      significant, dose-related increase in absolute and relative uterus weight in
      young female rats (17 days old at the start of treatment) fed the compound at 5,
      10, and 20 ppb in the diet for 4 days. Neither of the two stanol ester
      preparations caused any significant change in absolute or relative uterus weight
      when fed at a concentration of 8.3% in the diet for 4 days. Thus, under the
      conditions of testing used, neither the free stanols nor the stanol fatty acid
      ester preparations showed evidence of estrogenic or uterotrophic activity.

PMID- 10341154
TI  - 13-week oral toxicity study with stanol esters in rats.
AB  - Plant sterols and their saturated derivatives, known as stanols, reduce serum
      cholesterol when consumed in amounts of approximately 2 g per day. Stanol fatty
      acid esters have been developed as a highly fat-soluble form that may lower
      cholesterol more effectively than stanols. Stanol esters occur naturally in human
      diets, but at levels far below those known to lower cholesterol. The present
      study was conducted to assess the safety of stanol esters upon subchronic
      ingestion at levels comparable to or exceeding those recommended for lowering
      cholesterol. Two stanol fatty acid ester preparations, wood-derived stanol esters
      and vegetable oil-derived stanol esters, were fed to groups of 20 male and 20
      female Wistar rats for 13 weeks, at dietary concentrations of 0, 0.2, 1, and 5%
      total stanols (equivalent to 0, 0.34, 1.68, and 8.39% wood-derived stanol esters
      and 0, 0.36, 1.78, and 8.91% vegetable oil-derived stanol esters). Both
      preparations were well tolerated as evidenced by the absence of clinical changes
      or major abnormalities in growth, food and water consumption, ophthalmoscopic
      findings, routine hematological and clinical chemistry values, renal
      concentrating ability, composition of the urine, appearance of the feces, estrus
      cycle length, organ weights, gross necropsy findings, and histopathological
      findings. Plasma cholesterol and phospholipids were slightly decreased in males
      fed the stanol esters. In both sexes, plasma levels of plant sterols were
      decreased whereas those of stanols tended to increase. Fecal excretion of
      sterols, including cholesterol, and stanols was markedly increased in the stanol
      ester groups. Compared to controls, male rats fed stanol esters showed somewhat
      lower liver weights and more pronounced glycogen depletion. These hepatic changes
      were considered to reflect an altered nutritional condition and not a
      pathological condition. Plasma levels of vitamin E, vitamin K1, and, to a lesser
      extent, vitamin D were decreased in males and females fed the high-dose diets.
      Hepatic levels of vitamins E and D showed similar changes (vitamin K1 in the
      liver was not determined). For both preparations, the mid-dose level (1% total
      stanols in the diet) was a no-observed-adverse-effect level. This dietary level
      provided approximately 0.5 g total stanols/kg body wt/day.

PMID- 10341155
TI  - Developmental toxicity study of vegetable oil-derived stanol fatty acid esters.
AB  - In a standard developmental toxicity study, a mixture of vegetable oil-derived
      stanol fatty acid esters was administered in the diet to groups of 28 mated
      female HsdCpb:WU Wistar rats at concentrations that provided 0, 1, 2.5, and 5%
      total stanols (equivalent to 0, 1.75, 4.38, and 8.76% plant stanol esters). Test
      diets were adjusted with rapeseed oil to maintain an equivalent caloric content
      of fatty acids at each of the treatment levels. The treatment period extended
      from day 0 to 21 of gestation. No compound-related toxicity or clinical effects
      were seen in any of the treated groups. No statistically significant differences
      were seen in body weights or body weight gain in the low- or mid-dose groups,
      although slight but statistically significant decreases in mean body weight
      relative to controls were seen at gestation days 7 and 14 in the high-dose group.
      The decreases in body weight in the high-dose group may be attributable to the
      virtual lack of absorption of the dietary stanols. Body weight gains were
      equivalent to controls throughout the study except for a statistically
      significant decrease seen only in the 0- to 7-day gestation period in the high
      dose group. No significant effects were seen on food consumption in terms of
      g/rat/day, but a slight, statistically significant increase was seen in the mid
      dose group during gestation days 7-14. A significant increase was seen in the
      high-dose group during the 7- to 21-day period of gestation. Reproductive
      performance was not affected by the treatment. There were no statistically
      significant differences in uterine weight, placental weight, fetal weight, number
      of fetuses, number of implantation sites, number of corpora lutea, and early/late
      resorptions between the treated and control groups. In addition, there was no
      biologically meaningful effect on fetal sex ratio. Visceral and skeletal
      examinations did not show any significant increases in the incidence of
      malformations, anomalies, or variations that were considered to be treatment
      related. Dietary plant (8.76% plant stanol esters) stanol esters at
      concentrations up to 5% total stanols were concluded to have no adverse effects
      on reproduction or development.

PMID- 10341156
TI  - 90-Day oral toxicity study of D-tagatose in rats.
AB  - D-tagatose is a ketohexose, tastes like sugar and is useful as a low-calorie
      sweetener. To assess D-tagatose's safety, an oral 90-day toxicity study was
      conducted on male and female Crl:CDBR rats at dietary doses of 5, 10, 15, and 20%
      D-tagatose. One control group (dietary control) received only lab chow; a second
      control group received 20% cellulose/fructose in the diet. There were no
      treatment-related effects at 5% D-tagatose in the diet. At higher doses,
      treatment-related effects included transient soft stools in male and female
      animals from the 15 and 20% dose groups. This was anticipated as a result of the
      osmotic effect of a large dose of relatively undigested sugar and was not
      considered a toxic effect. All treatment groups gained weight over the study
      period; however, mean body weights were statistically significantly decreased in
      the 15 and 20% dose-group males and the 20% dose-group females at selected
      intervals compared to dietary control animals. No significant reduction in mean
      food consumption was noted in the treatment groups compared to the dietary
      control. Statistically significantly increased relative liver weights were noted
      in male and female animals from the 10, 15, and 20% dose groups compared to the
      dietary control. No gross pathological findings correlated with these increased
      liver weights. Minimal hepatocellular hypertrophy was observed in male and female
      animals from the 15 and 20% dose groups. An independent review of the liver
      slides concluded that histomorphologic changes associated with D-tagatose were
      restricted hepatocyte hypertrophy and hepatocyte glycogen accumulation.
      Therefore, it was concluded that increased liver weights and minimal hypertrophy
      were the result of adaptation to the high dietary levels (greater than 5% in the
      diet) of D-tagatose. No adverse effects were seen at 5% D-tagatose in the diet.

PMID- 10341157
TI  - Effect of D-tagatose on liver weight and glycogen content of rats.
AB  - D-tagatose is an incompletely absorbed ketohexose (stereoisomer of D-fructose)
      which has potential as an energy-reduced alternative sweetener. In an earlier 90
      day toxicity study, rats fed diets with 10, 15 and 20% D-tagatose exhibited
      increased liver weights, but no histopathological alterations. To determine
      whether there might be any toxicological relevance to this effect, three studies
      were conducted in male, adult Sprague-Dawley rats. In the first study, four
      groups received Purina diet (group A), Purina diet with 20% D-tagatose (group B),
      SDS diet (group C), or SDS diet with 20% D-tagatose (group D). For groups A and
      B, the 28-day treatment period was followed by a 14-day recovery period (Purina
      diet). Food remained available to all animals until the time of sacrifice. Groups
      of 10 rats were killed on days 14 (groups A and B), 28 (groups A-D), and 42
      (groups A and B). Body weights, as well as weights of wet and lyophilized livers,
      were determined. The lyophilized livers collected on day 28 from groups A and B
      were analyzed for protein, total lipid, glycogen, DNA, and residual moisture. By
      day 14, relative wet liver weights had increased by 23% in group B. On day 28,
      the increase was 38% in group B and 44% in group D. At the end of the recovery
      period, the increase had diminished to 14% in group B. On day 28, liver glycogen
      content (in %) was significantly increased, and liver protein, lipid, and DNA
      contents were significantly decreased in group B compared to group A. Total
      amounts per liver of protein, total lipid, glycogen, and DNA were significantly
      increased. In the second study, four groups of 20 rats each received SDS diet
      with 0, 5, 10, and 20% D-tagatose for 29-31 days. The food was available until
      the time of sacrifice. At termination, plasma was obtained from 10 rats/group for
      clinicochemical analyses. Five rats/group were subjected to whole-body perfusion,
      followed by processing of livers for qualitative and quantitative electron
      microscopic examination. Livers of 6 rats/group were analyzed for acyl-CoA
      oxidase and laurate 12-hydroxylase (cytochrome P450 4A1) activity, DNA synthesis
      (Ki-67 index), and number of nuclei per unit area of tissue. Liver weights were
      significantly increased in linear relation to the D-tagatose intake. Plasma
      transaminases (but not glutamyl transferase and alkaline phosphatase) were
      increased in the high-dose group. Except for glycogen accumulation, no
      ultrastructural changes were seen on electron microscopic examination of livers
      of the control and high-dose groups. Morphometric analysis confirmed the increase
      of glycogen and the absence of alterations of endoplasmatic reticulum,
      mitochondria, and Golgi apparatus. The Ki-67 index did not differ between the
      groups. A dose-related decrease of the number of nuclei per unit area signified
      some hepatocellular hypertrophy. Acyl-CoA oxidase and CYP4A1 activity were
      significantly increased in the mid- and high-dose groups, but these increases
      were small and not accompanied by electron-microscopic evidence of peroxisome
      proliferation. In the third study, four groups received SDS diet (groups A and C)
      or SDS diet with 5% D-tagatose (groups B and D). All animals were killed on day
      28. Groups A and B were fasted for 24 h before sacrifice; groups C and D had food
      available until sacrifice. Liver weights and liver composition were measured as
      in Study 1. Relative wet and dry liver weights were increased in response to the
      treatment in rats killed under the fed condition, but not in rats killed under
      the fasted condition. The livers of the treated rats (group D) had an increased
      glycogen content in comparison to the controls (group C). Taken together, these
      results demonstrate that D-tagatose at dietary levels of 5-20% increases liver
      glycogen deposition and relative liver weights in nonfasting rats. In fasted rats
      the 5% dose level is the no-effect level. (ABSTRACT TRUNCATED)

PMID- 10341158
TI  - Developmental toxicity study of D-tagatose in rats.
AB  - D-tagatose is a low-calorie sweetener that tastes like sucrose. The developmental
      toxicity of D-tagatose was investigated in Crl:CD(SD)BR rats administered D
      tagatose at three dose levels (4000, 12,000, and 20,000 mg/kg body wt/day) via
      gastric intubation on days 6-15 of gestation. No compound-related toxicity was
      seen among any of the maternal groups. No treatment-related clinical effects were
      seen in the maternal animals at the 4000 mg/kg/day dose level. At the mid- and
      high-dose levels, most maternal animals had unformed or watery stools; this
      effect was most prominent early in the treatment period (Gestation Days 6-8).
      This effect was attributed to the osmotic effect of the large amount of D
      tagatose given to the animals at these doses. Since D-tagatose is not digested or
      absorbed to a large extent, most of the sugar passes into the colon where it
      absorbs water and is fermented by colonic bacteria. Mean weight gain for the low-
      and mid-dose animals was comparable to the control; however, the high-dose group
      experienced a mean weight loss over the Gestation Day 6-9 interval. Over the
      entire treatment interval, however, mean weight gain for the high-dose animals
      was comparable to control. The decreased weight gain in the high-dose animals
      during the Gestation Day 6-9 interval was considered to be a direct result of
      laxation. In addition to the effect of laxation on body weight, reduced food
      consumption also contributed to the decreased weight gain. In the low-dose
      animals, no effect on food consumption was seen; however, both mid- and high-dose
      animals had food consumption values that were statistically significantly lower
      than the control. Food consumption was lowest during the Gestation Day 6-9
      interval, the period when laxation was most prominent. Food consumption rebounded
      and was statistically significantly higher than the control for the mid- and high
      dose animals during the posttreatment interval. Maternal liver weight for the low
      dose animals was comparable to the control. However, a statistically significant
      increase in mean maternal liver weight was noted for the mid-and high-dose
      animals. Based on a lack of any corresponding histopathology, the increased liver
      weights were not considered toxicologically significant. There were no adverse
      effects on reproductive performance noted in any treatment group. No adverse
      treatment-related fetal effects on fetal weight, sex distribution, liver weight,
      or external, skeletal, or visceral malformations were noted at any dose level.

PMID- 10341159
TI  - Genotoxicity tests on D-tagatose.
AB  - D-tagatose is a low-calorie sweetener that tastes like sucrose. Its genotoxic
      potential was examined in five standard assays: the Ames Salmonella typhimurium
      reverse mutation assay, the Escherichia coli/mammalian microsome assay, a
      chromosomal aberration assay in Chinese hamster ovary cells, a mouse lymphoma
      forward mutation assay, and an in vivo mouse micronucleus assay. D-tagatose was
      not found to increase the number of revertants per plate relative to vehicle
      controls in either the S. typhimurium tester strains or the WP2uvrA- tester
      strain with or without metabolic activation at doses up to 5000 microg/plate. No
      significant increase in Chinese hamster ovary cells with chromosomal aberrations
      was observed at concentrations up to 5000 microg/ml with or without metabolic
      activation. D-tagatose was not found to increase the mutant frequency in mouse
      lymphoma L5178Y cells with or without metabolic activation up to concentrations
      of 5000 microg/ml. D-tagatose caused no significant increase in micronuclei in
      bone marrow polychromatic erythrocytes at doses up to 5000 mg/kg. D-tagatose was
      not found to be genotoxic under the conditions of any of the assays described
      above.

PMID- 10341160
TI  - L-Sorbose but not D-tagatose induces hemolysis of dog erythrocytes in vitro.
AB  - Previous investigations have demonstrated that L-sorbose induces hemolysis of dog
      erythrocytes. This effect is probably the consequence of an ATP depletion of the
      red blood cells subsequent to inhibition of hexokinase, and thus the glycolytic
      pathway, by sorbose 1-phosphate. In the present study, the susceptibility of dog
      erythrocytes to D-tagatose, a stereoisomer of L-sorbose, was examined. Washed dog
      erythrocytes were suspended in Hanks' balanced salt solution (HBSS, containing
      5.6 mM glucose) with or without the addition of 0.6, 6, and 60 mM L-sorbose or D
      tagatose, or in HBSS with total glucose concentrations of 5.6, 6 and 60 mM D
      glucose. After incubation for 24 h at 34 degrees C, the suspensions were
      centrifuged, and the percentage of hemolysis was determined by measuring the
      hemoglobin in the sediment and the supernatant. The amount of hemoglobin released
      in the medium did not differ significantly between the control (HBSS) and the
      test incubations with glucose or D-tagatose supplementation. In contrast, the
      addition of 6 and 60 mM L-sorbose resulted in significant hemolysis. At the low
      dose (0.6 mM), L-sorbose did not have an adverse effect. It is concluded that D
      tagatose, unlike L-sorbose, does not have a hemolytic effect on canine
      erythrocytes.

PMID- 10341161
TI  - Disposition of D-[U-14C]tagatose in the rat.
AB  - The purpose of this experiment was to determine the disposition of D-tagatose,
      under development as a low-calorie sweetener, in conventional and germ-free male
      rats. One group of conventional rats was fed a diet containing D-tagatose (100
      g/kg) mixed with the nonpurified diet (900 g/kg) for 28 days. Then, [U-14C]
      labeled D-tagatose was administered as a single dose (approximately 220-380 kBq)
      to 4 of these adapted rats, as well as to 15 conventional and germ-free rats with
      no prior exposure (i.e., unadapted) to D-tagatose. Eleven of the 19 dosed animals
      (4 adapted conventional, 3 unadapted conventional and 2 unadapted germ-free, all
      dosed orally, plus 2 unadapted conventional dosed intravenously) were placed in
      metabolism chambers and samples of CO2, urine, and feces taken at regular
      intervals. At termination, a complete material balance was obtained based on the
      recovery of 14C. Over the 6-h digestive period, D-tagatose was metabolized to
      release 39.9 and 13.9% of the oral dose as CO2 in the adapted conventional rats
      and in the unadapted germ-free rats, respectively. Total releases approximated 68
      and 22%, respectively. The difference in CO2 evolution is ascribed to microbial
      fermentation of D-tagatose in the gut of the conventional rats. The role of
      adaptation was confirmed by finding 93% less D-tagatose in the feces of the
      adapted conventional rat than in the feces of the unadapted conventional rat. The
      intestinal absorption of D-tagatose in the rat is estimated to be 20%. The
      results demonstrate that D-tagatose is metabolized primarily by microorganisms in
      the gut of the rat, with an upper limit between 15 and 20% of oral dose
      metabolized by the host.

PMID- 10341162
TI  - Effects of acute and repeated oral doses of D-tagatose on plasma uric acid in
      normal and diabetic humans.
AB  - D-tagatose, a stereoisomer of D-fructose, is a naturally occurring ketohexose
      proposed for use as a low-calorie bulk sweetener. Ingested D-tagatose appears to
      be poorly absorbed. The absorbed portion is metabolized in the liver by a pathway
      similar to that of D-fructose. The main purpose of this study was to determine if
      acute or repeated oral doses of D-tagatose would cause elevations in plasma uric
      acid (as is seen with fructose) in normal humans and Type 2 diabetics. In
      addition, effects of subchronic D-tagatose ingestion on fasting plasma
      phosphorus, magnesium, lipids, and glucose homeostasis were studied. Eight normal
      subjects and eight subjects with Type 2 diabetes participated in this two-phase
      study. Each group was comprised of four males and four females. In the first
      phase, all subjects were given separate 75 g 3-h oral glucose and D-tagatose
      tolerance tests. Uric acid, phosphorus, and magnesium were determined in blood
      samples collected from each subject at 0, 30, 60, 120, and 180 min after dose. In
      the 8-week phase of the study, the normals were randomly placed into two groups
      which received 75 g of either D-tagatose or sucrose (25 g with each meal) daily
      for 8 weeks. The diabetics were randomized into two groups which received either
      75 g D-tagatose or no supplements of sugar daily for 8 weeks. Uric acid,
      phosphorus, magnesium, lipids, glycosylated hemoglobin, glucose, and insulin were
      determined in fasting blood plasma of all subjects at baseline (time zero) and
      biweekly over the 8 weeks. The 8-week test did not demonstrate an increase in
      fasting plasma uric acid in response to the daily intake of D-tagatose. However,
      a transient increase of plasma uric acid levels was observed after single doses
      of 75 g of D-tagatose in the tolerance test. Plasma uric acid levels were found
      to rise and peak at 60 min after such dosing. No clinical relevance was
      attributed to this treatment-related effect because excursions of plasma uric
      acid levels above the normal range were small and were of short duration.
      Consistent with earlier observations on fructose, the increase of plasma uric
      acid was associated with a slight decrease of plasma phosphorus and a slight
      increase of magnesium. The daily ingestion of D-tagatose for 8 weeks had no
      effect on fasting plasma magnesium, phosphorus, cholesterol, triglycerides,
      glycosylated hemoglobin, glucose, and insulin levels. The ingestion of three 25-g
      doses per day for a period of 8 weeks resulted in varying amounts of flatulence
      in seven of the eight subjects, and some degree of diarrhea in six subjects. D
      tagatose holds promise as a sweetener with no adverse clinical effects observed
      in these studies.

PMID- 10341163
TI  - Human tolerance to a single, high dose of D-tagatose.
AB  - The addition of 29 g D-tagatose added as a sweetener to a continental breakfast
      was tested for the appearance of gastrointestinal side effects in a double-blind
      randomized cross-over study with 29 g sucrose as a control treatment. The
      subjects reported the side effects during 72 h following the test meal on a
      questionnaire grading the symptoms on a five-level scale ranging from "none" to
      "very strong." Although "rumbling in the stomach," "distention," "nausea,"
      "rumbling in the gut," "flatulence, " and "diarrhea" scored significantly higher
      with D-tagatose, the sugar otherwise was well tolerated in most of the subjects.
      Two cases of vomiting after D-tagatose were recorded but in one of the cases its
      relation to the D-tagatose intake was questionable. Only the "distention" score
      remained higher with D-tagatose for more than 24 h. Nausea, vomiting, and
      perceived distension may be due to an osmotic effect in the small intestine of
      unabsorbed D-tagatose. The increased flatus is caused by D-tagatose being
      fermented in the large intestine. Diarrhea may be explained by osmotic effects in
      the colon from nondegraded D-tagatose or nonabsorbed short-chain fatty acids
      produced by the increased fermentation.

PMID- 10341164
TI  - Human gastrointestinal tolerance to D-tagatose.
AB  - D-Tagatose is a stereoisomer of D-fructose which is poorly absorbed in the small
      intestine and may, therefore, have potential as a reduced calorie bulk sweetener.
      However, one of the major limitations is the use of malabsorbed sugars is that
      their consumption may be associated with gastric discomfort. This is due to the
      osmotic impact of the sugar molecules remaining in the gut lumen for a prolonged
      period. We have performed a series of studies in which gastrointestinal symptoms
      have been recorded after the consumption of 29 or 30 g of D-tagatose. Nausea and
      diarrhea were reported with an incidence of 15.1 and 31.5%, respectively, in 73
      healthy young male subjects in a screening study. Increased flatulence after D
      tagatose was frequently reported in all the studies and the flatulence did not
      decline during a 15-day period with intake of 30 g in one dose daily. In most
      cases, symptoms were reported as light or moderate. However, the results suggest
      that 30 g taken at one time may be above the dose which should be recommended for
      ordinary use.

PMID- 10341165
TI  - Comparative gastrointestinal tolerance of sucrose, lactitol, or D-tagatose in
      chocolate.
AB  - D-tagatose is a potential new sugar substitute. Ingested D-tagatose is
      incompletely absorbed from the small intestine; unabsorbed D-tagatose reaches the
      colon where it is completely fermented. In a double-blind, controlled crossover
      study, the gastrointestinal effects were compared following acute consumption of
      40 g plain chocolates containing 20 g of sucrose, lactitol, or D-tagatose by 50
      healthy adults ages 18 to 24 years. Consumption of D-tagatose was not associated
      with a significant increase in the frequency of passing feces, or in the number
      of subjects passing watery feces. However, lactitol consumption was associated
      with an increase in both of these occurrences. Consumption of chocolate
      containing D-tagatose and lactitol resulted in significant increases in colic,
      flatulence, borborygmi, and bloating compared to consumption of the sucrose
      containing chocolate, but the majority of symptoms were described as only
      "slightly more than usual." D-tagatose-containing chocolate did not provoke
      significantly more of these symptoms than lactitol-containing chocolate. A
      significant number of subjects reported nausea following consumption of D
      tagatose chocolate compared to the sucrose chocolate control, and multiple
      symptoms occurred in some subjects. Overall, these results demonstrate that a 20
      g dose of D-tagatose is tolerated well in comparison to lactitol.

PMID- 10341166
TI  - Characteristics and significance of D-tagatose-induced liver enlargement in rats:
      An interpretative review.
AB  - This review addresses the issue of asymptomatic liver enlargement in rats. It was
      necessitated by the observation of significantly increased liver weights in rats
      fed diets with 10 to 20% D-tagatose, a potential new bulk sweetener, for between
      28 and 90 days. Increases of liver size without accompanying histopathological
      changes or impairment of organ function have been observed in rats in response to
      the ingestion of various xenobiotic compounds (including some food additives),
      changes of dietary composition (e.g. , high doses of fructose and sucrose),
      metabolic aberrations (e.g., diabetes), as well as normal pregnancy and
      lactation. The underlying mechanism(s) are not yet understood in detail but
      peroxisome proliferation, microsomal enzyme induction, increased storage of
      glycogen or lipids, and hyperfunction due to an excessive workload are well
      established causes of hepatomegaly in rats. In D-tagatose- and fructose-fed rats,
      a treatment-related increase of hepatic glycogen storage was identified as a
      likely cause of the liver enlargement. Dietary levels of 5% and about 15-20% were
      determined as no-effect levels (NOEL) for D-tagatose- and fructose-induced liver
      enlargement, respectively. At doses above the NOEL, D-tagatose is about four
      times more efficient than fructose in inducing liver enlargement. On the other
      hand, the estimated intake of D-tagatose from its intended uses in food is about
      four times lower than the actual fructose intake. Consequently, a similar safety
      margin would apply for both sugars. Considering the similarity of the liver
      effects in rats of fructose, a safe food ingredient, and D-tagatose, the absence
      of histopathological changes in rats fed a diet with 20% D-tagatose for 90 days,
      and the absence of adverse long-term consequences of glycogen-induced liver
      enlargement in rats, it is concluded that the observed liver enlargement in D
      tagatose-fed rats has no relevance for the assessment of human safety of this
      substance.

PMID- 10341167
TI  - Bacterial resistance to antimicrobial agents: selected problems in France, 1996
      to 1998.

PMID- 10341168
TI  - The cost effectiveness of vaccinating against Lyme disease.
AB  - To determine the cost effectiveness of vaccinating against Lyme disease, we used
      a decision tree to examine the impact on society of six key components. The main
      measure of outcome was the cost per case averted. Assuming a 0.80 probability of
      diagnosing and treating early Lyme disease, a 0.005 probability of contracting
      Lyme disease, and a vaccination cost of $50 per year, the mean cost of
      vaccination per case averted was $4,466. When we increased the probability of
      contracting Lyme disease to 0.03 and the cost of vaccination to $100 per year,
      the mean net savings per case averted was $3,377. Since few communities have
      average annual incidences of Lyme disease >0. 005, economic benefits will be
      greatest when vaccination is used on the basis of individual risk, specifically,
      in persons whose probability of contracting Lyme disease is >0.01.

PMID- 10341170
TI  - Bacterial vaccines and serotype replacement: lessons from Haemophilus influenzae
      and prospects for Streptococcus pneumoniae.
AB  - Conjugate vaccines have reduced the incidence of invasive disease caused by
      Haemophilus influenzae, type b (Hib), in industrialized countries and may be
      highly effective against Streptococcus pneumoniae. However, the serotype
      specificity of these vaccines has led to concern that their use may increase
      carriage of and disease from serotypes not included in the vaccine. Replacement
      has not occurred with the use of Hib vaccines but has occurred in trials of
      pneumococcal vaccines. Mathematical models can be used to elucidate these
      contrasting outcomes, predict the conditions under which serotype replacement is
      likely, interpret the results of conjugate vaccine trials, design trials that
      will better detect serotype replacement (if it occurs), and suggest factors to
      consider in choosing the serotype composition of vaccines.

PMID- 10341169
TI  - Use of antimicrobial growth promoters in food animals and Enterococcus faecium
      resistance to therapeutic antimicrobial drugs in Europe.
AB  - Supplementing animal feed with antimicrobial agents to enhance growth has been
      common practice for more than 30 years and is estimated to constitute more than
      half the total antimicrobial use worldwide. The potential public health
      consequences of this use have been debated; however, until recently, clear
      evidence of a health risk was not available. Accumulating evidence now indicates
      that the use of the glycopeptide avoparcin as a growth promoter has created in
      food animals a major reservoir of Enterococcus faecium, which contains the high
      level glycopeptide resistance determinant vanA, located on the Tn1546 transposon.
      Furthermore, glycopeptide-resistant strains, as well as resistance determinants,
      can be transmitted from animals to humans. Two antimicrobial classes expected to
      provide the future therapeutic options for treatment of infections with
      vancomycin-resistant enterococci have analogues among the growth promoters, and a
      huge animal reservoir of resistant E. faecium has already been created, posing a
      new public health problem.

PMID- 10341171
TI  - Iron loading and disease surveillance.
AB  - Iron is an oxidant as well as a nutrient for invading microbial and neoplastic
      cells. Excessive iron in specific tissues and cells (iron loading) promotes
      development of infection, neoplasia, cardiomyopathy, arthropathy, and various
      endocrine and possibly neurodegenerative disorders. To contain and detoxify the
      metal, hosts have evolved an iron withholding defense system, but the system can
      be compromised by numerous factors. An array of behavioral, medical, and
      immunologic methods are in place or in development to strengthen iron
      withholding. Routine screening for iron loading could provide valuable
      information in epidemiologic, diagnostic, prophylactic, and therapeutic studies
      of emerging infectious diseases.

PMID- 10341172
TI  - Human herpesvirus 6: An emerging pathogen.
AB  - Infections with human herpesvirus 6 (HHV-6), a beta-herpesvirus of which two
      variant groups (A and B) are recognized, is very common, approaching 100% in
      seroprevalence. Primary infection with HHV-6B causes roseola infantum or exanthem
      subitum, a common childhood disease that resolves spontaneously. After primary
      infection, the virus replicates in the salivary glands and is shed in saliva, the
      recognized route of transmission for variant B strains; it remains latent in
      lymphocytes and monocytes and persists at low levels in cells and tissues. Not
      usually associated with disease in the immunocompetent, HHV-6 infection is a
      major cause of opportunistic viral infections in the immunosuppressed, typically
      AIDS patients and transplant recipients, in whom HHV-6 infection/reactivation may
      culminate in rejection of transplanted organs and death. Other opportunistic
      viruses, human cytomegalovirus and HHV-7, also infect or reactivate in persons at
      risk. Another disease whose pathogenesis may be correlated with HHV-6 is multiple
      sclerosis. Data in favor of and against the correlation are discussed.

PMID- 10341174
TI  - Respiratory diseases among U.S. military personnel: countering emerging threats.
AB  - Emerging respiratory disease agents, increased antibiotic resistance, and the
      loss of effective vaccines threaten to increase the incidence of respiratory
      disease in military personnel. We examine six respiratory pathogens
      (adenoviruses, influenza viruses, Streptococcus pneumoniae, Streptococcus
      pyogenes, Mycoplasma pneumoniae, and Bordetella pertussis) and review the impact
      of the diseases they cause, past efforts to control these diseases in U.S.
      military personnel, as well as current treatment and surveillance strategies,
      limitations in diagnostic testing, and vaccine needs.

PMID- 10341173
TI  - Emergence of a unique group of necrotizing mycobacterial diseases.
AB  - Although most diseases due to pathogenic mycobacteria are caused by Mycobacterium
      tuberculosis, several other mycobacterial diseases-caused by M. ulcerans (Buruli
      ulcer), M. marinum, and M. haemophilum-have begun to emerge. We review the
      emergence of diseases caused by these three pathogens in the United States and
      around the world in the last decade. We examine the pathophysiologic similarities
      of the diseases (all three cause necrotizing skin lesions) and common reservoirs
      of infection (stagnant or slow-flowing water). Examination of the histologic and
      pathogenic characteristics of these mycobacteria suggests differences in the
      modes of transmission and pathogenesis, though no singular mechanism for either
      characteristic has been definitively described for any of these mycobacteria.

PMID- 10341175
TI  - Q fever in Bulgaria and Slovakia.
AB  - As a result of dramatic political and economic changes in the beginning of the
      1990s, Q-fever epidemiology in Bulgaria has changed. The number of goats almost
      tripled; contact between goat owners (and their families) and goats, as well as
      goats and other animals, increased; consumption of raw goat milk and its products
      increased; and goats replaced cattle and sheep as the main source of human
      Coxiella burnetii infections. Hundreds of overt, serologically confirmed human
      cases of acute Q fever have occurred. Chronic forms of Q fever manifesting as
      endocarditis were also observed. In contrast, in Slovakia, Q fever does not pose
      a serious public health problem, and the chronic form of infection has not been
      found either in follow-ups of a Q-fever epidemic connected with goats imported
      from Bulgaria and other previous Q-fever outbreaks or in a serologic survey.
      Serologic diagnosis as well as control and prevention of Q fever are discussed.

PMID- 10341176
TI  - Adhesins as targets for vaccine development.
AB  - Blocking the primary stages of infection, namely bacterial attachment to host
      cell receptors and colonization of the mucosal surface, may be the most effective
      strategy to prevent bacterial infections. Bacterial attachment usually involves
      an interaction between a bacterial surface protein called an adhesin and the host
      cell receptor. Recent preclinical vaccine studies with the FimH adhesin (derived
      from uropathogenic Escherichia coli) have confirmed that antibodies elicited
      against an adhesin can impede colonization, block infection, and prevent disease.
      The studies indicate that prophylactic vaccination with adhesins can block
      bacterial infections. With recent advances in the identification,
      characterization, and isolation of other adhesins, similar approaches are being
      explored to prevent infections, from otitis media and dental caries to pneumonia
      and sepsis.

PMID- 10341177
TI  - Tuberculosis in the Caribbean: using spacer oligonucleotide typing to understand
      strain origin and transmission.
AB  - We used direct repeat (DR)-based spacer oligonucleotide typing (spoligotyping)
      (in association with double-repetitive element polymerase chain reaction, IS6110
      restriction fragment length polymorphism [RFLP], and sometimes DR-RFLP and
      polymorphic GC-rich sequence-RFLP) to detect epidemiologic links and transmission
      patterns of Mycobacterium tuberculosis on Martinique, Guadeloupe, and French
      Guiana. In more than a third of the 218 strains we typed from this region,
      clusters and isolates shared genetic identity, which suggests epidemiologic
      links. However, because of limited epidemiologic information, only 14.2% of the
      strains could be directly linked. When spoligotyping patterns shared by two or
      more isolates were pooled with 392 spoligotypes from other parts of the world,
      new matches were detected, which suggests imported transmission. Persisting foci
      of endemic disease and increased active transmission due to high population flux
      and HIV-coinfection may be linked to the recent reemergence of tuberculosis in
      the Caribbean. We also found that several distinct families of spoligotypes are
      overrepresented in this region.

PMID- 10341178
TI  - Human rabies postexposure prophylaxis during a raccoon rabies epizootic in New
      York, 1993 and 1994.
AB  - We describe the epidemiology of human rabies postexposure prophylaxis (PEP) in
      four upstate New York counties during the 1st and 2nd year of a raccoon rabies
      epizootic. We obtained data from records of 1,173 persons whose rabies PEP was
      reported to local health departments in 1993 and 1994. Mean annual PEP incidence
      rates were highest in rural counties, in summer, and in patients 10 to 14 and 35
      to 44 years of age. PEP given after bites was primarily associated with
      unvaccinated dogs and cats, but most (70%) was not attributable to bites.
      Although pet vaccination and stray animal control, which target direct exposure,
      remain the cornerstones of human rabies prevention, the risk for rabies by the
      nonbite route (e. g., raccoon saliva on pet dogs' and cats' fur) should also be
      considered.

PMID- 10341179
TI  - Factory outbreak of Escherichia coli O157:H7 infection in Japan.
AB  - To determine the cause of a July 1996 outbreak of Escherichia coli O157:H7 among
      factory workers in Kyoto, Japan, we conducted cohort and case-control studies.
      Eating radish sprout salad during lunch at the factory cafeteria had been linked
      to illness. The sprouts were traced to four growers in Japan; one had been
      associated with an outbreak of E. coli O157:H7 among 6,000 schoolchildren in
      Sakai earlier in July.

PMID- 10341180
TI  - First case of yellow fever in French Guiana since 1902.
AB  - The first case of yellow fever in French Guiana since 1902 was reported in March
      1998. The yellow fever virus genome was detected in postmortem liver biopsies by
      seminested polymerase chain reaction. Sequence analysis showed that this strain
      was most closely related to strains from Brazil and Ecuador.

PMID- 10341181
TI  - Risk for rabies transmission from encounters with bats, Colorado, 1977-1996.
AB  - To assess the risk for rabies transmission to humans by bats, we analyzed the
      prevalence of rabies in bats that encountered humans from 1977 to 1996 and
      characterized the bat-human encounters. Rabies was diagnosed in 685 (15%) of
      4,470 bats tested. The prevalence of rabies in bats that bit humans was 2.1 times
      higher than in bats that did not bite humans. At least a third of the encounters
      were preventable.

PMID- 10341182
TI  - Australian bat lyssavirus infection in a captive juvenile black flying fox.
AB  - The newly emerging Australian bat lyssavirus causes rabieslike disease in bats
      and humans. A captive juvenile black flying fox exhibited progressive neurologic
      signs, including sudden aggression, vocalization, dysphagia, and paresis over 9
      days and then died. At necropsy, lyssavirus infection was diagnosed by
      fluorescent antibody test, immunoperoxidase staining, polymerase chain reaction,
      and virus isolation. Eight human contacts received postexposure vaccination.

PMID- 10341183
TI  - Bordetella holmesii-like organisms isolated from Massachusetts patients with
      pertussis-like symptoms.
AB  - We isolated Bordetella holmesii, generally associated with septicemia in patients
      with underlying conditions, from nasopharyngeal specimens of otherwise healthy
      young persons with a cough. The proportion of B. holmesii-positive specimens
      submitted to the Massachusetts State Laboratory Institute increased from 1995 to
      1998.

PMID- 10341184
TI  - New cryptosporidium genotypes in HIV-infected persons.
AB  - Using DNA sequencing and phylogenetic analysis, we identified four distinct
      Cryptosporidium genotypes in HIV-infected patients: genotype 1 (human), genotype
      2 (bovine) Cryptosporidium parvum, a genotype identical to C. felis, and one
      identical to a Cryptosporidium sp. isolate from a dog. This is the first
      identification of human infection with the latter two genotypes.

PMID- 10341185
TI  - Fatal case due to methicillin-resistant Staphylococcus aureus small colony
      variants in an AIDS patient.
AB  - We describe the first known case of a fatal infection with small colony variants
      of methicillin-resistant Staphylococcus aureus in a patient with AIDS. Recovered
      from three blood cultures as well as from a deep hip abscess, these variants may
      have resulted from long-term antimicrobial therapy with
      trimethoprim/sulfamethoxazole for prophylaxis of Pneumocystis carinii pneumonia.

PMID- 10341186
TI  - Application of data mining to intensive care unit microbiologic data.
AB  - We describe refinements to and new experimental applications of the Data Mining
      Surveillance System (DMSS), which uses a large electronic health-care database
      for monitoring emerging infections and antimicrobial resistance. For example,
      information from DMSS can indicate potentially important shifts in infection and
      antimicrobial resistance patterns in the intensive care units of a single health
      care facility.

PMID- 10341188
TI  - Chlorine inactivation of Escherichia coli O157:H7.
AB  - We analyzed isolates of Escherichia coli O157:H7 (which has recently caused
      waterborne outbreaks) and wild-type E. coli to determine their sensitivity to
      chlorination. Both pathogenic and nonpathogenic strains were significantly
      reduced within 1 minute of exposure to free chlorine. Results indicate that
      chlorine levels typically maintained in water systems are sufficient to
      inactivate these organisms.

PMID- 10341187
TI  - Sentinel surveillance for enterovirus 71, Taiwan, 1998.
AB  - Outbreaks of enterovirus 71 have been reported around the world since 1969. The
      most recent outbreak occurred in Taiwan during April-July 1998. This hand, foot,
      and mouth disease epidemic was detected by a sentinel surveillance system in
      April at the beginning of the outbreak, and the public was alerted.

PMID- 10341189
TI  - Fulminant meningococcal supraglottitis: An emerging infectious syndrome?
AB  - We report a case of fulminant supraglottitis with dramatic external cervical
      swelling due to associated cellulitis. Blood cultures were positive for Neisseria
      meningitidis. The patient recovered completely after emergency fiberoptic
      intubation and appropriate antibiotic therapy. We summarize five other cases of
      meningococcal supraglottitis, all reported since 1995, and discuss possible
      pathophysiologic mechanisms.

PMID- 10341190
TI  - Genetic evidence of Dobrava virus in Apodemus agrarius in Hungary.
AB  - Using nested polymerase chain reaction, we sequenced Dobrava virus (DOB) from the
      rodent Apodemus agrarius in Hungary. The samples we isolated group with DOB
      samples previously isolated from A. flavicollis. This grouping may indicate host
      switching.

PMID- 10341191
TI  - Bacterial resistance to ciprofloxacin in Greece: results from the National
      Electronic Surveillance System. Greek Network for the Surveillance of
      Antimicrobial Resistance.
AB  - According to 1997 susceptibility data from the National Electronic System for the
      Surveillance of Antimicrobial Resistance, Greece has high rates of ciprofloxacin
      resistance. For most species, the frequency of ciprofloxacin-resistant isolates
      (from highest to lowest, by patient setting) was as follows: intensive care unit
      > surgical > medical > outpatient. Most ciprofloxacin-resistant strains were
      multidrug resistant.

PMID- 10341192
TI  - Emergence of related nontoxigenic Corynebacterium diphtheriae biotype mitis
      strains in Western Europe.
AB  - We report on 17 isolates of Corynebacterium diphtheriae biotype mitis with
      related ribotypes from Switzerland, Germany, and France. Isolates came from skin
      and subcutaneous infections of injecting drug users, homeless persons, prisoners,
      and elderly orthopedic patients with joint prostheses or primary joint
      infections. Such isolates had only been observed in Switzerland.

PMID- 10341193
TI  - First case of human ehrlichiosis in Mexico.

PMID- 10341194
TI  - Paratyphoid fever in India: An emerging problem.

PMID- 10341196
TI  - Immunization of peacekeeping forces.

PMID- 10341195
TI  - Hepatitis C virus RNA viremia in Central Africa.

PMID- 10341197
TI  - Sexually transmitted diseases in Ukraine.

PMID- 10341198
TI  - Yellow fever vaccine.

PMID- 10341200
TI  - The polarization of the motile cell.
AB  - Polarization of the motile cell is associated with the formation of a distinct
      plasma membrane domain, the pseudopod, whose stabilization determines the
      directionality of cell movement. The rapid movement of cells over a substrate
      requires that an essential aspect of cell motility must be the supply of the
      necessary molecular machinery to the site of pseudopodial extension. Renewal of
      this pseudopodial domain requires the directed delivery to the site of
      pseudopodial protrusion of proteins which regulate actin cytoskeleton dynamics,
      cell-substrate adhesion, and localized degradation of the extracellular matrix.
      Polarized targeting mechanisms include the targeted delivery of beta-actin mRNA
      to the leading edge and microtubule-based vesicular traffic. The latter may
      include Golgi-derived vesicles of the biosynthetic pathway as well as clathrin
      dependent and clathrin-independent endocytosis and recycling. Coordination of
      protrusive activities and supply mechanisms is critical for efficient cellular
      displacement and may implicate small GTPases of the Rho family. While the
      specific molecular mechanisms underlying pseudopodial protrusion of the motile
      cell are well-characterized, discussion of these diverse mechanisms in the
      context of cellular polarization has been limited.

PMID- 10341201
TI  - Microtubule-associated protein 4 (MAP4) regulates assembly, protomer-polymer
      partitioning and synthesis of tubulin in cultured cells.
AB  - We depleted MAP4, a ubiquitously expressed microtubule (MT)-associated protein
      previously shown to be capable of stabilizing MTs, from HeLa cells by stably
      expressing antisense RNA. These HeLa-AS cells, in which the MAP4 level was
      decreased to 33% of the wild-type level, displayed decreased content of total
      tubulin (65% of the wild-type level). The partitioning of cellular tubulin into
      protomer and polymer was altered in HeLa-AS cells: polymeric tubulin was
      decreased to 46% of the level in control cells, while protomeric tubulin was
      increased to 226% of the level in control cells. Tubulin protein synthesis was
      decreased, consistent with the tubulin autoregulation model, which proposes that
      tubulin protomer inhibits its own synthesis. Following release from drug-induced
      depolymerization, MTs in HeLa-AS cells reformed more slowly, and showed an
      increased focus on the centrosome, as compared to control cells. HeLa-AS cells
      also appeared to be less bipolar in shape and flatter than control cells. Our
      data suggest that MAP4 regulates assembly level of MTs and, perhaps through this
      mechanism, is involved in controlling spreading and shape of cells.

PMID- 10341202
TI  - Trio amino-terminal guanine nucleotide exchange factor domain expression promotes
      actin cytoskeleton reorganization, cell migration and anchorage-independent cell
      growth.
AB  - Rho family GTPases regulate diverse cellular processes, including extracellular
      signal-mediated actin cytoskeleton reorganization and cell growth. The functions
      of GTPases are positively regulated by guanine nucleotide exchange factors, which
      promote the exchange of GDP for GTP. Trio is a complex protein possessing two
      guanine nucleotide exchange factor domains, each with adjacent pleckstrin
      homology and SH3 domains, a protein serine/threonine kinase domain with an
      adjacent immunoglobulin-like domain and multiple spectrin-like domains. To assess
      the functional role of the two Trio guanine nucleotide exchange factor domains,
      NIH 3T3 cell lines stably expressing the individual guanine nucleotide exchange
      factor domains were established and characterized. Expression of the amino
      terminal guanine nucleotide exchange factor domain results in prominent membrane
      ruffling, whereas cells expressing the carboxy-terminal guanine nucleotide
      exchange factor domain have lamellae that terminate in miniruffles. Moreover,
      cells expressing the amino-terminal guanine nucleotide exchange factor domain
      display more rapid cell spreading, haptotactic cell migration and anchorage
      independent growth, suggesting that Trio regulates both cell motility and cell
      growth. Expression of full-length Trio in COS cells also alters actin
      cytoskeleton organization, as well as the distribution of focal contact sites.
      These findings support a role for Trio as a multifunctional protein that
      integrates and amplifies signals involved in coordinating actin remodeling, which
      is necessary for cell migration and growth.

PMID- 10341203
TI  - Cellular expression of green fluorescent protein, coupled with high-resolution in
      vivo videomicroscopy, to monitor steps in tumor metastasis.
AB  - High resolution intravital videomicroscopy has provided a powerful tool for
      directly observing steps in the metastatic process, and for clarifying molecular
      mechanisms of metastasis and modes of action of anti-metastasis therapeutics.
      Cells previously have been identified in vivo using exogenously added fluorescent
      labels, limiting observations to a few cell divisions, or by natural markers
      (e.g. melanin) expressed only by specific cell types. Here we tested the utility
      of stable green fluorescent protein (GFP)-transfected cells for monitoring and
      quantifying sequential steps in the metastatic process. Using CHO-K1 cells that
      stably express GFP, we document the visualization and quantification by
      intravital videomicroscopy of sequential steps in metastasis within mouse liver,
      from initial arrest of cells in the microvasculature to the growth and
      angiogenesis of metastases. Individual, non-dividing cells, as well as micro- and
      macrometastases could clearly be detected and quantified, as could fine cellular
      details such as pseudopodial projections, even after extended periods of in vivo
      growth. We quantified the size distribution of micrometastases and their
      locations relative to the liver surface using 50 micrometer thick formalin-fixed
      tissue sections. The data suggest preferential growth and survival of
      micrometastases near the liver surface. Furthermore, we observed a small
      population of single cells that persisted over the 11 day observation period,
      which may represent dormant cells with potential for subsequent proliferation.
      This study demonstrates the advantages of GFP-expressing cells, coupled with real
      time high resolution videomicroscopy, for long-term in vivo studies to visualize
      and quantify sequential steps of the metastatic process.

PMID- 10341204
TI  - Keratinocyte growth regulation in fibroblast cocultures via a double paracrine
      mechanism.
AB  - Epithelial-mesenchymal interactions play an important role in regulating tissue
      homeostasis and repair. For skin, the regulatory mechanisms of epidermal-dermal
      interactions were studied in cocultures of normal human epidermal keratinocytes
      (NEK) and dermal fibroblasts (HDF) rendered postmitotic by alpha-irradiation
      (HDFi). The expression kinetics of different cytokines and their receptors with
      presumed signalling function in skin were determined at the RNA and protein level
      in mono- and cocultured NEK and HDFi. In cocultured HDFi, mRNA and protein
      synthesis of keratinocyte growth factor (KGF) (FGF-7) was strongly enhanced,
      whereas in cocultured keratinocytes interleukin (IL)-1alpha and -1beta mRNA
      expression increased compared to monocultures. Thus we postulated that IL-1,
      which had no effect on keratinocyte proliferation, induced in fibroblasts the
      expression of factors stimulating keratinocyte proliferation, such as KGF. The
      functional significance of this reciprocal modulation was substantiated by
      blocking experiments. Both IL-1alpha and -1beta-neutralizing antibodies and IL-1
      receptor antagonist significantly reduced keratinocyte proliferation supposedly
      through abrogation of KGF production, because IL-1 antibodies blocked the induced
      KGF production. These data indicate a regulation of keratinocyte growth by a
      double paracrine mechanism through release of IL-1 which induces KGF in
      cocultured fibroblasts. Thus IL-1, in addition to its proinflammatory function in
      skin, may play an essential role in regulating tissue homeostasis.

PMID- 10341205
TI  - Tenascin-C modulates tumor stroma and monocyte/macrophage recruitment but not
      tumor growth or metastasis in a mouse strain with spontaneous mammary cancer.
AB  - The local growth of tumors and their ability to metastasize are crucially
      dependent on their interactions with the surrounding extracellular matrix.
      Tenascin-C (TNC) is an extracellular matrix protein which is highly expressed
      during development, tissue repair and cancer. Despite the high levels of TNC in
      the stroma of primary and metastatic tumors, the function of TNC is not known. In
      the present study we have crossed TNC-null mice with a mouse strain where both
      female and male mice spontaneously develop mammary tumors followed by metastatic
      disease in the lungs. We report that the absence of TNC had no effect on the
      temporal occurrence of mammary tumors and their metastatic dissemination in
      lungs. Furthermore, the number and size of tumors, the number and size of
      metastatic foci in the lungs, the proliferation rate and apoptosis of tumor cells
      and tumor angiogenesis were not altered in the absence of TNC. Histological
      examination revealed that the tumor organisation, however, was modulated by TNC.
      In the presence of TNC both primary as well as metastatic tumors were organised
      in large tumor cell nests surrounded by thick layers of extracellular matrix
      proteins. In the absence of TNC these tumor cell nests were smaller but still
      separated from each other by extracellular matrix proteins. In addition, the TNC
      null stromal compartment contained significantly more monocytes/macrophages than
      tumor stroma from TNC wild-type mice. Using in vitro coculture experiments we
      show that TNC-null tumor cells were still able to activate the TNC gene in
      fibroblasts which express low basal levels of TNC. Altogether these data indicate
      that TNC has a very limited role during the spontaneous development and growth of
      mamary tumors and their metastasis to the lungs.

PMID- 10341206
TI  - Blockade of membrane transport and disassembly of the Golgi complex by expression
      of syntaxin 1A in neurosecretion-incompetent cells: prevention by rbSEC1.
AB  - The t-SNAREs syntaxin1A and SNAP-25, i.e. the members of the complex involved in
      regulated exocytosis at synapses and neurosecretory cells, are delivered to their
      physiological site, the plasma membrane, when transfected into neurosecretion
      competent cells, such as PC12 and AtT20. In contrast, when transfection is made
      into cells incompetent for neurosecretion, such as those of a defective PC12
      clone and the NRK fibroblasts, which have no endogenous expression of these t
      SNAREs, syntaxin1A (but neither two other syntaxin family members nor SNAP-25)
      remains stuck in the Golgi-TGN area with profound consequences to the cell:
      blockade of both membrane (SNAP-25, GAT-1) and secretory (chromogranin B) protein
      transport to the cell surface; progressive disassembly of the Golgi complex and
      TGN; ultimate disappearance of the latter structures, with intermixing of their
      markers (mannosidase II; TGN-38) with those of the endoplasmic reticulum
      (calreticulin) and with syntaxin1A itself. When, however, syntaxin 1A is
      transfected together with rbSec1, a protein known to participate in
      neurosecretory exocytosis via its dynamic interaction with the t-SNARE, neither
      the blockade nor the alterations of the Golgi complex take place. Our results
      demonstrate that syntaxin1A, in addition to its role in exocytosis at the cell
      surface, possesses a specific potential to interfere with intracellular membrane
      transport and that its interaction with rbSec1 is instrumental to its
      physiological function not only at the plasma membrane but also within the cell.
      At the latter site, the rbSec1-induced conversion of syntaxin1A into a form that
      can be transported and protects the cell from the development of severe
      structural and membrane traffic alterations.

PMID- 10341207
TI  - A dominant mutant of occludin disrupts tight junction structure and function.
AB  - The tight junction is the most apical intercellular junction of epithelial cells
      and forms a diffusion barrier between individual cells. Occludin is an integral
      membrane protein specifically associated with the tight junction which may
      contribute to the function or regulation of this intercellular seal. In order to
      elucidate the role of occludin at the tight junction, a full length and an N
      terminally truncated murine occludin construct, both FLAG-tagged at the N
      terminus, were stably introduced into the murine epithelial cell line CSG 120/7.
      Both constructs were correctly targeted to the tight junction, as defined by
      colocalization with another tight junction protein, ZO-1. The construct lacking
      the N terminus and extracellular domains of occludin was found to exert a
      dramatic effect on tight junction integrity. Cell monolayers failed to develop an
      efficient permeability barrier, as demonstrated by low transcellular electrical
      resistance values and an increased paracellular flux to small molecular mass
      tracers. Furthermore, gaps were found to have been induced in the P-face
      associated tight junction strands, as visualized by freeze-fracture electron
      microscopy. These findings demonstrate an important role for the N-terminal half
      of occludin in tight junction assembly and maintaining the barrier function of
      the tight junction.

PMID- 10341208
TI  - The nucleolar antigen Nop52, the human homologue of the yeast ribosomal RNA
      processing RRP1, is recruited at late stages of nucleologenesis.
AB  - We report the molecular characterization of a novel nucleolar protein, Nop52, and
      its subcellular distribution during the cell cycle and nucleologenesis. This
      protein was originally identified with human autoantibodies which were
      subsequently used to clone its corresponding cDNA. Transfection experiments in
      mammalian cells have confirmed that this cDNA encodes a nucleolar protein that
      accumulates in the nucleoli and at the periphery of the chromosomes. Nop52 is the
      putative human homologue of the yeast ribosomal RNA processing protein RRP1 which
      is involved in pre-rRNA processing from 27S to 25S and 5.8S. In nucleoli, Nop52
      is excluded from the ribosomal RNA transcription sites, accumulates in the
      granular external domain and mainly colocalizes with nucleolar proteins involved
      in the late processing step such as hPop1 and protein B23. During the building
      process of the nucleolus at the end of mitosis, a sequential order was observed
      in the assembly of nucleolar proteins of early and late processing mainly via the
      prenucleolar body pathway. The order is the following: fibrillarin, nucleolin,
      Nop52 together with protein B23 in the prenucleolar bodies, and simultaneously
      with hPop1, and finally Ki-67. The evolutionary conservation of Nop52 and the
      lethal effects observed in gene disruption experiments, predict a critical role
      for Nop52 in the generation of 28S rRNA.

PMID- 10341209
TI  - Transcription, biochemistry and localization of nematode annexins.
AB  - The transcription of three annexin genes in the nematode, Caenorhabditis elegans,
      was detected by reverse transcriptase/polymerase chain reaction amplification of
      messenger RNAs. The highest level of expression was from the nex-1 gene, with
      lower levels detected for the nex-2 and nex-3 genes. The expression of nex-1 was
      reduced in the Dauer larval stage relative to the other annexins, correlating
      with the absence of the spermathecal valves, a major site of nex-1 protein
      localization. Recombinant nex-1 protein was expressed in yeast, isolated by
      calcium-dependent binding to acidic phospholipids, and its membrane binding and
      aggregating activities characterized using bovine chromaffin granules as a
      representative intracellular substrate. Binding to granule membranes was promoted
      by calcium with half-maximal binding seen at 630 microM calcium. Chromaffin
      granule aggregation was similarly promoted by the nex-1 protein at 630 microM
      calcium. This low sensitivity to calcium suggests the annexin can only be
      activated in vivo near the plasma membrane or other sources of calcium. Sequences
      including the nex-1 promoter were fused to the gene for green fluorescent protein
      and this construct was introduced into nematodes by microinjection. Examination
      of transgenic offspring revealed specific nex-1 promoter activity in the pharynx,
      the hypodermal cells, the vulva, and the spermathecal valve, locations in which
      the annexin may function in collagen secretion/deposition and membrane-membrane
      interactions. A sensitive anti-nex-1 antibody labelled with rhodamine was
      injected into body cavities of the nematode but did not detect extracellular nex
      1 protein. Therefore, this annexin is apparently cytosolic and may function on
      the cytoplasmic side of the plasma membrane of the spermathecal valve to chaperon
      the folding of this membrane during the opening and closing of the valve.

PMID- 10341210
TI  - Vascular-endothelial-cadherin modulates endothelial monolayer permeability.
AB  - Vascular endothelial (VE)-cadherin is the endothelium-specific member of the
      cadherin family of homotypic cell adhesion molecules. VE-cadherin, but not the
      cell adhesion molecule platelet/endothelial cell adhesion molecule (PECAM-1),
      markedly colocalizes with actin stress fibers at cell-cell junctions between
      human umbilical vein endothelial cells. Inhibition of VE-cadherin-mediated, but
      not PECAM-1-mediated, adhesion induced reorganization of the actin cytoskeleton,
      loss of junctional VE-cadherin staining and loss of cell-cell adhesion. In
      functional assays, inhibition of VE-cadherin caused increased monolayer
      permeability and enhanced neutrophil transendothelial migration. In a
      complementary set of experiments, modulation of the actin cytoskeleton was found
      to strongly affect VE-cadherin distribution. Brief stimulation of the beta2
      adrenergic receptor with isoproterenol induced a loss of actin stress fibers
      resulting in a linear, rather than 'jagged', VE-cadherin distribution. The
      concomitant, isoproterenol-induced, reduction in monolayer permeability was
      alleviated by a VE-cadherin-blocking antibody. Finally, cytoskeletal
      reorganization resulting from the inactivation of p21Rho caused a diffuse
      localization of VE-cadherin, which was accompanied by reduced cell-cell adhesion.
      Together, these data show that monolayer permeability and neutrophil
      transendothelial migration are modulated by VE-cadherin-mediated cell-cell
      adhesion, which is in turn controlled by the dynamics of the actin cytoskeleton.

PMID- 10341212
TI  - PAF-induced elastase-dependent neutrophil transendothelial migration is
      associated with the mobilization of elastase to the neutrophil surface and
      localization to the migrating front.
AB  - One of the cardinal signs of acute inflammation is neutrophil (PMN) emigration
      across the endothelium and into the affected tissue. We have previously shown
      that human PMN migration across human umbilical vein endothelial cell (HUVEC)
      monolayers is dependent on PMN-derived elastase. However, whether migrating PMN
      release elastase into the extracellular milieu or retain it on the cell surface
      is unclear. In the present study, we show that when PMN are activated by platelet
      activating factor (PAF), elastase was mobilized to and retained in the cell
      membrane; no elastase activity was detected in the supernatant. Neutroplasts
      (enucleated cells devoid of granules) prepared from PAF-activated PMN contained
      twice as much elastase as did neutroplasts prepared from unstimulated PMN.
      Neutroplasts from PAF-activated PMN migrated across HUVEC monolayers in response
      to a chemotactic gradient (PAF), while those prepared from unstimulated PMN did
      not. The neutroplast transendothelial migration was inhibited (80%) by a
      monoclonal antibody against elastase. Using confocal microscopy, we noted that
      the localization of elastase on the cell surface of PMN, which were adherent to
      HUVEC but not migrating, was largely confined to the apical aspect of the PMN.
      There was little or no elastase detectable on the basal aspect of the PMN
      membrane in contact with the endothelium. By contrast, in migrating PMN the
      membrane-bound elastase was primarily localized to the migrating front, i.e.
      pseudopodia penetrating the HUVEC monolayers. Taken together, our findings
      indicate that migrating PMN localize their membrane-bound elastase to the
      migrating front where it facilitates transendothelial migration.

PMID- 10341211
TI  - Human sweat gland myoepithelial cells express a unique set of cytokeratins and
      reveal the potential for alternative epithelial and mesenchymal differentiation
      states in culture.
AB  - We have characterized precisely the cytokeratin expression pattern of sweat gland
      myoepithelial cells and have identified conditions for propagating this cell type
      and modulating its differentiation in culture. Rare, unstratified epithelioid
      colonies were identified in cultures initiated from several specimens of full
      thickness human skin. These cells divided rapidly in medium containing serum,
      epidermal growth factor (EGF), and hydrocortisone, and maintained a closely
      packed, epithelioid morphology when co-cultured with 3T3 feeder cells.
      Immunocytochemical and immunoblot analysis disclosed that the cells differed from
      keratinocytes in that they were E-cadherin-negative, vimentin-positive, and
      expressed an unusual set of cytokeratins, K5, K7, K14, and K17. When subcultured
      without feeder cells, they converted reversibly to a spindle morphology and
      ceased K5 and K14 expression. Under these conditions, EGF deprivation induced
      flattening, growth arrest, and expression of alpha-smooth muscle actin ((&agr;)
      sma). Coexpression of keratins and alpha-sma is a hallmark of myoepithelial
      cells, a constituent of secretory glands. Immunostaining of skin sections
      revealed that only sweat gland myoepithelial cells expressed the same pattern of
      keratins and alpha-sma and lack of E-cadherin as the cell type we had cultured.
      Interestingly, our immunocytochemical analysis of ndk, a skin-derived cell line
      of uncertain identity, suggests that this line is of myoepithelial origin.
      Earlier immunohistochemical studies by others had found myoepithelial cells to be
      K7-negative. We tested five K7-specific antibodies that can recognize this
      protein in western blots and in the assembled keratin filaments of mesothelial
      cells. Three of these antibodies did not recognize the K7 present in
      myoepithelial cell filaments or in HeLa cell filaments, indicating that some K7
      epitopes are masked when K7 pairs with K17 instead of with its usual keratin
      filament partner, K19.

PMID- 10341213
TI  - Direct observation of microtubule-f-actin interaction in cell free lysates.
AB  - Coordinated interplay of the microtubule and actin cytoskeletons has long been
      known to be crucial for many cellular processes including cell migration and
      cytokinesis. However, interactions between these two systems have been difficult
      to document by conventional approaches, for a variety of technical reasons. Here
      the distribution of f-actin and microtubules were analyzed in the absence of
      fixation using Xenopus egg extracts as an in vitro source of microtubules and f
      actin, demembranated Xenopus sperm to nucleate microtubule asters, fluorescent
      phalloidin as a probe for f-actin, and fluorescent tubulin as a probe for
      microtubules. F-actin consistently colocalized in a lengthwise manner with
      microtubules of asters subjected to extensive washing in flow chambers. F-actin
      microtubule association was heterogenous within a given aster, such that f-actin
      is most abundant toward the distal (plus) ends of microtubules, and microtubules
      heavily labeled with f-actin are found in close proximity to microtubules devoid
      of f-actin. However, this distribution changed over time, in that 5 minute asters
      had more f-actin in their interiors than did 15 minute asters. Microtubule
      association with f-actin was correlated with microtubule bending and kinking,
      while elimination of f-actin resulted in straighter microtubules, indicating that
      the in vitro interaction between f-actin and microtubules is functionally
      significant. F-actin was also found to associate in a lengthwise fashion with
      microtubules in asters centrifuged through 30% sucrose, and microtubules alone
      (i.e. microtubules not seeded from demembranated sperm) centrifuged through
      sucrose, indicating that the association cannot be explained by flow-induced
      trapping and alignment of f-actin by aster microtubules. Further, cosedimentation
      analysis revealed that microtubule-f-actin association could be reconstituted
      from microtubules assembled from purified brain tubulin and f-actin assembled
      from purified muscle actin in the presence, but not the absence, of Xenopus
      oocyte microtubule binding proteins. The results provide direct evidence for an
      association between microtubules and f-actin in vitro, indicate that this
      interaction is mediated by one or more microtubule binding proteins, and suggest
      that this interaction may be responsible for the mutual regulation of the
      microtubule and actomyosin cytoskeletons observed in vivo.

PMID- 10341214
TI  - EGF-and NGF-stimulated translocation of cytohesin-1 to the plasma membrane of
      PC12 cells requires PI 3-kinase activation and a functional cytohesin-1 PH
      domain.
AB  - ADP-ribosylation factors (ARFs) are small GTP-binding proteins that function as
      regulators of eukaryotic vesicle trafficking. Cytohesin-1 is a member of a family
      of ARF guanine nucleotide-exchange factors that contain a C-terminal pleckstrin
      homology (PH) domain which has been proposed to bind the lipid second messenger
      phosphatidylinositol 3,4,5-trisphosphate (PIP3). Here we demonstrate that in
      vitro, recombinant cytohesin-1 binds, via its PH domain, the inositol head group
      of PIP3, inositol 1,3,4, 5-tetrakisphosphate (IP4), with an affinity greater than
      200-fold higher than the inositol head group of either phosphatidylinositol 4, 5
      bisphosphate or phosphatidylinositol 3,4-bisphosphate. Moreover, addition of
      glycerol or diacetylglycerol to the 1-phosphate of IP4 does not alter the ability
      to interact with cytohesin-1, data which is entirely consistent with cytohesin-1
      functioning as a putative PIP3 receptor. To address whether cytohesin-1 binds
      PIP3 in vivo, we have expressed a chimera of green fluorescent protein (GFP)
      fused to the N terminus of cytohesin-1 in PC12 cells. Using laser scanning
      confocal microscopy we demonstrate that either EGF- or NGF-stimulation of
      transiently transfected PC12 cells results in a rapid translocation of GFP
      cytohesin-1 from the cytosol to the plasma membrane. This translocation is
      dependent on the cytohesin-1 PH domain and occurs with a time course that
      parallels the rate of plasma membrane PIP3 production. Furthermore, the
      translocation requires the ability of either agonist to activate PI 3-kinase,
      since it is inhibited by wortmannin (100 nM), LY294002 (50 microM) and by
      coexpression with a dominant negative p85. This data therefore suggests that in
      vivo cytohesin-1 can interact with PIP3 via its PH domain.

PMID- 10341215
TI  - Epidermal growth factor receptor relocalization and kinase activity are necessary
      for directional migration of keratinocytes in DC electric fields.
AB  - Human keratinocytes migrate towards the negative pole in DC electric fields of
      physiological strength. This directional migration is promoted by epidermal
      growth factor (EGF). To investigate how EGF and its receptor (EGFR) regulate this
      directionality, we first examined the effect of protein tyrosine kinase
      inhibitors, including PD158780, a specific inhibitor for EGFR, on this response.
      At low concentrations, PD158780 inhibited keratinocyte migration directionality,
      but not the rate of migration; at higher concentrations, it reduced the migration
      rate as well. The less specific inhibitors, genistein, lavendustin A and
      tyrphostin B46, reduced the migration rate, but did not affect migration
      directionality. These data suggest that inhibition of EGFR kinase activity alone
      reduces directed motility, and inhibition of multiple tyrosine kinases, including
      EGFR, reduces the cell migration rate. EGFR redistribution also correlates with
      directional migration. EGFR concentrated on the cathodal face of the cell as
      early as 5 minutes after exposure to electric fields. PD158780 abolished EGFR
      localization to the cathodal face. These data suggest that EGFR kinase activity
      and redistribution in the plasma membrane are required for the directional
      migration of keratinocytes in DC electric fields. This study provides the first
      insights into the mechanisms of directed cell migration in electric fields.

PMID- 10341216
TI  - Sto1p, a fission yeast protein similar to tubulin folding cofactor E, plays an
      essential role in mitotic microtubule assembly.
AB  - The proper functioning of microtubules depends crucially on the availability of
      polymerizable alpha/beta tubulin dimers. Their production occurs concomitant with
      the folding of the tubulin polypeptides and is accomplished in part by proteins
      known as Cofactors A through E. In the fission yeast, Schizosaccharomyces pombe,
      this tubulin folding pathway is essential. We have taken advantage of the
      excellent cytology available in S. pombe to examine the phenotypic consequences
      of a deletion of sto1(+), a gene that encodes a protein similar to Cofactor E,
      which is required for the folding of alpha-tubulin. The interphase microtubule
      cytoskeleton in sto1-delta cells is severely disrupted, and as cells enter
      mitosis their spindles fail to form. After a transient arrest with condensed
      chromosomes, the cells exit mitosis and resume DNA synthesis, whereupon they
      septate abnormally and die. Overexpression of Spo1p is toxic to cells carrying a
      cold-sensitive allele of the alpha- but not the beta-tubulin gene, consistent
      with the suggestion that this protein plays a role like that of Cofactor E.
      Unlike its presumptive partner Cofactor D (Alp1p), however, Sto1p does not
      localize to microtubules but is found throughout the cell. Overexpression of
      Sto1p has no toxic effects in wild-type cells, suggesting that it is unable to
      disrupt alpha/beta tubulin dimers in vivo.

PMID- 10341217
TI  - Differential regulation of hepatocyte growth factor/scatter factor by cell
      surface proteoglycans and free glycosaminoglycan chains.
AB  - Hepatocyte growth factor interacts with both heparan and dermatan sulphates, in
      addition to its specific signalling receptor, Met. However, the extent of
      glycosaminoglycan involvement in its biological activity remains uncertain. We
      have investigated the effects of exogenous glycosaminoglycan addition upon
      hepatocyte growth factor-stimulated motility of Madin-Darby canine kidney cells.
      Exogenous heparan/dermatan sulphate chains behave similarly as either
      potentiators or inhibitors of cell motility (depending upon the assay). Specific
      heparan sulphate oligosaccharides, of octasaccharide or larger, elicit similar
      effects, though with reduced potency. Additionally we have investigated the
      motility of cells made completely deficient in functional proteoglycans by
      metabolic inhibition of glycosaminoglycan sulphation, using chlorate. Such cells
      are completely unresponsive to hepatocyte growth factor, both in terms of
      downstream phosphorylation of mitogen-activated protein kinase and actual cell
      motility, though they do remain responsive to phorbol ester. Interestingly,
      although cell responsiveness to hepatocyte growth factor is not restored by
      exogenous heparan/dermatan sulphate chains, it is by an immobilised heparan
      sulphate proteoglycan substratum. These findings suggest that hepatocyte growth
      factor activity is not only critically dependent upon the presence of
      glycosaminoglycan, but specifically requires an intact proteoglycan structure
      located in close apposition to cell surface Met.

PMID- 10341218
TI  - Changes in association of the Xenopus origin recognition complex with chromatin
      on licensing of replication origins.
AB  - During late mitosis and early G1, a series of proteins are assembled onto
      replication origins that results in them becoming 'licensed' for replication in
      the subsequent S phase. In Xenopus this first involves the assembly onto
      chromatin of the Xenopus origin recognition complex XORC, and then XCdc6, and
      finally the RLF-M component of the replication licensing system. In this paper we
      examine changes in the way that XORC associates with chromatin in the Xenopus
      cell-free system as origins become licensed. Restricting the quantity of XORC on
      chromatin reduced the extent of replication as expected if a single molecule of
      XORC is sufficient to specify a single replication origin. During metaphase,
      XOrc1 associated only weakly with chromatin. In early interphase, XOrc1 formed a
      strong complex with chromatin, as evidenced by its resistance to elution by 200
      mM salt, and this state persisted when XCdc6 was assembled onto the chromatin. As
      a consequence of origins becoming licensed the association of XOrc1 and XCdc6
      with chromatin was destabilised, and XOrc1 became susceptible to removal from
      chromatin by exposure to either high salt or high Cdk levels. At this stage the
      essential function for XORC and XCdc6 in DNA replication had already been
      fulfilled. Since high Cdk levels are required for the initiation of DNA
      replication, this 'licensing-dependent origin inactivation' may contribute to
      mechanisms that prevent re-licensing of replication origins once S phase has
      started.

PMID- 10341219
TI  - Teneurin-1, a vertebrate homologue of the Drosophila pair-rule gene ten-m, is a
      neuronal protein with a novel type of heparin-binding domain.
AB  - The Drosophila gene ten-m is the first pair-rule gene not encoding a
      transcription factor, but an extracellular protein. We have characterized a
      highly conserved chicken homologue that we call teneurin-1. The C-terminal part
      harbors 26 repetitive sequence motifs termed YD-repeats. The YD-repeats are most
      similar to the core of the rhs elements of Escherichia coli. Related repeats in
      toxin A of Clostridium difficile are known to bind specific carbohydrates. We
      show that recombinantly expressed proteins containing the YD-repeats of teneurin
      1 bind to heparin. Furthermore, heparin lyase treatment of extracts of cells
      expressing recombinant YD-repeat protein releases this protein from high
      molecular mass aggregates. In situ hybridization and immunostaining reveals
      teneurin-1 expression in neurons of the developing visual system of chicken and
      Drosophila. This phylogenetic conservation of neuronal expression from flies to
      birds implies fundamental roles for teneurin-1 in neurogenesis. This is supported
      by the neurite outgrowth occurring on substrates made of recombinant YD-repeat
      proteins, which can be inhibited by heparin. Database searches resulted in the
      identification of ESTs encoding at least three further members of the teneurin
      family of proteins. Furthermore, the human teneurin-1 gene could be identified on
      chromosome Xq24/25, a region implied in an X-linked mental retardation syndrome.

PMID- 10341220
TI  - A nuclear localization signal can enhance both the nuclear transport and
      expression of 1 kb DNA.
AB  - Although the entry of DNA into the nucleus is a crucial step of non-viral gene
      delivery, fundamental features of this transport process have remained
      unexplored. This study analyzed the effect of linear double stranded DNA size on
      its passive diffusion, its active transport and its NLS-assisted transport. The
      size limit for passive diffusion was found to be between 200 and 310 bp. DNA of
      310-1500 bp entered the nuclei of digitonin treated cells in the absence of
      cytosolic extract by an active transport process. Both the size limit and the
      intensity of DNA nuclear transport could be increased by the attachment of strong
      nuclear localization signals. Conjugation of a 900 bp expression cassette to
      nuclear localization signals increased both its nuclear entry and expression in
      microinjected, living cells.

PMID- 10341221
TI  - Signal-mediated nuclear transport in the amoeba.
AB  - The evolutionary changes that occur in signal-mediated nuclear transport would be
      expected to reflect an increasing need to regulate nucleocytoplasmic exchanges as
      the complexity of organisms increases. This could involve changes in both the
      composition and structure of the pore complex, as well as the cytosolic factors
      that mediate transport. In this regard, we investigated the transport process in
      amoebae (Amoeba proteus and Chaos carolinensis), primitive cells that would be
      expected to have less stringent regulatory requirements than more complex
      organisms. Colloidal gold particles, coated with bovine serum albumin (BSA)
      conjugated with simple (large T) nuclear localization signals (NLSs), bipartite
      (nucleoplasmin) NLSs or mutant NLSs, were used to assay nuclear import. It was
      found that in amoebae (1) the diameter of the particles that are able to enter
      the nucleoplasm is significantly less than in vertebrate cells, (2) the simple
      NLS is more effective in mediating nuclear import than the bipartite NLS, and (3)
      the nucleoporins do not appear to be glycosylated. Evidence was also obtained
      suggesting that, in amoebae, the simple NLS can mediate nuclear export.

PMID- 10341222
TI  - Keratinocyte growth factor induces angiogenesis and protects endothelial barrier
      function.
AB  - Keratinocyte growth factor (KGF), also called fibroblast growth factor-7, is
      widely known as a paracrine growth and differentiation factor that is produced by
      mesenchymal cells and has been thought to act specifically on epithelial cells.
      Here it is shown to affect a new cell type, the microvascular endothelial cell.
      At subnanomolar concentrations KGF induced in vivo neovascularization in the rat
      cornea. In vitro it was not effective against endothelial cells cultured from
      large vessels, but did act directly on those cultured from small vessels,
      inducing chemotaxis with an ED50 of 0.02-0.05 ng/ml, stimulating proliferation
      and activating mitogen activated protein kinase (MAPK). KGF also helped to
      maintain the barrier function of monolayers of capillary but not aortic
      endothelial cells, protecting against hydrogen peroxide and vascular endothelial
      growth factor/vascular permeability factor (VEGF/VPF) induced increases in
      permeability with an ED50 of 0.2-0.5 ng/ml. These newfound abilities of KGF to
      induce angiogenesis and to stabilize endothelial barriers suggest that it
      functions in microvascular tissue as it does in epithelial tissues to protect
      them against mild insults and to speed their repair after major damage.

PMID- 10341223
TI  - Characterization of MALS/Velis-1, -2, and -3: a family of mammalian LIN-7
      homologs enriched at brain synapses in association with the postsynaptic density
      95/NMDA receptor postsynaptic complex.
AB  - Protein assembly at the postsynaptic density (PSD) of neuronal synapses is
      mediated in part by protein interactions with PSD-95/discs large/zona occludens-1
      (PDZ) motifs. Here, we identify MALS-1, -2, -3, a family of small synaptic
      proteins containing little more than a single PDZ domain. MALS-1, -2, and -3 are
      mammalian homologs LIN-7, a Caenorhabditis elegans protein essential for vulval
      development. In contrast to functions for LIN-7 in epithelial cells, MALS-1 and 
      2 are selectively expressed in specific neuronal populations in brain and are
      enriched in PSD fractions. In cultured hippocampal neurons, MALS proteins are
      clustered together with PSD-95 and NMDA type glutamate receptors, consistent with
      a postsynaptic localization for MALS proteins. Immunoprecipitation and affinity
      chromatography studies readily identify association of MALS with PSD-95 and an
      NMDA receptor subunit. The PDZ domain of MALS selectively binds to peptides
      terminating in E-T/S-R/X-V/I/L, which corresponds to the C terminus of NMDA type
      2 receptors and numerous other ion channels at the PSD. This work suggests a role
      for MALS proteins in regulating recruitment of neurotransmitter receptors to the
      PSD.

PMID- 10341224
TI  - Electron microscopic evidence against apoptosis as the mechanism of neuronal
      death in global ischemia.
AB  - It has been repeatedly claimed that neuronal death in the hippocampal CA1 sector
      after untreated global ischemia occurs via apoptosis. This is based largely on
      DNA laddering, nick end labeling, and light microscopy. Delineation of apoptosis
      requires fine structural examination to detect morphological events of cell
      death. We studied the light and ultrastructural characteristics of CA1 injury
      after 5 min of untreated global ischemia in gerbils. To increase the likelihood
      of apoptosis, some ischemic gerbils were subjected to delayed postischemic
      hypothermia, a treatment that mitigates injury and delays the death of some
      neurons. In these gerbils, 2 d of mild hypothermia was initiated 1, 6, or 12 hr
      after ischemia, and gerbils were killed 4, 14, or 60 d later. Ischemia without
      subsequent cooling killed 96% of CA1 neurons by day 4, whereas all hypothermia
      treated groups had significantly reduced injury at all survival times (2-67%
      loss). Electron microscopy of ischemic neurons with or without postischemic
      hypothermia revealed features of necrotic, not apoptotic, neuronal death even in
      cells that died 2 months after ischemia. Dilated organelles and intranuclear
      vacuoles preceded necrosis. Unique to the hypothermia-treated ischemic groups,
      some salvaged neurons were persistently abnormal and showed accumulation of
      unusual, morphologically complex secondary lysosomes. These indicate selective
      mitochondrial injury, because they were closely associated with normal and
      degenerate mitochondria, and transitional forms between mitochondria and
      lysosomes occurred. The results show that untreated global ischemic injury has
      necrotic, not apoptotic, morphology but do not rule out programmed biochemical
      events of the apoptotic pathway occurring before neuronal necrosis.

PMID- 10341225
TI  - Mitogenic signaling by ATP/P2Y purinergic receptors in astrocytes: involvement of
      a calcium-independent protein kinase C, extracellular signal-regulated protein
      kinase pathway distinct from the phosphatidylinositol-specific phospholipase
      C/calcium pathway.
AB  - Activation of ATP/P2Y purinergic receptors stimulates proliferation of
      astrocytes, but the mitogenic signaling pathway linked to these G-protein-coupled
      receptors is unknown. We have investigated the role of extracellular signal
      regulated protein kinase (ERK) in P2Y receptor-stimulated mitogenic signaling as
      well as the pathway that couples P2Y receptors to ERK. Downregulation of protein
      kinase C (PKC) in primary cultures of rat cerebral cortical astrocytes greatly
      reduced the ability of extracellular ATP to stimulate ERK. Because occupancy of
      P2Y receptors also leads to inositol phosphate formation, calcium mobilization,
      and PKC activation, we explored the possibility that signaling from P2Y receptors
      to ERK is mediated by a phosphatidylinositol-specific phospholipase C (PI
      PLC)/calcium pathway. However, neither inhibition of PI-PLC nor chelation of
      calcium significantly reduced ATP-stimulated ERK activity. Moreover, a
      preferential inhibitor of calcium-dependent PKC isoforms, Go 6976, was
      significantly less effective in blocking ATP-stimulated ERK activity than
      GF102903X, an inhibitor of both calcium-dependent and -independent PKC isoforms.
      Furthermore, ATP stimulated a rapid translocation of PKCdelta, a calcium
      independent PKC isoform, but not PKCgamma, a calcium-dependent PKC isoform. ATP
      also stimulated a rapid increase in choline, and inhibition of
      phosphatidylcholine hydrolysis blocked ATP-evoked ERK activation. These results
      indicate that P2Y receptors in astrocytes are coupled independently to PI
      PLC/calcium and ERK pathways and suggest that signaling from P2Y receptors to ERK
      involves a calcium-independent PKC isoform and hydrolysis of phosphatidylcholine
      by phospholipase D. In addition, we found that inhibition of ERK activation
      blocked extracellular ATP-stimulated DNA synthesis, thereby indicating that the
      ERK pathway mediates mitogenic signaling by P2Y receptors.

PMID- 10341226
TI  - Localization of type I inositol 1,4,5-triphosphate receptor in the outer segments
      of mammalian cones.
AB  - Calcium enters the outer segment of a vertebrate photoreceptor through a cGMP
      gated channel and is extruded via a Na/Ca, K exchanger. We have identified
      another element in mammalian cones that might help to control cytoplasmic
      calcium. Reverse transcription-PCR performed on isolated photoreceptors
      identified mRNA for the SII- splice variant of the type I receptor for inositol
      1,4,5-triphosphate (IP3), and Western blots showed that the protein also is
      expressed in outer segments. Immunocytochemistry showed type I IP3 receptor to be
      abundant in red-sensitive and green-sensitive cones of the trichromatic monkey
      retina, but it was negative or weakly expressed in blue-sensitive cones and rods.
      Similarly, the green-sensitive cones expressed the receptor in dichromatic retina
      (cat, rabbit, and rat), but the blue-sensitive cones did not. Immunostain was
      localized to disk and plasma membranes on the cytoplasmic face. To restore
      sensitivity after a light flash, cytoplasmic cGMP must rise to its basal level,
      and this requires cytoplasmic calcium to fall. Cessation of calcium release via
      the IP3 receptor might accelerate this fall and thus explain why the cone
      recovers much faster than the rod. Furthermore, because its own activity of the
      IP3 receptor depends partly on cytoplasmic calcium, the receptor might control
      the set point of cytoplasmic calcium and thus affect cone sensitivity.

PMID- 10341227
TI  - Presenilin 1 facilitates the constitutive turnover of beta-catenin: differential
      activity of Alzheimer's disease-linked PS1 mutants in the beta-catenin-signaling
      pathway.
AB  - Although an association between the product of the familial Alzheimer's disease
      (FAD) gene, presenilin 1 (PS1), and beta-catenin has been reported recently, the
      cellular consequences of this interaction are unknown. Here, we show that both
      the full length and the C-terminal fragment of wild-type or FAD mutant PS1
      interact with beta-catenin from transfected cells and brains of transgenic mice,
      whereas E-cadherin and adenomatous polyposis coli (APC) are not detected in this
      complex. Inducible overexpression of PS1 led to increased association of beta
      catenin with glycogen synthase kinase-3beta (GSK-3beta), a negative regulator of
      beta-catenin, and accelerated the turnover of endogenous beta-catenin. In support
      of this finding, the beta-catenin half-life was dramatically longer in
      fibroblasts deficient in PS1, and this phenotype was completely rescued by
      replacement of PS1, demonstrating that PS1 normally stimulates the degradation of
      beta-catenin. In contrast, overexpression of FAD-linked PS1 mutants (M146L and
      DeltaX9) failed to enhance the association between GSK-3beta and beta-catenin and
      interfered with the constitutive turnover of beta-catenin. In vivo confirmation
      was demonstrated in the brains of transgenic mice in which the expression of the
      M146L mutant PS1 was correlated with increased steady-state levels of endogenous
      beta-catenin. Thus, our results indicate that PS1 normally promotes the turnover
      of beta-catenin, whereas PS1 mutants partially interfere with this process,
      possibly by failing to recruit GSK-3beta into the PS1-beta-catenin complex. These
      findings raise the intriguing possibility that PS1-beta-catenin interactions and
      subsequent activities may be consequential for the pathogenesis of AD.

PMID- 10341228
TI  - Adenosine: a mediator of interleukin-1beta-induced hippocampal synaptic
      inhibition.
AB  - Interleukin-1 (IL-1) is a pleotrophic cytokine implicated in a variety of central
      activities, including fever, sleep, ischemic injury, and neuromodulatory
      responses, such as neuroimmune, and neuroendocrine interactions. Although
      accumulating evidence is available regarding the expression pattern of this
      cytokine, its receptors in the CNS, and its mechanistic profile under
      pathological levels, it is unclear whether this substance modulates central
      neurons under physiological concentrations. Further, in light of the functional
      and spatial overlap between the adenosine and IL-1 systems, it is not known
      whether these two systems are coupled. We report here that, in rat brain slices,
      brief application of sub-femtomolar IL-1beta causes a profound decrease of
      glutamate transmission, but not GABAergic inhibition, in hippocampal CA1
      pyramidal neurons. This decrease by IL-1beta is prevented by pharmacological
      blockade of adenosine A1 receptors. In addition, we show that IL-1beta failed to
      suppress glutamate transmission at room temperature. Because the production and
      release of adenosine in the CNS is thought to be metabolically dependent, this
      observation suggests that one of the functions of IL-1beta is to increase the
      endogenous production of adenosine. Together, these data suggest for the first
      time that sub-femtomolar levels of IL-1 can effectively modulate glutamate
      excitation in hippocampal neurons via an adenosine-dependent mechanism.

PMID- 10341229
TI  - Mice deficient for tenascin-R display alterations of the extracellular matrix and
      decreased axonal conduction velocities in the CNS.
AB  - Tenascin-R (TN-R), an extracellular matrix glycoprotein of the CNS, localizes to
      nodes of Ranvier and perineuronal nets and interacts in vitro with other
      extracellular matrix components and recognition molecules of the immunoglobulin
      superfamily. To characterize the functional roles of TN-R in vivo, we have
      generated mice deficient for TN-R by homologous recombination using embryonic
      stem cells. TN-R-deficient mice are viable and fertile. The anatomy of all major
      brain areas and the formation and structure of myelin appear normal. However,
      immunostaining for the chondroitin sulfate proteoglycan phosphacan, a high
      affinity ligand for TN-R, is weak and diffuse in the mutant when compared with
      wild-type mice. Compound action potential recordings from optic nerves of mutant
      mice show a significant decrease in conduction velocity as compared with
      controls. However, at nodes of Ranvier there is no apparent change in expression
      and distribution of Na+ channels, which are thought to bind to TN-R via their
      beta2 subunit. The distribution of carbohydrate epitopes of perineuronal nets
      recognized by the lectin Wisteria floribunda or antibodies to the HNK-1
      carbohydrate on somata and dendrites of cortical and hippocampal interneurons is
      abnormal. These observations indicate an essential role for TN-R in the formation
      of perineuronal nets and in normal conduction velocity of optic nerve.

PMID- 10341230
TI  - High tolerance and delayed elastic response of cultured axons to dynamic stretch
      injury.
AB  - Although axonal injury is a common feature of brain trauma, little is known of
      the immediate morphological responses of individual axons to mechanical injury.
      Here, we developed an in vitro model system that selectively stretches axons
      bridging two populations of human neurons derived from the cell line N-Tera2. We
      found that these axons demonstrated a remarkably high tolerance to dynamic
      stretch injury, with no primary axotomy at strains <65%. In addition, the
      axolemma remained impermeable to small molecules after injury unless axotomy had
      occurred. We also found that injured axons exhibited the behavior of "delayed
      elasticity" after injury, going from a straight orientation before injury to
      developing an undulating course as an immediate response to injury, yet gradually
      recovering their original orientation. Surprisingly, some portions of the axons
      were found to be up to 60% longer immediately after injury. Subsequent to
      returning to their original length, injured axons developed swellings of
      appearance remarkably similar to that found in brain-injured humans. These
      findings may offer insight into mechanical-loading conditions leading to
      traumatic axonal injury and into potential mechanisms of axon reassembly after
      brain trauma.

PMID- 10341231
TI  - Nitric oxide via cGMP-dependent mechanisms increases dye coupling and
      excitability of rat supraoptic nucleus neurons.
AB  - Unlike many neuron populations, supraoptic nucleus (SON) neurons are rich in both
      nitric oxide synthase (NOS) and the NO receptor-soluble guanylyl cyclase (GC),
      the activation of which leads to cGMP accumulation. Elevations in cGMP result in
      increased coupling among SON neurons. We investigated the effect of NO on dye
      coupling in SONs from male, proestrus virgin female, and lactating rats. In 167
      slices 263 SON neurons were recorded; 210 of these neurons were injected
      intracellularly (one neuron per SON) with Lucifer yellow (LY). The typically
      minimal coupling seen in virgin females was increased nearly fourfold by the NO
      precursor, L-arginine, or the NO donor, sodium nitroprusside (SNP). L-Arginine
      induced coupling was abolished by a NOS inhibitor. In slices from male and
      lactating rats who have a higher basal incidence of coupling, SNP increased
      coupling by approximately twofold over control (p < 0.03). SNP effects were
      prevented by the NO scavenger hemoglobin (20 microM) and by the selective blocker
      of NO-activated GC, ODQ (10 microM). These results suggest that NO released from
      cells within the SON can expand the coupled network of neurons and that this
      action occurs via cGMP-dependent processes. Because increased coupling is
      associated with elevated SON neuronal excitability, we also studied the effects
      of 8-bromo-cGMP on excitability. In both phasically and continuously firing
      neurons 8-bromo-cGMP (1-2 mM), but not cGMP, produced membrane depolarizations
      accompanied by membrane conductance increases. Conductance increases remained
      when depolarizations were eliminated by current-clamping the membrane potential.
      Thus, NO-induced cGMP increases SON neuronal coupling and excitability.

PMID- 10341232
TI  - Cloning and characterization of Aplysia neutral endopeptidase, a metallo
      endopeptidase involved in the extracellular metabolism of neuropeptides in
      Aplysia californica.
AB  - Cell surface metallo-endopeptidases play important roles in cell communication by
      controlling the levels of bioactive peptides around peptide receptors. To
      understand the relative relevance of these enzymes in the CNS, we characterized a
      metallo-endopeptidase in the CNS of Aplysia californica, whose peptidergic
      pathways are well described at the molecular, cellular, and physiological levels.
      The membrane-bound activity cleaved Leu-enkephalin at the Gly3-Phe4 bond with an
      inhibitor profile similar to that of the mammalian neutral endopeptidase (NEP).
      This functional homology was supported by the molecular cloning of cDNAs from the
      CNS, which demonstrated that the Aplysia and mammalian NEPs share all the same
      amino acids that are essential for the enzymatic activity. The protein is
      recognized both by specific anti-Aplysia NEP (apNEP) antibodies and by the [125I]
      labeled NEP-specific inhibitor RB104, demonstrating that the apNEP gene codes for
      the RB104-binding protein. In situ hybridization experiments on sections of the
      ganglia of the CNS revealed that apNEP is expressed in neurons and that the mRNA
      is present both in the cell bodies and in neurites that travel along the neuropil
      and peripheral nerves. When incubated in the presence of a specific NEP
      inhibitor, many neurons of the buccal ganglion showed a greatly prolonged
      physiological response to stimulation, suggesting that NEP-like metallo
      endopeptidases may play a critical role in the regulation of the feeding behavior
      in Aplysia. One of the putative targets of apNEP in this behavior is the small
      cardioactive peptide, as suggested by RP-HPLC experiments. More generally, the
      presence of apNEP in the CNS and periphery may indicate that it could play a
      major role in the modulation of synaptic transmission in Aplysia and in the
      metabolism of neuropeptides close to their point of release.

PMID- 10341233
TI  - Differential depression at excitatory and inhibitory synapses in visual cortex.
AB  - The function of cortical circuits depends critically on the balance between
      excitation and inhibition. This balance reflects not only the relative numbers of
      excitatory and inhibitory synapses but also their relative strengths. Recent
      studies of excitatory synapses in visual and somatosensory cortices have
      emphasized that synaptic strength is not a fixed quantity but is a dynamic
      variable that reflects recent presynaptic activity. Here, we compare the dynamics
      of synaptic transmission at excitatory and inhibitory synapses onto visual
      cortical pyramidal neurons. We find that inhibitory synapses show less overall
      depression than excitatory synapses and that the kinetics of recovery from
      depression also differ between the two classes of synapse. When excitatory and
      inhibitory synapses are stimulated concurrently, this differential depression
      produces a time- and frequency-dependent shift in the reversal potential of the
      composite postsynaptic current. These results indicate that the balance between
      excitation and inhibition can change dynamically as a function of activity.

PMID- 10341234
TI  - Sensory impairments and delayed regeneration of sensory axons in interleukin-6
      deficient mice.
AB  - Interleukin-6 (IL-6) is a multifunctional cytokine mediating inflammatory or
      immune reactions. Here we investigated the possible role of IL-6 in the intact or
      lesioned peripheral nervous system using adult IL-6 gene knockout (IL-6(-/-))
      mice. Various sensory functions were tested by applying electrophysiological,
      morphological, biochemical, and behavioral methods. There was a 60% reduction of
      the compound action potential of the sensory branch of IL-6(-/-) mice as compared
      with the motor branch in the intact sciatic nerve. Cross sections of L5 DRG of IL
      6(-/-) mice showed a shift in the relative size distribution of the neurons. The
      temperature sensitivity of IL-6(-/-) mice was also significantly reduced. After
      crush lesion of the sciatic nerve, its functional recovery was delayed in IL-6(-/
      ) mice as analyzed from a behavioral footprint assay. Measurements of compound
      action potentials 20 d after crush lesion showed that there was a very low level
      of recovery of the sensory but not of the motor branch of IL-6(-/-) mice. Similar
      results of sensory impairments were obtained with mice showing slow Wallerian
      degeneration (Wlds) and a delayed lesion-induced recruitment of macrophages.
      However, in contrast to WldS mice, in IL-6(-/-) mice we observed the
      characteristic lesion-induced invasion of macrophages and the upregulation of low
      affinity neurotrophin receptor p75 (p75LNTR) mRNA levels identical to those of IL
      6(+/+) mice. Thus, the mechanisms leading to the common sensory deficiencies were
      different between IL-6(-/-) and WldS mice. Altogether, the results suggest that
      interleukin-6 is essential to modulate sensory functions in vivo.

PMID- 10341235
TI  - A role of actin filament in synaptic transmission and long-term potentiation.
AB  - The role of actin filaments in synaptic function has been studied in the CA1
      region of the rat hippocampal slice. Bath application (2 hr) of the actin
      polymerization inhibitor latrunculin B did not substantially affect the shape of
      dendrites or spines. However, this and other drugs that affect actin did affect
      synaptic function. Bath-applied latrunculin B reduced the synaptic response.
      Several lines of evidence indicate that a component of this effect is
      presynaptic. To specifically test for a postsynaptic role for actin, latrunculin
      B or phalloidin, an actin filament stabilizer, was perfused into the postsynaptic
      neuron. The magnitude of long-term potentiation (LTP) was decreased at times when
      baseline transmission was not yet affected. Longer applications produced a
      decrease in baseline AMPA receptor (AMPAR)-mediated transmission. The magnitude
      of the NMDA receptor-mediated transmission was unaffected, indicating a specific
      effect on the AMPAR. These results suggest that postsynaptic actin filaments are
      involved in a dynamic process required to maintain AMPAR-mediated transmission
      and to enhance it during LTP.

PMID- 10341236
TI  - Calcium-induced calcium release contributes to action potential-evoked calcium
      transients in hippocampal CA1 pyramidal neurons.
AB  - Calcium-induced calcium release (CICR) is a mechanism by which local elevations
      of intracellular calcium (Ca2+) are amplified by Ca2+ release from ryanodine
      sensitive Ca2+ stores. CICR is known to be coupled to Ca2+ entry in skeletal
      muscle, cardiac muscle, and peripheral neurons, but no evidence suggests that
      such coupling occurs in central neurons during the firing of action potentials.
      Using fast Ca2+ imaging in CA1 neurons from hippocampal slices, we found evidence
      for CICR during action potential-evoked Ca2+ transients. A low concentration of
      caffeine enhanced Ca2+ transient amplitude, whereas a higher concentration
      reduced it. Simultaneous Ca2+ imaging and whole-cell recordings showed that
      membrane potential, action potential amplitude, and waveform were unchanged
      during caffeine application. The enhancement of Ca2+ transients by caffeine was
      not affected by the L-type channel blocker nifedipine, the phosphodiesterase
      inhibitor IBMX, the adenylyl cyclase activator forskolin, or the PKA antagonist H
      89. However, thapsigargin or ryanodine, which both empty intracellular Ca2+
      stores, occluded this effect. In addition, thapsigargin, ryanodine, and
      cyclopiazonic acid reduced action potential-evoked Ca2+ transients in the absence
      of caffeine. These results suggest that Ca2+ release from ryanodine-sensitive
      stores contributes to Ca2+ signals triggered by action potentials in CA1 neurons.

PMID- 10341237
TI  - The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response
      element binding protein phosphorylation in area CA1 of hippocampus.
AB  - Activation of the mitogen-activated protein kinase (MAPK) cascade recently was
      discovered to play an important role in synaptic plasticity in area CA1 of rat
      hippocampus. However, the upstream mechanisms regulating MAPK activity and the
      downstream effectors of MAPK in the hippocampus are uncharacterized. In the
      present studies we observed that hippocampal MAPK activation is regulated by both
      the PKA and PKC systems; moreover, we found that a wide variety of
      neuromodulatory neurotransmitter receptors (metabotropic glutamate receptors,
      muscarinic acetylcholine receptors, dopamine receptors, and beta-adrenergic
      receptors) couple to MAPK activation via these two cascades. In additional
      studies we observed that PKC is a powerful regulator of CREB phosphorylation in
      area CA1. MAPK plays a critical role in transcriptional regulation by PKC,
      because MAPK activation is a necessary component for increased CREB
      phosphorylation in response to the activation of this kinase. Surprisingly, we
      also observed that MAPK activation is necessary for PKA coupling to CREB
      phosphorylation in area CA1. Overall, these studies indicate an unexpected
      richness of diversity in the regulation of MAPK in the hippocampus and suggest
      the possibility of a broad role for the MAPK cascade in regulating gene
      expression in long-term forms of hippocampal synaptic plasticity.

PMID- 10341238
TI  - c-jun Is dispensable for developmental cell death and axogenesis in the retina.
AB  - Although a number of studies have implicated c-Jun in neuronal death and axonal
      regeneration, it is unknown whether Jun function is essential for either
      response. One approach to resolve this issue is to analyze knock-out mice.
      However, c-jun-null mice die at midgestation, precluding critical investigation.
      Therefore, a xenograft paradigm was used in which retinas from embryonic day 12.5
      (E12.5) c-jun nullizygous or wild-type mice were transplanted onto the superior
      colliculus of newborn rats. The rats were allowed to develop, and the grafts were
      assayed at various times for cell death and axon growth. Histologically, grafts
      of both genotypes developed in identical manners and had morphological
      characteristics of retinas. A functional c-jun allele was not essential for
      axogenesis, because ganglion cells in retinal grafts from c-jun nullizygous mice
      developed axons that projected into the colliculus. Programmed cell death (PCD)
      was also evident in the age-appropriate regions of the retina in both wild-type
      and c-jun-null grafts. Furthermore, there were no discernible differences in the
      number or location of dying cells in the two genotypes. That c-jun was not
      essential for PCD was supported by two additional findings. First, a c-jun-lacZ
      reporter gene was expressed in many cells in developing and grafted retinas,
      although only a few of these cells were destined to die. Second, in E12.5 c-jun
      null embryos there were normal levels of PCD in the trigeminal ganglion.
      Together, these data indicate that c-Jun is not essential for axon growth in the
      retina or for PCD in the retina and trigeminal ganglion.

PMID- 10341239
TI  - Neuroprotection at Drosophila synapses conferred by prior heat shock.
AB  - Synapses are critical sites of information transfer in the nervous system, and it
      is important that their functionality be maintained under stressful conditions to
      prevent communication breakdown. Here we show that synaptic transmission at the
      Drosophila larval neuromuscular junction is protected by prior exposure to heat
      shock that strongly induces expression of heat shock proteins, in particular
      hsp70. Using a macropatch electrode to record synaptic activity at individual,
      visualized boutons, we found that prior heat shock sustains synaptic performance
      at high test temperatures through pre- and postsynaptic alterations. After heat
      shock, nerve impulses release more quantal units at high temperatures and exhibit
      fewer failures of release (presynaptic modification), whereas the amplitude of
      quantal currents remains more constant than does that in nonheat-shocked controls
      (postsynaptic modification). The time course of these physiological changes is
      similar to that of elevated hsp70. Thus, stress-induced neuroprotective
      mechanisms maintain function at synapses by modifying their properties.

PMID- 10341240
TI  - Transplants of fibroblasts genetically modified to express BDNF promote
      regeneration of adult rat rubrospinal axons and recovery of forelimb function.
AB  - Adult mammalian CNS neurons do not normally regenerate their severed axons. This
      failure has been attributed to scar tissue and inhibitory molecules at the injury
      site that block the regenerating axons, a lack of trophic support for the
      axotomized neurons, and intrinsic neuronal changes that follow axotomy, including
      cell atrophy and death. We studied whether transplants of fibroblasts genetically
      engineered to produce brain-derived neurotrophic factor (BDNF) would promote
      rubrospinal tract (RST) regeneration in adult rats. Primary fibroblasts were
      modified by retroviral-mediated transfer of a DNA construct encoding the human
      BDNF gene, an internal ribosomal entry site, and a fusion gene of lacZ and
      neomycin resistance genes. The modified fibroblasts produce biologically active
      BDNF in vitro. These cells were grafted into a partial cervical hemisection
      cavity that completely interrupted one RST. One and two months after lesion and
      transplantation, RST regeneration was demonstrated with retrograde and
      anterograde tracing techniques. Retrograde tracing with fluorogold showed that
      approximately 7% of RST neurons regenerated axons at least three to four segments
      caudal to the transplants. Anterograde tracing with biotinylated dextran amine
      revealed that the RST axons regenerated through and around the transplants, grew
      for long distances within white matter caudal to the transplant, and terminated
      in spinal cord gray matter regions that are the normal targets of RST axons.
      Transplants of unmodified primary fibroblasts or Gelfoam alone did not elicit
      regeneration. Behavioral tests demonstrated that recipients of BDNF-producing
      fibroblasts showed significant recovery of forelimb usage, which was abolished by
      a second lesion that transected the regenerated axons.

PMID- 10341242
TI  - Floor plate and netrin-1 are involved in the migration and survival of inferior
      olivary neurons.
AB  - During their circumferential migration, the nuclei of inferior olivary neurons
      translocate within their axons until they reach the floor plate where they stop,
      although their axons have already crossed the midline to project to the
      contralateral cerebellum. Signals released by the floor plate, including netrin
      1, have been implicated in promoting axonal growth and chemoattraction during
      axonal pathfinding in different midline crossing systems. In the present study,
      we report experiments that strongly suggest that the floor plate could also be
      involved in the migration of inferior olivary neurons. First, we show that the
      pattern of expression of netrin receptors DCC (for deleted in colorectal cancer),
      neogenin (a DCC-related protein), and members of the Unc5 family in wild-type
      mice is consistent with a possible role of netrins in directing the migration of
      precerebellar neurons from the rhombic lips. Second, we have studied mice
      deficient in netrin-1 production. In these mice, the number of inferior olivary
      neurons is remarkably decreased. Some of them are located ectopically along the
      migration stream, whereas the others are located medioventrally and form an
      atrophic inferior olivary complex: most subnuclei are missing. However, axons of
      the remaining olivary cell bodies located in the vicinity of the floor plate
      still succeed in entering their target, the cerebellum, but they establish an
      ipsilateral projection instead of the normal contralateral projection. In vitro
      experiments involving ablations of the midline show a fusion of the two olivary
      masses normally located on either side of the ventral midline, suggesting that
      the floor plate may function as a specific stop signal for inferior olivary
      neurons. These results establish a requirement for netrin-1 in the migration of
      inferior olivary neurons and suggest that it may function as a specific guidance
      cue for the initial steps of the migration from the rhombic lips and then later
      in the development of the normal crossed projection of the inferior olivary
      neurons. They also establish a requirement for netrin-1, either directly or
      indirectly, for the survival of inferior olivary neurons.

PMID- 10341241
TI  - Anatomical correlates of functional plasticity in mouse visual cortex.
AB  - Much of what is known about activity-dependent plasticity comes from studies of
      the primary visual cortex and its inputs in higher mammals, but the molecular
      bases remain largely unknown. Similar functional plasticity takes place during a
      critical period in the visual cortex of the mouse, an animal in which genetic
      experiments can readily be performed to investigate the underlying molecular and
      cellular events. The experiments of this paper were directed toward understanding
      whether anatomical changes accompany functional plasticity in the developing
      visual cortex of the mouse, as they do in higher mammals. In normal mice,
      transneuronal label after an eye injection clearly delineated the monocular and
      binocular zones of area 17. Intrinsic signal optical imaging also showed
      monocular and binocular zones of area 17 but revealed no finer organization of
      ocular dominance or orientation selectivity. In normal animals, single
      geniculocortical afferents serving the contralateral eye showed great
      heterogeneity and no clustering consistent with the presence of ocular dominance
      patches. Growth and elaboration of terminal arbor continues beyond postnatal day
      40 (P40), after the peak of the critical period. After prolonged monocular
      deprivation (MD) from P20 to P60, transneuronal labeling showed that the
      projection serving the ipsilateral eye was severely affected, whereas the effect
      on the contralateral eye's pathway was inconsistent. Optical imaging also showed
      profound effects of deprivation, particularly in the ipsilateral pathway, and
      microelectrode studies confirmed continued functional plasticity past P40.
      Reconstruction of single afferents showed that MD from P20 to P40 promoted the
      growth of the open eye's geniculocortical connections without causing the closed
      eye's contralateral projection to shrink, whereas MD from P20 to P60 caused an
      arrest of growth of deprived arbors. Our findings reveal numerous similarities
      between mouse and higher mammals in development and plasticity, along with some
      differences. We discuss the factors that may be responsible for these
      differences.

PMID- 10341243
TI  - Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal
      differentiation.
AB  - Alzheimer's amyloid precursor protein (APP), the precursor of beta-amyloid
      (Abeta), is an integral membrane protein with a receptor-like structure. We
      recently demonstrated that the mature APP (mAPP; N- and O-glycosylated form) is
      phosphorylated at Thr668 (numbering for APP695 isoform), specifically in neurons.
      Phosphorylation of mAPP appears to occur during, and after, neuronal
      differentiation. Here we report that the phosphorylation of mAPP begins 48-72 hr
      after treatment of PC12 cells with NGF and that this correlates with the timing
      of neurite outgrowth. The phosphorylated form of APP is distributed in neurites
      and mostly in the growth cones of differentiating PC12 cells. PC12 cells stably
      expressing APP with Thr668Glu substitution showed remarkably reduced neurite
      extension after treatment with NGF. These observations suggest that the
      phosphorylated form of APP may play an important role in neurite outgrowth of
      differentiating neurons.

PMID- 10341244
TI  - Chemoattraction and chemorepulsion of olfactory bulb axons by different secreted
      semaphorins.
AB  - During development, growth cones can be guided at a distance by diffusible
      factors, which are attractants and/or repellents. The semaphorins are the largest
      family of repulsive axon guidance molecules. Secreted semaphorins bind neuropilin
      receptors and repel sensory, sympathetic, motor, and forebrain axons. We found
      that in rat embryos, the olfactory epithelium releases a diffusible factor that
      repels olfactory bulb axons. In addition, Sema A and Sema IV, but not Sema III,
      Sema E, or Sema H, are able to orient in vitro the growth of olfactory bulb
      axons; Sema IV has a strong repulsive action, whereas Sema A appears to attract
      those axons. The expression patterns of sema A and sema IV in the developing
      olfactory system confirm that they may play a cooperative role in the formation
      of the lateral olfactory tract. This also represents a further evidence for a
      chemoattractive function of secreted semaphorins.

PMID- 10341245
TI  - Collapsin-1/semaphorin-III/D is regulated developmentally in Purkinje cells and
      collapses pontocerebellar mossy fiber neuronal growth cones.
AB  - Most axons in the CNS innervate specific subregions or layers of their target
      regions and form contacts with specific types of target neurons, but the
      molecular basis of this process is not well understood. To determine whether
      collapsin-1/semaphorin-III/D, a molecule known to repel specific axons, might
      guide afferent axons within their cerebellar targets, we characterized its
      expression by in situ hybridization and observed its effects on mossy and
      climbing fiber extension and growth cone size in vitro. In newborn mice sema-D is
      expressed by cerebellar Purkinje cells in parasagittal bands located medially and
      in some cells of the cerebellar nuclei. Later, sema-D expression in Purkinje
      cells broadens such that banded expression is no longer prominent, and expression
      is detected in progressively more lateral regions. By postnatal day 16,
      expression is observed throughout the cerebellar mediolateral axis. Collapsin-1
      protein, the chick ortholog of sema-D, did not inhibit the extension of neurites
      from explants of inferior olivary nuclei, the source of climbing fibers that
      innervate Purkinje cells. In contrast, when it was applied to axons extending
      from basilar pontine explants, a source of mossy fiber afferents of granule
      cells, collapsin-1 caused most pontine growth cones to collapse, as evidenced by
      a reduction in growth cone size of up to 59%. Moreover, 63% of pontine growth
      cones arrested their extension or retracted. Its effects on mossy fiber extension
      and its distribution suggest that sema-D prevents mossy fibers from innervating
      inappropriate cerebellar target regions and cell types.

PMID- 10341246
TI  - Glutamate acting at NMDA receptors stimulates embryonic cortical neuronal
      migration.
AB  - During cortical development, embryonic neurons migrate from germinal zones near
      the ventricle into the cortical plate, where they organize into layers.
      Mechanisms that direct neuronal migration may include molecules that act as
      chemoattractants. In rats, GABA, which localizes near the target destination for
      migrating cortical neurons, stimulates embryonic neuronal migration in vitro. In
      mice, glutamate is highly localized near the target destinations for migrating
      cortical neurons. Glutamate-induced migration of murine embryonic cortical cells
      was evaluated in cell dissociates and cortical slice cultures. In dissociates,
      the chemotropic effects of glutamate were 10-fold greater than the effects of
      GABA, demonstrating that for murine cortical cells, glutamate is a more potent
      chemoattractant than GABA. Thus, cortical chemoattractants appear to differ
      between species. Micromolar glutamate stimulated neuronal chemotaxis that was
      mimicked by microM NMDA but not by other ionotropic glutamate receptor agonists
      (AMPA, kainate, quisqualate). Responding cells were primarily derived from
      immature cortical regions [ventricular zone (vz)/subventricular zone (svz)].
      Bromodeoxyuridine (BrdU) pulse labeling of cortical slices cultured in NMDA
      antagonists (microM MK801 or APV) revealed that antagonist exposure blocked the
      migration of BrdU-positive cells from the vz/svz into the cortical plate. PCR
      confirmed the presence of NMDA receptor expression in vz/svz cells, whereas
      electrophysiology and Ca2+ imaging demonstrated that vz/svz cells exhibited
      physiological responses to NMDA. These studies indicate that, in mice, glutamate
      may serve as a chemoattractant for neurons in the developing cortex, signaling
      cells to migrate into the cortical plate via NMDA receptor activation.

PMID- 10341247
TI  - Adult mammalian forebrain ependymal and subependymal cells demonstrate
      proliferative potential, but only subependymal cells have neural stem cell
      characteristics.
AB  - The adult derivatives of the embryonic forebrain germinal zones consist of two
      morphologically distinct cell layers surrounding the lateral ventricles: the
      ependyma and the subependyma. Cell cycle analyses have revealed that at least two
      proliferating populations exist in this region, one that is constitutively
      proliferating and one that is relatively quiescent and thought to include the
      endogenous adult neural stem cells. Earlier studies demonstrated that specific
      dissection of the region surrounding the lateral ventricles was necessary for the
      in vitro isolation of multipotent, self-renewing neural stem cells. However, in
      these studies, the ependymal layer was not physically separated from the
      subependymal layer to identify the specific adult laminar localization of the
      neural stem cells around the lateral ventricles. To determine which cellular
      compartment in the adult forebrain contained the neural stem cells, we isolated
      and cultured the ependyma separately from the subependyma and tested for the
      presence of neural stem cells using the in vitro neurosphere assay. We
      demonstrate that the ependymal cells can proliferate in vitro to form sphere-like
      structures. However, the ependymal cells generating spheres do not have the
      ability to self-renew (proliferate to form secondary spheres after dissociation)
      nor to produce neurons, but rather only seem to generate glial fibrillary acidic
      protein-positive ependymal cells when plated under differentiation conditions in
      culture. On the other hand, a subpopulation of subependymal cells do possess the
      self-renewing and multipotential characteristics of neural stem cells. Therefore,
      the adult forebrain neural stem cell resides within the subependymal compartment.

PMID- 10341248
TI  - Dendritic dynamics in vivo change during neuronal maturation.
AB  - In vivo imaging of optic tectal neurons in the intact Xenopus tadpole permits
      direct observation of the structural dynamics that occur during dendritic arbor
      formation. Based on images of single DiI-labeled neurons collected at daily
      intervals over a period of 6 d, we divided tectal cell development into three
      phases according to the total length of the dendritic arbor. During phase 1, the
      cell differentiates from a neuroepithelial cell type and extends an axon out of
      the tectum. The total dendritic branch length (TDBL) is <100 micrometers. During
      phase 2, when TDBL is 100-400 micrometers, the dendritic arbor grows rapidly.
      During phase 3, when TDBL is >400 micrometers, the dendritic arbor grows slowly
      and appears stable. Neurons at different positions along the rostrocaudal
      developmental axis of the tectum were imaged at 2 hr intervals over 6 hr and at
      24 hr intervals over several days. Images collected at 2 hr intervals were
      analyzed to determine rates of branch additions and retractions. Morphologically
      complex, phase 3 neurons show half the rate of branch additions and retractions
      as phase 2 neurons. Therefore, rapidly growing neurons have dynamic dendritic
      arbors, and slower-growing neurons are structurally stable. The change in growth
      rate and dendritic arbor dynamics from phase 2 to phase 3 correlates with the
      developmental increase in synaptic strength in neurons located along the
      rostrocaudal tectal axis. The data are consistent with the idea that strong
      synaptic inputs stabilize dendritic arbor structures and that weaker synaptic
      inputs are permissive for a greater degree of dynamic rearrangements and a faster
      growth rate in the dendritic arbor.

PMID- 10341249
TI  - Generation of tyrosine hydroxylase-producing neurons from precursors of the
      embryonic and adult forebrain.
AB  - We have explored the plastic ability of neuronal precursors to acquire different
      identities by manipulating their surrounding environment. Specifically, we sought
      to identify potential signals involved in the specification of forebrain
      dopaminergic neurons. Here we describe culture conditions under which tyrosine
      hydroxylase (TH) expression is induced in neuronal precursors, which were derived
      directly from the embryonic striatum and adult subependyma (SE) of the lateral
      ventricle or generated from multipotent forebrain stem cells. TH was successfully
      induced in all of these cell types by 24 hr exposure to basic fibroblast growth
      factor (FGF2) and glial cell conditioned media (CM). The greatest magnitude of
      the inductive action was on embryonic striatal precursors. Although FGF2 alone
      induced limited TH expression in striatal cells (1.1 +/- 0.2% of neurons), these
      actions were potentiated 17.5-fold (19.6 +/- 1.5% of neurons) when FGF2 was
      coadministered with B49 glial cell line CM. Of these TH-immunoreactive cells,
      approximately 15% incorporated bromodeoxyuridine (BrdU), indicating that they
      were newly generated, and 95% coexpressed the neurotransmitter GABA. To
      investigate whether precursors of the adult forebrain subependyma were competent
      to respond to the instructive actions of FGF2+CM, they were first labeled in vivo
      with a pulse of BrdU. Although none of the cells expressed TH in control, 0.2% of
      total cells showed TH immunoreactivity in FGF2+CM-treated cultures. Under these
      same conditions only, in vitro-generated precursors from epidermal growth factor
      responsive stem cells exhibited TH expression in 10% of their total neuronal
      progeny. Regulation of neurotransmitter phenotype in forebrain neuronal
      precursors, by the synergistic action of FGF2 and glial-derived diffusible
      factors, may represent a first step in understanding how these cells are
      generated in the embryonic and adult brain and opens the prospect for their
      manipulation in vitro and in vivo for therapeutic use.

PMID- 10341250
TI  - Supporting cells contribute to control of hearing sensitivity.
AB  - The mammalian hearing organ, the organ of Corti, was studied in an in vitro
      preparation of the guinea pig temporal bone. As in vivo, the hearing organ
      responded with an electrical potential, the cochlear microphonic potential, when
      stimulated with a test tone. After exposure to intense sound, the response to the
      test tone was reduced. The electrical response either recovered within 10-20 min
      or remained permanently reduced, thus corresponding to a temporary or sustained
      loss of sensitivity. Using laser scanning confocal microscopy, stimulus-induced
      changes of the cellular structure of the hearing organ were simultaneously
      studied. The cells in the organ were labeled with two fluorescent probes, a
      membrane dye and a cytoplasm dye, showing enzymatic activity in living cells.
      Confocal microscopy images were collected and compared before and after intense
      sound exposure. The results were as follows. (1) The organ of Corti could be
      divided into two different structural entities in terms of their susceptibility
      to damage: an inner, structurally stable region comprised of the inner hair cell
      with its supporting cells and the inner and outer pillar cells; and an outer
      region that exhibited dynamic structural changes and consisted of the outer hair
      cells and the third Deiters' cell with its attached Hensen's cells. (2) Exposure
      to intense sound caused the Deiters' cells and Hensen's cells to move in toward
      the center of the cochlear turn. (3) This event coincided with a reduced
      sensitivity to the test tone (i.e., reduced cochlear microphonic potential). (4)
      The displacement and sensitivity loss could be reversible. It is concluded that
      these observations have relevance for understanding the mechanisms behind hearing
      loss after noise exposure and that the supporting cells take an active part in
      protection against trauma during high-intensity sound exposure.

PMID- 10341251
TI  - Inhibition of dentate granule cell neurogenesis with brain irradiation does not
      prevent seizure-induced mossy fiber synaptic reorganization in the rat.
AB  - Aberrant reorganization of dentate granule cell axons, the mossy fibers, occurs
      in human temporal lobe epilepsy and rodent epilepsy models. Whether this
      plasticity results from the remodeling of preexisting mossy fibers or instead
      reflects an abnormality of developing dentate granule cells is unknown. Because
      these neurons continue to be generated in the adult rodent and their production
      increases after seizures, mossy fibers that arise from either developing or
      mature granule cells are potential substrates for this network plasticity.
      Therefore, to determine whether seizure-induced, mossy fiber synaptic
      reorganization arises from either developing or mature granule cell populations,
      we used low-dose, whole-brain x-irradiation to eliminate proliferating dentate
      granule cell progenitors in adult rats. A single dose of 5 Gy irradiation blocked
      cell proliferation and eliminated putative progenitor cells in the dentate
      subgranular proliferative zone. Irradiation 1 d before pilocarpine-induced status
      epilepticus significantly attenuated dentate granule cell neurogenesis after
      seizures. Two irradiations, 1 d before and 4 d after status epilepticus,
      essentially abolished dentate granule cell neurogenesis but failed to prevent
      mossy fiber reorganization in the dentate molecular layer. These results indicate
      that dentate granule cell neurogenesis in the mature hippocampal formation is
      vulnerable to the effects of low-dose ionizing irradiation. Furthermore, the
      development of aberrant mossy fiber remodeling in the absence of neurogenesis
      suggests that mature dentate granule cells contribute substantially to seizure
      induced network reorganization.

PMID- 10341252
TI  - Odor coding in a model olfactory organ: the Drosophila maxillary palp.
AB  - Odor coding relies on the activity of different classes of receptor neurons, each
      with distinct response characteristics. We have examined odor coding in a model
      olfactory organ, the maxillary palp of Drosophila. This organ contains only 120
      olfactory receptor neurons, compartmentalized in sensory hairs called sensilla,
      and provides an opportunity to characterize all neurons in an entire olfactory
      organ. Extensive extracellular recordings from single sensilla reveal that the
      neurons fall into six functional classes. Each of the 60 sensilla houses two
      neurons, which observe a pairing rule: each sensillum combines neurons of two
      particular classes, thereby yielding three sensillum types. The sensillum types
      are intermingled on the surface of the palp, but their distribution is not
      random. The neurons exhibit diverse response characteristics, providing the basis
      for an olfactory code. A particular odor can excite one neuron and inhibit
      another, and a particular neuron can be excited by one odor and inhibited by
      another. Some excitatory responses continue beyond the end of odor delivery, but
      responses to most odors terminate abruptly after the end of odor delivery, with
      some followed by a period of poststimulus quiescence. The specificity of odor
      response is examined in detail for the neurons of one sensillum, which were found
      to differ in their relative responses to a homologous series of esters.
      Adaptation and cross-adaptation are documented, and cross-adaptation experiments
      demonstrate that the two neurons within one type of sensillum can function
      independently. The analysis of all neuronal types in this model olfactory organ
      is discussed in terms of its functional organization and the mechanisms by which
      it encodes olfactory information.

PMID- 10341253
TI  - T-lymphocyte activation increases hypothalamic and amygdaloid expression of CRH
      mRNA and emotional reactivity to novelty.
AB  - Stimulation of T-cells with staphylococcal enterotoxin B (SEB) significantly
      elevates interleukin-2 (IL-2) and contemporaneous activation of the hypothalamic
      pituitary-adrenal (HPA) axis and c-fos in the paraventricular nucleus (PVN) of
      BALB/cByJ mice. Such neural signaling may promote cognitive and emotional
      adaptation before or during infectious illness. Because corticotropin-releasing
      hormone (CRH) is an anxiogenic neuropeptide that may mediate the stressor-like
      effects of immunological stimuli, we measured neuronal CRH mRNA alterations in
      mice challenged with SEB. Increased CRH mRNA levels were observed in the PVN and
      central nucleus of the amygdala (ceA) 4-6 hr after SEB administration. This was
      associated with plasma ACTH increases, which could be abrogated by the systemic
      administration of anti-CRH antiserum. Additional experiments did not support a
      role for IL-2 or prostaglandin synthesis in activating the HPA axis. Behavioral
      experiments testing for conditioned taste aversion did not confirm that SEB
      challenge promotes malaise. However, consistent with the notion that central CRH
      alterations induced by SEB may affect emotionality (e.g., fear), SEB challenge
      augmented appetitive neophobia in a context-dependent manner, being marked in a
      novel and stressful environment. It is hypothesized that immunological stimuli
      generate a cascade of events that solicit integrative neural processes involved
      in emotional behavior. As such, these data support the contention that affective
      illness may be influenced by immunological processes and the production of
      cytokines and are consistent with other evidence demonstrating that autoimmune
      reactivity is associated with enhanced emotionality.

PMID- 10341254
TI  - Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon
      terminals of specific hippocampal interneurons.
AB  - To understand the functional significance and mechanisms of action in the CNS of
      endogenous and exogenous cannabinoids, it is crucial to identify the neural
      elements that serve as the structural substrate of these actions. We used a
      recently developed antibody against the CB1 cannabinoid receptor to study this
      question in hippocampal networks. Interneurons with features typical of basket
      cells showed a selective, intense staining for CB1 in all hippocampal subfields
      and layers. Most of them (85.6%) contained cholecystokinin (CCK), which
      corresponded to 96.9% of all CCK-positive interneurons, whereas only 4.6% of the
      parvalbumin (PV)-containing basket cells expressed CB1. Accordingly, electron
      microscopy revealed that CB1-immunoreactive axon terminals of CCK-containing
      basket cells surrounded the somata and proximal dendrites of pyramidal neurons,
      whereas PV-positive basket cell terminals in similar locations were negative for
      CB1. The synthetic cannabinoid agonist WIN 55,212-2 (0.01-3 microM) reduced dose
      dependently the electrical field stimulation-induced [3H]GABA release from
      superfused hippocampal slices, with an EC50 value of 0. 041 microM. Inhibition of
      GABA release by WIN 55,212-2 was not mediated by inhibition of glutamatergic
      transmission because the WIN 55,212-2 effect was not reduced by the glutamate
      blockers AP5 and CNQX. In contrast, the CB1 cannabinoid receptor antagonist SR
      141716A (1 microM) prevented this effect, whereas by itself it did not change the
      outflow of [3H]GABA. These results suggest that cannabinoid-mediated modulation
      of hippocampal interneuron networks operate largely via presynaptic receptors on
      CCK-immunoreactive basket cell terminals. Reduction of GABA release from these
      terminals is the likely mechanism by which both endogenous and exogenous CB1
      ligands interfere with hippocampal network oscillations and associated cognitive
      functions.

PMID- 10341255
TI  - Contributions of tutor and bird's own song experience to neural selectivity in
      the songbird anterior forebrain.
AB  - Auditory neurons of the anterior forebrain (AF) of zebra finches become selective
      for song during song learning. In adults, these neurons respond more to the
      bird's own song (BOS) than to the songs of other zebra finches (conspecifics) or
      BOS played in reverse. In contrast, AF neurons from young birds (30 d) respond
      equally well to all song stimuli. AF selectivity develops rapidly during song
      learning, appearing in 60-d-old birds. At this age, many neurons also respond
      equally well to BOS and tutor song. These similar neural responses to BOS and
      tutor song might reflect contributions from both song experiences to selectivity,
      because auditory experiences of both BOS and tutor song are essential for normal
      song learning. Alternatively, they may simply result from acoustic similarities
      between BOS and tutor song. Understanding which experience shapes selectivity
      could elucidate the function of song-selective AF neurons. To minimize acoustic
      similarity between BOS and tutor song, we induced juvenile birds to produce
      abnormal song by denervating the syrinx, the avian vocal organ, before song
      onset. We recorded single neurons extracellularly in the AF at 60 d, after birds
      had had substantial experience of both the abnormal BOS (tsBOS) and tutor song.
      Some neurons preferred the unique tsBOS over the tutor song, clearly indicating a
      role for BOS experience in shaping neural selectivity. In addition, a sizable
      proportion of neurons responded equally well to tsBOS and tutor song, despite
      their acoustic dissimilarity. These neurons were not simply immature, because
      they were selective for tsBOS and tutor song relative to conspecific and reverse
      song. Furthermore, their similar responses to tsBOS and tutor song could not be
      attributed to residual acoustic similarities between the two stimuli, as measured
      by several song analyses. The neural sensitivity to two very different songs
      suggests that single AF neurons may be shaped by both BOS and tutor song
      experience.

PMID- 10341256
TI  - Involvement of the prelimbic-infralimbic areas of the rodent prefrontal cortex in
      behavioral flexibility for place and response learning.
AB  - The present experiments investigated the role of the prelimbic-infralimbic areas
      in behavioral flexibility using a place-response learning paradigm. All rats
      received a bilateral cannula implant aimed at the prelimbic-infralimbic areas. To
      examine the role of the prelimbic-infralimbic areas in shifting strategies, rats
      were tested on a place and a response discrimination in a cross-maze. Some rats
      were tested on the place version first followed by the response version. The
      procedure for the other rats was reversed. Infusions of 2% tetracaine into the
      prelimbic-infralimbic areas did not impair acquisition of the place or response
      discriminations. Prelimbic-infralimbic inactivation did impair learning when rats
      were switched from one discrimination to the other (cross-modal shift). To
      investigate the role of the prelimbic-infralimbic areas in intramodal shifts
      (reversal learning), one group of rats was tested on a place reversal and another
      group tested on a response reversal. Prelimbic-infralimbic inactivation did not
      impair place or response intramodal shifts. Some rats that completed testing on a
      particular version in the cross-modal and intramodal experiments were tested on
      the same version in a new room for 3 d. The transfer tests revealed that rats use
      a spatial strategy on the place version and an egocentric response strategy on
      the response version. Overall, these results suggest that the prelimbic
      infralimbic areas are important for behavioral flexibility involving cross-modal
      but not intramodal shifts.

PMID- 10341257
TI  - Spatiotemporal analysis of local field potentials and unit discharges in cat
      cerebral cortex during natural wake and sleep states.
AB  - The electroencephalogram displays various oscillation patterns during wake and
      sleep states, but their spatiotemporal distribution is not completely known.
      Local field potentials (LFPs) and multiunits were recorded simultaneously in the
      cerebral cortex (areas 5-7) of naturally sleeping and awake cats. Slow-wave sleep
      (SWS) was characterized by oscillations in the slow (<1 Hz) and delta (1-4 Hz)
      frequency range. The high-amplitude slow-wave complexes consisted in a positivity
      of depth LFP, associated with neuronal silence, followed by a sharp LFP
      negativity, correlated with an increase of firing. This pattern was of remarkable
      spatiotemporal coherence, because silences and increased firing occurred
      simultaneously in units recorded within a 7 mm distance in the cortex. During
      wake and rapid-eye-movement (REM) sleep, single units fired tonically, whereas
      LFPs displayed low-amplitude fast activities with increased power in fast
      frequencies (15-75 Hz). In contrast with the widespread synchronization during
      SWS, fast oscillations during REM and wake periods were synchronized only within
      neighboring electrodes and small time windows (100-500 msec). This local
      synchrony occurred in an apparent irregular manner, both spatially and
      temporally. Brief periods (<1 sec) of fast oscillations were also present during
      SWS in between slow-wave complexes. During these brief periods, the spatial and
      temporal coherence, as well as the relation between units and LFPs, was identical
      to that of fast oscillations of wake or REM sleep. These results show that
      natural SWS in cats is characterized by slow-wave complexes, synchronized over
      large cortical territories, interleaved with brief periods of fast oscillations,
      characterized by local synchrony, and of characteristics similar to that of the
      sustained fast oscillations of activated states.

PMID- 10341258
TI  - GABAB receptor antagonism: facilitatory effects on memory parallel those on LTP
      induced by TBS but not HFS.
AB  - The present experiments used CGP 35348, a selective GABAB receptor antagonist
      with a significantly higher affinity for post- versus presynaptic receptors, to
      dissociate the role of antagonist concentration versus stimulation mode in
      determining whether GABAB receptor blockade facilitates or suppresses long-term
      potentiation (LTP). The antagonist was applied by pressure ejection to one of two
      recording sites in area CA1 of hippocampal slices before LTP was induced at both
      sites with either theta burst or high-frequency stimulation (TBS or HFS). TBS
      produced a dose-dependent facilitation of potentiation that turned into
      depression at the highest concentration tested, a result reflecting the dose
      dependent balance between the drug's postsynaptic disinhibitory effect and its
      action on presynaptic autoreceptors regulating the release of GABA. In contrast,
      HFS-induced LTP increased monotonically with drug concentration, suggesting that
      blockade of postsynaptic GABAB receptors is the only factor contributing to HFS
      induced LTP. To test the relevance of the two sets of LTP results, we performed
      behavioral studies examining the effect of different dosages of antagonist on
      spatial retention and found that memory was enhanced at intermediate dosages but
      not at very low and high concentrations, reminiscent of the bell-shaped dose
      response curve obtained for TBS-induced LTP. These findings are consistent with
      the notion that LTP induced by electrical stimulation modeled after endogenous
      theta-modulated activity patterns bears more relevance to behavior than does
      potentiation induced by arbitrary tetanic trains.

PMID- 10341259
TI  - Immunohistochemical evidence of seizure-induced activation of trk receptors in
      the mossy fiber pathway of adult rat hippocampus.
AB  - Recent work suggests that limiting the activation of the trkB subtype of
      neurotrophin receptor inhibits epileptogenesis, but whether or where neurotrophin
      receptor activation occurs during epileptogenesis is unclear. Because the
      activation of trk receptors involves the phosphorylation of specific tyrosine
      residues, the availability of antibodies that selectively recognize the
      phosphorylated form of trk receptors permits a histochemical assessment of trk
      receptor activation. In this study the anatomy and time course of trk receptor
      activation during epileptogenesis were assessed with immunohistochemistry, using
      a phospho-specific trk antibody. In contrast to the low level of phosphotrk
      immunoreactivity constitutively expressed in the hippocampus of adult rats, a
      striking induction of phosphotrk immunoreactivity was evident in the distribution
      of the mossy fibers after partial kindling or kainate-induced seizures. The
      anatomic distribution, time course, and threshold for seizure-induced phosphotrk
      immunoreactivity correspond to the demonstrated pattern of regulation of BDNF
      expression by seizure activity. These results provide immunohistochemical
      evidence that trk receptors undergo activation during epileptogenesis and suggest
      that the mossy fiber pathway is particularly important in the pro-epileptogenic
      effects of the neurotrophins.

PMID- 10341261
TI  - Sensory feedback can coordinate the swimming activity of the leech.
AB  - Previous studies showed that sensory feedback from the body wall is important and
      sometimes critical for generating normal, robust swimming activity in leeches. In
      this paper, we evaluate the role of sensory feedback in intersegmental
      coordination using both behavioral and physiological measurements. We severed the
      ventral nerve cord of leeches in midbody and then made video and in situ
      extracellular recordings from swimming animals. Our electrophysiological
      recordings unequivocally demonstrate that active intersegmental coordination
      occurs in leeches with severed nerve cords, refuting earlier conclusions that
      sensory feedback cannot coordinate swimming activity. Intersegmental coordination
      can in fact be achieved by sensory feedback alone, without the intersegmental
      interactions conveyed by the nerve cord.

PMID- 10341260
TI  - The dopamine D2, but not D3 or D4, receptor subtype is essential for the
      disruption of prepulse inhibition produced by amphetamine in mice.
AB  - Brain dopamine (DA) systems are involved in the modulation of the sensorimotor
      gating phenomenon known as prepulse inhibition (PPI). The class of D2-like
      receptors, including the D2, D3, and D4 receptor subtypes, have all been
      implicated in the control of PPI via studies of DA agonists and antagonists in
      rats. Nevertheless, the functional relevance of each receptor subtype remains
      unclear because these ligands are not specific. To determine the relevance of
      each receptor subtype, we used genetically altered strains of "knock-out" mice
      lacking the DA D2, D3, or D4 receptors. We tested the effects of each knock-out
      on both the phenotypic expression of PPI and the disruption of PPI produced by
      the indirect DA agonist d-amphetamine (AMPH). No phenotypic differences in PPI
      were observed at baseline. AMPH significantly disrupted PPI in the D2 (+/+) mice
      but had no effect in the D2 (-/-) mice. After AMPH treatment, both DA D3 and D4
      receptor (+/+) and (-/-) mice had significant disruptions in PPI. These findings
      indicate that the AMPH-induced disruption of PPI is mediated via the DA D2
      receptor and not the D3 or D4 receptor subtypes. Uncovering the neural mechanisms
      involved in PPI will further our understanding of the substrates of sensorimotor
      gating and could lead to better therapeutics to treat gating disorders, such as
      schizophrenia.

PMID- 10341262
TI  - Increased excitability of afferent neurons innervating rat urinary bladder after
      chronic bladder inflammation.
AB  - The properties of bladder afferent neurons in L6 and S1 dorsal root ganglia of
      adult rats were evaluated after chronic bladder inflammation induced by 2 week
      treatment with cyclophosphamide (CYP; 75 mg/kg). Whole-cell patch-clamp
      recordings revealed that most (70%) of the dissociated bladder afferent neurons
      from control rats were capsaicin sensitive, with high-threshold long-duration
      action potentials that were not blocked by tetrodotoxin (TTX; 1 microM). These
      neurons exhibited membrane potential relaxations during voltage responses
      elicited by depolarizing current pulses and phasic firing during sustained
      membrane depolarization. After CYP treatment, a similar proportion (71%) of
      bladder afferent neurons were capsaicin sensitive with TTX-resistant spikes.
      However, the neurons were significantly larger in size (diameter 29.6 +/- 1.0
      micrometer vs 23.6 +/- 0.8 micrometer in controls). TTX-resistant bladder
      afferent neurons from CYP-treated rats exhibited lower thresholds for spike
      activation (-25.4 +/- 0.5 mV) than those from control rats (-21.4 +/- 0.9 mV) and
      did not exhibit membrane potential relaxation during depolarization. Seventy
      percent of TTX-resistant bladder afferent neurons from CYP-treated rats exhibited
      tonic firing (average 12.3 +/- 1.4 spikes during a 500 msec depolarizing pulse)
      versus phasic firing (1.2 +/- 0.2 spikes) in normal bladder afferent neurons.
      Application of 4-aminopyridine (1 mM) to normal TTX-resistant bladder afferent
      neurons mimicked the changes in firing properties after CYP treatment. The peak
      density of an A-type K+ current (IA) during depolarizations to 0 mV in TTX
      resistant bladder afferent neurons from CYP-treated rats was significantly
      smaller (42.9 pA/pF) than that from control rats (109.4 pA/pF), and the
      inactivation curve of the IA current was displaced to more hyperpolarized levels
      by approximately 15 mV after CYP treatment. These data suggest that chronic
      inflammation induces somal hypertrophy and increases the excitability of C-fiber
      bladder afferent neurons by suppressing IA channels. Similar electrical changes
      in sensory pathways may contribute to cystitis-induced pain and hyperactivity of
      the bladder.

PMID- 10341263
TI  - Differential expression of alpha1, alpha2, alpha3, and alpha5 GABAA receptor
      subunits in seizure-prone and seizure-resistant rat models of temporal lobe
      epilepsy.
AB  - Temporal lobe epilepsy remains one of the most widespread seizure disorders in
      man, the etiology of which is controversial. Using new rat models of temporal
      lobe epilepsy that are either prone or resistant to develop complex partial
      seizures, we provide evidence that this seizure susceptibility may arise from
      arrested development of the GABAA receptor system. In seizure-prone (Fast
      kindling) and seizure-resistant (Slow kindling) rat models, both the mRNA and
      protein levels of the major alpha subunit expressed in adult brain (alpha1), as
      well as those highly expressed during development (alpha2, alpha3, and alpha5),
      were differentially expressed in both models compared with normal controls. We
      found that alpha1 subunit mRNA expression in the Fast kindling strain was
      approximately half the abundance of control rats, whereas in the Slow kindling
      strain, it was approximately 70% greater than that of controls. However, Fast
      rats overexpressed the alpha2, alpha3, and alpha5 ("embryonic") subunits, having
      a density 50-70% greater than controls depending on brain area, whereas the
      converse was true of Slow rats. Using subunit-specific antibodies to alpha1 and
      alpha5 subunits, quantitative immunoblots and immunocytochemistry revealed a
      concordance with the mRNA levels. alpha1 protein expression was approximately 50%
      less than controls in the Fast strain, whereas it was 200% greater in the Slow
      strain. In contrast, alpha5 subunit protein expression was greater in the Fast
      strain than either the control or Slow strain. These data suggest that a major
      predispositional factor in the development of temporal lobe epilepsy could be a
      failure to complete the normal switch from the GABAA receptor alpha subunits
      highly expressed during development (alpha2, alpha3, and alpha5) to those highly
      expressed in adulthood (alpha1).

PMID- 10341264
TI  - Path integration absent in scent-tracking fimbria-fornix rats: evidence for
      hippocampal involvement in "sense of direction" and "sense of distance" using
      self-movement cues.
AB  - Allothetic and idiothetic navigation strategies use very different cue
      constellations and computational processes. Allothetic navigation requires the
      use of the relationships between relatively stable external (visual, olfactory,
      auditory) cues, whereas idiothetic navigation requires the integration of cues
      generated by self-movement and/or efferent copy of movement commands. The
      flexibility with which animals can switch between these strategies and the neural
      structures that support these strategies are not well understood. By capitalizing
      on the proclivity of foraging rats to carry large food pellets back to a refuge
      for eating, the present study examined the contribution of the hippocampus to the
      use of allothetic versus idiothetic navigation strategies. Control rats and
      fimbria-fornix-ablated rats were trained to follow linear, polygonal, and
      octagonal scent trails that led to a piece of food. The ability of the rats to
      return to the refuge with the food via the shortest route using allothetic cues
      (visual cues and/or the odor trail available) or using ideothetic cues (the odor
      trail removed and the rats blindfolded or tested in infrared light) was examined.
      Control rats "closed the polygon" by returning directly home in all cue
      conditions. Fimbria-fornix rats successfully used allothetic cues (closed the
      polygon using visual cues or tracked back on the string) but were insensitive to
      the direction and distance of the refuge and were lost when restricted to
      idiothetic cues. The results support the hypothesis that the hippocampal
      formation is necessary for navigation requiring the integration of idiothetic
      cues.

PMID- 10341265
TI  - Relationships between the prefrontal cortex and the basal ganglia in the rat:
      physiology of the cortico-nigral circuits.
AB  - The prelimbic/medial orbital areas (PL/MO) of the rat prefrontal cortex are
      connected to substantia nigra pars reticulata (SNR) through three main circuits:
      a direct nucleus accumbens (NAcc)-SNR pathway, an indirect NAcc-SNR pathway
      involving the ventral pallidum (VP) and the subthalamic nucleus (STN), and a
      disynaptic cortico-STN-SNR pathway. The present study was undertaken to
      characterize the effect of PL/MO stimulation on SNR cells and to determine the
      contribution of these different pathways. The major pattern of responses observed
      in the SNR was an inhibition preceded by an early excitation and followed or not
      by a late excitation. The inhibition resulted from the activation of the direct
      NAcc-SNR pathway because it disappeared after acute blockade of the glutamatergic
      cortico-striatal transmission by CNQX application into the NAcc. The late
      excitation resulted from the activation of the indirect NAcc-VP-STN-SNR pathway
      via a disinhibition of the STN because it disappeared after either CNQX
      application into the NAcc or blockade of the GABAergic striato-pallidal
      transmission by bicuculline application into the VP. The early excitation, which
      was markedly decreased after blockade of the cortico-STN transmission by CNQX
      application into the STN, resulted from the activation of the disynaptic cortico
      STN-SNR pathway. Finally, the blockade of the cortico-STN-VP circuit by CNQX
      application into STN or VP modified the influence of the trans-striatal circuits
      on SNR cells. This study suggests that, in the prefrontal cortex-basal ganglia
      circuits, the trans-subthalamic pathways, by their excitatory effects,
      participate in the shaping of the inhibitory influence of the direct striato
      nigral pathway on SNR neurons.

PMID- 10341266
TI  - Electrophysiological and morphological evidence for a GABAergic nigrostriatal
      pathway.
AB  - The electrophysiological and neurochemical characteristics of the nondopaminergic
      nigrostriatal (NO-DA) cells and their functional response to the degeneration of
      dopaminergic nigrostriatal (DA) cells were studied. Three different criteria were
      used to identify NO-DA cells: (1) antidromic response to striatal stimulation
      with an electrophysiological behavior (firing rate, interspike interval
      variability, and conduction velocity) different from that of DA cells; (2)
      retrograde labeling after striatal injection of HRP but showing immunonegativity
      for DA cell markers (tyrosine hydroxylase, calretinin, calbindin-D28k, and
      cholecystokinin); and (3) resistance to neurotoxic effect of 6-hydroxydomine (6
      OHDA). Our results showed that under normal conditions, 5-8% of nigrostriatal
      neurons are immunoreactive for GABA, glutamic acid decarboxylase, and
      parvalbumin, markers of GABAergic neurons, a percentage that reached 81-84% after
      6-OHDA injection. Electrophysiologically, NO-DA cells showed a behavior similar
      to that found in other nigral GABAergic (nigrothalamic) cells. In addition, the 6
      OHDA degeneration of DA cells induced a modification of their
      electrophysiological pattern similar to that found in GABAergic nigrothalamic
      neurons. Taken together, the present data indicate the existence of a small
      GABAergic nigrostriatal pathway and suggest their involvement in the
      pathophysiology of Parkinson's disease.

PMID- 10341267
TI  - Parallel fibers synchronize spontaneous activity in cerebellar Golgi cells.
AB  - Cerebellar Golgi cells inhibit their afferent interneurons, the excitatory
      granule cells. Such a feedback inhibition causes both inhibitory and excitatory
      neurons in the circuit to synchronize. Our modeling work predicts that the long
      granule cell axons, the parallel fibers, entrain many Golgi cells and their
      afferent granule cells in a single synchronous rhythm. Spontaneous activity of 42
      pairs of putative Golgi cells was recorded in anesthetized rats to test these
      predictions. In 25 of 26 pairs of Golgi cells that were positioned along the
      transverse axis, and presumed to receive common parallel fiber input, spontaneous
      activity showed a high level of coherence (mean Z score > 6). Conversely, 12 of
      16 Golgi cell pairs positioned along the parasagittal axis (no common parallel
      fiber input) were not synchronized; 4 of 16 of them showed only low levels of
      synchronicity (mean Z score < 4). For transverse pairs the accuracy of the
      coherence, measured as the width at half-height of the central peak of the cross
      correlogram, was rather low (29.8 +/- 12.5 msec) but increased with Golgi cell
      firing rate, as predicted by the model. These results suggest that in addition to
      their role as gain controllers, cerebellar Golgi cells may control the timing of
      granule cell spiking.

PMID- 10341268
TI  - Exacerbation of facial motoneuron loss after facial nerve transection in severe
      combined immunodeficient (scid) mice.
AB  - The immune system functions to protect an organism against microbial infections
      and may be involved in the reparative response to nerve injury. The goal of this
      study was to determine whether the immune system plays a role in regulating
      motoneuron survival after a peripheral nerve injury. After a right facial nerve
      axotomy, facial motoneuron (FMN) survival in C.B-17 (+/+) wild-type mice was
      found to be 87 +/- 3.0% of the unaxotomized left side control. In contrast,
      facial nerve axotomy in C.B-17 (-/-) severe combined immunodeficient (scid) mice,
      lacking functional T and B lymphocytes, resulted in an average FMN survival of 55
      +/- 3.5% relative to the unaxotomized left side control. This represented an
      approximately 40% decrease in FMN survival compared with wild-type controls. The
      reconstitution of scid mice with wild-type splenocytes containing T and B
      lymphocytes restored FMN survival in these mice to the level of the wild-type
      controls. These results suggest that immune cells associated with acquired
      immunity play a role in regulating motoneuron survival after a peripheral nerve
      injury.

PMID- 10341269
TI  - GABAergic antagonists block the inhibitory effects of serotonin in the lateral
      amygdala: a mechanism for modulation of sensory inputs related to fear
      conditioning.
AB  - Neurons in the lateral amygdala (LA) receive glutamatergic sensory input from the
      auditory thalamus and auditory cortex, and these inputs can be modulated by
      serotonin (5-HT). In the present study, we examined whether serotonergic
      inhibition of glutamatatergic excitation in the LA occurs via activation of
      GABAergic interneurons. Single-unit extracellular activity in the LA was recorded
      in response to iontophoretically applied glutamate. Concurrent application of 5
      HT reduced the number of glutamate-evoked action potentials in the majority of
      neurons tested. GABA antagonists were then iontophoresed with both glutamate and
      5-HT. Of the neurons that were inhibited by 5-HT, concurrent application of the
      GABA antagonists significantly reversed this effect. Application of the GABA
      antagonists alone had little or no effect on basal neuronal activity. We conclude
      that the 5-HT-induced inhibition of glutamatergic activity occurs in part through
      activation of serotonergic receptors on GABAergic interneurons.

PMID- 10341270
TI  - Multiple G protein-coupled receptors initiate protein kinase C redistribution of
      GABA transporters in hippocampal neurons.
AB  - Neurotransmitter transporters function in synaptic signaling in part through the
      sequestration and removal of neurotransmitter from the synaptic cleft. A
      recurring theme of transporters is that many can be functionally regulated by
      protein kinase C (PKC); some of this regulation occurs via a redistribution of
      the transporter protein between the plasma membrane and the cytoplasm. The
      endogenous triggers that lead to PKC-mediated transporter redistribution have not
      been elucidated. G-protein-coupled receptors that activate PKC are likely
      candidates to initiate transporter redistribution. We tested this hypothesis by
      examining the rat brain GABA transporter GAT1 endogenously expressed in
      hippocampal neurons. Specific agonists of G-protein-coupled acetylcholine,
      glutamate, and serotonin receptors downregulate GAT1 function. This functional
      inhibition is dose-dependent, mimicked by PKC activators, and prevented by
      specific receptor antagonists and PKC inhibitors. Surface biotinylation
      experiments show that the receptor-mediated functional inhibition correlates with
      a redistribution of GAT1 from the plasma membrane to intracellular locations.
      These data demonstrate (1) that endogenous GAT1 function can be regulated by PKC
      via subcellular redistribution, and (2) that signaling via several different G
      protein-coupled receptors can mediate this effect. These results raise the
      possibility that some effects of G-protein-mediated alterations in synaptic
      signaling might occur through changes in the number of transporters expressed on
      the plasma membrane and subsequent effects on synaptic neurotransmitter levels.

PMID- 10341272
TI  - Quantifying residual HIV-1 replication in patients receiving combination
      antiretroviral therapy.
AB  - BACKGROUND: In patients infected with human immunodeficiency virus type 1 (HIV
      1), combination antiretroviral therapy can result in sustained suppression of
      plasma levels of the virus. However, replication-competent virus can still be
      recovered from latently infected resting memory CD4 lymphocytes; this finding
      raises serious doubts about whether antiviral treatment can eradicate HIV-1.
      METHODS: We looked for evidence of residual HIV-1 replication in eight patients
      who began treatment soon after infection and in whom plasma levels of HIV-1 RNA
      were undetectable after two to three years of antiretroviral therapy. We examined
      whether there had been changes over time in HIV-1 proviral sequences in
      peripheral-blood mononuclear cells, which would indicate residual viral
      replication. We also performed in situ hybridization studies on tissues from one
      patient to identify cells actively expressing HIV-1 RNA. We estimated the rate of
      decrease of latent, replication-competent HIV-1 in resting CD4 lymphocytes on the
      basis of the decrease in the numbers of proviral sequences identified during
      primary infection and direct sequential measurements of the size of the latent
      reservoir. RESULTS: Six of the eight patients had no significant variations in
      proviral sequences during treatment. However, in two patients there was sequence
      evolution but no evidence of drug-resistant viral genotypes. In one patient,
      extensive in situ studies provided additional evidence of persistent viral
      replication in lymphoid tissues. Using two independent approaches, we estimated
      that the half-life of the latent, replication-competent virus in resting CD4
      lymphocytes was approximately six months. CONCLUSIONS: These findings suggest
      that combination antiretroviral regimens suppress HIV-1 replication in some but
      not all patients. Given the half-life of latently infected CD4 lymphocytes of
      about six months, it may require many years of effective antiretroviral treatment
      to eliminate this reservoir of HIV-1.

PMID- 10341271
TI  - Histochemically reactive zinc in plaques of the Swedish mutant beta-amyloid
      precursor protein transgenic mice.
AB  - Endogenous metals such as zinc may contribute to beta-amyloid (Abeta) aggregation
      and hence the plaque formation. In the present study, we examined brains of four
      Swedish mutant amyloid precursor protein (APP) transgenic mice at 12 months of
      age for histochemically reactive zinc in the plaques. Here, we report that all
      the Congo red (+) mature plaques contained chelatable zinc, as demonstrated by
      staining with the zinc-specific fluorescent dye 6-methoxy-8-quinolyl-para
      toluenesulfonamide (TSQ). On the other hand, Congo red (-) preamyloid Abeta
      deposits were not stained with TSQ. Interestingly, although cerebellum contained
      similar degree of preamyloid Abeta deposits as cerebral cortex, it was completely
      devoid of Congo red- or TSQ-stained mature plaques. Although zinc from plaques
      was only slowly and partially removed by a specific zinc remover, dithizone,
      treatment of brain sections with heparinase-III, which degrades heparan sulfate
      proteoglycan (HSPG), another major constituent of plaques, greatly fastened the
      zinc removal with dithizone. The present study has demonstrated the presence of
      histochemically reactive zinc in plaques, but not preamyloid Abeta deposits, of
      the Swedish mutant APP transgenic mice. Because preamyloid Abeta deposits fail to
      develop into congophilic plaques in cerebellum where synaptic vesicle zinc is
      deficient, the synaptic zinc may be a necessary element in the plaque formation.
      In holding zinc inside plaques, HSPG may contribute in addition to Abeta.

PMID- 10341273
TI  - Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in
      patients receiving potent antiretroviral therapy.
AB  - BACKGROUND AND METHODS: Although potent antiretroviral therapy can control
      infection with human immunodeficiency virus type 1 (HIV-1), a long-lived
      reservoir of infectious virus persists in CD4+ T cells. We investigated this
      viral reservoir by measuring the levels of cell-associated viral DNA and
      messenger RNA (mRNA) that are essential for HIV-1 replication. Approximately
      every 6 months, we obtained samples of peripheral-blood mononuclear cells from
      five men with long-standing HIV-1 infection who had had undetectable levels of
      plasma HIV-1 RNA for 20 months or more during treatment with potent
      antiretroviral drugs. RESULTS: Before treatment, plasma levels of HIV-1 RNA
      correlated with the levels of cell-associated unintegrated HIV-1 DNA and
      unspliced viral mRNA. After treatment, plasma levels of HIV-1 RNA fell by more
      than 2.7 log to undetectable levels. The decrease in cell-associated integrated
      and unintegrated HIV-1 DNA and mRNA occurred in two phases. The first phase
      occurred during the initial 500 days of treatment and was characterized by
      substantial decreases in the levels of DNA and mRNA, but not to undetectable
      levels. The concentrations of cell-associated unintegrated viral DNA, integrated
      proviral DNA, and unspliced viral mRNA decreased by 1.25 to 1.46 log. The second
      phase occurred during the subsequent 300 days or more of treatment and was
      characterized by a plateau in the levels of HIV-1 DNA and unspliced mRNA. After
      an initial rapid decline, the ratio of unspliced to multiply spliced viral mRNA
      (a measure of active viral transcription) stabilized and remained greater than
      zero at each measurement. CONCLUSIONS: Despite treatment with potent
      antiretroviral drugs and the suppression of plasma HIV-1 RNA to undetectable
      levels for 20 months or more, HIV-1 transcription persists in peripheral-blood
      mononuclear cells. Unless the quasi-steady state levels of HIV DNA and mRNA
      eventually disappear with longer periods of therapy, these findings suggest that
      HIV-1 infection cannot be eradicated with current treatments.

PMID- 10341275
TI  - Prion protein conformation in a patient with sporadic fatal insomnia.

PMID- 10341274
TI  - Benefit of abciximab in patients with refractory unstable angina in relation to
      serum troponin T levels. c7E3 Fab Antiplatelet Therapy in Unstable Refractory
      Angina (CAPTURE) Study Investigators.
AB  - BACKGROUND: In patients with refractory unstable angina, the platelet
      glycoprotein IIb/IIIa-receptor antibody abciximab reduces the incidence of
      cardiac events before and during coronary angioplasty. We investigated whether
      serum troponin T levels identify patients most likely to benefit from therapy
      with this drug. METHODS: Among 1265 patients with unstable angina who were
      enrolled in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina
      (CAPTURE) trial, serum samples drawn at the time of randomization to abciximab or
      placebo were available from 890 patients; we used these samples for the
      determination of troponin T and creatine kinase MB levels. Patients with
      postinfarction angina were not included. RESULTS: Serum troponin T levels at the
      time of study entry were elevated (above 0.1 ng per milliliter) in 275 patients
      (30.9 percent). Among patients receiving placebo, the risk of death or nonfatal
      myocardial infarction was related to troponin T levels. The six-month cumulative
      event rate was 23.9 percent among patients with elevated troponin T levels, as
      compared with 7.5 percent among patients without elevated troponin T levels
      (P<0.001). Among patients treated with abciximab, the respective six-month event
      rates were 9.5 percent for patients with elevated troponin T levels and 9.4
      percent for those without elevated levels. As compared with placebo, the relative
      risk of death or nonfatal myocardial infarction associated with treatment with
      abciximab in patients with elevated troponin T levels was 0.32 (95 percent
      confidence interval, 0.14 to 0.62; P=0.002). The lower event rates in patients
      receiving abciximab were attributable to a reduction in the rate of myocardial
      infarction (odds ratio, 0.23; 95 percent confidence interval, 0.12 to 0.49;
      P<0.001). In patients without elevated troponin T levels, there was no benefit of
      treatment with respect to the relative risk of death or myocardial infarction at
      six months (odds ratio, 1.26; 95 percent confidence interval, 0.74 to 2.31;
      P=0.47). CONCLUSIONS: The serum troponin T level, which is considered to be a
      surrogate marker for thrombus formation, identifies a high-risk subgroup of
      patients with refractory unstable angina suitable for coronary angioplasty who
      will particularly benefit from antiplatelet treatment with abciximab.

PMID- 10341276
TI  - Images in clinical medicine. Apoptosis in myelodysplastic syndromes.

PMID- 10341277
TI  - The association between hospital volume and survival after acute myocardial
      infarction in elderly patients.
AB  - BACKGROUND: Patients with chest pain thought to be due to acute coronary ischemia
      are typically taken by ambulance to the nearest hospital. The potential benefit
      of field triage directly to a hospital that treats a large number of patients
      with myocardial infarction is unknown. METHODS: We conducted a retrospective
      cohort study of the relation between the number of Medicare patients with
      myocardial infarction that each hospital in the study treated (hospital volume)
      and long-term survival among 98,898 Medicare patients 65 years of age or older.
      We used proportional-hazards methods to adjust for clinical, demographic, and
      health-system-related variables, including the availability of invasive
      procedures, the specialty of the attending physician, and the area of residence
      of the patient (rural, urban, or metropolitan). RESULTS: The patients in the
      quartile admitted to hospitals with the lowest volume were 17 percent more likely
      to die within 30 days after admission than patients in the quartile admitted to
      hospitals with the highest volume (hazard ratio, 1.17; 95 percent confidence
      interval, 1.09 to 1.26; P<0.001), which resulted in 2.3 more deaths per 100
      patients. The crude mortality rate at one year was 29.8 percent among the
      patients admitted to the lowest-volume hospitals, as compared with 27.0 percent
      among those admitted to the highest-volume hospitals. There was a continuous
      inverse dose-response relation between hospital volume and the risk of death. In
      an analysis of subgroups defined according to age, history of cardiac disease,
      Killip class of infarction, presence or absence of contraindications to
      thrombolytic therapy, and time from the onset of symptoms, survival at high
      volume hospitals was consistently better than at low-volume hospitals. The
      availability of technology for angioplasty and bypass surgery was not
      independently associated with overall mortality. CONCLUSIONS: Patients with acute
      myocardial infarction who are admitted directly to hospitals that have more
      experience treating myocardial infarction, as reflected by their case volume, are
      more likely to survive than are patients admitted to low-volume hospitals.

PMID- 10341278
TI  - Myelodysplasia.

PMID- 10341279
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 16-1999. A 71-year-old man with progressive weakness and a
      gammopathy.

PMID- 10341280
TI  - Editorial independence.

PMID- 10341281
TI  - Residual HIV-1 disease in the era of highly active antiretroviral therapy.

PMID- 10341282
TI  - Insomnia in prion diseases: sporadic and familial.

PMID- 10341283
TI  - The relation between volume and outcome in health care.

PMID- 10341284
TI  - Integrin-linked kinase and associated proteins (review).
AB  - Integrin-linked kinase (ILK) is a recently identified cytoplasmic protein
      serine/threonine kinase implicated in integrin-, growth factor- and Wnt-signaling
      pathways. It contains several structurally conserved motifs including ankyrin
      repeats, pleckstrin-homology (PH) domain and protein kinase catalytic domain that
      are critical for signal transduction. Recent studies have documented that ILK
      plays important roles in bi-directional ( and ) transmembrane signaling pathways
      via integrins and other proteins, leading to regulation of cell adhesion, growth,
      survival, extracellular matrix deposition and potentially differentiation.
      Furthermore, ILK is implicated in tumorigenesis and ILK appears to be a useful
      diagnostic marker of certain human tumors. The identification of novel ILK
      associated proteins will provide a better understanding of how ILK functions in
      intracellular signal transduction cascades and tumorigenesis.

PMID- 10341285
TI  - Isomeric and anomeric specificity of the metabolic and secretory response of rat
      pancreatic islets to glucose pentaacetate.
AB  - In the presence of 2.8 mM D-glucose, beta-D-glucose pentaacetate (1. 7 mM)
      augmented insulin release from isolated rat pancreatic islets more than alpha-D
      glucose pentaacetate. Likewise, the further increment in insulin output evoked by
      nateglinide (0.01 mM) was higher in islets exposed to beta- rather than alpha-D
      glucose pentaacetate. Inversely, in the presence of 2.8 mM unesterified D
      glucose, alpha-L-glucose pentaacetate, but not beta-L-glucose pentaacetate,
      significantly augmented insulin output. The higher insulinotropic potency of the
      beta-anomer of D-glucose pentaacetate coincided with the fact that it
      significantly increased the paired ratio between D-[U-14C]glucose oxidation and D
      [5-3H]glucose utilization, whereas alpha-D-glucose pentaacetate failed to do so.
      These findings are interpreted to support the concept that the stimulation of
      insulin release by these esters is largely attributable to their direct
      interaction with a stereospecific receptor, with preference for the configuration
      of the C1 common to beta-D-glucose pentaacetate and alpha-L-glucose pentaacetate.

PMID- 10341286
TI  - IAPP as a regulator of glucose homeostasis and pancreatic hormone secretion
      (review).
AB  - IAPP is a 37-amino acid peptide that is predominantly expressed in pancreatic
      beta cells. Despite co-secretion from islets the relative amounts of IAPP and
      insulin may vary. Since IAPP was first described as the major peptide constituent
      of amyloid in the islets of Langerhans of subjects with type 2 diabetes and
      insulinoma, many studies have been devoted to investigating the role of IAPP in
      formation of amyloid deposits and in diabetes pathogenesis. However, there is
      growing evidence for IAPP as an active islet hormone in addition to insulin and
      glucagon in glucose metabolic control. An inhibitory effect is seen by IAPP on
      gastric emptying, glycogen synthesis in skeletal muscle, islet insulin and
      glucagon secretion, whereas a stimulatory effect is seen on hepatic
      gluconeogenesis.

PMID- 10341287
TI  - Variable expression and absence of mutations in p73 in primary neuroblastoma
      tumors argues against a role in neuroblastoma development.
AB  - In neuroblastoma, a childhood tumor of neural crest, a tumor suppressor gene
      located at 1p36 has been implicated to play a major role in tumor aggressiveness
      and clinical prognosis. We have examined 30 different staged primary
      neuroblastoma tumors using RT-PCR, for expression of the p73 gene located at
      1p36.3, and its correlation to other clinical and biological features of these
      tumors. No correlation between expression of p73 and MYCN-amplification or 1p
      deletion could be found, five of ten 1p-deleted tumors showed detectable levels
      of p73, and no mutations could be detected, neither in the retained alleles nor
      in any other parts of the material. In five 1p-deleted cases the origin of
      deletion were determined, two were of maternal and three of paternal origin. Both
      tumors with maternal 1p-loss showed detectable levels of p73, whereas the three
      with paternal loss did not. This suggests that p73 is expressed from the paternal
      allele only in advanced staged neuroblastoma tumors. Furthermore, it suggests
      absence of correlation between p73-expression and stage in these tumors. In
      conclusion, we could find no evidence for p73 being the neuroblastoma tumor
      suppressor gene in 1p36.

PMID- 10341288
TI  - Dynamic redistribution of nuclear matrix proteins by adenovirus infection.
AB  - We analyzed the redistribution of nuclear proteins, PML protein, Ku70/Ku80, a
      putative spliceosome associated protein, pNMM102 and a nucleolar proliferating
      antigen, p120 after adenovirus 5 (Ad5) infection using immunofluorescent
      staining. These proteins remained after in situ fractionation. PML was located at
      irregular bars 6 h after infection from fine dots of uninfected cells.
      Distribution pattern of PML was not changed throughout the course of infection.
      Internal nuclear matrix network composed of Ku protein became much coarser in
      interphase cells at 12 h after infection. Ku protein was clumped at 18 h after
      infection, where EIA protein was colocalized. Speckles and interconnecting
      fibrils recognized by monoclonal antibody NMM102 disappeared early after
      infection, and reappeared at 18 h after infection in various patterns. The number
      and staining intensity of p120 containing domains increased markedly in early
      replication phase, and their shape became irregular with a few fine dots. A few
      Ad5 infected cells revealed diffuse nucleoplasmic as well as nucleolar p120 in
      late replication phase. Redistribution of four different nuclear matrix proteins
      by Ad5 infection indicates that the nuclear matrix is dynamically involved in
      gene expression.

PMID- 10341289
TI  - Differential involvement of small G proteins in Alzheimer's disease.
AB  - Alzheimer's disease (AD) is a neurodegenerative disease characterized by the
      progressive deterioration of cognitive function and memory in association with
      the wide-spread presence of senile plaques, neurofibrillary tangles and neuronal
      cell death. However, its pathophysiology remains unknown. GTP-binding proteins
      with molecular weights of approximately 20,000 are designated small G proteins.
      In the present study we quantitatively analyzed the small G proteins, Ras, Rap,
      Ral and Rab in brains removed at autopsy from controls and AD patients to examine
      whether small G proteins are equally or differentially affected in AD. Western
      blot analysis indicated that the protein level of Ras and RalB in both the
      cytosolic and membranous fractions and that of Rap2 in the cytosolic fraction was
      significantly decreased, while that of Rab8 in the membranous fraction was
      significantly increased in AD brains compared with controls. The protein level of
      other small G proteins was not different between control and AD brains. These
      results suggest a differential involvement of small G proteins in AD.

PMID- 10341290
TI  - Receptor-mediated interleukin-2 gene transfer into human hepatoma cells.
AB  - Receptor-mediated gene delivery is an attractive method for gene transfer in
      vitro and shows promise for in vivo gene therapy applications. In the current
      study, we have selected the cytokine interleukin-2 (IL-2) gene to explore the
      feasibility of receptor-mediated gene transfer into human hepatocellular
      carcinoma HepG2 cells, using Epstein-Barr virus (EBV)-based vectors. We have
      developed a targeted DNA delivery system for the treatment of liver cancer by
      gene therapy. This system utilizes the hepatocyte-specific asialoglycoprotein
      receptor, which is uniquely expressed on liver cell membranes but not present on
      other cell types. Galactosylated histone, a ligand to the asialoglycoprotein
      receptors, was synthesized, and a new EBV-based expression vector bearing the
      human IL-2 cDNA was constructed and conjugated to the ligand through ionic
      interactions. The ligand/IL-2 DNA complex was able to bind specifically to cell
      surface receptors on the target cell and, when incubated with HepG2 cells,
      resulted in elevated levels of IL-2 gene expression. These results indicate that
      therapeutic genes like IL-2 in ligand/DNA complex can be transferred into
      hepatoma cells via the hepatocyte receptor. This study constitutes an encouraging
      first step in the assessment of receptor-mediated gene transfer as a technique
      for gene therapy in liver cancer.

PMID- 10341291
TI  - CD2-mediated CD59 stimulation in keratinocytes results in secretion of IL-1alpha,
      IL-6, and GM-CSF: implications for the interaction of keratinocytes with
      intraepidermal T lymphocytes.
AB  - Normal epidermal keratinocytes are here shown to express membrane-associated
      complement inhibitory protein CD59 in vitro that protects keratinocytes from
      damage by complement because preincubation with blocking antibodies to CD59
      renders the cells susceptible to complement mediated lysis. CD59 expression in
      keratinocytes is constitutive and not modulated by inflammatory cytokines,
      phorbol myristate acetate (PMA), and a number of other agents tested. Antibody
      mediated cross-linking of CD59, however, revealed an additional function of CD59:
      keratinocytes in vitro are activated to secrete the cytokines IL-1alpha, IL-6,
      and GM-CSF. CD59 mediated induction of these cytokines is regulated at the
      transcriptional level. Binding of keratinocytes to HL60 cells that express CD59
      ligand CD2 induced the same pattern of secreted cytokines whereas binding to CD2
      negative HL60 cells did not. Induction of cytokine secretion was completely
      blocked by preincubation of keratinocytes with both anti-CD58 and anti-CD59
      antibodies together. The results demonstrate that CD2-mediated CD59 stimulation
      in human keratinocytes leads to synthesis of a particular set of cytokines
      implying a potential activation pathway in the interaction of keratinocytes with
      intraepithelial CD2+ T cells.

PMID- 10341292
TI  - Inhibitory effect of regucalcin on Ca2+/calmodulin-dependent protein phosphatase
      activity in rat brain cytosol.
AB  - The effect of Ca2+-binding protein regucalcin on neutral phosphatase activity in
      rat brain cytosol was investigated. Phosphatase activity was assayed in a
      reaction mixture containing the cytosolic protein in the presence of
      phosphotyrosine, phosphoserine, and phosphothreonine. The presence of calcium
      chloride (10(-5) and 10(-4) M) in the enzyme reaction mixture caused a
      significant increase in phosphatase activity toward three phosphoaminoacids. The
      enzyme activity toward phosphoserine and phosphothreonine was significantly
      enhanced by the addition of calmodulin (1 or 5 microg/ml) in the presence of
      calcium (10(-5) M). Such an effect was not seen in the presence of
      phosphotyrosine. Trifluoperazine (2x10(-5) M), an antagonist of calmodulin,
      completely inhibited calcium (10(-5) M)-increased phosphatase activity toward
      phosphoserine and phosphothreonine, whereas it had no effect on the enzyme
      activity toward phosphotyrosine. Regucalcin (10(-9) M) significantly inhibited
      phosphatase activity toward three phosphoaminoacids without or with Ca2+
      addition. The inhibitory effect of regucalcin (10(-10) and 10(-9) M) was also
      seen in the presence of Ca2+ (10(-5) M) and calmodulin (5 microg/ml). The
      presence of anti-regucalcin monoclonal antibody (20 or 50 ng/ml) in the enzyme
      reaction mixture caused a significant elevation of phosphatase activity toward
      three phosphoaminoacids; this effect was completely abolished by addition of
      regucalcin (10(-9) M). The present study suggests that the endogenous regucalcin
      has an inhibitory effect on Ca2+/calmodulin-dependent protein phosphatase
      activity in rat brain cytosol.

PMID- 10341293
TI  - Measurement of murine IgE antibody responses to dust mite allergens by in vitro
      assay.
AB  - In an analysis of murine immune responses to the dust mite allergen Der p 1,
      treatment with purified allergen induced a significant increase in the level of
      circulating IgE immunoglobulin (from less than 100 ng/ml in normal mice to 1,350
      ng/ml in mice receiving the allergen). Even so, specific IgE antibodies binding
      to purified Der p 1 were not detected in a conventional ELISA, and the major
      response appeared to be the induction of high titre IgG antibodies. Specific
      circulating murine IgE antibodies were however detected using the following assay
      format: murine IgE was captured to anti-murine IgE antibody coated wells; Der p 1
      was added and bound by immobilized anti-Der p 1 IgE antibodies; the captured Der
      p 1 was then detected by the addition of monoclonal IgG antibodies against Der p
      1 and these antibodies were measured by the addition of anti-murine IgG antibody
      enzyme conjugate with which colour development is produced after substrate
      addition. This assay establishes a procedure to measure circulating anti-Der p 1
      IgE antibodies which are present together with competing high titre IgG anti-Der
      p 1 antibodies.

PMID- 10341294
TI  - Autoimmune antigen megalin displays similarities with skeletal muscle ryanodine
      receptor/Ca2+ release channel.
AB  - Ryanodine receptors are a family of intracellular Ca2+ release channel proteins,
      which exist as tetrameric complexes of large ( approximately 5000 amino acid
      residue) polypeptide monomers. As well as controlling striated muscle contraction
      and neurotransmitter release, these channel proteins have been implicated in
      several pathological states. In order to characterise ryanodine receptors in
      various tissues, mouse monoclonal antibodies were developed against the type 1
      isoform isolated from skeletal muscle. Several of these antibodies recognise
      ryanodine receptor in skeletal muscle, as well as high molecular weight (k-HMW)
      protein in kidney microsomes. Like the ryanodine receptor, the k-HMW protein
      binds 45Ca2+ and sediments as a large complex upon sucrose density-gradient
      centrifugation. In contrast, the k-HMW protein does not bind ryanodine and is
      glycosylated. Furthermore, monoclonal and polyclonal antibodies generated against
      purified k-HMW protein do not recognise skeletal muscle ryanodine receptor.
      Characterisation of a cDNA clone encoding part of the k-HMW protein revealed that
      it is likely to be the rabbit homologue of human megalin, an autoimmune antigen
      in membranous glomerulonephritis. Potential consequences of immunological
      similarities between ryanodine receptors and megalin are discussed in terms of
      autoimmune disease.

PMID- 10341295
TI  - Protein kinase C regulates NO-cGMP pathway in muscarinic receptor activation by
      HIV+-IgA.
AB  - In this work we demostrate that IgA purified from HIV infected patients
      recognizes a band with a molecular weight corresponding to radiolabelled ileal
      muscarinic acethylcholine receptors (mAChR) by immunoblotting. HIV+-IgA triggers
      the signals that are the consequence of mAChR stimulation in the intestine,
      regulating protein kinase C (PKC) and nitric oxide synthase (NOS) activity as
      well as 3',5'-cyclic guanosine monophosphate (cGMP) formation. On the one hand
      PKC activation by HIV+-IgA induces NOS inhibition and as a consequence, low
      amounts of NO that could improve local immunosuppression in the intestine; on the
      other hand HIV+-IgA stimulates cGMP production which could potentiate ileal
      motility and loss of water/electrolytes involved in intestinal damage in AIDS.

PMID- 10341296
TI  - Fragile X syndrome (review).
AB  - Fragile X syndrome is the most common form of inherited mental retardation
      currently known, associated with a wide range of developmental disabilities in
      both males and females, caused by a large expansion of a (CGG)n repeat in the
      first exon of the FMR1 gene. Fragile X syndrome occurs in all racial and ethnic
      groups, and it is a condition of major epidemiological importance among mentally
      handicapped males. Therefore, this disease must be considered in the differential
      diagnosis of any child with developmental delay, mental retardation or learning
      disability. The fragile X syndrome is due to the shutdown of the FMR1 gene
      transcription, and the pathogenesis of this syndrome is a consequence of absence
      of the protein product of the FMR1 gene (FMRP). Since the great majority of
      fragile X patients have the same type of mutation in a specific location of the
      gene, molecular analysis is extremely accurate for diagnosis of the disease, and
      important for genetic counseling of family members. Others genetic disorders are
      also caused by expanded trinucleotide repeats.

PMID- 10341297
TI  - Induction of growth inhibition and apoptosis in pancreatic cancer cells by
      auristatin-PE and gemcitabine.
AB  - Pancreatic adenocarcinoma is the fifth leading cause of cancer related deaths in
      the United States. Treatment for this disease has largely been unsuccessful,
      which may partly be due to insufficient data regarding the molecular mechanisms
      of chemotherapeutic drugs currently being used as single agents or in combined
      modality regimens. In this study, we investigated the molecular mechanisms by
      which auristatin-PE, a newly developed experimental agent, and gemcitabine, a
      commercially available anti-cancer agent, exert their inhibitory effects on
      pancreatic cancer cell lines containing wild-type p53 (HPAC) and mutant p53 (PANC
      1). Our results showed that auristatin-PE and gemcitabine inhibited cell growth
      and induced cell cycle arrest in G2/M and S phase, respectively. Auristatin-PE
      also induced apoptosis in both cell lines. Western blot analysis showed that
      auristatin-PE up-regulated the expression of wt-p53, p21WAF1 and Bax, and down
      regulated Bcl-2 and cyclin B in HPAC cells, while only up-regulation of p21WAF1
      and Bax was observed in PANC-1 cells. These results suggest that auristatin-PE
      may induce apoptosis and p21WAF1 expression through p53-dependent or independent
      pathways, and that up-regulation of p21WAF1 and Bax and down-regulation of Bcl-2
      may be the molecular mechanism through which auristatin-PE inhibits cell growth
      and induces apoptosis. Furthermore, the up-regulation of p21WAF1 and down
      regulation of cyclin B may contribute to the G2/M cell cycle arrest. Combination
      of auristatin-PE and gemcitabine showed significantly greater inhibition of cell
      growth and up-regulated expression of p21WAF1 and Bax. From these results, we
      conclude that the selection of therapeutic agents based on their molecular
      mechanism may improve therapeutic outcome, and that auristatin-PE may be more
      effective in the treatment of pancreatic cancer when given in combination with
      gemcitabine, rather than as a single agent.

PMID- 10341298
TI  - Risk-informed selection of a highway trajectory in the neighborhood of an oil
      refinery.
AB  - A methodology for characterizing alternative trajectories of a new highway in the
      neighborhood of an oil-refinery with respect to the risk to public health is
      presented. The approach is based on a quantitative assessment of the risk that
      the storage facilities of flammable materials of the refinery pose to the users
      of the highway. Physical phenomena with a potential for detrimental consequences
      to public health such as BLEVE (Boiling Liquid Expanding Vapor Explosion),
      Unconfined Vapor Cloud Explosion, flash fire and pool fire are considered.
      Methodological and procedural steps for assessing the individual risk around the
      tank farm of the oil-refinery are presented. Based on the individual risk, group
      risk for each alternative highway trajectory is determined.

PMID- 10341300
TI  - Optimization of non-thermal plasma for the treatment of gas streams.
AB  - The decomposition of hazardous air pollutants (HAPs) has been described by using
      the ratio of power input to flow rate or of energy to gas flow rate (or specific
      energy density (SED), in joules/liter). However, we found that HAP decomposition
      was not constant for a given SED but rather depends on SED. Data were plotted to
      examine HAP decomposition with constant SEDs. The results indicated for most HAPs
      tested the soft plasma (the low voltage and high residence time) is the preferred
      operation for most HAP decomposition applications. This concept can lead to new
      insights for HAP decomposition and to the optimization of non-thermal plasma for
      the treatment of HAPs.

PMID- 10341299
TI  - Analysis of an accident at a solvent recovery plant.
AB  - An accident in a plant for solvent recovery from solvent-contaminated wastes was
      examined. An experimental investigation of the accident was carried out using
      calorimetric and thermogravimetric techniques. The immediate cause of the
      accident was an unforeseen exothermic decomposition reaction. The main underlying
      cause of the accident was the absence of safety culture in the plant management,
      that resulted in the lack of a testing procedure to evaluate the thermal
      stability of the process feed. A simplified screening procedure based on
      differential scanning calorimetry was used in order to test the thermal stability
      of the nonvolatile fraction of the solvent-contaminated wastes present on the
      plant in order to be processed. More than 75% of the samples examined showed
      exothermal decomposition phenomena starting at temperatures higher than 100
      degrees C. These phenomena were common to solvent wastes that originated from a
      number of different industrial activities. Thus, the thermal instability of the
      process feed is one of the main problems in solvent recovery operations. Our
      analysis of the accident suggested that the safe operation of waste solvent
      recovery processes requires an accurate characterization of the thermal stability
      of the process feed. Process safety is also increased by an adequate emergency
      vent and an accurate control of operating temperature, that may be reduced
      operating under vacuum. Safety devices may also include a water supply for
      emergency quench.

PMID- 10341301
TI  - Influence of water on the supercritical fluid extraction of naphthalene from
      soil.
AB  - Supercritical fluid extraction (SFE) is an innovative soil remediation
      technology. To aid system evaluation and design, thermodynamic and kinetic
      parameters have been measured using a naphthalene contaminated, loamy sand at
      various water contents. The experimental results show that supercritical carbon
      dioxide can easily extract naphthalene from soil when the water content is below
      10%. At low water contents, mass transfer is rapid and the equilibrium partition
      coefficient is independent of the soil's water content. However, the overall mass
      transfer coefficient, (kova), decreases by at least a factor of 200 as the water
      content increases from 10 to 20%.

PMID- 10341302
TI  - Comparison between supercritical carbon dioxide extraction and aqueous surfactant
      washing of an oily machining waste.
AB  - Mathematical models are developed to compare aqueous surfactant washing to
      supercritical carbon dioxide (SCCO2) extraction. These two cleaning processes are
      potentially competitive technologies which can be used to remove oily
      contaminants from a solid waste. In both processes, the cleaning efficiency for a
      batch of waste is evaluated by quantifying the residual oil content in the
      treated sample. A mass transfer model is used to simulate a semi-continuous
      washing process, and the experimental data, obtained in a batch operation, are
      used to estimate the equilibrium parameters in the model. For SCCO2 extraction, a
      linear desorption model is used to describe the supercritical desorption of oil
      from the solid phase into the CO2 phase and the simulated results agreed very
      well with the experimental data. The oil removal in aqueous surfactant washing is
      viewed to be controlled primarily by the diffusional transport of oil from the
      interiors of the waste elements to the surface, thus, it can be significantly
      affected by the size of the particles. A pre-cleaning pulverization is then
      recommended to improve the cleaning efficiency without increasing any other
      operation costs. In SCCO2 extraction, the desorption of oil from the solid waste
      is the controlling step and consequently, the solvent flow rate has no influence
      on oil removal. Our theoretical studies show that the difference between the
      cleaning efficiencies of these two technologies is not significant, with the oil
      concentration in the washing products approximately 5% lower than that in the
      extraction products.

PMID- 10341303
TI  - Effects of particle size and adding sequence of fine lactose on the deposition of
      salbutamol sulphate from a dry powder formulation.
AB  - Ternary mixtures composed of coarse lactose (CL) (90.8 microm), salbutamol
      sulphate (SS) (5.8 microm) and either micronised lactose (ML) (5 microm) or
      intermediate sized lactose (IML) (15.9 microm) in a ratio of 66.5:1:1 w/w were
      prepared using different mixing sequences of the various components. In addition,
      a binary mixture composed of CL and SS (67.5:1 w/w) was also prepared as the
      control. The in vitro deposition of SS was measured using a twin stage impinger
      after aerosolisation at 60 and 90 l min-1 via a Rotahaler. The aerodynamic
      particle size distribution of both the aerosolised SS and lactose was further
      analysed using an Andersen cascade impactor at 60 l min-1. All ternary mixtures
      produced a significantly higher (analysis of variance, P<0.01) fine particle
      fraction (FPF) and fine particle dose (FPD) of SS than the control after
      aerosolisation at either 60 or 90 l min-1. Formulations containing the ML
      produced significantly (P<0.05) higher FPF and FPD of SS than those containing
      the IML at both aerosolisation flow rates. Different mixing sequences were also
      shown to result in different deposition profiles of both SS and lactose after
      aerosolisation of the ternary mixtures containing ML at 60 l min-1. The
      formulation prepared by first blending ML with CL before mixing with SS produced
      a higher FPF and FPD of SS but a lower FPF of lactose than the same formulation
      in terms of composition but prepared using different mixing orders of the three
      components. In contrast, the formulations containing IML produced a similar
      deposition profile to SS, regardless of the mixing sequences, and so did the
      formulations containing ML aerosolised at 90 l min-1. These results suggest that
      the effect of mixing sequences on drug deposition may become more prominent at
      lower aerosolisation flow rates and by reducing the size of any added fine
      lactose.

PMID- 10341304
TI  - Rheology of polyol behenates and drug release from matrix monolithic capsules.
AB  - Three polyol behenates with similar melting points (MP) and different hydrophilic
      lipophilic balances (HLB) were studied (MP/HLB: 70/02, 63/05 and 57/13). After
      melting at MP+30 degrees C, the rheological behaviour of behenates was determined
      by adjustment of the rheograms to the Ostwald power-law and by statistical
      assessment of the flow index. Behenates showed slight shear thickening. This
      shear thickening increased when HLB of behenates decreased. This behaviour
      accounted for a reorganization of the particles under the shear, which became
      easier when the proportion of the polyethylene glycol chains in the wax
      decreased. Proxyphylline was used to prepare suspensions at a concentration of
      25% in the melted behenates, and to manufacture monolithic capsules by cooling.
      The suspensions had a shear-thinning behaviour with or without thixotropy.
      Colloidal particles and aggregates formed in these suspensions directly
      influenced the rheological properties, as observation of solidified suspensions
      by scanning electron microscopy confirmed. Extended release of proxyphylline was
      obtained with the three waxes. Behenates 63/05 and 70/02 gave inert matrices and
      released drug very slowly. Hydrodispersible behenate 57/13 swelled and made up a
      kind of hydrophilic matrix that released proxyphylline more quickly, due to
      slight erosion. In the three cases, the release mechanism was basically
      diffusional in nature.

PMID- 10341305
TI  - Morphological effect of microcrystalline cellulose particles on tablet tensile
      strength.
AB  - An attempt was made (1) to fractionate microcrystalline cellulose (MCC) particles
      of Avicel PH-101 (PH grade) and Ceolus KG-801 (KG grade) into four sieve
      fractions by using an air-jet sieve and (2) to disclose effects of morphology of
      the particle on tablet tensile strength, T. The morphology of MCC particles is
      one of the most important factors affecting T. T increased with an increase in
      the ratio of L/D for particles (L, length; D, width). KG grade consists of a
      larger number of rod-shaped particles than PH grade, giving significantly higher
      compressibility than PH grade.

PMID- 10341306
TI  - Labeling peptides with rhenium-188.
AB  - A direct labeling technique via EHDP for the preparation of 188Re-somatostatin
      analogue peptide beta-(2-naphthyl)-D-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-amide
      complex was developed. The influence of reaction conditions such as pH,
      temperature, weak ligand concentration and stannous chloride concentration were
      investigated. Methods of analysis were also established permitting identification
      of radiochemical impurities which may be present in the radiopharmaceutical
      solution. Results showed that under the procedure reported herein 188Re-peptide
      complex can be prepared with a radiochemical purity of 90% and a specific
      activity up to 1.8 GBq mg-1 without radiolytic degradation of the product.

PMID- 10341307
TI  - Design and characterization of a surfactant-enriched tablet formulation for oral
      delivery of a poorly water-soluble immunosuppressive agent.
AB  - The feasibility of incorporating significant quantities of the anionic
      surfactant, sodium lauryl sulfate (SDS), into an immediate release tablet
      formulation of a poorly water-soluble immunosuppressive agent was investigated.
      Despite the extremely poor compressibility of SDS and poor chemical stability of
      the drug, a commercializable, direct-compression tablet formulation with
      satisfactory mechanical properties and acceptable chemical stability was
      achieved. Optimal in vitro release of the drug from the tablet formulation was
      achieved by establishing the minimum molar uptake ratio necessary to achieve
      complete micellar solubilization of the drug, after which formulation studies
      were conducted to determine the influence of formulation and process variables on
      the rate and extent of drug release. A model-independent analysis of dissolution
      results in a reduced volume (250 ml) of modified simulated gastric fluid
      demonstrated that the rate and extent of drug release was highly dependent on the
      mean particle size of the bulk drug, but independent of compression force above
      that required to achieve a compact of acceptable mechanical strength. Employing
      the Korsmeyer-Peppas model of Fickian and non-Fickian drug release, it was
      further shown that release of the drug from the dosage form was governed largely
      by surface erosion of the surfactant-enriched tablet matrix.

PMID- 10341308
TI  - Effect of preparative variables on the properties of poly(dl-lactide-co
      glycolide)-methoxypoly(ethyleneglycol) copolymers related to their application in
      controlled drug delivery.
AB  - The effect of certain preparative variables, such as the composition of the feed,
      the reaction time and the reaction temperature, on the properties of prepared
      poly(dl-lactide-co-glycolide)-methoxypoly(ethyleneg lycol) (PLGA-mPEG) copolymers
      and on the yield of the reaction was investigated. The results with regard the
      molecular weight and yield were discussed in relation to a polymerization
      mechanism proposed recently (Du et al., 1995. Macromolecules 28, 2124-2132). The
      higher the PEG content of the feed the lower the molecular weight of the
      copolymer and the yield of the reaction. The breadth of the molecular weight
      distribution decreased initially with time, but appeared to stabilize later at
      low values. Both the ethylene oxide content and the lactide to glycolide molar
      ratio in the copolymer depended on the reaction temperature and varied with the
      reaction time. PLGA and mPEG appeared to be partially miscible, and copolymers
      containing approximately 40% mol or higher ethylene oxide exhibited
      crystallinity.

PMID- 10341309
TI  - Surface modification and electrostatic charge of polystyrene particles.
AB  - Particle surface modification by poloxamer adsorption can significantly alter the
      electrostatic charge, adhesion behaviour and consequently handling properties of
      a material. The charge reduction on polystyrene spheres achieved by this
      modification technique is dependent on the concentration, molecular weight and
      conformation of poloxamer at the particle surface. Adsorption isotherms of
      poloxamers on polystyrene particles follow a Langmuir profile and there is an
      apparent correlation between the extent of adsorption and ability of poloxamer to
      reduce electrostatic charge. Surface analysis techniques, X-ray photoelectron
      spectroscopy and Time of Flight Secondary Ion Mass Spectrometry have generated
      data on the thickness of the adsorbed poloxamer layer and provided evidence to
      suggest that the polypropylene oxide component of the poloxamer adsorbs to the
      polystyrene surface and there is a polyethylene oxide rich outer surface which
      may influence the charge alteration.

PMID- 10341310
TI  - Optical surface roughness study of starch acetate compacts.
AB  - Optical surface roughness of starch acetate compacts was investigated by specular
      reflection of a laser beam as a function of angle of incidence. The intensity
      data was fitted using the model of Gaussian and Lorentzian curves to solve
      numerical values for optical surface roughness which was observed to be order of
      1 microm with the present samples.

PMID- 10341311
TI  - Effects of tail alkyl chain length (n), head group structure and junction (Z) on
      amphiphilic properties of 1-Z-R-D,L-xylitol compounds (R = CnH2n+1).
AB  - In the family of 1-Z-R-D,L-xylitol, we have determined the main amphiphilic
      properties of esters (Z = OCO) as a function of alkyl chain length (R = CnH2n+1,
      n = 4-17). A classical decrease of critical micelle concentration with the
      increase in the alkyl chain has been found. With water, esters displayed lamellar
      phases at temperatures of 25 degrees C or higher. The extent of
      hydrophilic/lipophilic balance range obtained by emulsification method can be
      proven to be of interest for pharmaceutical applications. The results were
      compared with those obtained in previous investigations, i.e. for alkyl
      substituted xylitol, with thioether (Z=S) and ether (Z=O) linking groups in order
      to discuss the role of the junction nature. Likewise, they were compiled with the
      results related to their D-glucose homologues, in order to put forward the
      effects of the head group configuration, cyclic or acyclic.

PMID- 10341312
TI  - Measurement and pharmacokinetic study of unbound tropisetron in rat blood by
      microdialysis with high-performance liquid chromatography.
AB  - A microdialysis system coupled with liquid chromatography was applied for the
      measurement of unbound tropisetron in rat blood. The microdialysis probe was
      inserted into a jugular vein/right atrium of male Sprague-Dawley rats.
      Tropisetron (5 or 10 mg/kg, i.v.) was then administered via a femoral vein of
      rat. Samples were eluted with a mobile phase containing acetonitrile-100 mM
      monosodium phosphate (pH 5.0, 26:74, v/v). The UV detector wavelength was set at
      284 nm. The detection limit of tropisetron was 20 ng/ml. The in vivo recovery of
      microdialysis probe in rat jugular vein/atrium for tropisetron at 1, 2, and 5
      microg/ml were between 49 and 53% (n=5). Intra- and inter-assay accuracy and
      precision of the analyses were <10% in the range of 0.1-1 microg/ml. The method
      has been applied to pharmacokinetic analysis of unbound tropisetron in rat
      intravenous administration. Rapid distribution followed by a slower elimination
      phase was observed from the blood concentration-time curve. The disposition of
      tropisetron at each dose fitted well to a two-compartment model.

PMID- 10341313
TI  - Fracture in disordered media and tensile strength of microcrystalline cellulose
      tablets at low relative densities.
AB  - The purpose of this study is to establish a theoretical basis for the tensile
      strength of low density tablets. In a first step, a lattice model based on
      percolation theory is presented. As a theoretical result, a power law is obtained
      for the lattice strength. The exponent in this law is expected to be universal
      and as a numerical value Tf congruent with 2.7 is proposed. The result is
      identical with an earlier theoretical finding from an alternative approach
      proposed by. In a second step, the new model equation is applied to the tensile
      strength of low density tablets. The compacts were manufactured and tested with
      an universal testing instrument Zwick UPM 1478 (Zwick-Roell). Different types of
      microcrystalline cellulose Emcocel 50M, Emcocel 90M, Avicel PH101 and Avicel
      PH102 were assayed as model excipients because of their ability to form tablets
      at comparatively low relative densities (rhor). For determination of the tensile
      strength, two different strain rates 0.5 and 25 mm min-1 were examined. All
      experimentally determined exponents were in the same range with an average of
      Tf=3.2+/-0.1 and the critical solid fractions (rhorc), yielded values close the
      relative bulk densities. In a third step, the new model is compared to the
      Ryshkewitch-Duckworth equation. This exponential relationship of the tensile
      strength and porosity was found to have an inferior fitting adequacy than the new
      power law. As a conclusion, the lattice model presented is able to explain the
      power law behaviour of the tensile strength as a function of the relative density
      with an exponent close to three. The expected universal character of this
      exponent was supported by the results of the assayed substances at two different
      strain rates. Plus, in the case of the tested substances, the new relationship
      between the tensile strength and the relative density should be preferred to the
      often used exponential function. However, further studies have to be conducted to
      know more about the validity of the new model.

PMID- 10341314
TI  - Immunological mechanisms operative in allergen-specific immunotherapy.
AB  - Specific immunotherapy (SIT) is the practice of administering increasing doses of
      allergen extracts to selected subjects suffering from IgE-mediated
      hypersensitivity, with the ultimate aim of ameliorating the symptoms associated
      with exposure to the causative allergen. The process is often called
      hyposensitization or desensitization because one consequence of the treatment is
      a reduction in sensitivity of the target organ after challenge with the relevant
      allergen. SIT has been practiced as treatment of type I allergy caused by
      inhalant allergens and Hymenoptera venoms for more than 80 years on an empirical
      basis. Today, numerous double-blind, placebo-controlled studies prove the
      therapeutic effect of SIT. However, the immunological mechanisms underlying
      successful specific immunotherapy have still not been completely elucidated. This
      review focuses on recent attempts to characterize the immunological events
      associated with SIT.

PMID- 10341315
TI  - Expression of the T-cell markers CD3, CD4 and CD8 in healthy and atopic children
      during the first 18 months of life.
AB  - BACKGROUND: There is little information available about the development of T-cell
      immunity in healthy and atopic children. We have studied prospectively the mean
      fluorescence intensity of the T-cell receptor complex-associated CD3, CD4 and CD8
      in relation to atopic family history (AFH) and the development of atopic disease.
      METHODS: Children with a defined AFH (n = 172) were followed from birth to 18
      months and the cumulative history of atopic disease was recorded. Blood samples
      were obtained at birth and at 18 months, and in a subgroup of 78 children also at
      3, 6 and 12 months. Multicolour flow cytometry was used to analyse pan T-cells
      (CD3+CD45+CD14-), T-helper-(CD3+CD4+) and T-cytotoxic-(CD3+CD8+) cells. RESULTS:
      At 18 months, 31 children were atopic and 118 non-atopic. Children who developed
      atopic disease had a higher CD4 expression (mean fluorescence intensity, MFI) on
      CD4+CD3+ lymphocytes at birth and at 3 months, particularly as compared with non
      atopic children without AFH. Furthermore, the CD3 expression on CD3+CD45+CD14-
      lymphocytes increased more slowly with age in children with double atopic
      heredity, as compared with children with no or only one atopic family member.
      CONCLUSIONS: The higher expression of the CD4 receptor in early infancy in
      children who developed atopic disease compared with non-atopics suggests a
      delayed expression in T-helper cells. Children with a strong AFH had a slower
      increase in the expression of CD3, indicating a delayed T-cell maturation.

PMID- 10341316
TI  - On the role of T lymphocytes in stimulation of humoral immunity induced by
      peptidoglycan-monomer linked with zinc.
AB  - Effects of peptidoglycan linked with zinc (PGM-Zn) were investigated on plaque
      forming cell (PFC) generation to sheep red blood cell (SRBC) and SRBC-unrelated
      antibody production in primary and secondary immune response in mice depleted in
      vivo of CD4+ and/or CD8+ T lymphocytes. PGM-Zn in nondepleted mice stimulated the
      PFC generation and IgM or IgG and IgG1 production in primary and secondary
      reaction. Single depletion of CD4 or CD8+ T cells did not change this ability.
      The effects of PGM-Zn after CD8+ depletion were even greater than those in
      nondepleted mice. Depletion of both T cell subsets, however, completely abrogated
      immunostimulatory effects of PGM on PFC generation (primary and secondary
      response), as well as on primary SRBC-unrelated antibody production, leaving only
      the increase of IgG in secondary response unchanged. Immunostimulatory effects
      and isotype switching to IgG1 and IgG2a correlated with the changes in splenic
      CD4+, CD8+, CD5+ cells, pointing to the regulatory role of these cells and/or
      their cytokines in PGM-Zn-induced immunostimulation. Altogether the data suggest
      that PGM-Zn may potentiate the costimulatory signals coming from activated T
      cells and act on B cells without the T cell help.

PMID- 10341317
TI  - Soluble human interleukin-4 receptor is produced by activated T cells under the
      control of metalloproteinases.
AB  - BACKGROUND: Soluble interleukin 4 receptors (sIL-4R) are present in biological
      fluids. In contrast to mice, in man no distinct mRNA coding for sIL-4R has been
      described, suggesting that human sIL-4R is exclusively produced by proteolytic
      cleavage of the cell surface receptor. It is not known whether human sIL-4R is
      actively produced during an immune response. METHODS: Human purified T cells,
      CD4+, CD8+, CD45RA+ and CD45R0+ T cell subpopulations were activated in vitro.
      sIL-4R was determined in the supernatants, cell surface IL-4R was measured by
      flow cytometry and RT-PCR. RESULTS: Recombinant sIL-4R inhibited IL-4-mediated
      proliferation and IL-5 upregulation by T cells. sIL-4R could be detected at low
      levels in supernatants of nonactivated T cells, but at high levels following TCR
      engagement. This response was paralleled by enhanced transcription and de novo
      synthesis of the human cell surface IL-4R. Both, activated naive CD45RA+ and
      memory CD45R0+ T cells, produced sIL-4R with long-lasting kinetics. IL-4
      increased sIL-4R production by activated CD45RA+, but there was less of an
      increase by CD45R0+ T cells. In addition, interferon-gamma enhanced sIL-4R
      production. Cycloheximide and dexamethasone inhibited sIL-4R production by
      activated T cells, but did not abolish constitutive release of sIL-4R.
      Phosphoramidon and 1,10-phenanthroline dose-dependently inhibited shedding of the
      IL-4R, even in nonactivated T cells. CONCLUSION: The production of human sIL-4R
      by T cells is regulated by TCR stimuli, IL-4 and IFN-gamma and needs the activity
      of metalloproteinases. Thus, sIL-4R should be regarded as inducible and due to
      its IL-4-antagonizing activity an immunoregulatory molecule.

PMID- 10341318
TI  - Expansion and immunological study of human tumor infiltrating gamma/delta T
      lymphocytes in vitro.
AB  - Goffa/delta T cells have stimulated a lot of interest because of their unique
      features in antigen recognition and cytotoxicities to many autologous and/or
      allogeneic tumor cells. We have developed a novel method to selectively expand
      larger amounts of human tumor-infiltrating gamma/delta T lymphocytes (gamma/delta
      TILs) ex vivo by immobilized pan- anti-TCRgamma/delta monoclonal antibody in the
      presence of exogenous IL-2. The expanded gamma/delta TILs mainly expressed CD45RO
      and HLA-DR molecules and did not express CD4. CD8+ gamma/delta TILs accounted for
      19% of gamma/delta TILs. The expression of CD25 molecule on expanded gamma/delta
      T cells was inducible and downregulated following a time course. The Vdelta1 and
      Vdelta2 subsets amount to 37 and 58%, respectively. The expanded gamma/delta TILs
      show an IL-2-dependent proliferation, MHC class I-unrestricted and TCRgamma/delta
      related cytotoxicities to two MHC class I+ and two MHC class I+ allogeneic tumor
      cell lines in vitro.

PMID- 10341319
TI  - The respiratory burst activity of activated eosinophils in atopic asthmatics.
AB  - Although activated eosinophils in peribronchial tissue and peripheral blood are
      increased in patients with asthma, the mechanisms contributing to their presence
      and causing airway hyperreactivity are not well established. Recently, the
      respiratory burst activity on activated eosinophils can be evaluated by dual
      staining with monoclonal antibody EG2 and 2,7-dichlorofluorescein diacetate,
      which can be analyzed with the FACS analyzer. The severity of allergy and airway
      hyperreactivity can be evaluated by allergen-specific IgE and airway
      hyperresponsiveness to methacholine. In this study we evaluated the cell numbers
      with respiratory burst activity on activated eosinophils and correlated these
      cell numbers with the allergen-specific IgE and airway hyperresponsiveness to
      methacholine. Results showed that the cell number with respiratory burst activity
      of activated eosinophils was increased in those patients with more
      hyperresponsiveness to methacholine and correlated with PD20 of methacholine with
      r = -0.643 and p = 0.01. The number of activated eosinophils was also correlated
      with allergen-specific IgE with r = 0.641 and p = 0.025. There were increased
      cell numbers of activated eosinophils (EG2(+)/PMN) and cells with respiratory
      burst activity (DCF+EG2(+)/PMN) in the unstable asthmatic patients when compared
      to those of stable asthmatic patients. These results suggest that there is in
      vivo activation of eosinophils in the asthmatic patients, especially in the
      unstable patients and patients who have airways more hyperreponsive to
      methacholine. We concluded that the cell numbers with respiratory burst activity
      of activated eosinophils cannot only reflect the airway hyperresponsiveness but
      also the disease severity of asthmatic patients.

PMID- 10341320
TI  - Influx of neutrophils into the airway lumen at 4 h after segmental allergen
      challenge in asthma.
AB  - BACKGROUND: Segmental allergen challenge is a powerful tool to study inflammatory
      reactions in asthmatic airways. There is little information on the early events
      at 5 min and 4 h after allergen challenge with respect to the cell influx and the
      chemokine interleukin-8 (IL-8). METHODS: Seven mild to moderate allergic
      asthmatics (AA group), 5 allergic nonasthmatics (ANA group) and 5 nonallergic
      controls underwent segmental allergen challenge, with allergen doses based upon
      skin reactivity. Bronchoalveolar lavage (BAL) samples were obtained before, 5 min
      and 4 h postchallenge, and were analyzed for cell numbers and differential
      counts, eosinophil and neutrophil chemotactic activity, and levels of IL-8.
      RESULTS: At 5 min postchallenge, no changes were observed compared to baseline.
      At 4 h postchallenge, an increase was found in the number of neutrophils and the
      levels of IL-8, which was dependent on the dose of allergen in the AA and ANA
      group. At the same allergen dose, the increases in neutrophils and levels of IL-8
      were calculated to be 91 and 67 times higher, respectively, in AA than in ANA.
      Levels of IL-8 correlated with the number of neutrophils and with the in vitro
      neutrophil chemotactic activities in BAL fluid. CONCLUSIONS: Neutrophil
      chemotactic activity is increased in BAL fluid at 4 h after segmental allergen
      challenge. We suggest that apart from IgE-mediated mast cell degranulation,
      additional local factors in the airways determine the degree of IL-8 increase and
      neutrophil influx.

PMID- 10341321
TI  - Dual effects of TNF on synthesis of complement components by a gastric cancer
      derived cell line, KATO-III.
AB  - BACKGROUND: Complement components are synthesized extrahepatically, although
      hepatocytes are the major source of plasma complement. It is now clear that local
      production of complement is important in homeostasis and immune defense in
      tissue. METHODS: The secretion of complement components was studied in vitro with
      a gastric cancer-derived cell line, KATO-III (signet-ring cell carcinoma).
      Complement components C2 and C3 were estimated by functional assay and/or ELISA
      in culture medium obtained after incubation of KATO-III cells for 3 days in
      protein-free culture medium, with or without addition of tumor necrosis factor
      (TNF), in a humidified atmosphere of 5% CO2/95% air at 37 degrees C. RESULTS: (1)
      While a higher amount of C3 was detected in medium when KATO-III cells were
      cultured in the presence of TNF than in medium lacking TNF, higher C2 activity
      was detected when cultured in medium lacking TNF than in TNF-supplemented medium.
      (2) TNF suppressed C2 secretion and enhanced C3 secretion in a dose-dependent
      fashion. (3) C3 secretion remained less than 20 ng/10(6) cells/24 h but increased
      from the first day of TNF (10U/ml) addition (concentrations approached 108.6-
      115.6 ng/10(6) cells/24 h on the 3rd day) and decreased on the 1st day without
      TNF. In contrast, C2 activity, detected when cultured in the absence of TNF, was
      decreased on the 2nd day of TNF addition and increased again on the 1st day
      without TNF. The daily secretion of C2 in the absence of TNF was 3.75-6.30x10(7)
      effective molecules/10(6) cells. (4) Reversible inhibition of C2 and C3 secretion
      was observed when the cell line was cultured in the presence of cycloheximide,
      indicating that both components were synthesized de novo. CONCLUSION: It appears
      that TNF enhances C3 secretion and suppresses C2 secretion by KATO-III.

PMID- 10341324
TI  - Identification of the soybean hull allergens responsible for the Barcelona asthma
      outbreaks.
AB  - BACKGROUND: Soybean hulls were identified as the etiologic agent responsible for
      the asthma outbreaks that occurred in Barcelona and Cartagena, Spain. OBJECTIVE:
      To identify the main soybean hull allergens using the sera of 18 asthmatic
      epidemic patients from Barcelona and to compare the results to those previously
      reported. METHODS: Specific IgE to a soybean hull allergen extract was determined
      by radioimmunoassay and by sodium dodecyl sulfate-polyacrylamide gel
      electrophoresis (SDS-PAGE) in a 10-20% Tris-tricine gradient gel followed by
      Western blot. RESULTS: Specific IgE, which was detected in 15 of the 18 (83.3%)
      sera, indicated two nonoverlapping band patterns on the SDS-PAGE/Western blot:
      (1) pattern 1, present in 11 sera, consisted of three bands with estimated
      molecular weights (MWs) of 8, 7.5 and 7 kD, which are the MWs described for the
      allergens Gly m 2, Gly m 1A and Gly m 1B, respectively, and (2) pattern 2,
      present in 3 sera, consisted of a band with an estimated MW of 8.2-8.3 kD and
      four additional bands in a MW range of 25-36 kD. The remaining positive sera
      indicated very faint bands. CONCLUSIONS: This study confirms that soybean hulls
      contain three main allergens with MWs of 8, 7.5 and 7 kD, and indicates
      additional higher MW allergens, which selectively bind specific IgE of the sera
      that do not react with the three low MW components. This dichotomous and
      nonoverlapping pattern of allergen recognition has not been previously described.

PMID- 10341323
TI  - Correlation of lymphocyte proliferating cell nuclear antigen expression with
      dietary cow's milk antigen load in infants with allergy to cow's milk.
AB  - BACKGROUND: Controversial results have been reported on the participation and
      diagnostic value of lymphocyte reactivity in cow's milk (CM) allergy. In this
      study, we used a specific nuclear marker to evaluate lymphocyte proliferation in
      IgE-mediated CM allergy in infants, and examine its relation with diets
      containing different CM antigen loads. METHODS: Infants with IgE-mediated CM
      allergy, as assessed by open provocation and RAST, were grouped according to
      their exclusive diet, either CM formulae, breast feeding, or hydrolysed whey
      formulae. A group of non-atopic infants receiving CM was also examined.
      Lymphocyte proliferation to beta-lactoglobulin was evaluated by quantitation of
      the proliferating cell nuclear antigen (PCNA) expression in peripheral blood
      mononuclear cells, by flow cytometry. Immunophenotypic surface markers were also
      examined. RESULTS: A marked difference of PCNA expression between CM-fed allergic
      infants and healthy controls was observed (p<0.001). In this setting, PCNA
      expression >/=10% was highly specific and sensitive as a marker of CM allergy in
      CM-fed infants. Moreover, a significant correlation (p<0.001) between antigen
      load and PCNA was established in CM-allergic infants under different diets,
      higher values obtained with increasing antigen loads. In addition, within the
      group fed hydrolyzed formulae, low-molecular-weight products resulted in
      marginally lower PCNA expression than higher-molecular-weight formulae. No
      differences in immunophenotype were found, with the exception of a higher CD23
      expression in the breast-fed group. CONCLUSIONS: PCNA could be a useful marker in
      the assessment of lymphocyte proliferation to CM antigens. Low CM antigen diets
      are related with reduced lymphocyte reactivity, which may partly explain the
      clinical benefit observed with such diets.

PMID- 10341322
TI  - Chronic idiopathic urticaria: natural course and association with Helicobacter
      pylori infection.
AB  - BACKGROUND: Chronic urticaria is a common disease, though only few data on its
      natural course are available. In most cases the cause cannot be determined.
      Recently a relationship of chronic urticaria to infection with Helicobacter
      pylori (HP) has been postulated, but no controlled study has been performed to
      prove this association. METHODS: In this prospective study the clinical course
      and rate of HP infection in 46 patients with chronic 'idiopathic' urticaria were
      investigated. Infected patients were treated in a double-blind placebo-controlled
      crossover study with amoxycillin and lansoprazol. Eradication and clinical course
      were followed up 2 months after each treatment, respectively, 3 and 6 months
      after the first consultation. RESULTS: In 19/46 (41%) the chronic 'idiopathic'
      urticaria resolved within 6 months. 12 patients (24%) were infected with HP,
      which corresponds to the infection rate of the population at comparable ages
      without urticaria in Switzerland. Eradication of HP was achieved in 3, but only
      in 1 was the eradication associated with the resolution of urticaria.
      CONCLUSIONS: Our data show that in young patients with a rather short history of
      chronic urticaria frequently a rather favourable natural course of chronic
      idiopathic urticaria can be seen. No association between HP infection and chronic
      urticaria could be demonstrated.

PMID- 10341325
TI  - Images in allergy and immunology. Mast cell apoptosis.

PMID- 10341326
TI  - Genomic screening of blood donations - the new dawn arrives.

PMID- 10341327
TI  - Transmission rates of hepatitis C virus by different batches of a contaminated
      anti-D immunoglobulin preparation.
AB  - BACKGROUND AND OBJECTIVES: The aim of this study was to determine the hepatitis C
      virus (HCV) infection rate of recipients of different batches of anti-D
      immunoglobulin associated with an outbreak of HCV infection which occurred in
      1977 and its relationship to the polymerase chain reaction (PCR) status of the
      implicated batches. This study was undertaken to determine the predictive value
      of HCV genome detection and quantification for subsequent infection in recipients
      of an HCV-contaminated anti-D immunoglobulin product for intravenous use.
      MATERIALS AND METHODS: Sera from recipients of anti-D were tested by HCV enzyme
      immunoassay and if found positive were subsequently tested by recombinant
      immunoblot assay and HCV PCR in a national HCV anti-D screening programme set up
      in 1994. The HCV status of 1,342 known recipients of infectious or potentially
      infectious batches has been compared to the amount of HCV RNA in the anti-D batch
      they received so as to determine the value of PCR in the prediction of
      infectivity in immunoglobulin preparations. RESULTS: It has been demonstrated
      that HCV-infected plasma derived from batches of anti-D showing levels of viral
      genome in excess of 10(4) genomes per millilitre led to infection of up to 60% of
      recipients. In contrast, batches with undetectable levels of HCV genome very
      rarely transmitted infection. CONCLUSIONS: The presence of HCV RNA in intravenous
      immunoglobulin preparations which have not undergone a specific viral
      inactivation step is a predictor of HCV infection in recipients.

PMID- 10341328
TI  - Hepatic dysfunction in a population of antibody-deficient patients: prevalence,
      aetiology and outcome of PCR screening for hepatitis C and G viruses.
AB  - BACKGROUND AND OBJECTIVES: A group of 40 antibody-deficient patients receiving
      regular infusions of intravenous immunoglobulin underwent close monitoring in an
      attempt to identify hepatic dysfunction. The continuing risk of hepatitis virus
      transmission, especially hepatitis C virus via immunoglobulin products prompted
      this policy. We report our findings. METHODS: Screening included measurement of
      transaminase levels at each infusion. The patients were also tested for evidence
      of infection with hepatitis viruses B, C and G. RESULTS: Abnormal liver function
      tests were identified in 6 cases. However, a blood-borne viral aetiology was not
      found in any of these cases. Additional investigation allowed an alternative
      aetiology to be identified in most cases. One patient found to be positive for
      hepatitis G virus (HGV)-RNA by reverse transcriptase-polymerase chain reaction
      has no evidence to date of clinical problems as a result. INTERPRETATION: The
      results are reassuring in that definite iatrogenic hepatitis virus transmission
      has not been found in this cohort, despite long-term treatment with a wide range
      of immunoglobulin products. The source of infection of the single patient
      infected with HGV remains as uncertain as the pathogenic potential of this virus.
      However, as long as the risk of immunoglobulin-associated viral transmission
      continues, a strict monitoring programme such as ours should continue to
      facilitate prompt detection of cases with abnormal liver function. Liver
      dysfunction in this group requires full investigation and we cannot exclude
      infection with hitherto unidentified blood-borne viruses.

PMID- 10341329
TI  - Establishment of the first international standard for nucleic acid amplification
      technology (NAT) assays for HCV RNA. WHO Collaborative Study Group.
AB  - BACKGROUND AND OBJECTIVES: The aims of this study were the establishment of a WHO
      International standard for HCV RNA for nucleic acid amplification technology
      (NAT) assays and the determination of the HCV RNA content of the candidate
      standard. MATERIALS AND METHODS: Twenty-two laboratories evaluated three
      candidate materials (two lyophilised, AA and BB, which were derived from the same
      source and one a liquid preparation, CC). All samples were HCV genotype 1 with a
      concentration of approximately 10(5) genome equivalents/ml. The methods used
      included the Roche Amplicor assay (version 1), Chiron Quantiplex (bDNA) assay,
      Organon Teknika NASBA assay, Transcription Mediated assay and various in-house
      assays, using single or nested primers. RESULTS: There was reasonable agreement
      between the overall mean NAT detectable units/ml obtained by the different assays
      except for some of the in-house assays using single primers which gave
      substantially lower estimates. These titres were 5.0 log10 for samples AA and BB
      and 4.6 log10 for sample CC. CONCLUSIONS: Sample AA was accepted as the candidate
      standard and assigned a titre of 10(5) international units (IU)/ml. The
      International Standard consists of a batch of vials each containing 50,000
      IU/vial. Preliminary studies indicated that the material is stable at +4 degrees
      C and +20 degrees C for up to 200 days.

PMID- 10341330
TI  - Large-scale HCV RNA screening in first-time blood donors: the first step towards
      genomic screening of blood donations. HCV RNA Screening Study Group.
AB  - BACKGROUND AND OBJECTIVES: Individual genomic screening for viruses in blood
      donations is becoming increasingly pressing as an alternative to pool testing to
      improve the safety of the blood supply. MATERIALS AND METHODS: To determine the
      feasibility and, possibly, efficacy of genomic screening for hepatitis C virus
      (HCV) in the blood service setting, a representative population of first-time
      blood donors was screened individually with a semi-automated genomic
      amplification assay for HCV RNA. First-time blood donors in two blood centres in
      the United Kingdom were screened in parallel for anti-HCV and HCV RNA by RT-PCR.
      RESULTS: 8, 417 serum samples were screened. A 99.95% specificity was observed
      and one anti-HCV-positive, HCV-RNA-positive donation was found. No seronegative
      HCV-RNA-positive donations were detected. CONCLUSIONS: These results are
      consistent with the low prevalence of HCV infection in blood donors from the
      London area and demonstrate the high level of performance of the individual
      genomic screening method used in this study. When fully automated, such a method
      would be a highly suitable candidate for routine, automated genomic screening of
      HCV and, subsequently, of other pathogenic blood-borne viruses.

PMID- 10341331
TI  - Sensitivity of PCR assays for the determination of hepatitis A virus RNA in
      plasma pools. A collaborative study.
AB  - BACKGROUND AND OBJECTIVES: A collaborative study was organised to establish a
      hepatitis A virus (HAV) RNA standard for genomic amplification assays (GAT).
      MATERIALS AND METHODS: A panel of 10 samples consisting of a 10-fold serial
      dilution of wild-type HAV diluted in HAV-negative cryosupernatant and samples of
      the diluent were sent to 14 laboratories in duplicate for testing for HAV RNA by
      the polymerase chain reaction. RESULTS: Data returned by 12 laboratories
      indicated that the sensitivities of the assays performed by different
      laboratories were fairly close: there was a 100-fold difference in sensitivity
      between the majority of laboratories. Only one laboratory reported false-positive
      results. CONCLUSION: A 10-5 dilution of the virus in cryosupernatant could be an
      appropriate working reagent for GAT assays for HAV RNA in plasma pools.

PMID- 10341332
TI  - Prevalence of GBV C/HGV RNA and GBV C/HGV antibodies in French volunteer blood
      donors: results of a collaborative study.
AB  - BACKGROUND AND OBJECTIVES: Posttransfusion hepatitis still occurs at an incidence
      of about 1 in 118,000 for HBV and 1 in 220,000 for HCV. This collaborative study
      aimed to determine the prevalence of a novel flavivirus, GBV-C/HGV, even though
      its role in transfusion-associated hepatitis is uncertain. MATERIALS AND METHODS:
      GBV-C/HGV RNA was detected by PCR using either the Boehringer detection kit or by
      primers previously described. HGV antibodies were detected by a serological assay
      from Boehringer. RESULTS: The observed GBV-C/HGV RNA frequency was 3.4%. HGV
      antibodies occurred in 9.5% of donors. CONCLUSION: In our study, 12. 9% of the
      donors had been in contact with the GBV-C/HGV virus.

PMID- 10341333
TI  - Use of bovine viral diarrhoea virus as an internal control for amplification of
      hepatitis C virus.
AB  - BACKGROUND AND OBJECTIVES: Screening for hepatitis C virus (HCV) by polymerase
      chain reaction (PCR) will be mandatory for screening blood and plasma donors in
      Europe and elsewhere. This study describes an internally controlled, highly
      sensitive PCR method designed for screening blood donations in pools. MATERIAL
      AND METHODS: RNA extracted from bovine viral diarrhoea virus (BVDV) was used as
      an internal control to monitor the efficiency of extraction, reverse
      transcription and amplification steps in HCV PCR. RESULTS: Sensitivity of PCR for
      single molecules of HCV in the presence of 33 genome equivalents of BVDV RNA was
      achieved by reducing the efficiency of BVDV amplification. BVDV could be
      recovered at high efficiency from large volume pools (2-5 ml) by
      ultracentrifugation and by the NucliSens extraction method. CONCLUSION: Detection
      of BVDV validates the extraction, reverse transcription and amplification methods
      used for HCV detection in plasma pools and provides valuable quality assurance
      for negative results.

PMID- 10341334
TI  - A second outbreak of hepatitis C virus infection from anti-D immunoglobulin in
      Ireland.
AB  - OBJECTIVE: To investigate the infectivity for hepatitis C virus (HCV) of
      intravenous anti-D immunoglobulin batches manufactured in Ireland between 1991
      and 1994. METHODS: Women who had received anti-D manufactured between 1991 and
      1994 were screened for serological markers of HCV infection and for the presence
      of HCV RNA by RT-PCR amplification and virus genotyping. RESULTS: 44 women
      exposed to anti-D manufactured between 1991 and 1994 were polymerase chain
      reaction positive for HCV RNA, 19 of whom were infected with genotype 3a virus
      shown by phylogenetic analysis of the NS5B gene to be closely related to that
      from the single implicated donor. CONCLUSIONS: Anti-D manufactured in 1991-1994
      transmitted infection of HCV genotype 3a. The prevalence of HCV-specific antibody
      in anti-D recipients was relatively low (0.59%), consistent with the low level of
      virus RNA in these anti-D batches.

PMID- 10341335
TI  - Removal and inactivation of hepatitis B virus from contaminated pooled plasma in
      a large-scale manufacturing process for factor VIII and human serum albumin.
AB  - BACKGROUND AND OBJECTIVES: The Japanese Red Cross Society recalled one lot of
      monoclonal-antibody-purified factor VIII (F VIII) and two lots of human serum
      albumin (HSA) 5 months after preparation of the final products, because of a
      procedural error that led to contamination by a unit of plasma positive for
      hepatitis B surface antigen (HBsAg). We evaluated the effectiveness of virus
      inactivation/removal in a large-scale process for manufacturing F VIII and HSA.
      MATERIALS AND METHODS: HBV DNA in the retained samples in process was measured by
      the polymerase chain reaction (PCR). The kinetics of virus inactivation by
      solvent-detergent (S/D) treatment was examined using model viruses. We also did a
      look-back survey of the patients who received corresponding products. RESULTS:
      Contaminated hepatitis B virus (HBV) DNA became undetectable beyond fraction S IV
      I in the albumin process and immunoaffinity chromatography in the F VIII process,
      respectively. The model viruses were inactivated within 5 s by S/D treatment.
      There is no evidence that patients were infected by HBV after transfusion of
      these products. CONCLUSION: We conclude that virus inactivation/removal was
      effectively achieved in a large-scale manufacturing process for F VIII and HSA.

PMID- 10341336
TI  - Comparison of four HTLV-I and HTLV-I + II ELISAs.
AB  - BACKGROUND: Various countries require blood donor screening using assays applying
      specific HTLV-I and HTLV-II antigens. We evaluated the sensitivity and
      specificity of 4 anti-HTLV-I + II ELISAs (Abbott, Murex, Organon Teknika and
      Ortho). METHODS: Panel A consisted of HTLV-I-positive individuals (n = 41), panel
      B of Mixed Titer Performance Panel 204 (Boston Biomedica Inc. panels C and D of
      dilution series from HTLV-I-positive (n= 30) and HTLV-II-positive (n =20)
      individuals and panel E of sera from first-time blood donors (n = 1,055).
      RESULTS: In HTLV-I- and -II-positive samples, a sensitivity of 100% could be
      observed in all 4 ELISAs. In diluted HTLV-I- and -II-positive samples, probit
      analysis revealed that the Murex assay had the highest analytical sensitivity,
      followed by the ELISAs from Ortho, Abbott and Organon Teknika. In specimens from
      first-time donors, a specificity of 100% was observed in ELISAs from Murex,
      Organon Teknika and Ortho, and of 99.7% in the assay from Abbott. CONCLUSION: The
      4 anti-HTLV-I + II ELISAs studied were appropriate as screening tests.

PMID- 10341337
TI  - Persistence of HCV-RNA in a blood donor with negative antibody assays.

PMID- 10341338
TI  - Nucleic acid amplification tests for the detection of blood-borne viruses. 5th
      EPFA/NIBSC Workshop, Amsterdam 1998.

PMID- 10341339
TI  - [Usefulness of a pharmacokinetic approach for clinical antineoplastic
      chemotherapy evaluation].
AB  - Pharmacokinetics, which is the study of the drug becoming in the body, is an
      important approach of new drug evaluation. Anticancer drugs have mostly a very
      narrow therapeutic index which leads to a delicate clinical use. Pharmacokinetics
      permits the prediction of the occurrence of iatrogenic toxicities taking into
      account the interpatient variability of the pharmacokinetic parameters.

PMID- 10341340
TI  - [Cell cycle regulation after exposure to ionizing radiation].
AB  - When cells are exposed to ionizing radiation, they initiate a complex response
      that includes the arrest of cell cycle progression in G1 and G2, apoptosis and
      DNA repair. DNA is an important subcellular target of ionizing radiation, but
      oxydative damage to plasma membrane lipids initiates signal transduction pathways
      that activate apoptosis and that may play a role in cell cycle regulation. How is
      DNA damage converted into intracellular signals for cell cycle arrest? The ataxia
      telangectasia mutant (ATM) protein and/or the DNA-dependent protein kinase (DNA
      PK), that are both activated by DNA damage, may initiate cell cycle arrest by
      activating the p53 tumor suppressor protein. The p53 protein acts as a
      transcription factor and regulates expression of several components implicated in
      pathways that regulate cell cycle progression. The best known, p21WAF1/CIP1
      protein, is an inhibitor of cyclin-dependent kinases (CDK), a family of protein
      kinases known as key regulators of cell cycle progression. p21WAF1/CIP1 was shown
      to be able to inhibit several CDK, but is most effective toward G1/S cyclins.
      Other CDK inhibitors, p27KIP1 and p15INK4b are activated by irradiation and
      contribute to the G1 arrest. Moreover, radiation-induced G2 arrest was shown to
      require inhibitory phosphorylation of the kinase cdc2 via an ATM-dependent
      pathway. Mutations in cell cycle regulatory genes are common in human cancer and
      cell cycle regulatory deficiency can lead to increase resistance to ionizing
      radiation in cancer cells. The major function of p53-dependent G1 arrest may be
      elimination of cells containing DNA damage whereas G2 arrest following radiation
      has been shown to be important in protecting cells from death. Cell cycle
      checkpoints offer a new set of potential targets for chemotherapeutic compounds,
      especially the G2 checkpoint. Thus, abrogation of the G2 checkpoint with
      methylxanthines such as caffeine or protein kinase inhibitors such as
      staurosporine and UCN-01 (7-hydroxystaurosporine) was found to sensitize cells to
      ionizing radiation. These data did not lead to clinical applications, but confirm
      targeting of the G2 checkpoint may be an important strategy for cancer therapy.

PMID- 10341341
TI  - [Mechanisms of BTG2 activity, a transcriptional target of p53: evidences and
      hypothesis].
AB  - The human BTG2 gene is one of the four members of a newly identified
      antiproliferative genes family. BTG2 was first described as an immediate early
      gene whose expression is induced in response to mitogenic as well as
      differentiative and antiproliferative factors. More recently, we have shown that
      BTG2 expression is also induced in response to genotoxic stress through a p53
      dependent mechanism. Experimental overexpression of the BTG2 gene in NIH3T3 and
      PC12 cells leads to a partial inhibition of cell proliferation. BTG2 protein
      physically interacts with the protein CAF1, an element of a general transcription
      complex, and with a protein-arginine N-methyl transferase, PRMT1. We speculate on
      the role of BTG2 as a modulator of the intracellular signal transduction cascade.

PMID- 10341342
TI  - [Standards, options and recommendations (SOR) for clinical care of malignant
      thymoma. Groupe de Travail SOR].
AB  - CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in
      1993, is a collaboration between the Federation of the French Cancer Centres
      (FNCLCC), the 20 French Cancer Centres and specialists from French Public
      Universities, General Hospitals and Private Clinics. The main objective is the
      development of clinical practice guidelines to improve the quality of health care
      and outcome for cancer patients. The methodology is based on literature review
      and critical appraisal by a multidisciplinary group of experts, with feedback
      from specialists in cancer care delivery. OBJECTIVES: To develop clinical
      practice guidelines according to the definitions of Standards, Options and
      Recommendations for the clinical care of malignant thymoma in adult. METHODS:
      Data have been identified by literature search using Medline (december 1998) and
      the expert groups personal reference lists. Once the guidelines were defined, the
      document was submitted for review to national and international independent
      reviewers, and to the medical committees of the 20 French Cancer Centres.
      RESULTS: The main recommendations for malignant thymoma management are that: 1)
      the clinical diagnosis is based on appropriate clinical and radiological
      findings; 2) the final diagnosis is pathological and made from a biopsy, except
      in cases of well-encapsulated tumors which are completely resected. The biopsy,
      via anterior mediastinostomy, should be performed by the surgeon who will
      subsequently perform the definitive surgery; 3) surgical resection must be
      complete including thymus and perithymic fat and performed by an experienced
      surgeon; 4) the therapeutic strategy for malignant thymoma is based on the three
      current staging systems and involves surgery with radiotherapy given if the
      capsule is invaded or penetrated. Radiotherapy should be given in experienced
      centres. Inclusion of patients in prospective clinical trials is recommended in
      order to determine the usefulness of neoadjuvant chemotherapy and multimodality
      approaches; 5) treatment of metastatic malignant thymoma is based on
      chemotherapy. Secondary surgery may be performed with the aim of achieving
      complete resection. Inclusion in clinical trials is recommended; 6) at the
      present time, there are no clear data on which to base guidelines for timing and
      duration of follow-up studies in this condition. Because of late recurrence,
      follow-up should be long.

PMID- 10341343
TI  - [Mutation by deletion-insertion in BRCA-1 gene in three unrelated French
      breast/ovarian cancer families: possible implication of a mobile element].
AB  - A new type of mutation by deletion-insertion in BRCA-1 gene is found in three
      unrelated French breast/ovarian cancer families. Surprisingly, deletion and
      insertion occurred at the same nucleotide position at the end of exon 11
      (3958del5ins4), thus generating a truncated protein. This original mutation
      consists in a deletion of 5 bp (CTCAG) and in an insertion of 4 different bp
      (AGGC). Here, we proposed two hypothesis to explain this phenomenom. The first
      hypothesis is the formation of a hairpin stem-loop structure comprising the
      mutational site and the sequence corresponding to the duplication insertion 2
      nucleotides before the mutation. The second hypothesis, more speculative,
      consists in an abortive integration of a human mobile element as a human
      transposon (tigger 1) which involved a deletion of 5 bp during its excision and
      an insertion of 4 bases corresponding to the 5' extremity of the transposon.

PMID- 10341344
TI  - [High dose chemotherapy with autologous stem cell support in the treatment of
      germ cell tumors: experience of the centre Leon-Berard between 1982 and 1996].
AB  - More than 80% patients with metastatic germ cell tumors are cured by chemotherapy
      and surgery. Since 1980, intensive chemotherapy with autologous bone marrow was
      developed for the patients who where not cured by conventional chemotherapy. We
      present the experience of the Centre Leon-Berard, between 1982 and 1996, seventy
      five metastatic germ cell tumors patients were treated with high dose
      chemotherapy and autologous stem cell support. Forty-six patients received
      cisplatin, etoposide, ifosfamide (VIC regimen), 17 carboplatin, etoposide,
      cyclophosphamide (CarboPEC regimen), 9 cisplatin, etoposide, cyclophosphamide
      (PEC) and 10 had another regimen. The chemotherapy was administred in different
      situations: 31 patients with poor prognosis in first line, 15 in salvage of
      sensitive relapse, 15 in salvage of incomplete response, and 14 with a cisplatin
      refractory disease. The complete response rate was 31% among the 54 evaluable
      patients. Seven patients died as a consequence of the treatment. The two-year
      overall actuarial survival and the event free survival were respectively 67% and
      57% (median 42 months). Only 2 patients who had a refractory disease are
      continuously disease-free at 42 and 87 months after regimen. The renal toxicity
      was more severe with regimen VIC than with CarboPEC 30% versus 60%, whereas the
      hematologic toxicity are similar with both. This study shows the feasability of
      high dose chemotherapy. Two refractory patients are alive, and the results seem
      to be interesting for the patients in salvage treatment. But this treatment is
      not a standard for germinal cell tumors and randomized trials are ongoing.

PMID- 10341346
TI  - Asthma in the developing world.

PMID- 10341345
TI  - HIV-1 subtype F in single and dual infections in Puerto Rico: A potential
      sentinel site for monitoring novel genetic HIV variants in North America.

PMID- 10341347
TI  - The importance of successful passage.

PMID- 10341348
TI  - To do or not to do? That is the question. Pediatric constipation.

PMID- 10341349
TI  - Organic causes of constipation in infants and children.

PMID- 10341350
TI  - Functional constipation: a radiologist's perspective.

PMID- 10341351
TI  - Movers and shakers: a clinician's guide to laxatives.

PMID- 10341352
TI  - Constipation: physical and psychological sequelae.

PMID- 10341353
TI  - Encopresis in the child with a behavioral disorder: when the initial treatment
      does not work.
AB  - Behavioral disorders occur more commonly in children who fail the initial
      standard treatment protocol of cathartics and designated toileting time. Whether
      such disorders are causally related or the result of encopresis, these children
      require a much more intensive, multimodal therapy. Treatment failures should have
      an in-depth history that reviews the potential developmental, emotional,
      behavioral, and psychosocial issues that may be causative. Use of the treatment
      protocols that have been outlined in this article can be time-consuming and will
      often require the help of a behavioral therapist. However, if they are
      successfully implemented, research shows that positive behavioral changes
      frequently occur in the child. The pediatrician can be instrumental in preventing
      long-term family, emotional, and social consequences by aggressively treating
      these difficult cases.

PMID- 10341354
TI  - Defecation disorders in the neurologically impaired child.

PMID- 10341355
TI  - Resident's column. Pediatric constipation.

PMID- 10341356
TI  - Is there a future for neuropeptide receptor ligands in the treatment of anxiety
      disorders?
AB  - This review provides an overview of preclinical and clinical evidence of a role
      for the neuroactive peptides cholecystokinin (CCK), corticotropin-releasing
      factor (CRF), neuropeptide Y (NPY), tachykinins (i.e., substance P, neurokinin
      [NK] A and B), and natriuretic peptides in anxiety and/or stress-related
      disorders. Results obtained with CCK receptor antagonists in animal studies have
      been highly variable, and clinical trials with several of these compounds in
      anxiety disorders have been unsuccessful so far. However, future investigations
      using CCK receptor antagonists with better pharmacokinetic characteristics and
      animal models other than those validated with the classical anxiolytics
      benzodiazepines may permit a more precise evaluation of the potential of these
      compounds as anti-anxiety agents. Results obtained with peptide CRF receptor
      antagonists in animal models of anxiety convincingly demonstrated that the
      blockade of central CRF receptors may yield anxiolytic-like activity. However,
      the discovery of nonpeptide and more lipophilic CRF receptor antagonists is
      essential for the development of these agents as anxiolytics. Similarly, there is
      clear preclinical evidence that the central infusion of NPY and NPY fragments
      selective for the Y1 receptor display anxiolytic-like effects in a variety of
      tests. However, synthetic nonpeptide NPY receptor agonists are still lacking,
      thereby hampering the development of NPY anxiolytics. Unlike selective NK1
      receptor antagonists, which have variable effects in anxiety models, peripheral
      administration of selective NK2 receptor antagonists and central infusion of
      natriuretic peptides produce clear anxiolytic-like activity. Taken as a whole,
      these findings suggest that compounds targeting specific neuropeptide receptors
      may become an alternative to benzodiazepines for the treatment of anxiety
      disorders.

PMID- 10341357
TI  - The perturbation of apoptosis and mitosis by drugs and xenobiotics.
AB  - Drugs such as the barbiturate phenobarbitone and fibrate hypolipidaemic agents,
      in addition to a range of chemicals of environmental and industrial significance,
      are able to perturb rodent tissue homeostasis, leading to tissue enlargement.
      Many of these xenobiotics are rodent nongenotoxic carcinogens since they do not
      damage DNA, yet cause tumours in the rat and mouse. These nongenotoxic
      carcinogens display both species and tissue specificity; for example, rat and
      mouse hepatocytes display S-phase induction and a suppression of apoptosis in
      response to drugs such as phenobarbitone or the hypolipidaemic peroxisome
      proliferators (PPs). In contrast, human hepatocytes or other types of rodent
      cells are refractory to these effects. However, in the absence of a discrete
      mechanism of action, the clear species differences preclude extrapolation of
      rodent data to provide an accurate human risk assessment. Recent data have
      demonstrated that PPs activate the PP-activated receptor alpha in rodent liver,
      leading to enzyme induction, stimulation of S-phase, and a suppression of
      apoptosis. How these acute effects may lead to hepatocarcinogenesis and the
      relevance of this for humans will be discussed.

PMID- 10341358
TI  - Hypoxia and neuronal function under in vitro conditions.
AB  - Neurons in the mammalian CNS are highly sensitive to the availability of oxygen.
      Hypoxia can alter neuronal function and can lead to neuronal injury or death. The
      underlying changes in the membrane properties of single neurons have been studied
      in vitro in slice preparations obtained from various brain areas. Hypoxic changes
      of membrane potential and input resistance correspond to a decrease in ATP
      concentration and an increase in internal Ca2+ concentration. Functional
      modifications consisting of substantial membrane depolarization and failure of
      synaptic transmission can be observed within a few minutes following onset of
      hypoxia. The hypoxic depolarization accompanied by a hyperexcitability is a
      trigger signal for induction of neuronal cell death and is mediated mainly by
      activation of glutamate receptors. The mechanisms of the hypoxic
      hyperpolarization are more complex. Two types of potassium channels contribute to
      the hyperpolarization, the Ca(2+)- and the ATP-activated potassium channel. A
      number of neurotransmitters and neuromodulators is involved in the preservation
      of normal cell function during hypoxia. Therefore, hypoxia-induced cellular
      changes are unlikely to have a single, discrete pathway. The complexity of
      cellular changes implies that several strategies may be useful for
      neuroprotection and a successful intervention may be dependent upon drug action
      at more than one target site.

PMID- 10341359
TI  - The cannabinoid acids: nonpsychoactive derivatives with therapeutic potential.
AB  - The discovery of carboxylic acid metabolites of the cannabinoids (CBs) dates back
      more than three decades. Their lack of psychotropic activity was noted early on,
      and this resulted in a total absence of further research on their possible role
      in the actions of the CBs. More recent studies have revealed that the acids
      possess both analgesic and anti-inflammatory properties and may contribute to the
      actions of the parent drug. A synthetic analog showed similar actions at
      considerably lower doses. In this review, a brief survey of the extensive
      literature on metabolism of delta 9-tetrahydrocannabinol to the acids is
      presented, while more emphasis is given to the recent findings on the biological
      actions of this class of CBs. A possible mechanism involving effects on
      eicosanoids for some of these actions is also suggested. Finally, an analogy with
      a putative metabolite of anandamide, an endogenous CB, is discussed.

PMID- 10341360
TI  - Therapeutic aspects of polymorphic epithelial mucin in adenocarcinoma.
AB  - The gene MUC1 encodes a large membrane-associated glycoprotein, previously termed
      polymorphic epithelial mucin and now known as MUC1. The majority of the
      extracellular domain is made up of tandem repeats of 20 amino acids. In some
      epithelial malignancies, MUC1 is up-regulated, and as a result of changes in
      glycosyl and sialytransferases, the complex carbohydrate side chains are
      truncated, leading to exposure of novel peptide and carbohydrate epitopes.
      Cellular and humoral immune responses to MUC1 have been documented in malignant
      disease, and T-cell responses to MUC1 may not depend on presentation by the major
      histocompatibility complex. Several immunogens based on MUC1 are being
      investigated. These include cell lines expressing MUC1 given alone or fused with
      professional antigen-presenting cells and peptide epitopes, given either with
      conventional immunological adjuvants or coupled to mannan, which may target
      uptake into antigen-presenting cells. Cellular and humoral immune responses to
      these agents have been recorded in patients with advanced malignancy. Targeting
      of peptide epitopes may also be achieved using antibodies to MUC1 through
      induction of idiotypes and retrospective analyses in ovarian cancer have
      suggested a survival benefit for patients. The use of cDNA in coding MUC1 may
      allow endogenous processing of antigen. Phase I studies using vaccinia as a
      vector have been completed. Studies using carbohydrate antigens suggest that the
      ability to generate specific immune responses may influence survival of patients
      with metastatic epithelial malignancies. While examining the potential role of
      immunogens based on MUC1, it is also necessary to understand the nature of
      immunosuppression in patients with advanced malignancy in order to develop
      strategies to enhance the immunogenicity of potential cancer vaccines.

PMID- 10341361
TI  - The Ca2+/calmodulin signaling system in the neural response to excitability.
      Involvement of neuronal and glial cells.
AB  - Ca2+ plays a critical role in the normal function of the central nervous system.
      However, it can also be involved in the development of different
      neuropathological and neurotoxicological processes. The processing of a Ca2+
      signal requires its union with specific intracellular proteins. Calmodulin is a
      major Ca(2+)-binding protein in the brain, where it modulates numerous Ca(2+)
      dependent enzymes and participates in relevant cellular functions. Among the
      different calmodulin-binding proteins, the Ca2+/calmodulin-dependent protein
      kinase II and the phosphatase calcineurin are especially important in the brain
      because of their abundance and their participation in numerous neuronal
      functions. We present an overview on different works aimed at the study of the
      Ca2+/calmodulin signalling system in the neural response to convulsant agents.
      Ca2+ and calmodulin antagonists inhibit the seizures induced by different
      convulsant agents, showing that the Ca2+/calmodulin signalling system plays a
      role in the development of the seizures induced by these agents. Processes
      occurring in association with seizures, such as activation of c-fos, are not
      always sensitive to calmodulin, but depend on the convulsant agent considered. We
      characterized the pattern of expression of the three calmodulin genes in the
      brain of control mice and detected alterations in specific areas after inducing
      seizures. The results obtained are in favour of a differential regulation of
      these genes. We also observed alterations in the expression of the
      Ca2+/calmodulin-dependent protein kinase II and calcineurin after inducing
      seizures. In addition, we found that reactive microglial cells increase the
      expression of calmodulin and Ca2+/calmodulin-dependent protein kinase II in the
      brain after seizures.

PMID- 10341362
TI  - The role of microglia and macrophages in the pathophysiology of the CNS.
AB  - Microglia are a major ghal component of the central nervous system (CNS) and are
      extremely sessile. Only a subtype, the perivascular microglia, are regularly
      replaced from the bone marrow in adult animals. Microglia respond to virtually
      any, even minor pathological events in the CNS. In most pathological settings
      microglia are aided by infiltrating hematogenous macrophages. Upon activation
      microglia and macrophages share most phenotypical markers and can exert similar
      effector functions. After transection of a CNS fibre tract microglia are
      insufficiently activated and hematogenous macrophages do not significantly enter
      the degenerating nerve stump. Thereby myelin debris that contains neurite
      outgrowth inhibiting activity persists for long time. This is in sharp contrast
      to the peripheral nervous system in which hematogenous macrophages are rapidly
      recruited in response to axotomy and clear myelin debris allowing regrowth of
      axons from the proximal stump. However, CNS lesion paradigms with breakdown of
      the blood-brain barrier such as cerebral ischemia, brain abscesses and stab
      wounds elicit prompt microglial activation, macrophage recruitment and debris
      clearance. There is increasing evidence that microglia play an active part in
      degenerative CNS diseases. In Alzheimer's disease activated microglia appear to
      be involved in plaque formation. In experimental globoid cell dystrophy T-cell
      independent induction of major histocompatibility complex class II molecules on
      microglia accelerates demyelination. In autoimmune diseases microglia probably
      have dual functions. Microglia present antigen to infiltrating T cells and exert
      effector functions thereby locally augmenting immune responses. On the other
      hand, microglia have the capacity to downregulate T cell responses. In the human
      acquired immunodeficiency syndrome (AIDS) virus infected macrophages probably
      introduce the virus to the CNS and in concert with microglia are involved in the
      pathophysiology of the AIDS dementia complex.

PMID- 10341363
TI  - The role of basal forebrain neurons in tonic and phasic activation of the
      cerebral cortex.
AB  - The basal forebrain and in particular its cholinergic projections to the cerebral
      cortex have long been implicated in the maintenance of cortical activation. This
      review summarizes evidence supporting a close link between basal forebrain
      neuronal activity and the cortical electroencephalogram (EEG). The anatomy of
      basal forebrain projections and effects of acetylcholine on cortical and thalamic
      neurons are discussed along with the modulatory inputs to basal forebrain
      neurons. As both cholinergic and GABAergic basal forebrain neurons project to the
      cortex, identification of the transmitter specificity of basal forebrain neurons
      is critical for correlating their activity with the activity of cortical neurons
      and the EEG. Characteristics of the different basal forebrain neurons from in
      vitro and in vivo studies are summarized which might make it possible to identify
      different neuronal types. Recent evidence suggests that basal forebrain neurons
      activate the cortex not only tonically, as previously shown, but also phasically.
      Data on basal forebrain neuronal activity are presented, clearly showing that
      there are strong tonic and phasic correlations between the firing of individual
      basal forebrain cells and the cortical activity. Close analysis of temporal
      correlation indicates that changes in basal forebrain neuronal activity precede
      those in the cortex. While correlational, these data, together with the
      anatomical and pharmacological findings, suggest that the basal forebrain has an
      important role in regulating both the tonic and the phasic functioning of the
      cortex.

PMID- 10341364
TI  - Global ischemia and behavioural deficits.
AB  - Global cerebral ischemia in rodents is an established model in experimental
      research on cerebral ischemia which is characterized morphologically by a
      selective neuronal damage in the hippocampus, striatum and cortex. Using this
      model many studies have been performed to examine the pathophysiology of ischemic
      neuronal damage. Based upon these results it has been analysed whether substances
      which interact with the pathophysiological processes reduce the ischemic neuronal
      damage. Besides the morphological changes global ischemia leads to functional
      changes which can be assessed by behavioural studies. The Morris water maze
      examines the animals' abilities to learn, remember and go to a place in space
      only defined by its position relative to distal extramaze cues. In this test
      ischemic animals display a deficit in spatial learning as revealed by an increase
      in latency and in swim distance in the escape trials and a deficit in spatial
      memory as shown by reduced quadrant time and crossings over the former platform
      position during the probe trial. In several studies it could be demonstrated that
      neuroprotective strategies which reduce ischemic neuronal damage also attenuate
      or even completely prevent the ischemia-induced behavioural deficits in the water
      maze. Transplantation of fetal tissue which can also be used to achieve
      morphological recovery following global ischemia results in an amelioration of
      the ischemia-induced deficit. Thus, the water maze can clearly show that
      transplanted tissue can be functionally relevant. Data from the water maze seem
      to be a valuable completion to morphology which is especially important with
      respect to the relevance of experimental studies for clinical trials.

PMID- 10341365
TI  - The immune-inflammatory pathophysiology of fibromyalgia: increased serum soluble
      gp130, the common signal transducer protein of various neurotrophic cytokines.
AB  - Fibromyalgia is a chronic, painful musculoskeletal disorder characterized by
      widespread pain, pressure hyperalgesia, morning stiffness and by an increased
      incidence of depressive symptoms. The etiology, however, has remained elusive.
      The aim of the present study was to examine the inflammatory response system
      (IRS) in fibromyalgia. Serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL
      6R), sgp130, sIL-1R antagonist (IL-1RA) and sCD8 were determined in 33 healthy
      volunteers and in 21 fibromyalgia patients, classified according to the American
      College of Rheumatology criteria. Severity of illness was measured with several
      pain scales, dolorimetry and the Hamilton Depression Rating Scale (HDRS). Serum
      sgp130 was significantly higher and serum sCD8 significantly lower in
      fibromyalgia patients than in healthy volunteers. Serum sIL-6R and sIL-1RA were
      significantly higher in fibromyalgia patients with an increased HDRS score (> or
      = 16) than in normal volunteers and fibromyalgia patients with a HDRS score < 16.
      In fibromyalgia patients, an important part of the variance in sCD8 (50.3%) and
      IL-1RA (19.3%) could be explained by the HDRS score; 74.3% of the variance in sIL
      6R was explained by the combined effects of pain symptoms and the HDRS score; and
      25.9% of the variance in serum sgp130 was explained by stiffness. The results
      support the contention that pain and stiffness in fibromyalgia may be accompanied
      by a suppression of some aspects of the IRS and that the presence of clinically
      significant depressive symptoms in fibromyalgia is associated with some signs of
      IRS activation.

PMID- 10341366
TI  - Effects of Alzheimer's disease and gender on the hypothalamic-pituitary-adrenal
      axis response to lumbar puncture stress.
AB  - Differences in hypothalamic-pituitary-adrenal (HPA) axis responsiveness to lumbar
      puncture (LP) stress were studied in normal elderly subjects and Alzheimer's
      disease (AD) patients of both genders. Elderly normal subjects had larger peak
      cortisol and ACTH responses than AD patients. These results contrast with some
      previous reports of increased HPA-axis responsivity associated with AD and
      suggest that AD-related changes in HPA responsiveness depend on the type of
      stressor involved and are mediated 'upstream' to the final common pathway to ACTH
      secretion. HPA-axis responsiveness also differed by gender, with higher peaks and
      prolonged elevations in elderly female subjects than in elderly males.

PMID- 10341367
TI  - Intravenous injections of nicotine decrease the pulsatile secretion of LH by
      inhibiting the gonadotropin-releasing hormone (GnRH) pulse generator activity in
      female rats.
AB  - Whether nicotine inhibits the electrical activity of the gonadotropin-releasing
      hormone (GnRH) pulse generator to suppress pulsatile LH secretion, and whether
      this suppression of LH secretion by nicotine is mediated by opioid neurons, were
      studied in ovariectomized rats by examining changes in LH secretion and the
      multiunit activity (MUA) of the medial basal hypothalamus. Intravenous (i.v.)
      injection of nicotine (nicotine bitartrate, 100 micrograms) significantly
      increased the interval between characteristic increases (volleys) in MUA and LH
      pulses. This inhibitory effect of nicotine on the GnRH pulse generator activity
      was not blocked by the prior injection of an opiate receptor antagonist naloxone
      (naloxone hydrochlolide, 2 mg/kg bw), which was effective in significantly
      decreasing the interval between MUA volleys. The results suggest that nicotine
      alters the activity of the GnRH pulse generator, and that cholinergic neurons
      appear to be directly involved in suppressing pulsatile secretion of LH.

PMID- 10341369
TI  - Activating effects of cross-sex hormones on cognitive functioning: a study of
      short-term and long-term hormone effects in transsexuals.
AB  - In an earlier study we demonstrated that 3 months of cross-sex hormone treatment
      clearly influenced cognitive functioning in transsexuals. The aims of the present
      study were to examine: (a) whether we could replicate these findings in a new
      group of transsexuals; (b) whether a similar pattern of change could be found for
      novel tasks, i.e. tasks, not used in the previous study, that measured closely
      related cognitive abilities; (c) whether the cognitive changes following cross
      sex hormone treatment had stabilized after 3 months or continued to develop over
      a period of 1 year; and finally, (d) whether the effects were quickly reversible
      when the hormone treatment was temporarily stopped. Again a pronounced effect of
      androgen treatment was found on spatial ability in female-to-male transsexuals
      (FMs) over a period of one and a half years. As expected, untreated male-to
      female transsexuals (MFs) had higher scores on visuo-spatial tasks than untreated
      FMs; after 3 months of cross-sex hormone treatment, the group difference had
      disappeared, while after about 10 months of hormone treatment, the sex difference
      was reversed. These effects did not disappear after termination of cross-sex
      hormone therapy for a period of 5 weeks, but continued to change slightly in the
      same direction. Earlier findings of an opposite effect of cross-sex hormones on
      verbal fluency (i.e. MFs improved and FMs deteriorated after 3 months of cross
      sex hormone treatment) were not replicated in this study, nor did we find an
      hormonal influence on other cognitive functions. This study shows that
      testosterone had an enhancing, and not quickly reversible effect, on spatial
      ability performance, but no deteriorating effect on verbal fluency in adult women
      (FMs). In contrast, anti-androgen treatment in combination with estrogen therapy
      had no declining effect on spatial ability, nor an enhancing effect on verbal
      fluency in adult men (MFs).

PMID- 10341368
TI  - Blockade of the anxiolytic-like action of ipsapirone and buspirone, but not that
      of 8-OH-DPAT, by adrenalectomy in male rats.
AB  - The effect of the 5-HT1A agonists ipsapirone (5 mg/kg), buspirone (5 mg/kg) and 8
      OH-DPAT (0.5 mg/kg) on experimental anxiety was examined in sham-operated,
      adrenalectomized and adrenally demedullated male rats. The animal model of
      anxiety used was the defensive burying test. At the doses selected, all 5-HT1A
      compounds produced an anxiolytic-like action by reducing the burying behavior in
      both sham-operated and demedullated rats. However, in adrenalectomized subjects,
      while 8-OH-DPAT still reduced burying behavior, ipsapirone and buspirone lost
      their action. Data suggest that adrenocortical secretions play a role in the
      anxiolytic-like actions of buspirone and ipsapirone, but not in those of 8-OH
      DPAT. Buspirone and ipsapirone also produced a reduction in burying behavior
      latency in sham-operated animals that was not observed in adrenalectomized or
      adrenally demedullated rats. These data suggest that adrenaline may be
      participating in the action of these compounds on the burying behavior latency.
      Present findings support possible direct relationships between the stimulation of
      5-HT1A receptors and adrenal secretions.

PMID- 10341370
TI  - Menstrual synchrony in a sample of working women.
AB  - Menstrual synchrony has been typically studied among women who live together:
      dormitory roommates or family members sharing a bedroom or living in the same
      house. The current study examined menstrual synchrony in 51 pairs of women
      working together under conditions optimally conducive to synchrony. They had been
      together for at least 1 year, shared a relatively small office, worked there all
      day full time and contact with other people during the day was minimal.
      Prospective records of three menstrual dates showed a significant degree of
      synchrony for each of the 3 months. Menstrual onsets of close friends tended to
      occur on the average within 3.5-4.3 days of each other while onsets of co-workers
      who were not close friends were significantly more broadly ranged (7.7-9.0 days
      of each other). This is the first unequivocal demonstration of menstrual
      synchrony outside of the household.

PMID- 10341371
TI  - Effects of acute prednisone administration on memory, attention and emotion in
      healthy human adults.
AB  - We conducted a double-blind study in order to examine the effects of high doses
      of prednisone on memory, attention and emotion in humans. A total of 24 healthy
      undergraduate males self-administered either 160 mg of prednisone (n = 12) or a
      placebo (n = 12) for 4 consecutive days. We examined group differences in mood,
      regional brain electrical activity (EEG), the startle eyeblink response, memory
      recall and performance on an attention task after 4 days of treatment. We found
      significant group differences on measures of mood and frontal EEG alpha activity
      on 4-day treatment. Subjects treated with prednisone exhibited a significantly
      greater increase in self-reported negative emotion and greater relative right
      frontal EEG alpha activity on 4-day treatment compared with adults in the placebo
      group. We also found that subjects treated with prednisone recalled fewer objects
      on the memory task following treatment. No significant group differences were
      found on posterior EEG activity, the startle eyeblink measure, or the attention
      measure. These findings suggest that administration of high doses of exogenous
      prednisone may facilitate the experience of negative emotion and shifts in
      frontal EEG activity, and impair some aspects of cognitive functioning in humans.
      The multiple roles of glucocorticoids in memory, attention and emotion are
      discussed.

PMID- 10341372
TI  - [Synchronization between preverbal vocal behavior and motor action in early
      infancy. II: An acoustical examination of the functional significance of the
      synchronization].
AB  - Normal infants start to produce canonical babbling (CB) at the age of 6 to 10
      months. CB consists of reduplicated sequences of consonant-vowel syllables which
      have adult-like acoustical features. Therefore, onset of CB is considered to be a
      landmark in the development of spoken language. The previous study indicated that
      a behavioral synchronization of vocalizations with rhythmic actions occurred in
      infants before the onset of CB. The present study examined the function of
      synchronization. Acoustical analyses were conducted on vocalizations of four
      infants during three-months-period including the month when synchronization
      occurred most frequently. The results show that both utterance length and formant
      frequency transition duration of synchronized vocalizations are shorter than
      those of non-synchronized vocalizations. These acoustical features, which are
      required to produce CB, persisted even after the synchronization has disappeared.
      The present study suggests that synchronization of vocalizations with rhythmic
      actions has the function of prompting infants to produce CB.

PMID- 10341373
TI  - [Mood congruency and incongruency effects on sentence writing].
AB  - This study investigated the influence of positive and negative moods on sentence
      writing. Short animated video clips, inducing either a positive or negative mood,
      were shown to 60 female undergraduates. Then, they wrote five sentences under one
      of two conditions: the sentences were to begin with "I" or "M" (a third person)
      as the subject. Main results were as follows: with the first person pronoun as
      the subject, the negative mood group showed a mood-congruency effect for the
      first sentence, and a mood-incongruency effect for the second to fifth sentence,
      with "M" as the sentence subject, the negative mood group showed a mood
      incongruency effect for all the five sentences. The positive mood group showed a
      mood-congruency effect for all the sentences, regardless of "I" or "M" condition.
      Furthermore, under "I" condition, the students in the negative mood group
      reported their desire to change their mood. It is concluded that mood
      incongruency effect on writing depended on the subject of the sentence.

PMID- 10341374
TI  - [The underlying mechanism for process dissociation in recognition: performance,
      response latency, and eyeblink in a three-process model].
AB  - Jacoby (1991) proposed a process-dissociation procedure to estimate contributions
      of conscious and unconscious processes to cognitive task performance. The present
      research examined the inner processing mechanism underlying the procedure. Thirty
      two female undergraduates learned a list of visual stimulus words and another of
      auditory stimulus. They then performed recognition memory tasks in which
      conscious and unconscious memory components presumably either help or interfere
      with each other. Memory performance, response latency, and eyeblink activity were
      analyzed based on the framework of the process-dissociation procedure. A three
      process model of recognition, with an underlying hypothetical processing
      mechanism, was proposed to explain the complicated results obtained of the three
      dependent measures.

PMID- 10341375
TI  - [Influence of visual attention upon sound localization].
AB  - Previous studies on audio-visual interaction such as the ventriloquism effect
      have indicated cognitive (or context) factors as well as sensory (or synchronous)
      factors could make the interaction. In these studies, however, visual attention
      seems to have been neglected. Thus, it has been still unknown whether the visual
      attention affects the interaction or not. We investigated the contribution of the
      attention factors to the audio-visual interaction by comparing the sound
      localization biases made by attentional factors and those by synchronous factors.
      Three subjects participated in the localization tasks in horizontal and vertical
      orientations. As the results, we found small influence of the attentional factors
      upon the interaction in the horizontal orientation, and no influence in the
      vertical orientation. On the contrary, the effect of the synchronous factors was
      larger in the vertical orientation than in the horizontal orientation. We
      concluded that the visual attention could affect the audio-visual interaction
      slightly, and that the influences of the attentional factors and the perceptual
      factors upon the interactions were made in the different processes.

PMID- 10341376
TI  - [Effects of contextual changes between class and intermission on episodic
      memory].
AB  - Three naturalistic experiments were conducted to investigate the context
      dependent memory induced by contextual changes between class and intermission. In
      all the experiments, junior college students served as subjects. The experimenter
      in a class session was their teacher, and the experimenters in an intermission
      session were other students with whom the subjects were acquainted. In Experiment
      1, one group of subjects was tested in the same class as encoding, and another
      group was tested in the intermission at a different place, 60 seconds after their
      encoding of to-be-remembered items in class. In Experiment 2, the place factor
      (types of the room) and the non-place factor (class vs. intermission) were
      orthogonally manipulated. The retention interval was one week. In Experiments 1
      and 2, the results revealed clear context-dependent memory. Furthermore, the
      context-dependent memory was produced by the changes in the non-place component
      of the context but not by those in the place component. Experiment 3 confirmed
      that the results were due to the context-dependent memory rather than to any
      other factors of experimental design.

PMID- 10341377
TI  - [The factor structure of coping strategies and their effects on burnout among
      primary caregivers of impaired elderly persons].
AB  - The purpose of this study was to extract the factor structure of coping
      strategies and to examine their direct and indirect effects on burnout. Eight
      hundred thirty four valid responses obtained from primary caregivers of impaired
      persons aged 65 years old and over living in the community were analyzed. The
      results of covariance structural analysis were as follows: Three second order
      factors, including "Approach", and "Avoidance," and "Support seeking," were
      extracted. Five factors, "Keeping their own pace," "Positive acceptance of
      caregiving role," "Diversion," "Informal support seeking," and "Formal support
      seeking," were extracted as first order factors. "Keeping their own pace,"
      directly decreased burnout and "Diversion" indirectly decreased burnout through
      caregiving in involvement. "Informal support seeking" directly increased burnout
      and "Positive acceptance of caregiving role" indirectly increased burnout through
      caregiving involvement.

PMID- 10341378
TI  - The posterior basal diencephalon of rats enhances expression of an activated
      state.
AB  - STUDY OBJECTIVES: Various ablation studies have implicated the posterior basal
      diencephalon in the promotion of wakefulness. Although many studies have examined
      the role of this structure in promotion of cortical arousal, few investigations
      have attempted to examine its importance in regulation of motor activation
      (behavioral arousal). In the current study, recordings of freely moving
      decerebrate rats with and without a posterior basal diencephalon were performed.
      These studies allowed determination of the behavioral states expressed by the
      preparations and whether removal of the posterior basal diencephalon completely
      eliminated expression of both activated state with and activated state without
      limb movements. DESIGN: Muscle activity was recorded from limb and neck muscles.
      Eye movements and heart rate were also monitored. The percentage of time spent in
      various behavioral states and the proportion of limb movements expressed in each
      of these states were determined. MEASUREMENTS AND RESULTS: Rats with an intact
      posterior basal diencephalon cycled between all behavioral states. However, they
      spent most of the recording time in an activated state. In contrast, removal of
      the posterior basal diencephalon produced rats that spent most of the recording
      period in a quiescent state. Limb movements were expressed mainly by animals with
      an intact posterior basal diencephalon, and only when these animals were in the
      activated state. CONCLUSIONS: The results of this study suggest that the
      posterior basal diencephalon is required for expression of an activated state and
      specifically provide evidence for a descending projection from this region
      required for expression of this state and associated motor activation.

PMID- 10341379
TI  - Moderate to severe periodic limb movement disorder in childhood and adolescence.
AB  - The purpose of this study is to review clinical features of children with
      moderate to severe Periodic Limb Movement Disorder (PLMD). Because of our
      interest in both Restless Legs Syndrome (RLS) and Attention-Deficit Hyperactivity
      Disorder (ADHD), many of our patients had one or both of these conditions. We did
      a retrospective review of 129 children and adolescents who were found to have
      Periodic Limb Movements in Sleep (PLMS) > 5/hour of sleep. Sixty five had PLMS of
      5-10/hour of sleep, 48 had PLMS of 10-25/hour of sleep and 16 had PLMS > 25/hour
      of sleep. One hundred and seventeen of the original 129 had ADHD. Stimulant
      medication did not seem to play a role in the production of PLMS. In only 25 of
      the 129 cases did parents note the presence of PLMS before being specifically
      asked to look, and even after specific instructions to look, PLMS were not noted
      by the parents in 39 patients. The sub-group of 16 children and adolescents--6
      female, 10 male (average age 11.1 years--range 6-17 years) with moderate to
      severe PLMS > 25/hour of sleep are described in more detail. Fifteen of the 16
      patients had ADHD. Four of the 16 had RLS and 10 of 13 patients for whom a family
      history was available had a parent with RLS. Two of the 16 patients had their
      PLMS initially misdiagnosed as seizures. Sleep disturbance was present in all 16
      patients and 7 of the 16 had daytime somnolence which resolved with dopaminergic
      medications. To our knowledge this is the first clinical series of moderate to
      severe PLMS in children and adolescents to be fully described in the literature.

PMID- 10341380
TI  - The development of circadian rhythms in a human infant.
AB  - STUDY OBJECTIVES: This study examines the ontogeny and interaction of circadian
      rhythms of sleep, wake, temperature, melatonin, and feeding in the human newborn,
      and the influence of photic and non-photic factors on the initiation of
      entrainment. DESIGN: An infant's sleep-wake state, temperature, and salivary
      melatonin were monitored from birth to 6 months. Temperature was obtained every
      hour, and the infant's sleep/eating onset/termination were observed continuously
      and recorded until day 182. Salivary melatonin was obtained weekly for a 24-hour
      period, starting at week 3. SETTING: The infant slept in his parents' bedroom.
      All household members awakened, retired, and ate meals according to a fixed
      schedule during the study, while the infant ate, slept, and woke on demand.
      PARTICIPANTS: A healthy male infant was the subject. Biological parents gathered
      data continuously for six months. INTERVENTIONS: The infant's schedule was on
      demand; the household's was fixed. Illumination was restricted to sunlight.
      MEASUREMENTS AND RESULTS: The circadian rhythm of temperature appeared first,
      soon after birth, and became statistically significant within one week. The wake
      circadian rhythm appeared second, attaining significance at day 45; approximately
      the same time that increased melatonin concentration began to occur at sunset.
      The sleep circadian rhythm appeared last, attaining significance after day 56.
      Ninety to 120 minute zones of sustained wakefulness first appeared in the second
      month of life subsequent to awakening and prior to sleep onset. The infant's
      nocturnal sleep-onset was coupled to sunset before day 60 and subsequently to
      family bedtime, giving evidence of initial photic entrainment followed by social
      entrainment. CONCLUSIONS: Circadian rhythms appeared much more rapidly in this
      infant than previously reported; their rapid appearance was probably facilitated
      by maximal exposure to sunlight, and regular social cues. These lighting
      conditions replicate universal infant experience prior to the invention of
      artificial light.

PMID- 10341381
TI  - Sleeping with an electric blanket: effects on core temperature, sleep, and
      melatonin in young adults.
AB  - Previous studies have inferred a relationship between core temperature and sleep
      disruption from manipulations of core temperature such as heating prior to sleep
      or administration of hyperthermic substances. To examine the relationship more
      directly, this study aimed to produce a direct increase in core temperature
      during the sleep period. Following an adaptation night, 16 subjects underwent
      counter-balanced baseline and experimental conditions, on non-consecutive nights
      between 1900 and 0800h. In the experimental condition, subjects were heated
      between 0230h and wake up, which significantly increased mean core temperature
      from baseline levels between 0400 and 0700h by 0.18 +/- 0.03 degree C (mean +/-
      SEM, p < 0.05). This increase in core temperature was associated with a
      significant decrease in sleep efficiency between 0330 and 0730h of 5.5 +/- 0.9%
      (mean +/- SD, p < 0.05). Polysomnographic measures indicated a significant
      increase in the number of stage changes and the amounts of stage 0 and stage 1
      sleep (p < 0.05). Other stages of sleep and the number and duration of arousals
      were not significantly effected by heating. There was a strong trend toward and
      increase in the number of arousals (p = 0.054), however, core body temperature
      did not increase across arousals. Also, melatonin output was not effected by
      heating. Taken together, these results suggest that increased nocturnal core
      temperature alone may disrupt sleep. Additionally, the results support evidence
      suggesting that the circadian regulation of the sleep/wake cycle may be mediated
      via core temperature.

PMID- 10341382
TI  - Habituation of the infant arousal response.
AB  - STUDY OBJECTIVES: Arousal is considered to be an important protective response in
      a sleeping infant and its depression could leave an infant vulnerable to a life
      threatening stimulus. We found previously that arousal to a non-respiratory
      (tactile) stimulus occurs in a sequence of events that begins with spinal,
      followed by brainstem responses, and then a cortical electroencephalographic
      (EEG) arousal response. We hypothesized that repeated stimuli would depress the
      arousal responses by habituation and that spinal and brainstem responses would be
      more resistant to habituation than cortical responses. PARTICIPANTS: We studied
      22 normal infants. INTERVENTIONS: The infants underwent polysomnographic
      monitoring during a daytime nap. Tactile stimuli was applied to the infants foot
      at 5-second intervals. MEASUREMENTS AND RESULTS: We found that spinal, brainstem,
      and cortical responses occurred on the first trial of each test. Repeated trials
      during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep resulted
      in a decrease in the incidence of each individual response and eventually
      elimination of the arousal responses. Cortical responses were eliminated first,
      followed by brainstem responses and finally spinal responses. The elimination of
      each of the responses occurred more rapidly during REM sleep that during NREM
      sleep. CONCLUSIONS: Habituation of the infant arousal sequence occurs with
      repeated tactile stimulation. There is a serial habituation of responses from the
      cortical to the spinal level, which occurs more rapidly during REM sleep. Rapid
      habituation to innocuous stimuli is probably beneficial in avoiding detrimental
      sleep disruptions. However, in situations requiring the protective functions of
      arousal, such habituation could be detrimental to an infant.

PMID- 10341383
TI  - Short-term total sleep deprivations does not selectively impair higher cortical
      functioning.
AB  - Previous research has shown that total sleep deprivation produces impairment in
      sustained attention and vigilance especially if the deprivation period is greater
      than 48 hours. However little is known about the effects of sleep deprivation on
      performance of tasks considered to be measures of higher cortical functioning
      such as tests of cognitive flexibility and the capacity to shift from one
      response set to another. One current hypothesis is that sleep deprivation of a
      shorter duration (34-36 hours) adversely affects higher cortical function while
      effects on attention and vigilance tasks are relatively mild. Performance on an
      intelligence test, a test of sustained attention and tests designed to measure
      higher cortical function were compared in a group of 29 subjects who underwent 34
      36 hours of continuous sleep deprivation and 32 normal sleeping control subjects.
      No significant group performance differences in the hypothesized direction were
      noted on any measure. One night of total sleep deprivation does not appear to
      impair performance on tasks that are designed to assess higher cortical
      functioning.

PMID- 10341384
TI  - Effects of different sleep reductions on daytime sleepiness.
AB  - This study evaluated the effects of different amounts of sleep and SWS
      restriction on the ensuing day-time sleepiness. Six healthy selected males, after
      one adaptation night and an initial 8-hr baseline night, were allowed to sleep 5,
      4, 3, 2, and 1 hr with a 1-week interval between conditions. The following day, 4
      sleep onset MSLT trials and 2 Wilkinson Auditory Vigilance Task (WAVT) were
      administered. Before each MSLT, self evaluations of sleepiness and activation on
      a visual analogue scale (ADAS) were assessed. Each restriction night was followed
      by an 8-hr recovery night, and a final 8-hr baseline night was recorded. The day
      after each night the same diurnal tests were repeated. Results indicated a linear
      increase in the propensity to sleep (MSLT) and of subjective sleepiness as a
      function of the increase in sleep restrictions. Performance scores (WAVT) showed
      that vigilance is partially affected by sleep restrictions. For each measure,
      regression analyses showed that the effect of sleep reduction is better predicted
      by the total duration of sleep than by the amount of SWS. Correlations between
      measures were negligible with the exception of those between performance and
      subjective sleepiness measures.

PMID- 10341385
TI  - Nocturnal sleep and daytime sleepiness in normal subjects with HLA-DQB1*0602.
AB  - Narcolepsy, a neurological disorder characterized by excessive daytime sleepiness
      and abnormal REM sleep, is known to be tightly associated with the Human
      Leukocyte Antigen (HLA) DQ allele DQB1*0602. In this study, we have explored the
      possibility that normal subjects carrying this HLA allele (25% of the general
      population) could display subclinical REM sleep abnormalities and increased
      daytime sleepiness. Data from 525 middle-aged adults enrolled in the Wisconsin
      Sleep Cohort study were used for this analysis. Nocturnal polysomnography, sleep
      latency during the multiple sleep latency test (MSLT), and questionnaire items
      pertaining to excessive daytime sleepiness were compared between DQB1*0602
      positive (n = 132) and negative (n = 393) participants. Results indicate shorter
      REM latency whether or not the latency was adjusted for wake after sleep onset (p
      = 0.003) and p = 0.02 respectively), increased sleep efficiency (p = 0.06) and
      decreased percent time spent in stage I sleep (p = 0.02) during nocturnal
      polysomnography in DQB1*0602 subjects. Data gathered using the Multiple Sleep
      Latency Test or the Epworth and Stanford sleepiness scales did not differentiate
      between DQB1*0602 positive and negative subjects. These results support the
      hypothesis that polymorphisms at the level of HLA DQ modulates sleep tendencies
      in humans.

PMID- 10341386
TI  - A matched comparison of MMPI responses in patients with primary snoring or
      obstructive sleep apnea.
AB  - STUDY OBJECTIVE: To compare the MMPI responses between nonapneic primary snoring
      (PS) and obstructive sleep apnea (OSA). DESIGN: Cross sectional with matched
      samples. SETTING: University sleep disorders center. PATIENTS: All PS patients (n
      = 49) available in a series of 428 clinical referrals to a sleep disorders
      center, and age and gender-matched OSA patients (n = 49) selected from the 199
      available OSA patients in the series. INTERVENTIONS: Not applicable. MEASUREMENTS
      AND RESULTS: Subjects completed the MMPI prior to overnight diagnostic
      polysomnographic assessment and multiple sleep latency test (MSLT). OSA patients
      exhibited a mean of 2.3 elevated MMPI scales, which was significantly more than
      the PS mean of 1.6 elevations, and attributable to higher OSA scores on
      Depression (D) and Hypochondriasis (Hs). Approximately twice as many OSA patients
      than PS patients showed disturbed scores on D (49% vs. 25%, p < .05) and Hy (35%
      vs. 16%, p < .05). On nine of the ten MMPI clinical scales, both patient groups
      exceeded the elevation rate expected in nondistressed individuals. Among OSA
      patients, but not PS patients, number of MMPI elevations had a significant
      negative correlation with sleep efficiency and average blood saturation during
      NREM, and a significant positive correlation with wake time after sleep onset.
      CONCLUSIONS: Compared to patients with PS, those with OSA have more intense
      depressive symptoms (e.g., pessimism, inactivity, guilt) and somatic concerns.
      General psychopathology is associated with blood oxygen saturation only among OSA
      patients. Nonetheless, PS patients show psychological maladjustment that is
      qualitatively similar, but quantitatively less severe, than that characterizing
      OSA.

PMID- 10341387
TI  - MMPI correlates of sleep and respiratory disturbance in obstructive sleep apnea.
AB  - STUDY OBJECTIVE: To evaluate associations between polysomnographic variables in
      obstructive sleep apnea (OSA) and a variety of psychological responses (including
      depressive symptoms) as assessed by the Minnesota Multiphasic Personality
      Inventory (MMPI). DESIGN: Cross-sectional. SETTING: University sleep disorders
      center. PATIENTS: One-hundred seventy eight consecutive clinical OSA patients.
      INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: Patients completed the
      MPI prior to overnight diagnostic polysomnography. Fifty-eight percent
      demonstrated at least one MMPI elevation (mean = 1.8 elevations), with Depression
      (D) elevated for 32%, Hypochondriasis (Hs) for 30%, and Hysteria (Hy) for 21%.
      Thirty-eight percent demonstrated two or more elevations, with several variations
      of Hs-D and Hs-D-Hy configurations evident. "Conversion V" profiles were fairly
      rare, and a large number of miscellaneous configurations occurred once.
      Significant correlations were detected between several MMPI scale scores and
      total sleep time, the apnea-hypopnea index (AHI) during REM, and particularly
      arterial oxygen saturation, even when partialling out variance related to body
      mass index (BMI). In contract, D scores were not correlated with any
      polysomnographic parameters. Based upon MMPI configuration, the sample was
      subdivided into the following seven profile groups: Nonelevated (n = 74); Single
      D (n = 11); Single non-D (n = 25); Combined D plus (a) HS or HY (n = 7), (b) Hs
      and Hy (n = 10), or (c) other (n = 29); and Multiple non-D (n = 22). Multivariate
      analysis controlling for age and gender indicated higher AHI in the Single non-D,
      Combined D plus other, and Multiple non-D groups, compared to the Single D group.
      Also, there was lower average oxygen saturation in the Multiple non-D group,
      compared to Single D, Single non-D, and Nonelevated groups. The Combined D plus
      HS and/or Hy groups did not differ from each other or from other groups, even
      when merged. The Multiple non-D findings were unattributable to any specific
      scale or overall number of elevations. CONCLUSIONS: OSA patients who have core
      depressive symptoms (as measured by MMPI scale D) without significant
      psychological symptoms in other areas tend to have less severe OSA, whereas those
      with a diverse set of other psychological symptoms overshadowing depressive
      symptoms (e.g., somatic focus, emotional reactivity, family/marital problems,
      cognitive problems, etc.) tend to have greater AHI and lower oxygen saturation.
      Although it seems probable that these MMPI differences primarily reflect OSA
      effects, prospective research is needed to confirm this hypothesis.

PMID- 10341388
TI  - Ten-year trends in the pharmacological treatment of insomnia.
AB  - STUDY OBJECTIVE: To assess patterns of pharmacological treatment of insomnia
      during the period 1987-1996. DESIGN AND MEASUREMENTS: Data were obtained from the
      National Disease and Therapeutic Index (NDTI; IMS America, Ltd., Plymouth
      Meeting, PA) which samples office-based physicians in 24 specialties. Drug
      mentions, a measure of patient contacts in which drug therapy is recommended,
      with a physician-indicated desired action of "promote sleep" or "sedative night"
      were compiled for each year. Z-scores were calculated to determine statistical
      differences over time for total drug mentions, drug mentions by category
      (hypnotics, non-hypnotic benzodiazepines, antidepressants, or other), and for
      some individual drugs. RESULTS: Total drug mentions for the treatment of insomnia
      fell 24.4% from 1987 to 1996. From 1987 to 1996 hypnotic mentions decreased
      53.7%, antidepressants increased 146%, "other" drugs decreased by 63.2%, and
      benzodiazepine non-hypnotics remained relatively unchanged. CONCLUSIONS: Since
      1987, overall pharmacological treatment of insomnia has decreased substantially
      although surveys indicate a stable or increasing prevalence of sleep disturbance.
      There has also been a dramatic shift to use of antidepressants in lieu of
      hyponotics for the symptomatic treatment of insomnia despite a paucity of data
      regarding their efficacy and the potential for serious side effects.

PMID- 10341389
TI  - Correlation between wrist activity monitor and electrophysiological measures of
      sleep in a simulated shiftwork environment for younger and older subjects.
AB  - Although several studies have examined the correlation between nocturnal PSG and
      activity measurement, validation studies of actigraphically measured sleep in
      shiftworking populations have not been reported. This study investigates the
      correlation between sleep recorded using EEG and actigraphic techniques during a
      simulated 12-hour shift rotation. Thirty-two subjects were allocated to groups
      according to age. Group (1) included sixteen subjects mean (+/- s.d.) age of 21.2
      +/- 2.7 years, and Group (2) included sixteen subjects mean (+/- s.d.) age of
      43.9 +/- 6.8 years. An adaptation night was followed by two 12-hour day shifts (7
      am-7 pm), 24 hours off and then two 12-hour night shifts (7 pm-7 am). For the
      entire study subjects wore an activity monitor, and while in bed, sleep was
      recorded using polysomnography; both techniques were collected in 30-second
      epochs. A high epoch for epoch agreement between wrist activity monitoring and
      EEG measures of sleep was recorded for daytime and nighttime sleep periods (80
      90%). There was a high correlation between EEG and actigraphically recorded sleep
      duration in young (0.98-0.77) and older (0.78-0.96) subjects for all sleep
      periods. Sleep efficiency correlations were extremely variable for both the young
      (0.72-0.15) and older (-0.18-0.58) subjects for daytime and nighttime sleep
      periods. Taken together these results suggest that wrist activity monitoring is a
      valid measure of sleep/wake activity and sleep duration, in a simulated shiftwork
      environment. However, some caution should be used for more specific measures,
      such as sleep efficiency particularly in older subjects.

PMID- 10341390
TI  - History of the Japanese Society for Apheresis.

PMID- 10341391
TI  - Efficacy and safety measures for low density lipoprotein apheresis treatment
      using dextran sulfate cellulose columns.
AB  - Long-term low density lipoprotein (LDL) apheresis using dextran sulfate cellulose
      (DSC) columns is a well tolerated treatment for drug refractory
      hypercholesterolemia with coronary heart disease (CHD). Hypercholesterolemic
      patients may benefit from LDL apheresis combined with cholesterol lowering drug
      therapy in terms of the prevention of the progression of atherosclerosis,
      stabilization of atheromatous plaque, and reduction of cardiac events. The major
      adverse reaction of LDL apheresis is temporal hypotension caused by hypovolemia
      or vasovagal reactions due to extracorporeal circulation. Anaphylactoid reactions
      in patients administered angiotensin converting enzyme inhibitors (ACE-I) are
      other dextran sulfate cellulose column related adverse reactions, which must be
      carefully prevented by ceasing the administration of ACE-I before LDL apheresis
      treatment. ACE-I must not be administered to patients undergoing LDL apheresis.

PMID- 10341392
TI  - Therapeutic apheresis in neurological disorders.

PMID- 10341393
TI  - Plasmapheresis in collagen vascular diseases.

PMID- 10341394
TI  - Changes in CD4+ T lymphocyte subsets in circulating blood and synovial fluid
      following filtration leukocytapheresis therapy in patients with rheumatoid
      arthritis.
AB  - The purpose of this study is to determine the changes in CD4+ T lymphocyte
      subsets in the circulating blood and synovial fluid following filtration
      leukocytapheresis (LCP) therapy for patients with rheumatoid arthritis (RA). A
      Cellsorba column packed with polyester fibers was used for the removal of
      circulating leukocytes. For patients with RA, filtration LCP or sham procedures
      were performed 3 times with 1 week intervals between procedures. T lymphocyte
      surface markers in the peripheral blood and synovial fluid were measured by flow
      cytometry. The proportions of activated CD4+ T cells (CD4+DR+, CD4+CD25+, and
      CD4+CD71+) and CD4+CD29+ T cells increased significantly in the peripheral blood,
      but the counts of these cells were significantly reduced in the synovial fluid
      after 2 treatment sessions in the LCP group. No significant changes were observed
      in the proportion of these cells in the control group. Our findings suggest that
      filtration LCP may cause a redistribution of activated T cells from affected
      joints into the circulating blood.

PMID- 10341396
TI  - Therapeutic apheresis in Russia: is it just isolation or original development?

PMID- 10341395
TI  - Hydrazine-conjugated cellulose for adsorption of glycated proteins.
AB  - Glycated proteins and advanced glycation end-products are postulated to play an
      important role in the development of complications due to diabetes mellitus or
      renal failure. The purpose of this study was to assess the ability of hydrazine
      conjugated cellulose to adsorb glycated albumin. The samples used for adsorption
      test were artificially glycated albumin or the serum from patients with diabetes
      mellitus. The hydrazine-conjugated cellulose adsorbed more than 20% of the
      albumin glycated artificially over 77 days. The serum concentrations of glycated
      albumin in patients with diabetes mellitus (39.6 +/- 2.5% (mean +/- SEM), n = 14)
      were not decreased by incubation with cellulose alone (postincubation level, 39.7
      +/- 2.5%) whereas they were significantly (p < 0.0001) reduced to 38.0 +/- 2.4%
      after incubation with hydrazine-conjugated cellulose. There was a significant
      correlation (r = 0.75, p < 0.01) between the preincubation levels of glycated
      albumin and the degree of adsorption. The hydrazine-conjugated cellulose has a
      higher affinity for albumin with greater glycation.

PMID- 10341397
TI  - Small for gestational age is not a diagnosis.

PMID- 10341398
TI  - First-trimester nuchal translucency and maternal serum biochemical screening for
      Down's syndrome: a happy union?

PMID- 10341399
TI  - A screening program for trisomy 21 at 10-14 weeks using fetal nuchal
      translucency, maternal serum free beta-human chorionic gonadotropin and pregnancy
      associated plasma protein-A.
AB  - OBJECTIVE: To examine the potential impact of combining maternal age with fetal
      nuchal translucency thickness and maternal serum free beta-human chorionic
      gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in
      screening for trisomy 21 at 10-14 weeks of gestation. METHODS: Maternal serum
      free beta-hCG and PAPP-A were measured by Kryptor, a random access immunoassay
      analyzer using time-resolved amplified cryptate emission, in 210 singleton
      pregnancies with trisomy 21 and 946 chromosomally normal controls, matched for
      maternal age, gestation and sample storage time. In all cases the fetal crown
      rump length and nuchal translucency thickness had been measured by
      ultrasonography at 10-14 weeks of gestation and maternal blood had been obtained
      at the time of the scan. The distributions (in multiples of the median; MoM) of
      free beta-hCG and PAPP-A (corrected for maternal weight) and fetal nuchal
      translucency (NT) were determined in the trisomy 21 group and the controls.
      Likelihood ratios for the various marker combinations were calculated and these
      were used together with the age-related risk for trisomy 21 in the first
      trimester to calculate the expected detection rate of affected pregnancies, at a
      fixed false-positive rate, in a population with the maternal age distribution of
      pregnancies in England and Wales. RESULTS: In a population with the maternal age
      distribution of pregnancies in England and Wales, it was estimated that, using
      the combination of maternal age, fetal nuchal translucency thickness and maternal
      serum free beta-hCG and PAPP-A, the detection of trisomy 21 pregnancies would be
      89% at a fixed false-positive rate of 5%. Alternatively, at a fixed detection
      rate of 70%, the false-positive rate would be 1%. The inclusion of biochemical
      parameters added an additional 16% to the detection rate obtained using NT and
      maternal age alone. CONCLUSIONS: Rapid diagnostic technology like Kryptor, which
      can provide automated reproducible biochemical measurements within 30 min of
      obtaining a blood sample, will allow the development of interdisciplinary one
      stop clinics for early fetal assessment. Such clinics will be able to deliver
      improved screening sensitivity, rapidly and more efficiently, leading to reduced
      patient anxiety and stress.

PMID- 10341400
TI  - Nuchal translucency in fetuses affected by homozygous alpha-thalassemia-1 at 12
      13 weeks of gestation.
AB  - OBJECTIVE: Fetuses affected by homozygous alpha-thalassemia-1 are anemic in the
      first trimester. We studied their nuchal translucency (NT) measurements at 12-13
      weeks of gestation. METHODS: Nuchal translucency was measured prospectively in
      fetuses at risk of homozygous alpha-thalassemia-1. Measurements of those fetuses
      subsequently confirmed to be affected by homozygous alpha-thalassemia-1 but with
      a normal karyotype were compared to those of 440 controls. The controls were from
      the general obstetric population who had NT measurements at 12 or 13 weeks with
      known normal outcome. All the NT measurements were expressed as multiples of the
      median (MoM) for the gestational day. RESULTS: Between 1996 and 1998, 94 at-risk
      pregnancies were studied. Of these, 32 were subsequently confirmed to be affected
      by homozygous alpha-thalassemia-1. Chromosome study was not carried out in three
      cases and these were excluded from the analysis. Nuchal translucency MoMs for
      cases and controls were found to fit a log Gaussian distribution. The log means
      (standard deviation) for case and control NT MoM were 0.075 (0.156) and -0.0019
      (0.091), respectively. The median NT MoM (95% CI) for cases was 1.19 (1.08-1.62)
      and was significantly higher than that of the controls (p < 0.001). However,
      there was extensive overlap of NT between cases and controls. CONCLUSION:
      Overall, there was a 19% increase in NT MoM in fetuses affected by homozygous
      alpha-thalassemia-1. This represents a difference of only 0.3-0.4 mm, which is
      clinically insignificant. This finding indirectly suggests that the increased NT
      in trisomic fetuses cannot be explained by fetal anemia. Conversely, the presence
      of increased NT in a fetus at risk of homozygous alpha-thalassemia-1 should alert
      one to the possibility of chromosomal abnormality rather than being attributed to
      fetal anemia.

PMID- 10341401
TI  - Ultrasound during pregnancy and subsequent childhood non-right handedness: a meta
      analysis.
AB  - OBJECTIVE: A possible association between ultrasound during pregnancy and
      subsequent non-right handedness among children has been suggested. The
      association has been reported to be stronger among boys. The aim of the present
      study was to explore this further through a meta-analysis of two follow-up
      studies of three randomized controlled trials of routine ultrasonography during
      pregnancy. DESIGN: Handedness was assessed through a questionnaire to the
      parents, and 4715 children at the age of 8-9 years were included in the meta
      analysis. RESULTS: There was no statistically significant difference in the
      prevalence of non-right handedness between the ultrasound-screened children and
      the controls, but there was a statistically significant difference in a subgroup
      analysis among the boys. Exploratory analyses according to exposure or non
      exposure indicated an even stronger association between ultrasound and non-right
      handedness. CONCLUSIONS: A conservative analytical approach indicates no
      association between ultrasound in utero and subsequent non-right handedness. The
      results from the exploratory analyses must be interpreted with caution. There is
      still a need for further research.

PMID- 10341402
TI  - Doppler velocimetry of normal human fetal venous intrapulmonary branches.
AB  - OBJECTIVES: To describe the nature of flow velocity waveforms from fetal middle
      and distal venous pulmonary branches in the second half of normal pregnancy in
      relation to gestation, and to test repeatability and interrelationships of flow
      velocity waveform recordings from proximal, middle and distal venous pulmonary
      branches. DESIGN: Cross-sectional study. SUBJECTS/METHODS: A total of 111 normal
      singleton pregnancies between 20 and 40 weeks' gestation were studied using a
      color-coded Doppler ultrasound system. Pulmonary waveforms were obtained at the
      level of the fetal cardiac four-chamber view. Repeatability was tested from two
      recordings at 15-min time intervals in 25 separate normal pregnancies. RESULTS:
      The nature of middle and distal venous pulmonary flow velocity waveforms was
      comparable with that of proximal waveforms. Acceptable repeatability of pulmonary
      venous flow velocity waveforms with coefficients of variation below 15% was
      established for nearly all velocity parameters and their ratios. A gestational
      age-dependent change was found for all flow velocity waveform parameters
      including pulsatility index for veins at both middle and distal venous levels.
      Significant inter-pulmonary changes were observed for nearly all pulmonary venous
      waveform parameters. CONCLUSIONS: It is speculated that increase in volume flow
      and venous pulmonary pressure gradient plays a role in gestational age-dependent
      changes, whereas changes in vessel diameter and distance between the heart and
      more distal venous pulmonary vessels are responsible for inter-pulmonary changes.

PMID- 10341403
TI  - Myocardial motion imaging: a new application of power color flow and frequency
      based color flow Doppler in fetal echocardiography.
AB  - OBJECTIVE: Myocardial motion imaging is a new way of looking at the fetal heart
      using power color flow and frequency-based color flow Doppler to demonstrate
      heart wall movement in color. This study set out to assess the value of
      myocardial motion imaging in fetal echocardiography in a routine clinical
      setting. DESIGN: In our hospital, all patients at high risk of carrying a fetus
      with a cardiac abnormality are offered detailed ultrasound scanning, including
      fetal echocardiography, at 20 weeks' gestation. A prospective study was carried
      out over a 2-month period and, in addition to conventional fetal
      echocardiography, myocardial motion imaging was also carried out on all patients,
      by means of both power color flow and frequency-based color flow Doppler
      ultrasound. RESULTS: Myocardial motion imaging demonstrated fetal heart wall
      movement in 26 of the 27 patients. Myocardial motion imaging using power color
      flow gave a global view of fetal heart wall movement, demonstrating both atrial
      and ventricular contraction simultaneously. Myocardial motion imaging using
      frequency-based color flow Doppler demonstrated atrial and ventricular
      contractions separately. In addition, as the direction of fetal heart wall motion
      can be color coded, atrial contractions, ventricular relaxation and ventricular
      contraction were demonstrated, providing a functional assessment of fetal heart
      wall movement. Two cases of cardiac abnormality were also studied, one case of
      hypoplastic left heart syndrome and one case of atrioventricular septal defect.
      In both cases functional information was obtained using myocardial motion
      imaging, and the technique also highlighted the anatomical defect. CONCLUSIONS:
      Myocardial motion imaging produces both a global view of fetal cardiac anatomy
      and a functional assessment of individual chamber contraction in the normal and
      abnormal heart. It may prove to be a useful adjunct to conventional color flow
      Doppler assessment of the fetal heart.

PMID- 10341404
TI  - Non-invasive detection of alterations of the carotid artery in pregnant women
      with high-frequency ultrasound.
AB  - OBJECTIVE: To compare the thickness of the layers of the carotid artery wall in
      pregnant and fertile non-pregnant women. DESIGN: Prospective cross-sectional
      study. SUBJECTS: Fifty-one pregnant women at a mean gestational age of 38.9 weeks
      and 64 fertile non-pregnant women were examined at a University hospital.
      METHODS: The three layers (adventitia, media, intima) of the superficial wall of
      the left common carotid artery were identified and measured with high-resolution
      ultrasound (22.5 MHz). RESULTS: Pregnant women had a thinner intima layer (0.25
      +/- 0.07/0.29 +/- 0.08 mm) and a thicker media layer (0.31 +/- 0.08/0.27 +/- 0.09
      mm) compared with controls. A statistically significantly higher intima/media
      ratio was calculated for the pregnant women (1.14 +/- 0.03), compared with the
      non-pregnant women (0.88 +/- 0.04). CONCLUSION: There are differences in the
      thickness of the histological layers of the carotid artery wall in pregnant
      compared with non-pregnant women. This is likely to be due to the effect of
      different estradiol levels in these two groups.

PMID- 10341405
TI  - Direct intrauterine fetal therapy in a case of bronchopulmonary sequestration
      associated with non-immune hydrops fetalis.
AB  - Bronchopulmonary sequestration associated with non-immune hydrops fetalis is
      generally recognized as a uniformly fatal fetal condition without fetal surgical
      intervention. We describe here the first case of such a condition treated
      successfully with direct intrauterine fetal therapy using digoxin and frusemide.

PMID- 10341406
TI  - Fetal cataract in congenital toxoplasmosis.
AB  - We report a case of the prenatal diagnosis of fetal cataract due to congenital
      toxoplasmosis. To the best of our knowledge, this is the first report of such a
      case. We discuss the long-term ocular sequelae of the condition and how they
      should affect prenatal counselling.

PMID- 10341407
TI  - Enlarged nuchal translucency and low serum protein concentrations as possible
      markers for Zellweger syndrome.
AB  - We present a case of a fetus in which an enlarged nuchal translucency was
      detected at 12 weeks' gestation. The karyotype was normal. Subsequent ultrasound
      examination showed no obvious fetal abnormalities apart from a mild pericardial
      effusion. Serum screening revealed very low concentrations of estriol and human
      chorionic gonadotropin. After birth the diagnosis of Zellweger syndrome was made.
      Nuchal translucency screening, estriol level identification and detailed
      ultrasound scanning may help to identify fetuses affected by this syndrome.

PMID- 10341408
TI  - Antenatal sonographic diagnosis of epignathus at 15 weeks of pregnancy.
AB  - Epignathus is a rare, benign, congenital teratoma of the hard palate. Most of
      these teratomas are unidirectional and protrude through the mouth. Hence, the
      prognosis depends on the size of the tumor and the degree of face distortion and
      airway obstruction that it causes. However, some epignathi protrude
      bidirectionally, involving and destroying the brain tissue, resulting in a poor
      prognosis. This report presents a case of ultrasonographic detection of a
      bidirectional epignathus at 15 weeks of pregnancy.

PMID- 10341409
TI  - Fetal craniofacial structure and intracranial morphology in a case of Apert
      syndrome.
AB  - Apert syndrome is characterized by craniosynostosis, midfacial hypoplasia and
      bilateral syndactyly. We document in detail the intrauterine natural history of
      Apert syndrome by serial sonographic examination. Ultrasound examination of a 19
      week fetus revealed an abnormal appearance of the skull. The subsequent
      examination including transvaginal brain scanning demonstrated a deformed
      occipital part of the cerebrum and lateral ventricles, frontal bossing, a low
      nasal bridge and an abnormal appearance of the fetal hands and feet. The
      distortion of the fetal profile became progressively worse with advancing
      gestation. Towards the end of pregnancy, anterior prominence of the cerebrum,
      ventricles and corpus callosum was demonstrated and mild non-progressive
      ventriculomegaly was seen. The female 3152-g newborn with the typical facial
      appearance of Apert syndrome, bilateral syndactyly of the fingers and toes and
      isolated cleft palate was delivered at 37 weeks. Postnatal three-dimensional
      computed tomography scan demonstrated the fusion of the coronal suture and a wide
      mid-line calvarial defect, and cranial magnetic resonance imaging confirmed the
      prenatal sonographic findings. Although the karyotype was normal, genomic DNA
      analysis of the fibroblast growth factor receptor 2 revealed Ser252Trp, which is
      specified in the mutational basis of Apert syndrome. The time course of the
      prenatal findings in this case may help increase understanding of the
      intrauterine natural history of Apert syndrome.

PMID- 10341410
TI  - Ectopic pregnancy diagnosed by laparoscopic ultrasound scan.

PMID- 10341411
TI  - Dynamic observation of the fetal face by three-dimensional ultrasound.

PMID- 10341412
TI  - Value of end-points from multiple or worst case Doppler spectra for the
      assessment of ovarian masses.

PMID- 10341413
TI  - Laser coagulation of superficial vascular anastomosis in twin-to-twin transfusion
      syndrome.

PMID- 10341414
TI  - Three-dimensional power Doppler imaging of the fallopian tube.

PMID- 10341415
TI  - Presentation of the 1998 Ian Donald Gold Medal to Sturla Eik-Nes.

PMID- 10341416
TI  - Presentation of the Ian Donald Medal for Technical Development to Peter N. T.
      Wells.

PMID- 10341417
TI  - Vectors for rapid selection of integrants with different plasmid copy numbers in
      the yeast Hansenula polymorpha DL1.
AB  - Plasmids with different selectable markers were constructed and used to transform
      the Hansenula polymorpha strain DL1. It was shown that, depending on the host
      mutant strain, the use of these plasmids enables rapid selection of transformants
      with plasmids integrated in low (1-2), moderate (6-9) or high (up to 100) copy
      numbers. The vectors and mutant described are potentially useful for the
      construction of efficient producers of heterologous proteins in H. polymorpha.

PMID- 10341418
TI  - Effects of weak acids on cation accumulation, delta pH and delta psi in yeast.
AB  - With glucose as carbon source, as reported by other authors (Conway et al.,
      1950), yeast cells accumulated large amounts of CO2, carbonic acid, bicarbonate
      and K+ than when grown with ethanol. The addition of propionic acid to the cells
      produced an increase in the potassium ion accumulation when cells were incubated
      with ethanol as substrate, but not when incubated with glucose. In disagreement
      with Ryan et al. (1971) and Ryan and Ryan (1972), the internal pH of the cells
      with ethanol was lower than with glucose, eliminating this factor as the limiting
      factor for potassium accumulation. When the membrane potential difference was
      estimated, it was found that it was higher with glucose as substrate than with
      ethanol. In addition, with ethanol the addition of propionic acid produced an
      increase of the membrane potential, in agreement with the idea of an accumulation
      of the anions of monoprotic acids, which, being not diffusible, increase the
      negative membrane potential inside, which can drive the accumulation of larger
      amounts of monovalent cations. It was also found that the addition of propionic
      acid to cells incubated with glucose as substrate produced an efflux of CO2 from
      the cells, so that an exchange of the acid appears to take place.

PMID- 10341419
TI  - Disruption of the KEX1 gene in Pichia pastoris allows expression of full-length
      murine and human endostatin.
AB  - Endostatin is a potent angiogenesis inhibitor. In order to isolate sufficient
      quantities of soluble protein for in vivo studies in mice, we expressed murine
      endostatin in Pichia pastoris. Analysis of the expressed protein by mass
      spectrometry indicated that the protein was truncated. N-terminal sequence
      analysis determined that the N-terminus was intact, suggesting that the C
      terminal lysine was missing. In Saccharomyces cerevisiae, Kex1p can cleave lysine
      and arginine residues from the C-terminus of peptides and proteins. We
      hypothesized that the KEX1 homologue in P. pastoris is responsible for the loss
      of the C-terminal lysine of endostatin. To test this hypothesis, we cloned and
      disrupted the P. pastoris KEX1 gene. Although the overall amino acid identity
      between the P. pastoris and the S. cerevisae Kex1p is only 36%, the amino acid
      residues involved in the catalytic activity or close to the active residues are
      highly conserved. Disruption of the KEX1 reading frame allowed expression of
      murine and human endostatin with the C-terminal lysine. The KEX1 disruption
      strain may be a useful tool for the expression of other proteins with a C
      terminal basic amino acid. Addition of a lysine to the C-terminus of recombinant
      proteins may protect the C-terminus from degradation by other carboxypeptidases.

PMID- 10341421
TI  - Identification of a gene encoding the pyruvate decarboxylase gene regulator
      CaPdc2p from Candida albicans.
AB  - In a screen for Candida albicans genes encoding transactivating proteins, a
      pyruvate decarboxylase (EC 4.1.1.1.) regulator gene was isolated. An open reading
      frame (ORF) of 2511 bp was identified encoding a predicted protein of 836 amino
      acids with a molecular weight of 94.4 kDa. The protein showed glutamine- and
      proline-rich stretches typical for transcriptional activators. The amino acid
      sequence comparisons between CaPdc2p of C. albicans and both Pdc2p of
      Saccharomyces cerevisiae and Rag3p of Kluyveromyces lactis, revealed similarities
      of 40% and 39%, respectively. The CaPDC2 gene was localized on chromosome 1.
      Southern blot analysis indicated that CaPDC2 might be a single copy gene. The
      growth defect of a S. cerevisiae pdc2 delta mutant on glucose was compensated by
      transformation of the C. albicans CaPDC2 gene.

PMID- 10341420
TI  - Regulated expression of the Saccharomyces cerevisiae Fre1p/Fre2p Fe/Cu reductase
      related genes.
AB  - The Saccharomyces cerevisiae genome contains nine open reading frames (ORFs)-
      YLR214w (FRE1), YKL220c (FRE2), YOR381w, YNR060w, YOR384w, YLL051c, YOL152w,
      YGL160w and YLR047c--which, based on amino acid sequence similarity, fall in the
      category of iron/copper reductase-related genes. FRE1 and FRE2 are the first
      identified and studied genes of this family. They both encode for plasma membrane
      ferric/cupric reductases and their expression is regulated by iron and copper
      availability, mediated by the transcription factors Aft1p and Mac1p,
      respectively. We have studied the expression of the seven ORFs of unknown
      function by monitoring mRNA accumulation under different growth conditions,
      namely, their response to iron and copper availability in the medium, as well as
      the involvement of transcription factors Aft1p and Mac1p in their expression. A
      compilation of these results, together with sequence comparison data, permits a
      first classification of these genes under three major groups: genes mainly
      regulated by iron availability, genes mainly regulated by copper availability and
      genes not regulated by either metal.

PMID- 10341422
TI  - The KlPMR1 gene of Kluyveromyces lactis encodes for a P-type Ca(2+)-ATPase.
AB  - A novel P-type Ca(2+)-ATPase gene has been cloned and sequenced in the yeast
      Kluyveromyces lactis. The gene has been named KlPMR1 and is localized on
      chromosome I. The putative gene product contains 936 residues and has a
      calculated molecular weight of 102,437 Da. Analysis of deduced amino acid
      sequence (KlPmr1p) indicated that the encoded protein retains all the highly
      conserved domains characterizing the P-type ATPases. KlPmr1p shares 71% amino
      acid identity with Pmr1p of S. cerevisiae, 62% with HpPmr1p of Hansenula
      polymorpha, 56% with Y1Pmr1p of Yarrowia lipolytica and 52% with the Ca(2+)
      ATPase encoded for by the SPCA1 gene of Rattus norvegicus; these similarities
      place KlPmr1p in the SPCA group (secretory pathway Ca(2+)-ATPase) of the P-type
      ATPases. The K. lactis strain harbouring the Klpmr1 disrupted gene is not able to
      grow in presence of low calcium concentrations and shows hypersensitivity to high
      concentrations of EGTA in the medium. These defects are relieved by PMR1 of S.
      cerevisiae on a centromeric plasmid, demonstrating that KlPMR1 encodes for a
      functional Pmr1p homologue.

PMID- 10341423
TI  - Systematic analysis of yeast strains with possible defects in lipid metabolism.
AB  - Lipids are essential components of all living cells because they are obligate
      components of biological membranes, and serve as energy reserves and second
      messengers. Many but not all genes encoding enzymes involved in fatty acid,
      phospholipid, sterol or sphingolipid biosynthesis of the yeast Saccharomyces
      cerevisiae have been cloned and gene products have been functionally
      characterized. Less information is available about genes and gene products
      governing the transport of lipids between organelles and within membranes or the
      turnover and degradation of complex lipids. To obtain more insight into lipid
      metabolism, regulation of lipid biosynthesis and the role of lipids in organellar
      membranes, a group of five European laboratories established methods suitable to
      screen for novel genes of the yeast Saccharomyces cerevisiae involved in these
      processes. These investigations were performed within EUROFAN (European Function
      Analysis Network), a European initiative to identify the functions of unassigned
      open reading frames that had been detected during the Yeast Genome Sequencing
      Project. First, the methods required for the complete lipid analysis of yeast
      cells based on chromatographic techniques were established and standardized. The
      reliability of these methods was demonstrated using tester strains with
      established defects in lipid metabolism. During these investigations it was
      demonstrated that different wild-type strains, among them FY1679, CEN.PK2-1C and
      W303, exhibit marked differences in lipid content and lipid composition. Second,
      several candidate genes which were assumed to encode proteins involved in lipid
      metabolism were selected, based on their homology to genes of known function.
      Finally, lipid composition of mutant strains deleted of the respective open
      reading frames was determined. For some genes we found evidence suggesting a
      possible role in lipid metabolism.

PMID- 10341425
TI  - Current awareness on yeast.

PMID- 10341424
TI  - Generation of null alleles for the functional analysis of six genes from the
      right arm of Saccharomyces cerevisiae chromosome II.
AB  - Using PCR-ligated long flanking homology cassettes, null alleles of six open
      reading frames (ORFs) from chromosome II have been created in Saccharomyces
      cerevisiae. Deletants were constructed in three genetic backgrounds: FY1679, W303
      and CEN.PK2. Tetrad analysis of heterozygous deletants revealed that none of the
      ORFs is essential for vegetative growth. Basic phenotypic analysis of haploid
      deletants showed that deletion of the YBR283c ORF causes a slight growth defect
      at 30 degrees C and 37 degrees C on glycerol-complete, glucose-complete, and
      glucose-minimal media only in the FY1679 and W303 backgrounds. Transformation of
      these deletants with the corresponding cognate gene in a centromeric plasmid
      complements the defects. Deletion of the YBR287w ORF leads to poor growth on
      glucose-minimal medium at 15 degrees C in the FY 1679 background. None of the six
      ORFs seems to be involved in mating or sporulation.

PMID- 10341426
TI  - High-cell-density cultivation of microorganisms.
AB  - High-cell-density cultivation (HCDC) is required to improve microbial biomass and
      product formation substantially. An overview of HCDC is given for microorganisms
      including bacteria, archae and eukarya (yeasts). Problems encountered by HCDC and
      their possible solutions are discussed. Improvements of strains, different types
      of bioreactors and cultivation strategies for successful HCDC are described.
      Stirred-tank reactors with and without cell retention, a dialysis-membrane
      reactor, a gas-lift reactor and a membrane cyclone reactor used for HCDC are
      outlined. Recently modified traditional feeding strategies and new ones are
      included, in particular those for unlimited growth to very dense cultures.
      Emphasis is placed on robust fermentation control because of the growing
      industrial interest in this field. Therefore, developments in the application of
      multivariate statistical control, artificial neural networks, fuzzy control and
      knowledge-based supervision (expert systems) are summarized. Recent advances
      using Escherichia coli--the pioneer organism for HCDC--are outlined.

PMID- 10341427
TI  - Production of ketocarotenoids by microalgae.
AB  - Among the highly valued ketocarotenoids employed for food coloration, astaxanthin
      is probably the most important. This carotenoid may be produced
      biotechnologically by a number of microorganisms, and the most promising seems to
      be the freshwater flagellate Haematococcus pluvialis (Chlorophyceae), which
      accumulate astaxanthin in their aplanospores. Many physiological aspects of the
      transition of the flagellate into aplanospores have been described. Mixotrophic
      cultivation and suitable irradiance may result in fairly good yields (up to 40
      mg/l; 43 mg/g cell dry weight) within a reasonable time, under laboratory
      conditions. In order to compete with synthetic astaxanthin, suitable scaling-up
      is required. However, large-scale production in open ponds has proved
      unsatisfactory because of severe contamination problems. A selective medium might
      overcome this difficulty. Further research for the development of suitable
      strains is thus warranted.

PMID- 10341428
TI  - Cultivation of Tetrahymena thermophila in a 1.5-m3 airlift bioreactor.
AB  - A large-scale cultivation system for the mass cell production and extraction of
      the protozoon Tetrahymena thermophila has been developed on the basis of a low
      cost complex nutrient medium. Cell growth and the production of extracellular
      proteases were investigated using a 15-l stirred-tank reactor and 13-l and 1500-l
      airlift reactors. Processes using defined and complex medium formulations were
      compared. After cell mass production by 1200 l cell suspension in the large
      airlift bioreactor, two different extraction methods, based on the use of an
      extraction decanter and a sedimentation procedure, were compared and followed by
      cell lyophilization. Cell sedimentation was shown to be the more efficient
      extraction method as it enabled cell retention/separation while preserving the
      cell structure. Maximum cell growth was achieved in the stirred-tank bioreactor,
      supporting the hypothesis that higher shear forces reduce the particle size of
      the medium, which is responsible for an optimized nutrient supply. The highest
      glucose uptake rates were found in defined medium lacking the nutrient particles
      that are present in complex medium formulations. The cell-specific proteolytic
      activity in culture supernatants of airlift bioreactors using complex medium
      conditions was higher than that of a culture broth with cells grown under defined
      medium formulations.

PMID- 10341429
TI  - Purification and characterization of a soybean-milk-coagulating enzyme from
      Bacillus pumilus TYO-67.
AB  - Bacillus pumilus TYO-67 was isolated from tofu (soybean curd) as the best
      producer of a soybean-milk-coagulating enzyme, induced by the addition of soybean
      protein to the growth medium. The enzyme was purified approximately 30-fold with
      an 11% yield. The homogeneous preparation of the enzyme showed that it is a
      monomer with a molecular mass of about 30 kDa and has an isoelectric point at pH
      9.75. The results of amino acid composition analyses showed that the enzyme is
      rich in alanine, aspartic acid, glycine, serine and valine. Although the amino
      terminal amino acid (alanine) was identical with that of subtilisins, the amino
      terminal sequence was different from those of subtilisins. The alpha-helix
      content of the enzyme was calculated to be 28.2%. The optimum pH and temperature
      were observed at 6.0-6.1 and 65 degrees C respectively. The enzyme was
      significantly activated by the addition of 1 mM Mn2+, Ca2+, Mg2+, and Sr2+ ions
      in the reaction mixture, and its thermal stability was significantly increased by
      Ca2+ ion.

PMID- 10341430
TI  - Substrate selectivity of various lipases in the esterification of cis- and trans
      9-octadecenoic acid.
AB  - The substrate selectivity of numerous commercially available lipases from
      microorganisms, plants and animal tissue towards 9-octadecenoic acids with
      respect to the cis/trans configuration of the C=C double bond was examined by the
      esterification of cis- and trans-9-octadecanoic acid (oleic and elaidic acid
      respectively) with n-butanol in n-hexane. A great number of lipases studied, e.g.
      those from Pseudomonas sp., porcine pancreas or Carica papaya, were unable to
      discriminate between the isomeric 9-octadecenoic acids. However, lipases from
      Candida cylindracea and Mucor miehei catalysed the esterification of oleic acid 3
      4 times faster than the corresponding reaction of elaidic acid and therefore have
      a high preference for the cis isomer. Of all biocatalysts examined, only
      recombinant lipases from Candida antarctica favoured elaidic acid as substrate.
      While the preference of Candida antarctica lipase B for the trans isomer was
      quite low, Candida antarctica lipase A had an extraordinary substrate selectivity
      and its immobilized enzyme preparation [Chirazyme L-5 (3) from Boehringer]
      esterified elaidic acid about 15 times faster than oleic acid.

PMID- 10341431
TI  - Stereoselective reduction of ethyl 4-chloro-3-oxobutanoate by Escherichia coli
      transformant cells coexpressing the aldehyde reductase and glucose dehydrogenase
      genes.
AB  - The asymmetric reduction of ethyl 4-chloro-3-oxobutanoate (COBE) to ethyl (R)-4
      chloro-3-hydroxybutanoate [(R)-CHBE] using Escherichia coli cells, which
      coexpress both the aldehyde reductase gene from Sporobolomyces salmonicolor and
      the glucose dehydrogenase (GDH) gene from Bacillus megaterium as a catalyst was
      investigated. In an organic solvent-water two-phase system, (R)-CHBE formed in
      the organic phase amounted to 1610 mM (268 mg/ml), with a molar yield of 94.1%
      and an optical purity of 91.7% enantiomeric excess. The calculated turnover
      number of NADP+ to CHBE formed was 13,500 mol/mol. Since the use of E. coli JM109
      cells harboring pKAR and pACGD as a catalyst is simple, and does not require the
      addition of GDH or the isolation of the enzymes, it is highly advantageous for
      the practical synthesis of (R)-CHBE.

PMID- 10341432
TI  - Characterisation of cellulose-binding proteins that are involved in the adhesion
      mechanism of Fibrobacter intestinalis DR7.
AB  - Cellulose-binding proteins (CBP) isolated from cell envelopes of the cellulolytic
      bacterium Fibrobacter intestinalis strain DR7 were studied in order to
      investigate the adhesion mechanism. The proteins were examined for their reaction
      with antibodies that specifically block bacterial adhesion, response to
      glycosylation staining and monosaccharide composition. To this end, the effect of
      some monosaccharides (CBP components) on blocking of DR7 adhesion to cellulose
      was determined. Previous study had shown the occurrence of 16 CBP in the outer
      membrane and periplasm of DR7, of which 6 had endoglucanase activity (Miron and
      Forsberg 1998). Data from the present study show that most of the 16 CBP of DR7,
      except for the 38-, 90- and 180-kDa proteins, are glycosylated. Rabbit antibodies
      that specifically block DR7 adhesion were prepared by affinity preabsorption of
      antiserum against wild-type DR7 with bacterial cells of its adherence-defective
      mutant (DR7-M). The preabsorbed antibodies reacted positively in Western blotting
      with glycosylated CBP of 225, 200, 150, 70, 45 and < 38 kDa from the DR7 outer
      membrane, and reacted weakly with CBP of DR7-M. Modification of glycosidic
      residues attached to the CBP of DR7 by periodate oxidation prevented any reaction
      with the preabsorbed antibodies. Monosaccharide analysis by HPLC of isolated CBP
      from the outer membrane and periplasm of DR7 cells, showed that galactosamine,
      glucosamine, galacturonic acid, and glucuronic acid were the predominant
      monosaccharide components of CBP that can block the adhesion of DR7 cells to
      cellulose. It is suggested that some glycosylated residues of CBP may have a
      predominant role in the adhesion of DR7 to cellulose.

PMID- 10341433
TI  - Cometabolic biodegradation of methyl t-butyl ether by Pseudomonas aeruginosa
      grown on pentane.
AB  - A bacterial strain identified as Pseudomonas aeruginosa was isolated from a soil
      consortium able to mineralize pentane. P. aeruginosa could metabolize methyl t
      butyl ether (MTBE) in the presence of pentane as the sole carbon and energy
      source. The carbon balance for this strain, grown on pentane, was established in
      order to determine the fate of pentane and the growth yield (0.9 g biomass/g
      pentane). An inhibition model for P. aeruginosa grown on pentane was proposed.
      Pentane had an inhibitory effect on growth of P. aeruginosa, even at a
      concentration as low as 85 micrograms/l. This resulted in the calculation of the
      following kinetic parameters (mumax = 0.19 h-1, Ks = 2.9 micrograms/l, Ki = 3.5
      mg/l). Finally a simple model of MTBE degradation was derived in order to predict
      the quantity of MTBE able to be degraded in batch culture in the presence of
      pentane. This model depends only on two parameters: the concentrations of pentane
      and MTBE.

PMID- 10341434
TI  - Purification and properties of a novel raw starch degrading cyclomaltodextrin
      glucanotransferase from Bacillus firmus.
AB  - A novel raw starch degrading cyclomaltodextrin glucanotransferase (CGTase; E.C.
      2.4.1.19), produced by Bacillus firmus, was purified to homogeneity by
      ultrafiltration, affinity and gel filtration chromatography. The molecular weight
      of the pure protein was estimated to be 78,000 and 82,000 Da, by SDS-PAGE and gel
      filtration, respectively. The pure enzyme had a pH optimum in the range 5.5-8.5.
      It was stable over the pH range 7-11 at 10 degrees C, and at pH 7.0 at 60 degrees
      C. The optimum temperature for enzyme activity was 65 degrees C. In the absence
      of substrate, the enzyme rapidly lost its activity above 30 degrees C. K(m) and
      kcat for the pure enzyme were 1.21 mg/ml and 145.17 microM/mg per minute
      respectively, with soluble starch as the substrate. For cyclodextrin production,
      tapioca starch was the best substrate used when gelatinized, while wheat starch
      was the best substrate used when raw. This CGTase could degrade raw wheat starch
      very efficiently; up to 50% conversion to cyclodextrins was obtained from 150 g/l
      starch without using any additives. The enzyme produced alpha-, beta- and gamma
      cyclodextrins in the ratio of 0.2:9.2:0.6 and 0.2:8.6:1.2 from gelatinized
      tapioca starch and raw wheat starch with 150 g/l concentration respectively,
      after 18 h incubation.

PMID- 10341435
TI  - Optimization of pyrene oxidation by Penicillium janthinellum using response
      surface methodology.
AB  - At present, there is little information on the optimization of the degradation of
      polycyclic aromatic hydrocarbons (PAH) by deuteromycete filamentous fungi, a
      reaction catalyzed by cytochrome P450 monooxygenases. We utilized response
      surface methodology to determine the optimal growth conditions for the oxidation
      of the PAH pyrene by Penicillium janthinellum SFU403, with respect to the
      variables glucose concentration, nitrate concentration and bioconversion time.
      Models were derived for the relationship between the variables tested and the
      level of the pyrene oxidation products. 1-pyrenol (1-PY) and pyrenequinones (PQ).
      Production of 1-PY and PQ were optimized by the same glucose and nitrate
      concentrations: 2.5% glucose and 1.5% sodium nitrate. The optimized 1-PY and PQ
      bioconversion times were 71 h and 73 h respectively. These conditions improved
      the yield of 1-PY by fivefold and PQ were more than 100-fold higher than the
      baseline levels obtained in this study. The optimized PQ yield represented 95% of
      the initial pyrene, thus the total optimised pyrene bioconversion to 1-PY and PQ
      was approximately 100%. Concentrations of glucose exceeding 4.0% repressed pyrene
      hydroxylation. Pyrene hydroxylation occurred almost exclusively during the
      deceleration phase of culture growth.

PMID- 10341436
TI  - Aerobic degradation of a hydrocarbon mixture in natural uncontaminated potting
      soil by indigenous microorganisms at 20 degrees C and 6 degrees C.
AB  - A hydrocarbon mixture containing p-xylene, naphthalene, Br-naphthalene and
      straight aliphatic hydrocarbons (C14 to C17) was aerobically degraded without lag
      phase by a natural uncontaminated potting soil at 20 degrees C and 6 degrees C.
      Starting concentrations were approximately 46 ppm for the aromatic and 13 ppm for
      the aliphatic compounds. All aliphatic hydrocarbons were degraded within 5 days
      at 20 degrees C, to levels below detection (ppb levels) but only down to 10% of
      initial concentration at 6 degrees C. Naphthalene was degraded within 12 days at
      20 degrees C and unaffected at 6 degrees C. At 20 degrees C p-xylene was degraded
      within 20 days, but no degradation occurred at 6 degrees C. Br-naphthalene was
      only removed down to 30% of initial concentration at 20 degrees C, with no
      significant effect at 6 degrees C. The biodegradation was monitored with head
      space solid-phase microextraction and gas chromatography-mass spectrometry.

PMID- 10341437
TI  - Effects of nitrogen limitation on biofilm formation in a hydrocarbon-degrading
      trickle-bed filter.
AB  - The effect of nitrogen limitation on young and mature steady-state biofilm in a
      trickle-bed filter was studied. Toluene and n-heptane were the sole carbon
      source. Biomass concentration, respiration, substrate-induced respiration,
      metabolic quotient, and total hydrocarbon degradation efficiency were measured.
      The aim of the experiment was to control excess biomass production in the trickle
      bed filter by limiting the mineral nutrients and to achieve increased
      mineralization of the carbon source. Biofilm growth responded strongly to the
      amount of available nitrogen, whereas hydrocarbon degradation efficiency reached
      a maximum of 60% and could not be increased even by further addition of nitrogen.
      The experiments showed that 95% of the adsorbed carbon was mineralized completely
      and only 5% was used for biofilm formation. This complete mineralization can also
      be concluded from the metabolic quotient. The value of the latter was about 6-10
      mg CO2-C g-1 Cmic h-1, indicating an expanded energy demand due to stress effects
      in the presence of nutrient deficiency. It was postulated that determination of
      the metabolic quotient could be an simple instrument to measure the rate of
      mineralization of carbon sources and also the rate of biomass formation in
      trickle-bed filters or biofilters.

PMID- 10341438
TI  - Cannibalism facilitates the use of a novel environment in the flour beetle,
      Tribolium castaneum.
AB  - Cannibalism is well known to affect both the population dynamics and the
      competitive relationships of organisms. Cannibalistic behaviour commonly
      increases in stressful conditions, such as when density is high or food is
      scarce, and cannibals often obtain a nutritional benefit. Might cannibalism also
      increase in a novel environment to which a population is poorly adapted
      physiologically? Moreover, might cannibalistic behaviour provide enough of a
      nutritional advantage in a nutritionally stressful environment to rescue
      individuals from its adverse effects and thus permit colonization and range
      expansion? Previous work has shown that oat flour is a particularly stressful
      environment for Tribolium castaneum. In the study reported here, egg cannibalism
      by two strains of T. castaneum was significantly enhanced in oat flour, and egg
      eating rescued larvae from the adverse demographic effects of this poor
      environment. Development time of the cannibals was accelerated almost to the
      level seen for individuals reared in the nutritionally superior environment
      (wheat plus brewer's yeast). Their survival and fecundity also increased relative
      to individuals reared in oat flour without the opportunity to cannibalize. A sib
      analysis revealed that for larvae reared in the presence of victim eggs, the
      extent of cannibalism was genetically variable, so that this trait could evolve,
      given a selective benefit exceeding its cost. These results suggest that
      colonization of a marginal new environment could be facilitated by enhanced rates
      of cannibalism. The possible interplay between cannibalism and physiological
      adaptation to a new environment is discussed.

PMID- 10341439
TI  - Phosphorylation-dependent interactions between enzymes of plant metabolism and 14
      3-3 proteins.
AB  - Far-Western overlays of soluble extracts of cauliflower revealed many proteins
      that bound to digoxygenin (DIG)-labelled 14-3-3 proteins. Binding to DIG-14-3-3s
      was prevented by prior dephosphorylation of the extract proteins or by
      competition with 14-3-3-binding phosphopeptides, indicating that the 14-3-3
      proteins bind to phosphorylated sites. The proteins that bound to the DIG-14-3-3s
      were also immunoprecipitated from extracts with anti-14-3-3 antibodies,
      demonstrating that they were bound to endogenous plant 14-3-3 proteins. 14-3-3
      binding proteins were purified from cauliflower extracts, in sufficient quantity
      for amino acid sequence analysis, by affinity chromatography on immobilised 14-3
      3 proteins and specific elution with a 14-3-3-binding phosphopeptide. Purified 14
      3-3-binding proteins included sucrose-phosphate synthase, trehalose-6-phosphate
      synthase, glutamine synthetases, a protein (LIM17) that has been implicated in
      early floral development, an approximately 20 kDa protein whose mRNA is induced
      by NaCl, and a calcium-dependent protein kinase that was capable of
      phosphorylating and rendering nitrate reductase (NR) sensitive to inhibition by
      14-3-3 proteins. In contrast to the phosphorylated NR-14-3-3 complex which is
      activated by dissociation with 14-3-3-binding phosphopeptides, the total sugar
      phosphate synthase activity in plant extracts was inhibited by up to 40% by a 14
      3-3-binding phosphopeptide and the phosphopeptide-inhibited activity was
      reactivated by adding excess 14-3-3 proteins. Thus, 14-3-3 proteins are
      implicated in regulating several aspects of primary N and C metabolism. The
      procedures described here will be valuable for determining how the
      phosphorylation and 14-3-3-binding status of defined target proteins change in
      response to extracellular stimuli.

PMID- 10341440
TI  - Induction of RAB18 gene expression and activation of K+ outward rectifying
      channels depend on an extracellular perception of ABA in Arabidopsis thaliana
      suspension cells.
AB  - Important progress has been made regarding the characterization of the ABA
      signalling components using genetic and molecular approaches (Leung and Giraudat,
      1998). However, we do not yet know the mechanism of ABA perception. Conflicting
      results concerning the site of ABA perception have been published. The prevailing
      view is that since ABA controls many responses, different sites of perception for
      ABA might exist. In order to establish the cellular localisation of the ABA
      receptors in Arabidopsis thaliana suspension cells, we developed two
      physiological tests based upon the capacity of impermeant ABA-BSA conjugate to
      mimic permeant free ABA effects. We show that purified ABA-BSA conjugate is able
      to trigger RAB18 gene expression and that this response is strictly due to the
      natural (+)-ABA enantiomer. The rate of RAB18 gene expression was independent of
      the level of ABA uptake by the cells. Using the voltage-clamp technique we show
      that ABA-BSA, similarly to ABA, evokes a membrane depolarization and activates
      time- and voltage-dependent outward rectifying currents (ORC). We demonstrate
      that these ORC are due to a K+ efflux as assessed by tail currents and specific
      inhibition by both tetraethylammonium (TEA) and Ba2+. These observations provide
      evidence in favour of an extracellular site for ABA perception.

PMID- 10341441
TI  - Functional analysis of a Golgi-localized Kex2p-like protease in tobacco
      suspension culture cells.
AB  - Kex2p is the prototype of a Golgi-resident protease responsible for the
      processing of prohormones in yeast and mammalian cells. A Kex2p-like pathway was
      shown to be responsible for processing the fungal KP6 protoxin in transgenic
      tobacco plants. We previously described a chimeric integral membrane reporter
      protein that traffics through Golgi to the lytic prevacuole where it was
      proteolytically processed. As a first step to isolate and clone the Kex2p-like
      protease in plant cells, we designed and used a similar chimeric reporter protein
      containing Kex2 cleavage sites to assay the Kex2p-like activity and to determine
      its substrate specificity in tobacco cells. Here we demonstrate that the Kex2
      cleavage sites of the reporter were specifically processed by a protease activity
      with a substrate specificity characteristic of yeast Kex2p. This Kex2p-like
      protease in tobacco cells is also a Golgi-resident enzyme. Thus, the reporter
      protein provides a biochemical marker for studying protein traffic through the
      Golgi in plant cells. These results additionally should allow the design of
      synthetic substrates for use in biochemical purification of the plant enzyme.

PMID- 10341442
TI  - Isolation, characterization and immunolocalization of a novel, modular tomato
      arabinogalactan-protein corresponding to the LeAGP-1 gene.
AB  - Arabinogalactan-proteins (AGPs) are a family of hydroxy-proline-rich
      glycoproteins implicated to function in plant growth and development. This report
      focuses on a novel, modular AGP found in tomato, LeAGP-1, which was predicted by
      DNA cloning and herein verified at the protein level as a major AGP component.
      LeAGP-1 was isolated from tomato suspension-cultured cells and verified to be an
      AGP by precipitation with (beta-D-galactosyl)3 Yariv phenylglycoside and by amino
      acid composition analysis. Furthermore, LeAGP-1 was determined to correspond to
      LeAGP-1 clones based on three criteria: (1) amino acid composition identity, (2)
      amino acid sequence identity, and (3) specific immunoreactivity of glycosylated
      and deglycosylated LeAGP-1 with an antibody developed against the highly basic
      subdomain predicted from LeAGP-1 clones. The antibody was also used to
      immunolocalize LeAGP-1 in tomato to the cell surface of suspension-cultured
      cells, maturing metaxylem elements in young internodes and petioles, and stylar
      transmitting tissue cells. At the subcellular level, LeAGP-1 immunolocalized to
      the cell walls of these particular cells as well as to intercellular spaces
      between stylar transmitting tissue cells. LeAGP-1 now emerges as one of the most
      comprehensively studied AGPs in terms of (1) characterization at the genomic DNA,
      cDNA and protein levels, (2) known organ-specific and developmentally regulated
      mRNA expression patterns, (3) development of an antibody against a unique,
      peptide subdomain which specifically recognizes LeAGP-1 in its glycosylated and
      deglycosylated states, and (4) immunolocalization of a single, well-defined AGP
      molecule at the tissue and subcellular levels.

PMID- 10341443
TI  - Cell wall antibodies without immunization: generation and use of de-esterified
      homogalacturonan block-specific antibodies from a naive phage display library.
AB  - Homogalacturonan (HG) is a multi-functional pectic polysaccharide of primary cell
      walls involved in calcium cross-linking and gel formation, and the regulation of
      ionic status and porosity of the cell wall matrix, and is a source of
      oligosaccharins functioning in development and defence. Phase display monoclonal
      antibodies with specificity for de-esterified stretches ('blocks') of pectic HG
      have been isolated from a naive phage display library without the need for
      immunization of animals or conjugation of an oligosaccharide to protein. These
      antibodies, designated PAM1 and PAM2, bind specifically to de-esterified and un
      substituted HG. Assays with a series of pectins de-esterified by the action of
      plant or fungal pectin methyl esterases indicated that the antibodies were
      specific to de-esterified blocks resulting from the blockwise action of plant
      pectin methyl esterases. Analysis of antibody binding to a series of
      oligogalacturonides indicated that optimal binding required in the region of 30
      de-esterified GalA residues. The recognition of such a large epitope by these
      antibodies allows the HG block architecture of primary cell walls to be
      identified and localized for the first time. Furthermore, we have demonstrated
      that monoclonal antibodies with high specificity and avidity to cell wall
      epitopes can be generated using a 'single pot' phage display approach.

PMID- 10341444
TI  - The helicase domain of the TMV replicase proteins induces the N-mediated defence
      response in tobacco.
AB  - Tobacco mosaic virus (TMV) induces the hypersensitive response (HR) in tobacco
      plants containing the N gene. This defence response is characterized by cell
      death at the site of virus infection and inhibition of viral replication and
      movement. A previous study indicated that a portion of the TMV replicase
      containing a putative helicase domain is involved in HR induction. Here, this
      observation is confirmed and extended by showing that non-viral expression of a
      50 kDa TMV helicase fragment (p50) is sufficient to induce the N-mediated HR in
      tobacco. Like the HR elicited by TMV infection, transgenic expression of p50
      induces a temperature-sensitive defence response. We demonstrate that recombinant
      p50 protein has ATPase activity, as suggested by the presence of conserved
      sequence motifs found in ATPase/helicase enzymes. A point mutation that alters
      one of these motifs abolishes ATPase activity in vitro but does not affect HR
      induction. These results suggest that features of the TMV helicase domain,
      independent of its enzymatic activity, are recognized by N-containing tobacco to
      induce TMV resistance.

PMID- 10341445
TI  - A novel parsley 4CL1 cis-element is required for developmentally regulated
      expression and protein-DNA complex formation.
AB  - The phenylpropanoid enzyme 4-coumarate:coenzyme A ligase (4CL) participates in
      the biosynthesis of a wide range of secondary products with specialized function
      and tissue distribution in plants. The parsley 4CL1 promoter directs a complex
      tissue- and cell-specific pattern of reporter gene expression in transgenic
      tobacco, consistent with the distribution of phenylpropanoid products and sites
      of 4CL expression in tobacco vegetative and floral organs. We generated mutants
      in a 4CL1 promoter element previously implicated as a site for protein-DNA
      complex formation to analyze its role in vivo. Mutation of this element (FP56)
      reduced expression in some organs/tissues up to several hundredfold, with little
      effect on cell-specific expression patterns. Electrophoretic mobility shift
      assays indicated that the FP56 cis-element is the binding site for tobacco and
      parsley nuclear proteins, and that mutations in the same element that reduce
      reporter gene expression in transgenic plants greatly reduce or abolish protein
      DNA complex formation. DNAse I protection assays showed that the region of the
      4CL1 promoter surrounding the FP56 element is the site for formation of two large
      protein-DNA complexes, and that an intact FP56 element is required for formation
      of these complexes. Finally, the detergent deoxycholate was used to investigate
      the role of protein-protein interactions in FP56 complex formation. Our data
      suggest that the FP56 cis-element plays a central role in transcriptional
      activation from the 4CL1 promoter, and that its role may be to nucleate formation
      of a large protein complex on the promoter.

PMID- 10341446
TI  - Inter-organ signaling in plants: regulation of ATP sulfurylase and sulfate
      transporter genes expression in roots mediated by phloem-translocated compound.
AB  - Sulfate uptake and ATP sulfurylase activity in the roots of Arabidopsis thaliana
      and Brassica napus were enhanced by S deprivation and reduced following resupply
      of SO4(2-). Similar responses occurred in split-root experiments where only a
      portion of the root system was S-deprived, suggesting that the regulation
      involves inter-organ signaling. Phloem-translocated glutathione (GSH) was
      identified as the likely transducing molecule responsible for regulating SO4(2-)
      uptake rate and ATP sulfurylase activity in roots. The regulatory role of GSH was
      confirmed by the finding that ATP sulfurylase activity was inhibited by supplying
      Cys except in the presence of buthionine sulfoximine, an inhibitor of GSH
      synthesis. In direct and remote (split-root) exposures, levels of protein
      detected by antibodies against the Arabidopsis APS3 ATP sulfurylase increased in
      the roots of A. thaliana and B. napus during S starvation, decreased after SO4(2
      ) restoration, and declined after feeding GSH. RNA blot analysis revealed that
      the transcript level of APS1, which codes for ATP sulfurylase, was reduced by
      direct and remote GSH treatments. The abundance of AST68 (a gene encoding an
      SO4(2-) transporter) was similarly affected by altered sulfur status. This report
      presents the first evidence for the regulation of root genes involved in nutrient
      acquisition and assimilation by a signal that is translocated from shoot to root.

PMID- 10341447
TI  - Characterisation of a novel gene family of putative cyclic nucleotide- and
      calmodulin-regulated ion channels in Arabidopsis thaliana.
AB  - In plants, cyclic GMP is involved in signal transduction in response to light and
      gibberellic acid. For cyclic AMP, a potential role during the plant cell cycle
      was recently reported. However, cellular targets for cyclic nucleotides in plants
      are largely unknown. Here we report on the identification and characterisation of
      a new gene family in Arabidopsis, which share features with cyclic nucleotide
      gated channels from animals and inward-rectifying K+ channels from plants. The
      identified gene family comprises six members (Arabidopsis thaliana cyclic
      nucleotide-gated channels, AtCNGC1-6) with significant homology among the deduced
      proteins. Hydrophobicity analysis predicted six membrane-spanning domains flanked
      by hydrophilic amino and carboxy termini. A putative cyclic nucleotide binding
      domain (CNBD) which contains several residues that are invariant in other CNBDs
      was located in the carboxy terminus. This domain overlaps with a predicted
      calmodulin (CaM) binding site, suggesting interaction between cyclic nucleotide
      and CaM regulation. We demonstrated interaction of the carboxy termini of AtCNGC1
      and AtCNGC2 with CaM in yeast, indicating that the CaM binding sites are
      functional. Furthermore, it was shown that both AtCNGC1 and AtCNGC2 can partly
      complement the K(+)-uptake-deficient yeast mutant CY162. Therefore, we propose
      that the identified genes constitute a family of plant cyclic nucleotide- and CaM
      regulated ion channels.

PMID- 10341448
TI  - The GRAS gene family in Arabidopsis: sequence characterization and basic
      expression analysis of the SCARECROW-LIKE genes.
AB  - Mutations at the SCARECROW (SCR) locus in Arabidopsis thaliana result in
      defective radial patterning in the root and shoot. The SCR gene product contains
      sequences which suggest that it is a transcription factor. A number of
      Arabidopsis Expressed Sequence Tags (ESTs) have been identified that encode gene
      products bearing remarkable similarity to SCR throughout their carboxyl-termini,
      indicating that SCR is the prototype of a novel gene family. These ESTs have been
      designated SCARECROW-LIKE (SCL). The gene products of the GIBBERELLIN-INSENSITIVE
      (GAI) and the REPRESSOR of ga1-3 (RGA) loci show high structural and sequence
      similarity to SCR and the SCLs. Sequence analysis of the products of the GRAS
      (GAI, RGA, SCR) gene family indicates that they share a variable amino-terminus
      and a highly conserved carboxyl-terminus that contains five recognizable motifs.
      The SCLs have distinct patterns of expression, but all of those analyzed show
      expression in the root. One of them, SCL3, has a tissue-specific pattern of
      expression in the root similar to SCR. The importance of the GRAS gene family in
      plant biology has been established by the functional analyses of SCR, GAI and
      RGA.

PMID- 10341449
TI  - The main regulatory region in the murine PSP gene is a parotid gland enhancer.
AB  - The murine PSP gene is expressed at a high-level in the parotid glands. To extend
      the knowledge of parotid gland expression and develop tools for expression of
      heterologous proteins in this tissue, the regulation of the PSP gene was studied
      using transgenic mice. High-level parotid gland expression of the PSP gene was
      indicated to depend on a novel regulatory region situated between -8.0 and -6.5
      kb. Together with previous results this indicates that the main regulatory
      elements in the PSP gene are situated between -8.0 to -3.1 kb. This region was
      shown to activate a heterologus SV40 early promoter in the parotid glands of
      transgenic mice, suggesting that the PSP gene is controlled by enhancer
      sequences. A novel Psp derived 9.7 kb parotid gland expression cassette, Lama IV,
      carrying all known regulatory regions in the PSP gene was expressed at high
      levels in the parotid glands and should prove highly useful for expression of
      heterologous proteins in the saliva of transgenic mice.

PMID- 10341450
TI  - Conditional transgene expression in endothelial cells.
AB  - The ability to tightly control transgene expression in vivo provides an
      opportunity to determine the role of certain gene products at different times
      during development and/or in response to different stimuli. We have characterized
      and evaluated a tetracycline-responsive endothelial-specific binary system during
      mouse development, by engineering several transgenic lines which drive the
      expression of a tetracycline-controlled transactivator (tTA) under the control of
      either the Tek or Tie promoters (driver lines). We have also generated a
      responder line which carries multiple copies of the tTA DNA binding element
      (tetOS) upstream of a reporter gene coding for a nuclear targeted beta
      galactosidase (responder lines). No expression of the target transgene was
      detected in mice homozygous for the reporter transgene. On mating the driver
      lines with the responder line, expression of beta-galactosidase from the reporter
      transgene was detected within the endothelium. Responder transgene expression was
      repressed rapidly upon addition of doxycycline to the drinking water.
      Importantly, this repression was reversible upon withdrawal of the drug. This
      approach should be useful to deliver the expression of potentially toxic gene
      products or rescue embryonic mutations that affect either the endothelial lineage
      or production of growth factors which are secreted systemically.

PMID- 10341451
TI  - High-level constitutive expression of alpha 1-acid glycoprotein and lack of
      protection against tumor necrosis factor-induced lethal shock in transgenic mice.
AB  - alpha 1-Acid glycoprotein (AGP) is an acute phase protein produced by
      hepatocytes. Although its exact biological function remains controversial, it was
      shown to protect galactosamine-sensitized or normal mice against hepatitis and
      lethal shock induced by tumor necrosis factor (TNF). Rat-AGP-transgenic mice,
      constitutively producing several mg AGP per ml serum were tested for their
      response to a combined challenge with TNF and D-(+)-galactosamine. A previously
      characterized, single transgenic line (9.5-5) was used. In contrast to our
      expectations both heterozygous or homozygous transgenic mice were not protected
      by the endogenously overproduced AGP. However, both transgenic and non-transgenic
      mice were protected by pretreatment with interleukin-1, an effect which we
      believe is mediated by the induction of acute phase proteins like AGP.
      Furthermore, both types of mice were protected by exogenous bovine AGP,
      suggesting that the lack of protection by endogenous AGP is not because of a
      repressed response to AGP. Finally, we demonstrate that purified AGP from the
      serum of transgenic mice is as protective as the AGP from non-transgenic mice or
      rats. The results suggest that AGP is protective only when its concentration is
      rapidly induced, perhaps because the endogenous steady state synthesis of AGP, in
      non-transgenic as well as transgenic mice, is coupled to the production of an AGP
      binding factor. This study provides an interesting example of differences in
      outcome to a lethal challenge between an acute administered and a chronically
      produced protective protein.

PMID- 10341454
TI  - A global collaboration on carcinogenicity screening in transgenic mouse models.

PMID- 10341452
TI  - Stable production of human insulin-like growth factor 1 (IGF-1) in the milk of
      hemi- and homozygous transgenic rabbits over several generations.
AB  - One transgenic rabbit line was generated carrying a fusion gene consisting of the
      cDNA for human IGF-1 fused to a mammary gland specific expression cassette
      derived from bovine alpha-S1-casein sequences. Transgene expression was shown to
      be strictly tissue and lactation period specific. The transgenic rabbit line was
      bred for six generations. All transgenic animals showed stable production of
      biologically active IGF-1 over the generations and no apparent effect on the
      physiological or reproductive performance was observed. The absence of adverse
      effects on homozygous transgenic rabbits suggested the absence of insertional
      mutagenesis. Eight hemizygous transgenic offspring analysed produced on average
      363 +/- 12 micrograms/ml (ranging from 223 +/- 61 to 484 +/- 39 micrograms/ml)
      mature human IGF-1 in their milk, whereas three homozygous animals produced on
      average 543 +/- 41 micrograms/ml (ranging from 360 +/- 15 to 678 +/- 80
      micrograms/ml). Homozygous hulGF-1 females clearly showed a significantly
      increased production performance of the recombinant protein.

PMID- 10341453
TI  - I-cell disease-like phenotype in mice deficient in mannose 6-phosphate receptors.
AB  - Mannose 6-phosphate receptor deficient mice were generated by crossing mice
      carrying null alleles for Igf2 and the 300 kDa and 46 kDa mannose 6-phosphate
      receptors, Mpr300 and Mpr46. Pre- and perinatal lethality of mice nullizygous for
      Igf2, Mpr300 and Mpr46 was increased. Triple deficient mice surviving the first
      postnatal day had normal viability and developed a phenotype resembling human I
      cell disease. The triple deficient mice were characterized by dwarfism, facial
      dysplasia, waddling gait, dysostosis multiplex, elevated lysosomal enzymes in
      serum and histological signs of lysosomal storage predominantly in fibroblasts,
      but also in parenchymal cells of brain and liver. A paternally inherited Mpr300
      wild type allele that is normally inactive in mice due to imprinting was
      reactivated in some tissues of mice lacking IGF II and MPR 46 and carrying a
      maternal Mpr300 null allele. Inspite of the partial reactivation the phenotype of
      these mice was similar to that of triple deficient mice.

PMID- 10341455
TI  - [What is happening with teaching accreditation and reaccreditation for our
      primary care centers and tutors?].

PMID- 10341456
TI  - [Factors influencing the prescription of insulin and oral antidiabetics in
      primary care].
AB  - OBJECTIVES: To analyse the prescription of insulin and oral diabetic medication
      (ODM) in primary health care, and to evaluate which variables, depending on the
      prescribing doctor, work-place or population attended, explain quality and/or
      quantity variations in prescription. DESIGN: Crossover, observational study.
      SETTING: Malaga-Este Health District, Malaga. PARTICIPANTS: 21,166 prescriptions
      issued by 144 doctors in the Malaga-Este Health District during the first quarter
      of 1997 were analysed. MEASUREMENTS AND MAIN RESULTS: Insulin consumption of
      10.63 defined daily doses per 1,000 inhabitants and day (DID) and ODM of 18.51
      DID were calculated. No significant differences were observed in insulin or ODM
      prescription for sex, and few for age, job or doctors' specialty via MIR (intern)
      training. Working in a centre with MIR teaching and in a reformed centre were
      significantly associated with a greater use of insulin (p < 0.0001 and p < 0.02,
      respectively). Having a higher allocation of patients drawing pensions meant a
      greater consumption of insulin (p < 0.01) and even more of ODM (p < 0.0001). The
      population allocated being older was associated with greater consumption of ODM
      without any changes in insulin prescription. CONCLUSIONS: The personal features
      of doctors working in primary care affect very little the quantity and quality of
      insulin and ODM prescription. The characteristics of the work-place (reformed
      centre and centre entitled to teach) and the population attended (older and
      drawing a pension) are the main factors conditioning the amount of prescription
      of insulin and ODM, respectively. Nevertheless, in all cases ODM prescription
      quality is low.

PMID- 10341457
TI  - [Patient preference and stereotype about the gender of the family physician].
AB  - OBJECTIVE: To study the preferences of patients on the gender of the physician
      when consulting for particular health problems; and to know the gender
      stereotypes that patients assign to physicians. DESIGN: Cross-sectional study.
      SETTING: Five teaching health centres in Granada (Spain). PATIENTS: Randomised
      sample of patients that consulted 10 female and 20 female physicians during three
      months (17 patients per physician), for alfa = 5%, beta = 80%, to detect a
      difference of 12% between male and female physicians. MEASUREMENTS AND MAIN
      RESULTS: We used a questionnaire adapted from Fennema (Family Medicine Dept.,
      Wisconsin University, 1990) that was administered by interviewers after the
      consultancy, following a previous pilot study. Preference and stereotype scales
      comprised 10 items, with five reponses (neutral mid-point). Differences were
      analysed with chi 2 with correction for continuity. Non-reponders (33%) were
      replaced, and their age and sex did not bias the study results. Responders were
      210 males (40.9%) and 304 women (59.1%). For "flux in penis/vagina" and
      "haemorrhoids" 50-60% of the patients preferred a physician of the same sex, with
      the remainder expressing no preference. The women preferred female physicians for
      family problems (23%) and depression (23%). The male physicians were more often
      perceived to be unorganised than were the females (24% vs. 5%, p < 0.0005), while
      the female physicians were more often described as humane (15% vs. 10%, p <
      0.0005). Characteristics expressing technical competence were more often
      attributed to the male physicians than to the females, while those expressing
      empathy were more often attributed to the female physicians. CONCLUSIONS:
      Patients prefer physicians of the same gender for some health problems and not
      for others. Patients assign gender stereotypes to physicians. These findings will
      permit a better interpretation of doctor-patient relationships.

PMID- 10341458
TI  - [Prevalence of psychiatric disorders in primary care using the PRIME-MD
      questionnaire].
AB  - OBJECTIVE: To quantify the frequency of psychiatric disorders detected by primary
      care doctors, using the PRIME-MD questionnaire, and by psychiatrists using a
      structured clinical interview. DESIGN: An observational, descriptive, crossover
      study, using a questionnaire. One of each two patients was selected until
      reaching the total number of patients. SETTING: The study was conducted in five
      primary care centres in Madrid. PATIENTS: To be included in the study, patients
      had to consent verbally, be able to understand the questions asked and have been
      previously diagnosed as psychotic or demented. 395 patients were recruited, of
      which 312 completed the study. INTERVENTIONS: The primary care doctor
      administered the PRIME-MD questionnaire to each patient, and then a psychiatrist
      conducted the SCAN interview. RESULTS: The time spent by the doctor on the PRIME
      MD questionnaire was usually 10 minutes. The doctor had previously detected
      psychiatric pathology in 18.5% of his/her patients; with the PRIME-MD
      questionnaire he/she detected it in 53.5%. The psychiatrist with the SCAN
      detected psychiatric pathology in 41.3% of patients. CONCLUSIONS: The high
      frequency of psychiatric disorders in primary care patients and primary care
      doctors' lack of ability in detecting these disorders was confirmed by this
      study. The PRIME-MD questionnaire, an instrument for rapid detection of the most
      commonly found psychiatric disorders within primary care, may considerably
      improve this situation.

PMID- 10341459
TI  - [Description of the organizational climate in primary care teams in an autonomous
      community].
AB  - OBJECTIVE: To describe the organisational atmosphere (OA) in primary care teams
      (PCTs) in an autonomous community. DESIGN: Crossover and observational. SETTING:
      PCTs. PARTICIPANTS: A questionnaire on OA was administered after prior validation
      to all the doctors, nurses and social workers at 29 PCTs. MEASUREMENTS AND MAIN
      RESULTS: The OA in the different teams was described, comprehensively and by
      dimensions: team-work, cohesion and commitment. Multiple regression was used to
      find the relationship between OA (dependent variable) and the independent
      variables: age of the professionals, years of functioning of the PCT, teaching
      status, type, location (rural or urban) and profession (coordinators, doctors,
      nurses, clerical staff). Overall reply rate was 77.5% (402 professionals): it was
      higher for coordinators. Average score on the questionnaire was 3.53 (SD = 0.56):
      it was higher for nurses. Results by dimensions were: team-work 3.67 (SD = 0.59),
      cohesion 3.54 (SD = 0.71) and commitment 3.37 (SD = 0.72). OA was seen as better
      by teaching teams (p < 0.02), both overall and for the teamwork and cohesion
      dimensions. Coordinators had better self-perception of the OA, both overall and
      by dimensions (p < 0.01). Teams who had worked together for a long time thought
      the atmosphere was worse. The type of job and the number of years doing it did
      not affect the perception of OA. CONCLUSIONS: 1. The evaluation of OA is
      generally positive, though it can certainly be improved. 2. Perception is not
      uniform, as coordinators and teaching teams see the OA as better. 3. Teams
      working together for many years see the OA as worse.

PMID- 10341460
TI  - [Can we detect mental disorders in primary care? Usefulness and agreement of 2
      diagnostic instruments].
AB  - OBJECTIVES: The main objective was to evaluate the use of two diagnostic
      instruments for mental disorders in primary care (PC): the PRIME-MD and the
      Goldberg anxiety and depression scales. Second, to determine the concordance
      between the two tests and evaluate the quality of psychiatric diagnosis records
      in the clinical notes. DESIGN: Crossover observational study. SETTING: Luis Vives
      Health Centre (EAP 1), Alcala de Henares (Madrid). PATIENTS: 175 patients who
      attended for consultation on-demand over three months. MEASUREMENTS AND MAIN
      RESULTS: Each patient was given the PRIME-MD test for detecting disorders of
      depression, anxiety, food, alcohol and body form; and the Goldberg scale to
      evaluate anxiety and depression. The clinical records were then reviewed for
      previous psychiatric diagnoses. The two scales were compared and the level of
      concordance obtained. The PRIME-MD found that 78 patients (44.6%) had some mental
      disorder, the most frequent being depression (32.6% of the total). The Goldberg
      scale detected 89 patients (50.8%) with some suspected mental disorder: here too,
      the most common was depression (41.7% of the total). The best indication of
      concordance between the two tests was the diagnosis of anxiety disorders: kappa =
      0.68 (CI 95%, 0.53-0.82). CONCLUSIONS: Both scales seem useful instruments for
      detecting a pathology which is very common in PC clinics: mental disorders.
      Moreover, the concordance between the two scales is acceptable. There was poor
      recording of psychiatric diagnoses in clinical records.

PMID- 10341463
TI  - [Consumption of generic drugs in Area 1 of the Autonomous Community of Aragon].
AB  - OBJECTIVE: Assessing the economic impact that the only use of pharmaceutical
      products with genetic brand (Spanish Official Brand name or International Common
      Denomination) would have had in those cases where prescriptions and dispensations
      were made under fantasy brand names. DESIGN: Descriptive study. SETTING: All
      prescriptions dispensed during 1996 in area I of INSALUD, in the Autonomous
      Community of Aragon, both from primary care center physicians and hospital
      specialist doctors. MEASUREMENTS AND MAIN RESULTS: Daily defined doses were used
      in order to achieve homogeneity due to the wide variety of commercial
      presentations. Results are expressed in percentages of the total expenditure
      (using the prices for the final customer). In 1996, 1.14% of the pharmaceutical
      expenditure was spent in generic drugs in our Area. Brands name drugs for the
      same active principles accounted for a 7.68% of the total expenditure. Thus,
      8.82% of the pharmaceutical budget was spent in these selected active principles.
      If all the prescriptions had been written using the generic drugs, percentages
      between 0.86% and 1.67% of the total expenditure would have been saved.
      CONCLUSIONS: Promoting the use of generic products would increase the efficiency
      of public money since the efficacy and quality of treatment would be ensured at a
      lower cost. This is one of the feasible ways of getting a rational expenditure in
      pharmaceutical products, which account for an important percentage in the total
      amount of money devoted to health care.

PMID- 10341462
TI  - [Etiology and treatment of choice of respiratory infections in primary care.
      Opinion of the physicians of the URANO Group].
AB  - OBJECTIVE: To find the opinion of primary care doctors on the aetiology of
      respiratory infections and their treatment of choice. DESIGN: Crossover study,
      through interview with structured questionnaire. SETTING: Primary care.
      PARTICIPANTS: 400 PC doctors distributed by area in direct proportion to the
      number of doctors in each area. MEASUREMENTS AND MAIN RESULTS: Most doctors
      thought that S. pyogenes was the main cause of pharyngitis and tonsillitis; and
      H. influenzae or S. pneumoniae, of otitis media, sinusitis and exacerbation of
      acute bronchitis. 78% thought that pneumococci were the main causal agent of
      pneumonia. 20.5% and 19.8% thought that viruses were the main cause of
      pharyngitis and acute bronchitis. The treatment of choice depended on the
      clinical profile and what was thought the most likely cause. For pharyngitis,
      tonsillitis and acute bronchitis, first choice was aminopenicillins and second
      was amoxicillin/clavulanic acid. For otitis media, sinusitis and exacerbation of
      chronic bronchitis, cephalosporins were first choice, followed by
      amoxicillin/clavulanic acid. For pneumonia, it was aminopenicillins or
      penicillin, followed by macrolides. CONCLUSIONS: Spanish primary care doctors
      underestimate the viral aetiology of pharyngo-tonsillitis and acute bronchitis,
      which may lead to frequent and unnecessary use of antibiotics in these clinical
      cases. The cause of other infections is well-known, although there are some
      discrepancies as to the treatment of choice with what is recommended in several
      medical hand-books.

PMID- 10341461
TI  - [School failure in a cohort of adolescents].
AB  - OBJECTIVE: To evaluate a cohort of adolescents as to whether their personal
      characteristics and/or determined habits of health and social relations bore any
      relation to the state of their studies two years later. DESIGN: A prospective
      study following a cohort of adolescents. PARTICIPANTS AND SETTING: Third-year ESO
      (aged c. 14) adolescents from the four state secondary schools in Puerto de
      Sagunto. INTERVENTIONS: Once the cohort (n = 551) was defined, in November 1995
      the students themselves filled in a questionnaire on health and relationship
      habits. Two years afterwards they were located through school registers and
      classified as good if they were in the appropriate year, repeat if they were
      repeating a year and disappeared if they had left school. These last two
      categories were both considered school failures (SF). MEASUREMENTS AND RESULTS:
      222 students were classed as SF (40%). 118 of these (21.4%) had left and 104
      (18.9%) were repeating a year. There were statistically significant differences
      in the following characteristics measured at the start of the study: greater SF
      among boys than girls (46.4%/35.6%): the disappeared had a higher average age
      than the good students (14.98/14.17), higher average number of siblings
      (2.73/2.26), and higher average of nights they went out during the week
      (1.65/0.84). Mean family income was lower in the repeat group (1926087/2475436
      pesetas); the money students received weekly was higher in both SF groups (over
      900/641 pesetas). Students whose fathers have university degrees made up only
      7.4% of SF; and no student whose mother had a university degree was SF. 17.5% of
      those who said they spent their free time with their family were SF, whereas 53%
      of those who devoted their free time basically to enjoying themselves were SF. On
      drug consumption, those who replied they never smoked had 27.2% SF, never
      consumed alcohol 25.8% SF, never took marihuana 35.3% SF, and never consumed
      other drugs 39.5% SF. Students who said their relationships with family and
      teachers was bad had 70% and 62.2% of SF, respectively. 70% of those who felt
      depressed were SF. CONCLUSIONS: This study confirms that a favourable family
      atmosphere is important in preventing school failure. It also makes clear that
      young people's social relationships and health habits are closely associated to
      their being a standard student or a school failure.

PMID- 10341464
TI  - [Bibliographic searching. Introduction and theoretical basis].

PMID- 10341465
TI  - [Original article (IV): Tables and figures].

PMID- 10341466
TI  - [AIDS and primary care: homework still remains. Let's not allow any opportunity
      to escape].

PMID- 10341467
TI  - [Hormone replacement treatment and cardiovascular disease].

PMID- 10341468
TI  - [Anxiety and personal conflict caused by fixed drug eruption in the genital
      zone].

PMID- 10341469
TI  - [Why does not semFYC make a pronouncement about health care in childhood?].

PMID- 10341470
TI  - [Teaching].

PMID- 10341471
TI  - [Health professionals and tobacco: a question of incompatibilities].

PMID- 10341472
TI  - Sigmoidoscopy and rectal biopsy--failure of infection control.

PMID- 10341473
TI  - Hepatitis A vaccine: evidence of efficacy after exposure.

PMID- 10341474
TI  - Healthcare computing '99, Harrogate, England.

PMID- 10341475
TI  - A clinic on wheels. A paradigm shift in the provision of care and the challenges
      of information infrastructure.
AB  - The implementation of nontraditional healthcare delivery increases the need for
      information technology innovation, not only in use of computer-based patient
      records, but also in enabling infrastructures to support health information
      exchange. This is very apparent in mobile health clinics where care is provided
      to vulnerable community populations at locations far removed from academic and
      tertiary care settings. Several challenges of designing a computerized system for
      the University of Maryland School of Nursing's Wellmobile will be addressed in
      this article, as well as possible solutions to these challenges. It is the
      authors' belief that implications for further study will become apparent as these
      constraints and challenges are described.

PMID- 10341476
TI  - Recognizing through feeling. A physical and computer simulation based on
      educational theory.
AB  - This article focuses on the educational theory underpinning computer-based
      simulation in professional education. An innovative computer-based physical
      simulation to facilitate student learning of assessment and palpation skills in
      midwifery has been developed to prototype stage and preliminary evaluations
      conducted. The learning experience explicitly builds on the learning and teaching
      theory--a "conversational framework"--developed by Laurillard. A template
      incorporating all the dimensions of the Laurillard framework in the learning
      experience is presented and discussed. It is argued that this template could have
      wider application especially in clinically based health science courses. The case
      based learning environment allows the students to solve problems and make valid
      clinical judgments. Throughout the learning experiences, students effectively
      examine a pregnant woman while interrelating their experiences with the academic
      knowledge of the teacher (a world of "descriptions"). The structure for learning
      relies on a mechanism for identifying and addressing the misunderstandings
      students initially hold. The creation of situations of cognitive conflict in the
      student's world of action (Laurillard's concept of intrinsic feedback) is seen as
      central to the learning experience. Finally, the article will canvass the issues
      faced by a project team designing and developing a technology-based educational
      package around an educational theory.

PMID- 10341477
TI  - Predicting licensure success with a computerized comprehensive nursing exam. The
      HESI Exit Exam.
AB  - This study was designed to determine the accuracy of computerized comprehensive
      nursing exams, HESI Exit Exams (E2s), in predicting registered nurse and
      practical nurse students success on the licensing exam. Schools of nursing that
      administered E2s during the academic year 1996-97 were surveyed to determine how
      many students (n = 2809) predicted by the E2 to pass the licensure exam had
      failed, and if the exam administration was monitored or proctored. Based on the
      findings of this study, the E2 was determined to be an accurate predictor of
      students' success on the licensing exam. However, it was significantly more
      accurate (P = .05) when the exam was monitored (99.49%) than unmonitored
      (96.82%). The E2 was determined to be highly predictive of students' success on
      the licensing exam for all groups tested: associate degree, baccalaureate,
      diploma, and practical nursing students.

PMID- 10341478
TI  - An evaluation of an acuity system as it applies to a cardiac catheterization
      laboratory.
AB  - Patient care using patient volume rather than acuity has been a long-standing
      problem in a cardiac catheterization laboratory in a central New Jersey Medical
      Center. The current pattern of staffing results in some of the nursing staff
      becoming unproductive from a patient care perspective. This recently has become a
      concern of the Vice President of Nursing who has the unpopular task of
      consolidating nursing positions. There is a very effective acuity measurement
      system, the Medicus Acuity System, in place for the various inpatient areas. This
      system also exists in the Emergency Department and is called EMERGE. The system
      collects and objectively weighs information regarding severity of patient needs
      or acuity. These data are collected daily and provide unit managers with
      information regarding hours of direct nursing care on their particular units. The
      information over time shows trends in direct care hours and allows these managers
      to target the average patient population. The system gives insight into units
      that require more and less nursing hours by hour of the day, day of the week, and
      month of the year. This makes overall housewide use of nursing personnel more
      patient-care appropriate and more financially sound, for example, in the summer
      months when acuity is shown to be higher. In today's managed care environment
      this author believes the practice of staffing units based on bed occupancy is now
      regarded as antiquated, inefficient, and impractical. This study investigated a
      modified version of the EMERGE tool and its ability to capture patient acuity as
      it relates to staffing in the cardiovascular laboratory (CVL). During the 5 days
      of data collection, 87 patients were cared for in the CVL. The modified EMERGE
      cards were completed on 54 of the 87 patients that week. This represented 62% of
      that total patient population. Each day data for 60% or more of the patients were
      entered into the study. The interrater reliability of the data collected was
      better than 98% each day with overall accuracy being 99.5%. This interrater
      reliability was based on the findings by the expert panel, who compared two or
      three (approximately 10%) of the actual nurses' notes to the matching EMERGE
      cards each day. More than 80% of the 54 patients were classified as Type 3, well
      above the Type 1 standard patient acuity category for the EMERGE system.
      Telemetry units with a majority of EMERGE Type 3 patients would require between
      50 to 100 minutes of care per visit and would have a significant nursing
      workload. These units are where the CVL draws most of their patient population.
      In summary, this study reflects a growing trend in healthcare that requires
      justification of staffing through the productivity of workers. Acuity tools
      provide tangible and objective data about daily workload and productivity by
      measuring patient's needs. As managed care forces hospitals to cutt staff, acuity
      tools will become more important for evaluating productivity and retaining staff,
      especially nurses.

PMID- 10341479
TI  - A primary shift rotation nurse scheduling using zero-one linear goal programming.
AB  - In this study, the author discusses the effect of nurse shift schedules on
      circadian rhythm and some important ergonomics criteria. The author also reviews
      and compares different nurse shift scheduling methods via the criteria of
      flexibility, fairness, continuity in shift assignments, nurses' preferences, and
      ergonomics principles. In this article, a primary shift rotation system is
      proposed to provide better continuity in shift assignments to satisfy nurses'
      preferences. The primary shift rotation system is modeled as a zero-one linear
      goal programming (LGP) problem. To generate the shift assignment for a unit with
      13 nurses, the zero-one LGP model takes less than 3 minutes on average, whereas
      the head nurses spend approximately 2 to 3 hours on shift scheduling. This study
      reports the process of implementing the primary shift rotation system.

PMID- 10341480
TI  - An approach to the physical examination of young children.

PMID- 10341481
TI  - Multidisciplinary approach for the management of post-herpetic neuralgia in
      elderly patients.
AB  - Post-herpetic neuralgia is associated with significant distress and morbidity.
      The management of acute neuritis and/or post-herpetic neuralgia can be
      particularly difficult. A multidisciplinary approach is required. A team
      consisting of the primary care physician, pain specialist, neurologist,
      geriatrician, pain psychologist, psychiatrist, and a physiatrist with an
      integrated approach will provide the best results. Early interventional therapy
      with sympathetic nerve blocks may significantly decrease the need for long-term
      opioid therapy, as well as long-term use of anticonvulsants, antidepressants, or
      membrane stabilizers. Early referral to a multidisciplinary pain center may
      furthermore decrease the behavioral trauma and family disruption associated with
      this painful condition.

PMID- 10341482
TI  - Childhood blood lead screening in Arkansas: recommendations for health care
      providers.
AB  - Multiple studies documenting regional differences in prevalence of elevated blood
      lead levels suggest that children are not at equal risk for lead exposure. In
      late 1997, the Centers for Disease Control and Prevention (CDC) published
      guidelines to help states and communities make decisions regarding screening
      practices. To apply these guidelines to Arkansas Department of Health blood lead
      data for the 8,883 screens completed in state fiscal year 1997, along with 1990
      Census Bureau housing and poverty statistics, were compiled and reviewed. Based
      upon CDC criteria and other available information, conservative recommendations
      for blood lead screening are presented for each county in the state. Lead
      toxicity in children remains a significant public health concern in certain
      regions of the country. Between 1991-1994, it was estimated about 930,000 U.S.
      children one to five years old had lead levels > or = 10 micrograms/dL. Children
      most at risk include minorities, those residing in large central cities, and
      those living in poverty. Blood lead levels (BLL's) as low as 10 micrograms/dL
      have been linked with possible IQ deficits as well as learning and behavior
      problems. To date, no study has demonstrated benefit from reduction of blood lead
      levels in the 10-24 micrograms/dL range. Nonetheless, in 1991 the Centers for
      Disease Control and Prevention (CDC) published guidelines for screening and
      followup designed to detect lead levels this low, presumably in order to prevent
      additional exposure and perhaps shorten the duration of toxicity. These
      guidelines essentially called for universal screening of one- and two-year old
      children regardless of socioeconomic status or previous population-based results
      of lead screening in their locale. [table: see text] Since release of the
      controversial 1991 guidelines, several reports of lead toxicity prevalence
      surveys from diverse communities have demonstrated extreme variation in the
      magnitude of the problem. For example, in 1994 only 0.6% of Alaska Medicaid
      recipients six years or younger had lead levels > or = 10 micrograms/dL, with the
      highest being 11 micrograms/dL.

PMID- 10341484
TI  - Physical finding: pulsus alternans.

PMID- 10341486
TI  - Another look at Civil War medical care: Atlanta's Confederate hospitals.

PMID- 10341485
TI  - Radiological case of the month. Dialysis related amyloid arthropathy.

PMID- 10341487
TI  - Medicine in Macon--a history.

PMID- 10341488
TI  - Gaining new ground.

PMID- 10341489
TI  - Crawford W. Long, M.D.

PMID- 10341491
TI  - In the beginning ... the founding of the Medical Association of Georgia.

PMID- 10341490
TI  - Coke adds life to Emory medicine.

PMID- 10341492
TI  - A suitable memorial to Henry Grady.

PMID- 10341493
TI  - Emory's General Hospital 43.

PMID- 10341494
TI  - The Georgia Hospital Association 1929-1999 ... a history.

PMID- 10341495
TI  - Medicine in Columbus, Georgia during a time of great change, 1940-1950.

PMID- 10341496
TI  - Feeding the developmentally delayed child.

PMID- 10341497
TI  - Caring for children orphaned by AIDS.

PMID- 10341498
TI  - Human T-cell lymphotropic virus types I and II infections in mother-child pairs
      in Nigeria.
AB  - A community-based survey to determine the prevalence of human T-cell lymphotropic
      type I (HTLV-I) and type II (HTLV-II) virus infections in mothers and children in
      south-western Nigeria was carried out using blood samples collected in 1993. A
      multistage cluster, random sampling procedure was used to select 460 mother-child
      pairs (476 children because there were 16 sets of twins) from 14 enumeration
      areas. A commercially available, whole HTLV-I lysate antigen-based ELISA method
      was used to screen for HTLV-I and HTLV-II antibodies in the samples. A synthetic
      peptide antigen-based ELISA was then used to differentiate between antibody
      reactivity to either HTLV-I or HTLV-II. Reactivity to HTLV-I or HTLV-II
      antibodies was found in 4.3 per cent (20/460) of mothers and in 1.1 per cent
      (5/476) of children in both rural and urban communities and all the positive
      children were males. None of the 16 sets of twins in this study was positive for
      either HTLV-I or HTLV-II. Also none of the mother-child paired sera tested showed
      concordance for either HTLV-I or HTLV-II antibody positivity. The lack of
      concordance between mother and child sera suggests that vertical transmission may
      not be the major route of transmission of HTLV infection to children in south
      western Nigeria. Other modes of transmission, such as the re-use of unsterilized
      needles for injections and surgical knives in local scarification, which are
      common practices in the region, need to be investigated as they may prove to be
      more important than vertical transmission. These findings have important
      implications for any control programme for diseases that can be spread by the
      same routes as HTLV infection (the human immunodeficiency viruses, hepatitis B,
      and hepatitis C infections).

PMID- 10341499
TI  - Plasma fatty acids in children with grade III protein-energy malnutrition in its
      different clinical forms: marasmus, marasmic kwashiorkor, and kwashiorkor.
AB  - Plasma fatty acid patterns were analysed in 15 children aged 2 to 42 months
      (median = 12 months) admitted to the University Hospital, Faculty of Medicine of
      Ribeirao Preto, University of Sao Paulo, suffering from grade III protein-energy
      malnutrition in its different clinical forms: marasmus (n = 5), marasmic
      kwashiorkor (n = 5), and kwashiorkor (n = 5). A control group of eight children
      from the same population aged 3 to 22 months (median = 12 months) was also
      studied. Plasma fatty acids were analysed by gas liquid chromatography. The
      plasma fatty acid patterns detected in grade III protein-energy malnutrition
      indicated changes characteristic of essential fatty acid deficiency, with lower
      linoleic acid (C18:2) levels in the three groups (p < 0.05). The major metabolite
      of linoleic acid, arachidonic acid (C20:4), was lower in the kwashiorkor group
      than in the control group (p < 0.05). Linoleic acid (C18:2) levels were lower in
      the marasmus group than in the kwashiorkor group (p < 0.05). Several factors may
      have contributed to these changes, such as a decreased content of linoleic acid
      in the diet, plus malabsorption and/or poor utilization of fats, and changes in
      the synthesis or degradation of these fatty acids. Although many questions remain
      unanswered, we suggest that an adequate amount of linoleic acid be added to the
      rehabilitation diet of these children in the form of vegetable fat.

PMID- 10341500
TI  - Impact of prematurity on admissions to the neonatal nursery of a rural South
      African district hospital.
AB  - The objectives of this study were to determine causes of admission to a district
      hospital neonatal nursery; to describe outcomes; and to determine risk factors
      for these outcomes. The study was based at the neonatal nursery of Hlabisa
      hospital, KwaZulu/Natal; 149 consecutive admissions to the nursery between May
      and November 1995 were audited. The main outcome measures were diagnosis,
      gestational age, birthweight, critical event during admission (sepsis, severe
      vomiting, diarrhoea, jaundice, fits, apnoea), and outcome (discharged alive,
      death, discharged with deficit). Most admitted neonates (73; 54 per cent) were
      aged less than 37 weeks at birth, and 123 (84 per cent) weighed less than 2.5 kg.
      Prematurity and low birthweight accounted for 114 (81 per cent) admissions. In
      all, 58 (39 per cent) neonates experienced a total of 72 critical events, the
      most frequent being sepsis (39; 54 per cent). Although most (114; 77 per cent)
      were discharged well, 20 (15 per cent) died and three (3 per cent) were
      discharged with a significant deficit. Sepsis and apnoea were most frequent among
      the lightest and most immature babies, while fits were more frequent among
      heavier, mature babies. In a multivariate model, experiencing any critical event
      (odds ratio [OR] 15.6; 95 per cent CI 3.0-82.6, p = 0.001) was the only
      significant independent risk factor for mortality, although birthweight (p =
      0.068) and gestational age (26-30 vs. > or = 37 weeks; OR 5.6, 95 per cent
      confidence internal [CI] 0.3-95.7, p = 0.23), further contributed to risk of
      death. We conclude that a substantial proportion (around 27 per cent) of district
      perinatal mortality occurs in the neonatal nursery. Several simple and effective
      interventions exist to minimize neonatal loss in district hospitals in South
      Africa.

PMID- 10341501
TI  - Rotavirus subgroups, G serotypes, and electrophoretypes in cases of nosocomial
      infantile diarrhoea in Belem, Brazil.
AB  - From November 1992 to November 1994 stool samples were obtained from 237 children
      admitted to a public hospital in Belem. Rotaviruses were detected in 19.3 per
      cent (60/310) of faecal samples. Of these, 32.1 per cent (18/56), 20.9 per cent
      (38/181), and 5.4 per cent (4/73) were recorded in cases of nosocomial diarrhoea,
      community-acquired diarrhoea, and controls, respectively. Fifty-two (86.7 per
      cent) of the 60 rotavirus-positive specimens were subgrouped and the G serotypes
      of 55 (91.7 per cent) of them were determined. Subgroups I and II were detected
      in 50 per cent each of the 52 subgrouped strains. G type 2 was present in 46
      (83.6 per cent) of the 55 serotyped samples; serotypes G1 and (mixed) G1 and G4
      were found in 14.5 per cent and 1.8 per cent, respectively, of these specimens.
      Viral RNA electrophoresis showed 14 distinct patterns, including 56.7 per cent
      (34/60) and 43.3 per cent (26/60) of long and short profiles, respectively. In 40
      (66.6 per cent) of the 60 rotavirus-positive faecal samples no enteropathogens
      other than rotavirus were detected. There was an increased incidence of rotavirus
      infection from July 1993 to February 1994. The rotavirus-related episodes of
      diarrhoea were more severe than those of other aetiology and greater clinical
      severity was not related to a specific G type, subgroup, or electrophoretype.

PMID- 10341502
TI  - Fat absorption in persistent diarrhoea using 13C-labelled trioctanoin breath
      test.
AB  - A study was undertaken to investigate intestinal fat absorption in young children
      suffering from persistent diarrhoea in comparison with normal children of similar
      age. Absorption studies were performed using the breath test technique. Following
      oral administration of labelled triglyceride ([13C]trioctanoin), interval breath
      sampling was done for 6 h. The time course of excretion of 13CO2 in the breath
      was determined by isotope ratio mass spectrometric analysis of the gas samples.
      Excretion curves were constructed from the mean values of 13CO2 dose (per cent)
      excreted at each time point in breath samples and areas under the curve were
      determined for diarrhoea cases as well as for normal subjects. The time course of
      13CO2 excretions and areas under the curve thus obtained were compared with each
      other and also with a reference study in which data from known malabsorption
      cases were available. The time of peak 13CO2 excretion in diarrhoea cases ranged
      from 60 to 240 min (average 150 min) compared with 120 to 270 min (average 195
      min) for normal subjects, the level of peak of 13CO2 excreted/h was 4.8 +/- 1.2
      per cent in diarrhoea cases and 5.3 +/- 2.3 per cent in normal children (NS).
      Mean areas under the curve for the two groups were 18.9 +/- 3.4 per cent for
      normal and 17.6 +/- 4.1 per cent dose 13CO2 excreted/6 h for diarrhoea cases
      (NS). These results indicate that intestinal absorption of medium chain
      triglycerides was not impaired significantly in the cases of persistent diarrhoea
      studied.

PMID- 10341503
TI  - Clinical and laboratory study of kala-azar in children in Nepal.
AB  - Reports are scanty regarding kala-azar in children in Nepal. In this
      communication we document 20 children diagnosed to have kala-azar who were
      admitted and treated at B. P. Koirala Institute of Health Sciences, Dharan,
      Nepal. The children were between 2 and 14 years old. The duration of illness
      varied between 12 days and 24 months with a majority (65 per cent) of children
      being ill for less than 6 months. Hepatomegaly and splenomegaly were seen in 95
      and 90 per cent of cases respectively. Splenomegaly was not found in two (10 per
      cent) children. Anaemia, leucopenia, and thrombocytopenia were seen in 95, 60,
      and 75 per cent of children respectively. Amastigotes of Leishmania donovani (LD
      bodies) were demonstrated in Giemsa-stained smears of bone marrow aspirates in 16
      (80 per cent) children. All the children responded to treatment with sodium
      stibogluconate. No mortality was observed. This study emphasizes the importance
      of kala-azar in children in endemic areas of eastern Nepal.

PMID- 10341504
TI  - Measles immunization: early two-doses policy experience.
AB  - Before the implementation of the two-dose measles immunization policy in Saudi
      Arabia, 50 per cent of measles cases in children below the age of one year were
      reported for the age group 6-8 months. In 1991 two doses of measles vaccine, at 6
      months and 12 months, the second dose incorporated with MMR, were integrated into
      the expanded programme of immunization (EPI). Since 1993, vaccination coverage
      for the second dose has been above 90 per cent. While measles incidence remains
      stable in infants below 6 months of age, the incidence in children 9-11 months of
      age dropped by 50 per cent. The greatest impact was seen in the 6-8-month age
      group where the incidence dropped by more than 75 per cent. Moreover this two
      dose strategy resulted in a situation in which 80 per cent of the measles cases
      were in children above the age of 5 years, mostly those who had not had two doses
      of measles vaccine. Further control measures should include non-selective
      vaccination of school children against measles. The two-dose measles vaccination
      policy is visualized as a necessity if the goal of measles elimination is to be
      achieved. Routine monthly reports validated by surveys using the WHO standard 30
      cluster technique was used for the study.

PMID- 10341505
TI  - Intracranial haemorrhage due to vitamin K deficiency following gastroenteritis in
      an infant.
AB  - Breastfed infants who are not given supplemental vitamin K after birth may
      develop vitamin K deficiency following gastroenteritis. Severe intracranial
      haemorrhage may occur.

PMID- 10341506
TI  - Imerslund-Grasbeck syndrome in an African patient.
AB  - Imerslund-Grasbeck syndrome (IGS) is a rare cause of megaloblastic anaemia in
      young children. We wish to report the first case described from Africa. The
      diagnosis of IGS was made on the findings of a low vitamin B12 level, mild
      proteinuria, and a vitamin B12 absorption test unaffected by the intrinsic
      factor. The patient responded well to treatment with intramuscular vitamin B12.

PMID- 10341507
TI  - Cup feeding: an alternative to bottle feeding in a neonatal intensive care unit.
AB  - Cup feeding has been suggested as an alternative to bottle feeding to help
      promote breastfeeding by avoiding nipple confusion. To demonstrate the
      possibility and utility of cup feeding, records of 59 preterm and low birthweight
      babies (born before 37 weeks' gestation) admitted to a neonatal intensive care
      unit (NICU) from May 1995 to April 1996 were analyzed. Feeding was initiated on
      cup if swallowing was present and cup feeding was possible as early as 29 weeks'
      gestational age with a birthweight of 900 g. In the case of five infants (38 per
      cent) in the gestational age group 28-30 weeks, 19 infants (52 per cent) in the
      31-34 weeks' gestation group, and six (56 per cent) in the 35-37 weeks' gestation
      group, feeding could be commenced directly with a cup. Out of 59 infants, 33
      infants (56 per cent) could be discharged on exclusive breastfeeding. It was
      concluded that cup feeding is a useful alternative to bottle feeding and an
      effective method of feeding preterm and small infants in NICU. Cup feeding allows
      successful breastfeeding without causing 'nipple confusion'.

PMID- 10341508
TI  - Childhood ataxic syndromes: experience from Sokoto, north-western Nigeria.

PMID- 10341509
TI  - Ocular extramedullary myeloid cell tumour in children: an Indian study.
AB  - Thirty-two children with extramedullary myeloid cell tumour (EMT) who constituted
      41 per cent of children with acute myeloid leukaemia (AML) were studied to
      ascertain their laboratory characteristics and potential problems in diagnosis.
      The diagnosis, established by peripheral blood smear and/or bone marrow
      examination, was AML (n = 29) and refractory anaemia with excess blasts in
      transformation (RAEB-t; n = 3). The six referred patients in whom the diagnosis
      had been missed, and two cases wrongly reported as histiocytosis on aspiration
      cytology, were those in whom a peripheral blood smear had not been examined. It
      is concluded that diagnostic work-up of proptosis must include a full haemogram,
      meticulous peripheral blood smear examination, repeated if necessary, and bone
      marrow examination where relevant. RAEB-t cases with extramedullary myeloid cell
      tumour should be classified as acute myeloid leukaemia.

PMID- 10341510
TI  - The impact of breastfeeding practices on respiratory and diarrhoeal disease in
      infancy: a study from Sri Lanka.
AB  - A hospital-based descriptive recall study was conducted to assess the
      relationship, if any, between breastfeeding practices and morbidity from
      respiratory and diarrhoeal diseases in infants. A total of 343 infants (285
      admitted patients and 58 controls) were recruited. Clinical and sociodemographic
      data and details regarding breastfeeding practices, timing of the first
      respiratory or diarrhoeal illness, and the timing of the first admission for a
      respiratory or diarrhoeal illness, were carefully documented. Three broad groups
      of those who were exclusively breastfed for 3 months or less, 4 months or more,
      and those who were never breastfed were identified. There was no significant
      difference in the numbers of infants who developed a respiratory or diarrhoeal
      illness or were admitted to hospital with a respiratory or diarrhoeal illness
      during the period of exclusive breastfeeding, irrespective of the period of
      exclusive breastfeeding. However, significant numbers of patients who were
      breastfed for 3 months or less developed the first respiratory infection, the
      first episode of diarrhoea, and the first hospital admission for respiratory or
      diarrhoeal disease during the first 3 months following the introduction of other
      foods and in the subsequent 3 months following this period. Those who were never
      breastfed showed the worst results. Significantly fewer of those who were
      breastfed for 4 months or more fulfilled the same criteria. Identical findings
      were noted whether the additional feeds used to terminate exclusive breastfeeding
      were water, herbal tea, native medicines, or formula milk. Similar results were
      obtained in the control group. This study reiterates the extended protective
      effects of exclusive breastfeeding for periods of over 4 months against
      respiratory and diarrhoeal diseases using a novel set of outcome measures.

PMID- 10341511
TI  - Upper airway obstruction in an HIV-1 infected child with acute Epstein-Barr virus
      infection.

PMID- 10341512
TI  - Relationship between maternal and cord blood plasma iron concentrations.

PMID- 10341513
TI  - Relactation improves nutritional status in hospitalized infants.

PMID- 10341514
TI  - Introducing the law strip: a simple device to screen for, and improve
      documentation of, low birthweight babies in Nigeria.

PMID- 10341515
TI  - Long-term prophylaxis and immune parameters in haemophilia.

PMID- 10341516
TI  - Amphibian alert.

PMID- 10341517
TI  - Nutritional rehabilitation of severely malnourished children at domiciliary level
      through the Integrated Child Development Services (ICDS) scheme: a perspective
      study.

PMID- 10341518
TI  - [The study of professional risk in the Ukraine].
AB  - The authors studied duration of pathologic changes formation and determined
      actual values of occupational risk for pneumoconiosis and deafness. "Level-time
      effect" relationship was revealed for the former item and "dose-effect"
      relationship was found for the latter one. Conclusion is that length of service
      could be used to forecast risk of occupational disease.

PMID- 10341519
TI  - [Occupational aspects of modern work conditions in lead production].
AB  - Production of lead crystal, ceramic paints and roentgenologic grids is associated
      with air lead levels exceeding the MAC and occurrence of other toxic chemicals in
      air. Ambient air in populated area near crystal production appeared to contain
      high lead levels. The authors specified measures aimed to prevent lead influence
      on the exposed workers and population.

PMID- 10341520
TI  - [The role of biological factors in the formation of working conditions at
      agricultural enterprises].
AB  - The analysis of the results of hygienic studies carried out in agricultural
      sector: cattlebreeding farms, fodder production plants, the enterprises of
      process raw materials-meat refinery, allowed to consider biological factors as
      the major adversity factor. The main of them are organic dust of composite
      contents, microbial flora. It's determine the possible effect of physical,
      chemical and biological factors. The analyses consent to formulate the basic
      principles and priorities in researches connected with new biotechnologies.

PMID- 10341521
TI  - [Bronchial-pulmonary pathology and its early diagnosis in workers of combined
      fodder industry].
AB  - The article is devoted to the question of peculiarity of bronchopulmonary
      system's pathology in the workers of the animal fodder production. The production
      dust contains high concentrations of endotoxins and leads to the development of
      allergic reactions and diseases of respiratory system. The ODTS (organic dust
      toxic syndrome) revealed as an acute reaction of organism in (39.7 +/- 4.4) %
      workers of the 1st plant and in (14.7 +/- 6.0) % of the 2nd one. Among chronic
      diseases predominates chronic bronchitis: (26.4 +/- 4.0) % at the I and (8.8 +/-
      4.8) % at the II plants. We propose to use the obstruction of little bronchi and
      bronchial hyperresponsivennes as early diagnostical criterions of the influence
      of organic dust.

PMID- 10341522
TI  - [On the pathogenesis of chronic dust-related bronchitis (according to the status
      of immune and thrombin-plasmin systems].
AB  - As a result of the performed investigations there was revealed the injury of T
      link of the systemic immunity, as well, as the reduction of the immunoglobulin A.
      And in the sick with chronic dust bronchitis the state of local immunity was
      characterized by the increase of the per cent content of neutrophilic
      granulocytes in the bronchoalveolar washout, and also by the reduction of
      adgesive and absorptive ability of the alveolar macrophages at the background of
      significant activation of the oxygendependent metabolism. The investigation of
      coagulant blood system revealed the predomination of thrombinogenesis over the
      processes of fibrinolysis.

PMID- 10341523
TI  - [Justifying the approaches to occupational regulation of water-mixable lubricant
      coolants].
AB  - The authors summarized and analysed data on effects and usage of cutting fluids
      mixable with water in order to determine limits for rapid toxicologic and
      hygienic evaluation of these fluids if repeatedly cooled. Limitative
      characteristics are sensibilization and skin irritation caused by cutting fluids
      mixable with water. Synthetic compounds containing the fluids appeared
      carcinogenic and therefore require special attention.

PMID- 10341524
TI  - [The role of physical work capacity factor during occupational selection of
      teenagers for non-professional employment].
AB  - The authors revealed age-and sex-matched differences in physical efficiency and
      in functional cardiovascular state of individuals aged 15-17 years according to
      functional and ergometric studies. The findings are dependence between successful
      mastering of manual occupation and physical performance in teenagers. To conduct
      occupational selection, the authors suggested classification of teenagers'
      functional state in accordance with their age and sex.

PMID- 10341525
TI  - [Hot issues of occupational medicine in welding industrial sector in the
      Ukraine].

PMID- 10341526
TI  - [Aspects of CNS functional changes due to various levels of psycho-emotional
      stress].

PMID- 10341527
TI  - [Efficiency of papaya sublimate as a means for detoxication in chronic lead
      poisoning].

PMID- 10341529
TI  - [COPD guideline by the Japanese Society of Respiratory Society. Guideline of
      diagnosis and treatment of COPD (chronic obstructive lung disease)].

PMID- 10341530
TI  - Nonenteral routes of administration for psychiatric medications. A literature
      review.
AB  - In the treatment of psychiatric patients with complicating medical illness,
      clinicians may encounter patients who cannot take oral medications. This review
      will acquaint the practicing clinical psychiatrist with psychotropic medications
      available by nonenteral routes of administration. A computerized MEDLINE search
      was conducted of the literature 1981 to 1997. All articles citing nonenteral
      routes of psychotropic medication administration were reviewed. The results are
      summarized according to drug class and specific routes of administration
      (intravenous, intramuscular, sublingual, rectal). Psychotropic medications now
      available by these alternative routes are also listed in table form. The majority
      of the information available comes from small case series or case reports.
      Intravenous and intramuscular routes of administration of psychotropics are the
      most common. In addition, certain psychotropics are available by less common
      routes, such as sublingual or rectal administration. Consideration of alterations
      in pharmacokinetics, including poorer absorption and slower metabolism, are
      discussed. Clinicians may need to consider these novel routes of medication
      administration when dealing with patients unable to take oral medications.

PMID- 10341531
TI  - The Delirium Rating Scale. Its use in consultation-liaison research.
AB  - In addition to diagnostic criteria, delirium research requires standardized
      instruments to measure symptoms. This article reviews the literature about the
      Delirium Rating Scale (DRS), the most widely used scale to assess delirium that
      has been translated into at least seven other languages. The DRS has 10 items and
      is clinician-rated, but 7- or 8-item subscale adaptations have been used for
      repeated measurements. It has high scale characteristics, including internal
      consistency, validity, specificity, sensitivity and interrater reliability. The
      DRS distinguishes delirious from demented, schizophrenic, and depressed patients
      and is more accurate than cognitive tests in identifying delirium. Scores are
      sensitive to treatment of delirium. Principal components analyses find one
      underlying dimension that can be subdivided into two or three components. The DRS
      has been used in studies of phenomenology, physiology, treatment, outcome, and at
      risk populations. Tables summarize details from various studies. The DRS is used
      clinically and in research. It is currently being revised to enhance its use in
      phenomenologic and treatment research.

PMID- 10341532
TI  - Changing attitudes about end-of-life decision making of medical students during
      third-year clinical clerkships.
AB  - To better define the learning objectives of ethics curricula and evaluate changes
      in medical students' attitudes about end-of-life decision making, enrolled
      students (N = 96) of a pilot medical ethics program were surveyed at the
      beginning and end of their third-year clinical clerkship about their experiences
      and attitudes about end-of-life decision making. At the end of their clinical
      clerkship year, the majority of students had participated in end-of-life
      decisions, prioritized patient autonomy and quality-of-life issues, were
      concerned about legal liability, were polarized over issues such as physician
      assisted suicide, and gained confidence in their ethical decision-making ability.
      To train future physicians such that clinical practice is consistent with ethical
      guidelines and legislation on end-of-life care, medical ethics curricula should
      focus on symptom relief, clarification of legal issues, and resolution of
      conflicts between personal beliefs and public opinion about such issues as
      physician-assisted suicide. Appropriate role-modeling and mentoring by residents
      and attending physicians should also be emphasized.

PMID- 10341533
TI  - PTSD in heart transplant recipients and their primary family caregivers.
AB  - Posttraumatic stress disorder associated with transplantation (PTSD-T) is a
      complication for some heart transplant recipients. By using a structured,
      standardized interview and DSM-III-R criteria, the authors examined whether
      recipients (n = 158) and their family caregivers (n = 142) showed similar PTSD-T
      rates and clinical characteristics during the first year posttransplant. Among
      the recipients, 10.5% met full criteria for the disorder and an additional 5%
      were probable cases. Among the caregivers, 7.7% met full criteria and an
      additional 11.0% were probable cases. Severity and duration of disorder were
      similar across the groups. Being female, having a history of psychiatric illness,
      and having lower friend support were increased risks for PTSD-T.

PMID- 10341534
TI  - Phenotype of blood lymphocytes in PTSD suggests chronic immune activation.
AB  - Patients with posttraumatic stress disorder (PTSD) have a past history of
      extremely stressful experience and often present with somatic complaints.
      Peripheral blood lymphocytes (PBL) of patients with PTSD associated with a
      history of childhood sexual abuse were examined for changes in immune phenotype.
      The ratio of CD45RO-positive to CD45RA-positive lymphocytes (CD45RO/CD45RA), an
      index of lymphocyte activation, was higher (P = 0.04) in the PTSD subjects than
      in the normal subjects. No differences were observed for the number of PBL or the
      representation of major T, B, or NK lymphocyte subsets. These findings suggest
      the presence of increased lymphocyte activation in the PBL of patients with PTSD.

PMID- 10341535
TI  - Effectiveness of a psychiatric pain clinic.
AB  - Medical charts were reviewed for 101 consecutive outpatients seen between January
      1, 1993 and July 1, 1996 at a unidisciplinary, psychiatric pain clinic, which
      exists within a hospital-based, university-run, outpatient service with primary
      and specialty care clinics. Mean duration of pain was 7 years. Multiple sites of
      pain were present in 69% of patients. Eighty-eight percent fulfilled DSM-IV
      criteria for pain disorder. The patients had significantly fewer medical visits
      and diagnostic tests 6 months after attending the pain clinic, compared with 6
      months before (P < 0.0001). Interventions frequently included detoxification and
      reduction and substitution of medication, and always included psychotherapeutic
      approaches, particularly support and suggestions.

PMID- 10341536
TI  - A psychiatric study of nonorganic chronic headache patients.
AB  - Nonorganic chronic headache is a common, challenging presentation in clinical
      practice. The aim of this study was to investigate the frequency of associated
      psychiatric psychopathology, personality disorders, or traits. In addition, the
      study attempted to investigate possible relationships of nonorganic chronic
      headache with alexithymia, locus of control, and pain perception. Psychiatric
      pathology, personality traits, and pain profiles were examined in 100 randomized
      patients with chronic headache lacking an obvious organic basis, and they were
      compared with 100 subjects, 50 with headache of a known organic cause and 50
      seemingly healthy persons, by using structured clinical interviews. Somatoform
      pain disorder was diagnosed in 43% of the nonorganic and 20% of the organic
      headache group. Nine percent of the former group had major depression, 16% had
      dysthymia, and 8% had both. In the organic group, 56% had no psychiatric disorder
      and 20% had somatoform pain disorder. Seventy-seven percent of the patients in
      the nonorganic pain group had personality disorders, mostly of the mixed and
      multiple types, compared with 24% of the organic headache patients. The study
      sample was more alexithymic than the other groups (in 65% of subjects) and had a
      culturally influenced locus of control and a pain profile characterized by
      dramatization, vagueness, lower pain threshold, and lower pain tolerance. The
      nonorganic chronic headache patients showed a high prevalence of somatoform,
      depressive, and other forms of psychiatric disorders. The high frequency of
      personality disorders, mostly the mixed and multiple types, the high alexithymic
      pattern, and low pain threshold and tolerance in the study group should be taken
      into consideration in the evaluation and management of nonorganic headache
      patients.

PMID- 10341537
TI  - Interactive patterns of social support and individual coping strategies in
      melanoma patients and their correlations with adjustment to illness.
AB  - Combined patterns of social support and coping style and correlations with
      adjustment to cancer were investigated in early-stage melanoma patients. The
      authors studied 358 consecutive patients attending regular follow-up who answered
      standardized instruments that assess social support, coping behavior, and tumor
      related distress. Regression analyses identified high active and low depressive
      coping behavior as stronger predictors for perceived support than
      sociodemographic and clinical variables. Cluster analyses yielded four coping
      support patterns. High social support, combined either with active coping or with
      stoicism, was associated with good adjustment, whereas low perceived support in
      the subjects living alone or in the patients exhibiting depressive coping
      behavior was associated with poor adjustment.

PMID- 10341538
TI  - Religious and other predictors of psychosocial adjustment in cancer patients.
AB  - The authors tested the hypothesis that religious variables, such as a person's
      belief that his/her illness was God's will, would predict psychosocial adjustment
      in 50 patients who were predominantly Catholic Hispanic women attending a medical
      oncology clinic (42 women, 8 men). The patients were free of an Axis I mental
      disorder, cognitive impairment, and severe pain and were not undergoing intensive
      chemotherapy. By using the Psychosocial Adjustment to Illness Scale as the
      outcome measure, the authors found few associations with religious variables, but
      many to clinical variables.

PMID- 10341540
TI  - The varied neuropsychiatric presentations of Creutzfeldt-Jakob disease.

PMID- 10341539
TI  - Treatment of respiratory dyskinesia with olanzapine.

PMID- 10341541
TI  - Neuroleptic malignant syndrome associated with olanzapine therapy.

PMID- 10341542
TI  - Is inhibition of nitric oxide synthase a mechanism for SSRI-induced bleeding?

PMID- 10341543
TI  - The rational antidepressant drugs selection in medically ill patients.

PMID- 10341544
TI  - [The ubiquitin world: a novel cellular control system].

PMID- 10341545
TI  - [The ubiquitin-ligating system: from the discovery to the present].

PMID- 10341547
TI  - [De-ubiquitinating enzyme: a large gene family].

PMID- 10341546
TI  - [Ubiquitin-like proteins and its ligation systems].

PMID- 10341548
TI  - [Roles of the ubiquitin system in stress responses].

PMID- 10341549
TI  - [Molecular mechanism of ubiquitin proteasome-regulated quality control in the
      endoplasmic reticulum].

PMID- 10341551
TI  - [Near-field optics: principle and application to the studies of biosciences].

PMID- 10341550
TI  - [Human diseases associated with ubiquitin/proteasome proteolytic system].

PMID- 10341553
TI  - [Capillary electrophoresis. (4): Where is the capillary electrophoresis going?].

PMID- 10341552
TI  - [Techniques for automatic recording of the oxygen equilibrium curve: precision
      determination of gaseous ligand binding].

PMID- 10341554
TI  - [Justification of the current therapy applied to respiratory insufficiency].

PMID- 10341555
TI  - [Approach to diagnosis of respiratory insufficiency].

PMID- 10341556
TI  - [Pathophysiology of respiratory insufficiency based on the lung function].

PMID- 10341557
TI  - [Circulatory dynamics based on physiopathology of respiratory insufficiency].

PMID- 10341558
TI  - [Sleep and exercise dysfunction in respiratory insufficiency].

PMID- 10341559
TI  - [Etiology and physiopathology of acute exacerbation of respiratory
      insufficiency].

PMID- 10341560
TI  - [Etiology and physiopathology of diseases responsible for the development of
      respiratory insufficiency].

PMID- 10341561
TI  - [Pathology of diseases responsible for the development of respiratory
      insufficiency].

PMID- 10341562
TI  - [Therapy of respiratory insufficiency. Oxygen inhalation therapy, including home
      oxygen therapy].

PMID- 10341563
TI  - [Therapy of respiratory insufficiency. Comprehensive respiratory rehabilitation].

PMID- 10341564
TI  - [Treatment of respiratory insufficiency. Drug therapy].

PMID- 10341565
TI  - [Exercise therapy of respiratory insufficiency].

PMID- 10341566
TI  - [Noninvasive positive pressure ventilation (NIPPV) for the treatment of
      respiratory insufficiency].

PMID- 10341567
TI  - [Volume reduction surgery for the treatment of pulmonary edema].

PMID- 10341568
TI  - [Home mechanical ventilation for the treatment of respiratory insufficiency].

PMID- 10341569
TI  - [Nutritional care of patients with respiratory insufficiency].

PMID- 10341570
TI  - [Respiratory insufficiency: discussion].

PMID- 10341572
TI  - [Case of chronic renal failure with sudden progression of renal dysfunction due
      to furosemide hypersensitivity].

PMID- 10341571
TI  - [Case of hereditary spherocytosis complicated by human parvovirus B19-associated
      hemophagocytosis syndrome and aplastic crisis].

PMID- 10341573
TI  - [Case of diabetes mellitus succumbing to multiple organ failure due to
      hemophagocytic syndrome complicating mucormycosis].

PMID- 10341575
TI  - [Case of echinostomiasis].

PMID- 10341574
TI  - [Case of alveolar proteinosis associated with pulmonary aspergillosis].

PMID- 10341576
TI  - [Respiratory tract diseases and tumor markers].

PMID- 10341578
TI  - [Pathology of motor neuron diseases].

PMID- 10341577
TI  - [Cell adhesion, cytoskeleton, and kidney diseases--with special reference to
      cytoskeleton and adhesion control by a low molecular weight GTP-binding protein
      Rho].

PMID- 10341579
TI  - [Evidence-based medicine for Japanese that is necessary now].

PMID- 10341580
TI  - [Progress in genetic study of hypertension].

PMID- 10341581
TI  - [New aspects of environmental factors leading to hypertension].

PMID- 10341582
TI  - [Hypertension and vasoactive substances].

PMID- 10341585
TI  - [Progress in diagnosis of secondary hypertension].

PMID- 10341583
TI  - [Hypertension and insulin].

PMID- 10341586
TI  - [Isolated office hypertension].

PMID- 10341584
TI  - [Methods for diagnosis of hypertension].

PMID- 10341587
TI  - [A message from JNCVI (Joint National Committee-VI) on the treatment of
      hypertension].

PMID- 10341588
TI  - [Life style modification for the treatment of hypertension].

PMID- 10341590
TI  - [Timing for the start of antihypertensive therapy and the antihypertensive goal].

PMID- 10341589
TI  - [Antihypertensive treatment considering the home- and ambulatory blood pressure
      determination].

PMID- 10341591
TI  - [Treatment of hypertension with complications].

PMID- 10341592
TI  - [Treatment of hypertension in the aged].

PMID- 10341593
TI  - [Selection of antihypertensive agents in relation to organ protection].

PMID- 10341594
TI  - [Current topics on hypertension. Possibility for gene therapy].

PMID- 10341595
TI  - [Current topics on hypertension. At the conclusion of the 1998 meeting of the
      WHO/ISH Guideline Committee on the management of mild hypertension].

PMID- 10341596
TI  - [Trend in antihypertensive therapy: discussion].

PMID- 10341597
TI  - [Case of adult T-cell leukemia (ATL) with homologous bone marrow
      transplantation].

PMID- 10341598
TI  - [Case of pancreatic diabetes with improvement in carbohydrate and lipid
      metabolism brought about by injections of a small quantity of glucagon].

PMID- 10341599
TI  - [Case of nonfamilial idiopathic Liddle syndrome].

PMID- 10341600
TI  - [Case of infectious abdominal aneurysm complicating influenza septicemia].

PMID- 10341601
TI  - [Case of opsoclonus-myoclonus syndrome (OMS) developing during pregnancy].

PMID- 10341602
TI  - [Internal diseases and carbonyl stress].

PMID- 10341603
TI  - [Methodology of meta analysis and internal diseases-- therapy of hypertension
      complicated by diabetes as an example].

PMID- 10341604
TI  - [Respiratory tract diseases and instructions on smoking cessation].

PMID- 10341605
TI  - [From preclinical research to clinical application--my personal research
      experiences].

PMID- 10341606
TI  - [Myocardiopathies].

PMID- 10341607
TI  - [Physiopathology and treatment of diabetes mellitus].

PMID- 10341608
TI  - [Rational treatment of HIV infection].

PMID- 10341609
TI  - [Coagulation disorders--with special reference to thrombotic tendencies].

PMID- 10341610
TI  - [Pulmonary edema--from etiology to treatment].

PMID- 10341612
TI  - [New trends in management and treatment of hypertension (JNC-VI and the current
      status in Japan)].

PMID- 10341613
TI  - [Planning individualized therapeutic approaches for hypertensive patients].

PMID- 10341614
TI  - [From physiopathology to therapy: description of cardiac failure].

PMID- 10341615
TI  - [Treatment of heart failure to improve the prognosis].

PMID- 10341616
TI  - [Physiopathology and treatment of acute coronary syndrome].

PMID- 10341617
TI  - [Current therapeutic modalities for angina pectoris].

PMID- 10341618
TI  - [Selection of anti-arrhythmia agents--application of the Sicilian Gambit].

PMID- 10341619
TI  - [Anti-arrhythmia therapy--indication and planning of therapy].

PMID- 10341620
TI  - [Mechanism for the development of colonic cancer and genetic diagnosis].

PMID- 10341621
TI  - [Physiopathology and treatment of autoimmune liver diseases].

PMID- 10341622
TI  - [Therapy and prognosis of cholelithiasis].

PMID- 10341623
TI  - [Progress in the treatment of Parkinson's disease].

PMID- 10341624
TI  - [Creutzfeldt-Jakob disease].

PMID- 10341626
TI  - [Prevention and treatment of osteoporosis].

PMID- 10341625
TI  - [Treatment of diabetes mellitus].

PMID- 10341627
TI  - [Physiopathology and treatment of pollenosis].

PMID- 10341628
TI  - [Diagnosis and treatment of Sjogren's syndrome].

PMID- 10341629
TI  - [Consensus on the treatment of lung cancer].

PMID- 10341630
TI  - [Radiologic-pathologic correlation of respiratory tract diseases --with special
      reference to HRCT].

PMID- 10341631
TI  - [Circulatory diseases and anti-thrombotic therapy].

PMID- 10341632
TI  - [Echocardiographic diagnosis of circulatory diseases].

PMID- 10341633
TI  - [Emerging and re-emerging infectious diseases].

PMID- 10341634
TI  - [Kidney dysfunctions caused by collagen diseases].

PMID- 10341635
TI  - [Acute kidney failure of the aged].

PMID- 10341636
TI  - [Post-transfusion graft-vs-host disease].

PMID- 10341637
TI  - [Diagnosis and treatment of multiple myeloma].

PMID- 10341638
TI  - [Refractory liver diseases].

PMID- 10341639
TI  - [Autoimmune hepatitis: an epidemiological study].

PMID- 10341640
TI  - [Autoimmune hepatitis: description of its physiopathology].

PMID- 10341641
TI  - [Autoimmune hepatitis: Diagnostic standards and severity].

PMID- 10341642
TI  - [Autoimmune hepatitis: progress in its treatment].

PMID- 10341643
TI  - [Primary biliary cirrhosis: epidemiological analysis].

PMID- 10341644
TI  - [Primary biliary cirrhosis: a study on developmental pathology and
      physiopathology].

PMID- 10341645
TI  - [Primary biliary cirrhosis: diagnostic standards and the reference for its
      severity].

PMID- 10341647
TI  - [Primary biliary cirrhosis: liver transplantation].

PMID- 10341646
TI  - [Primary biliary cirrhosis: progress in its therapy].

PMID- 10341648
TI  - [Fulminant hepatitis: epidemiology and diagnosis].

PMID- 10341649
TI  - [Fulminant hepatitis: description of its physiopathology].

PMID- 10341650
TI  - [Fulminant hepatitis: diagnostic standard and the extent of severity].

PMID- 10341651
TI  - [Fulminant hepatitis: progress and the current status of treatment].

PMID- 10341652
TI  - [Fulminant hepatitis: liver transplantation].

PMID- 10341653
TI  - [Hepatocyte dysfunction and apoptosis].

PMID- 10341654
TI  - [Fulminant hepatitis and viral mutation].

PMID- 10341655
TI  - [Refractory liver diseases: progress in treatment. Discussion].

PMID- 10341656
TI  - [Case of malignant lymphoma associated with acute renal failure].

PMID- 10341657
TI  - [Case of post-Chlamydia perihepatitis adhesion (Fitz-Hugh-Curtis syndrome) with
      effective peritoneoscopic diagnosis].

PMID- 10341659
TI  - [Acute myelogenous leukemia with spontaneous remission simultaneous with
      improvement of severe infection: report of 2 cases].

PMID- 10341660
TI  - [Exacerbation of hepatitis B and the expression of M proteinemia during the
      treatment of malignant lymphoma: a case study].

PMID- 10341658
TI  - [Case of chronic inflammatory demyelinating polyneuropathy with its onset during
      infancy].

PMID- 10341661
TI  - [New management of hepatitis B virus].

PMID- 10341662
TI  - [Physiopathology and treatment of gout and hyperuricemia].

PMID- 10341663
TI  - [Leukocyte adsorption and removal for the treatment of ulcerative colitis].

PMID- 10341664
TI  - Determination of the secondary structural elements of chicken liver fatty acid
      binding protein by two-dimensional homonuclear NMR.
AB  - A conformational study in solution of the fatty acid binding protein from chicken
      liver is presented. The nearly complete sequence-specific 1H resonance assignment
      was achieved from homonuclear two-dimensional nmr experiments using a sample of
      native protein. The principal elements of secondary structure were identified: 10
      antiparallel beta-strands and one helical segment followed by a turn comprising 5
      residues. These elements correspond closely with those of the crystal structure
      of the related protein, and two new secondary structural features obtained from
      the nmr data are the beta-sheet conformation between the first and the last beta
      strand in the protein sequence, as well as a helical loop at the N-terminus of
      the polypeptide chain.

PMID- 10341665
TI  - Mouse acetylcholinesterase unliganded and in complex with huperzine A: a
      comparison of molecular dynamics simulations.
AB  - A 1 ns molecular dynamics simulation of unliganded mouse acetylcholinesterase
      (AChE) is compared to a previous simulation of mouse AChE complexed with
      huperzine A (HupA). Several common features are observed. In both simulations,
      the active site gorge fluctuates in size during the 1 ns trajectory and is
      completely pinched off several times. Many of the residues in the gorge that
      formed hydrogen bonds with HupA in the simulation of the complex now form
      hydrogen bonds with other protein residues and water molecules in the gorge. The
      opening of a "backdoor" entrance to the active site that was found in the
      simulation of the complex is also observed in the unliganded simulation.
      Differences between the two simulations include overall lower structural rms
      deviations for residues in the gorge in the unliganded simulation, a smaller
      diameter of the gorge in the absence of HupA, and the disappearance of a side
      channel that was frequently present in the liganded simulation. The differences
      between the two simulations can be attributed, in part, to the interaction of
      AChE with HupA.

PMID- 10341666
TI  - On the evolution of recombination and meiosis.
AB  - Theories on the evolution of recombination in regard to its ability to increase
      mean fitness require a consistent source of negative linkage disequilibrium among
      loci affecting fitness to show an advantage to recombination. Here we present
      evidence that, at least theoretically, genetic variation for recombination can
      spread in very large populations under a strictly multiplicative-fitness,
      deleterious-allele model. The model uses only Mendelian genetics in a multi-locus
      context to show that a dominant gene for recombination can spread when rare and
      resist invasion when common. In non-equilibrium populations driven by Muller's
      ratchet, the gene increases its probability of fixation by increasing the
      probability of being associated with the best individuals. This occurs at an
      optimal level of recombination. Its action results in both an immediate and a
      long-term advantage to recombination amongst the proto-meiotic organisms
      modelled. The genetic mechanism lends itself naturally to a model for the
      evolution of meiosis, where modern-day gametes are seen as derivative of ancient
      unicellular organisms.

PMID- 10341668
TI  - Are vegetarians an 'at risk group' for iodine deficiency?

PMID- 10341667
TI  - On the experimental design and data analysis of mutation accumulation
      experiments.
AB  - Characterizing deleterious genomic mutations is important. Most of the few
      current estimates come from the mutation-accumulation (M-A) approach, which has
      been extremely time- and labour-consuming. There is a resurgent interest in
      implementing this approach. However, its estimation properties under different
      experimental designs are poorly understood. By simulations we investigate these
      issues in detail. We found that many of the previous M-A experiments could have
      been more efficiently implemented with much less time and expense while still
      achieving the same estimation accuracy. If more than 100 lines are employed in M
      A and if each line is replicated at least 10 times during each assay, an
      experiment of 10 M-A generations with two assays (at the beginning and at the end
      of M-A) may achieve at least the same estimation quality as a typical M-A
      experiment. The number of replicates per M-A line necessary for each assay
      largely depends on the magnitude of environmental variance. While 10 replicates
      are reasonable for assaying most fitness traits, many more are needed for
      viability, which has an exceptionally large environmental variance. The
      investigation is mainly carried out using Bateman-Mukai's method of moments for
      estimation. Estimation using Keightley's maximum likelihood is also investigated
      and discussed. These results should not only be useful for planning efficient M-A
      experiments, but also may help empiricists in deciding to adopt the M-A approach
      with manageable labour, time and resources.

PMID- 10341669
TI  - Fetal origins of adult disease.

PMID- 10341670
TI  - Non-nutritional uses of vitamin B6.
AB  - Vitamin B6 is a water-soluble vitamin, and is readily metabolized and excreted,
      so it has generally been assumed to have negligible toxicity, although at very
      high levels of intake it can cause peripheral nerve damage. Nutritional
      deficiency disease is extremely rare, although a significant proportion of the
      population shows biochemical evidence of inadequate status, despite apparently
      adequate levels of intake. The vitamin has been used to treat a wide variety of
      conditions, which may or may not be related to inadequate intake. In some
      conditions use of vitamin B6 supplements has been purely empirical; in other
      conditions there is a reasonable physiological or metabolic mechanism to explain
      why supplements of the vitamin many times greater than average requirements may
      have therapeutic uses. However, even in such conditions there is little evidence
      of efficacy from properly conducted controlled trials.

PMID- 10341671
TI  - Physical exercise affects the lipid profile of mitochondrial membranes in rats
      fed with virgin olive oil or sunflower oil.
AB  - The effects of physical exercise on the lipid profile in mitochondrial membranes
      of liver and skeletal muscle were examined in rats fed with virgin olive oil or
      sunflower oil. Thirty male Wistar rats, 21 d old, were randomly assigned to four
      groups according to fat ingestion and physical activity over an 8-week period.
      For each type of oil, one group acted as a control group while rats from the
      other were trained to run for 40 min daily on a horizontal treadmill, at a speed
      of 35 m/min. The results show that diet affected the fatty acid profile of the
      mitochondrial membranes from skeletal muscle and liver. Physical exercise also
      modified the fatty acid profile of the mitochondrial membranes. Total
      monounsaturated fatty acids decreased (P < 0.001) in liver mitochondria of
      exercised animals. Total polyunsaturated fatty acids in mitochondrial membranes
      of liver increased (P < 0.005) after exercise but those in mitochondrial
      membranes of skeletal muscle decreased (P < 0.05). These changes due to the
      exercise may arise via several mechanisms, e.g. fluidity regulation; changes in
      the eicosanoid metabolism; differences in the availability or oxidation rate of
      the different fatty acids.

PMID- 10341672
TI  - The effect of low and moderate fat intakes on the postprandial lipaemic and
      hormonal responses in healthy volunteers.
AB  - Present literature indicates that whereas an acute fat intake of 5 g does not
      elicit a postprandial triacylglycerolaemic response, 20 g of fat does. Since 67%
      of fat intake occasions involve fat doses of less than 20 g, the present study
      examined the effect of a relatively low-fat (LF) meal (0.2 g/kg body weight; mean
      14 g) on postprandial triacylglycerol (TAG) metabolism, compared with a high-fat
      (HF) meal (0.6 g/kg body weight; mean 43 g), a fat dose which is more typical of
      laboratory studies. Plasma- and chylomicron-TAG concentrations increased
      significantly (P < or = 0.001) following both meals, and the increase was
      significantly (P < or = 0.02) greater after the HF meal. The postprandial areas
      under the curves and maximal postprandial TAG concentrations for plasma- and
      chylomicron-TAG were significantly higher following the HF meal (P < or = 0.05).
      Postprandial plasma insulin and gastric inhibitory polypeptide concentrations
      increased significantly (P < or = 0.001) after each meal, but there was no
      difference between the two meals. These data show that modest amounts of fat in a
      meal will elicit a measurable postprandial TAG response. Since postprandial
      lipaemia affects the composition and concentration of the TAG- and cholesterol
      rich lipoproteins, controlling dietary TAG supply may influence the metabolic
      fate of these lipoproteins.

PMID- 10341673
TI  - The 'Mini Nutritional Assessment' (MNA) and the 'Determine Your Nutritional
      Health' Checklist (NSI Checklist) as predictors of morbidity and mortality in an
      elderly Danish population.
AB  - The purpose of the present study was to evaluate the capacity of the 'Determine
      Your Nutritional Health' Checklist (NSI Checklist) and the 'Mini Nutritional
      Assessment' (MNA) methods to predict nutrition-related health problems. Data were
      from the Danish part of the 'Survey in Europe of Nutrition in the Elderly, a
      Concerted Action' (SENECA) baseline survey from 1988, and the follow-up study
      from 1993. Based on the baseline survey thirty-nine (19.3%) of the subjects were
      classified at high nutritional risk, 103 (51%) were considered at moderate
      nutritional risk and sixty (29.7%) were within the 'good' range according to the
      criteria in the NSI Checklist. With the MNA, 171 subjects were classified
      according to their nutritional risk into a well-nourished group, comprising
      78.4%, and a group who were at risk of undernutrition, comprising 21.6% at
      baseline. A total of 115 subjects participated in the follow-up study. The
      mortality rate and the prevalence of various morbidity indicators were compared
      between the different risk groups. The analysis showed that subjects with a high
      MNA score (> or = 24) had significantly lower mortality (rate ratio estimate:
      0.35; 95% Cl 0.18, 0.66) compared with subjects with a low MNA score (< or =
      23.5). In contrast, the NSI Checklist score was not a significant predictor of
      mortality (rate ratio estimate: 1.45; 95% Cl 0.78, 2.71). The sixteen Danes
      judged to be at high nutritional risk by the NSI Checklist in 1988, had more
      acute diseases (P < 0.001) than the rest of the participants, between 1988 and
      1993. No significant differences were found in the participation rates,
      hospitalization rates, physician visits, need of help or weight loss between the
      groups. The thirteen Danes judged to be at risk of undernutrition in 1988 by the
      MNA, had a lower participation rate (P < 0.01) and higher occurrence of acute
      disease (P < 0.05), need of help (P < 0.05), and weight loss (P < 0.001) than the
      well-nourished group, between 1988 and 1993. No significant differences were
      found in hospitalization rates and physician visits between the two groups. In
      conclusion, the results indicate that modified versions of the NSI Checklist and
      the MNA are capable of identifying a group of 70-75-year-old subjects with
      increased risk of certain nutrition-related health problems. Further, an MNA
      score < or = 23.5 predicts mortality in a Danish population.

PMID- 10341674
TI  - Effect of fatty acid chain length and saturation on the gastrointestinal handling
      and metabolic disposal of dietary fatty acids in women.
AB  - The gastrointestinal handling and metabolic disposal of [1-13C]palmitic acid, [1
      13C]stearic acid and [1-13C]oleic acid administered within a lipid-casein-glucose
      sucrose emulsion were examined in normal healthy women by determining both the
      amount and nature of the 13C label in stool and label excreted on breath as
      13CO2. The greatest excretion of 13C label in stool was in the stearic acid trial
      (9.2% of administered dose) whilst comparatively little label was observed in
      stool in either the palmitic acid (1.2% of administered dose) or oleic acid (1.9%
      of administered dose) trials. In both the palmitic acid and oleic acid trials,
      all of the label in stool was identified as being present in the form in which it
      was administered (i.e. [13C]palmitic acid in the palmitic acid trial and
      [13C]oleic acid in the oleic acid trial). In contrast, only 87% of the label in
      the stool in the stearic acid trial was identified as [13C]stearic acid, the
      remainder was identified as [13C]palmitic acid which may reflect chain shortening
      of [1-13C]stearic acid within the gastrointestinal tract. Small, but
      statistically significant, differences were observed in the time course of
      recovery of 13C label on breath over the initial 9 h of the study period (oleic
      acid = palmitic acid > stearic acid). However, when calculated over the 24 h
      study period, the recovery of the label as 13CO2 was similar in all three trials
      (approximately 25% of absorbed dose). These results support the view that chain
      length and degree of unsaturation may influence the gastrointestinal handling and
      immediate metabolic disposal of these fatty acids even when presented within an
      emulsion.

PMID- 10341675
TI  - Increased risk of iodine deficiency with vegetarian nutrition.
AB  - Observational studies primarily based on diet questionnaires or food records have
      reported that vegetarians can have a very low I intake. However, analytically
      ascertained data on the possible degree of I deficiency with this form of diet is
      lacking. Six healthy adult volunteers participated in the present controlled
      experimental diet study carried out in four separate 5 d diet periods. The study
      diets, normal, protein-rich, lactovegetarian, and repeat of the initial normal
      diet, were almost isoenergetic and contained no fish, sea food, iodized salt or
      processed foods fortified with I. During the last 48 h of each diet period two 24
      h urine samples were obtained from each subject. I analyses were performed in the
      urine samples and in representative samples taken from all ingested diets.
      Urinary I excretion was significantly lower with the lactovegetarian diet (36.6
      (SD 8.8) micrograms/d) than with the normal and the protein-rich diets (50.2 (SD
      14.0) and 61.0 (SD 8.0) micrograms/d respectively). Accordingly, a markedly
      reduced I intake was confirmed analytically for the lactovegetarian diet (15.6
      micrograms/d v. 35.2 and 44.5 micrograms/d respectively). Our results provide
      experimental confirmation of literature findings indicating that I supply is
      higher with non-vegetarian than with vegetarian diets. Specifically, the
      extremely low intake and urinary output of I as analytically determined for one
      exemplary vegetarian diet, demonstrate that dietary I may be limiting when strict
      forms of vegetarian dietary practices (no iodized salt, no I supplements) are
      followed. The present study is, therefore, the first diet-experiment-based
      pointer to the potential danger of I deficiency disorders due to strict forms of
      vegetarian nutrition, especially when fruits and vegetables grown in soils with
      low I levels are ingested.

PMID- 10341677
TI  - Influence of sodium fumarate addition on rumen fermentation in vitro.
AB  - The influence of sodium fumarate on rumen fermentation was investigated in vitro
      using batch and semi-continuous cultures of mixed rumen micro-organisms taken
      from three sheep receiving a basal diet of hay, barley, molasses, fish meal and a
      mineral-vitamin supplement (500, 299.5, 100, 91 and 9.5 g/kg DM respectively).
      Batch cultures consisted of 10 ml strained rumen fluid in 40 ml anaerobic buffer
      containing 200 mg of the same feed given to the sheep. Sodium fumarate was added
      to achieve a final concentration of 0, 5 or 10 mmol/l, as a result of the
      addition of 0, 250 or 500 mumol, equivalent to 0, 200 and 400 g/kg feed. CH4
      production at 24 h (360 mumol in the control cultures) fell (P < 0.05) by 18 and
      22 mumol respectively (SED 7.5). Total gas production was increased by the
      addition of fumarate without significant accumulation of H2. Substantial
      increases in acetate production (92 and 194 mumol; SED 26.7, P < 0.01) were
      accompanied by increases in propionate formation (212 and 396 mumol; SED 13.0, P
      < 0.001). Longer-term effects of fumarate supplementation on ruminal fermentation
      and CH4 production were investigated using the rumen simulation technique
      (Rusitec). Eight vessels were given 20 g basal diet/d, and half of them received
      a supplement of fumarate (disodium salt) over a period of 19 d. The response to
      the daily addition of 6.25 mmol sodium fumarate was a decrease in CH4 production
      of 1.2 mmol (SED 0.39, P < 0.05), equivalent to the consumption of 4.8 mmol H2,
      and an increase in propionate production of 4.9 mmol (from 10.4 to 15.3 (SED
      1.05) mmol/d, P < 0.01). The inhibition of CH4 production did not decline during
      the period of time that fumarate was added to the vessels. Thus, the decrease in
      CH4 corresponded well to the fraction of the fumarate that was converted to
      propionate. Fumarate had no significant (P > 0.05) effect on total bacterial
      numbers or on the number of methanogenic archaea, but numbers of cellulolytic
      bacteria were increased (8.8 v. 23.9 (SED 2.49) x 10(5) per ml, P < 0.01).
      Fumarate also increased DM digestibility of the basal diet after 48 h incubation
      (0.476 v. 0.508 (SED 0.0123), P < 0.05). Thus, it was concluded that sodium
      fumarate may be a useful dietary additive for ruminants, because it diverts some
      H2 from CH4 production and because it is able to stimulate proliferation of
      cellulolytic bacteria and digestion of fibre.

PMID- 10341676
TI  - Lack of influence of test meal fatty acid composition on the contribution of
      intestinally-derived lipoproteins to postprandial lipaemia.
AB  - The extent and duration of postprandial lipaemia have been linked to risk of CHD
      but the influence of dietary variables on, and the relative contributions of,
      exogenous (chylomicron) and endogenous (VLDL) triacylglycerols to the total
      lipaemic response have not been comprehensively evaluated. In the present study
      the triacylglycerol, apolipoprotein (apo) B-48 and retinyl ester (RE) responses
      to three test meals of varying monounsaturated (MUFA) and saturated fatty acid
      (SFA) content were measured in the triacylglycerol-rich lipoprotein (TRL)
      fraction of plasma (rho = 1.006 g/ml) for 9 h after meal consumption. Fifteen
      healthy normolipidaemic young men consumed, on separate occasions, three test
      meals which were identical apart from their MUFA and SFA contents. Expressed as a
      percentage of total energy the MUFA/SFA contents of the meals were: (1) 12%/17%;
      (2) 17%/12% and (3) 24%/5%. The contribution of the intestinally-derived
      lipoproteins (chylomicrons) to the lipaemic response was investigated by
      determining the time to reach peak concentration and the total and incremental
      areas under the time response curves (AUC and incremental AUC) for RE, apoB-48
      and triacylglycerol in the TRL fraction. No significant differences in these
      measurements were observed for the three meals. However, visual comparison of the
      postprandial responses to the three meals suggested that as meal MUFA content
      increased there was a tendency for the triacylglycerol, apoB-48 and RE responses
      to become biphasic as opposed to the typical monophasic response seen with the
      12% MUFA/17% SFA meal. Comparison of the apoB-48 and RE responses for the three
      test meals confirmed other workers' findings of delayed entry of RE relative to
      apoB-48 in TRL. The value of the two markers in investigating dietary fat
      absorption and metabolism is discussed.

PMID- 10341678
TI  - Dietary rhubarb (Rheum rhaponticum) stalk fibre stimulates cholesterol 7 alpha
      hydroxylase gene expression and bile acid excretion in cholesterol-fed C57BL/6J
      mice.
AB  - Both experimental and clinical studies have indicated that a novel source of
      dietary fibre, produced from rhubarb (Rheum rhaponticum) stalks, is potentially
      hypolipidaemic. The present study, using C57BL/6J mice, was undertaken to examine
      if this fibre source affects cholesterol degradation. Mice were maintained on
      semi-purified diets containing 50 g rhubarb fibre or cellulose/kg with or without
      5 g cholesterol/kg for 4 weeks. In cholesterol-supplemented mice, rhubarb fibre
      caused significant lowering of plasma cholesterol (-13%) and the hepatic
      concentrations of total cholesterol (-34%) and cholesteryl esters (-34%). In
      parallel to the reduction of hepatic cholesteryl ester content, animals fed on
      rhubarb fibre had significantly lower activity of acyl CoA: cholesterol
      acyltransferase (EC 2.3.1.26) than the mice maintained on a diet containing
      cellulose and cholesterol. Rhubarb-fibre feeding accelerated the faecal bile-acid
      loss and diminished the gall-bladder bile-acid pool in both the normal and the
      cholesterol-fed mice. The increase in the bile-acid excretion was positively
      correlated with an increased activity as well as mRNA abundance of cholesterol 7
      alpha-hydroxylase (EC 1.14.13.17). The increased excretion of bile acids and
      induction of cholesterol 7 alpha-hydroxylase activity may account for the
      hypocholesterolaemic effect of rhubarb fibre.

PMID- 10341680
TI  - Global energy requirements, ethnicity, representative samples and basal
      metabolism: what can we really tell the world?

PMID- 10341679
TI  - Maternal food restriction in the second half of pregnancy affects vascular
      function but not blood pressure of rat female offspring.
AB  - Food restriction during pregnancy in rats induces intrauterine growth retardation
      with consequences persisting into adulthood. In the present study we have
      investigated the hypothesis that malnutrition in pregnant rats may lead to
      altered cardiovascular function in adult female offspring. Perinatal growth
      retardation was induced by a 50% reduction of normal dietary intake in rats
      during the second half of pregnancy. Systolic and diastolic blood pressure values
      and heart rate were recorded in conscious female offspring (100 d old) using a
      femoral artery probe. No significant differences in heart rate, or in systolic
      and diastolic blood pressures were recorded between control offspring and
      offspring of nutritionally deprived rats. In order to ascertain whether
      cardiovascular variables in the offspring were influenced by lactation, subgroups
      of offspring from food-restricted dams were fostered with lactating dams fed on a
      normal diet. Blood pressure and heart rate were also found to be normal in these
      offspring. The rise in blood pressure associated with NO inhibition was similar
      in all groups. Isolated resistance artery function was assessed in vitro in
      offspring (100-120 d old) of a second group of semi-starved dams. Small
      mesenteric arteries from these animals showed reduced endothelium-dependent
      relaxation (to acetylcholine and bradykinin), but enhanced sensitivity to
      exogenous NO (sodium nitroprusside). We conclude that food restriction during the
      second half of pregnancy and/or lactation does not induce hypertension in adult
      offspring, but may effect subtle changes in vascular function.

PMID- 10341681
TI  - Medical exposures, health surveillance and the Medical Exposures Directive.

PMID- 10341682
TI  - The significance of spontaneous resolution of breast calcification.
AB  - Spontaneously resolving breast microcalcification is a rarely reported
      occurrence. A retrospective review was carried out on 33 cases of resolving
      benign and indeterminate microcalcification identified from 108,000 screening
      mammograms from the South West London Breast Screening Service. Four further
      cases are reported from The Jarvis Breast Screening Centre. No interval cancers
      were identified in women with microcalcification which initially showed benign
      appearances. However, 36.4% of the group with resolving indeterminate
      microcalcification subsequently developed cancers. It is recommended that this
      change should prompt full investigation and close follow-up or excision. While
      the majority of spontaneously resolving microcalcification is associated with
      benign processes, it is concluded that a significant proportion of disappearing
      indeterminate microcalcification is associated with malignancy.

PMID- 10341684
TI  - Rectal adenocarcinoma: assessment of tumour involvement of the lateral resection
      margin by MRI of resected specimen.
AB  - The aim of the present study was to investigate whether MRI could predict tumour
      involvement of the lateral resection margin on resected rectal cancer specimens.
      26 specimens obtained after total mesorectal excision were examined in the
      sagittal and axial plane on a clinical 1.5 T MR system using phased-array surface
      coils. The shortest distance between the deepest point of tumour penetration and
      the lateral resection margin was measured. This distance is referred to as LRM.
      The results were correlated to measurements on digital images of giant
      histopathological sections. The total number of lymph nodes and lymph node
      metastases was also counted. LRM was less than or equal to 1 mm (a distance
      considered for non-radically excised tumours) in eight of the histopathological
      specimens. On MR images of the resected specimen, LRM was less than or equal to 1
      mm in seven of these specimens. LRM was shorter in MR examinations than in
      histopathological giant sections in 11 specimens. The sensitivity, specificity,
      positive and negative predictive values for prediction of tumour involvement of
      the lateral resection margin (LRM < or = 1 mm) by MR of the resected specimen
      were 88%, 78%, 64% and 93%, respectively. Presence of lymph node metastases could
      not accurately be predicted by MR. However, it is concluded that the presence of
      a tumour free lateral resection margin can be predicted by MRI of resected rectal
      specimens when this exceeds 1 mm.

PMID- 10341683
TI  - Sonographic detection and characterization of musculoskeletal and subcutaneous
      tissue abnormalities in sickle cell disease.
AB  - Pain due to bone marrow infarction is common in homozygous sickle cell disease
      (SS disease). Musculoskeletal pathology may be responsible for persistent
      atypical symptoms. We have assessed the frequency and ultrasound appearances of
      soft tissue and joint abnormalities in SS disease. SS disease patients with
      atypical musculoskeletal symptoms were examined with ultrasound over a 2 year
      period. Ultrasound findings were correlated with those at surgery or percutaneous
      drainage. 31 episodes in 23 patients were referred for ultrasound. There were 36
      abnormalities in 18 patients: abscess (n = 15), effusions (n = 5), soft tissue
      induration (n = 12), fat necrosis (n = 2), haematoma (n = 1) and reactive lymph
      node (n = 1). Five examinations were normal. Soft tissue abnormalities in
      patients over the age of 14 years were associated with intramuscular injections:
      fat necrosis (n = 1), haematoma (n = 1), indurated soft tissue (n = 1) and
      abscess (n = 7). Soft tissue abnormalities with no underlying cause were seen in
      seven patients: abscess (n = 4), indurated soft tissue (n = 2) and fat necrosis
      (n = 1). Ultrasound is the imaging modality of choice for delineating these
      abnormalities and allows percutaneous drainage.

PMID- 10341685
TI  - Dynamic intravenous coronary angiography using 2D monochromatic synchrotron
      radiation.
AB  - A method of examination for coronary artery disease that is less invasive and
      easier than coronary angiography (CAG) has been sought. We have developed a
      dynamic intravenous coronary angiography (IVCAG) system using synchrotron
      radiation (SR) and have used it clinically. Four patients suspected of having
      angina pectoris underwent IVCAG. An SR beam was reflected asymmetrically with a
      silicon crystal to produce a wide (150 mm x 80 mm) and monochromatic (37 keV) X
      ray beam, with an energy level to achieve high sensitivity to the contrast agent.
      Following an intravenous injection of contrast agent, irradiation was applied for
      4 ms periods at 33 ms intervals for dynamic IVCAG at 30 images s-1. Images were
      acquired with an image intensifier and recorded with a digital fluorography
      system. The dynamic images permitted clear visualization of the coronary arteries
      and permitted evaluation of coronary anatomy. Two patients exhibited no stenotic
      lesions, one patient had a 90% stenosis in the right coronary artery, and the
      remaining patient had a 25% stenosis at the site of previous percutaneous
      transluminal coronary angioplasty in the left anterior descending artery (LAD).
      The total irradiation doses used for IVCAG were less than those for conventional
      angiography. Dynamic IVCAG can be readily used for the evaluation of coronary
      arteries.

PMID- 10341686
TI  - The diagnosis of cirrhosis by high resolution ultrasound of the liver surface.
AB  - The objective was to assess the clinical usefulness of high resolution ultrasound
      (US) analysis of the liver surface for the diagnosis of cirrhosis. In a
      prospective study, US evaluation of the ventral contour of the liver was
      performed using a 7.5 MHz linear transducer in 100 patients with suspected liver
      disease. Only reproducible diffuse ventral liver surface irregularities were
      considered as an objective US sign of cirrhosis. All patients underwent liver
      biopsy and/or laparoscopy in order to obtain a definitive diagnosis. Disease
      prevalence for cirrhosis was 49%. In nine cases the visualized US irregularities
      were both unconvincing and hardly reproducible. Consequently, they were
      considered as non-diagnostic and excluded from further analysis. On 91 diagnostic
      studies, the sensitivity of US for cirrhosis was 91.1%, the specificity 93.5% and
      the accuracy 92.3%. Positive and negative predictive values were 93.2% and 91.5%,
      respectively. Provided non-diagnostic cases were considered as technically
      satisfactory studies and included as true-positive and false-positive cases, this
      would slightly increase the sensitivity but decrease specificity and accuracy to
      91.8%, 84.3%, and 88.0%, respectively. High resolution US analysis of the ventral
      liver contour is a clinically reliable non-invasive test for the diagnosis of
      cirrhosis.

PMID- 10341687
TI  - An anthropomorphic phantom for receiver operating characteristic studies in CT
      imaging of liver lesions.
AB  - The purpose of the study was to develop a methodology that allowed quantitative
      assessment of image quality in CT and its relationship to dose. An
      anthropomorphic phantom was designed for use in receiver operating characteristic
      (ROC) studies of the detectability of liver lesions with CT. The lesions were
      simulated by different mixtures of glycerol and water that were filled into holes
      of different diameters in a liver tissue substitute. A pilot study was carried
      out on five different scanners that were operated at various exposure settings. A
      positive correlation was demonstrated for each of the scanners between the
      weighted CT dose index (CTDIW) and the area under the ROC curve. For the exposure
      settings used in the clinical routine in the five laboratories, the CTDIW ranged
      from 15 to 31 mGy. Three observers who read the corresponding set of five phantom
      images agreed, as judged from the areas under the ROC curves, that there was a
      marked difference in quality between the three best images and the other two. The
      two newest scanners in the study had the lowest CTDIW, and at the same time the
      best ROC results. The phantom and the ROC methodology may, with a set of
      suggested improvements, be used for comparison of the performance in different CT
      laboratories, and to establish the dose needed to ensure adequate image quality
      for a particular scanner.

PMID- 10341688
TI  - Multiple regression analysis of octanol/water partition coefficients of non-ionic
      monomeric radiographic contrast media with the combination of three molecular
      descriptors.
AB  - A multiple non-linear regression equation is calculated for the correlation of
      the octanol/water partition coefficient of nine non-ionic monomeric radiographic
      contrast media molecules with a combination of three molecule describing
      parameters (heat of formation, dipole and ovality). Good correlation is obtained
      (proportion of variance explained, R2, is 0.9093). This simple equation can be
      used prospectively in the design of new compounds analogous to the used series.
      It was used to calculate prospectively the partition coefficient of another
      compound of the same family, iomeprol.

PMID- 10341689
TI  - Radiographic exposure slide rules.
AB  - Before automatic exposure control was fitted to diagnostic X-ray sets,
      radiographers were faced with the problem of choosing the parameters that would
      give the best radiographic image. For a new X-ray set whose performance was
      unknown, this was no easy matter, and often required considerable trial and error
      because of the number of variables involved. To reduce the amount of work,
      special slide rules were invented which calculated the effect of some of these
      variables. Five such slide rules, dating from between about 1910 and 1950, are
      illustrated and discussed, including the light they shed on changes in
      radiographic practice over the years.

PMID- 10341690
TI  - Diagnostic image quality of mobile neonatal chest X-rays and the radiation
      exposure incurred.
AB  - A study was undertaken to identify the variation of entrance skin doses (ESDs) in
      mobile neonatal chest radiography with regard to the European Commission (EC)
      reference dose and to examine potential relationships with image quality and
      radiographic techniques. Five sites from the former North West Thames region
      participated. All mobile neonatal radiographic techniques were surveyed. Dose
      area product per examination was directly measured and the ESD calculated. Image
      quality criteria were developed from those published by the EC. Image quality was
      graded by two independent observers. Over the five sites, 144 examinations were
      recorded. Calculated ESDs ranged up to 160 microGy, with an appreciable variation
      not only between sites but also within sites. A clear relationship between actual
      rather than nominal speed and dose over all sites was demonstrated (r = -0.95, p
      = 0.013). No correlation between image quality and dose was noted (r = -0.044, p
      = 0.665). Neonatal imaging systems at participating sites, within the North
      Thames region, comply with EC guidelines on patient dose and image quality for
      mobile chest X-rays. Significant variation in ESDs was encountered between sites
      with no discernible relationship with image quality or the employed radiographic
      techniques as described by the EC. The strong inverse relationship between ESDs
      and actual rather than nominal speed suggests a neglected aspect of radiation
      protection.

PMID- 10341691
TI  - Determination of tumour regression rates during radiotherapy for cervical
      carcinoma by serial MRI: comparison of two measurement techniques and examination
      of intraobserver and interobserver variability.
AB  - Tumour regression rates of 11 patients with cervical carcinoma were estimated
      during external beam radiotherapy (EBRT) using serial MRI (average time interval
      7 days; range 3-15 days). An average of five investigations (range 4-8) was
      performed per subject. Tumour volume was measured by two observers using the
      Cavalieri method of modern design stereology in combination with (a) planimetry
      and (b) point counting. The mean precision of all the volume estimates obtained
      by manually tracing the outline of the tumour was 6.6%. The mean precision
      obtained by counting an average of 176 points per investigation on the same
      transects was 6.7%. The intraobserver repeatability of planimetry, interobserver
      reproducibility of planimetry and point counting were excellent with no
      significant difference between the volume estimates obtained using either
      technique. Based on the planimetry measurements, initial tumour volumes ranged
      from 6.5 to 222 cm3 (mean 63 cm3, median 44 cm3). Based on the point counting
      measurements, initial tumour volumes ranged from 7.2 to 235 cm3 (mean 68 cm3,
      median 46 cm3). Tumour regression began within a few days of commencing EBRT and
      showed an exponential relationship with time (p < 0.01). There was good agreement
      between the regression rates obtained by planimetry and those obtained by point
      counting. No significant correlation was found between initial tumour volume and
      tumour regression rate for either planimetry or point counting. Planimetry
      measurements were, on average, obtained in about half the time taken for point
      counting (i.e. 30 min and 50 min, respectively). Although point counting is
      generally likely to be the more efficient approach, planimetry may be the
      preferred approach for estimating tumour volume when a purpose built track ball
      is available and the tumour morphology is relatively simple. Volume measurement
      should be obtained using the Cavalieri method to ensure that the estimates are
      unbiased and that their precision can be predicted. The measured tumour
      regression rates may have important implications for improving local tumour
      control, optimum timing of brachytherapy and minimizing the risk of radiation
      damage.

PMID- 10341692
TI  - A comparison of two mammography film-screen combinations designed for standard
      cycle processing.
AB  - This paper presents comparisons of the Kodak Min-R 2000 mammography film-screen
      combination designed for standard-cycle processing with that of the older Min
      RM/Min-R combination. Comparisons were performed in terms of characteristic
      curves and relative image quality. The Min-R 2000 combination had a speed of 1.7
      relative to the Min-RM/Min-R combination to yield an optical density of 1.25; the
      maximum gradients of the characteristic curves for the two combinations were 4.6
      and 2.7, respectively. Image quality was evaluated in a breast detail phantom
      study. It was demonstrated that image qualities of the film-screen combinations
      were comparable.

PMID- 10341693
TI  - Electronic monitoring of clinical experience during undergraduate training in
      diagnostic radiography.
AB  - The clinical experience of a student radiographer has traditionally been recorded
      in a paper log book. Accurate maintenance of the book relied upon the student's
      diligence. The electronic logbook is a method of accurately recording the
      clinical experience of the student radiographer by retrieval of information from
      the database of a hospital information or radiology management system. The system
      requires minimal software modification in order to incorporate fields defining
      the ability of the student in association with the degree of infirmity of the
      patient. Retrieved information is processed by a specially designed software
      package at the Academic Centre and reports issued to Clinical Tutors. Benefits of
      the system include easy monitoring of student workload, ensuring that the student
      receives a wide and varied experience during training; improvement in student
      motivation; and use of a final report form in the student's portfolio.

PMID- 10341694
TI  - Metanephric adenoma in a solitary kidney.
AB  - A case of metanephric adenoma occurring in a solitary kidney of a 31-year-old man
      is presented. Metanephric adenoma is extremely rare and its diagnosis should be
      considered in a patient with a well circumscribed renal tumour and concomitant
      paraneoplastic syndromes. Radiological features of the tumour are non-specific
      and histopathological examination is essential to establish a definitive
      diagnosis. Recognition of the tumour is of potential importance as conservative
      treatment with complete surgical enucleation will suffice in all cases.

PMID- 10341695
TI  - Waldenstrom's macroglobulinaemia of the breast detected by colour Doppler
      ultrasound.
AB  - Waldenstrom's macroglobulinaemia (lymphoplasmacytoid lymphoma) is a low grade B
      cell non-Hodgkin's lymphoma. The majority of patients present with advanced
      disease. Lymphoma of the breast is rare and usually arises as part of a
      disseminated disease process. A case of disseminated Waldenstrom's
      macroglobulinaemia is reported in which the breast was involved. The findings
      using standard mammographic and ultrasound techniques were non-specific and only
      when colour Doppler examination was performed could an abnormality be detected.

PMID- 10341696
TI  - Calcification of presumed ovarian carcinoma brain metastases following
      radiotherapy.
AB  - Multiple brain metastases from ovarian carcinoma are rare. CT findings are
      reported in a case treated with whole brain radiation therapy and chemotherapy.
      Radiological complete-calcified brain metastases following treatment and long
      morphological changes occurred. Delayed neurological findings in relation to
      treatment are considered. Long survival with unmodified calcified lesions may
      suggest a stabilization of CNS disease.

PMID- 10341697
TI  - Intramedullary spinal metastasis from carcinoma of the cervix.
AB  - Intramedullary spinal metastases are rare and prior to the availability of MRI
      were seldom diagnosed antemortem. Lung and breast carcinoma are the most common
      primary sources. Cervical carcinoma is the least likely source of intramedullary
      spinal metastases. A case of intramedullary spinal metastases is described in a
      29-year-old woman with squamous cell carcinoma of the cervix.

PMID- 10341698
TI  - Computed tomography in abdominal tuberculosis.
AB  - The diagnosis of abdominal tuberculosis is often difficult because of its protean
      clinical manifestations and non-specific laboratory investigations. In the
      abdomen, tuberculosis may affect the intestinal tract, lymph nodes, peritoneum
      and solid viscera in varying combinations. CT, with its ability to provide a
      comprehensive overview of abdominal structures, is the imaging modality of choice
      for evaluation of such patients. This pictorial review illustrates the spectrum
      of CT appearances of abdominal tuberculosis which includes intestinal, lymph
      nodal, peritoneal, mesenteric, hepatic, splenic and pancreatic disease.

PMID- 10341699
TI  - A pain in the back!

PMID- 10341700
TI  - The derivation of tissue-maximum ratio from percentage depth dose requires peak
      scatter factor to be considered as a function of SSD.

PMID- 10341701
TI  - Perspective: cancer care and the new biology.
AB  - Over the past 25 years, measurable--albeit relatively modest--improvements in the
      outcome of treatment for patients with cancer have taken place. During a similar
      time period, there has been an explosion of information on the molecular biology
      and genetic basis of cancer, with the evolution of a remarkable array of new and
      powerful laboratory tools. The advances made in cancer care owe little to these
      developments in the laboratory. Looking forward, however, the opportunity now
      exists for the new knowledge to be harnessed, through a proper partnership of
      laboratory and clinical scientists, to provide significant further improvements
      in results. These should occur through developments in prevention, early
      diagnosis, and particularly in new forms of therapy. This will require a shift in
      emphasis on the part of all concerned, and there is already evidence that this is
      beginning to happen.

PMID- 10341703
TI  - Inherited and inducible chromosomal instability: a fragile bridge between genome
      integrity mechanisms and tumourigenesis.
AB  - Cancer is a multi-step process evolving as the result of the accumulation of a
      number of mutational events. The growing body of evidence implicating genetic
      instability as a key feature of this evolutionary process and the risk of
      malignancy associated with chromosomal instability syndromes highlight the
      importance of understanding the mechanisms that cells use to maintain the
      integrity of their genomes. Classic examples of inherited chromosomal instability
      with cancer predisposition are Bloom's syndrome, ataxia telangiectasia, and
      Fanconi anaemia, although the mechanisms involved are far from understood.
      Selected features of these inherited disorders are reviewed to provide a
      background to the more recently discovered inducible chromosomal instability, a
      phenotype in which apparently normal cells that have survived ionizing radiation
      and certain chemical insults may produce descendants exhibiting a high frequency
      of de novo chromosome aberrations and gene mutations. The phenotype is induced at
      frequencies considerably greater than conventional mutation frequencies but
      little is understood of the underlying mechanism(s). To date, chromosomal
      instability induced by ionizing radiation has been the most extensively studied
      phenotype and it is evident that the expression of inducible instability has a
      strong dependence on the type of radiation exposure, the cell type irradiated,
      and the genetic 'predisposition' of the irradiated cell.

PMID- 10341702
TI  - Molecular epidemiology of human cancer risk: gene-environment interactions and
      p53 mutation spectrum in human lung cancer.
AB  - The p53 tumour suppressor gene is at the crossroads of a network of cellular
      pathways including cell cycle checkpoints, DNA repair, chromosomal segregation,
      and apoptosis. These pathways have evolved to maintain the stability of the
      genome during cellular stress from DNA damage, hypoxia, and activated oncogenes.
      The high frequency of p53 mutations in human cancer is a reflection of the
      importance of p53 involvement in this network of pathways during human
      carcinogenesis. An electronic database containing p53 mutations from more than
      9000 cancers (http:/(/)www.iarc.fr/p53/homepage.html) can be used to generate
      hypotheses for further clinical, epidemiological, and laboratory investigations.
      For example, one can hypothesize that (a) p53 mutations vary in their
      pathobiological significance; (b) cellular content influences the selection of
      p53 mutations in clonally derived cancers; (c) the location and type of mutation
      within the p53 gene provide clues to functional domains in the gene product; and
      (d) the p53 mutation spectrum can be a molecular link between aetiological agents
      and human cancer. This review will focus on the role of p53 and cancer
      susceptibility genes in the molecular pathogenesis and epidemiology of human lung
      cancer.

PMID- 10341704
TI  - Chromosomes, 11Q and cancer: a review.
AB  - This review aims at providing a general understanding of how the multiple
      cytogenetic aberrations in cancer cells arise and exemplifies this by considering
      the specific role of chromosome 11q loci in carcinogenesis. Section I provides a
      theoretical molecular and structural framework for understanding the cytogenetic
      aberrations described in cancer. Given this background, Section II describes
      advances in the identification and localization of cancer susceptibility genes on
      chromosome 11q, highlighting ongoing areas of investigation.

PMID- 10341705
TI  - Perspective: chromosomal translocations can affect genes controlling gene
      expression and differentiation--why are these functions targeted?
AB  - Chromosomal translocations are important aetiological factors in many human
      cancers. These aberrant chromosomes cause enforced expression of oncogenes
      located near the breakpoints or results in tumour-specific fusion proteins. Among
      the characteristics which influence the tumourigenic effect, it is observed that
      the genes at translocation junctions are often transcription factors and often
      normally involved in developmental processes. Furthermore, protein-protein
      interactions are key elements in the mechanism by which the translocation gene
      products exert their pathogenic effects. In this review some of these salient
      features are discussed and generalizations are suggested which may be applicable
      to the influence of chromosomal translocations on acute forms of cancer.

PMID- 10341706
TI  - Insights into cancer from transgenic mouse models.
AB  - The generation of mice designed to overexpress activated forms of oncogenes or
      carrying targeted mutations in tumour suppressor genes, has allowed scientists to
      causally link the function of these genes with specific tumour processes, such as
      proliferation, apoptosis, angiogenesis or metastasis. In addition, these mice
      have been interbred to assess the extent of cooperativity between different
      genetic lesions in disease progression, leading to a greater understanding of the
      multi-stage nature of tumourigenesis. The effect of genetic mutations is often
      influenced by the genetic background of the mouse and by analysing strain
      dependent phenotypes, modifier loci have been identified. Although genetic
      mutations in mouse and humans do not always lead to the same tumour spectrum, the
      underlying molecular mechanisms are frequently relevant to both species.
      Furthermore, new technical approaches creating conditional mouse mutants which
      develop tumours in a tissue-specific manner, will allow the effect of mutation of
      certain genes to be studied in specific tissues, free from the fatal effects of
      the mutation in other clinically less relevant tissues. Several exising mouse
      strains have already been used to develop and test new therapies and conditional
      mutagenesis will undoubtedly increase the potential use of transgenic mice in
      understanding and treating cancer.

PMID- 10341707
TI  - Field cancerization, clonality, and epithelial stem cells: the spread of mutated
      clones in epithelial sheets.
AB  - There has been considerable debate about the origin of human tumours, whether
      they arise from a single cell and are clonal populations or whether there needs
      to be some sort of co-operativity between cells for the neoplastic process to
      begin. Current theories subscribe to the clonal view, where a series of mutations
      in one cell begins a process of selection and clonal evolution leading to the
      development of the malignant phenotype. This review approaches this problem by
      asking how mutated clones, once established, spread through tissues before
      becoming overtly invasive. While there is substantial evidence in favour of
      independent origins of each tumour from a unique mutated clone, there are
      instances where such clones expand and remain cohesive, often involving a large
      area of tissue. The main example is the movement of mutated clonal crypts through
      the colorectal epithelium, by the process of crypt fission. In passing, the
      clonal architecture of early, pre-invasive lesions is examined, often with some
      surprising results.

PMID- 10341708
TI  - Genetic events and the role of TGF beta in epithelial tumour progression.
AB  - The mouse skin model of chemical carcinogenesis has been very well characterized
      with respect to epigenetic changes, which occur during tumour cell initiation,
      promotion and progression. The use of transgenic and gene knock-out mice has
      contributed greatly to knowledge in this area. The H-ras genetic locus has been
      shown to undergo multiple genetic changes, including mutagenic activation,
      amplification of the mutant gene, and loss of the normal allele. These different
      genetic events lead to thresholds of ras activity which contribute to different
      stages along the pathway to neoplasia. The genetic and epigenetic events which
      lead to tumour invasion and metastasis have been less well characterized than
      studies on tumour initiation and promotion, despite the fact that it is
      metastases which ultimately kill the animal/patient. In the mouse skin model,
      loss of p53 contributes to malignant conversion. Gene deletion of the INK4 locus
      is associated with transformation to a highly invasive spindle cell tumor
      phenotype. This spindle cell transformation can also be induced in vitro or in
      vivo by TGF beta 1, possible by synergizing with mutant H-ras. TGF beta can have
      both positive and negative effects on tumourigenesis, acting early as a tumour
      suppresser, but later as a stimulator of tumour invasion. It is this latter
      effect which may be clinically more significant, since many human tumours
      overexpress TGF beta, yet the majority still retain the intracellular signaling
      systems necessary for the cell to respond to this growth factor.

PMID- 10341709
TI  - Perspective: tumour spread--the problems of latency.
AB  - Tumour latency, or dormancy, is a well-recognized clinical phenomenon and
      induction or maintenance of this state would appear to offer a novel therapeutic
      approach to limiting the effects of neoplastic disease. Current interest has
      focused on the role that neovascularization plays in this process and the
      consequences of shifts in the balance between angiogenic and anti-angiogenic
      peptides. Targeting tumour vasculature by the administration or induction of such
      anti-angiogenic peptides is close to clinical evaluation.

PMID- 10341710
TI  - Perspective: defects in cell cycle control and cancer.
AB  - The past several years have witnessed a dramatic accumulation of experimental and
      clinical evidence supporting the notion that the cell cycle machinery is commonly
      targeted on oncogenesis. While numerous cell cycle regulators qualify as proto
      oncogenes or tumour suppressors and their aberrations may provide direct
      proliferative advantage to cancer cells, defects in checkpoint mechanisms act
      more indirectly yet affect both tumour progression and response to anticancer
      therapy. In this review, the ways that cell cycle defects contribute to
      oncogenesis are briefly illustrated and the emerging benefits of the newly gained
      insights into the cell cycle clock for clinical oncology are critically
      considered. Given the many reviews on the subject, emphasis is put on concepts
      rather than comprehensive treatment of the selected topics, with particular
      attention given to controversial issues, unorthodox phenomena, and the challenge
      facing the 'cell cycle and cancer field' at the transition to the next
      millennium.

PMID- 10341711
TI  - Cellular senescence and cancer.
AB  - The proliferative lifespan of normal mammalian cells is limited by intrinsic
      controls, which desensitize the cell-cycle machinery to extrinsic stimulation
      after a given number of cell divisions. One underlying clock driving this process
      of 'replicative senescence' is the progressive erosion of chromosome telomeres,
      which occurs with each round of DNA replication. This appears to trigger growth
      inhibition via activation of the tumour suppressor gene (TSG) product, p53, and
      the consequent up-regulation of the cell-cycle inhibitor p21WAF1. Other
      inhibitory pathways are also activated (possibly by additional clocks), including
      the TSG p16INK4a and the less well-defined complementation group genes. Loss of
      one pathway can be compensated, after a limited extension of lifespan, by further
      up-regulation of the others, so that to escape mortality a developing tumour must
      overcome multiple 'proliferative lifespan barriers' (PLBs) by successive genetic
      events, each conferring a new wave of clonal expansion. This provides one
      explanation for the existence of multiple genetic abnormalities in human cancers;
      furthermore, the diversity in the nature and timing of these PLBs between
      different cell types may explain the variation in the spectrum of abnormalities
      observed between the corresponding cancers. Even if all senescence pathways are
      inactivated, immortalization can only be achieved if erosion of telomeres is
      halted, before their end-protecting function is lost. This usually requires
      either activation of telomerase during tumour development, if the cell of origin
      is telomerase-negative, or up-regulation if the normal cell already has some
      activity, but not enough to prevent erosion. In either case, cancers often
      maintain near-critical telomere lengths; hence pharmacological inhibition of
      telomerase remains an attractive approach to the selective killing of tumour
      cells.

PMID- 10341712
TI  - The p53 pathway.
AB  - Abnormalities of the p53 tumour suppressor gene are among the most frequent
      molecular events in human and animal neoplasia. Moreover, p53 is one of the most
      studied proteins in the whole of contemporary biology, with more than 12,500
      papers so far written! In this review the choice has been deliberately made not
      to be fully comprehensive in the coverage of the huge p53 literature. Rather
      attention is focused on a small number of recent developments which are reviewed
      in the context of modern models of p53 function. Progress in the analysis of
      signalling to p53 including phosphorylation cascades, and interactions with
      proteins such as mdm2 and ARF are highlighted. The plethora of protein-protein
      interactions is discussed, as are the strategies for defining downstream targets
      of p53. Finally, the emerging biology of p53 homologues is considered. The need
      for bridging the gap between reductionist, biochemical and biophysical studies
      and biological and genetic analysis is emphasized. Only this will provide the
      needed framework for utilizing the information in clinical care.

PMID- 10341713
TI  - Apoptosis and therapy.
AB  - The dogma that antineoplastic treatments kill tumour cells by damaging essential
      biological functions has been countered by the notion that treatment itself
      initiates a programmed cellular response. This response often produces the
      morphological features of apoptosis and is determined by a network of
      proliferation and survival genes, some of which are differentially expressed in
      normal and malignant cells. Correspondingly, mutations that interfere with the
      initiation or execution of apoptosis may produce tumour-cell drug resistance.
      Remarkably, many of the genes that modulate apoptosis in response to cytotoxic
      drugs also affect apoptosis during tumour development; hence, the process of
      apoptosis provides a conceptual framework for understanding how cancer genes can
      influence the outcome of cancer therapy. Although the relative contribution of
      apoptosis to radiation and drug-induced cell death remains controversial,
      clinical studies have associated anti-apoptotic mutations with treatment failure.
      While careful preclinical and clinical studies will be necessary to resolve this
      point, our current understanding of apoptosis should facilitate the design of
      rational new therapies.

PMID- 10341714
TI  - New approaches to cancer therapies.
AB  - Inactivation of the tumour suppressors p53 and p16INK4a or activating mutations
      in the ras oncogene are the most common genetic alterations found in human
      cancers. In this review, novel approaches designed to evaluate the effect of
      targeting intracellular molecules are described and it is shown how information
      derived from small synthetic peptides can stimulate novel approaches for cancer
      drugs. This review also gives an example of how molecular, biochemical, and cell
      biology studies of cancer-associated gene products can, via organic chemistry, be
      translated into active drugs ready for testing in clinical trials. New cancer
      treatments are directly springing out of studies related to tumour physiology,
      where the prime target is not the tumour cells but the tumour blood vessels; some
      of the different approaches that are being tested will be highlighted here.
      Finally, some of the difficulties and promises using cancer-associated genes in
      gene therapy are discussed.

PMID- 10341715
TI  - How shall we apply the new biology to diagnostics in surgical pathology?
AB  - Molecular technology plays an ever-increasing role in academic pathology and
      frequent claims are made that these technical developments will revolutionize
      diagnostic histopathology. In reviewing the role and potential utility of
      molecular genetics in the clinical practice of tumour pathology, it is evident
      that claims have outweighed facts, at least to date, and while molecular data
      have helped to clarify specific small areas of tumour classification and have
      facilitated the diagnosis of certain relatively rare tumours (especially on
      limited tissue), the overall impact on cancer management has been small. In
      particular, molecular markers of prognosis or tumour response have yet to impact
      substantially on the role of conventional light microscopic examination. We
      believe that these shortcomings have more to do with the generally different
      goals of basic medical science and clinical practice. In order to optimize the
      benefit to patients of modern molecular pathology, these techniques need to be
      rigorously appraised in the clinical setting and properly analysed in terms of
      cost-benefit. This requires close collaboration between the basic research
      community and histopathologists. Suggestions that 'H&E' pathology will be
      superceded in the near future are both premature and unrealistic.

PMID- 10341716
TI  - The Amoroso Lecture. The human spermatozoon--a cell in crisis?
AB  - A great deal of evidence has accumulated in recent years to suggest that there
      has been a gradual increase in male reproductive pathology over the past 30-40
      years, as evidenced by increased rates of testicular cancer and declining semen
      quality. The hypothesis is advanced that this phenomenon is causally related to
      the ability of male germ cells to generate reactive oxygen metabolites. When
      produced in low levels, such metabolites are thought to enhance sperm function by
      stimulating DNA compaction and promoting a redox-regulated cAMP-mediated pathway
      that is central to the induction of sperm capacitation. When produced in
      excessive amounts, the same metabolites stimulate DNA fragmentation and a loss of
      sperm function associated with peroxidative damage to the sperm plasma membrane.
      Free radical-induced mutations in the male germ line may also be involved in the
      aetiology of childhood cancer and recent increases in the incidence of seminoma.
      In light of these considerations, establishing the mechanisms for free radical
      generation by the male germ line and determining the factors that influence this
      activity are important objectives for future research in this area.

PMID- 10341717
TI  - Evidence of sex reversal in the gonads of chicken embryos after oestrogen
      treatment as detected by expression of lutropin receptor.
AB  - In chicken embryos, there is a difference between the sexes in the onset of
      lutropin receptor mRNA expression in the gonads. The effects of oestrogen on
      lutropin receptor expression were studied to investigate the mechanism
      controlling this difference. Lutropin receptor mRNA expression was detected in
      the ovaries of sesame oil-treated control female embryos on day 12 of incubation,
      while no expression was found in the testes of the male controls. Oestradiol
      administration to genetically male embryos before sexual differentiation resulted
      in gonadal sex reversal which was characterized histologically by the
      proliferation of cortical cords and the presence of lacunae. Lutropin receptor
      expression was detected in the feminizing testis on day 12 of incubation.
      Administration of aromatase inhibitor (CGS 16949 A) to genetically female embryos
      before sexual differentiation inhibited the formation of cortical cords, although
      a relatively weak expression of lutropin receptor was detected. These results
      indicate that early expression of the lutropin receptor is regulated by
      oestrogen.

PMID- 10341718
TI  - Effects of the presence of a dominant follicle and exogenous oestradiol on the
      duration of the luteal phase of the bovine oestrous cycle.
AB  - The presence of a developing dominant follicle may be a factor in the control of
      the luteolytic cascade mechanism and the number of follicular waves during the
      bovine oestrous cycle. In this study, ovaries of all animals were examined once a
      day by transrectal ultrasonography. It was expected that heifers (n = 18) would
      have two follicular waves if the second wave occurred later than day 10 after
      oestrus (Expt 1) and that cows (n = 14) would have three waves if the second wave
      occurred on or before day 10 (Expt 2). The objective of Expt 1 was to determine
      if absence of a large follicle late in the luteal phase delays luteal regression
      in heifers that are expected to have two follicular waves. Nine heifers were
      injected i.v. with 10 ml charcoal-treated bovine follicular fluid three times a
      day for 4 days, starting on the day after initiation of the second follicular
      wave, to delay growth of the second wave dominant follicle. Nine heifers were
      injected with 0.9% NaCl as controls. The duration of the luteal phase (calculated
      as the number of days that serum progesterone was > 0.5 ng ml-1) was greater (P <
      0.01) in the follicular fluid-treated group compared with the controls (18.7
      versus 14.1 days). FSH and follicular growth were suppressed during the period of
      injection of follicular fluid (P < 0.01 and 0.03, respectively). The objective of
      Expt 2 was to determine the effect of increased oestradiol on the duration of the
      luteal phase in cows that were expected to have three follicular waves. Seven
      cows were injected i.m. three times a day for 4 days with 1 ml oestradiol (100
      micrograms ml-1 in corn oil) and seven cows were similarly injected three times a
      day with 1 ml 0.9% NaCl (control) starting the day after cessation of growth of
      the second wave dominant follicle. Luteal phase duration was shorter in
      oestradiol-treated animals than in the controls (14.0 versus 19.0 days; P <
      0.04). Serum oestradiol concentrations were higher in the oestradiol-treated
      group during the period of injection (P < 0.01). In summary, luteolysis was
      delayed when follicular growth was suppressed with follicular fluid (Expt 1).
      Exogenous oestradiol administration during the development of uterine oestradiol
      responsiveness initiated luteolysis earlier compared with control animals (Expt
      2).

PMID- 10341719
TI  - Increased velocity and induction of chemotactic response in mouse spermatozoa by
      follicular and oviductal fluids.
AB  - The dynamic parameters of mouse sperm cells exposed to follicular and oviductal
      fluids were assessed. Spermatozoa were tracked on a chemotactic Zigmond chamber
      and recorded using a videomicroscopy system. The results were evaluated with
      computer-supported image analysis. Follicular fluid at a dilution of 10(-4)
      markedly increased the proportion of spermatozoa with high velocity, and
      stimulated chemotactic behaviour. The highest velocities were observed in sperm
      cells exposed to oviductal fluid, and a greater proportion of these cells had
      high velocity compared with those exposed to follicular fluid. Chemotaxis was
      induced in spermatozoa exposed to oviductal fluid at dilutions of 10(-3) and 10(
      5). These results suggest the presence of temporal subpopulations of responsive
      spermatozoa, considering the distance travelled towards both follicular and
      oviductal fluids and the proportion of sperm cells migrating towards the gradient
      in the highest distance ranges. This is the first report on the effect of
      isolated follicular and oviductal fluids on dynamic parameters and chemotaxis of
      mouse spermatozoa. The findings support previous work showing that the motility
      and directionality of mouse sperm cells is increased by factors in the
      microenvironment of the egg. Although the significance of these factors in vivo
      is unknown, it is possible that there is a relay mechanism involving sequential
      activity of both oviductal and follicular fluids to direct the male gametes
      towards the egg.

PMID- 10341720
TI  - Maturation-dependent modification of the protein phosphorylation profile of
      isolated goat sperm plasma membrane.
AB  - Highly purified plasma membranes, isolated by an aqueous two-phase polymer method
      from goat epididymal spermatozoa, were found to possess a kinase activity that
      causes phosphorylation of serine and threonine residues of several endogenous
      plasma membrane proteins. Cyclic AMP, cyclic GMP, Ca(2+)-calmodulin,
      phosphatidylserine-diolein, polyamines and heparin had no appreciable effect on
      this kinase. Autoradiographic analysis showed that the profile of the
      phosphorylation of membrane proteins by this endogenous cAMP-independent protein
      kinase underwent marked modulation during the transit of spermatozoa through the
      epididymis. In caput sperm plasma membrane, 18, 21, 43, 52, 74 and 90 kDa
      proteins were phosphorylated, whereas, in the corpus and cauda epididymal
      spermatozoa, a differential phosphorylation pattern was observed with respect to
      the 90, 74, 21 and 18 kDa proteins. The rate of phosphorylation of the 74 kDa
      protein decreased markedly during the early phase of sperm maturation (caput to
      distal corpus epididymides) whereas there was little change in kinase activity in
      sperm plasma membrane. In contrast, the rates of phosphorylation of the 18 and 21
      kDa proteins increased during the terminal phase (distal corpus to distal cauda
      epididymides) of sperm maturity, although the kinase activity of membrane
      decreased significantly during this phase. The modulation of the phosphorylated
      states of these specific membrane proteins may play an important role in the
      maturation of epididymal spermatozoa.

PMID- 10341721
TI  - Ultrasonic characterization of ovulatory follicular evacuation and luteal
      development in heifers.
AB  - The characteristics of follicle evacuation during ovulation and the development
      of the corpus luteum until day 5 (day 0 = ovulation) were studied in seven
      nulliparous Holstein heifers using real-time ultrasonography. Ovulation was
      induced and synchronized with a single injection of PGF2 alpha followed in 36 h
      by GnRH. Continuous scanning and videotaping was performed from apparent stigma
      formation until antral fluid was no longer detected. The beginning of follicular
      evacuation (second 0) was defined, retrospectively, after the antral area
      decreased 10% or more in 1 s. The completion of evacuation was defined as the
      inability to detect the antrum (the beginning of luteal development, 0 h).
      Corpora lutea development was monitored at 0, 4 and 20 h, and every 24 h
      thereafter until day 5. Changes in the maximal cross-sectional area of the
      antrum, luteal tissue, and central luteal cavities and in the pixel intensity of
      luteal tissue were determined using a computerized image program. The initial
      antral fluid evacuation occurred in two patterns that could be readily separated:
      (1) rapid, means of 58 and 89% evacuation in 1 and 4 s, respectively (four
      heifers); and (2) slow, means of 17 and 35% in 1 and 4 s, respectively (three
      heifers). The initial loss that distinguished the two patterns involved about 4
      and 20 s for rapid and slow evacuation, respectively. Thereafter, the loss
      patterns were similar for the two types. The time from the beginning to the
      completion of evacuation ranged from 6 s to 14.5 min. Mean luteal tissue area
      increased (P < 0.05) between completion of evacuation (91.2 +/- 6.5 mm2) and day
      3 (164.4 +/- 13.7 mm2) and between day 3 and day 4 (263.4 +/- 26.6 mm2). The
      growth rate of the luteal tissue area between day 3 and day 4 (103.2 +/- 16.0 mm2
      day-1) was greater (P < 0.05) than that between day 2 and day 3 (41.9 +/- 12.4
      mm2 day-1) and between day 4 and day 5 (49.7 +/- 22.0 mm2 day-1). In contrast to
      increasing luteal tissue area, mean pixel intensity decreased (P < 0.05)
      progressively between the completion of evacuation (78.4 +/- 6.3) and day 2 (60.4
      +/- 2.5) and did not change significantly thereafter. In conclusion, initial
      follicular fluid loss during ovulation occurred in two patterns, involving about
      4 and 20 s, respectively. The most intensive luteal tissue growth occurred
      between day 3 and day 4, and the echogenicity of the luteal tissue decreased
      between day 0 and day 2.

PMID- 10341722
TI  - Presence of an aromatase inhibitor, possibly heat shock protein 90, in dominant
      follicles of cattle.
AB  - In cattle, it has been suggested that follicular fluid has direct modulatory
      effects on follicular growth and maturation. In the first part of this study, an
      in vitro test using aromatase activity of follicular wall fragments as an end
      point was validated for cattle follicles and was used to test whether follicular
      fluid (from dominant or non-dominant follicles) modulates aromatase activity.
      Fluid from dominant follicles at a concentration of 24 or 12% (obtained during
      the luteal and follicular phases, respectively) significantly inhibited aromatase
      activity. Inhibitory activity was low or absent in fluid from non-dominant
      follicles. FSH-stimulated aromatase activity was also reduced by fluid from
      dominant follicles, but not to a greater extent than in basal conditions.
      Finally, charcoal-treated fluid from dominant follicles retained its inhibitory
      activity. In contrast, ovarian venous serum draining a dominant follicle had no
      activity at the three concentrations tested (6, 12 and 24%). In the second part
      of the study, identification of the compounds involved in this modulatory
      activity was attempted using SDS-PAGE. Comparison of the fluorographs from de
      novo synthesized proteins stored in follicular fluid (inhibitory medium) with
      those secreted in incubation medium (inactive medium) demonstrated that one
      protein (90 kDa, pI 5.8) was significantly (P < 0.05) more abundant in fluid from
      dominant follicles (2.0 +/- 0.09%) than in the culture medium (1.3 +/- 0.1% of
      the total proteins). This protein had characteristics similar to those of heat
      shock protein 90 (hsp 90). Therefore, in the final part of the study, the
      presence of hsp 90 in ovarian cells and follicular fluid was investigated using
      immunohistochemistry and western blot analysis. After immunohistochemistry, a
      positive signal was detected mainly in the granulosa cells of larger follicles
      and to a smaller extent in thecal cells and oocytes. Western blot analysis also
      demonstrated the presence of hsp 90 in follicular wall fragments and fluid. When
      blotting was achieved on a sample of follicular fluid resolved by two-dimensional
      PAGE, the spot detected had a similar location to that at 90 kDa and pI 5.8.
      Addition of purified hsp 90 to bovine follicles in vitro depressed aromatase
      activity by altering the K(m) value (and possibly the Vmax value) of the enzyme.
      It is proposed that hsp 90 is a functional regulator of follicular maturation
      through its action on aromatase.

PMID- 10341724
TI  - Maintenance of oestradiol production and expression of cytochrome P450 aromatase
      enzyme mRNA in long-term serum-free cultures of pig granulosa cells.
AB  - Studies were carried out to investigate the conditions required for maintenance
      of aromatase activity and expression in long-term cultures of pig granulosa
      cells. Cells from large (> 2 mm) and small (< or = 2 mm) follicles were cultured
      at 37 degrees C with 5% CO2 in McCoys 5a medium supplemented with 0.1% (w/v) BSA,
      testosterone (100 micrograms l-1), insulin (10 micrograms l-1) and long R3
      insulin-like growth factor I (IGF-I) (100 micrograms l-1). Cells were cultured
      with five concentrations of USDA pFSH-I-2 (0-100 micrograms l-1) for 48, 96 or
      144 h with or without fetal calf serum (FCS). The number of cells and oestradiol,
      progesterone and inhibin production were measured. In marked contrast to
      oestradiol production from cells cultured in plates precoated with FCS, 1
      microgram FSH l-1 was optimal for the maintenance of high oestradiol production
      by granulosa cells from large follicles after 144 h of serum-free culture.
      Culture with FCS promoted cell proliferation, reduced oestradiol production, and
      supported FSH-dependent (P < 0.01) increased progesterone and inhibin production
      indicating cellular luteinization. Northern blot analysis of total RNA from cells
      cultured with 1 microgram FSH l-1 detected 2.5 and 1.8 kb transcripts encoding
      aromatase cytochrome P450 (P450arom) and cholesterol side-chain cleavage
      cytochrome P450 (P450scc), respectively. Transcript expression was hormone
      sensitive, irrespective of the presence of FCS. High concentrations of FSH (100
      micrograms l-1) stimulated expression of P450scc, but inhibited P450arom
      expression as the cells luteinized after 144 h of culture. This serum-free
      system, which maintains the aromatase enzyme complex, is fundamental if
      physiologically relevant observations are to be made of the mechanisms regulating
      follicle hierarchy development from long-term cultures of pig cells.

PMID- 10341723
TI  - Production of interferon by the conceptus in red deer Cervus elaphus.
AB  - A type I interferon secreted by early sheep and cow conceptuses is responsible
      for the maternal recognition of pregnancy in these species. Interferon-tau (IFN
      tau) acts locally on the maternal endometrium to prevent luteolysis and prolong
      progesterone secretion. The production of IFN tau was investigated in early
      pregnancy in red deer, Cervus elaphus. The oestrous cycles of 14 hinds were
      synchronized using intra-vaginal controlled internal progesterone-releasing
      devices. Hinds were run with a fertile stag, then slaughtered on either day 20 (n
      = 10) or day 22 after withdrawal of progesterone (n = 11). Conceptuses were
      recovered after uterine excision and flushing with sterile saline. Conceptus RNA
      was reverse transcribed and amplified by PCR using primers designed from highly
      conserved regions of ovine and bovine IFN tau genes. The resulting PCR products
      were cloned and fully sequenced. Sequence comparisons indicate that the
      transcript characterized is closely related to the IFN tau and interferon-omega
      genes of bovids and giraffe, showing > 85% nucleotide sequence homology and > 74%
      predicted amino acid similarity with previously cloned genes. Northern blot
      analysis of total conceptus RNA using a homologous IFN tau probe confirmed the
      high expression of IFN tau which is encoded by a transcript of approximately 1
      kilobase. Anti-viral activity was measured in uterine flushes from pregnant hinds
      using a cytopathic effect inhibition assay (4.3 x 10(3) +/- 0.78 x 10(3) iu ml-1;
      n = 14), but was not detectable in flushes from non-pregnant hinds (n = 7),
      confirming that preimplantation red deer conceptuses release interferons. This is
      the first demonstration of IFN tau expression in a cervid conceptus and provides
      evidence that IFN tau may be involved in the maternal recognition of pregnancy in
      red deer.

PMID- 10341725
TI  - Reactivating tammar wallaby blastocysts oxidize fatty acids and amino acids.
AB  - The tammar wallaby, Macropus eugenii, has a ruminant-like digestive system which
      may make a significant concentration of amino acids and fatty acids available to
      the blastocyst via uterine fluids. Fluorescent and radioisotope analyses were
      performed to determine the rate of glutamine and palmitate use by blastocysts
      recovered on day 0, 3, 4, 5 and 10 after reactivation induced by removal of pouch
      young (RPY). Between day 0 and 4 glutamine uptake increased from 15.6 +/- 6.6 to
      36.1 +/- 2.7 pmol per embryo h-1 (P < 0.01) and ammonium production increased
      from 8.2 +/- 4.3 to 26.6 +/- 3.0 pmol per embryo h-1 (P < 0.01). Glutamine
      oxidation did not increase until day 10 after RPY (P < 0.01), but the percentage
      of glutamine oxidized increased from 4.5 +/- 3.1% during diapause to 31.2 +/-
      12.6% (P < 0.01) by day 5 after RPY and increased further to 51.0 +/- 15.8% (P <
      0.01) by day 10 after RPY. Palmitate oxidation also increased from 0.3 +/- 0.1 by
      day 0 blastocysts to 3.8 +/- 1.7 pmol per embryo h-1 (P < 0.01) by day 4
      blastocysts. This increase provides a greater potential for ATP production,
      possibly to supply increased demand due to the coincident resumption of mitoses.
      The ATP:ADP ratio within blastocysts had reduced by the time of the first
      measurement at day 3 (0.5 +/- 0.2 pmol per embryo h-1; P < 0.01) compared with
      day 0 blastocysts (1.4 +/- 0.3 pmol per embryo h-1). It is likely that metabolism
      of amino acids and fatty acids contributes to the energy supply during
      reactivation of tammar wallaby blastocysts after embryonic diapause.

PMID- 10341726
TI  - Immune cells and cytokine production in the bovine corpus luteum throughout the
      oestrous cycle and after induced luteolysis.
AB  - Immune cells and their cytokine products have powerful local effects within body
      tissues. There has been great interest in the potential role of these cells, not
      only during destruction of the corpus luteum but also during its functional
      lifespan. In this study, lymphocytes, macrophages and major histocompatibility
      complex class II molecules were quantified using immunohistochemistry and the
      reverse transcription-polymerase chain reaction was used to detect mRNA for
      tumour necrosis factor alpha and interferon gamma within corpora lutea from three
      groups of cows: (1) corpora lutea collected at an abattoir and assessed visually
      into four stages (stage I (days 1-5), stage II (days 6-12), stage III (days 13
      18) and stage IV (days 19-21) of the oestrous cycle); (2) corpora lutea collected
      around natural luteolysis (days 14-20); and (3) corpora lutea collected 6, 12 and
      24 h after prostaglandin F 2 alpha-induced luteolysis. The numbers of T
      lymphocytes (CD5+ and CD8+) were significantly higher (P < 0.05) at stage IV and
      from day 16 onwards, before functional luteolysis. There were significantly
      higher numbers (P < 0.01) of macrophages at stages I, III and IV compared with
      stage II in visually staged tissue. Major histocompatibility complex class II
      molecules were increased (P < 0.05) at stages I and IV compared to stage II and
      at all times after induced luteolysis. Using reverse transcription-polymerase
      chain reaction, mRNA encoding tumour necrosis factor alpha and interferon gamma
      was detected in all luteal tissue collected around natural luteolysis and after
      induced luteolysis. These findings, particularly the increase in T lymphocytes
      before functional luteolysis, provide further evidence of a significant role for
      the immune system in affecting reproductive function in cows.

PMID- 10341727
TI  - Factors affecting the number of teats in pigs.
AB  - The factors that affect the number of teats in pigs are of interest for both
      biological and practical reasons. Previous work indicates that there is a genetic
      component, principally from the dam. The proportion of males in a litter appears
      to be related to the anogenital distance of the gilts in the litter, possibly as
      a result of the intrauterine position effect. The present study investigated
      whether litter size, litter sex ratio, anogenital distance, crown-rump length,
      distance from base of skull to base of tail, and the number of teats on the dam
      and boar affected the number of teats on gilts. Stepwise multiple regression on
      litter mean values (adjusted r2 = 0.178) indicated that two factors were
      significant: the number of teats on the dam (standard coefficient 0.311) and the
      proportion of males in the litter (standard coefficient -0.282). A greater number
      of teats on the dam and a lower proportion of males in the litter resulted in a
      greater number of teats on the gilt. When the analysis was run using individual
      gilts as the independent units (adjusted r2 = 0.073), the number of teats on the
      dam (standard coefficient 0.207), the proportion of males in the litter (standard
      coefficient -0.135), and the weaning weight of the gilt (standard coefficient
      0.083) were all significant predictors of the number of teats. This evidence
      suggests that teat number in female pigs is related to the proportion of males in
      the litter.

PMID- 10341728
TI  - Hormonal regulation of oestrogen and progesterone receptors in cultured bovine
      endometrial cells.
AB  - Changes in the number of progesterone and oestradiol receptors in the endometrium
      are thought to play a role in the induction of luteolysis. The effect of
      oestradiol and progesterone on the regulation of their receptors in cultured
      bovine uterine epithelial and stromal cells was examined to determine the
      mechanisms involved in this process. Cells were obtained from cows at days 1-3 of
      the oestrous cycle and were cultured for 4 or 8 days in medium alone (RPMI medium
      + 5% (v/v) charcoal-dextran stripped newborn calf serum) or with oestradiol,
      progesterone or oestradiol and progesterone. At the end of culture, receptor
      binding was measured by saturation analysis. Specific binding of both [3H]ORG
      2058 (16 alpha-ethyl-21-hydroxy-19-nor (6,7-3H) pregn-4-ene-3,20-dione) and
      [3H]oestradiol to epithelial and stromal cells showed high affinities (Kd = 1.1 x
      10(-9) and 6 x 10(-10) mol l-1, respectively, for progesterone receptors; Kd =
      5.5 x 10(-9) and 7 x 10(-10) mol l-1, respectively, for oestradiol receptors). In
      the stromal cells, oestradiol (0.1-10 nmol l-1) increased the number of
      oestradiol receptors from 0.21 +/- 0.06 to 0.70 +/- 0.058 fmol microgram-1 DNA
      and the number of progesterone receptors from 1.4 +/- 0.83 to 6.6 +/- 0.70 fmol
      microgram-1 DNA in a dose-dependent manner after 4 days of culture (P < 0.01).
      After culture for 8 days, the stimulatory effect of oestradiol increased.
      Progesterone (50 nmol l-1) had no effect on the number of oestradiol or
      progesterone receptors (P > 0.05). However, progesterone inhibited the
      stimulatory effect of oestradiol. In epithelial cells, the lower concentrations
      of oestradiol (0.1 and 1 nmol l-1) stimulated the number of progesterone
      receptors (P = 0.05) after 4 days culture, whereas the highest concentration of
      oestradiol (10 nmol l-1), progesterone (50 nmol l-1) and progesterone (50 nmol l
      1) plus oestradiol (1 nmol l-1) had no effect. After culture for 8 days, the
      stimulatory effect of oestradiol decreased. In contrast to progesterone
      receptors, the number of oestradiol receptors increased with oestradiol
      concentration (P < 0.01). These data show that the number of progesterone
      receptors was higher in the stromal cells than in epithelial cells, whereas the
      number of oestradiol receptors was higher in the epithelial cells than in stromal
      cells. Oestradiol upregulates its own receptor and increases the number of
      progesterone receptors in both cell types in vitro, whereas progesterone has
      little effect, but inhibits the effects of oestradiol on progesterone receptors.

PMID- 10341729
TI  - Ovarian antral follicular dynamics and their relationships with endocrine
      variables throughout the oestrous cycle in breeds of sheep differing in
      prolificacy.
AB  - Transrectal ultrasonography of ovaries was performed each day in non-prolific
      Western white-faced (n = 12) and prolific Finn ewes (n = 7), during one oestrous
      cycle in the middle portion of the breeding season (October-December), to record
      the number and size of all follicles > or = 3 mm in diameter. Blood samples
      collected once a day were analysed by radioimmunoassay for concentrations of LH,
      FSH and oestradiol. A cycle-detection computer program was used to identify
      transient increases in concentrations of FSH and oestradiol in individual ewes.
      Follicular and hormonal data were then analysed for associations between
      different stages of the lifespan of the largest follicles of follicular waves,
      and detected fluctuations in serum concentrations of FSH and oestradiol. A
      follicular wave was defined as a follicle or a group of follicles that began to
      grow from 3 to > or = 5 mm in diameter within a 48 h period. An average of four
      follicular waves per ewe emerged during the interovulatory interval in both
      breeds of sheep studied. The last follicular wave of the oestrous cycle contained
      ovulatory follicles in all ewes, and the penultimate wave contained ovulatory
      follicles in 10% of white-faced ewes but in 57% of Finn ewes. Transient increases
      in serum concentrations of FSH were detected in all animals and concentrations
      reached peak values on days that approximated to follicle wave emergence.
      Follicular wave emergence was associated with the onset of transient increases in
      serum concentrations of oestradiol, and the end of the growth phase of the
      largest follicles (> or = 5 mm in diameter) was associated with peak serum
      concentrations of oestradiol. Serum FSH concentrations were higher in Finn than
      in Western white-faced ewes during the follicular phase of the cycle (P < 0.05).
      There were no significant differences in serum concentrations of LH between
      Western white-faced and Finn ewes (P > 0.05). Mean serum concentrations of
      oestradiol were higher in Finn compared with Western white-faced ewes (P < 0.01).
      It was concluded that follicular waves (follicles growing from 3 to > or = 5 mm
      in diameter) occurred in both prolific and non-prolific genotypes of ewes and
      were closely associated with increased secretion of FSH and oestradiol. The
      increased ovulation rate in prolific Finn ewes appeared to be due primarily to an
      extended period of ovulatory follicle recruitment.

PMID- 10341730
TI  - Role of interleukin 1 in the regulation of cyclooxygenase gene expression in rat
      endometrial stromal cells.
AB  - Interleukin 1 alpha (IL-1 alpha) stimulates prostaglandin production and
      cyclooxygenase activity in endometrial stromal cells isolated from the uteri of
      ovariectomized rats that have been sensitized for the decidual cell reaction. The
      aim of the present study was to examine the effect of IL-1 alpha on the amount of
      cyclooxygenase mRNA and protein in these cells. Treatment with IL-1 alpha (20 ng
      ml-1) for 24 h significantly increased steady-state concentrations of
      cyclooxygenase 2 (COX-2) mRNA and protein in the cells, as determined by northern
      and western blot analyses, respectively. Cyclooxygenase 1 (COX-1) mRNA and
      protein were not detected. Dexamethasone (5 mumol l-1) prevented the IL-1 alpha
      induced increase in COX-2 steady-state mRNA. Immunocytochemical staining of COX-2
      in the treated cells indicated that IL-1 alpha increased staining, while
      dexamethasone inhibited this increase. Furthermore, the changes in staining were
      generalized and not confined to a small subpopulation of cells. These data
      demonstrate that IL-1 alpha increases steady-state concentrations of COX-2 mRNA
      and protein in endometrial stromal cells isolated from the uteri of rats that
      have been sensitized for decidualization.

PMID- 10341731
TI  - Ovulation, fertilization and lambing rates, and peripheral progesterone
      concentrations, in ewes inseminated at a natural oestrus during November or
      February.
AB  - The objective of this study was to determine the relative importance of seasonal
      changes in ovulation rate, fertilization rate and embryo survival as the cause of
      reduced lambing rates in ewes mated in February compared with those mated in
      November. The study was conducted at 57 degrees N using mature Mule ewes and
      Suffolk rams. Sixty ewes were allocated equally to five groups: unbred (UB) or
      mated at a natural oestrus during November (N) or February (F) by natural (N) or
      cervical artificial (A) insemination. Groups were maintained separately at
      pasture supplemented with hay. A raddled vasectomized or non-vasectomized ram was
      present with UB, NN and NA groups from 26 October 1995 to 1 January 1996 and with
      UB, FN and FA groups from 25 January 1996 to 31 March 1996. Ewes marked by the
      ram were recorded twice a day, and those in groups NN, NA, FN and FA were
      inseminated at their second behavioural oestrus. For all ewes, blood samples were
      obtained once a day from introduction of the vasectomized rams until 30 days
      after mating (groups NN, NA, FN and FA) or 20 days after the first oestrus (group
      UB), and ovulation rate was measured by laparoscopy 7 days after the first
      oestrus. For ewes in groups NN, NA, FN and FA, ovulation rate was measured again
      after the second oestrus and ova were recovered from six ewes per group for
      assessment of fertilization before autotransfer. Pregnancy and lambing rates were
      recorded at term. Mean (+/- SE) dates of the first recorded oestrus for ewes in
      groups NN, NA and UB, and FN, FA and UB were 4 +/- 1.1 November and 4 +/- 0.9
      February, respectively, and intervals between the first and second oestrus were
      16 +/- 0.2 and 17 +/- 0.3 days (P < 0.01), respectively. Ovulation rates were 2.6
      +/- 0.08 and 2.0 +/- 0.05 (P < 0.001), and peripheral progesterone concentrations
      during the luteal phase were 8.5 +/- 0.25 and 7.6 +/- 0.31 ng ml-1 (P < 0.05),
      for November and February, respectively. The difference in peripheral
      progesterone concentration was not solely attributable to the difference in
      ovulation rate. There was no significant effect of month or method of
      insemination, or of embryo recovery and autotransfer procedures on pregnancy
      rates and the proportion of ewes that became pregnant were NN 0.92, NA 0.83, FN
      0.67 and FA 0.75. For ewes undergoing embryo recovery and autotransfer, ova
      recovered per corpus luteum were 1.00, 0.93, 1.00 and 0.92, fertilized ova per
      ovum recovered were 0.69, 0.92, 1.00 and 0.83, and lambs born per corpus luteum
      were 0.62, 0.79, 0.78 and 0.58 for NN, NA, FN and FA groups, respectively. There
      were no significant seasonal effects on fertilization rate or embryo survival. It
      is concluded that a seasonal decline in ovulation rate is the primary cause of
      reduced lambing rates in ewes mated in February compared with those mated in
      November. Pregnancy rates were high after mating in both periods and were not
      enhanced by the use of cervical insemination.

PMID- 10341732
TI  - In vitro growth of oocyte-granulosa cell complexes isolated from cryopreserved
      ovine tissue.
AB  - A culture system has been designed in which enzymatically isolated oocyte
      granulosa cell complexes from fresh and frozen-thawed ovine ovarian tissue can be
      grown to antral size in vitro. Oocyte-granulosa complexes ranging from 100 to 240
      microns in diameter were dissected from stromal tissue and grown individually in
      serum-free medium for 30 days. Complexes < 190 microns generally excluded their
      oocytes or lost three-dimensional structure early in the culture period. In
      contrast, complexes isolated from fresh or frozen-thawed tissue and measuring 190
      240 microns on the day of isolation formed antral cavities in 25 +/- 9% and 18 +/
      6% (mean +/- SEM) of cases, respectively. The effect of gonadotrophin
      supplementation to the culture medium was tested on frozen-thawed oocyte
      granulosa cell complexes only. In cultures supplemented with both FSH and LH or
      FSH alone, there was no significant difference in the number of oocyte-granulosa
      cell complexes that formed antral cavities (18 +/- 7%). However, antrum formation
      was significantly less frequent in cultures lacking gonadotrophin stimulation (7
      +/- 4%). All oocyte-granulosa cell complexes maintained a three-dimensional
      structure throughout culture and developed a functional P450 aromatase enzyme
      complex, as revealed by the induction of oestradiol production during 8 days of
      culture after antrum formation in serum-free medium containing testosterone.
      Oocytes recovered after 30 days of culture were viable and had increased in
      diameter from 78 +/- 2 microns on the day of isolation, to 131 +/- 3 microns at
      the end of culture. These results show that oocyte-granulosa cell complexes
      isolated from cryopreserved ovarian tissue can be grown to antral size in vitro
      with similar efficiency to those isolated from fresh tissue.

PMID- 10341733
TI  - Biochemical and biological effects of KN-93, an inhibitor of calmodulin-dependent
      protein kinase II, on the initial events of mouse egg activation induced by
      ethanol.
AB  - Calmodulin-dependent protein kinase II (CaMKII) is transiently activated in mouse
      eggs by the increase in calcium that occurs upon activation with ethanol. This
      study investigated the biological and biochemical effects of KN-93, a reported
      selective inhibitor of CaMKII, to explore the potential role of this kinase in
      the initial events of egg activation. Mouse eggs were incubated for 30 min in the
      presence of different concentrations of KN-93 and induced to activate by 7%
      ethanol. KN-93 elicited a dose-dependent inhibition of polar body emission that
      resulted from the failure of the eggs to undergo meiosis resumption and
      inactivation of maturation-promoting factor (MPF). Furthermore, 15 mumol KN-93 l
      1 produced a marked reduction in ethanol-induced loss of cortical granules. In
      vivo biochemical analysis revealed that 15 mumol KN-93 l-1 was responsible for
      significant inhibition of ethanol-stimulated CaMKII. The activity of the enzyme
      remained at a resting value, in spite of the presence of a calcium signal similar
      to that measured in control activated eggs. The inhibitory effects of KN-93 on
      the parameters tested in this study could not be mimicked by the inactive
      analogue KN-92. These results show that in mouse eggs, when ethanol-induced
      CaMKII activation was prevented, cortical granule exocytosis and meiosis
      resumption were inhibited. This suggests that CaMKII acts as a switch in the
      transduction of the calcium signal triggering mammalian egg activation.

PMID- 10341734
TI  - Cloning, sequencing and functional expression of zebra (Equus burchelli) LH.
AB  - Although donkey luteinizing hormone exhibits a very high degree of amino acid
      sequence identity with horse LH, its FSH activity in non-equine species is
      tenfold lower. The coding regions of the common zebra (Equus burchelli)
      glycoprotein hormone alpha-subunit and LH beta-subunit transcripts were cloned by
      reverse transcription-PCR from pituitary gland RNA to investigate more precisely
      the structure-function relationships of this gonadotrophin family. Zebra LH was
      then expressed in COS-7 cells and its LH and FSH activities were assessed in a
      rat Leydig cell bioassay (for LH) and in a cell line stably expressing the human
      FSH receptor bioassay (for FSH). The recombinant zebra LH, although displaying LH
      activity similar to that of recombinant donkey and horse LH, had no detectable
      FSH activity. The LH amino acid sequences of these three species are very
      similar, leaving only very few amino acids as potential candidates to explain the
      difference in their FSH activities. Moreover, according to the difference in FSH
      bioactivity and to the percentage identity between the sequences, the common
      zebra is phylogenetically closer to the donkey than it is to the horse.

PMID- 10341735
TI  - Role of oestradiol in the regulation of the seasonal antler cycle in female
      reindeer, Rangifer tarandus.
AB  - Reindeer (or caribou), Rangifer tarandus, is the only extant species of deer in
      which females as well as males normally develop antlers that are cast and regrown
      each year. This study investigated the role of ovarian oestradiol in the
      regulation of the seasonal antler cycle in female reindeer. Ovariectomized
      Norwegian reindeer living outdoors in northern Norway (69 degrees N) were treated
      with continuous-release subcutaneous Silastic implants containing oestradiol,
      which maintained the blood concentrations of oestradiol within the physiological
      range for the mating season from June to October-November. The treatment with
      oestradiol induced the synchronized maturation of the antlers and rapid cleaning
      of the velvet-like skin in August-September in the ovariectomized reindeer, a
      pattern very similar to that observed in ovary-intact controls living under the
      same conditions. The removal of the steroid implant in October-November caused
      the premature casting of the antlers in early winter in two of five animals,
      while the remainder cast at the normal time in spring; this response was seen
      whether the animals had received one or two oestradiol implants in autumn. The
      antlers developed by the ovariectomized, oestradiol-treated females were
      significantly heavier and carried more branches than the ovariectomized animals
      without oestradiol replacement, and were marginally heavier than the antlers of
      intact controls. These results support the view that oestradiol is the
      biologically active steroid secreted by the ovary in intact female reindeers that
      induces the normal development of the antlers. Oestradiol stimulates the growth
      and mineralization of the antler bone, the cleaning of the velvet, and suppresses
      the casting of the hard antlers. This endocrine control ensures that the hard
      antlers, which function as weapons, are retained throughout the autumn and winter
      when the females are normally pregnant and when competition between females over
      food in the snow is most intense; hence there is a reproductive advantage to
      explain the evolution of antlers in females.

PMID- 10341736
TI  - Influence of capacitation and fluids from the male and female genital tract on
      the zona binding ability of bull spermatozoa.
AB  - Before fertilization, inseminated spermatozoa acquire the ability to fertilize an
      egg, a phenomenon called capacitation. Bovine sperm capacitation is influenced by
      factors originating from both the male and female genital tract, and results in
      intracellular and membrane changes of the spermatozoa that facilitate the
      induction of the acrosome reaction. However, the effects of reproductive tract
      secretions and capacitation on the binding of spermatozoa to the zona pellucida
      have not been investigated. In this study, a sperm-egg binding assay was used to
      determine whether the ability of bull spermatozoa to bind to the zona pellucida
      was altered during in vitro capacitation by heparin or oviductal fluid, or by
      treatment of spermatozoa from the cauda epididymidis with accessory sex gland
      fluid. In addition, biotinylated solubilized zona pellucida proteins were used to
      visualize zona binding on spermatozoa. The ability of bull spermatozoa to bind to
      the zona pellucida was increased after both heparin and oviductal fluid induced
      in vitro capacitation. Exposure of spermatozoa from the cauda epididymidis to
      accessory sex gland fluid resulted in a direct increase in zona binding ability,
      followed by a further increase during capacitation in vitro. Binding of
      solubilized zona proteins was restricted to the acrosomal cap of bull
      spermatozoa. It is suggested that the observed increased ability of bull
      spermatozoa to bind to the zona pellucida enables optimal sperm-egg attachment,
      which also relates to the induction of the acrosome reaction by the zona
      pellucida. Thus, increased zona binding ability is likely to be an essential part
      of the process of capacitation.

PMID- 10341737
TI  - Active immunization with a synthetic fragment of pig inhibin alpha-subunit
      increases ovulation rate and embryo production in superovulated ewes but season
      affects its efficiency.
AB  - Two experiments were designed to determine the effects of active immunization
      against one of two synthetic peptides from humans (inhibin-like peptide) or pigs
      (inhibin alpha-subunit) on antibody titres, ovulation rate and embryo production
      in ewes superovulated with 16 U ovine FSH. In Expt 1, during the breeding season,
      30 ewes were subdivided into three groups: group I served as the non-immunized
      control; group II was immunized against inhibin-like peptide (100 micrograms
      inhibin-like peptide equivalent, followed by three booster injections); group III
      was immunized against pig inhibin alpha-subunit conjugated to human serum albumin
      (96 micrograms for the primary administration and 46 micrograms for the booster).
      In Expt 2, the efficiency of immunization against pig inhibin alpha-subunit on
      ovarian response and embryo production was evaluated during the non-breeding
      season in two groups of ewes (n = 12): group IV was a non-immunized control;
      Group V was immunized against pig inhibin alpha-subunit. During the breeding
      season, the ewes immunized against pig inhibin alpha-subunit showed higher
      antibody titres compared with the group immunized against inhibin-like peptide (P
      < 0.01) and a significant increase in ovulation rate (12.1) compared with both
      the control (5.0; P < 0.05) and the inhibin-like peptide-immunized group (3.1; P
      < 0.01). Immunization against pig inhibin alpha-subunit increased transferable
      embryo yield 4.5-fold (6.7 versus 1.5; P < 0.01) and improved embryo quality
      (94.6 versus 40.6%; P < 0.01). During the non-breeding season, immunization
      against pig inhibin alpha-subunit enhanced ovulation rate from 2.6 in the
      controls to 9.4 (P < 0.01) but did not affect transferable embryo production (3.9
      versus 2.1; P > 0.05) and significantly lowered their quality (54.1 versus 100%;
      P < 0.01). In conclusion, active immunization against pig inhibin alpha-subunit
      can improve superovulatory response during the breeding season, while it appears
      to be unable to increase embryo yield during the seasonal anoestrus.

PMID- 10341738
TI  - Effects of experimental exposure to triethylamine on vision and the eye.
AB  - OBJECTIVES: To determine the effect of triethylamine (TEA) on the cornea and to
      evaluate the cause of blurred vision. To find the lowest observed effect
      concentration of exposure to TEA. METHODS: Four people were exposed to TEA for 4
      hours at concentrations of 40.6, 6.5, and 3.0 mg/m3. Before and after every
      exposure, symptoms and ocular microscopy findings were recorded. Binocular visual
      acuity and contrast sensitivity at 2.5% contrast were also measured. Also, before
      and after the 40.6 mg/m3 exposure, corneal thickness was measured and ocular
      dimensions were recorded by ultrasonography, endothelial cells of the cornea were
      analysed, and serum and lacrimal specimens were collected for the analysis of
      TEA. RESULTS: After exposure to 40.6 mg/m3 TEA there was a marked oedema in the
      corneal epithelium and subepithelial microcysts. However, corneal thickness
      increased only minimally because of the epithelial oedema. The lacrimal
      concentrations of TEA were, on average (range) 41 (18-83) times higher than the
      serum TEA concentrations. The vision was blurred in all subjects and visual
      acuity and contrast sensitivity had decreased in three of the four subjects.
      After exposure to TEA at 6.5 mg/m3 two subjects experienced symptoms, and
      contrast sensitivity had decreased in three of the four subjects. There were no
      symptoms or decreases in contrast sensitivity after exposure to a TEA
      concentration of 3.0 mg/m3. CONCLUSIONS: TEA caused a marked oedema and
      microcysts in corneal epithelium but only minor increases in corneal thickness.
      The effects may be mediated by the lacrimal fluid owing to its high TEA
      concentration. Four hour exposure to a TEA concentration of 3.0 mg/m3 seemed to
      cause no effects, whereas exposure to 6.5 mg/m3 for the same period caused
      blurred vision and a decrease in contrast sensitivity.

PMID- 10341739
TI  - Abnormal tear dynamics and symptoms of eyestrain in operators of visual display
      terminals.
AB  - OBJECTIVES: To clarify the relation between the prevalence of dry eye syndrome
      and subjective symptoms of asthenopia in visual display terminal (VDT) operators.
      METHOD: 722 VDT workers (242 subject workers with symptoms of asthenopia and 480
      controls without such symptoms) without obvious organic ocular diseases received
      an ophthalmological examination consisting of refractometry and a tear function
      (phenol red thread) test. RESULTS: More than 30% of symptomatic workers were
      found to meet the criteria of dry eye, and the odds ratio compared with the
      controls was 4.61 (p < 0.001). This odds ratio was significantly greater than
      that obtained for refractive errors (2.31). CONCLUSIONS: Although this cross
      sectional study could not prove that dry eyes are the cause of asthenopia, the
      profound association of dry eyes with symptoms of asthenopia could be verified.
      It would be useful to carry out tear function tests in workers with symptoms of
      asthenopia.

PMID- 10341740
TI  - Oral and dermal absorption of chlorpyrifos: a human volunteer study.
AB  - OBJECTIVES: To determine the kinetics of elimination of urinary dialkylphosphate
      metabolites after oral and dermally applied doses of the organophosphate
      pesticide chlorpyrifos to human volunteers and to determine whether these doses
      affected plasma and erythrocyte cholinesterase activity. METHOD: Five volunteers
      ingested 1 mg (2852 nmol) of chlorpyrifos. Blood samples were taken over 24 hours
      and total void volumes of urine were collected over 100 hours. Four weeks later
      28.59 mg (81567 nmol) of chlorpyrifos was administered dermally to each volunteer
      for 8 hours. Unabsorbed chlorpyrifos was washed from the skin and retained for
      subsequent measurement. The same blood and urine sampling regime was followed as
      for the oral administration. Plasma and erythrocyte cholinesterase concentrations
      were determined for each blood sample. The concentration of two urinary
      metabolites of chlorpyrifos--diethylphosphate and diethyl-thiophosphate--was
      determined for each urine sample. RESULTS: The apparent elimination half life of
      urinary dialkylphosphates after the oral dose was 15.5 hours and after the dermal
      dose it was 30 hours. Most of the oral dose (mean (range) 93% (55-115%)) and 1%
      of the applied dermal dose was recovered as urinary metabolites. About half (53%)
      of the dermal dose was recovered from the skin surface. The absorption rate
      through the skin, as measured by urinary metabolites was 456 ng/cm2/h. Blood
      plasma and erythrocyte cholinesterase activity did not fall significantly during
      either dosing regime. CONCLUSION: An oral dose of chlorpyrifos was readily
      absorbed through the skin and almost all of the dose was recovered as urinary
      dialkylphosphate metabolites. Excretion was delayed compared with the oral dose.
      Only a small proportion of the applied dose was recovered during the course of
      the experiment. The best time to collect urine samples for biological monitoring
      after dermal exposure is before the shift the next day. The amounts of
      chlorpyrifos used did not depress acetyl cholinesterase activity but could be
      readily detected as urinary dialkylphosphate metabolites indicating that the
      urinary assay is a more sensitive indicator of exposure.

PMID- 10341741
TI  - Mortality in a cohort of licensed pesticide applicators in Florida.
AB  - OBJECTIVES: Although the primary hazard to humans associated with pesticide
      exposure is acute poisoning, there has been considerable concern surrounding the
      possibility of cancer and other chronic health effects in humans. Given the huge
      volume of pesticides now used throughout the world, as well as environmental and
      food residue contamination leading to chronic low level exposure, the study of
      possible chronic human health effects is important. METHODS: This was a
      retrospective cohort study, analysed by general standardised mortality ratio
      (SMR) of licensed pesticide applicators in Florida compared with the general
      population of Florida. A cohort of 33,658 (10% female) licensed pesticide
      applicators assembled through extensive data linkages yielded 1874 deaths with
      320,250 person-years from 1 January 1975 to 31 December 1993. RESULTS: The
      pesticide applicators were consistently and significantly healthier than the
      general population of Florida. As with many occupational cohorts, the risks of
      cardiovascular disease and of diseases associated with alcohol and tobacco use
      were significantly lower, even in the subpopulations--for example, men, women,
      and licence subcategories. Among male applicators, prostate cancer mortality (SMR
      2.38 (95% confidence interval (95% CI) 1.83 to 3.04) was significantly increased.
      No cases of soft tissue sarcoma were confirmed in this cohort, and non-Hodgkin's
      lymphoma was not increased. The number of female applicators was small, as were
      the numbers of deaths. Mortality from cervical cancer and breast cancer was not
      increased. Additional subcohort and exposure analyses were performed.
      CONCLUSIONS: Consistent with previous publications on farmers but at odds with
      current theories about the protective effects of vitamin D, prostate cancer was
      increased in these pesticide applicators. Female breast cancer was not increased
      despite theories linking risk of breast cancer with exposure to oestrogen
      disruptors--such as the organochlorines. The lack of cases of soft tissue sarcoma
      is at odds with previous publications associating the use of the phenoxy
      herbicides with an increased risk of these cancers.

PMID- 10341742
TI  - Predictors of dimercaptosuccinic acid chelatable lead and tibial lead in former
      organolead manufacturing workers.
AB  - OBJECTIVES: To identify predictors of tibial and dimercaptosuccinic acid (DMSA)
      chelatable lead in 543 organolead manufacturing workers with past exposure to
      organic and inorganic lead. METHODS: In this cross sectional study, tibial lead
      (by 109Cd K-shell x ray fluorescence), DMSA chelatable lead (4 hour urinary lead
      excretion after oral administration of 10 mg/kg), and several exposure measures
      were obtained on study participants, mean (SD) age 57.6 (7.6) years. RESULTS:
      Tibial lead concentrations ranged from -1.6 to 52.0 micrograms lead/g bone
      mineral, with a mean (SD) of 14.4 (9.3) micrograms/g. DMSA chelatable lead ranged
      from 1.2 to 136 micrograms, with a mean (SD) of 19.3 (17.2) micrograms. In a
      multiple linear regression model of tibial lead, age (p < 0.01), duration of
      exposure (p < 0.01), current (p < 0.01) and past (p = 0.05) cigarette smoking,
      and diabetes (p = 0.01) were all independent positive predictors, whereas height
      (p = 0.03), and exercise inducing sweating (p = 0.04) were both negative
      predictors. The final regression model accounted for 31% of the variance in
      tibial lead concentrations; 27% was explained by age and duration of exposure
      alone. DMSA chelatable lead was directly associated with tibial lead (p = 0.01),
      cumulative exposure to inorganic lead (y.microgram/m3, p = 0.01), current smoking
      (p < 0.01), and weight (p < 0.01), and negatively associated with diabetes (p =
      0.02). The final model accounted for 11% of the variance in chelatable lead. When
      blood lead was added to this model of DMSA chelatable lead, tibial lead,
      cumulative exposure to inorganic lead, and diabetes were no longer significant;
      blood lead accounted for the largest proportion of variance (p < 0.001); and the
      total model r2 increased to 19%. CONCLUSIONS: The low proportions of variance
      explained in models of both tibial and chelatable lead suggest that other factors
      are involved in the deposition of lead in bone and soft tissue. In
      epidemiological studies of the health effects of lead, evaluation of associations
      with both these measures may allow inferences to be made about whether health
      effects are likely to be recent, and thus potentially reversible, or chronic, and
      thus possibly irreversible. The data also provide direct evidence that in men the
      total amount of lead in the body that is bioavailable declines with age.

PMID- 10341743
TI  - Reappraisal of the relation between blood lead concentration and blood pressure
      among the general population in Taiwan.
AB  - OBJECTIVES: The relation between blood lead concentration (PbB) and blood
      pressure was examined in a Taiwan nationwide population survey of PbB from July
      1993 to June 1994. METHODS: After multistage sampling procedures, 2800 subjects
      (1471 males and 1329 females) with a mean (range) age of 44 (15-85) years were
      enrolled in this study. Anthropometric, blood pressure, and lifestyle factors
      were measured during household visits. The PbB was measured with a flameless
      atomic absorption spectrophotometer and all specimens were analysed in
      triplicate. RESULTS: The mean (range) PbB among all study subjects was 6.5 (0.1
      69.1) micrograms/dl; among males it was 7.3 (0.1-69.1) micrograms/dl and among
      females 5.7 (0.1-40.1) micrograms/dl). The mean (range) systolic blood pressure
      among all subjects was 123 (80-210) mm Hg, among males it was 127 (80-200) mm Hg
      and among females 119 (80-210) mm Hg. The diastolic blood pressure among all
      subjects was 78 (40-150) mm Hg; among males it was 80 (40-130) mm Hg; and among
      females 75 (40-150) mm Hg. Age, body height, body weight, and body mass index
      (BMI) were significantly correlated with systolic blood pressure or diastolic
      blood pressure in both sexes. The PbB (or the natural logarithmic transformed
      PbB) was not significantly correlated with blood pressure among males or females.
      After adjustment for the potential confounders of age, age2, BMI, milk intake,
      alcohol consumption, and cigarette smoking, systolic blood pressure was
      significantly associated with PbB among males with a regression coefficient
      (beta) of 0.185 (p = 0.015). No significant association between PbB and blood
      pressure was found among females. CONCLUSIONS: From this study, only a weak
      association between systolic blood pressure and PbB was found among males. There
      was no strong evidence that PbB was a good predictor of blood pressure. However,
      the possibility that long term high body lead burden could cause high blood
      pressure could not be ruled out on the basis of this survey.

PMID- 10341744
TI  - Mortality among residents near cokeworks in Great Britain.
AB  - OBJECTIVES: To investigate whether residents near cokeworks have a higher
      standardised mortality than those further away, particularly from cardiovascular
      and respiratory causes, which may be associated with pollution from cokeworks.
      METHOD: Cross sectional small area study with routinely collected postcoded
      mortality data and small area census statistics. Populations within 7.5 km of 22
      cokeworks in Great Britain, 1981-92. Expected numbers of deaths within 2 and 7.5
      km of cokeworks, and in eight distance bands up to 7.5 km of cokeworks, were
      calculated by indirect standardisation from national rates stratified for age and
      sex and a small area deprivation index, and adjusted for region. Age groups
      examined were all ages, 1-14, 15-64, 65-74, > or = 75. Only the 1-14 and 15-44
      age groups were examined for asthma mortality. RESULTS: There was a 3% (95%
      confidence interval (95% CI) 1% to 4%) excess of all deaths within 2 km of
      cokeworks, and a significant decline in mortality with distance from cokeworks.
      The excess of deaths within 2 km was slightly higher for females and elderly
      people, but excesses within 2 km and declines in risk with distance were
      significant for all adult age groups and both sexes. The size of the excess
      within 2 km was 5% (95% CI 3% to 7%) for cardiovascular causes, 6% (95% CI 3% to
      9%) for ischaemic heart disease, and 2% (95% CI -2% to 6%) for respiratory
      deaths, with significant declines in risk with distance for all these causes.
      There was a non-significant 15% (95% CI -1% to 101%) excess in asthma mortality
      in the 15-44 age group. There were no significant excesses in mortality among
      children but 95% CIs were wide. Within 2 km of cokeworks, the estimated
      additional excess all cause mortality for all ages combined related to region and
      mainly to the greater deprivation of the population over national levels was 12%.
      CONCLUSIONS: A small excess mortality near cokeworks as found in this study is
      plausible in the light of current evidence about the health impact of air
      pollution. However, in this study the effects of pollution from cokeworks, if
      any, are outweighed by the effects of deprivation on weighed by the effects of
      deprivation on mortality near cokeworks. It is not possible to confidently
      exclude socioeconomic confounding or biases resulting from inexact population
      estimation as explanations for the excess found.

PMID- 10341745
TI  - Perceived job stress and mental health in precision machine workers of Japan: a 2
      year cohort study.
AB  - OBJECTIVES: To determine whether perceived job stress affects mental health in
      occupational settings. METHODS: A 2 year cohort study was conducted. Initially, a
      survey including the general health questionnaire (GHQ) and a questionnaire about
      perceived job stress was carried out. Of 462 workers who initially showed a GHQ
      score of < or = 7,310 were successfully followed up for 2 years. The 2 year risks
      of developing mental ill health (a GHQ score > or = 8) were assessed relative to
      perceived job stress. To control for potential confounding factors, multiple
      logistic regression analyses were conducted. RESULTS: The overall 2 year risk for
      developing mental ill health was high at 57.7%. Workers who reported aspects of
      perceived job stress showed a greater 2 year risk than those without stress.
      Multiple logistic regression analyses showed that some components of perceived
      job stress were associated with a higher 2 year risk, among which "not allowed to
      make mistakes" showed the largest adjusted odds ratio (OR) (95% confidence
      interval (95% CI) of 2.37 (1.32 to 4.29). "Poor relationship with superior" had a
      significant effect on mental health only in women, with an adjusted OR (95% CI)
      of 3.79 (1.65 to 8.73). CONCLUSIONS: Certain specific items of perceived job
      stress seem to be associated with mental ill health in workers. These could
      broadly be described as job strain, or job demand items. The type of job stress
      that predicts mental health may be dependent on the characteristics of the
      workplace investigated.

PMID- 10341746
TI  - Shiftwork and myocardial infarction: a case-control study.
AB  - OBJECTIVES: Previous studies have indicated an association between shiftwork and
      coronary heart disease. The increased risk could be due to job strain, which
      could act as a mediator of disease. There is also a possibility that interaction
      between shiftwork and job strain could occur that may induce or modify the
      development of disease. We conducted this study to explore the relation between
      shiftwork, job strain, and myocardial infarction. METHODS: 2006 cases with acute
      first time myocardial infarction were compared with 2642 controls without
      symptoms of myocardial infarction, and obtained from the same population that
      gave rise to the cases (population based case-control study). RESULTS: Myocardial
      infarction risk was associated with shiftwork both in men (odds ratio (OR) 1.3,
      95% confidence interval (95% CI) 1.1 to 1.6) and women (OR 1.3, 95% CI 0.9 to
      1.8). In the age group 45-55, the relative risk was 1.6 in men and 3.0 in women.
      The results cannot be explained by job strain, age, job education level, or
      smoking. No interaction was found between shiftwork and job strain. CONCLUSIONS:
      The findings indicate that shiftwork is associated with myocardial infarction in
      both men and women. The mechanism is unclear, but the relation cannot be
      explained by job strain, smoking, or job education level.

PMID- 10341747
TI  - Mineral fibre analysis and routes of exposure to asbestos in the development of
      mesothelioma in an English region.
AB  - OBJECTIVES: To compare the concentrations of inorganic fibres in the lungs in
      cases of mesothelioma and controls: to determine whether concentrations of
      retained asbestos fibres differ with the different exposures identified from
      interview; and to investigate the existence of a cut off point in concentrations
      of asbestos fibres that indicates occupational exposure. METHODS: Case-control
      study; 147 confirmed cases of mesothelioma and 122 controls identified from
      deaths occurring in four districts of Yorkshire between 1979 and 1991. Surviving
      relatives were interviewed to determine lifetime exposure history to asbestos.
      Mineral fibre analysis was carried out on lung tissue from postmortem
      examinations. RESULTS: Odds on high concentrations of retained asbestos fibres
      were greater in cases than controls. After excluding subjects with occupational
      and paraoccupational exposure, the odds on high concentrations were still greater
      in cases than controls, but only significantly so for amphiboles. There was only
      a weak relation between probability of occupational exposure to asbestos and
      concentrations of retained asbestos fibres, and no significant difference in
      fibre concentrations was found between subjects who had been exposed to asbestos
      through different routes: these comparisons were only based on small groups.
      There was considerable overlap in concentrations of retained asbestos fibres
      between cases and controls with and without histories of occupational exposure.
      CONCLUSIONS: The study has confirmed previous results of higher concentrations of
      asbestos fibres in cases than controls, and has shown that this is still found in
      subjects with little evidence of occupational and para-occupational exposure. The
      overlap in concentrations of retained asbestos for different groups of subjects
      did not suggest a clear cut of value.

PMID- 10341749
TI  - A relative power table for nested matched case-control studies.
AB  - OBJECTIVE: To calculate relative powers for nested case-control studies for
      different values of both relative risk and numbers of controls per case, given a
      fixed number of cases available for analysis. METHODS: Algebraic and numerical
      methods. RESULTS: In nested case-control studies, statistical power is a function
      of relative risk, rarity of exposure, number of case-control sets, and the number
      of controls per case. CONCLUSION: The dictum that sufficient power will be
      obtained in a nested case-control study by selecting only four controls per case
      cannot be sustained. Appropriate numbers need to be calculated for specific
      studies.

PMID- 10341748
TI  - Risk factors for neck and upper limb disorders: results from 24 years of follow
      up.
AB  - OBJECTIVES: To investigate associations between different potential risk factors,
      related and not related to work, and disorders of the neck and upper extremities
      occurring up to 24 years later. METHODS: The study comprised 252 women and 232
      men, Swedish citizens, 42-59 years of age and in a broad range of occupations.
      Information about potential risk factors was available from a former study
      conducted in 1969. Data on disorders of the neck, shoulder, and hand-wrist
      disorders were obtained retrospectively for the period 1970-93. RESULTS: Risk
      factors were found to differ between the sexes. Among women over-time work, high
      mental workload, and unsatisfactory leisure time were associated with disorders
      in the neck-shoulder region. Interaction was found between high mental workload
      and unsatisfactory leisure time. Neck symptoms earlier in life were associated
      with recurrent disorders. Hand and wrist disorders were associated mainly with
      physical demands at work. Among men blue collar work and a simultaneous presence
      of high mental workload and additional domestic workload predicted disorders in
      the neck-shoulder region. CONCLUSIONS: Factors related and not related to work
      were associated with disorders of the neck, shoulders, and hands and wrist up to
      24 years later in life. These included factors related to working hours which
      previously have not been noted in this context. Interactions between risk factors
      both related and not related to work were commonly found.

PMID- 10341750
TI  - [The prognostic value of dobutamine stress echocardiography. A long-term follow
      up study].
AB  - BACKGROUND AND OBJECTIVE: The prognostic value of dobutamine stress
      echocardiography in patients with suspected or known coronary heart disease has
      not exactly been assessed. Purpose of the study was the assessment of the
      prognostic value of DSE regarding cardiac events, especially in patients with a
      normal DSE finding. PATIENTS AND METHODS: 316 patients (168 men, 148 women, mean
      age 61 +/- 10 years), included in this follow-up study, underwent DSE between
      January 1994 and December 1996 to evaluate clinically suspected or known coronary
      heart disease. DSE was classified according to resting and stress
      echocardiography as either "normal-normal (NN)", "normal-ischemic (NI)",
      "abnormal-normal (AN)", "abnormal-ischemic (AI)" or "inconclusive (C)". Follow-up
      by telephone took place between June 1997 and April 1998. "Events" were survived
      myocardial infarction and death. "Interventions" were revascularisation
      procedures, either percutaneous transluminal coronary angioplasty (PTCA) with or
      without stenting or aortocoronary bypass surgery. RESULTS: In 161 patients, DSE
      was NN, NI in 27 patients, AN in 55 patients, AI in 54 patients and C in 19
      patients. Mean follow-up duration was 28 months. Events occurred in 23 patients:
      survived myocardial infarction in 10, death in 13 persons. Interventions were
      carried out in 50 patients: PTCA with or without stenting in 19, aortocoronary
      bypass surgery in 31 persons. The event rate was significantly lower in patients
      with DSE classified as NN (P = 0.03 by log-rank) than in other groups. The
      intervention rate was significantly lower in the NN-group (P = 0.0001 by log
      rank) than in the other groups, too. CONCLUSION: Patients with a normal rest
      echocardiography and DSE had a good prognosis in a long-term follow-up study.

PMID- 10341751
TI  - [Renal tubular acidosis with severe hypokalemic tetraparesis after ibuprofen
      intake].
AB  - HISTORY: A 72-year-old woman was admitted because of severe acute tetraparesis,
      more marked proximally. For six months she had been taking ibuprofen, up to 4800
      mg daily, for a painful ulcer of the lower leg. INVESTIGATIONS: Biochemical tests
      revealed marked hypokalaemia (serum potassium 1.4 mmol/l) with a metabolic
      acidosis (pH 7.29). The ECG showed changes of hypokalaemia (ST-segment depression
      and U wave). TREATMENT AND COURSE: Within two days of administering potassium and
      bicarbonate the pareses completely regressed. Transitorily abnormal renal
      functions also rapidly normalized after ibuprofen had been discontinued.
      CONCLUSION: The biochemical findings suggest renal tubular acidosis, type 2, most
      likely caused by the excess intake of ibuprofen, a drug which can cause renal
      dysfunctions with life-threatening electrolyte abnormalities.

PMID- 10341753
TI  - [Wilson's disease. The making of a diagnosis by conventional and molecular
      biology methods].

PMID- 10341752
TI  - [Heparin-induced thrombocytopenia as the cause of persistent bleeding after
      pacemaker implantation].
AB  - HISTORY AND CLINICAL FINDINGS: A cardiac pacemaker was to be implanted in a 74
      year-old man, known for many years to have cardiac arrhythmias. Lown type IVb,
      because of the onset of severe bradycardic episodes. After appropriate
      preoperative preparation the patient's anticoagulant medication was changed over
      5 days from phenprocoumon (Marcumar) to heparin. The procedure and the immediate
      postoperative period were without complication. But two days later he had to be
      admitted to the intensive care unit because of cardiac failure and bleeding into
      the operation site. LABORATORY FINDINGS: One week after starting heparin the
      platelet count had fallen from 154 x 10(9)/l preoperatively to 92 x 10(9)/l.
      Haemoglobin concentration was 8.9 g/dl, haematocrit 26.7%. The Quick value of
      51%, partial thromboplastin time of 54.1 s, thrombin time of 17.6 s and plasma
      antithrombin level of 61% provided no further diagnostic pointers. An HIPA test
      and a PF4/heparin immunoassay, performed as heparin-induced type II
      thrombocytopenia was suspected, subsequently confirmed the diagnosis. TREATMENT
      AND COURSE: After the cardiac status had stabilized the operative wound was
      explored, but no bleeding site found. Other causes having been excluded (liver
      failure, disseminated intravascular coagulopathy, septicemia, dilution
      thrombocytopenia), heparin was discontinued 2 days later. Recombinant hirudin
      infusion, 0.025 mg/kg per hour, was begun. After 4 days the platelet count had
      improved, the other clotting parameters were stable within the therapeutic
      anticoagulant range and the diffuse bleeding had stopped. CONCLUSION: When
      changing from phenprocoumon to heparin preoperatively one must be aware of the
      rare risk of acquired heparin-induced thrombocytopenia. Intravenous recombinant
      hirudin proved to be a safe treatment until oral anticoagulation had been
      established, quickly normalizing the platelet count.

PMID- 10341754
TI  - [Monckeberg's medial sclerosis].

PMID- 10341756
TI  - [Protection against dismissal according to the law on the severely handicapped].

PMID- 10341755
TI  - [Recommendations for the diagnosis and therapy of cytomegalovirus infection after
      stem-cell transplantation. The Research Alliance on the Complications of Organ
      Transplantation due to Herpes Viruses].

PMID- 10341757
TI  - [The organization of rehabilitation. Rehabilitation in statutory health
      insurance].

PMID- 10341758
TI  - [Clinical research on human beings (1)].

PMID- 10341759
TI  - [A danger of thrombosis for cancer patients?].

PMID- 10341760
TI  - [The holmium-YAG laser: a suitable instrument for stone fragmentation in
      choledocholithiasis. The assessment of the results of its use under babyscopic
      control].
AB  - BACKGROUND AND OBJECTIVE: Stone fragmentation is required in ca. 5% of patients
      with choledocholithiasis to free the patients of stones. Several extra- and
      intracorporal methods of stone fragmentation (lithotripsy) have been available.
      We here report our experience with the recently available holmium-YAG laser, used
      under babyscopic monitoring. PATIENTS AND METHODS: Between September 1997 and May
      1998 lithotripsy was performed by holmium-YAG laser under monitoring in 20
      patients with choledocholithiasis in whom conventional methods had failed to
      achieve stone fragmentation. RESULTS: All stones were cleared in 19 of the 20
      patients. A second session was necessary in four patients, three sessions in one.
      There was no serious complication and no death during a 30-day follow-up.
      CONCLUSION: Holmium-YAG laser lithotripsy under babyscopic monitoring has been
      shown to be a suitable method in patients with choledocholithiasis in whom
      previous treatment has failed it is complementary to current methods of stone
      fragmentation.

PMID- 10341761
TI  - [Osteo-anabolic estrogen therapy in a transsexual man].
AB  - HISTORY AND ADMISSION FINDINGS: A 31-year-old man presented at the endocrinology
      out-patient clinic for the initiation of sex-change treatment. His manifestly
      transsexual male-to-female appearance was confirmed by a psychiatric-sexological
      expert report. The patient had been living as a woman for one year. Physical
      examination showed normal male physique with typical secondary hair growth and
      normal male genitals. INVESTIGATIONS: The serum testosterone level was at the
      upper limits of normal, that for oestrogen at the lower limit. Bone densitometry
      showed bone density at the upper limit of normal. Other laboratory tests were
      unremarkable. DIAGNOSIS, TREATMENT AND COURSE: During 30 months on cyproterone,
      100 mg daily, bone mass fell at the rate of 5% per year. Bone biopsy revealed
      high turnover osteoporosis. Bone mass rose by 4% per year after the additional
      oral intake of oestradiol valerate, 2 mg daily. Osteoblastic cells, isolated from
      part of the biopsy tissue, with the patient's consent, was found to be stimulated
      by oestradiol in vitro. CONCLUSION: The described bone mass changes indicate the
      important role played by sex hormones in the maintenance of bone mass acquired
      during adolescence. The findings confirm that in males not only testosterone but
      also oestrogens has an anabolic effect on bone.

PMID- 10341762
TI  - [Thrombosis of the deep leg and pelvic veins in congenital agenesis of the vena
      cava inferior].
AB  - HISTORY AND ADMISSION FINDINGS: Severe pain and increasing swelling in the region
      of the right lower leg occurred after unaccustomed physical activity in a 29-year
      old man. Physical examination showed painful swelling and livid discoloration of
      the right lower leg. INVESTIGATIONS: Laboratory tests were consistent with an
      acute inflammation. Colour Doppler duplex sonography of the leg and pelvic veins
      bilaterally revealed complete thrombosis of the deep leg and pelvic veins on the
      right. Spiral computed tomography of the abdomen confirmed deep pelvic vein
      thrombosis and also demonstrated complete agenesis of the inferior vena cava
      (IVC). TREATMENT AND COURSE: The patient was fully heparinized and compression
      bandage applied to the right leg, which was kept elevated, Ibuprofen, 3 x 400 mg
      daily, was given for pain relief. Anticoagulation treatment with phenprocoumon
      (Marcumar) was initiated. The patient was discharged much improved after ten
      days. Duplex sonography after 3 months demonstrated partial recanalization of the
      right pelvic and deep leg veins. CONCLUSION: Congenital malformations of the IVC
      are rare. Phlebothrombosis often results in affected patients. Treatment or
      prevention of thrombosis of the deep veins by anticoagulation is indicated.
      Additional risk factors for thrombosis--smoking, hormonal contraceptives,
      immobilization and unusual physical activity--should be strictly avoided.

PMID- 10341763
TI  - [The clinical picture and therapy of frontal lobe epilepsy].

PMID- 10341764
TI  - [Hypoxia in solid tumors].

PMID- 10341765
TI  - [The liver side effects of azathioprine].

PMID- 10341766
TI  - [Inoculation against FSME (early summer meningoencephalitis)--a questionable use
      of antibody determination for checking the immunity status].

PMID- 10341767
TI  - The human element of adverse events.

PMID- 10341768
TI  - Auditing trauma outcomes: Australia needs a national approach.

PMID- 10341769
TI  - What's the use of oral vitamin B12?

PMID- 10341770
TI  - Cardiovascular disease at the turn of the century.

PMID- 10341771
TI  - An analysis of the causes of adverse events from the Quality in Australian Health
      Care Study.
AB  - OBJECTIVE: To examine the causes of adverse events (AEs) resulting from
      healthcare to assist in developing strategies to minimise preventable patient
      injury. DESIGN: Descriptions of the 2353 AEs previously reported by the Quality
      in Australian Health Care Study (QAHCS) were reviewed. A qualitative approach was
      used to develop categories for human error and for prevention strategies to
      minimise these errors. These categories were then used to classify the AEs
      identified in the QAHCS, and the results were analysed with previously reported
      preventability and outcome data. RESULTS: 34.6% of the causes of AEs were
      categorised as "a complication of, or the failure in, the technical performance
      of an indicated procedure or operation", 15.8% as "the failure to synthesise,
      decide and/or act on available information", 11.8% as "the failure to request or
      arrange an investigation, procedure or consultation", and 10.9% as "a lack of
      care and attention or failure to attend the patient". AEs in which the cause was
      cognitive failure were associated with higher preventability scores than those
      involving technical performance. The main prevention strategies identified were
      "new, better, or better implemented policies or protocols" (23.7% of strategies),
      "more or better formal quality monitoring or assurance processes" (21.2%),
      "better education and training" (19.2%), and "more consultation with other
      specialists or peers" (10.2%). CONCLUSION: The causes of AEs or errors leading to
      AEs can be characterised, and human error is a prominent cause. Our study
      emphasises the need for designing safer systems for care which protect the
      patient from the inevitability of human error. These systems should provide new
      policies and protocols and technological support to aid the cognitive activities
      of clinicians.

PMID- 10341772
TI  - Management of severe trauma in intensive care units and surgical wards.
AB  - OBJECTIVE: To evaluate the management of severe trauma in intensive care, high
      dependency and general surgical wards of Victorian hospitals. DESIGN:
      Retrospective case review by multidisciplinary committees. SUBJECTS: The first
      256 people who died from road traffic accidents who were alive on the arrival of
      emergency services between 1 July 1992 and 30 June 1994. MAIN OUTCOME MEASURES:
      (1) Severity of injury according to clinical diagnosis, autopsy findings and
      recognised trauma-scoring methods; (2) errors in management, identified as
      contributing or not contributing to the cause of death, and categorised as
      "management", "system", "diagnostic" or "technique" errors. RESULTS: Most
      patients (61%) were admitted to an intensive care unit (ICU), and 19.5% were
      admitted to high dependency or general surgical wards. Of 2187 errors of care
      identified, 11.8% occurred in ICU and 6.7% in wards, with the remainder occurring
      during the earlier phases of care. Most errors were classified as management
      errors (82% of ICU errors and 88% of ward errors). Fifty-two per cent of ICU
      errors and 71% of ward errors were judged to contribute to the patient's death.
      CONCLUSIONS: A significant number of errors of trauma management occur in the
      intensive care and general surgical ward. Improvement in late trauma care may
      reduce the number of preventable trauma deaths.

PMID- 10341773
TI  - The extraction of quality-of-care clinical indicators from State health
      department administrative databases.
AB  - OBJECTIVE: To assess whether three proposed quality-of-care indicators (unplanned
      readmissions, hospital-acquired bacteraemia, and postoperative wound infection)
      can be accurately identified from State health department databases. DESIGN:
      Algorithms were applied to State health department databases to maximise the
      identification of individuals potentially positive for each indicator. Records of
      these patients were then examined to determine the percentage of cases that met
      the precise indicator definitions. SETTING: 10 public, acute-care hospitals from
      Victoria, South Australia and New South Wales. Data from the 1994-95 and 1995-96
      financial years were collected. PARTICIPANTS: Individuals 18 years of age or
      older who were identified from State health department administrative databases
      as potentially meeting the indicator criteria. MAIN OUTCOME MEASURES: The
      proportion of screened cases that met the precise indicator definitions, and the
      elements of the indicator definitions which could not be extracted from the
      administrative databases. RESULTS: The proportions of cases confirmed by medical
      record review to be positive for the indicator events were 76.3% for unplanned
      readmissions within 28 days, 20% for hospital-acquired bacteraemia, 43.5% for
      wound infections after clean surgery, and 34.8% for wound infections after
      contaminated surgery. The clinical elements of each indicator definition were not
      easily extracted from the administrative databases. CONCLUSIONS: The three
      proposed clinical indicators could not be extracted from current State health
      department databases without an extensive process of secondary medical record
      review. If administrative databases are to be used for assessing quality of care,
      more systematic recording of data is needed.

PMID- 10341774
TI  - Sudden death due to ischaemic heart disease in young aboriginal sportsmen in the
      Northern Territory, 1982-1996.
AB  - OBJECTIVE: To estimate the incidence of sport-related sudden cardiac death due to
      ischaemic heart disease (IHD) in competitive young Aboriginal sportsmen. SETTING:
      Northern Territory (NT), 1982-1996. DESIGN: Retrospective case series with cases
      identified from Australian Bureau of Statistics cause-of-death listings and NT
      coronial autopsy records. MAIN OUTCOME MEASURES: Circumstances and incidence of
      sport-related sudden cardiac deaths due to IHD; autopsy findings. RESULTS:
      Between 1982 and 1996, there were eight sudden cardiac deaths due to IHD and
      related to sporting activity among Aboriginal sportsmen aged 15-37 years in the
      NT. Six were associated with games of Australian (rules) football. All occurred
      in the Top End of the NT in the wet season, and all occurred after the first
      half, or within an hour of, a game. Four of the players had macrosopic myocardial
      abnormalities (hypertrophy or previous infarcts) on autopsy. The estimated
      incidence of IHD-related sudden cardiac death among Aboriginal Australian
      football players in the NT was 19-24 per 100,000 player-years, compared with 0.54
      per 100,000 player-years among Australian rules footballers of similar ages in
      Victoria. CONCLUSIONS: Incidence of sudden cardiac death attributable to
      underlying IHD was extremely high among young NT Aboriginal Australian
      footballers. Prevention will best be achieved by funding culturally appropriate
      long-term strategies to reduce the incidence of IHD. However, in the short-term,
      community-controlled programs with education of athletes, heat-stress reduction
      strategies, and cardiovascular screening should reduce the incidence of sudden
      cardiac death in sport.

PMID- 10341775
TI  - Impact of improved diagnosis and treatment on prevalence of gonorrhoea and
      chlamydial infection in remote aboriginal communities on Anangu Pitjantjatjara
      Lands.
AB  - OBJECTIVE: To evaluate the impact of a program to improve access to, and delivery
      of, diagnosis and treatment on prevalence of gonorrhoea and chlamydial infection
      in remote Aboriginal communities. DESIGN: Analysis of cross-sectional data from
      annual age-based screening. SETTING: Six remote Aboriginal communities and three
      homelands on the Anangu Pitjantjatjara Lands in the far north-west of South
      Australia, 1996-1998. PARTICIPANTS: All Aboriginal people aged 12-40 years listed
      on the Nganampa Health Council population register as resident on the Anangu
      Pitjantjatjara Lands. MAIN OUTCOME MEASURES: Prevalence of gonorrhoea and
      chlamydial infection, determined by urine polymerase chain reaction tests.
      RESULTS: The prevalence of gonorrhoea in people aged 12-40 years almost halved,
      from 14.3% in 1996 to 7.7% in 1998 (test for trend: P < 0.001). The fall in
      prevalence of gonorrhoea was comparable and statistically significant in both men
      and women. Prevalence of chlamydial infection also fell, from 8.8% in men and
      9.1% in women in 1996 to 7.2% in both men and women in 1998, but this decline was
      not statistically significant (test for trend: P = 0.174). CONCLUSION: This study
      documents a rapid reduction in prevalence of gonorrhoea, probably reflecting
      reduced duration of infectiousness due to advances in diagnosis, increased
      testing activity and reduced interval to treatment rather than behaviour change.
      These results demonstrate that, in remote communities, even with a highly mobile
      population, it is possible to implement effective control activities for sexually
      transmitted diseases.

PMID- 10341776
TI  - The Bibbulung Gnarneep Project: practical implementation of guidelines on ethics
      in indigenous health research.
AB  - Human rights and ethical principles justify Indigenous control of health research
      conducted in Indigenous communities, but also emphasise the need for scientific
      rigour, knowledge and expertise, much of which currently resides with the non
      Indigenous community. In 1994, we began development of the Bibbulung Gnarneep
      Project on Aboriginal maternal and child health in Perth, Western Australia. We
      describe the process of developing a protocol to ensure ethical conduct of this
      research through consultation and negotiation between Aboriginal and non
      Aboriginal people involved in the project.

PMID- 10341777
TI  - Aboriginal health: why is reconciliation necessary?
AB  - Many health professionals are deeply troubled by the persistent health inequities
      between Aboriginal and non-Aboriginal Australians. From a social and political
      perspective it is clear that, for there to be appreciable improvement in
      Aboriginal health, a process of reconciliation which acknowledges the past in the
      light of the present needs to be adopted across all sectors of society. We give
      some practical advice for promoting reconciliation.

PMID- 10341778
TI  - Palpitations: reassurance or more?
AB  - Palpitations are a common symptom and are caused by forceful or rapid beating of
      the heart. Palpitations can be caused by a variety of cardiac arrhythmias and
      careful history is invaluable in deciding appropriate investigations and
      management. Palpitations caused by anxiety-induced sinus tachycardia are common,
      but anxiety is also common in patients who have cardiac arrhythmias for which
      effective treatment is available. Management of palpitations depends on the type
      of cardiac arrhythmia; almost all arrhythmias can now be effectively treated.
      Radiofrequency ablation provides an effective cure for most patients with
      paroxysmal supraventricular tachycardia when the alternative is continuous drug
      therapy.

PMID- 10341779
TI  - Quinine-induced blindness during attempted heroin withdrawal.

PMID- 10341780
TI  - Oral vitamin B12 for B12 deficiency.

PMID- 10341781
TI  - Fetomaternal alloimmune thrombocytopenia treated with intragam.

PMID- 10341782
TI  - Adverse effect of nefazodone: hepatitis.

PMID- 10341783
TI  - Renewing Australia's mental health strategy.

PMID- 10341784
TI  - Posthumous conception and the need for consent.

PMID- 10341785
TI  - Decision making in CPR.

PMID- 10341786
TI  - Decision making in CPR.

PMID- 10341787
TI  - Kombucha.

PMID- 10341788
TI  - Opioid substitution to reduce adverse effects in cancer pain management.

PMID- 10341789
TI  - Oral health for the preschool child.

PMID- 10341790
TI  - [The value of MRT in the diagnosis of benign and malignant tumors of the uterus].
AB  - Magnetic resonance (MR) imaging gains a more and more important role in the
      diagnostic assessment of the female pelvis. The free selection of the imaging
      plane is of particular importance for the visualization of the uterus, and the
      high soft-tissue contrast presently offers the best possibilities for assessment
      of the zonal anatomy of the uterus. Advances in coil technology and the use of
      time-saving pulse sequences that, in addition, yield high-resolution images
      (e.g., fast spin-echo sequences) have made MR imaging a reliable diagnostic
      modality with a high image quality. There is no doubt that ultrasound continues
      to be the most widely used imaging modality besides the clinical examination.
      However, ultrasound is not only limited by high interexaminer variation but also
      by an insufficient tissue characterization and, above all, the lacking
      possibility of staging malignancies. Computed tomography has turned out to be
      inefficient in determining the local tumor stage due to its poor soft-tissue
      contrast and should thus only be used in advanced tumor stages. MR imaging, on
      the other hand, excellently depicts the morphologic details of the female pelvis
      and helps in the assessment of both benign and malignant masses of the uterus and
      has the highest diagnostic value in staging malignancies. Furthermore, recent
      studies have shown that MR imaging is also cost-effective as a pretherapeutic
      modality in cervical cancer.

PMID- 10341792
TI  - [The demonstration of microcalcification in breast core biopsies: DIMA specimen
      radiography (7x) compared to the histopathological findings].
AB  - PURPOSE: Comparing the sensitivity in detecting microcalcifications in
      stereotactically guided core biopsy specimen of the breast of direct
      magnification (DIMA) specimen radiography (x7) with the histological examination.
      MATERIALS AND METHODS: In 52 patients 509 stereotactically obtained core biopsy
      (14-gauge) specimens of the breast were radiographed by direct magnification
      (DIMA) specimen radiography (x7) and examined histologically. RESULTS: In 188
      specimen microcalcifications were detected by magnification radiography compared
      to 98 by histological examination. Only 3% of the specimen microcalcifications
      were seen exclusively in the histological examination. In core biopsies with
      malignancy the relative proportion of biopsies with radiologically detected
      microcalcifications was increased (59% versus 32%). CONCLUSION: Concerning the
      detection of microcalcifications in core biopsy specimen of the breast, the
      direct magnification (DIMA) radiography (x7) was superior compared to the
      histological examination. Due to the high relative proportion of biopsies with
      radiologically detected microcalcification and malignancy, we recommend a
      comprehensive histological examination of these specimen. Confirmation of
      microcalcifications in core biopsies should be achieved by magnification
      radiography to prove that the suspicious area in the breast was truly sampled.
      Specimen radiography simultaneously with the biopsy procedure can reduce the
      number of punctures in the process of documenting the presence of calcifications
      early in the biopsy procedure.

PMID- 10341791
TI  - [Hydro-MRT with fast sequences in Crohn's disease: a comparison with fractionated
      gastrointestinal passage].
AB  - PURPOSE: To compare the value of hydro-MRI with that of barium studies in
      patients with Crohn's disease. MATERIALS AND METHODS: After an oral bowel
      opacification using 1000 ml of a 2.5% mannitol solution, axial and coronal breath
      hold sequences (T2W HASTE +/- FS, contrast-enhanced T1W FLASH FS) were acquired
      in 46 patients with Crohn's disease at 1.0 T. The findings of hydro-MRI were
      compared with those of barium studies. RESULTS: In the stomach and the small
      bowel, hydro-MRI and barium studies demonstrated similar numbers of Crohn's
      involvements (39 vs. 36); in the colon, hydro-MRI showed clearly more affections
      (23 vs. 10). Hydro-MRI showed 12.7 cm of inflamed bowel per patient, on average
      (barium studies: 10.4 cm; p = 0.004). There was a good agreement between the two
      methods regarding the assessment of the extent of Crohn's disease and the
      severity of bowel stenoses (r = 0.89 and 0.88, respectively). CONCLUSIONS: For
      the assessment of Crohn's disease, hydro-MRI is preferable to the barium study
      because of the superior imaging quality and the lack of radiation exposure.

PMID- 10341793
TI  - [The MRT of focal liver lesions: the value of gadolinium-enhanced dynamic studies
      of the whole organ with a fast 3D-turbo-gradient echo sequence].
AB  - PURPOSE: To determine the value of a dynamic Gd-enhanced ultrafast T1-weighted 3D
      turbo-gradient-echo sequence (3D-TFE) in the detection and characterization of
      focal liver lesions. MATERIALS AND METHODS: 51 patients with 124 focal liver
      lesions (35 hemangiomas, 30 HCC, 24 metastases, 22 cysts, 5 FNH/adenoma, 8 other
      lesions) were examined using a 1.5 T system. The dynamic 3D-TFE sequence,
      achieving 40 slices with a thickness of 4.5 mm in a 17-s breath-hold, was
      compared with a fat-suppressed T2-weighted fast-spin-echo sequence (TSE SPIR),
      unenhanced and Gd-enhanced T1-weighted spin-echo sequences (SE), and a T1
      weighted gradient-echo sequence (FFE). RESULTS: On 3D-TFE images more lesions
      (107/124) were identified than on T1-weighted SE (101/124) and T1-weighted FFE
      images (106/124), but less compared to T2-weighted TSE SPIR images (115/124). The
      3D-TFE-sequence provided additional information in 65/107 (61%) detected lesions
      by delineating the dynamic enhancement pattern, most valuable in patients with
      HCCs in 90%. CONCLUSIONS: On dynamic 3D-TFE images more lesions could be depicted
      than on conventional T1-weighted SE and T1-weighted FFE images. Visualization of
      the dynamic enhancement pattern provided additional information for tumor
      characterization in 61% of the detected lesions on the 3D-TFE images.

PMID- 10341794
TI  - [The observed and chance-corrected agreement of the computed tomographic and
      histological staging results in renal-cell carcinoma].
AB  - PURPOSE: To assess the diagnostic value of abdominal computed tomography in the
      preoperative staging of renal cell carcinoma. METHODS: Computed tomograms of 87
      renal cell carcinomas were classified according to the TNM-System. The results
      were correlated with the histopathological categories. The usual parameters for
      diagnostic tests were calculated and chance correction of the observed agreement
      was performed using Cohen's Kappa (kappa) test. RESULTS: T-category staging
      showed an overall accuracy of 60% (kappa = 0.44). The pT1 category was correctly
      predicted in all cases. For perirenal invasion, an accuracy of 60% (kappa =
      0.27), a sensitivity of 90.5%, and a specificity of 51% were found. For venous
      involvement, accuracy was 92% (kappa = 0.59), sensitivity 86%, and specificity
      92%. All inconspicuous adrenals on CT were histologically normal as well. An
      accuracy of 80% for lymphadenopathy staging was attributable to chance (kappa =
      0.04). 7 distant metastases were detected in the scanned volume. CONCLUSIONS:
      Good CT staging results are obtained with discrimination between T1 tumors and
      higher categories, the assessment of venous invasion, the exclusion of adrenal
      involvement, and the detection of metastatic spread to abdominal organs.
      Insufficient results are seen with lymphadenopathy staging and the distinction of
      organ-confined and invasive tumors.

PMID- 10341795
TI  - [MRT, CT and sonography in the preoperative assessment of the primary tumor
      spread in malignant pleural mesothelioma].
AB  - PURPOSE: Evaluation of the diagnostic value of the imaging modalities computed
      tomography (CT), magnetic resonance imaging (MRI), and thoracic sonography in the
      preoperative staging of malignant pleural mesothelioma. MATERIALS AND METHODS:
      The diagnostic accuracy of CT (n = 41), MRI (n = 24), and thoracic sonography (n
      = 37) were evaluated in 51 patients with histologically proven diffuse malignant
      pleural mesothelioma. Values of sensitivity, specificity, positive and negative
      predictive values, and accuracy were calculated for the assessment of the
      diaphragm, lung, thoracic wall, pericardial wall, myocardium, and
      (retro)peritoneal space. RESULTS: The accuracy rates for CT were 85%, 98%, 83%,
      73%, 71%, and 83%. MRI had an accuracy of 71%, 92%, 71%, 83%, 71%, and 96%, the
      thoracic ultrasound examinations of 76%, 63%, 51%, 60%, 71%, and 89%.
      CONCLUSIONS: According to these results CT remains the method of choice in the
      preoperative assessment of T-stage of malignant pleural mesothelioma. MRI is of
      nearly the same value, but is not a must. Sonography may be supplementary method
      for operation planning.

PMID- 10341796
TI  - [1H-MR spectroscopy in anorexia nervosa: reversible cerebral metabolic changes].
AB  - PURPOSE: By using localized 1H-MR spectroscopy in the brain of patients with
      anorexia nervosa we wanted to verify our preliminary results and to look for a
      reversibility of the metabolic changes under therapy. METHODS: In 22 patients and
      17 healthy volunteers (11 follow-up examinations) single voxel 1H-MR spectroscopy
      (TE = 50 ms, TM = 30 ms, TR = 1500 ms, voxel (2 cm)3, acq.: 256) was used in two
      different localizations (thalamus and parieto-occipital region). The first
      examination of the patients was performed before therapy, the follow-up
      examination at the end of therapy. RESULTS: In both regions of the brain we found
      a statistically significant elevation of the Cho/Cr-ratio in comparison to normal
      controls. The follow-up examinations revealed reversibility of the metabolic
      changes under successful therapy. CONCLUSIONS: 1H-MR spectroscopy reveals
      metabolic changes in the brain of patients with anorexia nervosa, which are
      reversible under successful therapy. These metabolic changes can be conclusively
      explained using a biochemical model.

PMID- 10341797
TI  - [Anticoagulation control during neuroradiological interventions with ACT
      (activated clotting time)].
AB  - PURPOSE: To evaluate the effect of anticoagulation control by bedside ACT during
      interventional neuroradiological procedures with intraarterial heparin
      application. MATERIALS AND METHODS: The study included 168 patients with
      intraarterial anticoagulation. Depending on the expected duration of the
      intervention and the body weight, a heparin dose of 5000 i.u. (70 patients) or
      7500 i.u. (98 patients) was given through the catheter. The clotting time was
      measured with the Hemochrom 401 (Fa. Fresenius). RESULTS: The effect of
      anticoagulation with heparin was measurable a few minutes after administration.
      Within the first 20 minutes the ACT increased about two times above the normal
      ACT from 156.1 +/- 26.1 (5000 i.u. heparin) to 296 +/- 58.0 and from 146.5 +/-
      26.3 (7500 i.u. heparin) to 317.2 +/- 72.0. Additional administration of 2500
      i.u. heparin was necessary in 16 patients. An ACT monitored neutralisation with
      protamine hydrochloride took place in 15 patients with high ACT values at the end
      of the intervention. Three thromboembolic events and one bleeding complication
      occurred during the interventions. CONCLUSIONS: (1) The ACT is a useful and
      readily available parameter to monitor the anticoagulation status of patients in
      the interventional suits. (2) ACT detects heparin nonresponders. (3) Exact
      monitoring of heparin administration and neutralisation with protamine
      hydrochloride is helpful in preventing thromboembolic events and bleeding
      complications.

PMID- 10341798
TI  - [Transfemoral pelvic vein angiography with CO2: experiences with pressure- and
      volume-controlled injections].
AB  - PURPOSE: To evaluate the efficacy of CO2 in aortobifemoral DSA with a pressure-
      and volume-controlled injector. MATERIALS AND METHODS: In an intraindividual
      prospective study, 42 patients with arterial occlusive disease underwent stepwise
      aortobifemoral DSA with CO2 and with iopromid 300. RESULTS: With Co2, diagnostic
      images were obtained in 74% of the iliac, 98% of the femoral, 89% of the
      popliteal arteries, but in only 36% of the arteries of the lower leg. 73% of the
      stenoses were correctly identified. With therapeutic relevance 8% of the stenoses
      were overestimated. The length of 1 of 53 occlusions was overestimated and 3
      occlusions were simulated. No stenoses or occlusion was missed. There were no
      severe side-effects. The injector proved to be safe and easy to handle.
      Fragmentation of the CO2 bolus could be compensated by postprocessing with a
      minimum opacification summation mode. CONCLUSIONS: With the equipment used, CO2
      was a safe alternative to iodinated CM in routine stepwise aortobifemoral DSA of
      the iliac, femoral, and popliteal arteries. Because of the risk of
      overestimation, occlusions and high grade stenoses should be verified with
      selective injections or iodinated CM before PTA or operations.

PMID- 10341799
TI  - [Keyhole-true FISP: fast T2-weighted imaging for interventional MRT at 0.2 T].
AB  - PURPOSE: The aim of this study is to introduce a fast, T2 weighted true FISP
      keyhole sequence implemented on an open C arm low field magnetic resonance (MR)
      scanner for interventional procedure guidance. METHOD: Following the acquisition
      of a reference data set using a true FISP (fast Imaging with Steady Precision)
      sequence, only the 32 central raw data lines (keyhole) are acquired in a
      fluoroscopic-like mode enabling continuous image reconstruction and update. The
      keyhole true-FISP sequence was tested in animal experiments and used in MR-guided
      interventions in 10 patients. RESULTS: The described true FISP keyhole sequence
      is characterized by an image frame rate of 2.5 images per second and a T2-like
      contrast. Due to system constraints with respect to the reconstruction, the
      actual displaying of images was delayed by up to 180 ms. CONCLUSIONS: The use of
      the described keyhole sequence enabled a fluoroscopy-like guidance of
      interventional devices in an open, low-field system.

PMID- 10341800
TI  - [Transjugular liver biopsy with a modified Tru-Cut system: a retrospective study
      of its successes and complications].
AB  - PURPOSE: Evaluation of success and complications in transjugular liver biopsy
      with a semiautomatic device. METHODS: A retrospective analysis of 27 transjugular
      liver biopsies with a modified Tru-Cut system was performed on 25 patients
      between 3/95 and 12/97. RESULTS: In 26 of 27 biopsies (96.4%) histopathologically
      useful liver parenchyma could be obtained. In only one case unspecific connective
      tissue was found. There were no clinically evident complications, only one
      parenchymal hematoma was observed by ultrasound (1/27 = 3.6%). CONCLUSION: The
      tested device was highly successful in obtaining liver biopsies on patients
      suffering from coagulopathies with a low complication rate and a simple use.

PMID- 10341801
TI  - [The magnetic resonance tomography of complex congenital heart diseases in
      adults].
AB  - An increasing number of patients with complex congenital heart disease reaches
      adulthood, because treatment and patient outcome have improved considerably in
      recent years. Monitoring of these patients requires both definition of cardiac
      anatomy and assessment of function with good reproducibility. Complications after
      surgical repair such as restenoses of pulmonary arteries after surgical repair of
      tetralogy of Fallot, ventricular hypertrophy, stenoses or leakage of baffles, or
      stenosis and aneurysms of anastomoses have to be detected at an early stage.
      Magnetic resonance imaging (MRI) is an excellent tool to monitor these patients
      because of its noninvasive nature, its good interstudy and interobserver
      reproducibility, and because it allows assessment of both cardiac anatomy and
      function. This paper reviews the current applications of MRI in complex
      congenital heart disease in adults.

PMID- 10341802
TI  - [The wandering spleen--a rare differential diagnosis of acute abdomen].

PMID- 10341803
TI  - [Ureteral obstruction due to a surrounding inflammatory reaction after the
      implantation of a coated nitinol stent].

PMID- 10341804
TI  - [The involvement of the corpus callosum in systemic lupus erythematosus].

PMID- 10341805
TI  - [The use of high-resolution color-Doppler sonography in the diagnosis of temporal
      arteritis].

PMID- 10341806
TI  - Warnings on the use of isotretinoin.

PMID- 10341807
TI  - Tobacco Products Control Amendment Bill, 1998.

PMID- 10341808
TI  - Providing AZT in pregnancy--if not now then when?

PMID- 10341809
TI  - HIV surveillance in South Africa.

PMID- 10341810
TI  - Hyperbaric oxygen therapy for children with cerebral palsy.

PMID- 10341811
TI  - Hyperbaric oxygen therapy for children with cerebral palsy.

PMID- 10341812
TI  - [Acute anaphylactic reaction to latex].

PMID- 10341814
TI  - Primary Immunodeficiency Association of SA.

PMID- 10341813
TI  - Laparoscopic-assisted vaginal hysterectomy superfluous?

PMID- 10341815
TI  - Pneumoconiosis and tractor ploughing.

PMID- 10341816
TI  - USA managed care faces an uncertain future.

PMID- 10341817
TI  - Great expectations: a critical assessment of the managed care industry.

PMID- 10341818
TI  - Impaction of foreign bodies in the airways and oesophagus in children.

PMID- 10341819
TI  - Blackflies bite a resident of suburban Johannesburg.

PMID- 10341820
TI  - Fibrocaseous tuberculosis.

PMID- 10341822
TI  - Sowing seeds of doubt.

PMID- 10341823
TI  - Figures about firearms--what are the facts?

PMID- 10341821
TI  - A case of fever, confusion and anaemia in a young woman.

PMID- 10341824
TI  - A worldwide assessment of medical journal editors' practices and needs--results
      of a survey by the World Association of Medical Editors.
AB  - OBJECTIVES: To identify editors interested in participating in a global
      organisation and communication network of medical editors; to assess current use
      of the peer-review process; and to determine current computer capabilities,
      needs, and interests of medical journal editors around the world. DESIGN: Mail
      survey of senior editors at 727 medical journals. SETTING: Fifty-seven countries
      worldwide. RESULTS: Two hundred and sixty-nine editors (37%) responded. Eighty
      seven per cent of responding editors expressed interest in a global organisation
      of medical editors. Almost all editors (94%) reported using peer-review systems.
      Practices varied widely across journals, but in most cases were not highly
      correlated with the countries' level of development: 44% reported formal
      orientation for reviewers; 71% used specific instructions; 39% required reviewers
      to disclose conflicts of interest; 36% masked the identity of authors; and 42%
      graded reviews for quality. Seventy-eight per cent of editors reported using a
      computer in their work and 47% had Internet access; two-thirds of those without
      access expected to have Internet access within 18 months. CONCLUSIONS: There was
      strong interest among respondents in a global organisation for medical editors.
      Peer review was widely reported by medical journal editors throughout the world,
      although specific practices varied widely. Half of the responding editors
      reported having access to the Internet, making participation in a worldwide
      computer network of editors feasible.

PMID- 10341826
TI  - Firearm-related injuries and deaths among children and adolescents in Cape Town-
      1992-1996.
AB  - OBJECTIVE: To determine the epidemiological profile of firearm-related injuries
      among children and adolescents in Cape Town during recent years in order to
      further understand the epidemic of firearm violence as a public health problem in
      South Africa. DESIGN: A retrospective study was conducted of hospital, medico
      legal laboratory (mortuary) and police data. SETTING: Metropolitan Cape Town, 1
      January 1992-31 December 1996. STUDY POPULATION: All children and adolescents
      (under 19 years of age) with firearm injuries living in the Cape Town metropole
      during the study period. RESULTS: During the study period at least 1,736 children
      and adolescents were victims of firearm-related incidents; of these, 322 died
      (19%). The incidence of firearm injuries among this group almost tripled from
      20.2/100,000 in 1992 to 58.1/100,000 in 1996. The firearm mortality rate also
      almost tripled during the period under review from 3.8/100,000 in 1992 to
      10.3/100,000 in 1996. Approximately 60% of victims were coloured males, with 86%
      between 13 and 18 years of age. Twenty-one per cent of all victims aged over 12
      years who died were intoxicated. Other characteristics of the victims and the
      circumstances surrounding the incidents are presented. CONCLUSIONS: These
      findings demonstrate the escalating epidemic of firearm-related injuries and
      deaths among children and adolescents in Cape Town. In addition, the study
      indicates the need for an integrated injury and death reporting system. Further
      research is needed to understand firearm-related injuries among children and
      adolescents in South Africa, and to develop policies and programmes for
      prevention that are effective in this setting.

PMID- 10341825
TI  - A double-blind placebo-controlled trial of paroxetine in the management of social
      phobia (social anxiety disorder) in South Africa.
AB  - BACKGROUND: Social phobia, also known as social anxiety disorder, is a highly
      prevalent disorder with significant morbidity. Patients with social phobia
      frequently develop co-morbid psychiatric disorders such as depression and
      substance abuse, and the disorder impacts significantly on social and
      occupational functioning. It has been suggested that the selective serotonin
      reuptake inhibitors (SSRIs) are useful in the management of this disorder, but
      few controlled trials have been undertaken in this regard. There are also few
      data on the pharmacotherapy of social phobia in South Africa. METHODS: A double
      blind randomised placebo-controlled multi-site flexible-dose trial of paroxetine
      was undertaken over 12 weeks among patients with a primary diagnosis of social
      phobia. Primary response measures were the Global Improvement item on the
      Clinical Global Impression scale (CGI) and mean change from baseline in the
      patient-rated Liebowitz Social Anxiety Scale (LSAS) total score. Ninety-three
      patients participated at 9 South African sites; their data are reported here.
      RESULTS: There was a significant drug effect on both the CGI Global Improvement
      score and the LSAS at 12 weeks. In addition, there was no significant difference
      in overall rate of adverse experiences between those on paroxetine and those on
      placebo. CONCLUSIONS: Paroxetine is both effective and safe in the acute
      treatment of social phobia. The findings here are consistent with those of
      previous controlled studies of the SSRIs as well as with previous work done in
      the USA on the use of paroxetine in the treatment of this disorder. Early
      diagnosis and treatment of social phobia should be encouraged. However, further
      research on long-term pharmacotherapy of social phobia is needed.

PMID- 10341827
TI  - An outbreak of meningococcal meningitis in Gauteng, Spring 1996.
AB  - OBJECTIVE: To describe a Neisseria meningitidis outbreak in Gauteng during the
      period 1 July to 31 December 1996. DESIGN: A descriptive study. SETTING: Patients
      with meningococcal meningitis in Gauteng who had been diagnosed by laboratory
      means, or notified during the period 1 July to 31 December 1996. MAIN OUTCOME
      MEASURES: Data including age, sex, date of admission to hospital, N. meningitidis
      serogroup and outcome were collected from Gauteng notification lists, South
      African Institute of Medical Research (SAIMR) records, a linelist compiled by the
      Gauteng Health Department, and hospital records. RESULTS: A total of 201 patients
      was studied; of this number 87 (43%) had been notified. Seventy per cent of cases
      were below 30 years of age and 78% were male. More than half (54%) of the cases
      were from the West Rand. The case fatality rate for 70 cases of known outcome was
      14%. Serotyping of 85 isolates showed that a majority (76%) were serogroup A,
      with 57% being serogroup A clone I-1. Serogroup A clone III-1 accounted for 14%
      of the typed isolates. All isolates were sensitive to penicillin with minimum
      inhibitory concentrations of < 0.05 microgram/ml. CONCLUSION: In 1996 Gauteng
      experienced an epidemic of serogroup A meningococcal meningitis. The serotype
      that caused the majority of cases had been recorded in South Africa before, but
      serogroup A clone III-1, responsible for epidemics spreading across two
      continents, was recorded in South Africa for the first time. Notification of
      cases by health workers was inadequate in this epidemic.

PMID- 10341829
TI  - Adverse reactions possibly associated with the use of Emla cream.

PMID- 10341828
TI  - The role of the College of Medicine of South Africa Diploma in Anaesthesia in
      southern Africa.
AB  - OBJECTIVE: To determine the role that the College of Medicine Diploma in
      Anaesthesia (DA) plays in health services in southern Africa. DESIGN: A postal
      questionnaire. MAIN INFORMATION SOUGHT: Reasons for doing the DA, percentage of
      diplomates still actively involved in anaesthesia, career pathways of diplomates,
      perceived value of the DA, geography and type of anaesthetic practice of
      diplomates, and participation in continuing medical education. SUBJECTS: The
      1,096 candidates who passed the DA between 1974 and 1993. METHODS: Questionnaires
      were sent to all 861 diplomates with known addresses. RESULTS: The response rate
      was 62.1% (535/861). Over 70% of diplomates are still actively involved in
      anaesthesia. Approximately one-third of all diplomates specialize in anaesthesia.
      The majority of GP anaesthetists with the DA have trained in anaesthesia for more
      than 1 year. Thirty-three per cent of GP anaesthetists work in small towns or
      rural areas. Nearly 20% of GP anaesthetists spend more than 75% of their time in
      anaesthetic practice. Twenty-eight diplomates are working in southern African
      countries outside South Africa. The DA is perceived to have been of value by the
      majority of specialist and non-specialist diplomates. CONCLUSIONS: Diplomates are
      playing a valuable role in anaesthesia throughout the southern African region.

PMID- 10341830
TI  - Polymyositis associated with Klinefelter's syndrome.

PMID- 10341831
TI  - Plaque instability--the real challenge for atherosclerosis research in the next
      decade?

PMID- 10341832
TI  - Pathophysiology and clinical significance of atherosclerotic plaque rupture.
AB  - Atherosclerotic plaque rupture and resulting intracoronary thrombosis are thought
      to account for most acute coronary syndromes. These syndromes include unstable
      angina, non-Q-wave myocardial infarction (MI) and Q-wave MI. In addition, many
      cases of sudden cardiac death may be attributable to atherosclerotic plaque
      disruption and its immediate complications. Our understanding of the
      atherosclerotic process and the pathophysiology of plaque disruption has advanced
      remarkably. Despite these advances, event rates after acute coronary syndromes
      remain unacceptably high. This review will focus on the pathophysiology
      underlying atherosclerotic plaque development, the sequellae of coronary plaque
      rupture, and current therapies designed to treat the acute coronary syndromes. It
      is hoped that as our understanding of the atherosclerotic plaque improves,
      treatment strategies for the acute coronary syndromes will advance.

PMID- 10341833
TI  - Atherosclerotic plaque rupture--pathologic basis of plaque stability and
      instability.

PMID- 10341834
TI  - Fibrous cap formation or destruction--the critical importance of vascular smooth
      muscle cell proliferation, migration and matrix formation.
AB  - Endothelial activation and infiltration of monocyte macrophages are essential
      prerequisites for fibrous cap formation, which comprises proliferation and
      migration of smooth muscle cells and net matrix deposition. Macrophage foam cells
      and endothelium act as a source of growth factors and chemoattractants for smooth
      muscle cells. However, growth factors alone do not stimulate smooth muscle cell
      proliferation or migration. This requires, in addition, the remodelling of the
      extracellular matrix, at least partly mediated by metalloproteinases. In
      particular, loss of basement membrane components and contact with the
      interstitial matrix appears to be required to release a brake on proliferation
      and migration exerted by the basement membrane. Unless there is a change in the
      phenotype of macrophages in advanced lesions, it is not clear why fibrous cap
      destruction rather than formation should take place in macrophage-rich shoulder
      regions of plaques. Impaired cap formation caused by smooth muscle senescence,
      mummification and propensity to apoptosis may be as important as increased cap
      destruction in promoting plaque rupture.

PMID- 10341835
TI  - Apoptosis of vascular smooth muscle cells in vascular remodelling and
      atherosclerotic plaque rupture.
AB  - Apoptosis (programmed cell death) of vascular smooth muscle cells (VSMCs) has
      recently been identified as an important process in a variety of human vascular
      diseases, including atherosclerosis, arterial injury, and restenosis after
      angioplasty. VSMC apoptosis is regulated by interactions between the local cell
      cell and cytokine environment within the arterial wall, and the expression of pro
      and anti-apoptotic proteins by the cell, including death receptors, proto
      oncogenes and tumour suppressor genes. This review summarises our current
      knowledge of the occurrence and mechanisms underlying VSMC apoptosis in
      atherosclerosis and arterial remodelling.

PMID- 10341836
TI  - Mechanisms of plaque rupture: mechanical and biologic interactions.
AB  - Atherosclerotic vascular disease is the most common cause of morbidity and
      mortality in developed countries, and the world-wide importance of acute vascular
      syndromes is increasing. Acute events are usually triggered by the development of
      plaque disruption and subsequent thrombus formation. Histological studies have
      established specific structural features common among unstable plaques. The
      plaque has to bear remarkably increased mechanical stress at particular regions,
      and weakening of the extracellular matrix at these sites leads to fibrous cap
      rupture. The biologic factors that cause weakening of the plaque at these high
      stress locations are now emerging. Understanding the interplay of plaque
      architecture, mechanical properties and matrix biology is critical in the future
      development of therapies to stabilize lesions.

PMID- 10341837
TI  - Collagen synthesis in atherosclerosis: too much and not enough.
AB  - Fibrillar collagen is a critical component of atherosclerotic lesions.
      Uncontrolled collagen accumulation leads to arterial stenosis, while excessive
      collagen breakdown combined with inadequate synthesis weakens plaques thereby
      making them prone to rupture. This review discusses cellular sources of collagen
      synthesis in atherosclerosis, local and systemic factors modulating collagen gene
      expression, as well as temporal and spatial patterns of collagen production in
      human and experimental atherosclerotic lesions.

PMID- 10341838
TI  - Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti
      atherogenic actions of bilirubin and carbon monoxide?
AB  - Atherosclerosis is a major contributor to cardiovascular disease, and genetic
      disorders of lipoprotein metabolism are recognized risk factors in atherogenesis.
      The gaseous monoxides nitric oxide (NO) and carbon monoxide (CO), generated
      within the blood vessel wall, have been identified as important cellular
      messengers involved in the regulation of vascular smooth muscle tone. Microsomal
      heme oxygenases degrade heme to biliverdin and CO, and the cytosolic enzyme
      biliverdin reductase then catalyzes reduction of biliverdin to bilirubin, both
      powerful chain-breaking antioxidants. Two principal isozymes of heme oxygenase
      have been identified, a constitutive isoform HO-2 (M(r) approximately 34,000) and
      an inducible isoform HO-1 (M(r) approximately 32,000), which is expressed at a
      low basal level in vascular endothelial and smooth muscle cells and is induced by
      heavy metals, oxidative stress, inflammatory mediators and oxidized low density
      lipoproteins. Although NO and CO modulate intracellular cGMP levels, platelet
      aggregation and smooth muscle relaxation, CO has a much lower affinity for
      soluble guanylyl cyclase than NO. Decreased production or sensitivity to NO in
      atherosclerosis may be compensated for by an induction of HO-1, with bilirubin
      acting as a cellular antioxidant and CO as a vasodilator. This review examines
      the evidence that oxidized low density lipoproteins (LDL), hypoxia and pro
      inflammatory cytokines induce HO-1 expression and activity in vascular
      endothelial and smooth muscle cells, and evaluates the anti-atherogenic potential
      of the heme oxygenase signalling pathway.

PMID- 10341839
TI  - Cellular adhesion molecules on vascular smooth muscle cells.
AB  - Several studies during the last years have shown that, in addition to endothelial
      cells, vascular smooth muscle cells also express the cellular adhesion molecules
      ICAM-1 and VCAM-1 in atherosclerosis, restenosis and transplant vasculopathy. In
      vitro studies have characterized stimulatory and inhibitory factors that regulate
      the expression of ICAM-1 and VCAM-1 on cultured smooth muscle cells. There is
      evidence for a role of adhesion molecules on smooth muscle cells for leukocyte
      accumulation and activation of mononuclear cells. Some recent data suggest that
      the expression of adhesion molecules on smooth muscle cells are cell cycle
      dependent and influence smooth muscle cell proliferation and differentiation.
      Therefore, ICAM-1 and VCAM-1 on smooth muscle cells may contribute to the
      inflammatory reaction in the vascular wall and may actively be involved in the
      progression and stability of atherosclerotic plaques.

PMID- 10341840
TI  - Strategies to achieve coronary arterial plaque stabilization.
AB  - Acute coronary syndromes result from fissure, erosion or rupture of a vulnerable
      atherosclerotic plaque. The characteristics of a vulnerable plaque include a
      large lipid pool, an abundance of inflammatory cells and mediators, a reduced
      smooth muscle cell and collagen content and a thin overlying fibrous cap.
      Potential therapeutic strategies at achieving plaque stabilization have targeted
      these features. Lipid lowering agents, beta-adrenergic blockers, angiotensin
      converting enzyme inhibitors and antioxidants have been shown to reduce the
      incidence of acute coronary syndromes, presumably through plaque stabilization.
      Matrix metalloproteinase inhibitors as well as macrolide antibiotics and gene
      therapy approaches show promise in achieving plaque stabilization. The evidence
      supporting plaque stabilization by these agents and the mechanisms by which these
      agents stabilize plaques are discussed in detail in this review.

PMID- 10341841
TI  - Prevention of activation of blood coagulation during acute coronary ischemic
      syndromes: beyond aspirin and heparin.
AB  - Many of the acute coronary ischemic syndromes are triggered by spontaneous or
      mechanical disruption of atherosclerotic plaques with resultant activation of
      platelets and coagulation. Given the central role of platelets and thrombin in
      arterial thrombosis, current strategies for its prevention and treatment focus on
      both inhibition of platelet aggregation and control of thrombin generation and
      activity. Although aspirin and unfractionated heparin are the cornerstones of
      current treatment strategies, both have limitations. This review will describe
      these limitations and discuss new antithrombotic agents developed for use in
      acute coronary ischemic syndromes and as adjuncts for percutaneous coronary
      revascularization procedures.

PMID- 10341842
TI  - Stents covered by an autologous arterial graft in porcine coronary arteries:
      feasibility, vascular injury and effect on neointimal hyperplasia.
AB  - OBJECTIVE: The use of stents has improved results after balloon coronary
      angioplasty. Several materials have been proposed for covering the metallic
      surface of the stent to reduce the rate of subacute thrombosis and restenosis. In
      our institution, an autologous arterial graft was used for covering the external
      surface of a conventional stent. The angiographic and histological response in a
      porcine coronary artery model was investigated. METHODS: An autologous arterial
      graft was removed from the femoral artery and carefully prepared. Subsequently, a
      conventional stent was covered externally by the arterial graft. Twenty-two
      covered stents and 22 uncovered regular stents were implanted alternatively in
      the coronary arteries of 22 pigs. One animal died immediately after the
      procedure, due to thrombus formation in the uncovered stent. Six animals were
      sacrificed at seven days and the remaining animals were sacrificed at two months.
      Before the sacrifice, coronary angiography was performed in all animals. RESULTS:
      Thrombosis was detected in two control segments and in one covered stented
      segment. After seven days, the luminal surface of the covered stents was covered
      by a new endothelial layer in contrast to partial endothelial cell appearance in
      the control group. The angiographic parameters were similar between the two
      groups. Histologically, the covered stents were associated with less vascular
      injury compared to uncovered stents. In covered stents a trend towards reduction
      of maximal intimal hyperplasia was detected (covered: 116.6 +/- 47.75 vs
      uncovered: 150.25 +/- 46.81 microns, p = 0.08); also the thickness of the
      arterial media was reduced (covered: 21.34 +/- 10.28 vs uncovered: 102.63 +/-
      18.71 microns, p = 0.02). The luminal and vessel areas were similar in the two
      groups. CONCLUSIONS: The preparation and implantation of the autologous arterial
      graft-covered stent is technically safe and feasible. This type of covered stent
      results in accelerated endothelialization, less vascular injury, thinning of the
      arterial media and a trend to reduce the intimal hyperplasia in normal coronary
      arteries.

PMID- 10341843
TI  - Leucocyte recruitment in rupture prone regions of lipid-rich plaques: a prominent
      role for neovascularization?
AB  - OBJECTIVE: Microvessels in atherosclerotic plaques provide an alternative pathway
      for the recruitment of leucocytes in the lesions. The present study was designed
      to investigate the potential role of these microvessels in creating vulnerable
      sites in atherosclerotic plaques. METHODS: Thirty-four atherosclerotic plaques
      were obtained from 25 patients undergoing carotid endartherectomy (n = 16),
      femoral endartherectomy (n = 6) and aortic surgery (n = 12). Plaques were
      histologically classified as either lipid-rich (rupture prone, n = 21) or fibrous
      (stable, n = 13). Serial cryostat sections were immunohistochemically
      investigated using monoclonal antibodies against endothelial cells (ULEX-E and F
      VIII), vascular endothelial growth factor (VEGF), endothelial adhesion molecules
      (ICAM-1, VCAM-1, E-Selectin, CD40) and inflammatory cells (macrophages (CD68) and
      T lymphocytes (CD3). RESULTS: The microvessel density in lipid-rich plaques was
      significantly increased as compared to fibrous plaques. Most of these vessels
      were located in the shoulder-region of the plaque and at the base of the
      atheroma. Microvessels in lipid-rich plaques also expressed increased levels of
      ICAM-1, VCAM-1, E-Selectin and CD40. Moreover, inflammation was most abundantly
      present in the proximity of microvessels. VEGF was only observed on vessels and
      mononuclear cells in lipid-rich plaques, suggesting that this factor may play a
      role in microvessels formation. CONCLUSIONS: Neovascularisation and expression of
      adhesion molecules by microvessels at sites of vulnerable lipid-rich plaques may
      sustain the influx of inflammatory cells and hence, could contribute to plaque
      destabilization.

PMID- 10341844
TI  - Collagen-platelet interaction: Gly-Pro-Hyp is uniquely specific for platelet Gp
      VI and mediates platelet activation by collagen.
AB  - OBJECTIVE: Peptides consisting of a repeat Gly-Pro-Hyp sequence are potent
      platelet agonists. The aim of this study was: (1) to examine the specificity of
      this sequence for platelet activation; (2) to confirm its recognition by platelet
      glycoprotein VI; and (3) to assess with suitable peptides the relative importance
      of glycoprotein VI and integrin alpha 2 beta 1 in platelet activation by
      collagen. METHODS: Peptides were synthesized by standard Fmoc chemistry and
      tested for their ability to support adhesion of human platelets and HT 1080
      cells, induce platelet aggregation, bind integrin alpha 2 subunit A-domain and to
      cause tyrosine phosphorylation of platelet proteins. RESULTS: (1) Peptides
      consisting of a repeat Gly-Pro-Pro, Gly-Pro-Ala or Gly-Pro-Arg sequence exhibited
      little if any platelet-reactivity. (2) The platelet-reactive peptide consisting
      of a repeating Gly-Pro-Hyp sequence failed to induce tyrosine phosphorylation in
      glycoprotein VI-deficient platelets. Platelet adhesion to this peptide was
      inhibited by intact anti-glycoprotein VI antibody and its Fab fragment. The
      latter inhibited aggregation by the peptide and fibres of both collagens I and
      III. (3) A peptide containing a 15-mer alpha 2 beta 1-binding sequence in a
      repeat Gly-Pro-Pro structure supported alpha 2 beta 1-mediated platelet and HT
      1080 cell adhesion and bound alpha 2 A-domain, but failed to activate platelets
      or to induce tyrosine phosphorylation. Conversely, a peptide containing this
      sequence but with an essential Glu replaced by Ala and inserted in a repeat Gly
      Pro-Hyp structure did not recognize alpha 2 beta 1, but was highly platelet
      activatory. CONCLUSIONS: Platelet activation by collagen involves the highly
      specific recognition of the Gly-Pro-Hyp sequence by platelet glycoprotein VI.
      Recognition of alpha 2 beta 1 is insufficient to cause activation. Interaction
      between collagen and glycoprotein VI is unique since Gly-Pro-Hyp is common in
      collagens but occurs rarely in other proteins, and glycoprotein VI may be
      expressed solely by platelets. This sequence could provide a basis for a highly
      specific anti-thrombotic reagent to control thrombosis associated with plaque
      rupture.

PMID- 10341845
TI  - Angioscopic complex lesions are predominantly compensatory enlarged: an
      angioscopy and intracoronary ultrasound study.
AB  - OBJECTIVES: Atherosclerotic remodeling of the coronary artery may lead to
      compensatory enlargement or to shrinkage. Post-mortem data suggest a relation
      between compensatory enlargement and histopathological markers of plaque
      vulnerability. In patients that required a coronary intervention, we investigated
      retrospectively the relation between the angioscopic appearance and the
      remodeling mode of the culprit lesion. METHODS: In 34 patients, coronary
      angioscopy and intracoronary ultrasound (ICUS) imaging was performed across the
      culprit lesion before the intervention. Only single de novo lesions were
      included. With angioscopy, lesions with a smooth surface without thrombus were
      classified as smooth, whereas lesions with an irregular surface with or without
      thrombus were classified as complex. With ICUS, remodeling of the culprit lesions
      was determined by the relative cross-sectional vessel area (lesion vessel
      area/reference vessel area) x 100%. Lesions were divided into three groups:
      compensatory enlargement (relative vessel area > or = 105%), no-remodeling
      (relative vessel area between 95 and 105%) and shrinkage (relative vessel area <
      or = 95%). RESULTS: In 22 patients good images were obtained with both imaging
      modalities. More complex lesions were compensatory enlarged compared to shrunken
      lesions, whereas more smooth lesions were shrunken compared to compensatory
      enlarged lesions, 8/9 versus 2/7 and 5/7 versus 1/9, respectively (p = 0.035).
      CONCLUSIONS: In patients selected for coronary intervention, angioscopic complex
      atherosclerotic lesions were found predominantly in compensatory enlarged
      arterial segments, whereas smooth lesions were found predominantly in shrunken
      arterial segments.

PMID- 10341846
TI  - Expression of inducible nitric oxide synthase in human coronary atherosclerotic
      plaque.
AB  - OBJECTIVE: Macrophages in atherosclerotic plaque may express the inducible
      isoform of NO synthase (iNOS), which produces large amounts of NO. On one hand,
      the production of NO can be protective by its vasodilatory, antiaggregant and
      antiproliferative effects. On the other hand, the formation of peroxynitrite from
      NO may favour vasospasm and thrombogenesis. In this study, we investigated
      whether iNOS is present in human coronary atherosclerotic plaque, and we
      correlated these data with the clinical instability of the patients. METHODS:
      Fragments were retrieved by coronary atherectomy from 24 patients with unstable
      angina and 12 patients with stable angina. The presence of macrophages, and the
      production of TNF alpha, iNOS and nitrotyrosine were detected by
      immunocytochemistry. RESULTS: Macrophage clusters were found in 67% of stable
      patients and 87% of patients with unstable angina (NS). TNF alpha was expressed
      in about 50% of cases in both groups. iNOS was not expressed in fragments from
      stable patients but was found in macrophages from 58% of unstable patients (P <
      0.001). The expression of iNOS was associated with the presence of nitrotyrosine
      residues, a marker of peroxynitrite formation. Expression of iNOS was correlated
      both with complaints of angina at rest (P < 0.05) and with the presence of
      thrombus at morphological examination (P < 0.001). CONCLUSION: The expression of
      iNOS may be induced in human coronary atherosclerotic plaque and is associated
      with different factors of instability.

PMID- 10341847
TI  - Biphasic pattern of cell turnover characterizes the progression from fatty
      streaks to ruptured human atherosclerotic plaques.
AB  - OBJECTIVE: To study the amount and phenotype of DNA-synthesizing and apoptotic
      cells during atherogenesis. METHODS: Atherosclerotic lesions (n = 76), obtained
      at autopsy (N = 6) or during vascular surgery (N = 8), were classified [type I
      VI; American Heart Association (AHA) classification], immunolabeled with MIB 1 or
      the TUNEL technique and double stained with cell-type-specific antibodies.
      Subsequently, the labeled fractions were quantified. RESULTS: In type II-VI
      lesions, intimal DNA synthesis was increased compared to that of the non-diseased
      (ND) arterial wall. DNA synthesis peaked in early type II lesions (2.7 +/- 0.5
      vs. 0.02 +/- 0.02% in ND; p < 0.05), and declined to 0.7 +/- 0.2% in type V
      lesions (p < 0.05). Interestingly, a second peak of DNA synthesis of 1.7 +/-
      0.1%, was observed in type VI (ruptured plaque) lesions. Double staining revealed
      that DNA synthesis was mostly confined to the macrophage-derived foam cell
      (51.9%). In type II lesions, 100.0% of all DNA-synthesizing cells were present in
      the intimal foam cell-rich area, while in advanced type III, IV and V lesions,
      DNA synthesis had shifted to the shoulder region (74.8, 78.5 and 68.1%,
      respectively). In type VI lesions, DNA synthesis was present in the area
      underlying the plaque rupture (52.7%). Apoptosis was only elevated in advanced
      type IV, V and VI lesions (0.8 +/- 0.1, 0.8 +/- 0.1 and 1.1 +/- 0.1%,
      respectively, vs. 0.0 +/- 0.0% in ND) and was predominant in the lipid core
      (90.5% in type IV lesions; 54.2% in type V lesions) or equally divided between
      the lipid core and the region underlying the plaque rupture (31.8 and 34.6% in
      type VI lesions). In type III-VI lesions, 50.0, 38.9, 42.6 and 42.8% of the TUNEL
      positive cells were macrophages. CONCLUSIONS: In stable atherosclerotic lesions,
      DNA synthesis is an early event, while apoptosis is a late event. Ruptured
      plaques show a second peak of cell turnover. Lastly, cell turnover is mostly
      confined to the macrophage-derived foam cell.

PMID- 10341848
TI  - Role of smooth muscle cell death in advanced coronary primary lesions:
      implications for plaque instability.
AB  - OBJECTIVE: Instability of coronary atheroma leads to the onset of acute coronary
      syndromes including myocardial infarction and death, as well as to the
      progression of the arteriosclerotic disease. As yet, the underlying factors and
      mechanisms causing plaque rupture are not completely understood. Since a low
      content of smooth muscle cells (SMCs) apparently plays a key role, the question
      points to the events leading to the loss of intimal SMCs. METHODS: We compared
      coronary atherectomy specimens from 25 patients with unstable angina to those
      from 25 patients with stable angina. Transmission electron microscopy was used to
      identify intimal cell population, to detect stage and cell type of apoptosis, and
      to differentiate between apoptosis and necrosis. RESULTS: Plaques associated with
      unstable angina contained more macrophages/lymphocytes and significantly less
      SMCs (P = 0.01), compared with stable angina plaques. Specific cell death forms,
      apoptosis and necrosis, were present in all coronary atheroma. As key findings,
      both the proportion of SMCs undergoing apoptosis and the frequency of cytoplasmic
      remnants of apoptotic SMCs (matrix vesicles) were significantly increased in
      unstable versus stable angina lesions (P = 0.002 and P = 0.002). In addition,
      cellular necrosis was more frequent in the first coronary atheroma group (P =
      0.02). Positive correlations were found between the frequency of apoptotic cells
      and necrosis (r = 0.41, P = 0.04), and that of matrix vesicles and necrosis (r =
      0.63, P = 0.001) only in plaques with unstable angina, but not in those with
      stable angina. CONCLUSIONS: Our data demonstrate that high cell death due to
      apoptosis and necrosis is a basic in situ feature found in advanced coronary
      primary lesions associated with unstable angina, possibly explaining their low
      density of (viable) SMCs. Thus, antagonization of intimal cell death should be
      considered in order to stabilize the intimal plaque texture of coronary atheroma
      with the ultimate goal to prevent plaque rupture.

PMID- 10341849
TI  - Evidence for 12-lipoxygenase induction in the vessel wall following balloon
      injury.
AB  - OBJECTIVE: Vascular smooth muscle cell (VSMC) migration and proliferation are key
      events in the development of atherosclerosis and restenosis following
      angioplasty. These events are mediated by several growth factors and cytokines
      whose cellular effects include activation of phospholipases and arachidonic acid
      metabolism via the lipoxygenase (LO) pathway. Since 12-LO products have potent
      growth and chemotactic effects, we have examined if 12-LO is upregulated in the
      neointima of injured rat carotid arteries and also if LO inhibition could
      attenuate neointimal thickening. METHODS: The left common carotid arteries of
      male Sprague Dawley rats were injured using a 1.8 F PTCA balloon catheter. Four
      fourteen days after injury, injured and uninjured tissue samples were processed
      for histology, and immunohistochemistry or polymerase chain reaction (PCR) to
      examine 12-LO expression. RESULTS: Twelve days after injury, immunohistochemical
      staining with a 12-LO antibody revealed intense staining in injured left carotid
      arteries, mainly in neointimal VSMCs and inflammatory cells, but not in the
      uninjured right arteries. There was also a marked upregulation of 12-LO mRNA
      (over five-fold by competitive PCR) in the injured arteries. Treatment of the
      arteries with a LO inhibitor, phenidone, soon after injury resulted in
      significant inhibition of neointimal thickening. In contrast, a cyclooxygenase
      inhibitor, ibuprofen, had no effect. CONCLUSIONS: These results indicate for the
      first time that balloon injury results in marked induction of 12-LO mRNA and
      protein expression in the vessel wall. Furthermore, LO pathway activation may
      mediate, at least in part, the development of the lesion or plaque instability,
      suggesting a novel target for therapeutic intervention to block these
      pathological events.

PMID- 10341850
TI  - Cardiovascular disease and risk factors in adults with hypopituitarism.

PMID- 10341851
TI  - Y-chromosome mosaicism in girls with Turner's syndrome.

PMID- 10341853
TI  - Recent primary transnasal surgical outcomes associated with intraoperative growth
      hormone measurement in acromegaly.
AB  - OBJECTIVE: Since 1983, we have measured GH intraoperatively to improve the
      surgical outcome for acromegalic patients with GH secreting pituitary adenomas.
      Here, we present the recent results of primary surgery in patients with
      acromegaly to examine the effect of improved surgical techniques and experience.
      PATIENTS AND MEASUREMENT: Intraoperative GH concentrations were measured in 78
      consecutive acromegalic patients who had not previously undergone surgery between
      May 1992 and April 1994 (45 females and 33 males, age range, 21-70 years, mean,
      47.1 +/- 1.3). All patients were followed for at least 3 years. Direct transnasal
      tumour extirpation was performed. Intraoperative GH measurements were assayed 0,
      20 and 60 min after tumour removal. A plasma GH level < or = 4.5 micrograms/l at
      60 min after initial tumour removal was used as a criterion of radical tumour
      removal. In cases with intraoperative plasma GH concentrations > or = 40
      micrograms/l prior to tumour resection, the half-life of the GH concentration at
      20 min was used to assess completeness of tumour removal. In these cases, it was
      defined as having achieved a 50% reduction in plasma GH at 20 min compared to 0
      min after tumour resection. To obtain intraoperative GH measurements, mild
      anaesthesia was continued for an average of 82 +/- 23 min. RESULTS: Radical
      tumour removal was determined intraoperatively in 51 patients and subsequently
      confirmed in 50 patients (98.0%). In 18 of 27 patients with incomplete tumour
      removal, immediate reoperation was performed under continous anaesthesia. In 11
      of these 18 patients, endocrinological remission was achieved (14.1%; 11/78).
      None of the remaining nine patients who did not undergo secondary surgery
      achieved remission. Secondary surgery improved the remission rate from 85.7%
      (12/14) to 92.9% (13/14) in microadenomas and from 70.1% (38/54) to 88.9% (48/54)
      in non-invasive macroadenomas. Remission was not observed in patients with
      imageproven extrasellar extension. CONCLUSIONS: Secondary surgery based on
      intraoperative GH measurement improves the outcome of tumour resection in
      patients with non-invasive GH secreting macroadenomas.

PMID- 10341852
TI  - Y-chromosome identification by PCR and gonadal histopathology in Turner's
      syndrome without overt Y-mosaicism.
AB  - OBJECTIVE: The frequency of gonadoblastoma is high in patients with Turner's
      syndrome bearing cells with Y or partial Y-chromosome. About 60% of patients with
      Turner's syndrome have a 45,X karyotype. In 30% of them a Y-sequence is disclosed
      by DNA analysis. To identify patients at risk of developing gonadoblastoma, a PCR
      based assay with SRY, ZFY and DYZ3 specific primers was carried out to detect
      different Y-sequences in the DNA of peripheral lymphocytes from patients with
      Turner's syndrome. DESIGN AND PATIENTS: Peripheral blood karyotypes from 36
      patients with Turner's syndrome were studied. Patients with proven Y-chromosomal
      material were excluded. Genomic DNA was extracted from peripheral blood. SRY and
      ZFY genes and DYZ3 repetion of Y-chromosome were amplified by PCR. Patients with
      clinical signs of hyperandrogenism or with positive Y-sequences by PCR underwent
      gonadectomy. The gonadal tissues were examined for Y-sequences using PCR,
      morphology and immunohistochemical study. MEASUREMENTS: Turner's syndrome and
      signs of hyperandrogenism were evaluated both clinically and through laboratory
      tests. Haematoxylin and eosin staining was employed in gonadal morphology
      studies. The presence of testosterone was detected by immunohistochemistry using
      a monoclonal antibody. RESULTS: Two patients who had Y-positive blood samples and
      three hyperandrogenic (2 hirsutes, 1 virilized) Y-negatives underwent
      gonadectomy. PCR was carried out on their gonadal tissue. The tissue from the two
      patients without hyperandrogenism was Y-positive. The gonadal tissue from the
      three hyperandrogenics was Y-negative. Gonadal morphology disclosed hilus cell
      hyperplasia in the 3 hyperandrogenic Y-negatives and in one Y-positive patient;
      stromal luteoma and hyperthecosis in the virilized patient, cystadenofibroma in
      one hirsute patient and gonadoblastoma in one Y-positive. Testosterone was
      detected immunohistochemically in the hilus cell hyperplasia, stromal luteoma and
      hyperthecosis found in the hyperandrogenic patients. CONCLUSIONS: The molecular
      study was sensitive and useful in the evaluation of patients at risk of
      developing gonadoblastoma. Other nontumour, gonadotrophin-dependent and Y
      independent mechanisms which deserve the same medical approach may be involved in
      the genesis of hyperandrogenic signs in Turner's syndrome.

PMID- 10341855
TI  - A low individualized GH dose in young patients with childhood onset GH deficiency
      normalized serum IGF-I without significant deterioration in glucose tolerance.
AB  - OBJECTIVE: Many GH deficient (GHD) patients have impaired glucose tolerance and
      GH substitution in these patients has caused deleterious effects on glucose
      tolerance with hyperinsulinaemia. This further impairment of glucose tolerance
      might be due to an unphysiologically high dose of GH. Whether such a
      deterioration can be avoided by an optimal GH replacement dose is not known. In
      most previous studies, the GH dose was calculated according to body weight or
      body surface area and not adjusted according to the serum IGF-I response. DESIGN:
      The study was of open design and investigations were performed before the start
      of GH substitution and after nine months of treatment. The GH dose was adjusted
      according to the response in serum IGF-I, and in patients with sub-normal serum
      IGF-I levels (all but two) we aimed for a serum IGF-I level in the middle of the
      normal range. The median GH dose at the end of the study was 0.14 IU/kg/week.
      PATIENTS: Ten patients, eight males and two females, with childhood onset GHD
      were examined. Their median age was 27 years (range 21-28). MEASUREMENTS:
      Overnight and 24-h fasting levels of glucose, insulin and IGFBP-1 were measured.
      Directly after the 24-h fast an oral glucose tolerance test (OGTT), with
      measurements of glucose, insulin and IGFBP-1 was performed. An intravenous
      glucose tolerance test (IVGTT) was performed after overnight fasting. Body
      composition was measured with bio-impedance analysis (BIA) and quality of life
      was assessed using a self-rating questionnaire, Qol-AGHDA. RESULTS: After GH
      treatment, there were no significant changes in glucose tolerance, measured by
      overnight and 24-h fasting levels of glucose, insulin and IGFBP-1, an oral
      glucose tolerance test (after 24-h fasting) and an intravenous glucose tolerance
      test (after overnight fasting). Percentage fat mass and BMI correlated negatively
      with both the 24 h fasting IGFBP-1 levels and the IGFBP-1 responses after the
      OGTT. All patients decreased their percentage of fat mass measured by BIA [median
      -2.9%; range -1.0-(-6.6); P = 0.005]. The administered GH dose correlated
      negatively with the relative change in whole body resistance (r = -0.66; P =
      0.04). All, but one of the patients improved their quality of life score after GH
      therapy. CONCLUSIONS: In a group of young patients with childhood onset GH
      deficiency, 9 months of treatment with a low GH dose (median 0.14 IU/kg/week)
      caused no significant deterioration of glucose tolerance. The strong negative
      associations between BMI or percentage fat mass and IGFBP-1 suggest that serum
      IGFBP-1 is more closely related than insulin to body composition in GH deficient
      patients. It is important to consider which critical endpoints should determine
      the GH dose. We would suggest that, apart for normalizing the serum IGF-I level,
      another main endpoint should be normalization of, or at least avoidance of any
      deterioration in glucose tolerance.

PMID- 10341854
TI  - The effects of interleukin-2 treatment on endothelin and the activation of the
      hypothalamic-pituitary-adrenal axis.
AB  - OBJECTIVE: Recent reports suggest that complex interactions exist between the
      neuroendocrine and immune systems. It has been shown for example that cytokines
      are able to stimulate the hypothalamo-pituitary-adrenal axis. In addition, some
      studies present evidence that endothelin is able to modulate the activity of
      several hypothalamic-pituitary axes, e.g. by inducing the ACTH production.
      DESIGN: We investigated the effects of interleukin-2 on endothelin levels and the
      hypothalamo-pituitary-adrenal axis. We determined the interleukin-6, big
      endothelin, endothelin-1, ACTH, cortisol and AVP responses to intravenously and
      subcutaneously administered interleukin-2 in 8 cancer patients in a randomized
      placebo controlled trial. PATIENTS: 8 Patients (2 female and 6 male), age 44 +/-
      4.8 years, were enrolled. All patients had a World Health Organization
      performance status of 1 or less and a Karnofsky Index of at least 80%.
      MEASUREMENTS: Blood-samples were taken before and 15, 30, 45, 60, 120, 180, 240,
      300 and 360 min after interleukin-2 injection. Cytokine serum levels and the
      plasma levels of big-endothelin, endothelin, ACTH and AVP were analysed using
      radioimmuno-assays. Cortisol was assayed by an enzyme-linked immunosorbent assay.
      RESULTS: Interleukin-2 treatment significantly increased plasma big-endothelin
      levels (P < 0.01 vs basal) and endothelin-1 levels (P < 0.05 vs basal) within two
      hours and this was followed by an increase in ACTH (P < 0.01 vs basal) and
      cortisol (P < 0.05 vs basal) within three hours. Interleukin-6 levels increased
      two hours after interleukin-2 administration (P < 0.01 vs basal). Interleukin-2
      had no detectable effect on AVP, blood pressure or heart rate. CONCLUSIONS: Our
      data demonstrate that cytokines are able to activate the human hypothalamo
      pituitary-adrenal axis in vivo. On the basis of the observed time kinetics and in
      connection with previous findings from in vitro and animal models, we conclude
      that endothelin may be a link between cytokines and corticotrophin-releasing
      hormone, most probably functioning as a cytokine-induced neuromodulator
      controlling pituitary functions.

PMID- 10341856
TI  - Experience with transdermal testosterone replacement therapy for hypogonadal men.
AB  - BACKGROUND: None of the existing options for long-term testosterone replacement
      therapy (TRT) for hypogonadal men are ideal. Depot replacement at frequent
      intervals and implants are effective but invasive and inconvenient for the
      patient. Oral therapy results in poor hormone levels. Both are associated with
      undesirable metabolic changes. A transdermal formulation therefore represents a
      potential therapeutic advance for testosterone replacement. OBJECTIVE: To carry
      out a clinical audit of the acceptability and efficacy as a treatment for
      hypogonadism of the first transdermal testosterone therapy available in the UK
      (Andropatch, SmithKline Beecham) compared with existing androgen replacement
      options. PATIENTS AND MEASUREMENTS: Serum testosterone and questionnaire data on
      treatment efficacy, side-effects, therapy preference, sexual dysfunction and
      partner's attitudes to therapy were obtained from 50 hypogonadal men prescribed
      long-term testosterone replacement. RESULTS: Eighty per cent of the men returned
      analysable questionnaires. Eighty-four per cent experienced adverse effects with
      transdermal therapy, most commonly dermatological problems; 22% of the sample
      elected to continue with transdermal therapy, 72% returned to depot and 5%
      returned to oral therapy. The reservoir patches were judged to be too large,
      uncomfortable, visually obtrusive and noisy. Testosterone levels were comparable
      to those obtained with depot replacement with the added advantage of a more
      physiological pharmacokinetic profile. Men taking oral preparations were
      consistently under-replaced. CONCLUSIONS: Adverse events were substantially
      higher than reported from clinical trials but in keeping with the spectrum of
      yellow card reports received by the Committee on Safety of Medicines. The
      pharmacokinetic advantages are thus largely outweighed by low patient
      acceptability. In its present form transdermal therapy remains an expensive
      option for those who cannot tolerate depot testosterone replacement.

PMID- 10341857
TI  - An in vivo study of the cortisol-cortisone shuttle in subcutaneous abdominal
      adipose tissue.
AB  - OBJECTIVE: Previous in vitro studies have demonstrated significant 11-beta
      hydroxysteroid dehydrogenase (11 beta-HSD) oxo-reductase activity in visceral,
      but not subcutaneous adipose stromal cells. We have conducted an in vivo study of
      the cortisol-cortisone shuttle in subcutaneous abdominal adipose tissue. DESIGN:
      We measured arteriovenous (A-V) differences in serum cortisol and cortisone
      across subcutaneous abdominal adipose tissue and forearm muscle in a
      heterogeneous group of subjects. PATIENTS: We studied 34 subjects (male:female =
      12:22), age median (interquartile range) 45 (19-65) years, body mass index 32.7
      (20.4-77.1) kg m-2, total body fat 34.4 (5.6-119.1) kg. MEASUREMENTS: Serum
      cortisol and cortisone were measured in serum samples from a radial artery,
      superficial epigastric vein and deep forearm vein. Abdominal adipose and forearm
      blood flow rates were measured by 133Xenon washout and plethysmography,
      respectively. RESULTS: For cortisone, there was significant (P < 0.001) clearance
      by adipose tissue, with an A-V difference of 4 (1-7) nmol/l. For cortisol there
      was a trend for arterial concentrations (203 (142-292) nmol/l) to be lower than
      venous (225 (152-263) nmol/l), but this was not significant. The adipose tissue
      cortisone clearance rate correlated with total body fat (r = 0.35, P = 0.05).
      CONCLUSIONS: We have demonstrated 11 beta-HSD oxo-reductase activity in
      subcutaneous abdominal adipose tissue, which may be increased in obesity.

PMID- 10341858
TI  - Novel DAX1 mutations in X-linked adrenal hypoplasia congenita and
      hypogonadotrophic hypogonadism.
AB  - OBJECTIVE: Mutations of the DAX1 gene (Dosage-sensitive sex reversal-Adrenal
      hypoplasia congenita critical region on the X chromosome gene 1), which encodes a
      novel orphan nuclear receptor, have been identified in patients with X-linked
      adrenal hypoplasia congenita (AHC) and hypogonadotrophic hypogonadism (HHG). We
      have investigated two kindreds with AHC and HHG for DAX1 mutations. METHODS: Two
      kindreds with five affected males, four carrier females and four unaffected males
      were investigated. The gonadotrophin deficiency in three of the boys was observed
      to be partial until mid-puberty. DAX1 mutations in the entire 1413 bp coding
      region were sought by DNA sequence analysis. RESULTS: Two DAX1 mutations,
      situated within exon 1, were detected. These consisted of an insertional mutation
      at codon 183 that led to a frameshift and a premature Stop at codon 184, and a
      missense mutation Leu278Pro that involved a highly conserved leucine residue
      within the proposed ligand binding domain. Co-segregation of these mutations with
      the disease in each family, and their absence from 107 alleles in 73 (39 males
      and 34 females) unrelated control individuals, was demonstrated by allele
      specific oligonucleotide hybridization (ASO) analysis for the insertional
      mutation, and by Ban I restriction endonuclease analysis for the missense
      mutation. CONCLUSIONS: Two novel DAX1 mutations have been detected in two
      families with adrenal hypoplasia and hypogonadotrophic hypogonadism. The finding
      of partial gonadotrophin deficiency in the affected males from these families is
      notable and an early recognition of such a possibility in a patient, which may be
      facilitated by DAX1 mutational analysis, may help to prevent the sequelae of
      delayed androgen replacement therapy.

PMID- 10341859
TI  - The effect of chronic hexarelin administration on the pituitary-adrenal axis and
      prolactin.
AB  - OBJECTIVE: With the development of growth hormone (GH) releasing agents and their
      use in human subjects, it is clear that these agents are not specific for GH
      release. More recent studies in humans have demonstrated acute increases in
      adrenocorticotrophic hormone (ACTH), cortisol and prolactin (PRL) after boluses
      of intravenous or subcutaneous GHRPs. The potential adverse effects of repeated
      episodes of transient hyperprolactinaemia and hypercortisolaemia during long-term
      therapy with growth hormone releasing peptides (GHRPs) and similar agents have
      raised concern. We have therefore assessed the impact of chronic hexarelin
      administration on the pituitary-adrenal axis and serum prolactin levels. DESIGN:
      Each subject received twice-daily subcutaneous hexarelin therapy (1.5
      micrograms/kg body weight) for 16 weeks. The ACTH, cortisol and PRL responses to
      the morning subcutaneous injection of hexarelin were assessed. Hexarelin was
      administered at time 0 and blood samples were taken at -10, 0, 10, 20, 30, 40,
      50, 60, 90, 120, 170 and 180 min. The ACTH and PRL responses were assessed at
      baseline and after 16 weeks of therapy. The cortisol response was assessed at
      baseline, 16 weeks and also 4 weeks after completion of hexarelin therapy. Basal
      levels of cortisol binding globulin (CBG), 24-h urinary free cortisol (UFC)
      estimations, thyroid stimulating hormone (TSH) and total thyroxine (TT4) were
      performed at baseline, weeks 16 and 20. RESULTS: The mean (+/- SEM) area under
      the cortisol curve (AUCCORT) at baseline, week 16 and week 20 were 1506 (+/- 77)
      nmol/l/h, 1222 (+/- 92) nmol/l/h and 1586 (+/- 58) nmol/l/h, respectively. There
      was a significant change in AUCCORT over the study period (P = 0.008). Compared
      with baseline, AUCCOPRT had decreased significantly (P < 0.05) after 16 weeks of
      hexarelin therapy. Four weeks after completion of hexarelin therapy, the AUCCORT
      increased significantly compared with AUCCORT at week 16 (P < 0.01) and was no
      longer significantly different from baseline values. There were no significant
      changes in UFC (P = 0.3), basal cortisol measurements (P = 0.19), area under the
      ACTH curve (AUCACTH) (P = 0.24) or CBG (P = 0.6) over the study period. The mean
      (+/- SEM) area under the PRL curve (AUCPRL) at the baseline and week 16 were 624
      (+/- 82) mU/l/h and 641 (+/- 83) mU/l/h, respectively. There was no significant
      change in AUCPRL over the study period (P = 0.35). CONCLUSION: The present study
      demonstrates clearly that in this hexarelin dosage regimen, over-stimulation of
      the pituitary adrenal axis and prolactin secretion do not occur. In fact the
      impact of chronic hexarelin therapy on the pituitary-adrenal axis, i.e. decreased
      AUCCORT, contradict the findings reported after acute hexarelin administration
      and cannot be explained by changes in CBG. The lack of change in UFC, however,
      suggests that these changes are unlikely to be of clinical significance although
      the underlying mechanism requires further study.

PMID- 10341860
TI  - High precursor level in maternal blood results from the alternate mode of
      proopiomelanocortin processing in human placenta.
AB  - OBJECTIVE: ACTH-producing non-pituitary tumours are often associated with altered
      precursor processing, particularly in the most aggressive ones. Since placental
      tissue is characterized by its ability to express the proopiomelanocortin (POMC)
      gene and rapid cellular proliferation, we examined whether intact POMC could be
      released physiologically during human gestation. SUBJECTS: One hundred and fifty
      six normal pregnant women, 12 with multiple pregnancies, and 23 non-pregnant
      controls. Twenty-eight women were studied in the immediate postpartum period.
      MEASUREMENTS: We measured plasma POMC levels with a specific immunoradiometric
      assay (IRMA) using a combination of antibodies directed against ACTH and beta
      endorphin. Results obtained with this first IRMA were confirmed in 22 subjects
      with a second assay using the same beta endorphin antibody and a more distal
      antibody directed against the N-terminal fragment of POMC. Reverse transcription
      PCR detected full length, pituitary-like, POMC mRNA in human placenta. RESULTS:
      Plasma POMC was undetectable (< 60 U/ml) in 23 normal subjects. In normal
      monofetal pregnancies, POMC became detectable in most women by the third month
      and then increased steadily until midgestation: 168 +/- 108 (U/ml; mean +/- SD)
      between 12 and 15 weeks, 190 +/- 103 between 16 and 19 weeks, 324 +/- 180 between
      20 and 23 weeks, 276 +/- 171 between 24 and 27 weeks, 292 +/- 177 between 28 and
      31 weeks, 290 +/- 235 between 32 and 35 weeks and 308 +/- 210 between 36 weeks
      and parturition. Plasma POMC was significantly higher in multiple pregnancies
      with very high levels in three triplet-bearing mothers: 671, 941, and 1731 U/ml
      at 31, 33 and 32 weeks, respectively. POMC levels felt quickly in post partum,
      becoming undetectable in five of 13 women on day 1, seven of eight on day 2 and
      five of six on day 3. Plasma POMC displayed no diurnal variation, was not
      suppressed by glucocorticoid administration and did not correlate with plasma
      ACTH or cortisol. In contrast, plasma POMC positively correlated with plasma CRH.
      CONCLUSIONS: Pregnancy is the only condition in which POMC is produced and
      released physiologically, similar in some respects to the ectopic ACTH syndrome.
      POMC is derived solely from the placenta, with no interference from maternal
      pituitary secretion, and is thus a new and specific placental marker.

PMID- 10341861
TI  - Recombinant interferon alpha (rIFN-alpha) does not potentiate the effect of
      iodine excess on the development of thyroid abnormalities in patients with HCV
      chronic active hepatitis.
AB  - OBJECTIVE: To determine whether the administration of pharmacological quantities
      of iodine during interferon-alpha (rIFN-alpha) treatment of chronic viral
      hepatitis B and C (HCV) would exacerbate the potential adverse effects of rIFN
      alpha on thyroid function. DESIGN: Thyroid function tests were carried out in 48
      euthyroid patients before and during rIFN-alpha therapy of HCV. Twenty-one of
      these patients were also treated with 10 drops saturated solution of potassium
      iodine (SSKI, approximately 350 mg iodine daily). Eight patients with HCV but not
      treated with rIFN-alpha received 10 drops SSKI. PATIENTS: All patients were
      enthyroid prior to rIFN-alpha therapy for HCV or iodine and thyroid function
      tests were similar in the three groups. MEASUREMENTS: Serum free T4, free T3, and
      TSH concentrations were measured prior to and at 30 and 60 days of rIFN-alpha
      therapy in the three groups of patients. The serum TSH response to TRH was
      assessed before rIFN-alpha therapy and on day 60. Thyroid peroxidase antibodies
      were measured before and during therapy. RESULTS: During the 2-month study
      period, similar small but significant decreases in serum FT4 and FT3 and
      compensatory small significant increases in TSH concentrations were observed in
      the patients treated with rIFN-alpha + iodine and iodine alone but not in the
      patients receiving rIFN-alpha alone. Abnormal thyroid function tests were
      observed more frequently in patients receiving rIFN-alpha + iodine and iodine
      alone compared to those receiving rIFN-alpha alone. CONCLUSIONS: Excess iodine
      administered to patients treated with rIFN-alpha induced small changes in thyroid
      function similar to those observed in patients treated with iodine alone. Thus,
      rIFN-alpha and iodine do not appear to be synergistic in the development of
      abnormal thyroid function tests over a 2-month treatment period.

PMID- 10341862
TI  - Serum vascular endothelial growth factor (VEGF) in the normal menstrual cycle:
      association with changes in ovarian and uterine Doppler blood flow.
AB  - OBJECTIVE: To investigate whether changes in circulating serum vascular
      endothelial growth factor (VEGF) concentrations during the menstrual cycle are
      associated with changes in blood flow within the ovaries and uterus. PATIENTS AND
      MEASUREMENTS: Serum VEGF concentrations were measured and pulsed and colour
      Doppler blood flow waveforms recorded within the ovarian stroma and uterine
      arteries during the early follicular, the immediate preovulatory and the mid
      luteal phases of the menstrual cycle of 14 healthy women. RESULTS: Mean (+/- SD)
      serum VEGF concentrations rose from 2.44 +/- 0.1 ng/ml in the early follicular
      phase to 3 +/- 0.8 ng/ml in the pre-ovulatory phase and to 4.4 +/- 0.9 ng/ml in
      the mid-luteal phase (P < 0.0001) of the menstrual cycle. Mean peak systolic
      blood flow velocity (PSV) and time-averaged maximum flow velocity (TAMXV) were
      higher within the ovarian stroma of the ovary bearing the dominant follicle and
      the uterine arteries in the pre-ovulatory and mid-luteal phase than in the same
      sites during the early follicular phase of the menstrual cycle. PSV rose
      significantly from the early follicular phase (11 +/- 6 cm/s) to 14 +/- 4 cm/s in
      the pre-ovulatory phase and further in the mid-luteal phase (26 +/- 7 cm/s, P =
      0.0001). Within the uterine arteries, mean PSV rose significantly from 28 +/- 9
      cm/s in the early follicular phase to 31 +/- 8 cm/s in the pre-ovulatory phase
      and further in the mid-luteal phase (44 +/- 11 cm/s, P < 0.005). Serum VEGF
      correlated with serum progesterone concentrations in the luteal phase (r = 0.85,
      P < 0.001), with serum oestradiol concentrations in the early follicular (r =
      0.67, P = 0.009), pre-ovulatory (r = 0.57, P = 0.03) and luteal phases (r = 0.68,
      P < 0.005) and with serum testosterone in the early follicular phase (r = 0.63, P
      = 0.01). CONCLUSIONS: Cyclical changes in serum vascular endothelial growth
      factor concentrations are associated with coincident changes in ovarian and
      uterine blood flow.

PMID- 10341864
TI  - Addison's disease in Africa--a teaching hospital experience.
AB  - OBJECTIVE: Addison's disease may present with diverse and non-specific clinical
      and biochemical features. Contentious issues include the appropriate criteria for
      the interpretation of the ACTH stimulation test and the necessary extent of
      investigation to identify a specific aetiology for the hypoadrenalism. The
      experience of Addison's disease at a South African teaching hospital was reviewed
      to (1) record the aetiology and spectrum of presentation, (2) examine the
      performance of the ACTH stimulation test and (3) determine the utility of adrenal
      CT scan and biopsy. METHODS: Retrospective study of patients admitted to a South
      African teaching hospital from 1980 to 1997 with a diagnosis of acute Addison's
      disease. PATIENTS AND MEASUREMENTS: Fifty patients presenting with acute
      Addison's disease were identified by a search of hospital records. Pretreatment
      biochemical and haematological parameters were recorded. The cortisol response at
      20 and 60 min to an intravenous injection of 250 micrograms synacthen (Cortrosyn)
      was analysed. In a subgroup of affected subjects, the bone mineral density (BMD)
      in the lumbar spine and femoral neck was measured during long-term follow-up.
      RESULTS: Presenting features included hyperpigmentation (86%), weight loss (67%),
      abdominal pain (20%) and diarrhoea (16%). Thirty-nine patients (78%) were
      hyponatraemic, while 26 (53%) were hyperkalaemic. Nine patients (18%) were
      hypoglycaemic and 21% had hypercalcaemia. The mean basal cortisol was 148 nmol/l
      (range 10-487) and 16 patients (40%) had a normal basal cortisol. The mean
      cortisol 20 min after ACTH stimulation was 172 nmol/l (range 19-588). There was
      no significant increase in serum cortisol following ACTH stimulation (P > 0.05).
      Adrenal CT scans were performed in only 24 patients (48%) and were normal in 10,
      while abnormalities were detected in 14 patients (bilateral enlargement in 11,
      calcification in two and atrophic adrenals in one). Eight patients had a DEXA
      scan performed during follow-up--four were osteopaenic in the lumbar spine and
      five at the femoral neck. The probable aetiology of Addison's was idiopathic in
      42%, related to active TB in 18%, old TB in 16%, autoimmune in 12% and malignancy
      with metastases in 6%--single cases were due to sarcoid, iron overload and
      adrenoleukodystrophy. Adrenal biopsy was performed in two patients and was
      diagnostic of malignancy in both cases. The mortality within the first month
      after hospitalization was 12%. CONCLUSIONS: In our experience, Addison's disease
      is frequently idiopathic, presents with protean manifestations and should be
      considered in patients with unexplained hyperpigmentation or gastrointestinal
      complaints, particularly when associated with hyponatraemia and hyperkalaemia. A
      normal basal cortisol does not exclude the diagnosis which requires ACTH
      stimulation testing.

PMID- 10341863
TI  - Urocortin expression in the human central nervous system.
AB  - OBJECTIVE AND STUDY DESIGN: Urocortin is a recently identified neuropeptide of
      the corticotrophin-releasing factor (CRF) family in the mammalian brain and has
      been demonstrated to stimulate ACTH secretion from pituitary cells, but its
      expression in human brain tissue including the hypothalamus has not been
      examined. In this study, we first examined urocortin expression in the
      hypothalamus (20 cases) and pituitary stalks (17 cases) of human brain obtained
      from autopsy using immunohistochemistry and mRNA in situ hybridization. RESULTS:
      Neither urocortin immunoreactivity nor mRNA hybridization signals were detected
      in the hypothalami and pituitary stalks while CRF immunoreactivity was detected
      in the paraventricular nuclei of the hypothalami in 10/20 cases and in nerve
      fibres of the stalks in 17/17 cases. These results indicate that urocortin does
      not act on the hypothalamo-pituitary-adrenal axis, at least not in the same
      manner as CRF in humans. We then examined urocortin expression in various
      portions of the brain in 7 cases. Both urocortin immunoreactivity and mRNA
      hybridization were detected in Purkinje cells of the cerebellum and anterior horn
      cells of the spinal cord in specimens examined. Urocortin expression was,
      however, variably seen in superior olivary nuclei (two out of six cases examined)
      and in the Edingar-Westphal nuclei (one out of three cases examined).
      CONCLUSIONS: The distribution of urocortin in the human central nervous system
      suggests that urocortin may work as a neurotransmitter like other neuropeptides
      in the human.

PMID- 10341865
TI  - Laparoscopic adrenalectomy for phaeochromocytoma: endocrinological and surgical
      aspects of a new therapeutic approach.
AB  - OBJECTIVES: To evaluate the results of laparoscopic resection of
      phaeochromocytoma with a focus on pre- and intra-operative endocrinological and
      pharmacological aspects. DESIGN: Retrospective study based on review of case
      notes and intraoperative anaesthetic records. PATIENTS: Eight patients (four men,
      four women) aged 13 to 70 (median: 45) years with symptomatic phaeochromocytoma
      (two patients with MEN IIa syndrome) diagnosed 6-36 months before adrenalectomy
      in four patients and just before operation in the four remaining patients. All
      patients presented with hypertension. MEASUREMENTS: Pre- and postoperative blood
      pressure (BP) was assessed using a sphygmomanometer, intraoperative measurements
      being obtained by intra-arterial line. Adrenaline (A), noradrenaline (NA),
      metadrenaline (metA), normetadrenaline (normetA) and vanillylmandelic acid (VMA)
      were measured in 24-h urine samples. Adrenal imagery consisted in all patients of
      abdominal computed tomography and [131I] metaiodobenzylguanidine (MIBG)
      scintigraphy, and in 2 patients, adrenal magnetic resonance imaging and
      octreotide scintigraphy. Determination of plasma volume was performed by isotopic
      method. RESULTS: Median (range) preoperative systolic and diastolic BP was 140
      (130-240) and 90 (80-150) mm Hg, respectively. Predominant catecholamine
      secretion consisted of A in four patients (A pattern) and of NA (NA pattern) in
      the other four. Tumours smaller than 30 mm usually secreted A while larger ones
      secreted NA. Pre- and intra-operative BP control was straightforward in all but
      two patients with preferential NA secretion. The median number of systolic and
      diastolic BP peaks were higher in patients with NA pattern (n = 6, range: 3-9)
      than in those with A pattern (n = 1.5, range: 1-6). Total duration of
      pneumoperitoneum ranged from 120 to 240 (median: 195) min. Intra- and post
      operative complications included intra-abdominal bleeding, laparoscopically
      controlled (in one case), and upper pole kidney ischaemia in another.
      Postoperative hospital stay ranged from 4 to 11 days. All patients were
      asymptomatic postoperatively and pharmacologically controlled hypertension
      persisted in two of them. CONCLUSIONS: Laparoscopic adrenalectomy is a safe and
      efficient technique to remove phaeochromocytoma in terms of intra- and
      postoperative morbidity, with a low complication rate. Pre- and intra-operative
      pharmacological blood pressure control is as effective as in conventional
      adrenalectomy, with greater instability in noradrenaline secreting tumours.

PMID- 10341866
TI  - Antithyroid drugs and Graves' disease--prospective randomized assessment of long
      term treatment.
AB  - OBJECTIVE: Although antithyroid drugs (ATD) are widely used in the treatment of
      Graves' disease, management protocols, especially treatment duration, remain a
      subject of debate. The rate of relapse after short-term regimens of less than 6
      months with ATD at decreasing doses is higher than after longer treatments from
      12 to 24 months. As no prospective study has provided data on even longer
      protocols exceeding 2 years, we conducted a prospective trial to determine
      potential benefits of a 42-month treatment compared with an 18-month treatment.
      DESIGN, PATIENTS AND MEASUREMENTS: The aim of this prospective randomized trial
      was to compare relapse rates achieved two years after treatment withdrawal in
      patients who received carbimazole at decreasing doses for 18 months (n = 62) vs
      42 months (n = 72). In addition to clinical relapse rate, the percentage of
      patients who normalized antithyroperoxidase (TPO) antibody and anti-TSH receptor
      stimulating antibody (TSAb) levels and early iodine uptake at the end of
      treatment were assessed as outcome criteria. RESULTS: The relapse rate two years
      after discontinuation of treatment did not differ significantly in patients
      treated for 18 months from those treated for 42 months (36% vs 29%, NS). At the
      end of treatment, there was no significant difference between the two groups in
      the percentage of anti-TPO positive patients (53% vs 46%, NS) or early iodine
      uptake (27% vs 21%, NS). Although the percentage of patients with TSAb was
      significantly lower in the 42-month treatment group (18% vs 42%, P = 0.004) at
      treatment withdrawal, the percentage of TSAb-positive patients did not
      significantly decrease between 18 and 42 months in this group (27% vs 18%, NS).
      CONCLUSION: Treatment duration greater than 18 months did not improve remission
      rate determined 2 years after treatment withdrawal or immunological variables or
      early iodine uptake measured at the time of discontinuation of treatment. These
      findings would indicate that, when a defined duration treatment is planned,
      prolonging treatment beyond 18 months does not provide any additional benefit.

PMID- 10341867
TI  - Rosai-Dorfman disease presenting as a pituitary tumour.
AB  - A 45-year-old woman had pyrexia, headaches, collapse and hyponatraemia.
      Intracerebral abscess, bacterial meningitis and subarachnoid haemorrhage were
      excluded. She was given intravenous antibiotics and gradually recovered. One
      month later she was readmitted with diplopia, headache and vomiting. Serum sodium
      was low (107 mmol/l) and a diagnosis of inappropriate ADH secretion was made. MRI
      scan showed a suprasellar tumour arising from the posterior pituitary gland. A
      skin rash gradually faded. Serum cortisol, prolactin, gonadotrophins and thyroid
      hormone levels were low. A pituitary tumour was removed trans-sphenoidally, she
      had external pituitary radiotherapy, and replacement hydrocortisone and
      thyroxine. She was well for 12 months when she developed progressive weakness and
      numbness of both legs. Examination suggested spinal cord compression at the level
      of T2 where MRI scanning showed an intradural enhancing mass. This spinal tumour
      was removed and her neurological symptoms disappeared. Nine months after this she
      developed facial pain and nasal obstruction. CT scan showed tumour growth into
      the sphenoid sinus and nasal cavities. A right Cauldwell-Luc operation was done
      and residual tumour in the nasal passages was treated by fractionated external
      radiotherapy and Prednisolone. Histological examination of the specimens from
      pituitary, spinal mass, and nasal sinuses showed Rosai-Dorfman disease, a rare
      entity characterized by histiocytic proliferation, emperipolesis
      (lymphophagocytosis) and lymphadenopathy. Aged 48 she developed cranial diabetes
      insipidus. Although Rosai-Dorfman syndrome is rare, it is being reported with
      increasing frequency, and should be borne in mind as a possible cause of a
      pituitary tumour.

PMID- 10341868
TI  - Targeted gene repair.

PMID- 10341869
TI  - Catch VP22: the hitch-hiker's ride to gene therapy?

PMID- 10341870
TI  - Efficient adventitial gene delivery to rabbit carotid artery with cationic
      polymer-plasmid complexes.
AB  - Different lipids and cationic polymers were tested in vitro for their ability to
      transfect rabbit aortic smooth muscle cells and human endothelial cells with lacZ
      marker gene. Toxicity of the complexes was evaluated with MTT assay. Selected
      plasmid-polymer complexes with different charge ratios were then tested for in
      vivo gene transfer efficiency using adventitial gene transfer by placing a
      silastic gene delivery reservoir (collar) around the carotid artery. Transfection
      efficiency was determined by X-gal staining 3 days after the gene transfer. Based
      on in vitro experiments, fractured polyamidoamine dendrimers and
      polyethylenimines (PEI) were selected for in vivo experiments. Fractured
      dendrimers (generation 6, +/- charge ratio of 3) had the highest in vivo gene
      transfer efficiency (4.4% +/- 1.7). PEI with molecular size of 25 kDa (+/- charge
      ratio 4) was also effective (2.8% +/- 1.8) in this model. PEI of 800 kDa showed a
      constant but modest gene transfer efficiency (1.8% +/- 0.1) with all charge
      ratios. A low level gene transfer was also detected with naked DNA (0.5% +/-
      0.3). No signs of inflammation were seen in any of the study groups. We show here
      that in vitro cell culture experiments can be used to identify efficient in vivo
      gene transfer methods for arterial gene therapy, but the charge ratios for each
      complex must be optimized in vivo. It is concluded that fractured dendrimer and
      PEI are efficient gene delivery vehicles and can be used for arterial gene
      therapy via adventitial gene delivery route.

PMID- 10341871
TI  - Intercellular delivery of thymidine kinase prodrug activating enzyme by the
      herpes simplex virus protein, VP22.
AB  - We demonstrate that fusion proteins consisting of the herpes simplex virus (HSV)
      transport protein VP22 linked in frame to HSV thymidine kinase (tk) retain the
      ability to be transported between cells. In vivo radiolabelling experiments and
      in vitro assays show that the fusion proteins also retain tk activity. When
      transfected COS cells, acting as a source of the VP22-tk chimera, were co-plated
      on to gap junction-negative neuroblastoma cells, ganciclovir treatment induced
      efficient cell death in the recipient neuroblastoma cell monolayer. No such
      effect was observed with COS cells transfected with tk alone. Tumours established
      in mice with neuroblastoma cell lines expressing VP22-tk regressed upon
      administration of ganciclovir. Furthermore tumours established from 50:50
      mixtures of VP22-tk transduced and nontransduced cells also regressed while no
      significant effect was observed in similar experiments with cells transduced with
      tk alone. VP22 mediated transport may thus have application in a clinical setting
      to amplify delivery of the target protein in enzyme-prodrug protocols.

PMID- 10341872
TI  - Failure of wild-type p53 gene therapy in human cancer cells expressing a mutant
      p53 protein.
AB  - The introduction of exogenous wild-type p53 into human cancer cells bearing p53
      mutation does not necessarily result in inhibition of tumor growth. We have
      demonstrated this in MDA-MB468 breast cancer cells which are hemizygous for p53
      mutation and also in KM12SM colorectal carcinoma cells which are heterozygous for
      p53 mutation. The wtp53 transfectants decreased three- to four-fold the number of
      colonies compared with controls. Most wtp53-expressing cells died by apoptosis at
      early passages, but some cells were able to form colonies and their proliferation
      rate was similar to control transfectants. This reversion was observed in three
      of the six MDA-MB-468 clones selected. When MDA-wtp53 transfectants were
      implanted orthotopically in nude mice only one clone showed prolonged tumor
      latency. No differences were found in either tumor proliferation or apoptosis in
      tumors. Integration and expression of exogenous wtp53 was assessed in early and
      late passages in vitro, and in tumors growing in vivo. Consistently, we found
      mutations in the exogenous wtp53 gene of MDA-MB468 transfectants. Excision of the
      exogenous gene was an alternative to abrogate the wtp53 function that was
      extremely efficient in KM12 cells, although they maintained resistance to
      geneticin. These results were corroborated by the functional assay in yeast. In
      conclusion, wtp53 is inactivated in these cancer cells by different mechanisms.
      The presence of mutated p53 may confer genome instability and mutator ability,
      which allows cells to escape the effects of the exogenous wtp53 and contributes
      to the failure of wtp53 gene therapy.

PMID- 10341873
TI  - Enhanced plasma cholesterol lowering effect of retrovirus-mediated LDL receptor
      gene transfer to WHHL rabbit liver after improved surgical technique and
      stimulation of hepatocyte proliferation by combined partial liver resection and
      thymidine kinase--ganciclovir treatment.
AB  - In this study we report an improved method for in vivo gene transfer to liver.
      Repeated injections of Moloney murine leukemia virus-derived retroviruses
      containing LDL receptor cDNA were given to the portal vein in combination with a
      10% partial liver resection and stimulation of hepatocyte proliferation by
      plasmid/liposome-mediated thymidine kinase gene transfer and ganciclovir
      treatment. The method was used for the treatment of LDL receptor deficiency in
      Watanabe heritable hyperlipidemic rabbits. We demonstrate an increase in
      hepatocyte proliferation index by thymidine kinase and ganciclovir treatment from
      0.9 to 1.35% and a maximum of 35% decrease in total plasma cholesterol level 2-3
      months after the gene transfer. A 20% decline was still present after a 52-week
      follow-up period. A 50% decrease was also observed in plasma triglycerides. Liver
      function tests indicated a transient increase in plasma alkaline phosphatase
      level up to 12 weeks after the gene transfer. In situ PCR and RT-PCR analyses
      indicated that the transgene was present in periportal areas and was transcribed
      to mRNA 1 week after the gene transfer. Because of the relatively simple and
      controllable technique we suggest that repeated retrovirus injections via a
      portal vein catheter together with the limited partial liver resection and
      plasmid/liposome-mediated thymidine kinase gene transfer-ganciclovir treatment
      may be used to improve the results of retrovirus-mediated liver gene therapy.

PMID- 10341874
TI  - BP180 gene delivery in junctional epidermolysis bullosa.
AB  - Epidermolysis bullosa (EB) comprises a family of inherited blistering skin
      diseases for which current therapy is only palliative. Junctional EB (JEB)
      involves dissociation of the dermal-epidermal junction and results from mutations
      in a number of genes that encode vital structural proteins, including BP180 (type
      XVII collagen/BPAG2). In order to develop a model of corrective gene delivery for
      JEB, we produced a retroviral expression vector for wild-type human BP180 and
      used it to restore BP180 protein expression to primary keratinocytes from BP180
      negative patients with generalized atrophic JEB. Restoration of full-length BP180
      protein expression was associated with adhesion parameter normalization of
      primary JEB keratinocytes in vitro. These cells were then used to regenerate
      human skin on immune-deficient mice. BP180 gene-transduced tissue demonstrated
      restoration of BP180 gene expression at the dermal-epidermal junction in vivo
      while untransduced regenerated JEB skin entirely lacked BP180 expression. These
      findings provide a basis for future efforts to achieve gene delivery in human EB
      skin tissue.

PMID- 10341875
TI  - Transplantation of transduced nonhuman primate CD34+ cells using a gibbon ape
      leukemia virus vector: restricted expression of the gibbon ape leukemia virus
      receptor to a subset of CD34+ cells.
AB  - The transduction efficiencies of immunoselected rhesus macaque (Macaca mulatta)
      CD34+ cells and colony-forming progenitor cells based on polymerase chain
      reaction (PCR) analysis were comparable for an amphotropic Moloney murine
      leukemia virus (MLV) retroviral vector and a retroviral vector derived from the
      gibbon ape leukemia virus (GaLV) packaging cell line, PG13. On performing
      autologous transplantation studies using immunoselected CD34+ cells transduced
      with the GaLV envelope (env) retroviral vector, less than 1% of peripheral blood
      (PB) contained provirus. This was true whether bone marrow (BM) or cytokine
      mobilized PB immunoselected CD34+ cells were reinfused. This level of marking was
      evident in two animals whose platelet counts never fell below 50,000/microliter
      and whose leukocyte counts had recovered by days 8 and 10 after having received
      1.7 x 10(7) or greater of cytokine-mobilized CD34+ PB cells/kg. Reverse
      transcriptase(RT)-PCR analysis of CD34+ subsets for both the GaLV and amphotropic
      receptor were performed. The expression of the GaLV receptor was determined to be
      restricted to CD34+ Thy-1+ cells, and both CD34+ CD38+ and CD34+ CD38dim cells,
      while the amphotropic receptor was present on all CD34+ cell subsets examined.
      Our findings suggest that, in rhesus macaques, PG13-derived retroviral vectors
      may only be able to transduce a subset of CD34+ cells as only CD34+ Thy-1+ cells
      express the GaLV receptor.

PMID- 10341876
TI  - Adenoviral vectors capable of replication improve the efficacy of HSVtk/GCV
      suicide gene therapy of cancer.
AB  - A major obstacle to the success of gene therapy strategies that directly target
      cancer cells is the poor vector distribution within solid tumors. To address this
      problem, we developed an E1b 55 kDa attenuated, replication-competent adenovirus
      (Ad.TKRC) which expresses the herpes simplex-1 thymidine kinase (HSVtk) gene to
      sensitize tumors to ganciclovir (GCV). Efficacy of this combined strategy was
      tested in nude mice with subcutaneous human A375 melanoma and ME180 cervical
      carcinomas. Intratumoral injection of a replication-defective adenoviral vector
      expressing HSVtk (Ad.TK) followed by GCV treatment resulted in doubling of the
      survival time of mice bearing A375 tumors and 20% long-term survival of mice with
      ME180 tumors. Treatment of tumors with Ad.TKRC without GCV resulted in a similar
      antitumor effect, confirming that the replicating vector has an oncolytic effect.
      When GCV was initiated 3 days after Ad.TKRC injection, survival of mice with each
      tumor type was greatly prolonged, with 60% of animals with ME180 tumors surviving
      for over 160 days. These results confirm that both the oncolysis caused by a
      replicating virus and suicide/prodrug gene therapy with HSVtk/GCV have potent
      antitumor effects. When combined, these two approaches are complementary
      resulting in a significantly improved treatment outcome.

PMID- 10341877
TI  - Human tumor cell modification by virus infection: an efficient and safe way to
      produce cancer vaccine with pleiotropic immune stimulatory properties when using
      Newcastle disease virus.
AB  - Direct infection of tumor cells with viruses transferring protective or
      therapeutic genes, a frequently used procedure for production of tumor vaccines
      in human gene therapy, is an approach which is often limited by the number of
      tumor cells that can reliably be infected as well as by issues of selectivity and
      safety. We report an efficient, selective and safe way of infecting human tumor
      cells with a natural virus with interesting pleiotropic immune stimulatory
      properties, the avian paramyxovirus Newcastle disease virus (NDV). Two of the six
      viral genes (HN and F) modify the tumor cell surface by introduction of new
      adhesion molecules for lymphocyte interactions and other viral genes stimulate
      host cell genes and local production of cytokines and chemokines which can
      recruit a broad antitumor response in vivo. A large variety of human tumor cells
      is shown to be efficiently infected by NDV with viral replication being
      independent of tumor cell proliferation. Such properties make NDV a suitable
      agent for modification of noncultured freshly isolated and gamma-irradiated
      patient-derived tumor cells. For the apathogenic non-lytic strain NDV-Ulster
      which is used in our clinical vaccine trials, we demonstrate selective
      replication in tumor cells as compared with corresponding normal cells.
      Furthermore, we present evidence that new virions produced by infected tumor
      cells are non-infectious using three different quantitative test methods. Our
      results demonstrate feasibility and broad applicability of this strategy of human
      tumor vaccine modification. Post-operative vaccination with the autologous virus
      modified vaccine ATV-NDV thus provides a reasonable potential for pleiotropic
      modifications of the immune response of cancer patients against their own tumor.

PMID- 10341878
TI  - rAAV vector-mediated sarcogylcan gene transfer in a hamster model for limb girdle
      muscular dystrophy.
AB  - The limb girdle muscular dystrophies (LGMD) are a genetically and phenotypically
      heterogeneous group of degenerative neuromuscular diseases. A subset of the
      genetically recessive forms of LGMD are caused by mutations in the four muscle
      sarcoglycan genes (alpha, beta, gamma and delta). The coding sequences of all
      known sarcoglycan genes are smaller than 2 kb, and thus can be readily packaged
      in recombinant adeno-associated virus (rAAV) vectors. Previously, we have
      demonstrated highly efficient and sustained transduction in mature muscle tissue
      of immunocompetent animals with rAAV vectors. In this report, we utilize
      recombinant AAV containing the delta-sarcoglycan gene for genetic complementation
      of muscle diseases using a delta-sarcoglycan-deficient hamster model (Bio 14.6).
      We show efficient delivery and widespread expression of delta-sarcoglycan after a
      single intramuscular injection. Importantly, rAAV vector containing the human
      delta-sarcoglycan cDNA restored secondary biochemical deficiencies, with correct
      localization of other sarcoglycan proteins to the muscle fiber membrane.
      Interestingly, restoration of alpha-, as well as beta-sarcoglycan was homogeneous
      and properly localized throughout transduced muscle, and appeared unaffected by
      dramatic overexpression of delta-sarcoglycan in the cytoplasm of some myofibers.
      These results support the feasibility of rAAV vector's application to treat LGMD
      by means of direct in vivo gene transfer.

PMID- 10341879
TI  - Effective and safe gene therapy for colorectal carcinoma using the cytosine
      deaminase gene directed by the carcinoembryonic antigen promoter.
AB  - We have recently isolated carcinoembryonic antigen (CEA) promoter regions
      consisting of 419 bp and 204 bp from CEA-producing human colorectal carcinoma
      (CRC). We constructed CEA419/CD and CEA204/CD retroviruses carrying the bacterial
      cytosine deaminase (CD) gene directed by the CEA promoter regions. pCD2
      retroviruses carrying the CD gene directed by the retrovirus long terminal repeat
      promoter were also used. CEA419/CD or CEA204/CD retrovirus-infected CRC cells
      were found to be susceptible to 5-fluorocytosine (5-FC), while non-CRC cells
      infected with the same retroviruses were not. CD-transduced CRC xenografts in
      nude mice were sensitive to 5-FC treatment, resulting in arrest of tumor growth.
      When mice with intraperitoneally disseminated CRCs were given intraperitoneal
      injections of CEA419/CD retrovirus-producing cells followed by 5-FC treatment,
      significantly prolonged survival rates were observed compared with animals
      injected with pCD2 retrovirus-producing cells followed by 5-FC treatment.
      Importantly, bone marrow suppression was not observed in animals injected with
      CEA419/CD retrovirus-producing cells and 5-FC, while profound bone marrow
      suppression was observed in those injected with pCD2 retrovirus-producing cells
      and 5-FC. These results indicate that effective and safe in vivo gene therapy for
      advanced CRC may be feasible by transferring the CD gene controlled by the CEA
      promoter followed by 5-FC treatment.

PMID- 10341881
TI  - Pulmonary inflammation associated with repeated, prenatal exposure to an E1, E3
      deleted adenoviral vector in sheep.
AB  - Fetal gene therapy may prove useful in treating diseases that manifest in the
      perinatal or early postnatal period. Adenoviruses effectively transfer gene
      expression to a variety of tissues but also stimulate inflammatory and immune
      responses. The purpose of this study was to test the hypothesis that exposure of
      fetal sheep to a first generation adenovirus vector encoding bacterial beta
      galactosidase, Av1nBg, before the development of the immune system, is safe,
      minimizes inflammatory and immune responses and induces tolerance. A total of 22
      fetal sheep was studied; of these, two were born with respiratory distress, seven
      were electively killed and 13 died in utero. The incidence of mortality was
      higher than the < or = 10% we have experienced with other fetal sheep studies and
      was not likely related to complications arising from surgical or anesthetic
      procedures. Inflammatory and fibrotic responses were observed in the lungs and
      may represent untoward long-term consequences of in utero adenoviral gene
      therapy. Tolerance to Av1nBg was not established, and repeated exposure to Av1nBg
      before birth was associated with significant pathology and mortality.

PMID- 10341880
TI  - Intratumoral injection of oligonucleotides to the NF kappa B binding site
      inhibits cachexia in a mouse tumor model.
AB  - Cancer cachexia, characterized by anorexia, weight loss and progressive tissue
      wasting, has been postulated to be mediated by various cytokines. However, the
      precise mechanism of cachexia induction is not fully explained. We have developed
      synthetic double-stranded oligodeoxynucleotides (ODN) as 'decoy' cis-elements
      that block the binding of nuclear factors to promoter regions of targeted genes,
      resulting in the inhibition of gene transactivation in vivo as well as in vitro.
      This novel molecular strategy could be useful for treating a broad range of human
      diseases including cancer. In this study, we injected decoy ODN targeting the
      transcriptional factor, NF-kappa B (NF kappa B) binding cis-elements, which are
      essential for transactivation of gene expression of cytokines, directly into
      tumors of adenocarcinoma colon26 in mice, in order to examine whether or not
      cachexia is alleviated by inhibiting the action of cytokines. Tumor growth was
      not affected by transfection of NF kappa B decoy ODN as compared with scrambled
      decoy ODN. Nevertheless, transfection of NF kappa B decoy, but not scrambled
      decoy, ODN resulted in attenuation of the reductions in body weight, epididymal
      fat, gastrocnemius muscle mass and food intake, which were induced by the tumor
      presence. Interleukin 6 mRNA in the tumor was also markedly decreased by the
      transfection of NF kappa B decoy ODN. It is known that the transcriptional factor
      E2F plays a pivotal role in the coordinated transactivation of cell cycle
      regulatory genes. Therefore, we hypothesized that the introduction of synthetic
      double-stranded DNA with high affinity for E2F in vivo as 'decoy' cis-elements
      might inhibit the tumor growth of colon26, resulting in turn in inhibition of
      cachexia induction. However, injection of E2F decoy ODN failed to inhibit tumor
      growth and cachexia induction, as compared with mismatched decoy ODN. Overall,
      the present study demonstrated that cachexia induced by adenocarcinoma colon26
      was inhibited by blocking of NF kappa B, using a novel molecular decoy strategy,
      without an effect on tumor growth, and also that tumor growth and cachexia
      induction in the colon26 model were not affected by E2F decoy ODN. These results
      suggest that cytokines regulated by NF kappa B may play a pivotal role in the
      induction of cachexia by colon26, providing a new therapeutic strategy for cancer
      cachexia.

PMID- 10341882
TI  - Autologous transplantation of retrovirally transduced bone marrow or neonatal
      blood cells into cats can lead to long-term engraftment in the absence of
      myeloablation.
AB  - Autologous transplantation of retrovirally transduced bone marrow (BM) or
      neonatal blood cells was carried out on eight cats (ranging in age from 2 weeks
      to 12 months) with mucopolysaccharidosis type VI (MPS VI). The transducing vector
      contained the full-length cDNA encoding human arylsulfatase B (hASB), the
      enzymatic activity deficient in this lysosomal storage disorder. Following
      transplantation, the persistence of transduced cells and enzymatic expression
      were monitored for more than 2 years. Five of the cats received no myeloablative
      preconditioning, two cats received 370-390 cGy of total body irradiation (TBI),
      and one cat received 190 cGy TBI. Evidence of transduced cells, as judged by
      enzymatic activity and PCR detection of the provirus, was demonstrated in
      granulocytes, lymphocytes, or BM cells of the treated animals up to 31 months
      after transplantation. Radiation preconditioning was not required to achieve
      these results, nor were they dependent on the recipient's age. However, despite
      the long-term persistence of transduced cells, the levels of ASB activity in the
      transplanted animals was low, and no clinical improvements were detected. These
      data provide evidence for the long-term persistence of retrovirally transduced
      feline hematopoietic cells, and further documentation that engraftment of
      transduced cells can be achieved in the absence of myeloablation. Consistent with
      previous bone marrow transplantation studies, these results also suggest that to
      achieve clinical improvement of MPS VI, particularly in the skeletal system, high
      level expression of ASB must be achieved in the treated animals and improved
      techniques for targeting the expressed enzyme to specific sites of pathology
      (e.g. chondrocytes) must be developed.

PMID- 10341883
TI  - A novel SV40-based vector successfully transduces and expresses an alpha 1
      antitrypsin ribozyme in a human hepatoma-derived cell line.
AB  - Alpha 1-antitrypsin (alpha 1AT) deficiency disease is one of the more common
      hereditary disorders that affects the liver and lung. The liver disease of alpha
      1AT deficiency is generally thought to be caused by the accumulation of an
      abnormal alpha 1AT protein in hepatocytes, whereas the lung disease is thought to
      be due to a relative lack of the normal protein in the circulation. Therefore,
      one possible approach to prevent and treat alpha 1AT disease is to both inhibit
      the expression of the mutated alpha 1AT gene, and to provide a means of
      synthesizing the normal protein. To do this, we designed specific hammerhead
      ribozymes that were capable of cleaving the alpha 1AT mRNA at specific sites, and
      constructed a modified alpha 1AT cDNA not susceptible to ribozyme cleavage.
      Ribozymes were effective in inhibiting alpha 1AT expression in a human hepatoma
      cell line using a newly developed simian virus (SV40) vector system. In addition,
      the hepatoma cell line was stably transduced with a modified alpha 1AT cDNA that
      was capable of producing wildtype alpha 1AT protein, but was not cleaved by the
      ribozyme that decreased endogenous alpha 1AT expression. These results suggest
      that ribozymes can be employed for the specific inhibition for an abnormal alpha
      1AT gene product, the first step in designing a gene therapy for the disease. The
      findings also suggest that the novel SV40-derived vector may represent a
      fundamental improvement in the gene therapeutic armarmentarium.

PMID- 10341884
TI  - Gene expression and antitumor effects following direct interferon (IFN)-gamma
      gene transfer with naked plasmid DNA and DC-chol liposome complexes in mice.
AB  - Gene expression was assessed in three types of mouse solid tumors after direct
      injection of naked plasmid DNA encoding the luciferase gene (pCMV-Luc) and its DC
      chol liposome complexes. Intratumoral injection of 5 or 100 micrograms naked pCMV
      Luc into subcutaneously inoculated mouse colon tumor (CT-26), fibrosarcoma (MCA
      15) and bladder carcinoma (MBT-2) resulted in significant gene expression. A DC
      chol liposome formulation (5 micrograms pCMV-Luc complexed with 25 micrograms DC
      chol liposome) showed lower level of gene expression in the tumor models. Based
      on the results using the reporter gene, we examined the antitumor effect after
      direct interferon-gamma (IFN-gamma) gene transfer into CT-26 tumors. A
      significant IFN-gamma production and growth inhibition were obtained following
      direct intratumoral injection of IFN-gamma gene with naked plasmid DNA (pCMV-Mu
      gamma). Interestingly, pCMV-Mu gamma/DC-chol liposome complexes exhibited more
      pronounced growth inhibitory effect despite lower IFN-gamma production. Induction
      of CT-26 specific antitumor immunity by IFN-gamma gene transfer was confirmed by
      rejection of a CT-26 tumor challenge in the mice showing complete regression of
      CT-26 tumors after both treatments. Further analysis demonstrated that a
      significant cDNA-independent induction of IFN-beta and TNF-alpha occurred
      following injection with the liposome complexes, suggesting a nonspecific
      suppressive effect on CT-26 tumor growth by these cytokines. Thus, the present
      study has demonstrated that tumor tissue might be a promising target for direct
      IFN-gamma gene transfer with plasmid-based nonviral vectors. It is also suggested
      that immunomodulatory effects by various cytokines could be involved in antitumor
      effects after direct intratumoral injection of plasmid DNA formulations.

PMID- 10341885
TI  - Isolation of efficient antivirals: genetic suppressor elements against HIV-1.
AB  - The development of general approaches for the isolation of efficient antivirals
      and the identification and validation of targets for drug screening are becoming
      increasingly important, due to the emergence of previously unrecognized viral
      diseases. The genetic suppressor element (GSE) technology is an approach based on
      the functional expression selection of efficient genetic inhibitors from random
      fragment libraries derived from a gene or genome of interest. We have applied
      this technology to isolate potent genetic inhibitors against HIV-1. Two
      strategies were used to select for GSEs that interfere with latent virus
      induction and productive HIV-1 infection based on the expression of intracellular
      and surface antigens. The selected GSEs clustered in seven narrowly defined
      regions of the HIV-1 genome and were found to be functionally active. These
      elements are potential candidates for the gene therapy of AIDS. The developed
      approaches can be applied to other viral pathogens, as well as for the
      identification of cellular genes supporting the HIV-1 life cycle.

PMID- 10341886
TI  - Gene transfer with synthetic virus-like particles via the integrin-mediated
      endocytosis pathway.
AB  - The interaction between cationic DNA-containing particles and cell surface
      anionic proteoglycans is an efficient means of entering cultured cells.
      Therapeutic in vivo gene delivery levels, however, require binding to less
      ubiquitous molecules. In an effort to follow adenovirus, thiol-derivatized
      polyethylenimine (PEI) was conjugated to the integrin-binding peptide CYGGRGDTP
      via a disulfide bridge. The most extensively conjugated derivative (5.5% of the
      PEI amine functions) showed physical properties of interest for systemic gene
      delivery. In the presence of excess PEI-RGD, plasmid DNA was condensed into a
      rather homogeneous population of 30-100 nm toroidal particles as revealed by
      electron microscopy images in 150 mM salt. Their surface charge was close to
      neutrality as a consequence of the shielding effect of the prominent zwitterionic
      peptide residues. Transfection efficiency of integrin-expressing epithelial
      (HeLa) and fibroblast (MRC5) cells was increased by 10- to 100-fold as compared
      with PEI, even in serum. This large enhancement factor was lost when aspartic
      acid was replaced by glutamic acid in the targeted peptide sequence (RGD/RGE),
      confirming the involvement of integrins in transfection. PEI-RGD/DNA complexes
      thus share with adenovirus constitutive properties such as size and a centrally
      protected DNA core, and 'early' properties, i.e. cell entry mediated by integrins
      and acid-triggered endosome escape.

PMID- 10341887
TI  - Complement and anti-alpha-galactosyl natural antibody-mediated inactivation of
      murine retrovirus occurs in adult serum but not in umbilical cord serum.
AB  - Many retroviral vectors for hematopoietic cell and other clinical gene therapy
      are derived from murine packaging cell lines. The exposure of these retroviruses
      and packaging cell lines to adult human serum (AS) inactivates them by complement
      and anti-alpha-galactosyl natural antibody-mediated mechanisms. We show that
      virus stability and infection efficiency of CRIP/BAG, a murine packaging cell
      line derived amphotropic retrovirus vector is reduced > 95% following a 30-min
      incubation in AS. This inactivation is prevented by replacing AS with umbilical
      cord serum (CS), wherein full retroviral transduction efficiency is maintained
      after 30 min of incubation. The loss of retrovirus transduction efficiency in AS
      was smaller upon blockage of anti-alpha-galactosyl antibodies with galactose
      alpha 1-3-galactose. Serum levels of CH 100, as well as C1q complement which
      inactivates retroviruses by an antibody-independent mechanism were similar in AS
      and CS. The high stability of CRIP/BAG retrovirus vector in CS is likely due to
      its lower levels of maternally derived anti-alpha-galactosyl antibodies. These
      results have implications for in vivo gene transfer in adults and also in
      newborns since neonates do not produce natural antibodies during the initial
      months of life.

PMID- 10341888
TI  - Intercellular trafficking of VP22-GFP fusion proteins.
AB  - The herpes simplex virus protein VP22 exhibits the unusual property of
      intercellular transport whereby after being synthesised in a subpopulation of
      cells, in which it is largely cytoplasmic, the protein is transported to adjacent
      cells where it accumulates mainly in the nucleus. Here we examine the transport
      of a fusion protein consisting of VP22 linked to the green fluorescent protein
      (GFP). Intercellular transport, nuclear accumulation and chromatin binding of
      VP22-GFP could be detected by intrinsic GFP fluorescence in fixed cells. However,
      while the cytoplasmic localisation of VP22-GFP could be detected in live cells
      actively synthesising the protein, we were unable to detect intercellular
      transport by intrinsic GFP fluorescence in livecells, indicating that the levels
      of transported protein may be below those required for live detection, or that
      GFP fluorescence was quenched. The use of antibody to GFP was more sensitive than
      intrinsic GFP fluorescence and allowed ready detection of transport and nuclear
      accumulation of VP22-GFP. Intercellular transport was also confirmed in coplating
      experiments. Consistent with previous results showing a requirement for the C
      terminus of VP22 in transport of the native protein, a fusion protein consisting
      of GFP linked to the N-terminal 1-192 residues of VP22 failed to transport
      between cells. The results support the proposal that VP22 has the ability to
      transport cargo proteins between cells and that it has significant potential in
      the field of gene therapy.

PMID- 10341889
TI  - Heat-induced segmental necrosis after reaming of one humeral and two tibial
      fractures with a narrow medullary canal.
AB  - In three cases referred to our clinic (a simple fracture of the humeral shaft, a
      simple, closed fracture, and a wedge fracture of the mid-third of the tibia),
      bone necrosis had resulted from excessive heat produced by reaming extremely
      narrow medullary cavities (5-5.5 mm diameter) with the 9 mm front-cutting reamer
      as part of a reamed nailing procedure. In any one case, different degrees of
      damage can occur from the metaphysis to the diaphysis. Based on the clinical
      course and the histological evaluation, we postulate that heat-induced damage can
      be divided into four degrees of severity (0-3): Grade 0: no damage; no
      devascularization, no heat-induced damage. Grade 1: The heat damaged zone is cut
      away during subsequent reaming, the only damage is devascularization. Grade 2:
      The damaged zones are not eliminated by subsequent reaming. The bone is
      devascularized and heat damaged. Grade 3: The entire cross section of the bone
      including the periosteum is devitalized by exposure to excessive heat. Depending
      on the severity of additional damage to the soft tissues, grave consequences are
      to be expected and further operations are unavoidable. The effects of heat
      induced damage are particularly critical in the presence of infection (cases 2
      and 3). The fundamental aspects and the extent of heat necrosis will be
      discussed. After discussion with the AO Technical Commission on the cause of heat
      induced necrosis, we would recommend the following preventive measures: 1.
      preoperative measurement of the smallest diameter of the medullary cavity in two
      planes. 2. reaming with the standard instrumentation (9 mm) only if the medullary
      cavity has a diameter of at least 8 mm at its narrowest point. 3. Extremely
      narrow cavities should first be reamed manually or an alternative to nailing
      should be sought. 4. It is strongly recommended that only sharp reamers be used
      in such cases and blunt or damaged reamers replaced.

PMID- 10341890
TI  - The physics of heat generation during reaming of the medullary cavity.
AB  - Clinical experience of special cases of reaming of a small diameter medullary
      cavity has shown a remarkable temperature increase with associated thermal damage
      to the surrounding tissue. By applying known solutions of the heat conductivity
      equation to simplified models of a reamer to bone tube system, the effects of the
      most important parameters on heat generation and temperature distribution are
      explained. The results allow a quantitative assessment of reaming techniques for
      small cavities which gives rise to the following recommendations: reamers used
      consecutively should not increase more than 0.5 mm in diameter; blunt instruments
      must be replaced or sharpened; prepare very narrow medullary cavities with the
      small diameter hand reamer; if the reamer ceases to advance do not increase the
      axial force but withdraw it and check the reamer and the temperature. Cooling,
      cleaning and replacement of the reamer should be considered, if appropriate.

PMID- 10341891
TI  - Fracture healing in biological plate osteosynthesis.
AB  - In order to gain a better understanding of the healing processes after plate
      fixation and indirect reduction, Baumgaertel designed a reproducible fracture
      model for the sheep femur in 1992 so that the differences between anatomical
      (rigid) and biological (bridging) fixation could be investigated. It was
      demonstrated that indirect reduction and bridge plating was superior to direct
      fragment reduction and anatomical fixation in respect to radiology, biomechanics
      and microangiography. In this study, it was shown that bony bridging of the
      fracture gap and mineralization of callus occurred faster and more efficiently
      after indirect than after direct and anatomical reduction. Bone healing was
      identified as beginning in the 2.-3. week after indirect and only in the sixth
      week after direct reduction. The increased breaking strength of the indirectly
      reduced femora at 8 weeks can be attributed to this process. In addition, the
      consequences of applying the PC-Fix for biological plating were investigated. The
      values for bone healing were improved by applying a plate with only point contact
      to the bone, thus conserving the periosteal blood supply.

PMID- 10341892
TI  - Indirect reduction with a condylar blade plate for osteosynthesis of
      subtrochanteric femoral fractures.
AB  - Subtrochanteric fractures frequently occur as high energy trauma usually in
      younger patients and may lead to severe comminution of the medial cortex. The
      medial cortex of the proximal femur is exposed to high compressive forces which
      make fracture stabilization a difficult problem. Bone healing may be seriously
      compromised due to extensive comminution and fragment devitalization. This
      requires reduction techniques which do not cause additional damage to the
      vitality of the bone. With indirect reduction techniques and the use of a
      condylar blade plate the results have been significantly improved in these
      fracture types in our department (1). In this report the essential aspects of
      indirect reduction for subtrochanteric fractures using a condylar blade plate and
      the treatment results from our department from earlier years (1) and from the
      last 2 1/2 years will be presented. In the latter period, fifteen patients with a
      mean age of 49 years (19-87 years) were treated with this method. Fractures
      resulted from traffic incidents or falls from a great height in 11 cases (73%).
      Union was achieved in 14 cases (93%) with full weight-bearing after a mean of 3
      months (1-4 1/2 months). Malunion was seen in two cases (13%) without the need
      for further surgery. Non union occurred in one patient (7%) with a III B open
      injury due to early infection. After repeated debridements, bone grafting and
      decortication, the fracture was stabilized with a replacement condylar blade
      plate and healed uneventfully.

PMID- 10341893
TI  - CT-based analysis of the geometry of the distal femur.
AB  - When applying minimally invasive techniques (MIO, Minimally Invasive
      Osteosynthesis) to the fixation of the distal femur, the surgeon has access to a
      limited number of anatomical landmarks: namely the articular surface of the
      distal femur and a small portion of the distal lateral femoral cortex. A detailed
      knowledge of the local anatomy facilitates the technique and prevents
      complications. Using Kirschner wires placed at set positions in the distal femur,
      we analyzed the measurements obtained from the 3D reconstructed helical CT scans
      of 33 embalmed femora and we report on the anatomy of the distal femur as it
      relates to supracondylar fracture fixation.

PMID- 10341894
TI  - Combined internal and external osteosynthesis a biological approach to the
      treatment of complex fractures of the proximal tibia.
AB  - Lateral plating was combined with external fixation to treat 18 complex,
      proximal, tibial fractures with severe soft tissue injury. All patients were
      followed up until functional restoration of the limb had been achieved. In 15
      cases, bone healing was uneventful. One deep infection without knee joint
      arthritis, one delayed union and one malunion necessitated revision. Pin track
      complications were negligible and soft tissue breakdown was not observed. The
      short-term results regarding the functional outcome showed a painless condition
      and good function in all patients. The method of fixation described is more
      invasive than the currently proposed minimally invasive combined fixation
      techniques, but can be regarded as an optimization of the mechanical and
      biological advantages of the implants.

PMID- 10341895
TI  - Intraoperative control of axes, rotation and length in femoral and tibial
      fractures. Technical note.
AB  - In an effort to limit the amount of soft tissue dissection at the fracture site,
      indirect reduction and minimally invasive fixation techniques have been developed
      to treat femoral and tibial fractures. These techniques, which do not rely upon
      anatomical reduction of the fracture fragments, are technically difficult.
      Correct limb length, axial alignment in the frontal and sagittal plane, and
      rotation must be assessed using means other than open reduction. In this
      technical note, some simple and effective intraoperative clinical examination and
      radiographic techniques to determine limb alignment are described. These include:
      the 'cable techniques' for the determination of varus-valgus malalignment; the
      'hypertension test', 'radiographic recurvatum sign', 'tibial plateau sign', and
      'meterstick technique' for length analysis; and the 'hip rotation test', 'lesser
      trochanter shape sign', 'cortical step sign', and 'diameter difference sign' for
      rotational analysis. For each of the listed techniques, basic principles,
      technical instructions, limitations, advantages, and disadvantages are described.

PMID- 10341896
TI  - Steffee variable screw placement system in the management of unstable
      thoracolumbar fractures: a Third World experience.
AB  - Twenty consecutive patients with unstable thoracolumbar fractures were taken up
      for posterior spinal stabilization using the Steffee VSP system at the earliest
      opportunity. Patients were followed up from 20 to 38 months. 70% patients were
      operated within 3 weeks of sustaining injury (group 1) while injury-operation
      interval exceeded 3 weeks in 30% (group II). The average preoperative kyphotic
      angle was 19.35 degrees which improved to 8.70 degrees, the correction being much
      more in group I (17.60 degrees to 5.3 degrees) compared to group II (22.90
      degrees to 14.40 degrees). The average preoperative vertebral body height was
      57.75% which improved to 79.75%, the correction being much more in group I (61.20
      to 88.40%) compared to group II (51.40 to 63.70%). No patients deteriorated
      neurologically while 7 out of 16 patients with neurological deficit showed
      improvement by one or more Frankel Grade (43.75%). It is concluded that
      reasonable correction of deformity, fair chance of neurological recovery and
      significant reduction of recumbency associated complications can be expected even
      when surgery is delayed.

PMID- 10341897
TI  - Subtrochanteric missile fractures of the femur.
AB  - The treatment results of subtrochanteric missile fractures of the femur in 41
      casualties are analyzed. The wounds were inflicted by infantry weapon missiles in
      29 (70.7%) and by fragments of mine or explosive devices in 12 (29.3%)
      casualties. The associated neurovascular bundle injuries were present in 11
      (26.8%) patients. Fracture stabilization was done by external fixation in 25
      (62.5%): group A; and by plaster of Paris in 15 (37.5%) patients: group B. The
      postoperative period was uneventful in 14 (35.0%) and early or late complications
      occurred in 26 (65.0%) patients. Bone infection developed in six (15.0%) and
      fractures did not heal in four (10.0%) patients. Complications were present in 13
      (52.0%) patients from group A and in 13 (86.7%) patients from group B. Delayed
      fracture healing and fracture nonunion were present in group A and contractures
      of large joints in group B. Subtrochanteric missile fractures of the femur
      present very severe injuries where the treatment is followed by a very high
      percentage of complications. External fracture fixation in this region
      facilitates the care, stability, early covering of soft tissue defects and early
      physical therapy.

PMID- 10341898
TI  - Type four fracture of the medial epicondyle: a true indication for surgical
      intervention.
AB  - Fourteen consecutive cases with type 4 fracture of the medial epicondyle were
      evaluated following open reduction and internal fixation of the displaced medial
      epicondyle. The mean age was 9.7 years (range 6-16) and the mean follow-up was
      17.2 months (range 12-24). Operative treatment yielded excellent results with no
      loss of functional range of motion, residual deformity or instability. There were
      three cases with pre-operative symptoms of ulnar nerve injury which made a good
      recovery following neurolysis of the ulnar nerve. Type 4 fractures are commonly
      associated with intra-articular entrapment of the ulnar nerve and result from
      serious damage to the soft tissues on the medial side of the elbow. Assessing
      instability is therefore of key importance, as is the intra-operative gravity
      stress-valgus test in assessing instability.

PMID- 10341899
TI  - An aiming device for pin fixation at the iliac crest for external fixation in
      unstable pelvic fracture.
AB  - To improve the accuracy of pinning at the iliac crest during external fixation of
      the pelvic fracture, an aiming device has been designed. The device consists of 3
      parts: a sleeve which accommodates a 5.0 Shanz pin, a handle and guide points.
      The guide points were designed to grasp the iliac crest to allow proper pin
      fixation. The device has undergone trials to fix Shanz pins on the iliac crests
      of 10 cadavers by 10 recently graduated doctors. All pins were fixed in proper
      position and passed into the bone between the two tables of the iliac crest
      without penetrating the tables. The device has so far been used in 50 patients
      who had unstable pelvic fractures. All pins were in the proper positions and
      there had been no loosening at the time the pins were removed. The use of this
      aiming device for pinning the iliac crest for external fixation of pelvic
      fracture has given encouraging results.

PMID- 10341900
TI  - Relationship between foot length and the inter anterior superior iliac distance.
AB  - Reduction of unstable pelvic fracture by external fixator might be over or under
      corrected as there is no proper estimation from the surgical landmark.
      Radiographic evaluation after reduction must be carried out and improper
      reduction is found in a certain number. To find a better guide by normal surgical
      landmark the study was carried out as a survey research in 600 volunteers aged
      from 10 to 70 years. Simple caliper and tape were used to measure the height,
      foot length and inter anterior superior iliac spine distance. In 376/420 male
      volunteers (89%), the length between right heel and tip of the fourth toe was
      equal to the inter anterior superior iliac spine distance. In 173/180 female
      volunteers (96%), the length between right heel and tip of big toe was equal to
      the inter anterior superior iliac spine distance. The length of the right foot
      can be used as a reference in reducing unstable fractured pelvis by external
      fixation. These data were used in the management of 36 patients with unstable
      fractured pelvis with external fixation for reduction and stabilization. All had
      good results.

PMID- 10341901
TI  - Ultrastructural analysis of ruptured tendon from anabolic steroid users.
AB  - Tendon rupture has been linked with anabolic steroid abuse on the basis of a
      small number of published case reports. Although experimental data from animal
      models suggest steroids alter the biomechanical properties of tendon,
      ultrastructural evidence to support this theory is lacking. Indeed, microscopic
      analysis of human tendon from steroid users has not previously been reported. In
      this study, specimens of ruptured human tendon from four patients were biopsied
      during surgical repair. Two of the subjects were anabolic steroid users, and two
      subjects were used as nonsteroid-user controls. Ruptured tendon from both groups
      was examined using electron microscopy. No differences in collagen fibril
      ultrastructure were seen. We conclude that anabolic steroids did not induce
      ultrastructural collagen changes that might predispose to tendon rupture in
      humans.

PMID- 10341902
TI  - Cervical curvature in acute whiplash injuries: prospective comparative study with
      asymptomatic subjects.
AB  - The cervical curvature of 488 patients with acute whiplash injury was
      prospectively studied by comparison with 495 asymptomatic healthy volunteers.
      Plain radiography of the cervical spine in the neutral position was evaluated
      qualitatively. No significant difference was noted in frequencies of non-lordotic
      cervical curvature and local angular kyphosis between acute whiplash injury
      patients and asymptomatic subjects. No significant association was apparent
      between clinical symptoms and cervical curvature. These results suggest that non
      lordotic cervical curvature and angular kyphosis in acute whiplash injury
      patients constitute normal variants rather than pathological findings.

PMID- 10341903
TI  - Trauma admissions in the elderly: how does a patient's age affect the likelihood
      of their being admitted to hospital after a fracture?
AB  - In two projects we have studied patients presenting to Accident and Emergency
      (A&E) departments with a fracture, to examine how their age influences their
      likelihood of admission. Over 1 year from April 1994 we collected data on all
      6467 Cardiff residents who presented to the city's A&E department with a
      fracture. In total 1226 (19%) were admitted. Overall, only 12% of those under 65,
      but 47% of older patients required admission. This was largely a reflection of
      the age-distribution of hip fracture, an injury for which admission is
      inevitable. In a subsequent study of eight A&E departments in South Wales we
      therefore considered the proportion of patients admitted following fractures at
      specific anatomical sites. In people over the age of 55 we identified 6889
      fractures, 2115 (31%) of which led to admission. After standardisation to control
      for the age-distribution of incidence for different fracture sites, we found that
      the likelihood of admission was 22% greater for people aged over 65 years.
      Elderly people very often require hospital admission after a fracture, primarily
      as a consequence of the types of fractures that they tend to sustain. Admissions
      directly attributable to the effects of age and age-related medical, psychiatric
      and social comorbidity appear of more limited significance.

PMID- 10341904
TI  - Pre-operative planning in orthopaedics: a study of surgeons' opinions.
AB  - Pre-operative planning is important in orthopaedic surgery in both trauma and
      elective orthopaedic surgery. We know of no study into surgeons attitudes to pre
      operative planning. A postal questionnaire was used to ascertain attitudes to
      planning. 94% of consultants and 100% of trainees felt that planning was
      important but half, respectively, routinely planned fracture treatment. Only 24%
      of trainees and 44% consultants traced fracture configurations from radiographs.
      88% of trainees and 91% of consultants felt that planning should be undertaken
      more often with 94% of consultants expressing a view that trainees should do more
      planning. Pre-operative planning is good practice and from our study we have
      shown both trainees and consultants feel it should be undertaken more often.

PMID- 10341905
TI  - Spontaneous resolution of a traumatic false aneurysm of the peroneal artery.

PMID- 10341906
TI  - A simple technique for distal locking of tibial nails.

PMID- 10341907
TI  - Fracture of the shaft of the radius and dislocation of the ipsilateral radial
      head in children: beware of rare injuries.

PMID- 10341908
TI  - Closed interlocking nailing for fibular nonunion.

PMID- 10341909
TI  - Transverse divergent dislocation of the elbow with ipsilateral distal radius
      epiphyseal injury in a seven year old.

PMID- 10341910
TI  - Current concepts in the management of paediatric rhinosinusitis.
AB  - It is well recognized that adenoid hypertrophy and allergic rhinitis are common
      in children and that recurrent upper respiratory tract infections are a fact of
      life. The main causes of symptoms associated with rhinosinusitis in children are
      rhinorrhoea, nasal obstruction, mouth breathing, hyponasal speech and snoring.
      Most children grow out of adenoid hypertrophy and recurrent colds by the age of
      eight to 10 and this means that the main treatment strategy should therefore be
      conservative and not surgical. An explanation to anxious parents, simple non
      invasive measures such as teaching nose-blowing, the use of saline sprays or a
      trial of allergen avoidance and age-appropriate topical nasal anti-inflammatory
      sprays should be tried before surgery is even contemplated. Because repeated
      infections are so common, antibiotics given for chronic nasal discharge often
      have only short-lived effects. Rhinosinusitis in children is not a surgical
      disease and 'watchful waiting' is advised. Any treatment should first of all be
      safe, as even without any intervention the problem usually resolves with time. It
      is likely that growth and maturation of the immunological response to pathogens
      play a major role in resolution of the disease. There are few exceptions to this
      principle: nasal polyps (indicating possible cystic fibrosis), and periorbital
      cellulitis where an assessment of vision, parenteral antibiotics, and if there is
      concern about the possibility of a subperiosteal abscess, computerized tomography
      (CT) and drainage of any pus is indicated.

PMID- 10341911
TI  - Topical aminoglycosides in the management of active mucosal chronic suppurative
      otitis media.
AB  - Debate has currently re-emerged following a renewed warning issued from the
      Committee on the Safety of Medicines (CSM) regarding the relative risk of
      ototoxicity from the use of aminoglycoside-containing drops in patients with
      tympanic membrane perforations. We present the findings of a survey of ENT
      consultants, questioning their views and current practice, and we add to the
      debate by means of a review and discussion of the literature.

PMID- 10341912
TI  - Non-insulin-dependent diabetic microangiopathy in the inner ear.
AB  - Hearing loss has long been associated with diabetes mellitus. Microangiopathy,
      associated with thickening of the basement membranes of small vessels, has been
      implicated as a major source of multiple system organ disease. OBJECTIVE: This
      study was designed to evaluate changes in basement membrane thickness in the
      inner ear of laboratory animals suffering from non-insulin-dependent diabetes
      mellitus (NIDDM) with, and without, exposure to moderate intensity noise exposure
      in an attempt to extrapolate the same disease process in humans. DESIGN:
      Spontaneously hypertensive-corpulent non-insulin-dependent rats (SHR/N-cp) were
      selected as a genetic model for the above study. Both lean and obese rats were
      used in this study. A genetically similar control group of animals (LA/N-cp) were
      used as controls. These animals express both the lean and obese phenotypes, but
      they lack the NIDDM gene. Forty-eight animals in each group were sacrificed at
      the end of the study. The cochleas were dissected and fixed. The basement
      membrane of the stria vascularis was examined using transmission electron
      microscopy. SETTING: This study was a laboratory-based, standard animal study.
      MAIN OUTCOME: This study was designed to show microangiography of the inner ear
      as related to NIDDM with, and without, obesity and noise exposure.
      RESULTS/CONCLUSIONS: NIDDM alone does not cause statistically significant
      basement membrane thickening; however, NIDDM in combination with obesity and/or
      noise exposure did show significant thickening and the combination of all three
      showed the greatest thickening. NIDDM appeared to be the greatest contributing
      factor.

PMID- 10341913
TI  - Evaluation of the dizzy patient: experience from a multidisciplinary neurotology
      clinic.
AB  - In 1993 a multidisciplinary neurotology clinic was established at the Toronto
      Hospital, University of Toronto, where patients with symptoms of dizziness were
      assessed by both otolaryngologists and neurologists. The results from the first
      400 patients seen in consultation are described. The disease pathologies
      identified in this patient population with dizziness showed some significant
      differences from other published series, which we believe reflects the
      specialized tertiary nature of referrals to this clinic. A model for the
      collaborative investigation of the dizzy patient is provided consistent with the
      current trend towards multidisciplinary approaches in medicine.

PMID- 10341914
TI  - Microbiology of the middle meatus in children requiring adenotonsillectomy.
AB  - Middle meatus samples were cultured in 120 children undergoing adenotonsillectomy
      with, or without, insertion of ventilation tubes. Every child (except one) had
      positive cultures. Haemophilus influenzae (62 per cent of the children),
      Moraxella catarrhalis (53 per cent) and Streptococcus pneumoniae (48 per cent)
      were the most commonly isolated bacteria. The presence of Moraxella catarrhalis
      and (to a lesser extent) Streptococcus pneumoniae was higher in younger children,
      while Haemophilus influenzae was cultured independently of age. Culture results
      of these middle meatal samples, carefully taken in order to avoid any
      contamination, probably reflect some ongoing sinus infection in these children
      requiring adenotonsillectomy. The problems inherent in the interpretation of
      surface cultures are addressed.

PMID- 10341916
TI  - Acoustic evaluation of Isshiki type III thyroplasty for treatment of mutational
      voice disorders.
AB  - The goal of this study was to determine if there are acoustical differences
      between pre- and post-surgical voices and to evaluate the effectiveness of
      Isshiki type III thyroplasty in 11 male patients with mutational voice disorders.
      Acoustic measures were obtained both pre- and post-operatively. A comparison of
      pre- and post-operative fundamental frequency (Fo), voice frequencies, and vocal
      intensity obtained from a sustained vowel /i/ during different phonatory tasks
      was made. The results from the present study demonstrated that after operation
      the voice frequencies were significantly decreased (p < 0.05). The vocal
      intensity tended to reduce slightly as the voice frequency lowered. However,
      there were no statistically significant differences in the pre- and post
      operative measures of vocal intensity (p > 0.5). The pre-operative high pitched
      voices of all the male patients were lowered up to the normal value by the type
      III thyroplasty.

PMID- 10341915
TI  - Secondary tonsillectomy haemorrhage and non-steroidal anti-inflammatory drugs.
AB  - Modern non-steroidal anti-inflammatory drugs (NSAIDs), are now widely accepted
      analgesics for post-tonsillectomy patients, but their effect on secondary
      haemorrhage has not been fully evaluated. This study attempts to evaluate the
      influence of NSAIDs on the secondary haemorrhage rate, and also whether mode of
      dissection is an important factor. The records of 557 consecutive patients
      undergoing tonsillectomy were studied to determine if there was a relationship
      between the secondary haemorrhage rate and discharge prescription of NSAIDs.
      There was an overall secondary haemorrhage rate of 5.2 per cent (29) and a
      significantly increased secondary haemorrhage rate in those taking regular
      NSAIDs, 11 per cent, compared to those not taking NSAIDs, 1.47 per cent, (chi
      1(2) = 41.25, p < 0.001). There was a higher rate of secondary haemorrhages with
      bipolar dissection than with standard dissection for both those taking and not
      taking NSAIDs (13 per cent vs seven per cent and 2.75 per cent vs 0.87 per cent)
      however this was not statistically significant (chi 1(2) = 1.17, p = 0.19 and chi
      1(2) = 0.773, p = 0.17). Both bipolar dissection and standard dissection
      individually showed very significant increases in secondary haemorrhage rate when
      on regular NSAIDs (chi 1(2) = 14.03, p = 0.004 and chi 1(2) = 6.19, p = 0.003).
      Although NSAIDs are very good analgesics, they may cause an increased secondary
      haemorrhage rate, and should be prescribed at discharge prescription with
      caution.

PMID- 10341917
TI  - Update on paediatric tracheostomy tubes.
AB  - In the recent past there has been a significant expansion in the range of
      paediatric tracheostomy tubes available. This has mainly been in response to
      clinicians' requests. This article reviews those now available and the situations
      in which they are useful. A sizing chart is included for easy reference.

PMID- 10341918
TI  - Endoscopic ultrasound-guided brachytherapy of head and neck tumours. A new
      procedure for controlled application.
AB  - Brachytherapy is an established procedure in primary and in recurrent cancer. We
      perform afterloading brachytherapy during general anaesthesia. The target organ
      is punctured with hollow needles which are loaded with 192iridium via remote
      control. The depth and number of needles depend on tumour extension. In the
      interdisciplinary approach of our departments, this method has been improved and
      supplied by B-scan ultrasound control. Needles are positioned under continuous
      ultrasonographic guidance, and adjacent structures (e.g. the carotid artery) are
      localized ultrasonographically. Thus violation of the large vessels is avoided
      and the exact position of the needles within the tumour is improved. In this
      paper, we report results on 22 patients suffering from recurrent carcinoma of the
      head and neck following surgery and curative radiation, and 17 patients with
      first onset of cancer. We did not observe any severe complications such as
      haemorrhage, osteomyelitis, or dyspnoea. The only side-effect was temporary
      oedema, sometimes associated with a short-term increase of pain. No systemic side
      effects occurred. The method is described and results from both patient groups
      are reported in detail. We conclude from our data that ultrasonographically
      controlled endoscopic brachytherapy is a valuable procedure in locally-advanced
      primary, and in recurrent head and neck cancer.

PMID- 10341920
TI  - Unusual cases of congenital cholesteatoma of the ear.
AB  - Congenital cholesteatoma may originate at various sites in the temporal bone. For
      example, in the petrous apex, the cerebellopontine angle, the middle ear cavity,
      the mastoid process or the external auditory canal. The least common site being
      the mastoid process. We present two cases of congenital cholesteatoma of the
      mastoid process, each presenting with different symptoms and at different ages.
      Both patients underwent surgical treatment, which confirmed the diagnosis and
      radiological findings.

PMID- 10341919
TI  - Drainage after thyroid surgery: a prospective randomized study.
AB  - Between November, 1996 and May, 1997 a series of 100 consecutive unselected
      patients undergoing all types of thyroid surgery--including even those inducing
      large dead space e.g. substernal goitre and carcinoma thyroid with recurrent
      nerve dissection--were randomly allotted to either receive drainage (n = 43) or
      not (n = 57). Patients with cervical dissection for lymph node metastasis were
      not included. Severe intra-operative haemorrhage was not a reason for exclusion.
      No complications such as haematoma or seroma were found in the undrained group
      whereas only minor complications such as haematoma (n = 4) were noted in the
      drained group. Whatever the group, none of the patients required re-exploration.
      The difference in overall hospital stay (1.72 days in the group of undrained
      patients versus 2.09 days in the drained group) was not statistically
      significant.

PMID- 10341921
TI  - An aneurysm of the petrous internal carotid artery.
AB  - Internal carotid artery aneurysms are a rare cause of pulsatile tinnitus and
      conductive hearing loss but should be borne in mind when there is a suspected
      diagnosis of glomus jugulare or high-riding jugular bulb. Most cases are
      congenital. We present a case of otorrhagia which was initially thought to be a
      glomus jugulare, the diagnosis of internal carotid artery aneurysm was made at
      angiography and treated by balloon embolization.

PMID- 10341922
TI  - Clinical course of acute laryngeal trauma and associated effects on phonation.
AB  - We report the clinical course of blunt laryngeal trauma in three young patients.
      All three patients underwent several phoniatric examinations as well as indirect
      microlaryngoscopy and microstroboscopy. The follow-up period ranged from three to
      eight months. In the first case, there was isolated haemorrhage of the left vocal
      fold; in the second, dislocation of the arytenoid cartilage with formation of an
      adhesion in the area of the anterior commissure; and, in the third, non
      dislocated fracture of the thyroid cartilage with development of haematoma in the
      right hemilarynx and transient vocal fold paralysis. One patient required
      surgical treatment; however, repositioning of the arytenoid cartilage, attempted
      seven weeks following the injury, proved unsuccessful. In conclusion, all three
      patients showed significant limitation of vocal fold vibration many months after
      trauma which was unrelated to the extent of resulting tissue damage. In all three
      cases, patients developed secondary posttraumatic functional dysphonia requiring
      treatment.

PMID- 10341923
TI  - Laryngeal paraganglioma in a five-year-old child--the youngest case ever
      recorded.
AB  - A paraganglioma is a neuroendocrine neoplasm that originates from the
      paraganglion cells of the parasympathetic system. The average age of presentation
      is in the fifth decade. We report a case of laryngeal paraganglioma in a five
      year-old child, the youngest case ever recorded. The features of paraganglioma
      which differentiate it from other tumours are also discussed.

PMID- 10341924
TI  - An unusual case of stridor due to osteophytes of the cervical spine: (Forestier's
      disease).
AB  - Stridor is a noisy breathing caused by compromised airway in the larynx and
      trachea. The causes can either be due to intrinsic or extrinsic compression.
      Stridor resulting from extrinsic compression due to anterior cervical osteophytes
      is rare. We report an unusual case of acute stridor due to an osteophytic mass in
      the cervical vertebrae resulting in a mechanical upper airway obstruction. The
      underlying pathology was Forestier's disease or diffuse idiopathic skeletal
      hyperostosis (DISH). Stridor is a rare manifestation of DISH and it certainly
      represents the most life-threatening one. Only a few cases have been reported in
      the English literature and are mainly secondary to impaired function of the vocal
      folds, or postcricoid ulceration and oedema. We present such a case, in that
      stridor was the result of direct airway obstruction by the osteophytic mass and
      an emergency tracheostomy had to be performed to establish an airway.

PMID- 10341925
TI  - Corrosion of a silver Negus tracheostomy tube.
AB  - Corrosion of silver tracheostomy tubes has previously been reported. In all of
      these reports, it occurred at the junction between the neck plate and the outer
      tube where an alloy of inferior corrosion resistance, compared to silver, has
      been used in the brazed joint. We present, to our knowledge, a previously
      unreported case of corrosion of the main body of the outer tube of a silver Negus
      tracheostomy tube where no such alloy is present.

PMID- 10341926
TI  - Retropharyngeal abscess. A rare presentation of nasopharyngeal carcinoma.
AB  - Early symptoms of nasopharyngeal carcinoma (NPC) can often be deceptive and
      confusing. Most patients with nasopharyngeal carcinoma present at an advanced
      stage with metastatic cervical nodes present at the time of diagnosis. A deep
      neck abscess as the presenting feature has not been reported. We report two cases
      of nasopharyngeal carcinoma which presented with retropharyngeal abscesses and
      persistent lymphadenopathy. These two patients illustrate that refractory
      lymphadenopathy, despite adequate treatment of the associated infection, should
      prompt a search for underlying disease. The relationship between nasopharyngeal
      carcinoma and retropharyngeal abscess is discussed.

PMID- 10341927
TI  - Parathyroid cyst: a rare cause of an anterior neck mass.
AB  - Parathyroid cysts are rare. Most of them present in the anterior neck as cystic
      neck swellings. A case of cervical parathyroid cyst is presented, along with a
      brief review of the literature regarding the aetiology, clinical features,
      diagnosis and management of this condition.

PMID- 10341930
TI  - Kikuchi-Fujimoto's syndrome masquerading as tuberculosis.
AB  - We report a case of a 27-year-old Asian man presenting with the typical features
      of tuberculous cervical lymphadenitis who was commenced on anti-tuberculous
      therapy on the strength of the clinical presentation. Histological examination of
      an excised cervical lymph node however, revealed the diagnosis of Kikuchi's
      syndrome; a histiocytic necrotizing lymphadenitis which is usually self-limiting.

PMID- 10341929
TI  - Verruciform xanthoma of the nose.
AB  - We report a case of verruciform xanthoma of the nasal skin. The case is unique
      because the lesion both bled and has shown evidence of multicentricity.

PMID- 10341928
TI  - Access to the traumatized vertebral artery: an unusual approach.
AB  - Although injuries to the vertebral arteries are relatively uncommon, there are
      several different methods used to gain access to these vessels, and to control
      any bleeding arising from them. We describe a case of torrential oropharyngeal
      bleeding following a stab wound to the neck in which rapid access to the
      vertebral artery was gained using a paramedian mandibulotomy; this approach has
      not previously been documented. The other approaches are discussed.

PMID- 10341931
TI  - Past tense--future imperfect.

PMID- 10341932
TI  - Selective attention to specific location cues: the peak and center of a patch are
      equally accessible as location cues.
AB  - Asymmetric patterns have several spatially distinct cues for spatial
      localization. These cues include the peak of the luminance distribution, the
      centroid of the contrast distribution, zero-crossings in the second derivative of
      the luminance profile, and the midpoint of the visible area. If these cues are
      represented as primitives in the visual system, the observer should be able to
      access them at will. To examine whether observers can selectively attend to
      particular cues, we measured perceived alignment for an asymmetric pattern with
      two distinct instructions: "align the peak", and "align the center". We found
      that observers could align the patterns in accord with the instructions with
      identical precision, suggesting that the peak and the center cues were equally
      accessible by the observer. We conclude that multiple localization cues are
      represented in and can be selectively accessed by the visual system.

PMID- 10341933
TI  - Inattentional blindness as a function of proximity to the focus of attention.
AB  - The effect of the distance between the center of the focus of attention and an
      unexpected stimulus on detection was examined in two experiments with the use of
      the inattentional-blindness paradigm [Mack and Rock, 1998 Inattentional Blindness
      (Cambridge, MA: MIT Press)]. In experiment 1, the closer a stimulus was to the
      center of attention, the more likely it was to be detected. Experiment 2
      replicated this finding and controlled for retinal eccentricity. These results
      suggest that low-level stimulus characteristics (e.g. location) may play an
      important role in the detection of unexpected stimuli. The data are consistent
      with previous research on the spatial aspects of attention demonstrating that the
      distance to the focus of attention is a critical variable. This study
      demonstrates that the effect of distance is similar under conditions of
      inattention. Theories put forward to explain inattentional blindness should
      include 'early' attentional factors, as well as factors resulting from later
      stages of processing.

PMID- 10341934
TI  - Attentional modulation in perception of visual motion events.
AB  - Identical visual targets moving across each other with equal and constant speed
      can be perceived either to bounce off or to stream through each other. This
      bistable motion perception has been studied mostly in the context of motion
      integration. Since the perception of most ambiguous motion is affected by
      attention, there is the possibility of attentional modulation occurring in this
      case as well. We investigated whether distraction of attention from the moving
      targets would alter the relative frequency of each percept. During the
      observation of the streaming/bouncing motion event in the peripheral visual
      field, visual attention was disrupted by an abrupt presentation of a visual
      distractor at various timings and locations (experiment 1; exogenous distraction
      of attention) or by the demand of an additional discrimination task (experiments
      2 and 3; endogenous distraction of attention). Both types of distractions of
      attention increased the frequency of the bouncing percept and decreased that of
      the streaming percept. These results suggest that attention may facilitate the
      perception of object motion as continuing in the same direction as in the past.

PMID- 10341935
TI  - Aftereffect of high-speed motion.
AB  - A visual illusion known as the motion aftereffect is considered to be the
      perceptual manifestation of motion sensors that are recovering from adaptation.
      This aftereffect can be obtained for a specific range of adaptation speeds with
      its magnitude generally peaking for speeds around 3 deg s-1. The classic motion
      aftereffect is usually measured with a static test pattern. Here, we measured the
      magnitude of the motion aftereffect for a large range of velocities covering also
      higher speeds, using both static and dynamic test patterns. The results suggest
      that at least two (sub)populations of motion-sensitive neurons underlie these
      motion aftereffects. One population shows itself under static test conditions and
      is dominant for low adaptation speeds, and the other is prevalent under dynamic
      test conditions after adaptation to high speeds. The dynamic motion aftereffect
      can be perceived for adaptation speeds up to three times as fast as the static
      motion aftereffect. We tested predictions that follow from the hypothesised
      division in neuronal substrates. We found that for exactly the same adaptation
      conditions (oppositely directed transparent motion with different speeds), the
      aftereffect direction differs by 180 degrees depending on the test pattern. The
      motion aftereffect is opposite to the pattern moving at low speed when the test
      pattern is static, and opposite to the high-speed pattern for a dynamic test
      pattern. The determining factor is the combination of adaptation speed and type
      of test pattern.

PMID- 10341936
TI  - Stimulus eccentricity and spatial frequency interact to determine circular
      vection.
AB  - While early research suggested that peripheral vision dominates the perception of
      self-motion, subsequent studies found little or no effect of stimulus
      eccentricity. In contradiction to these broad notions of 'peripheral dominance'
      and 'eccentricity independence', the present experiments showed that the spatial
      frequency of optic flow interacts with its eccentricity to determine circular
      vection magnitude--central stimulation producing the most compelling vection for
      high-spatial-frequency stimuli and peripheral stimulation producing the most
      compelling vection for lower-spatial-frequency stimuli. This interaction appeared
      to be due, in part at least, to the effect that the higher-spatial-frequency
      moving pattern had on subjects' ability to organise optic flow into related
      motion about a single axis. For example, far-peripheral exposure to this high
      spatial-frequency pattern caused many subjects to organise the optic flow into
      independent local regions of motion (a situation which clearly favoured the
      perception of object motion not self-motion). It is concluded that both high
      spatial-frequency and low-spatial-frequency mechanisms are involved in the visual
      perception of self-motion--with their activities depending on the nature and
      eccentricity of the motion stimulation.

PMID- 10341937
TI  - Perceived object shape affects the perceived direction of self-movement.
AB  - The 'direct-perception' model of heading perception posits that heading is
      computed directly from optic flow without an intervening structural
      representation of environmental layout. Here, I give an example in which such a
      representation is seen to play a role in the interpretation of optic flow.
      Manipulating the outline of concave objects to give an erroneous percept of
      convexity caused the perceived direction of heading during a stimulated approach
      to change as well. Thus, the representation of environmental structure provides
      the context for using and interpreting image motion.

PMID- 10341938
TI  - The perception of depth and slant from texture in three-dimensional scenes.
AB  - The perception of depth and slant in three-dimensional scenes specified by
      texture was investigated in five experiments. Subjects were presented with
      computer-generated scenes of a ground and ceiling plane receding in depth.
      Compression, convergence, and grid textures were examined. The effect of the
      presence or absence of a gap in the center of the display was also assessed.
      Under some conditions perceived slant and depth from compression were greater
      than those found with convergence. The relative effectiveness of compression in
      specifying surface slant was greater for surfaces closer to ground planes (80
      degrees slant) than for surfaces closer to frontal parallel planes (40 degrees
      slant). The usefulness of compression was also observed with single-plane
      displays and with displays with surfaces oriented to reduce information regarding
      the horizon.

PMID- 10341939
TI  - Are there qualitative differences between face processing in photographic
      positive and negative?
AB  - The question whether face recognition in photographic negative relies more on
      external features and pictorial cues than in photographic positive was studied in
      five experiments. Recognition of whole faces as well as both external and
      internal features of the faces was compared in experiments 1 and 2. The
      conditions in which views of faces between learning and test were either
      identical (hence providing maximum pictorial cues) or different (hence reducing
      such cues) were compared in experiments 3, 4, and 5. The results showed that
      recognition of internal features in two-tone and multi-tone images suffered more
      from use of photographic negatives than recognition of external features. Testing
      with both multi-tone and two-tone images revealed that the deficit caused by view
      changes between learning and test was no more severe with negatives than with
      positives. Finally, removing external features made recognition of different
      views equally more difficult for positives and negatives. Overall, these results
      point to a qualitative rather than quantitative difference between processing
      face images in photographic positive and negative.

PMID- 10341940
TI  - Recognising the ageing face: the role of age in face processing.
AB  - The effect of age-induced changes on face recognition were investigated as a
      means of exploring the role of age in the encoding of new facial memories. The
      ability of participants to recognise each of six previously learnt faces was
      tested with versions which were either identical to the learnt faces, the same
      age (but different in pose and expression), or younger or older in age.
      Participants were able to cope well with facial changes induced by ageing: their
      performance with older, but not younger, versions was comparable to that with
      faces which differed only in pose and expression. Since the large majority of
      different age versions were recognised successfully, it can be concluded that the
      process of recognition does not require an exact match in age characteristics
      between the stored representation of a face and the face currently in view. As
      the age-related changes explored here were those that occur during the period of
      growth, this in turn implies that the underlying structural physical properties
      of the face are (in addition to pose and facial expression) invariant to a
      certain extent.

PMID- 10341941
TI  - Feature specific segmentation in perceived structure-from-motion.
AB  - Motion information is important to vision for extracting the 3-D (three
      dimensional) structure of an object, as evidenced by the compelling percept of
      three-dimensionality attainable in displays which are purely motion-defined. It
      has recently been shown that when subjects view a rotating transparent cylinder
      of dots simulated with parallel projection, they rarely perceive rotation
      reversals which are physically introduced (Treue, Andersen, Ando & Hildreth,
      Vision Research, 35;1995:139-148). We show however that when the elements
      defining the cylinder are oriented, the number of perceived reversals increases
      systematically to near maximum as the difference between element orientations on
      the two surfaces increases. These results imply that structure-from-motion
      mechanisms are capable of exploiting local feature differences between the
      different surfaces of a moving object.

PMID- 10341942
TI  - What pattern the eye sees best.
AB  - The visibility of gratings improves with increasing stimulus area. This effect is
      usually interpreted as being due to physiological summation within the extent of
      the largest spatial filter and due to probability summation between the outputs
      of linear, independent filters beyond that range. It is generally assumed that
      this improvement is isotropic to the patch configuration. In contrast, the
      existence of long-range facilitation that is configuration-specific suggests that
      the visibility of a local contrast is dependent on the spatial configuration of
      the stimuli. We measured contrast thresholds for circular and elongated Gabor
      patches with a static carrier. The patch envelope orientation was either the same
      as the bar orientation (collinear) or orthogonal to it. Contrast sensitivity was
      highest for elongated configurations that were collinear with the grating bars,
      and reached maximal efficiency at a length of about four grating cycles (eight
      bar widths), but a width of only one cycle.

PMID- 10341943
TI  - A true neuronal consensual pupillary reflex in chicks.
AB  - The existence of a true neuronal consensual pupillary reflex (CPR) in birds has
      long been debated. In this century Noll (Noll, A. (1915). Archiv fur Physiologie
      (Leipzig), 350-372.) claimed to observe a neuronal CPR in a pigeon, but this was
      contradicted by Levine (Levine, J. (1955). Science, 122, 699.), who observed a
      direct transillumination effect (Durchleuchtungs-effekt) due to the retinas of
      the two eyes of the pigeon being in close apposition. To determine if a neuronal
      CPR exists, we transected the optic nerves of 28 chicks and observed and
      videotaped the direct and indirect pupillary responses. Twenty-one of the chicks
      exhibited no direct response in the operated eye but did exhibit an indirect
      pupillary response. The non-operated eye showed a direct but no indirect
      response. These results conclusively demonstrate for the first time that a true
      neuronal CPR does exist in chickens.

PMID- 10341944
TI  - A deficit in strabismic amblyopia for global shape detection.
AB  - Using a task which relied upon the detection of sinusoidal deformations from
      circularity, we show that strabismic amblyopes exhibit deficits which are not
      critically dependent on either the scale of deformation or the spatial frequency
      characteristics of the stimulus (circular D4) itself. We show that this loss is
      not due to the restricted passband of the amblyopic eye. Furthermore, in a
      pedestal distortion experiment, we show that the suprathreshold form of this loss
      is consistent with an elevated level of 'intrinsic noise' rather than a loss in
      'sampling efficiency'.

PMID- 10341945
TI  - The extrinsic/intrinsic classification of two-dimensional motion signals with
      barber-pole stimuli.
AB  - The perceived direction of different barber-pole stimuli was assessed by
      adjusting an arrow on the screen. The terminator ratio (TR: number of terminators
      moving along the long side divided by the number of terminators moving along the
      small side) was either one or three. In this latter case, the aperture
      orientation was either vertical or horizontal. The grating was either in the same
      plane as the aperture (intrinsic condition) or behind the aperture--the frame
      containing the aperture had a crossed disparity relative to the grating-
      (extrinsic condition). A nested design with 120 observers was used for the whole
      study. Five grating orientations were intermingled within any session. With a
      terminator ratio of three, the results depend strongly on the aperture's
      orientation. When the rectangular aperture is horizontal, the perceived direction
      of an intrinsic grating is horizontal (the typical barber-pole illusion), whereas
      it is only slightly biased towards orthogonal one-dimensional (1D) motion signals
      (Vp) in the extrinsic condition. When the aperture is vertical, the perceived
      direction in the intrinsic condition is largely biased toward Vp, and on average
      it is close to Vp in the extrinsic condition. In this latter case, however,
      analysing the distributions of responses shows that many responses do not lie
      around Vp but are clustered near vertical or horizontal. This motion capture
      depends on the grating's orientation. With a terminator ratio of one, motion
      capture is present in both the extrinsic and intrinsic conditions. Moreover, a
      global bias toward horizontal is observed: this horizontal bias is much larger in
      the extrinsic condition. Altogether, these results suggest that binocular
      disparity alone is a weak determinant of the extrinsic/intrinsic classification
      of two-dimensional (2D) motion signals compared to the occlusion cues provided by
      unpaired regions in binocular images. Second, truly extrinsic 2D motion signals
      are not suppressed but rather actively compete against each other to capture the
      1D motion signals. This results in a perceptual multistability which is much
      stronger with extrinsic signals. Finally, given the inherent multistability of
      barber-pole stimuli, high-level factors can alter the strength of this
      competition and prime any of the 2D motion signals.

PMID- 10341946
TI  - Long range interactions between oriented texture elements.
AB  - Long range interactions between texture elements (short, oriented line segments)
      were examined. Specifically, we studied the influence of a background array of
      texture elements on the detectability of a target element (separated from the
      background by an intermediate textured region) using textures like those of
      Caputo (Vis. Res. 1996, 36, 2815-2826). We found that, in general, when the
      background elements were oriented orthogonally to the target element, detection
      of the target element was better than when the background elements had the same
      orientation as the target element. We discuss these interactions in terms of
      inhibitory and excitatory connections between orientation and spatial frequency
      selective linear filters (e.g. filters which mimic V1 simple cells) which would
      respond to the individual texture elements.

PMID- 10341947
TI  - Contour integration in the peripheral field.
AB  - Contour integration was measured in the normal peripheral field to determine if
      an explanation based solely on the known peripheral positional uncertainty was
      sufficient to explain performance. The task involved the detection of paths
      composed of micropatterns with correlated carrier orientations embedded in a
      field of similar micropatterns of random position and orientation (Field, D. J.,
      Hayes A., & Hess, R. F. (1993). Vision Research, 33, 173-193). The intrinsic
      positional uncertainty for each eccentric locus was measured with the same
      stimulus and it did not account for levels of peripheral performance. We show
      that peripheral performance on this task does not get worse with eccentricity
      beyond about 10 degrees and that these results can be modeled by simple filtering
      without any subsequent cellular linking interactions.

PMID- 10341948
TI  - Global motion processing is not tuned for binocular disparity.
AB  - An important goal of the visual system is the segmentation of image features into
      objects and their backgrounds. A primary cue for this is motion: when a region
      shares the same pattern of motion it is segregated from its surround. Three
      experiments were carried out to investigate whether the segmentation of image
      features on the basis of motion information is facilitated by the addition of
      binocular disparity. Coherence thresholds were measured for the discrimination of
      the global direction of motion of random dot kinematograms (RDKs) in which the
      relative disparity of the signal and noise dots was manipulated. When the signal
      dots were embedded in a three dimensional cloud of noise dots, coherence
      thresholds were similar to those measured when signal and noise dots were both
      presented with zero disparity. However, when the signal dots were separated from
      the noise dots in depth, global motion processing was strongly facilitated. These
      results were considered in terms of two models, one in which global motion is
      processed by disparity tuned mechanisms, the other in which the discrimination of
      the direction of motion is mediated by an attention-based system. It was
      concluded that global motion processing is not tuned for binocular disparity and
      that the facilitation of the discrimination of direction provided by binocular
      disparity in certain circumstances reflects the role of an attention-based
      system.

PMID- 10341949
TI  - Perceived distance, shape and size.
AB  - If distance, shape and size are judged independently from the retinal and extra
      retinal information at hand, different kinds of information can be expected to
      dominate each judgement, so that errors in one judgement need not be consistent
      with errors in other judgements. In order to evaluate how independent these three
      judgments are, we examined how adding information that improves one judgement
      influences the others. Subjects adjusted the size and the global shape of a
      computer-simulated ellipsoid to match a tennis ball. They then indicated manually
      where they judged the simulated ball to be. Adding information about distance
      improved the three judgements in a consistent manner, demonstrating that a
      considerable part of the errors in all three judgements were due to misestimating
      the distance. Adding information about shape that is independent of distance
      improved subjects' judgements of shape, but did not influence the set size or the
      manually indicated distance. Thus, subjects ignored conflicts between the cues
      when judging the shape, rather than using the conflicts to improve their estimate
      of the ellipsoid's distance. We conclude that the judgements are quite
      independent, in the sense that no attempt is made to attain consistency, but that
      they do rely on some common measures, such as that of distance.

PMID- 10341950
TI  - Transducer model produces facilitation from opposite-sign flanks.
AB  - Small spots, lines and Gabor patterns can be easier to detect when they are
      superimposed upon similar spots, lines and Gabor patterns. Traditionally, such
      facilitation has been understood to be a consequence of nonlinear contrast
      transduction. Facilitation has also been reported to arise from non-overlapping
      patterns with opposite sign. We point out that this result does not preclude the
      traditional explanation for superimposed targets. Moreover, we find that
      facilitation from opposite-sign flanks is weaker than facilitation from same-sign
      flanks. Simulations with a transducer model produce opposite-sign facilitation.

PMID- 10341951
TI  - Instability of torsion during smooth asymmetric vergence.
AB  - Several categories of torsional eye movements obey Listing's law; however,
      systematic deviations from this law occur during vergence. Two kinematic models
      attempt to incorporate these deviations, both of which are supported by
      experimental evidence; however, they lead to different torsion predictions. These
      discrepancies have been explained in terms of experimental procedures, but it now
      seems likely from several recent studies that individual differences in torsion
      patterns may also be important. This study therefore examines the variation of
      torsion during a smooth asymmetric vergence task in which a fixation target was
      moved along the line-of-sight of the right eye at 15 degrees elevation; each of
      five subjects observed five trials of both inward and outward target motion,
      repeated in two sessions several weeks apart. There were no significant group
      differences in left or right eye torsion between trials or sessions, suggesting
      that monocular torsion patterns were relatively stable over time. When examined
      more closely, however, the torsion patterns shown by some individuals did vary
      for inward versus outward target motion. Hence, monocular torsion was
      idiosyncratic and depended on the direction in which fixation was changing
      (convergence or divergence). In a binocular analysis, cycloversion varied
      dramatically between subjects and depended on the direction of target motion;
      however, this was not the case for cyclovergence. In summary, cyclovergence is
      relatively stable and depends on where the eyes are looking, whereas cycloversion
      (and hence monocular torsion) is relatively unstable and depends on how they came
      to be in that particular horizontal and vertical orientation. These findings help
      to explain the controversy surrounding the torsional behaviour of the human eye
      during vergence.

PMID- 10341953
TI  - Different motor systems use similar damped extraretinal eye position information.
AB  - Extraretinal eye position information (EEPI) shifts the directional significance
      of retinal loci by an angle roughly equal to that of an associated saccade, with
      the shift reported to begin 0-250 ms before the saccade and to continue apace
      with the saccade, or sluggishly, over a period as much as an order of magnitude
      longer. These different estimates of remapping initiation and duration could be
      due to various factors, including different localizing responses, retinal loci of
      probe flashes, and saccade target predictability. We compared manual and gaze
      pointing to probe flashes at controlled retinal loci under identical stimulus
      conditions and in the same subjects, and found that EEPI was similar: both hand
      and gaze pointing EEPI shifted over about 140 ms, beginning about 50 ms before
      the saccade. For both pointing responses, remapping appeared to be initiated
      later for parafoveal loci than for loci 10 degrees to either side. We found no
      effect of saccade target predictability. We show that variability in EEPI and
      sensory processing only slightly (approximately 5%) inflates estimates of EEPI
      shift duration. Based on our results, and comparisons with recent studies, we
      argue that similar EEPI parameters apply to hand pointing, eye pointing and
      visual comparisons, and that remaining differences across studies can reasonably
      be attributed to differences in stimulus conditions.

PMID- 10341952
TI  - Evidence for a mechanism sensitive to the speed of cyclopean form.
AB  - We measured Weber fractions for discriminating the speed of cyclopean gratings
      and Weber fractions for discriminating the speed of luminance gratings. Of our 14
      observers, five were unable to see the cyclopean grating sufficiently well to
      discriminate its speed. One observer experienced great difficulty in
      discriminating the speed of cyclopean gratings, even though her threshold for
      detecting cyclopean gratings was low, and even though she discriminated the speed
      of luminance gratings on the basis of the task-relevent variable. But several
      observers based their speed discriminations on trial-to-trial variations of the
      task-relevent variable while ignoring associated trial-to-trial variations in all
      task-irrelevant variables (specifically: displacement; temporal frequency;
      spatial frequency; and presentation duration). We conclude that the visual
      systems of these observers contain a specialized neural mechanism for the speed
      of cyclopean gratings that supports acute discriminations of speed (Weber
      fractions were as low as 0.05-0.07).

PMID- 10341954
TI  - Reading with simulated scotomas: attending to the right is better than attending
      to the left.
AB  - Persons with central field loss must learn to read using eccentric retina. To do
      this, most adopt a preferred retinal locus (PRL), which substitutes for the
      fovea. Patients who have central field loss due to age-related macular
      degeneration (AMD), most often adopt PRL adjacent to and to the left of their
      scotoma in visual field space. It has been hypothesized that this arrangement of
      PRL and scotoma would benefit reading. We tested this hypothesis by asking
      normally-sighted subjects to read with the left or right half of their visual
      field plus 3.2 degrees in the contralateral field masked from view. Letter
      identification, word identification, and reading were all slower when only the
      information in the left visual field was available. This was primarily due to the
      number of saccades required to successfully read to stimuli. These data imply
      that patients would be better off with PRL to the right of their scotoma than to
      the left for the purposes of reading.

PMID- 10341955
TI  - Herbert Dartnall--obituary.

PMID- 10341956
TI  - Colchicine causes excessive ocular growth and myopia in chicks.
AB  - Colchicine has been reported to destroy ganglion cells (GCs) in the retina of
      hatchling chicks. We tested whether colchicine influences normal ocular growth
      and form-deprivation myopia, and whether it affects cells other than GCs.
      Colchicine greatly increased axial length, equatorial diameter, eye weight, and
      myopic refractive error, while reducing corneal curvature. Colchicine caused DNA
      fragmentation in many GCs and some amacrine cells and photoreceptors, ultimately
      leading to the destruction of most GCs and particular sub-sets of amacrine cells.
      Colchicine-induced ocular growth may result from the destruction of amacrine
      cells that normally suppress ocular growth, and corneal flattening may result
      from the destruction of GCs whose central pathway normally plays a role in
      shaping the cornea.

PMID- 10341957
TI  - Peripheral and central delay in processing high spatial frequencies: reaction
      time and VEP latency studies.
AB  - Visually evoked potentials (VEP) and reaction time (RT) were recorded under
      stimulation with sinusoidal gratings. Grating spatial frequency (SF) was 0.5, 5
      or 12 cd and grating contrast was varied. Consistent with previous findings, both
      VEP latency and RT increased with the increase of grating SF and with the
      decrease of grating contrast. It was found, in addition, that RT and VEP latency
      increased by approximately the same amount when SF increased from 0.5 to 5 cd,
      thus suggesting that the main source of the RT delay at 5 cd in comparison with
      RT at 0.5 cd is of peripheral origin. However, in comparison with the data at 0.5
      and 5 cd, RT at 12 cd increased much more than VEP latency. We conclude that the
      RT delay at high SF involves a substantial central component in addition to the
      peripheral delay.

PMID- 10341958
TI  - Analysis of red/green color discrimination in subjects with a single X-linked
      photopigment gene.
AB  - Many subjects despite having only a single X-linked pigment gene (single-L/M-gene
      subjects) are able to make chromatic discriminations by Rayleigh matching,
      especially when large fields are used. We used a combination of psychophysics
      (Rayleigh match), electroretinograms (ERG), and molecular genetic techniques to
      rule out several possible explanations of this phenomenon. Use of rods for
      chromatic discrimination was unlikely since strong adapting fields were employed
      and the large-field match results were not consistent with rod participation. A
      putative mid- to long-wavelength photopigment that escapes detection by current
      molecular genetic analysis was ruled out by finding only a single L/M
      photopigment in flicker ERGs from 16 single-L/M-gene subjects. Large-field match
      results were not consistent with participation of S cones. Amino acid sequence
      polymorphisms in the S-pigment gene that might have shifted the S cone spectrum
      towards longer wavelengths were not found on sequencing. The mechanism of
      chromatic discrimination in the presence of a single photopigment therefore
      remains unknown. Further possible explanations such as variations in cone pigment
      density and retinal inhomogeneities are discussed.

PMID- 10341959
TI  - The spatial tuning of color and luminance peripheral vision measured with notch
      filtered noise masking.
AB  - We have measured the spatial bandwidths of the bandpass red-green chromatic and
      luminance mechanisms at four locations in the nasal visual field (0, 10, 20 and
      30 degrees) using a method of notch filtered noise masking which effectively
      removes the artifact of off-frequency looking for our stimuli. Detection
      thresholds were measured for luminance or isoluminant red-green Gaussian
      enveloped test gratings of 0.5 cpd embedded in 1/f noise. Firstly, thresholds
      were obtained as a function of increasing noise spectral density and were fitted
      using a standard noise masking model. These results support the existence across
      the visual field of independent, red-green chromatic and luminance mechanisms
      with similar sampling efficiencies. Secondly, we measured thresholds in notch
      filtered noise as a function of notch width and derived the spatial bandwidth of
      the detection mechanism. We find both color and luminance mechanisms have similar
      bandwidths which remain virtually constant across eccentricity. These results
      indicate strong overall similarities between the early processing of color and
      luminance vision, and lend support to the role of color as an 'intrinsic image'
      in spatial vision. The results are discussed in the light of the anchored channel
      and shifting channel models of peripheral contrast sensitivity and pattern
      detection.

PMID- 10341960
TI  - Evidence for the stochastic independence of the blue-yellow, red-green and
      luminance detection mechanisms revealed by subthreshold summation.
AB  - We investigated the manner in which the outputs of the three postreceptoral
      mechanisms (red-green, blue-yellow and luminance) combine to determine contrast
      threshold. We used a subthreshold summation paradigm to test whether the
      combination of the postreceptoral mechanism outputs could be described by a
      probability summation model which assumes stochastic independence of the
      mechanisms, and determined the best fitting summation exponent. Stimuli were
      Gaussian enveloped 1 c/d sinusoidal gratings represented in a 3D cardinal space
      transformed from cone contrast axes, and normalized to detection threshold. The
      use of this space avoids the presence of elongated threshold contours, allowing a
      reliable model fit to include the less sensitive blue-yellow and luminance
      mechanisms. Our results were well fitted by the probability summation model and
      hence support the underlying stochastic independence of the three postreceptoral
      mechanisms.

PMID- 10341961
TI  - Reading with central field loss: number of letters masked is more important than
      the size of the mask in degrees.
AB  - When the center of a readers, visual field is blocked from view, reading rates
      decline and eye movement patterns change. This is true whether the central visual
      field is blocked artificially (i.e. a mask) or through disease (e.g. a retinal
      scotoma due to macular degeneration). In past studies, when mask size was defined
      in terms of the number of letters masked from view, reading rates declined
      sharply as number of letters masked increased. Patients with larger central
      scotomas (in degrees of visual angle) also read slower. We sought to determine
      whether number of letters masked or size of the mask in degrees is the
      predominant factor affecting reading rates and eye movement behavior. By matching
      number of letters masked across several mask sizes (and compensating for reduced
      acuity in the periphery), we found that number of letters masked is the more
      important factor until mask size is quite large (> or = -7.5 degrees) and number
      of letters masked from view is more than seven.

PMID- 10341962
TI  - The oblique effect with colour defined motion throughout the visual field.
AB  - We assessed the extent of the oblique effect (OE) and the meridional orientation
      effect (MOE) for a chromatic motion task using red/green gratings throughout an
      80 degrees visual field. Four different stimulus orientations were tested.
      Generally, sensitivity to chromatic motion decreased with increasing eccentricity
      regardless of the visual field meridian. Also, sensitivity was highest for
      horizontal or vertical gratings, thus supporting the presence of an OE rather
      than of a MOE. The strength of the OE varied between subjects, but was present
      from the fovea to 20 degrees of eccentricity. At 40 degrees of eccentricity,
      chromatic motion was always perceived but the grating orientation did not
      consistently influence chromatic motion sensitivity. The present study confirmed
      our previous results on chromatic motion sensitivity and isoluminance ratios
      throughout the visual field. In addition, our data show that the chromatic system
      can exhibit OEs at lower spatial frequencies than is observed for the achromatic
      system.

PMID- 10341963
TI  - Orientation discrimination and tilt aftereffects with luminance and illusory
      contours.
AB  - Orientation discrimination and tilt aftereffects (TAEs) were measured to
      determine if the orientation of luminance and illusory contours are processed by
      separate mechanisms. The assumption was made that if a single mechanism supports
      the perception of both types of contours, then illusory and luminance contours
      that support the same level of orientation discrimination will be equally
      effective adapting patterns. Experiment I found that orientation discrimination
      psychometric functions for illusory and luminance contours are similar,
      confirming that performance could be matched. Experiment II measured orientation
      discrimination for a range of intensities for both contours. Experiment III
      measured TAEs following adaptation to illusory and luminance contours that
      supported a similar range of orientation discrimination. Similar TAEs were not
      observed, thus rejecting the single mechanism hypothesis. Experiments IV and V
      sought to validate the assumption that equivalent orientation discrimination
      predicts equivalent TAEs by using stimuli that seemed likely to be represented by
      the same visual mechanism. Luminance contours masked by randomly placed dots and
      unmasked luminance contours were used with the same procedures as experiments II
      and III. Equal TAEs were not observed for masked and unmasked contours matched on
      orientation discrimination, suggesting the assumption relating discriminability
      to adaptation was incorrect.

PMID- 10341964
TI  - Figure ground segregation modulates perceived direction of ambiguous moving
      gratings and plaids.
AB  - A translating oriented grating viewed through a circular aperture with an
      occluding area in the middle appeared to move alternately in an oblique or in a
      vertical direction depending on the foreground/background assignment on the
      central occluding area. The effect occurred even when the central area was simply
      removed from the display, thus giving rise to a 'subjective' occluder. Parametric
      studies revealed that the probability of seeing oblique or vertical motion was
      affected by the size of the central area but not by its contrast relationships
      with the grating. Similar phenomena of ambiguous motion direction were observed
      using changes in colour along a translating grating that produced neon colour
      spreading effects, or using oriented edge discontinuities that collapsed into
      subjective plaids composed of two one-dimensional gratings. These results are
      discussed with respect to the hypothesis that surface segmentation mechanisms
      play a crucial part in the interpretation of motion signals.

PMID- 10341965
TI  - Alignment of separated patches: multiple location tags.
AB  - Gaussian and Gabor patches can be accurately localized; however, it is not yet
      clear which cues (or location tags) the visual system utilizes for localization.
      To determine the cues used in spatial alignment, we measured and modelled the
      perceived shifts for asymmetric Gaussian and Gabor patches over a wide range of
      separations, patch sizes and orientations. For Gaussian patches we observed
      perceived shifts that were generally consistent with that of the centroid of the
      envelope. For Gabor patches we found that the perceived shift depends on the
      carrier orientation (whether co-axial or orthoaxial with the patch arrangement),
      separation (in units of carrier wavelength) and patch size (number of cycles per
      standard deviation). Gabor patches with the carrier orthoaxial (horizontal) to
      the three vertically arranged patches, were similar to Gaussian patches. However,
      Gabor patches with the carrier coaxial (vertical) to the three vertically
      arranged patches resulted in perceived shifts that were consistent with a number
      of alternate localization primitives. The selection of primitives was dependent
      on mainly the separation and patch size. Our results support the suggestion that
      the visual system can use multiple tags for location (Hess et al., Vis Res
      1994;34:2439-2451; Badcock et al., Vis Res 1996;36:1467-1472).

PMID- 10341966
TI  - Integration after adaptation to transparent motion: static and dynamic test
      patterns result in different aftereffect directions.
AB  - One of the many interesting questions in motion aftereffect (MAE) research is
      concerned with the location(s) along the pathway of visual processing at which
      certain perceptual manifestations of this illusory motion originate. One such
      manifestation is the unidirectionality of the MAE after adaptation to moving
      plaids or transparent motion. This unidirectionality has led to the suggestion
      that the origin of this MAE might be a single source (gain control) located at,
      or beyond areas that are believed to be responsible for the integration of motion
      signals. In this report we present evidence against this suggestion using a
      simple experiment. For the same adaptation pattern, which consisted of two
      orthogonally moving transparent patterns with different speeds, we show that the
      direction of the resulting unidirectional MAE depends on the nature of the test
      stimulus. We used two kinds of test patterns: static and dynamic. For exactly the
      same adaptation conditions, the difference in MAE direction between testing with
      static and dynamic patterns can be as large as 50 degrees. This finding suggests
      that this MAE is not just a perceptual manifestation of a passive recovery of
      adapted motion sensors but an active integrative process using the output of
      different gain controls. A process which takes place after adaptation. These
      findings are in line with the idea that there are several sites of adaptation
      along the pathway of visual motion processing and that the nature of the test
      pattern determines the fate of our perceptual experience of the MAE.

PMID- 10341967
TI  - Integration and segregation of local motion signals: the role of contrast
      polarity.
AB  - In the initial stages of visual processing in primates, more or less separated ON
      and OFF pathways have been shown to exist. There is ample evidence, that this
      separation includes the initial stages of motion processing. In the present
      study, experiments were conducted to investigate whether this ON versus OFF
      distinction persists into the integration stage of local motion information. We
      constructed stimuli that consisted of clusters of checks with equal contrast
      polarity, which could be varied in size, and compared them to stimuli with a
      random polarity distribution. We found that the ON versus OFF distinction remains
      partly intact, while interactions between the two systems are also apparent.
      These interactions prove to be highly correlated with the spatial structure of
      the stimulus. We propose a mechanism of contrast-sign specific integration of
      local motion signals, after which these separate ON and OFF pools engage in
      mutually inhibitory interactions.

PMID- 10341968
TI  - The effect of target size and eccentricity on reflex disparity vergence.
AB  - This study examined the effects of stimulus size and eccentricity on reflex
      disparity vergence: the small, involuntary corrections of eye alignment which
      serve to minimize the binocular disparity of fixated targets. Subjects were
      instructed to fixate steadily on a small, stationary mark superimposed on the
      center of a dynamic random dot stereogram. The stereogram was binocularly
      uncorrelated except for a fully correlated patch whose size and eccentricity were
      varied systematically across trials. The disparity of the patch was varied
      sinusoidally over time to stimulate vergence following movements. The overall
      purpose was to determine the relative contributions of various field loci in
      controlling binocular fixation by finding the smallest patch which would reliably
      drive vergence against the effort to fixate steadily. Psychophysical thresholds
      for detection of the correlated patch stimuli were also measured for comparison
      to the oculomotor results. Results showed that the smallest effective patch
      increased with eccentricity similarly for both vergence responses and
      psychophysical detection, suggesting they depend on a common, presumably cortical
      matching process. The dependence of response on eccentricity is roughly
      consistent with changes in the cortical magnification factor, suggesting that the
      area of cortex stimulated may be the determining factor in vergence responses to
      this class of stimulus.

PMID- 10341969
TI  - The oculomotor gap effect without a foveal fixation point.
AB  - Turning off a fixation point prior to or coincident with the appearance of a
      visual target reduces the latency of saccades to that target. We investigated
      this 'gap effect' when subjects fixated a central point or the center of a square
      formed by four points that were 4, 2 or 1 degree eccentric from the square's
      center. The fixation anchor vanished 200 ms prior to the appearance of a saccadic
      target in a Gap condition, coincident with the target's appearance in a 0-Gap
      condition, or remained on in an Overlap condition. Saccadic reaction time was
      reduced in the Gap relative to 0-Gap condition irrespective of the type of
      fixation anchor. However, saccadic reaction time was not reduced in the 0-Gap
      relative to Overlap condition when the points forming the square had
      eccentricities of 2 or 4 degrees. Results are interpreted in terms of a partial
      mediation of the gap effect by fixation cells in the rostral pole of the superior
      colliculus.

PMID- 10341970
TI  - Word ambiguity and the optimal viewing position in reading.
AB  - The optimal viewing position phenomenon discovered by (O'Regan, J. K., Levy
      Schoen, A., Pynte, J., Brugaillere, B. (1984). Convenient fixation location
      within isolated words of different length and structure. Journal of Experimental
      Psychology: Human Perception and performance. 10 (2), 250-257) is characterized
      by a minimization of gaze duration on a word and maximization of word recognition
      rates when the eye fixates a word near its center. Subsequent studies (Holmes, V.
      M., & O'Regan, J. K. (1987). Decomposing french words. In J. K. O'Regan, & A.
      Levy-Schoen, Eye movements: from physiology to cognition, North-Holland,
      Amsterdam, 459-466; O'Regan, J. K., & Levy-Schoen, A. (1987). Eye movement
      strategy and tactics in word recognition and reading. In M. Coltheart, Attention
      and performance XII: the psychology of reading, Erlbaum, Hillsdale N.J., 363-383)
      have shown that lexical structure can affect the location of the optimal viewing
      position. In this paper we show that the optimal viewing position is near to the
      position which minimizes word ambiguity arising from incomplete recognition of
      the letters in the word. This conclusion is supported by a statistical analysis
      based on inter-letter correlations in English and French word corpuses.

PMID- 10341971
TI  - Computing feature motion without feature detectors: a model for terminator motion
      without end-stopped cells.
AB  - Pointlike object features such as line-endings, have a privileged position in the
      computation of the veridical direction of object motion. Experiments confirm that
      the human visual system relies heavily on such features if they are present. It
      has been proposed that units such as end-stopped cells might be necessary for the
      computation of feature motion instead of the simple cells used in plaid motion
      models. Conventional plaid motion models have not been applied to feature motion.
      We present here a model, based on ordinary simple cells, using two parallel
      pathways (Fourier and non-Fourier) for the computation of the direction of two
      dimensional motion. Although similar in structure to popular models of plaid
      motion, our model includes a novel scheme for contrast normalisation and
      incorporates spatial pooling at the level of MT cells. The model predictions are
      consistent with psychophysical results for plaids. Furthermore, it computes
      directions within 5 degrees of the physical motion of line-endings. It is shown
      that the non-Fourier signal is necessary for the computation of veridical motion.

PMID- 10341972
TI  - Combined use of several preferred retinal loci in patients with macular disorders
      when reading single words.
AB  - To investigate the use of several preferred retinal loci (PRL) when attempting to
      read, two patients with bilateral central scotomas were asked to decipher single
      words, successively projected onto the retina using a scanning laser
      ophthalmoscope (SLO). Video-recordings of the fundus image, on which the
      projected targets were superimposed, were analyzed frame by frame. One patient
      used two PRL in association and the other used three, each PRL having a specific
      function. Single word reading made it easier than with full texts to correlate
      the images parts scrutinized and the retinal areas involved. Then, as patients
      were unable to describe their reading behavior, the examiner monitored refixation
      movements using the SLO and asked questions to help them to become aware of their
      reading behavior. Eventually, they could localize their PRL, describe their
      specific functions, and switch at will between them.

PMID- 10341973
TI  - Orientation-based texture segmentation in strabismic amblyopia.
AB  - Texture segmentation of 'target' Gabors from an array of 'background' Gabors was
      measured in terms of the difference in orientation between the two regions, as
      well as the difference in orientation within each region. Segmentation was shown
      to occur on the basis of local orientation differences at the boundary between
      the target and background regions (Nothdurft, H.C. (1992). Feature analysis and
      the role of similarity in preattentive vision. Perception and Psychophysics, 52,
      355-375.). We obtained similar results for both the amblyopic and non-amblyopic
      eye of three strabismic amblyopes, and showed also that the effects of texture
      undersampling and positional jitter were similar for the two eyes. This pattern
      of results is consistent with intact mechanisms of texture perception in
      amblyopic cortex, and suggests also that any amblyopic deficits in first-order
      cortical units (undersampling and/or positional uncertainty) do not limit higher
      order texture segmentation processes. Therefore, first- and second-order
      processes involved in perceptual grouping of oriented elements (that appear to be
      abnormal in amblyopic cortex; Kovacs, I., Polat, U., Norcia, A.M. (1996).
      Breakdown of binding mechanisms in amblyopia. Association for Research in Vision
      and Ophthalmology Abstracts; Mussap, A.J., Levi, D.M. (1995). Amblyopic deficits
      in perception of second-order orientation. Investigative Ophthalmology and Visual
      Science (Supplement), 36, S634; Mussap, A.J., Levi, D.M. (1998). Amblyopic
      deficits in perceptual grouping. Vision Research, submitted) do not contribute to
      texture perception based on orientation contrast.

PMID- 10341974
TI  - The optic nerve head component of the human ERG.
AB  - The local responses of the multifocal ERG reveal continuous changes in the second
      order waveforms from the nasal to the temporal retina. Scrutiny of these changes
      suggests the presence of an additive component whose latency increases with the
      distance of the stimulus from the optic nerve head. This observation led to the
      hypothesis of a contributing source in the vicinity of the optic nerve head whose
      signal is delayed in proportion to the fiber length from the stimulated retinal
      patch to the nerve head. The hypothesis was tested with two independent methods.
      In Method 1, a set of different local response waveforms was approximated by two
      fixed components whose relative latency was allowed to vary and the fit of this
      two component model was evaluated. In Method 2, two signals were derived
      simultaneously using different placements for the reference electrode. The
      placements were selected to produce a different ratio of the signal contributions
      from the retina and the nerve head in the two recording channels. The signals
      were then combined at a ratio that canceled the retinal component. Method 1
      yielded an excellent fit of the two component model. Waveforms and latencies of
      the hypothetical optic nerve head component derived from the two methods agree
      well with each other. The local latencies also agree with the propagation delays
      measured in the nerve fiber layer of the monkey retina. In combination, these
      findings provide strong evidence for a signal source near the optic nerve head.

PMID- 10341975
TI  - Time course of motion adaptation: motion-onset visual evoked potentials and
      subjective estimates.
AB  - The aim of this study was to quantitatively describe the dynamics of adaptation
      to visual motion with electrophysiological and psychophysical methods in man. We
      recorded visual evoked potentials (VEPs) to motion onset of random dot patterns
      from occipital and occipito-temporal electrodes during a succession of adaptation
      recovery sequences. In these sequences the test stimulus was used to set the
      adaptation level: seven trials with 70% motion duty cycle (adaptation) followed
      by seven trials of 7% motion duty cycle (recovery). In a similar paradigm we
      determined the length of the perceptual motion after-effect to obtain a
      psychophysical measure of the time course of motion adaptation. Our results show
      a highly significant reduction of the N2 amplitude in the maximally compared to
      the minimally adapted condition (P < 0.001). Electrophysiological and
      psychophysical results both indicate that adaptation to visual motion is faster
      than recovery: The data were fit with an exponential model yielding adaptation
      and recovery time constants, respectively, of 2.5 and 10.2 s for the N2 amplitude
      (occipito temporal derivation) and of 7.7 and 16.7 s for the perceptual motion
      after-effect. Implications for the design of motion stimuli are discussed, e.g. a
      motion stimulus moving 10% of the time may lead to about 30% motion adaptation.

PMID- 10341976
TI  - Position jitter and undersampling in pattern perception.
AB  - The present paper addresses whether topographical jitter or undersampling might
      limit pattern perception in foveal, peripheral and strabismic amblyopic vision.
      In the first experiment, we measured contrast thresholds for detecting and
      identifying the orientation (up, down, left, right) of E-like patterns comprised
      of Gabor samples. We found that detection and identification thresholds were both
      degraded in peripheral and amblyopic vision; however, the orientation
      identification/detection threshold ratio was approximately the same in foveal,
      peripheral and amblyopic vision. This result is somewhat surprising, because we
      anticipated that a high degree of uncalibrated topographical jitter in peripheral
      and amblyopic vision would have affected orientation identification to a greater
      extent than detection. In the second experiment, we investigated the tolerance of
      human and model observers to perturbation of the positions of the samples
      defining the pattern when its contrast was suprathreshold, by measuring a 'jitter
      threshold' (the amount of jitter required to reduce performance from near perfect
      to 62.5% correct). The results and modeling of our jitter experiments suggest
      that pattern identification is highly robust to positional jitter. The positional
      tolerance of foveal, peripheral and amblyopic vision is equal to about half the
      separation of the features and the close similarity between the three visual
      systems argues against extreme topographical jitter. The effects of jitter on
      human performance are consistent with the predictions of a 'template' model. In
      the third experiment we determined what fraction of the 17 Gabor samples are
      needed to reliably identify the orientation of the E-patterns by measuring a
      'sample threshold' (the proportion of samples required for 62.5% correct
      performance). In foveal vision, human observers are highly efficient requiring
      only about half the samples for reliable pattern identification. Relative to an
      ideal observer model, humans perform this task with 85% efficiency. In contrast,
      in both peripheral vision and strabismic amblyopia more samples are required. The
      increased number of features required in peripheral vision and strabismic
      amblyopia suggests that in these visual systems, the stimulus is underrepresented
      at the stage of feature integration.

PMID- 10341977
TI  - The influence of large scanning eye movements on stereoscopic slant estimation of
      large surfaces.
AB  - The results of several experiments demonstrate that the estimated magnitude of
      perceived slant of large stereoscopic surfaces increases with the duration of the
      presentation. In these experiments, subjects were free to make eye movements. A
      possible explanation for the increase is that the visual system needs to scan the
      stimulus with eye movements (which take time) before it can make a reliable
      estimate of slant. We investigated the influence of large scanning eye movements
      on stereoscopic slant estimation of large surfaces. Six subjects estimated the
      magnitude of slant about the vertical or horizontal axis induced by large-field
      stereograms of which one half-image was transformed by horizontal scale,
      horizontal shear, vertical scale, vertical shear, divergence or rotation relative
      to the other half-image. The experiment was blocked in three sessions. Each
      session was devoted to one of the following fixation strategies: central
      fixation, peripheral (20 deg) fixation and active scanning of the stimulus. The
      presentation duration in each of the sessions was 0.5, 2 or 8 s. Estimations were
      done with and without a visual reference. The magnitudes of estimated slant and
      the perceptual biases were not significantly influenced by the three fixation
      strategies. Thus, our results provide no support for the hypothesis that the time
      used for the execution of large scanning eye movements explains the build-up of
      estimated slant with the duration of the stimulus presentation.

PMID- 10341978
TI  - An orientation anisotropy in the effects of scaling vertical disparities.
AB  - Garding et al. (Vis Res 1995;35:703-722) proposed a two-stage theory of
      stereopsis. The first uses horizontal disparities for relief computations after
      they have been subjected to a process called disparity correction that utilises
      vertical disparities. The second stage, termed disparity normalisation, is
      concerned with computing metric representations from the output of stage one. It
      uses vertical disparities to a much lesser extent, if at all, for small field
      stimuli. We report two psychophysical experiments that tested whether human
      vision implements this two-stage theory. They tested the prediction that scaling
      vertical disparities to simulate different viewing distances to the fixation
      point should affect the perceived amplitudes of vertically but not horizontally
      oriented ridges. The first used elliptical half-cylinders and the 'apparently
      circular cylinder' judgement task of Johnston (Vis Res 1991;31:1351-1360). The
      second experiment used parabolic ridges and the amplitude judgement task of
      Buckley and Frisby (Vis Res 1993;33:919-934). Both studies broadly confirmed the
      anisotropy prediction by finding that large scalings of vertical disparities
      simulating near distances had a strong effect on the perceived amplitudes of the
      vertically oriented stimuli but little effect on the horizontal ones. When
      distances > 25 cm were simulated there were no significant differential effects
      and various methodological reasons are offered for this departure from
      expectations.

PMID- 10341979
TI  - Stereopsis based on monocular gaps: metrical encoding of depth and slant without
      matching contours.
AB  - It is often the case in binocular vision that one eye can see between two objects
      lying at different distances but the other eye cannot. We have found that the
      visual system is able to correctly interpret images produced this way in which a
      single solid rectangle in one eye is fused with two half-sized rectangles in the
      other eye separated by a vertical gap comprising the background. Two rectangles
      in depth are seen. It is as if the solid rectangle is treated as two components
      which each match one of the physically separated rectangles in the contralateral
      eye. The sign of the depth depends on which eye's view has the gap and its
      magnitude increases with gap width. Measured depth is found to be equivalent to
      real stereoscopic depth with a relative disparity equal to the monocular gap. If
      overall disparity differences are eliminated, between the left and the right
      images, variations in perceived slant of the two rectangles are still seen with
      increasing gap size. That two surfaces can be seen in metric binocular depth
      despite complete camouflage of their separation in one eye's view, suggests that
      stereopsis be regarded as a broad process of surface recovery not necessarily
      requiring image disparity at the location of the depth step.

PMID- 10341980
TI  - Optimal spatial localization is limited by contrast sensitivity.
AB  - Bisection is one of several spatial localization tasks that achieve hyperacuity
      performance levels. We find that optimal bisection thresholds, and hyperacuity
      tasks in general, are no better than might be expected from simple contrast
      detection and discrimination performance. The three-line bisection task can be
      described in terms of the test-pedestal paradigm where the test pattern is a
      horizontal dipole and the pedestal is a horizontal three-line pattern with equal
      spacing between the lines. When the dipole test is added to the center line, the
      line shifts up or down, depending on the test polarity. For low contrast pedestal
      lines at the optimal separation, the bisection threshold falls between the
      observer's own dipole contrast detection threshold and the bottom of the dipole
      contrast discrimination dipper function. At higher pedestal strengths performance
      degrades with a slope of about 0.5-0.7, similar to that found in contrast
      discrimination tasks. Therefore, bisection performance is compatible with
      expectations based on contrast discrimination data. At large pedestal line
      separations (> 10 min) bisection thresholds in min are about 1/60 the separation
      and relatively independent of pedestal strength. These findings are consistent
      with the idea that two processes are involved in limiting bisection performance;
      the first limit is based on contrast sensitivity of the system and the second
      limit to performance is based on a local sign or position tag processing.
      Finally, when bisection is compared with Vernier acuity and blur resolution
      tasks, where the test is also a dipole, bisection performance falls roughly
      midway, better than Vernier acuity but worse than blur resolution.

PMID- 10341981
TI  - Localization and identification tasks rely on different temporal frequencies.
AB  - The temporal frequencies underlying character localization and identification
      tasks are measured, as suggested by a model that assumes that the two tasks are
      processed in different cortical pathways and receive contributions from different
      populations of visual cortical neurons. Data from two-pulse and temporal contrast
      sensitivity experiments demonstrate that character localization depends upon much
      higher temporal frequencies than character identification when both are tested in
      the periphery. Foveal presentations demonstrate that detection and identification
      tasks rely on the same temporal frequencies. In a control experiment, the letters
      were blurred to restrict the range of spatial frequencies. However, these stimuli
      replicated earlier results and demonstrates that the use of higher temporal
      frequencies by the localization tasks cannot be attributed to the use of
      different spatial frequencies for different tasks. In addition, near-foveal
      presentations of the localization task replicate findings from the far periphery,
      suggesting that the localization task may be processed differently from the
      detection task regardless of location on the retina. Finally, the temporal
      frequency differences persist when a single sine-wave grating is used in
      localization and identification tasks. The results are consistent with any
      anatomical model that assumes that the neural substrates underlying localization
      receive or maintain a higher range of temporal frequencies than areas responsible
      for identification. The findings demonstrate how the time-course of different
      stimulus attributes can be quantified, and have implications for theories of
      information processing in which different stimulus attributes are combined.

PMID- 10341982
TI  - The effects of temporal noise and retinal illuminance on foveal flicker
      sensitivity.
AB  - We measured foveal flicker sensitivity with and without external added temporal
      noise at various levels of retinal illuminance and described the data with our
      model of flicker sensitivity comprising: (i) low-pass filtering of the flickering
      signal plus external temporal and/or quantal noise by the modulation transfer
      function (MTF) of the retina (R): (ii) high-pass filtering in proportion to
      temporal frequency by the MTF of the postreceptoral neural pathways (P): (iii)
      addition of internal white neural noise; and (iv) detection by a temporal matched
      filter. Without temporal noise flicker sensitivity had a band-pass frequency
      dependence at high and medium illuminances but changed towards a low-pass shape
      above 0.5 Hz at low luminances, in agreement with earlier studies. In strong
      external temporal noise, however, the flicker sensitivity function had a low-pass
      shape even at high and medium illuminances and flicker sensitivity was
      consistently lower with noise than without. At low luminances flicker sensitivity
      was similar with and without noise. An excellent fit of the model was obtained
      under the assumption that the only luminance-dependent changes were increases in
      the cut-off frequency (fc) and maximum contrast transfer of R with increasing
      luminance. The results imply the following: (i) performance is consistent with
      detection by a temporal matched filter, but not with a thresholding process based
      on signal amplitude; (ii) quantal fluctuations do not at any luminance level
      become a source of dominant noise present at the detector; (iii) the changes in
      the maximum contrast transfer reflect changes in retinal gain, which at low to
      moderate luminances implement less-than-Weber adaptation, with a 'square-root'
      law at the lowest levels; (iv) the changes of fc as function of mean luminance
      closely parallels time scale changes in cones, but the absolute values of fc are
      lower than expected from the kinetics of monkey cones at all luminances; (v) the
      constancy of the high-pass filtering function P indicates that surround
      antagonism does not weaken significantly with decreasing light level.

PMID- 10341983
TI  - Shape and contour detection.
AB  - Detectability of contours may be affected by long-range interactions between
      neurons in early stages of visual cortex. Specifically, neurons with receptive
      fields arrayed along the length of a contour may facilitate each other in a
      position- and orientation-dependent manner. Accordingly, the overall geometry of
      a contour should significantly influence both the strength of these long-range
      interactions and the contour's detectability. Psychophysical experiments
      measuring the detectability of sampled, curvilinear contours hidden by randomly
      oriented and -positioned noise elements revealed two main findings. First,
      changes in direction of curvature degraded contour detectability. Second, the
      effect of changes in magnitude of curvature were predicted by the average of
      local curvature along the length of the contour. While the first result
      emphasizes the importance of uniform direction of curvature, the second result
      rules out penalties for deviation from circularity.

PMID- 10341984
TI  - On the relationship between the spatial channels for luminance and disparity
      processing.
AB  - To determine the relationship between the spatial channels for luminance and
      shape-from-stereo-disparity processing we measured disparity modulation
      sensitivity as a function of disparity spatial frequency for sinusoidal
      modulations of a field of Gabor micropatterns of differing luminance spatial
      frequency. We first examine the effects of contrast, spatial bandwidth and
      element density and show that it is only the last of these which is critical for
      the shape of the disparity modulation threshold function. We show that the shape
      of this function depends on the luminance spatial frequency of the surface that
      is modulated in depth. Specifically, low corrugation frequencies enjoy a greater
      scale support from the early luminance spatial filters than do high corrugation
      frequencies. The results are consistent with higher spatial frequency disparity
      channels receiving a greater input from higher spatial frequency luminance
      channels.

PMID- 10341986
TI  - Orientation and luminance polarity tuning of the transient-vergence system.
AB  - Previously, Edwards, Pope & Schoor, Vision Research, 38, 705-717, demonstrated
      that transient disparity vergence appears to be mediated by a system that employs
      a single low-pass sensitive spatial channel whose performance is not reduced by
      dichoptic mixed contrasts (no contrast paradox) or dichoptic mixed spatial
      frequencies. This broadband tuning to both contrast and spatial frequency may be
      indicative of a second-order or non-linear envelope extraction system. The
      current study tests for lack of tuning to orientation and luminance polarity
      which are typically taken as evidence of a second-order system. We found that
      when the transient vergence system was simultaneously presented with both
      convergent and divergent disparities, there was a small but distinct bias in
      favor of responding in the direction defined by matched orientations or luminance
      polarities over unmatched pairs. Although less frequent, responses to orthogonal
      carriers or opposite luminance polarities were possible. The vergence system
      could match a horizontal with a vertical carrier, or a light gaussian with a dark
      gaussian. The degree of orientation or luminance polarity tuning varied inversely
      with the disparity magnitude over the range of 2.5-5 degrees, and the orientation
      tuning peaked at a spatial frequency about 2 cpd. At all disparities tested,
      however, the tuning was very broad, and other candidate features for mediating
      transient-vergence need to be investigated.

PMID- 10341987
TI  - Spatial attention and latencies of saccadic eye movements.
AB  - Recent theories of visual attention, such as the oculomotor readiness theory of
      Klein (1980) (Does oculomotor readiness mediate cognitive control of the visual
      attention. In: R. Nickerson, Attention and performance, Hillsdale: Erlbaum), the
      premotor theory of Rizzolati (1983) (Mechanisms of selective attention in
      mammals. In: J.P. Ewart, R.R. Capranica, D.J. Ingle, Advances in vertebrate
      Neuroethology (pp. 261-297). New York: Plenum) and the sequential attention
      theory of Henderson (1992) (Visual attention and eye movement control during
      reading and scene perception. In K. Rayner, Eye movements and visual cognition
      (260-283). New York: Springer-Verlag), propose a link between shifts in spatial
      attention and the generation of saccadic eye movements. In this paper we show
      that a winner-take-all model of spatial attention, combined with a simple model
      for the link between attention and eye movements, can account for the variation
      in saccadic latency observed in many oculomotor phenomena. These phenomena
      include the gap effect (Saslow M.G. (1967). Effects of components of displacement
      step stimuli upon latency for saccadic eye movement. Journal of the Optical
      Society of America, 57, 1024-1029), the effect of target jumps on saccadic
      latency (Becker W. & Jurgens R. (1979). An analysis of the saccadic system by
      means of double step stimuli. Vision Research, 19, 967-983), the increase of
      saccadic latency as target eccentricity drops (Kalesnykas R.P. & Hallett P.E.
      (1994). Retinal eccentricity and the latency of eye saccades. Vision Research,
      34, 517-531), and the modulation of saccadic accuracy using target predictability
      and saccadic latency (Coeffe C. & O'Regan J.K. (1987). Reducing the influence of
      non-target stimuli on saccade accuracy: predictability and latency effects.
      Vision Research, 27 (2), 227-240).

PMID- 10341985
TI  - Behavioural visual acuity of wild type and bcl2 transgenic mouse.
AB  - Since the advent of gene manipulating techniques, it has become increasingly
      important to study the neural functional properties of the mouse. The bcl2 gene
      has a powerful inhibitory action on naturally occurring cell death. As a
      consequence the brain of bcl2 overexpressing mouse is 1.5 times bigger than the
      brain of a wild type animal and the retina has more than twice the ganglion cells
      than normal (Martinou, Dubois-Dauphin, Staple, Rodriguez, Frankowski, Missotten,
      Albertini, Talabot, Catsicas, Pietra, & Huarte (1994). Neuron, 13: 1017-1030).
      Since in most mammals the upper limit of behavioural visual acuity is imposed by
      ganglion cells density, the visual acuity should be higher in bcl2 mice than in
      wild type mice. We measured behavioural visual acuity in wild type and transgenic
      mice and, contrary to the expectation, we found it to be of the same order (0.5
      0.6 c/deg) in the two groups of animals, indicating that an increase in ganglion
      cells density is not effective in improving visual resolution.

PMID- 10341988
TI  - Dissociating stimulus information from internal representation--a case study in
      object recognition.
AB  - Human object recognition is a function of both internal memory representation(s)
      and stimulus input information. The role of the latter has been so far largely
      overlooked, and the nature of the representation is often directly equated with
      recognition performance. We quantify stimulus information for three classes of
      objects in order of decreasing object complexity: unconnected balls, balls
      connected with lines, and balls connected with cylinders. In an object
      discrimination task, subjects' performance improved with the decreasing object
      complexity. We show that input information also increases with decreasing object
      complexity. Therefore, the results could potentially be accounted for either by
      differences in the object representations learned for each class of objects, or
      by the increased information about the three-dimensional (3D) structure inherent
      in images of the less complex objects, or by both. We demonstrate that, when
      image information is taken into account, by computing efficiencies relative to a
      set of ideal observers, subjects were more efficient in recognizing the less
      complex objects. This suggests that differences in subjects' performance for
      different object classes is at least partly a function of the internal
      representations learned for the different object classes. We stress that this
      conclusion cannot be achieved without the quantitative analysis of stimulus input
      information.

PMID- 10341989
TI  - A model for the depth-dependence of receptive field size and contrast sensitivity
      of cells in layer 4C of macaque striate cortex.
AB  - A model of LGN-input to layer 4C of macaque primary visual cortex has been used
      to test the hypothesis that feedforward convergence of P- and M-inputs onto layer
      4C spiny stellate neurons is sufficient to explain the observed gradual change in
      receptive field size and contrast sensitivity with depth in the layer. Overlap of
      dendrites of postsynaptic neurons between M- and P-input zones proved sufficient
      to explain change in the lower two-thirds of layer 4C, while more rapid change in
      upper 4C was matched by proposing two different M-inputs with partial overlap in
      upper 4C alpha.

PMID- 10341990
TI  - Characteristics of frequency-of-seeing curves for a motion stimulus in glaucoma
      eyes, glaucoma suspect eyes, and normal eyes.
AB  - This study compared frequency-of-seeing curves for a line displacement test in
      glaucoma patients and normals. Probit analysis of the frequency-of-seeing curves
      provided the motion thresholds and the slopes of the frequency-of-seeing curves,
      represented by the interquartile range. The thresholds and interquartile ranges
      were significantly elevated in the glaucoma eyes and suspect eyes, compared to
      controls. A logistic regression model incorporating both the interquartile range
      and threshold significantly improved the sensitivity of the motion test in the
      suspects. Abnormal shallowing of the slope of the motion frequency-of-seeing
      curve may represent one of the earliest changes in glaucoma.

PMID- 10341991
TI  - S-cone ERGs elicited by a simple technique in normals and in tritanopes.
AB  - PURPOSE: To measure changes in the relative spectral sensitivities of the dark
      adapted and light adapted ERG and thus to establish the possible contribution of
      rods to the 'blue cone' ERG elicited by flashes of blue light. BACKGROUND: Short
      wavelength stimuli in the light-adapted eye evoke small rounded b-waves which
      have been considered to be S-cone responses. We have recorded such responses from
      tritanopes, which called the assumptions into question. METHODS: Small ERGs were
      recorded to blue and green flashes. The stimulus was a Ganzfeld which employed
      light emitting diodes. ERGs were obtained in both the dark-adapted eye and after
      light adaptation to intense orange light (peak wavelength 610 nm). The change in
      sensitivity with light adaptation and the relative spectral sensitivity was
      determined from the voltage/log light intensity functions, using a 10 microV
      criterion. RESULTS: (1) peak times and changes in sensitivity did not help
      distinguish light-adapted rod from possible S-cone responses; (2) analysis of the
      change in the ratio of blue:green sensitivity from darkness to 4.4 log Td. 610 nm
      background suggests that in seven normal subjects, 90% or more of the ERG evoked
      by 440 nm flashes is generated by S-cones; (3) three tritanopes have
      insignificantly reduced S-cone responses. CONCLUSIONS: (1) clinical techniques
      used to isolate S-cone ERGs are appropriate; (2) there are at least two types of
      tritanope and in those we investigated, functional S-cones are probably displaced
      into the retinal periphery.

PMID- 10341992
TI  - Spatio-temporal contrast sensitivity, coherent motion, and visible persistence in
      developmental dyslexia.
AB  - Three experiments measured spatio-temporal contrast sensitivity, coherent motion,
      and visible persistence in a single group of children with developmental dyslexia
      and a matched control group. The findings were consistent with a transient
      channel disorder in the dyslexic group which showed a reduction in contrast
      sensitivity at low spatial frequencies, a significant reduction in sensitivity
      for coherent motion, and a significantly longer duration of visible persistence.
      The results were also examined by classifying the dyslexic group into dyseidetic,
      dysphonetic, and mixed (dysphoneidetic) subgroups. There were no differences
      between the control and dyseidetic groups in contrast sensitivity, in coherent
      motion and in visible persistence. In comparison to the control group, the mixed
      (dysphoneidetic) dyslexic subgroup was found to have a significant reduction in
      contrast sensitivity at low spatial frequencies, a significant reduction in
      sensitivity for coherent motion, and a significantly longer duration of visible
      persistence. In comparison to the control group, the dysphonetic group only
      showed a reduction in contrast sensitivity at low spatial frequencies.
      Comparisons between the dyseidetic, dysphonetic and mixed dyslexic subgroups
      showed that there were no substantive differences in contrast sensitivity,
      coherent motion, and visible persistence. The results support the proposal and
      findings by Borsting et al. (Borsting E, Ridder WH, Dudeck K, Kelley C, Matsui L,
      Motoyama J. Vis Res 1996;36:1047-1053) that a transient channel disorder may only
      be present in a dysphoneidetic dyslexic subgroup. Psychometric assessment
      revealed that all the children with dyslexia appear to have a concurrent disorder
      in phonological coding, temporal order processing, and short-term memory.

PMID- 10341993
TI  - Fixation disparity and nonius bias.
AB  - Fixation disparity, i.e. the vergence error within Panum's area, can be measured
      psychophysically with two nonius (vernier) lines that are presented
      dichoptically, i.e. one to each eye. The observer adjusts these nonius lines to
      subjective alignment; the resulting physical nonius offset indicates the amount
      of fixation disparity. The present experiments investigate the relation between
      fixation disparity and the nonius bias, which is the physical offset of the
      nonius lines that is adjusted by the observer in order to perceive them as
      aligned when both nonius lines are presented to both eyes (binocular nonius bias)
      or both to the left or both to the right eye (monocular nonius bias). It was
      found that (1) the fixation disparity is correlated with the binocular nonius
      bias in the horizontal and vertical meridian and (2) the binocular nonius bias
      can be predicted from the average of the right eye and left eye monocular nonius
      bias. To remove the influence of the nonius bias on measured fixation disparity
      it is possible to calculate the fixation disparity relative to the individual
      binocular nonius bias, rather than to the physical coincidence of the nonius
      lines. This procedure tends to increase the correlation between fixation
      disparity and the tonic resting position of vergence. We discuss the clinical
      relevance of the dichoptic nonius method for measuring fixation disparity and its
      limitations as compared to physical recordings of eye position.

PMID- 10341994
TI  - Blood tests for cognitive decline?

PMID- 10341995
TI  - Do blood levels of neuron-specific enolase and S-100 protein reflect cognitive
      dysfunction after coronary artery bypass?
AB  - BACKGROUND: Neuron-specific enolase (NSE) and S-100 protein have been used as
      markers for major brain damage. Cognitive dysfunction after cardiac surgery
      represents subtle brain damage that is detected by neuropsychological testing. We
      hypothesised that blood levels of NSE and S-100 protein would increase after
      coronary artery bypass surgery and that the change in blood level would correlate
      with the change in cognitive function. METHODS: We included 35 elderly patients
      undergoing coronary artery bypass surgery. Neuropsychological testing was
      performed before surgery and postoperatively at discharge from hospital and after
      3 months using a neuropsychological test battery. Serum levels of NSE and S-100
      protein were measured before surgery and postoperatively after 24 h and 48 h.
      RESULTS: Serum level of both NSE and S-100 protein increased significantly 24 and
      48 h after coronary artery bypass. Only the increase in NSE after 24 h was found
      to correlate with the degree of cognitive dysfunction at discharge from hospital.
      The increase in S-100 protein after 24 h correlated significantly with the
      duration of cardiopulmonary bypass. CONCLUSION: NSE seems to be a useful blood
      marker for early cognitive dysfunction after coronary artery bypass surgery.

PMID- 10341996
TI  - The role of arterial and venous pressure for volume regulation of an organ
      enclosed in a rigid compartment with application to the injured brain.
AB  - BACKGROUND: Treatment of increased intracranial pressure often includes an active
      change in arterial and venous pressure, sometimes with draining of cerebrospinal
      fluid. We evaluated tissue and perfusion pressure during corresponding
      interventions in an organ enclosed in a rigid compartment with capillaries
      permeable for electrolytes and impaired autoregulation, conditions comparable to
      those present in the injured brain. METHOD: An isolated cat skeletal muscle
      enclosed in a closed fluid-filled plethysmograph served as a model for the
      injured brain surrounded by cerebrospinal fluid and the cranium. Tissue pressure
      and blood flow were measured during variation in arterial and venous pressures
      and in intraplethysmographic fluid volume. Autoregulation was depressed by
      papaverine. RESULTS: 1) Tissue pressure was not influenced by the venous pressure
      when this was below the tissue pressure, hereby generating venous collapse and a
      venous outflow resistance. When venous pressure was higher than the tissue
      pressure (no venous outflow resistance), these two parameters changed in
      parallel. 2) A change in arterial pressure induced a similar large change in
      tissue pressure at steady state, whereas blood flow remained unchanged. 3)
      Variation in tissue pressure induced by a change in the intraplethysmographic
      fluid volume was transient. CONCLUSIONS: If applicable to the injured brain, the
      results indicate that 1) a venous pressure change has a small influence on the
      intracranial pressure when a venous outflow resistance is present, 2) brain
      oedema can be reduced by lowering of the arterial inflow pressure, and blood flow
      will be maintained, 3) the decrease in intracranial pressure obtained by draining
      cerebrospinal fluid will be transient.

PMID- 10341997
TI  - Interaction between fluconazole and midazolam in intensive care patients.
AB  - BACKGROUND: Midazolam is used for sedation of intensive care unit (ICU) patients
      and it is extensively metabolised by CYP3A4 enzymes. The antimycotic fluconazole
      is often used in these patients as well and has been shown to inhibit CYP3A4
      mediated drug metabolism. METHODS: In a study of the effect of fluconazole on
      midazolam in the ICU, ten mechanically ventilated patients (age 29 to 61 years, 8
      male) sedated with a stable midazolam infusion were enrolled after a decision to
      start fluconazole treatment. Fluconazole was infused for 30 min at intervals of
      24 h, with an initial dose of 400 mg and following doses of 200 mg. The midazolam
      infusion rate remained unchanged during the study period of 48 h. Plasma
      concentrations of midazolam, alpha-hydroxymidazolam, and alpha-hydroxymidazolam
      conjugate were determined at baseline, and at 6, 12, 18, 24, 36, and at 48 h
      thereafter. RESULTS: Concentrations of midazolam were significantly increased
      (range 0 to 4-fold, P < 0.05) after start of fluconazole treatment. These
      increases were most marked in patients with renal failure. During the study
      period, the ratio of alpha-hydroxymidazolam to midazolam decreased progressively
      (P < 0.05). CONCLUSION: In ICU patients receiving fluconazole, reduction of
      midazolam infusion rate should be considered if the degree of sedation is found
      to be increasing.

PMID- 10341998
TI  - Splanchnic circulation is maintained during passive hyperventilation in
      orthotopic liver recipients.
AB  - BACKGROUND: Mechanical hyperventilation is an established treatment to reduce
      brain edema and intracranial pressure in patients with encephalopathia caused by
      acute liver failure. Hyperventilation and ensuing hypocarbia may also affect
      central and systemic circulation and thereby influence graft performance in
      patients following orthotopic liver transplantation (OLT). METHODS: We measured
      the effects of normocapnia and hypocapnia on systemic hemodynamics, gastric
      tonometry, as a marker of splanchnic oxygenation, and the indocyanine green
      kinetic, as a global marker of graft function, in humans post OLT. RESULTS:
      Hyperventilation was performed to a PaCO2 of 4.2 +/- 0.4 kPa (31 +/- 3.4 mm Hg)
      for about 1 h in 14 liver transplant recipients. Systemic hemodynamics as well as
      indices of splanchnic oxygenation and indocyanine green kinetics remained
      statistically unchanged. CONCLUSION: We did not observe any statistically
      significant circulatory effects or changes in indocyanine green kinetics in liver
      transplant recipients in the immediate OLT postoperative period caused by short
      term mechanical hyperventilation.

PMID- 10342000
TI  - Cardiopulmonary cerebral resuscitation--present and future perspectives.

PMID- 10341999
TI  - Effect of prostaglandin E1 and nitroglycerin on portal venous flow during
      hypothermic extracorporeal circulation: assessment by transesophageal echography.
AB  - BACKGROUND: Although several vasodilators are used to control vascular resistance
      during cardiac surgery, their effects on splanchnic circulation during
      extracorporeal circulation are unknown. We designed the present noninvasive study
      to evaluate the effect of prostaglandin E1 and nitroglycerin on portal venous
      flow during extracorporeal circulation using transesophageal echography. METHODS:
      We included 26 patients undergoing cardiac surgery with moderate hypothermic
      extracorporeal circulation in this study. After obtaining hemodynamic stability
      under extracorporeal circulation, we measured portal venous diameter, mean flow
      velocity and the velocity time integral using transesophageal echography and
      calculated portal venous flow. The patients were assigned to two groups where
      either prostaglandin E1 (N = 13) or nitroglycerin (N = 13) was administered
      intravenously to maintain perfusion pressure at the level of 70 mmHg. We measured
      the same parameters 20 and 40 min following administration of the drug. RESULTS:
      Visualization of the portal vein was obtained by transesophageal echography in
      anesthetized patients. Calculated portal venous flow significantly increased in
      the prostaglandin E1 group, while it did not alter in the nitroglycerin group.
      CONCLUSION: The present results indicate that transesophageal echography may be a
      feasible tool to assess portal venous flow, and that prostaglandin E1 may improve
      the blood distribution to the splanchnic area and the liver during hypothermic
      extracorporeal circulation.

PMID- 10342001
TI  - Sevoflurane causes more postoperative agitation in children than does halothane.
AB  - BACKGROUND: An agitated recovery may occur after inhalation anesthesia. The aim
      of the present study was to assess the recovery quality after mask anesthesia
      with either halothane or sevoflurane in children. METHODS: Sixty-two children, 8
      months to 18 years of age, scheduled for minor surgery, were randomly assigned to
      receive either halothane or sevoflurane. The patients were premedicated with
      midazolam and anesthesia was induced i.v. with propofol or by inhalation and
      maintained with halothane or sevoflurane in N2O/O2 via face mask. Recovery was
      assessed by a "blinded" observer using a postanesthetic recovery score. Agitation
      and pain were judged using a visual analog scale. The incidence of vomiting was
      noted. The day after anesthesia older children and parents of younger children
      were interviewed about their experience of the anesthesia and recovery period.
      RESULTS: There were no differences between groups in respect of age, weight,
      length, or duration of surgery or inhalational gas exposure. Median time from end
      of administration of inhalational agent to spontaneous eye opening was less after
      sevoflurane (25 min) than after halothane (48 min), (P < 0.01). Likewise,
      recovery was faster after sevoflurane anesthesia (P < 0.05). Agitation, but not
      pain, occurred more frequently after sevoflurane than after halothane (P < 0.05)
      and agitation was significantly more common in younger children. There was no
      difference in duration of hospital stay between day-care patients in the two
      groups. CONCLUSION: Early postanesthetic agitation and recovery was faster after
      mask anesthesia with sevoflurane than after halothane. There was a higher
      incidence of agitation in younger children, without correlation to pain.

PMID- 10342002
TI  - Preoperative anxiety is associated with a high incidence of problematic behavior
      on emergence after halothane anesthesia in boys.
AB  - BACKGROUND: In our clinical experience, children who are crying before anesthesia
      are more likely to show agitated behavior on emergence. METHODS: One hundred and
      ten boys aged 3-6 years old (ASA 1) who underwent circumcision were studied. The
      children were assigned to one of two groups, depending on their attitude during
      induction: the anxious group and the calm group. Anesthesia was induced by
      inhalation of halothane in oxygen, and was maintained at 1% throughout surgery.
      For intra- and postoperative analgesia, caudal block with 0.5 ml/kg of 0.25%
      plain bupivacaine and topical infiltration with 1 to 2 ml of 1% lidocaine were
      provided for all patients. The incidence of delirium on emergence was compared
      between the groups. RESULTS: We excluded 4 boys showing signs of incomplete pain
      relief. Twenty of 27 boys in the anxious group showed a significantly greater
      incidence of problematic behavior on emergence, compared to 5 of 79 in the calm
      group. CONCLUSION: The boys who were anxious before anesthesia showed a
      significantly greater incidence of problematic behavior on emergence from
      halothane anesthesia, compared with the boys who were calm before anesthesia.

PMID- 10342003
TI  - EEG bispectral index monitoring in sevoflurane or propofol anaesthesia: analysis
      of direct costs and immediate recovery.
AB  - BACKGROUND: Recent studies have suggested that electroencephalogram (EEG)
      bispectral index (BIS) monitoring can improve recovery after anaesthesia and save
      money by shortening patients' postoperative stay. We wanted to evaluate the
      direct costs of BIS monitoring and to measure immediate recovery after
      anaesthesia in patients with or without BIS monitoring. METHODS: Eighty patients
      undergoing gynaecological surgery were studied. At first, 40 patients were
      randomized to receive either propofol or sevoflurane anaesthesia. In these
      patients, BIS was collected but the information was not displayed. Thereafter,
      the anaesthesiologists were trained to follow and understand the BIS information,
      and 40 patients were anaesthetized with aid of the monitoring. Recovery times
      were measured by a study coordinator. Drug consumption was calculated. RESULTS:
      BIS monitoring improved the immediate recovery after propofol anaesthesia, while
      no differences were seen in patients receiving sevoflurane. The consumption of
      both propofol and sevoflurane decreased significantly (29% and 40%,
      respectively). BIS monitoring increased direct costs in these patients; the break
      even times (704 min for propofol and 282 min for sevoflurane) were not reached.
      CONCLUSION: BIS monitoring decreased the consumption of both propofol and
      sevoflurane and hastened the immediate recovery after propofol anaesthesia.
      Detailed cost analysis showed that the monitoring increased direct costs of
      anaesthesia treatment in these patients, mainly due to the price of special EEG
      electrodes used for relatively short anaesthesias.

PMID- 10342004
TI  - A comparison of train-of-four monitoring: mechanomyography at the thumb vs
      acceleromyography at the big toe.
AB  - BACKGROUND: It is not known if the information on neuromuscular function obtained
      from the hand is interchangeable with that of the foot. In the present study the
      agreement of thumb mechanomyography with acceleromyography of the big toe was
      studied. METHODS: Ten healthy patients scheduled for oral surgery were studied.
      Anaesthesia was induced with fentanyl 2 micrograms kg-1 and propofol 2 mg kg-1,
      and maintained with propofol 100-175 micrograms kg-1 min-1, nitrous oxide 60-70%,
      and fentanyl 1-2 micrograms kg-1 h-1. Vecuronium 0.1 mg kg-1 was used for muscle
      relaxation. Mechanomyography (MMG) of the thumb (Myograph 2000) and
      acceleromyography (AMG) of the big toe (TOF-Guard) were recorded simultaneously
      in all patients, and onset, period of no-twitch response, duration of action, and
      spontaneous recovery time obtained from both muscle groups. The agreement between
      methods was tested by calculation of bias and limits of agreement. RESULTS: The
      onset time and duration of action were significantly shorter (87 s vs 154 s, and
      35 min vs 38 min, respectively), and the spontaneous recovery time significantly
      longer in the thumb than in the big toe (32 min vs 19 min). Period of no-twitch
      response was not significantly different in the two muscle groups. Limits of
      agreement (thumb big toe) were -21 to -113 s, -7 to 1 min, and -9 to 35 min, for
      onset time, duration of action, and spontaneous recovery time, respectively.
      CONCLUSIONS: We conclude that clinically acceptable agreement between thumb
      mechanomyography and big toe acceleromyography was found for the period of no
      twitch response, suggesting that the timing of supplemental doses of vecuronium
      can be guided by AMG at the big toe. However, the spontaneous recovery time
      agreement (to TOF ratio = 0.75) between the thumb and the big toe was poor.

PMID- 10342005
TI  - Enhancement of intrathecal lidocaine by addition of local and systemic clonidine.
AB  - BACKGROUND: Enhancement of local anesthetic-produced regional blocks by clonidine
      seems well established. There are insufficient data about dose-effect
      relationship of combinations of clonidine with individual agents, efficiency of
      local versus systemic administration of clonidine, and comparative evaluation of
      clonidine with vasoconstrictors. Because of unavailability of long-acting local
      anaesthetics at the time of study, our aim was to evaluate augmentation of
      lidocaine spinal block with local or systemic clonidine and to compare the
      results with the efficacy of intrathecal phenylephrine. METHODS: Ninety pts of
      age 50-72 yrs with ASA 1-4 physical status, scheduled for open prostatectomies,
      hysterectomies or ostheosynthesis of fractured hip were randomized to one of 6
      treatment groups, 15 pts in each. Patients received intrathecally (L3-L4) either
      100 mg of plain lidocaine (group L100); or a mixture of lidocaine 40 and 80 mg
      with clonidine 100 micrograms (groups L40-C100 and L80-C100); or a combination of
      lidocaine 40 and 80 mg with clonidine 300 micrograms orally 60 min before spinal
      puncture (L40-C300 and L80-C300). Addition of intrathecal phenylephrine 5 mg to
      80 mg of lidocaine was also investigated (L80-P5). RESULTS: There were no
      significant intergroup differences concerning demographic data or type of
      surgery. All operations (duration up to 150 min) were completed without need for
      analgesic supplementation. The addition of clonidine resulted in a significant
      reduction of the onset time of spinal block and prolongation of the duration of
      sensory and motor blocks compared to plain lidocaine or lidocaine with
      phenylephrine. In spite of the well-known hypotensive action of alpha 2-agonists,
      haemodynamic depression only in group L80-C300 was significantly more pronounced
      than in L100 and L80-P5 groups. The least decrease of BP and minimal need of
      rescue ephedrine among all patients studied were recorded in the group receiving
      low dosage of lidocaine with intrathecal clonidine (L40-C100). Sedation occurred
      in most patients receiving clonidine. CONCLUSION: Our results indicate that
      addition of clonidine to lidocaine, irrespective of the route of administration,
      prolongs the duration of spinal block and permits a reduction of the lidocaine
      dose needed for a given duration of block. Addition of phenylephrine results in a
      less pronounced statistically significant prolongation of anaesthesia. The
      regression of sensory block before restoration of motor function seems to be a
      specific (and unfortunate) effect of both clonidine and phenylephrine.

PMID- 10342006
TI  - Chronic pain after thoracic surgery: a follow-up study.
AB  - BACKGROUND: The incidence of long-term post-thoracotomy pain is reported to be up
      to 67%. A relationship between the severity of acute postoperative pain and the
      development of chronic post-thoracotomy pain has been suggested. METHODS:
      Patients scheduled for elective thoracotomy were interviewed before and one week
      after surgery to find out if they had pain before surgery and how much pain they
      experienced postoperatively. The amount of analgesics the patients were given
      were registered during the first 5 postoperative days. The patients were
      interviewed by letter 3, 6 and 12 months after surgery to find out if they still
      had pain due to surgery and to what extent this pain interfered with their daily
      activities. RESULTS: One hundred and ten patients entered the study. Information
      about the complete study period was obtained from 67 patients. The incidence of
      chronic post-thoracotomy pain was 80% at 3 months, 75% at 6 months and 61% one
      year after surgery. The incidence of severe pain was 3-5%. Chronic post
      thoracotomy pain interfered with the patient's normal daily life in more than
      half of the patients. High consumption of analgesics during the first
      postoperative week was associated with a higher risk of chronic post-thoracotomy
      pain. CONCLUSION: A significant proportion of patients undergoing thoracotomies
      will suffer from chronic pain. Surgeons and anaesthetists should be aware of this
      fact and they should look for effective means of preventing and treating this
      pain syndrome.

PMID- 10342007
TI  - Continuous epidural administration of midazolam and bupivacaine for postoperative
      analgesia.
AB  - BACKGROUND: Midazolam has been reported to have a spinally mediated analgesic
      effect. Clinically, single-shot epidural or spinal administration of midazolam
      has been shown to have an analgesic effect on perioperative pain. In this study,
      we investigated the analgesic effect of continuous epidural administration of
      midazolam with bupivacaine on postoperative pain. METHODS: Four groups of 20
      patients who underwent gastrectomy or cholecystectomy were studied. Continuous
      epidural infusion of bupivacaine 100 mg (Group C), bupivacaine 100 mg + midazolam
      10 mg (Group M10), or bupivacaine 100 mg + midazolam 20 mg (Group M20) in 40 ml
      per 12 h was started after surgery using the balloon infuser. Group I received
      intermittent epidural bupivacaine (2.5 mg.ml-1) 6 ml every 2 h. When necessary,
      an indomethacin suppository and then a single epidural shot of bupivacaine (2.5
      mg.ml-1) 6 ml was administered. Blood pressure, heart rate, respiratory rate,
      analgesic area, analgesia score, and sedation score were monitored for 12 h
      postoperatively. Memory and frequencies of supplemental analgesia (indomethacin
      suppositories and epidural bupivacaine) were also checked. RESULTS: Group M20
      showed a significantly wider area of pinprick analgesia and better analgesia
      scores than other groups. The need for rescue analgesics were significantly less
      in Group M20. Sedation and amnesia were more pronounced in Group M20 than the
      other groups. CONCLUSION: Adding midazolam (10 to 20 mg per 12 h) to continuous
      epidural infusion of bupivacaine for postoperative pain can provide a better
      analgesia, amnesia and sedation than bupivacaine alone.

PMID- 10342008
TI  - Sameridine--intrathecal injection in the rat. Morphometric and morphologic
      analysis after chronic administration and effects on spinal cord blood flow.
AB  - BACKGROUND: Sameridine is a type of compound with both local anaesthetic and
      analgesic effects with the clinical intention to be used intrathecally (i.t.) in
      order to provide both surgical anaesthesia and prolonged postoperative analgesia.
      Before new drugs are introduced for clinical use, they must be tested for
      potential toxic effects. METHODS: In the present study sameridine (5 or 10
      mg/ml), bupivacaine (5 mg/ml) or saline (9 mg/ml) was injected intrathecally in
      rats twice, daily (at 07:00 and 19:00), 5 days a week for 2 weeks. Thereafter,
      the rats were anaesthetised, perfused and the spinal cords were prepared for
      microscopic investigation. A morphologic method, using light and electron
      microscopic examination of the cross-section of the spinal cord, was combined
      with a quantitative morphometric analysis of the number and size of neuronal
      cells in the dorsal horn as a sensitive indicator of neurotoxicity. Using the
      laser-Doppler flowmetry technique, the effects of saline and sameridine (1, 5 and
      10 mg/ml) on spinal cord blood flow (SCBF) was studied. RESULTS: No signs of
      neurotoxicity could be seen in any of the animals and no significant differences
      were seen when comparing the cell number or cell sizes in the groups injected
      with sameridine, bupivacaine or saline. After i.t. administration of 10 mg/ml
      sameridine a significant, short-lasting, decrease in SCBF (72% of pre-drug value)
      was seen. CONCLUSION: In conclusion, our studies do not show any signs of
      neurotoxic effects of i.t. administration of sameridine in the rat. A transient
      decrease in SCBF was noted after i.t. injection of sameridine 10 mg/ml.

PMID- 10342009
TI  - Infiltration block for caesarean section in a morbidly obese parturient.
AB  - We report a case of a morbidly obese parturient (150 kg and 150 cm) for emergency
      lower segment caesarean section for dead foetus. Her pregnancy had been
      unsupervised. She presented with severe pre-eclampsia, generalized oedema and
      acute respiratory failure. Caesarean section was performed under infiltration
      block using lidocaine 0.5-1.0%. Her status improved postoperatively with
      aggressive physiotherapy, nursing in a semirecumbent position and oxygen
      supplementation.

PMID- 10342010
TI  - Alveolar soft part sarcoma: a review and update.
AB  - Alveolar soft-part sarcoma (ASPS) is one of the most unusual of the soft tissue
      sarcomas. Although it most commonly arises in the fascial planes or skeletal
      muscles of the lower extremities in adults, and in the head and neck region in
      children, it has also been documented in extraskeletal muscle locations,
      especially the female genital tract. Despite extensive investigation, the
      histogenesis of ASPS continues to be an unsettled issue a half century after its
      description. The most significant morphologic features are the organoid pattern
      and the ultrastructural demonstration of a secretory activity that ends in the
      formation of the characteristic crystals. Early suggestions that it was related
      to paragangliomas or had a Schwann cell derivation have been discounted. More
      recently, a possible skeletal muscle origin has been favored based on the
      immunohistochemical demonstration of various muscle-associated proteins,
      especially desmin. However, a report of immunoreactivity for the myogenic
      regulatory protein MyoD1 has not been confirmed in subsequent studies. Although
      some immunohistochemical studies have recently indicated that ASPS may have
      muscle differentiation, there is presently no conclusive evidence that it
      represents a unique type of muscle-derived tumor.

PMID- 10342011
TI  - Surgical excision margins: a pathologist's perspective.
AB  - The histopathologic status of excisional margins of malignant neoplasms has long
      been used as a potential indicator for recurrences and prognosis. The predictive
      ability of the margin, however, is far from satisfactory. Perhaps nowhere else in
      oncologic pathology has the significance of these margins been as intensively
      studied as in squamous cell carcinomas of the upper aerodigestive tracts. This
      review is, in part, a critique of current applications and the clinical
      implications of surgical margins for the removal of squamous cell carcinomas in
      these tracts. Specific points addressed in this article are: 1) postremoval
      (artifactual) changes in measurements; 2) the impact of margin status, as
      currently assessed, on recurrence and patient outcome; 3) margins and
      conservation surgery of the larynx; 4) margins and bone (mandible) invasion; and
      5) molecular (p53 and eIF4E) margins.

PMID- 10342013
TI  - Toward a clearer understanding of the link between viral infection of the heart
      and dilated cardiomyopathy.
AB  - This commentary discusses the current knowledge regarding the relationship
      between virus, myocarditis, and dilated cardiomyopathy. The concept of
      inflammatory cardiomyopathy is discussed. The possible role of HIV in the
      development of dilated cardiomyopathy in HIV-seropositive subjects is critically
      evaluated.

PMID- 10342012
TI  - The hereditary forms of pancreatic neuroendocrine tumors.
AB  - Pancreatic endocrine tumors occur sporadically or in the setting of multiple
      endocrine neoplasia type I (MEN-1) or von-Hippel-Lindau disease. In the latter
      circumstances, the tumors are often multiple. This commentary addresses the
      differences in clinical, pathologic, and molecular features of MEN-1 and von
      Hippel-Lindau disease associated pancreatic endocrine tumors.

PMID- 10342014
TI  - Thin-layer cytology meets viral hybrid capture.
AB  - This commentary addresses the benefits of liquid-based thin-layer cervical
      cytology, and the applicability of residual samples for human papilloma virus
      assay. The potential for use of this technology in wide-scale screening as well
      as the many unanswered issues, in particular cost-benefit ratio and financing,
      are also discussed.

PMID- 10342015
TI  - Osteoporosis: risk factors, fractures and figures.

PMID- 10342016
TI  - Targets in hypertension. Going nowhere or gone as far as we can go?

PMID- 10342017
TI  - Risk factors for osteoporosis and fracture in patients attending rheumatology
      outpatient clinics.
AB  - BACKGROUND: Bone mineral density (BMD) using dual energy X-ray absorptiometry
      (DXA) scanning is the best predictor of osteoporotic fracture but may not be cost
      effective for all patient groups. Risk factors (RF) other than BMD may be useful
      for fracture prediction. AIM: To assess the prevalence of RF for osteoporosis
      (OP) and fracture in patients attending a public hospital rheumatology clinic and
      to document physician awareness of these RF. METHODS: Two hundred and twenty
      rheumatology outpatients completed a self-administered questionnaire pertaining
      to known RF for OP and fracture. Initiatives were documented by the treating
      rheumatologist. RESULTS: One hundred and fifty-four females and 66 males
      completed questionnaires: 57% had an inflammatory disorder and 32% had received
      significant glucocorticoid therapy. Forty-five (68%) males and 126 (82%) females
      had three or more RF for OP and fracture. Diagnosis of rheumatoid arthritis or
      connective tissue disorder (CTD) was the variable most significantly associated
      with increasing numbers of RF. Antiosteoporotic medication (AOM) use at
      assessment (64/219, 29.2%) was accounted for primarily by the use of hormone
      replacement therapy in females between 45-54 years. Prednisolone use predicted
      intervention in 103 (48%) patients. CONCLUSION: Many rheumatology outpatients
      have multiple RF for OP and fracture. Infrequent AOM use could be explained by
      inadequate awareness of high risk patients and the lack of an ideal long term
      agent. With restricted outpatient resources, the feasibility of identifying high
      risk patients for OP and fracture would increase if the hierarchical status of RF
      was better understood.

PMID- 10342018
TI  - Identification of incident fractures: the Geelong Osteoporosis Study.
AB  - BACKGROUND: Complete fracture ascertainment is critical for fracture cost
      estimates and planning for future health care facilities. Virtually complete
      ascertainment is possible for hip fractures because they nearly always require
      hospitalisation. AIMS: To validate the use of radiological reports as a resource
      for ascertaining fracture cases, using hip fracture as a model. METHODS: Hip
      fracture rates obtained from radiological reports were compared with rates
      obtained from hospital discharge summaries of medical records using International
      Classification of Diseases-9 (ICD-9) codes 820.0-820.9 and 733.1 over a three
      year period. RESULTS: Hip fracture cases numbered 589 using radiological reports
      and 585 using medical records. Discharge summaries failed to identify 15 cases
      ascertained through radiology reports whereas 11 cases ascertained through
      medical records were not identified from X-ray reports. The age-specific
      incidence rates for radiological ascertainment were within the 95% confidence
      limits of the rates derived from medical records. CONCLUSIONS: Among a population
      of patients generally admitted to hospital for treatment of their fracture, we
      were able to identify more cases from radiological reports than from medical
      records. Incidence rates for hip fracture were comparable using the two methods.
      Radiological reports provide a valuable resource for identifying incident
      fractures. This method of case ascertainment would be suitable for identifying
      both major and minor fractures in regions with self-contained health services
      where access to all radiological reports is possible.

PMID- 10342019
TI  - Attitudes and information needs of Chinese migrant cancer patients and their
      relatives.
AB  - BACKGROUND: The information needs of ethnic minorities often differ from that of
      the dominant culture, leading to dissatisfaction among both patients and health
      professionals. AIMS: This research project aims to identify attitudes towards
      cancer and associated information and communication needs of Chinese patients and
      their relatives in Sydney, thereby providing a framework for the provision of
      culturally appropriate cancer care for Chinese-Australians. METHODS: A
      qualitative data collection strategy was selected as the most appropriate method,
      because no validated measures are available and no previous research has examined
      attitudes and needs of Chinese-Australian cancer patients. Patients were
      recruited from three major teaching hospitals in Sydney and from a Chinese cancer
      support organisation. Sampling was discontinued when informational redundancy was
      achieved. Four focus groups and 26 individual telephone interviews were conducted
      with a total of 36 cancer patients and 12 relatives born in China, Singapore and
      Malaysia. RESULTS: While individual differences were observed, a majority view
      was expressed on a range of issues. Non-disclosure of a poor prognosis was
      favoured, and the role of the family in liaising between health professionals and
      the patient was emphasised. Patients preferred a confident and clear diagnosis
      and treatment recommendation. Most patients wished to incorporate Chinese culture
      specific treatments into their care. The need for interpreters and psychological
      and spiritual support was emphasised. CONCLUSIONS: Providing information in a
      culturally sensitive manner will assist doctors in providing optimum care and
      support for ethnic minority groups in this country.

PMID- 10342021
TI  - Uncovering a multitude of sins: medication management in the home post acute
      hospitalisation among the chronically ill.
AB  - BACKGROUND: Sub-optimal use of prescribed medication is often associated with
      unplanned hospitalisation among the chronically ill. AIMS: To examine the extent
      of sub-optimal use of prescribed medication in a 'high risk' patient cohort
      recently discharged from acute hospital care. METHODS: Chronically ill patients
      discharged from acute hospital care (n = 342) were studied. At one week post
      discharge a home visit was performed by a nurse and a pharmacist during which
      medication management (including compliance and medication-related knowledge) was
      assessed. RESULTS: During the majority of home visits at least one medication
      related problem was detected: approximately half of the cohort subject to a
      'reliable' pill-count were found to be mal-compliant and almost all demonstrated
      inadequate medication-related knowledge. Mal-compliance was correlated with > or
      = five prescribed medications (Odds ratio [OR] 2.6: p < 0.002). Comparatively,
      lower medication-related knowledge was correlated with age > 75 years (OR 2.2: p
      < 0.001), exacerbation of a pre-existing chronic illness (OR 2.7: p = 0.044) and
      < or = six years formal education (OR 1.9: p = 0.004). Neither were modulated by
      extent of in-hospital counselling. Other previously unknown problems detected
      during the home visit included hoarding of previously prescribed medication (35%)
      and reducing medication intake to minimise costs (21%). CONCLUSIONS: Management
      of prescribed medications among chronically ill patients recently discharged from
      acute hospital care is often sub-optimal. Assessment of medication management in
      the home provides an invaluable opportunity to detect and address problems likely
      to result in poorer health outcomes.

PMID- 10342020
TI  - Osteolymphoma (primary bone lymphoma): an Australian review of 70 cases.
      Australasian Radiation Oncology Lymphoma Group (AROLG).
AB  - BACKGROUND: To examine prognostic factors, treatment outcomes and design future
      studies for Osteolymphoma (OL)--also known as primary bone lymphoma. METHODS:
      Between 1979 and 1993, 70 patients with OL were treated in nine Australian
      centres. The effect of patient-, tumour-, and treatment-related factors on local
      control, distant disease-free survival and overall survival were assessed by
      multivariate analysis. RESULTS: Most patients (94%) received radiotherapy (RT)
      (median dose 40 Gy) and 56% received chemotherapy. Multifocal disease was present
      in 20% of patients. The five year rates of overall survival and local control
      were 59% and 82%. Although there was a trend towards better results with the
      addition of chemotherapy, on multivariate analysis, there were no factors
      identified which appeared to impact upon overall and disease-free survival. Among
      the distant recurrences, there was a high proportion in bone (33%). Six patients
      suffered pathological fractures after treatment. CONCLUSION: High rates of local
      control were achieved by RT, but the overall survival remains relatively poor,
      worse than nodal lymphoma. The natural history of the disease suggests that OL
      may be a distinct entity, different to nodal lymphomas, so the results of
      clinical trials in nodal lymphoma may not be relevant to OL. Prospective studies
      could define the outcome of combined modality therapy and set a benchmark for
      testing further proposals, as well as improving our knowledge of the clinical
      features of OL.

PMID- 10342022
TI  - The economic cost of asthma in Singapore.
AB  - BACKGROUND: Asthma is a common chronic disorder. In Singapore, it is estimated
      that 140,000 individuals have current asthma and more than 100 individuals die of
      this disease annually. OBJECTIVE: This study estimates the economic cost of
      asthma, both direct and indirect, to the patient and community. METHOD: Direct
      cost estimates were based on all levels of medical care, which included inpatient
      care, emergency room visits, specialist outpatient and primary healthcare, and
      medication costs. Indirect costs were estimated from cost of time lost by
      patients and their families attending to medical needs and the loss of
      productivity due to absenteeism. These estimates were calculated to the 1992/93
      US dollar. RESULTS: The total cost of asthma in Singapore was estimated to be US
      $33.93 million per annum. This was made up of US $17.22 million in direct costs
      and US $16.71 million in indirect costs. Inpatient hospitalisation accounted for
      the largest proportion of direct medical expenditure, approximately US $8.55
      million. The loss of productivity from acute asthma accounted for the largest
      proportion of the indirect costs at US $12.70 million. The cost estimates did not
      include premature death due to disease. These estimates represent approximately
      US $238 per asthmatic person per year or US $11.90 per person per year.
      CONCLUSION: This study shows that the economic cost of asthma is also
      considerable in populations outside the Western hemisphere, and justifies the
      need for a concerted effort to reduce asthma morbidity worldwide.

PMID- 10342023
TI  - Shared rheumatoid epitope as a risk factor in determining outcome in rheumatoid
      arthritis.
AB  - BACKGROUND: A genetic component is thought to contribute to 30-40% of the
      expression of rheumatoid arthritis (RA) with the HLA-DR4, w4 (B1*0401), w14
      (B1*0404) genes (and associated shared rheumatoid epitope) constituting a
      substantial portion of this risk. AIM: Our objective was to determine the
      presence of these risk factors in a group of patients with RA and to correlate
      presence with disease outcome. METHOD: Forty-three RA patients who had been
      regularly assessed up to a ten year period since their initial entry into two
      gold treatment trials were studied. DR4, w4, w14 and shared rheumatoid epitope
      were determined on peripheral blood lymphocytes using flow cytometry and specific
      monoclonal antibodies. Disease outcome was measured by Health Assessment
      Questionnaire (HAQ) score and C-Reactive Protein (CRP) as a serological measure
      of joint inflammation. RESULTS: To confirm accuracy of the flow cytometric
      technique, DR typing and epitope status was compared with results obtained by
      genotyping in a subset of 14 patients. There was complete concordance between
      these two techniques for the rheumatoid epitope. However, concordance was not
      complete (both false positives and false negatives) for DR4, w4 and w14. Hence
      the presence of rheumatoid epitope was only evaluated further in the larger
      group. The presence of the shared rheumatoid epitope correlated positively with
      poorer outcome on serological assessment (p < 0.05). No significant correlation
      between HAQ score and rheumatoid epitope status was observed although a weak
      trend was noted. CONCLUSION: These studies suggest that determination of
      rheumatoid epitope status by flow cytometry may provide useful data concerning
      the long term outcome of patients with RA.

PMID- 10342024
TI  - Anti-transglutaminase antibodies and coeliac disease.
AB  - BACKGROUND: Anti-endomysial antibodies have high specificity for coeliac disease
      but measurements are limited by the requirement for monkey oesophagus, a
      substrate that is expensive, and of limited availability and ethical acceptance.
      Tissue transglutaminase has recently been identified as the endomysial
      autoantigen in coeliac disease. AIMS: To examine the validity of serum tissue
      transglutaminase antibody levels in patients with coeliac disease and to assess
      their sensitivity and specificity against standard serological tests. METHODS:
      Serum IgA anti-tissue transglutaminase antibody titres (measured by ELISA), IgA
      anti-gliadin antibody titres (measured by a commercial ELISA) and anti-endomysial
      antibody titres (measured by indirect immunofluorescence) were determined in 46
      untreated and 14 treated patients biopsy-proven coeliac disease and 145 disease
      and healthy controls. RESULTS: All patients with untreated coeliac disease were
      positive for anti-endomysial and anti-tissue transglutaminase antibodies
      (sensitivity 100%). Seventy-one per cent of treated coeliac patients were anti
      tissue transglutaminase antibody negative. Five of 145 disease and healthy
      controls had low titres of anti-tissue transglutaminase antibody (specificity
      97%); no controls were anti-endomysial antibody positive. CONCLUSIONS: Our
      results demonstrated the sensitivity and specificity of IgA anti-tissue
      transglutaminase antibodies to correlate highly with anti-endomysial antibodies
      in the diagnosis of coeliac disease. The ELISA for IgA anti-tissue
      transglutaminase antibodies is quantitative and easy to perform and is a valid
      alternative to indirect immunofluorescence for anti-endomysial antibodies in
      screening for suspected coeliac disease.

PMID- 10342025
TI  - Impact of an aggressive stenting strategy on initial and one-year follow-up costs
      in patients undergoing coronary angioplasty.
AB  - BACKGROUND: Although stents have been shown in randomised trials to reduce
      restenosis rates compared with balloon angioplasty, there are concerns regarding
      the cost-effectiveness of an aggressive stenting strategy. Stents were shown to
      increase medical costs over 12 months in the early trials. AIM: Our aim was to
      determine the economic impact of an aggressive stenting strategy using current
      stenting techniques compared with a conservative stenting strategy. METHODS:
      Initial and one year follow-up costs were determined in all patients who
      underwent successful revascularisation during June to December 1996 (aggressive
      stenting, n = 401), and compared to all patients treated in the corresponding
      months in 1995 (conservative stenting, n = 347). All patients had clinical follow
      up for one year. RESULTS: The proportion of patients receiving a stent increased
      from 22.5% in 1995 to 66.1% in 1996 (p < 0.0001). Requirement for repeat
      procedures in the 1995 group compared with 1996 was coronary angiography in 31%
      vs 16% (p < 0.001), coronary angioplasty in 11% vs 6% (p = 0.0044) and bypass
      surgery in 4.8% vs 2.5% (p = 0.054). The mean initial cost of the procedure was
      higher in the aggressive stenting group ($4319 +/- 1276 in 1995 vs $5131 +/- 1491
      in 1996, p < 0.0001), but after 12 months follow-up, total medical costs were
      equivalent ($5975 +/- 4143 in 1995 vs $5994 +/- 3476 in 1996, p = NS).
      CONCLUSION: An aggressive coronary stenting strategy is associated with higher
      initial costs compared with a conservative strategy, but lower costs during
      follow-up due to reduced need for repeat procedures, resulting in equivalent one
      year total medical costs.

PMID- 10342026
TI  - Type 2 diabetes towards the new millennium--the relative importance of glycaemic
      versus lipid control.
AB  - The prevalence of type 2 diabetes is set to increase. The UKPDS has shown that
      better average glycaemic control over time leads to a reduction in microvascular
      complications. Macrovascular outcomes are also reduced in overweight subjects
      treated with metformin. The UKPDS and our own data, however, show that the
      natural history of type 2 diabetes is one of progressive deterioration in
      glycaemic control despite treatment. Lipid parameters emerges as the strongest
      predictors of outcomes in type 2 diabetes and suggest where therapeutic
      endeavours might best be directed. Ongoing trials of lipid-modifying therapies in
      type 2 diabetes will help to substantiate this. In the meantime, efforts to
      improve glycaemic control should not be pursued to the exclusion of other
      abnormalities that may have a greater relevance to outcomes of type 2 diabetes.
      There is an urgent need for better prevention and intervention strategies as we
      approach the new millennium.

PMID- 10342027
TI  - Optimising care of the hospitalised elderly. A literature review and suggestions
      for future research.

PMID- 10342028
TI  - Aromatase inhibition alters vascular reactivity and arterial compliance in men: a
      possible vascular role for endogenous sex hormones in males.

PMID- 10342029
TI  - A case of encephalitis in central Australia due to Ross River virus?

PMID- 10342030
TI  - Helicobacter pylori and peptic ulcer disease.

PMID- 10342031
TI  - Thoracic hernia.

PMID- 10342032
TI  - Recurrent right pleural effusion in a young man.

PMID- 10342033
TI  - Severe adverse reaction to high dose epirubicin and cyclophosphamide for poor
      prognosis breast cancer.

PMID- 10342034
TI  - Monoclonal gammopathy: benign or not?

PMID- 10342035
TI  - Renal infarction presenting as hypertension following resection of a follicular
      dendritic sarcoma.

PMID- 10342036
TI  - Progressive hepatic failure secondary to adult polycystic kidney disease.

PMID- 10342037
TI  - Rubella antibody in antenatal clinic patients.

PMID- 10342038
TI  - Genitourinary sarcoidosis.

PMID- 10342039
TI  - The management of Behcet's syndrome: how are we doing?

PMID- 10342041
TI  - Characteristics of the protease activity in synovial fluid from patients with
      rheumatoid arthritis and osteoarthritis.
AB  - OBJECTIVE: To clarify which proteases are specifically activated in the lesions
      of rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: The activity
      levels of the serine proteases of the coagulation and fibrinolytic systems, and
      of elastase and collagenase as controls, in synovial fluid from 27 RA patients
      and 28 OA patients were measured using fluorogenic synthetic substrates which had
      methylcoumarylamide (MCA) at their COOH-termini. The thrombin-antithrombin III
      complex (TAT) content was also measured by ELISA. RESULTS: Among the proteases,
      thrombin-like activity was the highest in both RA and OA. The profiles of
      protease activity were similar in RA and OA, but their activities were in general
      significantly higher in RA than in OA (p < 0.01). The levels of both thrombin
      like activity and TAT were about 7.5-fold higher in RA than in OA, while the
      levels of CRP and fibrinogen were only about 2-fold higher. Biochemical
      characterization of the thrombin-like activity in the synovial fluid of RA
      patients showed that this activity was due to thrombin. Thrombin-like activity
      positively correlated with the TAT concentration in RA (r = 0.750, p < 0.0001),
      but not in OA. CONCLUSION: Activation of the coagulation system was more marked
      in RA than in OA, strongly suggesting that in RA there is an imbalance between
      thrombin and its inhibitors, and that thrombin is more closely linked to the
      pathogenesis of RA than to that of OA. Our results also show that analysis of the
      synovial fluid may be useful to estimate the activation of the coagulation system
      in RA, but not that of the fibrinolytic system.

PMID- 10342040
TI  - Effects of nimesulide and sodium diclofenac on interleukin-6, interleukin-8,
      proteoglycans and prostaglandin E2 production by human articular chondrocytes in
      vitro.
AB  - OBJECTIVES: The aim of this study was to investigate the effects of two
      nonsteroidal anti-inflammatory drugs (NSAIDs), nimesulide and sodium diclofenac,
      on the production of proteoglycans (PG), prostaglandin E2 (PGE2) and cytokines
      (IL-6 and IL-8) by human articular chondrocytes in vitro. METHODS: Enzymatically
      isolated chondrocytes were cultured under constant agitation in a well defined
      culture medium. Specific radioimmunoassays were used to quantify PG and PGE2
      production. Cytokine production (IL-6 and IL-8) was assayed by enzyme amplified
      sensitivity immunoassays (EASIAs). RESULTS: At a concentration of 3
      micrograms/ml, nimesulide did not affect the PG production by chondrocytes. This
      concentration was superior to the highest level of nimesulide found in the
      synovial fluid of patients with rheumatoid arthritis 3 hours after the last oral
      administration of nimesulide (100 mg twice daily for 7 days). At 6 micrograms/ml
      a significant reduction in the PG content was obtained in the cellular phase in 5
      out of the 8 cultures investigated. No similar effect was observed in the culture
      supernatants. Above this concentration nimesulide inhibited PG production in a
      dose-dependent manner. At concentrations ranging from 0.005 to 1 microgram/ml
      diclofenac did not significantly alter PG production. At therapeutic
      concentrations PGE2 production was totally inhibited by nimesulide, thus
      suggesting that PG inhibition is not linked to PGE2 production. Nimesulide
      inhibited PGE2 production by unstimulated (IC50 = 6 ng/ml) and IL-1 beta
      stimulated (IC50 = 6.9 ng/ml) chondrocytes. At these concentrations, PGE2
      production was fully inhibited by diclofenac. Furthermore, both nimesulide and
      diclofenac at therapeutic concentrations significantly decreased spontaneous and
      IL-1 beta-stimulated IL-6 production by human chondrocytes, but did not modify IL
      8 production. CONCLUSION: From the results of this study we conclude that
      nimesulide and diclofenac at therapeutic concentrations are potent inhibitors of
      PGE2 and IL-6 production while they do not modify proteoglycan or IL-8
      production.

PMID- 10342042
TI  - Systemic lupus erythematosus survival in Hungary. Results from a single centre.
AB  - OBJECTIVE: Systemic lupus erythematosus survival has improved worldwide. The
      authors present the first Hungarian survival results, analysing retrospectively
      data on 532 lupus patients who were followed at a single centre over the past 25
      years. RESULTS: Survival of SLE patients has improved in Hungary as indicated by
      the results of life-table analysis, and the increase in both the five- and ten
      year survival rates. The outcome was less favourable for males and for patients
      under 20 and over 50 years of age at the time of diagnosis. The mortality ratio
      decreased with disease duration, and the risk of death due to SLE was the highest
      within the first five years of the disease. The majority of young lupus patients
      were lost within this period. The mean cause of death was renal insufficiency in
      the younger patient population and in the early phase of the disease. Heart
      failure and a naturally increasing mortality rate must be taken into
      consideration in the patient group over 50 years of age. The prognostic
      importance of clinical and laboratory symptoms of SLE was determined by the
      calculation of relative risks. Skin eruptions positively influenced the outcome,
      while valvular heart disease, interstitial lung disease and haematological
      manifestations had a negative impact on survival. Surprisingly, renal and central
      nervous system involvement did not significantly influence survival. The number
      of patients who were lost to regular follow-up diminished. CONCLUSIONS: The
      present study indicates an improvement in lupus survival in Hungary. Survival is
      affected by age and gender differences and may also be influenced by the race and
      ethnic origin of the patients. Regular follow-up is an important factor in lupus
      survival.

PMID- 10342043
TI  - Soluble intercellular adhesion molecule-1 (ICAM-1), CD4, CD8 and interleukin-2
      receptor in patients with Behcet's disease and Vogt-Koyanagi-Harada's disease.
AB  - OBJECTIVES: In a search for serum markers of disease activity in uveitis, we
      measured the levels of the soluble form of ICAM-1 (sICAM-1), CD4 (sCD4), CD8
      (sCD8) and interleukin-2 receptor (sIL-2R) in the serum of patients with Behcet's
      disease (BD) and Vogt-Koyanagi-Harada's disease (VKH). METHODS: The study
      population consisted of 20 patients with active BD (treated with tacrolimus), 15
      patients with inactive BD, 24 patients with VKH [20 of them successfully treated
      with systemic corticosteroids (cured group) and 4 of them with two or more
      episodes of uveitis after withdrawal of systemic steroid (recurrence group)], and
      20 normal individuals. The levels of serum sICAM-1, sCD4, sCD8 and sIL-2R were
      measured by sandwich ELISA. RESULTS: Sera from patients with BD in the
      convalescent stage showed significantly higher levels of sICAM-1 than those in
      the acute stage. Patients with active BD in both stages or VKH in the acute stage
      had significantly higher levels of serum sCD4 and sIL-2R than the controls. The
      levels of sCD8 in patients with both diseases in both stages differed
      significantly compared to the controls. No difference was noted in the pattern of
      decline of these soluble markers after treatment in the cured and recurrence
      groups of VKH patients. A positive correlation was found between the serum levels
      of sCD4 and sIL-2R in patients with both diseases in the acute stage.
      CONCLUSIONS: The results suggest that these soluble markers may represent
      potentially useful parameters to monitor disease activity or chronic inflammation
      in certain types of autoimmune uveitis.

PMID- 10342044
TI  - CD44 expression on chondrocytes in knees of DBA/1 mice with type II collagen
      induced arthritis.
AB  - OBJECTIVE: To investigate aspects of CD44 expression in the cartilage destruction
      of the knees of mice with collagen-induced arthritis. METHODS: DBA/1 mice were
      immunized with bovine type II collagen emulsified with Freund's incomplete
      adjuvant. Histological changes in the knees were evaluated in sections stained
      with hematoxylin and eosin, toluidine blue, and immunostaining using anti-CD44
      monoclonal antibodies. RESULTS: CD44 expression was observed in the synovial
      lining and articular chondrocytes. A total of 10/10 knees had CD44-positive
      synovial lining cells at 6 weeks after immunization, which was higher than that
      at 4 weeks (7 of 10 knees, p < 0.05). At 4 weeks 3 of 10 knees with CD44-positive
      chondrocytes were observed, and 7 of 10 knees at 6 weeks after immunization. The
      number of knees at 6 weeks was higher than that at 4 weeks (p < 0.01). Nine of 10
      knees showed loss of metachromasia on toluidine blue staining at 6 weeks after
      immunization, which was higher than the number at 4 weeks. The grade of
      metachromasia loss and the length of time after immunization were significantly
      correlated (p < 0.05, Spearman rank correlation; p = 0.46). CONCLUSION: These
      findings suggest that CD44 may play some role in the early stage of cartilage
      destruction in DBA/1 mice immunized with type II collagen.

PMID- 10342045
TI  - Quantitative analysis of HLA-B27 by flow cytometry using CD3 gating in
      seronegative spondylarthropathies.
AB  - OBJECTIVE: To investigate the relationship in patients with spondylarthropathies
      (SpA) between the clinical features of the disease and quantitative flow
      cytometric expression of HLA-B27 by CD3 gating. METHODS: We performed
      quantitative analysis of HLA-B27 antigen by flow cytometry using CD3 gating in 61
      patients with seronegative and HLA-B27 positive SpA. The patients included 29
      with ankylosing spondy-litis (AS), 29 with undifferentiated spondylarthropathy
      (uSpA), and 3 with reactive arthritis (ReA). In addition, we compared the
      fluorescence intensity of HLA-B27 with the clinical characteristics of the
      patients. RESULTS: The fluorescence intensity of HLA-B27 was significantly higher
      in patients with AS than in patients with other SpAs (220.5 +/- 13.7% vs 182.8 +/
      11.7%, p = 0.04). However, there were no demonstrable correlations between the
      quantitative expression of B27 and clinical features such as age, disease
      duration, results of the Schober test, chest expansion, the WBC count,
      erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). There was also
      no difference in the quantitative expression of HLA-B27 based on the presence or
      absence of uveitis, peripheral arthritis or enthesopathy. However, multiple
      regression analysis showed that age, disease duration and CRP were independent
      factors influencing the quantitative expression of HLA-B27 in SpA (beta = 0.568,
      0.546, -0.437 and p = 0.006, 0.02, 0.04, respectively). CONCLUSIONS: Our data
      suggest that the quantitative expression of HLA-B27 may be related to some of the
      clinical features in patients with SpA.

PMID- 10342046
TI  - Cathepsin G in degenerating and healthy discal tissue.
AB  - OBJECTIVES: To assess the eventual presence, tissue localization, molecular
      forms, amount and activity of cathepsin G in the annulus fibrosus. METHODS:
      Normal non-autolytic disc tissue was collected from cadavers within six hours
      after death. Degenerate disc samples were collected from low back pain patients
      undergoing anterior interbody fusion due to severe, discographically verified and
      painful disc degeneration, and from the posterior parts of intervertebral discs
      from 10 patients undergoing microscopic discoidectomy because of intervertebral
      herniation. Avidin-biotinperxidase complex staining of cathepsin G was
      quantitated by morphometry. Cellular localization was analyzed using double
      immunofluorescence staining of cathepsin G and CD68, proline 4-hydroxylase or von
      Willebrand factor. Neutral salt extracts were analyzed by using synthetic
      cathepsin G substrate in spectrophotometry, dot-immunoblotting and Western
      blotting. RESULTS: Histological and morphometric image analysis showed increased
      cellularity, increased numbers of cathepsin G positive cells and
      neovascularization in degenerated discs compared to control discs. Neutral salt
      extract of disc tissue, degenerated or normal, in contrast to control material
      from synovial capsular tissue, did not contain measurable cathepsin G activity,
      although immunoreactive enzyme was detected in dot-immunoblotting. Western
      blotting demonstrated that the discal cathepsin G had an apparent molecular
      weight of 27 kDa. CONCLUSION: Due to its properties and localization in normal
      and pathologically altered tissue, cathepsin G probably plays both a direct and
      an indirect role in extracellular matrix degradation in the annulus fibrosus.
      Extracted cationic cathepsin G was immunoreactive, but was functionally inhibited
      by serpins or, more likely, by polyanionic proteoglycans and saccharins derived
      from the connective tissue matrix of the annulus fibrosus.

PMID- 10342048
TI  - Non-invasive assessment of pulmonary artery involvement in Takayasu's arteritis.
AB  - OBJECTIVE: To evaluate pulmonary involvement in Italian patients with Takayasu's
      arteritis (TA). METHODS: A prospective analysis of 15 Italian patients with TA
      was carried out, including evaluation by perfusion and ventilation lung
      scintigraphy (planar and tomographic), standard chest X-ray, spirography and
      color-doppler echocardiography. All the patients were free of respiratory
      symptoms when examined. RESULTS: In all patients standard chest X-rays and
      ventilation scintigraphies were normal. 9/15 patients showed unmatched segmental
      perfusion defects (41 by planar evaluation vs. 48 by SPET). The number of defects
      was greater in the right lung than in the left (26 vs 18), with a higher
      frequency of moderate or large defects. Thirteen patients underwent spirography,
      which proved to be abnormal in 5 cases. Two of these patients were also positive
      on scintigraphy. No patient showed alterations attributable to TA on color
      doppler echocardiography, except for 3 patients with mild to moderate aortic
      valve regurgitation. CONCLUSIONS: Our results show that vascular pulmonary
      involvement is frequent in TA (60% of cases) even in the absence of clinical
      signs. The planar image, simpler than the SPET to acquire, was sufficient to make
      an accurate diagnosis. Italian patients seem to show a pattern of extrapulmonary
      and pulmonary vascular involvement very similar to that reported in Japanese
      subjects, and different from that observed in other ethnic groups.

PMID- 10342047
TI  - Multicenter validation of recombinant, natural and synthetic antigens used in a
      single multiparameter assay for the detection of specific anti-nuclear
      autoantibodies in connective tissue disorders.
AB  - OBJECTIVES: We investigated the feasibility of using a single multi-parameter
      test based mainly on recombinant autoantigens for the detection of anti-nuclear
      autoantibodies, and analyzed the agreement between this test format and
      conventional techniques. METHODS: The presence of autoantibodies was determined
      by a line immunoassay (LIA) in 755 sera derived from patients with different
      autoimmune connective tissue disorders. All sera were previously tested by
      standard assays that are routinely used at the 8 participating European centers.
      RESULTS: The overall sensitivity and specificity of autoantibody detection by LIA
      was similar or higher as compared to combined conventional techniques (CCT). In
      particular, the detection of anti-Ro52 in systemic lupus erythematosus (SLE) sera
      (P = 0.004) and anti-LA in both SLE (P < 0.0009) and in Sjogren's syndrome (P <
      0.0009) sera was significantly more sensitive when using LIA compared to CCT. By
      contrast, CCT was never more sensitive than LIA for any of the markers.
      CONCLUSION: The LIA is a reliable alternative to a combination of conventional
      techniques for the detection of specific anti-nuclear autoantibodies. The multi
      parameter test also reveals autoantibody reactivities that may not be detected
      when only a limited number of conventional techniques are applied.

PMID- 10342049
TI  - Capillary density in patients with systemic sclerosis, as determined by
      microscopy counts and compared with computer-based analysis.
AB  - OBJECTIVE: To develop a method enabling capillary density to be determined
      rapidly and accurately in patients with systemic sclerosis. METHOD: Capillary
      density was determined in 11 controls and 22 patients: 5 with diffuse cutaneous
      systemic sclerosis (dSSc), 12 with limited cutaneous systemic sclerosis (lSSc),
      two with suspected systemic sclerosis (suspSSc), 2 with sclerodermatomyositis,
      and one with undifferentiated connective tissue disease. Using a microscope
      equipped with a graticule, nailfold capillaries were counted within a 3 mm length
      of the nailfold; these counts were made by 4 different observers. The results
      were compared with the corresponding values obtained by the computerbased
      analysis of photographs. RESULTS: The median capillary density according to the
      direct counts was 8.0 loops/mm (6.7-10.0) in the controls, 6.0 loops/mm (range
      4.8-8.8) in the dSSc subgroup, 5.6 loops/mm (4.2-6.5) in the lSSc subgroup, and
      7.2 loops/mm (6.2-8.2) in the suspSSc subgroup. In the series as a whole, there
      was no significant difference between the median values for the left hands and
      those for the right hands, nor between the median value for all digit IVs and the
      median value for all four digits analysed (II, III, IV, and V). Interobserver
      variation was small between the 4 different observers. Direct microscopy counts
      were slightly higher than the corresponding values obtained by computer-based
      analysis. CONCLUSION: Direct microscopy counting is a rapid, simple, and reliable
      means of determining capillary density for screening purposes.

PMID- 10342050
TI  - Hyponatremia due to inappropriate secretion of antidiuretic hormone in a patient
      with systemic lupus erythematosus.

PMID- 10342051
TI  - Severe cold agglutinin disease and cryoglobulinemia secondary to a monoclonal
      anti-Pr2 IgM lambda cryoagglutinin.
AB  - OBJECTIVE: To present a case of cold agglutinin disease/cryoglobulinemia
      secondary to a monoclonal anti-Pr2 IgM lambda antibody, and review the literature
      on the occurrence of this antibody in cold-induced disease and the clinical
      disease associated with it. METHODS: Cryoantibody characteristics were evaluated
      by cold precipitation. The antigen specificity of the monoclonal IgM lambda
      antibody was evaluated using techniques of selective red blood cell absorption.
      RESULTS: In our patient, we were able to identify an antibody with both
      cryoglobulinemic and cold agglutinin (cryoagglutinin) properties. This antibody
      was found to be monoclonal IgM lambda with specificity to the Pr2 antigen on red
      blood cells. CONCLUSIONS: Monoclonal IgM lambda anti-Pr is a rarely found cold
      agglutinin antibody. In this report we describe the clinical course of a patient
      who had this antibody, which not only agglutinated red cells in the cold but also
      had cryoglobulin properties. The clinical illness of this man was characterized
      by severe acrocyanosis and digital necrosis with eventual organ necrosis and
      death. We also review the literature on cold induced disease due to monoclonal
      anti-Pr IgM lambda antibody. Our patient was found to be unique among the reports
      reviewed. Our case is the first to report both cold agglutinin and
      cryoglobulinemic properties with the evaluation of the thermal amplitudes of
      these activities of the antibody. Also, unlike the lymphoproliferative malignancy
      observed in the cold agglutinin-associated disease in the other reports, our
      patient's disease was associated with a monoclonal B-cell expansion on the
      spectrum between benign monoclonal gammopathy and a low grade lymphoproliferative
      disorder.

PMID- 10342052
TI  - Primary polyarteritis nodosa presenting as acute symmetric quadriplegia.
AB  - We report a case of peripheral neuropathy presenting as acute symmetric areflexic
      quadriplegia in the setting of a well-defined clinical, histopathologic, and
      angiographic diagnosis of classic polyarteritis nodosa. While it is usually easy
      to recognize the typical clinical presentation of necrotizing angiopathy-induced
      peripheral neuropathy as a mononeuritis multiplex or a distal polyneuropathy in
      association with a collagen vascular disease, clinicians must be equally
      sensitive to a number of more challenging possibilities. Acute quadriplegia
      similar to that seen in Guillain-Barre syndrome can be secondary to primary
      classic polyarteritis nodosa and the former may be the chief or even the sole
      manifestation of the latter.

PMID- 10342053
TI  - Inclusion body myositis long after dermatomyositis: a report of two cases.
AB  - Dermatomyositis, polymyositis, and inclusion body myositis are rare illnesses
      which appear to be distinct in clinical and pathologic features, pathogenesis,
      natural history, and response to therapy. We report two patients who first
      developed dermatomyositis, and then, after a disease-free interval of many years,
      developed inclusion body myositis. This may have useful therapeutic implications
      for patients with dermatomyositis whose illness bocomes refractory to treatment.

PMID- 10342054
TI  - Collagen-induced arthritis in mice: an animal model to study the pathogenesis of
      rheumatoid arthritis.

PMID- 10342055
TI  - Osteopenia and osteoporosis in children.
AB  - The purpose of this paper is to review the normal physiologic processes of
      skeletal accretion, abnormalities that may occur in children with chronic
      illnesses, and therapeutic maneuvers that the clinician may be able to employ to
      prevent or partially correct abnormalities of skeletal growth. Skeletal
      maturation in children is dependent upon bone formation exceeding resorption,
      whereas in adults these two fundamental processes of homeostasis are closely
      balanced. Skeletal growth is effectively completed at the end of the period of
      adolescent growth acceleration with closure of the epiphyses. An important
      determinant of future fracture risk and osteoporosis is the peak bone mass
      achieved during this second decade of life. If the hereditarily determined peak
      bone mass is not established during that time, the patient will enter young
      adulthood with osteopenia, an increased fracture risk, and accelerated
      postmenopausal osteoporosis or involutional osteoporosis. Thus osteopenia and
      osteoporosis have their origins in childhood and adolescence.

PMID- 10342056
TI  - Abnormalities in the biochemical markers of bone turnover in children with
      juvenile chronic arthritis.
AB  - OBJECTIVE: To study the biochemical markers of bone turnover in children with
      juvenile chronic arthritis (JCA) and to compare these parameters with those in
      healthy children in order to evaluate the relationships between age, disease
      activity and biochemical variables. METHODS: Sixty-two children with JCA and 157
      healthy children were studied. Serum samples were analyzed for their
      concentrations of minerals, osteocalcin (OC) and bone-specific alkaline
      phosphatase (BAP). Urine samples were examined to monitor the excretion of
      hydroxyproline (HYP) and deoxypyridinoline crosslinks (DPD). RESULTS: OC, BAP,
      HYP/Cr, DPD/Cr values were decreased in healthy girls more than 12 years of age
      and in healthy boys more than 14 years of age compared to younger children from
      the same population. Lower levels of OC and BAP were observed in younger children
      with JCA (girls < or = 12 yrs.; boys < or = 14 yrs.) compared to healthy children
      of the same age. Older girls with JCA (> or = 13 yrs.) were found to have
      increased HYP/Cr and DPD/Cr values compared to older healthy children.
      CONCLUSION: These results indicate that abnormalities of bone metabolism occur in
      an age-related fashion in JCA. This was demonstrated by a reduction in the
      markers of bone formation in younger JCA patients. Moreover, in older girls the
      markers of bone resorption were found to be elevated. Taken together, these
      findings suggest that bone formation is reduced from early childhood to mid
      puberty, while resorption levels increase in children with JCA after this time.

PMID- 10342057
TI  - Clinical features of juvenile Adamantiades-Behcet's disease in Greece.
AB  - Adamantiades-Behcet's disease (A-BD) is a chronic relapsing vasculitis of unknown
      etiology. This disease is relatively rare in children and only recently have
      series of patients been reported. The objective of this study was to describe the
      clinical features of the disease in juvenile patients, and to compare them with
      adult cases and with those juveniles reported in the literature.

PMID- 10342058
TI  - Treatment of severe Raynaud's phenomenon and ischemic ulcerations with tissue
      plasimogen activator.

PMID- 10342059
TI  - Successful treatment of catastrophic antiphospholipid syndrome in a pregnant
      woman.

PMID- 10342060
TI  - HLA associations in a family with autoimmune phenomena.

PMID- 10342061
TI  - Coexistence of ankylosing spondylitis and mixed connective tissue disease in a
      single patient.

PMID- 10342062
TI  - Pamidronate in the treatment of progressive diaphyseal dysplasia (Camurati
      Engelmann disease)

PMID- 10342064
TI  - RS3PE syndrome and chronic lymphoid leukaemia.

PMID- 10342063
TI  - Possible mechanism underlying the efficacy of low dose cyclosporine in autoimmune
      diseases.

PMID- 10342065
TI  - Parvovirus B19 and systemic sclerosis.

PMID- 10342066
TI  - The investigation and management of inherited thrombophilia.

PMID- 10342067
TI  - Serum soluble transferrin receptor in the diagnosis of iron deficiency in chronic
      liver disease.
AB  - Fifty-one consecutive patients with chronic liver disease (CLD) underwent
      investigations of their iron status (full blood count, serum iron [Fe], total
      iron binding capacity [TIBC], transferrin saturation [TS], serum ferritin and
      serum soluble transferrin receptor [sTfR] level). Twenty-six patients were
      anaemic; 12 patients had iron deficiency, and 10 had iron deficiency anaemia
      (IDA). The median (range) sTfR in the IDA patients was 16.6 (11.2-24.8) mg/l.
      compared with 6.6 mg/l (11.2-24.8) in the 16 patients with anaemia due to other
      causes (P = 0.01). The sensitivity of sTfR for diagnosing iron deficiency in CLD
      was 91.6% (100% if only anaemic patients are included) and the specificity was
      84.6%. Patients with haemolysis and recent blood loss may have falsely elevated
      sTfR levels. The results suggest that the sTfR is as useful as serum ferritin in
      identifying a potentially treatable cause of anaemia in CLD.

PMID- 10342068
TI  - Red cell exchange in sickle cell disease.
AB  - Red cell exchange transfusion is frequently of use in the management of patients
      with sickle cell disease either electively or therapeutically. Modern cell
      separators allow this procedure to be performed rapidly, effectively and safely.
      These machines have a number of advantages over manual exchange procedures. The
      patient remains isovolaemic, there is little loss of plasma or platelets, the
      procedure is relatively short and in elective circumstances can be performed on
      an outpatient basis. In this series 66 exchanges were performed on 21 patients
      with an overall increase in HbA of 70%. The COBE Spectra gave a mean increase in
      HbA of 77%, with the majority of patients achieving an HbA of > 90% post
      exchange. Automated redcell exchange was well tolerated by most patients, and
      adverse effects were limited to symptoms of hypocalcaemia which were easily
      treated, and to transfusion reactions. Cell separators can therefore be
      recommended for exchange transfusion in patients with sickle cell disease, who
      require an increase in HbA levels either prophylactically or therapeutically.
      They are safe, effective, easy and quick to use.

PMID- 10342070
TI  - Automated counting of platelets on the Bayer ADVIA 120 analyser.
AB  - Precise counting of platelets is difficult particularly in the low
      thrombocytopenic range or when large platelets exist. The recently available
      Bayer ADVIA 120 analyser uses a method of counting platelets based on two
      dimensional laser light scatter. We have evaluated this technique on an analysis
      of 217 peripheral blood samples and found significant differences in platelet
      counts compared with values obtained by impedance technology, when the causes of
      thrombocytopenia were due to peripheral platelet consumption. Moreover, such
      differences were more marked in those samples from severely thrombocytopenic
      individuals with large platelets on the blood film. These differences, which
      warrant further study, may have significant implications for the management of
      patients with very low platelet counts.

PMID- 10342069
TI  - Comparative flow cytometric study of clonal excess in leukaemic peripheral blood
      from patients suffering from chronic lymphocytic leukaemia (B-CLL) by different
      antibodies, staining techniques and the effects of blood storage.
AB  - This investigation studied the effects of cell preparation methods, different
      antibody panels and blood storage on antigen expression of abnormal B lymphocytes
      from patients with B-CLL. Blood specimens collected in Heparin de novo were
      processed by using conventional Hypaque-Ficoll density gradient centrifugation
      and whole blood lysis. These were stored for 3 days at 4 degrees C, 24 degrees C
      and 30 degrees C. Although clonal excess was detected by all antibody panels,
      significant differences could be observed in terms of molecules of equivalent
      fluorochromes (MEF/MESF units). Evaluation of 'weak and strong' staining is
      dependent on the antibody panel used. Immunofluorescent values for CD19 and CD45
      were unchanged at 4 degrees C and 24 degrees C but immunoglobulin staining showed
      best results when blood was stored at 4 degrees C. Storage at 30 degrees C
      produced unreliable results. Abnormal B lymphocytes should be analysed
      immediately after the specimen is obtained. If shipment is necessary they should
      be kept at 4 degrees C. Surface immunoglobulins are the 'antigens' most sensitive
      to storage alterations. Sample alterations alone are sufficient to the correct
      classification of NHL, especially in the case of low-grade NHL.

PMID- 10342071
TI  - Solvent/detergent fresh frozen plasma as primary treatment of acute thrombotic
      thrombocytopenic purpura.
AB  - Three patients with acute thrombotic thrombocytopenic purpura (TTP) (one
      associated with E. coli infection) received as primary treatment pooled fresh
      frozen plasma (FFP) virus inactivated by the solvent/detergent (SD) method, plus
      prednisolone. All three patients attained platelet counts of > 50 x 10(9)/l by
      days 7, 3 and 10, respectively. Serum creatinine became corrected in parallel.
      Neurological features were slow to resolve in one patient, and developed de novo
      during plasma infusion in another with rapid reversal once intensive plasma
      exchange with SDFFP was instituted. All patients are in stable remission > 1
      years later. SDFFP was well tolerated with no febrile or other reactions, and all
      patients remained negative for markers of infection with HIV, hepatitis B and
      hepatitis C viruses. One patient was positive for antibodies for hepatitis A
      virus and parvovirus B19 prior to treatment. The other two patients remained
      antibody negative at the end of therapy.

PMID- 10342072
TI  - Evaluation of a novel ELISA screening test for detection of factor VIII
      inhibitory antibodies in haemophiliacs.
AB  - Treatment of patients with haemophilia A with coagulation factor concentrates may
      result in the development of inhibitory antibodies directed against factor VIII
      (FVIII). In this study, a previously unpublished ELISA test for FVIII inhibitor
      screening (Genetic Testing Institute [GTI] FVIII inhibitor, Brookfield, WI, USA)
      was evaluated in 131 blood samples (124 samples from patients with haemophilia A,
      and seven serial samples from one patient with an acquired FVIII inhibitor).
      Comparisons were made with the routine screening assay (based on recovery of
      FVIII) and confirmed where positive (< 90% recovery) with the New Oxford assay.
      The ELISA kit had a sensitivity of 97.7% and specificity of 78.4%. The high
      negative predictive value of this new test (98.6%) suggests it may be useful as a
      reliable, rapid (< 2 h) and flexible (microwell strip format) tool for inhibitor
      screening of samples from both patients with haemophilia A and those with
      suspected acquired FVIII inhibitors.

PMID- 10342073
TI  - Interpretation of iron studies in adolescent haemochromatosis.
AB  - We report the case of a 14-year-old girl who originally presented at the age of
      eight with a history of bloody stools, abdominal pain and weight loss. Initial
      iron studies showed raised serum iron and transferrin saturation but low ferritin
      and were interpreted as consistent with iron deficiency under treatment. As she
      had not taken any supplemental iron she later underwent genetic testing for the
      Cys282Tyr and His63Asp mutations of the HFE gene. On the basis of these results,
      she was diagnosed as having hereditary haemochromatosis (HH). This case
      highlights that a low serum ferritin does not exclude the diagnosis of HH and
      that the availability of genetic testing can now enable probands and affected
      family members to be identified.

PMID- 10342074
TI  - A second unrelated bone marrow transplant: successful quantitative monitoring of
      mixed chimerism using a highly discriminative PCR-STR system.
AB  - A second bone marrow transplant (BMT) might be considered as an option in
      patients with leukaemia with graft failure after BMT. We report the successful
      treatment of a patient with graft failure by a second stem cell transplant from
      another unrelated donor. We evaluated the usefulness of an unrelated donor as the
      source of the second BMT in this clinical setting. In addition to this, a penta
      PCR-STR system was tested and shown to be sensitive for monitoring of marrow
      engraftment. The conditioning regimen for the first transplantation consisted of
      busulfan and cyclophosphamide while anti-thymocyte globulin and CY were used for
      the second BMT. The patient successfully engrafted at day +11 after second BMT.

PMID- 10342075
TI  - Management of liver failure in a haemophilic patient co-infected with human
      immunodeficiency and hepatitis C viruses.
AB  - We present a case of liver failure in a haemophilic patient coinfected with
      transfusion acquired human immunodeficiency (HIV) and hepatitis C (HCV) viruses.
      The case illustrates the interaction of multiple viruses with accelerated
      progression to end stage liver disease and ultimately death. We report the impact
      on the patient management of two liver biopsies, which diagnosed an initial drug
      induced hepatitis and subsequently an atypical HCV related hepatitis.

PMID- 10342076
TI  - Aspergillus fumigatus endophthalmitis in a patient with acute myeloid leukaemia.
AB  - A 55-year-old patient developed progressive loss of vision in one eye following
      induction chemotherapy for acute myeloid leukaemia (AML). Aspergillus fumigatus
      was cultured from vitreal aspirates. The patient was treated with intravenous and
      intravitreal amphotericin B but suffered complete loss of vision in her right
      eye. We believe this is the first report of culture-proven Aspergillus fumigatus
      endophthalmitis in a patient treated for a haematological malignancy.

PMID- 10342077
TI  - Automated reticulocyte counting--an evaluation of GEN-S, Cell-Dyn 3500 and Cell
      Dyn 4000.

PMID- 10342078
TI  - British Society for Haematology slide session annual scientific meeting of BSH,
      Glasgow, 1998.

PMID- 10342079
TI  - Low-dose mifepristone 200 mg and vaginal misoprostol for abortion.
AB  - The objectives of this study were to determine the effectiveness, side effects,
      and acceptability of one-third the standard 600 mg dose of mifepristone (200 mg)
      to induce abortion. A prospective trial at seven sites enrolled women > or = 18
      years, up to 8 weeks pregnant, and wanting an abortion. The women received 200 mg
      mifepristone orally, self-administered 800 micrograms misoprostol vaginally at
      home 48 h later, and returned 1-4 days later for ultrasound evaluation. Surgical
      intervention was indicated for continuing pregnancy, excessive bleeding,
      persistent products of conception 5 weeks later, or other serious medical
      conditions. Of the 933 subjects, 906 (97%) had complete medical abortions, 22 had
      surgical intervention, two were protocol failures, and three were lost to follow
      up. Of the 746 subjects who had no or minimal bleeding before misoprostol, 80%
      bled within 4 h and 98% within 24 h of using misoprostol. By day 7, 95% of women
      had a complete abortion. Side effects were aceptable in 85% of subjects, and 94%
      found the procedure acceptable. Low-dose mifepristone followed by vaginal
      misoprostol was highly effective as an abortifacient.

PMID- 10342080
TI  - Comparing abortion induced with methotrexate and misoprostol to methotrexate
      alone.
AB  - This was a dual-cohort study performed to determine if, by using methotrexate
      alone, abortions could be induced with fewer side effects, without sacrificing
      effectiveness and patient satisfaction. The subjects were 358 consecutive
      patients who requested elective medical termination of pregnancy at < 7 weeks
      gestation. Women were given information and allowed to choose between
      methotrexate alone (50 mg/m2 intramuscularly) or methotrexate followed 4 days
      later by 800 micrograms misoprostol vaginally. The two groups were compared with
      respect to the number of surgical aspirations required, the number of days until
      the abortion was completed, side effects, and the number of women who would
      choose the same method again. The surgery rate for methotrexate was 17.2%,
      whereas for the combination it was 10.9%. The mean numbers of days until the
      abortion were complete was 23 and 12, respectively. Side effects, mean pain
      scores, total days of bleeding, and satisfaction rates were not significantly
      different in the two groups. The high failure rate with methotreaxate alone
      suggests that it should not be offered despite the high level of satisfaction.

PMID- 10342081
TI  - A randomized trial of the effect of moistening misoprostol before vaginal
      administration when used with methotrexate for abortion.
AB  - A prospective multicenter, randomized trial was performed to evaluate if
      moistened misoprostol results in a more rapid abortion and a higher rate of
      complete abortion compared with dry misoprostol when administered intravaginally
      for medical abortion after methotrexate. A total of 240 pregnant women < or = 49
      days gestation seeking elective abortion received 50 mg/m2 methotrexate
      intramuscularly followed 5-6 days later by 800 micrograms misoprostol vaginally.
      The misoprostol dose was repeated in 1-2 days if the abortion did not occur.
      Group 1 moistened the misoprostol before administration and group 2 used dry
      tablets. There was no statistically significant difference in the cumulative rate
      of abortion after the first misoprostol dose (73.0% vs 71.3%, p = 0.87), second
      misoprostol dose (84.1% vs 81.1%, p = 0.65), or by 35 days after methotrexate
      administration (95.2% vs 91.8%, p = 0.40) between groups 1 and 2, respectively.
      The proportion of subjects with embryonic cardiac activity 2 weeks after
      methotrexate injection was greater in group 2 (5.7%, 95% confidence interval [CI]
      1.0%, 9.9%) than in group 1 (2.4%, 95% CI 0%, 5.0%), although not statistically
      significant (p = 0.21). The immediate success rate in Pittsburgh was greater,
      albeit not statistically, for the women that moistened the misoprostol (87% vs
      76%, p = 0.19); these rates were also not statistically different in Havana (82%
      vs 86%, p = 0.62). The rate of side effects after methotrexate was not different
      between groups but women in group 1 had significantly more diarrhea (36% vs 21%,
      p = 0.02) and fever/warmth/chills (44% vs 30%, p = 0.04). Moistening misoprostol
      before vaginal administration in a medical abortion regimen with methotrexate
      does not statistically improve efficacy. This trial demonstrates the importance
      of prospective, randomized studies to prove the relative efficacy of any medical
      abortion treatment regimen.

PMID- 10342082
TI  - Effect of oral contraceptives containing 20 and 35 micrograms ethinyl estradiol
      on urinary prostacyclin and thromboxane metabolite levels in smokers and
      nonsmokers.
AB  - The interaction between smoking and oral contraceptive (OC) use with respect to
      thrombogenesis was investigated by studying the effects of OC and smoking on
      urinary prostacyclin (PGI2) and thromboxane A2 (TxA2) metabolite levels in
      smokers and nonsmokers. Sixty healthy women, aged 19-32 years, who were not
      taking any hormonal treatment for at least 3 months before initiating the study,
      were divided into three equal groups: OC users who smoked (N = 20), OC users who
      did not smoke (N = 20), and a control group of 10 smokers and 10 nonsmokers. Each
      OC treatment group was randomized to receive either norethindrone (NET) acetate
      (1 mg)/ethinyl estradiol (EE2) (35 micrograms) (N = 10) or NET acetate (1 mg)/EE2
      (20 micrograms) (N = 10) daily for 3 months. Overnight urine collections and
      fasting blood samples were obtained at baseline and at the end of the 3-month
      study. Serum levels of NET and EE2, as well as urinary levels of cotinine and the
      stable metabolites of PGI2 and TxA2, namely 6-keto-prostaglandin F1 alpha (6-keto
      PGF1 alpha) and thromboxane (TxB2), respectively, were measured by specific
      immunoassays. Analysis of pre- to posttreatment changes in mean urinary 6-keto
      PGF1 alpha and TxB2 levels for each subgroup, as determined by smoking status and
      EE2 dose, showed no statistically significant differences. Also, no significant
      differences were found in each subgroup with respect to changes in the 6-keto
      PGF1 alpha/TxB2 ratios. Large intersubject variability in urinary 6-keto-PGF1
      alpha and TxB2 levels were observed in all subgroups. The results of this study
      indicate that both low-estrogen-dose compounds, when used by smokers or
      nonsmokers, did not significantly alter the ratio of PGI2 to TXA2 metabolites,
      compared with pretreatment. However, the small number of subjects and the large
      intersubject variability in this study make it difficult to determine if there is
      a significant difference between the 20- and 30-microgram EE2 doses.

PMID- 10342083
TI  - Long-term depot-medroxyprogesterone acetate and bone mineral density.
AB  - The association between long-term use of depot-medroxyprogesterone acetate (DMPA)
      and bone mineral density (BMD) has been controversial, as seen in three case
      control studies in New Zealand, Thailand, and the United Kingdom. In the present
      case-controlled study of BMD, a group of 67 Chinese women who had used DMPA from
      5-15 years was compared with 218 women of the same age range who had not used any
      steroidal hormones. DMPA users were found to have a significantly lower BMD at
      lumbar vertebra (L2-4) (0.93 g/cm2), neck of femur (0.69 g/cm2), trochanter (0.59
      g/cm2), and Ward's triangle (0.58 g/cm2), as compared with the control group,
      whose corresponding BMD values were 1.03 g/cm2, 0.83 g/cm2, 0.71 g/cm2, and 0.78
      g/cm2, respectively (p < 0.001). The average percentage of bone loss per year was
      estimated to be 1.1% in L2-4, 2.3% in neck of femur, 2.4% in trochanter, and 3.5%
      in Ward's triangle. The percentage of bone loss in L2-4 was found to be more
      pronounced with age. This study provided information that the use of DMPA in a
      Chinese group for > 5 years in associated with bone loss, and a prospective study
      is needed to confirm these data, which are different from two case-control
      studies.

PMID- 10342084
TI  - Study of the effects of the implantable contraceptive Norplant on lipid and
      lipoprotein metabolism. UN Development Programme/UN Population Fund/WHO/World
      Bank, Special Programme of Research, Development and Research Training in Human
      Reproduction, Task Force on Long-Acting Systemic Agents for Fertility Regulation.
AB  - A 2-year longitudinal study was undertaken to investigate the effects of the
      implantable contraceptive Norplant on lipid and lipoprotein metabolism. A group
      of 177 Norplant implants acceptors was recruited in five centers (Bangkok,
      Jakarta, Mexico City, Singapore, and Stockholm) and monitored during one baseline
      menstrual cycle and 3, 5, 11, 16, and 22 months after implant insertion. They
      were compared with a group of 174 copper intrauterine (IUD) device users who had
      blood sampling performed at comparable time points. Lipid changes were greatest 3
      months after implant insertion and a slow reversal of these trends towards
      baseline was observed during the next 19 months. The main changes observed at 3
      months were a 10% drop in total cholesterol, and an 11% drop in high-density
      lipoprotein (HDL)-cholesterol and apolipoprotein AI levels, together with a 19%
      decline in serum triglycerides. Variations in low-density lipoprotein (LDL)
      cholesterol and apolipoprotein B levels were not significantly different from
      those observed in the group of IUD users. There was consistency in these findings
      between centers in that the changes were in the same direction but of different
      magnitude in different centers. It is concluded that lipid changes induced by
      Norplant implants will probably not affect the risk of atherosclerotic disease in
      women who use this contraceptive method.

PMID- 10342085
TI  - Optical testing of condoms.
AB  - Condoms provide one of the most important means of preventing pregnancy and the
      spread of human immunodeficiency virus (HIV) and other sexually transmitted
      diseases. Pinhole defects may lead to the passage of sperm or viruses through the
      condom wall. Embedded particles, which may become dislodged in handling or use,
      may represent latent pinhole defects. Thin regions in the condom wall may lead to
      breakage in use. Testing for such defects in regulatory laboratories, or in the
      factories as part of production screening or quality assurance efforts, is a
      major tool for ensuring condom reliability. A new optical method for testing
      condoms is presented, sensitive to pinholes, thin regions, and embedded
      particles. The method could supplement or replace the existing, less powerful,
      electrical test techniques in either regulatory testing laboratories or in the
      factory. The optical techniques presented provide quantitative data on the
      condoms tested, rather than just accept/reject decisions. They thus support
      detailed monitoring of production or lot characteristics that is generally not
      possible with existing electrical techniques. The ability of the optical
      techniques to separately test for and identify not only pinholes, but also thin
      regions and embedded particles, which are not separately tested for with the
      electrical technologies, is an especially important new capability. Further, the
      new optical techniques allow the locations of defects found to be precisely
      marked, making possible a microscopic examination of defects useful in studying
      their structure and possible causes. The optical technique is also totally
      nondestructive, in that it does not alter the defects whose structures are of
      interest. Initial results are reported on the testing of latex condoms purchased
      in retail stores. Condoms identified optically as being potentially defective
      were subjected to industry standard leak and burst testing. Results of the
      various tests are summarized. The data suggest that use of the new optical test
      techniques could have prevented an unexpectedly large number of condoms with
      significant pinhole and thin region defects from reaching the public. Optical
      test systems could be used to support either regulatory, quality assurance, or
      clinical field testing of latex or nonlatex condoms. Due to their high rate
      capability and level of automation, they could also be applied to 100% screening
      testing in the factory. The new test techniques could also be used to detect
      defects in a wide range of other thin sheets and membranes.

PMID- 10342086
TI  - Clinical acceptability of an ethylene-vinyl-acetate nonmedicated vaginal ring.
AB  - In an open study the acceptability of a newly designed vaginal ring was
      evaluated. The ring being developed for contraceptive purposes was made of
      ethylene-vinyl-acetate copolymer (EVA). In this study the ring did not contain
      active medication. Three groups of 20 healthy female volunteers were asked to use
      rings--with a diameter of 54 mm--for 21 consecutive days; each group was assigned
      rings with a different cross-sectional thickness of 3, 3.5, or 4 mm. Subjects
      were given diary cards to report on insertion and removal of the ring and on
      complaints. Of the 65 women who participated, 59 completed the study and used the
      ring for at least 21 days, giving an acceptability of 91% (59/65). No major
      differences were found between the three types of rings except for a sensation of
      expulsion, which was reported more often in the group assigned the smallest cross
      sectional-thickness ring. Expulsion was reported once during intercourse in the
      3.5-mm group. Insertion and removal of the rings were judged to be easy by the
      overall majority of the women. The ring was felt by the partner during
      intercourse in 35%-50% of couples. Further development of an active combined
      contraceptive EVA ring with a cross-sectional thickness of 4 mm seems a
      reasonable option. In future studies with the active ring, allowance for
      temporary removal of the ring during intercourse, if preferred, may be suggested.

PMID- 10342087
TI  - Uterine histopathologic changes after Cu-Fix intrauterine device insertion.
AB  - A study of uterine histopathologic changes after the insertion of the Cu-Fix
      intrauterine device (IUD) was carried out at the Obstetrics and Gynecology
      Department, Faculty of Medicine, Chulalongkorn University. Ten patients, who had
      cold conization for a suspicious Papanicolaou smear, were fitted with the Cu-Fix
      IUD. All patients were diagnosed as having carcinoma-in-situ of the cervix and
      were scheduled for hysterectomy at 6 weeks postconization. Preoperative
      ultrasonography showed the IUD anchoring at the uterine fundus, which
      corresponded with posthysterectomized findings. At the anchoring site of the
      nylon knot, which serves as a small retention body in the fundus, slight
      mononuclear cells infiltration in the myometrium was found in only one patient.
      However, in the endometrium, there was infiltration of mononuclear cells as well
      as a few plasma cells during the proliferative phase of the cycle. Evidence of
      local foreign body reaction was found in all patients. No patient had symptoms or
      signs of pelvic infection.

PMID- 10342088
TI  - Reactive oxygen intermediates and reactive nitrogen intermediates in copper
      intrauterine device users.
AB  - The mechanism of action of copper in copper intrauterine devices (Cu IUD) as an
      antimicrobial agent is not well understood. Copper and iron are supposed to be
      responsible for release of reactive oxygen intermediates (ROI) and reactive
      nitrogen intermediates (RNI), which are very active in the presence of infection.
      The copper in a copper IUD could be responsible for limiting pelvic inflammatory
      disease. The present study was composed of 20 IUD seekers in whom ROI and RNI
      were studied before insertion of Cu IUD and then at 1, 4, and 12 weeks afterward.
      ROI showed a rise after insertion, whereas RNI showed a steady decline. Hence, it
      is presumed that the rise in ROI could be responsible for both the bactericidal
      effect of Cu IUD and also for the fall in RNI.

PMID- 10342089
TI  - Contraception in the prepill era.
AB  - Although medical history has documented the desire to control fertility since
      ancient times, safe and effective contraception did not exist until this century
      and has not been equally available to all people. Strong moral sentiments,
      economic and social class factors, religious beliefs, familial and gender
      relations, and political as well as legal constraints have often limited the
      ability of physicians in favor of contraception to provide advice and methods of
      birth control to their patients. By the early 1900s, a constellation of factors-
      in particular, the large influx of poor immigrants, and feminist groups
      advocating women's rights--helped to move forward a birth-control movement in
      this country and abroad. In the early 20th century, Margaret Sanger became one of
      the most avid proponents of contraception in the United States. By 1950, she and
      Katharine McCormick had contracted with biologist Gregory Pincus to develop an
      effective birth control pill. A collaborative effort by Pincus and other
      researchers led to trials of the pill in Puerto Rico, Haiti, and Mexico between
      1956 and 1957, which provided the basis for an application to the Food and Drug
      Administration for approval of the first oral contraceptive.

PMID- 10342090
TI  - Introduction of the pill and its impact.
AB  - Introduction of the birth control pill in the United States in 1960 marked the
      end of a relatively short period of time (< 10 years) to intentionally produce an
      oral contraceptive, and the beginning of a relatively long period of controversy
      surrounding the use of the pill. Availability of the pill had an impact on
      various aspects of social life, including women's health, fertility trends, laws
      and policies, religion, interpersonal relationships and family roles, feminist
      issues, and gender relations, as well as sexual practices among both adults and
      adolescents. The pill proved to be highly effective from the outset. Although
      safety issues developed with the earlier formulations, continued evolution of
      pill hormones and doses has resulted in a greatly improved and safe oral
      contraceptive. A broad range of noncontraceptive health benefits also is
      associated with the pill. These health effects are significant, as they include
      protection against potentially fatal diseases, including ovarian and endometrial
      cancers, as well as against other conditions that are associated with substantial
      morbidity and potential hospitalization and associated costs. The popularity of
      the pill has remained high, with rates of use in the past 30 years in the United
      States ranging from one-quarter to almost one-third of women using contraception.
      Almost 40 years after its introduction, the pill's contraceptive efficacy is
      proven, its improved safety has been established, and the focus has shifted from
      supposed health risks to documented and real health benefits.

PMID- 10342091
TI  - Oral contraception: current use and attitudes.
AB  - Oral contraception (OC) has been available for almost four decades. During this
      time, changes in contraceptive use in general and OC in particular have occurred.
      Knowledge and attitudes about OC may not always reflect trends in use.
      Contraceptive use data from 1965-1995 show that OC continue to be the method
      chosen consistently by more than one-quarter of women contraceptors. Probably
      even more women would use the pill if they had more accurate information
      regarding the higher failure rates with barrier methods (especially the condom),
      if misperceptions about OC safety were put to rest, and if greater awareness of
      the noncontraceptive health benefits of OC could be achieved. Increased education
      and awareness of women as well as their healthcare providers has the potential to
      positively affect future contraceptive use.

PMID- 10342092
TI  - Cardiovascular risks: perception versus reality.
AB  - The high estrogen doses in the original oral contraceptive (OC) formulations were
      associated with an increased risk of cardiovascular events. Since then the
      steroid doses in OC have been reduced steadily, so that current low-estrogen-dose
      (< or = 35 micrograms) combination OC are associated with a lower risk of
      arterial and venous events than occurs with higher-estrogen-dose formulations.
      Based on the currently available epidemiologic evidence, the following
      conclusions can be made regarding the cardiovascular disease risks associated
      with use of low-dose OC by healthy, nonsmoking women: there is no increased risk
      of myocardial infarction (MI) or hemorrhagic or ischemic stroke; and there is a
      three- to fourfold increased risk of venous thrombosis and embolism (VTE). This
      risk is about half that associated with pregnancy. Smoking is the most important
      independent risk factor for MI, and is synergistic with OC use. Women smokers
      should be advised strongly to stop smoking, but those aged < 35 years may use any
      OC containing < or = 35 micrograms of estrogen. Women smokers aged > or = 35
      years should be advised to use a nonestrogen or nonhormonal contraceptive method.

PMID- 10342093
TI  - Breast cancer risk: perception versus reality.
AB  - Evidence that breast cancer is hormonally mediated has fueled women's concern
      that use of oral contraceptives (OC) will increase their risk of developing the
      disease. A recent reanalysis of combined worldwide epidemiologic evidence
      regarding the relationship between breast cancer risk and use of combination OC
      provides reassurance that there is little or no association between OC use and
      breast cancer. Ten or more years after discontinuation of OC use, there is no
      difference in cumulative risk of breast cancer among OC ever-users and never
      users. The risk of breast cancer diagnosis is slightly elevated in current OC
      users and remains slightly elevated until about 10 years after OC
      discontinuation. Once recency of use is taken into account, other characteristics
      have little additional effect. There is no increase in breast cancer risk with
      increasing dose or duration of OC use and no difference in risk related to type
      of estrogen or progestin used. Moreover, those breast cancers diagnosed in OC
      ever-users were found to be significantly more likely to be localized than those
      diagnosed in same-age never-users.

PMID- 10342094
TI  - Oral contraceptive health benefits: perception versus reality.
AB  - Many women remain unaware of classic oral contraceptive (OC) noncontraceptive
      health benefits even as new health advantages emerge from experience and
      research. An extensive body of evidence has established that OC protect women
      against dysmenorrhea and menorrhagia, menstrual cycle irregularities, iron
      deficiency anemia, ectopic pregnancy, pelvic inflammatory disease, ovarian cysts,
      benign breast disease, endometrial cancer, and ovarian cancer. In addition, the
      FDA has stated for the first time that an OC-triphasic norgestimate/35 micrograms
      ethinyl estradiol--is an effective treatment for moderate acne vulgaris. OC use
      also appears to prevent osteopenia in hypoestrogenic women. In addition to these
      noncontraceptive health benefits, OC have proven valuable in the management of a
      variety of gynecologic disorders, including dysfunctional uterine bleeding,
      persistent anovulation, premature ovarian failure, functional ovarian cysts,
      pelvic pain (including secondary dysmenorrhea), mittelschmerz, endometriosis, and
      the control of bleeding in women with blood dyscrasias. Educating healthcare
      providers and women about these important noncontraceptive health benefits will
      result in increased compliance, greater continuation, and fewer unintended
      pregnancies.

PMID- 10342095
TI  - Oral contraceptives: therapeutic uses and quality-of-life benefits--case
      presentations.
AB  - Numerous studies have shown that oral contraceptives (OC) provide protection
      against a wide variety of illnesses and conditions, including loss of bone
      density, ovarian cysts, menstrual cycle irregularities, dysmenorrhea and
      menorrhagia, ectopic pregnancy, pelvic inflammatory disease, benign breast
      disease, endometrial cancer, and ovarian cancer. How OC can be used not only for
      contraception but also to improve health among women throughout their
      reproductive years is illustrated by four case presentations: an adolescent with
      menstrual problems; a 25-year-old mulligravida who wishes to delay childbearing;
      a 35-year-old who has completed her family and requests tubal ligation; and a 45
      year-old with perimenopausal symptoms. In view of their numerous health benefits,
      OC are to reproductive-age women as hormone replacement therapy is to menopausal
      women.

PMID- 10342096
TI  - Clinician/patient interaction: communicating the benefits and risks of oral
      contraceptives.
AB  - Myths and misperceptions continue to influence women's opinions about oral
      contraceptives (OC), despite the immense body of evidence regarding OC safety and
      efficacy. Patient opinions about OC failure rates and health risks are often far
      from proven fact, and the health benefits of OC are too often unrecognized.
      Because successful OC use requires an informed patient, effective communication
      between clinicians and their patients is needed to correct misinformation,
      relieve unnecessary fears, and increase OC use. A variety of interactive
      counseling skills and attitudes can improve the process of patient counseling;
      they are especially crucial for adolescents, who may be reluctant or unable to
      easily articulate their concerns. Counseling messages can be geared specifically
      to the interests and concerns of particular age groups: adolescents, young
      adults, and perimenopausal women. With thoughtful planning and involvement of all
      members of the healthcare team, clinicians can create time and opportunities for
      the provision of consistent, appropriate counseling to all candidates for OC use.

PMID- 10342097
TI  - Molecular mechanisms of chromosomal rearrangement in fungi.
AB  - Both sexual and asexual fungi undergo chromosomal rearrangements, which are the
      main cause of karyotype variability among the populations. Different
      recombination processes can produce chromosomal reorganizations, both during
      mitosis and meiosis, but other mechanisms operate to limit the extent of the
      rearrangements; some of these mechanisms, such as the RIP (repeat-induced point
      mutations) of Neurospora crassa, have been well established for sexual fungi. In
      laboratory strains, treatments such as mutation and transformation enhance the
      appearance of chromosomal rearrangements. Different DNA sequences present in
      fungal genomes are able to promote these reorganizations; some of these sequences
      are involved in well-regulated processes (e.g., site-specific recombination) but
      most of them act simply as substrates for recombination events leading to DNA
      rearrangements. In Penicillium chrysogenum we have found that short specific DNA
      sequences are involved in tandem reiterations leading to amplification of the
      cluster of the penicillin biosynthesis genes. In some cases, specific chromosomal
      rearrangements have been associated with particular phenotypes (as occurs in
      adaptive-like mutants of Candida albicans and Candida stellatoidea), and they may
      play a role in genetic variability for environmental adaptation.

PMID- 10342098
TI  - Conventional and molecular methods for understanding probiotic bacteria
      functionality in gastrointestinal tracts.
AB  - The recent successes of probiotic application to limit colonization of foodborne
      pathogens in the gastrointestinal tracts of food animals ensures continued
      commercialization and widespread use of such cultures. Given that the the
      fermentation response and ecological balance of the probiotic consortium appears
      to be essential for the effectiveness of the cultures, it is essential to develop
      a methodology to accurately identify and quantitate these organisms during
      commercial production as well as successful in vivo colonization after
      administration. However, if further optimization of the effectiveness of defined
      cultures is to be achieved, methods to assess expression of key metabolic
      processes occurring during establishment of the probiotic culture as well as its
      subsequent ability to limit foodborne pathogen colonization are needed.
      Conventional methods to study individual probiotic gastrointestinal organisms
      include selective plating to identify specific nutritional groups, but the
      requirement of strict anaerobiosis for the obligate anaerobic members of these
      cultures can confound sample handling and preparation. Immunological methods can
      circumvent some of these problems but are somewhat limited for assessing
      functionality. The main advantage of using molecular tools is that the genetic
      diversity of the microflora, as well as their gene activity data are obtainable,
      both at the community level and at the single species level. Methods are
      currently available that permit studying individual members of microbial
      consortia, fluxes in community diversity, spatial distribution of consortia
      members, and the expression of specific microbial genes within communities. These
      methods involve the utilization of both DNA- and RNA-targeted probes, gene
      amplification protocols, and mRNA analysis. The study of mechanisms and
      functionality can only enhance the potential of probiotic cultures for limiting
      foodborne pathogen colonization.

PMID- 10342099
TI  - Intracellular life.
AB  - Intracellular parasites and endosymbionts are present in almost all forms of
      life, including bacteria. Some eukaryotic organelles are believed to be derived
      from ancestral endosymbionts. Parasites and symbionts show several adaptations to
      intracellular life. A comparative analysis of their biology suggests some general
      considerations involved in adapting to intracellular life and reveals a number of
      independently achieved strategies for the exploitation of an intracellular
      habitat. Symbioses mainly based on a form of syntrophy may have led to the
      establishment of unique physiological systems. Generally, a symbiont can be
      considered to be an attenuated pathogen. The combination of morphological
      studies, molecular phylogenetic analyses, and palaeobiological data has led to
      considerable improvement in the understanding of intracellular life evolution.
      Comparing host and symbiont phylogenies could lead to an explanation of the
      evolutionary history of symbiosis. These studies also provide strong evidences
      for the endosymbiogenesis of the eukaryotic cell. Indeed, an eubacterial origin
      for mitochondria and plastids is well accepted and is suggested for other
      organelles. The expansion of intracellular living associations is presented, with
      a particular emphasis on peculiar aspects and/or recent data, providing a global
      evaluation.

PMID- 10342100
TI  - Susceptibility testing of Clostridium difficile against metronidazole and
      vancomycin by disk diffusion and Etest.
AB  - A prospective study on the susceptibility of Clostridium difficile to
      metronidazole and vancomycin using the Etest and disk diffusion test was
      performed over a 6-month period. One hundred strains were tested; one strain was
      highly resistant to metronidazole (MIC = 64 micrograms/mL). The zone size of
      inhibition by the disk diffusion test correlated with the MIC as determined by
      the Etest (regression coefficient = -0.043 for metronidazole and -0.044 for
      vancomycin, p < 0.001 for both antibiotics). However, the correlation coefficient
      was low for both metronidazole (r = 0.574) and vancomycin (r = 0.473); hence the
      zone of inhibition by disk diffusion test could not predict the MIC
      satisfactorily. Metronidazole is still the first-line antibiotic for the
      treatment of C. difficile-associated diarrhea because the incidence of
      metronidazole resistant strains remains very low. However, the efficacy of
      metronidazole in the treatment of infections attributable to isolates with high
      level metronidazole resistance may be compromised because the fecal concentration
      of metronidazole is relatively low when compared with the MIC values of the less
      susceptible strains. Oral vancomycin is the drug of choice under such
      circumstances, as its fecal concentration is much higher than that of
      metronidazole.

PMID- 10342101
TI  - Molecular epidemiological survey of penicillin-resistant Streptococcus pneumoniae
      from Asia, Europe, and North America.
AB  - One hundred penicillin-resistant Streptococcus pneumoniae (PRSP) strains from
      Asia, Europe, and North America were analyzed using pulsed-field gel
      electrophoresis; fingerprinting of penicillin binding protein (pbp) genes; and
      BOX PCR. Results show that six PFGE patterns (three patterns comprising > or = 2
      serotypes) were found widespread and accounted for 64 of the 100 PRSP strains.

PMID- 10342102
TI  - Evaluation of three commercial enzyme-linked immunosorbent assay kits for
      diagnosis of Helicobacter pylori in Chinese patients.
AB  - Most of the commercial serological assays for H. pylori are developed and
      validated in western countries. We evaluated the accuracy of three popular
      commercial ELISA tests for H. pylori in the Chinese population. Eighty dyspeptic
      patients were recruited and diagnosis of H. pylori infection was based on biopsy
      urease test, histology and urea breath test. Thirty-six patients (45%) were
      positive for H. pylori infection by two or more positive reference tests. Anti-H.
      pylori IgG antibody was detected by three commercial ELISA tests: GAP IgG (Bio
      Rad), HM-CAP (Enteric Products) and Pyloriset EIA-G (Orion). The respective
      sensitivity, specificity, positive and negative predictive values of the three
      tests were: GAP IgG (50%, 97.4%, 93.8%, 71.7%), HM-CAP (72.7%, 68.4%, 66.7%,
      74.3%) and Pyloriset EIA-G (75%, 86.4%, 81.8%, 80.9%). Despite the high accuracy
      reported in the West, the performance of these commercial serological tests was
      unsatisfactory when used in Chinese patients.

PMID- 10342104
TI  - "Giant" blastoconidia of Candida albicans: morphologic presentation and concepts
      regarding their production.
AB  - Candida albicans normally produces blastoconidia measuring 2 to 8 microns in
      diameter. Markedly enlarged "giant" (approximately 30 microns) blastoconidia of a
      C. albicans isolate (designated BH) were observed after growth on commercially
      prepared chocolate agar already supplemented with IsoVitalex (BBL-Microbiology
      Systems, Cockeysville, MD, USA). Morphologically, "giant" blastoconidia presented
      a spectrum of forms such as blastoconidia with linear creases, with a single
      broad-based bud resembling Blastomyces dermatididis, with multiple buds
      resembling Paracoccidioides brasiliensis, or elliptical in shape. "Giant"
      blastoconidia contained a large oval clear vacuole occupying greater than 50% of
      the blastoconidium. Pseudohyphae emanating from these blastoconidia were also
      enlarged and contained a similar oval inclusion. Rarely observed were "giant"
      blastoconidia with either adherent or internalized blastoconidia uniformly
      arranged within the blastoconidium. "Giant" or enlarged blastoconidia production
      was constant, usually approaching 10 to 20% of the blastoconidial units
      comprising a single colony, irrespective of the number of subcultures. IsoVitalex
      supplementation of Remel (Lexana, KS, USA) chocolate agar but not a variety of
      other media also resulted in "giant" blastoconidia production. It is, therefore,
      theorized that a component(s) of IsoVitalex activates/blocks a gene present in
      select clones of C. albicans blastoconidia resulting in "giant" or enlarged
      blastoconidiogenesis.

PMID- 10342103
TI  - Distribution of Candida albicans genotypes among family members.
AB  - Thirty-three families (71 subjects) were screened for the presence of Candida
      albicans in mouthwash or stool specimens; 12 families (28 subjects) were culture
      positive for this yeast. An enrichment procedure provided a twofold increase in
      the recovery of C. albicans from mouthwash specimens. Nine of the twelve culture
      positive families had two positive members each, two families had three positive
      members each, and one family had four positive members. Genetic profiles were
      obtained by three methods: pulsed-field gel electrophoresis; restriction
      endonuclease analysis, and random amplification of polymorphic DNA analysis. DNA
      fingerprinting of C. albicans isolated from one body site three consecutive times
      revealed that each of the 12 families carried a distinct genotype. No two
      families shared the same strain, and two or more members of a family commonly
      shared the same strain. Intrafamily genotypic identity (i.e., each member within
      the family harbored the same strain) was demonstrated in six families. Genotypes
      of isolates from husband and wife differed from one another in five families. All
      three methods were satisfactory in determining genotypes; however, we concluded
      that restriction endonuclease analysis provided adequate resolving power.

PMID- 10342105
TI  - Simplified PCR set-up using a frozen preformulated mix for the detection of
      cytomegalovirus.
AB  - A simple PCR set-up for the detection of cytomegalovirus in clinical specimen was
      developed. All components of the PCR master mix including Taq DNA polymerase,
      uracil N-glycosilase, and primers were preformulated and stored frozen in
      aliquots. After thawing the master mix aliquots, the PCR was immediately started
      after the addition of sample DNA. This method gave excellent reproducible PCR
      results without loss of enzyme activities following storage at -20 degrees C for
      at least 4 months.

PMID- 10342106
TI  - Antimicrobial activity of gatifloxacin compared to seven other compounds tested
      against gram-positive organisms isolated at 10 cancer-treatment centers.
AB  - Gram-positive bacterial pathogens are important causes of disease in cancer
      patients and are becoming increasingly resistant to available antimicrobial
      agents. We examined the in vitro activity of gatifloxacin, a new fluoroquinolone,
      compared with other quinolones, ceftazidime, and traditional Gram-positive-active
      agents tested against pathogens isolated from patients at 10 cancer treatment
      hospitals in the United States. A total of 1,128 Gram-positive isolates were
      tested by the E-test method (AB BIODISK, Solna, Sweden) with results validated by
      concurrent quality control strain analysis. Gatifloxacin was more potent than
      either ciprofloxacin or levofloxacin against all Gram-positive species.
      Vancomycin was the most active agent tested against all species except Bacillus
      spp., which were more susceptible to the fluoroquinolones. When tested against
      these Gram-positive pathogens from patients with cancer, the spectrum of
      gatifloxacin was also greater than that of levofloxacin and ciprofloxacin.
      Gatifloxacin may have a role as part of prophylactic or therapeutic antimicrobial
      regimens for selected cancer patients with Gram-positive infections.

PMID- 10342107
TI  - Blood and charcoal added to acidified agar media promote the growth of
      Mycobacterium genavense.
AB  - Ten different agar media were tested for the in vitro growth of Mycobacterium
      genavense in primary cultures and in subcultures from BACTEC vials. These agar
      media were based on Middlebrook 7H9, 7H10 and 7H11, and supplemented with
      additives: mycobactin J, yeast extract, charcoal, or defibrinated sheep blood.
      Some media were acidified with phosphoric acid to a final pH of 6.2 +/- 0.2.
      Fourteen M. genavense strains from nude mouse organs as well as one
      decontaminated clinical specimen (from a bird) were tested. The optimal medium
      for primary cultures of M. genavense was Middlebrook 7H11 acidified to pH 6.2 +/-
      0.2 and supplemented with charcoal and sheep blood: on this medium, all strains
      produced colonies within 6-12 weeks of incubation in numbers approaching the
      number of bacilli inoculated. It was also the only medium to support the growth
      of the decontaminated clinical specimen. Added blood and charcoal appeared not as
      essential for subcultures as for primary cultures. Three media supported the
      growth of all strains within 1 month incubation: they were acidified, and were
      supplemented with yeast extract or pancreatic digest of casein, and with either
      blood or charcoal.

PMID- 10342109
TI  - Pitfalls and difficulties in histological diagnosis of human dirofilariasis due
      to Dirofilaria (Nochtiella) repens.
AB  - The authors have conducted a histologic study of over 90 cases of Dirofilaria
      infection in man due to Dirofilaria repens, the most extensive study of its kind
      in the world. On the basis of their findings, they illustrate the diagnostic
      difficulties that may arise when regressive phenomena render the parasite's
      morphologic characteristics largely or completely unrecognizable. These phenomena
      are due to the death of the filaria inside the inflammatory nodule weeks or
      months prior to surgical removal, and to the consequent invasion of inflammatory
      cells. They start at the nematode's natural orifices (mouth, vulva, anus, cloaca)
      and gradually spread throughout its body. In cases of difficult diagnosis,
      therefore, it is recommended that the nodule be sectioned at different points
      comprising caudal, cephalic and middle body aspects, so as to reveal the few
      morphologic features that are still recognizable and which may afford a correct
      diagnosis. The authors present examples of histologic sections in color plates in
      which the nematode was in an excellent state of preservation and others
      illustrating the full range of regressive phenomena, from slight to total
      disintegration of the bodily structure.

PMID- 10342108
TI  - Specific anti-toxoplasmic IgG antibody immunoblot profiles in patients with AIDS
      associated Toxoplasma encephalitis.
AB  - Among 186 suspected cases of Toxoplasma encephalitis (TE) in HIV-infected
      patients, 113 were classified as TE and 73 as non-TE. Serum Toxoplasma gondii
      (T.g.) antibodies were detected by ELISA in 97% of TE vs 71% of non-TE cases (p <
      0.001). In the 164 patients positive for T. g. antibodies, the IgG 27 and 32
      bands were more frequently present in TE than in non-TE (p = 0.003, p = 0.002,
      respectively). Among patients with positive T.g. serology, multivariate analysis
      showed that the presence of an IgG 32 (OR 3.1) or IgG 27 band (OR 2.7) on Western
      blot was highly indicative of TE independently of each other. Positive T.g.
      serology, but not anti-T.g. IgG antibody titres, was predictive. Thus, the
      positivity of IgG 27 and 32 bands on Western blot analysis provides useful data
      for improving the diagnosis of presumptive TE in HIV-infected patients with
      suspected TE and positive Toxoplasma serology.

PMID- 10342110
TI  - Bacterial pathogens isolated from patients with skin and soft tissue infections:
      frequency of occurrence and antimicrobial susceptibility patterns from the SENTRY
      Antimicrobial Surveillance Program (United States and Canada, 1997). SENTRY Study
      Group (North America).
AB  - As part of the SENTRY Antimicrobial Surveillance Program, 1562 bacterial isolates
      were recovered from hospitalized patients with skin and soft tissue infections
      (SSTIs) in 30 United States (U.S.) and 8 Canadian medical centers between October
      and December, 1997. The overall rank order of recovery of the six most common
      pathogens was Staphylococcus aureus (42.6%) > Pseudomonas aeruginosa (11.3%) >
      Enterococcus spp. (8.1%) > Escherichia coli (7.2%) > Enterobacter spp. (5.2%) >
      beta-hemolytic streptocci (5.1%). With one exception, essentially the same order
      was observed in both the U.S. and Canada. The single exception was the
      Enterococcus group, which were the third most common isolate in the U.S. (9.6%),
      but the seventh most common isolate in Canada (3.7). Of note, 24.0% of S. aureus
      isolates were oxacillin resistant; vancomycin was uniformly active. Vancomycin
      resistance among Enterococcus spp. (16.5%) was observed only in the U.S. Several
      antimicrobial agents remained broadly active for SSTI isolates of P. aeruginosa,
      including meropenem, amikacin, tobramycin, and piperacillin with or without
      tazobactam. Imipenem resistance (MICs, > or = 8 micrograms/mL) was observed in
      11.9% of isolates of P. aeruginosa and ceftazidime, and cefepime had equivalent
      activity (85.2% and 85.8% susceptible, respectively). Numerous beta-lactams,
      aminoglycosides and fluoroquinolones were broadly active against E. coli SSTI
      isolates (i.e. < 5% resistance). Extended-spectrum beta-lactamase production was
      uncommon both with E. coli and Klebsiella spp. in both nations. Cefepime,
      imipenem, and meropenem; the aminoglycosides; and fluoroquinolones were
      conspicuously more active against Enterobacter spp. than other agents tested.
      High-level, stably derepressed Amp C beta-lactamase production was commonly
      observed in this group (26.8%), but cefepime generally retained activity against
      these ceftazidime-resistant organisms. The results of this study serve to define
      the most common bacterial causes of SSTIs in North America, elucidate patterns of
      antimicrobial resistance and can be used as a basis for making initial empiric
      antimicrobial management decisions in hospitalized patients with such infections.

PMID- 10342111
TI  - Determination of the antimicrobial activity of 29 clinically important compounds
      tested against fastidious HACEK group organisms.
AB  - HACEK group organisms are very fastidious organisms (Haemophilus spp.,
      Actinobacillus actinomycetemcomitans, Cardiobacterium hominus, Eikenella
      corrodens, Kingella spp.) that can produce serious invasive infections such as
      endocarditis. Problems with susceptibility testing methods and their rarity of
      isolation limit available information of therapeutic choices, particularly among
      newer antimicrobial agents. Forty-two HACEK strains were tested by the Etest (AB
      BIODISK, Solna, Sweden) method against 29 antimicrobial agents. Nearly all
      compounds exhibited activity with best potency observed among the tested beta
      lactamase inhibitor combinations, "third- or fourth-generation" cephems,
      meropenem, fluoroquinolones, and rifampin. Numerous therapeutic options appear
      possible for initial parenteral treatment followed by oral "step-down" or switch
      therapy. Each case of HACEK infection therapy should be guided by accurate
      susceptibility tests, for which the Etest seems preferred for these fastidious
      species.

PMID- 10342112
TI  - A correlative morphometric and clinical investigation of hypoganglionosis of the
      colon in children.
AB  - Hypoganglionosis of the myenteric plexus of the colon is not clearly defined and
      seldom investigated. Colon segments from 15 children with an extended
      oligoeuronal hypoganglionosis up to the proximal resection end were
      morphometrically studied and compared to normally innervated colon segments. The
      study was performed with resected specimens from 7 children with isolated
      hypoganglionoses, 8 children with a Hirschsprung-associated hypoganglionosis, and
      12 colon segments with normal innervation. The resected colon specimens were
      caudo-cranial coiled. The native tissue was frozen at -80 degrees C on a cryostat
      carrier and cut at -20 degrees C in 15 microns-thick sections (equivalent to 4-5
      micron-thick paraffin sections). The air-dried sections underwent an enzyme
      histochemical procedure for an acetylcholinesterase reaction to stain the
      parasympathetically innervated myenteric plexus. For histological identification
      and morphometric measurements, ganglia and nerve cells were selectively stained
      using a lactic dehydrogenase reaction. The morphometric measurements were
      performed with an optic-electronic image analysis system that determined ganglion
      size, ganglion distances, nerve cell number per ganglion, and ganglion number per
      mm colon. The results showed that hypoganglionosis of the myenteric plexus is
      characterised by a 42% decrease in plexus area and a 55% decrease of the nerve
      cell number per mm length of colon. The number and area of myenteric ganglia
      showed a decrease of 59% and a doubling of the ganglion distances. The
      histopathological diagnosis of a hypoganglionosis of the colon was not
      necessarily an indication of a chronic constipation, but rather an indication of
      a disposition for constipation. A chronic constipation is often caused by a long
      hypoganglionic segment proximal to a resected short Hirschsprung segment.

PMID- 10342113
TI  - Ultrastructural features of nerve fascicles and basal lamina abnormalities in
      Hirschsprung's disease.
AB  - Although the pathogenesis of Hirschsprung's disease (HD) is not completely
      resolved, both the absence of nerve cells and the hypertrophy of nerve fascicles
      within the aganglionic colonic segment have been attributed to an abnormal
      intestinal microenvironment. Studies on animal models for HD revealed an altered
      ultrastructure of ingrowing nerve fascicles and abnormalities of basal laminae
      (BL). Therefore, the purpose of this study was to examine the ultrastructure of
      hypertrophied nerve fascicles in human HD with special reference to structural
      abnormalities of BL. Colonic specimens were obtained from patients with HD (n =
      10) and controls (n = 5) and processed for electron-microscopical examination.
      Hypertrophied nerve fascicles were characterized by a prominent perineural sheath
      surrounded by large amounts of collagen bundles, a collagen-filled endoneurium,
      vasa nervorum and abundant glial cells of extraenteric ultrastructure, which were
      arranged in mono- or oligoaxonal units and frequently displayed different stages
      of myelination. As these ultrastructural characteristics resembled typical
      features of extrinsic nerves and were similar to those observed in subserosal
      nerves, the prominent intramural nerve fascicles were considered to be of
      extraenteric origin. Most likely their overabundance contributes to the
      functional obstruction of the terminal colon. Morphological abnormalities of BL
      encountered in the aganglionic colonic segment consisted of an extensive
      multilamination of BL surrounding glial processes and an irregular thickening of
      BL surrounding perineurocytes and smooth muscle cells of the muscularis mucosae.
      Similar alterations in BL have also been described in inherited peripheral and
      diabetic autonomic neuropathies and attributed to reactivated schwann cells.
      Thus, the overproduction of BL material within the hypertrophied nerve fascicles
      in HD may reflect an increased activity of proliferating glial cells. Since the
      smooth muscle cells of the muscularis mucosae showed abnormalities of BL similar
      to those observed in murine models for HD, it is suggestive that also in human HD
      the aganglionic colon is affected by a disturbed intestinal micro-environment
      impairing the neuronal colonisation and promoting the ingrowth of extrinsic
      nerves. The ultrastructurally observed alterations in BL of both neuronal and non
      neuronal cells, as well as the increased amount of perineural and endoneural
      collagen provide further evidence that extracellular matrix components are
      abnormally distributed and overproduced within the bowel wall of patients
      affected by HD.

PMID- 10342114
TI  - Chronic intestinal pseudo-obstruction syndrome in pediatric patients.
AB  - The aim of this study was to report the presentation and outcome of 22
      consecutive children (13 female) who presented with a syndrome of chronic
      intestinal pseudo-obstruction with or without urinary tract involvement. We
      analyse the main clinical and histopathological features and discuss therapeutic
      management. Ten patients had signs of intestinal obstruction at birth, in which 6
      presented antenatally with megacystis on ultrasound. Six children presented with
      constipation and/or obstruction between 1 and 6 months of age and in 6 other
      patients diagnosis was made between the ages of 1 and 12 years. There was a
      family history in 4 patients. Investigations showed diffusely dilated gut on x
      ray with slow transit on small bowel follow through. Absent or abnormal motor
      migrating complex with low amplitude contractions were demonstrated on duodeno
      jejunal manometry in 12/13. Megacystis occurred in 15/21 and megaureter in 2/21.
      Full thickness biopsies (n = 22) revealed involvement of muscle layers in 8, and
      abnormal myenteric plexus on histochemistry in 13. In 1, the biopsies were
      inconclusive. Recurrent urinary tract infections occurred in all with structural
      urinary tract abnormality and most had bacterial overgrowth. Severe recurrent
      episodes of obstruction which required parenteral nutrition (PN) occurred in all
      patients. Drugs were unhelpful and decompression ileostomies or colostomies were
      performed in 20/22. Five children died from sepsis (n = 3) or sudden death.
      Eleven patients remain partially or totally dependent on PN despite decompression
      ileostomy in 10/11. Six patients underwent colectomy and ileorectal pull-through,
      2 of which remain on long-term PN, while the others are totally orally fed.
      Despite careful histological study pointing to 2 main forms, myopathy and
      neuropathy, the etiology of primary intestinal pseudoobstruction syndromes
      remains unknown. It may present antenatally while most of the time the gut and
      the urinary tract are diffusely involved. The condition has a high morbidity with
      a percentage requiring long-term PN. Although the mortality rate is high (23%),
      careful treatment of urinary tract infections and bacterial overgrowth,
      decompression surgery and judicious use of PN allows survival to adult life.

PMID- 10342115
TI  - Intestinal transit time in children with intestinal neuronal malformations
      mimicking Hirschsprung's disease.
AB  - A total of 106 consecutive children with intestinal neuronal malformations were
      included in a prospective study. The intestinal transit time was assessed using a
      modification of Hinton's method. The results of transit time studies, the
      associated specific histochemical findings, therapeutic procedures, and the
      clinical course on follow-up assessments over a mean period of 2.4 years were
      analysed. The intestinal transit time was prolonged in all 53 patients with
      aganglionosis and in 37 (69.8%) out of 53 children with other intestinal
      malformations. Eight out of 16 children with IND type B had an abnormal transit
      time, 1 underwent anterior resection, and 2 had a temporary colostomy. In 7 out
      of 8 children with hypoganglionosis and 9 out of 10 children with a reduced
      parasympathetic tone the transit time was prolonged. A resection was performed in
      7 and 2 of these children respectively. Both patients with heterotopia of the
      myenteric plexus had a prolonged bowel transit and parts of the large bowel had
      to be resected. Only 11 out of 17 children with heterotopia of the submucous
      plexus, dysganglionosis, or immature ganglia had a prolonged transit time, 2
      underwent sphincteromyotomy. At follow-up, all patients with malformations other
      than aganglionosis stated that symptoms had improved and they were willing to
      tolerate their complaints. However, 25 reported on persistent constipation, 6 on
      overflow encopresis. All children who required surgery had a prolonged intestinal
      transit time, but also 21 (56.8%) of 37 children who were successfully treated
      without surgery. None of the 16 children with normal transit had to be operated.
      It is concluded that specific histochemical findings do not always correlate with
      delayed intestinal transport. The determination of the intestinal transit time
      represents an important tool to identify the clinical relevance of histochemical
      findings in the individual patient.

PMID- 10342116
TI  - Preoperative enzymo-histochemical diagnosis of dysganglionoses associated with
      anorectal malformations (ARM) with recto-vestibular and recto-perineal fistula.
AB  - The posterior sagittal anorectoplasty (PSARP) is widely recognized as the best
      technique available today for the surgical treatment of anorectal malformations
      (ARM). However, different retrospective studies on the functional results of
      PSARP in the treatment of ARM have shown different postoperative degrees of
      constipation. In particular, even in patients with normal sacrum, about 70% of
      operated ARM with vestibular fistula and about 50% with perineal fistula can be
      complicated by fecal constipation and pseudoincontinence. In order to identify
      preoperatively whether ARM patients present abnormal innervation patterns of
      rectal pouch and fistula (as reported by Holschneider et al [7]), we decided to
      study suction rectal biopsies performed by introducing SBT-100 rectal suction
      biopsy tool into the fistula at 6, 4, 3 and 2 cm from the meatus. To date, this
      approach has been adopted in 22 ARM cases (15 females and 7 males, age range 7
      days-4 years), 6 of them with recto-vestibular fistula and 13 with recto-perineal
      fistula. Biopsies were frozen in isopentane at liquid nitrogen temperature and
      cryostatic sections were studied by acetylcholinesterase (AChE), succinic
      dehydrogenase (SDH) and alpha-naphthyl-esterase (ANE) enzymo-histochemical
      techniques. The results concerning the innervation-type of fistula and proximal
      rectal pouch were confirmed by the biopsies obtained during PSARP. Our overall
      incidence of rectal innervation intrinsic disorders was 81.82%. In particular,
      all our cases of vestibular fistula presented associated dysganglionoses. The
      incidence of associated Hirschsprung's disease was high, corresponding to 18% of
      cases. Our results suggest that the high frequency of constipation in low forms
      of ARMS depends on primary intestinal neuronal malformations and it cannot be
      ascribed to a denervation secondary to rectal dissection and to PSARP procedure.
      We propose the introduction of this type of preoperative enzymo-histochemical
      diagnosis in ARM cases because it can select those patients with severe
      associated dysganglionoses. In our opinion, if this diagnosis is available
      preoperatively, PSARP can be performed without using abnormally innervated
      structures and reducing postoperative functional complications.

PMID- 10342117
TI  - Anorectal manometry during the neonatal period: its specificity in the diagnosis
      of Hirschsprung's disease.
AB  - In this study the reliability of anorectal manometry (ARMM) in Hirschsprung's
      disease (HD) in the neonatal period is evaluated. ARMM was performed in 59
      patients (age ranging between 2 to 90 days) in whom HD was suspected. Rectal
      biopsy was performed in 23 newborn whose rectoanal inhibitory reflex (RAIR) was
      not identified in the ARMM study and in 13 RAIR-positive newborn due to strong
      clinical signs supporting HD or persistence of symptoms during their follow-up.
      Other RAIR-positive patients were followed up to 4 months to 3.5 years and no
      problems were encountered. Among the 36 newborn with rectal biopsies, if the
      results were compared to ARMM studies, there were one false-positive and two
      false-negative results. The sensitivity, specificity, positive predictive value,
      negative predictive value and accuracy of ARMM in the diagnosis of HD are 91.6%,
      95.6%, 84.6% and 91.6% respectively. We conclude that ARMM can be used as a
      screening test in patients in whom HD is suspected during the neonatal period,
      but for definitive diagnosis it must be combined with other diagnostic tests.

PMID- 10342118
TI  - Isolated longitudinal rupture of the posterior tracheal wall following blunt neck
      trauma.
AB  - The authors report 3 female children (4, 5 and 12 years old) who suffered an
      isolated rupture of the posterior tracheal wall (membranous part) following a
      minimal blunt trauma of the neck. Such tracheal ruptures often cause a
      mediastinal and a cutaneous thoraco-cervical emphysema, and can also be combined
      with a pneumothorax. The following diagnostic steps are necessary: X-ray and CT
      of the chest, tracheo-bronchoscopy and esophagoscopy. The most important
      examination is the tracheo-bronchoscopy to visualize especially the posterior
      wall of the trachea. Proper treatment of an isolated rupture of the posterior
      tracheal wall requires knowledge about the injury mechanisms. The decision
      concerning conservative treatment or a surgical intervention is discussed. In our
      3 patients we chose the conservative approach for the following reasons: 1) The
      lesions of the posterior tracheal wall were relatively small (1 cm, 1.5 cm, 3 cm)
      and showed a good adaptation of the wound margins. 2) No cases showed an
      associated injury of the esophageal wall. All of our patients had an uneventful
      recovery, the lesion healed within 10 to 14 days, and follow-up showed no late
      complications.

PMID- 10342119
TI  - Cricopharyngeal achalasia: case reports and review of the literature.
AB  - Primary cricopharyngeal achalasia (a = absence, chalasia = relaxation) is a rare
      cause of swallowing disorders in newborns. Two cases are reported which were
      successfully treated by a myotomy of the cricopharyngeal muscle. A thorough
      history is essential in differential diagnosis as well as observation of the
      feeding infant. Presence of anatomical obstruction to swallowing and existence of
      neurological defects should be ruled out. Cineradiography with lateral views by
      an experienced radiologist is the best diagnostic technique. Esophageal manometry
      may provide information regarding other esophageal dyskinetic problems. However,
      these studies are difficult to perform in neonates and infants. Endoscopy may be
      helpful to exclude vocal cord paralysis or mechanical obstruction. Balloon
      dilatation has been reported as being successful in several reports; however no
      comparison of efficacy has been made in any series between dilatation of the
      upper esophagus and surgical myotomy which remains in our mind, the optimal
      treatment of cricopharyngeal achalasia.

PMID- 10342120
TI  - Fatal cardiac tamponade as a late complication of central venous catheterization:
      a case report.
AB  - Central venous catheterization is a reliable technique in neonatal surgery.
      Nevertheless, the rate of mechanical catheter-related complications remains high.
      We report a neonate with gastroschisis in which the successful placement of a
      central venous catheter was followed later by a cardiac tamponade with a fatal
      outcome. This complication occurred without perforation of the cardiac wall. A
      similar finding has been reported in only one other pediatric patient. Vigilant
      observation is required in any neonate with a central venous line in place to
      prevent the occurrence of this life-threatening event.

PMID- 10342121
TI  - Ovarian cavernous hemangioma in an 8-year-old girl.
AB  - The case of an ovarian cavernous hemangioma with torsion in an 8-year-old girl is
      described. Current literature records less than 50 cases of which only 8 are in
      children. The presenting symptoms of acute abdomen and the ultrasonographic study
      led to the preoperative diagnosis of torsion of an ovarian tumor. Salpingo
      oophorectomy and appendicectomy were performed with an uneventful postoperative
      course. The histological pattern of the tumor was that of an entirely cavernous
      hemangioma. The case is reported in view of its rarity.

PMID- 10342123
TI  - Feminizing genital reconstruction, sigmoid vaginal replacement and anorectoplasty
      as a one-stage procedure for anorectal atresia associated with ambiguous
      genitalia.
AB  - Anorectal atresia associated with male pseudohermaphroditism presents both
      diagnostic and surgical challenges. In the past, multiple operations were
      necessary for feminizing genitoplasty in gender-reassigned children with
      ambiguous genitalia. We combined the repair of an imperforate anus with a
      feminizing genitoplasty, including sigmoid vaginal replacement using the
      posterior sagittal approach in a 3-months-old infant. We conclude that a primary
      complete reconstruction is advantageous and should be performed in this
      condition.

PMID- 10342122
TI  - Colonic stenosis after hemolytic-uremic syndrome.
AB  - Colonic necrosis and intestinal perforation are the usual surgical complications
      of hemolytic syndrome. We present a case of right transverse colon stricture
      following hemolytic-uremic syndrome.

PMID- 10342124
TI  - ICN during wartime: 1912-1947.
AB  - Over nearly four decades (1911-1947) ICN established itself as an enduring
      organization for nurses in the midst of turbulent international politics,
      pressing healthcare demands and hardships of war. As women, ICN leaders had
      devoted themselves to their mission to improve the cause of nursing,
      economically, professionally and culturally. In the process the unifying
      missionary spirit of the early leaders underwent important transformations. In
      part, because of tensions resulting from diverse views from within, but most of
      all because of external influences of profound social change and the upheaval of
      war, the postwar identity of ICN was different.

PMID- 10342125
TI  - Sowing the seeds of public health nursing--1920-39.
AB  - The Florence Nightingale International Foundation and the Florence Nightingale
      International Courses played an important role in the development of public
      health nursing leadership in Europe and remain an outstanding example of
      international collaboration. Through the International Courses 203 nurses from 40
      countries were prepared to organize and implement systems of public health
      nursing where none had previously existed; another 97 nurses were prepared for
      leadership as administrators and teachers. Below, how the courses started and
      their impact as viewed by nursing leaders of that era.

PMID- 10342126
TI  - Cross-cultural partnerships in nursing: Romania and Denmark. Part I.
AB  - ICN's theme for its centennial in 1999 is "Celebrating Nursing's Past; Claiming
      the Future". Cross-cultural partnerships to support and develop nurses'
      associations in financially deprived countries are one way the better-off nurses'
      associations are ensuring that nurses everywhere can claim their future. Such a
      cooperation project developed by the Danish Nurses' Organization in cooperation
      with the Romanian Nurses' Association and the UNICEF (United Nations Children's
      Fund) office in Romania is described below.

PMID- 10342127
TI  - Nursing in Thailand: western concepts vs Thai tradition.
AB  - Thailand's rigid hierarchy discourages independent thought and generates nurses
      unsuited to apply Western processes. Theories or frame-works can provide only a
      guideline, not a recipe. Western concepts do not match the demands of Thai
      nursing and need to be reinterpreted in the context of Thai culture.

PMID- 10342128
TI  - ICN on healthy ageing: a public health and nursing challenge.

PMID- 10342129
TI  - Ethical problems in care of the elderly: a Finnish perspective.

PMID- 10342131
TI  - [Pathophysiology of acute coronary syndromes].
AB  - Coronary atherosclerosis and plaque disruption with superimposed thrombosis are
      the main causes of the acute coronary syndromes of unstable angina, myocardial
      infarction, and sudden death. Coronary artery spasm has also been implicated in
      the pathogenesis of acute coronary syndromes. Other researchers and we have
      reported that the plasma levels of fibrinopeptide A, a sensitive marker of
      thrombin generation, and plasminogen activator inhibitor activity, an indicator
      of the impairment of fibrinolysis, increase in patients with unstable angina and
      acute myocardial infarction. We also showed that coronary artery spasm induced
      fibrinopeptide A generation and may lead to thrombus formation in the coronary
      artery involved, and plasminogen activator inhibitor activity increased after
      coronary spasm. Tissue factor is the primary initiator of the extrinsic
      coagulation cascade. We have recently demonstrated that the plasma TF antigen
      levels increase in patients with acute myocardial infarction and unstable angina.
      Furthermore, we examined directional coronary atherectomy specimens from 24
      patients with unstable angina and 23 with stable exertional angina. We have shown
      that tissue factor expression on macrophages was more frequent in coronary
      atherosclerotic plaques in patients with unstable angina. Tissue factor expressed
      on macrophages may play an important role in the thrombogenicity in coronary
      atherosclerotic plaques of these patients. In conclusion, increased coagulation
      cascade and impaired fibrinolysis occurs and leads to coronary thrombosis in
      patients with acute coronary syndromes. These phenomena also occur in patients
      with coronary spasm.

PMID- 10342130
TI  - [Histopathological findings of coronary arteries in cases with acute coronary
      syndromes].
AB  - A histopathological study of coronary arteries in patients with acute coronary
      syndromes was carried out. The results of this study are as follows: 1. A high
      incidence of thrombus formation, corresponding to the site of the infarction, was
      observed in cases with acute myocardial infarction. 2. Coronary thrombi
      containing plaque components such as foam cells, cholesterol clefts, and
      fractured intimal collagen fibers were detected. 3. Patients who succumbed
      suddenly after coronary attack had ruptured atheromatous plaque only, but not a
      thrombus. As these patients showed severe stenosis with recanalization in 2 of
      the 3 main coronary arteries, the rupture of the plaque caused significant
      occlusion of the remaining coronary artery. 4. Increase of intra-plaque pressure
      resulting from a honeycomb-like accumulation of foam cells, cholesterin clefts,
      and blood infiltration from lumen to plaque through the injured endothelial cells
      is the cause of rupture of the atheromatous plaque. This rupture into the lumen
      might precede, and be responsible for formation of the thrombus and onset of
      acute coronary syndromes.

PMID- 10342132
TI  - [The role of angioscopy and intravascular ultrasound imaging in acute coronary
      syndrome].
AB  - Evaluation of the severity of coronary atherosclerosis by intracoronary imaging
      may be closely relevant with the prevention and treatment of acute coronary
      syndromes. Coronary angioscopy as one of the innovative methods of imaging and
      intravascular ultrasound makes the insight visualization of coronary vessel wall
      and histological recognition possible recently. Yellow plaques rich in lipid
      materials and covered by thin membrane are more often ruptured than white ones to
      cause acute coronary syndromes. In patients with unstable angina and acute
      myocardial infarction, the yellow plaques with intimal flaps and irregularities
      are frequently observed by angioscopy. Angioscopy is also the most powerful tool
      to detect intracoronary thrombus. In patients with acute myocardial infarction,
      thrombosis occludes vessel lumen totally, but it does not in the unstable angina
      cases. After thrombolytic therapy, the white thrombus is more often observed than
      the red one. Although angioscopy is superior to any other examination in
      diagnosing thrombosis, some complicated plaques are difficult to distinguish from
      thrombus. In addition to measurements of vascular dimension and plaque volume,
      histological diagnosis of plaque is being made by intravascular ultrasound. More
      precise evaluation of plaque histology may be a clue to predict the occurrence of
      acute coronary syndrome. Intravascular ultrasound is not so useful enough to
      diagnose thrombosis. In conclusion, the applications of intravascular imaging
      technologies, such as angioscopy and intravascular ultrasound, may play a
      critical role in the diagnosis and treatment of acute coronary syndromes.

PMID- 10342133
TI  - [Aggressive diagnostic and therapeutic approach for acute coronary syndrome].
AB  - The purpose of this article is to propose an "aggressive strategy" in the
      treatment of patients with acute coronary syndrome (ACS), especially unstable
      angina. The indication and timing of emergent coronary angiography in patients
      with ACS remains to be validated. The results of TIMI III B trial, a randomized,
      controlled trial about this issue, show that an early invasive strategy reduced
      the average length of initial hospitalization and the incidence of
      rehospitalization within 6 weeks. However, the same kind of clinical trial named
      VANQWISH reported that no benefit was obtained from such an aggressive strategy.
      It is of paramount importance to note that these 2 studies were performed in the
      era of plain old balloon angioplasty. Now we can use many kinds of coronary stent
      which impart both excellent radial strength and flexibility. Recent studies have
      demonstrated that culprit lesions of ACS can be treated at the same success rate
      as those of stable effort angina. In our hospital, use of coronary stents in
      patients with ACS dramatically reduced the recurrence of ACS and the incidence of
      angiographic restenosis with the same initial procedure success rate. Since the
      mid-nineties, the radial artery has been used as a vascular access site of
      coronary intervention. The major advantage of this technique is lesser access
      site-related complications and increased patient comfort, which reduced hospital
      stay and cost. Recently it was demonstrated that ad-hoc transradial intervention
      can be applied in patients with unstable angina or even those with acute
      myocardial infarction by trained angioplasters. Thus, we would like to conclude
      that the best strategy in the management of ACS is to perform emergent coronary
      angiography from the radial artery as soon as possible after admission, and to do
      ad-hoc intervention using coronary stents suitable for the lesion anatomy.

PMID- 10342134
TI  - [Conservative management in patients with acute coronary syndrome].
AB  - Plaque rupture has been thought to cause acute coronary syndrome. To manage the
      patients with unstable angina, it is necessary to understand the patients'
      pathophysiology. Based on the classification of unstable angina, initial medical
      treatment including aspirin and oral isosorbide dinitrate should be started
      immediately after admission. Ca antagonist and beta-blocking agent should be
      added according to the symptoms. If ischemic symptoms continue after
      administration of those oral medical treatments, intravenous nitroglycerin and
      heparin should be started. K channel opener (nicorandil) may be effective to
      stabilize the symptom. However, high-risk patients should immediately receive
      coronary angiography to decide further medical or interventional therapy.

PMID- 10342135
TI  - [Secondary prevention of acute coronary syndrome].
AB  - The sudden conversion of a stable atherosclerotic plaque to an unstable and life
      threatening atherothrombotic lesion which is known as plaque rupture is the
      potential mechanism for the development of acute coronary syndrome (ACS).
      Accordingly, secondary prevention of ACS could be achieved with the prevention of
      the plaque rupture and thrombus formation. Coronary angioplasty and coronary
      bypass surgery have a limited value in the long-term prevention of ACS. Coronary
      risk factor modification is certainly the important strategy for secondary
      prevention. The drug treatment with lipid lowering agents, especially 3-hydroxy-3
      methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, beta-adrenergic
      receptor blockers, antiplatelet agents and anticoagulants, have been proven to be
      effective for the secondary prevention of myocardial infarction. Estrogen for
      postmenopausal women has also been reported to be beneficial. However, calcium
      channel blockers except verapamil, nitrates and angiotensin converting enzyme
      (ACE) inhibitors are not recommended for the secondary prevention of ACS.

PMID- 10342136
TI  - [Pathology of atrial fibrillation].
AB  - Atrial fibrillation is one of the most common arrhythmias which is associated
      with various organic heart diseases or systemic disorders. Although a
      pathological basis for atrial fibrillation has not been clarified, an anatomical
      substrate corresponding to long-term atrial fibrillation has been recently
      demonstrated. Age-related changes of the atrial myocardium were frequently
      observed in healthy people. Quantitative histological study of the sinoatrial
      node revealed no difference in the reduction of the nodal cells between 12
      patients with atrial fibrillation and 21 age-matched controls. The pathological
      findings of the myocardium including atrial preferential pathways in patients
      with long-term atrial fibrillation showed depletion of the muscular bundles,
      fibrosis and fatty metamorphosis of the atrial myocytes. These findings suggest
      that atrial fibrillation might be related to reentry in the residual muscular
      bundles including circumferential muscular bundles in the right atrium.

PMID- 10342137
TI  - [Historical perspectives on the mechanism of atrial fibrillation].
AB  - A number of experimental studies have been proposed to show that reentry is an
      important electrophysiological mechanism related to the development of atrial
      fibrillation. The beginning of the computer era enabled us to analyze the atrial
      activation during atrial fibrillation. The results of these studies were
      fascinating and allow for the development of theories and speculations on the
      mechanism of atrial fibrillation. Sophisticated computer techniques also allowed
      Moe to simulate atrial electrical activity during atrial fibrillation, and their
      team formulated so-called multiple wavelet theory which was subsequently
      supported by experimental evidence. Spiral wave for ventricular fibrillation was
      also proposed for the atrial activation mechanism during atrial fibrillation in
      the experimental model. The evidence available at the moment warrants the
      statement that atrial fibrillation is caused by multiple wavelet reentry. These
      studies will allow a better understanding of the relative importance of
      wavelength and structural inhomogeneities in the genesis of atrial fibrillation.

PMID- 10342138
TI  - [Pharmacological restoration and maintenance of sinus rhythm by antiarrhythmic
      agents].
AB  - Paroxysmal atrial fibrillation is defined as an atrial fibrillation that
      terminates spontaneously. It is desirable that atrial fibrillation should be
      terminated immediately after onset, and should be prevented from re-initiation to
      avoid atrial electrical remodeling or atrial stunning after cardioversion.
      Antiarrhythmic agents are used for these reasons. The important factors for
      pharmacological cardioversion of atrial fibrillation are thought to be
      prolongation of atrial refractory and suppression of conduction time in the
      atrium. Therefore, class Ia and Ic antiarrhythmic drugs, including bepridil as
      class IV because of its characteristics of class Ia, are administered to restore
      sinus rhythm. Verapamil and diltiazem, or beta adrenergic blocker, or digitalis
      decreases the ventricular response during atrial fibrillation for disturbance of
      atrioventricular nodal conduction, and then cardioversion of atrial fibrillation
      may occur. Suppression of supraventricular extrasystoles and atrial conduction
      time, or prolongation of atrial refractoriness will be needed to maintain sinus
      rhythm. Class I, III, or bepridil as class IV excepting lidocaine and mexiletine
      are used to prevent paroxysmal atrial fibrillation. In general, sodium channel
      blocker is superior for defibrillation and potassium channel blocker is superior
      for prophylaxis of atrial fibrillation. Considering efficacy, antiarrhythmic
      agents should be selected depending on the following factors: cardiac function,
      renal or hepatic function, underlying heart disease, exercise-induced or enhanced
      mental condition, cholinergic induced, drug-resistant atrial fibrillation or not.

PMID- 10342139
TI  - [Frontiers in prevention of thromboembolism in nonvalvular atrial fibrillation].
AB  - Atrial fibrillation, which has age-dependent exponentially rising high
      prevalence, is now well known to frequently predispose to systemic
      thromboembolism. In the past decade, several large-scale clinical randomized
      trials for prevention of thromboembolism in nonrheumatic atrial fibrillation have
      been performed for its primary and secondary preventions. The first five major
      trials (AFASAK, BAATAF, SPAF-I, CAFA, SPINAF) for primary prevention of stroke
      have demonstrated a significant risk reduction (68%) for stroke on oral
      anticoagulation without any significant increase in major hemorrhage. On the
      other hand, although AFASAK and SPAF I showed controversial results for
      comparison of aspirin and control, the collaborative analysis revealed a
      significant risk reduction (36%). In their analysis of risk factors for stroke,
      prior stroke, diabetes mellitus, and hypertension have been stressed as high risk
      factors. Recently, some additional trials have been done concerning secondary
      prophylaxis, primary prevention in high risk patients, the optimal dose of
      warfarin, the role of aspirin and so on. In EAFT, a secondary prevention trial,
      warfarin has reduced (66%) stroke from 12%/yr to 4%/yr, while aspirin alone to
      10%/yr. In SPAF III, it has been reported that adjusted-dose warfarin with target
      INR2.0 to 3.0 is effective and safe in high risk patients. However, SPAF II
      showed that warfarin was not useful in elder patients (75yr <) because of an
      increase in hemorrhage. That may be why warfarin was still underused (40% >).
      Anyway, it is of importance to think about the strategy for prevention on the
      individual level of patients with atrial fibrillation, taking into consideration
      echocardiographical and hematological data besides clinical risk factors.

PMID- 10342140
TI  - [Recent advances in radiofrequency catheter ablation for atrial fibrillation].
AB  - Failure to control the ventricular rate in atrial fibrillation (AF) can be
      treated by radiofrequency (RF), ablation or modification of atrioventricular (AV)
      node. AV nodal ablation with pacemaker and AV nodal modification are associated
      with significant improvement in symptoms and quality of life. But there is no
      evidence that these techniques influence survival, and in some cases these
      therapies must be followed by implantation of a permanent pacemaker (due to
      complete AV block), and anticoagulation (due to persistence of underlying AF).
      The maze operation attempts to abolish AF by channeling the atrial activation
      between a series of incisions. Early results are encouraging, and simultaneous
      surgery may be beneficial. RF ablation can be used to create long linear lesions
      for this purpose (catheter maze). Preliminary studies show a higher success rate
      when linear ablations are performed in the left atrium than in the right atrium
      and that arrhythmogenic foci play a significant role in atrial fibrillation.
      However, catheter mazes are prolonged, and it is difficult with current
      technology to create endocardial linear lesions consistently that act as barriers
      to conduction. It is required to optimize this to transform investigational
      technique into a routine procedure. In specific cases, focal ablation or catheter
      ablation of the right atrial only can prevent AF. It may be possible that
      different approaches of ablation may be required, depending on the etiology.
      Curative radiofrequency catheter ablation for patients with AF may not be far in
      the future.

PMID- 10342141
TI  - Treatment of congenital anophthalmos with self-inflating polymer expanders: a new
      method.
AB  - Congenital anophthalmos is a rare malformation in which the optic vesicle fails
      to develop. This leads to a small bony orbit, a constricted mucosal socket, short
      eyelids, reduced palpebral fissure and malar hypoplasia. The treatment includes
      both aesthetic and functional aspects. Therefore, a two-step procedure is
      described using a new self-inflating hydrogel expander. A lens-shaped expander
      with a diameter of 8 mm expands the lids and the mucosal socket to allow
      insertion of an eye prosthesis. As a second step, orbital expansion is performed
      with a spherical device. The expanders absorb lacrimal fluid from the mucosal
      socket or tissue fluid and start swelling when implanted in the orbital tissue.
      The insertion of an expander into the orbit as well as into the conjunctival
      pocket including its fixation by a single suture took only a few minutes and was
      an easy procedure. The expansion of the small conjunctival sockets was
      successfully completed in all cases within a period of 2-4 weeks. The weight (=
      volume in ml) of devices increased from 0.15-1.5 g (lens-shaped expander; weight
      in grams = volume in ml) respectively, 0.3-3.5 g (spherical device). The
      expanders inserted in orbital tissue increased from 0.4-4.4 g. This is equivalent
      to a 10 to 11 fold increase in their water-free volumes. Orbital expansion with
      spherical devices in combination with the inserted eye prosthesis enlarges the
      lid and palpebral fissures also. In contrast to conventional silicon balloon
      expanders, the procedure using self-inflating hydrogel expanders is simple and
      highly efficient.

PMID- 10342142
TI  - Positioning of dental implants using computer-aided navigation and an optical
      tracking system: case report and presentation of a new method.
AB  - A navigation system for computer-aided surgery (Virtual Patient System, VPS) has
      been described in previous studies for different indications in oral and
      maxillofacial surgery. The aim of the system is the intraoperative transfer of
      preoperative planning on radiographs or CT scans on the patient, in real-time,
      and independent of the position of the patient's head. Until now an
      electromagnetic tracking system has been used for intra-operative position
      measurement. For placement of dental implants, the electromagnetic tracking
      system is not suitable since the motor of the implant drill leads to a
      considerable distortion of the magnetic field, thus direct visualization of
      drilling the implant socket was not possible. To overcome this problem, an
      optical tracking system which is not disturbed by conductive materials was
      integrated in the VPS system. The first patient operated on with this system had
      a posttraumatic loss of the upper incisors; three implants have been placed
      according to the prosthetic axis previously planned on radiographs and CT scans.
      The experience gained in this intervention led to the conclusion that computer
      aided surgery provides a valuable tool in implant dentistry.

PMID- 10342143
TI  - Resorption of microsurgically vascularized bone grafts after augmentation of the
      mandible.
AB  - Vascularized bone grafts taken from the iliac crest to augment the extremely
      atrophied mandible are valued for their ability to maintain their contour.
      Reliable data on long-term performance, however, is not yet available. The
      purpose of this study was to investigate the long-term results of this method,
      evaluating the radiological documentation (lateral cephalograms,
      orthopantomograms) of six patients. The mean follow-up period was 7.3 years.
      Dental implants were not inserted into the bone grafts. The average increase in
      ridge height immediately after surgery was 17.8 mm in the symphyseal area, 17.1
      mm above the mental foramen and 13.9 mm in the molar region. In the first
      postoperative year, the average vertical loss was 3.0 mm in the symphyseal, 2.0
      mm in the premolar and 2.9 mm in the molar regions. After that the mean yearly
      rate of vertical resorption dropped to 0.24 mm in the symphyseal, 0.27 mm in the
      premolar and 0.34 mm in the molar regions, which corresponded to the
      physiological loss in ridge height due to aging. The fact that graft resorption
      was so slight portends a good long-term prognosis with this procedure. However,
      indication is restricted by the high operative burden for the patient and by the
      availability of alternative rehabilitation methods.

PMID- 10342144
TI  - Prospective study on post-traumatic and postoperative sensory disturbances of the
      inferior alveolar nerve and infraorbital nerve in mandibular and midfacial
      fractures.
AB  - In a prospective study (January 1999 to December 1997), 34 patients with 26
      mandibular and 20 midfacial fractures were investigated. All the fractures were
      managed by osteosynthesis. To evaluate the incidence and duration of recovery of
      post-traumatic and postoperative sensory disturbances, the following tests were
      carried out: sharp/blunt testing, and the two-point discrimination test as
      conventional clinical examination methods, and electromyographic recording of the
      masseter reflex to calibrate the clinical findings. To establish the sensory
      status of the inferior alveolar and the infraorbital nerves in the region of the
      fracture, and on the intact and control sides, the tests were performed pre
      operatively and postoperatively on the seventh day, after 4 weeks and after 3, 6
      and 12 months. The incidence of post-traumatic sensory disturbance was 46% for
      mandibular fractures and 65% for fractures to the midface (sharp/blunt test, two
      point discrimination test). The rate of postoperative sensory disturbance in
      surgical treatment of mandibular fracture involving the region of the intra bony
      course of the inferior alveolar nerve, including the post-traumatic sensory
      disturbance, was 76.9%, and 55% following surgical treatment of midfacial
      fractures. The incidence of persistent sensory disturbances following surgical
      treatment was 7.7% in the case of mandibular fractures, and 15% in the case of
      midfacial fractures (sharp/blunt test, two-point discrimination test, masseter
      reflex). Recovery of neurological function is delayed in the presence of a
      displaced fracture (> 1 mm) as compared with non-displaced fractures. For the
      postoperative calibration of sensory disturbances, electromyographic recording of
      the masseter reflex from the fourth postoperative week onwards has proved useful.

PMID- 10342146
TI  - A morphological study of the thoracic duct at the jugulo-subclavian junction.
AB  - Chylous fistulae are uncommon but serious complications of neck surgery,
      occurring with an incidence of 1-3% after radical neck dissection. The majority
      occur on the left side (75-92%) and are due to damage to the terminal segment of
      the thoracic duct as it drains into the great veins of the neck in the region of
      the venous angle. The risk of trauma to the terminal thoracic duct may be
      influenced by anatomical variations. The macroscopic arrangement of the
      termination of the thoracic duct in the left neck was examined in 24 UK cadavers.
      Twenty-one ducts terminated as a single vessel, two ducts showed a bifid
      termination and one duct had three terminal branches. The precise site of
      termination was variable. Five thoracic ducts showed branching and reanastamosing
      patterns prior to their termination, irrespective of the number of terminal
      branches. Subsidiary cervical lymph trunks were identified in four dissections.
      These variations are described and their relevance to surgery involving the left
      side of the neck is discussed.

PMID- 10342145
TI  - Late presentation of orofacial tumours.
AB  - One hundred and twenty-eight cases of tumours involving the oral and the
      maxillofacial region and the oropharynx were reviewed. The objective was to
      highlight the late presentation of orofacial tumours in Nigeria. Patients who
      presented with squamous cell carcinoma, ameloblastoma, Burkitt's lymphoma,
      fibrous dysplasia and pleomorphic adenoma between January 1993 and December 1997
      were selected. The socio-economic class of each patient was noted. Ignorance and
      poverty were the main reasons for the late presentation of 120 patients who
      belonged to the lower social class. Four middle-class patients and four upper
      class ones gave marital problems and a sense of despair as reasons for the delay
      in seeking treatment. Difficulties in their management are attributed to the
      advanced stage of the tumours and the high rate of patients' default. There is
      the need to emphasize not only the necessity for early presentation but also the
      establishment of adequate facilities in this country, and other developing
      countries, for effective treatment of these tumours.

PMID- 10342147
TI  - Fusion of maxillary and mandibular alveolar process together with a median
      mandibular cleft: a rare congenital anomaly.
AB  - Congenital fusion of the maxillary alveolar process and mandible is a very rare
      entity. A one day old male newborn was referred to our clinic with a diagnosis of
      a 'absence of oral cavity'. Physical examination revealed that there was no mouth
      opening bilaterally in the posterior region due to maxillary and mandibular bone
      fusion; and in the front there was only 1 mm of mouth opening. Examination of the
      intraoral space could not be achieved. No other congenital anomaly was detected
      on general examination. The infant, who was fed via a nasogastric tube for 1
      month, was operated on. An intra-oral device which separated maxillary and
      mandibular alveolar arches from each other was designed and used for 8 weeks to
      avoid recurrence of the fusion. An adequate mouth opening was obtained and the
      infant could be fed orally.

PMID- 10342148
TI  - Evaluation of condylar neck fracture plating techniques.
AB  - The purpose of this study was to compare the biomechanical stability of four
      different plating techniques used to fix condylar neck fractures and to decide
      which fixation systems are strong enough to withstand the functional load. Ten
      recently acquired formalin-fixed cadaver mandibles were used for this study. Each
      of the four sets of osteotomized condylar processes was fixed by one of four
      different fixation systems. The mandibles were then held in an angle vice so that
      the mandibles were oriented to simulate actual masticatory force loading on the
      temporomandibular joint and were loaded with an Instron loading machine. Data
      demonstrated that a two-miniplate system applied to the anterior and posterior
      regions of the condylar neck was more stable than single-plate repairs using
      either mini-dynamic compression plates or 2.4 mm plates. The two-miniplate
      fixation technique is indicated in cases of condylar neck fracture to achieve
      early mobility of the jaw and stability of the fracture site.

PMID- 10342149
TI  - Discectomy of the temporomandibular joint: an experimental study in monkeys.
AB  - Postoperative changes have been observed in the temporomandibular joint (TMJ)
      after discectomies. Animal models have often shown that interventions in the TMJ
      may heal uneventfully. Discectomies were performed on 14 Macaca fascicularis and
      macroscopic and microscopic examination performed after sacrifice of the animals.
      Two of the animals did not show any apparent macroscopic or microscopic changes.
      The remaining 12 joints showed minor to major changes. The most serious changes
      were seen in three joints with fibrous ankylosis and five joints showed marked
      destruction of the articular cartilage.

PMID- 10342150
TI  - The behaviour of titanium as a biomaterial: microscopy study of plates and
      surrounding tissues in facial osteosynthesis.
AB  - Titanium has become the biomaterial of choice for facial osteosynthesis. Titanium
      is considered a highly biocompatible and corrosion resistant material, although
      the ultrastructural behaviour of titanium in human tissues after bone fixation is
      not well documented. A prospective scanning electron microscopy study was carried
      out on 37 commercially pure titanium miniplates which were removed from 23
      patients who had undergone surgery for maxillofacial trauma or deformity. Twenty
      two cases were used as a control group. Implant-bone specimens were excised using
      tungsten burs and studied with a scanning electron microscope (Jeol JSM-T-300).
      Findings at the bone-titanium interface were analyzed, as well as the presence of
      contaminating bodies on the specimen surface. Biopsies were also obtained from
      the soft tissues adjacent to 20 miniplates, then sectioned and stained with
      Haematoxilin-Eosin for histological evaluation by light microscopy. The results
      showed good ultrastructural osseointegration of the osteosynthesis material in
      most cases (81.8%). Mobility was found upon removal in 80% of plates which showed
      clinical complications. A significant correlation was found between the degree of
      microscopical osseointegration and macroscopic fixation of the plate.
      Microscopical contamination was found in 100% of the nine plates with intraoral
      exposure, while only 36% of the 22 miniplates of the control group had
      contaminating elements (P < 0.001). Thirty-five point one percent of the plates
      showed hole-like substance loss images, whose size ranged from 10-25 mu. Light
      microscopy showed granular deposits in soft tissues surrounding the plates in 80%
      of the 20 specimens investigated. Our findings suggest a higher development of
      corrosion in titanium than previously reported. These findings are not
      correlated, however with the clinical complications.

PMID- 10342152
TI  - The mandibular canal of a Neanderthal: the La Chapelle-aux-Saints man anatomical
      radiological study.
AB  - The radiological study by panoramic and CT scan methods of the Neanderthal La
      Chapelle-aux-Saints mandible shows us that the mandibular canal very closely
      resembles that which we can see in modern man. The images obtained are of good
      quality and can be utilized for the analysis of the internal structure of
      fossils.

PMID- 10342151
TI  - Fixation of mandibular body osteotomies using biodegradable amorphous self
      reinforced (70L:30DL) polylactide or metal lag screws: an experimental study in
      sheep.
AB  - Mandibular body osteotomies were fixed in nine sheep using new totally amorphous
      (70L:30DL), self-reinforced, polylactide (SR-PLA) lag screws and in nine sheep
      using standard stainless steel lag screws. No intermaxillary fixation was used.
      During follow-up, radiological, histological and microradiological studies were
      undertaken at 3, 6, 12 and 24 weeks. In both groups, all osteotomies consolidated
      at similar rates and no adverse reaction to the screws was seen. However,
      displacements of the fixed osteotomy fragments were common in both groups during
      the first 3 weeks. The biocompatibility of SR-PLA during the follow-up period was
      found to be good. Only initial signs of biodegradation were seen. The results of
      this study indicate that (70L:30DL) SR-PLA has potential for use as a fixation
      screw material in oral and maxillofacial surgery, and that further studies using
      this material are justified.

PMID- 10342153
TI  - Finding-specific display presets for computed radiography soft-copy reading.
AB  - Much work has been done to optimize the display of cross-sectional modality
      imaging examinations for soft-copy reading (i.e., window/level tissue presets,
      and format presentations such as tile and stack modes, four-on-one, nine-on-one,
      etc). Less attention has been paid to the display of digital forms of the
      conventional projection x-ray. The purpose of this study is to assess the utility
      of providing presets for computed radiography (CR) soft-copy display, based not
      on the window/level settings, but on processing applied to the image optimized
      for visualization of specific findings, pathologies, etc (i.e., pneumothorax,
      tumor, tube location). It is felt that digital display of CR images based on
      finding-specific processing presets has the potential to: speed reading of
      digital projection x-ray examinations on soft copy; improve diagnostic efficacy;
      standardize display across examination type, clinical scenario, important key
      findings, and significant negatives; facilitate image comparison; and improve
      confidence in and acceptance of soft-copy reading. Clinical chest images are
      acquired using an Agfa-Gevaert (Mortsel, Belgium) ADC 70 CR scanner and Fuji
      (Stamford, CT) 9000 and AC2 CR scanners. Those demonstrating pertinent findings
      are transferred over the clinical picture archiving and communications system
      (PACS) network to a research image processing station (Agfa PS5000), where the
      optimal image-processing settings per finding, pathologic category, etc, are
      developed in conjunction with a thoracic radiologist, by manipulating the
      multiscale image contrast amplification (Agfa MUSICA) algorithm parameters. Soft
      copy display of images processed with finding-specific settings are compared with
      the standard default image presentation for 50 cases of each category. Comparison
      is scored using a 5-point scale with the positive scale denoting the standard
      presentation is preferred over the finding-specific processing, the negative
      scale denoting the finding-specific processing is preferred over the standard
      presentation, and zero denoting no difference. Processing settings have been
      developed for several findings including pneumothorax and lung nodules, and
      clinical cases are currently being collected in preparation for formal clinical
      trials. Preliminary results indicate a preference for the optimized-processing
      presentation of images over the standard default, particularly by inexperienced
      radiology residents and referring clinicians.

PMID- 10342154
TI  - Challenges associated with the incorporation of digital radiography into a
      picture archival and communication system.
AB  - Digital radiography (DR) has recently emerged as an attractive alternative to
      computed radiography (CR) for the acquisition of general radiographic studies in
      a digital environment. It offers the possibility of improved spatial and contrast
      resolution, decreased radiation dose due to improved efficiency of detection of x
      ray photons, and perhaps most importantly, holds out the promise of increased
      technologist productivity. To achieve maximum efficiency, DR must be completely
      integrated into existing information systems, including the hospital and
      radiology information systems (HIS/RIS) and, when present, the picture archival
      and communication system (PACS). The early experience with the integration of DR
      at the Baltimore Veterans Affairs Medical Center (VAMC) has identified several
      challenges that exist to the successful integration of DR. DR has only recently
      been defined as a separate Digital Imaging and Communications in Medicine (DICOM)
      modality and images obtained will, at first, be listed under the category of CR.
      Matrix sizes with some DR products on the market exceed the current size
      limitations of some PACS. The patient throughput may be substantially greater
      with DR than with CR, and this in combination with the larger size of image files
      may result in greater demands for network and computer performance in the process
      of communication with the HIS/RIS and PACS. Additionally, in a hybrid department
      using both CR and DR, new rules must be defined for prefetching and display of
      general radiographic studies to permit these examinations to be retrieved and
      compared together. Advanced features that are planned for DR systems, such as
      dual-energy subtraction, tomosynthesis, and temporal subtraction, will likely
      require additional workstation tools beyond those currently available for CR.

PMID- 10342155
TI  - Temporomandibular joint pantomography using charge-coupled device,
      photostimulable phosphor, and film receptors: a comparison.
AB  - Our objective was to compare the accuracy and practicality in use of three
      available imaging receptors for temporomandibular joint (TMJ) imaging; namely,
      two computer-assisted and one traditional analog x-ray film system. A
      standardized tissue-equivalent encased human skull specimen was imaged using
      lateral and posteroanterior (PA) pantomographic projections with the
      Orthopantomograph OP 100 (Instrumentarium Imaging, Tuusula, Finland) and three
      different receptor modalities: (1) Ektavision film with Ektavision screens
      (Eastman Kodak, Rochester, NY); (2) DenOptix photostimulable phosphor screens
      (Dentsply/Gendex, Chicago, IL); and (3) the charge-coupled device (CCD) receptor,
      DigiPan (TREX/Trophy Radiology, Marne-la-Vallee, France). The effective focal
      trough was found for each receptor using lead resolution grids placed at
      fractional millimeter distances along empirically determined beam projection
      angulations. The time to acquire and process images was also established. We
      found that the CCD system permitted real-time display, whereas the use of
      traditional film took 2 minutes to load the cassette in a darkroom and perform
      the exposure, and then a further 2 minutes to unload and process. The storage
      phosphor took 3 minutes to unload the cassette and process the image and a
      further 20 seconds to clear the plate following laser scanning. Film produced the
      greatest maximum resolution followed by the storage phosphor and the CCD. In
      conclusion, CCD-based TMJ pantomography provided an instant image. The
      photostimulable phosphor system used was the least satisfactory in terms of the
      time expended to obtain an image, but provided better spatial resolution than the
      CCD. Ektavision film/screens provided the best spatial resolution in this
      investigation.

PMID- 10342156
TI  - A comparison of wavelet and Joint Photographic Experts Group lossy compression
      methods applied to medical images.
AB  - This presentation focuses on the quantitative comparison of three lossy
      compression methods applied to a variety of 12-bit medical images. One Joint
      Photographic Exports Group (JPEG) and two wavelet algorithms were used on a
      population of 60 images. The medical images were obtained in Digital Imaging and
      Communications in Medicine (DICOM) file format and ranged in matrix size from 256
      x 256 (magnetic resonance [MR]) to 2,560 x 2,048 (computed radiography [CR],
      digital radiography [DR], etc). The algorithms were applied to each image at
      multiple levels of compression such that comparable compressed file sizes were
      obtained at each level. Each compressed image was then decompressed and
      quantitative analysis was performed to compare each compressed-then-decompressed
      image with its corresponding original image. The statistical measures computed
      were sum of absolute differences, sum of squared differences, and peak signal-to
      noise ratio (PSNR). Our results verify other research studies which show that
      wavelet compression yields better compression quality at constant compressed file
      sizes compared with JPEG. The DICOM standard does not yet include wavelet as a
      recognized lossy compression standard. For implementers and users to adopt
      wavelet technology as part of their image management and communication
      installations, there has to be significant differences in quality and
      compressibility compared with JPEG to justify expensive software licenses and the
      introduction of proprietary elements in the standard. Our study shows that
      different wavelet implementations vary in their capacity to differentiate
      themselves from the old, established lossy JPEG.

PMID- 10342157
TI  - Detection of cancerous masses for screening mammography using discrete wavelet
      transform-based multiresolution Markov random field.
AB  - When cancerous masses are embedded in and camouflaged by varying densities of
      parenchymal tissue structures, they are difficult to visually detect on
      mammograms. We present a novel algorithm based on the discrete wavelet transform
      (DWT) and multiresolution markov random field (MMRF) that will single out the
      suspicious masses to assist the attending radiologist in making decisions.

PMID- 10342158
TI  - Syntactic analysis and languages of shape feature description in computer-aided
      diagnosis and recognition of cancerous and inflammatory lesions of organs in
      selected x-ray images.
AB  - We present new algorithms for the recognition of morphologic changes and shape
      feature analysis, which have been proposed to be used in a diagnosis of
      pathologic symptoms characteristic of cancerous and inflammatory lesions. These
      methods have been used so far for early detection and diagnosis of neoplastic
      changes in pancreas and chronic pancreatitis based on x-ray images acquired by
      endoscopic retrograde cholangiopancreatography (ERCP). Preliminary processing of
      x-ray images involves binarization, and, subsequently, pancreatic ducts shown in
      the pictures are subjected to the straightening transformation, which enables
      obtaining two-dimensional width graphs that show contours of objects with their
      morphologic changes. Recognition of such changes was performed using attributed
      context-free grammars. Correct description and diagnosis of some symptoms (e.g.,
      large cavitary projections) required two-dimensional analysis of width graphs. In
      such cases, languages of shape feature description with special multidirectional
      sinquad distribution were additionally applied.

PMID- 10342159
TI  - Process reengineering: the role of a planning methodology and picture archiving
      and communications system team building.
AB  - The acquisition of a picture archiving and communications system (PACS) is an
      opportunity to reengineer business practices and should optimally consider the
      entire process from image acquisition to communication of results. The purpose of
      this presentation is to describe the PACS planning methodology used by the
      Department of Defense (DOD) Joint Imaging Technology Project Office (JITPO),
      outline the critical procedures for each phase, and review the military
      experience using this model. The methodology is segmented into four phases:
      strategic planning, clinical scenario planning, installation planning, and
      implementation planning. Each is further subdivided based on the specific tasks
      that need to be accomplished within that phase. By using this method, an
      institution will have clearly defined program goals, objectives, and PACS
      requirements before vendors are contacted. The development of an institution
      specific PACS requirement should direct the process of proposal comparisons to be
      based on functionality and exclude unnecessary equipment. This PACS planning
      methodology is being used at more than eight DOD medical treatment facilities.
      When properly executed, this methodology facilitates a seamless transition to the
      electronic environment and contributes to the successful integration of the
      healthcare enterprise. A crucial component of this methodology is the development
      of a local PACS planning team to manage all aspects of the process. A plan
      formulated by the local team is based on input from each department that will be
      integrating with the PACS. Involving all users in the planning process is
      paramount for successful implementation.

PMID- 10342160
TI  - Electronic imaging and clinical implementation: work group approach at Mayo
      Clinic, Rochester.
AB  - Electronic imaging clinical implementation strategies and principles need to be
      developed as we move toward replacement of film-based radiology practices. During
      an 8-month period (1998 to 1999), an Electronic Imaging Clinical Implementation
      Work Group (EICIWG) was formed from sections of our department: Informatics Lab,
      Finance Committee, Management Section, Regional Practice Group, as well as
      several organ and image modality sections of the Department of Diagnostic
      Radiology. This group was formed to study and implement policies and strategies
      regarding implementation of electronic imaging into our practice. The following
      clinical practice issues were identified as key focus areas: (1) optimal
      electronic worklist organization; (2) how and when to link images with reports;
      (3) how to redistribute technical and professional relative value units (RVU);
      (4) how to facilitate future practice changes within our department regarding
      physical location and work redistribution; and (5) how to integrate off-campus
      imaging into on-campus workflow. The EICIWG divided their efforts into two
      phases. Phase I consisted of Fact finding and review of current practice patterns
      and current economic models, as well as radiology consulting needs. Phase II
      involved the development of recommendations, policies, and strategies for
      reengineering the radiology department to maintain current practice goals and use
      electronic imaging to improve practice patterns. The EICIWG concluded that
      electronic images should only be released with a formal report, except in
      emergent situations. Electronic worklists should support and maintain the
      physical presence of radiologists in critical areas and direct imaging to
      targeted subspecialists when possible. Case tools should be developed and used in
      radiology and hospital information systems (RIS/HIS) to monitor a number of
      parameters, including professional and technical RVU data. As communication
      standards improve, proper staffing models must be developed to facilitate
      electronic on-campus and off-campus consultation.

PMID- 10342161
TI  - The importance of a picture archiving and communications system (PACS) manager
      for large-scale PACS installations.
AB  - Installing a picture archiving and communication system (PACS) is a massive
      undertaking for any radiology department. Facilities making a successful
      transition to digital systems are finding that a PACS manager helps guide the way
      and offers a heightened return on the investment. The PACS manager fills a
      pivotal role in a multiyear, phased PACS installation. PACS managers navigate a
      facility through the complex sea of issues surrounding a PACS installation by
      coordinating the efforts of the vendor, radiology staff, hospital administration,
      and the information technology group. They are involved in the process from the
      purchase decision through the design and implementation phases. They can help
      administrators justify a PACS, purchase and shape the request for proposal (RFP)
      process before a vendor is even chosen. Once a supplier has been selected, the
      PACS manager works closely with the vendor and facility staff to determine the
      best equipment configuration for his or her facility, and makes certain that all
      deadlines are met during the planning and installation phase. The PACS manager
      also ensures that the infrastructure and backbone of the facility are ready for
      installation of the equipment. PACS managers also help the radiology staff gain
      acceptance of the technology by serving as teachers, troubleshooters, and the
      primary point-of-contact for all PACS issues. This session will demonstrate the
      value of a PACS manager, as well as point out ways to determine the manager's
      responsibilities. By the end of the session, participants will be able to
      describe the role of a PACS manager as it relates to departmental operation and
      in partnership with equipment vendors, justify a full-time position for a PACS
      manager, and identify the qualifications of candidates for the position of PACS
      manager.

PMID- 10342162
TI  - Care and feeding of a staff for filmless radiology.
AB  - Texas Children's Hospital, a definitive care pediatric hospital located in the
      Texas Medical Center, has been constructing a large-scale picture archival and
      communications system (PACS) including ultrasound (US), computed tomography (CT),
      magnetic resonance (MR), and computed radiography (CR). Developing staffing
      adequate to meet the demands of filmless radiology operations has been a
      continuous challenge. Overall guidance for the PACS effort is provided by a
      hospital-level PACS Committee, a department-level PACS Steering Committee, and an
      Operations Committee. Operational Subcommittees have been formed to address
      service-specific implementation, such as the Emergency Center Operations
      Subcommittee. These committees include membership by those affected by the
      change, as well as those effecting the change. Initially, personnel resources for
      PACS were provided through additional duties of existing imaging service
      personnel. As the PACS effort became more complex, full-time positions were
      created, including a PACS Coordinator, a PACS Analyst, and a Digital Imaging
      Assistant. Each position requires a job description, qualifications, and
      personnel development plans that are difficult to anticipate in an evolving PACS
      implementation. These positions have been augmented by temporary full-time
      assignments, position reclassifications, and cross-training of other imaging
      personnel. Imaging personnel are assisted by other hospital personnel from
      Biomedical Engineering and Information Services. Ultimately, the PACS staff grows
      to include all those who must operate the PACS equipment in the normal course of
      their duties. The effectiveness of the PACS staff is limited by their level of
      their expertise. This report discusses our methods to obtain training from
      outside our institution and to develop, conduct, and document standardized in
      house training. We describe some of the products of this work, including policies
      and procedures, clinical competency criteria, PACS inservice topics, and an
      informal PACS newsletter. As the PACS system software and hardware changes, and
      as our implementation grows, these products must to be revised and training must
      be repeated.

PMID- 10342163
TI  - The process of converting to a near filmless operation at the University of Utah,
      Department of Radiology.
AB  - The Department of Radiology at the University of Utah Health Sciences Center has
      made the transition from a traditional film-based department to a near filmless
      operation. The University of Utah is a large teaching hospital and the transition
      from film in an educational facility will be discussed. This transition has had
      its difficulties and its success is dependent on the support of departmental
      leadership and hospital administration. We have had more than 100 years of
      experience with film, and current procedures were efficient given the limitations
      of the medium. While motivated by the traditional reasons for moving to a picture
      archival and communications system (PACS), such as film savings, unavailable
      films, and faster reports, we found the intangibles to be the larger issue, as
      well as a source for the largest benefits. This report will discuss the
      implementation process and the affect it had on all areas of the hospital,
      including its impact on hospital physicians, radiologists, file room personnel,
      and technologists. Procedure changes to the flow of patients, film, and
      electronic images will also be described. This process cannot be viewed as a one
      time change, but must be viewed as a continuous process as areas of improvement
      are identified and new and improved technologies are developed.

PMID- 10342164
TI  - Crossing the digital divide--moving from film to filmless radiology.

PMID- 10342165
TI  - Maintaining continuity of clinical operations while implementing large-scale
      filmless operations.
AB  - Texas Children's Hospital is a pediatric tertiary care facility in the Texas
      Medical Center with a large-scale, Digital Imaging and Communications in Medicine
      (DICOM)-compliant picture archival and communications system (PACS) installation.
      As our PACS has grown from an ultrasound niche PACS into a full-scale,
      multimodality operation, assuring continuity of clinical operations has become
      the number one task of the PACS staff. As new equipment is acquired and
      incorporated into the PACS, workflow processes, responsibilities, and job
      descriptions must be revised to accommodate filmless operations. Round-the-clock
      clinical operations must be supported with round-the-clock service, including
      three shifts, weekends, and holidays. To avoid unnecessary interruptions in
      clinical service, this requirement includes properly trained operators and users,
      as well as service personnel. Redundancy is a cornerstone in assuring continuity
      of clinical operations. This includes all PACS components such as acquisition,
      network interfaces, gateways, archive, and display. Where redundancy is not
      feasible, spare parts must be readily available. The need for redundancy also
      includes trained personnel. Procedures for contingency operations in the event of
      equipment failures must be devised, documented, and rehearsed. Contingency
      operations might be required in the event of scheduled as well as unscheduled
      service events, power outages, network outages, or interruption of the radiology
      information system (RIS) interface. Methods must be developed and implemented for
      reporting and documenting problems. We have a Trouble Call service that records a
      voice message and automatically pages the PACS Console Operator on duty. We also
      have developed a Maintenance Module on our RIS system where service calls are
      recorded by technologists and service actions are recorded and monitored by PACS
      support personnel. In a filmless environment, responsibility for the delivery of
      images to the radiologist and referring physician must be accepted by each
      imaging supervisor. Thus, each supervisor must initiate processes to verify
      correct patient and examination identification and the correct count and routing
      of images with each examination.

PMID- 10342166
TI  - Photostimulable storage phosphor image acquisition: evaluation of three
      commercially available state-of-the-art systems.
AB  - Photostimulable storage phosphor (PSP) image acquisition systems have been
      available for several years. The technology has had the opportunity to mature;
      however, there has not been an independent comparison of recently marketed
      commercial systems. For this study, three computed radiography (CR) systems using
      PSP technology (Kodak CR System 400 with autoloader [Eastman Kodak, Rochester,
      NY], Fuji FCR AC-3CS [Fuji Medical Systems, Stamford, CT], and Agfa ADC Compact
      [Bayer Corp, Ridgefield Park, NJ]) were connected to an IBM RadWorks diagnostic
      radiology workstation (IBM Corp, White Plains, NY) and evaluated for conformance
      to their performance specifications using guidance provided in the most recent
      draft acceptance testing protocol from Task Group No. 10, American Association of
      Physicists in Medicine. In addition, the physical requirements (e.g., space and
      power) and connectivity to another manufacturer's diagnostic workstation were
      examined. X-ray technologist comfort with each PSP imaging system and an
      assessment by our supporting biomedical equipment maintenance activity of their
      ability to service each PSP imaging system were also considered.

PMID- 10342167
TI  - Reengineering the picture archiving and communication system (PACS) process for
      digital imaging networks PACS.
AB  - Prior to June 1997, military picture archiving and communications systems (PACS)
      were planned, procured, and installed with key decisions on the system,
      equipment, and even funding sources made through a research and development
      office called Medical Diagnostic Imaging Systems (MDIS). Beginning in June 1997,
      the Joint Imaging Technology Project Office (JITPO) initiated a collaborative and
      consultative process for planning and implementing PACS into military treatment
      facilities through a new Department of Defense (DoD) contract vehicle called
      digital imaging networks (DIN)-PACS. The JITPO reengineered this process
      incorporating multiple organizations and politics. The reengineered PACS process
      administered through the JITPO transformed the decision process and
      accountability from a single office to a consultative method that increased end
      user knowledge, responsibility, and ownership in PACS. The JITPO continues to
      provide information and services that assist multiple groups and users in
      rendering PACS planning and implementation decisions. Local site project managers
      are involved from the outset and this end-user collaboration has made the
      sometimes difficult transition to PACS an easier and more acceptable process for
      all involved. Corporately, this process saved DoD sites millions by having PACS
      plans developed within the government and proposed to vendors second, and then
      having vendors respond specifically to those plans. The integrity and efficiency
      of the process have reduced the opportunity for implementing nonstandard systems
      while sharing resources and reducing wasted government dollars. This presentation
      will describe the chronology of changes, encountered obstacles, and lessons
      learned within the reengineering of the PACS process for DIN-PACS.

PMID- 10342168
TI  - Technology assessment and requirements analysis: a process to facilitate decision
      making in picture archiving and communications system implementation.
AB  - In a time of decreasing resources, managers need a tool to manage their resources
      effectively, support clinical requirements, and replace aging equipment in order
      to ensure adequate clinical care. To do this successfully, one must be able to
      perform technology assessment and capital equipment asset management. The lack of
      a commercial system that adequately performed technology needs assessment and
      addressed the unique needs of the military led to the development of an in-house
      Technology Assessment and Requirements Analysis (TARA) program. The TARA is a
      tool that provides an unbiased review of clinical operations and the resulting
      capital equipment requirements for military hospitals. The TARA report allows for
      the development of acquisition strategies for new equipment, enhances personnel
      management, and improves and streamlines clinical operations and processes.

PMID- 10342169
TI  - Parlaying digital imaging and communications in medicine and open architecture to
      our advantage: the new Department of Defense picture archiving and communications
      system.
AB  - The Department of Defense (DoD) undertook a major systems specification,
      acquisition, and implementation project of multivendor picture archiving and
      communications system (PACS) and teleradiology systems during 1997 with
      deployment of the first systems in 1998. These systems differ from their DoD
      predecessor system in being multivendor in origin, specifying adherence to the
      developing Digital Imaging and Communications in Medicine (DICOM) 3.0 standard
      and all of its service classes, emphasizing open architecture, using personal
      computer (PC) and web-based image viewing access, having radiologic telepresence
      over large geographic areas as a primary focus of implementation, and requiring
      bidirectional interfacing with the DoD hospital information system (HIS). The
      benefits and advantages to the military health-care system accrue through the
      enabling of a seamless implementation of a virtual radiology operational
      environment throughout this vast healthcare organization providing efficient
      general and subspecialty radiologic interpretive and consultative services for
      our medical beneficiaries to any healthcare provider, anywhere and at any time of
      the night or day.

PMID- 10342170
TI  - The philosophy of change and adaptation of radiology to the information age.

PMID- 10342171
TI  - The strategic and operational characteristics of a distributed phased archive for
      a multivendor incremental implementation of picture archiving and communications
      systems.
AB  - The long-term (10 years) multimodality distributed phased archive for the Medical
      Information, Communication and Archive System (MICAS) is being implemented in
      three phases. The selection process took approximately 10 months. Based on the
      mandatory archive attributes and desirable features, Cemax-Icon (Fremont, CA) was
      selected as the vendor. The archive provides for an open-solution allowing
      incorporation of leading edge, "best of breed" hardware and software and provides
      maximum flexibility and automation of workflow both within and outside of
      radiology. The solution selected is media-independent, provides expandable
      storage capacity, and will provide redundancy and fault tolerance in phase II at
      minimum cost. Other attributes of the archive include scalable archive strategy,
      virtual image database with global query, and an object-oriented database. The
      archive is seamlessly integrated with the radiology information system (RIS) and
      provides automated fetching and routing, automated study reconciliation using
      modality worklist manager, clinical reports available at any Digital Imaging and
      Communications in Medicine (DICOM) workstation, and studies available for
      interpretation whether validated or not. Within 24 hours after a new study is
      acquired, four copies will reside within different components of the archive
      including a copy that can be stored off-site. Phase II of the archive will be
      installed during 1999 and will include a second Cemax-Icon archive and database
      using archive manager (AM) Version 4.0 in a second computer room.

PMID- 10342172
TI  - Migration from hierarchal storage management to ASM storage server: a case study.
AB  - The Department of Radiology at the University of Utah Hospitals and Clinics had
      to make a change from its current hierarchical storage management (HSM) system.
      The HSM software is the heart of any near-line data storage system and any change
      in this software affects all near-line and on-line data storage. In this case,
      over a terabyte of data had been migrated in more than 2 million files. The
      traditional method of reading in the old data and then writing it out to the new
      system was calculated to take more than 60 years. Here, we will examine the
      reasons for making such a radical change in the HSM used. We will also discuss
      why ASM (the new HSM software) was selected, and the performance improvements
      seen. A second, less difficult transition was made a few months later, of
      upgrading to a newer faster tape technology. The two types of tapes were
      incompatible, but the storage software and robotics used allowed for a peaceful
      coexistence during the transition. The transition from HSM to ASM was not a
      trivial task. It required a reasonable implementation/migration plan, which
      involved finding the correct resources and thinking outside the norm for
      solutions. All sites that have any amount of data stored in near-line devices
      will face similar conversions. This presentation should help in the event that a
      data conversion plan is not already in place.

PMID- 10342173
TI  - Enhancing availability of the electronic image record for patients and caregivers
      during follow-up care.
AB  - PURPOSE: To develop a personal computer (PC)-based software package that allows
      portability of the electronic imaging record. To create custom software that
      enhances the transfer of images in two fashions. Firstly, to an end user, whether
      physician or patient, provide a browser capable of viewing digital images on a
      conventional personal computer. Second, to provide the ability to transfer the
      archived Digital Imaging and Communications in Medicine (DICOM) images to other
      institutional picture archiving and communications systems (PACS) through a
      transfer engine. METHOD/MATERIALS: Radiologic studies are provided on a CD-ROM.
      This CD-ROM contains a copy of the browser to view images, a DICOM-based engine
      to transfer images to the receiving institutional PACS, and copies of all
      pertinent imaging studies for the particular patient. The host computer system in
      an Intel based Pentium 90 MHz PC with Microsoft Windows 95 software (Microsoft
      Inc, Seattle, WA). The system has 48 MB of random access memory, a 3.0 GB hard
      disk, and a Smart and Friendly CD-R 2006 CD-ROM recorder (Smart and Friendly Inc,
      Chatsworth, CA). RESULTS: Each CD-ROM disc can hold 640 MB of data. In our
      experience, this houses anywhere from, based on Table 1, 12 to 30 computed
      tomography (CT) examinations, 24 to 80 magnetic resonance (MR) examinations, 60
      to 128 ultrasound examinations, 32 to 64 computed radiographic examinations, 80
      digitized x-rays, or five digitized mammography examinations. We have been able
      to successfully transfer DICOM images from one DICOM-based PACS to another DICOM
      based PACS. This is accomplished by inserting the created CD-ROM onto a CD drive
      attached to the receiving PACS and running the transfer engine application.
      CONCLUSIONS: Providing copies of radiologic studies performed to the patient is a
      necessity in every radiology department. Conventionally, film libraries have
      provided copies to the patient generating issues of cost of loss of film, as well
      as mailing costs. This software package saves costs and loss of studies, as well
      as improving patient care by enabling the patient to maintain an archive of their
      electronic imaging record.

PMID- 10342174
TI  - Content-based image retrieval in picture archiving and communications systems.
AB  - We propose the concept of content-based image retrieval (CBIR) and demonstrate
      its potential use in picture archival and communication system (PACS). We address
      the importance of image retrieval in PACS and highlight the drawbacks existing in
      traditional textual-based retrieval. We use a digital mammogram database as our
      testing data to illustrate the idea of CBIR, where retrieval is carried out based
      on object shape, size, and brightness histogram. With a user-supplied query
      image, the system can find images with similar characteristics from the archive,
      and return them along with the corresponding ancillary data, which may provide a
      valuable reference for radiologists in a new case study. Furthermore, CBIR can
      perform like a consultant in emergencies when radiologists are not available. We
      also show that content-based retrieval is a more natural approach to man-machine
      communication.

PMID- 10342175
TI  - Practical considerations for picture archiving and communications systems over
      the enterprise network.

PMID- 10342176
TI  - Establishing radiologic image transmission via a transmission control
      protocol/Internet protocol network between two teaching hospitals in Houston.
AB  - The technical and management considerations necessary for the establishment of a
      network link between computed tomography (CT) and magnetic resonance imaging
      (MRI) networks of two geographically separated teaching hospitals are presented.
      The University of Texas Medical School at Houston Department of Radiology
      provides radiology residency training at its primary teaching hospital and at a
      second county-run hospital located approximately 12 miles away. A direct network
      link between the two hospitals was desired to permit timely consultative services
      to residents and professional colleagues. The network link was established by
      integrating the county hospital free-standing imaging network into the network
      infrastructure of the Medical School and the main teaching hospital. Technical
      issues involved in the integration were reassignment of internet protocol (IP)
      addresses, determination of data transmission protocol compatibilities, proof of
      connectivity and image transmission, transmission speeds and network loading, and
      management of the new network. These issues were resolved in a planned stepwise
      fashion and despite the fact that the system has a rate-limiting T1 segment
      between the county hospital and the teaching hospital the transmission speed was
      deemed suitable. The project has proven successful and can provide a guide for
      planning similar projects elsewhere. It has in fact made possible several new
      services for the teaching and research activities of the department's faculty and
      residents, which were not envisaged before the implementation of this connection.

PMID- 10342177
TI  - Interfacing the radiology information system to the modality: an integrated
      approach.
AB  - The radiology information system (RIS) provides patient and examination
      information that is used in setting up and performing a radiologic procedure. In
      a digital imaging environment, information from the RIS can also be used to
      populate fields in the Digital Imaging and Communications in Medicine (DICOM)
      image header. Ideally, information from the RIS should be available at the
      modality at the time of the examination, and automatically be attached to the
      image in the appropriate DICOM fields before storage in the picture archiving and
      communications system (PACS). We have designed a highly integrated RIS interface
      for a digital radiography (DR) system. This interface employs browser technology
      to make RIS information conveniently available at the modality, and DICOM
      modality performed procedure step (MPPS) for RIS/DR information exchange. A novel
      feature of our approach is that a single display screen at the modality is used
      to alternatively display either the modality control window or the RIS window.
      Full access to RIS capabilities is available at the modality, including worklists
      and prior reports.

PMID- 10342178
TI  - A generic digital imaging and communications in medicine solution for a
      bidirectional interface between the modality and the radiology information
      system.
AB  - The Relay is a generic Digital Imaging and Communications in Medicine (DICOM)
      compliant software package. It is a bidirectional interface between the modality
      and the radiology information system (RIS) that uses DICOM modality worklist and
      modality-performed procedure step services. This device can eliminate
      discrepancies between patient demographic information contained in the RIS and
      that entered at the imaging modality. The Relay receives the worklist for a
      modality from the RIS. It verifies the accession number (ACC#) and medical record
      number (MRN) received from the RIS for a study against the ACC# and MRN entered
      at the modality after that study is pushed to the Relay by the modality. If the
      values for the ACC# and MRN contained in the image header coincide with the
      values stored on the RIS, the patient demographics and study protocol contained
      in the RIS is downloaded into the image header. The study is then automatically
      routed to the specified destination without technologist intervention. Images
      whose header does not coincide with data on the RIS are flagged for subsequent
      reconciliation by the technologist. When the study is completed, the Relay
      updates the status of the study in the RIS, if the RIS provides DICOM performed
      procedure step service. When required, the Relay is able to split a single study
      into two or more series and assign each an ACC#. Other Relay functionality
      includes sending studies to multiple DICOM devices, adding comments to the image
      header, and DICOM print service. Should the archive be unavailable to receive
      images for whatever reason, the Relay can store studies so image acquisition can
      continue without interruption or it can divert studies directly to a diagnostic
      workstation. This Relay provides redundancy and fault-tolerance capabilities for
      picture archiving and communications systems. It is vendor-independent and will
      function with any DICOM modality, RIS, or archive.

PMID- 10342179
TI  - Bridging the gap: linking a legacy hospital information system with a filmless
      radiology picture archiving and communications system within a nonhomogeneous
      environment.
AB  - A health level 7 (HL7)-conformant data link to exchange information between the
      mainframe hospital information system (HIS) of our hospital and our home-grown
      picture archiving and communications system (PACS) is a result of a collaborative
      effort between the HIS department and the PACS development team. Based of the
      ability to link examination requisitions and image studies, applications have
      been generated to optimise workflow and to improve the reliability and
      distribution of radiology information. Now, images can be routed to individual
      radiologists and clinicians; worklists facilitate radiology reporting;
      applications exist to create, edit, and view reports and images via the internet;
      and automated quality control now limits the incidence of "lost" cases and errors
      in image routing. By following the HL7 standard to develop the gateway to the
      legacy system, the development of a radiology information system for booking,
      reading, reporting, and billing remains universal and does not preclude the
      option to integrate off-the-shelf commercial products.

PMID- 10342180
TI  - Sophisticated hospital information system/radiology information system/picture
      archiving and communications system (PACS) integration in a large-scale
      traumatology PACS.
AB  - Picture archiving and communications system (PACS) in the context of an
      outpatient trauma care center asks for a high level of interaction between
      information systems to guarantee rapid image acquisition and distribution to the
      surgeon. During installation of the Innsbruck PACS, special aspects of
      traumatology had to be realized, such as imaging of unconscious patients without
      identification, and transferred to the electronic environment. Even with up-to
      date PACS hardware and software, special solutions had to be developed in-house
      to tailor the PACS/hospital information system (HIS)/radiology information system
      (RIS) interface to the needs of radiologic and clinical users. An ongoing
      workflow evaluation is needed to realize the needs of radiologists and
      clinicians. These needs have to be realized within a commercially available PACS,
      whereby full integration of information systems may sometimes only be achieved by
      special in-house solutions.

PMID- 10342181
TI  - Implementation and evaluation of workflow based on hospital information
      system/radiology information system/picture archiving and communications system.
AB  - The purpose of this presentation is to review and evaluate computerized workflow
      of selected sites that have integrated systems of the hospital information system
      (HIS), radiology information system (RIS), and picture archiving and
      communications system (PACS). We then focus on some essential points of
      integration of those systems, such as avoiding multiple entries of patients
      demographic data, prefetching current and previous images to the correspondent
      workstations, and workflow management. To realize them by integrating multiple
      subsystems such as HIS/RIS/PACS integration, there must be exchange of the
      workflow control information, and consistency of the information between
      subsystems.

PMID- 10342182
TI  - A picture archiving and communications system featuring multiple monitors using
      Windows98.
AB  - We present an effective approach to manage, review, and distribute Digital
      Imaging and Communications in Medicine (DICOM) images with multiple monitors
      using Windows98 (Microsoft Corp, Redmond, WA) that can be implemented in an
      office-based setting. Computed tomography (CT), magnetic resonance imaging (MRI),
      and angiographic DICOM images were collected, compressed, and stored using Medweb
      (Medweb, Inc, San Francisco, CA) software. The Medweb server used the Linux/UNIX
      operating system on a Pentium 333-MHz processor with 128 MB of RAM. Short-term
      storage capacity was about 2 weeks with routine usage of an 11-GB hard drive.
      Images were presented for reading on a dual-monitor Windows98 Pentium display
      station with 160 MB of RAM using a Medweb/Netscape (Netscape Communications Corp,
      Mountain View, CA) viewer. There was no significant discrepancy in diagnosis
      between electronic and conventional film images. Mean reading time for 32 cases
      was 118 seconds. The Medweb JAVA plug-in viewer loaded the first image within 30
      seconds of selecting the case for review. Full uncompressed 16-bit images allowed
      different window settings to better assess for pathology. Multiple monitors
      allowed viewing various hanging protocols. Cine viewing was also possible. Key
      diagnostic images were electronically transmitted to referring physicians. On
      call radiologists were able to access images through the Internet. By combining
      Medweb, DICOM, and web-browser software using desktop personal computers (PCs),
      an easily accessible picture archiving and communications system (PACS) is
      available to radiologists and referring physicians. Multiple monitors are easily
      configured and managed using Windows98. This system can sustain changes and can
      be extended to provide variable functions using inexpensive PCs.

PMID- 10342183
TI  - Seamless multiresolution display of portable wavelet-compressed images.
AB  - Image storage, display, and distribution have been difficult problems in
      radiology for many years. As improvements in technology have changed the nature
      of the storage and display media, demand for image portability, faster image
      acquisition, and flexible image distribution is driving the development of
      responsive systems. Technology, such as the wavelet-based multiresolution
      seamless image database (MrSID) portable image format (PIF), is enabling image
      management solutions that address the shifting "point-of-care." The MrSID PIF
      employs seamless, multiresolution technology, which allows the viewer to
      determine the size of the image to be viewed, as well as the position of the
      viewing area within the image dataset. In addition the MrSID PIF allows control
      of the compression ratio of decompressed images. This capability offers the
      advantage of very rapid image recall from storage devices and portability for
      rapid transmission and distribution using the internet or wide-area networks. For
      example, in teleradiology, the radiologist or other physician desiring to view
      images at a remote location has full flexibility in being able to choose a quick
      display of an overview image, a complete display of a full diagnostic quality
      image, or both without compromising communication bandwidth. The MrSID algorithm
      will satisfy Joint Photographic Experts Group (JPEG) 2000 standards, thereby
      being compatible with future versions of the Digital Imaging and Communications
      in Medicine (DICOM) standard for image data compression.

PMID- 10342184
TI  - Web-based viewing of picture archiving and communications systems images--Part I:
      Optimal personal computer configuration.
AB  - Now that picture archiving and communications systems (PACS) has matured, our
      challenge is to make the images available to the referring physician and, in a
      teaching institution, to make these images available for conferences and
      rounding. One solution is the distribution of the images using web-based
      technology. We investigated a web-based add-on to our PACS to determine the
      characteristics of the personal computer that will make this technology useful
      and affordable. We found that images can be viewed easily through a web-based
      system. We found that the optimal system to view these images at a reasonable
      speed and a reasonable cost is on with a medium-range processor (200 to 300 MHz)
      and a large amount of inexpensive RAM, at least 64 Mb.

PMID- 10342185
TI  - Web-based viewing of picture archiving and communications systems images--Part
      II: The effect of compression on speed of transmission.
AB  - Now that picture archiving and communications systems (PACS) has matured, our
      challenge is to make the images available to the referring physician and, in a
      teaching institution, to make these images available for conferences and
      rounding. One solution is the distribution of the images using web-based
      technology. We investigated a web-based add-on to our PACS to determine the
      characteristics of the personal computer that will make this technology useful
      and affordable. We found that images can be viewed easily through a web-based
      system. We found that the optimal system to view these images at a reasonable
      speed and a reasonable cost is on with a medium-range processor (200 to 300 MHz)
      and a large amount of inexpensive RAM, at least 64 Mb.

PMID- 10342186
TI  - The clinical display of radiologic information as an interactive multimedia
      report.
AB  - We regard the delivery of radiological information as an interactive multimedia
      report. We use a multimedia report model based on Extensible Markup Language
      (XML), rather than a traditional workstation model. Others have suggested a
      similar document-based approach. This display presentation includes image-related
      and text-based information and may contain interactive components (e.g., window,
      level and zoom). Using XML as a foundation for this multimedia presentation, we
      achieve flexibility and platform independence at a lower cost. XML allows for the
      separation of content and form. Content information, defined as elements (e.g.,
      images, radiologic reports, and demographic information), is treated as
      independent information objects. The behavior of the elements can be changed for
      different users and tasks. In addition, by separating format detail from content,
      the appearance of the elements within the report can be modified. XML does not
      replace existing standards (i.e., Digital Imaging and Communications in Medicine
      [DICOM], Transmission Control Protocol/Internet Protocol [TCP/IP]). Instead, it
      provides a powerful framework that is used in combination with existing standards
      to allow system designers to modify display characteristics based on user need.
      We describe our application of XML to the clinical display of radiologic
      information.

PMID- 10342187
TI  - Using commercially available off-the-shelf software and hardware to develop an
      intranet-based hypertext markup language teaching file.
AB  - This presentation describes the technical details of implementing a process to
      create digital teaching files stressing the use of commercial off-the-shelf
      (COTS) software and hardware and standard hypertext markup language (HTML) to
      keep development costs to a minimum.

PMID- 10342188
TI  - MammoWeb continuing medical education (CME): a web-based breast imaging CME
      program.
AB  - The ubiquity of the world-wide web allows unique educational opportunities for
      continuing medical education (CME). We have designed a comprehensive breast
      imaging CME curriculum to permit individual physicians in their homes or offices
      to use personal computers to ease the burden of this process. Category 1 CME
      credits can be earned off-hours without having the physician travel out of town.
      In addition, since the course is computer-based, the overall costs to the
      participant are substantially reduced. The program can be updated on an ongoing
      basis to include new technology or to provide additional information requested by
      the users.

PMID- 10342189
TI  - Clinical services assessment and reengineering: lessons learned.
AB  - Healthcare enterprises often "acquire and install" picture archiving and
      communications systems (PACS) without examining many of the care delivery
      processes and information flows that will be affected. Many times these
      unexamined factors can delay or be the cause of failure of the PACS project. This
      article presents issues that were worked through as part of a PACS clinical
      services assessment and reengineering analysis for several US military medical
      treatment facilities.

PMID- 10342190
TI  - New picture archiving and communications system plus new facility equals critical
      path planning challenge.
AB  - The architectural design and construction of a new imaging department is one of
      the most complex challenges in healthcare architecture. When a client also plans
      a simultaneous change in basic operating system technology from film-based to
      filmless imaging, the challenge for both hospital management and the
      facility/technology design team is even more complicated. A purposeful planning
      process plus a carefully composed team of internal and external experts are the
      two essentials for success in executing this difficult conversion of both
      facility and technology.

PMID- 10342191
TI  - Branching out with filmless radiology.
AB  - Texas Children's Hospital, a 456 bed pediatric hospital located in the Texas
      Medical Center, has been constructing a large-scale picture archiving and
      communications system (PACS), including ultrasound (US), computed tomography
      (CT), magnetic resonance (MR), and computed radiography (CR). Until recently,
      filmless radiology operations have been confined to the imaging department, the
      outpatient treatment center, and the emergency center. As filmless services
      expand to other clinical services, the PACS staff must engage each service in a
      dialog to determine the appropriate level of support required. The number and
      type of image examinations, the use of multiple modalities and comparison
      examinations, and the relationship between viewing and direct patient care
      activities have a bearing on the number and type of display stations provided.
      Some of the information about customer services is contained in documentation
      already maintained by the imaging department. For example, by a custom report
      from the radiology information system (RIS), we were able to determine the number
      and type of examinations ordered by each referring physician for the previous 6
      months. By compiling these by clinical service, we were able to determine our
      biggest customers by examination type and volume. Another custom report was used
      to determine who was requesting old examinations from the film library. More
      information about imaging usage was gathered by means of a questionnaire. Some
      customers view images only where patients are also seen, while some services view
      images independently from the patient. Some services use their conference rooms
      for critical image viewing such as treatment planning. Additional information was
      gained from geographical surveys of where films are currently produced, delivered
      by the film library, and viewed. In some areas, available space dictates the type
      and configuration of display station that can be used. Active participation in
      the decision process by the clinical service is a key element to successful
      filmless operations.

PMID- 10342193
TI  - Teleradiology in the operating room of the future.
AB  - Recent advances in magnetic resonance imaging (MRI) are rapidly making this
      modality the imaging method of choice for image-guided neurosurgical operations.
      However, to be ready for its prime time in the operating room (OR), utilization
      of MRI in the OR requires development of better techniques for image-guided
      navigation, as well as interactive real-time teleradiologic methods that will
      allow tele-collaboration between the surgeon and the radiologist. This
      presentation describes our work in progress toward achievement of teleradiology
      in the OR.

PMID- 10342192
TI  - Radiologist-patient interactions: implications for picture archiving and
      communications systems and teleradiology.
AB  - We analyzed radiologist-patient interactions and found that radiologic
      examinations can be classified into three categories: those involving direct
      interaction of the radiologist with each patient, those involving interaction of
      the radiologist with some of the patients, and those that do not involve
      interaction between the radiologist and the patient. We then analyzed the staff
      assignments of a large academic radiology practice and a moderate-sized radiology
      department. Both departments include a full range of inpatient and outpatient
      procedures. We concluded that about 50% of the radiologists in these practices
      could interpret examinations at a location independent of the site where the
      examination was performed. This type of analysis can be helpful in planning for
      the reengineering of radiology processes following implementation of picture
      archiving and communications systems (PACS) and teleradiology.

PMID- 10342194
TI  - Experience measuring performance improvement in multiphase picture archiving and
      communications systems implementations.
AB  - When planning a picture archiving and communications system (PACS) implementation
      and determining which equipment will be implemented in earlier and later phases,
      collection and analysis of selected data will aid in setting implementation
      priorities. If baseline data are acquired relative to performance objectives, the
      same information used for implementation planning can be used to measure
      performance improvement and outcomes. The main categories of data to choose from
      are: (1) financial data; (2) productivity data; (3) operational parameters; (4)
      clinical data; and (5) information about customer satisfaction. In the authors'
      experience, detailed workflow data have not proved valuable in measuring PACS
      performance and outcomes. Reviewing only one category of data in planning will
      not provide adequate basis for targeting operational improvements that will lead
      to the most significant gains. Quality improvement takes into account all factors
      in production: human capacity, materials, operating capital and assets. Once we
      have identified key areas of focus for quality improvement in each phase, we can
      translate objectives into implementation requirements and finally into detailed
      functional and performance requirements. Here, Integration Resources reports its
      experience measuring PACS performance relative to phased implementation
      strategies for three large medical centers. Each medical center had its own
      objectives for overcoming image management, physical/geographical, and
      functional/technical barriers. The report outlines (1) principal financial and
      nonfinancial measures used as performance indicators; (2) implementation
      strategies chosen by each of the three medical centers; and (3) the results of
      those strategies as compared with baseline data.

PMID- 10342195
TI  - Integration, acceptance testing, and clinical operation of the Medical
      Information, Communication and Archive System, phase II.
AB  - The Medical Information, Communication and Archive System (MICAS) is a
      multivendor incremental approach to picture archiving and communications system
      (PACS). It is a multimodality integrated image management system that is
      seamlessly integrated with the radiology information system (RIS). Phase II
      enhancements of MICAS include a permanent archive, automated workflow, study
      caches, Microsoft (Redmond, WA) Windows NT diagnostic workstations with all
      components adhering to Digital Information Communications in Medicine (DICOM)
      standards. MICAS is designed as an enterprise-wide PACS to provide images and
      reports throughout the Strong Health healthcare network. Phase II includes the
      addition of a Cemax-Icon (Fremont, CA) archive, PACS broker (Mitra, Waterloo,
      Canada), an interface (IDX PACSlink, Burlington, VT) to the RIS (IDXrad) plus the
      conversion of the UNIX-based redundant array of inexpensive disks (RAID) 5
      temporary archives in phase I to NT-based RAID 0 DICOM modality-specific study
      caches (ImageLabs, Bedford, MA). The phase I acquisition engines and workflow
      management software was uninstalled and the Cemax archive manager (AM) assumed
      these functions. The existing ImageLabs UNIX-based viewing software was enhanced
      and converted to an NT-based DICOM viewer. Installation of phase II hardware and
      software and integration with existing components began in July 1998. Phase II of
      MICAS demonstrates that a multivendor open-system incremental approach to PACS is
      feasible, cost-effective, and has significant advantages over a single-vendor
      implementation.

PMID- 10342196
TI  - Impact of electronic imaging on clinician behavior in the urgent care setting.
AB  - Although it is intuitively valuable that more expedient delivery of radiographic
      images and reports to clinicians would improve patient care, it is important to
      document these outcomes to validate further advances in these areas. We evaluated
      the care of 215 patients seen at a walk-in clinic to determine what benefit
      digital imaging is to the patient. Cohorts consisted of all patients for whom
      specified radiology examinations were ordered during a 7-day period. The first
      cohort was recruited when analog films were used. The second cohort received
      examinations performed with computed radiography (CR) acquisition and computer
      display, which had been in use for 2 years. Patients were categorized as to the
      type of study they received, as well as whether a staff radiologist was
      immediately available to read the study. Clinical behavior was characterized by
      outcome measures of time to final diagnosis, time to final treatment, and need
      for follow-up. Our analysis demonstrated a reduction in time to final diagnosis
      that was better appreciated during the times when a staff radiologist was not
      immediately available. It also suggested that greater time reductions were seen
      for patients who received extremity examinations than those who received chest,
      sinus, or rib films. These data suggest that digital imaging is a useful tool to
      improve clinical outcome of patients seen in the acute care setting.

PMID- 10342197
TI  - Evaluating the impact of workstation usage on radiology report times in the
      initial 6 months following installation.
AB  - Picture archiving and communications systems (PACS) workstations are reported to
      improve workflow by making studies immediately available for review upon their
      completion. This study tested the hypothesis that a workstation would decrease
      the time from completion of a study to dictation of results (report time). A four
      monitor, 2K x 2K workstation (Imation Cemax-Icon, Fremont, CA), was installed in
      a body imaging computed tomography (CT) reading room. Use of the workstation by
      the staff radiologists was voluntary. Images were also printed on film and films
      continued to be hung at the routine hanging times. To evaluate the workstation's
      maximum impact, data were collected for report times for studies completed during
      the routine day shift of the staff radiologist (Monday to Friday, 8 AM to 5 PM).
      Data were collected before workstation installation (August 1997 to November
      1997) and for the subsequent 6 months. Histograms of the number of studies (743 v
      103) versus report time (mean, 11.7 v 7.4 hours) showed a bimodal distribution,
      with peaks at approximately 6 and 24 hours, both before (8/97-11/97) and after
      (6/98) the workstation's installation. However, the number of studies dictated
      greater than 60 hours (25.2% v 20.4%) and the percentage of studies in the second
      peak (16 to 48 hours; 4.4% v 0%) both decreased. In conclusion, the workstation
      decreased the mean (11.7 v 7.4 hours) and standard deviation (19.8 v 9.1 hours)
      for report times. This was due to a decrease in both the number of cases dictated
      the day following their completion and the number of outliers (markedly delayed
      dictations). The decrease in outliers is probably due to a decrease in the number
      of "lost" film-based studies.

PMID- 10342199
TI  - Integrated diagnostic workstation.

PMID- 10342198
TI  - Electronic imaging impact on image and report turnaround times.
AB  - We prospectively compared image and report delivery times in our Urgent Care
      Center (UCC) during a film-based practice (1995) and after complete
      implementation of an electronic imaging practice in 1997. Before switching to a
      totally electronic and filmless practice, multiple time periods were consistently
      measured during a 1-week period in May 1995 and then again in a similar week in
      May 1997 after implementation of electronic imaging. All practice patterns were
      the same except for a film-based practice in 1995 versus a filmless practice in
      1997. The following times were measured: (1) waiting room time, (2)
      technologist's time of examination, (3) time to quality control, (4) radiology
      interpretation times, (5) radiology image and report delivery time, (6) total
      radiology turn-around time, (7) time to room the patient back in the UCC, and (8)
      time until the ordering physician views the film. Waiting room time was longer in
      1997 (average time, 26:47) versus 1995 (average time, 15:54). The technologist's
      examination completion time was approximately the same (1995 average time, 06:12;
      1997 average time, 05:41). There was also a slight increase in the time of the
      technologist's electronic verification or quality control in 1997 (average time,
      7:17) versus the film-based practice in 1995 (average time, 2:35). However,
      radiology interpretation times dramatically improved (average time, 49:38 in 1995
      versus average time 13:50 in 1997). There was also a decrease in image delivery
      times to the clinicians in 1997 (median, 53 minutes) versus the film based
      practice of 1995 (1 hour and 40 minutes). Reports were available with the images
      immediately upon completion by the radiologist in 1997, compared with a median
      time of 27 minutes in 1995. Importantly, patients were roomed back into the UCC
      examination rooms faster after the radiologic procedure in 1997 (average time,
      13:36) than they were in 1995 (29:38). Finally, the ordering physicians viewed
      the diagnostic images and reports in dramatically less time in 1997 (median, 26
      minutes) versus 1995 (median, 1 hour and 5 minutes). In conclusion, a filmless
      electronic imaging practice within our UCC greatly improved radiology image and
      report delivery times, as well as improved clinical efficiency.

PMID- 10342200
TI  - Acceptance testing of integrated picture archiving and communications systems.
AB  - An integrated picture archiving and communication system (PACS) is a large
      investment in both money and resources. With all of the components and systems
      contained in the PACS, a methodical set of protocols and procedures must be
      developed to test all aspects of the PACS within the short time allocated for
      contract compliance. For the Department of Defense (DoD), acceptance testing (AT)
      sets the protocols and procedures. Broken down into modules and test procedures
      that group like components and systems, the AT protocol maximizes the efficiency
      and thoroughness of testing all aspects of an integrated PACS. A standardized and
      methodical protocol reduces the probability of functionality or performance
      limitations being overlooked. The AT protocol allows complete PACS testing within
      the 30 days allocated by the digital imaging network (DIN)-PACS contract. AT
      shortcomings identified during the testing phase properly allows for resolution
      before complete acceptance of the system. This presentation will describe the
      evolution of the process, the components of the DoD AT protocol, the benefits of
      the AT process, and its significance to the successful implementation of a PACS.
      This is a US government work. There are no restrictions on its use.

PMID- 10342201
TI  - Patterns of use and satisfaction with a university-based teleradiology system.
AB  - The Radiology Department at the University of Arizona has been operating a
      teleradiology program for almost 2 years. The goal of this project was to
      characterize the types of cases reviewed, to assess radiologists' satisfaction
      with the program, and to examine case turnaround times. On average, about 50
      teleradiology cases are interpreted each month. Computed tomography (CT) cases
      are the most common type of case, constituting 65% of the total case volume.
      Average turnaround time (to generate a "wet read" once a case is received) is
      about 1.3 hours. Image quality was rated as generally good to excellent, and the
      user interface as generally good. Radiologists' confidence in their diagnostic
      decisions is about the same as reading films in the clinical environment. The
      most common reason for not being able to read teleradiology images is poor image
      quality, followed by lack of clinical history and not enough images.

PMID- 10342202
TI  - Performance and function of a high-speed multiple star topology image management
      system at Mayo Clinic Scottsdale.
AB  - Mayo Clinic Scottsdale (MCS) is a busy outpatient facility (150,000 examinations
      per year) connected via asynchronous transfer mode (ATM; OC-3 155 MB/s) to a new
      Mayo Clinic Hospital (178 beds) located more than 12 miles distant. A primary
      care facility staffed by radiology lies roughly halfway between the hospital and
      clinic connected to both. Installed at each of the three locations is a high
      speed star topology image network providing direct fiber connection (160 MB/s)
      from the local image storage unit (ISU) to the local radiology and clinical
      workstations. The clinic has 22 workstations in its star, the hospital has 13,
      and the primary care practice has two. In response to Mayo's request for a
      seamless service among the three locations, the vendor (GE Medical Systems,
      Milwaukee, WI) provided enhanced connectivity capability in a two-step process.
      First, a transfer gateway (TGW) was installed, tested, and implemented to provide
      the needed communication of the examinations generated at the three sites. Any
      examinations generated at either the hospital or the primary care facility
      (specified as the remote stars) automatically transfer their images to the ISU at
      the clinic. Permanent storage (Kodak optical jukebox, Rochester, NY) is only
      connected to the hub (Clinic) star. Thus, the hub ISU is provided with a copy of
      all examinations, while the two remote ISUs maintain local exams. Prefetching
      from the archive is intelligently accomplished during the off hours only to the
      hub star, thus providing the remote stars with network dependent access to
      comparison images. Image transfer is possible via remote log-on. The second step
      was the installation of an image transfer server (ITS) to replace the slower
      Digital Imaging and Communications in Medicine (DICOM)-based TGW, and a central
      higher performance database to replace the multiple database environment. This
      topology provides an enterprise view of the images at the three locations, while
      maintaining the high-speed performance of the local star connection to what is
      now called the short-term storage (STS). Performance was measured and 25 chest
      examinations (17 MB each) transferred in just over 4 minutes. Integration of the
      radiology information management system (RIMS) was modified to provide location
      specific report and examination interfaces, thereby allowing local filtering of
      the worklist to remote and near real-time consultation, and remote examination
      monitoring of modalities are addressed with this technologic approach. The
      installation of the single database ITS environment has occurred for testing
      prior to implementation.

PMID- 10342203
TI  - Transparent image access in a distributed picture archiving and communications
      system: the Master Database broker.
AB  - A distributed design is the most cost-effective system for small-to medium-scale
      picture archiving and communications systems (PACS) implementations. However, the
      design presents an interesting challenge to developers and implementers: to make
      stored image data, distributed throughout the PACS network, appear to be
      centralized with a single access point for users. A key component for the
      distributed system is a central or master database, containing all the studies
      that have been scanned into the PACS. Each study includes a list of one or more
      locations for that particular dataset so that applications can easily find it.
      Non-Digital Imaging and Communications in Medicine (DICOM) clients, such as our
      worldwide web (WWW)-based PACS browser, query the master database directly to
      find the images, then jump to the most appropriate location via a distributed web
      based viewing system. The Master Database Broker provides DICOM clients with the
      same functionality by translating DICOM queries to master database searches and
      distributing retrieval requests transparently to the appropriate source. The
      Broker also acts as a storage service class provider, allowing users to store
      selected image subsets and reformatted images with the original study, without
      having to know on which server the original data are stored.

PMID- 10342204
TI  - Evolution of a filmless digital imaging and communications in medicine-conformant
      picture archiving and communications system: design issues and lessons learned
      over the last 3 years.
AB  - This presentation describes our experience and lessons learned over the first 3
      years of developing and operating a filmless picture archiving and communications
      system (PACS) for all computed tomography (CT), magnetic resonance (MR),
      ultrasound, and nuclear medicine studies in our hospital. The PACS conforms to
      the Digital Imaging and Communications in Medicine (DICOM) standard and includes
      a sophisticated Worldwide Web (WWW)-based interface to complement the regular
      DICOM services. The PACS has undergone many design modifications from its
      inception, which have addressed performance, functionality, support, and
      maintenance issues. The lessons we have learned through making these
      modifications are described here and may prove to be helpful to anyone planning
      to deploy a PACS of their own.

PMID- 10342205
TI  - Virtual management of radiology examinations in the virtual radiology environment
      using common object request broker architecture services.
AB  - In the Department of Defense (DoD), US Army Medical Command is now embarking on
      an extremely exciting new project--creating a virtual radiology environment (VRE)
      for the management of radiology examinations. The business of radiology in the
      military is therefore being reengineered on several fronts by the VRE Project. In
      the VRE Project, a set of intelligent agent algorithms determine where
      examinations are to routed for reading bases on a knowledge base of the entire
      VRE. The set of algorithms, called the Meta-Manager, is hierarchical and uses
      object-based communications between medical treatment facilities (MTFs) and
      medical centers that have digital imaging network picture archiving and
      communications systems (DIN-PACS) networks. The communications is based on use of
      common object request broker architecture (CORBA) objects and services to send
      patient demographics and examination images from DIN-PACS networks in the MTFs to
      the DIN-PACS networks at the medical centers for diagnosis. The Meta-Manager is
      also responsible for updating the diagnosis at the originating MTF. CORBA
      services are used to perform secure message communications between DIN-PACS nodes
      in the VRE network. The Meta-Manager has a fail-safe architecture that allows the
      master Meta-Manager function to float to regional Meta-Manager sites in case of
      server failure. A prototype of the CORBA-based Meta-Manager is being developed by
      the University of Arizona's Computer Engineering Research Laboratory using the
      unified modeling language (UML) as a design tool. The prototype will implement
      the main functions described in the Meta-Manager design specification. The
      results of this project are expected to reengineer the process of radiology in
      the military and have extensions to commercial radiology environments.

PMID- 10342206
TI  - Meta-manager: a requirements analysis.
AB  - The digital imaging network-picture-archiving and communications system (DIN
      PACS) will be implemented in ten sites within the Great Plains Regional Medical
      Command (GPRMC). This network of PACS and teleradiology technology over a shared
      T1 network has opened the door for round the clock radiology coverage of all
      sites. However, the concept of a virtual radiology environment poses new issues
      for military medicine. A new workflow management system must be developed. This
      workflow management system will allow us to efficiently resolve these issues
      including quality of care, availability, severe capitation, and quality of the
      workforce. The design process of this management system must employ existing
      technology, operate over various telecommunication networks and protocols, be
      independent of platform operating systems, be flexible and scaleable, and involve
      the end user at the outset in the design process for which it is developed. Using
      the unified modeling language (UML), the specifications for this new business
      management system were created in concert between the University of Arizona and
      the GPRMC. These specifications detail a management system operating through a
      common object request brokered architecture (CORBA) environment. In this
      presentation, we characterize the Meta-Manager management system including
      aspects of intelligence, interfacility routing, fail-safe operations, and
      expected improvements in patient care and efficiency.

PMID- 10342207
TI  - Developing a framework for worldwide image communication.
AB  - The increasing mobility of the population and frequent changes in healthcare
      coverage, in both the government and private sectors, require integration of
      medical records not only longitudinally, but also across a variety of healthcare
      providers. Early in 1998, the federal government decided to solve this problem by
      constructing a framework for access to medical records by all of the government's
      health care facilities, called the Government Computer-Based Patient Record
      (GCPR). The government consortium chose a proposal by Litton PRC, a partnership
      of 11 companies with complementary areas of expertise. The framework is based on
      open systems, which use publicly available standards, and includes a Master
      Patient Information Locator that allows access to medical information from remote
      facilities, based on creating a unique identifier for each and every individual
      patient. PRC will use the Digital Imaging and Communications in Medicine (DICOM)
      imaging standard for radiology, supplemented by Health Level Seven (HL7).

PMID- 10342208
TI  - A desktop digital imaging and communications in medicine picture archiving and
      communications system with multiple monitors using Windows '98.

PMID- 10342209
TI  - Digital photography of digital imaging and communications in medicine-3 images
      from computers in the radiologist's office.
AB  - To fully take advantage of the widespread use of digital imaging systems and to
      update and eliminate redundant steps involved in medical radiographic
      publication, we present our experience of processing Digital Imaging and
      Communications in Medicine (DICOM)-3 digital images from the point of acquisition
      to the point of publisher-ready radiographic images without intervening
      hardcopies.

PMID- 10342210
TI  - Distributing digital imaging and communications in medicine data and optimizing
      access over satellite networks.
AB  - To improve radiology access to full uncompressed Digital Imaging and
      Communications in Medicine (DICOM) data sets, we evaluated satellite access to a
      DICOM server. Radiologists' home computers were connected by satellite to a
      Medweb DICOM server (Medweb, San Francisco, CA). A 10.2-kb data set containing a
      19-image head computed tomography (CT) scan was transferred using DirecPC (Hughes
      Electronics Corp, Arlington, VA) at three different times of the day; 6 AM, 3 PM,
      and 8 PM. The average transfer time for all 19 images from the DICOM server was 4
      minutes and 17 seconds (257 seconds). The slowest transfer rate of 670 seconds
      (121 kbps) was obtained at 8 PM. The best transfer rate of 2 minutes, 54 seconds
      (467 kbps) was obtained at 6 AM. The full 16-bit DICOM images were viewed with
      bone, brain, and soft tissue windows. The Medweb plug-in viewer loaded the first
      image within 30 seconds of selecting the case for satellite transfer. In
      conclusion, satellite internet transfer of radiology studies is suitable for
      timely review of full DICOM data sets and can expand the range of teleradiology
      consultation.

PMID- 10342211
TI  - High sensitive multiresolution analysis of low-contrast radiologic images based
      on the digital pseudocoherent holographic interferometry method.

PMID- 10342212
TI  - Integrated radiology information system, picture archiving and communications
      system, and teleradiology--workflow-driven and future-proof.
AB  - The proliferation of integrated radiology information system/picture archiving
      and communication system (RIS/PACS) and teleradiology has been slow because of
      two concerns: usability and economic return. A major dissatisfaction on the
      usability issue is that contemporary systems are not intelligent enough to
      support the logical workflow of radiologists. We propose to better understand the
      algorithms underlying the radiologists' reading process, and then embed this
      intelligence into the software program so that radiologists can interact with the
      system with less conscious effort. Regarding economic return issues, people are
      looking for insurance against obsolescence in order to protect their investments.
      We propose to future-proof a system by sticking to the following principles:
      compliance to industry standards, commercial off-the-shelf (COTS) components, and
      modularity. An integrated RIS/PACS and teleradiology system designed to be
      workflow-driven and future-proof is being developed at Texas Tech University
      Health Sciences Center.

PMID- 10342213
TI  - Integrating legacy systems: the information broker.

PMID- 10342214
TI  - Interactive web-based radiology teaching file.
AB  - This multimedia radiology teaching file was developed for medical students,
      residents, physicians, and researchers to present teaching components related to
      clinical studies. Patient studies are used to create teaching cases, user can
      also create lecture series and custom presentations (catalogs) by linking related
      text and images. The user is able to make and preserve his/her own notes related
      to reviewed information. From the computer workstation, the user can perform
      search our case library by American College of Radiology (ACR) codes, keywords,
      modalities, or text. Results are presented in custom pages and include text
      lists, thumbnails lists, rescaled images, and full-size images. Text can be
      easily printed in custom format or exported to an ASCI file. To preserve the
      privacy of the student, access to our database is granted to the web browser by
      log-in panel. Image and text can be imported from Digital Imaging and
      Communications in Medicine (DICOM)-compatible devices or entered by using web
      forms. In conclusion, we developed a multifunctional interactive teaching
      environment accessible for multiplatform internet users.

PMID- 10342215
TI  - Interhospital network system using the worldwide web and the common gateway
      interface.
AB  - We constructed an interhospital network system using the worldwide web (WWW) and
      the Common Gateway Interface (CGI). Original clinical images are digitized and
      stored as a database for educational and research purposes. Personal computers
      (PCs) are available for data treatment and browsing. Our system is simple, as
      digitized images are stored into a Unix server machine. Images of important and
      interesting clinical cases are selected and registered into the image database
      using CGI. The main image format is 8- or 12-bit Joint Photographic Experts Group
      (JPEG) image. Original clinical images are finally stored in CD-ROM using a CD
      recorder. The image viewer can browse all of the images for one case at once as
      thumbnail pictures; image quality can be selected depending on the user's
      purpose. Using the network system, clinical images of interesting cases can be
      rapidly transmitted and discussed with other related hospitals. Data transmission
      from relational hospitals takes 1 to 2 minutes per 500 Kbyte of data. More
      distant hospitals (e.g., Rakusai Hospital, Kyoto) takes 1 minute more. The mean
      number of accesses our image database in a recent 3-month period was 470. There
      is a total about 200 cases in our image database, acquired over the past 2 years.
      Our system is useful for communication and image treatment between hospitals and
      we will describe the elements of our system and image database.

PMID- 10342216
TI  - Process mapping in screening mammography.
AB  - Successful screening mammography programs aim to screen large numbers of women
      efficiently and inexpensively. Development of an effective screening mammography
      program requires skilled personnel, solid infrastructure, and a robust computer
      system. A group of physicians, technologists, computer support personnel, and
      administrators carefully analyzed a growing screening mammography program as a
      series of steps, starting with the request for the examination and ending with
      the receipt of a hard-copy consultation. The analysis involved a detailed
      examination of every step and every possible outcome in the screening process.
      The information gained through process mapping may be used for identification of
      systemic and personnel problems, allocation of resources, modification of
      workplace architecture, and design of computer networks. Process mapping is
      helpful for those involved in designing and improving screening mammography
      programs. Viewing a process (i.e., obtaining a screening mammogram) as a series
      of steps may allow for the identification of inefficient components that may
      limit growth.

PMID- 10342217
TI  - Testing optimum viewing conditions for mammographic image displays.
AB  - The viewbox luminance and viewing room light level are important parameters in a
      medical film display, but these parameters have not had much attention. Spatial
      variations and too much room illumination can mask real signal or create the
      false perception of a signal. This presentation looks at how scotopic light
      sources and dark-adapted radiologists may identify more real diseases.

PMID- 10342218
TI  - The Conquest Hospital picture archiving and communications system development,
      1992 to 1999.
AB  - Conquest Hospital was a UK regional development site for a pre-Digital Imaging
      and Communications in Medicine (DICOM) picture archiving and communication system
      (PACS). The initial system was installed in mid 1992. Identification has been
      made of data transfer, ergonomic and single point of failure issues in the
      original PACS, which was called "iLAN." This has informed respecification of a
      DICOM/HTML PACS, the first stages of which have been hospital renetworking and
      installation of new DICOM 3.0 computed radiography/fluorography and computed
      tomography/magnetic resonance imaging segments. Final PACS elements are at
      contract stage. Plans are being completed for linkage of PACS to a clinical
      information system to create a comprehensive electronic patient record system.

PMID- 10342219
TI  - Workflow management systems--a powerful means to integrate radiologic processes
      and application systems.
AB  - This presentation describes a research project investigating the suitability of
      model-based Workflow Management Systems (WfMS) to support radiological process.
      The following aspects are covered: process modeling, process enactment, and
      architecture of workflow-enabled application systems.

PMID- 10342220
TI  - Anatomy of picture archiving and Communications systems: nuts and bolts--image
      acquisition: getting digital images from imaging modalities.
AB  - Digital acquisition of data from the various imaging modalities for input to a
      picture archiving and communication system (PACS) is discussed. Essential
      features for successful clinical implementation including Digital Imaging and
      Communications in Medicine (DICOM) compliance, radiology information system
      (RIS)/hospital information system (HIS) interfacing, and workflow integration are
      detailed. Image acquisition from the inherently digital cross-sectional
      modalities are described, as well as digital acquisition of the conventional
      projection x-ray using computed radiography (CR), direct digital radiography
      (DDR), and film digitizers.

PMID- 10342222
TI  - Evaluating a picture archiving and communications system workstation.
AB  - An efficient environment for picture archiving and communications systems (PACS)
      in the radiology department and throughout a medical practice requires good
      hardware, good software, and integration of the information sources that exist in
      a radiology department and institution. This tutorial will describe some of the
      considerations in evaluating a PACS workstation, with a view to the hardware
      requirements, user interface designs, and integration with the information
      systems.

PMID- 10342221
TI  - Information systems integration in radiology.
AB  - Advances in information systems and technology in conjunction with outside forces
      requiring improved reporting are driving sweeping changes in the practice of
      radiology. In most academic radiology departments, there can be at least five
      separate information systems in daily use, a clinical picture archiving and
      communication system (PACS), a hospital information system (HIS), a radiology
      information system (RIS), a voice-recognition dictation system, and an electronic
      teaching/research file system. A PACS will have incomplete, incorrect, and
      inconsistent data if manual data entry is used. Correct routing of studies for
      diagnostic reporting and clinical review requires accurate information about the
      study type and the referring physician or service, often not easily entered
      manually. An HIS is a hospital-wide information system used to access patient
      information, reports from various services, and billing information. The RIS is
      typically a system specifically designed to place radiology orders, to receive
      interpretations, and to prepare bills for patients. Voice-recognition systems
      automatically transcribe the radiologist's dictation, eliminating transcription
      delays. Another system that is needed in a teaching hospital holds images and
      data for research and education. Integration of diverse systems must be performed
      to provide the functionality required by an electronic radiology department and
      the services it supports. Health Level 7 (HL7) and Digital Imaging and
      Communications in Medicine (DICOM) have enabled sharing of data among systems and
      can be used as the building blocks for truly integrated systems, but the user
      community and manufacturers need to specify the types of functionality needed to
      build clinically useful systems. Although technology development has produced the
      tools for interoperability for clinical and research/educational use, more work
      needs to be done to define the types of interaction that needs to be performed to
      realize the potential of these systems.

PMID- 10342223
TI  - Teleradiology: technology and practice.
AB  - Teleradiology increases the ability of radiologists to provide service to remote
      and underserved locations as well as coverage at times when direct reading of
      images is not possible. Good practices for teleradiology are described in the
      American College of Radiology (ACR) teleradiology standard. Teleradiology
      equipment is converging with picture archiving and communications systems (PACS)
      equipment so that diagnostic interpretation from remote locations is possible.
      Image capture can be directly from digital modalities or by film scanner.
      Transmission speed is still an issue. High transmission speeds were difficult to
      achieve but recent improvements may increase speeds and decrease costs.

PMID- 10342224
TI  - Effect of high pressure homogenization on microbial and chemico-physical
      characteristics of goat cheeses.
AB  - The objective of this work was to compare goat cheeses obtained from milk
      previously subjected to high pressure homogenization (1000 bar) with those
      produced from untreated milk and milk subjected to sanitization (61 degrees C; 20
      min) or to pasteurization (72 degrees C; 15 s). The pressure homogenization
      treatment had both direct and indirect effects on cheese characteristics and
      their evolution during ripening. The direct effects were principally linked to
      the change in water-binding capacity of proteins as shown also by the lower whey
      separation. The indirect effects involved the microbial growth or activity and,
      particularly, modifications of the population of the lactic acid bacteria that
      occurred naturally and their evolution as well as a more precocious yeast and
      mold growth with a consequent rapid rise in pH. Although the treatment proved to
      enhance both proteolytic and lipolytic activities according to Fourier transform
      infrared analysis, which was used to obtain a rapid description of the
      biochemical modification, the cheeses homogenized under high pressure showed
      relevant qualitative differences only in the zone corresponding to amide I and
      amide II signals of proteins. The activation of these enzymatic activities
      observed in the homogenized cheeses could be either an indirect effect of the
      shift of the microbial population or a consequence of a different exposure of the
      macromolecules to the enzymatic activity. Scanning electron microscopy analyses
      of goat cheeses revealed that cheeses homogenized under high pressure had a more
      homogeneous microstructure than did the others.

PMID- 10342225
TI  - Modulation of nonspecific mechanisms of defense by lactic acid bacteria:
      effective dose.
AB  - The purpose of this study was to determine the effect of a fermented milk product
      containing Lactobacillus johnsonii La1 (formerly known as Lactobacillus
      acidophilus La1) on the phagocytic activity of peripheral blood leukocytes in
      healthy adult volunteers. Furthermore, we sought to define the effective doses of
      the bacteria, examine the effect on respiratory burst activity, and, finally,
      examine the contribution made by the starter culture to the biological effects.
      Volunteers were randomly distributed among three groups; each subject received
      one pot (150 ml) of fermented milk each day for 3 wk. The first two groups
      received a freshly prepared product fermented by Streptococcus thermophilus
      (group A) alone or S. thermophilus and 10(7) cfu/ml L. johnsonii La1 (group B).
      Group C received a product stored for a period of 21 to 28 d and that contained
      S. thermophilus and 10(6) cfu/ml of L. johnsonii La1. Ingestion of L. johnsonii
      La1 did not significantly increase fecal lactobacilli counts. However, L.
      johnsonii La1 was able to survive intestinal transit and was only recovered from
      the feces of the volunteers of groups B and C. The fermented base alone showed a
      weak effect on respiratory burst but not on phagocytic activity. However, the
      product containing 10(7) cfu/ml L. johnsonii La1 significantly enhanced both
      functions. The product containing 10(6) cfu/ml of L. johnsonii La1 had no
      significant effect on either function. These results suggest that fecal
      persistence may not necessarily reflect in vivo colonization and may not be a
      prerequisite for all forms of immune reactivity.

PMID- 10342226
TI  - Fatty acid composition of caprine milk: major, branched-chain, and trans fatty
      acids.
AB  - The fatty acid composition of caprine milk fat was studied using capillary gas
      chromatography. Milk was obtained from five goat herds belonging to different
      breeders in the Murcia region (Spain) and collected monthly (from November to
      May). The results showed significant differences among herds mainly in long-chain
      fatty acids (C16:0, C18:0, and C18:2). There were five branched-chain fatty acids
      (iso- and anteiso-C15:0, iso- and anteiso-C17:0, and iso-C16:0) with > 0.1% of
      the total fatty acid methyl esters and another 31 (the most monomethylated) with
      < 0.1%, including 4-ethyloctanoate, which is implicated in goat-like flavors. To
      study the content of trans unsaturated fatty acids, the fatty acid methyl esters
      were previously fractionated by AgNO3-thin layer chromatography. The mean
      contents of trans-C16:1 and trans-C18:1 were 0.16 and 2.12%, respectively. The
      distribution profile of trans-C18:1 was also studied.

PMID- 10342227
TI  - Aspects of enzymology and biochemical properties of Brevibacterium linens
      relevant to cheese ripening: a review.
AB  - Brevibacterium linens is a major surface microorganism that is present in the
      smear of surface-ripened cheeses. The enzymology and biochemical characteristics
      of B. linens influence the ripening and final characteristics of smear surface
      ripened cheeses. Proteolytic, peptidolytic, esterolytic, and lipolytic
      activities, which are of particular importance in the ripening process, are
      discussed in detail. This review also describes the production of volatile
      compounds, especially sulfur-containing ones, by B. linens, which are thought to
      be important in respect to the flavor of smear surface-ripened cheeses. The
      unique orange-colored carotenoids and the factors effecting their production by
      B. linens are also presented. The catabolism of aromatic amino acids, bacteriocin
      production, plasmids, and miscellaneous biochemical and physiological properties
      (peptidoglycan type, antibiotic resistance, insecticide degradation, and
      biotechnological applications) of B. linens are discussed. The problem associated
      with the current taxonomical classification of B. linens strains caused by strain
      variation is evaluated. Finally, the application of B. linens cell extracts or
      its proteolytic enzymes as cheese ripening accelerants for semi-hard or hard
      cheese varieties is considered.

PMID- 10342228
TI  - Reproductive performance of dairy heifers after estrus synchronization and fixed
      time artificial insemination.
AB  - The reproductive performance of heifers after estrus synchronization and fixed
      time AI was compared with nonsynchronized heifers in 25 spring-calving herds.
      Within herds, heifers were divided into a synchronized (n = 1123) or a control (n
      = 1125) group. Heifers in the synchronized group were treated with a combination
      of progesterone, estradiol benzoate, and PGF2 alpha and were inseminated between
      50 and 54 h after progesterone treatment. Returns to first service were
      resynchronized with progesterone treatment between 16 and 21 d after the fixed
      time AI. The conception rate of synchronized heifers to the fixed-time AI (53.2%)
      and to AI after resynchronization (53.1%) was lower than that of control heifers
      (63.7%). However, pregnancy rate in the first 24 d was higher for the
      synchronized group (72.4%) than for the control group (67.8%). More control
      heifers (5.7%) than synchronized heifers (4.0%) failed to conceive. The interval
      from start of breeding to calving was earlier for synchronized (296.2 d) than for
      control (299.5 d) heifers. Jersey heifers had lower reproductive performance than
      did Friesian heifers. Synchronized heifers gave birth to more female calves
      (53.8%) than did control heifers (45.7%). It is concluded that the above program
      can be used successfully to synchronize dairy heifers for fixed-time AI.

PMID- 10342229
TI  - Bovine follicular dynamics, oocyte recovery, and development of oocytes
      microinjected with a green fluorescent protein construct.
AB  - The present study was carried out to 1) evaluate the viability of in vitro
      fertilized zygotes after microinjection of DNA, 2) assess the influence of oocyte
      quality upon the development rate of embryos when injected with DNA, and 3)
      determine the integration frequency of green fluorescent protein DNA into
      microinjected embryos. Oocytes were aspirated from ovaries of nine nonlactating
      Holsteins and were categorized into grades A, B, C, and D. At 16 h after in vitro
      fertilization, approximately half of the pronuclear stage presumptive zygotes
      were classified as having 1 pronucleus or 2 pronuclei, and they were
      microinjected with DNA constructs. A potential predictor of DNA integration
      frequency at d 10 was assessment of the incidence of green fluorescing embryos.
      The proportion of cleaved embryos that developed to morulae or blastocysts was
      not different between groups with 1 pronucleus injected (45%), 1 pronucleus
      uninjected (64%), or 2 pronuclei injected (49%). However, the development of
      morulae or blastocysts was higher in the group with 2 pronuclei uninjected (69%).
      The overall developmental score of green fluorescent protein-positive embryos was
      higher for grade A oocytes (1.3 +/- 0.1) than for grade B (0.8 +/- 0.1), C (0.6
      +/- 0.1), or D (0.3 +/- 0.1) oocytes. The results show that production of
      transgenic bovine blastocysts can occur from the microinjection of a presumptive
      zygote having only one visible pronucleus. Initial oocyte quality is an important
      factor in selection of oocytes suitable for microinjection of DNA and for
      preimplantation development to produce bovine transgenic embryos.

PMID- 10342230
TI  - Possible risk factors associated with penicillin-resistant strains of
      Staphylococcus aureus from bovine subclinical mastitis in early lactation.
AB  - A randomized controlled field study of selective dry cow therapy with 686 cows
      allocated to two control groups (sampling only or placebo) or two therapy groups
      was used to screen for possible factors associated with penicillin-resistant
      strains of Staphylococcus aureus after the dry period. Therapy was given either
      as a total dose of 400,000 IU of penicillin and 100 mg of neomycin per infected
      quarter as dry cow preparation or as a total dose of 1.2 million IU of penicillin
      and 1200 mg of dihydrostreptomycin per infected quarter as a lactation formula.
      Success cows had all quarters identified as being free of penicillin-resistant
      strains of Staphylococcus aureus both at calving and at 30 +/- 17 d after
      calving. Failure cows were those having penicillin-resistant strains of Staph.
      aureus in any quarter at both or one of these two samples after the dry period.
      Using logistic regression, four variables were found to be associated with
      penicillin-resistant strains of Staph. aureus after the dry period. These
      included the identification of penicillin-resistant strains of Staph. aureus
      either at 45 +/- 32 d before drying off and at drying off, treatment for acute
      clinical mastitis at least once during the previous lactation, the weighted SCC
      of all cows' milk by daily milk yield within the herd, and therapy in the
      lactation formula compared with the two control groups. Our finding that the use
      of lactation formula increases the risk of resistance development is
      contradictory to present arguments underlying Norwegian dry cow therapy strategy.

PMID- 10342231
TI  - Efficacy of an Escherichia coli J5 bacterin administered to primigravid heifers.
AB  - The efficacy of an Escherichia coli J5 bacterin for reducing the incidence of
      intramammary infections and clinical signs of mastitis was tested in first
      lactation heifers. Ten primigravid heifers were immunized with an E. coli J5
      bacterin. Four heifers received a placebo. The bacterin and placebo were injected
      subcutaneously approximately 60 d prior to calving, 28 d later, and within 48 h
      after calving. Vaccinated and placebo-injected heifers were challenged by
      intramammary infusion of E. coli 727 in one mammary gland between 23 and 37 d
      after calving. All challenged quarters were diagnosed with an intramammary
      infection within 6 h after bacteria were infused. The severity and duration of
      local signs of clinical mastitis were reduced in vaccinated heifers compared with
      placebo-injected heifers. Systemic signs of clinical mastitis were limited and
      did not differ between treatment groups. Bacteria counts in milk from challenged
      quarters were lower in vaccinated heifers than in control heifers at 12, 15, and
      48 h after challenge. Serum immunoglobulin G titers against whole-cell E. coli J5
      antigen at calving were higher in vaccinated heifers than they were in controls.
      Vaccinated heifers had higher immunoglobulin G titers than did controls in
      mammary secretions at calving and immediately prior to challenge. Immunization of
      primigravid heifers with an E. coli J5 bacterin during the last trimester of
      gestation and at calving reduced the severity and duration of clinical signs
      following intramammary challenge with a heterologous strain of E. coli.

PMID- 10342232
TI  - Modeling the effect of an outbreak of bovine herpesvirus type 1 on herd-level
      milk production of Dutch dairy farms.
AB  - One of the impacts of disease is its effect on milk production. In the present
      study the effect of an outbreak of bovine herpesvirus type 1 on milk production
      at the herd level of certified bovine herpesvirus type 1-free dairy farms was
      modeled. The objective was to study several linear models to quantify the effects
      of a bovine herpesvirus type 1 outbreak on milk production accounting for the
      repeated measurements and incorporating our assumptions about the most likely
      duration of effects of this virus. Because milk production is measured at regular
      intervals, the data consisted of repeated measurements at the herd and cow
      levels. A marginal model, a subject-specific random-effect model, and a
      transition model were developed. The effect of a bovine herpesvirus type 1
      outbreak was statistically significant in the random-effect model, and this model
      fitted the investigated farms best. However, a transition model might be a better
      model for generalizing the results to the whole population of Dutch dairy farms.
      The effect of a bovine herpesvirus type 1 outbreak on milk production derived
      from the random-effect model amounted to, on average, a loss of 0.92 kg of milk
      per cow per day during a period of 9 wk. The milk production loss varied from
      almost none to 2 kg of milk per cow per day. This reduction resulted in an
      average loss of Dfl 372 (Dfl1 = $US $0.50) with lower and upper confidence limits
      of, respectively, Dfl 12 and Dfl 730 per bovine herpesvirus type 1 outbreak.

PMID- 10342233
TI  - Method to monitor the precision of milk yields recorded at individual milking
      stalls on daily basis.
AB  - Automated systems to record individual milk weights of cows at each milking are
      now common on dairy farms. These data are used by Dairy Herd Improvement
      Association (DHIA) for testing purposes and by farmers to monitor herd
      performance. Despite the importance of these data, little effort has been made to
      monitor the function and reliability of milking stalls and recording equipment on
      a daily basis. Described is an algorithm that allows for continuous monitoring of
      the function of individual milking stalls. The basis of the algorithm is the
      comparison of milk yield of individual cows over a period of days. For each cow,
      milk production at a selected stall is compared with production of that same cow
      when milked at any other stall. These ratios are averaged across all cows milked
      at least once in the selected stall and once at any other stall. Ideally, the
      mean ratio for each stall should be 1. Stalls where the mean ratio deviates from
      1 by more than 5% are assumed to be malfunctioning. This algorithm was
      implemented as a computer program and was used to identify 3 malfunctioning
      stalls out of 12 at the USDA dairy facility (Beltsville, MD). The algorithm can
      easily be incorporated into existing management programs or used as a separate
      program. In either case, routine use of this algorithm can improve the
      reliability of DHIA test programs and potentially reduce the incidence of new
      mastitis infections by enabling detection of malfunctioning milking equipment.

PMID- 10342234
TI  - Different techniques to study rumen fermentation characteristics of maturing
      grass and grass silage.
AB  - Grass samples were harvested during the 1993 growing season after a precut on
      April 27, 1993 and were stored frozen or left to ensile in 30-L buckets. Effects
      on chemical composition and fermentation kinetics of the maturation of the grass
      and of ensiling were investigated. Chemical composition and fermentation kinetics
      were determined using the gas production technique, in vitro techniques, and the
      nylon bag technique. Two silage samples were also investigated in vivo.
      Maturation caused a decrease in crude protein content and organic matter
      degradability and an increase in neutral detergent fiber, acid detergent fiber,
      and lignin contents. Degradation rates were highest for the youngest samples and
      decreased as grass and silage matured. This result could be observed from the
      first derivative of the cumulative gas production curves (i.e., the rate of gas
      production) and from the gas production parameters. The rate of degradation of
      the nonsoluble fraction of the young samples, determined using the gas production
      technique, was relatively higher in rumen fluid from a cow fed silage from grass
      cut at a young stage. More mature samples were degraded relatively faster in
      rumen fluid from a cow fed mature grass silage, suggesting a specific adaptation
      of the rumen microorganisms to the grass properties. There was a good
      relationship among the second phase of gas production (i.e., fermentation of the
      nonsoluble fraction), maturity of the grass and grass silage samples,
      degradability determined with the Tilley and Terry technique, and degradability
      determined after 46 h of incubation in rumen fluid. Results obtained with both of
      the different in vitro techniques and the nylon bag technique were confirmed by
      the in vivo experiments involving the two silage samples.

PMID- 10342235
TI  - Influence of short- and long-term exposure to a hot environment on rumen passage
      rate and diet digestibility by Friesian heifers.
AB  - Effects of short- and long-term exposure to a hot environment on diet
      digestibility and rumen passage rate were studied in four, 10-mo-old Friesian
      heifers housed in a climatic chamber. The trial lasted 65 d. Twenty-five days
      were spent under thermal comfort (temperature-humidity index = 64), and 40 d were
      spent under hot conditions (temperature-humidity index = 84). Three digestibility
      and rumen passage rate trials were performed during the 65 d. Chromium oxide was
      used as an external marker. The first digestibility and rumen passage rate trial
      (trial 1) was performed under thermal comfort; trials 2 and 3 were performed
      under hot conditions. Exposure to the hot environment reduced dry matter intake
      and increased water intake and rectal temperature compared with those during the
      thermal comfort period. Digestibility coefficients for dry matter, organic
      matter, neutral detergent fiber, and acid detergent fiber were higher in trial 2
      than in trials 1 and 3. No statistical differences were found between trials 1
      and 3 for these variables. Rumen passage rate was more rapid in trial 1 than in
      trials 2 and 3. No difference was observed between trials 2 and 3. These results
      indicated that exposure to a hot environment can affect digestibility in a time
      dependent fashion, suggesting an adaptation of the digestive tract to hot
      environments.

PMID- 10342236
TI  - Effect of drastic undernutrition on digestion in Zebu cattle receiving a diet
      based on rice straw.
AB  - The effect of drastic undernutrition was studied in Bos indicus cows. Four
      nonlactating cows (body weight = 208 kg) fitted with ruminal cannulas were used
      in a crossover design. They received, in two 1-mo periods, a diet of 80% rice
      straw and 20% cotton-seed meal fed either at energy maintenance [3.91 kg of dry
      matter (DM)/d] or at one-third of this intake (1.30 kg of DM/d). The variation in
      digestibility was studied in relation to particle retention time and microbial
      events. Organic matter digestibility decreased with underfeeding (64.5 and 53.7%,
      respectively, at high and low intakes) without modification of mean ruminal or
      total tract retention times. This lower digestibility can be related to a
      decrease in protozoal population in the rumen; however, other characteristics of
      microbial activity did not vary, such as in situ DM degradability (41.9 and
      43.3%, respectively, at high and low intakes) and ruminal soluble Ca
      concentration, a factor involved in the attachment of microorganisms to feed
      particles. Mean size of ruminal particles was not modified, although more time
      spent chewing was observed at the low intake (165 and 221 min/kg of DM intake,
      respectively, at high and low intakes). This experiment confirms that, at intakes
      below maintenance, digestibility can decrease when feed intake is restricted,
      contrary to the general view described in the literature.

PMID- 10342238
TI  - Response of lactating dairy cows to a cellulase and xylanase enzyme mixture
      applied to forages at the time of feeding.
AB  - Fifty Holstein cows (20 primiparous and 30 multiparous) were used in an
      experiment to evaluate the dose response to a direct-fed cellulase and xylanase
      enzyme mixture applied to the forage portion (60% corn silage and 40% alfalfa
      hay) of a total mixed ration just prior to feeding. Cows were fed one of five
      treatment diets for 12 wk. Diets 1 through 4 were 55% forage: 45% concentrate and
      consisted of an untreated control and the control diet plus 0.7, 1.0, or 1.5 L of
      enzyme concentrate/tonne of forage dry matter, respectively. Diet 5 was an
      untreated 45% forage: 55% concentrate diet. Actual production of milk increased
      as much as 10.8% relative to the control diet with 1.5 L of enzyme, and
      production of fat and protein increased as much as 20 and 13%, respectively. The
      lowest concentration of enzyme treatment (0.7 L/tonne) accounted for
      approximately one-half of the production increases. The responses to enzyme
      treated forages occurred 2 to 4 wk after the cows started to consume the treated
      forages, and the same responses were maintained throughout the remainder of the
      experiment. Cows that started to receive enzyme-treated forage during the first
      100 d postpartum produced 9 to 15% more milk and 16 to 23% more energy-corrected
      milk than did cows fed the control diet. However, production was not increased
      when cows were in midlactation at the start of the experiment. Responses to
      enzyme-treated forages fed in 55: 45 forage to concentrate rations were similar
      to the response to increased proportions of concentrates fed with untreated
      forages at the 45:55 forage to concentrate ratio.

PMID- 10342237
TI  - Metabolic and production responses to dietary protein and exogenous somatotropin
      in late gestation dairy cows.
AB  - Forty-three multiparous Holstein cows were used in a completely randomized design
      to evaluate the effects of protein supplementation and the use of bovine
      somatotropin (bST; Posilac, Monsanto Co., St. Louis, MO) in late gestation on
      animal metabolism and productivity in the periparturient period. Treatments were
      initiated 28 d prior to expected calving date and continued through parturition.
      Diets contained either 13.3 or 17.8% crude protein and were formulated to be
      similar in profile of protein fractions. Within each dietary treatment, cows were
      assigned to receive either 0 or 500 mg of sustained released bST once every 14 d
      until parturition. Following parturition, all cows were subjected to the same
      management and dietary treatments, and production measurements were followed
      until 42 d in milk. The use of bST increased plasma glucose and decreased plasma
      nonesterified fatty acids and beta-hydroxybutyrate prior to calving. Despite
      these changes in metabolism, bST did not affect concentrations of fat and
      triglyceride in the liver prepartum or postpartum. Feeding the 17.8% protein diet
      failed to stimulate glucose metabolism and tended to elevate plasma beta
      hydroxybutyrate in late gestation. Cows treated with bST produced 3.3 kg/d more
      milk than did controls across the first 42 d of lactation; the difference was 4.6
      kg/d in wk 6 of lactation. The use of bST in late gestation has considerable
      promise to alter cow metabolism positively. The results of these and other
      possible periparturient responses to somatotropin may increase milk production in
      early lactation.

PMID- 10342239
TI  - Milk yield and composition of dairy cows fed concentrate based on naked oats.
AB  - A 1.5-yr study was designed to determine the effects of feeding isonitrogenous
      and isoenergetic concentrates based on naked oats, corn, or a mixture (50: 50 on
      as-fed basis) of naked oats and corn on milk yield and composition. In vitro dry
      matter (DM) digestibility and ruminal degradabilities of DM, N, and starch of
      naked oats were compared with those of covered oats. Twenty-seven multiparous
      Holstein cows were blocked by similar calving date and assigned to 9 replicates.
      All cows were fed a mixture of grass silage, protein supplement, concentrate, and
      a vitamin and mineral mix for ad libitum intake. Treatment diets were fed from 3
      to 36 wk of lactation. Milk yield and composition, yield of 4% fat-corrected
      milk, and yield of protein and fat were similar among treatments. Ruminal
      effective degradabilities of DM were higher for naked oats than for covered oats,
      but the ruminal degradabilities of crude protein and starch were similar. The
      rapidly degradable fractions of DM, crude protein, and starch were greater for
      naked than covered oats; the potentially degradable fractions were less. In vitro
      DM digestibility of naked oats was higher than was that of covered oats. Naked
      oats may be a good alternative to corn for milk yield.

PMID- 10342240
TI  - Intake and excretion of sodium, potassium, and nitrogen and the effects on urine
      production by lactating dairy cows.
AB  - The present study was designed to describe the relationship between mineral
      metabolism and urine production by lactating dairy cows. Regression studies were
      performed to predict urine volume from either observed concentrations of K, Na,
      and N in urine or observed intakes of K, Na, and N. In addition, empirical
      equations were derived to assist in the estimation of urinary excretion of K, Na,
      and N in practical situations. Data used to derive the relationships (n = 67
      observations) and to evaluate them (n = 62 observations) were obtained from a
      wide range of feeding conditions in 10 independent balance trials with lactating
      cows. Linear relationships of K, Na, and N that were excreted in urine or
      consumed were fitted against the observed urine production, which explained 89.8%
      (SE = 4.2 kg of urine/d) and 84.8% (SE = 5.2 kg of urine/d) of the variance. In
      evaluating these relationships, the observed variation in urine production was
      predicted with acceptable accuracy. Mean prediction errors were 4.5 and 5.6 kg of
      urine/d. Urine production could be predicted based on relationships between
      intakes of digestible Na, K, and N and their excretion in milk and urine.
      Reliable predictions of urine production are important as attention on the effect
      of manure production by dairy cows on nutrient management at the farm level
      increases.

PMID- 10342241
TI  - Effect of additional cobalt, copper, manganese, and zinc on reproduction and milk
      yield of lactating dairy cows receiving bovine somatotropin.
AB  - The objective of this study was to determine whether organically complexed Co,
      Cu, Mn, and Zn would improve the reproductive performance and milk and milk
      component production in lactating dairy cows that began receiving bovine
      somatotropin in the ninth week of lactation. Holstein (n = 50) and Jersey (n =
      10) cows were blocked by breed, lactation number, and incidence of retained fetal
      membranes. Two diets assigned within blocks and fed from parturition until 154 d
      of lactation were control or control supplemented daily with 26 mg of Co as Co
      glucoheptonate, 125 mg of Cu as Cu-Lys, 199 mg of Mn as Mn-Met, and 359 mg of Zn
      as Zn-Met. Cows were fitted with electronic pressure-sensing devices in the
      second week of lactation for detection of estrus. Ovarian structures were
      determined via transrectal ultrasonography at 7-d intervals from parturition
      until observation of the first corpus luteum. Blood samples were taken at 7-d
      intervals and analyzed for plasma concentrations of progesterone, insulin, and
      urea nitrogen. Onset of luteal activity was identified by progesterone
      concentrations > or = 1 ng/ml. Retained fetal membranes increased days to first
      estrus (detected via electronic estrous detection), first luteal activity, and
      first corpus luteum in control cows but not in supplemented cows. Days to first
      observed estrus were greater for control cows than for supplemented cows. Days to
      first service, days open, days from first service to conception, services per
      conception, milk yield, milk components, and somatic cell counts were similar for
      control and supplemented cows. Supplementation with complexed trace minerals
      effectively reduced days to first estrus.

PMID- 10342242
TI  - Associations between milk protein polymorphism and first lactation milk
      production traits in Finnish Ayrshire cows.
AB  - Genotypic effects of beta-casein (CN), kappa-CN, and beta-lactoglobulin (LG) on
      milk, fat, and protein production and fat and protein percentages were estimated
      for 18,686 Finnish Ayrshire cows in first lactation using an animal model. Casein
      genotype effects were estimated including individual beta-CN and kappa-CN
      simultaneously in a model and then as composite beta-kappa-CN. The A2 allele of
      beta-CN and the A allele of kappa-CN, as well as the A1 allele of beta-CN and the
      B or E allele of kappa-CN, appeared together more frequently than was expected.
      Because of linkage disequilibrium in the casein loci and, consequently,
      unbalanced data, some contradictory effects of casein genotypes were obtained
      with the two models. A well-founded way to estimate the effects of casein
      genotypes was to use beta-kappa-CN genotypes. Composite casein genotypes
      including the A2 allele of beta-CN were associated with the highest milk and
      protein production and the lowest fat content, those including the B allele of
      kappa-CN with the highest protein content, and those including the E allele of
      kappa-CN with the lowest protein content. The effect of the beta-kappa-CN
      genotypes on protein content was moderately strong, and the effect was somewhat
      smaller for other traits. The AA genotype of beta-LG had a favorable effect on
      milk and protein production, and the BB genotype had a favorable effect on fat
      content.

PMID- 10342243
TI  - Comparison of methods for genetic evaluation of sires for survival of their
      daughters in the first three lactations.
AB  - Several approaches for analysis of survival in the first three lactations were
      compared using data from approximately 700,000 Canadian Holsteins. Two approaches
      (linear model and threshold model) were used to analyze a binary measure of
      survival. Other approaches were survival analyses to evaluate two measures of the
      number of days that cows were in milk during their first three lactations. One
      measure restricted days per lactation to < or = 305; the other was based on the
      actual number of days in milk without an upper limit on days per lactation.
      Variance components and breeding values (EBV) were estimated. Sire models were
      used almost exclusively, but one set of EBV was obtained using a linear animal
      model. Effects in the models were herd-year of calving, age at first calving,
      interaction of several factors related to herd, and production. Thus, all EBV
      were for functional herd life. Heritabilities were approximately 0.04, 0.07, and
      0.10 from linear, threshold, and survival analyses, respectively. Correlations
      among sire EBV from all analyses using sire models were high, particularly for
      linear and threshold models (0.98). In contrast, correlations of EBV from sire
      models with EBV from the linear animal model were less than 0.90, regardless of
      the approach taken. In Canada, the current linear animal model remains in use for
      sire evaluation of herd life, but research with survival analyses will continue.

PMID- 10342244
TI  - Estimation of genetic and phenotypic parameters for clinical mastitis, somatic
      cell production deviance, and protein yield in dairy cattle using Gibbs sampling.
AB  - When including clinical mastitis in the breeding goal, it is useful to know what
      measure of the trait is most appropriate and its relationship to the primary
      production traits and indicator traits in the relevant population. In this paper,
      genetic and phenotypic parameters for clinical mastitis, somatic cell production
      deviance, and protein yield were estimated for the dairy breed Danish Red. In
      preliminary analyses, the heritability for clinical mastitis was found to be
      highest in early lactation, and its genetic correlation to clinical mastitis at
      other stages of lactation were high. Therefore, clinical mastitis defined in
      early lactation was the measure of clinical mastitis used in subsequent analyses.
      Two bivariate analyses were performed. Each analysis fitted clinical mastitis and
      either somatic cell production deviance or protein yield as a continuous trait.
      The bivariate model was composed of a Gaussian model for the continuous trait and
      a threshold model for mastitis. The analyses were performed in a Bayesian
      setting, using the Gibbs sampler. Point estimates (mean of marginal posterior
      densities) of heritability for mastitis on the underlying scale were estimated to
      be 0.10 and 0.12 in the two analyses. The genetic correlation between mastitis
      and protein yield was 0.43 and between mastitis and somatic cell production
      deviance was 0.80. These results make clear the importance of including clinical
      mastitis in the breeding goal and the usefulness of somatic cell production
      deviance as the indicator trait for clinical mastitis. The best measure of
      clinical mastitis was to consider only cases in early lactation.

PMID- 10342245
TI  - Supply of genetic information--amount, format, and frequency.
AB  - The volume and complexity of genetic information is increasing because of new
      traits and better models. New traits may include reproduction, health, and
      carcass. More comprehensive models include the test day model in dairy cattle or
      a growth model in beef cattle. More complex models, which may include nonadditive
      effects such as inbreeding and dominance, also provide additional information.
      The amount of information per animal may increase drastically if DNA marker
      typing becomes routine and quantitative trait loci information is utilized. In
      many industries, evaluations are run more frequently. They result in faster
      genetic progress and improved management and marketing opportunities but also in
      extra costs and information overload. Adopting new technology and making some
      organizational changes can help realize all the added benefits of the
      improvements to the genetic evaluation systems at an acceptable cost. Continuous
      genetic evaluation, in which new records are accepted and breeding values are
      updated continuously, will relieve time pressures. An online mating system with
      access to both genetic and marketing information can result in mating
      recommendations customized for each user. Such a system could utilize inbreeding
      and dominance information that cannot efficiently be accommodated in the current
      sire summaries or off-line mating programs. The new systems will require a new
      organizational approach in which the task of scientists and technicians will not
      be simply running the evaluations but also providing the research, design,
      supervision, and maintenance required in the entire system of evaluation,
      decision making, and distribution.

PMID- 10342246
TI  - Image quality assurance for CRT display systems--Part II.

PMID- 10342247
TI  - Image quality degradation by light scattering in display devices.
AB  - Veiling glare and ambient light reflection can significantly degrade the quality
      of an image on a display device. Veiling glare is primarily associated with the
      diffuse spread of image signal caused by multiple light scattering in the
      emissive structure of the device. The glare ratio associated with a test image
      with a 1-cm-diameter black spot is reported as 555 for film, 89 for a monochrome
      monitor, and 25 for a color monitor. Diffuse light reflection results from
      ambient light entering the display surface and returning at random emission
      angles. The diffuse reflection coefficient (luminance/illuminance, 1/sr) is
      reported as 0.026 for film, 0.058 for a monochrome monitor, and 0.025 for a color
      monitor with an antireflective surface coating. Both processes increase the
      luminance in black regions and cause contrast reduction. Specular reflections
      interfere with detail in the displayed scene. The specular reflection coefficient
      (luminance/luminance) is reported as 0.011 for film, 0.041 for a monochrome
      monitor, and 0.021 for a color monitor with an antireflective coating.

PMID- 10342248
TI  - Optimization of a contrast-detail-based method for electronic image display
      quality evaluation.
AB  - The authors previously reported a general technique based on contrast-detail
      methods to provide an overall quantitative evaluation of electronic image display
      quality. The figure-of-merit reflecting overall display quality is called maximum
      threshold contrast or MTC. In this work we have optimized the MTC technique
      through improvements in both the test images and the figure-of-merit computation.
      The test images were altered to match the average luminance with that observed
      for clinical computed radiographic images. The figure-of-merit calculation was
      altered to allow for contrast-detail data with slopes not equal to -1.
      Preliminary experiments also were conducted to demonstrate the response of the
      MTC measurements to increased noise in the displayed image. MTC measurements were
      obtained from five observers using the improved test images displayed with
      maximum monitor luminance settings of 30-, 50-, and 70-ft-Lamberts. Similar
      measurements were obtained from two observers using test images altered by the
      addition of a low level of image noise. The noise-free MTC and MTC difference
      measurements exhibited standard deviations of 0.77 and 1.55, respectively. This
      indicates good measurement precision, comparable or superior to that observed
      using the earlier MTC technique. No statistically significant image quality
      differences versus maximum monitor luminance were seen. The noise-added MTC
      measurements were greater than the noise-free values by an average of 4.08 pixel
      values, and this difference was statistically significant. This response is
      qualitatively correct, and is judged to indicate good sensitivity of the MTC
      measurement to increased noise levels.

PMID- 10342249
TI  - Application of the advanced communications technology satellite to teleradiology
      and real-time compressed ultrasound video telemedicine.
AB  - The authors have investigated the application of the NASA Advanced Communications
      Technology Satellite (ACTS) to teleradiology and telemedicine using the Jet
      Propulsion Laboratory (JPL)-developed ACTS Mobile Terminal (AMT) uplink. In this
      experiment, bidirectional 128, 256, and 384 kbps satellite links were established
      between the ACTS/AMT, the ACTS in geosynchronous orbit, and the downlink
      terrestrial terminal at JPL. A terrestrial Integrated Digital Services Network
      (ISDN) link was established from JPL to the University of Washington Department
      of Radiology to complete the bidirectional connection. Ultrasound video imagery
      was compressed in real-time using video codecs adhering to the International
      Telecommunication Union-Telecommunication Standardization Sector (ITU-T)
      Recommendation H.261. A 16 kbps in-band audio channel was used throughout. A five
      point Likert scale was used to evaluate the quality of the compressed ultrasound
      imagery at the three transmission bandwidths (128, 256, and 384 kbps). The
      central question involved determination of the bandwidth requirements to provide
      sufficient spatial and contrast resolution for the remote visualization of fine-
      and low-contrast objects. The 384 kbps bandwidth resulted in only slight tiling
      artifact and fuzziness owing to the quantizer step size; however, these motion
      artifacts were rapidly resolved in time at this bandwidth. These experiments have
      demonstrated that real-time compressed ultrasound video imagery can be
      transmitted over multiple ISDN line bandwidth links with sufficient temporal,
      contrast, and spatial resolution for clinical diagnosis of multiple disease and
      pathology states to provide subspecialty consultation and educational at a
      distance.

PMID- 10342250
TI  - Application of temporal subtraction for detection of interval changes on chest
      radiographs: improvement of subtraction images using automated initial image
      matching.
AB  - The authors developed a temporal subtraction scheme based on a nonlinear
      geometric warping technique to assist radiologists in the detection of interval
      changes in chest radiographs obtained on different occasions. The performance of
      the current temporal subtraction scheme is reasonably good; however, severe
      misregistration can occur in some cases. The authors evaluated the quality of 100
      chest temporal subtraction images selected from their clinical image database.
      Severe misregistration was mainly attributable to initial incorrect global
      matching. Therefore, they attempted to improve the quality of the subtraction
      images by applying a new initial image matching technique to determine the global
      shift value between the current and the previous chest images. A cross
      correlation method was employed for the initial image matching by use of blurred
      low-resolution chest images. Nineteen cases (40.4%) among 47 poor registered
      subtraction images were improved. These results show that the new initial image
      matching technique is very effective for improving the quality of chest temporal
      subtraction images, which can greatly enhance subtle changes in chest
      radiographs.

PMID- 10342251
TI  - The philosophy of benchmark testing a standards-based picture archiving and
      communications system.
AB  - The Department of Defense issued its requirements for a Digital Imaging Network
      Picture Archiving and Communications System (DIN-PACS) in a Request for Proposals
      (RFP) to industry in January 1997, with subsequent contracts being awarded in
      November 1997 to the Agfa Division of Bayer and IBM Global Government Industry.
      The Government's technical evaluation process consisted of evaluating a written
      technical proposal as well as conducting a benchmark test of each proposed system
      at the vendor's test facility. The purpose of benchmark testing was to evaluate
      the performance of the fully integrated system in a simulated operational
      environment. The benchmark test procedures and test equipment were developed
      through a joint effort between the Government, academic institutions, and private
      consultants. Herein the authors discuss the resources required and the methods
      used to benchmark test a standards-based PACS.

PMID- 10342252
TI  - Benchmark testing the Digital Imaging Network-Picture Archiving and
      Communications System proposal of the Department of Defense.
AB  - The Department of Defense issued a Request for Proposal (RFP) for its next
      generation Picture Archiving and Communications System in January of 1997. The
      RFP was titled Digital Imaging Network-Picture Archiving and Communications
      System (DIN-PACS). Benchmark testing of the proposed vendors' systems occurred
      during the summer of 1997. This article highlights the methods for test material
      and test system organization, the major areas tested, and conduct of actual
      testing. Department of Defense and contract personnel wrote test procedures for
      benchmark testing based on the important features of the DIN-PACS Request for
      Proposal. Identical testing was performed with each vendor's system. The Digital
      Imaging and Communications in Medicine (DICOM) standard images used for the
      Benchmark Testing included all modalities. The images were verified as being
      DICOM standard compliant by the Mallinckrodt Institute of Radiology, Electronic
      Radiology Laboratory. The Johns Hopkins University Applied Physics Laboratory
      prepared the Unix-based server for the DICOM images and operated it during
      testing. The server was loaded with the images and shipped to each vendor's
      facility for on-site testing. The Defense Supply Center, Philadelphia (DSCP), the
      Department of Defense agency managing the DIN-PACS contract, provided
      representatives at each vendor site to ensure all tests were performed equitably
      and without bias. Each vendor's system was evaluated in the following nine major
      areas: DICOM Compliance; System Storage and Archive of Images; Network
      Performance; Workstation Performance; Radiology Information System Performance;
      Composite Health Care System/Health Level 7 communications standard Interface
      Performance; Teleradiology Performance; Quality Control; and Failover
      Functionality. These major sections were subdivided into workable test procedures
      and were then scored. A combined score for each section was compiled from this
      data. The names of the involved vendors and the scoring for each is contract
      sensitive and therefore can not be discussed. All of the vendors that underwent
      the benchmark testing did well. There was no one vendor that was markedly
      superior or inferior. There was a typical bell shaped curve of abilities. Each
      vendor had their own strong points and weaknesses. A standardized benchmark
      protocol and testing system for PACS architectures would be of great value to all
      agencies planning to purchase a PACS. This added information would assure the
      purchased system meets the needed functional requirements as outlined by the
      purchasers PACS Request for Proposal.

PMID- 10342253
TI  - Easy-to-read consumer communications: a missing link in Medicaid managed care.
AB  - Effective consumer communication is key to successfully moving Medicaid
      recipients into managed care systems and realizing the promised cost savings from
      the upheaval. Yet, little attention has been paid to educating these consumers
      with easy-to-read materials. The Maine Area Health Education Center (AHEC) Health
      Literacy Center, with the support of the Center for Health Care Strategies, Inc.,
      addressed the problem by offering three national skills training workshops called
      Writing for the Medicaid Market. The training was marketed to public and private
      organizations providing Medicaid managed care services, including state Medicaid
      officials, health benefit counselor staff (enrollment brokers), managed care plan
      (HMO) staff, and consumer advocates. The training addressed the core issue in
      health literacy: the mismatch between the low literacy skills of the target
      population and the high reading level of most health and managed care materials.
      Posttraining survey data revealed that training was successful in skill building,
      but also that it addressed only the tip of the iceberg. Faulty and/or nonexistent
      communication planning limits the success not only of Medicaid, but of other
      large health and social programs as well. The authors outline the broad scope of
      the national health literacy problem, share their posttraining survey data,
      discuss lessons extrapolated from both their data and their experience, and
      propose a national agenda to address a vast and generally ignored public problem.

PMID- 10342254
TI  - Error in medicine: legal impediments to U.S. reform.
AB  - Error in medicine is common and can lead to significant patient injury. Although
      successful systematic efforts to reduce human error have been applied in other
      complex systems, the field of medicine has just begun to make a broad-based
      effort in this regard. However, both research in and implementation of patient
      safety measures may not occur without considering important legal issues that may
      impede these health policy efforts. Tort and contract law may interact with the
      vagaries of managed care to limit participation in these error reduction efforts
      by health care providers as well as by managed care organizations. Thus, for
      patient safety research to be successful, all members of the health care
      enterprise must participate in a coordinated effort to identify and establish
      effective practices that may reduce human error in medicine. But beyond this
      understanding, it is imperative that legal impediments be recognized and
      addressed before the goal of a continuously improving, increasingly safe health
      care system can become a reality.

PMID- 10342256
TI  - Utilization of health care services among subgroups of urban homeless and housed
      poor.
AB  - The objective of this study was to describe health services utilization by
      homeless and housed poor adults stratified by six-month primary sheltering
      arrangements. The primary method used in this study was a cross-sectional survey
      of 373 homeless adults. Interviews at twenty-four community-based sites (in
      Allegheny County, Pennsylvania) assessed demographic and clinical
      characteristics, reasons for homelessness, functional status and social support
      networks, and health services utilization during the previous six months.
      Multivariate logistic regression analysis identified factors independently
      associated with health services utilization. Subjects were classified as
      unsheltered, emergency-sheltered, bridge-housed, doubled-up, and housed-poor. The
      median age of the subjects was 38.4 years; 78.6 percent were African American and
      69.9 percent had health insurance. Overall, 62.7 percent reported health services
      use in the past six months, with significantly more use among emergency-sheltered
      and bridge-housed subjects than among unsheltered subjects. The study concludes
      that health services use among the homeless is substantial and is independently
      associated with sheltering arrangement, comorbid illness, race, health insurance,
      and social support.

PMID- 10342255
TI  - No-fault vaccine insurance: lessons from the National Vaccine Injury Compensation
      Program.
AB  - During the first eight years of the National Vaccine Injury Compensation Program
      (NVICP), 786 contested claims were resolved through published judicial opinions.
      The likelihood of compensation dependent in part on the closeness of the match
      between the described injury and a specified list of acknowledged untoward
      vaccine side effects. In addition, the chances of applicant success were
      influenced by the applicant's choice of attorney and expert witnesses, by the
      assignment of the Special Master to decide the case, and increasingly over time,
      by the applicant's ability to comply with procedural requirements. The majority
      of contested claims arose from pertussis immunizations. For pertussis claims, the
      goal of insulating manufacturers from product liability suits has been achieved
      by granting compensation to applicants whose injuries are not scientifically
      recognized effects of the vaccine. In spite of (or because of) this jarring
      contradiction between the legal and medical understanding of causation, vaccine
      availability and childhood immunization rates improved during the early years of
      the plan. The apparent success of the program may encourage the substitution of
      no-fault compensation plans for tort-based consumer protection for other
      products, both medical and nonmedical.

PMID- 10342257
TI  - Genuine federalism in the Russian health care system: changing roles of
      government.
AB  - The reforms that have affected the Russian health care system since the breakup
      of the Soviet Union, principally those in the general administration of the
      Russian Federation, have suffered from inconsistency and the absence of a
      strategy. The various reforms have caused a shift from a national health system
      characterized by highly centralized management and control, typical of the
      totalitarian uniform state, to a highly decentralized but fragmented multitude of
      state systems. Each of these systems is relatively centralized at the local level
      and run by local administrations with limited government infrastructure and
      experience. The role of government in the emerging system, and in particular the
      role of the federal government, remains ill defined. As a result, there is a
      grave risk that the Russian health care system may disintegrate as a national
      system. This undermines (a) the prevailing universal and fairly equitable access
      to care, (b) stabilization of the system following a long period of transition,
      and (c) the long-term reform that is required to bring the Russian health care
      system up to par with the health care systems in other developed countries. A
      rapid transition to a genuine federal health system with well-articulated roles
      for different levels of government, in tandem with implementation of the 1993
      Compulsory Health Insurance System, is essential for the stabilization and reform
      of the Russian health care system.

PMID- 10342258
TI  - Oregon's bold experiment: whatever happened to rationing?
AB  - In 1994 Oregon began rationing health care for its Medicaid population, offering
      health policy makers and analysts around the country a view of one alternative
      future for health care delivery. The question now, four years after the
      experiment began, is what does that future look like? The short answer is that it
      does not look all that different from the present, but it looks different enough
      to offer important lessons to other states and the federal government. The Oregon
      experiment, including the prioritization of services and the aggressive use of
      managed care, has facilitated the expansion of health care coverage to over
      100,000 additional Oregonians, helped decrease the percentage of the uninsured as
      well as reduce uncompensated care in hospitals, reduced the use of hospital
      emergency rooms, and reduced cost shifting. By most measures, the Oregon
      experiment appears to be a success.

PMID- 10342260
TI  - Social and political dis-ease.

PMID- 10342259
TI  - The Oregon Health Plan and the political paradox of rationing: what advocates and
      critics have claimed and what Oregon did.
AB  - The article proceeds in three sections. First, we very briefly review the
      original proposals and ensuing (and misleading) debate over rationing in Oregon.
      Next, we explore how the politics of rationing unfolded in Oregon from the
      enactment of OHP to its implementation. Finally, we consider the character of
      Oregon's innovation and the broader lessons that it holds for reform efforts
      elsewhere.

PMID- 10342261
TI  - Mosquitoes of Fort Campbell, Kentucky (Diptera: Culicidae).
AB  - A survey of the mosquito fauna of Fort Campbell, Kentucky (Christian County,
      Kentucky, and Montgomery County, Tennessee) was conducted from May 1996 to May
      1998. A total of 528 mosquito collection sites were sampled in the most
      comprehensive mosquito collection effort on the military installation since 1976.
      A total of 42 mosquito species were identified, including new locality records
      for 14 species.

PMID- 10342262
TI  - A male accessory gland protein that modulates female mosquito (Diptera:
      Culicidae) host-seeking behavior.
AB  - The male accessory gland product that modulates the host-seeking behavior of
      female Aedes aegypti (L.) mosquitoes was found to be a peptide of 7,600 mw. This
      peptide also prevented subsequent mating behavior and weakly stimulated
      oviposition. Neither whole glands nor gland fractions from Anopheles gambiae had
      any effect on Ae. aegypti females, but those from Aedes albopictus were active.

PMID- 10342263
TI  - Morphological abnormalities in species of the quadrimaculatus complex of
      Anopheles (Diptera: Culicidae).
AB  - This report provides results of the first detailed examination of morphological
      abnormalities occurring in adults, pupae, and 4th-instar larvae of a sibling
      species complex within the family Culicidae. Aberrant and/or anomalous setae or
      structures are reported, along with their frequency of occurrence, for the 5
      sibling species (Anopheles diluvialis, Anopheles inundatus, Anopheles maverlius,
      Anopheles quadrimaculatus, and Anopheles smaragdinus) of the Quadrimaculatus
      Complex of Anopheles. A total of 21,684 specimens were examined. In the pupal
      stage, the presence of seta 11-II was the most common anomaly, whereas in the 4th
      instar larva, branching of seta 2-C occurred most frequently. Abnormalities in
      the male genitalia usually involved the claspette or tergum IX. Other
      abnormalities in females, male genitalia, pupae, and 4th-instar larvae occurred
      infrequently.

PMID- 10342265
TI  - Comparative effectiveness of three adult mosquito sampling methods in habitats
      representative of four different biomes of California.
AB  - The effectiveness of New Jersey (NJ) light, dry ice baited, and gravid female
      traps for collecting adult mosquitoes was compared at representative habitats in
      the Coachella, San Joaquin, and Sacramento valleys and the Los Angeles basin of
      California. The NJ light traps effectively sampled Anopheles freeborni, Culex
      tarsalis, Psorophora columbiae, and several Aedes when abundance was high in
      rural areas with minimal competitive illumination. Dry ice-baited encephalitis
      virus surveillance or CDC style traps collected significantly more females of
      most species at most localities than did NJ light traps, regardless of background
      illumination. The Cummings modification of the Reiter gravid female trap baited
      with a bulrush (Schoenoplectus) infusion was the best method for collecting Culex
      pipiens complex females in most habitats. In the Los Angeles basin, gravid traps
      baited with bulrush infusion collected, on average, 4.5 times more Culex
      quinquefasciatus females than did traps baited with the Reiter infusion. The
      bulrush infusion in combination with the Cummings trap design seemed to provide
      resting site cues and collected males as well as empty and bloodfed females.
      Mosquito surveillance programs in California should include the systematic
      operation of dry ice-baited and gravid female traps to improve surveillance
      sensitivity for selected species in appropriate habitats.

PMID- 10342264
TI  - Malaria transmission in a region of savanna-forest mosaic, Haut-Ogooue, Gabon.
AB  - During the 2 years 1993 to 1995, an entomological survey was carried out in the
      savanna-forest area of Franceville, Gabon, investigating malaria transmission in
      one suburban district of Franceville (Akou) and in one rural village (Benguia).
      The biting rates of the Anopheles vectors were 10 times higher in the rural zone
      compared to the suburban zone. Anopheles funestus Giles was the predominant
      species in both zones followed by Anopheles gambiae s.l. Giles. The densities of
      Anopheles nili Theobald and Anopheles moucheti Evans were very low. In the
      suburban zone, transmission was maintained throughout the year by An. funestus
      and An. gambiae s.l., whereas in rural zones the secondary vectors An. nili and
      An. moucheti were also involved in transmission. Humans in a suburban setting
      received one infective bite per person every 4 days, whereas in the rural area
      the infective biting rate was 4 times higher. Considering each vector, the
      observed entomological inoculation rates (EIRs) were one infective bite per
      person every 6 and 17 days for An. funestus and An. gambiae s.l., respectively,
      at Akou. At Benguia, the EIRs were one infective bite per person every 2, 3, 6,
      and 19 days for the 4 An. funestus, An. gambiae s.l., An. nili, and An. moucheti,
      respectively. The predominance of An. funestus over An. gambiae s.l. and its high
      EIR make it the most important malaria vector in this region of Haut-Ogooue.

PMID- 10342266
TI  - Laboratory evaluation of biotic and abiotic factors that may influence larvicidal
      activity of Bacillus thuringiensis serovar. israelensis against two Florida
      mosquito species.
AB  - A technical powder of Bacillus thuringiensis serovar. israelensis (B.t.i.)
      (VectoBac TP, 5,000 international toxic units [ITU]/mg), an aqueous suspension
      (VectoBac 12AS, 1,200 ITU/mg), and a granular formulation (VectoBac CG, 200
      ITU/mg) were tested in the laboratory under different biotic and abiotic,
      conditions for efficacy against larvae of saltwater (Aedes taeniorhynchus) and
      freshwater (Culex nigripalpus) mosquitoes. Second-, 3rd-, and 4th-instar larvae
      of Cx. nigripalpus were 1.3-3-fold more susceptible to both VectoBac TP and
      VectoBac 12AS than were the respective larval instars of Ae. taeniorhynchus. For
      each species, 2nd-instar larvae were several-fold more susceptible to these
      B.t.i. preparations than were the 4th instars. In test cups, larvae under lower
      densities exposed to B.t.i. concentrations sustained 5-9-fold higher mortalities
      than larvae under high-density conditions. VectoBac TP and VectoBac 12AS stayed
      in suspension for up to 24 h with similar larvicidal efficacy, which was greater
      at 32-35 degrees C than at 15-20 degrees C. At 60 degrees C maintained for 24 h,
      VectoBac 12AS was adversely affected 2-3-fold in terms of potency, but VectoBac
      TP was not affected. Significant loss of potency of both VectoBac 12AS and
      VectoBac TP occurred when exposed to 35-37 degrees C under high light intensity
      (140,000-170,000 lux) for 6 h. Increasing salinity levels from 0 (fresh water) to
      50% sea water caused gradual efficacy declines of VectoBac 12AS and VectoBac TP
      against Ae. taeniorhynchus larvae. VectoBac CG caused insignificant initial and
      residual (up to 8 days) larval mortalities of both mosquito species. This
      formulation did not release the active ingredient of B.t.i. in any significant
      mosquito larvicidal concentration in surface layers of water, and the formulation
      was more effective in shallower water. Storage of all 3 formulations under
      constant laboratory and variable field conditions for up to 8 months did not
      produce detectable potency loss of these products.

PMID- 10342267
TI  - Laboratory evaluation of selected larvicides and insect growth regulators against
      field-collected Culex quinquefasciatus larvae from urban Dhaka, Bangladesh.
AB  - Five organophosphates (OPs) (chlorpyrifos, chlorpyrifos methyl, fenthion,
      malathion, and temephos), 3 pyrethroids (bifenthrin, cypermethrin, and
      permethrin), 1 phenyl pyrazole (fipronil), 2 microbial pesticides (Bacillus
      thuringiensis serovar. israelensis [B.t.i.] and Bacillus sphaericus), and 3
      insect growth regulators (IGRs) (diflubenzuron, methoprene, and pyriproxyfen)
      were evaluated against field-collected Culex quinquefasciatus larvae from urban
      Dhaka, Bangladesh. The LC90 values of all OPs, except for temephos (LC90 = 0.0096
      ppm), were high, ranging from 0.13 ppm (fenthion) to 2.882 ppm (chlorpyrifos
      methyl). Pyrethroid LC90 values were 0.021 ppm (bifenthrin), 0.00061
      (cypermethrin), and 0.017 ppm (permethrin). Fipronil exhibited a superior
      activity with LC90 value of 0.000896 ppm. Technical powders of B.t.i. and B.
      sphaericus (VectoBac TP and VectoLex TP) were considered highly effective against
      the Cx. quinquefasciatus larvae. The IGRs also were effective with pyriproxyfen
      (LC90 = 0.0011 ppm), being 3 times and 47 times more active than diflubenzuron
      (LC90 = 0.0034 ppm) and methoprene (LC90 = 0.052 ppm), respectively. In general,
      toxicity ranking of chemicals and microbials tested was phenyl pyrazole > IGRs >
      pyrethroids > microbials > OPs.

PMID- 10342268
TI  - Comparison of isozyme patterns of Aedes aegypti populations collected from pre-
      and post-Bacillus thuringiensis israelensis treatment sites in Thailand.
AB  - Isozyme patterns of 13 field-collected populations of Aedes aegypti from Thailand
      were compared using starch gel electrophoresis. Three populations were collected
      before the Bacillus thuringiensis var. israelensis, (B.t.i.) application was
      initiated. The other 10 populations were collected after the B.t.i. treatment.
      Results revealed that the number of polymorphic loci were lower in the B.t.i.
      treated populations as compared to controls. In addition, lower genetic
      variability was found in populations collected from B.t.i. treated sites (Mae Ka
      Sa [KS] and Mae Kud Luang [KL] village). These results are most likely due to a
      genetic bottleneck produced by the B.t.i. treatment. Heterozygosity increased in
      the months following B.t.i. treatment, probably because of immigration when the
      control program was withdrawn. However, the anticipated reduction in the expected
      heterozygosity was only observed in the KS site. This may be due to preexisting
      low heterozygosity in the KL population. No fixed differences in alleles were
      detected among the 13 populations.

PMID- 10342269
TI  - Pyrethroid cross resistance spectrum among populations of Anopheles gambiae s.s.
      from Cote d'Ivoire.
AB  - Field samples of Anopheles gambiae s.s. from Cote d'Ivoire were tested with 5
      pyrethroids (cyfluthrin, lambda-cyhalothrin, alpha-cypermethrin, deltamethrin,
      permethrin), 1 pseudo-pyrethroid (etofenprox), and an organochlorine (DDT). With
      the use of World Health Organization diagnostic tests, 5 out of 6 samples were
      found cross-resistant to these insecticides. A strong decrease in knockdown
      effect and mortality was also observed when testing deltamethrin-impregnated
      nettings. With a polymerase chain reaction amplification of specific alleles
      diagnostic test, resistance was found associated with the presence of a kdr
      mutation. The strong correlation between kdr allelic frequency and resistance to
      DDT or etofenprox indicated that kdr was the main resistance factor for these 2
      insecticides. On the contrary, a lower correlation was observed between kdr
      frequency and resistance to 4 of the 5 pyrethroids tested, suggesting that
      another mechanism was also involved, likely a metabolic detoxification. These
      results point out the necessity to monitor pyrethroid resistance and the presence
      of kdr before implementation of any impregnated bed-net programs for malaria
      control.

PMID- 10342270
TI  - Responses of male and female mosquitoes to repellents in the World Health
      Organization insecticide irritability test system.
AB  - A study was conducted to compare responses of male and female Aedes aegypti
      (Linn.) and Aedes taeniorhynchus (Wiedemann) to 9 olfactory repellents in the
      World Health Organization insecticide irritability test system. An irritant
      insecticide (permethrin) and a control were included for comparison. Aedes
      aegypti exhibited significantly more takeoffs than Ae. taeniorhynchus, and female
      mosquitoes exhibited significantly more takeoffs than males. Permethrin induced
      significantly more takeoffs than the control, but olfactory repellents did not.
      Certain 2- and 3-factor interactions of test materials, species, and sexes were
      statistically significant. This study supports a previous conclusion that the
      World Health Organization test method does not measure contact repellency
      (irritancy) and olfactory repellency equally.

PMID- 10342271
TI  - Cultural control of larval mosquito production in a fallow citrus grove used for
      disposal of secondary-treated sewage effluent.
AB  - Larval mosquito production was monitored for 16 months in the furrows of a 13.4
      ha citrus grove in east-central Florida used for disposal of secondary-treated
      sewage effluent. Twenty-one species of mosquito were collected, and the 2 most
      abundant species were Culex nigripalpus and Aedes vexans. An unplanned removal of
      all brush and trees from the site during the study resulted in an overall decline
      in larval production, but species diversity remained the same.

PMID- 10342272
TI  - Predation of aquatic stages of Anopheles gambiae by the Louisiana red swamp
      crawfish (Procambarus clarkii).
AB  - Laboratory experiments lasting 1-3 days were conducted in 10-liter glass aquaria
      to evaluate the ability of the Louisiana red swamp crawfish (Procambarus clarkii
      [Decapoda: Cambaridae]) to consume the aquatic forms of mosquitoes. With
      Anopheles gambiae as the target species, significantly fewer mosquito larvae or
      pupae survived in the presence of either juvenile or adult crawfish, relative to
      conditions without crawfish, regardless of whether crawfish had alternative food
      or not. When alternative food was excluded, juvenile and adult crawfish had a
      comparable ability to consume mosquito larvae. However, when alternative food was
      available, adult crawfish consumed significantly fewer mosquito larvae than did
      juveniles. In the case of pupae, juvenile crawfish consumed significantly more
      mosquito pupae than did the adults when alternative food was excluded. No
      significant difference, relative to controls, was found in the proportion of
      mosquito pupae surviving when adult crawfish had alternative food. Results of the
      present study show that P. clarkii has the ability to consume the aquatic forms
      of anopheline mosquitoes and, therefore, may have an impact on populations of
      pathogen-transmitting mosquitoes in an area of Kenya where the crawfish has
      become common.

PMID- 10342273
TI  - Colonization of Culex nigripalpus theobald (Diptera: Culicidae) by stimulation of
      mating using males of other mosquito species.
AB  - Culex nigripalpus Theobald (Diptera: Culicidae) was recolonized successfully by
      cohabiting Aedes taeniorhynchus males or males of other mosquito species starting
      in a large outdoor cage under natural light-dark cycles and temperatures and
      ending in a 1-ft.3 cage under artificial light-dark cycles at 24 degrees C
      without added stimulation.

PMID- 10342274
TI  - Eggshell sampling: quantitative or qualitative data?
AB  - This research evaluated the use of qualitative presence/absence data compared
      with quantitative real number counts of Aedes vigilax eggshell data to obtain
      information on the spatial distribution of eggshells in several salt marsh
      vegetation types. Eggshells were extracted by subsampling and flotation, a method
      that does not recover all eggshells. The results of the analysis of
      presence/absence data were compared with those of real numbers. The general
      conclusions were similar by either method, suggesting that presence/absence data
      may be sufficient to rapidly determine eggshell distribution patterns.

PMID- 10342275
TI  - The dorsal apotome of pupae and fourth-instar larvae of Culicidae (Diptera), a
      structure of phylogenetic significance.
AB  - The development of the pupal dorsal apotome was examined and compared in
      representatives of the families Culicidae, Chaoboridae, Corethrellidae, and
      Dixidae. Illustrations of the pupal dorsal apotome for 73 species, in 25 genera,
      are provided to show the differences and similarities between taxa. The 4th
      instar larval dorsal apotome is compared and illustrated for the 3 subfamilies of
      Culicidae. The phylogenetic significance of the dorsal apotome of the pupae and
      4th-instar larvae is discussed.

PMID- 10342276
TI  - Separation of fourth-instar larvae of Culex nigripalpus from Culex salinarius in
      Florida using the spiracular apodeme.
AB  - The spiracular apodeme of the 4th-instar larvae of Culex nigripalpus and Culex
      salinarius is described and illustrated. The development of this structure
      provides an additional character for separating these 2 species.

PMID- 10342277
TI  - Variation in tarsal claw morphology and the identification of Aedes (Stegomyia)
      demeilloni/segermanae and Aedes (Stegomyia) simpsoni/bromeliae (Diptera:
      Culicidae) in South Africa.
AB  - Individuals in families of Aedes (Stegomyia) mosquitoes reared from females
      collected at Kloof, KwaZulu-Natal, were identified as Aedes demeilloni or Aedes
      segermanae or were indeterminate because tarsal claw morphology, the
      distinguishing character, varied. Similarly, Aedes (Stegomyia) simpsoni and Aedes
      (Stegomyia) bromeliae reared from ovitraps exposed at Ndumu, northern KwaZulu
      Natal, showed variation in tarsal claw morphology. Variation existed between
      tarsal claws on individual specimens, which made identification difficult at
      Ndumu, indicating that tarsal claws may not be taxonomically significant.

PMID- 10342278
TI  - Regional blood flow distribution from the proximal arterial cannula during veno
      arterial extracorporeal membrane oxygenation in neonatal dog.
AB  - Extracorporeal membrane oxygenation (ECMO) is frequently used for treatment of
      patients with severe hypoxemia due to life-threatening respiratory failure. Due
      to this hypoxemia, the myocardium of these patients is insufficiently provided
      with oxygen, and consequently their cardiac function commonly deteriorates. But
      veno-arterial (V-A) ECMO provides oxygenated blood to the coronary arteries from
      ECMO circuit insufficiently. To increase the coronary blood flow distributed from
      ECMO, we placed the arterial cannula 1 cm above the aortic valve and evaluated
      the regional blood from the proximal arterial cannula in comparison with the
      distal cannula. Eight neonatal dogs weighting 1.8-2.5 kg were supported by V-A
      ECMO. The regional blood flow from the arterial cannula was measured by injection
      of colored microspheres into ECMO circuit. The site of the arterial cannula was
      changed under fluoroscopy. The bypass flow was maintained at either 50 or 100
      ml/min/kg. We found that the coronary blood flow distributed from the proximal
      arterial cannula was significantly higher than that from the distal cannula. The
      proximal arterial cannula appears necessary to provide sufficient oxygenated
      blood to the coronary circulation during V-A ECMO. Therefore, it is expected that
      the increased cardiac function may improved, and that the survival rate of the
      patients with retarded cardiac function due to severe hypoxemia may increase by
      proximal placement of the arterial cannula during V-A ECMO.

PMID- 10342280
TI  - Influence of cumulative feed intake during early and mid-lactation on luteinizing
      hormone secretion and weaning-to-estrus interval in primiparous sows.
AB  - Twelve pregnant gilts were assigned to a completely randomized block design with
      two treatments in two blocks (2 farrowing groups). The treatments were a feeding
      amount of 6 kg or 2 kg/day provided during lactation. The lactation diet
      contained 18.6% crude protein, 1.0% lysine, and 3.27 Mcal/kg metabolizable energy
      (as-fed basis). Litters were weaned at 2100 on day 21 after farrowing. Blood
      samples for luteinizing hormone (LH) measurements were taken at 15-min intervals
      for 8 hr on day 12 of lactation, and samples for glucose and insulin were
      collected at 1-hr intervals for 3 hr on day 12. The effects of feed intake
      treatments on LH pulse frequencies (2.9 vs 0.7) and insulin concentrations (15.0
      vs 8.9 IU/mL) were found (P < 0.05) on day 12 of lactation. In regression
      analysis, greater cumulative feed intake from 1 to 12 days was associated with
      higher insulin concentrations (P = 0.04), greater LH pulse frequencies (P = 0.01)
      on day 12 of lactation, and shorter weaning-to-estrus intervals (WEI) (P = 0.03).
      Furthermore, an association between insulin concentrations and LH pulse
      frequencies was found on day 12 of lactation (P = 0.01). Using regression models
      for weaning-to-estrus interval, when each cumulative feed intake from 4 to 21
      days was used as an independent variable, the R2 values increased from 0.24 to
      0.37. These results suggest that feed intake during early and mid-lactation
      influences LH secretion as early as day 12 after farrowing, and is associated
      with shorter WEI. This research also indicates that feed intake from 4 to 12 days
      of lactation is more important than that during the first few days after
      farrowing.

PMID- 10342279
TI  - Histopathology and physiopathology of gastric mucous hyperplasia in rats heavily
      infected with Taenia taeniaeformis.
AB  - Rats heavily infected with larval Taenia taeniaeformis show hyperplasia of the
      gastric mucosa accompanied by mucous cell proliferation, increase in the level of
      intragastric pH and hypergastrinemia. Sixty one rats were divided into 2 groups
      designed as infected (36 rats) and control (25 rats) group. These rats were
      examined with time course of the infection histopathologically and
      physiopathologically, during 14-112 days postinfection (DPI). In the infected
      rats, gastric mucosal hyperplasia began to be observed at 56 DPI, and the
      structural disturbance of zymogenic units in the corpus and mucous units in the
      antrum had increased with time. However, the degree of these changes in the
      antrum was weaker than those in the corpus. Alcianblue and/or PAS-positive cells
      increased in their numbers with time, and 4 types of cells other than typical
      surface mucous cell and mucous neck cell were observed by electron-microscopy.
      However, zymogenic and parietal cells decreased in their number after 56 DPI.
      Further, the infected rats showed changes in the serum concentration of alanine
      aminotransferase, aspartate aminotransferase, blood urea nitrogen, glucose and
      total protein. Some similarities with Menetrier's disease were discussed.

PMID- 10342281
TI  - A comparative study between hypothermic and normothermic cardiopulmonary bypass
      in open heart surgery in dogs--effects on systemic hemodynamics.
AB  - Open heart surgery was performed on two groups of dogs under extracorporeal
      circulation with or without hypothermia to investigate hemodynamic changes during
      extracorporeal circulation. During hypothermic cardiopulmonary bypass (CPB),
      arterial O2 tension and postoperative blood pressure were favorably maintained,
      indicating that hypothermic extracorporeal circulation can be performed for a
      long period of time. On the other hand, during normothermic CPB, the average
      surgical duration was significantly shorter, and marked shifts in the
      concentrations of various enzymes were suppressed. However, due to reductions in
      arterial O2 tension, the length of cardiac arrest time was restricted,
      demonstrating that this method is suitable for performing extracorporeal
      circulation for CPB of relatively short duration. If circulation circuitry can be
      improved, such as through the development of a surpassing oxygenator,
      normothermic CPB would incur less stress on the body, thus making it preferential
      to hypothermic CPB in most cases.

PMID- 10342282
TI  - B220 is expressed on apoptotic thymocytes induced by X-irradiation.
AB  - CD45 is cell surface glycoprotein and expressed on all haematopoietic cells
      except mature erythrocytes and platelets. Eight isoforms of CD45 are generated by
      alternative splicing of exons 4-6. B220 including all three exons is expressed
      specifically on pan-B cell lineage. Recently, it was reported that B220 was
      expressed on apoptotic T cells induced by staphylococcal enterotoxin B (SEB). In
      the present study, we investigated the expression of B220 on murine thymocytes
      after whole-body X-irradiation. We used the forward light scattering of flow
      cytometry as a parameter of cell size, and defined two populations; FSChigh
      (normal cell size) and FSClow (correspond to apoptotic cell in size) fraction.
      B220+ cells in FSChigh fraction reached a maximum value (35%) at 18 hr after
      irradiation. In FSClow fraction, 40-60% cells were positive for B220 at any time
      points. These results suggest that B220 is expressed on thymocytes in the pre
      apoptotic stage, because B220 was expressed on not only FSClow cells but also
      FSChigh cells.

PMID- 10342283
TI  - Localization of metallothioneins-I & -II and -III in the brain of aged dog.
AB  - Localization of metallothionein (MT) -I & -II and MT-III and its significance in
      the brain aging in dogs were examined using immunohistological and molecular
      pathological techniques. MT-I & -II immunohistochemistry showed positive staining
      in the hypertrophic astrocytes throughout the aged dog brains; these MT-I & -II
      immunoreactive astrocytes were predominant in the cerebral cortex and around the
      blood vessels in the brain. These findings dominated in the brain regions with
      severe age-related morphological changes. In situ hybridization using MT-I mRNA
      riboprobes also demonstrated signals for MT-I mRNA in these hypertrophic
      astrocytes. Immunohistochemistry using a guinea pig antiserum against a synthetic
      polypeptide of canine MT-III demonstrated positive MT-III immunoreactivity
      predominantly in neurons in the Zn-rich regions such as hippocampus and
      parahippocampus. The findings were supported by in situ hybridization using MT
      III mRNA riboprobes. Both MT-III immunoreactivity and signals for MT-III mRNA
      were demonstrated in neurons in the brain regardless of the intensity of the age
      related changes. These results suggest, first, MT-I & -II may be induced in
      relation to the progress of the age-related morphological changes in the brain,
      playing an important role in the protection of the brain tissue from the toxic
      insults responsible for the brain aging, and second, MT-III may play a role in
      maintenance of Zn-related essential functions of the brain.

PMID- 10342284
TI  - Effects of delta 9-tetrahydrocannabinol and diazepam on feeding behavior in mice.
AB  - The present study examined effects of diazepam (DZP) alone or in combination with
      delta 9-tetrahydrocannabinol (THC) on feeding behavior as well as body weight in
      male ddY strain mice at 5 weeks of age. Because we saw no hyperphagic effect of
      DZP with or without THC in mice, we explored the hyperphagia elicitable by DZP.
      THC [2 (THC2) or 4 (THC4) mg/kg/day s.c.] was given daily for 7 days. For the
      last day the mice were starved and injected i.p. with DZP (2 mg/kg) 10 min prior
      to a food or maze test. Controls received vehicle injections. Feeding behavior
      was measured after giving food for 2 hr. THC4 significantly reduced body weight
      gain. DZP, with or without THC, induced hyperphagia. THC4 alone also induced
      hyperphagia that was not significantly affected by DZP. Time taken to find food
      was extended by DZP and further with THC. Both DZP and THC can therefore interact
      on food ingestion but synergize on food seeking in mice through different
      mechanisms.

PMID- 10342285
TI  - Possible involvement of K+ channel opening to the interleukin-1 beta-induced
      inhibition of vascular smooth muscle contraction.
AB  - We have previously shown that interleukin-1 beta relaxes vascular smooth muscle
      by the NO-dependent and independent mechanisms (Takizawa et al.: Eur. J.
      Pharmacol. 330: 143-150, 1997). In this study, we investigated the mechanism of
      NO-independent relaxation. Treatment of the rat aorta with interleukin-1 beta for
      24 hr inhibited the high-K+ induced contraction by decreasing cytosolic Ca2+
      level ([Ca2+]i). The relationship between [Ca2+]i and tension in intact muscle
      and the pCa-tension curves in permeabilized muscle suggested that Ca2+
      sensitivity of contractile element was not changed after the interleukin-1 beta
      treatment. After a treatment with interleukin-1 beta for 24 hr, contractile
      effects of phenylephrine (1 microM-10 microM) were markedly inhibited in the
      presence of L-NMMA (100 microM) applied to inhibit NO synthesis. A blocker of ATP
      sensitive K+ channel, glibenclamide (1 microM), partially recovered the
      interleukin-1 beta-induced inhibition. In contrast, a blocker of Ca(2+)-activated
      K+ channel, charybdotoxin (0.1 microM), was ineffective. These results suggest
      that membrane hyperpolarization due to activation of ATP-sensitive K+ channels
      may partly be responsible for the NO-independent mechanism of interleukin-1 beta
      induced inhibition of vascular smooth muscle contraction.

PMID- 10342286
TI  - Establishment and characterization of the growth and pulmonary metastasis of a
      highly lung metastasizing cell line from canine osteosarcoma in nude mice.
AB  - Highly lung metastasizing model of canine osteosarcoma in nude mice was
      established from five subcutaneous implantation cycles of lung tumor deposits.
      The selection of cells with increased metastatic properties from the parent POS
      canine osteosarcoma cell line recovered medium sized and polygonal Highly
      Metastasizing POS cells (HMPOS). The doubling time of HMPOS and POS in culture
      averaged 30 +/- 1.2 hr and 32 +/- 1.3 hr respectively, and their cell growth
      patterns in vitro were comparable to their in vivo growth patterns. HMPOS cells
      produced more tumor deposits (> 20 nodules, > 1 -mm in diameter) of various sizes
      with replacement of lung tissues at 12 weeks after implantation. POS cells
      produced fewer and smaller lung deposits (< 10 nodules, 1-mm in diameter). Tumor
      size and number of metastatic tumor deposits showed a regular association. HMPOS
      cells developed an osteoblastic type of cellular differentiation subcutaneously
      and in the lungs. HMPOS micrometastasis along the alveolar walls and blood
      vessels at 4 weeks averaged 6-7 small tumor locus. Each micrometastatic locus
      contained an average of 5-7 tumor cells, and developed a pleomorphic osteoblastic
      type of cellular differentiation. An average of 4 macrometastatic nodules could
      be seen at 6 weeks, composed of an average of 23 tumor cells, 10 nodules at 8
      weeks, 12 nodules at 10 weeks and 20 nodules at 12 weeks. These model provides an
      opportunity for the evaluation of new treatments against canine lung metastatic
      osteosarcoma in a nude mice model.

PMID- 10342287
TI  - Rumen bacteria are involved in the onset of onion-induced hemolytic anemia in
      sheep.
AB  - The mechanism of onion-induced hemolytic anemia in ruminants was investigated.
      The ether-extract obtained from the mixture of rumen fluid and onion juice
      incubated at 38.5 degrees C for 9 hr induced oxidative damage in sheep
      erythrocytes in vitro, indicating the production of certain oxidants in the
      mixture. The increase of the oxidative effect in the mixture was inhibited
      completely by the removal of rumen microorganisms and partly by treatment with
      antibiotics and by oxygen gas. The sheep fed onions (50 g/kg body weight/day) for
      15 days developed more severe Heinz body hemolytic anemia than did the sheep fed
      the equivalent amount of onions with 5 g/day ampicillin sodium salt. The results
      indicated that certain rumen bacteria appear to be involved in the onset of onion
      induced hemolytic anemia in sheep.

PMID- 10342288
TI  - Detection of canine herpesvirus DNA in the ganglionic neurons and the lymph node
      lymphocytes of latently infected dogs.
AB  - To determine the site of latent infection of canine herpesvirus (CHV), tissues
      from dogs convalescent from acute infection with CHV were examined for the
      presence of viral genome DNA by the nested polymerase chain reaction. CHV DNA was
      detected in the trigeminal ganglia and the retropharyngeal lymph nodes. In situ
      hybridization study of the tissues revealed that CHV genome persisted in the
      nuclei of ganglionic neurons and lymphocytes.

PMID- 10342289
TI  - Expression of the spermatid-specific Hsp70 antigen is conserved in mammals
      including marsupials.
AB  - The anatomical location of testes in mammals ranges from a location close to that
      observed in the embryo to a lower position usually involving a pendant scrotum.
      In scrotal mammals, the abdominal position of the cryptorchid testis, which
      elevates its temperature, is detrimental to spermatogenesis and causes
      infertility. Spermatocytes are sensitive but late spermatids are relatively
      resistant to thermal stress suggesting that the latter might be protected in some
      way. In general, most organisms express Hsp70 proteins, which play a crucial role
      in the protection of cells against thermal stress. We have found previously that
      the Hsc70t protein, a member of the Hsp70 family of proteins, is constitutively
      expressed in the late spermatids of mice. Here, we have utilized
      immunohistochemistry with anti-mouse Hsc70t antiserum to examine the expression
      of the spermatid-specific Hsp70 antigen in the testes of several mammalian
      species with different degrees of testes migration. Our data indicate that the
      antigen is conserved in the mammals including marsupials. We also examined
      whether antigens of Hsp70-related proteins were expressed in non-mammalian
      vertebrates including not only homoiothermal but also poikilothermal animals. The
      spermatid-specific Hsp70 antigens were not detectable in the testes of the
      animals examined. From results of immunohistochemistry with BRM22 monoclonal
      antibody which reacts broadly with Hsp70 family proteins, however, we revealed
      constitutive expression of antigens of Hsp70-related proteins in spermatogenic
      cells of the vertebrates. These results suggest that the expression of spermatid
      specific Hsp70 protein may be involved in the developmental pathway during
      spermiogenesis in mammals rather than in thermotolerance.

PMID- 10342290
TI  - Antisense oligonucleotide complementary to the BamHI-H gene family of Marek's
      disease virus induced growth arrest of MDCC-MSB1 cells in the S-phase.
AB  - DNA synthesis was effectively inhibited by antisense oligonucleotide A1
      complementary to the BamHI-H gene family in Marek's disease virus (MDV)-derived
      lymphoblastoid MDCC-MSB1 cells. When a cell cycle distribution of a total cell
      population was analyzed by flow cytometry, the proportion of S-phase cells
      increased in the cell populations by treatment with oligonucleotide A1.
      Approximately 60-70% of the cells appeared in the S phase for 24 and 36 hr of
      incubation in the presence of oligonucleotide A1 (20-30% in the untreated control
      cells). The inhibition of cell cycle progression by treatment with
      oligonucleotide A1 was reversible. When the cells were treated with 5 microM
      aphidicolin for 12 hr, a similar pattern of cell cycle distribution was observed
      to that obtained after treatment with oligonucleotide A1. Aphidicolin is an
      inhibitor of cellular DNA polymerase alpha, and it halts progression of the cell
      cycle at the G1/S border or early S phase. When the cells were treated with
      aphidicolin for 12 hr and subsequently incubated with oligonucleotide A1, no
      significant difference was observed in the cycle phase distribution of cells in
      the presence and absence of oligonucleotide A1. In contrast, when the cells were
      treated with oligonucleotide A1 for 12 hr and subsequently incubated with
      aphidicolin, the cell cycle did not progress from the G1/S border or early S
      phase to the next phase.

PMID- 10342291
TI  - Bovine herpes virus expressing envelope protein (E2) of bovine viral diarrhea
      virus as a vaccine candidate.
AB  - The gene encoding the envelope protein (E2) of bovine viral diarrhea virus (BVDV)
      was expressed under the thymidine kinase (TK) promoter of Korean bovine
      herpesvirus 1 (BHV-1) isolate. Thymidine kinase negative (TK-) BHV-1 recombinants
      expressing E2 of BVDV were constructed and the expression of E2 was identified by
      immunofluorescence and Western blotting. Compared to wild type BHV-1, the
      recombinant BHV-1 had a delayed cytopathogenic effect in cells. The
      immunogenicity of the recombinant BHV-1 was examined in guinea pigs and cattle.
      Although an increase in body temperature was detected for a few days, the
      inoculated cattle returned to normal temperature with the development of
      neutralizing antibodies to BVDV.

PMID- 10342292
TI  - Cold-induced mRNA expression of angiogenic factors in rat brown adipose tissue.
AB  - Brown adipose tissue (BAT) is the major site of non-shivering thermogenesis in
      rodents. Rapid angiogenesis is induced in association with adaptive hyperplasia
      of this tissue when the animal is exposed to cold. We demonstrated previously
      adrenergic activation of mRNA expression of vascular endothelial growth factor
      (VEGF) in rat BAT and its possible contribution to the cold-induced angiogenesis
      in this tissue. In the present study, we examined the effect of cold exposure on
      mRNA expression of other two angiogenic factors, VEGF-B and basic fibroblast
      growth factor (bFGF), in rats. Conventional Northern blot analysis revealed
      abundant mRNA expression of VEGF-B as well as VEGF, but not bFGF, in BAT. When
      rats were exposed to cold at 4 degrees C, the VEGF mRNA level was increased by
      2.7-fold in 1-4 hr and returned to the basal level within 24 hr. In contrast, the
      VEGF-B mRNA level did not change throughout the course of cold exposure. A
      significant expression of bFGF mRNA was detected in BAT by reverse transcription
      polymerase chain reaction (RT-PCR). To evaluate the tissue bFGF mRNA level
      quantitatively, a competitive RT-PCR method was developed using a shorter RNA
      fragment as a competitor. The bFGF mRNA level in BAT was found to increase by 2.3
      fold in 4 hr and decreased to the basal level within 24 hr after cold exposure.
      These results suggest that cold exposure leads to induce VEGF and bFGF rapidly
      and transiently in BAT, which in turn stimulate the proliferation of vascular
      endothelial cells in this tissue.

PMID- 10342293
TI  - A new quantitative method for rabies virus by detection of nucleoprotein in
      virion using ELISA.
AB  - We have developed a new quantitative method for rabies virus (RV) detection using
      enzyme-linked immunosorbent assay (ELISA). The method named N-ELISA was based on
      the quantitation of nucleoprotein (N) in RV virions captured by RV-specific
      polyclonal antibodies on an ELISA plate. Both infective and defective interfering
      (DI) particles of RV could be detected by this method. When viruses were
      propagated in a medium of pH 7.4 adjusted with 7% NaHCO3, N-ELISA could detect
      them with titers of more than 10(6) pfu/ml, though the result did not correlate
      highly with that of the infectivity assay. The reason for this was considered to
      be that RVs included spikeless and damaged particles which were produced under
      conditions of low or high pH. However, in the time course of virus yield, titers
      of N-ELISA correlated well with those of the infectivity assay.

PMID- 10342294
TI  - Cloning and mapping of three pig acyl-CoA dehydrogenase genes.
AB  - To investigate the structure of porcine genes involved in the beta-oxidation of
      fatty acid, we isolated the short-chain acyl-CoA dehydrogenase (SCAD), medium
      chain acyl-CoA dehydrogenase (MCAD), and long-chain acyl-CoA dehydrogenase (LCAD)
      genes from the pig. The cDNA of SCAD, MCAD and LCAD genes were 1899 bp, 1835 bp
      1835 bp and 1704 bp long and coded for 413-aa, 422-aa and 430-aa precursor
      proteins, respectively. Three genes, SCAD, MCAD and LCAD were mapped to 14p16.2
      23.2, 6q32.4-33, and 15q24.2-26.3, respectively.

PMID- 10342295
TI  - Nasal nocardiosis in a calf.
AB  - Nasal nocardiosis was found in a female Japanese Black calf, 11 months of age.
      Macroscopically, the posterior half of the left nasal passage was completely
      obstructed by yellowish brown caseous substance and the mucosa was irregularly
      thickened. In the brain, a few soft brown foci were present in the olfactory bulb
      and frontal lobe. Microscopically, there were closely packed granulomas in the
      nasal cavity and brain. The lesions were characterized by a center of cellular
      debris surrounded by epithelioid macrophages, neutrophils, lymphocytes and
      multinucleated giant cells of the Langhans type. Special stains revealed the
      presence of a large number of filamentous branching gram-positive, partially acid
      fast organisms in these epithelioid cells and giant cells, and in cellular
      debris.

PMID- 10342296
TI  - Abscess of bovine brain stem diagnosed by contrast MRI examinations.
AB  - A 3-month-old, female Japanese Black calf that showed signs of neurological
      dysfunction soon after birth was twice examined by magnetic resonance imaging
      (MRI). Survey MR images showed changes in a hydrocephalus from mild to severe and
      the existence of a mass above the brain stem that could be distinguished from the
      surrounding cerebral parenchyma. Contrast MRI examinations using Gd-DO3A-butriol
      showed the mass to have a doughnut-like form. As the mass changed, the clinical
      signs aggravated. We diagnosed a brain stem abscess, which we confirmed
      pathologically. To our knowledge there are no other reports of the use of
      contrast MRI to examine cattle.

PMID- 10342297
TI  - Sequence comparison of the VP2 variable region of infectious bursal disease virus
      isolates from Vietnam.
AB  - The variable region in the VP2 gene of twenty-three infectious bursal disease
      virus (IBDV) isolates, collected in Vietnam in 1997 and 1998, was amplified as
      cDNA by using the reverse transcription-polymerase chain reaction and sequenced.
      Analysis of amino acid substitutions and phylogenetic relationships of the
      deduced amino acid sequences (residues 206-350) showed that the nineteen
      Vietnamese vv IBDVs clustered with the European vv IBDVs, Japanese vv IBDVs and
      Chinese vv strains, and that the four vietnamese virulent strains were closely
      related to European virulent strain 52/70. These results suggest that Vietnamese
      vv IBDVs, European vv IBDVs, Japanese vv IBDVs and Chinese vv strains have the
      same origin.

PMID- 10342298
TI  - Histological characteristics of canine deciduoma induced by intrauterine
      inoculation of E. coli suspension.
AB  - Canine deciduoma could be induced in the diestrous uterus by an intrauterine
      inoculation of a culture suspension of E. coli originally isolated from naturally
      occurring canine pyometra. These deciduomas had the same histological findings as
      those of naturally occurring canine pyometra with so called "Swiss cheese
      endometrium". This suggests a possibility that the canine pyometra is a kind of
      naturally occurring decidual reaction (deciduoma) induced by one of several
      triggers such as bacterial infection.

PMID- 10342299
TI  - Epidemiological analysis of Salmonella enteritidis from human outbreaks by pulsed
      field gel electrophoresis.
AB  - To determine the extent of genetic diversity among isolates of Salmonella
      enteritidis obtained from outbreaks in Fukuoka Prefecture, Japan, from 1989 to
      1994, we analyzed a total of 55 isolates of S. enteritidis obtained from 13
      distinct outbreaks with pulsed-field gel electrophoresis. These isolates showed
      three different patterns in pulsed-field profile with Bln I digestion. The groups
      A, B and C consisted of three outbreaks isolates (Dice coefficient, F = 1), of
      seven outbreaks (F = 0.56-0.94) and of three outbreaks (F = 0.65-0.78),
      respectively. This result suggests that a few limited clonal lines of S.
      enteritidis were successively causing outbreaks in this area from 1989 to 1994.

PMID- 10342300
TI  - Setaria digitata in cattle of Thailand identified by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis.
AB  - Adult Thai Setaria worms collected from cattle which were bred, housed and
      slaughtered in Thailand were morphologically identified as Setaria digitata.
      Furthermore, in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS
      PAGE) adult Thai S. digitata had the same protein profiles as adult Japanese S.
      digitata, but did not possess the protein with a molecular size of 69 kDa which
      was confirmed in adult S. marshalli. In addition, there were no differences in
      the protein profiles between male and female S. digitata. In point of the
      distribution pattern of the proteins ranging from 73 to 64 kDa revealed by 2D
      PAGE, there were no differences between Thai and Japanese S. digitata, and
      between male and female worms of the species.

PMID- 10342301
TI  - Women, writers, sufferers: Anne Conway and An Collins.

PMID- 10342302
TI  - Voltaire's complaint: illness and eroticism in La correspondance.

PMID- 10342303
TI  - Ellen Emerson and the tubercular muse.

PMID- 10342304
TI  - Seized by the muse: Dostoevsky's convulsive poetics in The idiot.

PMID- 10342305
TI  - Conrad Aiken and the seduction of suicide.

PMID- 10342306
TI  - A thirst for reverie: alcohol, despair, and dream space in Elizabeth Bishop's
      poetry.

PMID- 10342307
TI  - "Blood don't lie": the diseased family in Flannery O'Connor's Everything that
      rises must converge.

PMID- 10342308
TI  - Writing, time, and AIDS in the works of Herve Guibert.

PMID- 10342309
TI  - Potential for improved therapeutic index of FK506 in liposomal formulation
      demonstrated in a mouse cardiac allograft model.
AB  - BACKGROUND: FK506 is a potent immunosuppressant that has improved clinical
      outcomes in kidney and liver transplantation both as a primary and as a rescue
      immunosuppressive agent. Despite these benefits, the potential value of FK506 is
      limited by toxic side effects that result in a narrow therapeutic index. By
      encapsulating the active drug within liposomes (LipoFK506), a new formulation has
      been developed that might improve this therapeutic index. METHODS: The
      biodistribution of tritiated-FK506 administered i.v. showed that the drug
      remained associated with the liposomal carrier in vivo, and that its tissue
      distribution was increased in heart and spleen compared to nonliposomal FK506.
      The immunosuppressive efficacy of lipoFK506 compared with conventional FK506
      formulation was tested in vivo. CBA (H2k) mice were engrafted with BALB/c (H2d)
      mouse hearts with daily immunosuppression using either 1 mg/kg FK506, or 1 mg/kg
      LipoFK506, from day 0 to 14. RESULTS: At day 7 the blood trough level of FK506 in
      the FK506 group was 10-fold higher (25 microg/L) than that in the LipoFK506
      group. In both groups the median heart allograft survival was similar at around
      26 days. The possibility that FK506, or LipoFK506, might influence antibody
      mediated tolerogenesis was addressed in the same model: neither formulation
      prevented tolerance induction by CD4 and CD8 blockade. CONCLUSION: LipoFK506 is a
      novel formulation of FK506 that is efficacious at low blood trough FK506 levels.
      This property has a direct potential benefit for clinical organ transplantation.

PMID- 10342310
TI  - Preventing acute rejection, Epstein-Barr virus infection, and posttransplant
      lymphoproliferative disorders after kidney transplantation: use of aciclovir and
      mycophenolate mofetil in a steroid-free immunosuppressive protocol.
AB  - BACKGROUND: A widely held view is that any increase in the potency of an
      immunosuppressive agent will lead to an increase in infection and malignancy,
      such as life-threatening Epstein-Barr virus (EBV) induced posttransplant
      lymphoproliferative disorders (PTLD). We tested this paradigm by studying the
      effect of adding mofetil to a steroid-free protocol under cover of high-dose
      aciclovir prophylaxis on the number of acute rejections, EBV infections and PTLDs
      after kidney transplantation. METHODS: EBV serology was performed in 267
      consecutive renal transplantations (1990-1997). All were treated with
      cyclosporine with an initial 10-day antilymphocyte globulin course, supplemented
      from September 1995 with MMF. In 208 consecutive transplantations after June 1992
      aciclovir 3200 mg/day was given for 3 months posttransplantation. RESULTS: After
      an observation period of up to 7 years we found that: (1) primary or reactivated
      EBV infection (PREBV) was correlated to acute rejection (treated with OKT3;
      P<0.00005) and to the incidence of PTLD (P=0.03; P=0.01, if Hodgkin's disease is
      included); (2) aciclovir protected against PREBV (P<0.00005) and (3) adding
      mofetil to the immunosuppressive protocol reduced PREBV further (P=0.0001), (4)
      in 78 transplantations treated with cyclosporine/antilymphocyte globulin/mofetil
      we observed only 10 acute rejections (P=0.0001), 10 PREBVs (P<0.00005), and no
      PTLDs compared with the cyclosporine/antilymphocyte globulin group (P=0.04).
      CONCLUSIONS: Supplemental immunosuppression with mofetil protects against acute
      rejection. In combination with aciclovir, there is also a reduction in the number
      of PREBVs, apparently as a result of both direct viral prophylaxis and better
      rejection control, and in the incidence of EBV-induced PTLD.

PMID- 10342311
TI  - Analysis of the complications of the piggy-back technique in 1,112 liver
      transplants.
AB  - BACKGROUND: The "piggy-back" technique has gained acceptance in adult orthotopic
      liver transplantation during the last few years, especially in European
      countries. At the moment, however, there is controversy over advantages or
      specific complications (suprahepatic thrombosis or narrowing, etc.) related to
      this surgical technique. The aim of this study is to know of the immediate per
      and postoperative morbidity and mortality rates in 1112 orthotopic liver
      transplantations performed with a vena cava preservation technique. METHODS: All
      liver transplant units in Spain were sent a questionnaire on retrohepatic vena
      cava preservation during orthotopic liver transplantation. The number of
      orthotopic liver transplantations that had been performed in the seven centers
      that answered the questionnaire, because the beginning of the program, was 1674,
      with the vena cava preservation technique used in 1112. RESULTS: Twenty-eight
      patients (2.5%) had intraoperative complications related to the vena cava
      preservation technique, which were treated during the operation. Eleven patients
      (1%) had early postoperative complications (first week), the most frequent (nine
      cases) being an acute Budd-Chiari syndrome in the first 48 hr. Three patients
      developed symptoms of massive ascites between 2 and 3 months (late postoperative
      complications), with patency of the retrohepatic cava verified by cavography. A
      hemodynamic study revealed a hyperpressure at the suprahepatic veins. This
      chronic Budd-Chiari syndrome was controlled in all patients with diuretics. Only
      six patients (0.5%) died as a result of complications related to the "piggy-back"
      technique. These complications were more frequent when venous reconstruction was
      done using two suprahepatic veins than when the three veins were used (P<0.001).
      CONCLUSIONS: The vena cava preservation technique can be used routinely in
      orthotopic liver transplantation because it is safe and efficient and involves
      few surgical complications especially if for venous reconstruction we use the
      patch obtained by joining the three suprahepatic veins.

PMID- 10342312
TI  - Increased fracture rate in diabetes mellitus and females after renal
      transplantation.
AB  - BACKGROUND: Bone disease and fractures after organ transplantation pose severe
      clinical problems. About 20% of renal transplant patients have type 1 diabetes
      (IDDM). However, data are scarce in the literature about the occurrence of
      spontaneous fractures in IDDM patients posttransplantation. METHODS: In this
      cross-sectional study using a questionnaire and hospital records the prevalence
      of symptomatic bone disease was investigated in 193 renal transplanted patients
      with functioning renal grafts 6 months to 23 years after the transplantation.
      RESULTS: The frequency of IDDM was 18%. In the total group the rate of
      osteoporotic fractures posttransplantation was 17%, and the majority of fractures
      occurred within the first 3 years after the transplantation. A high rate of
      fractures, 40%, was noted in the diabetes group (P<0.001), compared with 11% in
      the nondiabetes group. Fractures seen in IDDM were often multiple and located
      mostly in the appendicular skeleton, i.e., in ankles and feet. Female gender was
      also associated with an elevated fracture rate, 23% (P<0.05). CONCLUSION: An
      increased incidence of osteoporotic fractures after renal transplantation was
      found in diabetic and female patients. The mechanism behind bone fragility in
      IDDM is multifactorial and despite a restored renal function bone disease may
      progress, and is probably enhanced by the immunosuppressive treatment.

PMID- 10342313
TI  - Predictors of renal transplant histology at three months.
AB  - BACKGROUND: The quality of a damaged kidney, the complexity of the surgery, and
      the events in the first weeks after transplantation, such as delayed graft
      function (DGF) and acute rejection, may influence its histological appearance and
      long-term survival. The aim of this study was to evaluate the importance of these
      factors in predicting renal allograft histology at 3 months. METHODS:
      Prospective, protocol kidney biopsy specimens (n=112), obtained 3 months after
      transplantation, were scored for chronic damage by the Banff schema and evaluated
      by multivariate analysis against donor factors, implantation histology, prior
      recipient sensitization, ischemia, perioperative factors, and subsequent clinical
      events, such as DGF and acute rejection. RESULTS: Adequate samples were obtained
      in 102 of 112 biopsies and classified as chronic Banff grade 0 (n=22), grade I
      (n=56), grade II (n=23), or grade III (n=1). Acute Banff scores were minimal. DGF
      occurred in 49% and was the strongest predictor of tubulointerstitial damage at 3
      months. DGF correlated with acute tubular necrosis on the implantation biopsy
      specimen and with the number of acute rejection episodes; DGF also correlated
      with the Banff grades of chronic glomerulitis, chronic interstitial fibrosis, and
      tubular atrophy scores (P<0.05-0.001) in the 3-month biopsy specimen. By
      multivariate analysis, chronic tubular atrophy was independently predicted by the
      presence of vascular disease in the donor biopsy specimen, DGF, and vascular
      rejection occurring within the first 3 months (P<0.05-0.001). Chronic
      interstitial fibrosis was unrelated to fibrosis in the donor biopsy specimen but
      was independently predicted by DGF, donor age, and vascular rejection (P<0.05
      0.001). Vascular disease in the donor biopsy specimen correlated with chronic
      intimal thickening (r=0.36, P<0.01) and arteriolar hyalinosis score (r=0.54,
      P<0.001) on the 3-month biopsy specimen. Banff chronic intimal vascular
      thickening was independently predicted by donor biopsy specimen vascular grade,
      prior vascular rejection episodes, and renal cold ischemia time (P<0.05-0.01).
      There were no correlates with the mean cyclosporine (CsA) dose, blood levels,
      diagnosis of CsA toxicity, or cellular rejection within the first 3 months.
      CONCLUSIONS: This study has demonstrated that the quality of the donor organ at
      implantation was strongly predictive of subsequent renal histology in grafts
      functioning at 3 months. Vascular rejection and DGF had a significant long-term
      effect on graft damage, but cellular rejection and simple measures of CsA
      exposure did not.

PMID- 10342314
TI  - Carbohydrate deficient transferrin for detection of alcohol relapse after
      orthotopic liver transplantation for alcoholic cirrhosis.
AB  - Early diagnosis and monitoring of an alcohol relapse in patients after orthotopic
      liver transplantation for alcoholic cirrhosis is of importance for the long-term
      outcome. A prospective study of 97 patients who underwent orthotopic liver
      transplant for alcoholic cirrhosis has been performed. All of the recipients
      considered for analysis survived for at least 3 months and were under the care of
      one specialist psychologist. Mean follow-up amounted to 48.5+/-1.4 months. The
      rates of alcohol relapse at 1 and 3 years after orthotopic liver transplant were
      6 and 9%, respectively. Carbohydrate-deficient transferrin is a biological marker
      for alcohol abuse independently of liver disease and has been used for the first
      time ever in liver graft recipients. A total of 830 values were included
      prospectively in the study population. Detection of alcohol relapse had a
      sensitivity of 92% and a specificity of 98%. Changes in carbohydrate-deficient
      transferrin levels indicated clandestine and sporadic drinking after
      transplantation. Furthermore, clinical events were not found to influence
      carbohydrate-deficient transferrin, either in patients with or without alcoholic
      relapse. In our opinion, carbohydrate-deficient transferrin is a useful screening
      marker for alcohol relapse in patients after orthotopic liver transplant for
      alcoholic cirrhosis, to select those patients who need special attention from the
      psychologist.

PMID- 10342315
TI  - Human herpes virus-8 and other risk factors for Kaposi's sarcoma in kidney
      transplant recipients. Groupe Cooperatif de Transplantation d' Ile de France
      (GCIF).
AB  - BACKGROUND: The exact reasons for the high incidence of Kaposi's sarcoma (KS)
      after kidney transplantation are still unknown. Immunosuppression is classically
      considered as the main risk factor, but the relative risk contributed by the
      patient's geographic origin and by human herpes virus (HHV)-8 infection still has
      to be determined. METHODS: We carried out a retrospective and a prospective study
      among kidney transplant recipients (TP) to identify the risk factors for
      posttransplantation KS. Each of 30 KS patients was matched with two controls to
      investigate the association with geographic origin, immunosuppressive regimen,
      HHV-8 antibodies before and after transplantation, and other infections. Among TP
      with new onset of KS, we prospectively evaluated HHV-8 serology and viremia in
      response to decreased immunosuppression. RESULTS: African and Middle East
      origins, past infection with hepatitis B, hemoglobin level <12 g/dl, lymphocyte
      count <750/mm3 at the time of diagnosis and initial use of polyclonal
      antilymphocyte sera were risk factors for KS. After multivariate analysis, origin
      in Africa or Middle East and use of antilymphocyte sera for induction remained as
      independent risk factors. Sixty-eight percent (17/25) of TP with HHV-8 antibodies
      before or after transplantation developed KS compared with 3% (1/33) of
      seronegative TP (P<0.00001). HHV-8 DNA was detectable in seven of nine peripheral
      blood mononuclear cells (PBMC) and in six of six KS lesions at diagnosis; it
      became negative in PBMC in three of five patients in parallel with tumor
      regression. CONCLUSION: African and Middle East geographic origins, HHV-8
      infection before and after kidney transplantation, and initial use of polyclonal
      antilymphocyte sera were independent risk factors for KS. The presence of HHV-8
      antibodies before or after transplantation was highly predictive of the emergence
      of posttransplantation KS and conferred a 28-fold increased risk of KS (odds
      ratio=28.4; 95% confidence interval: 4.9-279). Detection of HHV-8 DNA within PBMC
      and KS lesions seems related to tumor burden and evolution.

PMID- 10342316
TI  - Enhanced antitumor effects of bone marrow transplantation in combination with
      fibroblast-mediated IL-2 and IL-3 gene therapy.
AB  - BACKGROUND: Bone marrow transplantation (BMT) and gene therapy are potent
      approaches to the recovery of bone marrow depression and induction of antitumor
      immunity after chemotherapy for the treatment of malignancies. In the present
      study, enhanced antitumor effect of BMT in combination with fibroblast-mediated
      interleukin (IL)-2 and IL-3 gene therapy was observed in tumor-bearing mice after
      chemotherapy. METHODS: BALB/c mice were inoculated s.c. with J558L plasmacytoma
      cells and injected i.p. with cyclophosphamide 300 mg/kg 3 days later. 24 hours
      after chemotherapy syngeneic bone marrow cells in combination with NIH3T3
      fibroblast cells engineered to produce IL-2 (NIH3T3-IL-2) and/or NIH3T3 cells
      engineered to produce IL-3 (NIH3T3-IL-3) were implanted into the tumor-bearing
      mice. RESULTS: BMT in combination with implantation of either NIH3T3-IL-2 or
      NIH3T3-IL-3 cells exerted significant inhibition on the growth of J558L tumors
      and prolonged the survival period of the tumor-bearing mice as compared with the
      treatments with Hanks solution, BMT alone, or BMT plus implantation of NIH3T3
      cells transduced with Neo gene. Synergistic antitumor effect was observed in mice
      after combined BMT and cytokine gene therapy. The cytotoxicities of natural
      killer cells, cytotoxic T lymphocytes, and macrophages in mice increased markedly
      after the combined treatment. Recovery of CFU-GM, CFU-MK and CFU-E formation in
      mice after combined therapy was accelerated obviously in mice after combined
      therapy. CONCLUSIONS: BMT in combination with fibroblast-mediated IL-2 and IL-3
      gene therapy elicited augmented antitumor effects synergistically in tumor
      bearing mice after chemotherapy mainly through induction of antitumor immune
      response and accelerated recovery of hematopoiesis.

PMID- 10342317
TI  - Transfer of porcine endogenous retrovirus across hollow fiber membranes:
      significance to a bioartificial liver.
AB  - BACKGROUND: A porcine endogenous retrovirus (PERV) capable of infecting human
      cells has been identified. This study was designed to determine whether hollow
      fiber membranes, such as those used in a bioartificial liver, block the transfer
      of PERV. METHODS: Three hollow fiber cartridges (HFCs) were studied in duplicate:
      cellulose fibers with 70 kD nominal molecular weight cut-off (MWCO), polysulfone
      fibers with 400 kD MWCO, and mixed cellulose fibers with 200 nm porosity. PK15
      cells (porcine kidney cell line), known to produce PERV, were grown in the
      intraluminal compartment of HFCs fiber cartridges. Samples of medium were
      collected from both intraluminal and extraluminal compartments of the HFCs fiber
      cartridge during 14 days of culture. Samples were screened for PERV using reverse
      transcription polymerase chain reaction. All positive samples were tested for
      PERV infectivity in human 293 cells. RESULTS: PERV was detected in all samples
      from the intraluminal space and all intraluminal samples seemed to infect 293
      cells. All extraluminal samples from the fibers of 200 nm porosity tested
      positive for PERV. Detection of PERV in the extraluminal space was delayed by
      fibers of 400 kD MWCO and 70 kD MWCO until at least day 3 and day 7,
      respectively, after inoculation of PK15 cells. Positive extraluminal samples from
      fibers of 400 kD MWCO and 70 kD MWCO did not infect 293 cells. CONCLUSION: Pore
      size, membrane composition, and duration of exposure influenced the transfer of
      PERV across HFCs. Some HFCs decrease the risk of viral exposure to patients
      during bioartificial liver therapy.

PMID- 10342319
TI  - Cyclosporine induces the expression of the cyclin inhibitor p21.
AB  - BACKGROUND: Current immunosuppression strategies involve inhibition of T cell
      activation and/or lymphocyte proliferation. During T cell cycle
      progression/activation, the expression of cyclins and cyclin dependent kinases is
      increased. In this study, we examined whether cyclosporine A (CsA) suppresses the
      cell cycle progression through the induction of the cell cycle inhibitor p21.
      Because CsA induces the expression of transforming growth factor (TGF)-beta, and
      TGF-beta induces p21 expression, we also determined whether CsA's induction of
      p21 is dependent on or independent of TGF-beta. METHOD: Using reverse
      transcription assisted polymerase chain reaction and western blot analysis, we
      studied the induction of p21 mRNA and protein in human T cells and A-549 cells
      (human lung adenocarcinoma cells) by CsA. The stimulation of p21 promoter
      activity was studied by luciferase assay using p21-luc, chimeric plasmid DNA
      containing a p21 promoter segment, and luciferase reporter gene. The dependence
      of CsA's induction of p21 was studied using anti-TGF-beta antibody and TGF-beta
      altered A-549 cells. RESULTS: CsA induced p21 mRNA protein expression and
      stimulated its promoter activity in lymphoid (T cells) and nonlymphoid (human
      lung adenocarcinoma, A-549 cells).CsA's induction of p21 was inhibited both by a
      neutralizing anti-TGF-beta antibody and in TGF-beta-altered A-549 cells,
      consistent with its effects on p21 requiring TGF-beta. CONCLUSION: These data
      support the hypothesis that at least one component of CsA's antiproliferative
      effects may occur through the induction of p21 and that this induction is
      dependent on TGF-beta. Should p21 induction be a viable immunosuppressive
      strategy, inducing this molecule independent from the fibrogenic cytokine TGF
      beta might reduce the toxicity associated with current immunosuppression.

PMID- 10342318
TI  - Exploitation of the continuum between early ischemia/reperfusion injury and host
      alloresponsiveness: indefinite kidney allograft survival by treatment with a
      soluble P-selectin ligand and low-dose cyclosporine in combination.
AB  - BACKGROUND: We have shown previously that sPSGL, a soluble glycoprotein ligand
      for P and E selectins, reduces the events associated with ischemia/reperfusion
      injury of the kidney. In the present study, we have attempted to modulate
      differentially early inflammatory influences and later host alloresponsiveness in
      an LBNF1-Lewis renal graft model by treatment with sPSGL in combination with a
      marginally effective dose of cyclosporine (CsA). METHODS: Four experimental
      groups were studied: group 1=control animals receiving vehicle only; group
      2=sPSGL monotherapy alone; group 3=low-dose CsA; group 4=sPSGL plus low-dose CsA.
      Grafts were removed at 1, 3, 5, and 7 days (n=3/time point) and assessed by
      histology, immunohistology, and reverse transcriptase-polymerase chain reaction.
      Long-surviving grafts in recipients of groups 3 and 4 were followed functionally
      for more than 28 weeks. RESULTS: Graft function was prolonged indefinitely in
      recipients in group 4, all of which survived for more than 200 days. In contrast,
      survival of animals in groups 1 and 2 was not increased substantially, whereas
      only 4 of 17 animals in group 3 (23.5%) survived more than 24 days (P<0.01). Five
      days after engraftment, necrosis was relatively minimal in group 4 organs but
      pronounced in those of the other groups. By immunohistology, numbers of
      infiltrating CD4+ and CD8+ T cells and ED1+ macrophages were significantly
      diminished in group 4 allografts compared with those of the other groups. Serial
      assessment of chemokine and cytokine mRNA expression confirmed these findings.
      The long-term effects of CsA treatment alone were compared with those of sPSGL in
      combination with CsA. Proteinuria remained virtually absent in group 4
      recipients. Morphologically, the few long-surviving grafts in group 3 showed
      signs of chronic rejection; those in group 4 remained relatively normal.
      CONCLUSIONS: Although treatment with sPSGL alone showed no apparent influence on
      the acutely rejecting transplants, at least by the parameters examined in this
      study, it produced indefinite survival of kidney grafts when used in combination
      with low-dose CsA. The data support the influence of early nonspecific injury on
      later immunological rejection.

PMID- 10342320
TI  - Chronopharmacology for deoxyspergualin: toxicity and efficacy in the rat.
AB  - BACKGROUND: Deoxyspergualin (DSG), a potent immunosuppressive drug, has been
      clinically used as a rescue therapy for acute graft rejection. However, DSG has
      severe adverse effects that limits its use. Here, we examined the optimized
      therapeutic protocol for DSG using chronopharmacological profiles of it. METHODS:
      First, a dosing time-dependent difference in the toxicity and efficacy of DSG was
      determined using a heterotopic heart transplantation model. Second,
      chronokinetics of DSG were examined to reveal the mechanism for dosing time
      dependent differences in the effect. RESULTS: In rats treated with DSG at the
      active period, bone marrow suppression and damage of small intestine were
      significantly severe. However, no significant difference was found in cardiac
      allograft survival and pharmacokinetics according to the timing of drug
      administration. CONCLUSIONS: The toxicity of DSG varied with the dosing time,
      whereas its efficacy did not. The chronopharmacological approach may provide
      merits for immunosuppressive therapy with DSG in clinical organ transplantation.

PMID- 10342321
TI  - Early detection of human cytomegalovirus infection after kidney transplantation
      by nucleic acid sequence-based amplification.
AB  - BACKGROUND: The early detection of human cytomegalovirus infection after organ
      transplantation is a prerequisite for effective antiviral therapy. We evaluated
      the diagnostic value of monitoring the viral immediate-early (IE) 1 mRNA
      expression in blood leukocytes by nucleic acid sequence-based amplification
      (NASBA). METHODS: Nucleic acids were isolated from 489 blood samples collected
      from 42 kidney transplant recipients and subjected to amplification by IE NASBA.
      The IE NASBA results were compared to those from pp67 NASBA, pp65 antigenemia,
      cell culture (DEAFF and CPE), and serology. RESULTS: IE NASBA proved to be the
      most sensitive assay which detected the onset of both primary and secondary
      cytomegalovirus infection significantly earlier than the other assays.
      CONCLUSIONS: The early detection of cytomegalovirus infection with IE NASBA would
      enable the start of effective antiviral therapy at an early state of infection to
      prevent cytomegalovirus disease in patients at risk.

PMID- 10342322
TI  - Outcome of long-term ribavirin therapy for recurrent hepatitis C after liver
      transplantation.
AB  - Ribavirin therapy was initiated at a median of 181 days after liver
      transplantation in 18 patients with persistent elevation of alanine
      aminotransferase values and biopsy-proven hepatitis, and continued for 23 months
      (12-44 months). All patients had a prompt biochemical response, with alanine
      aminotransferase decreasing by 69%; complete normalization occurred in 5 (28%).
      Serum hepatitis C virus RNA levels did not change during therapy. Liver biopsies
      obtained after 17 months (9-38 months) of therapy showed no improvement in
      necroinflammation. However, worsening of fibrosis occurred in 12 patients; and
      cirrhosis developed in 5 patients (28%), with 3 patients progressing to graft
      failure. Biopsies from 27 untreated patients who did not fulfill treatment
      criteria (median follow-up, 38 months) and 4 patients who received 3 months of
      ribavirin (44 months) showed cirrhosis in 11 and 75%, respectively. Patient and
      graft survival rates for treated and untreated patients were similar. Although
      ribavirin improves alanine aminotransferase, it does not prevent the development
      or progression of fibrosis in patients with recurrent hepatitis C virus.

PMID- 10342323
TI  - A direct method for the calculation of alloreactive CD4+ T cell precursor
      frequency.
AB  - BACKGROUND: Direct measurement of the precursor frequency of alloreactive CD4+ T
      cells has been impossible due to the lack of a specific means of determining the
      absolute number of daughter cells generated with each division in a repertoire of
      stimulated T cells. METHODS: Responder lymphocytes were fluorescently labeled and
      adoptively transferred into irradiated allogeneic stimulator mice or incubated in
      vitro with irradiated stimulator splenocytes. After a 65- to 70-hr stimulation
      period, responder cells were analyzed by flow cytometry. RESULTS: The precursor
      frequency of dividing CD4+ T cells was determined both in vivo and in vitro. The
      observed number of alloreactive daughter cells generated with each round of
      division was used to calculate the frequency of alloantigen-specific CD4+ T
      cells. CONCLUSIONS: A novel method for the direct calculation of the frequency of
      alloreactive CD4+ T cells is described. This technique allows the determination
      of changes in the frequency of alloreactive T cells that might underlie tolerance
      to alloantigens.

PMID- 10342324
TI  - Contribution of CD40-CD154-mediated costimulation to an alloresponse in vivo.
AB  - BACKGROUND: Costimulation through CD40-CD154 plays an important role in T-cell
      activation. Although systemic administration of anti-CD154 antibody prevents or
      delays rejection of organ allografts in animal models, the molecular mechanisms
      responsible for this effect are not well defined. METHODS: We have previously
      demonstrated that priming of mice (H2d) with CD40-/- but not with wildtype naive
      B cells (H2b) leads to alloantigen-specific T-cell hyporesponsiveness in vitro.
      In the present study, we investigated whether such priming modifies allograft
      rejection in a major histocompatibility complex-mismatched murine cardiac
      transplantation model. RESULTS: Priming of hosts with donor-specific CD40-/- B
      cells delayed rejection of subsequently transplanted wild-type cardiac allografts
      by 8.0 days (P<0.001). The lack of CD40 on the cardiac graft delayed rejection in
      unprimed or primed hosts by 3-5 days. Prolongation of graft survival correlated
      with the failure of infused CD40-/- B cells to express B7.2 and ICAM-1 in vivo.
      CONCLUSIONS: Our data suggest that CD40-CD154 costimulation contributes to T cell
      priming to alloantigens in vivo and to a second set rejection phase in which
      donor antigens are presented to primed T cells.

PMID- 10342326
TI  - Comment on "Efficacy of azithromycin in the treatment of cyclosporine-induced
      gingival hyperplasia in renal transplant recipients" by Nash and Zaltzman.

PMID- 10342325
TI  - Successful use of lamivudine for severe acute hepatitis B virus infection in a
      cardiac transplant recipient.

PMID- 10342327
TI  - The IX Biennial Meeting of the International Society for Free Radical Research,
      Sao Paulo, Brazil, September 7-11, 1998.

PMID- 10342328
TI  - Oxysterols in cap and core of human advanced atherosclerotic lesions.
AB  - OBJECTIVE: Different parts of the advanced atherosclerotic lesion have
      characteristic differences in lipid content, but the distribution of lipid
      oxidation products has not been reported. This study provides novel data on
      oxysterol and hydroxyoctadecadienoic acids quantification in core versus cap. It
      compares the lipid composition of core and cap to assess the topographical
      distribution of evidence of lipid oxidation. METHODS: Lipids and oxidised lipids
      were analysed by gas chromatography (GC) and GC-mass spectrometry (GC-MS) in
      samples of human atheromatous lipid core and fibrous cap of individual advanced
      atherosclerotic plaques (Stary, Type V) in necropsy samples. RESULTS: The total
      lipid was of course massively greater in the core than in the cap. The oxidation
      products, cholest-5-en-3beta,26-diol (26-OH-CHOL) and cholest-5-en-3beta,7beta
      diol (7beta-OH-CHOL) were detected in all the samples. 26-OH-CHOL was more
      abundant in the core than in the cap when related both to wet weight and to
      cholesterol. 7Beta-OH-CHOL levels were significantly higher in the core than in
      the cap when related to wet weight but not when related to cholesterol. Because
      the processing included a sodium borohydride reduction step, the 7beta-OH-CHOL
      detected could partly originate from 7-ketocholesterol or 7
      hydroperoxycholesterol. Several isomeric hydroxyoctadecadienoic acids were
      detected in both core and cap, more in the cap when related to cholesterol
      content. Most of the components of the cap showed a high degree of cross
      correlation on linear regression analysis, but cross-correlations were weaker for
      the core. The core samples contained a larger proportion of linoleate relative to
      oleate than the fibrous cap. CONCLUSION: The findings suggest that the different
      lipid and oxidised lipid contents of cap and core may be due to variations in
      oxidative activity in different parts of the lesion.

PMID- 10342329
TI  - The role of N-acetylcysteine in protecting synovial fluid biomolecules against
      radiolytically-mediated oxidative damage: a high field proton NMR study.
AB  - High field proton (1H) NMR spectroscopy has been employed to evaluate the
      abilities of the antioxidant thiol drug N-acetylcysteine and exogenous cysteine
      to protect metabolites present in intact inflammatory synovial fluid samples
      against oxidative damage arising from gamma-radiolysis (5.00 kGy) in the presence
      of atmospheric O2. Although oxidation of urate to allantoin by radiolytically
      generated *OH radical was readily circumventable by pre-treatment of synovial
      fluids with N-acetylcysteine (1.00 or 3.00 x 10(-3) mol x dm(-3)) or cysteine
      (1.00, 2.00 or 5.00 x 10(-3) mol x dm(-3)), both thiols offered only a limited
      protective capacity with respect to hyaluronate depolymerisation and the
      production of formate from carbohydrates in general. Radiolytic products
      generated from the added thiols (predominantly their corresponding disulphides)
      were simultaneously detectable in 1H Hahn spin-echo spectra of gamma-irradiated
      synovial fluids, permitting a quantitative evaluation of the radioprotective
      capacity of these agents. It is concluded that the multicomponent analytical
      ability of high field 1H NMR spectroscopy provides much useful molecular
      information regarding mechanisms associated with the radioprotectant actions of
      thiols in intact biofluids.

PMID- 10342330
TI  - Investigation of the transport of intact glutathione in human and rat type II
      pneumocytes.
AB  - The aim of the study was to investigate whether there is transmembrane transport
      of intact glutathione ([3H]-GSH, 0.1 microCi) in rat and human type II
      pneumocytes (T2P), and if this transport might be dependent on the redox state of
      the extracellular fluid. The T2P were pretreated with acivicin (250 microM) to
      inhibit gamma-glutamyltransferase activity and with L-buthionine-[SR]-sulfoximine
      (1 mM) to inhibit intracellular GSH synthesis. After 48 h in culture, initial GSH
      influx rate was 0.70 +/- 0.20 nmol/min/mg protein (37 degrees C) and 0.35 +/-
      0.04 nmol/min/mg protein (4 degrees C) during the first 5 min in rat T2P. In
      human T2P, the initial GSH influx rate was 0.36 +/- 0.30 nmol/min/mg protein (37
      degrees C) and 0.32 +/- 0.06 nmol/min/mg protein (4 degrees C) during the first
      10 min. Thereafter no further influx was found. The influx of 1 mM GSH in freshly
      isolated rat and human T2P in suspension was 2.3 +/- 0.3 and 1.2 +/- 0.3 nmol/mg
      protein after 15 min at 37 degrees C, and 2.8 +/- 0.2 and 1.0 +/- 0.3 nmol/mg
      protein at 4 degrees C, respectively. When GSH influx was studied at different
      concentrations between 0 and 40 mM, a linear increase without saturation or
      difference between 37 degrees C and 4 degrees C was found. Pre-exposure to
      ouabain had no effect on GSH influx. Efflux of GSH was stimulated and influx
      inhibited by pre-exposure of the cells to reduced thiols, while disulphides
      inhibited efflux and favoured inward uptake. Thus, in human and rat T2P a GSH
      carrier exists which operates as an effluxer. At GSH concentrations in the
      physiological range no uptake is seen, but some uptake can be observed at GSH
      concentrations above normal physiological levels. The uptake appears to be energy
      independent and non-saturable. Efflux of GSH is stimulated and influx inhibited
      by reduced thiols, while disulphides inhibit the efflux and favour inward uptake.
      GSH uptake in T2P thus may depend on concentration gradients and driving forces,
      such as the redox state of the extracellular fluid.

PMID- 10342331
TI  - Compromised antioxidant status and persistent oxidative stress in lung transplant
      recipients.
AB  - Oxidative stress may be a key feature, and hence important determinant, of tissue
      injury and allograft rejection in lung transplant recipients. To investigate
      this, we determined the antioxidant status (urate, ascorbate, thiols and alpha
      tocopherol) and lipid peroxidation status (malondialdehyde) in bronchoalveolar
      lavage (BAL) fluid and blood serum of 19 consecutive lung transplant recipients 2
      weeks and 1, 2, 3, 6, and 12 months post-surgery. BAL fluid and blood samples
      from 23 control subjects and blood from 8 patients two days before
      transplantation were obtained for comparison. Before surgery, the antioxidant
      status of patients was poor as serum ascorbate and total thiol concentrations
      were significantly (p < 0.05) lower than control subjects. Two weeks post
      surgery, ascorbate and total thiol concentrations were still low and urate
      concentrations had fallen compared to control subjects (p < 0.01). At this time,
      BAL fluid urate concentration was higher (p < 0.01), ascorbate concentration was
      lower (p < 0.01) and reduced glutathione concentrations were similar to control
      subjects. MDA, a product of lipid peroxidation, was higher (p < 0.01) in both BAL
      fluid and serum obtained from transplant patients compared to control subjects.
      During the first 12 months post-surgery, little improvement in antioxidant status
      or extent of lipid peroxidation was seen in transplant recipients. Regression
      analysis indicated no difference in serum or BAL fluid antioxidant status in
      patients with acute rejection compared to those without. In conclusion, lung
      transplant recipients have a compromised antioxidant status before surgery and it
      remains poor for at least the first year following the operation. In addition,
      these patients have elevated MDA concentrations in both their lung lining fluid
      and blood over most of this time. Oxidative stress is not, however, a
      sufficiently sensitive endpoint to predict tissue rejection in this group.

PMID- 10342332
TI  - Aggrecan degradation in chondrocytes is mediated by reactive oxygen species and
      protected by antioxidants.
AB  - Reactive oxygen species (ROS) are implicated in aging of cartilage and in the
      pathogenesis of osteoarthritis. However, the biological role of chondrocytes
      derived ROS has not been elucidated. An in-vitro model was developed to study the
      role of chondrocyte-derived ROS in cartilage matrix degradation. The primary
      articular chondrocytes were cultured and the aggrecan matrix was radiolabeled
      with 35-sulfate. The labeled aggrecan matrix was washed to remove unincorporated
      label and chondrocytes were returned to serum free balanced salt solution. The
      cell-monolayer-matrix sensitivity to oxidative damage due to either hydrogen
      peroxide or glucose oxidase was established by monitoring the release of labeled
      aggrecan into the medium. Lipopolysaccharide (LPS) treatment of chondrocyte
      monolayer enhanced the release of labeled aggrecan. Catalase significantly
      prevented the release of labeled aggrecan in LPS-chondrocyte cultures, suggesting
      a role for chondrocyte-derived hydrogen peroxide in aggrecan degradation.
      Superoxide dismutase or boiled catalase had no such inhibitory effect. The effect
      of several antioxidants on LPS-chondrocyte-dependent aggrecan degradation was
      examined. Hydroxyl radical scavengers (mannitol and thiourea) significantly
      decreased aggrecan degradation. A spin trapping agent N-tert-butyl-phenylnitrone
      (but not its inactive analog tert-butyl-phenylcarbonate) significantly decreased
      aggrecan degradation. Butylated hydroxytoluene also inhibited aggrecan
      degradation, whereas the other lipophilic antioxidant tested, propyl gallate, had
      a marked dose-dependent inhibitory effect. These data indicate that general
      antioxidants, hydroxyl radical scavengers, antioxidant vitamins, iron chelating
      agents, lipophilic antioxidants, and spin trapping agents can influence
      chondrocyte-dependent aggrecan degradation. These studies support the role of a
      chondrocyte-dependent oxidative mechanism in aggrecan degradation and indicate
      that antioxidants can prevent matrix degradation and therefore may have a
      preventive or therapeutic value in arthritis. The enhancement of oxidative
      activity in chondrocytes and its damaging effect on matrix may be an important
      mechanism of matrix degradation in osteoarthritis.

PMID- 10342333
TI  - Iron release in erythrocytes from patients with beta-thalassemia.
AB  - Our previous studies have shown that iron is released in a free (desferrioxamine
      chelatable) form when erythrocytes undergo oxidative stress (incubation with
      oxidizing agents or aerobic incubation in buffer for 24-60 h (a model of rapid in
      vitro ageing)). The release is accompanied by oxidative alterations of membrane
      proteins as well as by the appearance of senescent antigen, a signal for
      termination of old erythrocytes. In hemolytic anemias by hereditary hemoglobin
      alterations an accelerated removal of erythrocytes occurs. An increased
      susceptibility to oxidative damage has been reported in beta-thalassemic
      erythrocytes. Therefore we have investigated whether an increased iron level and
      an increased susceptibility to iron release could be observed in the erythrocytes
      from patients with beta-thalassemia. Erythrocytes from subjects with thalassemia
      intermedia showed an extremely higher content (0 time value) of free iron and
      methemoglobin as compared to controls. An increase, although non-statistically
      significant, was seen in erythrocytes from subjects with thalassemia major. Upon
      aerobic incubation for 24 h the release of iron in beta-thalassemic erythrocytes
      was by far greater than in controls, with the exception of thalassemia minor.
      When the individual values for free iron content (0 time) seen in thalassemia
      major and intermedia were plotted against the corresponding values for HbF, a
      positive correlation (P < 0.001) was observed. Also, a positive correlation (P <
      0.01) was seen between the values for free iron release (24 h incubation) and the
      values for HbF. These results suggest that the presence of HbF is a condition
      favourable to iron release. Since in beta-thalassemia the persistance of HbF is
      related to the lack or deficiency of beta chains and therefore to the excess of
      alpha chains, the observed correlation between free iron and HbF, is consistent
      with the hypothesis by others that excess of alpha chains represents a prooxidant
      factor.

PMID- 10342334
TI  - The metabolic syndrome: all in the mind?

PMID- 10342335
TI  - Blood pressure control, microalbuminuria and cardiovascular risk in Type 2
      diabetes mellitus.
AB  - Type 2 (noninsulin-dependent) diabetes mellitus (DM) affects about 3% of the UK
      population. Diabetes often coexists with a cluster of other potent cardiovascular
      risk factors, including hypertension, dyslipidaemia and increased tendency for
      thrombosis, and increases the risk of early death from cardiovascular causes by
      about threefold. Microalbuminuria or proteinuria also may be present, further
      increasing the risk of cardiovascular mortality. Cardiovascular risk factors must
      be treated aggressively in patients with Type 2 diabetes and control of blood
      pressure at 140/85 mm Hg or lower is a priority. The management of hypertension
      in patients from some ethnic groups demands special consideration because they
      have a high incidence of diabetes and hypertensive complications. Patients must
      be urged to adopt appropriate lifestyle changes in the first instance but
      additional drug treatment for hypertension is usually required. All the major
      classes of antihypertensive agents lower blood pressure in Type 2 diabetic
      patients but have different effects on metabolic risk factors in different ways.
      Low-dose thiazide diuretics, beta-blockers, calcium channel blockers and
      angiotensin converting enzyme (ACE) inhibitors have been shown to reduce
      cardiovascular risk. Individually, the effects of low-dose thiazide diuretics and
      beta-blockers on glucose and lipid metabolism is clinically insignificant, though
      in combination much larger metabolic effects are seen. ACE inhibitors and calcium
      channel blockers have no, or small, beneficial effects on glucose and lipid
      metabolism, while the greater beneficial effects of alpha1-blockers on lipid
      profiles may render them especially useful in the Type 2 diabetic patient. Long
      acting calcium-channel blockers and ACE inhibitors protect renal function and are
      suitable as first line therapy in patients with microalbuminuria or proteinuria.
      Until results from the current batch of randomized, placebo-controlled trials
      comparing different classes of antihypertensive agents are available, the choice
      of antihypertensive agent is difficult. Addressing overall cardiovascular risk
      factors, rather than hypertension alone, is essential in the management of the
      hypertensive Type 2 diabetic patient.

PMID- 10342336
TI  - Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus.
AB  - AIMS: Type 2 diabetes mellitus (DM) develops when insulin resistance overcomes
      the capacity of compensatory insulin secretion. Insulin resistance may be induced
      via psychoneuroendocrine pathways, a possibility which has received little
      previous attention. METHODS: We have used salivary cortisol measurements to
      monitor the activity of the hypothalamic-pituitary-adrenal (HPA) axis, the major
      controller of hormones involved in the regulation of peripheral insulin
      sensitivity under everyday conditions. The influence of external challenges, as
      well as the sensitivity of feedback regulation, were followed in randomly
      selected middle-aged population samples. RESULTS: In health there is a
      rhythmicity of cortisol secretion, with a high plasticity and efficient feedback
      control. In contrast, a group of subjects were identified with a flat, rigid day
      curve and poor feedback control, who showed consistent abnormalities in stress
      related cortisol secretion, including inhibited secretions of sex steroids and
      growth hormone; insulin resistance; abdominal obesity; elevated leptin levels;
      hyperglycaemia; dyslipidaemia and hypertension with elevated heart rate. The
      endocrine abnormalities are probably responsible for the anthropometric and
      metabolic abnormalities. The circulatory perturbations seem to be induced by a
      parallel activation of the central sympathetic nervous system suggesting an
      'hypothalamic arousal syndrome', gradually developing into an independent risk
      for disease. An associated cluster of environmental factors, including
      psychosocial and socio-economic stress, traits of depression and anxiety, alcohol
      consumption and smoking, all factors known to activate hypothalamic centres, has
      been identified. A polymorphism of the glucocorticoid receptor gene, with 13.7%
      homozygotes in the male Swedish population, parallels receptor dysfunction, and
      may be responsible for the associated insulin resistance, central obesity and
      hypertension. CONCLUSIONS: This is the first detailed examination of
      psychoneuroendocrinological processes in the natural environment on a population
      basis in relation to somatic health. The results suggest that an hypothalamic
      arousal syndrome, with parallel activation of the HPA axis and the central
      sympathetic nervous system, is responsible for development of endocrine
      abnormalities, insulin resistance, central obesity, dyslipidaemia and
      hypertension, leading to frank disease, including Type 2 DM. We suggest that this
      syndrome is probably based on environmental pressures in genetically susceptible
      individuals.

PMID- 10342337
TI  - Long-term efficacy of humalog in subjects with Type 1 diabetes mellitus.
AB  - AIMS: To evaluate the long-term effectiveness of Humalog insulin in lowering post
      meal glucose excursions. METHODS: Twenty young subjects with Type 1 diabetes
      mellitus (DM) who had received insulin-lispro (Humalog) for a least 1 year (mean
      +/- SD 1.8+/-1.6 years) were studied on two occasions, 3-14 days apart. They
      consumed a similar breakfast consisting of 450-600 kCal having fasted overnight.
      The same amount of human soluble Humulin Regular or Humalog insulin was given 10
      min before the meal in a randomized, double-blind fashion. RESULTS: Postprandial
      glucose excursions at 30, 60, and 120 min were significantly lower (P<0.001,
      ANCOVA) when subjects received Humalog as compared to human soluble insulin.
      Serum-free insulin levels were significantly higher (P<0.001, ANOVA) at 30 and 60
      min when subjects received Humalog as compared with human soluble insulin.
      Humalog antibody levels after up to 5.4 years of receiving Humalog insulin were
      not elevated beyond the values at 1 year. CONCLUSIONS: We conclude that Humalog
      insulin is effective in lowering postprandial glucose excursions even after up to
      5.4 years of treatment.

PMID- 10342338
TI  - Natural course of kidney function in Type 2 diabetic patients with diabetic
      nephropathy.
AB  - AIMS: To determine the natural course of kidney function and to evaluate the
      impact of putative progression promoters in Caucasian Type 2 diabetes mellitus
      (DM) patients with diabetic nephropathy who had never received any
      antihypertensive treatment. METHODS: A long-term observational study of 13
      normotensive to borderline hypertensive Type 2 DM patients with diabetic
      nephropathy. Glomerular filtration rate (GFR) was measured approximately every
      year (51Cr-EDTA plasma clearance technique). Albuminuria, blood pressure (BP) and
      haemoglobin A1c (HbA1c) was determined 2-4 times per year and serum cholesterol
      every second year. RESULTS: The patients (12 males/one female), age 56+/-9 (mean
      +/- SD) years, with a known duration of diabetes of 10+/-6 years, were followed
      for 55 (24-105) (median (range)) months. GFR decreased from 104 (50-126) to 80
      (39-112) ml x min(-1) x 1.73 m(-2) (P = 0.002) with a median rate of decline of
      4.5 (-0.4 to 12) ml x min(-1) x year(-1). During follow-up, albuminuria rose from
      494 (301-1868) to 908 (108-2169) mg/24 h (P = 0.25), while BP, HbA1c and serum
      cholesterol remained essentially unchanged. In univariate analysis the rate of
      decline in GFR did not correlate significantly with neither baseline nor mean
      values during follow-up of BP, albuminuria, HbA1c and serum cholesterol.
      CONCLUSIONS: Our study suggests that normotensive to borderline hypertensive Type
      2 DM patients with diabetic nephropathy have a rather slow decline in kidney
      function, but we did not unravel the putative progression promoters responsible
      for the variation in rate of decline in GFR.

PMID- 10342339
TI  - Patterns of contraception in UK women with Type 1 diabetes mellitus: a GP
      database study.
AB  - AIM: To establish the patterns of contraceptive prescribing for women aged 15-49
      with Type 1 diabetes mellitus (DM) and compare them with the patterns in women
      without diabetes. METHODS: This was a cross-sectional study using a UK primary
      care database. RESULTS: Nine hundred and thirty-eight women with a diagnosis of
      Type 1 DM were identified. A comparison group of women aged 15-49 without
      diabetes (n = 10000) were randomly selected from the database. Twenty-five per
      cent of the women with diabetes and 32% without diabetes were prescribed a
      hormonal contraceptive in 1994. Women with Type 1 DM were more likely to be
      prescribed a combined oral contraceptive than a progestogen only pill (POP) but
      were 2.12 (95% CI 1.65-2.72) times more likely to be prescribed a POP than women
      without diabetes and were less likely to be prescribed a combined pill - odds
      ratio 0.53 (95% CI 0.44-0.64). The pregnancy rate in women with Type 1 DM over
      the age of 25 years was lower than for women without diabetes. Women under 25
      years with Type 1 DM seemed more likely to record a pregnancy. CONCLUSIONS:
      Differences between women with Type 1 DM and those without diabetes highlight the
      variation in the way that GPs and patients evaluate the risks and benefits when
      deciding on contraception.

PMID- 10342341
TI  - Insulin secretion and action in different stages of glucose tolerance in Asian
      Indians.
AB  - AIMS: To evaluate the sequence of changes in insulin secretion and action in
      different stages of glucose tolerance and the effect of obesity on insulin
      profile in South Indian adults. Blood samples from 260 consecutive cases with no
      known history of diabetes were collected. Plasma insulin levels were measured
      during a 75-g oral glucose tolerance test. Insulin resistance (IR) was
      calculated, using the homeostasis model assessment (HOMA). An index of insulin
      secretion was derived as the ratio of incremental insulin at 30 min divided by 30
      minute plasma glucose (delta I/G). RESULTS: Normoglycaemia was present in 164,
      impaired glucose tolerance (IGT) in 60 and diabetes in 36 subjects. Fasting and 2
      h insulin secretion showed bell shaped curves with increasing plasma glucose. The
      peak values corresponded to the cut-off values used for the diagnosis of clinical
      diabetes. IR was higher in obese than in nonobese, nondiabetic subjects but the
      effect of obesity on IR was not found in subjects with diabetes. IGT was
      associated with higher IR, but not with evidence of a beta-cell defect.
      CONCLUSIONS: Evaluation of insulin resistance and beta-cell function in different
      stages of glucose tolerance indicate that insulin resistance is manifested in the
      early stage of glucose intolerance in South Indians, i.e. IGT. A beta-cell defect
      was mostly found in people with diabetes. The beta-cell defect is more common in
      diabetes among the nonobese.

PMID- 10342340
TI  - Effect of different times of administration of a single ethanol dose on insulin
      action, insulin secretion and redox state.
AB  - AIMS: Ethanol (EtOH) can affect glucose metabolism by altering the redox state,
      insulin-mediated glucose uptake and insulin secretion. We sought to determine the
      effects of an acute oral EtOH load on insulin secretion and glucose tolerance and
      the importance of a different timing of administration relative to a glucose
      load. METHODS: Eleven subjects underwent a frequently sampled intravenous glucose
      tolerance test (FSIGT) on three occasions in random order. In one, EtOH was given
      50 min 'before' the FSIGT; on the second, the same amount was administered 6 min
      after the glucose pulse ('during' study); on the third no EtOH was given.
      RESULTS: Blood EtOH peaked at 4.43+/-0.24 mmol/l (mean +/- SD) in the 'during'
      and 4.16+/-0.31 mmol/l in the 'before' study. No differences were noticed in
      S(I), the index of insulin sensitivity, or in S(G), the glucose effectiveness,
      between the 'before', 'during' and control studies. There were no differences in
      the first-phase insulin secretion between the three studies but a significant
      increase in the sensitivity to glucose of second-phase dynamic insulin response,
      phi2, in the 'before' (0.062+/-0.036 pmol x min(-2) x (mg(-1) x dl(-1))(-1)) and
      'during' (0.063+/-0.059) studies, compared to the control study (0.017+/-0.010,
      P<0.05) was observed. No differences were observed in the hepatic extraction of
      insulin. In the 'before' study, there was a significant decline in NEFA (non
      esterified fatty acid) concentration from the baseline (mean 602+/-51 micromol/l)
      to the O min value (mean 353+/-37, P<0.01). During the FSIGT, the mean plasma
      NEFA concentration was significantly lower in the 'before' and in the 'during'
      than in the control study. CONCLUSION: An acute oral EtOH load does not impair
      glucose metabolism, at least in part because of an increased second-phase insulin
      secretion. Since this effect is observed irrespective of whether EtOH is consumed
      either before or during the glucose load, the existence of a priming effect is
      questioned.

PMID- 10342342
TI  - Susceptibility of low- and high-density lipoproteins from diabetic subjects to in
      vitro oxidative modification.
AB  - AIMS: To investigate the hypothesis that lipid peroxidation of both low-density
      lipoproteins (LDL) and high-density lipoproteins (HDL) is important in the
      development of atherosclerosis. METHODS: We have investigated whether LDL and HDL
      from patients with Type 1 diabetes mellitus (DM, n = 16) and Type 2 DM (n = 15)
      is more susceptible to Cu2+ -induced lipid peroxidation than LDL and HDL from a
      similar number of nondiabetic controls matched for age, gender and serum
      cholesterol. RESULTS: The vitamin E content of LDL and HDL from both groups of
      diabetic patients was not significantly different from controls. The LDL from
      Type 2 diabetic patients and HDL from both diabetic groups were significantly
      richer in triglyceride than controls. Phospholipid was decreased in LDL from Type
      2 diabetic patients and protein was decreased in HDL in Type 1 DM, but otherwise
      the composition of LDL and HDL in diabetic subjects was similar to controls. No
      significant differences were observed in the generation of conjugated dienes or
      lipid peroxides in either LDL or HDL when the two groups were compared with each
      other or with their respective controls. CONCLUSIONS: Increased lipid
      peroxidation occurring in vivo in diabetes is unlikely to be the result of
      increased susceptibility of lipoproteins to lipid peroxidation, but rather to
      increased generation of free radicals, to oxidation of lipids other than those
      present in serum lipoproteins or to decreases in antioxidant systems other than
      the fat-soluble antioxidants present in lipoproteins.

PMID- 10342343
TI  - Effect of pravastatin on erythrocyte rheological and biochemical properties in
      poorly controlled Type 2 diabetic patients.
AB  - AIMS: The rheological properties of erythrocytes are impaired in diabetes
      mellitus, especially because of changes in their membrane lipid composition. In
      hypercholesterolaemic patients, lowering plasma cholesterol is associated with an
      improvement of the erythrocyte rheological parameters. The aim of this study was
      to investigate the relationship between erythrocyte deformability, plasma lipids,
      lipid membrane composition and cytosolic cations in poorly controlled Type 2
      diabetic patients and to test the effects of a cholesterol-lowering treatment on
      these parameters. METHODS: We compared 37 poorly controlled Type 2 diabetic
      patients with 26 controls. In 22 of the diabetic patients who showed an
      impairment in erythrocyte deformability (filtration index >10.5 on the Hanss'
      haemorheometer), a double-blind randomized trial compared the effect of the
      inhibitor of HMG CoA reductase pravastatin 20 mg per day for 4 months vs. placebo
      on the erythrocyte parameters. RESULTS: Compared with controls, diabetic patients
      had higher filtration index (FI), erythrocyte sodium and calcium contents and
      lower free cholesterol-phospholipids ratio in erythrocyte membranes. Erythrocyte
      sodium content correlated positively with the FI and the membrane free
      cholesterol-phospholipids ratio. In the pravastatin-treated group (11 patients),
      fibrinogen decreased significantly, FI reached a normal value (<10) in six
      patients. Four of the five other patients who still had abnormal FI after 4
      months of treatment had either a high plasma triglycerides (> or =4.60 mmol/l) or
      a high plasma fibrinogen (> or =4 g/l) level at baseline. Only two of the 11
      placebo-treated patients achieved a normal FI. CONCLUSION: These data suggest
      that in poorly controlled Type 2 diabetic patients there is a link between the
      chemical composition and the rheological properties of erythrocytes. Erythrocyte
      deformability may be improved by lowering plasma cholesterol with a statin.

PMID- 10342344
TI  - Diabetes mellitus in the family: perceptions of offspring's risk.
AB  - AIMS: The study aimed to explore the beliefs and concerns of people with Type 2
      diabetes mellitus (DM) about their children's risk of developing the disease and
      the possibilities for prevention. METHODS: Questionnaires were posted to all
      patients with Type 2 DM in four randomly selected general practices in South
      London. Two hundred and thirteen (73%) responded. The main outcome measures were:
      estimated risk of Type 2 DM in their offspring; worry about diabetes in their
      offspring; knowledge about the possibilities for prevention of Type 2 DM and its
      complications. RESULTS: Of the 159 respondents with children, at least 35% and
      perhaps as many as 64% underestimated the risk of their offspring developing Type
      2 DM; 44% thought it possible to reduce the risk of Type 2 DM and its
      complications; 28% thought altering diet and 6% taking exercise might be useful
      preventive strategies; 49% worried about their children developing diabetes.
      CONCLUSIONS: Although risk of Type 2 DM was underestimated for their children and
      little was known about prevention, about half of the respondents worried about
      their children developing diabetes. Education and counselling about risk and
      prevention are needed. This is important in view of growing interest in and
      opportunities for both the primary and secondary prevention of Type 2 DM.

PMID- 10342345
TI  - Nesidioblastosis, myelodysplastic syndrome and nodular diabetic
      glomerulosclerosis in an elderly nondiabetic woman: an autopsy report.
AB  - Nesidioblastosis as the cause of hyperinsulinaemic hypoglycaemia in an adult is
      rare. We report here an additional case of nesidioblastosis, which resulted in
      fatal hyperinsulinaemic hypoglycaemia in a 72-year-old woman with an underlying
      myelodysplastic syndrome. The diagnosis of nesidioblastosis was established only
      after post-mortem examination with a careful exclusion of minute insulinoma. To
      our surprise, the renal pathology disclosed typical diabetic nodular
      glomerulosclerosis in the same patient who had no previous history of diabetes
      mellitus (DM). Nesidioblastosis has been reported to cause 'reversal' of Type 1
      DM and insulinoma causing 'reversal' of Type 2 disease. We therefore hypothesize
      that our patient might have had an undiagnosed DM in the past, which resulted in
      the typical diabetic nodular glomerulosclerosis. The nesidioblastosis caused a
      'reversal' of DM and even the ultimate development of hyperinsulinaemic
      hypoglycaemia.

PMID- 10342346
TI  - Comment on the provisional report from the WHO consultation. European Group for
      the Study of Insulin Resistance (EGIR)

PMID- 10342347
TI  - Safe extracapsular placement of proximal tibia transfixation pins.
AB  - OBJECTIVE: To identify the anatomic detail of the knee joint capsular insertion
      site on the proximal tibia, specifically as it relates to transfixation pins.
      DESIGN: Identification of capsular anatomy by anatomical dissection of cadaveric
      specimens, with radiography and arthroscopy of patients. SETTING: Cadaveric
      dissection. OUTCOME MEASURES: Anatomic observation of the capsular attachment
      site in relation to the tibial articular surface. RESULTS: The capsule inserts
      four to fourteen millimeters below the articular surface in a regular pattern.
      The anterior half of the circumference is close to the joint line (less than six
      millimeters). Posteromedially and posterolaterally, there are extensions distally
      to fourteen millimeters, occasionally communicating with the tibiofibular joint.
      CONCLUSION: Transfixing wires and half-pins can be placed in the proximal tibia
      without capsular penetration if kept more than fourteen millimeters from the
      subchondral line. If wire placement closer to the joint is required, wires should
      be placed in Zone 1 (the anterior half) and at least six millimeters from
      subchondral bone to avoid capsular penetration.

PMID- 10342348
TI  - Anatomy of the distal knee joint and pyarthrosis following external fixation.
AB  - OBJECTIVE: To determine the limits of the distal synovial reflection of the human
      knee joint. SPECIMENS: Six paired knees studied by magnetic resonance imaging
      (MRI), fluoroscopic arthrography, and gross dissection. The right knees of five
      patients with chronic idiopathic knee effusions were studied by MRI. Cadaveric
      knees were injected with saline prior to MRI. The joint capsules were dissected
      to visualize local anatomy and check for capsular tears. In each modality (MRI,
      fluoroscopy, and dissection), the most distal extent of knee synovial fluid was
      measured. RESULTS: The right versus left agreement for paired specimens was
      generally two to three millimeters. Some specimens showed asymmetric capsular
      reflection. Medial fluid was identified at distances greater than forty-nine
      millimeters from the subchondral bone in seven knees and less than fifteen
      millimeters in four knees (range 0 to 70 millimeters, mean thirty-three
      millimeters). Laterally, the range was ten to thirty-five millimeters (mean
      twenty-three millimeters). In six of the twelve cadaveric specimens, there was
      evidence of a communication between the knee joint and the proximal
      tibiofibularjoint. In the knees of volunteers, joint fluid tracked medially to a
      range of ten to fifty millimeters and laterally to a range of six to fifteen
      millimeters, with means of twenty-six and eleven millimeters, respectively. The
      knees of the volunteers had no evidence of tibiofibular joint communication with
      the knee. CONCLUSION: Insertion of external fixation pins within sixty to seventy
      millimeters of the proximal articular surface of the tibia is associated with a
      high probability of synovial penetration and possibly provides a conduit for the
      introduction of bacteria, which may be etiologic in iatrogenic pyarthrosis.

PMID- 10342349
TI  - Intraarticular anatomic risks of tibial nailing.
AB  - OBJECTIVE: To identify the risks to intraarticular structures of the knee during
      tibial portal creation and to identify the safe zone for tibial nail placement.
      STUDY DESIGN: Cadaveric anatomic. LOCATION: University trauma center. METHODS:
      Forty fresh frozen cadaveric knees were studied to elaborate the risks of tibial
      portal creation and nail placement to the intraarticular structures of the knee.
      Nails were placed through medial and lateral parapatellar approaches, and the
      distance from the nail portal to the intraarticular structures of the knee was
      measured. A safe zone for portal placement was determined. RESULTS: The tibial
      portal location averaged 4.4+/-3 millimeters lateral to the midline of the
      plateau. Actual intraarticular structural damage occurred in 20 percent of the
      specimens; however, an additional 30 percent demonstrated the nail to be
      subjacent to one of the menisci. A lateral paratendinous approach placed the
      lateral articular surface at most risk, and a medial paratendinous approach
      placed the medial meniscus at most risk. The safe zone for nail placement was
      identified and is located 9.1+/-5 millimeters lateral to the midline of the
      plateau and three millimeters lateral to the center of the tibial tubercle. The
      width of the safe zone averaged 22.9 millimeters and was as narrow as 12.6
      millimeters. CONCLUSION: Damage to the intraarticular structures of the knee is
      possible during tibial nailing with a superior portal. The safe zone for nail
      placement is small and can be exceeded if a reamed nail is used. The safest
      starting point for tibial nailing should be slightly lateral to the center of the
      tibial tubercle.

PMID- 10342350
TI  - No effect of low-intensity ultrasound on healing time of intramedullary fixed
      tibial fractures.
AB  - OBJECTIVE: To determine whether stimulation with low-intensity ultrasound will
      reduce the radiologic healing time of fresh tibial shaft fractures fixed with a
      reamed and statically locked intramedullary rod. DESIGN: Prospective, randomized,
      double blinded, and placebo controlled. PATIENTS AND METHODS: Thirty-two adult
      patients were included, fifteen in the active ultrasound group and seventeen in
      the placebo group. They all used an ultrasound device twenty minutes daily for
      seventy-five days without knowing whether it was active or inactive. Standardized
      radiographs were taken every third week until healing and at six and twelve
      months. All radiographs were assessed blinded and independently by a radiologist
      and an orthopaedic surgeon. The codes were not broken until all fractures had
      healed and all radiographs had been evaluated. RESULTS: The time until the first
      visible callus averaged 40+/-3 days for the active group and 37+/-3 days for the
      placebo (p=0.44). The healing time, defined as radiologic bridging of three
      cortices, was on average 155+/-22 days (median 113 days) for the active treatment
      group and 125+/-11 days (median 112 days) for the placebo group (p=0.76) as
      assessed by the radiologist and 128+/-13 days for the active group and 114+/-9
      days for the placebo group (p=0.40) as evaluated by the orthopaedic surgeon.
      CONCLUSION: We conclude that low-intensity ultrasound treatment did not shorten
      healing time in fresh tibial fractures treated with a reamed and statically
      locked intramedullary nail. Our results are not in accordance with previous
      findings reporting reduced healing time in nonoperatively treated tibial shaft
      fractures when subjected to ultrasound.

PMID- 10342351
TI  - Complications of intramedullary nailing for fractures of the humeral shaft: a
      review.
AB  - OBJECTIVES: The purpose of the present review is to document the complications
      associated with the use of locking humeral nails and to discuss the prevention
      and management of these complications. DATA SOURCES: Clinical and research
      experience supported by a Medline review of the English-language literature from
      1985 to 1998. STUDY SELECTION: The majority of (clinical) information available
      was contained in retrospective reviews; only three prospective or randomized
      studies were identified (all in abstract form). Anatomical research regarding
      locking humeral nailing was also identified and included. DATA EXTRACTION:
      Because there were so few prospective studies available, a formal meta-analysis
      of data was not performed. This review focuses on a descriptive assessment of
      available information on specific complication-related topics. CONCLUSIONS: The
      attractive theoretical advantages of locking humeral nails have not been borne
      out in clinical studies. Complications such as shoulder pain, delayed union or
      nonunion, fracture about the implant, iatrogenic fracture comminution, and the
      difficulty in the reconstruction of failures have diminished their usefulness.
      The precise role of locking nails in the treatment of humeral shaft fractures has
      yet to be defined. At present, open reduction and compression plating remain the
      treatment of choice for humeral shaft fractures that require operative
      intervention.

PMID- 10342352
TI  - Changes on magnetic resonance images after traumatic avascular necrosis of the
      femoral head.
AB  - SUMMARY: We describe two cases of avascular necrosis after traumatic fracture of
      the femoral neck. The size and signal intensity of the necrotic areas changed on
      follow-up magnetic resonance images. Magnetic resonance imaging is suitable for
      showing resolvable changes that radiographic study cannot demonstrate during the
      clinical course.

PMID- 10342353
TI  - Tibial fracture during removal of a tibial intramedullary nail.
AB  - SUMMARY: As tibial intramedullary nailing becomes the preferred treatment for
      tibial shaft fracture, removal of tibial nails will become more common. Removal
      of tibial intramedullary nails is not without complications, but a review of the
      literature found only one recent report of a fracture of the tibia during
      removal. A case report of a tibial fracture during removal of an Alta tibial nail
      is presented.

PMID- 10342354
TI  - High success rate with exchange nailing to treat tibial shaft aseptic nonunion.

PMID- 10342355
TI  - ISFR presidential address: new engineering technology transfer in bone fracture
      management for the next century. International Society for Fracture Repair.

PMID- 10342356
TI  - Diagnosis of Cushing's syndrome: re-evaluation of midnight plasma cortisol vs
      urinary free cortisol and low-dose dexamethasone suppression test in a large
      patient group.
AB  - We studied plasma cortisol levels at 00:00 h and 08:00 h in 103 patients with
      Cushing's syndrome and 144 patients in whom this diagnosis had been excluded.
      These patients were hospitalized in our department from 1975 to 1996.
      Additionally, we measured these parameters in 20 healthy volunteers and in 5
      patients with nonendocrine disease. Corresponding data of urinary free cortisol
      and low-dose dexamethasone suppression testing were included in the evaluation.
      Values (mean+/-SD) from patients with Cushing's syndrome: 510+/-232 nmol/l (range
      165-1488) for plasma cortisol 00:00 h, 574+/-242 nmol/l (range 236-1612) for
      plasma cortisol 08:00 h, 991+/-885 nmol/24 h (range 154-4866) for urinary free
      cortisol and 479+/-304 nmol/l (range 34 - 1,393) for plasma cortisol after 1.5 mg
      dexamethasone. Values from the patients excluded from Cushing's syndrome: 99+/-76
      nmol/l (range 5-371) for plasma cortisol 00:00 h, 393+/-136 nmol/l (range 119
      812) for plasma cortisol 08:00 h, 126+/-84 nmol/24 h (range 30-485) for urinary
      free cortisol, and 64+/-82 nmol/l (range 5-395) for plasma cortisol after 1.5 mg
      dexamethasone. Values of the healthy volunteers respectively patients with non
      endocrine disease: 59+/-30 nmol/l (range 25-130) respectively 127+/-80 nmol/l
      (range 62-265) for plasma cortisol 00:00 h and 388+/-144 nmol/l (range 157-651)
      respectively 498+/-113 nmol/l (range 302-581) for plasma cortisol 08:00 h. None
      of the Cushing patients exhibited a 00:00 h plasma cortisol below 140 nmol/l and
      only one had a urinary free cortisol below 200 nmol/24 h, whereas 4 were complete
      dexamethasone suppressors. The diagnostic value of these parameters was examined
      based on various cutoffs. We recommend determination of midnight plasma cortisol
      as an efficient and simple additional procedure for the diagnosis of Cushing's
      syndrome. The sensitivity and specificity of this procedure is similar to urinary
      free cortisol and slightly above the low-dose dexamethasone suppression testing
      in our hospitalized patients.

PMID- 10342358
TI  - Kinetics of red blood cell T3 uptake in hypothyroidism with or without hormonal
      replacement, in the rat.
AB  - L-triiodothyronine (L-T3) is taken up and accumulated into red blood cells (RBC)
      by means of a specific carrier-mediated system. The aim of this study was to
      evaluate the reactivity of this system in relation to induced alterations in
      thyroid hormone (TH) supply. We investigated the kinetic parameters (Vmax,
      maximal velocity and Km, Michaelis constant) of washed-RBC L-T3 uptake 1) in
      thyroidectomized (TXT) rats, 2) in TXT rats administered with low doses of L-T4
      (15 microg/kg/day x 14) to restore normal serum TH levels (REPL), 3) in TXT rats
      administered with high doses of L-T4 (200 microg/kg/day x 14) to achieve a large
      increase in serum TH levels (HIGH). Serum free T3 and T4 levels were
      significantly decreased in TXT rats (2.4 and 8.8 fold, respectively), not
      different in REPL rats and significantly increased in HIGH rats (2.4 and 3 fold,
      respectively) compared to sham-operated rats (SHAM). Both kinetics of RBC L-T3
      uptake were significantly increased in TXT rats (Vmax+/-SE in pmol/min/10(8)
      cells=235.1+/-11.1, p<0.05 and Km+/-SE in nM=190.1+/-9.0, p<0.05), not different
      in REPL rats (Vmax=1 84.8+/-7.6 and Km=151.9+/-7.1) and significantly decreased
      in HIGH rats (Vmax=168.0+/-4.1, p<0.01 and Km=131.9+/-4.6, p<0.01) compared to
      SHAM rats (Vmax=197.7+/-5.8 and Km=160.9+/-6.1). These results show that kinetics
      of RBC L-T3 uptake are modified in response to defect or excess in circulating TH
      levels. Since RBC play likely a role of a buffer system, the changes in carrier
      mediated influx of L-T3 could be seen as a compensatory mechanism that counteract
      the disturbances in the TH availability for the target tissues.

PMID- 10342357
TI  - Outcome of treatment of hyperthyroidism.
AB  - This is a retrospective study designed to evaluate the initial response to
      carbimazole in patients with Graves' disease (GD), possible determinants of that
      response, the frequency of occurrence of adverse effects during treatment with
      carbimazole and the frequency of transient and permanent hypothyroidism after
      treatment with 131I in patients with GD and multinodular goiter (MNG). Data were
      collected from patients who first presented with GD or MNG at the Department of
      Endocrinology of the Royal Infirmary of Edinburgh between 1 January 1993 and 31
      August 1996. Patients were divided into three groups: patients with GD treated
      with a daily dose of 40 mg carbimazole, patients with GD treated with a single
      dose of 400 MBq 1311, and patients with MNG treated with the same dose of 131I.
      Of the patients younger than 30 years, 50% remained biochemically hyperthyroid
      after 4-6 weeks of treatment with carbimazole, compared to 14% of patients over
      30. Other determinants of the response to carbimazole expressed as the fall in
      thyroid hormone levels after 4-6 weeks were: pretreatment levels of FT4, T3, TRAb
      and the 4 h 131I uptake, patients with the higher levels responding significantly
      better to carbimazole. Adverse effects were reported in 11.5% of patients. Of the
      patients with GD treated with 1311, 62.6% became hypothyroid, transient
      hypothyroidism occurred in only 2.4% of these cases. The main predictors of
      development of hypothyroidism were positive titres of antithyroid peroxidase
      antibodies (AbTPO) and antithyroglobulin antibodies (AbTg), with positive
      predictive values of 79.5 and 91.6 respectively. None of the patients with MNG
      became hypothyroid after treatment with 131I, a response significantly different
      from patients with GD. In conclusion, GD younger patients might benefit from
      higher initial doses of carbimazole. In patients with positive titres of AbTPO
      and AbTg, lower doses of 1311 might prevent hypothyroidism. Transient
      hypothyroidism was underestimated in this study. No permanent thyroxin
      replacement therapy should be started within the first six months after 131I
      treatment.

PMID- 10342359
TI  - Lack of association between thyroid and adrenal nodules: a histological study.
AB  - The prevalence of thyroid nodules is increased in patients with Cushing's
      disease, but the possibility of an association between thyroid and adrenal
      nodules in other patient groups has not been formally tested. We have evaluated
      the co-existence of thyroid and adrenal nodules in retrospective and prospective
      autopsy studies. Retrospective (83 autopsies) and prospective (29 autopsies)
      blinded studies of thyroid and adrenal gland histopathology were performed by two
      experienced histopathologists in unselected autopsies. The presence of nodules,
      defined as areas of tissue having discrete edges within the gland parenchyma seen
      as a step difference between the cells or architecture adjacent to the nodule,
      was determined for each gland. No association was found between the presence of
      adrenal and thyroid nodules in either the retrospective or prospective studies
      (p>0.2 for both). In the retrospective study, 23% of specimens had thyroid
      nodules and 28% adrenal nodules. In the prospective study, 24% of specimens had
      thyroid nodules and 7% adrenal nodules. The proportion of patients with adrenal
      nodules in the prospective study was significantly less than that in the
      retrospective study. In conclusion, thyroid and adrenal nodules are frequent
      autopsy findings in the general population but we have found no evidence of a
      relationship between the occurrence of nodules in these glands.

PMID- 10342360
TI  - Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH
      releasing peptide, in humans.
AB  - Reduced cardiac mass and performances are present in GH deficiency and are
      counteracted by rhGH replacement. GH and IGF-I possess specific myocardial
      receptors and have been reported able to exert an acute inotropic effect.
      Synthetic GH secretagogues (GHS) possess specific pituitary and hypothalamic but
      even myocardial receptors. In 7 male volunteers, we studied cardiac performance
      by radionuclide angiocardiography after iv administration of rhGH or hexarelin
      (HEX), a peptidyl GHS. The administration of rhGH or HEX increased circulating GH
      levels to the same extent (AUC: 1594.6+/-88.1 vs 1739.3+/-262.2 microg/l/min for
      90 min) while aldosterone and catecholamine levels did not change; HEX, but not
      rhGH, significantly increased cortisol levels. Left ventricular ejection fraction
      (LVEF), mean blood pressure (MBP) and heart rate (HR) were unaffected by rhGH
      (62.4+/-2.1 vs 62.1+/-2.3%, 90.6+/-3.4 vs 92.0+/-2.5 mm Hg, 62.3+/-1.8 vs 66.7+/
      2.7 bpm). HEX increased LVEF (70.7+/-3.0 vs 64.0+/-1.5%, p<0.03) without
      significant changes in MBP and HR (92.8+/-4.7 vs 92.4+/-3.2 mm Hg, 63.1+/-2.1 vs
      67.0+/-2.9 bpm). LVEF significantly raised at 15 min, peaked at 30 min and lasted
      up to 60 min after HEX. These findings suggest that in man, the acute
      administration of Hexarelin exerts a short-lasting, positive inotropic effect.
      This effect seems GH-independent and might be mediated by specific GHS myocardial
      receptors.

PMID- 10342361
TI  - Genetic analysis of the TSH receptor gene in differentiated human thyroid
      carcinomas.
AB  - Somatic mutations of the TSH receptor (TSHR) gene have been identified as the
      major cause of toxic thyroid adenoma. Recently, point mutations of the same gene
      have also been described in some differentiated thyroid carcinomas. The aim of
      the present study was to investigate the presence TSHR gene mutations in a series
      of thyroid specimens obtained from 22 consecutive patients with differentiated
      thyroid carcinomas (8 follicular and 14 papillary). Genomic DNA was extracted
      from fresh-frozen or paraffin-embedded tumor and normal surrounding parenchyma.
      Two fragments corresponding to the entire exon 10 and one fragment corresponding
      to exon 9 were amplified by PCR using biotinylated primers. PCR products were
      purified on streptavidin-coated magnetic beads and subjected to direct sequencing
      with Sequenase and 35(3)-labeled d-ATP-alphaS. Adenyl-cyclase activity in
      membrane preparations of 10 papillary carcinomas was also determined. No TSHR
      mutations were detected in these tumors. A polymorphism that encoded a single
      amino acid change Asp727Glu was identified in two follicular thyroid carcinomas.
      Adenyl-cyclase activity was normal in the ten papillary thyroid carcinomas we
      analyzed. In conclusion, our results suggest that clonal somatic mutations of the
      TSHR gene do not play a role in the pathogenesis of differentiated thyroid
      carcinoma.

PMID- 10342362
TI  - Personality disorders in relation to anthropometric, endocrine and metabolic
      factors.
AB  - Subjects with abdominal obesity show several signs of a perturbed regulation of
      the hypothalamic-pituitary-adrenal (HPA) axis. This is known to occur after
      chronic, submissive stress. Perceived environmental stress is depending on
      personality characteristics. Therefore, personality disorders (PD:s) were
      examined in relation to HPA axis status, other endocrine and metabolic variables
      as well as anthropometry. Men (no.=284) aged 51 years, recruited in similar
      subgroups of low, median and high waist/hip circumference ratio (WHR) from a
      sample of 1302 men. Measurements of personality disorders by Structured Clinical
      Interview for DSM-III-R, Axis II (SCID II), body mass index (BMI, weight,
      kg/height2, m2), WHR and abdominal sagittal diameter (D), dexamethasone
      suppression test (0.5 mg, salivary measurements of cortisol), insulin-like growth
      factor I (IGF-I), testosterone and metabolic variables. Men with cluster A
      (paranoid, schizotypal, schizoid) PD showed an increased BMI, WHR and D,
      independent of dexamethasone suppression. Testosterone was decreased in these men
      in relation to a blunted dexamethasone suppression. BMI, WHR and D were increased
      in men with cluster B (borderline, histrionic, narcissistic) and cluster C
      (avoidant, dependent, obsessive compulsive, passive aggressive) PD, only in
      relation to a blunted dexamethasone suppression. Furthermore, IGF-I was low in
      cluster B. Metabolic variables were differently associated to clusters of PD but
      generally followed obesity. Path-analytic models suggested that cluster B and C
      PD were followed by blunted dexamethasone suppression and obesity. Men with
      cluster A PD showed centralized body fat distribution, independently of
      dexamethasone suppression. In contrast, men with impulsive (cluster B) and
      anxious (cluster C) personality disorders seem often to have abdominal obesity
      only in combination with a blunted dexamethasone suppression test, suggesting a
      HPA axis disturbance. These results suggest that PD:s are involved in the
      development of abdominal obesity in men, with different endocrine and metabolic
      profiles depending on the type of PD. This might hypothetically be due to
      frequent exposure and/or an increased sensitivity to environmental stress
      factors, caused by aberrant personalities.

PMID- 10342363
TI  - Demonstration of thyrotropin receptor mRNA in orbital fat and eye muscle tissues
      from patients with Graves' ophthalmopathy by in situ hybridization.
AB  - There is a controversy regarding whether there are thyrotropin (TSH) receptors in
      orbital fat and eye muscle tissues that may play a role in the pathogenesis of
      Graves' ophthalmopathy. To elucidate whether there are TSH receptors in orbital
      fat and eye muscle tissues in patients with Graves' ophthalmopathy, we applied
      the method of in situ hybridization in orbital fat and eye muscle tissues
      obtained during the operation for patients with Graves' ophthalmopathy, to
      directly detect TSH receptor mRNA. To identify whether the cells with positive
      TSH receptor mRNA are fibroblasts, we also did vimentin immunoreactivity study.
      To further prove the transcript does have a full length of TSH receptor, the
      samples of total RNA preparations, extracted from orbital fat and eye muscle
      tissues, were used as a template for reverse transcriptase polymerase chain
      reaction (RT-PCR) using three primer sets to generate cDNA fragments and cloned
      for sequencing. The results showed that the expression of TSH receptor mRNA was
      demonstrated in adipocytes and fibroblasts of orbital fat, and perimysial
      fibroblasts within eye muscle tissues by in situ hybridization and vimentin
      immunoreactivity study. Also, by using the RT-PCR, cloning and sequencing, we
      further proved that the transcript does have a full length of TSH receptor. The
      present study suggested that there are TSH receptors expressed in orbital fat and
      eye muscle tissues.

PMID- 10342364
TI  - Visualisation of a paraganglioma by technetium-99m-sestamibi scintigraphy.
AB  - A 68-yr-old woman presented to our observation with multinodular goiter and a
      contiguous right laterocervical mass. In spite of ultrasound, technetium and
      iodine scan, CT and fine-needle biopsy, the precise origin of the mass remained
      uncertain. On additional multi-phase sestamibi scan, the neck region showed an
      early high uptake rapidly decreasing over time in the laterocervical mass, and a
      persistent inhomogeneous distribution in the thyroid gland. This behavior
      suggested that the laterocervical mass could derive from an anatomical structure
      other than the thyroid. Surgical exploration established the extrathyroid nature
      of the laterocervical mass and the histological examination confirmed that it was
      a typical paraganglioma. This finding is in keeping with a recent report of
      positive sestamibi uptake in a cervical paraganglioma, although our case showed a
      more rapid kinetic. This tumor should be therefore taken into consideration in
      the differential interpretation of focal sestamibi uptake.

PMID- 10342365
TI  - Inefficiency of the anticoagulant therapy in the regression of the radiation
      induced optic neuropathy in Cushing's disease.
AB  - Radiation-induced optic neuropathy is a rare complication (prevalence less than
      1%) following radiotherapy of the sellar region. However, the vasculopathy in
      Cushing's disease predisposes to radiation-induced injury. We report the case of
      a 24-year-old man with Cushing's disease since he was 16. The hormonal study
      including bilateral inferior petrosal sinus catheterization diagnosed a pituitary
      right lesion, but imagiology was always negative. He underwent a transsphenoidal
      microadenomectomy and the pathological study showed the presence of
      corticotrophic hyperplasia but no adenoma. Secondary hypothyroidism and
      hypogonadism as well as permanent diabetes insipidus were diagnosed and because
      the patient was not cured he underwent a second transsphenoidal total
      hypophysectomy. After that and because he was still hypercortisolemic, pituitary
      external irradiation was given in a total dose of 6000 rad. Six months later he
      developed progressive bilateral visual loss. Cerebral MR revealed focal
      enhancement of the enlarged optic nerves and chiasm, associated with
      demyelination areas of the posterior visual pathways. Treatment was tried first
      with high doses of corticosteroids and later with anticoagulants-heparin EV. 1000
      U/h during 7 days followed by warfarin, but unsuccessfully, probably because the
      patient was already amaurotic at the beginning of the last treatment.

PMID- 10342366
TI  - Shrinkage of a PRL-secreting pituitary macroadenoma resistant to cabergoline.
AB  - Cabergoline decreases both serum PRL levels and size of prolactinomas, including
      some tumors resistant to other dopamine-agonists. It is common observation that
      the shrinkage of the adenoma is preceded by suppression of PRL levels. A minority
      of patients, who do not show a significant decrease of PRL after a short trial
      with dopamine-agonists, undergoes neurosurgery or radiotherapy. We report on the
      case of a 14-year-old girl with a huge prolactinoma who showed, during
      cabergoline treatment (0.5 mg twice a week), a significant shrinkage of the
      pituitary mass but no decrease of the very high PRL values. She was referred to
      us after partial removal of the suprasellar extension of the pituitary tumor. The
      post-surgical evaluation showed very high PRL levels (9352 microg/l; 20941
      microg/l before surgery), which did not decrease during the 2-year treatment with
      cabergoline (nadir value: 8735 microg/l). However, one month after the beginning
      of therapy, MRI showed a significant shrinkage of the tumor (tumor volume 5.7 ml,
      compared with 45.1 ml prior to surgery and 24.4 ml after surgery). Subsequently
      MRIs demonstrated a progressive reduction of the size with a complete
      disappearance of the suprasellar and parasellar tissue (tumor volume 1.8, 0.9 and
      0.2 ml, at 3, 6 and 12 months, respectively). The MRI performed at the 24th month
      showed a secondary empty sella, with residual tumor tissue in the right
      sphenoidal sinus. Increasing cabergoline, up to 3 mg a week, failed to induce any
      decrease of PRL levels. In conclusion, in such macroprolactinomas the shrinkage
      of tumor is not strictly correlated with (or it is partially dissociated from)
      the inhibition of PRL hypersecretion. The choice of other therapeutic options in
      cabergoline-resistant macroprolactinomas needs careful neuroradiological
      evaluation after a short trial of pharmacological treatment.

PMID- 10342367
TI  - Radioiodine is an effective, inexpensive, and safe treatment for Graves'
      hyperthyroidism, its immunological effects must be taken into account.

PMID- 10342369
TI  - Dehydroepiandrosterone replacement in elderly individuals: still waiting for the
      proof of beneficial effects on mood or memory.

PMID- 10342368
TI  - Is the measurement of free IGF-I more indicative than that of total IGF-I in the
      evaluation of the biological activity of the GH/IGF-I axis?

PMID- 10342370
TI  - Intravitreal pharmacokinetics in rabbits of the foscarnet lipid prodrug: 1-O
      octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA).
AB  - PURPOSE: To evaluate the intraocular distribution and metabolism of the lipid
      prodrug of foscarnet, 1-O-octadecyl-sn-glycerol-3- phosphonoformate (ODG-PFA),
      following intravitreal administration. METHODS: Twenty rabbits received ODG
      [14C]PFA intravitreal injection, yielding 0.632 mM resultant intravitreal
      concentration. Two animals per group were sacrificed at different intervals post
      injection. The drug levels in ocular tissues were determined with counting the
      radioactivity by Tracor Mark III Liquid Scintillation Counter. Four rabbits were
      used for analysis of the drug metabolism in vitreous by lipid extraction
      technique. RESULTS: The drug level in vitreous was 526 microM at day one and 227
      microM at the fifth week. The vitreous half life was approximately four to five
      weeks. The retinal level of the drug was 292 microM at day one, 75 microM at the
      fifth week and 32 microM at the tenth week, which was still more than ten times
      higher than the IC90 against HCMV. Lipid extraction analysis showed that, in
      vivo, both ODG-PFA and PFA were present in vitreous, but in in vitro incubations
      with vitreous, ODG-PFA conversion to PFA was negligible. CONCLUSION: ODG-PFA
      possesses a long vitreous half life and sustained high drug level in retina. The
      vitreous did not metabolize drug but acted as a drug reservoir. Intravitreal
      liposomal ODG-PFA may be expected to be a long acting potent local therapy for
      CMV retinitis.

PMID- 10342372
TI  - A comparison of the early inflammatory effects of an agr-/sar- versus a wild type
      strain of Staphylococcus aureus in a rat model of endophthalmitis.
AB  - PURPOSE: We examined the ability of a wild type and an isogenic mutant strain of
      Staphylococcus aureus, deficient in the production of hemolysins and lipase (agr
      (-)/sar (-)), to induce endophthalmitis and inflammatory cell infiltration into
      the eye at 6, 24 and 48 hours after injection in a rat model of endophthalmitis.
      METHODS: Rat eyes were injected with 25 microl of viable S. aureus or sterile
      saline. Eyes were graded for clinical signs of inflammation daily, removed and
      processed for standard histologic analysis 6, 24 and 48 hours after injections.
      Comparisons of clinical scores and mean inflammatory cell numbers were made
      between S. aureus and control injected eyes. RESULTS: Both experimental groups
      developed clinical signs of endophthalmitis and demonstrated infiltration of
      inflammatory cells at 24 and 48 hours. Clinical inflammation in the Mutant I
      group was less than the wild type group at these times and significantly less at
      48 hours (p<0.05). No statistically significant difference in the number of
      inflammatory cells was detected between the wild type and Mutant I injected eyes
      at 24 hours. At 48 hours, inflammatory cells increased by 75.0% in the wild type
      group and decreased by 19.0% in the Mutant I group and a statistically
      significant difference was seen between these two groups (p<0.05). At all times,
      the majority of inflammatory cells were neutrophils. By 48 hours, an increase in
      monocytes-macrophages was noted. CONCLUSION: Both strains of S. aureus induced
      clinical signs of inflammation and inflammatory cell infiltration. Clinical
      inflammation and inflammatory cell numbers were less in rats injected with the
      Mutant I strain. These results suggest that hemolysins and lipase may be
      important in the early induction phase of the inflammatory response.

PMID- 10342371
TI  - Corneal epithelial wound healing increases the expression but not long lasting
      activation of the p85alpha subunit of phosphatidylinositol-3 kinase.
AB  - PURPOSE: Corneal epithelial wound healing is a complex process involving several
      growth factors whose interaction with tyrosine kinase receptors (RTK) leads to
      the recruitment of enzymes coupled to second messengers that propagate and
      amplify growth factor-induced signals inside the cells. Phosphatidylinositol-3
      kinase (PI-3K) is one such enzyme. Here we have investigated changes in PI-3K
      activity and expression during re-epithelialization after in vivo and in vitro
      corneal injury. METHODS: For the in vivo model, epithelium was collected from
      rabbit corneas at different stages of wound healing after complete de
      epithelialization. For in vitro studies, after 7 mm central scrape wounds were
      applied, rabbit corneas were maintained in organ culture. Immunoprecipitation and
      Western blot using anti-p85alpha antibodies were employed to determine PI-3K
      activity and expression of the p85alpha regulatory subunit of PI-3K. Two specific
      PI-3K inhibitors, Wortmannin and LY 294002 were used to study the effect of PI-3K
      activity on corneal epithelial wound healing. RESULTS: Two to four days after in
      vivo corneal epithelial wound healing, there was a 6-8 fold increase in the
      expression of the p85alpha subunit of PI-3K. By 8 days, the expression of
      p85alpha was similar to non-injured tissue. Increased expression of the 85kDa
      protein was observed mainly in the membrane fraction. Similarly, the expression
      of PI-3K was increased 24h after injured corneas were maintained in organ
      culture. Increase of p85alpha was confined to the wound region and surrounding
      area. No concomitant increase in PI-3K activity was observed in any of the wound
      models. Forty-eight hours after the central injury, Wortmannin and LY294002
      inhibited wound healing by about 50%. CONCLUSIONS: Association of most of the
      increased p85alpha with the membrane fraction and no detectable increase in PI-3K
      activity during corneal re-epithelialization indicates that PI-3K activation is
      transitory. The results also suggest a mechanism of down regulation of the enzyme
      to avoid uncontrollable growth and cellular hypertrophy after growth factor
      stimulation during wound healing.

PMID- 10342373
TI  - Diurnal variations in angiostatin in human tear fluid: a possible role in
      prevention of corneal neovascularization.
AB  - PURPOSE: Although overnight eye closure is known to result in hypoxia and release
      of potent angiogenic factors, even prolonged eye closure does not result in
      corneal neovascularization. This suggests that the closed eye tear film may
      contain factors that can impede neovascularization. Closed eye tear fluid is
      known to contain proteases capable of converting plasminogen/plasmin to
      angiostatin and other angiostatin-like A-chain fragments which are potent
      inhibitors of angiogenesis. This study was designed to characterize open and
      closed eye tear fluid for the presence of these entities. METHODS: Open and
      closed eye tears were collected by microcapillaries from normal individuals.
      Tears were centrifuged and the supernatants analyzed by SDS-PAGE and western
      blotting. Membranes were probed with antibodies specific for the A-chain of
      plasmin and plasminogen and with antibodies specific for conformational domains
      on the smaller N terminal kringles 1-->4 and kringles 1-->3 fragments which are
      known angiogenesis inhibitors. Supernatants were also analyzed after
      fractionation by HPLC and binding to lysine sepharose 4B. The isolated fragments
      were identified based on size, lysine-binding capabilities, antigenic properties
      and by comparison with standards. RESULTS: Open eye tear fluid from all normal
      individuals contained low levels of plasminogen, but no detectable antigens
      consistent with free A-chain or angiostatins. Tears collected after overnight eye
      closure contained significant amounts of plasminogen, A-chain antigen and various
      A-chain fragments including kringles 1-->4 and kringles 1-->3 and most likely
      free kringle 5, all known to have anti-angiogenesis properties. These were often
      present in concentrations likely to be physiologically significant. In samples
      collected from an atopic subject, the concentration of angiostatins in CTF
      increased markedly during active phases of the disease reaching levels of several
      ng/microl. In these instances and in similar samples obtained from other atopic
      individuals experiencing active reactions, angiostatin was often detectable in
      basal-type tear fluid. CONCLUSION: A-chain fragments, which can inhibit
      angiogenesis, are often present at physiologically significant levels in human
      tear fluid collected after overnight eye closure. These fragments may play a role
      in preventing neovascularization in the hypoxic closed eye environment and may
      well be up regulated during inflammatory reactions.

PMID- 10342374
TI  - The effect of abnormal fixational eye movements upon visual acuity in congenital
      nystagmus.
AB  - PURPOSE: The purpose of this study was to investigate the role that abnormal eye
      movements play in the degradation of visual acuity. METHODS: Visual acuity was
      measured monocularly in 10 normal subjects (26.7+/-4.3 years) and 5 subjects with
      congenital nystagmus (34.9+/-8.8 years), using Regan Repeat Letter charts (RRL)
      and a logMAR based test (LogMAR Crowded Acuity Test (CAT)) while eye movements
      were continuously recorded using a commercially available infrared limbal eye
      tracker (Type 54, Optoelectronic Developments, UK). The eye tracker was
      controlled via a virtual oscilloscope (Viewdac, Keighly Instruments, UK) on an
      IBM PC clone (Opus Technology 486). RESULTS: The mean visual acuity obtained with
      RRL was significantly higher than that obtained by CAT in the subjects with
      congenital nystagmus. A significant correlation was found between the root mean
      square value of the nystagmus waveform and the angular extent of CAT. Linear
      regression analysis revealed a correlation between the duration of the foveation
      periods and the linear acuity of the subjects with congential nystagmus. The
      nystagmus waveforms also demonstrated increased amounts of high frequency
      components (HFC: >3.0 Hz) when compared to the normal eyes. CONCLUSIONS: The
      results of this study reveal 1) RRL charts provide a measure of a subjects
      resolution limit which is less dependent on eye movements; 2) the duration of
      foveation periods has a significant effect on visual acuity measurements obtained
      using a linear test chart format; 3) the predominance of high frequency
      components in the congenital nystagmus waveforms lead to short foveation periods
      adding to the degree of fixation instability.

PMID- 10342375
TI  - Expression of vascular endothelial growth factor and its receptor (KDR/flk-1)
      mRNA in experimental choroidal neovascularization.
AB  - PURPOSE: Vascular endothelial growth factor (VEGF) is an angiogenic peptide that
      has been suggested to be important in the pathogenesis of choroidal
      neovascularization. We investigated the transcription of VEGF and its receptor
      KDR/flk-1 genes during the development of experimentally induced choroidal
      neovascularization. METHODS: Rat VEGF or KDR cDNA was inserted in PGEM or
      pBluescript to prepare antisense or sense riboprobes. Multiple krypton laser
      burns were applied to the posterior pole of pigmented rat eyes according to a
      previously described protocol which produces choroidal neovascularization. At
      intervals of up to 4 weeks after photocoagulation, the eyes were removed and cut
      into thin sections. The sections were subjected to in situ hybridization with
      digoxigenin (DIG)-labeled single-strand rat VEGF and KDR cDNA riboprobes.
      RESULTS: In normal adult rat retinas, VEGF and KDR mRNA expression was mainly
      observed in the ganglion cell and the inner nuclear layers. During the
      development of neovascularization, VEGF and KDR mRNAs were detected in retinal
      pigment epithelial-like cells, fibroblast-like cells and endothelial cells in
      neovascular lesions. The level of expression was strongest at 1 week after
      photocoagulation in lasered lesions, and decreased by 4 weeks after
      photocoagulation. CONCLUSIONS: Our findings demonstrate that expression of VEGF
      and its receptor KDR may play a role in the formation of experimentally induced
      choroidal neovascularization. In this study, VEGF and its receptor were co
      localized, suggesting that an autocrine and/or paracrine mechanism may be
      operative.

PMID- 10342376
TI  - Kinetics of cyclic AMP-dependent accumulation of novel intermediate filament
      proteins in cultured chick lens cells.
AB  - PURPOSE: To refine the parameters affecting the accumulation of cytoskeletal
      markers of lens fiber terminal differentiation. METHODS: Primary cultures of
      chick lens annular pad cells were treated with a lipid soluble cyclic AMP analog
      under various culture conditions. The accumulation of beaded filament proteins,
      unique markers of lens fiber terminal differentiation, was quantified with an
      ELISA assay. The incorporation of beaded filament proteins into macromolecular
      structures was followed with immunofluorescence microscopy. RESULTS: In a time-
      and dose-dependent manner, beaded filament protein levels were increased in
      cyclic nucleotide treated cells. The addition of serum to treated cells caused a
      further dose-dependent increase in beaded filament protein levels. The continuous
      presence of cyclic nucleotides for maximal beaded filament protein accumulation
      was also established. At the light microscopic level, cyclic nucleotide treatment
      produced much more extensive multilayering of cells and lentoid formation.
      Macromolecular structures containing beaded filament proteins also increased in
      both abundance and complexity after cyclic nucleotide treatment and were
      restricted to the multilayers/lentoids. CONCLUSIONS: These results indicate that
      multiple mechanisms (including cyclic AMP, serum factors, and the degree of cell
      cell interactions) affect the accumulation of beaded filament proteins during the
      normal differentiation of lens fibers.

PMID- 10342377
TI  - DNA repair and survival in human lens epithelial cells with extended lifespan.
AB  - PURPOSE: Ultraviolet-B radiation (290-320 nm) produces cataracts in animals and
      has been associated with human cataract formation in several epidemiological
      studies. UVB radiation decreases the long-term cell survival and changes the
      pattern of protein synthesis in cultured lens epithelial cells. However, the
      relationship between DNA photoproduct formation and long term cell survival in
      human lens epithelial cells is not known. In the present work, we used human lens
      epithelial cells with extended lifespan (HLE B-3 cells) to examine the kinetics
      of DNA repair and cell survival after UVB exposure. METHODS: Cyclobutane
      pyrimidine dimers and pyrimidine-pyrimidone (6-4) photoproducts were analyzed by
      radioimmunoassay. Long-term survival of the cells was determined by measuring
      their ability form colonies when plated at low density. RESULTS: HLE B-3 cells
      were repair competent after UVB (302 nm) exposure. Excision repair of the (6-4)
      photoproduct was more efficient than that of the cyclobutane dimer. Ninety five
      percent of the (6-4) photoproducts were repaired 24 h after 400 J/m2 UVB
      exposure, whereas 50% of the cyclobutane dimers were repaired during this time.
      When cells were split for the clonogenic assay immediately after irradiation,
      only 10% of the cells formed colonies following 7 days of culture in the serum
      containing medium. When cells were split for the clonogenic assay after a 48 hour
      incubation in serum-containing medium, the colony-forming ability of the
      irradiated cells increased to 60% following culture in a serum-containing medium.
      CONCLUSIONS: These results indicate a close correlation between the repair of
      cyclobutane dimers and the increase in the long-term survival of the cells as
      measured by their colony-forming ability. The extended lifespan human lens
      epithelial cells HLE B-3 may be a useful model to investigate the mechanism and
      regulation of UVB-induced DNA repair in human lens cells.

PMID- 10342378
TI  - Alterations in protein tyrosine kinase pathways following retinal vein occlusion
      in the rat.
AB  - PURPOSE: To determine whether an experimental retinal vein occlusion in the rat
      activates protein tyrosine kinase pathways and increases angiogenic growth
      factors in the retina. METHODS: Retinal vein occlusion (RVO) was induced in the
      rat retina with argon laser photocoagulation. Retinas were collected at 2 days,
      1, 2, and 4 weeks after RVO and divided into halves: one half represented an area
      within the distribution of the occluded vein [RVO(IN)] and the other half
      represented an area outside the distribution of the occluded vein [RVO(OUT)].
      RVO(IN) and (OUT) were examined by western blot analysis of tyrosine
      phosphorylated proteins, vascular endothelial growth factor (VEGF), basic
      fibroblast growth factor (bFGF), and 3 signal proteins in the tyrosine kinase
      pathways: phospholipase Cgamma (PLCgamma), phosphatidylinositol 3-kinase (PI3K),
      and mitogen-activated protein kinase (MAPK). RESULTS: RVO caused a severe
      capillary nonperfusion in RVO(IN). Overall tyrosine-phosphorylated proteins were
      increased after RVO, especially in RVO(IN) at 2 days and 1 week. VEGF and bFGF
      were markedly increased in RVO(IN) at 2 days and 1 week. Tyrosine-phosphorylated
      PLCgamma, PI3K, and MAPK were also increased in RVO(IN) at these time points.
      CONCLUSIONS: RVO caused an increase in overall protein tyrosine phosphorylation
      in the rat retina. This increase was associated with an increase in angiogenic
      growth factors (VEGF and bFGF). These results suggest that protein tyrosine
      kinase pathways are activated during retinal ischemia and may play a role in
      mitogenesis of vascular endothelial cells and other responses in the retina after
      RVO.

PMID- 10342379
TI  - Role of P-glycoprotein in distribution of rhodamine 123 into aqueous humor in
      rabbits.
AB  - PURPOSE: Examination of the contribution of functional P-glycoprotein (P-gp), an
      ATP-dependent efflux pump, in blood-aqueous barrier in rabbits. METHODS:
      Rhodamine-123 (Rho-123), a P-gp substrate, was administered intravenously via the
      marginal ear vein of rabbits. Rhodamine B (Rho-B), an analogue of Rho-123, was
      also injected with the same dose, as a reference compound. Quinidine at different
      concentrations was applied topically to the corneal surface by eye drops prior to
      the intravenous administration of a Rho compound. The aqueous distribution (a
      ratio of concentration in aqueous humor to that in plasma) of these Rho compounds
      was analyzed in relation to the aqueous concentration of quinidine. Transport
      study across Caco-2 cell monolayers was carried out to examine the involvement of
      P-gp in Rho-B transport. RESULTS: It was proved that Rho-B is not a P-gp
      substrate by a transport study across Caco-2 cell monolayers, in contrast to Rho
      123 (a P-gp substrate). The aqueous distribution of Rho-123 given intravenously
      was significantly lower than that of Rho-B. Topical quinidine (a P-gp inhibitor)
      markedly increased the aqueous distribution of Rho-123, depending on the aqueous
      concentrations of quinidine, though it did not affect the aqueous distribution of
      Rho-B. CONCLUSIONS: The contribution of functional P-gp in blood-aqueous barrier
      was clearly demonstrated by analyzing the aqueous distribution of Rho-123 in the
      presence or absence of quinidine. These experiments only allow us to address one
      part of the blood-aqueous barrier, the capillary endothelium, and, to do so by
      using different substrates for P-gp, a sort of chemical analogy with the presumed
      blood-aqueous barrier across capillary endothelia. The alteration of P-gp
      function by pharmacotherapy or in pathological state should be considered in the
      ophthalmic medical treatment.

PMID- 10342380
TI  - Development and characterisation of supramolecular autovectoring system for
      selective drug delivery.
AB  - Supramolecules since ages have been characterised as self-associating systems
      emanating the properties directly related to the mode of molecular association.
      Similar to supramolecules, liquid crystals may also be considered as an
      associated system. The liquid crystals are defined as the state of matter with
      the characterstic order of the crystal and the mobility of liquid. The system has
      been compared to the transporting form of cholesterol in body. The present study
      reports autovectoring potentials of the drug liquid crystals using diclofenac
      diethylammonium (DD) as a model. The drug based liquid crystals of DD were
      prepared employing temperature induced transformation of isotropic form to the
      liquid crystal form. The prepared liquid crystal systems were incubated with 1%
      phosphatidylcholine in order to stabilise the surface and restrict it into the
      liquid crystalline state. The system was characterised for viscosity variation, X
      ray diffraction pattern, partitioning behaviour and in vitro diffusion profile.
      In vivo vectorising potential of the developed system was evaluated using rats as
      test animal and studying for the organ level distribution and drug
      compartmentalisation. The system exhibited satisfactory vecterisation as
      significant amount of administered dose was localised selectively in liver.

PMID- 10342381
TI  - Anti-HIV-1 activity of combinations and covalent conjugates of negatively charged
      human serum albumins (NCAs) and AZT.
AB  - Negatively charged albumins (NCAs, with the prototypes Suc-HSA and Aco-HSA),
      modified proteins with a potent anti-HIV-1 activity in the nanomolar
      concentration range, were studied for several aspects of their antiviral
      mechanism. In addition we investigated the antiviral activity of combinations and
      covalent conjugates of these NCAs and the reverse transcriptase inhibitor AZT.
      Addition of NCAs to HIV-1-infected target cells in time-of-addition experiments
      could be delayed for 30 min after infection before significant loss of activity
      occurred. Syncytium formation of HIV-infected and uninfected T-cells was
      inhibited by the NCAs at concentrations of 1-4 microg/ml. The gp120-mediated
      virus/cell binding, however, was only inhibited by the NCAs at a 10-fold higher
      concentrations. The combined data are compatible with a preferential influence on
      virus/cell fusion. A subsynergistic activity against HIV-1 was observed with the
      non-covalent mixture of Aco-HSA and AZT. When AZT was covalently coupled to the
      NCAs, and added one hour after infection of the target cells, the anti-HIV-1
      activity of NCA-AZTMP was diminished by only 2-6-fold, while this was diminished
      at least 120-fold for the NCAs. Furthermore the addition of NCA-AZTMP could be
      delayed up to at least 3 h after infection without loss of antiviral activity. It
      is concluded that AZT that was coupled to the NCAs significantly contributes to
      the overall antiviral activity of the conjugates leading to complementary
      effects. These results highlight the potential of using NCA-AZTMP as dual
      targeting preparations against HIV-1 in which both the carrier and the coupled
      drug contribute to the therapeutic efficacy acting at a different level in the
      replication cycle.

PMID- 10342382
TI  - Organ selective delivery using a tissue-directed streptavidin--biotin system:
      targeting 5-fluorouridine via TNP-streptavidin.
AB  - Trinitrophenyl (TNP) modification of streptavidin (St) resulted in high and
      prolonged accumulation in mouse liver following intravenous administration of
      radioiodinated TNP streptavidin (TNP-St). Uptake, which is correlated with
      increased TNP substitution, was first observed at 2-3 h, increased to 40-50% of
      injected dose/gram tissue (%/g) at 24 h and slowly declined later on. A low
      degree of accumulation (10%/g) was observed in the spleen. TNP substitution of
      other proteins such as bovine serum albumin (BSA) or ovalbumin (Ova) led to a
      transient short-term liver uptake. The enzyme-resistance property of streptavidin
      and its biotin binding sites render TNP-modified streptavidin a potential
      targeting vehicle to the liver. 5-Fluorouridine (FUR) was attached to high
      molecular weight carrier carboxymethyldextran (CMdex, derived from 40 kDa
      dextran) and the dextran FUR conjugate was charged with 2-4 biotinyl groups (in
      the form of biotinyl-diaminopropionyl-tyrosine, BDT) for complexing to TNP-St.
      Biodistribution monitoring of the BDT-CMdex-FUR ligand, radiolabeled at the
      tyrosyl residue of BDT and targeted via non-radiolabeled TNP-St, showed that
      ligand accumulation in the liver was similar to TNP-St itself. Liver targeting of
      FUR was demonstrated by trace-labeling FUR with its structural analog 5,6
      [3H]uridine prior to conjugation to dextran hydrazide. Specific liver
      accumulation of [3H] radioactivity occurred following administration of the
      conjugate only when complexed to TNP-St. Hepatic levels of [3H] radioactivity
      were in the range of 25%/g or 35% per whole liver during a period of at least 8
      h, as compared to the rapid elimination of free FUR+[3H]uridine (4%/g at 20 min).
      [3H]-drug radioactivity disappeared at a faster rate as compared to 125I-dextran
      radioactivity, suggesting that metabolic processes required to generate the 5,6
      [3H]uracil-containing active metabolites took place.

PMID- 10342384
TI  - Light and electron microscopic findings in a model of human cutaneous candidosis
      based on reconstructed human epidermis following the topical application of
      different econazole formulations.
AB  - The effects of two commercially available econazole formulations (econazole
      nitrate cream, econazole liposome gel) on uninfected reconstructed human
      epidermis and on a model of human cutaneous candidosis were investigated. The
      morphological alterations of the reconstructed epidermis after infection and
      treatment were analysed with light and electron microscopy. The most important
      Candida albicans-specific alterations of the recently established in vitro model
      of human cutaneous candidosis were scaling, hyperkeratosis, parakeratosis,
      dyskeratosis and spongiosis. A single application of the cream to the uninfected
      reconstructed epidermis caused more epidermal barrier damage and irritative toxic
      effects than the liposome gel. Treatment of the modelled human cutaneous
      candidosis with the cream also resulted in increased toxic effects, e.g.,
      enhancement of scaling with invasion of Candida albicans blastospores into the
      stratum corneum and intracellular vacuoles. After application of the liposomal
      preparation invasion of Candida albicans in the stratum corneum could not be
      detected and toxic effects were reduced. Some of the Candida albicans-specific
      alterations such as hyperkeratosis, focal thickening of the stratum corneum,
      dyskeratosis and parakeratosis were completely eliminated. The liposomal
      formulation increased slightly the morphological alterations of the blastospores.
      Remnants of the cream formulation could be detected only very rarely in the
      stratum corneum or the blastospores. The liposomal preparation showed a strong
      affinity for the Candida albicans cells and the stratum corneum. Intact liposomes
      could even be observed in the intercellular spaces of the upper stratum corneum.
      As successful treatment depends on the ability to target the liposomal agent to
      the wanted site of action, this might be useful for more effective treatment of
      cutaneous candidosis.

PMID- 10342383
TI  - Pharmacokinetic evaluation of mannosylated bovine serum albumin as a liver cell
      specific carrier: quantitative comparison with other hepatotropic ligands.
AB  - To assess the feasibility of mannosylated macromolecules as a liver-specific
      carrier system, hepatic uptake characteristics of mannosylated bovine serum
      albumin (Man-BSA) were pharmacokinetically investigated. After intravenous
      injection, 111In-Man18-BSA accumulated in the liver up to 70% of dose at 2h; the
      endothelial cells and Kupffer cells contributed about 66% and 21% of the uptake,
      respectively. In single-pass perfusion experiments using rat liver at varying
      inflow concentrations (0.1-2.0 microg/ml), 111In-Man18-BSA and 111In-Man33-BSA
      were continuously extracted by the liver and their extraction ratios decreased
      with the increasing inflow concentrations. The outflow curves of each 111In-Man
      BSA at three concentrations were simultaneously fitted to a pharmacokinetic model
      including a binding to the cell surface and an internalization, by using a
      nonlinear regression program MULTI(RUNGE). The binding constant augmented with
      the increase in the number of mannose per BSA, whereas the internalization rate
      constant was quite comparable for both derivatives. The pharmacokinetic analysis
      has demonstrated that the uptake process of 111In-Man-BSA is characterized to
      possess fewer binding sites and a greater internalization rate in comparison with
      other liver-specific carriers such as galactosylated, succinylated and cationized
      BSAs. These results will provide useful information in designing drug targeting
      systems to the liver nonparenchymal cells via mannose receptors.

PMID- 10342385
TI  - Influence of the surfactant concentration on the body distribution of
      nanoparticles.
AB  - The rapid reticuloendothelial system (RES) uptake of nanoparticles after i.v.
      injection, especially by the liver, can be reduced and the body distribution can
      be altered by coating them with non-ionic surfactants. In the present work 2-14C
      poly(methyl methacrylate) nanoparticles were coated with poloxamine 908 and
      polysorbate 80, and the influence of different surfactant concentrations on the
      body distribution was investigated. These surfactants were chosen because earlier
      studies showed that poloxamine 908 was very effective in decreasing the liver
      uptake and keeping the nanoparticles in circulation, whereas polysorbate 80 was
      the most effective surfactant to direct the particles to organs that do not
      belong to the RES. Above nanoparticles were injected i.v. to rats and the animals
      were sacrificed after 30 min. Below a surfactant concentration of 0.1% the
      nanoparticle preparations behaved like uncoated particles. At a 0.1%
      concentration a very sudden and significant change in the body distribution
      occurred with poloxamine 908. The liver concentration decreased from about 75% of
      the dose to 13% and stayed at this level at higher surfactant concentrations.
      This decrease was combined with a similar sudden complementary increase in blood
      and other organ and tissue concentrations. With polysorbate 80 the decrease in
      liver concentration and increase in the blood and the other organ levels was
      gradual and became important only above 0.5% surfactant concentration. The
      results indicate that the type of interaction and the strength of the adsorptive
      binding to the nanoparticles are different with different surfactants. This in
      turn leads to different body distribution patterns after i.v. injection of
      surfactant coated nanoparticles.

PMID- 10342386
TI  - Musculoskeletal manifestations of osteomalacia: report of 26 cases and literature
      review.
AB  - OBJECTIVE: This study was undertaken to describe the musculoskeletal
      manifestations in a selected population of 26 patients with biopsy-proven
      osteomalacia (OM) and provide a literature update. METHODS: The 26 patients with
      biopsy-proven OM were selected from a total number of 79 patients who underwent
      anterior iliac crest biopsy. The diagnosis of OM was confirmed by the presence of
      an osteoid volume greater than 10%, osteoid width greater than 15 microm, and
      delayed mineralization assessed by double-tetracycline labeling. RESULTS: OM was
      caused by intestinal malabsorption in 13 patients, whereas six other patients
      presented with hypophosphatemia of different causes. Five elderly patients
      presented with hypovitaminosis D, and in two patients the OM was part of renal
      osteodystrophy. Twenty-three patients presented with bone pain and diffuse
      demineralization, whereas three other patients had normal or increased bone
      density. Characteristic pseudofractures were seen in only seven patients. Six of
      the 23 patients with diffuse demineralization had an "osteoporotic-like pattern"
      without pseudofractures. Prominent articular manifestations were seen in seven
      patients, including a rheumatoid arthritis-like picture in three, osteogenic
      synovitis in three, and ankylosing spondylitis-like in one. Two other patients
      were referred to us with the diagnosis of possible metastatic bone disease
      attributable to polyostotic areas of increased radio nuclide uptake caused by
      pseudofractures. Six patients also had proximal myopathy, two elderly patients
      were diagnosed as having polymalgia rheumatica, and two young patients were
      diagnosed as having fibromyalgia. One of the patients who presented with
      increased bone density was misdiagnosed as possible fluorosis. CONCLUSION: OM is
      usually neglected when compared with other metabolic bone diseases and may
      present with a variety of clinical and radiographic manifestations mimicking
      other musculoskeletal disorders.

PMID- 10342387
TI  - Pierre Cazenave and the first detailed modern description of lupus erythematosus.
AB  - OBJECTIVES: To provide an English translation of the first detailed description
      of lupus erythematosus along with a reproduction of the first color illustration
      of the disorder, as well as an interpretive analysis. METHODS: Review of primary
      and secondary historical sources. RESULTS: Although lupus as we know it was first
      mentioned in medieval times, the first, extensive, accurate classification and
      description of the condition represented an evolution of Pierre Cazenave's
      thinking over his 60-year professional career. CONCLUSIONS: Given his complete
      lack of effective diagnostic tools, Dr. Cazenave demonstrated tremendous
      intuitive powers of deduction in shaping our understanding of the disorder.

PMID- 10342388
TI  - Parvovirus infection mimicking systemic lupus erythematosus in a pediatric
      population.
AB  - OBJECTIVES: To assess the striking similarities of presentation in a pediatric
      population between human parvovirus B19 (HPV-B19) infection and systemic lupus
      erythematous (SLE). METHODS: Medical records of seven patients (ages 6 to 15)
      with HPV-B19 infection were reviewed retrospectively. RESULTS: Six of seven cases
      presented with a history of malar rash, and all seven had prolonged arthralgias
      and fatigue. Six of seven had a positive antinuclear antibody (ANA) titer ranging
      from 1:40 to greater than 1:640, with two patients having antibodies to Scl-70
      and others to Sm, RNP, SS-A (Ro), or SS-B (La). The erythrocyte sedimentation
      rate (ESR) varied from 2 to 68 mm/h. Two patients presented with elevated
      rheumatoid factor (RF) titers of 24 and 271 IU/mL, respectively. All had elevated
      IgM antibody levels to parvovirus at the onset, and markedly elevated IgG levels
      when evaluated throughout their disease course. Over the course of 2 to 3 months,
      three improved, but the other four continued to have symptomatology for 14, 40,
      78, and 120 weeks, respectively. Treatment was symptomatic, and no one developed
      classic SLE. CONCLUSIONS: HPV-B19 infection in a pediatric patient group may
      present with SLE-like symptomatology and positive serology suggestive of SLE. The
      course of the disease is usually self-limited, though it may be prolonged in some
      for up to 120 weeks.

PMID- 10342389
TI  - Human parvovirus B19 infection: its relationship with systemic lupus
      erythematosus.
AB  - OBJECTIVES: The clinical presentation and outcome of four cases of human
      parvovirus-B19 (HPV-B19) infection, initially diagnosed as systemic lupus
      erythematosus (SLE), were reviewed and compared with similar cases previously
      reported in the literature. The relationship between HPV-B19 infection and SLE is
      discussed. METHODS: The medical records of four patients with documented HPV-B19
      infection, initially diagnosed as SLE, were reviewed and studied in detail. A
      Medline search from 1985 to 1997 was performed to identify other cases reported
      in the literature in which a relationship between HPV-B19 and SLE had been
      identified in both adults and children. RESULTS: In all of our cases, the
      clinical findings (fever, rash, arthritis and malaise) and hematologic data
      (leukopenia, thrombocytopenia, anemia, presence of autoantibodies,
      hypocomplementemia, etc.) had initially suggested a diagnosis of juvenile SLE.
      Subsequently, evidence of HPV-B19 infection at the time of clinical presentation
      was ascertained. In three of these cases, the disease course was self-limiting
      with complete clinical remission and normalization of hematologic abnormalities
      within 18 months; one case, however, had persistent disease activity and repeated
      exacerbations. CONCLUSIONS: The occurrence of HPV-B19 infection has been
      documented in patients with SLE, in particular in relation to disease onset.
      Similarities in clinical and immunological features of viral infections and SLE
      at presentation may hinder the differential diagnosis between these two
      conditions. The family history, a self-limiting disease course and certain
      disease specific clinical aspects may help the pediatrician formulate an accurate
      diagnosis. In our patients, HPV-B19 infection may have mimicked the onset of SLE
      in three cases, but triggered the disease in one.

PMID- 10342390
TI  - Association of antiphospholipid antibodies with retinal vascular disease in
      systemic lupus erythematosus.
AB  - OBJECTIVES: To study the prevalence and characteristics of retinal vascular
      disease in patients with systemic lupus erythematosus (SLE) and to analyze their
      relationship with antiphospholipid antibodies (aPL) and other serological
      markers. PATIENTS AND METHODS: Eighty-two consecutive patients (77 women and 5
      men; mean age, 36 years) were studied. All patients fulfilled the 1982 revised
      criteria of the American College of Rheumatology for the classification of SLE.
      Ophthalmologic examination included assessment of best corrected visual acuity,
      tonometry, slit-lamp biomicroscopy, and fundus examination. Serologic studies
      included determination of anticardiolipin antibodies (aCL) (ELISA), lupus
      anticoagulant (LA) (coagulation tests), antinuclear antibodies (indirect
      immunofluorescence), anti-DNA (Farr's test), and anti-ENA antibodies
      (counterimmunoelectrophoresis). RESULTS: Retinal vascular disease was detected in
      13 (15%) of 82 SLE patients. The retinal lesions consisted of retinal vascular
      occlusions in six patients (five arterial and one venous), cotton-wool spots in
      three, optic disc edema in three, retinal hemorrhages in three, and ischemic
      optic neuropathy in one. Antiphospholipid antibodies were detected in 10 (77%) of
      these 13 patients: nine had aCL and two had the LA. When compared with patients
      without retinal vascular disease, patients with retinopathy had a higher
      prevalence of aPL (77% v. 29%, P = .005). CONCLUSIONS: Retinal vascular disease
      is frequent in patients with SLE. The presence of aPL is associated with a higher
      prevalence of retinal abnormalities in SLE patients.

PMID- 10342391
TI  - Media coverage of chronic diseases in the Netherlands.
AB  - OBJECTIVE: Little is known about the quantity or quality of information on
      rheumatic diseases provided by the mass media. The aim of this study was to gain
      insight into the media coverage of rheumatic diseases compared with other chronic
      diseases in the Netherlands. MATERIALS AND METHODS: Newspaper articles, magazine
      articles, and medical television programs that appeared or were broadcast during
      a 1-year period, and contained information on rheumatic diseases, heart disease,
      cancer, chronic lung disease, or diabetes mellitus, were selected for content
      analysis. For each article and program, it was determined whether coverage
      concentrated on treatment, influence of lifestyle, scientific progress, or
      disease consequences. It was also determined whether professional experts and
      patients were featured. RESULTS: Nine hundred seventeen newspaper articles, 304
      magazine articles, and 163 medical programs were found. Most dealt with cancer
      (43%) and heart disease (37%). The amount of media attention given to each of the
      five disease categories was found to correspond with mortality but not with
      prevalence. The contents of the articles and programs differed significantly
      according to disease topic. The main focus in rheumatic diseases was on patients'
      experiences, as well as regular and alternative medications. In heart disease and
      cancer, the main focus was on professional medical viewpoints, operations, and
      mortality, whereas in chronic lung disease and diabetes it was on treatments in
      the context of regular medications, scientific progress, and incurability. The
      influence of lifestyle on the disease process was mentioned most often in
      connection with diabetes, rheumatic disease, and chronic lung disease.
      CONCLUSIONS: The amount of attention a disease category received from the media
      depended on its fatality rates and not on its prevalence. Heart disease and
      cancer were portrayed as being more serious than the more lingering diseases.
      Surprisingly, the proportion of articles and programs that included the influence
      of lifestyle in their coverage was lowest for cancer and heart disease. More
      frequent and more accurate coverage of chronic diseases, especially rheumatic
      diseases, is needed if their image is to be brought into line with their
      importance for and impact on the community.

PMID- 10342392
TI  - The lack of associations between rheumatoid arthritis and both nulliparity and
      infertility.
AB  - OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease that occurs more
      commonly in women and frequently onsets in women of childbearing age. Pregnancy
      often causes disease remission, with a subsequent flare postpartum. Nulliparity
      may be a risk factor for RA, but the literature does not consistently report this
      finding. There may be a production of antibodies in women with RA that could lead
      to infertility, and subsequent nulliparity, but this has not been proved. We
      wanted to determine whether there was a relationship between nulliparity,
      infertility, oral contraceptive use, and adverse pregnancy outcome in women with
      newly diagnosed RA. METHODS: Through a case control study, using a mailed
      questionnaire, we compared the fertility and pregnancy outcome histories of 34
      women between the ages of 19 and 44 years with recent-onset RA with 68 healthy
      controls matched for age and marital status. The response rate was 97%. A review
      of the literature also was performed to study the associations between RA and
      infertility and nulliparity, using Medline searching key references. RESULTS: We
      found no association between infertility and the onset of RA. Seventy-one percent
      of women with RA and 68% of controls had been pregnant. There was a trend toward
      increased nulliparity in these patients, but the result was not statistically
      significant (odds ratio [OR], 1.4; P<.6). There were no differences in the number
      of children (2.6 v. 2.7; P<.6) and parity outcomes in the two groups. Age at
      first pregnancy was younger in the women with RA (22.6 v. 25.5 years; P<.008),
      but the education level was higher in the controls (P<.0001), which may explain
      these differences. Oral contraceptive use was lower in the RA women, but more RA
      women had long-term use (greater than or equal to 5 years), and neither result
      was statistically significant. Literature review shows that at best, there are
      weak negative associations between current estrogen use and RA, and no
      association with nulliparity and infertility. CONCLUSIONS: It appears that
      infertility, the number of pregnancies, and pregnancy outcome are not strongly
      associated with the risk of developing RA in women of childbearing age. However,
      in this study there may have been selection biases in the women with RA and the
      controls that differentially could have affected their reproductive outcomes.
      Thus, a true association could have been missed. Most other published studies
      find no association between nulliparity and RA.

PMID- 10342393
TI  - Peritoneal sarcoidosis: case report and review of the literature.
AB  - OBJECTIVES: This study was performed to report a patient with peritoneal
      sarcoidosis and review the literature for similar cases. METHODS: We described
      the clinical presentation, course, and outcome of the patient, and reviewed the
      medical literature from 1966 till 1997 using MEDLINE and the key words
      sarcoidosis, scar, and peritoneum. RESULTS: Our patient presented with a rapidly
      growing tumor-like mass at the site of an old appendectomy scar. Laparoscopy
      showed a large peritoneal mass and multiple small peritoneal nodules that were
      found to be noncaseating granulomas by pathology. The MEDLINE search uncovered
      only 16 cases of peritoneal sarcoidosis, most of which presented with ascites.
      CONCLUSION: This case illustrates the need to consider sarcoidosis, in addition
      to infections and neoplasms, in the differential diagnosis of peritoneal nodules
      and exudative ascites.

PMID- 10342394
TI  - Discriminative fear conditioning to context expressed by multiple measures of
      fear in the rat.
AB  - There has been a renewed interest in the neural basis of fear conditioning to
      context. These current approaches are accompanied by some limitations including
      the use of short testing windows, non-discriminative paradigms, and unitary fear
      response assessment. In an attempt to circumvent these limitations, a
      discriminative context procedure assessing multiple response measures of fear was
      used in the present study. Conditioning consisted of three training sessions and
      each session consisted of 2 days. On day one, the animals were placed in the
      paired context and received three foot shocks. On the other day, they were placed
      in the unpaired chamber in the absence of any aversive event. Animals were tested
      after each training session and the response measures of fear recorded included:
      preference, freezing, heart rate, ultrasonic vocalizations, defecation, body
      temperature, urination and locomotion. The results suggest that behavioral, as
      well as physiological changes evoked by fearful stimuli become associated with
      the context in which the aversive event occurred. In general these findings also
      suggest that there are different learning parameters for the measures of fear
      examined in this paradigm.

PMID- 10342395
TI  - Estrous cycle differences in cocaine-induced stereotypic and locomotor behaviors
      in Fischer rats.
AB  - This study was conducted to characterize female behavioral response to acute
      'binge' pattern cocaine administration (15 mg kg(-1) i.p., three times a day, at
      1 h intervals) during the different stages of the estrous cycle in Fischer rats.
      Cocaine administration significantly increased stereotypic behavior and
      locomotion in females. Animals in estrus showed significantly higher cocaine
      induced stereotypic and locomotive behavioral responses than those in other
      stages of the cycle. Plasma levels of the cocaine metabolite benzoylecgonine
      during metestrus diestrus were significantly higher than during estrus and
      proestrus probably reflecting more rapid biotransformation of cocaine. Therefore,
      it is likely that the hormonal fluctuations associated with the estrous cycle
      modulate both cocaine metabolism and the behavioral responses to cocaine in
      female rats. This in turn may have important implications in gender differences
      in behavioral responses to cocaine.

PMID- 10342396
TI  - Behavioural effects of a subconvulsive dose of kainic acid in rats.
AB  - Kainic acid can induce a continuum of non-convulsive seizures characterised by
      epileptic automatisms and convulsive motor seizures depending on the dose. There
      are scarce data on the behavioural effects of low doses of kainate inducing only
      non-convulsive seizures. Therefore, we studied spontaneous behaviour of adult
      male rats using a method of positive habituation based on a detailed analysis of
      patterns and attention of animals to a stimulus object. Twenty-three animals were
      individually tested in the experimental arena on two consecutive days. Comparing
      the data from the first two exposures, a conspicuous habituation in all animals
      was observed. On experimental day 3, 12 rats received kainate (6 mg/kg
      intraperitoneally) and the remaining 11 animals received a physiological saline.
      After 1 h, animals were put into the arena with an object localised in the
      centre. It was found that both kainate and saline treated animals exhibited a
      significant increase in the total number of central area visits, and both the
      total and mean time spent in the vicinity of the object. However, the mean time
      spent was significantly shorter in kainate treated rats. Furthermore. kainate
      rats exhibited a significant decrease in rearing as compared with the controls.
      In addition, an epileptic automatism (wet dog shakes) was observed in seven out
      of 12 animals given kainate. The comparison of transition matrices between
      consecutive behavioural categories showed significant differences between the
      kainate and control groups. Our results demonstrate that a non-convulsive dose of
      kainate induced changes in the structure of spontaneous behaviour and impaired
      the processes related to maintenance of attention.

PMID- 10342397
TI  - Visual representation of space in congenital and acquired strabismus.
AB  - The aim of the present work was to readdress the problem of altered spatial
      localization in strabismic subjects and to assess whether and how spatial
      representation is affected by the degree of plasticity of the brain. We therefore
      compared targeting performance in adult subjects affected by acquired strabismus
      versus children affected by congenital strabismus. Our data confirm the
      correlation between deviation of the eye and targeting errors, but they also show
      that this correlation is not present when strabismus occurs early in life. We
      suggest that the neuronal machinery involved in the building of an internal
      representation of space reaches its full maturity several years after birth and
      that this might explain the limited differences observed in targeting errors
      between normal and strabismic children.

PMID- 10342398
TI  - Behavioural and glial changes in old rats following environmental enrichment.
AB  - The effects of enriched environment on short-term memory for event durations and
      on astrocytes (cell density, cell area and % of GFAP immunoreactivity) in
      hippocampus (Hi), frontal cortex (FC) and corpus callosum (CC) were analysed in
      old rats housed from weaning to the end of behavioural testing (23 months) either
      in standard (SC) or in enriched (EC) conditions and in young adults (5 months)
      all housed in SC. Old SC and EC and young SC rats trained (for 2 months) or not,
      in a Symbolic Delayed Matching to Sample Task, had to discriminate and remember
      two (2- and 10-s) signals after short retention intervals. Results confirm the
      aging-related acquisition and memory deficit. EC reduced the slowness of
      acquisition, reversed the short-term memory deficit and promoted the retention of
      the short signal (choose short effect). Old SC naive rats had many hypertrophied
      astrocytes with long processes in Hi and CC while old EC rats had decreased
      astrocytes number and size. The behavioural testing resulted in young adult SC
      rats in Hi and CC, in increased astrocytes number, size and GFAP% and in their
      decrease in old SC rats. EC and testing have additive effects (very low
      astrocytes number, size and GFAP%) to compensate for the aging-induced gliosis,
      mostly in Hi.

PMID- 10342399
TI  - The effects of anxiolytic drugs on novelty-induced place preference.
AB  - Previous evidence has shown that rats exposed to a place preference apparatus
      prefer the novel compartment over the familiar. While this suggests that novelty
      is rewarding, an alternative interpretation is that rats avoid the familiar
      compartment because it is associated with some stress-related aversive event
      induced during the inescapable exposure sessions. To test this latter
      possibility, the benzodiazepine anxiolytic diazepam (0.1, 0.3, 1.0, 3.0 mg/kg)
      and the nonbenzodiazepine anxiolytic gepirone (0.1, 0.3, 1.0 mg/kg) were examined
      for their ability to alter novelty-induced place preference in rats. As expected,
      control animals showed a novelty-induced place preference. On the test day, this
      preference was disrupted by diazepam, but only at a dose (3 mg/kg) that also
      decreased locomotor activity. Gepirone failed to alter the preference behavior,
      even at a dose (1 mg/kg) that decreased locomotor behavior. In another
      experiment, rats spent more time in a familiar compartment that contained a novel
      object than in a familiar compartment with no object. These experiments indicate
      that preference for the novel compartment may reflect the rewarding effect of
      novelty rather than aversion to the familiar.

PMID- 10342400
TI  - Long-lasting inhibitory avoidance acquisition in rats submitted to the elevated T
      maze model of anxiety.
AB  - The present study was outlined in order to provide additional behavioral
      validation to the elevated T-maze as a model of anxiety and memory. In this
      model, rats acquire an inhibitory avoidance response after successive exposures,
      and memory can be estimated by retesting later. Two experiments were carried out
      with rats initially tested at the ages of 30, 60, 90 and 120 days. Experiment 1
      showed that, while 100% of subjects studied learned inhibitory avoidance,
      regardless of their ages, 60-day-old rats needed a higher number of trials in
      order to reach the criterion to stay 300 s inside the enclosed arm. Experiment 2
      explored the relevancy of the aversive stimulus in maintaining the learned
      experience by retesting the subjects monthly. The results showed that after
      acquisition of inhibitory avoidance there is remarkable long-lasting memory
      retrieval. Risk assessment behavior, increasing in the first trial of the retest
      day, revealed also the approach-avoidance conflict while on the enclosed arm. The
      results are discussed in terms of age effects and the implications of an enduring
      learned emotional response in animal models of anxiety and memory.

PMID- 10342401
TI  - Lesions of the medial or lateral perforant path have different effects on
      hippocampal contributions to place learning and on fear conditioning to context.
AB  - The axons of the neurons in the medial and lateral components of the entorhinal
      cortex (MEC and LEC) form the medial and lateral perforant paths (MPP and LPP)
      which represent the major source of cortical input to the hippocampus.
      Anatomical, physiological, and pharmacological studies have shown that MPP and
      LPP are distinct. Unfortunately, assessment of the functional significance of
      damage to either of these pathways has not used tasks known to be sensitive to
      hippocampal function in the rodent. In this study, we performed dissociated
      lesions of MPP and LPP using a combined physiological and anatomical method. Rats
      with lesions of either the MPP or the LPP were tested on place learning in the
      water task and on a discriminative fear conditioning to context task. The results
      indicated that the MPP, but not LPP, lesions resulted in impaired place learning.
      The context discrimination data revealed an amygdala-like, reduced fear effect of
      MPP lesions and an enhanced discriminative fear conditioning to context effect of
      LPP lesions. Consistent with a two-stage model of spatial learning proposed by
      Buzsaki (Buzsaki G. Two-stage model of memory trace formation: a role for 'noisy'
      brain states. Neuroscience 1989;31(3):551-570), the impairment in the water task
      can be interpreted as reflecting the higher efficiency of the MPP synapses in
      activating hippocampal neurons. The context discrimination results can be
      explained by either a dissociation of sensory information that reaches the MEC
      and LEC, or alternatively, by a dissociation between the limbic nature of the MEC
      and the sensory nature of the LEC.

PMID- 10342402
TI  - Song behavior, NGF level and NPY distribution in the brain of adult male zebra
      finches.
AB  - The aim of the present study was to investigate the role of nerve growth factor
      (NGF) and neuropeptide Y (NPY) in the higher vocal center (HVC) on singing
      behavior of adult male zebra finches. The results of our studies show: (a) that
      NGF is present in the brain of these birds and it is higher in the HVC than in
      the other neostriatal tissues; (b) that exogenous administration of NGF or NGF
      antibody had no discernible effect on singing behavior; and (c) that NGF enhances
      the NPY immunoreactivity in neurons and fibers localized in HVC and other areas
      of the neostriatum and hippocampus whereas anti-NGF decreased NPY stained cells
      in the hippocampus. These studies indicate that NGF is produced in the brain of
      zebra finch and that it plays a role in the regulation of NPY.

PMID- 10342403
TI  - The functional value of sound and exploratory behaviour in detelencephalated
      pigeons.
AB  - Exploratory behaviour in response to a sound previously paired to a shock was
      analyzed before and after massive telencephalic lesions. Six pigeons were
      submitted to sound shock associations, habituation tests, telencephalic lesion
      and habituation retesting. Eighteen birds divided into three sham-lesioned groups
      received sound shock pairing (Control 1), pre-exposure to sound stimulation
      (Control 2) or pre-exposure to electric shocks (Control 3) before the behavioural
      tests. The pre-surgery tests consisted of 25 1 s pulses of sound A (1000 Hz, 83
      dB) or B (500 Hz, 85 dB), every 30 s. Retests took place 10 days after surgery
      using the same sequence of procedures. The behaviour exhibited immediately after
      each sound stimulation was recorded manually and on video during the sessions.
      Analysis of variance showed an effect of group {F(3, 20)= 13.37, p < 0.0001)
      suggesting that pre-exposure to tone-shock association affected the exploration
      in response to the sound presented in another context. The Experimental and
      Control 1 birds showed no robust decrease in responses during the pre-surgery
      sessions. Post-surgery exploration data for detelencephalated birds showed a
      lower level of responding (p < 0.05). These data suggest a retardation in the
      typical reduction of responses to recurrent stimulation and support other
      evidences of the potentiating effect of sound shock association on responding.
      They are also indicative of telencephalic modulation of exploratory behaviour and
      strengthen the arguments for the subtelencephalic storage of associative
      information concerning the functional value of acoustic stimulation.

PMID- 10342404
TI  - Transcutaneous electrical nerve stimulation (TENS) improves the rest-activity
      rhythm in midstage Alzheimer's disease.
AB  - Nightly restlessness in patients with Alzheimer's disease (AD) is probably due to
      a disorder of circadian rhythms. Transcutaneous electrical nerve stimulation
      (TENS) was previously reported to increase the strength of coupling of the
      circadian rest activity rhythm to Zeitgebers in early stage Alzheimer's disease
      (AD) patients. It was investigated in the present study whether TENS could also
      improve the rest activity rhythm of patients in a midstage. Sixteen patients who
      met the NINCDS ADRDA criteria for probable AD, and the stage 6 criteria of the
      Global Deterioration Scale were treated with TENS or placebo. Rest activity
      rhythm was assessed using actigraphy. Compared to the control group, stimulated
      patients showed an improvement in the rest activity rhythm of similar magnitude
      as observed previously in patients in an early stage. It is concluded that TENS
      increased the coupling between the rest activity rhythm and supposedly stable
      Zeitgebers in an advanced stage of AD.

PMID- 10342405
TI  - Prospects for trichromatic color vision in male Cebus monkeys.
AB  - Polymorphic color vision is characteristic of many species of New World monkey. A
      fundamental feature of the polymorphism is that male monkeys are routinely
      dichromatic. A recent paper describes an experiment in which Cebus monkeys were
      required to discriminate between pairs of Munsell color chips (Pessoa VF, Tavares
      MCH, Aguiar L, Gomes UR, Tomaz C. Color vision discrimination in the capuchin
      monkey Cebus apella: evidence for trichromaticity. Behav Brain Res 1997;89:285
      288). The results were interpreted as demonstrating trichromatic color vision in
      male Cebus monkeys. An examination of the literature on Cebus. monkey
      photopigments and results from a replication of the discrimination experiment
      conducted with dichromatic human subjects cast doubt on this claim.

PMID- 10342406
TI  - Effect of septal lesions on male song and aggression in the colonial zebra finch
      (Taeniopygia guttata) and the territorial field sparrow (Spizella pusilla)
AB  - The present investigation assessed the effect of lesions of the septum on male
      courtship and aggression in the territorial field sparrow (Spizella pusilla) and
      the colonial zebra finch (Taeniopygia guttata). In addition, pair-bonding and a
      variety of other social behaviors were examined in the zebra finch and dawn song
      (both the strictly agonistic song type and the multipurpose song type) was
      examined in the field sparrow. Zebra finches were tested in three phases both
      before and after receiving bilateral electrolytic lesions of the septum or sham
      surgery. These phases were: (1) competition tests in which a subject and a
      stimulus male were exposed to a female in an adjacent cage; (2) sexual behavior
      tests with a female; and (3) 10-day group cage tests in which subjects were in a
      mixed-sex environment. Aggressive behaviors (chases, threats, beak fences and
      pecks) were significantly reduced by septal lesions but not by sham surgery.
      Directed song (courtship) was significantly reduced in sexual behavior tests,
      with similar trends in other testing phases. Male field sparrows were tested 2
      days pre-surgery and 2 days post-surgery in outdoor aviaries placed in their
      natural habitat. Tests consisted of dawn song observations and observations of
      courtship and aggression following introduction of a female to the subject's
      aviary, which was followed 10 min later by the introduction of another male
      (without removing the female). Septal lesions significantly facilitated both
      overt aggression (chases) and the number of simple (multi-purpose) songs. These
      results provide evidence that the septum participates in the regulation of male
      aggression and song in songbirds, and further suggest that variations in septal
      function may exist between territorial and colonial species.

PMID- 10342407
TI  - Are opioids effective in relieving neuropathic pain?
AB  - The purpose of this review is to identify important issues and to review the data
      that underlie the controversial effectiveness of opioids in relieving neuropathic
      pain. This controversy seems related to the use of multiple definitions of
      neuropathic pain together with its distinct mechanisms in both experimental
      animal models and human neuropathic pain syndromes, methodological shortcomings
      in available randomized controlled clinical trials, different methods of pain
      assessment, the inappropriate use of terms like efficacy and responsiveness,
      differential responses in spontaneous versus evoked pains, interindividual
      differences to specific opioids and opioid doses, and duration of follow-up. New
      randomized controlled clinical trials with opioids in neuropathic pain are still
      needed. These studies should include larger patient samples with rigorously
      defined homogeneous neuropathic pain syndromes. Active placebo's mimicking side
      effects should be included in the double-blind design, and control of unmasking
      should be performed. Individual titration of the opioid dose and active
      management of side-effects in long-term follow-up studies need to measure both
      pain relief and quality of life.

PMID- 10342408
TI  - Effects of trkB and trkC neurotrophin receptor agonists on thermal nociception: a
      behavioral and electrophysiological study.
AB  - Nerve-growth factor (NGF), a member of the neurotrophin family, plays an
      important role in nociceptor function. Prompted by a previous uinexpected finding
      that NT-4/5, as well as NGF sensitizes single nociceptors to noxious heat, we
      have explored the relative potency of all neurotrophins in eliciting thermal
      hyperalgesia. NGF, brain-derived neurotrophic factor (BDNF), NT-4/5 and NT-3 were
      injected locally into the hind paw of rats, and the behavioral response to
      noxious heat was compared with that from the other paw that received an identical
      injection of vehicle. Like NGF, agonists of tyrosine kinaseB (trkB) receptors (NT
      4/5 and BDN F) induced thermal hyperalgesia in the first 5 h after treatment (NT
      4/5 > BDNF) but the effect had worn off by 24 h. In contrast, the trkC agonist NT
      3 had no effect on the response to noxious heat. Electrophysiological recordings
      from single C-fibres in the in vitro skin-saphenous nerve preparation revealed
      sensitization to noxious heat stimuli after direct application of BDNF to the
      receptive field, as previously noted for NT-4/5, and in parallel with the
      behavioral findings. NT-3 was ineffective as in the behavioral studies. These
      results suggest that trkB agonists BDNF and NT-4/5 as well as the trkA agonist
      NGF can regulate nociceptive responses to noxious heat.

PMID- 10342409
TI  - Validation of the Chronic Pain Coping Inventory.
AB  - The Chronic Pain Coping Inventory (CPCI; Jensen, M.P., Turner, J.A., Romano, J.M.
      and Strom, S.E., The Chronic Pain Coping Inventory: development and preliminary
      validation, Pain, 60 (1995) 203-216) is a recently developed questionnaire
      comprising eight main subscales that measure coping strategies that are
      frequently targeted for change in interdisciplinary pain treatment programs.
      Preliminary research, carried out by the developers of the CPCI, supports the
      reliability and validity of the scale. The purpose of the present study was to
      further examine the validity of the CPCI independently. In the present study, 210
      patients were administered the CPCI, along with the Coping Strategies
      Questionnaire (CSQ; Rosenstiel, A.K. and Keefe, F.J., The use of coping
      strategies in low back pain patients: relationship to patient characteristics and
      current adjustment, Pain, 17 (1983) 33-44; Riley III, J.L. and Robinson, M.E.,
      CSQ: five factors or fiction? Clin. J. Pain, 13 (1997) 156-162), and the
      Multidimensional Pain Inventory (MPI; Kerns, R.D., Turk, D.C. and Rudy, T.E.. The
      West Haven-Yale Multidimensional Pain Inventory (WHYMPI), Pain, 23 (1985) 345
      356) as part of a pre-admission screening. Principal components analysis with
      oblique rotation was performed on the 64 main CPCI scale items. An eight-factor
      solution was identified as most appropriate. The original subscales were
      generally supported, however, some modifications to scoring of subscales were
      suggested. As a second step in the study, the relationship between the modified
      CPCI subscales and the CSQ subscales were examined and their relative ability to
      predict concurrent adjustment to pain (MPI subscales) was assessed. Results
      indicated that CPCI subscales tap coping constructs that are conceptually
      different than the CSQ subscales. Several CPCI subscales were also found to be
      significantly and uniquely related to measures of concurrent adjustment, even
      after taking CSQ subscales and demographic and pain-related variables into
      account. These results suggest the CPCI is a valuable tool, above and beyond
      established coping measures, in the clinical assessment and research of pain.
      Directions for future research are discussed.

PMID- 10342410
TI  - Self efficacy as a mediator of the relationship between pain intensity,
      disability and depression in chronic pain patients.
AB  - To clarify the relationships between physical, and psychosocial components of
      chronic pain, a path analytic model was tested conceptualizing self efficacy as a
      mediator of disability. In turn, disability was hypothesized to mediate
      depression. This model could help explain the circumstances under which
      disability develops and why so many chronic pain patients become depressed.
      Questionnaires from 126 chronic pain patients (without prior depression) were
      reviewed from three pain clinics. Hypothesized and alternate models were tested
      using separate regression equations to identified models which best fit these
      data. Regression analysis supported that self efficacy partially mediates the
      relationship between pain intensity and disability. This model accounted for 47%
      of the explained variance in disability (P < 0.001). Six additional variables
      that were significantly related to disability in preliminary analysis, added to
      the explained variance in disability (R2 = 0.56), with gender and pain location
      paths remaining significant. In separate regression analyses, disability was
      found to partially mediate the relationship between pain intensity and depression
      (b = 0.47-0.33). This model accounted for 26% of the explained variance in
      depression. The addition of self efficacy to this model supported it as a
      stronger mediator (R2 = 0.32), and suggested that support for disability as a
      mediator of depression was a spurious finding. Both pain intensity and self
      efficacy contribute to the development of disability and depression in patients
      with chronic pain. Therefore, the lack of belief in ones own ability to manage
      pain, cope and function despite persistent pain, is a significant predictor of
      the extent to which individuals with chronic pain become disabled and/or
      depressed. Nevertheless, these mediators did not eliminate the strong impact that
      high pain intensity has on disability and depression. Therefore, therapy should
      target multiple goals, including: pain reduction, functional improvement and the
      enhancement of self efficacy beliefs.

PMID- 10342411
TI  - Jaw electromyographic activity induced by the application of algesic chemicals to
      the rat tooth pulp.
AB  - The aim of this study was to determine if the application of mustard oil (MO), a
      small-fiber excitant and inflammatory irritant, or other algesic chemicals
      (capsaicin, CAP, and bradykinin, BK) to the rat maxillary molar tooth pulp
      induces electromyographic (EMG) activity of the masseter and digastric muscles,
      and also to determine if endogenous opioid mechanisms may be involved in any
      documented EMG changes. Application of MO to the tooth pulp induced a significant
      increase in EMG activity of the ipsilateral masseter up to 30 min. The
      application of mineral oil to the pulp or MO application to the pulp-extirpated
      tooth did not induce any significant EMG increases. The application of CAP or BK
      to the pulp in contrast had much weaker effects on EMG activity of the jaw
      muscles. CAP produced a small but prolonged increase in masseter EMG activity,
      and BK induced a short-lasting increase in digastric EMG activity. The systemic
      administration of the opiate antagonist naloxone significantly reactivated (i.e.
      rekindled) the EMG response evoked by MO application to the pulp. Naloxone did
      not produce any such significant rekindling effect on EMG activity following CAP,
      BK or mineral oil application to the pulp or following MO application to the pulp
      extirpated tooth. The MO, BK and especially CAP groups showed histological
      evidence of vasodilatation and polymorphonuclear leukocyte infiltration in the
      pulp tissue and a significant increase in plasma extravasation of Evans Blue dye,
      whereas mineral oil did not induce these changes. These findings suggest that
      pulp afferent inputs to the central nervous system evoked by BK. CAP and
      especially MO may induce enhanced jaw muscle activity. In addition, the naloxone
      data suggest that an opioid suppresive mechanism may be induced by the pulpal
      afferent inputs evoked by MO, and may serve to limit the jaw muscle activity
      elicited by these inputs.

PMID- 10342412
TI  - Behavioral manifestations of neuropathic pain and mechanical allodynia, and
      changes in spinal dorsal horn neurons, following L4-L6 dorsal root constriction
      in rats.
AB  - We investigated behavioral symptoms of neuropathic pain, and associated changes
      in dorsal horn neurons, in a rat model involving loose ligation of lumbar dorsal
      roots. The L4-L6 dorsal roots were exposed unilaterally and loosely constricted
      central to the respective ganglia with one (1-ligation) or two (2-ligation) silk
      7-O ligatures. In control groups the dorsal roots were exposed but not ligated
      (sham-operated), or sutures were placed lengthwise between the dorsal roots
      (suture control). There was a significant reduction in mechanical withdrawal
      threshold on the operated side in both 1- and 2-ligation groups which began at 3
      days, peaked at 2-5 week, and gradually recovered. A delayed threshold reduction
      was also seen on the non-operated side. Immediately post-surgery there was a
      significant increase (hypoalgesia) in thermal paw withdrawal latency (Hargreaves
      test) in 1- and 2-ligation groups on the operated (but not non-operated) side
      that recovered after 1 week. Significantly less weight was borne by the operated
      limb 1-5 weeks post-operatively in 1- and 2-ligation groups. The force of hind
      limb withdrawals elicited by graded noxious heat pulses (38-52 degrees C) was
      significantly lower 1 week post-surgery on the operated side (1-ligation group)
      followed by recovery. Withdrawal forces were higher 5-9 week post-surgery on the
      non-operated side in 1- and 2-ligation groups. We found no evidence of cold
      allodynia. Neither sham-operated nor suture controls showed any signs of
      allodynia or hyperalgesia. Following behavioral testing, rats were anesthetized
      with halothane for single-unit recordings from lumbar wide dynamic range-type
      (WDR) neurons. At 22 week post-surgery, the mean area of mechanosensitive
      receptive fields was significantly larger for units on the operated side in 1-
      and 2-ligation groups compared with those on the non-operated side or with those
      from sham-operated rats. Mean stimulus-response functions to graded noxious heat
      pulses (38-52 degrees C, 5 s) were not significantly different between operated
      and non-operated sides for 1- or 2-ligation groups, or compared with the 22-week
      sham-operated group. At 5 week post-surgery, the mean area of cutaneous receptive
      fields, and stimulus-response functions to graded noxious heat, were not
      significantly different between units recorded on operated versus non-operated
      sides, or compared with units from 5-week sham-operated rats. Spontaneous unit
      activity was significantly higher on the operated versus non-operated side in the
      2-ligation (22-week) and sham (5-week) groups. Enlarged cutaneous receptive
      fields of dorsal horn neurons may contribute to mechanical allodynia associated
      with dorsal root constriction. However, the slow (>5 week) development of
      receptive field enlargement does not match the rapid development of allodynia.
      The lack of effect of dorsal root constriction on thermal sensitivity of dorsal
      horn units ipsilaterally corresponds to the lack of marked thermal hyperalgesia
      observed behaviorally.

PMID- 10342413
TI  - Differential efficacy of intravenous lidocaine in alleviating ipsilateral versus
      contralateral neuropathic pain in the rat.
AB  - In the this study we have investigated the threshold plasma concentration of
      lidocaine for reversal of mechanical 'allodynia' in a neuropathic pain model in
      the rat, defined the concentration-dependent limits of that reversal and compared
      the acute reversal during intravenous drug infusion with the persistent relief of
      allodynia assayed 48 h later. Actions of i.v. lidocaine on ipsilateral and
      contralateral legs were also assessed. Forty rats were sorted into five groups (n
      = 7-10) and underwent spinal root (L5-6) ligation to produce allodynia, as
      quantified by a lower force of von Frey hairs at the plantar hindpaw required to
      elicit paw withdrawal (PWT, paw withdrawal threshold). During surgery,
      intravenous catheters were placed for programmed lidocaine infusion and in some
      animals arterial catheters were also inserted for assaying lidocaine blood
      levels. PWTs were measured in ipsilateral and contralateral paws before and after
      ligation and during infusions which, beginning at 5 days after surgery, were
      conducted every other day to incrementing levels (1.1-9.7 microg/ml plasma).
      Ligation produced allodynia in ipsilateral paws (PWT = 1.22 +/- 0.42 g (+/-SEM))
      and in contralateral paws (PWT = 4.99 +/- 0.61 g), both markedly lower than pre
      operative control values for either paw (11.31 +/- 0.41 g). The ipsilateral
      allodynia was partially, but significantly and permanently reversed (to PWT = 6-8
      g) after a lidocaine infusion to 2.1 microg/ml in two separate groups (n = 7, 8).
      Lower concentrations resulted in elevation of PWT during infusion but no
      sustained relief. The elevation of PWT during infusion at this threshold level
      among individual animals was positively correlated with the relief measured 48 h
      later, but higher lidocaine concentrations infused in subsequent dosings could
      exact no further sustained relief. The residual PWT level, after reversal by
      threshold lidocaine and greater, was constant for each individual rat tested over
      the next 14 days but varied substantially among individuals; some were restored
      to pre-operative PWTs and some were totally unresponsive to drug. Retrospective
      analysis revealed a significant and unanticipated correlation between the
      incidence of low pre-operative PWTs (< 10 g) and a lack of sustained reversal of
      post-operative allodynia by lidocaine. Contralateral allodynia, despite its acute
      reversal during infusion to 2.1 microg/ml and higher, was not persistently
      relieved after infusion of lidocaine to any concentration. Repeated infusions to
      subthreshold levels (<2 microg/ml) did not provide persisting relief of allodynia
      on either side, and infusions of saline were impotent. These findings show that
      experimental allodynia results from multiple factors, only some of which are
      sensitive to lidocaine treatment, and that prolonged reversal of allodynia is
      limited in extent and likely influenced by pre-existing factors.

PMID- 10342415
TI  - Epidemiology of complex regional pain syndrome: a retrospective chart review of
      134 patients.
AB  - Complex regional pain syndrome (CRPS) remains a poorly understood chronic pain
      disorder. Little data has been published assessing the epidemiology of CRPS (and
      reflex sympathetic dystrophy, RSD). This study assessed epidemiological variables
      in 134 CRPS patients evaluated at a tertiary chronic pain clinic in the US,
      including demographic, health care utilization and legal/workman's compensation
      measures. In addition, the frequency of physician-imposed immobilization of the
      CRPS limb was assessed, as was physical examination evidence of myofascial
      dysfunction. This study found that these patients had seen on average 4.8
      different physicians before referral to the pain center and had received an
      average of five different kinds of treatments both prior to and during pain
      clinic treatment. The mean duration of CRPS symptoms prior to pain center
      evaluation was 30 months. Seventeen percent had a lawsuit and 54% had a worker
      compensation claim related to the CRPS. Fifty-one patients received a bone scan,
      but only 53% of which were interpreted as consistent with the diagnosis of
      RSD/CRPS. Forty-seven percent had a history of physician-imposed immobilization,
      and 56% had a myofascial component present at evaluation. The duration of CRPS
      symptoms and the involvement of the upper extremity was significantly associated
      with the presence of myofascial dysfunction. Thus, this study found that most
      CRPS patients are referred to a pain specialty clinic after several years of
      symptoms and many failed therapies. The data also suggest the lack of utility of
      a diagnostic bone scan and highlight the prominence of myofascial dysfunction in
      a majority of CRPS patients.

PMID- 10342414
TI  - Topical lidocaine patch relieves postherpetic neuralgia more effectively than a
      vehicle topical patch: results of an enriched enrollment study.
AB  - This study compared the efficacy of topical lidocaine patches versus vehicle
      (placebo) patches applied directly to the painful skin of subjects with
      postherpetic neuralgia (PHN) utilizing an 'enriched enrollment' study design. All
      subjects had been successfully treated with topical lidocaine patches on a
      regular basis for at least 1 month prior to study enrollment. Subjects were
      enrolled in a randomized, two-treatment period, vehicle-controlled, cross-over
      study. The primary efficacy variable was 'time to exit'; subjects were allowed to
      exit either treatment period if their pain relief score decreased by 2 or more
      categories on a 6-item Pain Relief Scale for any 2 consecutive days. The median
      time to exit with the lidocaine patch phase was greater than 14 days, whereas the
      vehicle patch exit time was 3.8 days (P < 0.001). At study completion, 25/32
      (78.1%) of subjects preferred the lidocaine patch treatment phase as compared
      with 3/32 (9.4%) the placebo patch phase (P < 0.001). No statistical difference
      was noted between the active and placebo treatments with regards to side effects.
      Thus, topical lidocaine patch provides significantly more pain relief for PHN
      than does a vehicle patch. Topical lidocaine patch is a novel therapy for PHN
      that is effective, does not cause systemic side effects, and is simple to use.

PMID- 10342416
TI  - Intra-subject variability in post-operative patient-controlled analgesia (PCA):
      is the patient equally satisfied with morphine, pethidine and fentanyl?
AB  - Our previous study suggested that when compared between patients, morphine,
      pethidine and fentanyl were equally satisfactory for use in patient-controlled
      analgesia (PCA), although quantitative differences in their side-effect profiles
      were detectable. The present study evaluated whether individual patients could
      detect differences or express preferences for individual opioids when treated by
      PCA with all three in random sequence finishing with the first administered
      opioid. The main side effects were pruritus, nausea and vomiting. There were few
      differences in patients' responses to morphine, pethidine and fentanyl, or of
      satisfaction with these drugs, across patients, but individual patients'
      responses to the opioids could be highly variable. Some patients were able to
      tolerate all three opioids investigated, some were intolerant to all and some
      patients appeared to be sensitive to one or two of the opioids but show a
      preference for the remainder. These findings support the clinical practice of
      changing from one opioid to another (with good effect) in post-operative patients
      experiencing intolerable side-effects. The reasons for a patient responding
      differently to different opioids and even to the same opioid on separate
      occasions are not clear and appear inexplicable on the grounds of currently
      postulated receptor affinities or of physicochemical properties of the opioids
      studied. A plethora of factors will influence how an individual patient will
      respond to surgery and how he/she will recover. The physiological response to
      opioids is one variable which appears to be influenced by this complex set of
      factors and in turn will affect them. The findings of this study, like that of
      its predecessor, suggest that morphine, pethidine and fentanyl can be used
      successfully in PCA and that for some patients who are responding poorly,
      changing the opioid may be beneficial.

PMID- 10342417
TI  - Methylprednisolone prevents the development of autotomy and neuropathic edema in
      rats, but has no effect on nociceptive thresholds.
AB  - Corticosteroids are probably an effective treatment for some types of neuropathic
      pain and complex regional pain syndromes. This study examined the effects of
      systemic methylprednisolone (MP) on acute nociception and on pain behavior and
      hyperalgesia in normal and neuropathic rats. There was no dose-response to
      intraperitoneal MP (up to 12 mg/kg) for nociceptive thresholds to heat (Peltier)
      or mechanical (analgesy-meter and von Frey fibers) stimuli in normal rats.
      Chronic high dose MP (3 mg/kg per day for 21 days) also had no effect on acute
      nociceptive thresholds in normal rats. After sciatic nerve section in rats a
      saphenous nerve mediated hyperalgesia to heat and mechanical stimuli gradually
      developed over 21 days. High dose MP (3 mg/kg per day for 21 days) had no effect
      on this adjacent neuropathic hyperalgesia. When systemic MP was started
      immediately after bilateral sciatic and saphenous nerve transection there was a
      dose-dependent reduction in autotomy behavior. Substance P has been proposed as a
      mediator of neuropathic pain and edema. Single dose MP (12 mg/kg) slightly
      reduced the substance P mediated extravasation induced with electrical
      stimulation of the saphenous nerve. Chronic MP (3.4 mg/kg per day for 28 days)
      severely reduced the neurogenic extravasation induced with saphenous nerve
      stimulation. Sciatic sectioned rats developed hindpaw edema between 7 and 14 days
      after surgery, and this neuropathic edema did not develop in rats chronically
      treated with MP (3.4 mg/kg per day). These results demonstrate that
      corticosteroids did not affect nociceptive thresholds in normal or neuropathic
      hyperalgesic rats. Chronic steroid treatment did prevent the development of
      autotomy and neuropathic edema, and completely blocked neurogenic extravasation,
      findings consistent with the hypothesis that primary afferent substance P release
      mediates autotomy pain behavior and neuropathic edema. This may be a relevant
      model for examining the effects of corticosteroids on neuropathic pain and
      complex regional pain syndromes.

PMID- 10342418
TI  - A comparison of the burst activity of lateral thalamic neurons in chronic pain
      and non-pain patients.
AB  - Thalamic neurons are known to switch their firing from a tonic pattern during
      wakefulness to a bursting pattern during sleep. Several studies have described
      the existence of bursting activity in awake chronic pain patients and have
      suggested that this activity is abnormal and may be related to their pain.
      However, we have frequently observed bursting activity in awake non-pain patients
      suggesting that there may not be a causal relationship between thalamic bursting
      activity and chronic pain. To examine this issue more rigorously we compared the
      incidence and pattern of bursting activity of lateral thalamic neurons of both
      pain and non-pain patients in a state of wakefulness. Recordings were obtained
      from lateral thalamic areas of different groups of patients (n = 91) suffering
      from pain disorders (e.g. anaesthesia dolorosa, phantom limb pain, trigeminal
      neuralgia, post-stroke pain) and motor disorders (e.g. Parkinson's disease,
      essential tremor) during stereotactic surgical procedures for the treatment of
      pain and movement disorders. Burst indices (the number of bursting cells per
      electrode track) were computed for all the explorations in the two groups. The
      burst indices in the pain and non-pain groups (1.73 +/- 0.28 and 1.14 +/- 0.16,
      respectively) were not significantly different from each other. The bursts were
      analyzed to see if they fulfilled the criteria of low-threshold calcium spike
      (LTS)-evoked bursts characterized by (i) a shortening of the first interspike
      interval with an increase in the number of interspike intervals in the burst and
      also (ii) a progressive prolongation of successive interspike intervals. LTS
      evoked bursts were identified in 27/47 (57%) bursting cells in pain patients and
      15/32 (47%) cells in non-pain patients. These data demonstrate that the
      occurrence of bursting activity and of LTS-evoked bursts in the human thalamus is
      prevalent in both pain and non-pain patients. This suggests that the bursting
      activity of thalamic neurons in pain patients is not necessarily related to the
      occurrence of their pain.

PMID- 10342419
TI  - Chronic pain-associated behaviors in the nursing home: resident versus caregiver
      perceptions.
AB  - Pain assessment in nursing home residents poses challenges since many of these
      individuals are too cognitively impaired to respond to traditional self-report
      instruments. Assessment of pain behavior in this population offers a logical
      alternative. The purpose of this study was to compare perceptions of behaviors
      identified as being pain-related in 42 nursing home residents with chronic pain,
      as reported by residents themselves, their nursing home caregivers and their
      family caregivers. Our specific research agenda was to identify the most salient
      behaviors that signal pain in nursing home residents; to determine the test
      retest agreement of residents' self-perceived pain behaviors; to learn of the
      confidence that caregivers feel regarding assessment of residents' pain behavior;
      and to examine the agreement between caregivers and residents about pain
      behaviors in particular residents. We also wanted to compare residents' and
      caregivers' ratings of the residents' pain intensity. Finally, we explored the
      beliefs of nursing home staff about the influence of dementia on pain and pain
      assessment. Twenty-two of 26 pain-related behaviors identified by residents
      showed fair to perfect test-retest agreement (kappas 0.40-1). For the vast
      majority of pain-related behavior items, kappas for resident-caregiver agreement
      were <0.30. Agreement with regard to pain intensity was similarly poor (r = -0.19
      0.34). Confidence in pain rating was high for both nurse (on average, 7.2 on a
      scale of 0-10) and family (on average, 6.7) caregivers. Seventy-one percent of
      nurses felt that pain assessment is more difficult in demented individuals, but
      that cognitive function does not influence pain prevalence. While nursing home
      residents with chronic pain and their caregivers have different perceptions
      regarding which behaviors are pain-related, additional studies are required to
      determine the underpinnings of these differing perceptions and to determine the
      extent to which formal pain behavior observation protocols will be useful for
      evaluating nursing home residents with chronic pain.

PMID- 10342420
TI  - Adrenergic sensitivity of the sensory receptors modulating mechanical allodynia
      in a rat neuropathic pain model.
AB  - This study focuses on changes in adrenergic sensitivity in untransected sensory
      axons that innervate an area of skin made neuropathic by transection of
      neighboring nerves. The segmental nerve injury model is favorable for this since
      all axons in the L5 and L6 nerves are transected whereas the L4 axons are intact.
      Earlier findings are that pain behaviors develop after this injury and that these
      behaviors are ameliorated by sympathectomy. The present study shows that behavior
      indicating mechanical allodynia can be rekindled after sympathectomy by
      intradermal norepinephrine and alpha-2 but not alpha-1 adrenergic ligands and the
      rekindling can be blocked by alpha-2 but not alpha-1 adrenergic antagonists. By
      contrast neither intradermal norepinephrine nor other adrenergic agonists or
      antagonists have any demonstrable effects in the normal or after either
      neuropathic surgery or sympathectomy alone. These data suggest that the
      combination of neuropathic surgery and sympathectomy results in an upregulation
      of active alpha-2 adrenergic receptors on the undamaged sensory axons that
      provide the remaining sensory innervation to a neuropathic area partially
      denervated by segmental nerve lesions. These changes on undamaged axons
      presumably compliment similar changes on the transected axons and, thus play a
      role in the development of neuropathic pain.

PMID- 10342421
TI  - The effect of phorbol esters on spinal cord amino acid concentrations and
      responsiveness of rats to mechanical and thermal stimuli.
AB  - There is now mounting evidence supporting the hypothesis that pathological
      perceptual disorders described as secondary hyperalgesia and allodynia may be due
      to sensitization of spinal cord dorsal horn neurons. Protein kinase C (PKC) is
      thought to be one of the factors in the cascade of events leading from peripheral
      tissue damage to the sensitization of central neurons. In our experiments, we
      have used local microdialysis administration of the phorbol ester 12-O
      tetradecanoylphorbol-13-acetate (TPA) to activate PKC in the spinal cord dorsal
      horn in awake rats. In behavioral tests the responsiveness of the animals to von
      Frey filaments (1-1200 mN) and to heat stimuli applied to the hindpaws was
      tested. Thirty minutes after the TPA infusion the threshold for the paw
      withdrawal response was significantly decreased (from 160 to 6 mN) and the
      responses to suprathreshold stimuli were more robust. An increased mechanical
      sensitivity was no longer present when tested 1.5 and 5 h after the TPA
      application was terminated. When heat stimuli were tested, the TPA infusion
      resulted in a significantly prolonged time during which the animals held their
      hindpaws above the supporting surface after the heat stimulus (0.5 and 1.5 h
      after TPA), and in a decreased threshold for the heat stimulus (latency of
      withdrawal) 5 h after TPA. HPLC analysis of the perfusate obtained by
      microdialysis in vivo showed a significant increase in the extracellular levels
      of aspartate, glutamate, glycine and taurine, and a decrease of the glutamine
      level during TPA infusion. The levels of asparagine, serine, threonine and
      alanine did not change. Application of the inactive phorbol ester (alpha-TPA) did
      not evoke any change from the control values either in the AA concentrations or
      in the behavioral tests. Our results suggest that activation of PKC in the spinal
      cord evokes mechanical allodynia and thermal hyperalgesia and provides further
      evidence that PKC is involved in the process of the modulation of nociceptive
      information at the spinal cord level.

PMID- 10342422
TI  - Psychosocial correlates of long-term sick-leave among patients with
      musculoskeletal pain.
AB  - We studied the associations between psychosocial variables and sick-leave among
      patients with musculoskeletal pain. Patients (n = 586) seeking care to relieve
      their pain at health care and physiotherapy centres, completed a questionnaire
      about such variables as clinical characteristics (e.g. pain intensity),
      psychological well-being (e.g. burnout, depression) and coping strategies. The
      results show that the patients who had been on sick-leave for >30 days (n = 217),
      were significantly more often divorced, immigrants, blue-collar workers and less
      educated than the rest of the sample. Compared with the rest of the patients,
      they rated their pain as significantly more severe, frequent, complex and
      functionally impairing. They reported using more pain medication and
      tranquillizers, and having undergone more somatic treatments. These patients also
      showed higher scores on job strain, more symptoms of burnout, anxiety/depression
      and posttraumatic stress reactions, and poorer coping capacity. Logistic
      regression analyses revealed that an index related to perceived disability was a
      major predictor of sick-leave within the group. After controlling for possible
      confounders, multivariate regression analyses showed that the strongest
      predictors of the disability index were symptoms of burnout and posttraumatic
      stress reactions. The results confirm that emotional distress, coping style and
      perceived disability are associated with sick-leave, after controlling for pain
      parameters and sociodemographic variables. The high levels of emotional distress
      and the poor coping capacity reported by the patients with a long history of
      absence due to illness suggest that cognitive behavioural interventions ought to
      be integrated in the treatment of musculoskeletal pain.

PMID- 10342423
TI  - In the system: the lived experience of chronic back pain from the perspectives of
      those seeking help from pain clinics.
AB  - Narrative accounts of their lived experiences were collected from twenty back
      pain patients who were seeking help from two pain clinics in the UK. Following
      analysis using a phenomenological approach, five themes emerged which tell a
      typical story of back pain. One prominent emergent theme, 'in the system', is
      reported in which participants tell how they became entrapped within the medical,
      social security and legal systems. These systems, designed to treat or support
      those who are ill or disabled, effectively rendered participants powerless,
      helpless and angry. It is suggested that these accounts may help clinicians and
      researchers to gain a better understanding of the origins and nature of the
      negative attitudes exhibited by many back pain patients who seek help from pain
      treatment centres.

PMID- 10342424
TI  - Cost-of-illness of neck pain in The Netherlands in 1996.
AB  - The prevalence of neck pain in the general population ranges from 10 to 15%. The
      complaints can result in substantial medical consumption, absenteeism from work
      and disability. In this study we investigated the costs of neck pain in the
      Netherlands in 1996 to assess the financial burden to society. The study was
      based on prevalence data. Data sources included national registries, reports of
      research institutes and health care authorities. Direct health care costs were
      estimated for hospital care, general practice care and paramedical care. These
      costs were calculated using fees. Calculation of indirect costs (absenteeism and
      disability) was based on the Human Capital Method (HCM). As an alternative
      approach the Friction Cost Method (FCM) was used. The total cost of neck pain in
      The Netherlands in 1996 was estimated to be US $686 million. The share of these
      costs was about 1% of total health care expenditures and 0.1 % of the Gross
      Domestic Product (GDP) in 1996. Direct costs were $160 million (23%). Paramedical
      care accounted for largest proportion of direct costs (84%). When applying the
      HCM for calculating indirect costs, these costs amounted to $527 million (77%).
      The total number of sick days related to neck pain were estimated to be 1.4
      million with a total cost of $185.4 million in 1996. Disability for neck pain
      accounted for the largest proportion (50%) of the total costs related to neck
      pain in 1996 ($341). When applying the FCM for calculating the indirect costs,
      these costs were reduced to $96 million. The costs related to neck pain in 1996
      in The Netherlands were substantial. Some caution should be taken in
      interpretation, as a number of assumptions had to be made in order to estimate
      the total costs. The cost structure shown in this study, with high indirect
      costs, has also been found in other studies. From an economical point of view it
      seems to be important to prevent patients from having to take sick leave and
      disability. One way in achieving this goal is to develop and investigate more
      effective treatments for acute neck pain, in order to prevent patients developing
      chronic pain and disability. Another option is to protect chronic patients from
      sick leave and disability by careful management. Thus, also in the area of direct
      medical costs, there may be room for cost savings by stimulating and improving
      cost-efficiency and cost-effectiveness of the (para)medical care. In order to
      deal with the lack of specific disease information, more detailed information of
      medical consumption, sick leave and disability is required for future cost
      analysis.

PMID- 10342425
TI  - Topical EMLA pre-treatment fails to decrease the pain induced by 1% topical
      capsaicin.
AB  - Topical capsaicin has been reported to be beneficial for the treatment of
      neurogenic pain. However, due to the burning pain associated with topical
      capsaicin, many patients discontinue treatment before therapeutic benefits are
      obtained. This study assessed the efficacy of EMLA (eutectic mixture of 2.5%
      prilocaine and 2.5% lidocaine) to block pain induced by the topical application
      of 1% capsaicin. Nine healthy subjects (five males and four females) participated
      in the study. High dose topical capsaicin (1%) was applied to a 2.5 x 2.5 cm
      region of both volar forearms for 6 h. One arm was pretreated (for 2 h) and
      cotreated with EMLA, and the other arm served as vehicle control. Average and
      peak pain ratings were recorded at 15-min intervals using a 0 (no pain) to 10
      (worst possible pain) scale. Average and peak pain ratings were significantly
      lower at the EMLA site during the first 15-30 min of capsaicin treatment.
      However, for the remaining 5.5 h of capsaicin treatment, the pain ratings at the
      EMLA and vehicle sites were not significantly different. The 6 h treatment with
      high dose topical capsaicin (1%) produced significant desensitization to heat
      stimuli that was not affected by EMLA treatment. EMLA fails to produce a long
      lasting attenuation of the pain induced by topical application of 1% capsaicin.
      These results argue against the use of EMLA to block pain to topical capsaicin
      during the treatment of neurogenic pain.

PMID- 10342426
TI  - Acute amitriptyline in a rat model of neuropathic pain: differential symptom and
      route effects.
AB  - The present study was designed to determine whether amitriptyline, a prototypical
      tricyclic antidepressant, could produce pain relieving properties in a rat model
      of neuropathic pain. Nerve injury was produced by tight ligation of the lumbar
      5th and 6th dorsal roots and this resulted in persistent stimulus evoked
      neuropathic pain symptoms (tactile allodynia and thermal hyperalgesia). Thermal
      hyperalgesia was measured using a focused light beam directed at the ventral
      surface of the paw while tactile allodynia was determined using Semmes-Weinstein
      monofilaments applied to the ventral surface of the paw. Amitriptyline was
      administered systemically (intraperitoneal), spinally (intrathecal cannula), and
      locally (subcutaneously) via direct injection into the dorsal surface of the paw.
      Following systemic administration, amitriptyline completely reversed thermal
      hyperalgesia (10 mg/kg) in the injured paw. Spinal administration of
      amitriptyline (60 microg) also produced an antihyperalgesic effect.
      Interestingly, local administration of amitriptyline (100 nmol) had an immediate
      antihyperalgesic effect that persisted for 120 min following administration.
      Amitriptyline had no alleviating effect against mechanical allodynia regardless
      of the route of administration, but curiously, produced hyperaesthesia in the
      contralateral paw. These results indicate that in the rat model of spinal nerve
      ligation, amitriptyline is effective in alleviating thermal hyperalgesia
      (systemically, spinally and locally) but is ineffective against mechanical
      allodynia. The peripheral efficacy of amitriptyline suggests the possibility of
      the development of cream formulations that may be able to increase the local
      concentration of amitriptyline without increasing the systemic dose and the
      subsequent occurrence of side effects.

PMID- 10342427
TI  - The roles of child reactivity and parenting context in infant pain response.
AB  - This study examined the relative importance of and developmental changes in
      biologically-based child variables (infant vagal tone and infant difficultness)
      and parental contextual variables (maternal behavior during pain and maternal
      sensitivity) in the prediction of infant pain behavior during immunization. Sixty
      infant-mother dyads were assessed when infants were approximately 6 or 18-months
      of age. During the first session, mothers completed a measure of infant
      difficultness, infants' resting EKG signals were recorded, and maternal
      sensitivity was rated. During the second session, infants' immunizations were
      video-recorded and maternal vocalizations and infant pain behavior were rated. At
      6-months of age, 44% of the variability in infant pain behavior was predicted by
      infant difficultness and mothers' vocalizations during immunization. At 18-months
      of age, 35% of the variability in infant pain behavior was predicted by maternal
      sensitivity and infant vagal tone level. Children's emotion regulation skills and
      socialization histories may underlie age-related changes in the predictors of
      their pain.

PMID- 10342428
TI  - Sites of aspecific ATP-phosphohydrolase activity in the branchial region of chick
      embryos, with particular emphasis on the myogenic cell population.
AB  - The distribution pattern of unspecific ATP-phosphohydrolase (ATP-PH) activity was
      studied in serial sections through the branchial region of chick embryos from HH
      stage 14 to 27. A selective reaction was found in the prospective myogenic
      mesoderm of voluntary muscles of the first three branchial arches. This property
      initially characterized uncondensed myogenic cell populations in the mandibular
      and hyoid arches and appeared later on in the third arch. In each case, the
      positive premuscular mesoderm was closely apposed to the lateral wall of the
      corresponding aortic arch. Myogenic primordia retained a strong ATP-PH activity
      up to stage 27 when they began to segregate into smaller premuscular units.
      Discrete changes observed in the mandibular and hyoid blastemas suggested that
      non reacting cells probably of neural crest origin invade their proximal core and
      contribute to the subsequent pathfinding of muscular nerves. Other selective
      sites of ATP-PH reactivity were detected in the odd-numbered rhombomeres,
      rhombencephalic floorplate, notochord, arterial endothelial cells, prospective
      dermis and perichondrium.

PMID- 10342429
TI  - Comparative light and electron microscopic study of the auditory organs of two
      species of fishes (pisces): Hyphessobrycon simulans (Ostariophysi) and Poecilia
      reticulata (Acanthopterygii).
AB  - Hyphessobrycon simulans has a Weberian apparatus for transmission of sound energy
      to the auditory organ, whereas Poecilia reticulata does not. The fine structure
      of the auditory organs is identical in the two species. The better hearing -
      expressed by large bandwidth and high sensitivity - typical of the Ostariophysi -
      seems to be based exclusively on the presence of the Weberian apparatus. The
      sensory epithelium of the saccule and the lagena is made up of hair (sensory)
      cells and supporting cells. The vertically orientated macula sacculi is divided
      into a dorsal and a ventral cell area with oppositely arranged hair-cell
      kinocilia. The sagitta takes up the center of the saccule and shows only three
      small sites with connections to the otolithic membrane. Remarkably, the dorsal
      sensory cells are connected to the ventral part of the otolith, but the ventral
      cells are connected to the dorsal part. The macula of the lagena also comprises a
      dorsal and a ventral cell area with oppositely arranged hair cells. The sensory
      cells in all maculae are of type II. They exhibit a striking apical cell
      protrusion, the cuticular villus. It is partially fused with the kinocilium in
      the contact zones and joined to the otolithic membrane. The cuticular villus
      probably stabilizes the long kinocilia.

PMID- 10342430
TI  - Embryonic development of pineal gland vesicles: a morphological and
      morphometrical study in chick embryos.
AB  - Pineal cell aggregates in 5, 10 and 15 day-old chick embryos have been studied.
      Cell aggregates were classified into rosettes or vesicles and spheroid and
      ellipsoid vesicles distinguished. The number of pineal vesicles per unit of
      surface (vesicle density) was determined in three pineal portions: apical,
      anterior and posterior. By day 5, only cellular rosettes were found, mainly in
      the apical portion. After 10 and 15 days, the presence of rosettes was
      occasional. The posterior wall showed only small spheroid vesicles, while in the
      apical and anterior areas ellipsoid vesicles were also observed. Moreover, the
      spheroid/ellipsoid vesicle ratio increased from the 10th to the 15th day of
      incubation. The vesicle density decreased between the 10th and 15th day because
      of the increase in both vesicle and pineal size, without changes in the total
      number of vesicles. The results suggest that changes in vesicle morphology and
      density could be related to the functional activity of the pineal gland during
      embryonic development.

PMID- 10342431
TI  - Endophyll orients and organizes the early head region of the avian embryo.
AB  - By placing endophyll on the caudal area marginalis situated behind Rauber's
      sickle of avian unincubated blastoderms, we observed after using the quail-chick
      chimera system and culture the development of a (pre)neural plate or a miniature
      embryo, head-oriented towards this endophyll. A Rauber's sickle fragment placed
      in the same conditions gives no reaction. If we place endophyll close to Hensen's
      node (stage 4 Vakaet, 1962) on an isolated anti-sickle region of an avian
      unincubated blastoderm in vitro, a similar endophyll-oriented development takes
      place after culture. Under the same conditions, but in the absence of endophyll,
      a Hensen's node provokes a thickening of the upper layer in the immediate
      neighbourhood, eventually with formation of a neural axis, oriented according to
      the original caudocranial direction of the graft. Our study indicates that avian
      endophyll (from unincubated blastoderms) can induce in the upper layer a
      (pre)neural plate, with or without neural folds. By interaction with sickle
      endoblast coming from Rauber's sickle (the early gastrulation organizer:
      Callebaut and Van Nueten, 1994), or from Hensen's node (a later avian organizer:
      Waddington, 1932), it can orient or re-orient the head region and the
      caudocranial direction of an induced miniature embryo. The conclusions from our
      embryological experiments are in agreement with the results obtained by recent
      molecular biology studies.

PMID- 10342432
TI  - Some introductory notes on the organization of the forebrain in tetrapods.
AB  - As an introduction to the main theme of this conference an overview of the
      organization of the tetrapod forebrain is presented with emphasis on the
      telencephalic representation of sensory and motor functions. In all classes of
      tetrapods, olfactory, visual, octavolateral, somatosensory and gustatory
      information reaches the telencephalon. Major differences exist in the
      telencephalic targets of sensory information between amphibians and amniotes. In
      amphibians, three targets are found: the lateral pallium for olfactory input, the
      medial pallium for visual and multisensory input, and the lateral subpallium for
      visual, octavolateral and somatosensory information. The forebrains of reptiles
      and mammals are similar in that the dorsal surface of their cerebral hemisphere
      is formed by a pallium with three major segments: (a) an olfactory, lateral
      cortex; (b) a 'limbic' cortex that forms the dorsomedial wall of the hemisphere,
      and (c) an intermediate cortex that is composed entirely of isocortex in mammals,
      but in reptiles (and birds) consists of at least part of the dorsal cortex (in
      birds the Wulst) and a large intraventricular protrusion, i.e. the dorsal
      ventricular ridge. In birds, the entire lateral wall of the hemisphere is
      involved in this expansion. The intermediate pallial segment receives sensory
      projections from the thalamus and contains modality-specific sensory areas in
      reptiles, birds and mammals. The most important differences between the
      intermediate pallial segment of amniotes concern motor systems.

PMID- 10342433
TI  - The morphological pattern of the vertebrate brain.
AB  - Bergquist and Kallen as well as Puelles and collaborators have presented models
      of the developing vertebrate brain, the basic units of which are formed by
      intersection of transversely oriented neuromeres and longitudinally arranged
      zones. These units represent initially discrete, developmentally independent
      compartments, but during later development some (many?) are invaded by sizable
      numbers of neuroblasts generated in adjacent units. No consensus exists with
      regard to the number and arrangement of the units involved in the formation of
      the telencephalon and hypothalamus.

PMID- 10342434
TI  - Species-specific differences in the corticohypothalamic connections of lizards.
AB  - In lizards, information from the various senses is relayed to the hypothalamus
      via the cortico-septo-hypothalamic pathway. It appears that the anatomical
      organization of the incoming fibres in the medial cortex differs considerably
      between the various lizard species. In the present account it is shown that it is
      the location of the termination of the incoming fibres in the medial cortex that
      determines what kind of sensory information will reach the hypothalamic centres
      that are responsible for sexual and feeding behaviour.

PMID- 10342435
TI  - GABAergic cell types in the lizard hippocampus.
AB  - The neurochemical classification of GABAergic cells in the lizard hippocampus
      resulted in a further division into four major, non-overlapping subtypes. Each
      GABAergic cell subtype displays specific targets on the principal hippocampal
      neurons. The synaptic targets of the GABA/neuropeptide subtype are the distal
      apical dendrites of principal neurons. Calretinin- and parvalbumin-containing
      GABAergic cells synapse on the cell body and proximal dendrites of principal
      cells. Calbindin is expressed in a distinct group of interneurons, the synapses
      of which are directed to the dendrites of principal neurons. Finally, another
      subtype displays NADPH-diaphorase activity, but its synaptic target has not been
      established.

PMID- 10342436
TI  - Field homology: a meaningless concept.
AB  - Most biological homologues involve comparison of single characters in two or more
      taxa. It is possible, however, to recognize homologous characters between two or
      more taxa that involve the transformation of one character into many characters
      or many characters into one character. This type of homology is recognized as
      field homology and it has been widely used in comparative neuroanatomy. The
      emergence of the cladistic analysis of embryonic stages in the development of
      neural characters, however, strongly suggests that field homology is a
      meaningless concept. When it appears necessary to recognize field homologues, it
      is because comparisons are being made at an inappropriate level within a given
      biological hierarchy. Furthermore, recognition of field homologues restricts
      evolutionary mechanisms to a single mechanism of parcellation as defined by
      Ebbesson.

PMID- 10342437
TI  - GnRH-systems in the forebrain of cichlid fish.
AB  - The neuronal systems that contain gonadotropin-releasing hormone (GnRH) were
      quantitatively examined in the forebrain of two cichlid species (Oreochromis
      niloticus Lin. and Tilapia maria Boulenger) using tracing methods and
      immunostaining. In both species the nucleus olfacto-retinalis and a population of
      neurons in the basal preoptic region contained GnRH. The nucleus olfacto
      retinalis was divided into several neuronal subpopulations which differed with
      respect to cytology, projection pattern, and peptide content. GnRH cell number
      increased with body size, the rates being different for the different
      subpopulations. A sexual dimorphism was found in the basal preoptic region of
      Tilapia; males had significantly fewer GnRH-containing cells than females.
      Selective staining of the basal preoptic region demonstrated that this cell group
      is the main source of GnRH-innervation of the pituitary gland and indicate that
      the molecular forms of GnRH expressed in the two cell populations studied may be
      different.

PMID- 10342438
TI  - Choline acetyltransferase immunoreactivity in the hypothalamoneurohypophysial
      system of the lamprey.
AB  - The cholinergic innervation of the neurohypophysis of the lampreys Petromyzon
      marinus and Lampetra fluviatilis was studied by means of immunocytochemical
      techniques with antibodies directed against the enzyme choline acetyltransferase
      (ChAT). The results obtained in both species were basically similar. A rich
      innervation by ChAT-immunoreactive fibres was found throughout the
      neurohypophysis. These fibres originate from cholinergic neurons located in the
      preoptic region and the paraventricular nucleus. Some of these cholinergic
      neurons are in contact with the cerebrospinal fluid. Numerous axonal swellings
      were evident in the tuberal region of the sea lamprey, but not in the river
      lamprey. The possible pathways of cholinergic release in the lamprey hypophysis
      are discussed.

PMID- 10342439
TI  - The paraventricular organ of mormyrid fish: uptake or release of intraventricular
      biogenic amines?
AB  - The paraventricular organ of Gnathonemus petersii was investigated with light and
      electronmicroscopical techniques. It contains high concentrations of dopamine,
      noradrenaline and serotonin, but the synthesizing enzymes are not or hardly
      present. Consequently, the cerebrospinal fluid-contacting neurons might pick up
      their biogenic amines from the ventricular fluid. Dense subependymal axonal
      plexuses in the everted telencephalon probably release these substances into the
      ventricle. However, electronmicroscopical observations suggest release rather
      than uptake by the paraventricular organ. The possible significance of
      intraventricular release, transport and uptake of biogenic amines is discussed.

PMID- 10342440
TI  - Gonadal steroid-dependent neuronal circuitries in avian limbic and preoptic
      regions.
AB  - In the avian limbic and preoptic region, the sexually dimorphic medial preoptic
      nucleus and nucleus of the stria terminalis are characterized by the presence of
      a testosterone-dependent aromatase-immunoreactive neuronal population. In situ
      hybridization studies confirmed that testosterone is modulating the expression of
      aromatase gene. Both nuclei are also characterized by a sexually dimorphic,
      testosterone-dependent vasotocin system. Immunocytochemical and in situ
      hybridization data, demonstrated that dimorphism and testosterone-sensitivity of
      this system are both dependent by an embryonic organizational effect of the
      estradiol. Intracerebroventricularly injected vasotocin, has a profound
      inhibitory effect on the male sexual behaviour, and immunocytochemical
      investigations revealed close associations among vasotocin fibres and aromatase
      cell bodies. These data suggest that this neuropeptidergic system could have a
      key role in the circuitries controlling different aspects of male reproductive
      behaviour in the Japanese quail.

PMID- 10342441
TI  - Early postembryonic neural development in the zebrafish: a 3-D reconstruction of
      forebrain proliferation zones shows their relation to prosomeres.
AB  - Based on a section-by-section analysis of the morphology (combined silver/Nissl
      stain) and of the distribution of proliferation zones (immunohistochemical
      detection of the proliferating cell nuclear antigen) in the zebrafish (Danio
      rerio) forebrain at 5 days postfertilization, we created a three-dimensional
      reconstruction of proliferation zones of that developmental stage. The resulting
      model visualizes the size, number, location and morphology of forebrain
      proliferation zones. The latter foreshadow closely adult neuroanatomical
      forebrain entities. Furthermore, the detailed distribution of proliferation zones
      in the posterior forebrain - but not in the more anterior secondary
      prosencephalon - supports a segmental prosomeric organization.

PMID- 10342442
TI  - The chemoarchitecture of the forebrain of lampreys: evolutionary implications by
      comparisons with gnathostomes.
AB  - The distribution of substance P-, leucine-enkephalin-, tyrosine hydroxylase-, and
      serotonin-like immunoreactivities was studied in the forebrain of the silver
      lamprey and compared to other vertebrate groups. In silver lampreys, substance P
      and leucine-enkephalin provide a clear distinction between the pallium and
      subpallium as they do for gnathostomes. The pallium consists of three
      subdivisions which show striking similarities to the medial, dorsal and lateral
      pallia of gnathostomes. Boundaries of the preoptic area, the hypothalamus and
      posterior tubercle can be well defined by histochemical characteristics. These
      data refute the existence of a dorsal hypothalamic subdivision in silver lampreys
      and suggest rostral and caudal divisions of the hypothalamus.

PMID- 10342443
TI  - Distribution of GABA-immunolabeling in the early zebrafish (Danio rerio) brain.
AB  - The spatial and temporal pattern of GABA-expression in the brains of zebrafish
      (Danio rerio) embryos was studied by means of immunohistochemical techniques.
      GABA is said to exert neurotrophic actions in the early regulation of the
      differentiation of the central nervous system. In early stages GABAergic cells
      form distinct clusters throughout the CNS. As development progresses, more
      GABAergic clusters appear, and a pattern of GABAergic axonal projections is well
      defined. Although there is a corresponding pattern of distribution and appearance
      of GABA-expression in the brain of different teleosts, further studies are needed
      to establish its role during early morphogenesis of the CNS of vertebrates.

PMID- 10342444
TI  - Diencephalic neuronal populations projecting axons into the basal plate in a
      lizard (Gallotia galloti).
AB  - Lizard diencephalic populations sending axons into the basal plate were studied
      by the in vitro HRP technique in the lizard Gallotia. Retrograde labeled cells
      were concentrated in distinct neuronal groups within alar plates of prosomeres p1
      and p3, whereas the alar plate of p2 was poorly labeled. Efferent fibers from
      alar p1 and p3 populations entered the basal plate of the diencephalon along
      topologically dorsoventral courses, bifurcating thereafter into longitudinal
      ascending (rostral) and descending (caudal) trajectories. Thus, diencephalic
      segments p1 and p3 have alar cell populations contributing to the longitudinal
      premotor connectivity of the neural axis , whereas the alar p2 segment projects
      via the fasciculus retroflexus, the efferent tract of the epithalamus. However,
      the axons from the habenular complex bifurcate within or adjacent to the floor
      plate and not within the basal plate.

PMID- 10342445
TI  - Immunohistochemical characterization of forebrain areas in the collared dove
      (streptopelia decaocto).
AB  - The distribution of four neuroactive substances was studied in the telencephalon
      of the collared dove using enzyme- and immunohistochemistry. The distribution of
      acetylcholinesterase and dopamine was similar to that described in other birds.
      Galanin-immunoreactive fibres were found mainly in the paleostriatum primitivum ,
      the medial part of the parolfactory lobe (LPO) and the lateral septal nucleus;
      galanin may interfere with acetylcholine activity. Intense gastrin releasing
      peptide (GRP)-immunoreactivity was found in the neuropil of LPO, the ventral
      paleostriatum and the caudal archistriatum; further GRP-immunoreactive
      varicosities were found in the neostriatum and the hyperstriatum ventrale -
      particularly in its medial part - whereas GRP-immunoreactive cells occurred in
      the medial neostriatum, the hyperstriatum accessorium and the ventral
      archistriatum. These data help to define more precisely several functional
      telencephalic systems, but no indications for specific centers with a role in
      vocalization were found.

PMID- 10342446
TI  - Comparison of the mammalian and avian telencephalon from the perspective of gene
      expression data.
AB  - Pallial and subpallial morphological subdivisions of the mouse and chicken
      telencephalon were examined from the new perspective given by gene markers
      expressed in these territories during development. The rationale of this approach
      is that common gene expression patterns may underlie similar histogenetic
      specification and, consequently, comparable morphological nature. The nested
      expression domains of the genes Dlx-2 and Nkx-2.1 are characteristic for the
      subpallium (lateral and medial ganglionic eminences). Similar expression of these
      markers in parts of the mouse septum and amygdala suggests that such parts may be
      considered subpallial. The genes Pax-6, Tbr-1 and Emx-1 are expressed in the
      pallium. Complementary areas of the septum and amygdala shared expression of
      these genes, suggesting these are the pallial parts of these units. Differences
      in the relative topography of pallial marker genes also define different regions
      of the pallium, which can be partially traced into the amygdala. Importantly,
      there is evidence of a novel "ventral pallium" subdivision, which is a
      molecularly distinct pallial territory intercalated between the striatum and the
      lateral pallium. Its derivatives in the mouse apparently belong to the
      claustroamygdaloid complex. Chicken genes homologous sequence-wise to these mouse
      developmental genes are expressed in topologically comparable patterns during
      development. The avian subpallium -the paleostriatum- expresses Dlx-2 and Nkx
      2.1; expression extends as well into the septum and anterior and medial parts of
      the archistriatum. The avian pallium expresses Pax-6, Tbr-1 and Emx-1 and also
      contains a distinct ventral pallium, formed by the neostriatum and ventral
      intermediate parts of the archistriatum. The lateral pallium comprises the
      hyperstriatum ventrale, overlying temporo-parieto-occipital corticoid layer and
      piriform cortex, plus dorsal intermediate and posterior archistriatum. The dorsal
      pallium includes the dorsal, intercalated and accessory hyperstriatum, plus the
      dorsolateral corticoid area. The medial pallium contains the hippocampus and
      parahippocampal area. A dorsal part of the septum shares pallial molecular
      markers. Gene markers thus suggest common sets of molecular developmental
      determinants in either pallial or subpallial domains of the mouse and chicken
      telencephalon, extending all the way from the posterior pole (amygdala) to the
      septum. Ventral pallial derivatives identified as claustroamygdaloid in the mouse
      correlate with avian neostriatum and parts of the archistriatum.

PMID- 10342447
TI  - Evidences for shared features in the organization of the basal ganglia in
      tetrapods: studies in amphibians.
AB  - In a series of recent studies, the organization of the basal ganglia of
      amphibians, more in particular their connectivity and chemoarchitecture, has been
      thoroughly analyzed. The pattern of organization found for the amphibian basal
      ganglia includes dorsal and ventral striatopallidal systems, reciprocal
      connections between the striatopallidal complex and structures derived from the
      diencephalic and mesencephalic parts of the basal plate (striatonigral and
      nigrostriatal projections), and descending pathways from the striatopallidal
      system to the midbrain tectum and the reticular formation of the brain stem. A
      comparative analysis of the organization of the basal ganglia in tetrapods
      strongly supports the notion that a primitive pattern was most likely present in
      ancestral tetrapods, and that many features can still be recognized in extant
      amphibians and amniotes.

PMID- 10342448
TI  - Cholinergic and catecholaminergic neurons relay striatal information to the optic
      tectum in amphibians.
AB  - In the amphibians Rana perezi and Xenopus laevis, the involvement of cholinergic
      and catecholaminergic neurons in the relay of basal ganglia inputs to the tectum
      was investigated. Tract-tracing experiments, in which anterograde tracers were
      applied to the basal ganglia and retrograde tracers to the optic tectum, were
      combined with immunohistochemistry for choline acetyltransferase and tyrosine
      hydroxylase. The results of these experiments suggest that dopaminergic neurons
      of the suprachiasmatic nucleus and pretectal region, noradrenergic cells of the
      locus coeruleus and the cholinergic neurons of the pedunculopontine and
      laterodorsal tegmental nuclei mediate at least part of the basal ganglia input to
      the tectum in anurans.

PMID- 10342449
TI  - The functional anatomy of the basal ganglia of birds.
AB  - To study how the basal ganglia can control movement in birds, we have
      reinvestigated the connections of the pigeon dorsal pallidum. Our results
      indicate that avian basal ganglia appear to control movement through major
      projections to several premotor pretectal and tegmental centres which innervate
      the tectum, and through a minor projection to a possible motor thalamic centre
      which innervates the Wulst. For such control, separate striatopallidal output
      circuits appear to exist in birds that are remarkably similar to those described
      in mammals, suggesting that avian and mammalian basal ganglia may control
      movement through similar mechanisms, and that the morphological substrate for
      such control evolved earlier than previously thought.

PMID- 10342450
TI  - Cytoarchitecture and connectivity of the amphibian medial pallium.
AB  - We investigated the cytoarchitecture and connectivity of the medial pallium of
      amphibians by intracellular recording and biocytin labeling. The experiments were
      carried out in a whole-brain in vitro preparation in the painted frog,
      Discoglossus pictus. Four types of neurons with specific axonal projection
      patterns and position in the medial pallium are distinguished, three types with
      extratelencephalic and one type with only intratelencephalic projections. Our
      findings corroborate the assumption that the anuran medial pallium is homologous
      to the subiculum and Ammon's horn of the mammalian hippocampus at a gross level,
      while the specific axonal projection patterns differ. Due to the absence of
      hippocampal neurons with only intrinsic projections, there seems to be no portion
      homologous to the dentate gyrus.

PMID- 10342451
TI  - Forebrain and midbrain structures involved in prey-catching behaviour of toads:
      stimulus-response mediating circuits and their modulating loops.
AB  - In anurans, visual prey information is filtered in the retina and processed in
      interacting pretectal and tectal retinal projection fields. Neuropeptide Y is
      involved in pretecto-tectal inhibition. Information related to prey and its
      location in space is transmitted to the bulbar/spinal motor pattern generating
      systems by ensembles of efferent tectal and tegmental neurons. This basic
      stimulus-response (S-R) mediating circuit is influenced by forebrain loops. It is
      suggested that ventral striatum and lateral thalamic nucleus participate in a
      loop responsible for gating S-R. The hippocampal pallium modifies S-R via the
      anterior thalamus with regard to previous experience. Dopaminergic modulation
      influences prey-catching strategies.

PMID- 10342452
TI  - Significance of forebrain structures in acoustically guided behavior in anurans.
AB  - In order to test the hypothesis that the forebrain is involved in controlling
      acoustically guided behaviour, we carried out behavioural studies in combination
      with brain lesions, neuroanatomical and electrophysiological experiments in males
      and females of different species of frogs. Whereas the dorsomedial pallium plays
      no or only a minor role, the striatum, the septum, and the preoptic area
      potentially influence the behaviour because they send parallel descending
      projections to different premotor and motor networks in the brainstem. These
      parallel projections may be the basis for the variability seen in the behaviour.

PMID- 10342453
TI  - Influence of descending forebrain projections on processing of acoustic signals
      and audiomotor integration in the anuran midbrain.
AB  - We tested the role of descending projections for auditory processing and
      audiomotor integration in the anuran torus semicircularis. Intracellular
      recordings were made from isolated brain preparations, impaled neurons were
      stained. Auditory neurons responded to electrical stimulation of striatum and/or
      dorsal thalamus, they integrated forebrain and auditory nerve inputs. High
      frequency stimulation in striatum or thalamus changed the auditory response of
      torus neurons located in the laminar subnucleus. Our results suggest that the
      laminar nucleus is the primary target of forebrain projections, which provides a
      basis for modulation of acoustically guided behaviour.

PMID- 10342454
TI  - A polysensory pathway to the forebrain of the pigeon: the ascending projections
      of the nucleus dorsolateralis posterior thalami (DLP).
AB  - Visual evoked potentials (VEPs) in the associative neostriatum caudolaterale
      (NCL) have shorter latencies than those recorded in other visual forebrain areas.
      Therefore visual input into NCL probably stems from a subtelencephalic relay.
      Tracing experiments revealed a projection of the nucleus dorsolateralis posterior
      thalami (DLP) into those portions of NCL in which visual, auditory, and
      somatosensory afferents from intratelencephalic parasensory areas terminate.
      Since VEPs in NCL are abolished after DLP-lesions, this structure has to be the
      critical relay. However, DLP also projects to other associative forebrain areas
      and parts of the basal ganglia. Previous experiments had furthermore revealed
      that DLP-neurons integrate visual, auditory, and somatosensory inputs. Thus, the
      DLP-projection onto various associative forebrain areas represents a true
      polysensory thalamotelencephalic system.

PMID- 10342455
TI  - Organization of the motor centres for the innervation of different muscles of the
      tongue: a neuromorphological study in the frog.
AB  - Cobalt labelling studies on the localization and morphology of the frog's
      hypoglossal nucleus have revealed three subnuclei. The dorsomedial subnucleus
      innervates the geniohyoid, hyoglossus, genioglossus and the intrinsic tongue
      muscles. The ventrolateral subnucleus supplies the sternohyoid, geniohyoid,
      omohyoid and intrinsic tongue muscles. The intermediate subnucleus innervates the
      omohyoid, geniohyoid and intrinsic tongue muscles. Neurons innervating
      protractor, retractor and intrinsic tongue muscles differ in their soma surface
      area and in their dendritic arborization pattern. It is concluded that there
      exists a musculotopic organization in the frog's hypoglossal nucleus and that
      motoneurons subserving different function in tongue movements disclose
      characteristic morphological differences.

PMID- 10342456
TI  - The puzzle of hydrodynamic information processing: how are complex water motions
      analyzed by the lateral line?
AB  - We studied the discharges of neurons in the ascending lateral line pathway in
      response to the complex water motions generated by a moving object. The wave
      stimulus generated by the object was monitored with a hot-wire anemometer and
      with a custom-built particle imaging system. Responses of central lateral line
      neurons differ from those of primary afferent fibers in aspects like temporal
      discharge patterns and directional sensitivity. The data are consistent with the
      hypothesis that central lateral line neurons integrate input from many afferents
      innervating neuromasts distributed across large portions of the body surface.

PMID- 10342457
TI  - Orientation in the dark: brain circuits involved in the perception of electric
      signals in mormyrid electric fish.
AB  - Weakly electric fish produce electric signals with a specialised organ in their
      tail. In addition, they are electrosensitive and can perceive their self
      generated signals (for electrolocation) and electric signals of other electric
      fishes (for electrocommunication). Mormyrids possess three types of peripheral
      electroreceptor organs, one used for electrocommunication and two types involved
      in electolocation. They are innervated by afferent fibres, which project to
      different zones in the electrosensory lateral line lobe (ELL) in the medulla.
      Brain circuits for electrolocation and electrocommunication are separated almost
      throughout the whole brain. Electrolocation pathways run from the ELL-cortex to
      the torus semicircularis of the midbrain and then via the valvula cerebelli
      towards the telencephalon. Pathways involved in electrocommunication run from the
      nucleus of the ELL to another part of the torus and from there through the
      isthmic granule nucleus to the valvula. In addition, a pathway via the
      preglomerular complex to the telencephalon might exist. In both the
      electrolocation and the electrocommunication circuits, prominent recurrent
      pathways are present.

PMID- 10342458
TI  - In vitro and in vivo responses of saccular and caudal nucleus neurons in the
      grassfrog (Rana temporaria).
AB  - We present results from in vitro and in vivo studies of response properties of
      neurons in the saccular and caudal nuclei in the frog. In the in vitro studies
      the saccular nerve of the isolated brain was stimulated with electrical pulses.
      In the in vivo experiments, the neurons were stimulated by dorso-ventral
      vibrations of the intact animal. We identified six response types: (1) primary
      like cells with short latencies and follow repetition rates up to 100 Hz; (2)
      phasic cells responding only to the first pulse in a train; (3) bursting cells
      firing several spikes in response to any stimulation; (4) late responders with
      very long latencies; (5) integrator cells showing facilitated responses, and (6)
      inhibitory cells inhibited by saccular nerve stimulation. The cells have
      comparable sensitivity and frequency characteristics to the primary fibres (BF 10
      80 Hz, thresholds from 0.01 cm/s2) and enable a sophisticated analysis of
      vibrational stimuli.

PMID- 10342459
TI  - Specializations in the lumbosacral spinal cord of birds: morphological and
      behavioural evidence for a sense of equilibrium.
AB  - Birds have a variety of long known anatomical specializations both in the
      vertebrae and in the spinal cord of lumbosacral segments. In the present
      investigation additional morphological specializations are described for the
      pigeon. These consist of segmentally organized semicircular canal-like structures
      (lumbosacral canals) which together with specializations in the meninges of the
      spinal cord form a large liquor space above accessory lobes attached to the
      spinal cord. The whole system is thought to function as a sense of equilibrium.
      The neurons in the lobes are assumed to be sensory neurons which are stimulated
      by the inertia of the fluid during movements of the body. Such a function is
      supported by lesion experiments: opening of the fluid space was followed by
      severe disturbances of landing and walking behavior.

PMID- 10342460
TI  - An Alu insertion polymorphism in a baboon hybrid zone.
AB  - A novel polymerase chain reaction (PCR) primer pair was used to analyze the
      frequency of insertion of the first described, nonhuman, baboon-specific Alu
      repetitive element in populations from the Papio hamadryas anubis and the Papio
      hamadryas hamadryas subspecies, and from a number of anubis-hamadryas hybrids.
      The Alu insertion is found in intron 7 of the baboon lipoprotein lipase (LPL)
      gene. Each of the populations had different frequencies for the insertion, and
      the hybrids examined had a frequency intermediate to that of the parental
      populations. All hybrids and all P. h. anubis groups except the group of anubis
      sampled in 1973 exhibited higher-than-expected heterozygosity, while P. h.
      hamadryas and 1973 P. h. anubis showed lower-than-expected heterozygosity,
      supporting behavioral and other genetic observations of greater anubis
      outbreeding relative to hamadryas. This may include asymmetric introgression of
      the Alu insertion from hamadryas to the anubis population due to hybridization.

PMID- 10342461
TI  - Plasma phospholipid fatty acids in the central Canadian arctic: biocultural
      explanations for ethnic differences.
AB  - As part of the Keewatin Health Assessment Study, a comprehensive health interview
      and examination survey of Inuit and non-Inuit in the central Canadian Arctic
      during 1990-91, plasma samples were analyzed for phospholipid fatty acid
      composition. Compared to non-Inuit, the Inuit have reduced levels of dihomo-gamma
      linoleic (DGLA) and arachidonic acid (ratios of 0.41 and 0.46) and the sum of all
      n-6 fatty acids (ratio of 0.65), but increased level of eicosapentaenoic (EPA)
      acid (ratio of 1.37). These trends are consistent with those reported from other
      circumpolar Inuit populations, especially the reduced arachidonic acid and
      increased EPA, although the Inuit excess in EPA is much less pronounced due to
      the greater importance of caribou rather than sea mammals in most of the Keewatin
      communities. The high linoleic/arachidonic acid ratio suggests increased
      inhibition of the metabolic pathway regulated by the enzyme delta-5 desaturase,
      which can be explained by the presence of high levels of highly unsaturated fatty
      acids of dietary origin, and/or a genetic deficiency. In multiple linear
      regression models with the independent variable list consisting of Inuit status,
      age, sex, education, physical activity, spending time on the land and consumption
      of wild meat and local fish, Inuit status is independently associated with lower
      levels of the n-6 acids but not the n-3 acids. This indicates that factors other
      than diet and lifestyle, perhaps genetic ones, may account for the observed
      "ethnic" differences. However, for those fatty acids in which Inuit differ from
      non-Inuit, there is no dose-response relationship in terms of self-reported
      degree ofnon-Inuit admixture. Dietary fatty acids play an important role in the
      risk of cardiovascular diseases and diabetes, diseases of increasing importance
      in the health transition experienced by the Inuit. Association studies of plasma
      fatty acids and DNA markers of candidate genes for atherosclerosis and insulin
      resistance may provide a clearer picture of the genetic basis for the observed
      differences in plasma fatty acid composition between Inuit and non-Inuit.

PMID- 10342462
TI  - Reproductive hormone profiles in captive male orangutans: implications for
      understanding developmental arrest.
AB  - For many years researchers have described some male orangutans as "subadult."
      These males are of adolescent to adult age and are reproductive, but have little
      to no secondary sexual trait development. Until now the only endocrine study of
      this arrest of secondary sexual trait development was performed by Kingsley
      (1982, 1988). She found that "subadult" or arrested males have lower testosterone
      levels than similar age developing adolescents or adult males. In this study,
      urine samples were collected over a two-year period from 23 captive male
      orangutans in order to more fully define male endocrine profiles. Three study
      males were juveniles, seven were arrested adolescents, six were developing
      adolescents, and seven were mature adults. Morning samples were analyzed by
      radioimmunoassay for levels of testicular steroids and gonadotropins and group
      hormone profiles were compared by analysis of variance. Results illustrate that
      arrested adolescent orangutans have significantly lower testosterone and
      dihydrotestosterone (DHT) levels than developing adolescents, but significantly
      higher levels than juveniles. Luteinizing hormone (LH) levels also differed
      between arrested and developing adolescents, with arrested males having lower
      levels. However, follicle stimulating hormone (FSH) levels were similar in both
      morphs of adolescent male. The overall hormone profiles for arrested and
      developing adolescent male orangutans suggest that arrested males lack levels of
      LH, testosterone, and DHT necessary for development of secondary sexual traits.
      However, they have sufficient testicular steroids, LH, and FSH to fully develop
      primary sexual function and fertility. These endocrine data help define
      alternative developmental pathways in male orangutans. The authors discuss the
      relationship between these developmental pathways and male orangutan reproductive
      strategies, and hypothesize about their prepubertal socioendocrine determination.

PMID- 10342463
TI  - Cranial capacity and performance on delay-response task correlated with principal
      sulcus length in monkeys.
AB  - During the process of evolution, a selective advantage may have been gained by
      organisms that had the ability to utilize mentally stored information of a
      stimulus rather than the stimulus itself. The ability to temporarily store and
      mentally operate on stimulus information is often termed "working memory." Within
      the neocortex of primates, the functional anatomic subdivision surrounding the
      principal (rectus) sulcus plays an important role in modulating the performance
      of delay-response tasks in monkeys (representing working memory). However, it
      appears that no study has investigated the direct relationship between the length
      of the principal sulcus and performance on a delay-response task. Therefore, this
      paper investigates the relationships between principal sulcus length and
      performance on delay-response tasks. However, to control for the effect of
      overall brain size on this relationship, cranial capacity is analyzed with both
      principal sulcus length and delay-response performance. Results support a
      consistent and significant correlation between principal sulcus length and
      performance on delayed-response tasks in a variety of Old World and New World
      monkeys. Principal sulcus length is also significantly correlated with cranial
      capacity; however, cranial capacity is not significantly correlated with
      performance on delayed-response tasks. The results of this investigation provide
      a method for analyzing cranial capacity and working-memory abilities in select
      primates based on principal sulcus length, and may prove useful for interpreting
      endocasts in the primate fossil record.

PMID- 10342464
TI  - New body mass estimates for Omomys carteri, a middle Eocene primate from North
      America.
AB  - We report new body mass estimates for the North American Eocene primate Omomys
      carteri. These estimates are based on postcranial measurements and a variety of
      analytical methods, including bivariate regression, multiple regression, and
      principal components analysis (PCA). All body mass estimation equations show high
      coefficients of determination (R2), and some equations exhibit low prediction
      errors in accuracy tests involving extant species of body size similar to O.
      carteri. Equations derived from PCA-summarized data and multiple regression
      generally perform better than those based on single variables. The consensus of
      estimates and their statistics suggests a body mass range of 170-290 g. This
      range is similar to previous estimates for this species based on first molar area
      (Gingerich, J Hum Evol 10:345-374, 1981; Conroy, Int J Primatol 8:115-137, 1987).

PMID- 10342465
TI  - Articular surface defects in the third metatarsal and third cuneiform: nonosseous
      tarsal coalition.
AB  - Frequencies of articular surface defects on the third metatarsal and third
      cuneiform, seen as pits of varying sizes on the plantar one third of the
      tarsometatarsal articular face, were investigated in skeletal populations from
      North America and Japan, as well as in gibbon, orangutan, chimpanzee, and gorilla
      skeletons. The apes did not exhibit the defects, although the number of observed
      specimens of each type was small. The newly presented human frequencies
      corresponded well with those from other published sources. The defects appeared
      both unilaterally and bilaterally, with no apparent sex or side biases.
      Statistical tests between the various populations found that, in general,
      geographically close populations had more similar frequencies of the defect.
      Possible etiologies for the defect were investigated, including biomechanical
      influences, degenerative arthritis, infection, trauma, and a developmental
      condition known as tarsal coalition, which proved to be the best explanation.
      Tarsal coalition results from the failure of a joint space to form properly
      during fetal growth. It can occur between any two adjacent bones of the foot.
      Several clinically important coalitions, whose presence interferes with normal
      walking, are known. However, coalition between the third metatarsal and third
      cuneiform has not been reported in the clinical literature, suggesting that the
      defect causes little or no foot dysfunction. Tarsal coalition is thought to have
      a strong genetic component, suggesting that the pit defect may be useful as a
      skeletal nonmetric trait, as others have stated.

PMID- 10342466
TI  - A model of temporomandibular joint function in anthropoid primates based on
      condylar movements during mastication.
AB  - The hypothesis that the shape of the bony temporomandibular joint (TMJ) is
      functionally related to sagittal sliding of the condyle during mastication is
      tested, and a model of the relation of sagittal sliding to mandibular size, TMJ
      shape, and diet is developed. Sagittal sliding is defined as fore-aft motion of
      the condyle during mandibular translation and/or angular rotation. Ascending
      ramus height is used as a structural correlate of the distance between the
      condyle and the mandibular axis of rotation (CR). Cineradiographic data on
      sagittal sliding and gape during mastication in Ateles spp., Macaca fascicularis,
      Papio anubis, and Pan troglodytes in conjunction with comparative data on
      mandibular size and TMJ shape are used to evaluate the hypothesis. The results
      show that 1) linear and angular gape are highly positively correlated with
      sagittal sliding, 2) pure mandibular translation is rare during mastication, 3)
      the CR is rarely if ever located at the condyle during mastication, 4) angular
      gape should be standardized in interindividual comparisons of sagittal sliding,
      and 5) the height of the ascending ramus (and by inference the CR-to-condyle
      distance) is highly positively correlated with absolute sagittal sliding.
      Sagittal sliding relative to the length of the articular eminence was the
      variable used to explore the relation between TMJ shape and sliding. This
      variable standardized absolute sagittal sliding relative to joint size. The
      relative depth and orientation of the articular eminence were not correlated with
      relative sagittal sliding. The anteroposterior curvature of the condyle was
      highly negatively correlated with relative sagittal sliding. Flat condyles are
      associated with large amounts of relative sagittal sliding. A flat condyle
      increases joint contact area, which reduces joint stress. A flat condyle also
      increases joint congruence, and this may facilitate the combined sliding and
      rolling motion of the condyle when the sliding motion is relatively large. The
      shape of the entoglenoid process was also positively correlated with relative
      sagittal sliding. A relatively large entoglenoid process may help to guide
      sagittal sliding and prevent excessive mediolateral sliding of the condyle. The
      functional model makes a number of predictions about the correlations between
      food consistency and food object size, mandibular size, TMJ shape, and sagittal
      sliding of the condyle during mastication and incision.

PMID- 10342467
TI  - Morphological and taxonomic affinities of the Olduvai ulna (OH 36).
AB  - The OH 36 ulna derives from Upper Bed II in the Olduvai Gorge, and is dated to
      circa 1.1-1.2 Myr. Multivariate analyses incorporating data from samples of
      modern humans, common and pygmy chimpanzees, gorillas, orangutans, and two other
      early hominin ulnae, Omo L40-19 and KNM-BK 66, suggest that OH 36 belonged to an
      individual with powerful forearms consistent with a locomotor repertoire that
      included arboreal locomotion. However, there is no compelling evidence that it
      made regular use of its forelimbs as supports when travelling on the ground. When
      compared with levels of intra- and intertaxon size and shape variation in the
      comparative sample (humans, chimpanzees, gorillas), the differences between OH
      36, KNM-BK 66, and Omo L40-19 are compatible with OH 36 differing from the other
      two fossil hominin ulnae to the extent that modern humans differ from modern
      great apes. KNM-BK 66 and Omo L40-19 differ from each other in overall size and
      shape only to the degree that would be expected within any of the individual
      modern comparative samples. Based on these analyses, there is no evidence to
      support the hypothesis that OH 36 and Omo L40-19 belong to the same species of
      fossil hominin, or to two species that shared a similar forelimb locomotor
      repertoire. We suggest that OH 36 has the greater claim to be assigned to
      Paranthropus boisei, and we recommend that for the time being the latter be
      referred to the tribe Hominini gen. et sp. indet. The surprising result of these
      analyses is the overall size and shape similarity between Omo L40-19 and KNM-BK
      66, two fossils that are separated in time by more than 1.5 million years, and
      which have traditionally been assumed to represent hominin species with quite
      different locomotor patterns.

PMID- 10342468
TI  - Hardships of contact: enamel hypoplasias in Tupi-Monde Amerindians from the
      Brazilian Amazonia.
AB  - This paper presents an assessment of enamel defects (hypoplasias) in the
      permanent anterior teeth of three Tupi-Monde-speaking groups from the Brazilian
      Amazonia: the Gaviao, Surui, and Zoro. These are native societies that
      experienced the onset of permanent contact with Brazilian national society in
      different periods of the 20th century. Tupi-Monde dentition is highly
      hypoplastic, which is possibly related to exposure to adverse health and
      nutritional conditions. Data for the Gaviao, Surui, and Zoro are in agreement
      with results from other populations that show that certain teeth, the maxillary
      central incisors and the mandibular canines in particular, tend to be more
      hypoplastic. Although all types of teeth show hypoplasia concentrations at some
      enamel zones, there is substantial intertooth variation in the age at which peaks
      occur. It is argued that hypoplasia concentrations at certain ages are unlikely
      to be related to postweaning stresses for the Tupi-Monde. Statistically
      significant associations between presence of enamel defects and deficits in
      physical growth (height-for-age) were detected in children 7-11 years of age.
      Diachronic assessment of enamel defects, which rested upon the potential of
      enamel as "memory" of past periods of systemic physiological perturbation,
      allowed us to unravel aspects related to the dynamics of Tupi-Monde life during
      the 20th century. Frequencies of enamel zones with defects peaked during the
      contact years of each of the Tupi-Monde groups, attesting to the extreme social
      and biological hardships that characterized the contact experiences of these
      native societies with Brazilian national society.

PMID- 10342469
TI  - Child growth and nutritional status in a high-poverty community in eastern
      Kentucky.
AB  - The research reported in this paper examines the relationship between household
      socioeconomic measures, child growth, and nutritional status in a community in
      eastern Kentucky with a high rate of poverty. It is based on the premise that
      child growth and nutritional status reflect the social circumstances in which
      they occur. 21.6% of the children exhibited low height (<15th percentile of
      National Center for Health Statistics [NCHS] reference values), with 13% of the
      girls exhibiting stunting (<5th percentile). Thirty-three percent of the children
      exhibited overweight, and 13% exhibited obesity (>85th percentile and >95th
      percentile of National Health and Nutrition Examination Survey [NHANES] reference
      values, respectively); 21.4% of boys were obese, compared to 8.7% of girls.
      Analysis of variance indicated that child stature is best explained by the
      father's education level interacting with employment status, and by the mother's
      employment status interacting with household poverty level. Weight is best
      explained by the mother's employment status. However, the relationships among
      socioeconomic measures and growth outcomes differed by gender of the child. These
      issues are discussed in light of the anthropology literature and the situation in
      Bridges County, Kentucky where the research took place.

PMID- 10342470
TI  - Comparative evaluation of the antimicrobial activity of ACTICOAT antimicrobial
      barrier dressing.
AB  - This study evaluated the antimicrobial activity of ACTICOAT Antimicrobial Barrier
      Dressing (Westaim Biomedical Corp, Fort Saskatchewan, Alberta, Canada), a silver
      coated wound dressing, and compared it with silver nitrate, silver sulfadiazine,
      and mafenide acetate. The minimum inhibitory concentrations (MIC), minimum
      bactericidal concentrations (MBC), zone of inhibition, and killing curves were
      determined with 5 clinically relevant bacteria. The data indicate that ACTICOAT
      silver had the lowest MIC and MBC and generated similar zones of inhibition to
      silver nitrate and silver sulfadiazine. Viable bacteria were undetectable 30
      minutes after inoculation with the dressing, whereas it took 2 to 4 hours for
      silver nitrate and silver sulfadazine to achieve the same result. Mafenide
      acetate generated the biggest zones of inhibition, but it had the highest MICs
      and MBCs, and a significant number of bacteria still survived after 6 hours of
      treatment. The results suggest that ACTICOAT Antimicrobial Barrier Dressing has
      better antimicrobial performance than either of the existing silver-based
      products. ACTICOAT dressing killed the bacteria that were tested much faster,
      which is a very important characteristic for a wound dressing acting as a barrier
      to invasive infection to have. The study also suggests that a single
      susceptibility test such as a MIC or zone of inhibition test does not provide a
      comprehensive profile of antimicrobial activity of a topical antimicrobial agent
      or dressing. A combination of tests is desirable.

PMID- 10342471
TI  - Effects of cryopreservation and deconstruction on the dermal glycosaminoglycan
      content of human skin.
AB  - Since the concept of a fabricated skin replacement was first proposed, it has
      been recognized that a permanent skin replacement must contain a functional
      complex structure consisting of epidermis integrated with dermis. Although a
      practical solution for the replacement of missing epidermis exists through the
      culture expansion of the autologous epidermis, a practical solution for
      permanently replacing missing dermis has not been achieved. While it is generally
      recognized that the insoluble matrix components--largely collagen and elastin-
      are essential, the role of other matrix components such as glycosaminoglycans
      (GAGs) and proteoglycans remains undefined. This article describes both the
      qualitative and quantitative GAG composition of fresh and cryopreserved human
      dermis. Through the use of 2 different colorimetric assays and cellulose acetate
      electrophoresis, we found the following: 1) the principal dermal GAGs are those
      of the heparin family; 2) dermatan sulfate is the second most predominant GAG
      component; 3) chondroitin-6-sulfate is found at concentrations of 2 orders of
      magnitude less than the heparins; and 4) hyaluronan and keratan sulfate were both
      found as only minor constituents. When the GAG composition of fresh skin was
      compared with that of cryopreserved skin, no significant differences were
      observed. This study also examined the time course of GAG leaching during the
      preparation of deconstructed human dermis, which is human dermis reduced to the
      native insoluble matrix components by exhaustive saline soaking. We found that
      GAG leaching was readily detectable even within the first day. Sixty percent of
      total GAG leaching occurred by day 7. These investigations establish a benchmark
      for the reproduction of GAGs in synthetic dermal constructs. Further, the results
      of the leaching study generate important considerations for short-term skin
      storage and long-term skin banking. Because GAG leaching commences immediately,
      appropriate precautions must be taken to minimize the potential functional
      compromise of cryopreserved human dermis.

PMID- 10342472
TI  - Immunohistochemical analysis of burn depth.
AB  - Clinical assessment of burns is accurate for very deep and very shallow burns,
      but it has been suggested that there is a high degree of inaccuracy in the
      assessment of dermal burns. Histologic analysis has, by some, been considered too
      time-consuming for routine diagnosis. It also requires an expert skin
      histopathologist to categorize the depth. With the use of an in vitro model, we
      have found the use of cryosections and an immunofluorescent staining method to be
      quicker and more clear-cut than standard light microscopic techniques. We believe
      this method plays a role in helping to define burns that would benefit from early
      excision and grafting. However, further investigation is required to transform
      the method from an experimental model to standard practice in the clinical
      setting.

PMID- 10342474
TI  - Burns caused by the ignition of propane gas by an automobile catalytic converter.
AB  - An unusual accident is reported in which 2 patients were burned when propane gas
      draining from a tanker truck was ignited by the catalytic converter of a nearby
      parked car.

PMID- 10342473
TI  - Full-thickness burn to the hand from an automobile airbag.
AB  - An 18-year-old male was involved in a single car motor vehicle accident in which
      the driver's side airbag was deployed. He presented to the trauma center with
      complex injuries to the left hand, lacerations to the scalp, and a full-thickness
      burn to the ulnar aspect of the right hand that included the hypothenar area and
      the fifth digit. The patient was admitted to the trauma center and received
      immediate consultation from the burn service. He underwent debridement and split
      thickness skin grafting of 50 cm2 of the right hand on postburn day 3. The graft
      became necrotic and the patient underwent debridement of the skin and the
      abductor minimi muscle of the right hand on postburn day 32. Split-thickness skin
      grafting and release of flexion contracture were successfully completed 18 days
      later. The police and fire departments reported that the airbag showed signs of
      thermal destruction. Upon request, Honda motors submitted information from the
      TRW safety systems and material safety data sheet (Mesa, Ariz, issued 1989) that
      showed that airbag canisters contain the chemicals sodium azide and cupric oxide.
      Water may react with sodium azide to form highly toxic and explosive hyfrazoic
      acid. These chemicals are converted to sodium hydroxide, which can cause
      significant chemical burns. In addition, these chemicals may ignite when exposed
      to live electrical wires or temperatures greater than 300 degrees F. We conclude
      that burns associated with damaged deployed airbags in motor vehicle accidents
      may be the results of both chemical and thermal injury. The extent of the burn
      wound may be underestimated, as our case illustrates. Full-thickness burns
      resulting from airbag deployment may require more aggressive initial debridement
      and treatment.

PMID- 10342475
TI  - A regional medical center's experience with burns of the elderly.
AB  - For a 10-year period, the cases of 236 patients aged 60 years old or older were
      evaluated with regard to mortality and length of hospital stay. Multiple
      variables were evaluated. Total mortality for the entire group was 41.9%.
      Mortality was adversely affected by increased age and the development of
      complications after admission. Larger burn size increased mortality when it was
      considered in association with the presence of inhalation problems sufficiently
      severe to require a ventilator. Mean length of stay for survivors was 34.04 days.
      Length of stay (LOS) was increased in association with larger burn size,
      preexisting medical problems, and the development of complications after
      admission. The increase in the number of elderly patients as part of the in
      hospital burn population mandates evaluation of this growing group.

PMID- 10342476
TI  - The effect of partial-thickness facial burns on social functioning.
AB  - The impact of partial-thickness facial burns on the behavior of adults was
      investigated. Burn injuries of the face often have a deleterious effect on the
      psychologic well-being of the patient. Even when no skin grafting is performed,
      there seems to be significant deterioration of the physical and emotional
      function of adults after they have incurred partial-thickness burns of the face.

PMID- 10342477
TI  - Our chemical burn experience: exposing the dangers of anhydrous ammonia.
AB  - Although chemical injuries account for only a small number of one burn unit's
      cases, the diversity, resulting complications, and sequelae of these burns pose
      special problems. We reviewed a 19-year period of the chemical burn experience of
      our burn unit. The population of patients with these types of burns consisted of
      young men (mean age: 29.8 years), the majority of whom were injured on the job.
      Unique to our series is the largest collection of injuries (30%) resulting from
      the common fertilizer anhydrous ammonia. Another population of concern,
      accounting for 14% of the injuries in our unit, is that of patients injured at
      home with routine household cleaners. Nearly one half of those patients injured
      at home incurred injuries that required grafting. The cornerstone of chemical
      burn prevention and treatment involves education regarding the caustic nature of
      chemicals, proper handling, adequate protection, and copious irrigation of the
      wound at the scene. From the analysis of our retrospective review, adequate
      education and treatment at the scene appear to be well implemented in the
      industrial and farming communities. The focus of our education efforts should be
      directed toward the public and emphasize the safe use of household chemicals.
      Finally our review illuminated the potential benefit of immediate excision and
      grafting for decreasing the length of stay, complications, and loss of
      productivity.

PMID- 10342478
TI  - High frequency percussive ventilation in pediatric patients with inhalation
      injury.
AB  - The objective of this study was to present data that showed high frequency
      percussive ventilation (HFPV) was superior to traditional mechanical ventilation
      for the treatment of children with inhalation injuries. Inhalation injuries
      continue to be the number one cause of death of patients with thermal injuries in
      the United States. Therapy for this condition has consisted of conservative
      pulmonary toilet and mechanical ventilation. Despite improvements in the
      management of burn injury, patients with inhalation injury develop pneumonia and
      pneumothorax, leading to adult respiratory distress syndrome. Unfortunately,
      inhalation injury that is complicated by pneumonia has been shown to increase
      mortality by 60% in these patients. Cioffi has shown that prophylactic use of
      HFPV in adult patients with inhalation injury has been a successful method of
      reducing the incidence of pneumonia and mortality. The effects of HFPV on the
      incidence of pneumonia, peak inspiratory pressures, and arterial partial pressure
      of oxygen/fraction of inspired concentration of oxygen (P/F) ratios were
      retrospectively studied in 13 children with inhalation injuries and compared with
      historic controls treated with conventional mechanical ventilation. All patients
      were treated with our standard inhalation injury protocol and extubated when they
      met standard extubation criteria. Patients ranged in age from 6 to 9 years, and
      most had burns covering greater than 50% of their total body surface areas. No
      deaths occurred in either group, but the patients who were treated with HFPV had
      no cases of pneumonia (P < .05), better P/F ratios (P < .05), lower peak
      inspiratory pressures, and less work of breathing (P < .05) as compared with our
      control group. On the basis of our clinical experience and data, the use of HFPV
      seems to be an effective treatment for the reduction of pulmonary morbidity in
      pediatric patients with inhalation injuries.

PMID- 10342479
TI  - Pediatric patients experiencing postoperative nausea and vomiting after burn
      reconstruction surgery: an analysis.
AB  - Nausea and vomiting after a surgical procedure has a significant impact on a
      patient's hospital course. A perceived increased incidence of postoperative
      nausea and vomiting (PONV) in pediatric patients undergoing reconstructive scalp
      surgery had been clinically observed. A chart review to determine if a
      relationship existed between the surgical procedure and the incidence of PONV was
      conducted by selecting patients who were 5 to 12 years old and whose surgery fell
      between April 1995 and August 1995. Thirty-eight patients were evaluated for 46
      procedures; 8 patients were evaluated for both insertion and removal of scalp
      expanders. No differences were identified between groups for previous history of
      PONV, length of anesthesia, or position during surgery. Data from the
      retrospective review suggested that pediatric patients with reconstructive
      surgeries of the scalp experienced PONV at 100% (24 procedures), whereas only 45%
      (10 procedures) of patients whose surgeries did not involve the scalp experienced
      PONV. In addition, despite significant earlier return of bowel sounds, episodes
      of PONV and time to oral intake were also increased in the group of patients
      whose operations involved the scalp. On the basis of these findings, a
      prospective study has been initiated to determine if changes in the perioperative
      protocol will improve patient outcomes and reduce the incidence of PONV.

PMID- 10342480
TI  - Skeletal and dental disturbances in children after facial burns and pressure
      garment use: a 4-year follow-up.
AB  - Pressure garment use alters facial growth during rehabilitation after a facial
      burn injury. We previously studied 3 children with full facial burns and 3
      children with partial facial burns who wore pressure garments for 1 year, and we
      found that maxillary horizontal growth and mandibular anterior-inferior growth
      are inhibited during the time of pressure garment use. The purpose of this follow
      up study was to prospectively document skeletal and dental changes after pressure
      garment use was discontinued. We found that although the growth and development
      of the facial bones seem to return to normal, lasting changes remain. The use of
      pressure garments after skin grafting is still recommended. However, it is also
      recommended that an orthodontist be included in the team of burn care specialists
      for children with facial burns to monitor facial and dental development. Close
      attention to facial development during and after pressure garment use is
      necessary to maintain normal dental and facial relationships.

PMID- 10342481
TI  - An approach to the timely treatment of acute stress disorder.
AB  - A convergent postburn psychopharmacologic treatment for children for acute stress
      disorder (ASD) symptoms has not been established. Both the application of what
      has been learned through treatment of similar symptoms experienced by adults with
      posttraumatic stress disorder and the examination of safe treatment options for
      children led to the clinical decision to use imipramine for 25 pediatric patients
      with acute burns. The treatment histories of these patients were retrospectively
      reviewed to see if further exploration into the efficacy of imipramine was
      warranted. Eighty percent of the children experienced remission of hyperarousal
      symptoms (eg, trouble staying asleep, trouble falling asleep) and intrusive
      reexperiencing symptoms (eg, nightmares). Twelve percent of the children
      experienced a decrease in the frequency or intensity of ASD symptoms. Eight
      percent had no relief of ASD symptoms. Initial findings suggest that imipramine
      assists children who have postburn ASD symptoms by decreasing the hyperarousal
      and intrusive reexperiencing symptoms of ASD.

PMID- 10342482
TI  - Directional variance in skin movement.
AB  - Skin tension is known to affect the amount of movement in normal skin and has
      been theorized to have a possible influence on burn scars. This study measured
      the directional variance in skin movement, which is related to this theory.
      Twenty adult female volunteers had 5 predetermined skin sites tested; these sites
      were on the ventral surface of the upper extremities (UE), from the shoulder to
      the wrist. A 1 kg axial traction force was randomly applied to each skin site in
      both proximal and distal directions. The skin was load-cycled 6 times before
      movement was measured with the use of a laser beam projection. Analysis was
      performed for each site, and pooled data was normalized for the entire UE. Distal
      skin movement was significantly greater than proximal movement at each of the 5
      test sites and for the UE as a whole (P < .001). No significant differences were
      found among like-direction sites. Only subject height and length of UE correlated
      strongly (r = .88). This study demonstrates a difference in skin movement and
      discusses how these findings may relate to the theory that skin tension could be
      involved in burn scar contracture and hypertrophy.

PMID- 10342483
TI  - The use of the brachioradialis muscle flap for the coverage of burns of the acute
      elbow joint.
AB  - Early coverage of deep burns of the elbow is vital to preserving the range of
      motion. Although various methods are used for coverage of this site, the
      brachioradialis muscle flap provides good coverage after debridement, with
      minimal donor site morbidity.

PMID- 10342484
TI  - Massage in hypertrophic scars.
AB  - Various attempts have been made to intervene with the formation of hypertrophic
      scarring (HTS) or to ameliorate it once it has developed, but none have yet
      proved effective. Massage therapy is routinely used by therapists for the
      treatment of various conditions, and there have been reports of increased scar
      pliability and decreased scar banding with the use of massage. This study
      examines the use of friction massage over a 3-month period in a group of 30
      pediatric patients with HTS. The patients were randomly assigned to receive
      either therapeutic massage sessions of 10 minutes per day in combination with
      treatment with pressure garments or they were treated with pressure garments
      alone. A modified Vancouver Burn Scar Assessment Scale was used to measure the
      characteristics of the identified scars (10 cm by 10 cm) before and after the
      implementation of massage therapy. The study failed to demonstrate any
      appreciable effects of massage therapy on the vascularity, pliability, and height
      of the HTS studied, although there were reports of a decrease in pruritus in some
      patients. Further studies, with prolonged treatment intervals, are necessary to
      conclusively demonstrate the ineffectiveness of this therapy for HTS.

PMID- 10342485
TI  - Regarding postdischarge weight loss of younger pediatric patients with burns.

PMID- 10342486
TI  - Insulin secretion, DNA damage, and apoptosis in human and rat islets of
      Langerhans following exposure to nitric oxide, peroxynitrite, and cytokines.
AB  - Cytokine-induced damage may contribute to destruction of insulin-secreting beta
      cells in islets of Langerhans during autoimmune diabetes. There is considerable
      controversy (i) whether human and rat islets respond differently to cytokines,
      (ii) the extent to which cytokine damage is mediated by induction of nitric oxide
      formation, and (iii) whether the effects of nitric oxide on islets can be
      distinguished from those of reactive oxygen species or peroxynitrite. We have
      analyzed rat and human islet responses in parallel, 48 h after exposure to the
      nitric oxide donor S-nitrosoglutathione, the mixed donor 3-morpholinosydnonimine,
      hypoxanthine/xanthine oxidase, peroxynitrite, and combined cytokines (interleukin
      1beta, tumor necrosis factor-alpha and interferon-gamma). Insulin secretory
      response to glucose, insulin content, DNA strand breakage, and early-to-late
      stage apoptosis were recorded in each experiment. Rat islet insulin secretion was
      reduced by S-nitrosoglutathione or combined cytokines, but unexpectedly increased
      by peroxynitrite or hypoxanthine/xanthine oxidase. Effects on human islet insulin
      secretion were small; cytokines and S-nitrosoglutathione decreased insulin
      content. Both rat and human islets showed significant and similar levels of DNA
      damage following all treatments. Apoptosis in neonatal rat islets was increased
      by every treatment, but was at a low rate in adult rat or human islets and only
      achieved significance with cytokine treatment of human islets. All cytokine
      responses were blocked by an arginine analogue. We conclude: (i) Reactive oxygen
      species increased and nitric oxide decreased insulin secretory responsiveness in
      rat islets. (ii) Species differences lie mainly in responses to cytokines,
      applied at a lower dose and shorter time than in most studies of human islets.
      (iii) Cytokine effects were nitric oxide driven; neither reactive oxygen species
      nor peroxynitrite reproduced cytokine effects. (iv) Rat and human islets showed
      equal susceptibility to DNA damage. (v) Apoptosis was not the preferred death
      pathway in adult islets. (vi) We have found no evidence of human donor variation
      in the pattern of response to these treatments.

PMID- 10342487
TI  - Inducible nitric oxide production and expression of transforming growth factor
      beta1 in serum and CSF after cerebral ischaemic stroke in man.
AB  - A residual blood supply to the ischaemic brain is a crucial determinant for
      tissue survival. Early changes in the vascular network and subsequent
      angiogenesis may be mediated by short-lived molecules like nitric oxide (NO) or
      growth factors such as transforming growth factor-beta1 (TGF-beta1). Although TGF
      beta1 can inhibit NO production, this interaction has not been studied after
      ischaemia in humans. Serum samples were taken from patients at 24 h and 6 months
      and cerebrospinal fluid (CSF) samples at 24 h and 1 week later for possible
      correlation between the two factors. Tissue expression of TGF-beta1 and of the
      inducible isoform of NO synthase (NOS2) was assessed by immunohistochemistry. CSF
      levels of NO2-/NO3- as well as total (active + latent) TGF-beta1 were higher in
      stroke patients as compared to controls 24 h after the stroke. Both NO2-/NO3- and
      TGF-beta1 were lower 6 months after the stroke compared to 24 h. Levels of NO2
      /NO3- correlated with levels of TGF-beta1 within the time points (P = 0.041,
      Kendall correlation coefficient). There was a strong staining for NOS2 in brain
      tissue sections in neurones, reactive astrocytes, infiltrating white blood cells,
      and endothelial cells of larger microvessels. TGF-beta1 expression was mainly
      limited to neurones and reactive astrocytes. These findings suggest that the
      interaction between TGF-beta1 and NOS2 might be important for angiogenesis after
      cerebral ischaemia and may indicate that TGF-beta1 is upregulated as a negative
      feedback response to elevated levels of NO.

PMID- 10342488
TI  - Photolytic generation of nitric oxide through a porous glass partitioning
      membrane.
AB  - We report a new method of generating nitric oxide that possesses several
      potential advantages for experimental use. This method consists of a
      microphotolysis chamber where NO is released by illuminating photolabile NO
      donors with light from a xenon lamp. NO then diffuses through a porous glass
      membrane to the experimental preparation. We observed that the rate of NO
      generation is a linear function of light intensity. Due to a dynamic equilibrium
      between the mechanisms of NO generation and dissipation (by diffusion or
      oxidation) the NO concentration in the experimental cuvette can be reversibly and
      reproducibly controlled. The major potential advantages of this device include
      its use as a NO point source, and the ability to partition the NO donor compound
      from the experimental preparation by a porous glass membrane. The diffusion of
      the caging moiety through the membrane is insignificant as seen by absorption
      spectroscopy due to its large relative size to NO. In this way, the porous glass
      membrane protects the preparation from the potential bioactive effects of the
      caging moiety, which is an important consideration for biological experiments.

PMID- 10342489
TI  - Estrogen induces nitric oxide-mediated vasodilation of human mammary arteries in
      vitro.
AB  - Human internal mammary arteries (IMA) are relatively protected from
      atherosclerosis. Estrogen plays a protective role in cardiovascular disease. It
      causes in vitro and in vivo vasodilatation, but the mechanisms are contradictory.
      To investigate the in vitro vasomotor effect of estrogen on IMA and the role of
      endothelium, we studied 30 IMA segments harvested from 10 men during coronary
      artery bypass grafting surgery. Patients with diabetes mellitus,
      hypercholesterolemia, hypertension, and smoking were excluded. Twenty IMA rings
      had intact endothelium ((+)Endo) and 10 rings were denuded of endothelium ((
      )Endo). Vasomotor response of each ring was expressed as the percentage of
      maximal response to norepinephrine (NE). Acetylcholine (10(-8)-10(-5) M) given to
      (+)Endo and (-)Endo rings induced vasorelaxation of 72 +/- 30.4% and
      vasoconstriction of 48.5 +/- 20.1%, respectively. 17-Beta-estradiol (10(-8)-10(
      5) M) given after maximal precontraction with NE induced marked relaxation in
      (+)Endo (80.9 +/- 39.2%), but no significant vasomotor effect in (-)Endo rings (P
      < 0.0001). Vasorelaxation to 17-beta-estradiol (10(-6) M) in (+)Endo rings was
      64.5 +/- 18.4 and 8.6 +/- 8.4%, before and after 15-min treatment with nitric
      oxide synthase inhibitor, L-nitroarginine methyl ester, respectively (n = 14, P <
      0.0001). Tamoxifen (10(-6) M) decreased 17-beta-estradiol (10(-7) M)-induced
      relaxation by 71%. In conclusion, 17-beta-estradiol induces endothelium-dependent
      NO-mediated vasodilation of human mammary arteries in vitro. This response is
      mediated through estrogen receptors.

PMID- 10342490
TI  - Induction of nitric oxide production by the peritoneal macrophages after
      intraperitoneal or subcutaneous transplantation of AK-5 tumor.
AB  - We have investigated the role of host macrophages in the activation of effector
      functions in addition to their direct role in the induction of tumor cell death.
      Peritoneal macrophages from s.c. tumor-bearing animals were in an activated state
      and induced NO-mediated apoptotic death in AK-5 tumor cells. They also showed
      overexpression of inducible nitric oxide synthase both at the transcript and at
      the enzyme levels. However, macrophages from the i.p. tumor-bearing animals
      showed suppression of activation especially when the tumor load was high,
      suggesting thereby tumor-induced suppression of macrophage activation in i.p.
      tumor-transplanted hosts. Suppression of macrophage activation was also observed
      upon coculture of peritoneal macrophages with tumor cells in vitro. These studies
      suggest an important role played by the host peritoneal macrophages in the
      regression of AK-5 tumor. They also indicate suppression of macrophage activation
      by the tumor cells.

PMID- 10342491
TI  - Differential inhibition of Maillard protein fluorescence by nitric oxide donors.
AB  - The nitric oxide donors nitroprusside (NP) and S-nitroso-N-acetylpenicillamine
      (SNAP) were added repeatedly over a prolonged period into a protein fructation
      system of 0.05 M fructose and BSA. These additions inhibited Maillard reaction
      advanced-stage fluorescence generation in a dose-dependent manner without
      affecting initiation of glycation. NP caused 66% inhibition whereas SNAP caused
      only 30% inhibition at maximum dose. The lower inhibition by SNAP possibly
      reflects an interference caused by N-acetylpenicillamine and mediated by a metal
      dependent enhanced free-radical generation. We propose that the inhibition of
      fluorescence results from mutual annihilation between nitric oxide and free
      radicals, such as OH*, produced during fructation. In vivo generated nitric oxide
      may play a protective role in cells against the deleterious effect of free
      radicals that are associated with the augmented fructose autoxidation and
      fructation that occurs in diabetes.

PMID- 10342492
TI  - Nitric oxide release from the liver surface to the intraabdominal cavity during
      acute endotoxemia in rats.
AB  - Nitric oxide (NO) is produced by the liver during lipopolysaccharide (LPS)
      induced endotoxemia. The aim of this study was to examine whether NO, which is
      produced in the liver, is released from the liver surface to the intraabdominal
      cavity during endotoxemia. NO was quantitatively determined by chemiluminescence
      and a newly developed gas purge technique was used to directly measure NO
      released from the liver surface and the intraabdominal cavity of rats before and
      after LPS (0.1 mg/kg, intraperitoneally) or saline administration. The expression
      of inducible NO synthase (iNOS) mRNA in the liver was detected by Northern blot
      analysis. NO levels from both the liver surface and in the intraabdominal cavity
      were elevated at 2 h after LPS injection and peaked at 10 h and both the time
      course of NO level were well correlated with each other. Both NO levels were
      below the detectable range before LPS and after saline administration. Inducible
      NOS mRNA in the liver exhibited a sharp increase to a maximum level at 4 h after
      LPS injection. The present study indicates that the hepatic NO, which might have
      been produced by iNOS in the liver, is released from the liver surface to the
      intraabdominal cavity during endotoxemia.

PMID- 10342493
TI  - Fetal origins of cardiovascular disease.
AB  - Low birthweight, thinness and short body length at birth are now known to be
      associated with increased rates of cardiovascular disease and non-insulin
      dependent diabetes in adult life. The fetal origins hypothesis proposes that
      these diseases originate through adaptations which the fetus makes when it is
      undernourished. These adaptations may be cardiovascular, metabolic or endocrine.
      They permanently change the structure and function of the body. Prevention of the
      diseases may depend on prevention of imbalances in fetal growth or imbalances
      between prenatal and postnatal growth, or imbalances in nutrient supply to the
      fetus.

PMID- 10342494
TI  - Nutrition in early life: somatic growth and serum lipids.
AB  - This paper addresses the questions of whether early nutritional experience
      affects later somatic growth, the growth of the adipose tissue, or the levels of
      serum lipids among well-nourished children. The analyses are based on data from
      three prospective studies. Postnatal nutrition and growth: there were differences
      in growth between breast-fed and formula-fed children. There was no association
      between linear growth and differences in food energy or macronutrient intake.
      Birth size and postnatal growth: there was no association between ponderal index
      (PI) at birth and body mass index (BMI) in the second year. For boys, the PI at 3
      and 6 months of age was significantly positively correlated with BMI at the ages
      of 8 and 15 years, but not for girls. Childhood growth and lipids: there was no
      association between lipids at the age of 8 years and either birth weight or
      length, but children who had had a low PI at birth had higher lipid levels at the
      age 8 years. A positive association was found between serum lipids and abdominal
      fat and BMI. We conclude that, although early diet may influence growth rate
      beyond infancy, the evidence for fat patterning resulting from differences in
      fetal or early postnatal nutrition is still open to question.

PMID- 10342495
TI  - An update on familial hypercholesterolaemia.
AB  - A report of a World Health Organization consultation on familial
      hypercholesterolaemia (FH) was recently presented in Geneva. The report provides
      an update on several aspects of FH such as the molecular basis, DNA diagnosis,
      clinical criteria for the diagnosis, treatment of FH adults and children, the
      role of diet, psychosocial aspects of FH, contacting and helping relatives with
      FH and gives suggestions for government cooperation. The report is reviewed here.

PMID- 10342496
TI  - Role of genetic factors in childhood obesity and in susceptibility to dietary
      variations.
AB  - The concern about the current epidemic of obesity is heightened by recent data
      showing an increase in the prevalence of overweight and obesity in children and
      adolescents. As obese children are at increased risk of becoming obese adults,
      early identification of individuals at risk of becoming obese is important for
      the implementation of preventive measures. In that context, it is important to
      assess the role of genetic and nongenetic factors in childhood obesity as well as
      in susceptibility to dietary variations. This paper reviews recent data regarding
      the prevalence of obesity in childhood as well as the role of genetic factors in
      phenotypes related to obesity, with emphasis on studies conducted on children,
      when available. The existence of severe cases of obesity, such as those
      encountered in Mendelian syndromes of obesity or those caused by mutations in
      single genes, provides strong evidence for a role of genetic factors in the
      aetiology of childhood obesity. Furthermore, results from family studies suggest
      that the maximal heritability of obesity phenotypes ranges from about 30% to 50%
      and that the major affectors of body fat content, energy intake and energy
      expenditure are also influenced by genetic factors. Finally, there is increasing
      evidence that responsiveness to dietary intervention is genetically determined.

PMID- 10342497
TI  - Factors influencing children's food choice.
AB  - Although food habits are not stable and unchanging during a person's lifetime, a
      base for healthy food habits can be created in early childhood. Children's food
      habits can be assumed to be influenced by their parents' food habits and choices.
      The aim of this article is to review factors influencing food choice in children
      as well as in adults. The results demonstrate that the development of children's
      food habits is influenced by a multitude of factors. Parents play an important
      role in the formation of food habits and preferences of young children. They can
      influence their children's food choice by making specific foods available, by
      acting as models for their children and by their behaviour in specific
      situations. Children tend to be afraid of new foods and do not readily accept
      them. However, experience is known to enhance preference, and earlier experiences
      of a particular food are the major determinants of the development of children's
      food acceptance patterns. Thus, parents should be encouraged to make healthy
      foods easily available to the child and serve these foods in positive mealtime
      situations in order to help their child to develop healthy food habits.

PMID- 10342498
TI  - Imaging of subclinical atherosclerosis in children and young adults.
AB  - Atherosclerosis begins in childhood and has a long preclinical phase before
      ischaemic symptoms appear. This provides an opportunity for subclinical detection
      of the disease and identification of high-risk subjects. Recent advances in
      imaging technology have identified many early functional and structural vascular
      changes, some of which may reflect subclinical atherosclerosis, and therefore
      provide areas of potential interest for diagnostic tests of preclinical
      atherosclerosis. These early events include changes in arterial vasodilatory
      function, alterations in arterial elasticity, thickening of arterial walls and
      calcification of atherosclerotic lesions. Clinical testing for presymptomatic
      atherosclerosis should involve methods that are safe, noninvasive, reliable and
      reproducible, and which correlate with the extent of the atherosclerotic process.
      Although no such tests are currently widely used in clinical practice, potential
      methods for detecting the processes outlined above include ultrasound, positron
      emission tomography, magnetic resonance imaging and ultrafast computed
      tomography. With further developments, noninvasive imaging techniques for the
      study of arterial function and structure may soon provide clinically useful ways
      of detecting early atherosclerosis in high-risk asymptomatic subjects at a stage
      where preventive strategies are most likely to have important health benefits.

PMID- 10342499
TI  - Inflammation and the mental state before an acute coronary event.
AB  - Feelings of exhaustion have been found to belong to the precursors of acute
      coronary events. Guided by the current views of the pathogenesis of acute
      coronary syndromes, a two-stage model describing a feedback relationship between
      mental state and the disease process is presented. According to the presented
      model prolonged exposure to stress results in a state of exhaustion leading to
      increased susceptibility to inflammatory diseases. Inflammation, in turn,
      amplifies feelings of exhaustion and malaise through cytokine release. Results of
      a study of 15 exhausted and 15 nonexhausted angioplasty patients, showing
      elevated levels of interleukin-1beta and tumour necrosis factor-alpha in the
      exhausted patients, give empirical support to this model.

PMID- 10342500
TI  - Cardiovascular Risk in Young Finns Study: general outline and recent
      developments.
AB  - The Cardiovascular Risk in Young Finns Study is a collaborative effort of all
      university departments of paediatrics and several other institutions in Finland
      to study the risk factors of coronary heart disease (CHD) and their determinants
      in children and adolescents in different parts of the country. The main cross
      sectional study carried out in 1980 included 3596 3-18-year-old subjects. Follow
      up studies have been performed in 1983, 1986, 1989 and 1992; in the last of these
      studies the subjects were 15-30 years old. The findings in anthropometry, obesity
      and blood pressure have been rather similar to reports from other countries in
      Europe. However, serum cholesterol and low-density lipoprotein cholesterol
      concentrations were higher than in other countries, 4.83 mmol/L and 3.09 mmol/L,
      respectively in 1980. By 1992 a decrease of 8% took place, probably as a result
      of dietary changes. Apolipoprotein phenotypes E4E4 or E4E3 were relatively
      frequent (34%) in the sample. Tracking and clustering have also been studied.
      Serum insulin levels predicted the clustering of the typical risk factor profile
      associated with insulin resistance syndrome. The dietary polyunsaturated to
      saturated fat (P/S) ratio increased from 0.26 in 1980 to 0.39 in 1992, with no
      significant changes in the total energy derived from fat. 'Hard-driving' was
      found to be the psychological risk factor most consistently related to the CHD
      risk factor level.

PMID- 10342501
TI  - Cardiovascular disease risk factors in young children in the STRIP baby project.
      Special Turku coronary Risk factor Intervention Project for children.
AB  - Introducing nutritional principles of preventive cardiology to the care of young
      children may improve permanently adherence to a low-saturated-fat, low
      cholesterol diet later in life. This approach has not been readily adapted
      because of worries of the possible effects of such a diet on the growth and
      development of children. In the STRIP baby project, 1062 infants were randomized
      at 7 months of age into an intervention group (n = 540) or a control group (n =
      522). The counselling of the intervention children aimed at a fat intake of 30%
      of energy after the age of 1 year and to a 1:1:1 ratio in
      saturated:monounsaturated:polyunsaturated fat intake. Dietary intake, growth and
      serum lipid concentrations were monitored in the children regularly through the
      first years of life. The intake of total fat, saturated fat and cholesterol were
      lower and the intake of polyunsaturated fat and the ratio of polyunsaturated to
      saturated fat (P/S) in the diet were higher in the intervention children than in
      the controls. During the first 3 years of the trial, the serum cholesterol
      concentration was 3-6% lower in the intervention children than in the controls
      (95% CI for the mean difference between groups from -0.27 to -0.12 mmol/L). No
      differences in the growth of the children were observed between the groups. We
      conclude that repeated individualized counselling aiming at reduced consumption
      of saturated fat combined with regular follow-up is effective and does not
      restrict the growth of children.

PMID- 10342502
TI  - Errors in medication administration.

PMID- 10342504
TI  - Economic immunity in the ICU: continued support or pull the plug?

PMID- 10342503
TI  - The autopsy as a tool to monitor diagnostic error.

PMID- 10342505
TI  - Severe head injury: improvement of outcome.

PMID- 10342506
TI  - Electrophysiological monitoring of general intensive care patients.

PMID- 10342507
TI  - Medication errors at the administration stage in an intensive care unit.
AB  - OBJECTIVE: To assess the type, frequency and potential clinical significance of
      medication-administration errors. DESIGN: Prospective study using the observation
      technique as described by the American Society of HealthSystem Pharmacists but
      eliminating the disguised aspect. SETTING: Medical intensive care unit (ICU) in a
      university hospital. PATIENTS AND PARTICIPANTS: 2009 medication administration
      interventions by nurses. INTERVENTIONS: Pharmacist-performed observation of
      preparation and administration of medication by nurses, comparison with the
      original medical order and comparison with the data available in the literature.
      MEASUREMENTS AND RESULTS: 132 (6.6% of 2009 observed events) errors were
      detected. Their distribution is as follows: 41 dose errors, 29 wrong rate, 24
      wrong preparation technique, 19 physicochemical incompatibility, 10 wrong
      administration technique and 9 wrong time errors. No fatal errors were observed,
      but 26 of 132 errors were potentially life-threatening and 55 potentially
      significant. CONCLUSION: According to this first observation-based study of
      medication administration errors in a European ICU, these errors were due to
      deficiencies in the overall organisation of the hospital medication track, in
      patient follow-up and in staff training.

PMID- 10342508
TI  - Autopsy: quality assurance in the ICU.
AB  - OBJECTIVE: To examine the correlation between the clinical diagnosis and autopsy
      findings in adult patients who died in an intensive care unit (ICU). To determine
      the rate of agreement of the basic and terminal causes of death and the types of
      errors in order to improve quality control of future care. DESIGN: Retrospective
      study. SETTING: Adult ICU in a university hospital. PATIENTS: 30 adult patients
      who died in the ICU, with the exclusion of medicolegal cases. METHODS AND MAIN
      RESULTS: Anatomo-clinical meetings were held to analyze the pre- and postmortem
      correlations in 30 consecutive autopsies at the ICU of the University Hospital,
      School of Medicine of Botucatu/ UNESP, from January 1994 to January 1997. The
      rate of correct clinical diagnoses of the basic cause was 66.7%; in 23.3% of
      cases, if the correct diagnosis was made, management would have been different,
      as would have been the evolution of the patient's course (Class I error); in 10%
      of the cases the error would not have led to a change in management (Class II
      error). The rate of correct clinical diagnoses of terminal cause was 80%.
      CONCLUSIONS: The rate of recognition of the basic cause was 66.7%, which is
      consistent with the literature, but the Class I error rate was higher than that
      reported in the literature.

PMID- 10342509
TI  - Cost-effectiveness analysis of the terlipressin-glycerin trinitrate combination
      in the pre-hospital management of acute gastro-intestinal haemorrhage in
      cirrhotic patients.
AB  - OBJECTIVES: To assess the cost-effectiveness of an early treatment of upper
      gastro-intestinal haemorrages in cirrhotic patients. DESIGN: Utilization data
      linked to the results of a double-blind, placebo-controlled trial demonstrating
      the efficacy of the terlipressin-glycerin trinitrate combination (TER-GTN) in the
      reduction of mortality at day 42 for haemorragic patients due to rupture of
      oesophageal varices. SETTING: Hopital Jean Verdier, Bondy, Assistance Publique
      Hopitaux de Paris, France. SUBJECTS: Eighty-four patients included over 2 years
      by emergency services and hospitalized in an intensive care unit (ICU) for
      haemorrage, 41 in the "treated" group and 43 in the "placebo" group. MAIN OUTCOME
      MEASURES: Mortality at day 42, cost per death avoided. RESULTS: The mortality
      rate in the placebo group was 46.5% versus 27.5% in the treated group. The mean
      length of stay was 5 days longer in the treatment group. The excess cost per
      death avoided was 25,849 FF. Of this extra cost 27% was due to treatment and 24%
      was due to increased length of stay. The excess cost per case treated was FF
      5,097, 10% of the total cost per stay for rupture of oesophageal varices (ROV).
      CONCLUSIONS: Our results are of the same magnitude as those published by Mac
      Cormick et al. in the United Kingdom for similar treatment. The extra cost
      appears to be moderate, and much lower than monoclonal antibody therapy for
      sepsis. The impact on the study hospital budget did not exceed 1.7 10(-4).

PMID- 10342510
TI  - Intracranial hypertension in head injury: management and results.
AB  - OBJECTIVE: (1) To describe the pattern of intracranial pressure (ICP) and
      cerebral perfusion pressure (CPP) in a group of severe head-injured patients, (2)
      to quantify complications of ICP monitoring, and (3) to describe a management
      protocol and its results. DESIGN: Prospective observational study. SETTING:
      General intensive care unit in a teaching hospital. PATIENTS: 138 comatose
      patients, selected according to the following criteria: age > 16 years, coma
      [Glasgow Coma Scale (GCS) < or = 8] with at least one pupil reactive after
      resuscitation, digital recording of intracranial and arterial pressure, and
      jugular saturation measurements. MEASUREMENTS AND RESULTS: Median GCS was 5, and
      62 patients had significant extracranial injuries; 71 had intracranial hematomas,
      which were urgently evacuated. Mean ICP was 20.5 mmHg (SD 8.34), mean CPP was
      71.86 mmHg (SD 11.22); cerebral extraction of oxygen averaged 29 %. Medical
      therapy was used to control ICP in 130 cases; 93 patients required
      hyperventilation. Vasopressors were infused in 16 cases; in 14 cases a
      barbiturate infusion was started. In 6 patients all pharmacological treatments
      failed and surgical decompression was done. The only complication of ICP
      monitoring was meningitis in 3 patients. Outcome at 6 months was a good recovery
      and moderate disability for 82 patients (59.4%), severe disability and vegetative
      status for 37 (26.8%), and 19 patients died (13.7%). The severity of intracranial
      hypertension was related to poorer results at 6 months. CONCLUSIONS: Intracranial
      hypertension is very frequent in severe head injury but can be reasonably well
      controlled by combined surgical and medical therapy.

PMID- 10342511
TI  - Comparison of five sedation scoring systems by means of auditory evoked
      potentials.
AB  - OBJECTIVE: To review five sedation scoring systems and to determine their
      correlation with an objective method for assessing the level of sedation by means
      of auditory evoked potentials (AEP) in critically ill patients. DESIGN:
      Prospective clinical study. SETTING: Multidisciplinary intensive care unit in a
      university hospital. PATIENTS: Ninety-five consecutive patients requiring
      sedation during intensive care therapy. MEASUREMENTS AND RESULTS: Previous
      studies have shown that auditory evoked potentials, especially latencies of the
      midlatency component N(b), could serve as an indicator of depth of anaesthesia.
      In the present study we used this electrophysiological method to evaluate
      sedation during intensive care therapy. Changes in latency of peak N(b) were
      compared with various levels of sedation assessed by five established sedation
      scoring systems. As in anaesthesia, latencies of N(b) increased with increasing
      depth of sedation. Among the scoring systems, the one developed by Ramsay
      correlated best with changes in N(b) latency (r2=0.68). The coefficient of
      determination, r2, of the other scores ranged from 0.56 to 0.61. CONCLUSION: For
      the assessment of sedation, several scoring systems have been introduced into
      clinical practice, but the differentiation of deeper sedation levels, especially,
      remains poor. In this study we compared auditory evoked potentials, as an
      objective method with which to assess the level of sedation, with five different
      sedation scoring systems. In comparison with changes in latency of the midlatency
      component N(b), Ramsay's sedation score showed the closest correlation. Objective
      electrophysiological monitoring is desirable during long-term sedation.

PMID- 10342512
TI  - The comet-tail artifact: an ultrasound sign ruling out pneumothorax.
AB  - OBJECTIVE: Ultrasound artifacts arising from the lung-wall interface are either
      vertical (comet-tail artifacts) or horizontal. The significance of these
      artifacts for the diagnosis of pneumothorax was assessed. DESIGN: Prospective
      clinical study. SETTING: The medical ICU of a university-affiliated teaching
      hospital. PATIENTS: We compared 41 complete pneumothoraces with 146 hemithoraces
      in 73 critically ill patients in which computed tomography showed absence of
      pneumothorax. MEASUREMENTS: The anterior chest wall was investigated in supine
      patients using a portable device. The test was defined as positive for complete
      pneumothorax when only horizontal artifacts were visible, and negative when
      artifacts arising from the pleural line and spreading up to the edge of the
      screen (referred to as "comet-tail artifacts") were present. RESULTS: The
      feasibility was 98%. Ultrasound showed exclusive horizontal artifacts in all 41
      analyzable cases of complete pneumothorax. In the pneumothorax-free group, "comet
      tail artifacts" were present in 87 cases and exclusive horizontal artifacts in
      56. Ultrasound as well as computed tomography showed anterior consolidation or
      anterior pleural effusion in three cases. Horizontal artifacts had a sensitivity
      and a negative predictive value of 100% and a specificity of 60% for the
      diagnosis of pneumothorax. Horizontal artifacts and absent lung sliding, when
      combined, had a sensitivity and a negative predictive value of 100% and a
      specificity of 96.5%. CONCLUSIONS: Ultrasound detection of the "comet-tail
      artifact" at the anterior chest wall allows complete pneumothorax to be
      discounted.

PMID- 10342513
TI  - Application of SOFA score to trauma patients. Sequential Organ Failure
      Assessment.
AB  - OBJECTIVE: To assess the ability of the SOFA score (Sequential Organ Failure
      Assessment) to describe the evolution of organ dysfunction/failure in trauma
      patients over time in intensive care units (ICU). DESIGN: Retrospective analysis
      of a prospectively collected database. SETTING: 40 ICUs in 16 countries.
      PATIENTS: All trauma patients admitted to the ICU in May 1995. MAIN OUTCOME
      MEASURES AND RESULTS: Incidence of dysfunction/failure of different organs during
      the first 10 days of stay and the relation between the dysfunction, outcome, and
      length of stay. Included in the SOFA study were 181 trauma patients (140 males
      and 41 females). The non-survivors were significantly older than the survivors
      (51 years+/-20 vs 38+/-16 years, p < 0.05) and had a higher global SOFA score on
      admission (8+/-4 vs 4+/-3, p < 0.05) and throughout the 10-day stay. On
      admission, the non-survivors had higher scores for respiratory ( > 3 in 47% of
      non-survivors vs 17% of survivors), cardiovascular ( > 3 in 24% of non-survivors
      vs 5.7% of survivors), and neurological systems ( > 4 in 41% of non-survivors vs
      16% of survivors); although the trend was maintained over the whole study period,
      the differences were greater during the first 4-5 days. After the first 4 days,
      only respiratory dysfunction was significantly related to outcome. A higher SOFA
      score, admission to the ICU from the same hospital, and the presence of infection
      on admission were the three major variables associated with a longer length of
      stay in the ICU (additive regression coefficients: 0.85 days for each SOFA point,
      4.4 for admission from the same hospital, 7.26 for infection on admission).
      CONCLUSIONS: The SOFA score can reliably describe organ dysfunction/ failure in
      trauma patients. Regular and repeated scoring may be helpful for identifying
      categories of patients at major risk of prolonged ICU stay or death.

PMID- 10342514
TI  - Fatty acid composition of platelet membrane lipids after administration of two
      different fat emulsions in critically ill patients.
AB  - OBJECTIVE: To determine the effects on platelet membrane fatty acid composition
      following administration of two different fat emulsions. DESIGN: Prospective,
      randomized, double-blind study. SETTING: Intensive care unit in a university
      affiliated hospital. PATIENTS: 12 adult critically ill patients in need of total
      parenteral nutrition. INTERVENTIONS: Patients were treated with total parenteral
      nutrition (TPN) for 7 days, receiving for fat intake either a long-chain
      triglyceride (20% LCT) emulsion (group 1, n=6) or a medium-chain triglyceride-LCT
      (20% MCT/LCT) emulsion (group 2, n=6). MEASUREMENTS AND RESULTS: High-performance
      liquid chromatography of membrane fatty acids was carried out before and after 7
      days of TPN. In the LCT group, an increase in C18:2n-6 and a decrease in caprylic
      acid and docosahexaenoic acid, which resulted in a decreased ratio of n-3/n-6
      fatty acid content, was observed. In the MCT/LCT group, a reduced percentage of
      palmitoleic acid and arachidonic acid was shown. CONCLUSIONS: The observed
      changes in fatty acid composition are in agreement with the lipid composition of
      the fat emulsions used. Because the C18:2n-6/C18:3n-3 ratio in both emulsions is
      close (approximately 9.0), the observed changes in the fatty acid composition of
      platelets may not be relevant for platelet function.

PMID- 10342515
TI  - Renal effects of low-dose dopamine during vasopressor therapy for posttraumatic
      intracranial hypertension.
AB  - OBJECTIVE: To investigate the effects of low-dose dopamine (Dop) on renal
      hemodynamics and function in patients with brain trauma receiving norepinephrine
      (NE). DESIGN: Prospective clinical study. SETTING: Surgical intensive care unit
      of a university hospital. PATIENTS: 20 stable, non-septic, mechanically
      ventilated, sedated patients with brain trauma and normal renal function treated
      with intravenous NE (0.11-0.65 microg/kg per min) to maintain an adequate
      cerebral perfusion pressure (> 60 mmHg). INTERVENTIONS: Two successive 1-h study
      periods with NE alone then NE + Dop (2 microg/kg per min). During each period,
      creatinine (Cl(CREAT)), sodium (Cl(Na)), potassium (Cl(K)), osmolar (Cl(OSM)) and
      free water (Cl(H2O)), clearances were measured in all the patients. Effective
      renal blood flow (ERBF, para-aminohippurate clearance) and glomerular filtration
      rate (GFR, inulin clearance) were measured in 7 of the 20 patients. RESULTS: Dop
      during NE infusion induced increases in urine flow and natriuresis which were not
      correlated with possible changes in arterial pressure. Cl(CREAT), GFR and their
      difference remained unchanged, whereas ERBF tended to increase. Fractional sodium
      excretion [100 x (Cl(Na)/Cl(CREAT)] and C1(K) increased during Dop infusion.
      CONCLUSION: The mechanism of Dop-induced natriuresis during NE infusion in brain
      trauma patients seems mainly related to a direct tubular effect of the drug.

PMID- 10342516
TI  - Barbiturate coma for severe, refractory vasospasm following subarachnoid
      haemorrhage.
AB  - OBJECTIVE: To document the outcome of patients treated with barbiturate coma for
      severe symptomatic angioplasty-resistant vasospasm. To compare mortality with
      that predicted by admission APACHE II score, and neurological outcome with that
      of historical controls treated with barbiturate coma for vasospasm, and with
      historical controls with delayed ischaemic deficits from vasospasm treated with
      nimodipine. DESIGN: Cohort study. SETTING: Neurosurgical Intensive Care Unit of
      tertiary referral university teaching hospital. PATIENTS: Eleven (6.7%) of 164
      consecutive patients with aneurysmal SAH managed according to our protocol who
      were treated with thiopentone-induced burst suppression coma for severe
      symptomatic, angioplasty-resistant vasospasm. INTERVENTIONS: Chart, database and
      literature review. MEASUREMENTS AND RESULTS: All 11 patients survived to hospital
      discharge (mortality 0%) compared with first-day APACHE II predicted mortality of
      30.6% (p=0.15). Outcome at 6 months was: good recovery 8/11 (72.7%), moderate
      disability 2/11 (18.2%), vegetative survival 1/11 (9.1%). Ten of 11 (90.9%) had a
      good neurological outcome compared with 50.6% of historical controls with delayed
      ischaemic deficit from vasospasm (odds ratio 9.78, 95% confidence interval 1.24
      77.0, p=0.02), and 0% of previously reported patients treated with barbiturate
      coma for vasospasm (p < 0.01). CONCLUSION: Our results are better than previously
      published outcomes and suggest formal evaluation of barbiturate coma in the
      treatment of severe resistant symptomatic vasospasm following SAH is warranted.

PMID- 10342517
TI  - Differential lung physiotherapy using a double lumen tube in flail chest and
      refractory lung atelectasis.
AB  - The management of refractory lung atelectasis in a patient with flail chest can
      be difficult. Treatment of lung atelectasis is complicated by practical problems
      with the application of chest physiotherapy, postural drainage and incentive
      spirometry. Although double lumen endotracheal tubes have been used in such cases
      for the purpose of differential lung ventilation, the use of differential lung
      physiotherapy has not been reported before. This report describes the successful
      application of this technique in a patient with flail chest and refractory lung
      atelectasis.

PMID- 10342518
TI  - Right-to-left interatrial shunt in ARDS: dramatic improvement in prone position.
AB  - The mechanisms leading to shunting through a patent foramen ovale include high
      right-sided cardiac pressures and respiratory factors due to mechanical
      ventilation and also anatomical changes in the right atrium as described in the
      platypnea-orthodeoxia syndrome. We report a patient with the adult respiratory
      distress syndrome (ARDS) who had a right-to-left atrial shunt which decreased in
      the prone position, after which oxygenation improved. The patient was admitted to
      the intensive care unit because of ARDS due to an invasive fungal infection. He
      had a history of chronic lymphocytic leukemia and paradoxical embolisms through a
      patent foramen ovale. Despite mechanical ventilation and antifungal treatment he
      developed severe ARDS. He was therefore turned to the prone position. Blood gas
      values improved dramatically (arterial oxygen tension/fractional inspired oxygen
      ratio increasing from 59 to 278 torr). Transcranial Doppler sonography was
      performed with bubble study, which confirmed a massive right-to-left shunt in the
      supine position and which instantaneously decreased in the prone position. This
      case suggests that a decrease in right-to-left shunt in patients who have a
      patent foramen ovale could partly explain the improvement in hypoxemia in the
      prone position.

PMID- 10342519
TI  - Fatal herpetic hepatitis in adult following short corticotherapy: a case report.
AB  - Herpes simplex virus hepatitis (HSV hepatitis) is an uncommon and severe
      complication of HSV type 1 and HSV type 2 infection. HSV hepatitis affects mostly
      immunocompromised patients. We report the case of a young man without any
      previous known immunodeficiency who developed fatal HSV hepatitis in the first 8
      days of oral corticotherapy given for ulcerative colitis. A prompt diagnosis was
      possible because HSV was recovered from peripheral blood leukocytes.

PMID- 10342520
TI  - Scoring systems in the measurement of performance of ICUs.

PMID- 10342521
TI  - Liquid ventilation.

PMID- 10342522
TI  - Sound-musical stimulation of comatose patients: theoretical basis for a research
      program.

PMID- 10342523
TI  - Association of pericardial effusion with gastroschisis.

PMID- 10342524
TI  - Non-invasive mechanical ventilation: any role in ICU?

PMID- 10342525
TI  - Prolonged severe hypercapnia complicating near fatal asthma.

PMID- 10342526
TI  - Humane Neonatal Care Initiative.
AB  - The author has worked for many years in experimental departments in the former
      Soviet health system. Now, with integration into the western health system, many
      questions are being asked about high-technology neonatal medicine and whether it
      is sufficiently humane. The Baby Friendly Hospital Initiative (BFHI) movement is
      well known all over the world, but unfortunately it is only used for healthy
      children in maternity hospitals. A paradoxical situation has been created: the
      routines of maternity wards comply with the BFHI, whereas a neonatal intensive
      care unit in the same hospital may not meet the requirements of the BFHI. BFHI
      mainly cover breastfeeding in maternity hospitals. Humane Neonatal Care
      Initiatives include minimum aggressive therapy, minimum contact between sick
      newborns and medical staff, and maximum contact with mothers; the number of tests
      and examinations should be reduced to a minimum. Eleven steps towards the
      improvement of psychosocial and medical care in units for sick newborns are
      presented. This article is intended to provoke serious discussion.

PMID- 10342527
TI  - Thoughts about rates of breastfeeding.
AB  - Socio-economic and other factors which influence the duration of breastfeeding
      have been reviewed. We agree with the conclusion of WHO's multinational study
      that breastfeeding is a biological type of behaviour with deep roots in human
      societies, although there are great variations across settings.

PMID- 10342528
TI  - Gastro-oesophageal reflux in infants.

PMID- 10342529
TI  - Intensified treatment of acute childhood lymphoblastic leukaemia has improved
      prognosis, especially in non-high-risk patients. Nordic experience of 2648
      patients diagnosed between 1981 and 1996 by Gustafsson et al.

PMID- 10342530
TI  - Screening for neuroblastoma and age-specific incidence.

PMID- 10342531
TI  - Increasing prevalence of obesity among 18-year-old males in Sweden: evidence for
      early determinants.

PMID- 10342532
TI  - The Humane Neonatal Care Initiative.

PMID- 10342533
TI  - Speech and language skills in children who required neonatal intensive care. II.
      Linguistic skills at 6 1/2 years of age.
AB  - Linguistic skills at 6 1/2 y of age were examined in a cohort of 284 children
      requiring neonatal intensive care (NIC) and in 40 controls. Ten linguistic areas
      were assessed. The results are presented for gestational age groups. The 10th
      percentile score of the controls was identified in each linguistic area. Seventy
      percent of the controls and <27% of the NIC children had no score lower than the
      10th percentile score. Scores lower than the 10th percentile score were more
      common in NIC children born at term or at 23-31 wk, and within the latter group
      in those born at 28-31 wk, than in those born at 32-36 wk gestational age. The
      linguistic areas of auditory discrimination, imitation of articulatory positions
      and imitation of sentences were most frequently affected. NIC children born at 32
      36 wk performed better in the last two areas than those born at <32 wk. To be a
      twin and born at 28-31 wk was associated with an increased risk of having more
      than five scores lower than the 10th percentile score of the controls.

PMID- 10342534
TI  - Increased height in diabetes mellitus corresponds to the predicted and the adult
      height.
AB  - This study was conducted to analyse the effect of childhood-onset diabetes
      mellitus on adult height. The height at time of diagnosis of 35 children with
      insulin-dependent diabetes mellitus (IDDM) was compared with growth reference
      data. Predictions of the adult height were made at the time of diagnosis using
      the target height and the Tanner-Whitehouse II method. The adult height was
      compared with both the predicted values and the height of healthy adults. The
      height at time of diagnosis of the prepubertal children was increased compared
      with growth reference data, in contrast to pubertal children who had normal
      heights. Only the prepubertal boys were taller at time of diagnosis. The adult
      height of the prepubertal patients was taller than growth reference data. The
      mean adult height in all patients did not differ significantly from the predicted
      heights. In conclusion, the increased height at the start of IDDM in prepubertal
      children persists until adulthood.

PMID- 10342535
TI  - Factors affecting diabetes mellitus onset in cystic fibrosis: evidence from a 10
      year follow-up study.
AB  - This study reports the results of genotype characterization and of a 10-y
      prospective evaluation of clinical status, glucose tolerance and insulin
      secretion in 28 originally normoglycaemic patients with cystic fibrosis (CF). The
      aim of the study was to assess whether any genetic, clinical or metabolic
      parameters could identify in advance those patients at risk of developing
      diabetes mellitus over time. During the follow-up 42.8% of patients became
      diabetic. Neither gender, age nor clinical parameters were significantly
      different at entry in the patients who eventually developed diabetes compared
      with those who did not. Insulin secretion during oral glucose tolerance tests
      (OGTT) deteriorated over time in both groups, whereas a progressive deterioration
      of glucose tolerance was only evident in the patients who developed diabetes and
      increased baseline glucose areas were the only predictive parameter of diabetes
      onset. Genotype analysis revealed significant differences between patients with
      and without diabetes: deltaF508 homozygosis was more frequent in the first group
      and N1303K mutation in the second group. In conclusion, in CF: (i) increased
      glucose areas during OGTT and deterioration of glucose tolerance over time can
      predict the evolution towards diabetes; and (ii) deltaF508 homozygosis may
      predispose to the risk of diabetes, whilst N1303K mutation seems to play a
      protective role.

PMID- 10342536
TI  - In vivo and in vitro studies on the residual allergenicity of partially
      hydrolysed infant formulae.
AB  - AIM: Because allergen-reduced formulae are widely used in the prevention and
      treatment of cow's milk allergy in children and because anaphylactic reactions
      have been reported for some hydrolysed formulae, it is of clinical relevance to
      know about the residual allergenicity of so-called hypoallergenic formulae.
      METHOD: We therefore studied the reactions of 20 children (mean age 1.6 years)
      with proven cow's milk allergy to a variety of formulae, using skin prick test,
      specific IgE in serum, protein content and RAST inhibition. RESULTS: Whereas all
      but two children with a clinically relevant cow's milk allergy had a positive
      skin prick test to cow's milk, some children still showed positive responses to
      the partially hydrolysed formulae. No child had a positive skin test to the amino
      acid formula. Specific IgE to the partially hydrolysed whey formula (median 0.28
      U/ml) was significantly lower (p < 0.003) than to cow's milk. Specific IgE to the
      partially hydrolysed whey/casein formula, soy/pork collagen hydrolysate and the
      amino acid formula was in a low range (median values 0.19, 0.23 and 0.21 U/ml,
      respectively). While determination of the protein content of the formulae gave no
      valid information, RAST/EAST inhibition was highest for cow's milk, followed by
      the partially hydrolysed whey formula, partially hydrolysed whey/casein formula,
      soy/pork collagen formula, and the amino acid formula. CONCLUSION: Skin prick
      test and RAST inhibition test are suitable methods for determining the residual
      allergenicity of hydrolysed infant formulae, while determination of protein
      content using the applied modified Lowry method is not helpful.

PMID- 10342537
TI  - Soluble intercellular adhesion molecule-1 in paediatric connective tissue
      diseases.
AB  - The intercellular adhesion molecule-1 (ICAM-1) is a cytokine-induced glycoprotein
      involved in the recruitment of cells into tissues undergoing inflammatory
      responses. The aim of this study was to compare the levels of soluble ICAM-1 (s
      ICAM-1) in children with juvenile chronic arthritis (JCA) and systemic lupus
      erythematosus (SLE) and to evaluate the usefulness of this molecule as marker of
      disease activity. Levels of s-ICAM-1 were measured in sera using a monoclonal
      antibody sandwich enzyme-linked immunoassay. Serum levels (mean+/-SD) of s-ICAM-1
      in 37 children with JCA, 18 patients suffering from SLE and 25 healthy controls
      were 609+/-184, 513+/-139 and 210+/-95 ng/ml, respectively. A significant
      difference could be demonstrated between the levels of s-ICAM-1 in sera from each
      disease, as a group, and those of healthy controls. Higher levels of s-ICAM-1
      were recorded in JCA patients with systemic features and patients who had
      polyarthritis than in children who were pauciarticular. A positive correlation
      was observed between s-ICAM-1 levels and disease activity score in SLE patients.
      Moreover, s-ICAM-1 levels closely followed clinical conditions in five children
      with SLE during follow-up. The data show that s-ICAM-1 levels are increased in
      children suffering from connective tissue diseases and reflect disease status or
      activity, suggesting the usefulness of this molecule in the follow-up of these
      diseases.

PMID- 10342538
TI  - Comparison of the incidences of neuroblastoma for screened and unscreened
      cohorts.
AB  - The incidences of neuroblastoma in screened cohorts and unscreened cohorts were
      compared to evaluate the usefulness of neuroblastoma mass screening. Data for
      screened and unscreened populations were collected from annual reports from the
      Neuroblastoma Committee and the number of cases of neuroblastoma with information
      on the screening history was provided by the Japan Children's Cancer Registry,
      whose registration rate has been estimated to be 0.71. In the age category of 6
      11 months, the ratios of incidences per 10(6) person-years for unscreened to
      screened cohorts were 6.58 [95% confidence intervals (CI) 4.51-9.60] during the
      early period, 1985-1989, and 11.15 (95% CI 7.65-16.25) during the later period,
      1990-1994. However, they were 0.67 (95% CI 0.31-1.44) and 0.81 (95% CI 0.33-2.03)
      for the age categories of 1-4 y and 2-4 y during the early period and 1.32 (95%
      CI 0.63-2.76) and 1.17 (95% CI 0.48-2.89) for the age categories of 1-4 y and 2-4
      y, respectively. The incidences of neuroblastoma per 10(6) person-years were not
      different among screened and unscreened cohorts. Neuroblastoma mass screening has
      not contributed to any decrease in the incidence of neuroblastoma in children
      over 1 y of age.

PMID- 10342539
TI  - Hypnotherapy: an effective treatment modality for trichotillomania.
AB  - This study describes a non-pharmacological treatment modality for children with
      trichotillomania. Three children with trichotillomania were treated using a
      hypnotherapy technique. All patients were observed in the outpatient clinic for 8
      consecutive weeks and subsequently followed for 12-18 months. All children were
      cooperative in performing the hypnotherapy technique (relaxation/mental imagery).
      Two patients reported complete resolution of their complaints after 7-8 weeks and
      1 patient after 16 weeks. The latter, reporting recurrence of the complaint after
      4 weeks due to stressful school problems, was resolved after successful
      retreatment over 3 weeks. During a mean follow-up period of 16 months, there were
      no recurrences. In conclusion, hypnotherapy may be considered as a primary
      treatment modality for trichotillomania in children without associated emotional
      disorders.

PMID- 10342540
TI  - Factors associated with initiation and duration of breastfeeding in Italy.
AB  - To evaluate factors associated with initiation and duration of breastfeeding in
      Italy, 1601 (73%) respondents among 2192 randomly selected mothers were
      interviewed within 1 mo of delivery. Mothers who started breastfeeding (85%) were
      followed-up for 12 mo. A compliance rate of 100% was obtained. At multiple
      logistic regression analysis, mother having been breastfed herself (p < 0.01),
      nursing guidance in the maternity ward (p = 0.01) and higher social class (p =
      0.03) were positively associated with initiation of breastfeeding. We found that
      42%, 19%, 10% and 4% mothers were still breastfeeding at 3, 6, 9 and 12 mo after
      delivery, respectively. Cox multiple regression analysis showed a negative
      association between duration of breastfeeding and pacifier use (p < 0.01), and a
      positive association with a higher level of maternal education (p = 0.04).
      Formula supplementation in the maternity ward (given to 30% of infants) was
      associated with a shorter duration of exclusive breastfeeding (p = 0.03). Mothers
      need support with breastfeeding, particularly those from lower social backgrounds
      and with lower levels of education. Early use of the pacifier should be
      discouraged.

PMID- 10342541
TI  - Factors associated with the duration of breastfeeding amongst women in Perth,
      Australia.
AB  - Duration of breastfeeding was studied in 556 women delivering at 2 maternity
      hospitals in Perth, Australia. At discharge 83.8% of women were breastfeeding
      their infants, including 6% who were giving complementary feeds. At 3 and 6
      months, 61.8% and 49.9%, respectively, were still breastfeeding. In a Cox
      survival analysis of factors associated with duration of breastfeeding a positive
      association was found with maternal education, age and intended duration of
      breastfeeding. Male infants were more likely to be weaned before female infants
      and women whose partners were unemployed, or did not have a preference for
      breastfeeding, breastfed for shorter duration. There is still a need for
      programmes which support and encourage breastfeeding, focusing particularly on
      younger, less well-educated women who intend to breastfeed for less than the
      recommended 4-6 months.

PMID- 10342542
TI  - Pain evaluation in preschool children and by their parents.
AB  - The accurate assessment of pain in children constitutes a challenge for health
      professionals and, in the case of young children, parents are generally the main
      source of information. The objective of this study was to validate and to compare
      three pain scales in preschool children and their parents. A total of 104
      children between 4 and 6 y of age and their parents participated in the study
      while undergoing an immunization procedure in the outpatient department of a
      tertiary pediatric care hospital. Three pain scales were used, the McGrath Facial
      Affective Scale (FAS), the Hester Poker Chip Tool (HPCT) and the Multiple Size
      Poker Chip Tool (MSPCT). There were 47 (45%) boys and 57 (55%) girls, with 54
      (52%) 4-y-olds, 34 (33%) 5-y-olds and 16 (15%) 6-y-olds. Twenty-eight children
      (27%) had memories of pain experienced during a former hospitalization.
      Correlations were very high both in children (r = 0.78) and their parents (r =
      0.96) when comparing immunization pain scores obtained from the HPCT versus the
      MSPCT. Correlations between McGrath's FAS and HPCT or MSPCT ranged from r = 0.34
      0.43 in children and r = 0.38-0.39 in parents. There was a good correlation
      between parents and children during the immunization procedure on all three
      scales, with the highest correlation using the FAS (r = 0.76), followed by the
      MSPCT (r = 0.69), and the HPCT (r = 0.66). Subgroup analyses based on the
      criteria of age, sex and previous hospitalization showed no consistent
      relationship. Parents tended to underestimate their child's pain when using HPCT
      or MSPCT. It seems that both HPCT and MSPCT measure a similar dimension of pain,
      whereas the FAS addresses a different aspect of pain. Although parents play an
      important role in their child's pain assessment, they tend to underestimate the
      intensity of pain when using HPCT or MSPCT.

PMID- 10342543
TI  - Factors affecting maternal anxiety about child rearing in Japanese mothers.
AB  - In order to determine the factors causing anxiety in raising young children, data
      were collected from questionnaires completed by 1164 mothers of 3-y-old children
      at a standardized baby check-up. Factors concerning demographic characteristics,
      delivery and child rearing practice were used in multivariate logistic regression
      analysis. Stepwise logistic regression analysis showed that mothers rearing first
      children and toddlers who were susceptible to common illnesses were likely to
      worry. Improvements in the child rearing environment are needed.

PMID- 10342544
TI  - Trends in overweight and obesity among 18-year-old males in Sweden between 1971
      and 1995.
AB  - The aims of the study are to analyse Swedish trends in overweight and obesity-as
      measured by body mass index (BMI)-between 1971 and 1995, and to examine
      socioeconomic and geographic differences between groups of individuals on the
      basis of information on 18-y-old military conscripts. The study population
      comprises all males born in 1953, 1958, 1963, 1968, and between 1973 and 1977,
      reported to be living in Sweden at 17 y of age according to nationwide population
      registers (RTPs). Utilizing the unique personal ID number, sociodemographic data
      in the RTPs and in Population and Housing censuses were linked to data on BMI in
      the national Military Service Conscription Registry for the years 1971 to 1995.
      These data were obtained from compulsory medical examinations held at military
      induction at 18 y of age. BMI data were available for 448 732 (89%) of a total of
      503 689 subjects. Mean BMI increased by 6.6% over the study period-from 21.1
      kg/m2 in 1971 to 22.4 kg/m2 in 1995. Unadjusted trend analyses showed a 2.4 times
      increase in the prevalence of overweight among 18-y-old males over the period
      from 6.9% in 1971 to 16.3% in 1995. Over the same years, the prevalence of
      obesity increased 3.5 times-from 0.9% to 3.2%. After adjustment for muscle power,
      demographic factors, and living area, the prevalence of overweight was found to
      have increased 1.4 times, and obesity 1.7 times between 1971 and 1993. The
      prevalence of overweight was considerably higher among 18-y-old males from low
      educated families than among those from high-educated families in both 1971 and
      1995. The prevalence of overweight was also found to be higher in both 1971 and
      1995 among young men from rural and/or sparsely populated areas than among those
      living in Sweden's largest cities. Mean BMI, and the prevalence of overweight and
      obesity have increased among 18-y-old males in Sweden over the last 24 y. The
      increased risk of overweight among young men from low-educated families and those
      from rural and/or sparsely populated areas detected in 1971 was still evident in
      1995.

PMID- 10342545
TI  - Treatment of severely diseased newborns: a survey of attitudes among Danish
      physicians.
AB  - In order to describe the attitudes towards treatment of severely diseased
      newborns a questionnaire presenting four fictive situations concerning infants
      with myelomeningocele, trisomy 13, Down's syndrome and epidermolysis bullosa
      lethalis was mailed to all physicians employed at obstetric or paediatric
      departments in Denmark. The questionnaire was designed in two versions, differing
      as regards the parents' situation and attitude towards treatment in two of the
      situations. Each version was sent to half of the sample. Of 954 questionnaires
      664 (69.6%) were completed and returned. The parents' situation and attitude
      towards treatment played a role in forming the treatment choice to a significant
      proportion of the respondents, although the majority seemed to form their
      decisions independently of this factor. In the situations presenting the infants
      with myelomeningocele and Down's syndrome there was controversy concerning the
      level of active treatment, while only a minority would provide active treatment
      in the two other situations. In the case of epidermolysis bullosa lethalis most
      respondents would provide morphine in doses that could unintentionally hasten
      death, while few were in favour of legalizing active euthanasia.

PMID- 10342546
TI  - Social determinants of birthweight, ponderal index and gestational age in Sweden
      in the 1920s and the 1980s.
AB  - This study compared the effect of social class and marital status on birth
      outcomes in Sweden, using (i) data on all births at the Akademiska Hospital in
      Uppsala from 1920 to 1924 with socioeconomic information from records at birth;
      and (ii) a linkage of the Medical Births Registry for all births in Sweden in
      November/December 1985 to the 1985 Census. Preterm births (<37 weeks) have become
      less common during the 20th century. Between 1920-24 and 1985, mean and median
      birthweight increased, as did mean ponderal index, indicating a shift to the
      right of the birthweight and ponderal index distributions. In 1920-24,
      birthweight and ponderal index were associated with the social class of the
      household and with the marital status of the mother. Babies of single mothers
      were lighter and thinner, and had a much greater probability of being born
      preterm. In contrast, in 1985, maternal marital status (and cohabitation status)
      had a weaker effect on birthweight and ponderal index. The importance of
      household social class for ponderal index and preterm birth changed similarly,
      but its importance for birthweight remained. The mediating mechanism may have
      changed. Mothers from farming households now gave birth to the heaviest babies
      (nearly 200 g heavier than those of unskilled workers). Adjustment for a number
      of factors, including smoking, had a limited effect on these social class
      differences. In conclusion, biological processes during the foetal period are
      systematically linked to the social circumstances of the mother, but in a
      different way in the 1920s and in 1985.

PMID- 10342547
TI  - Outcome of congenital lung abnormalities detected antenatally.
AB  - To determine the outcome of congenital lung abnormalities, data were collected
      retrospectively between January 1991 and December 1996 on any foetus found to
      have a lung lesion on antenatal ultrasound. A total of 23 foetuses had lung
      lesions on antenatal ultrasound. In two foetuses the antenatal ultrasound showed
      bilateral enlarged "bright" echogenic lungs with evidence of hydrops. Both
      pregnancies were terminated and tracheal atresia was confirmed. In 15 foetuses
      the antenatal ultrasound appearance was of a unilateral "bright" echogenic lung.
      There was one case of bronchial atresia and two cases of congenital lobar
      emphysema, which all had surgery. In nine cases there was a reduction in the size
      of the lesion on serial antenatal ultrasounds and no lesion was detected after
      birth. In three cases a small lesion was present after birth on chest
      radiography. In six foetuses the antenatal ultrasound appearance was of
      unilateral cystic or mixed cystic and echogenic lung lesions. Two pregnancies
      were terminated; both had congenital cystic adenomatoid malformation. Four
      pregnancies were continued and three infants had surgery soon after birth and
      were confirmed to have had congenital cystic adenomatoid malformation. One infant
      has been managed conservatively. In conclusion, a definitive diagnosis cannot
      usually be made antenatally. A large lesion on initial scan does not necessarily
      predict a poor outcome. The natural history of small asymptomatic postnatal
      lesions is unknown and a long-term prospective study is needed to determine the
      outcome of these lesions.

PMID- 10342549
TI  - Unmasking anti-endomysial antibodies in coeliac subjects positive for anti-smooth
      muscle antibodies.
AB  - Anti-endomysial antibodies assayed by indirect immunofluorescence presently
      represent the most advanced in vitro method for diagnosing coeliac disease. While
      testing the serum of patients affected by coeliac disease for anti-endomysial
      antibodies, we noticed in some samples the presence of anti-smooth muscle
      antibodies. This led us to the hypothesis that anti-smooth muscle antibodies
      might mask the presence of anti-endomysial antibodies. The aim of our research
      was to develop a method that could confirm our hypothesis. Here we show that the
      AEA response can be effectively unmasked by increasingly diluting anti-smooth
      muscle antibodies-positive serum.

PMID- 10342548
TI  - Effects of early reduced light exposure on central visual development in preterm
      infants.
AB  - The aim of this study was to determine, in infants born at < or =29 weeks
      postmenstrual age until 32 weeks postmenstrual age, whether reduction to light
      stimulation by occlusion of eyes affected central visual development. The pattern
      visual-evoked potential responses at 41 and 51 weeks postmenstrual age and 3 y of
      age did not differ between infants subjected or not to ocular occlusion. Hence,
      an early marked reduction in light stimulation in preterm infants does not seem
      deleterious to visual development.

PMID- 10342550
TI  - Is oral albuterol effective for acute cough in non-asthmatic children?
AB  - Fifty-nine non-asthmatic children with acute cough were randomized to receive
      oral albuterol or placebo for 7 d. There was a similar, rapid rate of resolution
      of acute cough for the two groups, but more shaking or trembling in those treated
      with albuterol (5/30 vs 0/29; p = 0.05). In ambulatory children with acute cough
      who have no history of asthma and a normal chest examination, oral albuterol does
      not reduce the frequency or duration of cough.

PMID- 10342551
TI  - Cardiac involvement in Coffin-Lowry syndrome.
AB  - Coffin-Lowry syndrome is an X-linked recessive syndrome of mental retardation,
      characteristic facies and skeletal anomalies. In one patient with the syndrome,
      we observed early recurrent episodes of congestive heart failure with
      intercurrent normalization and the late development of mitral insufficiency due
      to annular dilation and congenital abnormalities of the valve apparatus. This
      unusual course of cardiac involvement, the non-adaptation of the left ventricular
      contractility to the aggravation of the mitral insufficiency and the
      postoperative persistence of the ventricular dysfunction, underline the possible
      role of an associated primary myocardial disease. This clinical observation
      demonstrates clearly that a mitral valve malformation can occur in patients with
      the syndrome, but also the role of a dilated cardiomyopathy, which can be
      secondary to the mitral regurgitation, but is more likely a myocardial disorder
      occurring as part of the syndrome.

PMID- 10342552
TI  - A different methodology for evaluating exhaled endogenous nitric oxide in
      newborns.

PMID- 10342553
TI  - Chronic Pseudomonas colonization of the skin, ear and eyes in a child with type I
      pseudohypoaldosteronism.

PMID- 10342554
TI  - Congenital heart disease and parental consanguinity in South India.

PMID- 10342555
TI  - Leukemia inhibitory factor, Interleukin 6, and other cytokines using the GP130
      transducing receptor: roles in inflammation and injury.
AB  - Inflammation refers to a complex set of mechanisms by which tissues respond to
      injury and infection. Among the many soluble mediators associated with this
      process, cytokines are known to be crucial in regulating a variety of cellular
      and molecular events. Leukemia inhibitory factor (LIF), interleukin 6 (IL-6), IL
      11, and possibly other members of this cytokine family are key mediators in
      various inflammatory processes such as the acute-phase reaction, tissue damage,
      and infection. These cytokines can act in both pro-inflammatory and anti
      inflammatory ways, depending on a number of variables. We emphasize here recent
      work utilizing knockout mice, which has highlighted the roles of LIF and IL-6,
      particularly in interactions between the immune and nervous systems.

PMID- 10342556
TI  - Functional roles of STAT family proteins: lessons from knockout mice.
AB  - STAT (signal transducers and activators of transcription) proteins are activated
      in response to a large number of cytokines, growth factors, and hormones. Upon
      activation following the binding of ligands to their receptors, STAT proteins
      dimerize, translocate to the nucleus, and bind to the promoters of specific
      target genes. To date, seven mammalian members of the STAT family have been
      identified. Although some cytokines and growth factors can activate multiple STAT
      proteins, some STATs are activated with considerable specificity. The
      physiological role of each individual STAT protein is now being examined through
      the study of "knockout" mice, harboring a null allele for the particular gene.
      STAT1-deficient mice exhibit a selective signaling defect in response to
      interferons. STAT4 and STAT6 are essential for Thl-and Th2-responses,
      respectively. STAT5a-deficient mice exhibit defective mammary gland development.
      A study of STAT5b-deficient mice indicates that STAT5b mediates the sexually
      dimorphic effects of growth hormone in the liver. STAT5a and 5b also play
      different biological roles in the immune system. STAT3-deficient mice die during
      early embryogenesis, but the role of STAT3 in adult tissues can be assessed by
      utilizing the CreloxP recombination system to ablate the gene later in life.
      Analyses of tissue-specific STAT3-deficient mice indicate that STAT3 plays a
      crucial role in a variety of biological functions, including cell growth,
      suppression of apoptosis, and cell motility.

PMID- 10342557
TI  - Effect of interleukin 10 on the hematopoietic progenitor cells from patients with
      aplastic anemia.
AB  - The overproduction of cytokines with inhibitory effects on hematopoiesis is
      considered to play a role in the pathogenesis of aplastic anemia. While
      interleukin 10 (IL-10) is a cytokine production inhibitory factor, the
      possibility of immunosuppressive therapy using IL-10 for aplastic anemia has not
      been explored. In this study, therefore, we examined the effect of IL-10 on
      progenitor cells obtained from seven patients with severe aplastic anemia. Our
      study indicated that IL-10 dramatically enhanced the erythroid colony formation
      in a dose-dependent manner in two of the seven cases examined. When we examined
      the concentration of cytokines in the culture supernatants of unstimulated bone
      marrow cells, the spontaneous production of interferon-gamma (IFN-gamma) was
      observed in one of these two cases, and this production was completely inhibited
      by addition of IL-10. These findings suggested that IL-10 enhanced the erythroid
      colony formation by inhibiting the pathological production of IFN-gamma in this
      case. This study provides an experimental support for the clinical application of
      IL-10 in some patients with aplastic anemia.

PMID- 10342558
TI  - Differential kinetics of primitive hematopoietic cells assayed in vitro and in
      vivo during serum-free suspension culture of CD34+ blood progenitor cells.
AB  - So far, blood progenitor cells (BPC) expanded ex vivo in the absence of stromal
      cells have not been demonstrated to reconstitute hematopoiesis in myeloablated
      patients. To characterize the fate of early hematopoietic progenitor cells during
      ex vivo expansion in suspension culture, human CD34(+)-enriched BPC were cultured
      in serum-free medium in the presence of FLT3 ligand (FL), stem cell factor (SCF)
      and interleukin 3 (IL-3). Both CD34 surface expression levels and the percentage
      of CD34+ cells were continuously downregulated during the culture period. We
      observed an expansion of colony-forming units granulocyte-macrophage (CFU-GM) and
      BFU-E beginning on day 3 of culture, reaching an approximate 2-log increase by
      days 5 to 7. Limiting dilution analysis of primitive in vitro clonogenic
      progenitors was performed through a week 6 cobblestone-area-forming cell (CAFC)
      assay, which has previously been shown to detect long-term bone marrow culture
      initiating cells (LTC-IC). A maintenance or a slight (threefold) increase of week
      6 CAFC/LTC-IC was found after one week of culture. To analyze the presence of BPC
      mediating in vivo engraftment, expanded CD34+ cells were transplanted into
      preirradiated NOD/SCID mice at various time points. Only CD34+ cells cultured for
      up to four days successfully engrafted murine bone marrow with human cells
      expressing myeloid or lymphoid progenitor phenotypes. In contrast, five- and
      seven-day expanded human BPC did not detectably engraft NOD/SCID mice. When FL,
      SCF and IL-3-supplemented cultures were performed for seven days on fibronectin
      coated plastic, or when IL-3 was replaced by thrombopoietin, colony forming cells
      and LTC-IC reached levels similar to those of control cultures, yet no human cell
      engraftment was recorded in the mice. Also, culture in U-bottom microplates
      resulting in locally increased CD34+ cell density had no positive effect on
      engraftment. These results indicate that during ex vivo expansion of human CD34+
      cells, CFC and LTC-IC numbers do not correlate with the potential to repopulate
      NOD/SCID mice. Our results suggest that ex vivo expanded BPC should be cultured
      for limited time periods only, in order to preserve bone-marrow-repopulating
      hematopoietic stem cells.

PMID- 10342559
TI  - The Notch/Jagged pathway inhibits proliferation of human hematopoietic
      progenitors in vitro.
AB  - The cell surface receptor Notch1 is expressed on CD34+ hematopoietic precursors,
      whereas one of its ligands, Jagged1, is expressed on bone marrow stromal cells.
      To examine the role of Notch signaling in early hematopoiesis, human CD34+ cells
      were cultured in the presence or absence of exogenous cytokines on feeder layers
      that either did or did not express Jagged1. In the absence of recombinant growth
      factors, Jagged1 decreased myeloid colony formation by CD34+ cells, as well as 3H
      thymidine incorporation and entry into S phase. In the presence of a strong
      cytokine signal to proliferate and mature, (interleukin 3 [IL-3] and IL-6, stem
      cell factor [SCF], and G-CSF), Jagged1 did not significantly alter either the
      fold expansion or the types of colonies formed by CD34+ cells. However, in the
      presence of SCF alone, Jagged1 increased erythroid colony formation twofold.
      These results demonstrate that Notch can modulate a growth factor signal, and
      that in the absence of growth factor stimulation, the Jagged1-Notch pathway
      preserves CD34+ cells in an immature state.

PMID- 10342560
TI  - Autologous stem cell transplantation for treatment of autoimmune diseases.

PMID- 10342561
TI  - The molecular perspective: p53 tumor suppressor.

PMID- 10342562
TI  - How can we assess outcomes without assessing treatment?

PMID- 10342563
TI  - Reliability and validity of a new method of measuring posterior shoulder
      tightness.
AB  - STUDY DESIGN: Repeated measures of shoulder flexibility on nonimpaired subjects
      and intercollegiate baseball pitchers. OBJECTIVES: To present a new objective
      method of measuring posterior shoulder tightness, define the intratester and
      intertester reliability of the measurement, and assess its construct validity.
      BACKGROUND: Posterior shoulder tightness has been linked to anterior humeral head
      translation and decreased internal rotation. The reliability of an objective
      assessment of posterior shoulder tightness has yet to be established in the
      literature. METHODS AND MEASURES: Five repeat measurements were made using a
      standardized protocol on 21 nonimpaired subjects to determine intratester
      reliability. To determine intertester reliability, 2 testers (blinded to their
      measurement) each performed 1 measurement on 49 shoulders. Twenty-two
      intercollegiate baseball pitchers were measured once by 1 tester to evaluate the
      construct validity of the measurement. RESULTS: Measurements of posterior
      shoulder tightness performed by the same physical therapist had high reliability
      (ICC dominant = 0.92, nondominant = 0.95). Intertester measures revealed good
      reliability (ICC = 0.80). Pitchers had reduced dominant arm internal rotation and
      increased external rotation ROM compared to their other arm whereas nonimpaired
      subjects had less reduction in external rotation compared to the nondominant arm
      (pitchers: dominant, 109.7 degrees +/-2.4 degrees, nondominant, 98.9 degrees +/
      1.6 degrees; nonimpaired subjects: dominant, 95.9 degrees +/-1.5 degrees,
      nondominant, 95.2 degrees +/-1.6 degrees) and internal rotation (pitchers:
      dominant, 50.0+/-2.0 degrees, nondominant, 69.5+/-2.5 degrees; nonimpaired
      subjects: dominant, 46.4+/-1.3 degrees, nondominant, 50.2+/-1.4 degrees).
      Pitchers had significantly greater posterior shoulder tightness compared to
      nonimpaired subjects (pitchers; dominant, 44.9+/-0.8 cm, nondominant, 37.5+/-0.7
      cm, nonimpaired subjects; dominant, 32.9+/-0.8 cm, nondominant, 31.4+/-0.8 cm)
      and manifested a significant correlation between posterior shoulder tightness and
      internal rotation (r = -0.61) that was not evident in nonimpaired subjects.
      CONCLUSIONS: Measurement of posterior shoulder tightness using this technique is
      objective and reliable when done by the same physical therapist. Validity of this
      measurement is supported from the observation of athletes thought to have tight
      posterior structures. Further study is needed to determine the relationship of
      this measurement to patients diagnosed with shoulder impingement syndrome.

PMID- 10342564
TI  - Testing isokinetic muscular fatigue of shoulder internal and external rotation in
      elite junior tennis players.
AB  - STUDY DESIGN: Single group, post-test only descriptive analysis of isokinetically
      measured shoulder internal and external rotation muscular fatigue. OBJECTIVES: To
      determine whether differences in isokinetically measured muscular fatigue exist
      between shoulder external (ER) and internal rotation (IR) and between the
      dominant (DOM) and nondominant (NDOM) extremity in elite junior tennis players.
      BACKGROUND: The importance of the rotator cuff in stabilizing the humeral head
      during repetitive athletic overhead motions has been identified in biomechanical
      investigations. The application of exercise to improve muscular function of the
      shoulder and prevent injury is a common practice in physical therapy, but
      shoulder fatigue in tennis players has received little attention in the
      literature. METHODS AND MEASURES: Seventy-two elite junior tennis players (ages
      12 to 18) underwent bilateral isokinetic testing with 90 degrees of glenohumeral
      joint abduction. A muscular fatigue protocol consisting of 20 maximal-effort
      concentric contractions of ER and IR was used to measure muscular fatigue at 300
      degrees/s. A relative fatigue ratio was calculated by dividing the work in the
      last 10 repetitions by the work in the first 10 repetitions. Higher fatigue
      ratios indicate improved muscular fatigue resistance. A 2x2 ANOVA was used to
      assess differences in fatigue in DOM versus NDOM arm, and in IR versus ER.
      RESULTS: Relative muscular fatigue ratios for ER and IR were 69.1+/-15.3% and
      82.93+/-14.81% for the DOM extremity, respectively. In the NDOM extremity, ER and
      IR fatigue ratios were 71.13+/-15.07% and 83.9+/-16.5%, respectively. These
      results indicate significant differences between the fatigue ratios for ER and
      IR. No significant difference between extremities in either ER or IR relative
      fatigue ratios was found. CONCLUSIONS: These data have implications for
      rehabilitation and conditioning of the rotator cuff musculature.

PMID- 10342565
TI  - Strategy of exercise prescription using an unloading technique for functional
      rehabilitation of an athlete with an inversion ankle sprain.
AB  - STUDY DESIGN: Case study. OBJECTIVES: To demonstrate how an exercise program can
      be designed with specific sets, repetitions, and rest periods, and to enhance the
      healing process in early stages of rehabilitation when injured tissues cannot
      tolerate full body weight. Our goal was to enhance ankle tissue healing by
      reducing gravitational force through a prescriptive exercise and unloading
      program. BACKGROUND: This report describes a treatment method that we used to
      rehabilitate a collegiate soccer player with a Grade II inversion ankle sprain.
      This athlete sprained his ankle 6 weeks before the start of rehabilitation and
      was unable to participate in soccer due to persistent pain and impaired function.
      METHODS AND MEASURES: A 2-week functional training program was implemented,
      consisting of exercises chosen for specific task simulation related to soccer.
      Gravitational force was mechanically altered by suspending the subject or by
      supporting the subject on a variable incline plane. Weight-bearing was controlled
      so that the subject could perform exercises without pain. The outcome measures
      were ankle range of motion (ROM), maximum pain-free isometric strength, vertical
      force during unilateral squats, and unilateral hop time and distance. RESULTS:
      Pain-free weight-bearing capacity increased over the 2-week course of
      rehabilitation and the subject was able to return to playing soccer without pain.
      The ratios (involved to uninvolved extremity) at time of discharge from physical
      therapy were 87% to 103% for ankle ROM, 75% to 93% for isometric ankle strength,
      91% for unilateral squats, 88% for unilateral hop time, and 86% for unilateral
      hop distance. CONCLUSIONS: Return to function can be achieved in a short period
      by exercise that is performed with a gradual increase in pain-free weight-bearing
      capacity.

PMID- 10342566
TI  - Sacroiliac joint dysfunction in elite rowers.
AB  - STUDY DESIGN: Cross-sectional, descriptive study. OBJECTIVES: To examine the
      occurrence of sacroiliac joint dysfunction (SIJD) in a group of elite rowers.
      BACKGROUND: Sacroiliac joint dysfunction is a common problem for elite athletes,
      but is largely unstudied in the medical literature. METHODS AND MEASURES: The
      United States Senior National Rowing Teams at the Pan American Games and the
      World Rowing Championships in 1995 were tested for SIJD through the standing
      flexion test followed by palpatory examination of anatomic landmarks. RESULTS:
      Sacroiliac joint dysfunction occurred in 54.1% of team members. Sacroiliac joint
      dysfunction was prevalent in both sweep rowers (66%) and scullers (34%).
      Prevalence of SIJD did not differ among the specific types of SIJD, the side of
      involvement, or for the handedness of sweep rowing. CONCLUSIONS: Sacroiliac joint
      dysfunction is an important orthopaedic problem in rowers. This information may
      be useful for clinicians who treat rowers and elite athletes.

PMID- 10342567
TI  - Lumbar spine kinesthesia in patients with low back pain.
AB  - STUDY DESIGN: Single-group, posttest only, using a sample of convenience.
      OBJECTIVE: To measure the repositioning error of subjects with low back pain for
      lumbar sagittal movement using a simple kinesthetic test previously described.
      BACKGROUND: Patients with low back pain are commonly observed to have difficulty
      in adopting a mid or neutral position of the lumbar spine. METHODS AND
      MEASUREMENTS: Twenty subjects with low back pain were required to reproduce an
      upright neutral posture of the lumbar spine following movement into flexion in a
      sitting position. Trunk positioning accuracy was measured with an electromagnetic
      tracking device. RESULTS: The mean absolute value of the repositioning error in
      the sagittal plane was 2.25 degrees +/-0.88 degrees on day 1 and 2.32 degrees +/
      1.62 degrees on day 2. The performance of patients with low back pain was similar
      to that of asymptomatic patients in a previous study, although subjects with low
      back pain overshot the neutral position more frequently (79%) than did
      nonimpaired subjects (50%). CONCLUSIONS: Subjects with low back pain may have
      attempted to use extra mechanoreceptive cues to compensate for some kinesthetic
      deficit. Nevertheless, the kinesthetic test used was not sensitive enough to
      detect any repositioning deficits, and reasons for this are explored.

PMID- 10342568
TI  - More on open and closed chains.

PMID- 10342569
TI  - The role of interleukin-12 in preserving the graft-versus-leukemia effect of
      allogeneic CD8 T cells independently of GVHD.
AB  - Interleukin (IL)-12 is a potent immunostimulatory cytokine and inducer of Th1
      cell activity and of cytotoxic T lymphocyte and natural killer cell function.
      This cytokine also has anti-tumor activity. Although IL-12 has been shown to be
      an important pathogenic cytokine in the induction of graft-versus-host disease
      (GVHD), injection of exogenous IL-12 to murine allogeneic bone marrow
      transplantation (BMT) recipients paradoxically leads to a significant delay in
      the onset of GVHD mortality in fully MHC plus multiple minor antigen-mismatched
      strain combinations, and to complete inhibition of GVHD in a single haplotype
      mismatched murine BMT model. IL-12-induced inhibition of GVHD is associated with
      reduced donor T cell activation and expansion, in part through an interferon
      (IFN)-gamma-mediated mechanism. Fas-mediated apoptosis of donor T cells also
      plays a significant role in IL-12-induced GVHD protection. Importantly, IL-12
      preserves the graft-versus-leukemia (GVL) effect of allogeneic CD8 T cells
      against EL4, a host-type leukemia/lymphoma, while inhibiting GVHD. Like the
      protective effect against GVHD, the GVL effect in IL-12-treated mice is dependent
      on IFN-gamma. Thus, treatment with IL-12 leads to separation of GVHD-promoting
      and GVL effects of allogeneic BMT via an IFN-gamma-dependent mechanism.

PMID- 10342570
TI  - Protease activation and glucocorticoid-induced apoptosis in chronic lymphocytic
      leukemia.
AB  - Chronic lymphocytic leukemia (CLL) is at present an incurable disease. All of the
      drugs used in the treatment of CLL induce apoptosis in the cells, and in vitro
      responses to glucocorticoid or analogs correlate with in vivo sensitivity to
      these agents. Since CLL lymphocytes accumulate rather than proliferate, the idea
      that CLL is a disease involving defective apoptosis is particularly attractive.
      Recent studies have identified many of the central components of the apoptotic
      pathway that appear to be conserved from one cell type to another. Thus,
      investigation into the functionality of these molecules should reveal where the
      defect(s) in apoptosis may lie in CLL cells. Protease activation is a central
      event during apoptosis. and leads to many of the familiar characteristics of
      apoptosis. Here we will examine the role of apoptotic proteases in CLL and
      speculate on their contribution to disease emergence and drug resistance.

PMID- 10342571
TI  - Serum CD44 in non-Hodgkin's lymphoma.
AB  - CD44 molecule is a cell surface glycoprotein involved in several cell-cell and
      cell-matrix interactions. It has been linked to the growth and spread of
      malignancies. The majority of non-Hodgkin's lymphomas (NHL) express CD44
      reflecting the CD44 expression of the normal lymphocytic counterparts. Cell
      surface CD44 has been suggested to be involved in hematogenous distribution of
      NHL, and elevated levels of serum CD44 (s-CD44) have been detected in various
      malignant diseases. Circulating s-CD44 has been found to be functionally active
      according to several functional studies. In patients with NHL increased s-CD44
      levels have been detected at the time of diagnosis and at progression of the
      disease and s-CD44 levels change in parallel with response to therapy. Moreover,
      a high s-CD44 level at diagnosis is associated with a high tumor burden, poor
      response to treatment and unfavorable outcome in NHL.

PMID- 10342572
TI  - Fish analysis at diagnosis in acute lymphoblastic leukemia.
AB  - Many recurrent cytogenetic abnormalities have been described in acute
      lymphoblastic leukemia (ALL). With improvement of survival, it became evident
      that some of these chromosomal changes had a major prognostic value:
      hyperdiploidy and t(12;21) are associated with very long disease free survival,
      whereas t(9;22) and 11q23 rearrangements correlate with a poor outcome. Because
      of this prognostic impact, detection of these four specific abnormalities has to
      be accurate and rapid at diagnosis. In order to reliably analyze ALL patients, we
      used fluorescence in situ hybridization (FISH). We selected specific probes
      enabling the detection of the structural rearrangements [t(9;22), t(12;21) and
      11q23 rearrangements] directly on interphase cells. Detection of hyperdiploidy
      was performed using comparative genomic hybridization (CGH). This technique
      enables to characterize chromosomal gains and losses without requiring metaphase
      obtention. We showed that this FISH-based approach was complementary to
      conventional cytogenetics, and should be systematically used in ALL at diagnosis.

PMID- 10342573
TI  - Epstein-Barr virus involvement in T-cell malignancy: significance in adult T-cell
      leukemia.
AB  - Epstein-Barr virus (EBV) was first reported as the causative virus of Burkitt's
      lymphoma in 1964. Since then, EBV has also been associated with infectious
      mononucleosis, AIDS and transplant-related B cell lymphomas, and nasopharyngeal
      cancer. The virus has further been linked with T cell lymphomas, Hodgkin disease,
      and NK leukemia or LGL leukemia, establishing a concept of a wide spectrum of EBV
      associated malignant disorders. EBV DNA encodes several proteins such as EBNA1-6,
      LMP 1, 2 and others. Recent studies have demonstrated that EBNA2, EBNA5, EBNA3A,
      EBNA 3C are essential for transformation, and that any gene product is not
      sufficient to transform cells by itself. Further there are different mechanisms
      of virus-associated transformation or carcinogenesis among EBV-associated
      malignant disorders. On the other hand, human T lymphotropic virus type I (HTLV
      I) is known as a causative virus of adult T cell leukemia (ATL). However, precise
      molecular mechanisms of leukemogenesis in ATL still remains unclear. Some
      additional factors to HTLV-I infection are supposed to be involved in complete
      leukemogenesis. We demonstrated that HTLV-I infected T cells and primary ATL
      cells express EBV receptor/CD21 on the cell surface. Therefore, it is possible
      that EBV infection is one of the factors. We further investigated this
      possibility in 6 HTLV-I infected T cell lines and primary ATL cells from 18
      patients with ATL. However, no EBV genome was detected in both T cell lines and
      primary ATL cells. EBV involved T-cell lymphoma has unique clinical
      manifestations as compared to non-EBV involved T-cell lymphoma. Therefore, it is
      still possible that a small group of ATL patients with unique clinical
      manifestations is associated with EBV.

PMID- 10342574
TI  - An Asian variant of intravascular lymphomatosis: an updated review of malignant
      histiocytosis-like B-cell lymphoma.
AB  - Malignant histiocytosis-like B-cell lymphoma (MH-like BCL) is characterized
      clinically by hemophagocytic syndrome (HPS), bone marrow involvement at
      presentation, and an aggressive clinical course. Yet, it remains an ill-defined
      disease entity. We recently described five cases of MH-like BCL and suggested
      that these may be regarded as a peculiar variant of intravascular lymphomatosis
      (IVL), based on clinical and pathological observation. Interestingly, this type
      of lymphoma has been reported exclusively among Asians, with few reports from
      Western countries, and therefore we propose that this variant be noted as an
      Asian variant of IVL(AIVL). To evaluate the incidence of this variant, we
      performed a literature search for English or Japanese studies dealing with MH
      like BCL or B-cell IVL associated with HPS (IVL with HPS). We found 18 reports of
      MH-like BCL and 16 reports of IVL with HPS and re-evaluated the clinicopathologic
      aspects of each study with respect to AIVL. Although several differences were
      noted, such as gender, presence of respiratory changes, bone marrow invasion and
      disseminated intravascular coagulopathy, there were also overlapping profiles and
      they appeared to be consistent with the AIVL single disease entity. Of particular
      note was the absence of peripheral lymphadenopathy and tumor formation which
      posed diagnostic problems in the initial phase of the presentations. Thus, based
      on analysis of the clinical findings of these 34 cases, the diagnostic criteria
      for AIVL consists primarily of cytopenia (anemia and/or thrombocytopenia),
      hepatosplenomegaly, absence of peripheral lymphadenopathy and tumor formation,
      and erythrocyte-hemophagocytosis along with intravascular proliferation of the
      neoplastic B cells. The pathologic findings of the 19 autopsied cases which
      fulfilled the criteria are also summarized, and they reveal morphologic,
      immunologic, and genotypic features of typical IVL.

PMID- 10342575
TI  - Transplantation of autologous peripheral blood progenitor cells procured after
      high-dose cytarabine-based consolidation chemotherapy for adults with secondary
      acute myelogenous leukemia in first remission.
AB  - Patients with acute myelogenous leukemia secondary to an antecedent hematologic
      disturbance or cytotoxic chemotherapy are considered to have a very low
      likelihood of leukemia-free survival regardless of the form of post-remission
      therapy. The purpose of this study is to evaluate, on the basis of intention to
      treat, the feasibility and efficacy of high-dose cytarabine/anthracycline
      consolidation chemotherapy followed by autologous transplantation of
      chemotherapy/rHuG-CSF-mobilized peripheral blood progenitor cells for seventeen
      adult patients (median age 63, range 27 to 68) with secondary acute myelogenous
      leukemia in first remission. Ten eligible patients underwent autologous
      transplantation of peripheral blood progenitor cells procured following high-dose
      cytarabine/mitoxantrone consolidation chemotherapy used as a method of in vivo
      purging. A median of 5 collections (range 2 to 13) were required to procure a
      median of 9.27 x 10(8) total mononuclear cells/kg (range 2.35 to 21.44 x 10(8)
      per kg). The median number of CD34-positive progenitor cells was 1.18 x 10(6) kg
      (range 0.34 to 30.9 x 10(6) kg). After preparative conditioning with 11.25 Gy
      total body radiation and cyclophosphamide (120 mg/kg) and autologous
      transplantation, the median time to neutrophil and platelet recovery were 18 days
      (range 12 to 29 days) and 25 days (range 8 to 158+ days), respectively. After a
      median follow-up for surviving patients of 33.4 months (range 7.5 to 54 months),
      9 of 17 patients (53%) remain alive with 7 in continued first remission. The
      median remission duration is 13 months (3 to 53 months) and actuarial leukemia
      free survival at 3 years is 51+/-25%. Toxicity of autologous peripheral blood
      progenitor cell transplant included serious liver and pulmonary toxicity in 2 and
      1 patient, respectively. Our results demonstrate that a postremission program of
      high-dose cytarabine-based consolidation chemotherapy followed by autologous
      transplantation of chemotherapy-mobilized peripheral blood progenitor cells is
      feasible for patients with secondary acute myelogenous leukemia producing
      prolonged leukemia-free survival with minimal toxicity.

PMID- 10342576
TI  - Cellular uptake and antiproliferative effects of therapeutic concentrations of
      idarubicin or daunorubicin and their alcohol metabolites, with or without
      cyclosporin A, in MDR1+ human leukemic cells.
AB  - Ways of restoring an altered drug sensitivity in P-170 glycoprotein (MDR1)
      positive leukemias are being actively sought for, mostly using MDRI negative
      regulators together with the MDR1-sensitive anthracycline-type drugs daunorubicin
      and mitoxantrone. Because idarubicin is less vulnerable to MDR1-mediated
      transport and could thereby represent a better companion to MDR1 inhibitors, we
      assessed the ability of the anti-MDR1 agent cyclosporin A to modulate this
      function in multidrug resistant T-lymphoblastic CEM cells challenged in vitro
      with either daunorubicin or idarubicin. In order to obtain information of
      potential interest for the design of a clinical trial, we adopted drug plus
      metabolite concentrations and exposure times close to the in vivo
      pharmacokinetics of equimyelotoxic doses of intravenous daunorubicin 45 mg/m2 or
      idarubicin 10-12 mg/m2, respectively, plus infusional cyclosporin A 16 mg/kg/d.
      Study methods were cytofluorimetry for the detection of intracellular drug
      uptake, retention and pro-apoptotic effects (binding of fluoresceinated annexin
      V), and the standard MTT assay as growth inhibition test. The results showed
      significantly greater drug uptake (at 30'), retention (at 12 hours), and
      apoptotic cell rates with idarubicin+/-idarubicinol than daunorubicin+/
      daunorubicinol (p<0.05), and a further potentiation of these effects by
      cyclosporin A. Differing from daunorubicin, idarubicin intracellular accumulation
      and, by inference, related apoptotic changes were increased by cyclosporin A only
      in the early phase of drug-cell interaction; a potential advantage towards a
      reduced toxicity by CsA delivered as short rather than prolonged infusion in the
      in vivo setting. MTT assay results were also in favour of idarubicin but greatly
      influenced by cyclosporin A itself. Altogether, study results in MDR1+ cells
      incubated with CsA 1500 ng/ml plus idarubicin+idarubicinol 100+20 ng/ml, that are
      peak levels achievable in vivo with an idarubicin dose > or = 12 mg/m2 plus
      cyclosporin A 16 mg/kg/d, were in the range of those obtained with standard-dose
      daunorubicin in MDR1- cells (p=n.s.). In summary, an idarubicin plus short-course
      cyclosporin A combination could be considered for the management of MDR1+
      leukemias, where it may represent a more effective and less toxic option than
      daunorubicin plus continuous infusion cyclosporin A.

PMID- 10342577
TI  - Expression of apoptosis-controlling proteins in acute leukemia cells.
AB  - The expression of Bcl-2 family proteins (Bcl-2, Bcl-X, Bcl-XL, Bcl-Xs, BAX, BAD,
      MCL-1) and of Interleukin-1 converting enzyme (ICE)-related proteins (ICE, CPP32,
      ICH- 1) was analyzed in acute leukemia cells by flow cytometry. Most proteins
      studied were detectable in cell lines such as KG1a, HL60, K562 (myeloblastic),
      REH, RAJI and MOLT4 (lymphoblastic) and VAL (B-cell lymphoma). However, BCL-Xs
      and BAK were weakly expressed in K562, as were Bcl-X, BAD and BAK in the VAL
      line. In acute myeloid leukemia (66 cases studied), the proteins were expressed
      in most cases in a high percentage of cells, especially BAX and CPP32, without
      correlation with hematological characteristics. However, Bcl-2 was expressed in a
      higher percentage of cells in FAB M1 and M5 cases, and in CD34-positive cases,
      whereas Bcl-Xs was more frequently expressed in M3 cases. No differences were
      observed regarding fluorescence intensity. Higher percentages of Bcl-2-positive
      cells were associated with low remission rate, while expression of Bcl-Xs was
      predictive of high remission rate. In acute lymphoblastic leukemia (36 cases),
      all proteins studied were expressed in a majority of cases. Bcl-Xs was more
      frequently detected in T-cell type, and was also associated with a higher
      remission rate. These results suggest that apoptosis-controlling proteins may
      have a role in the pathogenesis and response to therapy of acute leukemia.

PMID- 10342578
TI  - Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow
      autotransplants in newly diagnosed multiple myeloma.
AB  - There is controversy whether high-dose therapy and a bone marrow autotransplant
      or conventional chemotherapy is a better treatment for newly diagnosed multiple
      myeloma. Data from 1 comparative study and 1 randomized trial provide
      insufficient subject-level data to advise specific people whether to have an
      autotransplant. We analyzed appropriate use of high-dose therapy and bone marrow
      autotransplants in people with newly diagnosed, multiple myeloma using a modified
      Delphi-panel group judgment process. The panel consisted of 9 myeloma experts
      from diverse geographic sites and practice settings who reviewed Boolean MEDLINE
      searches of multiple myeloma and chemotherapy or autotransplants. The panel rated
      a metric of 64 clinical setting developed by permuting age, performance score,
      disease-stage and disease-related prognostic variables and response to initial
      therapy. Each panelist rated appropriateness of high-dose therapy and an
      autotransplant versus conventional-dose chemotherapy on a 9-point ordinal scale
      (1, most inappropriate, 9, most appropriate). An appropriateness index was
      developed based on median rating and amount of disagreement. Relationship of
      appropriateness indices to the permuted clinical variables was considered by
      analysis of variance and recursive partitioning. Autotransplants were rated
      appropriate in persons <55 years old with stage 3 disease and a complete or
      partial response or stable disease after initial chemotherapy, inappropriate in
      persons with stage 1 or 2 disease, a performance score <70% and a complete or
      partial response or stable disease after initial chemotherapy and uncertain in
      all other settings.

PMID- 10342579
TI  - Expression of Fas and Fas ligand in Hodgkin's disease.
AB  - Fas and Fas ligand expression were investigated in twenty two cases of classical
      Hodgkin's disease (HD) by immunohistochemistry. While Reed-Sternberg (RS) cells
      in 7/22 (32%) cases expressed Fas ligand, reactive lymphoid cells expressed Fas
      ligand in only 2 (9%) cases. In 20/22 (91%) cases, the RS cells expressed Fas. A
      higher proportion of RS cells in the nodular sclerosis subtype expressed Fas as
      compared to the mixed cellularity subtype. In 18/22 (82%) cases, Fas expression
      was also noted in the reactive lymphoid cells. In eight cases, the reactive
      lymphoid cells were also analyzed by flow cytometry and a majority of them were
      CD4+CD45RO+. Most of these activated T-cells expressed Fas but were negative for
      Fas Ligand. To investigate the co-expression of Fas and Fas Ligand in the RS
      cells, six cases were subjected to Fas and Fas ligand immunostaining on
      consecutive sections. The co-expression was documented in the RS cells in four of
      six cases. These six cases with expression of both Fas and Fas ligand were
      investigated for the incidence of apoptosis. There was no statistically
      significant relationship between expression of Fas on reactive cells, expression
      of FasL on RS cells and the proportion of apoptotic reactive cells. In all these
      cases apoptosis was not observed in the RS cells. Thus Fas - FasL interactions
      may not lead to apoptosis of the RS cells.

PMID- 10342580
TI  - Non-surgical treatment with primary chemotherapy, with or without radiation
      therapy, of stage I-II high-grade gastric lymphoma.
AB  - Morbidity, mortality and discomfort related to gastrectomy has led some
      investigators to treat patients with stage I-II primary gastric high-grade
      lymphoma (PGL) with a conservative strategy. Here we report a retrospective
      series of 21 patients with PGL treated with primary chemotherapy alone or
      followed by radiation therapy and analyze previously reported series, focusing on
      therapeutic results, treatment-related morbidity and stomach preservation rate.
      All 21 patients with stage I-II PGL received an initial anthracycline-containing
      chemotherapy, which was followed by involved field-radiation therapy in 8 cases.
      Data regarding toxicity, response and relapse rates and survival of this patient
      group and 14 previously published series, involving 316 patients treated with
      conservative modality, were also analyzed. In the present series two patients did
      not complete the planned treatment, while the remaining 19 achieved a complete
      remission (response rate: 90%). Three patients relapsed, all of whom had been
      treated with chemotherapy alone. Two patients died of lymphoma, one of sepsis and
      the other of lung cancer while still relapse-free. The survival rate at 50 months
      is 81%, and the 5-year actuarial cause-specific survival is 82%. The stomach
      preservation rate is 100%. Previously reported series showed a response rate
      ranged between 76% and 100%. Gastrointestinal bleeding was observed in only 3% of
      cases, while no cases of gastric perforation were reported. Treatment mortality
      rate was 2.5%. 5-year actuarial survival ranged between 73% and 90% and stomach
      preservation rate was 97%. Short-term chemotherapy obtained similar results to
      more prolonged treatment. In conclusion, conservative treatment with primary
      chemotherapy followed by involved field-radiation therapy should be used for the
      first-line treatment of patients with stage I/II PGL considering that it is
      associated with a high response and survival rates, and with an insignificant
      risk of bleeding or perforation, high stomach preservation rate and good quality
      of life.

PMID- 10342581
TI  - Intensive chemotherapy with hematopoietic cell transplantation after ESHAP
      therapy for relapsed or refractory non-Hodgkin's lymphoma. Results of a single
      centre study of 65 patients.
AB  - This study was designed to assess the results of protracted courses of ESHAP
      (etoposide, cytarabine, cisplatin, methylprednisolone) therapy followed by
      intensive chemotherapy and hematopoietic cell transplantation (IC+HCT) for
      relapsed or refractory non-Hodgkin's lymphoma (NHL). Treatment consisted of 3
      cycles of ESHAP; responsive patients (pts) then received 3 more cycles, and
      IC+HCT was used for pts in maintained partial (PR) or complete (CR) remission
      after the sixth ESHAP. Sixty-five pts entered the study. At enrollment, 27 pts
      had bone marrow (BM) and/or central nervous system (CNS) lymphomatous
      infiltration. Disease status was primary refractory lymphoma in 41 pts (63 %),
      and relapse in 24 pts (37 %). Results showed that two pts were not evaluable for
      the therapeutic response because of early treatment-related death. Thirty-nine
      (62 %) pts entered PR or CR after 3 cycles of ESHAP. Eleven pts subsequently had
      disease progression. Twenty-eight pts were in persistent CR or PR after 6 cycles
      of ESHAP. Refractory pts did not show a different response rate to relapsing pts
      (chi2= 1.73). Five pts were excluded from IC+HCT because of an inadequate graft
      or treatment-related toxicity. Twenty-three (35 %) pts completed the procedure.
      Five pts (22 %) relapsed after IC+HCT. The overall survival rate of the 39
      responsive pts is 45 % at 60 months, with a median survival time of 30 months.
      Median survival among the 35 pts in whom second-line chemotherapy failed is 7.1
      months, with a 4-year survival rate of 3 %. Despite the poor prognostic features
      of this group, 45% of pts responding to the first 3 cycles of chemotherapy are in
      prolonged remission, suggesting that rather than to transplant after just 2
      cycles of salvage therapy, pursuing second-line chemotherapy may better
      discriminate between patients more likely to benefit from a subsequent
      transplant.

PMID- 10342582
TI  - Correlation and prognostic value of serum soluble ICAM-1, beta-2 microglobulin,
      and IL-2alphaR levels in non-Hodgkin's lymphoma.
AB  - Serum levels of sICAM-1, sIL-2alphaR, and beta-2 microglobulin were measured in
      63 patients with non-Hodgkin's lymphoma (NHL). The correlation between these
      serum markers as well as their relationship with NHL features and disease outcome
      were analyzed. Although in high-grade NHL sICAM-1 levels correlated with tumor
      mass, no correlation was found between sICAM-1 levels and tumor burden in low
      grade NHL. When compared with sICAM-1 and beta-2 microglobulin, sIL-2alphaR
      showed the strongest correlation with the tumor burden. However, in multivariate
      analysis, including serum markers employed as continuous variables, the only
      parameteres which entered the regression model were beta-2 microglobulin
      (p=0.012) and sICAM-1 (p=0.019). In a dichotomized model, beta-2 microglobulin,
      aggressive histology, sICAM-1, age and number of nodal involved sites were found
      to be prognostically significant. Finally, by combining sICAM-1 and beta-2
      microglobulin serum levels, a simple prognostic model useful for NHL was
      obtained.

PMID- 10342583
TI  - Possible role of granulocyte colony-stimulating factor in increased serum soluble
      interleukin-2 receptor-alpha levels after allogeneic bone marrow transplantation.
AB  - Serum soluble interleukin-2 receptor - alpha (sIL-2R) levels markedly increased
      at the engraftment period in patients who underwent allogeneic bone marrow
      transplantation (BMT). Since serum G-CSF levels increased during G-CSF
      administration and decreased after the cessation, increased sIL-2R levels
      appeared to be induced by G-CSF administration. There was no increase in sIL-2R
      levels in a patient given macrophage colony-stimulating factor (M-CSF). The sIL
      2R levels at the engraftment period and the onset of acute graft-versus-host
      disease (GVHD) were higher in patients who developed acute GVHD during G-CSF
      administration than in those who developed acute GVHD after G-CSF cessation. This
      finding suggests that G-CSF administration may possibly augment acute GVHD.
      However, it appears to be unlikely, because in the entire population, 18 of 35
      patients had acute GVHD while only 6 of 17 patients had acute GVHD during G-CSF
      administration. Further analysis is still needed in order to draw definite
      conclusions. Preconditioning regimens did not appear to affect the sIL-2R levels,
      when the variable frequencies of methotrexate (MTX) administration were compared.

PMID- 10342585
TI  - Differentiation of leukemic cells induced by short-course high-dose
      methylprednisolone in children with different subtypes of acute myeloblastic
      leukemia.
AB  - Differentiation of myeloid leukemic cells to mature granulocytes by high-dose
      methylprednisolone (HDMP, 20-30 mg/kg/day) with a favorable antileukemic effect
      has previously been demonstrated in children with acute promyelocytic leukemia
      and acute myeloblastic leukemia (AML) M4. In the present study, three children
      with other morphological subtypes of AML (two AML M1, one AML M2) were given
      methylprednisolone (30 mg/kg/day) orally in a single dose. After a short-course
      (3 or 7 days) of HDMP treatment alone, a striking decrease in blast cells
      associated with an increase in maturing and abnormally nucleated
      polymorphonuclear-like cells some containing Auer rods were detected in all
      patients in peripheral blood or bone marrow smears. During HDMP treatment, in
      parallel to morphological improvements, marked increases in the percentage of
      cells expressing granulocytic antigen (CD15) were observed. The increase of CD15
      expression on myeloid cells, together with the steady expression of CD34 and
      CD117 antigens in Casel(AML M1) , is suggestive of aberrant CD34 + CD117 + CD15 +
      cells, which may indicate the leukemic origin of the maturing myeloid cells.
      These results suggest that HDMP treatment may induce differentiation of myeloid
      leukemic cells in some children with different morphological subtypes of AML, and
      that the differentiation-inducing effect of HDMP should be explored in other
      malignant diseases.

PMID- 10342584
TI  - Double G0/G1 peak in the DNA histogram of aberrant marker positive acute leukemia
      patients is associated with a poor clinical outcome.
AB  - In order to investigate the relationship between aberrant marker expression and
      DNA ploidy, 61 adult patients with acute leukemia (39 AML and 22 ALL) were
      studied. Aberrant marker expression was observed in 20 patients (16/39 of AML and
      4/22 of ALL patients). In flow cytometric DNA analysis aneuploidy was observed in
      18 patients (9/39 of AML and 9/22 of ALL patients). The incidence of aneuploidy
      in patients with aberrant marker expression was 35% whereas this was 26.8% in
      patients without aberrant marker expression. Furthermore, 7 patients with
      aberrant marker expression showed an aneuploid, double G0/G1 peaks appearance
      whereas the remaining 11 patients with aberrant marker expression had euploid DNA
      content. Double G0/G1 appearance was not observed in patients without aberrant
      marker expression. Further analyses revealed that this did not correlate with
      apoptosis. All 7 patients, who had both aberrant marker expression and double
      G0/G1 peak had a poor clinical outcome with a short survival and all died within
      three months whereas three-months survival was 67% for AML, 69% for ALL patients
      and 81% for patients with aberrant marker expression respectively (p<0.01). Our
      data indicate that the evaluation of the DNA ploidy in patients with aberrant
      marker expression may be of prognostic importance.

PMID- 10342586
TI  - Isolated tetrasomy 8 in minimally differentiated acute myeloid leukemia (AML-M0).
AB  - Tetrasomy 8 as a sole anomaly in hematological disorders is relatively rare. To
      the best of our knowledge, only 19 such cases have been described in the
      literature to date. Of them, acute myeloid leukemia (AML) in 13 (M1, one; M2,
      three; M4, one; M5, eight), acute lymphoblastic leukemia(ALL) in one,
      myelodysplastic syndrome(MDS) in 3, polycythemia vera(PV) and myelofibrosis(MF),
      one case each. Their median survival was 20 weeks. Here, we report the first case
      of a 29-year-old man with minimally differentiated AML (AML-M0) displaying a
      tetrasomy 8 clone. Immunophenotyping showed positivity with CD33, CD34 and
      intracellular MPO, but all lymphoid markers tested were negative. Conventional
      cytogenetics of bone marrow cells showed 84.9% of metaphases with tetrasomy 8 in
      addition to 15.1% with normal diploidy. However, Fluorescence in situ
      hybridization(FISH) using a centromeric probe specific for chromosome 8 revealed
      trisomy 8 in 14.2% of interphase nuclei besides tetrasomy 8 in 82.4%. The patient
      died four weeks after diagnosis without therapy. In conclusion, these findings
      suggest that tetrasomy 8 is associated with a heterogeneous group of myeloid
      disorders and heralds a bad prognosis. It may be a consequence of clonal
      evolution of trisomy 8.

PMID- 10342587
TI  - Morphometry and quality control for a May-Grunwald Giemsa stained preparation. A
      40 centers cooperative study.
AB  - A multicentric study including 40 medical centers has been done on May-Grunwald
      Giemsa (MGG) stain, to obtain precise information concerning the size, shape and
      color of cellular elements. A number of factors are taken into consideration
      including the zone of microscopic observation, the quality of staining, condition
      of grabbing images and the size of the sample. Morphometric and colorimetric
      measurements have been applied as objective tools for demonstrating the
      predominance of each Red/Green/Blue component, and more particularly their
      reciprocal ratio. The results obtained for each center may constitute a guideline
      for adjusting their procedure, in order to reach a consensus regarding similar
      staining by all centers.

PMID- 10342588
TI  - CD5+ persistent polyclonal B-cell lymphocytosis in a male.
AB  - Persistent polyclonal B-cell lymphocytosis with binucleate lymphocytes is a rare
      lymphoproliferative syndrome of uncertain cause that is strongly associated with
      HLA-DR7 positivity, cigarette smoking, and female sex. As yet, there is no
      explanation for the strong sex predilection. We report the third case of
      persistent polyclonal B-cell lymphocytosis in a male. Other notable findings in
      this case are lack of HLA-DR7 and strong positive CD5 markers in the polyclonal B
      cell population. To our knowledge, CD5 expression has not been mentioned or
      reported in association with this syndrome.

PMID- 10342589
TI  - Extramedullary relapse despite graft-versus-leukemia effect after bone marrow
      transplantation in a girl with juvenile myelomonocytic leukemia.
AB  - A 12 year-old girl with juvenile myelomonocytic leukemia (JMML) and monosomy 7
      underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched
      brother. To monitor the engraftment and the course of the disease we used
      fluorescence in situ hybridization (FISH) with probes specific for the
      centromeres of chromosomes X, Y and 7. Complete hematological remission was
      achieved and confirmed by the virtually exclusive presence of normal male cells
      in the bone marrow (BM). Acute graft-versus host disease (GvHD) was treated with
      prednisone and cyclosporine A (CSA) and female cells with monosomy 7 reoccurred
      in the peripheral blood (PB) and BM. After discontinuation of the
      immunosuppressive therapy, the leukemic cells with monosomy 7 disappeared again
      from these compartments. One year after transplantation, isolated extramedullary
      relapses occurred in lymph nodes and skin, followed by dissemination of blast
      cells into the BM, whereas the PB cells remained of donor origin. The fact that
      the leukemic cells fluctuated with the intensity of the immunosuppressive
      treatment provides evidence of a graft versus leukemia (GvL) effect in this
      unusually old girl with JMML with a unique extramedullary disease progression.

PMID- 10342590
TI  - Primary anaplastic large cell lymphoma of skeletal muscle presenting with
      compartment syndrome.
AB  - We describe a patient with primary anaplastic large cell lymphoma of the forearm
      presenting with compartment syndrome. Urgent decompression fasciotomy and
      combination chemotherapy resulted in durable remission status. This is followed
      by a review of primary skeletal muscle lymphoma in the English literature.

PMID- 10342591
TI  - Aplastic anemia responsive to cyclosporine complicating the evolution of
      polycythemia vera.
AB  - We report here a very unusual patient with Polycythemia vera treated with
      Pipobroman who developed severe aplastic anemia following administration of the
      drug. Six months later, because of lack of response, cyclosporine therapy was
      given there was rapid and complete hematological recovery, highly suggestive of
      an immune-mediated mechanism, in this case.

PMID- 10342592
TI  - Is Alexander's disease a nosologic entity or a common pathologic pattern of
      diverse etiology?

PMID- 10342593
TI  - Hypertensive encephalopathy, reversible occipitoparietal encephalopathy, or
      reversible posterior leukoencephalopathy: three names for an old syndrome.
AB  - Children with hypertension, seizures, lethargy, encephalopathy, headache, and
      occipital blindness are reviewed. After undergoing antihypertensive therapy, most
      children improve. Some patients have a similar syndrome associated with
      chemotherapy, transplantation, transfusion, or human immunodeficiency virus-1
      (HIV-1) infection. These latter children can develop symptoms with only minimal
      or no discernible elevations in blood pressure and improve, in the case of cancer
      associated encephalopathy, after discontinuing chemotherapy. The reported
      children with this distinctive clinical condition are compared to adults with
      reversible posterior leukoencephalopathy syndrome. Since both gray and white
      matter are involved, we had suggested previously that the name be changed to
      (reversible) occipitoparietal encephalopathy syndrome. However, reversible
      posterior leukoencephalopathy has been used in the adult population and probably
      should be employed in children for the sake of uniformity, since both children
      and adults have the same clinical presentation and presumably a similar
      pathophysiology for the encephalopathy syndrome. The diagnosis is confirmed by
      reversible posterior abnormalities seen on T2-weighted brain magnetic resonance
      imaging, and by the presence of either headache, altered mental status, seizures,
      or visual disturbances.

PMID- 10342594
TI  - Treatment of seizures in subcortical laminar heterotopia with corpus callosotomy
      and lamotrigine.
AB  - Focal and generalized cortical dysgeneses are sometimes seen on the magnetic
      resonance images (MRI) of patients with epilepsy. Subcortical laminar heterotopia
      are bilateral collections of gray matter in the centrum semiovale that resemble a
      band or "double cortex" on MRI. We studied one male and two female patients with
      subcortical laminar heterotopia who had moderate to severe developmental delay,
      early-onset epilepsy, and medically refractory seizures. Atonic, atypical
      absence, tonic, myoclonic, complex partial, and generalized tonic-clonic seizures
      were recorded. Interictal and ictal electroencephalographic patterns were
      generalized and, less commonly, multifocal. Two years after corpus callosotomy,
      one patient was free of generalized tonic-clonic and atonic seizures, but the
      other patient who had undergone callosotomy had no significant reduction in
      seizure frequency. With lamotrigine treatment, the patient who had not had
      surgery had complete cessation of monthly episodes of status epilepticus and a
      dramatic reduction of generalized tonic-clonic seizures, and the other patient
      who received lamotrigine had a 50% reduction of her atonic seizures. In patients
      with subcortical laminar heterotopia, atonic and generalized tonic-clonic
      seizures can be substantially reduced or eliminated by corpus callosotomy or
      treatment with lamotrigine.

PMID- 10342595
TI  - Characteristics and prognosis of epilepsy in children with cerebral palsy.
AB  - The aims of the study were to describe the prevalence and characteristics of
      epilepsy in a population of patients with cerebral palsy in a university referral
      center and to determine the rate of relapse caused by discontinuation of
      antiepileptic drugs after a 3-year seizure-free period. A total of 178
      consecutive patients with cerebral palsy and epilepsy were prospectively followed
      for 9.2 +/- 2.4 years after onset of seizures and compared to a control group of
      150 epileptic patients without cerebral palsy (median follow-up period, 10.5
      years). The overall prevalence of epilepsy was 36.1%. Patients with atonic
      diplegic, dystonic, tetraplegic, and hemiplegic cerebral palsy had a higher
      incidence of epilepsy (87.5%, 87.1%, 56.5%, and 42%, respectively). In all, 134
      (75.3%) patients were seizure free for more than 3 years and could discontinue
      therapy, whereas 44 patients (24.7%) were still on antiepileptic drugs. Eighteen
      of 134 patients relapsed after a 3-year seizure-free period and subsequent
      discontinuation of antiepileptic drugs, thus giving a relapse rate of 13.4%.
      First seizures occurred during the first year of life in 69.7% of the patients
      with epilepsy and cerebral palsy. Complete control of seizures could be achieved
      in 65.2% of the patients with cerebral palsy and epilepsy; however, regardless of
      the prognosis of seizures, epilepsy was a major prognostic factor regarding both
      the presence of mental retardation and the motor development of children with
      cerebral palsy.

PMID- 10342596
TI  - Stroke in Saudi children.
AB  - This study reports the clinical features and neuroimaging correlates of stroke in
      Saudi children seen over a 5-year period at the King Fahd Hospital of the
      University, Al-Khobar, Saudi Arabia. During the study period, 31 (18 boys, 13
      girls; mean age, 26.2 months) of the 20,895 children seen had stroke; the annual
      stroke incidence was 29.7 per 100,000 in the pediatric population. Ischemic
      strokes accounted for 90% and hemorrhagic 10% of the cases, respectively. The
      boys-to-girls ratio for ischemic stroke was 2:1. Cranial computed tomographic
      scans and magnetic resonance imaging findings were abnormal in 82% and 91%,
      respectively. The etiologic factor was undetermined in 65% of the cases. Our
      results suggest that stroke is uncommon in Saudi children. However, further
      studies evaluating a larger population in different clinical settings are
      required to provide a more comprehensive picture of stroke in children in this
      area.

PMID- 10342597
TI  - Attention-deficit hyperactivity disorder and developmental right-hemisphere
      syndrome: congruence and incongruence of cognitive and behavioral aspects of
      attention.
AB  - We studied clinical aspects of attention in three groups: children with
      developmental right-hemisphere syndrome and attention-deficit hyperactivity
      disorder (ADHD), children with ADHD only, and normal controls. The three groups
      (N = 54) were case-matched for age, sex, IQ, hand dominance, and socioeconomic
      status. ADHD was diagnosed clinically using the Diagnostic and Statistical Manual
      of Mental Disorders-III-Revised criteria and the Conners' Abbreviated Teacher
      Questionnaire. Additional aspects of attention and behavior were measured by the
      Child Behavior Checklist, a low-cognitive-load continuous performance task, and
      the visual target cancellation test (paper and pencil). Although the Child
      Behavior Checklist profile of attentional deficits in the two clinical groups was
      similar, we found that the developmental right-hemisphere syndrome group was more
      severely impaired on parameters of attention measured by the continuous
      performance task and visual target cancellation test than the children with ADHD.
      We conclude that the profile of attentional deficits in developmental right
      hemisphere syndrome is different than that seen in children with ADHD only,
      possibly reflecting disparate neurologic underpinnings for the two syndromes.

PMID- 10342598
TI  - Evaluation of gross and fine motor functions in children with hemidecortication:
      predictors of outcomes and timing of surgery.
AB  - The purpose of this study is three-fold: First, to determine the levels of gross
      and fine motor functions in children before and after hemidecortication, using
      standardized measurement tools; second, to investigate if predictors of these
      outcomes can be characterized; and third, to explore if both clinical measures
      and functional magnetic resonance imaging (MRI) potentially can identify optimal
      timing of surgery. The Gross Motor Function Measure and the Quality of Upper
      Extremity Skills Test are shown to be comprehensive, standardized outcome
      measures of movement performance in affected children. Age at surgery and
      interval between age at seizure onset and age at surgery could be the most
      reliable predictors of clinical outcomes. Functional MRI studies are valuable in
      exploring the potential of the cortical reorganization that sustains residual
      sensorimotor function. The combination of clinical measures with functional MRI
      is a promising method of inquiry into developmental and plasticity processes.

PMID- 10342599
TI  - Tics in Tourette syndrome: new treatment options.
AB  - Tourette Syndrome is a familial neurobehavioral disorder characterized by
      fluctuating involuntary motor and/or vocal tics. The most commonly used
      medications to treat Tourette's syndrome are haloperidol, pimozide, fluphenazine,
      and clonidine, all of which may have considerable side effects. We enrolled 450
      patients with tics/Tourette's syndrome to be treated with baclofen/botolinum
      toxin type A for their symptoms. Global severity of tic symptoms was rated by the
      Yale Global Tic Severity Scale and a quantified videotaped micro-structured
      analysis of tics. We found that baclofen/botolinum toxin type A are very
      effective, safe, and reliable in the treatment of tics/Tourette's syndrome. It is
      worthwhile considering this treatment approach in patients with tics/Tourette's
      syndrome in order to reduce or avoid the side effects of other medications.
      Further studies, however, are required.

PMID- 10342600
TI  - Alexander's disease: unique presentation.
AB  - Subacute necrotizing encephalomyelopathy (Leigh syndrome) refers to a nebulous
      disease entity characterized by lactic acidosis, a wide variety a clinical
      manifestations, and a consistent conglomeration of pathologic findings. Several
      abnormalities in metabolism have been delineated in association with Leigh
      syndrome, but many cases have no identified metabolic abnormality. We report a
      case that clinically, metabolically, and neuroradiologically appeared to be Leigh
      syndrome. In addition, our patient exhibited other unusual clinical findings,
      including ocular motility abnormalities. Neuropathologically, however, the
      diagnosis of Alexander's disease was confirmed. A review of the literature failed
      to find other cases of Alexander's disease reported with the metabolic
      abnormalities and clinical manifestations with which our patient presented.

PMID- 10342601
TI  - Abdominal cerebrospinal fluid pseudocyst in a severely handicapped patient with
      hydrocephalus.
AB  - We present a case of an abdominal cerebrospinal fluid pseudocyst as a rare
      complication of a ventriculoperitoneal shunt. The patient is a severely
      handicapped bedridden spastic quadriplegic with hydrocephalus. He underwent
      surgical reconstruction of a shunt tube because of shunt disconnection at the age
      of 12 years. Fever and frequent vomiting developed 2 months after surgery, and
      abdominal fullness gradually became severe. He was diagnosed as having an
      abdominal cerebrospinal fluid pseudocyst on abdominal ultrasonography. If a shunt
      dysfunction is suspected, this type of cyst should also be considered, and
      abdominal ultrasonography should be performed as one of the screening tests for
      determining the cause of the shunt dysfunction.

PMID- 10342602
TI  - Periventricular brain heterotopias in a child with adrenocortical insufficiency,
      achalasia, alacrima, and neurologic abnormalities (Allgrove syndrome).
AB  - We describe a previously unreported finding of periventricular heterotopias in a
      brain magnetic resonance imaging (MRI) study, in a girl with adrenocortical
      insufficiency, alacrima, achalasia, and neurologic deterioration (Allgrove
      syndrome). This finding could indicate that the underlying mechanism in this
      syndrome can be traced to the first half of fetal life and also might cause
      abnormal neuronal migration. This disorder recently has been linked to chromosome
      12q13. There could be several explanations for the clinical heterogeneity in this
      syndrome: a contiguous gene syndrome involving multiple genes, including one
      whose deletion causes heterotopias, or a deficiency of a gene for a neurotrophic
      factor active during pre- and postnatal life and responsible for both migration
      and survival of neurons could be the cause. The identification of the responsible
      gene(s) will lead to further understanding of this multisystem disorder.

PMID- 10342603
TI  - Persistent occipital electrographic status epilepticus.
AB  - A 13-year-old girl of normal intellect had clinically silent occipital
      electrographic status epilepticus that persisted for more than 3 years.
      Neurologic examination and cranial magnetic resonance imaging were entirely
      normal. [18F]Fluorodeoxyglucose positron emission tomography demonstrated a
      hypermetabolic focus in the right occipital lobe. Electrographic status lasting
      years can be seen in epilepsia partialis continua. However, the absence of focal
      clinical seizures, nonprogressive course, and normal magnetic resonance imaging
      study seen in this patient are not features characteristic of epilepsia partialis
      continua.

PMID- 10342604
TI  - Extensor toe sign unresolved.

PMID- 10342605
TI  - Extensor toe sign and statistical methods.

PMID- 10342606
TI  - The organization and delivery of craniofacial health services: the state of the
      art.
AB  - The dominant organizational structure providing care for cleft palate and other
      craniofacial conditions is the health care team. Various types of health care
      team organization are profiled, including intradisciplinary, multidisciplinary,
      and interdisciplinary teams. Effective team-based care delivery has the ability
      to address the fragmentation and dehumanization that can result when a variety of
      specialists and disciplines are required to provide assessment and technical
      care. A team's leadership and its hierarchy of professional authority can be
      expected to affect its ability to function effectively. Health reform and managed
      care are considered for their impact on the team and on the doctor-patient
      relationship. Trends in team regionalization, quality assurance, outcomes
      research, and consumer advocacy are reviewed. The cleft palate and craniofacial
      team is profiled as an organizational model that is being affected by the forces
      of health system change.

PMID- 10342607
TI  - Three-dimensional analysis of craniofacial form in a familial rabbit model of
      nonsyndromic coronal suture synostosis using Euclidean distance matrix analysis.
AB  - OBJECTIVE: Simple craniosynostoses produce predictable morphologies of the
      cranial vault, with growth deficits in a direction parallel to the synostosed
      suture and compensatory growth at sutures that are perpendicular to and attached
      to the synostosed one. In coronal suture synostosis, anteroposterior growth is
      inhibited, with compensatory growth in a transverse direction. Information on
      growth patterns and influence on other craniofacial regions are not as clear.
      This study tested the hypotheses that (1), both juvenile and adult rabbits with
      familial, nonsyndromic coronal suture synostosis exhibit significant size and
      shape differences of the entire craniofacial region relative to normal rabbits as
      a result of altered growth patterns and that (2), shape differences of the
      calvaria will precede those of the basicranium. DESIGN: Fifty anatomic landmarks
      were located on 94 New Zealand white rabbit crania. The crania were divided into
      a juvenile, six-week-old age category (n = 53) and an adult, 18-week-old category
      (n = 41) in order to assess shape differences at different ages. Each age
      category was sorted into three groups based on growth at the coronal suture:
      normal sutural growth, delayed onset synostosis, and complete synostosis.
      Landmarks were digitized in three-dimensions, and statistical analyses on shape
      differences were carried out using Euclidean distance matrix analysis (EDMA).
      RESULTS AND CONCLUSIONS: Results showed that delayed onset synostosis did not
      produce craniofacial morphology that was different from normal at any age.
      However, complete synostosis yielded predictable and global craniofacial shape
      differences at both ages relative to normal skulls, producing an overall shorter,
      wider cranium with the most markedly compensating regions in a posterosuperior
      position of the skull. In addition, delayed onset synostosed crania showed no
      shape differences in the basicranium, relative to normal crania, suggesting
      primacy of the calvaria in this model of coronal synostosis. However, further
      investigations are necessary to verify primacy of the calvaria in this model.

PMID- 10342609
TI  - A finite element model of the soft palate.
AB  - OBJECTIVE: As a step toward better understanding of normal and abnormal velar
      control, a finite element model of the soft palate was developed. DESIGN: A
      static two-dimensional midsagittal model of the velum was given physical
      dimensions to match that of a 10-year-old boy. Biomechanical properties of the
      tissues were inferred based on previous histologic studies. Velar movements were
      induced by the influence of three extrinisic velar muscles: the levator veli
      palatini, the palatoglossus, and the palatopharyngeus, which were simulated as
      external forces acting on the velar model. RESULTS AND CONCLUSIONS:
      Velopharyngeal opened and closed positions were simulated as well as a variety of
      intermediate steps between the two configurations. Velopharyngeal closure was
      also simulated in a manner appropriate for both high and low vowels. Future
      extensions of the model will incorporate the muscles as an intrinsic component of
      the model and will include a full time-dependent implementation, including
      inertial effects. Future studies will compare model predictions with experimental
      data from the laboratory, including both kinematic data and velopharyngeal
      closure forces.

PMID- 10342608
TI  - A multidisciplinary approach to the healing of cranial and residual maxillary
      cleft defects by means of allogenous demineralized osseous implants and
      polylactic acid casts in dogs.
AB  - OBJECTIVE: The aim of this study was to evaluate the healing of artificially
      induced bony defects in dogs by means of demineralized allogenous bone powder
      (DBP) implants covered with polyhydroxy lactic acid (PLA) casts compared with DBP
      implants without the casts. DESIGN: Prospective animal study. SETTING: Research
      university. SAMPLE: Following a pilot study in which two dogs were used, four
      mongrel dogs between the ages of 18 and 24 months and weighing approximately 20
      kg were used as subjects. INTERVENTIONS: Each experimental animal had bilateral
      maxillary alveolar clefts created. In a later procedure, each defect was repaired
      with a DBP implant, half of which were covered with a PLA96 matrix. Each animal
      also had a circular defect created in each parietal bone that was immediately
      covered with DBP implants, half of which were similarly covered with a PLA96
      disk. MAIN OUTCOME MEASURE: Repeated technetium-99m methylene-diphosphate (99mTC
      MDP) uptake measurements were performed to evaluate bone metabolism during the
      healing period, while at relevant intervals, radiographs were taken of the
      healing alveolar cleft defects to register bone repair. After 1 year, the animals
      were euthanized for macroscopic and histologic evaluation. RESULTS:
      Histologically, the grafts covered with PLA96 were at a more advanced stage of
      healing than those without, and the cranial defects similarly were more advanced
      in the healing process than the alveolar defects. Uptake of 99mTC MDP into the
      cranial implants was at its maximal level after 1 week and then gradually
      decreased until, after 7 weeks, it was not significantly different from zero.
      Cranial defects covered with a PLA95-enhanced implant showed a mean maximum count
      rate of 275, while the plain DBP side showed a mean maximal count rate of 150.
      Alveolar defects with the plain DBP implant showed a maximum count rate in the
      first week; those with the PLA95 enhanced implant showed maximum uptake during
      the second week. On both sides, there was a gradual decrease to the base value in
      the seventh week. The mean maximum count on the PLA96-enhanced side was 285,
      while on the plain DBP side, the corresponding value was 320. CONCLUSION:
      Although an advantage of the combination was established for parietal cranial
      defects, no advantage was seen for alveolar cleft defects in this experimental
      setup.

PMID- 10342610
TI  - Effect of placement of a speech appliance on levator veli palatini muscle
      activity during blowing.
AB  - OBJECTIVE: We have observed clinically that some speakers wearing a speech
      appliance for correction of velopharyngeal incompetence can blow with variable
      intensity without nasal air escape. This clinical finding suggests that tightness
      of velopharyngeal closure may be regulated in accordance with oral air pressure
      during blowing. The purposes of this electromyographic study were (1) to examine
      whether levator vell palatini muscle activity can be changed in relation to oral
      air pressure during blowing when the speech appliance is removed, (2) to clarify
      whether or not the change is related to the severity of velopharyngeal
      incompetence, and (3) to examine whether placement of a speech appliance can
      alter levator muscle activity into the equivalent of that of normal speakers
      during blowing. DESIGN: Eight patients with repaired cleft palate, who routinely
      wear a palatal lift prosthesis (PLP) or a hybrid speech appliance of a pharyngeal
      bulb and palatal lift (bulb-PLP), served as subjects. Subjects were classified
      into one of two groups according to their speech appliance (PLP group and bulb
      PLP group). Electromyography of the levator veli palatini muscle was recorded
      with a speech appliance in place and then with the speech appliance removed as
      the subject blew through a tube at three different effort levels. RESULTS: In the
      removed condition, the change in levator activity in relation to oral air
      pressure was variable across subjects in the bulb-PLP group, whereas levator
      activity changed in relation to oral air pressure change for all subjects in the
      PLP group. However, levator activity changed in relation to oral air pressure
      with either speech appliance in place for all subjects irrespective of their
      speech appliance types. CONCLUSION: The severity of velopharyngeal incompetence
      might be related in part to change in levator activity in association with oral
      air pressure. The effect of a speech appliance to correct velopharyngeal
      incompetence might consist not only of mechanical obturation of the velopharynx
      but also of alteration of velopharyngeal function to become similar to normal
      speakers. Moreover, it is likely that the velopharyngeal system could be well
      regulated so as to exhibit a consistent outcome of velopharyngeal function.

PMID- 10342611
TI  - Perception of middorsum palatal stops from the speech of three children with
      repaired cleft palate.
AB  - OBJECTIVE: The purpose of this study was to examine listeners' perception of the
      middorsum palatal stop, a compensatory articulation used by individuals with
      repaired cleft palates. DESIGN: This study tested whether listeners could
      discriminate middorsum palatal stops from matched alveolar (/t/) and velar (/k/)
      stops using a two-button "change/no-change" procedure. It also explored how
      listeners identified the palatal stop by rating each sound on a scale of one to
      eight. PARTICIPANTS: Twenty listeners, 10 untrained and 10 trained in general
      phonetics (graduate students in speech-language pathology), participated in
      discrimination and identification tasks during a 1-hour session in the Speech
      Perception Laboratory at the University of Buffalo. MEASURES: Discrimination was
      measured using d-prime, a score based on listeners' hits, correct rejections,
      misses, and false alarms to the changes/no changes in the stimuli. Identification
      was measured by the mean rating score for each class of stops. RESULTS: Listeners
      discriminated middorsum palatal stops from alveolar and velar stops, but their
      ratings for the middorsum palatal stops did not differ from those for the regular
      stop consonants. The two groups differing in phonetic training did not perform
      differently. CONCLUSIONS: Listeners can discriminate middorsum palatal stops from
      other stop articulations, but they did not identify them differently from
      alveolar and velar stop consonants. The results suggest that considerable
      training listening to middorsum palatal stops is necessary for listeners to be
      able to reliably identify them.

PMID- 10342612
TI  - Effect of stimulus length on nasalance scores.
AB  - OBJECTIVE: Nasalance measures were compared for speech stimuli of four different
      lengths. DESIGN: The standard for comparison was a 44-syllable passage. The 44
      syllable passage was compared to a 17-syllable passage, a 6-syllable sentence,
      and a 2-syllable word. All stimuli were devoid of nasal consonants and were
      composed only of low pressure consonants and vowels. SETTING: Academic and
      clinical craniofacial center. SUBJECTS: The subjects were 20 children at risk for
      velopharyngeal dysfunction and 5 children without history of communication
      disorder. MAIN OUTCOME MEASURE(S): The main outcome measures were the nasalance
      scores associated with speech samples of different lengths. RESULTS: The results
      showed that comparable measures of nasalance can be obtained using stimuli as
      short as a six-syllable sentence. Both the 17-syllable and the 6-syllable
      stimulus achieved high criterion validity, indicating that stimuli of that length
      could be substituted for the longer 44-syllable passage. The two-syllable word,
      however, had significantly lower criterion validity and could not be used to
      obtain valid estimates of nasalance. CONCLUSION: Valid assessment of nasalance
      can be achieved with speech samples as short as six syllables.

PMID- 10342613
TI  - Heterotopic nasopharyngeal brain tissue associated with cleft palate.
AB  - OBJECTIVE: The occurrence of extracranial brain tissue is rare. Most of the
      literature describes cases in which it is located around the nose and throat and
      has been classified as nasal glioma. Even more unusual is heterotopic brain
      tissue in the nasopharynx. We were able to find only 17 previously reported
      cases. Of these 17 cases, 6 had heterotopic brain tissue located in a cleft
      palate. This report comments on the identification and treatment of heterotopic
      brain tissue associated with cleft palate without connection to the central
      nervous system. Our case subject is a 10-month-old girl diagnosed with
      heterotopic nasophranygeal brain tissue associated with cleft palate. RESULTS:
      Excision and palatoplasty were performed conjunctively with excellent results.
      CONCLUSIONS: Simultaneous excision of heterotopic nasopharyngeal brain tissue and
      palatoplasty of the cleft palate is an excellent option for treatment of these
      cases.

PMID- 10342614
TI  - Advantages of percutaneous hollow needle technique for iliac bone harvest in
      alveolar cleft grafting.
AB  - OBJECTIVE: To evaluate the percutaneous hollow needle technique for bone harvest
      to determine if morbidity from the bone donor site can be reduced significantly.
      METHODS: A retrospective chart review was performed evaluating all patients
      undergoing alveolar bone grafting at our institution from January 1992 through
      December 1996. Patients who underwent additional major procedures were excluded.
      Group I consisted of 12 patients in whom the percutaneous technique was utilized.
      The patients had an average age of 11.1 years (range: 8 to 15 years). Six were
      male and six were female. One had a bilateral cleft. Group II consisted of 15
      patients in whom the conventional open technique for iliac crest bone harvest was
      used. They had an average age of 13.1 years (range: 7 to 31 years). Six were male
      and nine were female. Two had bilateral clefts. Minimum follow-up was 6 months.
      We evaluated intraoperative blood loss, total postoperative analgesia
      requirement, and length of hospital stay based on a retrospective hospital chart
      review. RESULTS: A significant difference was found between the two groups
      regarding intraoperative blood loss (group I: 83.3 cm3, group II: 208 cm3; p =
      .0015), postoperative total analgesia requirement (group I: 0.04 mg/kg, range: 0
      to 0.17 mg/kg; group II: 0.34 mg/kg, range: 0.03 to 0.74 mg/kg; p = .0002), and
      length of hospital stay (group I: 1.0 days, group II: 2.13 days; p = .0001).
      There was no significant change in these results when bilateral clefts were
      excluded. CONCLUSION: Iliac bone graft harvest using the percutaneous hollow
      needle technique results in less blood loss, decreased postoperative pain, and
      shorter hospital stays compared with the open technique.

PMID- 10342615
TI  - Sternocleidomastoid imbalance versus congenital muscular torticollis: their
      relationship to positional plagiocephaly.
AB  - OBJECTIVE: The purpose of this study was to investigate the existence of
      sternocleidomastoid (SCM) imbalance in a plagiocephalic population and further
      clinically describe its difference, if any, from congenital muscular torticollis
      (CMT). If SCM imbalance is different from CMT, then the development of
      terminology and a differential diagnosis may allow early recognition and
      intervention and possible prevention of positional plagiocephaly in the first
      place. DESIGN: This was a retrospective, random review of 100 patients referred
      for orthotic correction of their positional plagiocephaly. SETTING: The data was
      collected in a private orthotic clinic and was directed by a physical therapist.
      The patients were seen on a weekly or biweekly basis. PATIENTS: Eighty-three
      patients diagnosed with positional plagiocephaly that were referred for Dynamic
      Orthotic Cranioplasty during 1996 were studied. RESULTS: Sixty-four percent of
      the sample was identified as having SCM imbalance and 12% was diagnosed with CMT.
      There were no statistically significant differences between the characteristics
      of these two groups in relation to the etiological factors of positional
      plagiocephaly. The only observed difference was related to symptoms of the neck
      itself. CONCLUSIONS: Seventy-six percent of the sample was found to have some
      degree of SCM dysfunction, whether it be SCM imbalance or CMT. The finding that
      over three quarters of our population suffers from some form of SCM dysfunction,
      either SCM imbalance or CMT, suggests that any degree of SCM dysfunction may act
      as a precursor to positional plagiocephaly and therefore should be recognized and
      treated at the earliest opportunity.

PMID- 10342616
TI  - Assisted feeding is more reliable for infants with clefts--a randomized trial.
AB  - OBJECTIVE: To compare the effectiveness of squeezable and rigid feeding bottles
      for infants with clefts. DESIGN: Patients were randomly assigned at birth to
      feeding with a squeezable bottle (assisted feeding) or to feeding with a rigid
      bottle and were followed for 1 year. The data were analyzed on the basis of
      intention to treat. SETTING: The trial was conducted within the existing
      arrangements for hospital and home care for children with clefts within the
      National Health Service in the north of England. PATIENTS: The patients were 101
      consecutively born children with cleft lip and/or palate who were otherwise
      healthy. All patients completed the trial. Two were excluded from the analysis
      when unrelated developmental problems became apparent. MAIN OUTCOME MEASURES:
      Anthropometric measures-nude weight, crown-heel length (CHL), and occipito
      frontal circumference (OFC)-were recorded. RESULTS: There were statistically
      significant differences between the two groups in weight at 12 months (p = .038,
      with an adjusted mean difference of 0.43 kg) and in head circumference (p = .004
      with an adjusted mean difference of 0.77 cm), indicating increased growth in the
      squeezable bottle group. The difference in CHL was not significant at
      conventional levels (p = .082). Whereas 25 of 52 (48%) rigid bottles required
      modification by the health visitor, this was needed for only 4 of 49 (8%)
      squeezable bottles. There was a highly significant difference when numbers of
      modifications for each method were compared (p < .0001). Despite modifications,
      six infants feeding with a rigid bottle (11%) were transferred to a squeezable
      bottle due to problems with feeding, but none were transferred from squeezable to
      rigid bottles. Thus, the squeezable bottle generally appeared to be a more
      satisfactory method, requiring less support or intervention after initial
      instruction. CONCLUSIONS: Both feeding methods achieved similar anthropometric
      outcomes, with a beneficial effect on head circumference and weight in the
      assisted feeding group. We recommend that this last observation be treated with
      caution. The squeezable bottles were easier to use, and we recommend that they be
      routinely prescribed.

PMID- 10342617
TI  - Mandibular lengthening by distraction osteogenesis in children--a one-year follow
      up study.
AB  - OBJECTIVE: The present study was undertaken to document whether mandibular length
      could be increased by distraction osteogenesis in children and what happens to
      the mandibular position 1 year after the distraction. METHODS: Five patients with
      hemifacial microsomia (four unilateral, one bilateral) had distraction
      osteogenesis performed to lengthen the mandible. All patients had cephalometric
      and panoramic radiographs obtained before and 3, 6, and 12 months after the
      distraction osteogenesis. RESULTS: The total mandibular length (Co-Gn) on the
      affected side was increased by 11.2 mm after the distraction and remained stable
      during a 1-year observation period. However, the increased mandibular length
      tended to move the chin downward (8 mm) more than forward (2 mm) during the same
      period. CONCLUSIONS: Distraction osteogensis can be used to lengthen the
      hypoplastic mandible. However, most of the increased mandibular length moved the
      chin downward more than forward.

PMID- 10342618
TI  - The case for corticosteroids in the treatment of early rheumatoid arthritis.

PMID- 10342619
TI  - Corticosteroids in rheumatoid arthritis--the case against.

PMID- 10342620
TI  - Anniversary: 50 years of glucocorticoid treatment in rheumatoid arthritis.

PMID- 10342621
TI  - Angiogenesis and arthritis.
AB  - Indices of angiogenesis are increased in synovia from patients with arthritis,
      and vascular proliferation may contribute to the pathogenesis of synovitis,
      pannus growth, bone and cartilage destruction, and osteophyte formation.
      Pharmacological inhibition of angiogenesis therefore has potential as a
      therapeutic strategy in human arthritis. However, vascular growth is also
      essential for normal development, female reproduction and tissue repair.
      Selective inhibition of undesirable angiogenesis requires an understanding of the
      different regulatory mechanisms in pathological and physiological angiogenesis.
      This review outlines the evidence that the rate of angiogenesis is increased in
      the inflamed human synovium, and possible approaches to, and consequences of, the
      modulation of vascular growth.

PMID- 10342622
TI  - Changes in articular synovial lining volume measured by magnetic resonance in a
      randomized, double-blind, controlled trial of intra-articular samarium-153
      particulate hydroxyapatite for chronic knee synovitis.
AB  - OBJECTIVE: Magnetic resonance techniques have recently been investigated as tools
      with which to monitor inflammatory joint disease. Our aim was to use a contrast
      enhanced T1-weighted protocol to monitor the short-term changes in knee synovial
      lining volume in a double-blind, randomized, controlled trial of intra-articular
      samarium-153 particulate hydroxyapatite (Sm-153 PHYP). METHODS: Twenty-four out
      patients with chronic knee synovitis, from a cohort who had been recruited to a
      long-term clinical efficacy trial, were recruited for this study. Patients
      received either intra-articular Sm-153 PHYP combined with 40 mg triamcinolone
      hexacetonide or 40 mg intra-articular triamcinolone hexacetonide alone. Synovial
      lining volumes were calculated from three-dimensional T1-weighted contrast
      enhanced images made before and after contrast enhancement with thresholding and
      pixel counting, immediately before and 3 months after treatment. RESULTS: Paired
      pre- and post-treatment magnetic resonance data were obtained for 18/24 (75%)
      patients. There was no significant difference in mean pre-treatment synovial
      volume between the two treatment groups (139 vs 127 ml). A mean reduction in
      synovial lining volume was detected in the Sm-153 PHYP/steroid-treated group (139
      to 110 ml, P = 0.07) and in the steroid-treated group (127 to 58 ml, P < 0.001).
      The reduction was significantly greater in the steroid-treated group (-61% vs 
      23%, P < 0.05). CONCLUSIONS: Short-term changes in articular synovial lining in
      response to intra-articular treatment for chronic synovitis may be monitored by
      magnetic resonance imaging. After 3 months, a greater mean reduction in synovial
      lining volume had occurred in response to intra-articular steroid alone compared
      to combined Sm-153 PHYP/steroid injection.

PMID- 10342623
TI  - Giant cell arteritis and polymyalgia rheumatica: are pregnancies a protective
      factor? A prospective, multicentre case-control study. GRACG (Groupe de Recherche
      sur l'Arterite a Cellules Geantes).
AB  - OBJECTIVE: To assess the potential role of allo-immunization, either by former
      pregnancies, or by a history of blood transfusion, in the pathogenesis of giant
      cell arteritis and polymyalgia rheumatica. METHODS: Two hundred and eighty-five
      incident female cases and 186 age-matched, population-based female controls were
      prospectively included in a multicentre case-control study. RESULTS: The number
      of pregnancies was significantly lower in cases than in controls (nulliparous:
      21.55% vs 12.90%; > or =4 pregnancies: 16.25% vs 27.42%; Wilcoxon rank sum test:
      P = 0.0019) in biopsy-proven or negative temporal arteritis and, to a lesser
      extent, in polymyalgia rheumatica. No difference was found for history of blood
      transfusion. Pregnancies remained negatively associated with the disease in a
      multivariate analysis including cardiovascular risk factors such as smoking or a
      pre-existing peripheral vascular disease. CONCLUSION: Former pregnancies are not
      a risk factor for giant cell arteritis. Pregnancies may be protective thanks to
      an effect of the associated hyperoestrogenic state against alterations of the
      artery wall, as suggested in animal models.

PMID- 10342624
TI  - The 'instantaneous' compressive modulus of human articular cartilage in joints of
      the lower limb.
AB  - METHODS: The instantaneous compressive modulus of articular cartilage was
      surveyed in 11 sets of human lower limb joints obtained from the ipsilateral
      side. The average modulus for the entire joint surface of each joint and the
      topographical variations in the modulus within each joint were examined for all
      11 sets, and subjected to statistical analysis. RESULTS: Within each set of
      joints (hip, knee and ankle), the ankle always had a significantly greater mean
      compressive modulus than the hip and knee (P < 0.001-P < 0.05). In seven sets of
      joints, there was no significant difference between the mean compressive moduli
      of the knee and hip joints. In three sets of joints, the compressive modulus of
      the knee was significantly greater than that of the hip (P < 0.001-P < 0.01),
      while in only one set of joints was the compressive modulus of the hip
      significantly greater than that of the knee (P < 0.01). CONCLUSION: The
      topographical variations in the cartilage instantaneous compressive modulus over
      the surfaces of the lower limb joints were matched by differences in the stresses
      occurring in different areas of each joint. The results of the present study
      corroborate previous findings and show that the site-specific stresses and
      corresponding values of the instantaneous cartilage compressive modulus over the
      surfaces of lower limb joints were correlated (r = 0.82 at P < 0.01), thus adding
      credence to the conditioning hypothesis of cartilage by prevalent stress.

PMID- 10342625
TI  - Comparison of free and peptide-bound pyridinoline cross-links excretion in
      rheumatoid arthritis and osteoarthritis.
AB  - OBJECTIVE: To investigate urinary fractions of free and peptide forms of
      pyridinoline cross-links in arthritis. PATIENTS AND METHODS: The free and total
      forms of pyridinoline (Pyr) and deoxypyridinoline (Dpyr) were measured by high
      performance liquid chromatography (HPLC) in 30 pre-menopausal and 22 post
      menopausal normal women, 38 women with rheumatoid arthritis (RA) and 62 women
      with osteoarthritis (OA). Peptide forms were calculated as total minus free. Free
      Dpyr and peptide form were also measured by deoxypyridinoline and carboxy
      terminal telopeptide of type I collagen (CTx) immunoassays. RESULTS: In normal
      women, all fractions of Pyr and Dpyr and immunoassays were elevated in post
      menopause compared to pre-menopause. In post-menopausal normal women, the free
      form increased more than the peptide form. In RA, an increase in the fractions of
      Pyr was greater than Dpyr. Peptide and total cross-links correlated with the
      disease activity of RA and they were elevated in RA patients with high disease
      activity. Free Dpyr and CTx were significantly lower in OA than in normal women.
      Peptide and total Pyr and Dpyr, and immunoassayed Dpyr were significantly higher
      in the radiographic later stage of OA than in the early stage of OA. CONCLUSIONS:
      The menopause, RA and OA may have different effects on the urinary excretion of
      free and peptide-bound pyridinoline cross-links.

PMID- 10342626
TI  - Characteristics of septic arthritis in human immunodeficiency virus-infected
      haemophiliacs versus other risk groups.
AB  - The cases are presented of four haemophiliacs infected with human
      immunodeficiency virus (HIV) and with septic arthritis among the 340 patients
      followed at our centre. The data of these cases and 39 additional HIV-infected
      haemophiliacs with septic arthritis, identified in a literature search, are
      reviewed. The spectrum of bacterial pathogens is limited and somewhat different
      from that in other risk groups. The localization is exclusively to joints
      affected by haemophilic arthropathy. The laboratory picture is characterized by
      the absence of peripheral leucocytosis, varying CD4-helper cell counts, a high
      erythrocyte sedimentation rate and fever. The clinical picture mimics that of
      haemarthrosis, often causing a delay in diagnosis. Treatment with systemic
      antibiotics is often sufficient, obviating the need for arthrotomy and open
      drainage. Prognosis related to the joint function is relatively good, but poor
      when related to the medium- to long-term survival of the patient.

PMID- 10342627
TI  - A systematic review of randomized controlled trials of acupuncture for neck pain.
AB  - OBJECTIVE: To establish whether there is evidence for or against the efficacy of
      acupuncture in the treatment of neck pain. METHODS: A systematic literature
      review was undertaken of studies that compared needle or laser acupuncture with a
      control procedure for the treatment of neck pain. Two reviewers independently
      extracted data concerning study methods, quality and outcome. RESULTS: Overall,
      the outcomes of 14 randomized controlled trials were equally balanced between
      positive and negative. Acupuncture was superior to waiting-list in one study, and
      either equal or superior to physiotherapy in three studies. Needle acupuncture
      was not superior to indistinguishable sham control in four out of five studies.
      Of the eight high-quality trials, five were negative. CONCLUSIONS: In conclusion,
      the hypothesis that acupuncture is efficacious in the treatment of neck pain is
      not based on the available evidence from sound clinical trials. Further studies
      are justified.

PMID- 10342628
TI  - MIA (melanoma inhibitory activity): a potential serum marker for rheumatoid
      arthritis.
AB  - OBJECTIVE: MIA (melanoma inhibitory activity) is correlated with metastasis in
      patients with malignant melanoma. As MIA is not only produced by melanoma cells,
      but also by differentiated chondrocytes, we examined whether serum levels of MIA
      are correlated with inflammation and/or joint destruction in rheumatic diseases.
      METHODS: MIA serum concentrations of patients with different rheumatic diseases
      were examined and compared with healthy individuals and malignant melanoma
      patients. In addition, MIA concentrations were correlated to inflammatory
      parameters and joint destruction. RESULTS: Increased MIA serum concentrations
      were found only in patients with rheumatic diseases associated with joint
      destruction, such as rheumatoid arthritis (RA), osteoarthritis, HLA B27
      associated oligoarthritis, and psoriatic arthritis. Of these rheumatic diseases,
      a significant increase in MIA serum concentrations was seen only in patients with
      RA, associated with rheumatoid factor (RF) positivity and joint destruction.
      CONCLUSIONS: In addition to RF, MIA might therefore be useful in the differential
      diagnosis of RA vs non-destructive rheumatic diseases, and the presence of
      elevated levels of MIA in serum very likely reflects joint destruction in RA.

PMID- 10342629
TI  - Sensitivity and specificity of anti-Sa autoantibodies for rheumatoid arthritis.
AB  - OBJECTIVE: To assess the sensitivity and specificity of the recently described
      anti-Sa autoantibodies in order to determine their potential usefulness for the
      diagnosis of rheumatoid arthritis (RA). METHODS: Sera from 67 patients with RA
      (including 31 patients with early RA of <3 months duration), from 180 patients
      with other rheumatic diseases and from 30 healthy control subjects were
      investigated by immunoblotting employing partially purified Sa antigen.
      Additionally, all sera were tested for rheumatoid factor (RF), anti-A2/RA33,
      antinuclear antibodies (ANA) and ANA subsets. RESULTS: Twenty-one (31%) of the 67
      patients with RA, but only four of the 180 control patients, were anti-Sa
      positive; therefore, anti-Sa was approximately 98% specific for RA. Anti-Sa was
      not associated with either RF or with anti-A2/RA33. The latter antibody was
      present in 21 RA sera, only eight of which also contained anti-Sa. Thus, 34 RA
      sera (51%) showed at least one of these two autoantibodies and, importantly, 18
      of these sera were RF negative. Furthermore, of the 31 patients with early RA, 12
      (40%) were anti-Sa and/or anti-A2/RA33 positive. CONCLUSION: Although the numbers
      studied remain small, taken together, these data suggest that anti-Sa may
      represent a promising novel serological marker with high specificity for RA.

PMID- 10342630
TI  - The long-term course of shoulder complaints: a prospective study in general
      practice.
AB  - OBJECTIVE: Assessment of the long-term course of shoulder complaints in patients
      in general practice with special focus on changes in diagnostic category and
      fluctuations in the severity of the complaints. DESIGN: Prospective descriptive
      study. SETTING: Four general practices in The Netherlands. METHOD: All patients
      (101) with shoulder complaints seen in a 5 month period were included. Assessment
      took place 26 weeks and 12-18 months after inclusion in the study with a pain
      questionnaire and a physical examination. RESULTS: A total of 51% of the patients
      experienced (mostly recurrent) complaints after 26 weeks and 41% after 12-18
      months. Diagnostic changes were found over the course of time, mostly from
      synovial disorders towards functional disorders of the structures of the shoulder
      girdle, but also the other way round. Although 52 of the 101 patients experienced
      complaints in week 26, 62% of those patients considered themselves 'cured'. After
      12-18 months, 51% of the 39 patients experiencing complaints felt 'cured'.
      CONCLUSION: Many patients seen with shoulder complaints in general practice have
      recurrent complaints. The nature of these complaints varies considerably over the
      course of time, leading to changes in diagnostic category. Because of the
      fluctuating severity of the complaints over time, feeling 'cured' or not 'cured'
      is also subject to change over time.

PMID- 10342631
TI  - Prevalence of Sjogren's syndrome in Slovenia.
AB  - OBJECTIVE: The aim of our study was to determine the prevalence of Sjogren's
      syndrome (SS) in Slovenia. METHODS: A total of 889 randomly selected adults were
      invited to take part in our study. The classification of SS was based on the
      validated criteria reported by a multicentre study performed in Europe. The
      participants were asked six simple questions for assessing both ocular and oral
      involvement. Information on co-morbidities and related treatment was collected at
      the same time. All participants were subjected to a Schirmer-I test, an
      unstimulated salivary flow test, as well as serological studies (rheumatoid
      factor, antinuclear antibodies, anti-Ro/SS-A and anti-La/SS-B antibodies). When
      indicated, Rose Bengal score, salivary scintigraphy and histopathological
      investigation of the minor salivary glands were carried out until three out of
      the six European classification criteria for SS were shown to be negative or
      until SS was diagnosed. RESULTS: Out of the 889 invited subjects, 332 (37.3%)
      participated in our study: 183 females, mean age (+/- S.D.) 52.2 +/- 13.7 yr
      (range 20-84) and 149 males, mean age (+/- S.D.) 56.3 +/- 12.9 yr (range 23-84).
      After the first visit, 244 of the 332 (73.5%) participants proved to be negative
      for three out of the six above-mentioned criteria, and were eliminated from
      further tests. The remaining 88 participants were consecutively subjected to Rose
      Bengal score, salivary scintigraphy and minor salivary gland biopsy. Fifteen
      participants refused to perform either one or more of the proposed tests at the
      second study stage. Two females of the 332 study participants [0.60% (exact 95%
      CI 0.07%, 2.16%)] fulfilled the criteria for primary SS. CONCLUSIONS: The
      estimated prevalence of definite SS in Slovenia is 0.60%.

PMID- 10342632
TI  - Absence of association between interleukin 1 alpha and oligoarticular juvenile
      chronic arthritis in UK patients.
AB  - OBJECTIVE: To determine whether interleukin 1 alpha (IL-1alpha) polymorphisms are
      associated with UK oligoarticular juvenile chronic arthritis (JCA). PATIENTS AND
      CONTROLS: A well-characterized population of 164 UK Caucasian oligo-JCA patients
      and a control panel of 173 unrelated healthy UK Caucasian individuals. METHODS:
      The IL-1alpha promoter mutation at -889 was examined using a polymerase chain
      reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The cases and
      controls were also genotyped for an IL-1alpha intronic microsatellite repeat.
      RESULTS: No association was observed between IL-1alpha polymorphisms and UK
      oligoarticular JCA patients. In particular, no association between IL-1alpha
      polymorphisms and chronic anterior uveitis was found. CONCLUSIONS: IL-1alpha is
      not associated with oligoarticular JCA in UK patients. This differs markedly to
      findings for IL-1alpha in Norwegian JCA patients.

PMID- 10342633
TI  - Responsiveness of outcome measures in juvenile chronic arthritis. Italian
      Pediatric Rheumatology Study Group.
AB  - OBJECTIVE: To examine the responsiveness of the disease activity measures more
      commonly used in juvenile chronic arthritis (JCA) clinical trials. METHODS: Data
      were obtained from an open-label, non-controlled, multicentre trial designed to
      investigate the efficacy of methotrexate (MTX) in children with JCA. Outcome
      measures, including physician and parent global assessments, functional ability
      measures, articular variables, and laboratory indicators of systemic
      inflammation, were assessed at baseline and after 6 months of MTX treatment in
      132 patients. Responsiveness of endpoint variables was evaluated by assessing the
      effect size (ES) and the standardized response median (SRM). RESULTS: Physician
      and parent global assessments were the more responsive instruments, showing ES
      and SRM above 1.0. Erythrocyte sedimentation rate, C-reactive protein, functional
      status measures and articular variables showed intermediate responsiveness.
      Morning stiffness, haemoglobin and platelet count were the least responsive
      instruments. CONCLUSION: The results of our analysis indicate that subjective
      estimations of the disease activity, either by the physician or parents, are the
      most responsive instruments in the assessment of the therapeutic response in
      children with JCA. The responsiveness of outcome measures in JCA should be
      further investigated in prospective controlled studies.

PMID- 10342634
TI  - High-dose chemotherapy in rheumatoid arthritis: a report of five cases.

PMID- 10342636
TI  - Destructive joint lesions and bursitis in idiopathic hypereosinophilic syndrome.

PMID- 10342635
TI  - Successful treatment of polyarteritis nodosa related to hepatitis B virus with a
      combination of lamivudine and interferon alpha.

PMID- 10342637
TI  - Decreased TCR AV24AJ18+ double-negative T cells in rheumatoid synovium.

PMID- 10342638
TI  - Giant cell arteritis presenting as lateral medullary syndrome.

PMID- 10342639
TI  - Normotensive renal failure in a patient with systemic sclerosis and p
      antineutrophil cytoplasmic autoantibodies which developed into Paget's disease of
      bone after immunosuppressive therapy.

PMID- 10342640
TI  - The association of optic neuropathy with transverse myelitis in systemic lupus
      erythematosus.

PMID- 10342641
TI  - What's new in HIV.

PMID- 10342642
TI  - How I encourage my patients to take their antiretroviral therapy regularly.

PMID- 10342643
TI  - Long-term non-progression in HIV infection: clinico pathological issues.

PMID- 10342644
TI  - Long-term non-progression in HIV infection: definitions and epidemiological
      issues.

PMID- 10342645
TI  - The tuberculosis pandemic--which way now?

PMID- 10342646
TI  - Strain typing of Mycobacterium tuberculosis.

PMID- 10342647
TI  - Infective endocarditis: an epidemiological review of 128 episodes.
AB  - OBJECTIVES: The objective was to determine the current epidemiology of infective
      endocarditis. PATIENTS AND METHODS: All microbiologically positive episodes of
      infective endocarditis treated at The University Hospital of Wales over a 9-year
      period from March 1987 to March 1996 was reviewed. Patients originated from the
      catchment area of The University Hospital of Wales or were referred from other
      hospitals in Wales. Data extraction was from records held in the Microbiology
      Department and, whenever possible, from patients' casenotes. The epidemiological
      parameters were: (1) age and sex of patients; (2) distribution of affected sites;
      (3) frequency of predisposing risk factors (cardiac and extracardiac); (4)
      incidence of early prosthetic valve endocarditis; and (5) mortality rates.
      RESULTS: There were 128 microbiologically positive episodes of endocarditis in
      125 patients. The mean age of the population was 53.1 years and the aortic valve
      was the most frequently involved site of infection (51.6%). A presumed source of
      infection was identified in 20% if episodes. The commonest predisposing cardiac
      risk factor in native valve episodes was bicuspid aortic valve (16.7%) but there
      was no identifiable cardiac risk factor in a much larger proportion (37.7%) of
      native valve episodes. There was a low incidence (0.6%) of culture positive early
      prosthetic valve episodes and low mortality rates for both native and prosthetic
      valve endocarditis (12.3% and 24.5%) in this study. Viridans streptococci were
      the predominant organisms. In prosthetic valve episodes with onset after the 60th
      postoperative day but within one postoperative year the identity of the isolate
      suggested, in most cases, perioperative valve contamination. CONCLUSIONS: The
      epidemiology of infective endocarditis has undergone significant change.
      Inability to detect clinically common predisposing lesions, and the frequent
      absence of any identifiable predisposing cardiac risk factor mean that initial
      diagnosis is often difficult and demands a high index of suspicion. There was a
      low incidence of culture positive early prosthetic valve episodes and there were
      low mortality rates for both native and prosthetic valve endocarditis; these
      figures suggest improvements in cardiac care. The microbiological evidence
      indicates that the duration of the postoperative time period used for classifying
      prosthetic valve endocarditis into 'early' and 'late' episodes should be extended
      from 60 days to 1 year.

PMID- 10342648
TI  - Diagnostic usefulness of percutaneous liver biopsy in HIV-infected patients with
      fever of unknown origin.
AB  - OBJECTIVES: to determine the value of percutaneous liver biopsy (PLB) in the
      diagnosis of fever of unknown origin (FUO) in HIV-infected patients and establish
      a prediction model for its usefulness to enable diagnosis of FUO in these
      patients to be standardized. METHODS: a total of 58 HIV-infected patients who
      underwent PLB for the evaluation of FUO were studied at 'Carlos Haya' Hospital in
      Malaga, Spain. The patients were classified into three groups, according to the
      results of the PLB: (a) diagnostic PLB (when a definitive diagnosis was
      obtained); (b) helpful PLB (the tissue sample showed suggestive, but not
      definitive, findings); and (c) normal or non-specific PLB (no contribution to
      diagnosis, the findings being normal or irrelevant). Multivariate analysis was
      made to establish a prediction model for the diagnostic usefulness of PLB,
      calculating the positive (PPV) and negative (NPV) predictive values. RESULTS: PLB
      was carried out in 58 HIV-infected patients during diagnosis of FUO. Risk factors
      for HIV infection included intravenous drug use (72.4%), homosexual or bisexual
      activities (12.1%), and heterosexual transmission (15.5%). Fifty-two out of 58
      patients (89.6%) had previous AIDS-defining illnesses. The mean CD4 lymphocyte
      count +/-SD was 56.4+/-80.9/mm3. The mean duration of fever was 43 days.
      Diagnosis could be established in 51 (87.9%) patients, with tuberculosis (50%)
      and leishmaniasis (20.7%) being the most common. The PLB was diagnostic in 25
      cases (43.1%), helpful in 13 (22.4%), and normal or non-specific in the remaining
      20 (34.5%). Biopsy-associated complications occurred in two cases. The presence
      of hepatomegaly or splenomegaly were the most useful factors in predicting the
      usefulness of the PLB, with a PPV of 86.1% and NPV of 68.2%. In patients with
      tuberculosis, an increased alkaline phosphatase and hepatomegaly had a PPV of
      86.4% and a NPV of 71.4%. CONCLUSIONS: PLB is a useful technique for the
      diagnosis of FUO in HIV-infected persons. Early PLB should be considered in those
      patients with hepatosplenomegaly and increased alkaline phosphatase levels.

PMID- 10342649
TI  - Evidence that patients with rheumatoid arthritis have asymptomatic 'non
      significant' Proteus mirabilis bacteriuria more frequently than healthy controls.
AB  - OBJECTIVES: patients with rheumatoid arthritis (RA) are reported to have in their
      sera raised levels of antibody specific to Proteus mirabilis. The aim of the
      study was to verify this and to determine an explanation for it by investigating
      the frequency of P. mirabilis urinary tract infection in RA patients and matched
      controls. METHODS: freshly voided urine was examined for the presence, number and
      identity of infecting bacteria. The levels of antibody in blood and in urine of
      the IgM, IgA and IgG classes to the common O serotypes of P. mirabilis and the
      antigens to which they reacted were determined by enzyme-linked immunosorbent
      assay (ELISA) and immunoblotting. RESULTS: analysis of urine from 76 patients
      with RA and 48 age- and gender-matched healthy controls showed that only two (4%)
      of the control urines but 25 (33%) of those from the RA patients were infected.
      The commonest infecting organism in the RA patients' urine was Proteus mirabilis
      which occurred twice as frequently as Escherichia coli. Proteus mirabilis was
      found in 52% of the infected urines of the RA patients and was always detected as
      a pure growth and usually in insignificant (< 10(4)/ml) numbers. It is highly
      improbable that this finding was the outcome of differences in age, physical
      ability or medication between the RA and control patient groups. Comparison of
      antibody levels to P. mirabilis by ELISA showed RA patients had raised (P <
      0.0001, P = 0.001, P = 0.0063) levels of IgA, IgG and IgM respectively in their
      sera and raised (P < 0.0001, P < 0.0001, P = 0.0001) levels of IgG, IgM and IgA
      respectively in their urine compared with the control group. It was not possible
      to detect an antibody reacting to a P. mirabilis antigen that was specific to the
      RA patients. CONCLUSION: the results confirm that RA patients have raised levels
      of antibody to P. mirabilis not only in blood but also in urine and suggest that
      this arises because RA patients have an asymptomatic, non-significant P.
      mirabilis bacteriuria more frequently or more prolonged than control patients.
      This may be the trigger for their RA condition.

PMID- 10342650
TI  - Epidemiology and outcome of HIV infection in North-East Scotland (1985-1997).
AB  - OBJECTIVE: to assess the epidemiology of HIV infection in North-East Scotland.
      METHODS: retrospective casenote review of all HIV-infected patients who have had
      contact with the Infection Unit in Aberdeen. RESULTS: one hundred and forty-two
      HIV-infected patients were treated between April 1985 and December 1997. The risk
      behaviour related to the acquisition of the HIV infection was: 56 (39%)
      homosexually infected, 45 (32%) heterosexually-infected, 34 (24%) injecting drug
      users (IDUs), and seven (5%) blood products or not known. Sixteen of the 45 (36%)
      heterosexually-infected patients were native to Africa and 16 of the 34 (31%)
      IDUs were prisoners in Peterhead prison at the time of referral. Fifty-two (37%)
      of the cohort continue to attend the Infection Unit, 41 (29%) have relocated, 40
      (28%) have died and nine (6%) have been lost to follow-up. The ratio of
      heterosexual:homosexual men:IDUs changed significantly between the first 7 years
      (12:21:25) and the second 6 years (33:35:9) of the review, with significantly
      more patients being infected through heterosexual contact and fewer infected by
      IDU in the second period-P<0.001. The median AIDS survival was 17 months.
      Survival was significantly longer in those patients who took anti-retroviral
      therapy (median = 20 months) than in the patients who opted not to take anti
      retroviral therapy (median = 11 months)-P<0.01. CONCLUSIONS: Although homosexual
      contact represents the commonest risk group for HIV infection in this region, the
      number of heterosexually-infected patients has increased significantly in the
      last 5 years. Temporary residents account for one-third of the HIV-infected
      population cared for in NE Scotland. Almost half of those lost to follow-up have
      returned to Africa or been released from prison. The introduction of anti
      retroviral therapy has resulted in a dramatic improvement in AIDS survival in our
      cohort as it has done elsewhere.

PMID- 10342651
TI  - Desensitization to co-trimoxazole (trimethoprim-sulphamethoxazole) in HIV
      infected patients: is patch testing a useful predictor of reaction?
AB  - OBJECTIVE: To establish the safety and efficacy of desensitization to co
      trimoxazole in hypersensitive HIV-infected subjects. To assess if delayed
      hypersensitivity (type IV) to co-trimoxazole predicts those unable to be
      desensitized. METHOD: desensitization to co-trimoxazole, comprising trimethoprim
      (T) 0.4 mg and sulphamethoxazole (S) 2 mg initially with doubling dose daily,
      full strength co-trimoxazole (T/S 160 mg/800 mg) at 10 days. Patch testing with
      4.5% and 9% co-trimoxazole in yellow soft paraffin, CMI Multitest. RESULTS:
      nineteen patients, 18 male and one female, were recruited and completed the
      desensitization regime. Of these 80%(15) achieved successful desensitization.
      Three of those who reacted did so within 18 days. All patients were successfully
      managed in an outpatient setting. There were no major adverse reactions. Of those
      reacting none gave a positive patch test to co-trimoxazole and all showed absent
      delayed type hypersensitivity reactions to recall antigens. CONCLUSIONS: co
      trimoxazole desensitization is a safe and efficacious procedure, with a success
      rate of 80% using the above regime. Patch testing with co-trimoxazole gives no
      useful information about those that reacted.

PMID- 10342652
TI  - Herpes zoster and its complications in Italy: an observational survey.
AB  - OBJECTIVES: To estimate the rate of Herpes zoster and its complications in Italy.
      METHODS: this is an observational, retrospective study carried out by
      Dermatologists, Geriatric Doctors and General Practitioners. Details on
      demography, clinical and therapeutic aspects were reported on record forms. The
      rate of Herpes zoster was only calculated for patients aged 15 years or more,
      attending General Practitioners because this was the only group where the number
      of patients at risk was known. The hypothesis that the rate of complications
      depends on sex, age and number of affected dermatomes was explored through
      univariate (Chi-square tests) and multivariate (logistic regression) analysis.
      RESULTS: the number of cases of Herpes zoster examined by General Practitioners
      was 4.1 persons aged 15 years or more/1000/year. Usually, only one dermatome was
      affected, most frequently the thoracic one. Overall the rate of complications was
      26.1% The rate of complications is significantly higher (P = 0.001) in patients
      with two or more affected dermatomes, it is positively correlated to age while
      difference by sex is not significant (P = 0.297). Practically all patients
      received treatment for their disease. CONCLUSIONS: this is the first
      epidemiological study on Herpes zoster that has been conducted in Italy. It
      indicates that annually there are about 200 000 people aged 15 years and over
      suffering from Herpes zoster in Italy, with a considerable number of cases of
      post herpetic neuralgia.

PMID- 10342653
TI  - Prevalence of hepatitis A in an institution for the mentally retarded in an
      intermediate endemicity area: influence of age length of institutionalization.
AB  - OBJECTIVE: This study aimed to examine the prevalence of antibodies against
      hepatitis A (anti-HAV) in a population of institutionalized mentally retarded
      persons compared with that of institutionalized non-mentally retarded persons in
      an area with moderate endemicity of HAV infection. METHODS: The study population
      was a group of mentally retarded persons aged between 10 and 30 years,
      institutionalized in one residence in Madrid, Spain. A group of non-mentally
      retarded subjects in the same age range was chosen as controls. Information about
      demography and duration of institutionalization was obtained by the investigator.
      Four drops of whole blood were obtained from each person by finger-stick,
      collected on filter paper, air-dried and stored at +4 degrees C until antibody
      determination. Eluates were tested by an ELISA method. RESULTS: A total of 314
      institutionalized subjects were included: 157 mentally retarded (mean age and
      mean duration of institutionalization were 24.4+/-3 and 9.7+/-5 years
      respectively) and 157 non-mentally retarded (mean age and mean duration of
      institutionalization were 19.2+/-5 and 4.6+/-3 years respectively). The
      prevalence of anti-HAV antibody was 54% (95% confidence interval (CI) 50-58) in
      mentally retarded and 22% (95% CI 19-25) in non-mentally retarded [P<0.001; odds
      ratio (OR): 4.2 (95% CI 2.5-7)]. In both groups, these differences were not
      statistically significant for anti-HAV antibody prevalence between persons
      institutionalized for >5 years compared with those institutionalized for < or = 5
      years. CONCLUSIONS: There results indicate that in an area of moderate endemicity
      the institutionalized mentally retarded are at increased risk of having acquired
      hepatitis A infection compared to the non-mentally retarded. In these
      institutionalized persons, regardless whether they are mentally retarded or not,
      prevalence is not influenced by age or length of stay in institutions.

PMID- 10342654
TI  - Edwardsiella tarda bacteraemia--complicated by acute pancreatitis and pyomyoma.
AB  - Edwardsiella tarda (E. tarda) has recently become recognized as a pathogen in
      humans. Here we report a new case of E. tarda bacteraemia complicated by acute
      pancreatitis and pyomyoma. A 46-year-old female came to our emergency room
      complaining of sudden onset of left upper quadrant pain and vomiting for the
      previous few hours after drinking three bottles of wine. An abdominal computed
      tomography (CT) scan revealed multiple biliary stones, acute pancreatitis with
      extensive inflammatory change, and a large uterine myoma. Fever, watery
      diarrhoea, and mild suprapubic discomfort with vaginal spotting were noted soon
      after admission. The patient's blood cultures yielded E. tarda and symptoms
      subsided after antibiotic therapy. Fever and severe suprapubic pain with rebound
      tenderness developed 12 days later. Repeat abdominal CT scan revealed an enlarged
      uterine myoma with central necrosis. The patient subsequently underwent anterior
      total hysterectomy and bilateral salpingo-oophorectomy, revealing a uterine myoma
      with infarction and abscess formation. The patient recovered uneventfully and was
      discharged 1 week later.

PMID- 10342655
TI  - Septic arthritis caused by Corynebacterium amycolatum following vascular graft
      sepsis.
AB  - A case of septic arthritis caused by Corynebacterium amycolatum in a native hip
      joint occurred in an adult man following contralateral vascular graft sepsis, and
      was successfully treated with intravenous vancomycin followed by oral doxycycline
      and rifampicin. To the authors' knowledge, this is the only reported case of
      septic arthritis due to C. amycolatum.

PMID- 10342656
TI  - Fatal Clostridium sordellii ischio-rectal abscess with septicaemia complicating
      ultrasound-guided transrectal prostate biopsy.
AB  - Clostridium sordellii is a Gram-positive spore-forming anaerobic bacillus rarely
      encountered in human infection. A case of C. sordellii ischio-rectal abscess with
      rapidly fatal septicaemia is described which complicated ultrasound-guided
      transrectal biopsy of the prostate, despite ciprofloxacin prophylaxis. Neither C.
      sordellii ischio-rectal abscess nor ischio-rectal abscess complicating
      transrectal biopsy have been reported previously. Judging from our experience and
      the reviewed literature, the addition of prophylactic anti-anaerobe drugs should
      be strongly considered until an optimal prophylactic regimen will be defined by
      randomized controlled trials.

PMID- 10342657
TI  - Candida parapsilosis: an unusual organism causing prosthetic heart valve
      infective endocarditis.
AB  - We report a case of Candida parapsilosis prosthetic heart valve infective
      endocarditis in a 67-year-old man. The infection was successfully treated with
      liposomal amphotericin B (AmBisome) and flucytosine. Surgical replacement of the
      infected valve was necessary. Recurrence was prevented with oral fluconazole
      400mg daily as maintenance therapy. The patient remained well after 2 years of
      follow-up.

PMID- 10342658
TI  - Catalase-negative Staphylococcus aureus septicaemia.

PMID- 10342659
TI  - Postoperative adult respiratory distress syndrome (ARDS) due to Pasteurella
      multocida.

PMID- 10342660
TI  - 'Deep throat' cellulitis.

PMID- 10342661
TI  - Ochrobactrum anthropi meningitis in a pre-term neonate.

PMID- 10342662
TI  - The key role of histamine in the development of atherosclerosis and coronary
      heart disease.
AB  - Vitamin C-deficiency is known to cause a disturbance of cholesterol metabolism.
      Suboptimal plasma ascorbic acid levels also cause increased blood histamine
      levels, which are exaggerated by sleep-lack and other forms of stress.
      Histaminemia causes separation of vascular endothelial cells. It is here
      suggested that the histaminemia of stress and ascorbate depletion combine to
      cause damage to the arterial endothelium and predispose to atherosclerosis, the
      principal cause of myocardial infarction.

PMID- 10342663
TI  - Reduction of redundant neural network activation during the performance of a
      task: a functional model applied to problem-solving strategies.
AB  - Problem-solving is explained by various paradigms. For example, epistemological
      paradigms state that, when the task is novel, and pursued of one's free will,
      problem-solving occurs in discontinuous, discernable phases. It is then also a
      microdevelopmental process, i.e. involves the construction of knowledge through
      qualitatively different stages of thought. Quantitative methods are used to focus
      on the redundancy of function as well as the concept of selective activation of
      the brains's neural network during the performance of a task. In this model, the
      following are identified: (a) performance circuits: (i) NP, no performance; (ii)
      LP, low performance; (iii) MP, medium performance; (iv) HP, high performance; and
      (v) VHR, very high performance; (b) task performance groups: (i) NOU, no outline
      used; (serves as a control); (ii) OU, outline used; (iii) MOU, modified outline
      used; (iv) QMOU, qualitatively and quantitatively modified outline used. An
      example of a distribution that one obtains is (for the efficiency of activation
      of the HP): QMOU:MOU:OU. NOU is in the ratio of: 400:100:50:5 (out of 10(3)
      trials). The subject is hence educated as to the mechanism of various strategies
      that he may use in everyday problem-solving.

PMID- 10342664
TI  - Centriole duplication and orientation in mammalian cells.
AB  - The paper discusses a mechanism for semiconservative duplication of a pair of
      centrioles from a single parent. The mechanism accounts for the (transient or
      permanent) quasi-orthogonality of mammalian centrioles.

PMID- 10342665
TI  - Organ metabolic rates and aging: two hypotheses.
AB  - There is currently no satisfactory explanation for caloric restriction's (CR's)
      well-established ability to reduce the rate of aging. Pearl's rate of living
      theory postulates a direct relationship between metabolic rates and the rate of
      aging, but CR, exercise and cold-exposure studies have shown that this theory is
      not valid in rodents with respect to whole-body energy metabolism. The present
      paper describes a crude analysis of previously published data from rat CR, wheel
      running and cold exposure studies, which reached two main conclusions. The first
      is that there appears to be a direct relationship between organ metabolic rates
      and the rate of aging. The second is that organ basal metabolic rates (BMRs)
      decrease by about one-quarter during adulthood in the rat. On the basis of these
      findings, the following two hypotheses are proposed: (1) the rate of living
      theory is valid in mammalian organ; (2) organ BMRs decrease by about one-quarter
      in adulthood in mammals. This hypothesized decrease, if confirmed in humans,
      would be a major component of the well-established age-related decrease in whole
      body resting metabolic rate in humans.

PMID- 10342666
TI  - Etiology of ovarian cancer: a proposed mechanism.
AB  - The majority of ovarian cancers are derived from ovarian surface epithelial cells
      that are sequestered in inclusion cysts within the ovarian stroma. We propose
      that the Fas/Fas ligand system is responsible for the normal elimination of these
      inclusion cysts through apoptosis, thereby removing potential sites of ovarian
      tumors. Furthermore, we hypothesize that the failure of the Fas/Fas ligand's
      apoptotic signaling mechanism leads to the persistence of these inclusion cysts
      in the stroma, and the onset of ovarian tumorigenesis.

PMID- 10342667
TI  - Chronic inflammation and cancer: potential role of Bcl-2 gene family members as
      regulators of cellular antioxidant status.
AB  - The incidence of cancer is increased in all gastrointestinal (GI) tissues as a
      result of chronic inflammation. These cancers may develop in cells that are
      selected for resistance to inflammatory products by virtue of overexpressing the
      antioxidant protein Bcl-2 or other Bcl-2 gene family members that have
      antioxidant activity. Unfortunately, Bcl-2 also functions as an anti-apoptotic.
      Bcl-2 overexpression can increase cellular lifetime and increase the likelihood
      that other cancer-related mutations will accumulate in individual cells. Thus,
      Bcl-2 expression is cytoprotective, but its expression also increases the risk of
      cancer incidence. This is perhaps more evident in the GI tract, which is exposed
      to more potential mutagens relative to other tissues.

PMID- 10342668
TI  - Basic philosophy and concepts underlying scientific peer review.
AB  - The peer review system does not always detect fraud, plagiarism, poor quality or
      gross error and there is editorial reluctance to correct errors or to publish
      criticisms of sacred cows or 'controversial' or nonconformist views of sceptics
      and dissident minorities. Mediocrity is thereby perpetuated, with highly
      innovative science stifled by the conflict of interest and reviewer shortcomings
      underlying the review system. The effective court of appeal should be the editor.
      Self-correction of review procedures is recommended by: (i) improving the
      editorial quality control of peer reviews; (ii) abolition of the cloak of secrecy
      and anonymity of reviewers; and (iii) active encouragement of critical debate of
      unorthodox submissions.

PMID- 10342669
TI  - Histamine and prostaglandins in schizophrenia: revisited.
AB  - It has long been accepted that schizophrenia is primarily a physical illness
      resulting from a chemical imbalance in the brain. This paper will review evidence
      supporting the hypothesis that histamine and prostaglandins are both linked and
      primary in the etiology of schizophrenia. Furthermore, their etiological
      significance supersedes the role of dopamine as a primary causative factor.

PMID- 10342670
TI  - Pharmacotherapy and psychotherapy in the treatment of psychiatric disturbances.
AB  - The type of treatment that most psychiatric disturbances receive at present is a
      mixture of pharmacotherapy and psychotherapy, following the principle that mental
      functions are the result of the activities of brain machinery subsequent to the
      interaction between individuals and their external environment. We now know the
      molecular mechanism of action of several psychoactive drugs but have scant
      understanding of the correlation between molecular events and mental function. As
      for psychotherapy, we know that it may have beneficial effects on patients'
      behavior but ignore the issue of whether this has any correlate at molecular
      level. A black box still exists between drugs, neurotransmitters, receptors, and
      the higher brain functions defined as anxiety, emotion, arousal, etc. Yet mental
      treatments imply a therapeutic method in which the blend of drugs and words
      administered to patients is determined by the choice of the therapist and by the
      specific pathology recognized through clinical diagnosis. In this
      epistemologically confused situation, the pharmaceutical industry is playing a
      major role in orientating the medical profession towards the use of more and more
      powerful neurotropic substances with very detailed molecular actions and plenty
      of side-effects. Nevertheless, the use of psychotropic drugs has allowed the
      opening of the psychiatric hospitals and the 'liberation' of millions of
      psychiatric patients. This beneficial effect is counterbalanced by the dependency
      of millions of individuals on psychotropic drugs. The situation leads to a number
      of questions relative to the possible links among words, molecules, and
      behaviors. The present paper illustrates a theoretical model which can be used to
      compare and contrast psychotherapy and pharmacotherapy.

PMID- 10342671
TI  - The hypogonadal-obesity cycle: role of aromatase in modulating the testosterone
      estradiol shunt--a major factor in the genesis of morbid obesity.
AB  - Massive obesity in males is associated with decreased total and free testosterone
      levels as well as elevated estradiol levels. The decrease in testosterone occurs
      without the compensatory increases in gonadotropin and a progressive
      hypogonadotropic hypogonadal cycle develops. During the hypogonadal state, there
      is a preferential deposition of abdominal adipose tissue. With the increasing
      fatty-tissue accumulation, there is an increase of aromatase activity that is
      associated with a greater conversion of testosterone to estradiol (testosterone
      estradiol shunt). This results in further depression of testosterone
      concentrations and leads to the increased preferential deposition of abdominal
      fat that, in turn, leads to a progressive hypogonadal state. Testalactone, an
      aromatase inhibitor, interrupts this cycle and repairs the depressed testosterone
      concentrations and decreases estradiol levels. This increases the testosterone
      levels and reverses the preferential deposition of abdominal fat, while
      increasing muscle protein and fat-free mass.

PMID- 10342672
TI  - Free radical spin traps as adjuncts for the prevention and treatment of disease.
AB  - Free radical spin traps exhibit properties consistent with a role in the
      prevention or amelioration of diseases mediated by the formation of free radical
      species in excess of optimum constitutive requirements. At first view, it may be
      surprising that they have not found a place in clinical medicine. Some studies of
      diseases in which free radicals and oxidative stress are aberrantly over- or
      underabundant and which might be ameliorated by inhibiting or augmenting their
      formation have been reported. A number of pathophysiologic categories in which
      such agents have been or might be employed are briefly summarized.

PMID- 10342673
TI  - How HIV-1 lentivirus causes immune deficiency disease.
AB  - Human immunodeficiency virus (HIV-1) associated immune deficiency has the
      characteristics of chronic graft versus host disease (GVHD) caused by human
      leukocyte antigen (HLA) class 2 incompatibility. The envelope glycoprotein
      fragment TKAKRRVVEREKR mimics HLA class 1 C molecules serologically, and also
      mimics an immune regulatory T cell epitope, in the region of amino acids 67 to
      71, within the HLA DR beta chain. This beta chain alloepitopic region (between
      amino acids 67 to 80) furnishes peptides predicted to bind optimally to HLA class
      1 B alleles. The hypothesis predicts that viral parameters, such as viral load,
      and clinical parameters, such as rate of progress to acquired immune deficiency
      syndrome (AIDS) and severity of the associated immune deficient state, are linked
      to the HLA B and HLA DR beta chain haplotype in infected patients. Immune
      suppression is caused by HLA class 1 B restricted CD8+ T cells which normally
      regulate HLA class 2 DR restricted antigen specific responses. The hypothesis
      further predicts the severity of immune deficiency to be linked to those HLA DR
      beta chain allotypes which express the amino-acid glutamine (Q) in position 70.

PMID- 10342674
TI  - New genetic hypothesis of schizophrenia.
AB  - Lack of complete concordance for schizophrenia in monozygotic twins has been
      interpreted as indicative of non-genetic cofactors in transmission of the
      illness. We present an alternative hypothesis that can parsimoniously explain,
      using known genetic mechanisms, the heredity pattern, the phenotypic spectrum and
      the biological abnormalities found in schizophrenia. The inheritance of a single
      recessive mutated allele of a gene crucial in brain development if followed by a
      somatic mutation in the normal allele during critical periods of brain
      development could result in developmental abnormalities that are expressed
      behaviorally as schizophrenic illness. Acquisition of this somatic mutation is
      likely enhanced during periods of intense cell division; therefore, the window of
      opportunity would be restricted to key periods in neurodevelopment. The somatic
      mutation may not always occur, thus explaining the variability of expression seen
      in the clinical population. Because the single allele mutation is still
      transmissible, the equal incidence of schizophrenia in the offspring of
      monozygotic twins discordant for the disease could also be explained. This
      possibility has implications for the development of genetic models and the source
      of genetic material for studies isolating the gene(s) of schizophrenia.

PMID- 10342675
TI  - Manic-depression neural conduction speeds and action potential event
      dyscorrelation.
AB  - In manic-depressive disorder, the monotonic, humor/receptor, excess/deficit, i.e.
      gain, theories have prevailed for many years, even though there is increasing
      evidence of a timing abnormality that may or may not be related to gain. In
      addition, the manic-depressive course is clearly multimodal and unpredictable
      except in revealing but rare cases, yet the system is real, and thus presumably
      deterministic, clearly suggesting a dynamic instability. A wide range of
      disciplines was reviewed by the author. Those data that were significantly
      different by standard tests were considered. However, averaged values were always
      questioned. During this review, higher water compartmentalization differentials
      were found in manic-depressive patients. Also indicated, event-related potential
      components differed in latency correlations, suggesting action potential firing
      event dyscorrelation. In conclusion, the manic-depressive action potential firing
      events may be dyscorrelated in a space-time reference frame.

PMID- 10342676
TI  - Could antioxidant therapy reduce the incidence of deafness following bacterial
      meningitis?
AB  - Sensorineural hearing loss following acute bacterial meningitis could be caused
      by hydroxyl radicals generated by the inflammatory response. Obstruction of
      cerebrospinal fluid circulation through the tela choroidae of the choroid
      plexuses, with subsequent rupture of the tela choroidae, would expose the
      auditory nerve to selective radical damage. Acute administration of lipophilic
      antioxidants might provide the auditory nerve with increased protection.

PMID- 10342677
TI  - Worldwide trends in DDT levels in human breast milk.
AB  - BACKGROUND: Concern over human breast milk contamination with the pesticide DDT
      (1,1,1-trichloro-2,2-bis(chlorodiphenyl)ethane) has prompted numerous studies
      around the world during the last five decades. This article examines trends in
      reported DDT levels, and the apparent effect of restrictions on DDT use. METHODS:
      More than 130 published values for DDT in human milk since 1951 were compiled,
      and trend lines were fit for regions of the world. RESULTS: Population means have
      declined in much of the world, from 5000-10000 microg DDT/kg milk fat to around
      1000 today in many areas. Although different regions have different means, the
      decline seen in various countries corresponds to their restricting DDT use.
      DISCUSSION: DDT concentrations in human milk have declined in most areas of the
      world, consistent with restrictions on its use. Nevertheless, levels can be high
      in areas still using DDT, even higher than the World Health Organization's
      recommended limit for infants. These results indicate that population averages
      can be reduced by a predictable amount as DDT use is restricted.

PMID- 10342678
TI  - Breast cancer in Maori and non-Maori women.
AB  - BACKGROUND: Breast cancer is more common in Maori than in non-Maori women under
      the age of 40 years and is equally common in older women, despite Maori being
      generally of lower socioeconomic status and having had a higher fertility rate
      than non-Maori. METHODS: Data from a nationwide population-based case-control
      study of breast cancer in New Zealand women aged 25-54 years were used to compare
      the age-adjusted distribution of reproductive and other risk factors for breast
      cancer in self-identified Maori and non-Maori women from the control group.
      Separate analyses also were carried out for women aged 25-39 years and for those
      aged 40-54 years. The risk of breast cancer according to the proportion of Maori
      ancestry was estimated using multiple logistic regression simultaneously
      adjusting for several risk factors. RESULTS: Significant differences were found
      between self-identified Maori and non-Maori women in the age-adjusted frequencies
      for education level, socioeconomic status, age at first full-term pregnancy,
      parity, and duration of breastfeeding; the profile in all instances suggesting a
      lower risk of breast cancer for Maori than for non-Maori. There were no
      significant differences with respect to age at menarche, surgery for benign
      breast disease or a family history of breast cancer. Significantly more Maori
      than non-Maori were in the highest quartile of recent body mass index. Women self
      identified as Maori has an approximately twofold higher risk of breast cancer
      than non-Maori women. CONCLUSIONS: Maori have high rates of breast cancer despite
      having a more favourable profile than non-Maori for most identified risk factors.

PMID- 10342679
TI  - Diagnosis and treatment of cervical intraepithelial neoplasia grade 3: a registry
      based study in the Romagna region of Italy (1986-1993).
AB  - BACKGROUND: Treatment of cervical intraepithelial neoplasia grade 3 (CIN3) is one
      of the most unexplored issues of the monitoring of cervical cancer screening. We
      evaluated (1) the frequency of major patterns of diagnosis and treatment of CIN3
      (ICD-O code 8070.2), (2) the determinants of hysterectomy as a first choice
      treatment, and (3) the determinants of invasive cervical squamous carcinoma (CSC)
      detection among CIN3 cases treated by hysterectomy. METHODS: A population-based,
      retrospective, descriptive (objective 1) and analytical (objectives 2 and 3)
      study was conducted by the Romagna Cancer Registry (Northern Italy). Included
      were 316 CIN3 patients (median age, 38.5 years; range, 21-80) registered between
      1986 and 1993 and meeting one of the following eligibility criteria: histological
      diagnosis of CIN3 on biopsy with any subsequent treatment, histological diagnosis
      of CIN3 on conization, histological diagnosis of CIN3 on hysterectomy with
      previous negative/benign (< or = CIN2) biopsy or conization. Multivariate
      associations were evaluated by the multiple logistic regression. RESULTS: Of 316
      patients, 264 (84%) were first diagnosed on biopsy, 39 (12%) on conization, and
      13 (4%) on hysterectomy. Among the 264 patients diagnosed on biopsy, the first
      choice treatment was local destructive therapy for 16 (6%), conization for 155
      (59%) and hysterectomy for 93 (35%). Age was the strongest uni/multivariate
      predictor of hysterectomy (the most frequent first choice treatment >40 years)
      followed by adequacy of biopsy (inverse association) and place of treatment
      (decreased probability for patients treated outside the area and in the private
      sector). Among the 93 CIN3 patients undergoing hysterectomy, 23 (25%) had a CSC
      diagnosed. Multivariate analysis showed that the probability of CSC detection was
      related to adequacy of biopsy (inverse association), year of registration, and
      biopsy-to-treatment interval (inverse association). CONCLUSION: Hysterectomy was
      a common treatment for patients with CIN3 on biopsy. Only in a minority of
      hysterectomized patients was a CSC diagnosed. Difficulties and inefficiencies in
      the biopsy and assessment procedure were found to be important factors in the
      management and outcome of CIN3 patients.

PMID- 10342680
TI  - Hepatitis B carriage explains the excess rate of hepatocellular carcinoma for
      Maori, Pacific Island and Asian people compared to Europeans in New Zealand.
AB  - BACKGROUND: The aim of this research was to determine the hepatitis B surface
      antigen (HBsAg) carrier prevalence among cases of hepatocellular carcinoma (HCC),
      and the population attributable risk of HBsAg carriage for HCC, by ethnicity in
      New Zealand. METHODS: The hospital notes of HCC cases registered with the New
      Zealand Cancer Registry, for the years 1987-1994 inclusive, were viewed to
      determine the HBsAg status. Results The HBsAg status was determined for 193 cases
      of HCC. The HBsAg carrier prevalence for non-Europeans with HCC was markedly
      higher than that for Europeans, being 76.7% for Maori, 80.0% for Pacific Island
      people, and 88.5% for Asians, compared to 6.0% for Europeans. In addition to the
      effect of ethnicity, HCC cases aged <60 years were more likely to be HBsAg
      carriers than those aged > or = 60 years. The estimated population attributable
      risk of HBsAg for HCC, within each ethnic group, was only marginally less than
      the HBsAg prevalence due to the high relative risk of HBsAg carriage for HCC. The
      standardized incidence rate ratios of HCC for Maori, Pacific Island people and
      Asians compared to Europeans were 9.6, 20.4, and 22.3, respectively.
      Hepatocellular carcinoma attributable to HBsAg carriage explained 79%, 83%, and
      92% of the excess standardized rate of HCC, compared to Europeans, for Maori,
      Pacific Island people, and Asians, respectively. Conclusions The HBsAg carrier
      prevalence in non-European cases of HCC in New Zealand is between 75% and 90%.
      HBsAg carriage explains the majority of the excess rate of HCC in non-Europeans
      compared to Europeans in New Zealand.

PMID- 10342681
TI  - Incidence of myocardial infarction in the Danish MONICA population 1982-1991.
AB  - BACKGROUND: Cardiovascular mortality has been declining in Denmark over the past
      20 years. Trends in incidence of myocardial infarction (MI) over the period 1982
      1991 are described within the framework of the World Health Organization MONICA
      Project. METHODS: The DAN-MONICA heart register included all cases of MI in 25-74
      year-old men and women living in 11 municipalities around Glostrup County
      Hospital evolving over a period of 10 years. They were identified retrospectively
      based mainly on relevant ICD diagnoses in death certificates and hospital
      discharge reports. Cases meeting WHO-MONICA criteria for definite or possible MI,
      recurrent as well as first-ever MI, were registered. Subsequent tracing of cases
      through national registers on deaths and hospitalizations by means of the
      patient's civil registration number ensured the completeness of the registration.
      RESULTS: A total of 6025 cases of MI occurred in the period, 4532 among men and
      1493 among women. A total of 2923 men and 1047 women had a first-ever MI in the
      period. The age-standardized rates show a definite decline over the registration
      period for men and a less distinct decline for women. CONCLUSIONS: The DAN-MONICA
      heart register meets the requirements for completeness and uniformity throughout
      the registration period. Causes and magnitude of bias are well described. Even
      when possible sources of bias are taken into account, the incidence of MI
      decreased significantly over the 10-year-period 1982-1991 by an average of 5.0%
      per year for men and 3.5% per year for women.

PMID- 10342682
TI  - Assessment methods for alcohol consumption, prevalence of high risk drinking and
      harm: a sensitivity analysis.
AB  - BACKGROUND: There are no standardized ways to assess alcohol consumption in
      epidemiological studies. The main objective of the present study was to compare
      three widely used methods for assessing alcohol consumption with respect to
      resulting prevalence estimates for high risk drinking and harm as defined by
      morbidity and mortality indicators. METHODS: A within-subjects design was used to
      compare a quantity frequency, a graduated frequency, and a weekly drinking recall
      measure. Data consisted of a representative sample of 3961 adult residents of the
      province of Ontario, Canada, who participated in a multi-wave cross-sectional
      survey between 1990-1994. Cross-tabulation, Spearman correlation, and standard
      methodologies for prevalence-based cost-of-illness studies were used. RESULTS:
      The graduated frequency measure consistently yielded higher estimates of the
      prevalences of high risk drinking and harm. Differences were marked on all
      indicators, but were most pronounced for harmful drinking as defined by consuming
      an average of >60 g pure alcohol per day for males, and >40 g per day for
      females. Prevalence estimates of harmful drinking were almost five times higher
      for graduated frequency versus weekly drinking measures, and almost three times
      higher for graduated frequency versus quantity frequency measures. CONCLUSIONS:
      The characteristics of different measures of alcohol consumption should be
      considered in future research in epidemiology.

PMID- 10342683
TI  - Variations in 'avoidable' mortality: a reflection of variations in incidence?
AB  - BACKGROUND: Variations in 'avoidable' mortality may reflect variations in the
      quality of care, but they may also be due to variations in incidence or severity
      of diseases. We studied the association between regional variations in
      'avoidable' mortality and variations in disease incidence. For a selection of
      conditions we also analysed whether the proportion of in-hospital deaths can
      explain the regional variations in incidence-adjusted mortality. METHODS:
      Relative risks for mortality, incidence, incidence-adjusted mortality and in
      hospital mortality (1984-1994) were calculated by log-linear regression. Linear
      regression was used to examine the relationship between mortality and incidence
      on the one hand, and between incidence-adjusted mortality and in-hospital
      mortality on the other. RESULTS: Significant regional mortality variations were
      found for cervical cancer, cancer of the testis, hypertensive and cerebrovascular
      disease, influenza/pneumonia, cholecystitis/lithiasis, perinatal causes and
      congenital cardiovascular anomalies. Regional mortality differences in general
      were only partly accounted for by incidence variations. The only exception was
      cervical cancer, which no longer showed significant variations after adjustment
      for incidence. The contribution of inhospital mortality variations to total cause
      specific mortality variations varied between conditions: the highest percentage
      of explained variance was found for mortality from CVA (60.1%) and appendicitis
      (29.2%). CONCLUSIONS: Incidence data are a worthy addition to studies on
      'avoidable' mortality. It is to be expected that the incidence-adjusted mortality
      rates are more sensitive for quality-of-care variations than the 'crude'
      mortality variations. Nevertheless, further research at the individual level is
      needed to identify possible deficiencies in health care delivery.

PMID- 10342684
TI  - A Markov chain model to assess the efficacy of screening for non-insulin
      dependent diabetes mellitus (NIDDM).
AB  - BACKGROUND: The high prevalence and severe consequences of non-insulin dependent
      diabetes mellitus (NIDDM) in Taiwan calls for urgent measures to detect this
      disease in the asymptomatic phase. However, the efficacy of early detection of
      NIDDM is highly dependent on its natural history from the disease-free state,
      through the asymptomatic to the symptomatic phase and death from NIDDM or other
      causes. METHODS: In order to project the above progression, a five-state illness
      and-death Markov chain model was proposed to estimate these transition parameters
      using data from two rounds of a blood sugar screening programme for NIDDM in
      Puli, in central Taiwan. RESULTS: Results showed that the annual incidence for
      asymptomatic NIDDM was 10.67 per 1000 (95% CI: 8.26-13.79) and the average
      duration between the asymptomatic and symptomatic phases (the sojourn time) was 8
      years (95%CI: 5.74-11.29). The 10-year survival rate for asymptomatic NIDDM
      (79.35%) was better than that for symptomatic NIDDM (69.45%). Prediction of
      deaths from NIDDM was performed to assess how the efficacy of screening for NIDDM
      varied by different screening frequencies (annual, biennial, 4-yearly and the
      control group). Results indicated there is no substantial difference in mortality
      reduction from NIDDM among the annual, biennial and 4-yearly screening regimens.
      However, a 4-yearly screening regimen significantly reduced deaths from NIDDM by
      40% (95% CI: 26-51%). CONCLUSIONS: A long sojourn time and the substantial
      reduction in mortality suggest that a 4-yearly screening regime for NIDDM would
      be most effective and feasible in Taiwan. The proposed five-state Markov chain
      model can be applied to other similar NIDDM screening projects.

PMID- 10342685
TI  - Habitual physical activity and bone mineral density in postmenopausal women in
      England.
AB  - BACKGROUND: Reduced levels of physical activity have been found to be associated
      with an increased risk of osteoporotic fracture in a number of epidemiological
      studies, and intervention studies have shown beneficial effects of exercise
      regimes on bone mineral density. It is not yet established, however, which
      specific forms of customary physical activity are most strongly associated with
      bone mineral density in postmenopausal women. METHODS: A cross-sectional study
      was conducted in 580 postmenopausal women, aged 45-61 years, resident in
      Nottingham, England. The participants completed a detailed interviewer
      administered activity questionnaire. Physical activity was assessed as total
      hours of participation per week in activities including housework, walking,
      gardening and sports. Stair-climbing and self-reported walking pace were also
      reported. Bone mineral density measurements were made using dual energy x-ray
      absorptiometry, measurements at five sites were used in analysis. RESULTS: The
      strongest associations between the activity measures and bone mineral density
      were for stair-climbing and walking pace, which both gave statistically
      significant positive associations at the trochanter hip site and the whole body.
      In women reporting a fairly brisk or fast walking pace, bone mineral density at
      the proximal femur was also significantly and positively associated with the
      frequency of walking at least a mile. There were no significant associations with
      aggregate measures of total customary physical activity. CONCLUSIONS: This study
      has identified two forms of physical activity, namely stair-climbing and brisk
      walking which are associated with increased bone mineral density at the hip and
      whole body in postmenopausal women. Both are feasible forms of activity for
      promoting to middle-aged women.

PMID- 10342687
TI  - Recurrence of prolonged pregnancy.
AB  - BACKGROUND: We conducted a cohort study in an attempt to determine whether
      prolonged pregnancy in mother is a risk factor for prolonged pregnancy in
      daughter, and if previous prolonged pregnancy is a risk factor for prolonged
      pregnancy in subsequent pregnancy. METHODS: Data from the Swedish Medical Birth
      Registry were combined with a local registry of births (1955-1990). Mother
      daughter pairs (with events of delivery in each generation) were identified.
      Relative risk (RR) and its 95% confidence interval (CI) were calculated and
      population attributable proportion was estimated when appropriate. RESULTS: If
      mother had had prolonged pregnancy at delivery of daughter the relative risk (RR)
      of prolonged pregnancy in daughter was moderately raised (RR = 1.3; CI : 1.0-1.7)
      with population attributable proportions ranging between 2.1% and 4.6%. If
      previous pregnancy had been prolonged, the RR of prolonged pregnancy at
      subsequent birth was increased 2-3 fold with population attributable proportions
      of 12.5% to 15.8%. Possible confounders such as mother's parity, age and maternal
      age did not alter the risks. CONCLUSIONS: Although moderate, prolonged pregnancy
      in mother may be a risk factor for prolonged pregnancy in daughter. A previous
      prolonged pregnancy increases the risk of prolonged pregnancy in a subsequent
      birth. However, the familial factor of prolonged pregnancy explains just a minor
      part of its occurrence in the population (due to small population attributable
      proportions).

PMID- 10342686
TI  - The epidemiology of hearing impairment in an Australian adult population.
AB  - BACKGROUND: This study measured the prevalence of hearing impairment, and major
      demographic factors that influence the prevalence, in a representative South
      Australian adult population sample aged > or = 15 years. METHODS: The study group
      was recruited from representative population surveys of South Australians.
      Participants in these surveys who reported a hearing disability were then
      recruited to an audiological study which measured air and bone conduction
      thresholds. In addition a sample of those people who reported no hearing
      disability were recruited to the audiological study. RESULTS: The data reported
      in this study are the first in Australia to assess the prevalence of hearing
      impairment from a representative population survey using audiological methods.
      The data show that 16.6% of the South Australian population have a hearing
      impairment in the better ear at > or = 25 dBHTL and 22.2% in the worse ear at the
      same level. The results obtained in this representative sample compare well with
      those obtained in the British Study of Hearing, although some differences were
      observed. CONCLUSIONS: Overall, there are only a few studies worldwide that have
      audiologically assessed the impairment of hearing from a representative
      population sample. The overall prevalence of hearing impairment in Australia is
      similar to that found in Great Britain, although there are some differences
      between the estimates of severity of impairment and some sex differences. The
      corroboration of the two studies reinforces the status of hearing impairment as
      the most common disability of adulthood. The present study also showed that there
      are a large number of Australians who may benefit from a more systematic
      community-based rehabilitation programme including the fitting of hearing aids.
      Secondly, the study identified the need for health goals and targets for hearing
      to be based on an epidemiological approach to the problem.

PMID- 10342688
TI  - Artefactual increasing frequency of omphaloceles in the Northern Netherlands:
      lessons for systematic analysis of apparent epidemics.
AB  - BACKGROUND: While monitoring birth defects in a registry, statistically
      significant increases in prevalence occasionally occur. In the European
      Registration Of Congenital Anomalies (EUROCAT) in the Northern Netherlands 20000
      births are monitored every year. For omphaloceles, a steady increase in the
      prevalence from 0.86 per 10000 live- and stillbirths in 1981-1983 to 3.11 per
      10000 live- and stillbirths in 1994 was seen in the three northern provinces of
      The Netherlands. METHODS: A stepwise enquiry into this increase, which included
      checking for misclassification and change in coding and ascertainment when
      necessary, was done. All cases of omphalocele and associated or similar birth
      defects registered at the EUROCAT registry were retrieved and if necessary
      recoded. RESULTS: This study showed that the increase reported previously was not
      a true time trend. A few cases of e.g. diastasis recti and trisomy 18 were
      misclassified. The prevalence in more recent years is comparable with that in the
      rest of Europe, whereas it used to be lower. There was an increase in isolated
      omphalocele, but the numbers are small. CONCLUSIONS: The stepwise enquiry
      described should be a standard procedure after noticing an increasing prevalence
      in a registry. A better subdivision, e.g. in isolated cases versus children with
      multiple congenital anomalies, before monitoring can contribute to a lower number
      of false positive signals.

PMID- 10342689
TI  - Circumcision and neonatal tetanus: disclosure of risk and its reduction by
      topical antibiotics.
AB  - BACKGROUND: Previous case-control studies have paradoxically suggested that
      circumcisions protect against neonatal tetanus (NNT), but these observations have
      not been adjusted for differences in the length of survival of cases and
      controls. METHODS: Boy cases (n = 133) and their sex-matched controls (n = 399)
      were extracted from a population-based study of NNT undertaken in Punjab
      Province, Pakistan. In the resulting file, circumcisions were censored such that
      analysis was restricted to only those that occurred before onset in cases or
      before age of onset in the matched case for controls. The effect of topical
      antibiotics in circumcision wounds was then evaluated. RESULTS: After adjusting
      for confounders, circumcision before onset posed a significant risk for NNT
      (matched odds ratio [OR] = 3.1, 95% CI: 1.2-8.0). The risk of NNT in those
      circumcised before onset and treated with topical antibiotics did not differ
      significantly from the referent group who had not been circumcised before onset
      (matched OR = 1.1, 95% CI: 0.2-6.8), whereas the lack of topical use was
      associated with significant risk (matched OR = 4.2, 95% CI: 1.4-12.6). This
      suggests that topical antibiotics are likely to be highly effective in preventing
      NNT from circumcision wounds. We estimated an overall risk of about 16 fatal NNT
      cases per 1000 live boy births with circumcision wounds that were not protected
      by topical antibiotics, and that circumcision and umbilical wounds each accounted
      for about half of this overall risk in these boys. CONCLUSIONS: Topical
      antibiotics should be routinely applied to all wounds created by traditional
      circumcisions, to prevent NNT and sepsis from these frequently unsterile
      procedures.

PMID- 10342690
TI  - Variations in infant mortality rates among municipalities in the state of Ceara,
      Northeast Brazil: an ecological analysis.
AB  - BACKGROUND: Infant mortality rates vary substantially among municipalities in the
      State of Ceara, from 14 to 193 per 1000 live births. Identification of the
      determinants of these differences can be of particular importance to infant
      health policy and programmes in Brazil where local governments play a pivotal
      role in providing primary health care. METHODS: Ecological study across 140
      municipalities in the State of Ceara, Brazil. RESULTS: To determine the
      interrelationships between potential predictors of infant mortality, we
      classified 11 variables into proximate determinants (adequate weight gain and
      exclusively breastfeeding), health services variables (prenatal care up-to-date,
      participation in growth monitoring, immunization up-to-date, and decentralization
      of health services), and socioeconomic factors (female literacy rate, household
      income, adequate water supply, adequate sanitation, and per capita gross
      municipality product), and included the variables in each group simultaneously in
      linear regression models. In these analyses, only one of the proximate
      determinants (exclusively breastfeeding (inversely), R2 = 9.3) and one of the
      health services variables (prenatal care up-to-date (inversely), R2 = 22.8)
      remained significantly associated with infant mortality. In contrast, female
      literacy rate (inversely), household income (directly) and per capita GMP
      (inversely) were independently associated with the infant mortality rate (for the
      model including the three variables R2 = 25.2). Finally, we considered
      simultaneously the variables from each group, and selected a model that explained
      41% of the variation in infant mortality rates between municipalities. The
      paradoxical direct association between household income and infant mortality was
      present only in models including female illiteracy rate, and suggests that among
      these municipalities, increases in income unaccompanied by improvements in female
      education may not substantially reduce infant mortality. The lack of independent
      associations between inadequate sanitation and infant mortality rates may be due
      to the uniformly poor level of this indicator across municipalities and provides
      no evidence against its critical role in child survival. CONCLUSIONS: These
      results suggest that promotion of exclusive breastfeeding and increased prenatal
      care utilization, as well as investments in female education would have
      substantial positive effects in further reducing infant mortality rates in the
      State of Ceara.

PMID- 10342691
TI  - Can children's health be predicted by perinatal health?
AB  - BACKGROUND: The purpose of this paper was to investigate how well children's
      health until age 7 years can be predicted by perinatal outcome using routine
      health registers. METHODS: Follow-up of one year cohort (N = 60192) was performed
      by record linkages with personal identification number. The data came from the
      1987 Finnish Medical Birth Register, from six other national registers and from
      education registers of one county. RESULTS: All perinatal health indicators
      showed a strong correlation with subsequent health, and prediction of good health
      was satisfactory: 85% of children who were healthy in the perinatal period did
      not have any reported health problems in early childhood, and 91% of children
      healthy in early childhood had been healthy in the perinatal period. However, it
      was not possible to predict poor health outcome: 76% of the children with
      reported perinatal problems were healthy in early childhood, and 87% of the
      children with long-term morbidity in childhood did not have any perinatal
      problems. CONCLUSIONS: Our findings suggest that in assessing risk factors and
      health care technology, monitoring perinatal health is not enough and long-term
      follow-ups are needed.

PMID- 10342692
TI  - Variation in physical fitness between ethnic groups in nine year olds.
AB  - BACKGROUND: There is little information on cardio-respiratory fitness of
      children, especially in ethnic minorities in Britain. In this study we assess the
      associations of social factors, ethnicity, parental health related factors,
      child's anthropometry, blood pressure and cholesterol measurements with cardio
      respiratory fitness. METHODS: Power output against load at 85% of the maximum
      heart rate (PWC85%), was measured, using a cycle-ergometer test, in children aged
      8-9 years in 22 randomly selected areas in England, 14 in Scotland and in 20
      inner city areas in England. The subjects were 317 boys and 310 girls from the
      English sample, 152 boys and 140 girls from the Scottish sample and 242 boys and
      261 girls from the inner city sample. RESULTS: Short stature (P < 0.001), fatness
      (P < 0.001), and Indian subcontinent origin (OR = 0.34, 95% CI: 0.16, 0.68 in
      boys and OR = 0.22, 95% CI: 0.12, 0.40 in girls) were associated with inability
      to finish the test. In those who finished the test PWC85% was greater in taller
      children and in those with lower skinfold values (P < 0.001, except height in
      boys P = 0.017). The PWC85% in those originating in the Indian continent was
      lower (-0.17 watt/kg, 95% CI :-0.32, -0.01 in boys and -0.29, 95% CI: -0.43, 
      0.14 in girls) than in white children. CONCLUSIONS: Shorter and obese children
      have poorer physical fitness than other children. Physical fitness is lower in
      children originating in the Indian subcontinent than other British children. This
      seems to be unrelated to socioeconomic disadvantage. Physical inactivity and lack
      of cycling skills may explain our findings.

PMID- 10342693
TI  - Obesity: does it occur in African children in a rural community in South Africa?
AB  - BACKGROUND: Total body fatness and a centripetal fat patterning are recognized as
      risk indicators of cardiovascular disease in adulthood. In this study, the
      development of these risk factors in rural South African children during the
      preschool years and first years of formal schooling is explored. METHOD: The
      initial cross-sectional data from the Ellisras Longitudinal Investigations in
      Rural Community Children Project, ongoing since 1996, were used, involving 684
      boys and 652 girls, aged 3-10 years, in the Ellisras rural community. Overweight
      was measured using the body mass index (BMI) (kg/m2). Overfatness was based on
      the sum of the triceps and subscapular skinfold thicknesses. A centripetal fat
      patterning was measured by the sum of trunk skinfolds relative to limb skinfolds
      and the ratio of the subscapular to triceps skinfold. Further, the ratio of the
      subscapular to supraspinale skinfold was used as an indicator of lower body fat
      patterning. The 85th percentiles of the NHANES III were used as cutoff values for
      overweight, overfatness and a centripetal fat patterning. RESULTS: At ages 7 and
      8 years, mean BMI was statistically significantly higher in males compared to
      females (P < 0.05). The log transformed supraspinale skinfold thickness was
      larger in females compared to males at ages 4-7 years; the log transformed
      subscapular skinfold was larger in girls compared to boys aged 7-10 years. Less
      clear patterns were found for the extremity skinfolds and the skinfold ratios.
      Very few children (0-2.5% in males and 0-4.3% in females) had BMI values above
      the NHANES III 85th percentiles, indicating a very low prevalence of overweight
      children in the area. About 15% of the males showed overfatness at ages 3-4
      years, while low prevalence was found at older ages. CONCLUSION: Few Ellisras
      rural children had above normal values for BMI, indicating a low prevalence of
      obesity in this population. In the 3- and 4-year-old group more subjects were
      found to have excessive fat, as indicated by the sum of the triceps and
      subscapular skinfold thicknesses.

PMID- 10342694
TI  - Self-reporting versus parental reporting of acute respiratory symptoms of
      children and their relation to pulmonary function and air pollution.
AB  - BACKGROUND: Studies of acute effects of outdoor air pollution on acute
      respiratory symptoms in children generally rely on reports by parents. Little is
      known about the validity of parental reporting of symptoms of their children. We
      therefore compared symptoms reported by the parents with self-reported symptoms
      and measured pulmonary function of 741 7-11-year-old Dutch children. We also
      analysed the association of symptoms reported by the child or parent and outdoor
      air pollution. METHODS: The parents of the children completed a daily diary of
      symptoms of their children for about 3 months. The children reported presence of
      acute respiratory symptoms in the preceding week before a pulmonary function test
      was conducted (6-10 test days). RESULTS: Children reported between 80% and 220%
      more acute respiratory symptoms than their parents for them in the same period.
      The agreement between symptom reports by the parent and the child was low to
      moderate (Kappa between 0.22 for eye irritation and 0.43 for fever). Presence of
      cough reported by child or parent was associated with similar small decrements in
      forced vital capacity (FVC), forced expiratory volume in one second (FEV1.0) and
      especially peak expiratory flow (PEF) and maximal mid-expiratory flow (FEF25-75).
      The largest pulmonary function decrements were found when symptoms were reported
      by both parent and child. Symptoms reported by either child or parent were not
      associated with air pollution. CONCLUSIONS: Symptom reports of the children were
      more prevalent but did not agree well with parental reports. The similar
      association with pulmonary function suggested that self-reported symptoms were
      neither superior nor inferior to symptoms reported by the parents.

PMID- 10342695
TI  - The effect of water fluoridation and social inequalities on dental caries in 5
      year-old children.
AB  - BACKGROUND: Many studies have shown that water fluoridation dramatically reduces
      dental caries, but the effect that water fluoridation has upon reducing dental
      health inequalities is less clear. The aim of this study is to describe the
      effect that water fluoridation has upon the association between material
      deprivation and dental caries experience in 5-year-old children. METHODS: It is
      an ecological descriptive study of dental caries experience using previously
      obtained data from the British Association for the Study of Community Dentistry's
      biennial surveys of 5-year-old children. This study examined the following data
      from seven fluoridated districts and seven comparable non-fluoridated districts
      in England: 1) dental caries experience using the dmft (decayed, missing, filled
      teeth) index; 2) the Townsend Deprivation Index of the electoral ward in which
      the child lived; 3) whether fluoride was present at an optimal concentration in
      the drinking water or not. RESULTS: A statistically significant interaction was
      observed between material deprivation (measured by the Townsend Deprivation
      Index) and water fluoridation (P < 0.001). This means that the social class
      gradient between material deprivation and dental caries experience is much
      flatter in fluoridated areas. CONCLUSION: Water fluoridation reduces dental
      caries experience more in materially deprived wards than in affluent wards and
      the introduction of water fluoridation would substantially reduce inequalities in
      dental health.

PMID- 10342696
TI  - Epidemiology of child deaths due to drowning in Matlab, Bangladesh.
AB  - BACKGROUND: Although the recent decline in child mortality in Bangladesh is
      remarkable, death from causes other than infectious diseases and malnutrition
      remains an important component of child mortality. Death from drowning of
      children can be expected to be a problem in Bangladesh given the geographical
      features of the country. OBJECTIVE: The objectives of this study are to determine
      the trend, pattern, and correlates of drowning deaths. METHODS: Data are
      presented on deaths of children (1-4 years) due to drowning derived from a
      longitudinal, population-based surveillance system in operation in a rural area
      of Bangladesh in 1983-1995. Moreover, a case-control study was carried out to
      identify the risk factors associated with drowning. RESULTS: Deaths due to
      drowning ranged from about 10% to 25% of child deaths during 1983-1995. The
      absolute risk of dying from drowning remained almost the same over the study
      period but the proportion of drownings to all causes of death has increased.
      Drowning is especially prevalent in the second year of life. Age of the mother
      and parity have a significant impact on drowning. The risk of dying from drowning
      increases with the age of mother and much more sharply with the number of living
      children in the family. Two socioeconomic variables did not have an influence on
      the risk of drowning. CONCLUSIONS: A substantial proportion of child deaths could
      be averted if parents and other close relatives paid more attention to the safety
      of children. The Child Health Programme of the Ministry of Health and Family
      Welfare of Bangladesh should develop health education programmes for villagers
      alerting them to the dangers of drowning and measures to prevent it.

PMID- 10342697
TI  - Medical surveillance of multinational peacekeepers deployed in support of the
      United Nations Mission in Haiti, June-October 1995.
AB  - BACKGROUND: Multinational peacekeepers, both military and civilian, often deploy
      to areas of the world where significant health threats are endemic and host
      country public health systems are inadequate. Medical surveillance of deployed
      personnel enables leaders to better direct health care resources to prevent and
      treat casualties. Over a 5-month period, June to October 1995, a medical
      surveillance system (MSS) was implemented in support of the United Nations
      Mission in Haiti (UNMIH). Information obtained from this system as well as
      lessons learned from its implementation and management may help decrease casualty
      rates during future multinational missions. METHODS: Over 90% of UNMIH personnel
      (80% military from over 11 countries and 20% civilian from over 70 countries)
      stationed throughout Haiti participated in the MSS. A weekly standardized
      reporting form included the number of new outpatient visits by disease and non
      battle injury (DNBI) category and number of personnel supported by each
      participating UN medical treatment facility (MTF). Previously, medical reporting
      consisted of simple counts of patient visits without distinguishing between new
      and follow-up visits. Weekly incidence rates were determined and trends compared
      within and among reporting sites. The diagnoses and numbers of inpatient cases
      per week were only monitored at the 86th Combat Support Hospital, the facility
      with the most sophisticated level of health care available to UN personnel.
      RESULTS: The overall outpatient DNBI incidence rate ranged from 9.2% to 13% of
      supported UN personnel/week. Of the 14 outpatient diagnostic categories, the
      three categories consistently with the highest rates included orthopaedic/injury
      (1.6-2.5%), dermatology (1.3-2.2%), and respiratory (0.9-2.2%) of supported UN
      personnel/week. The most common inpatient discharge diagnoses included suspected
      dengue fever (22.3%), gastro-enteritis (15%), and other febrile illness (13.5%).
      Of the 249 patients who presented with a febrile illness, 79 (32%) had
      serological evidence of recent dengue infection. Surveillance results helped lead
      to interventions that addressed issues related to field sanitation, potable
      water, food preparation and vector control. CONCLUSIONS: Despite hurdles
      associated with distance, language, and communications, the MSS was a practical
      and effective tool for UNMIH force protection. UN requirements for standardized
      medical surveillance during deployments should be developed and implemented.
      Furthermore, planners should recognize that if ongoing medical surveillance and
      related responses are to be effective, personnel should be trained prior to
      deployment and resources dedicated to a sustained effort in theatre.

PMID- 10342698
TI  - Simple sample size calculation for cluster-randomized trials.
AB  - BACKGROUND: Cluster-randomized trials, in which health interventions are
      allocated randomly to intact clusters or communities rather than to individual
      subjects, are increasingly being used to evaluate disease control strategies both
      in industrialized and in developing countries. Sample size computations for such
      trials need to take into account between-cluster variation, but field
      epidemiologists find it difficult to obtain simple guidance on such procedures.
      METHODS: In this paper, we provide simple formulae for sample size determination
      for both unmatched and pair-matched trials. Outcomes considered include rates per
      person-year, proportions and means. For simplicity, formulae are expressed in
      terms of the coefficient of variation (SD/mean) of cluster rates, proportions or
      means. Guidance is also given on the estimation of this value, with or without
      the use of prior data on between-cluster variation. CASE STUDIES: The methods are
      illustrated using two case studies: an unmatched trial of the impact of
      impregnated bednets on child mortality in Kenya, and a pair-matched trial of
      improved sexually-transmitted disease (STD) treatment services for HIV prevention
      in Tanzania.

PMID- 10342699
TI  - Interpreting the decline in tuberculosis: the role of secular trends in effective
      contact.
AB  - BACKGROUND: The dramatic decline in tuberculosis (TB) in developed countries
      during the past century has been attributed to many factors, including
      improvements in living and social conditions and, more recently, effective
      treatment. Each of these changes should have reduced the average number of
      individuals 'effectively contacted' (i.e. sufficiently to transmit infection) by
      each infectious TB case. METHOD: Estimates of the average number of individuals
      effectively contacted by each infectious TB case, for each year since 1900 in
      England and Wales, are derived as the ratio between published estimates of the
      annual risk of infection and estimates of the prevalence of infectious cases, as
      derived using a published model of the epidemiology of TB. RESULTS: The results
      suggest that each infectious case contacted, on average, about 22 individuals in
      1900 sufficiently to transmit Mycobacterium tuberculosis infection, and that this
      number declined to about 10 by 1950 and to approximately one by 1990.
      CONCLUSIONS: Although several factors contributed to the decline in TB in
      developed countries during this century, a major contributor has been the decline
      in the number of effective contacts by each case over time. Similar declines have
      doubtless occurred over the past century for many infections in developed
      countries.

PMID- 10342700
TI  - Human immunodeficiency virus (HIV) infection in parenteral drug users: evolution
      of the epidemic over 10 years. Valencian Epidemiology and Prevention of HIV
      Disease Study Group.
AB  - BACKGROUND: Evaluation of acquired immunodeficiency syndrome (AIDS) prevention
      strategies requires an on-going follow up of the frequency of human
      immunodeficiency virus (HIV-1) infection. The aim of this study was to examine
      the trends in prevalence and incidence of HIV-1 infection among injecting drug
      users (IDU) during the period 1987-1996. METHODS: Transversal and cohort studies
      were designed which included a consecutive sample of 7132 IDU who attended three
      AIDS Prevention and Information Centres in the Region of Valencia (Spain) and
      voluntarily asked to be tested for HIV antibodies. The prevalence was estimated
      for each year based on the serological status of HIV-1 when the patient first
      visited the centre. The annual incidence rates were calculated based on the
      seronegative patients in which a new determination of HIV-1 was done. In order to
      control the possible effects on the estimations of age, sex and duration of
      addiction of the people studied, Poisson and logistic regression models were
      adjusted. RESULTS: Prevalence and incidence rates of HIV-1 infection showed
      parallel trends over time. The overall prevalence found was 43.6% (95% confidence
      intervals [CI]: 42.4-44.7%). Of the 4023 seronegative individuals, 1746 were
      followed up over the whole of the study period. The incidence rate observed was
      6.85 x 100 persons/year (95% CI : 6.04-7.66). The prevalence figures show a
      decrease, which is most marked from 1990 onwards and then they tend to stabilize
      over the past few years. The incidence rates increase slightly up to 1991 (9.8 x
      100 persons/year), and then begin to decrease. CONCLUSION: Trends of prevalence
      of HIV-1 infection approximate trends of subjacent incidence rate. Despite
      decrease in HIV-1 infection frequency observed over 10 years, both the prevalence
      and incidence figures continue to be high in absolute terms. It is necessary to
      intensify and adapt preventive measures to each subgroup at risk of infection and
      in the case of heterosexual transmission ensure that the failure observed in the
      case of IDU is not repeated.

PMID- 10342701
TI  - The effect of human immunodeficiency virus-1 infection and stunting on measles
      immunoglobulin-G levels in children vaccinated against measles in Uganda.
AB  - BACKGROUND: Measles is an important public health problem in developing nations
      and there is concern that immune response to measles vaccination may be
      compromised by paediatric human immunodeficiency virus (HIV) infection.
      Therefore, this study investigated the relationship of immunoglobulin-G (Ig-G)
      antibody levels in children vaccinated against measles and HIV-1 infection.
      Further analysis was done to assess the influence of nutritional status on this
      relationship. METHODS: The authors measured HIV and measles antibodies in 243
      vaccinated children aged 17-41 months from Kampala, Uganda. Children were from
      paediatric and HIV clinics. Potential confounders of this relationship included
      nutritional anthropometric measures, age at and time since vaccination, measles
      exposure, family crowding, vaccination clinic and gender. Univariable and
      multivariable analyses were used to study these associations. RESULTS: Fifty
      children (21%) were HIV infected. In univariable analysis, low measles antibody
      (<15 ELISA units/ml) was associated with HIV (P = 0.05; odds ratio (OR) = 1.86)
      and stunting (P = 0.06; OR = 1.68). Stunting, measured as height-for-age and
      defined as <-2 standard deviations of the reference population median, was a
      surrogate for chronic malnutrition. HIV was strongly associated with stunting (P
      = 0.0001; OR = 6.62). In multiple logistic regression, HIV was not associated
      with low measles antibodies; however, stunting (P = 0.04; OR = 1.81), and <3
      children in the home (P = 0.01; OR = 1.96) were. Conversely, being male (P =
      0.05; OR = 0.58), and measles in the home in the previous month (P = 0.04; OR =
      0.33) were associated with high antibody levels. CONCLUSIONS: These findings
      suggest that HIV in Ugandan children immunized for measles may indirectly
      interfere with measles antibody levels by causing malnutrition, the latter being
      the direct cause. Programmes to improve childhood nutrition, especially for HIV
      infected children, should accompany measles control programmes in developing
      nations for maximum benefit from measles vaccination. HIV infection per se should
      not change measles vaccination programmes.

PMID- 10342703
TI  - A community outbreak of Legionnaires' disease linked to hospital cooling towers:
      an epidemiological method to calculate dose of exposure.
AB  - BACKGROUND: From July to September 1994, 29 cases of community-acquired
      Legionnaires' disease (LD) were reported in Delaware. The authors conducted an
      investigation to a) identify the source of the outbreak and risk factors for
      developing Legionella pneumophila serogroup 1 (Lp-1) pneumonia and b) evaluate
      the risk associated with the components of cumulative exposure to the source
      (i.e. distance from the source, frequency of exposure, and duration of exposure).
      METHODS: A case-control study matched 21 patients to three controls per case by
      known risk factors for acquiring LD. Controls were selected from patients who
      attended the same clinic as the respective case-patients. Water samples taken at
      the hospital, from eight nearby cooling towers, and from four of the patient's
      homes were cultured for Legionella. Isolates were subtyped using monoclonal
      antibody (Mab) analysis and arbitrarily primed polymerase chain reaction (AP
      PCR). RESULTS: Eleven (52%) of 21 case-patients worked at or visited the hospital
      compared with 17 (27%) of 63 controls (OR 5.0, 95% CI : 1.1-29). For those who
      lived, worked, or visited within 4 square miles of the hospital, the risk of
      illness decreased by 20% for each 0.10 mile from the hospital; it increased by
      80% for each visit to the hospital; and it increased by 8% for each hour spent
      within 0.125 miles of the hospital. Lp-1 was isolated from three patients and
      both hospital cooling towers. Based on laboratory results no other samples
      contained Lp-1. The clinical and main-tower isolates all demonstrated Mab pattern
      1,2,5,6. AP-PCR matched the main-tower samples with those from two case-patients.
      CONCLUSION: The results of our investigation suggested that the hospital cooling
      towers were the source of a community outbreak of LD. Increasing proximity to and
      frequency of exposure to the towers increased the risk of LD. New guidelines for
      cooling tower maintenance are needed. Knowing the location of cooling towers
      could facilitate maintenance inspections and outbreak investigations.

PMID- 10342702
TI  - Early two-dose measles vaccination schedule in Guinea-Bissau: good protection and
      coverage in infancy.
AB  - BACKGROUND: Previous studies from Africa have suggested that there is little
      benefit to be gained from early two-dose measles vaccination schedules. Two-dose
      schedules have been associated with no improvement in coverage due to
      immunization of the same individuals on both occasions, low return rate, high
      refusal rate, low vaccine efficacy, and fear of blunting of the antibody
      response. Because of the poor results achieved previously with two-dose measles
      vaccination schedules, we studied patterns of participation, reasons for non
      participation, vaccination coverage and relative efficacy of a one-dose versus a
      two-dose schedule in connection with the implementation of an early two-dose
      trial in Guinea-Bissau. METHODS: Children born from September 1994 to January
      1996 were randomized into two groups receiving either two doses of measles
      vaccine at 6 and 9 months or one dose of inactivated polio vaccine (IPV) at 6
      months and measles vaccine at 9 months. RESULTS: At 6 months of age 86%
      (1869/2181) of the children participated, and at 9 months of age participation
      was 87% (1775/2035). The return rate for obtaining a second dose of vaccine was
      93% (1647/1773). The main reason for not participating was travelling (78%).
      Around 50% of those who did not take part in one vaccination took part in the
      other. When only children participating the first time they were called for a
      measles vaccination were included, the measles vaccination coverage in the one
      dose group was 59% versus 80% in the two-dose group, i.e. a 50% reduction in the
      risk of not being vaccinated (relative risk [RR] 0.50; confidence interval [CI]:
      0.43-0.57). Few measles cases have occurred in the study area since the
      implementation of the trial making precise estimation of the relative efficacy of
      the two vaccine strategies difficult, but all seven clinically diagnosed measles
      cases occurred in the one-dose group making the relative efficacy for the two
      dose group compared with the one-dose group 100% (95% CI: 35%-100%; two-tailed P
      = 0.016). When including maternal reports, the relative efficacy was 90% (95%
      exact confidence interval; two-tailed P = 25%-97%, P = 0.022). CONCLUSION: In
      this study of a two-dose measles immunization schedule at 6 and 9 months of age
      there was no sign of low participation or poor return rates. The risk of not
      being vaccinated was lower in the two-dose group than in the one-dose group, and
      the relative efficacy of a two-dose versus a one-dose schedule was high. Although
      our results were obtained within a trial where dedicated personnel informed every
      participant personally about the study, we believe our results indicate that with
      thorough information about the population it may be possible to achieve a higher
      coverage with a two-dose measles vaccination schedule than a one-dose schedule. A
      two-dose schedule may be a feasible way to resolve the problems of low coverage
      and severe measles infection among infants.

PMID- 10342704
TI  - Induction versus Popper: substance versus semantics.

PMID- 10342705
TI  - Induction versus Popper: substance versus semantics.

PMID- 10342706
TI  - Premature deaths and long-term mortality effects of air pollution.

PMID- 10342707
TI  - Dehydroepiandrosterone (DHEA) for serious disease, a possibility?

PMID- 10342708
TI  - An outsider's view on SLE research.

PMID- 10342709
TI  - Apheresis for lupus erythematosus.
AB  - Indications for the use of apheresis technologies in managing lupus erythematosus
      have undergone numerous conceptual changes since the procedure was automated in
      the 1960s and first attempted for systemic lupus erythematosus (SLE) in 1974.
      Once thought to be a promising treatment for a variety of aspects of SLE,
      apheresis has been relegated to occupying a few important niches as an adjunct in
      managing the disorder. This article will review the history, physiology and
      rationale of apheresis pertaining to SLE. A focused critical review of pertinent
      literature is presented, along with specific recommendations relating to the
      place of apheresis in the lupus therapeutic spectrum.

PMID- 10342711
TI  - Clinical characteristics and outcome of southern Chinese males with systemic
      lupus erythematosus.
AB  - The aims were to study the gender differences in clinical manifestations, disease
      course and organ damage in systemic lupus erythematosus (SLE). Clinical
      manifestations, autoantibody profile, relapses and damage scores were obtained
      from 51 Chinese males with SLE and compared with 201 consecutive female SLE
      controls. Fifty-one males were identified among 630 SLE patients who attended our
      clinics, giving a male prevalence of 8% and a female to male ratio of 11.4-1.
      Both the male SLE patients and the female controls had similar age and SLEDAI
      score at disease onset. Male SLE patients had less alopecia (P = 0.03), Raynaud's
      phenomenon (P = 0.01) and anti-Ro (P = 0.049) during the course of the disease
      but none of the differences were statistically significant after correction for
      multiple observations. The prevalence of major organ involvement in either sex
      was not different. Both groups of patients had a comparable mean duration of
      follow-up (104 vs. 102 months, P = 0.87). Males had a significantly lower rate of
      relapses (total No. of flares/patient-year: 0.23 in men vs. 0.33 in women, P =
      0.04), but the frequency of severe flares (No. of severe flares/patient-year in
      men 0.08 vs. 0.12 in women, P = 0.16) was not significantly different from the
      females. Male patients with positive anti-Ro had significantly less overall
      flares than their female counterparts who were anti-Ro positive (0.16 vs. 0.34, P
      = 0.006). However, the use of immunosuppressive agents for disease control in
      patients of both sexes was similar. 22 (43%) of the males and 78 (39%) of the
      females had organ damage. A higher percentage of male patients had impairment of
      renal function (P = 0.006) but the proportion of patients who required dialysis
      was not different (4% in men vs. 2% in females. P = 0.92). There was also a trend
      of more cardiovascular damage in the males but the difference was not
      statistically significant (P = 0.09). The mean SLICC/ACR scores were not
      significantly higher in the males than the females (0.71 vs. 0.60, P = 0.47).
      Males tend to differ from females in clinical manifestations, immunological
      profile and disease course in SLE. However, there was no gender difference in the
      involvement of major organs/systems. Males had less overall disease flares than
      the females but the rate of severe flares was not significantly lower. For
      patients who were anti-Ro positive, males had significantly less total number of
      flares/patient-year than their female counterparts. More renal impairment and
      cardiovascular damage was present in our male lupus patients but the overall
      damage scores were not significantly higher.

PMID- 10342710
TI  - A double-blind, placebo-controlled, clinical trial of dehydroepiandrosterone in
      severe systemic lupus erythematosus.
AB  - OBJECTIVE: To determine if dehydroepiandrosterone (DHEA) is beneficial in severe
      systemic lupus erythematosus (SLE). METHODS: A double-blinded, placebo
      controlled, randomized clinical trial in 21 patients with severe and active SLE,
      manifestated primarily by nephritis, serositis or hematological abnormalities. In
      addition to conventional treatment with corticosteroids +/- immunosuppressives,
      patients received DHEA 200 mg/d vs. placebo for 6 months, followed by a 6-month
      open label period. The primary outcome was a prospectively defined responder
      analysis, based on a quantitatively specified improvement of the principal severe
      lupus manifestation at 6 months. RESULTS: Nineteen patients were available for
      evaluation at 6 months. Baseline imbalance between the groups was noted, with the
      DHEA group having greater disease activity at baseline (P<0.05 by physician's
      global assessment). Eleven patients were responders: 7/9 patients on DHEA vs.
      4/10 patients on placebo (P<0.10). Of the secondary outcomes, mean improvement in
      SLE disease activity index (SLE-DAI) score was greater in the DHEA group (-10.3+/
      3.1 vs. -3.9+/-1.4. P<0.07). Bone mineral density at the lumbo-sacral spine
      showed significant reduction in the placebo group, but was maintained in the DHEA
      group. CONCLUSION: DHEA therapy, when added to conventional treatment for severe
      SLE, may at most have a small added benefit with respect to lupus outcomes, but
      baseline imbalances in the study population limit the generalizability of the
      results. DHEA appears to have a protective effect with respect to corticosteroid
      induced osteopenia in such patients.

PMID- 10342712
TI  - Systemic lupus erythematosus in three ethnic groups: III. A comparison of
      characteristics early in the natural history of the LUMINA cohort. LUpus in
      MInority populations: NAture vs. Nurture.
AB  - AIM: To determine and contrast the socioeconomic-demographic and clinical
      features of patients with recent onset (< or =5 y) systemic lupus erythematosus
      (SLE) from three ethnic groups, Hispanic, African-American and Caucasian (H, AA,
      C). SUBJECTS AND METHODS: SLE cases (American College of Rheumatology criteria)
      (incident (n = 56), prevalent (n = 173)), were enrolled in a longitudinal study
      at The University of Alabama at Birmingham, The University of Texas-Houston
      Health Science Center and The University of Texas Medical Branch at Galveston.
      Socioeconomic-demographic, clinical, immunological, behavioral and psychological
      data were obtained using validated instruments and standard laboratory
      techniques, and compared. RESULTS: 70 H, 88 AA and 71 C SLE patients constitute
      this cohort. H and AA patients were younger and of lower socioeconomic
      demographic status. They also had evidence of more frequent organ system
      involvement (renal, cardiovascular), more auto-antibodies, more active disease
      (after adjusting for discrepant socioeconomic-demographic features), lower levels
      of social support and more abnormal illness-related behaviors (more in H than in
      AA). H also were more likely to have an abrupt disease onset; C were more likely
      to be on antimalarials but less likely to be on corticosteroids. H, AA, and C
      used health care resources comparably. They had similar levels of pain and
      physical and mental functioning after adjusting for age, disease duration,
      income, education, social support, illness-related behaviors, and Systemic Lupus
      Activity Measure or SLAM scores. CONCLUSIONS: H and AA patients have more active
      SLE, at an earlier age of onset, and a less favorable socioeconomic-demographic
      structure (worse among the H than AA) which predispose them to a less favorable
      natural history.

PMID- 10342713
TI  - Antibodies to cardiolipin and beta2-glycoprotein-1 in HTLV-1-associated
      myelopathy/tropical spastic paraparesis.
AB  - Anticardiolipin and anti-beta2GP1 antibodies were measured in 50 patients with
      HTLV-1-associated Myelopathy-Tropical Spastic Paraparesis (HAM-TSP) and the
      results were compared with those obtained for 34 HTLV-1-positive and 35 HTLV-1
      negative controls, as well as 128 SLE patients. aCL but not anti-beta2GP1 was
      associated with HTLV-I infection. aCL was more prevalent than anti-beta2GP1 (32%
      vs. 8%) and was not associated with anti-beta2GP1 in HAM-TSP. IgA was the
      dominant isotype of aCL and anti-beta2GP1. The data suggest that tin HAM-TSP, IgA
      aCL are frequent and are associated with HTLV-1 infection.

PMID- 10342714
TI  - Chilblain lupus erythematosus is associated with antibodies to SSA/Ro.
AB  - Chilblain lupus erythematosus (CL) of Hutchinson is a subtype of lupus
      erythematosus (LE) characterized by erythematous lesions induced by cold, damp
      climates. A number of patients affected by CL eventually develop features of
      systemic lupus erythematosus (SLE). We report here 9 patients with chilblain
      cutaneous lesions, 6 of them were affected by SLE and 2 by SCLE. The onset of CL
      preceded the diagnosis of LE, from 1 to 10 years in 3 cases, it was concurrent in
      one case and was subsequent in the remaining 4 cases. Raynaud's phenomenon and
      photosensitivity were other prominent clinical features in patients with CL.
      Nailfold capillaroscopy revealed pathological changes in every patient examined.
      ANA and anti-SSA/Ro antibodies were detected in all nine patients. Anti-SSB/La
      were detected in 2 cases, anti-Sm in one case, and anti-Sm and anti-RNP in a one
      case. Antibodies to dsDNA and complement consumption were found in the six
      patients with SLE. The fine specificity of anti-SSA/Ro was determined by
      immunoblotting: anti-60kD and anti-52 kD were detected in three sera, anti-60kD
      alone in 5 sera, while one serum did not blot. In conclusion, the present study
      suggests that chilblain LE is associated with SSA/Ro autoantibodies, as is SCLE,
      hypergammaglobulinemic purpura and neonatal lupus erythematosus.

PMID- 10342715
TI  - Atherosclerosis-related markers in systemic lupus erythematosus patients: the
      role of humoral immunity in enhanced atherogenesis.
AB  - Systemic Lupus Erythematosus (SLE) patients experience premature atherosclerosis.
      A deranged lipid metabolism and use of immunosuppressive medications accounts
      partially for the accelerated process. The role of autoimmunity in
      atherosclerosis has recently been highlighted. Autoantigenic determinants thought
      to play a role in the development of atherosclerosis include: modified
      lipoproteins, heat shock proteins and beta2-glycoprotein I (a target of
      'autoimmune' anticardiolipin antibodies). In this present work we determined
      autoimmune markers which may be associated with premature atherosclerotic process
      found in SLE patients. We have found that antibodies to oxLDL were raised in the
      sera of lupus patients and cross-reacted with cardiolipin and with beta2GPI.
      OxLDL containing immune-complexes of the IgG and IgM isotypes were both elevated
      in the SLE patients as compared with healthy controls. Patients with high
      Lipoprotein (a) concentrations (>30 mg/dl) had higher levels of IgM oxLDL
      containing immune-complexes. IgM but not IgG anti-HSP-65 antibodies were elevated
      in the lupus patients and levels of oxLDL containing immune-complexes correlated
      positively with the presence of anti-HSP 65 antibodies. Lysophosphatidylcholine
      (LPC) is a peroxide-derivative formed during LDL oxidation, was shown to evoke a
      humoral response in healthy subjects. Antibodies to lysophosphatidylcholine of
      the IgG but not the IgM isotype were reduced in SLE patients compared with
      controls, suggesting it may be 'consumed' into oxLDL containing immune complexes.
      Therefore, SLE patients exhibit a humoral autoimmune response towards the
      antigenic candidates incriminated in the progression of atherosclerosis. These
      findings may help identify factors that are involved in accelerating
      atherogenesis in SLE patients.

PMID- 10342716
TI  - Responsiveness of peripheral blood B cells to recombinant CD40 ligand in patients
      with systemic lupus erythematosus.
AB  - OBJECTIVE: To investigate the immunopathological significance of CD40/CD40 ligand
      system for B cell hyperactivation in SLE patients, the expression and the
      function of CD40 on B cells were compared with those of normal controls. METHODS:
      Expression of CD40 was evaluated by flow cytometry. DNA synthesis of B cells were
      measured by 3H - TdR incorporation. Antibody production was assessed by ELISA.
      RESULTS: There was no significant difference between SLE and normal controls in
      CD40 expression on peripheral blood B cells. Recombinant CD40 ligand-leucine
      zipper fusion protein (CD40L-LZ) significantly enhanced 3H - TdR incorporation by
      both SLE and normal B cells (P<0.01). 3H - TdR incorporation of SLE B cells
      without stimuli (P<0.001) and with CD40L-LZ stimulation (P<0.05) were
      significantly lower in SLE patients compared with normal controls. Active SLE B
      cells spontaneously produced significantly larger amounts of total IgG than
      normal B cells (P<0.05). CD40L-LZ significantly increased the production of total
      IgG by SLE B cells (P<0.05), but not by normal B cells. Active SLE B cells
      spontaneously produced IgG anti-dsDNA and IgG anti-ssDNA antibodies. CD40L-LZ
      significantly increased the production of these autoantibodies by SLE B cells
      (P<0.05). B cells from normal controls do not produce these autoantibodies
      spontaneously nor in response to CD40L-LZ. CONCLUSION: These findings indicate
      that signalling via CD40 plays an important role in B cell proliferation and
      autoantibody production in human SLE.

PMID- 10342717
TI  - The BH1 idiotype defines a population of anticardiolipin antibodies closely
      associated with the antiphospholipid syndrome.
AB  - BACKGROUND: A human IgM monoclonal anticardiolipin antibody - BH1 - has
      previously been described, which has characteristics typical of antiphospholipid
      antibodies in the serum of patients with antiphospholipid syndrome (APS). It
      appears to be idiotypically distinct from other human monoclonal autoantibodies
      of different or overlapping ligand-binding specificities derived from patients
      with related conditions. AIM: To determine whether the idiotype of BH1 is
      expressed on particular populations of antibodies (antiphospholipid and anti
      beta2-glucoprotein I) in the serum of patients with APS and other conditions.
      METHODS: Sera from patients with APS (9), systemic lupus erythematosus without
      APS ('uncomplicated SLE' -9), and rheumatoid arthritis (RA 15), and from normal
      controls (15) were tested by enzyme-linked immunosorbent assay (ELISA) for
      reactivity with cardiolipin, beta2 glycoprotein I (beta2GPI), and a polyclonal
      anti-idiotype raised against BH1 (RIdBH1). Absorption experiments were
      subsequently performed on selected sera using micelles of cardiolipin or
      phosphatidyl choline. RESULTS: Eight out of nine patients with APS were positive
      for binding to RIdBH1 (IgG and/or IgM), while only one patient with uncomplicated
      SLE and none of the patients with RA or the healthy controls were positive.
      Although all of the patients with APS were positive for binding to beta2GPI,
      there was poor correlation between these results and levels of binding to
      cardiolipin and RIdBH1. Absorption of sera from patients with APS by cardolipin
      micelles resulted in a median reduction in IgG anticardiolipin and anti-beta2GPI
      activity of 81.6% and 6.3% respectively. For those sera positive for IgG
      reactivity with RIdBH1 the median reduction in this activity was 79.4%.
      Antibodies eluted from selected micelles showed activity against cardiolipin,
      beta2GPI and RIdBH1. Three anticardiolipin-positive sera from patients with RA
      were similarly absorbed; however the eluted antibodies failed to bind to RIdBH1.
      Absorption of all these sera with phosphatidyl choline resulted in no significant
      reduction in any of these activities. CONCLUSIONS: The BH1 idiotype defines a
      population of serum antibodies associated with features of APS. The antibody
      response in this condition, though diverse, may include the expression of a
      restricted group of variable region genes.

PMID- 10342718
TI  - A case of SLE with acute, subacute and chronic cutaneous lesions successfully
      treated with Dapsone.
AB  - We describe a patient with systemic lupus erythematosus (SLE) who exhibited
      severe cutaneous involvement characterized by the simultaneous presence of acute,
      subacute and discoid lesions in association with anti-S1 antibodies. After she
      failed to respond to chloroquine, medium to low dose steroids, steroid pulses,
      retinoids and cyclophosphamide, the patient was treated with Dapsone and a
      dramatic improvement in the cutaneous lesions was seen after only one month.

PMID- 10342720
TI  - Pustuloderma during cutaneous lupus treatment with thalidomide.

PMID- 10342719
TI  - Devic's neuromyelitis optica during pregnancy in a patient with systemic lupus
      erythematosus.
AB  - Neuropsychiatric forms of systemic lupus erythematosus (SLE) vary, most commonly
      consisting of seizures, psychiatric disturbances, or focal central nervous
      deficits. This is a new case of neuromyelitis optica or Devic's syndrome during
      the course of SLE. Few reports of this association exist in the literature. Our
      objective is to report this unique case of Devic's neuromyelitis optica during
      pregnancy in a patient with systemic lupus erythematosus. A 28-year-old woman had
      been diagnosed as having SLE with cutaneous and articular involvement in 1987
      when she was 17 years old. She was treated with a synthetic antimalarial agent
      associated with corticosteroids. In 1994, during the fourth month of pregnancy,
      she had signs of transverse myelitis with a sensory level at T6 associated with
      an optic neuropathy suggesting a Devic's syndrome. The patient was managed by
      plasmapheresis sessions and intravenous corticosteroids. Transverse myelitis
      recurred postpartum and three years later at the same thoracic level. Management
      by bolus administration of a steroid and cyclophosphamide resulted in remission
      again. There have only been around a dozen reports in the literature of patients
      who had both Devic's neuromyelitis optica and SLE. Magnetic resonance imaging is
      contributive to diagnosis and therapeutic follow-up, showing spinal cord lesions
      with increased intensity on T2-weighted sequences. Although the clinical course
      of the present patient has been favourable so far, the prognosis of this
      neurologic disease is generally considered to be poor with elevated mortality.

PMID- 10342721
TI  - Cardiac tamponade in SLE.

PMID- 10342722
TI  - Prolactin in rheumatoid arthritis.

PMID- 10342723
TI  - Medical negligence and the NHS: an economic analysis.
AB  - Medical negligence was estimated to cost the NHS in England 235m pounds sterling
      in 1996/1997, growing at rate of up to 25% per annum. Yet analysis of NHS
      accounts suggest that a change in accounting policy has led to growth rates and
      recurrent expenditure on medical negligence being over estimated. The main
      concern, however, is total societal cost, not the accounting cost to the NHS. The
      objective of policy should be to ensure that cost-effective investment in injury
      prevention takes place. Measures that simply shift cost to other social budgets
      or onto patients are not helpful. NHS arrangements changed in the 1990s with
      Trusts taking responsibility for claims against hospital doctors and a new NHS
      Litigation Authority providing insurance for Trusts. It is unclear, however,
      whether Trusts have had either the incentives or the ability to implement effect
      risk management policies. Estimates based on two US studies and one UK study
      suggest that negligence in the NHS in England may cause around 90000 adverse
      events per year involving 13500 deaths, but only resulting in around 7000 claims
      and 2000 payments. A priority must be the establishment of a comprehensive
      national database of claims information. Other policy measures are proposed to
      reinforce the incentives on Trusts and doctors to implement cost-effective risk
      management policies.

PMID- 10342724
TI  - Modelling the EuroQol data: a comparison of discrete choice conjoint and
      conditional preference modelling.
AB  - This article compares two measurement strategies for measuring EuroQol health
      state preferences: (a) conditional preference modelling, implemented using rating
      scale and standard gamble scaling methods and (b) discrete choice conjoint
      modelling. The nature of the model form of the EuroQol health status preference
      function and the predictive ability of each measurement strategy formed the basis
      of the comparison. Data were collected via personal interviews with 140 US
      patients, 139 of whom provided usable responses. Both strategies supported a
      multiplicative model form as representative of the EuroQol health status
      preference function and were acceptable in terms of predictive ability. The
      agreement of the two measurement strategies on the nature of the model form
      provides evidence of the convergent validity of the multiplicative nature of the
      EuroQol health status preference function in this patient population. Since both
      strategies were found to be acceptable in terms of predictive ability, further
      research comparing preference scores and measuring respondent evaluations of the
      methodologies is necessary to illustrate the relative strengths and weaknesses of
      different health state preference measurement methodologies.

PMID- 10342725
TI  - The weighting exercise for the Swedish version of the EuroQol.
AB  - The EuroQol weighting exercise consists of three parts. In the first, the
      respondents state their own health using five dimensions with three levels in
      each, and then they rate their own health state on a visual analogue scale. In
      the second part, respondents attach weights to some of the possible health
      states. The last part contains questions about background information. The
      present article presents such weights derived from a sample of the Swedish
      population. The sample of 1000 Swedish citizens was drawn randomly from a
      national address register. The overall response rate was 54.2%, though 315
      (31.5%) of the responses were ultimately deemed usable. Most of the health states
      included in the weighting exercise were well-chosen. Most of them were
      represented by at least one of the respondents. The respondent characteristics
      that had any influence on the valuation of health states in the weighting
      exercise was rating of own health, age and level of education, where a higher
      rating of own health, higher age and lower level of education resulted in higher
      valuations.

PMID- 10342726
TI  - Policy-induced changes in Maori mortality patterns in the New Zealand economic
      reform period.
AB  - New Zealand's pro-market reform process commencing in 1984, while generally
      popular, did not represent a net social benefit for all socio-economic, cultural
      and ethnic groups. The reforms imposed hardships on groups heavily dependent on
      manual jobs in the manufacturing sector, on groups experiencing above average
      rates of unemployment, and on groups dependent on social programmes for stability
      in income flows. One group possessing all three characteristics, and adversely
      affected, was New Zealand's aboriginal population--the Maori. Previous
      statistical analyses have established that the Maori are a low income group that
      suffered a substantial decline in relative income from 1984 to 1987. The
      statistical research in this study establishes that Maori aged 30-79 years also
      experienced an increase in mortality ratios relative to the rest of the
      population, commencing in 1987. It is postulated that the decline in economic
      stability was a source of stress for middle-aged Maori, and that this was a
      contributing factor to the increase in observed relative mortality.

PMID- 10342727
TI  - Varying health care provider objectives and cost-shifting: the case of retail
      pharmacy in the US.
AB  - In this paper we investigate the relationship between health care provider
      objectives, cost-shifting, and prices by exploring the relationship between state
      Medicaid pharmacy reimbursements and average prices paid by pharmacy retail
      customers for four distinct pharmaceutical products across the US in 1994. We
      develop a more general theory than past researchers to enable provider objectives
      to vary with Medicaid pharmacy reimbursement levels. We find that provider
      objectives and the direction of relationship between Medicaid pharmacy
      reimbursements and retail prices vary with Medicaid pharmacy reimbursement
      levels. At high Medicaid pharmacy reimbursement levels we find a consistent
      negative relationship across products. At low Medicaid pharmacy reimbursement
      levels, the direction of the relationship is product-specific. As a result,
      policy-makers should be aware that policies affecting reimbursements from
      government-sponsored health insurance will also affect retail customers that
      include the uninsured. Paradoxically, for certain products if a state cuts a
      generous Medicaid reimbursement level this could hurt uninsured patients, whereas
      cuts in a stingy Medicaid reimbursement rate may help uninsured patients.

PMID- 10342728
TI  - Internal markets and health care efficiency: a multiple-output stochastic
      frontier analysis.
AB  - This paper has two purposes. The first purpose is methodological and aims to
      extend previous work on efficiency analysis by implementing a multiple-output
      stochastic ray frontier production function model. This model generalizes the
      single-output stochastic frontier model to multiple-input, multiple-output
      technologies and allows simultaneous estimation of technical efficiency and
      analysis of influential variables on efficiency. The second, empirical, purpose
      is to test for existence and magnitude of the effect of purchaser/provider split
      combined with new reimbursement schemes on technical efficiency in the Swedish
      public hospital system. The analysis is carried out with a panel data set
      covering the total population of 26 Swedish County Councils from 1989 to 1995.
      Our empirical results support the frontier model specification and indicate that
      output-based reimbursement improves technical efficiency. The potential saving in
      costs due to a switch from budget-based allocation to output-based allocation is
      estimated to be almost 10%.

PMID- 10342729
TI  - Health knowledge and smoking among South African women.
AB  - While several studies of developed countries have attempted to understand
      individual smoking using economic models, no such studies have been conducted in
      South Africa. The purpose of this paper is to identify which factors influence
      individual South African women's choice to smoke cigarettes and their knowledge
      of the health risks of smoking. To allow for the implied correlation between the
      unobservable components of the reduced form equations for these health inputs the
      model is estimated as a bivariate probit. In order to identify those women who
      are most at risk of becoming smokers and those who are most likely to benefit
      from health education, the results show how the probability of being an
      uninformed non-smoker or an uninformed smoker vary across different socio
      economic groups.

PMID- 10342730
TI  - Ratio-based and net benefit-based approaches to health care resource allocation:
      proofs of optimality and equivalence.
AB  - Both incremental cost-effectiveness ratios and net benefits have been proposed as
      summary measures for use in cost-effectiveness analyses. We present a unifying
      proof of the optimality and equivalence of ICER- and net benefit-based approaches
      to the health resource allocation problem, including both 'fixed budget' and
      'fixed price' decision rules. If internally consistent willingness-to-pay values
      are used, ratio- and net benefit-based decision rules identify the same optimal
      allocation. Because they have identical resource allocation implications, use of
      one or other of the two approaches must be based on other criteria, such as their
      behaviour under conditions of uncertainty.

PMID- 10342731
TI  - Health economics has lost its way--or why David Kernick is (partly) right.

PMID- 10342732
TI  - US and UK health economics: a reply to Joe Newhouse's paper.

PMID- 10342733
TI  - Localization of C-X-C and C-C chemokines to renal tubular epithelial cells in
      human kidney transplants is not confined to acute cellular rejection.
AB  - Chemokines are important mediators of leucocyte chemoattraction to inflammatory
      sites. Previous work has shown that the expression of some chemokines is
      upregulated during renal transplant rejection. The objectives of the present
      study were to determine whether chemokine expression is increased during renal
      transplant rejection. Immunohistochemistry was used to localize the C-X-C (alpha)
      chemokine interleukin-8 (IL-8) and the C-C (beta) chemokines monocyte
      chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1beta (MIP
      1beta) in 30 needle biopsies of human kidney transplants taken for diagnosis of
      renal dysfunction. Urine samples from transplant patients taken immediately prior
      to biopsy were assayed for chemokine content using enzyme-linked immunosorbent
      assays (ELISAs). Results from groups of patients having different
      clinicopathological diagnoses were then compared. All three chemokines were
      detected in most renal transplant biopsies showing acute cellular rejection but,
      although infiltrating leucocytes were often positive, staining was predominantly
      localized to renal tubular epithelium. Staining for MCP-1 was generally weaker
      than for the other chemokines, and collecting tubules were usually stained more
      strongly than proximal convoluted tubules. Tubular epithelial staining was also
      found in biopsies from patients without signs of acute cellular rejection. There
      were significantly higher amounts of IL-8 in the urine of patients with acute
      cellular rejection, even when patients with urinary tract infections were
      excluded, but mean titres of urinary MIP-1beta did not differ between patient
      groups. This was also found when titres were normalized for urine volume and
      creatinine levels. Production of IL-8, MCP-1 and MIP-1beta is not confined to
      kidney transplants showing acute cellular rejection, and may be a relatively
      nonspecific response of tubular epithelial cells to renal damage.

PMID- 10342734
TI  - EBV-B cells as antigen presenting cells in characterization of the self/donor
      context of allorecognition by T lymphocytes.
AB  - Alloreactivity is caused by T cell recognition of foreign histocompatibility
      antigens according to two models: (i) indirect recognition, in which processed
      allogeneic antigens are presented by self-major histocompatibility complexes like
      any other foreign antigen, and (ii) direct recognition, where the foreign MHC
      itself is recognized breaking the T cell recognition rule of self-restriction.
      This paper uses these two cases of alloantigen presentation as illustrative
      examples to investigate (i) the capacity of Epstein-Barr virus-transformed B
      cells (EBV-B cells) to process alloantigens, and (ii) in vitro assays with EBV-B
      cell lysate as a source of alloantigen, in order to characterize alloreactive T
      cell populations. A microculture system was established using donor EBV-B cell
      lysate as a source of the allogeneic antigen and donor or recipient EBV-B cells
      as antigen presenting cells to investigate whether alloantigen is recognized by
      effector T cells from the recipient. T lymphocytes produced after expansion in
      the presence of interleukin-2 from four samples of liver biopsies (three
      patients) and four samples of bronchoalveolar lavages (four patients) were used
      as effector cells. Upon human leucocyte antigen class II typing, these expressed
      the patient phenotype. When the T lymphocytes were from liver grafts, the
      recognition involved donor antigens presented by donor EBV-B cells (direct
      recognition). On the other hand, when the T lymphocytes were cultured from lung
      grafts, they mainly recognized antigens of donor EBV-B cell lysates in a self
      restricted context (indirect recognition). These data suggest that EBV-B cells
      can provide allogeneic determinants recognized by T cells in donor or self
      contexts, i.e. through either direct or indirect recognition.

PMID- 10342735
TI  - T cell repertoire expression in murine recipients of bone marrow transplant after
      LF 08-0299 (Tresperimus) administration.
AB  - LF 08-0299 (Tresperimus), a novel immunosuppressive compound, has been previously
      shown to prevent graft-versus-host disease in murine models. In this study, we
      investigated the influence of LF 08-0299 on the TCR Vbeta repertoire of
      irradiated F1 recipient mice reconstituted with either syngeneic or parental bone
      marrow cells. We showed that a partial blockade of thymic differentiation
      occurred in normal mice under treatment at the transition CD4-/CD8- to CD4+/CD8+,
      and that this blockade was fully reversible. Despite the effect on the thymus,
      normal T cell repertoire negative selection was preserved following syngeneic
      bone marrow transplantation. We further assessed whether LF 08-0299
      administration could modify Vbeta T cell expression in irradiated recipients
      reconstituted with parental bone marrow cells. In our murine parental to F1
      transplant model, abnormal TCR Vbeta3, Vbeta5, Vbeta6 and Vbeta11 expression was
      demonstrated in peripheral lymph nodes of irradiated recipients. Moreover, Vbeta6
      and Vbeta3 T cell populations were overexpressed. Administration of LF 08-0299
      modified the pattern of Vbeta T cell expression. The expansion of Vbeta6 T cells
      was selectively inhibited under LF 08-0299 therapy and, in contrast, Vbeta5 T
      cells were overexpressed. Lymph node histological analysis showed that LF 08-0299
      administration fully prevented the graft-versus-host reaction occurring in
      untreated recipient mice.

PMID- 10342736
TI  - Impact of Flt-3 ligand on donor-derived antigen presenting cells and alloimmune
      reactivity in heart graft recipients given adjuvant donor bone marrow.
AB  - The influence of the haematopoietic growth factor Flt-3 ligand (FL) on the
      incidence and function of donor major histocompatibility complex (MHC) class II+
      cells in the lymphoid tissues of noncytoablated recipients of heart allografts
      and donor bone marrow (BM) cells was investigated. C3H (H2k) mice received a
      nonvascularized B10 (H2b) heart allograft in the dorsal ear pinna, followed by an
      i.v. infusion of 50 x 10(6) donor BM cells. They were given FL (10 microg/day
      i.p., x7 days), tacrolimus (2mg/kg/day i.p., x13 days) or both agents immediately
      following heart transplantation (HTx) and were killed 10 or 21 days later. Their
      BM cells were propagated in vitro in granulocyte macrophage colony stimulating
      factor (GM-CSF) and IL-4 for 5 days to promote the growth of dendritic cells
      (DC). Donor DC were identified by immunocytochemical staining. Spleens were
      harvested, and donor (IAb+) cells enumerated by immunohistochemical analysis.
      Donor MHC class II DNA was detected in spleens and cultured BM-derived cells by
      reverse transcriptase-polymerase chain reaction (RT-PCR). A striking increase in
      donor MHC class II+ cells was noted in both the spleen and BM of the BM +
      tacrolimus-treated group compared to either the BM alone, or BM + FL-treated
      groups. Addition of FL treatment to BM + tacrolimus led to a further increase in
      donor cells in spleen (three-fold at 10 days, and two-fold at 21 days). The
      increase in donor cells at 10 days was almost 140-fold compared to that with
      donor BM alone. PCR analysis at this time revealed enhanced donor DNA in the BM +
      FL + tacrolimus group compared to that in the BM + tacrolimus group. FL treatment
      augmented mixed leucocyte reactions (MLR) and cytotoxic T lymphocyte (CTL)
      activity of host spleen cells against donor alloantigens. These effects were
      reversed by tacrolimus administration. Histopathology of heart grafts from
      tacrolimus-treated animals at 10 and 21 days showed absence or substantial
      reduction in cellular infiltration, and the preservation of viable myocardium. By
      contrast, in untreated mice, or animals given BM or BM + FL alone, there was
      marked cellular infiltration, and features of accelerated rejection. Donor
      derived DC could be propagated in vitro from the BM of heart transplant
      recipients given donor BM, especially from mice that also received tacrolimus +/-
      FL. At day 21, donor-derived cells could only be propagated from the BM + FL +
      tacrolimus-treated group. These findings show that numbers of donor antigen
      presenting cells (APC) or their progenitors can be markedly increased in
      conventionally immunosuppressed organ allograft recipients given donor BM + a
      potent haematopoietic and DC-growth promoting cytokine. Although withdrawal of
      systemic immunosuppression appears to allow exhibition of the potential
      allostimulatory activity of these donor APC leading to rejection, the model
      provides a useful basis for further evaluation of the persistence and
      manipulation of donor haematopoietic cells and in particular, donor-derived APC,
      on the outcome of organ transplantation.

PMID- 10342737
TI  - Procalcitonin: a new marker for diagnosis of acute rejection and bacterial
      infection in patients after heart and lung transplantation.
AB  - The aim of the study was to investigate the reliability of procalcitonin (PCT), a
      new potential marker for detection of bacterial, fungal and protozoal infections,
      in order to differentiate these from viral infections and early rejections in
      heart, heart-lung and lung transplanted patients. PCT is a propeptide of
      calcitonin with unknown origin which is not detectable in plasma of healthy
      subjects. It increases rapidly and significantly under severe microbial
      infections. METHODS: PCT plasma levels were measured using an immuno-luminescence
      assay. C-reactive protein and white blood cells were quantified to validate the
      PCT values. RESULTS: Increased levels of PCT were found in all transplant
      patients with bacterial, fungal and protozoal infections. The magnitude of the
      values were clearly associated with the severity of the infection. Trauma of
      operation or inflammatory events such as viral infections and rejections did not
      trigger PCT-production. The release of PCT did not depend on the type of
      pathogens even though Aspergillum resulted in the highest levels measured.
      Sensitivity, specificity and prognostic value of PCT for systemic infections were
      higher than of the other parameters investigated. CONCLUSION: PCT is a highly
      specific analyte which shows significant diagnostic validities when nonviral
      infections are compared with rejection episodes. PCT discriminates between
      inflammatory events such as rejection or viral infections and nonviral-infections
      including bacterial, fungal and protozoal infections. The half-life of PCT is 24
      h indicating clearly a competent antibiotic treatment. Unnecessary antibiotic
      therapy can be avoided due to the early exclusion of bacterial and fungal
      infections.

PMID- 10342738
TI  - WOFIE augments the immunosuppressive potency of FK-506. Window of opportunity for
      immunological engagement.
AB  - Bidirectional recognition of donor- and recipient-derived immunocompetent cells
      has been proven to play a pivotal role for the induction of long-term
      unresponsiveness to allogeneic grafts. This study investigated the fate of
      heterotopic heart grafts with respect to the timing of subtherapeutic doses of FK
      506 and with respect to the time point and type of donor antigen application,
      leaving space for mutual adaptation of alloreactive lymphocytes, designated as
      the 'WOFIE-concept' (window of opportunity for immunological engagement),
      originally described by R Calne. METHODS: Heterotropic heart transplantation was
      performed using male DA (RT1.a) donor and LEW (RT1.1) recipient rats in the
      following groups (n = 6). FK-506 was applied intramuscularly (i.m.) using doses
      of 2 mg/kg x body weight per day. Donor antigen application was performed either
      by DA blood transfusion, 2 ml intravenously (i.v.), or by i.v. transfusion of 5 x
      10(7) DA splenocytes. (i) LEW --> LEW, untreated; (ii) DA --> LEW, untreated;
      (iii) DA --> LEW, FK-506 days 0, 4-7; (iv) DA --> LEW, FK-506 as group (iii) plus
      2 ml of DA blood 6 h post-Tx; (v) same as group (iv) but DA blood transfusion 24
      h post-Tx; (vi) DA --> LEW, FK-506 as group (iii) plus DA splenocytes 6 h post
      Tx; (vii) same as group (vi) but DA splenocyte transfusion 24 h post-Tx; (viii)
      DA --> LEW, FK-506 days 0-4 and (ix) DA --> LEW, FK-506 as group (viii) plus DA
      blood 6 h post-Tx. Immunohistochemical stainings (APAAP-method) of the allografts
      and flow cytometric analysis of recipient spleens were performed electively 3, 7
      and 14 days after organ reperfusion. RESULTS: The mean graft survival differed
      significantly between groups and comprised (mean +/- SD days): (i) >100, (ii) 6.5
      +/- 1.0, (iii) 31.6 +/- 12.1, (iv) 44.8 +/- 10.1, (v) 29.8 +/- 14.2, (vi) 27.2 +/
      4.7, (vii) 14.6 +/- 4.2, 17.5 +/- 4.2, (viii) 17.5 +/- 4.2 and (ix) 18.8 +/- 2.8
      days. Prolongation of graft survival and long-term unresponsiveness (group iv)
      revealed a substantially different pattern of graft infiltration. CONCLUSIONS:
      Effective treatment with unspecific immunosuppressants like FK-506 can be
      substantially improved if (i) mutual antigen recognition between donor and
      recipient immunocompetent cells is warranted, (ii) donor-derived blood-borne
      antigens are given immediately after graft reperfusion, and (iii) the type of
      inoculated donor antigen has a strong impact on graft survival as splenocytes
      which contain a large population of professional antigen-presenting cells failed
      to prolong graft survival after interrupted FK-506 treatment.

PMID- 10342740
TI  - Rebound effect of the allogenic T-cell response to donor and third-party
      lymphocytes after cyclosporine withdrawal in renal transplant recipients.
AB  - Mixed lymphocyte reaction (MLR) assays were performed serially over 24 months in
      19 first cadaver renal transplant recipients. Immunosuppression consisted of
      cyclosporine, methylprednisolone and azathioprine. Cyclosporine was withdrawn at
      6 months postoperatively. The MLR reactivity gradually decreased over the first 3
      months following transplantation. However, there was a significant increase in
      MLR reactivity at 12 months postoperatively after the cyclosporine withdrawal.
      This rebound effect in MLR reactivity following cyclosporine withdrawal could
      account for the increased incidence of acute rejection episodes.

PMID- 10342739
TI  - Inhibition of endothelial receptor expression and of T-cell ligand activity by
      mycophenolate mofetil.
AB  - The novel immunosuppressive drug mycophenolate mofetil (CellCept, MMF) blocks DNA
      synthesis by the inhibition of the enzyme inosine monophosphate dehydrogenase
      (IMDH). IMDH is also involved in the synthesis of adhesion receptors which are
      known to play an important role in the regulation of cell-cell contacts.
      Therefore, application of MMF might lead to a reduction of cellular infiltrates
      in the course of transplant rejection. To evaluate the therapeutic value of MMF,
      we investigated to what extent MMF blocks T-lymphocyte infiltration in vitro with
      regard to (a) adhesion to endothelial cells, (b) horizontal migration along these
      cells and (c) penetration through the endothelial cells. The results demonstrated
      a strong inhibition of both CD4+ and CD8+ T-cell adhesion and penetration by MMF.
      The ID50 value for CD4+ T-cell adhesion was calculated to be 0.03 microM and the
      ID50 value for CD4+ T-cell penetration 1.21 microM. MMF did not significantly
      influence the horizontal migration of T-lymphocytes along the human vascular
      endothelial cell (HUVEC) borders. FACS-analysis revealed a diminished E-selectin
      and P-selectin expression on endothelial cell membranes in the presence of MMF.
      Although MMF did not interfere with the synthesis of T-cell adhesion ligands, the
      binding activity of lymphocytic leucocyte function associated antigen 1 (LFA-1),
      very late antigen 4 (VLA-4) and PSGL-1 (P-selectin glycoprotein ligand 1) to
      immobilized intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion
      molecule 1 (VCAM-1) and P-selectin was impaired. Moreover, MMF prevented VLA-4
      and PSGL-1 receptor accumulation on the membranes of T-cell pseudopodia. It can
      be concluded that MMF possesses potent infiltration blocking properties. MMF
      evoked down-regulation of specific endothelial membrane molecules and the loss of
      protein localization in the lymphocyte protrusions might be predominantly
      responsible for the observed blockade of cell adhesion and penetration.

PMID- 10342742
TI  - Funding for transplant research.

PMID- 10342741
TI  - A transient increase in endogeneous erythropoietin levels after paediatric liver
      transplantation.
AB  - We investigated whether liver transplantation affects endogeneous erythropoietin
      (EPO) synthesis. Serum EPO levels were measured before transplantation and during
      the peri-transplant period in ten consecutive paediatric patients who had
      received a liver allograft without recombinant EPO therapy. All patients were
      anaemic on post-operative day 1 (POD 1); however, the haemoglobin levels of three
      patients gradually increased and required phlebotomy on POD 5-9. The serum levels
      of EPO in all patients were within the normal range before surgery, but six of
      the ten patients had a transient increased level of EPO at 1248 h after
      transplantation. A transient increase of endogeneous EPO following paediatric
      liver transplantation may be associated with extramedullary erythropoiesis in
      human liver grafts.

PMID- 10342743
TI  - Dendritic cell activation induced by various stimuli, e.g. exposure to
      microorganisms, their products, cytokines, and simple chemicals as well as
      adhesion to extracellular matrix.
AB  - Before the establishment of procedures to cultured dendritic cells (DCs) from
      peripheral blood or bone marrow progenitor cells using a combination of several
      cytokines, Langerhans cells (LCs) of the epidermis have been used as the best
      characterized dendritic cell population. The studies using LCs freshly isolated
      from the skin or DCs from the blood or spleen and cultured DCs from progenitors
      have elucidated that although DCs are a unique cell population characterized by
      their potent antigen presenting function, especially by their induction of
      primary antigen-specific T cell responses, they are immature and less potent in
      antigen presenting function immediately after isolated from the skin or from
      other non-lymphoid tissues. Therefore, DCs must be stimulated to augment their
      antigen presenting function and to initiate a naive T cell response. Recently, it
      becomes clear that a variety of signals, such as microorganisms, cytokines,
      adhesion to extracellular matrix, and simple chemicals like haptens, can induce
      this activation process in DCs, which is also called as DC maturation. In this
      paper, we discuss what kinds of stimuli effectively activate DCs.

PMID- 10342744
TI  - Accessory and adhesion molecules expressed on murine epidermal Langerhans cells
      and the modulation by cytokines.
AB  - Langerhans cells (LC) are MHC class II (Ia)-positive dendritic cells that act as
      an antigen-presenting cells for T cell-dependent immune responses. LC originate
      from cells in bone marrow and migrate into the epidermis through blood vessels.
      LC also migrate from the epidermis to regional lymph nodes after antigen
      stimulation where they present antigens to T cells. These are the essential
      features of LC. The morphological and functional properties of LC are modulated
      by external stimuli or various cytokines. In this review we focus on the
      accessory and adhesion molecules on LC and describe how these molecules are
      modulated by cytokines. We also describe the molecules participating in the
      migration of LC into and from the epidermis. Moreover, we introduce our data
      obtained from purified murine epidermal LC and from the transgenic mice
      overexpressing several cytokines in the epidermis.

PMID- 10342745
TI  - The effect of neuropeptides/hormones on Langerhans cells.
AB  - Neuropeptides/hormones have been shown to regulate the various functions of many
      immunocompetent cells. A number of neuropeptides/hormones has been demonstrated
      to be present in the skin and a close anatomical association between calcitonin
      gene-related peptide (CGRP)-containing nerves and Langerhans cells (LC) has been
      reported. In addition to the CGRP receptor, receptors for several neuropeptides
      including pituitary adenylate cyclase activating polypeptide (PACAP) and gastrin
      releasing peptide (GRP) are found on LC, suggesting these neuropeptides might
      have some effects on LC. CGRP inhibits alloantigen presentation and stimulation
      of a specific-antigen responsive T-cell clone by LC. Pre-treatment of LC with
      CGRP also inhibits the elicitation of delayed type hypersensitivity (DTH) in
      tumor immune mice. Upregulation of B7-2 expression on LC is suppressed by CGRP,
      which might be, in part, responsible for the inhibitory effect of CGRP in the
      functional assay. The production of some inflammatory cytokines such as IL-10 by
      LC-like cell line XS52 is regulated by CGRP and the functional effect of CGRP
      appears to be at least partially mediated through the autocrine regulation of IL
      10. Alpha-MSH is another neuropeptide, the effect of which has been well studied
      in the cutaneous immune system. Pre-treatment of mice with alpha-MSH produces
      inhibitory effects in contact hypersensitivity (CHS). IL-10 has been suggested to
      be involved in the inhibitory effect of alpha-MSH. The receptors and the
      functional effects of other proopiomelanocortin (POMC)-derived peptides including
      beta-endorphin and catecholamines on LC are under investigation.

PMID- 10342747
TI  - Roles of Langerhans cells in genetic immunization.

PMID- 10342746
TI  - Fc epsilon RI on dendritic cells: a receptor, which links IgE mediated allergic
      reaction and T cell mediated cellular response.
AB  - Dendritic cells (DC) are bone marrow derived cells with strong antigen presenting
      capacity and can induce primary immune responses by activating naive T cells.
      Cells of this lineage are called as professional antigen presenting cells (APC),
      because of their primary function as APC. Since the demonstration of IgE bound
      epidermal Langerhans cells (LC) in atopic dermatitis (AD) patients, a role of IgE
      bearing DC as a regulator of IgE mediated allergic reactions is emphasized.
      Indeed, IgE molecules on DC are functional. DC can take up, process and present
      IgE bound antigens to T cells more efficiently by means of their surface IgE
      receptor, FcepsilonRI. In addition to its role as an antigen focusing molecule,
      DC FcepsilonRI may have another function to induce co-stimulatory signals to T
      cells, by which Th2 type T cell activation is preferentially induced. Thus, this
      receptor could serve as an amplifying factor for T cell mediated allergic
      reactions.

PMID- 10342748
TI  - The proliferative properties of tumor cells differentially correlate with the
      host immune responses in anogenital Bowen's disease.
AB  - Bowen's disease is a squamous cell carcinoma in situ that rarely invades into the
      underlying dermis. In order to evaluate the relationship between the cytological
      properties of the tumor cells and the host immune response, we have examined the
      expression of p53 and proliferating cell nuclear antigen (PCNA), and the number
      of mitotic cells, clumping cells, koilocytes, Langerhans cells (LCs) and dermal
      lymphoid cell infiltration in 18 cases of anogenital Bowen's disease. When
      compared with normal anogenital skins (n = 10), a statistically significant
      number of p53-positive cells, PCNA-positive cells, mitotic cells, clumping cells,
      koilocytes and dermal lymphoid cells was observed in the cases of Bowen's
      disease. Importantly, there existed a very strong correlation between the number
      of PCNA-positive tumor cells and the number of infiltrated dermal lymphoid cells.
      Moreover, the number of mitotic cells significantly correlated with the number of
      intratumoral LCs. The in situ hybridization technique for human papilloma virus
      (HPV) demonstrated that the HPV-infected Bowen's disease showed a similar
      histological and immunohistological pattern as the HPV-non-infected counterparts,
      except for increased koilocyte formation and decreased p53 positivity. The
      present data suggest that the proliferative activity of Bowen's disease
      significantly correlates with the host immune reaction, and that the host immune
      system may differentially recognize the different cytological properties of tumor
      cells in the Bowen's disease.

PMID- 10342749
TI  - Endogenous neutralizing anti-IL-1 alpha autoantibodies in inflammatory skin
      diseases: possible natural inhibitor for over expressed epidermal IL-1.
AB  - Interleukin 1alpha (IL-1alpha) is thought to play a central role in inflammatory
      reactions of the skin. Its excessive production and discharge by keratinocytes
      has been implicated in psoriasis, bullous diseases and other skin diseases. In
      addition to the type 2 IL-1 receptor and the IL-1 receptor antagonist, anti-IL-1
      antibody in human serum has been proposed as a potential means to down regulate
      systemic responses attributable to IL-1. However, the relationship of these
      antibodies to disease and particularly to disease pathogenesis is still unclear.
      To understand this relationship, we characterized the anti-IL-1 autoantibody in
      sera from various skin diseases. IL-1alpha and IL-1beta radioimmunoassay, and
      immuno-blotting study showed the existence of IL-1alpha autoantibody but not
      autoantibodies to IL-1beta or pro-IL-1beta. High titer of anti-IL-1alpha
      autoantibodies were detected in the sera from inflammatory skin diseases with
      epidermal injury, including psoriasis, palmoplantar pustulosis, pustular
      psoriasis, pemphigus and lichen planus. In contrast, few samples from non
      epidermodestructive bullous pemphigoid, atopic dermatitis and healthy normal
      controls had autoantibodies. The titer of anti-IL-1alpha autoantibodies showed
      some relation to the clinical course of psoriasis and pemphigus. Anti-IL-1
      autoantibody neutralized rhIL-1alpha in D10.G4 assay and inhibited receptor
      binding of FITC-rhIL-1alpha. Taken together present data, the keratinocyte
      derived IL-1alpha could be a source of autoantigen that provokes production of
      endogenous anti-IL-1alpha autoantibody, which may regulate IL-1alpha mediated
      cutaneous inflammation.

PMID- 10342750
TI  - Increased cutaneous immunoreactive stem cell factor expression and serum stem
      cell factor level in systemic scleroderma.
AB  - Skin hyperpigmentation and itching are characteristic findings in systemic
      sclerosis (SSC) patients. Stem cell factor (SCF, c-kit ligand) is a
      multifunctional cytokine which can promote melanocyte and mast cell development.
      We investigated the SCF expression histopathologically in normal and SSC skin,
      and compared the expression with the serum SCF levels measured with a specific
      enzyme-linked immunosorbent assay. The epidermal and dermal immunoreactive SCF
      expression was markedly higher in the forearm skin of edematous phase SSC
      patients than in that of normal subjects. Tissue SCF expression declined from the
      sclerotic phase to the atrophic phase, where it was close to the normal level. In
      contrast, the elevated serum SCF level seen in the edematous phase samples was
      further increased in the sclerotic phase samples. The serum SCF level decreased
      in the atrophic phase, but it still remained at a level higher than that of the
      normal controls. Itching and increase of dermal mast cell number are
      characteristic of edematous phase SSC, and are in bears a parallel to the
      presently observed dermal SCF expression profile. Pigmentation is significant in
      sclerotic phase SSC and lasts to the atrophic phase, which may correspond to the
      serum SCF level observed here. These results indicate a contribution of the
      fibroblast membrane integral SCF in dermal mast cell development, and of the
      soluble serum SCF to melanocyte activation in SSC.

PMID- 10342751
TI  - Biology of spider silk.
AB  - Studies are beginning to show that spider silk can be highly variable in chemical
      composition and mechanical properties. Clearly, both external and internal
      conditions affect silk production and thus the mechanical properties of the
      finished thread. An argument can be made that silk is optimised for a wide range
      of conditions rather than maximised for strength or toughness. Moreover, it seems
      that the spider is able to induce rapid and temporary adaptations of silk
      properties.

PMID- 10342752
TI  - High molecular mass complexes of aquatic silk proteins.
AB  - Little is known about specific protein protein associations that take place
      during formation of Chironomus tentans silk. The aim of this study was to learn
      if C. tentans salivary glands contain biochemically discrete silk protein
      complexes. Examination of native extracts by non-denaturing agarose gel
      electrophoresis and immunoblotting revealed two SDS-resistant complexes: C1a,
      nominally containing silk proteins spIa, sp185 and sp140, and C1b, containing
      spIb, sp185 and sp140. The data also implied that C1a and C1b can further
      associate into SDS-sensitive homo- or hetero-oligomers. Sedimentation of extracts
      in preparative glycerol gradients resulted in a heterogeneous distribution of C1a
      and C1b centered near 30S. Examination of gradient fractions by denaturing
      polyacrylamide gel electrophoresis and immunoblotting indicated that C1a and C1b
      co-sediment with spIs, sp185, and sp140; however, these fractions also contained
      sp40, sp17 and sp12. In contrast, two other silk proteins sedimented throughout
      the gradient. Electron micrographs of a complex-containing fraction showed
      discrete, sometimes oligomeric lattice-like structures that, over time, assembled
      in vitro into multistranded beaded fibers. It is proposed that C1a and C1b are
      quaternary structures that are intermediates in the assembly pathway of C.
      tentans silk.

PMID- 10342753
TI  - Protein and amino acid composition of silks from the cob weaver, Latrodectus
      hesperus (black widow).
AB  - The silks from the cob weaving spider, Latrodectus hesperus (black widow), have
      been examined with the goal of expanding our understanding of the relationship
      between the protein structure and mechanical performance of these unique
      biomaterials. The scaffolding, dragline and inner egg case silks each appear to
      be distinct fibers based on mole percent amino acid composition and polypeptide
      composition. Further, we find that the amino acid composition of dragline and egg
      case silk are similar to the analogous silks produced by orb weaving spiders,
      while scaffolding silk may represent a novel silk. The black widow silks are
      comprised of multiple high molecular weight polypeptides, however, the egg case
      and scaffolding silks also contain some smaller polypeptides.

PMID- 10342754
TI  - A comparison of the composition of silk proteins produced by spiders and insects.
AB  - Proteins that are highly expressed and composed of amino acids that are costly to
      synthesize are likely to place a greater drain on an organism's energy resources
      than proteins that are composed of ingested amino acids or ones that are
      metabolically simple to produce. Silks are highly expressed proteins produced by
      all spiders and many insects. We compared the metabolic costs of silks spun by
      arthropods by calculating the amount of ATP required to produce their component
      amino acids. Although a definitive conclusion requires detailed information on
      the dietary pools of amino acids available to arthropods, on the basis of the
      central metabolic pathways, silks spun by herbivorous, Lepidoptera larvae require
      significantly less ATP to synthesize than the dragline silks spun by predatory
      spiders. While not enough data are available to draw a statistically based
      conclusion, comparison of homologous silks across ancestral and derived taxa of
      the Araneoidea seems to suggest an evolutionary trend towards reduced silk costs.
      However, comparison of the synthetic costs of dragline silks across all
      araneomorph spiders suggests a complicated evolutionary pattern that cannot be
      attributed to phylogenetic position alone. We propose that the diverse silk
      producing systems of the araneoid spiders (including three types of protein glues
      and three types of silk fibroin), evolved through intra-organ competition and
      that taxon-specific differences in the composition of silks drawn from homologous
      glands may reflect limited or fluctuating amino acid availability. The different
      functional properties of spider silks may be a secondary result of selection
      acting on different polypeptide templates.

PMID- 10342755
TI  - Atomistic modeling of interphases in spider silk fibers.
AB  - We present a structural description of the intercrystalline polymer interphase
      based on atomistic modeling for spider dragline silk fibers. In the model small
      crystallites are connected by interphases. The interphases are assumed to be thin
      layers (< 4 nm) of statistically arranged chains. The calculated mechanical
      moduli of these interphases are significantly greater than the isotropic
      amorphous material.

PMID- 10342756
TI  - Structure refinement and diffuse streak scattering of silk (Bombyx mori).
AB  - Reexamination of the crystal structure of silk (Bombyx mori) was carried out by X
      ray diffraction method. Four molecular chains are contained in the rectangular
      unit cell with parameters, a = 9.38 A, b = 9.49 A, and c (fiber axis) = 6.98 A,
      and the space group P2(1)-C(2)2. Silk assumes the statistical crystal structure,
      in which two antipolar-antiparallel sheet structures with different orientations
      statistically occupy a crystal site with the ratio 2:1. The molecular
      conformation is essentially the same pleated sheet structure as Marsh, Corey and
      Pauling proposed. However, the sheet structure formed by hydrogen bonds assumes
      the antipolar antiparallel structure different from that proposed by Marsh, Corey
      and Pauling, in which the methyl groups of alanine residues alternately point to
      both sides of the sheet structure along the hydrogen bonding direction. The
      crystalline region of silk is composed of stacking of two antipolar antiparallel
      sheet structures with different orientations.

PMID- 10342757
TI  - Finite element modeling of banded structures in Bombyx mori silk fibres.
AB  - Transmission electron microscopy studies have shown curved bands of contrast in
      degummed Bombyx mori fibres. This contrast implies a molecular difference between
      the light and dark bands, which in turn implies a periodic variation in
      mechanical properties along the fibre axis. Finite element modeling was used to
      compare the mechanical behaviour of fibres with various banded geometries.
      Lateral, longitudinal and diagonal lamellae were compared with V-shaped and
      parabolic cupped lamellae. The simulation results from the lamellar models were
      compared to laminar composite theory. The cupped parabolic and V-shaped
      geometrics both showed a redistribution of the axial stresses from the centre
      toward the edge of the fibre. This redistribution allowed for a substantial
      increase in the toughness compared to simple lateral lamella as well as a
      moderate increase in the initial modulus without a significant change in the
      yield strength.

PMID- 10342758
TI  - Microvoids in Bombyx mori silk. An electron microscope study.
AB  - The size and distribution of microvoids in Bombyx mori silk were examined by
      transmission electron microscopy of silver sulphide 'stained' filaments. Silver
      sulphide deposited in voids and accessible regions of molecular structure appears
      as dense particles in thin transverse and longitudinal sections of silk
      filaments. Small particles (about 8 nm or less in diameter) occur around or
      adjacent to the periphery of the filaments. Larger particles (around 10-15 nm in
      diameter) occur in the form of dendritic arrays in the core region of the
      filaments. The leading edges of the dendritic arrays are oriented towards the
      fibre periphery. The particles (microvoids) appear to be either spherical or rod
      like in shape and are aligned parallel to the long axis of the filament. A
      skin/core structure is proposed.

PMID- 10342759
TI  - Short and long range order of the morphology of silk from Latrodectus hesperus
      (Black Widow) as characterized by atomic force microscopy.
AB  - The surfaces of both stretched and unstretched silk threads from the cobweb
      weaver, Latrodectus hesperus (Black Widow) have been examined by atomic force
      microscopy (AFM). AFM images of cobweb scaffolding threads show both unordered
      and highly ordered regions. Two types of fibers within the threads were observed:
      thicker (approximately 300 nm in diameter) fibers oriented parallel to the thread
      axis and thinner (10-100 nm) fibrils oriented across the thread axis. While
      regions which lacked parallel fibers or fibrils were observed on threads at all
      strain values, the probability of observing fibers and/or fibrils increased with
      strain. High-resolution AFM images show that with increasing strain, both mean
      fiber and fibril diameters decrease and that fibrils align themselves more
      closely with the thread axis. The observation of fibers and fibrils within the
      cobweb threads has implications for current models of the secondary and tertiary
      structure and organization of spider silk.

PMID- 10342760
TI  - Investigation of the nanofibrillar morphology in silk fibers by small angle X-ray
      scattering and atomic force microscopy.
AB  - Small angle X-ray scattering (SAXS) and atomic force microscopy (AFM)
      measurements have been shown to be consistent with the presence of nanofibrils in
      the cocoon silk of Bombyx mori and the dragline silk of Nephila clavipes. The
      transverse dimensions and correlation lengths range from >> 59 to 220 nm and in
      the axial direction from >> 80 to 230 nm. Also, the two-dimensional Fourier
      transforms of the height profiles of AFM topographic images of interior surfaces
      of B. mori follow a power law approximately the same as that for the Porod region
      of the SAXS data. In this manner, the AFM can be used to help remove ambiguity
      about the scatterers responsible for SAXS patterns.

PMID- 10342761
TI  - Structural analysis of silk with 13C NMR chemical shift contour plots.
AB  - The polymorphic structures of silk fibroins in the solid state were examined on
      the basis of a quantitative relationship between the 13C chemical shift and local
      structure in proteins. To determine this relationship, 13C chemical shift contour
      plots for C alpha and C beta carbons of Ala and Ser residues, and the C alpha
      chemical shift plot for Gly residues were prepared using atomic co-ordinates from
      the Protein Data Bank and 13C NMR chemical shift data in aqueous solution
      reported for 40 proteins. The 13C CP/MAS NMR chemical shifts of Ala, Ser and Gly
      residues of Bombyx mori silk fibroin in silk I and silk II forms were used along
      with 13C CP/MAS NMR chemical shifts of Ala residues of Samia cynthia ricini silk
      fibroin in beta-sheet and alpha-helix forms for the structure analyses of silk
      fibroins. The allowed regions in the 13C chemical shift contour plots for C alpha
      and C beta carbons of Ala and Ser residues for the structures in silk fibroins,
      i.e. Silk II, Silk I and alpha-helix, were determined using their 13C isotropic
      NMR chemical shifts in the solid state. There are two area of the phi,psi map
      which satisfy the observed Silk I chemical shift data for both the C alpha and C
      beta carbons of Ala and Ser residues in the 13C chemical shift contour plots.

PMID- 10342762
TI  - Supercontracted spider dragline silk: a solid-state NMR study of the local
      structure.
AB  - The local structure of supercontracted dragline silk from the spider Nephila
      madagascariensis was investigated by solid-state nuclear magnetic resonance. Two
      dimensional (2D) spin-diffusion experiments did not show any significant
      conformational changes in short-range order (and the secondary structure of the
      protein) upon supercontraction. Our results are in accordance with the proposal
      by Vollrath et al. (Proc R Soc London B 1996;263:147-151) that urea
      supercontraction does not alter the local structure of spider dragline silk
      fundamentally. However, significant differences in the dynamics of the
      polypeptide chain upon supercontraction are detected at room temperature. At low
      temperature, these dynamics are frozen out. In addition, the role of the solvent
      (water) in the silk is investigated in Nephila edulis. Mobile water is detected
      at temperatures significantly below the freezing point of bulk water.

PMID- 10342763
TI  - Aspects of X-ray diffraction on single spider fibers.
AB  - Diffraction patterns of silk from several spider species have been obtained by
      synchrotron radiation using a beam size > or = 10 microm. Single fiber
      diffraction patterns were obtained for fiber diameters down to a few microns.
      Diffraction patterns recorded with a 10 microm wide X-ray beam displayed fiber
      texture. The presence of two fractions of different crystallinity was confirmed
      for a single Nephila clavipes fiber. The orientation distribution of the polymer
      chains of the crystalline fraction along the fiber axis was found to be about 23
      degrees full-width at half maximum (fwhm). The azimuthal spread of the short
      range order fraction was about 86 degrees fwhm.

PMID- 10342764
TI  - Silk I structure in Bombyx mori silk foams.
AB  - Single crystals of Bombyx mori silk fibroin in the metastable silk I polymorph
      have been produced using a new foaming technique. Foams of silk protein are
      generated by bubbling pure nitrogen gas through an aqueous solution of
      regenerated silk fibroin. The foamed material is collected, dried, and then
      sonicated to yield individual crystals which were examined using transmission
      electron microscopy and electron diffraction. It is found that slightly acidic
      conditions in the solution from which the foam was generated favor the formation
      of silk II while neutral to slightly basic solutions favor silk I formation. More
      dilute solutions favor the formation of silk II while more concentrated solutions
      (about 7 wt.% or greater) favor the formation of silk I. X-ray powder diffraction
      patterns from the dried silk I foams displayed features highly indicative of silk
      I. We also report the first single crystal electron diffraction patterns of silk
      I. These patterns indicate a large unit cell, possibly 22.66 x 5.70 x 20.82 A.
      with six chains of six residues, Gly-Ala-Gly-Ala-Gly-Ser. Although we have not
      fully characterized this complex structure it appears that the chain is nearly
      fully extended and thus our data is consistent with models possessing general
      features similar to those proposed by Fossey SA, Nemethy G, Gibson KD, Scheraga
      HA. (Biopolymers 1991;31:1529-1541).

PMID- 10342765
TI  - Orientation, structure, wet-spinning, and molecular basis for supercontraction of
      spider dragline silk.
AB  - This manuscript reviews work from our laboratory that addresses the orientation,
      secondary structure, wet-spinning, and molecular basis for supercontraction of
      spider silk. It identifies the poly(alanine) runs as the crystalline regions,
      establishes the degree of orientation of these regions, and identifies the
      secondary structural elements of the conserved L-G-X-Q (X = G, S, or N) regions.
      It also describes methods for spinning very small amounts of protein polymers and
      it sets forth several molecular-level hypotheses concerning supercontraction.

PMID- 10342766
TI  - Molecular chain orientation in supercontracted and re-extended spider silk.
AB  - The dragline silk from Nephila clavipes was studied by wide angle X-ray
      diffraction in its original state, after supercontraction to L/Lo = 0.46, and
      during re-extension to its original length Lo. The fibers were carefully dried
      before each exposure. The molecular orientation in the crystalline regions is
      found to follow the simple predictions of affine deformation, indicating that the
      crystals act as inert rigid filler particles. The crystals retain considerable
      orientation after supercontraction, when non-crystalline orientation is weak.
      This shows that crystallization occurs after orientation as the fiber forms. The
      oriented amorphous material, treated as a phase of constant volume fraction, also
      follows affine deformation. These results do not contain any indication of a
      special structure in the protein fiber.

PMID- 10342767
TI  - Spider (Araneus diadematus) cocoon silk: a case of non-periodic lattice crystals
      with a twist?
AB  - Transmission electron microscopy was used to investigate the supramolecular
      structure of Araneus diadematus (garden spider) cocoon silk. Electron diffraction
      patterns contain features which are consistent with the presence of non-periodic
      lattice crystals, i.e. highly frustrated crystalline regions as identified
      previously in the major ampullate silk (MAS, dragline) of Nephila clavipes
      spiders. The diffraction patterns further suggest that crystals in A. diadematus
      cocoon silk may be twisted parallel to the chain direction, offering a potential
      explanation for the lower tensile stiffness of this fibre relative to MAS.

PMID- 10342768
TI  - The effect of post-spin drawing on spider silk microstructure: a birefringence
      model.
AB  - Measurements of optical birefringence have been used to characterise the effect
      of mechanical history on supramolecular structure in major ampullate silk from
      Nephila clavipes (golden orb weaver) spiders. Birefringence modelling is
      demonstrated to be a powerful technique for obtaining quantitative information on
      supramolecular rearrangement in response to macroscopic strain. Temporary and
      permanent birefringence changes measured as a function of strain and strain rate
      are interpreted in terms of two types of microstructural response: increased
      molecular alignment in all the microstructural phases present is accompanied by
      decreased lateral register within crystallographically ordered phases.
      Significant implications of these studies for the commercial processing of silks
      and silk-like biopolymers are discussed.

PMID- 10342769
TI  - Bombyx mori silk fibroin liquid crystallinity and crystallization at aqueous
      fibroin-organic solvent interfaces.
AB  - A banded morphology has been observed for Bombyx mori silk fibroin films obtained
      from an aqueous hexane interface; the period of the banding is approximately 1
      microm. Morphology and diffraction from different regions of the banded structure
      suggest that it is a free surface formed by a cholesteric liquid crystal.
      Truncated hexagonal lamellar crystallites of B. mori silk fibroin have been
      observed in films formed in the surface excess layer of fibroin at the interface
      between aqueous fibroin and hexane or chloroform. Based on initial
      crystallographic evidence, a three-fold helical conformation has been ascribed to
      the fibroin chains within the crystals. The chain conformation and crystalline
      habit appear to be similar to the silk III structure previously observed at the
      air-water interface (Valluzzi R, Gido SP. Biopolymers 1997;42:705-717; Valluzzi
      R, Gido S, Zhang W, Muller W, Kaplan D. Macromolecules 1996;29:8606-8614) but the
      crystalline packing is different. Diffraction data obtained for the crystallites
      are similar to diffraction behavior for a collagen-like model peptide.
      Diffraction patterns obtained from crystallized regions of the banded morphology
      can be indexed using the same unit cell as the hexagonal lamellar crystallites.
      Surfactancy of fibroin and subsequent aggregation and mesophase formation may
      help to explain the liquid crystallinity reported for silk, which is long
      suspected to play a role in the biological silk spinning process (Valluzzi R,
      Gido SP. Biopolymers 1997;42:705-717; Willcox, P. J.; Gido, SP, Muller W, Kaplan
      DL. Macromolecules 1996:29:5106-5110; Magoshi J, Magoshi Y, Nakamura S. In:
      Kaplan D, Adams W, Farmer B, Viney C, editors, Mechanism of Fiber Formation of
      Silkworm. Washington, DC: American Chemical Society 1994:292-310; Magoshi J,
      Magoshi Y, Nakamura S. J Appl Polym Sci Appl Polym Symp 1985;41:187-204; Magoshi
      J, Magoshi Y, Nakamura S. Polym Commun 1985;26:309.).

PMID- 10342770
TI  - Orientation of silk III at the air-water interface.
AB  - A threefold helical crystal structure of Bombyx mori silk fibroin has been
      observed in films prepared from aqueous silk fibroin solutions using the Langmuir
      Blodgett (LB) technique. The films were studied using a combination of
      transmission electron microscopy and electron diffraction techniques. Films
      prepared at a surface pressure of 16.7 mN/m have a uniaxially oriented
      crystalline texture, with the helical axis oriented perpendicular to the plane of
      the LB film. Films obtained from the air-water interface without compression have
      a different orientation, with the helical axes lying roughly in the plane of the
      film. In both cases the d-spacings observed in electron diffraction are the same
      and match a threefold helical model crystal structure, silk III, described in
      previous publications. Differences in the relative intensities of the observed
      reflections in both types of oriented samples, as compared to unoriented samples,
      allows estimations of orientation distributions and the calculations of
      orientation parameters. The orientation of the fibroin chain axis in the plane of
      the interfacial film for uncompressed samples is consistent with the amphiphilic
      behavior previously postulated to drive the formation of the threefold helical
      silk III conformation.

PMID- 10342771
TI  - Structure and function of the silk production pathway in the spider Nephila
      edulis.
AB  - Our observations on the major ampullate gland of the spider Nephila edulis
      indicate that the exceptionally tough and strong core and coat composite
      structure of the dragline thread is formed by the co-drawing of two feedstocks
      through a single die. The cuticle that lines the gland's duct has the structure
      of an advanced hollow fibre dialysis membrane and is thought to facilitate a
      rapid removal of water and change in ionic composition involved in the spinning
      process. A structure previously termed the 'valve' is thought to advance the
      broken thread and act as a pump to restart spinning after the accidental internal
      rupture of a thread. Together, these observations indicate that the spider silk
      production pathway is highly optimised for the production of silk threads and
      shows considerable biomimetic potential.

PMID- 10342772
TI  - Swelling and dissolution of silk fibroin (Bombyx mori) in N-methyl morpholine N
      oxide.
AB  - Bombyx mori silk fibers were dissolved in N-methyl morpholine N-oxide (MMNO), an
      organic cyclic amine oxide used for the solvent spinning of regenerated
      cellulosic fibers. The commercial MMNO monohydrate used in this study as a
      solvent for silk is a hygroscopic compound crystalline at room temperature, which
      becomes an active solvent after melting at 76 degrees C. The degree of hydration
      of MMNO was checked by DSC measurements. The solvation power of MMNO towards silk
      fibroin drastically decreased at a water content > or = 20-21% w/w. Dissolution
      of silk required both thermal and mechanical energy. The optimum temperature was
      100 degrees C. At lower temperatures dissolution proceeded very slowly. At higher
      temperatures, rapid depolymerization of silk fibroin occurred. The value of the
      Flory-Huggins interaction parameter chi for the MMNO-H2O-silk fibroin system was 
      8.5, suggesting that dissolution is a thermodynamically favored process. The
      extent of degradation of silk fibroin was assessed by measuring the intrinsic
      viscosity and determining the amino acid composition of silk after regeneration
      with an aqueous methanol solution, which was effective in removing the solvent
      and coagulating silk. Regenerated silk fibroin membranes were characterized by
      infrared spectroscopy, differential scanning calorimetry and scanning electron
      microscopy. The prevailing molecular conformation of silk fibroin chains was the
      beta-sheet structure, as shown by the intense amide I-III bands at 1704, 1627,
      1515, 1260, and 1230 cm(-1). The value of the I1260/I1230 intensity ratio
      (crystallinity index) was 0.68, comparable to that of the fibers. The DSC
      thermogram was characteristic of a silk fibroin material with unoriented beta
      sheet crystalline structure, with an intense decomposition endotherm at 294
      degrees C. The SEM examination of fractured surfaces showed the presence of a
      dense microstructure with a very fine texture formed by densely packed roundish
      particles of about 100-200 nm diameter.

PMID- 10342773
TI  - Designing recombinant spider silk proteins to control assembly.
AB  - The consensus repeat sequence found in the dragline silk from the spider, Nephila
      clavipes, was redesigned to incorporate a redox trigger flanking the beta-sheet
      forming polyalanine sequences. The methionine redox trigger, in the oxidized
      state, was incorporated to prevent the formation of the beta sheets, while in the
      reduced state would not result in sterical limitations to beta sheet formation. A
      synthetic gene incorporating the trigger was constructed, cloned and then
      expressed in Escherichia coli. The purified protein, about 25 kDa, contained the
      expected amino acid composition and migration behavior on SDS-PAGE. The
      recombinant protein was analyzed by X-ray diffraction, TEM, electron diffraction
      and circular dichroism in both oxidized and reduced states. Based on the results,
      the incorporation of a redox trigger appears to be a powerful experimental
      strategy to explore the self-assembly of fibrous proteins such as silks.

PMID- 10342774
TI  - Hypotheses that correlate the sequence, structure, and mechanical properties of
      spider silk proteins.
AB  - Several types of silks and silk protein coding genes have been characterized from
      orb-web weaving spiders. When the protein sequences of major ampullate, minor
      ampullate, and flagelliform silks from Nephila clavipes are compared, they can be
      summarized as sets of shared amino acid motifs. Four of these motifs and their
      likely secondary structures are described. Each structural element, termed a
      module, is then associated with its impact on the mechanical properties of a silk
      fiber. In particular, correlations are drawn between an alanine-rich 'crystalline
      module' and tensile strength and between a proline-containing 'elasticity module'
      and extensibility.

PMID- 10342775
TI  - Material properties of cobweb silk from the black widow spider Latrodectus
      hesperus.
AB  - We present the material analysis of scaffolding silk from the cobweb of the black
      widow spider Latrodectus hesperus. 30 strands were tested from the webs of nine
      spiders. Strands were stretched at 0.211 mm/s as force and extension were
      recorded. Cross-sectional area was measured under 1000 x oil-immersion light
      microscopy. The stress strain curve shows that cobweb silk is a distinct material
      from other known spider silks. The average breaking point for this cobweb silk is
      1.1 +/- 0.5 GPa at 0.22 +/- 0.05 strain. All samples increased stiffness as they
      were stretched, but to different extents. Variation in stiffness might be due to
      differential crystallization or alignment of the silk proteins during stretching.

PMID- 10342776
TI  - Is the mechanical strength of spider's drag-lines reasonable as lifeline?
AB  - Drag-lines play a role as a lifeline for a spider to move and fall from trees.
      The mechanical strength of the drag-lines may be related to the spider's weight
      since spiders hang from them. The safety coefficient of drag-lines as the
      lifeline should be considered for the mechanical strength of the drag-lines
      consisting of double filaments. It was found that the elastic limit strength and
      breaking strength increase linearly with spider's weight, about twice the
      spider's weight corresponds to the elastic limit strength, and about six times
      the spider's weight corresponds to the breaking strength of drag-lines. In other
      words, the spider's weight corresponds to the elastic limit strength for the
      single filament. This means that a spider can act safely by one filament even
      though another filament is broken down. It should be an outcome from spider's
      long history of 400-million-years evolution. These findings may give a maximal
      efficiency for the mechanical strength of spider's drag-lines.

PMID- 10342777
TI  - Transmission of vibrations in funnel and sheet spider webs.
AB  - Behavior of the funnel web building spider, Hololena curta, was observed. The
      spider is dependent on vibratory signals transmitted through the web. Prey
      localization usually necessitates two to four pauses and reorientation, and
      cannot proceed if the prey ceases to struggle. Treating the web as a stretched
      membrane, we calculated fundamental and overtone normal frequencies and
      transmission velocities. Unlike the results reported for orb webs, resonance does
      appear to be a significant factor in the funnel web.

PMID- 10342778
TI  - The effect of solvents on spider silk studied by mechanical testing and single
      fibre Raman spectroscopy.
AB  - We used well-defined, fluorescence-free Raman spectra of single silk fibres to
      study silk ultrastructure. Major ampullate (MA) silk was reeled from the Araneus
      diadematus spider under controlled conditions. With a custom-built stress-strain
      gauge, we examined the mechanical properties of this silk both before and after
      supercontraction in a range of solvents. The solvents were found to modify the
      material properties considerably. We suggest that the solvents with their
      different polarities affect different regions of the silk's composite
      microstructure, in particular the conformation of the molecular chains.

PMID- 10342779
TI  - Variability in the mechanical properties of spider silks on three levels:
      interspecific, intraspecific and intraindividual.
AB  - The mechanical characteristics of dragline silks collected from a range of
      spiders drawn from the Argiopidae, Tetragnathidae, Theridiidae and Pisauridae
      displayed significant inter- and intraspecific differences. Dragline silks of the
      same species could show considerable variability probably dependent upon spider
      condition: starvation, for example, lead to decreased breaking elongation in
      Nephila edulis. Environmental conditions such as reeling speed affected silk
      properties such that (i) breaking elongation decreased, (ii) breaking stress
      increased and (iii) Young's modulus increased with increasing reeling speed.
      However, N. edulis and Araneus diadematus responded differently to the reeling
      speed treatments suggesting differences in basic silk properties.

PMID- 10342780
TI  - Ethnic differences in the identification of left ventricular hypertrophy in the
      hypertensive patient.
AB  - Left ventricular hypertrophy (LVH) is more prevalent in black than white
      hypertensives, but this difference is greater when identified by
      electrocardiography (ECG) than by echocardiography. We evaluated the proposal
      that current ECG criteria for LVH are less specific, and therefore, less useful,
      in blacks than whites. In a retrospective cross-sectional study, 408 subjects
      (271 white, 137 black) referred to a hypertension clinic for assessment of
      hypertension underwent measurement of blood pressure, ECG voltages (Sokolow-Lyon
      and Cornell sex-specific), and echocardiographic left ventricular mass index
      (LVMI). Black subjects had greater ECG voltages than whites, even when closely
      matched for LVMI. In black subjects, current ECG criteria were twice as sensitive
      as in whites (Sokolow-Lyon: 44.9% v 22.5%, P = .003. Cornell: 30.4% v 15.7%, P =
      .03). They were less specific in blacks using the Sokolow-Lyon criteria (73.5% v
      86.8%, P = .02) but this failed to reach significance using the Cornell criteria
      (83.8% v 91.8%, P = .07). When voltage criteria were adjusted to give matched
      sensitivities and specificities, respectively, differences in specificity and
      sensitivity were no longer apparent. Receiver operating characteristic curve
      analyses confirmed no significant differences in overall performance of either
      ECG criteria between blacks and whites. In conclusion, ECG detection of LVH is
      insensitive in both ethnic groups. Sensitivity is higher in blacks due to higher
      LVMI in those with LVH. Apparent differences in specificity are due to ethnic
      differences in ECG voltages that are unrelated to differences in LVMI. When these
      differences are taken into account, there are no overall differences in test
      accuracy. However, given the prognostic importance of the detection of LVH,
      currently accepted ECG voltage criteria for the detection of LVH remain of equal
      or greater value in black hypertensives compared with whites.

PMID- 10342781
TI  - Left ventricular mass, carotid wall thickness, and angiotensinogen gene
      polymorphism in patients with hypertension.
AB  - A missense gene mutation with methione-to-threonine amino acid substitution at
      codon 235 (M235T) of angiotensinogen (AGT) has been associated with higher plasma
      AGT levels and may influence the pathogenesis of cardiac hypertrophy and
      atherosclerosis. This study was undertaken to investigate the relationship of the
      M235T polymorphism of the AGT gene with left ventricular mass (LVM) and carotid
      intima-media thickness (IMT) in 175 Chinese patients with hypertension. The M235T
      mutation was detected by a mispairing primer method to create a BstUI restriction
      site in the polymerase chain reaction. The LVM was calculated with M-mode
      echocardiographic measures of the left ventricle. The IMT was measured in the
      common carotid and carotid bifurcation by B-mode ultrasound. Patients with the TT
      genotype (n = 106) were found to have significantly greater LVM index than those
      with the MM (n = 32) and MT (n = 37) genotypes (129.2 +/- 34.3 v 112.5 +/- 38.3
      and 107.4 +/- 30.0 g/m2, P = .002), but the carotid IMT showed insignificant
      differences among three genotypic groups (1.320 +/- 0.703, 1.349 +/- 0.777, and
      1.309 +/- 0.797 mm, P = .97). The M235T polymorphism (P = .004) was a significant
      predictor for LVM on multiple regression analysis, controlling all the potential
      confounding factors including age (P = .04), gender (P = .000), body mass index
      (P = .000), and so on, but the carotid IMT correlated only with age (P = .000),
      smoking (P = .02), and tissue plasminogen activator antigen (P = .02). These
      results indicated that the TT genotype of the AGT gene could be considered a risk
      factor for the development of cardiac hypertrophy, but not for carotid
      atherosclerosis in the hypertensive population.

PMID- 10342782
TI  - Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the
      renin-angiotensin-aldosterone system in normotensive and hypertensive subjects.
AB  - Although beta-adrenergic-blocking drugs suppress the renin system (RAAS), plasma
      angiotensin II (Ang II) responses during beta-blockade have not been defined.
      This study quantifies the effects of beta-blockade on the RAAS and examines its
      impact on prorenin processing by measuring changes in the ratio of plasma renin
      activity (PRA) to total renin. In normotensive (N = 14) and hypertensive (N = 16)
      subjects, blood pressure (BP), heart rate, PRA, plasma prorenin, plasma total
      renin (prorenin + PRA), ratio of PRA to total renin (%PRA), plasma Ang II, and
      urinary aldosterone were measured before and after 1 week of beta-blockade.
      Plasma renin activity, Ang II, and urinary aldosterone levels were similar for
      normotensive and hypertensive subjects. Plasma renin activity correlated with Ang
      II. Total renin, which is proportional to (pro)renin gene expression, was lower
      in hypertensive subjects and was inversely related to BP. Beta-blockade decreased
      BP and heart rate in both groups, with medium- and high-renin hypertensive
      subjects responding more frequently than those with low renin. Beta-blockade
      consistently suppressed PRA, Ang II, and aldosterone. Total renin was unchanged,
      thus, %PRA fell. These results indicate that beta-blockers suppress plasma
      angiotensin II levels, in parallel with the marked reductions in PRA and urinary
      aldosterone levels in normotensive and hypertensive subjects. The suppression of
      Ang II levels was comparable to that produced during angiotensin converting
      enzyme (ACE) inhibition. However, by reducing prorenin processing to renin, beta
      blockers do not stimulate renin secretion, unlike ACE inhibitors and Ang II
      receptor antagonists. This unique action of beta-blockers has important
      implications for the treatment of cardiovascular disease.

PMID- 10342783
TI  - Enhanced blood pressure response to mild sodium reduction in subjects with the
      235T variant of the angiotensinogen gene.
AB  - The relationship of high salt intake to elevated blood pressure levels has been
      demonstrated in most populations by cross-sectional, longitudinal, physiological,
      and clinical intervention studies. Variation within the angiotensinogen gene has
      been implicated in the genetic control of blood pressure levels and has been
      suggested to contribute to increased salt sensitivity. A total of 86 hypertensive
      men and women who had never been treated and who had participated in a 6-month
      randomized, placebo-controlled, clinical trial of low-sodium mineral salt (19%
      reduction in urinary sodium versus 12% increase in placebo group) were genotyped
      at the angiotensinogen M235T locus to test the hypothesis that the 235T allele is
      associated with a significant blood pressure response to a sodium reduction
      intervention whereas the 235M allele is not. After adjustment for gender and
      baseline blood pressure, persons with the TT and MT genotypes showed significant
      systolic blood pressure reductions on mineral salt compared with control subjects
      (P = .02 and P = .001, respectively) but not persons with the MM genotype (P =
      .10). Net adjusted diastolic blood pressure reductions also showed greater
      significance for persons with the TT and MT genotypes than for persons with the
      MM genotype (P = .08, P = .01, and P = .83, respectively). The net adjusted
      systolic and diastolic blood pressure reduction was -8.6/-3.9 mm Hg for persons
      with the TT genotype, -9.0/-5.2 mm Hg for the MT genotype, and -5.3/-1.0 mm Hg
      for the MM genotype. We conclude that the 235T allele of the angiotensinogen gene
      is associated with greater blood pressure decreases than the 235M allele after a
      sodium reduction intervention. The angiotensinogen gene accounts for some of the
      interindividual variation of the blood pressure response to sodium reduction.

PMID- 10342784
TI  - Adventitia as a source of inducible nitric oxide synthase in the rat aorta.
AB  - In the current study we used in vitro and in vivo models to determine the sites
      of nitric oxide production in rat aortic tissue following cytokine stimulation.
      In vitro studies in which intact rat aortic rings were incubated with endotoxin
      (1 microg/mL) or interferon-gamma (600 U/mL) indicated that the expression of
      inducible nitric oxide synthase (iNOS) activity was increased as measured by
      Northern blot analysis or determination of nitrite production. In situ
      hybridization showed iNOS mRNA in the endothelium and adventitia of the incubated
      aortic rings but not in the media. Immunohistochemical staining showed a similar
      localization for iNOS protein in the incubated rings. Additional studies were
      performed in which bacterial endotoxin (4 mg/kg) was administered to rats, and
      iNOS expression was assayed using in situ hybridization and immunohistochemistry.
      Clear increases in iNOS mRNA and protein were found in aortic tissue. Endothelial
      and adventitial cells were the major source of iNOS, with relatively low amounts
      of iNOS mRNA present in medial smooth muscle, consistent with in vitro findings.
      These studies indicate that the aortic adventitia is a potential source of NO,
      and suggest that the adventitial fibroblast may have an important paracrine role
      in regulating arterial structure and function.

PMID- 10342785
TI  - Higher level of plasma nitric oxide in spontaneously hypertensive rats.
AB  - We had detected a slightly, but significantly, higher level of plasma
      nitrite/nitrate in the spontaneously hypertensive rat (SHR) by using the nitric
      oxide (NO) analyzer (Sievers 280 NOA), which converts nitrate (including nitrate
      converted from nitrite) to NO. Here, we examined whether the release of NO from
      protein-bound dinitrosyl nonheme iron complexes (DNIC) contributes to the
      elevated plasma nitrate level in the SHR. The SHR and their genetic normotensive
      controls, Wistar-Kyoto rats (WKY), were anesthestized and cannulized for
      monitoring blood pressure, collecting a blood sample, and the administration of
      endotoxin (lipopolysaccharide [LPS]). The nitrate levels (an indicator of NO
      formation) in the plasma and the aorta were measured by an NO analyzer. In
      addition, the relaxation of acetylcholine (ACh) in the presence or absence of
      N(omega)-nitro-L-arginine methyl ester (L-NAME) was also examined in thoracic
      aortae obtained from both strains. The slight, but significant, increase of basal
      nitrate levels in the plasma and aorta were observed, and the former was further
      enhanced in SHR treated with LPS for 3 h. In vitro, the ACh-induced relaxation
      was attenuated in the aortae obtained from SHR. However, this difference between
      SHR and WKY (without LPS treatment) was abolished by treatment of rings with L
      NAME (30 micromol/L), suggesting that an impairment of NO formation was observed
      in the SHR. After rats were treated with LPS for 3 h, the ACh-induced relaxation
      was reduced in the WKY, but not in the SHR. In addition, a 10-fold increase of L
      NAME was needed to abolish the difference in ACh-induced relaxation between SHR
      and WKY, indicating an expression of inducible NO synthase in both strains
      treated with LPS. We suggest that the elevated plasma NO level in SHR may be due
      to the release of NO from DNIC in the vascular bed to combat the hypertensive
      state.

PMID- 10342786
TI  - Benidipine stimulates nitric oxide synthase and improves coronary circulation in
      hypertensive rats.
AB  - We evaluated the effects of long-term treatment with benidipine, a long-acting
      calcium antagonist, on endothelial cell-type nitric oxide synthase (eNOS)
      activity and eNOS mRNA expression in the left ventricle (LV) and its relation to
      coronary flow reserve, and microvascular remodeling in renovascular hypertensive
      rats (RHR: 2K-1C Goldblatt). Benidipine (5 mg/kg/day) was given to RHR (B-RHR, n
      = 11) for 6 weeks. Vehicle-treated RHR (U-RHR, n = 11) and age-matched sham
      operated rats (ShC, n = 11) served as control group. Coronary flow reserve was
      measured in conscious rats using colored microspheres. Fifty-micrometer slices of
      the LV were incubated with L-arginine to measure nitrite production using the
      Griess method and eNOS mRNA expression was determined by reverse transcription
      polymerase chain reaction. An increased blood pressure in RHR was significantly
      decreased by benidipine. Nitrite production and eNOS mRNA expression in the LV of
      U-RHR was significantly lower than that of ShC. This suppression of nitrite
      production and eNOS mRNA expression was significantly reversed in B-RHR. U-RHR
      demonstrated a significant decrease in coronary flow reserve and capillary
      density, and a significant increase in wall-to-lumen ratio, perivascular
      fibrosis, myocardial fibrosis, and myocyte cross-sectional area. These impaired
      factors were improved significantly by benidipine. These findings suggest that
      benidipine therapy may increase nitrite production and eNOS mRNA expression not
      only by lessening the endothelial damage by the reduction of blood pressure
      levels, but also by the stimulation of NOS activity and eNOS mRNA, and this
      increased NOS activity and eNOS mRNA expression may play a role in the
      amelioration of coronary flow reserve and microvascular remodeling.

PMID- 10342787
TI  - Chronic aminoguanidine attenuates renal dysfunction and injury in aging rats.
AB  - We have previously shown that aging is associated with increased lipid
      peroxidation, reductions in renal function, and increased glomerular sclerosis.
      The mechanism(s) responsible for these age-related changes are not clear. The
      purpose of the present studies was to determine if there was an increase in
      inducible nitric oxide synthase (iNOS) with aging, and if so, whether inhibition
      of iNOS would prevent aging injury by preventing free radical-mediated lipid
      peroxidation. iNOS protein expression in the kidney increased by approximately
      90% by 24 months. Inhibition of iNOS by aminoguanidine (0.1% in drinking water)
      for 9 months, beginning at 13 months of age, reduced blood pressure, improved
      glomerular filtration rate by 70%, and renal plasma flow by 40%, whereas
      glomerular sclerosis was considerably reduced. Renal F2-isoprostanes and
      malondialdehyde levels, markers of oxidative stress and lipid peroxidation, were
      not reduced by aminoguanidine. Aminoguanidine also did not attenuate
      immunostaining for advanced glycosylation end products (AGE) in the kidneys.
      These findings suggest that aminoguanidine attenuates aging renal dysfunction by
      inhibiting a pathophysiologic function of iNOS that is independent of free
      radical-mediated lipid peroxidation or significant effects on AGE deposition.

PMID- 10342789
TI  - Acute and chronic blood pressure response to recurrent acoustic arousal in rats.
AB  - Repetitive episodic hypoxia every 30 sec administered chronically to Sprague
      Dawley (SD) rats has been shown by previous studies to cause a sustained increase
      in daytime blood pressure (BP). Acoustic arousal in humans during wake or sleep
      produces an acute BP rise. The question then arises as to whether chronic
      episodic acoustic arousal applied with the same frequency and duration as
      episodic hypoxia induces elevated BP. We exposed 14-week-old (N = 10) SD rats in
      individual cages to recurrent buzzer noise (500 Hz, 100 dB) 6 out of every 30
      sec, 7 h/day for 35 days. Ten other rats were placed in similar cages daily but
      not exposed to noise, to provide a sham condition. An infrared beam with a
      detector was positioned at the end of each cage. This allowed us to quantify
      motion by registering the number of times the rat broke the beam per 7 h period.
      Mean intraarterial BP was measured in unrestrained conscious animals at baseline
      and at the end of 35 days of their respective conditions. Acute episodic acoustic
      stimulation caused an immediate response in BP and heart rate. Habituation
      occurred in that the movement response to 120 noises per hour was 75% in hour one
      and 20% in hours two through seven on day one. The movement response was further
      reduced by day 35 but remained significantly higher than in animals not
      stimulated by noise. The cardiovascular response to noise also showed signs of
      habituation. Chronic noise stimulation produced no sustained increases in BP
      after 35 days of exposure.

PMID- 10342788
TI  - Effect of luminal angiotensin II receptor antagonists on proximal tubule
      transport.
AB  - The proximal tubule can endogenously synthesize and secrete luminal angiotensin
      II at a concentration approximately 100- to 1000-fold higher than that in the
      systemic circulation. We have recently shown that this endogenously produced and
      luminally secreted angiotensin II regulates proximal tubule volume reabsorption,
      which is a reflection of sodium transport within this segment. In this study, we
      use in vivo microperfusion of angiotensin II receptor antagonists into the lumen
      of the proximal tubule to examine the role of the luminal AT1 and AT2 receptor in
      the regulation of volume reabsorption. Systemically administered (intravenous)
      AT1 and AT2 receptor antagonists, acting through basolateral angiotensin II
      receptors, have previously been shown to inhibit proximal tubule transport.
      Luminal perfusion of 10(-6) mol/L Dup 753 (AT1 antagonist) and 10(-6) mol/L PD
      123319 (AT2 antagonist) decreased proximal tubule volume reabsorption from 2.94
      +/- 0.18 to 1.65 +/- 0.18 and 1.64 +/- 0.19 nL/mm x min, respectively, P < .01.
      Luminal perfusion of 10(-4) mol/L CGP 42112A, another AT2 antagonist, similarly
      decreased volume reabsorption to 1.32 +/- 0.36 nL/nm x min, P < .01. The
      inhibition of transport with AT1 and AT2 antagonist was additive, as luminal
      perfusion of 10(-6) mol/L Dup 753 plus 10(-6) mol/L 123319 resulted in a decrease
      in volume reabsorption to 0.41 +/- 0.31 nL/mm x min, P < .001 v control, P < .05
      v Dup 753, and P < .01 v PD 123319. These results show that endogenously produced
      angiotensin II regulates proximal tubule volume transport via both luminal AT1
      and AT2 receptors.

PMID- 10342790
TI  - Adrenocortical activity in the newborn spontaneously hypertensive rat.
AB  - Blood pressure is reportedly elevated in the spontaneously hypertensive rat (SHR)
      neonate, the etiology of which remains unclear. Aberrations in the hypothalamic
      pituitary-adrenal axis have been implicated, as it is well accepted that excess
      corticosteroids are associated with hypertension. We examined aspects of
      adrenocortical activity in the neonatal SHR 1 to 21 days old and its normotensive
      genetic control, the Wistar-Kyoto rat (WKY). We found a fourfold greater
      abundance of P450scc mRNA in adrenals of SHR versus WKY day 1 neonates, and
      increasing but comparable abundance of adrenal P450c11B mRNA on neonatal days 1
      to 21. The pattern of P450c11AS mRNA expression was distinctly different in the
      adrenals of SHR and WKY neonates; the relative abundance of this mRNA in SHR
      increased 15-fold over the 21-day period examined, whereas that in WKY remained
      fairly stable. RT-PCR for the presence/abundance of adrenal P450c11B3 mRNA showed
      absence in day 1 SHR and WKY, comparable abundances on neonatal days 7 and 14,
      and a distinctly greater abundance in the day 21 SHR adrenals. Peripheral
      corticosterone levels were threefold greater in the day 1 SHR neonate;
      aldosterone levels were elevated in both the SHR and WKY day 1 neonate.
      Thereafter, corticosterone and aldosterone levels were comparable on days 7, 14,
      and 21, although the anticipated depression in circulating corticosterone levels
      typical of the stress hyporesponsive period was noted in both SHR and WKY
      neonates. Although patterns of adrenocortical activity differ in the newborn SHR
      and WKY rat, our findings do not support an etiologic role for corticosteroids in
      the reported hypertension of the SHR. However, observed differences in
      corticosteroid profiles may augment or have a permissive effect upon the
      etiologic factor(s).

PMID- 10342792
TI  - HpaII polymorphism in the atrial natriuretic peptide gene and hypertension.
AB  - This was an association study of genetic polymorphisms to compare the
      distribution of the genotypes and alleles of the HpaII polymorphism of the atrial
      natriuretic peptide (ANP) gene in hypertensive patients and normotensive
      controls. The setting was an outpatient clinic run by a University Department
      handling referrals from primary care. The patient cohort was composed of 217
      subjects, consisting of 109 healthy controls and 108 patients with newly
      diagnosed or documented hypertension. The genomic DNA was extracted from
      peripheral blood leukocytes, amplified by polymerase chain reaction, and digested
      with the restriction enzyme HpaII. H1 and H2 alleles were identified after
      electrophoresis. The main outcome measures were to identify the frequencies of
      ANP genotypes and alleles in hypertensive patients and normotensive controls. The
      H1H1, H1H2, and H2H2 genotypes occurred in 1%, 19%, and 80% of controls and 3%,
      18%, and 80% of hypertensive patients, respectively. The frequencies of the H1
      and H2 alleles were 0.11 and 0.89 in controls and 0.12 and 0.88 in hypertensive
      patients. The frequencies of the ANP genotypes and alleles did not differ
      significantly between controls and hypertensive patients. Our findings differed
      from previous reports and suggested that this polymorphism is not associated with
      hypertension in this population.

PMID- 10342791
TI  - Effects of interferon on circadian changes in blood pressure and heart rate
      variability in patients with chronic hepatitis.
AB  - We have determined the effects of interferon therapy on circadian changes in
      blood pressure and heart rate variability in normotensive hospitalized patients
      with chronic active hepatitis. Body temperature and pulse rate increased for the
      initial few days of interferon therapy without significant change in casual or
      ambulatory blood pressure. Interferon therapy failed to elicit any significant
      changes in the power spectrum of R-R intervals. In addition, urinary excretion of
      norepinephrine did not differ between before and during the therapy. These
      results suggest that interferon therapy caused transient increases in body
      temperature and pulse rate, but that it did not change either sympathetic or
      parasympathetic outflow, or the circadian rhythm of blood pressure and heart rate
      variability, in normotensive subjects.

PMID- 10342793
TI  - Low dose bendrofluazide (1.25 mg) effectively lowers blood pressure over 24 h:
      results of a randomized, double-blind, placebo-controlled crossover study.
AB  - Previous studies indicate that low dose bendrofluazide (1.25 mg/day) has no
      deleterious effect on insulin sensitivity in contrast to conventional doses. To
      evaluate the antihypertensive effect of 1.25 mg bendrofluazide across 24 h, we
      studied 12 subjects in a randomized, double blind, cross-over trial, comprising 8
      weeks of either 1.25 mg/day bendrofluazide or placebo. Twenty-four-hour blood
      pressure averages were significantly lower after bendrofluazide compared with
      placebo (systolic 125 +/- 4 v 136 +/- 3 mm Hg, P < .005; diastolic: 78 +/- 2 v 85
      +/- 2 mm Hg, P < .01). Trough:peak ratios were 0.67 +/- 0.07 for systolic and
      0.72 +/- 0.15 for diastolic blood pressure reduction. In conclusion, 1.25 mg
      bendrofluazide daily produced a useful antihypertensive effect across the full 24
      h period.

PMID- 10342794
TI  - Lysophosphatidic acid stimulates protein kinase C isoforms alpha, beta, epsilon,
      and zeta in a pertussis toxin sensitive pathway in vascular smooth muscle cells.
AB  - The natural phospholipid lysophosphatidic acid (LPA) has been characterized as an
      important vascular smooth muscle cell (VSMC) mitogen whose effects are mainly
      mediated by pertussis toxin (PTX)-sensitive guanosine triphosphate (GTP)-binding
      protein (Gi-protein). Protein kinase C (PKC) isoforms play an important role in
      intracellular signaling cascades and in growth of VSMC. In the present study we
      investigated the effect of LPA on activation of PKC isoforms alpha, beta,
      epsilon, and zeta in VSMC by Western blot of cytosolic and membrane fractions.
      Furthermore, we examined the role of PKC activation on LPA-induced growth of VSMC
      using PKC inhibitor 19-27. Stimulation of VSMC by 5 microg/mL LPA for 10 min
      increased the amount of PKC alpha, beta, epsilon, and zeta in the particulate
      fraction by 689%, 285%, 424%, and 510%, respectively, and returned to control
      level after 30 min. Correspondingly, the amount of PKC alpha, beta, epsilon, and
      zeta in the cytosolic fraction decreased by 32%, 94%, 44%, and 95%, respectively,
      compared to control. Furthermore, we could show that LPA-induced activation of
      PKC alpha, beta, epsilon, and zeta isoforms was PTX sensitive. Incubation of VSMC
      with nonspecific PKC inhibitor 19-27 (10 micromol/L) for 24 h resulted in a 30%
      inhibition of LPA-induced DNA synthesis as measured by [3H]thymidine
      incorporation. In conclusion, in VSMC LPA stimulated translocation of PKC
      isoforms alpha, beta, epsilon, and zeta in a PTX-sensitive manner. Furthermore
      stimulation of PKC might be critically involved in LPA-induced mitogenesis in
      VSMC.

PMID- 10342795
TI  - Self-reported blood pressure reliability problems exaggerated.

PMID- 10342796
TI  - More on reliability of self-measured blood pressure.

PMID- 10342797
TI  - Prisoners of the proximate: loosening the constraints on epidemiology in an age
      of change.
AB  - "Modern epidemiology" has a primary orientation to the study of multiple risk
      factors for chronic noncommunicable diseases. If epidemiologists are to
      understand the determinants of population health in terms that extend beyond
      proximate, individual-level risk factors (and their biological mediators), they
      must learn to apply a social-ecologic systems perspective. The mind-set and
      methods of modern epidemiology entail the following four main constraints that
      limit engagement in issues of wider context: 1) a preoccupation with proximate
      risk factors; 2) a focus on individual-level versus population-level influences
      on health; 3) a typically modular (time-windowed) view of how individuals undergo
      changes in risk status (i.e., a life-stage vs. a life-course model of risk
      acquisition); and 4) the, as yet, unfamiliar challenge of scenario-based
      forecasting of health consequences of future, large-scale social and
      environmental changes. The evolution of the content and methods of epidemiology
      continues. Epidemiologists are gaining insights into the complex social and
      environmental systems that are the context for health and disease; thinking about
      population health in increasingly ecologic terms; developing dynamic,
      interactive, life-course models of disease risk acquisition; and extending their
      spatial-temporal frame of reference as they perceive the health risks posed by
      escalating human pressures on the wider environment. The constraints of "the
      proximate" upon epidemiology are thus loosening as the end of the century
      approaches.

PMID- 10342798
TI  - Neighborhood social environment and risk of death: multilevel evidence from the
      Alameda County Study.
AB  - Recent reports suggest the importance of associations between residential area
      characteristics and health status, but most research uses only census data to
      measure these characteristics. The current research examined the effect of
      overall neighborhood social environment on 11-year risk of death. On the basis of
      data, the authors developed a three-component neighborhood social environment
      scale: 1) commercial stores; 2) population socioeconomic status; and 3)
      environment/housing. Data from the 1983 wave of the Alameda County Study (n =
      1,129) and deaths over 11 years were analyzed with two-level logistic regression
      models. Age- and sex-adjusted risk of death was higher for residents in low
      social environment neighborhoods (odds ratio = 1.58, 95% confidence interval 1.15
      2.18). Mortality risks were significantly higher in neighborhoods with a low
      social environment, even after account was taken of individual income level,
      education, race/ethnicity, perceived health status, smoking status, body mass
      index, and alcohol consumption. When each component of the neighborhood social
      environment characteristics score was examined separately, each was found to be
      associated with higher risk for mortality, independent of individual risk
      factors. These findings demonstrate the role of area characteristics as a health
      risk factor and point to the need for more focused attention to the meaning and
      measurement of neighborhood quality.

PMID- 10342799
TI  - Social differences of very preterm birth in Europe: interaction with obstetric
      history. Europop Group.
AB  - Social differences of very preterm birth (22-32 completed weeks of amenorrhea)
      were studied using data from a large case-control survey in Europe between 1994
      and 1997; 1,675 very preterm births and 7,965 full-term births were included. The
      relation between social factors and very preterm birth was studied according to
      obstetric history and the mode of delivery onset. Very preterm birth was
      significantly related to low educational level among women with no previous
      adverse pregnancy outcome (odds ratio (OR) = 2.67, 95 percent confidence interval
      (CI) 1.66-4.28) and among primigravid women and those with previous first
      trimester abortion (OR = 2.01, 95 percent CI 1.56-2.58). In this group,
      unemployment of all household members was associated with a double risk of very
      preterm birth. No significant association between very preterm birth and
      socioeconomic status was observed among women with previous second-trimester
      abortion or preterm birth. Socioeconomic indicators remained significantly
      associated with both spontaneous and induced very preterm births among women with
      no previous late fetal loss or preterm birth. The results are consistent with
      social factors affecting the risk of very preterm birth, but the relation differs
      according to obstetric history.

PMID- 10342800
TI  - Epidemiology of Crohn's disease and ulcerative colitis in a central Canadian
      province: a population-based study.
AB  - The aim of this study was to assess the accuracy and utility of administrative
      health data in identifying persons with inflammatory bowel disease on a
      population basis and to determine the incidence and prevalence of this disease in
      the Canadian province of Manitoba. The data from Manitoba Health (the province's
      single insurer) were used to identify residents with physician and/or hospital
      contacts for Crohn's disease or ulcerative colitis based on International
      Classification of Diseases, Ninth Revision, Clinical Modification, codes between
      1984 and 1995. Of 5,182 eligible individuals, 4,514 were mailed questionnaires
      and 2,725 responded. Cases were defined as individuals with five or more separate
      medical contacts with one of these diagnoses or three or more such contacts if
      they were resident for less than 2 years. The accuracy of the study case
      definitions was high when compared with either self-report or chart review. The
      1989-1994 age- and sex-adjusted annual incidence was 14.6/100,000 for Crohn's
      disease and 14.3/100,000 for ulcerative colitis. The prevalence of Crohn's
      disease in 1994 was 198.5/100,000, and that of ulcerative colitis was
      169.7/100,000. In conclusion, the authors have successfully established and
      validated a population-based database of inflammatory bowel disease based on
      administrative data. The high incidence rates and dynamic epidemiology of
      inflammatory bowel disease in Manitoba indicate the presence of important
      environmental risk factors, which warrants further investigation.

PMID- 10342801
TI  - Dietary factors and the risk of gastric cancer in Mexico City.
AB  - Dietary factors play an important role in gastric cancer risk but have not been
      investigated extensively in Mexico. The authors conducted a population-based case
      control study of gastric cancer in the Mexico City, Mexico, metropolitan area in
      1989-1990. A total of 220 patients with histologically confirmed gastric
      adenocarcinomas were interviewed. Controls were an age-stratified random sample
      of residents of the Mexico City metropolitan area. The dietary questionnaire was
      a 70-item semiquantitative food frequency adapted for the Mexican diet. Odds
      ratios were calculated for quartiles of consumption of food groups and were
      adjusted for age, gender, calories, chili pepper intake, cigarette smoking,
      socioeconomic status, added salt, and history of peptic ulcer disease. There was
      approximately a threefold increased risk of gastric cancer for frequent
      consumption (highest quartile) of both fresh meat (odds ratio (OR) = 3.1) and
      processed meat (OR = 3.2). Odds ratios were also significantly elevated for
      frequent consumption of dairy products (OR = 2.7) and fish (OR = 2.2). The
      authors observed a decreasing gradient of risk with increasing frequency of
      vegetable consumption due to a significant inverse trend for the yellow and
      orange vegetables. High intake of citrus fruits showed a slight inverse
      association. Consumption of salty snacks more than twice per month was associated
      with an 80 percent increased risk, and there was a significant positive trend.
      These findings are consistent with many studies around the world that indicate
      important roles for salt, processed meats, and vegetable consumption in gastric
      cancer risk.

PMID- 10342802
TI  - Familial risk of obesity and central adipose tissue distribution in the general
      Canadian population.
AB  - The purpose of this study was to determine the familial risk of obesity and of an
      android profile of fat distribution in the general Canadian population. A sample
      of 15,245 participants aged 7-69 years from 6,377 households from the Canada
      Fitness Survey of 1981 was used. The body mass index (BMI), sum of five skinfolds
      (SF5), ratio of trunk-to-extremity skinfolds, adjusted for SF5, and waist
      circumference, adjusted for BMI were used as indicators of obesity and central
      fat distribution. Age- and sex-standardized risk ratios (SRRs) for spouses and
      first-degree relatives of obese probands indicate that there is significant
      familial risk for obesity and an android fat distribution in the Canadian
      population. SRRs for spouses and first-degree relatives of probands exceeding the
      99th percentile are 3.01 and 4.96 for BMI, 7.36 and 4.15 for SF5, 1.41 and 3.18
      for ratio of trunk-to-extremity skinfolds, adjusted for SF5, and 1.02 and 2.18
      for waist circumference, adjusted for BMI, respectively. The SRRs are smaller for
      less extreme obesity (lower percentile cutoffs) than for more extreme obesity.
      The SRRs are greater in spouses than in first-degree relatives for SF5; however,
      the risk for BMI and an android fat distribution was greater among first-degree
      relatives than among spouses, suggesting a greater role for genetic factors.

PMID- 10342803
TI  - Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal
      women.
AB  - Flavonoids, a group of phenolic compounds found in fruits and vegetables, are
      known to have antioxidant properties. They prevent low density lipoprotein
      oxidation in vitro and thus may play a role in the prevention of coronary heart
      disease (CHD). In 1986, in a prospective study of 34,492 postmenopausal women in
      Iowa, the authors examined the association of flavonoid intake with CHD and
      stroke mortality. Over 10 years of follow-up, 438 deaths from CHD and 131 deaths
      from stroke were documented. Total flavonoid intake was associated with a
      decreased risk of CHD death after adjusting for age and energy intake (p for
      trend = 0.04). This association was attenuated after multivariate adjustment.
      However, decreased risk was seen in each category of intake compared with the
      lowest. Relative risks and 95% confidence intervals of CHD death from lowest to
      highest intake category were 1.0, 0.67 (95% confidence interval (CI) 0.49-0.92),
      0.56 (95% CI 0.39-0.79), 0.86 (95% CI 0.63-1.18), and 0.62 (95% CI 0.44-0.87).
      There was no association between total flavonoid intake and stroke mortality (p
      for trend = 0.83). Of the foods that contributed the most to flavonoid intake in
      this cohort, only broccoli was strongly associated with reduced risk of CHD
      death. The data of this study suggest that flavonoid intake may reduce risk of
      death from CHD in postmenopausal women.

PMID- 10342804
TI  - Application of computer-assisted interviews to sexual behavior research.
AB  - Collection of sensitive data with the use of video-enhanced, computer-assisted,
      self-administered interviews (V-CASI) has the potential to reduce interview bias
      and improve the validity of the study. The purpose of this study was to compare
      responses to sensitive questions elicited by V-CASI and by face-to-face interview
      (FTFI) methods. Women attending a New Orleans, Louisiana, public family planning
      or sexually transmitted disease clinic from July 1995 to July 1996, diagnosed
      with a Chlamydia trachomatis infection responded to eight close-ended behavioral
      questions (four socially undesirable, two socially desirable, and two neutral
      behaviors) using both FTFI and V-CASI techniques in a randomized crossover
      design. Of the 280 women included, the mean age was 23 years, 95 percent were
      African American, and 71 percent felt comfortable using computers. While kappa
      scores indicated good-to-excellent agreement between interview techniques, women
      tended to admit to socially undesirable behaviors more often on V-CASI compared
      with FTFI. Thirty percent of the women gave a discrepant response between V-CASI
      and FTFI toward social desirability. Women who reported a socially undesirable
      behavior in V-CASI (i.e., more than two sex partners and infrequent condom usage)
      were more likely to have a discrepant response. Utilization of the same logistic
      regression model to predict condom use yielded different results when data from V
      CASI were used compared with data from FTFI. The V-CASI technique can reduce
      social desirability bias and improve validity in research requiring information
      on sensitive sexual behaviors.

PMID- 10342805
TI  - Validity of drug use reporting in a high-risk community sample: a comparison of
      cocaine and heroin survey reports with hair tests.
AB  - Hair specimens were collected from 322 subjects and analyzed as part of an
      experimental study administering household surveys during 1997 to a high-risk
      community sample of adults from Chicago, Illinois. Toxicologic results were
      compared with survey responses about recent and lifetime drug use. About 35% of
      the sample tested positive for cocaine, and 4% tested positive for heroin. Sample
      prevalence estimates of cocaine use based on toxicologic results were nearly five
      times the survey-based estimates of past month use and nearly four times the
      survey-based estimates of past year use. With the hair test results as the
      standard, cocaine and heroin use were considerably underreported in the survey.
      Underreporting was more of a problem for cocaine than for heroin. Among those who
      tested positive, survey disclosure of cocaine use was associated with higher
      levels of cocaine detected in hair. In general, when recent drug use was
      reported, it was usually detected in hair. When a drug was detected in hair, use
      was usually not reported in the survey. When heroin was detected in hair, cocaine
      was almost always detected as well.

PMID- 10342806
TI  - Taking account of between-patient variability when modeling decline in
      Alzheimer's disease.
AB  - The pattern of deterioration in patients with Alzheimer's disease is highly
      variable within a given population. With recent speculation that the
      apolipoprotein E allele may influence rate of decline and claims that certain
      drugs may slow the course of the disease, there is a compelling need for sound
      statistical methodology to address these questions. Current statistical methods
      for describing decline do not adequately take into account between-patient
      variability and possible floor and/or ceiling effects in the scale measuring
      decline, and they fail to allow for uncertainty in disease onset. In this paper,
      the authors analyze longitudinal Mini-Mental State Examination scores from two
      groups of Alzheimer's disease subjects from Palo Alto, California, and
      Minneapolis, Minnesota, in 1981-1993 and 1986-1988, respectively. A Bayesian
      hierarchical model is introduced as an elegant means of simultaneously overcoming
      all of the difficulties referred to above.

PMID- 10342808
TI  - Transfection of human pancreatic islets with an anti-apoptotic gene (bcl-2)
      protects beta-cells from cytokine-induced destruction.
AB  - Apoptosis has been identified as a mechanism of pancreatic islet beta-cell death
      in autoimmune diabetes. Proinflammatory cytokines are candidate mediators of beta
      cell death in autoimmune diabetes, and these cytokines can induce beta-cell death
      by apoptosis. In the present study, we examined whether transfection of human
      islet beta-cells with an anti-apoptotic gene, bcl-2, can prevent cytokine-induced
      beta-cell destruction. Human islet beta-cells were transfected by a replication
      defective herpes simplex virus (HSV) amplicon vector that expressed the bcl-2
      gene (HSVbcl-2) and, as a control, the same HSV vector that expressed a beta
      galactosidase reporter gene (HSVlac). Two-color immunohistochemical staining
      revealed that 95+/-3% of beta-cells transfected with HSVbcl-2 expressed Bcl-2
      protein compared with 14+/-3% of beta-cells transfected with HSVlac and 19+/-4%
      of nontransfected beta-cells. The bcl-2-transfected beta-cells were fully
      protected from impaired insulin secretion and destruction resulting from
      incubation for 5 days with the cytokine combination of interleukin (IL)-1beta,
      tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. In addition, the
      bcl-2-transfected islet cells were significantly protected from cytokine-induced
      lipid peroxidation and DNA fragmentation. These results demonstrate that cytokine
      induced beta-cell dysfunction and death involve mechanisms subject to regulation
      by an anti-apoptotic protein, Bcl-2. Therefore, bcl-2 gene therapy has the
      potential to protect human beta-cells in pancreatic islets, or islet grafts, from
      immune-mediated damage in type 1 diabetes.

PMID- 10342807
TI  - Activators of peroxisome proliferator-activated receptor-alpha induce the
      expression of the uncoupling protein-3 gene in skeletal muscle: a potential
      mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene
      expression at birth.
AB  - The recently identified uncoupling protein-3 (UCP-3) gene, predicted to encode a
      new member of the family of uncoupling proteins, is preferentially expressed in
      skeletal muscle and has been related to phenotypes of obesity and type 2
      diabetes. We have established that during mouse ontogeny, the expression of the
      UCP-3 gene is switched on in skeletal muscle just after birth. The induction of
      UCP-3 gene expression is dependent on the initiation of suckling and particularly
      on lipid intake. Treatment of newborn mice with activators of peroxisome
      proliferator-activated receptors (PPARs), such as clofibrate, bezafibrate, or (4
      chloro-6-(2,3-xylidine)-pirimidinylthio)acetic acid (WY 14,643), mimics the
      action of food intake on UCP-3 gene expression. The specific ligand of PPAR-alpha
      WY 14,643 induces UCP-3 gene expression in a time- and dose-dependent manner,
      whereas the thiazolidinedione BRL 49653, specific for PPAR-gamma, has no effect.
      These treatments act without altering circulating free fatty acids. During
      development, skeletal muscle expresses constitutive levels of PPAR-delta mRNA,
      whereas expression of the PPAR-gamma gene is undetectable. PPAR-alpha gene
      expression is developmentally regulated in muscle as it is first expressed at
      birth, just before UCP-3 gene induction occurs. The induction of UCP-3 gene
      expression by WY 14,643 is impaired in skeletal muscle of premature neonates,
      which do not express PPAR-alpha. It is proposed that the UCP-3 gene is
      predominantly regulated in neonatal muscle by PPAR-alpha activation.

PMID- 10342809
TI  - Impaired beta-cell functions induced by chronic exposure of cultured human
      pancreatic islets to high glucose.
AB  - In type 2 diabetes, chronic hyperglycemia has been suggested to be detrimental to
      beta-cell function, causing reduced glucose-stimulated insulin secretion and
      disproportionately elevated proinsulin. In the present study, we investigated the
      effect on several beta-cell functions of prolonged in vitro exposure of human
      pancreatic islet cultures to high glucose concentrations. Islets exposed to high
      glucose levels (33 mmol/l) for 4 and 9 days showed dramatic decreases in glucose
      induced insulin release and in islet insulin content, with increased proportion
      of proinsulin-like peptides relative to insulin. The depletion in insulin stores
      correlated with the reduction in insulin mRNA levels and human insulin promoter
      transcriptional activity. We also demonstrated that high glucose dramatically
      lowered the binding activity of pancreatic duodenal homeobox 1 (the glucose
      sensitive transcription factor), whereas the transcription factor rat insulin
      promoter element 3b1 activator was less influenced and insulin enhancer factor 1
      remained unaffected. Most of these beta-cell impairments were partially
      reversible when islets first incubated for 6 days in high glucose were
      transferred to normal glucose (5.5 mmol/l) concentrations for 3 days. We conclude
      that cultured human islets are sensitive to the deleterious effect of high
      glucose concentrations at multiple functional levels, and that such mechanisms
      may play an important role in the decreased insulin production and secretion of
      type 2 diabetic patients.

PMID- 10342810
TI  - Insulin receptor-related receptor is expressed in pancreatic beta-cells and
      stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2.
AB  - The receptor-type protein tyrosine kinases in murine pancreatic islets were
      screened to identify possible growth/differentiation factors in pancreatic beta
      cells. The analysis revealed that insulin receptor-related receptor (IRR) is
      highly expressed in the islets as well as in several highly differentiated beta
      cell lines derived from transgenic mice. Islets predominantly contain IRR as
      uncleaved proreceptors compared with IRR as processed forms in the beta-cell
      lines, suggesting that the activity of IRR is regulated on the level of
      processing proteases in vivo. To examine the IRR signaling pathway, a chimeric
      receptor consisting of the extracellular domain of insulin receptor and the
      intracellular domain of IRR was expressed in Chinese hamster ovary cells. The
      hybrid receptor is functional because insulin is capable of tyrosine
      phosphorylating the catalytic domain in these cells. It also stimulates the
      tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2,
      indicating that both proteins serve as substrates of IRR-protein tyrosine kinase
      in intact cells. The phenotype of the IRS-2 knockout mouse recently reported
      suggests that an IRS-2-mediated signaling pathway controls the compensatory
      increase in pancreatic beta-cell mass in insulin-resistant states. From our
      findings of the specific expression of IRR and its ability of signaling to IRS-2,
      we speculate that this receptor might play a role in the regulation of beta-cell
      mass.

PMID- 10342811
TI  - Impaired free fatty acid uptake in skeletal muscle but not in myocardium in
      patients with impaired glucose tolerance: studies with PET and 14(R,S)
      [18F]fluoro-6-thia-heptadecanoic acid.
AB  - Free fatty acids (FFAs) are an important substrate for myocardial and skeletal
      muscle metabolism, and increased availability and oxidation of FFA are suggested
      to be associated with insulin resistance. This study was undertaken to assess
      whether myocardial or muscle uptake of FFA is altered in patients with impaired
      glucose tolerance (IGT). Eight healthy men (control group; age 48+/-1 years, BMI
      25+/-1 kg/m2, mean +/- SE) and eight men with IGT (glucose-intolerant group; age
      49+/-1 years, BMI 29+/-1 kg/m2) were studied in the fasting state. Myocardial
      oxygen consumption and blood flow and myocardial and femoral muscle FFA uptake
      rates were measured with positron emission tomography (PET) and [15O]O2,
      [15O]H2O, [15O]CO, and 14(R, S)-[18F]fluoro-6-thia-heptadecanoic acid
      ([18F]FTHA), a fatty acid tracer trapped into the cell after undergoing initial
      steps of beta-oxidation. Serum glucose and insulin concentrations were higher in
      the glucose-intolerant group during the PET study, but FFA concentrations were
      comparable between the groups. No differences between the groups were observed in
      the myocardial blood flow, oxygen consumption, fractional FTHA uptake rates, or
      FFA uptake indices (5.6+/-0.4 vs. 5.2+/-0.4 pmol x 100 g(-1) x min(-1), glucose
      intolerant versus control, NS). In the femoral muscle, fractional FTHA uptake
      (0.0062+/-0.0003 vs. 0.0072+/-0.0003 min(-1), P = 0.044) and FFA uptake indices
      (0.30+/-0.02 vs. 0.43+/-0.04 min(-1), P = 0.020) were significantly lower in the
      glucose-intolerant group than in the control group. In conclusion, when studied
      at the fasting state and normal serum FFA concentrations, subjects with IGT have
      similar myocardial but lowered femoral muscle FFA uptake. This finding argues
      against the hypothesis that an increased oxidation of serum FFA, via the
      competition of glucose and FFA as fuel sources, is the primary cause for impaired
      peripheral glucose utilization and insulin resistance commonly observed in IGT.

PMID- 10342812
TI  - Modifications of citric acid cycle activity and gluconeogenesis in streptozotocin
      induced diabetes and effects of metformin.
AB  - To better define the modifications of liver gluconeogenesis and citric acid
      cycle, or Krebs' cycle, activity induced by insulin deficiency and the effects of
      metformin on these abnormalities, we infused livers isolated from postabsorptive
      or starved normal and streptozotocin-induced diabetic rats with pyruvate and
      lactate (labeled with [3-13C]lactate) with or without the simultaneous infusion
      of metformin. Lactate and pyruvate uptake and glucose production were calculated.
      The 13C-labeling pattern of liver glutamate was used to calculate, according to
      Magnusson's model, the relative fluxes through Krebs' cycle and gluconeogenesis.
      These relative fluxes were converted into absolute values using substrate
      balances. In normal rats, starvation increased gluconeogenesis, the flux through
      pyruvate carboxylase-phosphoenolpyruvate carboxykinase (PC-PEPCK), and the ratio
      of PC to pyruvate dehydrogenase (PDH) flux (P < 0.05); metformin induced only a
      moderate decrease in the PC:PDH ratio. Livers from postabsorptive diabetic rats
      had increased lactate and pyruvate uptakes (P < 0.05); their metabolic fluxes
      resembled those of starved control livers, with increased gluconeogenesis and
      flux through PC-PEPCK. Starvation induced no further modifications in the
      diabetic group. Metformin decreased glucose output from the liver of starved
      diabetic rats (P < 0.05). The flux through PC-PEPCK and also pyruvate kinase were
      decreased (P < 0.05) by metformin in both groups of diabetic rats. In conclusion,
      insulin deficiency increased in this model of diabetes gluconeogenesis through
      enhanced uptake of substrate and increased flux through PC-PEPCK; metformin
      decreased glucose production by reducing the flux through PC-PEPCK.

PMID- 10342813
TI  - Triglyceride-induced diabetes associated with familial lipoprotein lipase
      deficiency.
AB  - Raised plasma triglycerides (TGs) and nonesterified fatty acid (NEFA)
      concentrations are thought to play a role in the pathogenesis of insulin
      resistant diabetes. We report on two sisters with extreme hypertriglyceridemia
      and overt diabetes, in whom surgical normalization of TGs cured the diabetes. In
      all of the family members (parents, two affected sisters, ages 18 and 15 years,
      and an 11-year-old unaffected sister), we measured oral glucose tolerance,
      insulin sensitivity (by the euglycemic-hyperinsulinemic clamp technique),
      substrate oxidation (indirect calorimetry), endogenous glucose production (by the
      [6,6-2H2]glucose technique), and postheparin plasma lipoprotein lipase (LPL)
      activity. In addition, GC-clamped polymerase chain reaction-amplified DNA from
      the promoter region and the 10 coding LPL gene exons were screened for nucleotide
      substitution. Two silent mutations were found in the father's exon 4 (Glu118 Glu)
      and in the mother's exon 8 (Thr361 Thr), while a nonsense mutation (Ser447 Ter)
      was detected in the mother's exon 9. Mutations in exons 4 and 8 were inherited by
      the two affected girls. At 1-2 years after the appearance of
      hyperchylomicronemia, both sisters developed hyperglycemia with severe insulin
      resistance. Because medical therapy (including high-dose insulin) failed to
      reduce plasma TGs or control glycemia, lipid malabsorption was surgically induced
      by a modified biliopancreatic diversion. Within 3 weeks of surgery, plasma TGs
      and NEFA and cholesterol levels were drastically lowered. Concurrently, fasting
      plasma glucose levels fell from 17 to 5 mmol/l (with no therapy), while insulin
      stimulated glucose uptake, oxidation, and storage were all markedly improved.
      Throughout the observation period, plasma TG levels were closely correlated with
      both plasma glucose and insulin concentrations, as measured during the oral
      glucose tolerance test. These cases provide evidence that insulin-resistant
      diabetes can be caused by extremely high levels of TGs.

PMID- 10342814
TI  - Acute intravenous leptin infusion increases glucose turnover but not skeletal
      muscle glucose uptake in ob/ob mice.
AB  - The mouse ob gene encodes leptin, an adipocyte hormone that regulates body weight
      and energy expenditure. Leptin has potent metabolic effects on fat and glucose
      metabolism. A mutation of the ob gene results in mice with severe hereditary
      obesity and diabetes that can be corrected by treatment with the hormone. In lean
      mice, leptin acutely increases glucose metabolism in an insulin-independent
      manner, which could account, at least in part, for some of the antidiabetic
      effect of the hormone. To investigate further the acute effect of leptin on
      glucose metabolism in insulin-resistant obese diabetic mice, leptin (40 ng x g(
      1) x h(-1)) was administered intravenously for 6 h in C57Bl/6J ob/ob mice. Leptin
      increased glucose turnover and stimulated glucose uptake in brown adipose tissue
      (BAT), brain, and heart with no increase in heart rate. A slight increase in all
      splanchnic tissues was also noticed. Conversely, no increase in skeletal muscle
      or white adipose tissue (WAT) glucose uptake was observed. Plasma insulin
      concentration increased moderately but neither glucose, glucagon, thyroid
      hormones, growth hormone, nor IGF-1 levels were different from phosphate-buffered
      saline-infused C57Bl/6J ob/ob mice. In addition, leptin stimulated hepatic
      glucose production, which was associated with increased glucose-6-phosphatase
      activity. Conversely, PEPCK activity was rather diminished. Interestingly,
      hepatic insulin receptor substrate (IRS)1-associated phosphatidylinositol 3
      kinase activity was slightly elevated, but neither the content of glucose
      transporter GLUT2 nor the phosphorylation state of the insulin receptor and IRS-1
      were changed by acute leptin treatment. Hepatic lipid metabolism was not
      stimulated during the acute leptin infusion, since the content of triglycerides,
      glycerol, and citrate was unchanged. These findings suggest that in ob/ob mice,
      the antidiabetic antiobesity effect of leptin could be the result of a profound
      alteration of glucose metabolism in liver, BAT, heart, and consequently, glucose
      turnover. Insulin resistance of skeletal muscle and WAT, while not affected by
      acute leptin treatment, could also be corrected in the long term and account for
      some of leptin's antidiabetic effects.

PMID- 10342816
TI  - Low plasma leptin levels contribute to diabetic hyperphagia in rats.
AB  - The adipocyte hormone leptin reduces food intake in normal animals. During
      uncontrolled type 1 diabetes, plasma leptin levels fall, whereas food intake
      increases. To test the hypothesis that low leptin levels contribute to diabetic
      hyperphagia, we investigated the effect on food intake of replacement of leptin
      at basal plasma concentrations for 7 days in Long-Evans rats with uncontrolled
      diabetes induced by streptozotocin (STZ). One group of STZ diabetic rats received
      saline (STZ + Sal) (n = 11), while the other group (STZ + Lep) (n = 15) received
      a subcutaneous infusion of recombinant rat leptin (100 microg x kg(-1) x day(-1))
      via osmotic minipumps. A nondiabetic control group (Con) (n = 11) received saline
      only. In the STZ + Sal group, plasma leptin levels decreased by 75% (P < 0.05)
      from 2.4+/-0.5 on the day before STZ/citrate buffer vehicle (Veh) injection (day
      0) to 0.6+/-0.2 ng/ml on day 7. In contrast, plasma leptin levels on days 3-7
      were comparable to pretreatment values in both the STZ + Lep group (day 0: 2.6+/
      0.4 vs. day 7: 2.5+/-0.3 ng/ml, NS) and the Con group (day 0: 3.8+/-0.4 vs. day
      7: 2.9+/-1.0 ng/ml, NS). In the STZ + Sal group, daily food intake increased
      gradually to values 43% above basal by day 7 (day 0: 24+/-2 to day 7: 33+/-3 g, P
      < 0.05), whereas food intake did not increase in either the STZ + Lep group (day
      0: 24+/-1 vs. day 7: 21+/-2 g, NS), or the Con group (day 0: 23+/-1 vs. day 7:
      23+/-2 g). Plasma glucose levels exceeded nondiabetic control values (7.7+/-0.2
      mmol/l) in both diabetic groups, but were lower in the STZ + Lep group (17.2+/
      1.8 mmol/l) than in the STZ + Sal group (24.3+/-1.1 mmol/l, P < 0.05). To
      determine if sensitivity to leptin-induced anorexia was affected by STZ
      treatment, a second experiment was performed in which the effect of
      intracerebroventricular leptin injection (at doses of 0.35, 1.0, or 3.5 microg)
      on food intake was measured 10 days after STZ or Veh treatment. Leptin suppressed
      both 4- and 24-h food intake in the two groups to an equal extent at every dose
      (by 15, 22, and 35%, respectively). These findings support the hypothesis that
      the effect of uncontrolled diabetes to lower leptin levels contributes to
      diabetic hyperphagia and that this effect is not due to altered leptin
      sensitivity.

PMID- 10342815
TI  - Free fatty acid-induced insulin resistance is associated with activation of
      protein kinase C theta and alterations in the insulin signaling cascade.
AB  - To examine the mechanism by which free fatty acids (FFAs) induce insulin
      resistance in vivo, awake chronically catheterized rats underwent a
      hyperinsulinemic-euglycemic clamp with or without a 5-h preinfusion of
      lipid/heparin to raise plasma FFA concentrations. Increased plasma FFAs resulted
      in insulin resistance as reflected by a approximately 35% reduction in the
      glucose infusion rate (P < 0.05 vs. control). The insulin resistance was
      associated with a 40-50% reduction in 13C nuclear magnetic resonance (NMR)
      determined rates of muscle glycogen synthesis (P < 0.01 vs. control) and muscle
      glucose oxidation (P < 0.01 vs. control), which in turn could be attributed to a
      approximately 25% reduction in glucose transport activity as assessed by 2-[1,2
      3H]deoxyglucose uptake in vivo (P < 0.05 vs. control). This lipid-induced
      decrease in insulin-stimulated muscle glucose metabolism was associated with 1) a
      approximately 50% reduction in insulin-stimulated insulin receptor substrate
      (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity (P < 0.05 vs.
      control), 2) a blunting in insulin-stimulated IRS-1 tyrosine phosphorylation (P <
      0.05, lipid-infused versus glycerol-infused), and 3) a four-fold increase in
      membrane-bound, or active, protein kinase C (PKC) theta (P < 0.05 vs. control).
      We conclude that acute elevations of plasma FFA levels for 5 h induce skeletal
      muscle insulin resistance in vivo via a reduction in insulin-stimulated muscle
      glycogen synthesis and glucose oxidation that can be attributed to reduced
      glucose transport activity. These changes are associated with abnormalities in
      the insulin signaling cascade and may be mediated by FFA activation of PKC theta.

PMID- 10342817
TI  - Opposite effects of acute hypoglycemia and acute hyperglycemia on glucose
      transport and glucose transporters in perfused rat skeletal muscle.
AB  - This study was undertaken to characterize the effects of glycemia per se (glucose
      effectiveness) on muscle glucose transport. Isolated rat hindlimbs were perfused
      in situ for 2 h with perfusate containing either low (2 mmol/l, n = 7), normal
      (6.5 mmol/l, n = 6), or high (20 mmol/l, n = 6) concentrations of glucose,
      without insulin, to simulate hypo-, eu-, and hyperglycemic conditions. The effect
      of varying glucose concentrations on muscle glucose transport was assessed by an
      ensuing 30-min perfusion with 5.5 mmol/l glucose perfusate without insulin. The 2
      h of low glucose perfusion induced significant increases in both muscle glucose
      clearance (approximately 2.3-fold, P < 0.01) and plasma membrane GLUT4 content
      (approximately 20%, P < 0.05) relative to normal. In contrast, high glucose
      perfusion decreased glucose clearance (approximately 1.7-fold, P < 0.01) and
      plasma membrane GLUT4 content (approximately 20%, P < 0.05). Glucose extraction
      during the following 30-min perfusion was 2.5-fold greater (P < 0.0001) in the
      low group and threefold less (P < 0.0001) in the high group, relative to normal.
      2-[3H]deoxyglucose-6-phosphate content in both red (soleus) and white (extensor
      digitorum longus) muscles increased approximately twofold after 2 h of low
      glucose perfusion (P < 0.0001) and decreased > or =2-fold after high glucose
      perfusion (P < 0.0001), relative to normal. It is concluded that glycemia
      regulates glucose transport in skeletal muscle independently of insulin, achieved
      at least partially via changes in plasma membrane GLUT4. We propose that high
      glucose levels can acutely downregulate GLUT4 and glucose clearance, thus
      limiting excessive glucose uptake in muscle. Conversely, low glucose-induced
      upregulation of muscle glucose clearance and GLUT4 can compensate for reduced
      glucose availability in the circulation.

PMID- 10342818
TI  - Effects of aggressive cholesterol lowering and low-dose anticoagulation on
      clinical and angiographic outcomes in patients with diabetes: the Post Coronary
      Artery Bypass Graft Trial.
AB  - Diabetic patients have greater risk for coronary heart disease (CHD) events after
      coronary artery bypass graft (CABG) surgery than nondiabetic patients. The Post
      CABG trial studied the effects of aggressive cholesterol lowering and low-dose
      anticoagulation in diabetic patients compared with nondiabetic patients. A double
      blind, randomized clinical trial in 1,351 patients (1-11 years after CABG), the
      Post CABG trial consisted of two interventions (aggressive cholesterol-lowering
      versus moderate lowering and low-dose warfarin versus placebo) on angiographic
      end points. Angiographic changes in saphenous vein graft conduits 4.3 years after
      entry were compared in 116 diabetic and 1,235 nondiabetic patients. Seven
      clinical centers participated in the trial, as well as the National Institutes of
      Health project office (National Heart, Lung, and Blood Institute), the
      coordinating center (Maryland Medical Research Institute), and the Angiogram
      Reading Center (University of Minnesota). Baseline characteristics of the
      diabetic patients differed from the nondiabetic patients in the following ways:
      percentage of women participants, 15 vs. 7%, P = 0.002; mean baseline weight,
      87.4 vs. 82.8 kg, P = 0.006; mean BMI, 29.5 vs. 27.6 kg/m2, P = 0.0002; mean
      systolic blood pressure, 141.7 vs. 133.6, P < 0.0001; mean triglyceride
      concentrations, 2.09 vs. 1.77 mmol/l, P < 0.0001; and mean HDL cholesterol
      concentrations, 0.93 vs. 1.02 mmol, P = 0.0001. The percentage of clinical events
      was higher in diabetic than nondiabetic patients (20.6 vs. 13.4, P = 0.033) and
      angiographic outcomes were not different. The benefits of aggressive cholesterol
      lowering were comparable in diabetic and nondiabetic patients for the
      angiographic end points. Warfarin use was not associated with clinical or
      angiographic benefit. Diabetic patients in the Post CABG trial had more CHD risk
      factors at study entry and higher clinical event rates during the study than
      nondiabetic patients. The benefits of aggressive cholesterol lowering in diabetic
      patients were comparable to those in nondiabetic patients for both angiographic
      and clinical end points. The small number of diabetic patients provided limited
      power to detect significant differences between diabetic and nondiabetic patients
      or between diabetic patients in the aggressive versus moderate cholesterol
      treatment strategies.

PMID- 10342819
TI  - Power spectral analysis of heart rate variability during hyperinsulinemia in
      nondiabetic offspring of type 2 diabetic patients: evidence for possible early
      autonomic dysfunction in insulin-resistant subjects.
AB  - Sympathetic activation has been considered as a link between insulin resistance,
      hyperinsulinemia, and hypertension. However, little is known about the
      association between insulin sensitivity and autonomic regulation or about the
      effect of acute hyperinsulinemia on cardiac sympathovagal balance. The aim of
      this study was to investigate heart rate variability (HRV) during the euglycemic
      hyperinsulinemic clamp in nondiabetic offspring of patients with type 2 diabetes.
      We studied 35 nondiabetic offspring of patients with type 2 diabetes and 19
      control subjects. Probands were chosen from a 10-year follow-up study of patients
      with well-characterized type 2 diabetes according to their fasting C-peptide
      level (selected from both ends of the distribution) and from control subjects to
      form three groups: 1) a group including subjects who were offspring of type 2
      diabetic patients with low C-peptide levels (deficient insulin secretion group
      [IS group], n = 17), 2) a group including subjects who were offspring of type 2
      diabetic patients with high C-peptide levels (insulin-resistant group [IR group],
      n = 18), and 3) a control group without a history of type 2 diabetes in first
      degree relatives (n = 19). HRV was assessed at baseline and at the steady state
      during the euglycemic-hyperinsulinemic clamp. Rates of whole-body glucose uptake
      (M value) were lower in the IR group than in the IS group and the control group
      (41+/-3 vs. 54+/-2 vs. 60+/-4 micromol x kg(-1) x min(-1), P < 0.01 and P < 0.01,
      respectively). In all groups, heart rate increased significantly during
      hyperinsulinemia. In the IR group, insulin infusion increased total power of HRV
      [from 7.70+/-0.15 to 8.05+/-0.15 ln(ms2), P < 0.01] and the low frequency-to-high
      frequency ratio (from 0.62+/-0.14 to 1.14+/-0.18, P < 0.01) and decreased power
      of the high frequency spectral component (from 5.73+/-0.17 to 5.43+/-0.16
      ln(ms2), P < 0.05), whereas in other groups, changes in HRV were not significant.
      We conclude that the HRV response to acute hyperinsulinemia in the offspring of
      type 2 diabetic probands was likely to be modulated by the type 2 diabetic
      phenotype of the parent. In insulin-resistant subjects, autonomic dysfunction may
      be an earlier defect than hitherto acknowledged.

PMID- 10342820
TI  - Endothelium-dependent vasodilatation, plasma markers of endothelial function, and
      adrenergic vasoconstrictor responses in type 1 diabetes under near-normoglycemic
      conditions.
AB  - It is unknown whether and to what extent changes in various endothelial functions
      and adrenergic responsiveness are related to the development of microvascular
      complications in type 1 diabetes. Therefore, endothelium-dependent and
      endothelium-independent vasodilatation, endothelium-dependent hemostatic factors,
      and one and two adrenergic vasoconstrictor responses were determined in type 1
      patients with and without microvascular complications. A total of 34 patients
      with type 1 diabetes were studied under euglycemic conditions on two occasions
      (11 without microangiopathy, 10 with proliferative and preproliferative
      retinopathy previously treated by laser coagulation, 13 with microalbuminuria,
      and 12 healthy volunteers also were studied). Forearm vascular responses to
      brachial artery infusions of N(G)-monomethyl-L-arginine (L-NMMA), sodium
      nitroprusside, acetylcholine (ACh), clonidine, and phenylephrine were determined.
      The ACh infusions were repeated during coinfusion of L-arginine. Furthermore,
      plasminogen activator inhibitor type 1 (PAI-1) activity, tissue plasminogen
      activator antigen levels, von Willebrand factor antigen levels, tissue factor
      pathway inhibitor (TFPI) activity, and endothelin-1 levels were measured. No
      differences in endothelium-dependent or endothelium-independent vasodilatation or
      adrenergic constriction were observed between the diabetic patients and the
      healthy volunteers. In comparison to the first ACh infusion, the maximal response
      to repeated ACh during L-arginine administration was reduced in the diabetic
      patients, except in the patients with proliferative and preproliferative
      retinopathy previously treated by laser coagulation. In these patients, the
      combined infusion of L-arginine and ACh resulted in an enhanced response. TFPI
      activity was elevated, and PAI-1 activity was reduced in the type 1 diabetic
      patients. Furthermore, PAI-1 activity was positively correlated with urinary
      albumin excretion (r = 0.48, P < 0.01) and inversely correlated with the
      vasodilatory response to the highest ACh dose (r = -0.37, P < 0.05). The response
      to the highest ACh and L-NMMA dose were positively correlated with mean arterial
      blood pressure (r = 0.32, P < 0.01; r = 0.41, P < 0.01, respectively). Forearm
      endothelium-dependent and endothelium-independent vasodilatation and adrenergic
      responsiveness were unaltered in type 1 diabetic patients with and without
      microvascular complications. Relative to healthy control subjects, endothelium
      dependent vasodilatation was depressed during a repeated ACh challenge (with L
      arginine coinfusion) in the diabetic patients without complications or with
      microalbuminuria. In contrast, this vasodilatation was enhanced in the patients
      with retinopathy. Elevation of TFPI was the most consistent marker of endothelial
      damage of all the endothelial markers measured.

PMID- 10342821
TI  - Dietary glycotoxins: inhibition of reactive products by aminoguanidine
      facilitates renal clearance and reduces tissue sequestration.
AB  - Evidence indicates that the metabolic turnover of food-derived reactive orally
      absorbed advanced glycation end products (AGEs) or glycotoxins (GTs) is delayed,
      possibly contributing to the tissue damage induced by endogenous AGEs, especially
      in patients with diabetes and kidney disease. The aim of this study was to
      explore whether pharmacologic inhibition of dietary AGE bioreactivity by
      aminoguanidine (AG) can improve turnover and renal excretion of these substances.
      Normal Sprague-Dawley rats were fed single-labeled [14C]AGE-ovalbumin, double
      labeled [14C-125I]AGE-ovalbumin, or control 125I-labeled ovalbumin diet plus free
      [14C]glucose, with or without AG (0.2% in water). [14C]AGE- and 125I-labeled
      peptide-associated radioactivity (RA) were compared with AGE immunoreactivity (by
      enzyme-linked immunosorbent assay) in tissues, serum, and 72-h urine samples. The
      effect of AG on dietary AGE bioreactivity was assessed by monitoring the
      inhibition of covalent complex formation between fibronectin (FN) peptide
      fragments and serum components, after a meal of labeled dietary AGE with or
      without AG. The radiolabeled AGE diet produced serum absorption and urinary
      excretion peaks kinetically distinct from those of free [14C]glucose or
      [125I]ovalbumin. Some 26% of the orally absorbed AGE-ovalbumin was excreted in
      the urine, whereas after AG treatment, urinary excre-tion of dietary AGEs
      increased markedly (to >50% of absorbed). More than 60% of tissue-bound RA was
      found covalently deposited in kidneys and liver, whereas after treatment with AG,
      tissue AGE deposits were reduced to <15% of the amount found in untreated AGE-fed
      controls. Sera enriched for dietary GTs formed covalently linked complexes with
      FN, a process completely inhibitable by AG cotreatment. Amelioration of dietary
      GT bioreactivity by AG improves renal elimination and prevents tissue deposition
      of food GTs. This may afford a novel and potentially protective use of AG against
      excessive tissue AGE toxicity in diabetic patients with renal disease.

PMID- 10342822
TI  - Protein kinase C activity is acutely regulated by plasma glucose concentration in
      human monocytes in vivo.
AB  - Activation of protein kinase C (PKC) by hyperglycemia is implicated in the
      pathogenesis of long-term diabetic complications. Monocyte activation and
      transformation into macrophages is a key step in the atherosclerotic process.
      Therefore, in this study, we sought to determine 1) the effect of hyperglycemia
      on monocyte PKC activity and on the distribution of Ca2+-dependent and
      diacylglycerol-sensitive PKC isoforms; and 2) whether the effects on these
      parameters are determined by hyperglycemia per se, independent of the diabetic
      state. The studies were performed in 19 type 2 diabetic patients and 14 control
      subjects. Plasma glucose concentration was higher and insulin sensitivity lower
      (both P < 0.01) in diabetic patients than in control subjects. Monocytes from
      diabetic patients showed similar cytosol PKC activity to those from control
      subjects but higher membrane PKC activity (78+/-6 vs. 50+/-5 pmol x min(-1) x mg(
      1) protein; P < 0.01). A direct correlation was observed between fasting plasma
      glucose and membrane PKC activity (r2 = 0.4008, P = 0.0001). In contrast, a
      reciprocal correlation was observed between membrane PKC activity and insulin
      sensitivity index (r2 = 0.28, P < 0.05). Using immunoblotting analysis, we found
      that membrane beta2, but not alpha, isoform of PKC was more abundant in monocytes
      from diabetic patients. In diabetic patients, when euglycemia was acutely
      induced, membrane PKC activity decreased by approximately 42% and beta2 isoform
      by approximately 15%. In two normal subjects in whom hyperglycemia was induced,
      membrane PKC increased from 63 and 57 to 92 and 128.6 pmol x min(-1) x mg(-1)
      protein, respectively. This increase was associated with an increase in the
      membrane isoform beta2; alpha isoform was unchanged. We conclude that 1)
      monocytes express the glucose-sensitive beta2 isoform of PKC; 2) the prevailing
      plasma glucose acutely regulates the activity of the membrane PKC and the content
      of membrane PKC beta2 isoform; and 3) this effect appears to be a direct effect
      of glucose per se, since the phenomenon was observed in normal control subjects
      when hyperglycemia was induced. Monocyte PKC activation may account for the
      accelerated atherosclerosis of patients with type 2 diabetes.

PMID- 10342824
TI  - Glycated low-density lipoprotein attenuates shear stress-induced nitric oxide
      synthesis by inhibition of shear stress-activated L-arginine uptake in
      endothelial cells.
AB  - Little is known about the mechanism(s) of endothelial dysfunction in diabetes. In
      this study, the effect of nonenzymatic glycated LDL, a phenomenon induced by
      elevated D-glucose levels associated with diabetes, on porcine aortic endothelial
      cells was investigated. Two fractions of LDL from diabetic patients were
      separated by affinity column chromatography and are referred to herein as
      fraction alpha (nonglycated LDL) and fraction beta (glycated LDL). Incubation of
      endothelial cells for 24 h with total LDL isolated from diabetic subjects (dLDL)
      increased the release of superoxide anions (*O2-) by fivefold, while no effect of
      LDL isolated from healthy individuals (nLDL) was found. Fraction beta, but not
      fraction alpha, evoked the *O2- release. In vitro-glycated LDL mimicked the
      effect of dLDL/fraction beta on *O2- release that correlated with its degree of
      glycation (R2 = 0.96). Moreover, nitric oxide (NO) stability (measured with a
      porphyrinic-based electrode) and NO bioactivity (measured by its ability to
      elevate cellular cGMP levels) were reduced in cells treated with dLDL by 46 and
      41%, respectively. dLDL (but not nLDL or fraction alpha) abolished shear stress
      induced L-arginine uptake. The inhibitory effect of dLDL on shear stress-induced
      L-arginine uptake was mimicked by in vitro-glycated LDL. The efficiency of in
      vitro-glycated LDL to diminish shear stress-evoked L-arginine uptake correlated
      with the extent of glycation (R2 = 0.88). Moreover, dLDL, but not nLDL or
      fraction alpha, reduced shear stress-mediated cGMP formation and NOx production
      by 47 and 88%, respectively. This effect was also mimicked by in vitro-glycated
      LDL, correlating with its degree of glycation (R2 = 0.86). Under these
      experimental conditions, glycated LDL reduced shear stress-induced increase in NO
      synthesis by inhibition of shear stress-stimulated L-arginine uptake and NO
      bioactivity due to increased endothelial cell *O2- release. These properties may
      contribute to the reduced vasodilatory response and the vascular complications in
      diabetes.

PMID- 10342823
TI  - Human diabetes is associated with hyperreactivity of vascular smooth muscle cells
      due to altered subcellular Ca2+ distribution.
AB  - Alterations of vascular smooth muscle function have been implicated in the
      development of vascular complications and circulatory dysfunction in diabetes.
      However, little is known about changes in smooth muscle contractility and the
      intracellular mechanisms contributing to altered responsiveness of blood vessels
      of diabetic patients. Therefore, smooth muscle and endothelial cell function were
      assessed in 20 patients with diabetes and compared with 41 age-matched control
      subjects. In rings from uterine arteries, smooth muscle sensitivity to K+,
      norepinephrine (NE), and phenylephrine (PE) was enhanced by 1.4-, 2.3-, and 9.7
      fold, respectively, and endothelium-dependent relaxation was reduced by 64% in
      diabetic patients, as compared with control subjects. In addition, in freshly
      isolated smooth muscle cells from diabetic patients, an increased perinuclear
      Ca2+ signaling to K+ (30 mmol/l >73%; 60 mmol/l >68%) and NE (300 nmol/l >86%; 10
      micromol/l >67%) was found. In contrast, subplasmalemmal Ca2+ response, which
      favors smooth muscle relaxation caused by activation of Ca2+-activated K+
      channels, was reduced by 38% in diabetic patients as compared with control
      subjects, indicating a significant change in the subcellular Ca2+ distribution in
      vascular smooth muscle cells in diabetic patients. In contrast to the altered
      Ca2+ signaling found in freshly isolated cells from diabetic patients, in
      cultured smooth muscle cells isolated from control subjects and diabetic
      patients, no difference in the intracellular Ca2+ signaling to stimulation with
      either K+ or NE was found. Furthermore, production of superoxide anion (*O2-) in
      intact and endothelium-denuded arteries from diabetic patients was increased by
      150 and 136%, respectively. Incubation of freshly isolated smooth muscle cells
      from control subjects with the *O2- -generating system xanthine
      oxidase/hypoxanthine mimicked the effect of diabetic patients on subcellular Ca2+
      distribution in a superoxide dismutase-sensitive manner. We conclude that in
      diabetic subjects, smooth muscle reactivity is increased because of changes in
      subcellular Ca2+ distribution on cell activation. Increased *O2- production may
      play a crucial role in the alteration of smooth muscle function.

PMID- 10342825
TI  - A novel polymorphism in the aldose reductase gene promoter region is strongly
      associated with diabetic retinopathy in adolescents with type 1 diabetes.

PMID- 10342826
TI  - Identification of the high-affinity tolbutamide site on the SUR1 subunit of the
      K(ATP) channel.
AB  - ATP-sensitive potassium channels (K(ATP)) are formed from four pore-forming
      Kir6.2 subunits complexed with four regulatory sulfonylurea receptor subunits
      (SUR1 in pancreatic beta-cells, SUR2A in heart). The sensitivity of the channel
      to different sulfonylureas depends on the SUR isoform. In particular, Kir6.2-SUR1
      but not Kir6.2-SUR2A channels are blocked by tolbutamide with high affinity. We
      made chimeras between SUR1 and SUR2A to identify the region of the protein
      involved in high-affinity tolbutamide block. Chimeric SURs were coexpressed with
      Kir6.2 in Xenopus oocytes, and macroscopic currents were measured in inside-out
      membrane patches. High-affinity tolbutamide inhibition could be conferred on
      SUR2A by replacing transmembrane domains (TMs) 14-16 with the corresponding
      region of SUR1. Conversely, high-affinity tolbutamide inhibition of SUR1 was
      abolished by replacing TMs 13-16 with the corresponding SUR2A sequence, or by
      mutating a single serine residue within this region to tyrosine (S1237Y). Binding
      of [3H]glibenclamide to membranes expressing SUR1 was abolished concomitantly
      with the loss of high-affinity tolbutamide block. These results suggest that a
      site in the COOH-terminal set of TMs of the SUR1 subunit of the K(ATP) channel is
      involved in the binding of tolbutamide and glibenclamide.

PMID- 10342827
TI  - So! Why women's health?

PMID- 10342828
TI  - Suppression of ligand-dependent estrogen receptor activity by bone-resorbing
      cytokines in human osteoblasts.
AB  - Estrogens are important for bone homeostasis and are classified as antiresorptive
      agents. One of the mechanisms for this effect is the inhibition of cytokine
      induced bone resorption, which is mediated in part through an interaction between
      the estrogen receptor (ER) and nuclear factor (NF)-kappaB in osteoblasts. We
      present evidence that bone-resorbing cytokines that activate NF-kappaB conversely
      inhibit ligand-dependent ER activity in the conditionally immortalized human
      osteoblast cell line, HOB-03-CE6. Treatment of HOB-03-CE6 cells with 17beta
      estradiol (17beta-E2) up-regulated reporter gene activity [ERE-thymidine kinase
      (tk)-luciferase] 3- to 5-fold in a dose-dependent manner (EC50 = 1.0 pM).
      However, cotreatment of the cells with 17beta-E2 and increasing concentrations of
      either tumor necrosis factor-alpha (TNF alpha), interleukin-1alpha (IL-1alpha),
      or IL-1beta completely suppressed ERE-tk-luciferase activity in a dose-dependent
      manner (IC50 = 0.05-5.0 pM). On the other hand, treatment of the cells with
      growth factors either up-regulated or had no effect on ERE-tk-luciferase
      expression. Neither TNF alpha, IL-1alpha, nor IL-1beta treatment affected basal
      reporter gene activity in the cells, and the TNF alpha effect was reversed by a
      neutralizing antibody to the cytokine. TNF alpha treatment also suppressed ligand
      dependent ER activity in MCF-7 human breast cancer cells, but not in Chinese
      hamster ovary cells that overexpressed human ER alpha, even though both cell
      lines responded to the cytokine as measured by the up-regulation of NFkappaB-tk
      luciferase activity. TNF alpha treatment did not affect the steady state levels
      of either ER alpha or ER beta messenger RNA expression by the HOB-03-CE6 cells,
      nor did it reduce [125I]17beta-E2 binding. Moreover, TNF alpha treatment only
      weakly inhibited ligand-dependent glucocorticoid receptor activity in the HOB-03
      CE6 cells. Bone-resorbing cytokines, which do not signal through the NF-kappaB
      pathway, did not suppress ERE-tk-luciferase activity in HOB-03-CE6 cells.
      Treatment of the cells with 17beta-E2 partially suppressed the activation of NF
      kappaB by TNF alpha, but did not block cytokine-induced IL-6 secretion. Finally,
      cotreatment of HOB-03-CE6 cells with an antisense oligonucleotide to NF-kappaB
      p50 partially reversed the suppression of ERE-tk-luciferase activity by TNF
      alpha. In summary, these data provide evidence for a potent feedback inhibition
      of estrogen action in human osteoblasts that is at least partly mediated by the
      activation of NF-kappaB.

PMID- 10342829
TI  - Steroidogenic factor-1 interacts with a gonadotrope-specific element within the
      first exon of the human gonadotropin-releasing hormone receptor gene to mediate
      gonadotrope-specific expression.
AB  - GnRH plays a pivotal role in regulating human reproductive functions. This
      hypothalamic peptide interacts with its receptor (GnRHR) on the pituitary
      gonadotropes to trigger the secretion of gonadotropins, which, in turn, regulates
      the release of sex steroids from the gonads. In light of the importance of GnRHR,
      the molecular mechanisms underlying the transcriptional regulation of the human
      GnRHR (hGnRHR) gene become a key issue in understanding human reproduction. In
      this report, the possible involvement of steriodogenic factor-1 (SF-1) as a key
      cell-specific regulator for hGnRHR gene expression was examined. By the transient
      luciferase reporter gene assays, the wild-type promoter, containing 2.3 kb ofthe
      hGnRHR gene 5'-flanking region relative to the ATG codon, was able to drive a 3.6
      +/- 0.2-fold (P < 0.05) increase in luciferase activity in the mouse alphaT3-1
      gonadotropes. Subsequent deletion analysis indicated that the most proximal 173
      bp within the first exon of the gene, although not a promoter itself, contains a
      critical regulatory element(s) essential for the basal expression of the hGnRHR
      gene. The functional roles of the putative gonadotrope-specific elements (GSE;
      consensus 5'-CTG(A)/(T)CCTTG-3') residing at positions -5, -134, and -396 were
      studied by site-directed mutagenesis, and it was found that only the mutation at
      position -134 significantly reduced the promoter activity (80% reduction; P <
      0.05). The attenuation effect of this GSE mutant was cell specific, as it was
      restricted to alphaT3-1 cells, but not to COS-7 and human ovarian adenocarcinoma
      (SKOV-3) cells. Competitive mobility shift assays using either alphaT3-1 nuclear
      extract or recombinant SF-1 protein clearly indicated that SF-1 is able to
      interact specifically with this GSE element positioned at -134. Using a SF-1
      antibody that completely abrogated complex formation in the gel shift assays, the
      involvement of endogenous nuclear SF-1 was further evidenced. By competitive gel
      shift assays using oligoprimers with 2-bp scanning mutations, the sequences
      essential for the interaction with SF-1 were identified (5'-TTG(A)/(T)CCCTG-3',
      underlined sequences were important). To study the in vivo function of SF-1,
      vector directing expression of sense or antisense SF-1 messenger RNA (mRNA) was
      cotransfected with the hGnRHR promoter-luciferase construct into alphaT3-1, SKOV
      3, and COS-7 cells. Overexpression of the SF-1 mRNA was able to enhance promoter
      activities in all of the cells tested. On the contrary, expression of the
      antisense SF-1 mRNA reduced the hGnRHR promoter activity only in alphaT3-1 cells,
      not in COS-7 or SKOV-3 cells. In summary, the data reported here provide
      conclusive evidence that SF-1 interacts with the GSE motif at position -134
      within the first exon of the hGnRHR gene to mediate its cell-specific expression.

PMID- 10342830
TI  - Differential response to exogenous and endogenous activin in a human ovarian
      teratocarcinoma-derived cell line (PA-1): regulation by cell surface follistatin.
AB  - The activin/follistatin system is implicated in growth and differentiation of
      various cell types. Follistatin (FS), through binding and neutralizing activin,
      plays a major role in the regulation of activin bioavailability. We previously
      reported that ovarian PA1 cells constitutively secrete FS and show a decreased
      proliferation rate in response to exogenous activin only if cell surface
      associated FS is first removed by heparin treatment. These observations suggest
      that cell-associated FS prevents exogenous activin from accessing its receptor.
      We hypothesized that cell surface FS would differentially regulate the
      bioavailability of endogenous and exogenous activin in these cells. To examine
      the effect of endogenous activin, PA1 cells were stably transfected with an
      activin betaA-subunit complementary DNA (cDNA). The proliferation rate of five
      activin-secreting clones was measured by [3H]thymidine incorporation and compared
      with the proliferation rate of untransfected cells. In clones secreting levels of
      activin ranging from 22.6 +/- 7.1 to 42.4 +/- 9.9 ng/ml, proliferation was
      decreased by 31-72% at 96 h of culture, whereas one cell line secreting lower
      levels of activin (0.4 +/- 0.1 ng/ml) proliferated similarly to the untransfected
      cells, in which activin was not detectable. To further assess activin signaling,
      wild-type PA1 cells and activin-secreting clones were transiently transfected
      with an activin response element-luciferase reporter construct. Basal luciferase
      activity was 6-fold higher in activin-secreting clones than in wild-type PA1
      cells. Exogenous activin (100 ng/ml) increased the transcriptional response of
      wild-type PA1 cells by 3-fold but did not increase reporter activity in activin
      secreting clones. Interestingly, the transcriptional response in activin
      secreting clones was always greater than the basal or activin-stimulated response
      in wild-type cells. Furthermore, we found that FS was removed from the cell
      surface by lipofectamine used for these transfections. Therefore, these results
      show that activation of the luciferase reporter gene occurs under conditions in
      which proliferation is affected, suggesting that the antiproliferative effect of
      activin could be due to a direct stimulation of activin signaling pathways. In
      summary, as opposed to exogenous activin, endogenous activin decreased
      proliferation of PA1 cells even in the presence of cell surface associated FS.
      These results are consistent with a model in which FS acts as a barrier for
      exogenous (endocrine-paracrine) but not for endogenous (autocrine) activin. In
      addition, the higher PA1 cell responsiveness to endogenous compared with
      exogenous activin, suggests that activin overexpression in PA1 cells may up
      regulate an activin signaling component, or down-regulate an activin signaling
      inhibitor.

PMID- 10342831
TI  - Endotoxin disrupts the estradiol-induced luteinizing hormone surge: interference
      with estradiol signal reading, not surge release.
AB  - Three experiments were conducted to investigate whether the immune/inflammatory
      stimulus endotoxin disrupts the estradiol-induced LH surge of the ewe.
      Ovariectomized sheep were set up in an artificial follicular phase model in which
      luteolysis is simulated by progesterone withdrawal and the follicular phase
      estradiol rise is reproduced experimentally. In the first experiment, we tested
      the hypothesis that endotoxin interferes with the estradiol-induced LH surge.
      Ewes were either infused with endotoxin (300 ng/kg/h, i.v.) for 30 h beginning at
      onset of a 48-h estradiol stimulus or sham infused as a control. Endotoxin
      significantly delayed the time to the LH surge (P < 0.01), but did not alter
      surge amplitude, duration, or incidence. The second experiment tested the
      hypothesis that the delaying effects of endotoxin on the LH surge depend on when
      endotoxin is introduced relative to the onset of the estradiol signal. Previous
      work in the ewe has shown that a 14-h estradiol signal is adequate to generate
      GnRH and LH surges, which begin 6-8 h later. Thus, we again infused endotoxin for
      30 h, but began it 14 h after the onset of the estradiol signal. In contrast to
      the first experiment, endotoxin given later had no effect on any parameter of the
      LH surge. In the third experiment, we tested the hypothesis that endotoxin acts
      during the first 14 h to disrupt the initial activating effects of estradiol.
      Estradiol was delivered for just 14 h, and endotoxin was infused only during this
      time. Under these conditions, endotoxin blocked the LH surge in five of eight
      ewes. In a similar follow-up study, endotoxin again blocked the LH surge in six
      of seven ewes. We conclude that endotoxin can disrupt the estradiol-induced LH
      surge by interfering with the early activating effects of the estradiol signal
      during the first 14 h (reading of the signal). In contrast, endotoxin does not
      disrupt later stages of signal processing (i.e. events during the interval
      between estradiol signal delivery and surge onset), nor does it prevent actual
      hormonal surge output. Thus, endotoxin appears to disrupt estrogen action per se
      rather than the release of GnRH or LH at the time of the surge.

PMID- 10342832
TI  - A comparative study on transforming growth factor-beta and activin A for
      preantral follicles from adult, immature, and diethylstilbestrol-primed immature
      mice.
AB  - Both transformation growth factor-beta (TGFbeta) and activin belong to the
      TGFbeta superfamily, and each receptor is structurally related. We have shown
      that the action of activin A on folliculogenesis is different in immature and
      adult mice, so it is of interest to study whether TGFbeta has such an action on
      follicular development. The effect of TGFbeta on folliculogenesis was studied in
      isolated preantral follicles from immature, adult, and diethylstilbestrol (DES)
      primed immature mice and was compared with that of activin A. TGFbeta caused a
      significant increase in follicular diameter and estradiol and immunoreactive
      inhibin secretion in adult mice in a dose-related manner, but did not affect the
      size of preantral follicles from immature mice. Activin A, on the other hand,
      caused a significant increase in the size of follicles from immature mice, but
      did not change the size of preantral follicles from adult mice. TGFbeta enhanced
      the effect of FSH, whereas activin A completely blocked the action of FSH on
      preantral follicles from adult mice. Such a specific action of TGFbeta and
      activin A was age dependent because preantral follicles obtained from 28-day-old
      mice, compared with those from 11- and 56-day-old mice, showed an intermediate
      reaction to TGFbeta and activin A. DES pretreatment of 11- and 28-day-old mice
      caused an enhanced response to FSH, but this response was completely inhibited by
      TGFbeta. These results indicate that both TGFbeta and activin A have
      proliferative action and cytodifferentiative action on granulosa cells, but the
      action of each is age dependent and opposite in direction. In conclusion,
      although both TGFbeta and activin A belong to the same family, and each receptor
      is structurally related, both share a specific role in early folliculogenesis
      before and after puberty.

PMID- 10342833
TI  - The alpha-subunit of human choriogonadotropin interacts with the exodomain of the
      luteinizing hormone/choriogonadotropin receptor.
AB  - The LH/CG receptor, a G protein-coupled receptor, consists of two parts, the N
      terminal extracellular segment (exodomain) and the membrane-associated C-terminal
      segment (endodomain). hCG initially binds the exodomain of the receptor and then,
      the hormone/exodomain complex is thought to make the secondary contact with the
      endodomain of the receptor and generate a hormone signal. However, little direct
      evidence is available about which hormone subunits (alpha or beta) interact with
      which domains of the receptor. To determine whether the alpha-subunit contacts
      the exodomain of its receptor, hCG containing [125I]alpha and truncated exodomain
      lacking the endodomain were prepared. They were chemically cross-linked, and the
      resulting cross-linked complexes were solubilized and electrophoresed. The
      results indicate that the alpha-subunit of hCG was directly and specifically
      cross-linked to the exodomain. To verify the cross-linked exodomain by the
      independent method, the Flag epitope was inserted between the signal sequence and
      the mature exodomain. hCG containing [125I]alpha was cross-linked to the Flag
      exodomain, and the resulting cross-linked hCG/Flag exodomain complexes were
      immunoprecipitated with anti-Flag antibody. The results show that the material
      cross-linked to hCG containing [125I]alpha is indeed the exodomain. In
      conclusion, our results show the direct interaction of the alpha-subunit with the
      exodomain and, therefore, its crucial role in the hormone-receptor interaction in
      addition to its involvement in signal generation.

PMID- 10342834
TI  - Scavenger receptor class B type I in the rat ovary: possible role in high density
      lipoprotein cholesterol uptake and in the recognition of apoptotic granulosa
      cells.
AB  - Scavenger receptor class B type I (SR-BI) mediates the selective uptake of high
      density lipoprotein cholesterol. SR-BI is expressed at high levels in the ovary,
      indicating that it plays a role in the delivery of cholesterol as substrate for
      steroid hormone production. However, SR-BI also binds anionic phospholipids with
      high affinity and could therefore be involved in the recognition of apoptotic
      cells. In this study we have characterized the expression of SR-BI in rat ovarian
      follicles undergoing atresia. Atretic follicles with cells undergoing apoptosis
      were identified by in situ DNA end labeling, and SR-BI expression was determined
      by in situ hybridization and immunohistochemistry. SR-BI was expressed in thecal
      cells at all stages of follicular development, including atretic follicles, and
      in corpus luteum. Isolated apoptotic granulosa cells (but not viable granulosa
      cells) bound annexin V, indicating that they display anionic phospholipids on the
      cell surface. Transfection of COS-7 cells with an expression vector carrying the
      rat SR-BI complementary DNA resulted in increased binding to apoptotic granulosa
      cells (46 +/- 2% of the SR-BI-expressing cells bound at least one granulosa cell
      compared with 24 +/- 3% for the mock-transfected cells; P < 0.0001), whereas the
      binding to viable granulosa cells was unchanged. Apoptotic granulosa cells also
      bound to isolated thecal shells. We conclude that thecal cells of both nonatretic
      and atretic follicles express SR-BI. The location of SR-BI expression in the
      ovary supports a role of this receptor in the uptake of high density lipoprotein
      cholesterol. In addition, our data suggest that SR-BI mediates the recognition of
      apoptotic granulosa cells by the surrounding thecal cells and that it therefore
      may play a role in the remodeling of atretic follicles to secondary interstitial
      cells.

PMID- 10342835
TI  - Transcriptional activation of insulin-like growth factor-binding protein-4 by
      17beta-estradiol in MCF-7 cells: role of estrogen receptor-Sp1 complexes.
AB  - Insulin-like growth factor-binding protein-4 (IGFBP-4) is expressed in MCF-7
      human breast cancer cells, and treatment of these cells with 17beta-estradiol
      (E2) resulted in induction of IGFBP-4 gene expression (>3-fold) and protein
      secretion (>6-fold). To identify genomic sequences associated with E2
      responsiveness, the 5'-promoter region (-1214 to +18) of the IGFBP-4 gene was
      cloned into a vector upstream from the firefly luciferase reporter gene, and E2
      induced a 10-fold increase in luciferase activity in MCF-7 cells transiently
      transfected with this construct. Deletion analysis of this region of the IGFBP-4
      gene promoter identified two GC-rich sequences at -559 to -553 and -72 to -64
      that were important for E2-induced trans-activation. Gel mobility shift assays
      using 32P-labeled -569 to -540 and -83 to -54 oligonucleotides from the IGFBP-4
      gene promoter showed that Sp1 protein bound these oligonucleotides to form a
      retarded band, and the intensity of the band was competitively decreased after
      coincubation with unlabeled IGFBP-4-derived and consensus Sp1 oligonucleotides.
      Mutation of the GC-rich sites within these sequences resulted in loss of the
      retarded band formation. Wild-type human estrogen receptor did not bind directly
      to the IGFBP-4 oligonucleotides; however, human estrogen receptor enhanced Sp1
      DNA binding in a concentration-dependent manner. The results of this study
      demonstrate that at least two GC-rich sequences at -559 to -553 and -72 to -64
      are required for induction of IGFBP-4 gene expression by E2 in MCF-7 cells.

PMID- 10342836
TI  - Gap junction connexin genes cx26 and cx43 are differentially regulated by ovarian
      steroid hormones in rat endometrium.
AB  - In rat endometrium, expression of gap junction connexin-26 (cx26) in the
      epithelium and cx43 in the uterine stroma is suppressed by progesterone before
      implantation. For further study of connexin gene regulation we analyzed
      expression of cx26, cx43, and cx32 in the endometrium of ovariectomized rats
      treated with different ratios of 17beta-estradiol (E2) and progesterone (P). A
      hormonal ratio of E2 to P that mimics conditions during pregnancy (0.1 microg E2
      and 4 mg P) suppressed expression of cx26 and cx43. By changing the ratio to
      higher E2 levels (1 microg E2), cx26, in contrast to cx43, was not suppressed
      even by application of a high P concentration (10 mg). Time-course experiments
      supplying E2 alone led to an early gene response of cx26 within 3 h, whereas
      induction of cx43 transcripts was not detected until 14 h after E2 treatment.
      Simultaneous application of the antiestrogen ICI 182780 abolished E2-mediated
      induction of both connexins. No hormonal regulation of cx32 could be detected. As
      already shown for cx43 gene induction in the myometrium, E2-mediated induction of
      cx26 expression in the endometrium also required newly synthesized transcription
      factors. It can be concluded that only a hormonal ratio resembling conditions
      during pregnancy is able to suppress the expression of both cx26 and cx43 and
      that cx26 gene expression is induced earlier by E2 and is likely to be more
      sensitive to a shift in the E2 to P ratio than cx43.

PMID- 10342837
TI  - Trans-activation functions of the Sp-related nuclear factor, basic transcription
      element-binding protein, and progesterone receptor in endometrial epithelial
      cells.
AB  - The present study examined the trans-activation potential of basic transcription
      element-binding protein (BTEB), a recently identified member of the Sp family of
      GC box-binding transcription factors, on the expression of the gene encoding the
      pregnancy-associated, epithelial-specific, and progesterone (P)-induced porcine
      uterine endometrial secretory protein, uteroferrin (UF). Endometrial expression
      of BTEB, P receptor (PR), and UF genes was analyzed by RT-PCR as a function of
      pregnancy stage and cell type and was correlated with the levels of endometrial
      BTEB that were quantified by Western blot and/or electrophoretic mobility shift
      assay. PR, BTEB, and UF messenger RNAs (mRNAs) were present in early (day 12) and
      mid(day 60) pregnancy pig endometrium, although expression levels varied for each
      mRNA (UF, day 12 << day 60; PR and BTEB, day 12 = day 60). Within the
      endometrium, glandular epithelial (GE) cells manifested higher amounts of UF mRNA
      than stromal fibroblastic cells, whereas both cell types had comparable amounts
      of BTEB and PR mRNAs. Expression of BTEB, however, was limited to endometrial GE
      cells. A BTEB expression vector (pcDNA-3BTEB) was used to examine the effect of
      increased BTEB protein on UF gene expression and promoter activity in primary
      cultures of pig endometrial GE cells. Cells transiently transfected with pcDNA
      3BTEB had 2-fold higher UF mRNA levels than those transfected with the empty
      expression vector (pcDNA-3). Further, cells cotransfected with a UF promoter
      luciferase (-1935UF-Luc) reporter gene and the BTEB expression vector had 2-fold
      higher Luc activity than those cotransfected with reporter gene and pcDNA-3. This
      effect of BTEB was not observed in transfected endometrial stromal fibroblastic
      cells, but was apparent in the human endometrial epithelial carcinoma cell lines
      ECC-1 and Hec-1-A, which exhibit low levels of BTEB protein and low or
      undetectable PR mRNA levels, respectively. The respective contributions of BTEB
      and PR to the modulation of UF promoter activity were examined by cotransfection
      of Hec-1-A and ECC-1 cells with expression plasmids for BTEB and PR and one of
      two UF promoter constructs (-831UF-Luc or -1935UF-Luc) in the absence or presence
      of P. The increase in UF promoter activity with BTEB was mimicked by PR in a P
      dependent manner in both cell lines. The combined effect of PR/P and BTEB
      appeared additive in Hec-1-A cells and was synergistic in ECC-1 cells. These
      results highlight the cell context dependence of the trans-activation potential
      of BTEB and suggest its unique role, in concert with PR, in directing the
      temporal expression of endometrial epithelial genes of pregnancy.

PMID- 10342838
TI  - Tachykinin receptor and neutral endopeptidase gene expression in the rat uterus:
      characterization and regulation in response to ovarian steroid treatment.
AB  - Tachykinin neuropeptides, such as substance P, are localized to a population of
      sensory fibers that innervate the mammalian female reproductive tract. In the
      present study, we have characterized tachykinin NK1 receptor (NK1R), NK2 receptor
      (NK2R), and NK3 receptor (NK3R) gene expression by semiquantitative RT-PCR in
      uteri from ovariectomized rats and studied their regulation in response to 17beta
      estradiol (E2), progesterone (P4), or a combination of both. In addition, we
      analyzed the expression and regulation of the neutral endopeptidase 24.11 (NEP),
      the most important enzyme involved in tachykinin degradation in the rat uterus.
      In uteri from control (olive oil-treated) rats, RT-PCR assays revealed single
      bands corresponding to the expected product sizes encoding complementary DNA for
      NK1R (232 bp), NK2R (491 bp), NK3R (325 bp), and NEP (221 bp). The identity of
      the amplified fragments was confirmed by DNA sequence analysis. Compared with
      control rats, NK1R messenger RNA (mRNA) was increased by 2-fold in uteri from
      rats treated with E2, was decreased by 3.3-fold in rats treated with P4, and was
      decreased by 1.8-fold in rats treated with both E2 and P4. Uterine NK2R mRNA
      levels were not altered by any steroid treatment. E2 treatment decreased by 15
      fold NK3R mRNA. P4 was without effect if administered alone and did not influence
      the E2-induced decrease in NK3R mRNA. NEP mRNA levels were about 4-fold lower in
      E2-treated than in P4-treated rats. Functional studies were carried out in uteri
      from E2- or P4-treated ovariectomized rats to characterize the contractile
      response evoked by the selective tachykinin receptor agonists
      [Sar9Met(O2)11]substance P (NK1R selective), [Nle10]NKA-(4-10) (NK2R selective),
      and [MePhe7]NKB (NK3R selective) in the presence of the NEP inhibitor
      phosphoramidon (1 microM). A marked correlation was observed between the
      magnitude of the contractile response to each agonist and the level of expression
      determined by RT-PCR for each tachykinin receptor. The present findings show that
      tachykinin NK1R, NK2R, NK3R, and NEP are expressed in the rat uterus and that
      ovarian steroids differentially regulate their expression.

PMID- 10342839
TI  - Complex interactions between sex steroids and cytokines in the human pregnant
      myometrium: evidence for an autocrine signaling system at term.
AB  - Little is known about the mechanisms controlling the expression of key proteins
      that regulate excitability and contractility in the human myometrium at term.
      However, evidence is accumulating to suggest that the cytokine transforming
      growth factor (TGF)beta may play a central role. TGFbeta1 and TGFbeta receptors
      are present in the myometrial cells, indicative of an autocrine signaling system.
      Furthermore, the levels of TGFbeta1 and the expression of its receptors increase
      in the myometrium at term suggesting that they are, in turn, regulated and form
      part of a physiological cascade of events involving a number of autocrine
      signaling associated proteins. The present experiments were done to identify
      factors that regulate the expression of TGFbeta1 and TGFbeta receptors and may
      form other elements of this cascade. Because IL-1 and IL-8 are found in the
      myometrium at term and have been implicated in the etiology in premature labor we
      focus on this cytokines. Receptors for IL-1 and IL-8 were detected in the
      myometrial cells. Using Western blot analysis, the levels of expression were
      found to vary. The expression of IL-1 receptor type I was highest in the
      nonpregnant tissue with lower levels in nonlaboring myometrium with a further
      reduction in the spontaneously laboring tissue. In contrast, the expression of IL
      8 receptor type B was highest in the pregnant nonlaboring tissue with a lower
      level in the spontaneously laboring tissue. Using an in vitro model, TGFbeta1 and
      TGFbeta receptor expression was up-regulated by IL-8, IL-1, and TGFbeta1 itself.
      However, IL-8 receptor expression was decreased by IL-8 and TGFbeta1. This
      suggests that in a cascade IL-8 would feed forward to promote the TGFbeta system,
      whereas TGFbeta1 feeds back to inhibit responsiveness to IL-8. Estrogen and
      progesterone increased the release of TGFbeta1. However, at high concentrations,
      estrogen and progesterone (100 nM 17beta-estradiol or 200 nM progesterone)
      decreased the level of TGFbeta receptor expression. Thus, the progressive rise of
      steroid levels in vivo might account for the observed changes in TGFbeta1 and
      TGFbeta receptor expression in vivo. Taken together, these observations support
      the idea that there is a cascade of autocrine signals that may play a major role
      in the physiological processes preparing the myometrium for parturition at term.

PMID- 10342840
TI  - Evidence for a role of the alternatively spliced ED-I sequence of fibronectin
      during ovarian follicular development.
AB  - This study was aimed at testing the hypothesis that different forms of
      fibronectin (FN), produced as a consequence of the alternative splicing of the
      precursor messenger RNA, play specific roles during development of the ovarian
      follicle. In particular, we were interested in determining the effect of the ED-I
      (also termed ED-A) type III repeat, which is absent in the plasma form. Analysis
      of FN levels in follicular fluids corresponding to different stages of
      development of bovine follicles revealed marked changes in the concentrations of
      ED-I+ FN, whereas total FN levels remained relatively constant. ED-I+ FN levels
      were higher in small follicles, corresponding to the phase of granulosa cell
      proliferation. The hypothesis of a physiological role for ED-I+ FN was further
      supported by the finding of a regulation of the alternative splicing of FN in
      primary cultures of bovine granulosa cells by factors known to control ovarian
      follicular development. cAMP produced a 10-fold decrease in the relative
      proportion of the ED-I region. In contrast, transforming growth factor-beta
      elicited a 2-fold stimulation of overall FN synthesis and a 4-fold increase in
      the synthesis of ED-I containing FN. This effect was evident at the protein
      (Western blots) and messenger RNA (Northern blots) levels. Although a negative
      correlation (P < 0.001) was detected between ED-I+ FN and estradiol levels in
      follicular fluid, this steroid was unable to modulate in vitro the alternative
      splicing of FN. A possible mitogenic effect of ED-I+ FN was suggested by the
      observation that a recombinant peptide corresponding to the ED-I domain
      stimulated DNA synthesis in a bovine granulosa cell line (BGC-1), whereas a
      peptide corresponding to the flanking type III sequences had no effect. The
      hypothesis of ED-I+ FN as a growth regulatory factor was further strengthened by
      the fact that depletion of FN from BGC-1-conditioned medium, which contained ED
      I+ FN, abrogated its mitogenic activity, whereas plasma FN was without effect. We
      propose that changes in the primary structure of FN may mediate some of the
      effects of gonadotropin and intraovarian factors during follicular development.

PMID- 10342841
TI  - Dimeric inhibin A and B production are differentially regulated by hormones and
      local factors in rat granulosa cells.
AB  - In the present study, we have examined the role of hormones and growth factors in
      regulating dimeric inhibin production in immature rat granulosa cells. Purified
      granulosa cells from estrogen-primed immature rats were cultured under defined
      conditions. Inhibins A and B in the culture media were measured using a two-site
      enzyme-linked immunosorbent assay specific for each dimer. Under basal
      conditions, granulosa cells produced 14-fold more inhibin A than inhibin B
      (inhibin A, 2.0; inhibin B, 0.14 ng/ml, measured against human standards; average
      A/B apparent ratio, 14). Addition of increasing doses of FSH elicited dose
      dependent increases in both inhibins, the effects being more pronounced on
      inhibin A than on inhibin B (9.4- and 4.1-fold increases, respectively; average
      A/B ratio, 34). Estradiol, when added alone, stimulated inhibin A production 3-
      to 6-fold, whereas minor changes were observed in inhibin B production. Insulin
      like growth factor-I produced a similar stimulation of both inhibins (3-fold
      stimulation over control). This growth factor, however, induced a marked
      dissociation in the sensitivity of inhibins A and B to FSH stimulation, with
      maximal stimulation of inhibin B observed at comparatively lower concentrations
      of the gonadotropin. Transforming growth factor-beta (TGF-beta, 5 ng/ml) had a
      more marked stimulatory effect on inhibin B than on inhibin A production (7- to
      14-fold vs. 2- to 5-fold for inhibin B and A, respectively). A more pronounced
      differential stimulation of inhibin B was also exerted by another member of the
      TGF-beta superfamily, activin A (A/B ratio, 0.66). This preferential stimulation
      of inhibin B by TGF-beta and activin A was amplified in the presence of FSH.
      Coculture of rat granulosa cells with freshly isolated bovine oocytes was also
      associated with a marked stimulation of inhibin B production (100-fold increase)
      and a comparatively lower stimulation of inhibin A (10-fold increase; A/B ratio,
      1). The discrepancy between the proportion of inhibin dimers in serum (A/B ratio,
      0.13) and those produced by untreated granulosa cells may suggest that
      intraovarian factors, such as TGF-beta, activin A, or oocyte-derived factor(s),
      are responsible for the shift of the ratio toward the predominance of inhibin B.

PMID- 10342842
TI  - Antioxidants mimic the ability of chorionic gonadotropin to suppress apoptosis in
      the rabbit corpus luteum in vitro: a novel role for superoxide dismutase in
      regulating bax expression.
AB  - We have recently reported that members of the bcl-2 gene family are expressed and
      estradiol regulated in rabbit luteal cells during corpus luteum (CL) regression,
      and that estradiol and hCG are effective inhibitors of apoptosis in the rabbit CL
      in vivo and in vitro. As Bcl-2 and related proteins are known to regulate levels
      of reactive oxygen species or their intermediates in cells as one possible
      mechanism to control apoptosis, the present studies were designed to examine if
      oxidative stress plays a role in luteal cell apoptosis during CL regression in
      the rabbit. In the first set of experiments, healthy CL obtained from day 11
      pseudopregnant rabbits were incubated in serum-free medium for 2 h in the absence
      or presence of superoxide dismutase (SOD; 1.5-150 U/ml), ascorbic acid (1-100
      mM), N-acetyl-L-cysteine (25 and 50 mM), or catalase (10-1000 U/ml). Cells within
      CL incubated in medium alone exhibited extensive apoptosis (examined by analysis
      of extracted DNA using 3'-end labeling), and this onset of apoptosis was blocked
      in a dose-dependent fashion by treatment with SOD, ascorbic acid, N-acetyl-L
      cysteine, or catalase. In the second set of experiments, expression of bax and
      bcl-x in CL after in vitro treatment without and with 100 U/ml SOD was examined.
      Although SOD treatment did not alter the levels of bcl-x messenger RNA (mRNA)
      over the 2-h incubation period, this antioxidant enzyme significantly reduced the
      levels of bax mRNA in incubated CL. In the final set of experiments, we observed
      that expression of mitochondrial- or manganese-containing SOD was significantly
      increased by treatment of isolated CL with 1 microg/ml hCG in vitro, whereas bax
      mRNA levels were significantly reduced under the same culture conditions.
      Collectively, these data indicate that the gonadotropin-mediated inhibition of
      apoptosis in rabbit luteal cells involves enhanced expression of the oxidative
      stress response gene, manganese-containing SOD, whose protein product may then
      function to protect luteal cells directly from the damaging effect of reactive
      oxygen species and/or indirectly by acutely down-regulating expression of Bax, a
      prooxidant member of the Bcl-2 protein family.

PMID- 10342843
TI  - High efficiency method for gene transfer in normal pituitary gonadotropes:
      adenoviral-mediated expression of G protein-coupled receptor kinase 2 suppresses
      luteinizing hormone secretion.
AB  - The level of LH secretion is determined by both alterations in gonadotrope
      responsiveness and alterations in GnRH secretion. The molecular mechanisms
      underlying gonadotrope responsiveness are unknown, but may include G protein
      coupled receptor kinases (GRKs). Typically, GRKs phosphorylate the intracellular
      regions of seven-transmembrane receptors permitting beta-arrestin to bind, which
      prevents receptor activation of its G protein. Previously, we reported that
      heterologous expression of GRK2, -3, and -6 in GnRH receptor-expressing COS cells
      by complementary DNA transfection suppressed GnRH-stimulated inositol
      trisphosphate production, and that coexpression of GRK2 and beta-arrestin-2 was
      more inhibitory than either expressed alone. Here, we have investigated the
      effect of GRK2 on GnRH-stimulated LH secretion using adenovirus-mediated gene
      transfer in normal pituitary gonadotropes. Pituitary cells were infected with
      adeno-GRK2 or adeno-beta-galactosidase constructs at a multiplicity of infection
      of 60 (number of viral particles per cell). Seventy-two hours later, GRK2
      expression was measured by enzyme-linked immunosorbent assay, and GnRH-stimulated
      LH secretion (10(-7) M GnRH-A for 90 min) was assayed by RIA. Adeno-beta
      galactosidase infected 96-99% of the cells based on X-Gal staining. Uninfected
      and adeno-beta-galactosidase-infected cells exhibited endogenous GRK
      immunoreactivity of about 0.5 (OD405), and LH secretion of 14.8-17.7 ng/ml. Adeno
      GRK2-infected cells showed a GRK2 immunoreactivity of about 2.5 (OD405) and LH
      secretion of 2.5 ng/ml. Therefore, adeno-GRK2 infection resulted in a 5-fold
      increase in the GRK2 OD405 value, which was accompanied by an 80-85% decrease in
      GnRH-stimulated LH secretion. GnRH-stimulated inositol trisphosphate production
      by gonadotropes also was inhibited, suggesting a site of action for GRK2 at
      phospholipase Cbeta or earlier in the signal transduction pathway. The
      significance of these findings is 2-fold: 1) adenoviral-mediated gene transfer
      permits investigation of the regulatory role of gene products in the cell of
      interest, the gonadotrope, rather than in heterologous cell systems; and 2)
      additional, stronger evidence is provided that supports a role for GRKs in
      setting the responsiveness of GnRH receptor signaling.

PMID- 10342844
TI  - A mouse model to study the effects of hormone replacement therapy on normal
      mammary gland during menopause: enhanced proliferative response to estrogen in
      late postmenopausal mice.
AB  - Hormone replacement therapy (HRT) with estrogen alleviates menopausal symptoms
      and is effective in reducing osteoporosis and cardiovascular disease when taken
      in early postmenopause. Older, late postmenopausal women who never previously
      received HRT are also believed to benefit from estrogen treatment. On the other
      hand, increased lifetime exposure of the mammary gland to estrogen may increase
      the risk of breast cancer. The development of suitable experimental animal model
      systems can advance our understanding of the effects of estrogen and the timing
      of HRT on the postmenopausal breast. Toward this end, early and late
      postmenopausal states were induced in mice by short vs. long term ovariectomy (1
      vs. 5 weeks), and the effects of 17beta-estradiol (E) on mammary gland
      morphology, cell proliferation, and progesterone receptor (PR) levels were
      investigated. We report that in late postmenopausal mice, E caused a pronounced
      enlargement of duct ends and 6.5- and 4-fold greater mitogenic responses in the
      duct end epithelium and adjacent stromal cells, respectively, compared with the
      response in early postmenopausal mice. Furthermore, after long term, daily
      treatment with E, steady state levels of proliferation remained 2-fold higher
      than those of similarly treated, early postmenopausal mice. E failed to increase
      mammary PR levels in late postmenopausal, but not in early postmenopausal mice.
      Stimulation of duct ends by E and lack of PR inducibility are characteristics of
      the immature pubertal mammary gland and indicate that the late postmenopausal
      mammary gland resembled the immature state. In contrast, minimal E-induced
      proliferation and increased PR inducibility, characteristics of the adult,
      sexually mature mammary gland, were retained in early postmenopausal mice. The
      lack of difference in the numbers of estrogen receptor-positive epithelial or
      stromal cells or in estrogen receptor cellular concentration after short vs. long
      term ovariectomy indicates that the observed greater efficacy of E is mediated at
      a step beyond receptor-ligand binding. This mouse model of experimentally induced
      early vs. late postmenopausal states should prove useful in better understanding
      alterations in hormone responsiveness and their implications for timing of HRT on
      the human breast.

PMID- 10342845
TI  - Expression of estrogen receptor-beta protein in rodent ovary.
AB  - Estrogen is an essential hormone for the LH surge and ovulation. The primary
      source of estrogen is from ovarian granulosa cells and in rats, estrogen, in
      turn, increases granulosa cell number and enhances FSH-stimulated gene expression
      in these cells. Thus, rat granulosa cells both respond to and synthesize
      estrogen. To further elucidate the mechanisms mediating the actions of estrogen
      in granulosa cells, we have identified and characterized the estrogen receptor
      beta (ER-beta) subtype in rodent granulosa cells. ER-beta protein was localized
      to the nuclei of rat granulosa cells in preantral and antral follicles by
      immunocytochemistry, coincident with the location of ER-beta messenger RNA
      (mRNA). Immunoprecipitation and Western blot analysis using ER-beta specific
      antisera demonstrated a protein of approximately 60 kDa in granulosa cells
      prepared from PMSG-primed immature mice and estrogen-treated immature rats.
      Extracts from granulosa cells specifically bound an estrogen response element and
      the complex was recognized by antisera to ER-beta. A synthetic steroid estrogen
      radioligand, [125I]-17alpha-iodovinyl-11beta-methoxyestradiol ([125I]-VME2),
      bound to cytosolic granulosa cell preparations with high affinity (estimated K(D)
      value of 401 +/- 83 pM, and Bmax value of 102 +/- 9 fmol/mg protein). ER-beta
      protein levels rapidly declined following hCG treatment consistent with the
      reported decrease in binding activity and ER-beta mRNA levels by high levels of
      gonadotropins. Overall, we have demonstrated that 1) ER-beta protein is the
      dominant estrogen receptor subtype present in rodent granulosa cells, 2) this
      receptor is functional, and 3) it is regulated by ovulatory doses of
      gonadotropins. Thus, ER-beta is likely to be a mediator of estrogen action in
      rodent granulosa cells during follicular development.

PMID- 10342846
TI  - Transgenic mice with chronically elevated luteinizing hormone are infertile due
      to anovulation, defects in uterine receptivity, and midgestation pregnancy
      failure.
AB  - Elevated levels of LH have been associated with infertility and miscarriage in
      women. Previously, we have reported generating a transgenic mouse model that
      hypersecretes LH. Female transgenics exhibit extensive pathology including
      enlarged, cystic, and hemorrhagic ovaries; elevated testosterone:estradiol
      ratios; and infertility primarily due to anovulation. Here we show that
      anovulation can be reversed in transgenics and that, despite development within a
      pathological ovary, oocytes from transgenics are remarkably healthy. Fertilized
      ova from transgenics are capable of normal development to term when transferred
      into nontransgenic pseudopregnant recipients. However, reciprocal transfers of
      nontransgenic embryos into transgenic recipients failed due to lack of uterine
      receptivity. In addition, while superovulated and mated transgenics appear to
      have normal early pregnancy, embryos are resorbed at midgestation due to maternal
      hormonal defects. Transgenic infertility can be rescued by ovariectomy with
      progesterone and estradiol replacement. These studies are particularly intriguing
      in light of data indicating an increased rate of miscarriage among women
      undergoing infertility treatments who are diagnosed with polycystic ovarian
      syndrome.

PMID- 10342847
TI  - Evidence for alternative pathways of granulosa cell death in healthy and slightly
      atretic bovine antral follicles.
AB  - Granulosa cell death is an early feature of atresia; however, there are many
      apparent contradictions in the literature concerning the mode of granulosa cell
      death. We have therefore examined this process in bovine healthy and atretic
      antral follicles, using a variety of established techniques. Light and electron
      microscopic observations indicated the presence of pyknotic or shrunken nuclei in
      both the membrana granulosa and the antrum. In the membrana granulosa, these
      nuclei were frequently crescent shaped and uniformly electron dense and were
      approximately the same size as healthy nuclei, all of which are typical of early
      apoptosis. However, these nuclei were within the membranes of a healthy granulosa
      cell, suggesting that phagocytosis by a neighboring granulosa cell is an
      unusually early event in the apoptotic pathway of granulosa cells. In the
      membrana granulosa, pyknotic nuclei stained intensely with hematoxylin but weakly
      with the DNA-intercalating stain propidium iodide. A percentage of these pyknotic
      nuclei stained by TUNEL (terminal deoxy-UTP nick end-labeling). However, in the
      antrum, the pyknotic nuclei and larger globules of DNA stained intensely with
      both hematoxylin and propidium iodide, but were not TUNEL positive. The comet
      assay of cell death produced a streak tail of randomly nicked DNA, rather than
      the plume of low mol wt apoptotic DNA. Globules collected from fresh follicular
      fluid stained intensely with propidium iodide and were shown by PAGE to contain
      DNA, the majority of which was high mol wt. In conclusion, granulosa cells within
      the membrana granulosa die by apoptosis, with phagocytosis by a neighboring cell
      preceding any potential budding of the nucleus or cell itself. Granulosa cells
      near the antrum are sloughed off into the antrum, and their death has features
      more consistent with that of other cell types that undergo death as a result of
      terminal differentiation.

PMID- 10342848
TI  - Biologically active estrogen receptor-beta: evidence from in vivo
      autoradiographic studies with estrogen receptor alpha-knockout mice.
AB  - Estrogen receptor-1 (ER beta) messenger RNA (mRNA) has been detected in the brain
      of wild-type and estrogen receptor-alpha knockout (ER alphaKO) mice. The present
      study used in vivo autoradiography to evaluate the binding of 125I-estrogen, a
      compound with a similar affinity for both ERs to ascertain whether ER beta mRNA
      is translated into biologically active receptor. Mice were injected with 125I
      estrogen, and sections were mounted on slides and opposed to emulsion. After
      exposure, labeled cells were seen in ER alphaKO brain regions where ER beta is
      expressed (preoptic and paraventricular nuclei of the hypothalamus; bed nucleus
      of the stria terminalis; amygdala; entorhinal cortex; and dorsal raphe).
      Competition studies with 17beta-estradiol eliminated binding in the ER alphaKO
      brain, whereas 16alphaIE2, an ER alpha selective agonist and dihydrotestosterone
      had no effect. In contrast, competition studies with 16alphaIE2 in wild-type mice
      eliminated 125I-estrogen binding to ER alpha and resulted in a pattern of
      residual binding comparable to that seen in the ER alphaKO brain. The results
      demonstrate that residual estrogen binding sites are present in regions of the ER
      alphaKO brain where ER beta is expressed, brain regions that were also seen after
      eliminating binding to ER alpha in wild-type mice. These data provide the first
      evidence that ER beta mRNA is translated into a biologically active protein in
      the rodent brain.

PMID- 10342849
TI  - Suppression of leptin during lactation: contribution of the suckling stimulus
      versus milk production.
AB  - Lactation in the rat is characterized by the suppression of pulsatile LH
      secretion, a large increase in food intake, and changes in energy balance due to
      the metabolic drain of milk production. The change in energy balance may be a
      major component in altering reproductive function. A number of factors may
      contribute to changing energy balance of a lactating animal; one is leptin, the
      product of adipose tissue, which is known to act partly as a satiety factor to
      decrease food intake. The aims of the present study were to determine whether
      there are changes in leptin levels during lactation, a state of high energy
      demand, and during periods of acute suckling in the presence or absence of
      changes in energy demand. Our goals were to determine whether lactation and the
      suckling stimulus influenced serum leptin levels and whether there was a
      potential role for leptin in the suppression of LH secretion during lactation.
      The first experiment was performed during diestrus of the estrous cycle, and
      chronic lactation, (day 9 post partum) in animals suckling 8 pups. The results
      showed that leptin levels were significantly decreased in both ovarian intact or
      ovariectomized lactators; this decrease parallels the suppression of pulsatile LH
      secretion. Serum insulin levels were not altered in the lactating animals. The
      second experiment was performed in ovariectomized lactators whose 8 pup litters
      were removed for 48 h, starting on day 9. On day 11, mothers received no pups or
      pups that were either nonfostered (resulting in no milk production) or fostered
      (resulting in milk production). The pups were allowed to suckle for 24 h.
      Following 24 h of acute suckling, serum leptin, and insulin levels correlated
      with the energy drain on the mother. The levels of leptin were normal and of
      insulin were elevated in mothers producing no milk. Conversely, leptin levels
      were suppressed and insulin levels normal in mothers producing milk. The third
      experiment used the same groups as described for the second experiment except
      that serial blood samples were collected for measurement of pulsatile LH
      secretion following 24 h of acute suckling. The results showed that regardless of
      whether leptin levels remained normal or were suppressed in response to acute
      suckling, pulsatile LH secretion was significantly inhibited compared with the
      nonsuckled control animals. In summary, these data suggest that the metabolic
      drain of milk production, and not the suckling stimulus itself, is the most
      likely factor responsible for the suppression of leptin secretion during
      lactation. Furthermore, although the decreased levels of leptin may be causally
      related to the inhibition of pulsatile LH secretion during chronic lactation,
      changes in leptin are not a prerequisite for the suppression of LH secretion in
      response to suckling.

PMID- 10342850
TI  - Estradiol induces galanin gene expression in the pituitary of the mouse in an
      estrogen receptor alpha-dependent manner.
AB  - Estradiol imprinting plays an important role in the regulation of galanin (GAL)
      gene expression in the rat. In the anterior pituitary gland, GAL gene expression
      is greatly induced by estrogen. The relative involvement that the two estrogen
      receptor subtypes, alpha and beta, have in regulating this induction is not
      known. We have utilized ER alpha-knock-out (ER alphaKO) mice to discriminate the
      roles of ER alpha and ER beta in the regulation of GAL gene expression in the
      anterior pituitary gland. Our goals were to measure the effects of estradiol on
      GAL gene expression by solution hybridization ribonuclease protection assay in
      wild-type mice and to determine the roles of ER alpha and, indirectly, ER beta by
      measuring the same response in the ER alphaKO mice. Estradiol treatment for one
      week elevated GAL gene expression 30-40 fold in the wild-type mouse pituitary.
      Evaluation of estrogen effects on GAL gene expression in the anterior pituitary
      of ER alphaKO animals revealed that ER alpha is essential, because no response to
      estrogen was observed in these animals. Since ER beta mRNA was identified in the
      anterior pituitary by RT-PCR, but estrogen had no effects on GAL gene expression
      in the ER alphaKO mice, the beta subtype of ER does not appear to participate in
      estrogen-evoked GAL gene expression in the mouse anterior pituitary.

PMID- 10342851
TI  - Activation of c-Src kinase is associated with in vitro decidualization of human
      endometrial stromal cells.
AB  - Tyrosine phosphorylation of cellular proteins, controlled coordinately by
      tyrosine kinases and phosphatases, is a critical element in signal transduction
      pathways involved in the regulation of biological responses including cell growth
      and differentiation. Decidualization is a dramatic progesterone-induced
      differentiation of the estrogen-primed endometrium, which is crucial for embryo
      implantation and maintenance of pregnancy. Here we have shown that the kinase
      activity of c-Src was increased, accompanied by altered tyrosine phosphorylation
      of several cellular proteins, during in vitro decidualization of human
      endometrial stromal cells. Withdrawal of both estrogen and progesterone from the
      cultures of decidualized stromal cells reduced c-Src kinase activity to the basal
      level and also changed the pattern of tyrosine phosphorylation of the several
      cellular proteins to the unstimulated state. The kinase activity of endometrial c
      Src appeared to inversely correlate with the level of its tyrosine
      phosphorylation. Moreover, although the endometrial stromal cells expressed
      another src-family kinase, Fyn, the activity of the Fyn kinase was almost
      undetectable during decidualization and thereafter upon steroid withdrawal. Our
      findings suggest that the activation of c-Src kinase may be a normal
      physiological event associated with decidualization, being specifically involved
      in the signaling cascades mediated by ovarian hormone stimulation.

PMID- 10342852
TI  - Deficits in female reproductive function in GH-R-KO mice; role of IGF-I.
AB  - Mice homozygous for targeted disruption of the GH receptor/GH binding protein
      gene (GH-R-KO mice; -/-) exhibit reduced plasma IGF-I levels, elevated plasma GH
      levels, and dwarf phenotype. Although most GH-R-KO mice are fertile, age at first
      conception is greatly delayed in -/- x -/- matings. Here we report that the age
      of vaginal opening is significantly delayed in GH-R-KO vs. normal mice, but it
      can be advanced by treatment with recombinant human (rh)IGF-I. In pregnant GH-R
      KO females, fetal size is reduced and pregnancy is prolonged while placental
      weight is, unexpectedly, increased. Alterations in fetal and placental weight are
      related to maternal rather than fetal genotype. Moreover, litter size and body
      weight of newborn pups are significantly reduced in GH-R-KO vs. normal females.
      Reduction in litter size reflects both dam and sire effects. We conclude that GH
      resistance and consequent reduction in peripheral IGF-I levels is associated with
      delay of female puberty, alterations in fetal and placental growth, delay of
      parturition, and reduced litter size.

PMID- 10342853
TI  - Localization, regulation and possible consequences of apoptotic protease
      activating factor-1 (Apaf-1) expression in granulosa cells of the mouse ovary.
AB  - The recent characterization of apoptotic protease-activating factor-1 (Apaf-1) in
      vertebrates as a putative homolog of the Caenorhabditis elegans gene, ced-4,
      indicates that the third major arm of the C. elegans programmed cell death
      machinery has also been conserved through evolution. Although apoptosis is now
      known to be important for ovarian follicular atresia in vertebrates, nothing is
      known of the role of Apaf-1 in ovarian function. Herein we show by
      immunohistochemical analysis that Apaf-1 is abundant in granulosa cells of early
      antral follicles whereas in vivo gonadotropin priming completely suppresses Apaf
      1 expression and granulosa cell apoptosis. Western blot analysis of fractionated
      protein extracts prepared from granulosa cells before and after in vitro culture
      without hormonal support to induce apoptosis indicated that mitochondrial
      cytochrome c release, a biochemical step required for the activation of Apaf-1,
      occurs in granulosa cells cultured in vitro. Moreover, Western blot analysis of
      procaspase-3 processing, a principal downstream event set in motion by activated
      Apaf-1, indicated that healthy granulosa cells possess almost exclusively the
      inactive (pro-) form of the enzyme whereas granulosa cells deprived of hormonal
      support rapidly process procaspase-3 to the active enzyme. Lastly, we show that
      serum-starved granulosa cells activate caspase-3-like enzymes both prior to and
      after nuclear pyknosis, as revealed by a single-cell fluorescent caspase activity
      assay. These data, combined with previous observations regarding the role of
      homologs of the two other C. elegans cell death regulatory genes, ced-9 (Bcl-2
      family members) and ced-3 (caspases), in atresia fully support the hypothesis
      that granulosa cell apoptosis is precisely coordinated by all three major arms of
      a cell death program conserved through evolution.

PMID- 10342854
TI  - Altered expression of agouti-related protein and its colocalization with
      neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation.
AB  - During lactation, the levels of neuropeptide Y (NPY), which plays an important
      role in mediating food intake, are significantly elevated in a number of
      hypothalamic areas, including the arcuate nucleus (ARH). To identify additional
      hypothalamic systems that might be important in mediating the increase in food
      intake and alterations in energy homeostasis during lactation, the present
      studies examined the expression of agouti-related protein (AGRP), a recently
      described homologue of the skin agouti protein. AGRP is found in the hypothalamus
      and has been suggested to play an important role in the regulation of food
      intake. In the first experiment, animals were studied during diestrus of the
      estrous cycle, a stage of the cycle when estrogen levels are basal and similar to
      lactation, or during days 12-13 postpartum. Lactating animals had their litters
      adjusted to eight pups on day 2 postpartum. Brain tissue sections were used to
      measure AGRP messenger RNA (mRNA) levels by in situ hybridization. AGRP mRNA
      signal was found mostly in the ventromedial portion of the ARH, which has been
      shown to contain a high density of NPY neurons. A significant increase in AGRP
      mRNA content was observed in the mid- to caudal portion of the ARH of lactating
      animals compared with diestrous females. No difference was found in the rostral
      portion of the ARH. In the second experiment, double-label in situ hybridization
      for AGRP and NPY was performed in lactating animals to determine the extent of
      colocalization of the two peptides in the ARH, using 35S-labeled and digoxigenin
      labeled antisense complementary RNA probes. It was found that almost all of the
      NPY-positive neurons throughout the ARH also expressed AGRP mRNA signal.
      Furthermore, AGRP expression was confined almost exclusively to NPY-positive
      neurons. Thus, the present study showed that during lactation, AGRP gene
      expression was significantly elevated in a subset of the AGRP neurons in the ARH.
      The high degree of colocalization of AGRP and NPY, coupled with previous reports
      from our laboratory demonstrating increased NPY expression in the ARH in response
      to suckling, suggests that AGRP and NPY are coordinately regulated and may be
      involved in the increase in food intake during lactation.

PMID- 10342855
TI  - Differential regulation and action of estrogen receptors alpha and beta in GH3
      cells.
AB  - The pituitary lactotroph, a well established target for estrogens, expresses
      estrogen receptor-alpha (ER alpha) and -beta (ER beta). A truncated isoform of ER
      alpha, named TERP, is expressed in the pituitary, but not in the uterus. In this
      study we used the somatolactotroph cell line, GH3 cells, to examine 1) the
      expression of ER alpha, TERP, or ER beta and their regulation by estradiol; 2)
      the presence of receptor proteins; and 3) the effects of overexpressing ER beta
      or TERP on estrogen induction of the PRL gene and activation of the estrogen
      response element (ERE). Incubation of GH3 cells with estradiol (0.1-10 nM)
      produced dose-dependent increases in messenger RNA levels of ER beta and TERP,
      but not ER alpha, as determined by quantitative RT-PCR. Cell incubation with 1 nM
      estradiol resulted in a time-dependent biphasic increase in TERP and a delayed
      rise in ER beta, suggesting activation by both direct and indirect mechanisms. A
      polyclonal ER beta antibody directed against an N-terminal synthetic peptide was
      generated. This antibody detected ER beta-positive cells in ovarian granulosa
      cells and in many cells throughout the pituitary; its specificity was
      demonstrated by preabsorption with the synthetic peptide. The antibody detected a
      58- to 60-kDa protein by Western blotting of ovarian, pituitary, and GH3 cell
      extracts. Cotransfection of ER beta and reporter genes (PRL promoter/luciferase
      or ERE/luciferase) into GH3 cells resulted in a dose-dependent increase in
      estrogen-induced PRL gene expression, with a lesser activation of the ERE. A 20
      kDa TERP protein was undetectable in untreated GH3 cells and was weakly induced
      by estradiol. Overexpression of TERP had no effect on estrogen induction of
      either PRL or ERE. We conclude that 1) both ER beta and TERP messenger RNAs in
      GH3 cells are increased by estradiol in a dose- and time-dependent manner,
      whereas ER alpha is not altered; 2) a 58-kDa ER beta protein is expressed in both
      the pituitary and GH3 cells; and 3) overexpression of ER beta increases estrogen
      induced PRL gene expression.

PMID- 10342856
TI  - Precocious differentiation of the virgin Wistar-Kyoto rat mammary gland.
AB  - The Wistar-Kyoto (WKY) rat strain expresses high levels of beta-casein in its
      virgin mammary glands. We found that the onset of beta-casein overexpression
      (BCO) occurs at 6 weeks of age, with morphological differentiation of the mammary
      gland detectable at 7 weeks of age. BCO was previously shown to be cell
      autonomous; however, we found that adrenal and ovarian hormones were permissive
      and necessary for the expression of the BCO phenotype, indicating that the
      genetic variation that initiates BCO from within the mammary epithelium can only
      manifest BCO in the presence of virgin hormone levels. Sequencing of the WKY and
      Wistar-Furth (WF) rat beta-casein promoters showed them to be identical. Culture
      of primary rat mammary epithelial cells (RMEC) under lactogenic conditions
      revealed that expression of beta-casein was independent of epidermal growth
      factor (EGF) in RMEC from virgin WKYv, but was dependent in WFv, RMEC. RMEC from
      a pregnant WFp responded similarly to WKYv RMEC, suggesting that EGF-independent
      beta-casein expression occurs naturally in differentiated rat mammary epithelium.
      However, induction of beta-casein expression in RMEC from immature WKY rats was
      also independent of EGF, indicating that the induction as well as maintenance of
      BCO do not require EGF. We suggest that an EGF-independent signaling pathway,
      arising from a trans-acting inherited effector(s), underlies BCO.

PMID- 10342857
TI  - Expression of cyclooxygenase-1 and -2 in the baboon endometrium during the
      menstrual cycle and pregnancy.
AB  - Cyclooxygenase (COX) is the rate-limiting enzyme in the biosynthesis of PGs. PGs
      together with ovarian steroids play important regulatory roles in the
      establishment and maintenance of pregnancy in a number of different species. In
      the primate, little is known about the role of PGs in these processes. In this
      study, the uterine expression of COX-1 and COX-2 throughout the menstrual cycle
      [late follicular, day 5 postovulation (PO), day 10 PO, and day 14 PO] and
      pregnancy (days 12-18, day 39, day 51, and near term) was analyzed using
      semiquantitative RT-PCR, in situ hybridization, and immunocytochemistry. During
      the menstrual cycle, the highest expression of COX-1 occurred in luteal phase
      endometrium and was localized to the surface and glandular epithelium. The
      stromal cells did not express detectable levels of COX-1 at any time. COX-2
      messenger RNA (mRNA) expression, as measured by RT-PCR, was evident at all stages
      of the menstrual cycle, and in situ hybridization showed specific localization
      for this mRNA in the epithelial cells during the cycle. Treatment of animals with
      the antiprogestin (ZK 137.316) for 9 days (beginning on the day of the LH surge)
      inhibited COX-1 expression in the epithelium when the tissue was analyzed on day
      10 PO, whereas COX-2 expression disappeared in the epithelium and increased in
      the stroma. With the onset of pregnancy, COX-1 expression in epithelial cells
      decreased dramatically. In contrast, COX-2 continued to be detected on the
      surface epithelium and was also strongly expressed specifically in the stromal
      cells at the site of implantation. Immunocytochemical staining for COX-2 showed
      the same pattern of expression for the protein as the message. Finally, near-term
      decidua expressed very little COX-1 or COX-2 mRNA. These studies suggest that in
      the baboon endometrium, COX-1 expression is regulated primarily by progesterone,
      whereas regulation of COX-2 expression may involve additional mediators of
      embryonic origin at the site of implantation.

PMID- 10342858
TI  - Characterization and localization of beta2-adrenergic receptors in the bovine
      oviduct: indication for progesterone-mediated expression.
AB  - Beta2-adrenergic receptors were detected in bovine oviductal epithelium by use of
      receptor binding studies and expression analysis. Complementary DNA cloning gave
      use to the first full-length bovine beta2-adrenoceptor messenger RNA sequence
      (2030 bases). Receptor bioactivity in oviduct epithelial cells was characterized
      by specific ligand interaction and consequent cAMP generation. Expression studies
      demonstrated an estrous cycle-dependent regulation, with higher transcript levels
      and significantly increased binding capacity during the luteal phase. After
      progesterone supplementation, oviduct epithelial cells showed elevated receptor
      expression in culture, supporting the hypothesis that progesterone up-regulates
      the beta2-adrenergic receptor within these cells. It seems likely that
      catecholamines from the circulation or from innervation might be able to
      influence reproductive success by regulating oviductal secretion.

PMID- 10342859
TI  - Anovulation in cyclooxygenase-2-deficient mice is restored by prostaglandin E2
      and interleukin-1beta.
AB  - Mice carrying a null mutation for either of the two cyclooxygenase (COX)
      isoenzymes, necessary for prostanoid production, exhibit several isotype-specific
      reproductive abnormalities. Mice deficient in COX-1 are fertile but have
      decreased pup viability, whereas mice deficient in COX-2 fail to ovulate and have
      abnormal implantation and decidualization responses. The present study identifies
      the specific contribution of each COX isoenzyme in hypothalamic, pituitary, and
      ovarian function and establishes the pathology and rescue of the anovulatory
      syndrome in the COX-2-deficient mouse. In both COX-1- and COX-2-deficient mice,
      pituitary gonadotropins were selectively increased, whereas hypothalamic LHRH and
      serum gonadotropin levels were similar to those in wild-type animals (+/+). No
      significant differences in serum estrogen or progesterone were noted among the
      three genotypes. Exogenous gonadotropin stimulation with PMSG and hCG produced a
      comparable 4-fold increase in ovarian PGE2 levels in wild-type and COX-1(-/-)
      mice. COX-2(-/-) mice had no increase in PGE2 over PMSG-stimulated levels. Wild
      type and COX-1(-/-) mice ovulated in response to PMSG/hCG; very few COX-2(-/-)
      animals responded to this regimen. The defect in ovulation in COX-2 mutants was
      attributed to both an abnormal cumulus oophorum expansion and subsequent stigmata
      formation. Gonadotropin stimulation and concurrent treatment with PGE2 or
      interleukin-1beta resulted in ovulation of COX-2(-/-) mice comparable to that in
      COX-2(+/+), whereas treatment with PGF2alpha was less effective. Collectively,
      these data demonstrate that COX-2, but not COX-1, is required for the
      gonadotropin induction of ovarian PG levels; that COX-2-related prostanoids are
      required for stabilization of the cumulus oophorum during ovulation; and that
      ovulation can be restored in the COX-2(-/-) animals by simultaneous treatment
      with gonadotropins and PGE2 or interleukin-1beta.

PMID- 10342860
TI  - Segregation of retinoic acid effects on fetal ovarian germ cell mitosis versus
      apoptosis by requirement for new macromolecular synthesis.
AB  - Retinoic acid (RA), a naturally occurring metabolite of vitamin A, plays an
      essential role in regulating cellular growth, differentiation, and death in a
      variety of tissues, particularly during fetal development. However, essentially
      nothing is known of the effects of RA on fetal gametogenesis. Using a recently
      validated system of culturing murine fetal ovaries, herein we sought to
      characterize the actions of RA on female germ cell proliferation and apoptosis
      during oogenesis. In the absence of trophic hormone support, approximately 90% of
      the oogonia and oocytes present in fetal ovaries at the start of culture
      underwent apoptosis over a 72 h culture period (P < 0.05), whereas provision of
      0.01-1 microM RA dose dependently maintained germ cell numbers. In fact, ovaries
      cultured with 0.1 microM RA for 72 h possessed approximately 30% more oogonia and
      oocytes as compared with the preculture mean number (P < 0.05). Additional
      experiments, using in situ DNA 3'-end-labeling and cellular morphology to assess
      apoptosis coupled with 5-bromo-2'-deoxyuridine incorporation to assess
      proliferation, revealed that RA acts as both a mitogen and a survival factor for
      female germ cells. Furthermore, the ability of RA to stimulate germ cell
      proliferation in cultured fetal ovaries was completely suppressed (P < 0.05) by
      cotreatment with inhibitors of transcription (alpha-amanitin, 0.1 microg/ml) or
      protein synthesis (cycloheximide, 1.0 microg/ml), whereas RA-mediated suppression
      of germ cell apoptosis was not affected by cotreatment with either macromolecular
      synthesis inhibitor (P > 0.05). Moreover, cotreatment of fetal ovaries with 5
      microM LY294002, an inhibitor of phosphatidylinositol 3'-kinase, had no effect on
      RA-promoted germ cell maintenance (P > 0.05). By comparison, the antiapoptotic
      effects of insulin-like growth factor I on germ cells in cultured fetal ovaries
      were significantly attenuated by cotreating ovaries with LY294002 (P < 0.05) but
      not with alpha-amanitin or cycloheximide (P > 0.05). Importantly, the effect of
      RA on the female germ line was also observed in vivo because a single oral
      administration of 100 mg/kg RA to timed-pregnant female mice resulted in a
      significantly (P < 0.05) larger endowment of primordial oocytes in female
      offspring. That these actions were mediated, at least in part, by specific
      retinoid receptors was demonstrated by the finding of retinoic acid receptor
      protein in fetal female gonocytes, as assessed by immunohistochemical
      localization experiments. Collectively, these data indicate that RA can function,
      in vitro and in vivo, as a potent germ cell survival factor and mitogen during
      fetal oogenesis in the mouse.

PMID- 10342861
TI  - Uterine decidual response occurs in estrogen receptor-alpha-deficient mice.
AB  - Embryo-uterine interactions leading to the attachment reaction is followed by
      stromal cell proliferation and differentiation into decidual cells
      (decidualization) at the sites of blastocyst apposition. In rodents,
      decidualization is also induced by application of an artificial stimulus
      (intraluminal oil infusion) in a pseudopregnant uterus, or to one that has been
      appropriately prepared by exogenous progesterone (P4) and estrogen. The process
      of decidualization is under the control of these steroids in the presence of
      blastocysts or deciduogenic stimuli. Although it is well known that estrogen is
      required for the induction of progesterone receptors in the uterus, the
      functional importance of estrogen in the process of decidualization is poorly
      understood. To better understand the role of estrogenic actions in
      decidualization, we used wild-type and estrogen receptor-alpha knock-out (ERKO)
      mice for induction of decidualization employing a defined steroid hormonal
      treatment schedule. Our results demonstrate that P4 alone induces decidualization
      in ovariectomized wild-type or ERKO mice in response to intraluminal oil infusion
      in the absence of estrogen. A combined treatment of either estradiol-17beta (E2)
      or its catecholmetabolite 4-hydroxyestradiol-17beta(4-OH-E2) with P4 does not
      potentiate the decidual response produced by P4 treatment alone in either
      ovariectomized wild-type or ERKO mice. The induction of decidual response was
      associated with up-regulation of decidual cell marker genes, such as progesterone
      receptor, metallothionein-1, and cyclooxygenase-2. The results suggest that the
      stromal cell sensitivity to decidualization is critically dependent on P4
      regulated events, and estrogenic induction of progesterone receptor via classical
      nuclear ER-alpha is not critical for this process.

PMID- 10342863
TI  - Cystatin-related epididymal spermatogenic protein colocalizes with luteinizing
      hormone-beta protein in mouse anterior pituitary gonadotropes.
AB  - The CRES (cystatin-related epididymal spermatogenic) protein, a member of the
      cystatin superfamily of cysteine protease inhibitors, exhibits highly restricted
      expression in the mouse testis and epididymis, suggesting roles in reproduction.
      Considering the well-established relationship that exists between the gonads and
      the neuroendocrine system, the present studies were undertaken to determine
      whether the CRES messenger RNA and protein are expressed in the anterior
      pituitary gland and, if so, whether the expression is regulated by hormones. RT
      PCR analysis of whole pituitary gland RNA preparations, and Northern blot
      analyses of pituitary gland cell lines, demonstrated that the CRES gene is
      expressed in the male and female anterior pituitary gland gonadotropes.
      Furthermore, Western blot analysis demonstrated that CRES protein was present in
      whole mouse pituitary glands and was synthesized and secreted by the LbetaT2
      gonadotrope cell line. Interestingly, whereas the predominant CRES proteins
      present in epididymal lysates, LbetaT2 secretory granules, and whole pituitary
      gland lysates were 19 and 14 kDa, the predominant CRES proteins present in the
      cell culture conditioned media were 17 and 12 kDa. Deglycosylation studies
      revealed that the higher-molecular-mass CRES proteins (19 and 17 kDa) were the
      result of N-linked glycosylation, caused by the presence of high mannose
      residues. Double-label immunofluorescence and confocal microscopic analysis of
      male and female mouse pituitary gland tissue confirmed the RNA studies and showed
      that CRES protein colocalized with LHbeta protein in the gonadotropes. Finally,
      gonadectomy and hormone replacement studies suggest that CRES protein in the
      gonadotropes is hormonally regulated. These studies suggest that CRES protein may
      perform a role in the gonadotrope-mediated control of reproduction.

PMID- 10342862
TI  - Uterine natural killer cells are targets for a trophoblast cell-specific
      cytokine, prolactin-like protein A.
AB  - PRL-like protein A (PLP-A) is a member of the PRL family expressed in trophoblast
      cells coincident with establishment of the chorioallantoic placenta. The purpose
      of this investigation was to identify targets for PLP-A. Using an alkaline
      phosphatase-tagging strategy, we show that PLP-A specifically interacts with a
      population of natural killer (NK) lymphocytes within the mesometrial compartment
      of decidua from pregnant and pseudopregnant rats. These observations are
      supported by the codistribution of PLP-A targets with cells expressing the rat NK
      cell surface marker, gp42, the absence of PLP-A binding in conceptuses from NK
      cell-deficient tg epsilon26 mice, and the specific interaction of PLP-A with a
      rat NK cell line, RNK-16. We have further demonstrated that PLP-A effectively
      suppresses RNK-16 cell cytolytic activities. Our results provide evidence for a
      new paradigm of embryonic-maternal communication involving a PLP-A signaling
      pathway between trophoblast cells and uterine NK lymphocytes.

PMID- 10342864
TI  - Targeted disruption of the estrogen receptor-alpha gene in female mice:
      characterization of ovarian responses and phenotype in the adult.
AB  - Targeted disruption of the mouse estrogen receptor-alpha gene (estrogen receptor
      alpha knockout; ERKO) results in a highly novel ovarian phenotype in the adult.
      The ERKO mouse model was used to characterize ER alpha-dependent processes in the
      ovary. Visualization of the ovaries of 10-, 20-, and 50-day-old wild-type (WT)
      and ERKO mice showed that the ERKO phenotype developed between 20 and 50 days of
      age. Developmental progression through the primordial, primary, and antral
      follicle stages appeared normal, but functional maturation of preovulatory
      follicles was arrested resulting in atresia or in anovulatory follicles, which in
      many cases formed large, hemorrhagic cysts. Corpora lutea were absent, which also
      indicates that the normal biochemical and mechanical processes that accomplish
      ovulation were compromised. Northern and ribonuclease protection analyses
      indicated that ERKO ovary FSH receptor (FSHR) messenger RNA (mRNA) expression was
      approximately 4-fold greater than in WT controls. Ovarian LH receptor (LHR) mRNA
      expression was also higher in the ERKO animals. Cellular localization studies by
      in situ hybridization analysis of ERKO ovaries showed a high level of LHR mRNA
      expression in the granulosa and thecal layers of virtually all the antral
      follicles. Ribonuclease protection analyses showed that ovarian progesterone
      receptor and androgen receptor mRNA expression were similar in the two groups.
      These results indicated that ER alpha action was not a prerequisite for LHR mRNA
      expression by thecal or granulosa cells or for ovarian expression of progesterone
      receptor mRNA. Ovarian estrogen receptor beta (ER beta) was detected
      immunohistochemically, was sharply compartmentalized to the granulosa cells, and
      was expressed approximately equally in the ERKO animals and the WT controls. In
      contrast, ER alpha staining was present in the thecal cells but not the granulosa
      cells of the WT animals. The summary findings indicate that in the adult the
      major cause of the ERKO phenotype is high circulating LH interacting with
      functional LHR of the theca and granulosa cells. These features result in a
      failure of the normal maturational events leading to successful ovulation and
      luteinization and presumably involve both hypothalamic-pituitary and intraovarian
      mechanisms dependent upon ER alpha action. The presence of ER beta in the
      granulosa cells did not rescue the phenotype of the ovary.

PMID- 10342865
TI  - Germ cell-specific cyclic adenosine 3',5'-monophosphate response element
      modulator expression in rodent and primate testis is maintained despite
      gonadotropin deficiency.
AB  - cAMP response element modulator (CREM) is an important component of the cAMP
      mediated signaling pathway and is essential for differentiation of haploid male
      germ cells. In the rodent, testicular expression of CREM is believed to be
      controlled by FSH. We studied the expression pattern of CREM and gonadotropic
      control in the nonhuman primate and rodent testis. Adult cynomolgus monkeys
      (Macaca fascicularis) received daily either vehicle or the potent GnRH antagonist
      (ANT) cetrorelix for periods of 25 and 56 days. Rats were also exposed to vehicle
      or ANT for periods of 14 and 42 days. ANT treatment suppressed pituitary
      gonadotropin secretion, reduced testis size, and altered spermatogenesis. A
      rabbit polyclonal antibody raised against recombinant CREM tau and reacting with
      CREM alpha, -beta, -gamma, -tau1, and -tau2 at similar affinities was used for
      immunocytochemistry and Western blotting. CREM expression was seen in round
      spermatids, with highest levels during spermatogenic stages V-VII, but declined
      with progression of spermatid development in the primate. Similar observations
      were made for the rat testis. Thus, CREM expression was maximal at the onset of
      acrosome formation and was low or undetectable upon initiation of spermatid
      elongation in both species. A weak, but specific, CREM signal was seen in mid- to
      late pachytene spermatocytes and during meiotic division in both species. After
      ANT exposure, the germ cell- and stage-specific pattern of CREM expression was
      quantitatively retained at all time points and in both species. Northern and
      Western blot analysis confirmed the maintenance of testicular CREM expression
      despite 25 days of ANT treatment. A retrospective immunocytochemical analysis of
      rat testes 14 days posthypophysectomy revealed CREM signals in round spermatids.
      These findings demonstrate that the testicular expression of CREM is not entirely
      dependent on gonadotropic hormones but, rather, on the maturational stage of
      haploid round germ cells.

PMID- 10342866
TI  - Regulation of neuronal and glial proteins by leptin: implications for brain
      development.
AB  - The complete absence of leptin causes severe obesity in mice and humans, but its
      physiological roles are incompletely defined. Earlier studies reported decreased
      brain weight and impaired myelination in ob/ob and db/db mice. Here we have
      examined the effects of leptin deficiency and postnatal leptin treatment on brain
      weight, the expression of a broad array of neuronal and glial markers, and
      locomotor activity. ob/ob and db/db mice have reduced brain weight and an
      immature pattern of expression of synaptic and glial proteins, with growth
      associated protein being elevated in the neocortex and hippocampus, and syntaxin
      1, synaptosomal-associated protein-25, and synaptobrevin being decreased. The
      expression of myelin basic protein, proteolipid protein, and glial fibrillary
      acidic protein was also decreased in the neocortex, hippocampus, and striatum of
      ob/ob and db/db mice. Six weeks of leptin treatment initiated at week 4 increased
      brain weight and protein content, increased locomotor activity, and normalized
      levels of growth-associated protein, syntaxin-1, and synaptosomal-associated
      protein-25 in ob/ob mice without affecting synaptobrevin and glial proteins. In
      contrast with ob/ob and db/db mice, obese agouti (AY/a) mice had normal brain
      weight and expression of synaptic and glial proteins. These findings suggest that
      leptin, a peripheral signal of energy stores in adult animals, is required for
      normal neuronal and glial maturation in the mouse nervous system.

PMID- 10342867
TI  - Regulation of growth hormone-releasing hormone receptor messenger ribonucleic
      acid expression by glucocorticoids in MtT-S cells and in the pituitary gland of
      fetal rats.
AB  - Regulation of GH-releasing hormone receptor (GHRH-R) messenger RNA (mRNA)
      expression was studied, with the ribonuclease protection assay, in the fetal rat
      pituitary gland and in MtT-S clonal cells. GHRH-R mRNA was first detected on
      embryonic day (E)19 and increased rapidly thereafter, to reach a maximum at E21.
      Incubation of E17 or E18 pituitaries with 50 nM dexamethasone (DEX), a synthetic
      glucocorticoid, induced GHRH-R mRNA expression, suggesting that glucocorticoids
      play a pivotal role in the developmental expression of this mRNA. In E19
      pituitaries, 24 h treatment with DEX increased GHRH-R mRNA by 60%, and GH mRNA by
      76%, but did not affect pit-1 mRNA level, suggesting that the effect of DEX is
      specific for expressions of GH mRNA and GHRH-R mRNA. The accumulation of GHRH-R
      mRNA by DEX was time dependent, and it was slightly enhanced by the protein
      synthesis inhibitor, puromycin (100 microM). In MtT-S cells (a pituitary cell
      line established from an estrogen-induced tumor), DEX induced GHRH-R mRNA
      expression within 2 h in a dose-dependent manner. This induction was augmented by
      puromycin (100 microM) or cycloheximide (3.5 microM). However, the RNA synthesis
      inhibitor Actinomycin D (1 microM) completely inhibited GHRH-R mRNA accumulation
      in response to either DEX or DEX plus puromycin, suggesting that glucocorticoids
      induce GHRH-R mRNA mainly through stimulation of mRNA transcription. These
      results suggest: that GHRH-R mRNA accumulation in the fetal pituitary gland of
      rats normally occurs at E19, probably because of the direct action of
      glucocorticoids on the pituitary gland, to stimulate GHRH-R mRNA transcription;
      and that the expression of glucocorticoid receptors is an important event in GH
      cell development in rats. Accordingly, immunocytochemical results suggest an
      increase in glucocorticoid receptors in immature GH cells between E17 and E18.
      The present results also imply that MtT-S cells may be a good model in which to
      further study the molecular mechanisms of the regulation of GHRH-R gene
      expression.

PMID- 10342868
TI  - Bovine thrombospondin-2: complete complementary deoxyribonucleic acid sequence
      and immunolocalization in the external zones of the adrenal cortex.
AB  - Given the variety of biological functions in the adrenal cortex that are
      controlled by ACTH, we hypothesized that some extracellular proteins act as
      biological relays for this systemic hormone. One candidate protein [corticotropin
      induced secreted protein (CISP)] was purified from the conditioned medium of
      bovine adrenocortical cells on the basis of a 5- to 14-fold increase in its
      synthesis after the addition of ACTH. We report here the cloning of overlapping
      complementary DNAs that span the sequence encoding the full-length protein (1170
      amino acids). The deduced CISP protein sequence is 89% identical to that of human
      thrombospondin-2 (TSP2), but only 61% identical to that of bovine TSP1,
      confirming that CISP is the bovine ortholog of TSP2. The bovine TSP2 sequence
      aligned perfectly with human, mouse, and chicken TSP2 sequences, except for a gap
      of 2 amino acids located in a linker region. All 58 cysteine residues that are
      conserved in other species were present in the bovine sequence as well as most of
      the functional domains. Most endocrine tissues (adrenal cortex, testis, ovary,
      and placenta) appeared to express TSP2, as determined by Western blot analysis.
      The highest levels of TSP2 protein were found in the adrenal cortex, followed by
      the heart, spleen, brain, and kidney. A differential extent of N-glycosylation or
      tissular proteolytic maturation may be responsible for the mol wt differences
      observed between bovine TSP2 detected in the medium from primary cultures and
      that in fresh tissue extracts. The immunohistochemical analysis of the
      distribution of TSP2 in the bovine adrenal gland revealed that the protein is
      much more abundant in the external zones (zona glomerulosa and zona fasciculata)
      than in the internal reticularis zone, a pattern similar to that reported for
      ACTH receptors. This distribution clearly suggests that TSP2 is a candidate relay
      protein for a subset of ACTH actions in the adrenal cortex.

PMID- 10342869
TI  - Stage- and region-specific expression of estrogen receptor alpha isoforms during
      ontogeny of the pituitary gland.
AB  - The expression time course of estrogen receptor alpha (ER alpha) was analyzed by
      RT-PCR in fetal and newborn rat pituitaries. In addition to the classical ER
      alpha messenger RNA (mRNA), three shorter transcripts were detected and
      subsequently cloned. Sequence analysis showed that they corresponded to ER alpha
      mRNAs lacking exon 3 (which encodes a zinc finger in the DNA-binding domain),
      exon 4 (which encodes the nuclear localization signal and part of the steroid
      binding domain), or both exons 3 and 4. As analyzed by RT-PCR and ribonuclease
      protection assay, the respective expression levels of the different transcripts
      varied dramatically during pituitary development; short forms appeared 4 days
      before full-length ER alpha mRNA. On Western blots from rat pituitaries of
      different ages, an ER alpha-specific antiserum labeled four protein bands of the
      expected molecular weights, revealing that all four ER alpha mRNAs are translated
      in vivo. Immunocytochemistry, using the same antiserum, showed the ER alpha to be
      present first in the cytosol of intermediate lobe cells (around embryonic day
      16). Only 5 days later, nuclear staining became detectable in the anterior lobe.
      We argue that the observed cytosolic staining will be essentially due to short ER
      alpha isoforms, which are indeed more abundantly expressed in the intermediate
      lobe. These data suggest that during pituitary development, the activity of the
      ER alpha might be specifically regulated by differential splicing of its primary
      transcript, resulting in a differential subcellular localization of the isoforms.

PMID- 10342870
TI  - Developmentally regulated expression of cyclin D3 and its potential in vivo
      interacting proteins during murine gametogenesis.
AB  - To begin to assess the function of the cell cycle regulator cyclin D3 during
      gametogenesis, the present study examined its expression, interacting partners,
      and associated kinase activity in the murine testis and ovary. In the early
      stages of postnatal testicular development, cyclin D3 protein was detected in
      spermatogonia and Leydig cells. In the adult testis, cyclin D3 was also expressed
      in terminally differentiating spermatids. In the embryonic ovary, detection of
      cyclin D3 was limited to somatic cells. In the postnatal ovary, its localization
      was predominantly in the nuclei of oocytes in primordial and small follicles, a
      localization that diminished with oocyte growth. Cdk4 and p27 were expressed in a
      similar subset of testicular and ovarian cells, suggesting that they may regulate
      cyclin D3 function during testicular and ovarian development in a cell type
      specific manner. Cyclin D3-associated kinase activity was detected in immature,
      but not adult, testes and ovaries. These observations suggest unique roles for
      cyclin D3 in the control of cell division and differentiation in the germ line
      and the differential regulation of mitotic and meiotic cell cycles during male
      and female gametogenesis.

PMID- 10342872
TI  - Sodium excretion and renin secretion after continuous versus pulsatile infusion
      of oxytocin in rats.
AB  - Neurohypophyseal oxytocin (OT), secreted continuously under conditions of
      hyperosmolality, is a potent natriuretic hormone in rats. In contrast, OT
      secretion during lactation is pulsatile and is not accompanied by increased
      urinary Na+ excretion. The present experiments compared the effects of continuous
      and pulsatile infusion of OT on natriuresis in rats. In male rats anesthetized
      with Inactin, continuous infusion of OT (125 ng/kg x h) increased plasma OT to
      about 70 pg/ml; renal Na+ excretion increased 10-fold, and urine volume and K+
      excretion also were elevated. However, when OT was administered i.v. in the same
      amount but in pulses given once every 5 or 10 min, to simulate the pattern of OT
      secretion during lactation, rats did not excrete significantly more urine, Na+,
      or K+ than did vehicle-treated animals. The plasma renin concentration, measured
      in these experiments because OT receptors are present in the macula densa,
      increased 2-fold when OT was infused either continuously or in pulses. These
      results indicate that the effects of OT administration on urinary Na+ excretion
      in rats varies depending on whether the infusion is pulsatile or continuous,
      whereas the effects of OT on renin secretion show no such difference.

PMID- 10342871
TI  - Neonatal estrogen exposure alters the transforming growth factor-beta signaling
      system in the developing rat prostate and blocks the transient p21(cip1/waf1)
      expression associated with epithelial differentiation.
AB  - Exposure of male rats to estrogens during the neonatal period retards prostate
      branching morphogenesis, blocks epithelial differentiation, and predisposes the
      adult prostate to hyperplasia and dysplasia. The mechanism of neonatal
      estrogenization is not well understood. The present study evaluated transforming
      growth factor-beta (TGFbeta) in the neonatally estrogenized ventral prostate to
      determine whether this paracrine/autocrine factor may in part mediate the effects
      ofestrogen on the developing prostate gland. Immunocytochemistry using antibodies
      against active TGFbeta1 and its latency-associated peptide localized this
      molecule to the periductal smooth muscle cells in the developing prostate.
      Although neonatal estrogenization increased the accumulation of total and active
      TGFbeta1 in the smooth muscle layer as early as day 6 of life, it was physically
      separated from the epithelial ducts by a proliferating layer of fibroblasts
      surrounding the basement membrane. RT-PCR demonstrated that alterations in
      TGFbeta1 levels were not due to alterations in TGFbeta1 transcription. TGFbeta2
      and TGFbeta3 were primarily immunolocalized to differentiating epithelial cells
      in developing prostates, and this was markedly dampened between days 10-30 after
      neonatal estrogen exposure. Immunocytochemistry for TGFbeta signaling components
      revealed that neonatal estrogenization transiently reduced TGFbeta type I
      receptor levels in the prostate epithelium, but not in stroma, between days 6-15,
      whereas there was no effect on TGFbeta type II receptor. Levels of the
      intracellular signal Smad2 (52 kDa) were detected in epithelial cells but were
      not altered after estrogenization. To analyze the functional status of the
      TGFbeta signaling pathway, immunocytochemistry was performed for p21(cip-1/waf
      1), a cyclin-dependent kinase inhibitor that is inducible by TGFbeta1 in the
      prostate. Transient nuclear localization of p21(cip-1/waf-1) was normally
      observed in epithelial cells between days 6-15 and was associated with entry of
      cells into a terminal differentiation pathway. Neonatal estrogenization prevented
      this transient expression of p21(cip-1/waf-1). The present findings demonstrate
      that the TGFbeta signaling system is perturbed at several levels in the
      estrogenized prostate, which may in part account for the epithelial cell
      differentiation blockade as well as the proliferation of periductal fibroblasts
      in this model.

PMID- 10342874
TI  - Genetic bases of estrogen-induced pituitary growth in an intercross between the
      ACI and Copenhagen rat strains: dominant mendelian inheritance of the ACI
      phenotype.
AB  - Estrogens stimulate cell proliferation in a variety of tissues and are widely
      believed to be contributing factors in the etiology of certain cancer types in
      humans. The molecular mechanisms through which estrogens regulate cell
      proliferation are currently unknown. Estrogens stimulate proliferation of the PRL
      producing lactotroph of the rat anterior pituitary gland and induce development
      of PRL-producing pituitary tumors in several inbred rat strains. Therefore, the
      lactotroph provides a well defined model for identifying the mechanisms through
      which estrogens regulate cell proliferation and/or survival. Data from our
      laboratory and others indicate that the relative sensitivity to the pituitary
      growth-promoting actions of estrogens is highly strain specific. This allows
      genetics-based approaches to be used to address the molecular mechanisms through
      which estrogens stimulate lactotroph proliferation and induce pituitary tumor
      development. In the present study we have examined the ability of
      diethylstilbestrol (DES) to induce pituitary growth in the genetically related
      AxC-Irish (ACI) and Copenhagen (COP) strains and their derived F1, F2, and
      backcross progeny. The data presented herein indicate that the anterior pituitary
      gland of the ACI strain displays approximately a 2-fold greater growth response
      to administered DES than does the pituitary gland of the COP strain. The average
      pituitary weight in male ACI rats was increased from 9.2 +/- 0.2 mg (mean +/- SD
      in untreated rats to 63.7 +/- 12.6 mg in rats treated with DES for 12 weeks,
      whereas in male COP rats, DES increased pituitary weight from 12.7 +/- 0.9 to
      38.1 +/- 8.2 mg. The ACI phenotype was inherited in the F1, F2, and backcross
      progeny of an ACI x COP intercross as a dominant genetic trait, and the
      approximately 30 mg of additional pituitary growth displayed by the DES-treated
      ACI rat, relative to that of the treated COP rat, appeared to result from the
      actions of a single locus. Moreover, in F1 progeny from an ACI x Brown Norway
      intercross, the ACI phenotype was inherited as a dominant or incompletely
      dominant genetic trait. These data, when compared with findings of previous
      studies using the Fischer 344 rat strain, provide the first indication that
      distinct genetic pathways contribute to regulation of estrogen-induced pituitary
      growth and induction of PRL-producing pituitary tumors in the ACI and F344 rat
      strains.

PMID- 10342873
TI  - Mullerian-inhibiting substance type II receptor expression and function in
      purified rat Leydig cells.
AB  - Mullerian-inhibiting substance (MIS), a gonadal hormone in the transforming
      growth factor-beta superfamily, induces Mullerian duct involution during male
      sexual differentiation. Mice with null mutations of the MIS ligand or receptor
      develop Leydig cell hyperplasia and neoplasia in addition to retained Mullerian
      ducts, whereas MIS-overexpressing transgenic mice have decreased testosterone
      concentrations and Leydig cell numbers. We hypothesized that MIS directly
      modulates Leydig cell proliferation and differentiated function in the maturing
      testis. Therefore, highly purified rat Leydig and Sertoli cells were isolated to
      examine cell-specific expression, binding, and function of the MIS type II
      receptor. These studies revealed that this receptor is expressed abundantly in
      progenitor (21-day) and immature (35-day) Leydig cells as well as in Sertoli
      cells. Prepubertal progenitor Leydig cells exhibit high affinity (Kd = 15 nM),
      saturable binding of MIS. No binding, however, is detected with either
      peripubertal immature Leydig cells or Sertoli cells at either age. Moreover,
      progenitor, but not immature Leydig cells, respond to MIS by decreasing DNA
      synthesis. These data demonstrate that functional MIS type II receptors are
      expressed in progenitor Leydig cells and support the hypothesis that MIS has a
      direct role in the regulation of postnatal testicular development.

PMID- 10342875
TI  - Differential in vivo regulation of the pituitary growth hormone-releasing hormone
      (GHRH) receptor by GHRH in young and aged rats.
AB  - In aging, alterations of pituitary GH-releasing hormone (GHRH) receptor (GHRH-R)
      binding sites have been proposed as one of the initiating factors contributing to
      the loss of somatotroph responsiveness to GHRH. Changes in the characteristics
      and/or concentration of the functional GHRH-R could take place in the course of
      aging and reduce the sensitivity of the somatotroph axis to GHRH. Because chronic
      exposure to GHRH has been proposed to resensitize aged somatotroph cells, better
      knowledge of its effects on the regulation of the somatotroph axis is required,
      particularly at the level of GHRH-R. Two- and 18-month-old male Sprague Dawley
      rats were treated for 14 days with a daily s.c. injection of 0.5 or 1.0 mg/kg BW
      human GHRH-(1-29)NH2 or saline. In 2-month-old rats, treatment with 0.5 mg/kg
      GHRH increased the number of high affinity pituitary GHRH-R-binding sites by 2
      fold (P < 0.05) and hypothalamic somatostatin (SRIF) content by 45% (P < 0.05).
      It did not affect hypothalamic GHRH content, serum total insulin-like growth
      factor I (IGF-I), or body weight gain. Treatment with 1.0 mg/kg GHRH decreased
      the number of high affinity pituitary GHRH-R-binding sites by 2.4-fold compared
      with that in rats treated with 0.5 mg/kg BW (P < 0.05) and increased hypothalamic
      SRIF content by 45% (P < 0.05), but did not affect GHRH content. It also
      decreased circulating levels of IGF-I by 13% (P < 0.05) and slowed the growth
      rate by 17% (P < 0.05). In 18-month-old rats, treatment with 0.5 mg/kg GHRH for
      14 days was not sufficient to rejuvenate pituitary GHRH binding parameters.
      However, treatment with 1.0 mg/kg GHRH restored the affinities of high and low
      affinity classes of GHRH-binding sites to values similar to those found in 2
      month-old rats. Binding capacities of the high and low affinity classes of sites
      were increased by 1.8- and 3-fold, respectively, although significance was only
      reached for the low affinity site (P < 0.05). These changes were associated with
      a normalization of the level of 2.5-kb GHRH-R messenger RNA transcript, which was
      decreased by 31% in aging rats (P < 0.05), and by a trend for an increase in the
      4-kb GHRH-R messenger RNA transcript, which was already increased by 49% in 18
      month-old rats (P < 0.05). A normalization of serum IGF-I levels, which were
      decreased by 11% in 18-month-old control rats (P < 0.01), was also observed. No
      treatment effect was detected on body weight or hypothalamic SRIF and GHRH
      contents. We conclude that a 14-day administration of GHRH induces a differential
      GHRH-R-mediated regulation at the level of the pituitary and probably the
      hypothalamus as a function of age.

PMID- 10342876
TI  - Nonresponsiveness of the rat hypothalamo-pituitary-adrenocortical axis to
      parturition-related events: inhibitory action of endogenous opioids.
AB  - During the last 2 days of pregnancy in rats, basal corticosterone secretion is
      enhanced, although the response of the hypothalamo-pituitary-adrenocortical (HPA)
      axis to emotional and physical stressors is blunted, independent of the action of
      endogenous opioids. In this study, alterations in the reactivity of the HPA axis,
      which may accompany parturition-related stimuli, and the involvement of
      endogenous opioids were examined in chronically catheterized rats. In vehicle
      treated controls (n = 9), ACTH and corticosterone secretion decreased in
      preparation for birth (P < 0.01) and further declined immediately after delivery
      of the second pup (P < 0.01), remaining low for 150 min. In contrast, in animals
      injected with the opiate antagonist naloxone (5 mg ml(-1) kg(-1), i.v., n = 6)
      after delivery of the second pup, ACTH and corticosterone release were enhanced
      within 20 min (ACTH, 5.0-fold; corticosterone, 2.3-fold; P < 0.01 vs. controls)
      and returned to control levels after 90 min. In confirmation of previous reports,
      oxytocin secretion into blood was elevated in control rats after the onset of
      parturition (P < 0.01) and was further enhanced in the naloxone group (1.4-fold,
      P < 0.01 vs. control). Plasma lactate concentration was increased, 30 min after
      the onset of delivery (1.9-fold, P < 0.01), independent of the treatment. The
      data indicate that parturition-related events do not trigger HPA axis hormone
      release because of an effective inhibition by endogenous opioids. This
      nonresponsiveness of the HPA axis is likely to protect the pups' well-being
      during birth.

PMID- 10342877
TI  - Mitogen-activated protein kinase-dependent stimulation of proliferation of rat
      lactotrophs in culture by 3',5'-cyclic adenosine monophosphate.
AB  - Intracellular cAMP regulates cell proliferation as a second messenger of
      extracellular signals in a number of cell types. We investigated, by
      pharmacological means, whether an increase in intracellular cAMP levels changes
      proliferation rates of lactotrophs in primary culture, whether there are
      interactions between signal transduction pathways of cAMP and the growth factor
      insulin, and where the dopamine receptor agonist bromocriptine acts in the cAMP
      pathway to inhibit lactotroph proliferation. Rat anterior pituitary cells,
      cultured in serum-free medium, were treated with cAMP-increasing agents, followed
      by 5-bromo-2'-deoxyuridine (BrdU) to label proliferating pituitary cells. BrdU
      labeling indices indicative of the proliferation rate of lactotrophs were
      determined by double immunofluorescence staining for PRL and BrdU. Treatment with
      forskolin (an adenylate cyclase activator) or (Bu)2cAMP (a membrane-permeable
      cAMP analog) increased BrdU-labeling indices of lactotrophs in a dose- and
      incubation time-dependent manner. The cAMP-increasing agents were also effective
      in increasing BrdU-labeling indices in populations enriched for lactotrophs by
      differential sedimentation. The stimulatory action of forskolin was observed,
      regardless of concentrations of insulin that were added in combination with
      forskolin. Inhibition of the action of endogenous cAMP by H89 or KT5720, a
      protein kinase A inhibitor, attenuated an increase in BrdU-labeling indices by
      insulin treatment. On the other hand, the specific mitogen-activated protein
      kinase inhibitor PD98059, which was effective in blocking the mitogenic action of
      insulin, markedly suppressed the forskolin-induced increase in BrdU-labeling
      indices. (Bu)2cAMP antagonized not only inhibition of BrdU labeling indices but
      also changes in cell shape induced by bromocriptine treatment, although forskolin
      did not have such an antagonizing effect. These results suggest that: 1)
      intracellular cAMP plays a stimulatory role in the regulation of lactotroph
      proliferation; 2) cAMP and insulin/mitogen-activated protein kinase signalings
      require each other for their mitogenic actions; and 3) the antimitogenic action
      of bromocriptine is, at least in part, caused by inhibition of cAMP production.

PMID- 10342878
TI  - Differential expression of a novel seven transmembrane domain protein in
      epididymal fat from aged and diabetic mice.
AB  - To identify novel seven transmembrane domain proteins from 3T3-L1 adipocytes, we
      used PCR to amplify 3T3-L1 adipocyte complementary DNA (cDNA) with primers
      homologous to the N- and C-termini of pancreatic glucagon-like peptide-1 (GLP-1)
      receptor. We screened a cDNA library prepared from fully differentiated 3T3-L1
      adipocytes using a 500-bp cDNA PCR product probe. Herein describes the isolation
      and characterization of a 1.6-kb cDNA clone that encodes a novel 298-amino acid
      protein that we termed TPRA40 (transmembrane domain protein of 40 kDa regulated
      in adipocytes). TPRA40 has seven putative transmembrane domains and shows little
      homology with the known GLP-1 receptor or with other G protein-coupled receptors.
      The levels of TPRA40 mRNA and protein were higher in 3T3-L1 adipocytes than in
      3T3-L1 fibroblasts. TPRA40 is present in a number of mouse and human tissues.
      Interestingly, TPRA40 mRNA levels were significantly increased by 2- to 3-fold in
      epididymal fat of 24-month-old mice vs. young controls as well as in db/db and
      ob/ob mice vs. nondiabetic control littermates. No difference in TPRA40 mRNA
      levels was observed in brain, heart, skeletal muscle, liver, or kidney.
      Furthermore, no difference in TPRA40 expression was detected in brown fat of
      ob/ob mice when compared with age-matched controls. Taken together, these data
      suggest that TPRA40 represents a novel membrane-associated protein whose
      expression in white adipose tissue is altered with aging and type 2 diabetes.

PMID- 10342879
TI  - Daily changes in hypothalamic gene expression of neuropeptide Y, galanin,
      proopiomelanocortin, and adipocyte leptin gene expression and secretion: effects
      of food restriction.
AB  - The participation of hypothalamic neuropeptide Y (NPY)-, galanin (GAL)-, and
      opioid-producing neurons in the restraint on food intake exerted by adipocyte
      leptin has recently been recognized. To further understand the interplay between
      the central appetite-stimulating- and peripheral appetite-inhibiting signals in
      the management of daily food intake, we have examined the daily patterns in
      expression of the hypothalamic neuropeptides and leptin receptor (R) and
      adipocyte leptin gene expression and secretion in freely feeding (FF) rats. These
      analyses were extended to determine the impact of food restriction (FR) to 4 h
      daily for 4 weeks. Groups of FF and FR rats were killed at 4-h intervals during a
      24-h period, and hypothalamic NPY, GAL, POMC, and leptin-R gene expression and
      leptin gene expression were evaluated by RNase protection assays and serum leptin
      and corticosterone (CORT) levels were estimated by RIA. The following new
      findings emerged: 1) In FF rats, hypothalamic NPY messenger RNA (mRNA) levels
      fluctuated during the course of 24 h with high levels at 0700 h and 1100 h
      followed by a decrease at 1500 h during the lights-on phase that was sustained
      throughout the dark phase (1900 h-0500 h) of the light-dark cycle. Hypothalamic
      GAL and POMC mRNA also displayed daily patterns but with a different time course;
      GAL and POMC gene expression were elevated 4 h later than NPY mRNA at 1100 h and
      1500 h. 2) Although FR to 4 h between 1100 h and 1500 h resulted in maintenance
      of body weight compared with a steady weight gain in FF rats, the daily patterns
      of fluctuations in hypothalamic neuropeptide gene expression were abolished. 3)
      In FF rats, hypothalamic leptin-R and adipocyte leptin gene expression and serum
      leptin levels displayed a daily pattern temporally different from that of
      hypothalamic neuropeptide gene expression. Adipocyte leptin mRNA remained low
      during the lights-on phase but increased at the onset of the lights-off phase
      (1900 h) and remained elevated through the dark phase. 4) Hypothalamic leptin-R
      gene expression, like that of adipocyte leptin gene expression, rose abruptly at
      the onset of nocturnal feeding behavior but receded progressively to low range
      thereafter. 5) On the other hand, a dichotomy in the daily rise in adipocyte
      leptin gene expression and leptin secretion was observed in FF rats. Unlike
      adipocyte leptin mRNA, serum leptin increased at 2300 h, 4 h after initiation of
      ingestive behavior. 6) In FR rats, adipocyte leptin gene expression fluctuated
      little over the 24-h period but, as in FF rats, leptin hypersecretion peaked 4 h
      after initiation of food intake. 7) In both FF and FR rats, increased serum CORT
      levels preceded serum leptin rise. Overall, these results show that in FF rats,
      gene expression of hypothalamic appetite stimulating peptides first rise and then
      fall to nadir during the lights-on phase when leptin levels are in low range;
      adipocyte leptin mRNA rises before impending ingestive behavior and increased
      leptin secretion reaching peak manifests itself during nocturnal feeding. The FR
      regimen, which curtailed the normal body weight gain, abolished these daily
      fluctuations in gene expression of hypothalamic orexigenic peptides and adipocyte
      leptin but permitted feeding-associated increased leptin secretion. Thus, it may
      be important to consider the daily patterns of gene expression and availability
      of hypothalamic orexigenic peptides in investigations aimed at elucidating the
      central mechanisms underlying the feedback action of the normal and altered
      leptin secretion patterns.

PMID- 10342880
TI  - Expression of the interleukin-6 gene is constitutive and not regulated by
      estrogen in rat vascular smooth muscle cells in culture.
AB  - Vascular smooth muscle cells (SMC) are major constituents of the medial layer of
      blood vessels and are involved in the development of atherosclerotic plaque. SMC
      secrete copious IL-6 under basal conditions that can be increased by cytokines
      such as tumor necrosis factor-alpha and interleukin-1beta (IL-1beta). The goal of
      our studies was to define the role of estrogen in IL-6 production by SMC. In a
      first series of experiments, the expression of specific messenger RNAs as well as
      the production of IL-6 bioactivity by rat SMC in culture could be demonstrated in
      basal and IL-1-stimulated conditions, but was unaffected by estrogen treatment.
      Different constructs containing deleted or mutated fragments of the human IL-6
      promoter driving luciferase or chloramphenicol acetyltransferase reporter gene
      were then transiently transfected in these cells. A significant basal activity
      that was increased 2- to 4-fold after IL-1beta stimulation was observed with the
      total IL-6 promoter. Deletion analysis indicated that the -158/+11 region
      containing activator protein-1 and cAMP response element sites was apparently the
      minimal region of IL-6 promoter to confer both constitutive and IL-1-inducible
      activities. Site-directed mutagenesis experiments suggest that basal activity is
      dependent upon the promoter sequence -158 to -112 containing the nuclear factor
      (NF)-IL6(-153) and Sp1 sites, whereas IL-1beta stimulation would depend on the
      residual -112 nucleotides containing NF-IL6(-75) and NF-kappaB sites. In contrast
      to the down-regulation of IL-6 expression by estrogen described in osteoblasts,
      ethinyl estradiol as well as 17beta-estradiol did not influence stimulated IL-6
      activity in our experimental conditions whatever the construct tested, even when
      either estrogen receptor alpha or beta was overexpressed. Thus, the
      atheroprotective properties of estrogen are probably not mediated through the
      regulation of IL-6 production by SMC.

PMID- 10342881
TI  - A receptor activity modifying protein (RAMP)2-dependent adrenomedullin receptor
      is a calcitonin gene-related peptide receptor when coexpressed with human RAMP1.
AB  - Adrenomedullin (ADM) and alpha- and beta-calcitonin (CT) gene-related peptide
      (alpha-, betaCGRP) are structurally related vasodilatory peptides with homology
      to CT and amylin. An originally orphan human CT receptor-like receptor (hCRLR) is
      a Gs protein-coupled CGRP or ADM receptor when coexpressed with recently
      identified human single transmembrane domain receptor activity modifying proteins
      1 (hRAMP1) or -2 (hRAMP2), respectively. Here, the function of the rat CRLR
      homologue (rCRLR) has been investigated in rat osteoblast-like UMR-106 cells and
      in COS-7 cells, in the absence and presence of hRAMP1 and -2 and combinations
      thereof. Transient expression of rCRLR in UMR-106 cells revealed an ADM receptor,
      and [125I]rat (r) ADM binding was enhanced with hRAMP2 and inhibited by 50% when
      hRAMP1 was coexpressed. Detectable [125I]h alphaCGRP binding required the
      presence of hRAMP1, and the expression of CGRP binding sites was unaffected by
      coexpressed hRAMP2. Specificity of ADM binding sites in [125I]rADM binding
      inhibition experiments was reflected by an over 1000-fold higher potency of rADM
      [half-maximal effective concentration = 0.19 +/- 0.05 nM (mean +/- SEM, n = 4)],
      compared with r alphaCGRP and r betaGRP, to induce a cAMP-responsive luciferase
      reporting gene (CRE-luc). In rCRLR and hRAMP1 cotransfected cells, expressing
      predominantly CGRP binding sites, r betaCGRP, r alphaCGRP, and rADM induced CRE
      luc with half-maximal effective concentration of 0.27 +/- 0.17 nM, 0.37 +/- 0.27
      nM, and 1.4 +/- 0.9 nM, respectively. In COS-7 cells, the results were
      comparable, but rCRLR required coexpressed hRAMP2 for ADM receptor function. This
      is consistent with higher levels of endogenous RAMP2 encoding messenger RNA in
      UMR-106, compared with COS-7 cells. In conclusion, the recognition of RAMP1 and 
      2 as mediators of CRLR expression as a CGRP or ADM receptor has been extended,
      with evidence that endogenous RAMP2 is sufficient to reveal an ADM receptor in
      UMR-106 cells. Inhibition of RAMP2-evoked ADM receptor expression by RAMP1 and
      generation of a CGRP receptor is consistent with competitive interactions of the
      different RAMPs with rCRLR.

PMID- 10342882
TI  - Inhibition of androgen synthesis in human testicular and prostatic microsomes and
      in male rats by novel steroidal compounds.
AB  - The C(17,20)-lyase and 5alpha-reductase are key enzymes in the biosynthesis of
      androgens. The effects of novel steroidal compounds were evaluated as inhibitors
      against both human C(17,20)-lyase and 5alpha-reductase in vitro. The
      concentrations of testosterone (T) and dihydrotestosterone (DHT) in the prostate,
      testis and serum and changes in the tissue weights were also determined in rats
      treated with the novel inhibitors. L-12 and L-26 showed potent inhibition of
      human testicular C(17,20)-lyase with IC50 values of 50 and 25 nM, respectively. L
      12, L-38, and I-47 showed moderate inhibition of human testicular C(17,20)-lyase
      with IC50 values of 75, 108, and 70 nM, respectively similar to ketoconazole (78
      nM). Interestingly, L-6, L-26, and L-38 also showed some inhibitory activity
      against 5alpha-reductase with IC50 values of 75, 125, and 377 nM, respectively.
      Finasteride, an inhibitor of 5alpha-reductase had an IC50 value of 33 nM.
      However, ketoconazole did not inhibit 5alpha-reductase nor did finasteride
      inhibit C(17,20)-lyase. Treatment of normal male rats with several of these novel
      inhibitors (50 mg/kg x day, s.c., for 14 consecutive days) caused about 45-91%
      decrease in serum, testicular and prostatic T concentration. Similarly, serum and
      prostatic DHT concentration were significantly decreased in rats treated with
      these novel compounds by 50-90% compared with controls. Surgical castration
      caused almost complete elimination of circulating T and DHT concentration in rat
      tissues. L-6 and L-12 were the most effective and reduced the wet weight of the
      prostate by 50%. Although future improvements in their bioavailability are
      necessary, these novel steroidal compounds show promise as potential agents for
      reducing T and DHT levels in patients with androgen dependent diseases.

PMID- 10342883
TI  - Vitamin D represses retinoic acid-dependent transactivation of the retinoic acid
      receptor-beta2 promoter: the AF-2 domain of the vitamin D receptor is required
      for transrepression.
AB  - Retinoic acid (RA)-dependent activation of the RA receptor beta2 (RARbeta2) gene
      in embryonal carcinoma cells is mediated by binding of retinoid receptor
      heterodimers (RAR/RXR) to a RA response element (RARE) located closely to the
      TATA box. We have analyzed the effect of vitamin D on the response of the
      RARbeta2 promoter to RA in pituitary GH4C1 cells that coexpress receptors for
      retinoids and vitamin D. Incubation with vitamin D markedly reduced the response
      to RA caused by transcriptional interference of the vitamin D receptor (VDR) on
      the RARE. This DNA element binds VDR/RXR heterodimers with high affinity, and
      these inactive heterodimers can displace active RAR/RXR from the RARE.
      Overexpression of RXR in GH4C1 cells, as well as incubation with BMS649 (a RXR
      specific ligand), increased the inhibitory effect of vitamin D, suggesting that
      the VDR/RXR heterodimer is the repressive species and that titration of RXR is
      not responsible for this inhibition. Although DNA binding could be required for
      full potency of the inhibitory activity of VDR, it is not absolutely required
      because a truncated receptor (VDR delta1-111), lacking the DNA binding domain,
      also displays repressor activity. Furthermore, the ability to mediate
      transrepression by vitamin D was strongly decreased when a mutant VDR in which
      the last 12 C-terminal aminoacids have been deleted (VDR deltaAF-2) was used.
      Because this region contains the domain responsible for ligand-dependent
      recruitment of coactivators, titration of common coactivators for VDR and RAR
      could be involved in the inhibitory effect of vitamin D. In agreement with this
      hypothesis, overexpression of E1A, which can act as a RARbeta2 promoter-specific
      coactivator, significantly reversed repression by vitamin D.

PMID- 10342884
TI  - Hepatocyte growth factor induces rat ovarian surface epithelial cell mitosis or
      apoptosis depending on the presence or absence of an extracellular matrix.
AB  - The present studies showed that sequential treatment with equine CG (eCG) and hCG
      not only induced an increase in ovarian weight, but also caused an estimated 4.6
      fold increase in the number of ovarian surface epithelial cells. In addition, eCG
      hCG treatment increased ovarian hepatocyte growth factor (HGF) messenger RNA
      levels. These studies also demonstrated that rat primary ovarian surface
      epithelial cells as well as a cell line derived from rat ovarian surface
      epithelium (i.e. ROSE-179 cells) do not express the LH (hCG) receptor. Both of
      these cells express c-Met, the receptor for HGF. To assess the effects of hCG and
      HGF on ovarian surface epithelial cell mitosis, ROSE-179 cells were cultured for
      24 h in serum-supplemented medium on either glass or the synthetic fibronectin
      like extracellular matrix protein, pronectin (RGD). The cells were then cultured
      for 24 h in serum-free medium in the presence or absence of hCG or HGF. The
      numbers of cells at 2, 24, and 48 h of culture were determined. The percentage of
      apoptotic cells was assessed by in situ DNA staining at 48 h of culture. In the
      serum-supplemented medium in the presence or absence of RGD, the number of ROSE
      179 cells doubled. In serum-free medium, cell proliferation was reduced, and the
      percentage of apoptotic nuclei ranged between 10-15% regardless of the substrate.
      Neither mitosis nor apoptosis was influenced by hCG in the presence or absence of
      RGD. For ROSE-179 cells cultured in serum-free medium on RGD, HGF induced
      mitosis, resulting in a 2.8 +/- 0.2-fold increase in cell number compared with
      the 24 h control values. On a glass substrate in serum-free medium, HGF did not
      induce mitosis, but increased the percentage of apoptotic nuclei. Time-lapse
      photographic analysis revealed that on RGD, cells undergoing HGF-induced mitosis
      showed a transient reduction in cell contact. On glass, HGF caused many cells to
      completely lose contact and separate from each other. Collectively, these data
      suggest that in vivo gonadotropins stimulate HGF expression and ovarian surface
      epithelial cell proliferation. Based on in vitro studies, it is likely that the
      mitogenic action of hCG is mediated by HGF. However, HGF only induces mitosis in
      the presence of an extracellular matrix.

PMID- 10342885
TI  - Regulation of type 3 iodothyronine deiodinase expression in cultured rat
      astrocytes: role of the Erk cascade.
AB  - The type 3 iodothyronine deiodinase (D3) metabolizes thyroid hormones to inactive
      metabolites in many tissues, including the brain. In the present studies, we have
      examined the mechanisms by which T3 (T3), retinoic acid, 12-O-tetradecanoyl
      phorbol 13-acetate (TPA), and basic fibroblast growth factor (bFGF) induce D3
      expression in primary cultures of neonatal rat astrocytes. In untreated cells, D3
      messenger RNA (mRNA) was essentially undetectable by Northern analysis and RT
      PCR. However, all four agents induced expression of a 2.4-kb D3 transcript as
      well as D3 activity. Induction of D3 by TPA and bFGF was more rapid than that by
      T3 and retinoic acid, and T3 potentiated the stimulatory effects of TPA and bFGF.
      D3 induction by TPA was blocked by GF 109203X, an inhibitor of protein kinase C.
      In addition, the effects of TPA and bFGF were partially prevented by PD 98059, a
      specific inhibitor of MEK and the Erk signaling cascade. These studies
      demonstrate that multiple growth factors and hormones regulate D3 activity in
      cultured astrocytes by inducing D3 mRNA expression. In addition, the stimulatory
      effects of TPA and bFGF on D3 mRNA and activity appear to be mediated at least in
      part by activation of the MEK/Erk signaling cascade.

PMID- 10342886
TI  - An amylin receptor is revealed following co-transfection of a calcitonin receptor
      with receptor activity modifying proteins-1 or -3.
AB  - Human receptor activity modifying proteins (RAMP) regulate the ligand specificity
      of the calcitonin-receptor-like-receptor (McLatchie et al., Nature 393:333-339
      (1998)). Here we have investigated binding of [125I]-labeled human (h) calcitonin
      ([125I]hCT) and rat amylin ([125I]amylin) to rabbit aortic endothelial cells
      (RAEC) co-transfected with the hCT receptor isotype 2 (hCTR2) and RAMP1, -2 or 
      3. Specific binding of 125 pM [125I]hCT to cells transfected with hCTR2 alone was
      6.7 +/- 0.7 fmol/50,000 cells (n=5), and was reduced by 45 +/- 2% and 86 +/- 3%
      (P < 0.001) in the presence of RAMP1 and -3, but remained unchanged with RAMP2.
      In the absence and presence of individual RAMPs [125I]hCT binding inhibition
      occured with similar IC50 of between 6 nM and 11 nM hCT, and human amylin was 24-
      to 54-fold less potent. Specific binding of 125 pM [125I]amylin to cells
      transfected with hCTR2 alone was 0.9 +/- 0.2 fmol/50,000 cells (n=6), and was
      increased by 262 +/- 48% (P < 0.005), 73 +/- 26% (P < 0.05) and 338 +/- 57% (P <
      0.005) with RAMP1, -2 or -3, respectively. [125I]amylin binding was inhibited
      with IC50 of 3.1 +/- 0.5 nM and 4.0 +/- 0.8 nM human amylin in cells co
      transfected with RAMP1 or -3, respectively, and hCT was 45 +/- 2- and 126 +/- 3
      fold less potent. In conclusion, RAMP1 and -3 decrease calcitonin receptor
      expression in RAEC transfected with hCTR2 encoding cDNA and simultanously reveal
      an amylin receptor.

PMID- 10342887
TI  - Identification of vitronectin as a novel insulin-like growth factor-II binding
      protein.
AB  - We have previously reported the presence of a 70 kDa insulin-like growth factor
      (IGF)-II-specific binding protein in chicken serum using Western ligand blotting
      approaches. In order to ascertain the identity of this 70 kDa IGF-II binding
      species, the protein has been purified from chicken serum using a combination of
      ion-exchange and gel-permeation chromatography. Interestingly, amino acid
      sequencing of the purified protein revealed that it has the same N-terminal
      sequence as chicken vitronectin (VN). The protein has the ability to specifically
      bind IGF-II and not IGF-I as determined by ligand blotting, cross-linking and
      competitive binding assay approaches. In addition, the protein binds 125I-des(1
      6)-IGF-II, suggesting that the interaction with IGF-II is different to those with
      other characterized IGF-binding proteins. Importantly, we have ascertained that
      both human and bovine VN also specifically bind IGF-II. These results are
      particularly relevant in the light of the recent report that the urokinase-type
      plasminogen activator receptor, a protein that also binds VN, has been shown to
      associate with the cation-independent mannose-6-phosphate/IGF-II receptor and
      suggest a possible role for IGF-II in cell adhesion and invasion.

PMID- 10342888
TI  - Acute respiratory distress syndrome: a clinical update.
AB  - BACKGROUND: Because of recent advances in the treatment and improved outcome of
      acute respiratory distress syndrome (ARDS), we present an overview of ARDS to
      update general practitioners on the management of this condition. METHODS AND
      RESULTS: We searched MEDLINE for original articles, editorials, and reviews on
      ARDS, acute lung injury, and mechanical ventilation. A large amount of data is
      available on this subject. We reviewed relevant articles that address definition,
      pathogenesis, clinical presentation, and management of ARDS, giving special
      emphasis to ventilatory support of patients with ARDS. CONCLUSION: Acute
      respiratory distress syndrome is a severe form of acute lung injury associated
      with significant mortality and morbidity. In recent years, significant progress
      has been made in the understanding of this condition, but the management of ARDS
      remains complex and requires multidisciplinary and specialized care.

PMID- 10342889
TI  - Diabetes in the managed care setting: a prospective plan.
AB  - BACKGROUND: As managed care organizations (MCOs) continue to expand into the care
      of the chronically ill, the concept of providing cost-effective care with a
      preventive approach is vital for primary care providers (PCPs) to embrace.
      Diabetes is an ideal disease to incorporate this concept. METHODS: We reviewed
      the literature using MEDLINE. We used the American Diabetes Association (ADA)
      Provider Recognition Program guidelines as the foundation for MCOs to establish a
      diabetes disease management program. RESULTS: The implementation of disease
      management protocols, the use of computerized management systems, and the team
      approach can provide cost-effective diabetic care. CONCLUSIONS: To compete in the
      managed care market, it is vital for providers to link with their Independent
      Practice Associations (IPA), the ADA, and MCOs to implement standard protocols
      and negotiate for adequate reimbursement.

PMID- 10342890
TI  - Organization of hospital-based acute pain management programs.
AB  - BACKGROUND: The management of acute pain is an aspect of hospital-based practice
      that has been neglected. Control of pain is important for ethical reasons, for
      compliance with new guidelines and standards, and for optimizing patient
      satisfaction and outcomes. METHODS: Be review the rationale for establishing
      priority to the control of acute pain, the importance of an institutional
      approach to improve pain management, and specific steps in the establishment and
      conduct of an acute pain program. RESULTS: Improvement in pain control depends on
      an institutional approach to facilitate changes in attitude and prioritization.
      Pain management programs should provide for patient and staff education, adequate
      documentation of care, institutional standards for pain control, quality
      assurance/continuous quality improvement (CQI) activities, and periodic review of
      practice and policy. CONCLUSIONS: Effective pain management can set the stage for
      a rehabilitational approach to postoperative care, which should lead to earlier
      recovery and improved outcomes.

PMID- 10342891
TI  - Systemic sclerosis from autoimmunity to alloimmunity.
AB  - BACKGROUND: The biologic significance of microchimerism from pregnancy in
      systemic sclerosis and other autoimmune diseases is not fully characterized.
      METHODS: We based this brief review on a systematic search of the MEDLINE
      database for all relevant articles published between 1980 and July 1998, indexing
      systemic sclerosis, microchimerism, and pregnancy as key words. We also searched
      textbooks, meeting proceedings, and reference lists. RESULTS: Fetal
      microchimerism and class II human leukocyte antigen (HLA) compatibility between
      mother and fetus are common among women with systemic sclerosis. Alternative
      sources of microchimerism include the engraftment of donor cells after a blood
      transfusion, from a dizygotic twin, or possibly from the mother. CONCLUSIONS:
      Systemic sclerosis could be a form of chronic graft-versus-host disease caused by
      fetal or maternal cells, which have crossed the placenta and have remained
      unrecognized by the host due to class II HLA compatibility.

PMID- 10342892
TI  - Use of combined oral narcotic and benzodiazepine for control of pain associated
      with bone marrow examination.
AB  - BACKGROUND: Bone marrow aspirate and biopsy is universally recognized as being
      painful. Few descriptions of effective analgesia or premedication for this
      procedure exist. In this study, we assessed an oral narcotic and benzodiazepine
      combination in controlling pain associated with bone marrow examination. METHODS:
      Twenty-four consecutive ambulatory, adult patients referred for bone marrow
      examination received oral medications 90 minutes before the scheduled procedure.
      Patients reported perceived pain, using both Likert numerical and "Faces Pain
      Rating Scale," immediately after bone marrow examination and within 1 week after
      the procedure. Physicians' and nurses' evaluations of patient tolerance and the
      patients' memories of the aspiration and biopsy were recorded. RESULTS: Two
      thirds (66%) of the respondents reported none or only mild pain (3 or less on a
      scale of 1 to 10). Memory of the procedure was vague or nonexistent in
      approximately half of the patients. There were no complications of biopsies or
      premedication. CONCLUSIONS: Premedication with oral narcotic and benzodiazepine
      is effective in preventing or lessening pain associated with bone marrow
      examination in adults. Premedication induces amnesia for some or most of the
      procedure in about half of the patients.

PMID- 10342893
TI  - Use of advance directives by health care workers and their families.
AB  - BACKGROUND: Advance directives (ADs) are advocated for many but executed by few.
      To ascertain the importance of education in the decision to execute an AD, I did
      this study to determine the rate at which health care workers (a medically
      educated group) and their families execute ADs. METHODS: All clinical staff at an
      urban tertiary care VA medical center were surveyed. RESULTS: Of 730 surveys
      mailed, 553 (76%) were returned, and 18% of respondents executed an AD. Age was
      the only variable that predicted execution of an AD. End-of-life medical decision
      making discussions with family members were reported frequently (with spouses
      74%, parents 50%). CONCLUSION: Health care workers do not appear to complete ADs
      at a rate any higher than the general population. Thus, education may be
      necessary, but alone it appears insufficient to increase use of ADs. Frequent
      family discussions occur among health care providers and their families. Such
      discussions may be an important outcome in their own right.

PMID- 10342894
TI  - Adverse drug reaction-related hospitalizations of nursing facility patients: a 4
      year study.
AB  - BACKGROUND: The purpose of this study was to document adverse drug reaction (ADR)
      related hospitalizations from a nursing facility population. METHODS: This 4-year
      prospective observational study used monthly repeated measures of 332 residents
      present for 30 or more days. The review included admission and monthly drug
      regimen review for each resident. Each probable ADR was sent with monthly reports
      to attending physicians and charge nurses. RESULTS: There were 64 ADR-associated
      hospitalizations in 52 of the 332 residents (15.7%). The most common events were
      for nonsteroidal anti-inflammatory drugs (NSAIDs) (30), psychotropic-related fall
      with fracture (14), digoxin toxicity (5), and insulin hypoglycemia (4). Five
      patients had recurrence of the hospitalization for the same problem. A
      significant factor noted between ADR hospitalized and non-ADR residents was the
      number of medications per patient (7.9 +/- 2.6 vs 3.3 +/- 1.3) for the same
      number of problems. CONCLUSIONS: Adverse drug reaction-related hospitalizations
      may affect as many as one of every seven nursing home residents and appear to be
      related to polypharmacy as well as inattention to patient history of
      contraindications and previous ADRs.

PMID- 10342895
TI  - Group A streptococcal pharyngitis in adults 30 to 65 years of age.
AB  - BACKGROUND: Although the frequency of group A streptococcal pharyngitis in adults
      is assumed to be low, there is little information on frequency other than in
      military populations. METHODS: A prospective, observational study was done to
      determine the frequency of group A streptococcal pharyngitis in adults seen in
      the emergency department. Throat swabs were obtained on adults (30 to 65 years of
      age) with sore throat and pharyngitis on examination. Swabs were also obtained in
      a group of control subjects. RESULTS: Of the 148 adults with pharyngitis, 65
      (44%) had throat specimens positive for group A streptococci. In the 50 control
      subjects, all throat cultures were negative for group A streptococci. A
      significant number of patients with group A streptococcal pharyngitis had school
      aged children at home. CONCLUSION: The high rate of detection of group A
      streptococci in adults outside the military has not been previously reported.

PMID- 10342896
TI  - Determinants of the excessive rates of lung cancer in northeast Florida.
AB  - BACKGROUND: Age-adjusted rates of lung cancer among whites, but not blacks, in
      Duval County Jacksonville), Florida, have been among the highest of any
      metropolitan area of the United States for three decades. METHODS: We conducted a
      case-control study, interviewing 507 patients with lung cancer diagnosed from
      1993 to 1996 and 1,007 control subjects, randomly selected from the county
      population. RESULTS: Cigarette smoking was the dominant cause of lung cancer
      (odds ratios, 59 among male current smokers; 30 among female current smokers).
      Both prevalence and intensity of smoking were excessive for whites but less for
      blacks when compared with national norms. Little association was found with
      residential patterns, indices of air quality, or occupation. Risk doubled with
      increased intake of dietary fat and with a family history of lung cancer.
      CONCLUSIONS: Life-style factors, especially smoking, but not environmental
      factors, appear responsible for the high rates of lung cancer in northeast
      Florida.

PMID- 10342897
TI  - Necrotizing vasculitis of the skin and uterine cervix associated with minocycline
      therapy for acne vulgaris.
AB  - In recent years, minocycline has become a commonly used agent for the treatment
      of acne vulgaris and rosacea. With this increased use have come reports of severe
      and in some cases life-threatening toxicity, often occurring in otherwise healthy
      young women after prolonged courses of minocycline. These adverse reactions
      include hepatotoxicity, drug-induced lupus erythematosus, eosinophilic
      pneumonitis, and hypersensitivity syndrome. We describe a 35-year-old woman who
      had necrotizing vasculitis of the skin and uterine cervix after 2 years of
      minocycline therapy for acne vulgaris. Skin and cervical biopsies revealed acute
      inflammation involving through-and-through necrosis of vessel walls with
      thrombosis, focal fibrinoid change, and a perivascular lymphohistiocytic
      infiltrate. The disease fully resolved within 3 months of discontinuance of the
      minocycline therapy. Patients should be informed of these rare but potentially
      serious adverse effects before the initiation of minocycline therapy. Early
      recognition of these complications can result in complete resolution.

PMID- 10342898
TI  - Familial inheritance of mandibular arch malformations affecting three individuals
      in one family.
AB  - Mandibular aplasia is defined as incomplete development of the mandibular process
      of the first brachial arch. Its prevalence is less than 1:70,000. It is usually
      associated with low-set ears, transposition of the viscera, congenital heart
      defects, and rib abnormalities, and is incompatible with life. In this case
      report, fetal demise at 26 weeks' gestation in a previous pregnancy revealed the
      phenotypic features listed. The second pregnancy described here resulted in
      therapeutic termination of a similar appearing fetus. Because of this recurrence
      and a positive family history, familial inheritance is postulated.

PMID- 10342899
TI  - Acute respiratory distress syndrome in a welder exposed to metal fumes.
AB  - A 43-year-old man began having malaise, chills, and fever 12 hours after cutting
      a galvanized steel grating with an acetylene torch at work. Over the next 72
      hours, his symptoms persisted and became worse with progressive shortness of
      breath. He was admitted to the hospital and begun on antibiotics and steroids.
      The next day his condition had deteriorated to the point that he had to be
      intubated. Chest x-ray film and computed tomography showed patchy and
      interstitial infiltration bilaterally, consistent with acute respiratory distress
      syndrome. Open lung biopsy showed focal mild interstitial pneumonia. Multiple
      laboratory studies were negative for an infectious or an immune process. The
      patient remained on mechanical ventilation for 10 days and was discharged from
      the hospital 2 days after extubation. He continued to improve, with minimal
      symptoms and a return to normal activity levels several months after the incident
      with no continued treatment. Re-creation of his exposure was done under
      controlled circumstances, with air sampling revealing elevated air levels for
      cadmium and zinc and borderline levels of arsenic, manganese, lead, and iron.

PMID- 10342900
TI  - Mesenteric lipodystrophy with fever of unknown origin and mesenteric
      calcifications.
AB  - Mesenteric lipodystrophy (ML) is a rare condition characterized by a nonspecific
      inflammatory process that involves the root of the mesentery in a lipoma-like
      lesion. Presenting features of ML include abdominal pain, weight loss, nausea,
      vomiting, diarrhea, and constipation. This case illustrates that ML should be
      included in the differential diagnosis of patients with fever of unknown origin
      and mesenteric calcifications.

PMID- 10342901
TI  - New considerations in the diagnosis and therapy of deep vein thrombosis.
AB  - The cause of thrombosis is often unknown but is universally ascribed to part of
      Virchow's triad: stasis, hypercoagulability, and intimal injury. Venous
      thromboembolic disease is a common and costly medical problem, with iliofemoral
      deep vein thrombosis (IFDVT) being a less common but often underestimated
      presentation of this condition. Treatment options for deep vein thrombosis (DVT)
      have expanded in recent years and now include systemic anticoagulation,
      thrombolytic therapy, and surgery. Several studies have shown the efficacy of
      catheter-directed thrombolytic therapy in resolution of IFDVT. There is also
      growing evidence that early lysis is more likely to preserve valve function
      leading to a decrease in the incidence of postthrombotic syndrome, which is a
      known long-term complication of DVT and IFDVT. The following case report
      describes a patient, without malignancy, who had an atraumatic iliac and femoral
      DVT and illustrates the diagnostic considerations and therapy of a patient with
      iliofemoral DVT.

PMID- 10342903
TI  - Asymptomatic intussusception of the appendix due to endometriosis.
AB  - We present the case of a 29-year-old woman with an asymptomatic intussuscepted
      appendix found incidentally during surgical evaluation for a pelvic mass in a
      patient with endometriosis. This case represents the rare nature of this
      presentation and the need to fully evaluate the gastrointestinal tract in
      patients with endometriosis.

PMID- 10342904
TI  - Fracture at fenestration of synthetic tracheostomy tube resulting in a
      tracheobronchial airway foreign body.
AB  - Tracheostomy tube fracture resulting in airway obstruction is a relatively rare
      but serious complication. We report the case of a 48-year-old man whose
      tracheostomy tube fractured and became lodged in the right primary bronchus.
      Recommendations are made for tracheostomy care to help prevent similar
      complications in patients with an indwelling tracheostomy tube.

PMID- 10342902
TI  - What if your patient prefers an alternative pain control method? Self-hypnosis in
      the control of pain.
AB  - Despite the availability of specialized treatments for chronic pain, including
      biofeedback training, relaxation training, and hypnotic treatment, most
      physicians rely on the traditional approaches of surgery or pharmacotherapy. The
      patient in this case study had severe and chronic pain but found little relief
      from pain medications that also caused side effects. She then took the initiative
      to learn and practice self-hypnosis with good results. Her physician in the
      resident's internal medicine clinic supported her endeavor and encouraged her to
      continue self-hypnosis. This patient's success shows that self-hypnosis can be a
      safe and beneficial approach to control or diminish the pain from chronic pain
      syndrome and can become a useful part of a physician's therapeutic armamentarium.

PMID- 10342905
TI  - Interaction between rifampin and levothyroxine.
AB  - Rifampin is a potent inducer of hepatic enzymes and is well documented to cause
      many clinically significant drug interactions. Studies in normal volunteers have
      shown its ability to decrease circulating levels of thyroid hormone, while having
      no effect on thyroid-stimulating hormone (TSH). Reports of rifampin's effects on
      patients on hormone replacement in the clinical setting are of interest since we
      believe only one such case has been described. We report the case of a man,
      stable on levothyroxine, who exhibited significantly elevated TSH levels during
      therapy with rifampin. Thyroid-stimulating hormone levels returned to baseline 9
      days after discontinuance of rifampin.

PMID- 10342906
TI  - Pigmented schwannoma of the ventral spinal cord.
AB  - Pigmented schwannomas of the spinal canal are rare entities. We present a case of
      such in an unusual, ventral intradural, extramedullary location in a 27-year-old
      man. Imaging and histopathologic findings, including electron microscopy, showed
      an intradural, extramedullary pigmented schwannoma, densely adherent to the
      leptomeninges of the anterior median septum. This lesion is demonstrative of the
      neuroectodermal origin of these lesions and represents a rare location of these
      tumors.

PMID- 10342907
TI  - To treat or not to treat pain.

PMID- 10342908
TI  - Comfort care: why wait until the end of life?

PMID- 10342909
TI  - Antiplatelet agents isolated from medicinal plants.
AB  - Platelet-vessel wall interaction is an important process in physiological
      hemostasis and pathological thrombosis. In oriental countries, some medicinal
      plants have been claimed for uses to improve circulation, induce fibrinolysis or
      prevent thrombosis. In cooperation with chemists using bioassay-based step-by
      step purification, some antiplatelet agents were isolated from plant sources.
      According to their effects on platelet aggregation, release reaction and signal
      transductions involved, these antiplatelet agents can be classified into eight
      groups: 1. platelet-activating factor (PAF) antagonists, 2. collagen-receptor
      antagonists, 3. thromboxane-receptor antagonists, 4. ADP-receptor agonists, 5.
      inhibitors of phosphoinositide breakdown, 6. inhibitors of thromboxane formation,
      7. agents increasing cyclic nucleotides, and 8. protein kinase C activators.
      These new pharmacological agents derived from medicinal plant sources may be
      useful as leads to develop as effective cardiovascular drugs.

PMID- 10342910
TI  - Effects of granisetron, a selective 5-HT3 receptor antagonist, on ouabain-induced
      emesis in ferrets.
AB  - The antiemetic effect of granisetron, a selective 5-HT3 receptor antagonist, on
      ouabain-induced emesis was studied using ferrets. In order to clarify the
      relationship between ouabain-induced emesis and serotonin (5-HT), we examined its
      effects on 5-HT release from the isolated ileum. Afferent vagal nerve activity
      was also determined. An intravenous bolus injection of ouabain (0.1-1.0 mg/kg)
      produced emesis in a dose-dependent manner. Ouabain-induced emesis was inhibited
      by pretreatment with granisetron. In the isolated ileum, ouabain induced a
      concentration-dependent increase of 5-HT. This release of 5-HT was suppressed by
      granisetron. Increases in vagal nerve discharges were observed immediately after
      the intravenous administration of ouabain (0.1-1.0 mg/kg). These increases were
      suppressed by granisetron. Taken together, ouabain activates 5-HT release from
      the mucosa in the gastrointestinal tract. Released 5-HT may activate the vagal
      afferent nerves, resulting in vomiting. Granisetron inhibited the ouabain-induced
      elevation of 5-HT and vagal nerve activity. Ouabain may induce emesis as well as
      negative chronotropic effects by activating the vagus. Our results suggest that
      ouabain-induced emesis is in part mediated by the 5-HT3 receptors of the
      peripheral gastrointestinal tract.

PMID- 10342911
TI  - Is increased IL-1 beta mRNA expression in spleen of tumor-bearing mice relevant
      to cancer cachexia?
AB  - Using C3H/He mice bearing MH-134 tumor cells, cytokine inductions of tumor
      necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6
      (IL-6) and interferon-gamma (IFN-gamma) were determined in spleens by reverse
      transcriptase-polymerase chain reaction (RT-PCR) analysis. Levels of IL-1 beta
      were significantly (p<0.05) increased in the spleens of tumor-bearing mice
      compared with those of freely fed control animals. In contrast, no significant
      increase of other cytokine mRNAs was observed. In addition, constitutive levels
      of IL-1 beta mRNA were present in spleens of tumor-bearing mice during the
      experimental period. These results suggest that the over-expression of IL-1 beta
      mRNA was relevant to clinical manifestations of cancer-burden states.

PMID- 10342912
TI  - Effects of propranolol on the pharmacokinetics of cyclosporine after intravenous
      and oral administration to control rats and rats with uranyl nitrate-induced
      acute renal failure.
AB  - Effects of propranolol on the pharmacokinetics of cyclosporine were investigated
      after intravenous and oral administration of the drugs to control rats and rats
      with uranyl nitrate-induced acute renal failure (U-ARF). Effects of intravenous
      propranolol, 3 mg/kg, on the pharmacokinetics of intravenous cyclosporine, 3 and
      30 mg/kg, to control rats, and 30 mg/kg, to rats with U-ARF seemed to be
      negligible. However, the effects of orally administered propranolol, 10 mg/kg, on
      the area under the blood concentration-time curve (AUC) of oral cyclosporine were
      significant after oral administration of cyclosporine, 10 and 100 mg/kg, to
      control rats. For example, the AUC of cyclosporine increased significantly (33.1
      versus 24.7 microg h/ml) at cyclosporine oral dose of 10 mg/kg, however, the
      value decreased significantly (167 versus 235 microg h/ml) at cyclosporine oral
      dose of 100 mg/kg. Effects of orally administered propranolol, 10 mg/kg, on the
      pharmacokinetics of orally administered cyclosporine, 100 mg/kg, seemed to be
      negligible in rats with U-ARF.

PMID- 10342913
TI  - Effect of streptozotocin on glutathione and lipid peroxide levels in various
      tissues of rats.
AB  - In this study, the effect of streptozotocin (STZ) on lipid peroxidation and
      glutathione (GSH) content was investigated in the liver, pancreas and kidney of
      rats. Lipid peroxide levels were significantly increased in homogenates and
      mitochondrial fractions of the liver, kidney and pancreas after STZ
      administration. GSH levels in hepatic and pancreatic tissues were decreased but
      unchanged in the kidney of diabetic rats. GSH content in hepatic mitochondrial
      fraction was also decreased compared to control group. On the other hand, the
      destruction of pancreatic beta-cells was also observed histopathologically. Our
      results indicate that oxidative stress may play an important role in STZ induced
      diabetes and mitochondrial fraction may be the target in this toxicity.

PMID- 10342914
TI  - The role of hemodynamics in the action of diltiazem on hepatic fatty acid
      metabolism.
AB  - The hemodynamic effects of diltiazem in the liver are strictly Ca2+ -dependent
      Consequently, Ca2+ -free perfusion can be used for investigating the metabolic
      effects of diltiazem without interference by hemodynamics. Livers were perfused
      with Krebs/Henseleit-bicarbonate buffer (pH 7.4). For performing Ca2+ -free
      perfusion the cation was omitted from the perfusion fluid and the cellular pools
      were exhausted by repeated phenylephrine infusions. Three conditions were
      investigated with and without Ca2+ : (1) substrate-free perfusion fluid; (2) 0.3
      mM [1-(14)C]octanoate infusion; (3) 0.3 mM [1-(14)C]palmitate infusion. The
      following results were obtained: 1. Oxygen uptake stimulation caused by octanoate
      and palmitate was abolished by 500 microM diltiazem in the presence of Ca2+; in
      the absence of Ca2+ there was no inhibition (octanoate) or it was much smaller
      (palmitate); 2. The 14CO2 production was inhibited in the presence of Ca2+; in
      the absence of Ca2+ there was no inhibition (palmitate) or even stimulation
      (octanoate). 3. Ketogenesis from endogenous sources, from palmitate and from
      octanoate was inhibited by diltiazem in the presence as well as in the absence of
      Ca2+. The beta-hidroxybutyrate/acetoacetate ratio was diminished in the presence
      and in the absence of Ca2+ . It was concluded that inhibition of fatty acid
      oxidation by diltiazem depends partly on the Ca2+ -dependent hemodynamic effects
      and partly on a Ca2+ -independent action on some enzymatic system.

PMID- 10342915
TI  - Swimming-exercise increases the capacity of perfused rat liver to produce urea
      from ammonia and L-glutamine.
AB  - We designed this study to determine whether the capacity of the liver to uptake
      ammonia and produce urea was affected by exercise (swimming at 24 degrees C with
      a 2.5% extra body-weight load). For this purpose, livers from sedentary rats at
      rest were perfused with a buffer containing increasing concentration of NH4Cl.
      The maximal hepatic capacity to produce urea was found at an NH4Cl concentration
      of 0.25 mM. Based on this finding all experiments with livers obtained from rats
      subject to swimming exercise were also carried out with a NH4Cl concentration of
      0.25 mM. Thus, employing this concentration of ammonia, livers from sedentary and
      endurance trained rats, (for a period of 11 days ), that had either been resting
      or had been subjected to swimming exercise for 5 min or until exhaustion, were
      perfused in situ and ammonia uptake and urea production were measured. Clearly,
      both parameters were increased by exercise. However, these changes were not
      affected by swimming training. In addition, we demonstrate that the effect of an
      acute exercise on hepatic metabolism is not restricted to ammonia metabolism
      since livers from sedentary rats which had been subjected to swimming exercise
      for 5 min or until exhaustion showed higher urea production from L-glutamine. Our
      results also suggest that part of the changes in ureogenesis induced by exercise
      is mediated by cortisol (increased ammonia uptake) and part of the changes is
      mediated by glucagon (urea production).

PMID- 10342916
TI  - Metabolism of glutathione in isolated non filtering rat kidneys.
AB  - The aim of this work was to study the metabolism of glutathione in the isolated
      non-filtering rat kidney. Kidneys were perfused with Krebs-Henseleit solution
      containing 1 mM of glutathione. The analysis of the peptide residues and their
      components was done in an aminoacid microanalyzer. The results showed that
      glutathione was significantly oxidized to a maximal concentration of 0.06 mM at
      end of 20 minutes (94%). Oxidized glutathione was formed showing a slight
      elevation in the first 20 minutes and declining thereafter, being degraded to its
      constituent amino acids to a final concentration of 0.05 mM (5%). The tripeptide
      produced glutamic acid, glycine and cysteine in increasing concentrations. The
      hydrolysis of glutathione allowed us to believe that gamma glutamyl
      transpeptidase, among other enzymes is present in the counterluminal membranes of
      the rat kidney contributing to the handling of glutathione. Our results open new
      ways to the study of glutathione metabolism.

PMID- 10342917
TI  - Human embryo experimentation: regulation and relative rights.

PMID- 10342918
TI  - Insulin lispro: new preparation. Faster acting.
AB  - Recombinant insulin lispro has a more rapid onset of action and shorter duration
      than human insulin.  The clinical file on insulin lispro is bulky: comparative
      trials versus human insulin have involved more than 2,000 patients, most of whom
      were treated for 6 months to 1 year.  These trials show that there is no
      difference in diabetes control according to the type of insulin used, in either
      type I or type II diabetes. Some cases of resistance to human insulin have been
      successfully treated with insulin lispro. According to a meta-analysis of trials
      comparing insulin lispro with human insulin, insulin lispro does not alter the
      risk of hypoglycaemia.  In practice, insulin lispro can be administered just
      before meals, which is an advantage over human insulin, that has to be
      administered 30 to 45 minutes before meals.  Both types of insulin must be kept
      in a refrigerator.

PMID- 10342919
TI  - Liposomal doxorubicin: new preparation. Useful in Kaposi's sarcoma.
AB  - The clinical file on liposomal doxorubicin in Kaposi's sarcoma is bulky and
      methodologically sound.  The most relevant clinical trial, involving 258
      patients, showed that fortnightly short infusions of 20 mg/m 2 liposomal
      doxorubicin yielded more partial or complete tumour reductions than the ABV
      protocol.  This provides a substantial cosmetic benefit for patients, even if the
      duration of remission and survival time are not affected, and even if other
      trials have shown that complete remission is obtained in only 6% of cases. 
      Overall, liposomal doxorubicin is better tolerated than the ABV protocol, with
      fewer depressing adverse effects such as hair loss and peripheral neuropathy. 
      Liposomal doxorubicin and liposomal daunorubicin have not been compared directly
      in clinical trials.

PMID- 10342920
TI  - Sustained-release nifedipine: new indication. Angina: safer drugs are available.
AB  - The efficacy of sustained-release osmotic tablets of nifedipine in the
      symptomatic treatment of stable angina is poorly documented.  The safety of
      nifedipine remains uncertain, as high-dose treatment with immediate-release
      preparations increased mortality in trials involving coronary patients.  In
      angina, nifedipine can be used only in combination with a betablocker, and only
      to treat patients with no recent history of myocardial infarction, or unstable
      angina. In stable angina with inadequate symptom control by betablockers, it is
      no more effective than other dihydropyridines also indicated in the treatment of
      angina, i.e. amlodipine and felodipine.  Furthermore, medium-term data on
      amlodipine are relatively reassuring. Nifedipine appears a little more effective
      than sustained-release nitrate derivatives, but less safe.

PMID- 10342922
TI  - Etoposide phosphate: new preparation. Makes outpatient therapy easier.
AB  - The clinical file on etoposide phosphate provides no new efficacy data. 
      Pharmacokinetic studies have shown that non esterified etoposide can be replaced
      by etoposide phosphate; the latter is rapidly metabolised and yields the same
      amount of bioavailable etoposide.  The only available comparative trial showed no
      difference in adverse effects between etoposide phosphate and non esterified
      etoposide.  The small size of this trial rules out conclusions on infrequent
      adverse effects such as those possibly due to the solvents in non esterified
      etoposide. The main value of etoposide phosphate is its simplicity of use, which
      should make it more suitable for treatment at home: contrary to non esterified
      etoposide it can be administered as a short infusion, is compatible with all
      infusion equipment, and appears to be stable in various types of aqueous
      solution.

PMID- 10342921
TI  - Reteplase: new preparation. Minimal value: bolus versus infusion.
AB  - The clinical file on reteplase is methodologically sound. A trial versus
      alteplase involving more than 15 000 patients seen less than 6 hours after
      myocardial infarction showed that mortality at 30 days was identical in the
      reteplase and alteplase treatment groups (7.3%).  The two treatment groups did
      not differ either in the frequency of strokes or severe bleeding.  Another trial
      involving more than 6 000 patients seen less than 12 hours after myocardial
      infarction showed that overall mortality 35 days after thrombolysis was 9% in
      both the reteplase and the streptokinase treatment groups. The two thrombolytics
      did not differ in terms of overall mortality at 6 months, the number of strokes,
      the number of bleeding events or the safety profile.  Reteplase is easy to
      administer (2 intravenous boluses of 10 U, 30 minutes apart).  Other reference
      thrombolytics (streptokinase and alteplase) are administered as an intravenous
      infusion.

PMID- 10342923
TI  - Ganciclovir ocular implant: new preparation. May benefit severely affected AIDS
      patients.
AB  - A clinical trial involving 188 HIV-infected patients with cytomegalovirus
      retinitis compared treatment with the ocular ganciclovir implant and intravenous
      ganciclovir.  Local treatment delayed progression of lesions on the fundus oculi,
      but the clinical impact on sight was not studied.  Local ocular treatment alone
      failed to delay the onset of retinitis in the other eye and, unlike intravenous
      treatment, did not protect patients against systemic cytomegalovirus infection. 
      The implants must be inserted surgically and renewed periodically. Local adverse
      effects are relatively frequent, and include a transient reduction in visual
      acuity lasting about 15 days, vitreal haemorrhage, retinal detachment and
      endophthalmia. These implants do not always avoid the need for systemic treatment
      with its inherent adverse effects (mainly haematological and infectious). In our
      opinion this local treatment should be reserved for patients with initially
      severe or rapidly progressive forms, or lesions likely to damage their sight
      rapidly.

PMID- 10342924
TI  - Felbamate: new preparation. May benefit multiresistant epileptic patients.
AB  - Efficacy of this antiepileptic in the Lennox Gastaut syndrome is limited but
      there are no really effective alternatives for this severe form of epilepsy. 
      Felbamate can have life-threatening adverse effects, including bone marrow
      aplasia and acute liver failure.  These adverse effects mean that felbamate must
      be reserved for patients who are refractory to other correctly prescribed and
      administered antiepileptics, alone or in combination.  Liver function tests and
      blood counts, including platelets, must be done before starting felbamate and
      then every fortnight during treatment. Felbamate can also interact with most
      antiepileptics, hence the need for close clinical monitoring to ensure the
      tolerability of the entire treatment regimen; plasma assays of the other
      antiepileptics may also be necessary.  There is, however, no reason to monitor
      plasma concentrations of felbamate, at least pending further data.

PMID- 10342925
TI  - Famciclovir: new preparation.  Slightly helpful in herpes zoster.
AB  - A comparative placebo-controlled trial involving 419 adults showed that a one
      week course of famciclovir started within 3 days of onset of skin lesions had no
      effect on the acute phase of zoster, the time required for scabs to fall, the end
      of skin lesion progression, or pain.  In this trial famciclovir failed to reduce
      the incidence of post-zoster pain, but it did reduce its median duration by
      approximately 2 months.  According to a subgroup analysis (not planned for by the
      protocol), only patients over 50 benefited from this effect. Three other trials
      suggest that the approved dose regimen in France (500 mg 3 times a day) may not
      be optimal.  The dose recommended in the United Kingdom (750 mg in one daily
      intake or 250 mg 3 times a day) seems to be more in line with the clinical
      assessment file. The three available comparative trials show no statistically
      significant difference between famciclovir and aciclovir in terms of efficacy or
      tolerability.  An indirect comparison suggests that the risk-benefit ratio of
      famciclovir and valaciclovir are probably similar.  However, the effects of
      famciclovir on post-zoster pain were observed in a clinical trial, while those of
      aciclovir were found only in meta-analyses.

PMID- 10342926
TI  - Insomnia: cognitive and behavioural alternatives to drug therapy.
AB  - "Stimulus control" and relaxation, combined with advice on sleep hygiene, should
      be a common approach to treating insomnia. Stimulus control, based on simple
      advice aimed at reinforcing the mental link between the bedroom and sleep is a
      simple method to apply after a short training period. Insomnia treatment should
      no longer be restricted to drugs.

PMID- 10342927
TI  - Chloral hydrate: a risky old psychotropic drug.
AB  - Chloral hydrate is an old psychotropic agent that has never been adequately
      assessed in the clinical setting. Its continued use in paediatric units in a
      single dose for premedication before painful examinations or care procedures may
      be justified. Apart from this use, repeated chloral hydrate administration for
      sedative or hypnotic purposes is not supported by studies in children or adults.

PMID- 10342928
TI  - Hypotension and coronary events on nifedipine: reassessing nifedipine safety.
AB  - Nifedipine administration for hypertensive emergencies can induce neurological
      and cardiac events due to abrupt hypotension.  Nifedipine also increase the risk
      of coronary events in case of unstable angina or recent myocardial infarction. In
      hypertensive emergencies, the potential advantages and risks of achieving a rapid
      fall in arterial pressure should be assessed case by case. In patients with
      coronary heart disease, nifedipine is contraindicated in case of recent
      myocardial infarction or unstable angina.  Nifedipine is only a second-line
      choice for stable angina, and should be combined with a betablocker.

PMID- 10342930
TI  - Homeopathy again: a questionable meta-analysis.
AB  - A meta-analysis published in the Lancet in September 1997 cautiously concluded
      that homeopathic drug activity is not fully explained by the placebo effect. A
      thorough examination of this meta-analysis reveals design errors that make the
      results untrustworthy. There is still nothing to suggest that homeopathic drugs
      are any more effective than a placebo.

PMID- 10342929
TI  - Angioedema due to ACE inhibitors: common and inadequately diagnosed.
AB  - The estimated incidence of angioedema during angiotensin-converting enzyme (ACE)
      inhibitor treatment is between 1 and 7 per thousand patients.  This potentially
      serious adverse effect is often preceded by minor manifestations that may serve
      as a warning.

PMID- 10342931
TI  - Medicare coverage and technology diffusion: past, present, and future.

PMID- 10342932
TI  - Mental health parity: unresolved issues affecting employers, consumers, and
      insurance coverage.

PMID- 10342933
TI  - Intensity and correlates of fear of falling and hurting oneself in the next year:
      baseline findings from a Roybal Center fear of falling intervention.
AB  - Fear of falling is highly prevalent and associated with restricted activity.  To
      help inform design of interventions, the authors examined the correlates of this
      fear.  Data came from baseline information on subjects in a community-based falls
      intervention study (N = 392). In a multivariate model, lower levels of fear of
      falling and hurting oneself in the next year were related to being younger,
      having higher levels of dysfunction, and having lower levels of perceived ability
      to manage falls, with the last two remaining significant even after controlling
      for generalized fearfulness.  When analyzing specific domains of dysfunction,
      higher levels of fear of falling and hurting oneself in the next year were
      associated with higher levels of physical dysfunction.  The findings lend support
      to the expanding awareness that fear of falling may imperil quality of life and
      suggest the importance of interventions aimed at enhancing ability to manage
      falls.

PMID- 10342934
TI  - Physical activity and self-rated health among 55- to 89-year-old Dutch people.
AB  - The aim of this study was to examine the effects of physical activity and the
      possible mediating role of perceived physical self-efficacy (PPSE) on self-rated
      health (SRH) in the 55- to 89-year-old Dutch population.  The data are based on a
      structured interview carried out in a random sample of 120 subjects--60 men and
      60 women with the average ages of 69 and 71 years, respectively--in Sassenheim,
      the Netherlands, as a pilot study of the Longitudinal Aging Study Amsterdam
      (LASA).  The results of linear multiple regression analyses showed that physical
      activity was a significant predictor of self-rated health.  Moreover, the results
      supported the role of PPSE as a mediator in the association between physical
      activity and self-rated health status even when age, gender, and chronic diseases
      were controlled. These findings suggest that in the elder population, increasing
      perceived physical self-efficacy may be more important for perceived health than
      raising the level of physical activity.

PMID- 10342935
TI  - Hunger and food insecurity in the elderly: its nature and measurement.
AB  - To better understand the nature of food insecurity in the elderly and to improve
      its measurement, in-depth interviews were conducted with 41 urban Black and rural
      White elderly in 35 households, followed by telephone administration of commonly
      used measures of food insecurity in 24 of these elderly.  Elderly food insecurity
      appears to follow a progression of severity, beginning with compromised diet
      quality, followed by food anxiety, socially unacceptable meals, use of emergency
      food strategies, and finally actual hunger.  The five quantitative measures
      tested were compared to each elderly person's food insecurity status based on the
      in-depth interview.  All measures had reasonable specificity, and good
      sensitivity for those experiencing severe food insecurity.  However, the Cornell
      Radimer, Community Childhood Hunger Identification Project (CCHIP) and Nutrition
      Screening Initiative (NSI) measures appeared more sensitive than the USDA food
      sufficiency or Urban Institute measures in correctly identifying those in the
      lesser stages of food insecurity.

PMID- 10342936
TI  - The relationship between nursing staffing levels and nursing home outcomes.
AB  - This study examined the effects of selected Minnesota nursing home attributes
      (size, ownership, noncompliance with a state correction order, and licensed and
      nonlicensed nursing hours) on specific outcomes (functional ability, discharge
      home, and death) for residents ages 65 and older, controlling for residents' age
      and previous functional ability.  The functional outcome was operationalized by
      calculating the resident's Total Dependence Score (TDS), the total score on the
      assessment of eight activities of daily living (score range: 0-33).  Ordinary
      least squares regression analysis was used to estimate the effects of facility
      attributes, admission TDS, and age on resident outcomes, and nonlinear
      probability analyses were used to estimate the effects of facility attributes,
      admission TDS, and age on the probability of death or discharge home.  In the
      year after admission, licensed (but not nonlicensed) nursing homes were
      significantly related to improved functional ability, increased probability of
      discharge home, and decreased probability of death, but when limited to chronic
      residents, the role of professional nursing hours virtually disappears.  Overall,
      the findings support greater use of licensed nurses in the nursing home setting.

PMID- 10342937
TI  - Osteoporotic fracture among older U.S. women: risk factors quantified.
AB  - The purpose of this study was to develop a predictive model for osteoporotic
      fracture among a national sample of 2,325 women ages 50 years and older. 
      Predictors for examination included age, race, heredity, body mass index (BMI),
      physical activity, smoking status, alcohol use, and dairy product use.  Analyses
      were conducted using Standard Analysis System (SAS) procedures.  Strong risk
      factors predicting osteoporotic fracture included age, race, low BMI, and
      inactivity.  Recommendations emphasize screening of high-risk women, achieving
      and maintaining health body weights for underweight women, and obtaining moderate
      physical activity.  Promotion of healthy body weights for women of all ages is
      emphasized.  Recommendations also include encouraging widespread physician,
      patient, and public education regarding osteoporotic fracture.

PMID- 10342938
TI  - Receiving the scepter: the generational transition and impact of parent death on
      adults.
AB  - Using grounded theory to investigate the impact of parent death on adult
      children, this qualitative study revealed a process quite distinct from the
      description of bereavement following other deaths. Three phases were identified
      that emphasized the familial nature of this grief.  As essential part of the
      recovery process for the griever was the complementary role played by the spouse.
      It was during this period that choices were made about the legacy of values that
      were to be passed to the next generation.  The interviews with participants
      provided a unique opportunity to view the process by which generational
      transitions occur.

PMID- 10342939
TI  - Suicide in the world: toward a population increase theory of suicide.
AB  - Using recently obtained suicide rates and economic development indicators for 60
      countries, this study investigates the effects of modernization on suicide
      throughout the world. Results support the hypothesis that high suicide rates are
      related to modernization but with revisions.  Although suicide is negatively
      correlated with population growth indicators and positively correlated with
      quality of life indicators, in multiple regression analyses with all other
      factors controlled, the population growth factor is a much better predictor of
      suicide rates than the quality of life factor.  This finding holds true for both
      developing and developed countries when the two subsamples were tested
      separately. The population increase theory of suicide is highlighted as an
      explanation of suicide rates in the world, and ramifications of the theory are
      discussed.

PMID- 10342940
TI  - A comparison of spousal anticipatory grief and conventional grief.
AB  - The purpose of the present investigation was to compare the degree of similarity
      between the grief experienced by spouses of terminally-ill patients prior to
      (anticipatory grief) and following the death (conventional grief).  Responses of
      this sample were also compared with those of two control groups: spouses of
      chronically-ill patients and spouses of relatively healthy individuals from the
      community. The impact of such factors as the quality of the marital relationship,
      perceived ability to cope, concurrent stressors, previous losses, perceived
      social support, and perception of spouse's pain and suffering on anticipatory and
      conventional grief was also systematically explored.  Results indicated that
      these two phenomena are statistically similar with regard to the majority of
      subscales on the Grief Experience Inventory.  Furthermore, when compared with
      conventional grief, anticipatory grief was unexpectedly associated with higher
      intensities of anger, loss of emotional control, and atypical grief responses.

PMID- 10342941
TI  - Methods for suicide in mainland China.
AB  - Data are presented from mainland China to illustrate the differences by region,
      gender, and age in the methods used for suicide.  Changes over time are also
      documented.  The data support an availability hypothesis for choice of method for
      suicide.  Differences by gender in the use of violent and nonviolent methods
      resemble those found in Western nations, except that the particular violent
      methods used are different in China.

PMID- 10342942
TI  - Labor market responses to rising health insurance costs: evidence on hours
      worked.
AB  - Increases in the cost of providing health insurance must have some effect on
      labor markets, either in lower wages, changes in the composition of employment,
      or both.  Despite a presumption that most of this effect will be in the form of
      lower wages, we document a significant effect on work hours as well.  Using data
      from the Current Population Survey (CPS) and the Survey of Income and Program
      Participation (SIPP), we show that rising health insurance costs during the 1980s
      increased the hours worked by those with health insurance by up to 3%.  We argue
      that this occurs because health insurance is a fixed cost, and as it becomes more
      expensive to provide, firms face an incentive to substitute hours per worker for
      the number of workers employed.

PMID- 10342943
TI  - Tiagabine: new preparation. Refractory partial epilepsy: another alternative.
AB  - (1) Tiagabine combination therapy has been assessed in quality clinical trials.
      (2) In patients with partial epilepsy placebo-controlled trials have shown that,
      in combination with an antiepileptic treatment considered ineffective, tiagabine
      reduces the frequency of seizures by at least 50% in approximately a quarter of
      patients. (3) Its efficacy does not appear to be superior to that of viga batrin,
      gabapentin, lamotrigine or progabide, but there have been no direct comparisons
      between tiagabine and these other antiepileptic drugs. (4) The main adverse
      effects of tiagabine are neuropsychological. No serious adverse effects have been
      described. (5) Tiagabine is not an enzyme inducer but efficacy can be reduced if
      it is combined with enzyme-inducing antiepileptics. (6) Tiagabine therapy cannot
      be monitored using plasma drug levels.

PMID- 10342944
TI  - Cefpodoxime: new dosage. A new, unproven, dose regimen.
AB  - (1) Oral cefpodoxime, a third-generation cephalosporin, has a reduced treatment
      duration for recurrent pharyngitis; but this is based on a single unblinded
      trial. (2) At the end of the 5-day treatment during the trial, the clinical
      efficacy of cefpodoxime was no different from that of a 10-day course of
      penicillin V or the amoxicillin + clavulanate combination. (3) The relapse rate
      at 6 months is uninterpretable because many patients were lost to follow-up and
      were not included in the statistical analysis.  To our knowledge the second
      indication granted for cefpodoxime, chronic tonsillitis, has not been validated
      in clinical trials. (4) Trivialising cefpodoxime may induce antibiotic
      resistance.

PMID- 10342945
TI  - Intravenous pamidronic acid: new indications. Useful palliative treatment for
      osteolysis.
AB  - (1) Pamidronic acid has no demonstrated influence on the survival time in
      patients with myeloma or bone metastases. (2) Two comparative placebo-controlled
      trials involving women with metastatic breast cancer show that a monthly infusion
      of pamidronic acid reduces the number of patients needing analgesic bone
      irradiation.  It is not known whether pamidronic acid affects analgesic intake.
      (3) In myeloma, a placebo-controlled trial has shown that a monthly infusion of
      pamidronic acid reduces the number of patients requiring analgesic bone
      irradiation. Pamidronic acid also reduces analgesic use and the number of
      pathological fractures. (4) Overall, in the two indications, pamidronic acid
      reduces the frequency of all bone events, and postpones those that occur. (5)
      Pamidronic acid seems to be well tolerated. The most frequent adverse effect is
      fever after infusion.

PMID- 10342946
TI  - No value of oral clodronic acid in malignant osteolysis.
AB  - The analgesic action of this diphosphonate has not been confirmed,and its value
      for patients with bone metastases has still not been documented.

PMID- 10342947
TI  - Glimepiride: new preparation. Just another hypoglycaemic sulphonylurea agent.
AB  - (1) Glimepiride is another addition to the list of available antidiabetic
      sulphonylureas.  The file contains nothing new on the potential clinical value of
      this type of treatment in noninsulin-dependent diabetes. (2) The efficacy of
      glimepiride was judged on the basis of fasting blood glucose and the level of
      glycated haemoglobin, i.e. laboratory end points.  The recommended dose regimen
      (1-6 mg/day in a single intake) is validated by an adequate number of placebo
      controlled trials. (3) Glimepiride was compared with two other antidiabetic
      sulphonylureas in large trials, one versus gliclazide in 459 patients and two
      versus glibenclamide, one of which included more than 1,000 patients.  These
      trials showed no difference in blood glucose control between glimepiride and the
      other two sulphonylureas after treatment periods of 6 months to 1 year. (4) The
      safety profile of glimepiride seems similar to that of gliclazide or
      glibenclamide, but more follow-up in normal conditions of use is required.  As a
      result, better-known sulphonylureas should be used in preference. (5) The fact
      that glimepiride can be administered in a single daily intake is not an
      advantage, as other sulphonylureas can also be used in this way.

PMID- 10342948
TI  - Tacrolimus in the prevention of graft rejection: new indication.  Helpful
      alternative to ciclosporin.
AB  - (1) In kidney and liver graft prophylaxis two large multicentre trials have
      compared tacrolimus to ciclosporin alone or combined with other
      immunosuppressants.  They showed that the mortality one or two years after
      transplantation, and the incidence of irreversible graft rejection, did not
      differ according to the treatments received. (2) The safety profile of tacrolimus
      seems similar to that of ciclosporin, but it is difficult to draw firm
      conclusions because of inadequate follow-up and recent progress in tacrolimus
      assay and dose-adjustment methods.  Hyperglycaemia, lymphoproliferative syndromes
      and cardiac effects might be more frequent on tacrolimus than on ciclosporin. (3)
      Until it is shown that the possible slight advantage of tacrolimus in terms of
      efficacy is not offset by greater toxicity, tacrolimus should be used only when
      ciclosporin is ineffective or poorly tolerated.

PMID- 10342949
TI  - Fluoride and bone: a second look. No use in osteoporosis.
AB  - (1) Data on fluoride efficacy in secondary prevention of osteoporotic fractures
      were contradictory when we last examined the file, in 1990. We now re-examine the
      clinical file on fluoride with more follow-up and new clinical trial data. (2) In
      354 postmenopausal women with a history of vertebral fracture (secondary
      prevention), a comparative trial (the FAVOS trial) showed that moderate-dose
      fluoride for 2 years did not reduce the incidence of new vertebral fractures
      relative to calcium plus vitamin D.  Furthermore, fluoride caused more cases of
      lower-limb pain. (3) In 110 postmenopausal women with a history of vertebral
      fracture, a trial showed that fluoride (sustained-release form) + calcium was
      more effective than calcium alone in preventing vertebral fractures. (4) No
      pertinent trial on fluoride in primary prevention has been published since 1991.

PMID- 10342950
TI  - Venlafaxine: new preparation. Just another antidepressant.
AB  - (1) Venlafaxine is a non tricyclic, non MAOI antidepressant which has been
      assessed mainly in placebo-controlled trials.  Some of the available trials
      against other antidepressants are methodologically unsound. (2) Placebo
      controlled trials have established the antidepressant efficacy of venlafaxine at
      a dose of 75-375 mg/day in ambulatory patients, and 350 mg/day in inpatients. (3)
      Two trials against fluoxetine and three against imipramine showed no difference
      in efficacy. (4) The adverse effect profile of venlafaxine is similar to that of
      serotonin reuptake inhibitors.  At high doses (over 200 mg/day), venlafaxine can
      provoke arterial hypertension. Amphetamine-like behavioural effects cannot be
      ruled out.

PMID- 10342951
TI  - Cardiovascular risk of oral contraceptives. Low, and mainly in women at risk.
AB  - (1) The precise cardiovascular risk of oral contraceptives is poorly known
      because of a lack of reliable clinical studies and the numerous potential biases
      in epidemiological studies. (2) The absolute risk of coronary events is very low
      in women under 35 who are non smokers, have no history of coronary heart disease
      and have normal blood pressure.  In women over 35, smoking over 10 cigarettes a
      day and arterial hypertension substantially increase the risk of coronary heart
      disease. (3) The absolute risk of stroke is low in young women who are not
      hypertensive and do not smoke.  It is higher in the case of arterial
      hypertension. (4) The absolute risk of deep vein thrombosis is increased but
      remains moderate.  Obesity, a family history of deep vein thrombosis, and
      hereditary clotting disorders are risk factors. (5) The cardiovascular risks
      linked to oral contraception seem to disappear after cessation. (6) The use of
      oral contraceptives with very low doses of oestrogen (less than 50 mug
      ethinylestradiol) reduces the associated risk of stroke.  The risk of deep vein
      thrombosis is probably higher with combined contraceptives containing a third
      generation progestagen (desogestrel or gestoden). (7) The coronary and
      cerebrovascular risks of progestagen-only contraceptives are poorly documented. 
      Low-dose progestagen-only oral contraceptives have little effect on clotting
      factors or on carbohydrate and lipid metabolism. There may be a risk of deep vein
      thrombosis, however, with this type of contraceptive. (8) History, physical
      examination and simple laboratory tests before prescribing or renewing oral
      contraceptives are sufficient to detect the main contraindications, i.e. arterial
      hypertension, a history of coronary or cerebrovascular conditions, deep vein
      thrombosis, hypercholesterolaemia exceeding 3 g/l, hypertriglyceridaemia
      exceeding 3 g/l, unusually severe headache on a combined oral contraceptive and
      prolonged immobilisation.  However, a combined oral contraceptive can be
      considered for some women with cardiovascular risk factors such as moderate
      hypercholesterolaemia or hypertriglyceridaemia, well-controlled insulin-dependent
      diabetes, uncomplicated cardiac valve disease, migraine not worsened by a
      combined oral contraceptive, varicose veins or a family history of deep vein
      thrombosis. (9) Pharmacists should be aware of these risk factors so that they
      can advise patients to see a doctor if new health problems arise between visits.

PMID- 10342952
TI  - Prevention of haemorrhagic disease of the newborn. Routine vitamin K1
      administration is justified.
AB  - (1) Haemorrhagic disease of the newborn is due to vitamin K deficiency.  Although
      rare, it is life-threatening and can have neurological sequelae.  Prevention is
      based on routine vitamin K1 administration at birth. (2) The oral route is
      suitable for healthy term neonates, but dosing must be repeated if the infant is
      mainly breastfed. (3) The intramuscular route is reserved for neonates at risk
      (prematurity, neonatal disease, maternal treatment with antiepileptics or
      antibiotics), because of a possible risk of carcinogenicity.

PMID- 10342953
TI  - When the helpers need a hand.
AB  - Family caregivers, who must balance work responsibilities, stretch their budgets
      and handle the added stress of looking after an elderly family member or friend,
      are an emerging market in need of respite services, targeted consumer goods and
      financial planning.

PMID- 10342955
TI  - Conference transcript: Socially-Assisted Dying: Media, Money & Meaning.

PMID- 10342954
TI  - Introduction to conference transcript: Socially-Assisted Dying: Media, Money &
      Meaning.

PMID- 10342956
TI  - Institutional analysis and physicians' rights after Vacco v. Quill.

PMID- 10342957
TI  - A modern scourge: parents scratch their heads over lice.

PMID- 10342959
TI  - Seductive cigars: new ways to addict the next generation.

PMID- 10342960
TI  - Hormone mimics: they're in our food; should we worry?

PMID- 10342958
TI  - Pain creams: can you find relief in a tube?

PMID- 10342961
TI  - Viagra: how safe is the new 'sex pill'?

PMID- 10342962
TI  - Checkups: are you getting what you need?

PMID- 10342963
TI  - Acupuncture: what the experts think now.

PMID- 10342964
TI  - Medicare: new choices, new worries.

PMID- 10342965
TI  - In search of quality health care.

PMID- 10342966
TI  - Cholesterol drugs: should you be taking one?

PMID- 10342967
TI  - Vulnerability factors in Sylvia Plath's suicide.
AB  - Using the conceptual framework of a developmental pathway, this study links
      together events in the life of Sylvia Plath, beginning with her father's death
      when she was 8 years old and ending with her suicide at age 30.  Unresolved grief
      for her father led to a symbiotic attachment to her mother characterized by a
      compulsive drive for achievement and praise.  After a near-fatal suicide attempt
      at age 20 following failure to meet perfectionistic ideals, she recompensated,
      transferring her dependency needs into a symbiotic marriage to an English poet
      she narcissistically idealized. Her suicide followed soon after the collapse of
      the marriage. Emphasis is placed throughout on her unwillingness to accept
      personal imperfections, as well as on the search for a father substitute.

PMID- 10342968
TI  - Sylvia Plath: a protocol analysis of her last poems.
AB  - Personal documents have a significant place in psychological research.  Suicide
      notes, diaries, novels, poems, and so on allow us to better understand the
      suicidal mind.  The works of Sylvia Plath--a poet who killed herself at age 30-
      are prime examples for such protocol study.  This article examines the last 6
      months of Plath's poetry, revealing a suicidal malaise.  Associating the results
      to the lives of Cesare Pavese and the case study of Natalie, a Terman-Shneidman
      subject of the intellectually gifted, the study shows a unit thema that
      facilitates the process of death.  The poems reveal such themes as unbearable
      pain, loss, and abandonment that likely contributed significantly to death
      becoming the only solution.

PMID- 10342969
TI  - Suicide and creativity: the case of Sylvia Plath.
AB  - This article explores the idea that although much can be learned by viewing
      Sylvia Plath's poetry as an expression of her thinking and affect, additional
      insights are afforded by reversing the typical direction of effect and by viewing
      Plath's affect, and in particular her depression, as a result of her writing.
      Consistent with this interpretation is Plath's huge investment in writing.  This
      may have contributed to the sensitivity that predisposed her to stress and
      depression.  This perspective is tied to the existing creativity literature and
      interwoven and contrasted with existing descriptions of Plath's work and tragic
      death.

PMID- 10342970
TI  - Theories of suicidal behavior applied to Sylvia Plath.
AB  - The suicide of Sylvia Plath is examined from the perspective of 15 theories of
      suicidal behavior and is found to fit best with psychoanalytic and cognitive
      theories of suicide, in particular those of Aaron Beck, Henry Murray, and Edwin
      Shneidman.

PMID- 10342971
TI  - The treatment of Sylvia Plath.
AB  - Although Sylvia Plath apparently sought psychotherapeutic help following her
      first suicide attempt in her twenties, she did not have access to specialized
      forms of suicide assessment and intervention available in the present day.  In
      this 'thought experiment,' the authors drew on material available in her journals
      and literary work to formulate a treatment plan for Plath, were she to be seen by
      a contemporary psychotherapist skilled in voice therapy. In particular, they
      focused on her inwardness, her preference for fantasy gratification, her self
      denial, her addictive attachment to her mother and husband, and her negative
      thoughts toward self and cynicism toward others.  The authors then sketched out
      suicide risk assessment procedures as they might be applied in her case, and
      illustrated a hypothetical voice therapy session designed to ameliorate her
      pertubation and lethality during her last suicidal crisis.

PMID- 10342973
TI  - When pain becomes never ending.

PMID- 10342972
TI  - Communicating to beneficiaries about Medicare+Choice: opportunities and pitfalls.

PMID- 10342974
TI  - Revising the TEC criteria.

PMID- 10342975
TI  - Intravenous immune globulin for multiple sclerosis.

PMID- 10342976
TI  - Ketogenic diet for the treatment of children with refractory epilepsy.

PMID- 10342977
TI  - Sacral nerve stimulation for the treatment of urge incontinence.

PMID- 10342978
TI  - Treatment of tobacco dependence: innovative regulatory approaches to reduce death
      and disease: preface.

PMID- 10342979
TI  - Federal regulation of tobacco products and products that treat tobacco
      dependence: are the playing fields level?

PMID- 10342980
TI  - Tobacco product regulation: context and issues.

PMID- 10342981
TI  - Tobacco-dependence medications: public health and regulatory issues.

PMID- 10342982
TI  - Conference on tobacco dependence: innovative regulatory approaches to reduce
      death and disease: selected excerpts from conference proceedings.

PMID- 10342983
TI  - The response to health care reform by the pharmaceutical industry.

PMID- 10342984
TI  - The FDA's regulation of pharmaceutical communications in the context of managed
      care: a suggested approach.

PMID- 10342985
TI  - Direct-to-OTC marketing of drugs: possible approaches.

PMID- 10342986
TI  - Lessons learned from good manufacturing practice noncompliance.

PMID- 10342987
TI  - Daubert v. Merrell Dow: missed opportunity.

PMID- 10342988
TI  - Patient package inserts: the proper prescription?

PMID- 10342989
TI  - Prescription for the Orphan Drug Act: the impact of the FDA's 1992 regulations
      and the latest congressional proposals for reform.

PMID- 10342990
TI  - Congressional control over agency rulemaking: the Nutrition Labeling and
      Education Act's hammer provisions.

PMID- 10342991
TI  - The preemptive scope of the Medical Device Amendments of 1976.

PMID- 10342992
TI  - Daubert v. Merrell Dow Pharmaceuticals: active judicial scrutiny of scientific
      evidence.

PMID- 10342993
TI  - Living with and reforming the Delaney Clause.

PMID- 10342994
TI  - A de minimis exception to the Delaney Clause: a reassessment of Les v. Reilly.

PMID- 10342995
TI  - The Dietary Supplement Health and Education Act.

PMID- 10342996
TI  - The changing environment in health care.

PMID- 10342997
TI  - Recent multistate enforcement initiatives: prescription drug promotional
      practices.

PMID- 10342998
TI  - Competition and antitrust enforcement in the changing pharmaceutical marketplace.

PMID- 10342999
TI  - Drug marketing from an Office of Inspector General enforcement perspective.

PMID- 10343000
TI  - Pharmaceutical industry restructuring and new marketing approaches: enforcement
      responses.

PMID- 10343001
TI  - Remarks by the Commissioner of Food and Drugs.

PMID- 10343002
TI  - Current issues in the pioneer versus generic drug wars.

PMID- 10343003
TI  - Dietary supplements of botanicals and other substances: a new era of regulation.

PMID- 10343004
TI  - The Federal Trade Commission's regulation of advertising claims for dietary
      supplements.

PMID- 10343006
TI  - USDA's agenda for change to improve food safety.

PMID- 10343005
TI  - The statutory basis for the FDA's Food Safety Assurance Programs: from GMP, to
      emergency permit control, to HACCP.

PMID- 10343007
TI  - Keeping food safe.

PMID- 10343008
TI  - Current regulatory issues related to animal drug use.

PMID- 10343009
TI  - The impact of the new products liability Restatement on prescription products.

PMID- 10343010
TI  - Assessments of pharmaceutical advertisements: a critical analysis of the
      criticism.

PMID- 10343011
TI  - Current product equivalency issues.

PMID- 10343012
TI  - Effects of products liability on bulk suppliers of biomaterials.

PMID- 10343013
TI  - Medical device regulation in the European Union.

PMID- 10343014
TI  - Medical technology and competitiveness in the world market: reinventing the
      environment for innovation.

PMID- 10343015
TI  - The Mammography Quality Standards Act of 1992: history and process.

PMID- 10343016
TI  - Challenges in human subject protection.

PMID- 10343017
TI  - The Food and Drug Administration's early access and fast-track approval
      initiatives: how have they worked?

PMID- 10343018
TI  - Stoning a dead bird: advertising limits on approved new drugs.

PMID- 10343019
TI  - Consumer-directed advertising of contraceptive drugs: the FDA, Depo-Provera, and
      product liability.

PMID- 10343020
TI  - How do we maintain U.S. global food edge?

PMID- 10343021
TI  - New packaging technologies.

PMID- 10343022
TI  - ERISA Health Plan denials: exploring models for external review.

PMID- 10343023
TI  - Protecting the confidentiality of health information.

PMID- 10343024
TI  - FDA and the 1997 Tobacco Settlement: no rules for twelve years?

PMID- 10343025
TI  - The right to a jury trial in actions under the Waxman-Hatch Act.

PMID- 10343027
TI  - Extralabel drug use and compounding in veterinary medicine.

PMID- 10343026
TI  - The reformation of animal drug law: the impact of 1996.

PMID- 10343028
TI  - Major issues in marketing regulation.

PMID- 10343029
TI  - Understanding government regulation of the marketing and advertising of medical
      devices, drugs, and biologics: the challenges of the Internet.

PMID- 10343030
TI  - The progress of global harmonization and mutual recognition efforts for medical
      devices.

PMID- 10343031
TI  - Are functional foods the solution to dysfunctional diets? A review of U.S.
      regulatory requirements and lessons from abroad.

PMID- 10343032
TI  - Update on implementation of the final rule on pathogen reduction and HACCP.

PMID- 10343033
TI  - Status of seafood HACCP.

PMID- 10343034
TI  - Delivering on HACCP's promise to improve food safety: a comparison of three HACCP
      regulations.

PMID- 10343035
TI  - The truth and consequences of "standards of identity".

PMID- 10343036
TI  - Quality control and good manufacturing practices: safety and efficacy of
      commercial herbals.

PMID- 10343037
TI  - Bibliography on physician-assisted suicide.

PMID- 10343038
TI  - Fifty years ago.

PMID- 10343039
TI  - Human biological drug regulation: past, present, and beyond the year 2000.

PMID- 10343040
TI  - Fifty years of cosmetic safety: a government and industry partnership.

PMID- 10343041
TI  - Trends and events in FDA regulation of medical devices over the last fifty years.

PMID- 10343043
TI  - The history of food law.

PMID- 10343042
TI  - Fifty years of drug amendments revisited: in easy-to-swallow capsule form.

PMID- 10343044
TI  - The FDA and "privatization"--the drug approval process.

PMID- 10343046
TI  - Performance measurement: honing our health care quality tools.

PMID- 10343045
TI  - California health care: the right road to travel?

PMID- 10343047
TI  - Retooling tax subsidies for health coverage: old ideas, new politics.

PMID- 10343048
TI  - Understanding hepatitis C infection.

PMID- 10343049
TI  - Designating research-urgent treatments.

PMID- 10343050
TI  - Herceptin : new treatment and new questions.

PMID- 10343051
TI  - The hidden fat: trans fat is unlabeled--and unhealthy.

PMID- 10343052
TI  - Will congressional action go up in smoke? Overcoming obstacles in granting the
      FDA jurisdiction over tobacco products.

PMID- 10343053
TI  - Section 8(c) of the proposed Restatement (Third) of Torts: is it really what the
      doctor ordered?

PMID- 10343054
TI  - Choosing ignorance in the manufacture of toxic products.

PMID- 10343055
TI  - Beyond asbestos and environmental litigation: coverage disputes in the twenty
      first century.

PMID- 10343056
TI  - Social network factors associated with perceived quality of life. The San Luis
      Valley Health and Aging Study.
AB  - Demographic and social network factors associations with perceived quality of
      life (PQOL) were examined in a sample of rural Hispanic and non-Hispanic White
      (NHW) elderly.  A 20-item PQOL scale measured participants' satisfaction with
      multiple facets of their lives.  Age, gender, marital status, and living alone
      were not associated with this outcome.  Hispanic persons with higher incomes had
      consistently higher ratings of quality of life compared to NHWs.  More education
      was associated with a higher PQOL rating only among NHWs.  More close friends and
      relatives, visiting in homes, and participation in outside activities were all
      independently related to PQOL.  Interaction tests showed that the impact of
      social networks was stronger in NHWs.  These findings suggest that network size
      and contact are important social factors that can improve quality of life for
      both ethnic groups. However, differences may need to be examined when judging the
      magnitude of these associations and when planning interventions.

PMID- 10343057
TI  - Significance of plasma and peripheral blood mononuclear cell derived HIV-1
      sequences in establishing epidemiologic linkage between two individuals multiply
      exposed to HIV-1.
AB  - Establishing epidemiologic linkage in individuals multiply exposed to HIV can be
      a difficult task. To date, only peripheral blood mononuclear cell (PBMC)-derived
      sequences have been used in studying HIV-1 transmission between individuals. So
      far, the combined utility of plasma and PBMC-derived HIV-1 sequences has not been
      assessed in establishing epidemiologic linkage in people involved in transmission
      of HIV. In this study, both PBMC (DNA) and plasma (RNA) derived viral
      quasispecies was used in establishing epidemiologic linkage between two infected
      individuals (B-90 and B-69) multiply exposed to HIV-1 via injecting drug use. A
      detailed sequence, and phylogenetic analyses of HIV-1V3 region quasispecies
      derived from these two compartments clearly demonstrated compartmentalization of
      viral quasispecies between PBMC and plasma. More importantly, these data also
      demonstrate that in order to establish epidemiologic linkage between individuals
      multiply exposed to HIV-1, analyses of viral strains from both plasma and PBMC
      compartments may be necessary. The PBMC compartment alone may not provide
      sufficient information on epidemiologic linkage, overall diversification of viral
      quasispecies, replacement of older strains and the emergence of new viral
      recombinant strains in vivo. These are the first analyses that demonstrate the
      incremental value of plasma derived sequences, when used in conjunction with PBMC
      derived sequences, in establishing the epidemiologic linkage between individuals
      multiply exposed to HIV parenterally. Further, the plasma derived HIV-1 sequences
      may prove to be invaluable in predicting a recent transmission between two
      epidemiologically-linked individuals.

PMID- 10343058
TI  - Comparison of the abilities of Salmonella typhimurium rpoS, aroA and rpoS aroA
      strains to elicit humoral immune responses in BALB/c mice and to cause lethal
      infection in athymic BALB/c mice.
AB  - Salmonella typhimurium rpoS and rpoS aroA mutants are effective live vaccines in
      the murine model of salmonellosis (Coynault et al., Mol. Microbiol. 1996; 22: 149
      60). Here, we further investigate the characteristics of these vaccines. The
      systemic humoral response induced by S. typhimurium rpoS, aroA and rpoS aroA
      vaccine candidates against S. typhimurium LPS was studied by ELISA. In BALB/c
      mice, the rpoS aroA strain induced a systemic anti-LPS humoral response similar
      to that induced by the rpoS and aroA strains. The virulence of aroA and rpoS aroA
      vaccines in nude (nu/nu) BALB/c mice was also compared. Salmonella typhimurium
      aroA and rpoS aroA vaccines both produced slowly progressing lethal infections in
      athymic mice inoculated i.p. but the rpoS aroA strain was more attenuated than
      the aroA strain, as determined by time to death and bacterial counts in spleens.
      Finally, a rpoS mutant of Salmonella dublin conferred protection in mice against
      an oral challenge with a wild-type strain of S. dublin whereas a rpoS mutant of
      S. typhimurium did not. This suggests that the protection provided by the S.
      typhimurium rpoS vaccine is serotype-dependent.

PMID- 10343060
TI  - Mechanisms of Staphylococcus aureus invasion of cultured osteoblasts.
AB  - Staphylococcus aureus is a bacterial pathogen causing approximately 80% of all
      cases of human osteomyelitis. This bacterium can adhere to and become
      internalized by osteoblasts and previous studies indicate that osteoblasts are
      active in the internalization process. In the current study, we examined the
      roles of microfilaments, microtubules and clathrin-dependent receptor-mediated
      endocytosis in the internalization of S. aureus by MC3T3-E1 mouse osteoblast
      cells. Microfilament and microtubule polymerization was inhibited with
      cytochalasin D and colchicine. Clathrin-coated pit formation was examined by
      using the transaminase inhibitor, monodanslycadaverine. The results of this study
      indicate that mouse osteoblasts utilize actin microfilaments, microtubules and
      clathrin-coated pits in the internalization of S. aureus; however, microfilaments
      seem to play the most significant role in the invasion process.

PMID- 10343059
TI  - Comparison of the humoral and cellular immune responses to two preparations of
      Cryptosporidium parvum CP15/60 recombinant protein.
AB  - This study compares the immune responses produced by immunising mice and rabbits
      with two preparations of the recombinant 15/60 kDa protein of Cryptosporidium
      parvum. Genomic C. parvum DNA was amplified and the recombinant protein was
      synthesized as a fusion protein with glutathione-S-transferase in Escherichia
      coli and in the eukaryotic system of baculovirus/insect cells. Both recombinant
      proteins induced similar levels of serum antibodies against the fusion
      recombinant protein, but the eukaryotic recombinant protein triggered a stronger
      humoral response to C. parvum. Similarly, increased lymphoproliferation occurred
      only after stimulation of spleen cells from mice immunised with the eukaryotic
      recombinant protein. This suggests that the eukaryotic protein is a better
      candidate for immunological studies on cryptosporidiosis.

PMID- 10343062
TI  - Volume contents and index 

PMID- 10343061
TI  - Cytokine profiles following interaction between bovine alveolar macrophages and
      Pasteurella haemolytica.
AB  - Pasteurella haemolytica is a gram negative bacterium frequently isolated from the
      lungs of calves suffering from a fibrinous pneumonic condition known as shipping
      fever. To understand the pathogenesis of this disease, we investigated the
      induction of cytokin gene expression in cultures of bovine alveolar macrophages
      (BAM) stimulated with heat-killed P. haemolytica. Northern blot analysis of total
      RNA showed that P. haemolytica induced early, abundant, and consistent synthesis
      of IL-1, TNF-alpha, and IL-8 mRNA. Cytokine mRNAs were detected within 1 hr post
      stimulation with heat-killed P. haemolytica. IL-1 and IL-8 mRNA accumulated to
      high levels with increase in stimulation time, whereas TNF-alpha mRNA clearly
      declined by 4 and 8 h post stimulation. IL-1, TNF-alpha, and IL-8 proteins were
      also secreted into the culture medium of BAM stimulated with heat-killed P.
      haemolytica. All three proteins were detected at high levels 8 and 12 h post
      stimulation with P. haemolytica. BAM cells treated with bovine interferon-alpha
      and then stimulated with P. haemolytica produced higher amounts of IL-1, IL-8 and
      TNF-alpha proteins compared to BAM stimulated with P. haemolytica alone. These
      findings demonstrate the powerful and selective induction of cytokine mRNA and
      protein synthesis in BAM stimulated with heat-killed P. haemolytica and may
      explain certain aspects of shipping fever pathogenesis.

PMID- 10343063
TI  - Understanding the Dynamics of Leadership: The Role of Follower Self-Concepts in
      the Leader/Follower Relationship.
AB  - In this paper we integrate recent theory and research on the self-concept with
      leadership theory. We conceptualize the self as being defined at three levels:
      the individual, interpersonal, and group levels. The effects of the self on
      information processing and behavior are mediated by the working self-concept,
      which is composed of self-views, possible selves, and goals (standards). Leaders
      are seen as producing short-run changes by influencing the working self-concept
      and more enduring changes through the development of chronic schema. Subordinates
      are also seen as influencing leaders' self-schema, both individually and
      collectively. Both practical and theoretical implications of this perspective are
      discussed. Copyright 1999 Academic Press.

PMID- 10343064
TI  - The Effects of Framing, Reflection, Probability, and Payoff on Risk Preference in
      Choice Tasks.
AB  - A meta-analysis of Asian-disease-like studies is presented to identify the
      factors which determine risk preference. First the confoundings between
      probability levels, payoffs, and framing conditions are clarified in a task
      analysis. Then the role of framing, reflection, probability, type, and size of
      payoff is evaluated in a meta-analysis. It is shown that bidirectional framing
      effects exist for gains and for losses. Presenting outcomes as gains tends to
      induce risk aversion, while presenting outcomes as losses tends to induce risk
      seeking. Risk preference is also shown to depend on the size of the payoffs, on
      the probability levels, and on the type of good at stake (money/property vs human
      lives). In general, higher payoffs lead to increasing risk aversion. Higher
      probabilities lead to increasing risk aversion for gains and to increasing risk
      seeking for losses. These findings are confirmed by a subsequent empirical test.
      Shortcomings of existing formal theories, such as prospect theory, cumulative
      prospect theory, venture theory, and Markowitz's utility theory, are identified.
      It is shown that it is not probabilities or payoffs, but the framing condition,
      which explains most variance. These findings are interpreted as showing that no
      linear combination of formally relevant predictors is sufficient to capture the
      essence of the framing phenomenon. Copyright 1999 Academic Press.

PMID- 10343065
TI  - Are Actions Regretted More Than Inactions?
AB  - Several researchers have claimed that negative outcomes produce greater regret
      when they result from actions rather than from failures to act (Gleicher et al.,
      1990; Kahneman & Tversky, 1982; Landman, 1987). We investigated this claim by
      asking participants to write descriptions of strongly regretted events in their
      own lives and to rate the intensity of the regrets. Participants reported more
      inaction than action regrets, and, contrary to prior research findings, regrets
      produced by actions and inactions were equally intense. We conjecture that many
      factors that affect the content of real-life regrets are eliminated in studies of
      hypothetical regret. In real life, actions and inactions do not generally produce
      the same outcomes. Furthermore, actions and inactions may differ in how easily
      one can anticipate the potential for harm. Specifically, it is plausible that
      people control their actions to avoid potential regrets, leaving themselves
      vulnerable to regrets from inactions. Copyright 1999 Academic Press.

PMID- 10343066
TI  - Introduction 

PMID- 10343067
TI  - The role of HHV-8 in Kaposi's sarcoma.
AB  - The epidemiology of Kaposi's sarcoma (KS) amongst North American and Northern
      European patients with AIDS suggests that an infectious agent other than HIV is
      involved in its pathogenesis. Several lines of evidence indicate that human
      herpesvirus 8 (HHV-8), also termed Kaposi's sarcoma associated herpesvirus, is
      the sought after agent. DNA of HHV-8 is invariably found in all forms of KS where
      the virus is present in the KS spindle cell. In contrast, HHV-8 DNA is not
      regularly detected in most other malignancies. Antibodies against HHV-8 are more
      frequently found in groups at risk of KS, and HHV-8 seroconversion precedes KS
      development. Several HHV-8 genes have been identified that exhibit transforming
      potential in cell culture systems. In addition, the virus encodes and induces
      several cytokines and angiogenic factors. This is of particular interest as
      models of KS pathogenesis developed before the discovery of HHV-8 emphasized the
      importance of inflammatory cytokines. Although the expression pattern of viral
      genes in KS is not certain yet, it appears likely that the pathogenetic role of
      HHV-8 in KS may be rather complex and differs from other virus-induced
      malignancies. 1999 Academic Press.

PMID- 10343068
TI  - The role of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) in
      lymphoproliferative diseases.
AB  - The Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus
      8 (HHV-8), has been found to be present in a limited subset of
      lymphoproliferative disorders. Among these are the primary effusion lymphomas,
      formerly designated body cavity-based lymphomas, a rare type of malignant
      lymphoma which possesses an unusual set of clinical and biologic features,
      suggesting that they represent a distinct disease entity. This virus is also
      present in a large proportion of cases of multicentric Castleman's disease,
      particularly those associated with HIV-infection. In addition, KSHV has been
      implicated in the pathogenesis of multiple myeloma, where it has been identified
      in bone marrow adherent cells but not in the neoplastic myeloma plasma cell
      population. However, the latter finding remains controversial. The discovery of
      KSHV in a subset of malignant lymphomas has allowed the development of lymphoma
      cell lines which now serve as biological reagents for propagating the virus, as a
      substrate for serologic assays, and as a model system for pathobiologic studies.
      This review discusses the features of KSHV-associated lymphoproliferative
      disorders and the evidence supporting its role in the pathogenesis of these
      diseases.

PMID- 10343069
TI  - Seroepidemiology of Kaposi's sarcoma-associated herpesvirus (KSHV).
AB  - Since the Kaposi's sarcoma-associated herpesvirus (KSHV also referred to as HHV
      8, human herpesvirus-8) was discovered it has been shown that the virus is
      associated with all cases of Kaposi's sarcoma (KS) classical, endemic, or AIDS
      associated. In the numerous countries where the seroprevalence of this virus has
      been studied, data demonstrate that the virus is not ubiquitous in general
      healthy human populations as is the case with other human herpesviruses. Many
      seroprevalence studies to detect antibodies to HHV-8 have now been conducted
      using a variety of immunologic techniques. While these assays are not in total
      agreement and may overstate or understate the positivity of sera in the general
      population, they all show similar general antibody trends. For general
      populations the seroprevalence in sub-Saharan Africa is the highest,
      approximately 40% positive; in Mediterranean countries the seroprevalence is
      approximately 10%; whereas northern European, southeast Asian, and Caribbean
      countries have seroprevalence rates in the 2-4% range. In the United States, a
      'mixing bowl' country the seroprevalence is in the range of 5-20%. In people with
      KS whether AIDS associated, classical, or endemic and other HHV-8 associated
      diseases such as multicentric Castleman's disease and certain body cavity
      lymphomas (BCL), also called primary effusion lymphoma (PEL) the seroprevalency
      rates are >90%. In populations with HIV-1 infection but no diagnosis of KS, the
      seroprevalency rates are elevated (20-50%) above those in the general population
      except in southeast Asia and the Caribbean where no AIDS associated KS has been
      reported. No correlation has been found between the presence of KSHV antibodies
      and other malignancies.

PMID- 10343070
TI  - KSHV strains: the origins and global spread of the virus.
AB  - Nucleotide sequence analysis at five distinct loci across the 140, 000 bp genomes
      of more than 60 KSHV samples from KS and PEL tumors from North America, Africa,
      the Middle East, Asia and the Pacific revealed that they cluster into four major
      subtypes (A, B, C and D) that have close associations with the geographic and
      ethnic background of the patients. In particular, the ORF-K1 protein subtypes
      encoded at the extreme LHS of the genome display up to 30% amino acid variability
      resulting from 85% non-synonymous nucleotide substitution rates. In addition, two
      alternative highly diverged forms of the complex spliced ORF-K15 gene (P or M)
      map at the extreme RHS of the genome and are essentially unlinked to the ORF-K1
      genotypes. We conclude that: (1) KSHV is an ancient human virus with several
      major subtypes that reflect the migrationary divergence of modern human
      populations over the past 35,000-60,000 years; (2) the novel immunoglobulin
      receptor-like signal transducing protein ORF-K1 is subject to unusually strong
      biological selective pressures; and (3) a minority of KSHV genomes have undergone
      recombination events with a related virus producing two different alleles of the
      ORF-K15 latency membrane protein.

PMID- 10343071
TI  - The descent of human herpesvirus 8.
AB  - Analysis of conserved herpesvirus genes shows that human herpesvirus 8 (HHV8)
      belongs to a clade of primate herpesviruses within the gamma2 sublineage.
      Overall, this clade has developed by cospeciation with host species. Seventeen
      genes of HHV8 and its nearest relatives lack simple homologues in other
      herpesviruses, and eight of these have known mammalian homologues, presumed to be
      the sources of the HHV8 versions. Comparative analyses yield further insights
      into the source or time of acquisition for several of these genes. All were
      acquired by the HHV8 lineage in the very distant past. Two unusual processes are
      manifest in the contemporary evolution of HHV8. First, the K1 gene is uniquely
      undergoing a process of extensive and positively selected substitution, of
      unknown significance. Secondly, the K15 gene has been substituted in some
      lineages by a distant homologue, presumably by recombination with an unknown
      herpesvirus. While available data are otherwise compatible with a cospeciational
      relationship between HHV8 and the human species, they do not exclude relatively
      recent transfer to humans from another primate host.

PMID- 10343072
TI  - VEGFs, receptors and angiogenesis.
AB  - Angiogenesis, the formation of new blood vessels from pre--existing ones, is
      central for both normal development and homeostasis as well as in certain
      pathological conditions. The vascular endothelial growth factors (VEGFs) and
      their receptors are prime regulators of both physiological and pathological
      angiogenesis. The different VEGFs have overlapping but specific roles in
      controlling the growth of new blood vessels. The VEGF receptors transduce signals
      mediating endothelial cell proliferation, migration, organization into functional
      vessels and remodeling of the vessel network. In recent years, rapid progress has
      been made in understanding the receptor-ligand interactions that orchestrate the
      neovascularization process.

PMID- 10343073
TI  - Viral encoded cyclins.
AB  - Cyclins are known effectors of cellular proliferation. While originally
      considered as the product of cellular genes, it is now clear that representatives
      of this class of proteins can be encoded by certain viruses. One of these viruses
      is HHV-8, a gamma herpesvirus implicated as a causative agent of Kaposi's Sarcoma
      and lymphomas in humans. The significance of the virally encoded cyclin proteins
      in viral propagation is as yet unclear. However, the fact that deregulation of
      cellular cyclin expression is a known event in tumour development suggests that
      the virally encoded cyclins could be part of a mechanism utilised by these
      viruses to induce tumour formation.

PMID- 10343074
TI  - Herpesvirus saimiri as a model for gammaherpesvirus oncogenesis.
AB  - Herpesvirus saimiri (HVS) causes T-lymphoproliferative dis-$borders in several
      New World and Old World primate species and in certain rabbits.In vitro infection
      leads to permanent growth of primary T cells of primate and human origins. The
      transformation-relevant proteins of HVS interact with cellular proto-oncoproteins
      which results in cell growth transformation. In addition, virus-encoded cellular
      homologues may contribute to transformation or persistence of HVS by altering
      cellular signal transduction and deregulating cell growth control. Because of the
      presence of a permissive cell culture system and in vitro Land in vivo
      transformation assays, HVS provides a unique opportunity to investigate the
      mechanisms of cancer induction by oncogenic herpesviruses.

PMID- 10343075
TI  - Homophilic PECAM-1(CD31) interactions prevent endothelial cell apoptosis but do
      not support cell spreading or migration.
AB  - PECAM-1 (CD31) is a highly abundant cell surface glycoprotein expressed on
      haemopoietic and endothelial cells. As well as mediating homophilic (PECAM
      1/PECAM-1) adhesion, PECAM-1 can also bind the integrin alphavbeta3. Both PECAM-1
      and alphavbeta3 have been shown to have roles in regulating angiogenesis,
      endothelial tube formation and in the case of alphavbeta3, endothelial cell
      apoptosis. In this study we show that despite being expressed at equivalent
      levels, endothelial alphavbeta3 is not a ligand for PECAM-1. Rather, PECAM-1
      supports homophilic binding on HUVEC with similar characteristics to those we
      have previously reported for leukocytes and becomes tyrosine phosphorylated after
      homophilic PECAM-1 and integrin/fibronectin engagement. Immunoprecipitation
      studies show that in addition to SHP-2, tyrosine phosphorylated PECAM-1 can
      interact with at least four other phosphoproteins in pervanadate stimulated
      HUVEC. While PECAM-1/PECAM-1 interactions support robust endothelial cell
      adhesion, they do not support cell spreading or migration. In addition PECAM-1
      homophilic adhesion rescues HUVEC from serum deprivation-induced apoptosis. Taken
      together our results indicate that PECAM-1 homophilic interactions play an
      important role in interendothelial cell adhesion, survival and signalling.

PMID- 10343076
TI  - Salt and hypertension in end-stage renal disease.
AB  - Salt and fluid overload play an important role in the pathogenesis of
      hypertension in patients with end-stage renal disease. However, in the individual
      patient, the relation between salt loading and blood pressure response is
      variable and appears to be influenced by various neurohumoral regulatory
      mechanisms. This may also have implications for the pathogenesis of structural
      cardiovascular abnormalities in patients with end-stage renal disease.

PMID- 10343077
TI  - Reduced blood bcl-2 protein concentration in patients on hemodialysis.
AB  - The concentrations of bcl-2 protein that can block programmed cellular death in
      various cell lines were evaluated in blood samples from 10 uremic patients on
      hemodialysis, 10 uremics not yet on hemodialysis, and in 10 healthy controls. The
      bcl-2 protein variations (in uremics on dialysis) were ascertained in patients
      during the dialysis session. Oxidative stress was evaluated in all groups by
      assaying the products of intraerythrocytic lipoperoxidation. Dialyzed and
      nondialyzed uremic patients had higher bcl-2 protein concentrations than healthy
      subjects. Dialysis causes a significant reduction in the concentrations of bcl-2
      protein which becomes statistically significant during the 3rd hour. In both
      groups of uremic patients a positive correlation was found between bcl-2 protein
      and products of lipoperoxidation.

PMID- 10343078
TI  - Impact of recombinant human erythropoietin treatment on left ventricular
      hypertrophy and cardiac function in dialysis patients.
AB  - The results of anemia correction by recombinant human erythropoietin (rHuEPO)
      therapy with regard to cardiac function and left ventricular hypertrophy in
      dialysis patients are controversially discussed. The aim of the study was to
      assess the effects of therapy rHuEPO on cardiac morphology and function in
      dialysis patients. We studied 11 clinically stable hemodialysis patients with
      severe renal anemia (hematocrit <27%) and increased left ventricular mass index
      (LVMi) with no history of coronary or valvular heart disease, systemic disease,
      severe hyperparathyroidism, hypertension stage 2 or higher, transfusion-dependent
      anemia, and concurrent rHuEPO treatment. The patients were treated with rHuEPO
      administered subcutaneously once or twice weekly at a mean dose of 80 +/- 31
      IU/kg week until the hematocrit was >30% and underwent a complete Doppler
      echocardiographic study at baseline and at follow-up (after 12.2 +/- 2.9 months).
      At follow-up, ejection fraction and fractional shortening significantly increased
      from 62.7 +/- 13.8 to 67.8 +/- 9. 7% (p < 0.05) and from 35.5 +/- 9.8 to 39.4 +/-
      7.1% (p < 0.05), respectively, whereas mean velocity of circumferential fiber
      shortening demonstrated a trend towards amelioration from 1.18 +/- 0. 23 to 1.27
      +/- 0.27 circ/s (n.s.). LVMi and morphological data remained unchanged throughout
      the study. Nevertheless, LVMi changes showed two different behaviors with respect
      to baseline values: in 6 patients with higher baseline values, LVMi decreased
      from 229 +/- 36 to 191 +/- 45 g/m2 (p < 0.05), while it worsened in 5 patients
      with less marked LVMi, increasing from 141 +/- 32 to 186 +/- 40 g/m2 (p < 0.05).
      Our data demonstrate that partial correction of renal anemia with rHuEPO therapy
      seems to improve cardiac performance and to induce a regression of left
      ventricular hypertrophy, particularly in patients with greater baseline
      hypertrophy, ultimately confirming the multifactorial pathogenesis of left
      ventricular hypertrophy.

PMID- 10343079
TI  - Modulation of neutrophil apoptosis by uremic plasma during hemodialysis.
AB  - During hemodialysis (HD), blood-membrane interactions lead to activation of
      several circulating cells and plasma proteins. The resultant activation and/or
      release of mediators can modulate the structure, function and survival of
      circulating neutrophils. Little is known of plasma factors that influence
      apoptosis of neutrophils in hemodialyzed patients. Hence, we investigated the
      effect of uremic plasma obtained during HD on the survival of neutrophils
      obtained from healthy volunteers. Neutrophils harvested from healthy volunteers
      were incubated in ultrafiltered culture medium supplemented with either 50%
      heterologous normal plasma obtained from healthy volunteers (n = 15) or 50%
      uremic plasma collected from long-term HD patients dialyzed with cuprophan (CU)
      (n = 8), cellulose triacetate (CTA) (n = 8) or polysulfone (PS) (n = 8)
      dialyzers. Plasma samples were drawn predialysis, 15 min after starting dialysis,
      and postdialysis. After 24-hour incubation, neutrophil aliquots were processed
      for quantification of apoptosis by flow cytometry, using propidium iodide DNA
      staining. In addition, tumor necrosis factor alpha (TNFalpha) and interleukin-10
      (IL-10) were measured in normal and predialysis uremic plasma samples.
      Neutrophils from healthy volunteers exposed to heterologous normal plasma samples
      exhibited 10.3 +/- 1.2% apoptosis. In contrast, the proportion of apoptosis was
      significantly higher among neutrophils exposed to predialysis (28.5 +/- 2.3%, p <
      0.0001), 15 min (23.0 +/- 2.4%, p < 0.0001), or postdialysis uremic plasma
      samples (25.7 +/- 2. 3%, p < 0.0001). Compared to neutrophils exposed to
      predialysis uremic plasma samples, a significantly lower proportion of apoptosis
      was observed in neutrophils exposed to the 15-min plasma samples among patients
      dialyzed with CU (26.4 +/- 2.9 vs. 18.2 +/- 3.5%; p < 0.001) but not with CTA or
      PS dialyzers. Further, CU membranes induced the greatest percentage decrease in
      neutrophil apoptosis at 15 min. There was a direct correlation between neutrophil
      apoptosis and plasma levels of TNFalpha (r = 0.424, p = 0.02) and IL-10 (r = 0.
      744, p < 0.0001). The results of the study suggest that normal neutrophils
      exposed to uremic plasma undergo accelerated in vitro apoptosis compared to those
      incubated with normal plasma. Further, during HD, the apoptosis-inducing activity
      of uremic plasma is modulated by the use of dialyzers with different degrees of
      biocompatibility. The identification of soluble factors that are responsible for
      the increased apoptosis-inducing activity of uremic plasma needs to be further
      investigated.

PMID- 10343080
TI  - A case of McLeod syndrome with chronic renal failure.
AB  - A 50-year-old man with the rare McLeod syndrome, associated with glomerular
      lesion to the end stage of chronic renal failure and death, is reported. McLeod
      syndrome is an X-linked recessive disorder on the basis of abnormal expression of
      the Kell blood group antigens and absence of erythrocyte surface Kx antigen. Most
      often the clinical and pathological findings are retinitis pigmentosa to
      blindness, progressive chronic neuropathy, cortical atrophy, dilated
      cardiomyopathy, and glomerular lesion with chronic renal failure. Among the
      laboratory parameters the most important are very low level of cholesterol and
      triglycerides, then various numbers of acanthocytes in peripheral blood smears
      and sometimes in urine (as in our case).

PMID- 10343081
TI  - Long-term extracorporeal bilirubin elimination: A case report on cascade resin
      plasmaperfusion.
AB  - Acute hepatic failure develops as a disease entity of rather diverse origin. With
      disease progression, toxic bilirubin levels may cause severe complications which
      include AV-nodal blockage, cardiac arrhythmia, impaired consciousness,
      generalized seizures, and status epilepticus. Treatment choices to prevent
      clinical deterioration comprise of costly and limited available orthotopic liver
      transplantation, utilization of extracorporeal bioartificial liver support
      devices and haemoperfusion/plasmaperfusion treatment with activated
      charcoal/anion exchange filters. Here, we present a patient with acute drug
      induced cholestatic hepatitis. Excessively elevated bilirubin levels were
      accompanied by cardiac and cerebral complications. Extracorporeal resin perfusion
      treatment (Plasorba, BR-350) was successfully performed over a 50-day period
      without activation of the coagulation system or side effects. Bilirubin levels
      were lowered to a minimum of 225 micromol/l, with concurrent clinical
      improvement. In conclusion, extracorporeal anion exchange plasmaperfusion may be
      a viable long-term treatment for hyperbilirubinaemic side effects in overt
      cholestatic hepatitis.

PMID- 10343082
TI  - A new method of measuring blood pressure excluding Korotkoff sounds 4 and 5 in
      the dialysis unit.

PMID- 10343083
TI  - Incorporation of dietary docosahexaenoic acid into the central nervous system of
      the yellowtail Seriola quinqueradiata.
AB  - In order to show the involvement of docosahexaenoic acid (DHA) in the development
      of the central nervous system (CNS) in carangid fish, we conducted tracer
      experiments by feeding radioactive DHA to larval yellowtail (Seriola
      quinqueradiata). Artemia nauplii were enriched with 14C-labeled DHA and fed to
      larval yellowtail for eight or ten days. Autoradiography of frozen sections,
      using both electric imaging plates and X-ray sensitive film, clearly showed that
      DHA was incorporated into and retained in the brain, spinal cord, and eyes. The
      brain, eyes, gill raker, liver, guts, and other muscle and bone structures were
      dissected, and radioactivity was measured in each organ by liquid scintillation
      counter. The results of this study suggest the incorporation of DHA into the
      brain. Considering our previous results indicating that DHA-free fish cannot form
      schools, we conclude that the incorporation of DHA into the brain might be a
      critical factor in the ontogeny of schooling behavior.

PMID- 10343084
TI  - Posthatching development of spinal motoneurons in the angelfish Pterophyllum
      scalare.
AB  - We investigated the posthatching developmental sequence of spinal motoneurons
      innervating the axial muscles in the teleost angelfish, Pterophyllum scalare, by
      means of retrograde labeling with horseradish peroxidase. Two discrete types of
      spinal motoneurons, primary-type motoneurons and secondary motoneurons were
      labeled in a temporally different sequence during the course of larval
      development. These two types of motoneurons were morphologically distinguishable
      from one other. Primary-type motoneurons are generated by day 1 posthatching and
      do not increase in number over the observed period (to day 12 posthatching). In
      contrast, the secondary motoneurons increase in number through posthatching day
      3. Differentiation of the spinal motoneurons appears to be nearly complete a few
      days before the onset of free swimming. In addition, the data suggest that the
      differentiation of secondary motoneurons precedes the development of the red
      muscle that is to be innervated by the motoneurons.

PMID- 10343085
TI  - Mating vocalizations of female frogs: control and evolutionary mechanisms.
AB  - Vocalization behaviors of anuran amphibians are universally sexually dimorphic.
      Usually, only male frogs give an advertisement call, while female frog calls are
      limited to a soft and simple release call which is specifically suppressed at
      mating. In a very few species, however, female frogs also give mating
      vocalizations. We examined possible mechanisms for control of this rare
      heterotypical behavior. At the peripheral level, most differences in temporal and
      spectral characteristics between female mating calls and the calls of conspecific
      males related directly to sexual dimorphisms in laryngeal and oblique muscle
      morphology. At the neural and hormonal level, we first developed an integrated
      model for control of vocalizations, based primarily on male frog data. When this
      model is applied to females, female mating vocalizations were most similar to
      male advertisement calls, rather than being modified release calls. Females may
      have conscripted preexisting androgen-sensitive neural pathways typically used
      only by males but present in both sexes. Female mating calls have been heard only
      during courtship and amplexus. Androgen levels in females at this time are
      significantly higher than even those levels in males. Because this situation is
      common in frogs, female mating vocalizations likely evolved independently
      multiple times. Character optimization suggests that mate location is the most
      common biological role for female mate calling, but the particular aspects of
      reproductive biology vary widely across species.

PMID- 10343086
TI  - Cytoarchitecture of vocal control nuclei in nestling budgerigars: relationships
      to call development.
AB  - Changes in the cytoarchitecture of vocal control nuclei were investigated in
      nestling budgerigars (Melopsittacus undulatus) from hatching to fledging (five to
      six weeks) in relation to changes in vocalizations produced by nestlings during
      this period. The nuclei investigated were the hypoglossal nucleus, dorsomedial
      nucleus of the intercollicular midbrain, central nucleus of the archistriatum,
      central nucleus of the lateral neostriatum, oval nucleus of the hyperstriatum
      ventrale, medial division of the oval nucleus of the anterior neostriatum, and
      magnocellular nucleus of the lobus parolfactorius. These nuclei have been shown
      to form functional circuits in adults related to vocal learning. Consistent with
      previously reported results, we found that call development could be described in
      terms of five different phases based on changes in the duration and segmentation
      of single and multiple segment food begging calls and the appearance of the first
      socially learned contact calls around the time of fledging. We also found that
      call segment duration exhibited an inverted U-shaped developmental function
      during the nestling period, as has been found for total call duration.
      Cytoarchitectonic studies revealed striking changes in the cellular architecture
      of vocal control nuclei during the first four weeks posthatching. At hatching the
      hypoglossal nucleus exhibits adult-like cytoarchitecture, and the central nucleus
      of the archistriatum and the central nucleus of the lateral neostriatum are
      distinguishable from surrounding fields. By one week posthatch, the central
      nucleus of the archistriatum exhibits an adult-like appearance, while other
      telencephalic vocal control nuclei do not exhibit adult-like cytoarchitecture
      until three to four weeks posthatching. By two weeks posthatching, the
      dorsomedial nucleus of the intercollicular midbrain also exhibits adult-like
      cytoarchitecture. We observed substantial decreases in the thickness of
      ventricular proliferation zones during this period, with decreases in ventricular
      zones occurring at about the same point that nuclei at corresponding levels come
      to exhibit adult-like cytoarchitectonic features. Of interest is the fact that
      cytoarchitectural development occurs asynchronously in different brain regions,
      with the appearance of adult-like characteristics in the hindbrain and midbrain
      occurring before the appearance of adult-like cytoarchitectonic characteristics
      in telencephalic nuclei. These results are consistent with recent lesion studies
      indicating that neither auditory feedback nor telencephalic vocal control nuclei
      are necessary for the production of food begging and other nestling calls until
      three to four weeks posthatching.

PMID- 10343087
TI  - Reliability of a new caries diagnostic system differentiating between active and
      inactive caries lesions.
AB  - Current scoring systems for dental caries do not consider the dynamic nature of
      the disease. The aims of the present study were to describe a new set of clinical
      caries diagnostic criteria which differentiate between active and inactive caries
      lesions at both the cavitated and non-cavitated levels and to evaluate the
      reliability of this criteria system in a population with high caries experience.
      Ten diagnostic codes were defined: 0 = sound; 1 = active (intact); 2 = active
      (surface discontinuity); 3 = active (cavity); 4 = inactive (intact); 5 = inactive
      (surface discontinuity); 6 = inactive (cavity); 7 = filling; 8 = filling with
      active caries; 9 = filling with inactive caries. Distinction between active and
      inactive caries lesions was made on the basis of a combination of visual and
      tactile criteria. The inter- and intra-examiner reliability was assessed through
      repeated examinations of 50 children by 2 recorders over a period of 3 years. The
      percentage agreement of caries diagnoses varied between 94.2 and 96.2%. The kappa
      values ranged between 0.74 and 0.85 for intra-examiner examinations and between
      0.78 and 0.80 for inter-examiner examinations; 81.6% of all misclassifications
      involved non-cavitated caries lesions. Disagreement between sound surfaces and
      non-cavitated active or non-cavitated inactive lesions (31.3 and 31.2%,
      respectively) was more common than disagreement between non-cavitated active and
      non-cavitated inactive lesions (10. 6%). The probability of reconfirming a sound,
      non-cavitated active or non-cavitated inactive caries lesion - given that the
      surface was diagnosed as either sound, non-cavitated active or non-cavitated
      inactive at the first examination - was 98.0, 68.7 and 72.5%, respectively. The
      results show that the use of a new set of clinical caries diagnostic criteria
      based on activity assessment can be performed with a high reliability, even when
      non-cavitated diagnoses are included in the criteria system.

PMID- 10343088
TI  - Performance and reproducibility of a laser fluorescence system for detection of
      occlusal caries in vitro.
AB  - The diagnosis of occlusal caries at non-cavitated sites remains problematic,
      especially since clinical visual detection has limited sensitivity. Electrical
      methods of detection show considerable promise, but specificity is reduced. The
      aims of this in vitro study were: (1) to assess the validity of a new laser
      fluorescence device--the DIAGNOdent--(and compare the values with those of a
      fixed-frequency electrical device); (2) to determine the optimum cut-off points
      of the new device for different stages of the caries process, and (3) to assess
      the reproducibility of the new laser device. For validity and determination of
      optimum cut-off points, 105 extracted teeth with macroscopically intact occlusal
      surfaces were measured by a single examiner, using both the laser fluorescence
      device (on both moist and dried teeth) and an Electronic Caries Monitor. The
      teeth were subsequently examined histologically to determine the specificity,
      sensitivity and likelihood ratio at the D2 (caries extending through more than
      half of the enamel thickness) and D3 (caries involving dentin) levels. The values
      obtained for the laser device ranged from 0.72 to 0.87 (specificity), 0.76 to
      0.87 (sensitivity) and 3.0 to 5.6 (likelihood ratio). Those for the ECM ranged
      from 0.64 to 0.78 (specificity), 0. 87 to 0.92 (sensitivity) and 2.4 to 4.1
      (likelihood ratio). To determine intra- and interexaminer reproducibility of the
      DIAGNOdent, 11 dentists recorded two different measurements at the same site on a
      separate set of 83 extracted molar teeth, and these were compared using Cohen's
      kappa (at D2 and D3 levels) and Spearman's correlation coefficient. The average
      intra-examiner kappa scores were 0.88 (D2) and 0.90 (D3), with a Spearman
      correlation of 0.97. For interexaminer reproducibility, the average kappa values
      were 0.65 (D2) and 0.73 (D3), with a Spearman correlation of 0.84. It is
      concluded that for occlusal caries (1) the new laser device has a higher
      diagnostic validity than the ECM, and (2) in vitro, measurements using the device
      are highly reproducible. Thus, the laser device could be a valuable tool for the
      longitudinal monitoring of caries and for assessing the outcome of preventive
      interventions.

PMID- 10343090
TI  - The remineralization of EDTA-treated human dentine.
AB  - The remineralization of whole human dentine treated with a neutral EDTA solution
      was investigated: the treatment periods were 15, 30 and 120 min. From the
      literature it is known that EDTA removes noncollagenous proteins (NCPs) from
      dentine powders. In order to extract more phosphoproteins from dentine lesions,
      in part of this work samples were also treated with 1 M NaCl or 4 M guanidine
      chloride solutions. All the dentine samples after the treatments mentioned were
      immersed subsequently in a remineralizing solution without fluoride for 2 weeks
      and microradiographed. To investigate the effects of fluoride, samples treated
      with EDTA for 120 min were also remineralized with 2 ppm fluoride in solution.
      The results presented show that: (1) Measurable remineralization did not occur
      when fluoride was free in the remineralizing solution. Because remineralization
      occurred neither at the lesion front nor in the nonmineral part of the surface
      softened tissue, presumably the NCPs (inhibitors) of underlying dentine diffused
      into the tissue during the remineralization period. (2) 2 ppm fluoride caused
      remineralization at the lesion front. In this case we assume fluoride either
      acted as nucleating agent or overcame the NCP effects at the lesion front.

PMID- 10343089
TI  - Altitude as a risk indicator of dental fluorosis in children residing in areas
      with 0.5 and 2.5 mg fluoride per litre in drinking water.
AB  - The purpose of this study was to assess the association between altitude and
      dental fluorosis among Ugandan children in two fluoride (F) districts while
      controlling for other factors related to fluorosis. A random sample of 481
      children aged 10-14 years was examined for fluorosis using the Thylstrup and
      Fejerskov (TF) index. The prevalence and severity of dental fluorosis increased
      significantly with increase in altitude (900 vs. 2,200 m in the low- and 1,750
      vs. 2,800 m in the high-F district) and in F concentration in the drinking water.
      In bivariate correlation analyses, F exposure from liquid (FEL), altitude, infant
      formula, vegetarianism and storing of drinking water in earthenware pots were
      significantly associated with the tooth prevalence of fluorosis (TPF), i.e. at a
      severity of TF score >/=1 (p<0.05); age and gender were not. The stepwise
      multiple linear regression explained 35 and 55% of the variance in TPF within the
      low- and high-F districts, respectively. The change in R2 due to FEL was 28 and
      51% points compared with 5 and 4% points due to altitude. The significant effect
      of FEL and altitude was confirmed by multiple logistic regression analyses. Thus,
      although most of the variation in the prevalence and severity of dental fluorosis
      was explained by the F intake from liquid, altitude was a significant risk
      indicator after controlling for potential confounders.

PMID- 10343091
TI  - Report of the eighth international workshop on the identification of transcribed
      sequences.

PMID- 10343092
TI  - Report of the fourth international workshop on human chromosome 15 mapping 1997.

PMID- 10343094
TI  - Chromosomal localization of zebrafish AluI repeats by primed in situ (PRINS)
      labeling.
AB  - Two zebrafish AluI repeats were localized in metaphase chromosomes by means of
      the primed in situ (PRINS) labeling technique, using oligonucleotide primers
      based on published sequences. An AT-rich, tandemly repeated, long AluI
      restriction fragment (RFAL1) labeled the (peri)centromeric regions of all
      chromosomes. The GC-rich short fragment (RFAS) was found to be localized in the
      paracentromeric regions of 17 chromosome pairs, which were mostly subtelocentric.
      The RFAS labeling pattern generally fits the previously described chromomycin A3
      (CMA3) staining pattern. The differential composition of heterochromatin in
      zebrafish chromosomes is discussed.

PMID- 10343093
TI  - Integrated genetic and physical map of the 1q31-->q32.1 region, encompassing the
      RP12 locus, the F13B and HF1 genes, and the EEF1AL11 and RPL30 pseudogenes.
AB  - The gene for autosomal recessive retinitis pigmentosa (RP12) with preserved para
      arteriolar retinal pigment epithelium was previously mapped close to the F13B
      gene in region 1q31-->q32.1. A 4-Mb yeast artificial chromosome contig spanning
      this interval was constructed to facilitate cloning of the RP12 gene. The contig
      comprises 25 sequence-tagged sites, polymorphic markers, and single-copy probes,
      including five newly obtained probes. The contig orders the F13B and HF1 genes,
      as well as five expressed sequence tags, with respect to the integrated genetic
      map of this region. Homozygosity mapping resulted in refinement of the candidate
      gene locus for RP12 to a 1. 3-cM region. Currently, approximately 1 Mb of the
      contig is represented in P1-derived artificial chromosome (PAC) clones. Direct
      screening of a cDNA library derived from neural retina with PACs resulted in
      identification of the human elongation factor 1alpha pseudogene (EEF1AL11) and a
      human ribosomal protein L30 pseudogene (RPL30). A physical and genetic map
      covering the entire RP12 candidate gene region was constructed.

PMID- 10343095
TI  - Molecular cloning of a SALL1-related pseudogene and mapping to chromosome Xp11.2.
AB  - SALL1 and SALL2 have been identified as two human homologs of the region-specific
      homeotic gene spalt (sal) of Drosophila, which encodes a zinc finger protein of
      characteristic structure. SALL1 has recently been found to be mutated in patients
      with Townes-Brocks syndrome (TBS, OMIM No. 107480). Here we report the isolation
      and mapping of another sal-like human gene, named SALL1P, on chromosome Xp11.2.
      This intronless gene closely resembles SALL1 but displays several mutations,
      suggesting that SALL1P represents a sal-related pseudogene. The high similarity
      of SALL1P to SALL1 is of considerable importance for mutation analysis of SALL1
      in TBS.

PMID- 10343096
TI  - Refined localization of the human alpha-tropomyosin gene (TPM1) by genetic
      mapping.

PMID- 10343097
TI  - Assignment of the Uroplakin 1b (Upk1b) gene to mouse chromosome 16 bands B5-C2 by
      in situ hybridization.

PMID- 10343098
TI  - Physical mapping of the CXC chemokine locus on human chromosome 4.
AB  - A physical map of the CXC chemokine locus on chromosome 4 has been constructed by
      PCR analysis and PFGE mapping of YAC clones. The genes for IL8, GRO1, PPBP, PF4,
      SCYB5 (ENA-78) and SCYB6 (GCP-2) have been co-localized on a 335-kb genomic
      fragment. The GRO2 and GRO3 genes did not map within this region and based on
      analysis of a YAC contig overlapping IL8 we speculate that GRO2 and GRO3 map
      downstream of this region. We have also assigned the novel CXC chemokine gene,
      SCYB9B (alias H174/betaR1) to chromosome 4q21, upstream and within 12 kb of
      INP10. Like INP10 and MIG, INP10 and SCYB9B are arranged in a head to tail
      manner. The chromosomal arrangement of these genes appears to reflect the
      evolution of this multigene family and supports the theory that it arose by gene
      duplication.

PMID- 10343099
TI  - GCMB, a second human homolog of the fly glide/gcm gene.
AB  - Glial cells play fundamental roles in neurogenesis. In addition, defective or
      abnormal gliogenesis is associated with severe diseases. To understand the
      molecular basis of such diseases, it is crucial to identify the genes promoting
      normal gliogenesis. Here we identify GCMB, which encodes a human protein
      homologous to the fly glial promoting factor glial cell deficient/glial cell
      missing (glide/gcm).

PMID- 10343100
TI  - Assignment of beta-centractin (CTRN2) to human chromosome 2 bands q11.1-->q11.2
      with somatic cell hybrids and in situ hybridization.

PMID- 10343101
TI  - Partial cloning and assignment of WNT6 to human chromosome band 2q35 by in situ
      hybridization.

PMID- 10343102
TI  - Assignment of a human cold shock domain protein A intronless pseudogene (CSDAP1)
      to human chromosome 16 band p11.2 by in situ hybridization.

PMID- 10343103
TI  - Cytogenetic study of some tissues and age-related changes in cell proportions in
      a goat-sheep chimera.
AB  - Different percentages of cells with a female sheep or male goat karyotype were
      found in kidney (12.0% vs. 88.0%) and lung (42.6% vs. 57.4%) cell cultures from a
      10-year-old chimera. Skin biopsies from patches with goat hair or sheep wool
      showed different, age-related goat-to-sheep fibroblast ratios. Karyotypic
      analysis of lymphocytes obtained from peripheral blood of the chimera at 6 and 10
      yr of age showed no chimerism. Two weeks after birth, however, lymphocytes with
      both sheep (54,XX) and goat (60,XY) karyotypes were apparent in the blood of this
      chimera. Twenty percent of the blood cells examined at 2 wk had a caprine
      karyotype; this proportion declined with time, until it was totally eliminated at
      age 6.

PMID- 10343104
TI  - Mapping of the alpha-1,6-fucosyltransferase gene, FUT8, to human chromosome
      14q24.3.
AB  - Alpha-1,6-Fucosyltransferase (alpha1,6FucT) is involved in the biosynthesis of
      asparagine-linked glycoprotein oligosaccharides. In this study, we isolated a
      genomic clone for the human alpha1,6FucT gene (FUT8) and mapped it by
      fluorescence in situ hybridization to chromosome 14q24.3. This study suggests a
      distinct localization of FUT8 from genes for other human fucosyltransferases
      reported to date.

PMID- 10343105
TI  - The karyotype of the Iberian imperial eagle (Aquila adalberti) analyzed by
      classical and DNA replication banding.
AB  - We report here for the first time the karyotype of the Iberian imperial eagle
      (Aquila adalberti). All eagles examined had a diploid number of 82 chromosomes
      and a greater number of microchromosomes (12 pairs) than has been found in all
      other species of the Accipitridae family. This karyotypic evidence corroborates
      the recent separation of A. adalberti from A. heliaca on the basis of molecular
      data. RB-FPG banding induced a specific banding pattern that allowed us to
      identify homologous chromosome pairs and revealed features about late and early
      replicating regions. Several chromosome banding techniques (C-, CMA3-, and
      restriction endonuclease banding and silver staining) were used to characterize
      the karyotype more accurately. Two GC-rich, late-replicating heterochromatin
      regions were found in the W chromosome. These regions are AluI resistant and can
      be used for sex determination in this species. All microchromosomes were
      heterochromatic, GC rich, and late replicating. Silver staining revealed active
      nucleolus organizing regions on a pair of microchromosomes that were entirely
      heterochromatic and stained intensely after CMA3-banding. Different chromosome
      rearrangements are discussed in order to establish the phylogenetic relationship
      between A. adalberti and its most closely related species, A. heliaca.

PMID- 10343106
TI  - Sperm analysis in a subfertile male with a Y;16 translocation, using four-color
      FISH.
AB  - Sperm analysis was performed in a male with oligoasthenoteratozoospermia (OAT)
      and a reciprocal t(Y;16) (q11. 21;q24), using four-color FISH. Intracytoplasmic
      sperm injection (ICSI) treatment in this patient had resulted in the birth of one
      chromosomally balanced and two chromosomally normal children. To assess the risk
      of having a chromosomally unbalanced conception after ICSI, morphologically
      normal spermatozoa were studied with a set of probes allowing detection of all
      segregation variants. There were 51% normal or balanced sperm cells. The fraction
      of sperm products resulting from alternate and adjacent I segregation was 87%,
      12% were products of 3:1 disjunction, and the other 1% had other types of
      aneuploidy. If morphologically abnormal cells were also included in the FISH
      analysis, nearly 90% of all the spermatozoa were unbalanced. We conclude that
      although the majority of males with a Y/autosome translocation are infertile due
      to azoospermia, our patient produces sufficient morphologically and chromosomally
      normal spermatozoa to have chromosomally normal or balanced offspring after ICSI.
      Assuming that ICSI with an unbalanced spermatozoon from this patient would result
      in a nonviable embryo in many cases, the combination of in vitro and subsequent
      in vivo selection probably results in a risk of unbalanced offspring of much less
      than 50%. Hence, FISH studies on the sperm of translocation carriers are useful
      for estimating the risk of having unbalanced offspring after ICSI and in
      understanding the mechanisms underlying infertility in such carriers.

PMID- 10343107
TI  - Assignment of type II iodothyronine deiodinase gene (DIO2) to human chromosome
      band 14q24.2-->q24.3 by in situ hybridization.

PMID- 10343108
TI  - Identification of BAIAP2 (BAI-associated protein 2), a novel human homologue of
      hamster IRSp53, whose SH3 domain interacts with the cytoplasmic domain of BAI1.
AB  - BAI1 (brain-specific angiogenesis inhibitor 1) was originally isolated as a p53
      target gene specifically expressed in brain. To clarify its function, we have
      been searching for cellular proteins that associate with the cytoplasmic domain
      of BAI1. Using its intracellular carboxyl terminus as "bait" in a yeast two
      hybrid system, we isolated a cDNA clone named BAIAP2 whose nucleotide sequence
      would encode a 521-amino acid protein showing significant homology to a 58/53-kDa
      substrate of insulin-receptor kinase in the hamster. As the expression profile of
      BAIAP2 examined by Northern blot analysis was almost identical to that of BAI1,
      BAIAP2 appears to be active mainly in neurons. In vitro binding assays confirmed
      that a proline-rich cytoplasmic fragment of BAI1 interacted with the Src homology
      3 (SH3) domain of BAIAP2. Double-color immunofluorescent analysis revealed that
      BAIAP2 was localized at the cytoplasmic membrane when it was coexpressed with
      BAI1 in COS-7 cells; BAIAP2 not associated with BAI1 was diffused in the
      cytoplasm. Predominant localization of BAI1 protein in a sub-cellular fraction
      enriched in growth cones indicated a possible role of BAI1 as a cell adhesion
      molecule inducing growth cone guidance. As a protein partner of BAI1, BAIAP2 may
      represent an important link between membrane and cytoskeleton in the process of
      neuronal growth.

PMID- 10343109
TI  - Assignment of a novel bifurcated SET domain gene, SETDB1, to human chromosome
      band 1q21 by in situ hybridization and radiation hybrids.
AB  - We have identified a human gene encoding an unusual bifurcated SET domain protein
      containing a large "insertion" between the most highly conserved parts of the SET
      domain. The existence of an evolutionarily related C. elegans gene encoding a
      similarly bifurcated SET domain suggests that SET domains may generally be
      composed of two functionally distinct subdomains. We mapped this gene, called
      SETDB1, to human chromosome 1q21. This region is targeted by a large number of
      recurrent translocations, suggesting that like the SET domain protein MLL, mutant
      forms of SETDB1 may be associated with human neoplasias.

PMID- 10343110
TI  - Assignment of the murine tumor susceptibility gene 101 (tsg101) and a processed
      tsg101 pseudogene (tsg101-ps1) to mouse chromosome 7 band B5 and chromosome 15
      band D1 by in situ hybridization.

PMID- 10343111
TI  - Assignment of the sodium-dependent dicarboxylate transporter gene (SLC13A2 alias
      NaDC-1) to human chromosome region 17p11.1-->q11.1 by radiation hybrid mapping
      and fluorescence in situ hybridization.

PMID- 10343112
TI  - Assignment of protooncogene MERTK (a.k.a. c-mer) to human chromosome 2q14.1 by in
      situ hybridization.

PMID- 10343113
TI  - Assignment of human interleukin 16 (IL16) to chromosome 15q26.3 by radiation
      hybrid mapping.

PMID- 10343114
TI  - Assignment of the human ADP-ribosylation factor 6 (ARF6) gene to chromosome
      7q22.1 by radiation hybrid mapping.

PMID- 10343115
TI  - Assignment of the human B3-1 gene (PSCDBP) to chromosome 2 band q11.2 by
      radiation hybrid mapping.

PMID- 10343116
TI  - Assignment of the human OB binding protein-2 gene (CD33L2) to chromosome 19q13.3
      by radiation hybrid mapping.

PMID- 10343117
TI  - Assignment of the L11 ribosomal protein gene (RPL11) to human chromosome 1p36.1-
      >p35 by in situ hybridization.

PMID- 10343118
TI  - cDNA cloning, characterization, and chromosome mapping of UBE2E3 (alias UbcH9),
      encoding an N-terminally extended human ubiquitin-conjugating enzyme.
AB  - A cDNA encoding a third member of human class III ubiquitin-conjugating enzymes
      (E2s), UBE2E3, was cloned from a human gastric adenocarcinoma cDNA library. The
      deduced 207-amino acid protein shares over 94% amino acid identity with the UBC
      domains of class III E2s, UbcH6, UBE2E2, UbcM2, UbcM3, and UbcD2. But the N
      terminal extension exhibited little homology among these, except for UbcM2, which
      showed 100% identity, and which is thought to be a mouse counterpart. Northern
      hybridization analysis exhibited a strong 1.9-kb band of UBE2E3 in skeletal
      muscle. Recombinant fusion protein of GST-UBE2E3 was found to form a thioester
      bond with ubiquitin (Ub) in an E1-dependent manner, demonstrating that the cDNA
      encodes a functional E2. In addition, a UBE2E3 mutant of cysteine-145 to serine
      failed in UBE2E3-Ub complex formation, indicating that the cysteine is essential
      for E2 function. Using FISH and PCR analysis of radiation hybrid and somatic cell
      hybrid panels the UBE2E3 gene was mapped to human chromosome 2q32.1 and showed
      strong linkage to SHGC-8506 (LOD = 11.52) between D2S1302 and D2S364.

PMID- 10343119
TI  - Assignment of steroid 5beta-reductase (SRD5B1) and its pseudogene (SRD5BP1) to
      human chromosome bands 7q32-->q33 and 1q23-->q25, respectively, by in situ
      hybridization.

PMID- 10343120
TI  - Assignment of the gene encoding the neuronal multidomain serine protease
      neurotrypsin (PRSS12) to human chromosome band 4q25-->q26 by in situ
      hybridization.

PMID- 10343121
TI  - Assignment of TCRB encoding the T-cell receptor beta chain gene to cat chromosome
      A2q25-q26 by fluorescence in situ hybridization.

PMID- 10343122
TI  - Fine mapping of distal 1p loci reveals TP73 at D1S468.
AB  - In the present study we establish a FISH fine-map of 1p36.3 loci. This region is
      frequently altered in different types of human tumors suggesting the existence of
      cancer-related genes. Identification of cosmids carrying both D1S468 and TP73
      sequences leads to the assignment of TP73 to the most frequently deleted locus in
      colon and breast cancer and integrates this gene in human genetic maps.
      Localization of other distal loci was determined as follows: distal-CDC2L1-D1Z2
      D1S94-TP73/D1S468-D1 S1615-proximal. D1S1615, earlier reported as a telomeric
      sequence, is considerably more proximal than previously thought.

PMID- 10343123
TI  - HOX11L1, a gene involved in peripheral nervous system development, maps to human
      chromosome 2p13.1-->p12 and mouse chromosome 6C3-D1.
AB  - HOX11L1 is a homeobox gene involved in peripheral nervous system development as
      confirmed by knockout mice exhibiting megacolon with enteric ganglia, a phenotype
      associated in human with Intestinal Neuronal Dysplasia (IND). Using FISH and
      radiation hybrids we have localized HOX11L1 to human chromosome 2p13.1-->p12, in
      a 14-cR interval between WI-5987 (D2S2088) and GCT1B4 (D2S2497), and confirmed
      the synteny between mouse 6C3-D1 and human 2p13.1-->p12 chromosomes by mapping an
      EST cDNA clone corresponding to mouse HOX11L1 (Tlx2).

PMID- 10343124
TI  - Assignment of ANGPT4, ANGPT1, and ANGPT2 encoding angiopoietins 4, 1 and 2 to
      human chromosome bands 20p13, 8q22.3-->q23 and 8p23.1, respectively, by in situ
      hybridization and radiation hybrid mapping.

PMID- 10343125
TI  - Synteny mapping of five human chromosome 7 genes on bovine chromosomes 4 and 21.
AB  - Five genes on human chromosome 7 (HSA 7) were assigned to bovine chromosome 21
      (BTA 21) and 4 (BTA 4) using a bovine-rodent somatic hybrid cell panel. These
      five genes were alpha-I subunit of adenylate cyclase-inhibiting G-protein
      (GNAI1), alpha/beta preprotachykinin (TAC1), reelin (RELN), c-AMP dependant
      protein kinase type II beta regulatory chain (PRKAR2B) and apolipoprotein A1
      regulatory protein 1 (TFCOUP2). Four genes mapped to BTA 4 (GNAI1, TAC1, RELN,
      PRKAR2B) while one gene mapped to BTA 21 (TFCOUP2). This study confirms the
      synteny conservation between HSA 7 and BTA 4, finely maps the breakpoints of
      conserved synteny on HSA 7 and defines a new synteny conservation between HSA 7
      and BTA 21.

PMID- 10343126
TI  - Genomic organization of the human complex I 13-kDa subunit gene NDUFA5.
AB  - We have characterized the human gene NDUFA5 encoding a 13-kDa subunit of the
      mitochondrial respiratory chain complex I (NADH: ubiquinone oxidoreductase). The
      gene contains 5 exons and 4 introns, and spans 14 kb of genomic DNA. In the
      untranscribed region we observed potential transcription factor binding sites. We
      determined a single nucleotide variant (C/T) at -318, and its frequency in the
      German population. The functional gene was localised by FISH to 7q31 and by
      radiation hybrid panel near marker D7S648 in YAC 883_a_2.

PMID- 10343127
TI  - Chromosomal localization of tumor protein, translationally-controlled 1 (TPT1)
      encoding the human histamine releasing factor (HRF) to 13q12-->q14.

PMID- 10343128
TI  - Assignment of the protein L-isoaspartate (D-aspartate) O-methyltransferase gene
      (PCMT1) to human chromosome bands 6q24-->q25 with radiation hybrid mapping.

PMID- 10343129
TI  - Splice variants of the mouse Tec gene are differentially expressed in vivo.
AB  - Tec is a cytoplasmic protein tyrosine kinase that participates in the signalling
      pathways of a broad range of cytokines. Up to five different Tec isoforms have
      been reported in the literature. We report here the genomic organisation of the
      mouse Tec gene and the tissue expression pattern of the two predominant
      transcripts, TecIII and TecIV. The mouse Tec gene consists of 18 exons, spans
      more than 86 kb, and is 2.6 kb 5' to the gene for Txk, a Tec family member.
      Comparison of mouse and human Btk, human TXK, and mouse Tec genomic structures
      shows a high level of conservation of exon/intron boundaries. Compared with
      TecIV, the TecIII transcript has a 66-bp deletion in the SH3 domain encoding
      region and is revealed here to arise by alternative splicing of exon 8. We show
      that both TecIII and TecIV are expressed as early as embryonic day 10.5 in mouse
      development, as well as in adult and embryonic organs. The ratio of TecIV to
      TecIII expression is markedly reduced in adult liver and kidney tissues and d16
      embryonic limb.

PMID- 10343130
TI  - Cytogenetic assignment of 53 microsatellites from the USDA-MARC porcine genetic
      map.
AB  - This study provides 53 new fluorescent in situ hybridization cytogenetic
      assignments for microsatellite markers linked on the swine genetic map. Forty
      microsatellites are physically assigned for the first time. The chromosomal
      locations of eight markers were either confirmed or refined, while five loci were
      assigned to locations different from those given in previous reports. Markers
      were selected to provide physical anchors based on their presumed proximity to
      centromeres or telomeres and at approximately 30 cM intervals across the genetic
      map. The number of physical anchors for pig (SSC) chromosomes 8, 15, and 18
      linkage groups was significantly improved. Centromeric regions were localized to
      areas less than 10 cM for SSC 1, 2, 3, 6, 7, 8, and 9. Although the recombination
      rate was generally higher across small biarmed chromosomes and lowest for large
      acrocentric chromosomes, two regions with particularly low (1q2.1-->q2.9 and
      13q2.3-->q4.1) and three regions with extremely high (5p1.5-->p1.2, 6p1.4-->p1.3,
      and 12p1.5-->p1.4) rates of recombination were detected. These assignments
      represent an overall 10% increase in the number of physically assigned markers in
      Sus scrofa and more than a 20% increase in the number of Type II loci assigned to
      the pig cytogenetic map.

PMID- 10343131
TI  - Evidence for decreased salivary function in patients with reflux esophagitis.
AB  - It has been speculated that impaired salivary flow contributes to abnormal acid
      clearance of the esophagus in gastroesophageal reflux and results in reflux
      esophagitis (RE). To test this hypothesis, salivary functions were measured by
      quantitative salivary scintigraphies in patients with RE and in age- and sex
      matched controls for comparison. Nineteen patients with RE and 36 healthy
      volunteers were enrolled in the study. After an intravenous injection of 5 mCi Tc
      99m pertechnetate, sequential images of 1 min/frame were acquired for 30 min. The
      1- and 15-min uptake ratios (UR) of the tracer in the four major salivary glands
      over the backgrounds were calculated. Saliva excretion was stimulated by 1 tablet
      of 200 mg ascorbic acid given orally 15 min after injection of the tracer, then
      the maximal excretion ratios (ER) of the four major salivary glands were
      calculated for the sialagogue stimulation. RE patients had lower values of 1st
      and 15th min UR and maximal ER than controls in the 4 major salivary glands. Poor
      salivary functions which represented a decrease in both UR and ER for patients
      with RE have been confirmed by quantitative salivary scintigraphy in this study.

PMID- 10343132
TI  - Helicobacter pylori in the oral cavity reflects handling of contaminants but not
      gastric infection.
AB  - Helicobacter pylori colonises the gastric mucosa, but can also be found within
      the oral cavity. The presence of H. pylori was monitored in the oral cavity of 22
      patients with duodenal ulcer, before and after antibiotic treatment and of 24
      hospital employees who were or were not professionally exposed to H. pylori.
      Gastric infection was determined by breath test. Bacteria in the oral cavity were
      detected by nested PCR of samples containing saliva and dental plaque, using
      primers specific for 16S rRNA and ureC genes. Before treatment, 9 out of 22
      infected ulcer patients harbored H. pylori in their oral cavity. Bacteria
      disappeared from the oral cavity of 3 of 7 cured patients. Twelve of 17 exposed
      subjects harbored H. pylori in their oral cavity, while no bacteria could be
      detected in the mouths of the 7 nonexposed subjects. Presence of bacteria in the
      oral cavity reflects handling of contaminants; it does not correlate with gastric
      infection and does not seem to promote it.

PMID- 10343133
TI  - Effect of whey-based culture supernatant of Lactobacillus acidophilus (johnsonii)
      La1 on Helicobacter pylori infection in humans.
AB  - BACKGROUND: Specific strains of Lactobacillus acidophilus are known to inhibit
      intestinal cell adhesion and invasion by enterovirulent bacteria. As L.
      acidophilus can survive transiently in the human stomach, it may downregulate
      Helicobacter pylori infection. METHODS: The ability of L. acidophilus (johnsonii)
      La1 supernatant to interfere with H. pylori bacterial growth, urease activity,
      and adhesion to epithelial cells was tested in vitro. Its effect on H. pylori
      infection in volunteers was monitored in a randomized, double-blind, controlled
      clinical trial, using a drinkable, whey-based, La1 culture supernatant. H. pylori
      infected volunteers were treated 14 days with 50 ml of La1 supernatant four times
      a day combined with either omeprazole 20 mg four times a day or with placebo.
      Infection was assessed by breath test, endoscopy, and biopsy sampling, performed
      at inclusion, immediately at the end of the treatment (breath test only), and 4
      weeks after the end of the treatment. RESULTS: La1 supernatant inhibited H.
      pylori growth in vitro, regardless of previous binding of H. pylori to epithelial
      cells. In 20 subjects (8 females, 12 males, mean age 33.1 years) a marked
      decrease in breath test values was observed immediately after treatment with La1
      supernatant, both in the omeprazole and in the placebo group (median 12.3 vs.
      28.8 and 9.4 vs. 20.4, respectively; p < 0.03). In both treatment groups, breath
      test values remained low 6 weeks after treatment (omeprazole treated 19.2,
      placebo treated 8. 3; p < 0.03 vs. pretreatment), but the persistence of H.
      pylori infection was confirmed in gastric biopsies. CONCLUSION: La1 culture
      supernatant shown to be effective in vitro has a partial, acid-independent long
      term suppressive effect on H. pylori in humans.

PMID- 10343134
TI  - Helicobacter pylori and the risk of colonic adenomas. Colorectal Adenoma Study
      Group.
AB  - AIMS: Previous studies have found a positive association between Helicobacter
      pylori infection and colorectal adenomas. The aim of the present study was to
      examine this association while taking possible confounding factors into account.
      METHODS: 98 serum samples were available from 182 patients with colorectal
      adenomas who entered a case-control study of colorectal adenomas and diet. The H.
      pylori status in patients was compared with a hospital control group and a
      population control group. RESULTS: H. pylori IgG antibodies were more common in
      colorectal polyp patients compared with either control group, the prevalence
      being 79% in cases compared with 62% in both control groups. The corresponding RR
      was 1.4 (0.76-2.6) compared with hospital controls and 2.1 (1.1-3.9) compared
      with population controls. After adjusting for possible confounding variables the
      association between H. pylori status and adenoma risk was even more marked. There
      was an RR of 1.6 (0.80-3.4) compared with hospital controls and an RR of 2.6 (1.3
      5.4) compared with population controls, the latter association being
      statistically significant. CONCLUSION: These findings suggest a statistically
      significant association between H. pylori infection and colorectal polyps. A
      possible mechanism might be increased gastrin levels in H. pylori-infected
      subjects which exhibit a trophic effect on colonic mucosa.

PMID- 10343136
TI  - Local downregulation of enterochromaffin-like cell histamine formation in ulcer
      healing: a study in rats.
AB  - BACKGROUND AND AIMS: Although enterochromaffin-like (ECL) cells are the major
      source of histamine for the regulation of gastric acid secretion, their role in
      ulcer healing has not been fully investigated. The present study aimed to
      investigate changes in ECL cell components as well as markers for somatostatin
      cells, parietal cells and macrophages during the healing of experimental ulcers
      in rats. METHODS: Standardised ulcer was induced directly in the rat gastric
      mucosa by brief application of acetic acid. At different time intervals following
      ulcer induction (1-15 days), histamine, histidine decarboxylase (HDC),
      chromogranin A, pancreastatin, vesicular monoamine transporter 2 (VMAT-2), H-K
      ATPase, somatostatin as well as ED1 and ED2 (macrophage markers) were localised
      by immunocytochemistry. ED1- and histamine-immunoreactive cells were counted at
      different time points. HDC- and VMAT-2-immunoreactive cells were demonstrated by
      double staining and counted. The mRNA of HDC, chromogranin A and somatostatin was
      demonstrated by in situ hybridisation and quantitated by computerised image
      analysis. RESULTS: HDC immunoreactivity and mRNA were markedly reduced in the ECL
      cells at the ulcer margin from day 1 following ulcer induction and onwards; after
      day 5 HDC immunoreactivity and mRNA rose gradually and had almost normalised by
      day 15. This local and transient downregulation of HDC was accompanied by a
      similar decrease in ECL cell histamine. In contrast to HDC and histamine, other
      ECL cell components (chromogranin A, pancreastatin, VMAT-2) as well as
      somatostatin and H-K ATPase were still demonstrable at the ulcer margin and
      displayed no major changes at any time point studied. Of the macrophage markers,
      ED1, but not ED2, could be identified at the ulcer margin, and the number of ED1
      immunoreactive cells was high in the ulcer margin from day 1 to day 5 after ulcer
      induction. The increase in ED1-positive cells and the decrease in HDC-expressing
      cells were coincident in time and localisation. CONCLUSION: The present results
      revealed a local and transient downregulation of HDC in the ECL cells at the
      ulcer margin. This may account for the decrease in ECL cell histamine observed.
      The local infiltration of macrophages into the ulcer margin suggests that
      inflammatory mediators are involved in the local suppression of ECL cell activity
      during ulcer healing.

PMID- 10343135
TI  - Fragmentation pattern of mucins in normal and diseased gastric mucosae: a
      glycoprotein fractionates with gastric mucins purified from mucosal scrapings of
      cancer and peptic ulcer patients.
AB  - BACKGROUND/AIMS: Gastric cancer, a fatal malignancy, is prevalent in the Western
      Cape region of South Africa. The aim of this study was a biochemical
      characterisation of gastric mucins in this disease, compared with gastric
      ulceration and controls from transplant donors. METHODS: Mucins were extracted in
      a denaturing medium (to prevent endogenous proteolysis) and purified by caesium
      chloride density gradient ultracentrifugation. Analysis of mucin was by gel
      filtration, SDS-PAGE and Western blotting methods. RESULTS: All samples of mucin
      when analysed by gel filtration were found to contain polymeric glycoprotein
      together with varying amounts of lower-molecular-weight glycoprotein. SDS-PAGE
      and Western blot analysis showed that diseased stomachs had glycopeptides of a
      wider range in size and antigenicity with a greater number of smaller fragments
      immunoreactive to monoclonal antibodies 2-12M1 and 9-13M1. We identified by SDS
      PAGE a glycoprotein which co-fractionates in a caesium chloride density gradient
      with mucins isolated from gastrectomy specimens resected for carcinoma and peptic
      ulceration and which was absent from mucins of the transplant donor control
      group. This neuraminidase-sensitive glycoprotein resisted dissociation from mucin
      during purification in a 3.5 M CsCl density gradient but was partially separable
      by Sepharose 2B gel chromatography and heat treatment (100 degrees C, 2.0 min) in
      SDS. Chemical analysis of the glycoprotein by HPLC favours it being an N-linked
      glycoprotein. Its non-ideal electrophoretic properties make its exact size
      estimation difficult and we ascribe to it a broad size range of Mr approximately
      55-65 kD. CONCLUSION: We conclude that mucins from diseased stomachs were more
      degraded than those from donors and that the diseased mucosa reproducibly
      secretes a Mr approximately 55-65 kD glycoprotein, the role of which needs to be
      established.

PMID- 10343137
TI  - Superoxide: a major factor for stress protein induction in reoxygenation injury
      in the intestinal cell line Caco-2.
AB  - BACKGROUND/AIMS: Acute intestinal ischemia is followed by cellular destruction
      and loss of mucosal barrier function. Posthypoxic injury of cellular proteins
      leads to the synthesis of heat shock proteins. The role of oxygen radicals in
      this process, however, is not fully established. METHODS: In the present study,
      using the intestinal cell line Caco-2, we investigated the relationship between
      the synthesis of the heat shock protein HSP70, detected by Western blot and
      oxygen radicals as well as lactate dehydrogenase (LDH) release, as measured in
      photometrical tests. RESULTS: Various periods of hypoxia and 30 min of
      reoxygenation resulted in an increased generation of superoxide as measured by
      the tetrazolium base 3-(4, 5-dimethylthiazol-2-yl)2,5-diphenyltetrazoliumbromide.
      The inhibitor of superoxide dismutase (SOD), diethyldithiocarbamate (DDC)
      increased and addition of SOD decreased intracellular superoxide levels. HSP70
      synthesis was detectable after 2 h of hypoxia. Similar to superoxide production,
      DDC increased and SOD reduced the HSP70 synthesis. In contrast, the increased LDH
      release from the cells observed after hypoxia was not significantly altered by
      DDC and SOD. CONCLUSION: The production of superoxide correlates with HSP70
      induction, but not with LDH release. We conclude that hypoxia/reoxygenation
      induces heat shock protein production, a result of protein damage, by increased
      superoxide generation, whereas superoxide does not correlate with membrane damage
      in Caco-2 cells.

PMID- 10343138
TI  - Localization of matrix metalloproteinases and tissue inhibitor of
      metalloproteinases-2 in normal human and rabbit stomachs.
AB  - BACKGROUND/AIMS: Matrix metalloproteinases (MMPs) are endopeptidases that degrade
      extracellular matrix and are involved in the pathogenesis of gastrointestinal
      ulcer and cancer along with tissue inhibitors of metalloproteinases (TIMPs). The
      purpose of this study is to examine their localization and functions in the
      normal stomach. METHODS: We examined the localization of MMP-1, MMP-2, MMP-9 and
      TIMP-2 in normal human and rabbit stomachs by light- and electron-microscopic
      immunohistochemistry and Western blotting, and the enzymatic activities of MMP-2
      and MMP-9 by gelatin zymography. RESULTS: Immunohistochemistry revealed their
      localization in parietal cells, and surface and foveolar epithelial cells.
      Electron-microscopic immunohistochemistry of parietal cells showed immunolabeling
      of MMP-2 and TIMP-2 in the cisternae of the rough endoplasmic reticulum, and that
      of MMP-1 and MMP-9 in tubular structures in their cytoplasm. Western blotting
      revealed that the densities of MMP-2 and MMP-9 bands were higher for the fundic
      gland region than for the pyloric gland region. Gelatin zymography revealed that
      tissue extracts of the fundic gland region exhibited higher enzymatic activity of
      MMP-2 and MMP-9 than those of the pyloric gland region. CONCLUSION: Normal rabbit
      and human stomachs contain MMP-1, MMP-2, MMP-9, and TIMP-2 and these are mainly
      localized in, and synthesized by parietal cells.

PMID- 10343139
TI  - Interaction of putrescine with nuclear oligopeptides in the enterocyte-like Caco
      2 cells.
AB  - Intestinal cells are able both to synthesize and take up putrescine, the main
      compound of the metabolic polyamine pathway. Polyamine binding to nuclear
      macromolecules is thougth to modulate DNA synthesis and transcription. Our aim
      was to study the fate of putrescine when taken up from the medium in the
      enterocyte-like Caco-2 cells and to analyze its binding to nuclear proteins.
      After having incubated the cells with 14C-putrescine (0.8 microM), during cell
      replication and differentiation, the nuclei were separated by sequential
      centrifugations in a sucrose gradient. About 20% of the putrescine taken up by
      Caco-2 cells resulted in the nuclei in both proliferating and differentiated
      cells. The binding of polyamines to nuclear proteins was studied on nuclear
      extracts, separated by both alkaline polyacrylamide gel electrophoresis in the
      presence of sodium dodecyl sulfate (SDS-PAGE) and gel permeation chromatography
      (GPC). No radioactivity was found in nuclear protein extracts when using the SDS
      PAGE method. Conversely, in replicating cells, GPC showed that the greatest
      amount of radioactivity was present in the nuclear peaks corresponding to
      oligopeptides with a molecular weight of 4,800-8,000 daltons. High-performance
      liquid chromatography analysis showed the presence of putrescine and spermidine
      in the 8, 000-dalton protein peak, whereas in the 4,800-dalton peak spermine was
      found in addition to putrescine. The radioactive count in the HPLC separated
      polyamines showed that a small percentage of the radioactivity present in the
      8,000 and 4,800-dalton GPC peaks was linked to spermine and spermidine,
      suggesting an interconversion of the supplemented putrescine. Conversely, in
      differentiated cells, the nuclear oligopeptides did not reveal any radioactivity
      or any polyamines, suggesting that the binding of polyamines to nuclear
      oligopeptides is exclusively concerned with replicating cells.

PMID- 10343140
TI  - Sequential treatment of anemia in ulcerative colitis with intravenous iron and
      erythropoietin.
AB  - BACKGROUND: Intravenous iron and erythropoietin have been shown to be effective
      in Crohn's disease-associated anemia. The aim of this study was to test the
      sequential treatment of anemia in ulcerative colitis with intravenous iron in the
      first phase and erythropoietin in the second. PATIENTS AND METHODS: Twenty
      patients with ulcerative colitis-associated anemia (hemoglobin < or = 10.5 g/dl)
      entered this open-label trial. In the first phase all patients received
      intravenous iron saccharate for 8 weeks. A response was defined as an increase in
      hemoglobin > or = 2.0 g/dl; a final hemoglobin >10.5 g/dl was regarded as full
      response, < or = 10.5 g/dl as partial response. A hemoglobin increase < 2.0 g/dl
      was regarded as nonresponse. In the second phase (n = 4) erythropoietin was
      initiated in patients without response. Patients with partial response were
      continued on iron saccharate for another 8 weeks. RESULTS: During the first phase
      the hemoglobin increased from 8.3 to 11.9 g/dl (mean hemoglobin difference 3.6+/
      2.3 g/dl, p < 0.001). Fifteen patients (75%) showed a full response (mean
      hemoglobin difference 4.5+/-1.5 g/dl), 1 (5%) a partial response (hemoglobin
      difference 2.1 g/dl) and 4 no response (mean hemoglobin difference 0.4+/-1.8
      g/dl) with a need for blood transfusions in a single patient. In the second study
      phase erythropoietin was highly effective in previous nonresponders (mean
      hemoglobin difference 3.3+/-1.9 g/dl). The single patient with partial response
      had a minor hemoglobin increase (hemoglobin difference 1.0 g/dl). CONCLUSION:
      Most patients with ulcerative colitis-associated anemia improve on intravenous
      iron alone. Erythropoietin is effective in those who do not respond.

PMID- 10343141
TI  - Anti-anisakis antibodies in the clinical course of Crohn's disease.
AB  - BACKGROUND: Human anisakidosis is a parasitic disease whose intestinal form
      shares several characterictics with Crohn's disease (CD), like the ileocolonic
      location predominantly and the presence of granuloma. METHODS: 73 CD patients
      diagnosed according to Lennard-Jones' criteria were studied. The disease activity
      was measured by means of Harvey-Bradshaw Index. Different clinical variables were
      analyzed. Antigenic extract of Anisakis simplex larvae extracted from blue
      whiting was prepared. Determination of IgG, IgM, IgA and total specific
      immunoglobulin against A. simplex were carried out in sera by enzyme-linked
      immunosorbent assay. Immunorecognition patterns of these sera were realized by
      immunoblotting analysis. Results were compared with prevalence of antibodies anti
      Anisakis in 251 healthy controls. RESULTS: 29% of CD patients showed detectable
      specific total Ig (G+M+A) against A. simplex (95% CI, 19-41). For IgG, IgM and
      IgA the percentages were 44, 18 and 53% (95% CI, 32-56, 10-26, and 41-65)
      respectively. In positive specific total Ig cases CD was localized mainly in
      ileum. In IgG-, IgM- and IgA-positive cases the location was predominantly
      ileocolonic. CD activity index was higher for groups with positive IgA (2.86 vs.
      5.55; p < 0.05). CONCLUSION: Patients with CD have high prevalence of specific
      immunoglobulin against A. simplex. Specific IgA are associated to higher activity
      index of CD.

PMID- 10343143
TI  - Impacted papilla minor stone in pancreas divisum causing severe acute
      pancreatitis: a case for early ERCP in acute pancreatitis of unknown origin.
AB  - This is the first description of severe acute pancreatitis in pancreas divisum
      caused by a solitary stone impacted in the minor papilla. Recovery was rapid
      after diagnostic endoscopic retrograde cholangiopancreaticography (ERCP) and
      endoscopic stone removal. Since other etiological factors accounting for the
      acute pancreatitis were carefully excluded, it seems that obstruction of the
      minor papilla by a solitary pancreatic concrement was the most likely cause of
      acute pancreatitis. This case report demonstrates the diagnostic importance of
      early ERCP in cases of etiologically unexplained acute pancreatitis.

PMID- 10343142
TI  - Validation of the spanish version of the inflammatory bowel disease questionnaire
      on ulcerative colitis and Crohn's disease.
AB  - The objective of this study is to validate the Spanish translation of the
      Inflammatory Bowel Disease Questionnaire (SIBDQ) on ulcerative colitis and
      Crohn's disease by assessing its convergence validity, discriminatory power,
      reliability and sensitivity to change. For that purpose, 211 patients with
      inflammatory bowel disease (116 with ulcerative colitis and 95 with Crohn's
      disease) completed the SIBDQ, the Psychological General Well-Being Index and the
      EuroQol. SIBDQ was repeated in those patients who remained in stable remission
      and in those with changes in clinical activity. Clinical activity was assessed by
      the Rachmilewitz and Harvey-Bradshaw indices. Correlations among scores of SIBDQ,
      EuroQol, Psychological General Well-Being Index and clinical indices of activity
      were all positive and comparable for both diseases (r = -0. 50 to r = -0.70, p <
      0.01). Analysis of variance showed that SIBDQ discriminates between different
      clinical degrees of activity. Cronbach's alpha was 0.96 in ulcerative colitis and
      Crohn's disease. SIBDQ was also highly reliable when it was repeated in
      clinically stable patients with ulcerative colitis (intraclass correlation
      coefficient = 0.82) and Crohn's disease (intraclass correlation coefficient =
      0.86). SIBDQ was sensitive to clinical changes in ulcerative colitis and in
      Crohn's disease, whether patients entered remission (effect size -1.88 and -1.81,
      respectively) or relapsed (effect size 1.70 and 8.04, respectively). In
      conclusion, the Spanish version of the IBDQ has proven to be a valid, reliable
      and sensitive instrument to detect clinical changes in patients with ulcerative
      colitis and Crohn's disease.

PMID- 10343144
TI  - Aspiration: a possible severe complication in colonoscopy preparation of elderly
      people by orthograde intestine lavage.
AB  - Total gut lavage is a widely recommended method in preparation for colonoscopy
      and there are almost no reports of severe complications in the literature.
      Application of orthograde lavage by a nasogastric tube may be necessary in
      disorientated patients, assisted by slight medical sedation, if necessary.
      Despite absolutely correct appliance of the method, a case of severe aspiration
      with subsequent hypoxemia and stroke in a senile female patient, suffering from a
      common hiatal hernia, is described.

PMID- 10343146
TI  - One-week triple regime therapy consisting of pantoprazole, amoxicillin and
      clarithromycin for cure of Helicobacter pylori-associated upper gastrointestinal
      diseases.
AB  - This study was designed to determine the efficacy and safety of 1-week triple
      therapy regime consisting of pantoprazole, amoxicillin and clarithromycin in the
      cure of Helicobacter pylori infection leading to duodenal ulcer disease and/or
      gastritis. Sixty-one patients (47 males, 14 females with a mean age of 34 years)
      belonging to different ethnic groups suffering from H. pylori-associated duodenal
      ulcer and/or gastritis for an average of 2.46 years were recruited. Having
      satisfied primary selection criteria, patients received pantoprazole 40 mg
      b.i.d., clarithromycin 500 mg b.i.d. and amoxicillin 1,000 mg b.i.d. for 7 days.
      All medications were stopped there after H. pylori eradication was determined 4-6
      weeks after treatment by a repeat endoscopy, a rapid urease test, H. pylori
      culture and histology assessment as indicators of cure. All three tests must be
      negative to consider the infection to have been successfully eradicated. Fifty
      seven patients completed the efficacy analysis per protocol. Dramatic symptomatic
      improvement was noted in most patients immediately after stopping treatment and
      it was sustained at 6 weeks. At the end of the study, the healing rate of
      duodenal ulcers (complete re-epithelialization) following 1-week treatment only,
      as indicated above, and without any maintenance therapy was 66.7%, that of
      gastritis was 55.7%, and that of erosions was 64.3%. The overall eradication rate
      for H. pylori, however, was 93% (95% CI 83.0-98.1%). Furthermore, histologic
      evaluation revealed a remarkable resolution in the activity of gastritis in all
      the patients who had successful eradication of the infection.

PMID- 10343145
TI  - Resolution of gastritis induced by Helicobacter pylori 4-5 weeks after successful
      eradication of infection using a triple therapy regimen of pantoprazole,
      amoxycillin and clarithromycin for one week.
AB  - This open-label study was designed to determine the extent of histological
      resolution of gastritis induced by Helicobacter pylori infection 4-5 weeks after
      successful eradication of the infection. Eradication was achieved using a triple
      therapy regimen consisting of a twice daily dose of pantoprazole 40 mg,
      clarithromycin 500 mg, and amoxicillin 1,000 mg taken for 1 week only. No other
      medications were given thereafter. Four biopsies were processed for histological
      examination of each patient, two from the antral and two from the corporeal
      mucosa, first at the start of the study and then again 4 weeks after cessation of
      the medication trial. Scoring for H. pylori colonization and the severity of
      gastritis was determined for each patient according to the Sydney system. 53 of
      57 patients in this study had their H. pylori infection successfully eradicated
      by the regimen mentioned and could be histologically evaluated. According to the
      severity of gastritis in the antral mucosa, patients were studied in 3 groups:
      mild, moderate and severe gastritis. 17 of 19 cases with mild gastritis showed
      complete resolution of the inflammation, with residual inflammatory changes
      persisting in 2 cases only. 22 of the 26 cases with moderate gastritis showed
      almost complete recovery except for minor residual inflammatory changes as judged
      by irregularity of intracytoplasmic mucine storage. Persistent residual
      inflammatory changes in the lamina propria were detected in 4 cases. Of the 8
      cases with severe gastritis 5 showed subsidence of the inflammatory changes, but
      the mucosa in these cases revealed some scarring, distortion of the glandular
      epithelium and atrophy. In 3 cases residual inflammation persisted. CONCLUSION:
      One-week therapy with a twice daily dose of pantoprazole 40 mg, clarithromycin
      500 mg and amoxicillin 1,000 mg, used to eradicate H. pylori causing active
      inflammation of the gastric mucosa, has led to subsidence of the acute
      inflammatory changes in all the cases with residual inflammation persisting in
      17%. Severe gastritis may cause irreparable damage to the gastric mucosa. The
      density of H. pylori colonization does not appear to be related to the severity
      of gastritis, nor to the successful eradication achieved.

PMID- 10343147
TI  - Febrile convulsions in 220 children--neurological sequelae at 12 years follow-up.
AB  - We report a 12-year follow-up study of children with febrile convulsions (FCs).
      The National General Practice Study of Epilepsy (NGPSE) is a large prospective
      community-based cohort study of 1,195 patients of all ages from first
      presentation with an identified seizure. Two hundred and twenty children with a
      first febrile convulsion were identified from the above study between 1984 and
      1987. Children were prospectively followed up to ascertain subsequent seizures,
      neurological problems and treatment. Two hundred and seven patients were followed
      for a minimum of 8.4 years (median 11.2 years). In the FC cohort, 6% of the
      children developed subsequent epilepsy, which compares with a population risk of
      about 1.4%. Ten percent had neurological sequelae. Eleven percent of the children
      had received medication to prevent recurrence of FC, and in one third of these
      cases, this was for simple FCs. Using a time-dependent covariate Cox proportional
      hazards model, the number of FCs was associated with an increased risk of
      epilepsy (hazard ratio 2.48; 95% confidence limits, CL 1.68, 3.65) up to a limit
      of 4. A statistically significant association between occurrence of complex FC
      and subsequent epilepsy was not found, but a review of other studies quantified
      the odds ratio for epilepsy after a complex first FC as 3.4 (95% CL 2.1, 5.4).
      Epilepsy is a significant if infrequent sequel to FCs. Factors associated with
      subsequent epilepsy are the number of FCs or a complex first FC. Overtreatment of
      this condition continues.

PMID- 10343148
TI  - Regional specific changes of cerebral metabolism in systemic lupus erythematosus
      identified by positron emission tomography.
AB  - In order to test the hypothesis whether the pathogenesis of cerebral systemic
      lupus erythematosus (SLE) may include an immune-mediated deficit in specific
      vulnerable brain regions, the regional cerebral metabolism in 9 patients with
      diffuse as well as focal cerebral symptoms was compared with that of 10 age
      matched control subjects. The cerebral distribution of 2-[18F]fluoro-2-deoxy-D
      glucose (FDG) uptake was measured by means of positron emission tomography.
      Subsequently performed statistical parametric mapping showed (i) a relative
      increase in metabolism in the striatum and (ii) regional decreases in the
      premotor cortex as a common feature in the patient group. Region of interest
      measurements of absolute FDG uptake confirmed these findings. The increased
      striatal activity may support the presence of a direct immune response against
      neuronal tissue in SLE, similar to the cross-reaction against inhibitory
      components in striatal tissue provoked by streptococcal antigens.

PMID- 10343149
TI  - Posturographic findings in patients with idiopathic cervical dystonia before and
      after local injections with botulinum toxin.
AB  - In this posturographic study, whole-body postural control was impaired in more
      than 75% of patients with idiopathic cervical dystonia (ICD) before local
      injections with botulinum toxin type A (BTX-A) and the impairment was independent
      of the direction of the torticollis. Six weeks after therapy with BTX-A, the
      number of pathological posturographic parameters had decreased by almost 30%, and
      the improvement reached statistical significance for sway path, sway area and
      anteroposterior sway during stance on foam with eyes closed. From a
      pathophysiological point of view, this improvement may be explained - at least in
      part - by a reduction of abnormal proprioceptive input from the neck.
      Accordingly, it seems possible that neck proprioceptive input plays a role in
      whole-body postural control in ICD patients, even though previous studies
      suggested that the neck input is relatively ignored in these patients.

PMID- 10343150
TI  - Assessment of colour vision in epileptic patients exposed to single-drug therapy.
AB  - Diplopia, blurred vision and colour disturbances are well-known side effects
      associated with anti-epileptic drugs (AEDs). Farnsworth-Munsell 100-hue colour
      test (F-100) is an accepted and sensitive tool to detect changes in colour
      perception. To determine the impact of AEDs upon colour vision, we evaluated 37
      consecutive patients with complex partial seizures exposed to monotherapy with
      phenytoin (PHT, carbamazepine (CBZ) or valproic acid (VPA). All had normal IQ and
      no congenital disturbances in colour vision or ocular diseases. Twenty normal
      controls were used for statistical analysis. Thirteen patients were exposed to
      PHT, 12 to CBZ and 12 to VPA. Visual colour perception was impaired in 30/37
      (82%) of the study group. The most significant abnormality was detected in the
      blue-yellow axis in 10/13 patients exposed to PHT (p < 0.02) and in 8/12 treated
      with CBZ (p < 0.009). In 8/12 patients taking VPA, no significant abnormality was
      observed (p < 0.06). None of the studied patients complained of colour vision
      disturbances. Our findings strongly support the negative effect of AEDs upon
      colour vision discrimination, most likely due to changes at the retinal
      processing level. F-100 proved to be very useful to assess early toxicity due to
      AEDs.

PMID- 10343151
TI  - COMT inhibition by tolcapone further improves levodopa pharmacokinetics when
      combined with a dual-release formulation of levodopa/benserazide. A novel
      principle in the treatment of Parkinson's disease.
AB  - The objective of the study reported here was the investigation of the effect of
      catechol-O-methyl transferase (COMT) inhibition by tolcapone on the
      pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after administration of a
      new dual-release formulation (dual-RF) of levodopa/benserazide (200/50). The
      study had a double-blind, placebo-controlled, randomized, crossover design and
      was conducted in 18 healthy young subjects. On the 2 treatment days, separated by
      a washout period of 7 days, the dual-RF was administered in combination (blinded)
      with tolcapone (200 mg) or placebo. Both treatment combinations were well
      tolerated. Tolcapone increased the bioavailability (AUC 0-infinity) and apparent
      elimination half-life (t(1/2)) of levodopa by 80 and 40%, respectively, compared
      to placebo. The maximal plasma concentration (Cmax) was slightly elevated by
      tolcapone. In the presence of tolcapone, formation of 3-OMD was substantially
      reduced. In conclusion, the effect of tolcapone on levodopa pharmacokinetics
      after administration of the dual-RF is similar to the one observed after
      immediate- and slow-RFs and leads to a marked improvement in levodopa
      pharmacokinetics and subsequently to an optimization of levodopa therapy.

PMID- 10343152
TI  - Amantadine hydrochloride treatment in olivopontocerebellar atrophy: a long-term
      follow-up study.
AB  - The efficacy of amantadine, a dopamine-releasing agent and antagonist of the N
      methyl-D-aspartate glutamate receptor, was evaluated in patients with
      olivopontocerebellar atrophy. By contrast to an untreated control group whose
      terminal performance deteriorated on 8 of 8 measurements of reaction time and
      movement time, patients treated with amantadine for a mean duration of over 40
      months had improved performances in 1 of 4 reaction time measurements and in 3 of
      4 movement time measurements and remained stable on the others. These results
      demonstrate long-term benefits of amantadine in olivopontocerebellar atrophy
      induced deficits of movement initiation and movement completion.

PMID- 10343154
TI  - Reproducibility of brain MRI lesion volume measurements in multiple sclerosis
      using a local thresholding technique: effects of formal operator training.
AB  - The assessment of lesion load (LL) on brain magnetic resonance imaging (MRI)
      scans from patients with multiple sclerosis (MS) is widely used to monitor
      disease evolution, natural or modified by treatments. In this study, we evaluated
      the effect of formal operator training on the intra- and inter-observer
      reproducibility of LL measurements obtained by several operators in a setting
      similar to that of clinical trials. Proton-density (PD)-weighted, unenhanced and
      enhanced T1-weighted brain MRI scans were obtained from 10 MS patients. Five
      naive technicians assessed LL on these images, using a semiautomated local
      thresholding technique for lesion segmentation and marked hardcopies as a
      reference. Measurements were performed twice before and twice after a 20-hour
      operator training. Mean intra-observer measurement coefficient of variations
      (COV) before and after the training were 3.1 and 1.6% for PD-weighted LL, 4.3 and
      1.8% for unenhanced T1-weighted LL (p < 0. 001), 4.9 and 2.0% for enhanced T1
      weighted LL (p = 0.002). Mean inter-observer COV were significantly reduced after
      training (from 10.0 to 5.6% for PD-weighted, from 11.0 to 7.3% for unenhanced T1
      weighted and from 16.0 to 6.8% for enhanced T1-weighted LL). Our data indicate
      that LL assessment on serial MRI scans from MS patients performed by technicians,
      using a local thresholding technique for lesion segmentation, is characterized by
      low measurement variability which may be significantly improved by a short and
      cost-effective training.

PMID- 10343153
TI  - The 14-3-3 protein detectable in the cerebrospinal fluid of patients with prion
      unrelated neurological diseases is expressed constitutively in neurons and glial
      cells in culture.
AB  - The 14-3-3 protein belongs to a family of 30-kD proteins originally identified by
      two-dimensional analysis of brain protein extracts. Recently, the detection of
      the 14-3-3 protein in the cerebrospinal fluid (CSF) is utilized as a highly
      reliable test for the premortem diagnosis of prion diseases such as Creutzfeldt
      Jakob disease. For the initial step, to clarify the biological implication of the
      CSF 14-3-3 protein in these diseases, its expression was investigated in neural
      tissues and cultures and CSF samples from patients with a variety of neurological
      diseases by Western blot analysis and immunocytochemistry. The constitutive
      expression of the 14-3-3 protein was identified in all neural and nonneural
      tissues examined. It was expressed in all neurons, astrocytes, oligodendrocytes,
      and microglia in culture with its location in both cytoplasmic and nuclear
      regions. The 14-3-3 protein was detected in the CSF of 8 out of 71 patients,
      including 1 Gerstmann-Straussler-Scheinker disease patient and 7 patients with
      prion-unrelated neurological diseases, such as meningoencephalitis of viral,
      bacterial, or tuberculous origin, multiple sclerosis, and mitochondrial myopathy,
      encephalopathy, lactic acidosis, and strokelike episodes. These results suggest
      that the 14-3-3 protein expressed constitutively at substantial levels in both
      neurons and glial cells might be released into the CSF as a disease-nonspecific
      consequence of the extensive brain damage and indicate that the analysis of the
      14-3-3 protein in the CSF is not useful as a screening test for prion diseases.

PMID- 10343155
TI  - Acute disseminated encephalomyelitis associated with tetanus vaccination.

PMID- 10343156
TI  - Reversible posterior encephalopathy possibly related to coeliac disease: a
      vitamin-depleted brain?

PMID- 10343157
TI  - Immunoglobulin allotypes among the Bicolanos of Sorsogon province, Luzon,
      Philippines: implications of phenotypes for filariasis.
AB  - Immunoglobulin (Ig) allotypes are polymorphic genetic systems that show distinct
      racial arrays, thus making them powerful tools for studies of genetic admixture
      and biological relationships. In the province of Sorsogon, southern Luzon,
      Philippines, allotyping was completed on 252 persons residing in two neighboring
      villages. The people demonstrated 14 GM and 3 KM phenotypes. The frequency of
      homozygous KM3, KM1 and heterozygous KM1,3 was identical in these villages;
      however, half of the GM phenotypes present in one village were significantly less
      frequent in the other village. The frequency of KM and GM haplotypes was
      different from those reported in Filipino aboriginal groups, but similar to a
      population on Samar Island, the only other Filipino group for which Ig allotype
      data exist. Variability in the prevalence of parasitic disease such as lymphatic
      filariasis may in part reflect differences in genetic susceptibility, resulting
      from allotypic heterogeneity between villages.

PMID- 10343158
TI  - No quantitative relationship between CR1 and Lutheran expression on erythrocytes:
      In(Lu) gene product is not a common regulator of CR1 expression on erythrocytes.
AB  - The density of CR1, the C3b/C4b receptor (CD35), on erythrocytes (E) (CR1/E) is
      genetically determined. However, the broad distribution of CR1/E within a given
      genotype suggests that other genetic elements might contribute to the regulation
      of CR1/E. In some pathological conditions, including systemic lupus erythematosus
      (SLE), AIDS and hemolytic anemia, CR1 deficiency parallels the severity of the
      disease. When compared to healthy individuals, an accelerated decrease in CR1/E
      in these patients has been demonstrated, but other mechanisms interfering with
      CR1 density regulation during erythropoiesis might also contribute. In
      exceptional circumstances, CR1/E can be dramatically decreased in healthy
      individuals by the effect of a regulatory gene, In(Lu), that switches off various
      surface molecules on E, the structure genes of which are located on four
      different chromosomes, suggesting a transcription regulatory role for In(Lu) gene
      products. The hypothesis that products of this gene could physiologically
      regulate the surface density of all these molecules has been tested by
      determining Lub density on E (Lub/E) using quantitative flow cytometry. Lub
      antigenic sites were then compared to CR1/E among healthy individuals of the
      different CR1 density phenotypes, SLE patients with and without CR1 deficiency,
      and an exceptional SLE patient totally lacking CR1/E and reticulocytes. No
      quantitative relationship was found between CR1 and Lub expression in either
      normal or pathological conditions. These data establish that In(Lu) products are
      not involved in normal or pathological CR1 density regulation.

PMID- 10343159
TI  - An unequal crossover between the RCCX modules of the human MHC leading to the
      presence of a CYP21B gene and a tenascin TNXB/TNXA-RP2 recombinant between C4A
      and C4B genes in a patient with juvenile rheumatoid arthritis.
AB  - The RCCX module of the human MHC class III region is comprised of four genes
      arranged in tandem: RP, complement C4, steroid 21-hydroxylase (CYP21), and
      tenascin X (TNX). Variations in the number and genes of the RCCX modules may lead
      to genetic and/or autoimmune diseases. Restriction fragment length polymorphism
      (RFLP) analysis was utilized to determine the RCCX modular variation in patients
      with juvenile rheumatoid arthritis (JRA). In JRA patient L1, RFLP analysis
      suggested the presence of a bimodular RCCX structure containing both C4A long and
      C4B short genes, yet missing the markers for the CYP21A and TNXA genes usually
      located between the C4A and C4B genes. The 7.5-kb genomic fragment spanning the
      CYP21-TNX-RP2 genes was cloned and sequenced, revealing that a genetic
      recombination occurred between TNXA of a bimodular RCCX chromosome and TNXB of a
      monomodular RCCX chromosome. This recombination results in a new MHC haplotype
      with a CYP21B gene and a TNXB/TNXA-RP2 recombinant between the two C4 genes.
      Elucidation of the breakpoint region provides further evidence for the
      instability of the MHC class III gene region as a result of the RCCX modular
      variation.

PMID- 10343161
TI  - Complement-mediated regulation of Trichomonas vaginalis infection in mice.
AB  - Trichomonas vaginalis is a flagellated protozoan which causes trichomoniasis, a
      sexually transmitted disease of the human genitourinary tract. The importance of
      the alternative complement pathway in host defence against T. vaginalis was
      investigated in vitro. Kinetic studies utilising immunofixation following
      electrophoresis showed that both a strongly and weakly virulent strain of T.
      vaginalis activated murine serum C3. In vivo studies with congenic-resistant, C5
      deficient, B10.D2/OSn- and C5-sufficient, B10.D2/nSn mice showed that the
      presence of C5 is a significant factor in the innate host resistance to primary
      infection with a strongly virulent, but not a weakly virulent trichomonad strain.

PMID- 10343160
TI  - Characterisation of the human central MHC gene, BAT1: genomic structure and
      expression.
AB  - The BAT1 gene (D6S81E) encodes a member of the DEAD-box family of RNA-binding
      proteins, and lies in the central MHC. This region contains genes which affect
      susceptibility to immunopathological diseases. A 14-kb section of the human MHC
      containing the BAT1 gene and a further 5-kb telomeric of BAT1 was sequenced using
      DNA from individuals homozygous for HLA-A1, B8, DR3 and HLA- A1, B57, DR7.
      Analysis of our sequences and the previously reported human cDNA sequence showed
      that the expressed sequence of the 8.1 and 57.1 haplotypes is identical with only
      minor substitutions in the introns. Phylogenetic analysis suggests BAT1 may be a
      translation initiation factor. Screening of cells and tissues for BAT1 mRNA
      suggests an abundant member of a family of proteins expressed in multiple cell
      types, notably macrophages and hepatocytes. Expression was independent of MHC
      haplotype, consistent with the lack of sequence polymorphism.

PMID- 10343162
TI  - Xenopus laevis pancreatic DNase I: purification and immunological
      characterization.
AB  - Deoxyribonuclease I (DNase I) was purified from Xenopus laevis pancreas to
      apparent electrophoretic homogeneity using a series of column chromatographies.
      The purified enzyme showed a molecular mass of about 36 kDa and maximum activity
      at pH 7.0-8.0, required divalent cations, Ca2+ and Mg2+, for its activity, and
      was inhibited by EDTA, EGTA and an antibody specific to the enzyme, but not by G
      actin. The N-terminal amino acid sequence of the enzyme up to the 37th residue
      shared 38-44% homology with that of mammalian DNases I derived from bovine,
      ovine, porcine, rat, mouse, rabbit and human. A systematic survey of DNase I
      activity distribution in 20 different kinds of frog tissues showed that the
      pancreas and rectum produced higher amounts than other tissues. This is the first
      report concerning the purification and chemical and immunological
      characterization of frog pancreatic DNase I.

PMID- 10343163
TI  - 'Genomics': buzzword or reality?
AB  - 'Genomics' has become a widely used term, covering a range of approaches that
      make use of the newly acquired wealth of genome data (both on man and on a number
      of model organisms) to gain new insights and accelerate research. This review
      attempts to present a clear and balanced view of developments in this field, to
      describe the four major approaches that contribute to genomics (bioinformatics,
      genetic analysis of extended populations, large-scale expression studies,
      functional approaches), and to indicate applications in basic and pharmaceutical
      research.

PMID- 10343164
TI  - Selenocysteine-containing proteins in mammals.
AB  - Since the recent discovery of selenocysteine as the 21st amino acid in protein,
      the field of selenium biology has rapidly expanded. Twelve mammalian
      selenoproteins have been characterized to date and each contains selenocysteine
      that is incorporated in response to specific UGA code words. These selenoproteins
      have different cellular functions, but in those selenoproteins for which the
      function is known, selenocysteine is located at the active center. The presence
      of selenocysteine at critical sites in naturally occurring selenoproteins
      provides an explanation for the important role of selenium in human health and
      development. This review describes known mammalian selenoproteins and discusses
      recent developments and future directions in the selenium field.

PMID- 10343165
TI  - On the mechanism of cesium-induced voltage and current tails in single
      ventricular myocytes.
AB  - The mechanisms by which different concentrations of cesium modify membrane
      potentials and currents were investigated in guinea pig single ventricular
      myocytes. In a dose-dependent manner, cesium reversibly decreases the resting
      potential and action potential amplitude and duration, and induces a diastolic
      decaying voltage tail (Vex), which increases at more negative and reverses at
      less negative potentials. In voltage-clamped myocytes, Cs+ increases the holding
      current, increases the outward current at plateau levels while decreasing it at
      potentials closer to resting potential, induces an inward tail current (Iex) on
      return to resting potential and causes a negative shift of the threshold for the
      inward current. During depolarizing ramps, Cs+ decreases the outward current
      negative to inward rectification range, whereas it increases the current past
      that range. During repolarizing ramps, Cs+ shifts the threshold for removal of
      inward rectification negative slope to less negative values. Cs+-induced voltage
      and current tails are increased by repetitive activity, caffeine (5 mM) and high
      [Ca2+]O (8.1 mM), and are reduced by low Ca2+ (0.45 mM), Cd2+ (0.2 mM) and Ni2+
      (2 mM). Ni2+ also abolishes the tail current that follows steps more positive
      than ECa. We conclude that Cs+ (1) decreases the resting potential by decreasing
      the outward current at more negative potentials, (2) shortens the action
      potential by increasing the outward current at potentials positive to the
      negative slope of inward rectification, and (3) induces diastolic tails through a
      Ca2+-dependent mechanism, which apparently is an enhanced electrogenic Na-Ca
      exchange.

PMID- 10343166
TI  - Muscarinic activation causes biphasic inotropic response and decreases cellular
      Na+ activity in canine cardiac Purkinje fibers.
AB  - In this study, the effects of carbachol (CCh) on twitch tension, intracellular
      Na+ activity (aiNa), and action potential were simultaneously measured in canine
      cardiac Purkinje fibers in order to examine the regulation of inotropy through
      muscarinic receptors and its relation to aiNa. In fibers driven at 1 Hz, CCh (10
      microM) initially and transiently decreased and then increased the twitch tension
      by 36 +/- 8%. The action potential showed a significant elevation of the plateau
      and a significant shortening of the duration at 90% repolarization (APD90), from
      403 +/- 7 to 389 +/- 7 ms. The aiNa decreased from 7.4 +/- 0.4 to 6.7 +/- 0.3 mM
      (n = 23, p < 0.05). Atropine (1 microM) decreased the twitch tension by 21 +/- 6%
      (n = 7, p < 0.05) without significant effects on the action potential and aiNa,
      and inhibited the effects of CCh. Cs+ (20 mM) increased the plateau height and
      APD90, enhanced the twitch tension by 66 +/- 24%, but decreased aiNa from 7.3 +/-
      0.3 to 6.3 +/- 0.4 mM (n = 6, p < 0.05). In the presence of 20 mM Cs+, some
      fibers generated slow responses. The addition of 10 microM CCh further increased
      the twitch tension and APD90, and decreased aiNa from 6.3 +/- 0.4 to 5.3 +/- 0.3
      mM. Ouabain (0.3 microM) increased the twitch tension and aiNa, and inhibited the
      CCh-induced decrease of aiNa. In the presence of ouabain, 20 mM Cs+ depolarized
      the fiber and generated slow responses with a decreased aiNa. The addition of 10
      microM CCh enhanced the slow action potential, and increased aiNa although there
      was a transient decrease during early exposure. These results suggest that
      activation of muscarinic receptors in canine Purkinje fibers results in an
      enhancement of the Na+-K+ pump activity and a biphasic inotropic response,
      probably via different receptor subtypes. The inhibitory effect, most likely
      through M2 receptors, is associated with the activation of K+ channels. The
      stimulatory effect, on the other hand, is probably due to the action on the M1
      receptors, resulting in increases in Ca2+ currents.

PMID- 10343167
TI  - Effects of serotonin depletion by p-chlorophenylalanine, p-chloroamphetamine or
      5,7-dihydroxytryptamine on central dopaminergic neurons: focus on
      tuberoinfundibular dopaminergic neurons and serum prolactin.
AB  - Three serotonin (5-HT) neurotoxins, p-chlorophenylalanine (PCPA, 125 and 250
      mg/kg, i.p.), p-chloroamphetamine (PCA, 10 mg/kg, i.p.) and 5,7
      dihydroxytryptamine (5,7-DHT, 200 microg/rat, i.c.v.) were used to examine
      whether depletion of central 5-HT has an effect on central dopaminergic (DA)
      neuronal activities or on prolactin (PRL) secretion. Adult ovariectomized Sprague
      Dawley rats primed with estrogen (polyestradiol phosphate, 0.1 mg/rat, s.c.) were
      treated with one of three neurotoxins and then decapitated in the morning after 3
      7 days. Blood sample and brain tissues were collected. The acute effect of PCA
      (from 30 to 180 min) was also determined. The concentrations of 5-HT, DA and
      their metabolites, 5-hydroxyindoleacetic acid and 3,4-dihydroxyphenylacetic acid,
      in the median eminence, striatum and nucleus accumbens were determined by HPLC
      electrochemical detection. All three toxins significantly depleted central 5-HT
      stores by 11-20%. Except for PCPA, neither PCA nor 5,7-DHT had any significant
      effect on basal DA neuronal activities or PRL secretion. PCA also exhibited an
      acute effect on the release and reuptake of 5-HT and DA. In summary, depletion of
      central 5-HT stores to a significant extent for 3-7 days did not seem to affect
      basal DA neuronal activity and PRL secretion.

PMID- 10343168
TI  - HIV-1 Rev promotes the nuclear export of unspliced and singly spliced RNAs in a
      mammalian cell-free export system.
AB  - Rev has been shown to promote the export of HIV-1 RNAs from Xenopus oocyte
      nuclei, but a system to examine the direct effect of Rev on HIV-1 RNA export in
      mammalian somatic cells does not exist. In this report, the development of a cell
      free RNA export system using COS cells is described. This system is capable of
      examining the movement of RNA from nuclei of COS cells transfected with an HIV-1
      proviral construct into reconstituted cytosol from nontransfected cells. A
      reproducible preparation of nuclei free of residual cytoplasmic RNA is
      demonstrated. Export of RNA from these nuclei into reconstituted cell-free
      extracts was saturable and dependent on temperature and energy. Further
      validation of the system was obtained by confirming that the nuclear export of
      HIV-1-unspliced and partially spliced RNAs was dependent upon the expression of
      HIV-1 Rev and that the presence of Rev appeared to decrease the export of an HIV
      1-spliced RNA. The system was also able to demonstrate that Rev did not appear to
      significantly enhance the export of an HIV-1 protease-containing RNA that has
      been shown to be dependent upon Rev for maximal expression. Consequently, the
      system appears useful for the examination of parameters of nuclear export of HIV
      1 and cellular RNAs.

PMID- 10343169
TI  - Analysis of potential phosphorylation sites in human T cell leukemia virus type 1
      Tax.
AB  - The human T cell leukemia virus type 1 (HTLV-1) Tax is a phosphoprotein, however,
      the contribution of phosphorylation to Tax activity is unknown. Previous studies
      have shown that phosphorylation of Tax occurs on serine residue(s), within one
      tryptic fragment, in response to 4beta-phorbol-12beta-myristate-13alpha-acetate,
      in both mouse and human cells. Studies were conducted in multiple cell lines to
      identify the specific phosphorylated serines as a prelude to functional analysis.
      The phosphorylation pattern of Tax was found to be different in 293T and COS-7
      cells in comparison with MT-4 and Px-1 cells. However, one tryptic fragment
      remained consistent in comigration analyses among all cell lines. Using selected
      Tax serine mutants a tryptic fragment containing a serine at residue 113 believed
      to be the site of phosphorylation of Tax did not comigrate with the common
      phosphorylated tryptic fragment. Analysis of selected Tax mutants for ability to
      trans-activate the cytomegalovirus promoter demonstrated mutation of serine 77 to
      alanine reduced trans-activation by 90% compared to wild-type Tax. However,
      examination of the phosphorylation pattern of the serine 77 mutant demonstrated
      that it is not the site of phosphorylation. These studies demonstrate the
      importance of using relevant cell lines to characterize the role of
      phosphorylation in protein function.

PMID- 10343170
TI  - Sodium vanadate inhibits apoptosis in malignant glioma cells: a role for Akt/PKB.
AB  - The dual signal hypothesis of apoptosis holds that a common signal can activate
      both apoptotic and proliferative pathways. The fate of a cell is dependent on
      which of these two pathways predominates. In the MAPK family of kinases, ERK and
      JNK have been proposed to mediate apoptosis whereas the PI3K-stimulated kinase,
      Akt/PKB, has been shown to inhibit apoptosis. The object of this study was to
      determine the role of these kinases in a glioma model of apoptosis. We have
      previously shown that K252a induces apoptosis and inhibits kinase activity. In
      this study we confirm these results and show that the protein tyrosine
      phosphatase inhibitor sodium vanadate activates ERK, JNK and Akt/PKB, but does
      not stimulate proliferation. Vanadate did protect T98G cells from K252a-induced
      apoptosis, an effect that was abolished by addition of the PI3K inhibitor
      wortmannin. This suggests that PI3K and Akt/PKB may be responsible for mediating
      vanadate's protective effect on glioma cells. We conclude that the intracellular
      balance between protein phosphorylation pathways is a critical determinant of
      both cell proliferation and cell death.

PMID- 10343171
TI  - Effect of selective blockade of catecholaminergic alpha and beta receptors on
      histamine-induced release of corticotropin and prolactin.
AB  - We investigated the role of adrenergic receptors in histamine (HA)-induced
      release of corticotropin (ACTH) and prolactin (PRL) in conscious male rats.
      Specific alpha- or beta-receptor antagonists were administered
      intracerebroventricularly in doses of 1 mmol at time -20 min, and HA (270 nmol),
      the H1 receptor agonist 2-thiazolylethylamine (2-TEA; 2,180 nmol) or the H2
      receptor agonist 4-methylHA (4-MeHA; 790 nmol) were administered
      intracerebroventricularly at -15 min. The animals were decapitated at 0 min, and
      plasma was analyzed for ACTH and PRL. Administration of HA and the histaminergic
      agonists stimulated ACTH secretion equally, while only HA and the H2 receptor
      agonist stimulated PRL secretion. Pretreatment with the adrenergic receptor
      antagonists had no effect on the ACTH response to the histaminergic compounds. In
      contrast, the PRL response to HA or 4-MeHA was inhibited or prevented by the
      alpha-receptor antagonists phenoxybenzamine and phentolamine, the alpha1-receptor
      antagonist prazocin, the beta-receptor antagonist propranolol and the beta1
      receptor antagonist atenolol, whereas the alpha2-receptor antagonist yohimbine or
      the beta2-receptor antagonist ICI-118-551 had no effect. The study indicates that
      histaminergic neurons interact with the catecholaminergic neuronal system in
      regulation of PRL secretion, and that this interaction is dependent upon
      activation of alpha1- and beta1-receptors. In contrast, histaminergic neurons
      stimulate ACTH secretion independently of adrenergic receptor activation.

PMID- 10343172
TI  - Simultaneous blockade of two glutamate receptor subtypes (NMDA and AMPA) results
      in stressor-specific inhibition of prolactin and corticotropin release.
AB  - Many neurons express simultaneously two or more isotypes of glutamate receptors,
      so that pharmacological modulation of more than one receptor may be necessary to
      reveal the role of glutamate in mediating physiological processes. The present
      studies were aimed at evaluating involvement of endogenous glutamate in
      triggering plasma prolactin (PRL) and adrenocorticotropic hormone (ACTH) levels
      in response to three different stress stimuli (footshock, immobilization and
      ether stress). Blockade of glutamate receptor subtypes was achieved by the
      administration of the NMDA antagonist dizocilpine (MK-801, 0.2 mg/kg) and the
      selective AMPA antagonist GYKI 52466 (10 mg/kg). Rats were pretreated for 4-5
      days and then exposed to stressful stimulation. Basal hormone levels were not
      affected by the antagonists. In male rats, combined, but not separate blockade of
      NMDA and AMPA/kainate subtypes of glutamate receptors prevented the rise in
      plasma PRL in response to footshock stress. In female rats, footshock-induced PRL
      release was inhibited even by separate blockade of NMDA receptors by dizocilpine,
      suggesting that the PRL system of females is more sensitive to the effect of NMDA
      antagonists than that of males. None of the treatments affected PRL release
      during immobilization or ether stress. Simultaneous blockade of NMDA and AMPA
      receptor subtypes resulted in a mild inhibition of immobilization-induced ACTH
      release without any effect on ACTH response to footshock or ether stress. The
      data suggest that involvement of glutamatergic pathways in neuroendocrine
      response during stress is selective for discrete stress stimuli and stress
      hormones. In addition a concerted action of glutamate on both NMDA and non-NMDA
      receptor subtypes is involved in the control of PRL release during footshock
      stress.

PMID- 10343173
TI  - Neurotransmitter modulation of glucocorticoid receptor mRNA levels in the rat
      hippocampus.
AB  - Glucocorticoids in the hippocampus mediate adaptive responses elicited by
      stressful stimuli. In this study we investigated glucocorticoid receptor gene
      expression in the rat hippocampus following acute stress. A significant decrease
      in glucocorticoid receptor mRNA levels was observed in the hippocampus less than
      1 h after the onset of stress. This decrease was inhibited by administering
      either MK-801, diazepam or propranolol prior to exposure to stress. The effect of
      diazepam on the stress-induced decrease in hippocampal glucocorticoid receptor
      mRNA was reversed by Ro-15-1788, suggesting that it is mediated by central
      benzodiazepine receptors, i.e. GABA-A. These results indicate that NMDA, GABA-A
      and beta-adrenergic receptors are involved in the mechanism of the stress-induced
      decrease in glucocorticoid receptor mRNA levels in the rat hippocampus.

PMID- 10343174
TI  - Long-lasting effects of stress on glucocorticoid receptor gene expression in the
      rat brain.
AB  - Stressful stimuli are known to affect glucocorticoid receptor (GR) mRNA levels in
      the rat brain. The aim of this study was to examine the duration of chronic
      stress-induced changes in GR gene expression in the male rat hippocampus and
      cerebellum. By using in situ hybridization histochemistry, we detected a
      statistically significant down-regulation of GR mRNA both in the hippocampus and
      in the cerebellum of rats stressed for 8, 10 and 14 days. The same degree of down
      regulation could also be detected in the above brain areas of rats stressed for
      14 days and left undisturbed for 48 h or 8 days after stress. To examine the
      effects of subsequent stressors on the expression of down-regulated GR mRNA in
      the hippocampus of chronically stressed rats, we determined, by Northern
      blotting, GR mRNA levels in the hippocampi of rats stressed for 14 days and
      subsequently exposed to either short- or long-duration stressors. The down
      regulated levels of GR mRNA remained practically unaffected when a subsequent new
      stressor was applied. Our results show that chronic stress-induced down
      regulation of GR mRNA in the rat brain can be extended for periods longer than
      the initial/causative stimulus, irrespective of the presence of a novel stimulus.

PMID- 10343175
TI  - Mineralocorticoids and glucocorticoids cooperatively increase salt intake and
      angiotensin II receptor binding in rat brain.
AB  - Mineralocorticoids, such as deoxycorticosterone acetate (DOCA), and angiotensin
      II (AngII) act synergistically in the brain to elicit salt appetite.
      Glucocorticoids, such as dexamethasone (DEX), also may enhance the behavioral
      effects of DOCA and AngII. However, the brain regions involved in these
      behavioral interactions have not been elucidated. This study tested the
      hypothesis that DEX potentiates the effects of DOCA on AngII binding, especially
      at the AT1 receptor. We confirmed that DEX potentiated the effects of DOCA on
      salt appetite. Concomitantly, steroid-specific and region-specific changes in AT1
      binding were noted. Specifically, in the hypothalamic paraventricular nucleus,
      treatment with DEX or DOCA + DEX increased AT1 binding. In the subfornical organ
      (SFO) and area postrema, there was an increase in AT1 binding when both steroids
      were combined, but not when given individually. However, there was no change in
      AT2 binding in any brain region studied and no change in AT1 or AT2 binding to
      either receptor subtype in the pituitary. The results indicate that DOCA and DEX
      may increase the sensitivity of the brain to the behavioral and physiological
      actions of AngII by upregulating AT1 receptors in the SFO and area postrema.

PMID- 10343176
TI  - Combined hypervolemia and hypoosmolality alter hypothalamic-pituitary-adrenal
      axis response to endotoxin stimulation.
AB  - Changes in corticotropin (ACTH) and glucocorticoid secretion have been described
      during disturbances of body fluid homeostasis and attributed to alterations in
      arginine vasopressin (AVP) secretion from magnocellular hypothalamic neurons. In
      order to further characterize the mechanisms involved in the interactions between
      body fluid alterations and pituitary adrenal function, we manipulated osmolality
      and volemia in sheep under stimulation of the pituitary-adrenal axis by acute
      injection of endotoxin. We have recently shown that endotoxin injection induces a
      long-lasting release of both corticotropin releasing hormone (CRH) and AVP into
      hypophysial portal blood, and an early stimulation of AVP secretion into
      peripheral vessels, thus suggesting a joint activation of magnocellular and
      parvocellular neurons of the PVN. We used the same experimental model to
      investigate the effect of combined volume loading and plasma dilution (achieved
      by 1-deamino-8-D-arginine (dDAVP) administration together with infusion of 2
      liters of 2.5% glucose solution) on CRH, AVP, ACTH and cortisol responses to
      endotoxin stimulation. In volume-loaded animals, ACTH and cortisol responses to
      endotoxin were significantly blunted and we observed a parallel decrease in
      portal CRH and jugular and portal AVP levels. These data show that hypoosmolality
      and/or hypervolemia reduce(s) ACTH and cortisol response to stress in sheep as in
      other species. They strongly suggest that this reduction in ACTH and cortisol
      responses to endotoxin involve not only magnocellular hypothalamic neurons
      secreting AVP, as usually assumed, but also PVN parvocellular neurons secreting
      both CRH and AVP.

PMID- 10343177
TI  - Role of glucocorticoids in the response of the hypothalamo-corticotrope, immune
      and adipose systems to repeated endotoxin administration.
AB  - The present study was designed to determine whether the glucocorticoid inhibitory
      feedback mechanism plays a role in the well-known tolerance of the neuroendocrine
      immune axis response to repeated endotoxemia. Adult male rats underwent
      adrenalectomy (ADX) and were implanted with a subcutaneous corticosterone
      (compound B, CB, 75 mg) pellet, or sham operated and implanted with a placebo
      pellet. On the morning of day 8 after surgery (experimental day, D1), all rats
      received an intravenous injection of lipopolysaccharide (LPS) (25 microg/kg body
      weight) which was repeated daily until D5. Blood was drawn via intravenous
      indwelling catheters before (sample time zero) as well as 1, 2, 3 and 4 h after
      LPS treatment on D1, 3 and 5 for measurements of corticotropin (ACTH), CB, tumor
      necrosis factor-alpha (TNF-alpha) and leptin. In sham animals, tolerance to
      repeated LPS administration was complete by D5 for the corticotrope axis and the
      immune response. In addition, LPS was found to stimulate leptin secretion on day
      1 in intact rats, an effect that also disappeared thereafter. ADX + CB rats
      showed only a partial tolerance of the corticotrope axis on D5, whereas tolerance
      of the immune response was similar to that found in sham animals. Interestingly,
      the acute stimulation of leptin secretion by LPS in ADX + CB rats was
      qualitatively similar to that of intact controls on D1, but plasma leptin levels
      were significantly reduced on D3 and 5 compared to controls. Our results
      demonstrate that the adrenal response tolerance of the hypothalamo-pituitary
      adrenal axis to repeated endotoxemia. In addition, our finding that TNF-alpha
      secretion follows the same pattern in sham-operated and in adrenalectomized
      animals suggests that unlike the corticotrope axis, tolerance of the immune
      response does not depend upon stimulated CB levels. The decrease in circulating
      levels of leptin following ADX is consistent with the stimulatory effects of
      glucocorticoids on leptin secretion. However, our finding of an acute stimulation
      of leptin secretion by LPS in ADX + CB animals demonstrates that this effect of
      endotoxemia is at least partially glucocorticoid independent.

PMID- 10343178
TI  - PC18, a specific aminopeptidase N inhibitor, induces vasopressin release by
      increasing the half-life of brain angiotensin III.
AB  - Angiotensin III (AngIII), which is metabolized in vivo by aminopeptidase N (APN),
      was previously shown to be one of the main effector peptides of the brain renin
      angiotensin system (RAS) in the control of vasopressin release. Recently, a
      potent APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol, methionine
      thiol), has been developed. In this study, we first checked the in vitro
      selectivity of PC18 towards APN, aminopeptidase A (APA) and aminopeptidase B
      (APB), three zinc metalloproteases with significant identity between their amino
      acid sequences. The Ki values of this compound on APN were found to be in the
      nanomolar range (Ki = 8.0 +/- 1.7 nM) but it was 2,150 and 125 times less active
      on APA and APB, respectively. Secondly, we evaluated in vivo the effect of brain
      APN inhibition with PC18 on the inactivation of brain AngIII and on vasopressin
      secretion in mice. For this purpose, mice received [3H]AngII
      intracerebroventricularly in the presence or absence of the APN inhibitor PC18
      (30 microg). At different times after the injection, [3H]AngIII levels were
      evaluated from hypothalamus homogenates after separation by cation-exchange
      chromatography. PC18 induced an accumulation of [3H]AngIII, increasing its half
      life 3.9 times as compared with control values. In addition, the effect of PC18
      on vasopressin release was studied in mice. PC18 (10-100 microgram) was injected
      intracerebroventricularly, and plasma vasopressin levels were estimated by
      radioimmunoassay. PC18 increased vasopressin levels in a dose-dependent manner.
      The maximal increase in vasopressin release (+220%) is observed for a dose of
      PC18 of 100 microgram and was inhibited 75% by the coadministration of the AngII
      receptor antagonist (Sar1-Ala8)-AngII (0.5 microgram). These results indicate
      that in vivo, in the mouse brain, APN inhibition by PC18 increases the half-life
      of endogenous AngIII, resulting in an enhanced vasopressin release.

PMID- 10343179
TI  - Oxidative stress and a murine superoxide dismutase-1 mutation promoting
      amyotrophic lateral sclerosis alter neurosecretion in the hypothalamo
      neurohypophyseal axis.
AB  - In this study, we examined the effects of oxidative stress on a nitric oxide (NO)
      regulated neuroendocrine function, the release of arginine vasopressin (AVP) by
      the hypothalamo-neurohypophyseal axis. Treatment of mouse-isolated hypothalami
      and neurointermediate lobes (NIL) with H2O2 increased AVP release. This effect
      was inhibited by copper-zinc superoxide dismutase-1 (SOD1) analogs. By measuring
      cGMP accumulation as an indicator of biologically active NO, we found that H2O2
      treatment decreased cGMP formation in both hypothalami and NIL. We have
      previously shown that NO inhibits AVP release by a cGMP-independent mechanism.
      Given that H2O2 stimulated AVP release, while it reduced cGMP production, our
      findings strongly suggest that oxidative damage affects neurosecretion by
      reducing NO availability. To test whether such a mechanism may operate under
      pathological conditions with pronounced oxidative stress, we compared
      neurosecretion in wild-type and transgenic mice carrying a mutated form of SOD1
      associated with human familial amyotrophic lateral sclerosis. Reminiscent of the
      data obtained from H2O2-treated tissues, hypothalami and NIL from SOD1 mutants
      displayed decreased cGMP accumulation and increased AVP release, compared with
      tissues from wild-type littermates. Since neuronal NO synthase expression was not
      modified, we conclude that the perturbed free radical metabolism associated with
      the SOD1 mutation is likely to trap NO, and thereby alter neurosecretion, a
      mechanism that can be exacerbated in specific physiopathological conditions.

PMID- 10343180
TI  - Activation of an inwardly rectifying K+ conductance by orphanin-FQ/nociceptin in
      vasopressin-containing neurons.
AB  - The orphanin-FQ/nociceptin (OFQ/N) receptor (previously, ORL1, LC132) has been
      shown to be coupled to an inwardly rectifying K+ conductance in several neuronal
      populations. Although OFQ/N receptor mRNA is densely expressed in the supraoptic
      nucleus (SON), little is known about its coupling to effector system(s). The
      present study examined the effects of OFQ/N on guinea pig magnocellular neurons
      within the SON using intracellular recording from hypothalamic slices. In the
      presence of tetrodotoxin, OFQ/N hyperpolarized 48 of 48 SON magnocellular
      neurons, 24 of which were subsequently identified by immunocytochemistry as
      arginine vasopressin positive (AVP+). Nineteen of the 48 SON neurons, including 7
      which were AVP+, responded to OFQ/N with an outward current that reversed at the
      K+ equilibrium potential (EK+) and a decrease in slope resistance consistent with
      the activation of an inwardly rectifying K+ channel. In 4 of these neurons, BaCl2
      significantly attenuated both the hyperpolarization and the decrease in slope
      resistance induced by OFQ/N. Twenty-one SON neurons, 13 of which were AVP+,
      responded to OFQ/N with an increase in slope resistance which did not reverse at
      EK+. An additional 5 neurons (2 were AVP+) were treated with the gap junction
      blocking agent carbenoxolone (CARB). CARB induced a small hyperpolarization,
      increased slope resistance and significantly reduced the subsequent OFQ/N-induced
      hyperpolarization. However, when the CARB and CARB plus OFQ/N hyperpolarizations
      were summed in these 5 cells, they were no different than the OFQ/N
      hyperpolarization alone. The effect of two putative OFQ/N receptor antagonists
      was also evaluated. The kappa3-opioid antagonist naloxone benzoylhydrazone was
      without effect (n = 3), and the 13-amino-acid [Phe1Psi(CH2-NH)Gly2]OFQ/N(1-13)NH2
      OFQ/N analog produced a small hyperpolarization on its own in addition to
      partially antagonizing the effects of OFQ/N (n = 3). Taken together, these
      results suggest that OFQ/N acts upon SON neurons through two mechanisms, one
      which hyperpolarizes the neuron by activating an inwardly rectifying K+
      conductance, and another which may increase membrane resistance by closing the
      low-resistance gap junctions.

PMID- 10343181
TI  - Incidence and risk factors of benign creatine phosphokinase elevations in chronic
      psychiatric patients.
AB  - There have been few studies focusing on the creatine phosphokinase (CPK)
      elevations in chronic psychiatric patients. The survey was conducted
      prospectively to investigate the incidence and risk factors of CPK elevations in
      chronic psychiatric patients during a 2-year follow-up period. Sixteen of 32
      (50%) patients had maximums of more than 230 U/l (upper limit of our normal
      range) and 7 (22%) patients had maximums of more than 500 U/l. Surprisingly, 4
      (13%) patients had maximums of more than 1,000 U/l after exercises such as
      swimming and walking. Nonetheless, none of the 16 patients with the CPK
      elevations developed severe conditions such as rhabdomyolysis despite an absence
      of therapeutic intervention, and their CPK elevations were proven to be benign.
      According to the path analysis, usual physical activity and neuroleptic doses
      seemed to underlie CPK elevations directly. The present findings suggest that not
      a few chronic psychiatric inpatients may have at least one CPK elevation per 2
      years. Patients engaging in more physical activity or receiving higher
      neuroleptic doses are at greater risk of developing such CPK elevations. However,
      most of these increases are benign, and it is not considered necessary to treat
      them.

PMID- 10343182
TI  - Lithium and haloperidol treatments differently affect the mononuclear leukocyte
      Galphas protein levels in bipolar affective disorder.
AB  - Despite numerous suggestions of the involvement of GTP-binding proteins in the
      mechanisms of action of psychoactive drugs in bipolar affective disorder, few
      studies have been conducted during the drug treatment of patients. The aim of the
      present study was to investigate the effects of a mood stabilizer and an
      antipsychotic drug on Galphas proteins. Patients with bipolar affective disorder
      under lithium treatment with or without haloperidol were assessed with respect to
      their mononuclear leukocyte (MNL) Galphas subunit protein. Galphas-45 protein
      subunit levels were analyzed by the Western immunoblot method. The subjects
      consisted of a group of 20 patients, all diagnosed as euthymic bipolars, and a
      comparison group of 15 drug-free healthy subjects. Results showed that Galphas
      levels were significantly decreased in the bipolar patients (BP) compared to drug
      free healthy subjects (Mann-Whitney U test, p < 0.002). The drug effect was
      evaluated by a factorial analysis of variance and showed significant differences
      between groups (Kruskal-Wallis H test, p < 0.02). Lithium-treated patients
      displayed the most decreased Galphas levels (normalized mean values 53.2 +/- 31
      vs. 122 +/- 45% for BP and controls, respectively, p < 0.001), while no change
      was observed in Galphas levels of haloperidol-treated patients compared to
      controls (mean values: 124.9 +/- 37%; NS). The data indicate that lithium and
      haloperidol affect the mechanism of Galphas protein signal transduction
      differently, consistent with previous animal studies.

PMID- 10343183
TI  - The effects of scopolamine on changes in regional cerebral blood flow during
      classical conditioning of the human eyeblink response.
AB  - We examined the effects of scopolamine on the functional anatomy of classical
      conditioning of the human eyeblink response. Ten healthy young normal female
      volunteers (mean age +/- SEM: 26.7 +/- 0.9 years) were administered 0.4 mg
      scopolamine intravenously 1 h before regional cerebral blood flow (rCBF) was
      measured with positron emission tomography (PET) and H215O. Scans occurred during
      three sequential phases: (1) explicitly unpaired presentations of the
      unconditioned stimulus (airpuff to the right eye) and conditioned stimulus
      (binaural tone), (2) paired presentations of the two stimuli (associative
      learning) and (3) explicitly unpaired presentation of the stimuli (extinction
      phase). Scopolamine impaired acquisition of the conditioned eyeblink response
      (54.7 +/- 4.9%) relative to 18 untreated subjects from two previous PET studies.
      Regions that showed significant relative increases in rCBF during conditioning
      included the right lateral occipital cortex, the right inferior occipital cortex,
      the right lateral temporo-occipital cortex, the left medial temporo-occipital
      cortex, the posterior cingulate, the right cerebellum/brain stem area and the
      medial cerebellum. Significant relative decreases in rCBF were measured in the
      thalamus, the left putamen/insula area, the right putamen and the left and middle
      cerebellar cortex. The data partially replicate previous findings in unmedicated
      young volunteers of conditioning-specific rCBF changes in the cingulate cortex,
      the cerebellar cortex, the insula and the lateral temporo-occipital cortex. Our
      finding of decreased rCBF in the thalamus and increased rCBF in the occipital
      cortex may be attributable to effects of scopolamine per se rather than
      conditioning. Our data lend further support to the notion that classical
      conditioning involves distributed changes in multiple systems within the central
      nervous system.

PMID- 10343184
TI  - The predictive value of benzodiazepine tolerance in persistently aggressive
      schizophrenia.
AB  - The aim of this study was to determine whether benzodiazepine tolerance might
      provide a predictive marker for persistent aggression in schizophrenia. Seventy
      seven male schizophrenic patients newly admitted to our psychiatric intensive
      care unit due to violent behavior during a 4-month period were examined. As a
      result, a high dose of benzodiazepine required for sedation or a short duration
      until regaining consciousness after the initial sedation, was related to severer
      aggression on waking up after sedation. Despite the small number of subjects
      examined, a conservative claim can be made that the level of the effect of
      benzodiazepine required for sedation seems to predict persistent severe
      aggression in schizophrenia.

PMID- 10343185
TI  - Effects of neonatal clomipramine treatment on locomotor activity, anxiety-related
      behavior and serotonin turnover in Syrian hamsters.
AB  - Day-night differences in locomotor and anxiety-related behavior and brain
      serotonin metabolism were examined in adult Syrian hamsters that received
      clomipramine (15 mg/kg) or vehicle from day 8 to day 21 of life. Locomotor
      activity was significantly greater at the beginning of scotophase (20.00 h) than
      at noon (12.00 h) and it was highest in hamsters treated with clomipramine at
      both examined times. Significant day-night differences in anxiety-related
      behavior, as measured in a plus-maze paradigm, were found in saline-treated
      hamsters only, with higher values at night. Clomipramine-treated hamsters
      exhibited augmented 5-hydroxyindoleacetic acid/serotonin ratio in hypothalamus
      and midbrain raphe, while serotonin content decreased in frontal cortex and
      hypothalamic areas. The results indicate that neonatal clomipramine treatment
      produces a long-lasting change in locomotion and anxiety-related behavior, as
      well as reduces brain serotonin content in hamsters.

PMID- 10343186
TI  - Neurotransmitters, neuroendocrine correlates of sensation-seeking temperament in
      normal humans.
AB  - Correlations between sensation-seeking (SS) personality dimension and plasma
      concentrations of norepinephrine (NE), epinephrine, and NE-dependent testosterone
      (T), cortisol and prolactin (PRL) were studied in 74 physically and
      psychologically healthy male volunteers, in order to see whether or not the
      noradrenergic system is involved in the modulation of this personality trait.
      Novelty-seeking scores by the Temperament and Character Inventory and SS scores
      on a Visual Analog Scale were positively correlated with plasma NE, T and PRL
      levels, suggesting that NE and the downstream cascade of NE-dependent hormones,
      together with other monoaminergic changes, might be responsible for the
      development and the degree of this temperamental character.

PMID- 10343187
TI  - Relationship of energy metabolism detected by 31P-MRS in the human brain with
      mental fatigue.
AB  - To search for a possible relationship between brain energy metabolism and mental
      fatiguability, 10 normal volunteers were examined by 31P-MRS (phosphorus-31
      magnetic resonance spectroscopy) in the occipital cortex during photic
      stimulation (PS), and Uchida-Kraepelin test (UKT), a standardized serial
      calculation task, was used for measurement of intraindividual characteristics of
      mental fatigue in these subjects. More decrease of phosphocreatine measured by
      31P-MRS during the PS was significantly associated with more effects of rest
      assessed by UKT (r = -0.86, p <0.005). More decrease in pH after PS was
      associated with steeper decline of performance (r = 0.78, p <0.01). These
      findings suggest that characteristics of brain energy metabolism in an individual
      may relate to intrinsic patterns of mental fatigability.

PMID- 10343188
TI  - EEG changes following scopolamine administration in healthy subjects.
      Quantitative analysis during rest and photic stimulation.
AB  - This study examined the effects of the anticholinergic drug, scopolamine (0.25
      mg) in 16 right-handed healthy volunteers. EEGs were recorded before and 60 min
      after intramuscular administration, and spectral analysis was performed on EEGs
      recorded at rest and during photic stimulation. Each subject was also evaluated
      by the Wechsler Memory Scale (WMS; form 1 or 2) before and 90 min after drug
      administration. In the resting EEG, the scopolamine administration resulted in a
      significant increase in the absolute power on the delta band (2.0- 3.8 Hz) and in
      the relative power on the delta and theta-1 bands (4.0-5.8 Hz) mainly over the
      central and parieto-occipital regions. In contrast, scopolamine significantly
      decreased the relative alpha-2 band (9.2-12.8 Hz) power mainly over the frontal
      regions and the absolute alpha-2 band power at most of the recording sites. The
      analysis of stimulus data showed that scopolamine significantly decreased
      fundamental photic driving responses elicited by photic stimulation at 15 Hz,
      with significant effects confined to the occipital regions. These EEG changes
      occurred in association with a significant reduction in total WMS scores as well
      as in scores of logical and visual memory subtests. These findings suggest that,
      in addition to cognitive impairments, central cholinergic dysfunction can cause
      EEG changes under both nonstimulus and stimulus conditions.

PMID- 10343189
TI  - A phase I study of paclitaxel and epirubicin, without and with filgrastim, for
      the treatment of platinum-resistant advanced ovarian cancer.
AB  - The aim of the study was to determine the maximum tolerated dose (MTD) of
      epirubicin combined with a fixed dose of paclitaxel, without and with support of
      filgrastim, in patients with platinum resistant or refractory ovarian cancer.
      Paclitaxel (150 mg/m2) and epirubicin (starting dose 90 mg/m2, 15 mg/m2
      escalation per level) were given on day 1, every 28 days for 4-6 cycles.
      Filgrastim (F) (5 microg/kg/die) was given in case of grade 4 leukopenia (levels
      without support) or from day 4 up to leukocyte count >10,000/mm3 after nadir
      (levels with support). Cohorts of 3 patients were enrolled at each level and
      further 3 patients were planned if 1 or 2 unacceptable toxic events (UTE) were
      registered. MTD was determined first without and then with filgrastim. Four
      levels were studied (90, 90+F, 105+F, 120+F) with 4, 6, 5 and 4 patients
      enrolled, respectively. UTE (grade 4 neutropenia) were observed in 3 patients at
      level 1. Thus, 90 mg/m2 was the MTD for epirubicin without filgrastim. MTD of
      epirubicin with filgrastim was not reached at 120 mg/m2. Hematological toxicity
      was mild. Grade 3 mucositis was reported in 1 patient. Among the 14 patients with
      measurable or evaluable disease, 3 objective responses were observed (1 complete
      and 2 partial) for an overall response rate of 21.4%. The combination of
      paclitaxel 150 mg/m2 and epirubicin at 120 mg/m2 with filgrastim is a feasible
      therapy. Grade 4 leukopenia is the dose limiting toxicity using epirubicin at 90
      mg/m2 without filgrastim.

PMID- 10343190
TI  - Therapeutic management of stage I-II high-grade primary gastric lymphomas.
AB  - The best treatment for primary gastric lymphomas (PGL) has not yet been defined.
      Eighty-three patients with stage I/II PGL are documented, focusing on prognostic
      factors, treatment-related morbidity and mortality, and therapeutic outcome.
      Chemotherapy improved survival in comparison to local treatments, i.e.
      gastrectomy (n = 15) or gastrectomy and radiotherapy (n = 5). Patients treated
      with primary chemotherapy and/or radiotherapy (n = 21), with gastrectomy and
      chemotherapy (n = 26) or with gastrectomy and chemotherapy and radiotherapy (n =
      16) showed a similar survival rate. Conservative treatment obtained a 5-year
      actuarial survival of 82% with a stomach preservation rate of 100%. Two treatment
      failures and 19 relapses (24%) were observed. Sixty patients (72%) are alive (59
      no evidence of disease) at a median follow-up of 58 months. Ten-year actuarial
      survival is 64%. Local control was influenced by stage, tumor size, depth of
      infiltration, LDH ratio, and therapeutic modality, while age, stage, LDH ratio,
      and the use of chemotherapy had independent prognostic value. Because of its
      efficacy and safety, conservative strategy should be considered as first-line
      treatment for high-grade PGL. Gastrectomy should be indicated only for urgent
      cases, in which surgery followed by chemotherapy appears the best choice,
      followed by radiotherapy in patients with stage II2 disease.

PMID- 10343191
TI  - A randomized controlled comparative study of oral medroxyprogesterone acetate
      1,200 and 600 mg in patients with advanced or recurrent breast cancer.
AB  - A randomized controlled comparative study of oral medroxyprogesterone acetate
      (MPA) 1,200 mg (arm I) and 600 mg (arm II) was conducted in 80 patients with
      advanced or recurrent breast cancer. There were no significant differences
      between arm I and arm II in terms of response rate, duration of response and
      survival, or in terms of incidence and severity of adverse reactions. The lowest
      serum MPA concentration in responders tended to be higher than that in
      nonresponders. In the cohort of this study, the lowest concentration in partial
      response was 17.4 ng/ml, suggesting that this level may be the required minimum
      serum concentration.

PMID- 10343192
TI  - A comparative study of intraperitoneal carboplatin versus intravenous carboplatin
      with intravenous cyclophosphamide in both arms as initial chemotherapy for stage
      III ovarian cancer.
AB  - Cisplatin (C) or carboplatin (CBP) plus cyclophosphamide (CTX) was until recently
      considered standard chemotherapy for advanced ovarian cancer (OC). Attempts to
      maximize platinum and its analog activity against OC include its administration
      directly into the peritoneal cavity. In the past we have shown that
      intraperitoneal (IP) CBP administration is a safe and effective treatment for OC
      [Polyzos et al: Proc Am Assoc Cancer Res 1990;31: 1120]. In the present study we
      aimed to compare the effectiveness and toxicity of CBP administration either
      intravenously (IV) or IP plus CTX IV. Since 1990, 90 evaluable patients with
      stage III OC were prospectively randomized to receive CBP 350 mg/m2 IV or IP plus
      CTX 600 mg/m2 IV (in both groups) every 3-4 weeks for six courses. The
      randomization incorporated stratification according to performance status and the
      amount of residual tumor (maximum diameter </=2 or >2 cm). Clinical assessment
      was performed with abdominal CT and serum CA-125. Responses were observed in
      33/46 = 72% (95/CI 56.5-84.0) of the IV group and in 33/44 = 75% (95/CI 59.7
      86.8) of the IP group with 48 and 45% clinical complete responses, respectively.
      Times to progression were 19 months (8-62+) for the IV group and 18 (6-72+) for
      the IP group. Median survivals were: 25 months (6-80+) and 26 months (6-72+),
      respectively. Significantly more patients in the IV group than in the IP group
      had grade 3 or higher leukopenia (p < 0. 01) and grade 3 thrombocytopenia (p <
      0.09). Morbidity due to infectious complications in the IP group was minimal. It
      seems that IP CBP is equally effective to IV administration in terms of response
      and survival with less myelotoxicity. The favorable results on survival
      demonstrated in studies with IP C administration in patients with small volume
      disease [Alberts et al: N Engl J Med 1996;335:1950-1965] could not be repeated in
      the present study applying CBP in patients with variable tumor size and a
      relatively small number of patients. The likelihood that patients with large
      volume disease would benefit from a regional approach compared to systemic
      administration is small and this explains the inability to detect a difference
      between the two arms.

PMID- 10343193
TI  - Phase II study of cisplatin and dacarbazine for metastatic colorectal carcinoma
      resistant to 5-fluorouracil.
AB  - Twenty-six patients with metastatic colorectal cancer were given cisplatin (CDDP)
      and dacarbazine (DTIC). Patients who relapsed while receiving adjuvant 5
      fluorouracil (FU) or had 5-FU-resistant metastatic disease were included. Median
      age was 52 years and the male-to-female ratio was 1. Performance status (ECOG)
      was 3 in 5 patients and 0-2 in the remainder. CDDP (20 mg/m2/day i.v.) and DTIC
      were given (250 mg/m2/day i.v.) on days 1-5. The treatment was repeated every 3
      weeks until disease progression. Total response rate was 19.2% (95% confidence
      interval: 4.5-34.3%) with one clinical complete response (3.8%) and 4 partial
      responses (15.4%). Median response duration was 5 months. Median survival for the
      whole group and for responders was 6 and 8 months, respectively. In conclusion,
      CDDP + DTIC combination has modest activity in patients with colorectal cancer
      resistant to 5-FU treatment.

PMID- 10343194
TI  - Phase I study of cisplatin, ifosfamide and irinotecan with rhG-CSF support in
      advanced non-small cell lung cancer.
AB  - A phase I study was conducted in advanced non-small cell lung cancer to determine
      the maximum tolerated dose (MTD) of irinotecan combined with a fixed schedule of
      cisplatin and ifosfamide with rhG-CSF support. In addition, efficacy including
      survival time was evaluated at 2 years after the completion of patient
      registration. Cisplatin (20 mg/m2) and ifosfamide (1.5 g/m2) were administered at
      fixed doses on days 1-4, and irinotecan was given on days 1, 8 and 15 starting at
      40 mg/m2, which was increased in 10 mg/m2 increments. This regimen was repeated
      every 4 weeks. rhG-CSF was administered subcutaneously at a dose of 50 microg/m2
      on days 5-18 except on the day of irinotecan treatment. Forty-five patients were
      registered and 35 had received no prior chemotherapy. MTD or irinotecan was
      defined according to toxicity and the dose during three courses was increased up
      to 70 mg/m2. The dose 60 mg/m2 was recommended for phase II study. The dose
      limiting factor was thrombocytopenia. The overall response rate was 57.8% and the
      median survival time was 492 days. In chemotherapy-naive patients, the response
      rate was 65.7% (95% CI; 50-81.4%), median response duration 161 days, median
      survival time 513 days, 1-year survival rate 62.4%, and 2-year survival rate
      27.3%.

PMID- 10343195
TI  - Prognostic value of immunohistochemical expression of beta-1 integrin in
      pancreatic carcinoma.
AB  - BACKGROUND: Prognostically relevant factors based on the histological assessment
      of the resected pancreas are known. However, the knowledge of additional factors
      associated with the prognosis is helpful in planning the therapy for an
      individual patient. beta1 Integrin expression is known to have a prognostic
      influence in some malignant tumors. No data are, however, available on the
      prognostic value of beta1 integrins in pancreatic carcinoma. METHOD: We
      investigated paraffin-embedded specimens of 19 patients undergoing surgical
      treatment for periampullary carcinoma and of 42 patients for ductal pancreatic
      carcinoma by immunohistochemistry to assess the expression pattern and the
      prognostic impact of beta1 integrins. Neither histomorphological parameters nor
      the survival time of the patients were known at the time of the investigation.
      RESULTS: No correlation was established between histomorphological parameters and
      beta1 integrin expression in periampullary or ductal pancreatic carcinoma,
      respectively. Patients with periampullary carcinoma and beta1 integrin
      overexpression had a significantly poorer prognosis than patients without
      overexpression of beta1 integrins (median survival: 18.3 vs. 58.4 months). In
      ductal pancreatic carcinoma beta1 integrin expression had no influence on
      prognosis. CONCLUSION: beta1 Integrins exert an influence on prognosis in
      periampullary carcinoma but not in ductal pancreatic carcinoma. However, further
      investigations in larger patient samples are required to confirm these results.

PMID- 10343196
TI  - Clinical significance of c-met oncogene alterations in human colorectal cancer.
AB  - Abnormalities of the c-met oncogene have been studied in cancers of many organs
      including thyroid, lung, pancreas, and stomach. However, little is known about
      the clinical significance of c-met oncogene abnormalities in colorectal cancer.
      We investigated the amplification and overexpression of the c-met gene in
      surgically resected samples from 43 patients with colorectal cancer using
      Southern blot analysis and reverse transcription-polymerase chain reaction (RT
      PCR). Four of 33 (12%) samples of colorectal cancer showed amplification of the c
      met gene. Twelve of 43 (30%) exhibited overexpression of the c-met gene. The
      patients with c-met overexpression showed greater tumor size, compared to those
      without c-met overexpression (p < 0.05). However, there were no differences in
      clinical stage, histological differentiation, tumor markers, or overall survival
      between two groups. The findings of the present study suggest that overexpression
      of c-met gene plays an important role in growth of colorectal cancer.

PMID- 10343197
TI  - Recurrences and relation to tumor growth potential and local immune response in
      node-negative advanced gastric cancer.
AB  - Biological characteristics and the prognosis for subjects with node-negative
      advanced gastric cancer have been given little attention in related literature.
      We analyzed data on 112 patients with serosally invasive gastric cancer who were
      lymph node metastasis-negative; all had been surgically treated in the Department
      of Surgery II, Kyushu University Hospital, between 1970 and 1992. Recurrences and
      relation to the growth potential of the tumor and local immune response were
      examined. Thirty patients died with a recurrence of the gastric cancer, and in
      these patients, the tumor was larger, the whole stomach was more frequently
      involved and infiltrative growth was more common, compared to findings in
      patients who were recurrence-free. Peritoneal recurrence was evident in half the
      number of patients and the 5-year survival rate was 74. 5%. Tumor growth
      potential was evaluated, based on the level of proliferating cell nuclear antigen
      (PCNA) of the primary tumor and on dendritic cell infiltration into the tumor,
      determined as a level of local immune function of the host. Higher growth
      potential and lower immune levels were more frequent in patients with
      recurrences. Multivariate analysis revealed that tumor size and PCNA labeling
      index were significant prognostic factors for node-negative gastric cancers. In a
      subset of advanced gastric cancers, there was no apparent distinct lymph node
      metastasis and the prognosis was better. However, cancer cells with a higher
      growth potential and a lower immune response in the host can biologically amplify
      and mainly infiltrate the gastric wall, extend to the serosa and disseminate
      transserosally into the peritoneum.

PMID- 10343198
TI  - Protective effect of transferrin C3 in lung cancer?
AB  - In a previous study of lung cancer patients and controls from the Stockholm area
      in central Sweden, we found a significantly decreased frequency of the
      transferrin (TF) variant C3 in small cell and squamous epithelial lung cancer but
      not in adenocarcinoma, suggesting a protective effect of TF C3 in small cell and
      squamous lung cancer. In an attempt to replicate this association we studied TF
      types in lung cancer patients and controls from two additional Swedish
      subpopulations, viz. northern Sweden and southwestern Sweden. We were able to
      confirm the significantly decreased frequency of TF C3, especially in small cell
      lung cancer, in northern Sweden but not in southwestern Sweden. Thus the eventual
      protective effect of TF C3 in small cell lung cancer is an open question. We
      hypothesize that the association between TF C alleles and lung cancer may be
      secondary and dependent on linkage disequilibrium with allelic variants of newly
      discovered tumor-associated genes known to map to the same position (3q21) as TF,
      e.g. NCK and H-RYK.

PMID- 10343199
TI  - Metallothionein expression correlates with the pathological response of patients
      with esophageal cancer undergoing preoperative chemoradiation therapy.
AB  - Immunohistochemical staining for metallothionein (MT) and p53 was performed on
      biopsy specimens of 30 patients with esophageal squamous cell carcinoma who had
      received curative resection following preoperative chemoradiation. The pathologic
      response to chemoradiation was a partial response in 19 cases and no change was
      observed in 11 cases. In 16 cases with MT-positive tumor, 10 (62.5%) showed no
      change. In 14 cases with MT-negative tumor, 13 (92.8%) showed partial response.
      In 8 patients with negative staining for p53 and MT, 7 were responders, whereas
      in 9 patients with positive staining for p53 and MT, 6 were nonresponders. The
      pathologic response was significantly associated with the prognosis (p = 0.
      0167). The survival rate of the responders was significantly better than that of
      the nonresponders. These findings suggest that MT might be a prognostic marker,
      and consequently we can select the patients who will benefit from preoperative
      chemoradiation.

PMID- 10343200
TI  - S100B protein detection in serum is a significant prognostic factor in metastatic
      melanoma.
AB  - The serum detection of S100B, a new melanoma marker, has shown clinical
      significance in early studies. The aim of our study of 1, 339 serum samples from
      412 different melanoma patients and 107 control patients was to prove the
      prognostic value of serum S100B levels in melanoma patients at different stages
      of disease and at follow-up (median: 30 months). Using a cutoff level of 0.2
      microgram/l S100B, 5 of 286 patients (1.7%) with primary tumors (stage I/II),
      14/73 (19.2%) patients with locoregional metastasis (stage III) and 57/84 (67.9%)
      patients with advanced disease (stage IV) were S100B positive (statistically
      significant differences for stage I/II vs. III, I/II vs. IV, and III vs. IV, p <
      0.001). The estimated overall survival time was significantly longer (p < 0.001)
      for patients with S100B values below 0.2 microgram/l compared to patients with
      elevated S100B levels (>/=0.2 microgram/l), which was independent of the stage of
      disease (I-IV). Regarding prognosis, we were furthermore able to distinguish
      different subgroups among stage III and IV patients using S100B serum levels (p <
      0.01). Patients with different cutaneous non-melanoma diseases served as S100B
      negative controls. S100B serum evaluations using the Sangtec(R)100 IRMA are
      highly specific and sensitive for the detection of metastatic melanoma. S100B has
      been shown to be a relevant prognostic factor for survival in a study with a
      large sample size of melanoma patients including close follow-up evaluations.

PMID- 10343202
TI  - Variegate porphyria: past, present and future.
AB  - Variegate porphyria, one of the acute hepatic porphyrias, is characterized by a
      partial reduction in protoporphyrinogen oxidase, the seventh enzyme of the heme
      biosynthetic pathway. For a long time, this disease has caused confusion among
      the porphyrias because it presents with clinical symptoms and biochemical
      findings that can be similar to those found in other types of porphyrias. Here,
      we provide an overview of historical, clinical, biochemical, genetical, and other
      aspects of variegate porphyria that might be helpful in providing more insight
      into this rare disorder.

PMID- 10343201
TI  - The genetic bases of the porphyrias.
AB  - The porphyrias are disorders that result from the inherited or acquired
      dysregulation of one of the eight enzymes in the porphyrin-heme biosynthetic
      pathway. The different types of porphyrias often show overlapping findings with
      regard to clinical and/or biochemical features. Therefore, the establishment of
      screening methods for the identification of underlying mutations on the basis of
      direct DNA analysis may provide a more reliable approach for diagnosis of the
      different types of porphyrias. Here, we provide an overview of molecular
      biological screening techniques for mutations and the molecular bases of the
      porphyrias.

PMID- 10343203
TI  - Porphyria cutanea tarda.
AB  - Porphyria cutanea tarda (PCT) is the most frequent form of porphyria. The
      underlying enzymatic defect in PCT is a reduced activity of the enzyme
      uroporphyrinogen decarboxylase (Uro-D). Four different types of Uro-D
      disturbances are known. Pseudoporphyrias such as porphyria cutanea uraemica or
      drug-induced PCT-like skin symptoms are distinguished from PCT. Porphyrinogens
      such as estrogens or alcohol, or other inducers of P450 isoenzymes provoke PCT.
      Polymorphisms of P450 isoenzymes, iron overload and infection with hepatitis C
      virus play an important role in the etiopathogenesis of disease manifestation.
      Dominant clinical symptoms are bullae, increased cutaneous vulnerability,
      hypertrichosis and elastosis. Biochemically, total porphyrin levels in urine are
      increased with a predominance of uroporphyrin and heptacarboxylic porphyrin.
      Isocoproporphyrin is demonstrable in feces. Best therapeutic strategies are the
      oral administration of chloroquine 125 mg twice a week and repetitive
      bloodlettings or the combination of both.

PMID- 10343204
TI  - Perspectives of photodynamic therapy for skin diseases.
AB  - Photodynamic therapy (PDT) is largely an experimental modality for the treatment
      of neoplastic and selected nonneoplastic diseases. This therapeutic procedure,
      through a cascade of events, leads to cell killing. In the past few years,
      dermatology has taken advantage of PDT for the treatment of skin cancer and other
      skin diseases. The skin has considerable attributes over many other organs for
      the application of PDT. These include the accessibility to all three PDT
      essential requirements; the drug (photosensitizing agent), visible light and
      oxygen. The major benefit of experimental PDT in dermatology is the ability to
      assess the clinical response visually and the relative ease in obtaining biopsies
      for precise biochemical and histological analysis. Currently, PDT has received
      approval worldwide for the ablation of various tumor types. In the United States,
      the Food and Drug Administration has approved PDT for the treatment of advanced
      esophageal cancer and selected patients with lung cancer. Clinical trials,
      employing several types of photosensitizers for PDT, are ongoing for a variety of
      dermatological lesions. This review summarizes current knowledge of PDT in
      dermatology and highlights future perspectives of this modality for effective
      management of skin diseases.

PMID- 10343205
TI  - Congenital erythropoietic porphyria.
AB  - Congenital erythropoietic porphyria (CEP) is one of the rarest autosomal
      recessive disorders of the porphyrin metabolism caused by the homozygous defect
      of uroporphyrinogen III cosynthase. High amounts of uroporphyrin I accumulate in
      all cells and tissues, reflected by an increased erythrocyte porphyrin
      concentration and excretion of high porphyrin amounts in urine and feces. Dermal
      deposits of uroporphyrin frequently induce a dramatic phototoxic oxygen-dependent
      skin damage with extensive ulcerations and mutilations. Splenomegaly and
      hemolytic anemia are typical internal symptoms. Skeletal changes such as
      osteolysis and calcifications are frequent. Up to date 130 cases of CEP have been
      published. Splenectomy and erythrocyte transfusions showed some beneficial
      effect. Bone marrow transplantation was performed in 3 patients and stem cell
      transplantation in 1. The best therapy is the avoidance of sunlight. We give a
      report on our latest cases of CEP.

PMID- 10343206
TI  - Photodynamic diagnosis and therapy in dermatology.
AB  - The topical application of delta-aminolevulinic acid (ALA) induces porphyrin
      formation in the skin, preferentially in tumor tissues. Irradiation of the
      porphyrin-enriched tumor tissue with Wood's light leads to emission of a brick
      red fluorescence. This principle may be used as a diagnostic procedure which may
      be termed photodynamic diagnosis (PDD). In ALA-PDD, tumors and precancerous
      lesions of the skin reveal a homogeneous, intensive red fluorescence. Psoriatic
      lesions also show a strong but inhomogeneous porphyrin fluorescence. ALA-induced
      porphyrin fluorescence in preoperative planning is a valuable method to determine
      the peripheral borders of a given tumor. The histopathological extensions of the
      tumors correlate well with the borders detected by the tumor-specific
      fluorescence. The main indications of PDD are the delineation of clinically ill
      defined skin tumors and the control of the efficacy of other tumor therapies.
      Photodynamic therapy (PDT) utilizes exogenously applied or endogenously formed
      photosensitizers and their activation by light to induce cell death via formation
      of singlet oxygen and other free radicals. PDT is highly efficient in the
      treatment of solar keratoses and superficial basal cell carcinomas. Initial
      squamous cell carcinomas also show good response to ALA-PDT. During the last
      decade, numerous studies on PDT for dermatologic diseases were published, the
      more important ones are reviewed here.

PMID- 10343207
TI  - Acute intermittent porphyria: mutation analysis and identification of gene
      carriers in a German kindred by PCR-DGGE analysis.
AB  - Acute intermittent porphyria (AIP) is the most frequent acute porphyria.
      Symptomatic patients and asymptomatic gene carriers are characterized by a
      reduction of their porphobilinogen-deaminase (PBG-D) activity to 50%, which is
      sufficient for porphyrin biosynthesis. PBG-D is encoded by two different mRNAs
      which are expressed in a tissue-specific manner. In classical AIP, the enzyme
      activity is reduced in erythroblasts and all other heme-forming body cells,
      whereas in the variant form of AIP, the PBG-D activity in erythroid tissues
      remains normal. Acute porphyria attacks can occur in gene carriers when the
      biosynthesis of heme is increased by drugs, low calorie intake, alcohol
      consumption or infections. Under these conditions, PBG-D cannot convert the
      precursors adequately so that PBG and delta-aminolevulinate accumulate. This may
      lead to neurovisceral symptoms and other neurological complications which are
      potentially life threatening. In patients with AIP, mutation analysis by PCR-DGGE
      (denaturing gradient gel electrophoresis) is becoming increasingly important
      since it also permits rapid identification of their presymptomatic relatives.
      Using this technique, more than 120 mutations have been identified in the PBG-D
      gene. When identified, the family members are informed about their genetic
      predisposition and are taught how to prevent porphyric attacks. Here, I
      illustrate this preventive strategy by describing a German kindred of an affected
      patient with the variant form of AIP with 17 family members.

PMID- 10343208
TI  - Efficacy and safety of intravenous propofol sedation during routine ERCP: a
      prospective, controlled study.
AB  - BACKGROUND: Adequate patient sedation is mandatory for diagnostic and therapeutic
      endoscopic retrograde cholangiopancreatography (ERCP). The short-acting
      anesthetic propofol offers certain potential advantages for endoscopic
      procedures, but controlled studies proving its superiority over benzodiazepines
      for ERCP are lacking. METHODS: During a 6-month period 198 consecutive patients
      undergoing routine ERCP randomly received either midazolam (n = 98) or propofol
      (n = 99) for sedation. Vital signs (heart rate, blood pressure, oxygen
      saturation) were continuously monitored and procedure-related parameters, the
      recovery time and quality (recovery score) as well as the patient's cooperation
      and tolerance of the procedure (visual analog scales) were prospectively
      assessed. RESULTS: Patients receiving propofol or midazolam were well matched
      with respect to demographic and clinical data, ERCP findings, and the performance
      of associated procedures. Propofol caused a more rapid onset of sedation than
      midazolam (p < 0.01). Clinically relevant changes in vital signs were observed at
      comparable frequencies with temporary oxygen desaturation occurring (< 85 %) in 6
      patients in the propofol group and 4 patients receiving midazolam (not
      significant). However, an episode of apnea had to be managed by mask ventilation
      via an ambu bag (lasting 8 minutes) in one of the patients receiving propofol
      sedation. Mean recovery times as well as the recovery scores were significantly
      shorter with propofol (p < 0. 01). Propofol provided significantly better patient
      cooperation than midazolam ( p < 0.01), but procedure tolerability was rated the
      same by both groups of patients (not significant). CONCLUSIONS: Intravenous
      sedation with propofol for ERCP is (1) more effective than sedation with
      midazolam, (2) safe under adequate patient monitoring, and (3) associated with a
      faster postprocedure recovery.

PMID- 10343209
TI  - A comparison of midazolam and diazepam for conscious sedation during colonoscopy
      in a prospective double-blind study.
AB  - BACKGROUND: Midazolam and diazepam are commonly used for conscious sedation, but
      their comparative respiratory depressive effects have not been accurately
      studied. We used a novel real-time, on-line, computerized data acquisition system
      to compare the two agents in a randomized double-blind study. METHODS: One
      hundred patients undergoing colonoscopy were studied. The maximum end-tidal
      carbon dioxide tension (PetCO2) and the minimum oxygen saturation by pulse
      oximetry (SpO 2) were recorded by computer every minute. Patients received
      meperidine (25 to 50 mg) and incremental doses of either midazolam or diazepam to
      an identical end point of slurred speech and/or ptosis. Sedation was scored from
      1 (unarousable) to 5 (wide awake). RESULTS: Sedation scores were 3.6 +/- 0.1
      (mean +/- standard error) after each agent. The doses of midazolam and diazepam
      were 0. 031 +/- 0.002 and 0.106 +/- 0.009 mg/kg, respectively. In the first 45
      minutes (PetCO2) was significantly higher with midazolam than with diazepam (p <
      0.05). SpO2 was significantly depressed for 80 minutes after each agent, and the
      number of minutes when the minimum Sp O2 was less than 90% did not differ between
      the two agents. CONCLUSIONS: Midazolam was 3.4 times more potent than diazepam.
      The duration of oxygen desaturation emphasizes the importance of monitoring SpO2
      until ventilation and oxygenation have recovered. Although the degree of
      hypoxemia was comparable, midazolam led to higher end-tidal carbon dioxide
      tensions.

PMID- 10343210
TI  - Risk of sedation for upper GI endoscopy exacerbating subclinical hepatic
      encephalopathy in patients with cirrhosis.
AB  - BACKGROUND: The risk of exacerbating subclinical hepatic encephalopathy
      associated with the administration of sedative drugs in patients with cirrhosis
      undergoing diagnostic upper gastrointestinal (GI) endoscopy for portal
      hypertension remains to be determined. METHODS: Ten adult patients with cirrhosis
      completed number connection tests before sedation for endoscopy and at discharge
      from the endoscopy unit 2 hours post-procedure. Control patients consisted of
      five patients with cirrhosis undergoing the same procedure for the same
      indication who did not receive sedation and 12 patients with no evidence of liver
      disease who received sedation before diagnostic endoscopy for a variety of GI
      complaints. The control populations were age, gender, education level, and, in
      the case of patients with cirrhosis, Child Pugh s score matched to the patients
      with cirrhosis who received sedation. RESULTS: The mean (+/- SEM) age of patients
      with cirrhosis who received sedation was 59.6 +/- 3.8 years. Seven of the ten
      (70%) were men. Their mean Child Pugh s score was 7.2 +/- 1.5. Nine of the ten
      (90%) had abnormal baseline number connection tests results (mean for the group
      52.3 +/- 6.7 seconds) the extent of which correlated with Child Pugh s scores (p
      < 0.005). Individually, the baseline number connection tests results were normal
      in one (10%), mild in six (60%), moderate in one (10%), and severe in two (20%).
      After the procedure (before discharge) the mean number connection tests result
      was 61.5 +/- 7.9 seconds (p = 0.01 when compared with baseline). The results were
      now normal in none (0%), mild in four (40%), moderate in four (40%), and severe
      in two (20%). Pre- and post-procedure number connection tests results did not
      change in the non-sedated cirrhotic or sedated non-liver disease control
      patients. CONCLUSIONS: The results of this study indicate that (1) the majority
      of patients with cirrhosis and suspected portal hypertension have evidence of
      subclinical hepatic encephalopathy, (2) the extent of encephalopathy correlates
      with the Child Pugh's score, (3) sedation with midazolam for upper GI endoscopy
      exacerbates the encephalopathy, and (4) this adverse effect is still evident 2
      hours after the procedure.

PMID- 10343211
TI  - Prospective comparative evaluation of video US endoscope.
AB  - BACKGROUND: Limitations in the technical capabilities of the fiberoptic
      echoendoscope often necessitate concurrent diagnostic endoscopy at the time of an
      endosonographic (EUS) examination. Our aim was to determine whether a new video
      echoendoscope would allow the performance of EUS without diagnostic endoscopy.
      METHODS: EUS examinations on all patients at two centers were initiated with a
      fiberoptic echoendoscope (period of 5 weeks) or a video echoendoscope (period of
      6 weeks). Note was made of need for concurrent diagnostic endoscopy. The
      endosonographer also rated the mechanical, optical, and sonographic performance
      of the video instrument using a 9-point comparative scale (1 = much worse, 5 =
      equal to, and 9 = much better than fiberoptic echoendoscope). RESULTS: A total of
      103 patients including 40 and 28 with mural lesions and 22 and 15 with
      retroperitoneal lesions were examined with the fiberoptic and video
      echoendoscopes, respectively. Mean values for parameters rating the video
      echoendoscope's mechanical performance ranged between 5.0 and 5.9, optical
      performance ranged between 6.6 and 7.5, and sonographic performance ranged
      between 4.6 and 4.9. Concurrent diagnostic endoscopy was required less frequently
      when patients with mural lesions (18% vs. 70%, p < 0.005) or patients with
      retroperitoneal lesions (0% vs. 14%, p = no significance) were examined with the
      video echoendoscope compared with the fiberoptic echoendoscope. CONCLUSIONS:
      Moderately improved optics and slightly better mechanical characteristics of the
      new video echoendoscope allow the performance of EUS without concurrent
      diagnostic endoscopy in the majority of patients.

PMID- 10343212
TI  - Interobserver and intraobserver variation in endoscopic assessment of GERD using
      the "Los Angeles" classification.
AB  - BACKGROUND: A new endoscopic classification of gastroesophageal reflux disease
      (GERD) has been proposed, and the term mucosal break has been introduced to
      describe mucosal damage. This new classification was evaluated by endoscopists
      with different levels of experience. METHODS: Fifty endoscopic photographs for
      each of 20 randomly selected patients with GERD were assessed retrospectively by
      three groups of seven endoscopists classified by experience: group 1 (100 to 500
      procedures), group 2 (500 to 3000), and group 3 (more than 3000). The new
      classification was modified by adding grade 0 to describe healed mucosal breaks,
      so that there were five grades. All photographs were assessed twice at an
      interval of more than 1 week, and kappa statistics were used to determine
      observer variation. RESULTS: Interobserver variation within group 3 (kappa =
      0.39, n = 21) and between groups 3 and 2 (kappa = 0.36, n = 49) was significantly
      different (p < 0.01) from that between groups 3 and 1 (kappa = 0.26, n = 49).
      Intraobserver variation in group 1 (kappa = 0.39, n = 7) was significantly
      different (p < 0.01) from that in group 2 (kappa = 0.51, n = 7) and group 3
      (kappa = 0.54, n = 7). CONCLUSIONS: Observer variation depends on level of
      endoscopic experience. Only experienced endoscopists should use the new
      classification for grading of GERD.

PMID- 10343213
TI  - A prospective study of pancreatic disease in patients with alcoholic cirrhosis:
      comparative diagnostic value of ERCP and EUS and long-term significance of
      isolated parenchymal abnormalities.
AB  - BACKGROUND: The prevalence of pancreatic disease in patients with alcohol-related
      liver cirrhosis is uncertain. We assessed the prevalence of pancreatic
      abnormalities in patients with alcoholic cirrhosis, and we compared endoscopic
      ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP)
      for the detection of chronic pancreatitis and other pancreatic lesions. In
      addition, we assessed the long-term significance of isolated pancreatic
      parenchymal abnormalities detected at EUS. METHODS: EUS and ERCP were performed
      in each patient. Subjects with minimal parenchymal changes at initial EUS
      underwent clinical follow-up and subsequent EUS and/or ERCP to document the
      occurrence, absence, or progression of these changes. RESULTS: Seventy-two
      patients with alcoholic cirrhosis were recruited. Chronic pancreatitis was
      diagnosed in 14 patients (19%) by both methods independently. Isolated
      parenchymal lesions were observed in 18 patients by EUS alone. After a mean
      follow-up of 22 months the EUS appearance was unchanged. Ten of the 18 patients
      underwent follow-up ERCP and this was normal in all cases. CONCLUSIONS: This
      study demonstrated that (1) 19% of patients with alcoholic cirrhosis have chronic
      pancreatitis, (2) an additional 25% have isolated pancreatic parenchymal changes
      at EUS, and (3) these parenchymal abnormalities do not progress during follow-up.

PMID- 10343214
TI  - Endoscopic pancreatic duct stenting to treat pancreatic ascites.
AB  - BACKGROUND: Management of pancreatic ascites with conservative medical therapy or
      surgery has met with limited success. Decompression of the pancreatic ductal
      system through transpapillary stent placement, an alternative strategy, has been
      reported in only a handful of cases of pancreatic ascites. METHODS: We reviewed
      all cases from 1994 to 1997 in which patients with pancreatic ascites underwent
      an endoscopic retrograde pancreatogram documenting pancreatic duct disruption
      with subsequent placement of a transpapillary pancreatic duct stent. Clinical end
      points were resolution of ascites and need for surgery. RESULTS: There were 8
      cases of pancreatic ascites in which a 5F or 7F transpapillary pancreatic duct
      stent was placed as the initial drainage procedure. Pancreatic ascites resolved
      in 7 of 8 patients (88%) within 6 weeks. Ascites resolved in the eighth patient,
      a poor candidate for surgery, following placement of a 5 mm expandable metallic
      pancreatic stent. No infections, alterations in ductal morphology, or other
      complications related to stent placement were noted. There was no recurrence of
      pancreatic ascites or duct disruption at a mean follow-up of 14 months.
      CONCLUSIONS: Our experience doubles the number of reported cases in which
      transpapillary pancreatic stent placement safely obviated the need for surgical
      intervention in the setting of pancreatic ascites. This therapeutic endoscopic
      intervention should be seriously considered in the initial management of patients
      with pancreatic ascites.

PMID- 10343215
TI  - The effect of endoscopic sphincterotomy on acute and chronic complications of
      biliary endoprostheses.
AB  - BACKGROUND: Endoscopically placed biliary stents have become routine therapy for
      bile duct obstruction and bile leaks. Controversy exists regarding the use of
      biliary sphincterotomy to facilitate placement of 10F plastic stents. METHODS: We
      retrospectively studied the effect of sphincterotomy on acute and chronic
      complications of 10F stent therapy. Data for acute complications, 30-day
      mortality and stent migration were obtained for 130 patients undergoing placement
      of a single 10F plastic biliary stent. For 109 patients in whom prolonged stent
      therapy was undertaken, the occurrence of and time to stent dysfunction were also
      analyzed. Sphincterotomy was performed in 48 cases (36.9%) based on physician
      preference. RESULTS: There were no failures in stent placement. The incidence of
      acute complications was higher in patients undergoing sphincterotomy (8.3% vs.
      1.2%, p = 0.04). Stent migration was more common in the no sphincterotomy group
      versus the sphincterotomy group (8.5% vs. 0, p = 0.03). CONCLUSIONS:
      Sphincterotomy is not necessary for placement of 10F plastic stents and increases
      acute procedural morbidity. Interestingly, a higher incidence of stent migration
      was seen in patients who did not undergo biliary sphincterotomy.

PMID- 10343216
TI  - Benefit of intravenous antispasmodic (hyoscyamine sulfate) as premedication for
      colonoscopy.
AB  - BACKGROUND: We sought to determine whether premedication for colonoscopy with
      intravenous hyoscyamine sulfate (Levsin) was helpful from the standpoint of the
      colonoscopist and the patient. METHODS: One hundred sixteen adult patients were
      randomized to receive either 0.5 mg hyoscyamine sulfate intravenous (n = 57) or
      placebo (n = 59). After administration of study drug, patients were given
      meperidine and midazolam. Parameters measured included the time required to reach
      the cecum, total procedure time, and the endoscopist's perception of the adequacy
      of sedation, difficulty of insertion, and amount of colonic spasm on insertion
      and withdrawal. Patients were given a postprocedure questionnaire assessing their
      experience. RESULTS: In patients receiving hyoscyamine, there was a shorter cecal
      intubation time (median 9.2 vs. 12.9 minutes; p = 0. 01), shorter total
      colonoscopy time (median 20.5 vs. 25.0 minutes; p = 0.01), better patient
      sedation (p = 0.02), easier colonic insertion (p = 0.001), and less spasm on
      insertion (p = 0.01). No difference was found in the amount of spasm during
      withdrawal or the total dosages of meperidine or midazolam used. Patients
      receiving hyoscyamine sulfate reported being more comfortable during their
      procedures ( p < 0.001) and were more willing to repeat colonoscopy in the future
      (p = 0.0001). The only adverse effect seen during the study was a 27% incidence
      of sinus tachycardia that occurred in patients receiving hyoscyamine.
      CONCLUSIONS: Premedication with intravenous hyoscyamine sulfate was beneficial in
      terms of the time required for cecal intubation, total procedure time, adequacy
      of sedation, and scales of patient comfort. However, the high frequency of sinus
      tachycardia seen with the dose used in our study, which was extremely rapid in
      two patients, indicates the need for further study before the drug can be
      recommended as a routine premedication for colonoscopy.

PMID- 10343217
TI  - Prospective determination of distal colon findings in average-risk patients with
      proximal colon cancer.
AB  - BACKGROUND: Recent guidelines indicate that colonoscopy and sigmoidoscopy are
      both acceptable options for screening average-risk patients for colorectal
      cancer. Retrospective studies have found that a majority of patients with cancer
      proximal to the splenic flexure have a normal screening flexible sigmoidoscopy.
      METHODS: This was a multicenter, prospective description of colonoscopic findings
      and family history in consecutive patients with proximal colon cancer. RESULTS:
      Among 116 prospectively identified average-risk patients with cancer proximal to
      the splenic flexure, 40 (34.5%) had neoplasia distal to the splenic flexure. The
      prevalence of patients with adenomas greater than or equal to 1 cm, with only one
      tubular adenoma less than 1 cm, and with only hyperplastic polyps were 16.4%,
      8.6%, and 6.9%, respectively. CONCLUSIONS: Most average-risk patients with cancer
      proximal to the splenic flexure will have a normal screening flexible
      sigmoidoscopy. These patients have an unexpectedly high prevalence of large
      distal adenomas, but the prevalence of both single small tubular adenomas and
      hyperplastic polyps alone is similar to that expected during screening of the
      general population. Clinicians and payers should continue to seek methods to
      improve the cost-effectiveness and availability of screening colonoscopy in
      average-risk persons.

PMID- 10343219
TI  - Serrated adenoma of the colorectum: colonoscopic and histologic features.
AB  - BACKGROUND: Serrated adenoma is a recently recognized epithelial neoplasm of the
      colorectum. The aim of this study is to clarify the colonoscopic features of
      serrated adenomas. METHODS: The endoscopic findings for 52 serrated adenomas of
      the colorectum were investigated; these were then divided into three groups
      according to surface features. The histologic type (tubular, tubulovillous or
      villous) and the incidence of high-grade dysplasia were compared among the three
      groups. RESULTS: The surface under chromoscopy showed a hyperplastic pattern in
      17 lesions, a cerebriform pattern in 18 lesions and a combined pattern in 17
      lesions. The tubular type of serrated adenoma was predominant in the hyperplastic
      pattern group (94%), whereas the tubulovillous or villous histologic types were
      frequent in the cerebriform pattern (89%) and combined pattern (82%) groups. High
      grade dysplasia was found in 18% of the combined pattern adenomas; the incidence
      was lower in hyperplastic (6%) or cerebriform pattern (0%) adenomas. CONCLUSIONS:
      Surface features of serrated adenomas have a close correlation with their
      histologic type. A combined hyperplastic-cerebriform surface pattern under
      chromoscopy was seen only in serrated adenomas.

PMID- 10343218
TI  - Large sessile colonic adenomas: use of argon plasma coagulator to supplement
      piecemeal snare polypectomy.
AB  - BACKGROUND: Residual adenoma is frequently found at the site of endoscopically
      resected large sessile adenomas on follow-up examination. We evaluated the
      efficacy of a thermal energy source, the argon plasma coagulator, to destroy
      visible residual adenoma after piecemeal resection of sessile polyps. METHODS:
      Seventy-seven piecemeal polypectomies with or without the use of argon plasma
      coagulator were analyzed retrospectively. All polyps were sessile, 20 mm or
      greater in size. The results from three groups of patients were compared. The
      study group was composed of patients who had visible residual adenoma after
      piecemeal polypectomy and had the base of the polypectomy site treated with the
      argon plasma coagulator. The first comparison group consisted of patients who
      underwent standard piecemeal polypectomy in whom the colonoscopist thought that
      all adenomatous tissue was removed and no further treatment was necessary. The
      second comparison group included patients in whom visible residual adenoma was
      left at the base after piecemeal resection of large adenomas. Follow-up
      colonoscopy was performed approximately 6 months after the initial procedure to
      check for recurrent/residual adenomatous tissue. RESULTS: The argon plasma
      coagulator was used after 30 piecemeal polypectomies in an attempt to eradicate
      visible residual adenomatous tissue; at follow-up, 50% of these cases had
      complete eradication of adenoma. The group in whom all visible tumor was removed
      by piecemeal polypectomy alone had an adenoma eradication rate of 54% on follow
      up colonoscopy. In the patients in whom visible residual adenoma was left at the
      site the recurrence rate was 100% on the follow-up examination. Bleeding
      necessitating endoscopic therapy occurred once (3.3%) in the argon plasma
      coagulator group; there were four (12.5%) bleeding episodes and one (3.1%)
      confined retroperitoneal perforation in the complete piecemeal polypectomy group
      and no complications in the group in which polypectomy was incomplete.
      CONCLUSIONS: Argon plasma coagulator ablation of residual adenomatous tissue at
      the polypectomy base is safe and useful. It helps to complete the eradication of
      large sessile polyps when there is visible evidence of residual polyp.

PMID- 10343220
TI  - Appendiceal orifice inflammation as a skip lesion in ulcerative colitis: an
      analysis in relation to medical therapy and disease extent.
AB  - BACKGROUND: Although several reports have claimed that the appendix can be
      involved as a skip lesion in ulcerative colitis, they do not exclude the
      possibility that this skip lesion occurs as a result of medical therapy. Also,
      little is known about the relation between the presence of appendiceal orifice
      inflammation and the extent of the disease. METHODS: The presence of appendiceal
      orifice inflammation was prospectively assessed both endoscopically and
      histologically in 94 patients with active ulcerative colitis, the extent of whose
      disease had not been beyond the hepatic flexure. To evaluate the effect of prior
      medical therapy on the prevalence of appendiceal orifice inflammation, all cases
      were divided into two groups. Group A consisted of 66 patients who had been
      treated before inclusion; group B was composed of 28 patients newly diagnosed at
      inclusion. RESULTS: Appendiceal orifice inflammation was diagnosed in 24 (26%) of
      94 patients with active subtotal ulcerative colitis, with no statistical
      difference observed between group A (23%) and group B (32%). In all 94 patients,
      the frequency of appendiceal orifice inflammation decreased significantly as the
      extent of disease increased, i.e., 37% in proctitis (n = 49), 17% in left-sided
      colitis (n = 36), and 0% in extensive colitis (n = 9) (p < 0.05). CONCLUSIONS:
      Appendiceal orifice inflammation as a skip lesion of ulcerative colitis is not
      rare, is more frequently observed in patients with less extensive disease, and is
      not the result of patchy improvement due to medical therapy.

PMID- 10343221
TI  - Risk factors for recurrent bleeding and mortality in human immunodeficiency virus
      infected patients with acute lower GI hemorrhage.
AB  - BACKGROUND: Little is known about lower gastrointestinal (GI) hemorrhage in the
      human immunodeficiency virus (HIV) infected population. Our aim was to determine
      the underlying causes, the clinical outcome, and the risk factors for recurrent
      bleeding and mortality in HIV-infected patients with acute LGIH. METHODS: We
      reviewed the medical records of consecutive HIV-infected patients with acute
      lower GI hemorrhage who were evaluated with endoscopy from January 1992 through
      January 1997 at Bellevue Hospital Center. RESULTS: During the 5-year study
      period, 312 patients with acute lower GI hemorrhage underwent colonoscopy (n =
      233) or flexible sigmoidoscopy (n = 79). Cytomegalovirus colitis (25.3%),
      lymphoma (12.2%), and idiopathic colitis (12.2%) were the most common causes
      identified. Within 30 days of presentation, recurrent bleeding occurred in 17.6%
      of patients. Independent predictors of recurrent bleeding included the presence
      of at least one comorbid illness, a hemoglobin level of less than 8 gm/dL, a
      platelet count of less than 100,000/mm3, and major stigmata of hemorrhage. The 30
      day mortality from lower GI hemorrhage was 14.4%, and the presence of comorbid
      disease, recurrence of bleeding, and surgical intervention were found to be the
      only independent predictors of mortality in this patient population. CONCLUSIONS:
      Acute lower GI hemorrhage in HIV-infected patients is most commonly caused by
      cytomegalovirus colitis and is associated with a high short-term morbidity and
      mortality.

PMID- 10343222
TI  - Results of EUS in detecting perirectal lymph node metastases of rectal cancer:
      the pathologist makes the difference.
AB  - BACKGROUND: Accurate preoperative staging of primary rectal cancer is mandatory
      because the result may affect therapeutic decisions. Endoscopic ultrasonography
      (EUS) is considered the most accurate method for locoregional staging, but the
      issue of possible variations in the assessment of its accuracy related to
      technical aspects of pathologic staging has never been raised. The aim of this
      study was to assess EUS results as determined by two different methods of
      dissection of surgical specimens. METHODS: Among all cases with primary rectal
      cancer staged with EUS from April 1991 to April 1997, 131 patients underwent
      surgery without preoperative radiotherapy; EUS results for nodal staging were
      compared with those obtained by pathology. Resected specimens were examined using
      two different techniques (conventional vs. special dissection). RESULTS: There
      was a significant decrease in diagnostic accuracy of EUS according to pathologic
      technique. Overall accuracy, sensitivity, specificity, positive and negative
      predictive values for conventional versus special dissection were as follows:
      74.6% vs. 43. 3% (p = 0.0001), 67.8% vs. 21.8% (p = 0.0002), 79.1% vs. 67.8% (p =
      0.14), 67.8% vs. 43.7% ( p = 0.02), and 79.1% vs. 43.2% (p = 0.0003),
      respectively. EUS sensitivity according to size of metastatic lymph nodes was
      significantly lower for nodes smaller than 5 mm in diameter (p = 0.025) when
      special dissection was performed because of a larger number of lymph nodes
      harvested. CONCLUSIONS: Our findings raise concern about the results of EUS
      staging of lymph node metastases in rectal cancer. Further prospective studies on
      a node-by-node basis could clarify the real diagnostic yield of EUS.

PMID- 10343223
TI  - Juvenile polyp emerging from the appendiceal orifice.

PMID- 10343224
TI  - Photodynamic therapy of cancer of the esophagus using systemic aminolevulinic
      acid and a non laser light source: a phase I/II study.
AB  - BACKGROUND: Surgery is the mainstay for the treatment of carcinoma of the
      esophagus and is also considered to be effective for palliation of dysphagia.
      Patients who are unfit for surgery represent a difficult therapeutic problem. The
      goal of the present study was to evaluate the effects of photodynamic therapy by
      using systemic administration of 5-aminolevulinic acid and a non laser light
      source on carcinoma of the esophagus. METHODS: Patients were given 60 mg/kg 5
      aminolevulinic acid orally. Twenty-four hours later gastroscopy was performed.
      After initial localization of the tumor with the use of white light, the light
      source was switched to the red light band at 100 J/cm2 for 600 seconds.
      Gastroscopy was repeated at 48 hours and 7 days after the treatment. The degree
      of dysphagia was recorded before and 14 days after treatment. RESULTS: Five
      patients with advanced nonresectable tumors or who were unfit for surgery were
      treated. Two patients had squamous cell carcinoma of the mid-esophagus and three
      had adenocarcinoma of the distal esophagus. Mild self-limiting photosensitivity
      was noted in all patients. Liver and renal function tests as well as hemoglobin
      level and white blood cell count were not affected by the treatment. Improvement
      of dysphagia was observed in four patients who had pretreatment dysphagia. The
      patient with the early stage of disease continued to eat a normal diet.
      CONCLUSIONS: Photodynamic therapy with systemic aminolevulinic acid as a
      photosensitizer and a non laser light source is feasible and safe in advanced
      stage esophageal cancer. It can be an effective modality for the relief of
      dysphagia in these patients.

PMID- 10343225
TI  - Endoscopic injection of bleeding esophageal varices with a poly-N-acetyl
      glucosamine gel formulation in the canine portal hypertension model.
AB  - BACKGROUND: It has been shown that poly-N-acetyl glucosamine produces rapid
      hemostasis by stimulating erythrocyte aggregation. Endoscopic injection of this
      substance may be effective in the treatment of bleeding varices. METHODS: In
      eight heparinized dogs with a bleeding esophageal varix greater than 2 mm in
      diameter, 2.5% to 3.5% poly-N-acetyl glucosamine gel was injected intravariceally
      and paravariceally. Endoscopy, endosonography, and histopathology were performed
      at 1, 7, 21, and 90 days after injection. RESULTS: In all cases, the variceal
      hemorrhage was stopped with three to four injections of a mean total gel volume
      of 1.9 mL. No recurrence of bleeding, ulceration, or stricture formation
      occurred. Through replacement of the gel by connective tissue, the varix was
      permanently obliterated in its whole course in five cases and in more than 70% of
      its length in three cases. No embolization and no poly-N-acetyl glucosamine
      antibodies were detected. CONCLUSIONS: Endoscopic injection of bleeding
      esophageal varices in this animal model with the use of poly-N-acetyl glucosamine
      gel was an effective and safe method for stopping the hemorrhage and inducing
      permanent varix obliteration.

PMID- 10343227
TI  - Treatment of spontaneous esophageal rupture with a covered self-expanding metal
      stent.

PMID- 10343226
TI  - First clinical application of a newly developed device for intragastric surgery
      for the treatment of pancreatic pseudocysts.
AB  - BACKGROUND: Instruments that have been used during GI endoscopy have always been
      confined to the accessory channel of the endoscope. We have therefore developed a
      device that allows transabdominal manipulation in the stomach under gastroscopic
      control. Here we report the first clinical application of this device, which was
      used for the drainage of pancreatic pseudocysts. METHODS: The device is similar
      to a PEG tube and consists of a 7 mm polyethylene tube that is inserted by the
      "thread pull through" method. A trocar valve is mounted at the external tip of
      the tube. Four pseudocysts were treated in three patients. The retrogastric
      pseudocysts were punctured through the device under endoscopic (n = 2) and CT (n
      = 2) guidance. External drainage was used for 3 to 5 days; thereafter the drain
      was cut and internalized. The device was also cut and sealed. After 10 days it
      was removed as with a standard PEG tube. RESULTS: No complications related to the
      device occurred. In two patients the pseudocysts resolved completely. One patient
      had to undergo pseudocystojejunostomy for an infected pseudocyst containing large
      amounts of necrotic material. CONCLUSIONS: We believe that our new device is
      valuable to the further development of intragastric surgery and can be used to
      safely perform pseudocystogastrostomy.

PMID- 10343228
TI  - Case of Boerhaave's syndrome successfully treated with a self-expandable metallic
      stent.

PMID- 10343229
TI  - Ability of EUS with fine-needle aspiration to document nodal staging and response
      to neoadjuvant chemoradiotherapy in locally advanced esophageal cancer: a case
      report.

PMID- 10343230
TI  - Colonic mucosal speckling detected by endoscopy: histopathologic differential
      diagnosis.

PMID- 10343231
TI  - Chronic pancreatitis resulting from primary hydatid disease of the pancreas: a
      case report and review of the literature.

PMID- 10343233
TI  - The use of endoprostheses in biliary fistula of hydatid cyst.

PMID- 10343232
TI  - Acute pancreatitis caused by hydatid membranes in the biliary tract: treatment
      with endoscopic sphincterotomy.

PMID- 10343234
TI  - A new technique to retrieve an intrabiliary stent: a case report.

PMID- 10343235
TI  - Propofol in the endoscopy suite: an anesthesiologist's perspective.

PMID- 10343236
TI  - An agenda for the start of the new millennium.

PMID- 10343237
TI  - Inoperable esophageal carcinoma.

PMID- 10343238
TI  - Comment 

PMID- 10343239
TI  - Fiberoptic flexible sigmoidoscopy and pelvic masses.

PMID- 10343240
TI  - Response 

PMID- 10343241
TI  - Endoscopic diagnosis of villous atrophy.

PMID- 10343242
TI  - Response 

PMID- 10343243
TI  - Renewal of endoscopic privileges: guidelines for clinical application. From the
      ASGE. American Society for Gastrointestinal Endoscopy.

PMID- 10343244
TI  - Endoscopy by non-physicians: guidelines for clinical application. From the ASGE.
      American Society for Gastrointestinal Endoscopy.

PMID- 10343245
TI  - Guidelines for training in electronic ultrasound: guidelines for clinical
      application. From the ASGE. American Society for Gastrointestinal Endoscopy.

PMID- 10343246
TI  - The role of endoscopy in the management of GERD: guidelines for clinical
      application. From the ASGE. American Society for Gastrointestinal Endoscopy.

PMID- 10343247
TI  - Infection control during gastrointestinal endoscopy: guidelines for clinical
      application. From the ASGE. American Society for Gastrointestinal Endoscopy.

PMID- 10343248
TI  - Quality improvement of gastrointestinal endoscopy: guidelines for clinical
      application. From the ASGE. American Society for Gastrointestinal Endoscopy.

PMID- 10343249
TI  - Principles of training in gastrointestinal endoscopy. From the ASGE. American
      Society for Gastrointestinal Endoscopy.

PMID- 10343250
TI  - Technology status evaluation: personal protective equipment: November 1998. From
      the ASGE. American Society for Gastrointestinal Endoscopy.

PMID- 10343251
TI  - Technology status evaluation: magnetic resonance cholangiopancreatography:
      November 1998. From the ASGE. American Society for Gastrointestinal Endoscopy.

PMID- 10343252
TI  - Technology status evaluation: sheathed endoscopes: November 1998. From the ASGE.
      American Society for Gastrointestinal Endoscopy.

PMID- 10343253
TI  - Adjuvant treatment of refractory lung transplant rejection with extracorporeal
      photopheresis.
AB  - BACKGROUND: Extracorporeal photopheresis is an immunomodulatory technique in
      which a patient's leukocytes are exposed to ultraviolet-A light after
      pretreatment with 8-methoxypsoralen (methoxsalen). There have been few reports
      describing the use of extracorporeal photopheresis in lung transplant recipients.
      METHODS: We reviewed our experience using extracorporeal photopheresis in 8 lung
      transplant recipients since 1992. All 8 patients had progressively decreasing
      graft function and 7 were in bronchiolitis obliterans syndrome grade 3 before the
      initiation of photopheresis. One patient had undergone a second transplant
      operation for obliterative bronchiolitis. Two patients had a pretransplantation
      diagnosis of chronic obstructive pulmonary disease, 1 alpha1-antitrypsin
      deficiency, 1 cystic fibrosis, 1 bronchiectasis, 1 idiopathic pulmonary fibrosis,
      and 2 primary pulmonary hypertension. Before refractory rejection developed, all
      patients had been treated with 3-drug immunosuppression and anti-T-cell therapy.
      The median time from transplantation to the start of extracorporeal photopheresis
      was 16.5 months and the median number of treatments was 6. RESULTS: The condition
      of 5 of 8 patients subjectively improved after extracorporeal photopheresis
      therapy. In these 5 patients photopheresis was associated with stabilization of
      the forced expiratory volume in 1 second. In 2 patients there was histologic
      reversal of rejection after photopheresis. With a median follow-up of 36 months,
      7 patients are alive and well. Three patients required retransplantation at a
      median of 21 months after completion of the treatments. Four patients have
      remained in stable condition after photopheresis. There were no complications
      related to extracorporeal photopheresis. CONCLUSION: We believe that this
      treatment is a safe option for patients with refractory lung allograft rejection
      when increased immunosuppression is contraindicated or ineffective.

PMID- 10343254
TI  - Maximal period of cryopreservation with the Bicell biofreezing vessel for rat
      tracheal isografts.
AB  - OBJECTIVE: The maximal period of cryopreservation for the trachea is still
      unsolved. We assessed the maximal period of cryopreservation using the Bicell
      biofreezing vessel as an easy and cheap slow-freezing instrument for viable
      tracheal grafts in 95 rats. METHODS: Each isograft was harvested from 17 donor
      rats, immersed in the preservative solution, and stored in a Bicell device in a
      deep freezer at -80 degrees C. The tracheal isografts were then randomly assigned
      to 9 groups according to cryopreservation periods ranging from 0 to 12 months.
      Included in the 9 groups were 2 subgroups (n = 6 per subgroup) that were observed
      immediately after being thawed and 1 month after heterotopic transplantation into
      the omentum after being thawed. Four subgroups (n = 6 per subgroup) were added
      according to the cryopreservation period for 1, 3, 6, and 12 months to evaluate
      the graft morphology 3 months after being thawed and transplanted
      heterotopically. RESULTS: A prolonged period of cryopreservation had a
      degenerative effect on both the epithelium and cartilage. One month after
      transplantation, degeneration was more pronounced in the cartilage than in the
      epithelium, as characterized by the viable chondrocyte ratio and the epithelial
      score of isografts undergoing cryopreservation for more than 9 months. Three
      months after transplantation, the morphology of the epithelium and cartilage in
      isografts undergoing cryopreservation for less than 3 months was better
      preserved, whereas the morphology of both deteriorated in isografts undergoing
      cryopreservation for more than 6 months. CONCLUSIONS: We conclude that the
      permissible period of cryopreservation to maintain tracheal isograft viability in
      this simple system using a Bicell biofreezing vessel is 3 months.

PMID- 10343255
TI  - Esophagectomy with gastric reconstruction for achalasia.
AB  - PURPOSE: Achalasia is a degenerative esophageal disorder that may result in
      esophageal failure necessitating resection for restoration of gastrointestinal
      function. This study evaluates a protocol of esophageal resection and gastric
      reconstruction for end-stage achalasia. METHODS: Hospital records, radiographic
      studies, and resection specimens of patients undergoing esophagectomy and gastric
      reconstruction were reviewed. Patient outcome was defined by an evaluation of
      symptoms (early satiety, dysphagia, regurgitation, and reflux), dietary
      restrictions, and ability to maintain or gain weight. Preoperative, operative,
      and postoperative variables and pathologic features in the resection specimens
      were analyzed to determine predictors of outcome. RESULTS: In a 10-year period,
      32 patients underwent esophagectomy with gastric reconstruction for achalasia; 30
      (94%) underwent elective surgery and 2 (6%), emergency surgery. No postoperative
      deaths occurred. Of 29 patients completing telephone interviews, 24 (83%) had no
      or mild dysphagia; 21 (72%), no or mild regurgitation; 20 (69%), no or mild
      reflux; and 19 (66%), no or mild early satiety. Twenty-four (83%) patients had no
      or minimal dietary restrictions; 26 (90%) had no or minimal social dietary
      restrictions. Postoperative weight was not different from preoperative weight. Of
      30 patients, 26 (87%) felt better after esophagectomy and 25 (83%) would have the
      operation again. There were few predictors of outcome. Younger patients were more
      likely to have dysphagia ( P =.03). CONCLUSIONS: Esophagectomy with gastric
      reconstruction relieves preoperative dysphasia and regurgitation in the majority
      of patients. Dietary function and weight maintenance are excellent, attesting to
      the durability of the procedure in patients with end-stage achalasia.

PMID- 10343256
TI  - Superior sulcus lung tumors: impact of local control on survival.
AB  - OBJECTIVES: Our goal was to assess patient survival and response to treatment for
      superior sulcus tumors treated with combined radiation therapy and surgery when
      possible, or with radiation alone when surgery was not possible. METHODS: Seventy
      three patients were treated for primary non-small cell carcinoma of the superior
      pulmonary sulcus. Thirty-four patients received combined resection and
      irradiation. Thirty-nine patients who had extensive primary disease, distant
      metastases, or who were medically unfit for surgery were treated with radiation
      alone. Thirty-one patients (91%) assigned to the resection/irradiation group
      completed treatment. Combined therapy patients routinely received 40 Gy before
      the operation, with additional postoperative irradiation based on the surgical
      findings. RESULTS: Overall survival at 5 years was 19% and disease-specific
      survival was 20% for all patients. Overall survival and disease-specific survival
      at 5 years for the resection/irradiation group were 33% and 38%, respectively.
      Significant indicators of poor prognosis included unresected primary disease, low
      performance score, T4 stage, or positive node status. Eighty-two percent of the
      patients who received irradiation alone were treated with palliative intent.
      Freedom from local-regional progression, achieved initially in 66% of these
      patients, was associated with a median survival of 8 months. Median survival for
      7 patients considered for definitive irradiation was 25 months. During the first
      18 months, distant failures occurred in approximately 35% of patients in each
      treatment group. CONCLUSIONS: Selection of medically fit patients with resectable
      disease for combined surgery and aggressive radiation therapy resulted in a high
      likelihood of local control. Overall survival for the resection/irradiation group
      was significantly poorer for patients with T4 stage, nodal disease, or Horner's
      syndrome. Distant metastases eventually developed in 56% of patients undergoing
      resection. Median survival in the resection/irradiation group was significantly
      prolonged for those patients who could tolerate high-dose radiation treatment.

PMID- 10343257
TI  - Completion pneumonectomy: experience in eighty patients.
AB  - OBJECTIVE: Because completion pneumonectomy is a procedure reputed to place
      patients at risk, we reviewed our results with the objective of identifying
      factors that influence complications and survival. METHODS: In a 25-year period,
      80 completion pneumonectomies were performed after first operations for 17 cases
      of benign disease and 63 cases of lung cancer (89% stages I and II), with 7 of
      the latter patients receiving postoperative radiotherapy. Completion
      pneumonectomy was performed in 18 cases of benign disease and 62 cases of lung
      cancer: 28 second primary cancers, 26 recurrent cancers, 3 metastases, and 5
      primary cancers in patients previously operated on for benign disease. RESULTS:
      No intraoperative deaths occurred. Postoperative mortality rates were 5% for the
      entire series, 6.4% for patients operated on for cancer, and 0% for patients
      operated on for benign diseases. Patients previously irradiated and those
      operated on for infectious disease were at risk for postoperative empyema and
      fistula formation. In the cancer treatment group the actuarial 5-year survival
      was 36%, without significant difference between patients with recurrent and
      second primary lung cancers. The actuarial 5-year survivals were 51% for patients
      with stage I disease, 42% for patients with stage II disease, and 18% for
      patients with stage IIIA disease (P <.05). CONCLUSIONS: Completion pneumonectomy
      can be performed with an acceptable operative mortality rate and offers a second
      chance for cure to patients with cancer. Patients previously irradiated and those
      requiring completion pneumonectomy for infectious benign disease are at risk for
      postoperative complications.

PMID- 10343258
TI  - Lobe-specific extent of systematic lymph node dissection for non-small cell lung
      carcinomas according to a retrospective study of metastasis and prognosis.
AB  - BACKGROUND: Complete lymphadenectomy of the mediastinum is advised for patients
      with lung cancer to provide prognostic information and possible survival benefit.
      The proper extent of dissection should be further defined. METHOD: The lymphatic
      metastatic patterns according to the primary site and prognoses were
      retrospectively analyzed in 166 patients with non-small cell carcinoma who
      underwent at least lobectomy with hilar and mediastinal lymphadenectomy. All
      patients had histologically proven mediastinal metastasis (pN2). RESULTS: Among
      54 right upper lobe tumors the most common site of metastasis was the lower
      pretracheal station (74%), whereas metastases to the subcarinal station were seen
      only in 13%. Among 8 patients with right middle lobe tumors and 41 patients with
      right lower lobe tumors, both superior mediastinal and subcarinal stations were
      involved. The 34 left upper segment tumors metastasized to the aorticopulmonary
      window most commonly (71%) and to the subcarina only in 12% of cases. Inversely,
      the 10 left lingular tumors metastasized to the subcarina most commonly (50%) and
      to the aorticopulmonary window only in 20% of cases. Among 44 left lower lobe
      tumors the subcarinal station was most common for metastasis (58%), with
      infrequent metastases to the aorticopulmonary window. The 5-year survival for all
      166 patients was 35%. Patients with single-station and single-node metastases had
      a significantly better prognosis than those with more extensive metastases. Right
      lower lobe tumors with superior mediastinal metastasis carried a particularly
      poor 5-year survival of only 4.1%. COMMENT: Subcarinal lymphadenectomy is not
      always necessary for tumors of the right upper lobe and left upper segment. For
      tumors of other lobes both superior mediastinal dissection and subcarinal
      dissection are advised. However, superior mediastinal metastasis should be
      recognized as an indicator of poor prognosis in tumors of both lower lobes.

PMID- 10343259
TI  - Tracheobronchial sleeve resection with the use of a continuous anastomosis:
      results of one hundred consecutive cases.
AB  - OBJECTIVE: We have used a continuous suture technique for all tracheal and
      bronchial anastomoses with satisfactory results in our institution. The objective
      of this article is to review our experience with sleeve resections using this
      technique and report the associated morbidity and mortality in 100 consecutive
      cases. METHODS: Our experience with sleeve resection using a continuous suture (3
      0 polypropylene) technique was reviewed in 100 consecutive cases. The median age
      of the patients was 53.3 years with a range of 21 to 81 years. There were 54 male
      patients and 46 female patients. Resection was undertaken for malignant disease
      in 81 patients, acquired stricture in 14 patients, benign tumor in 4 patients,
      and trauma in 1 patient. Among 28 patients in whom lung parenchyma was not
      resected, 16 patients had tracheal resection and 12 had bronchial sleeve
      resection. Sleeve pneumonectomy was undertaken in 2, sleeve lobectomy in 66, and
      sleeve segmentectomy in 4. RESULTS: There were 12 postoperative complications
      (12%) and 2 postoperative deaths resulting from bronchoatrial fistula and
      pneumonia (2%). Stricture as a late complication occurred in 5 patients, 2 of
      whom required a bronchial stent. Other late complications were bougienage,
      reanastomosis, and completion pneumonectomy (1 each). CONCLUSION: Our experience
      suggests that the results of continuous suture technique are comparable with
      those from reported series using interrupted suture technique for tracheal and
      bronchial anastomosis.

PMID- 10343260
TI  - Percutaneous balloon fenestration and stenting for life-threatening ischemic
      complications in patients with acute aortic dissection.
AB  - OBJECTIVES: Acute aortic dissection frequently causes life-threatening ischemia
      of end-organs, historically associated with mortality exceeding 60%. Reperfusion
      with the use of interventional radiologic methods has evolved as a promising
      treatment. We report results of our initial 6 years of experience with
      percutaneous balloon fenestration of the intimal flap and endovascular stenting.
      METHODS: Forty patients (32 male and 8 female) with a median age of 53 years
      (range 16-86 years) underwent percutaneous treatment for peripheral ischemic
      complications of 10 type A and 30 type B acute aortic dissections since 1991.
      Twenty patients had ischemia of multiple organ systems. Thirty patients had
      renal, 22 had leg, 18 had mesenteric, and 1 had arm ischemia. RESULTS: Fourteen
      patients were treated with stenting of either the true or false lumen combined
      with balloon fenestration of the intimal flap, 24 with stenting alone, and 2 with
      fenestration alone. Successful revascularization was achieved in 93% +/- 4% (+/
      70% confidence levels) of patients (37/40). Nine patients had procedure-related
      complications. The 30-day mortality rate was 25% +/- 7% (10/40), often related to
      irreversible ischemia of intra-abdominal organs that was present before the
      procedure. Of the remaining 30 patients, 5 have died and the remaining 25
      continue to have relief of ischemic symptoms at a mean follow-up of 29 months.
      CONCLUSION: Percutaneous balloon fenestration of the intimal flap and
      endovascular stenting is an effective treatment for life-threatening ischemic
      complications of acute aortic dissection.

PMID- 10343261
TI  - A randomized double-blind study of the effect of triiodothyronine on cardiac
      function and morbidity after coronary bypass surgery.
AB  - BACKGROUND: Although triiodothyronine deficiency has been described after
      cardiopulmonary bypass, data supporting its use have been conflicting. A double
      blind, randomized, placebo-controlled study was undertaken to further define the
      effect of triiodothyronine on hemodynamics and outcome after coronary artery
      bypass grafting. METHODS: A total of 170 patients undergoing elective coronary
      artery bypass grafting were enrolled and completed the study from November 1996
      through March 1998. On removal of the aortic crossclamp, patients were randomized
      to receive either intravenous triiodothyronine (0.4 microgram/kg bolus plus 0.1
      microgram/kg infusion administered over a 6-hour period, n = 81) or placebo (n =
      89). Outcome variables included hemodynamic profile and inotropic drug/pressor
      requirements at several time points (mean +/- standard error of the mean),
      perioperative morbidity (arrhythmia/ischemia/infarction), and mortality. RESULTS:
      Despite similar baseline characteristics, patients randomized to triiodothyronine
      had a higher cardiac index and lower inotropic requirements after the operation.
      Subjects receiving triiodothyronine demonstrated a significantly lower incidence
      of postoperative myocardial ischemia (4% vs 18%, P =.007) and pacemaker
      dependence (14% vs 25%, P =.013). Seven patients in the placebo group required
      postoperative mechanical assistance (intra-aortic balloon pump, n = 4; left
      ventricular assist device, n = 3), compared with none in the triiodothyronine
      group (P =.01). There were 2 deaths in the placebo group and no deaths in the
      triiodothyronine group. CONCLUSIONS: Parenteral triiodothyronine given after
      crossclamp removal during elective coronary artery bypass grafting significantly
      improved postoperative ventricular function, reduced the need for treatment with
      inotropic agents and mechanical devices, and decreased the incidence of
      myocardial ischemia. The incidence of atrial fibrillation was slightly decreased,
      and the need for postoperative pacemaker support was reduced.

PMID- 10343262
TI  - Coronary artery bypass grafting in patients with previous mediastinal radiation
      therapy.
AB  - OBJECTIVES: Our objectives were to characterize the outcome of coronary artery
      bypass grafting in patients with previous mediastinal radiation therapy and to
      identify special features of this condition that relate to surgical management.
      PATIENTS AND METHODS: We conducted a retrospective review of 47 patients (28
      women, 19 men) with a mean age of 63.5 +/- 12.8 years (range 31.0-82. 9 years)
      from 1976 through December 1996 undergoing coronary artery bypass graft after
      mediastinal radiation therapy. RESULTS: The mean interval between mediastinal
      radiation therapy and coronary artery bypass grafting was 15.1 +/- 9.8 years
      (range 1.1-37.8 years). In the 44 patients with isolated coronary surgery,
      operative mortality was 3 patients (6.8%). Sternal wound infection occurred in 3
      patients (6.8%). Actuarial survival at 1 and 5 years was 87.2% +/- 4. 9% and
      71.6% +/- 7.1%, respectively. Total follow-up was 293.7 patient-years (mean 6.2
      +/- 5.1 years). There were 17 late deaths (malignancy, n = 7; heart failure, n =
      6; stroke, n = 1; other noncardiac causes, n = 2; and sudden death, n = 1).
      Twelve of 43 discharged patients had the development of valvular disease
      demonstrated by follow-up echocardiography. CONCLUSIONS: The early results of
      coronary artery bypass grafting for the treatment of ischemic heart disease after
      mediastinal radiation therapy are good. Late survival, however, is limited by
      malignancy, either recurrent or new, and the development of heart failure.
      Inasmuch as 25 other patients after radiation therapy required concomitant valve
      surgery and 12 of 43 (28%) discharged patients had later development of valvular
      disease, with 2 requiring reoperation, careful assessment of any valvular lesion
      is important during the initial coronary artery bypass grafting. Careful follow
      up, including regular echocardiographic screening, is recommended in this patient
      population.

PMID- 10343263
TI  - Mechanical analysis of midline sternotomy wound closure.
AB  - OBJECTIVE: Unstable median sternotomy closure can lead to postoperative
      morbidity. This study tests the hypothesis that separation of the sternotomy site
      occurs when physiologic forces act on the closure. METHODS: Median sternotomy was
      performed in 4 human cadavers (2 male) and closed with 7 interrupted stainless
      steel wires. The chest wall was instrumented to apply 4 types of distracting
      force: (1) lateral, (2) anterior-posterior, (3) rostral-caudal, and (4) a
      simulated Valsalva force. Forces were applied in each direction and were limited
      to physiologic levels (< 400 N). Four sets of sonomicrometry crystals were placed
      equidistantly along the sternum to measure separation at the closure site.
      RESULTS: Sternal separation occurred as a result of the wires cutting through the
      bone. Less force was needed to achieve 2.0-mm distraction in the lateral
      direction (220 +/- 40 N) than in the anterior-posterior (263 +/- 74 N) and
      rostral-caudal (325 +/- 30 N) directions. More separation occurred at the lower
      end of the sternum than the upper. During lateral distraction, xiphoid and
      manubrial displacement averaged 1.85 +/- 0.14 and 0.35 +/- 0.12 mm, respectively.
      Anterior-posterior distraction caused 1.99 +/- 0.04-mm xiphoid displacement and
      0.26 +/- 0.12-mm manubrial displacement. During a simulated Valsalva force, more
      separation occurred in the lateral (2.14 +/- 0.11 mm) than in the anterior
      posterior (0.46 +/- 0.29 mm) or rostral-caudal (0.25 +/- 0.15 mm) directions.
      CONCLUSIONS: These data suggest that sternal dehiscence can occur under
      physiologic loads and that improved sternal stability may be readily achieved via
      mechanical reinforcement near the xiphoid. Closure techniques designed to
      minimize wire migration into the sternum should also be developed.

PMID- 10343264
TI  - Commentary 

PMID- 10343266
TI  - Commentary 

PMID- 10343265
TI  - Aortic root reconstruction with preservation of native aortic valve and sinuses
      in aortic root dilatation with aortic regurgitation.
AB  - BACKGROUND: We assessed the results of a modified technique for aortic root
      reconstruction including preservation of the native aortic valve and sinuses.
      METHODS: A modified technique for reconstruction of the aortic root was devised
      in which the native aortic sinuses are preserved and remodeled, the diameter of
      the sinotubular junction is reduced, the ventriculoaortic junction is reinforced
      with a Dacron prosthesis, and the coronary ostia are reimplanted. Since January
      1995, this modified operative technique was performed in 13 patients with a mean
      age of 54 +/- 21 years. The median grade of aortic regurgitation was 3; in 10
      patients it was caused by dilatation of the sinotubular junction, and 3 had
      additional annuloaortic ectasia. RESULTS: The aortic crossclamping time was 61 +/
      18 minutes. In-hospital mortality was 2 of 13 (15. 3%) patients, both deaths
      being related to complications of aortic dissection. In 1 patient aortic
      regurgitation increased to grade 3, necessitating aortic valve replacement. At a
      mean follow-up of 2.1 years, the remaining 10 patients had stable aortic valve
      function with a median grade of regurgitation of 1. The mean New York Heart
      Association functional class was 1.2. CONCLUSIONS: Aortic root reconstruction
      with preservation of the native aortic valve and sinuses allows symmetric
      reconstruction of the aortic sinuses and adaptation of the diameters of the
      sinotubular and ventriculoaortic junctions, thus optimizing aortic valve
      function. Moreover, it prevents contact of the aortic valve leaflets with the
      Dacron graft, which may enhance the durability of the repair.

PMID- 10343267
TI  - Manual debridement of the aortic valve in elderly patients with degenerative
      aortic stenosis.
AB  - OBJECTIVE: We prospectively analyzed the short- and long-term results of manual
      debridement of the aortic valve in elderly patients with severe degenerative
      aortic stenosis. METHODS: Between September 1988 and January 1997, 103 patients
      aged 73.7 +/- 6 years with degenerative aortic stenosis underwent the manual
      debridement technique. All had symptoms (angina or dyspnea, or both). Peak
      systolic gradient was 89 +/- 28 mm Hg. Forty-one patients (39.8%) had associated
      coronary artery disease necessitating revascularization. RESULTS: Follow-up time
      was 42 +/- 21 months (range 3-98 months). The Kaplan-Meier estimated survival at
      98 months was 50% (95% CI: 30%-70%). In-hospital mortality was 5.8% (6 patients),
      and late mortality was 21% (21 patients). No predictors of in-hospital mortality
      or of late mortality were detected. Nonfatal postoperative complications appeared
      in 25 patients (24%). At 8 years, freedom from endocarditis was 98% (95% CI: 95%
      100%) and freedom from thromboembolic events was 99% (95% CI: 96%-100%). No
      patient required long-term anticoagulation as a result of the procedure. Fourteen
      patients (14%) required reoperation for aortic insufficiency (n = 5), restenosis
      (n = 8), and mitral regurgitation (n = 1). The probability of reoperation at 98
      months was 23% (95% CI: 12%-35%). CONCLUSION: Manual aortic valve debridement has
      low rates of in-hospital mortality, perioperative complications, and
      thromboembolic and infectious events and it offers freedom from anticoagulation.
      However, the incidence of restenosis and reoperation is high in the long term. It
      may therefore be regarded as an alternative in aged patients with favorable valve
      anatomy (no distortion and calcium deposits only on the aortic surface of the
      cusps), especially in those with a small aortic anulus, associated coronary
      artery disease, and/or contraindication for anticoagulation.

PMID- 10343268
TI  - Oxygenation strategy and neurologic damage after deep hypothermic circulatory
      arrest. I. Gaseous microemboli.
AB  - OBJECTIVES: Recent studies suggest that myocardial reperfusion injury is
      exacerbated by free radicals when pure oxygen is used during cardiopulmonary
      bypass. Partial replacement of the oxygenator gas mixture with nitrogen, however,
      such as has already been adopted clinically in many centers, could increase the
      risk of gaseous nitrogen microembolus formation and therefore of brain damage
      because of the low solubility of nitrogen, particularly under conditions of
      hypothermia. METHODS: Ten 7- to 10-kg piglets were cooled for 30 minutes to 15
      degrees C on cardiopulmonary bypass and then rewarmed for 40 minutes to 37
      degrees C. In 5 piglets cardiopulmonary bypass was normoxic and in 5 it was
      hyperoxic. In each group 3 bubble oxygenators without arterial filters and 2
      membrane oxygenators with filters were used. Cerebral microemboli were monitored
      continuously by carotid Doppler ultrasonography (8 MHz) and intermittently by
      fluorescence retinography. RESULTS: Embolus count was greater with lower rectal
      temperature (P <.001), use of a bubble oxygenator (P <.001), and lower oxygen
      concentration (P =.021) but was not affected by the temperature gradient between
      blood and body during cooling or rewarming. CONCLUSIONS: Gaseous microemboli are
      increased with normoxic perfusion, but this is only important if a bubble
      oxygenator without a filter is used.

PMID- 10343269
TI  - Oxygenation strategy and neurologic damage after deep hypothermic circulatory
      arrest. II. hypoxic versus free radical injury.
AB  - OBJECTIVES: Laboratory studies suggest that myocardial reperfusion injury is
      exacerbated by free radicals when pure oxygen is used during cardiopulmonary
      bypass. In phase I of this study we demonstrated that normoxic perfusion during
      cardiopulmonary bypass does not increase the risk of microembolic brain injury so
      long as a membrane oxygenator with an arterial filter is used. In phase II of
      this study we studied the hypothesis that normoxic perfusion increases the risk
      of hypoxic brain injury after deep hypothermia with circulatory arrest. METHODS:
      With membrane oxygenators with arterial filters, 10 piglets (8-10 kg) underwent
      120 minutes of deep hypothermia and circulatory arrest at 15 degrees C, were
      rewarmed to 37 degrees C, and were weaned from bypass. In 5 piglets normoxia
      (PaO2 64-181 mm Hg) was used during cardiopulmonary bypass and in 5 hyperoxia
      (PaO2 400-900 mm Hg) was used. After 6 hours of reperfusion the brain was fixed
      for histologic evaluation. Near-infrared spectroscopy was used to monitor
      cerebral oxyhemoglobin and oxidized cytochrome a,a3 concentrations. RESULTS:
      Histologic examination revealed a significant increase in brain damage in the
      normoxia group (score 12.4 versus 8.6, P =.01), especially in the neocortex and
      hippocampal regions. Cytochrome a,a 3 and oxyhemoglobin concentrations tended to
      be lower during deep hypothermia and circulatory arrest in the normoxia group (P
      =.16). CONCLUSIONS: In the setting of prolonged deep hypothermia and circulatory
      arrest with membrane oxygenators, normoxic cardiopulmonary bypass significantly
      increases histologically graded brain damage with respect to hyperoxic
      cardiopulmonary bypass. Near-infrared spectroscopy suggests that the mechanism is
      hypoxic injury, which presumably overwhelms any injury caused by increased oxygen
      free radicals.

PMID- 10343270
TI  - The nature of the obstructive muscular bundles in double-chambered right
      ventricle.
AB  - OBJECTIVE: Our goal was to establish the morphologic nature of the obstructive
      muscular lesions in double-chambered right ventricle. METHODS: We based our
      morphologic observations on 10 normal hearts and on the surgical findings in 26
      patients, aged 0.5 to 24 years, with a mean of 6.9 years (SD 5.8 years). In the
      normal hearts, we measured the distance from the pulmonary valve to the apex of
      the right ventricle and from the takeoff of the moderator band to the ventricular
      apex. From angiograms available in 20 patients, using the frontal view, we then
      measured the distance from the pulmonary valve to the apex of the right ventricle
      and from the midpoint of the obstructive lesion to the apex of the right
      ventricle. This permitted calculations of multiple ratios. RESULTS: In the 10
      normal hearts, the moderator band took origin at a mean ratio of 0.48 (SD 0.16)
      of the ventricular length. On the basis of the angiographic findings, we
      identified 2 basic forms of double-chambered right ventricle. In 9 patients, the
      obstructive muscular shelf was positioned low and diagonally across the apical
      component, with a mean ratio of 0.38 relative to the ventricular length (SD
      0.02). In the other 11 patients, the obstructive shelf was high and horizontal,
      with a mean ratio of 0.27 (SD 0.02). The difference was statistically significant
      (P =.001). Surgical repair was performed successfully in all 26 patients through
      a right ventriculotomy. CONCLUSIONS: Double-chambered right ventricle is the
      consequence of a high or low muscular division of the apical component of the
      right ventricle. The abnormal muscular bundle probably represents accentuated
      septoparietal trabeculations, rather than always being an abnormal moderator
      band.

PMID- 10343271
TI  - Commentary 

PMID- 10343272
TI  - Atrioventricular discordance: results of repair in 127 patients.
AB  - OBJECTIVE: The conventional management of patients with atrioventricular
      discordance is directed at associated lesions, taking advantage of physiologic
      "correction"; however, the morphologic right ventricle and tricuspid valve
      support the systemic circulation. Questions surrounding survival using this
      approach led us to analyze our institutional results. METHODS: All patients with
      atrioventricular discordance undergoing biventricular repair were analyzed (n =
      127, 1959-1997), excluding those with functionally univentricular hearts. The
      ventriculoarterial connection associated with atrioventricular discordance varied
      and was most commonly discordant (87%), but occasionally concordant (6%), double
      outlet right ventricle (6%), or double-outlet left ventricle (1%). At initial
      presentation, the most common lesions associated with atrioventricular
      discordance were ventricular septal defect (86%), pulmonary stenosis (64%),
      tricuspid regurgitation (28%), and atrioventricular block (12%). Nine patients
      underwent a double switch procedure to create ventriculoarterial concordance and
      the remainder were managed conventionally without correcting discordant
      connections. RESULTS: Operative mortality was 6% and did not vary by associated
      lesion. Twenty years after repair, survival was 48%. Within 20 years, 56% of
      patients required reoperation, usually for atrioventricular valve incompetence (n
      = 16), pulmonary stenosis (n = 16), or both (n = 3). Pacemakers were required in
      50 patients, 4 before repair, 40 within 2 months of repair, and 6 remotely after
      repair. In early follow-up, the double switch procedure (n = 9) had equivalent
      mortality and a high pacemaker requirement for atrioventricular block.
      CONCLUSIONS: Analysis of conventional management of atrioventricular discordance
      revealed cumulative increases in mortality, systemic atrioventricular valve
      (tricuspid) replacement, complete atrioventricular block, and incidence of
      reoperation. Alternative management should be examined.

PMID- 10343273
TI  - A novel sialyl Lewis X analog attenuates cerebral injury after deep hypothermic
      circulatory arrest.
AB  - BACKGROUND: The initial step in the inflammatory process, which can be initiated
      by cardiopulmonary bypass and by ischemia/reperfusion, is mediated by
      interactions between selectins on endothelial cells and on neutrophils. We
      studied the effects of selectin blockade using a novel Sialyl Lewis X analog (CY
      1503) on recovery after deep hypothermic circulatory arrest in a piglet model.
      METHODS: Twelve Yorkshire piglets were subjected to cardiopulmonary bypass, 30
      minutes of cooling, 100 minutes of circulatory arrest at 15 degrees C, and 40
      minutes of rewarming. Five animals received a bolus of 60 mg/kg of CY-1503 and an
      infusion (3 mg/kg per hour) for 24 hours from reperfusion (group O), and 7
      randomly selected control piglets received saline solution (group C). Body weight
      and total body water content were evaluated 3 hours and 24 hours after
      reperfusion by a bio-impedance technique. Neurologic recovery of animals was
      evaluated daily by neurologic deficit score (0 = normal, 500 = brain death) and
      overall performance categories (1 = normal, 5 = brain death). The brain was fixed
      in situ on the fourth postoperative day and examined by histologic score (0 =
      normal, 5+ = necrosis) in a blinded fashion. RESULTS: Two of 7 animals in group C
      died. The neurologic deficit score was significantly lower in group O than in
      group C (postoperative day 1, P <.001; postoperative day 2, P =.02). The overall
      performance category was significantly lower in group O than in group C on
      postoperative day 2 (P =.01). Percentage total body water after cardiopulmonary
      bypass was significantly higher in group C than in group O (P =.03). Histologic
      score tended to be higher in group C than in group O, but this difference did not
      reach statistical significance (group O = 0.5 +/- 0.7; group C = 1.3 +/- 1.off
      CONCLUSION: Blockade of selectin adhesion molecules by saturation with a Sialyl
      Lewisx analog accelerates recovery after 100 minutes of deep hypothermic
      circulatory arrest in a piglet survival model.

PMID- 10343274
TI  - Computer-enhanced coronary artery bypass surgery.

PMID- 10343275
TI  - Commentary 

PMID- 10343276
TI  - Intraoperative evaluation of myocardial revascularization during minimally
      invasive direct coronary artery bypass by means of ultrasonic integrated
      backscatter.

PMID- 10343277
TI  - New alternative coronary bypass graft: first clinical experience with an
      autologous endothelialized cryopreserved allograft.

PMID- 10343278
TI  - Combined left ventricular aneurysm and thoracic aortic pseudoaneurysm caused by
      blunt chest trauma.

PMID- 10343279
TI  - No-React anticalcification tissue treatment results with stentless heart valves
      in two adolescents.

PMID- 10343280
TI  - Extravascular Doppler measurement of cardiac output in infants and children after
      operations for congenital heart disease.

PMID- 10343281
TI  - Phylogeny and evolution of chemical communication: an endocrine approach.
AB  - The present review assesses the phylogenetic history of information molecules
      (bioregulators pheromones, hormones, neuroactive compounds), receptors,
      transducers, second messengers) in uni- and multicellular organisms. Transitional
      stages between contemporary endocrine secretions including hormones and
      neuroactive materials, and primogenial exocrine compounds (pheromones) are
      proposed. Severalhypotheses have been developed to explain the origin and
      evolution of bioregulator/receptor units. Finally, how these primordial
      information molecules have either been co-opted or have changed their function
      during the course of biological evolution is analysed.

PMID- 10343282
TI  - Unique multifunctional HSD17B4 gene product: 17beta-hydroxysteroid dehydrogenase
      4 and D-3-hydroxyacyl-coenzyme A dehydrogenase/hydratase involved in Zellweger
      syndrome.
AB  - Six types of human 17beta-hydroxysteroid dehydrogenases catalyzing the conversion
      of estrogens and androgens at position C17 have been identified so far. The
      peroxisomal 17beta-hydroxysteroid dehydrogenase type 4 (17beta-HSD 4, gene name
      HSD17B4) catalyzes the oxidation of estradiol with high preference over the
      reduction of estrone. The highest levels of 17beta-HSD 4 mRNA transcription and
      specific activity are found in liver and kidney followed by ovary and testes. A 3
      kb mRNA codes for an 80 kDa (737 amino acids) protein featuring domains which are
      not present in the other 17beta-HSDs. The N-terminal domain of 17beta-HSD 4
      reveals only 25% amino acid similarity with the other types of 17beta-HSDs. The
      80 kDa protein is N-terminally cleaved to a 32 kDa enzymatically active fragment.
      Both the 80 kDa and the N-terminal 32 kDa (amino acids 1-323) protein are able to
      perform the dehydrogenase reaction not only with steroids at the C17 position but
      also with D-3-hydroxyacyl-coenzyme A (CoA). The enzyme is not active with L
      stereoisomers. The central part of the 80 kDa protein (amino acids 324-596)
      catalyzes the 2-enoyl-acyl-CoA hydratase reaction with high efficiency. The C
      terminal part of the 80 kDa protein (amino acids 597-737) facilitates the
      transfer of 7-dehydrocholesterol and phosphatidylcholine between membranes in
      vitro. The HSD17B4 gene is stimulated by progesterone, and ligands of PPARalpha
      (peroxisomal proliferator activated receptor alpha) such as clofibrate, and is
      down-regulated by phorbol esters. Mutations in the HSD17B4 lead to a fatal form
      of Zellweger syndrome.

PMID- 10343283
TI  - Steroidogenic factor 1-DNA binding: a kinetic analysis using surface plasmon
      resonance.
AB  - Basal expression of the glycoprotein hormone alpha-subunit gene in pituitary
      gonadotrophs is partially dependent on a gonadotroph specific element (GSE) which
      binds the nuclear receptor, steroidogenic factor-1 (SF-1). We have used surface
      plasmon resonance (SPR) to determine the association (kappa ass), dissociation
      (kappa diss) and affinity (KA) constants of SF-1 binding to immobilized
      oligonucleotides containing either the GSE consensus motif or a GSE mutant with a
      2 bp substitution in the GSE site (GSEMUT). In vitro translated SF-1 protein
      bound the consensus GSE with a threefold increase in affinity constant (P<0.01)
      compared with the GSEMUT. This was due primarily to a significant increase
      (P<0.05) in the kappa ass for SF-1 to the GSE and a slower kappa diss (P<0.05).
      The binding interaction was specific and could be significantly inhibited (P<0.
      001) by either anti-SF-1 antibody or excess non-biotinylated GSE. The addition of
      14 bp wild-type flanking sequences significantly reduced the affinity of SF-1 to
      both the GSE (P<0.05) and the GSEMUT (P<0.01). This was due to a significant
      (P<0.01) decrease in kappa ass for the wild-type and mutant long oligonucleotides
      compared with the short GSE. Nuclear extracts from alphaT3-1 gonadotroph cells
      also bound the GSE and GSEMUT, giving kappa diss values which were two- to
      threefold slower than those obtained with in vitro translated SF-1. Thus, SPR is
      a powerful technique for examining kinetic interaction between SF-1 and its
      binding site, and is able to demonstrate the effects of mutations and flanking
      sequences on that interaction.

PMID- 10343284
TI  - Gene and cDNA cloning and characterization of the mouse V3/V1b pituitary
      vasopressin receptor.
AB  - The gene of the mouse V3/V1b receptor was identified by homology cloning. One of
      the genomic clones contained the entire coding sequence. The cDNA presented high
      identity with rat (92%) and human (84%) sequences. Southern blot analysis
      indicated the existence of a single gene. Tissue distribution was studied by RT
      PCR. The major site of expression was the pituitary. A faint signal was also
      present in hypothalamus, brain, adrenal, pancreas and colon. The mouse
      corticotroph cell line, AtT20, did not express the transcript. In order to
      confirm the identity of the sequence, the V3/V1b receptor cDNA was cloned and
      stably expressed in CHO-AA8 Tet-Off cells under the control of tetracycline. When
      transfected cells were treated with arginine vasopressin (AVP), inositol
      phosphate production increased in a dose-dependent manner, indicating that the
      V3/V1b receptor couples to phospholipase C. Moreover, AVP did not stimulate cAMP
      production. Binding studies with [3H]AVP indicated that the affinity of the mouse
      V3/V1b receptor (Kd=0.5 nM) is similar to that reported for rat and human
      receptors. The rank order of potency established in competition binding
      experiments with different analogues was representative of a V3/V1b profile,
      distinct from V1a and V2. However, significant differences were found between
      human and mouse receptors tested in parallel. Thus the pharmacology of V3/V1b
      receptors can not be transposed among different species.

PMID- 10343285
TI  - Effect of growth hormone administration on IGF binding protein-3 mRNA levels in
      porcine tissues.
AB  - The effect of short-term GH treatment on steady-state insulin-like growth factor
      binding protein-3 (IGFBP-3) mRNA levels in liver, kidney, longissimus dorsi
      muscle, stomach and jejunum was examined in pigs. Ten female crossbred pigs were
      allocated to either saline or GH (70 microg/kg/day) treatment by subcutaneous
      injection for 4 days. They were allowed to feed ad libitum, and were weighed
      daily. At the end of the treatment period, the pigs were slaughtered and samples
      of liver, kidney, skeletal muscle, stomach and jejunum were collected and total
      RNA was extracted. Steady-state levels of IGFBP-3 mRNA were quantified by RNase
      protection assay and were compared with the level of IGF-I class 1 and class 2
      transcripts. IGFBP-3 mRNA increased in response to GH in both liver and kidney,
      but not in the other tissues sampled. Hepatic IGF-I mRNA responded to short-term
      GH treatment with a fourfold increase in IGF-I class 1 mRNA and an eightfold
      increase in IGF-I class 2 mRNA, which was liver specific. IGF-I class 1 mRNA was
      not responsive to GH treatment in other tissues. The short-term nature of this
      treatment suggests that the increase in hepatic IGFBP-3 and IGF-I transcripts is
      a relatively early response to treatment with GH, and that the increase in plasma
      concentrations of IGFBP-3 in response to GH are derived from the liver, the
      kidney, or both.

PMID- 10343286
TI  - Hyperexpression of biologically active human chorionic gonadotropin using the
      methylotropic yeast, Pichia pastoris.
AB  - Human chorionic gonadotropin (hCG), a heterodimeric glycoprotein hormone, is
      composed of an alpha subunit noncovalently associated with the hormone-specific
      beta subunit. The objective of the present study was recombinant expression of
      properly folded, biologically active hCG and its subunits using an expression
      system that could be used for structure-function studies while providing adequate
      quantities of the hormone for immunocontraceptive studies. We report here
      expression of biologically active hCG and its subunits using a yeast expression
      system, Pichia pastoris. The recombinant hCGalpha and hCGbeta subunits were
      secreted into the medium and the levels of expression achieved at shake culture
      level were 24 and 2.7-3 mg/l secretory medium respectively. Co-expression of both
      subunits in the same cell resulted in secretion of heterodimeric hCG into the
      medium. The pichia-expressed hCG was immunologically similar to the native
      hormone, capable of binding to the LH receptors and stimulating a biological
      response in vitro. Surprisingly, the maximal response obtained was twice that
      obtained with the native hCG. The level of expression of hCG achieved was 12-16
      mg/l secretory medium and is expected to increase several-fold in a fermentor.
      Thus the Pichia expression system is capable of hyperexpressing properly folded,
      biologically active hCG and is suitable for structure-function studies of the
      hormone.

PMID- 10343287
TI  - The human prolactin gene upstream promoter is regulated in lymphoid cells by
      activators of T-cells and by cAMP.
AB  - Prolactin (PRL) is produced in human thymocytes, T-cells and endometrium. In
      these extrapituitary tissues, PRL gene transcription is directed by an
      alternative upstream promoter, and it is thought to act as a locally produced
      cytokine, with relevance for immune regulation and modulation of T-cell function.
      We have studied PRL transcriptional regulation in the human T-lymphoblastoid
      Jurkat cell line transfected with a fragment of the upstream promoter linked to
      luciferase. A cAMP analogue (cptAMP) increased promoter activity rapidly and dose
      dependently. This increase was resistant to inhibition by cyclosporin A and thus
      independent of calcineurin phosphatase (CN). T-cell activation by phorbol
      myristate acetate (PMA) failed to enhance promoter activity but
      phytohaemagglutinin (PHA) alone or PHA+PMA increased it, and cptAMP acted in
      synergy with PMA or PHA to increase it further. H-89, a cAMP-dependent protein
      kinase A (PKA) inhibitor, inhibited the effect of cptAMP as did transfection with
      protein kinase inhibitor PKI, an expression vector of the specific inhibitor of
      PKA. A single point mutation in the CRE (cAMP response element) located at -25 bp
      in the PRL upstream promoter (TGACGT to TGCCGT) failed to reduce the response to
      cptAMP, while mutations or deletion of four nucleotides in the CRE to TACTCT
      diminished the response to cAMP by more than half. We conclude that activity of
      the human PRL upstream extrapituitary promoter can be induced by activators of T
      cells, as well as by a cAMP analogue. The signal is transmitted by PKA and the
      effect of cAMP is independent of CN. It is partly dependent on an intact proximal
      CRE motif but a more upstream enhancer may contribute to promoter regulation.

PMID- 10343288
TI  - Regulation of the expression and activity by progestins of a member of the SOX
      gene family of transcriptional modulators.
AB  - The mammalian testis-determining gene Sry and the related Sox genes define a
      family of transcriptional regulators widely expressed during embryogenesis.
      Tightly controlled temporal profiles of expression are a feature of the Sox gene
      family and may be required for initiation of a cascade of gene expression, yet
      the molecular mechanisms that control Sox gene expression are unknown. We now
      show that human SOX4 is expressed in the normal breast and in breast cancer
      cells. In these cells SOX4 is a progesterone-regulated gene, the expression of
      which is increased by progestins, leading to a marked increase in SOX-mediated
      transcriptional activity. Treatment of T-47D breast cancer cells with the
      synthetic progestin ORG 2058 directly increased SOX4 transcription, resulting in
      a 4-fold increase in SOX4 mRNA levels within 4 h of treatment. No effect of ORG
      2058 was noted on other SOX genes measured, nor were other hormone-regulated HMG
      box proteins detected in this system, suggesting that the observed ability of
      progestin to increase SOX mRNA expression was confined to SOX4. The increase in
      SOX4 transcription was reflected in increased SOX4 protein expression, as
      progestin treatment of T-47D cells transfected with a SOX-responsive reporter
      resulted in a marked increase in reporter gene expression. Progesterone is
      essential for normal development and differentiation of the female reproductive
      system, plays an essential role in regulating growth and differentiation of the
      mammary gland and is required for opposing the proliferative effects of estrogen
      in specific cell types. The detection of SOX4 expression in the normal and
      malignant breast and the demonstration that SOX4 expression is under progesterone
      control suggests that changes in SOX4 gene expression may play a role in
      commitment to the differentiated phenotype in the normal and malignant mammary
      gland.

PMID- 10343289
TI  - Expression of the vasotocin gene in the hypothalamus of intact and osmotically
      stimulated bullfrogs during metamorphosis.
AB  - To study the ontogeny of the vasotocin (VT) system and its contribution to anuran
      metamorphosis, VT mRNA levels were determined by Northern blot analysis in
      metamorphosing bullfrog tadpoles. Effects of osmotic stimulation on VT mRNA
      levels were also analyzed in order to follow the development of osmotic
      responsiveness of VT neurons. The intensity of hybridization signals for VT mRNA
      gradually increased during prometamorphic development. The increase became marked
      thereafter until metamorphic climax. Plasma osmolality and hematocrit remained
      unchanged before metamorphosis, and increased after metamorphic climax,
      indicating that climactic tadpoles in a semi-terrestrial environment were in a
      dehydrated condition. These increases correlated well with the increase in VT
      mRNA level. Immersion of tadpoles in 30% seawater (approximately 350 mOsmol) for
      3 days increased plasma osmolality at all stages. No significant changes were
      observed in the VT mRNA level in response to this treatment during premetamorphic
      stages. The VT mRNA levels were significantly higher in the treated tadpoles
      after preclimax stages. Hyperosmotic treatment also increased hematocrit until
      early metamorphic climax, but did not alter it in tadpoles at late metamorphic
      climax. These results suggest that the responsiveness of VT-producing neurons to
      hyperosmotic or hypovolemic stimulation, or both, is established by the time of
      the metamorphic climax in bullfrog. The marked increase in VT mRNA levels at
      metamorphic climax stages of intact individuals is probably induced by
      dehydration. VT-stimulated water absorption and reabsorption in the target organs
      probably prevented the increase in hematocrit at late metamorphic climax. Thus VT
      may contribute importantly to osmoregulatory mechanisms in relation to adaptation
      to a semi-terrestrial habitat through the metamorphosis.

PMID- 10343291
TI  - Dignity and Health: The UDHR's Revolutionary First Article.
AB  - The modern human rights revolution emerges boldly from the first article of the
      Universal Declaration of Human Rights. Given the care lavished upon each word and
      phrase in the course of its elaboration, the syntax which places dignity before
      rights merits consideration. Dignity is clearly of vital individual and societal
      importance - individuals and societies spend considerable energy in the daily
      effort to protect, enhance and sustain their dignity. Dignity seems to flow from
      two components, one internal ("how I see myself") and the other external ("how
      others see me"). The impact on health for people living in an environment
      characterized by repetitive, severe and sustained violations of individual and
      collective dignity is likely to be substantial. It is increasingly evident that
      violations of dignity are pervasive events with potentially devastating negative
      effects on physical, mental and social well-being.

PMID- 10343290
TI  - Selective activation of the probasin androgen-responsive region by steroid
      hormones.
AB  - Glucocorticoid and androgen receptors have been shown to function through the
      same palindromic glucocorticoid response element (GRE) and yet have differential
      effects on gene transcription. In this study, we examined the functional and
      structural relationship of the androgen and glucocorticoid receptors with the
      androgen responsive region (ARR) of the probasin (PB) gene containing two
      androgen receptor binding sites, ARBS-1 and ARBS-2. Transfection studies
      indicated that one copy of each cis-acting DNA element was essential for maximal
      androgen-induced chloramphenicol acetyltransferase (CAT) activity and that
      androgen selectivity was maintained when multiple copies of the minimal wild type
      (wt) androgen responsive region containing both ARBS-1 and ARBS-2 (-244 to -96)
      were subcloned in front of the thymidine kinase promoter. Furthermore, replacing
      the androgen response region with 1, 2 or 3 copies of either ARBS-1 or ARBS-2
      restored less than 4% of the biological activity seen with the wt PB ARR.
      Multiple copies of either ARBS-1 or ARBS-2 did not result in glucocorticoid
      induced CAT gene activity. By comparison, 1 or 2 copies of the tyrosine
      aminotransferase (TAT) GRE, as well as the mouse mammary tumour virus GRE, were
      strong inducers of CAT activity in response to both androgen and glucocorticoid
      treatment. In addition, band shift assays demonstrated that although the
      synthetic glucocorticoid receptor, GR-DNA binding domain (GR-DBD), and the
      synthetic androgen receptor, AR2, could interact with the TAT GRE (dissociation
      constants Kd of 63.9 and 14.1 respectively), only AR2 but not GR-DBD binding
      could be detected on ARBS-1 and ARBS-2. Our findings provide further evidence
      that androgen-induced regulation of gene transcription can occur through androgen
      specific DNA binding sites that are distinct from the common GRE.

PMID- 10343292
TI  - Third Class Medicine: Health Care for Refugees in Germany.
AB  - The fiftieth anniversary of the Universal Declaration of Human Rights provides an
      opportunity to scrutinize the policies of wealthier countries towards refugees
      and asylum seekers. Although Germany is host to two-thirds of all individuals
      seeking asylum in European countries, it is now taking a hard line with respect
      to asylum policies. This article examines the forces behind these policies which,
      contrary to their rationalization, do not save "tax money," but actually make
      life for the recipients as difficult as possible. Studies of asylum hearings show
      that clues indicating past trauma or torture of asylum seekers are often ignored.
      In addition, the administrative procedures required for the provision of health
      care to refugees and asylum seekers have resulted in inflated bureaucracy and
      excessive costs, all the while providing only third class medicine. International
      NGOs and human rights organizations must put pressure on governments to live up
      to the promises of the UDHR.

PMID- 10343293
TI  - For Better, For Worse.
AB  - This article addresses the extent to which provisions within Article 16 of the
      Universal Declaration of Human Rights have influenced subsequent developments in
      the field of sexual and reproductive health and rights. In particular, it
      assesses how the right to marry and to found a family, the requirement of free
      and full consent of intending spouses, and recognition of the family as the
      "natural and fundamental group unit of society" have affected service provision
      in this field. Other human rights instruments, such as the Women's Convention,
      have amplified these rights, but some issues within reproductive health continue
      to be limited by conventional interpretations of the family, as identified in the
      UDHR. While the language within Article 16 was clearly molded by the morality of
      the 1940s, it has, so far, proven to be flexible enough to encompass both social
      change and technological innovation.

PMID- 10343294
TI  - Freedom of Expression and the Healthy Society.
AB  - The links between freedom of expression and the health and well-being of the
      individual and of society seem readily apparent even if their full ramifications
      are not immediately clear. Health and health care are dependent on information,
      and the free exchange of this information is at the base of effective health
      protection and promotion. Equally, it is clear that such a widely-based concept
      as health intersects with, and is dependent on, a range of basic human needs.
      This article examines the links between provision of health care and the right of
      freedom of expression as set out in Article 19 of the Universal Declaration of
      Human Rights. It argues that both freedom of expression and commitment to health
      care are vital objectives but insufficient in and of themselves to realise a
      wider goal of human well-being. This article draws on examples from inner urban
      deprivation, women's health and HIV/AIDS to illustrate some of the factors and
      issues involved.

PMID- 10343295
TI  - Poverty and Health: Debt Relief Could Help Achieve Human Rights Objectives.
AB  - Article 25 of the Universal Declaration of Human Rights clearly emphasizes health
      as a human right. Poverty and social exclusion are the most important drivers of
      ill-health. The causes of increasing poverty are complex but one significant
      factor is international debt. This affects mainly sub-Saharan Africa but, with
      the global economic crisis in South East Asia, may spread. Structural adjustment
      policies which cut social spending compound the health effects of debt and
      poverty. Privatization of health care and user charges particularly affect women,
      children, the disabled, and other marginalized communities. To improve health,
      governments and international institutions have a duty to examine the
      determinants of health, including human rights and economic policy.

PMID- 10343296
TI  - Education, a Health Imperative: The Case of Afghanistan.
AB  - Education is not only a right, but an essential condition for the health and well
      being of individuals and the communities in which they live. Despite strong
      authority within Islamic law and traditions affirmatively promoting the education
      of both girls and boys, the Taliban regime has denied women this right in the
      name of religion and culture. Physicians for Human Rights (PHR) recently surveyed
      the health and human rights concerns of Afghan women. The case of Afghanistan
      dramatically illustrates that education is a health imperative. Taliban policies
      of systematic discrimination against women, including restrictions on education,
      undermine the physical, psychological and social well-being of Afghan women. Such
      discrimination and the suffering it causes constitute an affront to the dignity
      and worth of Afghan women, and humanity as a whole.

PMID- 10343297
TI  - The Right to a Just and Peaceful Social and International Order.
AB  - Article 28 of the Universal Declaration of Human Rights calls for the
      establishment of a "social and international order" in which the rights
      guaranteed by the UDHR "can be fully realized." The social and international
      order that will be needed for this purpose must be a just and peaceful one.
      Justice requires equitable economic development and equitable distribution of its
      benefits; development policies that avoid destruction of the environment; and
      international respect for the rule of law. Peace requires economic and social
      justice; abolition of weapons of mass destruction; sharply restricted transfer
      and use of conventional weapons; and vastly expanded support of nonviolent
      conflict resolution by the United Nations and other relevant institutions. Health
      workers, as influential members of civil society, have an important role to play
      in these efforts.

PMID- 10343298
TI  - Health, Medicine and Science in the Universal Declaration of Human Rights.
AB  - Using archival sources, the authors report on the debates and diverse
      perspectives of United Nations representatives responsible for formulating
      Article 25 (relating to health and medical care) and 27 (relating to science) of
      the Universal Declaration of Human Rights. These articles supply important
      normative guidelines for human rights and public health policy. The question of
      whether health-related rights should depend on state and/or private sponsorship
      was left open. There was agreement that scientists deserve freedom in their work
      but the elitist tone of Article 27 was modified by adding that the general public
      should share in its benefits. The political nature of drafting these articles
      shows they have no one dominant progenitor, but finally reflect hard-won
      consensus in a process ably chaired by Eleanor Roosevelt.

PMID- 10343299
TI  - The UDHR in National and International Law.
AB  - The Universal Declaration of Human Rights has been the foundation of much of the
      post-1945 codification of human rights, and the international legal system is
      replete with global and regional treaties based, in large measure, on the
      Declaration. Pending universal ratification of the Covenants and other treaties,
      it is to the Universal Declaration of Human Rights that most people will look to
      find the minimum rights to which they are entitled. This article sets out the
      status of the Declaration in national and international law, and gives examples
      of international and national provisions protecting the right to health. Legally,
      politically, and morally, the Universal Declaration remains even more significant
      today than when it was adopted a half-century ago.

PMID- 10343300
TI  - The UDHR and The Limits of Medical Ethics: The Case of South Africa.
AB  - The leadership of South Africa's medical profession remained silent in the face
      of gross human rights violations by the apartheid government or affirmatively
      defended the government's conduct. While there were strong cultural and economic
      reasons for this alliance between leaders of the medical profession and the
      apartheid state, the leadership also embraced western medical ethics. As a
      result, when confronted about its conduct, it continually sought to defend its
      behavior on traditional ethical grounds. This article looks at the nature of that
      "ethical defense" in three areas, torture in detention, racial discrimination in
      health services, and breach of confidentiality in the case of political
      activists. The article concludes that the rules of medical ethics left too great
      a space for making such a defense and urges that ethical rules consistent with
      the Universal Declaration of Human Rights be adopted.

PMID- 10343301
TI  - Introduction 

PMID- 10343302
TI  - Fiberoptic flexible sigmoidoscopy and pelvic masses 

PMID- 10343303
TI  - Complications of bowel cleansing with polyethylene glycol-electrolyte solution.

PMID- 10343304
TI  - "Another" white ball appearance on the ligated varix ruptured by suction during
      endoscopic variceal ligation.

PMID- 10343305
TI  - Use of a retroviral vector for expression of a foreign gene.

PMID- 10343306
TI  - Extraction of eicosanoids from biological fluids, cells, and tissues.

PMID- 10343307
TI  - Assessment of cyclooxygenase RNA expression by northern hybridization.

PMID- 10343309
TI  - Separation of hydroxyeicosatetraenoic acids and leukotrienes originating from
      kidney tissue by C-18 reverse-phase high-pressure liquid chromatography.

PMID- 10343308
TI  - Immunohistochemical analysis of cyclooxygenase expression in human skin.

PMID- 10343311
TI  - Assessment of cyclooxygenase protein expression by western blotting.

PMID- 10343310
TI  - Localization and distribution of cyclooxygenase-2 in brain tissue by
      immunohistochemistry.

PMID- 10343312
TI  - Assessment of arachidonic acid distribution into phospholipids of inflammatory
      cells.

PMID- 10343313
TI  - Determination of phospholipase A2s expression in mast cells by reverse
      transcriptase polymerase chain reaction.

PMID- 10343314
TI  - Enzyme immunoassays (EIAs) of eicosanoids.
AB  - Enzyme immunoassay of eicosanoids is a nonradioactive, highly sensitive method of
      determining the concentration of eicosanoids in biological samples. Although
      relatively easy to use, the assays require a high level of precise pipetting
      technique and familiarity with critical points in the assay procedure. Although
      assay kits complete with plates, buffers, antibodies, tracers, and color
      development reagents are available, it is more economical to develop the assay
      within the laboratory if the assay is to be performed routinely. The only major
      disadvantage with EIA is that the investigator is limited to measuring
      eicosanoids with commercially available enzyme-tracers and antibodies. The
      labeling of particular eicosanoids by enzyme tracers is rarely, if ever,
      performed outside of industry. Growing of antibodies is conducted in many
      laboratories but is beyond the scope of this chapter. It requires a significant
      level of commitment of time and resources to establish the specificity of the
      antibody (i.e., does the antibody cross-react with eicosanoids of similar
      structure). Furthermore, this will not solve the problem of availability of
      eicosanoid-tracer. On the other hand, it must be noted that with the exception of
      the cytochrome P-450 metabolites of arachidonic acid, most of the major
      eicosanoids that are biologically active and are known to play regulatory roles
      in physiology and/or pathology, have commercially available antibodies and enzyme
      tracers.

PMID- 10343316
TI  - Assessment of cellular localization of the thromboxane A2 receptor by
      immunocytochemistry.

PMID- 10343315
TI  - Transcellular regulation of eicosanoid biosynthesis.
AB  - Models for in vivo scenarios of transcellular biosynthesis provide invaluable
      information about the regulation of eicosanoid biosynthesis that is likely to
      occur during multicellular events in vivo. The experimental approach of studying
      eicosanoid generation during cell-cell interactions and receptor-mediated cell
      activation represents a significant advancement beyond initial observations of
      eicosanoid formation and bioaction in isolated cell types that were activated
      under less physiologically relevant conditions. The experimental models reviewed
      in this chapter should be viewed as specific examples or as approaches to the
      study of cell-cell interactions. These examples may serve as guidelines to
      investigate novel cell-cell scenarios (see Fig. 3) and advance the emerging area
      of transcellular biosynthesis of bioactive lipid mediators.

PMID- 10343317
TI  - Epoxyeicosatrienoic acids. Biosynthesis, regulation, and actions.

PMID- 10343318
TI  - Assessment of the expression of prostaglandin synthase-2 in Swiss 3T3
      fibroblasts.

PMID- 10343319
TI  - Assessment of 5-lipoxygenase activity and cellular distribution.

PMID- 10343320
TI  - Leukotrienes, lipoxins, and hydroxyeicosatetraenoic acids.

PMID- 10343321
TI  - Whole-blood assays for evaluation of thromboxane synthase inhibition.

PMID- 10343322
TI  - Novel eicosanoids. Isoprostanes and related compounds.
AB  - The discovery of IsoPs has been an interesting development for a number of
      reasons, apart from the fact that it involves novel biochemistry. The simple fact
      that prostanoids are produced nonenzymatically in prodigous quantities in vivo
      and in much greater quantities than prostaglandins generated by the
      cyclooxygenase enzyme was a remarkable finding. The observation that detectable
      quantities of F2-IsoPs are present in all tissues and human biological fluids
      carries interesting implications. Previously, there had been little convincing
      evidence for the occurrence of lipid peroxidation in vivo except under unusual
      conditions of severe oxidative stress. However, the finding that F2-IsoPs can be
      easily detected in normal humans suggests a continuous level of ongoing oxidative
      injury that is not completely suppressed by the elaborate system of antioxidant
      defenses that have evolved. Another very important aspect of the discovery of
      IsoPs is that it has brought to the field a long sought after reliable approach
      to assess oxidative stress status in vivo. The continuing and expanded use of
      measurements of IsoPs for this purpose will contribute in a very valuable way to
      advancing our understanding of the role of free radicals in human disease
      processes. Further, the finding that these compounds are not simply markers of
      oxidant injury but can also exert potent biological actions both by interaction
      with specific receptors and, in the case of IsoLGs and cyclopentenenone IsoPs, by
      virtue of their chemical reactivity, has identified several new classes of
      molecules that are produced by free radical-induced lipid peroxidation that may
      mediate some of the adverse sequela of oxidant injury. The elucidation of the
      variety of compounds that are produced as products of the IsoP pathway and more
      recently the NP pathway provides vast new areas for scientific inquiry that
      should yield new and interesting information as this area continues to advance.

PMID- 10343323
TI  - Morphological study of the entorhinal cortex, hippocampal formation, and basal
      ganglia in Rett syndrome patients.
AB  - Entorhinal cortex (EC), fascia dentata (FD), hippocampus (HP), and basal ganglia
      (BG) were studied in Rett syndrome (RS) cases and compared with control brains
      and an autism case. Kluver-Barrera and Golgi methods were used. In RS most of the
      areas of EC, HP, and FD showed severe cell hypochromia. In the EC all cells of
      layer II and most in layer III were in a state of total chromatolysis or were
      "ghost" cells, but the cells of layers V and VI were preserved and moderately
      hyperchromic. In FD and HP the majority of the granular cells and cells of CA3
      and CA4 fields were severely hypochromic, whereas in the CA1 field most cells
      were normal or slightly hypercaryochromic. In BG mostly mild or moderate
      aberration from normal cell structure was observed: in striatum, mild
      hypercaryochromia of small neurons and more expressive hyperchromia of large
      neurons were found; and in pallidum, mild or moderate hypercaryochromia to severe
      hyperchromia in pallidum internum was found. Degeneration of thick myelinated
      fibers was evident in pallidum. Large striatal and pallidal neurons showed signs
      of constructive changes in Golgi slices. These data allow the determination of
      the cause of the main symptoms of RS. The motor disorders, including specific
      stereotyped movements, could be related to the enhanced activity of BG cells due
      to their deafferentation from the side of the neocortex and to supposed
      hyperactivity of the EC-striatal pathway; the mental retardation and epileptic
      seizures could be due to FD-HP involvement.

PMID- 10343324
TI  - Expression of proteins linked to exocytosis and neurotransmission in patients
      with Creutzfeldt-Jakob disease.
AB  - In order to characterize synaptic involvement in human spongiform
      encephalopathies, the expression of synaptic vesicle-associated proteins,
      synaptophysin and synapsin-I, and presynaptic plasma membrane proteins,
      synaptosomal-associated protein of 25 kDa (SNAP-25) and syntaxin-I, was examined
      in the brains of four patients who had suffered from sporadic Creutzfeldt-Jakob
      disease. Nerve cell loss, spongiform degeneration, astrocytosis, and deposition
      of prion protein (PrP) were observed in the cerebral cortex in every case.
      Decreased immunoreactivity for synaptophysin, synapsin-I, SNAP-25, and syntaxin-I
      was observed in the cerebral cortex in every case, thus showing generalized
      reduction of proteins involved in exocytosis of synaptic vesicles in the brains
      of patients with spongiform encephalopathy. Upregulation of synaptophysin and
      SNAP-25, a feature associated with beta A4 deposits in Alzheimer's disease (AD),
      was not observed in associated with PrP deposition. The present results indicate
      that synaptic pathology is a major event in spongiform encephalopathy, and
      suggest that synaptic loss, together with neuron loss and selective involvement
      of certain populations of local-circuit neurons, as shown in other studies, may
      account for the dramatic neurological decay and for the main neurological
      symptoms in patients with CJD.

PMID- 10343325
TI  - Regional metabolic disturbances and cerebrovascular anatomy after permanent
      middle cerebral artery occlusion in C57black/6 and SV129 mice.
AB  - C57Black/6 and SV129 mice are widely used for the production of transgenic
      mutants in molecular stroke research but the ischemic susceptibility of these
      strains is influenced by differences in vascular anatomy and the responsiveness
      to excitotoxins and vasodilatory stimuli. To differentiate between these opposing
      effects on infarct size, the vascular territory of the two strains was correlated
      with the hemodynamic, metabolic, and morphological consequences of permanent
      middle cerebral artery (MCA) occlusion. The vascular anatomy was studied by latex
      infusion, brain infarction by vital staining, the size of the ischemic penumbra
      by imaging of ATP and protein synthesis, and blood flow by laser-Doppler
      flowmetry. In C57Black/6 mice the MCA-supplied vascular territory and the size of
      brain infarcts were significantly larger than in SV129 mice but the size of the
      penumbra and the residual blood flow in the center of the MCA-supplying territory
      were similar in both strains. These findings suggest that differences in infarct
      size in C57Black/6 and SV129 mice are determined mainly by the vascular anatomy
      and not by differences in collateral vascular responsiveness or excitotoxicity.

PMID- 10343326
TI  - N-Methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect
      cholinergic nucleus basalis neurons against beta-amyloid neurotoxicity.
AB  - Previous experimental data indicate the involvement of Ca(2+)-related excitotoxic
      processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in beta
      amyloid (beta A) neurotoxicity. On the other hand, other lines of evidence
      support the view that free radical generation is a critical step in the beta A
      induced neurodegenerative cascade. In the present study, therefore, a
      neuroprotective strategy was applied to explore the contributions of each of
      these pathways in beta A toxicity. beta A(1-42) was injected into the
      magnocellular nucleus basalis of rats, while neuroprotection was achieved by
      either single or combined administration of the NMDA receptor antagonist MK-801
      (2.5 mg/kg) and/or a vitamin E and C complex (150 mg/kg). The degree of
      neurodegeneration was determined by testing the animals in consecutive series of
      behavioral tasks, including elevated plus maze, passive avoidance learning, small
      open-field and open-field paradigms, followed by acetylcholinesterase (AChE),
      choline-acetyltransferase (ChAT), and superoxide dismutase (SOD) biochemistry.
      beta A injected in the nucleus basalis elicited significant anxiety in the
      elevated plus maze, derangement of passive avoidance learning, and altered
      spontaneous behaviors in both open-field tasks. A significant decrease in both
      AChE and ChAT accompanied by a similar decrement of MnSOD, but not of Cu/ZnSOD
      provided neurochemical substrates for the behavioral changes. Each of the single
      drug administrations protected against the neurotoxic events, whereas the
      combined treatment failed to ameliorate beta A toxicity.

PMID- 10343327
TI  - GAP-43 (B-50) and C-Jun are up-regulated in axotomized neurons of Clarke's
      nucleus after spinal cord injury in the adult rat.
AB  - The growth-associated protein GAP-43 (B-50) and the transcription factor C-Jun
      are involved in regeneration of the injured nervous system. In this study, we
      investigated the possibility of the induction of GAP-43 and C-Jun in axotomized
      neurons of Clarke's nucleus (CN) in adult rats, of which a large population
      undergoes degeneration several weeks after a low thoracic lateral funiculotomy of
      the spinal cord. In situ hybridization and immunohistochemistry revealed a
      transient up-regulation of GAP-43 mRNA, C-Jun protein, and its activated,
      phosphorylated form, peaking around 7 days after injury in preferentially large
      diameter CN-neurons ipsilateral and caudal to the lesion. Our results document
      that some populations of axotomized central nervous system neurons, similar to
      axotomized regenerating neurons of the peripheral nervous system, can up-regulate
      GAP-43 and C-Jun, even if they are destined to degenerate. This might reflect a
      transient regenerative capacity, which fails over time.

PMID- 10343328
TI  - Upregulation of the aromatic amino acid decarboxylase under neonatal asphyxia.
AB  - Perinatal hypoxic-ischemic cerebral injury is a major determinant of neurologic
      morbidity and mortality in the neonatal period and later in childhood. There is
      evidence that the dopaminergic system is sensitive to asphyxia. However, the
      respective enzyme activities have not yet been measured in the living neonatal
      brain. In this study, we have used 18F-labeled 6-fluoro-L-3,4
      dihydroxyphenylalanine (FDOPA) together with positron-emission tomography (PET)
      to estimate the activity of the aromatic amino acid decarboxylase (AADC), the
      ultimate enzyme in the synthesis of dopamine (DA), in the brain of newborn
      piglets. Simultaneously, the cerebral blood flow (CBF) was measured with colored
      microspheres. Asphyxia elicited an up to threefold increase of the CBF. Despite
      this, the blood-brain transfer of FDOPA as well as the clearance rate constants
      from brain were unchanged. However, the synthesis rate of FDA from FDOPA was
      significantly increased in frontal cortex, striatum, and midbrain. This increase
      of the AADC activity and the decrease of monoamine oxidase activity may
      contribute to the increase of extracellular DA during asphyxia which is expected
      to be involved in severe disturbances of neuronal metabolism, e.g., by generating
      free radicals.

PMID- 10343329
TI  - Differential expression of group I metabotropic glutamate receptors in rat spinal
      cord somatic and autonomic motoneurons: possible implications for the
      pathogenesis of amyotrophic lateral sclerosis.
AB  - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized
      by the progressive loss of somatic, but not autonomic, motoneurons. The reason
      for this selective vulnerability is unknown. The pathogenesis of ALS is thought
      to involve glutamatergic excitotoxic mechanisms. While overactivation of
      ionotropic glutamate receptors may trigger excitotoxicity, we have previously
      shown that stimulation of group I metabotropic glutamate receptors (mGluRs) can
      exert neuroprotective effects on cultured motoneurons. Using in situ
      hybridization, we found a differential expression of group I mGluRs (mGluR1 and
      5) in rat spinal cord. Autonomic motoneurons from the sacral parasympathetic
      Onuf's nucleus and thoracic sympathetic neurons, which are spared in ALS, express
      high levels of mGluR5, while somatic motoneurons do not. In addition, mGluR1 mRNA
      is found only in smaller somatic motoneurons, which seem to be less vulnerable in
      ALS. Thus, differential mGluR expression might provide a possible clue to the
      selective vulnerability of different motoneuronal subpopulations in ALS.

PMID- 10343330
TI  - Generalised linear mixed models analysis of risk factors for contamination of
      Danish broiler flocks with Salmonella typhimurium.
AB  - We present a retrospective observational study of risk factors associated with
      the occurrence of Salmonella typhimurium (ST) in Danish broiler flocks. The study
      is based on recordings from 1994 in the ante-mortem database maintained by the
      Danish Poultry Council. The epidemiological units are the broiler flocks (about
      4000 flocks) which are clustered within producers. Broiler flocks with ST
      infected parent stocks show increased risk of salmonella infection, and also the
      hatchery affects the salmonella status significantly. Among the rearing factors,
      only the use of medicine as well as the time of rearing, and the sampling method
      are significant. Epidemiological control would seem most efficient on starting at
      the top levels of the production hierarchy from which a major part of the ST
      contamination is derived. A secondary purpose of the study is to evaluate
      different statistical approaches and software for the analysis of a moderately
      sized data set of veterinary origin. We compare the results from five analyses of
      the generalised linear mixed model (GLMM) type. The first observation is that the
      results agree reasonably well and lead to similar conclusions. A closer look
      reveals certain patterns of bias and estimation accuracy that correspond well
      with theoretical findings and practical experience reported in the statistical
      literature.

PMID- 10343331
TI  - Spatial diffusion of raccoon rabies in Pennsylvania, USA.
AB  - Identification of the geographic pattern of diffusion of a wildlife disease could
      lead to information regarding its control. The objective of this study was to
      model raccoon-rabies diffusion in Pennsylvania to identify geographic constraints
      on the diffusion pattern for potential use in bait-vaccination strategies. A
      trend-surface analysis (TSA) was used as a spatial filter for month to first
      report by county location. A cubic polynomial model was fitted (R2 = 0.80).
      Velocity vectors were calculated from the partial derivatives of the model and
      mapped to demonstrate the instantaneous speed of diffusion at each location. A
      main corridor of diffusion through the ridge and valley section of the state was
      evident early in the outbreak. Once the disease reached the northern counties,
      the disease moved west toward Ohio. I believe that TSA was useful in identifying
      the pattern of raccoon-rabies diffusion across the stage from the inherent noise
      of disease-reporting data.

PMID- 10343332
TI  - Reproductive performance of farmed red deer (Cervus elaphus) in New Zealand: II.
      Risk factors for adult hind conception.
AB  - A 2-year longitudinal observational study of 15 red deer farms was carried out in
      New Zealand from March 1992. About 2600 adult hinds were individually monitored
      for reproductive success. After mating, hinds were pregnancy-tested by ultrasound
      and were classified as having conceived before 1 May, after 1 May or as being not
      pregnant. Risk factors potentially affecting the probability of conception before
      1 May or of conception that year were investigated using path analysis. Final
      path diagrams were used to formulate a putative management strategy for farmers
      to achieve the desired reproductive performance from adult hinds. To achieve a
      high pregnancy rate early in the mating season, farmers should wean calves early,
      exclude hinds which failed to rear a calf to weaning and hinds with a body
      condition score < or = 2.0 at mating, join hinds early with one or more sire
      stags, use only experienced sires for mating, limit the hind: stag ratio, use at
      least one back-up sire after the peak of mating, keep mating mobs away from
      disturbance and avoid shifting or handling mating mobs. The farmer should choose
      paddocks with high green pasture allowance and grazed down to no less than 5 cm
      high.

PMID- 10343333
TI  - Reproductive performance of farmed red deer (Cervus elaphus) in New Zealand: III.
      Risk factors for yearling hind conception.
AB  - A 2-year longitudinal observational study of 15 red-deer farms was carried out in
      New Zealand from March 1992. Seven hundred yearling hinds were individually
      monitored for reproductive success. After mating, hinds were pregnancy tested by
      ultrasound and were classified as having conceived before 1 May, after 1 May, or
      as being not pregnant. Risk factors potentially affecting the probability of
      conception before 1 May or of conception that year were investigated using path
      analysis. To increase the probability of conceiving early, this study suggests
      yearling hinds should be selected prior to mating for high bodyweight and height.
      Young stags and hinds should be joined late summer (14 months of age) before
      mating. Mobs of yearling hinds should not be combined with large mobs of adult
      hinds. Paddocks with limited gullies, hills and trees should be chosen for
      mating. Finally, paddocks for mating should be away from human disturbance. To
      increase the probability of yearling hinds conceiving that year, yearling hinds
      should be in moderate-to-low body condition (around 2.5), and nutrition during
      mating should be prioritised to ensure optimal growth rates. Short and/or
      lightweight hinds may be mated successfully if they are well fed but they
      generally conceive later. Trees should be limited in the mating paddocks.

PMID- 10343334
TI  - Evaluation of a fluorescence-polarization assay for the diagnosis of bovine
      brucellosis in Mexico.
AB  - A homogeneous fluorescence-polarization assay (FPA) was used for the serological
      diagnosis of bovine brucellosis in Mexico. The assay uses O-polysaccharide
      prepared from Brucella abortus lipoplysaccharide (20-30 kDa) conjugated with
      fluorescein isothiocyanate as a tracer. To measure the fluorescence polarization,
      a FPM-1 fluorescence-polarization analyzer was used with the procedure described
      by Nielsen et al. (1996b). A cut-off value of 90 millipolarization (mP) units was
      used for testing 560 bovine sera from different areas of Mexico. (305 positive
      sera and 255 negative sera according to the complement fixation test; CFT.) Some
      were tested with the Rose Bengal plate (RB) test (n = 490) and some with the
      rivanol-agglutination (RIV) test (n = 190). Sensitivities were 98.3%, 99.3% and
      99.0%, and specificities were 68.8%, 55.4% and 96.9%, respectively, for RB, RIV
      and FPA. The FPA gave a kappa coefficient of agreement with respect to CFT of
      0.96, while RB and RIV (relative to the CFT) gave coefficients of 0.70 and 0.61,
      respectively. Finally, ROC analysis suggested a cut-off value which agreed with
      the one recommended in the test procedure. We concluded that FPA is a suitable
      test to be used instead of the CFT in Mexican conditions.

PMID- 10343335
TI  - The Nutrition Society Medical Lecture. Obesity: from molecules to man.
AB  - Obesity is now a major public health problem in both developed and developing
      countries. In the UK over 16% men and 17.5% women are obese, an increase of more
      than 100% since 1980. However, interventions to prevent and treat obesity are
      hampered by an inadequate understanding of the aetiology of this condition. The
      present paper considers the current state of knowledge regarding the causes of
      obesity, including some of the genetic, metabolic, behavioural and environmental
      factors which influence energy balance. The present paper comprises The Nutrition
      Society Medal Lecture and focuses in particular on the research carried out at
      the MRC Dunn Nutrition Centre in Cambridge. It argues that despite decades of
      intensive research there is relatively little evidence of genetic or metabolic
      defects to explain the majority of cases of human obesity. Instead we must look
      to behavioural and/or environmental factors which may be underpinning the current
      epidemic of obesity.

PMID- 10343336
TI  - The Rudolf Schoenheimer Centenary Lecture. Isotopes in nutrition research.
AB  - The present lecture begins with a brief overview of the professional and
      scientific journey taken by Rudolf Schoenheimer, before turning to a discussion
      of the power of isotopic tracers in nutrition research. Schoenheimer's remarkable
      contributions to the study of intermediary metabolism and the turnover of body
      constituents, based initially on compounds tagged with 2H and later with 15N,
      spanned a mere decade. It is difficult, however, to overestimate the enormous
      impact of Schoenheimer's research on the evolution of biological science. After a
      relative hiatus, following Schoenheimer's death in 1941, in the use of stable
      nuclides as tracers in metabolism and nutrition, especially in human subjects,
      there is now an expanded and exciting range of techniques, experimental protocols
      and stable-isotope tracer compounds that are helping to probe the dynamic aspects
      of the metabolism of the major energy-yielding substrates, amino acids and other
      N-containing compounds, vitamins and mineral elements in human subjects. Various
      aspects of the contemporary applications of these tracers in nutrition research
      are covered in the present lecture.

PMID- 10343337
TI  - New techniques in nutritional assessment: body composition methods.
AB  - New techniques in air-displacement plethysmography seem to have overcome many of
      the previous problems of poor reproducibility and validity. These have made body
      density measurements available to a larger range of individuals, including
      children, elderly and sick patients who often have difficulties in being
      submerged underwater in hydrodensitometry systems. The BOD POD air-displacement
      system (BOD POD body composition system; Life Measurement Instruments, Concord,
      CA, USA) is more precise than hydrodensitometry, is simple and rapid to operate
      (approximately 1 min measurements) and the results agree closely with those of
      hydrodensitometry (e.g. +/- 3.4% for estimation of body fat). Body line scanners
      employing the principles of three-dimensional photography are potentially able to
      measure the surface area and volume of the body and its segments even more
      rapidly (approximately 10 s), but the validity of the measurements needs to be
      established. Advances in i.r. spectroscopy and mathematical modelling for
      calculating the area under the curve have improved precision for measuring
      enrichment of 2H2O in studies of water dilution (CV 0.1-0.9% within the range of
      400-1000 microliters/l) in saliva, plasma and urine. The technique is rapid and
      compares closely with mass spectrometry (bias 1 (SD 2) %). Advances in bedside
      bioelectrical-impedance techniques are making possible potential measurements of
      skinfold thicknesses and limb muscle mass electronically. Preliminary results
      suggest that the electronic method is more reproducible (intra- and inter
      individual reproducibility for measuring skinfold thicknesses) and associated
      with less bias (+12%), than anthropometry (+40%). In addition to these selected
      examples, the 'mobility' or transfer of reference methods between centres has
      made the distinction between reference and bedside or field techniques less
      distinct than in the past.

PMID- 10343338
TI  - Problems of nutritional assessment in the acute setting.
AB  - Surveys have shown that 20-50% of hospital admissions suffer from nutritional
      depletion and that there is failure to recognize its existence and significance.
      More emphasis must be placed in clinical medicine on identifying subjects who are
      at high risk of developing disease-related malnutrition. There is a need to
      screen patients on admission to hospital to identify those at risk of nutrition
      related complications. More formal determination of nutritional status should be
      carried out to define the nutritional status of the patient and to monitor
      changes in nutritional status during nutritional support. The most frequently
      used tests of nutritional status include dietary, anthropometric, biochemical and
      functional indices of nutritional status. It is important, and indeed is the
      skill of the nutritional care team (particularly the dietitian) to be able to
      evaluate these measurements, as many of them are affected by non-nutritional
      factors. There is no consensus on the best method for the accurate assessment of
      nutritional status. Practical difficulties arise with individual measurements and
      in their interpretation in the acute setting. The aim of the present paper is to
      identify the most relevant variables to measure in clinical medicine, and to
      discuss the limitations of their use in the acute setting.

PMID- 10343339
TI  - Problems of nutritional assessment in the community.
AB  - The present paper explores the problems associated with assessment of nutritional
      status in the community and reviews the literature related to this subject. The
      first problem is one of terminology, since a logical first step before assessment
      is screening, which identifies characteristics known to be associated with
      dietary or nutritional problems. Its purpose is to differentiate individuals who
      are at high nutritional risk or have poor nutritional status. There are certain
      factors which should alert the primary health care team to the fact that
      nutritional intake may be reduced and that risk of malnutrition is increased.
      These include disease condition, functional disabilities, inadequate or
      inappropriate food intake, poor dentition or difficulty swallowing, polypharmacy,
      alcoholism, depression, poor social circumstances or recent discharge from
      hospital. Patients suffering from these factors need to be identified so that
      screening becomes a routine part of their medical treatment. At-risk groups
      include the elderly, the chronically ill, those with cancer and neurological
      disorders, post-surgical patients and children with developmental disabilities.
      In the community, practice and community nurses see the majority of at-risk
      patients and should carry out screening. A number of screening tools have been
      developed for community use. Most are aimed at the elderly population, but there
      are others designed to assess nutritional risk in children with developmental
      disabilities and the general population. These are reviewed and problems of
      content and validity identified. Some problems associated with nutritional
      assessment are also reviewed.

PMID- 10343340
TI  - Treatment of obesity: theory into practice.
AB  - The purpose of the present paper is to outline the current situation in the
      management of obesity in adults, and to make some suggestions as to how health
      professionals involved in obesity treatment can best address this growing
      problem. Dietitians and nutritionists have long been involved in the treatment of
      obesity, and have a vital role to play in the battle to reverse the increasing
      prevalence of this major public health problem. However, the current management
      of obesity is far from ideal. There is evidence to suggest that in general health
      care, even when there are clearly effective clinical interventions, health
      professionals may not practise in the best way. Furthermore, some professionals
      may also hold negative attitudes towards the obese. These are the subject of a
      systematic review on improving health professionals' practice and organization of
      care in obesity treatment, the preliminary findings of which will be discussed in
      the present paper (Harvey et al. 1998a,b). A new approach to obesity is required,
      encompassing effective treatment and prevention strategies. A greater
      understanding of the problems faced by the obese individual in attempting to lose
      weight is also needed, with a range of treatment approaches on offer to
      acknowledge the heterogeneity of obesity. Those health professionals involved in
      obesity treatment must consider the impact of dietary advice given in a
      consultation against the impact of environmental cues that assail the patient as
      soon as they leave the room. Tackling the obesity epidemic requires action at the
      individual and population level if we are to see any reduction in prevalence.

PMID- 10343341
TI  - Eating habits and appetite control: a psychobiological perspective.
AB  - An individual's eating behaviour is shaped by factors ranging from economic
      conditions and cultural practices to biological influences. The physiological
      system controlling appetite appears to be adapted to solving the problem of an
      unevenness of food supply across time, and is fairly permissive in its response
      to undereating and overeating. Consequently, when food is abundant, the diet is
      energy dense and energy expenditure is low, there is a strong tendency to become
      obese (i.e. obesity is better viewed as due to a 'toxic' environment than to
      faulty physiological control of appetite). Under such conditions the most common
      method of avoiding obesity is through the cognitive control of eating. However,
      dietary restraint and dieting are demanding tasks, and are associated with
      psychological costs, including significant impairment of cognitive performance.
      Restraint is also prone to disinhibition, with the result that it can sometimes
      undermine eating control, even leading to the development of highly disordered
      eating patterns. In part, these difficulties are due to the self-perpetuating
      nature of dietary habits: for example, hunger tends to be diminished during
      strict unbroken dieting, but increased in individuals having a highly variable
      eating pattern (such as occurs when eating is frequently disinhibited). These
      features of appetite control provide both barriers and opportunities for changing
      behaviour. Accordingly, there is a need for future research to focus on the
      psycho-social factors and the dieting practices predicting successful eating and
      weight control, with the objective of identifying the actual cognitive and
      behavioural strategies used by the many dieters and restrained eaters who are
      able to achieve weight loss and maintain long-term weight stability.

PMID- 10343342
TI  - The influence of the maternal uterine immune response on placentation in human
      subjects.
AB  - The immunological relationship between the mammalian fetus and its mother during
      pregnancy has been considered similar to that between a transplanted allograft
      and its recipient ever since Medawar (1953) first proposed the concept of the
      'fetus as an allograft' in the early 1950s. Based on this analogy, it has been
      assumed that implantation of the fetal placenta in the uterus would be controlled
      similarly by a maternal immune response mediated by T-cells recognizing
      paternally-derived alloantigens expressed by the placenta. Surprisingly, recent
      evidence suggests that implantation might involve predominantly a novel
      allogeneic recognition system based on natural killer cells rather than T-cells
      (Loke & King, 1995). The cellular and molecular basis of this local immune
      interaction between the fetal placenta and maternal uterus is now the focus of
      intense research interest. Since aberrant implantation can cause a variety of
      clinical problems, including miscarriage, intrauterine growth retardation and pre
      eclampsia, an understanding of the immunological mechanism by which this process
      is controlled could lead to the development of regimens to improve fetal growth
      and development.

PMID- 10343343
TI  - Prematurity, immune function and infant feeding practices.
AB  - Recently, there has been much interest in the literature in the role of early
      nutrition and the health of the individual in adulthood. A majority of infants in
      the UK are born full term, while preterm infants account for 4-6% of the total
      births. Milk feeding practices are divided into three groups: breast, combination
      (breast-fed with formula as 'top-up') and bottle (formula). In studies conducted
      by our group and other researchers immune function in full-term and preterm
      infants has been assessed by monitoring total and specific immunoglobulin E and
      specific immunoglobulin G levels. Dietary modification by the pregnant mother
      with a history of allergy in the family has been shown to have a positive effect
      with respect to allergy outcome and prevention of atopic disease in the infant.
      However, this dietary modification has to occur before week 22 of pregnancy and
      continue until the end of lactation to achieve a beneficial outcome to the
      infant. The stress of mothers restricting their diets may be disadvantageous to
      the fetus, and therefore any gain due to the dietary restriction may be lost.
      Researchers have shown that the early introduction of complementary foods and the
      greater diversity of these foods appeared to result in an increase in the
      incidence of atopic disease in the infant. In conclusion, in order to reduce the
      risk in their babies, mothers with a family history of atopic disease should
      breast-feed for more than 15 weeks and introduce solid foods after 4 months,
      limiting the variety until at least 6 months.

PMID- 10343344
TI  - Effects of dietary antioxidants on the immune function of middle-aged adults.
AB  - The immune system is highly reliant on accurate cell-cell communication for
      optimal function, and any damage to the signalling systems involved will result
      in an impaired immune responsiveness. Oxidant-mediated tissue injury is a
      particular hazard to the immune system, since phagocytic cells produce reactive
      oxygen species as part of the body's defence against infection. Adequate amounts
      of neutralizing antioxidants are required, therefore, to prevent damage to the
      immune cells themselves. Many antioxidants can be obtained directly from the diet
      (e.g. ascorbic acid, alpha-tocopherol, carotenoids and polyphenolic flavonoids)
      or require micronutrients as integral components (e.g. Se in the metalloenzyme
      glutathione peroxidase (EC 1.11.1.9)). Numerous epidemiological studies have
      found strong associations between diets rich in antioxidant nutrients and a
      reduced incidence of cancer, and it has been suggested that a boost to the body's
      immune system by antioxidants might, at least in part, account for this. Although
      more striking effects have been observed in the elderly, there is also evidence
      that antioxidant nutrients can modify cell-mediated immune responses in younger
      individuals. Indeed, it might be essential to have an adequate intake of
      antioxidant nutrients from an early age in order to help prevent the development
      of, or at least delay the onset of, several degenerative disorders. The present
      paper will review the effects of specific nutrients on immune function in young
      to middle-aged human subjects, focusing on the antioxidant vitamins C and E, and
      on Se. A further review, dealing more specifically with the effects of
      carotenoids on human immune function, will be presented at a forthcoming meeting
      of the Nutrition Society.

PMID- 10343345
TI  - Immune response during disease and recovery in the elderly.
AB  - The present article reviews immune ageing and its relationship with nutritional
      ageing, with a particular insight into the influences of disease on both ageing
      processes. Immune ageing can be described primarily as the progressive appearance
      of immune dysregulations, mainly acquired immunity (mature: immature, naive:
      memory T lymphocyte subset decreases) leading to gradual increases in T-helper 2:
      T-helper 1 cells. This change is due initially to decreased thymic function, and
      later to accumulative antigen pressure over the lifespan. In contrast, innate
      immunity (macrophage functions) is preserved during the ageing process and in the
      elderly this leads to macrophage-lymphocyte dysequilibrium, which is particularly
      critical during on-going disease. Indeed, any disease induces long-lasting acute
      phase reactions in aged patients and leads to body nutritional reserve (mainly
      protein) losses. Episodes of disease in the aged patient progressively deplete
      body nutritional reserves and lead to protein-energy malnutrition, undernutrition
      associated immunodeficiency, and finally cachexia. Undernutrition is a common
      symptom in the elderly; protein-energy malnutrition is found in more than 50% of
      hospitalized elderly patients and in most elderly diseased subjects. In addition,
      micronutrient deficit or low levels are common in home-living self-sufficient
      apparently-healthy elderly subjects. All these nutritional deficits induce
      decreased immune responses, and micronutrient deficits are now thought to be
      partly responsible for the decreased immune responses (immune ageing?) observed
      in the apparently-healthy elderly. Indeed, several studies have shown that
      micronutrient supplements induce increased immune responses in the healthy
      elderly. The progression of infectious diseases depends on immune responses and
      on nutritional status before the onset of illness in aged subjects. In addition,
      recovery depends on the intensity of acute-phase responses in the undernourished
      elderly. In fact, chronic acute-phase responses, commonly associated with
      diseases in aged patients, lead to progressive lowering of metabolic responses in
      the undernourished elderly. This can be quantified by increased production of
      free radicals during treatment and these increases may explain the difficulty in
      successfully treating aged patients. Nutritive therapy in order to improve
      metabolic processes and also to maintain body reserves should be considered as a
      necessary adjuvant therapy in the treatment of elderly patients.

PMID- 10343347
TI  - What processes are involved in the appetite response to moderate increases in
      exercise-induced energy expenditure?
AB  - It is intuitive that an energy deficit induced by exercise induces an automatic
      increased drive for food (hunger and energy intake). However, the absence of a
      compensatory increase in energy intake (EI) in response to an exercise-induced
      increase in energy expenditure (EE) is now well documented. Thus, there is a weak
      coupling between exercise-induced increases in EE and EI. One paradox related to
      the phenomenon of a weak coupling between the exercise-induced EE and EI is the
      observation of a positive relationship between physical activity and food intake
      in the long-term free-living situation (i.e. tight coupling between EE and EI).
      It is possible, therefore, that a period of transition (uncoupling) occurs in the
      short-term, before a steady-state (coupling) condition is achieved. It is likely
      that a combination of physiological and behavioural adaptations occur in order to
      achieve a tight coupling between EE and EI. The precise physiological and
      behavioural changes that take place to obtain a new equilibrium (i.e. coupling
      between EE and EI) are still undetermined. The expectation that exercise-induced
      increases in EE should drive up hunger and food intake tends to be based on the
      concept of a strong coupling between physiology and behaviour. However, because
      of the individual's strong volitional control over eating behaviour, the
      psychological influences on the appetite response to exercise should not be
      undervalued. The psychological position of the individual (e.g. dietary
      restraint, food-related cognitions, reasons for exercising) could have a very
      strong influence on the food intake response to exercise. Misjudgements
      concerning the energy value of the food (EI) relative to the energy value of the
      exercise (EE) could be one possibility why exercise fails to be a successful
      method of weight loss for some individuals.

PMID- 10343346
TI  - Influence of intense physical activity on energy balance and body fatness.
AB  - The reduced contribution of physical activity to daily energy expenditure and the
      accessibility to high-fat foods have put an excessive burden on energy balance,
      resulting in an increase in the prevalence of obesity throughout the world. In
      this context, fat gain can be seen as a natural adaptation to deal with a
      fattening lifestyle, since the hormonal adaptations that accompany fat gain
      favour the readjustment of energy expenditure to energy intake. Intense physical
      activity would also seem to facilitate the regulation of energy balance, since it
      increases the energy cost of exercise, increases post-exercise energy expenditure
      and the potential of skeletal muscles to utilize lipids, and also favours a
      decrease in post-exercise intake. Moreover, the effects of intense exercise seem
      to be mediated by an activation of sympathetic nervous system activity that seems
      to be specific to skeletal muscle. It is also important to manipulate
      macronutrient composition in order to reduce fat intake, because unhealthy food
      habits can favour overfeeding and thus overcome the energy deficit caused by
      regular physical activity. Under free-living conditions, the combination of
      vigorous activity and healthy food practices can amount to a substantial weight
      loss which is comparable with that of other non-surgical approaches to treat
      obesity.

PMID- 10343348
TI  - The effect of inactivity on dietary intake and energy homeostasis.
AB  - Reduced physical activity commonly occurs in patients with disease or chronic
      disabilities, in the elderly, and in certain patients with obesity. Surprisingly,
      information on the effect of inactivity on energy homeostasis is scarce and often
      difficult to interpret. In models of reduced physical activity, such as space
      flights, bed-rest and confinement, subjects frequently lose weight (< 5%),
      predominantly in the form of fat-free mass. In some cases this is compensated by
      an increase in fat mass, which means that changes in weight are poor indicators
      of energy balance. The extent to which spontaneous reduction in energy intake (in
      most studies energy intake is fixed) compensates or overcompensates for the
      reduction in energy expenditure (mainly physical activity and to a small extent
      in BMR, typically < 6%) is largely underexamined. Preliminary observations
      suggesting that there is a preferential selection of low-energy-dense foods (low
      in fat) require confirmation under carefully controlled experimental conditions.
      It is concluded that a comprehensive and systematic evaluation is needed to
      address the effects and relevance of various degrees of physical inactivity to
      energy homeostasis, in relation to disease and space medicine.

PMID- 10343349
TI  - Preparing for inactivity: how insectivorous bats deposit a fat store for
      hibernation.
AB  - During late autumn insectivorous bats must deposit a fat store to cover their
      energy demands throughout the period of hibernation, yet the density of aerial
      insects by this time has already declined from its peak in midsummer. Krzanowski
      (1961) suggested that bats are able to deposit a fat store by manipulating their
      energy expenditure; specifically by selecting cold roosting locations rather than
      warm roosts, and depressing their body temperatures during the day roosting
      period. It was hypothesized that these behavioural changes result in very low
      daily energy demands, and despite reduced food intake the animals are still able
      to gain body fat. We made several tests of this hypothesis. First, we explored
      the thermo-selection behaviour of long-eared bats (Plecotus auritus) in the
      summer and in the pre-hibernal period. We found that in summer bats preferred
      temperatures of about 32-35 degrees (about thermoneutral), but in the pre
      hibernal period they preferred much colder temperatures of about 10 degrees.
      Second, using open-flow respirometry we found that in the cold pre-hibernal bats
      entered torpor for an average of 14 h each day. Compared with bats held at 30
      degrees (that did not go torpid), the bats at 7 degrees expended less energy. The
      extent of saving was sufficient to positively affect their mass balance, despite
      the fact that bats at lower temperature also had reduced digestive efficiencies.
      Our findings support the hypothesis that during the pre-hibernal period
      insectivorous bats manipulate their mass balance primarily by alterations in
      their energy expenditure, specifically utilizing energy-sparing mechanisms such
      as torpor.

PMID- 10343350
TI  - Modelling in nutrition: an introduction.
AB  - The purpose of the present paper is to provide an introduction to modelling,
      particularly mathematical modelling, for nutritional researchers with little or
      no experience of the modelling process. It aims to outline the function of
      modelling, and to give some guidance on factors to consider when designing
      protocols to generate data as part of the modelling process. It is not intended
      in any way to be a comprehensive guide to mathematical modelling. The paper
      discusses the uses of modelling, and presents a 'hydrodynamic analogy' to
      compartmental modelling, to explain the process to the non-mathematically-minded
      and to examine some of the pitfalls to be avoided when using stable-isotope
      tracers. Examples of the use of modelling in nutrition are presented, including
      methods for determining absorption, as well as a discussion of possible future
      avenues for nutritional modelling.

PMID- 10343351
TI  - The bioavailability of non-nutrient plant factors: dietary flavonoids and phyto
      oestrogens.
AB  - The bioavailability in human subjects of non-nutrient plant factors, including
      dietary flavonoids and phyto-oestrogens, is of great importance relative to their
      reported health protective effects. These effects include protection against
      heart disease, and also in the case of the phyto-oestrogens, hormone-dependent
      cancers. Epidemiological studies have shown flavonoid intake (mostly quercetin)
      to be inversely associated with mortality from CHD. Quercetin is a potent
      antioxidant in vitro, and protection against the oxidative damage to LDL
      implicated in atherogenesis has been suggested as a possible mechanism. Human
      subjects can absorb significant amounts of quercetin (particularly in the
      glucoside form) and it would appear to be sufficiently bioavailable to act as an
      antioxidant in vivo; however, following our recent study (J O'Reilly, TAB Sanders
      and H Wiseman, unpublished results), it is currently less clear whether quercetin
      really can act as an antioxidant in vivo. The isoflavone phyto-oestrogens
      genistein and daidzein are much less effective antioxidants than quercetin in
      vitro, however, they are well-absorbed by human subjects and appear to be
      sufficiently bioavailable to act as antioxidants in vivo. In our recent study
      (O'Reilly et al. 1998) lower plasma isoprostane concentrations and increased
      resistance of LDL to oxidation were observed following the high-isoflavone
      dietary phase compared with the low-isoflavone dietary phase. Considerable inter
      individual variation in isoflavone metabolite excretion has been observed, in
      particular the production of equol (the gut bacterial metabolite of daidzein; a
      more potent antioxidant and more oestrogenic than daidzein), and this appears to
      be influenced by habitual diet. Further studies on the bioavailability of these
      non-nutrient plant factors and related influencing factors are clearly still
      required.

PMID- 10343352
TI  - The regulation of mineral absorption in the gastrointestinal tract.
AB  - The absorption of metal ions in the mammalian single-stomached gut is fortunately
      highly selective, and both luminal and tissue regulation occur. Initially,
      assimilation of metal ions in an available form is facilitated by the intestinal
      secretions, chiefly soluble mucus (mucin) that retards hydrolysis of ions such as
      Cu, Fe and Zn. Metal ions then bind and traverse the mucosally-adherent mucus
      layer with an efficiency M+ > M2+ > M3+. At the mucosa Fe3+ is probably uniquely
      reduced to Fe2+, and all divalent cations (including Fe2+) are transported by a
      membrane protein (such as divalent cation transporter 1) into the cell. This
      minimizes absorption of toxic trivalent metals (e.g. Al3+). Intracellular metal
      binding molecules (such as mobilferrin) may be present at the intracellular side
      of the apical membrane, anchored to a transmembrane protein such as an integrin
      complex. This mobilferrin would receive the metal ion from divalent cation
      transporter 1 and, with part of the integrin molecule, transport the metal to the
      cytosol for safe sequestration in a larger complex such as ferritin or
      'paraferritin'. beta 2-Microglobulin and HFE (previously termed human leucocyte
      antigen H) may be involved in stabilizing metal mobilferrin-integrin to form this
      latter complex. Finally, a systemic metal-binding protein such as transferrin may
      enter the antiluminal (basolateral) side of the cell for binding of the
      sequestered metal ion and delivery to the circulation. Regulatory proteins, such
      as HFE, may determine the degree of ion transport from intestinal cells to the
      circulation. Gradients in pH and perhaps pCa or even pNa could allow the
      switching of ions between the different transporters throughout this mechanism.

PMID- 10343353
TI  - Bioavailability of carotenoids in human subjects.
AB  - There is growing need for accurate information regarding the bioavailability of
      carotenoids, both with respect to carotenoids per se and to the vitamin A value
      of provitamin A carotenoids in foods or supplement preparations. Little
      quantitative information is currently available, owing primarily to the lack of
      adequate methods to assess carotenoid bioavailability. Methods applied to
      xenobiotic drugs are in most cases not useful for carotenoids, many of which
      circulate in appreciable quantities in human plasma. Reported ranges of
      carotenoid bioavailability (% dose absorbed) range from 1-99, and variability is
      generally high both within and between treatments. With the current methods,
      relative bioavailability is more readily assessed than absolute bioavailability.
      The most commonly applied methods include measuring the increase in plasma
      carotenoid concentration following chronic intervention, and use of postprandial
      chylomicron (PPC) carotenoid or retinyl ester response following a single dose of
      carotenoid. The advantages and limitations of these approaches, together with
      examples of each, are discussed. A new PPC approach utilizing extrinsic-stable
      isotope-labelled vitamin A (2H4-labelled retinyl acetate) is under development in
      our laboratory, and examples of its application are presented. The currently
      available data suggest that oil solutions of carotenoids are more bioavailable
      than those from food matrices, and heating can improve the bioavailability of
      carotenoids from some food products. Increased availability of labelled
      carotenoids and retinoids should aid the development of reliable methods of
      carotenoid bioavailability assessment. Such data are needed for dietary
      recommendations, supplement formulation, and design of intervention strategies
      involving carotenoids.

PMID- 10343354
TI  - Lipoprotein atherogenicity: an overview of current mechanisms.
AB  - Raised serum cholesterol does not adequately explain the increased risk of CHD
      within populations or the relationship between diet and CHD. Nevertheless, the
      principal transport vehicle of cholesterol in the circulation, LDL, must still be
      regarded as the most atherogenic lipoprotein species, but not because of its
      contribution to serum cholesterol. The atherogenic potential of LDL in the
      majority of individuals arises from an increase in the number of small dense LDL
      particles and not from its cholesterol content per se. There is now a wealth of
      evidence from cross-sectional and prospective studies to show that LDL particle
      size is significantly associated with CHD and predictive of increased coronary
      risk. Moreover, there are a number of credible mechanisms to link small dense LDL
      with the atherogenic process. The rate of influx of serum lipoproteins into the
      arterial wall is a function of particle size, and will thus be more rapid for
      small dense LDL. Components of the extracellular tissue matrix in the intima,
      most notably proteoglycans, selectively bind small dense LDL with high affinity,
      sequestering this lipoprotein in a pro-oxidative environment. The oxidation of
      LDL promotes the final deposition of cholesterol in the arterial wall, and
      numerous studies have shown small dense LDL to be more susceptible to oxidative
      modification than its larger and lighter counterparts. An increase in the number
      of small dense LDL particles may originate from a defect in the metabolism of
      triacylglycerol-rich lipoproteins. One mechanism may involve the overproduction
      and increased residence time of large triacylglycerol-rich VLDL in the
      postprandial phase, a situation thought to arise through pathways of insulin
      resistance.

PMID- 10343355
TI  - The genetics of serum lipid responsiveness to dietary interventions.
AB  - CHD is a multifactorial disease that is associated with non-modifiable risk
      factors, such as age, gender and genetic background, and with modifiable risk
      factors, including elevated total cholesterol and LDL-cholesterol levels.
      Lifestyle modification should be the primary treatment for lowering cholesterol
      values. The modifications recommended include dietary changes, regular aerobic
      exercise, and normalization of body weight. The recommended dietary changes
      include restriction in the amount of total fat, saturated fat and cholesterol
      together with an increase in the consumption of complex carbohydrate and dietary
      fibre, especially water-soluble fibre. However, nutrition scientists continue to
      question the value of these universal concepts and the public health benefits of
      low-fat diets, and an intense debate has been conducted in the literature on
      whether to focus on reduction of total fat or to aim efforts primarily towards
      reducing the consumption of saturated and trans fats. Moreover, it is well known
      that there is a striking variability between subjects in the response of serum
      cholesterol to diet. Multiple studies have examined the gene-diet interactions in
      the response of plasma lipid concentrations to changes in dietary fat and/or
      cholesterol. These studies have focused on candidate genes known to play key
      roles in lipoprotein metabolism. Among the gene loci examined, APOE has been the
      most studied, and the current evidence suggests that this locus might be
      responsible for some of the inter-individual variability in dietary response.
      Other loci, including APOA4, APOA1, APOB, APOC3, LPL and CETP have also been
      found to account for some of the variability in the fasting and fed states.

PMID- 10343356
TI  - Strategies for altering population intakes of fats and fatty acids.
AB  - Quantitative dietary guidelines for fats were first issued in 1977 in the USA and
      these guidelines have changed little since then. In the UK only 14% of the
      population achieve the dietary goal for fat (33% energy) and only 3% achieve the
      target (10% energy) from saturated fatty acids. Analysis of the Dietary and
      Nutritional Survey of British Adults reveals that across quartiles of decreasing
      total fat intake, the actual fatty acid composition of this fat does not alter;
      i.e. when total fat is lowered, all fatty acid categories are equally lowered.
      This arises because 85% of total fat and of each of the categories of fatty acids
      are provided by just five foods (milk, meat, cereals, spreads and vegetables).
      When total fat in the UK is lowered, the intake of polyunsaturated fatty acids is
      lowered. The problem is that if the intake of polyunsaturated fatty acids falls
      below a threshold of about 5% energy, the cholesterol-raising properties of
      certain saturated fatty acids, e.g. myristic acid, are greatly augmented. In
      order to alter the balance of dietary fatty acids, more data are needed on food
      choices of those in the population achieving particular targets. These targets
      cannot be based on existing dietary goals, since so few people attain them. A new
      set of 'interim attainable dietary guidelines', based on prevailing dietary
      intakes, must be the basis for establishing sensible food-based dietary
      guidelines.

PMID- 10343357
TI  - Phyto-oestrogens: a potential role in the prevention of CHD?
AB  - CHD is a major cause of morbidity and mortality in women. The incidence of CHD in
      premenopausal women is low but increases substantially after the menopause, and
      this difference suggests that endogenous oestrogens are cardioprotective.
      Observational prospective studies have consistently shown that exogenous
      oestrogens also lower CHD risk. The biological mechanisms by which endogenous and
      exogenous oestrogens exert their protective effect are multifactorial, affecting
      lipids, carbohydrate metabolism, body fat distribution and blood pressure. The
      prevention of CHD with oestrogen therapy is therefore aimed both at correction of
      the traditional risk factors and at direct control of vessel structure and
      function. The wide international variation in rates of CHD together with the
      lower mortality in sub-groups of the population suggests that a considerable
      proportion of CHD may be prevented by dietary modification. Since phyto
      oestrogens are structually similar to oestrogen, they have the potential to mimic
      its effects in vivo. The hypocholesterolaemic effects of soyabean protein (rich
      in phyto-oestrogen precursors) are well established, but the underlying mechanism
      and atherogenic potential of these changes are unknown. One isoflavone,
      genistein, has been shown in vitro to exert effects which may slow the
      development of atherosclerotic disease. However, further studies are required to
      determine the dose-related changes induced by phyto-oestrogens on serum
      lipoproteins, haemostasis and vascular function.

PMID- 10343358
TI  - Dietary carbohydrates and triacylglycerol metabolism.
AB  - There is a growing body of scientific evidence which demonstrates that plasma
      triacylglycerol (TAG) concentration, especially in the postprandial state, is an
      important risk factor in relation to the development of CHD. Postprandial
      hypertriacylglycerolaemia is associated with a number of adverse metabolic risk
      factors, including the preponderance of small dense LDL, low HDL-cholesterol
      concentrations and elevated factor VII activity. Traditionally, a low-fat high
      carbohydrate diet was used to prevent CHD because it effectively reduces plasma
      cholesterol concentrations, but this dietary regimen increases plasma TAG
      concentrations and reduces HDL-cholesterol concentrations. There is substantial
      epidemiological evidence which demonstrates that high plasma TAG and low plasma
      HDL concentrations are associated with an increased risk of CHD. Thus, there is
      reason for concern that the adverse effects of low-fat high-carbohydrate diets on
      TAG and HDL may counteract or negate the beneficial effect of reducing LDL
      cholesterol concentrations. Although there have been no prospective studies to
      investigate whether reduced fat intake has an adverse effect on CHD, there is
      strong epidemiological evidence that reducing total fat intake is not protective
      against CHD. On the other hand, high-fat diets predispose to obesity, and central
      obesity adversely affects TAG metabolism. There is substantial evidence that in
      free-living situations low-fat high-carbohydrate diets lead to weight loss, which
      in turn will correct insulin resistance and plasma TAG metabolism. Clearly there
      is a need for prospective studies to resolve the issue as to whether low-fat high
      carbohydrate diets play an adverse or beneficial role in relation to the
      development of CHD.

PMID- 10343359
TI  - Language sample analysis in the 21st century.
AB  - Time requirements inherent in transcription and analysis of spontaneous language
      samples represent a significant barrier to the regular use of language sample
      analysis in clinical settings. Taking advantage of the options provided by new
      large, fast, and affordable personal microcomputers, two language analysis
      programs, the Systematic Analysis of Language Transcripts and The Child Language
      Data Exchange System have been developed to provide automated analysis of a wide
      range of language indices, as well as tools designed to reduce and simplify the
      time-intensive process of transcribing and analyzing children's language samples
      from both typical and clinical populations. In this article we provide a
      historical context for the development of these language analysis programs and a
      brief introduction to the transcription editors and language sample databases for
      both systems. In addition, a case study highlighting the interactive use of both
      analysis systems is provided.

PMID- 10343360
TI  - Technology applications in the assessment of children's language.
AB  - Technology can assist both standardized and nonstandardized language assessment.
      Standardized test records can be rapidly and accurately scored, and the potential
      exists for entirely computerized test administration. Sounds and images can be
      captured and then played or displayed on a computer, creating stimulus sets that
      elicit language for nonstandardized analysis. Clinician learning of linguistic
      principles and methods can be enhanced through software that offers systematic
      practice and corrective feedback. Once analytical skill is acquired, language
      assessment can be facilitated with software for evaluating a child's level of
      development and linguistic productivity in the subsystems of grammer, semantic
      relations, vocabulary, narrative, and prosody. The basic operations performed by
      language analysis software are tallying and searching of codes. However, in
      different programs those codes may result entirely from human user input or they
      may result from codes partly generated by intelligent software.

PMID- 10343361
TI  - Use of technology in phonological assessment: evaluation of early meaningful
      speech and prelinguistic vocalizations.
AB  - Technologies that assist in the assessment of phonological abilities in early
      meaningful speech and prelinguistic vocalizations are discussed. Computerized
      assessment of phonological abilities (CAP) software offers significant time
      savings for basic analyses and makes possible the completion of more detailed
      analyses. The programs discussed in this article allow flexibility in determining
      not only the most appropriate analyses for an individual client, but also the
      design of the optimal symbol system for representing the client's productions.
      Case studies are included to illustrate the clinical benefits of CAP technology.

PMID- 10343362
TI  - Technological applications in the assessment of acquired neurogenic communication
      and swallowing disorders in adults.
AB  - The role of technology is expanding rapidly in many aspects of the diagnostic
      process with patients who have neurogenic communication and swallowing disorders.
      In this article we discuss a broad selection of technological tools that enhance
      a wide range of diagnostic tasks, such as taking case histories, administering
      and scoring tests, performing acoustic, physiologic, cognitive, and linguistic
      analyses, making normative comparisons, profiling diagnostic results, and making
      diagnostic decisions. Clinicians are encouraged to scrutinize the relative value
      of all diagnostic tools to maintaining the quality of service. An appendix
      includes information for contacting vendors and manufacturers of the products
      discussed.

PMID- 10343363
TI  - Technology in the assessment of voice disorder.
AB  - The purpose of this article is to describe salient technologies available for
      assessing patients with disorders of voice. Measurements of jitter, shimmer,
      harmonic-to-noise ratio, fundamental frequency of the speaking voice, basal
      frequency, ceiling frequency, computation of pitch range, speaking intensity,
      intensity increase potential, vital capacity, laryngeal airflow during phonation,
      and laryngeal videoendoscopy-stroboscopy are covered. Some of the common
      instruments available to measure these voice components are described. Clinical
      case examples are provided to illustrate the importance of technology in the
      assessment of patients with voice disorder.

PMID- 10343364
TI  - Technical solutions for quantitative and qualitative assessments of speech
      fluency.
AB  - Current and emerging technical solutions for the differential diagnostic
      evaluation and assessment of speech fluency are reviewed and discussed. These
      systems were selected with just one intentional bias--the need for clinicians to
      carry out valid, reliable, and accurate measurements of speech fluency, its
      disruptions, and associated clinical features. Some seasoned technical solutions
      for the assessment and evaluation of stuttering have been known for many years,
      but have received little attention. Recently, a number of new options have
      appeared, and others are in the final stage of development. Empirical data about
      the performance or functionality of all of these technologies are lacking. As a
      result, clinicians who purchase them do not have access to adequate performance
      related data. This article should help clinicians make reasonable judgments about
      the effectiveness of emerging technologies specific to assessment of speech
      fluency.

PMID- 10343365
TI  - [Pyothorax in nine dogs].
AB  - Nine dogs with pyothorax were treated with systemic antibiotics, and drainage and
      lavage of the pleural space. All nine dogs recovered completely. Eight dogs were
      followed up for 6 months or longer and none showed signs of relapse. The results
      of this treatment are excellent compared with those for treatment with systemic
      antibiotics and drainage of the pleural space but without lavage. Apart from the
      addition of pleural lavage to the treatment protocol, this difference in efficacy
      may be due to the fact that migrating grass seed awns do not seem to play an
      important role in the pathogenesis of pyothorax in dogs in the Netherlands.

PMID- 10343366
TI  - [The prevention of pneumovagina and the effect of the Caslick operation on
      fertility: a retrospective study].
AB  - Mares with a large vulvar orifice have an increased risk of pneumovagina, which
      is associated with reduced fertility. Treatment is by means of the Caslick
      operation, by which size of the vulvar orifice is reduced. Factors that influence
      the occurrence of pneumovagina are the age and fertility status of the mare. In
      this study the risk factors for pneumovagina and the effect of the Caslick
      operation on fertility were investigated. In 1994, 1995, and 1996 a total of 967
      mares were sent for service at a stud. Of these mares, 116 underwent a Caslick
      operation. The operated mares were older than the non-operated mares. Mares
      younger than 5 years had a lower chance of pneumovagina than mares aged 5-12
      years, but mares aged 13 and older had an increased chance. Foals and barren
      mares were more likely than maiden mares to develop pneumovagina. Fertility was
      67% among the non-operated mares and 51% among the operated mares, even though,
      after the operation, the vulvar orifice of the operated mares was the same as
      that of the non-operated mares. This difference in fertility may be due to
      secondary endometritis that continues to exist after the operation. Further
      research is needed to determine whether mares with pneumovagina should also be
      treated for endometritis at the time of surgery.

PMID- 10343367
TI  - [Health advice report on antimicrobial growth promotion].

PMID- 10343368
TI  - [Equine protozoal myeloencephalitis (EPM) in the Netherlands?].

PMID- 10343369
TI  - [Practice situation plan of approach to the poultry meat sector].

PMID- 10343370
TI  - [Making the most of progesterone blood content during the prepartum period].

PMID- 10343371
TI  - Replacement of quarantine: the profession airs its concerns.

PMID- 10343372
TI  - Practice after 2000--what does the future hold?

PMID- 10343373
TI  - Veterinary nurse training: coming to terms with change.

PMID- 10343374
TI  - A study of the aetiology of pseudopregnancy in the bitch and the effect of
      cabergoline therapy.
AB  - Thirty-two permanently pseudopregnant bitches were treated with the anti
      prolactin drug cabergoline. They had all been ovariohysterectomised up to five
      months after their last season, in some cases over two years previously, when
      most were reported as showing no signs of the condition. The clinical signs were
      mainly behavioural, the majority being aggressive, and a small number were
      lactating. The efficiency of the cabergoline therapy was classified by the owners
      as 'excellent' or 'good' in 50 per cent of the cases, and fair in 36 per cent.
      The rate of success was markedly better than in similar cases treated with
      reproductive steroids. In all but one of the bitches, the plasma prolactin
      concentrations were basal.

PMID- 10343375
TI  - Acute phase proteins in cattle: discrimination between acute and chronic
      inflammation.
AB  - Acute phase proteins such as serum amyloid A, haptoglobin, and alpha 1-acid
      glycoprotein have been identified as markers of inflammation in cattle because
      they are produced by the liver in response to pro-inflammatory cytokines. This
      study was designed to assess whether they could be used to discriminate between
      acute and chronic inflammation. Their concentrations were measured in serum
      samples from 81 cattle in which inflammation was classified by thorough clinical
      examination, supported by postmortem findings, as being acute in severity in 31
      and chronic in 50. The classical haematological markers of inflammation were also
      determined in blood from the animals. Serum amyloid A had a maximum (100 per
      cent) clinical sensitivity in discriminating between the acute and chronic cases,
      and haptoglobin had the highest clinical specificity of 76 per cent; counts of
      neutrophils and band neutrophils had sensitivities of 71 per cent and 42 per cent
      and specificities of 30 per cent and 72 per cent, respectively. It was concluded
      that serum amyloid A and haptoglobin may be used to discriminate between acute
      and chronic inflammatory conditions.

PMID- 10343376
TI  - Economic benefits of prophylaxis with diclazuril against subclinical coccidiosis
      in lambs reared indoors.
AB  - One hundred and twenty weaned male lambs, naturally infected with Eimeria
      species, were used to assess the economic benefits of the prophylactic
      administration of diclazuril. They were randomly divided into four groups of 30
      lambs on the basis of their bodyweight and output of oocysts. The groups were
      either left untreated (group 1), treated orally with a simple dose of diclazuril
      at 1 mg/kg (group 2), with two doses two weeks apart (group 3), or with
      sulphadimethoxine at 50 mg/kg for five consecutive days (group 4). No clinical
      signs of coccidiosis were observed in any of the groups. The output of oocysts
      was significantly reduced on day 7 after treatment in group 2, on days 7, 14 and
      28 in group 3 and on days 7 and 14 in group 4. No significant differences were
      found between the treated and untreated groups for bodyweight, carcase weight and
      carcase classification. The mean fattening period was shorter for the treated
      lambs (52 and 55 days) than for the untreated controls (60 days). The average
      growth rate of the lambs treated twice with diclazuril and with sulphadimethoxine
      was improved and the feed conversion rates of the lambs treated once or twice
      with diclazuril were 7 per cent and 16 per cent better than that of the untreated
      lambs.

PMID- 10343378
TI  - Prevalence of foot and limb lesions in 528 weaned pigs from 15 units in south
      west England.

PMID- 10343377
TI  - Porcine reproductive and respiratory syndrome virus infection in neonatal pigs
      characterised by marked neurovirulence.
AB  - Neonatal pigs from three herds of pigs were somnolent and inappetent and had
      microscopic lesions characterised by severe meningoencephalitis, necrotic
      interstitial pneumonia and gastric muscular inflammation. Porcine reproductive
      and respiratory syndrome virus (PRRSV) infection was diagnosed and confirmed by
      virus isolation, fluorescent antibody examination of frozen lung sections,
      serology, immunohistochemistry and in situ hybridisation. Each herd had a history
      of PRRSV infection and was using or had used a modified-live vaccine. The
      isolates from the affected pigs were genetically distinct from the modified-live
      vaccine strain of the virus when compared by restriction enzyme analysis and
      nucleotide sequencing of PRRSV open reading frames 5 and 6. The virus was
      identified in macrophages or microglia of brain lesions by immunohistochemical
      staining of brain sections with an anti-PRRSV monoclonal antibody and an anti
      macrophage antibody. The replication of the virus in the brain was verified by in
      situ hybridisation. The meningoencephalitis induced by the virus in pigs from
      each of the herds was unusually severe and the brain lesions were atypical when
      compared with other descriptions of encephalitis induced by the virus, which
      should therefore be considered as a possible diagnosis for neonatal pigs with
      severe meningoencephalitis. In addition, field isolates of the virus which are
      capable of causing disease can emerge and coexist with modified-live vaccine
      virus in some pig herds.

PMID- 10343379
TI  - Isolation of Vibrio cholerae from diseased farm animals and surface water in The
      Netherlands.

PMID- 10343380
TI  - Isolation of bluetongue virus serotype 2 from native sheep in India.

PMID- 10343381
TI  - Welfare of animals in quarantine.

PMID- 10343382
TI  - Isolation of a bovine Neospora from a newborn calf in Italy.

PMID- 10343383
TI  - Changes in water structure induced by a hydrophobic solute probed by simulation
      of the water hydrogen bond angle and radial distribution functions.
AB  - In order to better characterize changes in water structure induced by a
      hydrophobic solute the oxygen-oxygen and hydrogen-hydrogen radial distribution
      functions (goo(r), ghh(r)) and the hydrogen bond angle distribution function
      p(theta) for water molecules in the first hydration shell of the tetramethyl
      ammonium (TMA) cation were computed using Monte Carlo simulations. goo(r) and
      ghh(r) were corrected for the effect of solute volume exclusion on the local
      solvent density so that intrinsic structural changes independent of local solvent
      density variations could be detected. Comparison of ghh(r) of TMA's first
      hydration shell water with ghh(r) for bulk water shows subtle but clear evidence
      of structure formation induced by the ion. These changes in ghh(r) are very
      similar to those seen experimentally for larger tetra-alkyl ammonium ions in
      previous neutron diffraction experiments. Larger changes in p(theta) in the first
      hydration shell of TMA were seen. Comparison of changes in p(theta) with changes
      in goo(r) and ghh(r) show that the angle distribution function provides the most
      sensitive way to analyze water structure changes associated with hydrophobic
      solvation.

PMID- 10343384
TI  - Effect of artificial periodicity in simulations of biomolecules under Ewald
      boundary conditions: a continuum electrostatics study.
AB  - Ewald and related methods are nowadays routinely used in explicit-solvent
      simulations of biomolecules, although they impose an artificial periodicity in
      systems which are inherently non-periodic. The consequences of this approximation
      should be assessed, since they may crucially affect the reliability of computer
      simulations under Ewald boundary conditions. In the present study we use a method
      based on continuum electrostatics to investigate the nature and magnitude of
      possible periodicity-induced artifacts on the potentials of mean force for
      conformational equilibria in biomolecules. Three model systems and pathways are
      considered: polyalanine oligopeptides (unfolding), a DNA tetranucleotide
      (separation of the strands), and the protein Sac7d (conformations from a
      molecular dynamics simulation). Artificial periodicity may significantly affect
      these conformational equilibria, in each case stabilizing the most compact
      conformation of the biomolecule. Three factors enhance periodicity-induced
      artifacts: (i) a solvent of low dielectric permittivity; (ii) a solute size which
      is non-negligible compared to the size of the unit cell; and (iii) a non-neutral
      solute. Neither the neutrality of the solute nor the absence of charge pairs at
      distances exceeding half the edge of the unit cell do guarantee the absence of
      artifacts.

PMID- 10343385
TI  - Comparison of the potentials of mean force for alanine tetrapeptide between
      integral equation theory and simulation.
AB  - The dielectrically consistent reference interaction site model (DRISM) integral
      equation theory is applied to determine the potential of mean force (PMF) for an
      alanine tetramer. A stochastic dynamics simulation of the alanine tetramer using
      this PMF is then compared with an explicit water molecular dynamics simulation.
      In addition, comparison is also done with simulations using other solvent models
      like the extended reference interaction site model (XRISM) theory, constant
      dielectric and linear distance-dependent dielectric models. The results show that
      the DRISM method offers a fairly accurate and computationally inexpensive
      alternative to explicit water simulations for studies on small peptides.

PMID- 10343386
TI  - Towards molecular dynamics simulation of large proteins with a hydration shell at
      constant pressure.
AB  - Molecular dynamics simulation of a large protein in explicit water with periodic
      boundary conditions is extremely demanding in terms of computation time.
      Consequently, we have sought approximations of the solvent environment that model
      its important features. Here, we describe our SAPHYR (Shell Approximation for
      Protein HYdRation) model in which the protein is surrounded by a shell of water
      molecules maintained at constant pressure. In addition to the usual pairwise
      interatomic interactions, these water molecules are subjected to forces
      approximating van der Waals and dipole-dipole interactions with the implicit
      surrounding bulk solvent. The SAPHYR model is tested for a system of one argon
      atom in water and for the protein ubiquitin, and then applied to cytochrome
      P450cam, a protein with over 400 residues. The results demonstrate that
      structural and dynamic properties of the simulated systems are improved by use of
      the SAPHYR model, and that this model provides a significant computational saving
      over simulations with periodic boundary conditions.

PMID- 10343387
TI  - Nucleic acid base-pairing and N-methylacetamide self-association in chloroform:
      affinity and conformation.
AB  - A recently developed computational method, 'mining minima', is used to examine
      the hydrogen-bonding interactions of nucleic acid base-pairs and of the N
      methylacetamide homodimer in chloroform. The mining minima algorithm aggressively
      samples molecular conformations, identifies the most important local minima, and
      computes their contributions to the overall free energy of the system. Here, the
      CHARMM 98 parameter set is used for the potential energy and the generalized
      Born/surface area solvent model is used to account for the influence of the
      solvent. Good agreement with experiment is obtained for the non-covalent binding
      affinities of a series of complexes. The computational approach used here is
      applicable to a range of molecular systems.

PMID- 10343388
TI  - ES/IS: estimation of conformational free energy by combining dynamics simulations
      with explicit solvent with an implicit solvent continuum model.
AB  - This paper reviews a recently developed method for calculating the total
      conformational free energy of a solute macromolecule in water solvent. The method
      consists of a relatively short simulation by molecular dynamics with explicit
      solvent molecules (ES) to produce a set of microstates of the macroscopic
      conformation. Conformational internal solute energy and entropy are obtained from
      the simulation, the latter in the quasi-harmonic approximation by analysis of the
      covariance matrix. The implicit solvent (IS) surface energy-dielectric continuum
      model is used to calculate the average solvation free energy as the sum of the
      free energies of creating the solute-size hydrophobic cavity, of the van der
      Waals solute-solvent interactions and of the polarization of water solvent by the
      solute's charges. We have earlier applied this method to calculate the
      conformational free energy of native and intentionally misfolded globular
      conformations of proteins (the EMBL set of deliberately misfolded proteins), and
      have obtained good discrimination in favor of the native conformations in all
      instances. These results are summarized and further analyzed to show that, on
      average, three major component terms of the free energy all contribute in favor
      of discrimination. We discuss possible improvements of the ES/IS method. It is
      shown how the force field can be made self-consistent by adapting the parameters
      for calculation of surface and polarization free energies closely to the
      molecular mechanics force field used in the dynamics simulation, using
      established simulation methods to compute free energies for cavity formation and
      a charging process with the molecular mechanics force field to provide a set of
      (quasi-experimental) reference data that can be used to refine the parameters of
      the continuum models. The molecular surface area together with a microscopic
      surface free energy near 70 cal/(mol A2) is found to be a consistent descriptor
      of the cavity free energy. Preliminary results indicate that a linear-response
      approximation for the polarization of water solvent reaction near typical polar
      and charged protein groups is accurate to within approximately 90%.

PMID- 10343389
TI  - Conformational change in bacterio-opsin on binding to retinal.
AB  - The detailed mechanism of retinal binding to bacterio-opsin is important to
      understanding retinal pigment formation as well as to the process of membrane
      protein folding. We have measured the temperature dependence of bacteriorhodopsin
      formation from bacterio-opsin and all-trans retinal. An Arrhenius plot of the
      apparent second-order rate constants gives an activation energy of 11.6 +/- 0.7
      kcal/mol and an activation entropy of -4 +/- 2 cal/mol deg. Comparison of the
      activation entropy to model compound reactions suggests that chromophore
      formation in bacteriorhodopsin involves a substantial protein conformational
      change. Cleavage of the polypeptide chain between residues 71 and 72 has little
      effect on the activation energy or entropy, indicating that the connecting loop
      between helices B and C is not involved in this conformational change.

PMID- 10343390
TI  - Structural and dynamical properties of two DNA oligomers with the same base
      composition and different sequence.
AB  - We compared the structural and dynamical properties of two DNA fragments, 27 bp
      long, having the same base composition but a different sequence. This work aims
      to understand how the base sequence on a purine rich strand in a double helix,
      which is important for many biological functions, is related to structural
      features and to measurable physical quantities. Structural characterization of
      the two samples was performed both by conventional spectroscopic methods
      (circular dichroism and UV denaturation experiments) and by means of a gamma-ray
      footprinting technique which gives information on fine conformational
      differences. Dynamical features of the samples were studied by fluorescence
      polarization anisotropy (FPA) measurements which allow the evaluation of some
      hydrodynamic parameters, such as the hydrodynamic radius and the elastic torsion
      constant of DNA. Using a gamma-ray footprinting technique, we observed that the
      interruption of the long homopurine-homopyrimidine run in the control sample, due
      to the 'scrambling' operation, alters the DNA three-dimensional structure, also
      at nucleotide level. Besides, an increase in thermal stability and in the
      torsional rigidity of the 'scrambled' sample was observed. A possible association
      between base-stacking interaction and torsional rigidity was inferred from the
      comparison of the two samples.

PMID- 10343391
TI  - Role of activin and other peptide growth factors in body patterning in the early
      amphibian embryo.
AB  - The amphibian body plan is established as the result of a series of inductive
      interactions. During early cleavage stages cells in the vegetal hemisphere induce
      overlying animal hemisphere cells to form mesoderm. The interaction represents
      the first major body-patterning event and is mediated by peptide growth factors.
      Various peptide growth factors have been implicated in mesoderm development,
      including most notably members of the transforming growth factor-beta
      superfamily. Identification of the so-called "natural" inducer from among the
      several candidate peptide growth factors is being achieved by employing several
      experimental strategies, including the use of a tissue explant assay for testing
      potential inducers, cloning of marker genes as indices of early induction events,
      and microinjection of altered peptide growth factor receptors to disrupt normal
      embryonic inductions. Activin emerges as the most likely choice for assignment of
      the role of endogenous mesoderm inducer, because it currently best fulfills the
      rigorous set of criteria expected of such an important embryonic signaling
      molecule. Activin, however, may not act alone in mesoderm induction. Other
      peptide growth factors such as fibroblast growth factor might be involved,
      especially in the regional patterning of the mesoderm. In addition, several genes
      (e.g., Wnt and noggin), which are expressed after the mesoderm is initially
      induced, probably assist in further definition of the mesoderm pattern. Following
      mesoderm induction, the primary embryonic organizer tissue (first described in
      1924 by Spemann) develops and contributes further to body patterning by its
      action as a neural inducer. Peptide growth factors such as activin may also be
      involved in the inductive event, either directly (by facilitating gene
      expression) or indirectly (by serving to constrain pathways).

PMID- 10343392
TI  - Calcium regulation of the actin-myosin interaction of Physarum polycephalum.
AB  - Plasmodia of Physarum polycephalum show vigorous cytoplasmic streaming, the
      motive force of which is supported by the actin-myosin interaction. Calcium is
      not required for the interaction but inhibits it. This calcium inhibition, a
      regulatory mode first discovered in Physarum, is the overwhelming mode of
      regulation of cytoplasmic streaming of plant cells and lower eukaryotes, and it
      is diametrically opposite to calcium activation of the interaction found in
      muscle and nonmuscle cells of the animal kingdom. Myosin, myosin II in myosin
      superfamily, is the most important protein for Ca2+ action. Its essential light
      chain, called calcium-binding light chain, is the sole protein that binds Ca2+.
      Although phosphorylation and dephosphorylation of myosin modify its properties,
      regulation of physiological significance is shown to be Ca-binding to myosin. The
      actin-binding protein of Physarum amplifies calcium inhibition when Ca2+ binds to
      calmodulin and other calcium-binding proteins. This review also includes
      characterization of this and other calcium-binding proteins of Physarum.

PMID- 10343393
TI  - Characteristics of skeletal muscle in mdx mutant mice.
AB  - We review the extensive research conducted on the mdx mouse since 1987, when
      demonstration of the absence of dystrophin in mdx muscle led to X-chromosome
      linked muscular dystrophy (mdx) being considered as a homolog of Duchenne
      muscular dystrophy. Certain results are contradictory. We consider most aspects
      of mdx skeletal muscle: (i) the distribution and roles of dystrophin, utrophin,
      and associated proteins; (ii) morphological characteristics of the skeletal
      muscle and hypotheses put forward to explain the regeneration characteristic of
      the mdx mouse; (iii) special features of the diaphragm; (iv) changes in basic
      fibroblast growth factor, ion flux, innervation, cytoskeleton, adhesive proteins,
      mastocytes, and metabolism; and (v) different lines of therapeutic research.

PMID- 10343394
TI  - Synaptic-like microvesicles in mammalian pinealocytes.
AB  - The recent deciphering of the protein composition of the synaptic vesicle
      membrane has led to the unexpected identification of a compartment of electron
      lucent microvesicles in neuroendocrine cells which resemble neuronal synaptic
      vesicles in terms of molecular structure and function. These vesicles are
      generally referred to as synaptic-like microvesicles (SLMVs) and have been most
      intensively studied in pancreatic beta-cells, chromaffin cells of the adrenal
      medulla, and pinealocytes of the pineal gland. This chapter focuses on the
      present knowledge of SLMVs as now well-established constituents of mammalian
      pinealocytes. I review the results of morphological, immunocytochemical, and
      biochemical studies that were important for the characterization of this novel
      population of secretory vesicles in the pineal organ. The emerging concept that
      SLMVs serve as a device for intercellular communication within the pineal gland
      is outlined, and unanswered questions such as those pertaining to the
      physiological function and regulation of pineal SLMVs are discussed.

PMID- 10343395
TI  - Invertebrate integrins: structure, function, and evolution.
AB  - Integrins are a family of molecules that have fundamental roles in cell-cell and
      cell-matrix adhesion. It is thought that all metazoan cells have one or more
      integrin receptors on their surface and that these molecules may have been key in
      the evolution of multicellularity. Knowledge of the structure, function, and
      distribution of integrin subunits in invertebrate phyla remains incomplete.
      However, through the recent use of polymerase chain reaction, integrin subunits
      have been identified in at least five phyla; sponges, cnidarians, nemadodes,
      arthropods, and echinoderms. The structure of all of the invertebrate subunits is
      remarkably similar to that of vertebrate integrin subunits. Some experimental
      data and patterns of expression indicate that invertebrate integrins have a range
      of functions similar to those of vertebrate integrins. The ligands are not well
      characterized but at least two laminin-binding receptors have been identified and
      two other receptors appear to bind using Arg-Gly-Asp motifs. Invertebrate
      integrins are present during development, in adults, and on a range of cell types
      including cells with immunological functions such as hemocytes and coelomocytes.
      Analysis of the invertebrate beta subunits indicates that the invertebrate
      integrins have diverged independently within each phylum. The two major clades of
      vertebrate integrins (beta 1, beta 2, beta 7 and beta 3, beta 5, beta 6, beta 8)
      appear to have radiated since the divergence of the deuterostomes and there are
      no distinct orthologous subunits in any of the invertebrate phyla. Since
      fundamental functions of integrins appear to be conserved, studies of
      invertebrate integrins have the potential of contributing to our understanding of
      this important group of receptors.

PMID- 10343396
TI  - Separation of enantiomers on a chiral stationary phase based on ovoglycoprotein.
      V. Influence of immobilization method on chiral resolution.
AB  - Ovoglycoprotein from chicken egg whites (OGCHI) was bound to aminopropyl-silica
      gels via an amino or carboxyl group(s) of OGCHI. In the former case, OGCHI was
      bound to N,N'-disuccinimidyl carbonate-activated aminopropyl-silica gels, while
      in the latter case OGCHI activated by a water-soluble carbodiimide and N
      hydroxysulfosuccinimide was bound to aminopropyl-silica gels. The obtained OGCHI
      materials were compared with regard to the bound amounts, retentivity and
      enantioselectivity. The OGCHI materials prepared via a carboxyl group(s) of OGCHI
      are suitable for chiral resolution of acidic solutes, and those via an amino
      group(s) of OGCHI are suitable for chiral resolution of basic solutes. It is
      suggested that the electrostatic interaction between an amino or carboxyl group
      of OGCHI and a charged solute should play an important role in chiral recognition
      of the solute.

PMID- 10343397
TI  - Fast C18 solid-phase desalting/delipidation of the human serum apolipoproteins
      for matrix-assisted laser desorption ionization and electrospray ionization mass
      spectrometric analysis.
AB  - A new method for the delipidation of human serum lipoproteins involving the use
      of a reversed-phase C18 solid-phase extraction (SPE) cartridge is introduced for
      use with matrix-assisted laser desorption ionization and electrospray ionization
      mass spectrometry. This method is compared with two other methods of lipoprotein
      delipidation. The SPE method of delipidation produces a higher and more
      reproducible protein yield than the conventional liquid-liquid methanol-diethyl
      ether delipidation technique. Furthermore, the SPE method implements a fast,
      sequential, desalting and delipidation of the lipoproteins for subsequent mass
      spectrometric analysis providing high quality spectra.

PMID- 10343398
TI  - Immobilised metal ion affinity chromatography purification of alcohol
      dehydrogenase from baker's yeast using an expanded bed adsorption system.
AB  - Alcohol dehydrogenase (ADH) from solutions of homogenised packed bakers' yeast
      has been successfully purified using immobilised metal-ion affinity
      chromatography in an expanded bed. Method scouting carried out using pure ADH
      solutions loaded onto 5-ml HiTrap columns charged with Zn2+, Ni2+ and Cu2+ and
      eluted using 0-50 mM EDTA gradient found that charging with Zn2+ gave the highest
      recovery and the lowest EDTA concentration required for elution. These results
      were used to develop a protocol for the expanded bed system and further tested
      using clarified yeast homogenate loaded onto XK16/20 packed beds (approximately
      30 ml) packed with Chelating Sepharose FastFlow matrix in order to determine the
      optimum elution conditions using EDTA. The ADH was found to elute at 5 mM EDTA
      and the dynamic and total binding capacities of Streamline chelating for ADH were
      found to be 235 U/ml and 1075 U/ml matrix, respectively. Expanded bed work based
      on a step EDTA elution protocol demonstrated that ADH could be successfully
      eluted from unclarified homogenised bakers' yeast diluted to 10 mg/ml total
      protein content with a recovery of 80-100% that was maintained over five
      consecutive runs with a vigorous clean-in-place procedure between each run.

PMID- 10343399
TI  - Boronate affinity adsorption of RNA: possible role of conformational changes.
AB  - Batch equilibrium adsorption isotherm determination is used to characterize the
      adsorption of mixed yeast RNA on agarose-immobilized m-aminophenylboronic acid.
      It is shown that the affinity-enhancing influence of divalent cations depends
      strongly on the precise nature of the cation used, with barium being far more
      effective than the conventionally-used magnesium. This adsorption-promoting
      influence of barium is suggested to arise primarily from ionic influences on the
      structure and rigidity of the RNA molecule, as the adsorption of ribose-based
      small molecules is not similarly affected. The substitution of barium for the
      standard magnesium counterion does not greatly promote the adsorption of DNA,
      implying that the effect is specific to RNA and may be useful in boronate-based
      RNA separations. RNA adsorption isotherms exhibit sharp transitions as functions
      of temperature, and these transitions occur at different temperatures with Mg2+
      and with Ba2+. Adsorption affinity and capacity were found to increase markedly
      at lower temperatures, suggestive of an enthalpically favored interaction
      process. The stoichiometric displacement parameter, Z, in Ba2+ buffer is three
      times the value in Mg2+ buffer, and is close to unity.

PMID- 10343400
TI  - Development of a simple sample preparation technique for gas chromatographic-mass
      spectrometric determination of nicotine in edible nightshades (Solanaceae).
AB  - The purpose of this study was to develop a rapid analytical method for the
      reliable determination of low concentrations of nicotine in foods for large
      numbers of samples. Food material was extracted using a simple liquid-liquid
      extraction method. For processed foods, further clean-up steps had to be employed
      to eliminate interfering compounds. The determination of nicotine was performed
      by gas chromatography-mass spectrometry. Quantitative analysis was accomplished
      using deuterium labeled nicotine as an internal standard. Recoveries of over 95%
      were obtained for a single step extraction, as well as for a multiple-stage
      extraction procedure, respectively. The method has been applied to the
      determination of nicotine in edible nightshades (i.e. tomatoes, potatoes and
      aubergines) and their processed products.

PMID- 10343401
TI  - Use of a partial-filling technique in affinity capillary electrophoresis for
      determining binding constants of ligands to receptors.
AB  - This work evaluates the concept of a partial-filling technique in affinity
      capillary electrophoresis (ACE) using two model systems: vancomycin from
      Streptomyces orientalis and carbonic anhydrase B (CAB, EC 4.2.1.1). In this
      technique the capillary is first partially-filled with ligand followed by a
      sample of receptor and non-interacting standard and electrophoresed. Analysis of
      the change in the mobility ratio, M, of the receptor, relative to the non
      interacting standard, as a function of the concentration of the ligand, yields a
      value for the binding constant. These values agree well with those estimated
      using other binding and ACE techniques. Data demonstrating the quantitative
      potential of this method is presented.

PMID- 10343402
TI  - Packed capillary liquid chromatography-electrospray mass spectrometry analysis of
      organophosphorus chemical warfare agents.
AB  - Packed capillary column liquid chromatography (LC)-electrospray mass spectrometry
      (ESI-MS) was used for the first time to detect and identify four common
      organophosphorus chemical warfare agents in aqueous samples. Aqueous samples
      containing the organophosphorus chemical warfare agents in the 0.01 to 0.1 mg/ml
      range were analyzed directly by packed capillary LC-ESI-MS with the chemical
      warfare agents and several minor related impurities being well resolved under
      acetonitrile-water gradient elution conditions. The ESI-MS data for isopropyl
      methylphosphonofluoridate (sarin or GB), O-ethyl N,N
      dimethylphosphoramidocyanidate (tabun or GA), cyclohexyl
      methylphosphonofluoridate (GF) and pinacolyl methylphosphonofluoridate (soman or
      GD) were acquired with a sampling cone voltage setting that promoted
      collisionally activated dissociation, and resulted in the acquisition of
      informative mass spectra containing both molecular and product ion information.
      The developed method appears to be an attractive alternative to GC-MS for the
      analysis of aqueous samples containing organophosphorus chemical warfare agents
      and their hydrolysis products, since they may be analyzed directly without the
      need for additional sample handling.

PMID- 10343403
TI  - Photosystem II activity and turnover of the D1 protein are impaired in the psbA
      Y112L mutant of Synechocystis PCC6803 sp.
AB  - Site-directed psbA mutants at the tyrosine Y112 position have been generated in
      Synechocystis PCC6803 cells. The mutation Y112F does not affect photosystem II
      (PSII) activity as compared with control 4 delta 1K cells. However, the Y112L
      mutant exhibits a photosynthetically impaired phenotype. PSII activity is not
      detectable in this mutant when grown at 30 mumol photons m-2 s-1, while low
      levels of the D1 and D2 proteins and oxygen evolution activity are present in the
      mutant cells grown at a low light intensity (0.5-1 mumol m-2 s-1). The
      recombination of the QB-/S2,3 states of PSII in the Y112L mutant cells as
      detected by thermoluminescence (TL) is altered. The TL signal emission maximum of
      these cells due to charge recombination of the S2,3/QB- occurs at 20 degrees C as
      compared to 35-40 degrees C for the wild-type cells, indicating a possible change
      in the S2,3/Yz equilibrium. The Y112L mutant cells are rapidly photoinactivated
      and impaired in the recovery of the PSII activity. These results suggest that
      replacement of the aromatic residue at position Y112 by a hydrophobic amino acid
      may alter the function of the donor-side activity and affects the degradation and
      replacement of the PSII core proteins.

PMID- 10343404
TI  - Effects of ultraviolet-B light on photosystem II phosphoproteins in barley wild
      type and its chlorophyll b-less mutant chlorina f2.
AB  - The effects of ultraviolet-B light on the level and steady-state phosphorylation
      of photosystem II proteins have been studied in barley wild type and its
      chlorophyll b-less mutant chlorina f2. In the wild type, ultraviolet-B radiation
      is found to promote dephosphorylation of all thylakoid phosphoproteins. In
      addition, for reaction-centre proteins D1 and D2, dephosphorylation is paralleled
      by degradation. Photosystem II core proteins in the mutant are not found to be
      significantly phosphorylated in any experimental conditions, and loss of D1 and
      D2 reaction-centre proteins is slightly faster than in the wild type. These
      results are consistent with the possibility that phosphorylation of reaction
      centre proteins affects their stability, possibly by slowing down the rate of
      degradation, as in the case of visible light.

PMID- 10343405
TI  - Effects of UV-B radiation on growth, photosynthesis, UV-B-absorbing compounds and
      NADP-malic enzyme in bean (Phaseolus vulgaris L.) grown under different nitrogen
      conditions.
AB  - The effects of UV-B radiation on growth, photosynthesis, UV-B-absorbing compounds
      and NADP-malic enzyme have been examined in different cultivars of Phaseolous
      vulgaris L. grown under 1 and 12 mM nitrogen. Low nitrogen nutrition reduces
      chlorophyll and soluble protein contents in the leaves and thus the
      photosynthesis rate and dry-matter accumulation. Chlorophyll, soluble protein and
      Rubisco contents and photosynthesis rate are not significantly altered by ambient
      levels of UV-B radiation (17 microW m-2, 290-320 nm, 4 h/day for one week).
      Comparative studies show that under high nitrogen, UV-B radiation slightly
      enhances leaf expansion and dry-matter accumulation in cultivar Pinto, but
      inhibits these parameters in Vilmorin. These results suggest that the UV-B effect
      on growth is mediated through leaf expansion, which is particularly sensitive to
      UV-B, and that Pinto is more tolerant than Vilmorin. The effect of UV-B radiation
      on UV-B-absorbing compounds and on NADP-malic enzyme (NADP-ME) activity is also
      examined. Both UV-B radiation and low-nitrogen nutrition enhance the content of
      UV-B-absorbing compounds, and among the three cultivars used, Pinto exhibits the
      highest increases and Arroz the lowest. The same trend is observed for the
      specific activity and content of NADP-ME. On a leaf-area basis, the amount of UV
      B-absorbing compounds is highly correlated with the enzyme activity (r2 = 0.83),
      suggesting that NADP-ME plays a key role in biosynthesis of these compounds.
      Furthermore, the higher sensitivity of Vilmorin than Pinto to UV-B radiation
      appears to be related to the activity of NADP-ME and the capacity of the plants
      to accumulate UV-B-absorbing compounds.

PMID- 10343406
TI  - Microsatellite evolution: polarity of substitutions within repeats and neutrality
      of flanking sequences.
AB  - Though extensively used in a variety of disciplines, the evolutionary pattern of
      microsatellite sequences is still unclear. We addressed several questions
      relating to microsatellite evolution by analysing historically accumulated
      mutation events in a large set of artiodactyl (CA)n repeats, through sequence
      analysis of orthologous bovine and ovine loci. The substitution rate in
      microsatellite flanking sequences was not different from that in intron
      sequences, suggesting that if intron sequences in general are selectively
      neutral, sequences close to microsatellites are similarly so. This observation
      thus does not support the idea that successful heterologous amplification of
      microsatellites across distantly related taxa would be due to flanking sequences
      generally being under some form of selection. Interestingly, the substitution
      rate at the first nucleotide positions flanking repeats was significantly higher
      than in sequences further away. Moreover, the substitution rate in repeat units
      in the very end of microsatellites was significantly higher than that in the
      middle of repeat regions. Together these observations suggest a relative
      instability close to the boundary between repetitive and unique sequences. We
      present three models that potentially could explain such a feature, all involving
      inefficiency of mismatch repair systems.

PMID- 10343407
TI  - The screw-helical voltage gating of ion channels.
AB  - In the voltage-gated ion channels of every animal, whether they are selective for
      K+, Na+ or Ca2+, the voltage sensors are the S4 transmembrane segments carrying
      four to eight positive charges always separated by two uncharged residues. It is
      proposed that they move across the membrane in a screw-helical fashion in a
      series of three or more steps that each transfer a single electronic charge. The
      unit steps are stabilized by ion pairing between the mobile positive charges and
      fixed negative charges, of which there are invariably two located near the inner
      ends of segments S2 and S3 and a third near the outer end of either S2 or S3.
      Opening of the channel involves three such steps in each domain.

PMID- 10343408
TI  - Changes in posture alter the attentional demands of voluntary movement.
AB  - Two simple experiments reveal that the ease with which an action is performed by
      the neuromuscular-skeletal system determines the attentional resources devoted to
      the movement. Participants were required to perform a primary task, consisting of
      rhythmic flexion and extension movements of the index finger, while being paced
      by an auditory metronome, in one of two modes of coordination: flex on the beat
      or extend on the beat. Using a classical dual-task methodology, we demonstrated
      that the time taken to react to an unpredictable visual probe stimulus (the
      secondary task) by means of a pedal response was greater when the extension phase
      of the finger movement sequence was made on the beat of the metronome than when
      the flexion phase was coordinated with the beat. In a second experiment, the
      posture of the wrist was manipulated in order to alter the operating lengths of
      muscles that flex and extend the index finger. The attentional demands of
      maintaining the extend-on-the-beat pattern of coordination were altered in a
      systematic fashion by changes in wrist posture, even though the effector used to
      respond to the visual probe stimulus was unaffected.

PMID- 10343409
TI  - The effects of local spatial structure on epidemiological invasions.
AB  - Predicting the likely success of invasions is vitally important in ecology and
      especially epidemiology. Whether an organism can successfully invade and persist
      in the short-term is highly dependent on the spatial correlations that develop in
      the early stages of invasion. By modelling the correlations between individuals,
      we are able to understand the role of spatial heterogeneity in invasion dynamics
      without the need for large-scale computer simulations. Here, a natural
      methodology is developed for modelling the behaviour of individuals in a fixed
      network. This formulation is applied to the spread of a disease through a
      structured network to determine invasion thresholds and some statistical
      properties of a single epidemic.

PMID- 10343410
TI  - An improved method for the measurement of the angiotensin-converting enzyme
      inhibitor lisinopril in human plasma by stable isotope dilution gas
      chromatography/negative ion chemical ionization mass spectrometry.
AB  - An improved method for the quantitative measurement of the angiotensin-converting
      enzyme inhibitor lisinopril in human plasma is presented. The assay is based on
      gas chromatography/negative ion chemical ionization mass spectrometry. The method
      involves solid phase extraction on C18 sorbent and derivatization to the
      pentafluorobenzyl diester trifluoroacetamide derivatives.

PMID- 10343411
TI  - Characterization of surface layer proteins from Clostridium difficile by liquid
      chromatography/electrospray ionization mass spectrometry.
AB  - Surface layers (S-layers) are regularly ordered protein subunits found as the
      outermost cell envelope component of many bacteria. Most S-layers are composed of
      a single protein or glycoprotein species with a molecular weight varying between
      40 and 200 kDa. Clostridium difficile is the most common cause of antibiotic
      associated diarrhea (AAD) and pseudomembranous colitis (PMC) in humans. Detection
      of the S-layer in some C. difficile strains, and preliminary characterization of
      two glycoproteins, P36 and P47, involved in the composition of the S-layer of one
      of these strains (C. difficile C253), led us to investigate the most appropriate
      conditions for purification and chemical characterization of these proteins. This
      work describes the results obtained when liquid chromatography (LC) coupled to
      mass spectrometry (MS) using electrospray ionization was applied to the analysis
      of C. difficile S-layer proteins (SLPs). In this way the molecular weights of the
      two SLP components, P36 and P47, were detected to be 34,258 +/- 2 and 39,545 +/-
      3 Da, respectively. These data deviate from sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis (SDS-PAGE) results by 1.85 and 7.5 kDa. To confirm the LC-MS
      results, an alternative molecular weight analysis was performed: the two S-layer
      proteins were isolated by semipreparative high performance liquid chromatography
      (HPLC), concentrated, and analyzed by matrix-assisted laser desorption/ionization
      time-of-flight (MALDI-TOF). The two SLP subunits were digested with protease V8,
      and the peptide maps were determined by LC-MS using a C18 column. Finally,
      preliminary results about peptide glycosylation were obtained.

PMID- 10343412
TI  - Effect of 1-phenyl-3-methyl-5-pyrazolone labeling on the fragmentation behavior
      of asialo and sialylated N-linked glycans under electrospray ionization
      conditions.
AB  - The advantages of labeling free N-linked oligosaccharides with 1-phenyl-3-methyl
      5-pyrazolone (PMP), for high performance liquid chromatography (HPLC) and
      electrospray ionization mass spectrometry (ESI-MS) are discussed. The study
      focuses on some asialo and sialylated sugars, and compares the HPLC and ESI-MS
      behaviors of the PMP-labeled substances vs. the native compounds. It is pointed
      out that native free N-linked carbohydrates have very low affinities for the C18
      reversed phases commonly used in HPLC. Native asialo oligosaccharides yield good
      ESI-MS sensitivity, although they are very susceptible to in-source collision
      induced dissociation (CID), and the fragments are produced from any of the
      branches of the molecules, i.e. do not give specific structural information.
      Native N-linked standards bearing one sialic acid residue yield a 10-fold loss of
      ESI-MS sensitivity vs. asialo compounds, and native sugars with two sialic acid
      moieties were not detectable. The PMP labeling of asialo and sialylated sugars
      yielded higher affinities for HPLC C18 columns and, even at the early stages of
      method development, it was possible to separate three PMP-labeled standards to a
      useful extent. In ESI-MS, PMP-asialo sugars did not yield a significant increase
      in sensitivity vs. the native species; however, fragmentation produced by in
      source CID was more directed as all predominant fragment ions contained the bis
      PMP label. This feature is particularly useful when structural determination of
      an unknown sugar is required. PMP-sialylated sugars gave rise to very clean and
      informative ESI mass spectra. The monosialo sugar yielded a 100-fold sensitivity
      improvement vs. its native analog and, in the case of the disialylated compound,
      a 100% improvement was obtained in the positive mode. Most fragment ions were
      informative and contained the reducing end on the molecules, thus facilitating
      spectral interpretation. The combination of PMP derivatization with on-line
      HPLC/ESI-MS is a promising method for the analysis of asialo and sialylated
      carbohydrate mixtures.

PMID- 10343413
TI  - A chromatographic and mass spectrometric strategy for the analysis of
      oligosaccharides: determination of the glycan structures in porcine
      thyroglobulin.
AB  - Oligosaccharides released from porcine thyroglobulin were first derivatised with
      2-aminoacridone (2-AMAC) and analysed by capillary electrophoresis to determine
      the complexity of this glycan pool. The same glycan mixture was then subjected to
      either a sialidase digest or a sialidase and fucosidase digest prior to
      derivatisation with 2-AMAC and analysis by normal phase high pressure liquid
      chromatography (HPLC). Comparison of the three chromatographic profiles with
      known standards allowed an initial identification of the glycan structures. The 2
      AMAC derivatised glycans were then collected from HPLC for matrix-assisted laser
      desorption/ionisation time-of-flight (MALDI-TOF) analysis and the molecular
      weights of predicted structures were confirmed. This study demonstrates that a
      two enzyme array and subsequent MALDI-TOF analysis can be used successfully to
      assign the major glycans present in a complex mixture.

PMID- 10343414
TI  - Selected ion flow tube mass spectrometry of urine headspace.
AB  - We describe the use of our selected ion flow tube mass spectrometric technique
      (SIFT-MS) for the analysis of the headspace above urine. Ammonia, nitric oxide,
      acetone, ethanol and methanol are identified as the dominant species. As
      expected, the ammonia is increased in the headspace by making the urine alkaline
      and the nitric oxide is increased by making the urine acidic. Nitric oxide is
      abnormally high in the headspace of acidified bacterially infected urine and
      nitrous acid is also detected. The potential clinical implications of analyses of
      urine by SIFT-MS are alluded to.

PMID- 10343416
TI  - Heading in soccer--time for a rethink?

PMID- 10343415
TI  - Serum and urine selenium concentrations as indicators of body status in patients
      with diabetes mellitus.
AB  - Serum and urine selenium levels were determined in patients with diabetes by
      hydride generation atomic absorption spectrometry. Mean serum selenium
      concentrations measured in patients with diabetes mellitus (64.9 +/- 22.8
      micrograms/l) were significantly lower than those determined in the control group
      (74.9 +/- 27.3 micrograms/l) (P < 0.05). Mean serum selenium concentrations were
      not significantly different between the two groups of diabetic patients
      considered (P > 0.05). Mean urine selenium concentration in diabetic patients
      (18.8 +/- 10.7 micrograms/l) were not significantly different from those measured
      in the control group (20.2 +/- 10.1 micrograms/l) (P < 0.05). No significant
      differences in serum and urine selenium levels were found if related to sex of
      patients (P > 0.05). Application of linear regression analysis to serum and urine
      selenium levels and patients' age showed a non-statistically significant
      correlation (P > 0.05). Given the marked overlap between the two ranges of the
      populations, the predictive values of serum selenium in diabetic patients are
      low.

PMID- 10343417
TI  - Valuing ethnic diversity in primary care.

PMID- 10343418
TI  - A novel method of guideline development for the diagnosis and management of mild
      to moderate hypertension.
AB  - BACKGROUND: There are large numbers of clinical guidelines available covering
      many clinical areas. However, the variable quality of their content has meant
      that doctors may have been offered advice that has been poorly researched or is
      of a conflicting nature. It has been shown that local involvement in guideline
      development increases the likelihood of their use. AIM: To develop a guideline to
      be used by general practitioners in six practices in Birmingham from existing
      evidence-based guidelines. METHOD: Recommendations from the four most cited
      international hypertension guidelines, and the more recently published New
      Zealand guidelines, were divided into subject areas and tabulated to facilitate
      direct comparison. Where there was complete or majority (> or = 3/5) agreement,
      the recommendation was taken as acceptable for inclusion in the new guideline.
      Where there was disagreement (< or = 2/5), recommendations were based on the best
      available evidence following a further MEDLINE literature search and critical
      appraisal of the relevant literature. Each recommendation was accompanied by a
      grade of evidence (A-D), as defined by the Canadian Hypertension Society, and an
      'action required' statement of either 'must', 'should', or 'could', based on the
      Eli-Lilly National Clinical Audit Centre Hypertension Audit criteria. The
      recommendations were summarized into a guideline algorithm and a supporting
      document. The final format of both parts of the guideline was decided after
      consultation with the practice teams. The practices individually decided on
      methods of data collection. RESULTS: The guideline was presented as a double
      sided, A4 laminated sheet and an A4 bound supporting document containing a
      synthesis of the original guidelines in tabular form, a table of the resulting
      recommendations, and appendices of current literature reviews on areas of
      disagreement. The content of the final Birmingham Clinical Effectiveness Group
      (BCEG) guideline differed minimally from any of the original guidelines.
      CONCLUSION: The main strength of this method of guideline development may lie,
      not in the actual content of the resulting guideline, but in the strength of
      ownership felt by the BCEG and the practices following its development. While the
      full process is unlikely to be possible for general practitioners working outside
      an academic environment, the techniques used could provide a framework for
      practitioners to adapt national and international guidelines for use at a local
      level.

PMID- 10343419
TI  - Primary care group commissioning of services: the differing priorities of general
      practitioners and district nurses for palliative care services.
AB  - BACKGROUND: General practitioners (GPs) have become more responsible for budget
      allocation over the years. The 1997 White Paper has signalled major changes in
      GPs' roles in commissioning. In general, palliative care is ranked as a high
      priority, and such services are therefore likely to be early candidates for
      commissioning. AIM: To examine the different commissioning priorities within the
      primary health care team (PHCT) by ascertaining the views of GPs and district
      nurses (DNs) concerning their priorities for the future planning of local
      palliative care services and the adequacy of services as currently provided.
      METHOD: A postal questionnaire survey was sent to 167 GP principals and 96
      registered DNs in the Cambridge area to ascertain ratings of service development
      priority and service adequacy, for which written comments were received. RESULTS:
      Replies were received from 141 (84.4%) GPs and 86 (90%) DNs. Both professional
      groups agreed that the most important service developments were urgent hospice
      admission for symptom control or terminal care, and Marie Curie nurses. GPs gave
      greater priority than DNs to specialist doctor home visits and Macmillan nurses.
      DNs gave greater priority than GPs to Marie Curie nurses, hospital-at-home, non
      cancer patients' urgent hospice admission, day care, and hospice outpatients. For
      each of the eight services where significant differences were found in
      perceptions of service adequacy, DNs rated the service to be less adequate than
      GPs. CONCLUSION: The 1997 White Paper, The New NHS, has indicated that the
      various forms of GP purchasing are to be replaced by primary care groups (PCGs),
      in which both GPs and DNs are to be involved in commissioning decisions. For many
      palliative care services, DNs' views of service adequacy and priorities for
      future development differ significantly from their GP colleagues; resolution of
      these differences will need to be attained within PCGs. Both professional groups
      give high priority to the further development of quick-response clinical
      services, especially urgent hospice admission and Marie Curie nurses.

PMID- 10343420
TI  - Our Healthier Nation: are general practitioners willing and able to deliver? A
      survey of attitudes to and involvement in health promotion and lifestyle
      counselling.
AB  - BACKGROUND: The recent Green Paper, Our Healthier Nation, identifies professional
      advice on healthier living as a key component of its national contract for
      health. General practitioners (GPs) are ideally placed for this work. However,
      previous research has reported a discrepancy between patients' expectations of
      lifestyle advice from GPs and their receipt of such advice. AIMS: To describe
      GPs' current attitudes to and involvement in health promotion and lifestyle
      counselling, and to track changes in these areas over recent years. METHOD: A
      postal questionnaire survey of a random sample of 430 GPs, one per practice, from
      all general practices in Leicestershire, Derbyshire, and Nottinghamshire. GPs who
      had not responded after two weeks received a reminder telephone call plus two
      follow-up questionnaires. RESULTS: Four hundred and eleven GPs were eligible for
      the survey, which yielded a response rate of 68% (n = 279). GPs reported spending
      an average 16% of practice time on prevention and 79% reported educating patients
      about lifestyle risk 'most' or 'all of the time'. Solo GPs spent more time on
      prevention than GPs from group practices. Most enquiries and interventions
      related to smoking behaviour. GPs felt most effective in changing patients' use
      of prescription drugs, and the largest reported difference between current and
      potential effectiveness in helping patient change lifestyle behaviour, after
      information and training, related to reducing alcohol consumption. CONCLUSIONS:
      Despite an increasing workload, GPs remain positive about health promotion and
      lifestyle counselling. Over the past 10 years, there has been an increase in
      routine enquiries about lifestyle behaviour, but confidence about effectiveness
      in helping patients changes lifestyle behaviour remains low. More training and
      support concerning lifestyle intervention is required by GPs in order for them to
      contribute effectively to the Government's health promotion programme.

PMID- 10343421
TI  - Randomized trial of nurse-assisted strategies for smoking cessation in primary
      care.
AB  - BACKGROUND: Brief advice to stop smoking from general practitioners (GPs) has
      been repeatedly shown to increase smoking cessation by a small, but measurable
      amount. Some studies have suggested that adding more intensive interventions to
      brief advice may increase its effectiveness, but it is unclear whether this is
      true in general practice. AIMS: To determine whether brief advice from a doctor
      together with counselling and follow-up from a trained practice nurse is more
      effective than brief advice alone in helping people to stop smoking. METHODS: The
      design was a randomized controlled trial. Four hundred and ninety-seven general
      practice patients aged older than 18 years and smoking at least one cigarette per
      day in six general practices in Oxfordshire, Berkshire, and Buckinghamshire were
      randomized to one of two interventions: brief verbal or written advice from a GP
      plus extended counselling and follow-up from a trained practice nurse; brief
      advice from a GP alone. The primary outcome was sustained abstinence from smoking
      at three and 12 months. A secondary outcome was forward movement in the stages of
      change cycle. RESULTS: The proportion showing sustained abstinence was 3.6% in
      the extended counselling group, and 4.4% in the brief advice group (difference = 
      0.8%; 95% confidence interval = -4.3% to 2.6%). Seventy-four (30%) of those
      randomized to extended counselling actually took up this offer. No significant
      progression in stages of change was detected between the two groups. CONCLUSIONS:
      In unselected general practice patients who smoke, brief advice from a GP
      combined with intensive intervention and follow-up by a practice nurse is no more
      effective than brief advice alone.

PMID- 10343422
TI  - Polypharmacy in general practice: differences between practitioners.
AB  - BACKGROUND: Polypharmacy, the simultaneous use of multiple drugs, is associated
      with adverse drug reactions, medication errors, and increased risk of
      hospitalization. When the number of concurrently used drugs totals five or more
      (major polypharmacy), a significant risk may be present. AIM: To analyse the
      interpractice variation in the prevalence of major polypharmacy among listed
      patients, and to identify possible predictors of major polypharmacy related to
      the practice. METHOD: Prescription data were retrieved from the Odense
      Pharmacoepidemiological Database, and individuals subject to major polypharmacy
      were identified. The age- and sex-standardized prevalence rate of major
      polypharmacy was calculated for each practice in the County of Funen in Denmark
      (n = 173), using the distribution of age and sex of the background population as
      a reference. The practice characteristics were retrieved from the Regional Health
      Insurance System. Possible predictors of major polypharmacy related to the
      general practitioners (GPs) were analysed using backward stepwise linear multiple
      regression. RESULTS: A six-fold variation between the practices in the prevalence
      of major polypharmacy was found (16 to 96 per 1000 listed patients; median = 42).
      Predictors related to the practice structure, workload, clinical work profile,
      and prescribing profile could explain 56% of the variation. CONCLUSION: A
      substantial part of the variation in major polypharmacy between practices can be
      explained by predictors related to practice.

PMID- 10343423
TI  - Moles and melanomas--who's at risk, who knows, and who cares? A strategy to
      inform those at high risk.
AB  - BACKGROUND: Malignant melanoma is uncommon but potentially fatal. Knowledge and
      attitudes play an important part in the early detection of this skin cancer. AIM:
      To assess knowledge, risk perception, and intended behaviour related to melanoma
      compared with actual risk status. To suggest measures to improve the primary and
      secondary prevention of melanoma in general practice for a high-risk group.
      METHOD: A prospective questionnaire survey was carried out on consecutive adults
      attending in 16 randomly selected group practices. Applying MacKie's personal
      risk factor chart for melanoma, the study assessed self-reported risk, knowledge
      of skin cancer--especially malignant melanoma--and self-reported preventive
      activity. RESULTS: A total of 3105 (69%) attenders completed the questionnaire.
      The responders showed greater concern for minor rather than major clinical signs
      in pre-existing moles. Young people and the professional classes were the least
      knowledgeable about skin cancer and exhibited the most risky behaviour in terms
      of sun exposure, failure to check their skin, and to seek medical advice about
      new or changing moles. The majority of an 8.7% high-risk group showed lack of
      awareness of their increased risk, and women in this group reported the highest
      desire for a suntan and the use of sunbeds. In addition to showing less concern
      than their low risk counterparts about moles growing in size, they were also
      reluctant to seek medical advice about new moles. CONCLUSION: Consideration
      should be given to targeting primary prevention and selective screening in
      general practice towards a high-risk group for malignant melanoma. Young people
      and the professional social class should receive particular attention.

PMID- 10343424
TI  - The quantity and quality of clinical practice guidelines for the management of
      depression in primary care in the UK.
AB  - BACKGROUND: Despite research evidence that guidelines can improve patient care,
      concerns remain over their cost-effectiveness. This is particularly so when there
      is a proliferation of guidelines for the same condition. Faced with differing
      recommendations, users will wish to make informed decisions on which guideline to
      follow. In creating a guideline appraisal instrument we have assessed guidelines
      developed in the United Kingdom (UK) for the management of a range of disorders
      including depression in primary care. AIM: To identify the number of UK clinical
      guidelines for the management of depression in primary care and to describe their
      quality and clinical content. METHOD: A survey was undertaken to identify all
      depression guidelines developed in the UK between January 1991 and January 1996.
      All guidelines produced by national organizations and a random sample of local
      guidelines were appraised using a validated instrument by six assessors: a
      national expert in the disease area, a general practitioner, a public health
      physician, a hospital consultant, a nurse specializing in the disease area, and a
      researcher on guideline methodology. The clinical content of each guideline was
      then assessed by one of the researchers (RB) according to a defined framework.
      RESULTS: Forty-five depression guidelines were identified. While there was a
      considerable range in the quality of the six national and three local guidelines
      appraised, at a group level their performance was similar to guidelines for other
      diseases. Clinical recommendations tended to reflect the joint consensus
      statement produced by the Royal College of General Practitioners and Royal
      College of Psychiatrists in 1992. The most obvious difference was in the style in
      which the guidelines were written and presented. CONCLUSION: A 'national
      template' was the starting place for most guidelines. Steps need to be taken to
      ensure that these templates are based on the best possible research evidence and
      professional opinion. Local clinicians should concentrate on effective
      dissemination and implementation strategies, rather than creating new guidelines.

PMID- 10343425
TI  - Assessing the psychosocial consequences of epilepsy: a community-based study.
AB  - BACKGROUND: Few studies have measured, using validated scales, the psychosocial
      handicap of epilepsy in a general practice setting. AIM: To assess the prevalence
      of psychosocial problems associated with epilepsy. METHOD: A survey was
      undertaken of 309 subjects, with one or more non-febrile epileptic seizures,
      drawn from two general practices in the United Kingdom (UK). The outcome measures
      were the Subjective Handicap of Epilepsy Scale (SHE), the SF-36, and the Hospital
      Anxiety and Depression scale (HAD). RESULTS: One-third of persons with active
      epilepsy were significantly handicapped by their condition. The severity of
      subjective handicap was related to seizure frequency and to the duration of
      remission of seizures. Between one-third and one-half of subjects scored as
      'cases' on the HAD scale and on the mental health subscale of the SF-36. Only one
      third of the psychiatric morbidity revealed by the questionnaires had been
      recognized by the general practitioner (GP). Scores on the SF-36 indicated that
      people with active seizures perceived themselves as significantly less healthy
      than those in remission, and that, for persons in remission, drug treatment had a
      detrimental effect on certain aspects of well-being. CONCLUSIONS: The occurrence
      of seizures, even at low frequencies, is associated with psychosocial handicap,
      and this may remain covert in general practice.

PMID- 10343426
TI  - Out-of-hours work: the effect of setting up a general practitioner cooperative on
      GPs and their families.
AB  - Since 1995 the number of general practitioner (GP) cooperatives set up to provide
      out-of-hours care has risen dramatically. This study demonstrates that the
      setting up of a cooperative in Chester is linked to an increase in the morale of
      the local GPs and their families.

PMID- 10343427
TI  - Applying the Sheffield tables to data from general practice.
AB  - Lowering cholesterol with drugs of the statin class reduces the risk of a
      coronary event. Recent guidelines recommend use of the 'Sheffield tables' to
      detect individuals who might be offered drug treatment in whom the annual
      absolute risk of a first coronary event is > or = 3%. Using these tables in a
      general practice cohort aged 35-68 years, we found that 3% of men and 0.05% of
      women were above the treatment threshold. Smokers aged over 50 accounted for 85%
      of people recommended for statin therapy. Almost all smokers would fall below the
      treatment threshold if they quit smoking.

PMID- 10343428
TI  - Atrial fibrillation in general practice: how useful is echocardiography in
      selection of suitable patients for anticoagulation?
AB  - All patients identified from records in two practices in West Lothian (n = 103)
      as having atrial fibrillation (AF) were offered a clinical examination,
      electrocardiogram (ECG), and echocardiography. Sixty-five patients attended the
      examinations. Of these, 26 (40%) were found to be in sinus rhythm. Many of those
      in AF were already on warfarin. Only eight who were found to have AF, who were
      not already on warfarin and who had no contraindications to it, had additional
      risk factors that suggested they be treated with warfarin. In no case did
      echocardiography alter management decisions.

PMID- 10343429
TI  - Shifting care: GP opinions of hospital at home.
AB  - Hospital at home (HaH) has become an increasingly popular model of care over the
      past few years. However, there is little evidence to suggest that this is a
      superior form of care when compared with standard inpatient care in terms of
      cost, satisfaction, or clinical outcomes. Despite concerns that these schemes
      increase general practitioner (GP) workload, there is also no published evidence
      on the effect of HaH on GPs. As part of a broader study, a survey was undertaken
      of all GPs in an inner London health authority for their views of HaH. Overall,
      GPs felt that such schemes increased their workload, but GPs who had used HaH
      were more strongly in favour of these schemes for a range of conditions.

PMID- 10343430
TI  - Is default from colposcopy a problem, and if so what can we do? A systematic
      review of the literature.
AB  - It has been reported that many women referred to outpatient colposcopy clinics
      fail to attend for their appointments. The aim of this paper is to search the
      literature to assess the extent of default from colposcopy and to identify
      interventions, suitable for implementation within primary care, to reduce the
      proportion of women defaulting. Searches were performed on MEDLINE, PsychLIT,
      Bids and Cancerlit from 1986 to September 1997 using the terms colposcopy or
      cervical/Pap smear in association with default, non-attendance, adherence,
      patient compliance, treatment refusal, patient dropouts, attendance, barriers or
      intervention. The inclusion criteria for primary papers were that they contained
      data that enables the calculation of default rates for colposcopy or the results
      of interventions aimed at improving the default rates. Thirteen publications
      describing default rates and four describing interventions were included as
      primary papers. Combining the data from these studies suggests default rates of
      3%, 11%, and 12% for assessment/treatment visits, first review, and second review
      respectively. The intervention studies suggested a need to tailor the
      intervention to the population and the type of information to suit the
      individual. Varying definitions make comparison of default rates difficult, and
      the use of a crude non-attendance rate may result in an overestimate of default
      rates. The vast majority of women invited to colposcopy eventually attend. It is
      questionable if there is a need for interventions to increase compliance. Where
      necessary, greater cooperation across the primary/secondary care interface and
      use of the extended primary care team may be a more cost-effective means of
      increasing compliance.

PMID- 10343431
TI  - The 'heartsink' patient revisited. The Welsh Philosophy And General Practice
      discussion Group.
AB  - The term 'heartsink patient' is now part of the vocabulary of general practice.
      But what and where is the heartsink? How should the phenomenon be studied? What
      are the implications of differing interpretations for general practice? The
      heartsink patient presents personal, social, and soteriological (pertaining to
      salvation) problems in physical terms. This poses a fundamental challenge to the
      philosophical foundations of general practice. Emphasizing a biomedical role
      justifies questioning the legitimacy of 'heartsinks' as patients. Alternatively,
      general practice should reassert its acceptance of suffering, whatever its origin
      and presentation. This would justify accommodating a far greater range of
      problems than simply those explained by biomedicine alone, and make general
      practice soteriological to the core.

PMID- 10343432
TI  - Chaos and complexity.

PMID- 10343433
TI  - Patient's lists.

PMID- 10343434
TI  - Methadone treatment practices.

PMID- 10343435
TI  - Volume of antibiotic use in England.

PMID- 10343436
TI  - A new practice strategy for CHD.

PMID- 10343437
TI  - A request for coil removal after four abortions.

PMID- 10343438
TI  - Key developments in treating coronary artery disease.

PMID- 10343439
TI  - Controversies in cardiology.

PMID- 10343440
TI  - Heart disease in older patients.

PMID- 10343441
TI  - Hypertension and the diabetic patient.

PMID- 10343443
TI  - Chlamydia screening would pay dividends.

PMID- 10343442
TI  - Food intolerance in children: a genuine problem.

PMID- 10343444
TI  - A mother who wants her son circumcised.

PMID- 10343446
TI  - Diagnosis and treatment of cutaneous bacterial infections.

PMID- 10343445
TI  - Key developments in infection.

PMID- 10343447
TI  - Cystitis: treat quickly, and suggest hygiene precautions.

PMID- 10343448
TI  - Chlamydial infection: who is at risk?

PMID- 10343449
TI  - A guide to the management of chronic sinusitis.

PMID- 10343450
TI  - Basal cell carcinoma.

PMID- 10343451
TI  - Video assessment.

PMID- 10343452
TI  - Viagra and penicillin: the same problem?

PMID- 10343453
TI  - [Multiple sclerosis. An example of a polygenic disease].

PMID- 10343454
TI  - [Ultrasonic biomicroscopy].

PMID- 10343455
TI  - [The personal identity of Philip II].

PMID- 10343456
TI  - [Physician writers versus medical writers (a humanistic facet of medicine)].

PMID- 10343457
TI  - [The growth hormone and aging].

PMID- 10343458
TI  - [The neuron as a work of art].

PMID- 10343460
TI  - [New indicators of the health of populations].

PMID- 10343459
TI  - [The setting of pediatric AIDS].

PMID- 10343461
TI  - [Neurospecificty and development].

PMID- 10343462
TI  - [New anatomical findings in the temporomandibular joint].

PMID- 10343463
TI  - Alteration of skin protein kinase C alpha protein and mRNA levels during induced
      mouse hair growth.
AB  - Protein kinase C (PKC) has been implicated in regulation of hair growth. In this
      study, the role of PKC alpha in induced mouse hair growth was studied. Hair
      growth in C57BL6 mice, a well known model for hair growth research, was induced
      by plucking the telogen hair. PKC alpha protein levels during the induced hair
      growth cycle were analyzed by Western immunoblot and mRNA levels were measured by
      RT-PCR. At 1 day and 4 days postdepilation, when the induced hair cycle was in
      early and midanagen, the PKC alpha protein level was decreased. At 10 days after
      depilation, when the induced hair cycle was in mature anagen, the PKC alpha
      protein level was increased. At 17 days after plucking the hair, when the induced
      hair cycle was in early catagen, PKC alpha protein returned to the control level.
      PKC alpha mRNA was relatively unchanged at 1 day and 4 days after plucking the
      hair but significantly elevated at 10 days postdepilation. At 17 days after hair
      growth induction, PKC alpha mRNA reverted to the control level. These results
      suggest that: 1) in early and mid anagen of the induced hair growth cycle, PKC
      alpha was downregulated posttranscriptionally. This downregulation may play a
      role in the induction of hair growth; 2) in mature anagen of induced hair growth
      cycle, PKC alpha was overexpressed, and this overexpression may play a part in
      maintaining the hair growth. Since the expression of PKC alpha was roughly
      correlated with mouse skin pigmentation, we hypothesize that PKC alpha may
      regulate hair growth partially through modulation of skin melanogenesis.

PMID- 10343464
TI  - The SAPASI is valid and responsive to psoriasis disease severity changes in a
      multi-center clinical trial.
AB  - We developed a structured Psoriasis Area Severity Index (PASI)-like instrument,
      the Self-administered PASI (SAPASI), that allows subjects to assess accurately
      the severity of their psoriasis. The major limitation of our previous SAPASI
      validity studies is that all were performed in a single academic center, raising
      questions about the generalizability of the instrument. We administered the
      SAPASI to 182 subjects in a 12-week, multicenter, double-blind clinical trial of
      topical tazarotene for psoriasis. On the same day, investigators blind to the
      SAPASI rating determined the degree of erythema, induration, scale, body surface
      area (BSA) affected, and overall lesion severity of the subjects' psoriasis.
      Using these data, we calculated an investigator PASI-Equivalent. Correlation
      analysis shows that for both initial and final assessments of psoriasis severity,
      the SAPASI score reflects the PASI-Equivalent score in a significant way (p =
      .0001), although the correlation is a modest one (r = 0.3 to 0.5). Significant (p
      = .0001), modest correlations were found between the subjects' reported BSAs and
      the investigators' reported BSAs. To assess responsiveness, the proportional
      changes of the SAPASI and PASI-Equivalent were found to be modestly significantly
      correlated (r = 0.2, p = .04). The results of this study support the general
      validity of the SAPASI and demonstrate that the SAPASI can detect changes in
      disease severity in a clinical trial. Significant correlations were also observed
      between SAPASI components and their investigator-reported counterparts in this
      multicenter trial. To the best of our knowledge, the current study represents the
      first multicenter validity study performed on a psoriasis severity instrument,
      and clearly demonstrates the value of this instrument in assessing the psoriasis
      severity in a population.

PMID- 10343465
TI  - Leukemia cutis in acute lymphocytic leukemia masquerading as viral exanthem.
AB  - Leukemia cutis is a specific skin lesion caused by infiltration of leukemic cells
      into the skin. It is uncommon in acute lymphocytic leukemia (ALL). It typically
      manifests as red or violaceous papules, nodules, or plaques, mainly on the face.
      Leukemia cutis presenting with a generalized viral exanthem-like maculopapular
      eruption appears to be rare in the English literature. We report such a case. A
      19 year-old man presented with a generalized purpuric maculopapular eruption of
      eight day's duration. Hematologic studies showed changes of acute lymphocytic
      leukemia, T-cell type. A skin biopsy specimen revealed a cuff-like, dense,
      perivascular infiltration of atypical lymphocytes in the upper and mid-dermis,
      consistent with leukemia cutis. The rash resolved in two weeks after
      chemotherapy. Our case illustrates that leukemia cutis should be considered in
      the differential diagnosis of a generalized morbilliform viral exanthem-like
      eruptions. Skin biopsy is important in establishing the diagnosis.

PMID- 10343466
TI  - Specific cutaneous lesions of the scalp in myelodysplastic syndrome with deletion
      of 20q.
AB  - We reported a specific skin lesion on the scalp in a patient with myelodysplastic
      syndrome (MDS), treated as refractory anemia with excess of blasts (RAEB).
      Histologically, a specimen from a nodule of the scalp consisted of a diffuse
      infiltration of atypical cells in the dermis and subcutaneous tissue. The patient
      died of acute leukemia 3 months later. Chromosomal examination of bone marrow
      cells revealed deletion of 20q and 21 trisomy. The specific cutaneous lesions in
      this patient were associated with acute transformation. The deletion of 20q and
      specific cutaneous lesions are regarded as signs of poor prognosis.

PMID- 10343467
TI  - Pityriasis rosea in a patient with Behcet's disease treated with interferon alpha
      2A.
AB  - Interferons have been used for the treatment of many diseases because of their
      immunomodulatory, antiviral, antitumoral, and antiproliferative effects. Systemic
      interferon alpha 2a (IFN-alpha 2a) is also efficacious in the management of
      Behcet's disease (BD). Many adverse cutaneous reactions related to IFN-alpha have
      been reported. In the light of the current literature, we report here the first
      case of Pityriasis rosea (PR) that developed while receiving IFN-alpha 2a for BD.
      However, since this is the first report on this association, further observations
      are needed to determine their clinical relevance.

PMID- 10343468
TI  - Cutaneous mucinous nodules associated with proliferating synovitis of rheumatoid
      arthritis.
AB  - Rheumatoid arthritis (RA) is occasionally associated with specific or non
      specific cutaneous conditions. In this report, we describe unusual cutaneous
      nodules arising on the skin overlying the inflamed joints of two patients with
      RA. The nodules were histopathologically characterized by mucinous granulation
      tissue associated with neutrophilic infiltration and proliferation of starry
      shaped mesenchymal cells. The affected joints of both cases showed synovitis with
      synovial tissue hyperplasia due to RA. Because hyaluronic mucin, which is the
      major component of synovial fluids, was deposited in the nodules, intradermal
      inoculation of synovial cells seemed to be responsible for the nodular
      development. The nodules of one patient spontaneously resolved in several months.
      We are unaware of any report describing similar cases. Such nodules should be
      included as a cutaneous complication of RA, distinct from neoplasias.

PMID- 10343469
TI  - Successful treatment of adolescent pemphigus vulgaris by immunoadsorption method.
AB  - A 15-year-old girl with pemphigus vulgaris did not respond to oral administration
      of prednisolone at 45 mg/day. The skin and oral mucous membrane lesions recurred
      after effective treatments with methylprednisolone pulse therapy and combination
      therapy with prednisolone and cyclosporine. The finally successful treatment
      involved eleven cycles of immunoadsorption using a tryptophan column and
      administration of a moderate dose of prednisolone. Serum gamma-globulin level and
      anti-intercellular antibody titer decreased from 1.08 g/dl to 0.5 g/dl and 1:320
      to 1:20, respectively. She has been well controlled with 21.5 mg/day prednisolone
      for 8 months after the final adsorption. Considering the physical, mental and
      social situation of adolescent student patients, immunoadsorption is a highly
      preferable choice among a variety of treatment modalities for pemphigus vulgaris
      because it makes the term of hospitalization shorter and avoids undesirable side
      effects from initial high dose corticosteroids.

PMID- 10343470
TI  - A case of classical Kaposi's sarcoma of the penis showing a good response to high
      energy pulsed carbon dioxide laser therapy.
AB  - Isolated Kaposi's sarcoma (KS) of the glans penis is rare; only 37 cases are
      reported in the literature. Treatment of KS consists mostly of old modalities,
      some old methods in updated improved versions, and some new and experimental
      therapies. We report a case of isolated classical Kaposi's sarcoma involving
      multiple sites of the penis in a 54-year-old man who was treated with high-energy
      pulsed carbon dioxide (CO2) laser therapy, resulting in complete resolution of
      the lesions and no evidence of recurrence.

PMID- 10343471
TI  - Squamous cell carcinoma in a renal transplant recipient with linear
      porokeratosis.
AB  - A 40-year-old man developed squamous cell carcinoma on a perianal lesion of
      linear porokeratosis after renal transplantation. The tumor metastasized to the
      left inguinal lymph node 25 months after the primary tumor was excised. p53
      overexpression was observed in the tumor cells, but not in the porokeratotic
      lesion. Interestingly, continuous subcutaneous infusion of peplomycin for the
      lymph node metastasis significantly improved the warty lesions of porokeratosis.
      In this patient, immunosuppressive agents might have accelerated the development
      of carcinoma on a skin area with malignant potential.

PMID- 10343472
TI  - Paget's disease arising near a male areola without an underlying carcinoma.
AB  - We report a 56-year-old man with Paget's disease occurring near the left areola
      without any underlying breast carcinoma. Histologically, there was no evidence
      suggesting continuity with a lactiferous duct, accessory breast, or microscopic
      gynecomastia. We review previous case reports of Paget's disease occurring in
      unusual sites and discuss their nomenclature from the histogenetic point of view.

PMID- 10343473
TI  - A poroid neoplasia arising close to a seborrheic keratosis and a
      trichoepithelioma.
AB  - A 69-year-old woman had a well-defined, slightly raised, brownish, keratotic
      plaque with an eccentric group of roughly circular, bluish, dome nodules on her
      right scapular area. Histological study revealed the presence of an eccrine
      poroma demonstrating features of eccrine poroma, hidroacanthoma simplex, and
      dermal duct tumor and arising in a lesion of seborrheic keratosis and a
      trichoepithelioma. In the eccrine poroma region, an area with malignant changes
      was evident. The findings in this case support the view of eccrine poroma as a
      spectrum of histological variants and the possibility of malignant transformation
      from a eccrine poroma towards porocarcinoma. The association with seborrheic
      keratosis is most probably coincidental, and the trichoepithelioma was probably
      due to induction of the tumoral stroma on adjacent follicular epithelia.

PMID- 10343474
TI  - Cerebriform intradermal nevus: a case of scalp expansion on the galea.
AB  - We report here a 7-year-old Japanese girl with cerebriform intradermal nevus
      (CIN). By placement of expanders on the galea, her scalp was expanded more easily
      with less discomfort than is expected when the expanders are placed under the
      galea. An immunohistochemical study on the expression of proliferating cell
      nuclear antigen suggested higher proliferative activity of nevus cells from the
      CIN lesion than that of cells from congenital or acquired intradermal nevi. The
      high proliferative activity appeared to be associated with a growth spurt of the
      lesion.

PMID- 10343475
TI  - Erythema multiforme-like eruptions associated with adenocarcinoma of the stomach
      in a patient with generalized prurigo simplex of two years duration.

PMID- 10343476
TI  - A computerized method of identifying potentially preventable heart failure
      admissions.
AB  - Heart failure (HF) is both highly prevalent and costly to society. Successful
      self-care is essential to effective HF management. This study sought to develop a
      method to identify, via medical records (International Classification of
      Diseases, 9th Revision, Clinical Modification) coding, HF admissions attributable
      to ineffective self-care. Expert panels completed an iterative series of mailed
      surveys to generate and validate a list of coded diagnoses that represent HF
      sequelae modifiable through self-care. Sixteen diagnoses resulted. Chart review
      at one hospital revealed that these modifiable sequelae were frequently present
      but not coded. A computerized method of identifying self-care deficits would
      allow nurses to identify patients in need of patient education.

PMID- 10343477
TI  - A multihospital effort to reduce inpatient lengths of stay for pneumonia.
AB  - Three large hospitals in the metropolitan area of Syracuse, New York, implemented
      a cooperative project to reduce hospital stays and resource utilization without
      adversely affecting patient outcomes for community acquired pneumonia. The
      project occurred under the leadership of nurse case managers and nurse managers.
      It was supported by active physician involvement. The project was implemented
      over a three-year period. It resulted in reductions of hospital stays through the
      standardization of patient care for pneumonia throughout the community.

PMID- 10343478
TI  - Improving nursing documentation for private-duty home health care.
AB  - Private-duty, home health care agencies have struggled in assuring compliance
      with accurate and complete nursing documentation. In this descriptive study, the
      author reports on an improvement and innovation project in a private-duty, home
      health care agency aimed at improving nursing documentation, as measured in chart
      review audits. Initial strategies were directed toward revising the documentation
      system, with implementation of a flow record, and conducting group nurse
      education. These efforts had a minimal effect on improving documentation
      compliance. A major, multifocus strategy was then implemented. The educational
      component stressed pre- and posttest. The chart audit tool was revised to track
      individual nurse behaviors. Nurses were mentored when documentation did not meet
      standards. Lastly, the nurse job description and corresponding performance
      appraisal document were revised to clarify nurse responsibility and strengthen
      nurse accountability; progressive discipline was initiated when warranted.
      Significant and sustained improvement was subsequently realized.

PMID- 10343479
TI  - Improving computer skills to support hospital restructuring.
AB  - A vital part of restructuring in hospitals is a continuing effort to find ways to
      meet the growing demands of caregivers for efficient ways to enter and retrieve
      patient information. The process of effectively meeting these demands was
      coordinated through the leadership and efforts of the chief nurse executive and
      the information manager for nursing at New York Veterans Affairs Medical Center.
      These efforts resulted in timely support for restructuring, improvement in the
      development of competency skills among nursing staff, and increase in the use of
      electronic methods for documentation of patient care. Discussion of the changes
      implemented include approaches and content of training for computer skills
      development, a position description for an expanded role of a nurse in the field
      of informatics, and the facility's structure that fits a patient-centered care
      model.

PMID- 10343480
TI  - Planned change to implement a restraint reduction program.
AB  - Physical restraints have been the standard of practice to manage certain types of
      patient behavior, such as unstable mobility, wandering, agitation, and
      interference with medical treatment. However, this intervention is not without
      serious negative consequences. Patients with neurological disorders or injuries
      are often at high risk for being restrained. The need to change to a more
      positive, patient-focused, restraint-free model was the goal of this project. A
      convenience sample of adult patients who were admitted to a neurological unit
      were studied. Outcome data that were assessed included (1) staff nurses'
      perception of restraints, (2) fall rate, (3) fall rate with injury, and (4)
      tube/line loss rate. Staff perceptions of restraints were assessed by
      administering the Perception of Restraints Use Questionnaire (PRUQ) before and
      after implementation of the restraint-reduced environment. The results of the
      outcome data support the change to a more restraint-reduced environment, as
      indicated by fall rate, fall rate with injury, and tube/line loss. Additionally,
      nurses' perceptions of restraints, as measured by the PRUQ, indicated a trend
      toward less emphasis on the use of restraints to control specific unsafe or
      undesirable patient behaviors.

PMID- 10343482
TI  - Nurses on quality improvement teams: how do they benefit?
AB  - As part of a randomized control trial to improve the delivery of preventive
      services, the authors studied the effect on clinic nurses in the roles of team
      leaders or facilitators of multidisciplinary, continuous quality improvement
      (CQI) teams. Our goal was to learn how these nurses felt about their experience
      with this project, specifically their satisfaction with process improvement,
      acquired knowledge and skills, and the impact on their nursing role. Overall, the
      nurses involved in this study reported significant gains in all three areas. This
      study suggests that CQI can be a valuable vehicle for improving and expanding the
      nursing role for clinic nurses.

PMID- 10343481
TI  - Do nurses know what patients think is important in nursing care?
AB  - In order for a nurse to provide quality care, she or he must know what patients
      expect from the nurse. Previous research into nurses' insight into patients'
      expectations of care have been based on idiosyncratic instruments or instruments
      that measure the perspective of the provider, not the patient. Using the 90 items
      from the Patient's Perception of Quality Scale-Acute Care Version, an instrument
      developed from qualitative interviews of patients, 448 patients and 350 nurses
      from the medical surgical units in seven hospitals ranked the items, patients
      from their perspective and nurses as they perceived patients would rank them.
      While the rank order of items was similar across patients and nurses, nurses
      consistently underestimated the extent to which patients valued most aspects of
      good nursing care.

PMID- 10343483
TI  - A not-so-distant mirror: J. Heyward Gibbes on the practice of medicine, 1927.

PMID- 10343484
TI  - Heyward Gibbes, the Oslerian tradition, and the identity of internal medicine.

PMID- 10343485
TI  - Current therapy for chronic rhinitis.

PMID- 10343487
TI  - Trojan horse advertising.

PMID- 10343486
TI  - Medicaid managed care.

PMID- 10343488
TI  - He hath the falling sickness.

PMID- 10343489
TI  - Medical genetics: past, present and future.

PMID- 10343490
TI  - Newborn screening program in Rhode Island: an update.

PMID- 10343491
TI  - Molecular genetics for the practitioner.

PMID- 10343492
TI  - Conventional and molecular cytogenetics in medicine.

PMID- 10343493
TI  - Cystic fibrosis.

PMID- 10343494
TI  - Presymptomatic testing for Huntington's disease: the role of genetic counseling.

PMID- 10343495
TI  - Rhode Island primary care physicians' attitudes toward genetic testing for breast
      cancer.

PMID- 10343496
TI  - Screening and management of hereditary breast cancer.

PMID- 10343497
TI  - National initiatives: management of heart disease and stroke.

PMID- 10343498
TI  - Congenital anomalies among hospital newborns.

PMID- 10343499
TI  - 0.08: a safer legal blood alcohol limit for drivers.

PMID- 10343500
TI  - Wrongful birth and the measure of damages in Rhode Island.

PMID- 10343501
TI  - Opinion: toward a rapid sterility test.

PMID- 10343502
TI  - Protein instability toward organic solvent/water emulsification: implications for
      protein microencapsulation into microspheres.
AB  - The objective of this study was to investigate the behavior of three proteins at
      an organic solvent/water interface. To simulate the first microencapsulation step
      of a water-in-oil-in-water emulsion technique, a water-in-oil emulsion was
      prepared by emulsifying an aqueous protein solution in either methylene chloride
      or ethyl acetate. Phase separation was then followed to collect protein samples
      from the aqueous phase and the organic solvent/water interface. Their properties
      were assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and
      size exclusion-HPLC. Bovine serum albumin was relatively unharmed during
      emulsification, compared to other proteins such as ovalbumin and lysozyme. In
      particular, the methylene chloride treatment on ovalbumin led to the formation of
      a large quantity of water-insoluble, solid-like aggregates and changes in the
      composition of monomeric and dimeric ovalbumin species. With regard to the
      question of ovalbumin recovery, only 9.74 approximately 37.72% of the used
      ovalbumin was present in the aqueous phases after emulsification. Similar
      penchant was noted with lysozyme. Water-insoluble aggregates brought with by
      emulsification were found to be covalently bound. Interestingly, less
      emulsification-induced denaturing effects were observed with ethyl acetate. Our
      study clearly demonstrated the emulsification-induced adverse events that were
      detrimental to the integrity of proteins and the importance of preserving protein
      stability toward microencapsulation.

PMID- 10343504
TI  - Foam fractionation as a method to separate endotoxin from recombinant
      biotechnology products.
AB  - The objective of this study was to evaluate the feasibility of foam fractionation
      for removal of contaminating endotoxin from biotechnology products, including
      plasmid DNA and recombinant proteins. After foam fractionation, alone and with
      bovine serum albumin and Triton X-100 as pro-foaming agents, FITC-labeled
      endotoxin remains in the bulk solution. These studies suggest that foam
      fractionation will be ineffective in the purification of plasmid DNA solutions,
      which are not surface-active and remain in the bulk solution with endotoxin.
      These data support the use of foam fractionation as an effective method for
      separating surface-active recombinant proteins, which will concentrate in the
      foam, away from endotoxin.

PMID- 10343503
TI  - Evaluation of the effects of fragmented steam exposure cycles on the survival of
      bacterial spores.
AB  - The purpose of this study was to examine the population and resistance
      characteristics of bacterial spores which have been exposed to an abbreviated
      steam sterilization cycle. The philosophy of many pharmaceutical manufacturers is
      to require a second complete terminal sterilization cycle in the event of an
      unplanned interruption during the terminal sterilization of a production batch.
      The impact of abbreviated steam sterilization cycles was examined for their
      effect on the survivability and resistance of bacterial spores following an
      inadequate sterilization cycle. Steam sterilization cycles of two minutes and
      four minutes were performed on separate groups of Biological Indicator spore
      strips. These groups were then held at room temperature and re-exposed to a range
      of sterilization conditions after 24, 48, and 72 hours, i.e., start cycle, abort,
      hold, start cycle, abort. Spore survivor curves were calculated and resistance
      estimations were determined. The results of the study indicated that the log
      level of the surviving spores remained fairly constant, but variability within
      groups increased as sterilization time increased. The resistance of these
      surviving spores, as measured by D value, also remained relatively constant
      throughout the holding period. Abbreviated cycles were similarly conducted on
      ampules containing a spore suspension, and the spore populations and moist heat
      resistances were determined over time. Contrary to the spore strip, the
      population of the subject ampules was less stable showing a gradual decline over
      the same observation period. The study also included a comparison of the
      surviving population of short and long fragmented cycles. The results of this
      study demonstrate that a second complete sterilization cycle is unnecessary to
      assure the absence of living matter in the sterilized units.

PMID- 10343506
TI  - Comparative methods for integrity testing of vials sealed at reduced pressures
      for lyophiles.

PMID- 10343505
TI  - The influence of the intravenous catheter composition on its hemocompatibility.
AB  - Varied kinds of raw materials have been used for intravenous catheter
      manufacturing, raising important questions related to their hemocompatibility. In
      order to evaluate the influence of these materials on the hemocompatibility,
      different catheters--made of polyurethane (PU) (Vianon or Tecoflex),
      polytetrafluorethylene (PTFE) or polyvinyl chloride (PVC)--employed in 129
      hospitalized patients, were analysed in this study. The used methodology involved
      careful catheter removal from patients, followed by chemical fixation and
      scanning electron microscopic evaluation of the adhered biological material. The
      results indicate that, on a decreasing scale of performance, PTFE catheters show
      better hemocompatibility than PU and PVC ones.

PMID- 10343507
TI  - Rat ultrasound model for measuring pain resulting from intramuscularly injected
      antimicrobials.
AB  - Rats emit ultrasonic vocalizations in situations involving anxiety or stress,
      defense, and submission. This study demonstrates the use of ultrasonic
      vocalizations as a quantitative measure of pain associated with intramuscular
      (i.m.) injections. Intramuscularly administered cephalosporins used in a
      comparative evaluation of pain in humans were chosen to validate this rat model.
      Three groups of four rats each received an intramuscular injection of either drug
      first, and then placebo, or placebo and then drug. The three drugs used in this
      study were cefonicid, cefoxitin, and cefamandole; saline was used as the placebo.
      Ultrasonic vocalizations were measured from 20 kHz to 100 kHz. The number of
      vocalizations ranged from 50 milliseconds to 500 milliseconds and most of the
      vocalizations occurred between 60 kHz and 80 kHz. Rats injected with cefoxitin,
      cefamandole, cefonicid, and saline vocalized an average of 36 +/- 11, 33 +/- 9,
      28 +/- 7, and 11 +/- 6 times respectively. The response to all three
      antimicrobials differed significantly when compared with placebo (p < 0.01),
      however, there was no significant difference between the number of vocalizations
      for each antimicrobial injection. Further research may allow the correlation of
      the total duration of each vocalization, with the individual frequencies such as
      the 22 kHz and the 55 kHz components and with the amount of pain associated with
      the injection. This correlation could then be used to further identify
      differences in the amount of pain associated with each antimicrobial injection
      without increasing the sample size.

PMID- 10343508
TI  - pKa of 4MP and chemical equivalence in formulations of free base and salts of
      4MP.
AB  - Fomepizole (4-Methylpyrazole, 4MP) is used as an antidote for ethylene glycol and
      methanol poisoning. In France it is administered intravenously as the sulfate or
      hydrochloride salt formulation and in the United States, as the free base
      formulation. Since its pKa was unknown, it was unknown if the free base,
      hydrochloride and sulfate salt formulations of 4MP are chemically equivalent, and
      if 4MP is in chemically equivalent forms in blood when these base and salt
      formulations are administered intravenously. Using UV spectrophotometry, the pKa
      of 4MP was determined to be 2.91 +/- 0.05 (n = 7) at a low concentration of 0.006
      M in formate buffers of various pH, and 3.00 +/- 0.16 (n = 7) when high
      concentration of 4MP (0.06 M) was titrated with HCl at 25 degrees C. The
      hydrochloride salt formulation (pH 6.64) was ionically and hence chemically
      equivalent to the free base formulation (pH 7.02), while the sulfate salt
      formulation, due to its lower pH of 2.33, showed presence of some ionized 4MP
      indicating chemical inequivalence. In order to determine chemical equivalence
      upon intravenous administration, these formulations were diluted with phosphate
      buffer (pH 7.4) with identical ionic strength and buffer capacity as blood. In
      spite of chemical inequivalence of the sulfate salt formulation, 4MP free base
      was observed from all three formulations when diluted with physiological buffer
      suggesting chemical equivalence under physiological conditions due to the strong
      buffering action of blood.

PMID- 10343509
TI  - Barriers, isolators and microbial control.

PMID- 10343510
TI  - [Social sciences and AIDS].

PMID- 10343511
TI  - [Condom use by men with non-stable partners in Mexico City].
AB  - OBJECTIVE: To analyze the association between sociodemographic variables and
      condom use during vaginal sexual relationships with non-stable partners. MATERIAL
      AND METHODS: Data were taken from a household probability survey on sexual
      behavior in 1992-1993 in the Mexico City Metropolitan Area. Of the completed
      survey were obtained 8,068 men of 15 to 60 years of age. 1,535 were selected
      because they reported that their last sexual relationship with vaginal
      intercourse had been with a non-stable partner. Principal component analyses were
      conducted to groups of variables with common underlying structures, these
      components and other variables were included in a logistic regressions. Condom
      use during last intercourse was the dependent variable. RESULTS: Feeling that sex
      with condoms or sex without penetration could be pleasurable, a high ranking in a
      scale on self-efficacy for condom use, compulsion for using a condom because of
      being afraid of contracting HIV/AIDS were positively associated with using a
      condom in the last sexual intercourse. Marital status, schooling, and the number
      of episodes of sexually transmitted diseases were significantly associated with
      condom use. Perception of inevitability of becoming infected due to lack of trust
      in condoms was negatively associated with its use. None of the variables
      regarding knowledge on HIV/AIDS, including means of transmission and ways to
      prevent its infection, showed any significant association with condom use.
      CONCLUSIONS: Even when information is considered important in educational
      strategies, it might be more important to promote a positive perception on
      condoms and safe sex as pleasurable (at the individual and social level), as well
      as the promotion of self-efficacy on being able to use a condom or enforce
      preventive behaviors against HIV infection.

PMID- 10343513
TI  - [Work conditions, labor fatigue and low birth weight among street vendors].
AB  - OBJECTIVE: This study presents the demographic, socioeconomic profile, working
      conditions and labor fatigue among fertile age street vendors in Mexico City.
      MATERIAL AND METHODS: 426 female street vendors were interviewed in Mexico City.
      This population was described and the association between the components labor
      fatigue and low birth weight (LBW) was analyzed by logistic regression in a
      subgroup of women who worked as street vendors during their last pregnancy.
      RESULTS: Of the interviewed group, 56% works more than 48 h per week, 87% had no
      social security, and 68% only had primary school level. The risk of LBW increased
      when workers had to cover selling quotes (OR 6.5, CI95% 1.3-31) when the
      merchandise were seasonal tools such as accessories or spare parts (OR 6.3, CI95%
      1.5-26), when women had to exhibit their merchandise on the floor or carry it (OR
      7.7 CI95% 1.8-32) and when financial support to initiate vending activities came
      from someone other than a close relative or friend (OR 7.4 CI95%, 1.2-44).
      CONCLUSIONS: These results contribute to identify the female vendors with higher
      risk of having child with LBW and suggest preventive actions.

PMID- 10343512
TI  - [Characteristics of sex behavior of men in Mexico City].
AB  - OBJECTIVE: To determine the major features of sexual behavior in men from Mexico
      City, such as the number of sexual partners, history of sexually transmitted
      disease (STD) and beliefs on AIDS. MATERIAL AND METHODS: A transversal
      epidemiologic study was conducted in 1995 based on multistage sampling with
      conglomerates. A total of 1,377 males from 15 to 49 years of age was interviewed
      by means of a structured questionnaire. Statistics such as Student's test and chi
      2 were applied to determine significance. RESULTS: Subject mean age was 17.7
      years (SD = 2.8 years) Overall proportion of condom use in the last intercourse
      was 24.6% depending on the type of partner: 18.8% used it with regular partners
      and 62.5% with multiple partners. Symptoms suggesting gonococcal uretritis were
      found in 2%. Finally, 97.5% understood the meaning of AIDS and knew some
      protective measures against infection. CONCLUSIONS: Some risky characteristics of
      sexual behavior were identified concerning the transmission of STD such as
      multiple sexual partners, not using condom and STD antecedents.

PMID- 10343514
TI  - [Evaluation of health status using Survey SF-36: preliminary results in Mexico].
AB  - OBJECTIVE: To establish a multidimensional profile of the health status in a
      population of southeastern Mexico and analyze the psychometric properties of a
      translation of the SF-36 survey authorized by the International Quality of Life
      Assessment Project. MATERIAL AND METHODS: The SF-36 was administered to 257
      volunteers of a clinic and a control group in a governmental institution. The
      methodology proposed by the author of the survey to build the health scales was
      used without modifications. The validity and reliability of the SF-36 adaptation
      to Mexico was psychometrically analyzed. RESULTS: Eight scales or health concepts
      related to physical function, physical role, body pain, general health, vitality,
      social function, emotional role and mental health were constructed. In the health
      service volunteers, the scale with the lowest mean was general health (63), and
      that with the highest (89) was physical role. In the control population, the
      lowest mean was general health (73) and the highest (94.6) was physical function.
      A comparison of the health scales of both groups showed significant differences
      in physical function, physical role, body pain, general health and vitality.
      CONCLUSIONS: Based on the psychometric evaluation, the SF-36 shows satisfactory
      consistency with its supposed validity and reliability, although the translation
      of certain items will be further analyzed for subsequent modifications.

PMID- 10343515
TI  - [Adrenal function and lipid metabolism in asthmatic children treated with
      budesonide].
AB  - OBJECTIVE: To assess the effect of low doses of inhaled budesonide on the adrenal
      function and lipid metabolism of asthmatic children. MATERIAL AND METHODS: The
      study included 10 asthmatic children (mean age, 8.8 years) treated with inhaled
      budesonide (200-300 micrograms/day) for a period longer than 3 months (group A);
      15 asthmatic children (mean age, 7.8 years) without steroid treatment (group B)
      and 10 non-asthmatic children (group C). Basal cortisol levels, as well as
      postACTH, adrenal androgens, lipids and urinary cortisol were determined.
      RESULTS: No significant differences were detected between groups A and B in the
      studied variables. In asthmatic children, urinary cortisol was significantly
      higher than in non-asthmatic children. Triglycerides, total cholesterol, low
      density lipoprotein cholesterol and atherogenic index levels were higher in
      asthmatic children with and without budesonide treatment, compared with non
      asthmatic children. CONCLUSIONS: Treatment of asthmatic children with low doses
      of inhaled budesonide did not modify the adrenal axis function nor lipid
      metabolism. Asthmatic patients showed an atherogenic lipid profile which could
      increase the risk of cardiovascular disease.

PMID- 10343516
TI  - [How women face a medical symptom: from the evaluation to health care selection].
AB  - OBJECTIVE: To describe, from the patients' point of view, the process they follow
      from the moment they face a symptom until they seek medical help. MATERIAL AND
      METHODS: Findings reported here are part of a qualitative study on the health of
      women from Colombia. Data were collected by semistructured interviews. The
      analysis was guided by grounded theory. RESULTS: When facing a symptom, women
      first evaluate it, then weigh their own capacities and assess their options, and
      last, they chose who might help them. These three stages form part of the process
      followed to seek medical help. CONCLUSION: Health professionals should be
      sensitive to patients' subjective experience and acknowledge their role in the
      diagnostic process and in health care.

PMID- 10343518
TI  - [Statistics of mortality related to reproductive health. Mexico, 1997].

PMID- 10343517
TI  - [Addition of vitamins and minerals to corn and wheat flour in Mexico].
AB  - In Mexico, marginal micronutrient deficiency is widespread and affects the health
      status and function of many Mexicans. A program to add nutrients to corn and
      wheat flour has been promoted by the Ministry of Health. This document describes
      the scientific and technological bases of the program. The main objective is to
      restore the nutrients which are lost during cereal processing to obtain flour and
      food products. Also, certain nutrients which are known to be deficient in a high
      proportion of Mexicans, and which should be supplemented in the diet for the
      benefit of the population are also included. In the definition of the formula to
      be added to flours various other factors were considered such as the absorption
      levels of the nutrients, potential interactions among them and a wide range of
      security to eliminate the risk of an adverse effect on health even at the highest
      level of food intake. Finally, the most appropriate compounds to be added to
      flours are suggested considering their reactivity and their possible negative
      effects on the stability of flour, as well as the bioavailability, market
      availability and cost. The recommended compounds were 5 mg/kg of thiamine
      (thiamine mononitrate), 3 mg/kg of riboflavin (riboflavin hydrochlorhidrate), 35
      mg/kg of niacine (nicotinamide), 30 mg/kg of iron (extrafine reduced iron) and 20
      mg/kg of zinc (Zinc oxide) for both types of flour, as well as 2 mg/kg and 0.5
      mg/kg of folic acid for wheat and corn flour, respectively.

PMID- 10343519
TI  - Evidence-based complementary medicine: a contradiction in terms?

PMID- 10343520
TI  - The shape of the distal femur: a palaeopathological comparison of eburnated and
      non-eburnated femora.
AB  - OBJECTIVES: To determine the difference in shape of the distal femur, viewed
      axially in two dimensions, between eburnated and non-eburnated femora. METHODS: A
      comparison of 52 non-eburnated and 16 eburnated femora drawn from a large
      archeological skeletal population. Eburnation was taken to indicate late stage
      osteoarthritis. Shape variability, based on landmarks, was quantified using a
      principal components analysis after a Procrustes alignment. RESULTS: A
      statistically significant difference was found between the two groups. This was
      with respect to the patellar groove and the shape of the medial condyle. The
      latter difference is consistent with bone remodelling as a knee stabilising
      mechanism. CONCLUSIONS: Anatomical shape can be quantified using an uncomplicated
      statistical technique. It was used to quantify the shape of the distal femur and
      demonstrate shape differences associated with osteoarthritis of the knee.

PMID- 10343522
TI  - Neuropsychiatric systemic lupus erythematosus is associated with imbalance in
      interleukin 10 promoter haplotypes.
AB  - OBJECTIVE: To investigate the association of interleukin 10 (IL10) promoter
      polymorphisms and neuropsychiatric manifestations of systemic lupus erythematosus
      (SLE). METHODS: IL10 haplotypes of 11 healthy volunteers were cloned to confirm
      that in the Dutch population, only the three common haplotypes (-1082/-819/-592)
      GCC, ACC and ATA exist. The IL10 promoter polymorphisms of 92 SLE patients and
      162 healthy controls were determined. The medical records of the SLE patients
      were screened for the presence of neuropsychiatric involvement. RESULTS: All
      cloned haplotypes were either GCC, ACC or ATA. Forty two SLE patients had
      suffered from neuropsychiatric manifestations (NP-SLE). In NP-SLE patients, the
      frequency of the ATA haplotype is 30% versus 18% in the controls and 17% in the
      non-NP-SLE group (odds ratios 1.9, p = 0.02, and 2.1, p = 0.04, respectively),
      whereas the GCC haplotype frequency is lower in the NP-SLE group compared with
      controls and non-NP-SLE patients (40% versus 55% and 61%, odds ratios 0.6, p =
      0.02 and 0.4 p = 0.006). The odds ratio for the presence of NP-SLE is inversely
      proportional to the number of GCC haplotypes per genotype when the NP-SLE group
      is compared with non-NP-SLE patients. CONCLUSIONS: The IL10 locus is associated
      with neuropsychiatric manifestations in SLE. This suggests that IL10 is
      implicated in the immunopathogenesis of neuropsychiatric manifestations in SLE.

PMID- 10343521
TI  - Influence of sulphasalazine, methotrexate, and the combination of both on plasma
      homocysteine concentrations in patients with rheumatoid arthritis.
AB  - OBJECTIVE: To study the influence of sulphasalazine (SSZ), methotrexate (MTX),
      and the combination (COMBI) of both on plasma homocysteine and to study the
      relation between plasma homocysteine and their clinical effects. METHODS: 105
      patients with early rheumatoid arthritis (RA) were randomised between SSZ (2-3
      g/day), MTX (7.5-15 mg/week), and the COMBI (same dose range) and evaluated
      double blindly during 52 weeks. Plasma homocysteine, serum folate concentrations,
      and vitamin B12 were measured. The influence of the C677T mutation of the enzyme
      methyl-enetetrahydrofolatereductase (MTHFR) gene was analysed. RESULTS: A slight
      trend towards increased efficacy and an increased occurrence of minor
      gastrointestinal toxicity was present in the COMBI group, no differences existed
      clinically between SSZ and MTX. Only a slight and temporary increase in plasma
      homocysteine was found in the SSZ group, in contrast with the persistent rise in
      the MTX group and the even greater increase in the COMBI patients. Patients
      homozygous for the mutation in the MTHFR gene had significantly higher baseline
      homocysteine, heterozygous MTHFR genotype induced a significantly higher plasma
      homoeysteine at week 52 compared with no mutation. No correlation was found
      between clinical efficacy variables and homocysteine. Patients with
      gastrointestinal toxicity had a significantly greater increase in homocysteine.
      CONCLUSION: A persistent increase in plasma homocysteine concentrations was
      observed in patients treated with MTX alone and more pronounced in combination
      with SSZ, in contrast with SSZ alone. An increase in plasma homocysteine is
      related to the C677T mutation in MTHFR. A relation in the change in homocysteine
      concentrations with (gastrointestinal) toxicity was found, no relation with
      clinical efficacy existed.

PMID- 10343523
TI  - 111Indium antimyosin antibody imaging of primary myocardial involvement in
      systemic diseases.
AB  - OBJECTIVE: The diagnosis of primary myocardial involvement in systemic diseases
      is clinically relevant but difficult in the absence of specific criteria.
      Whatever the underlying disease, myocytes degeneration is observed during the
      active phase of myocardial damage. The aim of this study was to assess the
      diagnostic value of scintigraphic imaging with 111Indium antimyosin antibody
      (AM), a specific marker of the damaged myocyte, for ongoing myocardial damage
      related to systemic diseases. METHODS: 40 patients with histologically confirmed
      systemic diseases were studied. They were classified into two groups according to
      the presence (group 1, n = 30), or the absence (group 2, n = 10) of clinical,
      electrocardiographic (ECG) or echocardiographic signs suggestive of myocardial
      involvement. Planar and tomographic acquisitions were obtained 48 hours after
      injection of AM (90 MBq). Rest 201thallium (T1) scintigraphy was also performed
      to assess myocardial perfusion and scarring. Clinical, ECG, and echocardiographic
      +/- scintigraphic evaluations were repeated during follow up (17 +/- 19 months)
      in 36 of 40 patients. RESULTS: In group 1, 13 of 30 patients (43%) showed diffuse
      significant AM uptake throughout the left ventricle (LV), and no or mild T1
      abnormality. Two of these were asymptomatic, four had normal ECG, and two had no
      clinical or echographic LV dysfunction. All patients in group 2 had negative AMA
      scintigraphy and normal T1 scintigraphy. During follow up of 12 AM positive
      patients, cardiac status improved after immunosuppressive treatment was
      intensified in nine cases, worsened in two cases, and remained stable in one.
      During follow up of 24 AM negative patients, cardiac status remained stable in 23
      cases despite treatment not being increased in 20, including two patients with
      sequellary myocardial involvement. The last patient developed mild LV dysfunction
      after 36 months. CONCLUSION: AM scintigraphy allows detection of active
      myocardial damage related to systemic diseases, with increased specificity
      compared with conventional methods, and increased sensitivity in some cases.
      Further studies are needed to assess the potential value of AM scintigraphy as a
      therapeutic guide.

PMID- 10343524
TI  - A quantitative method for detecting deposits of amyloid A protein in aspirated
      fat tissue of patients with arthritis.
AB  - OBJECTIVE: To describe a new, quantitative, and reproducible method for detecting
      deposits of amyloid A protein in aspirated fat tissue and to compare it with
      smears stained with Congo red. METHODS: After extraction of at least 30 mg of
      abdominal fat tissue in guanidine, the amyloid A protein concentration was
      measured by a monoclonal antibody-based sandwich ELISA. RESULTS: The
      concentrations in 24 patients with arthritis and AA amyloidosis (median 236,
      range 1.1-8530 ng/mg tissue) were higher (p < 0.001) than in non-arthritic
      controls, uncomplicated rheumatoid arthritis, and other types of systemic
      amyloidosis (median 1.1, range 1.1-11.6 ng/mg tissue). Patients with extensive
      deposits, according to Congo red staining, had higher concentrations than
      patients with minute deposits. CONCLUSION: This is a new, quantitative, and
      reproducible method for detecting deposits of amyloid A protein in aspirated fat
      tissue of patients with arthritis, even when minute deposits are present as
      detected in smears stained with Congo red.

PMID- 10343525
TI  - Optimised sample preparation of synovial fluid for detection of Chlamydia
      trachomatis DNA by polymerase chain reaction.
AB  - OBJECTIVE: To optimise sample preparation of synovial fluid for Chlamydia
      trachomatis (CT) specific polymerase chain reaction (PCR). METHODS: Serial
      dilutions of purified CT elementary bodies in synovial fluid were prepared. The
      synovial fluid pellet was processed by eight different methods of sample
      preparation. Then samples were analysed by CT specific PCR. The sensitivity of
      PCR was the basis of ranking of the eight different methods. RESULTS: Highest
      sensitivity was achieved by methods including an additional step of DNA
      isolation. Additional extraction of protein and polysaccharides by
      cetyltrimethylammonium bromide (CTAB) increased sensitivity. Addition of
      hyaluronidase did not increase sensitivity of QIAEX-DNA extraction but was
      necessary, however, before phenol-chloroform-DNA extraction. CONCLUSIONS: The
      method of synovial fluid sample preparation significantly influences the
      sensitivity of subsequent PCR. Additional DNA isolation and extraction of PCR
      inhibitors by CTAB led to higher sensitivity.

PMID- 10343526
TI  - Destruction of articular cartilage by alpha 2 macroglobulin elastase complexes:
      role in rheumatoid arthritis.
AB  - OBJECTIVE: Neutrophil elastase accounts for the ability of some fresh rheumatoid
      synovial fluids to degrade cartilage matrix in vitro. The aim of this study was
      to determine if enzyme activity could result from depletion of synovial fluid
      inhibitors or protection of the enzyme from inhibition. METHODS: The ability of
      synovial fluids to inhibit porcine pancreatic elastase was investigated together
      with chemical pretreatments capable of inactivating alpha 1 protease inhibitor
      (alpha 1PI) or preventing formation of alpha 2 macroglobulin (alpha 2M) elastase
      complexes. Subsequently, complexes of human neutrophil elastase with alpha 2M
      were prepared and applied to frozen sections of cartilage. Proteoglycan loss was
      quantified by alcian blue staining and scanning and integrating
      microdensitometry. Parallel studies were carried out using a low molecular weight
      chromogenic elastase substrate. The effects of alpha 1PI and SF on these systems
      were investigated. Finally, synovial fluids were subjected to gel filtration and
      the fractions assayed for elastase activity. High molecular weight fractions were
      pooled, concentrated, and tested for their ability to degrade cartilage sections.
      RESULTS: All synovial fluids reduced the activity of porcine pancreatic elastase,
      the inhibition mainly being attributable to alpha 1PI, whereas remaining activity
      resulted from complexes of elastase with alpha 2M. Complexes of human neutrophil
      elastase with alpha 2M were shown to cause proteoglycan degradation in frozen
      sections of human articular cartilage. Alpha 1PI prevented alpha 2M elastase
      complexes from degrading cartilage but not the chromogenic substrate. The data
      suggested that alpha 1PI does not inhibit elastase bound to alpha 2M but
      sterically hinders the complex. However, only one of five synovial fluids was
      able to completely block the actions of alpha 2M elastase complexes against
      cartilage. Gel filtration of rheumatoid synovial fluids showed elastase and
      cartilage degrading activity to be associated with fractions that contained alpha
      2M, and not with fractions expected to contain free enzyme. CONCLUSIONS: The data
      suggest that synovial fluid alpha 2M elastase complexes can degrade cartilage
      matrix in rheumatoid arthritis.

PMID- 10343528
TI  - Vitamin D receptors in the rheumatoid lesion: expression by chondrocytes,
      macrophages, and synoviocytes.
AB  - OBJECTIVES: The active form of vitamin D3, 1 alpha,25 dihydroxyvitamin D3
      (1,25D3), through its interaction with vitamin D receptors (VDR), is reported to
      effect a variety of anabolic and catabolic events, especially in bone and
      cartilage tissues. As cartilage degradation and tissue remodelling are
      characteristic features of the rheumatoid lesion, the distribution and expression
      of VDR at sites of cartilage erosion was examined. METHODS: Immunolocalisation
      techniques using a rat monoclonal antibody to VDR and an alkaline phosphatase
      conjugated avidin/biotin detection system were used to examine VDR in 18
      specimens of cartilage-pannus junction, 10 specimens of rheumatoid synovium or
      cartilage tissue, and four primary cultures of adherent rheumatoid synovial cells
      (RSC). For comparison, VDR expression was examined in 10 specimens of normal,
      healthy age matched articular cartilage. RESULTS: VDR was demonstrated in 15 of
      18 cartilage-pannus junctions either at the interface (8 of 18), within the
      pannus tissue (12 of 18), and by chondrocytes often close to the erosive lesion
      (10 of 18). All the rheumatoid synovial tissue and 5 of 10 cartilage specimens
      showed cells with positive staining, but the extent of this was variable.
      Negligible VDR staining was observed for normal cartilage. Primary cultures of
      RSC also showed variability in both the numbers and proportions of macrophages or
      synovial fibroblasts stained for VDR (range 10-50%), this being more common in
      cultures with a high proportion of macrophages. CONCLUSIONS: VDR expression has
      been demonstrated by most specimens of cartilage-pannus junction; was associated
      with various cell types, including chondrocytes, but not exclusively with CD68+
      macrophages. The focal nature of VDR expression within the rheumatoid lesion
      suggests a contributory role for 1 alpha,25D3 in the pathophysiological processes
      of rheumatoid arthritis.

PMID- 10343529
TI  - Reduced purine 5'-nucleotidase activity in lymphocytes of patients with systemic
      lupus erythematosus: results of a pilot study.
AB  - OBJECTIVE: To investigate purine metabolism in patients with systemic lupus
      erythematosus (SLE) for possible abnormalities that might be related to their
      overall impaired immune function. METHODS: This pilot study included 17 patients
      with SLE (2 men, 15 women). Enzyme activities of the purine enzymes 5'
      nucleotidase (5'NT), purine nucleoside phosphorylase (PNP), and hypoxanthine
      guanine-phosphoribosyltransferase (HGPRT) were measured in peripheral blood
      mononuclear cells (PBMC) and also in fractions of T cells (differentiation
      antigen CD3+) (n = 12) and B cells (CD19+) (n = 9). The activity of the
      thiopurine enzyme thiopurine-methyltransferase (TPMT) was measured in red cell
      lysate. Routine blood tests and indices of disease activity were measured as
      well. Results were compared with those of healthy volunteers. RESULTS: Compared
      with their controls, the female SLE patients had a more than 50% reduced activity
      of 5'NT in the T cell fraction (p = 0.001) and in PBMC (p < 0.000). 5'NT activity
      was also lower in B cells, but this was not statistically significant. Enzyme
      activities did not correlate with indices of disease activity, disease duration
      or the B cell/T cell ratio and no influence of medication was found. CONCLUSION:
      Reduced lymphocyte 5'NT activity is a novel finding in SLE. These results
      indicate that purine metabolism in SLE may be disturbed. Consequences of a low
      5'NT activity may be an intracellular accumulation of (deoxy)purine nucleotides
      and a reduction of adenosine production. It is hypothesised that these factors
      may play a part in the overall impaired immune function and in the chronicity of
      inflammation in SLE.

PMID- 10343530
TI  - Successful conservative treatment of rheumatoid subaxial subluxation resulting in
      improvement of myelopathy, reduction of subluxation, and stabilisation of the
      cervical spine. A report of two cases.
AB  - OBJECTIVE: To report the efficacy of conservative treatment with cervical
      traction and immobilisation with a Halo vest, in two consecutive rheumatoid
      arthritis patients with progressive cervical myelopathy caused by subaxial
      subluxation. METHODS: Description of neurological symptoms and signs and findings
      in plain radiography (PR) and magnetic resonance imaging (MRI) of the cervical
      spine before and after treatment of the subaxial subluxation by traction and
      immobilisation with a Halo vest during four months. RESULTS: During four months
      of traction and immobilisation neurological examination showed a considerable
      improvement of the signs and symptoms of cervical myelopathy. Afterwards PR and
      MRI of the cervical spine showed reduction of the subaxial subluxation.
      Eventually firm stabilisation was obtained in both patients without surgery of
      the cervical spine. CONCLUSION: Cervical traction and immobilisation with a Halo
      vest can be considered as an independent conservative treatment in rheumatoid
      arthritis patients with cervical myelopathy caused by subaxial subluxation.

PMID- 10343527
TI  - Genotyping for disease associated HLA DR beta 1 alleles and the need for early
      joint surgery in rheumatoid arthritis: a quantitative evaluation.
AB  - OBJECTIVE: To determine the value of HLA DR beta 1 disease associated epitope
      (DAE) and erythrocyte sedimentation (ESR) in predicting the need for major joint
      replacement in rheumatoid arthritis (RA). METHODS: Sixty five RA patients who had
      undergone hip, knee or shoulder arthroplasty within 15 years of disease onset and
      65 who had not. HLA DR beta 1 genotype was determined by polymerase chain
      reaction. ESR at first hospital visit was noted. RESULTS: Significantly more
      patients with two DAE required surgery, (32% v 9%), chi 2 = 13.9, p = 0.001, odds
      ratio = 5.4 (95% CI: 1.8, 16). Sensitivity was poor, 32%, specificity high, 91%.
      Presentation ESR was higher in surgery patients compared with non-surgery
      patients, 52 mm 1st h v 25 mm 1st h, p < 0.001, but was independent of DAE
      status. Sensitivity of an ESR of 30 mm 1st h was 75%, specificity 53%.
      CONCLUSION: The presence of two DAE is a risk factor for major joint surgery in
      RA and is independent of ESR, whereas in those with one or no DAE, a high ESR is
      an important predictor.

PMID- 10343531
TI  - Rheumatoid arthritis after human parvovirus B19 infection.

PMID- 10343532
TI  - Epidemiology of whiplash: an international dilemma.

PMID- 10343533
TI  - Association of oestrogen receptor gene polymorphisms with age at onset of
      rheumatoid arthritis.
AB  - OBJECTIVE: In view of the possible role of oestrogens in the pathogenesis of
      rheumatoid arthritis (RA), this study investigated the association between
      oestrogen receptor (OR) gene polymorphisms and RA. METHODS: Pvu II and Xba I
      restriction fragment length polymorphisms of the OR gene were analysed in 70 male
      and 240 female patients with RA, and in 300 male and 350 female controls. The
      absence or presence of restriction sites were represented as P, p (Pvu II) or X,
      x (Xba I). The distribution of OR genotypes was compared between the RA and
      control subjects by sex. RA patients were divided into subgroups according to
      their OR genotypes, then the age at onset, seropositivity, and rheumatoid nodule
      positivity were compared between the subgroups. RESULTS: The OR genotype
      frequency of distribution did not have significant differences between the male
      RA and male controls nor between the female RA and female controls. In women with
      RA, there was a significant difference of age at onset between the subgroups
      (uncorrected p = 0.047, corrected p = 0.94). Female patients with the OR genotype
      PPxx (homozygote of Px) tended to have developed RA at a younger age, whereas
      those with PPXX and ppxx (lack of Px haplotype) developed RA at an older age. In
      men with RA, there was no association between the OR genotype and age at onset.
      In seropositivity and rheumatoid nodule positivity, there was no significant
      difference between subgroups for either sex. CONCLUSIONS: Some variants of the OR
      gene are related to the onset of RA in women in certain age periods, suggesting
      the role of the interaction between the OR gene and serum concentrations of
      oestrogen at the onset of the disease.

PMID- 10343534
TI  - Mortality in rheumatoid arthritis patients with disease onset in the 1980s.
AB  - OBJECTIVE: Several previous studies have shown increased mortality in rheumatoid
      arthritis (RA) patients. This study investigated if this was true also for
      patients with disease onset in the 1980s. PATIENTS AND METHODS: The study group
      comprised 183 patients (67 men and 116 women) with definite RA participating in
      an ongoing prospective study. Mean age at onset of disease was 51 years, and mean
      duration of joint symptoms at inclusion was 11 months. The patients were included
      between 1985-89. Seventy five per cent of the patients were rheumatoid factor
      (RF) positive, 85% carried the shared epitope, and 90% became erosive. By 1
      September 1997 the number and causes of death, obtained from the death
      certificates, were recorded. Standardised mortality ratio (SMR) was calculated,
      comparing the observed number of deaths in the cohort with the expected number of
      deaths in the general population in the same area, age and sex matched. The
      predictive values of demographics, genotype, RF status, and clinical data at
      baseline were estimated using the Cox proportional hazards regression model.
      RESULTS: Eighteen patients (11 men and 7 women) had died compared with 20
      expected deaths. SMR with 95% confidence intervals was 87 (53, 136). There was no
      significant increase in the number of deaths at any time during follow up for
      either sex. RA was not the main cause of death in any of the cases. By reading
      the patient charts two cases were found where RA or its treatment could have
      contributed to death. No RA related variable contributed significantly to an
      increased risk of death. CONCLUSION: There was no increased mortality during the
      first 8-13 years of disease in this group of patients who developed RA in the
      1980s.

PMID- 10343535
TI  - Effectiveness of home exercise on pain and disability from osteoarthritis of the
      knee: a randomised controlled trial.
AB  - OBJECTIVE: To assess the effect of a home based exercise programme, designed to
      improve quadriceps strength, on knee pain and disability. METHODS: 191 men and
      women with knee pain aged 40-80 were recruited from the community and randomised
      to exercise (n = 113) or no intervention (n = 78). The exercise group performed
      strengthening exercises daily for six months. The primary outcome measure was
      change in knee pain (Western Ontario McMaster Osteoarthritis index (WOMAC)).
      Secondary measures included visual analogue scales (VAS) for pain on stairs and
      walking and WOMAC physical function scores. RESULTS: WOMAC pain score reduced by
      22.5% in the exercise group and by 6.2% in the control group (between group
      difference p < 0.05, unpaired t test). VAS scores for pain also reduced in the
      exercise group compared with the control group (p < 0.05). Physical function
      scores reduced by 17.4% in the exercise group and were unchanged in controls (p <
      0.05). CONCLUSION: A simple programme of home quadriceps exercises can
      significantly improve self reported knee pain and function.

PMID- 10343536
TI  - Bone scintigraphy in chronic knee pain: comparison with magnetic resonance
      imaging.
AB  - OBJECTIVE: To compare increased bone uptake of 99Tcm-MDP and magnetic resonance
      (MR) detected subchondral lesions, osteophytes, and cartilage defects in the knee
      in middle aged people with long-standing knee pain. METHODS: Fifty eight people
      (aged 41-58 years, mean 50) with chronic knee pain, with or without radiographic
      knee osteoarthritis, were examined with bone scintigraphy. The pattern and the
      grade of increased bone uptake was assessed. On the same day, a MR examination on
      a 1.0 T imager was performed. The presence and the grade of subchondral lesions,
      osteophytes, and cartilage defects were registered. RESULTS: The kappa values
      describing the correlation between increased bone uptake and MR detected
      subchondral lesions varied between 0.79 and 0.49, and between increased bone
      uptake and MR detected osteophytes or cartilage defects the values were < 0.54.
      The kappa values describing the correlation between the grade of bone uptake and
      the grade of the different MR findings was < 0.57. CONCLUSIONS: Good agreement
      was found between increased bone uptake and MR detected subchondral lesion. The
      agreement between increased bone uptake and osteophytes or cartilage defects was
      in general poor as well as the agreement between the grade of bone uptake and the
      grade of the MR findings.

PMID- 10343537
TI  - Thickness of human articular cartilage in joints of the lower limb.
AB  - OBJECTIVES: (a) To determine the topographical variations in cartilage thickness
      over the entire surfaces of cadaveric lower limb joints, and (b) to examine the
      correlations between: cartilage thickness and its site specific modulus;
      cartilage thickness and donor age, weight, height, and body mass index. METHODS:
      The cartilage thickness of 11 sets of cadaveric human joints each comprising an
      ankle, knee, and hip was measured using a needle probe technique. Statistical
      analysis was used to compare the cartilage thickness of the different lower limb
      joints and the differences in cartilage thickness over the surface of individual
      joints. It was further examined whether cartilage had a correlation with its
      stiffness, and any of the details of the specimen donors such as age, weight,
      height, and body mass index. RESULTS: The mean cartilage thickness of the knee
      was significantly greater than that of the ankle and hip (p < 0.001) in all 11
      sets of joints, while the cartilage thickness of the hip was significantly
      greater than that of the ankle in 10 sets of joints (p < 0.001). The mass of
      specimen donors was found to correlate with the mean cartilage thickness of all
      three lower limb joints. A correlation was also found between the height of
      donors and the mean cartilage thickness of the knee and hip joints, while only in
      the ankle joint was a correlation found between the mean cartilage thickness and
      the body mass index of the specimen donors. A further correlation was found
      between cartilage thickness and its modulus; the thinner the cartilage, the
      higher the modulus. CONCLUSIONS: The thickness of articular cartilage seems to be
      related to the congruance of a joint; thin cartilage is found in congruent joints
      such as the ankle, whereas thick cartilage is found in incongruent joints such as
      the knee. The correlations in this study imply that the larger and heavier was a
      donor the thicker was the cartilage in the lower limb joints. The data further
      suggest the presence of an inverse relation between the mean cartilage thickness
      and mean compressive modulus in each of the joints examined.

PMID- 10343538
TI  - Lysylhydroxylation and non-reducible crosslinking of human supraspinatus tendon
      collagen: changes with age and in chronic rotator cuff tendinitis.
AB  - OBJECTIVES: To investigate age related and site specific variations in turnover
      and chemistry of the collagen network in healthy tendons as well as the role of
      collagen remodelling in the degeneration of the supraspinatus tendon (ST-D) in
      rotator cuff tendinitis. METHODS: Collagen content and the amount of
      hydroxylysine (Hyl), hydroxy-lysylpyridinoline (HP), lysylpyridinoline (LP), and
      the degree of non-enzymatic glycation (pentosidine) were investigated in ST-D and
      in normal human supraspinatus (ST-N) and biceps brachii tendons (BT-N) by high
      performance liquid chromatography. RESULTS: In BT-N, tendons that served as
      control tissue as it shows rarely matrix abnormalities, pentosidine levels rise
      linearly with age (20-90 years), indicating little tissue remodelling (resulting
      in an undisturbed accumulation of pentosidine). A similar accumulation was
      observed in ST-N up to 50 years. At older ages, little pentosidine accumulation
      was observed and pentosidine levels showed large interindividual variability.
      This was interpreted as remodelling of collagen in normal ST after age 50 years
      because of microruptures (thus diluting old collagen with newly synthesised
      collagen). All degenerate ST samples showed decreased pentosidine levels compared
      with age matched controls, indicating extensive remodelling in an attempt to
      repair the tendon defect. Collagen content and the amount of Hyl, HP, and LP of
      ST-N and BT-N did not change with age. With the exception of collagen content,
      which did not differ, all parameters were significantly (p < 0.001) lower in BT
      N. The ST-D samples had a reduced collagen content and had higher Hyl, HP, and LP
      levels than ST-N (p < 0.001). CONCLUSIONS: Inasmuch as Hyl, HP, and LP levels in
      ST-N did not change with age, tissue remodelling as a consequence of
      microruptures does not seem to affect the quality of the tendon collagen. On the
      other hand, the clearly different profile of post-translational modifications in
      ST-D indicates that the newly deposited collagen network in degenerated tendons
      is qualitatively different. It is concluded that in ST-D the previously
      functional and carefully constructed matrix is replaced by aberrant collagen.
      This may result in a mechanically less stable tendon; as the supraspinatus is
      constantly subjected to considerable forces this could explain why tendinitis is
      mostly of a chronic nature.

PMID- 10343540
TI  - The immune suppressive effect of dexamethasone in rheumatoid arthritis is
      accompanied by upregulation of interleukin 10 and by differential changes in
      interferon gamma and interleukin 4 production.
AB  - OBJECTIVES: The influence of dexamethasone on interleukin 10 (IL10) production
      and the type 1 (T1)/type 2 (T2) T cell balance found in rheumatoid arthritis (RA)
      was studied. METHODS: Peripheral blood mononuclear cells (PB MNC) were isolated
      from 14 RA patients both before and 7 and 42 days after high dose dexamethasone
      pulse therapy. The ex vivo production of IL10, interferon gamma (IFN gamma) (T1
      cell), and IL4 (T2 cell) by PB MNCs was assessed, along with parameters of
      disease activity (erythrocyte sedimentation rate, C reactive protein, Visual
      Analogue Scale, Thompson joint score). In addition, the in vitro effect of
      dexamethasone (0.02, 0.2, and 2 microM) on PB MNC IL10, IFN gamma, and IL4
      production was studied. RESULTS: Dexamethasone pulse therapy resulted in a rapid
      and sustained decrease in RA disease activity. IL10 production increased after
      dexamethasone treatment and this was sustained for at least six weeks. A
      transient strong decrease in IFN gamma was seen shortly after corticosteroid
      treatment, while IL4 only decreased slightly. This led to an increased IL-4/IFN
      gamma ratio. In vitro, IL10 production was not detectable, IFN gamma and IL4
      decreased, but the effect was more pronounced for IFN gamma than for IL4, which
      again resulted in an increased IL4/IFN gamma ratio. CONCLUSION: Dexamethasone
      therapy in RA patients leads to a rapid, clinically beneficial effect. The
      upregulation of IL10 production may be involved in the prolonged clinical
      benefit. The strong immunosuppressive effect is most evident in the decrease in
      IFN gamma, and is therefore accompanied by a relative shift towards T2 cell
      activity. In vitro evaluation showed that this shift in T cell balance was a
      direct effect of dexamethasone and thus independent of the hypothalamic-pituitary
      adrenal axis.

PMID- 10343539
TI  - Anti-perinuclear factor compared with the so called "antikeratin" antibodies and
      antibodies to human epidermis filaggrin, in the diagnosis of arthritides.
AB  - OBJECTIVE: Antiperinuclear factor (APF), "antikeratin antibodies" ("AKA"), and
      antibodies to human epidermis filaggrin (AFA), are highly specific serological
      markers of rheumatoid arthritis (RA), which recognise epitopes on various
      isoforms of (pro)filaggrin. It was proposed that these antibodies are globally
      named antifilaggrin autoantibodies. Here the diagnostic value of the detection of
      each one is compared and the overlap between the three tests evaluated. METHODS:
      492 serum samples were tested, including 279 RA serum samples, taken from
      patients in France and Belgium. APF and "AKA" titres were estimated by indirect
      immunofluorescence, and AFA titres by immunoblotting on filaggrin enriched human
      epidermis extracts. RESULTS: By a convenient choice of the positivity thresholds,
      the diagnostic sensitivity and specificity of the tests were shown to be similar
      (0.52 and 0.97, respectively). Although the antibody titres were strongly
      correlated, the associations APF-AFA or AFA-"AKA" permitted more than 52% or 55%
      of RA to be diagnosed, with a specificity of 0.99. CONCLUSION: APF, "AKA", and
      AFA detection have a similar diagnostic value. However, because the three tests
      do not totally overlap, associating APF with "AKA" or AFA with "AKA" can improve
      diagnostic sensitivity. None of the three antigens used bear all the epitopes
      recognised by antifilaggrin autoantibodies.

PMID- 10343542
TI  - Lung involvement in primary Sjogren's syndrome is mainly related to the small
      airway disease.
AB  - OBJECTIVE: To evaluate lung involvement in patients with primary Sjogren's
      syndrome. METHODS: Sixty one consecutive, non-smoking patients, 58 women and
      three men, were evaluated clinically, physiologically, and radiologically. A
      bronchial and/or transbronchial biopsy was performed on 13 of the patients.
      Physiological data were compared with that of a control group of 53 healthy non
      smoking subjects matched for age and sex. RESULTS: In 41% of the patients the
      main symptom was dry cough. Physiological studies revealed that the patients
      presented significantly lower expiratory flow values (% pred) when compared with
      those of the control group: the forced expiratory volume in one second (FEV1)
      (mean (SD)) was 96% (16) v 111% (13) (p < 0.0001), the maximal expiratory flow at
      the 50% of the vital capacity (MEF50) was 72% (24) v 103% (17) (p < 0.0001), and
      the maximal expiratory flow at the 25% of the vital capacity (MEF25) was 49% (25)
      v 98% (20) (p < 0.0001). No significant difference was noted for the carbon
      monoxide diffusion value (% pred), between patients and controls. Blood gases
      were evaluated in 44 patients: mild hypoxemia was observed, and the alveolo
      arterial oxygen difference (P(A-a)O2) correlated significantly with MEF50 (r =
      0.35, p < 0.01) and MEF25 (r = 0.33, p < 0.01) values. Chest radiography showed
      mild, interstitial-like changes in 27 patients while slightly increased markings
      were present in 21. High resolution computed tomography of the lungs was
      performed in 32 patients (four with a normal chest radiograph, six with suspected
      interstitial pattern, 19 with apparent interstitial pattern, and three with
      hyperinflation) and revealed predominantly wall thickening at the segmental
      bronchi. All positive findings by computed tomography derived from the patients
      with abnormal chest radiographs. Transbronchial and/or endobronchial biopsy
      specimens in 10 of the 11 sufficient tissue samples revealed peribronchial and/or
      peribronchiolar mononuclear inflammation, while interstitial inflammation
      coexisted in two patients. CONCLUSION: The airway epithelia seem to be the main
      target of the inflammatory lesion of the lung in patients with primary Sjogren's
      syndrome. It seems to be common, subclinically leading to obstructive small
      airway physiological abnormalities.

PMID- 10343544
TI  - Effect of hormone replacement therapy on bone density in a patient with severe
      osteoporosis caused by anorexia nervosa.

PMID- 10343541
TI  - Thrombin receptor mediated signals induce expressions of interleukin 6 and
      granulocyte colony stimulating factor via NF-kappa B activation in synovial
      fibroblasts.
AB  - OBJECTIVE: To clarify the mechanism of thrombin receptor mediated signal
      transduction and the induction of cytokines by thrombin stimulation in rheumatoid
      synovial fibroblasts. METHODS: Cytokines were measured by enzyme linked
      immunosorbent assay (ELISA) in the supernatants of cultured rheumatoid synovial
      fibroblasts stimulated by thrombin. To assess the mechanism of thrombin receptor
      mediated signal transduction in the rheumatoid synovial fibroblasts,
      electrophoretic mobility gel shift assay (EMSA), immunoglobulin kappa
      chloramphenicol acetyltransferase (CAT) assay, and immunostaining for NF-kappa B
      subunit molecule was performed. RESULTS: Thrombin stimulation activated the
      inducible transcription factor NF-kappa B, and then induced subsequent
      expressions of interleukin 6 (IL6) and granulocyte colony stimulating factor (G
      CSF) in the cells. CONCLUSION: Thrombin receptor mediated signal transduction
      could induce the expressions of IL6 and G-CSF, and increase inflammatory events
      in the cavum articulare via NF-kappa B activation.

PMID- 10343543
TI  - Hug(h)e(s') ears: an unusual presentation of antiphospholipid syndrome.

PMID- 10343545
TI  - Unusual and memorable. Chrysiasis secondary to sodium aurothiomalate treatment.

PMID- 10343546
TI  - The quality agenda.

PMID- 10343547
TI  - Lawyers out of hospitals, doctors out of court.

PMID- 10343548
TI  - Introducing the Skills Development Centre of the Department of Surgery,
      University of Hong Kong.

PMID- 10343549
TI  - Using TV links for surgical teaching.

PMID- 10343550
TI  - Update on Perth: the Hill Skills Centre work in progress.

PMID- 10343551
TI  - ABS to MRCS at the RCS: philosophy, format and future.
AB  - After considering the ABS and CSiG parts of the FRCS examination and the standard
      for the new MRCS examination, it became important that the MRCS evolved away from
      the template of multiple true-false questions. Formats other than true-false
      questions can be used to test mental processes that are not simple factual
      recall. Formal mathematical tests can be evolved to equate different parts of the
      examination so that raw marks can be more clearly related to grades. Dispensing
      with the arbitrary requirement for five items in an MCQ question will enable
      better questions to be asked. Finally, an examination must be valid in context.
      With the above advances the examination will be effective, but its goal can be
      assessed only if the vision of the MRCS learning course is attained. The course
      aims to prepare surgeons for higher surgical training with a good general
      knowledge of surgery and an in-depth knowledge of the basic principles of
      surgery. The surgical trainee who has attained the MRCS should be able to manage
      a sick patient who suffers from the complications associated with surgery by
      using the principles of surgical anatomy, physiology and pathology. The trainee
      should know what to do initially during the 'golden hour' of opportunity, whom to
      call for help, and when.

PMID- 10343552
TI  - Basic surgical training: how good is it?

PMID- 10343553
TI  - An audit of bed usage in an acute surgical ward. Are we managing our resources
      effectively?

PMID- 10343554
TI  - Partial shifts or rota system for pre-registration surgical house officers: which
      do they prefer?

PMID- 10343555
TI  - How good are interim discharge summaries? A prospective audit.

PMID- 10343556
TI  - Problems from Calman: shorter or longer time to consultant appointment in general
      surgery?

PMID- 10343557
TI  - Surgical excellence--threats and opportunities.

PMID- 10343558
TI  - Delegation of orthopaedic workload.

PMID- 10343559
TI  - From surgical audit to clinical effectiveness.

PMID- 10343560
TI  - Clinical versus Surgical College Tutor--same goal, different team?

PMID- 10343562
TI  - From Faculty to Royal College. The Golden jubilee of the Faculty of Anaesthetists
      of the Royal College of Surgeons of England.

PMID- 10343561
TI  - The lives of the fellows.

PMID- 10343563
TI  - Appraisal and assessment.

PMID- 10343564
TI  - Lawyers out of hospitals, doctors out of court.

PMID- 10343565
TI  - Are surgical trainees being 'short-changed?'.

PMID- 10343566
TI  - Whither surgical training?

PMID- 10343567
TI  - Partial shifts or rota system for pre-registration surgical house officers: which
      do they prefer?

PMID- 10343568
TI  - Lord Smith of Marlow.

PMID- 10343569
TI  - The historical instrument collection: notes and queries.

PMID- 10343570
TI  - Communication between hospital and general practitioners after day case surgery:
      a patient safety issue.

PMID- 10343571
TI  - Consultants' opinions of anatomy demonstrating.

PMID- 10343573
TI  - What next for CME? A personal view.

PMID- 10343572
TI  - Competence, revalidation and continuing professional development--a business
      package.

PMID- 10343574
TI  - The changing face of orthopaedics.

PMID- 10343575
TI  - 'Old surgeons never die....'.

PMID- 10343576
TI  - What makes a surgeon? Knowledge, judgement, accountability.

PMID- 10343577
TI  - Lawyers out of hospitals, doctors out of court.

PMID- 10343579
TI  - Are basic surgical trainees being 'short-changed'?

PMID- 10343580
TI  - Slapped in the face.

PMID- 10343578
TI  - Lawyers out of hospitals, doctors out of court.

PMID- 10343581
TI  - The surgical training mountain.

PMID- 10343582
TI  - A longitudinal comparison of the psychological impact on mothers of neonatal and
      3 month repair of cleft lip.
AB  - PURPOSE: This study investigates whether the timing after birth of babies' cleft
      repairs influences the psychological status of mothers. METHODS: Mothers of
      infants born with a cleft lip completed psychological assessments and
      semistructured interviews at four time points: 2-3 weeks, 3 months and 6 months
      following the birth. In addition, a preoperative assessment and interview was
      completed within the first week of birth for those with infants undergoing
      neonatal repair and within the week before surgery for the 3 month repair group.
      RESULTS: There were no significant differences between mothers of infants with
      early (neonatal) and late (3 month) repairs on the emotional measures at any time
      point or preoperatively. Means of measures for anxiety and depressive symptoms
      and the Impact of Event Scale were within the normal range. Measures of
      interaction with the infant, perceived infant difficulty, bonding and parental
      competence failed to show any impact of timing of operation. Women's emotional
      status improved significantly over the 6 month period regardless of operation
      timing. Qualitative analysis of interview data indicated most mothers preferred
      their infant to receive neonatal repair. CONCLUSIONS: There was no evidence to
      support the idea that repair neonatally or at 3 months led to differential levels
      of anxiety or depressive symptoms or differences in attachment to the infant.
      Nevertheless mothers expressed a preference for and greater satisfaction with
      neonatal repair. In the absence of definitive evidence of differences in physical
      outcome, parental preferences should routinely be considered in deciding the
      timing of this procedure.

PMID- 10343583
TI  - Scar formation after skin injury to the human foetus in utero or the premature
      neonate.
AB  - A macroscopically visible scar was present at birth in three infants with a
      history of injury during amniocentesis at 16-20 weeks' gestation. In several
      neonates born between 21 and 31 weeks' gestation, chemical injury to the skin
      caused by extravasation of calcium gluconate healed by formation of a large scar.
      In the infant born at 21 weeks, biopsy of the injured area showed infiltration by
      large numbers of neutrophils and macrophages. It appears that a very immature
      neonate can mount a prominent inflammatory reaction and that both a midtrimester
      foetus and a very immature neonate heal injuries to the skin by scar formation
      and not by scarless healing.

PMID- 10343584
TI  - Do you CARE? A national register for cleft lip and palate patients.
AB  - The Cleft Palate Index and more recently the Craniofacial Anomalies Register-
      CARE--have been in operation since 1982. This paper summarises its development
      and plans for the future. CARE is a multi-disciplinary committee involving all
      specialties involved in the treatment of this group of patients. It therefore
      should and can be well placed to coordinate the cleft data arising from these
      patients.

PMID- 10343585
TI  - Posterior plagiocephaly: proactive conservative management.
AB  - The pathology, diagnosis and management of posterior plagiocephaly remains highly
      controversial. While the rationale for surgical management of true lambdoid
      synostosis is undisputed, opinions vary greatly on how to manage severe,
      unresolving, non-synostotic cases. We reviewed 39 cases of posterior
      plagiocephaly, 37 of which were treated conservatively. Of these, 34 patients had
      a significant improvement over the following year with sleep posture modification
      and/or physiotherapy. While only eight cases returned to complete normality, the
      remainder had deformities that were deemed mild by both mothers and surgeons, and
      did not merit surgery. Defining recalcitrant cases remains elusive as standard
      imaging is often unhelpful. While 3-D CT offers a much more accurate diagnosis of
      true lambdoid synostosis with bony union and allows objective assessment of the
      deformity, serial scans involve radiation doses that are difficult to justify.
      Clinical follow-up is the only reliable method at present.

PMID- 10343586
TI  - Audit of histologically incompletely excised basal cell carcinomas:
      recommendations for management by re-excision.
AB  - In an audit of 1392 basal cell carcinomas arising in 1165 patients, excised under
      the care of one consultant in the 10 years from 1988 to 1997, 99 (7%) were
      reported histologically as incompletely excised. Lateral margins alone were
      involved in 54 (55%), deep margins in 36 (36%) and both in 9 (9%). Although the
      policy throughout this period was to re-excise all such lesions, 74/99 (75%) were
      re-excised (compared with an average re-excision rate of 30% through other
      published series). For those patients undergoing re-excision, residual tumour was
      reported histologically in 40/74 (54%). Peri-orbital lesions showed an overall
      incomplete excision rate of 13% (range 11-17%); however, only 4/16 of re
      excisions in this area revealed residual tumour. Many clinicians have
      traditionally observed patients with incompletely excised basal cell carcinomas.
      The present study reports the largest series of re-excisions after incomplete
      excision of basal cell carcinoma, and has revealed that on the balance of
      probability such re-excisions will reveal residual tumour. Re-excision appears
      the appropriate course in almost all the anatomical areas studied although, with
      the exception of the inner canthus, periorbital lesions will have a low
      probability of residual tumour being identified.

PMID- 10343587
TI  - The use of otherwise redundant skin to provide nasal lining in the reconstruction
      of full-thickness alar defects by nasolabial flap repair.
AB  - The use of otherwise redundant nasolabial flap skin is described for lining in
      reconstruction of full-thickness alar defects. The techniques have been
      successfully used to reconstruct full-thickness alar defects in four patients.
      The overall procedure has the advantage of providing well-vascularised tissue of
      appropriate colour, texture and thickness for external skin and nasal lining in
      one-stage reconstruction.

PMID- 10343588
TI  - Complications of long operations: a prospective study of morbidity associated
      with prolonged operative time (> 6 h).
AB  - Reconstructive surgical procedures often take a long time to perform and duration
      of surgery is frequently cited as a major risk factor for postoperative
      complications. Whether operative time is an independent risk factor is unknown,
      as patients undergoing long operations may have numerous other risk factors. From
      September 1996 to September 1997, we prospectively assessed those patients
      undergoing reconstructive surgery lasting 6 h or more. A total of 62 patients
      were studied and they were grouped into three categories: head and neck surgery
      (n = 23), breast reconstruction (n = 18) and upper and lower limb surgery (n =
      21). Postoperative complications were recorded and the results of each group
      compared. Each of the three patient categories had a similar mean duration of
      surgery but there were large differences in postoperative morbidity between the
      three groups, e.g. within the head and neck group postoperative respiratory and
      wound complications occurred in 43% and 26% of patients, respectively. In the
      limb surgery group, however, only 5% of patients had respiratory complications
      and 5% had wound complications. Despite having similar duration of surgery the
      differences in postoperative complications between the three groups suggest that
      duration of surgery alone is not a major determinant of postoperative morbidity
      and that the type of surgery performed and the patient's general health are more
      important predictors of outcome.

PMID- 10343589
TI  - Sensory nerve repair in perforator flaps for autologous breast reconstruction:
      sensational or senseless?
AB  - The spontaneous return of sensation in autologously reconstructed breasts,
      especially in the Transverse Rectus Abdominis Myocutaneous (TRAM) flap, generated
      the belief that sensory reinnervation by nerve repair of the flap would be
      superfluous. This study compares the sensation of the following non-reconstructed
      and reconstructed breasts: (1) non-operated breasts; (2) flaps of patients
      reconstructed with the Deep Inferior Epigastric Perforator (DIEP) flap with
      sensory nerve repair; (3) flaps of patients reconstructed with the Deep Inferior
      Epigastric Perforator (DIEP) flap without nerve repair; and (4) flaps of patients
      reconstructed with the free TRAM flap without nerve repair. Statistically
      significant lower pressure thresholds were found for DIEP flaps with nerve repair
      through Semmes-Weinstein testing. More segments of the DIEP flaps with nerve
      repair reacted to cold, warm and vibratory stimuli compared to flaps without
      nerve repair. Delayed but satisfactory sensory evoked potential responses were
      obtained for all reconstructed breasts, but in 46% of TRAM flaps no response
      could be registered compared with 23% and 0% for DIEP flaps without and with
      nerve repair, respectively. Questionnaires confirmed the objective data and
      showed return of erogenous sensation in 30% of the patients with DIEP flaps with
      nerve repair. Our data reconfirm the possibility of spontaneous return of
      sensation in pedicled and/or free lower abdominal flaps without nerve repair.
      Nerve repair in free DIEP flaps nevertheless does restore sensation earlier
      postoperatively, increases the quality and quantity of sensation in the flap and
      has a higher chance of providing erogenous sensation. The benefits obtained
      outweigh the disadvantages of the increased operating time.

PMID- 10343590
TI  - A new technique of reduction mammaplasty: dermis suspension and elimination of
      medial scars.
AB  - In the last decades new techniques of reduction mammaplasty significantly
      improved the results obtained and led to a reduced incidence of complications.
      However, some important problems like the loss of a natural submammary fold and
      alteration in the shape of the breast with time still remained mostly unsolved
      and the medial scars in the inverted T techniques are aesthetically unsatisfying.
      A new strategy for reduction mammaplasty has been developed based on a
      combination of advantages of other techniques. The principle of using de
      epithelialized infra-areolar skin for dermis suspension prevents sagging of the
      remaining breast tissue behind the inframammary fold to create a long-lasting,
      natural shape of the reduced breast with an accentuated submammary fold. The
      central pedicle is favoured because of good modelling even in big reductions.
      Better vascular and nerve supply of the nipple-areola complex and the continuity
      of the lactiferous ducts are further advantages of the central pedicle. Secondary
      operations after reduction mammaplasty or augmentation usually dictate the use of
      a superior pedicle together with the dermis suspension technique. B-shaped skin
      incisions prevent medial submammary scars and can be used up to a 10 cm
      transposition distance of the nipple without disadvantage. The operative
      technique is described in detail. Examples are given for the primary procedure
      and the technique as a secondary correction. The principle of dermis suspension
      in combination with the prevention of a medial scar is applicable to reduction
      mammaplasty as well as mastopexy.

PMID- 10343591
TI  - Which technique for which breast? A prospective study of different techniques of
      reduction mammaplasty.
AB  - This study was designed to analyse the outcome of three different techniques of
      reduction mammaplasty with long-term follow-up. We developed a prospective
      protocol to record patient satisfaction and complaints as well as to objectively
      quantify the final result. The techniques used were the B-technique of Regnault,
      the Eren technique and the Frey technique. The technique was chosen according to
      a preoperatively applied protocol. Eighty-one women, all of whom exhibited
      physical symptoms of macromastia, were followed up postoperatively for 12 months
      to 5.4 years (mean 31.8 months). The relief of chronic back pain, improvement of
      mastodynia and overall satisfaction were rated by the patients subjectively and
      were reduced with all three techniques. Long-term stability of the postoperative
      result, especially of the vertical inframammary distance, was achieved in the
      techniques using a central pedicle and dermis suspension, namely the Eren and the
      Frey techniques. In smaller and medium-size reductions a medial submammary scar
      can be avoided using the Frey techniques. Complications, secondary scar and dog
      ear revisions were significantly less frequent in the techniques with B-shaped
      skin incisions. For reductions with nipple transpositions up to 10 cm we prefer
      the Frey technique. In reduction mammaplasties with nipple transpositions more
      than 10 cm the Eren technique should be performed. The free nipple-areola graft
      is the procedure of choice in the treatment of gigantomastia.

PMID- 10343592
TI  - Fasciocutaneous flaps based on fascial feeding vessels for defects in the
      periolecranon area.
AB  - Skin defects over the olecranon process are usually a result of wound dehiscence
      following trauma or following joint replacement. Rarely, breakdown occurs over
      the olecranon in degenerative joint diseases and as the result of pressure
      necrosis. We have used a fascial feeding vessel-based fasciocutaneous flap to
      reconstruct 10 defects in nine patients. The technique provides a thin and supple
      local flap that is easy to raise and is reliable.

PMID- 10343593
TI  - Long-term outcome of neurovascular palmar advancement flaps for distal thumb
      injuries.
AB  - Thirteen neurovascular palmar flaps for thumb tip coverage were reviewed: six
      O'Brien and seven Moberg flaps with a mean follow-up of 81 months. Both
      techniques were found to be safe and effective in preserving pulp sensibility,
      with a mean 2PD of 5 mm and a Semmes-Weinstein identical to the contralateral
      side in nine cases. The interphalangeal joint regained a normal range of motion,
      and did not seem to be affected by the perioperative flexion. The main residual
      complaints were persistent cold intolerance (present in all cases and severe in
      three), pulp instability (present in six and severe in two), and nail deformity.
      This last problem was more related to the injury. Despite these drawbacks,
      O'Brien and Moberg flaps remain the first choice for coverage of 1-2 cm pulp
      defects of the thumb.

PMID- 10343594
TI  - Balanitis xerotica obliterans complicating hypospadias repair.
AB  - We review the literature and report a series of eight cases of balanitis xerotica
      obliterans (BXO) developing in patients following primary hypospadias repair. The
      ages of these patients ranged from 8 to 25 years with BXO developing from 1 to 16
      years postoperatively. Six patients were treated by excision of the BXO tissue
      and two-stage urethroplasties with full-thickness grafts. Three of these patients
      had further recurrence of BXO and had re-do urethroplasty using a combination of
      bladder and buccal mucosa. The last two patients in this series had re-do
      urethroplasty using bladder mucosa only and bladder-buccal mucosa technique,
      respectively, as first choice for BXO complicating their hypospadias repair.

PMID- 10343595
TI  - Technical innovation. A modified neck incision for cervical lymphadenectomy and
      intraoral access.

PMID- 10343596
TI  - Case report. Reconstruction of damaged forehead with bilateral fasciocutaneous
      temporal V-Y-advancement island flaps.
AB  - Multiple contusions and lacerations of the anterior two-thirds of the forehead
      were treated by resection of the damaged skin and immediate reconstruction of the
      forehead with bilateral temporal artery fasciocutaneous advancement flaps.

PMID- 10343597
TI  - Case report. Initial manifestation of gout after carpal tunnel release.
AB  - A carpal tunnel release was performed on a patient with recurrent carpal tunnel
      syndrome and asymptomatic hyperuricaemia with no prior history of gouty
      arthritis. Intraoperatively, the patient was found to have tenosynovitis without
      crystals or tophaceous deposits in the carpal tunnel. Postoperatively, the
      patient developed an acutely inflamed hand, which responded dramatically to anti
      gout medications. We report this patient as an initial attack of gout after a
      carpal tunnel release.

PMID- 10343598
TI  - Clinical monitoring of free flaps in the UK.

PMID- 10343599
TI  - Consensus declaration of EQUAM.

PMID- 10343600
TI  - All foam sponges are not equal in vacuum dressings.

PMID- 10343601
TI  - Should spider naevi be treated with a large or small tunable dye laser beam
      diameter? An illustrative case report.

PMID- 10343602
TI  - A simple alternative to ear reconstruction.

PMID- 10343603
TI  - Discoloration following collagen injections.

PMID- 10343604
TI  - Genital herpes, "the new paradigm".

PMID- 10343605
TI  - DNA microsatellite instability in hyperplastic polyps, serrated adenomas, and
      mixed polyps: a mild mutator pathway for colorectal cancer?
AB  - AIM: To investigate the distribution of DNA microsatellite instability (MSI) in a
      series of hyperplastic polyps, serrated adenomas, and mixed polyps of the
      colorectum. METHODS: DNA was extracted from samples of 73 colorectal polyps
      comprising tubular adenomas (23), hyperplastic polyps (21), serrated adenomas
      (17), and mixed polyps (12). The presence of MSI was investigated at six loci:
      MYCL, D2S123, F13B, BAT-40, BAT-26, and c-myb T22, using polymerase chain
      reaction based methodology. MSI cases were classified as MSI-Low (MSI-L) and MSI
      High (MSI-H), based on the number of affected loci. RESULTS: The frequency of MSI
      increased in tubular adenomas (13%), hyperplastic polyps (29%), serrated adenomas
      (53%), and mixed polyps (83%) (Wilcoxon rank sum statistic, p < 0.001).
      Hyperplastic epithelium was present in nine of 12 mixed polyps and showed MSI in
      eight of these. MSI was mostly MSI-L. MSI-H occurred in two serrated adenomas and
      three mixed polyps. Clonal relations were demonstrated between hyperplastic and
      dysplastic epithelium in four of eight informative mixed polyps. CONCLUSIONS: The
      findings support the view that hyperplastic polyps may be fundamentally
      neoplastic rather than hyperplastic. A proportion of hyperplastic polyps may
      serve as a precursor of a subset (10%) of colorectal cancers showing the MSI-L
      phenotype, albeit through the intermediate step of serrated dysplasia. This
      represents a novel and distinct morphogenetic pathway for colorectal cancer.

PMID- 10343606
TI  - Reduced expression of alpha catenin is associated with poor prognosis in
      colorectal carcinoma.
AB  - AIMS: To investigate alpha catenin expression in surgically resected human
      colorectal cancers to evaluate its prognostic value during long term follow up.
      METHODS: Immunohistochemistry was used to compare the expression of alpha catenin
      with conventional prognostic factors in 187 colorectal cancer patients treated in
      Kuopio University Hospital and followed up for a mean of 14 years. The hypothesis
      that the intensity of expression of alpha catenin and its distribution in cancer
      cells is correlated with survival was tested with the long-rank test, hazard
      ratios, and their confidence intervals. RESULTS: Uniform membranous alpha catenin
      staining localised to the intercellular borders was observed in 46% of the
      tumours; 55% of all tumours had either heterogeneous or negative alpha catenin
      expression, and staining intensity was either negative or weak in 42% of the
      tumours. The cancer related and recurrence-free survival rates were lower among
      patients with a weak alpha catenin intensity in tumour epithelium (p < 0.001), a
      low fraction of positive tumour cells (p < 0.001), and an additional cytoplasmic
      accumulation of alpha catenin (p < 0.001). In multivariate analysis, the
      intensity of alpha catenin expression in tumour epithelium predicted cancer
      related survival independently; alpha catenin localisation in tumour epithelium
      was an independent prognostic factor of recurrence-free survival in the group as
      a whole and in the T1-3N0M0 tumour subgroup. CONCLUSIONS: A low proportion of
      positive carcinoma cells, additional cytoplasmic accumulation of alpha catenin,
      and reduced expression intensity in tumour epithelium predict a poor survival
      rate. The results suggest that alpha catenin has prognostic significance in
      colorectal cancer.

PMID- 10343608
TI  - Differential patterns of altered bone formation in different bone compartments in
      established osteoporosis.
AB  - AIM: To investigate the level of bone formation in the different bone
      compartments in cases of established osteoporosis, as previous work has
      concentrated on trabecular bone alone. METHODS: Bone formation rates were
      measured histomorphometrically, in the periosteal (P), cortical (C), subcortical
      (SC), and trabecular (T) compartments in iliac crest biopsies from 159 patients
      with established osteoporosis. The values were standardised using age and sex
      matched control data and patterns of differential change determined by analysis
      of parametric status (increased, normal, reduced). RESULTS: Mean bone formation
      was reduced in all four compartments. This was more marked (4.4/4.1 standard
      deviations below the mean in C/T, v 2.3/0.9 in P/SC) and more frequent (reduced
      in 81.5%/78.3% in T/C, v 43.3%/44% in P/SC) in the trabecular and cortical
      compartments than in the periosteal or subcortical bone. Parametric status was
      equal in trabecular and cortical bone in 85.4% of cases, and in periosteal and
      subcortical bone in 65.7%, but in all four compartments in only 35.1%, indicating
      differential alteration of bone formation in the two sets of compartments (T/C v
      P/SC). CONCLUSIONS: Altered trabecular bone formation is important in
      osteoporosis, but there are differential patterns of alteration in the other
      three compartments, emphasising the presence of different microenvironments in
      bone; thus the effect on the cortical compartment was similar to that on the
      trabecular, while the subcortical and periosteal compartments also showed
      linkage. The linkage between the two pairs was divergent, indicating different
      control of bone formation, with resultant different patterns of perturbation in
      osteoporosis.

PMID- 10343607
TI  - Distribution of 14 high risk HPV types in cervical intraepithelial neoplasia
      detected by a non-radioactive general primer PCR mediated enzyme immunoassay.
AB  - AIM: To evaluate the presence of high risk human papillomaviruses (HPV) in
      cervical smears showing intraepithelial neoplasia (CIN). METHODS: The presence of
      14 high risk HPV was evaluated in 114 cervical smears with CIN of different
      degrees, by comparing a non-radioactive polymerase chain reaction (PCR) enzyme
      immunoassay (EIA) with conventional PCR followed by radioactive Southern blot
      hybridisation. General primer PCR amplicons detecting low risk and high risk HPV
      were typed for 14 different high risk HPV types (HPV 16, 18, 31, 33, 35, 39, 45,
      51, 52, 56, 58, 59, 66, and 68) by a non-radioactive PCR-EIA. Virus load of HPV
      16 positive CIN was assessed using the semiquantitative PCR-EIA. RESULTS:
      Histological evaluation confirmed CIN I in 49 cases (mean age 29.0 years, range
      17 to 52), CIN II in 31 cases (mean age 30.8 years, 18 to 54), and CIN III in 34
      cases (mean age 31.1 years, 16 to 57). The non-radioactive PCR-EIA showed an
      overall agreement rate of 90% (kappa value 0.75) when compared with conventional
      general primer PCR followed by radioactive Southern blot hybridisation. High risk
      HPVs were detected in 47% of CIN I, 77% of CIN II, and 97% of CIN III (p < or =
      0.02). HPV types 39, 51, 56, and 58 were found in CIN I exclusively (between 2%
      and 8%). HPV 16 and HPV 31 were detected in 12% and 2% of CIN I, 35% and 21% of
      CIN II, and 74% and 13% of CIN III, respectively (p < or = 0.03 and p < or =
      0.04). The virus load estimated by the semiquantitative PCR-EIA of HPV 16 was
      similar in CIN I, CIN II, and CIN III. CONCLUSIONS: The PCR-EIA has high clinical
      sensitivity for detecting CIN II/III (90%). There was a significantly higher
      prevalence rate of HPV 16 and 31 in CIN III than in CIN I and II.

PMID- 10343609
TI  - Correlation between androgen receptor expression and FGF8 mRNA levels in patients
      with prostate cancer and benign prostatic hypertrophy.
AB  - AIM: To investigate the correlation between androgen receptor expression and
      fibroblast growth factor 8 (FGF8) mRNA levels. METHODS: 39 human prostate cancers
      and 14 benign prostatic hypertrophy specimens were examined immunohistochemically
      for androgen receptor expression and by in situ hybridisation and reverse
      transcription polymerase chain reaction for FGF8 expression. RESULTS: In 39
      tumours there was a statistically significant negative correlation between tumour
      grade and FGF8 expression and a positive correlation between FGF8 and androgen
      receptor expression. All 14 benign hypertrophy specimens expressed moderate to
      high levels of FGF8 and androgen receptor. CONCLUSIONS: Loss of FGF8 may be a
      factor involved in the development of prostatic cancer.

PMID- 10343610
TI  - Predictive value of malignancy grading systems, DNA content, p53, and
      angiogenesis for stage I tongue carcinomas.
AB  - AIM: To assess the clinical value of malignancy grading systems compared with
      nuclear DNA content, protein p53, and angiogenesis for predicting recurrence of
      stage I (UICC, 1987) tongue carcinomas. METHODS: Histopathological malignancy
      grading according to Jakobsson and tumour front grading according to Bryne et al
      were performed on haematoxylin and eosin slides. DNA analysis was performed by
      image cytometry. Protein p53 and angiogenesis were evaluated by
      immunohistochemical analysis using antibody CM1 and antibody against factor VIII
      related antigen, respectively. RESULTS: 49 patients with stage I carcinomas of
      the mobile tongue were included, all treated by local surgical excision alone.
      Eight patients (16%) suffered from local recurrence during follow up, and 13
      (27%) had regional recurrence. Both Jakobsson's malignancy grading system and p53
      immunoreactivity proved to be useful predictors of regional recurrence in a Cox
      multivariate regression analysis. CONCLUSIONS: Histopathological malignancy
      grading systems provide valuable prognostic information and can still compete
      with current biological markers in this respect.

PMID- 10343611
TI  - Differential expression of keratins 10, 17, and 19 in normal cervical epithelium,
      cervical intraepithelial neoplasia, and cervical carcinoma.
AB  - AIM: To examine the value of immunohistochemistry in defining a keratin profile
      to aid cervical histopathological diagnosis. METHODS: Immunohistochemical
      localisation of keratins 17, 10, and 19 was studied in 268 cervical biopsies from
      216 women including normal epithelia (with and without human papilloma virus),
      low and high grade cervical intraepithelial neoplasia, and invasive carcinoma.
      The percentage of positive immunostaining was scored using a Kontron MOP
      videoplan image analyser. RESULTS: All major categories of cervical epithelia
      expressed these keratins to varying degrees. The median percentage of
      immunostaining for keratin 10 was 40% in normal tissue compared with just 1% in
      invasive carcinoma (p < 0.0001). The medians for keratin 17 were 0% in the normal
      group and 80% in carcinomas (p < 0.0001). By contrast, there was no significant
      difference in staining for keratin 19. Using a combination of the keratin 10 and
      17 percentages, it was possible to separate the carcinomas from the benign
      conditions with a sensitivity of 100% and a specificity of 93%. Further analyses
      within the groups revealed more extensive staining for keratins 10 and 19 in
      reserve cell hyperplasia, immature squamous metaplasia, and congenital
      transformation zone. CONCLUSIONS: The morphological variety within the cervix is
      reflected, in part, by distinct keratin patterns. There are striking differences
      in the patterns of keratins 10 and 17 between infiltrating squamous carcinoma and
      normal cervical epithelia.

PMID- 10343613
TI  - Use of bar code readers and programmable keypads to improve the speed and
      accuracy of manual data entry in the clinical microbiology laboratory: experience
      of two laboratories.
AB  - AIM: To assess the effect of the use of bar code readers and programmable keypads
      for entry of specimen details and results in two microbiology laboratories.
      METHODS: The solutions selected in each laboratory are described. The benefits
      resulting from the implementation were measured in two ways. The speed of data
      entry and error reduction were measured by observation. A questionnaire was
      completed by users of bar codes. RESULTS: There were savings in time and in
      reduced data entry errors. Average time to enter a report by keyboard was 21.1 s
      v 14.1 s for bar coded results entry. There were no observed errors with the bar
      code readers but 55 errors with keystroke entries. The laboratory staff of all
      grades found the system fast, easy to use, and less stressful than conventional
      keyboard entry. CONCLUSIONS: Indirect time savings should accrue from the
      observed reduction in incorrectly entered data. Any microbiology laboratory
      seeking to improve the accuracy and efficiency of data entry into their
      laboratory information systems should consider the adoption of this technology
      which can be readily interfaced to existing terminals.

PMID- 10343612
TI  - Circulating antibodies to Saccharomyces cerevisiae (bakers'/brewers' yeast) in
      gastrointestinal disease.
AB  - AIM: To measure circulating antibodies to yeast organisms that could be used to
      characterise the yeast specific immune response in gastrointestinal disease.
      METHODS: A quantitative, isotype specific enzyme linked immunosorbent assay was
      developed to measure circulating antibodies to an aqueous extract of
      Saccharomyces cerevisiae (sacc). Comparisons of specific antibody concentrations
      were made between 224 healthy controls and 51 patients with Crohn's disease, 41
      with ulcerative colitis, 24 with indeterminate colitis, 23 with chronic liver
      disease, 17 with coeliac disease, and seven with irritable bowel syndrome.
      Additional comparisons were made between Crohn's disease and ulcerative colitis
      patients. Within the Crohn's disease group, the dependence of antibody levels on
      several clinical variables was assessed. RESULTS: IgG and IgA anti-sacc
      antibodies were significantly raised in Crohn's disease. IgG antibodies were also
      raised in patients with chronic liver disease. Among patients with Crohn's
      disease, IgG antibody concentrations were higher in those with serum alpha 1 acid
      glycoprotein (AAG) above the normal range and there was a strong trend towards
      increased IgG anti-sacc in the presence of small bowel disease, whereas IgA anti
      sacc correlated positively with disease duration. No differences were detected
      according to whether patients were taking steroids. Neither the Crohn's disease
      nor the chronic liver disease group differed from normal subjects in respect of
      IgG antibodies to bovine milk casein. On linear regression analysis of complete
      data from 39 Crohn's disease patients, AAG was found to be a significant
      predictor of both IgG and IgA antibodies, and male sex and disease duration to be
      additional predictors of IgA antibodies. There was a significant difference in
      IgG antibodies between Crohn's disease and ulcerative colitis. CONCLUSIONS:
      Raised antibodies to yeast, although not completely specific for Crohn's disease,
      may have a future role in diagnosis. The assays described here could be used to
      address this question in the context of a prospective study.

PMID- 10343614
TI  - Quantitation of Toxoplasma gondii DNA in a competitive nested polymerase chain
      reaction.
AB  - AIM: To quantify Toxoplasma gondii DNA using a specially constructed artificial
      template as competitor in a nested polymerase chain reaction (PCR). METHODS: The
      diagnostic assay was a nested PCR employing four primers that amplify part of the
      single copy gene for the P30 major surface antigen in T gondii. An artificial
      competitor containing the four primer binding sites was made first by creating a
      216 bp deletion in the native 914 bp full length PCR product using restriction
      enzyme digestion, ligation of selected digestion fragments, and cloning the
      ligation product into an E coli plasmid vector for production. Competitive nested
      PCR using three different quantities of T gondii genomic DNA with four
      corresponding 10-fold dilutions of the artificial competitor was then performed,
      and the results visualised with agarose gel electrophoresis. A standard curve was
      drawn by plotting the T gondii to competitor ratio readings against log10 of the
      competitor readings. RESULTS: The band intensities on agarose gel showed
      quantitative amplification in competitive nested PCR. The amount of competitor
      required to achieve equal molar amounts of PCR products is calculated by reading
      off the value of the competitor where the T gondii to competitor ratio equals 1
      on the standard curves. CONCLUSIONS: Competitive PCR is possible with a nested
      assay, and quantitative amplification is well preserved. The use of an artificial
      competitor containing the same primer binding sites as the target enables the
      absolute amount of T gondii DNA in unknown samples to be estimated. In addition,
      the competitor simultaneously serves as a control for detecting false negative
      results of failed reactions in individual assay runs.

PMID- 10343615
TI  - Human herpesvirus 6 latently infects mononuclear cells but not liver tissue.
AB  - AIM: To investigate whether human herpesvirus 6 (HHV-6) can cause latent
      infection of liver tissue. METHODS: Peripheral blood and liver tissue were
      collected from 25 living related liver transplant recipients at the time of
      transplantation. An avidin-biotin complex peroxidase method was used to identify
      HHV-6 antigen in the liver tissue. A nested polymerase chain reaction (PCR) was
      used to detect HHV-6 DNA in the liver tissue and mononuclear cells. Variant of
      HHV-6 was determined by the presence of the Hind III site in a second PCR
      product. RESULTS: Immunohistochemical analysis for HHV-6 antigen was negative in
      all the liver specimens. HHV-6 DNA was not detected in liver tissue. Virus DNA
      was detected in peripheral blood mononuclear cells in nine of 25 recipients. All
      nine HHV-6 identified in the mononuclear cells were variant B. CONCLUSIONS: HHV-6
      variant B latently infects mononuclear cells but not liver tissue.

PMID- 10343617
TI  - Small intestinal ulceration secondary to carcinoid tumour arising in a Meckel's
      diverticulum.
AB  - A solitary small intestinal ulcer associated with a carcinoid tumour in a nearby
      Meckel's diverticulum was found in a 77 year old man presenting with massive
      rectal bleeding. Angiography and a radioisotope study localised the bleeding to
      the ileum. At operation, the Meckel's diverticulum was identified, with bleeding
      from an ulcer just distal to it. Pathological examination revealed a small
      carcinoid tumour confined to the Meckel's diverticulum. Close to the opening of
      the diverticulum, within the ileum, a well demarcated ulcer was present.
      Histology showed a non-specific ulcer which eroded a large blood vessel. This is
      the first documented occurrence of solitary small intestinal ulceration in
      association with a carcinoid tumour. Carcinoid tumour should be added to the list
      of possible causes of small intestinal ulceration. The ulceration may be
      secondary to release of cytokines by the tumour.

PMID- 10343616
TI  - Infection by Rhodococcus equi in a patient with AIDS: histological appearance
      mimicking Whipple's disease and Mycobacterium avium-intracellulare infection.
AB  - Rhodococcus equi pneumonia with systemic dissemination is being reported
      increasingly in immunocompromised patients. This is the first case report of
      disseminated R equi infection with biopsy documented involvement of the large
      intestine. The patient was a 46 year old male with AIDS who was diagnosed with
      cavitating pneumonia involving the left lower lobe. R equi was isolated in
      culture from the blood and lung biopsies. Subsequently, the patient developed
      anaemia, diarrhoea, and occult blood in the stool. Colonoscopy revealed several
      colonic polyps. Histological examination of the colon biopsies showed extensive
      submucosal histiocytic infiltration with numerous Gram positive coccobacilli and
      PAS positive material in the histiocytes. Electron microscopy showed variably
      shaped intrahistiocytic organisms which were morphologically consistent with R
      equi in the specimen. Disseminated R equi infection may involve the lower
      gastrointestinal tract and produce inflammatory polyps with foamy macrophages
      which histologically resemble those seen in Whipple's disease and Mycobacterium
      avium-intracellulare infection.

PMID- 10343618
TI  - Comparison of different scoring systems for immunohistochemical staining.
AB  - AIM: To carry out an objective assessment of two systems of scoring
      immunohistochemical staining, evaluating interobserver and intraobserver error.
      METHODS: 92 cervical tumours underwent immunohistochemical staining for p53 and
      epidermal growth factor receptor. Staining was assessed using two methods: a
      standard 4 point scale and a descriptive method, performed by three observers.
      Interobserver and intraobserver error were assessed for both scoring methods.
      RESULTS: In terms of interobserver error between three observers, no difference
      was found between a simple 4 point scale method of evaluation and the use of a
      highly circumscribed method. In all evaluations, interobserver error was scored
      as moderate (kappa w 0.48-0.49). However, evaluation of immunohistochemical
      staining by a panel of observers led to a marked improvement in the interobserver
      error scores (kappa w 0.63). CONCLUSIONS: There should be standardisation of
      immunohistochemical staining and scoring methods. More attention should be paid
      to measurement of interobserver and intraobserver error in studies. Use of a
      panel of tissue control slides and consensus scoring by several observers can
      lead to improvement in reproducibility.

PMID- 10343619
TI  - KU activity.

PMID- 10343620
TI  - Bouin's fixed trephine biopsies.

PMID- 10343621
TI  - Helping people to stop smoking: the new smoking cessation guidelines.

PMID- 10343622
TI  - Medical students' knowledge of smoking.

PMID- 10343623
TI  - Re-assessing the evidence about inhaled corticosteroids in chronic obstructive
      pulmonary disease.

PMID- 10343624
TI  - Long term effects of inhaled corticosteroids in chronic obstructive pulmonary
      disease: a meta-analysis.
AB  - BACKGROUND: The role of inhaled corticosteroids in the long term management of
      chronic obstructive pulmonary disease (COPD) is still unclear. A meta-analysis of
      the original data sets of the randomised controlled trials published thus far was
      therefore performed. The main question was: "Are inhaled corticosteroids able to
      slow down the decline in lung function (FEV1) in COPD?" METHODS: A Medline search
      of papers published between 1983 and 1996 was performed and three studies were
      selected, two of which were published in full and one in abstract form. Patients
      with "asthmatic features" were excluded from the original data. Ninety five of
      the original 140 patients treated with inhaled corticosteroids (81 with 1500
      micrograms beclomethasone daily, six with 1600 micrograms budesonide daily, and
      eight with 800 micrograms beclomethasone daily) and 88 patients treated with
      placebo (of the initial 144 patients) were included in the analysis. The effect
      on FEV1 was assessed by a multiple repeated measurement technique in which points
      of time in the study and treatment effects (inhaled corticosteroids compared with
      placebo) were investigated. RESULTS: No baseline differences were observed (mean
      age 61 years, mean FEV1 45% predicted). The estimated two year difference in
      prebronchodilator FEV1 was +0.034 l/year (95% confidence interval (CI) 0.005 to
      0.063) in the inhaled corticosteroid group compared with placebo. The
      postbronchodilator FEV1 showed a difference of +0.039 l/year (95% CI -0.006 to
      0.084). No beneficial effect was observed on the exacerbation rate. Worsening of
      the disease was the reason for drop out in four patients in the treatment group
      compared with nine in the placebo group. In the treatment group six of the 95
      subjects dropped out because of an adverse effect which may have been related to
      the treatment compared with two of the 88 patients in the placebo group.
      CONCLUSIONS: This meta-analysis in patients with clearly defined moderately
      severe COPD showed a beneficial course of FEV1 during two years of treatment with
      relatively high daily dosages of inhaled corticosteroids.

PMID- 10343625
TI  - Relation of the perception of airway obstruction to the severity of asthma.
AB  - BACKGROUND: Patients with a poor perception of their symptoms of asthma seem to
      have an increased risk of an asthma attack. The influence of factors such as
      airway calibre, bronchial hyperresponsiveness, age and sex on the
      "perceptiveness" of a patient are poorly understood. It is of clinical importance
      to identify patients who are likely to have a poor perception of their symptoms.
      We have studied the perception of bronchoconstriction by asthmatic patients
      during a histamine provocation test and analysed the influence of bronchial
      obstruction, hyperresponsiveness, sex, and age. We were particularly interested
      to establish whether there was any difference in perception between subjects with
      a greater or lesser severity of asthma (expressed as bronchial obstruction,
      hyperresponsiveness). METHODS: One hundred and thirty four patients with allergic
      asthma underwent a histamine provocation test. The FEV1 was measured after each
      inhalation of histamine. Subjects were asked to rate subjective quantification of
      the sensation of breathlessness on a visual analogue scale (VAS). The
      relationship between changes in VAS values and the reduction in FEV1 as a
      percentage of the baseline value was analysed by determining the linear
      regression slope (alpha) between the two parameters and indicates the perception
      of airway obstruction. Multiple regression analysis was performed to investigate
      the effect of baseline FEV1, bronchial hyperresponsiveness, sex and age on the
      "perceptiveness" for bronchoconstriction. RESULTS: The median value of the slope
      alpha (indicating the perception of airway obstruction) was 0.91 (25-75th
      percentile: 0.48-1.45). Age and sex had no influence on the perception of
      bronchoconstriction. Both initial bronchial tone (baseline FEV1) and bronchial
      hyperresponsiveness (PC20) showed a significant correlation with the perception
      of bronchoconstriction. The regression coefficients for FEV1 and 2log PC20 in the
      multiple regression model were 0.20 and 0.10. Patients who had a low baseline
      FEV1 and/or a high bronchial responsiveness to histamine were more likely to show
      a low perceptiveness for bronchoconstriction during the challenge test.
      CONCLUSIONS: Low baseline FEV1 and high bronchial responsiveness are associated
      with a low degree of "perceptiveness" for bronchoconstriction. This suggests that
      patients with a more severe degree of asthma either show adaptation of
      "perceptiveness" for airway obstruction or that low perceptiveness leads to more
      severe asthma.

PMID- 10343626
TI  - 24 hour and fractionated profiles of adrenocortical activity in asthmatic
      patients receiving inhaled and intranasal corticosteroids.
AB  - BACKGROUND: As both rhinitis and asthma are allergic conditions, they frequently
      occur together. The objective of this study was to assess the diurnal
      adrenocortical activity in asthmatics receiving inhaled (inh) and intranasal (n)
      formulations of two different corticosteroids, fluticasone propionate (FP) and
      triamcinolone acetonide (TAA), both given at clinically recommended doses.
      METHODS: Twelve stable moderately severe asthmatic subjects of mean age 23.9
      years and mean forced expiratory volume in one second (FEV1) 84% predicted were
      recruited into a randomised placebo (PL) controlled two-way crossover study
      comparing nPL + inhPL, nPL + inhFP (880 micrograms bid), and nFP (200 micrograms
      once daily) + inhFP (880 micrograms bid) with nPL + inhPL, nPL + inhTAA (800
      micrograms bid) and nTAA (220 micrograms once daily) + inhTAA (800 micrograms
      bid), each given for five days with a 10 day washout period. Twenty four hour
      integrated and fractionated (overnight, 08.00 hours, daytime) serum cortisol
      levels and urinary cortisol/creatinine excretion were measured. RESULTS: For 24
      hour and fractionated serum cortisol levels and corrected urinary
      cortisol/creatinine excretion there were significant (p < 0.05) differences
      between all active treatments and placebo. For 24 hour integrated serum cortisol
      levels the ratio between inhaled TAA and FP was 2.3 fold (95% CI 1.2 to 4.3), and
      for 24 hour urinary cortisol/creatinine excretion the ratio was two-fold (95% CI
      1.2 to 3.4). For 24 hour urinary cortisol excretion, with all active treatments,
      individual abnormal low values of < 40 nmol (< 14.4 micrograms) occurred in 17/24
      with FP compared with 4/24 with TAA (p < 0.0005). The 24 hour serum cortisol
      profile was flattened by FP but not with TAA. The addition of nasal
      corticosteroid did not produce further significant suppression of mean cortisol
      values, although with intranasal FP there were three more abnormal values for 24
      hour urinary cortisol excretion than with inhaled FP alone. CONCLUSIONS: Both
      inhaled FP and TAA caused significant suppression of adrenocortical activity
      which was twice as great with FP, the latter being associated with significantly
      more individual abnormal values and loss of the normal diurnal circadian rhythm.
      Fractionated serum cortisol levels and urinary cortisol/creatinine excretion were
      as sensitive as the respective integrated 24 hour measurements. Although the
      addition of intranasal formulations did not produce further significant
      suppression of mean values, there were more individual abnormal cortisol values
      associated with the addition of intranasal FP.

PMID- 10343627
TI  - Respiratory symptoms and home environment in children: a national survey.
AB  - BACKGROUND: Respiratory diseases are common in childhood and may lead to chronic
      disease in adult life; environmental factors probably play an important part in
      their causation. METHODS: A survey of respiratory symptoms in children aged 12-14
      years was conducted throughout Great Britain as part of the International Study
      of Asthma and Allergies in Childhood (ISAAC). Information was obtained on certain
      aspects of the home environment in order to assess their importance as risk
      factors. RESULTS: The response rate was 79.3%, and 25,393 children in 93 schools
      participated. In a multiple regression analysis, wheeze was reported more often
      in nonmetropolitan areas and in association with active smoking, passive smoking,
      the presence of a furry pet, bottled gas, paraffin, and other unusual heating
      fuels; small regional differences persisted. Current smoking, previous smoking,
      and passive smoking accounted for 10.4%, 6.8%, and 6.5%, respectively, of
      wheezing in the past 12 months, and furry pets accounted for 5.0%. Cough and
      phlegm were associated with active and passive smoking and with the miscellaneous
      fuels; similar associations were found for rhinitis, but were less consistent for
      rhinitis occurring in spring and summer. Gas cooking showed little association
      with respiratory symptoms. CONCLUSIONS: Passive as well as active smoking is an
      important cause of respiratory symptoms in adolescence. Pets seem to increase the
      risk of wheeze and rhinitis, and fumes from certain unusual heating fuels may
      have adverse effects. Home environment and geographical location have independent
      effects on the prevalence of respiratory symptoms.

PMID- 10343628
TI  - Demonstration of bronchial eosinophil activity in seasonal allergic rhinitis by
      induced plasma exudation combined with induced sputum.
AB  - BACKGROUND: Patients with seasonal allergic rhinitis may develop bronchial
      hyperresponsiveness during the active disease period. Eosinophil activation may
      occur in the bronchial mucosa and may be reflected by increased sputum levels of
      eosinophil cationic protein (ECP), especially when ECP binding proteins such as
      alpha 2-macroglobulin pass through the lamina propria and across the epithelium
      into the airway lumen. A study was therefore undertaken to determine histamine
      airway responsiveness (FEV1) and bronchovascular responsiveness (exudation of
      alpha 2-macroglobulin) to histamine in subjects with seasonal allergic rhinitis,
      and to explore whether sputum ECP levels are increased by the use of induced
      exudation followed by induced sputum. METHODS: Eleven patients with seasonal
      allergic rhinitis were examined before and during a birch pollen season. Sputum
      was induced by inhalation of 4.5% saline twice before and twice during the pollen
      season. Histamine inhalations were given before the second of each pair of sputum
      inductions at increasing concentrations until FEV1 was reduced by 20%. Sputum
      levels of alpha 2-macroglobulin and ECP were determined as indices of bronchial
      exudation of plasma and activation of bronchial eosinophils, respectively.
      RESULTS: Bronchomotor responsiveness increased during the pollen season (median
      difference in the reduction of FEV1 9% (95% confidence interval (CI) -3 to 26))
      but histamine induced exudation of plasma was not increased. Baseline sputum
      levels of alpha 2-macroglobulin and ECP did not increase. Histamine induced
      exudation of alpha 2-macroglobulin was associated with increased sputum levels of
      ECP exclusively during the pollen season (median difference 8.2 ng/ml (95% CI 0.4
      to 562.0)). CONCLUSION: Bronchial hyperresponsiveness in seasonal allergic
      rhinitis may not be associated with bronchovascular exudative
      hyperresponsiveness. Sputum levels of ECP were increased only during the season,
      and only after induced exudation (potentially moving ECP to the mucosal surface).
      It is suggested that the combined method of induced exudation and induced sputum
      may significantly improve the yield of some markers of inflammation in sputum
      samples.

PMID- 10343629
TI  - Effect of methacholine challenge on cellular composition of sputum induction.
AB  - BACKGROUND: Induced sputum and methacholine inhalation challenge are routinely
      used for the assessment of airway inflammation and airway hyperresponsiveness,
      respectively. This study investigates whether a methacholine challenge performed
      one hour before sputum induction alters the cellular and biochemical constituents
      of sputum. METHODS: Sixteen stable asthmatic patients with lung function within
      the normal range underwent two sputum inductions within one week. One hour before
      one of the sputum inductions a methacholine challenge was performed. RESULTS:
      There were no significant differences in total cell count, macrophages,
      neutrophils, eosinophils, lymphocytes, epithelial cells, ECP, and albumin between
      the two challenges. The repeatability of cell counts was good for all cells, ECP
      and albumin, but poor for total cells. CONCLUSIONS: In patients with stable
      asthma a methacholine challenge carried out one hour before sputum induction does
      not significantly alter the cellular and biochemical constituents of sputum.

PMID- 10343630
TI  - Diagnosis of cystic fibrosis related diabetes: a selective approach in performing
      the oral glucose tolerance test based on a combination of clinical and
      biochemical criteria.
AB  - BACKGROUND: Cystic fibrosis related diabetes (CFRD) has become increasingly
      common with the increasing longevity of patients with cystic fibrosis. The
      diagnosis of CFRD is important as its development may lead to a clinical
      deterioration which may be reversed with treatment. The oral glucose tolerance
      test (OGTT) is the method of choice in the diagnosis of CFRD, but performing
      OGTTs on all patients is inconvenient for patients and labour intensive for
      staff. The aim of this study was to identify a more selective approach in
      performing OGTTs in the diagnosis of CFRD based on the use of a combination of
      clinical and biochemical criteria. METHODS: Clinically stable adult patients with
      cystic fibrosis not known to be diabetic attending the Royal Brompton Hospital
      Cystic Fibrosis Clinic for their annual review were invited to return within a
      month to have an OGTT. The result of the OGTT was compared with the results of
      tests performed during the annual review. The sensitivities and specificities of
      various methods used in the screening or diagnosis of CFRD were determined using
      OGTT as the "gold standard" diagnostic method. The combination of clinical and
      biochemical criteria which resulted in the highest sensitivity and specificity in
      the diagnosis of CFRD was determined. RESULTS: Between August 1996 and May 1997
      122 patients became eligible for the study, 91 of whom agreed to take part. The
      number of patients with normal, impaired, and diabetic glucose tolerance was 58
      (64%), 21 (23%), and 12 (13%), respectively. When used alone, abnormal
      glycosylated haemoglobin (HbA1c) was found to have the highest sensitivity (83%;
      95% CI 62 to 100) in the diagnosis of CFRD. The combination of an abnormal random
      blood glucose and/or abnormal HbA1c and/or symptoms of hyperglycaemia or weight
      loss was found to have the highest sensitivity (92%; 95% CI 76 to 100) in the
      diagnosis of CFRD. The specificity of this combination in the diagnosis of CFRD
      was 79% (95% CI 70 to 88). By selectively performing OGTTs in patients with one
      or more of the criteria cited above, 11 of the 12 patients with OGTT defined
      diabetes would have been identified. CONCLUSIONS: Patients with cystic fibrosis
      already have to undergo a large number of routine investigations. The selective
      approach in performing OGTTs described here has the potential to identify the
      majority of patients with CFRD without the need to perform this investigation on
      all patients. This approach is likely to be welcomed by patients and will lead to
      significant savings in terms of time and resources for patients and staff.
      Further larger studies are warranted to validate this selective approach in the
      diagnosis of CFRD.

PMID- 10343631
TI  - Specific IgG subclass antibody pattern to Aspergillus fumigatus in patients with
      cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA).
AB  - BACKGROUND: IgG and IgG subclass antibodies to Aspergillus fumigatus (A
      fumigatus) were measured in a large population of patients with cystic fibrosis
      to elucidate a putative antibody pattern specific for allergic bronchopulmonary
      aspergillosis (ABPA). METHODS: An ELISA technique using water soluble somatic
      hyphal (WSSH) A fumigatus antigens and subclass specific monoclonal antibodies
      was used for cross sectional quantification of IgG and IgG1-4 subclass antibody
      levels in the serum of 238 patients with cystic fibrosis and 107 healthy
      controls. RESULTS: In patients with cystic fibrosis persistently colonised with A
      fumigatus the subclass antibody levels were significantly increased compared with
      patients with cystic fibrosis never or rarely colonised (p < 0.001). The group of
      patients persistently colonised with A fumigatus with ABPA (+Af+ABPA) had
      significantly increased levels of IgG antibodies to A fumigatus (Af-IgG) (median
      69 ELISA units (EU) versus 31) and of subclasses Af-IgG1 (91 versus 27), Af-IgG2
      (143 versus 56), and Af-IgG4 antibodies (72 versus 20), but not of IgG3 (17
      versus 15), compared with the colonised patients without ABPA (+Af-ABPA).
      Patients with cystic fibrosis with no or only rare isolates of A fumigatus
      without ABPA (-Af-ABPA) also had significantly increased subclass antibody levels
      (Af-IgG1 9 versus 3, Af-IgG2 28 versus 5, Af-IgG4 16 versus 4; p < 0.001)
      compared with healthy controls. Low, although detectable, levels of antibodies
      were demonstrated in healthy controls. ABPA seemed to occur independently of
      Pseudomonas aeruginosa infection. Using diagnostic cut off levels for ABPA,
      sensitivity and specificity were calculated. The highest specificity was found
      for IgG4 (88%); sensitivity was between 65% and 73%. The positive predictive
      values (PPV) were moderate, whereas the negative predictive values (NPV) were
      high (96% in all subclasses except IgG3 with 94%). PPV increased to 50% if IgG1
      as well as IgG2 and IgG4 were included. CONCLUSIONS: In a large number of
      unselected patients with cystic fibrosis significantly increased levels of Af
      specific antibodies belonging to total IgG and all four subclasses were found in
      all groups of patients compared with healthy controls. In patients persistently
      colonised with A fumigatus these levels were significantly higher than in non
      colonised patients, and the significantly highest levels (with the exception of
      IgG3) were found in patients with ABPA. Using a sensitive ELISA technique,
      measurements of IgG and IgG subclass antibodies to A fumigatus might be of
      importance in the management of ABPA, especially as a screening test to exclude
      the presence of ABPA; other tests are needed to confirm the diagnosis.

PMID- 10343632
TI  - Circulating interleukin 6 and interleukin 10 in community acquired pneumonia.
AB  - BACKGROUND: Inflammatory cytokine concentrations correlate with severity of
      sepsis. We hypothesised that patients with community acquired pneumonia (CAP)
      associated with systemic inflammatory response syndrome (SIRS) would have greater
      interleukin 6 (IL-6) production due to activation of the inflammatory cytokine
      cascade, matched by a significant anti-inflammatory cytokine response.
      Interleukin 10 (IL-10) was evaluated as a potential surrogate marker of severity
      of sepsis in CAP and age related impairment of the cytokine response was studied
      in elderly patients with CAP. METHODS: Circulating immunoreactive IL-6 and IL-10
      levels were measured in 38 patients with CAP subdivided into a group fulfilling
      the criteria for SIRS (n = 28) and a non-SIRS group (n = 10) in a variety of age
      groups and correlated with APACHE II scores. RESULTS: 80% had circulating IL-6
      levels (median 46.7 pg/ml, range 4.6-27,000) and 60% had circulating IL-10 levels
      (median 15.5 pg/ml, range 2.5-765). Concentrations of both were significantly
      increased in patients with SIRS compared with non-SIRS patients. Those with
      activation of the inflammatory cytokine cascade (IL-6 positive) produced more IL
      10 than IL-6 negative patients. Older patients had a similar cytokine response.
      Both cytokines correlated positively with APACHE II scores. CONCLUSIONS: This is
      the first demonstration of circulating IL-10 in CAP. A greater counter
      inflammatory response in patients with SIRS and in IL-6 positive patients
      suggests a potential immunomodulatory role for IL-10 in controlling the
      inflammatory cytokine response in CAP. IL-10 concentrations correlate with
      severity of illness in CAP and may be of prognostic importance. There is no age
      related impairment in the cytokine response.

PMID- 10343633
TI  - Crystalline silica exposure, radiological silicosis, and lung cancer mortality in
      diatomaceous earth industry workers.
AB  - BACKGROUND: The role of silicosis as either a necessary or incidental condition
      in silica associated lung cancer remains unresolved. To address this issue a
      cohort analysis of dose-response relations for crystalline silica and lung cancer
      mortality was conducted among diatomaceous earth workers classified according to
      the presence or absence of radiological silicosis. METHODS: Radiological
      silicosis was determined by median 1980 International Labour Organisation system
      readings of a panel of three "B" readers for 1809 of 2342 white male workers in a
      diatomaceous earth facility in California. Standardised mortality ratios (SMR)
      for lung cancer, based on United States rates for 1942-94, were calculated
      separately for workers with and without radiological silicosis according to
      cumulative exposures to respirable crystalline silica (milligrams per cubic meter
      x years; mg/m3-years) lagged 15 years. RESULTS: Eighty one cases of silicosis
      were identified, including 77 with small opacities of > or = 1/0 and four with
      large opacities. A slightly larger excess of lung cancer was found among the
      subjects with silicosis (SMR 1.57, 95% confidence interval (CI) 0.43 to 4.03)
      than in workers without silicosis (SMR 1.19, 95% CI 0.87 to 1.57). An association
      between silica exposure and lung cancer risk was detected among those without
      silicosis; a statistically significant (p = 0.02) increasing trend of lung cancer
      risk was seen with cumulative exposure, with SMR reaching 2.40 (95% CI 1.24 to
      4.20) at the highest exposure level (> or = 5.0 mg/m3-years). A similar
      statistically significant (p = 0.02) dose-response gradient was observed among
      non-silicotic subjects when follow up was truncated at 15 years after the final
      negative radiograph (SMR 2.96, 95% CI 1.19 to 6.08 at > or = 5.0 mg/m3-years),
      indicating that the association among non-silicotic subjects was unlikely to be
      accounted for by undetected radiological silicosis. CONCLUSIONS: The dose
      response relation observed between cumulative exposure to respirable crystalline
      silica and lung cancer mortality among workers without radiological silicosis
      suggests that silicosis is not a necessary co-condition for silica related lung
      carcinogenesis. However, the relatively small number of silicosis cases in the
      cohort and the absence of radiographic data after employment limit
      interpretations.

PMID- 10343634
TI  - Simian virus 40 and human pleural mesothelioma.
AB  - BACKGROUND: An aetiological role for Simian virus 40 (SV40) in malignant
      mesothelioma has been suggested from studies in the USA and the UK but results
      have been conflicting. A study was undertaken to look for evidence of SV40 in
      stored tissue samples from pleural mesotheliomas. METHODS: DNA was extracted from
      paraffin embedded tissue. The presence of DNA was established by amplification of
      a 250 bp product from the betaglobin gene. Primers PYV.F and PYV.R were used in a
      concentration of 50 per mol each per reaction to amplify a 172 bp fragment of a
      conserved region of SV40 that codes for a portion of large T antigen that is
      common to SV40 and other polyoma viruses. RESULTS: Twelve of the 17 samples
      contained amplifiable betaglobin DNA. None of the samples (0/12, 95% CI 0 to
      26.5%) was positive for the polyoma large T antigen. CONCLUSIONS: These results
      do not lend any support to the hypothesis that SV40 infection may be
      aetiologically relevant to the increasing incidence of mesothelioma in the UK.

PMID- 10343635
TI  - Cough threshold in patients with chronic obstructive pulmonary disease.
AB  - BACKGROUND: Cough is an important symptom of patients with chronic obstructive
      pulmonary disease (COPD). The cough threshold to citric acid and capsaicin in
      patients with COPD and in normal volunteers was measured, as well as bronchial
      hyperresponsiveness to methacholine. METHODS: Nineteen patients with COPD and 22
      controls were recruited. Subjects underwent a methacholine bronchoprovocation
      test and a cough challenge to citric acid and capsaicin. RESULTS: The log citric
      acid cough threshold D2 (concentration causing two coughs) was significantly
      lower in patients with COPD (mean 2.17 versus 2.56, mean difference (95% CI) 0.39
      (0.04 to 0.74), p = 0.02) but not for capsaicin cough D2 (0.66 versus 0.8, p =
      0.41). Sixteen patients with COPD had bronchial hyperresponsiveness which was
      correlated with baseline FEV1 (r = 0.6, p = 0.01, 95% CI 0.15 to 0.84).
      CONCLUSIONS: Patients with COPD have a lower cough threshold to citric acid,
      possibly due to a differential effect of cigarette smoke on citric acid sensitive
      cough receptors.

PMID- 10343636
TI  - Genetics and pulmonary medicine 8: asthma.
AB  - The field of asthma genetics has evolved in a markedly short time into a research
      field which potentially can provide a new level of understanding on the
      pathophysiology of the disease. There is consensus over a number of candidate
      genes that are likely to be important in the disease and also in chromosomal
      regions likely to contain other novel genes. It is, however, clear that there is
      no single major genetic risk factor for the development of asthma and the
      development of the disease in an individual will depend upon the interaction of a
      number of genes of moderate effect with environmental factors.

PMID- 10343638
TI  - Application of functional genomics to study of inflammatory airways disease.

PMID- 10343637
TI  - Teaching medical students about tobacco.

PMID- 10343639
TI  - Elastic pressure-volume curves: what information do they convey?

PMID- 10343640
TI  - Mast cell chymase in pulmonary hypertension.
AB  - Mast cells are known to be involved in various types of tissue remodelling but
      their role in pulmonary hypertension is still poorly understood. Two subtypes of
      mast cells have recently been identified by demonstrating one protease, chymase.
      This enzyme might be implicated in vascular remodelling. The changes in mast
      cells in lung tissue from three patients with primary or secondary pulmonary
      hypertension were therefore investigated. Compared with tissue from four control
      subjects the number of mast cells in the three patients was markedly increased,
      which suggests that chymase containing mast cells are involved in tissue
      remodelling accompanied by fibrotic changes in primary and secondary pulmonary
      hypertension.

PMID- 10343641
TI  - Comparison of the in vitro and in vivo response to inhaled DNase in patients with
      cystic fibrosis.

PMID- 10343642
TI  - Domiciliary NIPPV in COPD.

PMID- 10343643
TI  - Burkholderia cepacia bronchiectasis.

PMID- 10343644
TI  - Childhood empyema.

PMID- 10343645
TI  - Adrenal function in asthmatic children.

PMID- 10343646
TI  - Serum angiotensin converting enzyme.

PMID- 10343647
TI  - 1998 Mutation Research Award for Scientific Excellence. Dr. Thomas Kunkel.

PMID- 10343648
TI  - Short interspersed DNA element-mediated detection of UVB-induced DNA damage and
      repair in the mouse genome, in vitro, and in vivo in skin.
AB  - We report a sensitive, SINE (Short Interspersed DNA Element)-mediated, PCR-based,
      DNA damage detection assay. Here, the SINE assay is used for detection of UVB
      induced DNA damage and repair in cultured mouse cells and in vivo, in mouse skin.
      The unique feature of the SINE assay is its ability to support simultaneous
      amplification of multiple, random segments of genomic DNA. This can be
      accomplished due to the remarkable abundance, dispersion and conservation of
      SINEs in mammalian genomes. The most abundant SINEs in the mouse genome are the
      B1 elements, at a copy number of 50,000-80,000. Due to their strong sequence
      conservation, primers complementary to the B1 consensus sequence anneal to the
      majority of their targets in the genome. Consequently, long segments of genomic
      DNA located between pairs of B1 elements are efficiently amplified by PCR. Thus,
      in conjunction with the fact that many types of DNA adducts form blocks for
      thermostable polymerase, the B1 element anchored PCR makes a sensitive and
      versatile tool for assessing the overall integrity of the transcribed regions in
      mouse genome. We measured UVB-dose (0.1-3 kJ m-2) dependent formation of
      photoproducts in DNA from cultured cells, and after 20 h observed a substantial
      removal of damage at doses lower or equal to 0.6 kJ m-2. The sensitivity of
      detection of UVB-photoproducts formation and repair was compared to that of the
      conventional, single locus-targeting QPCR. Using the SINE assay we also have
      shown the distribution of UVB and UVC induced DNA adducts at a single nucleotide
      resolution within the B1 elements in mouse DNA. Lastly, we demonstrated that the
      sensitivity of the SINE assay is adequate for measurement of UVB-dose (1-6 kJ m
      2) dependent formation and subsequent removal of photoproducts in vivo, in mouse
      skin.

PMID- 10343649
TI  - Analysis of intrachromosomal homologous recombination in mammalian cell, using
      tandem repeat sequences.
AB  - In all the organisms, homologous recombination (HR) is involved in fundamental
      processes such as genome diversification and DNA repair. Several strategies can
      be devised to measure homologous recombination in mammalian cells. We present
      here the interest of using intrachromosomal tandem repeat sequences to measure HR
      in mammalian cells and we discuss the differences with the ectopic plasmids
      recombination. The present review focuses on the molecular mechanisms of HR
      between tandem repeats in mammalian cells. The possibility to use two different
      orientations of tandem repeats (direct or inverted repeats) in parallel
      constitutes also an advantage. While inverted repeats measure only events arising
      by strand exchange (gene conversion and crossing over), direct repeats monitor
      strand exchange events and also non-conservative processes such as single strand
      annealing or replication slippage. In yeast, these processes depend on different
      pathways, most of them also existing in mammalian cells. These data permit to
      devise substrates adapted to specific questions about HR in mammalian cells. The
      effect of substrate structures (heterologies, insertions/deletions, GT repeats,
      transcription) and consequences of DNA double strand breaks induced by ionizing
      radiation or endonuclease (especially the rare-cutting endonuclease ISce-I) on HR
      are discussed. Finally, transgenic mouse models using tandem repeats are briefly
      presented.

PMID- 10343650
TI  - The effect of the Saccharomyces cerevisiae endo-exonuclease NUD1 gene expression
      on the resistance of HeLa cells to DNA-damaging agents.
AB  - HeLa cells transiently transfected with a mammalian expression DNA vector
      expressing the Saccharomyces cerevisiae endo-exonuclease (EE) NUD1 gene have
      exhibited changes in cell survival frequencies after treatment with different DNA
      damaging agents as compared to HeLa cells transfected with a control plasmid. The
      NUD1-transfected cells showed a dose-dependent increase in sensitivity to UV
      irradiation resulting in up to 58% decrease in cell survival. In response to
      gamma-irradiation NUD1 transfected cells featured an increased survival at doses
      equal to and greater than 2.0 Gy, reaching a maximum enhancement in survival
      frequency of 17%. At the same time, the NUD1-transfectants featured an increase
      in resistance to 0.25 microM-0.5 microM cis-platin (up to 58% increase in cell
      survival) and 1.0 mM EMS (11% increase). At higher concentrations of EMS NUD1
      expression resulted in a decreased cell survival of the transfected cells (17%
      decrease for 2.5 mM EMS). No difference in cell survival frequencies between the
      NUD1-transfectants and the controls was observed after treatment with different
      concentrations of chlorambucil and mechlorethamine. These results suggest
      possible roles played by EEs in different DNA repair pathways--being stimulatory
      for the repair of certain types of DNA lesions, such as double strand breaks
      (DSBs), and interfering with the endogenous DNA repair systems for the repair of
      other types of lesions. Furthermore, these results also provide additional
      indirect evidence for the role of EEs in homologous recombination.

PMID- 10343651
TI  - A new DNA polymerase species from Drosophila melanogaster: a probable mus308 gene
      product.
AB  - Harris et al. [P.V. Harris, O.M. Mazina, E.A. Leonhardt, R.B. Case, J.B. Boyd,
      K.C. Burtis, Molecular cloning of Drosophila mus308, a gene involved in DNA cross
      link repair with homology to prokaryotic DNA polymerase I genes, Mol. Cell.
      Biol., 16 (1996) 5764-5771.] reported the molecular cloning of Drosophila mus308
      gene, and its nucleotide and protein sequences similar to DNA polymerase I. In
      the present study, we attempted to find and isolate the gene product by purifying
      a DNA polymerase fraction not present in mus308 flies. A new DNA polymerase with
      properties different from those of any known polymerase species was identified
      and partially purified from the wild-type fly embryos through ten column
      chromatographies. The enzyme was resistant to aphidicolin, but sensitive to ddTTP
      and NEM. Human proliferating cell nuclear antigen (PCNA) and Drosophila
      replication protein A (RP-A) did not affect the polymerase activity. It preferred
      poly(dA)/oligo(dT) as a template-primer. The molecular mass was about 230 kDa
      with a broad peak region of 200 to 300 kDa in HiPrep16/30 Sephacryl S-300 gel
      filtration. These properties a different from those of all reported Drosophila
      polymerase classes such as alpha, beta, gamma, delta, epsilon and zeta and
      closely resemble those of the gene product expected from the nucleotide sequence.
      The new polymerase species appears to have ATPase and 3'-5' exonuclease
      activities as shown by the chromatographies.

PMID- 10343652
TI  - Misrejoining of DNA double-strand breaks in primary and transformed human and
      rodent cells: a comparison between the HPRT region and other genomic locations.
AB  - Many studies of radiation response and mutagenesis have been carried out with
      transformed human or rodent cell lines. To study whether the transfer of results
      between different cellular systems is justified with regard to the repair of
      radiation-induced DNA double-strand breaks (DSBs), two assays that measure the
      joining of correct DSB ends and total rejoining in specific regions of the genome
      were applied to primary and cancer-derived human cells and a Chinese hamster cell
      line. The experimental procedure involves Southern hybridization of pulsed-field
      gel electrophoresis blots and quantitative analysis of specific restriction
      fragments detected by a single-copy probe. The yield of X-ray-induced DSBs was
      comparable in all cell lines analyzed, amounting to about 1 x 10(-2)
      breaks/Mbp/Gy. For joining correct DSB ends following an 80 Gy X-ray exposure all
      cell lines showed similar kinetics and the same final level of correctly rejoined
      breaks of about 50%. Analysis of all rejoining events revealed a considerable
      fraction of unrejoined DSBs (15-20%) after 24 h repair incubation in the tumor
      cell line, 5-10% unrejoined breaks in CHO cells and complete DSB rejoining in
      primary human fibroblasts. To study intragenomic heterogeneity of DSB repair, we
      analyzed the joining of correct and incorrect break ends in regions of different
      gene density and activity in human cells. A comparison of the region Xq26
      spanning the hypoxanthine guanine phosphoribosyl transferase locus with the
      region 21q21 revealed identical characteristics for the induction and repair of
      DSBs, suggesting that there are no large variations between Giemsa-light and
      Giemsa-dark chromosomal bands.

PMID- 10343653
TI  - Case study of a deaf/blind person with a cochlear implant.
AB  - This paper accompanies a poster presentation demonstrating outcomes after
      cochlear implantation of a deaf/blind person. In particular, changes in the
      patients voice quality and improvements in her pragmatic skills will be
      discussed.

PMID- 10343654
TI  - The Speech and Language Therapy Research Unit at Frenchay Hospital, Bristol.

PMID- 10343655
TI  - Innovation and partnership: the voluntary sector contribution.
AB  - I CAN building on its long experience of integrating education and speech and
      language therapy in its specialist speech and language schools, has pioneered a
      variety of new approaches to collaborative working for the benefit of children.
      This paper describes three examples of relatively new services: Specialist
      nurseries; Teach Speech: a pilot project for primary aged children using
      videoconferencing; and Secondary School Language Resources within mainstream
      schools. Studies to evaluate the effectiveness of some of the services are also
      reported. All three types of service described demonstrate effective
      collaboration between at least two of the following three sectors: voluntary,
      statutory and private. The potential and benefits of this collaboration are
      highlighted.

PMID- 10343656
TI  - Changes in referral to speech and language therapy.
AB  - This is a retrospective study of data collected on an information system,
      developed specifically for the use of speech and language therapists and used by
      eleven health care providers since 1985. Information prior to 1987 contain the
      artefacts of new technology and backload logging. Thus this paper reflects data
      from 1987 to 1995. Information on 70,000 clients amalgamated from these trusts
      allow us to reflect upon the changes in speech and language therapy over that
      period. The annual referral rate to these eleven trusts in 1987 was 4,129. The
      annual referral rate for the same trusts in 1995 had risen to 11,945. The
      percentage referrals per head of population per year varies between 0.32% and
      0.58% of the population.

PMID- 10343657
TI  - Screening for primary speech and language delay: a systematic review of the
      literature.
AB  - Screening young children for developmental conditions such as speech and language
      delay is considered to be a part of the Child Health Surveillance programme in
      the UK. It is currently practised in many different ways throughout the country
      and like screening for other conditions conventionally identified in infancy, has
      been the subject of some concern for those responsible for providing such
      services. This systematic review (Law et al. 1998) was hypothesis driven and
      aimed to: i) establish whether, given the available evidence, there was
      sufficient evidence to warrant the introduction of universal screening for speech
      and language delays in children up to seven years of age; ii) identify gaps in
      the available literature; iii) identify priority areas in need of further
      investigation and iv); provide evidence-based recommendations for the future
      provision of services.

PMID- 10343658
TI  - The effect of intrathecal baclofen on functional intelligibility of speech.

PMID- 10343659
TI  - Supporting practitioner research in speech and language therapy.
AB  - This paper discusses the characteristics of action research and promotes its
      potential for speech and language therapists. Action research is an approach
      which involves the practitioner and has as its purpose the improvement of
      practice. Small-scale studies by practitioners can be used to examine practical
      applications and implications of larger-scale studies. A group of therapists,
      motivated by a wish to investigate their own practice, proposed the development
      of a group to support their work, facilitated by the author.

PMID- 10343660
TI  - Running a randomised controlled trial in a service setting: a progress report.
AB  - This paper will give a progress report on a randomised controlled trial which is
      currently underway in the Bristol area. Some of the key influencing literature
      will be summarised, followed by an overview of the study design. The paper will
      also highlight some of the methodological and practical advantages and
      disadvantages afforded by the service setting of the study.

PMID- 10343661
TI  - An audit tool for health visitors and SLTs working with the pre-school
      population.
AB  - This paper will present the preliminary findings of a national Royal College of
      Speech and Language Therapists audit of speech and language therapy and health
      visiting services to the pre-school population. The audit was carried out in six
      districts of the United Kingdom, representing a broad range of locations and
      models of service delivery. The purpose of the audit was to evaluate specific
      aspects of the management of children with speech and language difficulties.
      Audit tools were applied to referral and selection procedures, inservice training
      and parent programmes. Preliminary findings and their implications are discussed.

PMID- 10343662
TI  - CleftNet (Scotland): a network for the treatment of cleft palate speech using
      EPG.
AB  - Electropalatography (EPG) has proven its effectiveness in changing abnormal
      articulatory placement in cleft palate speech but clinicians often do not have
      ready access to such equipment. In order to improve access to EPG therapy, a
      network has been established which electronically links cleft palate centres
      throughout Scotland with EPG specialists based at Queen Margaret College (QMC),
      Edinburgh. The network was set up through a collaborative project entitled
      'CleftNet Scotland', funded by the Scottish Office Department of Health. In this
      paper, the rationale and overarching aims of CleftNet Scotland are described and
      the efficacy of this form of EPG therapy illustrated by descriptions of two
      cases.

PMID- 10343663
TI  - An audit of personal logs--1997.
AB  - Since 1991 all registered members of the Royal College of Speech and Language
      Therapists (RCSLT) have made a personal commitment to continuing education and
      continuing professional development (CPD). To support this commitment individual
      members have been required each year to complete a personal log of appropriate
      activities. The 1996-97 Department for Education and Employment (DfEE)/RCSLT
      'Lifetime Learning Project' aimed to enhance and develop CPD services for
      members. One strand of the project was to make more use of the data available
      through and audit of members' personal logs. The range of CPD activities recorded
      were examined in relation to the type of practive, location, grade and work
      setting of respondents.

PMID- 10343664
TI  - Outcome measurement for children with specific speech and language impairment.

PMID- 10343665
TI  - The use of a paediatric speech and language therapy outcome measurement scale.
AB  - This research aimed to evaluate the inter- and intra-rater reliability of a
      locally developed paediatric speech and language therapy (SLT) outcome measure,
      the NBOM (Northern Birmingham Outcome Measures), immediately after 15 speech and
      language therapists (SLTs) had taken part in training then after a period of
      time. It was found that SLTs who had received more than the basic orientation
      training achieved a higher level of reliability than those who had not but after
      5 months training effects were fading. It seems that as well as requiring
      training and practice on the scales, SLTs also needed increased scaling
      definition, protocols and anchor stimuli to help with the interpretation of
      information and the assigning of rating points. Finally, scales were apparently
      used more reliably within an 'overt' rating session than in everyday clinical
      settings.

PMID- 10343666
TI  - Communicate: organisational issues and their relevance for clinical evaluation.
AB  - This paper reports the first findings of a two year project funded by the NHS
      Executive North Thames to provide an independent evaluation of Communicate,
      Action for Dysphasic Adults' training programme for carers of older people with
      communication impairments. The project comprises an organisational evaluation
      (January-July 1998) to review the use of Communicate by purchasers nationally and
      in the North Thames health region, and (from September 1998) a clinical
      evaluation in North Thames region, to investigate outcomes for communicatively
      impaired people themselves and for training participants. The paper outlines the
      research design and progress so far before presenting initial findings. It
      concludes by discussing the relevance of organisational issues and social science
      research insights to the forthcoming clinical evaluation.

PMID- 10343667
TI  - Addressing the needs of a clinical service in the operational constraints of
      commissioning.
AB  - Limited resources, increased demand and current commissioning structures has put
      the rationalisation of health care high on the agenda. Any prioritisation process
      needs to be clinically led and client driven so reactive ad hoc arrangements are
      minimised and structures for good practice enabled. This paper argues that the
      current context be used as an opportunity to critically evaluate the services
      speech and language therapy aim to provide. By defining our aims and
      demonstrating the range and boundaries of our effect we can be proactive in
      structuring our services appropriately. Such an exercise currently underway in
      City and Hackney is outlined which aims to: describe an optimum structure for
      provision and the resources required, propose possible models within current
      resource and highlight the gap between the two.

PMID- 10343668
TI  - Three into one will go! Collaborative practice in practice.
AB  - This paper is concerned with three speech and language therapy services from
      neighbouring NHS trusts and the single education authority they all share. The
      authors have always been committed to working collaboratively with local services
      but found the competitive health care environment of the late 1980s and early
      1990s often-made this difficult. It describes how the three services came
      together to identify common service issues for children of school-age with speech
      and language difficulties and how these were addressed.

PMID- 10343669
TI  - What is the outcome of the outcomes? Evaluation of the therapy outcome measures.
AB  - In 1996, the Speech and Language Therapy Departments of First Community Health
      NHS Trust and Kidderminster Care NHS Trusts agreed to take part in a year's pilot
      study of the Therapy Outcome Measures developed by Enderby and John (1997). This
      paper will discuss the rationale for choosing to pilot these outcome measures and
      discuss the implementation of the project from a service manager's perspective.
      The discussion will focus upon what has been learnt from piloting the Therapy
      Outcome Measures.

PMID- 10343670
TI  - An audit of clinical placements.
AB  - Clinical teaching of students is a requirement of the majority of practicing
      therapists in the UK and yet there is little guidance as to the nature of the
      placement which needs to be offered. As models of service delivery change,
      placements must change to prepare the student for working life whilst also
      meeting the need for solid foundation experiences. The audit reported here
      examined current placements including the physical setting, level of supervision
      provided and the responsibilities described by the professional body (Royal
      College of Speech and Language Therapists 1996) The results are discussed in the
      context of their implications for the educational establishment and the clinical
      teaching setting.

PMID- 10343671
TI  - Developing critical practice: a South African's perspective.
AB  - The manner in which speech and language therapy (SLT) considers communicating
      evidence of practice with a multicultural clientele is considered in context of
      cultural imperialism. A conceptual framework (i.e., the curriculum of practice)
      developed from a South African study (Pillay 1997), is highlighted for use in
      understanding, evaluating and communicating evidence of practice with the
      clientele in focus. The lens (or paradigm) used by SLT to view its curriculum of
      practice may reveal different stories about the same subject. Given this, the
      critical paradigm is proffered over that of the empirical-analytical (or
      'scientific') and hermeneutic-interpretive types of paradigms. Finally,
      suggestions regarding the development of critical SLT are discussed.

PMID- 10343672
TI  - Setting speech and language therapy priorities: theory and practice.
AB  - Within speech and language therapy (SLT) systems for prioritising treatment
      waiting lists are emerging in response to demand exceeding resources and
      difficult decisions having to be made. This study evaluates the theoretical
      issues, the methods and criteria SLTs use to prioritise caseloads and the
      relationship between priority setting at the clinical, provider and purchaser
      levels. The results indicate that there is consensus about the priority criteria
      SLTs use and that the criteria can be ethically defended. Consensus is also found
      between SLTs and the purchasers and provider interviewed regarding the priority
      criteria that are valued but the relatively 'sophisticated' systems that exist at
      the clinical level are not reflected at these levels of the organisation. Three
      criteria are identified as being of relatively more importance and a framework
      for good practice is proposed.

PMID- 10343673
TI  - A hidden client group? Communication impairment in hospice patients.
AB  - Retrospective research has identified communication impairment in over a quarter
      of hospice patients (Jackson et al. 1996) but this field has not been
      investigated using speech and language therapy assessments. The present study
      assessed a sample of 12 hospice patients using tests of verbal learning and
      recall, word-finding, sentence comprehension and motor speech. Eleven patients
      experienced difficulties in one or more areas of assessment. Possible reasons are
      discussed, including the effects of patients' illness and treatment and changes
      in mood or cognitive functioning. A role for speech and language therapy is
      proposed, in terms of assessment, advice and training. Further research is
      suggested to help establish the extent of impairment and define a role for speech
      and language therapy.

PMID- 10343674
TI  - Prioritisation in speech and language therapy departments in Scotland and
      Malaysia.
AB  - This study investigates how prioritisation in health services have influenced
      speech and language therapy (SLT) services in Scotland in prioritising their
      caseload. Additionally, it evaluates how current prioritisation systems may
      contribute towards the development of the SLT service in Malaysia. Health,
      education and social agencies in Malaysia were contacted and a literature review
      was conducted. Information on prioritisation systems used in Malaysia was
      unavailable. Prioritisation systems from seven SLT departments within Scotland
      were investigated, of which three SLT managers took part in semi-structured
      interviews. The findings show that prioritisation is influenced by a combination
      of factors and that the principles could only be applied to the Malaysian SLT
      service if consideration is given to the political, economical, social,
      geographical and cultural factors.

PMID- 10343676
TI  - The measurement of psychological well-being in the person with aphasia.
AB  - This paper will introduce the construct of psychological well-being and discuss
      its relevance to speech and language therapy. Measures of psychological well
      being are used routinely in psychological contexts, both as diagnostic and
      research indicators, and also as outcome measures. There is not a tradition of
      measuring psychological well-being in the speech and language therapy context,
      yet the clinical significance of well-being to therapeutic outcome is recognised.
      This paper will evaluate the existing measures available and discuss the
      development and validation of the Visual Analogue Self Esteem Scale for use with
      aphasic speakers (Brumfitt and Sheeran, 1998). Problems inherent in evaluating
      self-knowledge in communicatively disordered speakers will be discussed.

PMID- 10343675
TI  - Providing appropriate training and skills in developing countries.
AB  - This paper looks at the content, methods and evaluation of training in
      communication therapy developed in Vietnam over a two year period using a wider
      approach to treatment than a medical one. It argues that training to institution
      staff needs to combine the needs of a community and principles of community based
      rehabilitation with a more traditional medical model. It examines the need to
      develop training programmes for trainers based on a sharing of attitudes and
      awareness between institutions and communities as well as some more prescriptive
      and activity-based training. It examines the selection and role of trainees who
      attend such training courses and skills required by the trainers. It also relates
      these skills to possible approaches to service delivery in this country.

PMID- 10343677
TI  - Enabling care staff to relate to older communication disabled people.
AB  - The need for staff training and support within the residential sector is now
      recognised but there are many limitations on implementation. Surveys have
      revealed high proportions of residents with communication disorders and care
      staff are likely to be expected to cope with a range of complex communication
      problems (Bryan and Drew 1989). This presentation will discuss a number of recent
      initiatives that address staff training and support in this care sector.

PMID- 10343678
TI  - Is anyone speaking my language?
AB  - This paper describes an on-going three-phase action research project undertaken
      by members of the Norwich Community Trust speech and language therapy adult
      services team. With the support of the Clinical Audit department the project was
      set up in order to: 1) investigate the characteristics, needs and aspirations of
      the population of dysphasic people in the community; 2) examine how dysphasic
      people and their families perceive the speech and language therapy service; 3)
      implement specific changes to the speech and language therapy service to
      dysphasic people and their families. These changes are based on proposals
      developed through a working partnership between the speech and language therapy
      department and dysphasic people and their families.

PMID- 10343679
TI  - Measuring client and carer perspectives.
AB  - Speech and language therapists (SLTs) seek to meet the needs of the
      clients/patients and carers attending therapy. Part of the process of providing
      appropriate interventions is understanding the areas which the client/patient and
      their carers perceive as important issues. There is a need to know their views,
      expectations and desired outcomes if intervention is to be effective. Since the
      1980s the National Health Service has placed emphasis on the need to include the
      views of users of health care in assessing service delivery and the outcomes of
      care. This paper explores the issues concerning measuring client perceptions,
      existing approaches to capturing client and carer views and summarises initial
      work from a pilot project to develop a Client Outcome Measure.

PMID- 10343680
TI  - Determinants of carer distress in non-acute stroke.
AB  - Carers of people with non-acute aphasic and non-aphasic stroke completed
      questionnaires assessing their distress, perceptions of stroke, generalised self
      efficacy, optimism, coping strategies, self-rated physical health and social
      support. At the same time, their relatives with the stroke were assessed on mood
      and ability measures. Results showed that whereas stroke disability/aphasia did
      not account for carer distress, carer factors accounted for a significant amount
      of the distress.

PMID- 10343681
TI  - Therapy using conversation analysis: helping couples adapt to aphasia in
      conversation.
AB  - This study focuses on the assessment and treatment of the conversations of a
      couple where one partner has aphasia. The assessment and treatment, informed by
      conversation analysis, are described, and some implications for the relation
      between language and psychosocial issues discussed.

PMID- 10343682
TI  - Developing clinical guidelines for the management of patients with stroke.
      Scottish Intercollegiate Guidelines Network (SIGN).
AB  - Clinical guidelines on the management of stroke have been developed for national
      use in Scotland. The guidelines were developed by the Scottish Intercollegiate
      Guidelines Network (SIGN) which was established by the Conference of the Royal
      Colleges and their Faculties in Scotland to sponsor and support the development
      of National Guidelines on a multi-professional basis.

PMID- 10343683
TI  - Treatment for aphasia following stroke: evidence for effectiveness.
AB  - A systematic review of SLT for aphasia following stroke, for the Cochrane
      Collaboration Stroke Group. Twelve randomised controlled trials were identified,
      however there was no standard comparison group amongst the trials. Based on this
      review, it is not possible to reach a conclusion about the effectiveness of the
      treatments evaluated in these trials. Further research is therefore indicated,
      and SLTs must base decisions about treatment for aphasia on other forms of
      evidence.

PMID- 10343684
TI  - Beliefs about effectiveness of treatment for aphasia after stroke.
AB  - A postal survey of SLTs in Scotland was conducted. 598 SLTs responded, 194 worked
      with people aphasic after stroke. A number of obstacles to the provision of the
      SLT service to aphasic people were identified. SLTs expressed concern about the
      effectiveness of the treatments they offered, and about factors which may
      influence effectiveness. A number of suggestions are made for further research
      into this area including into the problems of competing client groups.

PMID- 10343685
TI  - A framework for assessing communication in mental illness.
AB  - Many studies support the notion of semantic and/or pragmatic difficulties in
      people with mental illness. This paper describes a framework (based on a
      discourse analysis model) for the assessment and reassessment of communication in
      mentally ill persons.

PMID- 10343686
TI  - PATSy: a distributed multimedia approach to client assessment skills training.
AB  - This paper describes the development of an interactive distributed multimedia
      system (PATSy). When completed, it will serve as a repository of brain-injured
      clients and their test data for use by speech and language therapy students and
      researchers. In education, PATSy will be a resource which is flexible enough to
      accommodate various teaching pedagogies as well as support student learning in
      clinical assessment and diagnosis of various disorders.

PMID- 10343688
TI  - A survey of speech and language therapists' practice in the assessment of
      aphasia.
AB  - This paper reports some of the findings from a survey of speech and language
      therapists (SLTs) regarding their practice in the assessment of aphasia and their
      views on the assessments currently available. The reason for the survey was a
      desire to investigate whether the concerns about the adequacy of current
      approaches expressed in the research literature were in line with the perceptions
      of practising clinicians. It is also seen as a means of helping to ensure that
      any new instruments that may be developed are relevant to the needs of
      clinicians.

PMID- 10343687
TI  - Case weighting in a speech and language therapy service.
AB  - This study present an approach designed to calculate input provided by a speech
      and language therapy service. A case weighting system was developed in order to
      evaluate the cost of services, predict the need for intervention, balance and
      prioritise the caseload among therapists. It is suggested that this approach can
      be use widely in clinical practice.

PMID- 10343689
TI  - Volunteer stroke scheme revisited.
AB  - A project with several strands was carried out with a local Volunteer Stroke
      Scheme (VSS) which evaluated current practice; identified gaps in practice on
      which a training programme was based: and then evaluated the outcome of this
      training in subsequent activities.

PMID- 10343690
TI  - Single words are not enough: verbs, grammar and fluent aphasia.
AB  - This paper reports on a range of tests and assessments given to a group of six
      fluent aphasic speakers. Diverse profiles emerged with dissociations between the
      ability to name action pictures or construct sentences and the ability to produce
      grammatically well-formed spontaneous speech.

PMID- 10343691
TI  - A modality-specific mapping impairment: spoken versus written production.
AB  - A 29 year-old dysphasic woman (AF) presented with superior ability in written
      over spoken sentences. In contrast, her comprehension showed the reverse trend.
      Cognitive neuropsychological investigations revealed that her double dissociation
      was more apparent than real. AF's superior auditory comprehension was attributed
      to suspected dyslexic factors impeding written comprehension. However, an account
      of a strong dissociation between her written and spoken production was less
      obvious. The evidence suggested AF suffered from a procedural mapping deficit
      which had a disproportionate effect on spoken production. AF's performance
      challenge current models of lexical access which consider syntactic knowledge to
      be amodal. An alternative account is considered within Caramazza's (1997)
      Independent Network model of lexical access.

PMID- 10343692
TI  - 'Confabulation' in narrative discourse by schizophrenic patients.
AB  - There are many clinical reports of confabulation by schizophrenic patients. This
      study provides evidence of a form of confabulation by schizophrenic patients in
      tasks which do not include a memory component. It uses a linguistic framework to
      analyse the components of this confabulation.

PMID- 10343693
TI  - Treating word-finding difficulties--beyond picture naming.
AB  - This paper presents some preliminary findings from research into the phonological
      treatment of word-finding difficulties in aphasia focusing on two areas of
      investigation. Firstly we report on the effects of giving a choice of
      phonological cues on word-finding. Secondly we describe our findings concerning
      the reliability of a measure of real-life interaction.

PMID- 10343694
TI  - A case of verbal auditory agnosia: missing the word ... missing the sound....
AB  - The neuropsychological nature of verbal auditory agnosia is not fully understood.
      This study aims to describe the language deficits and the remediation strategies
      used in a person with verbal auditory agnosia. In addition, it will address the
      theoretical issues concerning the nature of the phenomenon and the clinical
      implications in the management of people with this disorder.

PMID- 10343695
TI  - An investigation into the drawing skills of aphasic adults.
AB  - A matched-pairs design was used to explore differences between drawings made by
      chronic aphasic people and their non-aphasic peers. Standardised and novel
      assessments of drawing skill were made and aphasic peoples' drawings found to be
      significantly different for four factors--placement, complexity, perspective and
      size. This is discussed using a cognitive neuropsychological framework for
      drawing production. The Short Aphasia Screening Test (Whurr, 1996) was a
      significant predictor of drawing performance, indicating its usefulness in client
      selection for drawing-based interventions. Assessment and facilitation of
      drawing, factors of age, severity and laterality are also discussed.

PMID- 10343696
TI  - Students, clinicians and university tutors: triangulation of clinical data.
AB  - The relationship between intuitive clinical awareness and scientific knowledge is
      reciprocal: clinical hunch fuels scientific theory which in turn informs clinical
      practice. This paper demonstrates how students may have a pivotal role in a data
      triangulation process by acting as a channel for the flow of information between
      speech and language clinicians and academic institutions involved in the
      education and training of speech and language therapists. The results of a
      preliminary survey of students' and clinicians' views about the usefulness of
      collaboration around clinical data are used as the basis for generating a model
      which shows the shared roles and responsibilities of the participants as well as
      the crucial focus on improved client management.

PMID- 10343697
TI  - Trainee specialist: meeting the needs of service provision and career
      development.
AB  - A two-year modular training scheme to enable qualified speech and language
      therapists (SLTs) to become specialists in the field of acquired neurological
      disorders in adults was set up to address problems of: difficulty recruiting to
      senior posts; lack of opportunity for inexperienced therapists to gain experience
      in this field and the need for structured supervision. The paper describes how
      time was found to devise and implement the modular Nine Box System, the problems
      encountered, the advantages and disadvantages of the scheme as a whole and future
      developments. The scheme has potential to meet the needs of managers in creating
      a pool of experienced specialists to recruit to senior posts. It meets the needs
      of junior SLTs in providing a structured means of preparing for specialisation
      with guaranteed supervision.

PMID- 10343698
TI  - The hidden determiner of student learning opportunity on clinical placement.
AB  - A qualitative study was undertaken to gain deeper insight into the nature of
      learning opportunities afforded to speech and language therapy (SLT) students on
      clinical placement. The study aimed to illuminate aspects of the placement
      learning environment that have a positive or negative influence. Indepth
      interviews were conducted with two groups of students (13 in total), five
      education-based clinical tutors and five National Health Service (NHS)-based
      clinical supervisors. Interviews were transcribed, indexed, charted and analysed.
      A previously unexplored theme emerged from the data--that of risk. This paper
      explores the concept of risk and looks at the ways in which risk defines the
      amount, timing and nature of clinical experience for students.

PMID- 10343699
TI  - Exploring the crisis in clinical training: looking to the future.
AB  - How can the crisis in training be understood? How can it be resolved? A context
      for this paper is provided in terms of relevant professional and educational
      policy. A critical review of nationally available data is presented. It will be
      argued that commonly cited reasons for not offering student placements might have
      obfuscated underlying dynamics, which are related to the model of education
      adopted in the United Kingdom. It will be argued that a shift in emphasis in
      initial and continuing professional education is relevant.

PMID- 10343700
TI  - Facilitating effective learning during clinical placement.
AB  - The aim of this pilot study was to employ a qualitative research methodology to
      explore students' perceptions of learning and assessment of that learning whilst
      on clinical placement. The students' perceptions were sampled by questionnaire
      both pre- and post-placement (ten weeks block placement). The analysis of the
      data was undertaken using principles from Grounded Theory (Strauss and Corbin
      1990). The analysis yielded a number of categories and bipolar paradigms relating
      to learning and assessment. However little change was seen between comments made
      pre and post-placement. The implications of this analysis are discussed.

PMID- 10343701
TI  - New approaches to learning on clinical placement.
AB  - Traditional models of clinical placements for students in speech and language
      therapy (SLT) are often based on a one-to-one model where the structure of the
      learning process is: theory, observation and practice. Literature relating to
      adult learning and professional education suggests alternative approaches to
      clinical training which may be relevant to SLT. Work in progress is discussed
      where alternative approaches to placements and student learning in a range of
      placement settings are being developed.

PMID- 10343702
TI  - Why are there so few ethnic minority speech and language therapists?
AB  - This report summarises the outcome of a pilot study to investigate the
      recruitment of ethnic minority students to speech and language therapy,
      physiotherapy and dietetics courses. The study also sought to identify factors
      contributing to the low representation of these students on the named courses
      through interviews and questionnaires to careers advisors, school students and
      course admissions tutors. Recommendations for changes in practice are made.

PMID- 10343703
TI  - 'Dysphagia Severity Score' system: clinical outcomes in paediatric dysphagia.
AB  - Clinical evaluation and analysis of therapeutic intervention, by means of a user
      friendly outcome measure system, is essential in the management of a paediatric
      dysphagia caseload. The objective of this study was to design a Dysphagia
      Severity Score (DSS) system and to evaluate its usefulness in profiling dysphagia
      outcomes. Clinical outcome data, based on ten clinical parameters describing
      dysphagic status pre- and post-intervention, were collated for 23 concurrent
      cases and recorded on a data base. Results indicate that all subjects scored an
      improvement in DSS percentage post-intervention, with an average improvement of
      21%. Dysphagia Severity Score profiles are presented for two patients and the
      limitations and applications are discussed.

PMID- 10343704
TI  - Nutritional assessment in elderly care--a team approach.
AB  - This work began in February 1996 when nationally questions were being asked about
      the nutritional care patients were receiving in hospital. Within the Elderly Care
      Unit the multi-disciplinary team was also questioning the nutritional care
      patients received. The main concern raised was the lack of consistent nutritional
      assessment occurring within the unit. A multi-disciplinary nutritional group was
      formed to address this area of concern. It developed an assessment tool that
      identifies those patients at risk and provides guidelines for appropriate action.

PMID- 10343705
TI  - Is a 'safe swallow' really safe?
AB  - The aim of this study was to look at whether full vocal cord adduction is
      achieved in 45 normal subjects when asked to hold their breath, as in the
      supraglottic safe swallow technique. Fiberoptic nasendoscopy was used to assess
      vocal cord adduction. Results show that 57.7% of normal subjects do not fully
      close their vocal cords for the complete duration of breath holding. This finding
      has implications for the efficacy of teaching methods of the supraglottic safe
      swallow technique.

PMID- 10343706
TI  - The dysphagia audit project.

PMID- 10343707
TI  - Variation in the management of dysphagia after stroke: does SLT make a
      difference?
AB  - Dysphagia is a frequent consequence of acute stroke. Previous studies have
      demonstrated better clinical outcomes for patients managed by dysphagia teams,
      which have always included a speech and language therapist (SLT). This study
      compares dysphagia management for stroke patients in two hospitals with differing
      involvement of SLTs in dysphagia services. There was a trend towards better
      identification of dysphagia, more complete documentation of nutrition and
      hydration management, less risky dysphagia management and less perceived need for
      chest physiotherapy at the hospital with locally-based SLT provision, compared
      with the hospital with extra-contractual referral (ECR) for SLT dysphagia
      assessment. The specific contribution of the SLT in the dysphagia team is
      discussed.

PMID- 10343708
TI  - Real-time speech pattern element displays for interactive therapy.
AB  - New developments are presented and discussed for the interactive display and
      separate measurement of frication and nasality in addition to voice quality.
      Different clinical problems require different therapeutic and quantitative
      approaches and these are ideally supported by appropriate combinations of speech
      pattern elements. Particular use has been made of the laryngograph signal in
      order to solve the problems of analysis and so that the displays can be given
      both a sense of immediacy and be highly accurate.

PMID- 10343709
TI  - Larynx synchronised stroboscopy--a new tool for outcome measures in the voice
      clinic.
AB  - Direct vocal fold synchronised stroboscopy is a new technique for obtaining
      useful images of pathological voice, with reduced requirements for both vocal
      fold cycle regularity and the duration of sustained phonation. Precise
      synchronisation of the firing of the stroboscope from the Laryngograph waveform,
      and the capture of images and waveforms into a computer, allows inspection of
      short periods of phonation (less than one second) as a continuous replay of the
      images. Replay can be continued indefinitely, automatically repeating the short
      period of image capture, eliminating the need to rewind a video-tape
      repetitively. This in turn avoids the need for the lengthy phonation otherwise
      required when clinical examination is based on the use of conventional live or
      video-taped stroboscopy. Since the LxStrobe system is based on digital
      processing, archiving and retrieval of images is much enhanced. A demonstration
      of the system, called the LxStrobe, is available on the world-wide-web at
      www.laryngograph.com.

PMID- 10343710
TI  - Aspects of voice quality: display, measurement and therapy.
AB  - One approach to outcome measures for speech and language therapy is to display
      measures of the physical, acoustic, correlates of the perceptually salient
      features of the structure of speech. A difficulty with this approach is that
      there is no simple mapping of physical correlates onto speech percepts. In this
      workshop the physical measures of voice fundamental frequency and larynx contact
      quotient are explored in relation to the perception, analysis and treatment of
      aspects of voice quality in a speech and language therapy clinic. A fundamental
      principle is to analyse samples of continuous speech. The workshop will focus on
      clients with unilateral vocal fold paralysis.

PMID- 10343711
TI  - Helping people to keep their voices healthy and to communicate effectively.
AB  - Voice is essential for all spoken languages. The mechanism of voice is taken for
      granted and its potential in human communication is overlooked. The combined
      expertise of specialist speech and language therapists and voice teachers in the
      Voice Care Network is focused on disseminating knowledge about care, development
      and effective use of the speaking voice. They cooperate, exchange ideas and
      develop practical voice workshops to prevent vocal problems and to support
      teachers, lecturers and others who depend on voice. A countrywide network of
      tutors runs workshops in universities and schools. Feedback shows appreciation of
      the overall benefits.

PMID- 10343712
TI  - Objective assessment of voice intervention: a clinical audit.
AB  - This clinical audit arose from research (Lockhart et al. 1997) which suggested
      timescales for the care episodes of diagnostically related groups of dysphonic
      clients, where SLT was directed at targeting the parameters of voice production
      most requiring change. The objectives of the audit were to examine current
      practice, compare it with the standards set and with the research findings,
      address any issues highlighted with regard to service delivery or staff training
      and to provide information to management on outcomes of care.

PMID- 10343713
TI  - The effect of perceptual training on ability to use the Vocal Profile Analysis
      Scheme.
AB  - The Vocal Profile Analysis Scheme (VPAS) (Laver et al. 1981) is the vocal
      perceptual scheme most often used by British speech and language therapists. In
      this study, the voices of four speakers with normal voices and four with a voice
      disorder were recorded in reading and independently rated on the VPAS protocol by
      Dr Sheila Wirz and by the author. Inter-judge reliability was established and
      agreement reached in judging the twenty vocal quality features for each speaker.
      Thirty eight speech and language therapists were assessed on their ability to
      describe the voices. Significant improvement was found in the ability to rate
      features. These findings suggest that the use of a perceptual scheme can be a
      reliable part of voice assessment in both therapy and research.

PMID- 10343714
TI  - Meta-analysis of botulinum toxin treatment of spasmodic dysphonia: a review of 22
      studies.
AB  - This meta-analysis focuses on the treatment effects of the use of botulinum toxin
      in laryngeal dystonia. The vocal symptoms are characterized by spasms of the
      laryngeal muscles thus the use of the term spasmodic dysphonia (SD). The
      objective of the intervention, i.e. botulinum toxin treatment, is to reduce or
      eliminate the vocal spasms and thus improve the acoustic regularity of the voice.
      The purpose of the present study was to assess the efficacy of botulinum toxin in
      the treatment of SD by engaging in a 'best synthesis' systematic summary of
      existing research. The average treated SD patient in the 22 studies subjected to
      meta-analysis obtained 97% improvement as a result of treatment with botulinum
      toxin.

PMID- 10343715
TI  - Issues in designing an assessment of British Sign Language development.
AB  - This paper reports on a collaborative project in progress to develop a
      standardised clinical assessment of British Sign Language development for use
      with deaf children. The need for such an assessment is highlighted following a
      survey of professionals working in this area (Herman, in press). The development
      of the assessment battery will be described in the context of research into the
      assessment of sign language development. Issues in selection of the
      standardisation population will be presented. Finally the need for collaboration
      between different professionals working in this area, in particular the key role
      of the deaf BSL user will be emphasised.

PMID- 10343716
TI  - The development of a bilingual phonology assessment.
AB  - This paper describes the development of a phonological assessment procedure for
      children speaking Mirpuri, Punjabi or Urdu in combination with English. The
      Rochdale Assessment of Mirpuri Phonology (RAMP) was produced in response to the
      practical difficulties of a monolingual therapist wishing to assess a child's
      phonological systems across all languages used. The assessment is currently being
      used both as a clinical tool within the Rochdale Healthcare NHS Trust Speech and
      Language Therapy Department and as a research tool in collaboration with the
      Department of Speech, University of Newcastle to provide further data on patterns
      of bilingual phonological acquisition. Outcomes include therapy targeted more
      accurately at deficits within each phonological system.

PMID- 10343717
TI  - Children's acquired aphasia screening test.
AB  - Diagnosis in acquired childhood aphasia (ACA) is a multi-stage process. After the
      medical condition has stabilised, the diagnostic evaluation requires careful
      assessment to establish a profile in the differential diagnosis of listening,
      understanding speaking, and gesture. Children with ACA were traditionally
      assessed on adapted batteries often used for adults. The Children's Acquired
      Aphasia Screening Test (CAAST) was specifically designed to evaluate linguistic
      and non-linguistic function in brain-damaged children aged between 3 and 7 years.

PMID- 10343718
TI  - Normative Scottish data on the CELF-RUK: a pilot study.
AB  - There are relatively few standardised tests available for assessing language
      abilities in older children. A widely used test in Britain is the Clinical
      Evaluation of Language Fundamentals-Revised (CELF-R, Semel et al. 1987). One
      potential problem with its use in the UK is that the test has been standardised
      on American children. In this investigation, the CELF-RUK was administered to
      twenty Scottish language-normal children, aged 12;0-12;11 years. The results
      showed that the Scottish children's scores were significantly lower than the
      American standardisation sample scores for the expressive subtests but not
      significantly different for the receptive subtests. The results suggest that
      further research is needed before the test can be used confidently with Scottish
      children with language impairment.

PMID- 10343719
TI  - Changing referral patterns to ensure earlier identification of dysfluent pre
      schoolers.
AB  - There has been a paucity of empirical research reported in the stuttering
      literature into dysfluency referral patterns and activities which promote early
      referral. Preliminary results of a three year UK-wide study are presented which
      illustrate how specific activities can positively influence the referral patterns
      of general practitioners, health visitors and other professionals. Analysis of
      pre-project data has identified current UK trends in paediatric dysfluency
      referrals (n = 2356), from which speech and language therapists (SLTs) can
      recognise specific aspects for individual service development. The current study
      describes the pre- and post-project referral trends of 12 community trusts. Data
      reveal that time lags can be reduced in order that more dysfluent pre-schoolers
      see a SLT at a clinically optimal time.

PMID- 10343720
TI  - An electropalatographic (EPG) study of the speech of two stuttering subjects.
AB  - Two stuttering subjects and two control subjects were used in a comparative pilot
      study using EPG. The subjects read twenty sentences and repeated three words, 'a
      deer', 'a clock' and 'a kitkat', ten times. These data allowed three main methods
      of EPG analysis: variability measures on the three words in isolation;
      qualitative comparison between stuttering and control speakers' production of
      perceptually fluent speech and analysis of specific disfluencies. Results showed
      that compared to control speakers the stuttering subjects displayed increased
      contacts for fluent alveolar and velar plosives and fricative undershoot. They
      also showed less temporal variability for velar stop articulations. The results
      suggest that EPG is a useful technique in the analysis of articulatory
      characteristics of stuttering behaviour.

PMID- 10343721
TI  - The use of clinical measures in the Lidcombe Programme for children who stutter.
AB  - This paper aims to demonstrate how the speech measures which are collected to
      inform the therapy process also have the potential to evaluate clinical change
      and effectiveness. Certain methodological issues pertinent to evaluating therapy
      for early stuttering are raised and the clinical measures that are a part of the
      Lidcombe Programme (Onslow 1993) are discussed in relation to these. Reference to
      a single case study is made to demonstrate how the measures contribute to
      clinical decision-making. Some initial results of the authors' use of the
      Lidocombe Programme in the UK is outlined.

PMID- 10343722
TI  - The value of single-case research.
AB  - This paper presents an argument in support of clinic based research. The role
      that the clinic-based speech and language therapist has in advancing our
      knowledge of communication disorders and their treatment is emphasised. The value
      of single-case research within the field of speech and language therapy is
      discussed and the arguments are presented with respect to stammering. A single
      case study of pre-school dysfluency is used to illustrate the potential for
      conducting research using this methodology in a clinical environment.

PMID- 10343723
TI  - The case for early intervention with pre-school dysfluent children.
AB  - This paper aims to provide support for the hypothesis that early intervention
      with young dysfluent children is more successful over a shorter period of time
      than if speech and language therapy is delayed. The case histories of children
      between the ages of 3;06 and 5;11 years and 8;00 and 10;11 years who attended the
      Michael Palin Centre in a one year period were analysed. Those children whose
      histories included four or more risk factors were included in the study. The
      amount and duration of speech and language therapy along with the outcome was
      measured. Outcome was measured by the presence of stammering and parental and
      child concern. Preliminary findings indicate that the hypothesis will be
      supported. Full statistical analysis will be presented at the conference.
      Implications of the findings for service delivery will be discussed.

PMID- 10343724
TI  - Outcome measurement in adult stuttering therapy: a self-rating profile.
AB  - The speech and language therapy profession is committed to the use of outcome
      measurement to maximise both efficiency and efficacy. However, measuring change
      in adult stuttering therapy is particularly problematic. It is proposed that
      outcomes of therapy should include stuttering behaviours, reactions to stuttering
      and handicap resulting from stuttering. Current methods of measuring change are
      reviewed. The Wright & Ayre Stuttering Self-Rating Profile (WASSP) is described
      which includes clients' perceptions of stuttering behaviours, avoidance, feelings
      and disadvantage. Issues of reliability and validity are considered.

PMID- 10343725
TI  - To engage or not to engage? Affecting the interactions of learning disabled
      adults.
AB  - An intervention, termed 'Individualised Sensory Environment' (ISE), was developed
      for use with adults with profound and multiple learning disabilities (Bunning
      1996). The aim was to affect positively the interactive behaviours displayed by
      clients in the natural environment: specifically; to reduce the level of non
      purposeful engagement, characterised by stereotypic actions, self-injury and
      neutral behaviour and to increase the levels of purposeful interaction with
      people and objects. Momentary time sampling was the chosen method of assessment.
      The results showed that the clients emitted high levels of non-purposeful
      behaviour at baseline. Post ISE intervention assessment revealed a decline in the
      level of non-purposeful behaviour and an increase in purposeful interactions.

PMID- 10343726
TI  - Evaluation of an approach for adults with profound learning difficulties.
AB  - A local day care unit for adults with profound learning disabilities is a popular
      community project. It receives many visits from students and volunteers and is
      also visited by a variety of support staff. The presence of these visitors makes
      an impact on the Unit's communication environment. A nursing and speech and
      language therapy project used photography to address the visitors' perceptions of
      the clients' communication and identify the visitors' information needs about the
      clients' communication skills. As a result of this evaluation the induction
      policy was changed and the leaflets were introduced. The time commitment to the
      initial project for therapy and nursing staff is discussed in relation to the
      effective and alternative use of therapeutic time for this client group.

PMID- 10343727
TI  - Evaluation of facilitated communication.
AB  - Two case studies are presented to demonstrate the effectiveness of Facilitated
      Communication (FC). A wide variety of sources of data have been examined and
      consistent behaviour found within FC interactions. There are indications that
      changes in behaviour of both people resulted at least in part from the use of FC.

PMID- 10343728
TI  - An anger management programme for adults with learning disabilities.
AB  - Speech and language therapy aims to increase the functional communication of
      adults with learning disabilities through the implementation of interaction group
      programmes but the full therapeutic benefit may be reduced because of individual
      clients' presenting challenging behaviours. The pilot Anger Management Programme
      aimed to reduce clients' challenging behaviour through increased communication
      use and with a focus on multidisciplinary collaborative NHS health trust and
      social work team working practices. An in-service training package and two client
      group programmes were devised and positively received both from a client
      provision and multidisciplinary skill-merge perspective. The paper details the
      introduction to the study, its objectives, methodology and qualitative analysis.

PMID- 10343729
TI  - When staff training isn't enough: an evaluation of a collaborative approach.
AB  - This paper describes an evaluation of a training workshop for staff working with
      people who have severe physical and learning disabilities and who need extensive
      support with eating and drinking. Training involved joint input from speech and
      language therapy, dietetics, occupational therapy and physiotherapy and was
      evaluated at three levels: participants' satisfaction, gains in knowledge and
      video-tapes of mealtimes pre- and post-training to assess changes in practice.
      Results indicated very positive staff perceptions of the workshops and highly
      significant increases in knowledge, both immediately (p < 0.001) and after six
      months (p < 0.001). However there was no evidence of significant change in
      practice. Results are discussed in the context of bringing about changes in staff
      behaviour.

PMID- 10343730
TI  - Challenging communication: people with learning disabilities who challenge
      services.
AB  - This paper describes a project designed to equip direct care workers with the
      knowledge and skills to address communication as a central factor in the lives of
      people with learning disabilities who challenge services. The elements of the
      approach taken--'Challenging Communication'--are described, outcomes discussed
      and possible implications for the speech and language therapy profession briefly
      considered.

PMID- 10343731
TI  - Processing load and the extended optional infinitive stage.
AB  - Spontaneous language data from fifteen language-impaired children in the Extended
      Optional Infinitive stage of morphosyntactic development are examined with
      respect to processing load. Clauses with a target finite verb form are
      categorised according to finiteness and their preverbal constituents. Patterns of
      occurrence are discussed with regard to the Optional Infinitive framework itself
      and the implications for remediation.

PMID- 10343732
TI  - DDK rates in the paediatric clinic: a methodological minefield.
AB  - There are substantial differences in the norms reported for speech
      diadochokinetic (DDK) rates among several published studies. These may well be
      due to differences in type of data used, methods of data collection and DDK rate
      calculation. Such differences doubtless also exist in the calculation of DDK rate
      in routine clinical assessment. Methodological problems in DDK rate measurement
      are identified and discussed and a detailed protocol for DDK measurement is
      described.

PMID- 10343733
TI  - Semantic pragmatic disorder with application of selected pragmatic concepts.
AB  - Children with semantic pragmatic disorder have been described as having
      difficulties in conversational interaction. The content of their conversations
      has been described as 'odd', 'loose', tangential', 'irrelevant' and
      'inappropriate' (Stubbs 1986). A diagnosis of semantic pragmatic disorder is
      currently made based on whether or not a child displays certain surface
      characteristics. The present study attempts to apply precision to the intuitive
      terms which have been used to describe these children's conversations. To this
      end conversation samples from three children identified by speech and language
      therapists as fitting the clinical diagnosis of semantic pragmatic disorder were
      analysed. Aspects of pragmatic theory which best explained the strengths and
      weaknesses which emerged in the conversations are discussed. Therefore this
      represents an essentially data driven study.

PMID- 10343734
TI  - When is a /k/ not a [k]? EPG as a diagnostic and therapeutic tool for abnormal
      velar stops.
AB  - This case study describes a boy who at the age of eight years did not have
      consistent or contrastive use of velar stops in his spontaneous speech. The use
      of electropalatography (EPG) revealed abnormal tongue-palate contact for both
      velar and alveolar stops, all of which were perceived as normal, there was excess
      contact in the palatal region for all alveolars and velars in a word initial
      position and double velar/palatal articulation for velars in a word final
      position. Therapy using EPG for visual feedback was highly successful and post
      therapy data showed normal-looking EPG patterns for alveolar and velar stops. The
      assessment, diagnostic and therapeutic implications are discussed.

PMID- 10343736
TI  - Efficacy of speech and language therapy for particular speech sounds in children.
AB  - At the present time there is a demand for research into the efficacy of speech
      and language therapy. This study aims to assess the efficacy of therapy provided
      in South Tees for children who do not use word-initial velar plosives. The study
      is in progress at the time of writing and it is expected that therapy will be
      completed by July 1998. Subjects are split randomly into an 'immediate treatment'
      and a 'deferred treatment' group. All subjects are reassessed after treatment of
      each group. It is of course possible that analysis of the results will not show a
      significant difference between pre- and post-treatment scores. Some children may
      acquire target sounds before entering therapy, whilst others may fail to learn
      them within the treatment period. Various factors are being noted to determine
      whether they appear to correlate with the outcome of therapy.

PMID- 10343735
TI  - The measurement of intervention effects in developmental phonological disorders.
AB  - The effectiveness of speech and language therapy for developmental phonological
      disorders has typically been measured in terms of the diminution of the
      application of phonological processes. Often substantial amounts of intervention
      and time may be needed to show up such changes. Shorter and more clinically
      realistic intervention regimes can result in small but significant changes in
      speech production which represent positive developments in the phonological
      system. In order to measure progress in this sort of therapy a sensitive
      instrument of measurement is required. In this paper we describe a research
      measurement tool, the probe scoring system, which was designed to detect small
      changes in the child's phonological system following therapy and contrast it to
      some of the instruments selected for use in other efficacy studies. The potential
      for wider clinical application is also considered.

PMID- 10343737
TI  - Speech processing abilities in children with speech vs speech and language
      difficulties.
AB  - This paper reports on the speech processing skills of a group of four year old
      children with specific speech difficulties and examines the impact of an
      additional language impairment on these skills. Forty seven children with speech
      difficulties were tested on two speech output measures and one speech input
      measure to assess the accuracy of their phonological representations. Their
      performance was compared to a matched control group n = 47 and analysed according
      to the presence/absence of an additional language impairment. It was found that
      children with both speech and language difficulties had poorer speech processing
      abilities compared to both the normal controls and the children with speech-only
      difficulties. The clinical implications of these findings are outlined.

PMID- 10343738
TI  - Can phonological awareness training facilitate minimal pair therapy?
AB  - This study evaluated a new therapy approach. 18 children with phonological
      disorders resistant to conventional therapy had phonological awareness training
      followed by conventional speech therapy. The children's speech production
      improved as did their phonological awareness. In this heterogeneous group, the
      patterns revealed in their individual responses to therapy proved diagnostically
      significant.

PMID- 10343739
TI  - Targeting speech processing strengths to facilitate pronunciation change.
AB  - This paper reports investigation and intervention with a 5 year old boy (AG) with
      unintelligible speech. Phonological analysis and psycholinguistic investigation
      allowed exploration of his speech processing strengths and difficulties as a
      basis for planning intervention. It was hypothesised that intervention which
      exploited his strengths, without focusing directly on his difficulties, would
      enable him to discover how to modify his pronunciation patterns. Significant
      positive changes had occurred by age 6 years.

PMID- 10343740
TI  - Perceptual strategies in phonological disorder: assessment, remediation and
      evaluation.
AB  - Evidence is presented that immature perceptual strategies are a contributory
      factor to developmental phonological disorder. The findings endorse the current
      re-focusing of attention on the role of perception in disordered speech and
      language acquisition and also highlight the need for more precise assessment and
      remediation techniques. Technical developments working towards providing these
      are reviewed and implications for future clinical practice discussed.

PMID- 10343741
TI  - Diadochokinetic skills: normal and atypical performance in children aged 3-5
      years.
AB  - Although diadochokinetic (DDK) tasks are a popular assessment tool in clinical
      practice, the interpretation of their results is often limited and obscure. This
      paper examines the development of DDK skills in normally developing children (age
      range 3-5 years) for comparison with three case studies of children with specific
      speech difficulties. The results are presented in terms of accuracy, rate and
      consistency of response. The normally-developing children increased the accuracy
      and consistency but not the rate of their responses between the ages of 3 and 5
      years. The three case study children (matched on severity of speech difficulty)
      not only performed differently from control children on some of the measures but
      also performed differently from each other. The diagnostic value of a
      developmental DDK profile is discussed.

PMID- 10343742
TI  - Language dominance in dual language children--do we need to bother assessing it?
AB  - As part of a doctoral investigation, the receptive lexical proficiency of 392
      Dual Language (DL) primary school children in Gibraltar was studied. Using the
      resultant data, the subjects' lexical proficiency was measured in Gibraltarian
      Spanish (Yanito) their first language (L1) and in English their second language
      (L2). Their receptive lexical dominance was also calculated. This paper focuses
      on the results of analyses conducted to calculate the subjects' receptive lexical
      dominance and dominance shift over the years. The results of these analyses are
      reported and some implications briefly discussed.

PMID- 10343743
TI  - 'Bilinguality' in dual language schoolchildren and its implications.
AB  - As part of a doctoral investigation, the receptive lexical proficiency of 392
      Dual Language (DL) primary school children in Gibraltar was studied. Using the
      resultant data, the subjects' lexical proficiency was measured in their first
      language (L1) Gibraltarian Spanish (Yanito) and in their second language (L2)
      English. Their bilinguality was also calculated. This paper focuses on the
      results of several analyses conducted to calculate the subjects' bilinguality.
      The results of these analyses are reported and some of their practical
      implications briefly discussed.

PMID- 10343744
TI  - Early intervention project: evaluation of WILSTAAR, Hanen and specialist
      playgroup.
AB  - This paper describes an early intervention project which combines a three tiered
      approach to speech and language provision for pre-school children. Jointly funded
      by I CAN, AFASIC, Dorset Healthcare NHS Trust and the Department of Health, this
      two and a half year project aims to reduce the numbers of children and severity
      of their speech and language difficulties on entering school. The project uses
      the following approaches--the Ward Infant Language Screening Test Assessment
      Acceleration Remediation (WILSTAAR), the Hanen parent programmes and a specialist
      speech and language playgroup. In this paper these approaches are described with
      an explanation of how each is being evaluated and where possible interim results
      have been presented.

PMID- 10343745
TI  - Encouraging speech and language development in exceptional circumstances.
AB  - An evaluation of the accessibility of the speech and language therapy service
      within Down Lisburn Trust and a needs assessment of the levels of speech and
      language difficulties in preschool children was conducted between October 1996
      and March 1997. Results highlighted that 42% of preschool children had speech and
      language difficulties, however only 17.8% were able to access the speech and
      language therapy service for remediation of their difficulties. A further 2-3
      year project is now planned. This aims to tackle the high levels of speech and
      language difficulties in children through prevention, early identification and
      remediation programmes. It also aims to ensure equitable access to the speech and
      language therapy service for all children.

PMID- 10343746
TI  - Undetected communication problems in children with behavioural problems.
AB  - There is an increasing amount of evidence for links between emotional and
      behavioural problems and communication difficulties. Many children who hav
      emotional and behavioural problems also have communication difficulties (Cohen
      and Lipsett 1991, Benaisch et al. 1993) and children who have communication
      difficulties are more likely to develop psychiatric illness than their peers
      (Cantwell and Baker 1985). More importantly there are many children with
      emotional and behavioural problems who have undiagnosed speech and language
      difficulties. These have been found in child psychiatric populations (Cohen, et
      al 1993) and special educational settings (Burgess and Bransby 1990). This paper
      reports on a small-scale study which found undetected communication problems in
      children looked after by the local authority. The implications for these children
      are explored.

PMID- 10343747
TI  - A comparison of training approaches for support assistants using the Hanen
      philosophy.
AB  - The introduction of the Hanen Programme (Watson, 1993) for parents of children
      who will in the future attend special schools can have training implications for
      their school's staff. These factors have led to a speech and language therapy
      service working in collaboration with its local schools to offer courses for
      special needs support assistants. The design, planning and delivery of the
      courses were based on Hanen philosophy. Some courses were exclusively for support
      assistants and others offered the opportunities for them to work in differing
      degrees of partnership with children's parents. The successes and the limitations
      of support assistants attending parents Hanen courses were evaluated.

PMID- 10343748
TI  - Pre-school assessment project comparing assessment in the clinic or home.
AB  - From clinical experience it has been found that it is often difficult to assess
      young children in a clinical environment. Therefore, the aim of this project was
      to assess the communication of children in either the home or the clinic
      environment and to determine whether a more realistic impression of the child's
      language was obtained from home initial assessment. The results of this study
      suggest that for children who are 39 months old or less on the date of referral
      to speech and language therapy, a more representative sample of communication
      skills does emerge from initial assessment in the home environment. The
      conclusions drawn also indicate that the attendance rates for home assessments
      were significantly better than those for clinic appointments and this in turn
      meant that there was a subsequent cost saving to the department.

PMID- 10343749
TI  - Evaluation of a nursery based language intervention in a socially disadvantaged
      area.
AB  - This longitudinal study was designed to evaluate the impact of a community-based
      speech and language project, set in an area of Plymouth known for its high levels
      of social disadvantage. The interventions include a specifically designed nursery
      programme, known as Wise Words for Nursery, and a modular series of parenting
      groups for the parents of pre-school children. The data were collected from five
      consecutive year groups entering a single primary school for the years 1993-1997.
      Each of the five cohorts underwent a battery of tests to collect data on their
      lexical development, information recall, reception of grammar, sentence length
      and speech clarity. Statistical analysis of the data showed a significant
      difference in the communication abilities of the most recent cohort when compared
      to the previous years. The findings provide considerable support for the efficacy
      of the approach employed.

PMID- 10343750
TI  - Modelling the consultation process in a secondary referral unit for children.
AB  - This paper overviews a detailed study of a consultation service for children with
      severe and/or intractable speech and language difficulties. The Speech Therapy
      Clinical Unit at the University of Central England in Birmingham (UCE) offered
      multidisciplinary, in-depth assessment of such children to speech and language
      therapists, parents and other professions involved in their management.
      Documentary materials generated by the service were analysed using Grounded
      Theory to develop a model of the process of assessment and consultation employed
      in the Unit. The implications of this model for clinical education and practice
      are discussed.

PMID- 10343751
TI  - Parents' beliefs and ideas about children's early speech and language
      difficulties.
AB  - This paper reports a qualitative investigation of the ideas and beliefs of
      parents about their pre-school children's speech and language difficulties. It
      forms part of a broader study of parental opinions about speech and language
      difficulties and the speech and language therapy (SLT) intervention they receive.
      Factors contributing to the development of professional interest in parental
      views will be reviewed, followed by an outline of the beliefs and ideas expressed
      by the parents in in-depth interviews. The paper will also discuss parents' views
      in their wider context and consider implications for SLT practice.

PMID- 10343752
TI  - A paradigm for improving effectiveness and efficiency of speech-language therapy.
AB  - This paper presents a paradigm that will help speech and language therapists
      learn how to improve their therapy and achieve the scientific goals of
      intervention more effectively and efficiently. The paradigm arises from the
      presenters' extensive clinical experience and represents a convergence of
      relatively diverse models of teaching and learning. Speech and language therapy
      which incorporates the critical characteristics from this paradigm is more
      stimulating and challenging for both the client and speech and language
      therapist.

PMID- 10343753
TI  - 'Partnership with parents'--a progressive pathway.
AB  - This paper presents the problems associated with the implementation of a new
      model of service delivery involving parent programmes. Factors affecting the cost
      effectiveness included the influence of the learning curve. Change, innovation
      and adoption will be discussed in relation to the new model of service delivery.
      The correlation with years of experience will also be considered.

PMID- 10343754
TI  - 'Partnership with parents' a pilot project.
AB  - This paper looks at a controlled study which aimed to measure the efficacy of a
      parent programme. The parents involved were all parents of pre-school children
      with specific expressive language delay (SELD). A number of measures were used to
      identify changes in mother-child interaction and language development.
      Significant differences were noted in the experimental group while the control
      group remained stable over time. The results indicate the potential effectiveness
      of this type of intervention for children identified as having SELD.

PMID- 10343755
TI  - Equitable service provision for inclusive education and effective early
      intervention.
AB  - This paper illustrates one model of providing an integrated paediatric speech and
      language therapy service which attempts to meet the demands of both inclusive
      education and effective early intervention. A move has been made from location
      oriented therapy provision to offering children and their families equal
      opportunities to have appropriate intervention according to need. The model
      incorporates the philosophy of inclusive education and supports the development
      of current specialist educational establishments into resource bases of expertise
      for children with special needs in mainstream schools.

PMID- 10343756
TI  - Making team working work--a real life experience.
AB  - Southern Derbyshire Speech and Language Therapy Department has a team of six
      specialist speech and language therapists who support children with Specific
      Language Impairment in their mainstream schools via joint commissioning with
      education. As the team expanded in October 1995 this coincided with health trust
      and education changes and produced great instability and insecurity within the
      team. This paper outlines the implementation of a formal team working package
      using a facilitator provided by the trust's quality team and shows how it is
      possible to problem solve and develop within a framework of group rules, such as
      honesty and openness. Following its success its principles have allowed us to co
      operate more effectively with both school staff and the community team and to
      support colleagues through a re-organisation of their service.

PMID- 10343757
TI  - Collaboration in Glasgow's primary school language units.
AB  - The quality of collaboration between teachers and speech and language therapists
      (SLTs) in Glasgow's four primary language units is discussed with reference to a
      scale of three levels of co-operation: nominal, convenient and committed.
      Although there are some aspects of the relationships that exist between teachers
      and SLTs which would be typical of committed co-operation, the overall quality
      appears to be at the level of convenient co-operation. In particular, inadequate
      role definition and a lack of structure are discussed with reference to joint
      work on language development and several suggestions are included as ways forward
      in this area. The need to evaluate models of working critically is discussed in
      relation to collaborative working.

PMID- 10343758
TI  - Speech and language therapist-teacher collaboration in a literacy summer school.
AB  - This paper describes the collaboration between a speech and language therapist
      and a special needs teacher to provide an intensive phonics-based programme of
      reading and spelling instruction in the context of a literacy summer school for
      students about to enter secondary school. The students' reading and spelling
      abilities were tested before and after the summer school. All the students
      benefited from the summer school in many ways. Various factors, such as innate
      language ability, attendance, completion of homework and age, appeared to
      contribute to the degree of improvement of individual students.

PMID- 10343759
TI  - Collaborative working with specific speech & language disorder in mainstream
      education.
AB  - Children with specific speech and language disorders are part of a special needs
      population whose educational and therapeutic needs have been provided for in a
      variety of settings over the last fifty years. Changes have been implemented in
      response to a range of legislation. This has also had implications for the
      delivery and type of provision of the children's education and therapy. The
      National Health Service and local education authorities (LEAs) have had to
      respond to legislation and continue to provide for the full range of specific
      speech and language disorders. This paper will outline how therapeutic input has
      had to adapt to the changing educational context. Changes in delivery have
      necessitated a redefinement of roles and adjustments in collaborative working.

PMID- 10343760
TI  - Specialised service to children with specific language impairment in mainstream
      schools.
AB  - The following report describes a three year project to develop, implement and
      evaluate a specialised speech and language therapy (SLT) service to children with
      specific language impairment (SLI) who attend mainstream schools and nurseries.
      The report describes how the service was set up and the package of care offered.
      A range of evaluation measures was designed and implemented and the results of
      these are discussed. The service aimed to enable key-workers to support children
      with SLI effectively within the context of the school environment. The results
      suggest that the package of care offered provided an effective and high quality
      service as judged by the parents, schools and therapists.

PMID- 10343761
TI  - Let's talk: a working party for special schools.
AB  - The Special Schools Working Party was formed in summer 1996 to improve
      communication channels and foster understanding between speech and language
      therapist, school and home. It consists of representatives from all three groups
      in the six schools involved. The Working Party has produced a document which
      describes everyone's role and agreed procedures for liaison and training. Its
      greatest benefit lies in the opportunities for discussion and exchange of ideas.
      In the future the Working Party is planning to audit customer satisfaction of the
      service and continue to develop ideas for improving its accessibility.

PMID- 10343762
TI  - An effective model for a speech and language therapy service in mainstream
      schools.
AB  - Health and Local Education Authority (LEA) personnel met in 1993 to consider how
      to meet the expanding caseload of children, needing speech and language therapy
      support in mainstream schools. The drive towards an inclusive policy for all
      children with special needs led to the joint funding of a peripatetic team of
      speech and language therapists (SLTs) and assistants. The preparatory training
      programmes for the team and school based staff focused on ensuring that differing
      perceptions, expectations and skills were acknowledged. Evaluation of the model
      has examined throughput, the opinion of consumers, pre- and post-therapy profiles
      of individual children and the team's view of their effectiveness in each school.
      The rotational service was implemented in 20 schools in January 1996 and 50
      schools now participate.

PMID- 10343763
TI  - 'Excellence for all children' a redefinition of the role of the speech and
      language therapist.
AB  - This paper describes two projects relating to a speech and language therapy
      service to mainstream primary schools. The aim of the projects has been to
      improve service delivery by collaborative working both at a strategic and
      operational level. The result has been a redefinition of the role of speech and
      language therapists within this context.

PMID- 10343764
TI  - Styles of interaction used by learning assistants: the effectiveness of training.
AB  - This study examines the effectiveness of a training day for classroom learning
      assistants (LAs), which aims to change the way LAs interact with language
      impaired children. The subjects were eight LA/language-impaired child dyads (with
      children aged 4;11 to 9;11 years) attending mainstream schools. The dyads were
      video recorded interacting at two times (before and after training) and in two
      contexts each time (sharing a book and in class). The training increased the
      percentage of facilitating utterances and recasts used by the LAs but did not
      decrease the percentage of controlling utterances used. Although the trained
      styles of interaction were used more frequently while sharing a book than in a
      classroom activity, the amount of change following training was not significantly
      different for these two settings.

PMID- 10343765
TI  - Working towards an inclusive curriculum.
AB  - The move towards an inclusive model of education presents teachers with the
      difficulty of differentiating the curriculum for children with speech, language
      and communication impairments. This paper focuses on the 'WiSaLT Curriculum
      Appendix'-a tool which can be used by teachers and speech and language therapists
      to help such children access the mainstream curriculum and to promote improvement
      in their language and communication skills. As well as highlighting potential
      areas of difficulty within each attainment target for key stage one, the appendix
      guides users to specific strategies and activities. Thus the speech and language
      therapist and teacher can identify which attainment targets might prove
      problematic for any one child and also have access to ideas which can help.

PMID- 10343766
TI  - Collaborative working practices in schools for children with physical
      disabilities.
AB  - Questionnaires were sent to speech and language therapists (SLTs) and teachers in
      83 special schools catering specifically for children with physical disabilities.
      Sixty two teachers and 47 SLTs responded. The results indicated that there were
      different patterns of collaborative working in these special schools than had
      been found in a previous study in schools for children with severe learning
      disabilities (SLD). The majority of SLTs and teachers were using alternative and
      augmentative communication systems (AAC) with the children and, in the main, the
      SLTs introduced the aids to the children and their families. These findings have
      implications for the specialist training of speech and language therapists.

PMID- 10343767
TI  - Team work and skillmix. Do they improve care for older patients?
AB  - The Jansson Memorial Lectures were instituted by the Council of the Royal College
      of Speech and Language Therapists in September 1960 as a result of a bequest left
      to the College in her will by Miss Gladys Astrild Jansson. Miss Jansson had died
      at the age of 74 years after having spent a life of unselfish devotion to the
      practice of speech therapy in the Bath area.

PMID- 10343768
TI  - Design of clinical trials in knee osteoarthritis: practical issues for debate.

PMID- 10343769
TI  - Pathophysiology of osteoarthritis.

PMID- 10343770
TI  - Femoral trabecular bone of osteoarthritic and normal subjects in an age and sex
      matched group.
AB  - OBJECTIVE: To describe changes to the cancellous structure of femoral bone from
      patients with severe primary osteoarthritis by comparison with age and sex
      matched controls. METHOD: Specimens were taken from 18 male and 18 female pairs.
      One of each pair was a normal control, the other having severe primary
      osteoarthritis which required hip arthroplasty. Undecalcified cancellous bone
      blocks were embedded in resin, sectioned and impregnated with silver.
      Histoquantitation was performed using image analysis. Using a plate model for the
      trabecular structure of bone, an estimate was made of bone volume, bone surface,
      trabecular thickness, trabecular separation and trabecular number. RESULTS: In
      osteoarthritis, pooled male and female data show a significant decrease in
      trabecular number together with an increase in trabecular thickness and
      separation. The statistical variance in the histomorphometric variables for each
      of the study groups was calculated and expressed as the ratio of osteoarthritic
      to control. This ratio shows that the variance of the osteoarthritic groups is
      significantly increased for each variable in the pooled data. The same trend is
      evident in the male and female groups. CONCLUSIONS: This quantitative study of
      cancellous bone architecture in the femoral head, infero-medial to the fovea, has
      found increased trabecular thickness and decreased trabecular number in patients
      with primary osteoarthritis. Increased morphometric variance has shown that
      severe osteoarthritis, contrary to osteoporosis, is associated with heterogeneous
      bone structures. These findings provide some basis for understanding how
      osteoarthritis may contribute to the prevention of osteoporotic fracture.

PMID- 10343771
TI  - Material properties and biosynthetic activity of articular cartilage from the
      bovine carpo-metacarpal joint.
AB  - OBJECTIVE: To determine the site variation of material properties and cellular
      biosynthetic activity, and to compare these at each site, of articular cartilage
      from the bovine carpo-metacarpal joint in order to test its usefulness as a model
      system for investigating the metabolic effects of mechanical stimuli. DESIGN: The
      mechanical properties and composition of full-depth biopsies of articular
      cartilage were measured at defined sites in bovine carpometacarpal joints.
      Metabolic activity at the same sites was assessed by incubating further biopsies
      in medium containing 35S-sulfate and 3H-leucine then measuring the incorporated
      radioisotope and cell density. These results were compared with an estimate of
      the distribution of forces across the joint. RESULTS: Topographical variation of
      water content, stiffness, cell count or incorporated radioisotope was not
      significant whereas collagen and glycosaminoglycan varied in different ways. A
      moderate correlation was found between water and collagen contents, but the
      correlation between water and glycosaminoglycan contents was poor. Neither
      compressive stiffness nor creep compliance was predicted strongly by any of the
      composition measurements. A negative correlation was found between metabolic
      activity and cell density. CONCLUSIONS: Defining the variation of tissue
      properties across the bovine carpometacarpal joint and the lack of variation in
      biosynthetic activity will enable proper matching of experimental and control
      groups of biopsies in studies of the effects of mechanical stimuli on the
      composition and mechanical properties of articular cartilage. In addition, the
      lack of correlation between stiffness, water and glycosaminoglycan contents is
      further evidence that the mechanical properties of the tissue depend
      significantly on factors other than these broad measures of composition.

PMID- 10343772
TI  - Osteoarthritic cartilage fibrillation is associated with a decrease in
      chondrocyte adhesion to fibronectin.
AB  - OBJECTIVE: Cartilage destruction in osteoarthritis (OA) is generally accepted as
      a failed repair process. Cell adhesion is implicated in tissue repair. Therefore,
      adhesion of OA chondrocytes to extracellular matrix proteins was investigated.
      DESIGN: Using chondrocytes from human OA femoral head cartilage, adhesion to
      fibronectin and type II collagen of cells from distinct areas showing an intact
      cartilage surface or a fibrillated cartilage surface was studied. Modulation of
      chondrocyte adhesion by both protein kinase C (PKC) inhibitors and glucosamine
      sulfate (GS) was also investigated. RESULTS: A significant (P < 0.05) decrease in
      adhesion to fibronectin of chondrocytes from fibrillated cartilage, relative to
      those from grossly normal OA cartilage, was demonstrated. Adhesion to type II
      collagen was not modified by the chondrocyte origins (either from normal or
      fibrillated OA cartilage). Adhesion to fibronectin of cells from grossly intact
      cartilage was decreased by the addition of PKC and calmodulin-dependent kinase
      inhibitors, W7 and sphingosine, to the cell culture. Adhesion to fibronectin of
      chondrocytes from fibrillated cartilage was significantly (P < 0.05) increased
      after glucosamine sulfate treatment. CONCLUSION: Fibrillation of cartilage from
      OA femoral head is associated with a defective adhesion of chondrocytes to
      fibronectin. The process is suggested to be dependent of PKC and/or calmodulin
      dependent kinases and potentially reversible. Conceivably, it could play a role
      in OA cartilage destruction.

PMID- 10343773
TI  - Maturation-related compressive properties of rabbit knee articular cartilage and
      volume fraction of subchondral tissue.
AB  - OBJECTIVE: Knowledge about the physiologic change in cartilage biomechanics,
      accompanying the structural remodeling of the cartilage bone unit during
      maturation, may have relevance to understand the development of joint disease.
      The purpose of this study was to investigate maturation-dependent changes of
      compressive properties of articular cartilage and volume fraction of subchondral
      tissue in healthy rabbit knees. METHODS: Cartilage compressive properties
      (instantaneous and creep moduli) were tested at seven defined knee joint regions
      of five young (ten weeks), five adolescent (eighteen weeks) and five adult (above
      thirty-one weeks) healthy rabbits with in-situ indentation tests. Morphometric
      analysis of volume fraction of subchondral tissue was carried out at four
      regions. RESULTS: Cartilage stiffness (instantaneous modulus) decreased between
      infancy and adolescence (P < 0.009), and stayed then the same. A simultaneous
      significant change in (50-second) creep modulus was only observed at one region,
      but both moduli correlated to each other. Subchondral tissue consisted of
      cancellous bone in the young, and formed a more solid bone plate not before
      adolescence. Its volume fraction increased from infancy to adolescence (P <
      0.001), but stayed then the same. There was a significant inverse correlation
      between the volume fraction of subchondral tissue and cartilage stiffness at the
      four measured regions (R2 = -0.59). The arrangement of collagen fiber bundles in
      the deeper cartilage layers changed from a mesh-like structure in the young to a
      more perpendicular alignment in the adolescent and adult. CONCLUSION: The
      maturation-related change in compressive properties coincided with a conspicuous
      change in volume fraction of the subchondral tissue. The main change appeared
      around puberty.

PMID- 10343774
TI  - Proteoglycan turnover during development of spontaneous osteoarthrosis in guinea
      pigs.
AB  - OBJECTIVE: The study was performed to clarify the metabolic background of the
      variations in proteoglycan concentrations, relating to ageing and the spontaneous
      development of osteoarthrosis in guinea pigs. METHODS: Six-, 9- and 12-month-old
      Hartley guinea pigs were injected intraperitoneally with Na2(35)SO4. The
      incorporation and degradation of various proteoglycans were analyzed in different
      areas of tibial articular cartilage during the development of osteoarthrosis.
      RESULTS: Proteoglycan synthesis was most active in the uncalcified cartilage of 6
      month animals and highest in the medial compartment with its presumably higher
      load. The breakdown of proteoglycans decreased with age. The onset of
      osteoarthrosis was associated with decreased synthesis of large and small
      proteoglycans, while the rate of degradation remained unchanged. CONCLUSION:
      During onset of osteoarthrosis the synthesis of large proteoglycans gradually
      becomes insufficient to compensate for the simultaneous degradation. This differs
      from findings in more rapidly progressing, experimental secondary osteoarthrosis,
      where a substantial increase in the rate of degradation is more conspicuous.

PMID- 10343775
TI  - Collagen type I antisense and collagen type IIA messenger RNA is expressed in
      adult murine articular cartilage.
AB  - OBJECTIVE: Articular cartilage has only limited capacities for repair and it is
      not known what is the exact mechanism of matrix restoration. It was investigated
      whether the reparative process in murine articular cartilage after moderate
      proteoglycan depletion is accompanied by a change in the chondrocyte phenotype
      either to hypertrophy or to a less differentiated phenotype as assayed by the
      expression of specific collagen subtypes. DESIGN: Moderate proteoglycan depletion
      was induced by injection of papain whereafter the expression of collagen type I
      mRNA, collagen IIA and IIB mRNA and type X collagen mRNA in patellar cartilage,
      as markers for chondrocyte phenotype, was investigated by RT-PCR during normal
      cartilage physiology and matrix restoration. In addition, in-situ expression of
      collagen subtypes was assayed by immunolocalisation. RESULTS: In normal articular
      cartilage collagen I, collagen IIB and collagen type X transcripts were easily
      detected. Surprisingly, collagen type I sense as well as antisense mRNA was
      detected and in addition to IIB transcripts collagen IIA transcripts were
      detected in a number of samples. During cartilage matrix restoration no change in
      the expression of collagen I, collagen IIA or IIB or collagen type X mRNA
      transcripts could be detected. Immunolocalization demonstrated the presence of
      type I (pericellular) and type II collagen in the extracellular matrix. The
      pericellular matrix of hypertrophic chondrocytes showed collagen type X staining
      in the calcified cartilage in normal and papain-injected knee joints. Increased
      staining for collagen type X was found in the upper cartilage layer in the
      interterritorial matrix from day 7 after papain injection. CONCLUSION: The
      absence of changes in collagen mRNA expression indicates that alteration of
      chondrocyte phenotype does not occur during the successful repair process after
      moderate proteoglycan depletion. Collagen type X appears to be deposited in the
      upper cartilage layer during this process.

PMID- 10343776
TI  - Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes
      isolated from human osteoarthritic articular cartilage in vitro.
AB  - OBJECTIVE: This study investigated the in-vitro effects of a crystalline
      glucosamine sulfate (GS) preparation on DNA synthesis and on proteoglycan (PG)
      and type II collagen (coll II) production by human articular chondrocytes
      isolated from human osteoarthritic articular cartilage in a 3-dimensional culture
      system for 4, 8, and 12 days. MATERIALS AND METHODS: Human articular chondrocytes
      from osteoarthritic femoral heads were isolated from their matrix by collagenase
      digestion and then cultured in suspension. Under constant agitation, cells
      aggregated and formed a cluster within a few days. The effects of GS (1-100
      micrograms/ml) on chondrocytes were determined by quantifying DNA synthesis (by
      measurement of [3H]-thymidine uptake) as well as PG and coll II production using
      radiommunoassays (RIAs) specific for coll II and to human human cartilage PG.
      Cross-reaction with GS in the RIAs was not detected. Moreover, PG size
      distribution was determined by exclusion chromatography under associative
      conditions to determine the association of PG monomers with hyaluronic acid (HA)
      to form large molecular weight PG aggregates. RESULTS: Under the above
      conditions, PG production in culture media and chondrocyte clusters was increased
      by GS (10-100 micrograms/ml). DNA synthesis and coll II production were not
      modified by GS. In addition, GS did not modify the physico-chemical form of PG
      produced by cells during culture. CONCLUSIONS: Glucosamine sulfate did not affect
      DNA synthesis nor coll II production but caused a statistically significant
      stimulation of PG production by chondrocytes from human osteoarthritic cartilage
      cultured for up to 12 days in 3-dimensional cultures.

PMID- 10343778
TI  - Comparison between the WOMAC and the Lequesne indices in patients with knee and
      hip osteoarthritis.

PMID- 10343777
TI  - Production of cartilage oligomeric matrix protein (COMP) by cultured human dermal
      and synovial fibroblasts.
AB  - OBJECTIVE: Cartilage oligomeric matrix protein (COMP) is a large disulfide-linked
      pentameric protein. Each of its five subunits is approximately 100,000 Da in
      molecular weight. COMP was originally identified and characterized in cartilage
      and it has been considered a marker of cartilage metabolism because it is
      currently thought not to be present in other joint tissues, except for tendon. To
      confirm the tissue specificity of COMP expression we examined cultured human
      dermal fibroblasts, human foreskin fibroblasts, and normal human synovial cells
      for the synthesis of COMP in culture. METHOD: Normal synovial cells and normal
      human dermal foreskin fibroblasts were isolated from the corresponding tissues by
      sequential enzymatic digestions and cultured in media containing 10% fetal bovine
      serum until confluent. During the final 24 h of culture, the cells were labeled
      with 35S-methionine and 35S-cysteine in serum- and cysteine/methionine-free
      medium. The newly synthesized COMP molecules were immunoprecipitated from the
      culture media with a COMP-specific polyclonal antiserum, or with monoclonal
      antibodies or affinity-purified COMP antibodies. The immunoprecipitated COMP was
      analyzed by electrophoresis in 5.5% polyacrylamide gels. For other experiments,
      synovial cells cultured from the synovium of patients with rheumatoid arthritis
      (RA) and osteoarthritis (OA) were similarly examined. RESULTS: A comparison of
      the amounts of COMP produced by each cell type (corrected for the DNA content)
      revealed that synovial cells produced > or = 9 times more COMP than chondrocytes
      or dermal fibroblasts. COMP could be easily detected by immunoprecipitation in
      all cell types. Electrophoretic analysis revealed a distinct band with an
      apparent MW of 115-120 kDa in samples from each of the three cell types,
      regardless of the antibody used. COMP expression in cultures of synoviocytes
      derived from OA and RA patients showed that OA and RA synovial cells produced
      similar amounts of monomeric COMP of identical size to those COMP monomers
      produced by normal synovial cells. The addition of TGF-beta to these cultures
      resulted in an increase in COMP production in normal, OA and RA synovial cells
      (45, 116 and 115% respectively). CONCLUSION: These studies demonstrate that
      substantial amounts of COMP are produced by several mesenchymal cells including
      synoviocytes and dermal fibroblasts. These findings raise important concerns
      regarding the utility of measurements of COMP levels in serum or in synovial
      fluid as markers of articular cartilage degradation because of the likelihood
      that a substantial proportion of COMP or COMP fragments present in serum or
      synovial fluid may be produced by cells other than articular chondrocytes.

PMID- 10343779
TI  - Dominant frequency content of ocular microtremor from normal subjects.
AB  - Ocular microtremor (OMT) is a high frequency tremor of the eyes present during
      fixation and probably related to brainstem activity (Coakley, D. (1983). Minute
      eye movement and brain stem function. CRC Press, FL.). Published observations on
      the frequency of OMT have varied widely. Ocular microtremor was recorded in 105
      normal healthy subjects using the Piezoelectric strain gauge technique. The
      dominant frequency content of a signal was determined using the peak counting
      method. Values recorded ranged from 70 to 103 Hz, the mean frequency being 83.68
      Hz (S.D. +/- 5.78 Hz).

PMID- 10343780
TI  - Looking behind a pathological blind spot in human retina.
AB  - Recent work suggests that dichoptic lateral interactions occur in the region of
      the visual field of one eye that corresponds to the physiological blind spot in
      the other eye (Tripathy, S. P., & Levi, D. M. (1994). The two-dimensional shape
      of spatial interaction zones in the parafovea. Vision Research, 34, 1127-1138.)
      Here we ask whether dichoptic lateral interactions occur in the region of the
      visual field of one eye that corresponds to a pathological blind spot, a retinal
      coloboma in the other eye. To address this question we had the observer report
      the orientation of a letter 'T' presented within this region in the presence of
      flanking 'T's presented to the other eye around the coloboma. A large drop in
      performance was seen due to the flanks, showing the existence of dichoptic
      lateral interactions in this monocular region. The presence of these dichoptic
      interactions in a region lacking direct retinal afferents from one eye is
      consistent with the proposition that long-range horizontal connections of the
      primary visual cortex mediate these interactions.

PMID- 10343781
TI  - Visual discrimination of direction changes based upon two types of angular
      motion.
AB  - We address the question of how the visual system analyses changes in direction.
      Using plaid stimuli, we define type O direction changes which entail a change in
      the orientations of the plaid components, and type V direction changes in which
      the orientations of the components remain constant, relative to the observer but
      their relative speeds change. Lower thresholds for discriminating type O and type
      V direction changes were compared. Type O thresholds for clockwise/anticlockwise
      direction change were very low (0.2-0.5 degree), were resistant to directional
      noise, and showed a low-pass relationship with drift velocity. Type V thresholds
      on the other hand were higher (1-5 degrees), and exhibited a bandpass
      relationship with drift velocity. Type O direction changes gave low thresholds at
      short inter-stimulus intervals (ISI) (< 160 ms) and higher thresholds (successive
      orientation discrimination) at long ISI (240 ms-12.8 s). Type V thresholds, on
      the other hand, exhibited no short-range process and performance at short ISI,
      was no better than for successive direction discrimination at long ISI. A two
      stage rotary motion model is sufficient to explain the discrimination of type O
      direction changes and results rule out a model based on velocity discrimination.
      For type V direction changes, a two-stage mechanism is insufficient and results
      are consistent with a minimum of three computational stages.

PMID- 10343782
TI  - A comparison of the dynamics of simple (Fourier) and complex (non-Fourier)
      mechanisms in texture segregation.
AB  - Models of texture segregation frequently feature two processing mechanisms:
      simple, linear channels (1st-order, Fourier mechanisms) and complex channels (2nd
      order, non-Fourier mechanisms). Using texture patterns designed to segregate
      primarily as a result of activity in one set of channels or the other, we
      employed the method of cued response to obtain speed-accuracy tradeoff (SAT)
      functions measuring the time course of texture segregation processing in simple
      and complex channels. Here, both simple-channel and complex-channel patterns are
      composed of Gabor-patch texture elements, thus equating input to simple channels
      and the first stage of complex channels. Subjects were required to identify the
      orientation of a rectangular texture-region embedded in a background field of a
      different texture. SAT functions were obtained by requiring subjects to respond
      within 200 ms after an auditory cue. We found that: (1) when segregation depended
      primarily on activity in simple channels, performance was faster and better than
      when it depended primarily on complex channels; (2) in contrast to a previous
      study (Sutter, A., & Graham, N. (1995). Investigating simple and complex
      mechanisms in texture segragation using the speed-accuracy tradeoff method.
      Vision Research, 35, 2825-2843), simple-channel (Fourier) patterns composed of
      two textured regions were just as easily segregated as simple-channel patterns in
      which one of the regions was blank instead of textured; (3) performance with
      complex-channel patterns composed of diagonally oriented Gabor-patches was
      considerably worse than performance with complex-channel patterns composed of
      vertically and/or horizontally oriented Gabor-patches; (4) among simple-channel
      patterns containing only one region of texture (background-only or rectangle
      only), there were minimal differences in performance; and (5) as in previous
      experiments, there were large individual differences in the segregation of
      complex-channel (non-Fourier) patterns. All of the above results can be explained
      within the framework of the simple- and complex-channels model of texture
      segregation.

PMID- 10343783
TI  - An optimal estimation approach to visual perception and learning.
AB  - How does the visual system learn an internal model of the external environment?
      How is this internal model used during visual perception? How are occlusions and
      background clutter so effortlessly discounted for when recognizing a familiar
      object? How is a particular object of interest attended to and recognized in the
      presence of other objects in the field of view? In this paper, we attempt to
      address these questions from the perspective of Bayesian optimal estimation
      theory. Using the concept of generative models and the statistical theory of
      Kalman filtering, we show how static and dynamic events occurring in the visual
      environment may be learned and recognized given only the input images. We also
      describe an extension of the Kalman filter model that can handle multiple objects
      in the field of view. The resulting robust Kalman filter model demonstrates how
      certain forms of attention can be viewed as an emergent property of the
      interaction between top-down expectations and bottom-up signals. Experimental
      results are provided to help demonstrate the ability of such a model to perform
      robust segmentation and recognition of objects and image sequences in the
      presence of occlusions and clutter.

PMID- 10343784
TI  - Biometric, optical and physical changes in the isolated human crystalline lens
      with age in relation to presbyopia.
AB  - The biometric, optical and physical properties of 19 pairs of isolated human eye
      bank lenses ranging in age from 5 to 96 years were compared. Lens focal length
      and spherical aberration were measured using a scanning laser apparatus, lens
      thickness and the lens surface curvatures were measured by digitizing the lens
      profiles and equivalent refractive indices were calculated for each lens using
      this data. The second lens from each donor was used to measure resistance to
      physical deformation by providing a compressive force to the lens. The lens
      capsule was then removed from each lens and each measurement was repeated to
      ascertain what role the capsule plays in determining these optical and physical
      characteristics. Age dependent changes in lens focal length, lens surface
      curvatures and lens resistance to physical deformation are described. Isolated
      lens focal length was found to be significantly linearly correlated with both the
      anterior and posterior surface curvatures. No age dependent change in equivalent
      refractive index of the isolated lens was found. Although decapsulating human
      lenses causes similar changes in focal length to that which we have shown to
      occur when human lenses are mechanically stretched into an unaccommodated state,
      the effects are due to nonsystematic changes in lens curvatures. These studies
      reinforce the conclusion that lens hardening must be considered as an important
      factor in the development of presbyopia, that age changes in the human lens are
      not limited to the loss of accommodation that characterizes presbyopia but that
      the lens optical and physical properties change substantially with age in a
      complex manner.

PMID- 10343785
TI  - Effects of a benzodiazepine, lorazepam, on motion integration and segmentation:
      an effect on the processing of line-ends?
AB  - Previous studies have shown that the perceptual integration of component motions
      distributed across space is inhibited whenever segmentation cues, such as line
      ends, are salient. Herein, we investigate to what extent enhanced inhibition
      induced by lorazepam, a benzodiazepine facilitating the fixation of GABA on GABAA
      receptors, modifies the balance between motion integration and motion
      segmentation at the behavioural level. Motion integration was tested in 16
      healthy volunteers taking a single and oral dose of either placebo or lorazepam
      (0.038 mg kg-1). The stimulus consisted of an outlined diamond presented behind
      four, otherwise invisible, apertures and translating along a circular trajectory
      (Lorenceau & Shiffrar (1992). Vision Research, 32, 263-273). Under these
      conditions, recovering the global diamond direction requires the integration of
      the component motions available within each aperture. The observers were asked to
      discriminate the global, clockwise or counter-clockwise, diamond direction under
      difficult--at high luminance contrasts--or easy--at low luminance contrasts-
      conditions. Overall, reaction times and error rates increased in the lorazepam
      group as compared to the placebo group, suggesting strong non-specific effects.
      However, the changes in performance in the lorazepam group are not homogeneous
      across conditions, suggesting that lorazepam also induces specific effects that
      modulate the integration/segmentation balance. Additional experiments performed
      with visible apertures or visible diamond vertices indicate that the effects of
      lorazepam are unlikely to reflect a deficit of motion processing or motion
      integration mechanisms since performance is only slightly impaired in the
      lorazepam as compared to the placebo group under these conditions. These results
      suggest that lorazepam might specifically modulate the saliency of line-ends,
      presumably because processing these features involves inhibitory mechanisms using
      GABA as a neuromediator, and in turn modify the balance between motion
      integration and segmentation.

PMID- 10343786
TI  - Hepatic retinopathia: changes in retinal function.

PMID- 10343787
TI  - Measurement of the eye's near infrared wave-front aberration using the objective
      crossed-cylinder aberroscope technique.
AB  - We used the crossed-cylinder aberroscope technique to obtain the near infrared
      (784 nm) wave-front aberration of the human eye. We compared the results with
      those obtained under the same conditions using red light (633 nm). Other than the
      greater retinal scattering of the near infrared light, third- and fourth-order
      wave-front aberrations are similar in both wavelengths. Values of the calculated
      near infrared point spread function show a typical half-height width of around 2
      arcmin, which is in good agreement with previous work.

PMID- 10343788
TI  - The depth-of-field of the human eye from objective and subjective measurements.
AB  - The depth-of-field (DOF) measured through psychophysical methods seems to depend
      on the target's characteristics. We use objective and subjective methods to
      determine the DOF of the eye for different pupil diameters and wavelengths in
      three subjects. Variation of image quality with focus is evaluated with a double
      pass technique. Objective DOF is defined as the dioptric range for which the
      image quality does not change appreciably, based on optical criteria. Subjective
      DOF is based on the accuracy of focusing a point source. Additional DOFs are
      obtained by simulation from experimental wavefront aberration data from the same
      subjects. Objective and subjective measurements of DOF are only slightly affected
      by pupil size, wavelength and spectral composition. Comparison of DOF from double
      pass and wavefront aberration data allows us to evaluate the role of ocular
      aberrations and Stiles-Crawford effect.

PMID- 10343789
TI  - Learning of interpolation in 2 and 3 dimensions.
AB  - We investigated learning of spatio-temporal interpolation in depth and its
      relation to spatio-temporal interpolation in two dimensions by means of a vernier
      discrimination task. Performance improved with training but improvement did not
      or only partially transfer between opposite directions of motion in depth.
      Improvement was also at least partly specific for the eye and for the direction
      of two-dimensional motion used during monocular training. This specificity might
      explain the apparent specificity of interpolation in three dimensions. Training
      with stimuli moving in two dimensions increased performance for a stimulus moving
      in depth. The results indicate that improvement in spatio-temporal interpolation
      occurs at least partly on a stage preceding stereoscopic vision, and are a rare
      example for transfer of improvement between different perceptual tasks.

PMID- 10343790
TI  - The time course of psychophysical end-stopping.
AB  - This study measured the time course of psychophysical end-stopping and compared
      it with the time course of masking. For a 10' D6 target on an 18' D6 pedestal,
      two abutting end-zone masks (each 13.5' long) covering the filter end-zones
      reduce masking. This facilitatory 'end-stopping' effect was measured over a range
      of exposure durations and stimulus onset asynchronies (SOAs). We found that
      psychophysical end-stopping has a delayed onset which is around 70-100 ms after
      stimulus onset, in contrast to masking which is robust immediately after stimulus
      onset, suggesting intracortical feedback processes in the generation of
      psychophysical end-stopping. The development course of psychophysical end
      stopping is relatively long and lasts for approximately 150-200 ms after stimulus
      onset, in contrast to that of masking which lasts for approximately 100-150 ms.
      Our results also showed that end-stopping occurs only when the center mask and
      the end-zone masks have sufficient temporal overlap, possibly indicating that the
      feedback process for generating end-stopping is triggered by the activation of
      the spatial filter center by the center mask. These results are in tune with
      current knowledge of intracortical feedback modulating activities of receptive
      fields, and have been incorporated into our model to describe the temporal
      dynamics within end-stopped spatial filters.

PMID- 10343792
TI  - Characteristics of accommodation toward apparent depth.
AB  - This paper deals with characteristics of accommodation evoked by perceived depth
      sensation and the dynamic relationship between accommodation and vergence,
      applying newly developed optical measurement apparatuses. A total of five
      subjects looked at three different two-dimensional stimuli and two different
      three-dimensional stimuli; namely a real image and a stereoscopic image. With
      regard to the two-dimensional stimuli, a manifest accommodation without any
      accompanying vergence was found because of an apparent depth sensation even
      though the target distance was kept constant. With regard to the three
      dimensional stimuli, larger accommodation and clear vergence were evoked because
      of binocular parallax and a stronger depth sensation. As for the stereoscopic
      image, a manifest overshoot (the accommodation peaked first and receded
      considerably) was found while the vergence remained constant. On the other hand,
      the overshoot of accommodation was smaller when subjects were watching the real
      image. These results reveal that brain depth perception has a higher effect on
      accommodation than expected. The relationship of accommodation and vergence
      toward the stereoscopic image suggests a reason why severe visual fatigue is
      commonly experienced by many viewers using stereoscopic displays. It has also
      paved the way for the numerical analysis of the oculomotor triad system.

PMID- 10343791
TI  - Which end is up? Two representations of orientation in visual search.
AB  - What is the orientation of an object? A simple line has an axis of orientation.
      That line, turned upside-down, is indistinguishable from the original line. Thus,
      the possible orientations of a line range from 0 to 180 degrees. Most objects,
      however, have an axis and a polarity. A polar object, turned upside-down, looks
      upside-down. Accordingly, the orientations of a polar object range from 0 to 360
      degrees. A series of visual search experiments were run to determine if
      preattentive processes represent orientation in a 180 or a 360 degrees framework.
      Results suggest that preattentive orientation is represented in 180 degrees.
      Experiments 1 and 4 show that search for a target rotated 90 degrees from the
      distractors is more efficient than search for a target rotated 180 degrees from
      the distractors. Experiments 2, 3, and 5 use a variety of different stimuli to
      demonstrate that search for targets rotated 180 degrees from distractors is
      inefficient.

PMID- 10343793
TI  - Spatial masking does not reveal mechanisms selective to combined luminance and
      red-green color.
AB  - Detection thresholds plotted in the L and M cone-contrast plane have shown that
      there are two primary detection mechanisms, a red-green hue mechanism and a light
      dark luminance mechanism. However, previous masking results suggest there may be
      additional mechanisms, responsive to combined features like bright and red or
      dark and green. We measured detection thresholds for a 1.2 c deg-1 sine-wave
      grating in the presence of a spatially matched mask grating which was either
      stationary, dynamically jittered or flickered. The stimuli could be set to any
      direction in the L,M plane. The appearance of selectivity for combined hue and
      luminance arose only in conditions where adding the test to the mask modified the
      spatial phase offset between the luminance and red-green stimulus components.
      Sensitivity was very high for detecting this spatial phase offset. When this
      extra cue was eliminated, masking contours in the L,M plane could be largely
      described by the classical red-green and luminance mechanisms.

PMID- 10343794
TI  - Cueing and pop-out.
AB  - We describe experiments on the dynamics of pop-out from orientation. Target lines
      at an oblique orientation and orthogonal background elements were presented with
      various onset delays, and subjects' performance in target detection was measured.
      Detection rates increased for short delays compared to synchronous stimulus
      presentation, with a maximum at delta t = 30-60 ms. Control experiments showed
      that this effect did not reveal specific interactions between target and
      background lines; a similar effect was obtained when targets were cued with non
      oriented stimuli presented shortly before stimulus onset. Specific and non
      specific cues improved the target detection rate even when four cues, at
      different potential target positions were shown simultaneously. Non-localized
      cues, however, and cues at positions irrelevant for the task did not improve
      performance. While the effect might partially resemble the temporal modulation
      transfer function of the visual system, we did not find evidence for other
      dynamic processes in the tested time intervals (10-300 ms), in particular not for
      synchronization effects as assumed to provide perceptual linking of background
      elements.

PMID- 10343795
TI  - On the apparent collapse of stereopsis in random-dot-stereograms at isoluminance.
AB  - We have investigated the apparent collapse of stereopsis obtained with random-dot
      stereograms at isoluminance. Contrast thresholds for both depth and form
      discrimination of targets in random-dot- and figural stereograms were measured at
      a number of disparitics, using both isoluminant and isochromatic stimuli. All
      contrast thresholds for stereoscopic tasks were normalised to contrast thresholds
      for detecting the appropriate stimulus. We found that at isoluminance contrast
      thresholds for depth judgements were not higher for random-dot compared to
      figural stereograms, even when normalised to the same thresholds obtained with
      isochromatic stimuli. On the other hand contrast thresholds for three-dimensional
      form judgements were much higher than those for depth judgements in isoluminant,
      compared to isochromatic random-dot-stereograms. This specific impairment of
      stereoscopic form (as opposed to depth) processing at isoluminance was confirmed
      in a further experiment in which subjects were required to judge the presence and
      orientation of depth corrugations in a disparity-modulated random-dot-stereogram.

PMID- 10343796
TI  - Eye movements of rhesus monkeys directed towards imaginary targets.
AB  - Is the presence of foveal stimulation a necessary prerequisite for rhesus monkeys
      to perform visually guided eye movements? To answer this question, we trained two
      rhesus monkeys to direct their eyes towards imaginary targets defined by
      extrafoveal cues. Independent of the type of target, real or imaginary, the
      trajectory of target movement determined the type of eye movement produced: steps
      in target position resulted in saccades and ramps in target position resulted in
      smooth pursuit eye movements. There was a tendency for the latency of saccades as
      well as pursuit onset latency to be delayed in the case of an imaginary target in
      comparison to the real target. The initial eye acceleration during smooth pursuit
      initiation elicited by an imaginary target decreased in comparison to the
      acceleration elicited by a real target. The steady-state pursuit gain was quite
      similar during pursuit of an imaginary or a real target. Our results strengthen
      the notion that pursuit is not exclusively a foveal function.

PMID- 10343797
TI  - Neuronal responses to plaids.
AB  - The majority of neurons in the visual cortex are orientation selective. When
      presented with a plaid, i.e. a stimulus generated by adding two gratings of
      different orientations, these neurons respond to the individual gratings making
      up the plaid. However, there are some pattern selective neurons in Area MT of the
      monkey visual cortex which respond in accordance with the combined plaid. The
      present study used computer simulation to investigate the response properties of
      simulated MT neurons to orthogonal plaids. The MT neurons were simulated by first
      multiplying the outputs of conventional orientation selective V1 neurons and then
      normalizing the product. It was discovered that pattern selective responses may
      emerge when the outputs from two orientation selective neurons, which differ in
      optimal orientation by more than about 50 degrees, are combined in this manner.
      This demonstrates that pattern selectivity may be the result of a very simple
      although nonlinear mechanism.

PMID- 10343798
TI  - The effects of ageing on reaction times to motion onset.
AB  - We have measured reaction time (RT) to motion onset in two groups of subjects
      (average ages: 70 and 29 years), for horizontal gratings of 1 c deg-1, modulated
      in either luminance or colour (equiluminant red-green), for various contrasts and
      speeds. For both old and young subjects, RTs depended on both speed and contrast,
      being faster at high speeds and high contrasts, and showed a stronger contrast
      dependency for chromatic gratings. The older subjects were systematically slower
      than the younger subjects. The difference between old and young RTs varied with
      condition, being 30-40 ms more at the slow than at the fast speed. The relative
      difference in RTs in different stimulus conditions shows that at least some of
      the increase in response time with age has a sensory origin. The results relate
      well to previous work on visual evoked potentials.

PMID- 10343799
TI  - Electrophysiological properties of a new isolated rat retina preparation.
AB  - A piece of rat retina was mounted in an open chamber and perfused with a Ringer
      solution at 37 degrees C. The electroretinogram (ERG) was recorded between an
      extracellular microelectrode in contact with the rod outer segments and a
      reference electrode under the retina. The addition of 250-500 microM of glutamate
      to the media prevented the b-wave from decaying in amplitude with time. Minor
      components of the ERG, the scotopic threshold response (STR) and oscillatory
      potentials (OPs), were well maintained with glutamate in the media. Experiments
      on the spatial properties of the recordings indicated that a small area
      immediately around the microelectrode contributes most strongly to the response.
      The similarity of ERGs recorded in vivo from the cornea to the transretinal ERGs
      from the isolated retina of the same animal indicated that the functional
      integrity of the isolated retina was well preserved in the media with glutamate.

PMID- 10343800
TI  - Uneven mapping of magnocellular and parvocellular projections from the lateral
      geniculate nucleus to the striate cortex in the macaque monkey.
AB  - Central vision is substantially over represented in the lateral geniculate
      nucleus (dLGN) and striate cortex. The over representation could be accompanied
      by a selective expansion of central vision in parvocellular dLGN, in which case
      the ratio of parvocellular to magnocellular inputs to striate cortex should
      change with retinal eccentricity. To test this, sample ratios were determined
      from counts of neurons in dLGN labelled retrogradely with WGA-HRP from striate
      cortex at the cortical representations of various eccentricities. Parvocellular
      to magnocellular ratios decreased from a mean of 35:1 at the fovea to 5:1 at 15
      degrees eccentricity. Furthermore, they exceeded the ratio of P beta to P alpha
      ganglion cells in central retina, but not in peripheral retina, showing that the
      uneven P to M ratio in the LGN does not merely mirror the distribution of
      ganglion cells in the retina. This provides direct evidence for selective over
      representation of central vision in parvocellular dLGN.

PMID- 10343801
TI  - Target detection against narrow band noise backgrounds.
AB  - We studied the detectability of narrow band random noise targets embedded in
      narrow band random noise backgrounds as a function of differences in center
      frequency, spatial frequency bandwidth and orientation bandwidth between target
      and the immediately adjacent background. Unlike most target detection experiments
      the targets were not added to the background; they replaced the underlying
      background texture. Simulations showed that target detection probabilities could
      be accounted for by a simple transformation on the summed outputs of a two layer
      filter model similar to the complex channels model proposed by Graham, Beck and
      Sutter (Graham, N., Beck, J., & Sutter, A. (1992). Vision Research, 32, 719-743).
      Subsequently, the model was tested on the detection of camouflaged vehicle
      targets with encouraging results.

PMID- 10343802
TI  - Axis-of-motion affects direction discrimination, not speed discrimination.
AB  - The motion of an object can be described by a single velocity vector, or
      equivalently, by direction and speed separately. Similarly, our ability to see
      subtle differences in the motion of two objects could be constrained by either a
      velocity-based sensory response, or separate sensory responses to direction and
      speed. To distinguish between these possibilities we investigated whether
      direction discrimination and speed discrimination were differentially affected by
      changes in the axis-of-motion. Psychophysical data from 12 naive observers
      indicated that direction discrimination depended on axis-of-motion, but speed
      discrimination did not. The difference suggests that a velocity-based sensory
      response is not the limiting factor on the two tasks. Instead, the results imply
      that the sensory response which constrains speed discrimination is at least
      partially independent from the sensory response which constrains direction
      discrimination.

PMID- 10343803
TI  - The perception and discrimination of speed in complex motion.
AB  - Random dot kinematograms were used to simulate radial, rotational and spiral
      optic flow. The stimuli were designed so that, while dot speed increased linearly
      with distance from the centre of the display, the density of dots remained
      uniform throughout their presentation. In two experiments, subjects were required
      to perform a temporal 2AFC speed discrimination task. Experiment 1 measured the
      perceived speed of a range of optic flow patterns against a rotational comparison
      stimulus. Radial motions were found to appear faster than rotations by
      approximately 10%, with a smaller but significant effect for spirals. Experiment
      2 measured discrimination thresholds for pairs of similar optic flow stimuli
      identical in all respects except mean speed. No consistent differences were
      observed between the speed discrimination thresholds of radial, rotational and
      spiral motions and a control stimulus with the same speed profile in which motion
      followed fixed random trajectories. The perceived speed results are interpreted
      in terms of a model satisfying constraints on motion-in-depth and object
      rigidity, while speed discrimination appears to be based upon the pooled
      responses of elementary motion detectors.

PMID- 10343804
TI  - Enhanced motion aftereffect for complex motions.
AB  - We measured the magnitude of the motion after effect (MAE) elicited by gratings
      viewed through four spatial apertures symmetrically positioned around fixation.
      The gratings were identical except for their orientations, which were varied to
      form patterns of global motion corresponding to radiation, rotation or
      translation. MAE magnitude was estimated by three methods: the duration of the
      MAE; the contrast required to null the MAE and the threshold elevation for
      detecting an abrupt jump. All three techniques showed that MAEs for radiation and
      rotation were greater than those for translation. The greater adaptability of
      radiation and rotation over translation also was observed in areas of the display
      where no adapting stimulus had been presented. We also found that adaptation to
      motion in one direction had equal effects on sensitivity to motion in the same
      and opposite directions.

PMID- 10343805
TI  - Global-motion detection with transparent-motion signals.
AB  - A number of experiments were conducted to compare the ability of observers to
      extract unidirectional and bidirectional (transparent) global-motion signals. In
      the unidirectional condition, the noise signal consisted of purely randomly
      moving dots while in the bidirectional condition, a number of the randomly moving
      dots were replaced by the same number of dots moving in a specific (secondary
      signal) direction. The threshold measure was the minimum number of signal dots
      required to determine the global-motion direction. For the bidirectional
      condition, parameters varied were the angular separation between the global
      motion and secondary-signal directions and the strength of the secondary signal.
      Thresholds for unidirectional and bidirectional conditions were the same when the
      angular difference between global-motion and secondary-signal directions were 90
      degrees or greater, i.e. the ability of observers to extract a transparent signal
      was the same as their ability to extract a unidirectional one. Similarly, with
      motion-in-depth signals, thresholds for extracting a centripetal signal were not
      elevated by replacing a number of the randomly-moving noise dots with the same
      number centrifugally-moving dots. The results are interpreted as indicating that
      motion signals moving between 90 and 180 degrees to the global-motion direction
      provide uniform masking of the global-motion signal. For angular separations less
      than 90 degrees, a suprathreshold secondary signal resulted in threshold
      elevation. This result could be due, to stronger inhibition from motion units
      tuned to similar (< 90 degrees) directions, broad directional-tuning of the
      underlying motion units (changing the task from signal detection to a signal
      discrimination) or a combination of the two.

PMID- 10343806
TI  - Retinal ganglion cell response properties in the transcorneal electrically evoked
      response of the visual system.
AB  - To identify the retinal origin of a cortical evoked potential elicited by
      transcorneal electrical stimulation of the visual system (EER), the response
      properties of retinal ganglion cells (RGCs) of cats to transcorneal electrical
      stimuli were studied. The discharge latency of RGCs to transcorneal stimulation
      had two peaks with a high temporal resolution. The latency of early components of
      the EER is associated with the discharge latency of RGCs. Some RGCs showed
      prominent oscillatory discharges after transcorneal stimulation. Discharges of ON
      bipolar cells responding to transcorneal stimulation were significantly inhibited
      by intravitreal injection of DL-2-amino-4-phosphonobutyrate (APB), which blocks
      the ON-pathway. These findings indicate that the EER has far-field potentials
      that might relate to oscillatory discharges of RGCs, and that ON bipolar cells
      and their related synaptic sites are involved in transcorneal electrical stimuli.
      The far-field potentials of the EER may have clinical applications, similar to
      those of somatosensoric evoked potentials and auditory brain stem potentials.

PMID- 10343807
TI  - Early visual impairment is independent of the visuocognitive and memory
      disturbances in Alzheimer's disease.
AB  - Static and dynamic contrast sensitivity (SCS and DCS), semantic object
      identification, and verbal recall functions were evaluated in 20 Alzheimer's
      disease (AD) patients and in 20 control subjects. We found general SCS and DCS
      loss in the 0.48-14.34 c deg-1 spatial frequency range. In relation to the
      cognitive functions, semantic object identification was intact, whereas explicit
      memory was markedly impaired in the AD group. There was no significant
      correlation between the CS and the memory disturbances. The results suggest that
      early visual impairment and higher-level cognitive disturbances are independent
      in AD.

PMID- 10343808
TI  - Coherence and the judgment of spatial displacements in retinitis pigmentosa.
AB  - We used a motion coherence paradigm to test the hypothesis that patients with
      retinitis pigmentosa (RP) have difficulty discriminating the direction of spatial
      displacements because of a random loss of motion-sensitive units owing to cone
      photoreceptor dropout. Minimum (Dmin) and maximum (Dmax) displacement thresholds
      of patients with typical RP or Usher syndrome were compared with those of age
      similar, visually normal subjects. Two-frame random dot cinematograms were used,
      in which a group of target dots, which comprised 40-100% of the dot array in
      steps of 20%, were displaced in one of four directions, whereas the non-target
      dots were randomly repositioned between frames. Reducing the dot coherence in
      this way increased Dmin and reduced Dmax for both the RP patients and control
      subjects. Furthermore, the displacement thresholds of the RP patients were
      displaced laterally from normal along a log coherence axis, consistent with the
      hypothesis that the patients had a reduced effective (intrinsic) coherence.
      However, the displacement thresholds of control subjects, when measured at a
      reduced coherence, did not mimic those of RP patients at full coherence when both
      groups were tested with a range of dot contrasts and dot areas. These apparently
      discrepant findings can be reconciled if it is assumed that the patients'
      effective coherence varies with stimulus visibility.

PMID- 10343809
TI  - Rods induce transient tritanopia in blue cone monochromats.
AB  - Transient tritanopia is a cone-cone post-receptoral interaction between short
      wavelength (S) cones and medium (M) and long (L) wavelength cones. Blue cone
      monochromats have rods and S cones of normal sensitivity but lack functional M/L
      cones. All blue cone monochromats tested (n = 8) show significant amounts of
      transient tritanopia mediated by rods. Attempts to find a similar rod-S cone
      interaction while silencing the L/M cones in normals yielded only a small amount
      of S cone sensitivity loss. The results suggest an exaggerated influence of rods
      on the S cone pathway in the retina of blue cone monochromats.

PMID- 10343810
TI  - Identifying inner retinal contributions to the human multifocal ERG.
AB  - Contributions to the multifocal electroretinogram (ERG) from the inner retina
      (i.e. ganglion and amacrine cells) were identified by recording from monkeys
      before and after intravitreal injections of n-methyl DL aspartate (NMDLA) and/or
      tetrodotoxin (TTX). Components similar in waveform to those removed by the drugs
      were identified in the human multifocal ERG if the stimulus contrast was set at
      50% rather than the typically employed 100% contrast. These components were found
      to be missing or diminished in the records from some patients with glaucoma and
      diabetes, diseases which affect the inner retina.

PMID- 10343811
TI  - The role of optical defocus in regulating refractive development in infant
      monkeys.
AB  - Early in life, the two eyes of infant primates normally grow in a coordinated
      manner toward the ideal refractive state. We investigated the extent to which
      lens-induced changes in the effective focus of the eye affected refractive
      development in infant rhesus monkeys. The main finding was that spectacle lenses
      could predictably alter the growth of one or both eyes resulting in appropriate
      compensating refractive changes in both the hyperopic and myopic directions.
      Although the effective operating range of the emmetropization process in young
      monkeys is somewhat limited, the results demonstrate that emmetropization in this
      higher primate, as in a number of other species, is an active process that is
      regulated by optical defocus associated with the eye's effective refractive
      state.

PMID- 10343812
TI  - Light scattering model for donor lenses as a function of depth.
AB  - The amount of light scattered by normal donor lenses (n = 15, ages 43-82 years)
      from a 1 x 0.1 mm white slit beam was measured as a function of depth in the lens
      for seven angles from 10 to 165 degrees, and for four wavelengths from 400 to 700
      nm. Apart from the most superficial layers, the data could be described with a
      model that consisted of three components. (1) small sized protein particles
      (alpha-crystallin), (2) large sized protein particles and (3) spectrally neutral
      rough surface reflectance ('zones of discontinuity'). Component (1) and (3)
      dominate backward scattering. Component (2) dominates forward scattering, but
      occupies only around 0.000006 of the lens volume, with the lowest values in the
      nucleus. Component (3) is important for a small range of backward directions
      only, being much stronger in extranuclear areas than in the nucleus.

PMID- 10343813
TI  - Rival ideas about binocular rivalry.
AB  - Binocular rivalry has been used to investigate neural correlates of visual
      awareness. For this investigation to succeed, however, it is necessary to know
      what rivals during binocular rivalry. Recent work has raised questions about
      whether rivalry is between eyes or between stimuli. We find that stimulus rivalry
      occurs only within a limited range of spatial and temporal parameters--otherwise
      eye rivalry dominates.

PMID- 10343814
TI  - Spatial distortions in rotating radial figures.
AB  - A white sector on a black rotating disk appears spatially compressed. We found
      that apparent shrinkage: (1) for sectors ranging from 15 to 150 degrees and
      rotating at 1.25 rps varied in an inverted U-shaped manner from 3 to 16 degrees
      and back to 11 degrees (corresponding to 20, 16, and 7.5%, respectively); (2)
      increased with speed of rotation producing maximal compressions of between 7 and
      30 degrees for velocities ranging from 0.8 to 2 rps; and (3) affected the leading
      and the trailing portions of the rotating sector equally, while allowing for
      apparent expansion of the middle region. Consistent with these findings we found
      that (4) two black lines 20 mm apart across the center of the rotating disk and
      extending outward towards the edge appeared to converge when they were actually
      parallel and were seen as parallel when their end points were physically diverged
      by 6 degrees. Our findings suggest a foreshortening process which ensures that
      the shapes of moving stimuli are perceived approximately correctly, irrespective
      of whether they are actually sharp or blurred.

PMID- 10343815
TI  - Second-order motion discrimination by feature-tracking.
AB  - When a plaid pattern (the sum of two high spatial frequency gratings oriented +/-
      84 degrees from vertical) jumps horizontally by 3/8 of its spatial period its
      contrast envelope, a second-order pattern, moves in the opposite direction to its
      luminance waveform. Observers report that the pattern moves in the direction of
      the contrast envelope when the jumps are repeated at intervals of more than 125
      ms and in the direction of the luminance profile when they are repeated at longer
      intervals. When a pedestal [Lu, Z.-L. & Sperling, G. (1995). Vision Research, 35,
      2697-2722] is added to the moving plaid a higher contrast is required to see
      motion of the contrast envelope but not to see the motion of the luminance
      profile, suggesting that the motion of the contrast envelope is sensed by a
      mechanism that tracks features. Static plaids with different spatial parameters
      from the moving pattern are less effective at raising the contrast required to
      see the motion of the contrast envelope and simple gratings of low or high
      spatial frequency are almost completely ineffective, suggesting that the feature
      tracking mechanism is selective for the type of pattern being tracked and rejects
      distortion products and zero-crossings.

PMID- 10343816
TI  - On the mechanism for scale invariance in orientation-defined textures.
AB  - Texture perception is generally found to be scale invariant, that is, the
      perceived properties of textures do not change with viewing distance. Previously,
      Kingdom, F. A. A., Keeble, D. R. T., & Moulden, B. (Vision Research, 1995, 35, 79
      91) showed that the orientation modulation function (OMF), which describes
      sensitivity to sinusoidal modulations of micropattern orientation as a function
      of modulation spatial frequency, was scale invariant--peak sensitivity occurred
      at a modulation spatial frequency which was invariant with viewing distance when
      modulation frequency was plotted in object units, e.g. cycles cm-1. We have
      attempted to determine the mechanism underlying the scale invariant properties of
      the OMF. We first confirmed that the OMF was scale invariant using Gabor
      micropattern textures. We then measured OMFs at a number of viewing distances,
      while holding constant various stimulus features in the retinal image. The
      question was which stimulus feature(s) disrupted scale invariance when
      manipulated in this way. We found that the scale (size) of the micropatterns was
      a critical factor and that the most important scale parameter was the
      micropatterns' carrier spatial frequency. Micropattern length and density were
      shown to have a small influence on scale invariance, while micropattern width had
      no influence at all. These results are consistent with the idea that scale
      invariance in orientation-defined textures is a consequence of 'second-stage'
      texture-sensitive mechanisms being tied in spatial scale selectivity to their
      'first-stage' luminance-contrast-sensitive inputs.

PMID- 10343817
TI  - Stereoscopic depth but not shape perception from second-order stimuli.
AB  - Depth can be seen using either linear (first-order) or non-linear (second-order)
      stereo micropatterns when, in the latter, contrast envelopes contain the
      disparity information. We examined whether a second-order mechanism can
      contribute to the perception of 3-D surface shape. Using a variety of different
      stimulus types, we show that for each, shape is easy to see with linear stimuli.
      Over a wide range of parameters however, none of our observers perceived shape,
      however faintly, from the non-linear stimuli. To explore why these elements
      failed, we simplified our stimulus to a step-edge in depth and measured
      performance while varying the number of elements. We show how performance
      declined when more than two non-linear elements were used. We discuss reasons for
      the limitation found for non-matching elements, including a dissociation for
      stereopsis between seeing surface shape and depth.

PMID- 10343818
TI  - Temporal constraints on the grouping of contour segments into spatially extended
      objects.
AB  - The speed of contour integration was investigated in a task that can be solved by
      grouping contour segments into elongated curves. Subjects had to detect a
      continuous curve, which could be intersected by one or two other curves. At
      locations where these curves came in close proximity, the assignment of contour
      segments to the different curves could be based on collinearity. Reaction times
      exhibited a strong dependence on (1) the presence of intersections among curves;
      and (2) the context provided by the stimulus set from which individual stimuli
      were selected. Reaction times were shortest when grouping of contour segments
      depended on information at a single location in the visual field. In this
      condition, responses to stimuli containing an intersection were faster than
      responses to stimuli that did not. When responses were determined by information
      at spatially separate locations, responses were delayed, and every intersection
      increased the reaction time considerably. This result contrasts with earlier
      investigations which have suggested that contour integration on the basis of
      collinearity is performed pre-attentively but is in accordance with studies on
      curve tracing. We propose that the assignment of contour segments to equally
      coherent curves, a process which may be called figure-figure segregation, is a
      function of object-based attention. Moreover, the protracted reaction times for
      some of the stimuli indicate that spread of attention within an object costs
      time. This implies that object recognition is not always as fast as is sometimes
      assumed.

PMID- 10343819
TI  - Simultaneous color constancy: how surface color perception varies with the
      illuminant.
AB  - In two experiments simultaneous color constancy was measured using simulations of
      illuminated surfaces presented on a CRT monitor. Subjects saw two identical
      Mondrians side-by-side: one Mondrian rendered under a standard illuminant, the
      other rendered under one of several test illuminants. The matching field was
      adjusted under the test illuminant so that it (a) had the same hue, saturation,
      and brightness (appearance match) or (b) looked as if it were cut from the same
      piece of paper (surface match) as a test surface under the standard illuminant.
      Matches were set for three different surface collections. The surface matches
      showed a much higher level of constancy than the appearance matches. The
      adjustment in the surface matches was nearly complete in the L and M cone data,
      and deviations from perfect constancy were mainly due to failures in the
      adjustment of the S cone signals. Besides this difference in amount of
      adjustment, the appearance and surface matches showed two major similarities.
      First, both types of matches were well described by simple parametric models. In
      particular, a model based on the notion of von Kries adjustment provided a good,
      although not perfect, description of the data. Second, for both types of matches
      the illuminant adjustment was largely independent of the surface collection in
      the image. The two types of matches thus differed only quantitatively, there was
      no qualitative difference between them.

PMID- 10343820
TI  - Visual attention modifies spectral sensitivity of nystagmic eye movements.
AB  - If we look out of the window of a travelling train our eyes move rapidly back and
      forth (saccadic movement). With no attention to individual objects, gaze velocity
      is low but nystagmic frequency is high (stare nystagmus). If we are interested in
      individual objects, the angular velocity of gaze is high and the nystagmic
      frequency low (look nystagmus) (Ter Braak, J.W.G. (1936). Untersuchungen ueber
      optokinetischen Nystagmus. Archives Neerlandaises de Physiologie de L'homme et
      des Animaux, 21, 309-376). We show that the spectral sensitivities of the two
      types of nystagmus differ and that the short-wavelength-sensitive cones
      significantly contribute only to look nystagmus.

PMID- 10343821
TI  - Saccades require focal attention and are facilitated by a short-term memory
      system.
AB  - We performed two sets of experiments in which observers were instructed to make
      saccades to an odd colored target embedded in an array of distractors. First, we
      found that when the colors of the target and distractors switched unpredictably
      from trial to trial (the mixed condition), saccadic latencies decreased with
      increasing numbers of distractors. In contrast, saccadic latencies were
      independent of the number of distractors when the color of the target and
      distractors remained the same on each trial (the blocked condition). This pattern
      of results mirrors visual search tasks in which focal rather than distributed
      attention is required (Bravo, M.J., Nakayama, K. (1992). The role of attention in
      different visual search tasks. Perception and Psychophysics, 51, 465-472.).
      Second, we found that saccades to an odd target were made more quickly and
      accurately when the target was the same color as on previous trials than when it
      changed color. This priming of the target color accumulates across five to seven
      trials over a period of approximately 30 s. A similar priming effect has been
      previously shown for the deployment of focal attention (Maljkovic, V., Nakayama,
      K. (1994). Priming of popout: III. Role of features. Memory and Cognition, 22(6),
      657-672.). Thus, we show a close congruence between the pattern of saccadic eye
      movement latencies and the deployment of focal attention. This supports the view
      that (1) the execution of saccades requires focal as opposed to distributed
      attention and that (2) this focal attention is guided by a short term memory
      system which facilitates the rapid refixation of gaze to recently foveated
      targets.

PMID- 10343822
TI  - Peripheral vision and oculomotor control during visual search.
AB  - The present study concerns the dynamics of multiple fixation search. We tried to
      gain insight into: (1) how the peripheral and foveal stimulus affect fixation
      duration; and (2) how fixation duration affects the peripheral target selection
      for saccades. We replicated the non-corroborating results of Luria and Strauss
      (1975) ('Eye movements during search for coded and uncoded targets', Perception
      and Psychophysics 17, 303-308) (saccades were selective), and Zelinsky (1996)
      (Using eye movements to assess the selectivity of search movements. Vision
      research 36(14), 2177-2187) (saccades were not selective), by manipulating the
      critical features for peripheral selection and discrimination separately. We
      found search to be more selective and efficient when the selection task was easy
      or when fixations were long-lasting. Remarkably, subjects did not increase their
      fixation durations when the peripheral selection task was more difficult. Only
      the discrimination task affected the fixation duration. This implies that the
      time available for peripheral target selection is determined mainly by the
      discrimination task. The results of the present experiment suggest that, besides
      the difficulty of the peripheral selection task, fixation duration is an
      important factor determining the selection of potential targets for eye
      movements.

PMID- 10343823
TI  - Morphology of transient VEPs to luminance and chromatic pattern onset and offset.
AB  - Characteristics of the visual evoked response to chromatic and luminance
      modulated stimuli reflect the activity of underlying neural mechanisms, although
      selective neuronal activity depends upon stimulus parameters. In the present
      study, the behaviour of the transient visual evoked response to low spatial and
      temporal frequency chromatic stimuli is investigated at a range of colour
      luminance ratios. Our results show that the response to pattern-offset may be
      used in addition to the pattern-onset response as part of the signature of the
      evoked response to luminance-modulated or isoluminant chromatic stimuli.

PMID- 10343824
TI  - The effects of temperature on the dark-adapted spectral sensitivity function of
      the adult zebrafish.
AB  - In goldfish and other cold-blooded vertebrates, temperature can influence the
      rhodopsin/porphyropsin contributions to the rod photoreceptors. This study
      examined the effects of temperature on the spectral sensitivity function of the
      dark-adapted zebrafish. Zebrafish were housed in either a warm (28-30 degrees C)
      or cold (22-25 degrees C) tank prior to testing. Fish were dark-adapted for at
      least 1 h and electroretinogram (ERG) responses to 200 ms stimuli of various
      wavelengths and irradiances were obtained. Results show that water temperature
      affected the spectral sensitivity function of the ERG b-wave. Subjects housed in
      the warm temperatures had a spectral sensitivity consistent with the rhodopsin
      absorption curve; however, fish housed in the colder temperatures had a spectral
      sensitivity function that was the result of a rhodopsin/porphyropsin mixture. In
      addition, ultraviolet cones (lambda max: 362 nm) contributed to the dark-adapted
      spectral sensitivity function under both temperature conditions. Consistent with
      the results from other fish, the dark-adapted visual system of the zebrafish can
      be influenced by water temperature. The results of this study demonstrate the
      necessity of maintaining a stable environment when examining the contributions of
      the photoreceptors to the visual response.

PMID- 10343825
TI  - Effects of adenosinergic agents on the vascular resistance and on the optic nerve
      response in the perfused cat eye.
AB  - The function of A1- and A2a-adenosine receptors in the control of vascular
      resistance and in the modulation of light-evoked neuronal activity was
      investigated in the isolated perfused cat eye. The A1 agonist CCPA, the A1
      antagonist CPT, the A2a agonist CGS 21680 and the A2 antagonist DMPX were used.
      The agents were applied intra-arterially at concentrations in the low nanomolar
      to micromolar range during rod-selective photic stimulation. The flow rate of
      perfusate, reflecting vascular resistance and the light-evoked optic nerve
      response (ONR) were recorded. Our results show a vasodilating effect of both A1
      and A2 agonists and a vasoconstricting effect of the respective antagonists. The
      dose-effect relationships are suggestive, however, of an A2a receptor-mediated
      mechanism. The amplitude of the ONR-ON component was decreased during application
      of both adenosine-agonists. Analysis of the dose-effect relationships and the
      blockade of the CCPA-induced decrease by CPT suggests that inhibition is mediated
      by A1 receptors. However, CGS 21680-mediated inhibition cannot be explained by
      unspecific binding at A1 receptors alone and suggests the involvement of
      inhibitory A2a receptors.

PMID- 10343826
TI  - Reproducibility of ERG responses obtained with the DTL electrode.
AB  - Previous investigators have suggested that the DTL fibre electrode might not be
      suitable for the recording of replicable electroretinograms. We present
      experimental evidence that when used adequately, this electrode does permit the
      recording of highly reproducible retinal potentials.

PMID- 10343827
TI  - Optics of the developing fish eye: comparisons of Matthiessen's ratio and the
      focal length of the lens in the black bream Acanthopagrus butcheri (Sparidae,
      Teleostei).
AB  - Matthiessen's ratio (distance from centre of lens to retina:lens radius) was
      measured in developing black bream, Acanthopagrus butcheri (Sparidae, Teleostei).
      The value decreased over the first 10 days post-hatch from 3.6 to 2.3 along the
      nasal and from four to 2.6 along temporal axis. Coincidentally, there was a
      decrease in the focal ratio of the lens (focal length:lens radius).
      Morphologically, the accommodatory retractor lentis muscle appeared to become
      functional between 10-12 days post-hatch. The results suggest that a higher focal
      ratio compensates for the relatively high Matthiessen's ratio brought about by
      constraints of small eye size during early development. Combined with differences
      in axial length, this provides a means for larval fish to focus images from
      different distances prior to the ability to accommodate.

PMID- 10343828
TI  - Human heading judgments and object-based motion information.
AB  - In four experiments, we explored observers' ability to make heading judgments
      from simulated linear and circular translations through sparse forests and with
      pursuit fixation on one tree. We assessed observers' performance and information
      use in both regression and factorial designs. In all experiments we found that
      observers used three sources of object-based information to make their judgments-
      the displacement direction of the nearest object seen (a heuristic), inward
      displacement towards the fovea (an invariant) and outward deceleration (a second
      invariant). We found no support for the idea that observers use motion
      information pooled over regions of the visual field.

PMID- 10343829
TI  - Does visual sensitivity improve between 5 and 8 years? A study of automated
      visual field examination.
AB  - In 74 normal subjects (62 children aged 5-8 years and 12 adults), we tested the
      widely-held belief that visual sensitivity improves substantially during
      childhood. Maturation of the retino-striate pathways is generally invoked to
      account for age-related changes in visual sensitivity. We evaluated the extent to
      which attentional factors unduly emphasized the effect of age on the purely
      physiological mechanisms. After a specially-designed familiarization procedure,
      sensitivity was fully evaluated at two locations in the superior temporal field
      using a bracketing technique (Octopus 2000R). False-positive (FP) and false
      negative (FN) catch-trials were interspersed with the sequence of stimuli.
      Analyses demonstrated that: (1) age affected sensitivity; and (2) the general
      level of attentiveness varied not only with age, but also among subjects in the
      same age group. We then estimated the extent to which improved visual sensitivity
      may reflect a concomitant evolution of vigilance. Firstly, controlled variance
      analyses indicated that factors for evaluating attentiveness (rate of FN
      responses, slope of the psychometric function at the median, and goodness of fit)
      were indeed much better predictors than age of the sensitivity measured. Secondly
      and more significantly, the grouping of subjects into homogeneous subgroups, on
      the basis of their attentional performance, showed that children as young as 5
      years may have a visual sensitivity that is only marginally lower than that of
      adults.

PMID- 10343830
TI  - What motion distributions yield global transparency and spatial segmentation?
AB  - We have examined the ability of observers to parse bimodal local-motion
      distributions into two global motion surfaces, either overlapping (yielding
      transparent motion) or spatially segregated (yielding a motion boundary). The
      stimuli were random dot kinematograms in which the direction of motion of each
      dot was drawn from one of two rectangular probability distributions. A wide range
      of direction distribution widths and separations was tested. The ability to
      discriminate the direction of motion of one of the two motion surfaces from the
      direction of a comparison stimulus was used as an objective test of the
      perception of two discrete surfaces. Performance for both transparent and
      spatially segregated motion was remarkably good, being only slightly inferior to
      that achieved with a single global motion surface. Performance was consistently
      better for segregated motion than for transparency. Whereas transparent motion
      was only perceived with direction distributions which were separated by a
      significant gap, segregated motion could be seen with abutting or even partially
      overlapping direction distributions. For transparency, the critical gap increased
      with the range of directions in the distribution. This result does not support
      models in which transparency depends on detection of a minimum size of gap
      defining a bimodal direction distribution. We suggest, instead, that the
      operations which detect bimodality are scaled (in the direction domain) with the
      overall range of distribution. This yields a flexible, adaptive system that
      determines whether a gap in the direction distribution serves as a segmentation
      cue or is smoothed as part of a unitary computation of global motion.

PMID- 10343831
TI  - How is a grating detected on a narrowband noise masker?
AB  - Thresholds were measured for detecting 4 cpd gratings added to maskers consisting
      of nine sinusoidal components spanning 1 octave around the signal frequency.
      Phases of all mask components were randomized on every presentation. To assess
      their importance, contrast differences were either rendered unreliable by
      introducing contrast jitter between-intervals, or eliminated by equating contrast
      energy within the octave band across intervals and trials. The deleterious
      effects of contrast jitter and the similarity of grating detection and contrast
      discrimination thresholds argues that contrast cues are being used. Those cues
      are not the only ones available, because contrast jitter has less than the
      expected effect, and equating contrast energy only raises threshold a few dB.
      Computer simulations reveal that there is sufficient information in several
      spatial pattern cues to support detection performance.

PMID- 10343832
TI  - Horizontal and vertical disparity, eye position, and stereoscopic slant
      perception.
AB  - The slant of a stereoscopically defined surface cannot be determined solely from
      horizontal disparities or from derived quantities such as horizontal size ratio
      (HSR). There are four other signals that, in combination with horizontal
      disparity, could in principle allow an unambiguous estimate of slant: the
      vergence and version of the eyes, the vertical size ratio (VSR), and the
      horizontal gradient of VSR. Another useful signal is provided by perspective
      slant cues. The determination of perceived slant can be modeled as a weighted
      combination of three estimates based on those signals: a perspective estimate, a
      stereoscopic estimate based on HSR and VSR, and a stereoscopic estimate based on
      HSR and sensed eye position. In a series of experiments, we examined human
      observers' use of the two stereoscopic means of estimation. Perspective cues were
      rendered uninformative. We found that VSR and sensed eye position are both used
      to interpret the measured horizontal disparities. When the two are placed in
      conflict, the visual system usually gives more weight to VSR. However, when VSR
      is made difficult to measure by using short stimuli or stimuli composed of
      vertical lines, the visual system relies on sensed eye position. A model in which
      the observer's slant estimate is a weighted average of the slant estimate based
      on HSR and VSR and the one based on HSR and eye position accounted well for the
      data. The weights varied across viewing conditions because the informativeness of
      the signals they employ vary from one situation to another.

PMID- 10343833
TI  - Texture segregation shows only a very small lower-hemifield advantage.
AB  - Possible hemifield differences in texture segregation were investigated for both
      simple (Fourier, linear) and complex (non-Fourier, second-order) texture
      channels. There was only a very small lower-field advantage for texture
      segregation, consistent with the notion that the major processing in texture
      segregation is quite low level, perhaps V1. Complex-channel tasks do not show
      larger hemifield asymmetries than do simple-channel tasks, which suggests that
      the processes in complex texture channels are not higher level than those in
      simple.

PMID- 10343834
TI  - Eye movements affect the perceived speed of visual motion.
AB  - Eye movements add a constant displacement to the visual scene, altering the
      retinal-image velocity. Therefore, in order to recover the real world motion, eye
      movement effects must be compensated. If full compensation occurs, the perceived
      speed of a moving object should be the same regardless of whether the eye is
      stationary or moving. Using a pursue-fixate procedure in a perceptual matching
      paradigm, we found that eye movements systematically bias the perceived speed of
      the distal stimulus, indicating a lack of compensation. Speed judgments depended
      on the interaction between the distal stimulus size and the eye velocity relative
      to the distal stimulus motion. When the eyes and distal stimulus moved in the
      same direction, speed judgments of the distal stimulus approximately matched its
      retinal-image motion. When the eyes and distal stimulus moved in the opposite
      direction, speed judgments depended on the stimulus size. For small sizes,
      perceived speed was typically overestimated. For large sizes, perceived speed was
      underestimated. Results are explained in terms of retinal-extraretinal
      interactions and correlate with recent neurophysiological findings.

PMID- 10343835
TI  - S-cone contribution to pupillary responses evoked by chromatic flash offset.
AB  - On a green or red background, the action spectrum of the pupillary responses
      evoked following the offset of chromatic test flashes shows a prominent short
      wavelength lobe and suggests the contribution from photoreceptors other than the
      previously inferred M- and L-cones (Kimura & Young, Vision Research (1996). 36,
      1543-1550), most likely from S-cones. Systematic changes in the shape of the
      intensity versus amplitude functions with test wavelengths and in the shape of
      the short-wavelength lobe with response amplitude criteria suggest an
      antagonistic interaction involving the short- and longer-wavelength
      photoreceptors.

PMID- 10343836
TI  - A two-dimensional model of brightness perception based on spatial filtering
      consistent with retinal processing.
AB  - We have applied a multiple scale, 2-D model of brightness perception to a broad
      range of brightness phenomena. The filters encapsulate only processing that is
      well established to occur in retinal ganglion cells. Their outputs are then
      combined in the simplest way compatible with the earliest levels of cortical
      processing. Not only essential features of a number of the phenomena but also
      more subtle shading effects are reproduced. Because of the retinal nature of this
      model, these results would appear to support previous speculation that much of
      the ground work for brightness perception is performed at the retinal level.

PMID- 10343837
TI  - Development of brightness matching and colour vision deficits in juvenile
      diabetics.
AB  - We studied hue discrimination and brightness matching throughout the spectrum in
      ten juvenile patients suffering from diabetes mellitus (Type I) with no (eight
      patients) or mild (two patients) retinopathy. In addition, the FM 100-Hue test
      was performed. The data were collected once every year over 5 years. Over the 5
      years, the diabetics show a continual change in the shape of their brightness
      matching function. Wavelength discrimination ability remains quite stable with
      time at the long end of the spectrum but is variable at short wavelengths. FM-100
      error scores remain similar over the period tested, at a level slightly higher
      than that of a control group. Additional experiments show that the sensitivity of
      the S-cone in the diabetic group is similar to that of controls. The results can
      be explained by an early relative reduction in the sensitivity of post-receptoral
      processes in juvenile diabetics.

PMID- 10343838
TI  - Temporal sequence of changes in rat retina after UV-A and blue light exposure.
AB  - Two spectral types of retinal light damage were induced in pigmented rats by
      irradiating small retinal patches at either 380 or 470 nm. The temporal sequence
      of changes in the retina was followed for up to 2 months by funduscopy and
      histology. For both damage types, fundus changes were best visible after 3 days.
      Histology showed that 380 nm specifically damaged photoreceptor cells,
      particularly the rods. All cell compartments of the rods, including the nucleus
      were affected already after 3 h. In the next days, damaged rods degenerated. At
      high doses (2.5 x the funduscopic threshold dose) all rods in the irradiated area
      were lost, resulting in a local photoreceptor lesion, which was still present at
      2 months after the irradiation. At 470 nm, damage occurred both in the
      photoreceptor layer and in the pigment epithelium. Acute changes, at 1 h after
      irradiation, consisted mainly of damaged mitochondria in these layers. Next, the
      pigment epithelium showed swelling, an altered melanin distribution and, at high
      doses (2.5 x threshold), interruptions of the monolayer. Degeneration of
      photoreceptor cells was initially limited to a few scattered cells, but 3 days
      after high doses focal areas of massive degeneration were seen. At late stages,
      the cells of the pigment epithelium recovered and the photoreceptor layer showed
      a loss of cells. The results show that the spectral damage types are distinct in
      the early phases, indicating that different mechanisms are involved. Yet, the end
      effect of both damage types after exposure at doses up to 2.5 x the funduscopic
      threshold is remarkably similar and consists of local photoreceptor lesions.

PMID- 10343839
TI  - Immunohistochemical study of rabbit choroidal innervation.
AB  - Immunocytochemical methods with antibodies to the light (68 kDa), medium (160
      kDa), and heavy (200 kDa) chain subunits of the neurofilament triplet have been
      used to visualize neuronal structures in rabbit choroids. Choroidal nerve fibers
      were present in the suprachoroid and vascular laminae and absent in the
      choriocapillary layer. These fibers may be classified as perivascular and
      intervascular. Perivascular fibers surround all arterial and venous blood vessels
      and form a network; these fibers were labeled with the three NF antibodies,
      although they were more easily visualized with anti NF-160 and anti NF-200 than
      anti NF-68. Intervascular fibers formed two groups. The first group consisted of
      fibers situated between the blood vessels and parallel to the blood vessel wall
      surface (paravascular fibers); these fibers were better observed using anti NF
      160 and NF-200 than anti NF-68. The second group consisted of fibers which travel
      the entire length of the choroid until they reach the nerve plexus of the ciliary
      body (long tract fibers). The plexus was observed with anti NF-68, anti NF-160
      and anti NF-200; however, the long tract fibers were more clearly visualized with
      anti NF-160 and anti NF-200 than with anti NF-68. Two types of choroidal cell
      were also labeled: ganglion cells and melanocytes. Ganglion cells are small,
      scarce neurons situated in the peripheral choroid; they were labeled with anti NF
      160 and anti NF-200. The melanocytes were only labeled with anti NF-200 and they
      were the only non neuronal structure visualized using antibodies against
      neurofilaments.

PMID- 10343840
TI  - On potential causes of presbyopia.

PMID- 10343841
TI  - Stereoscopic occlusion and the aperture problem for motion: a new solution.
AB  - Recent work has shown that the ability of moving contour terminators to determine
      the perceived motion of untextured contours is strongly constrained by whether
      contour terminators are classified as intrinsic (belonging to a moving contour)
      or extrinsic (belonging to a surface occluding a moving contour). It has also
      been demonstrated that stereopsis can play a decisive role in this
      classification. Specifically, Shimojo, Silverman and Nakayama (1989, Vision
      Research 29, 619-626) argued that the efficacy of stereopsis in classifying
      moving contour terminators as intrinsic or extrinsic stemmed from the relative
      depth relationships specified by binocular disparity. Here, evidence is presented
      which demonstrates that the visual system relies on the presence of unpaired
      contour terminators to classify stereoscopic contour terminators as extrinsic.
      The author shows that the tendency to perceive untextured contours translating in
      a single rectangular aperture in a direction parallel to the longer axis of the
      aperture (the barberpole illusion) was not abolished by stereoscopic depth
      differences when the contour terminators were interocularly paired. However, the
      illusion was abolished when the contours terminators along the longer axis of the
      aperture were interocularly unpaired. Moreover, contours translated within a
      square aperture revealed a systematic shift towards the direction of motion
      signaled by the binocularly paired contour terminators along the horizontal edges
      of the aperture. These results demonstrate that the classification of
      stereoscopic contour terminators along an extrinsic-intrinsic dimension results
      from the presence of local, unpaired contour terminators rather than the relative
      depth or disparity differences per se, or via the global integration of contour
      terminators across multiple apertures when multiple apertures are present.

PMID- 10343842
TI  - Texture filling-in and texture segregation revealed by transient masking.
AB  - When a texture pattern was briefly presented followed by a small annular mask, it
      was found that the central area of the texture was strongly suppressed within the
      mask. Analogous to filling-in of brightness in a uniform luminance area
      (Paradiso, M. A. & Nakayama, K. (1991) Vision Research, 31, 1221-1236), this
      phenomenon demonstrates filling-in of texture; the texture area was unperceived
      because filling-in of the texture area was interrupted by the contour in the
      mask. However, odd local features within the texture, which were assumed to pop
      out, were selectively perceived while other features were suppressed within the
      mask. These results suggest that: (1) rapid pattern segregation occurs before
      and/or separately from texture filling-in, and that (2) filling-in is initiated
      at boundaries between surfaces rather than at luminance gradients.

PMID- 10343843
TI  - Perceptual learning in primary and secondary motion vision.
AB  - Specific improvements of perceptual capabilities with practise are thought to
      give some clues about cortical plasticity and the localisation of cortical
      processing. In the present study, perceptual learning is used as a paradigm to
      separate mechanisms underlying the perception of different classes of motion
      stimuli. Primary motion stimuli (phi-motion), are characterised by displacements
      of the luminance distribution. However, for secondary motion stimuli the movement
      is not accompanied by a corresponding luminance shift. Instead, moving objects
      are defined by their temporal frequency composition (mu-motion) or by motion
      itself (theta-motion). On theoretical grounds, the perception of secondary motion
      requires a higher degree of nonlinearity in the processing stream than the
      perception of primary motion but debate continues as to whether there might be a
      unique mechanism underlying the perception of both motion classes. In a large
      group of subjects, coherence thresholds for direction discrimination in random
      dot kinematograms of phi-, mu-, and theta-motion were repeatedly measured in a
      staircase paradigm. Training effects were found on different timescales, within
      short sessions containing multiple staircases and over training periods of
      several months. They were fairly stable over long breaks without testing. When
      subjects were trained with two different motion stimuli in a sequence, an
      asymmetry in the transfer of perceptual learning was revealed: sensitivity
      increases achieved during practise of theta-motion are largely transferred to phi
      motion, but theta-motion perception does not profit from prior exposure to phi
      motion. This finding supports the view derived from modelling of motion
      processing that there must be at least partially separate systems. A primary
      motion detection mechanism falls short of discriminating direction in secondary
      motion stimuli, whereas a mechanism able to extract secondary motion will be
      inherently sensitive to primary motion.

PMID- 10343844
TI  - Colour at edges and colour spreading in McCollough effects.
AB  - Broerse and O'Shea [(1995) Vision Research, 35, 207-226] proposed that the
      subjective colours in McCollough effects (MEs) consist of two components: edge
      colours appearing along the edges of contours, and spread colours radiating from
      edge colours into adjacent uncontoured regions of test patterns. This proposal
      was examined in five experiments. First, we demonstrated that fine coloured lines
      located immediately adjacent to the edges of otherwise achromatic square-wave
      gratings (i.e. colour-fringed gratings) are sufficient to induce MEs comparable
      in strength to MEs induced with desaturated versions of traditional uniformly
      coloured gratings (Experiments 1 & 2). We then quantified edge and spread colours
      while varying light/dark duty cycles (white-bar width) in gratings with colour
      fringed edges (Experiment 3), uniformly-coloured gratings (Experiment 4), and in
      achromatic gratings tinged with ME colours after adaptation to colour-fringed
      gratings (Experiment 5). Whereas the perceived magnitude of edge colours remained
      constant in all cases, spread colours remained constant only for uniformly
      coloured gratings. For both MEs and gratings with colour-fringed edges, spread
      colours decreased as a function of increasing duty cycle, confirming that
      conventional MEs may be simulated by gratings with colour-fringed edges. We
      propose that edge colours arise as a consequence of neural operations correcting
      for the eye's chromatic aberration, while spread colours reveal a neural filling
      in process operating to achieve colour constancy. In seeking to implement these
      suggestions, we present a putative framework based on the receptive-field
      properties of single cells described in contemporary neurophysiological
      investigations of colour.

PMID- 10343845
TI  - Search for feature and for relative position: measurement of capacity
      limitations.
AB  - Palmer and his associates (Palmer, Ames & Lindsey (1993). Journal of Experimental
      Psychology: Human Perception and Performance, 19, 108-130; Palmer (1994). Vision
      Research, 34, 1703-1721) have confirmed that searches for simple feature targets
      are not limited by perceptual processing capacity and the effect of set size on
      performance can be accounted for by integration stage processes only. In this
      study I used a similar difference threshold method with target and distractor
      stimuli defined by the relative position of their elements (line drawings of
      bisected squares) and found clear capacity limitations. Feature search condition,
      however, with nearly comparable bisected square stimuli did replicate the results
      of Palmer and associates. This experiment demonstrates that a search for targets
      defined by relative position in the set of line drawing type of stimuli is
      fundamentally different from a search for more simple (feature) stimuli and may
      conform to a strict capacity limited model.

PMID- 10343846
TI  - Remodelling colour contrast: implications for visual processing and colour
      representation.
AB  - Colour contrast describes the influence of one colour on the perception of
      colours in neighbouring areas. This study addresses two issues: (i) the accurate
      representation of the colour changes; (ii) the underlying visual mechanisms.
      Observers viewed a haploscopic display in which a standard display was presented
      to one eye and a matching display to the other. The matches could be represented
      accurately using a diagram that is a logarithmic transformation of the MacLeod
      Boynton (r, b) (1979) chromaticity diagram. Since haploscopic presentation has
      been described as isolating retinal processes (Whittle, P., & Challands, P.D.C.
      (1969). The effect of background luminance on the brightness of flashes. Vision
      Research, 9, 1095-1110; Chichilnisky, E.J., & Wandell, B.A. (1995). Photoreceptor
      sensitivity changes explain color appearance shifts induced by large uniform
      backgrounds in dichoptic matching. Vision Research, 35, 239-254), the results are
      discussed in terms of receptor sensitivity changes and the ratio of receptor
      contrasts.

PMID- 10343847
TI  - Stereopsis, cyclovergence and the backwards tilt of the vertical horopter.
AB  - It is generally recognized that the vertical horopter has a backwards tilt such
      that it passes through the fixation point and a point near the feet of the
      observer. The basis of the tilt has been attributed to either a shear in
      binocular retinal correspondence along the vertical meridian or the presence of
      cyclovergence eye movements. In an attempt to determine empirically the
      mechanisms underlying the tilt of the vertical horopter, retinal correspondence
      along the vertical meridian was investigated as a function of viewing distance.
      In addition, binocular measurements of torsional eye position were made in the
      same observers under similar viewing conditions. The vertical horopter was
      determined using two criteria. In the first instance, increment depth
      discrimination thresholds for both crossed and uncrossed disparities were
      measured as a function of retinal eccentricity along the vertical meridian, up to
      5 degrees superiorly and inferiorly, and the horopter was defined by the region
      in space which had the lowest stereo-threshold. Secondly, subjective alignment of
      dichoptically presented nonius lines defined the horopter by identical visual
      directions. Both criteria were used to determine the horopter at 2 m while only
      the criterion of identical visual direction was used at the nearer distance of 50
      cm. The vertical horopter showed a backwards tilt that decreased from an average
      of about 12 degrees at 2 m to 3 degrees at 50 cm, with some variability between
      observers. Torsional eye position did not change significantly between fixation
      distances. These results confirmed the geometric relation between the backwards
      tilt in the vertical horopter and fixation distance and support Helmholtz's
      original contention that the tilt is a consequence of a shear in retinal
      correspondence in the vertical meridian.

PMID- 10343848
TI  - Ocular responses to radial optic flow and single accelerated targets in humans.
AB  - Self-movement in a structured environment induces retinal image motion called
      optic flow. Optic flow on one hand provides information about the direction of
      self-motion. On the other hand optic flow presents large field visual motion
      which will elicit eye movements for the purpose of image stabilization. We
      investigated oculomotor behavior in humans during the presentation of radial
      optic flow fields which simulated forward or backward self-motion. Different
      conditions and oculomotor tasks were compared. In one condition, subjects had to
      actively pursue single dots in a radial flow pattern. In a second condition,
      subjects had to pursue single dots over a dark background. These dots accelerated
      or decelerated similar to single dots in radial optic flow. In a third condition,
      subjects were asked to passively view the entire optic flow stimulus. Smooth
      pursuit eye movements with high gain were observed when dots were actively
      pursued. This was true for single dots moving over a homogeneous background and
      for single dots in the optic flow. Passive viewing of optic flow stimuli evoked
      eye movements that resembled an optokinetic nystagmus. Slow phase eye movements
      tracked the motion of elements in the optic flow. Gain was low for simulated
      forward self-motion (expanding optic flow) and high for simulated backward
      movement self-motion (contracting optic flow). Thus, voluntary pursuit and
      passive optokinetic responses yielded different gain for the tracking of elements
      of an expanding optic flow pattern. During passive viewing of the optic flow
      stimulus, gaze was usually at or near the focus of radial flow. Our results give
      insights into the oculomotor performances and needs for image stabilization
      during self-motion and in the role of gaze strategy for the detection of the
      direction of heading.

PMID- 10343849
TI  - Saccade selection in visual search: evidence for spatial frequency specific
      between-item interactions.
AB  - We present two experiments in which subjects were required to make a saccade to a
      target amongst distractors. Targets were oriented Gabor patches. Analysis of
      errors, when subjects fail to make a saccade to the target, showed two
      interesting features. First, most error saccades were directed towards a
      distractor and not to the blank space between distractors. This suggests that
      although the location of the target may not be encoded correctly, the locations
      of the items in the display are encoded. Second, when the display items were all
      of the same spatial frequency, a long-range effect occurred whereby the
      likelihood of an error saccade in a specific direction decreased systematically
      as the distance from the target increases. This systematic influence of the
      target location extended over practically the whole display. The long-range
      effect appeared whenever all display items had the same spatial frequency and
      showed little dependence on the spatial frequency of the display items. However,
      when the items had different spatial frequencies the long-range effects were
      absent.

PMID- 10343850
TI  - A self-organizing neural system for learning to recognize textured scenes.
AB  - A self-organizing ARTEX model is developed to categorize and classify textured
      image regions. ARTEX specializes the FACADE model of how the visual cortex sees,
      and the ART model of how temporal and prefrontal cortices interact with the
      hippocampal system to learn visual recognition categories and their names. FACADE
      processing generates a vector of boundary and surface properties, notably texture
      and brightness properties, by utilizing multi-scale filtering, competition, and
      diffusive filling-in. Its context-sensitive local measures of textured scenes can
      be used to recognize scenic properties that gradually change across space, as
      well as abrupt texture boundaries. ART incrementally learns recognition
      categories that classify FACADE output vectors, class names of these categories,
      and their probabilities. Top-down expectations within ART encode learned
      prototypes that pay attention to expected visual features. When novel visual
      information creates a poor match with the best existing category prototype, a
      memory search selects a new category with which classify the novel data. ARTEX is
      compared with psychophysical data, and is bench marked on classification of
      natural textures and synthetic aperture radar images. It outperforms state-of-the
      art systems that use rule-based, backpropagation, and K-nearest neighbor
      classifiers.

PMID- 10343851
TI  - Abnormal depth perception from motion parallax in amblyopic observers.
AB  - Many similarities exist between the perception of depth from binocular stereopsis
      and that from motion parallax. Moreover, Rogers (1984, cited in, Howard, I. P., &
      Rogers, B. J. (1995). Binocular vision and stereopsis. Oxford Claridon, New
      York.) suggests a relationship between an observer's ability to use disparity
      information and motion parallax information in a depth perception task. To more
      closely investigate this relationship, depth perception was studied in normal
      observers and amblyopic observers with poor stereo vision. As expected, amblyopic
      observers performed much worse than normal observers on depth discriminations
      requiring use of binocular disparity. However, amblyopic observers also performed
      much worse than normal observers on depth discriminations based on motion
      parallax. This result provides supporting evidence for a psychoanatomical link
      between the perception of depth from motion and the perception of depth from
      binocular disparity.

PMID- 10343852
TI  - The growing eye: an autofocus system that works on very poor images.
AB  - It is unknown which retinal image features are analyzed to control axial eye
      growth and refractive development. On the other hand, identification of these
      features is fundamental for the understanding of visually acquired refractive
      errors. Cyclopleged chicks were individually kept in the center of a drum with
      only one viewing distance possible. Defocusing spectacle lenses were used to
      stimulate the retina with defined defocus of similar magnitude but different
      sign. If spatial frequency content and contrast were the only cues analyzed by
      the retina, all chicks should have become myopic. However, compensatory eye
      growth was still always in the right direction. The most likely cues for
      emmetropization, spatial frequency content and image contrast, do therefore not
      correlate with the elongation of the eye. Rather, the sign of defocus was
      extracted even from very poor images.

PMID- 10343853
TI  - Mechanics of accommodation of the human eye.
AB  - The classical Helmholtz theory of accommodation has, over the years, not gone
      unchallenged and most recently has been opposed by Schachar at al. (1993) (Annals
      of Ophthalmology, 25 (1) 5-9) who suggest that increasing the zonular tension
      increases rather than decreases the power of the lens. This view is supported by
      a numerical analysis of the lens based on a linearised form of the governing
      equations. We propose in this paper an alternative numerical model in which the
      geometric non-linear behaviour of the lens is explicitly included. Our results
      differ from those of Schachar et al. (1993) and are consistent with the classical
      Helmholtz mechanism.

PMID- 10343854
TI  - A visual evoked potential correlate of global figure-ground segmentation.
AB  - Human observers discriminated the global orientation of a texture-defined figure
      which segregated from a texture surround. Global figure discriminability was
      manipulated through within-figure collinearity, figure-surround interaction, and
      figure connectedness, while the local orientation contrast at edges between
      figure and surround was kept constant throughout all the experiments. Visual
      evoked potentials (VEPs) were recorded during onset-offset stimulation in which
      the figure cyclically appeared and disappeared from a uniform texture background.
      A difference component was obtained by subtraction of offset-from onset-VEP. Two
      negative peaks of the difference component are found with latencies around 140
      160 and 200-260 ms, respectively. Enhanced discriminability of the global figure
      reduced (11-25 ms) the latency of the second peak, hence indicating that the 200
      260 ms component was produced by global figure-ground segmentation.

PMID- 10343855
TI  - Seeing better at night: life style, eye design and the optimum strategy of
      spatial and temporal summation.
AB  - Animals which need to see well at night generally have eyes with wide pupils.
      This optical strategy to improve photon capture may be improved neurally by
      summing the outputs of neighbouring visual channels (spatial summation) or by
      increasing the length of time a sample of photons is counted by the eye (temporal
      summation). These summation strategies only come at the cost of spatial and
      temporal resolution. A simple analytical model is developed to investigate
      whether the improved photon catch afforded by summation really improves vision in
      dim light, or whether the losses in resolution actually make vision worse. The
      model, developed for both vertebrate camera eyes and arthropod compound eyes,
      calculates the finest spatial detail perceivable by a given eye design at a
      specified light intensity and image velocity. Visual performance is calculated
      for the apposition compound eye of the locust, the superposition compound eye of
      the dung beetle and the camera eye of the nocturnal toad. The results reveal that
      spatial and temporal summation is extremely beneficial to vision in dim light,
      especially in small eyes (e.g. compound eyes), which have a restricted ability to
      collect photons optically. The model predicts that using optimum spatiotemporal
      summation the locust can extend its vision to light intensities more than 100,000
      times dimmer than if it relied on its optics alone. The relative amounts of
      spatial and temporal summation predicted to be optimal in dim light depend on the
      image velocity. Animals which are sedentary and rely on seeing small, slow images
      (such as the toad) are predicted to rely more on temporal summation and less on
      spatial summation. The opposite strategy is predicted for animals which need to
      see large, fast images. The predictions of the model agree very well with the
      known visual behaviours of nocturnal animals.

PMID- 10343856
TI  - Contrast dependency of foveal spatial functions: orientation, vernier,
      separation, blur and displacement discrimination and the tilt and Poggendorff
      illusions.
AB  - To examine the effect of reducing luminance contrast in human foveal vision,
      discrimination thresholds were measured in four tasks and also a numerical
      measure of two visual illusions were obtained by a nulling technique. The
      patterns used for all tasks were made very similar to facilitate comparison
      between them--all featured luminance step edges whose contrast could be varied
      from near unity down to the detection threshold. Orientation, vernier and blur
      discrimination thresholds rise on average 5-6-fold when the contrast is reduced
      from near unity to a Michelson value of 0.03. Jump displacement thresholds are
      somewhat more robust to contrast reduction, and the curve of separation
      discrimination versus contrast is much shallower, rising by a factor of about 2.
      The magnitude of the Poggendorff and tilt illusions changes very little until the
      inducing contours are barely detectable.

PMID- 10343857
TI  - Temporal sensitivity of human luminance pattern mechanisms determined by masking
      with temporally modulated stimuli.
AB  - Target contrast thresholds were measured using vertical spatial Gabor targets in
      the presence of full field maskers of the same spatial frequency and orientation.
      In the first experiment both target and masker were 2 cpd. The target was
      modulated at a frequency of 1 or 10 Hz and the maskers varied in temporal
      frequency from 1 to 30 Hz and in contrast from 0.03 to 0.50. In the second
      experiment both target and masker had a spatial frequency of 1, 5 or 8 cpd. The
      target was modulated at 7.5 Hz and the same set of maskers was used as in the
      first experiment. The results are not consistent with a widely used model that is
      based on mechanisms in which excitation is summed linearly and the sum is
      transformed by an S-shaped nonlinear excitation-response function. A new model of
      human pattern vision mechanisms, which has excitatory and divisive inhibitory
      inputs, describes the results well. Parameters from the best fit of the new model
      to the results of the first experiment show that the 1 Hz and 10 Hz targets were
      detected by mechanisms with temporal low-pass and band-pass excitatory
      sensitivity, respectively. Fits to the second experiment suggest that at 1 cpd,
      the excitatory tuning of the detecting mechanism is band-pass. At 5 and 8 cpd,
      the mechanisms are excited by a broad range of temporal frequencies. Mechanism
      sensitivity to divisive inhibition depends on temporal frequency in the same
      general way as sensitivity to excitation. Mechanisms are more broadly tuned to
      divisive inhibition than to excitation, except when the target temporal frequency
      is high.

PMID- 10343858
TI  - Context-dependent changes in visual sensitivity induced by Muller-Lyer stimuli.
AB  - We measured the detectability of a single line (target) flanked by high-contrast
      inward- or outward-pointing arrowheads (context). We show that as a function of
      target contrast, context angle, and context position there is a continuum of
      contextual modulations of target detectability that vary from strong inhibition
      (target detection is impaired) to strong excitation (target detection is
      facilitated), but target detection is not affected when the context is presented
      at low contrasts. The results show striking correlations with the perceived
      length distortions in the Muller-Lyer illusion, i.e. an inward-pointing arrowhead
      results in improved target detectability and increased perceived length of the
      bar, whereas an outward-pointing arrowhead results in diminished target
      detectability and decreased perceived length of the bar. Both suppressive and
      facilitatory effects diminish as target contrast, arrowhead angle, and line
      arrowhead spatial disparity are increased. At larger distances between line and
      arrowhead the suppressive effects become facilitatory (the Muller-Lyer illusion
      reverses). When concurrent Muller-Lyer extent experiments are run, we found that
      the perceived length of the target stimulus is overestimated or underestimated as
      it is flanked by high-contrast inward or outward-pointing arrowheads, the
      magnitude of the length distortion effects diminishing as target contrast
      increases. To explain the nature of both context-induced suppression and
      facilitation in contrast detection we present a population model of orientation
      detectors in visual cortex that relies on short and long-range horizontal
      cortical connections, and suggest that that the same type of mechanism that
      accounts for contrast detection may account for perceived extent.

PMID- 10343859
TI  - Motion-transparent inducers have different effects on induced motion and motion
      capture.
AB  - To assess the relationship among the underlying mechanisms of induced motion,
      motion capture, and motion transparency, directions of the former two illusions
      in the presence of motion-transparent inducers were examined. Two random-dot
      patterns (inducers) were superimposed upon a stationary disk (target), and moved
      in orthogonal directions. Either a high-contrast target (for induced motion) or a
      low-contrast target (for motion capture) was used. The task was to report the
      perceived direction of the target. The depth order of inducers was controlled
      either by adding binocular disparity or by asking the subject to report
      subjective depth order. For induced motion, the target appeared to move in the
      direction opposite to the inducer that had a disparity closer to the target; when
      there was no difference in disparity, induced motion occurred oppositely to the
      'vector sum' of the inducers' directions. For motion capture, the target was
      captured by the inducer that subjectively appeared behind. These results suggest
      that the underlying mechanism of motion capture utilizes the output from the
      process for motion transparency, whereas induced motion has no clear relationship
      to the output of the process for motion transparency.

PMID- 10343860
TI  - One spatial filter limits speed of detecting low and middle frequency gratings.
AB  - Reaction times for detecting sinusoidal gratings depend jointly on grating
      contrast and spatial frequency. We examine whether the effect of spatial
      frequency results from low-pass filtering in a single channel or reflects
      processing of different frequencies by two or more different processing streams.
      Observers performed a speeded two-alternative spatial forced-choice detection.
      Errors and reaction times were measured. Contrasts varied from 0.05 to 0.67, and
      spatial frequencies from 0.72 to 6.51 cpd. No effect of uncertainty about spatial
      frequency was found, arguing against multiple channels. The data are well fit by
      a single channel model driven by a low pass filter.

PMID- 10343861
TI  - Short term modification of disparity vergence eye movements.
AB  - Dynamics of disparity vergence eye movements can be modified by adaptive stimuli
      that generate large transient disparities. These modifications were observed for
      convergence as well as divergence eye movements. After modification, the peak
      velocities of the step responses for convergence and divergence were
      substantially higher than in normal baseline responses, a change observed in all
      four subjects studied. The change in peak velocity of a step response occurred
      very rapidly after presentation of the adaptive stimuli. Main sequence plots
      showed that first-order dynamic characteristics increased for post-adaptive
      responses with respect to normal step responses. Hence, response modification
      could be quantified as a change in gain accompanied with an increase in the
      effective response time constant. The adaptive responses to convergent and
      divergent 'disappearing' step stimuli revealed that the adaptation process
      modifies the high-velocity component of both disparity convergence and divergence
      eye movements. Moreover, a gain change in this component alone could account for
      both the gain and the time constant modifications seen in the overall response. A
      process of recovery or de-adaptation was also observed for both convergence and
      divergence eye movements. This observed short-term modification demonstrates a
      unique control mechanism for vergence eye movements that is effective in either
      direction.

PMID- 10343862
TI  - A back-propagation neural network predicts absorption maxima of chimeric human
      red/green visual pigments.
AB  - The absorption spectra of human red and green visual pigments have peak
      wavelengths, lambda max, that differ by 31 nm, yet the opsins differ in only 15
      amino acids. Mutagenesis studies have demonstrated that seven of the 15 amino
      acids determine the spectral shift. We trained neural networks to predict the
      lambda max of any red/green chimeric protein. Seven mutants were excluded from
      the original training set. The trained networks were able to predict the lambda
      max for the excluded mutants. As an additional test, five new chimeric pigments
      were constructed and lambda max determined. The neural networks correctly
      predicted the lambda max of all five mutants. The use of neural networks is a
      novel approach to the problem of wavelength modulation in visual pigments.

PMID- 10343863
TI  - The role of perspective information in the recovery of 3D structure-from-motion.
AB  - When investigating the recovery of three-dimensional structure-from-motion (SFM),
      vision scientists often assume that scaled-orthographic projection, which removes
      effects due to depth variations across the object, is an adequate approximation
      to full perspective projection. This is so even though SFM judgements can, in
      principle, be improved by exploiting perspective projection of scenes on to the
      retina. In an experiment, pairs of rotating hinged planes (open books) were
      simulated on a computer monitor, under either perspective or orthographic
      projection, and human observers were asked to indicate which they perceived had
      the larger dihedral angle. For small displays (4.6 x 6.0 degrees) discrimination
      thresholds were found to be similar under the two conditions, but diverged for
      all larger stimuli. In particular, as stimulus size was increased, performance
      under orthographic projection declined and by a stimulus size of 32 x 41 degrees
      performance was at chance for all subjects. In contrast, thresholds decreased
      under perspective projection as stimulus size was increased. These results show
      that human observers can use the information gained from perspective projection
      to recover SFM and that scaled-orthographic projection becomes an unacceptable
      approximation even at quite modest stimulus sizes. A model of SFM that
      incorporates measurement errors on the retinal motions accounts for performance
      under both projection systems, suggesting that this early noise forms the primary
      limitation on 3D discrimination performance.

PMID- 10343864
TI  - Assessment of cortical dysfunction in human strabismic amblyopia using
      magnetoencephalography (MEG).
AB  - The aim of this study was to use the technique of magnetoencephalography (MEG) to
      determine the effects of strabismic amblyopia on the processing of spatial
      information within the occipital cortex of humans. We recorded evoked magnetic
      responses to the onset of a chromatic (red/green) sinusoidal grating of
      periodicity 0.5-4.0 c deg-1 using a 19-channel SQUID-based neuromagnetometer.
      Evoked responses were recorded monocularly on six amblyopes and six normally
      sighted controls, the stimuli being positioned near the fovea in the lower right
      visual field of each observer. For comparison, the spatial contrast sensitivity
      function (CSF) for the detection of chromatic gratings was measured for one
      amblyope and one control using a two alternate forced-choice psychophysical
      procedure. We chose red/green sinusoids as our stimuli because they evoke strong
      magnetic responses from the occipital cortex in adult humans (Fylan, Holliday,
      Singh, Anderson & Harding. (1997). Neuroimage, 6, 47-57). Magnetic field strength
      was plotted as a function of stimulus spatial frequency for each eye of each
      subject. Interocular differences were only evident within the amblyopic group:
      for stimuli of 1-2 c deg-1, the evoked responses had significantly longer
      latencies and reduced amplitudes through the amblyopic eye (P < 0.05).
      Importantly, the extent of the deficit was uncorrelated with either Snellen
      acuity or contrast sensitivity. Localization of the evoked responses was
      performed using a single equivalent current dipole model. Source localizations,
      for both normal and amblyopic subjects, were consistent with neural activity at
      the occipital pole near the V1/V2 border. We conclude that MEG is sensitive to
      the deficit in cortical processing associated with human amblyopia, and can be
      used to make quantitative neurophysiological measurements. The nature of the
      cortical deficit is discussed.

PMID- 10343865
TI  - Retinal ganglion cell dysfunction in humans following post-geniculate lesions:
      specific spatio-temporal losses revealed by pattern ERG.
AB  - Nasal and temporal hemifield (14 x 24 degrees) pattern electroretinograms (PERGs)
      were recorded in eight patients (age range: 21-72 years) suffering from different
      post-geniculate lesions (documented by CT scan and/or MRI of the brain) and
      homonymous hemianopia at visual field testing. In total eight age-matched normal
      subjects served as controls. PERGs were elicited by alternating, sinusoidal
      gratings (90% contrast), whose spatial and temporal characteristics, 6 Hz-5 c deg
      1 and 15 Hz-0.58 c deg-1, were chosen to enhance the relative contributions of
      parvo- (P) and magno- (M) retinal ganglion cell (GC) subsystems, respectively.
      Amplitudes and phases of the Fourier analyzed PERG 2nd harmonics were measured.
      In normal subjects, PERG amplitudes to 15 Hz-0.58 c deg-1, but not those of the 6
      Hz-5 c deg-1 stimuli were on average larger (P < 0.05) in nasal than in temporal
      hemiretinae. In hemianopic patients, PERG amplitudes of 6 Hz-5 c deg-1 stimuli
      were on average reduced (P < 0.05) in the hemiretinae corresponding to blind
      hemifields, in comparison to those in the hemiretinae corresponding to functional
      hemifields. No differences between hemiretinae were observed for responses of the
      15 Hz-0.58 c deg-1 stimuli. In both normal subjects and patients, average PERG
      phases did not differ between hemiretinae, while changing significantly (P <
      0.01) across stimulus conditions. The PERG naso-temporal asymmetries observed in
      normal subjects are consistent with the reported asymmetries in GC density
      observed histologically (Curcio & Allen. (1990). Journal of Comparative
      Neurology, 300, 5-25). The results in patients indicate that the PERGs to
      specific spatio-temporal stimuli (i.e. of relatively low-temporal and high
      spatial frequency), presented in the hemianopic field, are reduced in amplitude.
      This suggests, in agreement with the experimental findings in monkeys (Cowey &
      Stoerig. (1991). Trends in Neuroscience, 14, 140-145), that retrograde trans
      synaptic dysfunction of P-GCs, with relative sparing of the M-subsystem, may
      occur in humans following lesions of post-geniculate pathways.

PMID- 10343866
TI  - The refractive development of untreated eyes of rhesus monkeys varies according
      to the treatment received by their fellow eyes.
AB  - To determine the extent to which the visual experience of one eye may influence
      the refractive development of its fellow eye, we analyzed the data of untreated
      (UT) eyes of monkeys that received different types of unilateral pattern
      deprivation. Subjects were 15 juvenile rhesus monkeys, with five monkeys in each
      of three treatment groups: aphakic eyes with optical correction (AC), aphakic
      eyes with no correction (ANC), and eyes that were occluded with an opaque contact
      lens (OC). Under general anaesthesia, refractive error (D) was determined by
      cycloplegic retinoscopy and axial length (mm) was determined with A-scan
      ultrasonography. For measurements of refractive error of the UT eyes, there was a
      significant main effect of groups according to the treatment of the fellow eyes,
      F(2, 12) = 6.6. While UT eyes paired with AC fellow eyes (mean = +4.2 D) were
      significantly more hyperopic than the eyes of age-matched normal monkeys (mean =
      +2.4 D), t(25), = 2.5, UT eyes paired with OC fellow eyes (mean = -0.5 D) were
      significantly more myopic than the eyes of normal monkeys, t(25) = -9. UT eyes
      paired with ANC fellow eyes (mean = +1.9 D) were not significantly different from
      normal eyes. For measurements of axial length there was also a significant main
      effect of groups, F(2, 12) = 6.9. While UT eyes paired with AC fellow eyes (mean
      = 16.9 mm) were significantly shorter than the eyes of age-matched normal monkeys
      (mean = 17.5 mm), t(25) = 2.3, UT eyes paired with OC fellow eyes (mean = 18.1
      mm) were significantly longer than the eyes of normal monkeys, t(25) = 2.3. UT
      eyes paired with ANC fellow eyes (mean = 17.5 mm) were not significantly
      different from the eyes of normal monkeys. The measurements of axial length and
      of refractive error of the UT eyes were also significantly correlated with one
      another, probably indicating that the differences in refractive error were due to
      differences in axial length, r = -0.8. The present data reveal that despite
      normal visual experience, UT eyes can have their refractive development altered,
      systematically, simply as a function of the type of pattern deprivation received
      by their fellow eyes. These data add to the growing evidence that there is an
      interocular mechanism that is active during emmetropization. As a consequence,
      future models of eye growth will need to consider both: (1) the direct influence
      of visual input on the growing eye; as well as (2) the indirect influence coming
      from the fellow eye.

PMID- 10343867
TI  - Analysis of pharmacologically isolated components of the ERG.
AB  - An harmonic analysis was applied to the electroretinogram (ERG) measured in
      intact cat eyes in control conditions and after pharmacological isolation of the
      components attributed to photoreceptors (PIII) and bipolar neurons (PII). The
      frequency response curves obtained in various conditions showed that the
      bandwidth of the PII component extends over a range of stimulus frequencies
      higher than the bandwidth of PIII. The enhancement of the PII response to stimuli
      of high temporal frequency suggests the presence of a frequency dependent gain
      control located either pre- and/or post-synaptically in the transmission line
      between the phototransductive cascade and bipolar neurons. A possible role of
      these processes is to enhance relevant visual information whilst selectively
      attenuating low frequency signals originating in the transductive cascade.

PMID- 10343868
TI  - Effects of blocking the hyperpolarization-activated current (Ih) on the cat
      electroretinogram.
AB  - The temporal properties of the electroretinogram (ERG) recorded from cat eyes
      were analyzed in the presence of either Cs+ or zatebradine which are known to
      inhibit the hyperpolarization activated current (Ih) in retinal rods. Both Cs+
      and zatebradine reduce the ERG response to high-frequency sinusoidal stimuli of
      high mean luminance and contrast. Conversely, blockade of Ih has no effect on the
      frequency response characteristics of the isolated receptor component (PIII).
      These observations support the idea that Ih plays an important role in the
      transfer of signals from photoreceptors to second order neurons by suppressing
      the slow components originated in the phototransductive cascade. The result of
      this operation is an enhancement of the light response in a range of temporal
      frequencies relevant to vision.

PMID- 10343869
TI  - Spatial integration and effective spectral density of one-dimensional noise
      masks.
AB  - When masking one-dimensional gratings, the strongest masking effect is achieved
      by using one-dimensional spatial noise, which can be regarded as a special case
      of two-dimensional noise where the noise check height is equal to the grating
      height. The extent of spatial integration in the human visual system is limited,
      however. Hence, our aim was to investigate whether the effective height of noise
      checks of one-dimensional noise is similarly limited. We measured detection
      thresholds for vertical sinusoidal gratings with added spatial noise. The width
      of the noise checks remained constant, but their height increased until equal to
      the height of the image window which made noise one-dimensional. The contrast
      energy thresholds increased in direct proportion to increasing noise check height
      and the spectral density of noise, calculated by taking into account both the
      height and the width of the noise checks. The increase levelled off, however,
      after the critical noise check height (nyc). The critical noise check height in
      grating cycles changed as a function of spatial frequency (f) as nyc = 4.7 [1 +
      (1.4/f)2]-0.5. According to our results the effective height of noise checks was
      thus limited in accordance with studies on spatial integration, showing scale
      invariance above 1.4 c/deg.

PMID- 10343870
TI  - Infants code the direction of chromatic quadrature motion.
AB  - The present experiment uses a quadrature motion paradigm to investigate the
      motion correspondence cues used by young infants for coding the direction of
      motion of red/green isoluminant gratings. Three-month-old infants and adults were
      tested with 0.25 c/d luminance-modulated or red/green isoluminant gratings,
      either moving continuously or shifted in spatial quadrature. Both direction-of
      motion and detection thresholds were measured, and motion:detection (M:D)
      threshold ratios were examined. Infants, like adults, could code the direction of
      motion of red/green quadrature-shifted gratings. In adults, M:D ratios were
      similar for continuous and quadrature motion. In infants, M:D ratios were higher
      for quadrature than for continuous motion, but elevations of similar magnitude
      were seen for both luminance-modulated and red/green gratings. The results
      suggest that frequency-doubled signals, such as those often seen in the
      magnocellular (M-cell) pathway, are not necessary for coding the direction of
      motion of isoluminant gratings in infant subjects. Two other theoretical options-
      mediation by the scatter of isoluminance points in the M-cell population, and
      parvocellular (P-cell) mediation--are discussed.

PMID- 10343871
TI  - Second-order processing of four-stroke apparent motion.
AB  - In four-stroke apparent motion displays, pattern elements oscillate between two
      adjacent positions and synchronously reverse in contrast, but appear to move
      unidirectionally. For example, if rightward shifts preserve contrast but leftward
      shifts reverse contrast, consistent rightward motion is seen. In conventional
      first-order displays, elements reverse in luminance contrast (e.g. light elements
      become dark, and vice-versa). The resulting perception can be explained by
      responses in elementary motion detectors turned to spatio-temporal orientation.
      Second-order motion displays contain texture-defined elements, and there is some
      evidence that they excite second-order motion detectors that extract spatio
      temporal orientation following the application of a non-linear 'texture-grabbing'
      transform by the visual system. We generated a variety of second-order four
      stroke displays, containing texture-contrast reversals instead of luminance
      contrast reversals, and used their effectiveness as a diagnostic test for the
      presence of various forms of non-linear transform in the second-order motion
      system. Displays containing only forward or only reversed phi motion sequences
      were also tested. Displays defined by variation in luminance, contrast,
      orientation, and size were effective. Displays defined by variation in motion,
      dynamism, and stereo were partially or wholly ineffective. Results obtained with
      contrast-reversing and four-stroke displays indicate that only relatively simple
      non-linear transforms (involving spatial filtering and rectification) are
      available during second-order energy-based motion analysis.

PMID- 10343872
TI  - Oscillatory motion but not pattern reversal elicits monocular motion VEP biases
      in infantile esotropia.
AB  - Patients with early disruptions of binocularity show cortical directional
      asymmetries in their steady state monocular VEP response to oscillatory motion.
      The VEP directional asymmetry is characterized by significant first harmonic
      components that show a 180 degrees difference in the response phase between the
      two eyes. By contrast, the normal response is dominated by even-order response
      harmonics, although some normal observers also have measurable responses at the
      first harmonic. Experiments and simulations were conducted to determine if the
      first harmonic in patients could reasonably be attributed to direction selective
      mechanisms. A secondary goal was to determine whether the first harmonic response
      of normals was also due to imbalances in direction selective mechanisms.
      Monocular steady state VEPs were elicited by oscillating 3 c/deg gratings
      presented at 6 and 10 Hz in normal observers and observers with infantile
      esotropia. Responses were also obtained to phase-reversing gratings of the same
      spatial and temporal frequencies. Phase reversal eliminated the majority of first
      harmonic responses which were recorded for normal observers to oscillatory
      motion. However, phase reversal did not elicit the cortical motion asymmetry in
      infantile esotropia. Modeling results suggest that the first harmonic response to
      oscillatory motion arises due to non-linearities in both direction selective and
      non-direction-selective mechanisms, with the latter being dominant in patients
      with early onset strabismus.

PMID- 10343873
TI  - Colour and polarity contributions to global motion perception.
AB  - The influence of the image segmentation cues based on colour and polarity on a
      motion coherence task were examined. In line with previous reports, when the
      signal and noise were given unique identities thresholds were much lower than
      when they were the same, suggesting a strong influence of segmentation. In
      another paradigm extra noise elements that differed in colour or polarity
      interfered despite this perceptual segmentation. We suggest that the results when
      signal and noise have unique identities are attributable to the subjects' ability
      to attend to a particular location(s) in space. When this strategy was eliminated
      by presenting the stimuli in the near-periphery or very briefly the effect of the
      colour or polarity information disappears.

PMID- 10343874
TI  - Comparison of color and luminance contrast: apples versus oranges?
AB  - Using a spatial, forced-choice, matching protocol, we have measured observers'
      ability to equate the contrasts of sinusoidal gratings which vary along differing
      directions in a 3-dimensional color space. In a given experiment, the observer
      obtained a perceptual match between the contrasts of two gratings whose
      chromaticities or luminances varied along differing chromatic directions which
      were selected from among five axes: an achromatic luminance axis (lum), an
      isoluminant axis where only S-cone activation varied (S-axis), an isoluminant
      axis where L- and M-cone activation varied in a complementary manner (LM-axis),
      an axis where only L-cone activation varied (L-axis), and an axis where only M
      cone activation varied (M-axis). Even though these chromatic axes were chosen to
      activate independent mechanisms involved in the early stages of spatiochromatic
      visual processing, and despite the distinctly differing appearance of patterns
      from variations along differing directions, we find that observers can reliably
      make such pairwise contrast matches. Furthermore there is reasonable consistency
      of matching contrasts among observers and the pairwise contrast matches exhibit
      the properties of homogeneity and transitivity. This observed homogeneity and
      transitivity allows, for each color direction, the specification of a single
      scaling factor which relates perceptual contrast to physical contrast.

PMID- 10343875
TI  - Measuring perceived 3D shape at multiple spatial scales.
AB  - We present and test a novel multiscale representation of perceived 3D surface
      orientation: the orientation path. Using a multiscale probe, we measure perceived
      surface orientation at multiple spatial scales; linking the measurements for a
      given surface location yields that location's orientation path. The multiscale
      data obtained show that observers consistently see different surface orientations
      at different spatial scales. We demonstrate that such multiscale data can reveal
      multiscale differences between observers' percepts of a stimulus and the stimulus
      geometry. We also demonstrate the use of the orientation path in evaluating the
      multiscale effects of adding a depth cue to a 3D display.

PMID- 10343876
TI  - Spatial sensitization of increments and decrements: a border-contrast process and
      a net-excitation process.
AB  - We investigated the spatially local factors that adjust the sensitivity of the
      human visual system within a small patch of visual space. A very small adapting
      field was varied in diameter to map out the strength and extent of the spatially
      local processes that adjust sensitivity for both increments and decrements. The
      results demonstrated antagonistic center/surround adaptation regions with a
      decremental test probe comparable to those demonstrated previously for
      incremental probes (Westheimer, G., 1965. Spatial interaction in the human retina
      during scotopic vision, Journal of Physiology 81, 812-894; Westheimer, G., 1967.
      Spatial interaction in human cone vision, Journal of Physiology 190, 139-154)
      implying comparable antagonistic regions in the ON and OFF channels. In addition
      to spatial interactions based on light adaptation, we report a weaker effect that
      is based on the location of a border (luminance edge) and is governed by the
      contrast of this edge. Finally, we show that these effects are elicited by both
      highly localized edges (1' ring pairs) and radial lines (Ehrenstein figure) as
      well. We conclude that both a border-contrast mechanism and a net-excitation
      mechanism govern the spatially local adaptation of the visual system and that
      this view fits well with the behavior of single units reported previously.

PMID- 10343877
TI  - Local and global stereopsis in the horse.
AB  - Although horses have laterally-placed eyes, there is substantial binocular
      overlap, allowing for the possibility that these animals have stereopsis. In the
      first experiment of the present study we measured local stereopsis by obtaining
      monocular and binocular depth thresholds for renal depth stimuli. On all
      measures, the horses' binocular performance was superior to their monocular. When
      depth thresholds were obtained, binocular thresholds were several times superior
      to those obtained monocularly, suggesting that the animals could use stereoscopic
      information when it was available. The binocular thresholds averaged about 15 min
      arc. In the second experiment we obtained evidence for the presence of global
      stereopsis by testing the animals' ability to discriminate between random-dot
      stereograms with and without consistent disparity information. When presented
      with such stimuli they showed a strong preference for the cyclopean equivalent of
      the positive stimulus with the real depth. These results provide the first
      behavioral demonstration of a full range of stereoscopic skills in a lateral-eyed
      mammal.

PMID- 10343878
TI  - Nonlinearities of near-threshold contrast transduction.
AB  - The existence of analytic threshold nonlinearities was probed with 2AFC
      incremental threshold functions for both local and extended test patterns on
      stationary matched pedestals of the same and opposite sign. In contrast to the
      facilitation effect with same-sign pedestals, sensitivity with opposite-sign
      pedestals first deteriorated up to the mask detection level, abruptly improved
      and then deteriorated again. Analytic solutions for the transducer function with
      additive noise were derived to account for the incremental data in all
      conditions. The results for positive difference-of-Gaussian (DoG) stimuli (whose
      increment made the central spot lighter) and for 10 c deg-1 Gabor stimuli were
      consistent with accurate hard-threshold behavior with best-fitting d' powers from
      17 to 358. The 10 c deg-1 data further implied that contrast gain control was
      operating throughout the subthreshold range. The results for negative DoGs (whose
      increment corresponds to the darkening of the central spot) and 2 c deg-1 Gabor
      profiles were consistent with mild nonlinearities having d' powers of 1.6-3.
      Significant differences between the nonlinearities for positive and negative DoGs
      indicate that only a small portion, if any, of the near-threshold nonlinearity
      could be attributed to uncertainty. Our analysis suggests that, with low spatial
      frequency gratings, detection was based on those bars that become darker; with
      high-frequency gratings, on the bars that become brighter.

PMID- 10343879
TI  - Computational analysis of disparity modulation sensitivity: an explanation in
      terms of a Bayesian surface reconstruction.
AB  - Sensitivity to binocular disparity modulation has been shown to have a bandpass
      nature. This paper presents a computational account for the disparity modulation
      function (DMF) in terms of a Bayesian surface reconstruction. The Bayesian
      approach suggests that prior assumptions about surface structure will affect the
      perception of disparity modulation. Taking into account a prior constraint of
      surface smoothness being imposed on the perceived surfaces, we propose that
      computing the first derivatives of the surfaces determines the bandpass shape of
      the DMF. Based on this idea, we derive an analytical prediction of the DMF. It is
      then shown that the prediction gives a good fit to the empirical data.
      Implications for possible mechanisms underlying the DMF are discussed.

PMID- 10343880
TI  - Models for the description of angioscotomas.
AB  - To describe small scotomas in visual field examinations several statistical
      models are proposed and applied to the evaluation of angioscotoma in 13
      ophthalmologically normal subjects. A special perimetric grid is used where
      thresholds can be estimated along a line of narrow-spaced test points which
      crosses the predicted location of the retinal vessel. A two-stage analysis
      employs single estimations to fit a threshold curve by means of a special
      parametric description of the luminance difference sensitivity threshold as a
      function of stimulus position. An alternative model incorporates the threshold as
      a function of position into the probabilistic description of the binary response
      (stimulus seen/not seen).

PMID- 10343881
TI  - Angioscotoma detection with fundus-oriented perimetry. A study with dark and
      bright stimuli of different sizes.
AB  - Fundus-oriented perimetry (FOP) was used to evaluate the effectiveness of
      different-sized bright and dark stimuli in detecting and quantitatively measuring
      angioscotoma. The foveolas and optic disks of digitized fundus images were
      aligned with their psychophysical counterparts to construct individual grids of
      perimetric stimuli. Each grid included a linear set of test point locations
      crossing a retinal vessel. Angioscotomas immediately became visible in nine of 13
      healthy normal volunteers tested with FOP. Additional mathematical processing of
      local loss of differential light sensitivity (dls) disclosed an angioscotoma for
      at least one stimulus condition in all persons tested. The angioscomas were
      usually deeper for small (12) targets than for large (32') ones. On the other
      hand, the overall noise at dls thresholds was generally higher for small than for
      large stimuli regardless of whether the stimuli were bright or dark. No
      noteworthy differences were found in detection rates or signal-to-noise ratios
      under different stimulus conditions (dark/bright/small/large). FOP permits the
      individual arrangement of stimuli for specific morphological conditions and is
      thus capable of detecting even minute visual field defects such as angioscotomas.

PMID- 10343883
TI  - The intersection of genetics, public health, and preventive medicine.

PMID- 10343882
TI  - Kentucky legislators' views on tobacco policy.
AB  - CONTEXT: Kentucky leads the nation in adult and teen smoking prevalence. Even
      though Kentucky is one of the most tobacco-dependent states, tobacco policy is
      subject to change in light of possible national tobacco legislation. OBJECTIVE:
      To describe the degree of agreement among Kentucky legislators regarding tobacco
      control and tobacco farming policy, and to discover whether use of the policy
      Delphi method produces a shift toward consensus on tobacco policy. DESIGN: A two
      round policy Delphi study was conducted using in-person interviews. SETTING:
      Legislators' offices in Frankfort, Kentucky. PARTICIPANTS: Volunteer sample of
      116 Kentucky legislators (84% response rate). MAIN OUTCOME MEASURES: Degree of
      agreement on tobacco control and tobacco farming policies. RESULTS: Lawmakers
      were highly supportive of policies to lessen the state's dependence on tobacco,
      and were favorable toward stronger tobacco control policies. There were
      discrepancies, however, between what policies legislators thought were desirable
      and what policies were realistic. Tobacco interests were identified as possible
      explanations for this disparity. Tobacco allotment ownership was associated with
      less support for tobacco control and tobacco farming policies. A shift toward
      consensus on tobacco policy was achieved in the second round for 45% of the
      interview items common to both rounds. CONCLUSIONS: Kentucky legislators were
      highly supportive of reducing the state's dependence on tobacco and more
      supportive of tobacco control policies than expected. The policy Delphi method
      has the potential for shifting opinions about tobacco policies among state
      legislators. The findings of this study identify opportunities for public health
      policy change in one of the most tobacco-dependent states in the United States.

PMID- 10343884
TI  - BRCA1 and BRCA2 gene mutations and risk of breast cancer. Public health
      perspectives.
AB  - CONTENT: Breast cancer is the most common cancer and the second most common cause
      of cancer death among U.S. women. In 1998, about 178,700 new cases will be
      diagnosed and 43,500 women will die from the disease. Mutations in the BRCA1
      gene, which was cloned in 1994 and is located on chromosome 17q, have been
      identified as causes of predisposition to breast, ovarian, and other cancers. A
      second breast cancer gene, BRCA2, has been localized to chromosome 13q. Using
      inferential procedures, the overall carrier frequency of BRCA1 gene mutations has
      been estimated at 1 in 500 in the general U.S. population. Recent studies have
      indicated that the carrier frequency of a specific BRCA1 allele, the 185delAG
      mutation, may be as high as 0.8% to 1% among women of Ashkenazi Jewish descent.
      CONCLUSIONS: Due to the proliferation of laboratories offering genetic tests for
      breast cancer susceptibility, their appropriate use in public health needs
      careful scrutiny. Several issues are raised when such genetic tests are
      considered for population-based prevention programs for breast cancer. Public
      health agencies, such as the Centers for Disease Control and Prevention, are
      important to monitoring and evaluating genetic testing done outside of research
      protocols. If genetic tests for breast cancer are to be incorporated into future
      prevention programs, evaluation is needed of whether the testing can have the
      intended effect.

PMID- 10343885
TI  - Public health perspectives on testing for colorectal cancer susceptibility genes.
AB  - CONTEXT: About 131,600 new cases of colorectal cancer will be diagnosed in the
      United States in 1998. About 27,900 men and 28,600 women will die from colorectal
      cancer in 1998. Mutations to the hMSH2 gene on chromosome 2p and to the hMLH1
      gene on chromosome 3p have been identified as causes of colorectal cancer. These
      mismatch repair genes, which have recently been cloned, account for most cases of
      hereditary nonpolyposis colorectal cancer (HNPCC), one of the most common cancer
      susceptibility syndromes known. The carrier frequency of hMSH2 and hMLH1 gene
      mutations in the U.S. population is unknown. An adenomatous polyposis coli (APC)
      gene variant (I1307K allele), which was recently reported in 1 in 17 Ashkenazi
      Jewish persons, may double the risk for colorectal cancer in that population.
      CONCLUSIONS: The use of genetic tests for susceptibility to cancer of the colon
      and other sites needs careful scrutiny. Several issues must be addressed before
      such tests can be recommended for population-based prevention programs. For
      example, the screening of population subgroups raises concern about potential
      discrimination and stigmatization. Before genetic tests for colorectal cancer are
      incorporated into future programs, the safety, effectiveness, and quality of
      these tests must be evaluated.

PMID- 10343886
TI  - Future scenarios for the prevention and delay of Alzheimer disease onset in high
      risk groups. An ethical perspective.
AB  - CONTEXT: Alzheimer disease (AD) presents a major scientific and social challenge
      in our aging society. Strategies to prevent or delay onset of symptoms, as well
      as to prevent the decline into the advanced stage, are urgently needed. While
      these strategies do not yet exist in a proven and clinically applicable form, the
      science is progressing rapidly. OBJECTIVES: The pre-eminent goal is to identify
      asymptomatic persons at high risk for AD and to then apply pharmacologic and
      lifestyle interventions that delay onset of disease. In this scenario, genetic
      susceptibility testing may eventually prove accurate enough to be of use in
      identifying at-risk individuals decades before probable onset, allowing maximal
      preventive efforts. Second, an important goal is to delay or prevent the onset of
      moderate and advanced AD through applying compounds that slow the progression of
      disease, thereby allowing patients to die of unrelated ailments of old age before
      they lose their capacities to recognize loved ones and to communicate by speech.
      CONCLUSIONS: This article provides a discussion of these strategies with
      attention to a variety of ethical issues that should be of concern to physicians
      and caregivers. An assessment of the scientific evidence for preventing or
      delaying AD should be coupled with values analysis.

PMID- 10343887
TI  - What should be the role of public health in newborn screening and prenatal
      diagnosis?

PMID- 10343888
TI  - Preventing morbidity and mortality from sickle cell disease. A public health
      perspective.
AB  - CONTEXT: Sickle cell disease is a group of conditions characterized by production
      of abnormal hemoglobin, with clinical manifestations that vary by genotype and
      age. OBJECTIVE: To discuss current public health issues associated with sickle
      cell disease, and approaches to preventing complications from these conditions in
      the United States. DESIGN: Literature review. RESULTS: Most clinical
      interventions for people with sickle cell disease discussed in the medical
      literature can be classified as tertiary prevention: for example, therapy to
      ameliorate anemia, reduce the frequency of pain crises, or prevent stroke
      recurrences. A form of secondary prevention, newborn screening, has emerged as an
      important public health approach to identifying affected children before they
      develop complications. Newborn screening is the starting point for simple public
      health strategies such as parental education, immunization, and penicillin
      prophylaxis. Identification of affected families by newborn or community
      screening programs has also been an entry point for genetic counseling, although
      utilization of prenatal testing has varied by factors such as geographic
      location. Public health agencies have had significant involvement with funding,
      policy making, and formulation of laboratory and clinical guidelines for sickle
      cell disease. Since the introduction of penicillin prophylaxis policies, newborn
      screening, new immunizations, and comprehensive medical care centers, the
      survival of young children with sickle cell disease has improved. CONCLUSIONS:
      Although the efforts of preventive medicine providers in public health programs
      are not solely responsible for the improved survival of children with sickle cell
      disease, such programs remain an important component in preventing sickle cell
      complications.

PMID- 10343889
TI  - Coronary heart disease. At the interface of molecular genetics and preventive
      medicine.
AB  - BACKGROUND: Susceptibility to common chronic diseases such as coronary heart
      disease (CHD) appears to be influenced by "context-dependent effects," which
      include interactions among genes (genetic epistasis) and among genes and
      environmental factors (gene-environment interactions). METHODS: A synthesis of
      current knowledge and research findings demonstrates the importance of
      integrating genetic research on cardiovascular disease with preventive medicine
      and public health initiatives. RESULTS: A variety of candidate genes have been
      implicated in risk for CHD, but only limited examples of context-dependent
      effects have been described. Interactions between genetic and environmental
      factors appear to influence lipid metabolism, plasma homocysteine levels, and
      pharmacologic response to many commonly prescribed medications. Quantification of
      genetic effects associated with increased disease risk that are modifiable by
      interventions such as diet, exercise, and smoking cessation is an important
      interface between molecular genetics and preventive medicine. CONCLUSIONS: As a
      primary focus of preventive medicine expands to encompass early detection and
      treatment of asymptomatic individuals at risk for disease, the ability to
      quantify the influence of context-dependent effects on disease risk will be
      critical for determining drug safety and effectiveness in diverse patient
      populations and for implementing effective prevention and treatment programs.

PMID- 10343890
TI  - Screening for hemochromatosis. A public health perspective.
AB  - CONTEXT: The discovery of the HFE gene in 1996 has introduced DNA testing as a
      possible tool for screening and diagnosis of hemochromatosis and increased
      interest in the disorder. Population screening using transferrin saturation has
      been advocated by experts to permit early detection and treatment with phlebotomy
      before the onset of clinical disease. METHODS: Based on a literature review, we
      consider the relative risks and merits of two screening tests as part of a
      broader look at the evidence required for the recommendation of universal
      screening for hemochromatosis. RESULTS: Several questions must be answered before
      universal screening can be recommended. Uncertainties remain about the penetrance
      and preventable disease burden, laboratory standardization, and optimal
      strategies to minimize potential risks of screening for hemochromatosis.
      CONCLUSIONS: As a common genetic disorder with simple, effective therapy,
      hemochromatosis offers a model for other genetically influenced chronic diseases
      that some day may have interventions to improve prognosis. Resolution of
      questions related to prevention of chronic diseases from hemochromatosis,
      therefore, will have broad usefulness in the future.

PMID- 10343891
TI  - Host genes and infectious diseases. HIV, other pathogens, and a public health
      perspective.
AB  - INTRODUCTION: The global impact of infectious diseases is tremendous. In 1996,
      the 17 million deaths from infectious diseases accounted for one third of all
      deaths worldwide, while the acute and chronic morbidity from infectious diseases
      adds an additional great burden on global health. Multiple factors, host and
      nonhost, influence the susceptibility of individuals and populations to
      infectious diseases, as well as the severity of the illness once infected.
      METHODS: We review the influence of host genes on the susceptibility to and
      severity of viral, bacterial, parasitic and fungal infectious diseases, on
      vaccine responsiveness and on treatments for infections. HIV/AIDS is discussed in
      detail because it is an example of an infectious disease influenced by multiple
      host genes and because of its impact. Although the HIV/AIDS pandemic dates only
      since the late 1970s, it has claimed the lives of 11 million people worldwide
      and, today, more than 30 million people are estimated to be HIV infected.
      CONCLUSION: Our greater understanding of the genetic factors that influence
      morbidity and mortality of infectious disease leads to new avenues of prevention
      and treatment that can improve the health of individuals and populations.

PMID- 10343893
TI  - n-butanol purification of dye terminator sequencing reactions.

PMID- 10343892
TI  - Aberrant DNA sequence pattern caused by a heterozygosity.

PMID- 10343894
TI  - Fluorescence in situ hybridization of micronuclei in binucleate fibroblasts: a
      protocol for cytoplasm preservation.

PMID- 10343895
TI  - Combination of cross-species RNA solution hybridization and immunoprecipitation
      aids in the cloning of RT-PCR products.

PMID- 10343896
TI  - pBBR1-GFP: a broad-host-range vector for prokaryotic promoter studies.

PMID- 10343897
TI  - Simplified PCR-mediated, linker-scanning mutagenesis.

PMID- 10343898
TI  - Increased efficiency of arbitrarily primed PCR by prolonged ramp times.

PMID- 10343899
TI  - Retrieval of flanking DNA using a PCR-based approach with restriction enzyme
      digested genomic DNA template.

PMID- 10343900
TI  - Pit-stop PCR: an approach to increase final product yield of multiplex PCR.

PMID- 10343901
TI  - Adaptation of inverse PCR to generate an internal deletion.

PMID- 10343902
TI  - Reduction of false positives in prokaryotic mRNA differential display.

PMID- 10343903
TI  - Transfection of adipocytes by gene gun-mediated transfer.
AB  - Studies of the gene expression, metabolism and intracellular signaling of
      adipocytes have been hindered by the difficulty of transfecting cultured
      adipocytes using standard methods. Here, we demonstrate the utility of gene gun
      mediated genetic transfer for transfection of differentiated 3T3-L1 adipocytes.
      Transfection of adipocytes with the Helios Gene Gun yielded a transfection
      efficiency that was consistently 5%-10% of total cells. We have used this
      technique to overexpress the transcription factor CCAAT/Enhancer Binding Protein
      alpha (C/EBP alpha) and transactivate an obese gene promoter-luciferase
      construct. This method has broad utility for transfection of other cell types
      that are resistant to transfection.

PMID- 10343904
TI  - The primer generator: a program that facilitates the selection of
      oligonucleotides for site-directed mutagenesis.
AB  - Site-directed mutagenesis is a powerful tool that has enabled molecular
      biologists to perform functional analysis of altered nucleic acids and proteins.
      Newer PCR-based mutagenesis techniques have reduced the process of mutagenesis to
      as little as one day. While each technique has its advantages, both require a
      strategy to isolate the desired clone from a population that contains mutagenized
      and wild-type genes. In this report, we describe a World Wide Web-based computer
      program that facilitates the design of mutagenic primers such that successfully
      mutagenized clones can be identified by the presence or absence of a unique
      restriction site.

PMID- 10343905
TI  - Two-stage PCR protocol allowing introduction of multiple mutations, deletions and
      insertions using QuikChange Site-Directed Mutagenesis.
AB  - We developed a two-stage procedure, based on the QuikChange Site-Directed
      Mutagenesis Protocol, that significantly expands its application to a variety of
      gene modification experiments. A pre-PCR, single-primer extension stage before
      the standard protocol allows the efficient introduction of not only point
      mutation but also multiple mutations and deletions and insertions to a sequence
      of interest.

PMID- 10343906
TI  - pIRES-CD4t, a dicistronic expression vector for MACS- or FACS-based selection of
      transfected cells.
AB  - To facilitate the selection of cell lines expressing transfected genes of
      interest, a plasmid vector has been constructed that directs the co-expression of
      heterologous cDNAs and a 3'-positioned cassette encoding a truncated CD4 marker.
      An encephalomyocarditis virus internal ribosomal entry site (IRES) mediates
      translational initiation from this 3' cassette, and a cytomegalovirus promoter
      drives dicistronic transcript expression. To test the utility of this vector, a
      luciferase reporter gene was inserted, and this construct (pIRES-CD4t-luc) was
      electrotransfected into myeloid FDCW2 cells. As monitored by flow cytometry and
      luciferase assays, three rounds of magnetic cells sorting (MACS) yielded > or =
      90% CD4t-positive cells with an average density of 17,000 CD4t molecules per
      cell. In ten clonal sublines analyzed, luciferase expression was uniformly high
      and stable over a test period of three months. Finally, a comparison of MACS- vs.
      FACS-based isolation of transfected cells showed two to three rapid rounds of
      MACS to be somewhat more effective. Thus, pIRES-CD4t should prove useful in the
      direct and rapid selection of relevant stably or transiently transfected cells.

PMID- 10343907
TI  - Microsatellites obtained using strand extension: an enrichment protocol.
AB  - A new method is described to enrich genomic libraries for clones containing
      microsatellite repeats. The method involves selection on completed M13 genomic
      libraries rather than on genomic DNA before library construction. It uses two
      reactions, in which microsatellite oligonucleotides prime strand extension. The
      first reaction uses a biotinylated primer allowing vectors with microsatellite
      containing inserts to be selected with streptavidin-coated magnetic beads. This
      reaction may be dependent on the strand displacement activity of the Klenow
      fragment of DNA Polymerase I. The second strand extension reaction is included to
      improve the relative transformation efficiency of microsatellite-containing
      clones. In control experiments starting with 0.7% microsatellite-containing
      clones, enrichment averaged 99.5%. The method was tested empirically on
      antechinus and abalone genomic libraries in which enrichment for (CA)n
      microsatellites was efficient enough that clones could be sequenced without
      further screening. This protocol is technically straightforward and permits the
      isolation of a large number of microsatellite markers in less time than is
      required to execute traditional protocols involving rounds of filter
      hybridization.

PMID- 10343908
TI  - Selection of an anti-CD20, single-chain antibody by phage ELISA on fixed cells.
AB  - Cloning the correct genes that code for antibody-variable domains from hybridomas
      is often complicated by the presence of several immunoglobulin transcripts, some
      of them arising from a myeloma cell line. For the rapid functional evaluation of
      recombinant antibody fragments against cell-surface antigens, we established an
      efficient expression and screening system using phagemid antibodies and fixed
      cells. VL and VH-polymerase chain reaction (PCR) products, amplified from
      hybridoma cDNA, were cloned into the phagemid vector pSEX81. After transduction
      into E. coli and phage rescue, clones were tested for antigen binding using a
      phage-enzyme-linked immunosorbent assay (ELISA) procedure with whole cells fixed
      to ELISA wells. This procedure facilitated the successful cloning of a functional
      anti-CD20, single-chain antibody from hybridoma cDNA. The CD20 B-lymphocyte
      surface antigen expressed by B-cell lymphomas is an attractive target for cancer
      treatment using immunoconjugates or bi-specific antibodies.

PMID- 10343909
TI  - Modification of the AFLP protocol applied to honey bee (Apis mellifera L.) DNA.
AB  - The established amplified fragment-length polymorphism (AFLP) protocol was
      simplified and optimized for honey bee DNA (Apis mellifera L.). Compared to the
      original method, the following simplifications were made: (i) the digestion of
      DNA and ligation of the adapters are performed in one reaction vs. two, (ii) one
      restriction enzyme is used vs. two and (iii) amplification is accomplished in one
      reaction vs. two. PCR products are resolved in agarose-Synergel instead of
      polyacrylamide and are visualized by ethidium bromide staining rather than by
      autoradiography of labeled primers. Using the modified procedure for honey bee
      DNA, high reproducibility of the band patterns of PCR products and low
      sensitivity to the amplification conditions were seen. Analysis of honey bee DNA
      revealed considerable genetic variability within and between African and European
      bee samples. African- and European-specific fragments were found.

PMID- 10343910
TI  - Sequential chemiluminescent detection of target DNAs without stripping and
      reprobing.
AB  - We present a simple method for sequential chemiluminescent detections of two
      different DNA loci on a single Southern blot. First, an enzyme-linked DNA probe
      for a unique sequence is detected with a horse-radish peroxidase (HRP) substrate
      followed by the detection of another enzyme-linked DNA probe for a different
      unique sequence with an alkaline phosphatase (AP) substrate that simultaneously
      inhibits the chemiluminescence generated by HRP. Such sequential detection steps
      eliminate the need to strip and reprobe blots and can be performed with no
      intervening steps.

PMID- 10343912
TI  - Real-time bioluminometric method for detection of nucleoside diphosphate kinase
      activity.
AB  - A real-time, simple and sensitive method for detection of nucleoside diphosphate
      (NDP) kinase activity has been developed. The assay is based on detection of ATP,
      generated in the NDP kinase reaction between a nucleoside triphosphate and
      adenosine diphosphate (ADP), by the firefly luciferase system. In the presence of
      0.3 mM dGTP, the Km for ADP was found to be approximately 30 microM for the NDP
      kinase from Baker's yeast. In the presence of 250 microM ADP, the Km for dATP
      alpha S, dTTP alpha S, dGTP, dTTP, dCTP and GTP was found to be approximately
      0.01, 0.03, 0.05, 0.25, 0.75 and 0.2 mM, respectively. The assay is sensitive and
      yields linear responses between 0.05-50 mU. The detection limit was found to be
      0.05 mU of NDP kinase. The method was used to detect NDP kinase contamination in
      commercial enzyme preparations.

PMID- 10343913
TI  - Water-soluble, meso-substituted cationic porphyrins--a family of compounds for
      cellular delivery of oligonucleotides.
AB  - The delivery of oligonucleotides to appropriate intracellular compartments is
      crucial to their development as tools in gene function studies and as
      therapeutics. Here, we report the characterization of meso-substituted cationic
      porphyrins as a large class of water-soluble reagents for oligonucleotide
      delivery. These porphyrins form non-covalent complexes with single-stranded
      oligonucleotides and deliver these molecules into the nuclei of cell lines in
      culture. The porphyrins protect oligonucleotides from nuclease degradation, and
      delivery is unaffected by the presence of serum. Delivery capacity is dependent
      on the charge ratio and concentration of the oligonucleotide and porphyrin used
      to form the complex, on the chemical substituents of the oligonucleotide and on
      the identity of the cationic porphyrin. This class of molecules provides a
      versatile set of water-soluble delivery reagents that could contribute to the
      development of oligonucleotide drugs.

PMID- 10343911
TI  - Use of PCR to screen for promoter elements in genomic DNA library clones.
AB  - We report a modified PCR strategy to screen for promoter elements of genes of
      interest that is based upon consecutive rounds of PCR and appropriate subcloning.
      Following preliminary identification and sequencing of intron 1 by standardized
      PCR, the application of a suited cDNA/intron primer combination renders a
      succeeding PCR-mediated screening of cosmid or P1-derived artificial chromosome
      (PAC) libraries possible, thus identifying genomic clones comprising the searched
      promoter elements. We tested our approach in comparison with a commercially
      available promoter finder kit by searching the promoter elements of the CENP-C
      gene from the human and mouse genomes. Applying the kit system, we amplified the
      anticipated promoter from mouse, but failed in isolating human promoter elements.
      Our approach made use of a 5'-UTR/intron 1 primer combination in the second round
      of PCR, enabling the identification of positive clones from genomic DNA within a
      human PAC library possible. Subcloning and final PCR amplification revealed the
      successful isolation of the human promoter. Therefore, we conclude that our
      approach might represent a helpful alternative to identify promoter elements,
      especially when prior art genome walking, STS-based strategies or anchored PCR
      failed.

PMID- 10343914
TI  - Reversible gels for electrophoresis and isolation of DNA.
AB  - Here, the application of the gel-forming carbohydrate polymer, gellan gum, for
      the electrophoresis and isolation of DNA is detailed. Gellan gun forms gels in
      the presence of divalent metal cations, and the gels can be converted back to a
      solution by the addition of a chelating agent such as EDTA. Also, gellan
      electrophoresis gels can be formed using diamines. These gels are reversible by
      increasing the pH, which results in the deprotonation of the diamine. Gellan
      electrophoresis gels were used for separations at concentrations as low as 0.03%.
      Native gellan electrophoresis gels have significant electroosmosis and were
      generally run overnight. A gellan electrophoresis gel (0.1%) showed good
      resolution of DNA from approximately 50-1 kbp. The addition of linear polymers,
      such as hydroxethyl cellulose, to the gellan gum before casting greatly reduced
      the electroosmosis. The additional polymer increased the resolution of low
      molecular-weight DNA down to approximately 200 bp and allowed gels to be run in a
      few hours. DNA isolated from gellan electrophoresis gels could be cut by common
      restriction enzymes and ligated in the presence of the gellan gum. The presence
      of gellan gum did not significantly inhibit the transformation of competent E.
      coli cells by plasmid DNA.

PMID- 10343915
TI  - Centrifugal assay for fluorescence-based cell adhesion adapted to the analysis of
      ex vivo cells and capable of determining relative binding strengths.
AB  - Cell adhesion assays are widely used to identify novel cellular ligands, novel
      cell surface receptors for these ligands and to elucidate the mechanisms
      responsible for the underlying cellular and molecular interactions. We report
      here the development of a novel centrifugal assay for fluorescence-based cell
      adhesion (CAFCA) that offers a number of advantages over the currently available
      assays. CAFCA is based on two centrifugation steps: one to allow for the
      synchronization of the initial cell-substratum contact and one to enable both a
      defined removal force to be exerted onto the cells for displacement of unbound
      cells and determination of the relative binding strengths of adhering cells. The
      fluorescently tagged cells are monitored in specifically devised, disposable
      microplate assemblies by a two-sided fluorescence detection through the computer
      interfaced SPECTRAFLUOR microplate fluorometer. The assay is rapid, accurate,
      reproducible and adaptable to small numbers of delicate primary cells that can
      ideally be labeled with the fluorochrome calcein AM (or analogous vital
      fluorescent dyes). Most uniquely, CAFCA provides (i) means of assessing the
      precise number of cells bound to a given substratum out of the total amount of
      cells contained within the population to be analyzed and (ii) a means of
      establishing the attachment strengths (i.e., dynes/cell) in a high number of
      samples/conditions simultaneously. CAFCA is therefore expected to make a
      substantial methodological and conceptual contribution to the range of available
      assays aimed at examining cellular interactions in vitro and promises the
      potential of being able to transpose automated versions of these tests for
      routine use in laboratories.

PMID- 10343916
TI  - Cloning of porcine prepro-orexin cDNA and effects of an intramuscular injection
      of synthetic porcine orexin-B on feed intake in young pigs.
AB  - Early growth is an important determinant of gain and efficiency in growing pigs.
      A major limiting factor of piglet growth is feed intake. Orexins, newly
      discovered neuropeptides, may be important regulators of appetite. The orexin
      gene, which encodes orexin-A and -B, was recently identified in rodents and man.
      The objectives of this study were to clone the cDNA for porcine orexin, utilize
      the cDNA sequence information to produce synthetic hormone, and evaluate the
      effect of orexin administration on feed intake in weanling pigs. Oligonucleotide
      primers were designed for reverse transcription polymerase chain reaction
      production of porcine orexin cDNA. The polymerase-chain-reaction products were
      cloned, sequenced, and found to be 88.5% homologous to the human orexin sequence.
      Predicted translation of porcine orexin cDNA revealed orexin-A and -B amino acid
      sequences that were 100% and 96% homologous to the known human peptides,
      respectively. Porcine orexin-B was synthesized according to the predicted
      sequence. Twenty-six cross-bred piglets were utilized in three replicates (n = 8
      10/replicate). Piglets were weaned between 2-3 wk of age. One week after weaning,
      equal numbers of animals in each replicate received intramuscular (i.m.)
      injections of orexin-B (3 mg/kg body weight) or vehicle (sterile water). Feed
      intake was monitored from -24 to 24 h relative to injection (time 0). The orexin
      injected pigs ingested an additional meal at 12 h when compared with the control
      animals (P = 0.02). Cumulative feed intake was increased by orexin-B
      administration from 12 to 24 h postinjection (P < or = 0.05). Total feed intake
      at 24 h was improved by 18% in orexin-treated pigs (P = 0.05). The ability to
      stimulate appetite during critical periods of early growth, particularly
      following weaning, could result in significant improvements in swine-production
      efficiency.

PMID- 10343917
TI  - Moderate doses of porcine somatotropin do not increase plasma insulin-like growth
      factor-I (IGF-I) or IGF binding protein-3.
AB  - The growth rate of the young pig is generally much less than its potential and
      may be constrained by endocrine status as well as by nutrient intake. The aim of
      this study was to determine whether porcine somatotropin (pST) could increase
      growth in the nursing pig. Fourteen sows nursing litters of 6 (n = 7) or 12 (n =
      7) piglets were utilized to establish a high and low plane of nutrition for
      sucking pigs. On Day 4 of lactation, the median two male pigs from each litter
      were randomly allocated to one of two doses of pST (0 or 60 micrograms/kg/d)
      until weaning on Day 31. Pigs were bled on Days 4, 13, 22, and 31 of lactation
      and the plasma was analyzed for insulin-like growth factor (IGF)-I, IGF-II, and
      IGF binding protein-3 (IGFBP-3). Pigs were weaned into conventional accommodation
      and further weighed on Days 63, 91, and 119. Pigs from litters of 6 grew more
      quickly and weighed 2.2 kg (P = 0.01) and 3.5 kg (P = 0.04) more than pigs from
      litters of 12 at 31 and 63 d of age, respectively. There was no effect of pST on
      preweaning growth of sucking pigs (261 vs. 258 g/d, P = 0.68), although growth
      rate increased in the final 3 d before weaning at 31 d (241 vs. 294 g/d, P =
      0.01). IGFBP-3 was greater (1.09 vs. 0.78 micrograms/ml, P < 0.001), whereas IGF
      I tended to be greater (206 vs. 176 ng/ml, P = 0.14), in pigs from the small
      litters. There was no effect of pST on plasma IGF-I (182 vs. 195 ng/ml, P =
      0.454) or IGFBP-3 (0.93 vs. 0.94 microgram/ml, P = 0.85) concentrations. Plasma
      IGF-I and IGFBP-3 were highly correlated with the growth rate of nursing pigs (R
      = 0.638 and 0.756, respectively). There were no effects of pST (340 vs. 328
      ng/ml, P = 0.48) or litter size (336 vs. 333 ng/ml, P = 0.88) on IGF-II. In
      conclusion, pST had no little or no effect on growth performance or plasma IGF-I,
      IGF-II, or IGFBP-3 in sucking pigs on either a high or low plane of nutrition.

PMID- 10343918
TI  - Injection of neuropeptide Y into the third cerebroventricle differentially
      influences pituitary secretion of luteinizing hormone and growth hormone in
      ovariectomized cows.
AB  - Hypothalamic neurons that control the luteinizing hormone (LH) and growth hormone
      (GH) axes are localized in regions that also express neuropeptide Y (NPY).
      Increased hypothalamic expression of NPY due to diet restriction has been
      associated with suppressed secretion of LH and enhanced secretion of GH in
      numerous species. However, these physiological relationships have not been
      described in cattle. Thus, two studies were conducted to characterize these
      relationships using ovariectomized (Experiment 1) or ovariectomized estrogen
      implanted (Experiment 2) cows. In Experiment 1, four well-nourished,
      ovariectomized cows received third cerebroventricular (TCV) injections of 50 and
      500 micrograms of NPY in a split-plot design. Venous blood was collected at 10
      min intervals from -4 hr (pre-injection control period) to +4 hr (postinjection
      treatment period) relative to TCV injection. NPY suppressed (P < or = 0.04) tonic
      secretion of LH irrespective of dose and tended to stimulate (P < or = 0.10) an
      increase in tonic secretion of GH. In Experiment 2, six ovariectomized cows that
      were well nourished and implanted with estradiol received TCV injections of 0,
      50, or 500 micrograms of NPY in a replicated 3 x 3 Latin Square. Both doses of
      NPY suppressed (P < 0.06) mean concentration of LH relative to the 0-microgram
      dose. The 50-microgram dose of NPY tended (P < 0.10) to increase the amplitude of
      GH pulses. In conclusion, TCV injection of NPY suppressed pituitary secretion of
      LH and simultaneously tended to increase pituitary secretion of GH.

PMID- 10343919
TI  - Influence of dose, frequency, and duration of infused gonadotropin-releasing
      hormone on secretion of luteinizing hormone and follicle-stimulating hormone in
      nutritionally anestrous beef cows.
AB  - Nutritionally induced anovulatory cows were ovariectomized and used to determine
      the relationships between dose, frequency, and duration of exogenous gonadotropin
      releasing hormone (GnRH) pulses and amplitude, frequency, and concentrations of
      luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in serum. In
      Experiment 1, cows were given pulses of saline (control) or 2 micrograms of GnRH
      infused i.v. during a 0.1-, 1.25-, 5-, 10-, or 20-min period. Concentrations of
      LH and FSH during 35 min after GnRH infusion were greater than in control cows (P
      < 0.01), and FSH concentrations were greater when GnRH infusions were for 10 min
      or less compared with 20 min. In Experiment 2, the effect of GnRH pulse frequency
      and dose on LH and FSH concentrations, pulse frequency, and pulse amplitude were
      determined. Exogenous GnRH (0, 2, or 4 micrograms) was infused in 5 min at
      frequencies of once every hour or once every 4th hr for 3 d. There was a dose of
      GnRH x frequency x day effect on LH and FSH concentrations (P < 0.01), indicating
      that gonadotropes are sensitive to changes in pulse frequency, dose, and time of
      exposure to GnRH. There were more LH pulses when GnRH was infused every hour,
      compared with an infusion every 4th hr (P < 0.04). Amplitudes of LH pulses were
      greater with increased GnRH dose (P < 0.05), and there was a frequency x dose x
      day effect on FSH pulse amplitude (P < 0.0006). We conclude that LH and FSH
      secretion in the bovine is differentially regulated by frequency and dose of GnRH
      infusions.

PMID- 10343920
TI  - Oxytocin-neurophysin I mRNA abundance in equine uterine endometrium.
AB  - A positive-feedback loop between luteal oxytocin and uterine prostaglandin F2
      alpha (PGF) is a major signal for luteolysis in ruminants. Likewise, uterine PGF
      causes luteolysis in mares, but the involvement of oxytocin in this process is
      unclear. We wanted: 1) to determine if the oxytocin-neurophysin I (OT-NP I) gene
      is transcribed into mRNA in the endometrium of mares; and, if so, 2) to analyze
      relative changes in abundance of endometrial OT-NP I mRNA throughout the estrous
      cycle and during early stages of pregnancy. Endometrial biopsies were obtained
      from nonbred mares during estrus, and 5, 10, and 15 d after ovulation (n = 3/d).
      Biopsies were also obtained from pregnant mares 10, 15, and 20 d after ovulation
      (n = 3/d). Relative amounts of OT-NP I and glyceraldehyde-3-phosphate
      dehydrogenase mRNA in endometrium were assessed by reverse transcription
      polymerase chain reaction and Southern blotting. Endometrial OT-NP I mRNA
      abundance changed with day of the cycle or pregnancy, and levels at estrus were
      higher than at any other days examined. The OT-NP I mRNA levels were negatively
      correlated with serum progesterone across all days examined and positively
      correlated with serum estradiol in nonbred mares. The reverse transcription
      polymerase chain reaction products for both OT-NP I and glyceraldehyde-3
      phosphate dehydrogenase were cloned into vectors and sequenced. Each shared
      greater than 89% nucleotide and predicted amino acid identities with the
      respective human, bovine, ovine, and rat products. Uterine oxytocin may be
      involved in regulation of reproductive tract function during the estrous cycle
      and/or establishment of pregnancy in horses.

PMID- 10343921
TI  - Retinal phototoxicity.
AB  - Phototoxic retinal lesions are a product of advances in operative technology. Use
      of more powerful light sources in both anterior and posterior segment cases and
      an increase in surgical complexity requiring longer operative times (especially
      during ophthalmic training) have rendered photic injury a real danger for all
      surgeons. Though we enjoy the enhanced view offered by modern light sources, we
      must also keep in mind the additive, detrimental effect of prolonged light
      exposure. With increased awareness of this potential hazard, surgeons can take
      steps to minimize the chance of generating a sight-threatening phototoxic lesion.

PMID- 10343922
TI  - Laser injuries of the eye.
AB  - With the increasing use of lasers in the military and industry, a moderate number
      of significant retina injuries have occurred. These injuries have been due to
      lasers in the visible and near-infrared spectrum primarily, with a pulse duration
      in the nanosecond range. Use of lasers in the ophthalmic community has resulted
      also in structural damage to the cornea, lens, IOL, and retina. Because we have
      no proven treatment for most injuries to the retina, we must continue to strongly
      emphasize the use of wavelength-specific protective goggles to try to prevent
      future eye injuries.

PMID- 10343923
TI  - Retinopathy of prematurity and associated factors.

PMID- 10343924
TI  - Detection and prevention of maculopathy associated with antimalarial agents.
AB  - Rheumatologists use both cholorquine and hydroxychloroquine in the treatment of
      systemic arthritic and immune disease. Hydroxychloroquine is much more expensive
      but is better tolerated by patients. My experience in watching patients being
      switched from one drug to another suggests that chloroquine is more effective in
      some patients than is hydroxychloroquine. Reynes thought that a review of the
      literature suggests that chloroquine is more toxic at 250 mg/day as compared to
      400 mg of hydroxychloroquine if dose is based on these dosages. This theory may
      be related, in part, to the observation by Raines and associates that chloroquine
      crosses the blood-retinal barrier whereas hydroxychloroquine does not. Patients
      should be assessed 6 months after starting antimalarials. Routine automated
      perimetry is not indicated. An appropriate examination would include visual
      acuity testing, color-vision testing, Amsler grid testing, and corneal
      assessment. Patients should be dosed on the basis of ideal body weight (not
      actual body weight) to reduce the incidence of macular toxicity. Patients with no
      risk factors should be examined no more than once a year.

PMID- 10343925
TI  - The eye at altitude.

PMID- 10343926
TI  - Ocular toxicity of mitomycin-C.

PMID- 10343927
TI  - Toxicity of ocular surgical solutions.
AB  - Intraocular medications, solutions, and instruments are an integral component of
      intraocular surgery. The ionic composition, pH, and osmolality should approximate
      aqueous humor to prevent damage to the corneal endothelium. Intraocular
      medications should be evaluated for their intrinsic properties and presence of
      vehicles or preservatives. Many new cleaning procedures and promising new
      intraocular drugs are likely to be introduced in the future. The responsibility
      of ocular surgeons is to protect their patients from drug-, solution-, or
      instrument-related toxicity.

PMID- 10343928
TI  - Adverse events associated with commonly used glaucoma drugs.

PMID- 10343929
TI  - Markers of risk for preterm delivery.
AB  - Clinical and experimental evidence indicate that PTD results from four primary
      pathogenic mechanisms: activation of the maternal or fetal HPA axis;
      amniochorionic-decidual or systemic inflammation; decidual hemorrhage; and,
      pathologic distention of the myometrium. Each of these four pathways has a
      distinct epidemiological and clinical profile, and unique biochemical and
      biophysical pathways initiating parturition, but shares a common final
      biochemical pathway involving myometrial activation and stimulation, and enhanced
      genital tract protease activity promoting PPROM and cervical change. Traditional
      methods of predicting women at risk relying on obstetrical history or symptoms
      and epidemiological risk factors are neither sensitive nor specific. Recent
      approaches to predicting PTD, including sonographic measurement of cervical
      length and biochemical assays for hCG, cytokines, fFN, MMPs, estrogens, and CRH,
      are more sensitive than traditional methods. Moreover, given the heterogeneous,
      interactive etiopathogeneses of PTD, multiple biochemical markers should not only
      increase sensitivity and specificity, but also permit the detection of the
      relative contribution of each pathogenesis to the overall risk of PTD.

PMID- 10343930
TI  - Prenatal screening with evaluated high risk scores.
AB  - This paper reviews data that support the effectiveness of the French approach of
      using risk scoring for evaluating the risk of preterm delivery. This approach,
      which was developed in 1969 and spread to obstetricians and midwives throughout
      France in the early 1970s, includes systematic information about the recognition
      of uterine contractions, advice about reduction of physical exercise, and the
      prescription of work-leave for women with heavy or physically demanding work
      loads. The effectiveness of this prevention strategy is assessed using three
      different data sets: an evaluation of a preterm prevention program in the Alsace
      Region of France, five successive French national sample surveys which collected
      data on pregnant women, and a study of the effectiveness of a prevention program
      for twins in the district of Haut de Seine near Paris. The authors show that the
      rate of preterm birth in France declined substantially, but that the decline was
      concentrated among singleton spontaneous births. Since the 1970s induced preterm
      births have increased, and, interventions have not reduced the high rates of
      preterm birth among twins.

PMID- 10343932
TI  - Antibiotics: treatment of preterm labor.
AB  - Our intention is to review recent data and provide recommendations for the use of
      antibiotics in cases of preterm labor or preterm premature rupture of the
      membranes (pPROM). Various studies assessing antibiotics as treatment for preterm
      labor demonstrate neonatal or maternal benefits only in certain circumstances.
      Antibiotic treatment should be given to patients with bacterial vaginosis and
      Trichomonas vaginalis. Currently, antibiotics should not be applied routinely to
      prolong pregnancy in women with preterm labor and intact membranes. However,
      antibiotic therapy should be given to patients with pPROM to prolong pregnancies
      at 24 to 32 weeks' gestation. Our management of pPROM up to 32 weeks' gestation
      includes use of corticosteroids, antibiotic (extended spectrum penicillins) and
      tocolytic treatment for preterm labor and pregnancy prolongation. We consider
      expectant management previous to evidence of intrauterine infection. In women
      with pPROM at 32 to 34 weeks we found it beneficial to deliver 24 hours after
      administration of corticosteroids or, in cases of intrauterine infection,
      immediately. Finally, we report on our research work regarding fetal brain
      development in preterm birth. Further studies will be necessary to clarify the
      role of the interleukin-6/interleukin-6 receptor pathway in the development of
      intracerebral hemorrhage frequently occuring in premature infants.

PMID- 10343931
TI  - Prostaglandin dehydrogenase and the initiation of labor.
AB  - In summary, these studies have suggested that prostaglandin dehydrogenase may
      have a central role to play in the mechanisms which determine biologically active
      prostaglandin concentrations within human fetal membranes and placenta at the
      time of labor, at term or preterm. Moreover, our studies indicate that the
      regulation of PGDH may by multifactorial (figure 3). In certain regions of the
      membranes, we suggest that PGDH expression may be influenced by levels of anti
      inflammatory and pro-inflammatory cytokines. In other regions of the membranes,
      we suggest that PGDH may be regulated at a transcriptional level by competing
      activities of progesterone and cortisol. The action of progesterone could be
      effected through systemically-derived steroid, or by locally synthesized steroid,
      acting in a paracrine and/or autocrine fashion. The effects of cortisol in
      placenta must be due to glucocorticoid derived from the maternal or fetal
      compartment, since the placenta lacks the hydroxylases required for endogenous
      cortisol production. However, metabolism of cortisol by 11 beta-HSD-2 reduces the
      potency of this glucocorticoid in placental tissue. In chorion however, cortisol
      may be formed locally, from cortisone, in addition to its being derived from the
      maternal circulation and/or from the amniotic fluid. Our current studies do not
      allow us to delineate whether the effects of progesterone and cortisol on PGDH
      are exerted through the glucocorticoid receptor (GR) or progesterone receptor
      (PR) or both. It is possible that through pregnancy, PGDH activity is maintained
      by progesterone acting either through low levels of PR in membranes, or, more
      likely, acting through GR. At term, elevated levels of cortisol compete with and
      displace progesterone from GR, resulting in inhibition of PGDH transcription and
      activity. In this way, local withdrawal of progesterone action would be effected
      within human intrauterine tissues, without requiring changes in systemic,
      circulating progesterone concentrations. Since glucocorticoids appear also to
      increase expression of prostaglandin synthesizing enzymes within the amnion and
      chorion, directly by upregulating PGHS-2, or indirectly through the intermediary
      action of a paracrine effector such as CRH, their role in coordinating processes
      of parturition remains central. Further understanding of the regulation of PGDH
      may be of therapeutic importance. For example, it is possible that PGDH activity
      in lower segment chorion may be reduced in those patients with premature cervical
      softening, or may be particularly high in those patients with an unfavorable
      cervix, presenting with a low Bishop score and poor progression at the time of
      labor. If the enzyme in this region crucially determines the passage and
      availability of biologically active prostaglandins from amnion and chorion to
      underlying cervix, then pharmacologic manipulation of PGDH activity may
      effectively regulate PG transfer in these clinical conditions. Glucocorticoids
      appear to have a central role in promoting production of agents that are
      uterotonic to myometrial activity. It is likely that these activities explain the
      transient increments in uterine contractility reported in patients receiving
      prenatal corticosteroids to promote fetal pulmonary maturity [11]. Recognition of
      this physiology suggests that careful monitoring of these patients is advised,
      and would argue further against repeated, indiscriminate, use of glucocorticoids
      in patients with an inappropriate diagnosis of threatened preterm labor.

PMID- 10343933
TI  - Systematic reviews in perinatal medicine.

PMID- 10343934
TI  - Changes in the cervical extracellular matrix during pregnancy and parturition.
AB  - The key function of the uterine cervix to maintain pregnancy is biochemically
      characterized by an increased synthesis of proteins (e.g., collagen),
      proteoglycans, and glycoproteins (e.g., fibronectin) as well as by defined
      interactions between these components of the extracellular matrix. In contrast to
      the slow phase of the cervical ripening process in late pregnancy, cervical
      dilatation during parturition requires the rapid production and action of
      catabolic enzymes leading mainly to collagen degradation and changes in its
      architecture but also to degradation of other fundamental matrix proteins.
      Evidence suggests that an increased production of TNF-alpha and IL-1 beta, e.g.,
      induces a rise in the expression of endothelial adhesion molecules with
      subsequent extravasation of neutrophils into the cervical stroma and that the
      chemotaxis and degranulation of these cells is triggered by an increased
      concentration of IL-8. Rising concentrations of hyaluronan at this time have been
      considered as potent inducers of IL-1 beta and TNF-alpha synthesis by various
      leukocyte populations. The increase in IL-6 synthesis stimulates prostaglandin
      and leukotriene production causing dilatation of cervical vessels and further
      promoting the extravasation of leukocytes. The proteases released after
      degranulation of neutrophils encounter an already destabilized collagenous fiber
      network. Since a sustained action of proteases may lead to severe tissue damage,
      this process is strictly limited in time and is controlled by increasing
      concentrations of tissue inhibitors of protease in the lower uterine segment
      immediately after delivery. The clinical consequences of this basic research is
      to develop new concepts in a more causal treatment of cervical pathology during
      pregnancy and parturition.

PMID- 10343935
TI  - Treating previable twin-twin transfusion syndrome with fetoscopic laser surgery:
      outcomes following the learning curve.
AB  - AIMS: We have performed fetoscopic laser occlusion of chorioangiopagous vessels
      (FLOC) in previable pregnancies affected by twin-twin transfusion syndrome (TTTS)
      since 1988. Treatment outcomes obtained after the procedure's learning curve are
      presented and compared to those from other centers performing FLOC or other
      treatment methods. METHODS: A total of 100 cases of FLOC have been performed at
      our centers. The later 67 TTTS patients had a mean gestational age of 21.1 +/-
      1.7 weeks (range 18-24.5) with a mean fundal height of 33.1 +/- 4.9 cm (range 27
      44) when treated. Eighteen (27%) had failed another treatment method before FLOC.
      RESULTS: All 67 cases have delivered with 82% (55/67) having at least one
      surviving twin and 93/134 (69%) of the twins surviving overall. Thirty-eight have
      surviving twins, 17 have one survivor (5 neonatal and 12 fetal deaths), and 12
      have none. The mean duration of pregnancy following FLOC was 9.9 +/- 5.5 weeks
      (range 1.0-19). Only 4 of 93 (4.3%) survivors have significant handicaps at a
      mean follow-up of 14.3 +/- 10.1 months (range 1.0-34). CONCLUSION: Fetoscopic
      laser occlusion of chorioangiopagous vessels within the vascular equator limits
      the duration of fetal pathophysiology in TTTS and results in neonatal outcomes
      superior to the modified procedure and other treatment methods.

PMID- 10343936
TI  - Rapid development of hydrops fetalis in the donor twin following death of the
      recipient twin in twin-twin transfusion syndrome.
AB  - Intrauterine death of one fetus in monochorionic twinning is associated with high
      rates of perinatal morbidity and mortality in the surviving fetus. Subsequent
      development of hydrops fetalis in the donor twin after fetal demise of the
      recipient twin has been described in only two case reports and pathophysiology
      remains unclear. We report on a monochorionic-diamniotic twin pregnancy
      complicated by severe twin-twin transfusion syndrome. Ultrasound examination at
      20 weeks of gestation showed discrepant twins with oligohydramnios in the smaller
      twins' sac and polyhydramnios in that of the larger twin. Repeated amniocenteses
      permitted prolongation of the pregnancy. However, the recipient twin developed
      deteriorating hydrops fetalis and died at 28 weeks of gestation. After this
      event, subsequent development of hydrops fetalis in the surviving donor twin
      could be observed, as well as an increase of amniotic fluid. An elective cesarean
      section was performed at 29 weeks of gestation. Initial hypoxemia could be
      effectively treated by high frequency oscillatory ventilation, surfactant therapy
      and inotropic support. The infant was discharged in good condition at the age of
      2 months. Although rare, antenatal demise of the recipient twin in a
      monochorionic pregnancy can be associated with the subsequent development of
      hydrops fetalis in the surviving donor twin. We speculate that this phenomenon is
      due to ischemia-reperfusion injury of the previously poorly perfused twin.

PMID- 10343937
TI  - EEMCO guidance for the assessment of skin topography. The European Expert Group
      on Efficacy Measurement of Cosmetics and other Topical Products.
AB  - Numerous factors can modify the visibility or the actual dimensions of the skin
      microrelief and wrinkles. To quantify these changes, several methods, including
      clinical and non-invasive ones, have been proposed. This article reviews the
      advantages et drawbacks of all of them and lists some experimental
      recommendations to make the results of studies using these methods, more
      reliable.

PMID- 10343939
TI  - Glycolic acid peeling in the treatment of acne.
AB  - BACKGROUND: Glycolic acid chemical peels have been widely accepted as a useful
      modality in many cutaneous conditions characterized by abnormalities of
      keratinization. OBJECTIVE: The aim of this study is to evaluate the use of
      glycolic peels in the main clinical forms of acne. METHODS: Between January 1995
      and December 1996, 80 women, aged 13-40 years, were visited for acne and selected
      for the study at the Cagliari University Dermatology Department (Italy). The type
      and severity of acne in each patient was assessed following the Leeds technique.
      The chemical peels were performed with a 70% glycolic acid solution, for times
      that varied in a range between 2 and 8 minutes. The number and frequency of the
      applications depended on the intensity of the clinical response. RESULTS: The
      main clinical forms were comedonic acne in 32 cases, papulo-pustular acne in 40
      cases and nodule-cystic acne in the remaining eight cases. The most rapid
      improvement was observed in comedonic acne. In the papulo-pustular forms an
      average of six applications was necessary. Although nodular-cystic forms required
      eight to ten applications, a significant improvement of the coexisting post-acne
      superficial scarring was noted. The procedure was well tolerated and patient
      compliance was excellent. CONCLUSION: Glycolic acid chemical peels are an
      effective treatment for all types of acne, inducing rapid improvement and
      restoration to normal looking skin.

PMID- 10343938
TI  - Immunopathological examination of esophagus as a useful criterion of cure in
      pemphigus vulgaris.
AB  - BACKGROUND: We performed histopathological and immunopathological examinations of
      the esophagus in patients with pemphigus vulgaris during clinical remission.
      METHODS: In the group of 14 patients without serum antibodies, five were treated
      with low doses of steroids and cyclophosphamide (as maintenance treatment), while
      nine had already completed the therapy. RESULTS: In all five cases under
      maintenance treatment we found bound pemphigus antibodies in vivo. Acantholysis
      was present in two of these. In all nine non-treated patients, acantholysis and
      immunopathological findings were negative. CONCLUSIONS: Our studies reveal that
      the absence of bound 'pemphigus vulgaris' antibodies in the esophagus by
      immunological examination could be regarded as proof of complete cure and could
      be the decisive finding to stop pemphigus treatment.

PMID- 10343940
TI  - The risk of coronary heart disease in men with androgenetic alopecia.
AB  - BACKGROUND: The meaningful association of androgenetic alopecia and coronary
      heart disease has been well documented, but few studies have focused on the
      importance of lipid parameters, such as total cholesterol, triglycerides, high
      density lipoprotein-cholesterol, low density lipoprotein-cholesterol, lipoprotein
      (a), apolipoprotein A1 and apolipoprotein B in patients with androgenetic
      alopecia. OBJECTIVE: The aim of this study is to investigate the relation between
      androgenetic alopecia and coronary heart disease and to determine the
      significance of certain lipid parameters on this relationship. SUBJECTS: Forty
      one men with vertex type androgenetic alopecia (study group) and 36 men, age
      matched, with normal hair status (control group) were the subjects of this study.
      RESULTS: We found significant differences in serum lipoprotein (a) and
      triglyceride levels between the study and control groups (P < 0.05). Forty-seven
      percent of patients and 30% of controls had a lipoprotein (a) level more than 30
      mg/dl higher than the level critical for atherosclerotic heart disease.
      CONCLUSION: Dermatologists should investigate lipid profile, especially
      lipoprotein (a), of patients with androgenetic alopecia and refer to a
      cardiologist if necessary.

PMID- 10343941
TI  - Risk factors of non-melanoma skin cancer in United States veterans patients: a
      pilot study and review of literature.
AB  - OBJECTIVE: To identify risk factors of non-melanoma skin cancer (NMSC) in US
      veterans patients. BACKGROUND: There are an estimated one million new NMSC cases
      annually in the United States alone. While other studies with varying foci have
      evaluated risk factors in different subsets of the general populace, none have
      examined veterans as a group with potentially unique exposures and risks.
      METHODS: An investigation of risk factors for skin cancer through questionnaire
      and physical examination on 145 veteran patients with skin cancer and 59 veteran
      patients without a history of skin cancer was conducted. RESULTS: Parents'
      ethnicity, actinic keratosis on the face or other anatomic sites, solar elastosis
      of the neck, facial telangiectasias, age of first sunburn, and residency in
      Indiana were risk factors significantly associated with the development of skin
      cancer. Other possible risk factors included smoking and radiation therapy.
      CONCLUSIONS: We documented several risk factors which significantly increased the
      chance of developing skin cancer among veterans. These included ethnic background
      and solar damage of the skin among others. A review of the literature confirms
      these risks in the general population, but also further study is warranted to
      address risk factors like smoking and radiation, particularly in veterans
      populations. Identification of pertinent risk factors will help to identify high
      risk individuals, allow detection of new skin cancer at its earliest stage, and
      develop a profile of favorable lifestyle characteristics that reduce NMSC risk.

PMID- 10343943
TI  - Serum level of sELAM-1 in psoriatic patients correlates with disease activity.
AB  - BACKGROUND: Endothelial leucocyte adhesion molecule-1 (ELAM-1) acts as an
      adhesion ligand for neutrophils and monocytes and the expression of this molecule
      on the vascular endothelium may reflect its ability to recruit neutrophils from
      circulation. The next step is the transendothelial migration of neutrophils into
      lesional psoriatic skin. ELAM-1 may also exist in a soluble form. METHODS: We
      determined the serum levels of ELAM-1 by ELISA in 41 patients with psoriasis and
      20 controls. RESULTS: Patients with acute psoriasis displayed higher levels of
      ELAM-1 (85.45 +/- 47.72 ng/ml) than controls (36.02 +/- 15.60 ng/ml) and patients
      with chronic disease (61.24 +/- 27.91 ng/ml). In 25 patients we measured the
      serum level of ELAM-1 twice: at the beginning and after treatment of the disease
      and we did not find any significant changes. We also found a correlation between
      serum ELAM-1 and PASI score. CONCLUSIONS: These data suggest that there is a high
      serum level of E-selectin in psoriatic subjects even after clearing of the
      disease. Serum E-selectin may reflect the general activation of endothelial cells
      in the disease and may be a new sensitive marker of disease activity.

PMID- 10343942
TI  - Tobacco smoking contributes little to facial wrinkling.
AB  - BACKGROUND: The potential detrimental effects of tobacco smoking have been widely
      cited. Tobacco smoking has been linked with facial wrinkling, but some previous
      studies have failed to take into account a number of potential confounders or
      were unblinded and thus subjective to bias. OBJECTIVE: This study was designed to
      determine if there was increased facial wrinkling in smokers directly associated
      with tobacco usage after controlling for solar risk behavior. SUBJECTS: Eighty
      two smokers (> 10 cigarettes per day) and 118 non-smokers (< 100 lifetime
      cigarettes) were recruited. Caucasian participants completed a questionnaire
      designed to assess demographic variables and other suspected factors related to
      wrinkling. METHODS: Three dermatologists, blinded to demographic information,
      reviewed three photographs of each subject and rated the wrinkling on a 100 mm
      visual analog scale. Stepwise linear regression was performed on all variables
      which attained a P < 0.1 level of independent significance. RESULTS: Overall the
      model accounted for 75.4% (P = 0.0001) of the variance in wrinkling, and
      predictive variables (P < or = 0.02) included age (partial R2 = 0.69), smoking
      pack years (R2 = 0.04), hours of outdoor work (R2 = 0.008), freckling (R2 =
      0.007), and eye color (R2 = 0.004). A second model was created excluding age
      which accounted for 37.8% of the variance. The predictive variables in the second
      model (P < 0.08) included education (partial R2 = 0.08), smoking pack years (R2 =
      0.05), hours of outdoor work (R2 = 0.03), weight change (R2 = 0.02), female sex
      (R2 = 0.02), hours of lifetime sun (R2 = 0.03), tanning bed use (R2 = 0.01), and
      sunscreen use (R2 = 0.02). CONCLUSIONS: Smoking may significantly contribute to
      facial wrinkling, but accounts for only 6% of the explained variance. If there is
      a role for tobacco smoking in causing wrinkling, this role is a minor one.

PMID- 10343944
TI  - Chlamydia trachomatis and male infertility: chlamydia-IgA antibodies in seminal
      plasma are C. trachomatis specific and associated with an inflammatory response.
AB  - BACKGROUND: There is controversy over the role of asymptomatic genital tract
      infection by Chlamydia trachomatis, its optimal diagnosis, and its place in the
      etiology of male infertility. OBJECTIVE: Comparison of direct detection of
      Chlamydia trachomatis in semen with the presence of chlamydia-antibodies in
      seminal plasma and serum, together with parameters of the spermatogram, in men of
      infertile relationships. STUDY DESIGN: Prospective clinical study. SETTING:
      University hospital tertiary referral center. SUBJECTS AND METHODS: Two groups of
      consecutive andrological patients (n = 89 and n = 36) were investigated as
      follows: semen analysis, including concentration of granulocyte-elastase;
      detection of C. trachomatis in semen samples and first void urine by polymerase
      chain reaction (PCR) and antigen-ELISA (Celisa); detection of chlamydia
      antibodies in serum and seminal plasma by recombinant antibody-enzyme-linked
      immunosorbent assay (rELISA) and of Chlamydia trachomatis specific antibodies by
      the ImmunoComb-Chlamydia-Bivalent test. RESULTS: In 2/125 (1.6%) semen samples
      Chlamydia trachomatis DNA was detected by PCR. Genus specific anti-chlamydia-IgA
      was found in 12/122 (9%) of the seminal plasmas. This IgA appeared to be specific
      for C. trachomatis. Seminal plasmas with chlamydia-IgA antibodies showed higher
      PMN-elastase levels than IgA negative samples (P < 0.04). Chlamydia-IgG
      antibodies were present in 27/89 (30%) of the sera, but in only five of these 27
      sera (19%) were the antibodies detected specific for C. trachomatis. There were
      no associations between any of these variables and the parameters of the routine
      semen analysis. CONCLUSION: IgA-chlamydial antibodies in seminal plasma appeared
      to be specific against C. trachomatis and were associated with an inflammatory
      response in the male genital tract.

PMID- 10343945
TI  - Squamous cell carcinoma of the penis arising on lichen sclerosus et atrophicus.
AB  - Squamous cell carcinoma of the penis arising on lichen sclerosus et atrophicus is
      rarely reported. A case is described in a 63-year-old man who had been diagnosed
      of lichen sclerosus et atrophicus 3 years before. The previously reported cases,
      the association of these diseases in women and men, and the possible pathogenesis
      are discussed.

PMID- 10343946
TI  - Livedo reticularis and cerebrovascular accidents (Sneddon's syndrome) as a
      clinical expression of antiphospholipid syndrome.
AB  - We present two patients with livedo reticularis and cerebrovascular accidents
      (Sneddon's syndrome) and positive anticardiolipin antibodies. We suggest that
      these antibodies may be pathophysiologically related to the clinical
      manifestation observed in some patients with this syndrome. When Sneddon's
      syndrome is associated with positive anticardiolipin antibodies it could be
      regarded as antiphospholipid syndrome and fall into this category of nosological
      entity.

PMID- 10343947
TI  - Watermelon-stomach as a cause of chronic iron deficiency anemia in a patient with
      systemic sclerosis.
AB  - Watermelon-stomach is a rare cause of gastrointestinal bleeding. There has been
      an increasing number of reports on the association of this lesion with diseases
      of the scleroderma group, causing chronic, sometimes severe gastrointestinal
      blood loss. The present report presents the case of a 75-year-old female with
      limited cutaneous systemic sclerosis and watermelon-stomach, which was the cause
      of her long-standing sideropenic anemia.

PMID- 10343948
TI  - Bockenheimer's syndrome.
AB  - A case of a very extensive form of the rare Bockenheimer's syndrome (genuine
      diffuse phlebectasia) in a 45-year-old female patient is presented. The subject
      presented phlebectasias of the upper right leg, the vulva and the right side of
      the abdomen. The diagnostic and therapeutic possibilities for cases of patients
      with Bockenheimer's syndrome are described.

PMID- 10343949
TI  - Rhodotorula rubra fungaemia in an immunosuppressed patient.
AB  - We report the case of a patient who, following surgical removal of an extensive
      tumour of the bowel, developed fungaemia. The yeast was isolated from repeated
      blood and urine cultures and identified as Rhodotorula rubra on the basis of
      macroscopic and microscopic features. Following treatment with amphotericin B,
      the patient's condition improved and the cultures became sterile.

PMID- 10343950
TI  - Laugier-Hunziker syndrome: case report and treatment with the Q-switched Nd-Yag
      laser.
AB  - We report the case of a 46-year-old Caucasian female presenting with
      mucocutaneous pigmentation on the lips, oral mucosa, hands, feet and nails, as
      well as on a psoriatic plaque. She was successfully treated with Q-switched Nd
      Yag laser, with double frequency, for both the mucosal and cutaneous lesions.

PMID- 10343952
TI  - Non-specific scalp crusting as a presenting feature of Brunsting-Perry
      cicatricial pemphigoid.

PMID- 10343951
TI  - Primary tuberculosis of the penis.
AB  - We present a case of primary tuberculosis of the inner lining of the prepuce in a
      63-year-old man. The condition resembled carcinoma. The diagnosis was based on
      histopathology and on M. tuberculosis culture. Successful treatment was by a
      combined medical and surgical approach. The rarity of the case is emphasized.

PMID- 10343953
TI  - Mometasone furoate versus betamethasone vale-rate in the treatment of allergic
      contact dermatitis.

PMID- 10343954
TI  - Diffuse erythema multiforme-like contact dermatitis caused by disperse blue 124
      in a 2 year old child.

PMID- 10343955
TI  - Recombinant human erythropoietin alpha in the correction of anaemia in
      epidermolysis bullosa.

PMID- 10343956
TI  - Carbamazepine induced eczematous eruption-clinically resembling atopic
      dermatitis.

PMID- 10343957
TI  - Extramammary Paget's disease associated with intraepithelial neoplasia of the
      vulva.

PMID- 10343958
TI  - Coexistence of psoriasis vulgaris and bullous disorders.

PMID- 10343959
TI  - Differential diagnosis of cutaneous and subcutaneous tumours assessed by 7.5 MHz
      ultrasonography.

PMID- 10343960
TI  - Paraneoplastic pityriasis lichenoides chronica.

PMID- 10343961
TI  - Neurofibromatosis and cutaneous melanoma coincidence or association?

PMID- 10343962
TI  - Twenty-nail dystrophy in monozygotic twins.

PMID- 10343963
TI  - Minimal erythema dose on the buttock and volar forearm in previously UV unexposed
      Caucasians.

PMID- 10343964
TI  - Milia en plaque.

PMID- 10343965
TI  - Generalized pustular drug eruptions.

PMID- 10343966
TI  - Cyclosporine treatment of psoriatic erythroderma complicated by bacterial sepsis.

PMID- 10343967
TI  - Anticonvulsant activity of 4-urea-5,7-dichlorokynurenic acid derivatives that are
      antagonists at the NMDA-associated glycine binding site.
AB  - Twelve 4-urea-5,7-dichlorokynurenic acid derivatives were synthesized by reacting
      the 4-tosylimino derivative of 5,7-dichlorokynurenate methyl ester first with
      triphosgene and then with a secondary amine. Compounds were screened in mice for
      anticonvulsant activity using maximal electroshock (MES), subcutaneous
      pentylenetetrazole (Met), and threshold tonic extension (TTE) tests. A rotorod
      test was used to determine neurotoxicity. Seven of the derivatives had
      anticonvulsant activity in TTE testing at 100 mg/kg. One compound, 2-methyl
      carboxylate-5,7-dichloro-4-([?diphenylamino?-carbonyl]amino)-quino line, had an
      ED50 value of 134 mg/kg (95% conf. int.: low-78.5, high-205.7; slope 1.9, SE =
      0.44) in TTE testing. Two derivatives had MES activity. Only one compound, an N,N
      diethylamino derivative, was neurotoxic in the rotorod test. Compounds were
      screened at a 10-microM concentration for activity in displacing 5,7
      dichlorokynurenic acid from synaptosomal membrane fragments. Since 9 of the 12
      compounds synthesized and tested have demonstrated anticonvulsant activity, this
      class of chemicals offers promise for the production of useful therapeutic
      agents.

PMID- 10343968
TI  - Age-related changes in activity of Fischer 344 rat brain acetylcholinesterase
      molecular forms.
AB  - Total acetylcholinesterase (AChE) and the molecular forms of the enzyme from six
      brain regions were compared in young adult (6 mo) and aged (24 mo) Fischer 344
      rats. Total AChE activity was significantly reduced in aged striatum (48.7%),
      parietal cortex (39%), cerebellum (30.2%), and medulla/pons (23.1%). Forebrain of
      aged rats showed nonsignificant reduction of AChE (18.4%), but olfactory bulbs
      exhibited no differences in aged rats. The ratio of G4/G1 molecular forms, as
      isolated on sucrose density gradients, was unaltered in all aged rat brain
      tissues examined. These results indicate that aged rats exhibit reduced brain
      AChE, but there is no evidence for selective effects on individual molecular
      forms.

PMID- 10343969
TI  - Temporal profile of connexin 43 mRNA expression in a tetanus toxin-induced
      seizure disorder.
AB  - The messenger ribonucleic acid (mRNA) of gap junction protein connexin 43 was
      quantified in the tetanus toxin rat model of focal epilepsy following injection
      of toxin into the left amygdala. Animals were monitored electrographically at
      weekly intervals with bilateral amygdala electrodes. Cohorts of 3 rats were
      sacrificed at weeks 1, 2, 3, 4, 6, 8, and 10, and bilateral regions containing
      the amygdala and posterior cerebral cortex were sampled, frozen, and later pooled
      for northern blot analysis. Spike generation was manifest in all animals during
      the first 4 wk followed by variable attenuation and cessation by 10 wk. Electrode
      implantation alone was shown by regression analysis to cause significant (p <
      0.05) elevation of connexin mRNA in weeks 1-4. Injection of toxin diminished
      connexin mRNA expression in the amygdala when compared to electrode implantation
      alone. No trend in connexin mRNA expression was established over time in either
      amygdala or cerebral cortex in the acute epileptic or chronic postepileptic
      phase. No association between connexin 43 mRNA expression and the development of
      epileptogenicity was found in the context of a self-limiting animal model of
      focal epilepsy.

PMID- 10343970
TI  - Evidence of neuronal degeneration in C57B1/6 mice infected with the LP-BM5
      leukemia retrovirus mixture.
AB  - Mice infected with LP-BM5 develop a severe immunodeficiency accompanied by
      learning and memory deficits, gliosis, and neurotransmitter abnormalities. The
      neurochemical alterations are consistent with elevated excitotoxin levels,
      suggesting that infected mice may incur neuronal damage. Although the number of
      neocortical neurons was unchanged in mice 12 wk after LP-BM5 infection, the
      expression of cytoskeletal proteins declined, particularly in the frontal and
      parietal cortex as indicated by MAP2, NF-200, and synaptophysin immunoreactivity.
      In contrast, the number of striatal neurons decreased 19%. The remaining neurons
      were smaller, with fewer synaptic boutons, and showed decreased synaptophysin and
      NF-200, immunoreactivity. Immunoblots of cortex and striatum confirmed decreases
      in MAP2, NF-200 and synaptophysin expression. Finally, although NCAM expression
      decreased in the striatum, it increased in the cortex. These results indicate
      that LP-BM5-infected mice sustain significant neuronal damage, which may
      contribute to their behavioral deficits. Moreover, the increase in cortical NCAM
      expression suggests active synaptic remodeling to compensate for the persistent
      excitotoxic environment in these mice, whereas striatal neurons degenerate. These
      concurrent degenerative and compensatory processes may also occur in the brains
      of patients with AIDS dementia complex (ADC), who suffer extensive degeneration
      of the basal ganglia and cerebral cortex.

PMID- 10343971
TI  - Regional changes of membrane phospholipid concentrations in rabbit spinal cord
      following brief repeated ischemic insults.
AB  - Changes in the concentration of membrane-bound phospholipids following single (25
      min) spinal cord ischemia and 3 h of reperfusion were determined. These were
      compared with the changes following brief repeated (8-, 8-, and 9-min) ischemia
      followed each time by reperfusion for 1 h, or the same periods of ischemia
      followed by 8 h, 8 h, and 24 h of reperfusion, respectively. Phosphatidylcholine
      (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS),
      phosphatidylinositol (PI), and sphingomyelin (SM) were assayed in regions of the
      spinal cord of the rabbit, including gray matter, white matter, dorsal horns,
      intermediate zone, and ventral horns. The brief repeated ischemia with 1-h
      reperfusions produced more extensive degradation of phospholipids in almost all
      regions compared with the equivalent time of ischemia (25 min) in a single
      period. After a lengthy reperfusion after repeated ischemia, the phospholipids
      were resynthesized with the exception of the phosphatidylinositol in the gray
      matter. The resynthesis was most pronounced in the dorsal horns and in the white
      matter.

PMID- 10343972
TI  - Aging modulates nitric oxide synthesis and cGMP levels in hippocampus and
      cerebellum. Effects of amyloid beta peptide.
AB  - The biological roles of nitric oxide (NO) and cGMP as inter- and intracellular
      messengers have been intensively investigated during the last decade. NO and cGMP
      both mediate physiological effects in the cardiovascular, endocrinological, and
      immunological systems as well as in central nervous system (CNS). In the CNS,
      activation of the N-methyl-D-aspartic acid (NMDA) type of glutamatergic receptor
      induces Ca(2+)-dependent NOS and NO release, which then activates soluble
      guanylate cyclase for the synthesis of cGMP. Both compounds appear to be
      important mediators in long-term potentiation and long-term depression, and thus
      may play important roles in the mechanisms of learning and memory. Aging and the
      accumulation of amyloid beta (A beta) peptides are important risk factors for the
      impairment of memory and development of dementia. In these studies, the mechanism
      of basal- and NMDA receptor-mediated cGMP formation in different parts of adult
      and aged brains was evaluated. The relative activity of the NO cascade was
      determined by assay of NOS and guanylate cyclase activities. In addition, the
      effect of the neurotoxic fragment 25-35 of A beta (A beta) peptide on basal and
      NMDA receptor-mediated NOS activity was investigated. The studies were carried
      out using slices of hippocampus, brain cortex, and cerebellum from 3- and 28-mo
      old rats. Aging coincided with a decrease in the basal level of cGMP as a
      consequence of a more active degradation of cGMP by a phosphodiesterase in the
      aged brain as compared to the adult brain. Moreover, a loss of the NMDA receptor
      stimulated enhancement of the cGMP level determined in the presence of cGMP
      phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was observed in
      hippocampus and cerebellum of aged rats. However, this NMDA receptor response was
      preserved in aged brain cerebral cortex. A significant enhancement of the basal
      activity of NOS by about 175 and 160% in hippocampus and cerebellum,
      respectively, of aged brain may be involved in the alteration of the NMDA
      receptor response. The neurotoxic fragment of A beta, peptide 25-35, decreased
      significantly the NMDA receptor-mediated calcium, and calmodulim-dependent NO
      synthesis that may then be responsible for disturbances of the NO and cGMP
      signaling pathway. We concluded that cGMP-dependent signal transduction in
      hippocampus and cerebellum may become insufficient in senescent brain and may
      have functional consequences in disturbances of learning and memory processes. A
      beta peptide accumulated during brain aging and in Alzheimer disease may be an
      important factor in decreasing the NO-dependent signal transduction mediated by
      NMDA receptors.

PMID- 10343973
TI  - Immunohistochemical assessment of constitutive and inducible heat-shock protein
      70 and ubiquitin in human cerebellum and caudate nucleus.
AB  - The distributions of constitutive and inducible 70-kDa heatshock proteins (Hsc70
      and Hsp70, respectively) and ubiquitin (Ub) were investigated in autopsy
      specimens from 24 adult human brains. The objectives were to verify that the
      milder fixation and celloidin embedding applied to those specimens preserved
      protein immunoreactivity in the tissue sections, even with extended intervals
      between death and fixation, and to determine the typical pattern of distribution
      of the proteins in aged human cerebellum and caudate nucleus. To achieve these
      objectives, the patterns of immunoreactivity in human specimens were compared
      with those in normal rat brain after three methods of immersion fixation: 1. 1%
      Formalin; 2. 10% Formalin; 3. Methacarn (a modification of Carnoy's solution).
      Additionally, some rats were left refrigerated, but unfixed for up to 24 h to
      mimic the postmortem interval that commonly occurs prior to fixation of human
      autopsy material. Tissues were embedded in celloidin, sectioned at 100 microns,
      and the celloidin dissolved to permit immunostaining. Immunoreactivity for all
      antigens was greatly diminished in the rat brain by fixation in 10% formalin
      compared to 1% formalin or methacarn. Rat and human brain tissues fixed in the
      latter two solutions showed similar patterns of low levels of Hsp70
      immunostaining in gray matter and other areas where neuronal somata were
      concentrated, whereas Hsc70 immunostaining was much greater in those same areas.
      Little Hsc70 or Hsp70 immunoreactivity was detected in the white matter from
      either source, but immunoblots of human gray and white matter suggested that
      white matter contained more Hsc70 and Hsp70 than apparent by tissue section
      immunoreactivity. Ubiquitin immunostaining in rat and human brain showed the same
      high levels as Hsc70 in gray matter, but unlike Hsc70, was also visible in white
      matter. These patterns remained the same in rat brains even if fixation was
      delayed for 24 h. In three human brain specimens, elevated Hsc70 staining, but
      not Hsp70 or Ub, was found in a ring pattern similar to that described as the
      ischemic penumbra in experimentally induced brain ischemia. These results
      indicated that dilute formalin preserved Hsc/Hsp70 and Ub antigenicity well, and
      that the proteins had similar distributions in human and rat brains, despite the
      extended postmortem delay in fixation of the former. They also suggested that
      evidence of premortem, localized cellular metabolic stress may be preserved in
      the postmortem human brain by an alteration in the typical distribution of Hsc70.

PMID- 10343974
TI  - The impact of diabetes on CNS. Role of bioenergetic defects.
AB  - To address the problem of the pathogenesis in diabetic neuropathy, rats were made
      diabetic by streptozotocin administration, and discrete brain regions, such as
      cortex, cerebellum, brainstem, thalamus, and hypothalamus, were sampled for assay
      of activities of electron transport chain complexes I-IV at 1 and 3 mo after
      induction of diabetes. Significant decrease was seen in activities of
      dinitrophenylhydrazine DNPH-coenzyme Q reductase (complex I), coenzyme Q
      cytochrome-c reductase (complex III), and cytochrome-c oxidase (complex IV) from
      discrete brain regions with more pronounced changes in complex I. The decline in
      the complex I, III, and IV activity was more severe in the 3-mo group. Succinate
      dehydrogenase (SDH) coenzyme Q reductase (complex II), which is an enzyme shared
      by tricarboxylic acid (TCA) cycle and electron transport chain, showed a
      significant increase under the same set of conditions. These results suggest that
      the bioenergetic impairment has an important role in the pathophysiology of
      diabetes.

PMID- 10343975
TI  - The effect of 4 beta-phorbol-12,13-dibutyrate and staurosporine on the
      extracellular glutamate levels during ischemia in the rat striatum.
AB  - Hypothermia diminishes the ischemia-induced protein kinase C (PKC) translocation
      and inhibition, and also reduces transmitter release during ischemia. To study
      the role of PKC in the mechanism of glutamate release during ischemia, we
      measured extracellular glutamate levels in the striatum with the microdialysis
      technique, in the presence and absence in the dialysate of the PKC activator 4
      beta-phorbol-12,13-dibutyrate (PDBu) and the protein kinase inhibitor
      staurosporine. We confirm that hypothermia attenuates the elevation of
      extracellular levels of glutamate in the striatum during ischemia. In the
      presence of PDBu, the glutamate levels in the dialysate increased from 0.3
      mumol/L to an end ischemic level of 4.8 mumol/L during hypothermic ischemia (33
      degrees C). These levels were significantly higher than in hypothermic ischemia
      (33 degrees C) without added PDBu. Staurosporine significantly mitigated the
      glutamate levels during normothermic ischemia. Our data suggest that PKC is
      involved in the temperature-dependent elevations of extracellular glutamate
      levels in the striatum during ischemia, and we propose that compounds preventing
      PKC activation may mimic the hypothermic protective action against ischemic brain
      damage.

PMID- 10343976
TI  - L-deprenyl induces aromatic L-amino acid decarboxylase (AADC) mRNA in the rat
      substantia nigra and ventral tegmentum. An in situ hybridization study.
AB  - L-Deprenyl is a complex drug, and number of mechanisms have been proposed to
      explain its effects. These include blockade of dopamine metabolism, amplification
      of dopamine responses, induction of superoxide dismutase or delaying apoptosis.
      Using in situ hybridization techniques, we have shown that L-deprenyl (5-10 mg/kg
      intraperitoneally, killed after 24 h) increases aromatic L-amino acid
      decarboxylase (AADC) mRNA levels in rat substantia nigraventral tegmental area.
      In human brain tissue, AADC is present at low levels, suggesting a possible rate
      limiting role in monoamine synthesis. This is particularly important in
      parkinsonian patients, since the therapeutic efficacy of L-DOPA is attributed to
      its enzymatic decarboxylation to dopamine. The present findings support that one
      of the effects of L-deprenyl may be to facilitate the decarboxylation of L-DOPA
      by increasing the availability of AADC.

PMID- 10343977
TI  - Localization of GTPase-activating protein-(GAP) like immunoreactivity in mouse
      cerebral regions.
AB  - GTPase-activating protein is known to regulate the conversion between ras-GTP and
      ras-GDP. We studied the basal expression of GTPase-activating protein-like
      immunoreactivity in mouse cerebral regions using a polyclonal anti-GTPase
      activating protein antibody. Cells with GTPase-activating protein-like
      immunoreactivity were distributed in frontal cortical layers IV and V, and in the
      parietal cortex, piriform cortex, amygdaloid area, septum, lateral thalamus, and
      hypothalamus. The GTPase-activating protein-like immunoreactivity was also
      observed in fiber-like structures in the caudate putamen, stria terminalis,
      internal capsule, and medial forebrain bundle, and around CA2 pyramidal cells in
      Ammon's horn. These results imply that GTPase-activating protein is
      constitutively expressed in mouse brain regions and may have physiological
      functions in specific neuronal pathways in the brain.

PMID- 10343978
TI  - A light and electron microscopic study of the metabotropic glutamate receptor
      mGluR1a in the normal and kainate-lesioned rat hippocampus.
AB  - The distribution of the metabotropic glutamate receptor mGluR1a was studied in
      the normal and kainate-lesioned rat hippocampus using a monoclonal (MAb) and a
      polyclonal antibody to mGluR1a. Many labeled nonpyramidal neurons were observed
      in the stratum oriens of CA1 in sections incubated with MAb. In comparison, fewer
      labeled neurons were observed in this layer in sections incubated with polyclonal
      antibody. Many nonpyramidal neurons were observed in the stratum lucidum of CA3
      and the hilus of the dentate gyrus, with both antibodies. The cell bodies of
      pyramidal neurons were unlabeled. A dense network of labeled processes was
      observed in the neuropil of the CA fields at electron microscopy. Some dendrites
      were very densely labeled and did not contain dendritic spines. These were
      identified as dendrites of nonpyramidal neurons. Other dendrites contained
      lightly labeled dendritic shafts, but densely labeled dendritic spines, and were
      identified as dendrites of pyramidal neurons. Intravenous kainate injections
      resulted in destruction of pyramidal neurons and a massive decrease in mGluR1a
      immunoreactivity in the CA fields. This decrease was obvious even at 1-5 d
      postinjection, when the nonpyramidal neurons in the stratum oriens remained
      densely labeled, suggesting that pyramidal neurons contributed significantly to
      mGluR1a staining in the CA fields. We conclude that the dendritic spines of
      hippocampal pyramidal neurons contain mGluR1a, even though little staining is
      observed in their parent dendritic shafts or cell bodies.

PMID- 10343980
TI  - Reduction in the cesarean section rate in nulliparous patients after
      administration of intravenous propranolol.
AB  - OBJECTIVE: A preliminary investigation to test the efficacy of intravenous
      propranolol in reducing the cesarean section rate in nulliparas in active labor
      and evaluate its effect on neonatal and maternal outcomes. METHODS: Fifty seven
      nulliparous patients admitted in active labor were randomly divided into two
      groups: a control group consisting of 23 patients, and a treatment group
      consisting of 34 patients given 2 mg of propranolol intravenously every 4 hours
      until delivery. Total length of labor, time from first administration of
      medication to delivery, incidence of cesarean section, APGAR scores, maternal and
      fetal morbidity were assessed. RESULTS: A total of 4 cesarean sections were
      performed in each group (11.7% in the treatment group and 17.3% in the control
      group). The rate of cesarean section due to dystocia was 6.25 and 13.6%
      respectively (P = .367). Statistical significance was not reached due to the
      small number of subjects (students t test analysis). There was no increase in the
      incidence of low APGAR scores, intensive care unit admissions, abnormal heart
      rate patterns during labor, cesarean sections for fetal distress or maternal
      morbidity in the treated group. CONCLUSIONS: Intravenous administration of 2 mg
      of propranolol every four hours is safe and not associated to increased neonatal
      or maternal morbidity. A 50% decrease in the incidence of cesarean sections can
      be documented among nulliparous patients treated with propranolol although the
      small numbers and overall low incidence of cesarean section in our population
      (14%) did not permit these differences to reach statistical significance.

PMID- 10343979
TI  - Alterations in free radical scavenger system profile of type I diabetic rat
      brain.
AB  - The activities of the enzymes related to glutathione synthesis, degradation, and
      functions as well as reactive oxygen scavenging enzymes were analyzed in
      different brain regions, such as cerebral hemisphere, cerebellum, brainstem,
      thalamus, and hypothalamus after 1 and 3 mo of streptozotocin-induced diabetes in
      rats. Parallel studies were also made in age-matched control rats and insulin
      treated diabetic rats. The content of glutathione (GSH) and its synthesizing
      enzyme gamma-glutamylcystein synthetase and also superoxide dismutase (SOD) and
      catalase activities (reactive oxygen scavenging enzymes) were significantly
      decreased from almost all the brain regions studied. However, glutathione
      peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST),
      gamma-glutamyl transpeptidase (gamma-GTP), and glutamine synthetase (GS)
      activities were increased in the diabetic rat brain. Insulin treatment to the
      diabetic rats resulted in partial to full recovery in these enzymes activities.
      The present results emphasize the potentially serious alterations of brain free
      radical scavenger system in uncontrolled Type I diabetes.

PMID- 10343981
TI  - The Fifth Carlos E. Rubio Memorial Lecture. Sclerosing cholangitis: pathogenesis,
      pathology, and practice.
AB  - Primary sclerosing cholangitis is a generally progressive, sometimes fatal,
      chronic hepatobiliary disorder for which no effective medical or surgical therapy
      now exists. The syndrome occurs most frequently in young men and is characterized
      by chronic cholestasis, frequent association with CUC, a paucity of serologic
      markers, hepatic copper overload, and characteristic abnormalities in some liver
      biopsy specimens and in virtually all cholangiograms. The natural history of the
      syndrome is still somewhat unclear; the disease likely progresses slowly and
      relentlessly over a decade or longer from an asymptomatic stage to a condition
      characterized by symptoms of cholestasis and complicated by cirrhosis and portal
      hypertension and carcinoma of the bile ducts. Management should first involve a
      thoughtful decision to observe, which is reasonable in the asymptomatic patient
      with early disease, or to intervene, particularly in patients with symptoms.
      Therapeutic goals should be defined and should concentrate on either alleviating
      symptoms, dealing with complications, or attempting to affect the underlying
      hepatobiliary disease. Symptomatic treatment and therapy for complications is
      similar to that employed in other chronic liver diseases, but also involves
      balloon dilatation of dominant strictures in appropriately selected symptomatic
      patients. Biliary tract reconstructive surgery may alleviate symptoms in selected
      patients with PSC, but its effect on the natural history of the syndrome has not
      been determined. Proctocolectomy for CUC in a patient with CUC and PSC does not
      beneficially affect the progression of the underlying hepatobiliary disease. In
      contrast, orthotopic liver transplantation may be life-saving for patients with
      advanced disease. Medical therapy directed at arresting the progression of the
      underlying hepatobiliary disease is currently experimental and includes
      cupruretic, immunosuppressive, antifibrogenic, and choleretic agents. Although a
      single recently completed controlled trial makes it unlikely that cupruretic
      agents will be helpful in this syndrome, immunosuppressive (i.e. cyclosporin A
      and methotrexate) and choleretic (i.e. ursodeoxycholic acid) agents alone or in
      combination are currently undergoing evaluation in randomized trials.

PMID- 10343982
TI  - Asthma knowledge among internal medicine residents.
AB  - OBJECTIVES: To assess the medical knowledge about asthma among residents from the
      Accreditation Council on Graduate Education (ACGME) accredited Internal Medicine
      programs. BACKGROUND: Asthma prevalence and morbidity has increased significantly
      in the last 20 years. Recent morbidity data suggests that approximately 14 to 15
      million Americans suffer from asthma and 5,000 of them die annually due to this
      illness. Previous studies have suggested that Puerto Ricans are disproportionally
      affected by asthma. In order to impact both morbidity and mortality relates to
      asthma, primary care givers should be knowledgeable about the disease. METHODS:
      Based in the 1993 National Heart, Lung and Blood Institute (NHLBI) guidelines, a
      questionnaire was developed to evaluate the knowledge of asthma in physicians in
      the Internal Medicine Residency Programs. It consisted of 27 questions covering
      the areas of diagnosis and treatment of asthma. RESULTS: The questionnaire was
      answered by 90% of the 138 residents active at the moment of the study. Fifty-one
      percent of the residents failed to obtain a score of 70% or greater. Score on
      asthma diagnosis was less than 70% and did not improve through year of training.
      Score obtained on asthma treatment improved through training year although no
      statistical difference was obtained. CONCLUSIONS: In view of these results it is
      imperative to reinforce the state of the art asthma education of physicians.
      Research initiatives must evaluate educational strategies to improve asthma
      education.

PMID- 10343983
TI  - [Methodological aspects of biostatistics and epidemiology in a clinical trial].
AB  - Various methodological issues in biostatistics and epidemiology which are
      relevant for the development of a clinical trial are discussed. A brief set of
      definitions regarding clinical trials and methods for the assignment of
      treatments is presented. In addition, methods to reduce the possibility of bias
      that may be introduced into a clinical trial are summarized. The different
      elements that must be included in the informed consent form are defined. General
      considerations for data analysis and for sample size required to obtain an
      adequate statistical power are illustrated. Finally, critical questions that can
      be used for the review of the literature on clinical trials are suggested.

PMID- 10343984
TI  - Bioethics committees--a health communication approach.
AB  - The modern health care system is being transformed as a consequence of scarce
      resources and better informed consumers. In this transformed health care system
      human communication has become a crucially important process. This essay examines
      the health communication functions performed by bioethics committees in health
      care delivery and makes recommendations for promoting the effective use of these
      groups within the modern health care system. The essay describes how bioethics
      committee can help establish a climate in which physicians and other committee
      members can share relevant health information, learn about patient and family
      concerns, promote health education and informed consent, and facilitate effective
      decision making about complex health care practice issues. It is argued that
      clear recognition and attention to the central role of effective communication
      within the bioethics committee is essential for the survival of the modern health
      care system since ethics committees depend on sharing relevant information to
      diagnose health problems, provide health care, promote health education, help in
      the formulation of new health care policies, and provide much-needed decision
      making support to health care providers and consumers. The role that health
      communication expertise can perform in the effective operation and utilization of
      bioethics committees is described. We conclude that in order to provide needed
      support in addressing the many complexities of modern health care, bioethics
      committees must develop clear communication processes, norms, and roles.

PMID- 10343985
TI  - [Medical profession and physician-assisted suicide].
AB  - Health care professionals, specially physicians, are frequently exposed to end of
      life situations that interfere with the traditional processes patient care. The
      right to die has become an important movement that calls for self-determination
      with outcomes related to the legalization of physician assisted suicide in
      various countries. In this paper the 1997 resolution approved by the American
      Medical Student Association is examined in relation to the criteria to be
      considered in situations of legal assisted suicide. Some arguments regarding the
      legalization of physician-assisted suicide as well as its impact in the
      contemporary practice of medicine are also identified. A description of current
      legislation in the area is exposed. Presently there is no legislation regarding
      physician-assisted suicide in Puerto Rico.

PMID- 10343986
TI  - [The pharmaceutical care and pain caused by cancer].
AB  - Pharmaceutical care is the philosophy of practice of the University of Puerto
      Rico, School of Pharmacy. Pharmacy students enrolled in the Oncology Clerkship
      providedpharmaceuticalcare to 35 patients with advanced cancer. The objectives
      were to provide pharmacy students the opportunity to practice pharmaceutical care
      and to implement published guidelines for the management of cancer pain.
      Activities included the assessment of pain intensity and of patients' educational
      needs, identification of drug related problems, intervention with patients and
      physicians to solve problems, and documentation of processes and outcomes
      measures. Thirty three patients had pain due to their disease with an average
      "worst pain" intensity of 5.5 on a 0-10 scale. Drug related problems were:
      subtherapeutic dosage, 24.2%; lack of treatment, 18.2%; adverse drug reactions,
      12%; improper drug selection, 9.1%; and not taking the prescribed drug, 3%.
      Outcomes of pharmaceutical services were: reduction of pain, increased knowledge
      about therapy, improved compliance, improved physician prescribing, and change in
      cost of medication. Students evaluated the clerkship favorably. The study
      provides data that supports a randomized trial to further study the impact of
      pharmaceutical care on the management of cancer pain. Outcomes evaluation should
      include clinical, humanistic and economic measures.

PMID- 10343987
TI  - [Sociodemographic profile of a group of sex workers in Puerto Rico].
AB  - This research explored the sociodemographic characteristics, the health
      perceptions and the distinctive aspects of the sexual work of a group of women
      sexual workers (n = 311). The study interest was generating data relative to the
      use of injectable drugs, the prevalence of sexually transmitted diseases (STD),
      the prevalence of HIV and the risk behaviors of this population group. A
      remarkable characteristic of the group of women studied was their history of
      pregnancies at and early age. A high proportion of illness apparently related to
      the presence of sexually transmitted diseases and limited health care was
      observed.

PMID- 10343988
TI  - [Family structures: social disadvantage of women].
AB  - A perspective on the family, based on scientific knowledge and on its
      appreciation as a unit for health care, is suggested. The contemporary family
      because of its independent links with society has lived and resisted the
      consequences of a series of economic, political, technological, cultural and
      ideological transformations. These forces act as influential forces in the family
      and it responds adopting new forms to temper to these new times. For these
      reasons, society at present is characterized by a plurality of family structures.
      As part of that diversity in families, at present, there are families: nuclear
      biological, nuclear in series, father or mother alone, extended, and those that
      share the same sexual orientation. The term family should be redefined to enclose
      all those types of cohabitation. Is imperative that support is given to families
      with the greatest social disadvantages such as those families made up of women
      alone as they are expected to continue growing in all societies both developed
      and underdeveloped.

PMID- 10343989
TI  - [A hiatus in the life of the Medical Association of Puerto Rico].

PMID- 10343990
TI  - Occult aspiration of a chicken wishbone as a cause of hemoptysis.
AB  - Aspiration of foreign bodies is more common in children than adults. The clinical
      and radiological findings between these two age groups are different. It is a
      clinical diagnosis often overlooked in adults. We hereby present an elderly male
      patient who was referred to us due to a one year history of hemoptysis. He was
      heavy smoker, so the initial working diagnosis was malignancy. Upon bronchoscopic
      evaluation, a foreign object was found which is very uncommon in adults. The
      unusual location of the aspirated material is another interesting feature of our
      case. Clinicians should be aware that aspiration of foreign objects may occur
      also in adults.

PMID- 10343991
TI  - [Need of teaching bioethics as a critical discipline].

PMID- 10343992
TI  - [Mandibular distraction using a dynamic osteosynthesis system: MD-DOS. Concepts
      and surgical technic].
AB  - MD-DOS (mandibular distraction with a dynamic osteosynthesis system) is an intra
      oral mandibular distractor that can be placed via the oral route, enabling
      application under local anesthesia. The aim of the article is to describe the
      technical-surgical aspects of the treatment concept, based on an initial
      experience of 35 cases. The device is characterised by a single horizontal
      posterior fixation screw-implant, a vertical hinge that copes with the lateral
      force vector in the condyles, a telescopic distraction module, and an anterior
      fixation unit that is fixed with monocortical screws. The main indication was
      mandibular lengthening in Angle Class II, deep bite cases. The third molars could
      be removed in the same session. Of importance was the horizontal placement of the
      posterior fixation unit (PFU), together with the distraction module, in order not
      to interfere with lateral jaw movements and with the lower sulcus. Equally
      important was the use of at least one 7.5 mm long osteosynthesis screw together
      with at least three 5.5 mm screws. Near complete mobilisation of the segments,
      firmly blocking the posterior fixation unit with the vertical hinge in a
      perpendicular position, and placing MD-DOS as close as possible to the dental
      arch, were also important parameters for success.

PMID- 10343993
TI  - [Microvascular mandibular reconstruction and implantology. A study of the
      stability of long-term results, apropos of 2 cases followed for 8 years].
AB  - The objective of this study was to determine the long term stability of implants
      on mandibles reconstructed by microvascular bone transfer. We present two cases
      of mandible reconstruction, the first one was performed after tumor resection and
      the second one after gunshot injury. The reconstructions were performed by iliac
      crest osseous and osteocutaneous free flaps and the mean follow-up period was 8
      years. The implant was an IMZ Titanium and a classic prosthetic system was used.
      No complication was observed (mucous ulceration, infiltration around the
      implant), and the feared friction phenomenon between the neo mucosa and the
      reconstructed bone has not been a problem for long term follow-up.

PMID- 10343994
TI  - [Gardner syndrome. Maxillofacial management of an extremely advanced form].
AB  - Gardner's syndrome is a very rare hereditary disease resulting from an embryo
      genesis disorder involving all three ectodermal, mesodermal and endodermal
      layers. Generally non-digestive tract signs disclose the syndrome. Underlying
      silent digestive anomalies should be investigated. Endodermal anomalies may have
      a fundamental effect on prognosis. Manifestations in our case were severe, with
      ectodermal and mesodermal anomalies occurring late. Maxillofacial management was
      required because of the critical esthetic and functional implications.

PMID- 10343995
TI  - [Spheno-mandibular ankylosis. A case].
AB  - A rare case of spheno-mandibular ankylosis is reported in a 12 year-old child.
      The patient only complained of a restricted mouth opening; no particular
      etiologic factors were found to explain what was perhaps a myositis ossificans of
      the pterygoid muscles. However, neither the anatomic presentation at surgery, nor
      the histologic findings could confirm this diagnosis. An intra-oral route was
      chosen for the ankylosis resection, and the reconstruction of the resected upper
      part of the ramus was performed by a costo-chondral graft. The patient was free
      of recurrence 3 years after follow up.

PMID- 10343996
TI  - [Basocellular nevomatosis. Follow-up of 3 generations].
AB  - We report on Gorlin-Goltz syndrome observed in 4 patients belonging to three
      generations of the same family. We present the clinical findings and emphasize
      recent genetic discoveries. We discuss the difficulty in following these patients
      and propose a series of simple explorations which can be helpful.

PMID- 10343997
TI  - [Fibrous dysplasia: management of a severe case of pseudo-leontiasis ossea].
AB  - We report the case of a 75-year-old woman who consulted for suppurative
      gingivitis and maxillary deformation with slow progression and associated severe
      joint disorder. The patient suffered both esthetic prejudice and functional
      impairment. Clinical signs and radiographic findings suggested the diagnosis of
      fibrous dysplasia, in its leontiasis ossea form, rarely reported in the
      literature. Primum non nocere guided our management. Abstention, a simple
      remodeling resection, or extensive resection and reconstruction would have been
      inappropriate in this elderly patient. We opted for an orthognatic attitude in
      spite of the vascular risk inherent in the orthodontic preparation and the
      osteotomy on an abnormal dystrophic bone. Outcome was satisfactory.

PMID- 10343998
TI  - In memoriam. Thomas Harrison Hunter (1913-1997).

PMID- 10343999
TI  - Memorial. Samuel Preston Martin III. 1916-1996.

PMID- 10344000
TI  - Memorial. Irving Sherwood Wright 1901-1997.

PMID- 10344001
TI  - Ensuring physician competence.

PMID- 10344002
TI  - Do better outcomes mean better quality care?

PMID- 10344003
TI  - A new frontier in medical education.

PMID- 10344004
TI  - Systems of care for frail older persons. InterRAI.

PMID- 10344005
TI  - Chronic airway disease: the infection connection.

PMID- 10344007
TI  - Esther Everett Lape--the American Foundation and American medicine 50 years ago.

PMID- 10344006
TI  - Thrombophilia: a genetic predisposition to thrombosis.

PMID- 10344008
TI  - The Gordon Wilson Lecture. From basic virology to human gene therapy.

PMID- 10344009
TI  - Gene therapy for a lethal genetic blistering disease: a status report.

PMID- 10344010
TI  - Infarct artery patency and survival following myocardial infarction.

PMID- 10344011
TI  - Theodore E. Woodward Award. Ischemic heart disease in women: the role of coronary
      microvascular dysfunction.

PMID- 10344013
TI  - Developing regulations for research involving adults who lack decision-making
      capacity.

PMID- 10344012
TI  - The role of oxidative stress in atherosclerosis: the hope and the hype.
AB  - Numerous lines of investigation support the importance of oxidative stress in the
      development of atherosclerosis. Results from studies in isolated cells and in
      animal models of atherosclerosis are compelling, as are those from a select
      number of clinical trials. Unfortunately, the results of prospective, randomized
      clinical studies have been disappointing and may reflect our current inability to
      accurately assess oxidative risk and the response to antioxidant therapy. Only
      when it is possible to accurately and easily measure oxidative stress will it be
      possible to accurately determine the efficacy of different antioxidant
      approaches.

PMID- 10344014
TI  - The Jeremiah Metzger Lecture. Academe confronts a future of growing diversity:
      will we lead or will we follow?

PMID- 10344015
TI  - Anatomy of a joint venture: Dana Farber/Partners Cancer Care.

PMID- 10344017
TI  - Elimination of syphilis transmission in the United States: historic perspectives
      and practical considerations.

PMID- 10344016
TI  - Positron emission tomography (PET) in the evaluation of patients with cancer.

PMID- 10344018
TI  - The thyroid gland 1998: new ideas about an ancient structure.

PMID- 10344019
TI  - Development and implementation of a teaching practice plan in a department of
      medicine (1995-1998): relative teaching units (RTU's).

PMID- 10344020
TI  - Phoneme awareness in children: a function of sonority.
AB  - This study tested the hypothesis that the sonority of phonemes (a sound's
      relative loudness compared to other sounds with the same length, stress, and
      pitch) influences children's segmentation of syllable constituents. Two groups of
      children, first graders and preschoolers, were assessed for their awareness of
      phonemes in coda and onset positions, respectively, using different phoneme
      segmentation tasks. Although the trends for the first graders were more robust
      than the trends for the preschoolers, phoneme segmentation in the two groups
      correlated with the sonority levels of phonemes, regardless of phoneme position
      or task. These results, consistent with prior studies of adults, suggest that
      perceptual properties, such as sonority levels, greatly influence the development
      of phoneme awareness.

PMID- 10344021
TI  - Identifying the null subject: evidence from event-related brain potentials.
AB  - Event-related brain potentials (ERPs) were recorded during spoken language
      comprehension to study the on-line effects of gender agreement violations in
      controlled infinitival complements. Spanish sentences were constructed in which
      the complement clause contained a predicate adjective marked for syntactic
      gender. By manipulating the gender of the antecedent (i.e., the controller) of
      the implicit subject while holding constant the gender of the adjective, pairs of
      grammatical and ungrammatical sentences were created. The detection of such a
      gender agreement violation would indicate that the parser had established the
      coreference relation between the null subject and its antecedent. The results
      showed a complex biphasic ERP (i.e., an early negativity with prominence at
      anterior and central sites, followed by a centroparietal positivity) in the
      violating condition as compared to the non-violating conditions. The brain reacts
      to NP-adjective gender agreement violations within a few hundred milliseconds of
      their occurrence. The data imply that the parser has properly coindexed the null
      subject of an infinitive clause with its antecedent.

PMID- 10344023
TI  - Definition of high blood pressure, epidemiology and goals of hypertension
      treatment.

PMID- 10344022
TI  - Comparing single and cumulative dosing procedures in human triazolam
      discriminators.
AB  - This study evaluated a cumulative dosing procedure for drug discrimination with
      human participants. Four participants learned to discriminate triazolam (0.35
      mg/70 kg) from placebo. A crossover design was used to compare the results under
      a single dosing procedure with results obtained under a cumulative dosing
      procedure. Under the single dosing procedure, a dose of triazolam (0, 0.05, 0.15,
      or 0.35 mg/70 kg) or secobarbital (0, 25, 75, or 175 mg/70 kg) was administered
      45 min before assessment. Determining each dose-effect curve thus required four
      sessions. Under the cumulative dosing procedure, four doses of triazolam (0,
      0.05, 0.10, and 0.20 mg/70 kg) or secobarbital (0, 25, 50, and 100 mg/70 kg) were
      administered approximately 55 min apart, producing a complete dose-effect curve
      in one four-trial session. Regardless of procedure, triazolam and secobarbital
      produced discriminative stimulus and self-reported effects similar to previous
      single dosing studies in humans. Shifts to the right in cumulative dose-effect
      curves compared to single dose-effect curves occurred on several self-report
      measures. When qualitative stimulus functions rather than quantitative functions
      are of interest, application of cumulative dosing may increase efficiency in
      human drug discrimination.

PMID- 10344024
TI  - Cardiovascular risk: which is the most important in blood pressure?

PMID- 10344025
TI  - Optimal management of hypertensive patients with LVH and dyslipidaemia.

PMID- 10344026
TI  - Optimal management of hypertensive patients with type 2 diabetes and
      microalbuminuria.

PMID- 10344027
TI  - Treating large and small airways.

PMID- 10344028
TI  - Structural alterations and inflammation of bronchi in asthma.
AB  - The structural and inflammatory changes occurring in the bronchi of asthmatics
      have been examined in specimens from subjects dying in status asthmaticus and
      from bronchial biopsies of subjects with mild asthma. Histological changes in the
      bronchi of asthmatics include shedding and damage of the airway surface
      epithelium and thickening of the reticular basement membrane. Exposure of an
      asthmatic subject to an allergen results in an immediate allergic response
      characterised by mast cell degranulation. This may be followed by a late-phase
      response involving eosinophil degranulation and differentiation of a
      myofibroblast phenotype which may be the precursor of increased amounts of
      bronchial smooth muscle present in chronic severe asthma. These changes are
      accompanied by vasodilatation, vascular congestion and consequent oedema, and
      result in thickening of the airway wall and reduction of the airway lumen. Mucus
      secretion further increases airflow resistance and, in conjunction with an
      inflammatory exudate, forms tenacious airway plugs which are characteristic of
      severe life-threatening attacks.

PMID- 10344029
TI  - Small airway inflammation and asthma.
AB  - Evidence derived from large airways has shown that asthma involves mucosal
      inflammation and structural airway changes including fibroblast proliferation and
      collagen deposition. Techniques, such as transbronchial biopsy and
      bronchoalveolar lavage as well as analysis of resected or post-mortem tissue,
      indicate that similar inflammatory and structural airway changes exist in the
      small airways in asthma. This paper reviews the evidence that inflammatory and
      structural changes occur throughout the airways in asthma and discusses the
      relevance of these considerations. In addition, analysis of resected lung tissue
      from asthmatic subjects has revealed increased numbers of activated eosinophils
      within the small airways, when compared with the large airways. Transbronchial
      biopsy studies in patients with nocturnal asthma have now also identified
      eosinophilic inflammation within the alveolar walls which correlates with the
      nocturnal physiological changes. The implications of these findings is that anti
      inflammatory treatment needs to be directed to both the large and small airways
      to achieve the maximal suppression of inflammation throughout the airways.

PMID- 10344030
TI  - Targeting inhaled steroids.
AB  - Asthma is a disease of the entire respiratory tract and successful asthma therapy
      requires drug delivery throughout the large and small airways. The most commonly
      prescribed inhaled corticosteroid for the treatment of asthma is beclomethasone
      dipropionate (BDP) delivered by a metered-dose inhaler (MDI) containing
      chlorofluorocarbons (CFCs). CFC-BDP MDIs produce relatively large particles and
      when used optimally deposit less than 10% of the dose in the lungs, primarily in
      the large airways, with more than 90% being deposited in the oropharynx. The new
      hydrofluoroalkane (HFA)-BDP inhaler developed by 3M Pharmaceuticals (Qvar)
      delivers a particle size of approximately 1.1 microns. Animal and mechanical
      models predict more than 50% lung deposition with this formulation. Clinical
      results, with radiolabelled Qvar in patients with asthma and volunteers, have
      demonstrated that 50-60% of the dose is deposited throughout the airways with
      approximately 30% being deposited in the oropharynx. 3M Pharmaceuticals have
      developed the breath-actuated Autohaler which provides the same lung deposition
      as an optimally used Qvar MDI by automatically delivering the drug very early in
      the inhalation. Neither device routinely requires the use of a spacer.

PMID- 10344031
TI  - Improvements in delivery with an extra fine beclomethasone aerosol.
AB  - The reformulation of beclomethasone dipropionate (BDP) in a chlorofluorocarbon
      (CFC)-free propellant, hydrofluoroalkane (HFA), has resulted in improved delivery
      of medication to the large and small airways, the target site of action of anti
      asthmatic therapy. It is hypothesised that this improved delivery of BDP to the
      airways will translate into improved clinical efficacy in comparison with the
      previous CFC formulation. This paper reviews the results of three large-scale
      clinical trials that were designed to test this hypothesis by comparing the
      efficacy of various doses of Qvar (3M Pharmaceuticals' HFA-BDP formulation) with
      CFC-BDP in asthmatic patients. It was found that the dose-response relationship
      of Qvar is shifted to the left compared with CFC-BDP, such that equivalent
      improvements in asthma control are seen with half the daily dose of Qvar compared
      with the CFC formulation.

PMID- 10344032
TI  - Steroid safety: the endocrinologist's view.
AB  - Asthma guidelines recommend the use of inhaled glucocorticoids (GCS). However,
      high doses increase the risk of systemic effects including suppression of the
      hypothalamic-pituitary-adrenal (HPA) axis by negative feedback, reduction of bone
      mass, inhibition of growth in children and skin thinning. Plasma concentration
      depends on the dose delivered from the inhaler, the distribution of delivery
      (ratio of lung to gut), and the degree of first-pass metabolism. Improving lung
      delivery increases lung absorption and reduces gut absorption and, depending on
      the extent of first-pass metabolism, may have significant effects on the systemic
      drug load. Qvar (3M Pharmaceuticals' hydrofluoroalkane beclomethasone
      dipropionate (HFA-BDP)), which produces an extra fine aerosol, improves lung
      delivery without producing clinically significant HPA suppression within the
      recommended dose range. Within this range Qvar produces no more HPA suppression
      than an equal dose of CFC-BDP and, in addition, lower doses of Qvar are effective
      in asthma control.

PMID- 10344033
TI  - What should a new thrombolytic bring us?

PMID- 10344034
TI  - Mode of action and pharmacology of saruplase.

PMID- 10344036
TI  - Clinical profile of saruplase: mortality and safety.
AB  - The data from 6775 patients treated with saruplase were analysed to provide an
      overview of the clinical profile of this thrombolytic agent. Death and
      reinfarction rates were calculated to assess efficacy. Thirty-day mortality was
      5.7% and the reinfarction rate was 5.3%. Total stroke rate was 1.3% (cerebral
      haemorrhage 0.6%), whereas severe bleeding was seen in 2.5% of patients. Finally,
      there was no conclusive evidence of allergic reactions following drug
      administration. As compared with other currently available thrombolytic agents,
      saruplase appears to be safe and effective.

PMID- 10344035
TI  - Clinical profile of saruplase: angiographic findings.
AB  - Saruplase is a relatively new fibrinolytic drug. Dose finding studies indicated
      that 70-80 mg saruplase given intravenously results in a high perfusion rate.
      With a 20 mg bolus followed by a 60 mg infusion over 1 h, a rapid and complete
      restoration of blood flow can be achieved in a fairly high number of patients.
      This dose regimen was used in subsequent studies comparing saruplase with other
      thrombolytic agents. The PRIMI (Pro-urokinase In Myocardial Infarction) study
      compared saruplase with streptokinase. Early patency rate at 60 min (TIMI grade 2
      and 3 flow) was significantly higher with saruplase (71.8%) than with
      streptokinase (48.0%). In the SESAM (Study in Europe with Saruplase and Alteplase
      in Myocardial Infarction) study comparing saruplase with alteplase, at 60 min
      patency rate was 79.9% versus 75.3%, respectively, and at 90 min the rate was
      79.9% versus 81.4%, respectively. In the LIMITS (Liquemin in Myocardial
      Infarction during Thrombolysis with Saruplase) study a heparin bolus of 5000 IU
      was shown to have an important impact on patency rate. Both heparin and
      acetylsalicylic acid are recommended as adjunctive therapy before fibrinolysis
      with saruplase. The reocclusion rates within 24-40 h were between 0.9% and 2.4%
      in the saruplase studies. There is some variation in estimating whether patency
      rates are higher with anterior or with inferior infarctions. Saruplase appears to
      be equally effective in the treatment of infarction in both locations.

PMID- 10344037
TI  - Saruplase versus other fibrinolytic agents.

PMID- 10344038
TI  - Thrombolytic therapy. Future aspects.

PMID- 10344039
TI  - Hypertension: setting the treatment targets--a consensus emerges.

PMID- 10344040
TI  - Management of NIDDM by family doctors in Hong Kong: a questionnaire survey.
AB  - The management approach to non-insulin-dependent diabetes mellitus among family
      doctors in Hong Kong was studied using two case histories. In 1996, all 804
      fellows, members and associate members of the Hong Kong College of Family
      Physicians were sent a letter and a questionnaire. Of the 512 who responded, 405
      were male and 95 were female (12 were discarded) with ages ranging from 24 to 77
      years (median 40). For the 48-year-old obese man who showed improvements in blood
      glucose and symptoms after diet for 6 weeks (Case 1), most respondents suggested
      adding a sulphonylurea (39.0%) or metformin (21.1%), or continuing diet (35.2%).
      Younger and more junior doctors tended to use metformin plus diet. Of 192
      respondents who wanted to use a sulphonylurea, gliclazide (45.8%) and
      glibenclamide (42.7%) were chosen most often. For the 76-year-old overweight
      woman with symptomatic diabetes despite diet therapy (Case 2), most respondents
      suggested adding a sulphonylurea (41.9%), metformin (25.6%) or both (19.2%).
      Younger and more junior doctors tended to use metformin plus diet, whereas older
      doctors tended to use insulin plus diet. Older and more experienced doctors
      tended to use diet plus metformin and sulphonylurea. Of 208 respondents who
      wanted to use a sulphonylurea, gliclazide (47.8%) and glibenclamide (30.1%) were
      chosen most often. The management approach to NIDDM varied with the age and
      experience of the doctor.

PMID- 10344041
TI  - Screening for acute myocardial infarction in elderly patients with collapse,
      confusion and falls.
AB  - Falls, collapse and confusion are frequent causes of admission to hospital in the
      elderly, and myocardial infarction (MI) can present atypically. The study was
      designed to assess the incidence of MI in this group of patients and provide
      information on the value of screening methods. A total of 142 elderly patients
      with a mean age of 83 years (range 76-99) were admitted with unexplained
      collapse, confusion or falls. Serial ECGs and cardiac enzymes were performed.
      Eighty-two patients (59%) had normal ECGs; of these, 80 (98%) had normal or non
      significantly elevated cardiac enzymes; 72/108 patients without chest pain had
      normal ECGs compared with 10/32 who had chest pain (p < 0.01). Cardiac enzymes
      were elevated in 5/108 without chest pain and 10/32 with chest pain (p < 0.01).
      Thirty-two (23%) had chest pain, 14 (10%) had an acute MI. In those presenting
      with chest pain, 32% had an MI, compared with only 1.9% of those without chest
      pain (p < 0.01); 18% of patients with an initially abnormal ECG had an MI
      compared with only 5% of those with a normal ECG (p = 0.02). None of the patients
      with a normal ECG who were free of chest pain were subsequently proven to have an
      MI. Cardiac enzymes are often non-specifically elevated in this group of patients
      due to muscle injury. The incidence of MI is low in patients without chest pain
      and we would not advocate routine screening with serial cardiac enzymes, unless
      there is chest pain or an abnormal 12-lead ECG on admission.

PMID- 10344042
TI  - The effect of previous antibiotic therapy on the bacteriology of the tonsils in
      children.
AB  - The bacteriology of the tonsillar surface and core in 30 children undergoing
      tonsillectomy was studied. Antibiotics taken in the six months before surgery
      were recorded. Haemophilus influenzae and Staphylococcus aureus were the
      commonest isolates; Streptococcus pyogenes was relatively rare. Eight children
      had received no antibiotics, the others had been prescribed 65 different courses
      of 13 different types. No relationship between the various antibiotic regimens
      prescribed and tonsillar bacteriology could be demonstrated, and it would appear
      that the tonsillar bacteriology at the time of tonsillectomy is not altered by
      antibiotics prescribed in the previous six months.

PMID- 10344043
TI  - The incidence of cough: a comparison of lisinopril, placebo and telmisartan, a
      novel angiotensin II antagonist. Telmisartan Cough Study Group.
AB  - Dry cough is a troublesome side-effect associated with certain antihypertensive
      agents that act by modulating aspects of the renin-angiotensin-aldosterone
      system. The incidence of dry cough associated with two of these therapies, the
      novel All receptor antagonist telmisartan and the ACE inhibitor lisinopril, was
      assessed in a multicentre, randomised, parallel-group, double-blind, placebo
      controlled, 8-week study of 88 patients with mild to moderate hypertension who
      previously demonstrated ACE inhibitor-related cough. Patients received either
      telmisartan 80 mg, lisinopril 20 mg, or placebo once daily. Cough incidence,
      measured at each visit by a self-administered symptom assessment questionnaire,
      was significantly higher with lisinopril (60%) than with telmisartan (15.6%) or
      placebo (9.7%). A visual analogue scale demonstrated a similar trend for cough
      frequency. Thus the incidence of cough with telmisartan 80 mg is significantly
      less than that seen with lisinopril 20 mg and is comparable to placebo.

PMID- 10344044
TI  - Transfusion in the management of patients with megaloblastic anaemia.
AB  - Transfusion has been associated with significant morbidity and mortality in
      megaloblastic anaemia (MA). This retrospective study was undertaken to examine
      the usefulness of transfusion in the management of MA. Fifty-two patients with MA
      were identified. Of the 20 transfused patients 13 were treated with diuretics and
      six with potassium supplements. The mean haemoglobin (Hb) of the transfused group
      was 6.5 g/dl (range 4.8-10.4 g/dl), and of the 32 non-transfused patients 10.5
      g/dl (range 5.6-17.0 g/dl). The Hb and packed cell volume (PCV) were
      significantly lower in the transfused group. Only two of 32 non-transfused group
      were given potassium supplements. In this small group of patients with MA,
      transfusion appeared to be safe and no complications of transfusion were
      identified. However, advice was not being followed. We would suggest that,
      although transfusion has a minor role in the management of MA, consideration must
      be given to the general hazards of transfusion.

PMID- 10344045
TI  - Telephone follow-up of relatives after sudden death: a survey of relatives'
      views.
AB  - The report of the Working Group on Bereavement Care in A&E departments
      recommended both the provision of follow-up for relatives and the audit of
      bereavement care as examples of good practice. In our adult A&E department follow
      up contact is made by support workers, who have often been involved with the
      family at the time of death, making telephone contact four to five days later.
      This paper describes the role of the support workers and the results of a
      questionnaire sent to relatives to seek their views on this telephone follow up.
      In a six-month period 98 families had relatives who died in A&E; 38 (39%) of them
      returned completed questionnaires. The telephone call was thought to be helpful
      by 37 (97%) of the respondents. The commonest reasons given were: 'It showed you
      cared' (95%) and 'It enabled me to ask questions' (46%). We have found that the
      experience and, more importantly, availability of the support workers allows a
      level of consistency and continuity in follow-up care which can otherwise be
      difficult to achieve.

PMID- 10344046
TI  - Atrial fibrillation, thromboembolism and antithrombotic therapy.
AB  - Atrial fibrillation is the commonest sustained disorder of cardiac rhythm and is
      associated with increased risk of stroke and thromboembolic events. Warfarin
      (dose-adjusted to a target INR of 2.0-3.0) has been well established to reduce
      this risk of stroke by 68% (95% CI 50-79%), while aspirin provides a risk
      reduction of 21% (95% CI 0-38%). Nevertheless, warfarin confers a risk of
      bleeding and the inconvenience of regular monitoring checks, while aspirin seems
      effective only for certain low-risk subgroups. Thus there have been strenuous
      efforts to improve thromboprophylaxis in atrial fibrillation, by using low
      intensity anticoagulation regimens, combination antiplatelet therapy and
      refinement of risk stratification strategies. Attempts at using a low-intensity,
      fixed-dose warfarin regimen have, however, been disappointing. For now, a
      strategy of risk stratification should be adopted to identify highest risk
      patients with atrial fibrillation who would benefit from anticoagulation.

PMID- 10344047
TI  - Drawing up clinical guidelines.
AB  - This report describes the processes involved in compiling a set of guidelines,
      locally developed by informal consensus, for the management of common paediatric
      medical problems in a teaching hospital.

PMID- 10344049
TI  - Topical immunotherapy in dermatology.
AB  - Topical immunotherapy of skin diseases has been used since the 1970s to treat
      conditions thought to result from an altered immunological state, mainly
      extensive alopecia areata and resistant viral warts. Despite its effectiveness,
      only a handful of dermatology departments in the UK currently provide such
      treatment. Any of three universal contact sensitisers may be used for topical
      immunotherapy; but diphencyprone (DCP) has advantages over dinitrochlorobenzene
      (DNCB) and squaric acid dibutyl ester (SADBE). Sensitisation of medical, nursing
      and pharmacy staff may be avoided by careful handling of the solutions. Local
      blistering and eczematous eruptions are the most common risks in patients
      undergoing treatment; vitiligo and erythema multiforme-like reactions are rare
      complications. Topical immunotherapy using DCP with close supervision is a useful
      option for severe alopecia areata and resistant viral warts.

PMID- 10344048
TI  - Evidence-based medicine and osteoporosis: a comparison of fracture risk reduction
      data from osteoporosis randomised clinical trials.
AB  - The goal of osteoporosis therapy is to prevent fractures, and many therapies are
      available for this disease. Regarding proven fracture benefit, however, the
      quality of the randomised clinical trial evidence varies substantially among
      therapies. The purpose of this paper is, therefore, to review the published
      osteoporosis randomised clinical trial literature and to assess the quality of
      the evidence. Although more than 35 randomised trials for different therapies
      were reviewed, only alendronate and vitamin D plus calcium have clearly
      demonstrated a fracture benefit, with alendronate providing the greatest relative
      risk reduction. Quality clinical trial fracture data for calcitonin, etidronate,
      fluoride, hormone replacement therapy, parathyroid hormone, calcitriol (and other
      vitamin D preparations), vitamin D and calcium monotherapy, and selective
      oestrogen receptor modulators are either lacking or inconclusive or published
      only as abstracts.

PMID- 10344050
TI  - Biochemical identification of alcohol abuse.
AB  - Biochemical test abnormality can indicate chronic alcohol abuse with good
      clinical sensitivity and specificity. Serum gamma glutamyltransferase and
      carbohydrate-deficient transferrin are the tests most frequently abnormal.

PMID- 10344051
TI  - Is a man's facial appearance predictive of how he will die?
AB  - The ability of a range of health professionals including an oncologist, a
      haematologist, a cardiologist, a general practitioner and a counsellor to predict
      the cause of death from facial appearance has been evaluated. Each participant
      was asked to predict the cause of death from facial photographs of 200 caucasian
      male doctors whose cause of death was known to be due to either arterial disease
      or neoplasia. Statistically significant concordance was found between the
      oncologist and both the GP and the counsellor in their predictions of cause of
      death, although the individual accuracy was no greater than would be expected by
      chance. This suggests that common judgments based on facial appearances may be
      shared among certain health professionals.

PMID- 10344052
TI  - Pulmonary arteriovenous malformation as a cause of severe exertional dyspnoea.
AB  - A 48-year-old woman presented to the respiratory clinic with progressive
      exertional dyspnoea and an abnormal chest radiograph. Examination revealed
      mucosal telangiectasia and pulmonary angiography confirmed the presence of two
      pulmonary arterial venous malformations (PAVM). After therapeutic coil
      embolisation, dyspnoea was markedly improved, and exercise tolerance increased.
      Comparison of exercise test responses before and after this therapeutic
      intervention provides new insights into the physiological mechanisms of
      exertional dyspnoea in this condition.

PMID- 10344053
TI  - Bronchogenic carcinoma presenting as a bronchopericardial fistula.
AB  - A case is reported in which an undiagnosed bronchogenic carcinoma presented
      clinically with sudden onset shortness of breath and cardiac failure due to the
      development of an acute bronchopericardial fistula.

PMID- 10344054
TI  - Unilateral adrenal medullary hyperplasia: another form of curable hypertension?
AB  - A case of unilateral adrenal medullary hyperplasia is presented in a 49-year-old
      caucasian female without multiple endocrine neoplasia association. The patient
      presented with episodic hypertension and paroxysms suggesting an underlying
      phaeochromocytoma. Biochemical supported this diagnosis but no discrete tumour
      was found on preoperative localising studies or at the time of surgery. The
      patient underwent a unilateral adrenalectomy with confirming adrenal medullary
      hyperplasia with complete resolution of her symptoms for six months.

PMID- 10344055
TI  - Priapism induced by chlorpromazine.
AB  - Priapism is a pathologically prolonged and painful penile erection, usually
      unassociated with sexual desire or intercourse. Causes include certain oral
      medications, although the mechanism for drug-induced priapism is unknown. We
      describe two cases of priapism attributed to chlorpromazine who have presented
      within the past two years.

PMID- 10344056
TI  - Mivacurium apnoea: a trap for the unwary.
AB  - We present a case of unanticipated postoperative apnoea in a patient with
      associated medical illness to illustrate the diagnostic difficulty that can arise
      in the detection and subsequent management of mivacurium apnoea. A high index of
      suspicion is essential in the presence of concomitant medical conditions that may
      cause prolonged apnoea. To our knowledge, no report exists documenting the
      unanticipated occurrence of mivacurium apnoea in a patient with previously
      undiagnosed pseudocholinesterase deficiency and concomitant medical illness who
      has previously undergone 'balanced' general anaesthesia.

PMID- 10344057
TI  - Recognising and rewarding good performance: the importance of being valued.

PMID- 10344058
TI  - The treatment of end-stage heart failure: does cardiac pacing have anything to
      offer?

PMID- 10344059
TI  - A survey of hospital morbidity, mortality and quality of life following coronary
      artery bypass surgery in a UK Indo-Asian population.
AB  - To survey the in-hospital morbidity, mortality, length of stay in the intensive
      therapy unit (ITU) and hospital and quality of life in patients of Indo-Asian
      origin following coronary artery bypass (CABG) surgery, 345 consecutive patients
      (mean age 58 years; SD 8.9; range 32-88 years) undergoing primary, isolated CABG
      were studied. Non-elective CABG was undertaken in 41% of patients. The left
      anterior descending artery (LAD) was grafted in 89%, although in 30% of these the
      internal mammary artery (IMA) was not used. Following CABG, the hospital
      morbidity and mortality was within the expected range, although there was a trend
      towards higher in-hospital mortality in the Parsonnet low risk group of patients.
      The length of ITU and hospital stay was not prolonged. Using the SF-36
      questionnaire in postoperative patients, low quality of life scores were obtained
      for six of the eight modalities tested including physical functioning, bodily
      pain and general health perception. The low quality of life scores and IMA usage
      in Indo-Asians needs to be addressed.

PMID- 10344060
TI  - Ideal pain relief following laparoscopic cholecystectomy.
AB  - In a previous report the effectiveness of intraperitoneal bupivacaine in reducing
      pain following laparoscopic cholecystectomy was demonstrated. Other methods of
      pain relief are commonly used but none has been compared following laparoscopic
      cholecystectomy. In two further studies we have compared the analgesic effect of
      intraperitoneal bupivacaine against wound infiltration with bupivacaine, and
      against intraperitoneal bupivacaine with the addition of a non-steroidal anti
      inflammatory drug (NSAID) in patients undergoing laparoscopic cholecystectomy.
      Two consecutive studies were performed. In the first, patients in group 1 were
      given 20 ml of 0.25% bupivacaine into the peritoneal cavity; patients in group 2
      were given 20 ml of 0.25% bupivacaine injected into the trocar wounds. In the
      second study, patients in group 1 were given 20 ml of 0.25% bupivacaine into the
      peritoneal cavity; patients in group 2 were given 20 ml of 0.25% bupivacaine into
      the peritoneal cavity and a diclofenac suppository (100 mg) one hour before
      surgery. Postoperative pain was assessed with a visual analogue pain scale. There
      was no difference in pain scores in the two groups in either study.
      Intraperitoneal bupivacaine is as effective as wound infiltration. The addition
      of an NSAID makes no difference in the reduction of postoperative pain following
      laparoscopic cholecystectomy.

PMID- 10344061
TI  - A cost minimisation analysis of cardiac failure treatment in the UK using CIBIS
      trial data. Cardiac Insufficiency Bisoprolol Study.
AB  - The clinical benefits of beta-blockers in heart failure are currently subject to
      intense debate and are being investigated. The economic impact of beta-blockade,
      however, has largely remained unexplored. The Cardiac Insufficiency Bisoprolol
      Study (CIBIS), while failing to show statistically significant reduction in
      mortality over conventional therapy, demonstrates that the administration of
      bisoprolol adjuvant to standard therapy leads to a significant reduction in
      hospital admission. The present study is a cost minimisation analysis based on
      CIBIS data for the UK and is restricted to direct costs only. The costs of
      bisoprolol medication and inpatient treatment of heart failure are considered.
      The 'base case' analysis and the sensitivity analyses carried on all cost driver
      parameters show that administering bisoprolol to heart failure patients
      adjuvantly to the standard therapy is at least cost neutral. Additional drug
      costs incurred by bisoprolol are compensated by the inpatient treatment costs of
      heart failure avoided. All other non-quantifiable clinical benefits such as
      improvement of New York Heart Association functional class are positive extras to
      patients and the National Health Service.

PMID- 10344063
TI  - Handling and acceptability of the Easi-Breathe device compared with a
      conventional metered dose inhaler by patients and practice nurses.
AB  - This study compared the handling and acceptability of the Easi-Breathe, a breath
      actuated metered dose inhaler (MDI), with that of a conventional MDI. A total of
      104 patients and 14 practice nurses took part in interviews at a central
      location. An additional 100 practice nurses were interviewed in a telephone
      study. Significantly more patients (86%) found Easi-Breathe easier than a
      conventional MDI to use correctly (p < or = 0.001). Overall, more patients
      preferred Easi-Breathe (82% vs 18%; p < or = 0.001), ease of use and confidence
      in successful dose delivery being the main reasons for their preference. Nurses
      thought that Easi-Breathe was easier for the vast majority of patients (97%) to
      use correctly, as well as being easier to teach and to use correctly in a crisis
      (p < or = 0.001). Overall, 79% of nurses preferred the Easi-Breathe to the
      conventional MDI (p < or = 0.001), ease of use and ease of teaching being the
      main reasons for their preference.

PMID- 10344062
TI  - First-dose response to angiotensin-converting enzyme inhibition in congestive
      cardiac failure: a Malaysian experience.
AB  - Despite their proven value in reducing morbidity and mortality in different
      grades of heart failure, angiotensin converting enzyme (ACE) inhibitors continue
      to be underused. One reason for this is clinicians' apprehension of first-dose
      hypotension. We conducted a double-blind, randomised, placebo-controlled parallel
      group study to investigate the effect of various ACE inhibitors on first-dose
      hypotension. Eighty unselected patients were randomised into five treatment
      groups: placebo, captopril 6.25 mg, enalapril 2.5 mg, perindopril 2 mg and
      lisinopril 2.5 mg. Blood pressure was measured at baseline, half hourly for two
      hours and hourly for three hours after drug treatment. The maximum drops in mean
      arterial pressure (in mmHg +/- SD) were placebo 5.89 +/- 2.65, perindopril 5.29
      +/- 2.49, enalapril 13.28 +/- 3.31, lisinopril 15.04 +/- 5.74 and captopril 16.76
      +/- 5.74 (all p < 0.05 vs placebo except for perindopril). Perindopril, unlike
      the other ACE inhibitors studied, did not produce first-dose hypotension
      following its initiation in patients with congestive heart failure.

PMID- 10344064
TI  - Improved blood pressure control by monitoring compliance with antihypertensive
      therapy.
AB  - Compliance with antihypertensive therapy was monitored for three months using an
      electronic medication dispenser in 35 patients remaining hypertensive despite the
      once-daily administration of a blood pressure lowering drug (either as
      monotherapy or as fixed-dose combination therapy). During the monitoring of
      compliance, the treatment was unchanged but blood pressure decreased
      significantly (p < 0.001) from 167.9/100.4 +/- 16.3/7.2 mmHg (mean +/- SD) to
      152.5/90.9 +/- 20.9/11.5 mmHg. The percentage of days with one opening per day
      was 80.8 +/- 20.5. Thus, discussing with the patient about compliance with the
      prescribed drug regimen and monitoring compliance for a few months allows better
      control of blood pressure. This most likely reflects increased compliance with
      antihypertensive drug therapy.

PMID- 10344065
TI  - The antiphospholipid or Hughes' syndrome: an underdiagnosed cause of thrombosis.
AB  - The antiphospholipid or Hughes' syndrome is the association between
      antiphospholipid antibodies, recurrent venous and arterial thromboses and
      recurrent fetal loss. There are many clinical manifestations arising from this
      acquired thrombophilia and these are described in the article. The pathogenic
      mechanism by which the antibodies cause thrombosis is the subject of much debate,
      and current theories are described. The diagnosis and management of patients with
      the syndrome are also discussed.

PMID- 10344066
TI  - Recent advances in the non-surgical management of atrial fibrillation.
AB  - Atrial fibrillation is the commonest clinical arrhythmia, and is associated with
      significant morbidity and mortality. The treatment of choice is to restore and
      maintain sinus rhythm. Although certain antiarrhythmic drugs are more effective
      than placebo in maintaining sinus rhythm, recurrence of atrial fibrillation post
      cardioversion remains common. The use of antiarrhythmic drugs can be associated
      with serious adverse effects due to their negative inotropic and proarrhythmic
      effects. Radiofrequency ablation of the AV junction is a safe and effective
      palliative treatment option in patients who have failed drug therapy. Ventricular
      rate control without the need for permanent pacing can be achieved by AV nodal
      modification using radiofrequency energy. There is also interest in the role of
      catheter ablation as a possible curative procedure for atrial fibrillation.
      Atrial pacing can reduce the incidence of atrial fibrillation in certain
      subgroups of patients. Finally, low energy intracardiac atrial defibrillation has
      been shown to be feasible in humans.

PMID- 10344067
TI  - Androgenetic alopecia in men: the scale of the problem and prospects for
      treatment.
AB  - While the precise incidence of androgenetic alopecia is unknown, it is
      universally acknowledged to be the most common hair problem in men. Balding is
      generally associated with ageing; consequently, the desire to prolong a youthful
      appearance inevitably leads to demands for effective treatments. Further,
      changing attitudes in modern society have resulted in people becoming concerned
      about their appearance and less tolerant about conditions that might be
      alleviated by medical intervention. The importance of hair loss upon quality of
      life has been underestimated by the medical profession. Clinicians failing to
      accept hair loss as an important medical problem ignore the real distress
      suffered by a significant proportion of those affected. New options for treatment
      that selectively target the metabolic pathways involved in the balding process
      are showing promise. The first generation of such drugs, Propecia, is now
      available in some countries and other molecules are currently under development.

PMID- 10344068
TI  - The role of lipid lowering in transplantation.
AB  - Transplantation is an increasingly common procedure. Yet the contribution of
      accelerated atherosclerosis to the reduction of graft life is often
      underestimated. This review examines the evidence for the involvement of
      hyperlipidaemia and other cardiovascular disease risk factors in the aetiology of
      chronic graft failure in renal, cardiac, liver and pancreatic transplantation.
      The evidence for the role of lipid lowering therapy in the prevention of
      accelerated atheroma in these patients is reviewed.

PMID- 10344069
TI  - Efavirenz in the management of HIV infection.
AB  - Efavirenz, which is likely to be licensed in the UK and throughout Europe
      shortly, represents a major advance in the treatment of HIV infection. It belongs
      to the non-nucleoside reverse transcriptase (NNRTI) class of drugs and, as such,
      it should only be prescribed with other potent therapies to avoid the development
      of resistance. However, in the pivotal head-to-head comparison of efavirenz with
      lamivudine and zidovudine, treatment over a 24-week period proved superior to
      treatment with a standard regimen containing indinavir. The results from
      prolonged follow-up of this study are eagerly awaited but it is clear that a
      combination of efavirenz with nucleoside analogues provides a potent proteinase
      inhibitor-sparing regimen which may have less toxicity. Additional data also
      indicate that the combination of a proteinase inhibitor (indinavir) with
      efavirenz provides an extremely potent regimen which is well tolerated and
      produces complete inhibition of plasma HIV viraemia over prolonged periods of
      follow-up. In common with many other currently available potent anti-HIV
      therapies, the optimum use of this drug is being determined by ongoing clinical
      studies but it is clear that ease of administration (once-daily), freedom from
      serious side-effects and potency when used in combination are likely to represent
      a very considerable advance in the management of HIV infection.

PMID- 10344070
TI  - Nisoldipine coat-core and heart rate response during treatment of hypertension.
AB  - Nisoldipine coat-core (nisoldipine CC), an extended-release once-daily
      formulation, is an effective treatment for mild-to-moderate hypertension,
      providing sustained blood pressure control over the 24-hour dosing interval.
      Nisoldipine CC is highly vascular selective. It causes neither reflex tachycardia
      nor symptomatic bradycardia; it lacks significant negative inotropy at
      therapeutic doses; and it does not affect circadian variation in blood pressure
      or heart rate. Data suggest that the lack of reflex sympathetic activation in
      response to the blood pressure-lowering effect of nisoldipine CC is due to the
      smooth onset of action of nisoldipine CC, causing resetting of the baroflex. The
      neutral heart rate profile of nisoldipine CC confers potential therapeutic
      advantages over several other calcium channel blockers, in particular, the short
      acting agents, in the treatment of hypertension.

PMID- 10344071
TI  - Deep vein thrombosis as a presenting symptom of congenital interruption of the
      inferior vena cava.
AB  - Infrahepatic interruption of the inferior vena cava is a congenital anomaly,
      resulting in venous drainage of the lower extremities by way of a compensatory
      enlarged vena azygos system. We report the case of a 37-year-old male who
      presented with symptoms of deep vein thrombosis of the entire right lower
      extremity. A right-sided mediastinal mass on the chest X-ray was mistaken for a
      haematological malignancy but proved later to represent an enlarged azygos vein.
      The case illustrates that in a case of deep vein thrombosis, especially in
      younger patients, interruption of the inferior vena cava should be considered. A
      right-sided paratracheal mass on the chest X-ray may give a clue in making the
      correct diagnosis.

PMID- 10344072
TI  - An unusual case of ileocaecal tuberculosis in an 80-year-old Caucasian male.
AB  - An 80-year-old Caucasian male presented with a seven-week history of diarrhoea
      and weight loss. Distal duodenal biopsies showed partial villous atrophy but he
      failed to respond to a gluten-free diet. Subsequently he developed a right iliac
      fossa mass associated with radiological evidence of ileocaecal ulceration.
      Colonoscopic biopsies from the caecum showed non-caseating granulomata and Ziehl
      Neelsen (ZN) staining and culture for acid-fast bacilli (AFB) were negative.
      Crohn's disease was diagnosed and he was started on steroids. Although he showed
      an initial response, his condition then deteriorated and he died after six weeks.
      ZN staining of tissue at postmortem showed AFBs. Although a rare diagnosis in the
      UK, a high index of suspicion should be maintained for ileocaecal TB in patients
      with appropriate clinical features, even if classical risk factors for TB are
      absent.

PMID- 10344073
TI  - Myomectomy in pregnancy: incarcerated pedunculated fibroid in an umbilical hernia
      sac.
AB  - We describe a rare case of a 31-year-old woman at 28 weeks of pregnancy
      presenting with an incarcerated pedunculated fibroid in an umbilical hernia sac.
      She had a successful myomectomy and hernia repair and proceeded to have
      spontaneous vaginal delivery at term. Incarceration of a pedunculated fibroid
      presents a diagnostic puzzle which can be successfully treated by myomectomy.

PMID- 10344074
TI  - A foreign body in the bronchus still presents problems.
AB  - Aspiration of a foreign body in young children is rare but can still cause
      considerable morbidity and mortality. The case of a 5 1/2-month-old infant with
      aspiration of a piece of apple is presented, together with a review of the
      literature.

PMID- 10344076
TI  - The determination of TBA-reactive substances and alkenals in the presence of
      antioxidants.
AB  - This study investigated the inhibitory efficiency of all-rac-alpha-tocopherol,
      2,6-ditert-butyl-p-cresole (BHT), and 6-hydroxy-2,5,7,8-tetramethyl-chroman-2
      carbonic acid (Trolox) on determination of thiobarbituric acid-reactive
      substances (TBARS) and short-chain alkenals in rat liver homogenates. The
      concentration of TBARS was measured fluorophotometrically. Aldehydes were
      determined after derivatization with methylhydrazine by gas chromatography (GLC).
      The concentrations of alkenals and TBARS in liver homogenates were diminished
      when antioxidants were present during the sample preparation. It is suggested
      that in the absence of antioxidants the samples are autoxidized further during
      the preparative procedures. For the aldehyde determination all-rac-alpha
      tocopherol was the most effective antioxidant to reduce the bias due to
      autoxidation, whereas for TBARS it was Trolox.

PMID- 10344077
TI  - Yersinia ruckeri septicaemia in experimentally infected carp (Cyprinus carpio L.)
      fingerlings.
AB  - The presence of Yersinia ruckeri, the causal agent of enteric redmouth disease
      (ERM) in salmonids and a few other freshwater fish, has so far been reported from
      a variety of sources including the intestine of healthy carp. Since there are no
      data on the pathogenicity of this bacterium for carp, 15 fingerlings were
      experimentally infected by intraperitoneal injection of about 5 x 10(5) cells.
      Thirteen injected fish were moribund or died within 4 days with septicaemic
      lesions. Two survivors were sampled on Day 28 after infection. Yersinia ruckeri
      was reisolated from the internal organs of all experimental fish. By
      histopathological examination moribund fish had generalised bacteriaemia with
      inflammation, degeneration and necrotic foci in kidney, liver and spleen,
      corresponding to findings described previously in ERM of rainbow trout. Survivors
      of challenge on Day 28 had a chronic disease characterised by prominent
      peritonitis and enteritis, exhaustion of the erythroid, granuloid and lymphoid
      components in haematopoietic kidney tissue as well as focal degeneration and
      necrosis in organs. These data indicate a high sensitivity of carp to
      intraperitoneal infection with a relatively low dose of Y. ruckeri.

PMID- 10344075
TI  - Are day case inguinal hernia repair and varicose vein surgery substitutes for
      inpatient treatment?

PMID- 10344078
TI  - Determination of acrinathrin residues in honey and beeswax.
AB  - The Asian bee mite (Varroa jacobsoni Oud.) causes variable damage in Hungarian
      apiaries due to the different and changing conditions. Plastic and wooden strips
      impregnated with synthetic pyrethroid-type active ingredients show a high
      efficacy against the mites. These treatments, however, may leave residues in bee
      products (honey, propolis, wax). After experimental treatment with Gabon PA 92,
      the levels of active ingredient (acrinathrin) residues were determined in honey
      and beeswax samples. The analytical results proved that the average concentration
      of acrinathrin residues was less than 0.01 mg/kg in honey and less than 0.10
      mg/kg in beeswax. From the food-hygienic point of view it is favourable that the
      honey did not become 'contaminated' with acrinathrin during the experimental
      treatment. The analytical results serve as a basis for the registration of this
      veterinary product in Hungary.

PMID- 10344079
TI  - Study of the soil-plant (carrot)-animal cycle of nutritive and hazardous minerals
      in a rabbit model.
AB  - Carrots were grown on soils polluted by heavy metal salts. Each particular
      microelement reached a high concentration [molybdenum (Mo) 39.00, cadmium (Cd)
      2.30, lead (Pb) 4.01, mercury (Hg) 30.00, and selenium (Se) 36.20 mg/kg dry
      matter] in the carrot. In a metabolic balance trial conducted with 15 male and 15
      female New Zealand White rabbits, the control animals (n = 5) were fed ad libitum
      with concentrate as basal diet, while the other rabbits received the basal diet
      and carrots containing the particular microelement. Blood samples were taken to
      determine the activity of serum enzymes. To investigate the metabolism of Mo, Cd,
      Pb, Hg and Se, samples were taken from the heart, liver, lungs, kidneys, spleen,
      ovaries/testicles, entire digestive tract, adipose tissue, femur, hair, faeces
      and urine. Carrot had significantly higher digestibility for all nutrients than
      the rabbit concentrate. Carrot samples of high Pb content had the lowest
      digestibility of crude protein. The microelements differed in their rate of
      accumulation in the organs examined: Mo and Cd accumulated in the kidneys, Pb in
      the kidneys, liver, bones and lungs, Hg in the kidneys and liver, while Se in the
      liver, kidneys and heart. The proportions of microelements eliminated from the
      body either via the faeces and urine (Mo 80.18% and Se 47.41%) or via the faeces
      (Cd 37.86%, Pb 66.39%, Hg 64.65%) were determined. Pathohistological examination
      revealed that the rate of spermatogenesis was reduced in the Mo, Cd, Pb and Hg
      groups compared to the control. Lead, Cd and Hg intake resulted in a considerable
      decrease in gamma-glutamyltransferase (GGT) and in an increase of alkaline
      phosphatase (ALP) activity because of damages to the kidneys and bones. All
      experimental treatments decreased the activity of cholinesterase (CHE) because of
      lesions in the liver.

PMID- 10344080
TI  - Effect of rumen protected methionine supplementation on early lactational
      responses of dairy cows fed a grass silage and cereals diet.
AB  - To investigate the milk production limiting potential of a diet based on grass
      silage (40%), hay (15%), dried sugar beet pulp (13%) and grain compound mixture
      (32%), 28 multiparous cows in early lactation were randomly assigned to two
      treatment groups: a control group and a group receiving supplementary rumen
      protected methionine (RPMet) treatment (12 g intestinally available
      methionine/cow/day, given 1-120 days postpartum; Smartamine; RPAN's technology).
      The diet was formulated to meet the requirements for protein and net energy.
      RPMet supplementation had no significant effect on DMI (kg/cow/day), milk dry
      mass, milk lactose and milk urea contents. Responses for mean daily milk yield,
      mean milk fat and milk protein yields were significantly higher (P < 0.05) in
      cows supplied with RPMet than in controls. Mean daily milk yield, milk protein
      and milk fat yields increased by 2.4 kg, 108 g and 124 g, respectively. The mean
      daily milk protein and casein contents were increased by 1.8 g and 0.9 g and milk
      fat content by 1.2 g in 1 kg of milk, respectively. The results suggest that in
      cows fed grass silage and a grain compound mixture milk production is limited by
      methionine insufficiency, but milk production performance can be increased
      significantly by the addition of RPMet to the diet.

PMID- 10344082
TI  - Massive goitre (struma parenchymatosa) in geese.
AB  - In a goose flock consisting of 2300 birds of 6 months of age severe goitre was
      diagnosed. To the best of our knowledge this is the first report of naturally
      occurring goitre in geese, which is not related to the feeding of rapeseed meal.
      The major pathological findings included retarded growth and plumage development,
      significantly (300%) increased relative thyroid weight, fat accumulation in the
      mesenteric and abdominal region, and lipid infiltration of liver and kidney
      cells. Subsequent hormone analysis showed undetectable thyroxine (T4) levels and
      a dramatic drop in triiodothyronine (T3) plasma levels of the diseased geese.
      Thyroidal histology displayed the typical signs of struma parenchymatosa. In
      order to get more information about the possible causes of the goitre, 10 geese
      from the affected farm were transferred into the laboratories of the Central
      Veterinary Institute. The geese were allotted into two groups. Group I received
      iodine supplementation for 55 days, while the other group served as sick control
      (Group S). Iodine treatment caused a dramatic improvement in the birds' clinical
      condition except in plumage growth in Group I, while the clinical and main
      pathological signs of goitre remained unchanged or worsened in the untreated
      Group S. Contrary to this, the serum levels of thyroid hormones and
      responsiveness to thyrotropin releasing hormone (TRH) improved not only in Group
      I but also in Group S. Almost euthyroid biochemical parameters were found after
      55 days of iodine treatment in Group I and, surprisingly, a considerable
      improvement (especially in serum T3 levels) occurred also in Group S. These
      findings confirm the diagnosis of goitre but also call attention to the fact that
      iodine deficiency was not the only factor eliciting the disorder. The underlying
      possible goitrogenic substance could not be traced down.

PMID- 10344081
TI  - Study on the course of Cryptosporidium baileyi infection in chickens treated with
      interleukin-1 or indomethacin.
AB  - The effects exerted by human recombinant interleukin-1 beta (hrIL-1 beta) and the
      prostaglandin inhibitor indomethacin on the course of Cryptosporidium baileyi
      infection in chickens were studied. Daily oocyst shedding was monitored by a
      quantitative method throughout the experiment. Humoral immune response to C.
      baileyi was assessed by ELISA at 3 weeks of age while the level of cellular
      immune response to phytohaemagglutinin-P (PHA-P) by a skin test at 23 days of
      age. Parenteral application of hrIL-1 beta decreased oocyst shedding to 62%, but
      the infection ran a similar course in treated and control birds. The PHA-P skin
      test demonstrated increased cellular immune reaction in chickens receiving IL-1
      beta, but there was no significant difference in the humoral responses of the two
      groups as detected by ELISA. On the other hand, indomethacin mixed to the feed
      lessened oocyst shedding to 13.7% and also shortened its duration. Immunological
      parameters as reflected by PHA-P skin test and ELISA results indicated enhanced
      cellular but unaltered humoral immune response. These data suggest that the
      systemic application of interleukin-1 can induce partial protection against C.
      baileyi in chickens and that prolonged, abundant oocyst shedding is due to an
      indomethacin-sensitive immunodepression via the prostaglandin pathway.

PMID- 10344083
TI  - Effects of cimetidine on broiler fattening and on stress-induced gizzard erosion
      in chicken.
AB  - The work describes the effects of cimetidine on stress-induced gizzard erosions
      (Experiment A) and the influence of the long-term application (42 days) of the
      same drug on weight gain and feed consumption during broiler fattening
      (Experiment B). For Experiment A, 60 male, three-day-old chicks were divided into
      two groups: C (n = 30)--control chicks treated with 0.5 ml saline; CIM (n = 30)-
      chicks treated with cimetidine in a dose of 5 mg/kg body weight (b. w.)
      intragastrically. All chicks were stressed using a modified water-immersion
      stress method according to which the chicks, after 24 h of feed deprivation, were
      immersed in tap water (17 degrees C) for a few seconds. Under chloroform
      anaesthesia ten chicks from each group were killed 1, 2 and 3 h after the
      stressing. The morphometric analysis of gizzard erosion (GE) and
      histopathological examinations of gizzards were performed for each chick. In
      Experiment B, 32 one-day-old broilers of both sexes were used. The control group
      was untreated (n = 16) while the CIM group (n = 16) was fed the same diet
      supplemented with 10 mg of cimetidine per kilogram of feed throughout the
      fattening period (42 days). The results of Experiment A showed decreased mean
      length of the GE in the cimetidine-treated birds as compared with the GE lesions
      of the controls. In Experiment B, the treated chicks had reduced liveweight
      (1835.1 g), carcass weight (1474.6 g) and increased feed consumption (2115 g of
      feed per kilogram of weight gain) compared to the controls in which the same
      parameters were 1898.5 g, 1574.2 g and 1797 g, respectively. The results show
      that while stress-induced GE of chicks can be medicated pharmacologically, long
      term application of the same substance impairs the results of fattening.

PMID- 10344084
TI  - Disposition kinetics and dosage regimen of ceftriaxone in crossbred calves (short
      communication).
AB  - Disposition kinetics and urinary excretion of ceftriaxone were investigated in
      healthy crossbred calves after its single intravenous administration (10 mg kg
      1). Based on kinetic parameters, an appropriate dosage regimen of ceftriaxone in
      calves was calculated. The peak plasma level of ceftriaxone at 1 min was 84.0 +/-
      1.55 micrograms ml-1 which declined to 0.43 +/- 0.05 microgram ml-1 at 8 h. The
      value of elimination half-life (t1/2 beta), volume of distribution Vd (area) and
      total body clearance (ClB) were 4.39 +/- 0.63 h, 1.91 +/- 0.19 L kg-1 and 0.31 +/
      0.01 L kg-1 h-1, respectively. Approximately 41 per cent of total administered
      drug was recovered in the urine within 24 h of its administration. The plasma
      protein binding of ceftriaxone was found to be concentration dependent with an
      overall mean of 38.55 per cent. The binding capacity of ceftriaxone to plasma
      proteins and the dissociation rate constant of protein-drug complex were 20.1 x
      10(-8) +/- 18.4 x 10(-8) mole g-1 and 1.07 x 10(-6) +/- 0.52 x 10(-6) mole,
      respectively. An appropriate intravenous dosage regimen of ceftriaxone in cattle
      would be 12 mg kg-1 repeated at 24 h.

PMID- 10344085
TI  - Effect of an oxytocin antagonist on prostaglandin F2 alpha secretion and the
      course of luteolysis in sows.
AB  - The role of oxytocin (OT) in the regulation of prostaglandin F2 alpha (PGF2
      alpha) secretion during luteolysis in gilts was studied using a highly specific
      OT antagonist (CAP-581). In Experiment 1 gilts on Days 14 to 19 of the oestrous
      cycle in Latin square design were used, to determine the dose and time of
      application of OT and CAP. In Group I (n = 6) gilts were treated intravenously
      with saline or with 10, 20 and 30 IU of OT. Concentrations of the main PGF2 alpha
      metabolite i.e. 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) were measured
      in blood samples as uterine response to the treatment. Twenty IU of OT was the
      most effective to stimulate PGFM release and this dose was used after CAP
      treatment in gilts of Groups II, III and IV. Gilts of Group II (n = 3) were
      injected into the uterine horns (UH) with saline (5 ml/horn) or CAP (2 mg, 3 mg
      and 4 mg; half dose/horn) and OT was injected (i.v.) 30 min thereafter. Any of
      the CAP doses given into the UH affected PGFM plasma concentrations stimulated by
      OT. In Group III (n = 4) gilts were infused (i.v.) for 30 min with CAP (9 mg, 14
      mg and 18 mg/gilt) followed by 20 IU of OT. All doses of CAP effectively
      inhibited OT-stimulated PGF2 alpha release, therefore 9 mg was selected for the
      further studies. Gilts of Group IV (n = 4) received OT 4, 6 and 8 h after CAP to
      define how long CAP blocks the OT receptors. Concentrations of PGFM increased
      after any of this period of time. Thus, we concluded that 9 mg of CAP infused
      every 4 h will effectively block OT receptors. In Experiment 2, gilts (n = 4)
      received CAP as a 30-min infusion every 4 h on Days 12-20 of the oestrous cycle.
      Control gilts (n = 3) were infused with saline. CAP infusions diminished the
      height of PGFM peaks (P < 0.05). Frequency of the PGFM (P < 0.057) and OT (P <
      0.082) peaks only tended to be lower in the CAP-treated gilts. Peripheral plasma
      concentrations of progesterone (P4) and oestradiol-17 beta (E2) and the time of
      luteolysis initiation as measured by the decrease of P4 concentration were the
      same in CAP- and saline-treated gilts. The macroscopic studies of the ovaries in
      gilts revealed lack of differences between groups. We conclude that OT is
      involved in the secretion of luteolytic PGF2 alpha peaks but its role is limited
      to controlling their height and frequency. Blocking of OT receptors did not
      prevent luteolysis in sows.

PMID- 10344086
TI  - Sperm collection from shot red deer stags (Cervus elaphus) and the utilisation of
      sperm frozen and subsequently thawed.
AB  - Sperm samples were collected from the epididymides of 11 hunter-killed stags
      (Cervus elaphus hippelaphus) within 2 to 17 h post mortem in September 1991.
      Progressively motile spermatozoa were diluted and deep-frozen in tris-yolk
      extender by a procedure routinely used for bovine semen. The pre-freezing
      motility of spermatozoa from 6 stags was higher than 80%, while the sperm of 5
      animals was found to be unsuitable for dilution. In the post-thawed sperm of six
      stags 40-50% of the spermatozoa showed progressive motility and the number of
      viable spermatozoa ranged from 8.6 to 26.7 x 10(6) per 0.25 ml straw. Two years
      later, three hinds were superovulated by the use of a progesterone-releasing
      intravaginal device (CIDR type G, Carter, Holt Harvey Plastic Products Group
      Ltd., Hamilton, New Zealand) for a period of 14 days and with follicle
      stimulating hormone (Folicotropin inj., Spofa, Prague). Each hind was inseminated
      artificially 60 h after the withdrawal of CIDR with thawed sperm injected into
      the uterus via the vagina. Seven days later the uteri were flushed out, as a
      result of which 3 early blastocysts + 1 ovum, 3 morulae + 4 ova, and 1 morula + 7
      ova, respectively, were recovered from the three hinds. Deer embryos were frozen
      according to a glycerol-based freezing protocol. A further two years later two
      hinds were oestrus-synchronised with CIDR type G and 300 IU PMSG (Folligon inj.,
      Intervet, NL), and two of the thawed embryos were transplanted into two recipient
      hinds 7 days after heat. One of these gave birth to a normal stag fawn in June
      1996. This was the first deer born in Hungary from embryo transfer. The results
      obtained indicate that sperm from top stags shot in the course of hunting can
      prove useful for the preservation of genetic material or in the development of
      the farmed deer system.

PMID- 10344087
TI  - Model field study of Sumithion 50 EC and Fusilade S on pheasants.
AB  - Toxicological studies on wild animals play an important role in the
      ecotoxicological examination of pesticides. The applied model tests enable the
      assessment of toxicological consequences with particular regard to the life and
      nutrition of wild animals in the ploughed field among plants treated with
      pesticides. The application of different pesticide formulations on plough-land
      may pose a simultaneous chemical burden to wild birds. In this model study,
      manifestations of the interaction between an insecticide and a herbicide were
      studied in pheasants. The birds were placed on lucerne in cages (48 m2) and
      sprayed once. The applied doses were: Sumithion 50 EC 1 litre/ha + Fusilade S 6
      litres/ha (practical doses) and Sumithion 50 EC 5 litres/ha + Fusilade S 30
      litres/ha. The analytically determined pesticide concentration of the lucerne was
      taken as a basis in the further treatment of fodder. The fodder of pheasants
      contained the following chemicals: 85 mg/kg Sumithion 50 EC + 510 mg/kg Fusilade
      S and 425 mg/kg Sumithion 50 EC + 2250 mg/kg Fusilade S. Sporadic deaths observed
      among the pheasants were of traumatic origin and not due to a toxic effect. The
      decrease of body weight was significant only at the higher dose levels.
      Acetylcholinesterase (AChE) activity of the blood decreased significantly in both
      dose groups. On the basis of the results obtained it can be established that at
      the dose level used in the practice the pesticides studied do not give rise to a
      toxic interaction in pheasants.

PMID- 10344088
TI  - An outbreak of toxin A negative, toxin B positive Clostridium difficile
      associated diarrhea in a Canadian tertiary-care hospital.

PMID- 10344090
TI  - Outbreak of cryptosporidiosis in north west England.

PMID- 10344091
TI  - Clostridium difficile in Leicester hospital.

PMID- 10344092
TI  - [Has the moment arrived for quinolones in the treatment of respiratory
      infections?].

PMID- 10344093
TI  - [Comparison of the in vitro activity of trovafloxacin and 11 antimicrobial agents
      against 476 strains of Streptococcus pneumoniae].

PMID- 10344094
TI  - [Other communal respiratory pathogens and new fluoroquinolones].

PMID- 10344095
TI  - [Microbiology of atypical community-acquired pneumonia. Clinical needs and
      contribution of new antibiotics].

PMID- 10344096
TI  - [Indications for use of fluoroquinolones in the treatment of community acquired
      pneumonia].

PMID- 10344097
TI  - [Pharmacokinetics and safety of trovafloxacin].

PMID- 10344098
TI  - [Is trovafloxacin an antibiotic exclusively for the treatment of respiratory
      infections?].

PMID- 10344099
TI  - Journalism as inquiry, public relations, and advertising.

PMID- 10344100
TI  - Demographics may not be destiny.

PMID- 10344101
TI  - Systematic reviews and the practice of evidence-based dentistry: professional and
      policy implications.
AB  - A definition and introduction is provided for evidence-based dentistry and dental
      practice. The impact of this approach to providing care is traced for quality of
      care and professionalism. Policy implications are drawn and the impact of
      evidence-based dentistry for dental education and research are discussed.

PMID- 10344102
TI  - Conditions and tools for evidence-based dental practice.
AB  - Before evidence-based dentistry becomes a norm in practice, several conditions
      must be met. These include an attitude of questioning authority and training in
      how to use the literature, a supportive environment from colleagues and practice
      based research. Some new tools--in the form of journals with more user-friendly
      formats and direct access to databases--are also necessary.

PMID- 10344103
TI  - Evidence-based dentistry: a practitioner's perspective.
AB  - Basing practice decisions on evidence is neither contestable nor new. There are
      some concerns, however, that must be addressed. First, all published "evidence"
      is not of equal quality. Second, the practical experience of dentists must be
      recognized as constituting evidence. Additionally, third parties should not be
      allowed to use evidence if that use interferes with practitioners' judgment.
      Fourth, the call for more evidence may place a burden on dental schools already
      struggling to keep up with their demands of teaching basic dental skills. The
      Dental Practice Parameters developed by the ADA may provide a more realistic
      alternative because they preserve practitioner discretion.

PMID- 10344104
TI  - Evidence-based dental plans: dentistry's future is now.
AB  - Evidence-based dental practice is defined in terms of systematically collected
      and analyzed data on treatment outcome. By making this the common ground among
      dentists, patients, insurers, and others, it is possible to improve both the
      effectiveness and cost-efficiency of oral health care.

PMID- 10344105
TI  - Practical approach to evidence-based management of caries.
AB  - This paper discusses evidence-based management of dental caries with regard to:
      (1) need to adopt new office methods, (2) potential barriers to change, and (3)
      possible practical solutions to aid change. The need for classifying individual
      patients into low-, medium-, and high-risk caries groups is justified from a
      review of the epidemiological characteristics of caries. In addition, a
      deficiency is identified in traditional caries recording methods since they are
      unable to grade the severity and activity of individual lesions. The traditional
      basis of six-monthly recall examinations for all patients is shown from the
      literature to have no scientific support. It is suggested a three-twelve month
      recall interval be used, depending on a patient's risk group classification. Some
      barriers to change are identified as: (1) the collection of more comprehensive
      history and clinical caries data, (2) the complexity of evidence-based decision
      making, and (3) dentists' difficulty in standardizing decision-making. A new
      pictorial classification for caries severity and activity is described. A
      demonstration decision-support system is presented in terms of assisting
      collection of data, automatic identification of risk factors, patient risk
      classification, and generation of a suggested treatment plan. Evidence-based
      management may result in change of professional manpower levels.

PMID- 10344106
TI  - Faux ethics and the ethical community.

PMID- 10344107
TI  - Professional development.
AB  - The current program of continuing education is unnecessarily restricted by
      outdated conceptions of professionalism and learning; thus it fails to serve the
      needs of dentists today. A new model--professional development--is proposed,
      based on new ideas about what it means to be a professional and what
      professionals learn. The central role of practice is emphasized.

PMID- 10344108
TI  - Inhibition of topoisomerase II alpha subunit de novo synthesis by specific
      antisense oligonucleotides suppresses human glioma T98G cell growth.
AB  - Deoxyribonucleic acid (DNA) topoisomerases are enzymes which resolve topological
      problems in eukaryotic DNA, and may be involved in cell proliferation. The
      involvement of topoisomerase II in cell proliferation was examined in the human
      glioma cell line T98G. The growth rate of T98G cells was suppressed by treatment
      with topoisomerase II antisense oligonucleotides dose-dependently, with
      significant suppression at concentrations greater than of 0.1 mM. The growth rate
      of T98G treated with control oligonucleotide was suppressed at concentrations
      greater than 3.0 mM. The activity of topoisomerase II in T98G cells treated with
      0.5 mM topoisomerase II antisense oligonucleotide was one fourth of that in cells
      treated with control oligonucleotide. When topoisomerase II translation was
      suppressed, the activity of topoisomerase I was increased. These results suggest
      that de novo synthesis of the topoisomerase II protein is required to maintain a
      normal growth rate in cultured T98G cells. These topoisomerases may be
      functionally related, and might provide compensatory mechanisms in the case of
      compromised function.

PMID- 10344109
TI  - Functional prognosis after treatment of spinal dural arteriovenous fistulas.
AB  - Functional prognosis after treatment for spinal dural arteriovenous fistulas
      (SDAVFs) was retrospectively analyzed in 13 consecutive patients aged 38 to 73
      years (mean 57 years) treated during the last 5 years. The duration of symptoms
      before diagnosis ranged from 3 to 72 months (mean 23 months). Neurological
      symptoms were examined before and 6 months after the treatment. Seven patients
      underwent embolization as the initial treatment. In four of six patients, N-butyl
      2-cyanoacrylate (NBCA) embolization achieved complete obliteration of SDAVF. The
      other two patients with incomplete embolization and one embolized with polyvinyl
      alcohol particles underwent subsequent surgical treatment. Six patients were
      treated by direct surgery. Complete disappearance of SDAVF was confirmed in all
      nine patients treated surgically. Improvement of gait and micturition disturbance
      after the treatment was noted in six of 10 and three of six patients,
      respectively. Long duration of symptoms and high grade of neurological symptoms
      were associated with a poor functional outcome. NBCA embolization and surgery are
      curative treatments for SDAVF, but the functional prognosis is not always
      satisfactory. Embolization is the first choice of treatment for SDAVF because it
      is less invasive and relatively safe. However, when complete obliteration is not
      achieved, prompt surgery is recommended because a long duration of symptoms will
      result in a poor functional prognosis.

PMID- 10344111
TI  - Neurovascular decompression for trigeminal neuralgia in elderly patients.
AB  - The operative findings and outcomes of neurovascular decompression for trigeminal
      neuralgia were compared between patients aged 75 years and older (elderly group,
      17 patients) and patients aged under 75 years (nonelderly group, 115 patients).
      There were no statistically significant differences in the operative findings or
      outcomes between the two groups, except in the percentage of patients who had
      been treated with carbamazepine. Neurovascular decompression for trigeminal
      neuralgia can be performed in elderly patients with the same operative results as
      in nonelderly patients. If other treatments (especially carbamazepine treatment)
      prove ineffective, neurovascular decompression should be considered in elderly
      patients before they become too old to undergo surgery. However, neurovascular
      decompression in elderly patients requires great care, as the venous system,
      including the superior petrosal vein, should be preserved and retraction of the
      cerebellum should be avoided whenever possible to maintain correct blood
      circulation in the cerebellum and brainstem.

PMID- 10344110
TI  - Retrolabyrinthine presigmoid transpetrosal approach for selective subtemporal
      amygdalohippocampectomy.
AB  - The retrolabyrinthine presigmoid transpetrosal approach is a modification of the
      subtemporal approach which is suitable for complete amygdalectomy. By drilling
      away the retrolabyrinthine presigmoid petrosal bone, at least 1 cm more space
      below and 1 cm more space medially is obtained than in the subtemporal approach,
      and temporal retraction pressure is diminished when approaching from below.
      Operative results according to the Engel's classification of seizure control, and
      pre- and postoperative Wechsler Adult Intelligence Scale (WAIS), revised WAIS,
      and Wechsler Intelligence Scale for Children scores were measured in 16 patients
      treated by normal or modified subtemporal amygdalohippocampectomy. Postoperative
      follow-up ranged from 8 to 79 months. There has been no morbidity or mortality
      among these 16 patients, and postoperative seizure frequency has been diminished
      to less than 10% of the preoperative level in 15 of the 16. In eight patients,
      seizures have been eliminated totally. Subtemporal amygdalohippocampectomy
      achieved significantly increased performance and full scale intelligence quotient
      within 2 months after surgery, compared to preoperative levels. Subtemporal
      amygdalohippocampectomy is an alternative to the transsylvian approach, but is
      less invasive.

PMID- 10344112
TI  - Heading injury precipitating subdural hematoma associated with arachnoid cysts-
      two case reports.
AB  - A 14-year-old boy and a 11-year-old boy presented with subdural hematomas as
      complications of preexisting arachnoid cysts in the middle cranial fossa,
      manifesting as symptoms of raised intracranial pressure. Both had a history of
      heading the ball in a soccer game about 7 weeks and 2 days before the symptom
      occurred. There was no other head trauma, so these cases could be described as
      "heading injury." Arachnoid cysts in the middle cranial fossa are often
      associated with subdural hematomas. We emphasize that mild trauma such as heading
      of the ball in a soccer game may cause subdural hematomas in patients with
      arachnoid cysts.

PMID- 10344113
TI  - Cervical epidural rhabdomyosarcoma with a leukemia-like presentation in an aged
      patient--case report.
AB  - A 77-year-old female presented with rhabdomyosarcoma manifesting as leukemia-like
      indications. Neuroimagings detected cervical and paravertebral masses.
      Immunohistochemical study of the surgically excised mass lesion from the cervical
      spine established the correct diagnosis. This leukemia-like presentation of
      rhabdomyosarcoma requires a multidisciplinary approach to establish the correct
      diagnosis and treatment.

PMID- 10344114
TI  - Cerebral metastasis of a uterine leiomyosarcoma--case report.
AB  - A 38-year-old female presented with sudden neurological deterioration 6 years
      after an operation and chemotherapy for uterine leiomyosarcoma. An extremely rare
      metastasis of the uterine leiomyosarcoma to the brain was identified and totally
      resected. Whole brain irradiation (50 Gy) was given. A recurrence of the
      metastasis was resected 10 weeks later. She ultimately died of a second
      recurrence. Aggressive surgical management of cerebral metastasis of uterine
      leiomyosarcoma may achieve an improved outcome.

PMID- 10344115
TI  - Cerebral gumma showing spontaneous regression on magnetic resonance imaging study
      -case report.
AB  - A 75-year-old male presented with the complaint of headache. Magnetic resonance
      (MR) imaging demonstrated a low-signal intensity area on both T1- and T2-weighted
      images with ring-like enhancement and adhesion of the dura appearing as dural
      tail sign. Follow-up MR imaging demonstrated spontaneous regression, so the
      preoperative diagnosis was malignant lymphoma. Histological examination revealed
      typical granuloma. Treponema pallidum hemagglutination assay tests of serum and
      cerebrospinal fluid were positive for active syphilis. The enhanced mass totally
      disappeared after 4 months of erythromycin therapy. The final diagnosis was
      cerebral gumma. The incidence of syphilis is increasing, so cerebral gumma should
      be included in the differential diagnosis of hypovascular tumors that involve
      both the parenchyma and dura even in the presence of spontaneous regression.

PMID- 10344116
TI  - Surgical treatment of intractable epilepsy originating from the primary sensory
      area of the hand--case report.
AB  - A 14-year-old right-handed girl presented with intractable epilepsy originating
      from the primary sensory area of the hand, manifesting as sensory partial
      seizures in the left hand with secondary generalization. Neurological examination
      showed no abnormal findings. Magnetic resonance imaging, magnetoencephalography,
      and cortical stimulation using chronic subdural electrodes demonstrated a lesion
      located in the primary sensory cortex of the hand, in which the ictal onset zone
      was identified by 24-hour intracranial electroencephalographic recording.
      Surgical resection of the lesion and multiple subpial transections of the
      adjacent cortices were performed. The histological diagnosis was dysembryoplastic
      neuroepithelial tumor (DNT). She was completely free of seizures without
      permanent sensory deficits postoperatively. DNT located in the primary sensory
      hand area may be resectable without causing postoperative sensory deficits, if
      accurate functional mapping and surgical resection are performed.

PMID- 10344118
TI  - Pediatric brain tumors.

PMID- 10344117
TI  - Spontaneous cerebrospinal fluid leakage detected by magnetic resonance
      cisternography--case report.
AB  - A 49-year-old male with no history of head trauma suffered cerebrospinal fluid
      (CSF) discharge from the left nostril for one month. Coronal computed tomography
      (CT) showed lateral extension of the sphenoid sinus on both sides and CSF
      collection on the left side. CT cisternography could not identify the site of CSF
      leakage. Heavily T2-weighted magnetic resonance (MR) imaging (MR cisternography)
      in the coronal plane clearly delineated a fistulous tract through the sphenoid
      bone into the sphenoid sinus. Patch graft with muscle fragment completely
      relieved the CSF rhinorrhea. Postoperative three-dimensional CT showed the two
      bone defects identified during surgery. Small bony dehiscences in the sphenoid
      bone and lateral extension of the sphenoid sinus predisposed the present patient
      to CSF fistula formation. MR cisternography in the coronal and sagittal planes is
      superior to CT scanning or CT cisternography for detection of the site of active
      CSF leakage.

PMID- 10344119
TI  - What price progress.

PMID- 10344120
TI  - DSSNY's Medicaid lawsuit. The whys & wherefores.

PMID- 10344121
TI  - Patient-friendly financial options.
AB  - Having flexible payment options ensures that patients will have all of the
      motivation and information they need to accept care in your office. The HCCC
      simply offers the chance to make more expensive treatment available to those who
      need or want it. The small cost of using a HCCC program more than pays for itself
      -in fact, it costs less than one-third of what you would spend if you were to
      bill these patients instead. Having consistent financial policies and flexible
      payment options can dramatically increase your office's productivity and
      profitability, while expressing your commitment to customer service and high
      quality dentistry.

PMID- 10344122
TI  - Pulp therapy in the primary dentition.
AB  - Pulp therapy in the primary dentition is an area undergoing continual changes.
      Treatment involves numerous methods and the use of a variety of dental materials.
      This article discusses various techniques and materials used in pulp therapy in
      the primary dentition. It includes a summary of the morphology, indications,
      contraindications, techniques for pulpotomies and pulpectomies, and contemporary
      treatment modalities used in the primary dentition.

PMID- 10344123
TI  - Accessible dental care for children.
AB  - The development of a school-based comprehensive and cost-efficient oral health
      care program requires careful planning centered on the needs expressed by the
      community. Gaining the support and the cooperation of school officials and
      parents creates an environment that has a significantly greater opportunity for
      success. Location, appropriate design of the facility and support from a local
      charitable organization further insure excellent access and expeditious care.

PMID- 10344124
TI  - A dose of implant reality.
AB  - Welcome to the dark side of implant reality: complications, esthetic, prosthetic
      and implant failures, accompanied by personal and patient disappointments.
      Information on the "implant experience" gained personally and through
      communication with colleagues has been distilled into a dosage format to aid in
      reducing the more stressful aspects of implant dentistry.

PMID- 10344126
TI  - Data linking hydrogen peroxide and cancerous lesions is withdrawn.

PMID- 10344125
TI  - Reuse of lead from dental X-rays.

PMID- 10344127
TI  - A friendly dissent.

PMID- 10344128
TI  - Domestic violence: report card revisited.

PMID- 10344129
TI  - Curses, foiled again!

PMID- 10344130
TI  - Arsenic poisoning seen at Duke Hospital, 1965-1998.

PMID- 10344131
TI  - Pesticide poisoning cases in North Carolina, 1990-1993. A retrospective review.

PMID- 10344132
TI  - Center for Child and Family Health-North Carolina. What is it? And why?

PMID- 10344133
TI  - A less than Pacific odyssey: the use of kava.

PMID- 10344134
TI  - Mental stress and coronary disease. The Smart-Heart Study.

PMID- 10344135
TI  - Conjoint report to the North Carolina Medical Society and the North Carolina
      Commission for Health Services.

PMID- 10344136
TI  - A report on my headaches.

PMID- 10344137
TI  - Seizures and Creutzfeldt-Jakob disease. A case report and series review.

PMID- 10344138
TI  - [Management of craniofacial fractures with titanium mini-plate osteosynthesis and
      primary bone transplantation].
AB  - The frontobasal traumatic lesions are often combined with several type of midface
      fractures therefore the authors adopted the craniofacial injury definition. In
      the years 1995-1997, 534 patients with head trauma were operated on by
      maxillofacial surgeon and neurosurgeon of which 35 (6.5%) cases showed
      concomitant combined frontonaso-orbital-skull base involvement. In the complex
      management of the severe craniofacial lesions the cooperative team-work of
      maxillofacial surgeon, neurosurgeon, otolaryngologist and ophthalmologist is
      required. Stabilized midface and the "watertight" dura closure or plasty are
      basically important conditions for the ceasing of cerebrospinal fluid leak. In
      the instance of optic nerve lesion the exploration and decompression within the
      eight hours is mandatory by transcranial-subcranial approach. At their cases
      authors preferred the early, definitive one-stage management with step-by step
      titanium miniplate reconstructive osteosynthesis and primary bone grafting
      correct bony restoration could be achieved. According their experiences of new
      treatment method with definitive one-stage management of complex craniofacial
      injuries they decreased the incidence of postoperative complications, the time of
      hospitalisations obtained optimal functional and cosmetic results.

PMID- 10344139
TI  - [Value of CT-guided biopsy compared to fluoroscopy-guided transthoracic biopsy
      and bronchoscopic sampling in the diagnosis of pulmonary nodules].
AB  - CT-guided histological sampling is nowadays used routinely in the differential
      diagnosis of focal lung diseases with no characteristic morphology. The aim of
      this study was to determine the value of the method. CT-guided core biopsy was
      performed in 25 patients with pulmonary nodules. 16 patients underwent
      bronchoscopy where cytological sampling was also carried out, while 5 patients
      underwent fluoroscopically guided biopsy. The histological diagnosis resulting
      from CT-guided biopsy specimens was compared with the findings from the other
      diagnostic procedures (bronchoscopy or fluoroscopically guided biopsy), with the
      results of surgery and/or chemotherapy and with the follow-up data. The result of
      CT-guided biopsy was true in 20/25 and falls in 5/25 cases. Of the 16/25 patients
      undergoing bronchoscopy, 13/16 gave negative results. In 11/16 cases, the result
      of the CT-guided biopsy was positive. The fluoroscopically guided biopsy was
      negative in 4/5 cases, and in 3/5 of these cases the diagnostic CT-guided
      biopsies proved positive. Our results demonstrate the better diagnostic value of
      CT-guided core biopsy relative to fluoroscopically guided biopsy or bronchoscopic
      sampling in those cases where the size and localization of the nodule make it
      inaccessible with the latter two methods.

PMID- 10344140
TI  - [Presence of antibodies to human herpesvirus type 6 and 7 in Hungarian children].
AB  - Prevalence of antibodies to variants HHV-6A and B as well as HHV-7, the time of
      primary infections are not know in Hungarian children. Therefore, antibodies to
      these viruses were studied in 21 healthy children aged between 6 and 18 months.
      Lymphoid cultures were infected with standard virus strains for indirect
      immunofluorescence. IgM, IgG and high avidity IgG after 8M urea treatment were
      quantified in serial dilutions of sera. It was established that, three of 13 boys
      had low level (1:20) IgG or IgM antibodies to HHV-6A, but all girls were
      negative. With exception of one girl and one boy, all had antibodies to HHV-6B in
      different titres (1:20 to 1:640 by immunofluorescence), in 9 cases only IgM, in
      further 4 cases only low avidity IgG were detected. Children studied gradually
      acquired symptom-free HHV-6B infection between age of 8 and 18 months. Antibodies
      to HHV-7 were found in 3 boys and one girl before their age of 12 months, but the
      majority were infected after that age. Approximately three quarters of children
      acquired either HHV-6B or HHV-7 before age of 18 months. More than half of the
      children were infected with HHV-6B prior to HHV-7. Antibody level to HHV-6B was
      slightly higher in boys, while that to HHV-7 was higher in girls. In Hungary,
      childhood infection with HHV-6A seems to be a very rare event. Epidemiology of
      HHV-6B primary infection is similar to that of industrial countries, while that
      of HHV-7 resembles data of developing world: onset of antibodies occurs 1 or 2
      years earlier than in the industrial nations.

PMID- 10344141
TI  - [Calculated gastric intramucosal pH changes in the early phase of acute
      pancreatitis].
AB  - Based on the literature dysfunction of splanchnic circulation may be assumeol in
      the development of severe acute pancreatitis. Abnormal gut functions investigated
      by routinely used clinical examination is not available. Gastric tonometry
      indirectly gives information about gut function. Authors followed prospectively
      12 patients who suffered from acute pancreatitis. Four patients recovered without
      complications, 4 patients had different complications and 4 patients died.
      Gastric intramucosal pH (pHi) was measured by TRIP NGS catheter and Tonocap
      monitor. Measurements were started at the time of hospitalisation and repeated
      every six hours on the first 3 days. Intramucosal acidosis (pHi < 7.3) could be
      measured independently from aetiology. Gastric pHi showed strong correlation with
      Acute Physiology and Chronic Health Evaluation II. (APACHE II) score (p = 0.02).
      APACHE II scores were significantly higher in-group pHi < 7.2 (13.9 +/- 1.7)
      compared to group pHi > 7.2 (7.33 +/- 1.06) (p = 0.002). 24-hour changes in
      APACHE II scores were significantly greater in the cases of pHi < 7.2 (3.3 +/-
      1.47) versus pHi > 7.2 (-0.6 +/- 0.97) (p = 0.03). Changes of pHi in the early
      phase of acute pancreatitis indicate that splanchnic circulation is already
      involved and the pHi may have a prognostic value.

PMID- 10344142
TI  - [Smart card systems in health care (protection, key-functions, divided data
      bases, applications)].
AB  - Barely more than 15 years have passed since electronic memory cards appeared,
      their popularity has grown rapidly (first of all as a cash-saving device and
      later for other purposes, as well). This is due also to the growing interest
      towards development of the intelligence of information systems for the follow-up
      of patients' health condition and medical care in countries with a highly
      developed health and insurance system (need for the creation of data bases
      divided for individuals) and also to their commitment towards a better control of
      the quality and costs of health care. We can come to the conclusion that the aim
      of research, development and the creation of systems in health informatics is to
      prevent illness and to give a direct informatic support to medical and nursing
      activity carried out in the patients' interests. The smart card and the
      surrounding application systems are certainly the appropriate means for the
      achievement of these aims.

PMID- 10344143
TI  - [The role of inflammation mediators in bronchial asthma and chronic obstructive
      pulmonary disease].
AB  - Bronchial asthma and chronic obstructive pulmonary disease (COPD) are chronic
      inflammatory diseases of the bronchial tree. Some products of eosinophils,
      neutrophils and other cells have been implicated in causing bronchial mucosal
      damage and may play important role in monitoring degree of airway inflammation
      and differentiation between bronchial asthma and COPD. The author described some
      of them.

PMID- 10344144
TI  - [Diagnostic value of osteotropic bone scintigraphy in maxillary sinus diseases].
AB  - The authors described the application of facial bone scintigraphy in 6 patients
      with acute and 47 patients with chronic sinusitis, 4 patients with cyst of
      maxillary sinus, 4 patients with sinus maxillary neoplasm and 4 patients with
      pyocele of frontal sinus. Facial bone scintigraphy was performed by gamma-camera
      Siemens Gammasonics ZLC-750 after intravenous administration of 15 mCi of
      99mTcMDP in anteroposterior projection. The index of accumulation of the tracer
      (JAT) in maxillary sinus region was counted separately in men and in women in the
      reference group. In patients with purulent sinusitis marked JAT was predominated.
      Correlation between JAT and symptoms and rhinological signs has been shown in
      patients with chronic purulent sinusitis. In patients with sinus maxillary
      neoplasm high JAT was predominated.

PMID- 10344145
TI  - [Pleural needle biopsy in the diagnostic standards of pleural diseases in the
      past and today].
AB  - Pleural needle biopsy (PNB) maintained its value in spite of introduction of
      videothoracoscopy. Diagnostic possibilities of PNB using Abrams needle were
      evaluated during 1989-1998 in 114 patients aged 17-82 years. In histological
      examinations of the biopsy specimens were diagnosed: neoplasms--in 47 (41%)
      patients, tuberculosis--in 10 (9%) and chronic nonspecific pleuritis--in
      remaining 57 patients. Data from further course of the disease confirmed
      diagnosis of neoplasms and tuberculosis. Complication of PNB was encountered only
      in 1 patient (pneumothorax). Among 47 patients with malignant infiltration of the
      pleura in the biopsy specimen only in 20 (42%) neoplastic cells were demonstrated
      in cytologic examination of the pleural fluid. PNB remains still useful in the
      diagnosis of causes of pleural diseases. Specificity of this method can be
      enhanced by more precise localization of the pleural lesions using imaging
      technics (USG, CT, MRI). PNB should be more widely performed in the diagnosis of
      pleural diseases of unknown etiology particularly when videothoracoscopy is not
      feasible.

PMID- 10344146
TI  - [Beta-lactam-resistance patterns of some gram-negative rods].
AB  - Antibiotic susceptibility to ampicillin of 290 E. coli, 56 Klebsiella sp. And 167
      P.mirabilis strains was evaluated by the disk diffusion method. Data were
      interpreted according to the NCCLS criteria. 37.9% of E. coli, 85.7% of
      Klebsiella sp. And 65.9% of P. mirabilis strains were resistant to ampicillin. In
      all resistant to ampicillin strains were performed resistance patterns to
      following antibiotics: piperacillin, amoxicillin/clavulanic acid, cefoxitin,
      cefuroxime, ceftazidime, cefotaxime and imipenem. The strains resistant to
      ampicillin were divided into four groups depending on resistance patterns.

PMID- 10344147
TI  - [The influence of nitrates on platelet oxygen metabolism: in vitro studies].
AB  - Our investigations were carried out on human blood platelets obtained from
      persons aged 20-23, free from any systemic diseases. Drugs were incubated with
      blood platelets. Changes of antioxidant enzymes were detected. Glyceryl
      trinitrate increased the activity of Zn Cu-SOD (4.62%) and GPx (275.91%),
      concentration of ATP (13.01%) and the blood platelets aggregations (17.88%).
      Izosorbide dinitrate increased the activity of ZnCu-SOD (19.46%), GPx (150.36%)
      and Cat (15.62%), increased concentration of ATP (23.73%) and blood platelets
      aggregation (3.64%). Both preparats decreased concentration of MDA (Sustonit-
      30.79%, Iso-Mack--35.04%). Gliceryl trinitrate decreased the activity of catalase
      otherwise izosorbide dinitrate increased the activity of this enzyme.

PMID- 10344148
TI  - [The quality of life after chemotherapy in advanced non-small cell lung cancer
      patients].
AB  - The intensity of complains, short survival and great number of patients makes
      many oncologists to apply chemotherapy in advanced non-small cell lung
      cancer/NSCLC/. The achieved median duration of life after chemotherapy was 6 to
      12 month. From the other hand non small cell lung cancer chemotherapy is a big
      burden even to healthy persons. It can worsen the quality of life. That was the
      reason we evaluated the quality of life after chemotherapy in advanced non small
      cell lung cancer patients. Taking into account, that the evaluation of quality of
      life, used in most diseases is useless in advanced NSCLC patients, for
      appreciation the quality of life in these cases the lung cancer symptoms
      scale/LCSS/was adopted. In 110 non small cell lung cancer patients in stage IIIB
      and IV, who received combined chemotherapy by Le Chevalier/Vindesine, Cisplatin,
      Cyclophosphamide, Lomustin/or by Rosell/Mitomycin, Cyclophosphamide,
      Cisplatin/the quality of life was evaluated. In 20-persons control group all
      patients received the symptomatic treatment. In observed group of 110 patients,
      tumor regressions after 4 courses of chemotherapy allowed to resect cancer in 14
      cases, to apply radiotherapy in 42 and to continue chemiotherapy in 23 persons.
      In every person from above mentioned group the quality of life was evaluated on
      the basis of intensity of cancer symptoms, accordingly to LCSS. The intensity of
      cancer symptoms was compared before and after treatment. There were compared; the
      innensity of complains, weakness, appetite, malnutrition, and hematological,
      neurological, performans state as well as respiratory sufficiency, infections,
      cardiac disorders and pain. Apart it, the side effects of applied therapy were
      assessed in 5 degree scale. The level of hemoglobin, the number of leucocytes,
      thrombocytes, bilirubine and transaminases in peripheral blood, hematurie,
      proteinurie, bleedings, appetite, nausea, vomitings, diarrhea, mucosal lesions,
      infections, skin lesions, cardiac lesions, neurological lesions, respiratory
      disorders, allergy, alopecia. It was established that, chemotherapy in the most
      patients improved the performance status and minimized cancer symptoms
      especially, after good response to treatment. After anticancer therapy more
      frequently severe infections and cardiac disorders, independently to results of
      treatment were seen. In non-responders, the cancer symptoms were intensified by
      side effects of antineoplastic-therapy. In this group of patients the severe side
      effects of therapy more frequently were seen.

PMID- 10344150
TI  - [Pharmacological action of paclitaxel].
AB  - Paclitaxel (taxol, Tax) is a novel plant product isolated from the Pacific yew
      (Taxus brevifolia). It has a unique mechanism of action, because it induces very
      stable and dysfunctional microtubules. Paclitaxel has a broad spectrum of
      antineoplastic activity. It has been successfully used in the treatment of
      ovarian cancer, metastatic breast cancer, lung cancer, carcinoma of the head and
      neck, malignant melanoma and other human neoplasms. Tax has response rates of 20
      36% in patients with refractory ovarian cancer. Toxic effects include
      myelosuppresion, hypersensitivity reactions, peripheral neuropathy, cardiac
      disturbances, alopecia. However, studies evaluating the drug still are ongoing
      paclitaxel seems to be one of the most promising antineoplastic agents.

PMID- 10344149
TI  - [The level of soluble forms of interleukin-2 receptor and adhesive molecules ICAM
      1 and VCAM-1 in platelets of multiple sclerosis patients].
AB  - The levels of sIL-2R alpha, sICAM-1, and sVCAM-1 in sera of patients with
      clinically probable multiple sclerosis (ms) during the first relapse were
      assessed. In ms patients the levels of these 3 soluble molecules were
      significantly increased in comparison with the results obtained in controls. The
      results reflected activation of lymphocytes T and enhancement expression of
      adhesion molecules on brain endothelial cells, therefore they could serve
      indirectly as markers of immunological activation in multiple sclerosis. Any of
      the levels of soluble molecules in sera did not correlate with the severity of
      the disease.

PMID- 10344151
TI  - [Leukostasis syndrome in a case of chronic lymphocytic leukemia].
AB  - The leukostasis syndrome is rare complication of leukemias with extremely high
      white cell counts. It occurs most frequently in chronic myelosis or acute
      leukemias and is exceptional in chronic lymphocytic leukemia (CLL). A severe
      leukostasis syndrome was observed in a case of CLL with peripheral lymphocyte
      count of 1,120 G/L. Typical symptoms of respiratory and central nervous system
      were developed (tachypnoe, hypoxia, headache, slurred speech, somnolence and
      confusion). Leukapheresis decreased the lymphocyte count to 305 G/l rapidly and
      reversed the leukostasis syndrome.

PMID- 10344152
TI  - ["Putting on a stake"-type of trauma as a cause of multiple injuries in abdominal
      and thoracic cavities].
AB  - "Pale sink" trauma in 16 years old boy has been described as a cause of multi
      organ injuries.

PMID- 10344153
TI  - [Pleural effusion in cancer patients:pathophysiology, diagnosis and treatment].
AB  - Pleural effusion is a clinical problem considered by internists from the
      diagnostic point of view. Physiology of pleural cavity and its pathophysiology
      are of great interest for clinicians. Diagnostic procedures give the
      possibilities to find a culprit of pleural effusion. Moreover, oncologists seek
      the best treatment procedures to fight against the pleural effusion.

PMID- 10344154
TI  - [The role of bacteria in allergic and pseudoallergic reactions].
AB  - The variety of microbial pathogenic factors and relations between human and
      bacterial cells in allergo-inflammatory diseases are presented. A special
      attention have been paid to sugar-lectin interactions in pseudoallergic
      processes. The role of specific antibodies as modifiers of basophils
      releaseability is considered.

PMID- 10344155
TI  - [Role of oxygen free radicals in the pathogenesis of lung diseases].
AB  - The authors have tried to compose the characteristics of the free radicals and
      their role in the pathogenesis od various diseases. They show up both the ways
      the free radicals appear and the biochemical compounds negating their toxic
      effects. They stress the meaning of the dynamic equilibrium between them, and
      asses its value in the lung cancer pathogenesis. They also quote the examples of
      the medicines, which work towards neutralizing the free radicals.

PMID- 10344157
TI  - [Extrapleural mesothelioma].
AB  - Malignant mesothelioma of the peritoneum, pericardium and tunica vaginalis is a
      rare neoplasm usually associated with exposure to asbestos. The disease is most
      common in males over the age 40 years with sings and symptoms of neoplastic
      disease with or without a palpable abdominal mass, abdominal pain and ascites.
      Diagnosis is often possibly only after direct vision and histologic examination.
      Different types of peritoneal mesothelioma occur in adults and in children. Only
      small proportion of all patients with mesothelioma can be cured surgically. Both
      radiotherapy and standard chemotherapy have only limited usefulness. The optimal
      management malignant mesothelioma continues to be defined.

PMID- 10344156
TI  - [The significance of radioisotopic methods in internal diseases diagnosis].
AB  - The present article is an attempt to show the best diagnostic radioisotopic
      methods which are practically applied in the internal diseases diagnostics. It
      was shown both the most important indications for performing these examinations
      and expected advantages. In particular, it was paid attention to achieved
      progress in the diagnostics of some diseases owing to radioisotopic methods
      application. In addition, a general availability and non-invasity of these
      methods advocates in support of using them.

PMID- 10344158
TI  - [Immunosuppressive treatment and risks of neoplasms].
AB  - The risk of neoplasma depends on the amount of mutagenic factors and the ability
      of immunological system to eliminate neoplasma cells. Immunosuppressive treatment
      administered in hematology, transplantology, nephrology, rheumatology and
      dermatology impairs the function of immunological system. The review of
      literature referring neoplasma epidemiology in the disciplines of medicine,
      mentioned above was made. The incidence of neoplasma in patients undergoing
      immunosuppressive treatment is much higher than in rest of population and depends
      on many factors: primary disease, type of treatment and kind of organ
      transplanted.

PMID- 10344159
TI  - [Hepatitis C: contemporary views on molecular biology of HCV].
AB  - During last years knowledge about HCV virus was growing very fast. Because of
      that some reviews on molecular structure of this virus was presented. They are
      clinically important for diagnosis, prognosis of treatment and possibility of
      production a new antiviral drugs.

PMID- 10344160
TI  - [Vitamin C in medicine: "normal concentration" in serum].
AB  - Vitamin C functions in a human organism have been discussed. Connection with many
      diseases and its systemic deficiency has been emphasized. A review of current
      application of this vitamin in medicine has been made. Problems accompanying the
      use of reference sources of vitamin C "normal concentrations" in blood plasma
      have been characterised. 10 ranges of concentrations given by medical handbooks
      and textbooks have been compared in detail with 15 parallel ranges taken from
      scientific papers, paying attention to their significant discrepancies. Basing on
      source values, performing basic statistical calculations, a reliable mean range
      of vitamin C "normal concentrations" in blood plasma has been obtained: 36.1-79.4
      mumol/l.

PMID- 10344161
TI  - [Glycosilphosphatidylinositol-anchored cell surface protein deficiency in Mexican
      mestizo patients with aplastic anemia].
AB  - The peripheral blood cells of ten patients with biopsy-proven aplastic anemia
      were studied by means of flow-cytometry in order to assess the expression of two
      phosphatidylinositol-anchored surface proteins: CD55/DAF (decay accelerating
      factor) and CD59/MIRL (membrane inhibitor of reactive lysis). An abnormal
      expression was found in five of these ten patients, whereas the "traditional"
      tests for paroxysmal nocturnal hemoglobinuria (PNH) were positive only on two of
      these five individuals. Five of the aplastic patients were treated with anti
      thymocyte globulin and cyclosporin-A and three entered a complete remission; of
      the latter, one had CD55/CD59 deficiencies whereas two did not. Along the study
      period one patient with a hemolytic pattern of PNH was identified. It is
      concluded that CD55 and/or CD59 abnormalities are frequent in Mexican mestizo
      patients with aplastic anemia, that the aplastic presentation of PNH is more
      frequent in Mexico than the hemolytic presentation, that the flow-cytometric
      identification of CPI-anchored proteins is more sensitive than the "traditional"
      PNH tests, and that some patients with PNH-aplasia may respond to intensive
      immunosuppressive treatment. The flow-cytometric identification of GPI-anchored
      cell surface proteins should replace the "traditional" tests in the
      identification of patients with PNH.

PMID- 10344163
TI  - [Atypical biological behavior of alveolar rhabdomyosarcoma in five patients].
AB  - Five cases of alveolar rhabdomyosarcoma with atypical clinical features are
      reported. Three patients showed lymphadenopathy as the first clinical
      manifestation, mimicking a lymphoma or a non identified primary tumor with lymph
      node metastases. One patient presented systemic neoplastic disease and two had
      the primary tumor in atypical locations, such as the mediastinum and
      retroperitoneum. All patients died and in four of them an autopsy was performed.
      The histological diagnosis was confirmed by immunohistochemical studies on four
      cases. The alveolar rhabdomyosarcoma has a poor prognosis and can have a variable
      clinical presentation and morphology, simulating lymphomas, leukemias and
      systemic metastatic disease with an unknown primary neoplasm, such as in the
      cases here in reported.

PMID- 10344162
TI  - [CD-34 expression in elastofibroma. Clinicopathological, histochemical, and
      immunohistochemical study of four cases].
AB  - OBJECTIVE: To explore the immunohistochemistry of elastofibromas and to evaluate
      four elastic strain methods for the histological diagnosis of elastofibroma.
      MATERIAL AND METHODS: Four elastofibromas were obtained from the surgical
      pathology files of the ABC Medical Center. All patients were women whose lesions
      were present in the subescapular region. Immunohistochemistry was performed for
      CD34, actin, desmin, vimentin, S-100 protein and bcl-2 and four elastic stain
      methods were evaluated (Verhoff, Gallego's, Reyes-Mota and Russel-Movat).
      RESULTS: In the four cases there were numerous miofibroblasts
      (vimentin/actin/desmin positive). An unpreviously reported positive CD34
      dendritic cells, were present diffusely in all four cases. Verhoff and Reyes-Mota
      stains remains the most useful methods to reveal the elastic fibers. Russel-Movat
      method may be use to contrast different connective tissue components. CONCLUSION:
      The cell of elastofibromas were originally considered fibroblasts. The presence
      of actin/desmin/vimentin suggests that they are miofibroblasts. We describe for
      the first time, variable numbers of CD34(QBend/10) positive spindle shaped and
      dendritic cells in all elastofibromas. These cells may be a reactive population
      of cells of the "dendritic cell system". There was no immunoreactivity for bcl-2
      in these cells.

PMID- 10344164
TI  - [Treatment of anastomotic leakage following low anterior resection for rectal
      adenocarcinoma].
AB  - BACKGROUND: The most important complication after low anterior resection for
      rectal cancer is the anastomotic leakage. Its frequency ranges between 0%-17%
      and, it's associated mortality ranges between 0%-25%. OBJECTIVE: To analyze the
      treatment results of the above mentioned complication. MATERIAL AND METHODS:
      Between January 1990 and July 1998, 176 patients with rectal cancer underwent low
      anterior resection. 13 (7.3%) of them developed anastomotic leakage. The results
      of the treatment due to, this surgical complication were analyzed. RESULTS: There
      were 9 males and 4 females with a mean age of 64.3 years. Seven of these patients
      received preoperative radiotherapy. The tumor mean size was 5.5 cm. The tumor and
      distance of the anastomoses were located at a mean distance of 8 cm and 5 cm
      respectively, above the anal verge. All patients presented one or more of the
      following symptoms: increase of drainage (n = 10); prolonged ileus and abdominal
      pain (n = 9), fever and leucocytosis (n = 8). The surgical treatments were:
      drainage of abdominal or pelvic cavity (n = 11); loop transversostomy (n = 9);
      end colostomy, and Hartmann's procedure (n = 3). One patient received only
      enteral nutrition. In eight patients, the surgical treatment was performed during
      the first 24 hours of the initial symptoms and in four after 24 hours. The mean
      hospital stay in the former groups was 9.2 days vs 26.8 days of the later group
      (p = 0.02). No mortality was observed. CONCLUSION: The early diagnosis of the
      following symptoms: drainage increase; prolonged ileus; postoperative abdominal
      pain; fever, and leucocytosis after low anterior resection, should guide us to
      the diagnosis of anastomotic leakage and therefore, to initiate surgical
      treatment during the first 24 hours as to avoid major morbidity and mortality.

PMID- 10344165
TI  - [Critical reading for medical residents in main specialties].
AB  - OBJECTIVE: To explore ability for critical reading of clinical research reports
      in groups of residents of four specialties: internal medicine, pediatrics,
      general surgery and gynecology/obstetrics. MATERIAL AND METHODS: A research was
      carried out in medical residents of 12 hospitals of the Instituto Mexicano del
      Seguro Social: 143 of internal medicine, 119 of pediatrics, 74 of general surgery
      and 74 of gynecology/obstetrics. An instrument was built and validated in order
      to explore the critical reading by three domains: interpretation, judgements and
      proposals. RESULTS: No significant effect of years of training on the critical
      reading of clinical research reports was observed. The overall scores were low
      (maximum: 120): internal medicine = 35, pediatrics = 29, general surgery = 24.5
      and gynecology/obstetrics = 25. 116 students (28%) obtained scores below of the
      level expected by chance. CONCLUSIONS: This study suggest that the training is
      not very fruitful in the development of the critical reading ability of clinical
      research reports, a low development of this ability was observed in medical
      residents.

PMID- 10344166
TI  - [Cavernous hemangioma of the tympanic membrane. Otoscopic image].
AB  - Cavernous hemangiomas of the tympanic membrane are extremely rare. Only 9 cases
      have been published in the literature. We describe a case with clinical
      characteristics, otoscopic image and diagnostic studies. Alternatives in
      treatment are discussed and a review of the literature was carried out.

PMID- 10344167
TI  - [Coccidioides immitis: primary infection of the central nervous system. Case
      report and literature review].
AB  - A case of primary coccidiodal meningitis without pulmonary, osseous or dermic
      affection due to Coccidioides immitis in a 27 years old male patient with
      hypertensive brain of one month of evolution, was reported. The patient was
      resident of Northern California, and he was previously healthy. The cerebrospinal
      fluid (CSF) showed a glucose of 22 mg/dL, proteins 62 mg/dL, white blood cells
      100/mm3 (97% PMN, 3% MN). CT SCAN showed bilateral ventricular dilatation.
      Diagnosis of coccidioidal meningitis was made based on antibodies against
      anticoccidioides (IgM 6.8 mg/dL and IgG 4.9 mg/dL, normal < 2 mg/dL) and growth
      of Coccidioides immitis. The chest radiograph was normal and the detection of
      antibodies against human immunodeficiency virus was negative. A VP shunt was
      placed and the patient was treated with intravenous amphotericin B and intratecal
      amphotericin B through on Ommaya reservoir. Even with antifungal treatment the
      patient deteriorated neurologically after an initial transient improvement, he
      died two weeks later in his hometown.

PMID- 10344168
TI  - [Idiopathic ascites associated with hemodialysis. Case report and literature
      review].
AB  - BACKGROUND: Idiopathic dialysis ascites (IDA) is an uncommon disease
      characterized by the absence of a cause that can explain its presentation. CASE
      REPORT: Thirty year old female, with diabetic nephropathy under chronic
      hemodialysis, with massive ascites. Treatment with intensive ultrafiltration was
      non-successful, and we had poor clinical results with consecutive paracentesis.
      The study of ascitic fluid was normal. We discarded cardiovascular, hepatic,
      infectious, neoplastic, and metabolic etiologies and laparoscopy with hepatic and
      peritoneal biopsies were non-diagnostic. Finally, after renal transplantation, a
      rapid decrease of the ascites was observed and the diagnosis of IDA was
      established. DISCUSSION: IDA is a rare entity that does not seem to be related
      with uremia as it is usually present after the start of hemodialysis.
      Malnutrition and hypoproteinemia are frequently associated and could be part of
      the etiology of IDA, which explains the lack of response to ultrafiltration and
      salt restriction, usual treatment for ascites control. The pathophysiological
      explanation of the dramatic response of this patients to renal transplantation is
      unclear.

PMID- 10344169
TI  - [Biology of hematopoietic stem cells].
AB  - All the cells comprising the hemopoietic system are derived from a common
      precursor, the totipotent hemopoietic cell (THC), which, through processes of
      proliferation and differentiation, gives rise to all the mature cells found in
      the blood and lympho-hemopoietic organs. In order that the processes of
      proliferation, survival, apoptosis, and differentiation from THCs to mature cells
      take place, the participation of proteins denoted collectively as cytokines is
      required. Their role is to promote and regulate one or several functions
      (depending on the cell type and stage of development), and to participate in one
      or several stages of cell development of the THCs. By the use of different tissue
      culture techniques, it was concluded that other non-hemopoietic cell types have
      an important role. These cells are those comprising the stroma in the bone
      marrow: fibroblasts, endothelial cells and adipocytes among others. The
      contribution of the stroma lies in the production of cytokines, as well as
      providing sustenance for the THCs. Even when it could seem that cytokines are
      fundamental factors in the regulation of the main functions of the hemopoietic
      cells, two models have been proposed to explain the process of hemopoiesis: the
      deterministic and the stocastic. Both models provide some evidence to support
      their postulates, however, to this date it is not possible, in view of the data,
      to decide which of the models is more accurate without incurring controversy.
      Even though the study of the THCs promotes a great number of questions about the
      basic mechanisms that regulate them, in several laboratories in the world a new
      aspect of research: their use in transplants, using THCs as a substitute for
      whole bone marrow transplant and, still in the initial stages, their use as
      targets for gene therapy for deficiency diseases or even for therapy against
      cancer.

PMID- 10344170
TI  - Venobronchial fistula following and indwelling implanted central venous access
      catheter for chemotherapy delivery. A case report.

PMID- 10344171
TI  - [Nicolau syndrome caused by intramuscular administration of diclofenac].

PMID- 10344172
TI  - Methamphetamine abuse and emergency department utilization.
AB  - Methamphetamine (MAP) abuse continues to increase worldwide, based on morbidity,
      mortality, drug treatment, and epidemiologic studies and surveys. MAP abuse has
      become a significant health care, environmental, and law enforcement problem.
      Acute intoxication often results in agitation, violence, and death. Chronic use
      may lead to infection, heart failure, malnutrition, and permanent psychiatric
      illness. MAP users frequently use the emergency department (ED) for their medical
      care. Over a 6-month period we studied the demographics, type, and frequency of
      medical and traumatic problems in 461 MAP patients presenting to our ED, which
      serves an area noted for high levels of MAP production and consumption.
      Comparison was made to the general ED population to assess use patterns. MAP
      patients were most commonly Caucasian males who lacked health insurance. Compared
      to other ED patients during this time, MAP patients used ambulance transport more
      and were more likely to be admitted to the hospital. There was a significant
      association between trauma and MAP use in this patient population. Our data
      suggest MAP users utilize prehospital and hospital resources at levels higher
      than the average ED population. Based on current trends, we can expect more ED
      visits by MAP users in the future.

PMID- 10344173
TI  - Fracture epidemiology and control in a developmental center.
AB  - During 3.5 years, 182 fractures occurred among 994 residents of a developmental
      center. The fracture rate was 5.2 per 100 person-years (1.7 times greater than
      the rate in the US population). Fracture rate was significantly greater in
      residents with: epilepsy, older age, male gender, white race, independent
      ambulation, osteoporosis, and residence in intermediate care (versus skilled
      nursing) units; it was not affected by severity of mental retardation. Hand and
      foot bones were fractured in 58% of cases. Femur fracture occurred in 13 cases
      (7%). Fracture was caused by a fall in 41 cases (23%); its cause was
      indeterminable in 105 cases (58%). Fractures, occurring without significant
      injury, may be an important cause of preventable disability in this population.
      Control measures are suggested.

PMID- 10344174
TI  - Type 2 diabetes mellitus in Navajo adolescents.
AB  - Diabetes mellitus afflicts over one-fifth of the Navajo population aged over 20
      years, but the prevalence of diabetes in Navajo adolescents is unclear. We
      conducted voluntary testing for diabetes mellitus at two high schools on the
      Navajo reservation to clarify the prevalence as well as to assess the utility of
      a high-school based screening program. Body mass index measurements (BMI), oral
      glucose tolerance tests, and hemoglobin A1C measurements were obtained in
      consenting high school students. Of the 276 students that participated, 234 were
      Navajo. Only one Navajo student (0.4%) had diabetes mellitus, although eight (3%)
      had impaired glucose tolerance or impaired fasting glucose. Participant BMI did
      not differ significantly from nonparticipant BMI. No correlation existed between
      BMI or impaired glucose handling, and significant overlap existed between the
      hemoglobin A1C values of students with impaired glucose handling and students
      without impaired glucose handling. Increased participation in screening programs
      may reveal higher disease prevalence, but high school-based screening is not
      justified by this study, despite the high rates of diabetes mellitus in the
      Navajo population.

PMID- 10344176
TI  - Update on the status of Africanized honey bees in the western states.
AB  - The Africanized honey bee (AHB), Apis mellifera scutella--perhaps better known as
      the "killer bee"--has arrived in the western United States and in southern
      California, following a nearly 50-year north-ward migration across South and
      Central America. First detected near Hidalgo, Texas in October 1993, the bees
      continue to advance 100 to 300 miles per year by colonizing existing hives or
      forming new hives in the wild. Although the AHB's "killer" reputation has been
      greatly exaggerated, the presence of AHBs will increase the chances of people
      being stung.

PMID- 10344175
TI  - Methamphetamine and the expanding complications of amphetamines.
AB  - During the past 10 years, the use of methamphetamine has increased rapidly in the
      West and throughout the United States. Because of this increase, our attention
      has focused on methamphetamine's toxicity. Methamphetamine and related compounds
      generate many of the same toxic effects as cocaine. Because of methamphetamine's
      widespread use, clinicians should be familiar with its medical effects and
      toxicity and with treatment options for acute and long-term effects of
      methamphetamine abuse.

PMID- 10344178
TI  - Description of an ethics curriculum for a medicine residency program.
AB  - This paper examines the attempts to develop and implement an ethics curriculum
      for the Internal Medicine Residency Program at the University of Maryland Medical
      Center. The objectives of the curriculum were to enhance moral reasoning skills
      and to promote humanistic attitudes and behavior among the residents. The diverse
      methodologies used to achieve these objectives included case discussions,
      literature reading, role playing, writing, and videos. These activities occurred
      predominantly within the forum of morning report sessions and ethics ward rounds.
      The author also describes efforts to overcome the initial constraints associated
      with the implementation of this curriculum and concludes by exploring future
      directions for the curriculum.

PMID- 10344177
TI  - Mass envenomations by honey bees and wasps.
AB  - Stinging events involving honey bees and wasps are rare; most deaths or
      clinically important incidents involve very few stings (< 10) and anaphylactic
      shock. However, mass stinging events can prove life-threatening via the toxic
      action of the venom when injected in large amounts. With the advent of the
      Africanized honey bee in the southwestern United States and its potential for
      further spread, mass envenomation incidents will increase. Here we review the
      literature on mass stinging events involving honey bees and wasps (i.e.,
      yellowjackets, wasps, and hornets). Despite different venom composition in the
      two insect groups, both may cause systemic damage and involve hemolysis,
      rhabdomyolysis, and acute renal failure. Victim death may occur due to renal
      failure or cardiac complications. With supportive care, however, most victims
      should be able to survive attacks from hundreds of wasps or approximately 1000
      honey bees.

PMID- 10344179
TI  - The problem of methamphetamine toxicity.

PMID- 10344180
TI  - An "old timer" reflects on the use of the "placebo effect".

PMID- 10344181
TI  - Death of a truck driver: fatal nicotinamide poisoning associated with intravenous
      drug use.

PMID- 10344182
TI  - Biological warfare.

PMID- 10344183
TI  - Varieties of inhibition: manifestations in cognition, event-related potentials
      and aging.
AB  - Inhibition and facilitation are the driving forces of selective attention. Some
      important and still unresolved conceptual issues with respect to facilitation and
      inhibition are: (a) are they separate processes with different neural substrates
      (b) what is their time course and (c) what is their temporal locus: do they
      operate at the level of early sensory, central or response-related selection
      processes? In this introductory article we present a overview of relevant
      experimental paradigms that are also (in part) reflected in the contributions of
      this special volume, and discuss the major behavioral and psychophysiological
      findings from which inhibitory processes have been inferred. The global pattern
      of the results indicates that there are multiple inhibitory systems and processes
      in the central nervous system that may be expressed in many different ways. Our
      overview of paradigms together with the aging-related literature leads us to
      propose a framework for conceptualizing inhibitory processes in terms of three
      distinct but interacting neural systems at the level of anterior and posterior
      cortices and the brain stem.

PMID- 10344184
TI  - Prefrontal cortex regulates inhibition and excitation in distributed neural
      networks.
AB  - Prefrontal cortex provides both inhibitory and excitatory input to distributed
      neural circuits required to support performance in diverse tasks. Neurological
      patients with prefrontal damage are impaired in their ability to inhibit task
      irrelevant information during behavioral tasks requiring performance over a
      delay. The observed enhancements of primary auditory and somatosensory cortical
      responses to task-irrelevant distractors suggest that prefrontal damage disrupts
      inhibitory modulation of inputs to primary sensory cortex, perhaps through
      abnormalities in a prefrontal-thalamic sensory gating system. Failure to suppress
      irrelevant sensory information results in increased neural noise, contributing to
      the deficits in decision making routinely observed in these patients. In addition
      to a critical role in inhibitory control of sensory flow to primary cortical
      regions, and tertiary prefrontal cortex also exerts excitatory input to activity
      in multiple sub-regions of secondary association cortex. Unilateral prefrontal
      damage results in multi-modal decreases in neural activity in posterior
      association cortex in the hemisphere ipsilateral to damage. This excitatory
      modulation is necessary to sustain neural activity during working memory. Thus,
      prefrontal cortex is able to sculpt behavior through parallel inhibitory and
      excitatory regulation of neural activity in distributed neural networks.

PMID- 10344185
TI  - Inhibitory motor control in stop paradigms: review and reinterpretation of neural
      mechanisms.
AB  - What is the neurophysiological locus of inhibition when preparation for a manual
      response is countermanded? This paper evaluates data and models that pertain to
      inhibitory mechanisms operating in stop paradigms. In a model of De Jong, Coles
      and Logan (1995), (Strategies and mechanisms in nonselective and selective
      inhibitory motor control. Journal of Experimental Psychology: Human Perception
      and Performance, 21, 3, 498-511), a mechanism for nonselective inhibition
      operates peripheral to the motor cortex, while a selective mechanism operates at
      a central cortical level. We argue, however, that a peripheral mechanism of
      inhibition is incorrectly inferred from inhibition data available to date.
      Neurophysiological and psychophysiological data suggest that inhibitory processes
      always involve the cortex, and inhibitory effects are exerted upstream from the
      primary motor cortex. The prefrontal cortex and basal ganglia are candidate
      agents of response inhibition, whereas possible sites of inhibition are the
      thalamus and motor cortex.

PMID- 10344186
TI  - Neural aspects of anticipatory behavior.
AB  - Anticipatory behavior reveals itself in the perceptual domain and in the motor
      domain. Expectant attention and motor preparation are characterized by selection,
      aimed at an amelioration of the signal-to-noise ratio in the information to be
      processed. The functional similarity of anticipatory attention and motor
      preparation is reflected in the underlying anatomical substrate. The prefrontal
      cortex, involved in a number of different networks, organizes anticipatory
      behavior in a top-down way by activating cortico-cortical loops and thalamo
      cortical loops to sensory and motor areas. The sensory areas are set to receive
      the impinging stimulus presentation, the motor areas are set to implement and
      execute the different motor programs. Thalamic nuclei are also activated from the
      prefrontal cortex, especially the large association nuclei, the dorsomedial
      nucleus and the pulvinar. In different models of selective attention the
      reticular nucleus of the thalamus has a special role in the distribution of the
      inhibitory control upon the information processing in the "relay" nuclei. It is
      hypothesized that it has the same pivotal position in motor preparation. Although
      the anatomical relations do not allow a direct test of the proposed hypothesis,
      the available psychophysiological evidence does not contradict it.

PMID- 10344188
TI  - ERP components in Go/Nogo tasks and their relation to inhibition.
AB  - In visual Go/Nogo tasks the ERP usually shows a frontal negativity after Nogo
      stimuli ("Nogo-N2"), which possibly reflects an inhibition process. However, the
      Nogo-N2 appears to be very small after auditory stimuli, which is evidence
      against the inhibition hypothesis. In the present study we tested this hypothesis
      by evaluating performance differences between subjects. Assuming that for Ss with
      a high false alarm rate the inhibition process is weakened and/or delayed, they
      should reveal a smaller and/or later Nogo-N2 than Ss with a low false alarm rate.
      This prediction was confirmed, which supports the inhibition hypothesis. However,
      the Nogo-N2 was again much smaller and had a different topography after auditory
      than after visual stimuli despite similar performance in both modalities. This
      modality asymmetry was explained by assuming that the inhibitory mechanism
      reflected in the Nogo-N2 is located at a pre-motor rather than at the motor
      level. In the second part of the study we compared the Nogo-N2 with a similar
      phenomenon, the error negativity (Ne), which occurs in trials with commission
      errors (false alarms). Earlier work suggests that the Ne is a correlate of error
      detection or inhibition. This raises the possibility that the Ne is a delayed
      Nogo-N2, i.e., the Ne may reflect a late and hence unsuccessful attempt to
      inhibit the response after a nontarget. However, the Ne amplitude showed no
      difference between performance groups and stimulus modalities, as found for the
      Nogo-N2. Moreover, Ne and Nogo-N2 had different scalp topographies. This suggests
      that different mechanisms and generators underlie the Ne and the Nogo-N2.

PMID- 10344187
TI  - Cortico-spinal inhibition reflects time but not event preparation: neural
      mechanisms of preparation dissociated by transcranial magnetic stimulation.
AB  - Changes in cortico-spinal excitability related to time and event preparation were
      investigated by transcranial magnetic stimulation (TMS) of the motor cortex
      during the foreperiod of a movement-precuing task. Subjects performed a four
      alternative choice reaction time (RT) task involving a button-press with the
      index or middle finger (FI) of the left or right hand. Advance information about
      the to-be-signaled response was provided by a precue, which preceded the response
      signal by a 1 s foreperiod. The precue either indicated the hand (right or left)
      or FI (index or middle) with which the response would be executed or was
      uninformative. TMS was delivered to the left or right cortical hand area at one
      of five possible times during the foreperiod: -1000, -500, -333, -166 or 0 ms
      prior to the response signal. Surface EMG activity from a prime mover involved in
      flexion of the response FIs (Flexor digitorum superficialis) was used to measure
      the magnitude of the motor evoked potential (MEP) elicited by TMS. Cortico-spinal
      excitability--as assessed by the magnitude of the MEP evoked in the target muscle
      contralateral to the stimulated hemisphere--progressively decreased during the
      foreperiod. The identity of the precued responses, however, had no effect on MEP
      magnitude. These results suggest that preparation to respond at a particular time
      inhibited excitability of the cortico-spinal tract, while advance preparation to
      perform specific responses affected more central structures only.

PMID- 10344189
TI  - Facilitatory and inhibitory effects of masked prime stimuli on motor activation
      and behavioural performance.
AB  - Three experiments investigated the impact of information provided by masked
      stimuli on motor activation. Masked primes were presented prior to target stimuli
      and these primes were identical to the target on compatible trials, identical to
      the target mapped to the opposite response on incompatible trials and task
      irrelevant on neutral trials. A previous study [Eimer, M., & Schlaghecken, F.
      (1998). Effects of masked stimuli on motor activation: Behavioural and
      electrophysiological evidence. Journal of Experimental Psychology: Human
      Perception and Performance, 24, 1737-1747] found performance costs for compatible
      trials and benefits for incompatible trials. Experiment 1 showed that these
      effects are not due to 'perceptual repetition blindness'. Experiments 2 and 3
      obtained evidence for an initial response facilitation triggered by the primes
      that was followed by inhibition. With short intervals between prime presentation
      and response execution, performance benefits were found for compatible trials and
      these turned into costs at longer intervals. It is argued that an early response
      facilitation mediated by direct perceptuo-motor links is subsequently inhibited
      by a central mechanism operating to prevent behaviour from being controlled by
      irrelevant information.

PMID- 10344190
TI  - Task coordination and aging: explorations of executive control processes in the
      task switching paradigm.
AB  - A number of models of cognitive aging suggest that older adults exhibit
      disproportionate performance decrements on tasks which require executive control
      processes. In a series of three studies we examined age-related differences in
      executive control processes and more specifically in the executive control
      processes which underlie performance in the task switching paradigm. Young and
      old adults were presented with rows of digits and were required to indicate
      whether the number of digits (element number task) or the value of the digits
      (digit value task) were greater than or less than five. Switch costs were
      assessed by subtracting the reaction times obtained on non-switch trials from
      trials following a task switch. Several theoretically interesting results were
      obtained. First, large age-related differences in switch costs were found early
      in practice. Second, and most surprising, after relatively modest amounts of
      practice old and young adults switch costs were equivalent. Older adults showed
      large practice effects on switch trials. Third, age-equivalent switch costs were
      maintained across a two month retention period. Finally, the main constraint on
      whether age equivalence was observed in task switching performance was memory
      load. Older adults were unable to capitalize on practice under high memory loads.
      These data are discussed in terms of their implications for both general and
      process specific cognitive aging models.

PMID- 10344191
TI  - Goal neglect and inhibitory limitations: dissociable causes of interference
      effects in conflict situations.
AB  - Interference effects on task performance in conflict situations might reflect
      real limitations in inhibitory capabilities or failures to fully or consistently
      utilize such capabilities in executive control of task performance. We propose
      that useful clues regarding the actual cause of interference effects may be
      obtained from examination of their robustness within and between experimental
      conditions. We illustrate this approach for two major types of interference
      effects that have commonly been attributed to fundamental inhibitory limitations:
      Stroop-type interference and residual switch costs. We present results that
      indicate that these effects may not be unavoidable consequences of fundamental
      inhibitory limitations but may stem from goal neglect, i.e., failures to fully or
      effectively deploy inhibitory capabilities. These results indicate that, in
      addition to mean performance levels, variability of task performance may provide
      a valuable source of evidence regarding the actual cause of performance
      limitations or deficits in conflict situations.

PMID- 10344192
TI  - Protein prenylation in plants: old friends and new targets.

PMID- 10344193
TI  - Molecular characterization of a plant mitochondrial chaperone GrpE.
AB  - Escherichia coli DnaK (Hsp70) cooperates with DnaJ and GrpE in its essential role
      as a molecular chaperone. Function of mitochondrial Hsp70 (mHsp70) in protein
      folding and organellar import in eukaryotes is critically dependent on GrpE. We
      cloned two genes from tobacco (Nicotiana tabacum) BY2 cells based on peptide
      sequences from a purified protein. The predicted amino acid sequences of both
      clones resembled that of GrpE from E. coli and its homologues from eukaryotes,
      and a cDNA clone from Arabidopsis thaliana. One gene (Type 1) encoded a deduced
      protein that was identical to the purified protein while the other (Type 2)
      encoded a deduced protein that has 80% sequence identity to Type 1. Both tobacco
      and Arabidopsis thaliana GrpE homologues bound to DnaK and ATP inhibited this
      binding. The tobacco GrpE homologue contained a typical N-terminal mitochondrial
      target presequence of 64 residues and the presequence directed the green
      fluorescent protein to tobacco mitochondria. The tobacco GrpE homologue also
      associated with mHsp70 when reintroduced into BY2 protoplasts, and this
      association was disrupted by ATP. A three-dimensional structure for the tobacco
      GrpE homologue was modeled based on the X-ray structure of E. coli GrpE complexed
      with DnaK. The modeled structure has the same overall structure as E. coli GrpE.
      We propose that the tobacco GrpE homologue interacts with mHsp70 in a manner
      analogous to E. coli GrpE with DnaK and designate it as tobacco mitochondrial
      GrpE (NtmGrpE).

PMID- 10344194
TI  - Isolation and molecular characterization of gibberellin-regulated H1 and H2B
      histone cDNAs in the leaf of the gibberellin-deficient tomato.
AB  - After differential screening we isolated cDNA clones encoding a histone H1 (leH1)
      and three variants of histone H2B (leH2B-1, -2 and -3) from the gibberellin (GA)
      deficient mutant of tomato (gib-1). The deduced polypeptide of leH1 is 271 amino
      acids long and exhibits the typical tripartite structure of histones H1. The full
      length cDNA clone leH2B-1 encodes for a protein of 142 amino residues and shows
      the tripartite organization of histones H2B. The histones leH1 and leH2B, which
      show no tissue specificity, are developmentally expressed in the leaf. The mRNA
      accumulation was higher in organs which contain meristematic tissue and/or which
      have a high proportion of actively cycling cells. In the leaf of the gib-1 mutant
      we demonstrated GA-enhanced histone leH1 and leH2B expression which was not
      observed in the wild type. GAs of the early-13-hydroxylated pathway (GA1 and GA3)
      caused most enhanced transcription compared to GAs of the early-non-hydroxylation
      pathway (GA4 and GA9). Application of GA to the mutant increased histone
      expression that could correlate with enhanced DNA replication in leaf tissue.
      Increased chromosome replication may indicate that there is a higher rate of cell
      division and/or increase of endopolyploidy which both may be dependent on cell
      elongation induced by GAs.

PMID- 10344195
TI  - Delta7-sterol-C5-desaturase: molecular characterization and functional expression
      of wild-type and mutant alleles.
AB  - An Arabidopsis thaliana recessive monogenic mutant (ste1-1) presenting a
      deficiency of the delta7-sterol-C5(6)-desaturase step in the sterol pathway has
      been reported previously [12]. To further characterize ste1-1, Arabidopsis,
      Nicotiana tabacum and Homo sapiens cDNAs encoding delta7-sterol-C5(6)-desaturases
      were isolated and identified on the basis of their ability to restore ergosterol
      synthesis in erg3, a yeast null mutant whose gene encoding the delta7-sterol
      C5(6)-desaturase was disrupted. Overexpression of the Arabidopsis cDNA driven by
      a 35S promoter in transgenic ste1-1 plants led to full complementation of the
      mutant. This result demonstrates that STE1 was the impaired component in the
      desaturation system. Four independent reverse transcriptions of ste1-1 RNA
      followed by polymerase chain reactions (RT-PCRs), yielded a single product.
      Alignment of the wild-type ORF with the RT-PCR derived ste1-1 ORF revealed a
      single amino acid substitution: Thr-114 in the wild-type is changed to Ile in
      ste1-1. Expression in erg3 resulted in a 6-fold lowered efficiency of the ste1-1
      ORF in complementing the yeast biosynthetic pathway when compared to the wild
      type ORF. The presence of this mutation in the mutant ste1-1 genomic sequence
      (and no additional modification between ste1-1 and wild-type genes) demonstrates
      that the change of the Thr-114 to Ile is necessary and sufficient to create the
      leaky allele ste1-1. The occurrence of a hydroxylated amino acid (Thr or Ser) at
      the position corresponding to Thr-114 in the five delta7-sterol-C5(6)-desaturases
      identified so far suggests that this amino acid is important for normal enzymatic
      function.

PMID- 10344197
TI  - Analysis of programmed cell death in wheat endosperm reveals differences in
      endosperm development between cereals.
AB  - Although maize endosperm undergoes programmed cell death during its development,
      it is not known whether this developmental feature is common to cereals or
      whether it arose inadvertently from the selection process that resulted in the
      enlarged endosperm of modern maize. Examination of wheat endosperm during its
      development revealed that this tissue undergoes a programmed cell death that
      shares features with the maize program but differs in some aspects of its
      execution. Cell death initiated and progressed stochastically in wheat endosperm
      in contrast to maize where cell death initiates within the upper central
      endosperm and expands outward. After a peak of ethylene production during early
      development, wheat endosperm DNA underwent internucleosomal fragmentation that
      was detectable from mid to late development. The developmental onset and
      progression of DNA degradation was regulated by the level of ethylene production
      and perception. These observations suggest that programmed cell death of the
      endosperm and regulation of this program by ethylene is not unique to maize but
      that differences in the execution of the program appear to exist among cereals.

PMID- 10344198
TI  - Analysis of Arabidopsis genome sequence reveals a large new gene family in
      plants.
AB  - A detailed analysis of the currently available Arabidopsis thaliana genomic
      sequence has revealed the presence of a large number of open reading frames with
      homology to the stigmatic self-incompatibility (S) genes of Papaver rhoeas. The
      products of these potential genes are all predicted to be relatively small,
      basic, secreted proteins with similar predicted secondary structures. We have
      named these potential genes SPH (S-protein homologues). Their presence appears to
      have been largely missed by the prediction methods currently used on the genomic
      sequence. Equivalent homologues could not be detected in the human, microbial,
      Drosophila or C. elegans genomic databases, suggesting a function specific to
      plants. Preliminary RT-PCR analysis indicates that at least two members of the
      family (SPH1, SPH8) are expressed, with expression being greatest in floral
      tissues. The gene family may total more than 100 members, and its discovery not
      only illustrates the importance of the genome sequencing efforts, but also
      indicates the extent of information which remains hidden after the initial trawl
      for potential genes.

PMID- 10344196
TI  - Regulation of the chitinase gene expression in suspension-cultured rice cells by
      N-acetylchitooligosaccharides: differences in the signal transduction pathways
      leading to the activation of elicitor-responsive genes.
AB  - Expression patterns of chitinase transcripts induced by N
      acetylchitooligosaccharide elicitor were analyzed by northern blot hybridization
      in order to reveal a signal transduction pathway leading to the activation of
      class I chitinase genes (Cht-1 and Cht-3), which may play an important role in
      producing N-acetylchitooligosaccharide elicitor. The transcription level of both
      genes was enhanced in response to N-acetylchitooligosaccharides larger than
      pentaose at subnanomolar concentrations. These structure and dose dependencies
      were consistent not only with those for a 75 kDa high-affinity binding protein
      for N-acetylchitooligosaccharide elicitor in the plasma membrane, but also with
      other series of cellular responses including phytoalexin production and the
      expression of elicitor-responsive genes (EL2, EL3). Therefore, the elicitor
      signal to evoke these cellular responses including the activation of the
      chitinase genes could be common and transmitted into cells through the 75 kDa
      protein. However, the signal transduction pathway for the activation of the
      chitinase gene appeared to diverge from those for the other elicitor-responsive
      genes shortly after the signal perception. It was shown that the induction of
      chitinase expression by N-acetylchitooligosaccharide would require protein
      phosphorylation, but not de novo protein synthesis. The oxidative burst was
      demonstrated not to be necessary for transcriptional induction of the all four
      elicitor-responsive genes (Cht, PAL, EL2, EL3) by N-acetylchitooligosaccharide.

PMID- 10344199
TI  - Differential expression of two spermidine synthase genes during early fruit
      development and in vegetative tissues of pea.
AB  - Two cDNAs from young pea fruits coding for functional spermidine synthases (EC
      2.5.1.16) were isolated. The corresponding genes were named psSPDSYN1 and
      psSPDSYN2. Both cDNAs complemented spe3delta gene when introduced into the Y480
      strain of Saccharomyces cerevisiae, which is a null mutant for the spermidine
      synthase gene. psSPDSYN1 and psSPDSYN2 are regulated differentially. psSPDSYN1 is
      up-regulated early after fruit set whereas psSPDSYN2 is expressed later.
      Spermidine synthase activity was detected in pea ovaries, and correlates with the
      pattern of expression of psSPDSYN1. In the pea plant, psSPDSYN1 is highly
      expressed in actively growing tissues, whereas the highest level of psSPDSYN2
      mRNA was detected in fully elongated stem.

PMID- 10344200
TI  - Involvement of a maize proline-rich protein in secondary cell wall formation as
      deduced from its specific mRNA localization.
AB  - A clone encoding a proline-rich protein (ZmPRP) has been obtained from maize root
      by differential screening of a maturing elongation root cDNA library. The amino
      acid sequence deduced from the full-length cDNA contains a putative signal
      peptide and a highly repetitive sequence containing the PEPK motif, indicating
      that the ZmPRP mRNA may code for a cell wall protein. The PEPK repeat is also
      found in a previously reported wheat sequence but differs from the repeated
      sequences found in hydroxyproline-rich glycoproteins (HRGP) and in dicot proline
      rich proteins (PRP). In the maize genome, the ZmPRP protein is encoded by a
      single gene that is expressed in maturing regions of the root, in the hypocotyl
      and in the pericarp. In these organs, the ZmPRP mRNA accumulates in the xylem and
      surrounding cells, and in the epidermis. No ZmPRP mRNA was found in the phloem.
      The pattern of mRNA accumulation is very similar to the one observed for genes
      coding for proteins involved in lignin biosynthesis and, like most cell wall
      proteins, ZmPRP synthesis is also induced by wounding. These data support the
      hypothesis that ZmPRP is a member of a new class of fibrous proteins involved in
      the secondary cell wall formation in monocot species.

PMID- 10344201
TI  - Heterologous expression in Saccharomyces cerevisiae of an Arabidopsis thaliana
      cDNA encoding mevalonate diphosphate decarboxylase.
AB  - Sequence comparison with the mevalonate diphosphate decarboxylase (MVD) amino
      acid sequence of Saccharomyces cerevisiae identified an EST clone corresponding
      to a cDNA that may encode Arabidopsis thaliana MVD (AtMVD1). This enzyme
      catalyses the synthesis of isopentenyl diphosphate, the building block of sterol
      and isoprenoid biosynthesis, and uses mevalonate diphosphate as a substrate.
      Sequencing of the full-length cDNA was performed. The predicted amino acid
      sequence presents about 55% identity with the yeast, human and rat MVDs. The
      sequence of the genomic region of A. thaliana MVD was also obtained and Southern
      blot analysis on genomic DNA showed that A. thaliana could have at least one
      homologous MVD gene. In order to allow heterologous expression in S. cerevisiae,
      the MVD open reading frame (ORF) was then cloned under the control of the yeast
      PMA1 strong promoter. When expressed in yeast, the A. thaliana cDNA complemented
      both the thermosensitive MN19-34 strain deficient in MVD, and the lethal
      phenotype of an ERG19 deleted strain. However, the wild-type sterol content was
      not fully restored suggesting that the A. thaliana MVD activity may not be
      optimal in yeast. A two-hybrid assay was also performed to evaluate homodimer
      formation of the A. thaliana MVD and heterodimer formation between the plant and
      yeast heterologous enzymes.

PMID- 10344202
TI  - Homology modelling of the core domain of the endogenous lectin comitin:
      structural basis for its mannose-binding specificity.
AB  - The N-terminal core domain of comitin from the slime mold Dictyostelium
      discoideum has been modelled from the X-ray coordinates of the monocot mannose
      binding lectin from snowdrop (Galanthus nivalis). Docking experiments performed
      on the three-dimensional model showed that two of the three mannose-binding sites
      of the comitin monomer are functional. They are located at both ends of the
      comitin dimer whereas the actin-interacting region occurs in the central hinge
      region where both monomers are non covalently associated. This distribution is
      fully consistent with the bifunctional character of comitin which is believed to
      link the Golgi vesicles exhibiting mannosylated membrane glycans to the actin
      cytoskeleton in the cell.

PMID- 10344203
TI  - Selection of Arabidopsis mutants overexpressing genes driven by the promoter of
      an auxin-inducible glutathione S-transferase gene.
AB  - Transgenic arabidopsis plants were isolated that contained a T-DNA construct in
      which the promoter of an auxin-inducible glutathione S-transferase (GST) gene
      from tobacco was fused to the kanamycin resistance (nptII) as well as to the beta
      glucuronidase (gusA) reporter gene. Subsequently, seeds were treated with EMS to
      obtain mutants in which both reporter gene fusions were up-regulated. Northern
      analysis showed that the mRNA level of a related, endogenous auxin-inducible GST
      gene of Arabidopsis was increased in some of these mutants as well. Two of the
      gup (GST up-regulated) mutants were characterized in more detail and roughly
      mapped. Both had epinastic cotyledons and leaves, a phenotype that turned out to
      be linked to the gup mutation.

PMID- 10344204
TI  - Characterization of NtCDPK1, a calcium-dependent protein kinase gene in Nicotiana
      tabacum, and the activity of its encoded protein.
AB  - We have isolated a cDNA encoding a calcium-dependent protein kinase (CDPK) in
      Nicotiana tabacum, which we designated NtCDPK1. The deduced amino acid sequence
      of NtCDPK1 suggests that this protein contains the kinase domain at the amino
      terminus and the autoregulatory and calmodulin-like domains at the carboxy
      terminus. NtCDPK1 is highly homologous to DcCPK1, a CDPK of carrot, showing 76.5%
      amino acid sequence identity. NtCDPK1 transcripts are present in roots, stems and
      flowers, but are almost undetectable in leaves. In leaves, NtCDPK1 mRNA
      accumulation is stimulated by phytohormones (ABA, GA and cytokinin), Ca2+, methyl
      jasmonate, wounding, fungal elicitors, chitosan, and NaCl. The recombinant full
      length NtCDPK1 protein is catalytically active and highly stimulated by Ca2+. A
      truncated recombinant NtCDPK1 which lacks the C-terminal calmodulin-homologous
      domain also undergoes autophosphorylation, but the kinase activity is not
      stimulated by Ca2+. Phosphoamino acid analysis showed that NtCDPK1 phosphorylates
      serine and threonine residues. Finally, a 60 kDa protein which matches the
      expected size of NtCDPK1 was immunodetected in the membrane fraction by an
      antiserum reacting with NtCDPK1. Immunoprecipitation and in vitro phosphorylation
      using the antiserum also generated a 60 kDa phosphoprotein only in the membrane
      fraction. These results suggest that NtCDPK1 is associated with the membrane.

PMID- 10344205
TI  - The arabinose kinase, ARA1, gene of Arabidopsis is a novel member of the
      galactose kinase gene family.
AB  - The arabinose-sensitive ara1-1 mutant of Arabidopsis is deficient in arabinose
      kinase activity. A candidate for the ARA1 gene. ISA1, has been previously
      identified through the Arabidopsis genome sequencing initiative. Here we
      demonstrate that (1) the ARA1 gene coincides with ISA1 in a positional cloning
      strategy; (2) there are mutations in the ISA1 gene in both the ara1-1 mutant and
      an intragenic suppressor mutant; and (3) the ara1-1 and suppressor mutant
      phenotypes can be complemented by the expression of the ISA1 cDNA in transgenic
      plants. Together these observations confirm that ISA1 is the ARA1 gene. ARA1 is a
      member of the galactose kinase family of genes and represents a new substrate
      specificity among this and other families of sugar kinases. A second gene with
      similarities to members of the galactose kinase gene family has been identified
      in the EST database. A 1.8 kb cDNA contained an open reading-frame predicted to
      encode a 496 amino acid polypeptide. The GAL1 cDNA was expressed in a galK mutant
      of Escherichia coli and in vitro assays of extracts of the strain expressing GAL1
      confirmed that the cDNA encodes a galactose kinase activity. Both GAL1 and ARA1
      cross-hybridise at low stringency to other sequences suggesting the presence of
      additional members of the galactose kinase gene family.

PMID- 10344206
TI  - PTK, the chloroplast RNA polymerase-associated protein kinase from mustard
      (Sinapis alba), mediates redox control of plastid in vitro transcription.
AB  - The major RNA polymerase from mustard chloroplasts is a multi-subunit enzyme
      consisting of core components and associated factors. Among the latter is a
      heterotrimeric factor named PTK (plastid transcription kinase) because of its
      serine/threonine-type protein kinase activity. PTK activity itself depends on its
      phosphorylation state. In addition, we show that it responds to glutathione but
      not to other redox-reactive reagents that were tested, and both glutathione and
      phosphorylation act antagonistically. Using a homologous in vitro system, we find
      that PTK selectively phosphorylates subunit(s) of plastid RNA polymerase and is
      involved in determining the level of faithful transcription from the chloroplast
      psbA promoter. Together, these results establish a role for phosphorylation and
      redox state in the regulation of plastid gene expression.

PMID- 10344207
TI  - Signals controlling the expression of cytosolic ascorbate peroxidase during
      pathogen-induced programmed cell death in tobacco.
AB  - In plants ascorbate peroxidase (APX) is an important H2O2-detoxifying enzyme. The
      expression of APX is rapidly induced in response to stresses that result in the
      accumulation of reactive oxygen species (ROS). We have recently reported that the
      steady-state level of transcripts encoding cytosolic APX (cAPX) is dramatically
      induced during the hypersensitive response (HR) of tobacco plants infected with
      tobacco mosaic virus (TMV). Because cAPX expression is closely linked to the
      production of ROS in plant cells, studying the regulation cAPX mRNA can reveal
      some of the signal transduction events associated with ROS metabolism during the
      HR. Analysis of cAPX mRNA induction during the HR suggested that the expression
      of cAPX is under the control of the HR signal transduction pathway. The
      activation of cAPX expression followed signaling events such as changes in
      protein phosphorylation and induction of ion fluxes. Expression of cAPX was
      suppressed under conditions of low oxygen pressure, and could only be mimicked by
      enhancing the intracellular generation of ROS. Interestingly, salicylic acid
      (SA), which is thought to be involved in ROS metabolism during the HR, did not
      affect the induction of cAPX mRNA during TMV-induced HR. Using cAPX expression as
      a marker for the production of ROS, it is suggested that SA may not be involved
      in the formation of ROS during the HR of tobacco to TMV, and that ROS may not be
      involved in the induction of the pathogenesis-related protein, PR-1, during this
      process.

PMID- 10344208
TI  - Molecular structure and chromosomal localization of major repetitive DNA families
      in the chickpea (Cicer arietinum L.) genome.
AB  - Three major repetitive DNA sequences were isolated from a genomic library of
      chickpea (Cicer arietinum L.) and characterized with respect to their genomic
      organization and chromosomal localization. All repetitive elements are genus
      specific and mostly located in the AT-rich pericentric heterochromatin. Two
      families are organized as satellite DNAs with repeat lengths of 162-168 bp
      (CaSat1) and 100 bp (CaSat2). CaSat1 is mainly located adjacent to the 18S rDNA
      clusters on chromosomes A and B, whereas CaSat2 is a major component of the
      pericentric heterochromatin on all chromosomes. The high abundance of these
      sequences in closely related species of the genus Cicer as well as their
      variation in structure and copy number among the annual species provide useful
      tools for taxonomic studies. The retrotransposon-like sequences of the third
      family (CaRep) display a more complex organization and are represented by two
      independent sets of clones (CaRep1 and CaRep2) with homology to different regions
      of Ty3-gypsy-like retrotransposons. They are distributed over the pericentric
      heterochromatin block on all chromosomes with extensions into euchromatic
      regions. Conserved structures within different crossability groups of related
      Cicer species suggest independent amplification or transposition events during
      the evolution of the annual species of the genus.

PMID- 10344209
TI  - Characterization of matrix attachment sites in the upstream region of a tobacco
      chitinase gene.
AB  - The nuclear matrix is thought to partition the genome into functional and
      structural loop domains, and it has been implicated in several cellular
      processes, such as the replication and transcription of DNA and the processing of
      RNA. Therefore, the analysis of scaffold/matrix-associated DNA regions (S/MARs)
      might enhance our understanding of the functional roles of the higher-order
      organization of chromatin. In this study, the upstream region between positions 
      3320 and -1095 of the basic class I chitinase gene, CHN50, was shown to have
      specific affinity for the tobacco nuclear scaffold. Detailed analysis of nuclear
      scaffold-DNA binding in vitro revealed that two regions (positions -3320 to -2621
      and -2221 to -1371) bound specifically to the nuclear scaffold. These S/MAR
      elements, designated S/M I and S/M II, are A+T-rich sequences with 75% and 74%
      A+T residues, respectively, and may include a number of sequence motifs that have
      frequently been found in other S/MARs. Moreover, S/M II contains a curved DNA
      sequence with anomalous mobility on polyacrylamide gels. A circular permutation
      assay revealed that the center of this curved region was located between
      positions -1767 and -1759. The possible functions and structural features of the
      S/MAR elements in the upstream region of CHN50 are discussed.

PMID- 10344210
TI  - A transcript encoding translation initiation factor eIF-5A is stored in
      unfertilized egg cells of maize.
AB  - Differential screening of cDNA libraries of unfertilized egg cells and in vitro
      zygotes of maize resulted in the isolation of more than 50 different genes whose
      expression is up- or down-regulated after in vitro fertilization (IVF). Among
      these genes, we identified a cDNA encoding the eukaryotic translation initiation
      factor eIF-5A. This highly conserved factor is thought to be necessary for
      selective mRNA stabilization and translation. It is also the only known protein
      that contains the unusual amino acid hypusine which is required for biological
      activity. High transcript amounts are stored in the egg cell, which is, in terms
      of metabolism, relatively inactive. Upon fertilization transcript amounts
      decrease, in contrast to metabolically inactive embryos in which the transcript
      cannot be detected and transcript levels increase upon germination. The
      expression pattern during the first embryonic cell cycle is also different from
      that observed during the somatic cell cycle: egg cells in the G0 phase contain
      high transcript levels, while arrested suspension cells contain few transcripts.
      In the somatic cell cycle, eif-5A is strongly induced during the G1 phase and
      transcripts are continuously degraded during the S, G2 and M phases until new
      induction during the G1 phase of the next cycle. eif-5A, a member of a small gene
      family in maize, is expressed in most maize tissues investigated. Based on our
      results, we suggest that the unfertilized egg cell of maize, although relatively
      inactive regarding its metabolism, is prepared for selective mRNA translation
      that is quickly triggered after fertilization. We also suggest that the
      regulation of eif-5A in the first embryonic cell cycle is different from the
      somatic cell cycle.

PMID- 10344211
TI  - Modulation of the differentiation status of cultured prostatic smooth muscle
      cells by an alpha1-adrenergic receptor antagonist.
AB  - BACKGROUND: Prostatic stromal cells are believed to be a key factor in the
      pathogenesis of benign prostatic hyperplasia (BPH). The effect of phenylephrine,
      an alpha1-adrenergic receptor agonist, and doxazosin, an alpha1-adrenergic
      receptor-specific antagonist, on the expression of smooth muscle myosin-heavy
      chain isotypes SM-1 and SM-2 was tested in an in vitro model of prostatic smooth
      muscle cells (SMC). METHODS: Primary prostatic stromal cells, grown in SMC
      specific medium, were treated with 10 microM of phenylephrine or 1 microM of
      doxazosin or a combination of both. SM-2 to SM-1 mRNA ratios and expression of
      alpha1-adrenergic receptor subtypes were determined by means of reverse
      transcriptase polymerase chain reaction (RT-PCR) techniques. Cell growth was
      measured by a cell viability assay. RESULTS: SM-1 mRNA and only very low levels
      of SM-2 mRNA were detected in prostatic SMC cultures grown for 4 days in a serum
      free base medium. After 6 days of treatment, SM-2 expression increased, highest
      in the doxazosin-treated cultures. In comparison to unstimulated cells, a
      statistically significant 10-fold increase of the SM-2:SM-1 ratio was measured in
      doxazosin-treated cultures. Analysis of alpha1-adrenergic receptor subtype
      expression revealed the presence of mRNAs of subtypes 1d and 1b mRNAs. Subtype 1a
      was not expressed. Phenylephrine and doxazosin showed no significant effect on
      cell proliferation and on alpha1d-adrenergic receptor expression. CONCLUSIONS:
      SMC can differentiate from a proliferative to a contractile phenotype, which is
      accompanied by increased expression of isotope 2 of smooth muscle myosin heavy
      chain. Our results suggest that doxazosin seems to have a long-term effect on the
      differentiation of prostatic stromal cells, indicating that alpha1-adrenergic
      receptor antagonists do not act solely on SMC contractility.

PMID- 10344212
TI  - Effect of finasteride and/or terazosin on serum PSA: results of VA Cooperative
      Study #359.
AB  - BACKGROUND: Medical management of benign prostatic hyperplasia (BPH) giving rise
      to lower urinary tract symptomatology (LUTS) has emerged as the mainstay for
      first-line therapy. Prostate-specific antigen (PSA) is the most important method
      of detecting prostate carcinoma. The effect of finasteride on PSA has been widely
      reported. Little data exist with respect to alpha-adrenergic blocking therapy in
      men treated for BPH. In the present investigation we set out to evaluate the
      effect of these two forms of therapy. METHODS: Patients enrolled in the VA
      Cooperative Study #359 trial were evaluated. This study evaluated men with
      moderate LUTS owing to BPH in four treatment groups: placebo (P), finasteride
      (F), terazosin (T), and combination of finasteride plus terazosin (C). Men were
      recruited at 31 VA medical centers and had a baseline in 52-week PSA
      determination at the respective sites. RESULTS: There was no significant
      difference in baseline PSA between four groups (mean range, 2.0-2.9 ng/ml).
      Statistically significant reduction in PSA levels was observed at 52 weeks in the
      F and C arms (P < 0.001), whereas significant increases were observed in the T
      and P arms (P < 0.01). Additionally, there was no significant difference in PSA
      response between the T and P arms. Thirty percent of men in the C or F arms had
      more than 40-60% reduction of PSA. In contrast, the majority of men on T or P had
      less than 40% change in PSA. Only 35% of men on F or C had the expected 40-60%
      reduction in PSA level. CONCLUSIONS: These data demonstrate no clinically
      significant effect of T on PSA level. The heterogeneity of PSA response to F may
      make monitoring patients for the development of prostate cancer problematic.

PMID- 10344213
TI  - Unique morphological aspects of the rat ventral prostate gland revealed by
      vascular corrosion casting.
AB  - BACKGROUND: There is growing interest as to the potential role of the prostatic
      vascular system in mediating the effects of androgenic steroids on growth control
      of the prostate. Here we describe the use of a vascular corrosion casting
      technique that enables the visual characterization of the vascular system of the
      rat ventral prostate and the description of some unique morphological features of
      the mature rat prostate gland that were never previously observed. METHODS:
      Anesthetized adult male Sprague-Dawley rats were vascularly perfused with a
      fixative solution and then with a catalyzed methacrylate-based casting solution
      that was allowed to polymerize in situ. Ventral prostate glands were dissected
      from these rats and the tissues were subsequently dissolved in a corrosive
      solution, leaving residual vascular casts. The casts were then examined by
      scanning electron microscopy for pertinent morphological features. RESULTS:
      Vascular corrosion casts of individual lobes of the mature rat ventral prostate
      revealed a complex vascular structure that entered into the prostate near the
      base of the bladder. The morphological correspondence of the prostatic
      vasculature to the previously described ductal organization of the prostate was
      readily apparent. Examination of the entire vascular complex (under low-power
      scanning electron microscopy) revealed three differing surface features of the
      tissue and suggested that the glandular elements of the ventral prostate were
      directionally oriented towards a single surface (the anterior-lateral surface).
      An opposing face (posterior-medial) of the tissue demonstrated some unique spiral
      vessels, suggesting the need for a potential stretch-compensation mechanism at
      the prostate surface immediately adjacent to the bladder. CONCLUSIONS: Vascular
      casts of the rat ventral prostate gland reveal the obvious ductal organization of
      the prostatic parenchyma and demonstrate that these ducts are directionally
      oriented so that the glands of the prostate (at the distal tips of the ducts)
      uniformly lie near the anterior-lateral surface of the tissue. Unusual spiral
      arterioles found proximal to the bladder surface suggest that the rat ventral
      prostate gland has acquired the means to adapt to an anatomical position adjacent
      to a tissue (bladder) that acutely varies in size during the micturition cycle.

PMID- 10344214
TI  - Osteomimetic properties of prostate cancer cells: a hypothesis supporting the
      predilection of prostate cancer metastasis and growth in the bone environment.
AB  - BACKGROUND: Unlike most other malignancies, prostate cancer metastasizes
      preferentially to the skeleton and elicits osteoblastic reactions. METHODS: We
      present a hypothesis, based upon results obtained from our laboratory and others,
      on the nature of progression of prostate cancer cells and their predilection to
      growth and metastasis in the bone microenvironment. We propose the hypothesis
      that osseous metastatic prostate cancer cells must be osteomimetic in order to
      metastasize, grow, and survive in the skeleton. The reciprocal interaction
      between prostate cancer and bone stromal growth factors, including basic
      fibroblast growth factor (bFGF), hepatocyte growth factor/scatter factor
      (HGF/SF), and especially the insulin growth factor (IGF) axis initiates bone
      tropism, and is enhanced by prostate secreted endothelin-1 (ET-1) and urokinase
      type plasminogen activator (uPA). Growth factors and peptides that have
      differentiating activity, such as transforming growth factor beta (TGF-beta),
      parathyroid hormone-related protein (PTH-rp), and the bone morphogenetic proteins
      (BMPs), can shift local homeostasis to produce the characteristic blastic
      phenotype, via interaction with prostate-secreted human kalikrein 2 (hK2), and
      prostate-specific antigen (PSA). This proposal asserts that altering the
      expression of certain critical transcription factors, such as Cbfa and MSX in
      prostate cancer cells, which presumably are under the inductive influences of
      prostate or bone stromal cells, can confer profiles of gene expression, such as
      osteopontin (OPN), osteocalcin (OC), and bone sialoprotein (BSP), that mimic that
      of osteoblasts. RESULTS AND CONCLUSIONS: Elucidation of common proteins,
      presumably driven by the same promoters, expressed by both prostate cancer and
      bone stromal cells, could result in the development of novel preventive and
      therapeutic strategies for the treatment of prostate cancer skeletal metastasis.
      Agents developed using these strategies could have the potential advantage of
      interfering with growth and enhancing apoptosis in both prostate cancer and bone
      stromal compartments. The selective application of gene therapy strategy, driven
      by tissue-specific and tumor-restricted promoters for the safe delivery and
      expression of therapeutic genes in experimental models of prostate cancer
      metastasis, is discussed.

PMID- 10344215
TI  - Links between genetic and environmental factors and prostate cancer risk.
AB  - BACKGROUND: Genetic polymorphisms and expression of steroid receptors may explain
      why some individuals are more at risk of developing prostate cancer. Some risk
      factors often discussed are androgen stimulation, and vitamin A and D deficiency.
      Long CAG-repeats in exon 1 of the androgen receptor (AR) gene on the X chromosome
      seem to have a protective role against androgen overstimulation. Likewise, long
      vitamin D receptor alleles in the poly-A tract may prevent vitamin D stimulation.
      METHODS: Blood samples from 59 Swedish patients with sporadic prostate cancers,
      59 with hereditary prostate cancer, and 34 Japanese prostate cancer patients were
      compared with benign controls. Tissue specimens from 37 Swedish and 23 Japanese
      prostate cancer patients with matching blood samples were investigated by
      immunohistochemical techniques. RESULTS: The number of CAG-repeats was identical
      in sporadic and hereditary prostate cancer patients, but the repeats were
      significantly shorter than in benign controls. Benign Japanese controls were
      similar to Swedish controls, but Japanese prostate cancers had longer repeats
      than did controls. Both the vitamin D and A receptor staining was stronger in
      Japanese than in Swedish prostate cancer specimens. Prostate cancer occurs
      approximately 5 years later in Japanese compared with Swedish men. CONCLUSIONS:
      Varying lengths of CAG-repeats of the androgen receptor cannot fully explain
      racial differences in clinical prostate cancer incidence. A larger content of
      vitamin A and D receptors may be linked to a delayed onset of clinical prostate
      cancer in Japanese men.

PMID- 10344216
TI  - Inhibition of caspase activity does not prevent the signaling phase of apoptosis
      in prostate cancer cells.
AB  - BACKGROUND: Caspases are a family of cysteine proteases capable of
      characteristically cleaving after an aspartic acid residue. Various members of
      the caspase family (e.g., caspases 8 and 9) have been implicated as critical
      initiators in the signaling phase, while others (e.g., caspases 3, 6, and 7) have
      been implicated in the effector or execution phase of apoptosis. Thapsigargin
      (TG) is capable of inducing cell proliferation-independent apoptosis of prostate
      cancer cells. This study was undertaken to determine if caspase inhibition can
      prevent TG- or 5-fluorodeoxyuridine (5-FrdU)-induced apoptosis in prostate cancer
      cells. METHODS: Caspase activity was evaluated by Western blot analysis of the
      cleavage of retinoblastoma (Rb) protein, a caspase substrate during TG-induced
      death of prostate cancer cells. In addition, hydrolysis of caspase-specific
      fluorescent peptide substrates was assayed in lysates from TG-treated cells.
      Clonogenic survival assays were performed following treatment of rat AT3 and
      human TSU-Pr1 prostate cancer cell lines with TG and 5-FrdU in the presence and
      absence of peptide caspase inhibitors. AT3.1 cells transfected with the crmA
      gene, encoding a viral protein with caspase-inhibitory activity, were also tested
      for clonogenic survival following TG and 5-FrdU exposure. RESULTS: During
      treatment with TG, Rb is first dephosphorylated and then proteolytically cleaved
      into 100-kDa and 40-kDa forms, indicative of caspase activity. A 6-8-fold
      increase in class II (i.e., caspases 3, 7, and 10) hydrolysis of the caspase
      substrate Z-DEVD-AFC was observed after 24 hr of TG or 5-FrdU. AT3 cells
      expressing crmA (i.e., an inhibitor of caspases 1, 4, and 8) were not protected
      from apoptosis induced by TG or 5-FrdU. The caspase inhibitors Z-DEVD-fmk (i.e.,
      an inhibitor of caspases 3, 7, and 10) and Z-VAD-fmk (i.e., a general caspase
      inhibitor) were also unable to protect TSU and AT3 cells from apoptosis induced
      by TG or 5-FrdU. CONCLUSIONS: Caspase activation may play a role in the
      downstream effector phase of the apoptotic cascade; however, in this study,
      caspase inhibition did not prevent the signaling phase of apoptosis induced by
      two agents with distinct mechanisms of cytotoxicity, TG or 5-FrdU. These results
      suggest that caspase inhibition by recently described endogenous caspase
      inhibitors should not lead to development of resistance to TG. A strategy for
      targeting TG's unique cytotoxicity to metastatic prostate cancer cells is
      currently under development.

PMID- 10344217
TI  - No evidence for a role of BRCA1 or BRCA2 mutations in Ashkenazi Jewish families
      with hereditary prostate cancer.
AB  - BACKGROUND: Two genes responsible for hereditary breast cancer (BRCA1 and BRCA2)
      have been identified, and predisposing mutations identified. Several studies have
      provided evidence that germline mutations in BRCA1 and BRCA2 confer an increased
      risk of prostate cancer. Based on these findings, one might expect to find an
      increased frequency of mutations in these genes in family clusters of prostate
      cancer. The Ashkenazi Jewish population is unique in that it has an approximate
      2% incidence of specific founder BRCA1 and BRCA2 mutations (i.e., 185delAG and
      5382insC in BRCA1, and 6174delT in BRCA2). METHODS: To address the question of
      whether or not mutations in either of these genes were overrepresented in
      prostate cancer families, we searched for these mutations in germline DNA samples
      collected from affected and unaffected members of 18 Ashkenazi Jewish families,
      each having at least 3 first-degree relatives affected with prostate cancer.
      RESULTS: No mutations were found in the BRCA1 gene in any of the 47 individuals
      tested. One individual possessed a BRCA2 mutation (6174delT). This individual was
      unaffected at the time of analysis, but had an affected paternal uncle, and an
      affected first cousin, neither of whom harbored the mutant gene. CONCLUSIONS: In
      this sample of Ashkenazi prostate cancer families, the frequency of founder BRCA1
      and BRCA2 mutations was not elevated, suggesting that such mutations will account
      for only a small, perhaps minimal, fraction of familial prostate cancer.

PMID- 10344218
TI  - Transforming growth factor-beta in benign and malignant prostate.
AB  - BACKGROUND: The present review summarizes the cellular action of TGF-beta in
      benign and malignant growth of the prostate. METHODS: TGF-beta is a pleiotropic
      growth factor. It plays an important role in the regulation of growth and
      differentiation in many cells. In benign prostatic epithelia, its action is
      mediated through a paracrine mechanism. It inhibits proliferation and induces
      apoptosis in prostatic epithelia. It provides a mechanism to maintain epithelial
      homeostasis in the prostate. In prostatic stroma, its continual action leads to
      smooth muscle differentiation. This effect of TGF-beta may regulate the
      development of prostatic smooth muscle nodules in benign prostatic hyperplasia.
      RESULTS: As prostatic epithelial cells undergo malignant transformation, two
      major events occur regarding TGF-beta action. These include the loss of
      expression of functional TGF-beta receptors and overproduction of TGF-beta in
      malignant cells. The loss of expression of functional TGF-beta receptors provides
      a growth advantage to cancer cells over their benign counterparts. The
      overproduction of TGF-beta by cancer cells has a multitude of adverse
      consequences. TGF-beta can promote extracellular matrix production, induce
      angiogenesis, and inhibit host immune function. The biological consequence of
      these activities is an enhanced tumorigenicity in prostate cancer. Results of our
      recent studies with a rat prostate cancer model suggest that the
      immunosuppressive effect of TGF-beta seems to be the primary cause of tumor
      progression. This is because, if these cancer cells were engineered to reduce the
      production of TGF-beta, tumor growth was inhibited in syngeneic hosts but not in
      immune compromised hosts. CONCLUSIONS: Our future research should take advantage
      of this knowledge to devise therapeutic strategies aimed at eradicating prostate
      cancer.

PMID- 10344219
TI  - GM-CSF as a systemic adjuvant in a phase II prostate cancer vaccine trial.
AB  - BACKGROUND: Recombinant human granulocyte-macrophage colony-stimulating factor
      (GM-CSF; Leukine [sargramostim], Immunex Corp., Seattle, WA) was administered to
      a subgroup of 44 patients in a phase II clinical trial for prostate cancer using
      DC pulsed with HLA-A2-specific prostate-specific membrane antigen (PSMA)
      peptides. Our purpose was to determine if GM-CSF caused any enhancement of
      patients' immune responses, including enhancement of clinical response to the DC
      peptide treatment. This report compares the clinical responses to DC-peptide
      infusions with and without systemic GM-CSF treatment. METHODS: GM-CSF was
      administered by subcutaneous injection at a dose of 75 microg/m2/day for 7 days
      with each of six infusion cycles. Prefilled syringes were supplied to the
      patients for self-administration. RESULTS: One complete and 8 partial responders
      were identified among 44 patients who received GM-CSF, as compared to 2 complete
      and 17 partial responders among 51 patients who did not receive GM-CSF. For
      patients who received GM-CSF and were tested by delayed-type hypersensitivity
      (DTH) skin test, 3 cases of improved immune response were identified, compared to
      5 cases of improvement in patients who did not receive GM-CSF. The main GM-CSF
      side effects reported were local reactions at the site of injection, fatigue,
      pain, and fever. Most reported side effects were of mild severity, with some
      cases of moderate severity leading to discontinuation of GM-CSF. CONCLUSIONS: Our
      results suggest GM-CSF as employed in this trial did not detectably enhance
      clinical response to DC-peptide infusions, or significantly enhance the measured
      immune response.

PMID- 10344220
TI  - Monoclonal antibody to prostate cancer nuclear matrix protein (PRO:4-216)
      recognizes nucleophosmin/B23.
AB  - BACKGROUND: The nuclear protein B23, nucleophosmin, is an RNA-associated
      nucleolar phosphoprotein reported to be more abundant in malignant and growing
      cells than in normal nondividing cells. We examined the levels of B23 in fresh
      human prostate tissue and in five human prostate cancer cell lines with
      monoclonal antibodies (mAb) to nucleophosmin (alpha-B23) and to human prostate
      cancer nuclear matrix proteins (PRO:4-216). METHODS: mAb PRO:4-216 and mAb alpha
      B23 were used for protein level detection. Nuclear matrix proteins (NMPs) were
      prepared from prostate tumor and five human prostate cancer cell lines: LNCaP,
      TSU, DU145, PC-3, and PPC-1. The NMPs were run on one-dimensional and two
      dimensional (2D) electrophoresis gels for Western blot analysis with the two
      mAbs. Histologic sections from paraffin-embedded normal and cancerous prostate
      tissue were stained immunohistochemically with both mAbs. RESULTS: PRO:4-216 and
      B23 mAbs identified a 40-kD protein (pI approximately 5.0) by Western blot
      analysis in the human prostate cancer cell lines and on two-dimensional blots of
      human prostate cancer NMPs. Immunohistochemical staining demonstrated large
      punctate nuclear dots in most cancer nuclei, while staining of normal tissue was
      less intense or absent. Predominant reactivity was of epithelial nuclei, with
      some minor reactivity of stromal nuclei. Red blood cells (RBCs) and white blood
      cells (WBCs) were routinely negative. CONCLUSIONS: PRO:4-216, previously
      characterized as recognizing prostate cancer nuclear matrix proteins, recognized
      B23/nucleophosmin. PRO:4-216 and alpha-B23 showed intense immunohistochemical
      staining of B23/nucleophosmin in cancer nuclei compared to adjacent normal cells
      in paraffin-embedded prostate tissue. This preliminary study showed the potential
      of B23 as a tumor marker for human prostate cancer.

PMID- 10344221
TI  - Prevention of prostate-related cancers in Lobund-Wistar rats.
AB  - BACKGROUND: Since prostate cancer (PC) development involves a combination of
      genetic predisposition and promotional mechanisms, especially the metabolic
      conversion of testosterone to 5alpha dihydrotestosterone (DHT) by 5alpha
      reductase, how do mechanisms in man relate to prostate-seminal vesicle (P-SV)
      tumor development in Lobund-Wistar (L-W) rats? The disease in man and in L-W rats
      shares developmental mechanisms and characteristics to the extent that prevention
      of P-SV tumors in L-W rats could be predictive of similar results in man. The
      epidemiology of PC in man and P-SV tumors in L-W rats indicates that both are
      hormone-related diseases based on genetic predisposition, high production of
      androgens (which are activated to DHT by 5alpha reductase), and early development
      of androgen-dependent and metastasizing late androgen-independent stages of
      adenocarcinomas, all after long latency periods. METHODS: L-W rats at risk of
      developing spontaneous or induced P-SV tumors were subjected to putative
      antitumor agents or procedures. These included dietary restriction, testosterone
      ablation, soybean-derived isoflavones, antiangiogenic linomide, tamoxifen, and a
      vitamin D analogue. RESULTS: L-W rats subjected to 1) early onset of dietary
      restriction manifested suppression of spontaneous and induced development of P-SV
      tumors; 2) testosterone-ablation by nonesterified DHT (NE-DHT) suppressed early
      onset of induced P-SV tumors and to a lesser extent late onset of spontaneous
      tumors; 3) diets containing soy protein isolate (high isoflavones) manifested
      marginal suppressive effects against induced P-SV tumors, but in 12-month-old
      rats, the development of spontaneous tumors was reduced in incidence; 4) early
      administrations of antiangiogenic linomide suppressed development of induced P-SV
      tumors and of transplanted prostate adenocarcinoma III (PA-III) tumors, but
      linomide had little antitumor effect against large advanced stage tumors; and 5)
      tamoxifen and vitamin D analogue suppressed development of P-SV tumors. Results
      in conditions 1-3 were negative when tested against PA-III tumors. CONCLUSIONS:
      Developing stages of P-SV tumors were prevented in L-W rats with autochthonous
      spontaneous and induced tumors, but most of the agents tested were of no
      therapeutic benefit against advanced-stage and transplanted PA-III tumors.
      However, early administrations of antiangiogenic linomide suppressed early growth
      of induced and transplanted PA-III tumors.

PMID- 10344222
TI  - Origin and racial distribution of glandular tissue in the anterior compartment of
      the prostate: an autopsy study.
AB  - BACKGROUND: We previously reported that African-American men (AAM) have tumors
      located in the anterior compartment more often than American Caucasian men (ACM)
      in radical prostatectomy specimens [Tiguert et al.: Prostate 37:230-235, 1998].
      In this study, we evaluated the distribution of glandular tissue in the anterior
      compartment of normal prostate specimens, with specific attention to the anterior
      fibromuscular area, in order to determine the frequency and origin of glands in
      this region. METHODS: We analyzed 94 prostatectomy specimens obtained from
      autopsied men between ages 20-30 years. Men in this age group were chosen because
      few pathological changes are present in the prostate in this age range. The
      anterior compartment of the prostate was defined by drawing a horizontal line,
      anterior to the urethra, through the midpoint of the anterior-posterior diameter
      parallel to the rectal surface. In each slide, anterior compartment prostatic
      tissue was identified and characterized as peripheral zone, transitional zone,
      and fibromuscular stroma. Any glandular elements identified in the anterior
      prostatic compartment were recorded in terms of zonal origin and number of
      glands. RESULTS: Prostates from 76 AAM and 18 ACM were examined. Overall,
      prostatic glands were absent in the anterior compartment in only 2% of cases.
      Glands were derived from the peripheral zone only in 6 (6.5%) cases, peripheral
      zone and transitional zone in 53 (56.5%), transitional zone only in 13 (14%), and
      anterior fibromuscular stroma in 20 (21%). There was no difference between the
      two races in terms of the number of glands present. The morphology of the
      peripheral zone was not different between the two races, with glands from the
      peripheral zone joining in the anterior compartment in 33% of AAM compared to 56%
      of ACM (P = 0.123). CONCLUSIONS: Anterior prostatic glands can arise from the
      peripheral zone, transitional zone, or fibromuscular stroma. There are no racial
      differences in terms of the number of anterior glandular elements, and also in
      the architecture of the peripheral zone.

PMID- 10344223
TI  - Predictors for biopsy outcome in the European Randomized Study of Screening for
      Prostate Cancer (Rotterdam region).
AB  - BACKGROUND: In the European Randomized Study of Screening for Prostate Cancer
      (ERSPC, Rotterdam region), men aged 55-74 years are screened for prostate cancer
      by prostate-specific antigen (PSA) sampling, digital rectal examination (DRE),
      and transrectal ultrasound investigation (TRUS). All men with a PSA > or =4 ng/ml
      and/or a suspicious DRE and/or a suspicious TRUS are biopsied. METHODS: Logistic
      regression analysis was applied to derive a predictive index that equals the
      chance to find prostate cancer in a biopsy given the outcomes of the screening
      tests. This model was used to assess the number of cancers that could have been
      detected if all men had been biopsied (extrapolation). Furthermore, the model was
      used to study the possibilities for improvement of the current screening
      protocol. RESULTS: PSA was the dominant predictor for prostate cancer in a
      biopsy, followed by prostate volume, DRE, and TRUS result. It is assessed that
      69% (95% CI, 52-86%) of cancers that could be identified if all men were biopsied
      are currently detected. Application of the same methods to screening data
      obtained in Goteborg (the Swedish ERSPC partner) yielded almost identical
      results. It was found that, in the Rotterdam protocol, a considerable number of
      men were biopsied according to the screening protocol with an assessed lower
      chance to have prostate cancer than men who were not biopsied according to the
      protocol. CONCLUSIONS: The chance to detect prostate cancer in a biopsy can be
      modeled quite accurately as a function of serum PSA, prostate volume, DRE, and
      TRUS results. Important improvements in the screening protocol can be achieved by
      the application of the predictive index.

PMID- 10344224
TI  - The real final exam.

PMID- 10344225
TI  - Inhibition of agonist-induced vasocontraction and impairment of endothelium
      dependent vasorelaxation by extract of motorcycle exhaust particles in vitro.
AB  - The in vitro effects of motorcycle exhaust particulate extract (MEPE) on blood
      vessels were studied in thoracic aorta isolated from Wistar rat. The MEPE relaxed
      the phenylephrine-precontracted aorta with an EC50 value of 0.05 +/- 0.004 mg/ml.
      This relaxing effect of MEPE persisted in endothelium-denuded aorta, suggesting
      that the relaxation induced by MEPE is endothelium-independent. The phenylephrine
      induced vasocontraction and inositol 1,4,5-triphosphate formation were inhibited
      concentration dependently in aorta pretreated with MEPE. However, the high-K+
      induced vasocontraction and the Ca2+ sensitivity of the contractile proteins were
      not significantly affected by MEPE. In addition to the inhibitory effects on
      agonist-induced contraction, the vasorelaxing effects both of acetylcholine and
      of sodium nitroprusside were impaired by MEPE. The inhibitory effects of MEPE on
      acetylcholine and sodium nitroprusside, but not phenylephrine, were reversed by
      cotreatment with superoxide dismutase. These results showed that the MEPE, added
      in vitro, inhibited the phenylephrine-induced, but not depolarization-induced,
      vasocontraction of aorta. The MEPE also impaired the vasorelaxation induced by
      acetylcholine in a superoxide anion-dependent manner.

PMID- 10344226
TI  - Evaluation of sensory irritation of delta3-carene and turpentine, and acceptable
      levels of monoterpenes in occupational and indoor environment.
AB  - The standard mouse bioassay was used for obtaining the RD50 (i.e., the
      concentration that causes a 50% decrease in respiratory frequency) and for
      estimating the irritation properties of d-delta3-carene (i.e., (+)-delta3-carene)
      and commercial turpentine. The chemicals studied possess mainly sensory
      irritation properties similar to the previously studied monoterpenes, pinenes.
      The irritation potency of d-delta3-carene (RD50 = 1345 ppm) was almost equal to
      that of d-pinenes. Thus, d-delta3-carene was about four times more potent as a
      sensory irritant than I-beta-pinene, whereas the difference with I-alpha-pinene
      was more marked; as a sensory irritant, I-alpha-pinene is almost inactive. Based
      on sensory irritation potency and physicochemical and structural properties of
      pinenes and delta3-carene, the potency of a closely related monoterpene,
      limonene, is discussed. For commercial turpentine, a mixture of monoterpenes
      (mainly d-delta3-carene, I-beta-pinene, alpha-pinenes, and limonenes), the RD50
      (1173 ppm) was the same order of magnitude as those of d-pinenes and d-delta3
      carene. Apparently, d-monoterpenes are responsible for the sensory irritation
      caused by turpentine. In the wood industry and in the indoor air of nonindustrial
      environments, monoterpenes are thought to be one of the causative agents for
      irritation symptoms. The occupational exposure limit (OEL) of turpentine (100 ppm
      in Finland and the United States) is also used for individual monoterpenes,
      excluding limonene. Using results from this and our previous study, proposed OELs
      and recommended indoor levels (RILs) for selected monoterpenes and turpentine
      were determined based on their RD50 values. According to our studies, the present
      OEL of turpentine (100 ppm; 560 mg/m3) in Finland and in the United States seems
      to be suitable only for I-pinenes. For d-monoterpenes and turpentine, an OEL
      about three times lower is suggested. Our results show that recommended indoor
      levels (RILs) for monoterpenes are high compared to the concentrations measured
      indoors in nonindustrial environments. Thus, it is very unlikely that
      monoterpenes alone can cause irritation symptoms in homes or offices under normal
      conditions.

PMID- 10344227
TI  - Amplified proinflammatory cytokine expression and toxicity in mice coexposed to
      lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol).
AB  - A single oral exposure to the trichothecene vomitoxin (VT) has been previously
      shown in the mouse to increase splenic mRNA levels for several cytokines in as
      little as 2 h. Since one underlying mechanism for these effects likely involves
      superinduction of transiently expressed cytokine genes, VT may also potentially
      amplify cytokine responses to inflammatory stimuli. To test this possibility, the
      effects of oral VT exposure on tumor necrosis factor-alpha (TNF-alpha),
      interleukin-6 (IL-6), and IL-1beta expression were measured in mice that were
      intraperitoneally injected with lipopolysaccharide (LPS), a prototypic
      inflammatory agent. As anticipated, VT alone at 1, 5, and 25 mg/kg body weight
      increased splenic mRNA expression of all three cytokines after 3 h in a dose
      response fashion. LPS injection at 1 and 5 mg/kg body weight also induced
      proinflammatory cytokine mRNA expression. There was a synergistic increase in TNF
      alpha splenic mRNA levels in mice treated with both VT and LPS as compared to
      mice treated with either toxin alone, whereas the effects were additive for IL-6
      and IL-1beta mRNA expression. When relative mRNA levels were examined over a 12-h
      period in mice given LPS (1 mg/kg) and/or VT (5 mg/kg), significant enhancement
      was observed up to 6, 12, and 3 h for TNF-alpha, IL-6, and IL-1beta,
      respectively. When plasma cytokine concentrations were measured, TNF-alpha was
      found to peak at 1 h and was significantly increased at 1, 3, and 6 h if mice
      were given LPS and VT, whereas LPS or VT alone caused much smaller increases in
      plasma TNF-alpha Plasma IL-6 peaked at 3 h in LPS, VT, and LPS/VT groups, with
      the combined toxin group exhibiting additive effects. Plasma IL-1beta was not
      detectable. The potential for VT and LPS to enhance toxicity was examined in a
      subsequent study. Mortality was not observed up to 72 h in mice exposed to a
      single oral dose of VT at 25 mg/kg body weight or to an intraperitoneal dose of
      LPS at 1 or 5 mg/kg body weight; however, all mice receiving VT and either LPS
      dose became moribund in less than 40 h. The principal histologic lesions in the
      moribund mice treated with VT and LPS were marked cell death and loss in thymus,
      Peyer's patches, spleen, and bone marrow. In all of these lymphoid tissues,
      treatment-induced cell death had characteristic histologic features of apoptosis
      causing lymphoid atrophy. These results suggest that LPS exposure may markedly
      increase the toxicity of trichothecenes and that the immune system was a primary
      target of these interactive effects.

PMID- 10344228
TI  - Pharmacologic effects of cocoa and rye flour extracts on isolated guinea pig
      trachea.
AB  - Confectionery workers are exposed to a wide variety of organic dusts and
      aerosols. Previous studies with workers in a confectionery plant working with
      cocoa and rye flour indicate that these workers are at risk of developing adverse
      respiratory symptoms and lung function impairment. The effects of cocoa and rye
      flour extract on isolated guinea pig tracheal smooth muscle were studied using
      water-soluble extracts from cocoa and rye flour obtained from the studied
      confectionery plant. Dose-related contractions of nonsensitized guinea pig
      tracheal rings were demonstrated using both cocoa and rye flour extracts.
      Pharmacologic studies were performed by pretreating guinea pig tracheal tissue
      with drugs known to modulate smooth muscle contraction: atropine, indomethacin,
      pyrilamine, nordihydroguaiaretic acid (NDGA), acivicin, bromophenacyl bromide
      (BPB), 3,4,5-trimethoxybenzoate 8-(N,N-diethylamino)octyl ester (TMB8),
      captopril, and capsaicin. Constrictor effects of the dust extracts were inhibited
      by these agents, the pattern of which depended on the dust extract. Atropine
      consistently and significantly reduced the contractile effects of both extracts.
      These observations suggest a release of parasympathetic mediators by these
      extracts or more directly an interaction with muscarinic receptors. In addition,
      the constrictor effect of cocoa and rye flour extracts was significantly, but
      only partially, reduced by indomethacin, pyrilamine, BPB, and TMB8. Acivicin also
      partially decreased the constrictor effect of cocoa extract. Pretreatment of
      tracheal tissue with capsaicin also decreased the constrictor effects of high
      concentrations of cocoa and rye flour extracts. Data suggest that cocoa and rye
      flour extracts cause a dose-related constriction of airway smooth muscle by non
      immunological mechanisms involving cholinergic pathways and airway mediators such
      as histamine and the products of the arachadonic acid cascade. This effect is not
      dependent on the presensitization of guinea pigs.

PMID- 10344229
TI  - Genotypes and phenotypes.
AB  - Within the framework of a pilot project on the analysis of the mouse proteome, we
      investigated C57BL/6 mice (Mus musculus), a standard inbred strain of the mouse,
      starting with the analysis of brain, liver and heart proteins. Tissue extraction
      and the separation of proteins were performed with techniques offering a maximum
      of resolution. Proteins separated were analyzed by mass spectrometry. Gene
      protein identification was performed by genetic analyses using the European
      Collaborative Interspecific Backcross (EUCIB), established from the two mouse
      species Mus musculus and Mus spretus. On the basis of protein polymorphisms we
      mapped hundreds of genes on the mouse chromosomes, allowing us new insight into
      the relationship between genotype and phenotype of proteins. In particular, the
      results showed that protein modifications can be genetically determined,
      therefore representing their own class of protein phenotypes. In this context,
      results are discussed suggesting that phenotypes of single protein species may
      result from several genes. Accordingly, proteins are considered as polygenic
      traits. In contrast, one example demonstrates that proteins may also have
      pleiotropic effects: a single gene mutation (a single altered protein) may affect
      several other proteins. From these studies we conclude that gene-related
      functional proteomics will show in the future that genetic diseases, defined
      today by clinical symptoms and considered as etiological entireties, can be
      subdivided into different diseases according to different affected genes.

PMID- 10344230
TI  - Replication-induced protein synthesis and its importance to proteomics.
AB  - Replication-induced protein synthesis (RIPS) can occur following the passage of
      the replisome due to transcription initiated by RNA polymerase in association
      with: (i) negative supercoiling trailing the replisome / replication fork, (ii)
      hemimethylation prior to the action of dam methylase, (iii) transient
      derepression following passage of the replisome/replication fork and prior to
      renewed synthesis of the repressor gene-product, and (iv) 'sliding clamp'
      accessory DNA-binding proteins binding to the lagging strand DNA duplex to retard
      rotational upstream propagation of supercoils. The latter include subunits of DNA
      polymerase III in Escherichia coli and gp45 in T4 bacteriophage. By far the most
      convincing evidence for the existence of RIPS comes from the pulse of protein
      synthesis which follows the passage of the replisome in late T4 bacteriophage,
      the dynamics of replication in Escherichia coli, recent results from cDNA high
      density expression arrays in yeast and the workings of the lac-operon. More
      circumstantial evidence is provided by 'leaky' or 'aberrant' protein expression
      in genetic systems where attempts have been made to turn off protein synthesis by
      molecular means. In higher vertebrates, RIPS may have a potentially important
      role in explaining the mechanisms by which thymic and peripheral immune self
      tolerance is established, either directly through antigen presentation on
      dendritic cells or through the presentation of peptides derived from T-cells. The
      latter model is preferred, as young T-cells will have recently divided and will
      be dying in large numbers near the antigen-presenting dendritic cells in the
      thymus. The functional utility of RIPS would appear to be linked to both
      facilitating cellular metabolism and an improved survival during stress. RIPS, as
      a potentially universal molecular phenomenon, presents proteomics with numerous
      challenges and opportunities, both technical and commercial.

PMID- 10344231
TI  - Advances in protein solubilisation for two-dimensional electrophoresis.
AB  - Two-dimensional (2-D) electrophoresis remains the highest resolution technique
      for protein separation and is the method of choice when complex samples need to
      be arrayed for characterisation, as in proteomics. However, in current proteome
      projects the total number of proteins identified from 2-D gels is often only a
      small percentage of the predicted proteome. In addition, there is an almost
      complete lack of hydrophobic proteins on 2-D gels, especially those using
      immobilised pH gradients. Recently there have been a number of publications
      reporting reagents which improve protein solubilisation prior to isoelectric
      focusing. The improved solubilization possible with these reagents has increased
      the total number of proteins able to be visualised on 2-D gels and also allowed
      the separation of hydrophobic proteins, such as integral membrane proteins.

PMID- 10344232
TI  - Proteomics and automation.
AB  - Proteome analysis is concerned with the global changes in protein expression as
      visualized most commonly by two-dimensional gel electrophoresis and analyzed by
      mass spectrometry. A drastic increase in the rapidity and reproducibility of
      protein isolation and identification is needed for proteome analysis to become a
      useful complement to global mRNA analysis. Simplification and standardization,
      based on innovation in both hard- and software, are prerequisites to the creation
      of automated proteomics platforms that are both robust and user-friendly, and
      will allow many more laboratories access to this technique. In this review we
      highlight the weak points in the chain of analysis (such as sample handling,
      protein separation and digestion) and summarize recent trends toward automation
      in instrumentation and software and offer our own personal view of future
      developments in the field.

PMID- 10344233
TI  - Genomes and proteomes: towards a multidimensional view of biology.
AB  - The third Siena proteomics conference held August 31-September 4, 1998, heralded
      a change in emphasis from technology development to using proteomics to assist in
      resolving biological questions. In this review, proteomics is placed in context
      with other major influences in the way discovery research is conducted in
      biology. The current status of genomics is examined in its broadest sense,
      including how such studies may influence the development of proteomics. It is
      suggested that we are entering a new phase in biology where information is no
      longer limiting and integration of different technologies is required to attack
      the big problems of biology. While much of the focus of funding bodies, both in
      the public and private sector, is on practical outcomes (new drugs, etc.), the
      new technologies are equally amenable to attacking long-standing fundamental
      challenges, such as cell division, cell patterning and morphogenesis.

PMID- 10344234
TI  - The potential use of laser capture microdissection to selectively obtain distinct
      populations of cells for proteomic analysis--preliminary findings.
AB  - Proteomics-based studies offer a powerful complementary approach to DNA/RNA-based
      investigations and are now being applied to investigate aspects of many diseases
      including cancer. However, the heterogeneous nature of tissue samples often makes
      interpretation difficult. We have undertaken a study into the potential use of a
      novel laser capture microdissection (LCM) system to isolate cells of interest for
      subsequent proteomic analysis. Retrieval of selected cells is achieved by
      activation of a transfer film placed in contact with a tissue section, by a laser
      beam (30 or 60 microm diameter) which is focused on a selected area of tissue
      using an inverted microscope. The precise area of film targeted by the laser
      bonds to the tissue beneath it and these cells are then lifted free of
      surrounding tissue. Although the technique has been shown to be readily
      compatible with subsequent analysis of nucleic acids, little information is yet
      available regarding the application of protein-based analyses to the captured
      tissue. We report here preliminary data regarding the potential use of the LCM
      system in combination with two-dimensional electrophoresis to examine protein
      profiles of selected tissue areas. Electrophoretic profiles of proteins from
      normal and malignant renal tissue samples showed little change following LCM,
      nine selected proteins showed identical mass spectrometric sequencing profiles,
      and two selected proteins retained antigenicity. Dissection of epithelial tissue
      from a sample of normal human cervix resulted in enrichment of some proteins
      compared with analysis of the whole tissue. LCM will be a valuable adjunct to
      proteomic studies although further detailed validation is necessary.

PMID- 10344235
TI  - Extraction of Escherichia coli proteins with organic solvents prior to two
      dimensional electrophoresis.
AB  - Compared to soluble proteins, hydrophobic proteins, in particular membrane
      proteins, are an underrepresented protein species on two-dimensional (2-D) gels.
      One possibility is that many hydrophobic proteins are simply not extracted from
      the sample prior to 2-D gel separation. We attempted to isolate hydrophobic
      proteins from Escherichia coli by extracting with organic solvents, then
      reconstituting the extracted proteins in highly solubilising sample solution
      amenable to 2-D electrophoresis using immobilized pH gradients (IPGs). This was
      conducted by an extraction with a mixture of chloroform and methanol, followed by
      solubilisation using a combination of urea, thiourea, sulfobetaine detergents and
      tributyl phosphine. Peptide mass fingerprinting assisted in the identification of
      13 proteins, 8 of which have not previously been reported on 2-D gels. Five of
      these new proteins possess a positive hydropathy plot. These results suggest that
      organic solvent extractions may be useful for selectively isolating some proteins
      that have previously been missing from proteome maps.

PMID- 10344236
TI  - Towards the recovery of hydrophobic proteins on two-dimensional electrophoresis
      gels.
AB  - An extensive proteomic approach relies on the possibility to visualize and
      analyze various types of proteins, including hydrophobic proteins which are
      rarely detectable on two-dimensional electrophoresis (2-DE) gels. In this study,
      two methods were employed for the purification of hydrophobic proteins from
      Arabidopsis thaliana leaf plasma membrane (PM) model plants, prior to analysis on
      2-DE immobilized pH gradient (IPG) gels. Solubilization efficiency of two
      detergents, (3-[(3-cholomidopropyl)-1-propanesulfonic acid (CHAPS) and C8phi,
      were tested for the recovery of hydrophobic proteins. An immunological approach
      was used to determine the efficiency of the above methods. Fractionation of
      proteins by Triton X-114 combined with solubilization with CHAPS resulted in the
      inability to detect hydrophobic proteins on 2-DE gels. The use of C8phi for
      protein solubilization did not improve this result. On the contrary, after
      treatment of membranes with alkaline buffer, the solubilization of PM proteins
      with detergent C8phi permitted the recovery of such proteins on 2-DE gels. The
      combination of membrane washing and the use of zwitterionic detergent resulted in
      the resolution of several integral proteins and the disappearance of peripheral
      proteins. In the resolution of expressed genome proteins, both large pH gradients
      in the first dimension and various acrylamide concentrations in the second
      dimension must be used. Notwithstanding, it is important to combine various
      sample treatments and different detergents in order to resolve soluble and
      hydrophobic proteins.

PMID- 10344237
TI  - Recent developments in two-dimensional gel electrophoresis with immobilized pH
      gradients: wide pH gradients up to pH 12, longer separation distances and
      simplified procedures.
AB  - Wide-range immobilized pH 3-12 and 6-12 gradients were generated. Depending on
      the extraction method of sample preparation, proteins with p/s up to pH 11.7 were
      resolved. Highly reproducible protein patterns, focused to the steady-state with
      round-shaped spots up to the basic end were obtained. Moreover, because a strong
      water transport from cathode to anode (reverse electroendosmotic flow) inherent
      to narrow immobilized pH gradients (IPGs) exceeding pH 11, such as IPG 10-12, was
      negligible, the wide-range IPGs 3-12 and 6-12 could be run under standard
      conditions as originally described by Gorg et al (Electrophoresis 1988, 9, 531
      546). The wide-range immobilized pH gradient 3-12 proved to be perfectly suited
      for an overview separation of total cell extracts. Resolution could be increased
      by extending the separation distance from 18 to 24 cm. Furthermore, two
      dimensional gel electrophoresis with IPGs (IPG-Dalt) was simplified by the use of
      an integrated system (IPGphor) where sample application by in-gel rehydration and
      isoelectric focusing (IEF) are performed automatically in a one-step procedure,
      overnight, without human assistance.

PMID- 10344238
TI  - Steady-state electrolysis of a solution of nonamphotheric compounds.
AB  - The problem of stationary electrolysis of a solution of nonamphotheric compounds
      (acids or bases) is considered. The analysis is performed by taking into account
      the mobility dependence on pH. The properties of such a system are also compared
      with the ones pertaining to the solution of an amphoteric substance. It is
      anticipated that steady-state electrolysis of free acids and bases, in a
      convection-free system, might be useful for creating narrow pH gradients in
      rather acidic and alkaline milieus, which might be adopted for focusing without
      resorting to conventional carrier ampholytes or immobilized pH gradients.

PMID- 10344239
TI  - Modified immobilized pH gradient gel strip equilibration procedure in SWISS
      2DPAGE protocols.
AB  - In the present paper we report a revised protocol for immobilized pH gradient
      (IPG) gel strip equilibration involving a procedural modification between the
      first- and second-dimensional separation in both analytical and preparative two
      dimensional polyacrylamide gel electrophoresis (2-D PAGE). By changing the pH of
      the equilibration buffer (pH 8.0), the concentration of alkylating reagent (125
      mM iodoacetamide) and the time of incubation (15 min), it has been possible to
      achieve increased cysteine (Cys) alkylation to completion with only one adduct of
      carboxyamidomethyl-Cys formed. Importantly, the modification does not alter the 2
      D proteome patterns and therefore maintains the integrity of the existing SWISS
      2DPAGE entries. Results are presented for comparative analyses using human
      plasma, and for Cys analysis of human albumin to illustrate the advantages of the
      improved protein reduction and Cys alkylation. The modified step of IPG gel strip
      equilibration will assist protein digestion for matrix-assisted laser
      desorption/ionisation - time-of-flight - mass spectrometry analysis, and make Cys
      quantitation possible without further in-gel or on-blot alkylation.

PMID- 10344240
TI  - Microchannel networks for electrophoretic separations.
AB  - UV excimer laser photoablation was used to micro-machine polymer substrates not
      only to drill microchannel structures but also to change the surface physical
      properties of the substrates. We first describe how UV laser photoablation can be
      used for the patterning of biomolecules on a polymer and discuss parameters such
      as surface coverage of active antibodies and equilibration time. Secondly, we
      show how to design a single-use capillary electrophoresis system comprising an on
      chip injector, column and electrochemical detector. The potential of this
      disposable plastic device is discussed and briefly compared to classical systems.
      Finally, preliminary results on protein separation by isoelectric focusing on a
      disposable microchip are presented.

PMID- 10344242
TI  - Studies of quantitative analysis of protein expression in Saccharomyces
      cerevisiae.
AB  - In the present study amino acid analysis is applied to quantitation of
      Saccharomyces cerevisiae proteome expression. The quantitation levels obtained
      are compared to data using densitometric analysis of silver or amido black
      staining and to the theoretical expression level (codon bias) of the identified
      proteins determined from their amino acid analysis (AAA). The results show that
      relative volume ratio (%vol) using Melanie II is a better parameter for spot
      quantitation than relative optical density ratio (%OD), and amino black staining
      provides good linearity within the range 1-100 pmol protein. However, AAA shows
      that theoretical expression levels are not well correlated with actual protein
      expression level, although there is better correlation when isoforms of the
      expressed protein are identified and included. It is concluded that amino acid
      analysis provides accurate protein quantitation and has a continuing role in
      proteome studies in terms of the rapid and inexpensive quantitation of proteins
      displayed on proteome maps. We do however recognize that in the context of future
      clinical applications and large-scale proteome discovery projects, quantitation
      and post-translational modification need to be analyzed by 'proteomatic' (i.e.,
      proteome automatic bioinformatic analysis directly from the gel) techniques.

PMID- 10344241
TI  - Proteome analysis of polyacrylamide gel-separated proteins visualized by
      reversible negative staining using imidazole-zinc salts.
AB  - Identification and characterization of proteins isolated from natural sources by
      polyacrylamide gel electrophoresis has become a routine technique. However,
      efficient sample proteolysis and subsequent peptide extraction is still
      problematic. Here, we present an improved protocol for the rapid detection of
      polyacrylamide gel-separated proteins, in situ protein modification, proteolytic
      digestion and peptide extraction for subsequent protein identification and
      characterization by capillary high-performance liquid chromatography/tandem mass
      spectrometry. This simple technique employs the rapid imidazole-zinc reverse
      stain, in-gel S-pyridylethylation and proteolytic digestion of microcrushed
      polyacrylamide gel pieces with proteases. This technique obviates the need for
      buffer exchange or gel lyophilisation due to all of the sample manipulation steps
      being carried out at near neutral pH and thus lends itself readily to automation.

PMID- 10344243
TI  - High sensitivity mass spectrometric methods for obtaining intact molecular
      weights from gel-separated proteins.
AB  - The molecular weight measurement of intact Escherichia coli proteins separated by
      isoelectric focusing-immobilized pH gradient (IEF-IPG) gels and analyzed by mass
      spectrometry is presented. Two methods are discussed: (i) electrospray ionization
      (ESI) mass spectrometry (MS) of extracted proteins, and (ii) matrix-assisted
      laser desorption/ionization (MALDI)-MS analysis directly from IEF-IPG gels. Both
      ESI and MALDI methods yield sub-picomole sensitivity and good mass measurement
      accuracy. The use of an array detector for ESI-MS was essential to discriminate
      against contaminating background ions and to selectively detect high mass protein
      ions. MALDI-MS offers high-throughput analysis of one- and potentially two
      dimensional (2-D) gels. The "virtual 2-D" gel method with first-dimensional IEF
      separation and the second dimension as molecular mass determination by MS, is a
      particularly promising method for protein analysis due to its ultra high
      sensitivity and correspondence to classical 2-D gels. Further sensitivity
      enhancements for the MALDI-MS method are provided by post acceleration detection
      optimized for high mass time-of-flight analysis.

PMID- 10344245
TI  - New algorithmic approaches to protein spot detection and pattern matching in two
      dimensional electrophoresis gel databases.
AB  - Protein spot identification in two-dimensional electrophoresis gels can be
      supported by the comparison of gel images accessible in different World Wide Web
      two-dimensional electrophoresis (2-DE) gel protein databases. The comparison may
      be performed either by visual cross-matching between gel images or by automatic
      recognition of similar protein spot patterns. A prerequisite for the automatic
      point pattern matching approach is the detection of protein spots yielding the
      x(s),y(s) coordinates and integrated spot intensities i(s). For this purpose an
      algorithm is developed based on a combination of hierarchical watershed
      transformation and feature extraction methods. This approach reduces the strong
      over-segmentation of spot regions normally produced by watershed transformation.
      Measures for the ellipticity and curvature are determined as features of spot
      regions. The resulting spot lists containing x(s),y(s),i(s)-triplets are
      calculated for a source as well as for a target gel image accessible in 2-DE gel
      protein databases. After spot detection a matching procedure is applied. Both the
      matching of a local pattern vs. a full 2-DE gel image and the global matching
      between full images are discussed. Preset slope and length tolerances of pattern
      edges serve as matching criteria. The local matching algorithm relies on a data
      structure derived from the incremental Delaunay triangulation of a point set and
      a two-step hashing technique. For the incremental construction of triangles the
      spot intensities are considered in decreasing order. The algorithm needs neither
      landmarks nor an a priori image alignment. A graphical user interface for spot
      detection and gel matching is written in the Java programming language for the
      Internet. The software package called CAROL (http://gelmatching.inf.fu-berlin.de)
      is realized in a client-server architecture.

PMID- 10344244
TI  - Method for identification and quantitative analysis of protein lysine methylation
      using matrix-assisted laser desorption/ionization--time-of-flight mass
      spectrometry and amino acid analysis.
AB  - Protein methylation is a post-translational modification that might have
      important functional roles in cell regulation. We present a new technique with
      sufficient sensitivity (sub-pmol level) for analysis of methylation of proteins
      in abundances typically found on proteome maps produced by two-dimensional (2-D)
      gel electrophoresis. The method involves the identification and quantitation of
      lysine (Lys) methylation using Fmoc (9-fluorenylmethyl chloroformate)-based amino
      acid analysis (AAA). Tri- and monomethyl-Lys were baseline-separated from other
      amino acids using a modified buffer system. Trimethyl-Lys was quantitatively
      recovered after acid hydrolysis and AAA of two known methylated proteins - yeast
      cytochome c and human calmodulin. The methylated peptides from tryptic digestion
      of those two proteins were identified by high sensitivity matrix-assisted laser
      desorption/ionization - time-of-flight (MALDI-TOF) mass spectrometry (MS). An
      automated mass-screening approach is proposed for the study of various post
      translational modifications to understand the distribution of those protein
      isoforms separated by two-dimensional polyacrylamide gel electrophoresis. It is
      concluded that the combination of AAA and MALDI-TOF-MS provides a high
      sensitivity quantitative tool for the analysis of protein post-translational
      methylation in the context of proteome studies.

PMID- 10344246
TI  - Mining protein data from two-dimensional gels: tools for systematic post-planned
      analyses.
AB  - There is a considerable need to develop comprehensive, systematic mechanisms to
      analyze the vast number of proteins that orchestrate various cellular functions
      and to identify proteins associated with disease or that are affected by
      pharmacological agents. Two-dimensional polyacrylamide gel electrophoresis (2-D
      PAGE) continues to be relied upon to analyze protein constituents of cells and
      tissues. We have developed a Laboratory Information Processing System (LIPS) as a
      computer-based tool for capturing quantitative and qualitative changes in
      thousands of proteins detected in 2-D gels of various types. Protein databases
      have been developed to serve as a repository for data processing of the basic and
      derived data and of findings derived from different studies. There have been
      remarkable advances both in database technology as well as in the computer
      hardware that have benefited our effort at mining protein data from 2-D gels. We
      here review our current efforts aimed at improving the performance and features
      of our 2-D related protein databases, with particular emphasis on the tools we
      utilize for database mining via a systematic analysis of information known as
      post-planned analysis.

PMID- 10344247
TI  - Effects of interferon gamma on Chlamydia trachomatis serovar A and L2 protein
      expression investigated by two-dimensional gel electrophoresis.
AB  - Chlamydia trachomatis is an obligate intracellular bacterium causing human ocular
      and genital disease. The lymphokine interferon gamma (IFN-gamma) is an important
      immune effector exerting antimicrobial effects towards several intracellular
      parasites, the chlamydia included. IFN-gamma has been reported to inhibit the
      chlamydial replication in vitro in part by depleting intracellular levels of
      tryptophan in a dose-dependent manner. In addition, down-regulation of important
      immunogens has been described. These findings are extended in this paper, in
      which we are combining pulse labeling with [35S]methionine and two-dimensional
      gel electrophoresis with immobilized pH gradients in order to investigate changes
      in the protein expression of C. trachomatis serovar A and L2 caused by treatment
      with IFN-gamma. In contrast to what was observed in C. trachomatis L2, our
      results showed that, in C. trachomatis A, down-regulations of the chlamydia major
      outer membrane protein and of several other proteins were detectable upon IFN
      gamma treatment. In addition, we report the up-regulations of C. trachomatis A
      and L2 proteins with molecular masses of approximately 30 kDa and 40 kDa which
      may be part of an, as yet, uncharacterized chlamydial response to IFN-gamma
      treatment.

PMID- 10344249
TI  - Characterization of periplasmic Escherichia coli protein expression at high cell
      densities.
AB  - We have used two-dimensional electrophoresis (2-DE) to analyze changes in protein
      expression profiles during a microbial cultivation process on an industrial
      scale. An Escherichia coli strain W31 10 containing the gene for recombinant
      human growth hormone production was used. Samples were taken at time intervals
      ranging from fast to slow growth rate (late growth phase at high cell
      density/starvation) and 2-DE analysis combined with image analysis using the
      PDQuest software showed significant alterations in expression levels of a number
      of proteins. Twenty-four protein spots were identified using a combination of
      matching with SWISS-2DPAGE E. coli map, N-terminal sequence analysis and mass
      spectrometry matrix-assisted laser desorption/ionization (MALDI). Two of the most
      abundant proteins expressed at late growth phase (pI 5.4/28 kDa and pI 5.5/28
      kDa) were subjected to N-terminal sequence analysis after electrotransfer of the
      proteins from a preparative 2-DE gel to polyvinylidene difluoride (PVDF)
      membrane. Sequence tags of five amino acids in combination with approximate pI
      and Mr identified both proteins as deoxyribose phosphate aldolase (gene name
      deoC). In addition, both spots were subjected to tryptic in-gel digestion and
      analyzed using MALDI. Peptide mass fingerprints from both spots showed similar
      MALDI spectra and 10 of 10 tryptic fragments confirmed the identity as deoC. The
      identification of the acidic variant of deoC on 2-DE gels and the observation of
      this variant as induced during late growth phase is novel.

PMID- 10344248
TI  - Induction of heat shock proteins in response to primary alcohols in Acinetobacter
      calcoaceticus.
AB  - Cells of Acinetobacter calcoaceticus 69-V, a species able to metabolize a range
      of aliphatic hydrocarbons and alcohols, were confronted with ethanol, butanol,
      hexanol or heat shock during growth on acetate as sole source of carbon and
      energy. The primary alcohols and the heat shock led to the synthesis of new
      proteins or amplified expression of specific, common and general proteins, which
      were detected by silver staining after two-dimensional gel electrophoresis. Some
      of the alcohol-inducible proteins were identified as heat shock proteins by
      comparing protein patterns of alcohol-shocked cells with those of heat-shocked
      cells, and by N-terminal amino acid sequencing. DnaK was found to be amplified
      after all treatments, but GroEI only after heat shock and ethanol treatment. The
      N-terminal amino acid sequence of the protein, which was considerably amplified
      after alcohol treatment and heat shock, shows homology to HtpG (high temperature
      protein G). Some of the heat shock proteins induced by ethanol differ from those
      induced by butanol and hexanol, suggesting there are at least two different
      signals for the induction of some heat shock proteins by primary alcohols. This
      could be due to the different localization of ethanol, butanol and hexanol in the
      membrane, or because higher cytoplasmic concentrations of ethanol than of butanol
      or hexanol were applied in these tests in order to keep concentrations of the
      alcohols in the membrane roughly similar. Besides heat shock proteins, a group of
      proteins were observed which were only induced by butanol and hexanol, possibly
      indicating the existence of a further defense mechanism against high
      concentrations of hydrophobic substrates preventing protein denaturation and
      membrane damage.

PMID- 10344250
TI  - Proteome analysis of factor for inversion stimulation (Fis) overproduction in
      Escherichia coli.
AB  - The factor-for-inversion stimulation protein (Fis) is a global regulatory protein
      in Escherichia coli that activates ribosomal RNA (rRNA) transcription by binding
      to three upstream activation sites of the rRNA promoter and enhances
      transcription 5- to 10-fold in vivo. Fis overexpression results in different
      effects on cell growth depending on nutrient conditions. Differential proteome
      analysis of Fis-expressing cells shows ten protein spots corresponding to Fis
      overexpression in both rich (YT) and minimal (M9+glucose) media. Three of these
      spots have been identified as elongation factor TS, histidine-binding periplasmic
      protein precursor, and ketol-acid reductoisomerase.

PMID- 10344251
TI  - Investigation of translation dynamics under cell-free protein biosynthesis
      conditions using high-resolution two-dimensional gel electrophoresis.
AB  - A cell-free extract from Escherichia coli, generated through a routine procedure
      according to Chen and Zubay (Methods Enzymol. 1983, 101, 674-690), was used for
      an in vitro protein synthesis. High-resolution two-dimensional gel
      electrophoresis (2-DE) was exploited to investigate the protein composition of
      the cell-extract and its dynamic development during a 24 h-period of cell-free
      protein synthesis performed in a membrane reactor device. Green fluorescent
      protein (GFP) was chosen as a target protein to be produced in a cell-free
      reactor because of its functional activity, which can easily be monitored by
      measurement of fluorescence, and because of its high sensitivity. GFP synthesis
      was observed by a standard fluorescence assay and was correlated to a
      quantitative assessment of the silver-stained GFP spot appearing on 2-DE gel
      maps. A constant protein synthesis rate was obtained for at least 8 h of process
      operation. While declining continuously, protein synthesis stopped entirely after
      24 h. Both, the total protein content and total number of detectable spots were
      found to decrease over the reaction time, due to proteolytic digestion and
      protein precipitation. Certain proteins taking part in the translation process,
      such as the elongation factors (EF-Tu, EF-Ts) and the ribosomal protein RP-L9,
      were identified by Edman N-terminal sequencing and have thus been considered for
      reaction evaluation. The dynamics obtained during the entire process suggest that
      these translational factors were likewise affected by proteolytic decay.

PMID- 10344252
TI  - Regulation of virulence genes by environmental signals in Salmonella typhimurium.
AB  - Sensing and responding to environmental signals is a crucial element of bacterial
      pathogenicity. For a successful progression of infection, virulence gene
      expression is coordinated in response to habitat-specific environmental signals
      from the host organism. We are interested in identifying environmental cues
      affecting the expression of genes within Salmonella Pathogenicity Island 2
      (SPI2), a virulence locus important for systemic infections by S. typhimurium. We
      describe our approach starting with the identification of new virulence genes,
      and analysis of the regulation of these genes by environmental signals leading to
      the proteome analysis in order to define the SPI2 regulon.

PMID- 10344253
TI  - Proteome analysis of the model microsymbiont Sinorhizobium meliloti: isolation
      and characterisation of novel proteins.
AB  - Sinorhizobium meliloti is an agriculturally and ecologically important microbe
      due to its capacity to establish nitrogen-fixing symbiosis with plant legumes.
      Two-dimensional gel electrophoresis of total cellular protein was used to
      establish a proteome reference map for the model microsymbiont Sinorhizobium
      meliloti strain 1021. The extent of changes in the gene expression of cells grown
      in a defined medium at different growth phases was established. After examination
      of over 2000 resolved protein spots, a minimum of 52 reproducible changes in
      protein expression levels were detected when early exponential phase cells were
      compared to late exponential phase cells. In contrast, induction of nodulation
      gene expression by the addition of the flavonoid luteolin to cells did not result
      in detectable changes in protein expression at either early or late exponential
      phase. N-terminal microsequencing of eighteen unknown constitutive proteins plus
      four proteins, induced or up-regulated in late exponential phase cells, allowed
      the identification of proteins not previously described in rhizobia. These
      included an amide-binding protein, a putative hydrolase of the glyoxalase II
      protein family, a nucleoside diphosphate kinase, and a 5'-nucleotidase. N
      terminal microsequencing was also valuable in revealing N-terminal post
      translational processing and assigning a subcellular location to the analysed
      protein. Proteome analysis will provide a powerful analytical tool to complement
      the sequencing of the genome of strain 1021.

PMID- 10344254
TI  - Comparison of yeast cell protein solubilization procedures for two-dimensional
      electrophoresis.
AB  - Three different procedures for the solubilization of yeast (S. cerevisiae) cell
      proteins were compared on the basis of the obtained two-dimensional (2-D)
      polypeptide patterns. Major emphasis was laid on minimizing handling steps,
      protein modification or degradation, and quantitative loss of high molecular mass
      proteins. The procedures employed were sonication, followed by (i) protein
      solubilization with "standard" lysis buffer (9 M urea, 2% 3-[(3
      cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), 1% dithiothreitol
      (DTT), 2% v/v carrier ampholytes, (ii) presolubilization of proteins with sodium
      dodecyl sulfate (SDS) buffer, consisting of 1% SDS and 100 mM
      tris(hydroxymethyl)aminomethane (Tris)-HCl, pH 7.0, followed by dilution with
      "standard" lysis buffer, and (iii) boiling the sample with SDS during cell lysis,
      followed by dilution with thiourea/urea lysis buffer (2 M thiourea/ 7 M urea, 4%
      w/v CHAPS, 1% w/v DTT, 2% v/v carrier ampholytes). All procedures tested were
      rapid and simple. However, with the first procedure (i), considerable degradation
      of high Mr proteins occurred. In contrast, protein degradation was minimized by
      boiling the sample in SDS buffer immediately after sonication (method ii).
      Protein disaggregation and solubilization of high Mr proteins were further
      improved by pre-boiling with SDS and using thiourea/urea lysis buffer instead of
      "standard" lysis buffer (procedure iii).

PMID- 10344255
TI  - A nondenaturing protein map of human plasma proteins correlated with a denaturing
      polypeptide map combining techniques of micro two-dimensional gel
      electrophoresis.
AB  - Human plasma proteins were separated by combining four types of two-dimensional
      electrophoresis (2-DE) techniques to obtain systematic information on proteins
      and their constituent polypeptides. A micro gel system was employed to facilitate
      the analysis. A plasma sample was first analyzed under nondenaturing conditions
      of electrophoresis (Type I 2-DE) to characterize the properties of proteins under
      physiological conditions. The sample was then analyzed, employing nondenaturing
      isoelectric focusing in the first dimension and sodium dodecyl sulfate (SDS)
      electrophoresis in the second dimension (Type II 2-DE), to study the dissociation
      of noncovalently bound protein subunits. In the third type of 2-DE (Type III 2
      DE), proteins were separated by nondenaturing isoelectric focusing and treated
      with urea/mercaptoethanol/SDS and then subjected to second-dimension SDS
      electrophoresis, to study the dissociation of disulfide-bonded polypeptides. In
      the fourth type of 2-DE (Type IV 2-DE), the conditions of denaturing 2-DE were
      employed; the sample was treated with SDS-mercaptoethanol-urea-Nonidet P-40,
      separated by denaturing isoelectric focusing, and then subjected to SDS
      electrophoresis. The combined 2-DE technique will be useful to construct a
      comprehensive database of plasma proteins combining a "nondenaturing protein map"
      (a protein map) and a "denaturing protein map" (a polypeptide map).

PMID- 10344256
TI  - Proteins of rat serum: III. Gender-related differences in protein concentration
      under baseline conditions and upon experimental inflammation as evaluated by two
      dimensional electrophoresis.
AB  - We have previously described the major components of rat serum (Electrophoresis
      1998, 19, 1484-1492 and 1493-1500). In this report we examine sex-related
      differences in protein concentrations, both in control animals and upon
      experimentally induced inflammation. Under baseline conditions approximately one
      third of the spots resolved in serum by two-dimensional electrophoresis (2-DE)
      are expressed at levels > or =25% higher in female rats than in male rats and a
      further 10% at levels > or =25% lower. Inflammation increases the expression of
      the positive acute-phase reactants: hemopexin, ceruloplasmin, alpha1-antitrypsin
      (all approximately 2-fold), C-reactive protein (3- to 5-fold), serine protease
      inhibitor-3 (4- to 5-fold), thiostatin (> 5-fold in females, >20-fold in males),
      clusterin, orosomucoid, haptoglobin chains and alpha2-macroglobulin. The baseline
      level of the last four markers is below the detection limit, hence no percent
      increase can be computed. Conversely, negative acute-phase reactants are reduced
      on inflammation: alpha1-inhibitor III, alpha2-HS-glycoprotein, kallikrein-binding
      protein and transthyretin (all reduced to between 1/2 to 1/3 of the baseline
      levels), retinol-binding protein (to about 1/2 to 1/4) and albumin (to 2/3).
      Except for thiostatin, the changes in acute-phase protein levels are similar in
      male and female rats.

PMID- 10344257
TI  - Proteins of rat serum IV. Time-course of acute-phase protein expression and its
      modulation by indomethacine.
AB  - Changes in the concentration of major serum proteins were monitored from day 0 to
      day 4 in three experimental groups: rats injected with turpentine, rats receiving
      the turpentine shot and daily doses of indomethacine, and rats given
      indomethacine alone. In inflamed animals, peak changes for acute-phase reactants,
      evaluated by two-dimensional electrophoresis (2-DE), were usually observed
      between 48 and 72 h after the phlogistic stimulus. By itself, indomethacine was
      found to affect the synthesis of most proteins (except one of the thiostatin
      variants and ceruloplasmin); the changes in serum levels, whether positive or
      negative, were the same as upon inflammation (except for kallikrein-binding
      protein), but their extent and/or timing usually differed. When inflamed animals
      were given indomethacine, a clear-cut difference in the concentration of some
      proteins was observed versus inflamed rats not given medication, at 24 h after
      the start of the treatments. Proteins mainly affected were alpha2-macroglobulin,
      alpha2-HS-glycoprotein, C-reactive protein and kallikrein-binding protein.

PMID- 10344258
TI  - Improved two-dimensional gel electrophoresis representation of serum proteins by
      using ProtoClear.
AB  - ProtoClear is a proprietary technique for clearing albumin and immunoglobulin G
      (IgG) from human serum samples. Albumin constitutes 57-71% of total serum protein
      and IgG ranges from 8-26%. Removal of these two proteins alone clears
      approximately 75% of the total protein present in serum and allows the detection
      of the remaining proteins that are present in far lower concentrations.
      ProtoClear effectively removed >95% of human serum albumin (HSA) and >97% of
      human IgG as measured by an anti-HSA competitive immunoassay and a radial
      immunodiffusion assay, respectively. ProtoClear was far more specific at removing
      albumin and IgG than Cibracon Blue Dye chromatography (Cibracon Blue), the
      typically utilized alternative. Comparing two-dimensional (2-D) gels of serum
      cleared by either Cibracon Blue or by ProtoClear, it was apparent that Cibracon
      Blue removed a number of proteins in addition to albumin. Following removal of
      albumin and IgG from serum, we found a significant improvement in the resolution
      of polypeptide spots detected on two-dimensional gels.

PMID- 10344259
TI  - Identification of proteins in a human pleural exudate using two-dimensional
      preparative liquid-phase electrophoresis and matrix-assisted laser
      desorption/ionization mass spectrometry.
AB  - Pleural effusion may occur in patients suffering from physical trauma or systemic
      disorders such as infection, inflammation, or cancer. In order to investigate
      proteins in a pleural exudate from a patient with severe pneumonia, we used a
      strategy that combined preparative two-dimensional liquid-phase electrophoresis
      (2-D LPE), matrix-assisted laser desorption/ionization time-of-flight mass
      spectrometry (MALDI-TOF-MS) and Western blotting. Preparative 2-D LPE is based on
      the same principles as analytical 2-D gel electrophoresis, except that the
      proteins remain in liquid phase during the entire procedure. In the first
      dimension, liquid-phase isoelectric focusing allows for the enrichment of
      proteins in liquid fractions. In the Rotofor cell, large volumes (up to 55 mL)
      and protein amounts (up to 1-2 g) can be loaded. Several low abundance proteins,
      cystatin C, haptoglobin, transthyretin, beta2-microglobulin, and transferrin,
      were detected after liquid-phase isoelectric focusing, through Western blotting
      analysis, in a pleural exudate (by definition, >25 g/L total protein). Direct
      MALDI-TOF-MS analysis of proteins in a Rotofor fraction is demonstrated as well.
      MALDI-TOF-MS analysis of a tryptic digest of a continuous elution sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) fraction confirmed the
      presence of cystatin C. By applying 2-D LPE, MALDI-TOF-MS, and Western blotting
      to the analysis of this pleural exudate, we were able to confirm the identity of
      proteins of potential diagnostic value. Our findings serve to illustrate the
      usefulness of this combination of methods in the analysis of pathological fluids.

PMID- 10344260
TI  - Two-dimensional polyacrylamide gel electrophoresis map of bovine ovarian fluid
      proteins.
AB  - Molecular mechanisms underlying the cystic degeneration of ovarian follicles in
      the dairy cow have not been clarified yet. A useful approach for complementing
      endocrinological and clinical studies could be represented by the systematic
      analysis of the protein patterns in follicular and cystic fluid. With this aim, a
      two-dimensional polyacrylamide gel electrophoresis map of proteins contained in
      fluid from bovine ovarian follicles at different stages of development and from
      bovine ovarian cyst has been obtained. About 200 spots were detected after silver
      staining. Polypeptides from nine spots or series of spots have been identified by
      N-terminal sequencing, and further analysis of the map has been performed by gel
      comparison. Alpha-1-antitrypsin, albumin, serotransferrin and apolipoprotein A-I
      and A-IV were located on the map. Comparison between protein patterns revealed
      the differential expression of some spots among follicles of smaller diameter,
      follicles of larger diameter, and cysts. This could represent the first step
      toward the identification of proteins differentially expressed and associated
      with ovarian cyst development.

PMID- 10344261
TI  - Two-dimensional electrophoresis and computer imaging: quantitation of human milk
      casein.
AB  - Because human casein does not precipitate from milk at its isoelectric point as
      does bovine casein, there is no easy method of quantitation. Casein represents
      only approximately 30% of the protein fraction in human milk, and the complex
      methods necessary for isolation cannot be used easily with small samples in a
      survey of a large number of mothers. Two-dimensional electrophoresis coupled with
      computer imaging has the potential to compare and quantitate proteins
      expeditiously using a small sample size. IsoDalt, a denaturing methodology,
      separates the casein micelle into its component parts, beta-casein, kappa-casein,
      parakappa-casein and casomorphins. Identification of these spots was made by
      immunoassay of a Western blot with monoclonal anti-human casein. Two spots at 24
      kDa and 26 kDa, thought to be phosphorylated isomers of beta casein, were
      selected for quantitation. Milk samples from 20 mothers, 8 weeks post partum,
      were run on two-dimensional (2-D) gels; a slide was taken of each silverstained
      gel with a Kodak control strip; the slide was scanned into powerMac Photoshop 3
      with a Polaroid-Sprintscan; spots were isolated using "threshold", "mask" with
      IPTK (Imaging Processing Tool Kit, Reindeer Games) a Photoshop plug-in, and
      transferred to the NIH-Image program. Using an NIH-Image gel macro (Thomas
      Seebacher), the area and integrated density of the spots were measured. The Kodak
      control scale provided calibration and conversion to OD units. Visual scanning of
      the gels and computer units indicated a wide range of concentrations. To
      understand the range in units of weight, a standard was generated using bovine
      alpha casein (Sigma). Measurements will be used in a statistical program,
      Statview (Abacus), in an attempt to correlate information from a questionaire
      with casein concentration.

PMID- 10344262
TI  - Analysis of tear protein patterns by a neural network as a diagnostical tool for
      the detection of dry eyes.
AB  - The electrophoretic patterns of tears from patients with dry-eye disease (n = 43)
      and from healthy subjects (n = 17) were analyzed by means of multivariate
      statistical methods and an artificial neural network (ANN), following sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). From each
      electrophoretic pattern a data set was created, randomly divided into test
      (unknown samples) and training patterns (known samples), with ANN training by one
      of these sets. After training, the performance of the ANN was checked by
      presenting the test data set to the ANN. Furthermore, the data was classified
      using multivariate analysis of discriminance. The groups were significantly
      different from each other (P<0.05). The statistical procedure yielded 97% (known
      samples) and 71% (unknown samples) correct classifications. The ANN revealed 89%
      of correct classifications using the test set (unknown samples). The use of
      pruning algorithms (optimization procedure which automatically eliminates small
      weighted neurons) or genetic algorithms (optimization procedure which performs
      genetically induced changes of the neural net) resulted in a slight decrease of
      correct classifications compared to those of the nonoptimized neural network. The
      results reveal significant differences between the two groups. Using the ANN we
      were able to classify the electrophoretic tear protein pattern for diagnostic
      purposes.

PMID- 10344263
TI  - Demonstration of different forms of the anti-inflammatory proteins lipocortin-1
      and Clara cell protein-16 in human nasal and bronchoalveolar lavage fluids.
AB  - The anti-inflammatory proteins lipocortin-1 and Clara cell protein-16 (CC-16)
      were studied in two-dimensional gel electrophoresis (2-DE) protein patterns of
      human nasal lavage fluids (NLFs) and bronchoalveolar lavage fluids (BALFs). Seven
      forms of lipocortin-1 were detected with Western immunoblots: three isoforms with
      an apparently normal Mr of 38 kDa and pI of 5.9, 6.0 and 6.1, and four truncated
      variants with pI/kDa 6.0/36, 6.4/36, 7.0/33, and 7.4/34. Four 6 kDa isoforms of
      CC-16 were found with pI 4.6, 4.8, 4.9, and 5.2. Lipocortin-1 and CC-16 were
      expressed in all individuals tested although not all variants were found in each
      individual. The overall levels of lipocortin-1 were higher in BALF than NLF and
      there were significant differences in the distribution of the different
      lipocortin-1 forms between BALFs and NLFs. One patient with occupational asthma
      and four children with rhinitis had increased levels of one of the truncated
      lipocortin-1 forms in NLF (pI/kDa: 7.4/34) and decreased levels of the major CC
      16 form (pI/kDa: 4.8/6). The levels of CC-16 but not of lipocortin-1 were higher
      in BALF from smokers than from nonsmokers. These results indicate that the levels
      of lipocortin-1 and CC-16 in NLF and BALF may be altered in inflammatory airway
      disorders. Furthermore, the identification of different forms of the two proteins
      makes possible more detailed studies on the role of these proteins in
      inflammatory disease processes and anti-inflammatory therapies.

PMID- 10344264
TI  - A two-dimensional electrophoresis database of rat heart proteins.
AB  - More than 3000 myocardial protein species of Wistar Kyoto rat, an important
      animal model, were separated by high-resolution two-dimensional gel
      electrophoresis (2-DE) and characterized in terms of isoelectric point (pI) and
      molecular mass (Mr). Currently, the 2-DE database contains 64 identified
      proteins; forty-three were identified by peptide mass fingerprinting (PMF) using
      matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), nine by
      exclusive comparison with other 2-DE heart protein databases, and in only 12
      cases of 60 attempts N-terminal sequencing was successful. We used the Make2ddb
      software package downloaded from the ExPASy server for the construction of a rat
      myocardial 2-DE database. The Make2ddb package simplifies the creation of a new 2
      DE database if the Melanie II software and a Sun workstation under Solaris are
      available. Our 2-DE database of rat heart proteins can be accessed at URL
      http://gelmatching.inf.fu-berlin.de/pleiss/2d.

PMID- 10344265
TI  - Bovine dilated cardiomyopathy: proteomic analysis of an animal model of human
      dilated cardiomyopathy.
AB  - Bovine hereditary dilated cardiomyopathy (bCMP) is endemic in Switzerland and
      hearts from diseased animals display important clinical and biochemical
      similarities to human DCM. Recent research has identified at least one protein
      (myoglobin) to be significantly reduced in bovine DCM. Using a proteomic
      approach, we have separated over 1125 protein species from bovine ventricular
      tissue. Gel analysis and protein characterisation have identified a number of
      proteins whose abundance is significantly altered in bovine DCM. Twenty-four
      proteins are of decreased abundance in diseased tissue, whilst 11 proteins are of
      increased abundance in the diseased state. A combination of amino acid
      compositional analysis, peptide mass profiling, N-terminal microsequencing and
      MultiIdent (http://www.expasy.ch/sprot/multiident. html) has been employed in
      order to elucidate the identities of the differentially expressed proteins. Using
      these techniques we have currently determined the identity of 12 of the 35
      altered proteins. We have also detected three proteins that are differentially
      expressed in genotypically diseased but phenotypically normal animals,
      identifying a possible mechanism for the onset of the disease. The possibility
      that inappropriate ubiquination of proteins plays an important role in the
      disease is discussed. A database of bovine proteins is currently being
      established. The identity of the proteins affected, together with a comparison of
      the human and bovine expression patterns, is displayed.

PMID- 10344266
TI  - Two-dimensional map of human brain proteins.
AB  - Samples of human brain from the parietal cortex lobe were analyzed by two
      dimensional gel electrophoresis, using immobilized pH gradient strips covering
      the various pH regions. The protein spots were visualized with colloidal
      Coomassie blue stain and identified by matrix-assisted laser
      desorption/ionization mass spectrometry. Approximately 400 spots were identified,
      corresponding to 180 different brain proteins. The list of identified proteins
      includes a large number of structural proteins and of enzymes or enzyme subunits
      with various catalytic activities. The majority of proteins are localized in the
      cytoplasma and in mitochondria. The two-dimensional map may be useful as a
      reference database to study changes in the protein level caused by various
      disorders, such as Alzheimer's disease, major depression and schizophrenia.

PMID- 10344267
TI  - Analysis of proteins from membrane-enriched cerebellar preparations by two
      dimensional gel electrophoresis and mass spectrometry.
AB  - Two-dimensional polyacrylamide gel electrophoresis and mass spectrometry is a
      powerful combination for the separation of complex protein mixtures in biological
      samples and the subsequent identification of individual polypeptides. We have
      used this approach to construct a database of proteins of the porcine cerebellum,
      with emphasis on membrane-bound proteins, as part of our studies on the structure
      and function of the central nervous system. We compared the ability of different
      solubilization conditions (using zwitterionic and nonionic detergents; urea and
      thiourea) to improve the resolution of high molecular weight and hydrophobic
      proteins, and found the combination of 3-[(3-cholamidopropyl)dimethylammonio]-1
      propane-sulfonate (CHAPS), Tris, thiourea and urea to give the best results in
      our experiments. As a marker membrane protein, the NR1 subunit of the N-methyl D
      aspartate receptor, a 120 kDa hydrophobic protein, was identified using a
      monoclonal antibody in combination with Western blotting. Sodium chloride
      treatment of the membrane preparation prior to solubilization caused further
      enrichment of membrane proteins. Fifty-six spots were identified using matrix
      assisted laser desorption/ionization time-of-flight and nanoelectrospray mass
      spectrometry.

PMID- 10344268
TI  - Decreased levels of synaptosomal associated protein 25 in the brain of patients
      with Down syndrome and Alzheimer's disease.
AB  - Synaptosomal associated protein 25 kDa (snap-25) is a widely distributed membrane
      associated protein in the brain, mainly localized in nerve terminals. In nerve
      terminals, snap-25 participates in docking and/or fusion of synaptic vesicles
      with the plasmalemma, a process essential for synaptic vesicle exocytosis. Recent
      work suggests a role in brain development, forming presynaptic sites by
      regulating axonal outgrowth and nerve growth-induced neurite elongation. In Down
      syndrome (DS) brain, it is abnormally developed from early life, and brain
      pathology becomes even more pronounced when Alzheimer's disease (AD) develops in
      the fourth decade. This information led us to examine snap-25 in the brain of
      patients with DS and AD. We studied snap-25 and glial fibrillary acidic protein
      (GFAP) brain levels in five individual brain areas of 9 aged patients with DS, 9
      patients with AD and 9 controls, applying two-dimensional gel electrophoresis.
      Decreased snap-25 levels were found in the five brain regions of the patients
      with DS and AD. Increased expression levels of GFAP were found in the frontal,
      parietal, temporal and occipital cortex regions of the DS and AD patients.
      Decreased snap-25 protein levels in the brain of DS and AD may reflect impaired
      synaptogenesis or represent neuronal loss. Findings of increased GFAP, a marker
      for neuronal loss, along with data from literature would support the notion of
      decreased snap-25 secondary to neuronal decay in both neurodegenerative
      disorders.

PMID- 10344269
TI  - A proteome analysis of livers from obese (ob/ob) mice treated with the peroxisome
      proliferator WY14,643.
AB  - The PPAR (peroxisome proliferator activated receptor) transcription factors are
      ligand-activated receptors which regulate genes involved in lipid metabolism and
      homeostasis. PPARalpha is preferentially expressed in the liver and PPARgamma
      preferentially in adipose tissue. Activation of PPARalpha leads to peroxisome
      proliferation in rodents and increased beta-oxidation of fatty acids. PPARgamma
      activation leads to adipocyte differentiation and improved insulin signaling of
      mature adipocytes. Both of these PPAR receptors are potential targets for
      treatment of dyslipidemia in man. Studies by others using a proteomics approach
      have characterized the effects of PPARalpha agonists in livers from lean healthy
      mice. However, we wanted to map the effects of a therapeutic dose of a PPARalpha
      agonist in a disease model of insulin resistance and diabetes, the obese diabetic
      ob/ob mouse, by proteomics. Therefore, ob/ob mice, which have highly elevated
      levels of plasma triglycerides, glucose and insulin, were treated for one week
      with WY14,643 (180 micromol/kg/day), a well-characterized selective PPARalpha
      agonist. Plasma triglycerides, glucose and insulin levels were determined and we
      found significant therapeutic effects on triglycerides and glucose levels. The
      liver protein compositions were investigated by high-resolution two-dimensional
      gel electrophoresis which showed that WY14,643 produced up-regulation of at least
      16 spots. These were identified by mass spectrometry and 14 spots were found to
      be components of the peroxisomal fatty acid metabolism. Thus, WY14,643 at a
      therapeutic dose, caused induction of peroxisomal fatty acid beta-oxidation in
      obese diabetic mice.

PMID- 10344270
TI  - Regional protein alterations in rat kidneys induced by lead exposure.
AB  - Lead is a potent neuro- and nephrotoxin in humans and a renal carcinogen in rats.
      Previous studies have detected lead-induced increases in the activities of
      specific detoxification enzymes in distinct kidney cell types preceding
      irreversible renal damage. While preferential susceptibility of the highly
      vascularized cortex to the effects of lead is clear, lead effects on the
      medullary region have remained unexplored. The present study was undertaken to
      investigate the extent to which regional renal protein expression differs and to
      determine which, if any, regionally distinct protein markers indicative of lead's
      renotoxic mechanism might be detected in kidney cortical and medullary cytosols.
      We examined protein expression in these two functionally and anatomically
      distinct regions, and identified several proteins that are differentially
      expressed in those regions and were significantly altered by lead. Kidney
      cytosols from rats injected with lead acetate (114 mg/kg, three consecutive daily
      injections) were separated by two-dimensional electrophoresis. Lead exposure
      significantly (P<0.001) altered the abundance (either or) of 76 proteins in the
      cortex and only 13 in the medulla. Eleven of the proteins altered in the protein
      patterns were conclusively identified either by matrix-assisted laser
      desorption/ionization mass spectrometry/electrospray ionization-mass spectrometry
      (MALDI-MS/ESI-MS) analysis of peptide digests, immunological methods, or by gel
      matching. Several of the cortical proteins altered by lead were unchanged in the
      medulla while others underwent similar but lesser alterations. These observations
      reflect the complexity of lead's nephrotoxicity and endorse the application of
      proteomics in mechanistic studies as well as biomarker development in a variety
      of toxicologic paradigms.

PMID- 10344271
TI  - Functional proteomics of signal transduction by membrane receptors.
AB  - Functional proteomic methods have been developed and applied to the investigation
      of signal transduction systems involving platelet-derived growth factor (PDGF),
      endothelin and bradykinin receptors. Mouse fibroblast cells have been stimulated
      with PDGF or endothelin. Phosphorylation/dephosphorylation of several hundred
      proteins has been followed as a function of time following stimulation using 2-D
      gel electrophoresis and anti-phosphotyrosine or anti-phosphoserine antibodies. Up
      to 100 of these proteins showed strong changes in phosphorylation with minutes of
      receptor stimulation. Identification of some of these proteins by mass
      fingerprinting using matrix-assisted laser desorption/ionization-time of flight
      (MALDI-TOF) mass spectrometry and by partial peptide sequencing with ion trap
      electrospray mass spectrometry has identified proteins which were previously
      known to be associated with PDGF signaling, proteins which have been shown to be
      involved in other signaling pathways, but not PDGF and proteins not previously
      associated with signal transduction. Parallel to these studies, new methods for
      rapid, single-step isolation of peptide receptors using a peptide coupled to a
      (dA)30 oligonucleotide have been developed and applied to mass spectrometric
      studies of post-translational modifications of the endothelin B and bradykinin B2
      receptors under in vivo conditions. Both receptors have been shown to undergo
      extensive phosphorylation as well as palmitoylation. The patterns of post
      translational modifications are more complex than previously recognized and
      provide new indications of possible roles for these modifications in the
      regulation and response of these receptors.

PMID- 10344272
TI  - Modulation of signal transduction pathways and global protein composition of
      macrophages by ionizing radiation.
AB  - It is assumed that the exposure of cells to ionizing radiation modulates their
      signal transduction pathways, which then govern the early and late radiation
      induced alterations in gene expression. In this study we tested the effects of
      low doses of X-irradiation on the cell signaling and global protein composition
      of an HL-60 human promyelocytic leukemia cell line differentiated along a
      macrophage-like cell pathway by 4beta-phorbol-12-myristate-13-acetate (PMA).
      Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)
      followed by immunoblotting of anti-phosphotyrosine immunoprecipitates, we found
      radiation-induced changes in the level of phosphorylation of proteins with
      molecular masses of 45 and 48 kDa, but in the most intensively stained area,
      ranging from 54 to 60 kDa, no alterations were observed. When two-dimensional
      electrophoresis (2-DE) immunoblotting was applied, only proteins from this
      heavily stained region were visualized and in addition the evident differences in
      tyrosine phosphorylated protein patterns between nonirradiated and irradiated
      cells were found in this area. Furthermore, the immunostaining of extracellular
      signal-regulated kinase 2 (ERK2) which did not prove its tyrosine phosphorylation
      demonstrated the existence of several ERK2 charge isoforms showing differential
      expression after X-irradiation. Comparing the whole protein profiles we found
      after the simultaneous quantitation of 1000 matched spots two proteins whose
      expression was regulated in an opposite manner in nonirradiated and X-irradiated
      cells. The quantities of both spots showed increases or decreases by a factor of
      2 or more between irradiated and nonirradiated samples and both these changes
      were statistically significant (P<0.05).

PMID- 10344273
TI  - Characterisation of stem cell expression using two-dimensional electrophoresis.
AB  - Stem cells were isolated from foetal human brain tissue and induced to
      proliferate using the mitogens epidermal growth factor (EFG) and fibroblast
      growth factor (FGF). Under these conditions the dividing cells formed spheres
      which could be maintained in an undifferentiated state for extended periods of
      time. Following removal of the mitogen and addition of serum, the human stem
      cells rapidly began to differentiate. Samples from differentiated and
      undifferentiated cultures were lysed and analysed using two-dimensional (2-D)
      electrophoresis, a powerful technique for the separation and characterisation of
      proteins in complex mixtures. After 1 h post-differentiation, marked differences
      in protein expression could be observed between undifferentiated and
      differentiated stem cell samples.

PMID- 10344274
TI  - The characterization of human spermatozoa membrane proteins--surface antigens and
      immunological infertility.
AB  - The aim of this study was to isolate and characterize highly enriched membrane
      proteins by two-dimensional (2-D) electrophoresis and to identify surface
      antigens binding sperm autoantibodies (SpAb). The presence of SpAb may reduce
      fertility by affecting sperm motility and acrosome reaction. The presence of the
      SpAb was shown to prevent sperm penetration of cervical mucus, to inhibit sperm
      zona pellucida interaction, and to interfere with the sperm-egg fusion. The swim
      up method was used to separate mature and motile sperm. Sperm membranes were
      obtained by hypoosmotic swelling, homogenization and sonication. Membranes were
      further isolated by differential centrifugation steps. The highly purified human
      sperm membrane proteins were separated by two-dimensional gel electrophoresis and
      electrotransferred to polyvinylidene difluoride (PVDF) membrane. The antigens
      were identified by bound SpAb, the sources of which were seminal plasma samples
      of infertile patients or of patients following vasectomy. Fourteen surface
      antigens were detected. Their identification may be (i) important for
      understanding the mechanism by which SpAb impair sperm fertilization capacity,
      (ii) suitable as a basis of new methods of fertility regulation, and (iii)
      helpful in developing reproducible and reliable methods for determinations of
      SpAb.

PMID- 10344275
TI  - Mapping and identification of HeLa cell proteins separated by immobilized pH
      gradient two-dimensional gel electrophoresis and construction of a two
      dimensional polyacrylamide gel electrophoresis database.
AB  - The HeLa cell line, a human adenocarcinoma, is used in many research fields,
      since it can be infected with a wide range of viruses and intracellular bacteria.
      Therefore, the mapping of HeLa cell proteins is useful for the investigation of
      parasite host cell interactions. Because of the recent improvements of two
      dimensional gel electrophoresis with immobilized pH gradients (IPG) compared to
      isoelectric focusing with carrier ampholytes, a highly reproducible method for
      examining global changes in HeLa cell protein expression due to different stimuli
      is now available. Therefore, we have initiated the mapping of
      [35S]methionine/cysteine-labeled HeLa cell proteins with the 2-D PAGE (IPG)
      system, using matrix-assisted laser desorption/ionization-mass spectrometry
      (MALDI-MS) and N-terminal sequencing for protein identification. To date 21
      proteins have been identified and mapped. In order to make these and future data
      accessible for interlaboratory comparison, we constructed a 2-D PAGE database on
      the World Wide Web.

PMID- 10344276
TI  - Mapping and identification of interferon gamma-regulated HeLa cell proteins
      separated by immobilized pH gradient two-dimensional gel electrophoresis.
AB  - Interferon gamma (IFN-gamma) is a potent immunomodulatory lymphokine, secreted by
      activated T-lymphocytes and NK-cells during the cellular immune response. Actions
      of IFN-gamma are mediated through binding to the IFN-gamma-receptor, present on
      most cells, and the subsequent activation of a great magnitude of IFN-gamma
      responsive genes has been reported previously. Our goal is to identify and map
      IFN-gamma-regulated HeLa cell proteins to the two-dimensional polyacrylamide gel
      electrophoresis with the immobilized pH gradient (IPG) two-dimensional
      polyacrylamide gel electrophoresis (2-D PAGE) system. A semiconfluent layer of
      HeLa cells was grown on tissue culture plates, and changes in protein expression
      due to 100 U/mL IFN-gamma were investigated at different periods after treatment,
      using pulse labeling with [35S]methionine/cysteine in combination with 2-D PAGE
      (IPG). The identity of eight protein spots was elucidated by matrix-assisted
      laser desorption/ionization-mass spectrometry (MALDI-MS), and several variants of
      the IFN-gamma-inducible tryptophanyl-tRNA synthetase (hWRS) were detected by
      immunoblotting.

PMID- 10344277
TI  - A two-dimensional protein map of Chinese hamster ovary cells.
AB  - Chinese hamster ovary (CHO) cells are used extensively for the expression of
      biopharmaceutical protein products. As part of our effort to better understand
      CHO cell physiology and protein expression changes caused by modified culture
      conditions, we have begun to map CHO cell polypeptides. A parental cell line
      reference map was established using two-dimensional gel electrophoresis with
      immobilized pH gradients (pH 3-10) in the first dimension and a linear acrylamide
      gradient (9-18%T) in the second dimension. The map is composed of over 1000
      silver-stained protein spots. Protein identification is proceeding using a
      combination of immunostaining, NH2-terminal sequencing, and mass spectrometric
      analyses. Among the proteins so far identified are glucose-regulated protein 78
      (GRP78), protein disulfide isomerase (PDI), galectin-1, and several heat-shock
      proteins. The goal is to generate a database which emphasizes those proteins most
      relevant to the use of CHO cells as a host for recombinant protein expression.

PMID- 10344278
TI  - Two-dimensional gel electrophoresis as analytical tool for identifying Candida
      albicans immunogenic proteins.
AB  - This paper reports the usefulness of two-dimensional gel electrophoresis followed
      by Western blotting with sera from patients with systemic candidiasis in the
      identification of the major Candida albicans antigens. In order to have different
      patterns of protein expression and subcellular localization, three types of
      protein preparations were obtained: cytoplasmic extracts, protoplast lysates and
      proteins secreted by protoplasts regenerating their cell wall. These proteins
      were separated by high-resolution two-dimensional electrophoresis using an
      immobilized pH gradient. Western blotting with sera from patients with systemic
      candidiasis allowed the detection of more than 18 immunoreactive proteins. Some
      of these proteins had different isoforms. All sera reacted with at least three C.
      albicans proteins and the most reactive serum detected up to eleven proteins.
      Some of these antigens, e.g., enolase and glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH), have been identified on the 2-D map. The most reactive
      proteins were enolase and a 34 kDa protein in the acidic part of the gel (pI 4
      4.4) that was only detected in regenerating protoplast-secreted proteins. The
      identification of all these antigens would be useful for the development of
      diagnostic strategies.

PMID- 10344279
TI  - Biochemical analysis of membrane proteins from an early maturation stage of
      phagosomes.
AB  - We used an improved technique for pulse-chase labeling of phagosomes using custom
      made magnetic microparticles. With the help of a permanent magnet we purified
      both newly formed, nascent and early matured (i.e., 5-min-old) condensed
      phagosomes in high amounts. The protein patterns of membrane proteins of newly
      formed phagosomes and 5-min-old condensed ones were compared by two-dimensional
      (2-D) electrophoresis. The protein patterns allowed the detection of protein
      spots that changed in abundance between these two stages. Three protein spots
      abundant in condensed phagosomes only and one spot well-stained in both stages
      were collected from ten preparative Coomassie brilliant blue-stained 2-D gels.
      Following microdigestion, selected purified oligopeptides were sequenced by Edman
      degradation. While the oligopeptide sequences of proteins from two spots showed
      high homology to an already sequenced 25 kDa calcium binding protein, the other
      two showed no significant homology to protein sequences available in sequence
      databases. Presently polymerase chain reaction (PCR) and cloning experiments are
      set up to reveal the cDNAs of these proteins in order to study their function by
      knock-out and gene replacement experiments.

PMID- 10344280
TI  - A computer-assisted two-dimensional gel electrophoresis approach for studying the
      variations in protein expression related to an induced functional repression of
      NFkappaB in lymphoblastoid cell lines.
AB  - Strategies are needed for conclusive interpretation of two-dimensional gel
      electrophoresis (2-D PAGE) maps in order to identify pertinent differences in
      protein expression during regulation of the transcription of discrete sets of
      genes. The model used in this study was a human lymphoblastoid cell line in which
      a functional repression of the transcription factors NFkappaB was obtained by
      induction of overexpression of IkappaBalpha, a physiological inhibitor of
      NFkappaB. The analytical methodology used relies on the comparison of two sets of
      2-D PAGE maps for detecting differences in protein expression between samples
      overexpressing or not overexpressing IkappaBalpha. The analysis was based on a
      combination of an automatic computerized analysis, constituting an actual aid for
      deciding, and of an interactive visual validation, corresponding to the
      interpretation of computer propositions. This strategy is proposed as a rapid way
      to detect potential variations in protein expression applicable to any biological
      model. In this study, correspondence analysis data made it possible to discrimate
      between the samples overexpressing or not overexpressing IkappaBalpha, and
      pointed out some of the potential meaningful spots characterizing the samples in
      which NFkappaB was active. Then, after visual validation of the computer data, 53
      polypeptides were considered to be different in the two classes of gels. Five
      polypeptides were specifically found in both samples overexpressing IkappaBalpha.
      The overexpression of IkappaB also induced a lower expression of 11 polypeptides.
      Finally, 15 polypeptides were only expressed in samples in which IkappaBalpha was
      not overexpressed and, consequently, in which NFkappaB factors were active. Thus,
      these polypeptides are candidates for further analysis as putative target gene
      products of NFkappaB.

PMID- 10344281
TI  - Technology development at the interface of proteome research and genomics:
      mapping nonpolymorphic proteins on the physical map of mouse chromosomes.
AB  - Data obtained from protein spots by peptide mass fingerprinting are used to
      identify the corresponding genes in sequence databases. The relevant cDNAs are
      obtained as clones from the Integrated Molecular Analysis of Genome Expression
      (I.M.A.G.E.) consortium. Mapping of I.M.A.G.E. clones is performed in two steps:
      first, cDNA clones are hybridized against a 10-hit genomic mouse bacterial
      artificial chromosome (BAC) library. Second, interspersed repetitive sequence
      polymerase chain reaction (IRS-PCR) using a single primer directed against the
      mouse B1 repeat element is performed on BACs. As each cDNA detects several BACs,
      and each individual BAC has a 50% chance to recover an IRS-PCR fragment, the
      majority of cDNAs produce at least a single IRS-PCR fragment. Individual IRS
      fragments are hybridized against high-density spotted filter grids containing the
      three-dimensional permutated pools of yeast artificial chromosome (YAC) library
      resources that are currently being used to construct a physical map of the mouse
      genome. IRS fragments that hybridize to YAC clones already placed into contigs
      immediately provide highly precise map positions. This technology therefore is
      able to draw links between proteins detected by 2-D gel electrophoresis and the
      corresponding gene loci in the mouse genome.

PMID- 10344282
TI  - Active dissociation of the fluorescent dye Hoechst 33342 from DNA in a living
      cell: who could do it?
AB  - It is assumed that DNA in mammalian cells is a dynamic conformationally unstable
      system. This instability provides the cell with a mechanism for dissociating a
      large number of substances that bind tightly but not covalently to DNA. Among
      these is the fluorescent dye Hoechst 33342, which binds to DNA in the minor
      groove. We have selected cell lines with a high capability for active
      dissociation of Hoechst 33342. Comparative protein analysis of these lines by
      means of two-dimensional (2-D) electrophoresis was performed. Cell and nuclear
      proteins were analyzed from these and normal strains. A few proteins with
      significantly changed quantities have been found. The preliminary search of the 2
      D database allowed us to identity some known and unknown cellular proteins that
      could participate in active dissociation of the dye from DNA.

PMID- 10344283
TI  - Two-dimensional gel analysis of protein expression in ovarian tumors shows a low
      degree of intratumoral heterogeneity.
AB  - The process of tumor progression leads to the emergence of multiple clones, and
      to the development of tumor heterogeneity. One approach to the study of the
      extent of such heterogeneity is to examine the expression of marker proteins in
      different tumor areas. Two-dimensional gel electrophoresis (2-DE) is a powerful
      tool for such studies, since the expression of a large number of polypeptide
      markers can be evaluated. In the present study, tumor cells were prepared from
      human ovarian tumors and analyzed by 2-DE and PDQUEST. As judged from the
      analysis of two different areas in each of nine ovarian tumors, the intratumoral
      variation in protein expression was low. In contrast, large differences were
      observed when the protein profiles of different tumors were compared. The
      differences in gene expression between pairs of malignant carcinomas were
      slightly larger than the differences observed between pairs of benign tumors. We
      conclude that 2-DE analysis of intratumoral heterogeneity in ovarian cancer
      tissue indicates a low degree of heterogeneity.

PMID- 10344285
TI  - Characterization of colonic polyps by two-dimensional gel electrophoresis.
AB  - To identify proteins that may specifically characterize colonic polyps we have
      investigated the abundance of numerous proteins in epithelial cells from 15
      normal colon specimens and 13 colonic polyps, using two-dimensional gel analysis
      to detect possible differences in expression. Silver-stained digitized images of
      the gels were analyzed with Melanie II 2.1 software. We consistently detected
      more than 700 protein spots on each gel, and found that the intensity of 59 of
      them was significantly altered in polyp specimens (Wilcoxon test assuming P< or
      =0.05). Immunostaining, microsequencing and mass spectrometry (matrix-assisted
      laser desorption/ionization - time of flight; MALDI-TOF) techniques were used to
      identify these proteins and selected others that did not show differential
      regulation. The expression of numatrin (nucleophosphine/B23), hsp 70, and hsp60
      was increased in polyps; levels of fatty acid binding protein (L-FABP), 14-3-3
      sigma, citokeratin 20, cytochrome c oxidase polypeptide Va, Rho GDP-dissociation
      inhibitor (Rho GDI), and beta- and gamma-actins were decreased. Although the
      levels of expression of a given protein often varied among polyp specimens, it
      generally held true that the direction of variation (up or down) remained
      constant across the panel. We concluded that proteins showing constant
      differential regulation across all or most of the polyp specimens represent the
      most characteristic regulatory pathways in colon polyps, while more sporadic
      variations reflect characteristics of individual polyps.

PMID- 10344286
TI  - Protein changes associated with ionizing radiation-induced apoptosis in human
      prostate epithelial tumor cells.
AB  - Ionizing radiation (IR) is an important component in the therapy of localized
      prostate cancer. Identification of protein alterations during IR-induced
      apoptosis prostate cancer cells is an important step toward understanding the new
      metabolic status of the dying cell. In the present study, we report changes in
      protein profile that define the execution phase of the apoptotic response in the
      in vitro model of tumorigenic radiation-transformed SV40-immortalized human
      prostate epithelial cells (267B1-XR), induced to undergo programmed cell death by
      IR. We employed an approach that involves use of analytical two-dimensional
      polyacrylamide gel electrophoresis (2-D PAGE) coupled with Western blotting with
      specific antisera. Our results point out that apoptotic cells experience
      significant reduction in the levels of the intermediate filament proteins,
      keratins-18, 19, vimentin and the associated 14-3-3 adapter proteins. At the same
      time, molecular chaperones such as glucose-regulated protein 94, calreticulin,
      calnexin, and protein disulfide isomerase exhibit marked accumulation in these
      dying cells. The present data indicate that apoptosis-associated processes in
      prostate epithelial cells include solubilization of the rigid intermediate
      filament network by specific proteolysis as well as increased levels of
      endoplasmic reticulum (ER) proteins with chaperone functions.

PMID- 10344284
TI  - The analysis of S100A9 and S100A8 expression in matched sets of macroscopically
      normal colon mucosa and colorectal carcinoma: the S100A9 and S100A8 positive
      cells underlie and invade tumor mass.
AB  - The expression of calcium-binding protein S100A9 was investigated in 23 matched
      sets of colorectal carcinoma and normal colon mucosa using two-dimensional gel
      electrophoresis. We found that, from a group of 23 patients, the level of S100A9
      protein, in comparison with matched normal colon mucosa, was significantly
      increased in malignant tissues of 16 patients (70%). Furthermore, an additional
      protein, identified by matrix-assisted laser desorption/ionization - mass
      spectrometry (MALDI-MS) as S100A8, exhibited an increased expression in the same
      specimens of malignant tissues as the S100A9 protein. The immunohistological
      analysis revealed the accumulation of S100A9 positive cells, macrophages and
      polymorphonuclear leukocytes along the invasive margin of colorectal carcinoma.
      The S100A8 protein was found to be produced in the same location. The possible
      participation of both proteins and, especially, its heterodimeric complex
      calprotectin in colorectal carcinoma regression could be taken into account.

PMID- 10344287
TI  - Two-dimensional electrophoresis of prostate-specific antigen in sera of men with
      prostate cancer or benign prostate hyperplasia.
AB  - Prostate-specific antigen (PSA), the main marker for prostate cancer (PCa), is
      released from the prostate into the blood stream at nanogram level and may
      increase in PCa and nonmalignant disease such as benign prostate hyperplasia
      (BPH). More recently, advantage was taken of PSA's ability to bind to protease
      inhibitors in serum in order to improve discrimination between PCa and BPH, using
      the free PSA to total PSA ratio. The understanding of this phenomenon at
      molecular level, which is still unknown, may promise new improvements in the
      field of diagnostics. For this purpose, we determined the pattern of PSA forms in
      PCa and BPH sera, using the high resolving power of two-dimensional
      electrophoresis (2-DE) in conjunction with the high sensitivity of
      chemiluminescence detection. Serum PSA differs drastically from seminal PSA:
      apart from complexed forms, serum PSA shows few cleaved forms. Moreover, 2-DE
      patterns from PCa are relatively homogeneous, whereas patterns from BPH may in
      some cases present a higher proportion of cleaved forms and in other cases
      present slightly more basic spots. We therefore demonstrated, for the first time,
      that an increase in the free to total PSA ratio in BPH cases may be due to
      cleaved PSA forms (which are enzymatically inactive and unable to bind
      inhibitors), or possibly related to basic free PSA, which may represent the
      zymogen forms.

PMID- 10344288
TI  - A novel isoform ratio switch of the polypyrimidine tract binding protein.
AB  - In this report we present evidence for a novel switch in the ratio of the two
      major isoforms of the polypyrimidine tract binding protein (PTB) in two related
      prostate cancer cell lines. The existence of different isoforms of PTB is thought
      to be the result of alternative splicing. We used UV cross-linking to identify a
      PTB doublet in the DT3 cell line, which is a rat prostate epithelial cancer line
      that is androgen-dependent and nonmetastatic. The AT3 cell line, a metastatic,
      androgen-independent cell line derived from the same tumor as the DT3 cells, was
      noted here to have a different isoform ratio of PTB. The two most prevalent
      isoforms of PTB were found to bind to an RNA probe containing a pyrimidine
      stretch. Western blot analysis demonstrated that these isoforms are indeed
      expressed differently in the two cell lines and that the observed binding is the
      result of this differential expression. These two cell lines are derived from the
      original Dunning prostate tumor, which is a model for studying tumor progression
      in the prostate. This ratio switch may be an important event in tumor progression
      in this model system of prostate cancer.

PMID- 10344289
TI  - Glial fibrillary acidic protein and its fragments discriminate astrocytoma from
      oligodendroglioma.
AB  - In the last few years it has been shown that anaplastic oligodendrogliomas, in
      contrast to anaplastic astrocytomas, are responsive to a three drug regimen
      chemotherapy. The histologic criteria for the discrimination between
      oligodendrogliomas and astrocytomas are subject to substantial interobserver
      variability, particularly in anaplastic and mixed gliomas. In the present study a
      two-dimensional electrophoresis technique (2-DE) has been applied to glioma
      samples in an attempt to discriminate the glioma subtypes. It was found that the
      presence of glial fibrillary acidic protein (GFAP) fragments distinguishes
      oligodendroglioma from astrocytoma. One-dimensional (1-DE) immunoblots were
      compared with immunohistologically stained tissue sections in which various GFAP
      positive cell types were seen. It is concluded that 2-DE and 1-DE GFAP
      immunoblotting provide accurate information for the reliable discrimination of
      anaplastic astrocytomas and oligodendrogliomas.

PMID- 10344290
TI  - Identification of HSP-60 as the specific antigen of IgM produced by BRG-lymphoma
      cells.
AB  - In previous studies we described a patient with Burkitt's lymphoma and AIDS,
      whose cells recognized a molecule expressed by normal and malignant breast cells.
      In the present study, we identified this antigen by two-dimensional (2-D)
      electrophoresis and Western blotting using the antibody produced by lymphoma
      cells. The antigen so identified consisted of two clusters of spots with a
      molecular mass (Mr) of 60 and 50 kDa, respectively. Preparative immobilized pH
      gradient (IPG) was subsequently used to isolate the clusters of spots of higher
      molecular masses, from which peptide fragments of approximately 10 aa were
      separated on reverse-phase chromatography and sequenced. This procedure enabled
      the identification of the antigen recognized by the lymphoma cells as HSP-60. By
      means of serological analyses it was possible to identify the lower molecular
      mass cluster of spots as a molecule related to HSP-60. It is hypothesized that
      this molecule is a membrane form of HSP-60 that differs from HSP-60 in a COOH
      terminal portion.

PMID- 10344291
TI  - Separation and characterization of needle and xylem maritime pine proteins.
AB  - Two-dimensional gel electrophoresis (2-DE) and image analysis are currently used
      for proteome analysis in maritime pine (Pinus pinaster Ait.). This study presents
      a database of expressed proteins extracted from needles and xylem, two important
      tissues for growth and wood formation. Electrophoresis was carried out by
      isoelectric focusing (IEF) in the first dimension and sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE) in the second. Silver staining made
      it possible to detect an average of 900 and 600 spots on 2-DE gels from needles
      and xylem, respectively. A total of 28 xylem and 35 needle proteins were
      characterized by internal peptide microsequencing. Out of these 63 proteins, 57
      (90%) could be identified based on amino acid similarity with known proteins, of
      which 24 (42%) have already been described in conifers. Overall comparison of
      both tissues indicated that 29% and 36% of the spots were specific to xylem and
      needles, respectively, while the other spots were of identical molecular weight
      and isoelectric point. The homology of spot location in 2-DE patterns was further
      validated by sequence analysis of proteins present in both tissues. A proteomic
      database of maritime pine is accessible on the internet
      (http://www.pierroton.inra.fr/genetics/2D/).

PMID- 10344292
TI  - Two-dimensional electrophoretic analysis of proteins associated with somatic
      embryogenesis development in Cupressus sempervirens L.
AB  - Two-dimensional gel electrophoretic analysis and histological studies were
      performed on somatic embryos in cypress. Embryogenic cultures were obtained from
      in vitro culture of immature seeds. On a modified Murashige and Skoog (MS) medium
      they showed an intense and repetitive cleavage polyembryogenesis phenomenon which
      maintained them in a continuous proliferating status instead of undergoing a
      complete embryogenic development. Only the addition of bovine serum albumin to
      the culture allowed somatic embryo development and maturation. Major histological
      differences were noticed between developing and nondeveloping embryogenic
      cultures. Attempts to find proteins that could be associated with developmental
      stages of somatic embryos have been achieved. Proteins were extracted and
      analyzed by two-dimensional electrophoresis from nondeveloping embryogenic
      cultures (S0) and from embryogenic cultures at three different stages of somatic
      embryo development: small size and rounded shape embryos (S1), increased size
      embryos with a well-developed suspensor (S2) and embryos with two well-separated
      cotyledons (S3). The results revealed some qualitative and quantitative protein
      variations between the two cultures. Some could be connected with the induction
      of pro-embryo differentiation whereas others should be more related to the
      mechanisms involved in somatic embryo development and maturation. Specific
      polypeptides associated with the presence of bovine serum albumin (BSA) in the
      medium have been detected.

PMID- 10344293
TI  - Short-term hypoxia downregulates epithelial cell desquamation in vivo, but does
      not increase Pseudomonas aeruginosa adherence to exfoliated human corneal
      epithelial cells.
AB  - PURPOSE: This study evaluates the effect of hypoxic and hypercapnic stress on
      bacterial adherence to surface corneal epithelial cells, as well as tear LDH
      levels, surface cell desquamation, and corneal swelling in normal human subjects.
      METHODS: Sixteen eyes of eight human volunteers were successively exposed to
      three gas mixtures (air, 100% N2, 95% N2-5% CO2) through tightly fitted goggles
      for six hours at two-week intervals. Exfoliated epithelial cells were collected
      and counted using a modified corneal irrigation chamber. Bacterial binding was
      determined by measuring Pseudomonas aeruginosa (PA) adherence to exfoliated
      corneal epithelial cells. The effects of hypoxic or hypercapnic stress on the
      corneal surface were also assessed by tear LDH measurement, and quantification of
      surface epithelial cell size and epithelial and stromal thickness were determined
      by in vivo confocal microscopy. RESULTS: Short-term precorneal hypoxia
      significantly decreased corneal epithelial cell desquamation. Both short-term
      hypoxia alone and combined with hypercapnia induced significant corneal stromal
      swelling (7 to 8%) but did not significantly enhance PA adherence to exfoliated
      human corneal epithelial cells. CONCLUSIONS: This study demonstrates, for the
      first time, that short-term precorneal hypoxia downregulates corneal epithelial
      cell desquamation in humans. These results also demonstrate that short-term
      hypoxia alone or combined with hypercapnia does not significantly increase PA
      adherence to exfoliated epithelial cells from the human cornea. The results
      reveal that either longer hypoxic exposure or other interactive factor(s),
      including but not limited to the mechanical effect of the contact lens itself,
      may be required for promotion of increased epithelial cell-PA binding following
      lens wear in humans.

PMID- 10344295
TI  - Comparison of tear lactate dehydrogenase activities of different types of contact
      lens wearers and normal control group.
AB  - PURPOSE: The purpose of this study was to compare the lactate dehydrogenase (LDH)
      activities in the tears of patients wearing different types of contact lenses
      with each other and to individuals who have never worn contact lenses (controls).
      METHODS: Tear LDH activities were determined in 13 normal subjects who had never
      worn contact lenses, 12 daily wear and ten extended wear soft contact lens
      wearers, and 14 daily wear and eight extended wear rigid gas permeable (RGP)
      contact lens wearers(Dk125). Tear samples were collected from all subjects at the
      same time of day from the inferior meniscus by using a microcapillary tube. The
      measurements were determined using a Sigma diagnostic LDH reagent and a
      spectrophotometer. RESULTS: There was no statistically significant difference in
      the LDH activities between soft and RGP contact lenses--used either as daily or
      extended wear--when compared with each other. However, individuals wearing
      extended wear soft contact lenses had significantly higher tear LDH activities
      than the control group. CONCLUSION: Tear LDH activity may be a useful method in
      evaluating the physiologic response of extended soft contact lens wear.

PMID- 10344294
TI  - The relationship between contact lens oxygen permeability and binding of
      Pseudomonas aeruginosa to human corneal epithelial cells after overnight and
      extended wear.
AB  - PURPOSE: We designed a 3-year, prospective, randomized, masked clinical trial to
      evaluate the relationship of contact lens oxygen transmissibility and bacterial
      adherence to exfoliated surface epithelial cells in human overnight and extended
      lens wearers in a single center; corneal cell desquamation rate, surface
      epithelial cell size, and tear lactate dehydrogenase (LDH) levels were also
      determined concurrently. METHODS: One hundred nine human volunteers were
      successfully fit with test lenses prospectively and completed this study. Seven
      soft and three rigid gas permeable (RGP) lenses with stratified oxygen
      transmissibility were evaluated. After one week adaptation to daily wear,
      patients continually wore test lenses bilaterally for three months on a six
      nights wear, one night off basis. Before and after 24 hour, 1 month, and three
      months extended contact lens wear, exfoliated surface epithelial cells were
      collected using a modified corneal irrigation chamber. Bacterial binding was
      determined by measuring Pseudomonas aeruginosa (PA) adherence to exfoliated
      corneal epithelial cells. The number of exfoliated cells with adherent bacteria
      were counted using fluorescence microscopy. The effects of contact lens wear on
      the corneal surface were further assessed by alterations in tear LDH, and by
      surface epithelial cell size and epithelial thickness using in vivo tandem
      scanning confocal microscopy (TSCM). Baseline values of outcome measures served
      as controls for individual patients; a concurrent group of controls were also
      followed to monitor seasonal or possible individual fluctuations. RESULTS:
      Quantitative evidence demonstrated that lens physical oxygen transmissibility
      properties and not lens type significantly correlated inversely with binding of
      PA to human exfoliated corneal epithelial cells after overnight and extended wear
      (R=0.258, P=0.0084); there was a significant decrease in surface epithelial cell
      desquamation and a significant increase in surface cell size following wear for
      all test lenses (P<0.05). Epithelial thinning was also observed following lens
      wear (P<0.05). CONCLUSIONS: These results establish for the first time a
      significant correlation between contact lens-induced increases in epithelial PA
      binding and lens oxygen transmissibility in humans. New ultra-oxygen permeable
      test lenses did not appear to increase bacterial binding over individual control
      levels; all test lenses suppressed surface epithelial cell shedding. Taken
      together, these findings suggest that a new generation of contact lenses
      constructed from ultra-transmissible oxygen materials may offer a significant
      potential advance in safety for extended wear.

PMID- 10344297
TI  - Effects of eyelid scrubbing on the lid margin.
AB  - PURPOSE: To compare the effects of eyelid scrubbing with an eyelid cleansing
      solution (ECS) to eyelid scrubbing with ECS and the addition of antibacterial or
      anti-inflammatory pharmaceuticals on the clinical appearance, microbial status,
      tissue histology, and the inflammatory cell profile of the normal eyelid margin.
      METHODS: Eyelid scrubbing was performed twice daily using ECS; ECS with the
      antibacterial sulfacetamide (ECS+); and ECS with sulfacetamide and prednisolone
      acetate (ECS++) over a 21 day period on three groups of 16 rabbits with
      clinically normal eyelids. RESULTS: Significant hyperemia of the margin occurred
      in all three groups over the 3 week period; however, the degree of hyperemia was
      less with ECS+ (P<0.05) and ECS++ (P<0.05). Chemosis, tearing, mucus discharge,
      and the microbial status were not significantly different than controls. There
      were no marked histologic differences in the tissues, except for increased red
      blood cell packing in the small vessels near the lid margins in scrubbed eyelids,
      consistent with hyperemia. The inflammatory cell profile showed minimal changes
      that were not statistically significant in any of the three groups, except that
      >50% of mast cells showed evidence of degranulation. CONCLUSIONS: Use of ECS with
      an antibiotic, or an antibiotic and steroid solution, resulted in less
      inflammation than scrubbing with ECS alone.

PMID- 10344296
TI  - Papillary hypertrophy of the upper tarsal conjunctiva during contact lens wear: a
      4-month study with ethyl-6-O-decanoyl-glucoside.
AB  - PURPOSE: We studied the potential effect of ethyl-6-O-decanoyl-glucoside (EDG) on
      papillary hypertrophy in contact lens wearers who were recruited on the basis of
      papillary hypertrophy and a long history of contact lens wear. The contact lens
      care solutions were 0.00025% chlorhexidine acetate (CHX) with or without 0.005%
      EDG. METHODS: Nineteen subjects wearing both ionic and non-ionic contact lenses
      for 6-18 hours used either CHX or CHX+EDG as a cleaning and disinfecting agent.
      CHX and CHX+EDG was used simultaneously by each subject but in different eyes
      during two consecutive periods of 8 weeks. Symptoms and signs were recorded at
      three examinations during the study. The protein content of contact lenses and
      tryptase activity of tear fluids were measured. RESULTS: The degree of papillary
      hypertrophy did not decrease in either the CHX or CHX+EDG groups. Also, there
      were no differences in protein content of lenses nor tryptase activity of tear
      fluids in either group. There was a significant correlation between papillary
      hypertrophy and tryptase activity during the study. CONCLUSIONS: Despite the
      earlier finding that EDG prevents development of papillary hypertrophy in contact
      lens wearers, EDG still cannot reverse established signs of papillary
      hypertrophy.

PMID- 10344298
TI  - Differentiating contact lens induced warpage from true keratoconus using corneal
      topography.
AB  - PURPOSE: Superior corneal flattening associated with inferior corneal steepening
      is a videokeratoscopic topography pattern that usually describes both keratoconus
      and contact lens induced warpage. To differentiate these two conditions
      topographically, we analyzed ten different corneal topographic shape variables
      and found that two distinct conditions were described. Three unique measurements
      of corneal geometry: shape factor (SF), irregularity (CIM), and apical toricity
      (TKM) were analyzed and evaluated as an additional method for differentiating
      these two conditions. METHODS: A retrospective series of 100 eyes with a medical
      diagnosis of either contact lens induced warpage or true keratoconus were mapped
      using the Humphrey Atlas Corneal Topographer (San Leandro, CA) and their
      individual topographic indices were analyzed in an attempt differentiate the two
      conditions with videokeratoscopy. Variables included Flat Keratometry Reading,
      Maximum Axial Curvature, Maximum Tangential Curvature, Corneal Astigmatism,
      Corneal Shape Factor, Reference Sphere, Corneal Irregularity Measure (CIM),
      Maximum Elevation, and Mean Reference Toric K (TKM). All patients wore rigid gas
      permeable contact lenses. RESULTS: True keratoconic eyes had steeperflat K
      readings (46.9+/-3.7 D vs. 43.04+/-1.18 D; P<6.3E-13) with greater variations in
      maximum axial curvature (54.1+/-4.76 D vs. 43.6+/-1.5 D; P<2.4E-15) and maximum
      tangential curvature (55.1 7+/-4.56 D vs. 47.7+/-1.5 D; P<5.4E-16) than did eyes
      with contact lens induced warpage. The amount of corneal toricity (-3.43+/-2.29 D
      vs. -1.33+/-0.88 D; P<1.5E-07) was also greater for true keratoconus. True
      keratoconic eyes had larger and more variable shape factors (0.61+/-0.26 vs.
      0.02+/-0.13; P<2.5E-19) and CIM's (2.30+/-1.16 vs. 1.03+/-0.37; P<7.5E-10) than
      those with contact lens induced warpage. Steeper reference spheres (47.58+/-3.55
      D vs. 43.6+/-0.37 D; P<2.2E-10), greater maximum elevation over their respective
      reference spheres (15.51+/-9.91 microns vs. 6.2+/-3.0 microns; P<8.1E-08) and
      steeper, more variable toric mean reference spheres (51.88+/-4.01 D vs. 43.82+/
      1.82 D; P<3.9E-17) are also present in true keratocon us. True keratoconic eyes
      can be separated from contact lens induced warpage eyes with a sensitivity of
      98%, while identification of contact lens induced warpage demonstrates 94%
      specificity using corneal topography. CONCLUSIONS: While contact lens induced
      warpage and true keratoconus exhibit similar corneal topography patterns
      (superior flattening and inferior steepening), they demonstrate two uniquely
      different geometric shapes that can be readily differentiated using the various
      corneal shape indices of videokeratoscopy with a high degree of accuracy and
      specificity.

PMID- 10344299
TI  - Bilateral Pseudomonas corneal ulcer in a disposable contact lens wearer.
AB  - PURPOSE: To describe a case of bilateral corneal ulcers caused by Pseudomonas in
      a disposable soft contact lens wearer. This case study discusses the role of
      patient examination, contact lens care instruction, and adequate patient
      supervision in reducing the risk of serious potential complications. METHODS AND
      RESULTS: A 17 year old student who had been using disposable soft contact lenses
      on an extended wear basis for 6 months presented complaining of pain in the left
      eye. When he was examined, a corneal ulcer with surrounding infiltrate was
      observed in the superior middle periphery of the left eye. Samples were collected
      for culture, and treatment with fortified cefalotin and gentamicin was started.
      After 8 hours the patient returned, now complaining of pain in the right eye.
      Examination of the right eye revealed a diffused keratitis with a mucopurulent
      discharge. A culture was taken, and the same treatment was instituted. The
      laboratory tests revealed Pseudomonas in both eyes. The bilateral corneal ulcers
      responded to therapy after 1 week of treatment. CONCLUSIONS: We discuss the
      factors involved in the occurrence of infectious keratitis in contact lens
      wearers, and stress that even disposable contact lens wear can be associated with
      serious complications. This case also highlights extended wear as one of the main
      risk factors for complications in disposable soft contact lens wear.

PMID- 10344300
TI  - Surgical anatomy of the mediastinum.
AB  - After a short description of mediastinal anatomy and embryology, the authors
      illustrate the division of the mediastinum, based on criteria of either surgical
      anatomy or radiological anatomy. Lastly, they discuss the topographical
      distribution of the mediastinal masses in anterior, visceral, and posterior
      compartments of the mediastinum.

PMID- 10344301
TI  - Diagnosis of mediastinal masses and principles of surgical tactics and technique
      for their treatment.
AB  - The diagnosis of a mediastinal mass is first based on clinical features,
      supplemented by epidemiological data and laboratory results providing information
      on the nature and localization of the mass. The diagnosis is then defined further
      on the basis of imaging studies. The first examinations required are standard
      radiographs, ultrasound scan or computed tomography scan and occasionally
      magnetic resonance imaging (MRI), angiography, and scintigraphy. These studies
      are followed by a thoracoscopy, mediastinoscopy, and the necessary biopsy
      techniques. Finally, the author describes the general principles of surgical
      tactics and techniques that generally lead to a total regression of the disease.

PMID- 10344302
TI  - Preanesthetic evaluation of children with anterior mediastinal masses.
AB  - Respiratory collapse is a well-recognized complication of general anesthesia in
      patients with an anterior mediastinal mass. Although numerous case reports
      document this occurrence, only recently have several series provided some
      guidance in defining which patients are at risk for respiratory collapse. Safe
      lower limits for two parameters at which general anesthesia can be used appear to
      be a tracheal area measured by computed tomography (CT scan), which is at least
      50% of the area predicted for normals and peak expiratory flow rates, which are
      at least 50% of predicted. The problems with prebiopsy treatment are presented,
      and methods of obtaining diagnostic material by aspiration of a pleural effusion
      or performance of an anterior thoracotomy under local anesthesia are discussed.

PMID- 10344303
TI  - Lymphomas of the anterior mediastinum.
AB  - Lymphomas are the most common cause of masses in the pediatric mediastinum. More
      than 50% of children with lymphoblastic lymphoma present with an anterior
      mediastinal mass, and more than one third of all patients with non-Hodgkin's
      lymphoma have their primary sites in the mediastinum. Hodgkin's disease also
      frequently involves this anatomic compartment with approximately two thirds of
      all pediatric cases manifesting mediastinal adenopathy. Although surgical
      resection generally is not involved in the primary treatment of these diseases,
      surgeons often play a key role in obtaining adequate tissue for proper diagnostic
      analysis. Surgical access to the mediastinum often is required in the acquisition
      of a specimen.

PMID- 10344304
TI  - Posterior mediastinal neurogenic tumors in infants and children.

PMID- 10344305
TI  - Germ cell, mesenchymal, and thymic tumors of the mediastinum.
AB  - Germ cell, mesenchymal, and thymic tumors of the mediastinum are an uncommon and
      heterogeneous group of neoplasms. Together they account for less than 25% of
      mediastinal tumors in childhood. The majority of these tumors are found in the
      anterior and superior mediastinum, but germ cell tumors and mesenchymal tumors
      may be located in all compartments. They share a broad range of histological
      subtypes and clinical behavior, tendency to be large in size, and a requirement
      for complete surgical excision as the major requirement for successful therapy.

PMID- 10344306
TI  - Vascular anomalies of the mediastinum.
AB  - Vascular anomalies, including hemangiomas and vascular malformations, comprise 3%
      to 6% of mediastinal masses in childhood. These lesions, whether in the
      mediastinum or elsewhere, often are misdiagnosed and treated inappropriately.
      Correct diagnosis almost always can be established by history, external physical
      examination of associated anomalies, bronchoscopy, and/or radiographic studies.
      Hemangiomas are benign tumors that involute spontaneously but may require
      antiangiogenic therapy or laser ablation to maintain airway patency prior to
      involution. Vascular malformations, most commonly lymphatic in origin, will not
      involute nor respond to drug therapy. Resection and/or sclerotherapy often are
      indicated.

PMID- 10344307
TI  - Genetics and pediatric orthopaedics.

PMID- 10344308
TI  - Changes of elastic fibers in musculoskeletal tissues of Marfan syndrome: a
      possible mechanism of joint laxity and skeletal overgrowth.
AB  - The aim of the study was to analyze by histochemical, ultrastructural, and
      morphometric methods the musculoskeletal tissues in three humans affected with
      Marfan syndrome. Histochemical and morphometric data demonstrated that the
      content of elastic fibers in the perichondrium, periosteum, and knee capsule of
      the individuals with Marfan syndrome was dramatically reduced in comparison with
      control tissues. Ultrastructurally the elastic fibers appeared fragmented and
      indented, because of the presence of discontinuous aggregates of elastin among
      randomly dispersed filaments. These abnormalities of the articular capsule argue
      that these fibers could be functionally incompetent to resist normal stress,
      predisposing to joint laxity. Moreover, alterations in both perichondrium and
      periosteum seems to support our previous hypotheses about the control of long
      bone growth exerted by elastic fibers.

PMID- 10344309
TI  - Management of thrombocytopenia-absent radius (TAR) syndrome.
AB  - Thrombocytopenia-absent radius (TAR) syndrome is defined by bilateral absence of
      the radius and hypomegakaryocytic thrombocytopenia (<150,000/mm3). Lower
      extremity and nonorthopaedic anomalies also are frequently present. Charts and
      radiographs of 23 patients with TAR syndrome were reviewed, with extremity and
      other anomalies documented. Upper and lower extremity management, which included
      surgery and multiple attempts at orthotic and prosthetic fitting, was evaluated.
      Upper extremity prostheses were generally rejected, as most patients were able to
      perform tasks by approximating themselves closely enough to an object to use
      their own hands. Adaptive devices for feeding, dressing, and toileting were well
      tolerated. In the lower extremity, most affected patients either rejected any
      lower extremity intervention or had involvement that eventually precluded
      functional ambulation, necessitating power wheelchair or motorized cart use. The
      greatest degree of independence for these patients comes not from surgical,
      prosthetic, or orthotic intervention, but from the use of simple adaptive devices
      and powered mobility aids if required.

PMID- 10344310
TI  - The SAPHO syndrome in children: a rare cause of hyperostosis and osteitis.
AB  - The SAPHO syndrome is a rare constellation of signs and symptoms characterized by
      synovitis, acne, pustulosis, hyperostosis, and osteitis. The most common
      musculoskeletal complaints are hyperostosis, causing pain, tenderness, and
      swelling of the anterior chest wall, although any part of the axial and
      appendicular skeleton may be affected. There is a great degree of variability in
      the dermatologic involvement of this syndrome. A combination of clinical,
      radiographic, and pathological investigation is required to establish the correct
      diagnosis. No single treatment has been found to be effective, although
      nonsteroidal antiinflammatory drugs have been the most frequently used. Because
      there is no mention of SAPHO syndrome in the English orthopaedic literature, and
      pediatric orthopaedic surgeons may be the first caregivers to treat these
      children, we thought it appropriate to share our experience with a 5-year-old boy
      with SAPHO syndrome recently under our care.

PMID- 10344311
TI  - Congenital bone malformations in patients with neurofibromatosis type 1 (Nf1).
AB  - To address the prevalence of congenital bone malformations in neurofibromatosis
      type 1 (Nf1; compared with Nf1 bone anomalies and tumors), we studied the Nf1
      population of 135 children (70 boys, 65 girls) seen at the neurofibromatosis
      clinic, University of Catania, Italy, in the period 1990 through 1996. Twelve
      (8.8%) of the 135 children had congenital bone malformations: unilateral or
      bilateral postaxial polydactyly type A (n = 1) and type B (n = 1), bilateral
      postaxial polydactyly type A in association with preaxial polydactyly type 1 (n =
      1) and bilateral preaxial polydactyly (n = 1); clynodactyly (n = 1); multiple
      segmentation anomalies of the vertebrae (n = 6), and complex costovertebral
      anomalies (n = 1). We found a higher frequency of polydactyly (2.9%) in
      comparison to that in the general population (0.014-0.12%) and in our national
      (0.027%) and regional (0.066%) population, and a higher frequency of vertebral
      (5.1%) and costovertebral (0.7%) malformations. This is the first study to state
      the overall prevalence of congenital bone malformations in an Nf1 population.
      Interestingly, polydactyly (postaxial type) and Nf1 was previously reported only
      once.

PMID- 10344312
TI  - Management of chronic posttraumatic radial head dislocation in children.
AB  - We describe a new procedure for the management of chronic posttraumatic radial
      head dislocation, which uses two drill holes in the proximal ulna. The holes are
      placed at the original attachments of the annular ligament and thereby allow
      repair of the annular ligament (frequently avulsed from one attachment and
      impinged within the joint) or reconstruction of the annular ligament with
      whatever tissue or material desired (triceps tendon is convenient). It secures
      the radial head in its normal position from any dislocated position. It also
      allows for osteotomy of any accompanying deformity of the ulna or radius. This
      operation developed gradually between 1967 and 1995 while we treated seven female
      patients. The average age at time of injury was 5 years 10 months (range, 3 years
      4 months to 8 years 11 months). The interval between injury and operation
      averaged 30 months (range, 3 months to 7 years). The age at time of surgery
      averaged 8 years 4 months (range, 5 years 4 months to 13 years 5 months). The
      only criterion for surgery was a normal concave proximal radial articular
      surface. Follow-up averaged 48 months. At final follow-up, all patients were
      fully active and had no elbow pain or instability. Analysis of these cases
      suggests that the criteria for surgical repair should be based on two features:
      (a) normal concave radial head articular surface, and (b) normal shape and
      contour of the ulna and radius (deformity of either should be corrected by
      osteotomy). The age of the patient and duration of the dislocation are
      unimportant.

PMID- 10344313
TI  - T-condylar fractures of the distal humerus in children and adolescents.
AB  - This was a retrospective review of 17 T-condylar fractures in children and
      adolescents, aged 9-16 years. It examined the results by sex, age, arm injured,
      hand dominance, mechanism of injury, radiologic appearance, operative findings,
      operative procedure, outcome, and complications. There was a male-to-female ratio
      of 2.4:1. The large majority of patients received their fractures as a result of
      a fall. The majority of patients injured their nondominant left distal humerus.
      Five patients had a neuropathy, all of which spontaneously resolved. Fifteen
      patients underwent open reduction, internal fixation, with a mean postoperative
      follow-up of 16 months. The posteromedial (Bryan-Morrey) and the olecranon
      osteotomy approach resulted in a statistically significant better extension than
      the triceps-splitting approach (p < or = 0.05). Patients with articular damage
      had statistically significantly less extension at follow-up (p < or = 0.001). The
      use of continuous passive motion (CPM) in the immediate postoperative period
      resulted in a functional range of motion sooner and yielded a statistically
      significant increase in flexion at follow-up examination than when not used (p <
      or = 0.05).

PMID- 10344314
TI  - A prospective evaluation of upper extremity tendon transfers in children with
      cervical spinal cord injury.
AB  - Three children (five hands) between 6 and 11 years of age with cervical level
      spinal cord injuries underwent tendon transfers to restore voluntary lateral
      pinch. Repeated measures of pinch force and the Grasp and Release Test (GRT) were
      obtained before surgery and at regular intervals after tendon transfers. The
      Functional Independence Measure (FIM) was administered before surgery and at 12
      months after surgery. Responses to open-ended questions were used to supplement
      the FIM data at 1 year after surgery. Before surgery, no measurable force was
      obtained in any hand; after tendon transfers, pinch and finger flexion forces
      increased throughout the follow-up period. On the GRT, manipulation of the heavy
      objects was possible only after tendon transfers. Improvements were realized in
      feeding, grooming, bladder management, play, and school tasks. Each child
      requested surgery to restore pinch in the nondominant hand. Two hands required
      tenolysis procedures. Despite capsulotomies and aggressive therapy, three hands
      continued to have range limitations at the metacarpophalangeal joints.

PMID- 10344315
TI  - Intramedullary Kirschner wire fixation of open or unstable forearm fractures in
      children.
AB  - This retrospective review evaluates the efficacy of standard intramedullary
      Kirschner wires (K-wires) for the treatment of open or unstable diaphyseal
      forearm fractures in 32 children with a mean follow-up of 13 months. Thirty-one
      patients had an excellent result, and one patient had a good result. Average time
      to bridging cortex was 3 months. Four patients lacked full pronation and
      supination, with none lacking >20 degrees, and no patients had evidence of growth
      plate arrest. Nine complications occurred in eight patients: lost reduction after
      K-wire removal (three), refracture (two), deep infection (one), pin-site
      infection (one), transient anterior interosseous nerve palsy (one), and skin
      ulcer over buried K-wire (one). Both infections occurred in cases in which the K
      wire ends were left outside the skin. Each case of lost reduction occurred in
      single-bone fixation cases when the K-wires were removed before 4 weeks. In
      children, intramedullary fixation by using standard K-wires plus cast
      immobilization provides effective treatment for the problematic open or unstable
      diaphyseal forearm fracture when closed management has failed. Refinement of the
      technique may help to avoid complications. We now recommend burying the K-wires
      under the skin for 3-5 months and stabilizing both the radius and ulna with an
      intramedullary K-wire.

PMID- 10344316
TI  - Decompression and stable internal fixation of femoral neck fractures in children
      can affect the outcome.
AB  - Pediatric femoral neck fracture is rare and known to be associated with a high
      complication rate. The effect of early decompression and operative fixation is
      not frequently reported in the literature. This is a retrospective study of 14
      patients younger than 16 years with traumatic fractures of the femoral neck and
      intertrochanteric region over a 10-year period with a follow-up of 2-11 years
      (mean, 4.6 years). Road traffic accidents and falls from a height were the main
      causative factors, and the fractures were subclassified into transcervical, 58%;
      intertrochanteric, 29%; transepiphyseal, 7%; and cervicotrochanteric, 7%. Of all
      the fractures, 10 (71%) were displaced. Decompression of the hip by aspiration
      and closed reduction and internal fixation was performed for all the displaced
      fractures within 24 h after admission. Three cases required open reduction.
      Complete fracture healing and functional recovery was achieved in 13 patients
      with only one delayed union. No patient had radiographic evidence of avascular
      necrosis. When compared with earlier studies, the current aggressive management
      protocol for displaced fracture significantly minimized the complications of
      avascular necrosis, non-union, delayed union, and premature physeal closure.

PMID- 10344317
TI  - A 10-year study of the changes in the pattern and treatment of 6,493 fractures.
AB  - A total of 6,493 fractures was studied from 6,389 children younger than 16 years
      admitted as inpatients to one center in a 10-year period. The boy-to-girl ratio
      increased from 1.4:1 in the infants to 4.9:1 in the adolescents. The most common
      fractures were the distal radius (20.2%), supracondylar fracture of the humerus
      (17.9%), forearm shaft (14.9%), and the tibial shaft (11.9%). A distinct age
      specific fracture pattern also was found, with supracondylar fracture of the
      humerus being the most common fracture in the age 0- to 3-year (26.7%) and the 4-
      to 7-year (31.6%) groups and distal radius in the 8- to 11-year and the 12- to 16
      year groups (24.3 and 25.7%, respectively). Although the overall pattern of the
      major fractures had not changed over the 10-year period, significant changes in
      the treatment pattern were observed. The closed-reduction and percutaneous
      pinning rates increased from 9.5 to 38.7% in fracture of the distal radius, 4.3
      to 40% in the supracondylar humerus, and 1.8 to 22% in the forearm shaft. The
      changes in treatment pattern were also accompanied by a corresponding decrease in
      the open-reduction rate and hospital stay periods from <10% to 38% of patients
      being discharged within 1 day of admission in the 10-year period.

PMID- 10344318
TI  - Universal lower-extremity positioning device for the spica frame.

PMID- 10344319
TI  - Interrelationships of strength and gait before and after hamstrings lengthening.
AB  - Muscle-tendon lengthenings are an essential part of the orthopaedic management of
      static and dynamic joint contractures associated with cerebral palsy. Although
      these procedures typically have a positive biomechanical effect on joint
      alignment, the potential negative effects of alterations in tendon length on
      muscle strength and gait function have not been well documented in these
      patients, in whom muscle weakness is a prevalent clinical symptom. The purpose of
      this study was to examine the change in strength values of the hamstring and
      quadriceps muscle groups during a 9-month postoperative period in patients who
      had undergone hamstring tendon lengthenings, in comparison to an operative "no
      hamstring surgery" control group, and to relate baseline strength and
      postoperative changes to gait function in these patients. Results for the
      "hamstring surgery" group indicated that although hamstring strength declined
      initially, the strength increased with time and was similar to preoperative
      values by 9 months. Quadriceps strength measured at 30 degrees of knee flexion
      increased significantly during the recovery period as a direct result of
      improvements in knee extension. Although hamstring surgery produced an immediate
      effect on passive motion and knee-joint alignment, functional improvement, as
      evidenced by increased stride length, was not evident until strength values
      approximated or exceeded preoperative values.

PMID- 10344320
TI  - Glenoid version in children with obstetric brachial plexus palsy.
AB  - Glenoid version in a group of 29 children with obstetric brachial plexus
      paralysis and posterior dislocation of the shoulder was studied by using computed
      axial tomography (CT). The CT scan in most patients was done before an open
      release and reduction of the shoulder. A comparison was made between the normal
      and affected sides in regard to glenoid version and structure. In the study
      population, there were 16 girls and 13 boys with an average age at the time of
      initial CT of 2.8 years. Sixteen of the patients had posterior dislocations of
      the right shoulder, and none was bilateral. In 18 patients, the neurologic lesion
      was confined to the upper roots of the brachial plexus, with the remaining
      patients having whole plexus involvement. A significant difference in glenoid
      version between normal and affected sides was found in these patients. The mean
      glenoid version for the dislocated side was -29.5 +/- 2.5 degrees and that of the
      normal side was -6.9 +/- 2.4 degrees. Glenoid structure was different in
      dislocated shoulders. The glenoid articular surface was observed to be laterally
      convex in the majority of cases, and in these cases, the posterior rim of the
      glenoid was often hypoplastic and rounded.

PMID- 10344321
TI  - Role of exercise testing in the functional assessment of cerebral palsy children
      after botulinum A toxin injection.
AB  - The purpose of this clinical prospective study was to assess the effect of
      intramuscular injections of botulinum toxin A on energy cost of movement and
      walking endurance in 15 children with cerebral palsy, aged 4 to 13 years, by
      using incremental walking treadmill protocol to voluntary exhaustion. Oxygen
      uptake response to exercise stress and endurance time were analyzed before and 2
      and 6 months after botulinum toxin A injection. Endurance time was significantly
      improved 2 months after botulinum toxin A injection in 13 patients, and a
      residual improvement was still present 6 months after injection in some of them.
      The effect of botulinum toxin A on energy cost of movement was very variable.
      This study provides clinical evidence of the efficacy of botulinum toxin A in
      reducing the energy cost of movement and in improving the endurance of spastic
      muscles in children with cerebral palsy.

PMID- 10344323
TI  - Brace treatment in neuromuscular spine deformity.
AB  - We reviewed 90 consecutive patients with various neuromuscular diseases and a
      progressive spine deformity treated with a prefabricated Boston-type underarm
      corrective brace. Of these, 38 patients had spastic tetraplegia; seven, syndrome
      related muscular hypertonia; 24, muscular hypotonia; and 21, myelomeningocele.
      The mean age at the treatment start was 9.2 years (range, 1.4-17.7 years). Twenty
      four were ambulating and 66 wheelchair-bound. Hypotonia was the dominant type of
      muscle involvement in 49, spasticity in 28, and athetosis in 13 patients. The
      mean pretreatment Cobb angle was 47 degrees, with a range from 23 to 95 degrees.
      The mean brace-induced Cobb-angle correction was 60%, thus well comparable to
      that in idiopathic scoliosis. However, this did not predict favorable treatment
      results. At the follow-up, on average 3.1 years (range, 1-5.5 years) after
      weaning from the brace, the brace treatment was successful in 23 patients.
      Successful was defined as <10 degrees curve progression during the observation
      time and a good brace compliance. Forty-one patients discontinued the brace
      treatment, and 19 progressed despite adequate brace wear. Five patients are still
      in treatment, and two have died. Successful treatment was seen in ambulating
      patients with muscle hypotonia and short thoracolumbar/lumbar curves measuring
      <40 degrees as well as in nonambulating patients with spastic short lumbar
      curves. These types of neuromuscular scoliosis may be the only ones to respond to
      brace treatment. In other cases, the brace treatment cannot be expected to have a
      lasting corrective effect although it can be used as sitting support.

PMID- 10344322
TI  - Muscle-tendon surgery in diplegic cerebral palsy: functional and mechanical
      changes.
AB  - A prospective assessment of muscle-tendon (M-T) surgery was conducted on 30
      patients with spastic diplegia. Muscle-tendon surgery consisted of recessions or
      releases to improve gait function by correcting restricted joint motion and joint
      malalignment. Functional-outcome measures included the Gross Motor Function
      Measure (GMFM) and temporal gait factors. Kinematic gait data were evaluated to
      determine the mechanical effects. The mean age at surgery was 8.7 years (4-20
      years), and 3.5 muscle tendon units per extremity were recessed or released at
      surgery. The primary kinematic change for the hip and the knee was a shift in the
      sagittal joint position with minimal effects on overall excursion. Changes in
      ankle-joint dynamics after gastrocsoleus recessions included a reduction in
      plantarflexion and a shift in the timing of maximal dorsiflexion to later in
      stance. Improvements in walking velocity and stride length were evident by 6
      month after surgery. Functional changes from M-T surgery included a 25% increase
      in velocity and an 18% increase in stride length over preoperative values seen at
      9 months after surgery. Improvements in these parameters were maintained at 2
      years after surgery. The GMFM total score showed minimal change after surgery
      with improvements occurring primarily in the standing dimension and the walking,
      running, and jumping dimensions.

PMID- 10344324
TI  - Behavior of tendons during lower-leg lengthening in dogs using the Ilizarov
      method.
AB  - Twenty-two dogs were provided with a circular fixator. Lengthening of the right
      lower leg by 2.5 cm was performed on 18 dogs 5 days after tibial osteotomy using
      a distraction rate of 0.5 mm, twice per day. Nine dogs with leg lengthening and
      two dogs of the control group without leg lengthening were sacrificed at the end
      of the distraction phase of 25 days and the remaining dogs after another 25 days.
      Post mortem, the tendons of the tibialis anterior, extensor digitorum longus,
      peroneus longus, and the Achilles tendon were taken from the operated-on right
      side and the left nonoperated-on control side and were analyzed histologically.
      The control group showed no histologic changes in the tendons of either side nor
      in those of the unlengthened left side of the operated-on dogs. Thirty-three
      tendons (41%) of dogs with leg lengthening were seen to have undergone
      histomorphological changes. An increase of the peritendinous connective tissue
      was seen, combined with chronic inflammatory cell infiltration in the tendons
      and/or the epitendinous tissues, edema, tendon fragmentation, necrosis, scarring
      of the tendons with dystrophic calcification and/or ossification, and broadening
      of the tenosynovial sheath. Furthermore, signs of histoneogenesis with growth in
      the tendons were found. Degenerative changes occurred far more often in the
      tendons of the ventral side of the lower leg and a slight pes equinus was
      regularly observed in the lengthened extremity. Therefore, pes equinus prevention
      and physiotherapy are important in the therapeutic use of lower-leg lengthening
      to minimize possible stress-induced damage of the ventral tendons.

PMID- 10344325
TI  - Simultaneous ipsilateral femoral and tibial lengthening with the Ilizarov method.
AB  - Eight pediatric patients who underwent nine simultaneous ipsilateral femoral and
      tibial lengthenings with the Ilizarov external fixator were reviewed. The
      patient's demographics, diagnoses, corticotomy levels, mechanical axes, healing
      indices, amounts of lengthening, and complications were recorded. The patients'
      average age was 8 years 10 months (5 years 4 months-15 years 10 months) with an
      average follow-up of 49 months (30-88 months). The percentage of femoral
      lengthening averaged 16.7% (8-23%) with an average healing index of 28 days/cm
      (20-38 days/cm). The percentage of tibial lengthening averaged 18% (9.6-23.6%)
      with an average healing index of 29 days/cm (1940 days/cm). Four complications in
      three patients occurred as a direct result of the lengthening process. Three of
      the complications involved soft-tissue contractures, which were each successfully
      treated with one additional surgical procedure, whereas the fourth complication
      involved poor bone regeneration and required bone grafting and additional
      immobilization.

PMID- 10344326
TI  - Leg lengthening in spinal dysraphism.
AB  - Spinal dysraphism may lead to limb inequality and foot deformities. Fears have
      been expressed regarding limb lengthening in such patients because of potential
      sequelae in relation to their peripheral neurologic abnormalities. We performed
      Ilizarov lengthening of the lower limb on seven community walkers with spinal
      dysraphism. The procedure was well tolerated with no increase in sepsis, soft
      tissue, or bony complications compared with patients undergoing lengthening for
      reduction anomalies. All the patients mobilised rapidly after frame application
      and returned to their previous functional level within 3 months of plaster
      removal.

PMID- 10344327
TI  - Complications following metatarsal lengthening by callus distraction for
      brachymetatarsia.
AB  - We performed six metatarsal lengthenings in four patients for brachymetatarsia of
      the fourth toe by callus distraction from 1991 to 1995. Healing was achieved in
      all cases. The average amount of lengthening was 30% (range, 15-41%) of the
      original length. The average healing index was 82 days/cm (range, 66-113
      days/cm). After the operation, range of movement of the metatarsophalangeal joint
      decreased in all cases (120 degrees before and 57 degrees after surgery). In two
      cases in which the lengthening exceeded 40% of the original length, stiffness of
      the joint (20 degrees and 0 degrees each) and joint deformity occurred. These two
      cases also had angulation of the metatarsal. Corrective osteotomy and release
      surgery was performed in one case. Angulation of the metatarsal was corrected,
      but the range of movement of the joint did not much recover after surgery.
      Another case was left untreated because the patient had no complaints. In
      metatarsal lengthening by callus distraction, the amount of lengthening should
      not exceed 40% of the original length.

PMID- 10344328
TI  - Transplantation of epiphyseal plate allografts between animals of different ages.
AB  - The purpose of the experiment was to study growth of epiphyseal plate allografts
      after transplantation into subjects of a different age, thus preparing for future
      transplantation of epiphyseal plate or extremity allografts in children.
      Microvascular transplantation of proximal tibial epiphyseal plate allografts was
      performed in skeletally immature New Zealand White female rabbits. The growth of
      9-week-old epiphyseal plate allografts was examined in both 9-week-old and 17
      week-old recipients, as was the growth of 17-week-old epiphyseal plate allografts
      in 17-week-old recipients. Immunosuppression was with cyclosporine (Cyclosporine
      A). Successful transplants were confirmed with 99mTc-MDP isotope scanning, and
      growth was evaluated with weekly standardized radiographs until death. Growth
      rate was found to depend on the age of the donor epiphyseal plate and was
      independent of the age of the recipient. This has clinical implications for the
      procurement of donor tissue in potential transplantation of epiphyseal plate
      allografts in children.

PMID- 10344329
TI  - Congenital cleft-foot deformity treatment.
AB  - A retrospective review of congenital cleft foot was done on 16 patients with 32
      involved feet. The average age at the time of surgery was 4 years (range, 5
      months to 13 years). The average follow-up after surgery was 7.8 years, with a
      range of 2-45 years. A simple classification based on severity of deficiency was
      developed. Twenty-three of the 24 procedures performed gave a satisfactory
      result. Six of the nine untreated feet were satisfactory. Based on our
      classification, the following treatment is recommended: type I, central partial
      forefoot cleft was treated by a soft-tissue syndactylism and a partial hallux
      valgus correction, if needed. Type II, for a complete forefoot cleft to the
      tarsus, soft-tissue syndactylism with first-ray osteotomy if necessary before age
      5 years is recommended. First-ray amputation is advised after age 5 years. Type
      III: Complete absence of first through fourth ray did not need forefoot surgery.

PMID- 10344330
TI  - Transmission electron microscopic pathoanatomy of congenital trigger thumb.
AB  - Previous studies of trigger digits in children have been limited to gross
      morphology and light-microscopic histology. Nine children with 11 trigger thumbs
      formed a preliminary study group for electron-microscopic evaluation of tendon
      nodules and A-1 pulleys. This pathoanatomic investigation was not previously
      reported. Comparison was made with light-microscopic sections. Large amounts of
      mature collagen was observed. Fibroblasts with prominent rough endoplasmic
      reticulum were present. No degenerative or inflammatory changes were noted in
      either tendon or sheath. We believe that although the etiology of trigger digits
      is still uncertain, an infectious, inflammatory, or degenerative process is
      unlikely.

PMID- 10344331
TI  - Community-acquired methicillin-resistant Staphylococcus aureus: a cause of
      musculoskeletal sepsis in children.
AB  - Between August 1996 and August 1997, 130 children were admitted to our pediatric
      orthopaedic unit with Staphylococcus aureus musculoskeletal infection. Twenty-six
      of the 130 staphylococcal isolates were resistant to methicillin, an incidence of
      20%. All but one of the infections, a femoral fixator-pin infection, were
      community-acquired. Twenty-two of the infections were superficial; however, there
      were four cases of deep musculoskeletal sepsis due to methicillin-resistant S.
      aureus. In areas where methicillin-resistant S. aureus is prevalent in the
      community, methicillin resistance should be considered in any overwhelming
      staphylococcal infection not responding to conventional antibiotics despite
      adequate surgical debridement.

PMID- 10344332
TI  - The patient with IgA glomerulonephritis--what is the role of steroid treatment?

PMID- 10344333
TI  - Thin basement membrane--do we have a window for understanding the molecular
      pathogenesis?

PMID- 10344334
TI  - Night time blood pressure in diabetic patients--the submerged portion of the
      iceberg?

PMID- 10344335
TI  - Does hydration prevent radiocontrast-induced acute renal failure?

PMID- 10344336
TI  - Vitamin D receptor polymorphisms as a determinant of bone mass and PTH secretion:
      from facts to controversies.

PMID- 10344337
TI  - How to identify the haemodialysis access at risk of thrombosis? Are flow
      measurements the answer?

PMID- 10344338
TI  - Hepatitis C virus in the haemodialysis units: novel insights by new techniques?

PMID- 10344339
TI  - Ischaemic heart disease after renal transplantation: how to assess and minimize
      the risk.

PMID- 10344340
TI  - What is the role of decorin in diabetic kidney disease?
AB  - The small proteoglycan decorin may intercept the activity of the TGF-beta system.
      Decorin administration has been advocated as potential therapy in renal fibrotic
      diseases, because of the findings of a relative deficiency of decorin and a
      relative excess of TGF-beta in acute glomerulonephritis. Does a similar situation
      pertain in diabetic kidney disease? Activation of TGF-beta seems to be crucial to
      tissue injury in diabetic nephropathy, but until recently it has not been
      established whether decorin plays any role in the manifestations of this disease.
      We review evidence that a surfeit rather than a deficit in decorin expression
      exists in diabetic renal disease, and that there exists a negative feed-back loop
      whereby TGF-beta1 induces down-regulation of decorin expression. Rat and mouse
      mesangial cells as well as mouse proximal tubular cells in culture exhibit
      increased decorin mRNA levels in high ambient glucose. Decorin mRNA level in the
      kidney of streptozotocin-induced diabetes in mice is rapidly and significantly
      increased following the induction of diabetes. Thus, the available evidence
      suggests that renal decorin is not deficient in this disorder and hence decorin
      supplementation does not seem to be warranted. Rather, interception of the
      effects of TGF-beta seems to be an approach most likely to yield beneficial
      results in diabetic nephropathy.

PMID- 10344341
TI  - The doctor who is a patient: conflicting or complementary roles?

PMID- 10344342
TI  - Annual Report of the German Renal Registry 1998. QuaSi-Niere Task Group for
      Quality Assurance in Renal Replacement Therapy.
AB  - During the past 3 years, the basis of a German Renal Registry has been
      established. An agreement between end-stage renal disease (ESRD) therapy
      providers, insurance companies and the government has been reached to fund and
      support the registry office and its electronic data base. An overall acceptable
      compliance has been achieved to provide data voluntarily, although in the future
      the data submission will have to be mandatory to achieve complete data sampling
      within an acceptable time frame. In Germany, 713 patients per million population
      (p.m.p.) are on renal replacement therapy (RRT). The incidence of new patients
      commencing RRT is 156 p.m.p. These numbers are comparable with those reported
      from other European countries such as France, Italy and Spain, but significantly
      lower than those reported from the US or Japan. More than 92% of all dialysis
      patients are treated by haemodialysis and only a limited number with peritoneal
      dialysis. Approximately 25% of the patients have a functioning kidney graft. The
      transplantation rate of 25 p.m.p. is far from sufficient if compared with Spain,
      Austria or the US. Although an increasing number of diabetic patients commenced
      RRT, the percentage, i.e. approximately 30%, is less than in the US or Japan. The
      annual growth of the population on renal replacement cannot currently be given
      precisely because the database is still limited, but it seems to be approximately
      3-4%.

PMID- 10344343
TI  - ESRD patients without co-morbid risk factors at the start of haemodialysis are
      ideal as survival comparison population.
AB  - BACKGROUND: Our aim was to identify co-morbid risk factors in ESRD patients at
      the start of the treatment, to select patients in the low-risk group (LRG) and to
      compare overall survival, adjusted overall survival and LRG survival in three
      centres (A, B and C). METHODS: Population includes 531 patients entering
      haemodialysis from 1 January 1981 to 31 December 1996 (mean age 59.6 +/- 16.7
      years). Demographics and co-morbidity data collected at the start of HD were
      independent variables for the analysis. Univariate and multivariate analysis of
      survival were used to identify significant prognostic factors (Kaplan-Meier and
      Cox hazard regression model respectively). According to this analysis the LRG was
      defined by the absence of the identified significant mortality risk factors
      except age. RESULTS: The overall median survival was 7.92 years, with 92.0%
      survival at 1 year, 65.2% at 5 years and 40.4% at 10 years. The median survival
      in centre C (10.83 years) was significantly higher than median survival in centre
      A (7.0 years) and in centre B (7.83 years). Centres A and B were afterwards
      analysed together (A-B). In the multivariate analysis, five variables (starting
      age, diabetes, cancer, smoking habit, and arteriosclerotic heart disease) were
      associated with survival. The variable centre (A-B or C) was not significant. The
      adjusted survival curve for centres A-B and C were not different. The LRG
      included patients of any age, without diabetes, cancer, smoking habit, and
      arteriosclerotic heart disease. The frequency of the patients in the LRG was
      66.3% in centre C and 45.7% in centre A-B (P = 0.0004). Taking into account only
      the LRG, the survival comparison between centres A-B and C, did not show
      significant differences (P = 0.196). CONCLUSIONS: We conclude that for purposes
      of comparison of mortality in ESRD, low-risk population is better than overall
      ESRD population.

PMID- 10344344
TI  - Combined therapy with prednisolone, azathioprine, heparin-warfarin, and
      dipyridamole for paediatric patients with severe IgA nephropathy--is it relevant
      for adult patients?

PMID- 10344345
TI  - No common final pathogenetic pathway in haemolytic uraemic syndromes.

PMID- 10344346
TI  - Molecular studies of leptin: implications for renal disease.

PMID- 10344347
TI  - Reversal of left ventricular hypertrophy with angiotensin converting enzyme
      inhibition in hypertensive patients with autosomal dominant polycystic kidney
      disease.
AB  - BACKGROUND: Hypertension occurs commonly and early in the natural history of
      autosomal dominant polycystic kidney disease (ADPKD), affecting both renal and
      patient outcome. Activation of the renin angiotensin aldosterone system due to
      cyst expansion and local renal ischaemia plays an important role in the
      development of ADPKD related hypertension and left ventricular hypertrophy (LVH),
      a known important risk factor for cardiovascular morbidity and mortality. The aim
      of this study was to investigate the effects of an angiotensin converting enzyme
      (ACE) inhibitor, enalapril, on renal function, blood pressure and LVH in
      hypertensive ADPKD patients. METHODS: Fourteen hypertensive ADPKD patients (11
      men, 3 women; mean age: 40 years) were included in the study. All patients had
      LVH and creatinine clearance (Cer) greater than 50 ml/min/1.73 m2. The patients
      were followed for 7 years on enalapril therapy. The effects of enalapril on renal
      function, blood pressure and LVH were investigated. RESULTS: Baseline
      measurements of mean arterial pressure (MAP), Ccr and left ventricular mass index
      (LVMI) were 110 +/- 2 mmHg, 84 +/- 6 ml/min/1.73 m2 and 146 +/- 4 g/m2,
      respectively. After one year of enalapril therapy there was a significant
      decrease in MAP (94 +/- 3 mmHg, P < 0.005) which remained stable until the end of
      the study at 7 years (94 +/- 1 mmHg, P < 0.005 vs baseline). There was also a
      significant decrease in LVMI (131 +/- 6 g/m2, P < 0.05) after year 1 which
      continued to decrease until the end of the study reaching 98 +/- 6 g/m2 (P < 0.01
      vs year 1 and baseline). Although Ccr remained stable after year 1, a significant
      decrease was observed after 7 years of follow-up (59 +/- 6 ml/min, P < 0.001 vs
      year 1 and baseline). CONCLUSIONS: ACE inhibition in hypertensive ADPKD patients
      provided long-term reversal of LVH in association with a mean 3.6 ml/min/year
      decline of Ccr. These preliminary results have potential important implications
      for cardiovascular and renal protection in ADPKD.

PMID- 10344348
TI  - Expression and physical association of Fc alpha receptor and Fc receptor gamma
      chain in human mesangial cells.
AB  - BACKGROUND: Most intensive investigations on the pathogenesis of IgA nephropathy
      have focused on the process before IgA deposition and the characteristics of
      IgA/IgA immune complex (IgA IC), but it still remains uncertain whether mesangial
      IgA ICs may cause glomerular injuries directly or are only secondary events of
      another pathological process. To assess the role of IgA ICs in IgA nephropathy,
      we investigated the characteristics of Fc alpha receptor (Fc alphaR) and FcR
      gamma chain which is a signalling subunit of FcR in human mesangial cells (MCs).
      METHODS: Gene expression of Fc alphaR and FcR gamma chain of human cultured MCs
      was examined by RT-PCR and subsequent Southern blot analyses. Sequence analyses
      after subcloning were also performed for further confirmation. Expression of Fc
      alphaR and FcR gamma chain at the protein level and their physical association in
      MCs were determined by immunoprecipitation after stimulation of the cells with
      heat-aggregated IgA. RESULTS: Two distinct cDNA products were amplified from each
      cultured MC line. The sequence of the major product of approximately 900 bp was
      completely identical to that of Fc alphaR previously described. The smaller
      product had a 288 bp deletion which corresponded to exon 2 encoding the
      extracellular domain 2 of Fc alphaR. Gene expression of FcR gamma chain was also
      confirmed. Furthermore, we proved the physical association of Fc alphaR with the
      FcR gamma chain by co-immunoprecipitation under stimulation with a high dose of
      the heat-aggregated IgA. CONCLUSION: These findings suggested that polymeric IgA
      and/or IgA IC can directly activate MCs via Fc alphaR associated with the gamma
      chain. Our data also indicated that phenotypic variations of Fc alphaR occur on
      MC, such as splicing forms, the chain association and/or the alpha chain
      expression itself, which may contribute to the pathogenesis of IgA nephropathy.

PMID- 10344349
TI  - Role of thromboxane in the altered vascular reactivity of pregnant rats with
      adriamycin nephropathy.
AB  - BACKGROUND: Pregnant rats with adriamycin nephropathy (ADRP rats) develop
      hypertension and have an increased vascular reactivity to noradrenaline in the
      isolated mesenteric bed in vitro. We have shown previously that the
      administration of daltroban, a specific thromboxane receptor antagonist,
      prevented hypertension in ADRP rats. METHODS: We measured the effect of daltroban
      (10(-5) mol/l) on the vasoconstrictory response to noradrenaline (1-10
      micromol/l) in the isolated mesenteric bed of ADRP rats at the end of pregnancy,
      as compared with normal pregnant and adriamycin-treated virgin rats. In further
      experiments, we measured the changes of flow induced by increasing concentrations
      of the thromboxane analogue, U46619 (10(-7)-10(-6) mol/l). Finally, changes of
      flow were assessed in arteries maximally constricted with U46619 (10(-6) mol/l),
      during perfusion in the presence of increasing concentrations of daltroban (10(
      7)-10(-5) mol/l). RESULTS: Daltroban diminished the response to noradrenaline in
      all groups, shifting the concentration-effect curve to the right. However, at
      maximal concentrations of noradrenaline, daltroban was ineffective in all rats,
      except in ADRP animals. The vasoconstrictory response to U46619 was significantly
      reduced in all pregnant rats, both normal and adriamycin-treated. Daltroban
      progressively released the vasoconstriction induced by U46619 in all groups.
      However, this vasodilator response was attenuated in the adriamycin-treated rats,
      the slopes of their curves being smaller than those of the respective untreated
      groups (0.038 +/- 0.006 in virgin rats vs 0.063 +/- 0.011 in controls, P < 0.05;
      and 0.015 +/- 0.005 in ADRP vs 0.028 +/- 0.008 in normal pregnancy, P < 0.05).
      CONCLUSIONS: The findings could be explained by enhanced occupancy of thromboxane
      receptors by an endogenous agonist, possibly PGH2, as a consequence of either
      increased levels of the autacoid or increased number of affinity receptors.

PMID- 10344350
TI  - Microalbuminuria after pregnancy complicated by pre-eclampsia.
AB  - BACKGROUND: Microalbuminuria is an important risk factor for underlying vascular
      disease. Its detection after pregnancy complicated by pre-eclampsia may have
      predictive value for the later development of chronic hypertension or renal
      disease. METHOD: The study group consisted of 48 women in whom pregnancy had been
      complicated by pre-eclampsia. Urinary albumin excretion rate, blood pressure, and
      renal function parameters were assessed 2-4 months and 3-5 years after the
      pregnancy. Results were compared with those in 44 women after normal pregnancy.
      RESULTS: Mean urinary albumin excretion rate was significantly higher in the
      study group than in the controls both at 2-4 months after delivery (27.0 +/- 33
      vs 6.1 +/- 3.3 mg/24 h) and at 3-5 years after delivery (23.5 +/- 26.8 vs 6.7 +/-
      2.8 mg/24 h) (P = 0.001). The rate of occurrence of microalbuminuria was not
      significantly different between the early (58%) and late (42%) time-points within
      the study group or between the nulliparous and the multiparous women.
      CONCLUSIONS: A history of pregnancy complicated by pre-eclampsia is associated
      with a high occurrence of microalbuminuria. Whether the presence of
      microalbuminuria reflects a possible underlying vascular disease in affected
      patients needs to be further investigated in large-scale studies.

PMID- 10344351
TI  - Impact of the endothelin system on water and sodium excretion in patients with
      liver cirrhosis.
AB  - BACKGROUND: Impaired renal function in patients with liver cirrhosis is a serious
      complication and is characterized by sodium and water retention in the absence of
      identifiable specific causes of renal dysfunction. The endothelin system has been
      shown to be activated in liver cirrhosis and might contribute to impaired renal
      function. However, the mechanisms leading to an activation of the endothelin
      system in these patients and the effects of an activated endothelin system on
      renal function in these patients are as yet unknown. METHODS: To determine the
      correlation between the activity of the endothelin system and the ability to
      excrete water and sodium in patients with liver cirrhosis, we measured plasma
      endothelin-1 concentrations by reversed phase-HPLC followed by an endothelin RIA
      and performed an oral water load tests in 10 healthy control subjects and 43
      patients with liver cirrhosis. In addition, we analysed possible
      mechanisms/factors like plasma endotoxin that might contribute to the activation
      of the endothelin system in liver cirrhosis. RESULTS: This study showed that the
      endothelin system is activated in patients with liver cirrhosis in a disease
      stage-dependent manner. Patients with Child C liver cirrhosis have a 5.45-fold
      increased plasma ET-1 concentration compared to healthy controls, whereas plasma
      ET-1 is only increased 2.74-fold in Child A patients. An oral water load test
      revealed a highly significant (P < 0.0001) inverse correlation between the plasma
      endothelin-1 concentrations and the ability to excrete a given water load. Plasma
      endotoxin, a well-known stimulus of ET-1, is significantly (P < 0.03) correlated
      with plasma ET-1 in cirrhotic patients. The ET-1 concentrations in the ascites of
      patients with liver cirrhosis were lower and not related to plasma ET-1.
      CONCLUSION: The activity of the endothelin system in patients with liver
      cirrhosis depends on the severity of liver impairment. Plasma endotoxin might be
      an important stimulus of the endothelin system in liver cirrhosis. We observed a
      highly significant inverse correlation between the plasma endothelin-1
      concentrations and the ability to excrete a given water and sodium load,
      suggesting that the endothelin system plays a role in the regulation of water
      excretion in patients with liver cirrhosis.

PMID- 10344353
TI  - Prevention of radiocontrast-media-induced nephropathy in patients with pre
      existing renal insufficiency by hydration in combination with the adenosine
      antagonist theophylline.
AB  - BACKGROUND: Radiographic contrast media (CM) application causes a decline in
      renal function, especially in patients with pre-existing renal dysfunction. In
      addition to hydration, several vasodilating substances have been evaluated for
      their ability to prevent renal damage after CM application. In a prospective,
      double-blind, placebo-controlled study we investigated the effect of the oral
      administration of theophylline, an adenosine receptor antagonist, on changes in
      renal haemodynamics and tubular injury induced by CM in well-hydrated patients
      with mild-to-moderate renal insufficiency. METHODS: We studied 80 patients with
      pre-existing chronic renal insufficiency (creatinine > 1.5 mg/dl) who received
      more than 100 ml iopromide. Hydration (either oral or intravenous) started at
      least 24 h before and lasted until 24 h after CM application. In addition,
      patients were randomly assigned to receive either theophylline (810 mg daily) or
      placebo. Serum creatinine and creatinine clearance were measured before and for 3
      days after CM application. Urine was collected to measure N-acetyl-beta
      glucosaminidase (NAG) enzymuria for the same period. Sixty-four patients
      completed the entire study protocol (theophylline, n = 35 and placebo, n = 29).
      RESULTS: During the study period serum creatinine concentration and creatinine
      clearance did not change significantly in either group. Acute renal failure
      (increase of serum creatinine of at least 0.5 mg/dl) could be observed in two
      patients from the theophylline group (5.7%) and one from the placebo group
      (3.4%). The increase in NAG excretion reached statistical significance (P < 0.05)
      in the placebo group on days 2 and 3 after CM application. CONCLUSIONS: Our
      results indicate a role for adenosine in CM-induced tubulotoxicity. However, the
      glomerular filtration rate is preserved by hydration alone in these patients. The
      application of theophylline did not bring an additional benefit. The use of
      adenosine antagonists may be beneficial in patients where sufficient hydration
      may be impossible or in patients with a concomitant decrease in renal blood flow
      (e.g. congestive heart failure).

PMID- 10344352
TI  - Beneficial and harmful effects of L-arginine on renal ischaemia.
AB  - BACKGROUND: The role of nitric oxide (NO) in acute renal failure (ARF) is not yet
      completely understood. L-Arginine (L-arg) is protective against different ARF
      models, while L-arg addition in isolated proximal tubules enhances
      hypoxia/reoxygenation (H/R) injury. The aim of this study was to evaluate the
      effects of L-arg on renal ischaemia. METHODS: In in vivo studies, Wistar rats
      were subjected to 60 min renal artery clamping, and renal function was evaluated
      2 and 15 days after ischaemia. Four groups were studied: (1) control; (2) acute L
      arg (50 mg/kg/bw i.v.); (3) L-nitro-arginine-methyl esther (L-NAME; 0.5 mg/kg/bw
      i.v.); and (4) chronic L-arg (L-arg 0.25% in drinking water/7 days). For the in
      vitro studies, proximal tubules (PTs), isolated by collagenase digestion and
      Percoll gradient, were studied from three groups: (1) untreated; (2) L-arg
      treated (L-arg 0.25% in drinking water/7 days); and (3) L-NAME-treated rats (3
      mg/kg in drinking water/7 days). PTs were kept oxygenated or subjected to 15 min
      hypoxia (H-15) and 35 min reoxygenation (R-35). In some experiments, additional
      doses of L-arg and L-NAME were administered. Cell injury was assessed by lactate
      dehydrogenase (LDH) release. NO production was evaluated by NO2-/NO3- measurement
      (Griess reaction) in both urine and isolation medium. RESULTS: After 2 days, L
      arg infusion protected against ischaemia compared with control rats (0.4 vs 0.2
      ml/min/100 g, P < 0.001), while neither L-NAME nor chronic L-arg supplementation
      ameliorated renal function. After 15 days, both acute and chronic L-arg groups
      showed a higher glomerular filtration rate (0.6 and 0.75 ml/min/100 g) compared
      with control rats (0.3 ml/min/100 g, P < 0.05) and L-NAME-treated rats (0.2
      ml/min/100 g, P < 0.05). Despite similar recovery in both L-arg groups, the
      mortality rate was 25% in the chronic L-arg group. Tubular function was also
      better preserved in the acute L-arg group. PTs isolated from L-arg-treated rats
      were more sensitive to isolation injury. L-Arg addition enhanced H/R injury (44.9
      vs 51.8%, P < 0.05), whereas L-NAME addition protected (44.9 vs 24%, P < 0.001)
      in untreated rats. In L-arg-treated rats, addition of L-arg did not enhance H/R
      injury (49.6 vs 53.5%, NS) and L-NAME was still protective (49.6 vs 32.3%, P <
      0.001). In PTs from L-NAME-treated rats, L-arg addition also did not enhance H/R
      injury (50 vs 54%, NS) whereas L-NAME was protective (50 vs 27%, P < 0.001). NO2
      /NO3- production paralleled L-arg and L-NAME supplementation. CONCLUSION: It was
      demonstrated that acute L-arg infusion was beneficial in in vivo renal ischaemia
      while it was harmful in isolated H/R tubules. In contrast, chronic L-arg
      supplementation was deleterious both in in vivo and in vitro renal ischaemia,
      suggesting that injurious effects had overcome the beneficial effects during
      excess NO exposure.

PMID- 10344354
TI  - Production of platelet-activating factor in patients with sepsis-associated acute
      renal failure.
AB  - BACKGROUND: Studies in experimental animals have suggested that platelet
      activating factor (PAF) is a mediator of sepsis-associated acute renal failure
      (ARF). In the present study we have evaluated whether an increased concentration
      of PAF within circulation or urine of septic patients correlated with the
      worsening of renal function. METHODS: The concentration of PAF and selected
      cytokines (TNF, IL-1, IL-6, IL-8) was evaluated in blood and urine of 12 patients
      with septic shock and ARF for 4 consecutive days. RESULTS: The data obtained
      indicate that blood and urinary concentrations of PAF and of IL-1, IL-6 and IL-8
      were significantly higher in septic patients than in controls subjects and in
      patients with chronic renal failure. The concentration of TNF was significantly
      increased only in urine. A significantly positive correlation was found among
      blood concentration of PAF and heart rate (r = 0.4193, P < 0.017), serum
      creatinine (r = 0.3671, P < 0.038), serum IL-6 (r = 0.5475, P < 0.005) and urine
      excretion of IL-8 (r = 0.3984, P < 0.044), whereas a negative correlation was
      present with the number of circulating platelets (r = -0.4285, P < 0.018).
      Moreover, a positive correlation among the concentration of PAF in urine and the
      serum concentration of IL-6 (r = 0.5654, P < 0.006) and urine excretion of IL-6
      (r = 0.6589, P < 0.0008) and IL-8 (r = 0.6371, P < 0.0004) were found.
      CONCLUSIONS: These results demonstrate in humans during ARF associated with
      septic shock the production of PAF, a mediator that has been previously
      implicated in the pathogenesis of experimental endotoxin-induced shock and renal
      injury. The observation that blood and urinary concentrations of PAF correlated
      with some of the clinical and laboratory parameters related to the severity of
      ARF and sepsis suggests that PAF may contribute to the development of renal
      injury in septic patients.

PMID- 10344355
TI  - Acute renal failure following cardiac surgery.
AB  - BACKGROUND: Acute renal failure requiring dialysis (ARF-D) occurs in 1.5% of
      patients following cardiac surgery, and remains a cause of major morbidity and
      mortality. While some preoperative risk factors have been characterized, the
      influence of preoperative and intraoperative factors on the occurrence of ARF
      following cardiac surgery is less well understood. METHODS: Preoperative and
      intraoperative data on 2843 consecutive adult patients undergoing cardiac surgery
      with cardiopulmonary bypass (CPB) from February 1, 1995 to February 1, 1997 were
      recorded and entered into a computerized database. Two definitions of renal
      failure were employed: (i) ARF defined as a rise in serum creatinine (Cr) of 1
      mg/dl above baseline; and (ii) ARF-D defined as the development of ARF for which
      some form of dialytic therapy was required. The association between preoperative
      and intraoperative variables and the development of ARF was assessed by
      multivariate logistic regression. RESULTS: A total of 2672 of the 2844 patients
      underwent isolated coronary artery bypass grafting (CABG) surgery, the remaining
      172 underwent valve surgery with or without bypass grafting. Of the CABG patients
      7.9% developed ARF and 0.7% developed ARF-D. The mortality for patients who
      developed ARF was 14% (OR 15, P = 0.0001) compared with 1% among those who did
      not develop ARF. The mortality for CABG patients who developed ARF-D was 28% (OR
      20, P = 0.0001) compared with 1.8% among those who did not require dialysis.
      Variables that were significantly associated with the development of ARF by
      multivariate analysis included: increased age, elevated preoperative serum Cr,
      duration of CPB, presence of a carotid artery bruit, presence of diabetes,
      reduced cardiac ejection fraction and increased body weight. Variables
      independently associated with ARF-D included serum Cr, duration of CPB, carotid
      artery bruit and presence of diabetes. The utility of these models for predicting
      the development of ARF and ARF-D was confirmed by bootstrapping techniques.
      Because of the small number of patients who underwent valve surgery, none of
      these variables were significantly associated with the development of ARF or ARF
      D in this group of patients. CONCLUSION: The development of ARF or ARF-D is
      associated with a high mortality following CABG surgery. We have identified
      perioperative variables, which may be useful in stratifying risk for the
      development of ARF.

PMID- 10344356
TI  - Physical symptoms and quality of life in patients on chronic dialysis: results of
      The Netherlands Cooperative Study on Adequacy of Dialysis (NECOSAD)
AB  - BACKGROUND: So far, little attention has been paid to the value of dialysis
      adequacy for patients' quality of life (QL). Therefore we studied the impact of
      demographic, clinical, and dialysis characteristics on physical symptoms and
      perceived QL. METHODS: The study population consisted of 120 incident chronic
      haemodialysis (HD) and 106 peritoneal dialysis (PD) patients, starting dialysis
      treatment in 13 Dutch centres. Data were collected 3 months after the start of
      dialysis. Nine physical symptoms were assessed with a self-administered
      questionnaire. Patient's self-assessment of QL was measured with the 36-item MOS
      Short Form (SF-36). RESULTS: The most common symptoms in HD and PD were fatigue
      (respectively 82 and 87%) and itching (73 and 68%). In HD only a medium to high
      comorbidity--age risk index was associated with greater symptom burden. In PD
      also a lower percentage lean body mass, a lower rGFR, and past episodes of
      underhydration were associated with greater symptom burden. The explained
      variance by these variables was only 12% in HD and 21% in PD. However, greater
      symptom burden explained a substantial additional amount of impaired physical and
      mental QL on top of demographics and clinical status. Dialysis variables were
      associated neither with symptoms nor with QL. CONCLUSION: Symptom burden can be
      explained to a limited extent by demographic and clinical variables and not by
      dialysis characteristics. Addition of symptom burden to the other variables makes
      it possible to explain one-third of perceived QL. This underlines the importance
      of symptom reduction in order to improve patient's QL.

PMID- 10344357
TI  - Synergistic effect of desferrioxamine and recombinant erythropoietin on erythroid
      precursor proliferation in chronic renal failure.
AB  - BACKGROUND: Desferrioxamine (DFO) has been suggested to improve erythropoiesis in
      end-stage renal failure independently of its aluminium (Al)-chelating effect. A
      possible synergistic effect of DFO and recombinant human erythropoietin (r-HuEpo)
      could be very useful in treating anaemia of chronic renal failure. METHODS: In
      order to verify whether a synergistic action of DFO and r-HuEpo exists, we
      enrolled 11 patients undergoing chronic haemodialysis and r-HuEpo treatment. All
      had a negative DFO test, very low serum Al levels (< 20 microg/l), ferritin > 100
      ng% and iPTH < 200 pg/l. Samples were drawn for a basal erythroid precursor
      (burst-forming unit-Erythroid, BFU-E) evaluation. After isolation by Ficoll
      Hypaque, a 14 day incubation was carried out with: (i) r-HuEpo 3 U/ml; (ii) r
      HuEpo 30 U/ml; and (iii) r-HuEpo 30 U/ml + DFO 167 microg/ml. Patients then
      received 5 mg/kg DFO infused during the last hour of each dialysis session for 12
      weeks. New BFU-E evaluations were performed after 2, 6 and 12 weeks of treatment.
      BFU-E colonies were counted in duplicate with an inverted microscope after 14
      days. Haemoglobin (Hb), ferritin, transferrin, reticulocytes, hypochromic
      erythrocytes, soluble transferrin receptor and serum erythropoietin were also
      evaluated at the same time. RESULTS: High dose r-HuEpo achieved greater
      proliferation than low dose r-HuEpo cultures during all phases of the study. At
      baseline, r-HuEpo and DFO culture had a greater number of colony units than high
      dose r-HuEpo culture ( 103.7 +/- 50.2 vs 95.1 +/- 50.5, NS). This increase became
      significant after 2 weeks (145 +/- 59.3 vs 122.9 +/- 59.6, P < 0.02), and
      remained so at 6 (167.4 +/- 60.3 vs 149 +/- 55.6, P < 0.01) and 12 weeks (191 +/-
      64.5 vs 155.1 +/- 56.3, P < 0.01). An increased proliferation was observed after
      DFO therapy in all culture studies: low dose r-HuEpo culture increased from 69.4
      +/- 38.2 to 86.6 +/- 48.5, 115 +/- 39 and 123 +/- 46; high dose r-HuEpo culture
      increased from 95.1 +/- 50.5 to 122.9 +/- 59, 149 +/- 55.6 and 155.1 +/- 56.3 and
      r-HuEpo plus DFO culture from 103.7 +/- 50.2 to 145 +/- 59.3, 167 +/- 60.3 and
      191 +/- 64.5 at 2, 6 and 12 weeks, respectively (all P < 0.01 by ANOVA).
      Haemoglobin, reticulocytes and soluble transferrin receptor were slightly
      increased, while ferritin decreased. Hypochromic erytrocytes were variable.
      CONCLUSIONS: DFO increases erythroid precursor proliferation and has a
      synergistic in vivo effect with r-HuEpo in patients with chronic renal failure.
      Further investigations are needed to evaluate whether such an effect may have
      clinical application.

PMID- 10344358
TI  - Effect of permeability on indices of haemodialysis membrane biocompatibility.
AB  - BACKGROUND: Increases in plasma anaphylatoxins frequently are used as an index of
      haemodialysis membrane biocompatibility; however, their plasma levels may be
      influenced by the loss of anaphylatoxins into the dialysate compartment. METHODS:
      We compared the generation and compartmental distribution of anaphylatoxins, C3a
      and C5a, in a high flux and a low flux polysulfone membrane dialyser when whole
      human blood was recirculated through an in vitro haemodialysis circuit. RESULTS:
      Plasma C3a levels in high flux polysulfone (2.31 +/- 0.81 microg/ml) and low flux
      polysulfone (3.02 +/- 0.98 microg/ml) dialysers were comparable after 120 min (P
      = NS). In contrast, dialysate C3a in high flux polysulfone (0.65 +/- 0.31
      microg/ml) accounted for 37.5 +/- 7.0% of the total detected (plasma + dialysate)
      C3a mass in the dialysers, while dialysate C3a in low flux polysulfone dialysers
      (0.01 +/- 0.01 microg/ml) accounted for only 0.3 +/- 0.3% of the total mass (P <
      0.05; high flux vs low flux). Anaphylatoxin C5a was undetectable in the dialysate
      compartment of either dialyser examined. CONCLUSIONS: Our results indicate that
      anaphylatoxins readily traverse certain high flux dialysis membranes;
      consequently, plasma C3a levels may not accurately reflect the C3-activating
      potential of these membranes.

PMID- 10344360
TI  - Molecular epidemiology of a hepatitis C virus outbreak in a haemodialysis unit.
      Multicentre Haemodialysis Cohort Study on Viral Hepatitis.
AB  - BACKGROUND: Haemodialysis patients are at high risk of infection by hepatitis C
      virus. The aim of this study was to investigate a hepatitis C virus outbreak
      which occurred in a haemodialysis unit, using epidemiological and molecular
      methods. METHODS: Five seroconversions to hepatitis C virus antibody (anti-HCV)
      were observed over a 6 month period and these were added to the four previously
      recorded anti-HCV-positive patients. All nine patients involved in the outbreak
      were tested for HCV RNA by reverse transcription-polymerase chain reaction and
      hepatitis C genotype determination was accomplished by a reverse hybridization
      assay. Furthermore, part of the NS5 region of hepatitis C genome (nucleotide
      positions 7904-8304) was amplified and sequenced in all HCV RNA-positive
      patients. Then, phylogenetic analysis of the nucleotide sequences obtained was
      carried out in order to investigate any possible epidemiological linkage among
      patients. Detailed epidemiological records were also available for all
      haemodialysis patients. RESULTS: Samples from all five incident cases and three
      out of four prevalent HCV infections were found positive for HCV RNA. HCV
      genotyping studies revealed that all incident cases were classified as 4c/d,
      whereas one and two prevalent cases were 1a and 4c/d respectively. Sequence
      comparisons and phylogenetic tree analysis revealed that six of the patients
      harboured very similar strains and clustered together, including all incident and
      one prevalent case, which was implicated as index case. Further epidemiological
      analysis was consistent with patient to patient transmission. CONCLUSIONS:
      Molecular and epidemiological analysis suggested that horizontal nosocomial
      patient to patient transmission was the most likely explanation for the virus
      spread within the haemodialysis unit under study.

PMID- 10344359
TI  - Physical performance and associated electrolyte changes after haemoglobin
      normalization: a comparative study in haemodialysis patients.
AB  - BACKGROUND: To determine the effects of different haemoglobin (Hb) levels on
      exercise performance and associated electrolyte changes, a prospective,
      randomized, double-blinded crossover study was completed in 14 haemodialysis
      patients. METHODS: Performance and changes in arterial [K+] and lactate were
      compared at rest and during a maximal incremental cycling exercise at a Hb
      concentration ([Hb]) of 10 g/dl ([Hb]10) and 14 g/dl ([Hb]14) following an
      initial baseline test (Hb: 8.3 +/- 0.2 g/dl, mean +/- SEM). Ages ranged from 23
      to 65 years and patients were divided into younger (age 23-45 years, n = 9) and
      older (aged 55-65 years, n = 5) groups. RESULTS: Peak work rate and VO2 peak were
      higher at [Hb]14 than at [Hb]10. 145 +/- 9 vs 134 +/- 9 W, mu +/- SEM, P < 0.01,
      and 1.90 +/- 0.11 vs 1.61 +/- 0.11 l/min, P < 0.01, respectively. Improvements
      were demonstrated in both younger and older groups at the higher target [Hb],
      with an improved aerobic performance evident particularly in younger patients.
      However, performance remained below that predicted for comparable sedentary
      controls. Resting plasma [K+] was raised at both [Hb]10 and [Hb]14 compared with
      baseline (P < 0.01) although the change in [K+] from rest to peak exercise
      (delta[K+]) was similar at each level. The delta[K+] per unit work performed
      (used as a marker of K+ regulation) was, however, inversely related to the [Hb]
      (baseline: 80 +/- 12 micromol/l/kJ vs [Hb]10, 61 +/- 8, P < 0.01, vs [Hb]14. 49
      +/- 7, P < 0.05). Exercise induced a significant but similar rise in lactate
      concentration at both target [Hb] (P < 0.001), which remained markedly elevated
      for at least 10 min after exercise in both younger and older groups. CONCLUSIONS:
      These data demonstrate that a physiological [Hb] improves, but does not
      normalize, exercise performance in end-stage renal failure. Both younger and
      older patients appear to benefit similarly from the enhanced oxygen transport.
      Impaired K+ regulation is apparently related to [Hb] and could well contribute to
      the observed limitations in performance.

PMID- 10344361
TI  - Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat
      small intestine.
AB  - BACKGROUND: We recently reported that the administration of niceritorol (a
      nicotinic acid derivative which improves lipid metabolism and peripheral
      circulation, and is used for the treatment of hyperlipidaemia and impaired
      peripheral circulation) to patients with hyperphosphataemia undergoing dialysis
      decreased the serum phosphate (Pi) concentration. We found that this was due to
      an acceleration of faecal Pi excretion by niceritrol. METHODS: Intestinal brush
      border membrane vesicles (BBMVs) were prepared from rat jejunum, and the Na+
      dependent and Na+-independent Pi transport activities in these vesicles were
      measured. In addition, the functional Pi transporter from rat small intestine was
      injected in Xenopus oocytes, and the effect of nicotinamide on the levels of its
      expression were measured by northern blotting. RESULTS: The Na+-dependent
      component was significantly decreased in the BBMVs isolated from rats treated
      with nicotinamide, while the Na+-independent component was not changed. Kinetic
      studies demonstrated that the decreased activity was due to reduction of the Vmax
      value and not an elevation of the Km values. When poly(A)+RNA from rats treated
      with nicotinamide was microinjected into Xenopus oocytes, the Pi transport
      activity was significantly decreased compared with that in the control animals.
      In addition, there were no significant changes in Na/Pi cotransporters and
      activators, but the vitamin D receptor mRNA level was reduced to 80% of the
      control level. CONCLUSIONS: These observations suggest that nicotinamide may
      regulate the expression of a major functional Na/Pi cotransporter in the rat
      small intestine.

PMID- 10344362
TI  - Change from conventional haemodiafiltration to on-line haemodiafiltration.
AB  - BACKGROUND: On-line haemodiafiltration (HDF) is a technique which combines
      diffusion with elevated convection and uses pyrogen-free dialysate as a
      replacement fluid. The purpose of this study was to evaluate the difference
      between conventional HDF (1-3 l/h) and on-line HDF (6-12 l/h). METHODS: The study
      included 37 patients, 25 males and 12 females. The mean age was 56.5 +/- 13 years
      and duration of dialysis was 62.7 +/- 49 months. Three patients dropped out for
      transplantation, three patients died and three failed to complete the study
      period. Initially all patients were on conventional HDF with high-flux membranes
      over the preceding 34 +/- 32 months. Treatment was performed with blood flow (QB)
      402 +/- 41 ml/min, dialysis time (Td) 187 min, dialysate flow (QD) 654 +/- 126
      ml/min and replacement fluid (Qi) 4.0 +/- 2 l/session. Patients were changed to
      on-line HDF with the same filtre and dialysis time, QD 679 +/- 38 ml/min (NS), QB
      434 +/- 68 ml/min (P < 0.05) and post-dilutional replacement fluid 22.5 +/- 4.3
      l/session (P < 0.001). We compared conventional HDF with on-line HDF over a
      period of 1 year. Dialysis adequacy was monitored according to standard clinical
      and biochemical criteria. Kinetic analysis of urea and beta2-micro-globulin
      (beta2m) was performed monthly. RESULTS: Tolerance was excellent and no pyrogenic
      reactions were observed. Pre-dialysis sodium increased 2 mEq/l during on-line
      HDF. Plasma potassium, pre- and post-dialysis bicarbonate, uric acid, phosphate,
      calcium, iPTH, albumin, total proteins, cholesterol and triglycerides remained
      stable. The mean plasma beta2m reduction ratio increased from 56.1 +/- 8.7% in
      conventional HDF to 71.1 +/- 9.1% in on-line HDF (P < 0.001). The pre-dialysis
      plasma beta2m decreased from 27.4 +/- 8.1 to 24.2 +/- 6.5 mg/l (P < 0.01). Mean
      Kt/V (Daugirdas 2nd generation) was 1.35 +/- 0.21 in conventional HDF compared
      with 1.56 +/- 0.29 in on-line HDF (P < 0.01), Kt/Vr (Kt/V taking into
      consideration post-dialysis urea rebound) 1.12 +/- 0.17 vs 1.26 +/- 0.20 (P <
      0.01), BUN time average concentration (TAC) 44.4 +/- 9 vs 40.6 +/- 10 mg/dl (P <
      0.05) and protein catabolic rate (PCR) 1.13 +/- 0.22 vs 1.13 +/- 0.24 g/kg (NS).
      There was a significant increase in haemoglobin (10.66 +/- 1.1 vs 11.4 +/- 1.5)
      and haematocrit (32.2 +/- 2.9 vs 34.0 +/- 4.4%), P < 0.05, during the on-line HDF
      period, which allowed a decrease in the erythropoietin doses (3861 +/- 2446 vs
      3232 +/- 2492 UI/week), (P < 0.05). Better blood pressure control (MAP 103.8 +/-
      15 vs 97.8 +/- 11 mmHg, P < 0.01) and a lower percentage of patients requiring
      antihypertensive drugs were also observed. CONCLUSION: The change from
      conventional HDF to on-line HDF results in increased convective removal and fluid
      replacement (18 l/session). During on-line HDF treatment, dialysis dose was
      increased for both small and large molecules with a decrease in uraemic toxicity
      level (TAC). On-line HDF provided a better correction of anaemia with lower
      dosages of erythropoietin. Finally, blood pressure was easily controlled.

PMID- 10344363
TI  - Epidermal growth factor modifies the expression and function of extracellular
      matrix adhesion receptors expressed by peritoneal mesothelial cells from patients
      on CAPD.
AB  - BACKGROUND: Efficient peritoneal dialysis depends on an intact layer of
      mesothelial cells that line the peritoneal membrane. This layer is disrupted in
      patents on continuous ambulatory peritoneal dialysis during episodes of
      peritonitis (acute injury) and replaced by fibrous tissue during extended
      dialysis (chronic injury). Little is understood of human peritoneal mesothelial
      cell (HPMC) responses to wounding and episodes of peritonitis. METHODS: HPMC were
      harvested from spent peritoneal dialysis effluent and maintained under defined in
      vitro conditions. Adhesive interactions with extracellular matrix (ECM) molecules
      and chemotactic and wound-healing responses were measured in vitro using purified
      ECM molecules. RESULTS: HPMC express multiple functional cell receptors
      recognizing and binding to ECM molecules, including several members of the
      integrin family. HPMC exhibit directed migration in wound healing and chemotaxis
      assays with ECM molecules. Epidermal growth factor (EGF) stimulates a reversible
      change to a fibroblastic phenotype, accompanied by increased expression of beta1
      integrins, particularly alpha2beta1, increased adhesion to type I collagen, and
      significantly greater HPMC migration on type I collagen in wound healing and
      chemotaxis assays. CONCLUSIONS: HPMC possess the migratory capacity to contribute
      to the efficient repair of damaged peritoneal membrane after acute injury, and
      growth factors, such as EGF, facilitate peritoneal membrane healing by augmenting
      cell adhesion and migration.

PMID- 10344364
TI  - Response to hypertonicity in mesothelial cells: role of Na+/myo-inositol co
      transporter.
AB  - BACKGROUND: During peritoneal dialysis, the peritoneal mesothelium is exposed
      continually to hypertonic dialysates. The purpose of this study is to see if rat
      mesothelial cells have an osmoregulatory mechanism to adapt to hypertonic
      environment. METHODS: The intracellular content of organic osmolytes was measured
      by HPLC methods. Myo-inositol transport activity was measured by Na+-dependent
      uptake of [3H]myo-inositol. mRNA abundance for the Na+/myo-inositol co
      transporter (SMIT) was examined by Northern and slot-blot analyses. RESULTS: In
      isotonic mesothelial cells, only myo-inositol could be detected. After switching
      to hypertonic medium made by addition of NaCl, myo-inositol content gradually
      increased and peaked at 48 h after the switch. The myo-inositol content in
      hypertonic cells increased > 7-fold over the value in isotonic cells. The
      contents of betaine and glycerophosphorylcholine (GPC) also increased but were
      less than that of myo-inositol. Sorbitol was not accumulated in this condition.
      When glucose was used to increase medium osmolality, all of the four osmolytes
      were increased by hypertonicity (myo-inositol > sorbitol > GPC > betaine). Thus,
      myo-inositol is the most abundant osmolyte in the mesothelial cells. Na+
      dependent myo-inositol uptake in hypertonic cells was approximately 7-fold the
      uptake in isotonic cells, reaching a maximum 16 h after switching to a hypertonic
      medium. The uptake rate increased as medium osmolality increased from 300 to 500
      mosm/kg. SMIT mRNA rapidly increased after increasing medium osmolality, reaching
      a maximum 8 h after the switch. The relative increase in the mRNA abundance was
      approximately 11 times isotonic levels. CONCLUSIONS: Mesothelial cells respond to
      extracellular hypertonicity by increasing SMIT mRNA abundance, myo-inositol
      transport activity and accumulating myo-inositol into the cells.

PMID- 10344365
TI  - The influence of automated peritoneal dialysis on the decrease in residual renal
      function.
AB  - BACKGROUND: Automated peritoneal dialysis (APD) has been increasingly used in
      recent years. Our purpose was to investigate whether the good preservation of
      residual renal function (RRF) that has been reported in patients on continuous
      ambulatory peritoneal dialysis (CAPD) is also observed in APD. METHODS: RRF was
      determined and compared prospectively over 1 year in two groups of peritoneal
      dialysis (PD) patients: 18 consecutive new patients starting on APD (12
      continuous cyclic peritoneal dialysis (CCPD) patients and six nightly
      intermittent peritoneal dialysis (NIPD) patients) and 18 selected patients who
      had started on CAPD at the same time and were matched for baseline
      characteristics. RRF was assessed on normalized creatinine clearance (ml/min/1.73
      m2) measured before the start of PD, at 6 months, and at 1 year. Wilcoxon's rank
      sum test was used to compare differences between the two groups. RESULTS:
      Creatinine clearance (ClCr) was 6.1 ml/min in the APD group and 6 ml/min in the
      CAPD group at the start of PD. The monthly rate of ClCr decrease was
      significantly higher in the APD group: -0.28 ml/min vs -0.1 ml/min (P = 0.04) at
      6 months and -0.26 ml/min vs -0.13 ml/min (P = 0.005) at 1 year. RRF decreased at
      the same rate in patients treated with NIPD or CCPD. The daily instilled volume
      of 3.86% glucose dialysis solution (l/day) was higher in APD patients than in
      CAPD patients: 2.5 vs 0 at 6 months and 1 year but there was no significant
      difference in ultrafiltration rate (l/day) between APD and CAPD patients at these
      timepoints: 0.53 vs 0.6 and 0.88 vs 0.7 respectively. There was no difference
      between the two groups in body weight and blood pressure, which remained stable
      in both groups throughout the study period. CONCLUSIONS: RRF declined rapidly in
      APD patients whereas it was well preserved in CAPD patients. This may be
      explained by the less stable fluid and osmotic load together with the
      intermittent nature of APD and the larger use of hypertonic dialysate. RRF should
      be closely monitored in APD patients in order to adjust PD prescriptions and
      maintain adequacy.

PMID- 10344366
TI  - Familial relapsing haemolytic uraemic syndrome and complement factor H
      deficiency.
AB  - BACKGROUND: In a recent study of three families we have found that inherited
      haemolytic uraemic syndrome (HUS) maps to a region of chromosome 1q containing
      the gene for complement factor H. In one of these families and also in a case of
      sporadic D-HUS, we have identified mutations in the factor H gene. A further
      family with inherited HUS has therefore been investigated. METHODS: DNA extracted
      from the family members and DNA extracted from archival post-mortem material from
      a deceased family member, was studied. Review of renal biopsies and study of
      complement components was also undertaken. RESULTS: This family demonstrates an
      inherited deficiency of complement factor H. Non-diarrhoeal HUS has affected at
      least two family members with half normal levels of factor H. CONCLUSION: These
      findings represent further evidence of the association between factor H
      dysfunction and HUS.

PMID- 10344367
TI  - Glomerular expression of nephrin is decreased in acquired human nephrotic
      syndrome.
AB  - BACKGROUND: Nephrin recently has been identified as a putative adhesion molecule,
      expressed in the glomerulus, in which mutations cause congenital nephrotic
      syndrome of Finnish type. We sought to determine whether expression of nephrin is
      altered in human glomeruli in patients with acquired nephrotic syndrome. METHODS:
      We performed PCR amplification of nephrin cDNA, using cDNA previously prepared
      from single human glomeruli plucked fresh from the surface of human renal
      biopsies. We had available four cases of nephrotic syndrome (one membranous,
      three minimal change) and six normal controls. PCR product quantitation was by
      gel densitometry, confirmed by enzyme-linked immunosorbent assay using a specific
      oligonucleotide probe. Results were corrected for reaction efficiency and
      glomerular cellularity by expression as a ratio to levels of the 'housekeeping
      gene' glyceraldehyde phosphate dehydrogenase. RESULTS: Glomerular levels
      ofnephrin mRNA are significantly decreased in cases of minimal change nephrotic
      syndrome. An apparent reduction was also seen in the single case of membranous
      nephropathy which was available for study. CONCLUSIONS: Abnormalities of nephrin
      expression appear to be associated with acquired as well as congenital causes of
      human nephrotic syndrome.

PMID- 10344368
TI  - The benefits of hormone replacement therapy in pre-menopausal women with
      oestrogen deficiency on haemodialysis.
AB  - BACKGROUND: Impaired sexual function is an important cause of depression in
      uraemic females. Hyperprolactinaemia is frequent, and often associated with
      decreased serum oestradiol concentration, which can significantly contribute to
      accelerated bone loss. The aim of the study was to evaluate the effect of hormone
      replacement therapy (HRT) on sexual function, serum 17beta-oestradiol and
      prolactin, and bone mineral density (BMD) in pre-menopausal women undergoing
      haemodialysis. METHODS: Among 63 women on haemodialysis, aged 18-45 years, 23
      with secondary amenorrhoea and serum oestradiol < 30 pg/ml were enrolled into the
      1 year study. They were divided into: group I (n = 13) treated with transdermal
      oestradiol with cyclic addition of noretisterone acetate, and control group II (n
      = 10). BMD was measured with dual energy X-ray absorptiometry (DEXA). RESULTS: No
      important changes in sexual function and hormonal profile were observed in the
      control group, whereas in all women from group I the treatment induced regular
      menses and a marked improvement of libido and sexual activity. Serum 17beta
      oestradiol increased after the first month from 20.5 +/- 11.7 to 46.8 +/- 13.6
      pg/ml (P < 0.001) and remained at that level until the end of the study,
      accompanied by a decrease of serum prolactin (from 1457 +/- 1045 to 691 +/- 116
      mIU/ml after 12 months; P < 0.001). In group I, the treatment induced an increase
      in BMD, although significant only in L2-L4 (P < 0.05), whereas in group II a mild
      insignificant decrease was observed. However, a comparison of BMD values after 12
      months in both groups revealed marked (P < 0.01-P < 0.05) differences at all
      studied sites. CONCLUSIONS: Transdermal HRT allows sustained physiological serum
      oestradiol concentrations in pre-menopausal women with oestrogen deficiency on
      haemodialysis, with the restoration of regular menses and a marked improvement in
      their sexual function. The treatment inhibits bone demineralization and can play
      an important role in the prevention of early osteoporosis in this group of
      patients.

PMID- 10344370
TI  - Glomerular filtration rate estimation from plasma creatinine after inhibition of
      tubular secretion: relevance of the creatinine assay.
AB  - BACKGROUND: Estimation of glomerular filtration rate (GFR) from plasma creatinine
      concentration after inhibition of tubular creatinine secretion with cimetidine
      provides a good assessment in patients with various nephropathies and with non
      insulin-dependent diabetes mellitus (NIDDM). The aim of this study was to compare
      cimetidine-aided GFR estimations using various creatinine assays. METHODS: In 30
      outpatients with NIDDM GFR was measured as the urinary clearance of continuously
      infused [125I]iothalamate. Plasma creatinine concentration was analysed after
      oral cimetidine with an alkaline picrate (AP) method, with an enzymatic (PAP)
      assay and with HPLC. GFR estimations were calculated with the Cockcroft Gault
      formula (CG). RESULTS: AP creatinine concentrations were significantly higher
      than PAP or HPLC values. GFR estimations by AP (CG(AP) 66 +/- 19 ml/min/1.73 m2,
      mean SD) were significantly lower than GFR (89 +/- 30), whereas CG(PAP) (85 +/-
      30) and CG(HPLC) (84 +/- 34 ml/min/1.73 m2) were not. Bland and Altman analysis
      showed a difference between CG(AP) and GFR of -22.4 +/- 17.7 ml/min/1.73 m2; this
      difference becomes larger when the GFR increases. The difference between CG and
      GFR was only -3.8 +/- 14.8 ml/min/1.73 m2 for PAP and -4.4 +/- 17.5 ml/min/1.73
      m2 for HPLC, without any systematic difference. CONCLUSION: A good assessment of
      the GFR from plasma creatinine after cimetidine administration is possible when
      creatinine is measured with an enzymatic assay or with the less convenient HPLC
      method. The more widespread and cheaper alkaline picrate assay is not suitable
      for GFR-estimation.

PMID- 10344369
TI  - Polycystic kidney disease as a risk factor for post-transplant diabetes mellitus.
AB  - BACKGROUND: Insulin resistance with compensatory hyperinsulinaemia has been
      reported in adult polycystic kidney disease (APKD) patients. Diabetes mellitus is
      a common complication following transplantation and previous studies have
      demonstrated that inadequate insulin secretion was a prerequisite for the
      development of post-transplant diabetes mellitus (PTDM). We conducted a
      retrospective study to determine whether APKD is a risk factor for PTDM. METHODS:
      Twenty-six consecutive patients transplanted because of end-stage renal disease
      due to APKD were studied. A control patient matched for age, gender,
      immunosuppressive therapy and transplant year was selected for each APKD patient.
      PTDM was defined by fasting glycaemia exceeding 7.8 mmol/l and the need for
      insulin or oral antidiabetic therapy. RESULTS: Age, renal function,
      immunosuppressive regimen, number of acute rejection, cumulative dose of steroids
      and haemodialysis duration before transplantation were similar in both groups.
      PTDM occured in 10 APKD patients and four controls (34.6% vs 15.3%; P < 0.005).
      Among diabetic patients, six APKD patients and two controls required insulin
      therapy (60% vs 50%; P = n.s.). Diabetic patients were significantly older (55.8
      +/- 7 years vs 50.2 +/- 11 years; P < 0.05). CONCLUSION: Although retrospective,
      this study suggests that APKD confers an increased risk of PTDM.

PMID- 10344371
TI  - Axillo-axillary arteriovenous fistula as a suitable surgical alternative for
      chronic haemodialysis access.

PMID- 10344372
TI  - The use of a channel-cleaning brush for malfunctioning Tenckhoff catheters.
AB  - BACKGROUND: Tenckhoff catheter malfunction causes morbidity in some patients on
      continuous ambulatory peritoneal dialysis (CAPD). Various methods of treatment of
      malfunction have been described; we report our experience of the use of a channel
      cleaning brush for this problem. METHOD: Ten patients on CAPD who developed
      catheter malfunction were identified. The causes of malfunction were catheter
      migration in one patient, catheter obstruction due to fibrin and clots in six,
      probable omental wrapping in one, and pain on draining of PD fluid in two
      patients. A channel-cleaning brush was manipulated repeatedly in and out of the
      catheters using aseptic technique and fluoroscopy guidance in an attempt to
      restore patency or dislodge the catheter to another site. RESULTS: CAPD was
      successfully re-established after this procedure in eight patients (80%), two
      catheters were removed from those patients in whom the use of the brush was
      unsuccessful. CONCLUSION: In this study a channel-cleaning brush was effective
      and safe in the treatment of Tenckhoff catheter malfunction.

PMID- 10344373
TI  - Running repairs: renal artery dissection following extreme exertion.

PMID- 10344374
TI  - Acute interstitial nephritis induced by crack cocaine binge.

PMID- 10344375
TI  - Chronic drug-induced tubulointerstitial nephritis with renal failure associated
      with propylthiouracil therapy.

PMID- 10344376
TI  - Simultaneous IgA nephropathy and Wegener's granulomatosis--overlap or coincidence
      (the role of renal biopsy).

PMID- 10344377
TI  - Disseminated cutaneous plasmacellular granuloma associated with membranous
      glomerulonephritis.

PMID- 10344378
TI  - Successful treatment of hepatitis B virus (HBV)-associated membranoproliferative
      glomerulonephritis (MPGN) with alpha interferon.

PMID- 10344379
TI  - Glomerulocystic kidney disease in an adult presenting as end-stage renal failure.

PMID- 10344380
TI  - Two cases of psoas abscess with discitis by methicillin-resistant Staphylococcus
      aureus as a complication of femoral-vein catheterization for haemodialysis.

PMID- 10344381
TI  - Continuous venovenous haemofiltration in hyperammonaemic coma of an adult with
      non-diagnosed partial ornithine transcarbamylase deficiency.

PMID- 10344382
TI  - Reversible lymphoproliferative disorder with isolated lung involvement in a renal
      transplant patient.

PMID- 10344383
TI  - Successful medical eradication of tuberculous paranephric abscess in renal
      transplantation.

PMID- 10344384
TI  - Fatal varicella with primary fibrinolysis in a renal transplant recipient.

PMID- 10344385
TI  - Resection of an aortic aneurysm in a renal transplant recipient using hypothermic
      perfusion.

PMID- 10344386
TI  - Pseudoaneurysm of the inferior epigastric artery--a rare complication of
      Tenckhoff catheter removal.

PMID- 10344387
TI  - Retroperitoneal fibrosis and systemic lupus erythematosus.

PMID- 10344388
TI  - Retroperitoneal fibrosis and membranous nephropathy. Improvement of both diseases
      after treatment with steroids and immunosuppressive agents.

PMID- 10344389
TI  - Multiple venous thrombosis and massive pulmonary artery thrombus as the
      presenting features of steroid-responsive nephrotic syndrome.

PMID- 10344390
TI  - 'Flash pulmonary oedema' in a patient 24 years after aorto-renal vein graft.

PMID- 10344392
TI  - The patient with two renal diseases: crescentic glomerulonephritis and renal AA
      amyloid.

PMID- 10344391
TI  - The unusual diabetic patient with advanced renal insufficiency on ACE inhibitors.
      What is the explanation for her persisting hypokalaemia?

PMID- 10344394
TI  - An unusual complication of pregnancy.

PMID- 10344393
TI  - Cardiovascular consequences of renal anaemia and erythropoietin therapy.
AB  - Cardiovascular disease is the leading cause of increased mortality in patients
      with renal failure and vigorous attention to cardiovascular risk factors is
      therefore required to improve patient outcome. The availability of recombinant
      human Epo has focused the interest on the role of chronic anaemia in the
      pathogenesis of cardiovascular disease. Severalfold evidence indicates that
      anaemia can contribute to cardiac volume overload and together with
      overhydration, fistula flow and the pressure overload secondary to arterial
      hypertension, it may play a significant role in the development of cardiac
      hypertrophy. As in the general population left ventricular hypertrophy is a
      severe adverse risk factor in renal patients. In addition, in the presence of
      ischaemic heart disease anaemia may further worsen cardiac oxygen supply. This
      dual effect of anaemia probably explains why epidemiological studies have shown
      that a 1 g/dl decrease in haemoglobin levels is an independent, statistically
      significant risk factor for the development of cardiac morbidity and mortality.
      Follow-up examinations have demonstrated that partial correction of anaemia with
      recombinant Epo can improve cardiac oxygen supply and partially reverse
      pathological changes in left ventricular geometry. However, although partial
      anaemia correction regularly reduces left ventricular volume, the effects on wall
      thickness are far less significant. Moreover, in patients with advanced cardiac
      disease it has recently not been possible to demonstrate that a normalization of
      haemoglobin levels provides further benefit. It is not unlikely therefore that
      the development of severe anaemia has to be prevented by early implementation of
      Epo therapy in order to achieve the maximum benefit with respect to the
      cardiovascular system.

PMID- 10344395
TI  - The description of renal 'arterio-capillary fibrosis' by William W. Gull.

PMID- 10344396
TI  - Hypernatraemia and tonicity balance.

PMID- 10344397
TI  - Abnormalities of kidney and urinary tract in epidermolysis bullosa.

PMID- 10344398
TI  - Familial distal renal tubular acidosis.

PMID- 10344399
TI  - Inferior vena cava thrombosis in a patient with chlorpromazin-induced
      anticardiolipin antibodies.

PMID- 10344400
TI  - Endothelial cell dysfunction in diabetes.

PMID- 10344401
TI  - The vitamin D receptor gene polymorphism and parathyroid function.

PMID- 10344402
TI  - Neuropsychiatric complications following quinolone overdose in renal failure.

PMID- 10344403
TI  - Isolation of HCV patient is efficient in reducing the annual incidence of HCV
      infection, but is it really necessary?

PMID- 10344404
TI  - The effect of alpha interferon therapy and short-interval intradermal
      administration on response to hepatitis B vaccine in haemodialysis patients.

PMID- 10344405
TI  - Target haematocrit during erythropoietin treatment in dialysis patients. Which
      value is 'true-functional haematocrit'?

PMID- 10344406
TI  - Tuberculosis after renal transplantation.

PMID- 10344407
TI  - Kaposi's sarcoma after renal transplantation: treatment with liposomal
      doxorubicin.

PMID- 10344408
TI  - Kaposi's sarcoma after renal transplantation--withdrawal of immunosuppression or
      local irradiation?

PMID- 10344409
TI  - Immunosuppressive treatment for sclerosing peritonitis.

PMID- 10344410
TI  - Effects of serotonin re-uptake inhibition on ventilatory control in goats.
AB  - Fluoxetine (Prozac) inhibits serotonin (5-HT) re-uptake. thereby enhancing
      serotonergic effects. Since serotonin is known to affect ventilation in a variety
      of circumstances, we investigated the effects of chronic serotonin re-uptake
      inhibition with fluoxetine on selected ventilatory responses including: (1)
      eupnea; (2) the hypercapnic ventilatory response at rest; (3) the exercise
      ventilatory response and (4) repeated trials of hypercapnic exercise. Ventilatory
      and arterial blood gases were measured in goats (n = 5) at rest, during steady
      state treadmill exercise, and during successive rest/exercise trials with
      increased respiratory dead space (0.4-0.6 L). Fluoxetine was administered (> or =
      4 weeks, 1 mg/kg, SQ, SID) and protocols were repeated. Following fluoxetine,
      PaCO2 was increased in most conditions studied; however, no differences were seen
      in exercise PaCO2 regulation or ventilatory responses pre- versus post
      fluoxetine. We conclude that chronic fluoxetine slightly depresses respiratory
      control at rest, but, has minimal effects during exercise or with mild
      hypercapnia during rest or exercise in goats.

PMID- 10344411
TI  - Effects of oxygen deprivation on parapyramidal neurons of the ventrolateral
      medulla in the rat.
AB  - We characterized the electrophysiological properties and responses of neurons
      located in the parapyramidal region of the ventral aspect of the rat medulla
      oblongata (parapyramidal neurons, PP neurons) to oxygen deprivation, in order to
      understand the mechanisms involved in hypoxia induced respiratory depression. The
      responses of PP neurons to oxygen deprivation were compared to those of the
      functionally dissimilar neurons of the dentate gyrus (DG). Neurons from the PP
      region were found to fire spontaneously with a frequency of 3-3.5 spikes/sec in
      both adults and neonates and responded to an anoxic insult with a complete loss
      of spontaneous firing. Discrete metabolite analysis showed a small (about 17%)
      decrease in tissue adenosine triphosphate (ATP) levels of the PP neurons during
      an anoxic insult and the decrease was significantly smaller than in the DG cell
      region (28%). In contrast to the DG neurons, the PP neurons recovered from an
      anoxic insult lasting more than 30 min, indicating a greater survival capacity of
      the PP neurons during oxygen deprivation. The PP neurons were also capable of
      withstanding successive anoxic insults better than the DG cells as demonstrated
      by their complete recovery following reoxygenation. It is suggested that the PP
      neurons may depress their electrical activity as an energy conservation
      mechanism, and thereby survive anoxic insults longer than the dentate neurons,
      whereas the loss of cellular activity in the DG neurons may be a result of energy
      depletion.

PMID- 10344412
TI  - Measuring central-chemoreflex sensitivity in man: rebreathing and steady-state
      methods compared.
AB  - We compared the central-chemoreflex sensitivities estimated from steady-state
      tests with those estimated from rebreathing tests in five subjects. In one
      laboratory, each subject underwent nine dynamic end-tidal forcing experiments.
      Three repetitions of 3, 6 and 9 mmHg step changes in the end-tidal partial
      pressure of carbon dioxide, from a pre-step partial pressure 1.5 mmHg above
      resting, were used to establish four points of the steady-state ventilatory
      response to carbon dioxide. In another laboratory, each subject underwent two
      rebreathing experiments, one using Read's rebreathing technique and the other a
      modified rebreathing method which included a prior hyperventilation. The central
      chemoreflex sensitivities, estimated from the slopes of the ventilatory responses
      to carbon dioxide using different combinations of the four steady-state points.
      were compared to those estimated from the slopes of the rebreathing responses.
      The steady-state sensitivities were significantly lower than the Read rebreathing
      sensitivities. The ratio of modified rebreathing sensitivities to steady-state
      sensitivities was closest to one when steady-state sensitivities were estimated
      from the two middle points of the ventilatory responses. The mean (SE) ratio of
      the sensitivities was 1.22 (0.21) in this case. We identify a number of factors
      that may affect the estimation of central-chemoreflex sensitivity using each
      technique. These include a maximum limit of the ventilation response at high
      partial pressures of carbon dioxide, an inability to sustain high ventilation for
      the duration of the steady-state tests and the inclusion of parts of the
      ventilatory response whose carbon dioxide partial pressures lie below the central
      chemoreflex threshold. We conclude that the modified rebreathing method provides
      the best estimate of central-chemoreflex sensitivity of the three methods.

PMID- 10344413
TI  - Effects of prosthetic reconstruction of the abdominal wall on respiratory
      mechanics in rats.
AB  - Respiratory mechanics and thoracoabdominal morphometry were determined in four
      sets of animal experiments before and after surgery. In group RRA the rectus
      abdominus muscles were removed; in RRAH rats the muscle resection was followed by
      lung hyperinflation; in PPM animals the defect was repaired by suturing a
      polypropylene mesh (Marlex); and in PPMH lung hyperinflation was performed after
      abdominal wall reconstruction. Lung and chest wall elastances, and chest wall
      viscoelastic/inhomogeneous pressures increased in RRA, RRAH and PPM groups.
      Static lung elastance was progressively smaller in the following order: RRA, PPM,
      and PPMH. In conclusion, removal of the rectus abdominus muscles and abdominal
      wall reconstruction could account for higher energy losses against viscoelastic
      and elastic forces acting on the chest wall, and these are related to a cephalad
      deviation of the diaphragm. Furthermore, hyperinflation reverses lung elastic
      modification after abdominal wall reconstruction with PPM, without beneficial
      effects in the presence of abdominal wall defect.

PMID- 10344414
TI  - Computerized image analysis of lung expansion patterns in surfactant treated
      immature newborn rabbits.
AB  - This study evaluates the alveolar stereological profile of immature rabbit lungs
      after treatment with various surfactant preparations, deliberately modified to
      represent different rates of film adsorption, minimum surface tension and
      compressibility. Surfactant was isolated from porcine or bovine lungs, and some
      of these preparations were enriched with dipalmitoylphosphatidylcholine and other
      synthetic lipids. Alveolar stereological parameters were evaluated in
      histological lung sections by computerized interactive image analysis. Surfactant
      treatment enhanced lung expansion, with a significant correlation coefficient
      between dynamic compliance and alveolar volume density in all groups of animals.
      Surfactant treatment also significantly increased alveolar image area. Enrichment
      of surfactant with synthetic lipids did not improve stereological parameters, but
      caused a significant increase in the coefficient of variation for alveolar
      perimeter and image area, suggesting more heterogeneous expansion pattern.
      Experimental evaluation of exogenous surfactants in immature newborn animals
      should include assessment of alveolar stereological parameters to detect
      deviations from the uniform expansion pattern seen after treatment with an
      optimal surfactant substitute.

PMID- 10344415
TI  - Effect of the compression ratio on properties of lung surfactant (bovine lipid
      extract surfactant) films.
AB  - Using axisymmetric drop shape analysis (ADSA) and a captive bubble technique, the
      properties of lung surfactant (BLES) films under different compression ratios
      (i.e. the ratio of maximum to minimum surface area of the bubble) were
      investigated. In particular, the effect of the compression ratio of the films on
      the shape of the volume area surface tension-time (VAST) graphs and on the shape
      of the surface tension relative area (gamma-A ) graphs was examined at the air
      liquid interface. Under relatively low compression ratios of the films, the VAST
      and gamma-A graphs indicate that the cycling is reversible (i.e. the gamma-A
      graphs are identical for expansion and compression). When the compression ratio
      of the films increases, failure tends to occur when the surface film can not
      support the increasing surface pressure, causing a hysteresis loop in the gamma-A
      graph. It was also found that low surface tension (i.e. below 5 mJ/m2) at the
      interface could be attained with a 30% compression ratio and collapse of the
      films always occurs near or below 1 mJ/m2.

PMID- 10344416
TI  - Effects of immersion in cool water on lung-exhaled nitric oxide at rest and
      during exercise.
AB  - Lung nitric oxide (NO) has been postulated to relax airway and vascular smooth
      muscle at rest and during exercise. As a cold environment is a common cause of
      respiratory distress, lung exhaled NO was measured during skin and core body
      cooling at rest and during a progressive cycle exercise. Ten healthy male
      subjects were immersed in water at a water temperature (Tw) which was thermal
      neutral (35 degrees C) at 30 degrees C Tw, at which only skin temperature is
      decreased; and at 20 degrees C Tw, at which the core temperature is decreased
      (0.05 degrees C). At rest, V(O), and V(E) increased while exhaled NO
      concentration [NO] and the rate of expiration of NO (V(NO)) decreased with
      decreased Tw. V(O2) and ventilation (V(E)) increased with workload (W) and the
      values at all Tw were not different, whereas, [NO] decreased with W and the
      values during exercise were progressively less at all Ws as Tw declined. These
      results indicate that lung NO output is reduced in a graded fashion during body
      cooling at rest and during exercise. This suggests that lower lung NO may
      contribute to airway obstruction in cold environments and NO may contribute to
      regulation of lung heat and water exchange.

PMID- 10344417
TI  - Evidence for oxygenation-induced endothelin release from isolated lungs of
      chronically hypoxic rats.
AB  - In lungs from chronically hypoxic (CH, 3 weeks at 10% inspired O2) rats,
      oxygenation (20% O2, 5% CO2, 75% N2; PO2 121 mmHg) of the perfusate increases
      pulmonary perfusion pressure (PPP) and lung weight (LW). Hypoxic perfusate (95%
      N2, 5% CO2; PO2 5.5 mmHg) had no effect on PPP in lungs from CH rats.
      Indomethacin and nitro-L-arginine (L-NOARG) augmented the oxygen-induced increase
      in PPP. In contrast, the free radical scavengers superoxide dismutase (SOD) plus
      catalase delayed the onset of oxygen-induced vasoconstriction, while the
      endothelin (ET)B receptor antagonist BQ788 inhibited it. The ET(A) receptor
      antagonist BQ123 did not affect the PPP changes. This suggests a role for
      endogenous endothelins and ET(B) receptors in mediating the oxygenation-induced
      pulmonary vasoconstriction. Indomethacin had no effect on oxygen-induced lung
      weight (LW) changes while BQ788 and L-NOARG reduced the LW increase. This
      evidence shows that ET(B) receptor activation and NO generation are involved in
      the LW changes. In conclusion, oxygenation of the perfusate in isolated lungs
      from CH rats leads to pulmonary vasoconstriction which involves endothelins and
      activation of ET(B) receptors. In addition, increased NO production associated
      with ET(B) receptor activation is the prime stimulus for observed LW increase.

PMID- 10344418
TI  - Characteristics of nasal airflow and the effect of a nasal dilator in normal
      human subjects.
AB  - Nasal resistance contributes to negative airway pressure during breathing. We
      sought to define normal patterns of nasal flow and the effects of mechanical
      dilatation and splinting of the nares on flow during forced inspiration and
      expiration. Maximal inspiratory and expiratory flow volume loops (FVL) were
      determined in 17 normal subjects. Oral FVL were obtained with nares clamped and
      nasal FVL through a mask with and without dilatation of nares using a plastic
      splint (Nozovent). Oral FVL were normal in all. Two patterns of nasal FVL were
      observed: one indicating 'variable' extrathoracic obstruction, the other
      indicating 'fixed' extrathoracic obstruction. Maximal inspiratory flow at 50% of
      vital capacity (FiF50) was improved by the Nozovent only in those with a
      'variable' pattern (FIF50 (L/sec): 1.54 +/- 0.3 to 2.86 +/- 0.5; P < 0.05, versus
      1.92 +/- 0.3 to 2.21 +/- 0.3: P = 0.5). In subjects with a fixed pattern, failure
      of dilatation of the nares to increase flow suggests that the site of inspiratory
      flow limitation is within the bony nostril.

PMID- 10344420
TI  - Bioethics and the press.

PMID- 10344419
TI  - Mucosal modulation of agonist-induced myosin phosphorylation and contraction in
      airway smooth muscle.
AB  - We investigated the mechanism of mucosal modulation of airway smooth muscle
      contraction by measuring concentration- and length dependencies of carbachol
      induced active stress and myosin phosphorylation in mucosa-intact and mucosa-free
      bovine tracheal smooth muscle. The concentration dependencies of carbachol
      induced active stress in mucosa-intact and mucosa-free smooth muscles were
      significantly different in maximum but not in half-maximal concentration (EC50).
      Similar mucosa-dependent difference in maximum was also observed in the
      concentration dependence of carbachol-induced myosin phosphorylation. As a
      result, the myosin phosphorylation-active stress relations in mucosa-intact and
      mucosa-free smooth muscles were not significantly different. Length dependence of
      carbachol-induced active stress was significant in mucosa-intact smooth muscle,
      and accompanied by significant length dependence of myosin phosphorylation. These
      results suggest that the primary effect of mucosal modulation is inhibition of
      myosin light chain phosphorylation without uncoupling of active stress from
      myosin phosphorylation in airway smooth muscle.

PMID- 10344421
TI  - The journalist's role in bioethics.
AB  - In the late 1950s and early 1960s, emerging advances in the biomedical sciences
      raised insufficiently noticed ethical issues, prompting science reporters to
      serve as a sort of Early Warning System. As awareness of bioethical issues
      increased rapidly everywhere, and bioethics itself arrived as a recognized
      discipline, the need for this early-warning press role has clearly diminished. A
      secondary but important role for the science journalist is that of investigative
      reporter/whistleblower, as in the Tuskegee syphilis trials and the government's
      secret plutonium experiments. Because the general public gets most of its
      information from the popular media, ways are suggested for journalists and
      bioethicists to work together.

PMID- 10344422
TI  - Improving our aim.
AB  - Bioethicists appearing in the media have been accused of "shooting from the hip"
      (Rachels, 1991). The criticism is sometimes justified. We identify some reasons
      our interactions with the press can have bad results and suggest remedies. In
      particular we describe a target (fostering better public dialogue), obstacles to
      hitting the target (such as intrinsic and accidental defects in our knowledge)
      and suggest some practical ways to surmont those obstacles (including seeking out
      ways to write or speak at length, rather than in sound bites). We make use of our
      own research into the way journalists quote bioethicists. We end by suggesting
      that the profession as a whole look into this question more fully.

PMID- 10344423
TI  - Bioethics as several kinds of writing.
AB  - Three different models are described of the relationship of bioethics to the
      press. The first two are familiar: bioethicists often are interviewed by
      journalists seeking background and short quotes to insert in a story;
      alternately, bioethicists sometimes themselves act as journalists of a sort,
      writing op-eds, articles or even longer works designed for wide readership. These
      models share the notion that bioethicists can provide information and ideas that
      increase the quality of people's thinking on moral matters. They share also a
      common difficulty: do the constraints the media impose on bioethical discourse
      keep bioethicists from deepening public reflection, and if not, how can those
      constraints be most effectively kept from distorting what bioethicists wish to
      say? The third model reverses--in part--the presupposition that bioethics bestows
      moral sophistication on a public naive about ethical issues, holding rather that
      matters run both ways; bioethicists stand to learn a great deal from their
      interactions with various publics and the media that serve them. On this view,
      the constraints imposed by media conventions constitute opportunities for new and
      potentially important forms of bioethical writing. Various concerns generated by
      the first two models are surveyed. It is concluded that while none of the
      difficulties constitute knock-down arguments against these forms of collaborating
      with the press, the worries are problematic enough to provide some support for
      considering the less familiar third approach. Further reason for taking the third
      model seriously draws on moral theoretic considerations.

PMID- 10344424
TI  - Bioethics and the newspapers.
AB  - Many bioethics questions are resistant to journalistic exploration on account of
      their inherently philosophical dimensions. Such dimensions are ill-suited to what
      we may term the internal goods (in MacIntyre's sense) of the newspapers and mass
      media generally, which constrain newspaper coverage to an abbreviated form of
      narrative that, whilst not in itself objectionable, is nonetheless inimical to
      the conduct of philosophical reflection. The internal goods of academic
      bioethics, by contrast, include attention to philosophical questions inherent in
      bioethical issues and value-enquiry. The danger for bioethics is that its agenda
      for reflective enquiry will, if dictated by this abbreviated narrative, be
      distorted in terms of both range and priorities, to the inevitable neglect of
      questions having a philosophical dimension to them. This danger can be avoided by
      a constructive partnership between the media and academic bioethics. The success
      of this partnership relies on four suggested provisos, for the meeting of which
      both journalists and academics bear responsibility.

PMID- 10344425
TI  - Philosophy as news: bioethics, journalism and public policy.
AB  - News media accounts of issues in bioethics gain significance to the extent that
      the media influence public policy and inform personal decision making. The
      increasingly frequent appearance of bioethics in the news thus imposes
      responsibilities on journalists and their sources. These responsibilities are
      identified and discussed, as is (i) the concept of "news-worthiness" as applied
      to bioethics, (ii) the variable quality of bioethics reportage and (iii)
      journalists' reliance on ethicists to pass judgment. Because of the potential
      social and other benefits of high quality reporting on ethical issues, it is
      argued that journalists and their bioethics sources should explore and
      accommodate more productive relationships. An optimal journalism-ethics
      relationship will be one characterized by "para-ethics," in which journalistic
      constraints are noted but also in which issues and arguments are presented
      without oversimplification and credible disagreement is given appropriate
      attention.

PMID- 10344426
TI  - Depth of insertion at flexible sigmoidoscopy: implications for colorectal cancer
      screening and instrument design.
AB  - BACKGROUND AND STUDY AIMS: The depth of insertion at flexible sigmoidoscopy is
      variable, depending upon bowel preparation, patient tolerance and distal colonic
      anatomy. Many endoscopists routinely aim to insert the 60 cm flexible
      sigmoidoscope to the splenic flexure; however internal endoscopic markers are
      unreliable, making the true anatomical extent of the examination difficult to
      assess. The aim of this study was to assess the depth of insertion at flexible
      sigmoidoscopy. PATIENTS AND METHODS: Two separate studies were done. In the first
      (study 1), magnetic endoscopic imaging was used to determine the final depth of
      insertion at non-sedated, screening flexible sigmoidoscopy. In the second (study
      2), "real-time" imaging was utilized to determine sigmoid looping and the
      anatomical location of the endoscope tip after 60 cm of instrument had been
      inserted during total or limited colonoscopy. A total of 117 consecutive average
      risk patients, aged 55-65 years participated in study 1, and 136 patients
      underwent either limited, (33) or attempted total colonoscopy (103) in study 2.
      RESULTS: In study 1 the median insertion distance was 52 cm, range 20-58. In 61 %
      of patients the imaging system showed that the descending colon had not been
      visualized by the end of the procedure. Failure to reach the sigmoid/descending
      junction occurred in 29 (24%) patients. Reasons for failure included poor
      tolerance of the procedure due to pain (23 patients) inadequate preparation (3
      patients) and, excessive looping (3 patients). In study 2, after 60 cm of
      instrument had been inserted, the splenic flexure or beyond was reached in 29%
      and the descending colon in 9%, whilst in 62 % the endoscope tip had not passed
      beyond the sigmoid/descending colon junction. A sigmoid loop formed in 70% of
      patients, and unusual loops such as the alpha, reverse alpha and reverse sigmoid
      spiral loop occurred more frequently in women compared to men (P = 0.0249). In
      those 104 patients where the splenic flexure was reached the mean maximum length
      of instrument inserted prior to reaching the flexure was 75.4 cm, (SD = 21.9).
      CONCLUSIONS: Examination of the entire sigmoid was not achieved in approximately
      one-quarter of patients undergoing screening flexible sigmoidoscopy, mainly
      because of discomfort. The descending colon is intubated in a minority of cases
      (using standard instruments), even after 60 cm has been inserted. Alternative
      instruments with different shaft characteristics (floppy, narrow calibre, 80-100
      cm in length) may be necessary to ensure deeper routine intubation in nonsedated
      patients.

PMID- 10344427
TI  - Tracheobronchial stenting in patients with esophageal cancer involving the
      central airways.
AB  - BACKGROUND AND STUDY AIMS: Locoregional progression of esophageal cancer can
      result in respiratory distress aving to tracheoesophageal (T-E) fistula or
      central airways stenosis. We report our experience of airway stenting in 51
      patients with esophageal carcinoma involving the central airways. PATIENTS AND
      METHODS: All data were recorded retrospectively. Fifty-one patients (44 men and
      seven women), with a mean age of 58.6 years, were analyzed. All had an esophageal
      squamous cell carcinoma. Severe respiratory impairment due to tumor invasion or
      to a tracheobronchial fistula (n= 14) was present in all patients. Nine of the 14
      patients with fistula had dysphagia. Among the 37 patients without fistula, 19
      had dysphagia. RESULTS: Sixty-six tracheobronchial stents were inserted in 51
      patients: 65 Dumon stents and one Wallstent. Forty stents were implanted in the
      trachea, 16 in the left main bronchus and 10 in the right main bronchus. In 47
      patients there was a significant improvement of respiratory symptoms. Esophageal
      intubation, carried out in nine patients, allowed eating and drinking in all
      cases. Mean survival was 107.7 days, with the longest follow-up 587 days. There
      was no difference between mean survival in the patients with fistulae (103.3+/
      days) and the others (109.3+/-days). In two cases stent placement was responsible
      for death (massive hemoptysis and pneumonia). The main complications were
      migration (n=6), granuloma (n=2), pneumonia (n=2) and pneumothorax (n = 2). In 13
      patients tumor progression in the airways was noted from one to 11 months after
      stenting, inducing a relapse of dyspnea. CONCLUSIONS: Complications are easily
      detected by the appearance of respiratory symptoms and do not necessitate
      systematic flexible bronchoscopy, but only preventive measures such as regular
      aerosol therapy, adapted respiratory physiotherapy and regular clinical follow
      up.

PMID- 10344428
TI  - Endoscopic hydrogen peroxide spray may facilitate localization of the bleeding
      site in acute upper gastrointestinal bleeding.
AB  - BACKGROUND AND STUDY AIMS: A major problem encountered in the emergency
      endoscopic management of acute upper gastrointestinal (UGI) bleeding is poor
      localization of the bleeding site, which can be obscured by blood or clots.
      Traditional attempts to overcome this problem have been by physical methods,
      which have usually proved unsatisfactory. The aim of this prospective study was
      to show that hydrogen peroxide can be used as a dissolution agent, resulting in
      an alteration of the characteristics of blood clots and allowing a clearer visual
      field. PATIENTS AND METHODS: Twenty patients with acute UGI bleeding (13 male,
      seven female) were included in the study. The suspected site of bleeding was
      initially sprayed with 200 ml of saline and then with 25-175 ml of 3 % H2O2.
      Pictures of the visual field were taken before and after irrigation with both
      saline and H2O2. These pictures were evaluated by three gastroenterologists and
      scored using the following visual clearance scoring system: -3, marked worsening
      of visual field; -2, moderate worsening; -1, slight worsening; 0, no change; +1,
      slight improvement; +2, moderate improvement; + 3, marked improvement. In cases
      of active oozing or spurting, after initial hemostasis was achieved the bleeding
      point was injected with pure ethanol or cauterized with a heater probe. In order
      to assess the safety of 3 % H2O2 endoscopic biopsies of the antrum and the
      duodenal bulb were performed before and 30 minutes after its use and examined by
      a pathologist. RESULTS: There was a significant improvement in the mean visual
      clearance score after irrigation with H2O2 compared to irrigation with saline
      alone (2.13 vs. 0.43, P<0.001). During endoscopic examination there were 19
      patients with active oozing from the ulcer base covered by an adherent blood
      clot; 12 of these (63.1%) achieved initial hemostasis after H2O2 spraying. Eleven
      of 18 (61.1 %) patients complained of a mild epigastric burning sensation during
      H2O2 irrigation. There was no clinically significant change in the histology of
      the antrum and the duodenal bulb after H2O2 therapy. CONCLUSIONS: We concluded
      that H2O2 is a safe and effective way to clear the visual field, facilitating the
      localization of the bleeding site during emergency endoscopy for acute UGI
      bleeding, with only mild side effects. In some cases H2O2 therapy can also induce
      temporary hemostasis. We recommended the use of hydrogen peroxide to improve
      endoscopic visualization, especially in cases where an adherent blood clot covers
      the suspected bleeding site.

PMID- 10344429
TI  - The role of endoscopic retrograde cholangiopancreatography in the management of
      hepatic hydatid disease.
AB  - BACKGROUND AND STUDY AIMS: Hydatid disease of the liver, and its complications,
      causes serious morbidity and mortality. We evaluated the role of endoscopic
      retrograde cholangiopancreatography (ERCP) in the management of hepatic hydatid
      disease. PATIENTS AND METHODS: This retrospective analysis includes 28 patients
      with hepatic hydatid disease who underwent ERCP. ERCP was performed
      preoperatively in 11 patients, for acute cholangitis (n =7), acute pancreatitis
      (n = 1) and right upper quadrant pain (n = 3), and in eight asymptomatic cases to
      search for fistulae between the cyst and the biliary tree. In a further nine
      patients ERCP was performed for early (< 30 days; n = 7) and late (n = 2)
      postoperative biliopancreatic problems. RESULTS: In all seven patients with
      cholangitis preoperative ERCP with EST and ductal clearance of daughter cysts and
      debris led to substantial clinical improvement, including four acutely ill
      elderly patients who stabilized and were later able to undergo surgery. EST in
      two of the three patients with pain who had papillary stenosis led to resolution
      of the abdominal pain. Six of the seven postoperative fistulae could be
      successfully treated endoscopically using EST. CONCLUSIONS: This study
      demonstrates the usefulness of ERCP in symptomatic patients with hepatic hydatid
      cysts; EST enables clearance of the common bile duct and allows healing of
      postoperative fistulae in the majority of patients. We do not, however, recommend
      performing routine preoperative ERCP in asymptomatic patients with the disease.

PMID- 10344430
TI  - The standard of laparoscopic intraoperative cholangiography: a quality control
      study.
AB  - BACKGROUND AND STUDY AIMS: One reason why many surgeons do not attempt
      laparoscopic cholangiography is that it is considered to be technically difficult
      and to produce poor-quality images. PATIENTS AND METHODS: A retrospective
      comparison was made of twenty randomly selected intraoperative cholangiograms
      taken during laparoscopic cholecystectomy for each year from 1991 to 1994 (n =
      80) by assigning a score (0-4) on the basis of anatomical parameters and
      radiographic quality. Twenty randomly selected intraoperative cholangiograms
      taken during open cholecystectomy (OC) were used as controls. RESULTS: The
      average score for the laparoscopic cholangiograms (LCs) was significantly lower
      than the average for OC cholangiograms (2.3 vs. 3.4, P< 0.001). In addition, a
      learning curve was demonstrated, which showed significant improvement in the
      quality of LCs over the years. Analysis showed that in LCs, only 34 % succeeded
      in demonstrating the entire biliary tree and only 49% managed to show the
      extrahepatic duct system. Choledocholithiasis could only be ruled out in 53 % of
      LC films, compared with 80 % of controls. CONCLUSIONS: Despite an improvement in
      the quality of laparoscopic cholangiography, it remains inferior to
      cholangiography during open cholecystectomy. Recommendations are made regarding
      ways in which improvements could be achieved.

PMID- 10344431
TI  - Spiral nitinol biliary stents in a porcine model: evaluation of the potential for
      use in benign strictures.
AB  - BACKGROUND AND STUDY AIMS: Self-expanding spiral nitinol stents are potentially
      removable and may be useful in the treatment of benign strictures. We evaluated
      the histologic response to stent placement and technical aspects of their
      placement and removal in a porcine model. METHODS: Nine animals were studied.
      Stents were placed above the papilla in six surviving animals. After intervals of
      one, two or three months cholangiography and attempted stent removal was
      performed. Four animals were then sacrificed acutely with their stent in place,
      and two were sacrificed after a one-month healing interval. The results of
      placement, follow-up cholangiography and histology are reported. RESULTS:
      Cholangiography and stent placement succeeded in 26 of 27 and 11 of 16 attempts,
      respectively. Three placement failures were attributed to stent/duct size
      disparity or a faulty release mechanism, resulting in stent kinking and/or duct
      twisting. Among the successfully deployed stents, two animals developed
      strictures where stents traversed bifurcations and one exhibited partial luminal
      compromise by tissue entrapment between coils. Fluoroscopically guided removal
      was successful in two of five stents positioned above the papilla. Histology was
      non-specific but minimally changed in those given a one-month healing interval
      after removal. Others exhibited moderate inflammation, fibrosis and an intramural
      abscess at sites of induced stricture. CONCLUSIONS: Spiral metal stents for the
      treatment of benign strictures remain experimental. Care must be taken to deploy
      them in bile ducts of adequate diameter and endoscopic removal is not yet
      demonstrably reliable and safe.

PMID- 10344432
TI  - The thermodilator: an effective instrument in the palliative therapy concept of
      malignant bile duct stenosis.
AB  - BACKGROUND AND METHODS: In the case of incurable malignant bile duct stenosis the
      aim of therapy is to secure the bile flow. Sometimes dilation of the stenosis is
      necessary to enable the introduction of a biliary duodenal stent or the
      replacement of a small-bore stent by a large-bore one. The previously most
      commonly used methods - bougienage and balloon dilation - can be unsuccessful
      with severe stenoses, which means that an extension of the endoscopic therapeutic
      instrumentarium is desirable. We examined the success rates and complications of
      a thermodilator which can be used to dilate bile duct stenoses. RESULTS AND
      CONCLUSIONS: In 21 out of 24 applications the therapeutic objective was achieved.
      In one case we observed an endoscopically controllable bile duct hemorrhage. The
      thermodilator is therefore a valuable addition to the endoscopic treatment
      possibilities of malignant bile duct stenosis.

PMID- 10344434
TI  - The reach of flexible sigmoidoscopy--not enough?

PMID- 10344435
TI  - Endoscopic preoperative colonic tattooing: a clinical and surgical complication.
AB  - Endoscopic colonic tattooing is the simplest and most economic technique for
      identifying small lesions or polypectomy sites during open and laparoscopic
      surgery. Moreover, it is useful for the endoscopic follow-up of polypectomy
      sites. India ink is the agent of choice because of its long-lasting stain and the
      low risk of adverse reaction and toxicity. Very few cases of complications have
      been reported. We report here the case of a patient in whom colonic tattooing in
      preparation for surgical resection was followed by clinical complications such as
      fever and abdominal pain. An abscess-type inflamed pseudotumor was found at
      laparotomy. Histological examination revealed chronic granulomatous inflammation.

PMID- 10344433
TI  - Endorectal ultrasound in infectious colitis may predict development of chronic
      colitis.
AB  - BACKGROUND AND STUDY AIMS: In a previous study, we have shown that rectal
      endoscopic ultrasound (EUS) could be used to differentiate ulcerative colitis
      from Crohn's disease by demonstrating the presence of pathological lymph nodes
      around the rectum and sigmoid colon which were characteristic of ulcerative
      colitis. The aim of the present study was to evaluate the endosonographic
      features of infectious colitis and their potential clinical relevance. PATIENTS
      AND METHODS: We carried out rectal endosonography in 17 patients with infectious
      colitis of various etiologies. Wall features and perirectal lymph nodes were
      documented systematically. RESULTS: In 15 patients no pathological lymph nodes
      were seen and the EUS wall features were also normal. In two patients where EUS
      showed pathological lymph nodes, follow-up confirmed ulcerative colitis several
      weeks later. CONCLUSIONS: This preliminary study suggests that, in patients with
      infectious colitis, EUS may be able to suggest the diagnosis of associated
      ulcerative colitis; further studies with larger patient numbers are necessary.

PMID- 10344436
TI  - Diagnosis and hazards of unexpected diaphragmatic hernias during colonoscopy:
      report of two cases.
AB  - Two cases of diaphragmatic hernias are reported. Both cases were previously
      undiagnosed and were found during diagnostic colonoscopy. In one case sudden
      respiratory distress occurred during the endoscopic procedure owing to a
      barotraumatic perforation in a left-sided hernia with tension pneumothorax. The
      diagnoses were made by fluoroscopy without delay. Endoscopists should be aware of
      the possible occurrence of diaphragmatic hernias and their risk as life
      threatening complications. To avoid such dangerous complications access to X-ray
      facilities with fluoroscopy is recommended in endoscopic units where
      colonoscopies are performed.

PMID- 10344437
TI  - Damage to the instrumentation channel of a gastroscope due to endoscopic variceal
      ligation.

PMID- 10344438
TI  - Immediate and late bleeding after endoscopic sphincterotomy.

PMID- 10344439
TI  - The role of therapeutic endoscopy associated with extracorporeal shock-wave
      lithotripsy and bile acid treatment in the management of Caroli's disease.

PMID- 10344440
TI  - "Cobblestone" appearance of esophagus: an unusual endoscopic presentation of
      Barrett's esophagus.

PMID- 10344441
TI  - Distortion of an esophageal nitinol coil stent.

PMID- 10344442
TI  - Titanium clips causing duodenal ulcer penetration with life-threatening
      hemorrhage.

PMID- 10344443
TI  - Ulcer on Bauhin's valve induced by oral iron therapy.

PMID- 10344444
TI  - A post-laparoscopy sphincterotomy technique.

PMID- 10344445
TI  - Removal of a common bile duct stone via percutaneous cholecystostomy.

PMID- 10344446
TI  - Hemobilia causing acute biliary pancreatitis after percutaneous liver biopsy.

PMID- 10344447
TI  - An unusual complication of intraoperative cholangiography during laparoscopic
      cholecystectomy.

PMID- 10344448
TI  - Endoscopic appearance of isosporiasis.

PMID- 10344449
TI  - Massive gastrointestinal hemorrhage from pseudocyst with fistula and splenic
      artery aneurysm rupture.

PMID- 10344450
TI  - Gastroduodenal intussusception secondary to a gastric leiomyoma resulting in an
      ulceration.

PMID- 10344451
TI  - Unusual summertime foreign body in the esophagus.

PMID- 10344452
TI  - Endoscopic sphincterotomy and balloon sphincteroplasty for common bile duct
      stones: a Chinese experience.

PMID- 10344453
TI  - Inspiratory muscle adaptations following pressure or flow training in humans.
AB  - Skeletal muscle adapts differently to training with high forces or with high
      velocities. The effects of these disparate training protocols on the inspiratory
      muscles were investigated in ten healthy volunteers. Five subjects trained using
      high force (pressure) loads (pressure trainers) and five trained using high
      velocity (flow) loads (flow trainers). Pressure training entailed performing 30
      maximal static inspiratory efforts against a closed airway. Flow training
      entailed performing 30 sets of three maximal dynamic inspiratory efforts against
      a minimal resistance. Training was supervised and carried out 5 days a week for 6
      weeks. Inspiratory flow rates and oesophageal pressure-time curves were measured
      before and after training. Peak inspiratory pressures during maximal static and
      dynamic efforts and peak flows during the maximal dynamic efforts were
      calculated. The time-to-peak pressure and rate of rise in peak pressure during
      maximal static and dynamic manoeuvres were also calculated before and following
      training. Maximal static pressure increased in the pressure training group and
      maximal dynamic pressure increased in the flow training group. Both groups
      increased the rate of pressure production (dP/dt) during their respective maximal
      efforts. The post-training decrease in time-to-peak pressure was proportionately
      greater in the flow trainers than in the pressure trainers. The differences in
      time-to-peak pressure between the two groups were consistent with the different
      effects of force and velocity training on the time-to-peak tension of skeletal
      muscle.

PMID- 10344454
TI  - Effect of vitamin E supplementation on post-exercise plasma lipid peroxidation
      and blood antioxidant status in smokers: with special reference to
      haemoconcentration effect.
AB  - The oxidative effects were investigated of exhausting exercise in smokers, and
      the possible protective role of 400 mg day(-1) vitamin E (Vit E) supplementation
      over a period of 28 days. The subjects exercised to exhaustion including
      concentric-eccentric contractions following maximal cycling. The haematocrit and
      haemoglobin, leucocyte (WBC), plasma lactic acid (La) and malondialdehyde (MDA),
      erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GPx), serum
      Vit E and ceruloplasmin (CER) concentrations were measured pre and post exercise.
      Supplementation increased Vit E concentrations 28% and 31% in the controls and
      the smokers, respectively. Cigarette smoking and/or Vit E supplementation did not
      influence plasma lipid peroxidation or the antioxidant status at rest. Exercise
      caused significant haemoconcentration in all groups. When the post-exercise
      concentrations were adjusted for haemoconcentration, a significant elevation in
      La concentrations due to exercise was observed in all groups. Similarly, there
      were significant elevations in the adjusted WBC counts in all groups except the
      Vit E supplemented controls. The MDA concentrations on the other hand, when
      adjusted for haemoconcentration, did not exhibit any difference due to exercise.
      Exercise did not affect the GPx and CER activities either, while causing a SOD
      activity loss in all groups except the Vit E supplemented non-smokers. Serum Vit
      E concentrations diminished significantly in all groups after exercise. Post
      exercise plasma MDA and blood antioxidant concentrations were not altered by
      smoking. The results would suggest that plasma volume changes should always be
      taken into account when assessing post-exercise plasma concentrations and that
      smoking and exercise do not have an additional collective effect on plasma lipid
      peroxidation and the dose of Vit E administered was insufficient to maintain the
      serum concentrations after exercise.

PMID- 10344455
TI  - Performance and physiological responses to a 5-week synchronized swimming
      technical training programme in humans.
AB  - A synchronized swimming team routine (TR) is composed of figures of varying
      degrees of difficulty. Swimmers able to perform these figures separately
      underwent a 5-week technical training programme (TTP) to assemble a TR. Little is
      known about the physiological responses to this kind of TTP. A group of 13
      trained synchronized swimmers [mean age 14 (SD 1) years] were tested before and
      after a 5-week TTP. The TR lasted 5 min, and 45% of that time was spent
      underwater. The swimmers' technique scores in the TR improved significantly from
      4.5 (SD 1.9) before to 5.8 (SD 2.3) points after the TTP (P < 0.01), but their
      swimming performances, peak oxygen uptake (VO2peak), blood lactate concentration,
      and heart rate measured during a 400-m swim were lower after the TTP. The
      improvement in the technique scores correlated negatively with the change in
      VO2peak (r = -0.57; P < 0.05). The greater the improvement in the technique
      score, the greater the decrease in VO2peak. The overall synchronized swimming
      skill was assessed by the best score the swimmers obtained in four to six
      competitions over a season. This score was related to the 400-m swimming
      performance, VO2peak, maximal distance covered in apnoea, and the breath-hold
      time. The 5-week TTP therefore improved technical performance during the TR
      without improving physiological, swimming or apnoea performances. However, the
      physiological profile of each swimmer was linked to the synchronized swimming
      skill.

PMID- 10344457
TI  - Aerobic and anaerobic energy during a 2-km race simulation in female rowers.
AB  - The maximal aerobic power (VO2max) and maximal anaerobic capacity (AODmax) of 16
      female rowers were compared to their peak aerobic power (VO2peak) and peak
      anaerobic capacity (AODpeak, respectively) during a simulated 2-km race on a
      rowing ergometer. Each subject completed three tests, which included a 2-min
      maximal effort bout to determine the AODmax, a series of four, 4-min submaximal
      stages with subsequent progression to VO2max and a simulated 2-km race. Aerobic
      power was determined using an open-circuit system, and the accumulated oxygen
      deficit method was used to calculate anaerobic capacities from recorded
      mechanical power on a rowing ergometer. The average VO2peak (3.58 l min(-1)),
      which usually occurred during the last minute of the race simulation, was not
      significantly different (P > 0.05) from the VO2max (3.55 l min(-1)). In addition,
      the rowers' AODmax (3.40 l) was not significantly different (P > 0.05) from their
      AODpeak (3.50 1). The average time taken for the rowers to complete the 2-km race
      simulation was 7.5 min, and the anaerobic system (AODpeak) accounted for 12% of
      the rowers' total energy production during the race.

PMID- 10344456
TI  - Vascular endothelial growth factor in exercising humans under different
      environmental conditions.
AB  - It was the aim of this study to investigate the time course of changes in the
      serum concentrations of vascular endothelial growth factor (VEGF) during a
      regular survival training programme combined with food and fluid deprivation and
      during a high altitude marathon run. We studied soldiers of the Austrian Special
      Forces performing survival training at sea-level and marathon runners of the
      Posta Atletica who crossed the border between Chile and Argentina at altitudes up
      to 4722 m. Baseline data collected before the 1-week of survival training showed
      that the soldiers had normal VEGF [n = 8, 246.7 (SD 118.5) pg.ml(-1)] serum
      concentrations which remained unchanged during the course of the study. Before
      the high altitude marathon the subjects showed normal VEGF serum concentrations
      [178 (SD 84.5) pg.ml(-1)]. After the run VEGF concentrations were found to be
      significantly decreased [41.0 (SD 41.6) pg ml(-1), P < 0.01]. It was concluded
      that prolonged physical stress during normobaric-normoxia did not alter the VEGF
      concentrations whereas during severe hypobaric-hypoxia decreased VEGF serum
      concentrations were measured, at least temporarily, after prolonged physical
      exercise which might have been due to changes in production, release, removal
      and/or binding of circulating VEGF.

PMID- 10344458
TI  - The effect of dynamic exercise on resting cold thermoregulatory responses
      measured during water immersion.
AB  - The purpose of this study was to evaluate the effect of exercise on the
      subsequent post-exercise thresholds for vasoconstriction and shivering measured
      during water immersion. On 2 separate days, seven subjects (six males and one
      female) were immersed in water (37.5 degrees C) that was subsequently cooled at a
      constant rate of approximately 6.5 degrees C x h(-1) until the thresholds for
      vasoconstriction and shivering were clearly established. Water temperature was
      then increased to 37.5 degrees C. Subjects remained immersed for approximately 20
      min, after which they exited the water, were towel-dried and sat in room air (22
      degrees C) until both esophageal temperature and mean skin temperature (Tsk)
      returned to near-baseline values. Subjects then either performed 15 min of cycle
      ergometry (at 65% maximal oxygen consumption) followed by 30 min of recovery
      (Exercise), or remained seated with no exercise for 45 min (Control). Subjects
      were then cooled again. The core temperature thresholds for both vasoconstriction
      and shivering increased significantly by 0.2 degrees C Post-Exercise (P < 0.05).
      Because the Tsk at the onset of vasoconstriction and shivering was different
      during Pre- and Post-Exercise Cooling, we compensated mathematically for changes
      in skin temperatures using the established linear cutaneous contribution of skin
      to the control of vasoconstriction and shivering (20%). The calculated core
      temperature threshold (at a designated skin temperature of 32.0 degrees C) for
      vasoconstriction increased significantly from 37.1 (0.3) degrees C to 37.5 ( 0.3)
      degrees C post-exercise (P < 0.05). Likewise, the shivering threshold increased
      from 36.2 (0.3) degrees C to 36.5 (0.3) degrees C post-exercise (P < 0.05). In
      contrast to the post-exercise increase in cold thermal response thresholds,
      sequential measurements demonstrated a time-dependent similarity in the Pre- and
      Post-Control thresholds for vasoconstriction and shivering. These data indicate
      that exercise has a prolonged effect on the post-exercise thresholds for both
      cold thermoregulatory responses.

PMID- 10344459
TI  - Increased concentrations of interleukin 1-beta in whole blood cultures
      supernatants after 12 weeks of moderate endurance exercise.
AB  - The aim of the study was to investigate whether a regular moderate endurance
      exercise programme influenced the in vitro cytokine synthesis by stimulated whole
      blood cultures. To this end, eight healthy subjects exercised moderately by
      running for 3-5 h a week over a period of 12 weeks, whilst seven other healthy
      subjects served as the control group. The intensity of the exercise was
      determined by lactic acid concentrations in the blood which were maintained
      between 1.8 and 2.5 mmol x l(-1). Over the period of training the running
      velocity producing the 4 mmol x l(-1) lactic acid threshold increased from 2.86
      (SD 0.83) m x s(-1) to 3.06+/-0.79 m x s(-1) (P < or = 0.008). Blood samples were
      taken at rest before and after the training programme. The following blood
      parameters were determined: leucocyte count, differential leucocyte count,
      lymphocyte subpopulations [CD14 positive (+)/CD45+, CD4+/ CD25+, CD8+,
      CD16+/CD122+]. Whole blood cultures were stimulated with lipopolysaccarides
      [interleukin (IL)-1 beta and IL-6] and staphylococcal enterotoxin B [IL-2,
      soluble interleukin 2 receptor (sIL2-R) and interferon (IFN)-gamma]. Cytokine
      concentrations in the supernatants were measured using an enzyme-linked
      immunosorbent assay. The white blood cell count, differential leucocyte count,
      lymphocyte subset distribution and the expression of the CD25 and CD122 antigen
      on lymphocytes were unchanged by training. After the training programme the IL-1
      beta production changed significantly [1496 (SD 264) pg ml(-1) before, compared
      to 2127 (SD 672) pg ml(-1) after training, P < or = 0.008]. In the control group
      these parameters remained unchanged. With respect to changes in the values in
      both groups the syntheses of IL-1 beta (P < or = 0.023) and IL-6 (P < or = 0.021)
      were significantly higher after regular training. The syntheses of IL-2, sIL-2
      and INF-gamma were not significantly influenced. Regular endurance exercise
      influenced the in vitro production of monocyte derived cytokines, while the
      effect of exercise on the cytokines synthesized by T-cells appeared to be of
      lesser importance.

PMID- 10344460
TI  - Co-activation of vastus lateralis and biceps femoris muscles in pubertal children
      and adults.
AB  - Determining the mechanisms of co-activation around the knee joint with respect to
      age and sex is important in terms of our greater understanding of strength
      development. The purpose of this study was to examine the effects of age, sex and
      muscle action on moment of force and electromyographic (EMG) activity of the
      agonist and antagonist muscle groups during isokinetic eccentric and concentric
      knee extension and flexion. The study comprised nine pubertal boys [mean age 12.6
      (SD 0.5) years], nine girls [12.7 (SD 0.5) years] nine adult men [23.1 (SD 2.1)
      years] and nine adult women [23.7 (SD 3.1) years] who performed maximal isometric
      eccentric and concentric efforts of knee extensors and flexors on a dynamometer
      at 30 degrees x s(-1). The moment of force and surface EMG activity of vastus
      lateralis and biceps femoris muscles were recorded. The moment of force:agonist
      averaged EMG (aEMG) ratios were calculated. The antagonist aEMG values were
      expressed as a percentage of the aEMG activity of the same muscle, at the same
      angle, angular velocity and muscle action when the muscle was acting as agonist.
      Three-way analysis of variance (ANOVA) designs indicated no significant effects
      of age or sex on moment:aEMG ratios. Eccentric ratios were significantly higher
      than the corresponding concentric ones (P < 0.05). The results also indicated no
      significant effect of age and sex on the aEMG of the vastus lateralis and biceps
      femoris muscles when acting as antagonists. The antagonist aEMG was significantly
      greater during concentric agonist efforts compared with the corresponding
      eccentric ones (P < 0.05). These findings would suggest that the moment exerted
      per unit of agonist EMG and the antagonist activity are similar in children
      compared with adults and are not sex dependent. Future comparisons between
      eccentric and concentric moments of force and agonist ENG should take into
      consideration the antagonist effects, irrespective of age or sex.

PMID- 10344461
TI  - Breathing pattern in highly competitive cyclists during incremental exercise.
AB  - The purpose of our investigation was to analyse the breathing patterns of
      professional cyclists during incremental exercise from submaximal to maximal
      intensities. A group of 11 elite amateur male road cyclists [E, mean age 23 (SD
      2) years, peak oxygen uptake (VO2peak) 73.8 (SD 5.0) ml kg(-1) min(-1)] and 14
      professional male road cyclists [P, mean age 26 (SD 2) years, (VO2peak) 73.2 (SD
      6.6) ml kg(-1) min(-1)] participated in this study. Each of the subjects
      performed an exercise test on a cycle ergometer following a ramp protocol
      (exercise intensity increases of 25 W x min(-1)) until the subject was exhausted.
      For each subject, the following parameters were recorded during the tests: oxygen
      consumption (VO2), carbon dioxide output (VCO2), pulmonary ventilation (VE),
      tidal volume (VT), breathing frequency (fb), ventilatory equivalents for oxygen
      (VE x VO2(-1)) and carbon dioxide (VE x VCO2(-1)), end-tidal partial pressure of
      oxygen and partial pressure of carbon dioxide, inspiratory (tI) and expiratory
      (tE) times, inspiratory duty cycle (tI/tTOT, where tTOT is the time for one
      respiratory cycle), and mean inspiratory flow rate (VT/tI). Mean values of VE
      were significantly higher in E at 300, 350 and 400 W (P < 0.05, P < 0.05 and P <
      0.01, respectively); fb was also higher in E in most moderate-to-maximal
      intensities. On the other hand, VT showed a different pattern in both groups at
      near-to maximal intensities, since no plateau was observed in P. The response of
      tI and tE was also different. Finally, VT/tI and tI/tTOT showed a similar
      response in both P and E. It was concluded that the breathing pattern of the two
      groups differed mainly in two aspects: in the professional cyclists, VE increased
      at any exercise intensity as a result of increases in both VT and fb, with no
      evidence of tachypnoeic shift, and tE was prolonged in this group at high
      exercise intensities. In contrast, neither the central drive nor the timing
      component of respiration seem to have been significantly altered by the training
      demands of professional cycling.

PMID- 10344462
TI  - Maximal aerobic power and leg muscle mass and strength related to age in non
      athlethic males and females.
AB  - To investigate the relationships between the age-associated decline in peak
      oxygen uptake (peak VO2), leg muscle mass (LMM) and leg strength (LS) under the
      modulating effect of gender and level of physical activity (LPA, as assessed by
      questionnaire), we evaluated 71 sedentary subjects [males(M):females(F), 34:37],
      aged 20-80 years. Peak VO2 at maximum cycle ergometry was related to LMM (dual
      energy X-ray absorptiometry) and LS (isokinetic dynamometry) using both standard
      (y x x(-1)) and power function ratios (allometry). Absolute values of all
      variables were higher in males and declined with age (P < 0.01). Differences
      between the genders disappeared after peak VO2 x LS(-1.46(M)or -1.62(F))
      adjustment but remained significant between peak VO2 LMM-(-0.51 (M)or -0.45(F))
      and LS LMM- (-091(M) or -1.10(F)) corrected values. Allometric correction of peak
      VO2 and LS by LMM slowed their age-related declines; the flattening effect
      however, was more evident in the females. Interestingly, while no age-related
      decrement in peak VO2 LS(-1) was found, power function ratio values also declined
      with age, and at a slower rate in females. These findings are consistent with
      those obtained following a multiple regression analysis using LPA as an
      independent covariate (P < 0.01). We conclude that using adequate scaling methods
      and controlling by LPA: (1) no gender differences are observed in peak VO2
      adjusted for LS, (2) loss of LS and LMM are important determinants of the age
      associated reduction in physical fitness in both genders but (3) age per se has
      an LS- and LMM-independent influence on the functional decline, although this
      intrinsic effect of senescence is less pronounced in females.

PMID- 10344463
TI  - Nonselective beta blockade attenuates the recruitment of CD62L(-)T lymphocytes
      following exercise.
AB  - Exercise induces a selective redistribution of CD62L(-) T lymphocytes. This study
      examined the effects of beta adrenergic receptor blockade on this phenomenon.
      Twelve healthy men were exercised to exhaustion on a treadmill prior to and
      following 1 week of treatment with the nonselective beta antagonist propranolol
      or the beta1 selective antagonist metoprolol. Dynamic exercise resulted in a
      significant lymphocytosis (p < 0.001). CD8(+)CD62L(-) T cells showed a greater
      than 3-fold increase in response to exercise (p < 0.001) as compared to
      CD8(+)CD62L(+) T cells, which showed a more modest increase. Treatment with the
      nonselective beta antagonist propranolol significantly attenuated the
      preferential increase of circulating CD8(+)CD62L(-) lymphocytes (p = 0.01) but
      had no effect on CD8(+)CD62L(+) T cells. Treatment with the beta1 selective
      antagonist metoprolol did not affect the response of either subset. Our findings
      replicate a prior study indicating that CD62L expression influences T lymphocyte
      trafficking in response to exercise and extends those findings by showing that
      this phenomenon is mediated, in part, via the beta2-adrenergic receptor.

PMID- 10344464
TI  - Skin-prick blood samples are reliable for estimating Hb mass with the CO-dilution
      technique.
AB  - Investigation of the impact of environmental stimuli such as altitude exposure on
      hemoglobin mass currently rely on invasive techniques that require venous blood
      sampling. This study assessed the feasibility of lancet skin pricks as an
      alternative to venepuncture to estimate hemoglobin mass with the carbon monoxide
      (CO) dilution technique, with the intent of making the technique accessible to
      technicians without phlebotomy training. Sixteen healthy volunteers rebreathed CO
      via a small-volume rebreathing apparatus. Blood was sampled simultaneously with a
      glass syringe (VEN) from a superficial forearm vein and with a capillary tube
      from either a lanced fingertip or earlobe (CAP). As a control, VEN blood was then
      aliquoted into capillary tubes (CONTROL-CAP). Samples were assayed for carboxy
      hemoglobin (HbCO) using a diode-array spectrophotometer. Mean %HbCO was higher in
      CAP than VEN (bias 0.3+/-0.2%HbCO, p < 0.01), but VEN and CONTROL-CAP were not
      different (p = 0.55). Compared to VEN, Hb mass derived from CAP samples was
      overestimated by 1.7% (15+/-22 g Hb, p = 0.01). CAP samples to estimate Hb mass
      demonstrated a technical error of measurement of 2.7%, which is comparable to the
      1.9% reported previously with VEN samples. We conclude that using CAP samples
      gives a reliable measure of %HbCO, and will make the estimation of Hb mass with
      the CO-technique accessible to technicians without phlebotomy training.

PMID- 10344465
TI  - The red wine maximization test: drinking histamine rich wine induces a transient
      increase in plasma diamine oxidase activity in healthy volunteers.

PMID- 10344466
TI  - Treatment with polymyxin B-immobilized fiber reduces platelet activation in
      septic shock patients: decrease in plasma levels of soluble P-selectin, platelet
      factor 4 and beta-thromboglobulin.
AB  - OBJECTIVE: To clarify whether plasma concentrations of soluble P-selectin,
      platelet factor-4 (PF-4) and beta-thromboglobulin (betaTG) are altered in
      patients with septic shock and whether polymyxin B-immobilized fiber (PMX-F)
      treatment affects these changes. SUBJECTS: Thirty patients with septic shock who
      were treated with PMX-F (group A), 20 such patients who received conventional
      therapies (group B) and 20 healthy control subjects(group C). METHODS: ELISA
      using commercial kits. Endotoxin elimination by direct hemoperfusion using PMX-F.
      RESULTS: Blood endotoxin levels decreased significantly from 49.4+/-8.8 pg/ml to
      13.0+/-4.5 pg/ml after PMX-F treatment. The pretreatment plasma concentrations of
      soluble P-selectin, PF-4 and betaTG in patients in groups A and B were
      significantly higher than those in group C (p<0.001). Plasma concentrations of
      these factors decreased significantly in group A after PMX-F treatment (p<0.01);
      however, the concentrations in group B were not altered after conventional
      treatment. The survival rate of group A (60%) was higher than that of group B
      (30%). CONCLUSIONS: Our findings suggest that soluble P-selectin, PF-4 and betaTG
      may be associated with septic shock and that PMX-F is effective in reducing these
      markers in patients with septic shock.

PMID- 10344467
TI  - Inhibition of serum diamine oxidase discloses a constitutive putrescine release
      from cultured vascular smooth muscle cells.
AB  - OBJECTIVE: To determine if putrescine and the higher polyamines spermidine and
      spermine are released from cultured vascular smooth muscle cells. MATERIAL:
      Vascular smooth muscle cell line A7r5. TREATMENT: Cells were treated with
      aminoguanidine (10 or 100 microM) for 1 to 24 h with or without fetal calf serum
      (10%) present in the culture medium. METHODS: Cellular and medium concentrations
      of polyamines were determined by liquid chromatography. Total cellular protein
      was determined by the Bradford procedure. Student's two-tailed t-test was used
      for statistical calculations. RESULTS: A constitutive release of putrescine was
      disclosed within 5 h if serum diamine oxidase was inhibited by 10 microM
      aminoguanidine. The release was linear with time for 24 h and specific for
      putrescine in the sense that the higher polyamines spermidine and spermine,
      despite similar cellular concentrations, were not released. Similar amounts of
      putrescine were released from the smooth muscle cells whether or not culture
      medium contained serum. Cells, that had been cultured in medium from which fetal
      calf serum had been omitted for last 48 h, contained less putrescine, spermidine
      and protein than those that persisted in medium that contained serum. CONCLUSION:
      A constitutive putrescine release from vascular smooth muscle cells is disclosed
      in the presence of aminoguanidine.

PMID- 10344468
TI  - Bone resorbing activity released from zymosan-activated mouse peritoneal
      macrophages--the role of prostanoids and interleukin-1.
AB  - OBJECTIVE: To study the effect of zymosan on the release of osteoclast
      stimulating activity from macrophages. MATERIALS: Calvarial bones from neonatal
      mice and peritoneal macrophages were incubated in the absence and presence of
      zymosan for 72 h and supernatants harvested for subsequent analysis of bone
      resorbing activities and prostaglandin concentration. METHODS: Bone resorption
      was assessed in vitro by analysing the release of 45Ca and 3H from neonatal mouse
      calvarial bones prelabelled in vivo by injections of [45Ca]CaCl2 or [3H]-proline.
      Prostaglandin E2 (PGE2) and I2 (PGI2) were analyzed using radioimmunoassays.
      RESULTS: Supernatants from macrophages treated with zymosan stimulated the
      release of 45Ca and 3H. The amount of bone resorbing activity present in the
      macrophage supernatants was dependent on the concentration of zymosan (0.1-100
      microg/ml), as well as the number of macrophages present. The 45Ca release
      induced by zymosan treated macrophages was inhibited by three different
      inhibitors of osteoclastic bone resorption (calcitonin, acetazolamide, amino
      bisphosphonate). The bone resorbing activity released by the zymosan-activated
      macrophages was lost after ultrafiltration using a filter with a molecular weight
      cut off of 30,000 Daltons, but retained when using a filter with a cut off of
      3000 Daltons. Time-course studies of the production of bone resorbing activity in
      macrophages showed that activity increased during the first hour of exposure to
      zymosan and then reached a plateau for 96 h. PGE2 and PGI2 release from
      macrophages was increased during the first three hours of exposure to zymosan.
      This prostanoid production, together with bone resorbing activity, was abolished
      by indomethacin. The bone resorbing activity present 3-72 h after zymosan
      exposure, however, was not inhibited by indomethacin. Bone resorption stimulated
      by conditioned media from zymosan treated macrophages after 3 h was inhibited by
      60-75% in the presence of anti IL-1alpha, 0-20% by anti IL-1beta, and completely
      by antisera neutralizing both IL-1alpha and IL-1beta. In addition, an IL-1
      receptor antagonist abolished the stimulatory effect of conditioned media from
      zymosan treated macrophages. CONCLUSIONS: These data indicate that treatment of
      mouse peritoneal macrophages with zymosan results in production of activities
      capable of stimulating bone resorption in vitro. The activity released initially
      appears to be due to a zymosan induced burst of prostanoid production, while the
      activity released during prolonged exposure to zymosan is due primarily to IL
      1alpha.

PMID- 10344469
TI  - Mast cell degranulation prior to ischemia decreases ischemia-reperfusion injury
      in the canine small intestine.
AB  - OBJECTIVE: To determine the impact of previous mast cell degranulation on
      intestinal ischemia-reperfusion-induced mucosal damaged. MATERIALS: The
      hemodynamic and morphological consequences of complete arterial occlusion were
      evaluated in anesthetized dogs. The mast cell degranulator Cremophor-E1 (n = 5)
      and Compound 48/80 (n = 5) were used to investigate the involvement of
      gastrointestinal mast cells in ischemia-reperfusion-induced tissue reactions.
      Seven dogs subjected to complete segmental arterial occlusion served as controls.
      Intestinal biopsies taken at the end of 120-min ischemia and after 120 min of
      reperfusion were evaluated histologically. METHODS: The number of mast cells was
      determined and the degree of mucosal damage was evaluated according to the 5
      grade Chiu scale. Mucosal histidine decarboxylase activity was measured in tissue
      samples and the rate of release of histamine was determined from the venous
      effluent of the ileal segment. RESULTS: In the control group, 120-min reperfusion
      significantly increased the plasma histamine level, and induced a severe tissue
      injury. In the compound 48/80 and Cremophor-E1-pretreated groups, the reduction
      in the baseline number of mast cells in the villi was 37% and 53%, respectively,
      and the ischemia-reperfusion-induced release of histamine was significantly
      decreased. In these groups, the basal mucosal histidine decarboxylase activity
      was significantly increased and the degree of damage of the intestinal mucosa was
      significantly reduced. CONCLUSION: It is proposed that mast cell degranulation
      prior to ischemia may induce a potentially protective mechanism in the small
      bowel mucosa and decreases ischemia-reperfusion injury in the dog.

PMID- 10344470
TI  - Osteogenic protein-1 (OP-1) blocks cartilage damage caused by fibronectin
      fragments and promotes repair by enhancing proteoglycan synthesis.
AB  - OBJECTIVE AND DESIGN: The abilities of osteogenic protein-1 (OP-1) and TGF-beta1
      to affect cartilage damage caused by fibronectin fragments (Fn-fs) that are known
      to greatly enhance cartilage proteoglycan (PG) degradation were compared.
      MATERIAL: Articular cartilage was obtained from 18 month old bovines. TREATMENT:
      To test blocking of damage, cartilage was cultured with or without OP-1 or TGF
      beta in the presence of 100 nM Fn-fs. To test restoration of PG, cartilage was
      first cultured with Fn-fs and the cartilage then treated with factors. METHODS:
      Cartilage PG content was measured in papain digests using the dimethylmethylene
      blue assay. PG synthesis was measured by incorporation of 35S labeled sulfate.
      RESULTS: OP-1 blocked damage and restored PG in damaged cartilage, apparently due
      to enhanced PG synthesis. However, TGF-beta1 alone decreased PG content.
      CONCLUSIONS: These results clearly demonstrate differences between OP-1 and TGF
      beta1, both members of the TGF-beta superfamily and illustrate the efficacy of OP
      in blocking Fn-f mediated damage.

PMID- 10344471
TI  - The effect of erdosteine and its active metabolite on reactive oxygen species
      production by inflammatory cells.
AB  - OBJECTIVE: We examined the effect of erdosteine (KW-9144), an expectorant, and
      related compounds on inflammatory cell-derived reactive oxygen species which are
      involved in airway inflammation. METHODS: Neutrophils were isolated from
      peritoneal lavages of casein-injected rats and from peripheral blood of healthy
      human donors. Eosinophils were isolated from peritoneal lavages of horse serum
      injected guinea pigs. These cells were stimulated with phorbol 12-myristate 13
      acetate (PMA) and the production of reactive oxygen species was measured with
      luminol-dependent chemiluminescence (LDCL). RESULTS: M1, an active metabolite of
      erdosteine, significantly inhibited PMA-induced LDCL of the all cell populations
      with treatment before stimulation. The effects of S-carboxymethylcysteine (S
      CMC), ambroxol and N-acetylcysteine (NAC) on the LDCL response were weaker than
      those of M1. Furthermore, PMA-induced LDCL was decreased by posttreatment with
      M1. CONCLUSION: These results suggest that M (an active metabolite of erdosteine)
      may exert an antiinflammatory effect by scavenging inflammatory cells-derived
      reactive oxygen species.

PMID- 10344472
TI  - Down-regulation of liver RNA breakdown by turpentine administration in the
      starved rat: autophagy and relevant factors.
AB  - OBJECTIVE AND DESIGN: To determine whether the inhibition of RNA breakdown
      observed in ad libitum fed rats 24 h after turpentine administration still occurs
      in inflamed rats fasted for 24 h and to examine the mechanism and factors
      involved. METHODS: RNA breakdown was measured during cyclic in situ perfusion of
      livers by the accumulation of [14C] cytidine after in vivo RNA labelling.
      Autophagic activity was determined by the morphometric analysis of lysosomal
      structures. RESULTS: The decrease in RNA breakdown (53%) observed in the inflamed
      rats was accompanied by a 38% drop in the fractional cytoplasmic volume of
      initial and digestive autophagic vacuoles. Among amino acids, only the portal
      levels of glutamate were significantly enhanced by 83%. In vivo suppression of
      glucocorticoid activity using RU 38486 in inflamed rats did not affect the
      inhibition of RNA breakdown. CONCLUSIONS: The results show that turpentine
      induced inflammation in fasted rats inhibits RNA degradation as well as autophagy
      and that glucocorticoids do not seem to be involved.

PMID- 10344473
TI  - In vitro effect of the extract and the 1,7-dihydroxy-2,3-dimethoxy xanthone from
      Polygala cyparissias on the contractions induced by inflammatory mediators and
      ovalbumin in normal and actively sensitised trachea from guinea pig.
AB  - OBJECTIVE: This study describes the in vitro action of the hydroalcoholic extract
      and the 1,7-dihydroxy-2,3-dimethoxy xanthone isolated from P. cyparissias on
      agonist and ovalbumin induced contractions in trachea, from normal and actively
      sensitised guinea pigs. RESULTS: The hydroalcoholic extract of P. cyparissias
      (0.125 to 1 mg/ml), incubated with the guinea-pig trachea for 20 min, had no
      effect on the resting tone of the preparations, but caused a concentration
      dependent, reversible and non competitive inhibition of contractions induced by
      acetylcholine, histamine, compound 48/80, bradykinin, substance P, prostaglandin
      E2 and the stable analogue of thromboxane A2 mimetic U 46619. The calculated mean
      IC50 values for the hydroalcoholic extract were: 0.37, 0.51, 0.06, 0.32, 0.48,
      0.3 and 0.17 mg/ml, respectively. Also, the extract of P. cyparissias (0.125 to
      0.5 mg/ml) antagonised, in a graded manner (IC50 of 0.46 mg/ml) ovalbumin-induced
      contractions in guinea-pig trachea obtained from animals which had been actively
      sensitised to this antigen. Pre-incubation of the preparations with the purifed
      xanthone isolated from P. cyparssias (2.5 to 80 microg/ml; 10.0 to 310.0 microM)
      caused significant and concentration-dependent, reversible and noncompetitive
      inhibition of the contractile responses elicited by acetylcholine, histamine,
      bradykinin, substance P, U 46619 and prostaglandin E2. The calculated mean IC50
      values for these effects were: 132.0, 73.0, 9.2, 32.0, 110.6 and 66.0 microM,
      respectively. At very high concentrations (I55.0-620.0 microM) the xanthone also
      antagonised contraction induced by KCl in guinea-pig trachea (IC50 of 190.0
      microM). CONCLUSIONS: Taken together these and our previous in vivo results are
      consistent with the view that the active principles present in P. cyparissias,
      including the 1,7-dihydroxy-2,3-dimethoxy xanthone, antagonise, in a non
      competitive but, reversible manner the contractions induced by chemical
      inflammatory mediators in the guinea pig trachea in vitro. Thus, these results
      might explain at least in part, the medicinal use of this plant in the management
      of inflammation, asthma and allergy.

PMID- 10344474
TI  - A comparison of the inhibitory effects of budesonide, beclomethasone
      dipropionate, dexamethasone, hydrocortisone and tixocortol pivalate on cytokine
      release from leukocytes recovered from human bronchoalveolar lavage.
AB  - OBJECTIVE: The potency of budesonide, beclomethasone dipropionate (BDP),
      dexamethasone, hydrocortisone and tixocortol pivalate as inhibitors of
      interleukin-5 (IL-5) and interferon-gamma (IFNgamma) release from human
      bronchoalveolar lavage cells in vitro were compared. METHODS: BAL leukocytes were
      obtained from patients undergoing bronchoscopy for diagnostic purposes. BAL
      leukocytes were activated with PHA (10 microg/ml) and PMA (10 ng/ml) and cultured
      for 48 h in the presence or absence of glucocorticoids. Culture supernatants were
      assayed for cytokines by ELISA. RESULTS: Budesonide (10(-9) to 10(-7) M) and BDP
      (10(-8) to 10(-6) M) were the most potent glucocorticoids tested. Dexamethasone
      (10(-7) to 10(-5) M) was less potent, and the maximum inhibitory effect of
      dexamethasone was less than that produced by than budesonide or BDP. Tixocortol
      pivalate (10(-6) to 3 x 10(-5) M) caused a concentration-related inhibition of IL
      5 release but only the highest concentration tested inhibited the release of
      IFNgamma. Hydrocortisone (10(-4) M) inhibited IL-5 and IFNgamma release.
      CONCLUSION: We conclude that, unlike the other glucocorticoids tested, tixocortol
      pivalate appeared to be a selective inhibitor of IL-5 release. Possible
      mechanisms for this selectivity are discussed.

PMID- 10344475
TI  - Usefulness of the European standard series for patch testing in children. A 3
      year single-centre study of 337 patients.
AB  - Results of patch tests in 337 children aged 1 to 15 performed in our paediatric
      unit during the past 3 years have been analysed retrospectively in order to
      optimize the patch test series and to assess their relevance. This study
      represents the most important single-centre study reported so far over a short
      period. We found a positive patch test rate of 66%, with a peak incidence among
      children less than 3 years of age (88% versus 58.9%). The most common allergens
      were metals, especially nickel, fragrances and, less frequently, rubber
      chemicals. Concerning nickel, positive reactions rarely correlated with a
      relevant exposure and were difficult to interpret, especially in patients with
      atopic dermatitis, who are probably more likely to have irritant or false
      positive reactions to metals. Based on the results and their relevance, we
      propose a shortened standard series of patch tests for paediatric patients.

PMID- 10344476
TI  - Contact sensitivity to cigarettes and matches.
AB  - The results of patch testing with a series containing components of cigarettes
      and matches were reviewed. 2 years were reviewed, 1987 and 1997. 314 patients
      were patch tested to this series, 203 in 1987 and 111 in 1997. 31 patients had
      clinically relevant positive reactions to the series, 25 in 1987 and 6 in 1997.
      26 patients had relevant positive tests to cigarette components in the series.
      There were 14 relevant positive reactions to phosphorus sesquisulfide in 1987 and
      one in 1997. All patients with relevant positive reactions to red match tips also
      had reactions to phosphorus sesquisulfide. There was a significant association
      between cigarette and fragrance hypersensitivity. The eczema in 3 of 4 patients
      who stopped smoking improved. A series containing match heads, smoked cigarette
      filters and remnants of tobacco from smoked cigarettes may be useful in smokers
      with eczema of the face, neck or hands.

PMID- 10344477
TI  - Skin susceptibility of atopic individuals.
AB  - The relevance of the irritant skin reaction of individuals with an atopic history
      (atopic dermatitis, rhinoconjunctivitis or atopic asthma) to sodium lauryl
      sulfate (SLS), a widely used irritant, is still controversial. The aim of this
      study was to evaluate transepidermal water loss (TEWL) as an indicator of stratum
      corneum integrity, before and after SLS patch testing, in various groups of
      atopic individuals with and without atopic dermatitis. 95 volunteers were divided
      into 4 groups: (1) individuals with active atopic dermatitis; (2) individuals
      with a history of atopic dermatitis but without active skin lesions; (3)
      individuals with rhinoconjunctivitis or atopic asthma without any symptoms at the
      time of testing; (4) healthy individuals serving as controls. The volunteers were
      patch-tested at the unaffected volar side of the forearm with aqueous SLS 0.5%
      for 48 h. TEWL was measured before application and after removal of the patch.
      Individuals with active atopic dermatitis showed a significantly higher TEWL
      value after SLS and a tendency to a higher basal TEWL as compared to the 3 other
      groups. There were no significant differences in TEWL between individuals who
      were classified as atopic but without active dermatitis, individuals with
      rhinoconjunctivitis or atopic asthma and healthy controls, either at the basal or
      at the post-SLS measurement. Enhanced skin susceptibility is only present in
      individuals with active dermatitis. The skin susceptibility of atopic individuals
      might therefore be increased as soon as the skin becomes eczematous, suggesting a
      reduced epidermal integrity probably caused by the endogenous atopy and/or
      respiratory allergens. When interpreting the atopy score in relation to skin
      susceptibility, the actual condition of the skin should hence be taken into
      consideration.

PMID- 10344478
TI  - Intra-and inter-individual variations in transepidermal water loss on the face:
      facial locations for bioengineering studies.
AB  - The volar forearm is the favored location for bioengineering studies. However,
      transepidermal water loss (TEWL), which is an important indicator of the function
      of the epidermal barrier, shows regional variations, and for the evaluation of
      cosmetic formulations, facial skin would be more suitable. In this study, we have
      compared 10 facial locations with 1 test site on the volar forearm for absolute
      TEWL values, reproducibility, and correlation. Measurements were performed over 3
      consecutive days. The TEWL values of the facial test sites were higher compared
      to forearm values and did not correlate with the forearm. On the face, there was
      a good correlation between the values of the right compared to the left side of
      the face. The sites superior to the nervus supraorbitalis, the medial borders of
      the musculus masseter, and the center of the chin proved to be locations with
      relatively stable TEWL values. There was a greater variability at the center of
      the forehead and at the center of the cheeks. It is recommended that TEWL
      measurements on facial locations with stable TEWL values are used for the
      evaluation of cosmetic formulations.

PMID- 10344479
TI  - Late-type allergy to the X-ray contrast medium Solutrast (iopamidol).
AB  - In the past few years, there have been an increasing number of publications on
      delayed intolerance reactions, including rashes, following the use of X-ray
      contrast media. We report a patient in whom infiltrated erythema of the face and
      generalized maculopapular rashes occurred on 2 occasions, within 1 day, following
      the use of the X-ray contrast medium Solutrast (iopamidol) for coronary
      angiography. The allergological investigations for clarification included prick
      tests and patch tests using a series of contrast media, as well as individual
      intravenous provocation tests. We found the cause to be a late-type allergy to
      the active substance iopamidol contained in the contrast medium Solutrast. We
      found a concomitant cross-reactivity to the contrast media iopromid and iomeprol.
      All 3 contrast media represent the monomeric, non-ionic type.

PMID- 10344480
TI  - Objective non-invasive assessment of patch tests with the laser Doppler perfusion
      scanning technique.
AB  - The laser Doppler perfusion scanning technique is an objective, non-invasive
      assessment method that may be used to assess patch tests. The purpose of this
      paper is to focus on its clinical use in individuals with light skin, tested with
      non-pigmented test materials. A laser Doppler perfusion imager PIM 1.0 (LDPI) is
      used to study different set-ups of the instrument that may affect readings. These
      set-ups are studied through simulated light-absorbing patch tests. The results
      have served as a base for clinical experiments comparing visual and LDPI
      assessments of normal skin, irritant patch-test reactions, and more than 25,000
      allergic patch-test assessments of reactions of different intensities and control
      patches. This paper reviews the clinical experiments to suggest a set-up of the
      LDPI for patch-test readings. Such a set-up makes it possible to compare intra-
      and inter-individual test results and to obtain meaningful assessment values
      among users. Some subject-related factors that may affect reading results are
      studied, and the effect of non-subject related factors on readings are
      considered. Use of the technique is illustrated by images of perfusion and a
      perfusion profile of a patch-test reaction followed over time.

PMID- 10344481
TI  - Comparison between 2 test models in evaluating the effect of a moisturizer on
      irritated human skin.
AB  - The purpose of the present study was to compare 2 experimental models of
      moisturizer efficacy on the recovery of irritated skin on the hands and the volar
      forearms. 12 healthy volunteers had their hands immersed in sodium lauryl sulfate
      (SLS) 10 min 2x daily for 2 days, and at the same time the volunteers had patch
      tests with SLS (0.125%, 0.25% and 0.5%) applied on their forearms for 24 h. After
      irritation of the skin, the volunteers had a moisturizer applied on one arm/hand
      3x daily for the following 9 days. The other arm/hand served as untreated
      control. Evaluation was done on days (D) 1, 3, 5, 8 and 12 by transepidermal
      water loss, electrical capacitance, laser Doppler flowmetry and
      DermaSpectrometry. Both models were found useful, and the moisturizer was found
      to accelerate regeneration of the skin barrier function in both the hands (D8,
      p<0.05) and the volar forearms (0.5% SLS, D5 and D8, p<0.01). When the forearm
      model is used in the present set-up, a relatively high concentration of SLS
      (>0.25%) should be used and evaluation measurements are best performed on D5-D8.
      The forearm model proved reliable and easy to handle and we suggest that this
      model is used in future studies on moisturizer evaluation.

PMID- 10344482
TI  - Chronic fatigue syndrome and nickel allergy.
AB  - 50 patients with chronic fatigue syndrome (CFS) and 73 controls were patch tested
      with 8 metal allergens. We found an overrepresentation of allergies among the CFS
      patients, which was not significant. However, allergy to nickel occurred in 36%
      of patients in the CFS group and in 19% of subjects in the control group
      (p<0.05). The high frequency of nickel allergy was more noteworthy in females in
      the CFS group than among female controls (52% and 24%, respectively, p<0.05).
      Similarly, in the males the figures were 14% and 9%. We suggest that in vivo
      immunoactivation by ions of nickel, or metal cross-reacting with nickel, could be
      an etiological factor in CFS.

PMID- 10344483
TI  - Compositae mix is a more sensitive test for Compositae dermatitis than the
      sesquiterpene lactone mix.
AB  - Over the past 2 decades, Compositae dermatitis has increasingly been recognized
      as a cause of exposure-pattern dermatitis. The introduction of the sesquiterpene
      lactone (SL) mix as a screening test has contributed to this improved
      recognition. However, there is growing evidence that the SL mix fails to detect a
      substantial number of genuine Compositae allergies. We therefore investigated
      whether another screening reagent (the Compositae mix) might be more sensitive in
      detecting cases of Compositae allergy than the SL mix. Over a 1-year period, we
      tested 656 consecutive unselected patch test patients to both SL mix and
      Compositae mix. 31 patients were found to have genuine Compositae allergies. Of
      these, 28 had reacted to the Compositae mix but only 13 had reacted to the SL
      mix. The Compositae mix failed to detect only 2 genuine Compositae allergies,
      whereas the SL mix missed 17 such allergies. On the other hand, the Compositae
      mix led to 9 irritant reactions, while there was only 1 irritant reaction with
      the SL mix. We conclude that Compositae dermatitis is still being underdiagnosed
      with the current screening method, and that the Compositae mix is significantly
      more sensitive in detecting Compositae allergy than the SL mix.

PMID- 10344484
TI  - Patch test sensitization after use of the Compositae mix.

PMID- 10344485
TI  - A 15-year study of patch testing to (meth)acrylates.

PMID- 10344486
TI  - 4-Vinylpyridine-induced dermatitis in a laboratory worker.

PMID- 10344487
TI  - ZnSO4 treatment of NiSO4-positive patients.

PMID- 10344488
TI  - Contact allergy to PVP/eicosene copolymer.

PMID- 10344489
TI  - Occupational allergic contact dermatitis from a glue, containing isothiazolinones
      and N-methylol-chloroacetamide, in a carpenter.

PMID- 10344490
TI  - Chloroacetamide as a cause of contact dermatitis in hairdressing.

PMID- 10344491
TI  - Patch testing in contact cheilitis.

PMID- 10344492
TI  - Contact allergy to prednicarbate: frequency of positive reactions in
      consecutively-patch-tested patients.

PMID- 10344493
TI  - Patch testing with nickel sulfate versus nickel chloride.

PMID- 10344494
TI  - Occupational allergic contact dermatitis from the mushroom White Pom Pom
      (Hericium erinaceum).

PMID- 10344495
TI  - Allergic contact dermatitis from military camouflage.

PMID- 10344496
TI  - Allergic contact dermatitis from acylamide local anesthetics.

PMID- 10344497
TI  - Colorimetric competitive inhibition method for the quantification of avidin,
      streptavidin and biotin.
AB  - A colorimetric competitive inhibition assay for avidin, streptavidin and biotin
      was developed. The method for avidin or streptavidin was based on the competitive
      binding between avidin or streptavidin and a streptavidin-enzyme conjugate for
      biotinylated dextrin immobilized on the surface of a microtitre plate. For biotin
      quantitation the competition is between free biotin and the immobilized biotin
      for the streptavidin-enzyme conjugate. The limits of detection which was
      determined as the concentration of competitor required to give 90% of maximal
      absorbency (100% inhibition) was approximately 20 ng/100 microl per assay for
      avidin and streptavidin and 0.4 pg/100 microl per assay for biotin. The methods
      are simple, rapid, highly sensitive and adaptable to high throughput analysis.

PMID- 10344498
TI  - Evaluation of phase transition errors in heat capacity calorimeters using SPICE
      simulated RC models.
AB  - A technique is presented which allows the development of extremely complex (>
      5000 components) RC models of calorimeters and provides simulation under a wide
      variety of inputs. A commercially available circuit simulation program (SPICE) is
      used to 'build' RC models of relaxation and scanning calorimeter designs used to
      measure heat capacity. The instrument models are constructed using subcircuits to
      represent small elements of the materials used in the designs. Only simple linear
      equations are needed to evaluate the RC values in the subcircuit. The subcircuits
      also use voltage controlled switches to simulate phase transitions where lambda,
      C, and delta h can change value instantaneously at predetermined temperatures.
      The resulting simulations of the two designs provide an ability to predict
      instrument sensitivity to lambda and C independently. Simulated outputs agree
      with measured outputs within 10%. Model simulations show serious errors in the
      heat capacity determinations from both designs during phase transitions.
      Interactions between lambda, C, and delta h are shown for both designs. The
      technique provides a means to construct, evaluate, and optimize a calorimeter
      design completely in software.

PMID- 10344499
TI  - A comparative study on the extraction of membrane-bound bilirubin from
      erythrocyte membranes using various methods.
AB  - In this study, we used three different methods for the extraction of membrane
      bound bilirubin (EMB) from erythrocyte membranes. Use of 2.5% albumin, pH 7.4,
      for elution of EMB resulted in only 34% of the total EMB which was estimated
      after the solubilization of bilirubin-loaded erythrocyte membranes (BLEMs) with
      1% SDS. On the other hand, incubation of BLEMs with 38 mM sodium carbonate
      solution containing 5 mM EDTA, pH 11.0, yielded 77% of the total EMB. Application
      of Fog's reaction for the estimation of EMB directly on the BLEMs resulted in the
      estimation of 75% of the total EMB. These results suggest that either of the
      above methods, i.e. use of albumin or high pH, or direct Fog's reaction cannot
      estimate the total EMB correctly. Increase in ionic strength from 0.15 to 0.45
      did not release any EMB from erythrocyte membranes. Therefore, the best method
      for the estimation of total EMB is the solubilization of membrane with 1% SDS
      followed by Fog's reaction method.

PMID- 10344500
TI  - Microplates: a new tool for manipulation and mechanical perturbation of
      individual cells.
AB  - We present a new type of microinstrument allowing manipulation and mechanical
      perturbation of individual cells under an optical microscope. These instruments,
      which we call microplates, are pulled from rectangular glass bars. They have flat
      tips, typically 2 microm thick x 20 microm wide, whose specific shape and
      stiffness can be adjusted through the pulling protocol. After appropriate
      chemical treatment, microplates can support cell adhesion and/or spreading. Rigid
      microplates are used to hold cells, whereas more flexible ones serve as stress
      sensors, i.e. their deflexion is used to probe forces in the range of 1-1000 nN.
      The main advantages of microplates are their simple geometry and surface
      properties, and their ability to provide mechanical measurements. In this
      methodological paper, we give details about microplate preparation and
      adhesiveness, manipulation set-up, force calibration, and image analysis. Several
      manipulations have already been carried out on fibroblasts, including uniaxial
      deformation, micropipet aspiration of adherent cells, and cell-substrate
      separation. Our results to date provide new insights into the morphology,
      mechanical properties, and adhesive resistance of cells. Many future applications
      can be envisaged.

PMID- 10344501
TI  - Quantitative determination of the main glucose metabolic fluxes in human
      erythrocytes by 13C- and 1H-MR spectroscopy.
AB  - Information displayed by homonuclear and heteronuclear spin-coupling patterns in
      13C- and 1H-MR spectra allowed us to identify the major lactate isotopomers
      produced either from [1-(13)C]-glucose or from [2-(13)C]-glucose by human
      erythrocytes. Relative concentrations of detectable isotopomers were determined
      by integrating the corresponding MR signals. The interpretation of these data in
      terms of the fractional glucose metabolised through glycolysis and pentose
      phosphate pathway was performed by a computer simulation of the metabolism that
      took into account metabolic schemes pertaining to glycolysis and to the F-type of
      pentose phosphate pathway. The simulation was organised in a way to anticipate
      the populations of the isotopomers produced from any precursor at a priori
      established metabolic steady state. By the simulation, isotopomer populations
      were determined according to different values of pentose cycle, defined as the
      flux of glyceraldehyde 3-phosphate originating from pentose phosphate pathway at
      unitary glucose uptake. The populations of the isotopomers originating from [2
      (13)C]-glucose were described by polynomials, and ratios between the polynomials
      were used in conjunction with 13C- and 1H-MR data to determine pentose cycle
      values. The knowledge of glucose uptake and of pentose cycle value allowed us to
      perform accurate measurement of the pentose phosphate pathway flux, of the
      hexokinase and phosphofructokinase fluxes as well as, indirectly, of the carbon
      dioxide production.

PMID- 10344502
TI  - Sensitive detection of the binding of E2F to its promoter by exonuclease III- and
      BssHII-protection PCR assays.
AB  - For the non-radioactive, sensitive detection of the binding of transcription
      factor E2F to its binding site (E2 promoter), exonuclease III (ExoIII)- and
      BssHII-protection PCR assays were established. The binding of glutathione S
      transferase E2F-1 (GST-E2F-1) fusion protein to its promoter protected the
      promoter against ExoIII- and BssHII-digestion. For the BssHII-protection PCR
      assay, a BssHII restriction site was made in the E2 promoter sequence by changing
      one base-pair next to its sequence. To detect E2F binding in ExoIII- or BssHII
      protection PCR assays, the use of 3.13 fmol (5.00 ng) or 2.33 fmol (4.62 ng) of
      DNA (containing E2 promoters) and 0.325 microg (3.70 pmol) or 0.175 microg (2.00
      pmol) of GST-E2F-1 protein, respectively, were found to be sufficient.

PMID- 10344503
TI  - Capillary isoelectric focusing with whole column imaging detection for analysis
      of proteins and peptides.
AB  - Whole column imaging detection has been developed for capillary isoelectric
      focusing (CIEF) of proteins and peptides. In this imaged C1EF technique, a
      solution of sample and ampholytes was introduced into a short (4-5 cm),
      internally coated capillary stabilized by a cartridge. After applying high DC
      voltage, the isoelectric focusing process takes place and the focused zones are
      monitored in a real-time mode using the imaging detectors developed. Three types
      of imaging detectors have been developed including refractive index gradient,
      laser-induced fluorescence (LIF), and absorption. Of these, absorption imaging
      detection is the most practical at the present time due to its quantitative
      ability and universal characteristics. Whole column imaging detection eliminates
      the mobilization step required for single point detection after the focusing
      process. Therefore, it provides a fast analysis speed (3-5 min for each sample),
      and avoids the disadvantages associated with the mobilization process, such as
      distortion of pH gradient and loss in resolution. In this paper, we review the
      methodology of imaged CIEF as well as progress in instrumental development, IEF
      performed on a microchip, and the application to protein and peptide analysis.

PMID- 10344504
TI  - Bioassay of biotin concentration with a Escherichia coli bio deletion mutant.
AB  - Biotin concentration was determined unequivocally with the E. coli bio mutant.
      The results demonstrate that this simple and efficient method can determine
      biotin concentration in the range of 10 pg to 50 ng/ml. The present method can
      also clearly distinguish biotin from its precursor and analog, dethiobiotin.

PMID- 10344505
TI  - Enhancement in the lysozyme activity of the hen egg white foam matrix by cross
      linking in the presence of N-acetyl glucosamine.
AB  - Lysozyme naturally present in raw hen egg white was immobilized by cross-linking
      the egg white foam with glutaraldehyde. Inclusion of N-acetyl glucosamine, a
      competitive inhibitor of lysozyme, was found to enhance the yield of lysozyme
      activity by fivefold.

PMID- 10344506
TI  - Consequences of the anatomy of deep venous outflow from the brain.
AB  - The deep venous system is best defined as the entire territory served by the
      great vein of Galen and the basal veins. This comprises not only the choroid
      plexuses and the deep grey matter of the thalamus and striatum, but also the
      periventricular white matter and corpus callosum, hippocampus and the cortical
      areas of the limbic lobe including the cingulate and parahippocampal gyri, the
      visual cortex, the diencephalon and rostral brain stem, and part of the
      cerebellum. The superficial venous system comprises the remaining neocortex (with
      the cortex of the entire convexity) together with a layer of subcortical white
      matter, separated from the periventricular white matter by a venous watershed.
      Outflow towards the great vein of Galen and straight sinus can be substituted by
      collateral channels towards the basal vein. The basal vein in turn is connected
      not only to the great vein of Galen, but also to the superior petrosal sinus (via
      the lateral mesencephalic vein), and in the adult configuration to the cavernous
      sinus and pterygoid plexus (via the deep and superficial sylvian veins). Evidence
      from pathological anatomy indicates that the venous watershed exists not only in
      the white matter of the hemispheres, but between the entire territories of the
      deep and superficial venous systems. Because of their anastomotic
      interconnections, only simultaneous obstruction of veins of Galen and basal veins
      wil effectively obstruct deep venous outflow. This can occur in the tentorial
      incisura, from swelling or displacement of the midbrain due to brain oedema,
      haematoma or tumour. Complete obstruction of great vein of Galen and basal veins
      leads to rapid death. In patients who survive incomplete obstruction, various
      combinations of damage to parts of the deep venous territory exist. This is
      possible because very many tributaries of the deep system unite below and
      sometimes above the tentorial incisura. The hallmarks these varying deep venous
      obstructions have in common are sparing of the subcortical white matter of the
      convexity, and cortical involvement limited to the limbic lobe and visual cortex.
      Obstruction of cerebral venous outflow explains many pathological phenomena.
      Treatment must aim at relieving this obstacle to blood flow.

PMID- 10344507
TI  - MRI of acute cerebral infarcts, increased contrast enhancement with continuous
      infusion of gadolinium.
AB  - We compared contrast enhancement on T1-weighted MRI of acute cerebral infarcts
      after conventional bolus administration and continuous infusion of gadolinium. We
      examined 12 patients with a history of acute stroke with contrast-enhanced MRI
      once a week for a 1 month. Only ischaemic lesions were investigated after
      cerebral haemorrhage had been excluded by CT. Each MRI study included T2- and
      proton density-weighted sequences for determination of the size and site of the
      infarct, immediate postinjection T1-weighted imaging after bolus administration
      of 0.1 mmol/kg gadolinium-DPTA and delayed T1-weighted imaging after additional
      continuous infusion of 0.1 mmol/kg over 2 h. A total of 42 MRI studies was
      performed. In the first week after the onset of stroke, most infarcts (8 of 10)
      did not enhance after bolus administration, whereas all showed distinct contrast
      enhancement after the infusion. In the following weeks all but two infarcts
      showed contrast enhancement after bolus administration; after continuous infusion
      contrast enhancement could be seen in all cases. While contrast enhancement after
      bolus administration showed the typical gyriform pattern, enhanced areas were
      more extensive after the infusion and usually covered the entire infarcted area
      shown on T2- and proton density-weighted images. We presume that the disturbed
      blood-brain barrier in ischaemic areas favours delivery of contrast medium to the
      infarcted tissue if it is offered continuously so that a steady state can
      develop.

PMID- 10344508
TI  - Do acute lesions of Wernicke's encephalopathy show contrast enhancement? Report
      of three cases and review of the literature.
AB  - Contrast medium was given intravenously to three nonalcoholic patients who
      underwent MRI or CT in the acute stage of Wernicke's encephalopathy. Lesions
      enhancement was not seen in one patient examined within 4 days of clinical onset,
      was mild in a another 3 days after clinical deterioration and marked in a patient
      examined 12 days after admission. Contrast enhancement of lesions was present in
      half of 12 cases of acute disease reported previously. There was a substantial
      overlap in the time interval between clinical onset and contrast-enhanced CT or
      MRI in the groups of enhancing and nonenhancing lesions. Since contrast
      enhancement may be absent in acute WE, proton-density and T2-weighted images are
      more useful for diagnosis of this reversible but potentially fatal condition.

PMID- 10344509
TI  - Masked assessment of MRI findings: is it possible to differentiate neuro-Behcet's
      disease from other central nervous system diseases? [corrected].
AB  - Two neuroradiologists reviewed MRI studies of 34 patients with neuro-Behcet's
      disease (NBD), 22 with multiple sclerosis (MS) and 7 with systemic lupus
      erythematosus (SLE) with central nervous system involvement, masked to the
      clinical diagnosis, age and sex of the patients. Of the patients with NBD 12 were
      in an acute attack; the others had chronic disease. MRI was assessed using a set
      of criteria, looking at atrophy, the site of discrete parenchymal lesions,
      regions of predominant involvement and the extent of the lesion(s). The observers
      also made a guess at the clinical diagnosis. The brain stem and/or basal ganglia
      were the most predominantly involved sites in all patients with acute NBD; 75% of
      these lesions were large and confluent, mainly extending from the brain stem to
      the diencephalon and basal ganglia. However, in chronic cases, the predominant
      involvement was in the brain stem and/or basal ganglia in only 36%, and in
      cerebral hemisphere white matter in another 36%; 27% of these patients showed no
      parenchymal lesion. Hemisphere white-matter lesions were equally distributed
      between periventricular and other areas in NBD, while in MS more were
      periventricular, and in SLE more were nonperiventricular. Brain-stem atrophy was
      seen in 21% of patients with NBD, with a specificity of 96.5%. In the absence of
      cortical atrophy, its specificity was 100%. The attempt at making a radiological
      diagnosis was successful in all cases of acute NBD and 95.5% of patients with MS,
      but in only 40% of patients with chronic NBD. Most of this latter groups MRI
      studies were interpreted as MS. An extensive lesion involving the brain stem and
      basal ganglia seemed to be diagnostic of acute NBD. However, hemisphere white
      matter lesions could not be differentiated from those in MS.

PMID- 10344510
TI  - Interobserver agreement in the assessment of cerebral atrophy on CT using
      bicaudate and sylvian-fissure ratios.
AB  - To assess the interobserver variability of cerebral-atrophy measures on CT, three
      investigators measured the bicaudate ratio (BCR) and the sylvian-fissure ratio
      (SFR) on 20 CT studies of patients with ischaemic stroke. The intraclass
      correlation coefficient of BCR measurements was 0.82 [95% confidence interval
      (CI) 0.75-0.94], and that of SFR measurements 0.69 (95% CI 0.57-0.89). The range
      of pairwise-calculated Pearson correlation coefficients was smaller for
      measurement of the BCR (0.89-0.92) than for the SFR measurements (0.66-0.84).

PMID- 10344511
TI  - New MRI findings in Creutzfeldt-Jakob disease: high signal in the globus pallidus
      on T1-weighted images.
AB  - We report a 49-year-old woman with Creutzfeldt-Jakob disease (CJD). In addition
      to typical high-signal lesions on proton-density and T2-weighted images there was
      high signal in the globus pallidus bilaterally on T1-weighted images. The latter
      feature has not been described previously and probably due to deposition of prion
      protein, as found at autopsy.

PMID- 10344512
TI  - Monoparesis of the right hand following a localised infarct in the left
      "precentral knob".
AB  - A patient with acute weakness of the righ arm showed a focal lesion on MRI in the
      left 'precentral knob', not visible on CT.

PMID- 10344513
TI  - MRI of the spinal cord in myelopathy complicating vitamin B12 deficiency: two
      additional cases and a review of the literature.
AB  - Focal spinal cord lesions have been present in all previously reported cases of
      MRI appearances in myelopathy complicating vitamin B12 deficiency. We describe
      two further cases showing mild atrophy only and review the salient features of
      the previous 11 publications. MRI findings reflect quite closely the known
      pathological changes in this condition.

PMID- 10344514
TI  - Neurological deficit following spinal anaesthesia: MRI and CT evidence of spinal
      cord gas embolism.
AB  - A 62-year-old diabetic woman developed permanent neurological deficits in the
      legs following spinal anaesthesia. MRI showed oedema in the spinal cord and a
      small intramedullary focus of signal void at the T10 level, with negative density
      at CT. Intramedullary gas bubbles have not been reported previously among the
      possible neurological complications of spinal anaesthesia; a combined
      ischaemic/embolic mechanism is hypothesised.

PMID- 10344515
TI  - Osteoblastoma in lumbar vertebral body.
AB  - We report a young man with low back pain suspected to have a disc protrusion.
      Imaging suggested a tumour of the dorsal portion of the fifth lumbar vertebral
      body. Operation suggested a giant-cell tumour and subsequent histology showed an
      osteoblastoma. All typical imaging features of osteoblastoma are demonstrated in
      this rather uncommon location. Contrast-enhancing bone-marrow oedema on MRI, with
      mild enhancement of the tumour, together with the CT appearances were the clues
      to the diagnosis.

PMID- 10344517
TI  - Transient globus pallidus T1 shortening associated with polycythaemia and
      dystonia.
AB  - We report a child who concurrently developed polycythaemia, dystonia, and T1
      shortening in the globus pallidus, medial cerebral peduncle and superior
      cerebellar peduncles on MRI. With spontaneous resolution of the polycythaemia
      after about 2 1/2 years, the dystonia and MRI abnormalities also resolved.
      Although the physiological cause of the T1 shortening is not known, this appears
      to be another cause of T1 shortening in the basal ganglia.

PMID- 10344516
TI  - Virchow-Robin spaces in childhood migraine.
AB  - Virchow-Robin spaces (VRS) are pia-lined extensions of the subarachnoid space
      which surround penetrating arteries as they enter the brain on its surface. Using
      high-resolution MRI, which shows small penetrating arteries, we studied a
      possible association of accentuated VRS in children with tension-type headache
      (TTH) or migraine. We studied 58 children aged 3-14 years (mean 10.8 years) with
      a clinical diagnosis of migraine (31) or TTH (27), who underwent cerebral MRI,
      and 30 headache-free patients of the same age (mean 10.2 years) and 30 adult
      migraineurs with postpubertal onset of symptoms, who served as controls. The
      images were reviewed for structural abnormalities in the regions of the small
      penetrating arteries. Accentuated VRS were found in 61% of the children with
      migrainous headaches and in 22% of children of those with TTH. Prominent VRS were
      seen in 27% of the control children and in only 13% of the adults. Small infarcts
      and gliosis were rare in children with or without headache, but were seen in 30%
      of the adult migraineurs. Our findings show that accentuated VRS are
      significantly more common in children with migraine than in those with TTH or
      headache-free controls. Detection of accentuated VRS may therefore enhance
      differential diagnosis of primary headaches in children, contributing to an
      improvement in management.

PMID- 10344518
TI  - Accuracy of single-sequence MRI for investigation of the fluid-filled spaces in
      the inner ear and cerebellopontine angle.
AB  - We prospectively studied 163 patients referred for MRI of the temporal bone. A
      presumed diagnosis was made using only one of three sequences: a single thick (12
      mm) slice fast T2-sequence, 3D fourier transform constructive interference in
      steady state (3DFT-CISS) sequence and a gadolinium-enhanced T1-weighted sequence.
      The visibility of the cochlea, vestibule and superior, lateral and posterior
      semicircular canals of normal temporal bones was assessed on the T2-weighted
      images: they were almost always visible (98-100%), with exception of the superior
      semicircular canal, seen in only 35% of cases. The images were interpreted as
      abnormal in 34 patients (21%). Using only the fast T2-weighted, 3DFT-CISS and
      gadolinium-enhanced T1-weighted sequences a presumed false positive diagnosis was
      made in 5, 1 and 0 cases and a false negative diagnosis in 2, 2 and 4 cases
      respectively. The overall reliability of the thick-section fast T2-weighted
      images is limited. This study suggests that a combination of gadolinium-enhanced
      T1-weighted and 3DFT-CISS images can be considered the gold standard for temporal
      bone MRI and neither sequence performed separately is as accurate as both
      together.

PMID- 10344519
TI  - Recurrent pleomorphic adenoma of the head and neck.
AB  - We reviewed the clinical and imaging files of 15 patients with pathologically
      confirmed recurrent pleomorphic adenomas of the head and neck. The primary
      tumours were in the lacrimal gland (1 case), cheek (2), palate (5), parotid gland
      (4), and submandibular gland (3). Recurrence was generally late, with an average
      of 14.9 years between initial surgery and recurrence. Multiple recurrent tumours,
      measuring 5-50 mm were found in eight patients. In all palatal cases recurrence
      was large and solitary. Most recurrent pleomorphic adenomas were well delineated
      with smooth margins, like most primary tumours. Irregularity of the margins was
      seen in four patients. In four of the five tumours of the palate and in the
      orbital lesion, the recurrent tumours caused bone destruction, thus mimicking
      malignant lesions. Irregular-margined recurrences seem to be rather small and
      found among multiple recurrent nodules.

PMID- 10344520
TI  - Giant-cell tumor of the skull base.
AB  - Giant cell tumors are uncommon primary bone tumors. They primarily occur in the
      long bones. Giant cell tumors are extremely rare in the skull and head and neck.
      When it does occur, the maxilla and mandible are the common sites to be involved.
      We described two cases of giant cell tumor in the temporal bone. In the
      noncontrast enhanced CT, the lesion presents as a soft tissue density mass with
      expansion of the bone. The bony cortex is usually intact. The adjacent soft
      tissues and cerebral parenchyma show no infiltration or edema. The post contrast
      scan reveals homogenous enhancement of the mass.

PMID- 10344521
TI  - Tentorial dural arteriovenous fistulae: endovascular treatment with transvenous
      coil embolisation.
AB  - Tentorial arteriovenous dural fistulae are uncommon. They are aggressive lesions:
      of all intracranial dural fistulae they are the most likely to present with
      haemorrhage. Treatment options include surgical excision or interruption of
      leptomeningeal draining veins and arterial embolisation in isolation or in
      combination with surgery. There has been one case report of treatment by
      percutaneous transvenous coil embolisation. We describe successful transvenous
      coil embolisation of two tentorial dural fistulae presenting with subarachnoid
      haemorrhage.

PMID- 10344522
TI  - Functional assay of NF-kappaB translocation into nuclei by laser scanning
      cytometry: inhibitory effect by dexamethasone or theophylline.
AB  - Nuclear factor-kappa B (NF-kappaB)/Rel transcription factors play an important
      role in the inducible regulation of a variety of cytokine genes in epithelial
      cells. We assessed accumulation of fluorescence-stained NF-kappaB into propidium
      iodide-stained nuclei using laser scanning cytometry. "Activity-specific"
      antibodies to the Rel A (p65) and NF-kappaB1 (p50) subunits of NF-kappaB were
      detected in the nuclei of A549 cells (an immortalized human type II alveolar
      epithelial cell line). Exposure to TNF-alpha caused p65 and p50 to translocate
      into nuclei in a dose- and time-dependent manner. Preincubation with
      dexamethasone for 24 h or 30 min, or with theophylline for 30 min before TNF
      alpha stimulation attenuated the nuclear translocation of Rel A and p50. These
      findings suggest that theophylline, as well as dexamethasone, may inhibit
      translocation of NF-kappaB.

PMID- 10344523
TI  - Staurosporine directly blocks Kv1.3 channels expressed in Chinese hamster ovary
      cells.
AB  - The effects of staurosporine (ST), a widely used protein kinase C (PKC)
      inhibitor, were examined on Kv1.3 channels stably expressed in Chinese hamster
      ovary (CHO) cells using the whole-cell and excised inside-out configurations of
      the patch clamp technique. In whole-cell recordings, ST, at external
      concentrations from 300 nM to 10 microM, accelerated the rate of inactivation of
      Kv1.3 currents and thereby reduced the current at the end of the depolarizing
      pulse in a concentration-dependent manner with an IC50 of 1.2 microM. The actions
      of ST were unaffected by pretreatment with another selective PKC inhibitor,
      chelerythrine, or by including the PKC pseudosubstrate peptide inhibitor, PKC 19
      36, in the intracellular solution. Rp-cAMPS, a specific protein kinase A
      inhibitor, included in intracellular solution did not affect the effects of ST.
      Furthermore, the same effects of ST on Kv1.3 were also observed in excised inside
      out patches when applied to the internal face of the membrane. These effects were
      completely reversible upon washing. Current-voltage relations for Kv1.3 currents
      at the end of voltage steps indicated that ST reduced Kv1.3 currents over a wide
      voltage range. The blockade exhibited a shallow voltage dependence between -10 mV
      and +40 mV, increasing at more positive potentials. ST had no effect on the
      voltage dependence of steady-state inactivation. It reduced the tail current
      amplitude and slowed the deactivation time course, resulting in a crossover
      phenomenon. These results suggest that the action of ST on Kv1.3 is independent
      of PKC and PKA inhibition. ST blocks the open state of Kv1.3 channels to produce
      an apparent acceleration of the inactivation rate.

PMID- 10344524
TI  - Analysis of the receptor involved in the central hypotensive effect of
      rilmenidine and moxonidine.
AB  - The aim of this study was to determine whether alpha2-adrenoceptors or
      imidazoline I1-receptors are responsible for the central sympathoinhibition
      produced by rilmenidine and moxonidine, two clonidine-like antihypertensive
      drugs. Rilmenidine and moxonidine were compared with the indirectly acting alpha2
      adrenoceptor agonist alpha-methyldopa. Three antagonists were used. Yohimbine and
      SK&F86466 were used as selective alpha2-adrenoceptor antagonists. They were
      compared with efaroxan which is also an alpha2-adrenoceptor antagonist, but, in
      addition, possesses affinity for imidazoline I1-receptors. According to some but
      not all studies, the affinity of efaroxan for I1-receptors is much higher than
      its affinity for alpha2-adrenoceptors. Drugs were administered into the cisterna
      cerebellomedullaris of conscious rabbits by a catheter implanted previously under
      halothane anaesthesia. Rilmenidine (10 microg kg(-1)), moxonidine (0.3 microg kg(
      1)) and alpha-methyldopa (0.4 mg kg(-1)) lowered blood pressure and the plasma
      noradrenaline concentration; the degree of sympathoinhibition produced by the
      three agonists was very similar. When injected after the agonists, efaroxan (0.1
      14 microg kg(-1); cumulative doses), yohimbine (0.4-14 microg kg(-1)) and
      SK&F86466 (0.4-44 microg kg(-1)) counteracted the effects of the agonists on
      blood pressure and the plasma noradrenaline concentration. Efaroxan was about
      tenfold more potent than yohimbine and SK&F86466 at antagonizing the hypotensive
      effects of alpha-methyldopa. Similarly, efaroxan was two- to tenfold more potent
      than yohimbine and SK&F86466 against rilmenidine and moxonidine. Finally,
      efaroxan was about as potent against alpha-methyldopa as against rilmenidine and
      moxonidine. The results confirm previous observations that selective alpha2
      adrenoceptor antagonists are capable of completely antagonizing effects of
      rilmenidine and moxonidine. The effects of the alpha2-adrenoceptor antagonist
      with an additional high affinity for imidazoline I1-receptors, efaroxan, can also
      be explained by blockade of alpha2-adrenoceptors. Efaroxan was more potent
      against rilmenidine and moxonidine than the selective alpha2-adrenoceptor
      antagonists. This was probably due to the fact that the affinity of efaroxan for
      alpha2-adrenoceptors is higher than the affinity of yohimbine and SK&F86466,
      since efaroxan was also the most potent of the three antagonists against the
      indirectly acting alpha2adrenoceptor agonist alpha-methyldopa. The observation
      that efaroxan was equally potent against rilmenidine and moxonidine and against
      alpha-methyldopa suggests that the same receptors were involved in the effects of
      the three agonists, alpha2-adrenoceptors; this observation is not compatible with
      the high I1/alpha2 selectivity of efaroxan and the hypothesis that rilmenidine
      and moxonidine activate I1-receptors, whereas alpha-methyldopa activates alpha2
      adrenoceptors. Thus, the data do not indicate involvement of I1 imidazoline
      receptors in the central sympathoinhibition elicited by rilmenidine and
      moxonidine in rabbits. It is likely that rilmenidine and moxonidine produce
      sympathoinhibition by activating the same receptors which are activated by the
      indirectly acting catecholamine alpha-methyldopa, namely alpha2-adrenoceptors.

PMID- 10344525
TI  - Aniracetam, 1-BCP and cyclothiazide differentially modulate the function of NMDA
      and AMPA receptors mediating enhancement of noradrenaline release in rat
      hippocampal slices.
AB  - Aniracetam, 1-(1,3-benzodioxol-5-yl-carbonyl)piperidine (1-BCP) and
      cyclothiazide, three compounds considered to enhance cognition through modulation
      of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors,
      were evaluated in the 'kynurenate test', a biochemical assay in which some
      nootropics have been shown to prevent the antagonism by kynurenic acid of the N
      methyl-D-aspartate (NMDA)-evoked [3H]noradrenaline ([3H]NA) release from rat
      hippocampal slices. Aniracetam attenuated the kynurenate (100 microM) antagonism
      of the [3H]NA release elicited by 100 microM NMDA with high potency (EC50< or
      =0.1 microM). Cyclothiazide and 1-BCP were about 10 and 100 times less potent
      than aniracetam, respectively. The effect of aniracetam persisted in the presence
      of the AMPA receptor antagonist 6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3
      dione (NBQX) added at 5 microM, a concentration that did not affect NMDA
      receptors; in contrast, NBQX reduced the effect of 1-BCP and abolished that of
      cyclothiazide. The AMPA-evoked release of [3H]NA from hippocampal slices or
      synaptosomes was enhanced by cyclothiazide, less potently by 1-BCP and weakly by
      aniracetam. High concentrations of kynurenate (1 mM) antagonized the AMPA-evoked
      [3H]NA release in slices; this antagonism was attenuated by 1 microM
      cyclothiazide and reversed to an enhancement of AMPA-evoked [3H]NA release by 10
      microM of the drug, but was insensitive to 1-BCP or aniracetam. It is concluded
      that aniracetam exerts a dual effect on glutamatergic transmission: modulation of
      NMDA receptor function at nanomolar concentrations, and modulation of AMPA
      receptors at high micromolar concentrations. As to cyclothiazide and 1-BCP, our
      data concur with the idea that both compounds largely act through AMPA receptors,
      although an NMDA component may be involved in the effect of 1-BCP.

PMID- 10344526
TI  - Chronic haloperidol and clozapine administration increases the number of cortical
      NMDA receptors in rats.
AB  - The aim of the present study was to examine the influence of 3-month
      administration of haloperidol (1 mg/kg per day) and clozapine (30 mg/kg per day)
      in drinking water on cortical NMDA (N-methyl-D-aspartate) receptors in rats. On
      day 5 of withdrawal, the animals were killed and their brains were removed. The
      binding of [3H]MK-801 ([3H](5R, 10S)-(+)-5-methyl-10,1 11-dihydro-5H
      dibenzo[a,d]cyclohepten-5,10-imine) and [3H]CGP 39653([3H]D,L-(E)-2-amino-4
      propyl-5-phosphono-3-pentenoic acid) to NMDA receptors in different cortical
      areas, as well as the binding of [3H]spiperone to dopamine D2 receptors in the
      striatum, were analysed by quantitative autoradiography. Haloperidol increased
      the binding of [3H]CGP 39653 in frontal, insular and parietal cortices. Clozapine
      increased the binding of [3H]CGP 39653 in insular and parietal cortices.
      Haloperidol, but not clozapine, increased the binding of [3H]spiperone in the
      striatum. None of the neuroleptics influenced the binding of [3H]MK-801 to
      cortical NMDA receptors. An additional assay revealed an increase in the Bmax
      value, with no significant changes in the K(D) of [3H]CGP 39653 binding in
      parieto-insular cortical homo-genates as a result of haloperidol and clozapine
      administration. The present results suggest that long-term treatments with
      haloperidol and clozapine increase the number of NMDA receptors in different
      cortical regions.

PMID- 10344527
TI  - Mesolimbic NMDA receptors are implicated in the expression of conditioned
      morphine reward.
AB  - Systemic administration of a variety of N-methyl-D-aspartate (NMDA) receptor
      antagonists inhibits morphine's rewarding properties in the conditioned place
      preference test. In this study, we investigated the anatomical loci implicated in
      the inhibition of expression of morphine's reward by bilateral microinjections of
      a selective NMDA antagonist into the mesolimbic areas, including ventral
      tegmental area and nucleus accumbens. During conditioning, injections of 1 mg/kg
      morphine were associated with placing rats in one chamber of the place preference
      box; the exposures to the other chamber were associated with placebo
      administration. On the test day, drug-free control subjects demonstrated a marked
      preference for the morphine-associated chamber. Systemic administration of 5
      mg/kg and 10 mg/kg of the competitive NMDA antagonist, NPC 17742 (2R,4R,5S-2
      amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid), significantly reduced the
      expression of morphine-induced conditioned place preference; the dose of 10 mg/kg
      produced also an inhibition of locomotor activity. Similar attenuation of the
      expression of morphine-induced conditioned place preference was observed in rats
      receiving 15.6 and 62.5 ng/0.5 ml side of NPC 17742 injected bilaterally into the
      nucleus accumbens and ventral tegmental area. While the higher intra-accumbal
      dose of NPC 17742 produced behavioral stimulation, intra-tegmental injection did
      not affect locomotor activity. These findings suggest that activation of NMDA
      receptors in the nucleus accumbens and ventral tegmental area is necessary for
      the elicitation of approach by environments previously associated with morphine's
      rewarding action.

PMID- 10344528
TI  - G protein coupling of CGS 21680 binding sites in the rat hippocampus and cortex
      is different from that of adenosine A1 and striatal A2A receptors.
AB  - The effect of guanine nucleotide-binding protein (G protein) modifiers on the
      binding of the adenosine A2A receptor agonist 2-[4-(2-p-carboxyethyl[3H])phenyl
      amino]-5'-N-ethylcarboxamidoadenosine ([3H]CGS 21680) and of the adenosine A1
      receptor agonist [3H]R-phenylisopropyladenosine ([3H]R-PIA) to rat cortical and
      striatal membranes was studied. Guanosine 5'-(beta,gamma-imido)triphosphate (1
      300 microM), which uncouples all G proteins, more effectively inhibited [3H]CGS
      21680 (30 nM) binding in the cortex than [3H]R-PIA (2 nM) binding to cortical or
      striatal membranes or [3H]CGS 21680 (30 nM) binding in the striatum. N
      Ethylmaleimide (1-300 microM) or pertussis toxin (1-100 microg/ml), which
      uncouple G(i)/G(o) protein-coupled receptors, more effectively inhibited [3H]R
      PIA binding to cortical or striatal membranes and [3H]CGS 21680 binding in the
      cortex than [3H]CGS 21680 binding in the striatum. Cholera toxin (2.5-250
      microg/ml), which uncouples G(S) protein-coupled receptors, more effectively
      inhibited [3H]CGS 21680 binding in the striatum than [3H]CGS 21680 binding in the
      cortex and less effectively inhibited [3H]R-PIA binding to cortical or striatal
      membranes. Treatment of solubilised cortical membranes with pertussis toxin (50
      microg/ml) decreased [3H]CGS 21680 (30-100 nM) binding which almost fully
      recovered after reconstitution with G(i)/G(o) proteins. The K(i) for displacement
      of [2-3H]-(4{2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin+ ++-5
      ylamino]ethyl}phenol) ([3H]ZM 241385, 1nM) by CGS 21680 was 110 nM (95%CI: 98-122
      nM) in non-treated, 230 (167-292) nM in pertussis toxin (25 microg/ml)-treated
      and 222 (150-295) nM in cholera toxin (50 microg/ml)-treated cortical membranes;
      in contrast, the K(i) for displacement of [3H]-5-amino-7-(2-phenylethyl)-2-(2
      furyl)-pyrazolo(4,3-e)-1,2,4-triazol o(1,5-c)pyrimidine ([3H]SCH 58261, 1 nM) by
      CGS 21680 was 74 (57-91) nM in non-treated, 71 (44-100) nM in pertussis toxin
      treated and 147 (100-193) nM in cholera toxin-treated cortical membranes.
      Finally, CGS 21680 displaced monophasically the binding of the A1 antagonist,
      [3H]8-cyclopentyl-1,3-dipropylxanthine (2 nM), and the A1 agonist, [3H]R-PIA (2
      nM), in 2 or 10 mM Mg(2+)-medium, either at 25 degrees C or 37 degrees C, in
      cortical or striatal membranes. These results indicate that CGS 21680 does not
      bind to A1 receptors and that limbic CGS 21680 binding sites differ from striatal
      like A2A receptors since they couple to G(i)/G(o) proteins, as well as to G(s)
      proteins.

PMID- 10344529
TI  - Comparison between uptake2 and rOCT1: effects of catecholamines, metanephrines
      and corticosterone.
AB  - Active and specialized transmembrane transport systems are responsible for the
      functional inactivation of catecholamines. Uptake2, the classical extraneuronal
      uptake system, and rOCT1, a recently cloned organic cation transporter, share a
      number of properties. The present study was undertaken to investigate putative
      differences between these two transporters that might clarify their relative
      physiological roles. Uptake of [3H]MPP+ ([3H]1-methyl-4-phenylpyridinium) by Caki
      1 cells (to study uptake2) and by primary cultured rat hepatocytes (to study
      rOCT1) was kinetically and pharmacologically characterized. In both cell types,
      [3H]MPP+ was avidly taken up and accumulated. All compounds tested
      (catecholamines, metanephrines and corticosterone) inhibited [3H]MPP+ uptake,
      albeit with different potencies. In Caki-1 cells, the ranking order of inhibitory
      potency was: (-)isoprenaline > (-)adrenaline >> (-)noradrenaline > dopamine.
      Metanephrine and normetanephrine were equipotent. Corticosterone had an IC50 of
      102 nM. In cultured hepatocytes, the ranking order of inhibitory potency was: (
      )isoprenaline > dopamine > (-)adrenaline >> (-)noradrenaline. Metanephrine was
      about seven times more potent than normetanephrine. Corticosterone had an IC50 of
      72 microM, being about 700-fold less potent in inhibiting rOCT1 than uptake2. The
      results showed that uptake2 and rOCT1 can be clearly distinguished on a
      functional basis. On the one hand, uptake2 prefers adrenaline among the
      endogenous catecholamines, whereas rOCT1 has similar affinity for adrenaline and
      dopamine. On the other hand, corticosterone and normetanephrine are significantly
      more potent in inhibiting uptake2 than rOCT1. The results are compatible with a
      possible physiological role of corticosteroids in the modulation of adrenaline
      effects in tissues equipped with uptake2, without significant interference with
      the hepatic and renal excretion of catecholamines.

PMID- 10344530
TI  - Selective activation of beta3-adrenoceptors by octopamine: comparative studies in
      mammalian fat cells.
AB  - Numerous synthetic agonists selectively stimulate beta3-adrenoceptors (ARs). The
      endogenous catecholamines, noradrenaline and adrenaline, however, stimulate all
      the beta-AR subtypes, and no selective physiological agonist for beta3-ARs has
      been described so far. The aim of this study was to investigate whether any
      naturally occurring amine can stimulate selectively beta3-ARs. Since activation
      of lipolysis is a well-known beta-adrenergic function, the efficacy and potency
      of various biogenic amines were compared with those of noradrenaline,
      isoprenaline, and beta3-AR agonists 4-(-{[2-hydroxy-(3-chlorophenyl)ethyl]-amino}
      propyl)phenoxyacetate (BRL 37,344) and (R,R)-5-(2-{[2-(3-chlorophenyl )-2
      hydroxyethyl]-amino} propyl)-1,3-benzo-dioxole-2,2-dicarboxylate (CL 316,243) by
      testing their lipolytic action in white fat cells. Five mammalian species were
      studied: rat, hamster and dog, in which selective beta-AR agonists act as full
      lipolytic agents, and guinea-pigs and humans, in which beta3-AR agonists are less
      potent activators of lipolysis. Several biogenic amines were inefficient (e.g.
      dopamine, tyramine and beta-phenylethylamine) while others (synephrine,
      phenylethanolamine, epinine) were partially active in stimulating lipolysis in
      all species studied. Their actions were inhibited by all the beta-AR antagonists
      tested, including those selective for beta1- or beta2-ARs. Octopamine was the
      only amine fully stimulating lipolysis in rat, hamster and dog fat cells, while
      inefficient in guinea-pig or human fat cells, like the beta3-AR agonists. In rat
      white fat cells, beta-AR antagonists inhibited the lipolytic effect of octopamine
      with a relative order of potency very similar to that observed against CL
      316,243. Competitive antagonism of octopamine effect resulted in the following
      apparent pA2 [-log(IC50), where IC50 is the antagonist concentration eliciting
      half-maximal inhibition] values: 7.77 (bupranolol), 6.48 [3-(2-ethyl-phenoxy)
      1[(1 S)-1,2,3,4-tetrahydronaphth-1-ylaminol]-(2S)2-propanol oxalate, SR 59230A, a
      beta3-selective antagonist], 6.30[erythro-D,L-1(7-lethylindan-4-yloxy)-3
      isopropylamino-+ ++butan-2-ol, ICI 118,551, a beta2-selective antagonist] and
      4.71 [(+/-)-[2-(3-carbomyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1- methyl-4
      trifluoromethyl-2-imidazolyl)-phenoxy]2-propanolmethane sulphonate, CGP 20712A, a
      beta1-selective antagonist]. Octopamine had other properties in common with beta3
      AR agonists: stimulation of oxygen consumption in rat brown fat cells and very
      low affinity in displacing [3H]CGP 12,177 binding to [beta1- or beta2-ARs in dog
      and rat adipocyte membranes. In Chinese hamster ovary (CHO) cells expressing
      human beta3-ARs, octopamine inhibited [125I]ICYP binding with only twofold less
      affinity than noradrenaline while it exhibited an affinity around 200-fold lower
      than noradrenaline in CHO cells expressing human beta1- or beta2-ARs. These data
      suggest that, among the biogenic amines metabolically related to catecholamines,
      octopamine can be considered as the most selective for beta3-ARs.

PMID- 10344531
TI  - Control of mesenteric arterial tone in vitro in humans and rats.
AB  - The majority of the findings concerning arterial physiology and pathophysiology
      originate from studies with experimental animals, while only limited information
      exists about the functional characteristics of human arteries. Therefore, the aim
      of the present work was to compare the control of vascular tone in vitro in
      mesenteric arterial rings of corresponding size (outer diameter 0.75-1 mm) from
      humans and Wistar-Kyoto rats. The relaxations to acetylcholine (ACh) were clearly
      less marked in the mesenteric arteries of humans when compared with rats.
      However, when calcium ionophore A23187 was used as the vasodilator, the
      endothelium-mediated relaxations did not significantly differ between these
      species. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME)
      attenuated the relaxations to ACh and A23187 in both groups. The endothelium
      independent relaxations to the beta-adrenoceptor agonist isoprenaline and the
      nitric oxide (NO)-donor nitroprusside were somewhat lower in human arteries,
      while vasodilation induced by the K+ channel opener cromakalim was similar
      between humans and rats. Arterial contractile sensitivity to noradrenaline and
      serotonin was slightly lower in human vessels, whereas contractile sensitivity to
      KCl was similar between these species. The contractions induced by cumulative
      addition of Ca2+ with noradrenaline as the agonist were effectively inhibited in
      both groups by the calcium channel blocker nifedipine, the effect of which was
      clearly more pronounced in human arteries. In conclusion, the control of vascular
      tone of isolated arteries of corresponding size from humans and rats appeared to
      be rather similar. The most marked differences between these species were the
      impaired endothelium-mediated dilation to ACh and the more pronounced effect of
      nifedipine on the Ca2(+)-induced contractions in human arteries.

PMID- 10344532
TI  - Changes in systemic and regional haemodynamics during 5-HT7 receptor-mediated
      depressor responses in rats.
AB  - The 5-hydroxytryptamine (5-HT)-induced late depressor response in rats is mainly
      mediated by vascular 5-HT7 receptors. The present study was devoted to
      determining the systemic and regional haemodynamic changes during this response,
      with particular emphasis on localising vascular beds that may contribute to the
      increase in total systemic vascular conductance. In vagosympathectomised,
      pentobarbital-anaesthetised rats pretreated with the 5-HT2 receptor antagonist
      ritanserin (50 microg kg(-1), i.v.), 5-HT (1, 3 and 10 ug kg(-1) min(-1) during
      10 min; i.v.) produced a dose-dependent decrease in mean arterial blood pressure
      by up to 46+/-3%. This decrease was accompanied by increases in systemic vascular
      conductance by up to 83+/-15%; cardiac output was unaffected. 5-HT increased
      regional vascular conductance in skeletal muscle, carcass, mesentery/pancreas and
      adrenals by up to 740+/-14%, 117+/-18%, 135+/-26% and 88+/-22%, respectively, but
      decreased 'lung' (mainly arteriovenous anastomotic) conductance by up to 81+/-2%.
      Pretreatment with R(+)lisuride (100 microg kg(-1), i.v.) abolished all 5-HT
      induced systemic and regional haemodynamic effects. In contrast, i.v.
      pretreatment with S(-)lisuride (100 microg kg(-1)) or GR127935 (300 microg kg(
      1)) did not affect the 5-HT-induced systemic haemodynamic changes. The above
      results suggest that hypotension induced via 5-HT7 receptor activation was
      exclusively caused by vasodilatation of the systemic vasculature, confined to
      skeletal muscle, carcass, mesentery/pancreas and adrenal vascular beds.
      Furthermore, this study shows that blockade of vasorelaxant 5-HT7 receptors by
      lisuride is stereoselective.

PMID- 10344533
TI  - Concomitant blockade of P2X-receptors and ecto-nucleotidases by P2-receptor
      antagonists: functional consequences in rat vas deferens.
AB  - In order to assess the consequences of a concomitant blockade of P2X-receptors
      and ecto-nucleotidases, effects of 13 P2-receptor antagonists were investigated
      on contractions of the rat vas deferens elicited by alpha,beta-methylene ATP
      (alpha,beta-MeATP) and ATP and on the removal of ATP from the incubation medium
      by vas deferens tissue. Increasing concentrations of all antagonists reduced and
      finally abolished contractions elicited by alpha,beta-MeATP (3 microM), with IC50
      values ranging from 1.1 to 100 microM. Pyridoxalphosphate-6-azophenyl-2',4'
      disulphonate (PPADS), 6-azophenyl-4-amino-5-hydroxy-naphthalene-1,3-disulphonate
      (NH02), 4,4'-diisothiocyanatostilbene-2,2'-disulphonate (DIDS) and uniblue A also
      progressively reduced and finally abolished contractions elicited by ATP (1 mM).
      8,8'-[Carbonylbis(imino-3, 1-phenylenecarbonyl-imino)]-bis-(1,3,5
      naphthalenetrisulphonate ) (NF023), suramin, pyridoxalphosphate-6-azophenyl-2',5'
      disulphonate (iso-PPADS), trypan blue and reactive blue 19, in contrast, caused
      only partial blockade, by 34-43% maximally; reactive blue 2 and reactive red 2
      had no effect; and 6,6'-(1,1'-biphenyl-4,4'-diylbisazo)-bis-4-amino-5-hydroxy
      naphtha lene-1,3-disulphonate (NH01) and Evans blue even enhanced the response to
      ATP. For antagonists causing full or partial inhibition, the IC50-values against
      ATP were close to those against alpha,beta-MeATP. All antagonists attenuated the
      removal of ATP, with IC25%-values ranging from 0.8 microM to >320 microM. The
      results confirm the frequent combination, in one antagonist molecule, of P2
      receptor blockade and blockade of ecto-nucleotidases. This dual action underlies
      the effect of such compounds on contractions of the vas deferens elicited by ATP
      which, for certain substances (e.g., suramin, reactive blue 2), can be explained
      by a simple model in which the antagonist simultaneously blocks the degradation
      of ATP and a single contraction-mediating receptor (P2X1). Several observations,
      however, do not conform with this model, and the existence of multiple
      contraction-mediating receptors for ATP or multiple, pharmacologically distinct
      ecto-nucleotidases has to be considered.

PMID- 10344534
TI  - Hyperplasia of gastric mucosa in donor rats orally infected with Taenia
      taeniaeformis eggs and in recipient rats surgically implanted with the larvae in
      the abdominal cavity.
AB  - Rats heavily infected with Taenia taeniaeformis larvae in the liver show a
      remarkable increase in their stomach weight, hyperplasia, and hypergastrinemia.
      However, it is unknown what causes these phenomena. Hence, as a preliminary study
      to investigate the importance of larval parasitism in the liver, two experiments
      were done. In the first experiment, 14 donor rats were orally inoculated with
      3,000 T. taeniaeformis eggs. In the second experiment, 136-300 of the larvae
      obtained from the rats were surgically implanted into the abdominal cavity of 7
      recipient rats. Gastrin levels and histopathological changes in the gastric
      mucosa were investigated. In all, 11 donor rats showed hypergastrinemia and
      hyperplasia, 5 recipient rats showed gastric mucosal hyperplasia accompanied by
      excessive mucous cell proliferation, and 2 recipient rats showed
      hypergastrinemia. These results suggest that parasitism of the liver by the
      larvae is not essential for the development of hyperplasia and that factors from
      the larvae might cause these phenomena.

PMID- 10344535
TI  - Postcystic development of Blastocystis hominis.
AB  - A concentrated suspension of Blastocystis hominis cysts was inoculated into
      Jones' medium and removed after 24 h for study of their development at the
      ultrastructural level. The parasite divides in the cyst, and up to three daughter
      cells can be seen. During this process the cyst wall dissolves, leaving behind
      thin membranous remnants. Excystation occurs mostly by the emergence of the
      daughter cells through an aperture in the outer fibrillar coat. Before
      excystation the vacuolar and the granular stages form and the daughter cells
      develop their own fibrillar layer.

PMID- 10344536
TI  - Analysis of the antigenicity in mice of biotinyl enzymes from Anisakis simplex
      and other nematodes.
AB  - We analyzed the antigenicity of biotinyl enzymes contained in somatic extracts
      from Anisakis simplex and other parasite nematodes and show in this report that
      these molecules are an important source of cross-reactivity problems among these
      nematodes. Cross-reactivity was most pronounced among members of the superfamily
      Ascaridoidea. These results suggest that the presence of biotinyl enzymes in
      whole somatic extracts of A. simplex and other parasites may make serodiagnostic
      assays based on this kind of antigenic preparation unreliable.

PMID- 10344537
TI  - Evidence that antisulfatide autoantibodies from rats experimentally infected with
      Trypanosoma cruzi bind to homologous neural tissue.
AB  - Earlier studies in Trypanosoma cruzi-infected rats revealed an increased antibody
      activity against sulfatide, a specific constituent of both myelin sheaths of
      peripheral nerves and T. cruzi epimastigotes. To investigate further the
      characteristics of such anti-sulfatide antibodies, we analyzed their IgG isotypes
      as well as their ability to bind to homologous neural host structures.
      Antisulfatide IgG-enriched fractions were obtained from rats acutely infected
      with T. cruzi. Immunoglobulin isotypes were determined by an enzyme-linked
      immunosorbent assay (ELISA) method to show that IgG2a and, more significantly,
      IgG2b were the predominant isotypes of antisulfatide autoantibodies. Further
      immunofluorescence studies carried out in coronal sections of the rat forebrain
      revealed, in turn, that antisulfatide antibodies were capable of reacting with
      homologous neural tissues. Specific binding of these rat autoantibodies to
      sulfocerebroside on cell surfaces in vivo may in theory play some detrimental
      role, given the reported ability of rat IgG2b to fix complement or to mediate
      antibody-dependent cell-mediated cytotoxicity reactions.

PMID- 10344538
TI  - Importance of the mutation of amino acid 200 of the isotype 1 beta-tubulin gene
      in the benzimidazole resistance of the small-ruminant parasite Teladorsagia
      circumcincta.
AB  - In this work we demonstrated that the acquisition of benzimidazole (BZ)
      resistance in the small-ruminant parasite Teladorsagia circumcincta is linked to
      the selection of individuals that are characterized by a tyrosine (Tyr) at amino
      acid 200 of their isotype 1 beta-tubulin gene. This mutation appears to be
      recessive, since only homozygous mutant (Tyr/Tyr) individuals survived after BZ
      treatment of two resistant populations in which the three genotypes (rr, rs, ss)
      were initially present. In comparison with natural BZ-susceptible populations, a
      decrease in the restriction polymorphism (RFLP) of the isotype 1 beta-tubulin
      gene was observed in natural resistant populations. It seems that this decrease
      in beta-tubulin polymorphism results from the selection of homozygous mutant
      individuals.

PMID- 10344539
TI  - Microneme antigens of Eimeria bovis recognized by two monoclonal antibodies.
AB  - Two IgG1 monoclonal antibodies (mAbs 8-23F9 and 9-21G9) were developed after
      immunization of mice with homogenates of Eimeria bovis first-generation
      merozoites. Both mAbs reacted with antigens in the apical two-thirds of the
      parasites and immune electron microscopy determined the micronemes as targets.
      When tested by immunoblotting, mAb 8-23F9 failed to react with antigens separated
      under reducing conditions; under nonreducing conditions it recognized two
      components of >200 kDa. mAb 9-21G9 bound to antigens of 135 and 180 kDa after
      electrophoresis under reducing conditions and to a series of components when
      separated without reduction. The epitope of mAb 8-23F9 was destroyed by treatment
      of the antigen with endoglycosidase H and removal of phosphocholine (PC) by
      phospholipase C. Since mAb 8-23F9 does not recognize cytidine-linked PC, the data
      suggest that PC in combination with N-linked sugars and/or N-glycans is part of
      its epitope. In the case of mAb 9-21G9, endoglycosidase H did not alter the
      epitope. When E. bovis merozoite antigen was treated with phospholipase C the
      number of mAb 9-21G9-reactive constituents increased, suggesting that PC may
      otherwise mask the epitope. mAb 8-23F9 also bound to the apical area and the
      surface of E. bovis sporozoites and recognized a >200-kDa sporozoite component.
      When sporozoites invaded Vero cells in vitro, epitope-bearing components were
      released onto the host cell surface and became part of the early parasitophorous
      vacuole wall. At day 5 the binding of the mAb was again confined to the
      intracellular parasite. mAb 9-21G9 did not react with sporozoites but recognized
      the apical area of intra-cellular trophozoites on day 5 after invasion of host
      cells in vitro. When testing was done against a variety of other Apicomplexa in
      various assays, the only cross-reaction observed occurred with mAb 8-23F9, which
      bound to a conformationally determined 180-kDa component of Toxoplasma gondii
      cystozoites.

PMID- 10344540
TI  - Oxidative stress and changes in liver antioxidant enzymes induced by experimental
      dicroceliosis in hamsters.
AB  - The purpose of our study was to assess the effects of experimental dicroceliosis
      on the antioxidant defense capability of the liver in hamsters. Studies were
      carried out at 80 and 120 days after infection with an oral dose of 40
      metacercariae of Dicrocoelium dendriticum. The parasitic pathology was
      ascertained by the presence of fluke eggs in feces, increased serum ALT and AST
      activities, and histological findings. The concentration of thiobarbituric acid
      reactive substances (TBARS) and the ratio of oxidized to reduced glutathione
      (GSSG/GSH), measured as markers of oxidative stress, were significantly increased
      [TBARS: +40% and +84% at 80 and 120 days postinfection (p.i.), respectively;
      GSSG/GSH: +200% and +117%]. Dicroceliosis increased Se-dependent glutathione
      peroxidase (GPx) activity in both cytosol (+24% and +46%) and mitochondria (+73%
      and +41%). Superoxide dismutase activity was significantly reduced in cytosol (
      19% and -38%) and mitochondria (-20% and -39%). No significant change was found
      in the activity of Se-independent GPx or catalase. The ratio of glutathione
      peroxidase/glutathione reductase at 80 and 120 days p.i. was increased by 25% and
      63%, respectively. Gamma-glutamyl cysteinyl synthetase activity was increased by
      27% and 20%, respectively. Our data indicate that although dicroceliosis courses
      with activation of antioxidant enzymes and glutathione synthesis, inefficient
      scavenging of reactive oxygen species takes place, resulting in oxidative liver
      damage.

PMID- 10344541
TI  - Effects of the antitubulin drug trifluralin on the proliferation and
      metacyclogenesis of Trypanosoma cruzi epimastigotes.
AB  - Trypanosoma cruzi epimastigotes were exposed to varying micromolar concentrations
      of the dinitroaniline antitubulin trifluralin. The effects of trifluralin on
      parasite proliferation, metacyclogenesis, morphology, and uptake of horseradish
      peroxidase (HRP) were investigated. Parasites exposed to the antitubulin showed
      some ultrastructural alterations, i.e., formation in some parasites of large,
      membrane-delimited vacuoles and a significant decrease in the number of HRP
      positive reservosomes. Whereas there was no perceptible change in the morphology
      of either subpellicular or flagellar microtubules, there was a significant
      inhibition of proliferation and metacyclogenesis at trifluralin concentrations in
      excess of 100 microM. These concentrations were considerably higher than those
      reported to produce similar results in Leishmania spp. and T. brucei brucei.

PMID- 10344542
TI  - Biomphalaria glabrata embryonic cells express a protein with a domain homologous
      to the lectin domain of mammalian selectins.
AB  - We have cloned from Biomphalaria glabrata, the intermediate host of the helminth
      parasite Schistosoma mansoni, a 36-kDa apparent-molecular-mass molecule (BgSel)
      that shares sequence identity with selectins of the cell-adhesion-molecule
      superfamily. BgSel exhibited in its C-terminal part a putative C-type lectin
      domain similar to the selectin lectin domain. Using antibodies to the recombinant
      BgSel protein, we demonstrated the presence of BgSel in snail hemocytes as well
      as in the cell line derived from B. glabrata embryos (Bge). Anti-BgSel antibodies
      specifically recognized a 79-kDa component in Bge-cell-secreted products that was
      supposed to represent the native form of BgSel, as was confirmed after
      glycosidase treatment. Lectins are known to be implicated in recognition
      mechanisms participating in humoral and cellular immunity in molluscs. The
      possible role of BgSel in the interaction between sporocysts and Bge cells,
      particularly in the in vitro model of sporocyst development dependent on Bge cell
      factors, remains to be determined.

PMID- 10344543
TI  - Effect of zinc on Entamoeba histolytica pathogenicity.
AB  - The present study analyzes the effects of zinc on Entamoeba histolytica activity
      and on its pathogenicity. Metal activity was evaluated in vitro with regard to
      the parasite's viability, replication, and adhesion to epithelial cells and in
      vivo with regard to its pathogenicity. The results obtained in vitro show that
      zinc at 1.0 mM concentration does not affect amebic viability; however, it does
      decrease amebic replication and adhesion (P < 0.001). In vivo studies performed
      on a model of experimental liver abscess in the hamster indicate that the
      intraperitoneal administration of a single dose of zinc at 48 h after the
      intrahepatic inoculation of amebic trophozoites significantly inhibits (P <
      0.001) abscess development. The results indicate that zinc alters the
      functionality of the ameba in vitro as reflected by a decrease in replication and
      adhesion and in vivo as manifested by inhibition of amebic pathogenicity.

PMID- 10344544
TI  - Detection of Entamoeba dispar DNA in macaque feces by polymerase chain reaction.
AB  - We used the polymerase chain reaction (PCR) to determine the prevalence of
      Entamoeba histolytica and E. dispar in the wild population of macaque monkeys
      (Macaca fuscata) in Mt. Takasaki, Oita Prefecture, Japan. Of the 101 samples
      collected, 41 (42.57%) were found to be positive for E. dispar. However, no E.
      histolytica was detected from the collected samples. The results of this survey
      demonstrate the high prevalence of E. dispar in macaque monkeys in the study
      area. Moreover, they provide additional baseline information on naturally
      acquired infectious agents of macaque monkeys and offer an accurate tool for
      detection of E. histolytica and E. dispar, which are needed for biomedical
      research using nonhuman primate models.

PMID- 10344545
TI  - Eimeria separata: method for the excystation of sporozoites.
AB  - A method is described for the excystation and collection of infective sporozoites
      of Eimeria separata. The procedure uses conditions that resemble the in vivo
      environment. The first treatment of the oocysts in a 0.4% pepsin/HCl solution
      alters the oocyst wall, which becomes thinner. The second treatment in a 0.4%
      trypsin/0.75% taurocholate solution breaks the oocyst wall and sporocysts are
      released. A third incubation of the oocyst-sporocyst mixture in trypsin-free
      medium with 0.75% taurocholate and an additive of MgCl2 followed by a final
      incubation in RPMI medium supplemented with 1% fetal calf serum yields a
      sporozoite excystation rate of up to 90%.

PMID- 10344546
TI  - A monoclonal antibody reacts species-specifically with amylopectin granules of
      Eimeria bovis merozoites.
AB  - An IgG1 monoclonal antibody (mAb 35B9) developed against first-generation
      merozoites of Eimeria bovis was shown by immunoelectron microscopy to react
      selectively with antigens localized in amylopectin granules. Amylopectin does not
      contribute to the epitope, as enzymatic degradation of carbohydrates in the
      parasite did not alter the binding pattern of mAb 35B9. When tested by
      immunoblotting, despite its organelle specificity the mAb recognized a variety of
      E. bovis merozoite I components with predominant molecules of 135 and 200 kDa.
      The epitope was not affected by treatment with endoglycosidase H; thus, N-linked
      sugar residues should not be involved in it. Alkaline cleavage (beta
      elimination), however, destroyed the epitope; thus, the involvement of O-linked
      carbohydrates cannot be excluded. Treatment of E. bovis merozoite extract with
      phospholipase C changed the binding pattern of mAb 35B9 in a way that suggests
      the presence of phosphorylcholine molecules on several antigens recognized by the
      mAb, albeit not belonging to the epitope but rather masking it. The epitope was
      not found in free sporozoites of E. bovis or young intracellular parasites up to
      day 4 after invasion of cells in vitro, whereas 5-day-old trophozoites were found
      to contain it. It seems to be species-specific, as it could not be shown in
      sporozoites or merozoites of E. tenella or in stages of several other Coccidia.

PMID- 10344547
TI  - Specificity and sensitivity of random amplified polymorphic DNA analysis for the
      identification of single larvae of Trichinella after experimental infection of
      pigs.
AB  - Single muscle larvae (ML) of Trichinella belonging to 5 species and 2 genotypes
      collected from 126 experimentally infected pigs and preserved in 75% ethyl
      alcohol at room temperature were identified by random amplified polymorphic DNA
      (RAPD) analysis to evaluate the specificity and sensitivity of this assay. A
      double-blind protocol was used to ensure that the interpretation of
      electrophoretic patterns after RAPD amplification was not influenced by an
      expected result. RAPD analysis of one larva from each sample showed a sensitivity
      of 100% when only samples with undamaged DNA were considered, and the specificity
      resulted in an 88% match with the species or genotype that had been used to
      infect pigs, whereas the identification reached 100% specificity when an
      additional one to four ML were examined.

PMID- 10344548
TI  - Partial anaerobiosis induces infectivity of Leishmania infantum promastigotes.
AB  - Leishmania infantum stationary-phase promastigotes could acquire infectivity via
      preincubation in a partially anaerobic medium (95% air/5% CO2) for 16 h before
      the infection, whereas promastigotes were efficiently destroyed when no CO2 was
      present. Incubation of L. infantum promastigotes with additional glucose (20 and
      50 mM) greatly increased infection parameters in the absence of CO2; this is
      consistent with a "reverse Pasteur effect." Results showed that culture at 33
      degrees C permitted survival and amastigote multiplication (a nearly 10-fold
      increase in amastigotes as compared with those observed in 37 degrees C
      cultures). This finding was obtained with the two strains of L. infantum tested
      (Doba and PB75).

PMID- 10344549
TI  - Characterization of Giardia lamblia groups A and B from North India by isoenzyme
      and random amplified polymorphic DNA analysis.
AB  - Giardia lamblia (syn. G. intestinalis) infection in young adults leads to
      acute/chronic diarrhea in some individuals and is asymptomatic in others.
      Recently, G. lamblia strains have been characterized as group A (symptomatic) and
      group B (asymptomatic or control) by advanced isoenzyme and molecular biology
      studies. In the present brief pilot study, ten G. lamblia isolates obtained from
      five symptomatic (group A) and five asymptomatic (group B) persons were
      characterized by isoenzyme and random amplified polymorphic DNA (RAPD) analysis.
      Isoenzyme analysis demonstrated remarkable homogeneity in seven enzyme patterns,
      the exception, being that of phosphoglucomutase, for which two zymodemes (I and
      III) were observed. In contrast, RAPD analysis showed homogeneity for eight
      primers; exceptions were two primers, A02 and B05, which separated group A G.
      lamblia isolates into two rapdemes (A(R1) and A(R2)) and group B G. lamblia
      isolates into four rapdemes (B(R1), B(R2), B(R3) and B(R4)). Further phenetic
      analysis showed average genetic distances of 0.105 within group A and 0.121
      within group B G. lamblia isolates according to Jaccord's distance scale, which
      suggests that both lineages appear to consist of a range of variants with no
      significant (P < 0.05) genetic diversity. The two techniques demonstrated a
      positive association with regard to differentiation between group A and group B
      G. lamblia isolates. These very preliminary results indicate that RAPD analysis
      could be a potentially useful substitute for isoenzyme analysis.

PMID- 10344551
TI  - Reticulocytes and solvents: an epidemiological study.
AB  - OBJECTIVES: The aim of the study was to look for a rise in reticulocyte levels in
      workers exposed to various solvents, in comparison to non exposed control
      subjects. METHODS: A cohort of exposed workers was selected on the criterion of
      exposure to solvents, among employees regularly attending the Centre of
      Occupational Medicine of Molsheim (France) during the second trimester of 1995.
      Controls were selected over the same period from the voluntary blood donors of
      the Transfusion Centre of Strasbourg (France). Complete blood counts and flow
      cytometric reticulocyte counts were determined in all blood samples. RESULTS:
      Analysis of the haematological parameters displaying significant differences
      revealed the existence of higher levels of circulating reticulocytes and
      lymphocytes in workers exposed to solvents than in control subjects. These
      variations did not appear to depend on the intensity or length of exposure.
      CONCLUSIONS: This study demonstrates the occurrence of an increase in circulating
      reticulocytes in relation to occupational exposure to solvents, without as yet
      providing sufficient information to allow elucidation of the underlying
      mechanism. An increase in total circulating lymphocytes was observed in the same
      group of exposed workers. The concomitant rise in absolute values of these two
      elements of the blood counts is to our knowledge described here for the first
      time in an epidemiological study.

PMID- 10344550
TI  - Low dose T-cell lymphocyte infusion combined with marrow T-cell depletion as
      prophylaxis of acute graft vs host disease for HLA identical sibling bone marrow
      transplantation.
AB  - T-cell depletion (TCD) of the bone marrow graft remains the most effective method
      to prevent severe graft versus host disease after allogeneic bone marrow
      transplantation. Early studies of HLA-identical sibling transplants showed that
      although T-cell depletion decreased GVHD, T-cell depleted transplants had higher
      risks of graft failure and leukemia relapse, leukemia free survival (LFS) was not
      improved compared to non-T-cell depleted transplants. In order to avoid graft
      failure and increased risk of relapse associated with this approach, we initiated
      a pilot study of T-cell depletion of the marrow graft combined with reinfusion of
      a fixed quantity of CD2+ peripheral blood T-cells. Depletion technique consisted
      in negative purging using CD2 and CD7 monoclonal antibodies (MoAbs) followed by
      rabbit complement cytolysis. This approach was associated with an intensified
      conditioning regimen using total body irradiation, high-dose cytosine arabinoside
      and melphalan (TAM) for all but one patient. Twenty-one patients were included
      with a mean age of 40 years. Only one acute severe Graft Versus Host Disease
      (GVHD) was observed and all patients engrafted. At 63 months, probability of
      survival is 42.86% with a relapse risk of 19.89%, two patients died from B-cell
      lymphoproliferative disease, seven other died from the procedure partially
      because of the use of the TAM as pretransplant regimen. This approach is being
      pursued by a gene therapy trial using herpes-simplex - 1 thymidine kinase gene
      expressing peripheral donor T-cells.

PMID- 10344552
TI  - Evaluation of the monocyte counting by the ABX Vega. Comparison with the manual
      method and fluoro-flow cytometry.
AB  - This study allowed evaluation and comparison of the precision (20 samples) and
      agreement (200 samples) of the relative and absolute values of the monocyte count
      using three methods: microscopic, flow cytometry and the automated ABX Vega
      hematology analyzer. Flow cytometry is the most precise method, even if the
      coefficient of variation of the automated analyzer is very similar. The
      coefficient of correlation between the ABX Vega and the flow cytometer is very
      satisfactory (r=0.8042). This study of the agreement also made it possible to
      confirm the difficulty that automated hematology analyzers have in
      differentiating between some granulocytes and monocytes and their propensity to
      overstimate the latter when the sample includes immature forms of granulocytes.
      This fact stresses the importance of the microscopic method, despite its lack of
      precision. The observed discrepancies did not lead to any difficulties in
      clinical interpretation; however, this finding should be taken into
      consideration, particularly in myleoproliferative syndromes and the laboratory
      monitoring of chemotherapy.

PMID- 10344553
TI  - High dose chemotherapy with haematopoietic rescue in breast cancer.
AB  - High dose chemotherapy (HDC) for breast cancer has been used for some 15 years.
      All studies demonstrate a high response rate with approximately 20% prolonged (>
      3 years) disease free survival among patients who achieved complete remission
      (CR) following HDC. Debate about the value of HDC has centered around the issue
      of patient selection, including selection by chemotherapy response. Results of
      one randomised, published trial of HDC versus conventional dose treatment,
      however, demonstrate a better outcome for the HDC group with a higher CR rate and
      prolongation of survival. These results have been updated and continue to show a
      stable proportion of long term complete remitters. In the adjuvant setting one
      recent trial has demonstrated no benefit from HDC 'consolidation' in 'high-risk'
      patients. Results of a number of other studies are pending and will help to
      settle this issue. The article reviews issues including patient selection by
      prior chemotherapy response, other methods of selection, the chemotherapy
      regimens used and the timing of HDC. While additional and confirmatory studies
      are required HDC for breast cancer remains an effective treatment modality.

PMID- 10344554
TI  - Remote tumor cells in the case of breast cancers: significance of their presence
      for prognosis [corrected].
AB  - Through two clinical studies, tumor cells were searched for in the bone biopsies
      and cytapherisis of patients suffering from inflammatory tumors and who had
      undergone intensive therapy and autografts (Pegase 2 program). In these studies
      we used immunocytochemical test with two monoclonal antibodies. The results have
      shown the presence of tumor cells in 14% of the patients (respectively 18%), with
      no correlation to the appearance of metastases after 4 years in the first study.
      Nevertheless, the presence of these tumor cells seems to be an important factor
      in the number of relapses. It seems important to develop research into tumor
      contamination especially in the selection of grafts over the next few years.

PMID- 10344555
TI  - [Intensive chemotherapy and autograft of hematopoietic stem cells in the
      treatment of metastatic cancer: results of the national protocol Pegase 04].
AB  - We report hereby the results of the french multicentric randomized PEGASE 04
      protocol established to evaluate the impact on survival of high-dose chemotherapy
      over conventional chemotherapy for MBC patients. PATIENTS AND METHODS: Inclusion
      criteria were: age < or = 60 year, PS < 2, adenocarcinoma initially metastatic or
      in first relapse, chemosensitive disease. Randomization was done after 4-6
      courses of conventionnal chemotherapy between high-dose (Mitoxantrone, 45 mg/m2,
      Cyclophosphamide: 120 mg/kg, Melphalan: 140 mg/m2), and the pursuit of the same
      conventionnal chemotherapy. Between 09/92 and 12/96, 61 chemosensitive patients
      were enrolled: 29 were referred to standard chemotherapy, 32 to intensive
      therapy. At randomization, 13 pts (21.3%) were in complete response and 48 in
      partial response. RESULTS: The median progression-free survivals were 20 and 35.3
      months in the standard and intensive groups (p=0.06). The relapse rates were
      respectively 79.3% vs 50.8% at 3 years and 90.8% vs 90.7% at 5 years. The median
      overall survivals were 20 and 43.4 months, with an overall survival rate of 18.5%
      vs 29.8% at 5 years (p=0.12). CONCLUSION: The CMA regimen could prolong the
      progression-free survival of MBC patients, however without any significant impact
      on overall survival.

PMID- 10344556
TI  - [Ex-vivo expansion of hematopoietic stem cells: study in the primate model].

PMID- 10344557
TI  - The role of autologous hematopoietic progenitor and cell reinfusion for intensive
      chemotherapy in women with poor-prognosis breast cancer. Clinical studies with ex
      vivo expanded cells produced with the Aastrom Replicell technology.
AB  - In recent years, we have initiated two clinical studies, to evaluate the
      usefulness of ex-vivo expanded cells in patients with breast cancer who receive
      sequential high-dose chemotherapy. Ex-vivo expanded cells were produced from
      autologous cryopreserved bone marrow nucleated cells, using a biomedical device.
      The Aastrom Replicell system cultures cells in animal serum-replete medium, with
      a combination of flt3-L, PIXY321 and Epo, for 12 days. The initial pilot trial
      was set up to establish the feasibility and safety of the technique: 6 patients
      completed the study. An ongoing randomized study searches to establish whether ex
      vivo expanded cells provide a clinical benefit.

PMID- 10344558
TI  - Ex-vivo expansion of hematopoietic progenitor cells: preliminary results in
      breast cancer.
AB  - Ex-vivo expanded progenitor cells have been proposed as a source of cells to
      support high-dose chemotherapy and to decrease or eliminate the period of
      neutropenia following transplantation. To date, no clinical studies using ex vivo
      expanded cells, have demonstrated any decrease in the time to neutrophil or
      platelet recovery, although a number of clinical studies have been performed
      using a variety of growth factor cocktails and culture conditions. Over the past
      6 years we have developed a static culture system that results in optimal
      expansion of myeloid progenitor cells. We have initiated a clinical study to
      evaluate this culture system in breast cancer patients receiving peripheral blood
      progenitor cells (PBPC) to support high-dose chemotherapy. CD34 selected cells
      were cultured for 10 days in 800 ml of defined media (Amgen Inc.) containing 100
      ng/ml each of rhSCF, rhG-CSF and rhMGDF in 1L teflon bags (American Fluoroseal)
      at 20,000 to 50,000 cells per ml. After culture the cells were washed with 3
      volumes of PBS to remove all media and growth factors and reinfused on day 0 of
      transplant followed by daily administration of rhG-CSF. On day +1 the patients
      received an unexpanded PBPC product to ensure the durability of the graft.
      Patients transplanted with expanded PBPC cells recovered neutrophil counts (ANC >
      500/microl) as early as day 4 post transplant with a median of 6 days (range 4 to
      14 days). In comparison, our historical control group of patients (N=175) had a
      median time to neutrophil engraftment of 9 days (range 7 to 24 days). A second
      cohort of patients were transplanted with expanded cells alone and a similar
      rapid engraftment was obtained. The first patients are now over 70 days post
      transplant with durable engraftment. No effect on platelet recovery has been
      observed in any patients to date. These data demonstrate that PBPC expanded under
      the conditions defined can significantly shorten the time to engraftment of
      neutrophils.

PMID- 10344559
TI  - Phosphatoquinones A and B, novel tyrosine phosphatase inhibitors produced by
      Streptomyces sp.
AB  - Phosphatoquinones A and B were isolated from the cultured broth of Streptomyces
      sp. TA-0363 and their structures were elucidated by spectroscopic analyses.
      Phosphatoquinones A and B inhibited the protein tyrosine phosphatase activity
      prepared from human Ball-1 cells with IC50 of 28 microM and 2.9 microM,
      respectively.

PMID- 10344560
TI  - Purification and characterization of 2-deoxy-scyllo-inosose synthase derived from
      Bacillus circulans. A crucial carbocyclization enzyme in the biosynthesis of 2
      deoxystreptamine-containing aminoglycoside antibiotics.
AB  - The biosynthesis of 2-deoxystreptamine, the central aglycon of a major group of
      clinically important aminoglycoside antibiotics, commences with the initial
      carbocycle formation step from D-glucose-6-phosphate to 2-deoxy-scyllo-inosose.
      This crucial step is known to be catalyzed by 2-deoxy-scyllo-inosose synthase,
      which has not yet been characterized so far. Reported in this paper is the first
      purification of 2-deoxy-scyllo-inosose synthase from butirosin-producing Bacillus
      circulans SANK 72073 to electrophoretic homogeneity. The enzyme was isolated as a
      heterodimeric protein comprising from a 23 kDa- and a 42 kDa polypeptide chains.
      The Km of the enzyme for D-glucose-6-phosphate was estimated to be 9.0 x 10(-4) M
      and that for NAD+ 1.7 x 10(-4) M, kcat for D-glucose-6-phosphate being 7.3 x 10(
      2) s(-1). The presence of Co2+ was essential for the enzyme activity, but Zn2+
      was totally inhibitory. While the reaction mechanisms are quite similar, 2-deoxy
      scyllo-inosose synthase appears to be distinct from dehydroquinate synthase in
      the shikimate pathway, with respect to the quaternary structure, metal ion
      requirement, and the kinetic parameters.

PMID- 10344561
TI  - Isolation and characterisation of a prenylated p-terphenyl metabolite of
      Aspergillus candidus possessing potent and selective cytotoxic activity; studies
      on mechanism of action.
AB  - We describe the discovery and properties of a prenylated p-terphenyl metabolite
      of the fungus Aspergillus candidus. The compound (1) possesses potent cytotoxic
      activity against a range of tumour and other hyper-proliferative cell lines. Cell
      cycle analysis shows that in mouse keratinocyte (BALB/MK) cells treated with 1,
      the cell cycle is arrested in early S phase, indicative of an antimetabolite
      effect. Furthermore, cellular cytotoxicity can be reversed by addition of
      exogenous pyrimidine but not purine nucleosides to the cell culture medium. It is
      therefore likely that compound 1 selectively inhibits pyrimidine biosynthesis,
      and it is this property which accounts for its potent cytotoxic properties.

PMID- 10344562
TI  - Biosynthesis of polyketomycin produced by Streptomyces diastatochromogenes Tu
      6028.
AB  - The biosynthesis of polyketomycin was investigated by feeding 13C-labeled acetate
      and propionate to the growing cultures of Streptomyces diastatochromogenes Tu
      6028. 13C NMR spectral analysis demonstrated the polyketide origin of the
      aglycone and the dimethylsalicyloyl moieties. The O-methyl group and 6-CH3 of the
      aglycone as well as 3B-CH3 of L-axenose and 3C-CH3 of the salicyloyl residue were
      labeled by feeding L-[methyl-13C]methionine. Both deoxysugars emerged from D
      glucose. The biosynthesis of the aglycone and the assembly of the glycoside are
      discussed. The polyketomycin producing strain may be a candidate for further
      exploration in combinatorial biosynthesis.

PMID- 10344563
TI  - Production of nikkomycins Bx and Bz by mutasynthesis with genetically engineered
      Streptomyces tendae Tu901.
AB  - The previously described Streptomyces tendae nikC::aph mutant was used to
      mutasynthesize nikkomycins Bx and Bz. The mutant is deficient in L-lysine 2
      aminotransferase, which transaminates lysine to form piperideine 2-carboxylate,
      the precursor of the peptidyl side chain of the biologically active nikkomycins
      I, J, X, and Z, and is therefore unable to produce these nikkomycins. The mutant
      accumulates the biologically inactive biosynthetic nucleoside precursors
      nikkomycins Cx and Cz. Resting cell cultures of the mutant fed with benzoic acid
      produced the biologically active nikkomycins Bx and Bz, which contain 2-amino-4
      hydroxy-3-methyl-4-(4'-hydroxyphenyl)butanoic acid as the peptidyl side chain.
      The structures of nikkomycins Bx and Bz were confirmed by mass spectrometry and
      NMR. Nikkomycins Bx and Bz exhibit significantly higher pH stability than their
      analogues nikkomycins X and Z.

PMID- 10344564
TI  - Bioconversion of milbemycin-related compounds: biosynthetic pathway of
      milbemycins.
AB  - Streptomyces hygroscopicus subsp. aureolacrimosus SANK 60286 and SANK 60576
      produce many kinds of milbemycins. Among them, milbemycin alpha11, alpha14, A3,
      and A4 have the most effective acaricidal activity. In this study, we
      investigated the terminal biosynthetic pathway to milbemycin alpha14 and A4 which
      accumulated as the final products in these strains. Using cerulenin, a specific
      inhibitor of fatty acid and polyketide biosynthesis, we conducted bioconversion
      experiments with cultures of several mutants, including milbemycin A4- and
      alpha14-producing strains. The bioconversions of milbemycin beta6 to milbemycin
      A4 and milbemycin A4 to milbemycin alpha14 could be identified. For the
      biosynthesis of milbemycin A4 from milbemycin beta6 in the milbemycin A4-high
      producing strain, there appeared to be two separate pathways exhibiting different
      sequences of furan ring formation and C-5 keto reduction steps.

PMID- 10344565
TI  - Biosynthesis of the pyrroindomycins by Streptomyces rugosporus LL-42D005;
      characterization of nutrient requirements.
AB  - Streptomyces rugosporus LL-42D005 was shown to produce the novel pyrroindomycin
      antibiotics. Production of pyrroindomycin (alpha) and chloro-pyrroindomycin
      (beta) was characterized in a semi-defined fermentation medium containing
      glucose, casein, phosphate, vitamins and minerals. Accumulation of pyrroindomycin
      beta increased with increasing concentrations of glucose, reaching maximum titers
      at approximately 5g/L glucose. Glucose concentrations greater than 7.5 g/L
      decreased pyrroindomycin beta yields. Inhibition of pyrroindomycin accumulation
      at higher glucose concentrations could be reversed by increasing the casein
      concentration. Ammonium chloride, arginine or glutamine could replace casein as
      the sole nitrogen source for growth and pyrroindomycin production. Glucose,
      fructose or mannitol were utilized as the sole carbon source, while sucrose,
      maltose, glycerol, corn oil and starch were poorly metabolized. Incubation of
      this isolate in a vitamin-deficient medium resulted in a delay in growth and
      pyrroindomycin production; this delay was eliminated by the addition of biotin.
      Addition of L-tryptophan to the medium resulted in the production of
      pyrroindomycin alpha as the major species.

PMID- 10344566
TI  - Time and concentration dependent influence of dirithromycin on neutrophils
      oxidative burst.
AB  - Dirithromycin is a 14-membered macrolide antibiotic, well known to yield high
      intragranulocytic levels after several hour exposure. We chose therefore to
      investigate oxidative metabolism after prolonged incubation periods with
      neutrophils. Neutrophil generation of reactive oxygen species, represented by
      superoxide anion, was assessed after fMLP or Staphylococcus aureus-induced
      activation of the respiratory burst. Cellular uptake of the drug was assessed
      concurrently, in order to attempt a correlation with time-dependent modifications
      of the cellular oxidative status. For 1 hour exposure time, a pro-oxidant effect
      was reported for lower concentrations, achievable during therapeutic
      administration, whereas the highest ones promoted a potent anti-oxidant effect.
      After prolonged incubation times, the anti-oxidant effect alone was reported,
      with time-dependent modifications of IC50 values. These values could be
      correlated with intracellular accumulation of the drug. The anti-inflammatory
      activity reported here for high dirithromycin concentrations, could be
      nevertheless clinically relevant, since dirithromycin cellular uptake extends
      beyond 4 hours.

PMID- 10344567
TI  - (-)-Phenylahistin arrests cells in mitosis by inhibiting tubulin polymerization.
AB  - (-)-Phenylahistin, a fungal diketopiperazine metabolite composed of phenylalanine
      and isoprenylated dehydrohistidine, arrested cells in mitosis and inhibited the
      proliferation of A549 cells. The microtubule network in A549 cells was disrupted
      by (-)-phenylahistin, which also inhibited the polymerization of both microtubule
      protein from bovine brain and phosphocellulose-purified tubulin in vitro.
      Competitive binding studies indicated that (-)-phenylahistin interacted with the
      colchicine binding site on tubulin but not with the vinblastine binding site.

PMID- 10344568
TI  - Structure-activity relationships of carbapenems to the antagonism of the
      antipseudomonal activity of other beta-lactam agents and to the beta-lactamase
      inducibility in Pseudomonas aeruginosa: effects of 1beta-methyl group and C-2
      side chain.
AB  - The antagonism of the antipseudomonal activity of ceftazidime by meropenem (1a)
      was much less than those by imipenem (2a) and panipenem (2b). To reveal the major
      structural features of carbapenem compounds responsible for the antagonism, we
      investigated the structure-activity relationships of carbapenems to their
      antagonism of the antipseudomonal activity of ceftazidime and to their beta
      lactamase-inducibility in P. aeruginosa. The antagonistic effect of 1a was less
      than that of desmethyl-meropenem (1b). Two other meropenem-analogues (3, 4), with
      the highly basic C-2 side chain, showed greater antagonistic effects than that of
      1a, which has a weakly basic C-2 side chain. The beta-lactamase-inducibility of
      1a in P. aeruginosa was lower than those of 2a, 1b and 4. These results indicated
      that the antagonism of the antipseudomonal activity of ceftazidime by carbapenems
      was due to the induction of beta-lactamase in P. aeruginosa. As a result of the
      study on the structure-activity relationships, we clarified that the introduction
      of a 1beta-methyl group and/or the reduction of the basicity (cationic character)
      of the C-2 side chain in carbapenem skeleton decreased the antagonistic effect of
      carbapenems on the antipseudomonal activity of ceftazidime resulted mainly from
      the decreasing the beta-lactamase inducibility.

PMID- 10344569
TI  - First total synthesis of N-4909 and its diastereomer; a stimulant of
      apolipoprotein E secretion in human hepatoma Hep G2 cells.
AB  - Both (R)- and (S)-3-hydroxy-13-methyltetradecanoic acids were prepared via a
      lipase-catalyzed enantioselective acylation. The total synthesis of N-4909 and
      its diastereomer were achieved by a coupling of either (R)- or (S)-3-hydroxy-13
      methyltetradecanoic acid moiety with a hexapeptide moiety and by a cyclization
      with HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
      hexafluorophosphate) and HOAt (1-hydroxy-7-azabenzotriazole) in a high dilution
      condition. The R configuration of 3-hydroxy-13-methyltetradecanoic acid was found
      to be important for stimulating the activity of apolipoprotein E secretion in
      human hepatoma Hep G2 cells.

PMID- 10344570
TI  - Structure-specific inhibition of cholesteryl ester transfer protein by
      azaphilones.
AB  - The effect of thirteen different fungal azaphilones, which have a common 6-iso
      chromane-like ring, was tested on cholesteryl ester transfer protein (CETP)
      activity in vitro. Chaetoviridin B showed the most potent inhibitory activity
      with an IC50 value of < 6.2 microM, followed by sclerotiorin with an IC50 value
      of 19.4 microM. Rotiorin, chaetoviridin A and rubrorotiorin had moderate
      inhibitory activity (IC50 ; 30 approximately 40 microM), but others showed very
      weak or no inhibitory activity. The relationship between the structures and their
      inhibitory activity indicated that the presence of an electrophilic ketone(s)
      and/or enone(s) at both C-6 and C-8 positions in the isochromane-like ring is
      essential for eliciting CETP inhibitory activity. The transfer activity of both
      CE and TG was inhibited by sclerotiorin to approximately the same extent (IC50:
      14.4 and 10.3 microM, respectively). A model of the reaction suggested that
      sclerotiorin reacts with a primary amine of amino acids such as lysine in the
      protein to form a covalent bond.

PMID- 10344571
TI  - 11-Keto-9(E),12(E)-octadecadienoic acid, a novel fatty acid that enhances
      fibrinolytic activity of endothelial cells.

PMID- 10344572
TI  - SNA-4606-1, a new member of elaiophylins with enzyme inhibition activity against
      testosterone 5 alpha-reductase.

PMID- 10344573
TI  - BE-40665D, a new antibacterial antibiotic produced by an Actinoplanes sp.

PMID- 10344574
TI  - Korormicin, an antibiotic specific for gram-negative marine bacteria, strongly
      inhibits the respiratory chain-linked Na+-translocating NADH: quinone reductase
      from the marine Vibrio alginolyticus.

PMID- 10344575
TI  - In vitro anti-methicillin-resistant Staphylococcus aureus activity found in
      extracts of marine algae indigenous to the coastline of Japan.

PMID- 10344576
TI  - Structural elucidation of a novel erythromycin, 13-cyclopentyl-13-desethyl
      erythromycin B, from a recombinant Saccharopolyspora erythraea strain, NRRL 2338
      pIG/1.

PMID- 10344577
TI  - Absolute stereochemistry determination of 16-methyloxazolomycin produced by a
      Streptomyces sp.

PMID- 10344578
TI  - Adxanthromycin: a new inhibitor of ICAM-1/LFA-1 mediated cell adhesion from
      Streptomyces sp. NA-148.

PMID- 10344579
TI  - Production of erythromycin E by pathogenic Nocardia brasiliensis.

PMID- 10344580
TI  - How to use light and dark to produce circadian adaptation to night shift work.
AB  - The circadian rhythms of night shift workers do not usually adjust to their
      unusual work and sleep schedules, reducing their quality of life and producing
      potentially dangerous health and safety problems. This paper reviews field
      studies of simulated night work in which shifted light-dark cycles were
      constructed with artificial bright or medium-intensity light to produce circadian
      adaptation, ie the shifting of circadian rhythms to align with night work and day
      sleep schedules. By using these studies we describe fundamental principles of
      human circadian rhythms relevant to producing circadian adaptation to night shift
      work at a level designed for the reader with only a basic knowledge of circadian
      rhythms. These principles should enable the reader to start designing work/sleep
      light/dark schedules for producing circadian adaptation in night shift workers.
      One specific schedule is presented as an example. Finally, we discuss phase
      response curves to light and clarify common misconceptions about the production
      of circadian rhythm phase shifts.

PMID- 10344581
TI  - Medical problems in adult women with Turner's syndrome.
AB  - Turner's syndrome, the most common chromosome abnormality in females, is the
      consequence of complete absence or partial deletion of one X chromosome. It is
      associated with a wide spectrum of clinical features of which short stature and
      gonadal dysgenesis are almost invariably present. Women with Turner's syndrome
      have a reduced life expectancy primarily as a result of cardiovascular disease.
      They are also susceptible to a number of other disorders including autoimmune
      thyroiditis, osteoporosis, renal and gastrointestinal disease. Thus, women with
      Turner's syndrome should be followed up by a multidisciplinary team of physicians
      with an interest in the disorder following discharge from paediatric care. This
      review aims to highlight the problems associated with Turner's syndrome in
      adulthood and to discuss important management strategies.

PMID- 10344582
TI  - Pregnancies in women with Turner's syndrome.
AB  - Ovarian failure is a typical feature in Turner's syndrome. Therefore, hormone
      replacement therapy (HRT) is necessary to achieve the development of normal
      female sexual characteristics and to prevent cardiovascular complications and
      osteoporosis. Spontaneous puberty occurs in 5-10% of women with Turner's
      syndrome, and 2-5% of them become pregnant spontaneously. Sexually active young
      women with Turner's syndrome need contraception. It can be administered as
      contraceptive pills, which also serve as HRT. Oocyte donation is now a treatment
      option for infertility of these women. Excellent results have been obtained with
      46% of embryo transfers resulting in pregnancy. The pregnancies carry high risks
      and have to be followed up carefully. The children born following oocyte donation
      have no additional risks. Risks can be reduced by transferring only one embryo at
      a time to the uterus, thus avoiding twin pregnancies. Ovarian tissue from young
      girls with Turner's syndrome could be cryopreserved for infertility treatment in
      the future, but the optimal age of ovarian biopsy has to be studied, and methods
      of replantation and maturation of oocytes in vitro have still to be developed.
      Fertility counselling has become important in the treatment of girls with
      Turner's syndrome.

PMID- 10344583
TI  - Cloning of the APECED gene provides new insight into human autoimmunity.
AB  - Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the
      only autoimmune disease characterized so far that is caused by a defect in a
      single gene. We have recently isolated the defective gene in this disease by
      positional cloning and have identified several different mutations in APECED
      patients. This novel gene, AIRE, contains two plant homeodomain (PHD)-type zinc
      finger motifs and a newly described putative DNA-binding domain SAND. We have
      further shown that the protein encoded by the AIRE gene is localized to the
      nuclear body-like structures of cell nuclei. Similar discrete speckles within the
      nucleus have been suggested to be involved in the regulation of transcription,
      oncogenesis and differentiation of cells. Together with the predicted structural
      features of the APECED protein the new data obtained both in vitro and ex vivo
      suggest that this protein participates in the regulation of gene expression in a
      restricted set of tissues and cells.

PMID- 10344584
TI  - Differences in gene expression during sleep and wakefulness.
AB  - Compared with our understanding of the electrophysiological correlates of sleep
      and wakefulness, the search for correlates at the molecular level is still in its
      infancy. However, the evidence obtained so far supports the hypothesis that
      reliable molecular correlates do exist. As will be summarized in this review,
      levels of receptor binding, second messengers and protein phosphorylation differ
      between sleep and wakefulness. Moreover, compelling data obtained in different
      animal species suggest that the transition between sleep and wakefulness is
      accompanied by significant changes in gene expression. Many immediate early
      genes, transcription factors, plasticity-related genes and mitochondrial genes
      are expressed at higher levels in wakefulness than in sleep, while a few still
      unknown genes are up-regulated during sleep. The ongoing systematic screening of
      gene expression across behavioural states should prove crucial in elucidating the
      regulatory mechanisms of sleep homeostasis and the functions of sleep.

PMID- 10344585
TI  - Adenosine in sleep and wakefulness.
AB  - Sleep propensity increases in the course of wakefulness: the longer the previous
      wakefulness period is, the longer and deeper (measured as delta power in EEG
      recordings) is the following sleep. The mechanisms that regulate the need of
      sleep at the cellular level are largely unknown. The inhibitory neuromodulator,
      adenosine, is a promising candidate for a sleep-inducing factor: its
      concentration is higher during wakefulness than during sleep, it accumulates in
      the brain during prolonged wakefulness, and local perfusions as well as systemic
      administration of adenosine and its agonists induce sleep and decrease
      wakefulness. Adenosine receptor antagonists, caffeine and theophylline, are
      widely used as stimulants of the central nervous system to induce vigilance and
      increase the time spent awake. Our hypothesis is that adenosine accumulates in
      the extracellular space of the basal forebrain during wakefulness, increasing the
      sleep propensity. The increase in extracellular adenosine concentration decreases
      the activity of the wakefulness-promoting cell groups, especially the cholinergic
      cells in the basal forebrain. When the activity of the wakefulness-active cells
      decreases sufficiently sleep is initiated. During sleep the extracellular
      adenosine concentrations decrease, and thus the inhibition of the wakefulness
      active cells also decreases allowing the initiation of a new wakefulness period.

PMID- 10344586
TI  - Circadian regulation of human sleep and age-related changes in its timing,
      consolidation and EEG characteristics.
AB  - The light-entrainable circadian pacemaker located in the suprachiasmatic nucleus
      of the hypothalamus regulates the timing and consolidation of sleep by generating
      a paradoxical rhythm of sleep propensity; the circadian drive for wakefulness
      peaks at the end of the day spent awake, ie close to the onset of melatonin
      secretion at 21.00-22.00 h and the circadian drive for sleep crests shortly
      before habitual waking-up time. With advancing age, ie after early adulthood,
      sleep consolidation declines, and time of awakening and the rhythms of body
      temperature, plasma melatonin and cortisol shift to an earlier clock hour. The
      variability of the phase relationship between the sleep-wake cycle and circadian
      rhythms increases, and in old age sleep is more susceptible to internal arousing
      stimuli associated with circadian misalignment. The propensity to awaken from
      sleep advances relative to the body temperature nadir in older people, a change
      that is opposite to the phase delay of awakening relative to internal circadian
      rhythms associated with morningness in young people. Age-related changes do not
      appear to be associated with a shortening of the circadian period or a reduction
      of the circadian drive for wake maintenance. These changes may be related to
      changes in the sleep process itself, such as reductions in slow-wave sleep and
      sleep spindles as well as a reduced strength of the circadian signal promoting
      sleep in the early morning hours. Putative mediators and modulators of circadian
      sleep regulation are discussed.

PMID- 10344587
TI  - Effects of sex steroids on sleep.
AB  - Sex steroid secretions are generally synchronous with the circadian rhythm and
      sleep, and there is evidence that prolactin secretion is sleep-dependent.
      Polysomnographically assessed changes in sleep during the menstrual cycle are
      characterized by increased EEG activity in the 14-15-Hz (sleep spindle) range in
      the luteal phase accompanying an increase in core temperature. There are no other
      consistent changes in sleep architecture associated with the menstrual cycle. The
      hot sweats which disturb sleep in menopausal women are attributable to oestrogen
      deficiency and are reduced by oestrogen replacement therapy. Although it is often
      assumed that the psychological changes during the menopause are attributable to
      chronic sleep disturbance caused by hot sweats, the evidence for this is
      uncertain. Sex steroids have also been shown to have a role in the aetiology of
      obstructive sleep apnoea and its treatment. It is clear that the sex steroids are
      all implicated in sleep and thermoregulatory processes, although we cannot as yet
      define their precise roles.

PMID- 10344588
TI  - Transcriptional activity in the brain during sleep deprivation.
AB  - Molecular biological techniques combined with experimental sleep deprivation have
      revealed alterations in gene transcriptional activity of several proteins which
      may mediate the effects of prolonged wakefulness in the brain. During sleep
      deprivation gene transcription is altered in neuronal systems known to
      participate in the regulation of vigilance and sleep, ie the norardenergic and
      cholinergic systems, and several neuropeptides and cytokines. The study of
      immediate early genes during sleep deprivation has revealed increased
      transcriptional activity in those brain areas that are active during wakefulness.
      Systemic search for alterated levels of messenger RNA in sleep-deprived brain has
      revealed signal transduction proteins and metabolic enzymes which may mediate
      changes in neuronal function during prolonged wakefulness. The purpose of this
      article is to give a short overview of those genes whose transcription is
      affected by sleep deprivation according to the current literature, and to
      characterize the possible role of these genes in sleep regulation.

PMID- 10344589
TI  - Energy metabolism of synaptosomal subpopulations from different neuronal systems
      of rat hippocampus: effect of L-acetylcarnitine administration in vivo.
AB  - The maximum rate (Vmax) of some enzyme activities related to glycolysis, Krebs'
      cycle, acetylcholine catabolism and amino acid metabolism were evaluated in
      different types of synaptosomes obtained from rat hippocampus. The enzyme
      characterization was performed on two synaptosomal populations defined as "large"
      and "small" synaptosomes, supposed to originate mainly from the granule cell
      glutamatergic mossy fiber endings and small cholinergic nerve endings mainly
      arising from septohippocampal fiber synapses, involved with cognitive processes.
      Thus, this is an unique model of pharmacological significance to study the
      selective action of drugs on energy metabolism of hippocampus and the sub-chronic
      i.p. treatment with L-acetylcarnitine at two different dose levels (30 and 60 mg
      x kg(-1), 5 day a week, for 4 weeks) was performed. In control animals, the
      results indicate that these two hippocampal synaptosomal populations differ for
      the potential catalytic activities of enzymes of the main metabolic pathways
      related to energy metabolism. This energetic micro-heterogeneity may cause their
      different behaviour during both physiopathological events and pharmacological
      treatment, because of different sensitivity of neurons. Therefore, the micro
      heterogeneity of brain synaptosomes must be considered when the effect of a
      pharmacological treatment is to be evaluated. In fact, the in vivo administration
      of L-acetylcarnitine affects some specific enzyme activities, suggesting a
      specific molecular trigger mode of action on citrate synthase (Krebs' cycle) and
      glutamate-pyruvate-transaminase (glutamate metabolism), but mainly of "small"
      synaptosomal populations, suggesting a specific synaptic trigger site of action.
      These observations on various types of hippocampal synaptosomes confirm their
      different metabolic machinery and their different sensitivity to pharmacological
      treatment.

PMID- 10344590
TI  - Alteration of oxygen consumption and energy metabolism during repetitive exposure
      of mice to hypoxia.
AB  - Changes in oxygen consumption, body temperature and energy metabolism were
      studied while mice were repeatedly exposed to a sealed environment. The average
      tolerance limits of environmental oxygen level (vol%) and the average oxygen
      consumption rates (ml/g x min) were exponentially decreased and the average body
      rectal temperatures (degrees C) were linearly declined while the average
      tolerable times (min) to hypoxia were linearly increased as animals were
      repeatedly exposed to hypoxia for 5 runs. The average survival times (min) in
      sealed environments after administration of normal saline, iodoacetic acid,
      malonic acid, potassium cyanide, and potassium cyanide plus iodoacetic acid in
      group exposed repeatedly to hypoxia for three runs were, respectively, 3.1, 3.9,
      1.4, 2.6, and 2.8 times those of the control groups that had corresponding
      administration of the different chemicals, but no exposure to hypoxia. The
      results indicate that progressive increase in hypoxia tolerance is related to
      progressively lower rate of oxygen consumption and heat production, and the
      lowered energy requirement during repetitive exposure to hypoxia is achieved
      mainly via pathways of the respiratory chain and glycolysis.

PMID- 10344592
TI  - Tubulin and glial fibrillary acidic protein gene expression in developing fetal
      human brain at midgestation.
AB  - Developmental alterations in the expression of glial fibrillary acidic protein
      (GFAP) and alpha-tubulin were examined at the level of mRNA and protein in human
      fetal brain between weeks 13-23 of gestation. Except for a transient increase at
      week 15, GFAP expression in the cytoskeletal (CSK) fraction was low until week
      17, when it increased steadily to week 23, corresponding to the phase of glial
      proliferation. The developmental profile of alpha-tubulin in the CSK fraction
      displayed a biphasic pattern, with an initial rise between weeks 13-16 coinciding
      with the early phase of neuroblast multiplication, and a second rise between
      weeks 17-23 corresponding to the phase of glial proliferation. No significant
      difference in the spatial distribution of alpha-tubulin was found in different
      region of brain but GFAP expression varied with a higher level in cerebellum than
      that in cerebrum at late midgestation.

PMID- 10344591
TI  - Nitric oxide modulates muscarinic acetylcholine receptor binding in the cerebral
      cortex of gerbils.
AB  - To determine whether nitric oxide (NO) acts as a modulator of muscarinic
      acetylcholine receptor (mACh-R) function, we performed a radioligand receptor
      assay using [3H]quinuclidinyl benzylate ([3H]QNB), the NO radical (NO*) donor 3
      (2-Hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamin e (NOC7) and a
      gerbil brain cortical membrane preparation. NOC7 (at 10 microM, 100 microM or 1
      mM concentrations) significantly reduced the [3H]QNB binding Kd values (from
      0.196 +/- 0.009 nM in the control, to 0.151 +/- 0.013, 0.144 +/- 0.012 and 0.153
      +/- 0.007 nM respectively). NOC7 did not alter the displacement curves of
      atropine or carbachol. Reduction of SH groups with dithiothreitol, in the
      presence of the NO donor, significantly increased [3H]QNB binding affinity
      whereas alkylation by N-ethylmaleimide markedly decreased it. The observed
      enhancing effect on mACh-R binding affinity for [3H]QNB, may reflect
      conformational changes in the receptors mediated by the NO generated, and these
      changes might be explained by NO reactions with such groups through conditions
      supporting redox reactions intrinsic to the NO molecule, similar to those
      occurring in redox regulatory sites reported for other neurotransmitter pathways
      in the CNS.

PMID- 10344593
TI  - Regulation of glial Na+/K+-ATPase by serotonin: identification of participating
      receptors.
AB  - The purpose of the present study was the characterization of the receptors
      participating in the regulatory mechanism of glial Na+/K+-ATPase by serotonin (5
      HT) in rat brain. The activity of the Na+ pump was measured in four brain regions
      after incubation with various concentrations of serotoninergic agonists or
      antagonists. A concentration-dependent increase in enzyme activity was observed
      with the 5-HT1A agonist R (+)-2-dipropylamino-8-hydroxy-1,2,3, 4
      tetrahydronaphthalene hydrobromide (8-OH-DPAT) in homogenates or in glial
      membrane enriched fractions from cerebral cortex and in hippocampus. Spiperone, a
      5-HT1A antagonist, completely inhibited the response to 8-OH-DPAT but had no
      effect on Na+/K+-ATPase activity in cerebellum where LSD, a 5-HT6 agonist,
      elicited a dose-dependent response similar to that of 5-HT. In brainstem, a lack
      of response to 5-HT and other agonists was confirmed. Altogether, these results
      show that serotonin modulates glial Na+/K+-ATPase activity in the brain,
      apparently not through only one type of 5-HT receptor. It seems that the receptor
      system involved is different according to the brain region. In cerebral cortex,
      the response seems to be mediated by 5-HT1A as well as in hippocampus but not in
      cerebellum where 5-HT6 appears as the receptor system involved.

PMID- 10344594
TI  - Age-related changes in expression of hippocalcin and NVP2 in rat brain.
AB  - Expression of hippocalcin and neural visinin-like calcium-binding protein 2
      (NVP2) in aging rat brain was investigated by immunoblot and immunohistochemical
      analyses. In 3-month old rats, hippocalcin and NVP2 were present at high
      concentrations in hippocampal and cerebral pyramidal cells and dentate granule
      cells, with hippocalcin protein levels being five to ten times higher than NVP2
      levels. Hippocalcin levels in hippocampus and cerebral cortex decreased by
      approximately 20% at 24 months. While the number of hippocalcin-positive cells in
      CA3, dentate gyrus and cerebral cortex were preserved, staining intensity
      decreased. In contrast, the number and staining intensity of hippocalcin-positive
      cells in CA1 were maintained. NVP2 levels in hippocampus and cerebral cortex
      decreased by approximately 30% at 24 months. In cerebral cortex, the number and
      intensity of NVP2-positive cells decreased. In CA1 through CA3 and in dentate
      gyrus, NVP2-positive cell numbers were preserved, but staining intensity
      decreased. In summary, the loss of hippocalcin and NVP2 in aging rat brain may be
      associated with age-related impairment of postsynaptic functions.

PMID- 10344595
TI  - Clozapine's antipsychotic effects do not depend on blockade of 5-HT3 receptors.
AB  - Sixteen known 5-HT3 receptor blockers, including clozapine, fully or partially
      reverse the inhibitory effect of 1 microM GABA on [35S]TBPS binding, indicating
      that they are also GABA(A) antagonists, some of them selective for subsets of
      GABA(A) receptors. The 5-HT3 receptor blocker, ondansetron, has been reported to
      produce some antipsychotic and anxiolytic effects. However, no antipsychotic
      effects have been reported for a large number of highly potent 5-HT3 receptor
      blockers. Like clozapine, ondansetron partially reverses the inhibitory effect of
      GABA on [35S]TBPS binding. Additivity experiments suggest that ten 5-HT3 receptor
      blockers tested at low concentrations preferentially block subtypes of GABA(A)
      receptors that are among those blocked by clozapine. Wiley and Porter (29)
      reported that MDL-72222, the most potent GABA(A) antagonist described here,
      partially generalizes (71%) with clozapine in rats trained to discriminate an
      interoceptive clozapine stimulus, but only at a dose that severely decreases
      responding. Tropisetron (ICS-205,930) exhibits both GABA-positive and GABA
      negative effects. R-(+)-zacopride is 6-fold more potent than S-(-)-zacopride as a
      GABA(A) antagonist. We conclude that the observed antipsychotic and, possibly,
      anxiolytic effects of some 5-HT3 receptor blockers are due to selective
      antagonism of certain GABA(A) receptors, and not to blockade of 5-HT3 receptors.
      We speculate that the anxiolytic and sedative effects of clozapine and several
      other antipsychotic drugs may be due to selective blockade of alpha1beta2gamma2
      GABA(A) receptors which are preferentially located on certain types of GABAergic
      interneurons (probably parvalbumin positive). Blockade of these receptors will
      increase the inhibitory output of these interneurons. So far, no highly potent
      GABA(A) antagonists with clozapine-like selectivity have been identified. Such
      compounds may exhibit improved clozapine-like antipsychotic activity.

PMID- 10344597
TI  - Cerebral blood flow threshold and regional heterogeneity of heat shock protein 72
      induction following transient forebrain ischemia in rats.
AB  - Heat shock proteins (HSPs) induced by brain ischemia may play an important role
      in neuroprotection from neuronal degeneration. In this study, we examined the
      cerebral blood flow (CBF) threshold to produce regional differences in HSP72
      induction after transient forebrain ischemia in spontaneously hypertensive rats
      (SHRs). Female SHRs were subjected to 20 min of cerebral ischemia induced by
      bilateral carotid artery occlusion. The CBF was measured by laser Doppler
      flowmetry. At forty-eight hours after cerebral ischemia and reperfusion, the rats
      were decapitated and the brains were removed. Specific areas (hippocampal CA1,
      CA2-3, dentate gyrus, dorsolateral and ventromedial striatum, and parietal
      cortex) were thereafter dissected from the brain. The amounts of HSP72 in these
      samples were determined using Western blot analysis. In the hippocampus, HSP72
      was induced when the CBF decreased to less than 18-25% of the resting level. The
      mean values of HSP72 produced in the CA1 area, CA2-3 area, and the dentate gyrus
      following ischemia and reperfusion treatment were 4.44 +/- 1.43 (+/-SD) ng/microg
      protein, 3.51 +/- 0.72 ng/microg protein and 3.77 +/- 1.05 ng/microg protein,
      respectively. In the parietal cortex, the amount of HSP72 induction was less
      pronounced (2.55 +/- 0.40 ng/microg protein), while HSP72 was hardly detected at
      all in the striatum, even under conditions of very severe CBF reduction and
      reperfusion. We demonstrated the existence of both a CBF threshold (i.e.,
      approximately 20% of the resting level) for HSP72 induction and regional
      heterogeneity for the induction of HSP72 protein.

PMID- 10344596
TI  - Activation of cPLA2, PKC, and ERKs in the rat cerebral cortex during
      ischemia/reperfusion.
AB  - Release of the excitotoxic amino acid, glutamate, into the extracellular space
      during ischemia/reperfusion contributes to neuronal injury and death. To gain
      insights into the signal transduction pathways involved in glutamate release we
      examined the time course of changes in enzyme levels and activities of cPLA2, PKC
      and ERKs in the rat cerebral cortex after four vessel (4VO) ischemia followed by
      reperfusion. Measurement both by enzymatic assay and Western blot analysis showed
      significant increases in the activity and protein levels of cPLA2 during 10-20
      min of ischemia. Activity remained elevated at 10 min and 20 min of reperfusion,
      whereas cPLA levels had returned to base line levels after 20 min of reperfusion.
      PKC activity increased significantly in the particulate, but not in the
      cytosolic, fractions both during ischemia and reperfusion. Increases in PKCgamma
      levels were recorded in the particulate fraction during ischemia and reperfusion,
      and in the cytosolic fraction during ischemia. Western blot analysis with a
      phosphospecific antibody for characterization of MAPK (ERKs) activation revealed
      significantly increased phosphorylation of ERK1 and ERK2 in the particulate
      fraction, of ERK2 in the cytosolic fraction, during ischemia and of both enzymes
      in the particulate and cytosolic fractions after 10 min of reperfusion. The
      relevance of the results to glutamate release is discussed.

PMID- 10344598
TI  - Ceramide induces apoptosis to immature cerebellar granule cells in culture.
AB  - A recent study revealed that ceramide acts as a second messenger in the
      sphingomyelin pathway and thus plays an important regulatory role in programmed
      cell death (apoptosis) to cell the lines induced by tumor-necrosis factor (TNF)
      alpha and interleukin (IL)-1beta, although its effect remains controversial
      regarding primary neuronal culture. We investigated the effect of a cell
      permeable ceramide analog (C2-ceramide) on cultures of cerebellar granule cells,
      which is thought to have active sphingomyelin pathway during development. The
      presence of C2-ceramide decreased the number of cerebellar granule cells (CGCs)
      in a concentration-dependent manner when added at DIV 1 (1 day in vitro). The
      ED50 was 60 microM. After DIV 2, CGCs became less sensitive to C2-ceramide and
      the ED50 was 200 microM at DIV 7. DNA staining with Hoechst 33258 showed the
      morphology of apoptotic nuclei in the degenerating neurons. Internucleosomal DNA
      degradation could also be observed by gel electrophoresis. Protein and RNA
      synthesis inhibitors prevented the death of neurons. C2-dihydroceramide, which
      lacks the 4-5 trans double bond and failed to induce neuronal death. These
      results thus demonstrated that C2-ceramide induces apoptosis to the CGCs at the
      early stage in vitro, however the CGCs were found to be less sensitive to C2
      ceramide at the later stage in vitro.

PMID- 10344599
TI  - Role of 1,25-dihydroxyvitamin D3 and extracellular calcium in the regulation of
      proliferation in cultured SH-SY5Y human neuroblastoma cells.
AB  - This study examines the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on SH
      SYSY human neuroblastoma cells cultured in the presence of medium containing
      varying concentrations of calcium (0.1, 0.9, 1.4, 1.8 mM). Pyruvate kinase
      activity was assayed in SH-SY5Y cells incubated in variable calcium medium with
      or without 1, 10 or 100 nM 1,25(OH)2D3 for 48 h. The enzyme levels showed a
      significant increase in comparison with control, when the cells were incubated
      with 100 nM hormone in the presence of 0.1 mM calcium, while pyruvate kinase
      activity decreased, when the cells were treated with 100 nM 1,25(OH)2D3 in the
      presence of 1.8 mM calcium. The proliferative activity of SH-SY5Y was dependent
      on the extracellular concentration of calcium, being the highest at 1.8 mM
      calcium and completely absent at 0.1 mM calcium. In the presence of 1,25(OH)2D3,
      at the three concentrations used and after 48 h incubation, a significant
      decrease in cell number was always observed, without a direct correlation between
      1,25(OH)2D3 effect and calcium concentration in the medium. [3H]Thymidine
      incorporation in SH-SY5Y cells significantly increased in comparison with
      control, when the 48 h incubation with 1, 10 or 100 nM 1,25(OH)2D3 was carried
      out in the presence of 0.1 mM calcium, while, at the other calcium
      concentrations, the hormone did not cause any significant change in this
      parameter. The treatment of SH-SYSY cells with 1 nM 1,25(OH)2D3 for 48 h did not
      affect cell morphology, when 0.1 mM calcium was present, while, in the medium
      containing 1.8 mM calcium, the treated cells showed a slight trend to
      differentiation. The differentiating effect of 10 microM all-trans retinoic acid,
      even if incomplete after 48 h treatment, was only observed in the cultures grown
      in 1.8 mM calcium, in comparison with those maintained in 0.1 mM calcium.

PMID- 10344600
TI  - 3Beta [N-(N',N'-dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol)-mediated
      gene delivery to primary rat neurons: characterization and mechanism.
AB  - Cationic lipid formulations consisting of 3beta [N-(N', N'-dimethylaminoethane)
      carbamoyl] cholesterol (DC-Chol) and the helper lipid
      dioleoylphosphatidylethanolamine (DOPE) (1.5: 1 molar ratio) were prepared by
      solvent evaporation and sized by high pressure extrusion. Liposomes made of 1:1
      molar ratio 1 ,2-dioleoyl-3-trimethyl-ammonium-propane (DOTAP)/DOPE were used as
      controls in the study. The two formulations were characterized and evaluated for
      their efficiency in transfecting SKnSH (neuroblastoma) and primary rat neuronal
      cell lines. DC-Chol/DOPE liposomes were more efficient at transfecting both the
      SKnSH and the primary rat neuronal cells and also less toxic compared to the
      DOTAP/DOPE liposomes. The cellular-associated signal of rhodamine-labeled DC
      Chol/DOPE liposomes into SKnSH and primary rat neuronal cells was higher than the
      rhodamine-labeled DOTAP/DOPE liposomes. These results demonstrate that DC
      Chol/DOPE cationic liposomes provide an efficient vehicle for the delivery of
      plasmids into SKnSH and primary neuronal cells compared to DOTAP/DOPE liposomes.
      DC-Chol/DOPE liposomes may provide a good non-viral candidate for transfecting
      primary rat neuronal cells.

PMID- 10344601
TI  - Decrease in spontaneous motor activity and in brain lipid peroxidation in
      manganese and melatonin treated mice.
AB  - In the present study, we have evaluated whether melatonin (MEL) modulates Mn
      induced decrease in spontaneous motor activity (SMA) and lipid peroxidation,
      estimated as malondialdehyde (MDA) formation, in several brain regions. In mice
      treated with manganese a decrease in SMA after 2 weeks of treatment was observed.
      In the group treated with Mn+MEL a significant greater reduction in SMA was
      detected at 4 weeks. MDA levels were reduced in both MEL and Mn treated mice. In
      the animals treated with MEL + Mn a higher reduction in MDA levels was observed.
      These results suggest that MEL modulates the effect of Mn on SMA and brain lipid
      peroxidation.

PMID- 10344603
TI  - Advisory panel hears contradictory evidence, backs keeping troglitazone on
      market.

PMID- 10344602
TI  - GFAPbeta mRNA expression in the normal rat brain and after neuronal injury.
AB  - GFAPbeta mRNA is an alternative transcript of the glial fibrillary acidic protein
      (GFAP) gene, whose transcriptional start site is located 169 nucleotides upstream
      to the classical GFAPalpha mRNA. By an RT-PCR method with primers on separate
      exons, we were able to confirm the presence of GFAP transcripts with a longer 5'
      untranslated region in all the examined areas of rat brain and in primary
      cultures of astroglial cells. Northern blot analysis, using an oligoprobe
      specific for the 5' region of GFAPbeta, revealed a single hybridization band of
      2.9 kb in all the brain regions examined and in primary cultures of astroglial
      cells. The availability of the quantitative Northern blot assay allowed further
      studies on the regulation of GFAPbeta expression in vivo. Since it is well-known
      that neuronal brain injury is one of the most powerful inducers of GFAP, we
      examined the expression of GFAPalpha and beta after a neurotoxic lesion in the
      rat hippocampus. Results obtained show a parallel increase in both GFAP
      transcripts with an identical time-course, suggesting that regulatory regions of
      the gene influence in similar way the rate of transcription at the two different
      start sites (alpha and beta) or that a similar post-transcriptional mechanism is
      involved in regulating both mRNA isoforms.

PMID- 10344604
TI  - NCQA draft accreditation standards for 2000 address formularies. National
      Committee for Quality Assurance.

PMID- 10344605
TI  - Antidepressants, rhinosinusitis are topics of new AHCPR evidence reports.

PMID- 10344606
TI  - Promoting optimal use of beta-blockers after myocardial infarction.

PMID- 10344607
TI  - Televideo technology for patient counseling and education.

PMID- 10344608
TI  - Medication misadventures: a policy of openness and learning.

PMID- 10344609
TI  - Management of toenail onychomycosis.
AB  - The treatment of toenail onychomycosis is reviewed. Onychomycosis contributes to
      40% of all nail disorders and appears to be increasing in frequency. Mycotic nail
      infections are usually caused by dermatophytes, yeasts, and nondermatophyte
      molds. Most cases of toenail onychomycosis are caused by dermatophytes. Mycotic
      nail infections do not always resolve spontaneously and may have a substantial
      impact on the patient's quality of life. Current treatment modalities for
      onychomycosis include surgery, topical antifungals, and oral antifungals. Surgery
      is generally not recommended as first-line therapy. Broad-spectrum topical and
      oral antifungal agents are the most frequently used treatments. Topical treatment
      is well tolerated but is usually not effective because of poor patient compliance
      and inadequate penetration of the nail. Oral antifungals are more successful but
      carry greater risks. Griseofulvin and ketoconazole have been oral antifungals
      traditionally used for onychomycosis, but these agents are associated with
      relatively low cure rates. Itraconazole and terbinafine are both safe and
      effective first-line agents, with reported overall cure rates of 50-90% for
      dermatophyte-related onychomycosis. Intermittent oral antifungal therapy may
      reduce the risk of systemic adverse effects and the cost of therapy; more study
      of this approach is needed. Oral antifungal agents offer patients with toenail
      onychomycosis greater likelihood of a cure than topical antifungals, but oral
      therapy carries greater risks and requires closer monitoring.

PMID- 10344610
TI  - Comparison of two concentrations of amphotericin B bladder irrigation in the
      treatment of funguria in patients with indwelling urinary catheters.
AB  - The efficacy of amphotericin B bladder irrigation at two concentrations was
      studied. Patients with funguria (> or =15,000 colony-forming units of yeast per
      milliliter of urine), an indwelling urinary catheter, and a physician order for
      amphotericin B continuous bladder irrigation were randomly assigned to receive 10
      or 50 mg of amphotericin B per liter of sterile water as a continuous irrigation
      for 72 hours at the rate of 42 mL/hr. Before the bladder irrigation began, the
      indwelling catheter was changed to a three-way catheter. Repeat urine cultures
      were performed 24 hours after the irrigation was discontinued. A total of 28
      patients were enrolled from November 1993 to May 1995. The rate of eradication of
      the infection was 100% in the 50-mg/L group and 67% in the 10-mg/ L group.
      Subject enrollment was stopped prematurely because all the treatment failures
      occurred in the 10-mg/L group. Dose was the only variable significantly
      associated with outcome. Bladder irrigation with amphotericin B was more
      effective when the drug concentration was 50 mg/L rather than 10 mg/L.

PMID- 10344611
TI  - Stability and compatibility of topotecan hydrochloride with selected drugs.
AB  - The physical and chemical compatibility of topotecan 56 microg/mL (as the
      hydrochloride) with 18 other drugs during simulated Y-site injection was studied.
      A vial of topotecan hydrochloride was reconstituted under aseptic conditions with
      sterile water for injection to yield a solution containing 1 mg of topotecan base
      per milliliter and further mixed with 0.9% sodium chloride injection or 5%
      dextrose injection. Equal volumes of topotecan solution and each secondary drug,
      also prepared in 0.9% sodium chloride injection or 5% dextrose injection, were
      mixed in sterile vials. All mixtures were stored at 20-23 degrees C under normal
      fluorescent light. Samples were taken initially and at four hours for analysis by
      high-performance liquid chromatography, visual inspection, and pH measurement.
      With a few exceptions, the drug combinations exhibited no visible change in color
      or clarity initially or after four hours, and the concentration of topotecan
      hydrochloride and of the secondary drugs was 95% or more of the initial
      concentration. The concentration of topotecan hydrochloride dropped to 88.7% of
      the initial concentration after four hours when the drug was mixed with
      ticarcillin disodium and with clavulanate potassium in 5% dextrose injection. An
      intense yellow color and a slight haze developed immediately after topotecan
      hydrochloride was mixed with dexamethasone sodium phosphate or with fluorouracil
      in 0.9% sodium chloride injection. The topotecan-mitomycin combination in both
      diluents became pale purple immediately and turned dark pink-lavender within four
      hours, after which analysis showed 15-20% degradation of mitomycin. During
      simulated Y-site injection, topotecan hydrochloride was physically and chemically
      compatible with 15 of 18 drug products.

PMID- 10344612
TI  - Cost impact of Pharm.D. candidates' drug therapy recommendations.

PMID- 10344613
TI  - Use of pharmacists' cognitive services in home health care assessment.

PMID- 10344614
TI  - ASHP guidelines on surgery and anesthesiology pharmaceutical services. American
      Society of Health-System Pharmacists.
AB  - Pharmaceutical services in surgery and anesthesiology should be the standard of
      practice in health care organizations across the United States. Although not
      essential, an onsite satellite pharmacy would help in the provision of these
      services. A majority of distribution-related activities should be done by
      technicians. The availability of automated devices and other technology may
      lessen, to some extent, the time devoted to drug distribution. It is important
      for the OR pharmacist to concentrate on the provision of clinical services, such
      as medication-use management, drug information services, medication-use
      evaluations, formulary management, and pharmacoeconomic analyses of anesthesia
      related medications. These activities provide the best opportunity for the
      pharmacist to contribute to improving patient care and outcomes and containing
      costs. Finally, pharmaceutical services in surgery and anesthesiology should be
      periodically assessed for patient care and financial effectiveness.

PMID- 10344615
TI  - Nurses' perspective on a serious adverse drug event.

PMID- 10344616
TI  - A pharmacy manager's perspective on a serious adverse drug event.

PMID- 10344617
TI  - Twenty qualities of a desirable pharmacy environment.

PMID- 10344618
TI  - Experience of a home infusion organization with a performance measurement
      company.

PMID- 10344619
TI  - Blurred vision from ipratropium bromide inhalation.

PMID- 10344620
TI  - Losartan-induced cough after lisinopril therapy.

PMID- 10344621
TI  - Journal references.

PMID- 10344622
TI  - The history of the double blind test and the placebo.

PMID- 10344623
TI  - Clinical consequences of the biphasic elimination kinetics for the diuretic
      effect of furosemide and its acyl glucuronide in humans.
AB  - This review discusses the possibility of whether furosemide acyl glucuronide, a
      metabolite of furosemide, contributes to the clinical effect of diuresis. First
      an analytical method (e.g. HPLC) must be available to measure both parent drug
      and furosemide acyl glucuronide. Then, with correctly treated plasma and urine
      samples (light protected, pH 5) from volunteers and furosemide-treated patients,
      the kinetic curves of both furosemide as well as its acyl glucuronide can be
      measured. The acyl glucuronide is formed in part by the kidney tubules and it is
      possible that the compound is pharmacologically active through inhibition of the
      Na+/2Cl-/K+ co-transport system; up to now the mechanism of action has been
      solely attributed to furosemide. The total body clearance of furosemide occurs by
      hepatic and renal glucuronidation (50%) and by renal excretion (50%).
      Enterohepatic cycling of furosemide acyl glucuronide, followed by hydrolysis,
      results in a second and slow elimination phase with a half-life of 20-30 h. This
      slow elimination phase coincides with a pharmacodynamic rebound phase of urine
      retention. After each dosage of furosemide, there is first a short stimulation of
      urine flow (4 h), which is followed by a 3-day recovery period of the body. The
      following clinical implications arise from study of the elimination kinetics of
      furosemide. Repetitive dosing must result in accumulation of the recovery period.
      Accumulation of furosemide and its acyl glucuronide in patients with end-stage
      renal failure results from infinite hepatic cycling. Impaired kidney function may
      result in impaired glucuronidation and diuresis. While kidney impairment normally
      requires a dose reduction for those compounds which are mainly eliminated by
      renal excretion, for diuretics, a dose increment is required in order to maintain
      a required level of diuresis. The full clinical impact of the accumulation of
      furosemide and its acyl glucuronide in patients with end-stage renal failure has
      to be determined.

PMID- 10344624
TI  - Influence of pH and temperature on kinetics of ceftiofur degradation in aqueous
      solutions.
AB  - The objective of this study was to evaluate the stability of ceftiofur (1 mg mL(
      1)) in aqueous solutions at various pH (1, 3, 5, 7.4 and 10) and temperature (0,
      8, 25, 37 and 60 degrees C) conditions. The ionic strength of all these solutions
      was maintained at 0.5 M. Ceftiofur solutions at pH 5 and 7.4 and in distilled
      water (pH = 6.8) were tested at all the above temperatures. All other solutions
      were tested at 60 degrees C. Over a period of 84 h, the stability was evaluated
      by quantifying ceftiofur and its degradation product, desfuroylceftiofur, in the
      incubation solutions. HPLC was used to analyse these compounds. At 60 degrees C,
      the rate of degradation was significantly higher at pH 7.4 compared with pH 1, 3,
      5 and distilled water. At both 60 degrees C and 25 degrees C, degradation in pH
      10 buffer was rapid, with no detectable ceftiofur levels present at the end of 10
      min incubation. Degradation rate constants of ceftiofur were 0.79+/-0.21, 0.61+/
      0.03, 0.44+/-0.05, 1.27+/-0.04 and 0.39+/-0.01 day(-1) at pH 1, 3, 5, 74 and in
      distilled water, respectively. Formation of desfuroylceftiofur was the highest
      (65%) at pH 10. The rate of degradation increased in all aqueous solutions with
      an increase in the incubation temperature. At pH 7.4 the degradation rate
      constants were 0.06+/-0.01, 0.06+/-0.01, 0.65+/-0.17, and 1.27+/-0.05 day(-1) at
      0, 8, 25, 37 and 67 degrees C, respectively. The energy of activation for
      ceftiofur degradation was 25, 42 and 28 kcal mol(-1) at pH 5, 7.4 and in
      distilled water, respectively. Desfurylceftiofur formation was the greatest at
      alkaline pH compared with acidic pH. Ceftiofur degradation accelerated the most
      at pH 7.4 and was most rapid at pH 10. The results of this study are consistent
      with rapid clearance of ceftiofur at physiological pH.

PMID- 10344625
TI  - Colon-specific delivery of budesonide with azopolymer-coated pellets: therapeutic
      effects of budesonide with a novel dosage form against 2,4,6
      trinitrobenzenesulphonic acid-induced colitis in rats.
AB  - The objective of this study was to achieve colon-specific delivery of budesonide
      using azopolymer-coated pellets and to accelerate healing of 2,4,6
      trinitrobenzenesulphonic acid sodium salt (TNBS)-induced colitis in rats. After
      oral administration of azopolymer-coated pellets containing budesonide, a
      significant increase was observed in the therapeutic effects of the drug
      accompanied by a decrease in its systemic adverse effects when compared with oral
      administration in saline or rectal administration by enema. In addition, with the
      use of the colon-specific oral dosage form the dose of budesonide could be
      reduced. These results suggested that azopolymer-coated pellets may be a useful
      dosage form for the colon-specific delivery of budesonide as an anti-inflammatory
      steroid drug to bring about the healing of TNBS-induced colitis in rats.

PMID- 10344626
TI  - Adrenal effects and pharmacokinetics of CFC-free beclomethasone dipropionate: a
      14-day dose-response study.
AB  - Since equivalent efficacy is achieved with lower doses of the reformulated
      beclomethasone dipropionate in the chlorofluorocarbon (CFC)-free propellant HFA
      134a (HFA) than with the original CFC-beclomethasone dipropionate formulation, it
      is possible the HFA-beclomethasone dipropionate may have less safety concerns
      than the CFC formulation. Despite its chronic use, the steady-state
      pharmacokinetics of beclomethasone dipropionate has never been studied before.
      This double-blind study examined adrenal effects and pharmacokinetics after 14
      days of dosing with HFA-beclomethasone dipropionate. Forty-three steroid-naive
      asthmatic patients were randomised into 5 parallel groups and dosed every 12 h
      for 14 days with: HFA-placebo; 200, 400 or 800 microg day(-1) HFA-beclomethasone
      dipropionate; or 800 microg day(-1) CFC-beclomethasone dipropionate. After two
      weeks of dosing, the 24-h urinary free cortisol of all but one patient remained
      within the normal range, showing that all doses were well tolerated from a
      systemic safety perspective. The active HFA-beclomethasone dipropionate treatment
      groups showed a dose-related fall in 24-h urinary free cortisol. Total
      beclomethasone (beclomethasone dipropionate and metabolites) pharmacokinetics
      after either the first dose of HFA-beclomethasone dipropionate or CFC
      beclomethasone dipropionate were not substantially affected by subsequent doses.
      The extent of drug absorption from 800 microg day(-1) HFA-beclomethasone
      dipropionate and CFC-beclomethasone dipropionate was in the ratio of 1.7 : 1. A
      non-linear correlation between 24-h urinary free cortisol and the pharmacokinetic
      parameters was observed, reflecting smaller changes in 24-h urinary free cortisol
      than in pharmacokinetics as the dose was increased. No clinically meaningful
      change in the pharmacokinetics of beclomethasone dipropionate plus metabolites
      was seen on multiple dosing. The greater systemic availability of HFA
      beclomethasone dipropionate was still associated with adrenal effects comparable
      with that of the CFC formulation at the same dose.

PMID- 10344627
TI  - Drug permeation through the three layers of the human nail plate.
AB  - The in-vitro permeation characteristics of a water soluble model drug, 5
      fluorouracil, and a poorly water soluble model drug, flurbiprofen, were
      investigated through three layers of the human nail plate (namely, the dorsal,
      intermediate and ventral nail plates), using a modified side-by-side diffusion
      cell. The dorsal-filed nail plate, the ventral-filed nail plate and the dorsal
      and-ventral-filed nail plate were prepared to known thicknesses and then used
      with the full-thickness nail plate to investigate the permeation characteristics
      of each single layer. Most of the lipids in the human nail plate were found in
      the dorsal and ventral layers. The rank orders of the permeation fluxes for 5
      fluorouracil and flurbiprofen were both: dorsal-and-ventral-filed nail plate >
      dorsal-filed nail plate > ventral-filed nail plate > full-thickness nail plate.
      With respect to 5-fluorouracil permeation through each single layer, the
      permeability coefficient of the intermediate layer was higher than those of other
      single layers. However in the case of flurbiprofen, the permeability coefficient
      of the ventral layer was higher than other single layers. The diffusion
      coefficients of 5-fluorouracil and flurbiprofen in the dorsal layer were the
      lowest of any single layer. The drug concentration in each layer was estimated
      using each respective permeation parameter. The drug concentration in the nail
      plate was observed to be dependent on the solubility and the flux of the drug.
      From these findings, we suggest that the human nail plate behaves like a
      hydrophilic gel membrane rather than a lipophilic partition membrane and that the
      upper layer functions as the main nail barrier to drug permeation through its low
      diffusivity against the drugs.

PMID- 10344628
TI  - The presence of an Na+/spermine antiporter in the rat renal brush-border
      membrane.
AB  - This study was aimed at determining the driving force for spermine transport in
      rat renal proximal tubular brush-border membrane. The uptake of spermine and
      trientine, a spermine-like drug used for treating Wilson's disease, into rat
      renal brush-border membrane vesicles was significantly stimulated by an outwardly
      directed Na+ gradient. The Na+-dependent uptake was temperature dependent and
      saturable. A kinetic analysis of the initial uptake of spermine with an Na+
      gradient gave a Km value of 1.44 microM and a Vmax value of 6.31 pmol (mg
      protein)(-1)/30s. The Na+ dependent uptake of [3H]spermine was inhibited by
      spermine, trientine and tetraethylene-pentamine. Substrates of the H+/organic
      cation transporter (cimetidine and tetraethyl-ammonium), physiological polyamines
      (putrescine and spermidine) with 2 or 3 amino groups and aminoglycosides
      (amikacin and tobramicin) with 4 or 5 cationic amines did not affect the uptake
      of spermine in the presence of an outwardly directed Na+ gradient. These results
      suggest that the renal tubular secretion of spermine is mediated by an
      Na+/spermine antiport system which is specific for a straight-chain polyamine
      compound with more than 4 amino groups.

PMID- 10344629
TI  - Inhibition by magnolol of formylmethionyl-leucyl-phenyl alanine-induced
      respiratory burst in rat neutrophils.
AB  - The influence of the plant product magnolol on neutrophil superoxide anion (O2-*)
      generation has been investigated in the rat. Intraperitoneal injection of
      magnolol (30mg kg(-1)) significantly inhibited the formylmethionyl-leucyl
      phenylalanine (fMLP)-induced respiratory burst in rat whole blood ex-vivo.
      Magnolol also inhibited the 02-* generation with an IC50 (concentration resulting
      in 50% inhibition) of 15.4+/-1.6 microM and O2 consumption in rat neutrophils in
      vitro. Magnolol weakly inhibited the O2-* generation in the xanthine-xanthine
      oxidase system, decreased cellular cyclic AMP level and had no effect on cyclic
      GMP levels. It weakly inhibited neutrophil cytosolic protein kinase C activity
      but did not alter porcine heart protein kinase A activity. Magnolol attenuated
      fMLP-induced protein tyrosine phosphorylation with an IC50 of 24.0+/-1.9 microM
      and the phosphorylation of mitogen-activated protein kinase p42/44 with an IC50
      of 28.5+/-4.5 microM. However, magnolol alone activated neutrophil phospholipase
      D activity as determined by the formation of phosphatidic acid and phosphatidyl
      ethanol in the presence of ethanol. In the presence of NADPH, the arachidonate
      activated NADPH oxidase activity in a cell-free system was weakly suppressed by
      magnolol. These results suggest that the inhibition of respiratory burst in fMLP
      activated neutrophils by magnolol is probably attributable mainly to the
      attenuation of protein tyrosine phosphorylation and p42/44 mitogen-activated
      protein kinase activation, and partly to the suppression of protein kinase C and
      NADPH oxidase activities.

PMID- 10344630
TI  - Ca2+/calmodulin-dependent protein kinase II inhibitors potentiate superoxide
      production in polymorphonuclear leukocytes.
AB  - The possible role of Ca2+/calmodulin-dependent protein kinase II (CaMK II) in
      superoxide anion (O2-) production induced by formyl-methionyl-leucyl
      phenylalanine (FMLP) was investigated in mouse polymorphonuclear leukocytes
      (PMNs). KN-93 and KN-62, specific CaMK II inhibitors, augmented FMLP-induced O2-
      production. KN-92, an analogue which did not inhibit CaMK II, did not affect O2-
      production. W-7, a calmodulin inhibitor, augmented O2- production when
      administered at 30 mM for 5 min. KN-93 and recombinant mouse tumour necrosis
      factor-alpha (rmTNF-alpha) each augmented the maximal production of O2- induced
      by FMLP, and an additive effect of a combination of KN-93 and rmTNF-alpha was
      observed. CaMK II activity in the PMNs was increased by FMLP, and the increase
      was inhibited by KN-93 but not by rmTNF-alpha. These results suggest that the
      inhibition of CaMK II resulted in the augmentation of FMLP-induced O2- production
      in PMNs by a mechanism different from that of the augmentation shown by TNF
      alpha.

PMID- 10344631
TI  - Insulin lispro: in-vivo potency determination by intravenous administration in
      conscious rabbits.
AB  - Insulin lispro is a monomeric analogue of human insulin, produced by genetic
      engineering, and has been reported to have a more rapid absorption following
      subcutaneous injection than insulin. Since it has been shown to have a similar
      hypoglycaemic action to insulin in clinical studies and comparable properties in
      radioimmunoassay, the feasibility of using a bioassay which was designed
      originally for insulin, to measure insulin lispro potency was evaluated in this
      investigation. A random-dose bioassay protocol, in which insulin lispro and two
      insulin standards were administered intravenously in a random sequence, was used
      and validated in nine conscious healthy rabbits. The decline in blood-glucose
      levels, following the intravenous injection of a dose of insulin or its lispro
      analogue, was monitored by a continuous glucose monitoring system. A glucose
      response curve was generated, from which various pharmacodynamic parameters were
      determined. Compared with the insulin standards, the potencies of insulin lispro
      determined from nadir, basal glucose normalized nadir, glycaemic reduction and
      ABGC (area of the blood-glucose response curve under baseline) were observed to
      have mean (95% confidence limits) values of 97.0 (69.5-124.6)%, 106.3 (72.4
      140.2)%, 949 (51.8-138.0)% and 102.4 (76.3-128.5)%, respectively. In addition,
      the coefficients of variation for correspondent parameters were 36.9, 41.5, 59.1
      and 33.2%, respectively. The results indicated that the hypoglycaemic potency
      calculated from the ABGC values was the most accurate (102.4%) with the least
      coefficient of variation (33.2%). In conclusion, the potency of insulin lispro
      can be determined accurately from the ABGC values measured by the random-dose
      bioassay used.

PMID- 10344632
TI  - Assessment of the adrenergic effects of orphenadrine in rat vas deferens.
AB  - The peripheral adrenergic effects of orphenadrine, an antiparkinsonian drug, have
      been evaluated in the rat vas deferens to investigate whether these properties
      are the same as those of other phencyclidine ligands. In the low micromolar
      range, orphenadrine enhanced electrically-evoked and exogenous noradrenaline
      contractile responses in the epididymal portion of rat vas deferens. It also
      induced spontaneous activity that was inhibited by prazosin (1 microM) but not by
      atropine (20 nM). It inhibited accumulation of [3H]noradrenaline in rat vas
      deferens (IC50 = 14.2+/-2.3 microM). Orphenadrine competitively inhibited
      [3H]nisoxetine binding in rat vas deferens membranes (Ki = 1.05+/-0.20 microM).
      It can be concluded that orphenadrine, at low micromolar concentrations,
      interacts with the noradrenaline reuptake system inhibiting its functionality and
      thus potentiating the effect of noradrenaline.

PMID- 10344633
TI  - Neuropsychopharmacological profile of the methanolic fraction of Bryophyllum
      pinnatum leaf extract.
AB  - Neuropharmacological studies were conducted in experimental animals (rats and
      mice) with the methanolic fraction of Bryophyllum pinnatum leaf extract. The
      fraction produced alteration of behaviour pattern, caused dose-dependent
      potentiation of pentobarbitone sleeping time and had significant analgesic
      activity. Significant reduction of exploratory behaviour and loss of residual
      curiosity were among the effects observed with the fraction. The observations
      suggest that the methanolic fraction of Bryophyllum pinnatum possesses a potent
      CNS depressant action.

PMID- 10344634
TI  - Simple O-acylated derivatives of lysergol and dihydrolysergol-I: synthesis and
      interaction with 5-HT2A, 5-HT2C and 5-HT1B receptors, and alpha1 adrenergic
      receptors.
AB  - A series of simple O-acylated derivatives of the naturally occurring clavine
      alkaloids lysergol and dihydrolysergol-I were synthesized and tested in-vitro for
      their ability to interact with 5-HT2A receptors in rat tail artery, 5-HT2C
      receptors in piglet choroid plexus, 5-HT1B receptors in guinea-pig iliac artery
      and alpha1-adrenergic receptors in rat aorta. In contrast to the classical
      ergoline 5-HT2A receptor antagonists methysergide and LY53857, the compounds
      produced competitive antagonism of the 5-HT response in rat tail artery.
      Affinities of ergolines 3-14 were higher (pA2 values of 7.33-8.40) than those of
      the parent alcohols lysergol (1) and dihydrolysergol-I (2), respectively. The
      introduction of an isopropyl substituent at the N(1) position of the compounds
      failed to enhance 5-HT2A receptor affinity. Compounds 3-14 exhibited lower
      affinities for alpha1-adrenergic receptors than for 5-HT2A receptors. In
      particular, those lysergol derivatives that had an isopropyl substituent at the
      N(1) position were highly specific 5-HT2A receptor antagonists (ratio 5
      HT2A/alpha1 = 302-3548). Selected derivatives of lysergol (3-5, 9-11) which were
      assayed for radioligand binding at 5-HT2C receptors in piglet choroid plexus had
      affinities that were similar to those found in rat tail artery. Additionally,
      lysergol and its N(1)-unsubstituted derivatives were found to be partial agonists
      (alpha of 0.2-0.4) for 5-HT2C receptor-mediated inositol phosphate accumulation
      in piglet choroid plexus. On the other hand, analogues with an isopropyl
      substituent at N(1) showed no measurable agonist activity. The observation that
      N(1)-unsubstituted derivatives of lysergol possessed agonist properties at 5-HT2C
      receptors whereas their agonist activity at 5-HT2A receptors was marginal (alpha
      of 0.05 for compound 3 at 1 microM) or not measurable, suggests that these
      compounds have different abilities to cause conformational change at the two
      receptor types. Selected derivatives of lysergol (3-5, 9-11) which were examined
      as ligands for 5-HT1B receptors in guinea-pig iliac artery caused insurmountable
      blockade of the contractile effect of 5-HT. N(1)-isopropyl derivatives had 30-50
      fold lower affinities for 5-HT1B receptors of this tissue than their N(1)
      unsubstituted analogues. It is concluded that O-acylated derivatives of the
      clavine alkaloids lysergol and dihydrolysergol-I mimic therapeutically relevant
      ergolines due to the complexity of their pharmacological profile as partial
      agonists and antagonists at 5-HT2A, 5-HT2C and 5-HT1B receptors, and at alpha1
      adrenergic receptors.

PMID- 10344635
TI  - Inhibition by leukotriene inhibitors, and calcium and platelet-activating factor
      antagonists, of acute gastric and intestinal damage in arthritic rats and in
      cholinomimetic-treated mice.
AB  - The leukotrienes, platelet activating factor and intracellular calcium have been
      implicated in the development of gastro-intestinal lesions induced by non
      steroidal anti-inflammatory drugs (NSAIDs) but the relative significance of these
      inflammatory mediators in lesion formation has not been established in sensitive
      and specific models of gastro-intestinal ulceration. In the present study the
      effects of drugs affecting 5-lipoxygenase activity, the actions of platelet
      activating factor and intracellular calcium on the development of gastric and
      intestinal ulceration induced by NSAIDs were investigated in highly sensitive
      models of ulcerogenicity induced by treatment with either the cholinomimetic,
      acetyl-beta-methyl choline chloride, in mice (gastric mucosal lesions) or
      adjuvant-induced polyarthritis in rats (gastric and intestinal mucosal lesions)
      as well as in normal mice (intestinal mucosal lesions). The 5-lipoxygenase
      inhibitors, such as MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol
      2-yl]-2,2-+ ++dimethylpropanoic acid), given at doses shown to reduce the
      indomethacin-induced increase in mucosal leukotriene B4 concentrations were found
      to partially prevent the development of gastric and intestinal lesion induced by
      indomethacin and gastric lesions from aspirin, but the same doses of MK-886 did
      not affect gastric lesions from diclofenac. Pretreatment with these inhibitors at
      both 3-5 h and 0-0.25 h was required to achieve protection against gastric
      mucosal damage from indomethacin. Immediate prior administration of platelet
      activating factor antagonists (e.g. WEB-2086) with the 5-lipoxygenase inhibitors
      did not affect gastric or intestinal lesions induced by indomethacin. The calcium
      antagonist, verapamil, was slightly protective against gastric and intestinal
      lesions induced by indomethacin. Gastric lesions were further prevented by
      combinations of a single dose of verapamil with a platelet activating factor
      antagonist but not combined with a 5-lipoxygenase inhibitor; other combinations
      of verapamil with lipoxygenase inhibitors or platelet-activating factor
      antagonists being without inhibitory effects on gastric or intestinal lesions
      compared with the drugs alone. These results show that 5-lipoxygenase products
      and intracellular calcium play a major role in acute gastric and intestinal
      damage by the NSAIDs, but platelet-activating factor has little or no appreciable
      involvement.

PMID- 10344636
TI  - Effects of an essential oil from the bark of Croton cajucara Benth. on
      experimental gastric ulcer models in rats and mice.
AB  - Croton cajucara Benth. (Euphorbiaceae) is widely used in Amazonian folk medicine
      for the treatment of a wide range of gastrointestinal symptoms. The essential oil
      from its bark was investigated for acute toxicity in mice and for its ability to
      prevent the formation of ulceration of the gastric mucosa in different models of
      experimentally induced gastric ulcer in mice and rats. When previously
      administered orally at a dose of 100 mg kg(-1), the essential oil significantly
      reduced (P < 0.01) the gastric injury induced by hypothermic restraint stress
      (48%), indomethacin (47%), ethanol (86%) and pylorus ligature models (87%) in
      rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of
      100 and 200 mg kg(-1), the essential oil from C. cajucara significantly reduced
      (P < 0.01) the formation of gastric lesions by 52% and 67%, respectively, when
      compared with the control group. In rats submitted to pylorus ligature, the
      essential oil given orally increased the volume of gastric juice when compared
      with the control group (P < 0.01). When the essential oil (100 mg kg(-1)) was
      administered intraduodenally to mice, significant modifications were found in
      gastric parameters such as pH and total acid content after oil treatment. We
      observed significant changes (P < 0.01) in gastric juice parameters such as an
      increase in volume and a decrease in gastric acidity (pH and total acid content).
      The acute toxicologic effects of the essential oil from C. cajucara were assessed
      in mice. The LD50 values were 9.3 g kg(-1) by the oral route and 680 mg kg(-1) by
      the intraperitoneal route. The good yield of essential oil obtained from dried C.
      cajucara bark (1%) as well as its anti-ulcerogenic activity and low toxicity
      suggest that pharmacological studies of this substance as a potential new anti
      ulcerogenic drug are warranted.

PMID- 10344637
TI  - Pharmacokinetics of BOF-4272, a xanthine oxidase inhibitor, after single
      intravenous or oral administration to male mice and rats.
AB  - BOF-4272, (+/-)-8-(3-methoxy-4-phenylsulphinylphenyl) pyrazolo [1,5-a]-1,3,5
      triazine-4 (1H)-one), is a new drug intended for the treatment of hyperuricaemia.
      This report describes the detailed pharmacokinetics of BOF-4272 in mice and rats
      after intravenous or oral administration. Plasma concentrations of BOF-4272 at 2
      8h after intravenous administration were significantly higher in mice than in
      rats. Plasma concentrations of BOF-4272 after oral administration were
      significantly higher in fed mice than in fasted mice, but were similar in fasted
      and fed rats. The elimination half-life of the distribution phase (t1/2(alpha))
      was similar in mice (0.158 h) and rats (0.210 h). The elimination half-life of
      the terminal elimination phase (t1/2(beta)) in mice was 1.936 h, while that in
      rats was 0.742 h. The volume of the central compartment (V1) was almost the same
      in mice (415 mL kg(-1)) and rats (440 mL kg(-1)). However, the volume of the
      peripheral compartment (V2) in mice was 1068 mL kg(-1), while that in rats was 92
      mL kg(-1). The steady-state volume of distribution (Vss) was 2.8 times larger in
      mice than in rats. The area under the plasma concentration-time curve (AUC) in
      mice was 5332 ng h mL(-1), while that in rats was 3806 ng h mL(-1). The AUC0-24 h
      after oral administration was 2.5 times greater in fed mice than in fasted mice,
      and was 1.4 times greater in fasted rats than in fed rats. The correlation
      coefficients of Cmax and AUC0-24 h in both mice and rats after oral
      administration were greater than 0.997 in the dose range 1 - 125 mg kg(-1),
      indicating that the linear range of absorption or elimination (or both) of BOF
      4272 is very wide. The results of the present study demonstrate that the mouse is
      a suitable animal species for evaluating the clinical pharmacokinetics of BOF
      4272.

PMID- 10344638
TI  - Fate of the flavonoid quercetin in human cell lines: chemical instability and
      metabolism.
AB  - Although cell cultures are increasingly being used as models for studying the
      biological actions of flavonoids, no information on the fate, such as uptake and
      metabolism, exists for these natural products in these models. This study
      examined the elimination of quercetin, one of the most abundant flavonoids, from
      the cultured human hepatocarcinoma cell line Hep G2 using [14C]-labelled compound
      with HPLC and LC/MS for structure characterization. These cells showed a 9.6-fold
      accumulation of quercetin and the formation of an O-methylated metabolite,
      isorhamnetin. However, a rapid elimination of quercetin, with no unchanged
      compound present beyond 8 h, was mainly due to oxidative degradation. The initial
      intermediate reaction appears to involve peroxidation, leading to a dioxetan, as
      evidenced by a 32-amu increase in the molecular ion by LC/MS. Subsequently,
      opening of the C-ring leads to the formation of carboxylic acids, the major one
      identified in this study as protocatechuic acid. A separate reaction results in a
      polymeric quercetin product which is highly retained on a reversed-phase C18 HPLC
      column. It is postulated that these degradative and metabolic changes contribute
      to the multiple biological actions reported for quercetin, using cell culture
      models. Interestingly, part of the degradative pathway could be inhibited by
      including nontoxic concentrations of EDTA in the cell culture medium.

PMID- 10344639
TI  - Effect of acute renal failure on the disposition of cefoperazone.
AB  - The effect of acute renal failure on the disposition of cefoperazone was
      investigated. Rats, 3 days after uranyl nitrate treatment, were used to model
      acute renal failure. Although plasma-protein binding of cefoperazone decreased
      significantly in acute renal failure compared with control rats, the plasma
      clearance of total (bound plus unbound) drug after intravenous administration (50
      mg kg(-1)) did not differ significantly between the two groups (5.61+/-2.37 mL
      min(-1) for control and 4.75+/-2.82 mL min(-1) for acute renal failure).
      Consequently the plasma clearance of the unbound drug in acute renal failure
      (6.14+/-1.16 mL min(-1)) was significantly lower than in control rats (15.6+/-3.7
      mL min(-1), P < 0.025). Plasma clearance of the drug (both total and unbound) was
      also dependent on bile flow, and clearance of the unbound drug in acute renal
      failure rats was lower than in control rats with identical bile flow rates. To
      examine the mechanism of reduced unbound cefoperazone clearance, an in-vitro
      experiment using a simultaneous perfusion system of rat liver and kidney was
      performed. By changing perfusate plasma protein from bovine serum albumin to
      human serum albumin, the plasma clearance of the total cefoperazone changed to
      one-sixth in proportion to the unbound cefoperazone in the perfusate plasma. On
      the other hand, the plasma clearance of the total and unbound drug in acute renal
      failure rats decreased significantly compared with controls. These results
      demonstrate that the plasma clearance of unbound cefoperazone, which is mainly
      eliminated by the liver, decreased in acute renal failure in rats, probably due
      to changes in hepatic transport.

PMID- 10344640
TI  - First-degree atrioventricular block in alprazolam overdose reversed by
      flumazenil.
AB  - This report describes a case of alprazolam overdose associated with marked first
      degree atrioventricular block reversed by flumazenil. Animal and human evidence
      suggests activity of certain benzodiazepines at peripheral benzodiazepine
      receptors in the myocardium and elsewhere. Myocardial benzodiazepine receptor
      ligands appear to affect calcium-channel activity, which may explain the clinical
      findings. Benzodiazepines may behave like weak calcium-channel blockers. This
      case raises the possibility of a potential role for flumazenil as an adjunct in
      the management of calcium-channel blocker toxicity.

PMID- 10344641
TI  - Morphometry and acetylcholinesterase activity of the myenteric neurons of the
      mouse colon in the chronic phase of experimental Trypanosoma cruzi infection.
AB  - The myenteric plexus of the proximal colon, midcolon, and distal colon was
      studied in mice chronically infected with the Y strain of Trypanosoma cruzi by
      means of histochemical methods for NADH-diaphorase and acetylcholinesterase
      (AChE) on whole mount preparations. Ganglia of infected mice displayed an
      irregular distribution, with neurons severely altered in form and were found side
      by side with slightly degenerated or morphologically normal ones. Significant
      reductions of at least 36% in the numbers of neurons were recorded in all regions
      of the colons of infected animals, especially in the distal colon where the
      neuron number decreased by more than 44%. Measurements of neuron size suggest
      that the neuronal destruction caused by T. cruzi affected the medium and large
      neurons. The small neurons apparently were not affected by the infection. The
      histochemical demonstration of AChE by the direct coloring copper ferrocyanide
      method showed that in the control animals, most of the neurons of the plexus
      displayed AChE activity in the cytoplasm although the neurons showed different
      reaction intensities. The AChE activity was also present, but at a lower
      intensity, in the myenteric plexus of the colons of infected animals. These
      results suggest that the T. cruzi infection affects some categories of neurons
      and implies that some particular enteric neurotransmitter systems could be
      affected and the potency of their action upon intestinal function consequently
      reduced.

PMID- 10344642
TI  - Myocardial parasite persistence in chronic chagasic patients.
AB  - The persistence of Trypanosoma cruzi tissue forms was detected in the myocardium
      of seropositive individuals clinically diagnosed as chronic chagasic patients
      following endomyocardial biopsies (EMBs) processed by immunohistochemical
      (peroxidase-anti-peroxidase [PAP] staining) and molecular (polymerase chain
      reaction [PCR]) techniques. An indirect immunofluorescent technique revealed
      antigenic deposits in the cardiac tissue in 24 (88.9%) of 27 patients. Persistent
      T. cruzi amastigotes were detected by PAP staining in the myocardium of 22
      (84.6%) of 26 patients. This finding was confirmed with a PCR assay specific for
      T. cruzi in 21 (91.3%) of 23 biopsy specimens from the same patients. Statistical
      analysis revealed substantial agreement between PCR and PAP techniques (k = 0.68)
      and the PCR and any serologic test (k = 0.77). The histopathologic study of EMB
      specimens from these patients revealed necrosis, inflammatory infiltrates, and
      fibrosis, and made it possible to detect heart abnormalities not detected by
      electrocardiogram and/or cineventriculogram. These indications of myocarditis
      were supported by the detection of T. cruzi amastigotes by the PAP technique or
      its genome by PCR. They suggest that although the number of parasites is low in
      patients with chronic Chagas' disease, their potential for heart damage may be
      comparable with those present during the acute phase. The urgent necessity for
      testing new drugs with long-term effects on T. cruzi is discussed in the context
      of the present results.

PMID- 10344643
TI  - Red blood cell deformability as a predictor of anemia in severe falciparum
      malaria.
AB  - Decreased erythropoiesis and increased clearance of both parasitized and
      noninfected erythrocytes both contribute to the pathogenesis of anemia in
      falciparum malaria. Erythrocytes with reduced deformability are more likely to be
      cleared from the circulation by the spleen, a process that is augmented in acute
      malaria. Using a laser diffraction technique, we measured red blood cell (RBC)
      deformability over a range of shear stresses and related this to the severity of
      anemia in 36 adults with severe falciparum malaria. The RBC deformability at a
      high shear stress of 30 Pa, similar to that encountered in the splenic sinusoids,
      showed a significant positive correlation with the nadir in hemoglobin
      concentration during hospitalization (r = 0.49, P < 0.002). Exclusion of five
      patients with microcytic anemia strengthened this relationship (r = 0.64, P <
      0.001). Reduction in RBC deformability resulted mainly from changes in
      unparasitized erythrocytes. Reduced deformability of uninfected erythrocytes at
      high shear stresses and subsequent splenic removal of these cells may be an
      important contributor to the anemia of severe malaria.

PMID- 10344644
TI  - Short report: Diagnosis of tick-borne relapsing fever by the quantitative buffy
      coat fluorescence method.
AB  - The quantitative buffy coat (QBC) parasite detection method is a sensitive and
      specific tool for the diagnosis of malaria parasites. It is also useful for the
      diagnoses of other hemoparasites, including Trypanosoma, Babesia, and Leptospira.
      We report a case of relapsing fever diagnosed by this technique in a short-term
      traveler from Senegal. The diagnosis was confirmed by the standard Giemsa
      hemoscopy and by the identification of significant titers of antibodies to
      Borrelia spp. of tick-borne relapsing fevers by specific immunofluorescence and
      Western blot tests. The QBC technique seems to be useful in the diagnosis of tick
      borne relapsing fever in blood samples and should be included in the management
      of fever in the traveler returning from tropical regions.

PMID- 10344645
TI  - Utility of the polymerase chain reaction in detection of Trypanosoma cruzi in
      Guatemalan Chagas' disease vectors.
AB  - For effective control programs, accurate assessment of Trypanosoma cruzi
      infection in vectors is essential and has traditionally been performed by
      microscopic examination. For particular vectors and not others, polymerase chain
      reaction (PCR) analysis of fecal samples recently has been shown to be an
      effective means of detection. The sensitivities of the PCR and microscopy for
      detection of T. cruzi in different anatomic sites were compared in the two major
      vectors of Guatemala, Triatoma dimidiata and Rhodnius prolixus. Preliminary
      studies established that T. cruzi can be detected by the PCR in the presence of
      90% T. rangeli. One hundred thirty-five vectors were collected, and samples were
      obtained from the rectum, intestines, and stomach and analyzed by microscopy and
      the PCR. For Triatoma dimidiata rectal samples, the PCR sensitivity (39.1% T.
      cruzi positive) and the microscopic sensitivity (24.6% positive) was not
      significantly different. However, in R. prolixus, the PCR proved significantly
      more sensitive than microscopy: 57.6% positive by PCR compared with 22.7% by
      microscopy. Rectal samples showed the highest rates of infection followed by
      intestine and stomach samples. However, 10.5% of the Rhodnius infections would
      have been missed if only the rectal sample had been analyzed. Thus, the PCR is
      significantly more sensitive than microscopy for detection of T. cruzi in R.
      prolixus. Analysis of anatomic sites in addition to the rectal sample may be
      necessary for accurate assessment of infection in particular vectors.

PMID- 10344646
TI  - Short report: Diagnosis of human fascioliasis: detection of anti-cathepsin L
      antibodies in blood samples collected on filter paper.
AB  - We have developed an ELISA for the diagnosis of human fascioliasis based on the
      detection of IgG4 antibodies to Fasciola hepatica cathepsin LI cysteine protease.
      Use of this assay in the Bolivian Altiplano, a region with a high prevalence of
      the disease, was hampered by the reluctance of the indigenous population to
      provide blood. To overcome this problem, we have investigated the method of
      collecting small quantities of blood from the finger onto filter paper, followed
      by the elution of antibodies for use in the diagnostic assay. Serum samples and
      blood samples collected onto filter paper were obtained from 57 individuals
      living in the village of Cutusuma in 1987 and from 11 individuals in Chijipata in
      1996. Analysis of the IgG4-ELISA results revealed that there is highly
      significant linear relationship (P < 0.001) between the two methods of sampling.
      Most importantly, a reliable diagnosis was made with the blood-filter samples
      from Cutusuma, which had been stored for 10 years at 40 degrees C. While some
      deterioration of the blood-filter samples from Cutusuma had occurred over the 10
      year storage period, no deterioration occurred with the Chijipata samples, which
      were stored for one year. Therefore, the method of collecting blood onto filter
      paper should prove useful for large-scale epidemiologic studies on human
      fascioliasis in the Bolivian Altiplano and in other regions where this disease is
      prevalent.

PMID- 10344647
TI  - Short report: Immunodiagnosis of human fascioliasis using recombinant Fasciola
      hepatica cathepsin L1 cysteine proteinase.
AB  - Our laboratory recently developed a diagnostic test (ELISA) for human
      fascioliasis based on the detection of serum IgG4 antibodies reactive with
      Fasciola hepatica cathepsin L1 (CL1). In the present study, we have used
      recombinant CL1, generated by functional expression of the cDNA in Saccharomyces
      cerevisiae, in this immunodiagnostic test and compared its performance with
      native CL1. Sera obtained from 64 individuals living in Cutusuma village in the
      northern Altiplano of Bolivia, a region with a high prevalence of human
      fascioliasis, were analyzed by the IgG4-ELISA. A highly statistically significant
      correlation (r2 = 0.751, P < 0.001) was demonstrated between the absorbances
      obtained using the recombinant and native proteins. These assays showed that 38
      (59%) of the individuals tested were seropositive for fascioliasis, whereas only
      26 of them were coprologically positive for F. hepatica eggs. All seronegative
      patients were also coprologically negative. Serum from individuals infected with
      schistosomiasis mansoni, cysticercosis, hydatidosis, and Chagas disease did not
      contain antibodies reactive with the recombinant or native CL1. Therefore,
      recombinant CL1 shows excellent potential for the development of the first
      standardized assay for the sensitive and specific diagnosis of human
      fascioliasis. Finally, our data supports earlier reports on the high prevalence
      of human fascioliasis in the Bolivian Altiplano, which collectively suggest that
      the disease has been endemic there for more than a decade.

PMID- 10344648
TI  - No serologic evidence of an association found between Gulf War service and
      Mycoplasma fermentans infection.
AB  - Occult occupational infection with Mycoplasma fermentans has been proposed as a
      cause for illness among Persian Gulf War veterans. Symptom data and sera from a
      1994-1995 cross-sectional survey of Navy Seabees were used to select symptomatic
      and asymptomatic Gulf War veterans and nondeployed veterans to evaluate this
      hypothesis. Survey sera from 96 Seabees were matched to prewar (before September
      1990) archived sera. Immunoblot serologic analyses were performed for M.
      fermentans in a controlled, blinded fashion. Both Gulf War veterans and
      nondeployed veterans had prewar and postwar serologic evidence of M. fermentans
      infection consistent with natural infection data. Among study subjects
      collectively, and stratified by Gulf War service, none of the immunoblot banding
      profiles (prewar or postwar) or their changes over time were associated with
      postwar symptoms. These serologic data do not support the hypothesis that Gulf
      War veterans have experienced Gulf War-related morbidity from M. fermentans
      infection.

PMID- 10344649
TI  - Increased postwar symptoms and psychological morbidity among U.S. Navy Gulf War
      veterans.
AB  - To investigate reports on war-related morbidity, 527 active-duty Gulf War
      veterans and 970 nondeployed veterans from 14 Seabee commands were studied in
      1994 with a questionnaire, sera collection, handgrip strength, and pulmonary
      function testing. The questionnaire assessed postwar symptoms, war exposures, and
      screened for chronic fatigue syndrome, post-traumatic stress disorder, and
      psychological symptoms suggesting neurosis (Hopkins Symptom Checklist). Sera were
      tested with four nonspecific reactant assays: C-reactive protein, transferrin,
      ferritin, and haptoglobin. Gulf War veterans reported a higher prevalence for 35
      of 41 symptoms, scored higher on psychological symptom scales, were more likely
      to screen for post-traumatic stress disorder, had lower handgrip strength, and
      had higher serum ferritin assay results. Numerous comparisons of these morbidity
      outcomes with 30 self-reported exposures demonstrated many associations, but no
      unique exposure or group of exposures were implicated. Morbidity data are
      consistent with other postwar observations, but the etiology for morbidity
      findings remains uncertain.

PMID- 10344650
TI  - Differential perpetuation of malaria species among Amazonian Yanomami
      Amerindians.
AB  - To determine whether malaria perpetuates within isolated Amerindian villages in
      the Venezuelan Amazon, we surveyed malaria infection and disease among 1,311
      Yanomami in three communities during a 16-month period. Plasmodium vivax was
      generally present in each of these small, isolated villages; asymptomatic
      infection was frequent, and clinical disease was most evident among children less
      than five years of age (odds ratio [OR] = 6.3, 95% confidence interval [CI] = 1.4
      29.2) and among persons experiencing parasitemias > or = 1,000 parasites/mm3 of
      blood (OR = 45.0, 95% CI = 5.5-370.7). Plasmodium falciparum, in contrast, was
      less prevalent, except during an abrupt outbreak in which 72 infections resulted
      in symptoms in all age groups and at all levels of parasitemia, and occasionally
      were life-threatening. The observed endemic pattern of P. vivax infection may
      derive from the capacity of this pathogen to relapse, while the epidemic pattern
      of P. falciparum infection may reflect occasional introductions of strains
      carried by immigrants or residents of distant villages and the subsequent
      disappearance of this non-relapsing pathogen.

PMID- 10344651
TI  - Effect of chemotherapy on malaria transmission among Yanomami Amerindians:
      simulated consequences of placebo treatment.
AB  - To determine whether chemotherapy effectively reduces Plasmodium falciparum
      malaria transmission in isolated human populations, we followed two abrupt
      sequential outbreaks of malaria infection among Yanomami Amerindians and modeled
      the effect of chemotherapy and the consequences if no drug was available. A
      Macdonald-type mathematical model demonstrated that both outbreaks comprised a
      single epidemic event linked by an invisible outbreak in vector mosquitoes. The
      basic reproductive number, R0, from fitted values based on the treated epidemic
      was 2 during the initial phase of the epidemic, and waned as vector density
      decreased with the onset of the dry season. In the observed epidemic, 60 (45%) of
      132 village residents were affected, and the treated outbreak ended after two
      months. Although the initial chemotherapy regimen was only marginally effective,
      the duration of human infectivity was reduced from an expected nine months to two
      weeks. In the absence of this intervention, the initial R0 value would have been
      40, more than 60% of the population would have been infected, and more than 30%
      would have remained parasitemic until the next rainy season (about six months
      later). Another outbreak would then have ensued, and malaria probably would have
      remained endemic in this village. Our simulated placebo treatment permits us to
      conclude that even partially effective chemotherapeutic interventions, such as
      those in our study, interrupt serial transmission of P. falciparum among isolated
      human populations that are exposed to infection seasonally.

PMID- 10344652
TI  - Vector-related case-control study of severe malaria in Kilifi District, Kenya.
AB  - A case-control study examined vector-related and environmental parameters
      associated with severe malaria in Kilifi District along the coast of Kenya. Over
      an 11-month period, 119 children identified with severe malaria infections at the
      Kilifi District Hospital were matched by age with control children who reported
      to the outpatient clinic with nonsevere infections. Intensive mosquito sampling
      was done in each of the case-control houses over a four-day period, beginning
      within a week of index case admission. A total of 109 environmental, demographic,
      behavioral, and animal husbandry variables were characterized for each household.
      Vector species (Anopheles gambiae s.l. and An. funestus) were detected in 40.1%
      and 36.1% of case and control houses, respectively. The relative abundance of
      vectors in individual houses was stable over the two-week resampling periods (r =
      0.9). Both the overall abundance of anopheline mosquitoes (odds ratio [OR] = 1.5)
      and P. falciparum sporozoite rates (OR = 1.5) were not significantly different
      between case and control houses. In a matched analysis, 11 of 109 house variables
      associated significantly with severe malaria were also associated with vector
      abundance, as determined by chi-square linear trend analysis. Under conditions of
      year-round, low-level transmission on the coast of Kenya, the risk of severe
      disease in children is multifactorial and not governed strictly by transmission
      intensity or environmental heterogeneity affecting vector abundance and
      distributions. This suggests that current interventions that appear to be
      achievable only in areas where transmission is already low to moderate should be
      appropriate. However, such interventions should be monitored so that
      inappropriate and possibly disastrous control activities can be avoided in
      Africa.

PMID- 10344653
TI  - Rickettsia serosurvey in Kimberley, Western Australia.
AB  - To determine if antibodies to rickettsiae (scrub typhus, spotted fever, and
      typhus group rickettsiae) occur among persons living in the Kimberley (northern
      tropical) region of Western Australia, 920 sera collected in a non-random manner
      in 1996 from patients in Kununurra, Broome, Fitzroy Crossing, Wyndham, Derby, and
      Halls Creek were tested by micro-immunofluorescence for antibodies to a panel of
      rickettsial antigens. Of 920 sera examined, 52 (5.6%) were positive for
      antibodies to one or more of the three groups of rickettsial microorganisms. The
      largest group of sera (24; 2.6%) were positive for scrub typhus (Orientia
      tsutsugamushi). Eleven other sera (1.2%) were positive for scrub typhus and
      spotted fever group rickettsiae and four (0.4%) were positive for scrub typhus,
      spotted fever group, and typhus group rickettsiae. In addition 13 sera (1.4%)
      were positive only for spotted fever group rickettsiae. In this study, only
      titers > or = 1:256 were considered significant. Thus, there is serologic
      evidence for scrub typhus and spotted fever group rickettsial infections in the
      Kimberley region of Western Australia. Because of the method of serum collection,
      it is not possible to determine the prevalence of seropositivity, but the data
      support the need for a proper epidemiologic study of rickettsial diseases in this
      region of Australia.

PMID- 10344654
TI  - Decreased seroprevalence for Toxoplasma gondii in Seventh Day Adventists in
      Maryland.
AB  - Despite its widespread prevalence, uncertainties remain about the relative
      contribution of various routes of transmission to the overall rate of infection
      with Toxoplasma gondii, particularly in developed countries. To explore the
      hypothesis that meat consumption is an important risk factor for infection, a
      cross-sectional seroprevalence study was performed on healthy adults in one
      region in the state of Maryland. The population included Seventh Day Adventists
      who as a group follow a diet containing no meat, and control community volunteers
      who were not Seventh Day Adventists. Thirty-one percent of the population had
      serologic evidence of T. gondii infection. People with T. gondii infection were
      older (49 versus 42 years old; P < 0.01, by t-test) and less likely to be Seventh
      Day Adventists (24% versus 50%; P < 0.01, by chi-square test) than people without
      T. gondii infection. When adjustments were made for age and gender through
      multiple logistic regression, Seventh Day Adventists had a significantly
      decreased risk of T. gondii infection (odds ratio = 0.21, 95% confidence interval
      = 0.09-0.46, P = 0.0001) compared with the controls. While the basis for this
      effect remains to be determined, one possible protective factor is the general
      adherence of Seventh Day Adventists to a diet that does not contain meat.

PMID- 10344655
TI  - Risk factors for infection with Toxoplasma gondii for residents and workers on
      swine farms in Illinois.
AB  - Risk factors for Toxoplasma gondii infection in workers and residents of swine
      farms were studied on 43 farms in Illinois. Blood samples were collected from 174
      adults in 1993. The T. gondii seroprevalence was 31%. An interview was conducted
      with each participant, obtaining information on demographic characteristics and
      behaviors suspected to affect the risk of T. gondii infection. Factors associated
      with increased risk of T. gondii seropositivity were a higher number of
      seropositive cats trapped on the farm, male sex, rearing pigs on pasture, and
      gardening. Factors associated with a decreased risk were handling of pig feed and
      presence of cats inside the pig facilities. Thus, infection of cats with T.
      gondii increased the risk of human infection, and contact with soil was a likely
      mechanism for transmission. The increased risk of seropositivity in males is
      attributed to less attention paid to cleanliness in food preparation and eating.

PMID- 10344656
TI  - Survey of Bartonella species infecting intradomicillary animals in the
      Huayllacallan Valley, Ancash, Peru, a region endemic for human bartonellosis.
AB  - The natural cycle of Bartonella bacilliformis remains uncertain, and the
      suspected existence of animal reservoirs for the bacterium has never been
      convincingly demonstrated. We conducted a survey of Bartonella species infecting
      intradomicillary animals in a bartonellosis-endemic region of Peru, obtaining
      blood from 50 animals living in the homes of 11 families whose children had
      recently had bartonellosis. Bartonella-like bacteria were recovered from four of
      nine small rodents included in the study, but from none of the 41 domesticated
      animals. Identification and comparison of these isolates, and two Bartonella-like
      isolates obtained from Phyllotis mice in a different endemic region of Peru using
      serologic and genotypic methods indicated that although none were strains of B.
      bacilliformis, five were probably representatives of three previously
      unrecognized Bartonella species and one was a likely strain of the pathogenic
      species B. elizabethae.

PMID- 10344657
TI  - Seroepidemiology of California and Bunyamwera serogroup (Bunyaviridae) virus
      infections in native populations of Alaska.
AB  - This study investigated the geographic distribution and prevalence of antibodies
      to California and Bunyamwera serogroup viruses in Native populations of Alaska,
      and demographic and ecologic risk factors associated with exposure. Sera (n =
      1,635) from 18 communities were screened using an ELISA. All age groups were
      tested for antibodies to Jamestown Canyon (JC), Inkoo (INK), snowshoe hare (SSH),
      and Northway (NOR) viruses; persons > or = 45 years old (n = 90) from six
      communities were additionally tested for antibodies to Tahyna (TAH), Batai (BAT),
      Cache Valley (CV), and Sindbis (SIN) viruses. Thirty free-ranging mammals were
      tested by a plaque reduction neutralization test (PRNT) for antibodies to all
      eight viruses and to Getah (GET) virus. In Natives, overall antibody prevalence
      was 24.9% (JC = 17.6%, monotypic JC = 6.5%, INK = 11.1%, monotypic INK = 0.6%,
      SSH = 6.8%, monotypic SSH = 3.5%, and NOR = 6.2%). Five TAH, CV, and BAT virus
      exposures may be serologic cross-reactions, and no SIN virus antibodies were
      detected. Sindbis-like virus antibodies were found in 30% of the mammals. Most
      mammals had antibodies to NOR (83.3%) and California serogroup (70.0%) viruses;
      no GET virus exposures were found. Significant risk factors for human bunyavirus
      exposures were age group, ethnic-linguistic group, biotic province, climate zone,
      terrestrial vegetation, and presence of some ungulates and small mammals in
      communities. Sex was not a significant risk factor.

PMID- 10344658
TI  - Emergence of Schistosoma mansoni infection in upper Egypt: the Giza governorate.
AB  - We found an unexpectedly high prevalence of Schistosoma mansoni in a village in
      the Upper Egyptian governorate of Giza. Historically, S. mansoni is endemic in
      the northern Egyptian Nile Delta rather than in the southern Upper Egypt. This
      observation was made during an evaluation of a rural health care schistosomiasis
      surveillance program using a cross sectional survey for S. haematobium and S.
      mansoni in the village of El-Gezira El-Shakra El-Saf district in the Upper Egypt
      Giza Governorate. A 10% systematic random sample of households of the village was
      chosen. All persons in the selected houses were invited to submit urine and stool
      samples. All students from a primary school were also included in the study.
      Urine was screened by a polycarbonate filtration method and stool was examined
      using modified Kato-Katz technique. The prevalence of S. mansoni in the
      population sample and in the school children was 33.7% and 57.7%, respectively,
      whereas the prevalence of S. haematobium infection in the population sample and
      the school children was 7.4% and 10.6%, respectively. The prevalence of infection
      was highest in the younger age groups, and males were infected more than females.
      Review of Ministry of Health records showed that both species of vector snails,
      Bulinus truncatus and Biomphalaria alexandrina, were present from 1991 to 1995,
      and that B. alexandrina was more abundant than B. truncatus in the canals
      surrounding this village. The unexpected high prevalence of S. mansoni in this
      village indicates an urgent need to include training programs for S. mansoni
      surveillance in the primary health care facilities of Giza and to educate
      villagers to request examinations for S. mansoni as well as for S. haematobium
      infection.

PMID- 10344659
TI  - Seroepidemiology of schistosomiasis in Puerto Rico: evidence for vanishing
      endemicity.
AB  - The current study summarizes our findings of anti-schistosome egg antibody by the
      circumoval precipitin test for two different populations in Puerto Rico. One
      group, exclusively males more than 40 years of age and from all municipalities on
      the island, was from the Veterans Administration Hospital for the period 1988
      1997. The second group resided southeast of San Juan, around the municipality of
      Caguas and adjacent municipalities east of Caguas, was of both sexes and mostly
      until 1997 of undetermined ages for the period 1993-1997. Results reveal a yearly
      decrease in testing requests from the Veterans Administration Hospital from 148
      in 1988 and 1989 with 16% positive to three in 1996 through 1998 with none
      positive. This decrease in testing requests was because of a decrease of
      suspicion of schistosomiasis in this group. The other patient population from the
      Caguas region showed a gradual but continuous decrease in seropositive
      individuals from 21% in 1993 to 12% in 1996, with precipitous decrease to 5% in
      1997 and only 1% in 1998. Moreover, there were four patients from which at least
      two serum samples were obtained one or two years apart and tested. In each
      instance the more recently obtained sample had lower antibody reactions than the
      first as reflected in lower percentages of positive egg reactors. The fact that
      they were treated with praziquantel after the first testing also suggests that
      the infected population was being eliminated through chemotherapy. These combined
      results suggest the elimination of infections with Schistosoma mansoni in the
      traditionally high prevalence regions east of San Juan in the absence of any
      proactive control efforts in Puerto Rico. Because of the rapid urbanizing of
      Puerto Rico, the one identifiable control effort is economic development and well
      being.

PMID- 10344660
TI  - Prophylactic activity of atovaquone against Plasmodium falciparum in humans.
AB  - The prophylactic antimalarial activity of atovaquone was determined in a
      randomized, double-blind, placebo-controlled study of healthy volunteers who were
      challenged by the bite of Plasmodium falciparum-infected Anopheles stephensi.
      Subjects were randomly assigned to one of three groups: six received seven daily
      doses of 750 mg of atovaquone, starting the day before challenge; six received a
      single dose of 250 mg of atovaquone the day before challenge; and four received
      placebo. Polymerase chain reaction- and culture-confirmed parasitemia developed
      in all four placebo recipients, but in none of the drug recipients, indicating
      that either of the atovaquone regimens provides effective prophylaxis (P =
      0.005). However, in low-dose recipients, the drug levels by day 6.5 were
      profoundly subtherapeutic, indicating that parasites were eliminated prior to the
      establishment of erythrocytic infection. Atovaquone thus protects non-immune
      subjects against mosquito-transmitted falciparum malaria, and has causal
      prophylactic activity.

PMID- 10344661
TI  - Failure of amphotericin B colloidal dispersion in the treatment of
      paracoccidioidomycosis.
AB  - Although amphotericin B desoxycholate is considered the most effective treatment
      for disseminated Paracoccidioides brasiliensis infections, little is known about
      the efficacy of lipid-based formulations of amphotericin B in this infection. In
      this study, we treated four adults with the juvenile form of
      paracoccidioidomycosis with 3 mg/kg/day of amphotericin B colloidal dispersion
      for at least 28 days. Although all of the patients initially responded by
      clinical observation, all four patients relapsed within six months. The use of
      amphotericin B colloidal dispersion for the initial induction of
      paracoccidioidomycosis failed to cure this infection. Possible reasons for
      failure include dose, duration, or reduced efficacy of this lipid preparation.
      For many fungal infections, lipid-based preparations have been shown to have a
      therapeutic-toxic advantage, but our experience with Paracoccidioides infections
      suggests that more careful studies will need to be performed before they can be
      recommended for use in this mycosis.

PMID- 10344662
TI  - Necator americanus (human hookworm) aspartyl proteinases and digestion of skin
      macromolecules during skin penetration.
AB  - The infective larvae of Necator americanus were shown to secrete all mechanistic
      classes of proteolytic enzymes with two overall pH optima of 6.5 and 8.5 using
      fluorescein isothiocyanate-labeled casein as the substrate. Since infective
      larvae are obligate skin penetrators, the effect of each of these enzyme classes
      against macromolecules derived from human skin was examined. Larval secretions
      were shown to degrade collagen types I, III, IV, and V, fibronectin, laminin, and
      elastin. All the skin macromolecules tested were hydrolyzed by aspartyl
      proteinase activity, which was inhibitable by pepstatin A. Collagen and elastin
      was also hydrolyzed by metalloproteinase activity, while the serine proteinase
      activity hydrolyzed only elastin. As a consequence of these experiments, the
      effect of proteinase inhibitors on the penetration of live larvae through hamster
      skin was tested. Larval penetration was significantly inhibited only by pepstatin
      A, confirming the importance of the aspartyl proteinase activity during the skin
      penetration process.

PMID- 10344663
TI  - Long-term persistence of cellular hyporesponsiveness to filarial antigens after
      clearance of microfilaremia.
AB  - The persistence of parasite-specific cellular hyporesponsiveness after clearance
      of blood microfilariae (mf) was studied in 18 individuals who had been treated
      with a single dose of ivermectin, diethylcarbamazine, or a combination 2-3 years
      previously and who had initially cleared their parasitemia. At recruitment into
      the present study, 50% were again mf+ and 50% remained mf-. There were no
      significant differences between the mf+ and mf- groups in the amount of
      interferon-gamma (IFN-gamma) produced by peripheral blood mononuclear cells in
      response to adult or microfilarial antigens, although IFN-gamma production in
      response to purified protein derivative was greater in the mf+ group (geometric
      mean [gm] = 3,791 pg/ml; P = 0.02) than in the mf- group (gm = 600 pg/ml). These
      data suggest that although microfilaremic individuals may temporarily regain the
      ability to produce IFN-gamma to parasite antigens post-treatment, they
      subsequently revert to a state of hyporesponsiveness to mf-containing antigens
      that appears to be independent of the recurrence of microfilaremia and the
      response to nonparasite antigens.

PMID- 10344664
TI  - Phlebotomine sand fly (Diptera: Psychodidae) seasonal distribution and infection
      rates in a defined focus of Leishmania tropica.
AB  - A two-year study was conducted of phlebotomine sand fly fauna in a defined focus
      of Leishmania tropica. A total of 17,947 sand flies representing 10 species were
      collected from the location. Phlebotomus guggisbergi, a vector of L. tropica in
      Kenya, was the most prevalent species through the entire period, representing
      about 80% of the total catch. There was marked seasonal fluctuation in the
      populations of the three most common species, with highest population levels
      reached in December and lowest levels reached in July and August. Leishmania-like
      infections were encountered in 489 P. guggisbergi. No flagellate infections were
      observed in any other species of sand fly. Although infected P. guggisbergi were
      collected during each month of the year, the percent parous infected flies was
      highest (27.5%) during the November through January time period. These data show
      that the greatest risk of transmission to humans at this focus occurs during
      December, when the vector is prevalent and infections are common.

PMID- 10344665
TI  - Automated measurement of oxygen consumption by the yellow fever mosquito, Aedes
      aegypti.
AB  - Oxygen consumption of single mosquitoes was measured using a differential
      pressure transducer (DPT) connected to two small chambers. A mosquito was placed
      in the experimental chamber (P1) and was separated from NaOH by 4 cm2 of
      marquisette mesh. The reference chamber (P2) contained the same amount of NaOH
      and the marquisette mesh but without a mosquito. When these two chambers were
      sealed, removed O2 from P1 resulted in a pressure decrease with respect to P2.
      This pressure differential was transduced into an output voltage that was
      directly proportional to the amount of O2 consumed by the mosquito. An array of
      eight DPTs was interfaced with an IBM 486 PC using an ADAC 5500MF analog to
      digital converter and software from ADAC (Direct View) to automate the recording
      procedure. We determined that our apparatus was sensitive enough to detect subtle
      differences in O2 consumption in mosquitoes subjected to different physiologic
      conditions.

PMID- 10344666
TI  - Imported African tick bite fever: a case report.
AB  - We describe a patient with African tick-bite fever who acquired his infection
      while visiting rural areas of South Africa and then became sick after returning
      to the United States. The dominant clinical feature of his illness was the
      presence of multiple, ulcerated lesions (tache noires). Physicians in the United
      States and other non-African countries who see travelers returning from southern
      parts of Africa who give a history of recent tick bite and/or present with
      multiple, crusted or vesicular skin lesions should be alert to this diagnosis and
      institute treatment with doxycycline.

PMID- 10344667
TI  - Cryptosporidium infection in young children with diarrhea in Rawalpindi,
      Pakistan.
AB  - Fecal excretion of Cryptosporidium parvum oocysts was determined in 625 children
      less than five years old who presented at the pediatric clinic of a teaching
      hospital in Rawalpindi, Pakistan. Single stool specimens were collected from 475
      children with acute diarrhea and from 150 children without diarrhea. The
      Cryptosporidium infection rate was significantly higher in children with diarrhea
      than in children without diarrhea (10.3% versus 3.3%). The C. parvum infection
      rate was highest in children 19-24 months of age (21.8%). There was no
      significant difference in the Cryptosporidium infection rate among male and
      female children of any age group studied. Sociodemographic information, drinking
      water supply, and contact with domestic animals had no significant role in the
      acquisition of C. parvum infection in our study population. The data suggest that
      C. parvum is relatively endemic in young children in the Rawalpindi area and that
      C. parvum may be an important pathogen associated with diarrhea.

PMID- 10344668
TI  - Diarrheal disease in patients infected with human immunodeficiency virus in
      Bangkok, Thailand.
AB  - Diarrheal disease and its associated morbidities occur frequently in patients
      infected with human immunodeficiency virus (HIV) and may be associated with a
      decreased quality of life. We studied the spectrum of symptoms, measures of
      nutritional status, and the enteric pathogens associated with diarrheal disease
      in a group of 24 patients infected with HIV in Bangkok, Thailand compared with a
      group of 19 patients infected with HIV without diarrhea cared for at the same
      clinic. Patients with diarrhea appeared to have more advanced disease by CD4 cell
      counts and complained more frequently of symptoms such as anorexia, gas, and
      bloating than patients without diarrhea. Patients with diarrhea had a tendency
      toward a lower nutritional status, as measured by body mass index and mid arm
      circumference. Stool culture and examination revealed that enteric pathogens
      including Salmonella species and Cryptosporidium parvum sporidia were recovered
      at equal frequencies in patients with and without diarrhea (27% of the patients
      with diarrhea and 25% of the patients without diarrhea). Microsporidia was
      identified in one patient with diarrhea. It was not possible to identify a
      pathogen in 73% of the patients with diarrhea and 75% of the patients without
      diarrhea, suggesting that additional agents or factors may be responsible for the
      diarrheal symptoms in the patients with diarrhea. More extensive studies to
      identify potentially treatable pathogens in HIV-infected patients with diarrhea
      in Thailand are warranted and further attempts to better define the syndrome of
      pathogen-negative diarrheal disease in patients infected with HIV might result in
      the development of more targeted interventions in these patients.

PMID- 10344669
TI  - Reduced soluble transferrin receptor concentrations in acute malaria in Vanuatu.
AB  - Soluble transferrin receptor (sTfR) concentration is a sensitive index of iron
      deficiency when used in conjunction with ferritin measurements in adults. One
      advantage of this assay is that unlike ferritin it does not appear to be affected
      by a range of infectious and inflammatory conditions or by pregnancy, rendering
      it a promising adjunct to the diagnosis of iron deficiency in tropical
      populations. We have measured plasma sTfR concentrations in a group of malaria
      patients (n = 21) and asymptomatic (18) and aparasitemic (76) controls in
      Vanuatu. Plasma sTfR concentration was significantly reduced in individuals with
      acute malaria (P = 0.003). While this observation provides evidence that
      erythropoeitic suppression may be an important etiologic component in malarial
      anemia, it also suggests that malaria may be a confounding factor when
      interpreting sTfR concentrations in such populations. The role of sTfR in the
      diagnosis of iron deficiency in tropical populations remains to be established.

PMID- 10344670
TI  - Leiomyosarcoma of the esophagus in a patient with chagasic megaesophagus: case
      report and literature review.
AB  - Leiomyosarcoma constitutes approximately 0.5% of the malignant neoplasias of the
      esophagus and its association with megaesophagus has not been described. We
      report on a case of a woman with dysphagia that was slowly progressive from the
      age of 19 due to chagasic megaesophagus. The woman was subjected to cardiomyotomy
      at the age of 49. She presented a rapid worsening of the dysphagia due to
      leiomyosarcoma at the age of 61, and was subjected to subtotal esophagectomy with
      cervical esophagogastroplasty. She developed pulmonary and hepatic metastases 14
      months after surgery and died six months later.

PMID- 10344671
TI  - Regulation of the mucosal immune response.
AB  - Infectious diseases continue to exact an extensive toll on populations living
      closest to the equatorial regions of the globe. A substantial proportion of these
      infections gain access to the host via the mucosal tissues. Thus, the development
      of new vaccines that enhance mucosal immunity is considered to be of paramount
      importance in order to prevent or limit the impact of these infections. Mucosal
      immune responses must discriminate between commensal flora within the lumen and
      potential pathogens. These responses are highly adapted to induce protection
      without excessive amounts of inflammation. The balances that regulate mucosal
      immune and inflammatory responses have to be understood if effective mucosal
      immunity is to be induced through local immunization. This review will summarize
      some of the unique properties of mucosal immune responses and focus on recent
      advances that have significantly influenced our understanding of the regulation
      of immune and inflammatory responses following infection.

PMID- 10344672
TI  - Intestinal mucins in colonization and host defense against pathogens.
AB  - Intestinal mucins are key components of the first line of host defense against
      intestinal pathogens. These large glycoconjugates secreted by specialized
      exocrine goblet cells form viscous gels that trap microorganisms and irritants
      and limit their diffusion to the intestinal epithelium. Moreover, they allow for
      colonization by indigenous bacterial flora that prevents attachment of pathogenic
      microbes. The interaction between microbes and mucins involves mucin carbohydrate
      side chains and microbial adhesin molecules. Certain microorganisms and disease
      states may alter mucin biochemistry or expression. Although these alterations
      most likely contribute to disease processes, the full impact of these phenomena
      are still unclear. The development of mucin-secreting cell lines has facilitated
      the study of mucin biology and aided our understanding of mucin-microbial
      interactions.

PMID- 10344673
TI  - Immune-epithelial interactions in host defense.
AB  - Over the past 15 years, it has become very clear that the immune system can have
      profound effects on epithelial function. Acute immune-mediated changes in
      epithelial physiology are beneficial to host defense against enteric pathogens.
      For example, ion secretion washes out noxious luminal contents and increased
      permeability allows phagocytic cells and antibodies to enter the gut lumen.
      However, ongoing immune activation results in chronic effects that may be
      pathophysiologic. Responses are mediated by soluble immune mediators that act
      directly on the epithelium, or indirectly via nerves that also serve to amplify
      the epithelial response. Here, we will review some of the recent advances that
      have been made in the field of immunophysiology. The effect of mast cells on
      transport functions of the epithelium will be reviewed, with emphasis on the
      consequence of interactions between mast cells and nerves. The use of in vitro
      coculture systems has recently provided considerable information on the effects
      of neutrophils, eosinophils, monocytes, and lymphocytes on epithelial functions;
      the contribution of each immunocyte will be highlighted. Finally, we will
      describe evidence for the active participation of the epithelium in mucosal
      immune activation, including pathogen or cytokine induced epithelial cytokine
      synthesis or secretion and adhesion molecule expression.

PMID- 10344674
TI  - Integration of neuro-endocrine immune responses in defense of mucosal surfaces.
AB  - Neuro-endocrine immunology, a field arising from curiosity about the mind-body
      connection, is evolving rapidly. From intriguing, but seemingly unexplainable
      observations with human infections and disease, experimental systems have been
      developed that provide a solid scientific basis for new understanding. There have
      been major efforts to understand influences of the nervous system on immune and
      inflammatory responses, e.g., innervation of the immune system, molecular
      communication pathways, and complex phenomena such as conditioning of immune
      responses and mechanisms of host defenses. In turn, the immune system
      communicates with the neuro-endocrine systems. Imbalances in the neuro-endocrine
      immunologic circuitry are relevant in host defenses and in injury and repair.
      Examples of these themes in neuro-endocrine-immunology arise in several host
      parasite models of neurogenic inflammation, immediate hypersensitivity responses,
      and granuloma formation. The hypothalamic-pituitary-adrenal axis and the cervical
      sympathetic trunk-submandibular gland axis provide important models to enhance
      understanding of this poorly known component of the host-parasite relationship.

PMID- 10344676
TI  - Impact of surgeon's technique on outcome after treatment of rectal carcinoma.
AB  - PURPOSE: The aim of this study was to analyze the impact of institutions and
      individual surgeons on long-term prognosis after curative resection of rectal
      carcinoma. METHODS: We used univariate and multivariate analysis of data from a
      German prospective, multicenter, patient-care evaluation study. RESULTS: The
      locoregional recurrence rates and the observed and cancer-related survival rates
      showed a considerable interinstitutional and intersurgeon variability.
      Multivariate analysis confirmed the institution and the individual surgeon as
      significant independent factors influencing locoregional recurrence and survival.
      There was a statistically highly significant correlation between the rate of
      locoregional recurrence and survival rate. CONCLUSIONS: The surgeon's technique
      and skill has to focus on prevention of locoregional recurrence to achieve good
      long-term outcome after curative resection for rectal carcinoma. New clinical
      trials on adjuvant treatment have to include quality assurance for surgery and
      pathology and documentation of the surgeon (as local code).

PMID- 10344675
TI  - Strategies for mucosal vaccine development.
AB  - Vaccines able to induce both secretory IgA for protection of mucosal surfaces and
      systemic immunity to pathogens invading the host are of great interest in the war
      against infectious diseases. Mucosal vaccines trigger immune cells in mucosal
      inductive sites and thus can induce immunity in both the mucosal and systemic
      compartments. This review presents a critical survey of adjuvants and delivery
      systems currently being tested for mucosal immunization. A better understanding
      of cellular and molecular factors involved in the regulation of mucosal immunity
      will help in the design of safer mucosal vaccines to elicit the appropriate
      protective immune response to a given pathogen.

PMID- 10344677
TI  - Major 20th-century advancements in the management of rectal cancer.

PMID- 10344678
TI  - Manage indirect practice expense the way you practice medicine: with information.
AB  - PURPOSE: Surgeons are increasingly faced with the pressures of maintaining the
      highest quality of patient care, while at the same time maintaining financial
      viability. The purpose of this project was to provide a framework for analyzing
      practice costs for colorectal surgeons using an activity-based cost accounting
      model. METHODS: A survey of 11 practices that were diverse in terms of geography,
      managed care penetration, academic vs. private practice style, and case
      distribution was performed. In activity-based costing the assignment of typical
      costs such as staff salaries are assigned to the appropriate business process.
      The business processes employed in this study were service patients in the
      office, perform in-office procedures, schedule cases in facilities, service
      patients in the hospital, insurance authorization, maintain medical records,
      billing, collections, resolve billing disputes, interaction with third parties,
      maintain professional education, sustain and manage the practice, maintain the
      facility, teaching and research, and performing drug studies. The final step is
      to assign the cost associated with all appropriate business processes to the
      appropriate cost object. The cost objects in this study were defined as a charge
      office visit, no-charge office visit, charge hospital visit, in-office
      procedures, in-facility procedures, and performing drug studies. The data were
      then analyzed to allow a comparison of four similar practices within the study
      group. RESULTS: The data demonstrated that the cost of seeing a charge office
      visit ranged from $55 to $105. Similarly, the cost of seeing a no-charge office
      visit during the global period ranged from $43 to $100. The study analyzed
      possible explanations for the wide variability in these costs. CONCLUSIONS: It is
      essential that physicians clearly understand the sources of expenses generated by
      the operation of their practices. A clear comprehension of costs will lead
      colorectal surgeons to make appropriate decisions regarding such important issues
      as office staffing ratios, office square footage, and instrumentation
      acquisitions.

PMID- 10344680
TI  - Strictureplasty is an effective option in the operative management of duodenal
      Crohn's disease.
AB  - INTRODUCTION: Duodenal Crohn's disease requiring surgery has traditionally been
      managed with a bypass procedure. We compared our experience with duodenal
      strictureplasty with this traditional approach. METHODS: Records of patients
      operated on for duodenal Crohn's disease since 1980 were retrospectively
      reviewed. Patients having strictureplasty or bypass were compared with regard to
      demographics, indications, complications, and outcome. RESULTS: Since 1980, 34
      patients were operated on for duodenal Crohn's disease. Mean age was 38.9 (range,
      16-68) years, and 20 of 34 patients were females, with no significant differences
      between operative groups. Obstruction was the presenting symptom in 33 of 34
      patients, and all had strictures. The basis for diagnosis of duodenal Crohn's
      disease was macroscopic appearance and the presence of Crohn's elsewhere in 29 of
      34 patients, with only 5 of 34 having either duodenal or contiguous antral
      granulomas. Thirty-seven strictures were present in the 34 patients; 24 were in
      the proximal duodenum (8 strictureplasty, 16 bypass), 9 were in the midduodenum
      (4 strictureplasty, 5 bypass), and 4 were in the distal duodenum (3
      strictureplasty, 1 bypass). Bypass was performed in 21 patients, with two
      operative complications, and at a mean follow-up of 8 years, 1 of 21 patients
      required reoperation for recurrent disease. Strictureplasty was performed in 13
      patients, with two operative complication, and at a mean follow-up of 3.6 years,
      1 patient required reoperation for recurrence also. Vagotomy was performed in 16
      of 21 bypasses and 7 of 13 strictureplasties. CONCLUSIONS: Although follow-up is
      shorter, strictureplasty is a safe and effective operation for duodenal Crohn's
      disease and should be considered when feasible.

PMID- 10344679
TI  - Comparison of different J-pouches vs. straight and side-to-end coloanal
      anastomoses: experimental study in pigs.
AB  - PURPOSE: Functional results after low anterior resection with straight coloanal
      anastomosis are poor. Although certain functional aspects are improved with
      coloanal J-pouch anastomosis, evacuation difficulties are encountered in some of
      these patients. The aim of the study was to investigate the functional results of
      different reconstruction methods after low anterior resection in a standardized
      pig model. METHODS: Thirty-two adult Gottinger mini pigs were randomly assigned
      either to straight end-to-end (Group 1), side-to-end (Group 2), small (4-cm limb
      length) J-pouch (Group 3), or large (8-cm limb length) J-pouch (Group 4) coloanal
      anastomosis after low rectal excision. The animals were investigated 12 weeks
      after the operation by measuring neorectal compliance and ceruletide-induced
      defecation. Eight pigs without operation were used as controls (Group 5).
      RESULTS: Compliance was lowest in Groups 1 and 2, which were significantly
      different compared with both pouch designs and controls. Neorectal compliance of
      pigs with either small or large pouches did not differ significantly compared
      with one another or controls. Defecation was significantly impaired in pigs with
      a large pouch compared with all other groups. Pigs with side-to-end anastomoses
      had as rapid an evacuation as animals with straight coloanal reconstruction.
      CONCLUSION: Coloanal J-pouch reconstruction adequately restores reservoir
      capacity after low anterior resection of the rectum. From a functional point of
      view, side-to-end is not superior to straight coloanal anastomosis. Compared with
      small pouches, a large pouch design does not lead to better neorectal compliance
      in the pig model, whereas pouch evacuation seems to be considerably compromised.

PMID- 10344681
TI  - Crohn's disease-associated genetic marker is seen in medically unresponsive
      ulcerative colitis patients and may be associated with pouch-specific
      complications.
AB  - PURPOSE: Genetic markers have been used to define subgroups of patients within
      the broad categories of Crohn's disease and ulcerative colitis that may differ in
      clinical course and response to medical therapy. The tumor necrosis factor
      microsatellite haplotype a2blc2d4e1 has been found previously to be present in 24
      percent of patients with Crohn's disease and only 5 percent of patients with
      ulcerative colitis. This study examined associations between this microsatellite
      haplotype and the postoperative clinical course of patients with ulcerative
      colitis undergoing ileal pouch-anal anastomosis. METHODS: As part of a large,
      controlled, prospective study to correlate genetic markers with clinical
      phenotypes, tumor necrosis factor microsatellite alleles at five loci (a, b, c,
      d, and e) were determined from genomic DNA by polymerase chain reaction in 32
      patients with a clinical and histopathologic diagnosis of ulcerative colitis who
      underwent ileal pouch-anal anastomosis for medically unresponsive disease. All
      patients with ileal pouch-anal anastomosis were also studied prospectively for
      pouch-specific complications. RESULTS: The tumor necrosis factor haplotype
      a2blc2d4e1 was present in 11 patients. Median follow-up was 19 months. Thirteen
      patients had a pouch-specific complication (12 pouchitis and 1 pouch-perineal
      fistula). Six of 11 patients (55 percent) with the haplotype had a pouch-specific
      complication compared with 7 of the 21 patients (33 percent) who did not possess
      this haplotype (P = 0.22). Median time from surgery to pouch-specific
      complication was eight months. Patients with the haplotype had a median time to
      pouch-specific complication of three months, whereas patients without the
      haplotype had a median time of 11 months (P = 0.04). In addition, 36 percent of
      patients with the haplotype had chronic pouch complications vs. only 10 percent
      of patients without the haplotype (P = 0.05). CONCLUSION: The Crohn's disease
      associated tumor necrosis factor haplotype a2blc2d4e1 may define a subgroup of
      medically unresponsive patients with ulcerative colitis who are predisposed to a
      higher incidence of pouch-specific complications after ileal pouch-anal
      anastomosis.

PMID- 10344682
TI  - Repair of fistulas-in-ano using autologous fibrin tissue adhesive.
AB  - PURPOSE: Our goal was to determine if autologous fibrin tissue adhesive derived
      from the precipitation of fibrinogen using a combination of ethanol and freezing,
      could be used to completely close both simple and complex fistulas-in-ano.
      METHODS: A 26-patient pilot study was performed in which 100 ml of a patient's
      blood was drawn 90 minutes before surgery. Autologous fibrin tissue adhesive was
      prepared. In the operating room the patient underwent an examination under
      anesthesia, and the primary and secondary fistula tract openings were attempted
      to be identified. The fistula tract was curetted, and autologous fibrin tissue
      adhesive was injected into the secondary fistula tract opening until fibrin glue
      was seen coming from the primary opening. A petroleum jelly gauze was then
      applied over the secondary opening, and the patient was sent home. Follow-up
      visits were scheduled for one week, one month, three months, and one year later.
      RESULTS: Twenty-six patients received autologous fibrin tissue adhesive fistula
      injections, with a mean follow-up of 3.5 months. Initial results were
      encouraging. Twenty-one of 26 patients (81 percent) had successful initial
      closure of their fistulas. Two of five failures were injected a second time, and
      one closed, giving an overall successful closure rate of 85 percent (22/26
      patients). Of five patients who failed, mean time to failure was 3.8 weeks. In
      addition, there was no evidence of infection or complications related to the
      procedure. CONCLUSION: Our initial results are optimistic and require further
      support through longer follow-up data. Fibrin glue treatment of anorectal
      fistulas offers a unique mode of management that is safe, simple, and easy for
      the surgeon to perform. By using autologous fibrin tissue adhesive the patient
      avoids the risk of anal incontinence and the discomfort of prolonged wound
      healing which may be associated with fistulotomy.

PMID- 10344683
TI  - Sodium hyaluronate carboxymethylcellulose-based bioresorbable membrane
      (Seprafilm)--does it affect tumor implantation at abdominal wound sites?
AB  - PURPOSE: This study examines the effects of a sodium hyaluronate-based
      bioresorbable membrane (Seprafilm) on tumor implantation at surgical wound and
      laparoscopic trocar sites. METHODS: GW-39, an established human colon cancer line
      carried in immunocompetent golden Syrian hamsters was used as the experimental
      model. Under general anesthesia, a 2-cm midline incision was made to allow
      placement of four 5-mm abdominal trocars. Hamsters were then randomly assigned to
      preSeprafilm, postSeprafilm, and control (no Seprafilm) groups. In the
      preSeprafilm group 0.5 ml of a 5 percent (vol/vol) suspension of the GW-39 tumor
      cells (approximately 1.675 x 10(6) cells) was injected into the abdomen of each
      hamster via midline incision. Trocars were removed, the wounds were closed, and 1
      cm2 of Seprafilm was placed on the peritoneal surface of each trocar site. In the
      postSeprafilm group the membrane was placed at each site before injection of
      tumor cells. The control group did not receive Seprafilm. The animals were killed
      after seven weeks, and the abdominal wound sites were excised. Sites without
      gross tumor underwent histologic evaluation. RESULTS: One hundred thirty-two
      animals were randomly assigned to the three groups. The preSeprafilm group had an
      87 percent tumor implantation rate. The postSeprafilm group had a 90 percent
      tumor implantation rate. The control group had an 88 percent tumor implantation
      rate. Chi squared analysis demonstrated that these total tumor implant rates and
      mean tumor mass were similar at all wound sites and between groups. No toxicity
      was observed in any of the experimental groups. CONCLUSIONS: Sodium hyaluronate
      based bioresorbable membrane (Seprafilm) does not influence GW-39 human colon
      cancer implantation at abdominal wound sites in this hamster model.

PMID- 10344684
TI  - Pelvic reservoir with S-pouch: can surgeons evaluate the results of their own
      operations?
AB  - PURPOSE: This study was designed to evaluate whether operating surgeons could
      follow up the functional outcome of their own operations, without bias, by using
      standardized methods at follow-up. METHODS: Fifty-five patients who received a
      pelvic reservoir with an S-pouch were evaluated regarding functional outcome
      after at least one year postoperative follow-up. The functional surgical outcome
      was evaluated by an internist especially trained in gastroenterology and the
      operating surgeon by using a standardized scale comprising eight functional
      variables. RESULTS: None of the variables analyzed reached statistically
      significant difference between the two observers, and a high degree of agreement
      could be shown by using kappa and weighted kappa analysis. CONCLUSIONS: Our
      results indicate that it is possible for an operating surgeon to assess the
      postoperative surgical outcome using standardized methods at follow-up.

PMID- 10344685
TI  - Continent perineal colostomy after abdominoperineal resection: outcome after 63
      cases.
AB  - PURPOSE: For patients with distal rectal or anal tumors, quality of life can be
      compromised after abdominoperineal resection and iliac colostomy. This study
      examines our experience with a continent perineal colostomy constructed from a
      colonic smooth-muscle cuff wrap. METHODS: Between 1987 and 1996, 63 patients with
      distal rectal or anal tumors (0-5 cm from the anal verge) underwent
      abdominoperineal resection and construction of a colonic smooth-muscle cuff at
      the site of the perineal colostomy. Postoperatively, all patients required
      colonic irrigations daily or every two days. The complications, continence at 6
      and 12 months, and degree of satisfaction were prospectively evaluated using a
      standard questionnaire. RESULTS: Early complications included partial perineal
      dehiscence in 14 (22.5 percent) patients, pelvic abscess in 2 (3 percent)
      patients, and colostomy necrosis in 1 (1.6 percent) patient. Late complications
      were colostomy stricture in 7 (11.8 percent) patients, perineal sinus tract in 4
      (6.7 percent) patients, and mucosal prolapse in 12 (20 percent) patients.
      Satisfactory continence (complete continence to stool and incontinence to gas) at
      6 and 12 months was achieved in 30 (55.6 percent) and 27 (59 percent) patients,
      respectively. Patient satisfaction was noted in 85 percent. CONCLUSION: Continent
      perineal colostomy can serve as an alternative to conventional iliac colostomy.
      Most patients were satisfied. The modest complication rate can be minimized with
      patient selection.

PMID- 10344686
TI  - Hepatic resection for colorectal metastases: analysis of prognostic factors.
AB  - PURPOSE: Hepatic resection affords the best hope of survival for patients with
      colorectal carcinoma metastatic to the liver. However, recurrences are observed
      in about 60 percent of patients after curative hepatic resection. The purpose of
      this study was to examine the prognostic factors of patients undergoing curative
      hepatic resection for colorectal metastases. METHODS: Between April 1984 and
      September 1997, 168 patients underwent curative hepatic resection for colorectal
      metastases. The clinicopathologic factors studied for prognostic value were
      gender, age, primary site, nodal status of primary tumor, time of metastases,
      preoperative serum level of carcinoembryonic antigen, hepatic tumor size and
      distribution, number of metastases, type of hepatic resection, resection margin,
      presence of micrometastases in resected specimen and microscopic fibrous
      pseudocapsule between the hepatic tumor and surrounding hepatic parenchyma, nodal
      status of hepatoduodenal ligament, adjuvant regional chemotherapy, and
      perioperative transfusion. RESULTS: The overall survival was 42 percent at three
      years and 26 percent at five years, including a 3.5 percent 60-day surgical
      mortality rate. Thirty-one percent of patients had micrometastases located at a
      median distance of 3 mm from the metastatic tumor edge. Presence of microscopic
      fibrous pseudocapsule was observed in 28 percent of patients. Univariate and
      multivariate analyses showed that significant prognostic factors for survival
      were nodal status of primary tumor, number of metastases, resection margin,
      microscopic fibrous pseudocapsule, and adjuvant regional chemotherapy.
      CONCLUSIONS: We conclude that 1) hepatic resection is effective in select
      patients with colorectal metastases; 2) adequate resection margin and adjuvant
      regional chemotherapy can improve outcome; and 3) microscopic fibrous
      pseudocapsule may offer additional postoperative information as an independent
      prognostic factor.

PMID- 10344687
TI  - Distribution of carcinoembryonic antigen and biologic behavior in colorectal
      carcinoma.
AB  - PURPOSE: Carcinoembryonic antigen is assumed from the results of several
      experiments to be associated with invasion of colorectal carcinoma by adhesion or
      contact inhibition. The patterns and the intensity of carcinoembryonic antigen
      distribution in colorectal carcinoma were assessed to verify whether they were
      correlated with malignant potential from those biologic characteristics. METHODS:
      Carcinoembryonic antigen distribution was tested in the archival samples of 149
      colorectal carcinomas by immunohistochemistry, using three characterized anti
      carcinoembryonic antigen monoclonal antibodies: T84.66, PR1A3, and PR3B10. The
      distribution patterns in neoplastic tissue were categorized into unstained,
      apicoluminal, and diffuse cytoplasmic patterns. Tumor, invasive tumor margin, and
      tissue surrounding the tumor were examined. RESULTS: Although all three
      antibodies revealed a positive correlation, T84.66 showed better discrimination
      than the others. Although none of the negative staining of the tumor or invasive
      tumor margin showed recurrence, the apicoluminal pattern showed recurrence, and
      the diffuse pattern showed the most frequent recurrence (P < 0.01). Recurrence
      was also associated with staining intensity in the apicoluminal pattern in both
      the tumor and invasive tumor margin (P < 0.05). Infiltrative tumor growth and
      lymph node metastasis were more frequent in cases of positive staining in tissue
      surrounding the tumor. Patients with the apicoluminal pattern achieved longer
      survival than patients with the diffuse-cytoplasmic pattern in the invasive tumor
      margin (P = 0.024) by a multivariate analysis including tumor stage and
      histologic differentiation. CONCLUSION: The distribution of carcinoembryonic
      antigen in tumors and surrounding tissue seems to be closely correlated with
      invasiveness and metastatic behavior in colorectal carcinoma. Carcinoembryonic
      antigen immune staining can be considered as an efficient tool to determine
      groups with risk of recurrence.

PMID- 10344688
TI  - Perianal diseases in HIV-positive patients compared with a seronegative
      population.
AB  - PURPOSE: The aim of this report was to present our cases showing the prevalence
      and cause of perianal diseases in human immunodeficiency virus-positive patients.
      METHODS: We compared 1,860 human immunodeficiency virus-positive patients to
      1,350 human immunodeficiency virus-negative outpatients with perianal diseases,
      examined from January 1989 to December 1996, and the results obtained with the
      treatment methods for seropositive patients. Among them, 88.7 percent were males,
      mostly in the age range from 30 to 50 years old. RESULTS: Condylomas, ulcers,
      hemorrhoids, fistulas, fissures, abscesses, and tumors were the most frequently
      diagnosed diseases. Two or more anal diseases occurred in 16.7 percent of
      patients. Among the human immunodeficiency virus-negative patients we noticed the
      same incidence of gender, and most were in the age range of 40 to 60 years old.
      Hemorrhoids, fistulas, skin tags, and fissures were diagnosed. CONCLUSIONS: From
      statistical analysis we may conclude that human immunodeficiency virus-positive
      patients have more condylomas, ulcers, tumors, fistulas, and abscesses than human
      immunodeficiency virus-negative patients, who have more hemorrhoids. Incidence of
      fissures was similar in the two groups.

PMID- 10344690
TI  - Frequency of advanced neoplasia in the proximal colon without an index polyp in
      the rectosigmoid.
AB  - PURPOSE: Screening endoscopy has the potential to reduce colorectal cancer
      mortality. However, the efficacy of screening flexible sigmoidoscopy compared
      with colonoscopy strongly depends on the frequency of advanced proximal neoplasms
      without an index polyp in the rectosigmoid. We have therefore determined this
      frequency in our endoscopy population. METHODS: Endoscopic and histologic data
      were analyzed from all patients on whom integral colonoscopy was performed
      between 1980 and 1995. Advanced neoplasia was defined as cancer or adenomas >10
      mm in diameter, adenomas with a villous component, or severe dysplasia. Patients
      with polyposis syndrome or inflammatory bowel disease were excluded. RESULTS:
      Colonoscopy was performed on 11,760 patients. 2,272 (19.3 percent) had at least
      one colorectal neoplasm, of which 39 percent had the neoplasm above the
      rectosigmoid. Twenty-two percent of all patients with neoplasia had no index
      polyp in the rectosigmoid and 16 percent of these had no index polyp, but at
      least one advanced proximal neoplasm. CONCLUSIONS: Although 39 percent of
      patients had neoplasms above the rectosigmoid, only 16 percent had an advanced
      proximal neoplasm without an index polyp in the rectosigmoid. This gives a figure
      on which to base the evaluation of screening sigmoidoscopy programs against those
      of screening colonoscopy.

PMID- 10344689
TI  - Functional results of operative treatment of rectal prolapse over an 11-year
      period: emphasis on transabdominal approach.
AB  - PURPOSE: A variety of surgical procedures have been developed to treat rectal
      prolapse, but there is still no consensus on the operation of choice. The aim of
      this study was to evaluate the functional results of operative treatment of
      rectal prolapse during an 11-year period in our department. METHODS: All patients
      treated for complete rectal prolapse during an 11-year period, from 1985 to 1995,
      in a single university hospital were included. Of the 123 patients, 22 were men,
      and the mean age was 59 (range, 15-88) years. The medical records of all patients
      were reviewed retrospectively, and a questionnaire on bowel symptoms before and
      after surgery was sent to all 95 living patients. RESULTS: The majority of the
      procedures (91 percent) were performed by abdominal approach, and the most
      frequently used open technique was posterior rectopexy with mesh (78 percent). Of
      the incontinent patients, 35 (63 percent), all those less than 40 years of age
      and 64 percent of those 40 years or older, were continent postoperatively (P =
      0.0001) after a median follow-up of five (range, 1-72) months. According to the
      questionnaire, after a median follow-up of 85 (range, 16-144) months, only 38
      percent of the incontinent patients in the mesh or suture group, 78 percent of
      patients less than 40 years of age (n = 18), and 52 percent of those 40 years or
      older (n = 47) claimed to be continent postoperatively. The proportion of
      patients with constipation was greater after the operation than preoperatively (P
      = 0.02) and more patients used medication for constipation after than before the
      operation (P = 0.0001). The overall complication rate was 15 percent, and the
      mortality rate was 1 percent (1/123). In the mesh or suture group there were 6 (6
      percent) recurrent complete prolapses and 11 (12 percent) mucous prolapses.
      CONCLUSION: Posterior rectopexy with mesh gave good results in our hands. Older
      age and longer follow-up seem to have a negative effect on the functional outcome
      of the operation and on the recurrence rate.

PMID- 10344691
TI  - Ratio of primary and secondary bile acids in feces: possible marker for
      colorectal cancer?
AB  - PURPOSE: Increases in fecal bile acids may play a role in colorectal
      carcinogenesis. The authors tested the hypothesis that high concentrations of
      primary and secondary bile acids are more common in patients with colon cancer
      than in patients with other gastrointestinal diseases. METHODS: In this
      retrospective study the secondary bile acid deoxycholic acid and the primary bile
      acid cholic acid were measured in the feces by enzyme-linked immunoabsorbent
      assay in 63 patients with colorectal cancer, 24 patients with gastric cancer, 11
      patients with biliary disorders, and 47 healthy volunteers. RESULTS:
      Preoperatively, the mean deoxycholic acid values tended to be higher and the
      cholic acid values were significantly lower in patients with colorectal cancer
      than in healthy subjects. Patients with other gastrointestinal diseases had lower
      deoxycholic acid and cholic acid values than healthy subjects. In healthy
      subjects the deoxycholic acid to cholic acid ratio ranged from 0.10 to 2.86
      (mean, 0.88), but in almost two-thirds, the ratio did not exceed 1. In contrast,
      the mean preoperative ratio in patients with colorectal cancer was 2.26 (range,
      0.06-7.17; P < 0.0001) and tended to be higher in patients with advanced cancer
      and in those with sigmoid and rectal tumors. If 1.1 is taken as the upper limit
      of normal for deoxycholic acid to cholic acid ratio, 67 percent of patients with
      colorectal cancer had an abnormal value preoperatively. CONCLUSION: A high
      deoxycholic acid concentration and deoxycholic acid to cholic acid ratio may be
      indicators of colorectal cancer. Further study is needed to improve sensitivity
      and specificity, perhaps by combining fecal bile acid measurements with other
      tests, and a large prospective trial may be warranted to determine whether these
      measurements have value in screening for this common cancer.

PMID- 10344692
TI  - Colorectal cancer recurrence during pregnancy--unique and poorly understood
      clinical entity: report of a case.
AB  - The detection of primary or recurrent colorectal cancer during pregnancy is a
      rare event. Early diagnosis is difficult, because symptoms are often attributed
      to pregnancy. Here we describe a case of recurrent adenocarcinoma of the colon in
      a 23-year-old pregnant patient. The relationship between various hormonal and
      immunological changes of pregnancy and colorectal cancer is discussed.

PMID- 10344693
TI  - Small-intestinal enteroliths--unusual cause of small-intestinal obstruction:
      report of three cases.
AB  - PURPOSE: The aim of this study was to report on a rare cause of small-intestinal
      obstruction caused by small-intestinal enteroliths. METHODS: We present three
      different cases of enterolith formation in the small intestine. One occurred
      after nontropical sprue, one patient had multiple jejunal diverticula, and
      another patient had enterolith formation in a blind loop after a small-bowel side
      to-side anastomosis. RESULTS: After initial conservative therapeutic approach all
      patients underwent surgery. In two patients the enteroliths were removed by
      ileotomy or jejunostomy. In the third patient the bowel anastomosis had to be
      revised after removal of the enterolith. CONCLUSION: Small-intestinal enteroliths
      may cause small-bowel obstruction. The first therapeutic approach is nonsurgical;
      however, if obstruction proceeds, surgical removal with or without revision of
      underlying pathology is necessary. We discuss the causes and therapeutic
      management of enteroliths and give a review of related literature.

PMID- 10344694
TI  - Use of anal endosonography in diagnosis of endometriosis of the external anal
      sphincter: report of a case.
AB  - PURPOSE: Perianal endometriosis is an infrequent form of extragenital
      endometriosis and is usually situated in episiotomy scars. METHODS: We report a
      rare case involving the external anal sphincter in a 24 year-old female. The
      precise anatomical location of the endometriotic lesion was confirmed using
      preoperative and intraoperative anal endosonography. CONCLUSION: We believe this
      procedure to be essential when history, digital examination, and proctoscopy are
      not conclusive in the differential diagnosis of perianal pain or mass. Although
      hormonal suppression often is the therapy of choice in extrapelvic endometriosis,
      we think surgical excision, respecting the anatomical fiber architecture of the
      anal sphincter, is the best treatment for perianal endometriosis. Surgical
      excision is required for histological diagnosis, which is imperative in view of
      the albeit rare development of malignancy in extragenital endometriosis.

PMID- 10344695
TI  - Disposable device and a minimally invasive technique for rubber band ligation of
      hemorrhoids.
AB  - A disposable syringe-like hemorrhoid ligator was invented to simplify the banding
      procedure for both patient and surgeon. This single-operator ligator, with its
      own suction mechanism and easy loading features, was designed for use without the
      need of an assistant or an anoscope. By pointing the ligator directly toward the
      appropriate site and by measuring the distance from the anal margin using
      reference markings on the ligator, the bands can be placed accurately in a blind
      manner inside the rectum for the treatment of symptomatic internal hemorrhoids.
      Before the band is discharged, rotating the ligator through 180 degrees while
      applying suction will cause pain and give warning if the application site is not
      appropriate. In 480 patients treated to date, this technique was found to be well
      accepted and accurate, and the final results seem to be comparable to other
      methods of banding.

PMID- 10344696
TI  - Continent ileostomy can be offered as an option to patients who fail the ileal
      pouch-anal anastomosis (IPAA)

PMID- 10344698
TI  - Soiling and recurrence after internal sphincterotomy for anal fissure.

PMID- 10344697
TI  - Peritoneal cytology in colorectal cancer.

PMID- 10344699
TI  - Anal sphincter repair: what's in a name?

PMID- 10344700
TI  - Nurses' judgments regarding seclusion and restraint of psychiatric patients: a
      social judgment analysis.
AB  - Clinical judgment of psychiatric nurses was investigated using judgment analysis
      within the framework of social judgment theory. Nine nurses at a short-term
      psychiatric care facility made recommendations concerning restraint and seclusion
      for 80 patients described on paper in terms of 17 characteristics (cues). Nurses
      generally favored close observation of patients over seclusion and restraint, and
      information about current behavior and functioning had more impact on nurses'
      judgments than did patient history. Nurses had good insight into the nature of
      their own judgments. However, individual differences in cue utilization and
      inconsistency in strategy usage led to disagreement among nurses about specific
      recommendations for particular patients. No one patient received identical
      recommendations from all nurses, and nurses agreed with each other on specific
      recommendations only about a third of the time. The lack of agreement has
      implications for development of staff training programs and further research on
      the clinical judgment processes of nurses.

PMID- 10344701
TI  - The conceptual structure of research utilization.
AB  - Despite the fact that the nursing literature is replete with calls to make the
      practice of nursing research based, little is known about the structure and
      function of research utilization. The purpose of this study was to explore the
      conceptual structure of research utilization. Data were collected from a randomly
      selected sample of 600 registered nurses practicing in western Canada. Using the
      techniques of structural equation modeling (with LISREL), competing models
      representing conceptual structures of research utilization were developed and
      evaluated. In the first model, a simplex style of model, the investigator
      proposed that a nurse's early responses would influence subsequent responses to
      the question measuring research utilization, implying a time ordered causal
      sequence. In the second style of model, a common cause (or factor-like) model,
      the investigator proposed a stable underlying concept, research utilization, that
      was relatively insensitive to prompting and time ordering. The simplex style of
      model failed to reach acceptable indices of fit. The common cause model fit the
      data well, suggesting that instrumental, conceptual, and persuasive research
      utilization exist and that a global measure of research utilization may be
      defensible.

PMID- 10344702
TI  - Nursing care and the development of sleeping and waking behaviors in preterm
      infants.
AB  - The relationship between nursing care and the development of sleep-wake behaviors
      of 71 medically high-risk preterms was examined. The development of preterm
      infants' sleep-wake states, jitteriness, and negative facial expressions were
      influenced not only by the presence of the nurse, but also by the type of
      caregiving the nurse provided. The infant was awake more often when with
      caregivers than when alone. Waking states increased over time only when the
      infant was with caregivers, whereas quiet sleep increased only when the infant
      was alone. Infant behaviors and sleep-wake development were related to the
      intrusiveness of care. For example, negative facial expressions and sleep-wake
      transitions increased over time during the most intrusive caregiving. The
      development of sleeping and waking in preterm infants appears to depend not only
      on biological maturation but also nursing stimulation. As long-term developmental
      effects of nurse caregiving are unknown, additional research is needed.

PMID- 10344703
TI  - Testing a theory for health-related quality of life in cancer patients: a
      structural equation approach.
AB  - The purpose of this study was to test a Roy Adaptation Model-based theory of
      health-related quality of life in patients with newly diagnosed cancer. Using a
      structural equation model, health-related quality of life (HRQOL) was regarded as
      a latent variable measured by 4 empirical indicators representing the 4
      biopsychosocial response modes of the Roy Adaptation Model (RAM). The response
      modes are physiologic, self-concept, interdependence, and role function. These
      were empirically represented by physical symptoms, affective status, social
      support, and functional support, respectively. In this secondary analysis, 3 RAM
      propositions were tested in a sample of 375 newly diagnosed postsurgical cancer
      patients 60 years and over. These were: (a) that the 4 response modes are
      interrelated; (b) that environmental stimuli of gender, race, age, income,
      marital status, cancer treatment, and severity of illness influence the
      biopsychosocial response modes; and (c) that the biopsychosocial responses soon
      after diagnosis predict biopsychosocial responses 3 months later. The analyses
      did not support the proposition that all 4 response modes were interrelated. The
      results, however, revealed that severity of illness and adjuvant cancer treatment
      had the strongest association with the biopsychosocial responses and should be
      considered the focal environmental stimuli. The remaining environmental stimuli
      can be considered contextual. Also, the proposition that initial biopsychosocial
      responses predicted later responses was supported.

PMID- 10344704
TI  - Sex differences in leukocyte invasion in injured murine skeletal muscle.
AB  - The three aims of this study were to describe the time course of leukocyte
      invasion in injured soleus muscles of male and female mice, to determine if
      differential subsets of leukocytes accumulate in intramyofiber and interstitial
      sites, and to determine if significant sex differences exist in invading
      leukocyte concentrations. Fifty sexually mature C57BL/6J mice (aged 11-12 weeks)
      underwent unilateral hindlimb muscle injury induced by lengthening contractions.
      This procedure models the muscle injury that can occur through strenuous exercise
      or overuse in humans. After 1, 3, 5, or 7 days of recovery, the injured and
      contralateral, uninjured solei were dissected and prepared for morphologic
      analysis. We found that leukocytes had invaded injured myofibers at 1-day
      postinjury for both sexes. Different subsets of leukocytes accumulated within
      damaged myofibers and the interstitium. Significantly fewer myofibers were
      invaded by acid phosphatase-positive leukocytes in females. Interstitial ER-BMDM1
      leukocyte concentrations peaked in females at 7 days postinjury in comparison to
      5 days postinjury in males. These findings expand nursing's knowledge base
      regarding the potential effect of gender on recovery from acute muscle injury.

PMID- 10344705
TI  - The effects of perceived and preferred control on nurses' job satisfaction in
      long term care environments.
AB  - The purpose of this study is to explore how perceived and preferred clinical
      control and organizational control are associated with nurses' job satisfaction
      in long-term care settings. A sample of 113 nurses who work in long-term care
      units of a community hospital or a teaching hospital completed a questionnaire
      that included a job satisfaction scale, an organizational control scale, and a
      set of vignettes specific to long-term care developed to examine clinical
      control. There was a positive relationship between perceived organizational
      control and job satisfaction and a negative relationship between preferred
      clinical control and job satisfaction. Furthermore, as predicted, congruence
      between perceived and preferred control in the clinical and in the organizational
      domains were related to job satisfaction. Counter to prediction, organizational
      control explained more variance in job satisfaction than clinical control. The
      challenges of conceptualizing clinical control and its measurement are discussed.

PMID- 10344706
TI  - The analysis of the data for two-way contingency tables.
AB  - One of the best ways, if not the best way, to analyze data displayed in a two-way
      contingency table is to use a method originally due to Williams (1952) and later
      embellished upon by Guttman (1971) and others. This method applies the principles
      of canonical correlation analysis to contingency table data and obviates the need
      for the a priori specification of scale values for the two variables whose
      relationship is explored. In this article the method is described and compared
      with other approaches, and several examples of its application are provided.

PMID- 10344707
TI  - Neonatal respiratory care and infant mortality in emerging countries.

PMID- 10344708
TI  - Is management of neonatal respiratory distress syndrome feasible in developing
      countries? Experience from Karachi (Pakistan)
AB  - There is a marked paucity of data on the prevalence, management, and outcome of
      respiratory distress syndrome (RDS) among newborn infants born in developing
      countries. We reviewed the clinical profile, presentation, mode of therapy, and
      immediate and 12-month outcomes in 200 consecutive infants with documented RDS
      admitted to the Neonatal Intensive Care Unit at Aga Khan University Hospital,
      Karachi. One hundred fifty-six (79%) of these infants required assisted
      ventilation. Infants requiring ventilatory assistance had higher rates of
      maternal antenatal complications, were more frequently asphyxiated at birth, and
      were hypothermic on admission. The overall mortality was 39%, and a further 3
      infants died in early infancy after discharge. The mean duration of
      hospitalization for ventilated survivors (n = 122) was 24.6 +/- 21.1 days, with
      an average cost of therapy per survivor of Rs 50,067 (US $1,391). While our
      experience from Karachi indicates that it is possible to provide successful
      respiratory support at comparatively low cost to newborn infants weighing >1,000
      g with severe RDS, there is considerable room for improvement in outcome with the
      use of preventive measures such as antenatal steroids, appropriate intrapartal
      care, and attention to early stabilization after birth.

PMID- 10344710
TI  - Effects of different modes of delivery on lung volumes of newborn infants.
AB  - The aim of our study was to examine the effect of labor and birth canal
      compression on the rate of clearance of lung fluid. We recruited 10 babies born
      by vaginal delivery and 10 born by elective cesarean section (ECS). Thoracic gas
      volume (TGV) was measured using total body plethysmography, and functional
      residual capacity (FRC) by argon dilution, at ages 4-6 h and 24 h. Additional
      measurements were obtained at age 48 h in the infants born by ECS. Our results
      showed significant increases in mean TGV (from 23.1 mL/kg to 27.4 mL/kg, P =
      0.002) and FRC (from 21.2 mL/kg to 24.1 mL/kg, P = 0.04) between 4-6 h and 24 h
      of age after ECS delivery. Lung volumes did not change significantly over the
      next 24 h (TGV, 27.4 mL/kg, P = 0.97; FRC, 25.5 mL/kg, P = 0.42). In those
      infants born by vaginal delivery, the mean TGV at 4-6 h and 24 h were 26.7 and
      28.7 mL/kg, respectively (P = 0.09), and the mean FRC results were 23.1 and 24.9
      mL/kg, respectively, P = 0.08). The TGV tended to be lower at 4-6 h in those born
      by ECS than in infants born vaginally (23.1 vs. 26.7 mL/kg, P = 0.05). We
      conclude that there is a delay of up to 24 h in the establishment of final lung
      volumes in babies born without exposure to labor or passage through the birth
      canal, and that this may explain the increased respiratory morbidity associated
      with delivery by ECS.

PMID- 10344709
TI  - Comparative trial of artificial and natural surfactants in the treatment of
      respiratory distress syndrome of prematurity: experiences in a developing
      country.
AB  - We conducted a randomized clinical trial to compare the effects of a synthetic
      (Exosurf) and natural (Survanta) surfactant in infants with neonatal respiratory
      distress syndrome. Eighty-nine patients were randomly allocated to receive one of
      the two surfactants. Primary outcome variables were the acute and long-term
      effects of the surfactant preparations, i.e., ventilatory requirements at 24 h of
      age as judged by the oxygenation index (OI), and the combined incidence of
      chronic lung disease or death at 28 days. The OIs in the Exosurf and Survanta
      groups at 24 h were the same (10.1 and 7, respectively; P > 0.05). The magnitude
      and rapidity of response, however, were greater for Survanta than for Exosurf.
      When arterial/alveolar oxygen tension ratios (a/A) were compared, the Exosurf
      group had a significantly worse a/A ratio at 24 h than the Survanta group (0.21
      Exosurf vs. 0.37 Survanta; P < 0.05). The long-term outcome as judged by the
      combined incidence of death or chronic lung disease was not different in the two
      groups (18.6% Exosurf vs. 15.2% Survanta; P > 0.05). When the complications of
      prematurity were compared, there were no statistically significant differences
      between the two groups. We conclude that both preparations are reasonable choices
      for the treatment of respiratory distress syndrome of prematurity.

PMID- 10344711
TI  - Phagocyte-induced lipid peroxidation of lung surfactant.
AB  - Surfactant therapy is given routinely to premature newborns with respiratory
      failure. However, alterations in surfactants have been shown to be a significant
      factor in some forms of respiratory failure in newborns in animal models of lung
      injury. To investigate whether antioxidant supplementation might help to protect
      exogenous surfactant from damage by oxygen free radicals, we examined the
      influence of vitamin E in combination with surfactant on superoxide production as
      estimated by the nitroblue tetrazolium reduction test, and measured surfactant
      peroxidation with a new colorimetric method with or without addition of
      superoxide dismutase (SOD) or vitamin E. Our results showed that surfactant
      interacts with free radicals; surfactant reduced superoxide production by
      neutrophils and was peroxidized when incubated with resting and with stimulated
      cells. Vitamin E supplementation decreased superoxide radical production and in a
      dose-dependent manner decreased surfactant peroxidation. The decrease in lipid
      peroxidation by SOD was not significant. These findings suggest that phagocytes
      induce lipid peroxidation of lung surfactant, a reaction that might be prevented
      by antioxidants.

PMID- 10344712
TI  - Effects of mean and swing pressures on piston-type high-frequency oscillatory
      ventilation in rabbits with and without acute lung injury.
AB  - To determine whether low mean airway pressure (MAP) and/or stroke volume (SV)
      settings cause lung injury during piston-type high-frequency oscillatory
      ventilation (HFOV), we investigated the influence of various combinations of MAP
      and SV on the amplitude of the pressure swing at four different sites in the
      normal lung of rabbits. We also examined the effects of these factors on
      progression of lung injury in lavaged surfactant-deficient lungs. We measured
      changes in the mean pressure (MP) and swing pressure (SP) during HFOV at MAPs
      ranging between 5-30 cm H2O in combination with SVs ranging from 5-30 mL in 13
      rabbits at four different sites: 1) the proximal airway, 2) the distal end of the
      endotracheal tube, 3) the bronchi, and 4) the pleural space. Lung lavage was
      performed in 8 rabbits and differences in MP and SP between normal and surfactant
      deficient rabbits were investigated. In the remaining 5 rabbits, lungs were
      lavaged and subjected to two trials of sustained inflation to 30 cm H2O for 15 s
      to reverse atelectasis, and the resulting SP was measured. In normal lungs, SP
      increased at the bronchial and pleural sites as MAP was increased. Alterations in
      SV did not affect MP in normal or lavaged lungs. In the lavages, surfactant
      deficient lungs at MAPs < or = 15 cm H2O, there were significant increases in SP
      at the distal end of the endotracheal tube and the bronchial sites. SP decreased
      to the prelavaged level following sustained inflation to 30 cm H2O for 15 s. We
      conclude that low MAP settings are insufficient to open alveoli in the low
      compliance lung and allow for development of atelectasis rather than air
      trapping. SP was markedly increased in the presence of atelectasis, possibly
      leading to excessive expansion of the airway. In the clinical setting, such
      overexpansion of the distal airways may contribute to lung injury. Our findings
      suggest that physicians should use caution in reducing MAP during piston-type
      HFOV until lung compliance has normalized, especially in infants with respiratory
      distress syndrome.

PMID- 10344714
TI  - Resolution of obstructive sleep apnea syndrome after adenoidectomy in congenital
      central hypoventilation syndrome.
AB  - We report on a 2 1/2-year-old boy who is currently ventilated at home by positive
      pressure ventilation through a nasal mask during the night because of congenital
      central hypoventilation syndrome (CCHS). Up to age 2 he had developed normally. A
      reevaluation was performed because of symptoms suggestive of obstructive sleep
      apnea syndrome (OSAS), including snoring, nocturnal sweating, frequent nighttime
      awakenings, speech impairment, daytime fatigue, and failure to thrive. A sleep
      study indicated obstructive apnea episodes lasting up to 40 s and arterial
      desaturations below 50% during spontaneous sleep. During mechanical ventilation
      snoring persisted, and capillary PCO2 rose to 60 mm Hg. Partial upper airway
      obstruction, leaking around the mask, and arousal movements developed on passive
      flexion of the neck to 20 degrees. After adenoidectomy, symptoms of OSAS
      resolved. There were no more obstructive apneas during spontaneous sleep, but
      obstructive apneas could be provoked by neck flexion to 20 degrees. During
      ventilation, neck flexion of 20 degrees was tolerated, but a 40 degrees flexion
      led to partial obstruction. In CCHS patients, the problem of upper airway
      obstruction is rarely noted because most patients are ventilated through a
      permanent tracheostomy. Today, noninvasive ventilation strategies are becoming
      more common. Reduced activity of upper airway muscles and impaired reflex
      mechanisms could lead to upper airway obstruction during face mask positive
      pressure ventilation in children with CCHS. Enlarged adenoids worsened this
      problem in our patient, leading to insufficient ventilation and OSAS.
      Adenoidectomy resolved symptoms of OSAS and enabled successful nasal mask
      ventilation. Close follow-up of the patient avoided hypoxia and sequelae from
      OSAS such as pulmonary hypertension.

PMID- 10344713
TI  - Pulmonary echinococcosis (hydatidosis) in children: results of surgical
      treatment.
AB  - From 1986-1996, 33 children with 49 pulmonary hydatid cysts underwent surgical
      treatment in Vienna and Istanbul. Cysts were unilateral in 28 and bilateral in 5
      cases; unruptured cysts (URC) were diagnosed in 19 patients, and 14 children
      presented with ruptured cysts (RC). Ten patients had cysts in other organs
      (liver, spleen, central nervous system) in addition to pulmonary cysts. Diagnosis
      was primarily based on chest X-ray and computed tomography scan. In Austrian
      children, a new combination of serological tests was used successfully (71%
      positive). The standard surgical procedure was cystotomy followed by capitonnage.
      The main postoperative complications were fever and wound infection. There were
      two recurrences after a mean follow-up of 4.8 years, and one patient died because
      of multiple organ involvement. We conclude that the therapy of choice in
      pediatric pulmonary hydatidosis is complete surgical elimination of the cyst by
      cystotomy and capitonnage, whereas more extended resections should be avoided.
      Ideally, benzimidazole treatment should be combined with surgery. New serological
      tests can improve diagnostic accuracy.

PMID- 10344715
TI  - Pulmonary fibrosarcoma in childhood: fiber-optic bronchoscopic diagnosis and
      review of the literature.
AB  - Primary pulmonary fibrosarcoma is a rare malignant tumor in childhood. In the
      absence of metastases, complete resection is curative. An 8-year-old boy suffered
      from unresolving pneumonia due to an obstructing lesion in the left main
      bronchus. Cytology of the bronchoalveolar lavage fluid and histology of bronchial
      biopsy revealed the diagnosis of pulmonary fibrosarcoma. The tumor did not
      respond to chemotherapy, and a total lobectomy with sleeve resection was
      performed with complete removal of the neoplasm. Two years after the operation
      the child has no evidence of disease.

PMID- 10344716
TI  - Moderate hemoptysis of unknown etiology.
AB  - The underlying cause and treatment of hemoptysis should be addressed promptly to
      avoid potentially life-threatening complications. We report on a previously
      healthy 11-year-old white boy who presented with acute hemoptysis. On
      bronchoscopy, bleeding was noted from the right upper and lower lobes. Right
      bronchial arteriography revealed multiple regions of abnormal "blushing"
      throughout the right bronchial arterial distribution which was successfully
      controlled by right bronchial arterial embolization. In spite of an extensive
      work-up, we were not able to determine the cause of bleeding. The patient has
      been followed for 18 months without any recurrence and without evidence of any
      systemic disease. Our patient does not fit any diagnostic category of pulmonary
      bleeding and further case reports are needed to delineate this entity.

PMID- 10344717
TI  - Anaerobic pneumonitis in a seven-year-old girl.

PMID- 10344718
TI  - Elevated expression of FGF-2 does not cause prostate cancer progression in LNCaP
      cells.
AB  - BACKGROUND: Androgen-independent (AI) prostate cancer (CaP) resulting from
      progression of disease is untreatable. Such progression may relate to
      upregulation and autocrinicity of growth factor expression. We studied one
      candidate growth factor, basic fibroblast growth factor (FGF-2). METHODS: LNCaP
      cells made autocrine for FGF-2 by stable transfection with FGF-2 were examined
      for cancer progression, measured by 1) altered response to androgen, 2) ability
      to grow more quickly when cocultured with bone cells in vitro or to form tumors
      when coinoculated with bone cells in vivo, or 3) increase in metastatic ability.
      RESULTS: Stably transfected lines differed in FGF-2 protein expression. LNCaP-HF
      (high production of FGF-2) expressed more FGF-2 than LNCaP-LF (low production of
      FGF-2); controls were negative. In vitro, compared with LNCaPs, LNCaP-HF cells
      showed a slightly increased growth rate, reduced proliferation in response to
      androgen but not to estrogen or progesterone, and a decreased proliferative
      response to epidermal growth factor (EGF) and FGF-2. Although giving a slightly
      faster take rate, LNCaP-HF cells without Matrigel only formed small, fast
      regressing tumors in male nude mice, and with Matrigel, did not differ from
      LNCaPs in growth rate or tumor size. No metastases occurred. No tumors grew in
      females. Mixed growth of FGF-2 transfectants with human fetal osteoblasts failed
      to cross-stimulate in vitro, or to allow tumor formation in vivo. CONCLUSIONS:
      Although FGF-2 is overexpressed in AI CaPs, our experiments show that
      upregulation of FGF-2 expression is not sufficient to cause androgen
      independence, tumorigenicity, or metastases production (i.e., prostate cancer
      progression) in LNCaP cells.

PMID- 10344719
TI  - Downregulated gelsolin expression in hyperplastic and neoplastic lesions of the
      prostate.
AB  - BACKGROUND: Because of its role in cell motility and growth regulation, gelsolin,
      an actin-binding protein, has been considered a tumor suppressor and a potential
      prognostic marker in some neoplasias, such as breast and bladder cancer. Little
      is known about its immunoexpression in prostatic adenocarcinoma (PCA). METHODS:
      Formalin-fixed, paraffin-embedded tissues of 72 prostatectomy specimens with
      adenocarcinoma and 8 nonneoplastic prostates from autopsies were stained with a
      gelsolin monoclonal antibody using the Avidin-biotin-peroxidase complex (ABC)
      method after microwave antigen retrieval. Immunoreactivity was evaluated in PCA,
      prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH),
      and nonproliferative glandular tissue and stroma. The results were statistically
      analyzed. RESULTS: Consistent gelsolin immunoreactivity was seen in prostatic
      stromal cells, smooth muscle, endothelia, and nerves. Variable gelsolin
      expression was seen in 20-100% (average (A) = 65.5%) of glandular cells in
      nonproliferative tissue (N = 75); 0-50% (A = 9.7%) in BPH (N = 59); 0-80% (A =
      8.9%) in PIN (N = 61); and 0-90% (A = 9.3%) in PCA (N = 71). The level of
      gelsolin expression in nonproliferative prostatic tissue was similar between
      prostates with PCA (A = 63.4%) and nonneoplastic prostates (A = 67.5%). The level
      of gelsolin expression did not correlate with age, tumor size, Gleason score, or
      stage. CONCLUSIONS: Gelsolin is decreased in PCA, PIN, and BPH in comparison to
      nonproliferative tissue. The role of this downregulation in the development of
      PCA is not clear. The similar reduction seen in PIN and BPH suggests that this
      event takes place indiscriminately in hyperplasia and early tumorigenesis in the
      prostate, which might limit its prognostic significance in PCA.

PMID- 10344720
TI  - Microsatellite instability and loss of heterozygosity in prostatic carcinomas:
      comparison of primary tumors, and of corresponding recurrences after androgen
      deprivation therapy and lymph-node metastases.
AB  - BACKGROUND: The molecular mechanisms leading to prostate cancer progression are
      poorly understood. In particular, those changes which are responsible for
      androgen-independent growth and metastatic spread in prostate cancer are an issue
      of current investigations. METHODS: To gain more insight into these processes,
      paired microdissected samples from both untreated, locally advanced primary
      tumors (n = 20) and recurrences (n = 20) after conventional androgen-deprivation
      therapy (ADT) were analyzed retrospectively for microsatellite instability (MSI)
      and loss of heterozygosity (LOH) at nine loci on chromosomes 8, 18, and X by
      polymerase chain reaction. In parallel, 12 prostatic carcinomas treated by
      radical prostatectomy and nine corresponding lymph-node metastases were analyzed
      in the same way. RESULTS: The group treated with ADT showed a total of 10 MSI in
      7 of the primary tumors (35%): 4 of these (20%) at one locus, and 3 of these
      (15%) at two loci. In the recurrences, MSI was observed in 4 cases (20%): 3 of
      these at one locus (15%), and 1 of these (5%) at two loci. LOH was found in 8
      cases (40%) before as well as after ADT. In the radically resected carcinomas,
      MSI could be detected at two chromosomal loci in one of the primary tumors (8%)
      and in one of the metastases (11%); LOH was found in 2 primaries (16%) and 3
      metastases (33%). CONCLUSIONS: Although MSI can be found in advanced prostatic
      carcinomas, it apparently does not play a major role in the progression of
      prostate cancer regarding androgen-independent growth or lymphogenous spread.

PMID- 10344721
TI  - Can histopathology predict treatment outcome following high-energy transurethral
      microwave thermotherapy of the prostate? Results of a biopsy study.
AB  - BACKGROUND: Despite good results of high-energy transurethral microwave
      thermotherapy (TUMT) in the treatment of benign prostatic hyperplasia, it is
      still difficult to predict the response to treatment on an individual basis.
      Besides clinical baseline parameters, intrinsic histological parameters are
      suggested to play a role in the response variance after TUMT. In this study we
      analyzed histological parameters (vessel density and epithelium-stroma (E/S)
      ratio) in patients who were selected for high-energy TUMT and related these
      parameters to clinical outcome. METHODS: We treated 42 patients with high-energy
      TUMT, who prior to treatment agreed upon ultrasonographic investigation of the
      prostate in combination with biopsies of the peripheral and transitional zones of
      the prostate. For all separate biopsy locations, the histological stained
      prostate slides were morphometrically quantified with computer assistance and
      analyzed for E/S ratio and vessel density. Response to treatment was measured by
      using standardized response evaluation criteria and was correlated with
      histological outcome. RESULTS: The E/S ratio in the inner gland biopsies tended
      to be higher in the good response group compared to the very poor responders.
      Furthermore, a clear trend was seen towards a lower vessel density in good
      responders. Large prostates and prostates with a high E/S ratio responded well to
      the high-energy thermotherapy. CONCLUSIONS: Histopathological parameters of the
      prostate tend to be moderately predictive for clinical response in this research
      population. Poor responders appeared to have a somewhat higher vessel density in
      all prostate biopsy sides, and there was also a trend towards a lower E/S ratio
      in these patients.

PMID- 10344723
TI  - Early induction of apoptosis in androgen-independent prostate cancer cell line by
      FTY720 requires caspase-3 activation.
AB  - BACKGROUND: We previously reported that FTY720, a metabolite from Isaria
      sinclairii, induced some cancer cells to undergo apoptosis, and that FTY720
      induced apoptosis was not related to Fas-antigens. In this study we investigated
      whether FTY720 was able to induce apoptosis in an androgen-independent prostate
      cancer cell line, DU145, which is not only resistant to androgen-withdrawal
      induced apoptosis but also Fas- and TNF-alpha-mediated apoptosis. METHODS: Cell
      survival and morphological change were examined and apoptosis was confirmed by
      DNA isolation and analysis of DNA fragmentation. Caspase activation was studied
      by using anti-caspase-1 and anti-caspase-3 antibodies. To determine whether
      caspase activation is central to FTY720-induced apoptosis, caspase inhibitor was
      added to the media 24 hr prior to the addition of FTY720. RESULTS: We found that
      FTY720 rapidly induced apoptosis in DU145 cells, and that caspase-3 was activated
      during FTY720-induced apoptosis. In contrast, normal human prostate stromal cells
      were resistant to FTY720. Furthermore, FTY720-induced apoptosis was prevented by
      caspase-3 inhibitor. CONCLUSIONS: The data in this report show that FTY720 is a
      potential strong antitumor agent for cell line DU145, and provide the first
      evidence for involvement of caspase-3 in apoptosis of an androgen-independent
      prostate cancer cell line. Activation of such caspases may provide a means for
      eliminating androgen-independent prostate cancer in humans.

PMID- 10344722
TI  - Coordinate alterations in the expression of BRCA1, BRCA2, p300, and Rad51 in
      response to genotoxic and other stresses in human prostate cancer cells.
AB  - BACKGROUND: BRCA1 and BRCA2 participate in cell cycle progression, apoptosis, and
      DNA repair pathways. The latter role may be mediated by interaction with DNA
      recombinase Rad51. The purpose of this study was to evaluate the effects of
      genotoxic and other cytotoxic agents on expression of DNA damage-response genes
      (BRCA1, BRCA2, p300, and Rad51) in human prostate cancer cells. METHODS:
      Subconfluent proliferating cultures of Tsu-Prl or DU-145 cells were treated with
      various stressful agents and assayed 24 hr later for alterations in: 1) mRNA
      expression (by semiquantitative reverse transcription-PCR); 2) cell viability (by
      trypan blue dye exclusion); and 3) protein expression (by Western blotting).
      RESULTS: Of 26 agents screened, BRCA1 and BRCA2 mRNA reductions were observed in
      both cell lines after exposure to adriamycin (ADR), camptothecin (CPT), sodium
      selenite (SLN), and ultraviolet radiation (UV), while nitrogen mustard (HN2)
      caused mRNA reduction in DU-145 but not in Tsu-Prl. Inhibition of BRCA1/2
      expression by ADR and HN2 was blocked by cycloheximide, suggesting that this
      requires new protein synthesis, while inhibition by CPT, SLN, and UV did not
      require protein synthesis. Reduction of p300 and Rad51 mRNA levels occurred in
      parallel with that of BRCA1/2, suggesting coordinate regulation of these genes.
      The ability of an agent to inhibit mRNA expression was not directly correlated
      with cytotoxicity. ADR, CPT, UV, and SLN also caused reduction of protein levels;
      but the kinetics of decreases in protein vs. mRNA differed. After ADR treatment,
      high molecular weight (Mr hyperphosphorylated) BRCA1 decreased more rapidly than
      the low Mr species. BRCA2 showed a more rapid decrease in protein than mRNA,
      while Rad51 showed the opposite. By 48 and 72 hr post-ADR, all four mRNAs and
      proteins were reduced to well below control levels, except for Rad51 protein,
      which was only moderately decreased. CONCLUSIONS: Selected DNA-damaging agents
      (ADR, CPT, and UV) and a reducing agent (SLN) inhibited BRCA1/2, p300, and Rad51
      expression in prostate cancer cells, although decreases in mRNA vs. protein did
      not coincide. We postulate that temporal changes in relative protein levels
      affect different phases of the stress response, and that the ultimate
      downregulation of all four genes promotes prostate cancer survival.

PMID- 10344724
TI  - Correlation between preoperative predictors and pathologic features in radical
      prostatectomy specimens in PSA-based screening.
AB  - BACKGROUND: Measurement of percent free prostate-specific antigen (PSA), PSA
      density, and PSA-transition zone density (PSA-TZ density) in addition to total
      PSA is known to improve the specificity of PSA-based prostate cancer screening.
      We evaluated the ability of total PSA, percent free PSA, PSA density, and PSA-TZ
      density to predict pathologic features in radical prostatectomy specimens.
      METHODS: The levels of total PSA, percent free PSA, PSA density, and PSA-TZ
      density assessed prior to the diagnosis of prostate cancer were correlated with
      the pathologic findings in 102 prostate glands with cancer obtained at radical
      prostatectomy. The entire organs were examined histologically; Pearson
      correlation coefficients were used for statistical analysis. RESULTS: High levels
      of total PSA, PSA density, and PSA-TZ density correlated significantly with
      capsular penetration, high Gleason scores, and large cancer volumes in the
      prostatectomy specimens. Free PSA was found to correlate well with high Gleason
      scores, high percentages of cancer, and large cancer volumes, but not with
      capsular penetration. The four parameters were evaluated by means of logistic
      regression, which showed that only percent free PSA and total PSA were
      significant predictors of Gleason scores > or =7 and cancer volumes > or =0.5 cc.
      With regard to clinically insignificant cancers, only percent free PSA and the
      Gleason score obtained at biopsy were significant predictors. CONCLUSIONS: In men
      whose prostate cancers are detected by PSA-based screening, high total PSA levels
      in combination with low percent free PSA levels are suggestive of a potentially
      more aggressive type of prostate cancer. This may help both patient and clinician
      in selecting the most appropriate therapeutic approach.

PMID- 10344725
TI  - Micronuclei formation with chromosome breaks and gene amplification caused by
      Vpr, an accessory gene of human immunodeficiency virus.
AB  - Vpr, an accessory gene of human immunodeficiency virus, induces cell cycle
      abnormality by accumulating cells at the G2-M phase. We reported recently that
      Vpr caused both micronuclei formation and aneuploidy. Here, we show that Vpr also
      induced chromosome breaks and gene amplification. Expression of Vpr induced more
      than 10-fold increase of colonies resistant to N-(phosphonacetyl)-L-aspartate, an
      inhibitor of pyrimidine de novo synthesis. Fluorescence in situ hybridization
      analysis detected that 4 of 10 N-(phosphonacetyl)-L-aspartate resistant clones
      studied had intrachromosomal amplification of carbamyl-phosphate
      synthetase/aspartate transcarbamoylase/dihydroorotase gene. Another single clone
      had dicentrics. Data suggested that the Vpr-induced chromosome breaks leading to
      gene amplification, followed by bridge-breakage-fusion cycle, were one of the
      possible mechanisms of Vpr-induced genomic instability.

PMID- 10344727
TI  - A novel immunological model for the study of prostate cancer.
AB  - The Dunning R-3327 rat prostatic adenocarcinoma is a widely accepted model for in
      vivo experimental studies of prostate cancer. We have previously derived
      phenotypically distinct cell lines from a s.c. tumor resulting from the
      inoculation of the R-3327-5 subclone into Copenhagen rats. In this study, we
      report studies using a gelatin sponge model for the delivery of tumor cells and
      the retrieval of tumor-specific leukocytes responsive to different prostatic cell
      lines. S.c. preimplanted sponges were inoculated with tumor cells previously
      selected for differential properties of tumor formation and metastasis and
      examined for leukocyte content at time points of 1, 3, and 5 weeks after tumor
      cell inoculation. Cytospin and flow cytometric analyses revealed fewer tumor
      associated leukocytes present in sponges inoculated with tumorigenic R-3327-5'
      and R-3327-5'B lines, with lesser sponge degradation, than in experiments with
      the nontumorigenic R-3327-5'A line, suggestive of a tumor cell-induced
      immunomodulatory mechanism. Morphological studies indicate an intermittent tumor
      growth pattern that gradually disappears in sponges inoculated with the
      nontumorigenic R-3327-5'A cells but a robust growth pattern in sponges inoculated
      with the tumorigenic cell lines. Cytokine analyses show the secretion of higher
      levels of active transforming growth factor-beta by the more invasive and
      metastatic lines. Total transforming growth factor-beta levels are higher in the
      epithelial, tumorigenic R-3327-5'B line. Additionally, the more tumorigenic lines
      secrete interleukin 10, a potent immunosuppressive molecule. In this report, we
      demonstrate the ability to retrieve viable leukocyte populations from a prostate
      tumor line bearing sponges, which offers an important model for further in vitro
      and in vivo manipulations and holds promise for testing adoptive
      immunotherapeutic strategies.

PMID- 10344728
TI  - Helicobacter pylori inhibits the G1 to S transition in AGS gastric epithelial
      cells.
AB  - Infection with the bacterium Helicobacter pylori is associated epidemiologically
      with development of gastric cancer. To better understand the role of H. pylori in
      carcinogenesis, we examined the effects of H. pylori on cell cycle-related events
      in the AGS gastric cancer cell line. During coculture, wild-type, toxigenic, cagA
      positive H. pylori induced both apoptosis and inhibition of cell cycle
      progression at G1-S in AGS cells. These effects were most apparent in AGS cells
      synchronized by serum-deprivation and then stimulated to progress through the
      cell cycle by refeeding. An isogenic cagA-negative mutant H. pylori, produced
      similar effects. In contrast to changes induced by 5-fluorouracil, the inhibition
      of cell cycle progression from G1 to S caused by H. pylori was not accompanied by
      sustained changes in p53 or p21cip1, but was associated with reduced expression
      of p27kip1 and inhibition of transcriptional activation of the serum-response
      element of c-fos. Our results indicate that H. pylori inhibits cell cycle
      progression at G1-S and induces apoptosis, associated with reduced expression of
      p27kip1 in AGS gastric cancer cells. In vivo, similar effects as a result of H.
      pylori infection may lead to potentially deleterious compensatory
      hyperproliferation by nonneoplastic gastric epithelial cells.

PMID- 10344729
TI  - Decay accelerating factor (CD55): a target for cancer vaccines?
AB  - The 791Tgp72 antigen has been used successfully as a target for tumor imaging and
      T-cell immunotherapy. We have characterized this antigen using the monoclonal
      antibody 791T/36 as a 72/66 kDa doublet. NH2-terminal protein sequencing of the
      two bands revealed identity with the complement regulatory protein CD55.
      Antibodies recognizing different domains of CD55 were also shown to bind to the
      purified 791Tgp72, although sequence analysis of the cDNA cloned from 791T tumor
      cells showed 100% homology with CD55 and transfection of the cDNA into antigen
      negative CHO cells resulted in binding of 791T/36. This identifies the tumor
      antigen 791Tgp72 as CD55. This protein protects cells from complement attack;
      however, it can also transduce signals in lymphocytes and is a ligand for CD97,
      expressed by activated T cells. These results suggest that CD55 plays a role in
      signaling between the innate and adaptive immune responses. It is therefore a
      very intriguing target, because absence of the molecule makes the tumor cells
      susceptible to complement, whereas protective overexpression results in the
      antigen being a target for T-cell immunotherapy.

PMID- 10344730
TI  - Major histocompatibility complex class I restricted cytotoxic T cells specific
      for natural melanoma peptides recognize unidentified shared melanoma antigen(s).
AB  - CTLs were generated in vitro from two healthy donors and one melanoma patient by
      stimulation of CD8+ T cells with autologous dendritic cells pulsed with natural
      melanoma peptides (NMPs), obtained by acid treatment of HLA-matched melanoma
      cells. CTLs showed MHC class I-restricted melanoma-specific cytolytic activity.
      Importantly, CTLs from the patient, induced with NMPs obtained from an allogeneic
      HLA-A-matched melanoma, killed the autologous tumor. COS-7 cells cotransfected
      with the cDNA of 13 melanoma antigens and the HLA-A1-restricting allele did not
      induce cytokines release from NMP-specific CTLs, suggesting that they recognize
      unidentified shared melanoma antigens and that they may be valuable for
      identification of new tumor antigens. These results strongly support the use of
      autologous and/or allogeneic NMP-pulsed dendritic cells as cancer vaccines in
      patients whose neoplasms do not express or have lost expression of known tumor
      antigens.

PMID- 10344731
TI  - Methylation of CpGs as a determinant of transcriptional activation at alternative
      promoters for transforming growth factor-beta3.
AB  - The human transforming growth factor-beta3 (TGF-beta3) gene has a typical CpG
      island, the core of which is centered just upstream of its principle promoter.
      Activation of an alternative downstream promoter, leading to the production of a
      truncated mRNA lacking the portion of the 5' noncoding region responsible for
      translational inhibition of TGF-beta3 mRNA, is only evident in breast cancer
      cells. We compared the methylation status of genomic DNA isolated from a panel of
      breast (SKBR-3 and T47-D) and non-breast cancer (HT-1080, A673, and A375) cell
      lines by sequencing sodium metabisulfite-treated DNA. In all cell lines, the core
      of the TGF-beta3 CpG island was predominantly unmethylated, irrespective of
      promoter usage associated with that cell line. In contrast, we observed a marked
      difference in methylation at 19 CpG sites immediately flanking and downstream of
      the alternative promoter's transcription initiation site. Specifically, the non
      breast cancer cell lines exhibited nearly complete methylation of these CpG
      sites, whereas in the breast cancer cell lines, these CpGs were predominantly
      unmethylated. Our data support the hypothesis that methylation of a limited
      number of CpGs at the periphery of an otherwise unmethylated CpG island underlies
      the transcriptional repression of the downstream promoter in non-breast cancer
      cells, thereby serving to regulate the use of alternative promoters for TGF
      beta3.

PMID- 10344726
TI  - Overexpression of H-Ryk in mouse fibroblasts confers transforming ability in
      vitro and in vivo: correlation with up-regulation in epithelial ovarian cancer.
AB  - Abnormalities in the function of receptor tyrosine kinases (RTKs) have been
      demonstrated to be important in the pathogenesis of cancer. H-Ryk, a new member
      of the RTK family, is an unusual RTK in that it is catalytically inactive because
      of amino acid substitutions of conserved residues in the catalytic domain. We
      show by immunohistochemistry that it is expressed in the epithelium, stroma, and
      blood vessels of normal tissues. Evaluation of a panel of 33 primary ovarian
      tumors (2 benign, 8 borderline, and 23 malignant) was performed. H-Ryk was
      overexpressed in borderline and malignant ovarian tumors. In serous and clear
      cell subtypes, there was increased expression in the epithelium, stroma, and
      blood vessels. Consistent with this observation, overexpression of H-Ryk in the
      mouse fibroblast cell line NIH3T3 induces anchorage-independent growth and
      tumorigenicity in nude mice. This implies that overexpression of the receptor can
      be transforming and may therefore be significant in the pathogenesis of ovarian
      cancer.

PMID- 10344732
TI  - D-type cyclins complex with the androgen receptor and inhibit its transcriptional
      transactivation ability.
AB  - D-type cyclins regulate distinct cellular processes, such as mitotic cell cycle
      control, differentiation, and transcription. We have previously shown that the D
      type cyclins are critical for the androgen-dependent proliferation of prostate
      cells. Here, we sought to determine whether cyclin D1 directly influences the
      transactivation potential of the androgen receptor, a transcription factor that
      strongly influences androgen-dependent proliferation. We found that ligand
      mediated transcriptional activation of a physiological target, prostate-specific
      antigen, by the androgen receptor was inhibited by cyclins D1 and D3. The ability
      of D-type cyclins to inhibit androgen receptor transactivation was not shared
      with other cyclins, and cyclin D1 was as effective as dominant negative mutants
      of the androgen receptor in inhibiting transactivation. This function of cyclin
      D1 was independent of its role in cell cycle progression and is likely elicited
      through its ability to form a specific complex with the androgen receptor. These
      data underscore the various mechanisms through which the androgen receptor is
      regulated and also point to a negative feedback role for cyclin D1 in controlling
      androgen-dependent growth.

PMID- 10344733
TI  - CpG island hypermethylation in human colorectal tumors is not associated with DNA
      methyltransferase overexpression.
AB  - The molecular basis of aberrant hypermethylation of CpG islands observed in a
      subset of human colorectal tumors is unknown. One potential mechanism is the up
      regulation of DNA (cytosine-5)-methyltransferases. Recently, two new mammalian
      DNA methyltransferase genes have been identified, which are referred to as DNMT3A
      and DNMT3B. The encoded proteins differ from the predominant mammalian DNA
      methyltransferase DNMT1 in that they have a substantially higher ratio of de novo
      to maintenance methyltransferase activity. We have used a highly quantitative 5'
      nuclease fluorogenic reverse transcription-PCR method (TaqMan) to analyze the
      expression of all three DNA methyltransferase genes in 25 individual colorectal
      adenocarcinoma specimens and matched normal mucosa samples. In addition, we
      examined the methylation patterns of four CpG islands [APC, ESR1 (estrogen
      receptor), CDKN2A (p16), and MLH1] to determine whether individual tumors show a
      positive correlation between the level of DNA methyltransferase expression and
      the frequency of CpG island hypermethylation. All three methyltransferases appear
      to be up-regulated in tumors when RNA levels are normalized using either ACTB
      (beta-actin) or POLR2A (RNA pol II large subunit), but not when RNA levels are
      normalized with proliferation-associated genes, such as H4F2 (histone H4) or
      PCNA. The frequency or extent of CpG island hypermethylation in individual tumors
      did not correlate with the expression of any of the three DNA methyltransferases.
      Our results suggest that deregulation of DNA methyltransferase gene expression
      does not play a role in establishing tumor-specific abnormal DNA methylation
      patterns in human colorectal cancer.

PMID- 10344735
TI  - Identification of the TCL1/MTCP1-like 1 (TML1) gene from the region next to the
      TCL1 locus.
AB  - The region on chromosome 14q32.1 is frequently involved in chromosomal
      translocations and inversions with one of the T-cell receptor loci in human T
      cell leukemias and lymphomas. The breakpoints of the different rearrangements
      segregate into two clusters: inversion on the centromeric side and simple
      balanced translocations on the telomeric side. If the target gene activated by
      these different types of chromosomal rearrangements is the same, the gene must
      reside between the two clusters of breakpoints in a region of approximately 160
      kb. By screening of a placenta cDNA library using genomic probes derived from the
      vicinity of TCL1 locus, we have identified a gene coding for a 1.7-kb transcript
      that is expressed in leukemic cells carrying a t(14;14)(q11;q32) chromosome
      translocation. The cognate cDNA sequence reveals an open reading frame of 384
      nucleotides encoding a Mr 15,000 protein with approximately 30% of homology with
      both p14TCL1 and p13MTCP1 oncoproteins. The genomic organization of the TML1
      locus was characterized, with three exons located 15 kb from and tail-to-tail in
      relation to TCL1 locus. Because of its location and sequence similarity with TCL1
      and MTCP1 oncoproteins, this gene, named TML1 (TCL1/MTCP1-like 1) is a candidate
      gene that is potentially involved in leukemogenesis.

PMID- 10344734
TI  - Identification of differentially methylated sequences in colorectal cancer by
      methylated CpG island amplification.
AB  - CpG island methylation has been linked to tumor suppressor gene inactivation in
      neoplasia and may serve as a useful marker to clone novel cancer-related genes.
      We have developed a novel PCR-based method, methylated CpG island amplification
      (MCA), which is useful for both methylation analysis and cloning differentially
      methylated genes. Using restriction enzymes that have differential sensitivity to
      5-methyl-cytosine, followed by adaptor ligation and PCR amplification, methylated
      CpG rich sequences can be preferentially amplified. In a model experiment using a
      probe from exon 1 of the p16 gene, signal was detected from MCA products of a
      colorectal cancer cell line but not in normal colon mucosa. To identify novel CpG
      islands differentially methylated in colorectal cancer, we have applied MCA
      coupled with representational difference analysis to the colon cancer cell line
      Caco2 as a tester and normal colon mucosa as a driver. Using this strategy, we
      isolated 33 differentially methylated DNA sequences, including fragments
      identical to several known genes (PAX6, Versican, alpha-tubulin, CSX, OPT, and
      rRNA gene). The association of hypermethylation of the clones obtained and
      transcriptional suppression in colorectal cancer was confirmed by examining the
      Versican gene, which we found to be silenced in methylated cell lines and
      reactivated by the methylation inhibitor 5-aza-2'-deoxycytidine. We therefore
      propose that MCA is a useful technique to study methylation and to isolate CpG
      islands differentially methylated in cancer.

PMID- 10344736
TI  - Adenovirus-mediated gene transfer of MMAC1/PTEN to glioblastoma cells inhibits S
      phase entry by the recruitment of p27Kip1 into cyclin E/CDK2 complexes.
AB  - Genetic alterations in the MMAC1 tumor suppressor gene (also referred to as PTEN
      or TEP1) occur in several types of human cancers including glioblastoma. Growth
      suppression induced by overexpression of MMAC1 in cells with mutant MMAC1 alleles
      is thought to be mediated by the inhibition of signaling through the
      phosphatidylinositol 3-kinase pathway. However, the exact biochemical mechanisms
      by which MMAC1 exerts its growth-inhibitory effects are still unknown. Here we
      report that recombinant adenovirus-mediated overexpression of MMAC1 in three
      different MMAC1-mutant glioblastoma cell lines blocked progression from G0/G1 to
      S phase of the cell cycle. Cell cycle arrest correlated with the recruitment of
      the cyclin-dependent kinase (CDK) inhibitor, p27Kip1, to cyclin E
      immunocomplexes, which resulted in a reduction in CDK2 kinase activities and a
      decrease in levels of endogenous phosphorylated retinoblastoma protein. CDK4
      kinase activities were unaffected, as were the levels of the CDK inhibitor
      p21Cip1 present in cyclin E immunocomplexes. Therefore, overexpression of MMAC1
      via adenovirus-mediated gene transfer suppresses tumor cell growth through cell
      cycle inhibitory mechanisms, and as such, represents a potential therapeutic
      approach to treating glioblastomas.

PMID- 10344737
TI  - Elevated levels of peritumoral chondroitin sulfate are predictive of poor
      prognosis in patients treated by radical prostatectomy for early-stage prostate
      cancer.
AB  - The disease course of localized prostate cancer is highly variable, and patients
      potentially curable by aggressive management are not readily identified by
      current clinical practice. Chondroitin sulfate (CS) glycosaminoglycan is a
      candidate biomarker as elevated levels of CS in peritumoral stroma of prostate
      cancer have been associated with prostate-specific antigen (PSA) failure.
      Immunoreactive CS was measured using image analysis of archived radical
      prostatectomy tissues, obtained from 157 men with a median of 47 months (range,
      16-111 months) clinical follow-up. CS level, Gleason score, and preoperative
      serum PSA levels were independent predictors of PSA failure by Cox's multivariate
      analysis. Patients with low CS levels had significantly fewer PSA failures after
      radical prostatectomy than patients with high levels of CS (Kaplan-Meier plot;
      32% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0
      versus 50% for CS > or = 7.0, P = 0.0001). In the subgroup of patients with
      preoperative serum PSA levels < 10 ng/ml, CS was particularly useful in
      discriminating retrospectively those patients most suited for surgery (Kaplan
      Meier plot; 14% PSA failures at 5 years for CS mean integrated absorbance cut
      point < 7.0 versus 47% for CS > or = 7.0, P = 0.0001). We conclude that
      measurements of CS level can assist in predicting patient outcome after surgery.
      Additionally, our data suggest that the combination of CS and PSA measurements
      may improve outcome prediction for patients with intermediate Gleason scores.

PMID- 10344739
TI  - Association of breast cancer progression with a vitamin D receptor gene
      polymorphism. South-East Sweden Breast Cancer Group.
AB  - The vitamin D3 receptor gene (VDR) contains a TaqI RFLP that is associated with
      increased VDR mRNA stability, increased serum levels of 1alpha,25
      dihydroxyvitamin D3 (1,25-D3), and decreased risk for prostate cancer.
      Determination of the TaqI genotype, in a group of young women with breast cancer
      (n = 111; age, <37 years) and a control population (n = 130), revealed no overall
      association to risk for breast cancer. However, patients without TaqI site (TT
      genotype) showed a significantly increased risk for lymph node metastasis
      (relative risk, 1.8, 95% confidence interval, 1.3-2.6). Furthermore, a tendency
      toward an increased survival was found among estrogen receptor-positive,
      tamoxifen-treated patients who were homozygous for the TaqI site (P = 0.075). We
      conclude that polymorphism in the VDR gene may influence tumor progression and
      tamoxifen treatment response in early-onset breast carcinomas.

PMID- 10344738
TI  - Methylation of the CD44 metastasis suppressor gene in human prostate cancer.
AB  - Previous studies demonstrated that CD44 is a metastasis suppressor gene for
      prostate cancer and that the expression of CD44 both at mRNA and protein levels
      is down-regulated during prostate cancer progression, with down-regulation being
      correlated with higher tumor grade, aneuploidy, and distant metastasis. In this
      study, we evaluated DNA hypermethylation as a potential mechanism accompanying
      this decreased CD44 expression in human prostate cancer. Nucleotide sequence
      analysis revealed a CpG island in the CD44 transcriptional regulatory region. We
      found that cytosine methylation of CD44 promoter occurs in CD44-negative prostate
      cancer cell line (i.e., LNCaP) but not in prostate cancer cell lines (i.e., TSU,
      PC3, and DU145) expressing this gene. In addition, we examined methylation status
      of CD44 in 84 matched normal and cancer prostate specimens. Hypermethylation of
      the 5' CpG island of CD44 gene was observed in 31 of 40 primary prostate cancer
      specimens, 3 of 4 distant organ site metastases obtained at autopsy from men who
      died of prostate cancer, and 4 of the 40 matched normal tissues. These results
      demonstrated that methylation of the 5' CpG island of CD44 gene is closely
      associated with transcriptional inactivation, resulting in a decreased expression
      of CD44 in human prostate cancer.

PMID- 10344740
TI  - Motility inhibition and apoptosis are induced by metastasis-suppressing gene
      product CD82 and its analogue CD9, with concurrent glycosylation.
AB  - Metastasis-suppressing gene product CD82 and its analogue CD9 are considered to
      suppress the malignancy of various human cancers, although the rationale for this
      effect is unknown. The present study addresses phenotypic changes in Chinese
      hamster ovary mutant cell line ldlD deficient in UDP-Glc 4-epimerase and
      expressing CD82 or CD9 by cDNA transfection. Only CD82- or CD9-expressing cells
      grown in Gal-supplemented medium showed reduced motility and massive cell death,
      which are characteristic of apoptosis, after a latent period. Under this
      condition, endogenous GM3 synthesis was observed as a common factor, and N
      glycosylation occurred at a high level in CD82 and to a lesser extent in CD9.
      Thus, the malignancy-suppressing effect of CD82 or CD9 is based partially on cell
      motility inhibition and apoptosis induction promoted by concurrent GM3 synthesis
      and N-glycosylation.

PMID- 10344741
TI  - Overexpression and amplification of c-myc in the Syrian hamster kidney during
      estrogen carcinogenesis: a probable critical role in neoplastic transformation.
AB  - An estrogen receptor-driven, multistep process for estrogen carcinogenesis in the
      Syrian hamster kidney is proposed. Because in this species the reproductive and
      urogenital tracts arise from the same embryonic germinal ridge, it is evident
      that the kidney has carried over genes that are responsive to estrogens. Using in
      situ hybridization, overexpression of early estrogen-response genes, i.e., c-myc
      and c-fos, has been shown to be localized preferentially in early renal tumor
      foci after 3.5-4.0 months of estrogen treatment. This event coincides with an
      increased number of S-phase proliferating cell nuclear antigen-labeled cells in
      these tumor foci, along with a rapid rise in aneuploid frequency in the kidney.
      Western blot analyses of c-MYC and c-FOS protein products support the
      overexpression of these genes. Amplification of c-myc, 2.4-3.6-fold, but not of c
      fos, was detected in 67% of the primary renal tumors examined, by Southern blot
      analyses. Consistent chromosomal gains, common to both diethylstilbestrol- and
      estradiol-induced renal neoplasms, were observed in chromosomes 1, 2, 3, (6), 11,
      (13), 16, 20, and 21 (chromosome number alterations are indicated in
      parentheses). Using fluorescence in situ hybridization, the c-myc gene was
      localized to hamster chromosome 6qb. Chromosome 6 exhibited a high frequency of
      trisomies and tetrasomies in the kidney after 5.0 months of estrogen treatment
      and in primary renal tumors. The data presented indicate that estrogen-induced
      genomic instability may be a key element in carcinogenic processes induced by
      estrogens.

PMID- 10344742
TI  - Inhibitory effects of caffeic acid phenethyl ester on the activity and expression
      of cyclooxygenase-2 in human oral epithelial cells and in a rat model of
      inflammation.
AB  - We investigated the mechanisms by which caffeic acid phenethyl ester (CAPE), a
      phenolic antioxidant, inhibited the stimulation of prostaglandin (PG) synthesis
      in cultured human oral epithelial cells and in an animal model of acute
      inflammation. Treatment of cells with CAPE (2.5 microg/ml) suppressed phorbol
      ester (12-O-tetradecanoylphorbol-13-acetate; TPA) and calcium ionophore (A23187)
      mediated induction of PGE2 synthesis. This relatively low concentration of CAPE
      did not affect amounts of cyclooxygenase (COX) enzymes. CAPE nonselectively
      inhibited the activities of baculovirus-expressed hCOX-1 and hCOX-2 enzymes. TPA-
      and A23187-stimulated release of arachidonic acid from membrane phospholipids was
      also suppressed by CAPE (4-8 microg/ml). Higher concentrations of CAPE (10-20
      microg/ml) suppressed the induction of COX-2 mRNA and protein mediated by TPA.
      Transient transfections using human COX-2 promoter deletion constructs were
      performed; the effects of TPA and CAPE were localized to a 124-bp region of the
      COX-2 promoter. In the rat carrageenan air pouch model of inflammation, CAPE (10
      100 mg/kg) caused dose-dependent suppression of PG synthesis. Amounts of COX-2 in
      the pouch were markedly suppressed by 100 mg/kg CAPE but were unaffected by
      indomethacin. These data are important for understanding the anticancer and anti
      inflammatory properties of CAPE.

PMID- 10344744
TI  - Differential protection against benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide
      induced DNA damage in HepG2 cells stably transfected with allelic variants of pi
      class human glutathione S-transferase.
AB  - The pi class glutathione S-transferase (GSTP1-1), which is polymorphic in human
      populations, is believed to play an important role in detoxification of the
      ultimate carcinogen of widespread environmental pollutant benzo[a]pyrene [(+)
      anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide [(+)-anti-BPDE]]. The allelic
      variants of human GSTP1-1 (hGSTP1-1) differ in their structures by the amino
      acids in positions 104 (isoleucine or valine) and/or 113 (valine or alanine).
      Here, we have determined the protective effect of overexpression of allelic
      variants of hGSTP1-1, through stable transfection in HepG2 cells, against (+)
      anti-BPDE-induced DNA modification. Clonal transfectants of HepG2 cells
      corresponding to the three allelic variants of hGSTP1-1 [(I104,A113),
      (V104,A113), and (V104,V113), denoted hGSTP1(IA), hGSTP1(VA), and hGSTP1(VV),
      respectively] with similar levels of hGSTP1 protein were identified and
      characterized for their GST activity and (+)-anti-BPDE-induced DNA modification.
      The glutathione S-transferase activity toward (+)-anti-BPDE was significantly
      higher (approximately 3.0-3.6-fold) in cells transfected with hGSTP1(VA)
      [HepG2(VA)] and hGSTP1(VV) [HepG2(VV)] compared with hGSTP1(IA) transfectant
      [HepG2(IA)]. The formation of (+)-anti-BPDE-DNA adducts was significantly reduced
      in HepG2(VA) and HepG2(VV) cells compared with cells transfected with insert-free
      vector (HepG2-vect). Maximum protection against (+)-anti-BPDE-induced DNA damage
      was afforded by the hGSTP1(VV) isoform. The results of this study indicate that
      the allelic variants of hGSTP1-1 significantly differ in their ability to provide
      protection against (+)-anti-BPDE-induced DNA damage. Thus, hGSTP1-1 polymorphism
      may be an important factor in differential susceptibility of individuals to
      tumorigenesis induced by benzo[a]pyrene.

PMID- 10344743
TI  - A bile acid-induced apoptosis assay for colon cancer risk and associated quality
      control studies.
AB  - Bile acids are important in the etiology of colorectal cancer. Bile acids induce
      apoptosis in colonic goblet cells at concentrations comparable to those found in
      fecal water after high-fat meals. Preliminary evidence indicated that cells of
      the normal-appearing (nontumorous) portion of the colon epithelium of colon
      cancer patients are more resistant to bile salt-induced apoptosis than are cells
      from normal individuals. In the present study, 68 patients were examined, and
      biopsies were taken at 20 cm from the anal verge, cecum, and descending colon.
      The patients included 17 individuals with a history of colorectal cancer, 37
      individuals with adenomas, and 14 individuals who were neoplasia free. The mean
      bile salt-induced apoptotic index among normal individuals was 57.6 +/- 3.47
      (SE), which differed significantly (P < 0.05) from the mean value of 36.41 +/-
      3.12 in individuals with a history of colon cancer. The correlation between
      independent observers was 0.89 (P < 0.001), indicating good interobserver
      reliability. Components of variance comparing interindividual versus
      intraindividual sources of variation suggested that site-to-site variability,
      both between regions of the colon and for adjacent biopsies, was larger than the
      interpatient variability for individuals with a history of neoplasia. Therefore,
      there was "patchiness" of the susceptibility of regions of the colon to bile acid
      induced apoptosis in individuals with a history of neoplasia (a patchy field
      effect). There was no obvious correlation of low-apoptotic index regions with
      regions in which previous neoplasias had been found and removed. On the other
      hand, for normal, i.e., neoplasia-free, individuals, there was relatively less
      intraindividual variation compared to interindividual variation. Our assay shows
      an association between resistance to bile acid-induced apoptosis, measured at 20
      cm from the anal verge, and colon cancer risk. Thus, this assay may prove useful
      as a biomarker of colon cancer risk.

PMID- 10344745
TI  - Alterations of intratumoral pharmacokinetics of 5-fluorouracil in head and neck
      carcinoma during simultaneous radiochemotherapy.
AB  - The kinetics of local drug uptake and metabolism of the anticancer drug 5
      fluorouracil (5-FU) has been monitored by means of 19F nuclear magnetic resonance
      spectroscopy in 17 patients with neck tumors during concurrent radiochemotherapy.
      All of the patients underwent an accelerated hyperfractionated, concomitant-boost
      radiochemotherapy with 5-FU [600 or 1000 mg/m2 of body surface (b.s.)] and
      carboplatin (70 mg/m2 of b.s.). Serial 19F nuclear magnetic resonance spectra
      were obtained during and after the administration of 5-FU in a 15-T scanner with
      the use of a 5-cm diameter surface coil positioned on a cervical lymph node
      metastasis. Examinations were performed at day 1 of therapy and, in 13 patients,
      also after 43.5 Gy of irradiation at day 1 of the second chemotherapy cycle.
      Resonances of 5-FU and the catabolites 5,6-dihydro-5-fluorouracil (DHFU) and
      alpha-fluoro-beta-alanine (FBAL) were resolved in the tumor spectra. The median
      of the 5-FU and FBAL levels was significantly higher (more than 2-fold) at the
      second compared with the first examination, whereas the level of DHFU did not
      change. This effect could indicate an increased delivery of 5-FU into the
      interstitial space of the tumor in the course of the combined treatment, which
      would result in an enhanced exposure of the tumor cells to the drug. A potential
      mechanism for synergy between radio- and chemotherapy is discussed, but
      alternative mechanisms are also being considered. The findings indicate that a
      method is available to rationally address the design of dosing schedules in
      concurrent therapy regimens.

PMID- 10344746
TI  - Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a
      potential tumor suppressor protein for prostate cancer.
AB  - Insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1) has been
      shown to have decreased expression in the progression from benign to malignant
      prostate epithelial cells (V. Hwa et al., J. Clin Endocrinol. Metab., 83: 4355
      4362, 1998). The present study was undertaken to determine the effects of the re
      expression of IGFBP-rP1 in a cell line from a model of human prostate cancer,
      M12, in which IGFBP-rP1 expression had been demonstrated to decrease from the
      parent epithelial cell, P69, to the malignant subline, M12. An IGFBP-rP1 cDNA
      encoding the protein was transfected into M12 cells in a plasmid that resulted in
      constitutive-expression of IGFBP-rP1. Clones of transfected M12 cells were
      selected for low (L) and high (H) levels of expression, and the plasmid vector
      alone was transfected into M12 as a control. After transfection, there was a
      marked alteration in the morphology of the M12 cells such that the H clones had
      an elongated appearance when compared with the M12 control cells. The M12 clones
      overexpressing IGFBP-rP1 had a dose-related increase in population doubling time,
      decreased colony formation in soft agar, an increased propensity to undergo
      apoptosis in response to 6-hydroxyurea, and decreased tumor formation in male
      athymic, nude mice. These data suggest that IGFBP-rP1 may have a suppressive
      effect on prostate cancer development.

PMID- 10344747
TI  - A novel animal model for hemangiomas: inhibition of hemangioma development by the
      angiogenesis inhibitor TNP-470.
AB  - Hemangiomas represent the most frequent tumors of infancy. However, the
      pathogenesis of these tumors is still largely unknown, and current treatment of
      juvenile hemangiomas remains unsatisfactory. Here we present a novel animal model
      to study proliferating hemangiomas and to evaluate the effect of angiostatic
      compounds on their growth. Intraperitoneal (i.p.) infection of 4-day-old rats
      with murine polyomavirus resulted in the development of multiple cutaneous,
      intramuscular (i.m.), and cerebral hemangiomas with 100% frequency. Histological
      examination of the brain revealed the formation of immature lesions as soon as 4
      days postinfection (p.i.). The subsequent exponential growth of the hemangiomas,
      both in number and size, was associated with severe hemorrhage and anemia. The
      cerebral, cutaneous, and i.m. lesions consisted of blood-filled cysts,
      histologically similar to human cavernous hemangiomas and stained positive for
      proliferating cell nuclear antigen, urokinase-type plasminogen activator, and
      vascular endothelial growth factor. Mature cerebral hemangiomas also expressed
      von Willebrand factor. Cerebral lesions caused death of the untreated animals
      within 19.2 +/- 1.1 days p.i. Remarkably fewer and smaller hemangiomas developed
      in animals that had been treated s.c. with the angiogenesis inhibitor TNP-470.
      Accordingly, TNP-470 (50 mg/kg), administered twice a week from 3 days p.i.,
      significantly delayed tumor-associated mortality [mean day of death, 28.2 +/- 3.3
      (P < 0.001)]. Even if therapy was initiated when cerebral hemangiomas were
      already macroscopically visible (i.e., 9 days p.i.), a significant delay in
      hemangioma-associated mortality was observed. Also, the IFN-inducer polyinosinic
      polycytidylic acid caused a delay of 9 days (P < 0.005) in tumor-associated
      mortality when administered i.p. at 5 mg/kg, twice a week, starting at day 3 p.i.
      The model described here may be useful for investigating (a) the angiogenic
      mechanism(s) underlying hemangioma progression; and (b) the effect of anti
      angiogenic compounds on vascular tumor growth.

PMID- 10344748
TI  - Vesicular stomatitis virus G pseudotyped retrovector mediates effective in vivo
      suicide gene delivery in experimental brain cancer.
AB  - Direct in vivo tumor-targeting with "suicide" viral vectors is limited by either
      inefficient gene transfer (i.e., retroviral vectors) or indiscriminate transfer
      of a conditionally toxic gene to surrounding nonmalignant tissue (i.e.,
      adenoviral vectors). Retrovectors pseudotyped with the vesicular stomatitis virus
      G protein (VSVG) may serve as a remedy to this conundrum. These retroviral
      particles differ from standard murine retroviruses by their very broad tropism
      and the capacity to be concentrated by ultracentrifugation without loss of
      activity. We propose that a VSVG-typed retrovector can be used for efficient and
      tumor-specific herpes simplex virus thymidine kinase (TK) gene delivery in vivo.
      To test this hypothesis, we developed a bicistronic retroviral vector that
      expresses TK and green fluorescence protein (pTKiGFP). The 293GPG packaging cell
      line was used to generate vTKiGFP retroparticles. In cytotoxicity assays, vTKiGFP
      transduced human glioma cell lines were sensitized to the cytotoxic effects of
      gangciclovir (GCV) 10,000-fold. Subsequently, virus was concentrated by
      ultracentrifugation to a titer of 2.3 x 10(10) cfu/ml. We tested the antitumor
      activity of vTKiGFP retroparticles in a rat C6 glioma model of brain cancer.
      Concentrated retrovector stock (9 microl volume) was injected stereotactically in
      preestablished intracerebral tumor. Subsequently, rats were treated with GCV for
      10 days. Control rats (no GCV) had a mean survival of 38 days (range, 20-52
      days). Sections performed on postmortem brain tissue revealed large tumors with
      evidence of high efficiency retrovector transfer and expression (as assessed by
      GFP fluorescence). Fluorescence was restricted to malignant tissue. In the
      experimental group (GCV treated), 8 of 12 remain alive and well >120 days after
      glioma implantation. In conclusion, vTKiGFP is very efficient at transducing
      human glioma cell lines in vitro and leads to significant GCV sensitization.
      Recombinant retroviral particles can be concentrated to titers that allow in vivo
      intratumoral delivery of large viral doses. The therapeutic efficiency of this
      reagent has been demonstrated in a preclinical model of brain cancer.

PMID- 10344749
TI  - Sustained in vivo regression of Dunning H rat prostate cancers treated with
      combinations of androgen ablation and Trk tyrosine kinase inhibitors, CEP-751 (KT
      6587) or CEP-701 (KT-5555).
AB  - The indolocarbazole analogue CEP-751 is a potent and selective tyrosine kinase
      inhibitor of the neurotrophin-specific trk receptors that has demonstrated
      antitumor activity in nine different models of prostate cancer growth in vivo. In
      the slow-growing, androgen-sensitive Dunning H prostate cancers, which express
      trk receptors, CEP-751 induced transient regressions independent of effects on
      cell cycle. Because androgen ablation is the most commonly used treatment for
      prostate cancer, we examined whether the combination treatment of CEP-751 with
      castration would lead to better antitumor efficacy than either treatment alone.
      For a 60-day period, H tumor-bearing rats received treatment with either
      castration, CEP-751 (10 mg/kg once a day s.c. for 5 days every 2 weeks), a
      combination of both, or vehicle. Castration caused tumor regression, followed by
      tumor regrowth in 4-6 weeks, whereas intermittent CEP-751 treatments resulted in
      tumor regressions during each treatment, which were followed by a period of
      regrowth between intermittent drug treatment cycles. Overall, both monotherapies
      significantly inhibited tumor growth compared with the vehicle-treated control
      group. However, the combination of castration and concomitant CEP-751 produced
      the most dramatic results: sigificantly greater tumor regression than either
      therapy alone, with no signs of regrowth. A related experiment using an orally
      administered CEP-751 analogue (CEP-701), as the trk inhibitor, and a
      gonadotrophin-releasing hormone agonist, Leuprolide, to induce androgen ablation
      demonstrated similar results, indicating that these effects could be generalized
      to other forms of androgen ablation and other trk inhibitors within this class.
      In addition, when CEP-701 was given sequentially to rats bearing H tumors, which
      were progressing in the presence of continuous androgen ablation induced by
      Leuprolide, regression of the androgen-independent tumors occurred. In summary,
      these data demonstrate that CEP-751 or CEP-701, when combined with surgically or
      chemically induced androgen ablation, offer better antitumor efficacy than either
      monotherapy and suggest that each therapy produces prostate cancer cell death
      through complementary mechanisms.

PMID- 10344751
TI  - A new in vivo method to study P-glycoprotein transport in tumors and the blood
      brain barrier.
AB  - Drug resistance is a major cause of chemotherapy failure in cancer treatment. One
      reason is the overexpression of the drug efflux pump P-glycoprotein (P-gp),
      involved in multidrug resistance (MDR). In vivo pharmacokinetic analysis of P-gp
      transport might identify the capacity of modulation by P-gp substrate modulators,
      such as cyclosporin A. Therefore, P-gp function was measured in vivo with
      positron emission tomography (PET) and [11C]verapamil as radiolabeled P-gp
      substrate. Studies were performed in rats bearing tumors bilaterally, a P-gp
      negative small cell lung carcinoma (GLC4) and its P-gp-overexpressing subline
      (GLC4/P-gp). For validation, in vitro and biodistribution studies with
      [11C]daunorubicin and [11C]verapamil were performed. [11C]Daunorubicin and
      [11C]verapamil accumulation were higher in GLC4 than in GLC4/P-gp cells. These
      levels were increased after modulation with cyclosporin A in GLC4/P-gp.
      Biodistribution studies showed 159% and 185% higher levels of [11C]daunorubicin
      and [11C]verapamil, respectively, in GLC4 than in GLC4/P-gp tumors. After
      cyclosporin A, [11C]daunorubicin and [11C]verapamil content in the GLC4/P-gp
      tumor was raised to the level of GLC4 tumors. PET measurements demonstrated a
      lower [11C]verapamil content in GLC4/P-gp tumors compared with GLC4 tumors.
      Pretreatment with cyclosporin A increased [11C]verapamil levels in GLC4/P-gp
      tumors (184%) and in brains (1280%). This pharmacokinetic effect was clearly
      visualized with PET. These results show the feasibility of in vivo P-gp function
      measurement under basal conditions and after modulation in solid tumors and in
      the brain. Therefore, PET and radiolabeled P-gp substrates may be useful as a
      clinical tool to select patients who might benefit from the addition of a P-gp
      modulator to MDR drugs.

PMID- 10344750
TI  - O6-benzylguanine: a clinical trial establishing the biochemical modulatory dose
      in tumor tissue for alkyltransferase-directed DNA repair.
AB  - Early phase evaluation of anticancer drugs has traditionally used toxicity
      (usually hematological) rather than efficacy end points to establish appropriate
      dosing schedules. To establish a biochemical efficacy end point for overcoming
      alkylguanine DNA alkyltransferase (AGT)-mediated tumor cell resistance to 1,3
      bis(2-chloroethyl)-1-nitrosourea, we performed a novel dose escalation clinical
      trial for the AGT-depleting agent O6-benzylguanine (BG). The dose of BG required
      to deplete AGT to undetectable levels (BMD(T)) in sequential computed tomography
      guided tumor tissue biopsies before BG and 18 h after BG was determined. Thirty
      patients received doses of BG ranging from 10 to 120 mg/m2. In tumor tissue, AGT
      depletion >86% of baseline was demonstrated at all doses tested. Residual tumor
      AGT activity, present 18 h after BG doses of 10-80 mg/m2, was eliminated at the
      120 mg/m2 dose and is thus the BMD(T) of BG. BG pharmacokinetics are
      characterized by the rapid, dose-independent clearance of BG from plasma
      Metabolism of BG to its biologically active metabolite, 8-oxo-benzylguanine (8
      oxo-BG), was found. The t(1/2) of 8-oxo-BG is longer than BG. Plasma
      concentrations of 8-oxo-BG well above 200 ng/ml 18 h after the end of the BG
      infusion were observed at the highest dose levels tested and appeared to
      correlate with depletion of AGT activity to undetectable levels in tumor tissue.
      AGT activity in peripheral blood mononuclear cells at baseline did not correlate
      with tumor tissue AGT activity. Depletion of AGT activity to undetectable levels
      in peripheral blood mononuclear cells occurred at lower doses and was not a
      reliable predictor for tumor tissue depletion. No serious side effects were
      observed with administration of BG alone or in combination with 13 mg/m2 1,3
      bis(2-chloroethyl)-1-nitrosourea. This is the first clinical study in which
      biochemical analyses from pre- and posttreatment tumor biopsies have been used as
      an efficacy end point for the clinical development of an anticancer agent. From
      our tumor tissue biopsy data, we have established that a BG dose of 120 mg/m2
      infused over 1 h should be used in Phase II clinical trials.

PMID- 10344752
TI  - Purine analogue 6-methylmercaptopurine riboside inhibits early and late phases of
      the angiogenesis process.
AB  - Angiogenesis has been identified as an important target for antineoplastic
      therapy. The use of purine analogue antimetabolites in combination chemotherapy
      of solid tumors has been proposed. To assess the possibility that selected purine
      analogues may affect tumor neovascularization, 6-methylmercaptopurine riboside (6
      MMPR), 6-methylmercaptopurine, 2-aminopurine, and adenosine were evaluated for
      the capacity to inhibit angiogenesis in vitro and in vivo. 6-MMPR inhibited
      fibroblast growth factor-2 (FGF2)-induced proliferation and delayed the repair of
      mechanically wounded monolayer in endothelial GM 7373 cell cultures. 6-MMPR also
      inhibited the formation of solid sprouts within fibrin gel by FGF2-treated murine
      brain microvascular endothelial cells and the formation of capillary-like
      structures on Matrigel by murine aortic endothelial cells transfected with FGF2
      cDNA. 6-MMPR affected FGF2-induced intracellular signaling in murine aortic
      endothelial cells by inhibiting the phosphorylation of extracellular signal
      regulated kinase-2. The other molecules were ineffective in all of the assays. In
      vivo, 6-MMPR inhibited vascularization in the chick embryo chorioallantoic
      membrane and prevented blood vessel formation induced by human endometrial
      adenocarcinoma specimens grafted onto the chorioallantoic membrane. Also, topical
      administration of 6-MMPR caused the regression of newly formed blood vessels in
      the rabbit cornea. Thus, 6-MMPR specifically inhibits both the early and the late
      phases of the angiogenesis process in vitro and exerts a potent anti-angiogenic
      activity in vivo. These results provide a new rationale for the use of selected
      purine analogues in combination therapy of solid cancer.

PMID- 10344754
TI  - Protein transfer of glycosyl-phosphatidylinositol-B7-1 into tumor cell membranes:
      a novel approach to tumor immunotherapy.
AB  - Modification of tumor cells with one or more costimulatory adhesion molecules has
      been proposed as a means to develop therapeutic cancer vaccines for use in human
      immunotherapy. Expression of B7-1 (CD80) in tumors by gene transfer creates an
      immunogenic tumor cell that induces antitumor immunity and protects mice from
      further challenge with wild-type tumor cells. In this report, we demonstrate that
      protein transfer of glycosyl-phosphatidylinositol (GPI)-anchored costimulatory
      molecules into tumor cell membranes could be used as an alternative to gene
      transfer for tumor immunotherapy. Incubation of isolated tumor membranes with
      purified GPI-anchored B7-1 results in stable incorporation of B7-1 on tumor cell
      membranes within a few hours. Immunization of C57BL/6 mice with EG7 tumor
      membranes modified to express GPI-B7-1 by protein transfer induces tumor-specific
      T-cell proliferation and CTLs. In addition, immunization with these EG7 membranes
      protects mice from parental tumor challenge. The protein transfer approach used
      here does not require foreign vectors or live tumor cells and is completed within
      a matter of hours. Irradiated cells or membrane preparations from fresh or frozen
      tumor tissue can be used. Therefore, protein transfer of glycolipid-anchored
      molecules provides an efficient and novel approach to modify tumor membranes for
      human immunotherapy. This approach is not limited to costimulatory molecules
      because any cell surface protein can be converted to a GPI-anchored form by
      recombinant techniques.

PMID- 10344753
TI  - Cisplatin inhibits paclitaxel-induced apoptosis in cisplatin-resistant ovarian
      cancer cell lines: possible explanation for failure of combination therapy.
AB  - Combination chemotherapy using paclitaxel with a platinum-based regimen is
      currently the standard first-line therapy for ovarian cancer after surgical
      cytoreduction. Whereas cisplatin-paclitaxel combination chemotherapy has shown
      significant efficacy over previous drug combinations in ovarian cancer, 20-30% of
      patients fail to respond to this combination. These patients are deemed cisplatin
      paclitaxel resistant, although it is unclear whether the tumors are resistant to
      one or both drugs. Because the options available to ovarian cancer patients for
      second-line therapy are limited, and knowing that mechanistic differences exist
      between cisplatin and paclitaxel, we assessed the efficacy of combination drug
      therapy on cisplatin-resistant (cisplatinR) ovarian cancer cells. We found that
      paclitaxel induced apoptosis in cisplatinR cells as well as in the cisplatin
      sensitive parental cell lines. In cisplatinR C-13 cells, the concomitant addition
      of cisplatin blocked paclitaxel-induced apoptosis as determined by DNA
      fragmentation assays, fluorescence microscopy, and flow cytometry. Paclitaxel
      induced multimininucleation was also inhibited when the cells were exposed
      sequentially to paclitaxel and then cisplatin. Cisplatin did not block paclitaxel
      induced stabilization of microtubules or prevent paclitaxel-induced loss of Bcl-2
      expression in cisplatinR cells. Conversely, paclitaxel did not inhibit p53
      protein accumulation by cisplatin. These results suggest that cisplatin blocks
      paclitaxel-induced apoptosis at a point downstream of Bcl-2 degradation and
      independent of microtubule stabilization. Our research shows that cisplatin can
      inhibit the effectiveness of paclitaxel in cispatinR cell lines. Therefore, the
      establishment of a clinical protocol to evaluate the efficacy of paclitaxel alone
      versus another second-line regimen in patients with cisplatin-paclitaxel
      resistant ovarian cancer is warranted.

PMID- 10344755
TI  - Elevated frequency of loss of heterozygosity in mammary tumors arising in mouse
      mammary tumor virus/neu transgenic mice.
AB  - Loss of heterozygosity (LOH) analysis was performed on 62 mammary tumors that
      were induced in (BALB/c x C57BL/6)F1 mouse mammary tumor virus/neu transgenic
      mice. Eighty-six simple sequence length polymorphism markers were used to cover
      all of the somatic chromosomes. Frequency of LOH was observed to be significant
      for chromosomes 4 (50%), 19 (32%), and 8 (21%). On chromosome 4, at least three
      distinct regions of allelic deletions could be identified: one proximal to 22 cM;
      the second close to the p16INK4a/p15INK4b locus, which is commonly deleted in
      various tumors; and the third one in the proximity of Mom1. The frequency of LOH
      on chromosome 19 was the same for the four markers used. Our data suggested the
      presence of two distinct LOH loci, one proximal to 47 cM and the other at the
      distal region. On chromosome 8, possibly two distinct LOH loci could be
      recognized, one around 52 cM and the other one at 67 cM or distal to it. These
      regions map close to E-cadherin (Cdh1) and M-cadherin (Cdh15) loci, respectively.
      Because LOH sites are thought to harbor tumor suppressor genes, this allelotype
      screening has allowed the mapping of putative tumor suppressor genes that may be
      implicated, in collaboration with the erbB-2/neu oncogene, in the development of
      mammary tumors in these transgenic mice.

PMID- 10344757
TI  - Resistance to apoptosis in CTLL-2 cells overexpressing B-Myb is associated with B
      Myb-dependent bcl-2 induction.
AB  - Transcriptional regulators of the Myb family play important roles in cell
      proliferation, differentiation, and survival. To investigate the role of Myb
      proteins in the regulation of apoptosis, we studied the apoptotic response of
      interleukin 2-dependent CTLL-2 cells stably transfected with B-Myb. B-Myb
      overexpressing cells showed a diminished cytokine dependence and were resistant
      to apoptosis induced by doxorubicin, ceramide, and dexamethasone. Overexpression
      of B-Myb was associated with enhanced expression of bcl-2, which was dependent,
      at least in part, on increased transcription. In transient transfection assays in
      T-lymphoblastic cells, B-Myb was able to stimulate the promoter activity of the
      bcl-2 5' flanking region linked to the chloramphenicol acetyltransferase reporter
      gene. A segment of the bcl-2 promoter (nucleotides +34 to +58 relative to the
      transcription initiation site) contained a putative Myb-binding site and was
      shown to specifically interact with B-Myb and to confer B-Myb responsiveness to a
      bcl-2/chloramphenicol acetyltransferase reporter construct. These results
      indicate that B-Myb promotes T cells survival by enhancing the expression of bcl
      2 and identify bcl-2 as a B-Myb target gene regulated in a DNA binding-dependent
      manner.

PMID- 10344758
TI  - Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation
      induced apoptosis.
AB  - Alkyl-lysophospholipids (ALPs) represent a new class of antitumor drugs that
      induce apoptotic cell death in a variety of tumor cell lines. Although their
      precise mechanism of action is unknown, ALPs primarily act on the cell membrane,
      where they inhibit signaling through the mitogen-activated protein kinase (MAPK)
      pathway. Because stimulation of the stress-activated protein kinase/c-Jun NH2
      terminal kinase (SAPK/JNK) pathway is essential for radiation-induced apoptosis
      in certain cell types, we tested the effect of ALPs in combination with ionizing
      radiation on MAPK/SAPK signaling and apoptosis induction. Here, we present data
      showing that three ALPs, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine,
      hexadecylphosphocholine, and the novel compound octadecyl-(1,1-dimethyl
      piperidinio-4-yl)-phosphate (D-21266) induce time- and dose-dependent apoptosis
      in the human leukemia cell lines U937 and Jurkat T but not in normal vascular
      endothelial cells. Moreover, in combination with radiation, ALPs strongly enhance
      the induction of apoptosis in both leukemic cell lines. All tested ALPs not only
      prevented MAPK activation, but, like radiation, stimulated the SAPK/JNK cascade
      within minutes. A dominant-negative mutant of c-Jun inhibited radiation- and ALP
      induced apoptosis, indicating a requirement for the SAPK/JNK pathway. Our data
      support the view that ALPs and ionizing radiation cause an enhanced apoptotic
      effect by modulating the balance between the mitogenic, antiapoptotic MAPK, and
      the apoptotic SAPK/JNK pathways. This type of modulation of specific signal
      transduction pathways in tumor cells may lead to the development of new
      therapeutic strategies.

PMID- 10344756
TI  - Activated Ki-Ras suppresses 12-O-tetradecanoylphorbol-13-acetate-induced
      activation of the c-Jun NH2-terminal kinase pathway in human colon cancer cells.
AB  - Although the frequency of activated Ki-ras genes is high in human colorectal
      tumors, much less is known of activated Ki-ras-mediated signaling pathways. Using
      gene targeting, we examined HCT116 cells that contain the Gly-13-->Asp mutation
      of Ki-ras and activated Ki-ras-disrupted clones derived from HCT116. 12-O
      Tetradecanoylphorbol-13-acetate (TPA) induced immediate early genes, such as c
      Jun, c-Fos, and Egr-1 in activated Ki-ras-disrupted clones, whereas c-Jun
      induction was rare in HCT116. TPA induced both phosphorylation of stress
      activated protein kinase kinase 1 (SEK1) and c-Jun NH2-terminal kinase (JNK) in
      the activated Ki-ras-disrupted clones but not in HCT116. On the other hand, TPA
      induced mitogen-activated protein kinase kinase 1/2 (MEK1/2)-extracellular signal
      regulated kinase (ERK) activation was equally induced between HCT116 and the Ki
      ras-disrupted clones. Furthermore, TPA-induced SEK1-JNK activation was observed
      in a DLD-1-derived activated Ki-ras-disrupted clone but not in DLD-1. The TPA
      induced SEK1-JNK activation in these disrupted clones was completely inhibited by
      the protein kinase C (PKC) inhibitor, GF109203X (1 microM), but not by another
      PKC inhibitor, H7 (50 microM), whereas TPA-induced MEK1/2-ERK activation was
      partially and completely inhibited by GF109203X (1 microM) and H7 (50 microM),
      respectively. A phosphoinositol 3-kinase inhibitor, LY294002, did not inhibit the
      TPA-induced SEK1-JNK activation. Taken together, these results suggest that
      activated Ki-Ras-mediated signals are involved in the SEK1-JNK pathway through a
      PKC isotype that is distinct from that involved in MEK1/2-ERK activation in human
      colon cancer cells and independent of phosphoinositol 3-kinase activation, and
      the imbalance between ERK and JNK activity caused by activated Ki-Ras may play
      critical roles in human colorectal tumorigenesis.

PMID- 10344759
TI  - Loss of the ARF tumor suppressor reverses premature replicative arrest but not
      radiation hypersensitivity arising from disabled atm function.
AB  - The alternative reading frame product (p19ARF) of the mouse INK4a/ARF locus is
      induced by oncoproteins such as Myc and E1A as part of a checkpoint response that
      limits cell cycle progression in response to hyperproliferative signals. ARF
      binds directly to Mdm2 to prevent down-regulation of p53 and thereby promotes p53
      dependent transcription and cell cycle arrest. However, ARF is not required for
      p53 induction in response to ionizing radiation or other forms of DNA damage.
      Animals lacking a functional ataxia telangiectasia (Atm) gene are exquisitely
      sensitive to ionizing radiation; Atm-null mouse embryo fibroblasts (MEFs) undergo
      premature replicative arrest, which is relieved by the loss of p53. Here we show
      that the loss of ARF expands the life expectancy of Atm-null MEFs, but alters
      neither the sensitivity of Atm-null mice to ionizing radiation nor their
      propensity to develop lymphomas early in life. Therefore, whereas ARF and Atm
      signal to p53 through distinct pathways, the loss of ARF can modify p53-dependent
      features of the Atm-null phenotype.

PMID- 10344760
TI  - Overexpression of cyclins D1 and E is frequent in bronchial preneoplasia and
      precedes squamous cell carcinoma development.
AB  - Increased protein expression of the G1 cyclins D1 and E is reported in invasive
      non-small cell lung carcinoma. However, during transformation of the bronchial
      epithelium, overexpression of these species occurs, and their relationship to
      aberrant expression of p53 and retinoblastoma (Rb) has not been described
      previously. To determine the expression of these cell cycle regulators during the
      development of invasive squamous cell carcinoma (SCC) of the lung, the
      immunohistochemical expression patterns in normal bronchial epithelium (n = 36),
      squamous metaplasia (SM; n = 28), and epithelial atypia (n = 34) were compared
      with that in low-grade dysplasia (LGD; n = 17), high-grade bronchial dysplasia
      (HGD; n = 30), and SCC (n = 36). Monoclonal anti-p53 Pab1801, polyclonal anti
      cyclin D1 DCS6, monoclonal anti-cyclin E HE12, and monoclonal anti-Rb OP-66
      antibodies were used. Cyclin D1 was not expressed in normal bronchial epithelium
      but was detected in 7% of SMs, 15% of atypias; 18% of LGDs, 47% of HGDs, and 42%
      of SCCs. Cyclin E was not detected in normal epithelium (n = 24), SM (n = 16), or
      LGD (n = 12), but it was found in 9% of atypias (2 of 22), 33% of HGDs (7 of 21),
      and 54% of SCCs (13 of 24). p53 was not expressed in normal epithelium, SM, and
      LGD, but it was overexpressed in 6% of atypias, 53% of HGDs, and 61% of SCCs.
      Abnormal Rb expression was found only in 2 of 36 cases of SCC. A total of 91% of
      HGDs and 92% of SCCs exhibited overexpression of at least one of the p53, cyclin
      D1, or cyclin E species. However, no link was observed between overexpression of
      p53 and the overexpressed G1 cyclins in preneoplastic lesions. Overexpression of
      cyclin D1, cyclin E, and p53 occurs frequently and independently in pulmonary SCC
      and is detected in lesions before the development of invasive carcinoma. In
      contrast, altered Rb expression is a late and infrequent event in squamous cell
      carcinogenesis.

PMID- 10344761
TI  - Expression and up-regulation of retinoic acid receptor-beta is associated with
      retinoid sensitivity and colony formation in esophageal cancer cell lines.
AB  - Retinoids exhibit chemotherapeutic and chemopreventive activities, possibly due
      to their ability to modulate cell growth, differentiation, and apoptosis. These
      effects are thought to be mediated by nuclear retinoic acid (RA) receptors (RARs)
      and retinoid X receptors, each of which includes three subtypes (alpha, beta, and
      gamma) that act as transcription factors. To determine whether RARs play a role
      in mediating the effects of RA on human esophageal cancer (HEC) cells, we
      analyzed the effects of RA on: (a) the growth, differentiation, and apoptosis in
      seven HEC cell lines; (b) receptor expression; (c) receptor modulation by RA; and
      (d) expression of receptors in 20 surgical HEC specimens. RA inhibited the growth
      of five of seven cell lines and also the constitutive expression of the squamous
      differentiation markers cytokeratin 1 and transglutaminase I in all cell lines.
      The growth inhibition by RA was due to the induction of apoptosis in the five
      cell lines. All seven cell lines expressed RAR-alpha and RAR-gamma, and four cell
      lines showed some changes by RA, but not associated with apoptosis. In contrast,
      RAR-beta was expressed in five of seven cell lines and up-regulated by RA in
      these five cell lines, which were associated with apoptosis. Two cell lines that
      failed to express RAR-beta showed no growth inhibition or apoptosis and no RAR
      beta inducibility. Interestingly, only these two cell lines were able to form
      colonies in soft agar. RAR-alpha, RAR-beta, and RAR-gamma mRNAs were expressed in
      all 20 adjacent normal esophageal tissues. The expression of RAR-alpha and RAR
      gamma remains positive in HEC specimens, but RAR-beta expression was detected in
      only 6 of 20 HEC specimens. These data suggest that the expression of RAR-beta is
      associated with response of HEC cells to RA and that the loss of RAR-beta
      expression may be associated with HEC development.

PMID- 10344762
TI  - HMGI(Y) and HMGI-C genes are expressed in neuroblastoma cell lines and tumors and
      affect retinoic acid responsiveness.
AB  - HMGI-C and HMGI(Y) are architectural DNA-binding proteins that participate in the
      conformational regulation of active chromatin. Their pattern of expression in
      embryonal and adult tissues, the analysis of the "pygmy" phenotype induced by the
      inactivation of the HMGI-C gene, and their frequent qualitative or quantitative
      alteration in experimental and human tumors indicate their pivotal role in the
      control of cell growth, differentiation, and tumorigenesis in several tissues
      representative of the epithelial, mesenchymal, and hematopoietic lineages. In
      contrast, very little information is available on their expression and function
      in neural cells. Here, we investigated the expression of the HMGI(Y) and HMGI-C
      genes in neuroblastoma (NB), a tumor arising from an alteration of the normal
      differentiation of neural crest-derived cells and in embryonal and adult adrenal
      tissue. Although HMGI(Y) is constitutively expressed in the embryonal and adult
      adrenal gland and in all of the NB cell lines and ex vivo tumors examined, its
      regulation appears to be associated to growth inhibition and differentiation
      because we observed that HMGI(Y) expression is reduced by retinoic acid (RA) in
      several NB cell lines that are induced to differentiate into postmitotic neurons,
      whereas it is up-regulated by RA in cells that fail to differentiate.
      Furthermore, the decrease of HMGI(Y) expression observed in RA-induced growth
      arrest and differentiation is abrogated in cells that have been made insensitive
      to this drug by NMYC overexpression. In contrast, HMGI-C expression is down
      regulated during the development of the adrenal gland, completely absent in the
      adult individual, and only detectable in a subset of ex vivo NB tumors and in RA
      resistant NB cell lines. We provide evidence of a causal link between HMGI-C
      expression and resistance to the growth arrest induced by RA in NB cell lines
      because exogenous HMGI-C expression in HMGI-C-negative and RA-sensitive cells is
      sufficient to convert them into RA-resistant cells. Therefore, we suggest that
      HMGI-C and HMGI(Y) may participate in growth- and differentiation-related tumor
      progression events of neuroectodermal derivatives.

PMID- 10344764
TI  - Relationship between hyaluronan production and metastatic potential of mouse
      mammary carcinoma cells.
AB  - To investigate the roles of hyaluronan produced by cancer cells in cancer
      metastasis, the metastatic potential of the highly metastatic mouse mammary
      carcinoma FM3A HA1 cell line was compared with those of hyaluronan-deficient
      mutant cells. Five different mutant clones showed markedly reduced hyaluronan
      production and lacked the ability to form hyaluronan-rich pericellular coats.
      These mutant clones displayed significant decreases in metastatic ability
      compared with the parental cells after i.v. injection into syngeneic mice. These
      results suggested that the decreased hyaluronan production caused not only the
      lack of matrix formation but also decreased metastatic potential of the cancer
      cells. Expression of mouse hyaluronan synthase 1 (HAS1) by transfection into HAS-
      cells defective in hyaluronan synthase activity rescued hyaluronan matrix
      formation as well as hyaluronan production. Lung metastasis after i.v. injection
      of HAS1 transfectants was also recovered significantly. The results provide
      direct evidence for the involvement of hyaluronan in cancer metastasis.

PMID- 10344763
TI  - Mediation of N-(4-hydoxyphenyl)retinamide-induced apoptosis in human cancer cells
      by different mechanisms.
AB  - The induction of apoptosis by the synthetic retinoid N-(4
      hydroxyphenyl)retinamide (4HPR) has been documented in vitro in various cancer
      types. A role for reactive oxygen species (ROS) in apoptosis induced by 4HPR in
      some cancer cells has been demonstrated recently. We studied five different human
      head and neck and five lung cancer cell lines to determine whether the ROS play a
      general role in 4HPR-induced apoptosis. We found that 4HPR induced apoptosis in
      all of the cell lines; however, this effect was blocked by antioxidants in only 2
      of the 10 cell lines. 4HPR induced a greater than 4-fold increase in the
      generation of intracellular ROS in these two cell lines compared with a much
      lower effect in other cell lines. Furthermore, these two cell lines were most
      sensitive to the induction of apoptosis by 4HPR. The level of the cellular
      antioxidant thiol and superoxide dismutase activity were relatively lower in
      cells, which responded to 4HPR with a high level of ROS generation. These results
      indicate that although ROS can mediate 4HPR-induced apoptosis in some cells,
      which may have a low endogenous cellular antioxidant levels, other mechanisms
      exist for 4HPR-induced apoptosis. One such mechanism may involve retinoic acid
      receptors (RARs) because an RAR antagonist was able to block partially 4HPR
      induced apoptosis. In conclusion, 4HPR-induced apoptosis involves at least three
      different mechanisms, which are complex and can overlap in the same cell line:
      (a) one mechanism involving 4HPR-induced ROS; (b) one involving RARs; and (c) at
      least one that does not involve ROS or RARs and remains unclear.

PMID- 10344765
TI  - Octopamine in the locust brain: cellular distribution and functional significance
      in an arousal mechanism.
AB  - This review summarizes the distribution of octopamine-like immunoreactive neurons
      in the brain of the locust and the functional significance of a subset of them in
      an arousal mechanism in the visual system. A small set of identifiable octopamine
      immunoreactive neurons lies in the ventromedial brain. Their cell bodies are
      large and readily accessible, which allows their removal and analysis of their
      biogenic amine content using gas-chromatography mass-spectrometry to confirm that
      they are genuinely octopaminergic. The neurons project from the central brain to
      the optic lobes where they arborize extensively in the medulla and lobula. There
      they release octopamine in response to multimodal input in the central brain.
      This evokes dishabitution in the locust's movement-detection system, suggesting
      an arousal mechanism.

PMID- 10344766
TI  - Multifactorial control of the release of hormones from the locust retrocerebral
      complex.
AB  - The retrocerebral complex of locusts consists of the corpus cardiacum, the
      corpora allata, and the nerves that connect these glands with the central nervous
      system. Both corpus cardiacum and corpora allata are neuroendocrine organs and
      consist of a glandular part, which synthesizes adipokinetic hormones and juvenile
      hormone, respectively, and of a neurohemal part. The glandular adipokinetic cells
      in the corpus cardiacum appear to be subjected to a multitude of regulatory
      stimulating, inhibiting, and modulating substances. Neural influence comes from
      secretomotor cells in the lateral part of the protocerebrum. Up to now, only
      peptidergic factors have been established to be present in the neural fibres that
      make synaptic contact with the adipokinetic cells. Humoral factors that act on
      the adipokinetic cells via the hemolymph are of peptidergic and aminergic nature.
      In addition, high concentrations of trehalose inhibit the release of adipokinetic
      hormones. Although there is evidence that neurosecretory cells in the
      protocerebrum are involved in the control of JH biosynthesis, the nature of the
      factors involved remains to be resolved.

PMID- 10344767
TI  - GABA and serotonin immunoreactivity during postembryonic brain development in the
      beetle Tenebrio molitor.
AB  - Analysis of the serotonin immunoreactive neurons in the central brain of the
      beetle Tenebrio molitor during postembryonic development shows that the basic
      structural characteristics of larval brain resemble those of the adult. Most, if
      not all, serotonin immunoreactive central brain neurons persist with
      metamorphosis. Their fate can be followed during development. GABA
      immunoreactivity occurs in about 360 neurons assembled in ten different clusters
      of somata in the larval midbrain. During metamorphosis no additional clusters are
      formed. However, the number of immunoreactive neurons increases to 450. Their
      morphological analysis is restricted to location of the somata and the
      distribution of arborizations within neuropil areas. Metamorphic transition of
      glomerular sub-units in the antennal lobes as well as ellipsoid body development
      can be followed by GABA immunohistochemistry. Furthermore, the study of these
      transitions proved useful in displaying changes during metamorphic pattern
      formation induced by sublethal application of the pyrethroid insecticide
      fenvalerate.

PMID- 10344768
TI  - Second messenger pathways in the honeybee brain: immunohistochemistry of protein
      kinase A and protein kinase C.
AB  - As in other model systems for investigating mechanisms of learning, second
      messenger regulated protein phosphorylation are implicated in processes of
      associative learning in the honeybee Apis mellifera. Since the cAMP-dependent
      phosphorylation via protein kinase A (PKA) and the Ca2+/phospholipid-dependent
      phosphorylation by protein kinase C (PKC) contribute to different aspects of
      associative olfactory learning in the honeybee, the localization of PKA and PKC
      in the neuronal circuitry is of general interest. The presented
      immunohistological study compares the distribution of PKA and PKC in honeybee
      brain focusing on the antennal lobes and the mushroom bodies, neuropiles
      implicated in olfactory learning. While PKA, is found in all neuropiles and
      somata throughout the honeybee brain, the Ca2+/phospholipid-dependent PKC is
      concentrated in the antennal lobes and the mushroom bodies. In the antennal
      lobes, the primary neuropiles of olfactory information processing, PKAII is
      localized in sensory neurons and interneurons. In contrast, the PKC
      immunolabeling is exclusively due to interneurons with a characteristically
      strong labeling of the central area of the antennal lobes. The mushroom bodies
      show the highest PKC- and PKAII-immunostaining of the brain. PKAII and PKC are
      expressed at different levels in different subsets of the mushroom body intrinsic
      Kenyon cells. This different distribution of PKAII and PKC in the antennal lobes
      and the mushroom bodies, at least in part, accounts for the different roles of
      PKAII and PKC mediated phosphorylation in olfactory learning.

PMID- 10344769
TI  - Histochemistry of classical neurotransmitters in antennal lobes and mushroom
      bodies of the honeybee.
AB  - This paper summarizes histochemical and immunocytochemical investigations of
      cholinergic, GABAergic, and glutamatergic pathways in the central brain and
      suboesophageal ganglion of the honeybee. Acetylcholinesterase histochemistry,
      immunocytochemical staining for nicotinic acetylcholine receptors, and mapping
      for alpha-bungarotoxin binding sites indicate cholinergic synaptic interactions
      in the antennal lobe and a cholinergic pathway via a subset of olfactory
      projection neurons into the mushroom bodies. Calcium imaging experiments in cell
      cultures prepared from mushroom bodies demonstrate the expression of nicotinic
      cholinergic receptors on Kenyon cells. Neurons synthesizing GABA and glutamate
      are stained with well-defined polyclonal antisera against the amino acids. GABA
      immunoreactivity is mainly localized in local interneurons of the antennal lobe
      and in extrinsic neurons innervating the mushroom bodies. High levels of
      glutamate-immunoreactivity are found in motoneurons of the suboesophageal
      ganglion, the dorsal lobe, and also in interneurons. A subgroup of the Kenyon
      cells shows distinct but weaker levels of glutamate-immunoreactivity. The
      detailed knowledge about the chemical neuroanatomy of the bee provides a
      framework for behavioral pharmacological approaches, which implicate the
      involvement of cholinergic mechanisms in olfactory learning and GABAergic
      mechanisms in odor discrimination.

PMID- 10344770
TI  - Microvasculature of the bovine claw demonstrated by improved micro-corrosion
      casting technique.
AB  - A new and improved technique for microvascular corrosion casting was developed
      and verified by examination of corrosion casts of 90 bovine limbs. The described
      technique renders a complete filling of the vasculature of the claw even in
      regions that hitherto proved to be difficult regarding completeness of filling
      such as the dorsal area of the claw. This is demonstrated by an exemplary
      examination of all regions of the claw. The advantages and disadvantages of the
      new method are discussed.

PMID- 10344771
TI  - Preparation for TEM of layered samples with fragile microstructure and weak layer
      interface.
AB  - The objective of this work was to prepare for transmission electron microscopy
      (TEM) a layered structure of materials with fragile microstructure. The samples
      consisted of two layers of different materials, silicon nitride and borosilicate
      glass, loosely bonded together. The low strength of the sample resulted in
      fragmentation during more conventional preparation. However, it was possible to
      prepare the fragments by mounting them in a titanium specimen carrier with
      aluminium strips as support. After grinding and polishing, a technique of low
      angle ion milling was used to obtain electron beam transparent areas at the
      nitride/glass interface.

PMID- 10344772
TI  - Experimental models used to measure direct and indirect ethanol teratogenicity.
AB  - The teratogenic effects of ethanol have been widely studied in a variety of
      experimental models. In humans, ethanol teratogenicity results from both direct
      and indirect effects. This paper reviews the differences between direct and
      indirect effects of ethanol on the developing fetus. Experimental paradigms are
      discussed that attempt to differentiate between direct and indirect effects. For
      the purpose of this review, direct effects of ethanol are caused by ethanol
      interacting with the fetal cell. Indirect effects of ethanol teratogenicity are
      defined as any perturbation of the developing fetus resulting from ethanol
      exposure but not caused by ethanol's interacting with the fetal cell. Indirect
      effects of ethanol teratogenicity include: ethanol-induced maternal
      undernutrition; ethanol-induced placental dysfunction and acetaldehyde
      teratogenicity.

PMID- 10344773
TI  - Alcohol-histamine interactions.
AB  - Alcohol and histamine metabolic pathways in the body have the common enzymes
      aldehyde dehydrogenase and aldehyde oxidase. The metabolite of ethanol,
      acetaldehyde, can effectively compete with the metabolites of histamine,
      methylimidazole acetaldehyde, and imidazole acetaldehyde. At the periphery,
      alcohol and acetaldehyde liberate histamine from its store in mast cells and
      depress histamine elimination by inhibiting diamine oxidase, resulting in
      elevated histamine levels in tissues. Histamine mediates alcohol-induced gastric
      and intestinal damage and bronchial asthma as well as flushing in Orientals. On
      the other hand, alcohol provokes food-induced histaminosis and histamine
      intolerance, which is an epidemiological problem. There are many controversial
      reports concerning the effect of H2 receptor antagonists on ethanol metabolism
      and the activity of alcohol dehydrogenase in the stomach. In addition, alcohol
      affects histamine levels in the brain by modulating histamine synthesis, release,
      and turnover. Histamine receptor antagonists can affect ethanol metabolism and
      change the sensitivity of animals to the hypnotic effects of alcohol. In contrast
      to other neurotransmitters, the involvement of the brain histamine system in the
      mechanisms of the central actions of alcohol and in the pathogenesis of
      alcoholism is poorly studied and understood.

PMID- 10344774
TI  - The alcohol patient and surgery.
AB  - Alcohol abusers have a threefold increased risk of post-operative morbidity after
      surgery. The most frequent complications are infections, cardiopulmonary
      insufficiency, and bleeding episodes. Pathogenesis is suppressed immune capacity,
      subclinical cardiac dysfunction, and haemostatic imbalance. The economic
      implications of alcohol abuse in surgical patients are tremendous. Interventional
      studies are required to reduce future increases in post-operative morbidity.

PMID- 10344775
TI  - Does the concept of a standard drink apply to viticultural societies?
AB  - The use of standard drink units (SDUs) in the measurement of individual alcohol
      consumption has become widely popular in recent years. However, the ethanol
      content of drinks varies from country to country and is usually arrived at
      without scientific backing. The present study was designed to establish an SDU
      for a predominantly wine-drinking country (Spain). Two field studies were
      simultaneously conducted to gather data about home and public alcohol consumption
      in eight regions of the country with a total of 10751 subjects. The average
      alcohol content of a drink was very similar for wine and beer, whereas in the
      case of spirits it was almost double. Relevant differences were found across
      regions, drinking settings and city sizes. A Spanish SDU was set at 10 g of
      ethanol for wine and beer, with a measure of spirits accounting for two SDUs. The
      use of SDUs should be encouraged in primary health care settings. However,
      dispersion of data suggests that, when SDU is used as a screening tool,
      additional information should always be obtained in borderline cases.

PMID- 10344776
TI  - Isolation from beer and structural determination of a potent stimulant of gastrin
      release.
AB  - Beer was subjected to five successive chromatographic procedures to isolate the
      gastrin release-inducing activity, guided by bioassay of the fractions in
      anaesthetized Donryu rats. The procedures were: (1) hydrophobic interaction
      chromatography (aqueous effluent with an HP20 column); (2) weak cation-exchange
      chromatography (1 M acetic acid eluate with a CM Sephadex C-25 column); (3) gel
      filtration (methanol eluate with a Sephadex LH-20 column); (4) same as (2); (5)
      high-performance liquid chromatography (YMC-Pack ODS-AM with 7% acetonitrile-0.01
      M HCl). The active component finally isolated had a specific activity
      approximately 10000 times higher than that of beer. It was identified by means of
      mass, 1H- and 13C-nuclear magnetic resonance spectral analyses as N
      methyltyramine (NMT). The dose of NMT giving maximal gastrin-releasing activity
      was 25 microg/kg, and the 50% effective dose was approximately 10 microg/kg on
      oral administration to rats. NMT was isolated and identified as a gastrin release
      inducer in beer. Its concentration in beer is sufficient to account for most of
      the activity of beer.

PMID- 10344777
TI  - Chronic ethanol consumption induces hypomotility in the portal vein of Sardinian
      alcohol-preferring rats.
AB  - In order to study the physiopathological effects of chronic ethanol intake on the
      smooth muscle of the vascular system, we have assessed the length-tension
      relationship in isolated portal veins of Sardinian alcohol-preferring (sP) rats.
      Significant differences in motor performance were found between sP naive and sP
      rats exposed to ethanol consumption (12% w/v) for 48 weeks. Isolated portal veins
      of sP rats which consumed ethanol chronically showed a marked decrease of
      spontaneous and KCl-induced contraction waves when compared to sP naive rats. At
      optimum length (140% Lr) for maximal contractile performance, the mean amplitude
      wave in the portal veins of sP drinker rats was about five times less than in sP
      naive veins. Furthermore, in the veins of sP drinkers, the active curve showed
      lower values of tension at each elongation of the vascular segment, the maximum
      value of active tension (7.32 +/- 0.54 mN) represented a reduction in amplitude
      of about 32% with respect to sP naive veins. These results indicate that long
      term ethanol consumption impairs portal vein motility.

PMID- 10344778
TI  - Blockade of the acquisition of ethanol-induced conditioned place preference by N
      methyl-D-aspartate receptor antagonists.
AB  - We have examined the influence of two different N-methyl-D-aspartate (NMDA)
      receptor antagonists on acquisition of the reinforcing properties of ethanol
      measured in the conditioned place preference (CPP) paradigm in rats. After
      receiving 15 daily injections of ethanol (0.5 g/kg, i.p.) before the conditioning
      trials, rats acquired the preference to the compartment paired with ethanol
      injections during conditioning. Both dizocilpine (0.1 mg/kg, i.p.), a non
      competitive antagonist of the NMDA receptor, and L-701,324 (5 mg/kg, per os), an
      antagonist acting at the strychnine-insensitive glycine site of NMDA receptor
      complex, when co-administered repeatedly with ethanol, prevented the acquisition
      of ethanol-induced CPP. Dizocilpine alone provoked the development of CPP, having
      some intrinsic rewarding properties. In contrast, L-701,324 alone did not affect
      the CPP. These results suggest that the rewarding properties of ethanol could be,
      at least in part, due to its action at the NMDA receptor complex. Additionally,
      we can speculate that NMDA receptor antagonists can be useful in the treatment of
      ethanol dependence. Glycine receptor antagonists having no abuse potential might
      have advantages in terms of safety compared to non-competitive NMDA receptor
      antagonists.

PMID- 10344779
TI  - Five-year outcome in alcohol dependence. A naturalistic study of 850 patients in
      Catalonia.
AB  - A prospective, multicentre study was designed to evaluate the impact of a
      treatment programme in alcohol-dependent patients (n = 850). Drinking status and
      measures related to quality of life such as morbidity, mortality, alcohol-related
      problems, and psychological and social functioning were assessed 5 years from the
      initial contact with the patient. Five years after the initial visit, drinking
      status followed a bimodal distribution: 371 patients (43.6%) were found to be
      abstinent, 323 (38%) were heavy drinkers, and only 55 (6.5%) were controlled
      drinkers. A total of 65 (7.6%) patients died during the study, 33 (3.9%) patients
      were lost to follow-up and three (0.3%) patients were not collaborative.
      Differences in health-related issues were identified for each of the drinking
      status categories. Abstinent patients presented with significantly better
      outcomes than controlled and heavy drinkers on most medical, socio-economic and
      psychological measures. Heavy drinkers showed significantly worse outcomes than
      controlled drinkers.

PMID- 10344780
TI  - Introduction: craving and relapse in alcoholism: neurobio-psychosocial
      understanding.

PMID- 10344781
TI  - A three-pathway psychobiological model of craving for alcohol.
AB  - In this article, by reviewing the psychological, psychophysiological,
      neurobiological, and psychopharmacological literature on craving for alcohol, it
      is argued that converging evidence from several disciplines suggests a three
      pathway psychobiological model of craving. Essential to this model is the
      appreciation of the role of individual differences in affect regulation
      strategies or personality styles, conditionability, sensitivity to alcohol's
      effects, and related dysregulations in distinct neural circuitries or
      neurotransmitter systems. These factors are of crucial importance to a proper
      understanding of the nature of craving, its underlying mechanisms and different
      manifestations. As a first pathway, it is suggested that reward craving or desire
      for the rewarding, stimulating and/or enhancing effects of alcohol might result
      from either dopaminergic/opioidergic dysregulation or a personality style
      characterized by reward seeking or a combination of both. As a second pathway, it
      is suggested that relief craving or desire for the reduction of tension or
      arousal might result from either gamma-aminobutyric acid
      (GABA)ergic/glutamatergic dysregulation or a personality style characterized by
      stress reactivity or a combination of both. Obsessive craving, the result of the
      third pathway, can be defined as lack of control over intrusive thoughts about
      drinking resulting in impaired functioning. This type of craving might result
      either from a serotonin deficiency or a personality style characterized by low
      constraint or disinhibition or a combination of both. The putative implications
      of this three-pathway model for the assessment of alcohol craving, diagnosis and
      treatment of alcoholism, and future research on craving, are discussed.

PMID- 10344783
TI  - Long-term alcohol self-administration with repeated alcohol deprivation phases:
      an animal model of alcoholism?
AB  - In order to study the neurobiological and molecular mechanisms of alcohol
      dependence and addiction, appropriate animal models are warranted. Although
      animal models cannot incorporate all aspects and criteria of an addictive
      behaviour to alcohol seen in human alcoholics, they can at least reflect some of
      the criteria given in the fourth edition of Diagnostic and Statistical Manual of
      Mental Disorders (DSM-IV) of the American Psychiatric Association (1994). Novel
      aspects of addictive behaviour to alcohol, craving and relapse might be uncovered
      by animal models of long-term, free-choice, alcohol self-administration followed
      by alcohol deprivation phases. After several months of voluntary alcohol
      consumption, the drug-taking behaviour following a deprivation (withdrawal) phase
      is characterized by increased alcohol intake and preference (alcohol deprivation
      effect) and changes in alcohol intake patterns where animals consume large
      amounts of highly concentrated alcohol solutions even at inappropriate times
      (e.g. during the inactive light phase when drinking activity is minimal).
      Altogether, alcohol drinking following alcohol deprivation seems to become
      uncontrolled and inelastic, reflecting an incentive demand for the drug in such a
      model. Furthermore, the alcohol deprivation effect outlasts very long abstinence
      phases, which indicates the persistence of a drug memory for alcohol.

PMID- 10344782
TI  - Craving for alcohol: findings from the clinic and the laboratory.
AB  - This paper presents a review of the current status of empirical research in the
      area of alcohol craving. After an introduction on the origins of the construct of
      craving, we first present clinical studies that have examined craving as a
      hallmark symptom of alcohol dependence and demonstrated its sensitivity as an
      outcome measure in assessing change in pharmacotherapy trials of alcohol
      dependence. There is also discussion regarding new multifactorial self-report
      instruments of alcohol craving with good reliability and predictive validity,
      that may be sensitive to detecting alcohol craving and assessing change in
      craving as it relates to relapse during treatment. Next, we examine the
      experimental paradigms that have been used to induce alcohol craving in the
      laboratory. Further, the methodological issues affecting laboratory-based
      paradigms are presented, while also elucidating the potential use of effective
      laboratory-based craving induction paradigms, both in clinical studies as well as
      in laboratory studies that examine the brain mechanisms associated with the
      concept of craving. Finally, directions for future research on craving in the
      laboratory and the clinic are presented in the context of developing more
      effective treatments for different phases of recovery from alcohol dependence.

PMID- 10344784
TI  - The role of serotonin in craving: from basic research to human studies.
AB  - Increasing evidence suggests that craving may play a central role in the
      mechanisms of addiction. The experience of craving is largely characterized by
      obsessional thoughts about drugs, triggering compulsive drug-seeking and drug
      taking behaviour. In the present article the possible involvement of brain 5
      hydroxytryptamine (5-HT) in the mechanisms of craving and relapse is discussed by
      integrating the results of basic research with those obtained in human studies.
      Based on studies suggesting that the brain serotonergic system plays a central
      role in the regulation of impulse-control mechanisms, it is proposed that 5-HT
      deficiency may contribute to the loss of control over drug-taking, which is a
      crucial factor for the maintenance of addictive behaviour.

PMID- 10344785
TI  - Craving and relapse measurement in alcoholism.
AB  - This paper attempts to summarize the measurement of craving with four different
      craving instruments and to relate this to definitions and measurement of relapse.
      The definitions of relapse may vary between studies and researchers, but are
      usually well defined. Five commonly used methods to measure relapse are: (1)
      quantity/frequency of drinking; (2) cumulative duration of abstinence (CDA); (3)
      post-withdrawal abstinent period; (4) stable recovery period; (5) the time line
      follow-back method. The definition of craving is much less clear and is mostly
      described as an emotional-motivational state or as obsessive-compulsive
      behaviour. Four self-rating instruments are briefly discussed and compared: the
      Obsessive-Compulsive Drinking Scale, OCDS, the Lubeck Craving Scale, LCRR, the
      Alcohol Craving Questionnaire, ACQ-Now-SF-R, and ordinal scales (e.g. visual
      analogue, Likert, or verbal descriptive scales). These instruments measure
      different aspects or dimensions of craving over different periods. The different
      dimensions measured suggest that there is still a need to conceptualize a
      standard interpretation of the word craving. There is a need also to measure an
      emotional-motivational dimension, a cognitive-behavioural dimension,
      expectancies, and effects on positive and negative reinforcement with different
      instruments or with one multidimensional instrument. It is suggested that
      different patients are expected to have different craving profiles.

PMID- 10344786
TI  - A comparison of home detoxification and minimal intervention strategies for
      problem drinkers.

PMID- 10344787
TI  - Can ethyl glucuronide be determined in post-mortem body fluids and tissues?

PMID- 10344788
TI  - Isolation of the 5'-flanking region for human brain sodium channel subtype II
      alpha-subunit.

PMID- 10344789
TI  - Temporal relations among amyloid beta-peptide-induced free-radical oxidative
      stress, neuronal toxicity, and neuronal defensive responses.
AB  - Amyloid beta-peptide (Abeta), the main constituent of senile plaques in
      Alzheimer's disease (AD) brain, is hypothesized to be a key factor in the
      neurodegeneration seen in AD. Recently it has been shown that the neurotoxicity
      of Abeta occurs in conjunction with free-radical oxidative stress associated with
      the peptide. In the present study, we investigated the temporal relations among
      the formation of Abeta-associated free radicals, the oxidative damage to, and the
      activation of antioxidant defense mechanisms in rat embryonic hippocampal
      neuronal culture subjected to toxic Abeta(25-35). Temporal electron paramagnetic
      resonance (EPR) spectroscopy results show that synthetic Abeta(25-35) forms free
      radicals rapidly after solubilization with a high signal intensity at initial
      time points. At those time points, neuronal toxicity and oxidative stress
      gradually increase as assessed by reduction of 3-[4,5-dimethylthiazol-2-yl)-2,5
      diphenyl] tetrazolium bromide, trypan blue exclusion, formation of reactive
      oxygen species, and detection of protein carbonyl levels. The latter occurs
      before neurotoxicity. When the EPR signal intensity of Abeta solution decreases
      at later time points, neuronal toxicity levels off and remains the same until the
      end of the experiment. The oxidative-sensitive enzyme creatine kinase (CK) (brain
      isoform) (CK-BB) content increases at initial points of the Abeta treatment in
      correlation with the EPR signal to keep the CK activity constant, presumably to
      overcome the Abeta-induced oxidative insult. CK-BB content returns to normal
      levels by the end of the experiment. CK activity normalized to CK content implies
      the presence of inactivated CK molecules during the treatment. Both Mn SOD and
      Cu/Zn superoxide dismutase (SOD) mRNA levels show robust increases initially,
      which later return to control level with decreasing oxidative insult. These
      results are consistent with the notion that Abeta(25-35) promotes a rapid free
      radical oxidative stress to neurons, which respond by modulating various
      oxidative stress-handling genes.

PMID- 10344790
TI  - Differential interaction of voltage-gated K+ channel beta-subunits with
      cytoskeleton is mediated by unique amino terminal domains.
AB  - To define the molecular characteristics of K+ channel beta-subunit polypeptides,
      we have studied their biochemical properties and subcellular distribution in
      transfected mammalian cells. We find that the recombinant voltage-dependent K+
      (Kv) beta1.1 and Kvbeta2 polypeptides have distinct detergent solubility
      properties owing to a novel association of Kvbeta1.1 with the actin-based
      cytoskeleton. Mutational and chimeric protein analyses show that the unique
      aminoterminus of Kvbeta1.1 is both necessary and sufficient for mediating the
      association of beta-subunits with cytoskeleton. Thus, the interaction with
      cytoskeleton is mediated through the amino-terminal domain previously shown to be
      necessary for modulating alpha-subunit inactivation, but not necessary for
      interaction with alpha-subunit polypeptides. These data reveal that different
      domains of beta-subunit polypeptides mediate interactions with cytoskeleton and
      with alpha-subunits, and provide a structural basis for previous reports that
      linked the extent of beta-subunit-induced inactivation to the state of the actin
      cytoskeleton.

PMID- 10344791
TI  - An immortalized, type-1 astrocyte of mesencephalic origin source of a
      dopaminergic neurotrophic factor.
AB  - Rat embryonic d 14 (E14) mesencephalic cells, 2.5% of which are glioblasts, were
      incubated in medium containing 10% of fetal bovine serum for 12 h and
      subsequently expanded in a serum-free medium using basic fibroblast growth factor
      (bFGF) as the mitogen. On a single occasion, after more than 15 d in culture,
      several islets of proliferating, glial-like cells were observed in one dish. The
      cells, when isolated and passaged, proliferated rapidly in either a serum-free or
      serum-containing growth medium. Subsequent immunocytochemical analysis showed
      that they stained positive for GFAP and vimentin, and negative for A2B5, O4,
      GalC, and MAP2. Serum-free conditioned medium (CM) prepared from these cells
      caused a fivefold increase in survival and promoted neuritic expansion of E14
      mesencephalic dopaminergic neurons in culture. These actions are similar to those
      exerted by CM derived from primary, mesencephalic type-1 astrocytes. The pattern
      of expression of the region-selective genes; wnt-1, en-1, sis showed that 70% of
      the cells were heteroploid, and of these, 50% were tetraploid. No apparent
      decline in proliferative capacity has been observed after 25 passages. The
      properties of this cell line, named ventral mesencephalic cell line one (VMCL1),
      are consistent with those of an immortalized, type-1 astrocyte. The mesencephalic
      origin of the cell line, and the pattern and potency of the neurotrophic activity
      exerted by the CM, strongly suggest that the neurotrophic factor(s) identified
      are novel, and will likely be strong candidates with clinical utility for the
      treatment of Parkinson's disease.

PMID- 10344792
TI  - Recombinant caprine 3H-[N-acetylglucosamine-6-sulfatase] and human 3H-[N
      acetylgalactosamine-4-sulfatase]: plasma clearance, tissue distribution, and
      cellular uptake in the rat.
AB  - The use of recombinant lysosomal enzymes for enzyme replacement therapy (ERT) is
      likely to be a necessary component of effective treatment regimens for lysosomal
      storage diseases (LSDs). The mechanism and rate of uptake into target cells, rate
      of disappearance of the enzyme from plasma, and its tissue distribution are
      important factors to assess the need for possible modifications to the enzyme,
      particularly for LSDs that affect the central nervous system (CNS). Two
      recombinant lysosomal enzymes, caprine N-acetylglucosamine-6-sulfatase (rc6S) and
      human N-acetylgalactosamine-4-sulfatase (rh4S), deficient in MPS IIID and MPS VI,
      respectively, were radiolabeled and purified. The major portion (>77%) of each
      recombinant enzyme contained the mannose-6-phosphate (M6P) recognition marker as
      demonstrated by their ability to bind to a M6P receptor affinity column. The
      uptake of 3H-rc6S and 3H-rh4S into cultured rat brain cells was also inhibited by
      the addition of 5 mM M6P to the culture medium. After iv administration of 0.4
      0.5 mg/kg of 3H-rc6S and 1 mg/kg of 3H-rh4S to the rat, both enzymes were rapidly
      lost from the circulation in a biphasic fashion (t1/2 for 3H-rc6S = 1.25+/-0.15
      min and 37.17+/-23.29 min; t1/2 for 3H-rh4S = 0.41 and 5.3 min). At this dose,
      about 6% of 3H-rc6S, but only 0.49% of 3H-rh4S, remained in the plasma 4 h after
      administration, whereas approx 30% of 3H-rc6S and more than 50% of 3H-rh4S was
      found in the liver. At doses of 1.6-2.0 mg/kg of 3H-rc6S and 1 mg/kg 3H-rh4S, but
      not at the lower dose of 3H-rc6S, trace levels of both 3H-rc6S and 3H-rh4S were
      detected in the brain. The low level of enzyme recovered from the brain suggests
      that modification of rc6S will be necessary to achieve sufficient enzyme uptake
      into the CNS for effective therapy of MPS IIID.

PMID- 10344793
TI  - Altered residual ATP content in rat brain cortex subcellular fractions following
      status epilepticus induced by lithium and pilocarpine.
AB  - Changes in residual ATP concentrations were investigated following subcellular
      fractionation of rat brain cortex after a prolonged period of status epilepticus
      induced by sequential administration of lithium and pilocarpine. After 2 h of
      continuous high-amplitude rapid spiking on EEG, we found significantly decreased
      levels of residual ATP in the homogenate and mitochondria fractions from status
      epilepticus rat brains compared to matched controls. No difference in residual
      ATP level was observed in the synaptosomal preparations of status epilepticus
      animals compared to controls. Inorganic phosphate concentration in the status
      animals was higher than controls in the cytosolic fraction only. F1-ATPase
      activity, an enzymatic indicator of mitochondrial ATP synthesis rate, was
      significantly higher in the status brains, whereas other mitochondrial enzymes
      were not different in the status and control rat groups. These findings, together
      with our earlier report of reduced synaptosomal ecto-ATPase activity, suggest
      that either the corresponding in vivo ATP concentrations were reduced as a result
      of status epilepticus or other biochemical changes had occurred that facilitated
      the hydrolysis of ATP following decapitation. Controls for and measurement of
      such other changes failed to provide an explanation for the observed changes in
      residual ATP.

PMID- 10344794
TI  - Production and functional expression of an epitope-tagged human choline
      acetyltransferase.
AB  - cDNA containing the entire coding region of the human choline acetyltransferase
      gene (hChAT) was fused to the influenza virus hemagglutinin (HA) epitope preceded
      by a Kozak sequence. The recombinant HA-hChAT was then inserted into an
      expression vector under the transcriptional control of the cytomegalovirus (CMV)
      promoter. After transient transfection into COS-1 cells, expression was assayed
      by Northern and Western blot analysis and immunofluorescence. The chimeric HA
      hChAT protein was compared to native hChAT for its ability to synthesize
      acetylcholine. It behaves identically to unmodified hChAT showing that the HA
      epitope does not affect ChAT activity. This approach enables one to distinguish
      the expression of the HA-hChAT from endogenous ChAT. Genetically engineered cells
      that express a high level of HA-hChAT could be used as a promising experimental
      tool for gene transfer and neurografting techniques as well as to produce and
      study transgenic mice.

PMID- 10344795
TI  - Astrocytosis and proliferating cell nuclear antigen expression in brains of
      scrapie-infected hamsters.
AB  - Scrapie is a neurodegenerative disease in sheep and goats. Neuropathological
      examination shows astrocytosis. One issue is whether the astrocytosis seen in
      scrapie is a function of an increase in reactivity of individual cells, or
      whether there is actual replication of astrocytes. We used double-label
      immunohistochemistry for proliferating cell nuclear antigen (PCNA) and for glial
      fibrillary acidic protein (GFAP) to determine the mitotic state of cells and to
      confirm their identity as astrocytes. Brain sections from hamsters (strain
      LVG/LAK) infected with 139H or 263K scrapie isolates were examined. GFAP
      immunostaining was increased in astrocytes in most regions of the brains of
      scrapie-infected hamsters. These qualitative observations were confirmed by
      computerized image analysis quantification. A proportion of the hypertrophic
      astrocytes (0.5-10.8%, depending on specific location) were PCNA immunoreactive.
      The PCNA-immunopositive astrocytes were most frequently found in cerebral cortex,
      corpus callosum, subependymal areas, fimbria, caudate, thalamus, hypothalamus,
      hippocampus, and dentate gyrus. Our results suggest that the astrocytosis seen in
      scrapie-infected animals is, at least in part, owing to actual replication of
      astrocytes in these animals. We hypothesize that the astrocytes may be an
      important locus for the disease process.

PMID- 10344797
TI  - Institute of Health Record Information and Management. Management Guidelines
      November 1998. Dealing with suspected bogus calls.

PMID- 10344798
TI  - Institute of Health Record Information and Management. Management Guidelines
      November 1998. Organisation and structure of health records services.

PMID- 10344796
TI  - Analysis of allelic association between D6S461 marker and multiple sclerosis in
      Ashkenazi and Iraqi Jewish patients.
AB  - A genetic factor contributing to multiple sclerosis (MS) disease risk is evident
      by the increased prevalence of disease among siblings of probands. A recent
      genome screen on Canadian sib pairs suffering from MS identified linkage between
      the genetic marker D6S461 and MS, and showed disequilibrium in transmission of
      its 260-bp allele from heterozygous parents to affected siblings (Ebers et al.,
      1996). The present study examined the allelic segregation of this marker among MS
      patients of Iraqi Jewish and Ashkenazi origin, two homogeneous ethnic groups that
      differ considerably from Caucasians. The frequency of the 260-bp allele reached
      28.3% among Iraqi MS patients (n = 30) and 25.2% among the Ashkenazi patients (n
      = 121) compared with 19.6% (n = 28) and 21.3% (n = 115) in respective origin
      matched controls (for the combined data set, p = 0.18). A secondary analysis of
      the frequency of the 260-bp allele in clinical subgroups showed a frequency of
      38.1% among patients with juvenile MS (i.e., onset by 21 yr of age) of Ashkenazi
      origin (n = 21, p = 0.019) and 38.8% in the combined pool (n = 27, p = 0.0045).
      Most (90%) of the juvenile MS patients belonged to the relapsing-remitting
      subgroup, which itself showed a frequency of 28.5% of the 260-bp allele (n = 121,
      p = 0.045). The results suggest that the D6S461 region may contain a locus
      contributing to an early onset of relapsing-remitting MS.

PMID- 10344799
TI  - Challenges of health care delivery system beyond 2000 AD.

PMID- 10344800
TI  - Financial disclosure by clinical investigators--FDA. Final rule; action on
      petition for reconsideration.
AB  - The Food and Drug Administration (FDA) is revising the requirements regarding
      financial disclosure by clinical investigators in order to add material to the
      codified language that was inadvertently omitted and to clarify the compliance
      dates to, in some cases, restrict the retroactive application of certain
      requirements of the rule. FDA is making these changes in order to respond to
      concerns raised by the Pharmaceutical Research Manufacturers Association
      (hereinafter referred to as "PhRMA"). By making these changes, FDA will be
      reducing the administrative burden for manufacturers and other affected parties
      while, at the same time, ensuring that the agency obtains the information that is
      most relevant to its review of clinical data submitted in marketing applications.

PMID- 10344801
TI  - Cost-of-living adjustments and headstone or marker allowance rate--VA. Notice.
AB  - As required by law, the Department of Veterans Affairs (VA) is hereby giving
      notice of cost-of-living adjustments (COLAs) in certain benefit rates and income
      limitations. These COLAs affect the pension, parents' dependency and indemnity
      compensation (DIC), and spina bifida programs. These adjustments are based on the
      rise in the Consumer Price Index (CPI) during the one year period ending
      September 30, 1998. VA is also giving notice of the maximum amount of
      reimbursement that may be paid for headstones or markers purchased in lieu of
      Government-furnished headstone or markers in Fiscal Year 1999, which began on
      October 1, 1998.

PMID- 10344802
TI  - Where health expenditures have been, and where they are likely to go.

PMID- 10344803
TI  - Can administration find cure for Medicare+Choice ills?

PMID- 10344804
TI  - Compensation monitor. Swim at your own risk.

PMID- 10344805
TI  - Risk adjustment's arrival promises greater fairness.

PMID- 10344806
TI  - A new model for managing care.

PMID- 10344807
TI  - Service often too slow when HMOs use 'McLabs'.

PMID- 10344808
TI  - Thinking globally, acting locally.

PMID- 10344809
TI  - Code could be right prescription to give pharmacy more credence.

PMID- 10344810
TI  - Stark II makes it easier to terminate bad contracts.

PMID- 10344811
TI  - Managed care outlook. To get or to skip care? Coverage makes the difference.

PMID- 10344812
TI  - Three generations look at health care.

PMID- 10344813
TI  - A community approach to managing uncompensated care.
AB  - Estimated at more than $15 billion annually, uncompensated care accounts for most
      of the community benefit costs reported by the nation's hospitals. Reflecting the
      most basic of all hospital goals, these expenditures are designed primarily to
      benefit patients rather than communities.

PMID- 10344814
TI  - Recapturing the joy in health care.
AB  - Competition, consumerism, advancing technology and changes in public policy are
      transforming the nation's health care system. Federal and state governments have
      imposed forms of price controls to stem rising costs, and private sector
      insurance companies and health plans have introduced managed care (translated
      managed cost) initiatives for the same reason.

PMID- 10344815
TI  - That was then, this is now. Look out for the new millennium.
AB  - How can we improve the process of patient care and satisfaction? One way is to
      improve methods of transmitting, storing and manipulating information. That
      answer puts technology at the very core of health care.

PMID- 10344816
TI  - Building stronger neighborhoods.

PMID- 10344817
TI  - Ready, aim, hire.

PMID- 10344818
TI  - Intuition: the new-era trump card.
AB  - Welcome to the new era--one largely defined by rapid change and unprecedented
      access to information. If you are worried about keeping up, you are not alone.
      But take heart, many corporations are rapidly adapting to this chaotic new
      environment by using one of the oldest, most powerful tools in our history-
      intuition.

PMID- 10344820
TI  - What road will you take? Charting an organizational course for community
      accountability.
AB  - Across the country, numerous perception studies have been conducted to gauge the
      public's opinion of America's health care system and the role local providers
      play in serving community health needs. The results consistently show that, in
      general, people are unaware of the myriad of benefits above and beyond the
      provision of general acute care services provided by not-for-profit community
      health care organizations.

PMID- 10344819
TI  - Building healthy communities in the 21st century.
AB  - A profound set of changes is occurring all around us in health care. Many of our
      organizations are going through a merger or consolidation; some are struggling to
      grow their net revenue; some are prospering in the new competitive environment;
      others are trying to figure out just how to survive. Our task is to create health
      care organizations that work, especially in a world where everything constantly
      seems up in the air. We know that fundamental change is required. The changes
      that effect our health care organizations can often times have a profound effect
      on our communities.

PMID- 10344822
TI  - No place for half-hearted efforts.

PMID- 10344821
TI  - Back to nature.
AB  - I am going to draw your attention to natural systems--what nature has spent
      millions of years perfecting--and suggest that nature has the road map for health
      care's future even if we have a little less time to work on it.

PMID- 10344823
TI  - Back to the future. The challenges of governing community health partnerships.
AB  - As the new century approaches, trustees of hospitals and health systems are
      facing a bewildering array of choices and challenges. The prospect of
      comprehensive health care reform has faded, the promise of managed care is
      disintegrating, and escalating costs and declining revenues continue to batter
      our health care organizations.

PMID- 10344824
TI  - Financial prep for Y2K.
AB  - The financial impact of Y2K will be significant and, in some cases, devastating.
      Careful analysis will help health care organizations prepare for all
      contingencies and set aside the necessary resources to become compliant.

PMID- 10344825
TI  - How to provide care for 78 million seniors.

PMID- 10344826
TI  - Including the ultimate: a spiritual focus treatment program in an inpatient
      psychiatric area of a hospital in partnership with a pastoral counseling center.
AB  - Describes how an American Association of Pastoral Counselor (AAPC) accredited
      pastoral counseling center and a community medical center developed in inpatient
      psychiatric treatment program which integrated the spiritual/religious resources
      of patients. Outlines the process of collaboration, some basic principles of the
      integration of faith resources, the ways that staff resistance surfaced and
      substantially was overcome, and the positive responses of patients. Notes the
      decision to base treatment on the religious/spiritual position of patients
      (rather than of therapists), the role of the therapist in this model, and some
      relevant isomorphic replications.

PMID- 10344827
TI  - Hope in the midst of challenge: evidence-based pastoral care.
AB  - Describes the origins and characteristics of evidence-based pastoral care and
      utilizes a case with a person with cerebral palsy demonstrating this approach.
      Draws on evidence from research and critically evaluates evidence. Notes the
      dynamic relationship between research and clinical practice and makes suggestions
      about utilizing evidence-based pastoral care in chaplaincy.

PMID- 10344828
TI  - Bioethics education in a clinical pastoral education program.
AB  - Notes that contemporary health care delivery and the interface of clinical
      professionals with patients and families are marked by complexity and pluralism
      and that within this modern matrix patients, families, professionals, and
      administrators frequently struggle with difficult ethical issues. Observes that
      these realities have significant implications for chaplains and for chaplains-in
      training, a factor which has received the attention of the Bioethics Committee of
      the Professional Chaplains Association through its Bioethics Committee and
      resulting in a set of guidelines for the chaplain's appropriate roles in
      bioethical issues and for their role on bioethics committees. Describes the
      establishment of a bioetchics modulate at the Cleveland Clinic Foundation (CCF)
      in which chaplain residents are enabled to function as professional peers with
      other healthcare professionals and as competent chaplains with patients and
      families in bioethical decision making. Reports on the methods and the results of
      a pilot study based on the model described.

PMID- 10344829
TI  - Nursing home retro.

PMID- 10344830
TI  - Responsibility and response-ability: no small gift.

PMID- 10344831
TI  - Patience, empathy, and grace: a medical triune.

PMID- 10344832
TI  - Blues streak continues. Three Northeastern plans will affiliate, falling in line
      with a nationwide consolidation trend.

PMID- 10344833
TI  - Million-dollar man. Not-for-profit trade association treats retiring CEO very
      well.

PMID- 10344834
TI  - Big sell consolidates small-city hospitals, formerly combatants.

PMID- 10344835
TI  - Lobbying hits and misses. Healthcare associations worked hard in Washington last
      year but weren't entirely successful.

PMID- 10344837
TI  - Tenet takes control. For-profit chain begins high-profile efforts to rescue
      foundering AHERF facilities.

PMID- 10344836
TI  - Chock-full of change. Opportunities, and perils, abound as industry continues to
      evolve.
AB  - Tighten your belt and hold onto your wallet: Another year of change looms for
      healthcare. In a 1999 outlook report, our staff tells all about Medicare
      cutbacks, managed-care turbulence and a looming crisis in skilled nursing. And
      everyone is braced for the appearance of that ugly year-2000 computer bug.

PMID- 10344838
TI  - Quantifying nursing's impact--slowly. The ANA's year-old documentation effort is
      just beginning to take shape.

PMID- 10344839
TI  - Conn. system uses circle power in ads.

PMID- 10344840
TI  - Hospitals' financials wilt in Garden State.

PMID- 10344841
TI  - Hospitals fear additional Medicare trims.

PMID- 10344842
TI  - Sites set for Medicare pilot program.

PMID- 10344843
TI  - Some admire, some show ire. Clinton's long-term-care gambit--a $1,000-a-year tax
      break--draws a mixed reaction.

PMID- 10344844
TI  - Group works to ban for-profit conversions.

PMID- 10344845
TI  - Hospital profits rise amid down signs.

PMID- 10344846
TI  - AHA coverage bid falls short of goal.

PMID- 10344847
TI  - Another hit on premiums. Small businesses that can't self-insure are affected the
      most by insurance rate increases.

PMID- 10344848
TI  - AHCPR posts clinical practice guidelines.

PMID- 10344849
TI  - Home health cuts hit counties hard.

PMID- 10344850
TI  - Hospital industry balks at Oryx change.

PMID- 10344851
TI  - Eldercare plan a study in moderation.

PMID- 10344852
TI  - A year of more and less. Number of hospital deals drops, but more facilities
      change hands. 1998 hospital mergers, acquisitions, joint ventures, long-term
      leases and other partnerships.
AB  - 1998 wasn't quite as busy a year for hospital dealmakers as 1997, but those who
      went shopping bought in volume. Although the number of deals decreased by almost
      9%, 687 hospitals changed hands last year, according to our fifth annual tally of
      merger and acquisition activity.

PMID- 10344853
TI  - Panel floats options for Medicare reform ... National Bipartisan Commission on
      the Future of Medicare.

PMID- 10344854
TI  - Viewing radiology patients in 3-D.

PMID- 10344855
TI  - Providers push for protection from HMOs.

PMID- 10344856
TI  - Radiology won't avoid the plague of the millennium bug.

PMID- 10344857
TI  - How to accredit your practice for stereotactic biopsies.

PMID- 10344858
TI  - Neuro CT angiography emerges as front-line imaging tool.

PMID- 10344859
TI  - Evaluate before you leap into PET/coincidence detection imaging.

PMID- 10344860
TI  - Ultrasound spans globe in telemedicine experiment.

PMID- 10344861
TI  - Scientists identify warheads as steady source of isotopes.

PMID- 10344862
TI  - Radiology providing higher percentage of total patient care.

PMID- 10344863
TI  - Feds step up investigation of fraud and abuse in medicine.

PMID- 10344864
TI  - 24-hour coverage improves the quality of patient care.

PMID- 10344865
TI  - So you think MRI payments in the U.S. are low?

PMID- 10344866
TI  - Radiologists can climb healthcare's value chain by talking to patients.

PMID- 10344867
TI  - Meet high expectations for mammography with high-quality services.

PMID- 10344868
TI  - First CT reads often miss stroke-related pathologies.

PMID- 10344869
TI  - Demand rises in U.S. and Latin America for used equipment.

PMID- 10344870
TI  - Market drivers: preparing for the future.
AB  - Developing a market strategy is a complex task. Analysts need to identify a
      diverse range of issues and correctly assess their impact. This article uses
      political, economic, social and technology analysis to assess the market drivers
      that are affecting all medical device companies. The wide-ranging implications of
      the euro are also examined.

PMID- 10344871
TI  - Plasma surface modification in biomedical applications.
AB  - New medical products, materials and surgical procedures keep improving current
      health-care practices. Many of these innovations involve polymeric devices that
      must meet certain clinical and cost requirements. Chief among these pressures is
      the need for biocompatibility between the physiological environment and the
      biomaterial surface. Plasma surface modification can improve biocompatibility and
      biofunctionality. This article reviews the capabilities and applications of the
      technology.

PMID- 10344872
TI  - PVC in Scandinavia.
AB  - Poly(vinyl chloride) is a versatile material that is used to manufacture many
      vital single-use medical devices. Yet, concerns continue regarding its safe use
      and disposal. This article examines the risk-assessment investigations that have
      been conducted in Scandinavia and the related discussion. Future scrutiny will
      focus on modifying the material through the use of different additives.

PMID- 10344873
TI  - The in vitro diagnostic directive countdown.

PMID- 10344874
TI  - Contract manufacturing. Sharing the risk.

PMID- 10344875
TI  - Developing winning products, Part II.
AB  - Traditionally, the roles and methodologies of new-product designers and engineers
      have seemed diametrically opposed. This article discusses a development method
      that optimally embraces both roles and, with careful planning, may allow
      successful new products to be brought to market quicker than the competition.

PMID- 10344876
TI  - Chitin and chitosan fibres.
AB  - Chitin and chitosan are natural polymers extracted from various plants and
      animals. Recently, they have attracted much interest in the biomedical industry
      because of their biodegradability, biocompatibility and accelerated wound healing
      properties. This article reviews how chitin and chitosan fibres are produced and
      their potential.

PMID- 10344877
TI  - Catgut sutures: an exercise in discretion.
AB  - In last month's column, the workings of the Scientific Committee on Medicinal
      Products and Medical Devices of the European Commission were discussed and
      reference was made to a detailed risk assessment that had been undertaken with
      respect to surgical catgut. This article discusses that assessment.

PMID- 10344878
TI  - Avoiding unreasonable reliance on subcontractor certification.
AB  - Increasingly, subcontractors who provide products and services to device
      manufacturers are obtaining quality system certification. This is a laudable
      activity and should lead to improvements in the products and services being
      provided. However, some manufacturers place far too much reliance on this
      certification in their subcontractor assessment programmes. This article will
      discuss some of the dangers of this practice.

PMID- 10344879
TI  - Notifying the competent authorities.
AB  - The Medical Device Directive requires manufacturers or persons designated by them
      to provide Competent Authorities with certain types of information on some
      categories of medical devices. However, this requirement is often misinterpreted
      and there are some national variations related to the notification of Competent
      Authorities. This article will discuss Article 14 of the Directive, some frequent
      misinterpretations and, briefly, Germany's notification requirements.

PMID- 10344880
TI  - Microtechnology in modern health care.
AB  - Microsystems are set to contribute much to the medical device market. New
      microfabrication processes allow the mass production of microcomponents in a
      variety of materials. These processes are described together with examples of
      miniaturized medical devices and components that are now possible.

PMID- 10344881
TI  - Developing winning products, Part I.
AB  - Successful product development relies on several factors. This two-part article
      explores the role of the designer in creating winning products that people really
      want to buy. Part I examines two important issues: identifying under-exploited
      market need and the designer as champion of the end-user.

PMID- 10344882
TI  - Medical devices in Germany.
AB  - Pressure from health-insurance companies, difficulties in getting innovative
      products to market and a new breed of purchasing associations are threatening the
      future livelihood of manufacturers in Germany. This article puts forward a
      cooperative concept that may suit every player's needs.

PMID- 10344883
TI  - From BSE to MDT, scientific opinion and public policy on risks in medical
      devices.
AB  - Risk management is not always straightforward, especially if it has to be based
      on inadequate data. When the arguments are fuelled by fears for public health,
      politicians are forced to take difficult decisions and all too frequently it is
      the scientists who come into the firing line over the provision of advice. This
      is the first of two articles that addresses some specific issues that relate to
      risks with medical devices in the context of the European Commission.

PMID- 10344884
TI  - A consumer perspective.

PMID- 10344885
TI  - A family perspective.

PMID- 10344886
TI  - A UK experience.

PMID- 10344887
TI  - A US experience: consumer responsive quality of life measurement.
AB  - OBJECTIVE: In the United States, interest in quality of life and social
      disabilities associated with mental illness intensified in the wake of the
      deinstitutionalization of the late '60s and '70s. Although mental health
      professionals in the United States have begun to recognize the importance of
      quality of life considerations to patient management and treatment outcomes,
      review of the literature shows there is minimal research in mental health on this
      important topic. As a result, little theoretical or methodological progress has
      been made. Quality of life has not been clearly conceptualized or defined and
      there are no agreed-upon standards or criteria for measurement. This presentation
      will: (a) review important conceptual issues in quality of life research, (b)
      discuss the benefits of and obstacles to incorporating consumer values in
      judgments of quality of life, and (c) present data from the Wisconsin Quality of
      Life Index (W-QLI; Becker et al., 1993) to illustrate the usefulness of a
      consumer responsive model of quality of life and the importance of incorporating
      consumer values in the assessment of quality of life of persons with
      schizophrenia. METHODS: The W-QLI was administered to a convenience sample of
      psychiatric outpatients with a DSM-IV diagnosis of schizophrenia. The W-QLI is a
      self-administered individually preference-weighted index that measures nine
      separate domains encompassing quality of life. The W-QLI scoring method results
      in separate scores for each domain and allows for the relationships among
      separate domains to be studied. The nine separate domains include: (a)
      satisfaction level for different objective quality of life indicators, (b)
      occupational activities, (c) psychological well-being, (d) physical health, (e)
      social relations, (f) economics, (g) activities of daily living, (h) symptoms,
      and (i) goal attainment. RESULTS: Study findings are consistent with previous
      theory and empirical research which supports the independence of component
      quality of life domains. Results show that while consumers' and clinicians'
      judgments of outcome correlated, there were important differences. Clinicians
      systematically rated function higher and social relations lower than did
      consumers, and there were significant differences in consumer and provider goals
      for improvement with treatment. Overall ratings of quality of life and function
      are only weakly correlated with psychopathology. The findings support the
      importance and feasibility of incorporating consumer values and judgments of
      quality of life in outcome measurement.

PMID- 10344889
TI  - Quality of life in mental health. Conclusions and recommendations.

PMID- 10344888
TI  - The Canadian experience.

PMID- 10344890
TI  - Quality of life measurement in mental health. Introduction and overview of
      workshop findings.
AB  - The Quality of Life Measurement Workshop was designed to address a number of
      specific questions relating to measurement and use of quality of life indicators
      among persons with chronic and severe mental illnesses. The issues surrounding
      measurement of quality of life among severely and persistently mentally ill
      people proved to be considerably more complex than originally imagined. Workshop
      discussions concentrated on the clear elaboration of the scope and nature of
      these complexities rather than on their complete resolution. Important themes
      that emerged were: the importance of quality of life for consumers/survivors and
      their family members, and as a basis for evaluating program effectiveness and the
      progress of mental health reform; the fact that persons with mental illness
      experience lower life satisfaction than the population as a whole; the importance
      for consumers/survivors of having a sense of control, companionship, feelings of
      optimism, and a purposeful and meaningful life; the subjective and personal
      nature of quality of life perspective and the need for flexible measurement
      instruments that permit differential weighting of factors to take account of
      these different views; the lack of attention to social stigma and family or
      caregiver burden in current conceptualizations and measurement approaches and the
      importance of these factors to consumers/survivors and family members; the overt
      focus on psychiatric symptomatology and the relative neglect of key quality of
      life considerations that are important to consumers/survivors and their families;
      the need for more operational measures, such as those in the health-related
      quality of life field, to be used as a basis for evaluating the worth of new and
      alternate models of service delivery; the potential for competing interests with
      respect to program accountability to consumers/survivors and their families, on
      the one hand, and funders on the other, and the importance of striking a balance;
      the importance of including quality of life measurements within the context of
      controlled clinical trials; the need for multiple measurement approaches,
      ensuring that scales are appropriately matched to study goals and objectives,
      recognizing that scales differ in their sensitivity to treatment change; commonly
      used measures such as rates of hospital recidivism or psychiatric symptomatology
      are ultimately too narrow and, when used alone, are un-satisfactory measures of
      quality of program outcomes; the importance of minimizing data collection burden
      by ensuring that routine data collection systems have clinical utility within the
      context of the consumer/provider encounter; the need for extreme caution when
      directly linking quality of life outcomes to program funding within the context
      of outcomes-management systems; the need to gain a greater understanding of
      determinants of quality of life such as gender, age, diagnosis, comorbidities,
      stage of illness, or cognitive and emotional impairments; the importance of
      normative data and the need to develop statistical benchmarks; the importance of
      distinguishing quality of life outcomes on which specific interventions can have
      an impact (proximal outcomes) from the broader socioeconomic determinants of
      quality of life over which programs and interventions have little direct control
      (distal outcomes); the added cost of collecting quality of life outcome data on a
      routine basis and the general lack of technical resources available to most
      intervention programs; the potential for quality of life outcomes to be misused
      within the context of accountability frameworks given their embryonic stage of
      development, a lack of understanding of what constitutes appropriate clinical or
      statistical benchmarks, and the risk of data degradation when outcomes are tied
      to program funding; and the need for client-based research which incorporates
      consumers/survivors and their family members into all facets of the research
      process from study design to interpretati

PMID- 10344892
TI  - Adding to the equation. Using a rehabilitation nursing team in the home health
      care setting.

PMID- 10344891
TI  - Redesigning the American workplace.

PMID- 10344894
TI  - Cardiopulmonary rehabilitation.

PMID- 10344893
TI  - Pressure ulcers.

PMID- 10344895
TI  - The future of amputee rehabilitation.

PMID- 10344896
TI  - Assistive technology funding.

PMID- 10344897
TI  - HCFA opens up. Understanding the Medicare coverage process for medical technology
      and services.

PMID- 10344898
TI  - Controlling utilization.

PMID- 10344899
TI  - Following the paper trail. Completing the application for managed care plans.

PMID- 10344900
TI  - New hope for the future. Mitigating the effects of disabilities in a
      technological age.

PMID- 10344901
TI  - The rehab community goes to battle.

PMID- 10344902
TI  - Does managed care fuel pharmaceutical industry growth?
AB  - Managed-care organisations and the pharmaceutical industry have diametrically
      opposing objectives, though there is hidden common ground. On one hand, most
      managed-care organisations now want to reduce the cost of drugs or at least
      maintain drug costs as a hedge against inflation. On the other, the
      pharmaceutical industry wants to sell more of their often expensive branded drug
      products in the setting of ever expanding managed care. This has sparked a
      variety of strategies aimed to meet objectives in what could be an endless game.
      Presently, this exchange is a dynamic process with shifts of momentum between
      managed-care organisations and the pharmaceutical industry. Forces that now
      favour the pharmaceutical industry's growth include movement of prescription
      payment from out-of-pocket to payment by insurers and the numbers of available
      innovative drug products. Common ground between managed care and the
      pharmaceutical industry may be found when more of both of their efforts are
      invested in investigating the effects of innovative drugs on total healthcare
      costs of patients. To date, available marketing data indicate that the
      pharmaceutical industry is fuelled by managed care, which is a somewhat ironic
      twist.

PMID- 10344903
TI  - Mega-mergers in the pharmaceutical industry. In whose interests?
AB  - Companies merge to achieve economies of scale. In an industry such as the
      pharmaceutical industry which relies on a high level of investment in research
      and development, such mergers appear rational. However, it is not at all obvious
      that a higher level of investment by a smaller number of firms will necessarily
      lead to an increased rate of genuine innovations. There is a risk that conflicts
      of interest and the pursuit of short term gains may encourage more mergers than
      is optimal for the industry. The impact of mega-mergers in the pharmaceutical
      industry on research output, employees, shareholders, financial advisers,
      managers and patients is discussed. A healthy pharmaceutical industry, able to
      invest the necessary resources in the development of innovative medicines is in
      the interest of patients and shareholders alike. Over-concentration may interfere
      with innovative activity and lead to monopolistic power. Close scrutiny of merger
      activity is important but in a deregulated world, governments may have little
      power to act. In any case, a drug-specific monopolistic industry may be
      beneficial to some countries which may therefore be reluctant to act in the
      interest of the world as a single community in search of more effective
      medicines.

PMID- 10344904
TI  - The problem of protocol driven costs in pharmacoeconomic analysis.
AB  - The increasing number of economic evaluations of healthcare interventions and of
      drug therapies in particular has been well documented. Surveys of the quality of
      studies have demonstrated that standards of conduct of such studies have not
      similarly increased. Concerns over the standards have led to increased calls that
      economic analyses be more closely linked to randomised controlled clinical trials
      (RCT). Seven potential threats to the external validity of results limit the
      generalisability of studies based on RCTs. One such threat is the existence of
      protocol driven costs. There are two main types of protocol driven costs.
      Protocol prescribed costs arise as a result of resource use mandated by the
      clinical trial design. Protocol derived costs occur when increased clinical
      investigations mandated by trial protocols lead to atypical disease management.
      Methods to control for protocol driven costs within pharmacoeconomic study
      designs are available. Modelling studies can be based on data within clinical
      trials combined with observational data representing more typical resource use.
      The adoption of pragmatic clinical trial designs provide greater external
      validity though reduced internal validity. Refinements to explanatory clinical
      trials can also lead to reduced protocol driven costs. The extent that current
      studies control for such costs is unclear due to the lack of transparency in the
      reporting of study methods. A review of published studies found little
      consideration of protocol driven costs although in several studies there was
      evidence of their existence. Future studies conducted alongside RCTs should
      explicitly address how the issue of protocol driven costs was handled within the
      study framework.

PMID- 10344905
TI  - A review of the economics of the prevention and control of rabies. Part 1: Global
      impact and rabies in humans.
AB  - The existing literature on the economics of rabies and its control can be
      characterised as a poorly documented set of cost estimates with insufficient
      information to allow replication of the analyses. Most articles have numerous
      'violations' of the standard recommended procedures for assessing the burden of
      disease and the cost and benefits of interventions. Per capita costs are often
      crudely extrapolated from small to large populations without allowing for
      geographic differences in incidence. Furthermore, most studies do not distinguish
      between financial charges and true economic costs, and only a few articles
      contain a multiyear framework, complete with discounting of future costs and
      benefits. With the exception of the increase in average incidence of postexposure
      prophylaxes (PEPs) in Asia, the average incidences of both human-rabies cases and
      PEPs in Africa, the Americas and Europe have not changed significantly over time.
      There are, however, large differences between countries within a region and
      regional averages can conceal notable changes in incidences over time for a given
      country. The largest number of human-rabies cases occur in developing countries
      due to the low levels of vaccination among dogs, the high cost of biologicals for
      PEP and problems of availability. The costs (1995 values) of PEP range from
      $US1707 per person in Massachusetts, US, to $US2.50 for a complete series of
      vaccinations (without immunoglobulin) using sheep-derived vaccines in Karachi,
      Pakistan. Most studies which reported the cost of PEP, however, provided only
      direct medical costs and did not consider indirect costs such as lost
      productivity due to death, permanent disability or time spent while receiving
      medical care. Given the expense of controlling rabies in dogs and wildlife, there
      is an urgent need to develop a cheaper human-rabies vaccine or further refine the
      'low-dose' PEP regimes. PEP is often given unnecessarily, and experience with
      expert consultations systems and algorithms has shown that the rate, and
      therefore total cost, of PEP can be significantly reduced. However, because it
      may be difficult to identify lesions from a bite by a bat, algorithms may be of
      less value when dealing with possible exposure to bat rabies. Using US prices and
      values, only 2 individuals per 1000 possible contacts have to be at risk from bat
      rabies in order for it to be economically justifiable to give PEP to all those
      potentially exposed to bat rabies. With regard to pre-exposure vaccination,
      routine use of pre-exposure has generally not been shown to be cost effective.

PMID- 10344907
TI  - The burden of illness of hypopituitary adults with growth hormone deficiency.
AB  - OBJECTIVE: The negative metabolic and psychosocial consequences of growth hormone
      deficiency (GHD) in adults are now well established. In the present study, an
      attempt was made to quantify the burden of illness, in terms of lost productivity
      and increased medical consumption, associated with hypopituitarism and untreated
      GHD. DESIGN AND SETTING: The study population consisted of 129 Belgian adults
      with untreated GHD associated with hypopituitarism after pituitary surgery. The
      Short-Form 36 Health Survey (SF-36) was used to assess health status, and the
      Health and Labour Questionnaire was used to measure production losses and labour
      performance. Data on medical consumption were also collected. MAIN OUTCOME
      MEASURES AND RESULTS: Hypopituitary patients reported a lower health status than
      that of the general population in all but two dimensions of the SF-36 (pain and
      physical functioning). Nearly 11% of the patients reported being incapacitated
      for paid employment due to health problems, compared with 4.8% of the general
      Belgian population. Patients in paid employment reported a mean of 19.8 days of
      sickness leave per year, which is twice that in the general population. The
      annual number of visits to general practitioners and specialists was also higher
      in the patients (9.6 and 6.5 visits, respectively, for the patients compared with
      corresponding figures of 2.1 and 1.5 for the general Belgian population). The
      average annual number of days spent in hospital was 3.5 for the patients compared
      with 2.3 in the general population. The annual healthcare costs and costs due to
      production losses calculated for hypopituitary patients who had received
      pituitary surgery amounted to 135,024 Belgian francs (BeF) or $US4340 (1995
      values). This compares with the mean annual cost per person for the Belgian
      population as a whole of BeF68,569 or $US2204. CONCLUSIONS: Hypopituitary
      patients with untreated GHD therefore have a higher cost to society in terms of
      lost production and medical consumption than the average Belgian population.

PMID- 10344906
TI  - Economic impact of aminoglycoside toxicity and its prevention through therapeutic
      drug monitoring.
AB  - Therapeutic drug monitoring (TDM) of aminoglycoside antibacterials with the goal
      of minimising toxicity and maximising effectiveness has become routine.
      Successful management of serious infections requires the ability to achieve
      therapeutic peak concentrations, while maintaining low trough concentrations will
      assist in avoiding nephrotoxicity. Reported nephrotoxicity rates range from 1.7
      to 58% and depend on the definition used, the patient group studied, concomitant
      drug therapy used and whether TDM services have been provided. TDM services have
      been shown to reduce aminoglycoside nephrotoxicity. The costs of providing TDM
      averages $US301.87 (1997 values) per patient and the cost for each use of
      nephrotoxicity is estimated at $US4583 (1997 values). In order for the costs of
      providing a TDM service to 100 patients ($US30,187) to be offset by cost savings
      due to decreasing nephrotoxicity, the service would need to be able to reduce
      nephrotoxicity by 6.6%, resulting in a saving of $US30,248. The ability to
      achieve this saving is dependent on the characteristics of the population in
      which aminoglycoside therapy is used. In populations where high rates of
      nephrotoxicity (e.g. > 15%) would be expected, TDM services are cost justified.
      In populations where nephrotoxicity is low (e.g. < 5%), TDM service is not
      justified for this purpose. In order to provide a cost-efficient approach to TDM,
      resources should be focused on providing service to high risk patient groups.

PMID- 10344908
TI  - A method to select an instrument for measurement of HR-QOL for cross-cultural
      adaptation applied to dermatology.
AB  - OBJECTIVE: The objective of this study was to develop a process to obtain an
      instrument to measure dermatology specific health-related quality of life (HR
      QOL), and to adapt it into another culture, namely the Spanish-speaking
      community. DESIGN AND SETTING: By consensus, a multi-disciplinary team determined
      the qualities of an 'ideal' questionnaire as follows: need (absence of any such
      instrument), utility, multi-dimensionality, psychometric development, simplicity,
      high degree of standardisation, and accessibility. A bibliographic search was
      conducted on Medline, EMBASE and IME (Spanish Medical Index), using 'dermatology'
      and 'quality of life' as the key words, from January 1990 through to September
      1997, supplemented by a second level reference search, to identify the
      instruments already in existence. Rather than develop a questionnaire ex novo, it
      was decided to make a cultural adaptation of an existing one. The questionnaires
      identified in the literature search were classified according to their generic or
      specific scope and it was decided to adapt a dermatology specific instrument. To
      select and compare the instruments, a model was developed which would provide an
      Adaptation Index (ADAPT), which includes the degree of development of
      psychometric properties, the formal design and the degree of standardisation at a
      given moment in time. RESULTS: Six dermatology specific scales were identified:
      Impact of Skin Disease Scale (IMPACT), Dermatology Life Quality Index (DLQI),
      Skindex, Dermatology Quality-of-Life Scales (DQOLS), Dermatology Specific Quality
      of Life (DSQL) and Qualita di Vita Italiana in Dermatologia (QUAVIDERM). The
      ADAPT Index for each of the above was determined at the time of the study and the
      DLQI was chosen for adaptation (ADAPT = 77, October 1997). CONCLUSIONS: The study
      showed the utility of ADAPT Index to assist in the selection process of the
      questionnaire to adapt. The results of the analysis indicate that in order to
      introduce and systematically use dermatology specific HR-QOL instruments, the
      indices require consolidation and improvement. There is a special need for an
      effort to be made in developing transculturally equivalent instruments suitable
      for international research.

PMID- 10344909
TI  - Threshold analysis of Helicobacter pylori therapy.
AB  - OBJECTIVE: Conflicting recommendations have been made on whom to treat with
      antibacterials to eradicate Helicobacter pylori. The present analysis aims to
      explain the basis of such discrepancies. DESIGN AND SETTING: The decision in
      favour of or against antibacterial therapy in patients with upper
      gastrointestinal symptoms is modelled as a threshold analysis. The threshold is
      the lowest probability for a given diagnosis at which the decision in favour of
      antibacterial therapy yields a higher expected outcome than the decision against
      it. A strong indication for antibacterial therapy is shown by a low threshold
      value. MAIN OUTCOME MEASURES AND RESULTS: In patients with suspected peptic ulcer
      disease, both the high success rate of antibacterial therapy and its low cost
      make it the most favourable treatment option, its threshold being less than 35%.
      In ulcer patients receiving nonsteroidal anti-inflammatory drugs, the threshold
      is 73% if based on success rates of different treatment modalities, but only 7%
      if treatment costs are considered. The relatively poor success rate of
      antibacterial therapy in non-ulcer dyspepsia raises the diagnostic threshold for
      antibacterial therapy to 76% if based on therapeutic success rates. The small
      marginal cost of antibacterial therapy lowers the diagnostic threshold to 16%.
      CONCLUSION: If therapeutic success is the primary concern, patients with vague
      abdominal symptoms should not be given antibacterial therapy, unless H. pylori
      has been established as a probable cause of their symptoms. If healthcare costs
      are the driving force for choosing one type of therapy over another, a trial of
      antibacterials appears indicated irrespective of any firm validation of H. pylori
      playing a role in the patient's disease.

PMID- 10344910
TI  - Cost effectiveness of fluvoxamine in the treatment of recurrent depression in
      France.
AB  - OBJECTIVE: The objective of this study was to examine the cost effectiveness of
      fluvoxamine compared with tricyclic antidepressants (TCAs) in the treatment of
      patients with depressive episodes. DESIGN AND SETTING: A Markov process model was
      constructed to model the effectiveness, as measured by time without depression,
      and the costs of both treatments. The model examined a period of 18 months in
      order to capture the influence of both relapses and recurrences on the outcomes.
      Data for the construction of the model came from the published literature, an
      expert panel and a large multicentre randomised clinical trial. Costs were
      obtained from published sources. The setting for this study was France. MAIN
      OUTCOME MEASURES AND RESULTS: The results of the baseline analysis showed that
      the use of fluvoxamine in the maintenance treatment (recurrence prevention) of
      depressive disorders was less costly than TCAs with total costs (direct and
      indirect costs) of 40,232.40 French francs (FF) and FF52,257.53, respectively
      (1996 values). In addition, due to the prevention of relapse and recurrence,
      effectiveness favoured fluvoxamine as it was associated with a longer period of
      time without depression when compared with TCAs (79% of the study period vs 71%).
      Sensitivity analyses confirmed the robustness of these findings. CONCLUSION: In
      conclusion, on the basis of the assumptions used in the model, the use of
      fluvoxamine as maintenance therapy is clinically and economically justified in
      patients with depressive disorders.

PMID- 10344911
TI  - Docetaxel. A pharmacoeconomic review of its use in the treatment of metastatic
      breast cancer.
AB  - Advanced breast cancer has a poor prognosis (median duration of survival about 2
      years); thus, treatment options are largely palliative. Recent studies with the
      taxoids docetaxel and paclitaxel suggest that these agents are effective second
      line therapy in patients with metastatic breast cancer. Objective response rates
      range from 30 to 57% with docetaxel monotherapy in clinical trials in patients
      with advanced disease who had failed to respond to previous therapy, and the
      median time to disease progression ranges from 17 to 20 weeks. Currently
      available pharmacoeconomic data relating to docetaxel in the treatment of women
      with metastatic breast cancer include a cost-minimisation study and 3 cost
      utility studies which relate to the UK, French and US healthcare systems. All
      analyses compared docetaxel with paclitaxel. Since no direct clinical comparisons
      of these 2 agents have been performed, model assumptions were based on available,
      rather than comparative, clinical data. The French model also considered
      vinorelbine monotherapy as a comparator. Considering direct costs only, costs
      associated with docetaxel ranged from < 0.3% less to 13% more than those of
      paclitaxel. When utilities were evaluated, docetaxel was associated with
      incremental gains versus paclitaxel of 33 and 75 additional days of quality
      adjusted health in the UK and US studies, respectively, and 22 additional days of
      quality-adjusted progression-free survival (QPFS) in the French analysis. Thus,
      the incremental cost utility of docetaxel versus paclitaxel was an estimated
      Pounds 2431 per quality-adjusted life-year (QALY) in the UK analysis (1994
      values) and US$8615 per QALY in the US analysis (1997 values). The French model
      found that docetaxel cost 700 French francs less for the extra days of QPFS (1993
      costs). CONCLUSIONS: Cost-utility analyses, compiled in the absence of direct
      comparative data, show that docetaxel offers utility gains versus paclitaxel in
      the treatment of metastatic breast cancer. The incremental cost for these gains
      is within the accepted range for healthcare interventions.

PMID- 10344912
TI  - Willingness to pay. What's in a name?
AB  - Despite renewed enthusiasm for the use of willingness to pay (WTP) in healthcare
      applications, there are still a lot of objections, resentment and scepticism
      regarding the desirability and feasibility of this technique. Objections can be
      classified into different categories: e.g. theoretical, feasibility of
      measurement, misunderstanding of economic concepts and emotional. In this
      commentary, I have tried to explain the nature of the 'emotional' objections to
      the use of WTP. I argue that such objections are not helpful and distract
      attention from the proper scientific debates about the important topics of
      theoretical foundation for economic evaluations and feasibility of measurement of
      individuals' WTP. I believe that some of the emotional objections to WTP stem
      from perceptions about the relationship between the WTP measure and actual
      payment for health services. Hence, I discuss the use of the WTP methodology in 2
      distinct contexts--cost-benefit analysis (CBA) and market research. Understanding
      the difference between these 2 most common areas of use will help alleviate
      objections based on emotions, allow us to use the technique where there seems to
      be no objections to its use (i.e. market research) and concentrate on the
      scientific debate where objections exist (i.e. the case of CBA).

PMID- 10344913
TI  - Pharmaceutical reference prices. How do they work in practice?
AB  - Reference pricing systems are reimbursement ceilings set by payers in an effort
      to constrain pharmaceutical expenditure for a private or public drug benefit. In
      recent years, many governments have adopted reference pricing either as a
      replacement or in addition to product specific price controls. Programme
      administrators should consider whether these policies are providing the intended
      benefits or whether there may be a more effective method. This article provides a
      review of reference pricing in Europe, North America and other countries. There
      are many similarities in the reference price policies but the markets to which
      they apply are more likely to be different. The European experience gives a 'once
      for-all' lowering effect on pharmaceutical expenditure, often at the expense of
      compromises on prescribing. In Germany and The Netherlands, reference pricing has
      been relatively ineffective in lowering expenditure which has led to a succession
      of other interventions to achieve expenditure control goals. The US also has
      reference pricing, but it occurs in a very competitive market which may be
      responsible (at least in part) for the relatively modest growth in expenditure
      compared with European countries. The review of countries with reference pricing
      policies suggests that such policies are less effective than competitive markets
      in moderating pharmaceutical expenditure. Nonetheless, governments continue to
      pursue reference pricing strategies.

PMID- 10344914
TI  - A review of the economics of the prevention and control of rabies. Part 2: Rabies
      in dogs, livestock and wildlife.
AB  - Although rabies in domestic and wild animals represents a significant threat to
      public health and can cause economic losses among livestock, there are very few
      studies that examine the economics of rabies in animals. The literature that does
      exist can be characterised as poorly documented estimates of costs, with
      insufficient information to allow replication of the analyses. Most papers have
      numerous 'violations' of the standard recommended procedures for assessing burden
      of disease and the cost and benefits of interventions. For example, most studies
      do not distinguish between financial charges and true economic costs. Further,
      despite the fact that controlling rabies in animal populations is often a multi
      year task, only a few papers contain a multi-year framework, complete with
      discounting of future costs and benefits. Globally, dog-transmitted rabies
      represents the largest threat to human health. In order to prevent the
      transmission of rabies in a dog population, it is theoretically necessary to
      vaccinate a minimum of 60 to 70% of the dogs. Even countries with potentially
      sufficient resources, however, do not often meet and sustain these rates. One
      reason for such failure might be that individual dog owners might feel that it is
      too expensive to vaccinate their pets. Recent estimates in the US of the cost of
      vaccinating dogs range from $US16 to $US24 per dog. In developing countries,
      estimates range from $US0.52 in Thailand, to $US1.19 in the Philippines, to
      $US2.70 in Malawi. None of these estimates include indirect costs accured by the
      pet owners. Lethal methods of dog population control are even more expensive, and
      attempting to control rabies by reducing dog populations has not worked for any
      extended period. Rabies in livestock is often reported, but the impact in the US
      and most developed countries appears relatively small. Vampire bat-transmitted
      rabies in Latin America appears to be the most serious rabies problem in
      livestock. The largest cost due to wildlife rabies is the cost of vaccinating
      domestic animals, both large and small. In the US, domestic animals face multiple
      sources of wildlife rabies. Attributing the entire cost of vaccinating domestic
      animals to 1 species can result in the over estimation of the benefits of
      immunising a given wildlife population via vaccine-laden baits. For example,
      despite a definite decline in the number of rabid foxes, it has been difficult to
      obtain the promised benefits of using oral vaccines in Europe to control fox
      rabies. Other authors maintain that the use of oral vaccines to control fox
      rabies is cost beneficial, but there are no convincing data supporting that
      claim. Additionally, vaccinating raccoons with an oral vaccine requires
      approximately 4 times more vaccine-laden baits vaccinating foxes, which makes it
      highly questionable if it would be cost beneficial to use oral vaccine to attempt
      raccoon rabies elimination in areas where it is already enzootic. The economics
      of using oral vaccines to prevent raccoon rabies invading uninfected areas has
      yet to be examined.

PMID- 10344915
TI  - A review of quality of life in Alzheimer's disease. Part 1: Issues in assessing
      disease impact.
AB  - There are numerous methods available for assessing patients with Alzheimer's
      disease (AD) or other forms of dementia. Quality-of-life (QOL) assessment is
      unique among these methods, because the QOL concept itself includes a subjective
      component that is fundamental to its measurement. It could be argued that
      measuring quality of life is just as important as measuring disease severity,
      disease progression, symptom response, cognition, behavioural disturbance and
      activities of daily living when assessing the impact of disease and intervention
      in dementia. The subjective nature of quality of life provides healthcare
      professionals with the opportunity of incorporating the value systems of patients
      and their carers into their assessments. A systematic review was carried out to
      include the published data (and some unpublished data) on QOL assessment tools
      and instruments that claim to measure quality of life in dementia. Literature for
      this review was identified by a thorough search of computer databases (1980-1997)
      that included Medline, Embase, PsychLit and International Pharmaceutical
      Abstracts. Reports concerning the conceptualisation, development, validation,
      reliability, reproducibility, comprehensiveness, practicality and use of QOL
      instruments in dementia/AD were selected for review as well as papers documenting
      clinical drug trials in this therapeutic area. A number of measures or methods
      used in the literature for assessing the quality of life of patients with
      dementing illnesses were identified. It was decided to present the resulting
      review in 2 parts that correspond to the 2 main groups into which the instruments
      were categorised. The first (part 1) looks at measures used to assess the impact
      of disease as well as instruments at a developmental or testing stage. The second
      (part 2) includes instruments that claim to measure quality of life in studies
      documenting the impact of a drug in this therapeutic area. There are as yet no
      validated methods of assessing the quality of life of both patients with dementia
      and their carers at the same time. QOL outcomes for these 2 groups is closely, if
      not fundamentally, linked and yet most studies identified in this review
      concentrate on measuring the quality of life of either the patient or the carer
      alone. Although some researchers may be getting close conceptually, an instrument
      has yet to satisfy all the criteria necessary to become accepted as a gold
      standard for QOL assessment in dementing illness. The ideal instrument must show
      that it can reliably, reproducibly and comprehensively assess quality of life for
      patients with dementia and their carers. It should also demonstrate that it can
      measure quality of life effectively using a practical administration technique
      that does not place any unnecessary burden on either informal carers, other
      healthcare workers involved or the patient themselves. Further cross-sectional
      and longitudinal research is required to psychometrically test the available
      instruments as well as continuing conceptual research to explore new ways of
      assessing quality of life in this important area.

PMID- 10344916
TI  - Urge incontinence. Quality of life and patients' valuation of symptom reduction.
AB  - OBJECTIVE: Previous studies have demonstrated the effect of incontinence, and
      urge incontinence in particular, on patients' quality of life. This study
      assessed the effects of urge incontinence on quality of life and measured the
      value of a reduction in symptoms. DESIGN: A self-administered questionnaire was
      mailed to 591 patients with urge or mixed incontinence. 495 (83.8%) surveys were
      returned with complete quality of life and symptom data. Of the total sample, 411
      patients received the willingness-to-pay (WTP) survey, from which 257 (62.53%)
      returns were judged complete and reliable. Information was collected about the
      number of micturitions and urinary leakages. Health-related quality of life (HR
      QOL) was measured using the Short Form 36 (SF-36) Health Survey. Socioeconomic
      characteristics were also recorded. Value was assessed with a binary WTP
      question. MAIN OUTCOME MEASURES AND RESULTS: Quality of life among the sample
      population was significantly lower in 5 of 8 dimensions compared with the general
      US population, and was significantly related to the severity of the symptoms in 6
      of 8 dimensions. The median (mean) willingness to pay was $US27.24 ($US87.74) per
      month for a 25% reduction in micturitions and leakages, and $US75.92 ($US244.54)
      per month for a 50% reduction in micturitions and leakages. As expected, the
      willingness to pay was significantly related to the size of the reduction in
      micturitions and leakages, and household income. CONCLUSIONS: Patients with
      incontinence perceive substantial benefits from a reduction in the number of
      micturitions and leakages.

PMID- 10344917
TI  - Cost effectiveness of pramipexole in Parkinson's disease in the US.
AB  - OBJECTIVE: Pramipexole was recently approved in the US for treatment of the
      symptoms of idiopathic Parkinson's disease (PD). Although pramipexole has been
      found to be safe and efficacious when compared with placebo, little data are yet
      available on its cost effectiveness when compared with baseline treatment. The
      aim of this study was to estimate the costs and cost effectiveness (cost utility)
      of pramipexole compared with baseline treatment in patients with early and
      advanced PD. DESIGN AND SETTING: We developed a cost-effectiveness (CE) model in
      the US setting that linked Unified Parkinson's Disease Rating Scale (UPDRS) Part
      II (activities of daily life) and III (motor) scores to disease progression,
      costs and patient utility. Data for the model were obtained from clinical trials,
      a literature review and a survey of 193 patients' health resource use and
      utility. We used cost and quality-adjusted life-year (QALY) estimates from the
      model to estimate the incremental cost effectiveness of pramipexole relative to
      baseline treatment patterns. We performed separate analyses for patients with
      early and advanced PD. We also performed extensive sensitivity analyses by adding
      other dopamine agonists to the no-pramipexole treatment regimen and varying
      disease progression parameters. The study was conducted from the societal
      perspective, although data presentation allows interpretation of cost
      effectiveness from either the societal or payer perspective. MAIN OUTCOME
      MEASURES AND RESULTS: For patients with both early and advanced PD, treatment
      with pramipexole had higher costs but was more effective than baseline treatment.
      For patients with early onset of PD, the incremental total CE ratio for
      pramipexole was $US8837/QALY. For patients with advanced PD, the incremental CE
      ratio was $US12 294/QALY (1997 costs). These ratios were lower than the CE ratios
      of many widely used medical treatments. CONCLUSIONS: Subject to the inherent
      limitations of modelling chronic disease progression and subsequent healthcare
      costs and patient utility, the results suggested that pramipexole was a cost
      effective treatment for patients with early and advanced PD in the US.

PMID- 10344919
TI  - Economic evaluation of nimesulide versus diclofenac in the treatment of
      osteoarthritis in Greece.
AB  - OBJECTIVE: To evaluate, from a social security system perspective, the economic
      consequences of treating rheumatic diseases with nimesulide or diclofenac.
      DESIGN: Cost-minimisation analysis was used to estimate the incremental direct
      medical cost and the cost of gastrointestinal adverse events for 15 days'
      treatment with nimesulide compared with diclofenac. Cumulative incidence of
      adverse events was calculated through meta-analysis of the results of double
      blind randomised clinical trials. The therapeutic pathway for ambulatory care
      resource use was determined by a panel of experts, and direct hospital costs were
      estimated from a sample of 43 patients. MAIN OUTCOME MEASURES AND RESULTS: The 15
      day treatment cost with nimesulide was 35.9% lower compared with diclofenac due
      to the lower incidence of adverse events. Our analysis showed that nimesulide
      generated a cost saving of $US20.98 per patient depending on the dosage of
      diclofenac used.

PMID- 10344918
TI  - Cost effectiveness of multi-therapy treatment strategies in the prevention of
      vertebral fractures in postmenopausal women with osteoporosis.
AB  - OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of multi
      therapy treatment strategies in the prevention of vertebral fractures in
      postmenopausal women with osteoporosis. DESIGN: A retrospective, incremental cost
      effectiveness analysis was conducted from a societal perspective. It compared 9
      treatment strategies over 3 years and incorporated the willingness of patients to
      initiate and continue each therapy. MAIN OUTCOME MEASURES AND RESULTS: Four
      nondominated strategies formed the efficient frontier in the following order: (i)
      calcium-->no therapy; (ii) ovarian hormone therapy (OHT)-->calcium-->no therapy
      [166 Canadian dollars ($Can)]; (iii) OHT-->etidronate-->calcium-->no therapy
      ($Can2331); and (iv) OHT-->alendronate-->calcium-->no therapy ($Can40,965). The
      figures in parentheses are the incremental costs per vertebral fracture averted
      to move to that strategy from the previous strategy for patients who had
      undergone a hysterectomy. CONCLUSIONS: We identified 4 efficient multi-therapy
      strategies for the treatment of vertebral osteoporosis in postmenopausal women, 2
      of which were consistent with the practice guidelines of the Osteoporosis Society
      of Canada. Decision-makers may select from among these efficient strategies on
      the basis of incremental cost effectiveness.

PMID- 10344920
TI  - Development of an economic model for the management of upper gastrointestinal
      disease in primary care. Preliminary findings.
AB  - Health economic models for identifying therapeutic options that maximise health
      benefits from limited healthcare resources are being developed in a number of
      therapeutic areas. The development of such a model for upper gastrointestinal
      (UGI) symptoms to support decision-making by primary care clinicians is of
      particular importance, given the prevalence of this symptomatology. This economic
      model was based upon the clinical guidelines aimed at improving the management of
      UGI disorders at the primary care level that were developed by the International
      Gastro Primary Care Group. This paper discusses the derivation, methodology and
      results of the economic model developed to assess the resource implications
      arising from these clinical guidelines. In order to construct the economic model,
      it was necessary to identify the following: every therapeutic pathway followed by
      patients resource use along each pathway the probabilities of following
      alternative pathways. One crucial factor underlying the interpretation of results
      obtained from any economic model is the time period covered by the model. The
      model presented here analysed the initial 12-month treatment period of 'new'
      patients presenting with UGI symptoms. In order to test the implications of a
      longer term perspective, the model is currently being developed to analyse
      resource use over a 24-month period. The model demonstrates that utilising the
      predominant symptom approach to the diagnosis and treatment of patients with UGI
      disorders appears to provide significant benefits in terms of patient management
      and effective resource use. This factor, together with the more intensive use of
      Helicobacter pylori eradication therapy, provides the potential to reduce the
      cost of drugs for the treatment of UGI disorders by approximately 15% in the UK.
      A major strength of the model is its adaptability to a wide range of clinical and
      cost scenarios. Such adaptability enables the model to effectively reflect the
      potential resource implications in countries exhibiting significantly different
      levels of cost and patient management. In this manner, the model provides one
      valuable method by which clinicians can be supported in optimising the management
      of UGI disorders within current resource constraints.

PMID- 10344921
TI  - Modelling different approaches to the management of upper gastrointestinal
      disease.
AB  - A treatment algorithm for the management of upper gastrointestinal (UGI) disease
      in general practice has been developed by an international group of general
      practitioners [the International Gastro Primary Care Group (IGPCG)]. When the
      algorithm was evaluated to consider the overall cost per patient, it was shown to
      offer savings over current practice in the UK. Adjustments to the algorithm have
      been proposed, usually on the basis of variations in the place and timing of
      Helicobacter pylori testing and eradication, with or without endoscopy. This
      paper evaluates the current cost of UGI disease in the UK, the base IGPCG
      algorithm and the 5 major alternative scenarios. The original IGPCG algorithm was
      the least costly option of all those considered, with additional H. pylori
      testing for all patients with suspected ulcer being the second least expensive
      option. Routine endoscopies for all patients or for all patients aged more than
      45 years were the most expensive scenarios and would require a 16- or 13-fold
      increase, respectively, in the provision of endoscopy services in the UK. The use
      of routine endoscopy for all patients aged more than 45 years who were presenting
      with UGI symptoms for the first time was a mid-priced option, but would still
      require a 5-fold increase in the provision of endoscopy services. The modelling
      process highlights the fact that early stratification of patients into diagnostic
      and treatment groups, on the basis of history and symptom cluster, is a less
      costly approach than that of early routine endoscopy or H. pylori testing. If H.
      pylori testing is to be used routinely, then the least costly way is to apply the
      method to those patients who have symptoms that are more indicative of ulcer
      disease. All the scenarios considered resulted in lower drug costs than current
      average UK drug costs per patient per year, and in fewer prescriptions and
      general practitioner surgery visits per patient. There are several ways in which
      the management of UGI disease in the UK could be improved with regard to costs
      and resource utilisation, some of which are presented here. This process
      emphasises the value of modelling techniques to investigate the consequences of
      different patient management scenarios.

PMID- 10344922
TI  - Customising an international disease management model to the needs of individual
      countries. Application to upper gastrointestinal disease.
AB  - The baseline economic model for upper gastrointestinal (UGI) disease was
      developed in the context of patterns of care and resource use within the UK. It
      provided the opportunity to evaluate the extent to which an economic model
      developed in one country could be applied to meet the pharmacoeconomic
      information needs of decision makers in another. The choice of countries for
      analysis was restricted to countries within the International Gastro Primary Care
      Group (IGPCG) who had previously agreed on the appropriateness of the basic
      clinical algorithm to their domestic healthcare environment. This provided a
      potential sample of 9 countries (Australia, Austria, Germany, Italy, The
      Netherlands, Sweden, Switzerland, the UK and the USA) of which the UK, Germany,
      Sweden and Switzerland were chosen as providing a broad spectrum of strategic and
      operating environments in which to test the international transferability of the
      economic model. The process and results obtained provide valuable evidence of the
      extent to which economic analyses can be transferred across national borders.

PMID- 10344923
TI  - Consensus guidelines for evaluating and treating patients with upper
      gastrointestinal symptoms in the primary care setting.
AB  - Upper gastrointestinal (UGI) disease represents a significant part of the primary
      care physician's workload and is ultimately responsible for a major portion of
      the costs relating to his or her drug prescribing. This paper outlines the scale
      of the problem and the possibility of a structured management plan for UGI
      disease. Although this type of strategy is not new, the International Gastro
      Primary Care Group (IGPCG) has approached it from a practical standpoint that
      addresses the concerns of general practitioners and the fears and anxieties of
      patients. In addition, the direct representation of this model with a cost
      effective programme is the first opportunity to develop strategies, in primary
      care, for testing a protocol for the management of UGI disease. The approach is
      aimed at the primary care setting and is adaptable for use in different cultural
      groups and healthcare systems.

PMID- 10344925
TI  - Computer modelling. The need for careful evaluation and public audit.

PMID- 10344924
TI  - Management of dyspepsia in general practice. A critical assessment.
AB  - The International Gastro Primary Care Group (IGPCG) Upper Gastrointestinal
      Disease Management Plan is mainly characterised by the proposal that management
      of patients with upper gastrointestinal syndromes be based on the predominant
      symptom, rather than on symptom clusters. Although no study has directly tested
      this hypothesis in general practice, some data indirectly support the proposal.
      Classification based on the relevance of specific symptoms could identify
      distinct subgroups of patients with functional dyspepsia with at least partially
      different features. Data obtained from the literature are discussed and evaluated
      in relation to the suggested algorithm. Overall, this management plan for
      patients with dyspepsia seems to be both safe and effective. However, there is a
      need for prospective studies evaluating its actual validity.

PMID- 10344926
TI  - Decrease hassles and costs by integrating your plans' formularies.

PMID- 10344927
TI  - Do-it-yourself disease management.

PMID- 10344929
TI  - Is there a physician union in your future?

PMID- 10344928
TI  - What the hospitalist movement means to family physicians.

PMID- 10344930
TI  - Getting patients off hold and online.

PMID- 10344931
TI  - Measuring patient satisfaction: how to do it and why to bother.

PMID- 10344932
TI  - How does your practice sound on the phone?

PMID- 10344933
TI  - Commentary on the closing of a social health maintenance organization.

PMID- 10344934
TI  - The mixed-population issue in state-subsidized elderly housing: management
      problems posed by nonelderly and elderly tenants.
AB  - The management experiences of all Local Housing Authorities (LHAs) in Connecticut
      were investigated concerning younger disabled tenants in state-subsidized elderly
      housing. While as a group younger disabled tenants were more likely to violate
      the terms of their lease, including disrupting other tenants' enjoyment of their
      homes, management problems with younger disabled tenants were not reported by all
      LHAs. In general, serious, recurrent problems involving younger disabled tenants
      were concentrated among a relatively small group of LHAs. Emphasizing the
      diversity that characterizes the experiences of LHAs, the discussion emphasizes
      the need for caution in drawing conclusions about the issue of a mixed
      population. It also focuses on examples of how some LHAs have addressed the
      integration of younger disabled tenants in senior housing and proposes
      recommendations for viewing the issue in the broader context of public policy.

PMID- 10344935
TI  - A cross-national test of propositions from the neo-pluralist perspective on
      Social Security expenditures.
AB  - Much of the existing literature on cross-national differences in retirement wage
      policy has focused on the inception of programs and the factors leading to their
      introduction. The explanations may be less adequate in accounting for post-war
      changes in social security programs. To interpret the evolution of programs in
      the post-war period, we stress the importance of divisions among workers
      themselves. We argue here that such divisions may occur along three fault lines:
      (1) ethnic, racial, and linguistic differentiation (2) the split between heavily
      urbanized and other segments of the working population and (3) fractionalization
      brought about by domination of a single industry. Using a longitudinal design to
      measure changes in social security expenditures in 34 nations between 1965 and
      1983, we test hypotheses asserting that fragmentation among workers is inversely
      correlated with expanded investment in benefits for workers. We find general
      support for these hypotheses.

PMID- 10344936
TI  - Discrimination and pension income among aging women.
AB  - Using data from the National Longitudinal Survey of Labor Market Experience,
      Mature Women's Cohort, this study examined the extent to which discrimination
      influenced pension receipt and levels of pension income among women aged 55-69 in
      1992. It found that discrimination affected the level of pension income beyond
      that of demographic and human capital variables, when controlling for wage
      related income, only among moderate-to-affluent near-elderly women. No relation
      was found between discrimination and receipt of pension income.

PMID- 10344937
TI  - A comparative study of elderly SSI recipients, denied applicants, and eligible
      nonapplicants.
AB  - Based on data from the 1982 Social Security New Beneficiary Survey (NBS), the
      1991 New Beneficiary Follow-up (NBF), and Social Security administrative records,
      this study analyzed determinants of the elderly's Supplemental Security Income
      (SSI) participation, denied application, and nonapplication. In the analysis, SSI
      application is conceptualized as an outcome of a complex interaction among
      financial, sociodemographic, health, and informational factors as well as those
      indicative of elderly persons' subjective perception of need. The findings indeed
      confirmed that objective financial need does not automatically lead to SSI
      application. Sociodemographic and health-related factors mediating the objective
      financial need are identified, although the subjective perception of need and
      informational barriers requires further evaluation. Policy implications include
      continued dissemination of information about SSI and relaxation of the resource
      test to qualify more low-income elderly.

PMID- 10344939
TI  - NHS 50: past achievements and future goals.

PMID- 10344940
TI  - Regional library and information services in the NHS--why, where, what and
      whither?
AB  - A general introduction showing the need for a regional structure, how the
      regional networks were set up, what they do and how they facilitate better
      library and information services (LIS) for their users, is followed by
      descriptions of the setting up, work and development of four different regions;
      South West England, Midland, Wales and Scotland. A list with contacts is given
      for all the regional networks, the NHS Regional Librarians Group (RLG) and the
      LINC Health Panel.

PMID- 10344938
TI  - Health system reform and the elderly: the case of Israel.
AB  - Following the implementation of the National Health Insurance Law in January
      1995, major changes have taken place in the provision of health services by
      Israel's sick funds and the way these services are funded. This article presents
      the principal changes that have occurred and assesses their impact on those aged
      65 and older, using findings of a survey conducted one year after the law's
      enactment. While the findings show that the elderly's situation has improved in
      some areas, they also raise concerns that the elderly are having difficulty
      navigating the reformed health system and that they are not benefiting from the
      new competition among the sick funds.

PMID- 10344941
TI  - SWEHSLinC + WRLIN = SWRLIN: the past, present and future of health care library
      co-operation in the South West of England.

PMID- 10344942
TI  - West Midlands Health Libraries Network.

PMID- 10344943
TI  - NHS library and information services in Wales.

PMID- 10344944
TI  - Association of Scottish Health Sciences Librarians (now SHINE--Scottish Health
      Information Network).

PMID- 10344945
TI  - Performance indicators in NHS libraries.
AB  - Performance indicators (PIs), workload statistics and accreditation are different
      ways to assess the quality of a library information service (LIS), and can be
      used together to give an overall picture of how well a LIS is performing its
      functions. PIs point out how something has been done. They are comparative
      values, often expressed partly as ratios or percentages, which indicate the
      quality or level of services and can be used to compare similar services, or the
      same service across time. PIs, performance ratios or performance standards are
      derived from performance measures, which show how much of it has been done. This
      paper looks at some aspects of performance measurement and suggests other areas
      for statistics collection in order to make better use of existing data, and
      considers the usefulness and derivation of PIs in NHS LIS.

PMID- 10344946
TI  - Using biomedical databases in everyday clinical practice: the Front-Line Evidence
      Based Medicine project in North Thames.
AB  - The aims of this project were to assess the feasibility of using biomedical
      databases in everyday clinical settings, and the infrastructure needed to support
      such practice. Fourteen firms or units whose lead clinician was enthusiastic for
      the principles of evidence-based medicine were provided with 24-h access to
      databases in their clinics or offices. All members of the firms were trained in
      the principles of evidence-based practice and in the use of databases for finding
      evidence. The firms were volunteers from a variety of specialties in both
      hospital and community Trusts in North Thames Region. Assessment of changes in
      practice was carried out by questionnaire and interview. Also, any changes needed
      to improve the use of primary research data in everyday clinical settings was
      investigated. Seven firms found that the project had made their journal clubs and
      their clinical discussion meetings more structured and focused, with research
      evidence for and against interventions discussed. The use of evidence in a case
      related form was limited by the time available. The other seven firms were:
      dissatisfied with their training, dissatisfied with their computer facilities or
      lacked time. The changes necessary to improve the utilization of research data
      included: closer collaboration with librarians, continuing training and fast
      delivery of documents. The limitations of this study are that initial data were
      not recorded and the assessments made were subjective. Using biomedical databases
      in everyday clinical practice could be feasible provided that there is a
      coordinated implementation strategy, which requires a significant commitment of
      time and resources from all parties involved (clinicians, other health care
      professionals, librarians and managers).

PMID- 10344947
TI  - Fifty years of patients' libraries.
AB  - This article uses a thematic approach to describe 50 years of hospital libraries
      for patients under the National Health Service. The strengths and weaknesses of
      the patients' library movement in the United Kingdom are discussed, followed by a
      number of recommendations for future opportunities in this field.

PMID- 10344948
TI  - NHS records: past, present and future.

PMID- 10344949
TI  - A look back at over 50 years of NHS record keeping.

PMID- 10344950
TI  - Confidentiality of patient records.

PMID- 10344951
TI  - Supporting clinical care with electronic patient records.

PMID- 10344952
TI  - NHSweb Directory: pointing NHSweb users to relevant knowledge bases.

PMID- 10344953
TI  - Centre for Health Information Quality.

PMID- 10344954
TI  - Accreditation for health care libraries in the United Kingdom.

PMID- 10344956
TI  - Library consortium to bring AHIMA members expanded service.

PMID- 10344955
TI  - Practice brief. Telecommuting. American Health Information Management
      Association.

PMID- 10344957
TI  - The technology of telemedicine.

PMID- 10344958
TI  - Technology and the 21st century.

PMID- 10344959
TI  - New roles, new responsibilities.
AB  - As healthcare changes, HIM professionals must act as individuals to keep pace
      with the transformation. Educational changes in HIM curricula are evolving, but
      HIM professionals must take responsibility for their education to take advantage
      of opportunities presented by new information technologies.

PMID- 10344960
TI  - The CPR in long term care.

PMID- 10344961
TI  - Understanding CPR architecture: an HIM professional's guide.
AB  - The continued evolution of the CPR offers numerous career opportunities for HIM
      professionals. But a knowledge and understanding of the fundamental concepts is
      critical for those who would take advantage of these opportunities. The authors
      offer an overview of the differences and interaction between the CPR component
      parts, the basic clinical and business functions they support, and the technology
      used to implement the CPR.

PMID- 10344962
TI  - Research/decision support analyst: an evolving role.

PMID- 10344963
TI  - An HIM survival kit for the year 2000.
AB  - Is your organization ready for the Year 2000? The "millennium bug" offers some
      useful lessons in risk assessment. Here's how to build a contingency plan to
      ensure business continuity on January 1, 2000.

PMID- 10344964
TI  - Physician liaison program brings improvement.

PMID- 10344965
TI  - Leading change: a piano lesson.

PMID- 10344966
TI  - Summary of ICD-9-CM Coordination and Maintenance Committee meeting.

PMID- 10344967
TI  - Clarification of clinical data sets, vocabularies, terminologies, and
      classification. AHIMA's Coding Policy and Strategy Committee.

PMID- 10344968
TI  - Benchmarking a world-class image.

PMID- 10344969
TI  - Firewalls and bridges.

PMID- 10344971
TI  - Physician profiling legislation.

PMID- 10344970
TI  - Professionalism, managed care, and the human rights movement.

PMID- 10344972
TI  - The Medicare+Choice program.

PMID- 10344974
TI  - Withdrawal of life support.

PMID- 10344973
TI  - Women CABG patients require more blood, ventilator time.

PMID- 10344975
TI  - Reaching Medicaid patients on their terms.
AB  - Healthcare providers targeting the Medicaid population have developed a variety
      of strategies to improve patients' access to care, ensure appropriate utilization
      and improve outcomes. Many of the most successful programs take into account
      patients' other needs, including transportation, clothing, nutrition and
      maternal/child services. In some cases, providers have found it worthwhile to
      team with other community organizations to meet a range of patient needs with a
      single program.

PMID- 10344976
TI  - Translating health information across cultures.
AB  - Patient education materials can't simply be translated from one language to
      another. To make sure patients get the whole message, one California health plan
      works with a team of education specialists, bilingual staff and customer service
      representatives to tailor each document to the needs of its Hispanic and
      Vietnamese patients.

PMID- 10344977
TI  - Implementing a clinical pathway for congestive heart failure: experiences at a
      teaching hospital.
AB  - Clinical pathways are processes of care that use a multidisciplinary team effort
      to move patients toward a designed outcome. This article details the challenges
      of a Quality Enhancement and Clinical Resource Management Team in designing and
      implementing a successful congestive heart failure pathway at a teaching
      hospital. Academic institutions have the resources as part of their research
      mission, to enhance the development of clinical pathways and assess their
      outcomes.

PMID- 10344978
TI  - Enhancing clinical pathway placement.
AB  - Soaring health care costs have fueled the immense growth in managed care. To
      contain these costs, health care organizations have turned to clinical pathways.
      However, clinical pathways cannot do an effective job if health care personnel
      are not aware of their existence. The article presents a simple, effective, and
      efficient method to increase placement of clinical pathways in inpatient medical
      records.

PMID- 10344979
TI  - Evaluating expert systems: how to ensure an independent assessment.
AB  - Evaluation of an expert system provides unique challenges in an organizational
      setting. Often the proposed system is provided by an independent supplier who is
      not in a position to provide an unbiased assessment of the effectiveness or merit
      of the system. Even when the system is developed by personnel within the same
      firm or by the users themselves, these individuals, being instrumental in the
      design and development of the system, lack the autonomy necessary to evaluate the
      system. This article describes one evaluation process which was applied by the
      authors. It is an adaptable approach which provides the needed independent
      assessment without being excessively cumbersome or difficult to administer.

PMID- 10344980
TI  - Systems coherence: a method for evolving relationships and measuring system
      change.
AB  - To see the world systematically through the practice of systems thinking means to
      see the relationship in the phenomena we experience. The systems view is not just
      another way of improving an object, a process, or even services. It should not be
      viewed as a method that is focused only on "quality." The intrinsic value of
      systems thinking is in the movement of relationships.

PMID- 10344981
TI  - Evaluating the quality control system for managed care in the United States.
AB  - Though idiosyncratic, the system for controlling managed care in the United
      States is surprisingly robust. This article reviews the mechanisms available to
      providers, patients, insurers, and governments to assess ongoing quality of care.
      It suggests that those contracting for care use the Donabedian Matrix to assess
      where contracts are strong and where the provisions are weak.

PMID- 10344982
TI  - Evaluation of two intervention strategies to stimulate quality improvement
      projects in the hospital: the H. pylori example.
AB  - A multistate quality improvement project conducted to improve the care of
      hospitalized Medicare patients with peptic ulcer disease is described. This
      randomized control study design compared the effectiveness of two intervention
      strategies (mailed information vs. on-site presentations with feedback) in
      stimulating hospitals to conduct diagnostic journeys to determine root causes for
      performance deficits and to develop and implement plans to improve performance.

PMID- 10344983
TI  - Outcome-based quality improvement in home health care: the OASIS indicators.
AB  - The outcomes movement in home health care is expanding rapidly, with strong
      support from both the industry and Medicare. The Federal government has proposed
      requiring all Medicare-certified agencies to collect data items from the Outcome
      and Assessment Information Set (OASIS) to form the basis for standardized risk
      adjusted outcome reporting as part of a systematic outcome-based quality
      improvement (OBQI) approach. In addition to contributing to improving patient
      outcomes, OASIS data items, when combined with other assessment information,
      utilization data, and cost information, can provide home health care agencies
      with a powerful integrated information set for internal management and strategic
      planning.

PMID- 10344984
TI  - All-vegetarian cafeterias & catering pose unique challenges for hospitals.

PMID- 10344985
TI  - Hospitals accept the HACCP (Hazard Analysis Critical Control Point) challenge.

PMID- 10344986
TI  - Microbe management.

PMID- 10344987
TI  - One hospital's cook-chill experience.

PMID- 10344988
TI  - Tray delivery systems simplify hospital mealtimes.

PMID- 10344989
TI  - HFM's Giuffrida discusses "bottom line food service for the 90's and beyond".

PMID- 10344991
TI  - Meeting the press: tricks of the trade for giving interviews.

PMID- 10344992
TI  - Compliance plan for third-party medical billing companies.

PMID- 10344990
TI  - From nutritional education to special diets, dietitians' duties vary in different
      types of facilities.

PMID- 10344993
TI  - Use media to confront drug abuse.

PMID- 10344994
TI  - Digital radiography in emergency medicine.

PMID- 10344995
TI  - Use real-time data to reduce delays.

PMID- 10344996
TI  - The good, the bad and the ugly: subacute industry reacts to prospective payment
      rule.

PMID- 10344998
TI  - MDS completion, locking and transmission requirements.

PMID- 10344997
TI  - Accurate, timely completion of the MDS is critical to success under PPS.

PMID- 10344999
TI  - 24-hour tracking, correct scoring of activities of daily living critical to
      proper PPS payments.

PMID- 10345000
TI  - How to score ADLs on the MDS.

PMID- 10345002
TI  - R & D: the genesis of innovation.

PMID- 10345001
TI  - Modern medicine; modern consumerism.
AB  - If there is any one thing that is missing in today's health care delivery system,
      it is consumerism. This will be remedied as more and more Americans start taking
      direct responsibility for how their health care dollars are spent. Hand in hand
      with such developments will be increasing opportunities for developers and
      sellers of health-related products and services to promote their wares directly
      to medical consumers, who will either buy them outright or influence their
      healthplans to make the purchases. Purveyors of new technology and capital
      medical equipment will be especially likely to abet the new medical consumers and
      to derive financial benefits from them. From the perspectives of the many medical
      consumers who inquire to AMC about access to and use of radiologic services, the
      areas of greatest interest include high resolution ultrasonography, routine and
      functional magnetic resonance imaging, interventional radiology, gamma-knife
      surgery, and tumor-specific and patient-specific radiotherapy. Brain tumor and
      prostate cancer patients and their caregivers are particularly likely to be
      concerned about the radiotherapy modalities available.

PMID- 10345003
TI  - Virtual ergonomic studies in endoscopic intervention.
AB  - Virtual instrumentation provides a strong platform for the rapid design and
      prototyping of biomedical instruments. Virtual instrument software written using
      a block diagram approach familiar to instrument designers quickly turns a
      personal computer into a custom biomedical instrument. The portable VIs we have
      developed for ergonomic analysis of video-endoscopic surgery are quick to set up
      and convenient to use. We have collected a large amount of ergonomic data in a
      short time with these VIs because of their custom design and because we can take
      them to sites where there are many willing surgeon-subjects. We are preparing to
      use these VIs in studies of actual surgery.

PMID- 10345004
TI  - The science of spirituality in medicine.

PMID- 10345005
TI  - Work performance follows human enhancement.

PMID- 10345006
TI  - The patient commodification syndrome.

PMID- 10345007
TI  - Global infrastructure and a new international healthcare delivery system.

PMID- 10345008
TI  - Hospital executives speak frankly about managed care changes.

PMID- 10345009
TI  - Study says everyone rides cost-cutting bandwagon.

PMID- 10345010
TI  - What should you expect from an HMO? Tips from HMOs with high client satisfaction.

PMID- 10345011
TI  - Common features of people-pleasing HMOs.

PMID- 10345013
TI  - New electronic security measures proposed.

PMID- 10345012
TI  - Deciphering the maze of Stark II regulations takes work.

PMID- 10345014
TI  - Pennsylvania PHO chooses mission and cuts costs.

PMID- 10345015
TI  - Learn a little risk management.

PMID- 10345016
TI  - Hospital-owned practices succeed with solid teams.

PMID- 10345017
TI  - Learning the business of medicine.

PMID- 10345018
TI  - Looking for next contracting trend? Reverse capitation has its day.

PMID- 10345019
TI  - IRS rule could mean fines for expensive physicians.

PMID- 10345020
TI  - 'Showdown in Cow Town': Texas MDs balk at contract.

PMID- 10345021
TI  - Survey: physicians work harder for money.

PMID- 10345022
TI  - Communication is key in post-merger marketing.

PMID- 10345023
TI  - 'Truth in scheduling' solves access problems.

PMID- 10345024
TI  - Too many doctors or not too many doctors? Depends on who you ask.

PMID- 10345025
TI  - Salaries not keeping up with production.

PMID- 10345026
TI  - Waking up from nightmare of reference checks.

PMID- 10345027
TI  - National campaign gets local twist.

PMID- 10345028
TI  - Learn the fine art of win/win negotiation.

PMID- 10345029
TI  - By seizing opportunities, MDs emerge winners.

PMID- 10345030
TI  - Physician assistant concept takes off.

PMID- 10345031
TI  - Lack of job autonomy can have deadly effect.

PMID- 10345032
TI  - Training helps doctors connect with patients.

PMID- 10345033
TI  - Five hearts or thumbs up: health plans rank MDs.

PMID- 10345034
TI  - When trouble intrudes on star employees' work.

PMID- 10345035
TI  - A liability nightmare come true: radiologist wins $1 million.

PMID- 10345036
TI  - Adult learning principles key to staff training.

PMID- 10345037
TI  - Compliance: the medical group perspective.

PMID- 10345038
TI  - Common elements of a successful business process redesign, methodologies--keeping
      it simple makes it work.

PMID- 10345039
TI  - Community health information networks: a strategic view.

PMID- 10345040
TI  - Y2K: it's about more than just your computers.

PMID- 10345041
TI  - The epidemiology of bony metastases: a comparison of metastatic disease rates of
      the past 20 years.

PMID- 10345042
TI  - Perspectives. Numbers game: uncertainties in long-term spending forecasts return
      to haunt bipartisan Medicare Commission.

PMID- 10345043
TI  - Marketplace. The individual health insurance market: can it handle a demand
      surge?

PMID- 10345044
TI  - Perspectives. Healthy People 2010: brave new objectives aim high, but what is
      feasible?

PMID- 10345045
TI  - Perspectives. Flush economy, impeachment trial color Clinton FY2000 budget.

PMID- 10345046
TI  - AARP joins administration assault on Medicare fraud.

PMID- 10345047
TI  - Democratic electoral surprise renews push for Patient Bill of Rights.

PMID- 10345048
TI  - Preferred provider organizations vs. non-directed networks: a provider dilemma.

PMID- 10345049
TI  - Medicare: where do we go from here?

PMID- 10345050
TI  - A conversation with ... Dennis O'Leary, M.D. President, Joint Commission on
      Accreditation of Healthcare Organizations.

PMID- 10345051
TI  - Medicare Commission at impasse.

PMID- 10345052
TI  - Tracking system helps ED slash wait times, staff costs.

PMID- 10345053
TI  - Successful integration requires data on disease distribution and utilization
      patterns.
AB  - Planning and development: Where should integrated networks locate or establish
      contracts with physician offices, hospitals, nursing homes or other facilities? A
      close look at demand and supply data is the only way to effectively determine
      your community's needs. Sources abound for such data, but there are a few things
      you need to be careful about when using national or regional information.

PMID- 10345054
TI  - NCHS offers data on patient visits, diagnoses, procedures.

PMID- 10345055
TI  - New data tool provides wealth of clinical, financial benchmarks by census region.
AB  - Data Library: Compare your departmental expenses, administrative expense ratio,
      length of stay, and other clinical-financial data to benchmarks for your census
      region. A new CD-rom product that provides access to four years of Medicare Cost
      Report data for every reporting hospital in the nation allows users to slice and
      dice the data by more than 200 different performance measures.

PMID- 10345056
TI  - Don't forget to measure the results of your hospital reengineering effort.
AB  - Making sure re-engineering efforts can be quantified: Reorganizing a hospital
      into patient-focused care units must be a results-oriented, data-driven process.
      A New Jersey hospital developed baseline measures for a variety of outcomes for
      each new care center so improvement could be ensured and proven using hard and
      fast data.

PMID- 10345057
TI  - JCAHO, NCQA join up to coordinate data gathering requirements.

PMID- 10345058
TI  - Building capacity and changing the culture: Volunteers of America yields a fund
      raising turnaround.

PMID- 10345059
TI  - 77 reasons why people give.

PMID- 10345060
TI  - The donor profile.

PMID- 10345061
TI  - Wealthy & wise. How you and America can get the most out of your giving through
      "Newtithing".

PMID- 10345062
TI  - Looking a gift horse in the mouth.

PMID- 10345063
TI  - Roundtable. Educating fund raisers.

PMID- 10345064
TI  - The art of asking: how to solicit for your organization.

PMID- 10345065
TI  - Is Medicare risk a feasible strategy for providers?

PMID- 10345066
TI  - Exempla faces financial and clinical challenges.

PMID- 10345067
TI  - Medicaid managed care helps states pay providers less; HMOs do negotiating.

PMID- 10345068
TI  - Surveying patient satisfaction among disadvantaged managed care customers.

PMID- 10345069
TI  - Medical groups are squeezed; relief coming.

PMID- 10345070
TI  - Turning around a troubled MSO: a strategic approach.

PMID- 10345072
TI  - Atlanta's WellStar Health System puts 'tithing' concept to work.

PMID- 10345071
TI  - Program evaluation: a value-added approach to hospital cost reduction.
AB  - As the pace of provider integration and aggregation begins to diminish, many
      systems are looking for ways to get more value from their new organizations.
      Brett Turner, a principal with Hamilton/HMC, explains both broad-based and
      targeted approaches to evaluating programs to determine whether they should be
      continued.

PMID- 10345073
TI  - Tenet hospitals leading way in trend toward bloodless surgeries.

PMID- 10345074
TI  - Excellence in patient care demands a clear vision in action.
AB  - Health systems must continue to keep their visions focused on excellent patient
      care, even when distracted by changing financing mechanisms, new technologies,
      and growing integrated systems, warns Ruth Williams-Brinkley, group vice
      president of Catholic Health Initiatives in Louisville, Ky.

PMID- 10345075
TI  - Integrated systems reassess strategies.
AB  - Integrated health care delivery systems are reassessing their strategies and
      goals in light of recent experience. The latest data on HMOs suggests more are at
      least partially owned by integrated systems and hospitals and that integrated
      systems' hospitals are gaining market share, writes Donald E. L. Johnson.

PMID- 10345076
TI  - Designing facilities to be patient-focused.

PMID- 10345077
TI  - Capitation, quality issues make domestic violence a 'medical' issue.

PMID- 10345078
TI  - The 'ideal' domestic violence program for health systems.

PMID- 10345079
TI  - Methods for improving emergency department operational process.
AB  - It's not just the pain or injury that gives patients a natural aversion to
      visiting the emergency department, but the ED's entire operational process.
      William Schumacher, M.D., a board-certified emergency medical physician, writes
      about ways to improve efficiency and make the ED experience more agreeable.

PMID- 10345080
TI  - Looking critically at your system's health care businesses.

PMID- 10345081
TI  - In new American Healthcare Corp.'s book, rural's better.
AB  - Giant hospital chains like Columbia/HCA are continuing to sell off the urban
      facilities they purchased over the past few years, but several smaller chains are
      continuing to grow and thrive by acquiring rural hospitals. Ed Egger writes about
      one of them, New American Healthcare Corporation.

PMID- 10345082
TI  - HMOs may be ready to drop costly physicians.
AB  - After expanding their physician panels for several years in an effort to attract
      new enrollees, HMOs appear to be reversing course in an effort to control
      expenditures. In some areas, 20% to 30% of physicians could lose their HMO
      contracts, writes Donald E. L. Johnson.

PMID- 10345083
TI  - Health care without walls responding to telehealth's emerging legal issues.

PMID- 10345084
TI  - Capacity assessments and the role of the clinical expert: the Ontario experience.

PMID- 10345085
TI  - Primary care in Ontario--legal issues.

PMID- 10345086
TI  - How to think about medical secrecy.

PMID- 10345087
TI  - Two solitudes: psychiatry and primary care family medicine--a growing
      relationship.

PMID- 10345088
TI  - Non-resident hospitalization fees.

PMID- 10345089
TI  - Claims for "mental suffering": an enquiry into Canada's judicial response.

PMID- 10345090
TI  - The limits of doctor-patient confidentiality in Canada.

PMID- 10345091
TI  - Staff training: 'key to foiling abduction in maternity, pediatric units'.

PMID- 10345092
TI  - Duke Med Center installs camera system that captures areas between cars.

PMID- 10345093
TI  - New salary surveys: hospital security execs still trail most industries.

PMID- 10345094
TI  - An interview with: Paul Lew of Lev Zetlin on design considerations for more
      secure parking.

PMID- 10345095
TI  - Protecting domestic abuse victims: what hospitals and their security departments
      can do.
AB  - One of the keys to a safe workplace is the ability to help patients and staff who
      are subject to violence or abuse at home and bring their problems to the
      hospital. At two hospitals, Children's Hospital of Pittsburgh, Pittsburgh, PA,
      and Massachusetts General Hospital, Boston, the security department plays a
      critical role in supporting and protecting victims of domestic violence. Details
      of both programs are presented in this report.

PMID- 10345096
TI  - How faith and public policy intersect.

PMID- 10345097
TI  - The new EMTALA squeeze.

PMID- 10345098
TI  - DSH hospitals: still caring for the poor.

PMID- 10345099
TI  - CHAusa helps members secure corporate compliance.

PMID- 10345100
TI  - Healthcare providers can use special knowledge to prevent teen violence.

PMID- 10345101
TI  - Dealing with fraud issues.

PMID- 10345102
TI  - Approaching the millennium. How can Catholic healthcare best celebrate the "Year
      of the Lord's Favor"?

PMID- 10345103
TI  - Five years of collaboration. Baton Rouge Health Forum focuses on community needs.

PMID- 10345104
TI  - Putting patients first response. Improving elderly care.

PMID- 10345105
TI  - Serving diverse populations. "Cultural competence" not optional for healthcare
      organizations.

PMID- 10345106
TI  - Spiritual care for foreigners. Immigrants have special needs for support and
      understanding.

PMID- 10345107
TI  - Marketing in a multifarious world. Catholic healthcare organizations are reaching
      out to culturally diverse populations.

PMID- 10345108
TI  - Navajo surgeon combines approaches. Interview by Judy Cassidy.

PMID- 10345109
TI  - Mission and diversity. An experience in integration. Stories of our founders and
      discussing shared values help workers participate in the mission of Jesus.

PMID- 10345111
TI  - Demonstrating value. Healthcare organizations can document positive outcomes from
      their community-benefit services.
AB  - When challenged to demonstrate their contributions to the community, Catholic and
      other not-for-profit hospitals have traditionally reported the sum of their
      charity care, free programs, and unprofitable services. But critics of tax-exempt
      healthcare now say this is insufficient and ask such hospitals for descriptions
      of the outcomes of their contributions. There are seven basic measures for
      gauging outcomes: participation, mind states, behavior, health status, sickness
      care utilization, sickness care expenditures, and community value. Some of these
      measures will, when used singly, fail to produce clear and convincing results.
      Moreover, all of them must be accompanied by a foundation for attribution.
      Finally, the hospital must be able to show that the outcomes have significant
      value for the community. But documenting the complete set of effects is worth the
      effort spent on it. Hospitals that carefully weigh the results of their
      contributions increase the likelihood that their community will truly benefit
      from them, and will themselves benefit from their ability to show that this is
      so.

PMID- 10345110
TI  - Compensation in Catholic healthcare. A roundtable discussion.

PMID- 10345112
TI  - A system of services for the elderly. Loretto brings community organizations
      together to provide a continuum of care in central New York.

PMID- 10345113
TI  - Form 990 is going public. New IRS regulations will make information about
      nonprofit healthcare providers widely available.

PMID- 10345114
TI  - Hospitals enroll children in Medicaid. Facilities in Indiana and New York work
      closely with state social services.

PMID- 10345115
TI  - Community networks. St. Francis Healthcare System of Hawaii and Catholic
      Charities, Honolulu.

PMID- 10345116
TI  - Diabetics learn while they shop in disease-management program.

PMID- 10345117
TI  - On the front lines of health care.

PMID- 10345118
TI  - Surviving a helicopter crash.

PMID- 10345119
TI  - Chronic on-the-job fatigue.

PMID- 10345120
TI  - Smart cart coming through.

PMID- 10345121
TI  - The JEMS 1999 Resource Directory.

PMID- 10345123
TI  - Saving sirens. Profiles of women in EMS.

PMID- 10345122
TI  - Girl talk. An EMS educator reports her findings on the state of women in the
      industry.

PMID- 10345124
TI  - Terrorism. Part III--Response procedures for terrorist/tactical violence
      incidents.
AB  - A safe and effective response to a terrorist/tactical violence incident involves
      the following critical factors: Identify and train all potential convergent
      responders. 2-in/2-out--your partner is your life; have a plan to rescue the
      rescuers. Orient all responders to LACES. Search your command, staging and
      treatment areas for a secondary device. Restrict media coverage. Control the
      scene and relocate/evacuate if necessary. Alert medical receiving facilities
      early in the event chain to enable them to prepare for a patient onslaught.

PMID- 10345125
TI  - National medical response teams.

PMID- 10345126
TI  - Integrating criminal investigation into major EMS scenes.

PMID- 10345127
TI  - 2 1/2-mile MCI on the Whiskey Bay Bridge.

PMID- 10345128
TI  - Closing pathway loop with automation, teamwork.

PMID- 10345130
TI  - Policy curbs observers in the OR.

PMID- 10345129
TI  - Patient death raises issue of new technology in ORs.

PMID- 10345132
TI  - How well informed are patients?

PMID- 10345131
TI  - Two-challenge rule averts errors, improves safety.

PMID- 10345133
TI  - Mind-body-spirit healing in the OR.

PMID- 10345134
TI  - A supply chain with stronger links.

PMID- 10345135
TI  - Monitoring infections for outpatients.

PMID- 10345136
TI  - Pew seeks ongoing competence review. Pew Commission recommendations.

PMID- 10345137
TI  - New glue, zipper for closing wounds.

PMID- 10345138
TI  - More RNs lower risk of UTIs, pneumonia.

PMID- 10345139
TI  - Ultrasound proves clinical usefulness in osteoporosis.

PMID- 10345140
TI  - New law mandates Medicare coverage of bone mass exams.

PMID- 10345141
TI  - Ultrasound units make densitometry cheaper and more accessible to PCPs.

PMID- 10345142
TI  - Densitometry society seeks to educate and certify users.

PMID- 10345143
TI  - Bone mass measurement also predicts breast cancer.

PMID- 10345144
TI  - Spine studies to remain part of bone analysis.

PMID- 10345145
TI  - New measurement methods require reassessment of WHO criteria.

PMID- 10345146
TI  - DXA remains gold standard for assessing spine and femoral head.

PMID- 10345147
TI  - Flat panels advance IR and digital fluoro.

PMID- 10345148
TI  - Tuberculous peritonitis in a geriatric patient: a case report.
AB  - In geriatric patients with exudative ascites, malignant ascites is a common
      etiology. Tuberculous peritonitis is rarely seen and usually overlooked. We
      describe a 67-year-old man who suffered from exudative ascites for 1 month before
      admission. None of the noninvasive diagnostic methods utilized enabled us to make
      a correct diagnosis. Peritoneoscopic examination demonstrated multiple whitish
      miliary nodules and some larger nodules in the parietal and visceral peritoneum.
      Excisional biopsy confirmed the diagnosis of tuberculous peritonitis. This case
      reminds us that although malignant ascites is more prevalent in geriatric
      patients with exudative ascites, peritoneoscopy is indicated when noninvasive
      diagnostic methods allow no definite diagnosis.

PMID- 10345149
TI  - Quinolones: clinical use and formulary considerations.
AB  - Quinolones are broad-spectrum antibiotics active primarily against aerobic gram
      negative organisms. All quinolones have activity against oral anaerobes, but only
      trovafloxacin provides coverage against Bacteroides fragilis, the primary
      anaerobe of the abdomen/pelvis. In addition, quinolones are very active against
      atypical pulmonary pathogens, e.g., Legionella, but trovafloxacin is the least
      active against Chlamydia. As with other antibiotics, the selection of quinolones
      depends not simply on the degree of microbiologic activity but also on safety
      profile and cost. Ciprofloxacin and trovafloxacin are associated with central
      nervous system side effects. Photosensitivity reactions may occur with
      sparfloxacin. Trovafloxacin is associated with more adverse reactions than any
      other quinolone, and its gastrointestinal side effects are most frequent among
      the quinolones. Resistance potential is highest with ciprofloxacin and lowest
      with levofloxacin. Sparfloxacin and grepafloxacin are available only as oral
      formulations. Among the parenteral quinolones, ciprofloxacin and trovafloxacin
      are the most expensive, levofloxacin, the least expensive. Levofloxacin is
      preferred for general use alone or in combination because it has virtually no
      side effects, induces no resistance, and is the least expensive and most
      versatile quinolone currently available.

PMID- 10345150
TI  - Ginkgo biloba (EGb 761) in the treatment of equilibrium disorders.
AB  - In an open, controlled study, 44 patients complaining of vertigo, dizziness, or
      both, caused by vascular vestibular disorders were randomly treated with extract
      of Ginkgo biloba (EGb 761) 80 mg twice daily or with betahistine dihydrochloride
      (BI) 16 mg twice daily for 3 months. A complete neuro-otologic and
      equilibrimetric examination was performed at baseline and after 3 months of
      treatment, with evaluation of clinical findings. In the first month of therapy,
      vertigo and dizziness improved in 64.7% of patients treated with BI and in 65% of
      those who received EGb 761. Compared to baseline, no statistically significant
      changes were observed in cranial scans for patients with a "central" cranial
      pattern. Likewise, no changes versus baseline were observed in both groups for
      the equilibrium score. The comprehensive test battery showed the following
      findings: EGb 761 induced a slight decrease of saccadic delay and considerably
      increased saccadic velocities; BI improved saccadic accuracy but did not modify
      delay; EGb 761 improved smooth pursuit gain at 0.4 Hz 40 degrees/s three times
      more than BI; both drugs asymmetrically reduced nystagmus maximum velocity at 40
      degrees/s; both drugs asymmetrically improved the sinusoidal vestibulo-ocular
      reflex; BI considerably reduced--whereas EGb 761 considerably improved-
      visuovestibular ocular reflex. No side effects were recorded during the trial
      except for transient mild headache and gastric upset in 2 patients receiving EGb
      761 and transient cyanosis of nails and lips in 1 patient given BI. These results
      suggest that EGb 761 and BI operate at different equilibrium receptor sites and
      show that EGb 761 can considerably improve oculomotor and visuovestibular
      function.

PMID- 10345151
TI  - Four-week supplementation with a natural dietary compound produces favorable
      changes in body composition.
AB  - The purpose of this study was to determine whether a natural dietary supplement
      produced favorable changes in body composition during a 4-week diet- and-exercise
      program. The active compound contains a patented combination of chromium
      picolinate, inulin, capsicum, L-phenylalanine, and other lipotropic nutrients. A
      double-blind, weight-loss intervention design was used. Participants were
      randomly assigned to either a diet/exercise/supplement group (n = 56) or a
      diet/exercise/placebo group (n = 67). Caloric intake was reduced to 1500 kcal/d
      and participants walked for 45 minutes, 5 days a week, to attain between 60% and
      80% of predicted maximal heart rate. Analysis of covariance (ANCOVA) showed
      significant differences (P < .05) between groups in percent body fat, fat mass,
      and fat-free mass; no significant differences were found (P > .05) in body
      weight, body mass index, or energy intake. Independent t tests showed no
      significant differences (P > .05) in diet composition between groups. Results
      indicate that the addition of a natural dietary supplement during a 4-week diet
      and-exercise weight-loss program accelerates the rate of body fat loss and helps
      maintain fat-free mass (lean tissue), thereby producing favorable changes in body
      composition.

PMID- 10345152
TI  - Proteomic databases: roadmaps for drug discovery.

PMID- 10345153
TI  - Evaluating test performance criteria: concepts and practices--Part 2: Source of a
      statistical measure of error.

PMID- 10345154
TI  - Effect of pH on enzyme immunoassay and analysis of urine.

PMID- 10345155
TI  - What's an outcome? How should it be valued?

PMID- 10345156
TI  - The use of meta-analysis in cost-effectiveness analysis. Issues and
      recommendations.
AB  - Meta-analysis is used to statistically pool the results from individual studies,
      usually randomised trials, to obtain an estimate of the summary effect size
      across studies. The summary measure from a meta-analysis is often used to derive
      the probability of treatment success in a cost-effectiveness analysis. Recently,
      LeLorier and colleagues questioned the ability of meta-analysis to accurately
      predict the results of a subsequent large-scale trial, implying that the use of a
      summary measure from a meta-analysis may be inappropriate in an economic
      evaluation. We comment on this potential shortcoming by first providing an
      outline of the use of meta-analysis results in a cost-effectiveness analysis.
      Then, using examples of discrepancies between meta-analyses and subsequent large
      trials noted by LeLorier and colleagues, we examine the potential impact of using
      the results from a small trial versus a meta-analysis. We found that the meta
      analyses were comparable to or better than small trials at predicting the results
      of subsequent large trials. We, therefore, argue that a meta-analysis of
      homogeneous studies can provide a reasonable estimate of the treatment effect for
      use in a cost-effectiveness analysis when no large, definitive clinical trial has
      been performed. However, care must be taken not to over-interpret the precision
      of the estimate, since both the homogeneity and quality of the primary studies
      need to be considered. We conclude by providing guidance on the appropriate use
      of summary measures derived from meta-analyses for cost-effectiveness studies.

PMID- 10345157
TI  - Evaluating Health-related quality-of-life outcomes in patients with congestive
      heart failure. A review of recent randomised controlled trials.
AB  - Congestive heart failure (CHF) is a chronic disorder characterised by fatigue,
      shortness of breath and congestion. Treatment is designed to relieve symptoms,
      halt or delay progression of the disease, prolong life and, ultimately, improve
      quality of life. The purpose of this paper is to identify recent trends in the
      assessment of health-related quality-of-life (HR-QOL) outcomes in randomised,
      controlled trials evaluating treatment effectiveness in patients with CHF. 41
      studies using HR-QOL as an explicit outcome and published in English between 1990
      and September 1998 were reviewed. Trends in the measurement of HR-QOL and
      evidence of treatment effectiveness are presented followed by a discussion of the
      implications for future research. Results suggest that pharmacological and
      nonpharmacological treatment regimens can have a positive impact on HR-QOL.
      However, treatment-related improvement in exercise capacity in patients with CHF
      was not consistently associated with improvement in all domains of HR-QOL. The
      primary HR-QOL domain affected by treatment appears to be the performance of
      daily activities, which may or may not be accompanied by enhanced well-being.
      This suggests that functional status should be considered a primary HR-QOL end
      point in clinical intervention trials. Preference-based or utility assessment,
      ethnic group differences in treatment effectiveness, caregiver burden and cost
      effectiveness are understudied outcomes in CHF research.

PMID- 10345159
TI  - Cost-benefit analysis of Haemophilus influenzae type b vaccination in children in
      Spain.
AB  - OBJECTIVE: Invasive disease caused by Haemophilus influenzae type b (Hib),
      including meningitis, pneumonia, sepsis and epiglottitis, is associated with high
      mortality and serious neurological sequelae in children under 5 years of age. The
      availability of an efficacious vaccine suggests the need to perform an economic
      evaluation of its use. The objective of this study was to evaluate the costs and
      benefits of introducing a universal vaccination programme for children under 1
      year of age in Spain. DESIGN & SETTING: A cost-benefit analysis (CBA) was
      conducted over a 5-year period from the societal perspective in the Spanish
      healthcare setting. Both direct and indirect costs were included in the analysis
      [using 1996 Spanish pesetas (Pta); Pta126.5 = $US1 in April 1996]. PATIENTS AND
      PARTICIPANTS: The target population used for cost and benefit estimation was the
      384,883 Spaniards aged 1 year or less in the last Spanish Population and Housing
      Census of 1991. MAIN OUTCOME MEASURES AND RESULTS: The introduction of the
      universal Hib vaccination programme would imply vaccinating 346,395 children
      under 1 year of age, with a global expense of Pta2,444,855,910. For an average
      incidence of 15 cases of invasive disease per 100,000 children per year
      nationwide, the programme would prevent 219 cases of invasive disease and 8
      deaths over a 5-year period, with a benefit of Pta2,182,868,907, a net benefit
      (i.e. benefit minus cost) of -Pta261,987,003, a benefit/cost ratio of 0.89 and a
      benefit per case prevented of -Pta1,196,288. Benefit/cost ratios above 1 would be
      obtained in the regions of highest incidence of invasive disease. CONCLUSION: The
      decision to implement a universal vaccination programme should not be based only
      on economic factors, but our results suggest that the economic returns of the
      programme for children under 1 year of age in Spain would be at least of a
      similar magnitude as its expenses.

PMID- 10345158
TI  - Pharmacoeconomics of lipid-lowering agents for primary and secondary prevention
      of coronary artery disease.
AB  - Cardiovascular disease is the leading cause of death and the leading source of
      healthcare expenditure in the US and most other industrialised countries.
      Cholesterol lowering by pharmacological means prevents atherosclerotic plaque
      progression and has been shown to reduce both fatal and nonfatal coronary events
      in patients with or without coronary artery disease (CAD). Because of their
      excellent efficacy and safety profiles, the introduction of 3-hydroxy-3-methyl
      glutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known an 'statins') in
      1987 raised hopes for demonstrating the survival benefit of cholesterol
      reduction. In the past decade, several large-scale placebo-controlled trials with
      statin therapy have revisited the relationship between cholesterol reduction,
      cardiovascular disease and mortality. The West of Scotland Coronary Prevention
      Study (WOSCOPS) [pravastatin] and the Air Force/Texas Coronary Atherosclerosis
      Prevention Study (AFCAPS/TexCAPS) [lovastatin] have shown significant
      cardiovascular disease reduction in primary prevention trials of patients with
      elevated and normal cholesterol levels, respectively. The Scandinavian
      Simvastatin Survival Study (4S), the Long-Term Intervention with Pravastatin in
      Ischaemic Disease (LIPID) Study and the Cholesterol and Recurrent Events (CARE)
      trial [pravastatin] have shown significant cardiovascular disease reduction in
      patients with a previous history of CAD with high, moderate and normal
      cholesterol levels, respectively. Three of these studies (4S, WOSCOPS and LIPID)
      have shown significant reduction in all-cause mortality, while all the statin
      secondary prevention trials (4S, CARE and LIPID) have demonstrated significant
      reduction in cerebrovascular disease/ Earlier cholesterol reduction cost
      effectiveness studies with nonstatin treatments (bile acid resins, fibrates,
      niacin and diet) suggested that only patients at extremely high risk could be
      treated with lipid therapy in a cost-effective manner. More recently, rigorous
      outcomes evidence demonstrates that statins, particularly for simvastatin for
      secondary prevention and lovastatin for primary prevention, have a broadly
      favourable cost-effectiveness profile. Based on US medical price levels and the
      available clinical trial data on statins, it would be cost effective [e.g. cost
      less than $US50,000/year of life saved] to intervene with statin therapy in any
      patient with an annual CAD risk exceeding 1%. This includes all patients with pre
      existing CAD or diabetes mellitus, and many more primary prevention patients than
      are currently contemplated by the US National Cholesterol Education Panel
      treatment guidelines. Achieving such a goal will require enormous changes in
      patient education, clinical perspective, healthcare practice and healthcare
      finances. But any proven opportunity for saving the lives of 25% of those dying
      from cardiovascular disease each year deserves to be considered with the utmost
      seriousness and urgency.

PMID- 10345161
TI  - Willingness to pay as a measure of health benefits.
AB  - In this paper, we discuss the use of cost-benefit analysis (CBA) for evaluating
      new healthcare interventions, present the theoretical basis for the use of
      willingness to pay as a method for valuing benefits in a CBA and describe how to
      obtain willingness-to-pay (WTP) measures of health benefits and how to use these
      values in a CBA. We review selected economic studies on consumer demand and
      consumer surplus and studies presenting WTP estimates for healthcare
      interventions. The theoretical foundations of willingness to pay as a measure of
      commodity value are rooted in consumer demand theory. The area under the fixed
      income consumer demand curve represents the consumer's maximum willingness to pay
      for the commodity. We identify 3 types of potential benefits from a new
      healthcare intervention, namely patient benefits, option value and altruistic
      value, and suggest WTP questions for valuing different combinations of these
      benefits. We demonstrate how responses to these questions can be adjusted for
      income effects and incorporated into economic evaluations. We suggest that the
      lack of popularity of CBAs in the health area is related to the perceived
      difficulty in valuing health benefits as well as concern over how CBA
      incorporates the distribution of income. We show that health benefits can be
      valued using simple survey techniques and that these values can be adjusted to
      any desired income distribution.

PMID- 10345160
TI  - Cost analysis of 2 empiric antibacterial regimens containing glycopeptides for
      the treatment of febrile neutropenia in patients with acute leukaemia.
AB  - OBJECTIVE: Patients with cancer-associated neutropenia are at high risk of
      developing severe infections which can be fatal if treatment is not promptly
      administered. For this reason, fever is treated as soon as possible with broad
      spectrum antibacterial therapy. The objective of this study was to conduct a cost
      analysis in Italy comparing 2 empiric glycoprotein-containing antibacterial
      regimens for the treatment of febrile neutropenia in patients with acute
      leukaemia. DESIGN AND SETTING: A retrospective cost analysis was conducted, using
      the records of 527 febrile neutropenic patients with acute leukaemia who
      participated in an 18-month multicentre (29 Italian haematological units)
      randomised trial during 1991. All patients received either of the following 2
      empiric intravenous regimens, each containing 3 antibacterial agents: ceftazidime
      (2 g, 3 times daily) and amikacin (15 mg/kg/day, in 3 separate doses) plus
      teicoplanin (6 mg/kg, in a single dose) or vancomycin (30 mg/kg/day, in 2
      separate doses). Economic analyses were carried out from a hospital perspective.
      Only the direct costs per patient, i.e. mean antibacterial treatment and
      management cost, mean overall treatment failure cost and mean cost of adverse
      effects, were included. MAIN OUTCOME MEASURES AND RESULTS: No differences were
      found in the clinical response, defined as the improvement in the rate of fever
      or infection (if documented), between the 2 regimens. However, tolerability,
      defined as the incidence of adverse effects probably or definitely related to the
      assigned treatment, was reported to be better with the teicoplanin-rather than
      the vancomycin-containing regimen. CONCLUSIONS: Thus retrospective cost analysis
      showed that despite the higher acquisition cost of teicoplanin relative to
      vancomycin, the lower incidence of adverse effects associated with teicoplanin
      and its ease of administration (single daily dose) resulted in equivalent overall
      treatment costs between teicoplanin- and vancomycin containing regimens.

PMID- 10345164
TI  - Internet addicts get help online.

PMID- 10345163
TI  - Maine area ties up to telemedicine project.

PMID- 10345162
TI  - Economic evaluation of antibacterials in the treatment of acute sinusitis.
AB  - OBJECTIVE: The objective of this study was to compare costs, efficacy and cost
      efficacy of alternate oral antibacterial regimens for the ambulatory treatment of
      acute sinusitis. A public third-party perspective was adopted. DESIGN: The
      analysis was based on a decision tree and considered the episode of care from the
      decision to initiate an antibacterial until the end of the first course of
      treatment or the end of a subsequent course of treatment when needed. Efficacy
      data were retrieved from published clinical trials. Direct medical costs included
      the costs of physician visits, diagnostic tests and medications. SETTING: The
      study pertained to adults treated in a primary-care setting in the Canadian
      province of Quebec. INTERVENTIONS: The antibacterials studied were amoxicillin,
      amoxicillin/clavulanate, azithromycin, cefaclor, cefuroxime axetil and
      clarithromycin. MAIN OUTCOME MEASURES AND RESULTS: The main outcome measured was
      the proportion of patients showing resolution or improvement of their symptoms.
      Initiating a treatment with amoxicillin was associated with similar efficacy and
      lower overall costs when compared with the other antibacterials. Low dosages of
      clarithromycin and azithromycin followed amoxicillin in terms of cost-efficacy
      ratio. CONCLUSIONS: This study confirms the place of amoxicillin as a first
      choice agent for acute sinusitis, with low dose clarithromycin and azithromycin
      as second choices.

PMID- 10345165
TI  - Wireless, satellite communications to fill gaps.

PMID- 10345166
TI  - Telemedicine helps make a Lithuanian boy's dream a reality.

PMID- 10345167
TI  - Heart surgery on the 'net.

PMID- 10345168
TI  - Japanese hospital links to Belarus Clinic.

PMID- 10345169
TI  - South Africa readies telemedicine program.

PMID- 10345170
TI  - Telemedicine obstacles can be overcome.

PMID- 10345171
TI  - Telemedicine initiatives within the Department of Defense.

PMID- 10345172
TI  - American Accreditation HealthCare Commission cites. Four organizations for
      telephone triage standards.

PMID- 10345173
TI  - World diabetes self-care market to reach $7.6 billion in 1998.

PMID- 10345174
TI  - Doctors provide AIDS education via teleconference.

PMID- 10345175
TI  - Home access health offers services to blood centers.

PMID- 10345176
TI  - UK earmarks 1 billion Pounds for information technology.

PMID- 10345179
TI  - Virtual reality becomes reality for plastic surgeons.

PMID- 10345178
TI  - Telemedicine initiatives within the DoD.

PMID- 10345177
TI  - AOL puts a doctor online.

PMID- 10345180
TI  - Shuttle leaves telemedicine package on the ground.

PMID- 10345181
TI  - Telemedicine to play key role in combating fetal alcohol syndrome on the prairie.

PMID- 10345182
TI  - Thirty million to go online for health information.

PMID- 10345183
TI  - Blue Cross of California gets $1.8 million for rural telemedicine program.

PMID- 10345184
TI  - Home telemedicine identifies innovations.

PMID- 10345185
TI  - Library of Medicine and 200 public libraries link up in pilot health program.

PMID- 10345186
TI  - Merck-Medco and physicians' on-line plan Internet applications.

PMID- 10345187
TI  - Plastic surgery procedures performed live on the Internet.

PMID- 10345189
TI  - Teleglobe demonstrates ATM capabilities for telemedicine.

PMID- 10345188
TI  - Argentina, ITU to develop telehealth projects.

PMID- 10345190
TI  - Tokyo, Illinois universities to experiment with high-speed Internet.

PMID- 10345191
TI  - Doctors use virtual reality scalpel to train for head surgery.

PMID- 10345192
TI  - Telemedicine initiatives within the DoD.

PMID- 10345193
TI  - Bristol-Myers Squibb pushes BuSpar compliance.

PMID- 10345194
TI  - Elderly patients embrace touch-screen technology.

PMID- 10345195
TI  - Measuring community mobilization in the Seattle Minority Youth Health Project.
AB  - This article assesses the validity and reliability of the approach used to
      measure community mobilization in the Seattle Minority Youth Health Project (MY
      Health), a neighborhood-based program to prevent drug use, violence, teen
      pregnancy, and sexually transmitted diseases (STDs). Two constructs were
      measured: neighborhood cooperation in solving problems, and sense of pride and
      identification with the neighborhood. The convergent validity of the measurement
      approach was assessed by comparing several independent measures of community
      mobilization generated from surveys of key neighborhood leaders, youth, and
      parents. For the neighborhood cooperation construct, correlations were uniformly
      positive across measures from different surveys and statistically significant
      about a quarter of the time. The correlations for the neighborhood pride
      construct were weaker and generally not statistically significant. Interrater
      reliability was low for all of the surveys, possibly reflecting varying ideas
      about what community mobilization meant among survey respondents.

PMID- 10345196
TI  - Deadbeat dads or inept states? A comparison of child support enforcement systems.
AB  - This article provides information on the effectiveness of state child support
      enforcement systems. We use individual level data from the Child Support
      Supplements of the Current Population Surveys (1978-1992) to create an index of
      state effectiveness that captures success at securing child support awards,
      setting award levels, and collecting obligations. We identify states that were
      performing above or below the national average in the late 1980s to early 1990s
      and states that showed substantial improvement or decline in child support
      effectiveness during the 1980s. Identifying successful states will help
      researchers to determine what policies and practices are associated with
      successful enforcement. These variations in state effectiveness also suggest that
      low levels of child support are not due to deadbeat dads alone but also to inept
      states.

PMID- 10345197
TI  - Illuminating crime. The impact of street lighting on calls for police service.
AB  - This study reports on an evaluation of the effects of street lights on crime in
      several Indianapolis neighborhoods. Crime was measured in terms of calls for
      police service (CFS). Using a quasiexperimental design, we performed analyses on
      four multiblock areas, three intersections, and two aggregated address groups.
      Two control areas were matched to two multiblock areas that received enhanced
      lighting. Of the nine target areas, six showed evidence of lower CFS volumes
      after more lighting. We analyzed the mean weekly CFS in the pre- and
      postinstallation periods. Two lighted areas had a lower mean weekly CFS after
      installation. The more illuminated target area experienced a greater reduction in
      average CFS for property and miscellaneous crimes than did the control area.

PMID- 10345198
TI  - Enhancing response rates to a smoking survey for enlisted U.S. Navy women.
AB  - This study examined the effectiveness of a stepped approach for increasing
      response rates to a mailed follow-up smoking survey among newly enlisted women in
      the navy. The effect of the stepped approach on response rates and on the
      characteristics of respondents was evaluated. Also, costs were estimated for each
      of the steps to determine their relative benefits. Results showed that the
      stepped approach was effective in more than doubling the survey response rate
      among smokers. Reluctant respondents did not differ from on-time respondents in
      terms of demographics or baseline smoking, although nonrespondents were less
      educated and heavier smokers than on-time and reluctant respondents. Strategies
      documented here could well apply to survey efforts with other hard-to-reach
      populations.

PMID- 10345200
TI  - 1999 resource guide. Your reference to IT products, vendors, services and
      associations.

PMID- 10345199
TI  - Assessing data for precursors of CO2 and methane in King County, Washington,
      1990.
AB  - Evaluation of policies designed to reduce emissions of global warming gases will
      require valid data about in-use quantities of these gases' precursors. This
      article assesses the quality of available data for many significant precursors of
      CO2 and methane in King County, Washington, which is an area with minimal
      variations in climate as well as rapid population growth and development.
      Available data support an estimate of 21,000,000 metric tons of CO2-equivalent
      gases emitted in 1990 from selected precursors. There is also evidence that
      electricity conservation programs and recycling both reduce CO2 emissions.
      Requirements for adequate baseline data include constant and valid data
      definitions as well as monthly time series. To evaluate policies over periods of
      years, databases must be designed to withstand frequent and rapid changes in
      national economies; they must also permit analysis of consumer choices affecting
      fossil fuels and other precursors of warming gases. In almost every case, current
      data do not satisfy these requirements.

PMID- 10345201
TI  - ALL Kids initiative: Alabama hospitals help with outreach efforts.

PMID- 10345202
TI  - The Dr. will see you now--right now! Hospitalists finding increasing role in
      health care system.

PMID- 10345203
TI  - Stories of health & healing.

PMID- 10345204
TI  - Regulating managed care and protecting patients' rights.

PMID- 10345205
TI  - ERISA and medical professional liability.

PMID- 10345206
TI  - The Robert Wood Johnson Health Policy Fellowship.

PMID- 10345207
TI  - Stunning patient satisfaction turnaround starts with employees.

PMID- 10345208
TI  - Nowhere to hide.

PMID- 10345209
TI  - Shrinking the (growing) company.

PMID- 10345210
TI  - Accreditation. Why employers don't demand it.

PMID- 10345211
TI  - How well does your PBM perform?

PMID- 10345212
TI  - What's next? At 25, the Washington Business Group on Health looks ahead.

PMID- 10345213
TI  - Employee feedback: not just a whine line.

PMID- 10345214
TI  - DataWatch. Boom time for alternative medicine.

PMID- 10345215
TI  - Sunrise or sunset for PPMs? Impact of recent developments on integrated
      healthcare systems.

PMID- 10345217
TI  - U.S. health care spending stable in 1997.

PMID- 10345216
TI  - System vs. subsidiary boards of directors. How can you rationalize their
      respective roles?

PMID- 10345218
TI  - The amazing smoke screen. The anti-tobacco crusade is a reverse Robin Hood
      arrangement. It robs the poor to pay the rich.

PMID- 10345219
TI  - Heading for the hills. Fear of the Y2K bug is pushing some to extremes.

PMID- 10345220
TI  - Cancer & diet.

PMID- 10345221
TI  - Death wish.

PMID- 10345222
TI  - Thinking differently. Brain scans give new hope for diagnosing ADHD.

PMID- 10345223
TI  - An overture, again, on health reform.

PMID- 10345224
TI  - Becoming customer-driven in a "report card" marketplace.

PMID- 10345225
TI  - Preparing for a consumer-driven marketplace: 10 action steps.

PMID- 10345226
TI  - Will health care consumers actually use report cards?

PMID- 10345227
TI  - HCFA announces additional procedures excluded from consolidated billing; industry
      groups had hoped for more.

PMID- 10345228
TI  - Industry group challenges HCFA guidance on link between MDS assessment, Medicare
      payment.

PMID- 10345229
TI  - Report calls for sweeping changes in Pennsylvania nursing facilities; providers
      point to ongoing efforts.

PMID- 10345230
TI  - Importance of nursing rehab, restorative care grows under SNF PPS.

PMID- 10345231
TI  - HCFA goes back to the drawing board with proposed practice expense rule.

PMID- 10345232
TI  - Teaching hospitals fight back against PATH rulings.

PMID- 10345233
TI  - Internist says 'no' to all managed care contracts.

PMID- 10345234
TI  - EDs faring better under managed care.

PMID- 10345235
TI  - Group aims for consistency in quality measurement.

PMID- 10345236
TI  - AMAP gains steam as first physicians accredited.

PMID- 10345237
TI  - How physician stress can hurt your practice.
AB  - Physicians are under increasing pressure to see more patients, take on more
      management responsibilities, and still provide the best care. That is leading to
      a variety of problems--everything from general malaise and burnout to early
      retirement and unionization. Stressed-out physicians can have a disastrous effect
      on the bottom line of practices. Productivity drops, staff become demoralized,
      turnover increases, and patients become less satisfied with the care they receive
      -both from the physician and support staff. There are clear warning signs of
      physicians under too much pressure. There are also some simple steps a practice
      can take to minimize the occurrence of burnout and deal with it effectively when
      it occurs.

PMID- 10345238
TI  - Stats & facts. The wide-ranging effects of health premium increases.

PMID- 10345239
TI  - Where does the failure of physician practice managers leave physicians?

PMID- 10345240
TI  - Proofs and explanations within complementary and alternative medicine: an
      expanded perspective on research.

PMID- 10345241
TI  - Cost and quality implications of inappropriate anti-infective use.

PMID- 10345242
TI  - The effectiveness of an antibiotic use program.
AB  - Bacterial resistance to antibiotics continues to grow, and inappropriate
      diagnoses and prescriptions are to blame. The authors report on a pilot program
      undertaken in California that seeks to decrease the unnecessary use of
      antibiotics for viral-based ailments.

PMID- 10345243
TI  - The effect of new pharmaceutical agents on pharmacy budgets.

PMID- 10345244
TI  - Developing a successful volunteer program.

PMID- 10345245
TI  - The anatomy of a complaint.

PMID- 10345246
TI  - The year 2000 & your computers. Don't let the millennium bug bite.

PMID- 10345247
TI  - Reduce the risk. Redesigning the workforce for a competitive market.

PMID- 10345248
TI  - As 105th session ends, Congress passes massive omnibus spending bill.

PMID- 10345249
TI  - Preparing for surveys.

PMID- 10345250
TI  - The medical record. Your best friend or worst enemy?

PMID- 10345251
TI  - Physician gainsharing: a model for implementing best practices.

PMID- 10345252
TI  - Achieving clinical improvements through gainsharing.

PMID- 10345253
TI  - Pioneer in automated patient data gets dramatic results.

PMID- 10345254
TI  - A population-based approach to diabetes management in a primary care setting:
      early results and lessons learned.
AB  - OBJECTIVE: To determine the effect of a multifaceted program of support on the
      ability of primary care teams to deliver population-based diabetes care. DESIGN:
      Ongoing evaluation of a population-based intervention. SETTING/PARTICIPANTS:
      Group Health Cooperative of Puget Sound, a staff model HMO in which more than 200
      primary care providers treat approximately 15,000 diabetic patients.
      INTERVENTION: A program of support to improve the ability of primary care teams
      to deliver population-based diabetes care was implemented. The elements of the
      program are based on an integrated model of well-validated components of delivery
      of effective care to chronically ill populations. These elements have been
      introduced since the beginning of 1995, and some aspects of the program were
      pilot-tested in a few practice sites before being implemented throughout the
      organization. The program elements include 1) a continually updated on-line
      registry of diabetic patients; 2) evidence-based guidelines on retinal screening,
      foot care, screening for microalbuminuria, and glycemic management; 3) improved
      support for patient self-management; 4) practice redesign to encourage group
      visits for diabetic patients in the primary care setting; and 5) decentralized
      expertise through a diabetes expert care team (a diabetologist and a nurse
      certified diabetes educator) seeing patients jointly with primary care teams.
      MAIN OUTCOME MEASURES: Patient and provider satisfaction through existing system
      wide measurement processes; process measures, health outcomes, and costs are
      tracked continuously. RESULTS: Patient and provider satisfaction have improved
      steadily. Interest in and use of the electronic Diabetes Registry have grown
      considerably. Rates of retinal eye screening, documented foot examinations, and
      testing for microalbuminuria and hemoglobin A1c have increased substantially.
      CONCLUSIONS: Providing support to primary care teams in several key areas has
      made a population-based approach to diabetes care a practical reality in the
      setting of a staff model HMO. It may be an important mechanism for improving
      standards of care for many diabetic patients.

PMID- 10345255
TI  - Chronic disease management: what will it take to improve care for chronic
      illness?

PMID- 10345256
TI  - Blood pressure control to reduce cardiovascular morbidity and mortality: today
      and tomorrow.

PMID- 10345257
TI  - Does professional advice influence aspirin use to prevent heart disease in an HMO
      population?
AB  - OBJECTIVE: Aspirin use seems to reduce coronary artery disease events in some
      groups of patients. Factors associated with use of aspirin to prevent heart
      disease in an HMO population were examined. DESIGN: A population-based survey.
      SETTING: A large HMO in the midwestern United States. PARTICIPANTS: 8000 health
      plan members 40 years of age and older. MAIN OUTCOME MEASURES: The survey
      assessed use of aspirin, professional advice to use aspirin, and coronary heart
      disease risk factors and status. The sample was stratified by whether members had
      none, one, or more than one of the following chronic conditions: diabetes,
      hypertension, lipid disorder, or heart disease. The mailed survey had a corrected
      response rate of 82.4%. RESULTS: Overall, 38% of respondents reported using
      aspirin at least three times a week to prevent heart disease. Aspirin use did not
      vary in owned versus contracted clinics. Aspirin use was 71.3% in patients with
      and 27.7% in patients without diagnosed coronary heart disease (P < 0.001). In
      logistic regression models, professional advice to take aspirin was strongly
      associated with self-reported use of aspirin (odds ratio, 13.86) (P < 0.001)
      after adjustment for age, sex, level of education, and chronic disease status.
      CONCLUSIONS: Aspirin is widely used by HMO members with coronary artery disease
      to prevent subsequent coronary artery disease events. Professional advice to use
      aspirin seems to be strongly related to aspirin use.

PMID- 10345258
TI  - The case of the missing clinical preventive services systems.
AB  - OBJECTIVE: To examine the presence and comprehensiveness of organized processes
      and systems in a sample of primary care clinics shown to have high variation in
      rates of providing preventive services. DESIGN: Survey study. SETTING: 44 primary
      care clinics recruited for a scientific trial of a quality improvement
      intervention to improve preventive services. PARTICIPANTS: 647 clinicians and
      nurses. MEASUREMENTS: The presence of 10 organized prevention processes for eight
      adult preventive services as reported by those clinicians and nurses on a
      detailed written survey. RESULTS: In more than 50% of clinics, 7 of the 10
      prevention processes were reported to be absent for all eight services. Only the
      follow-up process was commonly present; this was also the only process that was
      usually present for most applicable services. CONCLUSIONS: The paucity of
      recognizable organized processes to support the systematic delivery of adult
      preventive services in clinics with highly varying rates of providing these
      services supports the idea that lack of systems may be an important source of the
      variability and low rates. Most of the existing processes are fragmented and do
      not function across multiple preventive services.

PMID- 10345259
TI  - Detection and treatment of depression in primary care.

PMID- 10345260
TI  - Computer-generated intervention for asthma population care management.

PMID- 10345261
TI  - Promising therapy methodology: a new process at HealthPartners for improving
      coverage decision making.

PMID- 10345262
TI  - Management of diabetes mellitus in the Lovelace Health Systems' EPISODES OF CARE
      program.
AB  - OBJECTIVE: To design and implement the Lovelace Diabetes EPISODES OF CARE program
      in a managed care setting. This program is intended to address the complex needs
      of patients with type 2 diabetes mellitus by using specific physician-provider
      and patient interventions. DESIGN: Observational study. SETTING: Lovelace Health
      Systems, the second-largest and most fully integrated health care delivery system
      in New Mexico. The main facility is located in Albuquerque. PARTICIPANTS:
      Lovelace Health Plan members with type 2 diabetes. INTERVENTIONS: Physician
      provider interventions included practice guidelines medical profile screens, and
      provider support reports. Patients interventions included diabetes education;
      improved access to care, with focused diabetes clinic visits and "Diabetes Days";
      and reminder systems. MAIN OUTCOME MEASURES: Glycohemoglobin values, dilated eye
      examination rates, and access to education. RESULTS: Significant lowering of
      glycohemoglobin values, dilated eye examination rates exceeding benchmark
      measures, and increases in educational access rates have occurred since the
      Lovelace Diabetes EPISODES OF CARE program was implemented. CONCLUSIONS: An
      integrated health care delivery system with a comprehensive, diabetes disease
      management program can substantially improve outcomes.

PMID- 10345263
TI  - The waiver of Medicare copayments and deductibles: a primer.

PMID- 10345264
TI  - Ambulatory and ancillary joint ventures involving tax-exempt entities.

PMID- 10345265
TI  - Benchmarking performance in MCO market growth and retention.

PMID- 10345266
TI  - It's not too early to get ready for system reintegration.

PMID- 10345267
TI  - Service line success factors.

PMID- 10345268
TI  - Patient and physician satisfaction is aim of new program.

PMID- 10345269
TI  - Market research helps healthcare systems in Atlanta and Seattle define their
      "brand" and refine their missions.

PMID- 10345270
TI  - Branding strategies discussed by the experts. Trends that will shape strategy in
      1998.
AB  - This month the focus is on branding. The Alliance Advisory Council's discussion
      of this topic, led by Joel English (a senior vice president with BVK/McDonald,
      Milwaukee, WI), identifies the key issues on branding as: 1) the debate between
      the local and regional nature of healthcare delivery, and the need to provide
      customers with the trust and security of a larger entity behind the individual
      provider; 2) the challenge of identifying and agreeing on a consistent message
      for all parts of the system; and 3) the difficulty of keeping the promise implied
      by a brand across these many components.

PMID- 10345271
TI  - Brand, image, reputation.

PMID- 10345272
TI  - Reevaluating traditional hospital care as a sustainable business.

PMID- 10345273
TI  - Using a market staging approach in appealing directly to the consumer.

PMID- 10345274
TI  - If you build it, make sure they come: promoting your Web site.

PMID- 10345275
TI  - Vertical integration. '80s fad or healthcare's future?

PMID- 10345276
TI  - Peggy Leatt and the Department of Health Administration.

PMID- 10345277
TI  - Beyond the rhetoric: hospital teams apply the quality process to create
      measurable benefits.

PMID- 10345278
TI  - Innovations in healthcare food services.

PMID- 10345279
TI  - Hospitals in the UK health system: lessons for Canada.

PMID- 10345280
TI  - Top 10 web sites for hospital managers.

PMID- 10345281
TI  - Healthcare delivery in rural Canada, Part I: Ontario's new policy.

PMID- 10345282
TI  - The horse you are riding.

PMID- 10345283
TI  - Quarterly index. Canadian Institute for Health Information.

PMID- 10345284
TI  - Reengineering and integrating health care delivery: what have we learned in the
      1990s?

PMID- 10345285
TI  - Private health services in Canada: the potential, the politics and the
      propaganda.

PMID- 10345286
TI  - Public/private partnerships in Australia.

PMID- 10345287
TI  - Public and private places in Canadian healthcare.

PMID- 10345288
TI  - Healthcare institution partnerships--the ethical perspective.

PMID- 10345289
TI  - Disaster planning: St. Boniface General Hospital. A case study of the flood of
      the century.

PMID- 10345290
TI  - Anatomy of a partnership inside the Toronto Medical Labs.

PMID- 10345291
TI  - Triage through technology: New Brunswick Tele-Care service reduces ER visits.

PMID- 10345292
TI  - Policy group on health reform.
AB  - Clearly, the building blocks are in place for true reform of the healthcare
      system. Leadership and political fortitude will be needed to direct the reform
      process and remove existing obstacles. It is the intention of the Policy Group on
      Health Reform to continue to develop and articulate new thinking and act as a
      catalyst for implementing solutions, respecting health reform.

PMID- 10345294
TI  - Who is accountable for the well-being of the patient? Analysis by a focused group
      of experts.

PMID- 10345293
TI  - Rural emergencies: Saskatchewan volunteers make minutes count.

PMID- 10345295
TI  - Managing change: ten learning tips from a CIBC restructuring initiative.

PMID- 10345296
TI  - Health research Web sites.

PMID- 10345297
TI  - Public and private partnerships: exploring the use of shared resources.

PMID- 10345298
TI  - Quarterly index. Utilization review key factor in promoting appropriate service.

PMID- 10345299
TI  - Consumer perspectives on healthcare reform.

PMID- 10345300
TI  - Forging a partnership in information systems. The case of Vancouver Hospital.

PMID- 10345302
TI  - Ethics of resource allocation: dimensions for healthcare executives.

PMID- 10345301
TI  - Brave new world: banks and hospitals working together.

PMID- 10345303
TI  - Private financing of healthcare projects in the United Kingdom.

PMID- 10345304
TI  - Striking the deal: legal considerations on structuring shared-service
      arrangements.

PMID- 10345305
TI  - Disposition of hospital assets: the legal issues.

PMID- 10345306
TI  - Philanthropy: a key ingredient of institutional change.

PMID- 10345307
TI  - Process not litigation: dealing with physician incompetence and impairment in a
      hospital.

PMID- 10345308
TI  - Investment in information technology: the dilemma of comparing costs to benefits.

PMID- 10345309
TI  - Acquisition of an electronic patient record system.

PMID- 10345310
TI  - The balanced scorecard solution at Peel Memorial Hospital.

PMID- 10345311
TI  - Hospitals and the year 2000: a legal perspective.

PMID- 10345312
TI  - Healthcare in rural Nova Scotia improves with support for physicians.

PMID- 10345313
TI  - Healthcare economics vs. economics of healthcare.

PMID- 10345314
TI  - Knowledge is care: without information we have neither.

PMID- 10345315
TI  - Quarterly index. Impact of age and gender on use of acute care hospitals.

PMID- 10345316
TI  - Evidence-based medicine in Canada: "Its time has come".

PMID- 10345317
TI  - Disease management: what does it mean for health system integration?

PMID- 10345318
TI  - Tuberculosis: an inter-sectoral disease-management approach.

PMID- 10345319
TI  - Shaping the healthcare environment through evidence-based medicine: a case study
      of the ICONS project.

PMID- 10345320
TI  - Improving women's health quality: the value of closing the care gap.

PMID- 10345321
TI  - Women's health: the impetus for emerging models of healthcare.

PMID- 10345322
TI  - Lessons in crisis management and ... the forging of an alliance. Notes from an
      interview with Jane Pepino, Chair, Women's College Hospital. Interview by W.
      Anton Hart.

PMID- 10345323
TI  - Private money for public hospitals.

PMID- 10345324
TI  - A status report on hospital restructuring in Ontario.

PMID- 10345325
TI  - The road to change and transition: resizing, reinvestment and restructuring in
      Ontario's health system.

PMID- 10345326
TI  - Top choices for evidence-based Web sites.

PMID- 10345327
TI  - Quarterly index. Discharge planning varies by hospital type.

PMID- 10345328
TI  - Boost physician productivity with performance data.

PMID- 10345329
TI  - Health system mines financial data to unearth clinical conclusions, improvements.
AB  - Making clinical conclusions from your financial data. Using artificial
      intelligence to provide cleaner and less biased data, Sentara Health System in
      Norfolk, VA, has changed the way care is delivered for 25 top inpatient and
      outpatient conditions and procedures--and saved $4 million in the last three
      years as a direct result. Here's a look at how Sentara is mining clinical
      information from financial data.

PMID- 10345331
TI  - Small physician practice tracks outcomes of diabetes care, revamps based on
      results.
AB  - When your data finds patient outcomes don't justify program expense. Princeton
      Medical Group in San Antonio tracked the outcomes of its diabetes patients and
      determined that an expensive case management program wasn't worth the cost.
      Here's how the group practice measured care and costs, and what physicians are
      doing now to revamp the program to make it more effective.

PMID- 10345330
TI  - Concurrent coding provides more accurate data for outcomes and performance
      reports.
AB  - Preventing GIGO with concurrent, accurate coding. With so much riding on the
      accuracy of claims data, including outcomes and performance ratings, more should
      be done to improve the process of gathering this all-important information.
      That's the case at the University of Washington Medical Center, where coders
      actually work on the patient care floors, coding concurrently, interacting with
      physicians, and actually observing patients' treatment. Here's how the program
      works.

PMID- 10345332
TI  - Utilization rates vary based on HMO ownership, finds study of comparative
      hospital data.
AB  - Data Library: This month's column takes a look at utilization rates at hospitals
      that own HMOs vs. those that don't--and you might be surprised by the findings.
      Those hospitals that don't own HMOs have consistently lower utilization rates for
      inpatient and outpatient services. Here are the actual numbers.

PMID- 10345333
TI  - Data-driven effort standardizes low back pain outcomes.

PMID- 10345335
TI  - Clinical performance measures focus on process steps.
AB  - Performance measures go beyond mortality and cost: Using process steps as
      performance measures allows providers to easily determine where action needs to
      be taken to improve quality. One consultant has developed a list of 37
      performance measures in nine disease categories and tracks performance using a
      software program. Here are the details, plus some disease-specific benchmarks.

PMID- 10345334
TI  - CHF disease management program slashes LOS, costs with innovative tracking,
      analysis.
AB  - Tracking care across the continuum for congestive heart failure patients:
      Evanston/Northwestern Healthcare's provider-driven disease management program for
      CHF patients crosses the boundaries of inpatient, outpatient, and home care. But
      that requires the savvy manipulation of data to ensure patients are tracked
      efficiently and resources are used appropriately. Here's how the program works.

PMID- 10345336
TI  - Scrutinizing data helps team target high-cost DRGs, improve costly tracheostomy
      care.
AB  - Targeting high-cost DRGs using data collection, analysis: A hospital team
      analyzed DRGs with the highest excess charges and found DRG 483 (tracheostomy)
      had astronomical charges. Here's the step-by-step story of how they analyzed
      individual physician resource utilization, care progression through the hospital,
      and admission source to identify areas for clinical improvement, plus their
      findings and how they're putting them to use to improve care and reduce costs.

PMID- 10345337
TI  - Impact of managed care varies by payer and region.
AB  - Data Library: What effect will managed care penetration have in your area of the
      country? Fewer patient days, fewer beds, fewer discharges? What toll will managed
      Medicare and Medicaid take? This month's column looks at projections on the
      effects of managed care on inpatient utilization by payer and by region. Some
      areas of the country might be alarmed by the numbers.

PMID- 10345338
TI  - Health system takes outcomes data to new levels.

PMID- 10345339
TI  - NICU care redesigned using outcomes chain approach to analyzing, using data.
AB  - Outcomes chain in practice: Hospital saves an astounding $90,000 in costs per
      preterm CV patient. When researchers at an IHC hospital found they could change
      the way preterm babies are ventilated and avoid the lung injuries caused by
      conventional ventilation, they drilled down into the process of caring for these
      patients and found hundreds of other opportunities for change. Mini-teams handled
      individual processes, flow-charting them, asking how and why at each step,
      gathering data, making changes, and measuring outcomes.

PMID- 10345340
TI  - Network's cardiology data help member groups benchmark performance, market
      services.
AB  - Data-driven cardiac network improves outcomes, reduces costs. Thirty-seven high
      volume network member hospitals are using detailed demographic, procedure, and
      outcomes data in benchmarking and marketing efforts, and network physicians are
      using the aggregate data on 120,000 angioplasty and bypass procedures in research
      studies. Here are the details, plus sample reports.

PMID- 10345341
TI  - Hospital outpatient surgery cost, reimbursement, and utilization data find
      Medicare a loser.
AB  - Data Library: Outpatient surgery costs, reimbursement, and utilization
      benchmarks. This new CHIPS survey finds providers consistently lose money for 56
      outpatient procedures under Medicare. The only winners are those in high managed
      care areas and high-volume facilities. The data offer some valuable benchmarks by
      geographic area, managed care penetration, as well as age and sex.

PMID- 10345342
TI  - Don't rely on MCOs--take systems approach to physician practice data collection.
AB  - Physician practices can thrive under capitation with proper data collection.
      Practices should take a systems approach to managing the financial, operations,
      and clinical aspects of their businesses--and this requires data. While some of
      it may be acquired from MCOs, most physicians will have to rely on IPAs or PHOs
      to do the dirty work. Here's a laundry list of data to collect, plus report
      templates.

PMID- 10345343
TI  - Overcome info overload to improve decision-making.

PMID- 10345344
TI  - Use cost data to make 'go/no-go' managed care contract decisions.
AB  - Just say no to MCO?: An Arizona specialty physician group did, after carefully
      reviewing its costs to deliver care and determining the MCO's contract terms
      could lead to financial ruin. Making the "go/no-go" decision on managed care
      contracts can't possibly be made without reliable data on your organization's
      costs to deliver care. Here's how this 23-physician group evaluates contracts.

PMID- 10345345
TI  - Are you getting the right data to track your risk contracts?
AB  - Are you collecting the right data? Your organization may be collecting claims
      payment profiles, stop loss and recovery reports, financial statements, activity
      reports, and reconciliation reports ... but are you sure you're collecting and
      presenting the right data to encourage improvement in clinical practice? Here's
      point-by-point advice, plus laundry lists of essential data reports and some
      benchmark data.

PMID- 10345346
TI  - Use these LOS and cost data for top DRGs and procedures at community hospitals.

PMID- 10345347
TI  - Available to commercial market, government 'secret' software integrates 70 health
      applications.
AB  - Government's secret weapon is yours for just $25! The Department of Veterans
      Affairs VISTA software system could be the answer to less expensive systems
      integration for many health care organizations. That's what a Georgia hospital
      has found since installing the core of the software, including the surgery module
      that tracks a variety of data and outputs nine different types of reports. Here
      are the details on the product, and how you can order it.

PMID- 10345348
TI  - Electronic clinical logic revamps medical management.

PMID- 10345349
TI  - Study provides LOS benchmark data on 57 conditions, by ICD-9 and DRG codes.
AB  - Data Library: Length-of-stay benchmarks by ICD-9, DRG codes, managed care vs.
      FFS. A new study comparing thousands of discharges within 57 different categories
      shows HMO lengths of stay similar to FFS. The data come from practicing surgeons'
      opinions and guidelines from actuarial firm Milliman & Robertson. See how your
      rates compare.

PMID- 10345350
TI  - One-page profile shows physicians how practice patterns stack up against
      standards.
AB  - Save millions by profiling clinical guideline compliance, not cost and
      utilization data? United HealthCare has switched its focus from physician cost
      and utilization reports to clinical profiles that chart compliance with
      guidelines in six common conditions. Here's the story, plus a sample profile
      showing how a physician stacks up to peers and nationally accepted standards in
      particular areas of care.

PMID- 10345351
TI  - Data from ED patient tracking system help identify X-ray cycle time improvements.
AB  - Innovative use of data enables ED to reduce X-ray cycle time, improve patient
      satisfaction. Here are the details of how a large urban hospital tapped its
      patient tracking system to identify operational problems that were jeopardizing
      patient satisfaction. The result: a revamped X-ray process that cuts cycle time
      by more than half, shorter LOS for all ED patients, and greater ED capacity.

PMID- 10345352
TI  - Apply APGs to claims data to calculate impact of new reimbursement levels.
AB  - How are changes in outpatient reimbursement going to affect your bottom line? By
      analyzing Medicare's proposed APGs' effects on your past claims data, you can
      determine where to hone in on improving coding skills, making process changes to
      bring costs in line, or even touting specific services that will be profitable.
      Here's expert advice, plus benchmark data on APG impacts.

PMID- 10345353
TI  - Data drives hefty reductions in cost of materials.

PMID- 10345354
TI  - Analyzing functional status data helps hospital improve knee and hip
      replacements.
AB  - Collect and interpret functional status data to improve patient care. A Florida
      hospital tracks patients' functional status for a year after hip and knee surgery
      to analyze the effectiveness of the surgery and change clinical pathways when
      needed. Project leaders overcame low survey return rates and difficulty in
      segmenting patient populations to allow physicians to compare like patients.

PMID- 10345355
TI  - Understand consumers' attitudes about health care to promote healthier patient
      lifestyles.
AB  - Data Library: Engagement is a key strategy to retain consumers and promote
      healthier lifestyles. When providers engage consumers through services and
      testing, they increase both satisfaction and loyalty. The data included here show
      which population groups are using preventive tests and services and reveal the
      attitudes toward health care of healthy and unhealthy groups.

PMID- 10345356
TI  - Charges and LOS for deliveries vary widely by geographic region, analysis
      concludes.
AB  - How do your numbers compare? The second part of the Data Library features LOS and
      geographic hospital and physician charges for uncomplicated vaginal births,
      cesarean births, and vaginal births after previous cesarean deliveries.

PMID- 10345357
TI  - Publicly reported data impacts administrative procedures, contracting decisions.
AB  - Publicly reported data can positively impact cost and quality of care--especially
      when hospitals use the data to improve their administrative procedures. After
      reading published data on the cost, mortality, and length of stay related to
      coronary artery bypass graft surgery at 44 Pennsylvania hospitals, 77% of
      hospital CEOs responding to a survey said they used the data to make
      institutional decisions.

PMID- 10345358
TI  - Provider revamps data program through integration.

PMID- 10345359
TI  - Center's pain management program revamped thanks to data analysis, tracking.
AB  - Take control of costly pain management using a data-driven approach. A QI team at
      this Wisconsin hospital identified best practices in pain management, then set
      out to revamp the facility's pain management policy. Here are the details, plus
      actual forms used and some interesting pain treatment benchmarks from 16
      facilities.

PMID- 10345360
TI  - Adjust utilization for case mix and make physicians responsible for remaining
      variation.
AB  - "But my patients are sicker!" Health Source/CIGNA put a stop to this physician
      complaint by switching to quarterly physician profiles that are case mix adjusted
      using clinical algorithms based on ICD-9 diagnosis codes. The new method levels
      the playing field, and helps to more accurately identify inefficient use of
      services. A sample physician profile is included in this report.

PMID- 10345361
TI  - Study provides admission, payment data for academic vs. non-academic providers.
AB  - Data Library: Admissions and cost data. This month's column looks at a Medstat
      study on the use of academic facilities and costs per admission compared to non
      academic providers--under both managed care and fee-for-service scenarios and
      comparing national figures with those of highly penetrated managed care areas of
      the country.

PMID- 10345362
TI  - Study finds purchasers aren't using providers' outcomes data, quality report
      cards.
AB  - Are your data collection efforts for naught? A recent study shows that employers
      and purchasers overlook provider outcomes data and quality report cards when
      choosing health plans and providers--opting instead for customer satisfaction,
      HEDIS, and cost data. Here are the details on the study, plus advice from one of
      the study's authors.

PMID- 10345363
TI  - Improve disease management efforts with best data.

PMID- 10345364
TI  - Health system creates brand identity with clinical paths, outcomes data, report
      cards.
AB  - Using data to woo consumers: A four-hospital system in southern California is
      aggressively capturing and touting systemwide data in an effort to directly reach
      consumers with the message that health care is of consistently high quality
      across the system. A systemwide report card doesn't even break the data out by
      hospital but instead is an attempt to "brand" health care. Here's the story, plus
      some unique data charts from the consumer report card.

PMID- 10345365
TI  - Stroke and TIA charges, LOS show wide geographic variation.
AB  - Data Library: How do your rates compare? This month's column features geographic
      hospital and physician charge and LOS data for high-cost stroke and T/A patients,
      which vary as much as 159% between states.

PMID- 10345366
TI  - Don't let data become too much of a good thing in clinical path, outcomes
      tracking efforts.
AB  - Too much of a good thing? Are you collecting too much data? At University of Iowa
      Hospitals and Clinics, caregivers were tracking every variance to every item on
      every clinical pathway. It was just too much work, and the reports weren't even
      useful. A new variance tracking system includes targeting three to 10 key events
      for each pathway and has resulted in greater tracking compliance and data
      accuracy.

PMID- 10345367
TI  - Detailed hospital utilization, cost data now available on the Web.

PMID- 10345368
TI  - Improve performance by giving employees data tools.

PMID- 10345369
TI  - Spider diagram helps hospital cut the fat using clinical quality and patient
      satisfaction data.
AB  - A balancing act: When it became apparent that a 900-bed hospital in Detroit
      needed to cut costs to stay viable, leaders decided making across-the-board cuts
      would be as dangerous as making no cuts. Instead, they began measuring four
      different types of indicators on a new service-line basis using a spider diagram
      to ensure they were balancing the needs of administration, physicians, patients,
      and the community.

PMID- 10345371
TI  - Use these data to compare mortality rates by patient volume.
AB  - Data Library: In this era of provider accountability, tracking mortality rates is
      as important as ever. This month's study offers some good benchmarks on mortality
      rates by orthopedic DRG and patient volume.

PMID- 10345370
TI  - Providers: hold yourself accountable before payers, others do it for you.
AB  - Financial performance data: Drilling down into comparative data can help health
      care providers quickly identify where costs are out of line. See samples of easy
      to-read graphs you can adopt for your organization for everything from broad
      hospital measures to specific physician ordering practices.

PMID- 10345372
TI  - Outcomes tracking prototype follows OB patients from conception to postpartum.
AB  - Tracking outcomes across the continuum of care: A pilot OB/Neonatology computer
      system prepares a large health care network for developing a comprehensive
      automated outcomes management program. The system tracks prenatal, inpatient, and
      postpartum outcomes, and allows clinicians to keep an eye on the effects of a new
      23-hour normal vaginal delivery LOS and an accompanying home health program.

PMID- 10345373
TI  - Case management revamped with new data program.

PMID- 10345374
TI  - Real-time data, aggressive intervention slash diabetes costs and increase
      satisfaction.
AB  - Improve your disease management programs with real-time tracking of clinical
      data: With care managers and physician service coordinators in the field
      interacting with patients and physicians and using a computer program to track
      every type of data imaginable, patients don't fall through the cracks of this
      comprehensive diabetes disease management program. Collecting, processing,
      analyzing, and interpreting data in real-time are essential to making your
      disease management programs work. Here's why, plus details on how this program
      operates--and some good cost and outcomes benchmarks.

PMID- 10345375
TI  - Data-based pharmacy utilization review identifies those at-risk, improves care,
      cuts utilization.
AB  - Track pharmacy utilization to improve care, reduce costs: This New Jersey HMO's
      data-driven pharmacy utilization program flags problem cases and gets high-risk
      patients into case management and disease management programs. See how the system
      works and which key indicators alert officials to potential pharmacy problems.
      Plus, a sample report from an actual member pharmacy profile.

PMID- 10345376
TI  - Study provides regional comparisons of utilization data.
AB  - Data Library: Nationwide trends show hospital acute care capacity and utilization
      still on the decline. With shorter lengths of stay and medical advances,
      hospitals are downsizing by cutting the number of beds in service. This month's
      column shows exactly how many beds have been cut and in which parts of the
      country. Use these data to compare your organization's discharge numbers,
      occupancy rates, and average lengths of stay by region and nationally.

PMID- 10345377
TI  - Cut costs, improve services without offending physicians.

PMID- 10345378
TI  - Data-driven QI effort helps hospital adhere to restraint compliance standards.
AB  - Using data to meet regulatory and internal standards: Here's an excellent case
      study of a New Jersey hospital that developed an effective and efficient tracking
      mechanism to improve patient restraint compliance. The result? Restraint use fell
      dramatically and administrators learned the real reasons why nurses changed their
      restraint-use behavior. Here are all the tools and tips you'll need to adopt the
      same kind of program at your facility.

PMID- 10345379
TI  - Regional data on low back pain point to improvement potential.
AB  - Data Library: Benchmark your organization's treatment of low back pain. There's
      wide variation in specialty provider use, utilization of services, and costs of
      this high-volume medical problem--despite federal guidelines stipulating
      treatment recommendations. These data are broken out by specialty and on a
      regional basis.

PMID- 10345380
TI  - Tracking long-term functional outcomes helps refine inpatient care, post
      discharge support.
AB  - Taking patient satisfaction one step further: Are your patients happy six months
      or a year down the road? Did their surgery or medical treatment improve their
      quality of life? MCOs will want to know. Here's how one hospital tracks
      functional status outcomes and makes use of the data to improve inpatient and
      post-discharge care.

PMID- 10345381
TI  - How do your organization's IT capabilities, goals compare to health industry
      trends?
AB  - How does your organization's IT capabilities and goals measure up to industry
      trends? A recent survey provides an interesting snapshot of information
      technology at health care organizations. See if your organization is up to
      standard--or behind the curve.

PMID- 10345382
TI  - Hospital lets physician numbers do the talking.

PMID- 10345383
TI  - Tracking key clinical data gets to the heart of program's goal: quality, cost
      effective care.
AB  - Using data to demonstrate program's strong selling points: better care at lower
      costs. Vanderbilt University Medical Center's heart failure program tracks
      patient clinical data, as well as data on hospitalization rates and satisfaction
      of the population as a whole. The program's success, as well as its wealth of
      data on patients' severity of illness, should provide an edge in negotiations
      with managed care companies.

PMID- 10345384
TI  - Diabetes and asthma costs, utilization calculated for entire episodes of
      treatment.
AB  - Data Library: Diabetes and asthma national and regional benchmarks. Treating
      diabetes and asthma requires a combination of inpatient, outpatient, physician,
      and pharmaceutical services. This month's column looks at costs and utilization
      by episodes of these illnesses as a whole, providing a clearer picture of the
      balance between different types of services in overall treatment of these
      diseases.

PMID- 10345385
TI  - Health plan finds answers with data warehouse that stores 4,500 data elements.
AB  - A gold mine of information, not just for computer geeks: Pardon the stereotype,
      but managers of health care have also stereotyped the data warehouse--as more of
      an unwieldy behemoth. But at Blue Cross/Blue Shield of Tennessee, more than 200
      users log on regularly. Quality management, HEDIS reporting, managed care
      contracting, provider profiling, utilization management, product management, and
      forecasting all have been made easier with this tool that allows operational data
      to become a gold mine of information.

PMID- 10345386
TI  - More health care organizations collecting data, but exactly what?
AB  - Is your organization collecting the right information? A new study of the
      industry finds tracking costs, utilization of services, and member satisfaction
      at the top of most organizations' lists. Here are the details of what's hot,
      what's not.

PMID- 10345387
TI  - Organizing for empowerment: an interview with AES's Roger Sant and Dennis Bakke.
      Interview by Suzy Wetlaufer.
AB  - The topic of empowerment is receiving a lot of attention, but how many employees
      are truly empowered? At the global electricity giant AES Corporation, the answer
      is all 40,000 of them. In this interview, chairman Roger Sant and CEO Dennis
      Bakke reflect on their trials and triumphs in creating an exceptional company and
      explain how their employee-run company works. When they founded AES in 1981, Sant
      and Bakke set out to create a company where people could have engaging
      experiences on a daily basis--a company that embodied the principles of fairness,
      integrity, social responsibility, and fun. Putting those principles into action
      has created something unique--an ecosystem of real empowerment. What does that
      system look like? Rather than having a traditional hierarchical chain of command,
      AES is organized around small teams that are responsible for operations and
      maintenance. Moreover, AES has eliminated functional departments; there's no
      corporate marketing division or human resources department. For the system to
      work, every person must become a well-rounded generalist--a mini-CEO. That, in
      turn, redefines the jobs of the people at headquarters. Instead of setting
      strategy and making the "the big decisions," Sant and Bakke act as advisers,
      guardians of the principles, accountability officers, and chief encouragers. Can
      other companies successfully adopt the mechanics of such a system? Not unless
      they first adopt the shared principles that have guided AES since its inception.
      "Empowerment without values isn't empowerment," says Sant. "It's just technique,"
      adds Bakke.

PMID- 10345390
TI  - Is your company ready for one-to-one marketing?
AB  - One-to-one marketing, also known as relationship marketing, promises to increase
      the value of your customer base by establishing a learning relationship with each
      customer. The customer tells you of some need, and you customize your product or
      service to meet it. Every interaction and modification improves your ability to
      fit your product to the particular customer. Eventually, even if a competitor
      offers the same type of service, your customer won't be able to enjoy the same
      level of convenience without taking the time to teach your competitor the lessons
      your company has already learned. Although the theory behind one-to-one marketing
      is simple, implementation is complex. Too many companies have jumped on the one
      to-one band-wagon without proper preparation--mistakenly understanding it as an
      excuse to badger customers with excessive telemarketing and direct mail
      campaigns. The authors offer practical advice for implementing a one-to-one
      marketing program correctly. They describe four key steps: identifying your
      customers, differentiating among them, interacting with them, and customizing
      your product or service to meet each customer's needs. And they provide
      activities and exercises, to be administered to employees and customers, that
      will help you identify your company's readiness to launch a one-to-one
      initiative. Although some managers dismiss the possibility of one-to-one
      marketing as an unattainable goal, even a modest program can produce substantial
      benefits. This tool kit will help you determine what type of program your company
      can implement now, what you need to do to position your company for a large-scale
      initiative, and how to set priorities.

PMID- 10345389
TI  - A report card on diversity: lessons for business from higher education.
AB  - Institutions of higher learning in the United States have long played a
      disproportionate role in supplying leadership talent to the world's business and
      professional organizations. For 30 years, the most selective schools have been
      working to increase diversity in their student bodies. New research by the former
      presidents of Princeton and Harvard suggests that the experiences and initiatives
      of these academic institutions can provide business leaders with insight into how
      to create diverse organizations that succeed. The first insight has to do with
      clarity of mission. It is not enough to pursue diversity because it is "the right
      thing to do." In an insert, Raymond Gilmartin, the CEO of Merck, echoes that
      view, discussing the relationship between diversity and Merck's competitiveness.
      The second insight concerns recruiting. The authors challenge what they call "the
      myth of pure merit," the notion that recruiting is a precise science based only
      on grades and test scores. Instead, they argue, merit is about assembling a team
      by deciding which applicants, considered individually and collectively, will
      contribute most to achieving the company's goals. The third insight concerns how
      organizations help employees perform to their potential. Of the factors
      contributing to high graduation rates at the most selective schools, higher
      expectations and the efforts of mentors stand out as most important. Finally, the
      fourth insight is about how to achieve accountability in a corporate setting.
      Boards must ask: Are our recruiting policies working? and How are recruited
      employees doing?

PMID- 10345388
TI  - The new landscape for nonprofits.
AB  - For most of this century, society's caring functions have been the work of
      government and charities. But social services in the United States are in a
      period of transition. Today the U.S. government no longer considers nonprofits to
      be entitled--or even best qualified--to provide social services. Profit-seeking
      companies like Lockheed Martin are now winning contracts for such services.
      William Ryan describes how government outsourcing and a new business mind-set
      have changed the landscape of social services. The change raises fundamental
      questions about the mission and future of nonprofits. Ryan attributes the growth
      of for-profits in the social service industry to four factors: size, capital,
      mobility, and responsiveness. While those attributes give for-profits an
      advantage in acquiring new contracts, nonprofits have not yet lost their
      foothold. Ryan cites examples of organizations like the YWCA and Abraxas to
      demonstrate various ways that nonprofits are responding--from subcontracting to
      partnership to outright conversion to for-profit status. By playing in the new
      marketplace, nonprofits will be forced to reconfigure their operations and
      organizations in ways that could compromise their missions. Because nonprofits
      now find themselves sharing territory with for-profits, sometimes as
      collaborators and sometimes as competitors, the distinctions between these
      organizations will continue to blur. The point, Ryan argues, is not whether
      nonprofits can survive opposition from for-profits. Many have already adjusted to
      the new competitive environment. The real issue is whether nonprofits can adapt
      without compromising the qualities that distinguish them from for-profit
      organizations.

PMID- 10345391
TI  - Can this merger be saved?
AB  - In this fictional case study, a merger that looked like a marriage made in heaven
      to those at corporate headquarters is feeling like an infernal union to those on
      the ground. The merger is between Synergon Capital, a U.S. financial-services
      behemoth, and Beauchamp, Becker & Company, a venerable British financial-services
      company with strong profits and an extraordinarily loyal client base of wealthy
      individuals. Beauchamp also boasts a strong group of senior managers led by
      Julian Mansfield, a highly cultured and beloved patriarch who personifies all
      that's good about the company. Synergon isn't accustomed to acquiring such
      companies. It usually encircles a poorly managed turnaround candidate and then,
      once the deal is done, drops a neutron bomb on it, leaving file cabinets and
      contracts but no people. Before acquiring Beauchamp, Synergon's macho men offered
      loud assurances that they would leave the tradition-bound company alone-provided,
      of course, that Beauchamp met the ambitious target numbers and showed sufficient
      enthusiasm for cross-selling Synergon's products to its wealthy clients. In
      charge of making the acquisition work is Nick Cunningham, one of Synergon's more
      thoughtful executives. Nick, who was against the deal from the start, is the face
      and voice of Synergon for Julian Mansfield. And Mansfield, in his restrained way,
      is angry at the constant flow of bureaucratic forms, at the rude demands for
      instant information, at the peremptory changes. He's even dropping broad hints at
      retirement. Nick has already been warned: if Mansfield goes, you go. Six
      commentators advise Nick on how to save his job by bringing peace and prosperity
      to the feuding couple.

PMID- 10345392
TI  - The human moment at work.
AB  - In the last decade or so, technological changes--mainly voice mail and e-mail-
      have made a lot of face-to-face interaction unnecessary. Face-to-face contact has
      also fallen victim to "virtuality"--many people work at home or are otherwise off
      site. Indeed, most people today can't imagine life without such technology and
      the freedom it grants. But Edward Hallowell, a noted psychiatrist who has been
      treating patients with anxiety disorders--many of them business executives--for
      more than 20 years, warns that we are in danger of losing what he calls the human
      moment: an authentic psychological encounter that can happen only when two people
      share the same physical space. And, he believes, we may be about to discover the
      destructive power of its absence. The author relates stories of business-people
      who have dealt firsthand with the misunderstandings caused by an overreliance on
      technology. An e-mail message is misconstrued. Someone forwards a voice-mail
      message to the wrong people. A person takes offense because he was not included
      on a certain circulation list. Was it an accident? Often the consequences of such
      misunderstandings, taken individually, are minor. Over time, however, they take a
      larger toll--both on individuals and on the organizations they work for. The
      problem, however, is not insoluble. The author cites examples of people who have
      worked successfully to restore face-to-face contact in their organizations. The
      bottom line is that the strategic use of the human moment adds color to our lives
      and helps us build confidence and trust at work. We ignore it at our peril.

PMID- 10345393
TI  - Judo strategy. The competitive dynamics of Internet time.
AB  - Competition on the Internet is creating fierce battles between industry giants
      and small-scale start-ups. Smart start-ups can avoid those conflicts by moving
      quickly to uncontested ground and, when that's no longer possible, turning
      dominant players' strengths against them. The authors call this competitive
      approach judo strategy. They use the Netscape-Microsoft battles to illustrate the
      three main principles of judo strategy: rapid movement, flexibility, and
      leverage. In the early part of the browser wars, for instance, Netscape applied
      the principle of rapid movement by being the first company to offer a free stand
      alone browser. This allowed Netscape to build market share fast and to set the
      market standard. Flexibility became a critical factor later in the browser wars.
      In December 1995, when Microsoft announced that it would "embrace and extend"
      competitors' Internet successes, Netscape failed to give way in the face of
      superior strength. Instead it squared off against Microsoft and even turned down
      numerous opportunities to craft deep partnerships with other companies. The
      result was that Netscape lost deal after deal when competing with Microsoft for
      common distribution channels. Netscape applied the principle of leverage by using
      Microsoft's strengths against it. Taking advantage of Microsoft's determination
      to convert the world to Windows or Windows NT, Netscape made its software
      compatible with existing UNIX systems. While it is true that these principles
      can't replace basic execution, say the authors, without speed, flexibility, and
      leverage, very few companies can compete successfully on Internet time.

PMID- 10345395
TI  - Health services technology: Part 1, Policy and managerial considerations.

PMID- 10345394
TI  - Creating new market space.
AB  - Most companies focus on matching and beating their rivals. As a result, their
      strategies tend to take on similar dimensions. What ensues is head-to-head
      competition based largely on incremental improvements in cost, quality, or both.
      The authors have studied how innovative companies break free from the competitive
      pack by staking out fundamentally new market space--that is, by creating products
      or services for which there are no direct competitors. This path to value
      innovation requires a different competitive mind-set and a systematic way of
      looking for opportunities. Instead of looking within the conventional boundaries
      that define how an industry competes, managers can look methodically across them.
      By so doing, they can find unoccupied territory that represents real value
      innovation. Rather than looking at competitors within their own industry, for
      example, managers can ask why customers make the trade-off between substitute
      products or services. Home Depot, for example, looked across the substitutes
      serving home improvement needs. Intuit looked across the substitutes available to
      individuals managing their personal finances. In both cases, powerful insights
      were derived from looking at familiar data from a new perspective. Similar
      insights can be gleaned by looking across strategic groups within an industry;
      across buyer groups; across complementary product and service offerings; across
      the functional-emotional orientation of an industry; and even across time. To
      help readers explore new market space systematically, the authors developed a
      tool, the value curve, that can be used to represent visually a range of value
      propositions.

PMID- 10345396
TI  - Showdown: the dark side of medical power and academic pandering.

PMID- 10345397
TI  - Case management: formulating a better health equation.

PMID- 10345398
TI  - Effects of supplemental coverage on use of services by Medicare enrollees.
AB  - This article estimates the extent to which private insurance supplements affect
      use of services by Medicare enrollees. Three types of supplements to Medicare's
      coverage are examined--Health Maintenance Organizations (HMOs), medigap (MGP)
      plans, and employment-based indemnity (EBI) plans. While each kind of supplement
      reduces cost sharing on Medicare-covered services, only HMOs do so without
      increasing enrollees' overall use of services. Use of services by HMO enrollees
      is about 4 percent lower than use by similar Medicare enrollees with no insurance
      supplement. By contrast, use of services by enrollees with MGP coverage is 28
      percent higher, and use of services by enrollees with EBI plans is 17 percent
      higher.

PMID- 10345399
TI  - Patient centered long-term care.
AB  - Drawing upon an individual's needs, values, and expectations to guide
      decisionmaking and care giving is integral to long-term care (LTC). Articles in
      this issue demonstrate that client values and preferences can be elicited and
      used to guide decisionmaking about LTC. Service delivery and payment features can
      be shaped to support the patient/consumer, as well as to support and strengthen
      her or his informal caregivers. Significant constraints to making LTC more client
      centered are also identified. Key issues relate to the availability of and
      methods to process information as well as pressures on provider staff that impede
      their ability to support clients and their families. More broadly, access to
      appropriate LTC services is being shaped by programmatic shifts and legal forces
      that may enhance or impede the ability to place patients/clients at the center of
      LTC.

PMID- 10345400
TI  - Consumer and professional ratings of the importance of functional status
      components.
AB  - As the population ages and chronic disease becomes the more dominant form of
      illness, measures of functional loss and disability assume greater importance in
      the assessment of both quality of life and the cost-effectiveness of care. The
      authors studied the responses of consumers and health care professionals
      regarding the impact on dependency of various levels of disability. Striking
      differences in perception were noted, raising concerns about the ability of those
      providing care to assume that the recipients share their values about what is
      important. This study makes clear the need for more research on functional
      outcome measurements that incorporate the values of consumers.

PMID- 10345401
TI  - Utilization of services in Arizona's capitated Medicaid program for long-term
      care beneficiaries.
AB  - The Arizona Long-Term Care System (ALTCS), Arizona's Medicaid program for long
      term care (LTC) beneficiaries, capitates contractors to provide a full range of
      acute and LTC services to financially-eligible beneficiaries determined to be at
      risk of institutionalization. This article compares the acute care utilization
      experience of LTC beneficiaries in ALTCS with those in a fee-for-service (FFS)
      Medicaid program, linking data from both the Medicare and the Medicaid program
      files. Patterns of use observed in Arizona seem more consistent with a managed
      care environment than those observed in the FFS comparison. Rates of acute care
      utilization observed for both the capitated and the FFS program should be of
      interest to States considering incorporating LTC beneficiaries into their
      Medicaid managed care program.

PMID- 10345402
TI  - Determinants of enrollment among applicants to PACE.
AB  - During the 1970s and 1980s, a new approach to the integration of acute and long
      term care (LTC) services was conceived and refined at On Lok, an organization in
      the Chinese community of San Francisco. Since then, On Lok and 10 Federal
      demonstration sites have tested this model which is today called the Program of
      All-Inclusive Care for the Elderly (PACE). This program has gained considerable
      political support and as a result, the 1997 Balanced Budget Agreement establishes
      PACE as a permanent provider under Medicare. The Federal demonstration of PACE
      was designed as a voluntary program. By exploiting its voluntary enrollment
      design, this study analyzes the determinants of program participation within a
      group of screened applicants. Findings of this study support the theory that the
      capitated payment structure of PACE creates incentives for program staff to avoid
      costly individuals. However, home ownership and provider attachment also act as
      important and significant barriers to enrollment.

PMID- 10345403
TI  - Medicare beneficiaries' attitudes about seeking health care: 1996.

PMID- 10345404
TI  - Hospital, employment, and price indicators for the health care industry: second
      quarter 1997.

PMID- 10345405
TI  - Beneficiary centered care in services to persons with developmental disabilities.
AB  - This article provides an overview of the findings from the Evaluation of
      Medicaid's Community Supported Living Arrangements (CSLA) Program. Results
      suggest that CSLA provided a useful model of beneficiary centered care for
      persons with developmental disabilities. The implications of the findings of this
      evaluation for current management of Medicaid programs are discussed.

PMID- 10345407
TI  - Determining consumer preferences for a cash option: Arkansas survey results.
AB  - As long-term care (LTC) expenditures have risen, policymakers have sought ways to
      control costs while maintaining consumer satisfaction. Concurrently, there is
      increasing interest within the aging and disability communities in consumer
      directed care. The Cash and Counseling Demonstration and Evaluation (CCDE) seeks
      to increase consumer direction and control costs by offering a cash allowance and
      information services to persons with disabilities, enabling them to purchase
      needed assistance. The authors present results from a telephone survey conducted
      to assess consumer preferences for a cash option in Arkansas and describe how
      findings from the four-State CCDE can inform consumer information efforts and
      policymakers.

PMID- 10345409
TI  - Barriers to physician care for Medicare beneficiaries.

PMID- 10345408
TI  - Caregiver supports: outcomes from the Medicare Alzheimer's disease demonstration.
AB  - A randomized 3-year study assessed the effect of expanded community-based
      services and case management on 5,254 caregivers of dementia clients. A tested
      policy concern was whether the financing of formal care would result in a
      reduction of informal assistance. Unmet needs task assistance for the
      demonstration's treatment group caregivers decreased by 30 percent within 6
      months and by about 20 percent over 36 months relative to controls. While
      treatment group members used slightly more formal care over time, there were no
      differences between treatment and control groups in primary caregiver hours after
      36 months, or in the number of tasks in which primary or secondary caregivers
      provided assistance.

PMID- 10345406
TI  - Improving hospital discharge planning for elderly patients.
AB  - Hospital discharge planning has become increasingly important in an era of
      prospective payment and managed care. Given the changes in tasks, decisions, and
      environments involved, it is important to identify how to move such planning from
      an art to an empirically based decisionmaking process. The authors use a decision
      sciences framework to review the state-of-the-art of hospital discharge planning
      and to suggest methods for improvement.

PMID- 10345410
TI  - Hospital, employment, and price indicators for the health care industry: third
      quarter 1997.

PMID- 10345411
TI  - Profile of Medicare beneficiaries with AIDS: application of an AIDS casefinding
      algorithm.
AB  - This profile of Medicare beneficiaries with acquired immunodeficiency syndrome
      (AIDS) was developed by applying a casefinding algorithm to virtually all
      Medicare claims from 1991-93. The algorithm identified more than 37,000
      beneficiaries with AIDS, approximately 21,000 of whom were living at the end of
      1993. These estimates suggest that as many as 12 percent of people living with
      AIDS at the end of 1993 were covered by Medicare. Medicare expenditures for these
      beneficiaries averaged more than $2,400 per month and totaled more than $500
      million in 1993. These expenditures are likely to rise as more people with AIDS
      live long enough to qualify for Medicare coverage.

PMID- 10345412
TI  - State implementation of the AIDS drug assistance programs.
AB  - Acquired immunodeficiency syndrome (AIDS) drug assistance programs (ADAPs)
      provide access to medications for people who lack other health coverage. In this
      article, the authors present the results of a 1997 survey identifying how 48
      States implemented ADAPs, focusing on the number of beneficiaries, medical and
      financial eligibility criteria, the administration of waiting lists, and the
      coverage of drugs including protease inhibitors. Increased funding for ADAPs is
      necessary to maintain this important part of the public sector safety net for
      human immunodeficiency virus (HIV) care.

PMID- 10345413
TI  - Cost and financing of care for persons with HIV disease: an overview.
AB  - This article explores the impact of new combination drug therapies on the cost
      and financing of human immunodeficiency virus (HIV) disease. Evidence indicates
      that the proportion of costs attributable to drugs has increased significantly
      since the diffusion of new combination drug therapies, and that the proportion of
      costs attributable to hospital inpatient care has decreased. The absence of
      timely data is the major difficulty in analyzing the impact of recent changes.
      Only two studies have examined costs since the diffusion of new combination drug
      therapies, and there are no recent studies of the insurance status of persons
      with HIV disease.

PMID- 10345414
TI  - Health-based payment for HIV/AIDS in Medicaid managed care programs.
AB  - In recent years, State Medicaid programs have begun adopting health-based payment
      systems to help ensure quality care for people living with human immunodeficiency
      virus (HIV) and acquired immunodeficiency syndrome (AIDS), and to ensure equity
      for the managed care organizations (MCOs) in which these people are enrolled. In
      this article, the authors discuss reasons why such payment systems are needed and
      describe AIDS-specific capitation rates that have been adopted in several State
      Medicaid waiver programs. The authors also examine comprehensive risk-adjustment
      systems both within Medicaid and outside the program. Several research questions
      needing further work are discussed.

PMID- 10345415
TI  - Stability of disability among PACE enrollees: financial and programmatic
      implications.
AB  - This article examines the experience of the first 11 Program of All-inclusive
      Care for the Elderly (PACE) programs. It investigates changes in functional
      status of participants in relation to length of enrollment in the program and
      individual risk characteristics. Our findings indicate that mature programs
      experience stable disability mix over time, supporting the rationale for the
      current PACE payment method. However, significant differences exist between
      programs, suggesting that payment rates could be more program specific. Analysis
      of the effect of patient characteristics at admission on the likelihood of
      improvement in functional status identified areas for quality improvement. The
      implications of this study have increasing importance in light of the expected
      expansion of PACE to approximately 100 sites by the year 2000.

PMID- 10345416
TI  - Planned Parenthood Golden Gate ... when violence and tragedy began.

PMID- 10345417
TI  - Charges. One for the road.

PMID- 10345418
TI  - Primary care groups. Supra troupers.
AB  - Research in Birmingham involving GPs, the health authority and the local medical
      committee found support for umbrella arrangements for some primary care group
      functions. Clinical governance and strategic city-wide planning emerged as
      particularly suitable for these arrangements. A range of support arrangements are
      likely to emerge as PCGs develop.

PMID- 10345419
TI  - Staff welfare. Counsel business.

PMID- 10345420
TI  - Millennium bug. When the chips are down.

PMID- 10345421
TI  - Joint working. One for the boys.
AB  - An increase in the number of complications following male circumcisions performed
      by non-professionals led to the establishment of a special clinic for religious
      circumcisions. The clinic is jointly funded by health organisations, the local
      authority and the Muslim community. Parents pay 45 pounds for the service, which
      is acceptable to the local Muslim community.

PMID- 10345422
TI  - Primary care. Making their marker.
AB  - The performance indicators currently in use are not reliable for assessing
      individual GPs or identifying poor performers. The practice assessment visit used
      for GP registrars is probably the most objective system. Primary care groups
      boards should consider supplying individual GPs with information on their
      practice in a form which allows them to compare themselves with local colleagues.

PMID- 10345423
TI  - Think or swim. Clinical engineers: are you on a collision course with managed
      care?

PMID- 10345424
TI  - It's easy being green. Need an energy-saving partner? Call the EPA.

PMID- 10345425
TI  - How to limit liability on home health care equipment. Home safe.

PMID- 10345426
TI  - Secondhand woes. FDA rethinking the rules on refurbished devices. What could that
      mean for you?

PMID- 10345428
TI  - Germ warfare! Arm yourself for the next millennium.

PMID- 10345427
TI  - Left in the dust. It could happen--if the ES staff disappeared.

PMID- 10345429
TI  - Making the grade. Train new workers, OSHA says, but how? Check out these case
      studies.

PMID- 10345430
TI  - Dare to compare. Do your operating costs measure up? Check out this database.

PMID- 10345431
TI  - Risk business. Here's how to start up a building maintenance program.

PMID- 10345432
TI  - Infection patrol. Two steps to safety.

PMID- 10345433
TI  - New anti-fraud data bank to start in '99; negotiated rulemaking committee makes
      progress.

PMID- 10345434
TI  - OIG issues provider self-disclosure protocol.

PMID- 10345435
TI  - Overcoming geographic isolation.
AB  - There are a lot of advantages to living in an isolated area, away from the hustle
      and bustle of the big city. We work hard to provide services more commonly
      located in a metropolitan area. There is satisfaction in being self-sufficient
      and able to spread your wings and start a new venture such as an off-campus
      diagnostic center or a courier route. We enjoy certain advantages in this
      environment. Changes in medical care delivery systems get to us slowly, giving us
      time to plan for the impact. Antibiotic-resistant organisms are slower to move in
      and are easier to control. The blood donor population is loyal and at a low risk
      for disease. Community involvement in many activities is easy to find and major
      cultural and sports events are within 1-3 hour's drive in any direction. All
      these factors combine to make our remote facility an attractive, yet challenging
      place to work.

PMID- 10345436
TI  - Mediation: a positive alternative in conflict resolution for clinical
      laboratories.

PMID- 10345437
TI  - Gaining staff support for laboratory outreach.

PMID- 10345438
TI  - A trade in the winds? Two Hawaiian systems enter talks to merge money-losing
      health plans, possibly more.

PMID- 10345439
TI  - IHC tax case could have broad impact.

PMID- 10345440
TI  - Can they talk? Latest AHA-Joint Commission riff centers on communication,
      performance measurement program.

PMID- 10345441
TI  - Hospital report-card model in peril.

PMID- 10345442
TI  - For-profit data defy widespread perceptions.

PMID- 10345443
TI  - Mo. hospitals bag their merger plans.

PMID- 10345444
TI  - Medicare aided hospitals' bottom line.

PMID- 10345445
TI  - Reform bill has one-time allies at odds.

PMID- 10345446
TI  - The AHA gets an 'A' for effort. Insurance-coverage campaign positions hospitals
      well.

PMID- 10345447
TI  - Helping hospitals learn from their mistakes.

PMID- 10345448
TI  - 1999 Trustees of the Year.

PMID- 10345449
TI  - AHA tries marginalizing profit figures.

PMID- 10345450
TI  - Calif. doc groups on the bleeding edge.

PMID- 10345451
TI  - Quality healthcare can be cost-effective.

PMID- 10345452
TI  - 1998 bond sales shatter record.

PMID- 10345453
TI  - High court strikes down 'dumping' standard.

PMID- 10345454
TI  - Another hospital-owned HMO loses big. New Orleans Advantage Health a victim of
      high costs, pricing, management problems.

PMID- 10345455
TI  - Cash-back deal. Premier restructuring to give member hospitals greater share of
      alliance's net income.

PMID- 10345456
TI  - Brown set to take AHA post at confab.

PMID- 10345457
TI  - Taking competition to court. San Francisco's St. Luke's Hospital files antitrust
      suit against cross-town rival California Pacific.

PMID- 10345458
TI  - One hand giveth ... hospital groups find mixed bag in Clinton healthcare agenda.

PMID- 10345459
TI  - Budget Q & A. Clinton healthcare finance advisor Mendelson previews eventful year
      in Washington. Interview by Eric Weissenstein.

PMID- 10345460
TI  - A good shouldn't have died in '74 ... universal healthcare coverage plan.

PMID- 10345461
TI  - Outlook for Washington: unclear. Impeachment clouds chances for a grab bag of
      healthcare reform and provider relief.

PMID- 10345462
TI  - What is Medicare's future? Many wonder if panel's report will result in a grand
      scheme or give dust bunnies a bed.

PMID- 10345463
TI  - Financial pressures downsize deals.

PMID- 10345464
TI  - FHS hooks up with Access Health Group. Calif. HMO will outsource its telephone
      medical advice services to Colo. company.

PMID- 10345465
TI  - Rough flight for fledgling hospital operator.

PMID- 10345466
TI  - RICO presents new way to sue insurers.

PMID- 10345467
TI  - Levin: mergers fell sharply in '98.

PMID- 10345468
TI  - AMA fighting turf war. Association faces challenge to its monopoly on coding
      system for physician services.

PMID- 10345469
TI  - Consolidation backlash. A disillusioned N.H. community calls for the dissolution
      of its merged Optima hospitals.

PMID- 10345470
TI  - Monopoly is for the Benefis of none.

PMID- 10345471
TI  - Texas hospitals riding tall. While hospitals post robust profit margins, HMOs are
      saddled with mounting losses.
AB  - In Texas, they do things differently, and they do things big. Hospitals in the
      Lone Star State have been banding together more often and more effectively than
      elsewhere. Swinging their lassos, they are riding herd on HMOs, enjoying record
      profits and making ever-larger deals.

PMID- 10345472
TI  - Mass. docs to start PSO-like business.

PMID- 10345473
TI  - Kings County, N.Y., avoids dethroning.

PMID- 10345474
TI  - 1999 Health Care Hall of Fame. Helping Medicare become a reality.

PMID- 10345476
TI  - 1999 Health Care Hall of Fame. Nation's first hospital offers a large dose of
      history.

PMID- 10345475
TI  - 1999 Health Care Hall of Fame. Putting problem-solving into action.

PMID- 10345477
TI  - 1999 Health Care Hall of Fame. The visionary who built a better Ford.

PMID- 10345478
TI  - 1999 Health Care Hall of Fame. Past inductees.

PMID- 10345479
TI  - HCFA's Hash: a rare D.C. straight shooter.

PMID- 10345480
TI  - Hospitals cool to payment rate freeze.

PMID- 10345481
TI  - Wash. systems dismantle doc network.

PMID- 10345482
TI  - Practices with the best practices. With many doc groups losing money, MGMA study
      shows what makes a 'better performer'.

PMID- 10345483
TI  - AHA tentatively backs Medicare revision.

PMID- 10345484
TI  - Feds amend their ways with Columbia.

PMID- 10345485
TI  - DOJ advises against "not my job" attitude regarding compliance.

PMID- 10345486
TI  - Should a late claim result in a lost payment?

PMID- 10345487
TI  - Physician fee schedule final rule published, spawns lawsuit.

PMID- 10345488
TI  - Optimizing collection agency performance.

PMID- 10345489
TI  - Long-term care reform loses ground.

PMID- 10345490
TI  - Managing medications under PPS.

PMID- 10345491
TI  - Pricing assisted living packages.

PMID- 10345492
TI  - Understanding administrative appeals.

PMID- 10345493
TI  - Preventing abuse and neglect.

PMID- 10345494
TI  - Industry foes fume over the tobacco deal. They insist it won't slow teenage
      smoking.

PMID- 10345495
TI  - Dr. Patch--a clown doctor, hailed by Hollywood, dreams of giving free medical
      care to children.

PMID- 10345496
TI  - Outfoxing pathways of pain. 'COX-2' drugs are easier on stomach.

PMID- 10345497
TI  - Significant developments in biochemistry, urinalysis, and ligand assays.

PMID- 10345498
TI  - Urinary HIV-1 antibody patterns by western blot assay.
AB  - Diagnosis of human immunodeficiency virus infection (HIV-1) is normally carried
      out by serum testing for HIV-1 antibody. Recently, antibody testing in other body
      fluids such as saliva and urine have been attempted. In this study, we examined
      HIV-1 antibody patterns in urine by Western blot assay as compared to that found
      in serum. Out of 44 sero-positive samples by Western blot assay we found 43 to be
      HIV-1 antibody positive in the urine, whereas all 40 sero-negative samples were
      negative in urine. Thus the sensitivity of urine testing was 97.7% with 100%
      specificity when compared to serum testing by the Western blot assay. In the
      analysis of the antibody pattern in urine, we found 6.8% of p17, 68% of p24, and
      47.7% of p39 in the core proteins; 72.7% of p31, 61.4% of p51, and 68.2% of p66
      in the polymerase; and 63.6% of gp41, 75% of gp120, and 97.7% of gp160 in the
      envelope proteins. The data obtained supports the selection of the HIV-1 antigen
      subtype-E to develop a home test kit using urine. Urine testing for HIV-1
      antibody is convenient, non-invasive, safe, and easily performed at home.
      However, if the urine is positive, the confirmation test on serum is needed.

PMID- 10345500
TI  - Apoptosis: molecular mechanism for physiologic cell death.
AB  - Molecular biology is fast becoming the wave of the future in research as well as
      in the clinical laboratory. This trend toward determining cell function at this
      level is opening up doors to new techniques in evaluating and diagnosing such
      diseases as AIDS and cancer. This article focuses on apoptosis or programmed cell
      death, its morphological characteristics, its comparison to necrosis, its
      occurrence in development and homeostasis of multicellular organisms, its genetic
      regulation, and its involvement in diseases.

PMID- 10345499
TI  - Tracing our roots: the broadening horizons of clinical laboratory practice (1945
      62).
AB  - OBJECTIVE: To describe how the field of clinical laboratory science responded to
      the shortage of qualified laboratory personnel in the 1950s, and to review
      educators' responses to the changes in clinical laboratory practice. DESIGN: A
      survey of literature on the history of clinical laboratory science was conducted.
      References consulted include various books and professional journals. CONCLUSION:
      Between 1945 and 1962, the demand for certified medical technologists grew as a
      result of public demand for more health services, including laboratory testing.
      The shortage of qualified laboratory personnel, coupled with the introduction of
      new, more complex methods of analysis and the addition of different types of
      tests gave rise to specialization in each of the clinical laboratory disciplines.
      These developments also stimulated a renewed interest in creating another class
      of laboratory worker, the laboratory assistant, who could be assigned to perform
      simple procedures under the supervision of a certified medical technologist. The
      broadening horizons of clinical laboratory practice created new opportunities and
      new challenges for medical technologist educators.

PMID- 10345501
TI  - Toxicity associated with iron overload found in hemochromatosis: possible
      mechanism in a rat model.
AB  - Hemochromatosis is characterized by pathologic iron overload which often leads to
      various pathological conditions. The mechanism by which excess iron induces these
      conditions is not clearly understood. Using rats as the model, this investigation
      was conducted to explore the mechanism of toxicity associated with iron overload.
      Sprague-Dawley male rats were fed a 3% carbonyl iron-supplemented diet for eight
      weeks to achieve iron accumulation. Liver iron reached approximately 2 mg/g which
      is more than 16 times the control values (mean +/- SD, 0.12 +/- 0.02 mg/g, p <
      0.001). Serum iron was consistently higher in the experimental rats (mg/L): 3.41
      +/- 0.58 versus 1.89 +/- 0.18, p < 0.001. The high levels of iron accompanied
      enhanced oxidative damage in the hepatic nuclear DNA when 8-hydroxy-2'
      deoxyguanosine (8-OHdG) was measured as a product of DNA oxidation. The levels of
      8-OHdG in the experimental samples were significantly higher than the controls (8
      OHdG X 10(-5)/dG): 4.22 +/- 1.82 versus 1.84 +/- 0.33, p < 0.05. The results of
      serum enzyme assays suggest that iron overload caused mild hepatocellular damage:
      alanine transaminase significantly increased; lactate dehydrogenase did not
      change; alkaline phosphatase decreased. Since the accumulation of 8-OHdG in the
      nuclear DNA is highly deleterious to cells, these data suggest oxidative damage
      in the nuclear DNA may be a critical factor in inducing diseases associated with
      iron overload.

PMID- 10345502
TI  - Introduction to platelet update.

PMID- 10345503
TI  - Platelet specific alloantigens.
AB  - The ability of platelets to aggregate and to form a platelet plug is central to
      the maintenance of normal hemostasis. When platelets have normal function, the
      severity of bleeding is related to the degree of thrombocytopenia. In patients
      with normal platelet production, the most common cause of thrombocytopenia is due
      to immune mechanisms that results in platelet injury and removal from the
      circulation. These mechanisms involve the binding of platelet-associated
      immunoglobulins and are classified as immune. Immune thrombocytopenias can be
      caused by autoantibodies (autoimmune thrombocytopenia), alloantibodies (isoimmune
      thrombocytopenia), or drug-induced immune complexes and conditions secondary to
      autoimmune disorders such as systemic lupus erythematosus. In this paper the
      focus is on alloimmune thrombocytopenias resulting from the formation of
      alloantibodies to platelet specific antigens. The clinical importance of the
      platelet alloantigens is due to their ability to elicit alloantibody production.
      Alloantigens, also referred to as isoantigens, are substances that induce the
      production of alloantibodies when they are infused into individuals of the same
      species who lack the specific alloantigen.

PMID- 10345504
TI  - von Willebrand factor in the pathophysiology of thrombotic thrombocytopenic
      purpura.
AB  - Thrombotic thrombocytopenic purpura (TTP) is a disorder of systemic platelet
      aggregation. Evidence has accumulated that the aggregating agonist in TTP of all
      types is likely to be von Willebrand factor, especially unusually large von
      Willebrand factor multimers derived from endothelial cells. Recent evidence
      indicates that a metalloproteinase involved in von Willebrand factor breakdown is
      not present in adequate amounts in children with chronic relapsing TTP. Chronic
      relapsing TTP is, therefore, likely to be a congenital deficiency of von
      Willebrand factor metalloproteinase. In adults with single episode or
      intermittent types of TTP, the von Willebrand factor metalloproteinase is
      inhibited by autoantibodies that are present either transiently or intermittently
      in patient blood. Single episode and intermittent types of TTP in adults are,
      therefore, autoimmune processes of a short-term and recurrent nature,
      respectively.

PMID- 10345505
TI  - Platelet function testing by flow cytometry.
AB  - The availability of fluorescent monoclonal antibodies and probes now provides a
      powerful tool for examining platelet function by flow cytometry. These techniques
      cna be employed to determine the resting and stimulated expression of platelet
      glycoprotein receptors, the activation status of platelets assessed by secretion
      of granule contents (including expression of activation-dependent neoantigens),
      adhesion ligand binding to platelets, and intracellular calcium flux after
      exposure of platelets to agonist. In addition, flow cytometry has now been used
      to study the functional properties of stimulated platelets, including
      microparticle generation, platelet aggregation, and platelet-heterotypic cell
      conjugate formation. This brief review is presented as a general outline of the
      literature that uses flow cytometric methodology to examine in vivo and ex vivo
      platelet function.

PMID- 10345506
TI  - Smoke-free restaurant ordinances do not affect restaurant business. Period.

PMID- 10345507
TI  - The campaign to enact New York City's Smoke-Free Air Act.
AB  - On January 10, 1995, New York City's mayor signed into law a bill restricting
      smoking in most public facilities including restaurant dining areas, workplaces,
      and sports stadiums. This law was the subject of extensive public debate and was
      considered quite controversial at the time it was enacted. Passage of the smoking
      law (known as the New York City Smoke-Free Air Act) helped pave the way for other
      localities in New York to enact similar restrictions on smoking in public
      facilities. This article documents the process of enacting the New York City
      Smoke-Free Air Act.

PMID- 10345508
TI  - Analysis of taxable sales receipts: was New York City's Smoke-Free Air Act bad
      for restaurant business?
AB  - This article examines the results of a study to determine if the New York City
      Smoke-Free Air Act has had an adverse economic impact on the taxable sales
      receipts from the city's restaurant and hotel industries. The study found that
      real taxable sales from eating and drinking places and hotels in New York City
      increased by 2.1 percent and 36.9 percent, respectively, compared with levels two
      years before the smoke-free law took effect. During the same period, real taxable
      sales for eating and drinking establishments and hotels in the rest of the state
      experienced a 3.8 percent decrease and a modest 2.4 percent increase in sales,
      respectively.

PMID- 10345509
TI  - Restaurant employment before and after the New York City Smoke-Free Air Act.
AB  - The purpose of this study was to observe trends in the number of restaurants and
      restaurant employees two years before and two years after the New York City Smoke
      Free Air Act took effect in April, 1995. Between April 1993 and April 1997, New
      York City added 19,347 new restaurant jobs (18% increase) while the rest of the
      state outside the immediate metropolitan area added 7,423 new jobs (5% increase).
      The rate of growth in the number of restaurants was comparable among New York
      City, neighboring counties, and the rest of the state. The data suggest that the
      New York City Smoke-Free Air Act did not result in job losses for the city's
      restaurant industry.

PMID- 10345510
TI  - Consumer response to the New York City Smoke-Free Air Act.
AB  - The objective of this study was to assess consumer response to the New York City
      Smoke-Free Air Act. The overwhelming majority of respondents reported they were
      largely unaffected by the law or dined out more frequently since the law took
      effect; however, there was a small percentage of consumers that reported dining
      out less frequently. There were few reports of consumers who stopped dining out
      altogether or left or entered the city with the specific purpose of dining in a
      place that suited their smoking preference. The New York City Smoke-Free Air Act
      appears to have had little impact on the dining out patterns of consumers.

PMID- 10345511
TI  - Restaurateur reports of the economic impact of the New York City Smoke-Free Air
      Act.
AB  - The objective of this study was to determine the extent to which restaurateurs
      have reported a change in business since the New York City Smoke-Free Air Act
      took effect. A population-based cross-sectional telephone survey of 434
      owners/managers of restaurants located in New York City was conducted by an
      independent survey firm during November and December 1996. There is no evidence
      to suggest that the smoke-free law has had a detrimental effect on the city's
      restaurant business.

PMID- 10345512
TI  - Compliance with the New York City Smoke-Free Air Act.
AB  - This study's objective was to determine the level of compliance with the New York
      City Smoke-Free Air Act. Three data sources were used: (1) a population-based
      telephone survey of 251 New York City restaurant owners/managers; (2) independent
      inspections of the 251 surveyed restaurants; and (3) complaint records from the
      New York City Department of Health from April 1995 to March 1997. Ninety percent
      of restaurant owners/managers reported their indoor dining area was smoke-free in
      compliance with the law. Most New York City restaurants were able to comply with
      the smoke-free law with relative ease and little expense.

PMID- 10345513
TI  - The economic effect of smoke-free restaurant policies on restaurant business in
      Massachusetts.
AB  - The objective of the study was to determine if local smoke-free restaurant
      policies in Massachusetts affected restaurant sales. The authors used a pre-/post
      quasi-experimental design to compare town-level meals tax data before and after
      the imposition of local smoke-free restaurant policies. Data for 235 towns
      (including 32 adopting communities) were entered into a fixed effects regression
      model to estimate changes in restaurant sales over time. The study failed to find
      a statistically significant effect of local smoke-free policies on restaurant
      business. It provides evidence that local smoke-free policies do not cause a
      large decline in communities' restaurant industries.

PMID- 10345514
TI  - Local restaurant smoking policy enactment in Massachusetts.
AB  - The objective of this study was to identify differences between communities that
      enact local restaurant smoking policies in Massachusetts and those that do not.
      Using data from 314 reporting cities and towns, the authors determined that
      communities with restaurant smoking policies were typically medium-sized towns
      and had a lower proportion of blue-collar workers than non-adopting communities.
      Highly restrictive communities had higher median incomes and educational
      attainment than non-adopting communities. Since the creation of the Massachusetts
      Tobacco Control Program, the number and strength of restaurant smoking policies
      have grown.

PMID- 10345515
TI  - Smoky bars and restaurants: who avoids them and why?
AB  - The objective of this study was to provide new insight into who avoids smoky
      places, the types of places they avoid, and the reasons they give. A
      representative sample of Massachusetts adults (N = 4,929) was surveyed by
      telephone during 1995 and 1996. Forty-six percent of non-smokers reported having
      avoided a smoky place. Reasons were aversion to the lingering smell (34.8%) and
      health issues (31.9%). Many adults avoid restaurants and bars because of the
      expectation of excessive environmental tobacco smoke (ETS). Patronage may
      increase after smoke-free policies are implemented and nonsmokers become aware of
      the opportunity to dine in establishments free of ETS.

PMID- 10345516
TI  - Hepatitis C screening and notification: hospitals under new FDA regulations.

PMID- 10345517
TI  - Infection control programs for behavioral health care settings.

PMID- 10345518
TI  - Practice brief. Protecting patient information after a facility closure
      (updated). American Health Information Management Association.

PMID- 10345519
TI  - Electronic signatures, digital signatures, and digital certificates.

PMID- 10345520
TI  - Federal legislation on confidentiality: possibility or insurmountable challenge?

PMID- 10345521
TI  - HIPAA, security, and electronic signature: a closer look.
AB  - A recent notice of proposed rule making for an electronic signature standard, if
      adopted, will affect the way health information is managed for years to come.
      Here's what you need to know about electronic signature and what the proposed
      standard may mean for HIM.

PMID- 10345523
TI  - Building a better CPR in ambulatory care.

PMID- 10345522
TI  - Implementing the CPR: a journey.
AB  - Implementing a CPR system is a major change for any organization. The author
      offers an approach to managing this change, including critical factors,
      characteristics of winning solutions, and the highlights of this journey.

PMID- 10345524
TI  - Operationalizing ORYX: an integrated system's experience.

PMID- 10345525
TI  - Joint Commission sentinel event policy and procedures update.

PMID- 10345526
TI  - Getting the next generation to work for you.

PMID- 10345527
TI  - Benchmarking with national ICD-9-CM coded data.

PMID- 10345528
TI  - In pursuit of a value-added entity.

PMID- 10345529
TI  - On the public record. Interview by Jane E. Blumenthal.

PMID- 10345530
TI  - Practice expenses and the 1999 Medicare fee schedule.

PMID- 10345531
TI  - Ernest A. Codman: the improper Bostonian.

PMID- 10345532
TI  - Building strong grassroots: how not to be a victim.

PMID- 10345533
TI  - The power of words in malpractice litigation.

PMID- 10345534
TI  - Mission impossible? For San Francisco's last stand-alone major hospital, mission
      is strategy.

PMID- 10345535
TI  - Bucking the trend: is consolidation inevitable?

PMID- 10345536
TI  - Benchmarking. VHA study reveals best practices in emergency services.

PMID- 10345537
TI  - Prioritization in community health planning: combining methods to achieve
      implementable priorities.
AB  - Community Health Planning (CHP) is one of the tools that states and localities
      use to develop health policies and programs. The author argues that, for CHP to
      succeed, it must include both positive/hierarchic data as well as interpretive
      information. To augment the discussion, the author discusses the State of
      Tennessee's effort to revamp its public health mission and strategies as
      specifically implemented in one county. The author contrasts the two types of
      data generated and argues that each has a legitimate claim in the CHP process:
      the "positive" data in the form of epidemiological statistics to inform the
      stakeholders and the "interpretive data" in the form of stakeholder participation
      for ownership of the process. The author then draws implications for states and
      localities to use diverse information sources as they improve services and
      service delivery to citizens and recipients.

PMID- 10345539
TI  - Ensuring quality and accountability in managed care.
AB  - The rapid growth of new forms of managed care in the United States in recent
      decades has brought with it increasing concerns regarding the quality of care
      delivered by practitioners in these plans. This article examines the various
      regulatory demands that are being placed on Managed Care Organizations (MCOs).
      The authors look at the major determinants that are likely to bring about
      significant changes in the health care sector for both patients and providers and
      predict how these shifts will affect the quality of health care services in the
      near future. They discuss how the quality of health care, rather than the cost of
      those services, can become and remain the primary factor in the delivery of
      health care services. Ultimately, they conclude that increased participation by
      the federal government is required to protect the rights of patients and ensure
      better quality and accountability for health care services delivered by MCOs.

PMID- 10345538
TI  - State-funded medical assistance programs: sources of coverage for HIV-related
      health care.
AB  - Preliminary research found that a number of states implement medical assistance
      programs (MAPs) funded only with state and/or local government funds. A review of
      the literature was unable to discover any published research that discusses state
      funded MAPs. The objective of this article is to describe these MAPs and to
      discuss how these programs can be used to provide health services to people
      infected with HIV who lack other coverage. A two-step survey process was used to
      identify 20 states implementing MAPs and to identify eligibility criteria, the
      health services covered, and payment-level policies. Typically, MAPs implement
      restrictive eligibility policies and set low reimbursement levels for the care
      covered. However, most MAPs cover a comprehensive range of health services needed
      by people inflected with HIV, including community-based care and support
      services.

PMID- 10345540
TI  - Strategic decision-making processes in health care organizations.
AB  - Health care represents a promising area of research due to its uniqueness. In
      recent years, considerable progress has been made in strategic decision-making
      processes research but not the study of health care strategy research. This
      article reviews strategic decision-making in health care domains. Adopting
      Rajagopalan, Rusheed, and Datta's (1993) framework, the authors evaluate the
      theoretical and empirical contributions of this research. The limitations and
      theoretical implications of these efforts are also explored.

PMID- 10345541
TI  - Power, politics, and top management team characteristics: do they matter?
AB  - This study assesses the contributions of the leader power and top management team
      characteristics to perceived strategic capability. Low age heterogeneity and low
      tenure heterogeneity were found to have a positive association with perceived
      adaptability. High diversity in educational specialization was also found to be
      positively associated with adaptability. Top management perceptions of CEO power
      were, however, lower among high adaptors. Implications for leadership research,
      senior management recruitment, and the design of management development for top
      management teams are discussed.

PMID- 10345542
TI  - Bureaucracy, institutional theory and institutionaucracy: applications to the
      hospital industry.
AB  - The health care industry is experiencing rapid change and uncertainty. Hospitals,
      in particular, are redesigning structures and processes in order to maximize
      efficiencies and remain economically viable. This article uses two organizational
      theory perspectives (bureaucracy and institutional theory) to examine many of the
      trends and transitions which are occurring throughout the hospital industry. It
      suggests that many of the key tenets of bureaucracy (rationality, efficiency,
      productivity, control, etc.) have been incorporated into the institutional
      environment as normative expectations. This synthesis or blending of these two
      perspectives is labeled institutionaucracy, implying that, as productivity and
      efficiency considerations become institutionalized, hospitals conforming to such
      operational standards will gain legitimacy and additional resources from their
      environment.

PMID- 10345543
TI  - Confidentiality of electronic medical records in the managed care environment.
AB  - Over the past three decades, increasing sophistication in the application of
      information technology has created new opportunities to improve both the efficacy
      and efficiency of the health care delivery system. Electronic data transfer,
      facilitated by linkages between computers, allow physicians and others to access
      records of interest rapidly and easily. It is anticipated that the health care
      industry will eventually be served by an integrated electronic communication
      network allowing any agency within the industry to exchange information and
      process transactions with any other agency within the system. This capability
      could drastically reduce both administrative and health care delivery costs.
      Unfortunately, the very strength of the envisaged industry-wide communication
      network is also its weakness. The network's ability to access vast amounts of
      health care information rapidly and easily, which could be profoundly sensitive
      and private, effectively decentralizes the physicians' control on intelligence
      gained thorough a highly personal relationship of trust. This article explores
      alternatives available to the health care industry for assurance of
      confidentiality and privacy to the patient.

PMID- 10345544
TI  - Children at risk: outcome and cost measures needed.
AB  - Sporadic reports in the media focus on the inability of America's social welfare
      leadership to protect children at risk and to allocate judiciously scarce
      resources. These criticisms suggest the importance of arriving at valid
      conclusions in both socio-psychological and economic terms so that human service
      specialists can evaluate the efficacy of three key strategies used for children
      at risk: reunification, foster care; and adoption. Rather than continuing to
      modify public policy without much empirical evidence, this article calls for
      creating a comprehensive data base that supplies the most critical treatment
      variables leading to reasonable successes and to the average cost per case when
      comparing children reunified with a biological parent to those who are placed
      into out-of-home settings and to those who are adopted. This proposed analysis
      should include public and private expenditures for the services provided by human
      services-welfare, special education, judicial, correctional, mental health,
      medical, and other related organizations.

PMID- 10345545
TI  - 1999 resource guide.

PMID- 10345546
TI  - Period of adjustment. Health plans experiment with new clinical risk adjustment
      strategies.
AB  - Health plans are moving forward with the concept of clinical risk adjustment-
      essentially, paying physicians more for taking on sicker patients--in a variety
      of forms. The challenges, from the policy and strategy levels to the data
      collection and analysis level, are many. Yet, despite some concerns on the part
      of provider execs, observers say clinical risk adjustment's time has come.
      Meanwhile, the issues remain many for both plans and providers.

PMID- 10345547
TI  - The view from the ground: when seniors get shafted.
AB  - In the November issue, Medical Network Strategy Report looked at the broader
      policy and strategic issues surrounding the flight from Medicare risk contracting
      on the part of major health plans this fall. In this issue, we look at one of the
      difficult results of the current situation: the harsh impact on Medicare
      enrollees themselves, as seen in one California county with a high Medicare risk
      penetration rate.

PMID- 10345549
TI  - Marketplace. Syracuse doctors unite, hospitals affiliate, but health care
      community stays friendly.

PMID- 10345548
TI  - The BBA expands the role of physician extenders ... with major implications for
      provider-employers.

PMID- 10345550
TI  - Perspectives. Time to rethink? Providers ponder plan sponsorship anew.

PMID- 10345551
TI  - Perspectives. New twist on guideline dissemination stirs professional debate,
      gets slap from FDA.

PMID- 10345552
TI  - Marketplace. Why health plans are embracing outside reviews of treatment denials.

PMID- 10345553
TI  - Perspectives. Health gains of seniors may offset some new Medicare technology
      costs.

PMID- 10345554
TI  - Polarity management: the key challenge for integrated health systems.
AB  - Integrated health systems are confronted with numerous dilemmas that must be
      managed. Many of these dilemmas are an inherent part of the system's structure,
      given that multiple competing hospitals, medical groups, and (sometimes) health
      plans are often under one organizational roof. This article presents an analysis
      of these dilemmas--referred to in the management literature as polarities--as
      they are found in six integrated health systems in Illinois. The nine polarities
      that must be managed include (1) hospital systems that want to be organizations
      of physicians; (2) system expansion by growing the physician component; (3)
      system centralization and physician decentralization; (4) centripetal and
      centrifugal forces involving physicians; (5) system objectives and physician
      interests; (6) system centralization and hospital decentralization; (7) primary
      care physicians and specialists; (8) physician autonomy via collectivization; and
      (9) vertical and virtual integration. The article identifies some of the
      solutions to the polarities that have been enacted by systems. In general,
      executives and physicians in integrated health systems must attend to the
      processes of integration as much as or more than the structures of integration.

PMID- 10345555
TI  - Morris A. Graham, President, Graham and Associates and author of The Horizontal
      Revolution. Interview by James A. Johnson.

PMID- 10345556
TI  - Incentives for vertical integration in healthcare: the effect of reimbursement
      systems.
AB  - In the United States, many healthcare organizations are being transformed into
      large integrated delivery systems, even though currently available empirical
      evidence does not provide strong or unequivocal support for or against vertical
      integration. Unfortunately, the manager cannot delay organizational changes until
      further research has been completed, especially when further research is not
      likely to reveal a single, correct solution for the diverse healthcare systems in
      existence. Managers must therefore carefully evaluate the expected effects of
      integration on their individual organizations. Vertical integration may be
      appropriate if conditions facing the healthcare organization provide
      opportunities for efficiency gains through reorganization strategies. Managers
      must consider (1) how changes in the healthcare market have affected the dynamics
      of production efficiency and transaction costs; (2) the likelihood that
      integration strategies will achieve increases in efficiency or reductions in
      transaction costs; and (3) how vertical integration will affect other costs, and
      whether the benefits gained will outweigh additional costs and efficiency losses.
      This article presents reimbursement systems as an example of how recent changes
      in the industry may have changed the dynamics and efficiency of production.
      Evaluation of the effects of vertical integration should allow for reasonable
      adjustment time, but obviously unsuccessful strategies should not be followed or
      maintained.

PMID- 10345557
TI  - Managing environmental uncertainty: an analysis of executive behavior in the
      health and social service sector.
AB  - Executives who are involved in a variety of professional associations may be in a
      more favorable position to manage environmental uncertainty because of their
      ability to access information through the informal network. This study examined
      the professional involvement of 116 executives in the health and social service
      sector and found that leadership status within a professional association
      influenced contractual agreements between executives and a regional area agency
      on aging.

PMID- 10345559
TI  - Leadership--an introduction.

PMID- 10345558
TI  - Telemedicine, hospital viability, and community embeddedness: a case study.
AB  - Many hospitals today struggle to remain competitive through the adoption of
      medical technology or expansion of hospital services. This article presents a
      case study of one hospital's attempt to remain viable through the adoption of
      telemedicine. Through a 17-year analysis of local hospital-related news reports,
      it is argued that a hospital's relationship to the local community can affect the
      success and potential of such innovations. Establishing a pattern of trust and
      support between the local community and hospital should therefore be an important
      step in increasing hospital viability.

PMID- 10345560
TI  - Programme budgeting and marginal analysis: pragmatism and policy.

PMID- 10345562
TI  - Primary care and the US health care system.

PMID- 10345561
TI  - Is hospital performance related to expenditure on management?
AB  - OBJECTIVES: Reducing the costs of management appears an easy target for those
      seeking to generate savings or to promote better spending in the National Health
      Service (NHS). However, an assessment of the appropriate amount of spending on
      management requires an evaluation of how much management contributes to
      organizational performance. METHODS: Using routinely available NHS acute hospital
      data, an econometric analysis was undertaken to test the hypothesis that there is
      a relationship between the proportion of a hospital's income spent on management
      and the performance of the hospital measured along three dimensions: the
      achievement of financial targets; performance against waiting time standards
      defined in the Patient's Charter; and costs of service provision. RESULTS: No
      general relationship was found between management costs and hospital performance.
      However, there was some evidence of a quadratic relationship between management
      spending and the amount of operating surplus generated and performance against
      the three-month waiting time standard for an inpatient admission specified in the
      Patient's Charter. These results suggest that performance returns reach an
      optimum when management expenditure is around 5-6% of hospital income.
      CONCLUSIONS: The evidence is not yet strong enough to draw a general conclusion
      that management costs in NHS acute hospitals are too high or that an
      undiscriminating reduction in management costs would have no detrimental effects
      on hospital performance. However, the findings should prompt managers to identify
      ways in which their activities are productive and how these can be measured, and
      what distinguishes effective from ineffective management.

PMID- 10345563
TI  - Effect of Japanese government policy on hospital pharmaceutical profit levels.
AB  - OBJECTIVES: Our main objective is to examine whether the Japanese government's
      pharmaceutical price reduction policy has reduced the size of pharmaceutical
      profit traditionally enjoyed by health care providers. We discuss alternative
      measures that the government could introduce in an attempt to control drug costs.
      METHODS: We review Japan's pharmaceutical reimbursement system. We then analyse
      published and unpublished data in an attempt to reach our main objective.
      Calculations are made from raw data, provided by the National Hospital Federation
      of Japan, in order to discover the extent to which hospitals are experiencing
      financial difficulties. RESULTS: Due to pharmaceutical product shifting by
      hospitals from older, less profitable drugs to newer, more profitable ones, drug
      profit margins may not have fallen to the extent that is often reported in the
      Japanese press. Furthermore, increased prescribing, possibly due to the ageing of
      the population, may have maintained the total drug profits of hospitals, to a
      large extent, despite any reduction in profit margins. CONCLUSIONS: Although drug
      price reduction policy has had some success in controlling pharmaceutical
      expenditure, there is little evidence to suggest that total pharmaceutical
      profits for the provider units have been seriously undermined, despite the
      prevalence of this notion among hospital administrators. Nevertheless, in order
      to promote the more efficient and effective manufacture and utilization of
      pharmaceuticals, the government should seriously consider alternative methods for
      controlling pharmaceutical costs.

PMID- 10345564
TI  - Point of care testing in the accident and emergency department: a cost analysis
      and exploration of financial incentives to use the technology within the
      hospital.
AB  - OBJECTIVES: To compare the costs of current arrangements for testing emergency
      blood samples from patients attending an accident and emergency (A&E) department
      in a large teaching hospital in England with point of care testing (POCT).
      METHODS: Estimates were made of the fixed and variable costs of two options: a
      supplemental option, in which POCT was introduced to A&E only; and a replacement
      option, in which POCT was introduced to A&E and the intensive therapy unit (ITU),
      thereby entirely replacing an existing process. RESULTS: For the supplemental
      option, current arrangements cost 68,466 Pounds in total per year; average costs
      per test were 5.53 Pounds (venous in the central laboratory) and 3.60 Pounds
      (arterial on the ITU). Introducing POCT would increase total hospital costs by
      35,929 Pounds, and average costs per test would be 5.32 Pounds (venous) and 4.28
      Pounds (arterial). For the replacement option, current arrangements cost 132,630
      Pounds in total, and average cost per test (for all tests) was 4.06 Pounds.
      Introducing POCT would make hospital savings ranging from 8332 Pounds to 20,000
      Pounds, and average cost per test would be 3.78 Pounds. CONCLUSIONS: Introducing
      POCT results in lower average costs per test. The supplemental option will result
      in significantly increased costs to the hospital. The replacement option can lead
      to significant savings. The internal cross-charging arrangements between
      departments that exist in this hospital may mean that supplemental implementation
      of POCT could be potentially 'profitable' for the A&E department, but would
      result in higher expenditure for the hospital as a whole.

PMID- 10345565
TI  - The case for combining qualitative and quantitative approaches in health services
      research.
AB  - A judicious combination of qualitative and quantitative methods can play a
      valuable role in health services research. This paper reviews the main reasons
      for combining methods: for different stages in a project; to compensate for the
      shortcomings of individual methods; and for the purpose of 'triangulation'. It
      examines the potential for qualitative approaches to contribute to quantitative
      work--by providing insights into the process of data construction, identifying
      relevant variables to be studied, furnishing explanations for unexpected or
      anomalous findings, and generating hypotheses or research questions for further
      investigation. Similarly, qualitative work can be enhanced by using quantitative
      techniques--albeit often in a modified form--in analysing data, developing
      sampling strategies, and amalgamating findings from separate qualitative studies.
      Although there is potential to develop multi-method approaches, there remains an
      important role for rigorous studies employing either qualitative or quantitative
      methods.

PMID- 10345567
TI  - Systematic reviews and meta-analysis: a structured review of the methodological
      literature.
AB  - OBJECTIVE: To systematically review methods for systematic review/meta-analysis
      in order to identify the different methodological and statistical methods that
      have been proposed. A summary of the main findings is presented here, with
      emphasis given to health services research topics. METHODS: A thorough systematic
      search for methodological papers was carried out using a variety of methods,
      including the use of electronic databases. Approximately 1000 potentially
      relevant references were identified, a number of them from education, psychology
      and sociology. RESULTS: After briefly reviewing the procedural methods required
      to carry out a review, and the basic statistical methods used to combine study
      estimates, less established methods are discussed. These include methods for
      dealing with publication bias, meta-regression, meta-analysis of individual
      patient data, the synthesis of non-randomized evidence alone and in combination
      with randomized studies. Bayesian modelling and economic evaluation through meta
      analysis. Recommendations for meta-analytical practice are given; these are
      either distilled from previous guidelines, or constructed where there appears to
      be a broad consensus across the literature. CONCLUSIONS: It is hoped that this
      review will provide a consistent and comprehensive, but concise, description of
      the methods available for synthesizing evidence, that it will promote better
      quality reviews of the results of health services research and identify specific
      areas which require methodological development.

PMID- 10345566
TI  - Choosing an appropriate unit of analysis in trials of interventions that attempt
      to influence practice.
AB  - The choice of an appropriate unit of analysis in evaluations in health policy is
      problematic and errors are frequently made which may undermine study conclusions.
      This paper describes the structure of randomized trials, issues concerning
      randomization and replication, and the factors that should be considered when
      deciding upon the appropriateness of a unit of analysis.

PMID- 10345568
TI  - Mulling over equity.

PMID- 10345569
TI  - Fairness, public expenditure and the cost of new treatments in the UK.
AB  - Current differences in standards for allocating resources in the UK for, on the
      one hand, drugs and surgery, and on the other, chronic community and social care
      and social security lead to significant inequality. Using a case study of
      hypothetical patients, it can be shown that adoption of new treatments, at high
      cost, to make marginal improvements in well-being would lead to much greater
      spending on some patients than on others with similar problems from different
      causes. Inequality occurs because society tolerates tighter constraints on
      community and social care and social security than on acute care and drug budgets
      for new treatments. Resolution of the inequality would involve establishing
      fairly the resources to increase the welfare of patients with different chronic
      diseases to some target level of welfare. However, this would make overt the
      current rationing of community and social services and demonstrate the low levels
      of welfare of many with chronic diseases. Governments concerned with lower
      taxation might prefer to avoid exposing such issues.

PMID- 10345570
TI  - Do managers pay their way? The impact of management input on hospital
      productivity in the NHS internal market.
AB  - INTRODUCTION: Levels of management staffing in the UK National Health Service
      (NHS) have received considerable political and media attention in the last four
      years or so. Both the previous and current governments committed themselves to
      reducing management expenditure in the health service, and significant cuts
      appear to have been made in this area in the last year or so. Few systematic
      evaluations have been undertaken of the value of general management input,
      however, and policy changes appear to have been largely determined by popular
      opinion. This study attempts to quantify the effect of management input on
      hospital productivity for the first three years of the NHS internal market
      (1991/2-1993/4). METHODS: An average cost function was used to model the effect
      of management inputs on hospital costs after adjustment for the levels of outputs
      produced, input costs, and internal and external exogenous constraints on
      hospital functioning. Two measures of management input were used: the proportion
      of total spending consumed by top level management, and the proportion consumed
      by all administrative activities. Cross-sectional and longitudinal models with
      contemporaneous and lagged management input effects were estimated. RESULTS:
      Higher spending on top level management was associated with poorer productivity
      levels in most instances. Total administrative inputs had a weaker, but still
      generally negative, association with productivity. CONCLUSIONS: No evidence was
      found that increasing management inputs was associated with improved
      productivity. On the contrary, spending more on top level managers appeared in
      fact to be associated with lower productivity levels. Results would thus appear
      to be in line with decisions to reduce the level of expenditure on management in
      NHS hospitals. Quality differences could not be measured, however, and it is
      possible that management input is associated with quality improvements which
      might reduce or reverse observed productivity losses.

PMID- 10345571
TI  - Physician groups give disease management the thumbs-up.

PMID- 10345572
TI  - Managed comorbidities in individuals with CHF for optional outcomes.

PMID- 10345573
TI  - An A to Z directory of "value" vendors.

PMID- 10345574
TI  - Moving toward the next millennium: health informatics in Canada.

PMID- 10345575
TI  - Benchmarking comparisons of the efficiency and quality of care of Canadian
      teaching hospitals.

PMID- 10345576
TI  - The Toronto Academic Health Science Council Management Practice Atlas.

PMID- 10345577
TI  - Performance measures and accountabilities in England.

PMID- 10345578
TI  - Public dissemination of provider performance comparisons in the United States.
AB  - As competition among healthcare providers has increased in the U.S., there has
      been a rapid growth in the amount of comparative information on provider
      performance made available to consumers. This availability requires hospitals to
      have information systems that will allow them to prepare proactively for the
      public dissemination of comparative performance data. The information contained
      in provider report cards can be a valuable tool for hospitals to use for internal
      management and planning.

PMID- 10345579
TI  - Meeting the challenge of year 2000.

PMID- 10345580
TI  - OHA (Ontario Hospital Association) responds to year 2000 issues.

PMID- 10345581
TI  - Connected care. The Andover Working Group.

PMID- 10345582
TI  - Clinical information systems: the blue sky.

PMID- 10345583
TI  - Integrating home healthcare into your IT strategy.

PMID- 10345585
TI  - Accountability of foundations. The regulators are hovering and the public wants
      results.

PMID- 10345584
TI  - Physicians in integrated health systems.

PMID- 10345586
TI  - How the private sector can save Medicare.

PMID- 10345587
TI  - Ice storm: a crisis management diary.

PMID- 10345589
TI  - Benchmarking Web sites.

PMID- 10345588
TI  - Supreme Court declares failure to provide sign language interpretation during
      medical care unconstitutional.

PMID- 10345590
TI  - Whither health information systems?

PMID- 10345591
TI  - Quarterly index. Evaluating changes in practice with resource intensity weights.

PMID- 10345592
TI  - Key to successful MD profiling: keep it simple!

PMID- 10345593
TI  - Huge geographic variation in PTCA and CABG charges, LOS.
AB  - Data Library: How do your numbers compare? This month's column features
      geographic hospital and physician charge and LOS data for high-cost CABG and PTCA
      procedures, which vary as much as 116% between states.

PMID- 10345594
TI  - How to outsmart biases in health plan claims data.
AB  - Before negotiating your next contract, heed this expert advice for reducing risk
      when setting PMPM rates and case rates using frequently biased and incomplete HMO
      historical data. Here are 8 tips for using HMO-provided data, plus some benchmark
      utilization projections for commercial and Medicare populations.

PMID- 10345595
TI  - Hospital's resource management program uses data to fuel cost control, quality
      improvement.
AB  - A behind-the-scenes look at Mt. Diablo Medical Center's data-driven clinical
      resource management program shows how this California provider got control of
      overhead, admission rates, LOS, and resource utilization. See how they used data
      to target areas for quality improvement and cost cutting, and linked QI
      initiatives throughout the organization. Plus, see their scoring system and
      benchmark data.

PMID- 10345596
TI  - Automated patient surveys link risk assessment, satisfaction to action--in real
      time.
AB  - A New Hampshire physician network's unique yet simple and inexpensive patient
      risk assessment surveys are administered, completed, and acted upon in real time-
      resulting in measurably improved quality and outcomes. Here's how the surveying
      program works, how physician buy-in is achieved, and samples of a survey and
      feedback form.

PMID- 10345597
TI  - Grouping patients by episode helps managers compare 'apples to apples'
      performance.
AB  - Apples to apples: When health care organizations group care by illness episode
      and include inpatient, outpatient, and pharmaceutical claims data, they can more
      appropriately compare physician practice patterns, identify targets for disease
      management efforts, and pinpoint particular aberrations in their data. Here's how
      Episode Treatment Groups (ETGs) make analysis easier for organizations, such as
      Oxford Health Plans--plus some sample ETG-driven reports.

PMID- 10345598
TI  - Manager "tool box" improves HMO customer service productivity, quality.
AB  - A tool box full of productivity and quality reports: Kaiser Permanente has
      dramatically improved the quality and productivity of its 12 member services
      offices thanks to a toolbox of five different reports to track staff
      productivity, case flow, quality of reps' work, and projected staffing levels.
      Use these templates and tips from Kaiser to develop your own easy-to-use
      spreadsheet tools.

PMID- 10345599
TI  - Use patient feedback and process modeling data to improve patient satisfaction.
AB  - What would happen if...? Patient satisfaction in a busy day surgery unit was at
      an all-time low when managers decided to put their data to use. They established
      baselines, collected data to conduct process mapping, and used that information
      to simulate different levels of staffing. The results include dramatic
      improvements in patient satisfaction, LOS reductions, and cost savings. Here are
      the details, plus some useful data tools used at the University of Texas Medical
      Branch in Galveston.

PMID- 10345600
TI  - Flow charting and time studies key to reengineering.

PMID- 10345601
TI  - Physicians in home care: past, present, & future.
AB  - Physician house calls began declining in the 1960s and still are relatively rare.
      What caused this distancing of physicians from home care, and what needs to be
      done to bridge the gap?

PMID- 10345602
TI  - Pushing the creative envelope. Collaborative practice models between physicians &
      agencies.
AB  - How does a home care agency meet the demands of an ever-changing and competitive
      marketplace? By having the willingness to change the way it does business. The
      Visiting Nurse Association of Boston has proven that developing unique
      relationships with key customers opens doors to many opportunities.

PMID- 10345603
TI  - Cutting paperwork and phone calls with physician-based care teams.

PMID- 10345605
TI  - The case for medical direction in home care agencies.
AB  - Good medical directors can add value across all areas of agency operations. With
      relevant training, good communication, and fair reimbursement, agencies can
      benefit from the knowledge and expertise of physicians who are committed to home
      care.

PMID- 10345604
TI  - Home care physician referrals: a guide for home health providers.
AB  - By exercising a strong due diligence process before making referrals to
      physicians providing house calls, home care agencies can protect themselves,
      patients, the industry's reputation, and Medicare funds from fraud and abuse by
      groups seeking to enter the field for the money they can make.

PMID- 10345606
TI  - The important role of the physician in home care in the Kingdom of Saudi Arabia.
AB  - Home care in Saudi Arabia is beginning to establish itself as an important part
      of the health care system. Even though programs may differ, the focus remains the
      same: to provide the highest quality home health care services to the citizens
      and to provide the necessary medical and supportive services that each individual
      needs. Physicians play a critical role in ensuring the success of home care in
      this country.

PMID- 10345607
TI  - The role of physicians in Brazil's home care system.

PMID- 10345608
TI  - Home care in Spain: teamwork is the standard.
AB  - Primary health care teams work together to provide home care services in Spain.
      These teams are the point of entrance to Spain's health care system and they
      therefore function not only as providers of home care services, but also as
      gatekeepers for public health care.

PMID- 10345610
TI  - Identify physician issues with surveys.

PMID- 10345609
TI  - Physicians and home care in Bermuda: a natural alliance.

PMID- 10345611
TI  - Electronic tracking: new applications for tried-and-true technology.
AB  - High-tech solutions to situations abound nowadays; however, the most advanced
      technology may not always provide the best answer. Electronic tracking offers
      many benefits and uses good old telephone lines.

PMID- 10345612
TI  - At a glance. Average annual change in Medicare payments by type of service (per
      Medicare beneficiary)

PMID- 10345613
TI  - Saving Medicare: what will it cost and whom will it benefit?

PMID- 10345614
TI  - How to divest acquired physician practices.
AB  - When an integrated delivery system (IDS) determines it must divest itself of a
      previously acquired physician practice, it must manage the transaction with care.
      The IDS most likely will want to maintain a positive ongoing relationship with
      the physician practice, while avoiding concessions to the practice that could be
      construed as violations of state and Federal laws. Before proceeding, the IDS
      should evaluate the reasons for divesting the practice, assess legal issues
      involved in terminating contracts with the practice, decide how to deal with the
      practice's assets and office facilities, consider whether covenants not to
      compete should be enforced, ensure continued access to essential medical records,
      consider whether to incorporate a "non-disparagement" clause in the termination
      agreement, and determine what mutual general releases may be necessary.

PMID- 10345615
TI  - Making the connection between physician performance and pay.
AB  - Cost competition in health care, the demand for physician performance data, and
      the need to minimize fixed costs, such as automatic, annual physician pay
      increases, have prompted healthcare organizations to develop physician
      compensation structures that deemphasize fixed salaries and introduce variable
      pay tied to measurable performance goals. Case studies of this shift in approach
      to physician compensation at two organizations--a large, multispecialty group
      practice and a medical school affiliated with an academic medical center--show
      how replacing traditional pay systems that were ineffectual in fostering
      organizational improvements with compensation systems that tied pay to
      performance resulted in both improved physician performance and lower overhead
      costs.

PMID- 10345616
TI  - IT integration options for integrated delivery systems.
AB  - Development of an integrated delivery system (IDS) does not necessarily require
      complete integration of the information technology (IT) functions of the care
      delivery components that make up the IDS. With an adequate IT infrastructure
      throughout the IDS, however, the IT-related services and functions that most
      often can be integrated effectively among the various components of the IDS
      include: an organizationwide master patient index and clinical data repository,
      central financial and business office applications, a patient scheduling
      function, "value-added" services for physicians, decision-support and outcomes
      applications, and management service organization operations. Challenges to full
      integration include the need to anticipate future advances in technology,
      increased capital expenses, lack of sufficient savings to offset increased
      expenses, internal disruptions during the integration process, and the need for
      additional staff to support an organizationwide IT network.

PMID- 10345617
TI  - Inpatient clinical decision-support systems: determining the ROI.
AB  - Healthcare providers faced with increasing pressure to provide high-quality, cost
      effective care have implemented clinical decision-support programs to drive the
      appropriate process improvement activities needed to achieve successful care
      outcomes. Each of these activities requires the commitment of the necessary
      technology and human resources. To measure the return on investment (ROI) of
      decision-support activities, providers need to establish a methodology for
      capturing the costs and benefits of implementing decision-support-directed
      process-improvement activities.

PMID- 10345618
TI  - Bringing a health system into year 2000 compliance: a case study.
AB  - To meet the challenge of ensuring total year 2000 compliance across a large
      health system, HealthCare Colorado, a statewide not-for-profit management and
      contracting organization, has undertaken a massive effort to identify and correct
      year 2000 deficiencies. The health system's board decided to concentrate first on
      ensuring that all of the system's PCs were year 2000 compliant, focusing
      initially on PCs in the health system's numerous physician offices. The board
      engaged a consulting firm and appointed a project team to oversee the effort. A
      process was developed in which a tool provided by the consulting firm was used to
      test each PC, the consulting firm analyzed the results, hardware deficiencies
      were corrected, and PCs that required corrections were retested to verify
      compliance.

PMID- 10345619
TI  - Year 2000 compliance starts in 1999 for financial systems.
AB  - Preparing for the potential year 2000 computer date problem should have begun
      long ago. Healthcare organizations should be well along in testing their
      information systems to ensure that both financial and clinical applications are
      year 2000 compliant. Some organizations may have started to experience problems,
      particularly with their financial systems. A noncompliant financial system that
      generates incorrect data without creating error messages or rejecting
      transactions poses particularly serious problems for providers.

PMID- 10345620
TI  - Will the year 2000 affect your organization's investments?
AB  - Healthcare financial managers responsible for the investments of their healthcare
      organizations should identify the extent of their investment programs' exposure
      to year-2000-related problems. A letter should be sent to investment-related
      vendors requesting specific information and assurances regarding the vendors'
      efforts to contain or eliminate the year 2000 problem. An internal timetable also
      should be established to move the year 2000 compliance program forward in a
      timely and organized fashion.

PMID- 10345621
TI  - Independent assessment is key to financial well-being.
AB  - Both traditional group practices and IPAs have felt the impact of changes brought
      about by managed care. Group practices need to ensure that their financial
      reporting and cost-accounting methods capture information that is key to decision
      making. An independent assessment of financial procedures helps identify any
      outstanding issues and maintain financial well-being. This assessment should be
      conducted at least quarterly so that potential problems can be resolved, income
      opportunities explored, and cost-saving measures adopted in a timely manner.

PMID- 10345622
TI  - Warning: your patient may become a fraud investigator.

PMID- 10345623
TI  - EDI helps IPAs, PHOs manage risk.

PMID- 10345624
TI  - Data trends. Key organizational performance indicators.

PMID- 10345625
TI  - Supply chain management: new paradigms for customers and suppliers.
AB  - Companies are constantly looking for ways to increase their effectiveness and
      improve their bottom lines. One area of renewed interest is supply chain
      management. By managing their supply chains better, companies are able to become
      more flexible, offer defect-free products, eliminate unnecessary delays, and keep
      costs down. This article briefly describes the objectives of supply chain
      management and lists some of the tools that can be used to achieve them.

PMID- 10345626
TI  - Breakthroughs in supplier partnerships: profiting from win-win relationships.
AB  - The changes occurring in manufacturing companies today are more significant than
      any that have occurred in the past decade. Customers want products and services
      with less lead time, higher quality, and lower cost than ever before. These
      requirements have caused manufacturers to rethink how they view their supply
      chains. This article highlights the importance of improving supplier
      partnerships.

PMID- 10345627
TI  - JIT II: the ultimate customer-supplier partnership.
AB  - JIT II, conceived and implemented by the Bose Corporation in 1987, is currently
      being reviewed and tried in other U.S. companies, possibly because it fits well
      with two cutting-edge concepts, partnering and concurrent reengineering. This
      article presents a brief introduction to JIT II, lists the benefits that Bose has
      been able to obtain by implementing it, and indicates where it can be used to
      best effect.

PMID- 10345628
TI  - Affecting the value chain through supplier kaizen.
AB  - In the aerospace industry, typically 60 percent of a product's cost and 70
      percent of the lead time are due to purchased material. To affect price and
      customer responsiveness, improvement initiatives must be extended into the supply
      chain. Many companies have developed supply base management systems that include
      long-term agreements with suppliers, partnering with suppliers in risk taking and
      product design, information sharing, and quality and delivery rating systems. The
      premise is that suppliers are an extension of the factory. But to take full
      advantage of customer-supplier relationships, the suppliers must be "developed"
      in the same manner as a manufacturing unit. Supplier kaizen is a method of
      bringing suppliers to the same level of operations as the parent company, through
      training and improvement projects, to ensure superior performance and nurture the
      trust that is required for strong partnerships. This article describes Sikorsky
      Aircraft's use of kaizen to improve its supply base management.

PMID- 10345629
TI  - The role of certification in the buyer/planner position: a case study at Harley
      Davidson Motor Company.
AB  - The use of buyer/planners may becoming more popular. If they are, the reason is
      probably that many companies are integrating materiel management skill sets as a
      way of increasing the effectiveness of their supply chains. Harley-Davidson
      recently created a supply management function composed of buyer/planners. This
      article describes the method it used to achieve the transition, the training plan
      it implemented to support the process, and the role management played in
      achieving success.

PMID- 10345631
TI  - The basics of high-performance supplier certification.
AB  - Certification of supplier generally means that the supplier provides acceptable
      quality, on-time delivery at the lowest cost. Companies have devised numerous
      methods, criteria, formats, and approaches to certifying suppliers. Many of these
      are too complicated, not understandable, administratively difficult, or fail to
      be objective. If you have struggled with how to fashion a supplier certification
      program and how to have suppliers effectively embrace your program, this article
      is for you. It describes how to reduce the requirements to simple one-page
      format; details; three basic measures of performance that deal with quality,
      delivery, and cost; and provides several measurement-driven improvement actions.
      Supplier certification provides a simple, objective, mutually beneficial method
      of achieving high-quality, on-time delivery at the lowest cost.

PMID- 10345630
TI  - Designing automatic resupply systems.
AB  - This article outlines the process for designing and implementing autoresupply
      systems. The planning process includes determination of goals and appropriate
      participation. Different types of autoresupply mechanisms include kanban,
      breadman, consignment, systems contracts, and direct shipping from an MRP
      schedule.

PMID- 10345632
TI  - The receiving simplification partnership: a win-win approach to better service
      and higher profitability.
AB  - To achieve competitive advantage, customers and suppliers are increasingly
      forming logistics partnerships to improve supply chain performance and reduce
      costs. The partnerships are typically motivated by the need to solve a particular
      problem, but with attention and open communication, new program ideas can
      develop, sometimes even breakthrough concepts. During the course of their
      partnership, Avery Dennison and United Stationers created a program that
      dramatically simplifies and speeds receiving and put-away of shipments with the
      aim of reducing workloads, improving service, and increasing profitability. The
      program involves optimizing order quantity increments to full-pallet, layer, and
      case volumes based on demand and warehouse configurations. Within six weeks, the
      results included a 50 percent reduction in shipment line items and 92 percent
      fewer put-away pieces, despite unchanged inventory levels.

PMID- 10345633
TI  - When supply chain strategy changes, what doesn't change?
AB  - Although implementation of an assemble-to-order supply chain strategy can often
      improve customer service, the transition to an assemble-to-order system requires
      many new processes, organizations, and skills. This article, in describing how
      Etec Systems, a leader in patterning solutions for the semiconductor and
      electronics industries, has implemented an assemble-to-order strategy,
      illuminates some of the issues that will be faced by any company choosing such a
      strategy.

PMID- 10345634
TI  - Supply chain management.
AB  - This article describes how Do It Best Corp. has used technology to improve its
      supply chain management. Among other topics it discusses the company's use of
      electronic data interchange, the Internet, electronic forecasting, and warehouse
      management systems to gain substantial savings and increase its competitiveness.

PMID- 10345635
TI  - Management of quality, capacity, and productivity at Merck.
AB  - Merck is one of the largest manufacturers of drugs in the world. With emphasis on
      research and development and quality, it invents, develops, and markets a wide
      variety of human and animal health products. Merck-Medco is the industry leader
      in managed pharmaceutical care. Merck's productivity increases are largely
      attributed to procurement, inventory policies, capacity initiatives, and
      strategic alliances.

PMID- 10345636
TI  - Reengineering the front office: cashing in on the cash cow.
AB  - If a company can reengineer its business processes into modules that can be
      linked, unlinked, and relinked inexpensively, seamlessly, and instantly, it will
      be able to provide unique value to each and every customer. A modular approach
      presents a unique opportunity to create significant value and offer customers a
      proposition that is impossible or at least extremely difficult for your
      competition to duplicate. This article explains how to reengineer individual
      processes in light of the overall business strategy chosen by a company.

PMID- 10345638
TI  - Information systems. Quality information, quality care.

PMID- 10345637
TI  - Security. For your eyes only?

PMID- 10345639
TI  - Information systems. Paris nexus.

PMID- 10345640
TI  - Strategy. Beacon work it out.

PMID- 10345641
TI  - Patient records. On the records.

PMID- 10345643
TI  - Buildings. More bricks than kicks.

PMID- 10345642
TI  - Health Management Awards. Winners all.

PMID- 10345644
TI  - Hospital admissions. Cold remedies.
AB  - The closure of a casualty department provoked a crisis in Hillingdon in the
      winter of 1996-97. Worried by the publicity, elderly people contacted the health
      authority to ask what would happen to them if they became ill. An all-day
      workshop, attended by elderly people, chief executives, nurses, social workers
      and representatives from the community health council and ambulance services, led
      to several initiatives, including a rapid response home service, which helped
      prevent a crisis last winter.

PMID- 10345645
TI  - Guide to hernia repair. Strain of thought.

PMID- 10345646
TI  - Radiology. X-rated.

PMID- 10345647
TI  - Mental health. Special agents.

PMID- 10345648
TI  - Drug prescribing. Licensing flaws.

PMID- 10345649
TI  - Bangs and M*A*S*H.

PMID- 10345650
TI  - Health authorities. HAs beens?
AB  - Health authorities are likely to emerge as the poor relations in the current NHS
      reorganisation, just as they did following the 1990 reforms. Planning for health
      is a key NHS task and primary care groups will not be large enough to take it on.
      Radical thinking is needed. Future options include abolishing HAs and making
      local authorities, regional government or NHS regions responsible for planning.
      Another option would be creating fewer, bigger authorities for strategic
      planning.

PMID- 10345651
TI  - First person. Panel games.

PMID- 10345652
TI  - Community care. Home service.
AB  - A nurse-led scheme to prevent hospital admissions by providing emergency services
      in the community for up to 72 hours cared for 155 people in its first six months.
      The scheme operated well below full capacity partly because of initial opposition
      from GPs. The mean age of service users was 79 and the main reasons for referral
      were chest infections, pneumonia and the need for support following an injury.
      More than three quarters of those cared for were fit to be discharged from the
      scheme within 72 hours.

PMID- 10345653
TI  - Middle management. Courtin' the middle.
AB  - Middle managers are essential to organisations but are often unsupported by those
      above them and reviled by those they supervise. Effective middle managers keep
      top managers in touch with reality and reinterpret policy and strategy so
      operational staff understand the point. Organisations should reassure middle
      managers about the validity of their work and provide continuing education.

PMID- 10345654
TI  - Winter pressures. Lazy days of summer.
AB  - The relationship between increased emergency admissions and longer waiting lists
      in winter has not been proven. Waiting lists are more likely to be affected by
      patterns of elective work than emergency admissions. Slowdown in elective work in
      summer is at the root of winter problems.

PMID- 10345656
TI  - The liability insurance you didn't know you needed.

PMID- 10345655
TI  - First person. We ain't seen nothing yet.

PMID- 10345657
TI  - Going toe-to-toe with Blue Shield--for $110,000.

PMID- 10345658
TI  - The PPM meltdown. How FPA's implosion buried its doctors.

PMID- 10345659
TI  - The PPM meltdown. If your group collapsed, where would you go?

PMID- 10345660
TI  - The PPM meltdown. What practices are worth in today's market.

PMID- 10345662
TI  - Health promotion. Employers are pushing preventive care--hard.

PMID- 10345661
TI  - The family kept hoping for a miracle.

PMID- 10345663
TI  - The clock is ticking on patient privacy.

PMID- 10345664
TI  - Why I pay all the bills for our practice.

PMID- 10345665
TI  - Hospitalists are a lousy idea.

PMID- 10345666
TI  - 10 lessons you can learn from my malpractice suit.

PMID- 10345667
TI  - Do yourself a favor--take care of nursing-home patients.

PMID- 10345668
TI  - Giving kids a head start on health.

PMID- 10345669
TI  - Midlevel providers: making their mark in doctors' offices.

PMID- 10345670
TI  - What kind of patient would rather see a nurse practitioner?

PMID- 10345671
TI  - You and midlevel providers--a good fit?

PMID- 10345672
TI  - Intimations of mortality.

PMID- 10345673
TI  - Compensation. A ho-hum year for group doctors' pay.

PMID- 10345674
TI  - Warning from Dallas: doctors, grab your slingshots!

PMID- 10345675
TI  - Is Medicare in worse shape than we think?. Interview by Michael Pretzer.

PMID- 10345676
TI  - Here's a switch: a group that's happy with its PPM deal.

PMID- 10345677
TI  - Patients you learn from--and never forget.

PMID- 10345678
TI  - The jury cleared me--and I had to know why.

PMID- 10345679
TI  - How to get up to speed on alternative medicine.

PMID- 10345680
TI  - Half empty or half full? How doctors are recapturing the joy of medicine.

PMID- 10345682
TI  - How I'm going to make doctoring fun again.

PMID- 10345681
TI  - Four happy doctors: what's their secret?. Interview by Neil Chesanow.

PMID- 10345683
TI  - In my business, my MD didn't count.

PMID- 10345684
TI  - My partner's privacy had a price--and I paid it.

PMID- 10345685
TI  - Medicare's top doctor tells what's coming. Interview by Michael Pretzer.

PMID- 10345687
TI  - Always running behind? Try these time-management tips.

PMID- 10345686
TI  - A dying man on Death Row: testing the Hippocratic oath.

PMID- 10345689
TI  - SEIU alliance targets docs.

PMID- 10345688
TI  - Coram posts smallest loss in two years.

PMID- 10345690
TI  - Health Midwest mega-deal shakes out. System gets almost 35% of market share in
      Kansas City area--and avoids antitrust review.

PMID- 10345691
TI  - Goodbye Cleveland. Columbia to sell stake in controversial joint venture;
      hospitals to regain not-for-profit status.

PMID- 10345692
TI  - HCIA study assesses heart programs.

PMID- 10345693
TI  - Ruling allows alternative-care law to proceed.

PMID- 10345694
TI  - Lawmakers define medical necessity.

PMID- 10345695
TI  - Inspector general uses midlevel penalties.

PMID- 10345697
TI  - Uninsured may be part of shell game.

PMID- 10345696
TI  - Hospitals warming up to JCAHO policy. Number of sentinel events has remained
      constant, but more hospitals are self-reporting.

PMID- 10345698
TI  - There's no place like home. Despite the IPS, home health agencies can survive if
      they do research and tailor their services.

PMID- 10345700
TI  - ACHE honors healthcare executive. Rulon Stacey built a five-hospital system in
      Colorado from foundation of employee trust.

PMID- 10345699
TI  - It's lucrative at the top. IRS filings of not-for-profit healthcare associations
      show top execs are well paid.
AB  - It truly pays to be the chief executive of a not-for-profit healthcare
      association. In many cases it pays extremely well. How much do they make? To
      answer that question Modern Healthcare took a look at IRS Forms 990 filed by 34
      of the leading healthcare organizations. See page 46 to match the faces on the
      cover with their salaries.

PMID- 10345701
TI  - Executives to receive Gold Medals. 'Outstanding individuals' Leo Greenawalt, Gail
      Warden achieve highest ACHE award.

PMID- 10345702
TI  - Foreign-born workers still in limbo. INS' delay in developing guidelines for 1996
      law has generated procedural snafus, lawsuit.

PMID- 10345703
TI  - Davidson recuperating from heart surgery.

PMID- 10345704
TI  - Bailing out. Washington state HMOs cite mounting losses, flawed state programs as
      they drop coverage.

PMID- 10345705
TI  - Lower-rated hospitals take a beating ... but even mightiest systems have fallen.

PMID- 10345706
TI  - Disputing the record. New York hospitals furious over state report showing
      industry posted record profits in '97.

PMID- 10345707
TI  - Dallas-area behemoths set to affiliate.

PMID- 10345708
TI  - Kickback trial begins. Defendants charged with illegally referring patients to
      hospitals.

PMID- 10345709
TI  - The outcome is innovation. BJC Health System wins national award for quality
      improvement program.

PMID- 10345710
TI  - VA needs funding, not privatization. Department has provided medical advances,
      quality care that couldn't be repeated elsewhere.

PMID- 10345711
TI  - Growing strong. New government programs, building boom among positive vital signs
      for children's hospitals.
AB  - With 85% of kids in the U.S. covered by insurance, and their number expected to
      rise to 80 million by 2020, children's hospitals aren't just playing games.
      They're building new campuses, expanding existing hospitals, and taking advantage
      of private donations and the "kid-care" program.

PMID- 10345712
TI  - Fla. hospital partnership investigated.

PMID- 10345713
TI  - Healthcare IT innovations win awards.

PMID- 10345714
TI  - When the continuum starts at home. Some systems building low-income housing to
      serve patients, create a steady client base.

PMID- 10345715
TI  - HIMSS is wired to help zap the Y2K bug.

PMID- 10345716
TI  - Washington hospital out of bankruptcy.

PMID- 10345717
TI  - Panel hits snag over prescription benefits.

PMID- 10345718
TI  - AHA makes changes in executive ranks.

PMID- 10345719
TI  - Hospital profits up, care for poor down.

PMID- 10345720
TI  - Merger backlash. Vicksburg officials think hospitals betrayed agreement.

PMID- 10345721
TI  - Healthcare on trial. Kansas City conspiracy case could have broad impact on the
      industry's business practices.
AB  - Seven Kansas City hospital executives, physicians and lawyers are on trial for
      running an illegal patients-for-cash scam. But also on trial is the
      corporatization of healthcare, which began when the federal government changed
      the way Medicare and Medicaid pay providers for care.

PMID- 10345722
TI  - Down on its luck. Rural Nevada hospital receives cash infusion, but its long-term
      outlook remains dicey.

PMID- 10345723
TI  - Taking a new spin. Catholic providers road-test an integrated delivery system.

PMID- 10345724
TI  - ACHE preview. Raising management to lofty standards.

PMID- 10345725
TI  - ACHE preview. A strategy for healthy communities.

PMID- 10345726
TI  - ACHE preview. Healthcare in the new millennium.

PMID- 10345727
TI  - ACHE preview. Strategies for boosting revenues.

PMID- 10345728
TI  - ACHE preview. An exploration of alternative medicine.

PMID- 10345729
TI  - ACHE preview. Integrating business, clinical applications.

PMID- 10345730
TI  - ACHE preview. Hospitals, docs benefit from gain-sharing.

PMID- 10345731
TI  - ACHE preview. The logic behind anti-fraud laws.

PMID- 10345732
TI  - ACHE preview. Maximizing payments for post-acute care.

PMID- 10345733
TI  - ACHE preview. Networking helps execs get ahead.

PMID- 10345734
TI  - ACHE preview. An everyday approach to JCAHO compliance.

PMID- 10345735
TI  - Y2K: the budget-eating bug takes over. Survey shows healthcare organizations are
      delaying other information system improvements.

PMID- 10345736
TI  - Buyers of practices become pickier.

PMID- 10345738
TI  - Healthcare giant on a diet. After four years of digesting mergers and
      acquisitions, Tenet plans to shed 20 hospitals.

PMID- 10345737
TI  - Bruising battles ahead for providers, HMOs.

PMID- 10345739
TI  - HCFA raises the bar for fraud detection.

PMID- 10345740
TI  - Breaking up in New Jersey. Systems abandon deal, citing disagreement over
      integration; Catholic network to dissolve.

PMID- 10345741
TI  - HMOs cause systems' rating hits. And when plans are sold, the outlook may
      improve.

PMID- 10345742
TI  - Bad-debt write-offs on the rise.

PMID- 10345743
TI  - Docs' suit puts spotlight on referrals.

PMID- 10345744
TI  - Physician execs are happy with careers.

PMID- 10345745
TI  - Clinton seeks checkmate on entitlements.

PMID- 10345746
TI  - What we've learned from AHERF. Trustees on healthcare boards can use audits to
      improve relationships with their communities.

PMID- 10345748
TI  - Consolidation is king in San Francisco market. Four systems control the Bay Area,
      independent hospitals depart.

PMID- 10345747
TI  - Y2K: ready or not ... survey: millennium bug is sapping time and resources, but
      execs are glancing beyond 2000.
AB  - Healthcare systems looking to power their networks with state-of-the-art
      information systems have been stung by the millennium bug. But if there is a
      silver lining to this infestation, it's that senior executives have come to find
      out the real value of their computer networks.

PMID- 10345749
TI  - A casualty of Medicare. Skilled-nursing facilities provide higher level of care
      yet receive fewer funds under new PPS.

PMID- 10345750
TI  - More hospitals buy into device recycling. The practice of reprocessing disposable
      products is moving into the medical mainstream.

PMID- 10345751
TI  - REITs fall out of favor with CFOs, investors.

PMID- 10345752
TI  - Receiving the buck. IS professionals say they have resources to battle Y2K bug.

PMID- 10345753
TI  - PhyCor to sell clinic to Healthshare Group.

PMID- 10345754
TI  - Madness comes a month early. February was chock full of corporate retrenchments,
      broken deals and red ink.
AB  - After a slew of retrenchments, split-ups and sliding profits last month,
      healthcare companies are learning that they probably need to change their game
      plans and get back to basics. Experts say the same cycle has occurred in other
      industries and is expected in healthcare.

PMID- 10345755
TI  - Columbia endures a week of setbacks.

PMID- 10345756
TI  - Trial date set to test joint agreements.

PMID- 10345757
TI  - Bipartisanship sinking. Democrats on commission charge 'premium support' plan a
      ruse to privatize Medicare.

PMID- 10345758
TI  - Providers learn to adapt in tough Albuquerque market. Resources are limited, but
      a new heart hospital is under way.

PMID- 10345760
TI  - Screenings in the bag at Cincinnati stores.

PMID- 10345759
TI  - Dealing with docs. Dropping money-losing practices can be a costly decision.

PMID- 10345761
TI  - HCFA issues procedures for imposing penalties for Medicare/Medicaid violations.

PMID- 10345762
TI  - Interfacing legacy billing and contract management systems: a case study.

PMID- 10345763
TI  - OIG compliance guidance for third-party billing companies released.

PMID- 10345764
TI  - Telemedicine finds its way into the Outback.

PMID- 10345765
TI  - Special report: emerging technologies. Body language.

PMID- 10345766
TI  - Date with destiny.
AB  - The focus of healthcare IT has tended to be on the back end: billing, financial
      systems and administration. This is now changing as healthcare facilities realize
      that patients are customers, and more emphasis must be placed on that first
      patient contact: scheduling.

PMID- 10345767
TI  - The latest word. 1999 pre-HIMSS industry glossary.

PMID- 10345768
TI  - The bug zapper. CIOs reveal red flags in Y2K compliance efforts.

PMID- 10345769
TI  - Avoid the paper chase. Real-time, wireless patient documentation helps therapists
      save both time and money.
AB  - Good Shepherd Medical Center's physical therapy clinic, Longview, Texas. PROBLEM:
      Streamlining documentation processes in hard-to-reach areas of an off-site
      facility. SOLUTION: Implementing handheld, point-of-care devices for real-time
      documentation. RESULTS: Reduction in the time and effort physical therapists
      spend on "back office" documentation procedures. KEYS TO SUCCESS. "With the
      wireless link the staff doesn't have to concern itself with technical terms,
      uploads and network logons. They just enter their information by answering pre
      programmed prompts. The information flows over to the host computer in real
      time."

PMID- 10345771
TI  - Stand and deliver. Better access to clinical decision support promises better
      care management.

PMID- 10345770
TI  - Future shock. Lutheran Medical Center builds network for tomorrow's applications.
AB  - Lutheran Medical Center, a 501-bed acute care teaching hospital in Brooklyn, with
      eight health centers located throughout New York City. PROBLEM: Lutheran's
      current patient care systems did not have enough scalability or bandwidth to
      support its applications. SOLUTION: A networking partner to deliver an
      infrastructure designed to meet Lutheran's applications' needs. RESULTS: An
      efficient, effective and easy-to-manage network. Routing performance and capacity
      issues are no longer a problem. KEYS TO SUCCESS: "Ask yourself what networking
      applications your organization will need in 2008 and then upgrade your systems to
      meet those needs."

PMID- 10345772
TI  - Needlestick-prevention devices.

PMID- 10345773
TI  - The people vs HMOs.

PMID- 10345774
TI  - Coaching children to participate in healthcare decisionmaking.

PMID- 10345775
TI  - Taking uncertainty out of asthma treatment.
AB  - Physicians at Texas Children's Hospital developed the following asthma action
      plans--one for primary care, the other for discharge from acute care or the
      emergency department--to help parents determine when to seek treatment for their
      children and when and how to treat them at home for minor events.

PMID- 10345776
TI  - Study links morbidity risk to number of primary care physicians seen.

PMID- 10345777
TI  - Collaboration helps N.E. hospitals improve cardiac surgery.

PMID- 10345778
TI  - Focusing on children's healthcare quality.
AB  - Clinicians trying to improve healthcare for children are challenged by a relative
      scarcity of data and children's dependence on their parents. Innovative programs
      are looking at children's health at home and in the community, and involving
      schools and parents in tackling asthma and other pediatric health problems.

PMID- 10345779
TI  - Assessment of U.S. helicopter emergency medical services' planning and
      preparedness for disaster response.
AB  - INTRODUCTION: Helicopter emergency medical services (HEMS) roles in disaster
      response vary significantly from routine operation, and as reported in the
      literature, such responses have not been without difficulty. We identified nine
      criteria (written policy, triage and incident command training disaster drill
      participation, ground and air communications plan, critical incident stress
      management, annual review, policy sharing) that may significantly affected an air
      medical program's disaster preparedness, response, and recovery. Of these
      criteria, a written policy is considered of primary importance. METHODS: A
      written survey was developed and mailed in July 1995 to 187 U.S. rotor-wing
      members of the Association of Air Medical Services. The survey was designed to
      identify the programs that had a written policy and fulfilled the guideline
      criteria, had a written policy and partially fulfilled the criteria, or did not
      have a written policy. RESULTS: Surveys were returned from 104 (56%) programs. Of
      the 103 qualifying respondents, 16 (16%) meet the criteria, 55 (53%) partially
      met the criteria, and 32 (31%) did not have written policies. CONCLUSION: Most
      U.S. HEMS programs have not fully addressed disaster preparedness, response, and
      recovery. HEMS disaster response guidelines should be established, and these
      criteria should be incorporated.

PMID- 10345780
TI  - Air medical program merger and stress.
AB  - INTRODUCTION: How does the stress of a program merger affect job stress in air
      medical transport? METHODS: This study was an anonymous survey of 104 transport
      personnel in a Mid-western critical care transport program with merged air and
      ground components. Tools included the Social Readjustment Rating Scale (SRRS),
      which quantitates stressful life events on a weighted scale that allows summation
      as a score, and the Medical Personnel Stress Survey (MPSS), which quantitates
      work stress in four categories: organizational stress (OS) related to work
      environment, frustration/exhaustion (FE) related to patient care, job
      satisfaction (JS) related to decreased self-worth, and psychosomatic complaints
      (PC), stress manifested as personal illness. Statistical analysis was performed
      with a variety of tools. RESULTS: Fifty of 104 personnel responded completely.
      The average SRRS was low at 130.9; only 20% had scores above 200. No significant
      differences in MPSS occurred in personnel with high and low SRRS scores.
      Additionally, the SRRS correlated weakly with OS (r = -0.297, P < 0.05). Within
      the MPSS, OS correlated with FE and JS (r = 0.493, P = 0.0005; r = -0.593, P <
      0.0001) and FE correlated with JS (r = -0.36, P = 0.01). CONCLUSION: The overall
      personnel stress levels in this air medical program with merged air and ground
      components were low and appeared to be unrelated to organizational stress. This
      finding may be a result in part of the careful attention paid to stress and the
      elimination of stressors during the merger process.

PMID- 10345782
TI  - Basics of research (Part 14). Survey research methodology: designing the survey
      instrument.

PMID- 10345781
TI  - Efficacy of 24-hour shifts: prepared or impaired? A prospective study.
AB  - BACKGROUND: The effect of duty duration on performances is unknown. In a
      prospective cohort study model using repeated measures, we evaluated the effect
      of shift length on a battery of neuropsychologic performance indicators using our
      flight program as the test site. METHODS: Flight nurses completing 24- and 12
      hour shifts were tested on memory, attention, reasoning, motor, and speed
      measures. Ratings of stress, fatigue, sleep quality, and logged amount of work
      and sleep were evaluated from personal journals kept for this purpose. Data were
      analyzed by linear regression and repeated measures multivariate analysis of
      variance (MANOVA) and analysis of variance (ANOVA). Clinical significance was set
      at P < 0.05. RESULTS: Fifteen subjects completed the testing and evaluation
      process. Neuropsychologic testing demonstrated that performance was not predicted
      by shift length, time of shift (day versus night), amount or quality of sleep
      before or during shift, or fatigue ratings. Age, gender, and education did not
      mediate shift length/test performance relationships. Uninterrupted sleep, stress
      ratings, and number of flights per shift modestly reduced some test scores.
      Predictably, repeated testings resulted in practice effects that reduced analysis
      power. We found that 24-hour shifts per se do not result in a cognitive decline
      compared with 12-hour shifts. Inconsistent sleep, number of flights, and the
      stressfulness of flights may have greater impact.

PMID- 10345783
TI  - Did you bring two isolettes? Transport of conjoined twins.

PMID- 10345784
TI  - Business principles for air medical professionals. Part 4: Bringing financial
      statements to life.

PMID- 10345785
TI  - A descriptive analysis of air medical directors in the United States.
AB  - INTRODUCTION: The purpose of this study was to describe the characteristics and
      functions of U.S. physician air medical directors. METHODS: This descriptive
      study included physician directors of U.S. rotor-wing and fixed-wing air medical
      services. Data were obtained using a standardized survey in regard to the
      training, education, and roles/responsibilities of directors of critical care air
      medical services (AMSs). RESULTS: Data from 153 of 276 surveys (55.4%) were
      analyzed and reported in this study. Air medical directors' residency training
      varied, but emergency medicine was the most frequently reported training type
      (38.0%). Most directors reported less than 5 years of job experience in AMS
      (57.3%), had neither residency/fellowship-based flight experience (63.9%) nor
      practical flight experience (60.5%), and performed director functions on a part
      time basis (93.2%). The six most commonly reported medical director activities
      were medical protocol development (87.6%), quality improvement activities
      (86.3%), medical crew training (80.4%), administrative negotiations (79.1%), on
      line medical control (71.9%), and personnel hiring (59.5%). The three most common
      sources of continuing education for medical directors were literature review
      (95.8%), attendance at medical conferences (79.2%), and participation in
      professional organizations (59.7%). CONCLUSION: These data describe the
      characteristics of U.S. air medical directors and identify physician
      contributions to patient care in the aviation environment.

PMID- 10345786
TI  - Confidence in health care at what cost? Results from the 1998 Health Confidence
      Survey.
AB  - This Issue Brief presents the findings from the 1998 Health Confidence Survey. It
      focuses on Americans' satisfaction with the health care system and their
      confidence in the system's future. Only 5 percent of Americans give an excellent
      rating to health care in America today. However, while just over one-half rate
      health care as excellent, very good, or good, almost one-half (46 percent) rate
      it as fair or poor. When asked what they consider to be the most critical issue
      in America today, 15 percent of Americans cite health care. Overall, Americans
      are not extremely confident about various aspects of health care in the next 10
      years. Only 10 percent are extremely confident that they will be able to get the
      medical treatments they need during this period, while 22 percent are not
      confident. Americans are even less confident that they will have access to
      quality health care (26 percent not confident), that they will have enough
      freedom to choose their health care provider (36 percent not confident), and that
      they will be able to afford health care without suffering financial hardship (41
      percent not confident). The nonelderly population is even less confident about
      health care once they become eligible for Medicare. Americans are clearly
      confused about the meaning of managed care and whether they are enrolled in a
      managed care plan. While 70 percent of those who were determined to be enrolled
      in a managed care plan label the plan correctly, only 21 percent report that they
      are currently enrolled in a managed care plan. Most American have opinions about
      managed care. However, only 28 percent of Americans form their opinions about
      managed care based on their own personal experience. Twenty-three percent base
      their opinion on what they learn from family and friends, and 29 percent base it
      on what they hear or see in the media. While few Americans give managed care an
      excellent rating, few give it a poor rating. Most Americans rate managed care
      somewhere in the middle. Americans are particularly concerned about health care
      costs. Over 30 percent are not satisfied with the cost of their health insurance
      over the last 2 years, and 37 percent are not satisfied with the health care
      costs that are not covered by their health plan. These numbers compare with
      higher satisfaction levels concerning choice of physician, quality of care
      received, treatments received, hospitals used, and benefits covered by health
      plans.

PMID- 10345787
TI  - What is your savings personality? The 1998 Retirement Confidence Survey.
AB  - This Issue Brief presents the findings of the 1998 Retirement Confidence Survey
      (RCS). The survey tracks Americans' retirement planning and saving behavior and
      their confidence regarding various aspects of their retirement. It also
      categorizes workers and retirees into six distinct groups, based on their very
      different views on retirement, retirement planning, and saving. The six
      personality types identified in the RCS are Deniers (10 percent of the
      population), Strugglers (9 percent), Impulsives (20 percent), Cautious Savers (21
      percent), Planners (23 percent), and Retiring Savers (17 percent). The survey
      shows that working Americans have become more focused on retirement; 45 percent
      have tried to determine how much they need to save before they retire, up from 32
      percent in 1996. Americans' growing attention to their retirement has not
      increased their retirement income confidence. Since 1993, the portion of working
      Americans who are very confident that they will have enough money to live
      comfortably throughout retirement has consistently ranged from 20 percent to 25
      percent. Sixty-three percent of Americans have begun to save for retirement.
      Fifty-five percent of those not saving for retirement say it is reasonably
      possible for them to save $20 per week (over $1,000 per year). In addition, 57
      percent of workers who have begun to save say that it is reasonably possible for
      them to save an additional $20 per week. The findings demonstrate the continuing
      need for broad-based educational efforts designed to make retirement savings a
      priority for individuals. The good news is the evidence that education can have a
      real impact at the individual level. For the first time the 1998 RCS examined
      retirement planning, saving, and attitudes across ethnic groups (African
      Americans, Hispanic-Americans, Asian-Americans, and whites). African-Americans
      are the least confident that they will have enough money to live comfortably in
      retirement. African-Americans and Hispanic-Americans are less likely than whites
      and Asian-Americans to have saved any money for retirement. Among those saving
      for retirement, individuals' confidence that they are investing their retirement
      savings wisely does not differ among ethnic groups. Hispanic-Americans are less
      likely than whites and Asian-Americans to have made an attempt to determine how
      much money they will need to have saved by the time they retire.

PMID- 10345788
TI  - Features of employment-based health plans.
AB  - This Issue Brief focuses on changes to the health care financing and delivery
      system as implemented by employers. It discusses health plan costs, cost sharing,
      plan funding, health care delivery systems, services covered under various health
      plan types, coverage limitations, and retiree health coverage. National health
      expenditures are estimated at $1.035 trillion, representing 13.6 percent of Gross
      Domestic Product in 1996, up from $699.5 billion and 12.2 percent in 1990. Rising
      health care spending is also evident at the employer level: In 1996, employer
      spending on private health insurance totaled $262.7 billion, up from $61.0
      billion in 1980. Business health spending as a percentage of total compensation
      increased from 3.7 percent in 1980 to a high of 6.6 percent in 1993, and declined
      to 5.9 percent in 1996. Employment-based health plans are the most common source
      of health insurance coverage among the nonelderly population in the United
      States, providing coverage to nearly two-thirds of those under age 65. Despite
      the growth of many cost-sharing provisions, individuals are paying a smaller
      percentage of total health care costs. In 1960, 69 percent of private health care
      expenditures were paid out of pocket. Between 1993 and 1996, only 37 percent of
      private health expenditures were paid out of pocket. One of the most significant
      developments of the 1980s, which has continued throughout the 1990s, is the
      growth of managed care plans. As recently as 1994, traditional indemnity plans
      were the most commonly offered type of employment-based health plan. As fewer
      employers offered traditional indemnity plans, participation in these plans
      declined and participation in managed care plans increased. In 1997, 15 percent
      of employees participating in a health plan were enrolled in an indemnity plan,
      compared with 52 percent in 1992. Since 1993, employment-based health benefit
      cost inflation has been virtually nonexistent. Employers have kept cost increases
      low by using managed care and making other changes. Workers have been shifted to,
      have been induced to choose, or have voluntarily selected managed care health
      plans. Preferred provider organization (PPO) and point-of-service (POS) plans
      have experienced relatively strong gains in enrollment. Employers have also
      increased the use of utilization review for active workers, and cut back on
      health benefits for retirees. These changes are in stark contrast to the pre-1993
      period, which saw even faster change, with rising health care costs and
      increasing deductibles and coinsurance for workers in non-HMOs.

PMID- 10345789
TI  - Small employers and the challenge of sponsoring a retirement plan: results of the
      1998 Small Employer Retirement Survey.
AB  - Forty-two million individuals work for small employers; 9 million are
      participating in an employment-based retirement plan, while 33 million are not
      participating in a plan. This Issue Brief examines the barriers that prevent
      small employers from sponsoring a retirement plan, their level of knowledge about
      plans, and changes that might lead to plan sponsorship. It also examines the
      motivations of small employers that sponsor retirement plans. Small employers
      identify three main reasons for not offering a plan: employees' preferences for
      wages and/or other benefits, administrative costs, and uncertain revenue that
      makes it difficult to commit to a plan. Small employers without plans report
      being familiar with 401(k) and profit-sharing plans, but little else. Forty-seven
      percent report never having heard of the savings incentive match plan for
      employees (SIMPLE), and 55 percent report never having heard of simplified
      employee pensions (SEPs). There is apparent misunderstanding about retirement
      plans among small employers that do not sponsor one, especially with regard to
      costs. For example, 35 percent do not know that a plan can be set up for less
      than $2,000. What changes would lead to serious consideration of retirement plan
      sponsorship? In order of reported importance: increased company profits (66
      percent), a business tax credit (64 percent), reduced administrative requirements
      (50 percent), demand from employees (49 percent), allowing key executives to save
      more in the plan (49 percent), and easing, i.e., lengthening, of vesting
      requirements (40 percent). Many small employers that sponsor a retirement plan
      cite business reasons among their motivations. Sixty-eight percent cite a
      "positive effect on employee attitude and performance" as a major reason for
      offering a plan. Fifty-six percent cite a "competitive advantage in employee
      recruitment and retention" as a major reason. Small employers with a retirement
      plan report direct benefits from sponsorship, but many of those without plans
      appear unaware of these potential benefits. The 1998 SERS indicates that
      effective public policy must educate workers regarding the need to make
      retirement planning and saving a priority, in addition to addressing employer
      concerns about offering plans. Furthermore, there is a need to educate small
      employers about the options available to them and what these options entail.
      Finally, it appears that many employers need to be informed of the potential
      benefits from plan sponsorship.

PMID- 10345790
TI  - Individual social security accounts: issues in assessing administrative
      feasibility and costs.
AB  - Whether to add individual accounts (IAs) to the Social Security system is a
      highly political issue. But almost lost in the debate so far have been any
      practical considerations about how to administer such accounts. Any discussion of
      whether to create individual accounts must also address the basic but critical
      questions of how they would work: Who would run them? What would they cost?
      Logistically, are they even possible? This EBRI Issue Brief provides an overview
      of the most salient administrative issues facing the current Social Security
      reform debate--issues that challenge proponents to carefully think through how
      their proposals could be implemented so as to achieve their policy goals. The
      options and difficulties in administering IAs raise concerns that cut across
      ideology. The object of this report is neither to dissuade the advocates nor
      support the critics of individual accounts. Rather, it is to bring practical
      considerations to a political debate that has largely ignored the pragmatic
      challenges of whether IAs would be too complex for participants to understand or
      too difficult for record keepers to administer. The major findings in this
      analysis include: Adding individual accounts to Social Security could be the
      largest undertaking in the history of the U.S. financial market, and no system to
      date has the capacity to administer such a system. The number of workers
      currently covered by Social Security--the largest single entitlement program in
      the nation--is at least four times higher than the combined number of all tax
      favored employment-based retirement accounts in the United States, which are
      administered by hundreds of entities. Direct comparisons between employment-based
      retirement savings plans and Social Security reform are tenuous at best. Social
      Security covers workers and businesses that are disproportionately excluded from
      employment-based plans. Because of these differences, a system of individual
      Social Security accounts would be more difficult to administer than employment
      based plans, and total administrative expenses would be larger relative to
      benefits. Credit-based systems such as the current Social Security program are
      less difficult to administer than cash-based systems, which must account for
      every dollar. Inherent in the "privatization" debate is generally the presumption
      that IA benefits would be based on cash contributions and investment returns. The
      current credit-based system tolerates small errors in wage reporting, because
      they rarely affect benefits. But every dollar counts in a cash-based IA system.
      To ensure that benefits are properly provided, an IA system would require more
      regulation, oversight, and error reconciliation than the current Social Security
      program. Social Security individual accounts cannot be administered like 401(k)
      plans without adding significant employer burdens--especially on small
      businesses. Under the current wage reporting and tax collection process, it would
      take at least 7-19 months for every dollar contributed to an individual's account
      to be sorted out from aggregate payments and credited to his or her IA. This 7-19
      month "float period" could result in substantial benefit losses over time.
      Options for preventing such losses involve difficult trade-offs, such as
      increased government responsibility, increased complexity, greater employer
      burdens, and/or investment restrictions for beneficiaries. If legally considered
      personal property, the IAs of married participants could pose significant
      administrative challenges. Social Security today must obtain proof of marriage
      only at the time spousal benefits are claimed. But some IA proposals would
      require contributions to be split between spouses' individual accounts, requiring
      records on participants' marital status to be continuously update to ensure that
      contributions are correctly directed. Also, dealing with claims on individual
      account contributions in divorce cases could place IA record keepers in the
      middle o

PMID- 10345791
TI  - Sources of health insurance and characteristics of the uninsured: analysis of the
      March 1998 Current Population Survey.
AB  - This Issue Brief provides summary data on the insured and uninsured populations
      in the nation and in each state. It discusses the characteristics most closely
      related to individuals' health insurance status. Based on EBRI analysis of the
      March 1998 Current Population Survey, it represents 1997 data--the most recent
      data available. In 1997, private or public health insurance, or both, covered
      81.7 percent of Americans (193.1 million) at some point. Seventy-one percent of
      the nonelderly population had private insurance, 64.2 percent through an
      employment-based plan. Almost 15 percent of the nonelderly had public health
      insurance. In 1997, 18.3 percent of the nonelderly population was uninsured,
      compared with 14.8 percent a decade earlier, in 1987. The percentage of uninsured
      Americans has been increasing since at least 1987. While the increase in the
      uninsured between 1987 and 1993 can be attributed to the erosion of employment
      based health benefits, the portion of Americans covered by employment-based
      health insurance increased between 1993 (63.5 percent) and 1997 (64.2 percent).
      The decline in public sources of health insurance would mostly explain the recent
      increase in the uninsured population. For example, between 1994 and 1996 the
      percentage of nonelderly Americans covered by CHAMPUS/CHAMPVA declined from 3.8
      percent to 2.9 percent, in large part due to downsizing in the military.
      Similarly, between 1996 and 1997, the percentage of nonelderly Americans covered
      by Medicaid (the federal-state insurance program for the poor) declined from 12.1
      percent to 11.0 percent as people left welfare for the private sector. This
      follows a decline in Medicaid participation between 1995 and 1996. Between 1996
      and 1997 the percentage of nonelderly Americans without health insurance coverage
      increased from 17.7 percent to 18.3 percent. Further examination indicates that
      adults ages 18-64 accounted for almost all of this increase. In 1996, 14.8
      percent of children and 18.9 percent of persons ages 18-64 were uninsured,
      compared with 15.0 percent of children and 19.7 percent of persons ages 18-64 in
      1997. The decline in Medicaid coverage among nonworking and working adults
      appears to account for the overall increase in the uninsured. Employment and
      income play a dominant role in determining an individual's likelihood of having
      health insurance. In addition, age, gender, firm size, hours of work, and
      industry are all important determinants of an individual's likelihood of having
      coverage; however, these variables are also closely linked to employment status
      and income. Some of the widest variations involve factors that are not always
      examined in traditional demographic assessments, such as citizenship. However,
      variations by race, ethnicity, and citizenship are also closely linked to
      employment status and income.

PMID- 10345792
TI  - A different kind of house call.

PMID- 10345793
TI  - Leading an expedition.

PMID- 10345795
TI  - Are your systems really ready for year 2000?

PMID- 10345794
TI  - Assembling the records puzzle.

PMID- 10345796
TI  - Luring new recruits.

PMID- 10345797
TI  - Avoiding medication errors.

PMID- 10345798
TI  - Repricing claims on the Web.

PMID- 10345799
TI  - Top 10 health care trends for 1999.

PMID- 10345800
TI  - Review of 1998 trends was ninety percent accurate.

PMID- 10345801
TI  - Risk adjustment wrinkle.
AB  - Health plans and providers contracting under Medicare risk want greater equity
      and the right incentives. Clinical risk adjustment, already being tried in
      various forms on the private health insurance side, seems to offer a good
      solution. But the tremendous lack of outpatient data for risk adjustment is
      throwing up a very big obstacle to the evolution of the Medicare+Choice program,
      and could result in bad public policy, some industry observers warn. Is the
      federal government about to make a policy misstep at a critical moment in the
      Medicare program's development?

PMID- 10345802
TI  - Feeling the backhand of capitation.

PMID- 10345803
TI  - Ready for the empowered consumer? Providers need retailer's attitude.
AB  - The aging of baby boomers and the rise in popularity of the internet are creating
      a new kind of consumer who demands quality, service, and convenience from health
      care. To find out how to meet those demands, providers are beginning to benchmark
      with retail companies experienced in catering to consumers. Retailers can offer
      help for such processes as inpatient admitting, marketing, billing, sales,
      product development, and recruiting and retaining employees.

PMID- 10345804
TI  - Asthma project cuts hospitalizations by 95%.
AB  - Multidisciplinary asthma care team members see patients and develop treatment
      plan during one office visit. Education sessions and packets teach patients how
      to handle flare-ups without going to the emergency room. Patients are monitored
      for correct use of peak flow meters and metered dose inhalers.

PMID- 10345805
TI  - Hospitals improve service benchmarking with Disney.

PMID- 10345806
TI  - Providers benchmark to reduce medication errors.

PMID- 10345807
TI  - Doctors, county team up to offer free health care.
AB  - A public/private partnership in North Carolina has resulted in free health care
      for 13,000 indigent patients a year. 85% of the physicians in the county's
      medical society volunteer to take patients into their practice for free. The
      county government pays $250,000 a year for medications and administrative costs,
      leveraging $3.5 million in free care.

PMID- 10345808
TI  - ICU cuts hospital-acquired pneumonia by 43%.
AB  - Western Medical Center in Santa Ana, CA, reduced its hospital-acquired pneumonia
      rate by 43% using kinetic therapy and early nutritional intervention. A formal
      evaluation tool identifies high-risk patients within 24 hours of admission.
      Clinicians were also educated on appropriate hand washing, suctioning, assessment
      techniques, and circuit changes, as well as the modes of transmission.

PMID- 10345809
TI  - Examine your emergency department, stat! ED is key to hospital reputation.
AB  - Hospitals say meeting patient expectations in the emergency department (ED) is
      key to survival. The best indicator of patient satisfaction in the ED is waiting
      times, which seem to matter more to some patients than clinical expertise. Few
      national standards on emergency waiting times exist; your best bet for
      benchmarking is to identify better performers such as the hospitals in this
      special report.

PMID- 10345810
TI  - ED slashes treatment time for heart attack drugs.
AB  - A New Jersey hospital cut its time for thrombolytic treatment for heart attack
      patients from 61 minutes to less than 25 minutes. Improvements included a one
      page time-to-treatment assessment tool and a five-minute protocol for walk-in
      patients. Emergency department leaders suggest focusing on clinical processes to
      get medical staff buy-in.

PMID- 10345811
TI  - ED pledge: see doc in 30 minutes or visit is free.
AB  - Hospital's pledge to see ED patients in 30 minutes gets 70% of patients released
      in less than two hours. The money-back guarantee has been expanded to four other
      hospitals in the New Jersey network. Revised scheduling, "fast-track" area, and
      restructured registration are keys to success.

PMID- 10345812
TI  - Creativity catches on with ED staff.
AB  - Tennessee hospital emergency staff vie for appointments to the "PIT Crew," a
      performance improvement team that is racing to cut waiting times. Arkansas
      emergency department director uses military humor to impress upon staff the
      importance of improving patient satisfaction. Improvements include protocols for
      common complaints, portable two-way radios, and a glassed-in area for patients
      waiting for test results.

PMID- 10345813
TI  - Benchmarking: one of your CEO's favorite tools.
AB  - Benchmarking ranked third in an annual survey by Bain & Co., a Boston-based
      consulting firm, of the top management tools used around the world. Benchmarking
      is the only tool in the survey that has consistently risen in popularity over the
      last five years. Bain & Co. says there is a correlation between financial success
      and the ways tools such as benchmarking are used.

PMID- 10345814
TI  - Benchmarking saves hospital $1 million.
AB  - Sarasota (FL) Memorial Health care System compared its pharmacy charges with peer
      hospitals and found it was $15 million below average. A quality improvement team
      found the pharmacy wasn't charging for all medications at the point of
      distribution, resulting in lost charges. THE SOLUTION: a simple process change
      that saved the hospital $1 million.

PMID- 10345815
TI  - Supply chain redesign saves hospital system $10 million.

PMID- 10345816
TI  - Silver-coated catheter reduces hospital UTIs, associated costs.
AB  - IDEA BANK: Silver-coated catheter reduces hospital UTIs, associated costs.
      Catheter-associated UTI can extend a patient's hospital stay by 3.8 days,
      increasing costs significantly. Find out what new study says about a new catheter
      that decreased the incidence of UTIs in the study population.

PMID- 10345817
TI  - Hospital charges for colorectal cancer vary widely among states.
AB  - DATA BENCHMARKS: A nationwide study of 300,000 health plan members shows dramatic
      variations in in-hospital charges for colorectal cancer treatment. The average
      charge for inpatient treatment was $17,800, but the Pacific region's average was
      37% higher than that found in the East South Central area, where average charges
      were the lowest of the bunch. The hospital portion of the insurance bill
      accounted for about three-quarters of the total charge. Review more details of
      the study.

PMID- 10345818
TI  - Hospital redesign takes unexpected $2 million bite out of food service costs.
AB  - Revamping food service can take a big bite out of costs. Saint Francis Medical
      Center in Peoria, IL, jump-started a hospitalwide redesign program by tapping a
      benchmarking firm and saved $2 million in food services alone. Learn how the
      hospital identified savings opportunities and maximized that potential by coming
      up with some creative alternatives to business as usual.

PMID- 10345819
TI  - ED staff and clinicians learn essential human relations skills.
AB  - Smile training for the emergency department? An increasingly popular customer
      service training program for physicians and staff in the emergency department
      teaches how to improve personal interactions with patients. Without focusing on
      how patients are treated beyond their medical ailments, course developers warn,
      hospitals may be alienating patients who might decide not to pay their hospital
      bill or might take their business elsewhere in the future.

PMID- 10345820
TI  - Look for changes to your Medicare risk contract in 1999.

PMID- 10345821
TI  - Hospitalist model holds potential for big bed day reductions, huge savings in
      Medicare risk.
AB  - Can you cut your Medicare risk inpatient bed days in half? Proponents of
      hospitalist programs say you can, and you can claim big savings--some as high as
      the upper $20s PMPM--when you apply the model to Medicare risk. Find out how to
      generate such savings, and learn from the experience of the Riverside Physician
      Network, a California IPA that uses hospitalists to care for its 10,200 seniors.

PMID- 10345822
TI  - Clothing exchanges for Medicaid members boost immunizations, encourage well-child
      visits.
AB  - Want your Medicaid members to get their vaccinations and well-child visits? Try
      encouraging them with an incentive system that offers something they can use,
      like children's clothing. Arizona Physicians IPA Inc., a Phoenix-based Medicaid
      managed care organization, uses clothing exchanges to encourage preventive
      utilization and give members access to community outreach programs.

PMID- 10345823
TI  - MedPac data dispel myths, outline trends in Medicare risk contracting.

PMID- 10345824
TI  - Use these strategies to fight compliance problems.

PMID- 10345825
TI  - Hospital puts diabetes education, screening on patients' grocery lists.

PMID- 10345826
TI  - Timely access to patient information cuts CHF costs.

PMID- 10345827
TI  - New diagnostic tool for flu reduces ER visits, admissions.
AB  - A new definite diagnostic test for influenza can get your sick patients better
      sooner, prevent the spread of this infection to high-risk patients, and above all
      dramatically reduce complications that lead to hospitalization and higher health
      care costs. Use this two-part plan to implement your own influenza DM program.

PMID- 10345829
TI  - Supporting CPR development with the commercial off-the-shelf systems evaluation
      technique: defining requirements, setting priorities, and evaluating choices.
AB  - This article describes the circumstances that led the Department of Defense (DoD)
      to adopt a standard streamlined business process to support its computer-based
      patient record (CPR) system. The DoD used the commercial off-the-shelf systems
      evaluation technique (COSSET) to accomplish this goal.

PMID- 10345828
TI  - Total joint replacement program prevents costly complications.
AB  - Doctors at one suburban Maryland hospital knew there was plenty to gain from
      using a disease management approach to total joint replacement. Now, thanks to a
      nurse practitioner and strict adherence to protocols, patients are going home
      from the hospital sooner and achieving renewed movement faster.

PMID- 10345830
TI  - Computer-based patient records can accelerate software component commerce.

PMID- 10345831
TI  - Critical success factors for evolving a hospital toward an electronic patient
      record system: a case study of two different sites.

PMID- 10345832
TI  - Preparing the organization for the computer-based patient record.

PMID- 10345833
TI  - Benefits of the worldwide government computer-based patient record framework.
AB  - The G-CPR organization composed of the DoD, VA, IHS, and the LSUMC presents an
      opportunity to facilitate the exchange of clinical data across existing
      healthcare information systems with new business practices. The organization's
      ability to reengineer existing healthcare delivery processes through the G-CPR
      framework will improve the sharing of information and will ultimately provide for
      better-quality healthcare, improved access to care, greater cost efficiencies,
      and enhanced medical readiness of the DoD healthcare beneficiaries. The projected
      benefits that are by-products of the organization sharing effort tend to be
      focused in two broad categories: improving access to clinical data and creating a
      mechanism to gather information across large clinical populations. Both of the
      two categories include various benefits that accrue to members of the
      organization relative to their ability to use the G-CPR framework as a business
      reengineering tool. As information management processes are refined through
      reengineering initiatives, benefits will be observed at multiple program levels-
      from the DoD enterprise level down to the operational level at individual
      treatment facilities. Using comprehensive data to quantify precise benefits and
      ROI strategies is difficult because the development of the G-CPR framework is
      still in its early stage. Formal performance-based outcome studies are envisioned
      to demonstrate these results once the G-CPR framework attains greater functional
      definition. Through the future development of benefits performance metrics, these
      benefits can be shown to have substantial impact on achieving the strategic goals
      of the MHS and the organization while helping to improve the cost and quality of
      healthcare, access to care, and the medical readiness posture within the DoD.

PMID- 10345834
TI  - Investigating changes in end-user satisfaction with installation of an electronic
      medical record in ambulatory care settings.

PMID- 10345835
TI  - Managing care through managing information: are we headed in the right direction?
AB  - Healthcare organizations adopt HIMS to manage the large amount of data available
      in the patient medical record. The CPR, however, must be more than a mirror image
      of the paper record to yield analyzable data necessary to answer the consumer's
      questions about cost and quality of care. Although organizations strive to
      achieve standardization of medical recording required for analysis, they must
      also be attuned to factors necessary to achieve end-user compliance and comfort
      with data input. The closer organizations move to ease of conversion to
      computerized medical records, the further they may be moving away from data
      integrity. What is more, the optimal balance point may be different for each
      organization.

PMID- 10345836
TI  - The best little data warehouse.

PMID- 10345837
TI  - Integration reconsidered: five strategies for improved performance.

PMID- 10345838
TI  - Using 'pull' marketing to create brand dominance at the service line level.

PMID- 10345839
TI  - Track IBNR (incurred but not reported) carefully to minimize financial risk.

PMID- 10345840
TI  - Consider these performance targets when building a capitation program.

PMID- 10345841
TI  - Sift through these cap rates to glean contracting patterns.

PMID- 10345842
TI  - Use these rheumatology benchmarks to break into the capitation game.

PMID- 10345843
TI  - Can you match these hospital cost benchmarks?

PMID- 10345844
TI  - Survey of CEOs offers glimpse at risk contracting trends.

PMID- 10345845
TI  - Health risks raise costs even in 'healthy' populations.

PMID- 10345846
TI  - Cash flow model offers 'snapshot' analysis of percent-of-premium deals.

PMID- 10345847
TI  - Medicare rates tell a tale of two markets.

PMID- 10345848
TI  - Physicians not yet reaping rewards of productivity gains.

PMID- 10345849
TI  - Medicaid risk contracts offer higher rates, higher risk.

PMID- 10345850
TI  - Pharmacy data offer benchmarks for risk contractors.

PMID- 10345851
TI  - Physicians expect increased involvement with capitation.

PMID- 10345852
TI  - Specialty PMPM benchmarks can help guide distribution of risk pool revenues.

PMID- 10345853
TI  - Survey offers wealth of medical practice cost data.

PMID- 10345855
TI  - Use these data to target medically unnecessary services.

PMID- 10345854
TI  - Don't underestimate prevalence of costly chronic illnesses in your capitated
      population.

PMID- 10345856
TI  - Don't neglect opportunities to reduce your fixed costs.

PMID- 10345857
TI  - Study the details of your cap contract before accepting risk.

PMID- 10345858
TI  - Survey reveals weak focus on membership retention.

PMID- 10345859
TI  - Costs in check, but competition will erode capitation margins.

PMID- 10345860
TI  - Compare your cap rates to these anecdotal benchmarks.

PMID- 10345861
TI  - How much does managed care affect specialty referrals?

PMID- 10345862
TI  - How does your organization stack up to these HEDIS performance benchmarks?

PMID- 10345863
TI  - Electronic medical records may be a godsend for at-risk provider groups.

PMID- 10345864
TI  - Physicians increasingly selective about health plan partners.

PMID- 10345865
TI  - Nation's health trendsetters offer sneak peek at the future.

PMID- 10345866
TI  - MD group's experience shows value of risk adjustment.

PMID- 10345867
TI  - Cost variances by industry illustrate wisdom of refining risk adjustment
      methodology.

PMID- 10345868
TI  - Use these forms to help manage hospital capitation.

PMID- 10345869
TI  - Capitated plans provide better access to teaching hospitals at lower rates.

PMID- 10345870
TI  - Mental Health Parity Act to produce modest cost increases in capitated plans.

PMID- 10345871
TI  - Consider costs carefully before accepting risk for the severely mentally ill.

PMID- 10345872
TI  - What's a reasonable health plan administrative cost?

PMID- 10345873
TI  - Dental HMO survey finds utilization down, rates up.

PMID- 10345874
TI  - Texas PMPM rates, utilization data reveal wide fluctuations.

PMID- 10345875
TI  - 'Preventable' hospitalization data may be misleading.

PMID- 10345876
TI  - Collision of consolidation, capitation presents major challenges for hospitals.

PMID- 10345878
TI  - HMO's data-driven cardiac network brings new meaning to provider competition.
AB  - Ensuring quality of cardiac care: Providers hoping to join Anthem Blue Cross Blue
      Shield's cardiac care network not only had to pass a stringent and complicated
      data-driven scorecard process, but once they were in they had to collect data on
      400 different elements on CABG and PTCA. Here's how the data-intensive program
      works, plus some useful cardiology benchmarks on performance, complication rates,
      mortality, and more.

PMID- 10345877
TI  - Cost accounting data crucial to contracting success.

PMID- 10345879
TI  - Use these targets to benchmark state, regional LOS efficiency.
AB  - Data Library: New York State is the big loser in this month's column, which makes
      state-by-state comparisons of length-of-stay data compared to Milliman &
      Robertson's findings on the most efficient LOS. M & R's Index shows efficiency
      drops as you move east across the country, with the most extreme example being
      New York, where lengths of stay are 88% higher than the country's most efficient.

PMID- 10345880
TI  - Minimize risk and costly adverse events with data gathering, reporting program.
AB  - Benchmarking errors and adverse events: Studies show adverse events affect up to
      35% of all patients, add up to 15% to each hospital's bottom line, and cost the
      country billions in health care dollars. But you can measure how often and where
      these events are occurring--and begin making improvements. Here's how to track
      incidents, aggregate the data, and use it to benchmark against other facilities
      and pinpoint improvement efforts-plus, sample reports from two hospitals.

PMID- 10345881
TI  - Motorcycle medics. Delivering patient care from the back of a bike.

PMID- 10345882
TI  - Don't back out of EMS!

PMID- 10345883
TI  - EMS incident management: emergency medical logistics.
AB  - If you had to get x amount of supplies to point A or point B, or both, in 10
      minutes, how would you do it? The answer lies in the following steps: 1. Develop
      a logistics plan. 2. Use emergency management as a partner agency for developing
      your logistics plan. 3. Implement a push logistics system by determining what
      supplies/medications and equipment are important. 4. Place mass casualty/disaster
      caches at key locations for rapid deployment. Have medication/fluid caches
      available at local hospitals. 5. Develop and implement command caches for key
      supervisors and managers. 6. Anticipate the logistics requirements of a
      terrorism/tactical violence event based on a community threat assessment. 7.
      Educate the public about preparing a BLS family disaster kit. 8. Test logistics
      capabilities at disaster exercises. 9. Budget for logistics needs. 10. Never
      underestimate the importance of logistics. When logistics support fails, the EMS
      system fails.

PMID- 10345884
TI  - Diggin' for donors.

PMID- 10345885
TI  - Commended hospital shares its success secrets.

PMID- 10345886
TI  - Do you have right policies for sales reps in OR?

PMID- 10345887
TI  - What should Beth Israel nurses have done? Write procedures for bringing in new
      equipment.

PMID- 10345888
TI  - Keep the improvement concept steady.

PMID- 10345889
TI  - Cutting RNs a false economy?

PMID- 10345890
TI  - Are your volunteers up to snuff?

PMID- 10345891
TI  - Physician choice directories: the impact on HMO members' perceptions.
AB  - It is a generally held belief that enrolled members of a health maintenance
      organization (HMO) will be more satisfied with their HMO and physicians if those
      members have a relationship with a personal physician. Public relations and
      marketing managers, therefore, in an attempt to encourage the establishment of
      such relationships, spend significant resources producing physician choice
      directories for their HMO members. But to what extent do these directories impact
      members? Do the HMO members read them? If so, do they take advantage of the
      opportunity to choose a personal physician? And if they do choose, what affect
      does that choice behavior have on satisfaction levels? The experience of one
      large, group model HMO suggests that physician choice directories enhance
      members' confidence in their physicians and their satisfaction with personalized
      care.

PMID- 10345892
TI  - Alternative medicine as a carve-out in managed care.
AB  - A major philosophical shift continues to occur in how health care is delivered in
      the United States. Traditional western medicine continues to develop new
      technologies that require new delivery systems, however, other factors are
      affecting this shift as well. Alternative medicine is one of these factors and is
      rapidly gaining attention. Alternative medicine is comprised of homeopathy,
      chiropractic, naturopathy, and cultural beliefs and practices such as those of
      the Native Americans or the Mexican Folk healers. Several managed care plans are
      now including alternative medicine as part of their product lines. Employers are
      moving from a passive role to an aggressive one in the selection of health care
      services available to their work force. This is in response to the changing
      demographics of the United States and the increased sensitivity to diversity in
      the work-place. Managed care companies have a marketing opportunity to increase
      their share of the market by looking at alternative medicine as a new product
      line designed to attract new subscribers. As with behavioral medicine,
      alternative medicine does not fit into the systems developed for delivering
      medical-surgical services. It, however, does not fit the systems developed for
      behavioral medicine either and appears to be a carve-out onto itself.

PMID- 10345894
TI  - Toward a better understanding of the future of the solo medical practitioner in
      health care industry: a conceptual review.
AB  - Even a brief conceptual review of the current developments in the health care
      industry indicates that the future of independent medical practitioners is rather
      challenging. It may be necessary for these parties to pursue proactive and
      aggressive marketing strategies to be able to compete with the managed care
      organizations. Accordingly, this paper outlines some of the current trends in
      health care marketing as they relate to the ongoing changes to which solo medical
      practitioners need to respond. It is hoped that the review of the issues raised
      in this paper can provide an initial basis for a better understanding of some of
      the challenges to come up with more comprehensive and effective strategy
      decisions.

PMID- 10345893
TI  - Academic preparation for healthcare executive-track personnel.
AB  - This study focuses on career aspirations of executive-track health care
      administrative personnel and their perceptions of the competencies required to
      become hospital chief executive officers (CEOs). This article examines these
      topics using the results of a 1994 survey of 162 junior- and mid-level healthcare
      managers who work in hospitals in a western state. Respondents included 34 CEO
      aspirants and 128 CEO nonaspirants. The majority of both groups reported high
      satisfaction with several work-related activities. Significantly more CEO
      nonaspirants than CEO aspirants perceived a need for additional self-development
      in several work areas. CEO aspirants reported that CEOs five years from now would
      need improved strategy formulation and negotiation skills. CEO aspirants also
      perceived that in the future, successful CEOs will have to be more proficient in
      several areas, such as interpersonal skills and medical staff relations. Three
      lists of academic subject matter considered important to career preparation were
      generated from (1) the Association of University Programs in Health
      Administration (AUPHA) undergraduate standards, combined with curriculum graduate
      standards of the Accrediting Commission on Education for Health Services
      Administration (ACEHSA); (2) study participants' responses; and (3) professional
      literature. When compared for relatedness, the contents of the three lists were
      not significantly different statistically. The implications of these findings for
      health administration education are discussed.

PMID- 10345895
TI  - Factors of patient satisfaction with medical services: the case of G.P. practices
      in the U.K.
AB  - This paper investigates whether factors previously identified in the literature
      are also important in the U.K. primary healthcare system. In a survey based on
      the SERVQUAL scale, 182 patients were personally interviewed. The analysis shows
      that the demographic variable age and gender are of little importance in
      determining satisfaction with G.P. services but the fundholding-non-fundholding
      divide is. For nearly every aspect of G.P. services the results clearly show that
      patients from fundholding surgeries are happier than patients from nonfundholding
      surgeries.

PMID- 10345896
TI  - Information source preferences for selecting dental services among elderly
      consumers.
AB  - This manuscript presents the results of a primary research study conducted among
      the elderly to determine the sources of information they prefer for the selection
      of dental services. The results of the study are presented in terms of source
      preferences by dental need (generalist or specialist), source preferences by
      gender (male or female), source preferences by level of education (low or high),
      and source preferences by income level (low or high). Conclusions are drawn from
      the results of the research, and suggestions are made regarding the use of
      information source preferences for the marketing of dental services to the
      elderly.

PMID- 10345897
TI  - Inconsistent positions doom plaintiffs in disability cases. Two appellate
      decisions in ADA cases go against plaintiffs.

PMID- 10345898
TI  - Kentucky Supreme Court rules home health aide's injury compensable. Olsten
      Kimberly Quality Care v. Parr.

PMID- 10345899
TI  - Blood-bank debt. Surgeries are postponed as shortages grow critical in a changing
      blood-donor business.

PMID- 10345900
TI  - Sacrificing breasts before cancer strikes. Can a mastectomy lessen a woman's
      risk?

PMID- 10345901
TI  - Making sense of context-level influences on health.

PMID- 10345902
TI  - Understanding pedestrians' road crossing decisions: an application of the theory
      of planned behaviour.
AB  - This paper reports a study applying the Theory of Planned Behaviour (TPB) to the
      prediction of pedestrians' road crossing intentions. Respondents (N = 210)
      completed questionnaires which included scenarios of three potentially dangerous
      road crossing behaviours, followed by measures of attitude, subjective norm,
      perceived behavioural control, self-identity and intention. The results indicated
      that the social psychological variables under consideration were able to explain
      between 39 and 52% of the variance in intentions to cross the road in the manner
      depicted in the scenarios. The perceived behavioural control component of the TPB
      emerged as the strongest predictor of pedestrians' intentions, suggesting that
      perceptions of control have an important role to play in road safety behaviour.
      The results are discussed in relation to the predictive utility of the TPB in
      this area and possible interventions to encourage safe road crossing behaviour.

PMID- 10345903
TI  - Health education in television entertainment--Medisch Centrum West: a Dutch drama
      serial.
AB  - World-wide a number of groups have sought ways to incorporate health messages
      into television entertainment like popular drama and soap serials. In the
      Netherlands, the Heart Foundation incorporated its cardiovascular health message
      in several episodes of a popular Dutch hospital serial called Medisch Centrum
      West. To obtain greater insight into the impact of this so-called 'entertainment
      education (E & E) strategy', an evaluation study was carried out. Medisch Centrum
      West was both entertaining and informative at the same time. Although viewers
      were well aware that the programme included a health message, they did not find
      it intrusive to their enjoyment of the storyline. It was interesting to learn
      that fans were more tolerant and positive towards the E & E strategy than non
      fans. Age, sex and education level explained only 5% of the variance.

PMID- 10345904
TI  - Older women's illness representations of cancer: a qualitative study.
AB  - This paper investigates the role of illness representations in older women's
      utilization of cancer screening. Older women's own beliefs, or illness
      representations, of cancer and cancer screening in relation to breast cancer and
      cervical cancer were explored using relatively unstructured, face-to-face
      interviews. Twenty women aged between 45 and 70 were interviewed, half of whom
      were regular screeners and half under-screeners. A comparison of the illness
      representations of the screeners with the under-screeners indicates some
      differences regarding cancer in general, and substantial differences regarding
      the treatment and cure of cancer. The screeners expressed less concern about
      cancer and gave more positive examples of the successful treatment of cancer. The
      under-screeners were more likely to express cynicism about the medical
      profession, to indicate that a person would have symptoms if they had cancer,
      that they would not want most of the treatment available for cancer, that
      screening is more important for younger women and that the use of alternative
      therapies negates the need for cancer screening. Few differences emerged between
      the two groups regarding the causes of cancer.

PMID- 10345905
TI  - Health education to increase screening for cervical cancer among Lumbee Indian
      women in North Carolina.
AB  - Although age-adjusted mortality rates from cancer among Native-Americans are
      generally lower than for the US population as a whole, cervical cancer mortality
      rates are higher. This report presents results from a National Cancer Institute
      funded health education program conducted among the Lumbee tribe in North
      Carolina that was designed to increase the proportion of women, age 18 and older,
      who receive Pap smears to screen for cervical cancer. The Solomon Four Group
      research design was used for this project. Participants were selected at random
      from the enrollment records of the Lumbee tribe and data collection was carried
      out during face-to-face interviews. The health education program was provided one
      on-one in women's homes by a trained lay health educator and included verbal,
      print and videotape information. A total of 979 women were enrolled in the study,
      and 125 were lost to follow-up between the pre-test and post-test. Women who
      received the education program were found to be more likely to have knowledge of
      the Pap smear and to report a Pap smear in the past year at the post-test than
      those in the control group, regardless of whether they received the pre-test
      interview, P < 0.05. Women most likely to respond to the education program were
      also likely to have reported that they receive an annual physical examination.
      Women with better knowledge of the Pap smear tended to have more education,
      higher income and greater identification with Native-American culture than those
      with less knowledge. We conclude that the health education program was associated
      with greater knowledge about cervical cancer prevention and higher proportions of
      Lumbee women obtaining Pap smears in the past year.

PMID- 10345906
TI  - Nationwide implementation of guided supermarket tours in The Netherlands: a
      dissemination study.
AB  - The purpose of this study was to assess adoption, implementation and maintenance
      of a guided supermarket tour program of nutrition education by Dutch Public
      Health Services (PHSs), and the factors associated with program dissemination. A
      first questionnaire was sent to all 60 PHSs, and measured program adoption,
      perceived program attributes, and characteristics of the adopting organization
      and person. A second questionnaire was only sent to adopting PHSs, and measured
      extent and success of implementation, intentions to continue the program, and
      characteristics of the main implementing person. Of the 59 PHSs who responded, 30
      adopted the program and 17 implemented it sufficiently. Perceived program
      complexity, social influence within the PHS toward program participation and
      existence of a separate health education department were predictors of adoption.
      Perceived program complexity was also a predictor of extent of implementation.
      The number of health educators within each PHS was a predictor of sufficient
      implementation. It was concluded that adoption and implementation of the program
      was reasonable, considering the limited dissemination strategy. Dissemination
      might have been more successful if the program had been less complex and required
      less effort, if positive social influence had been generated, and if specific
      attention had been given to PHSs without a separate health education department.

PMID- 10345907
TI  - Initial results of 'Language for Health': cardiovascular disease nutrition
      education for English-as-a-second-language students.
AB  - Low literacy skills may negatively affect health through misuse of medication,
      inability to follow medical directions or due to limitations placed on the
      consumer's ability to access health information. The association between low
      literacy among adults and cardiovascular disease has not been thoroughly
      investigated in some ethnic groups. The purpose of this comprehensive study is to
      describe the results of a nutritional-related cardiovascular health program for
      limited English proficient adults enrolled in English-as-a-second-language (ESL)
      classes. Subjects (n = 408), nearly 87% of whom were Latino, were exposed to
      either nutrition education (intervention group) or stress management (attention
      placebo control group) classes designed specifically for ESL classes. Subjects
      completed physiological measures assessing blood pressure, total and high-density
      lipoprotein (HDL) cholesterol, waist and hip circumference, and body mass. Self
      report surveys were administered to collect students' nutrition-related
      knowledge, attitudes and behaviors. Data were collected at baseline, 3 month post
      test and 6 month follow-up. Analyses showed that differential group change was
      seen for fat avoidance, nutrition knowledge, HDL and total cholesterol:HDL ratio,
      but, for the two latter variables, the effect was not maintained at the 6 month
      follow-up. Both groups showed positive changes in blood pressure, total
      cholesterol and nutrition-related attitudes. Results showed moderate success of
      the intervention, but suggest contamination between experimental groups may have
      occurred.

PMID- 10345908
TI  - Worksite and family education for dietary change: the Treatwell 5-a-Day program.
AB  - The National Cancer Institute's '5-a-Day for Better Health Campaign is examining
      the efficacy of interventions in increasing the consumption of fruits and
      vegetables to five or more servings a day. This paper presents the study design,
      intervention and baseline survey results of the Treatwell 5-a-Day project, a
      randomized, controlled worksite-based intervention study. Twenty-two community
      health centers were randomly assigned to either a Minimal Intervention, Worksite
      Intervention or Worksite Plus Family Intervention. The Worksite Intervention
      included participation of employee advisory boards, programs aimed at individual
      behavior change and programs aimed at changes in the worksite environment. The
      Worksite Plus Family Intervention incorporated family-focused interventions into
      the worksite program, including a learn-at-home program, family newsletter,
      family festival and materials mailings. A self-administered survey was conducted
      prior to randomization (mean response rate: 87%, n = 1359). Twenty-three percent
      reported consuming five or more servings of fruits and vegetables a day.
      Consumption of fruits and vegetables was directly associated with level of
      household support for healthy eating. The Treatwell 5-a-Day intervention model
      has the potential to enhance existing worksite-based intervention through
      incorporation of its family focus, especially given the association of household
      support with individual eating habits.

PMID- 10345910
TI  - Assessing public health capacity to support community-based heart health
      promotion: the Canadian Heart Health Initiative, Ontario Project (CHHIOP).
AB  - This paper presents initial findings of the Canadian Heart Health Initiative,
      Ontario Project (CHHIOP). CHHIOP has two primary objectives. The programmatic
      objective is to coordinate and refine a system for supporting effective,
      sustained community-based heart health activities. This paper addresses the
      scientific objective: to develop knowledge of factors that influence the
      development of predisposition and capacity to undertake community-based heart
      health activities in public health departments. A systems theory framework for an
      ecological approach to health promotion informs the conceptualization of the key
      constructs, measured using a two-stage longitudinal design which combines
      quantitative and qualitative methods. This paper reports the results of the first
      round of quantitative survey data collected from all health departments in
      Ontario (N = 42) and individuals within each health department involved in heart
      health promotion (n = 262). Results indicate low levels of implementation of
      heart health activities, both overall and for particular risk factors and
      settings. Levels of capacity are also generally low, yet predisposition to
      undertake heart health promotion activities is reportedly high. Analyses show
      that implementation is positively related to capacity but not predisposition,
      while predisposition and capacity are positively related. Overall, results
      suggest predisposition is a necessary but not sufficient condition for
      implementation to occur; capacity-related factors appear to be the primary
      constraint. These findings are used to inform strategies to address CHHIOP's
      programmatic objective.

PMID- 10345909
TI  - The effects of a health education intervention initiated at first grade over a 3
      year period: physical activity and fitness indices.
AB  - A health education intervention was carried out for three consecutive years on
      primary school Cretan children. Baseline measures were obtained from 962 pupils
      (509 boys and 453 girls) registered in first grade in 1992. The health education
      intervention programme was directed at both the children of the intervention
      group and their parents, and has a projected duration of 6 years. After the
      completion of the 3 years of intervention and while pupils were in fourth grade,
      measures were obtained for evaluation purposes on a random subsample of 393
      pupils of the original cohort. Statistically greater improvements in the
      intervention, as opposed to the control group, were observed for both children's
      and parents' health knowledge, and children's standing broad jump, sit-ups (SUP),
      sit-and-reach, handgrip and endurance run test (ERT). Furthermore, time spent on
      moderate to vigorous physical activities out of school significantly increased
      for intervention group children compared to the control group. Statistically
      smaller increases in the intervention as opposed to the control group were
      observed in suprailiac skinfold and body mass index. The degree of improvement in
      both SUP and ERT related positively to parent's baseline physical activity score.
      Finally, the parental attitude of health-related hedonism related negatively to
      SUP improvement.

PMID- 10345911
TI  - Where to look for good clinical policies.

PMID- 10345912
TI  - Ground rules for dealing with health care plans.

PMID- 10345913
TI  - Cost and price in the NHS: the importance of monetary value in the decision
      making framework--the case of purchasing renal replacement therapy.
AB  - This paper examines the role of cost, price and health economic evaluation in the
      National Health Service as demonstrated by reference to renal replacement therapy
      for patients with end-stage renal failure. In particular, it aims to highlight
      the problems with monetary value and to illustrate how it may be manipulated by
      legitimate techniques to produce varying outcome values which may be misleading
      and thereby distort the healthcare decision-making process. The paper argues for
      standardization of costing methods and health economic evaluation to enable
      meaningful intra- and inter-hospital comparisons to be made.

PMID- 10345914
TI  - Determinants of hospital bad debt: multivariate statistical analysis.
AB  - Although the issue of uncompensated care (bad debt plus charity care) has been
      actively debated in the public arena, there has been little discussion of the bad
      debt issue alone. This issue is important since issues of bad debt, charity care
      and uncompensated care are significantly different from each other. Based on 1992
      State of Missouri data, the results of our study indicate that more efficient
      hospitals (measured by occupancy rate), hospitals with more patients covered by
      prospective payment systems (measured by Medicare discharges), and for-profit
      hospitals incurred significantly less bad debt cost than other hospitals.
      However, the difference in bad debt between for-profit hospitals and not-for
      profit hospitals is dissipated when using a multivariate statistical model. In
      addition, this study also reveals that hospitals which provide more charity care
      have the lowest bad debt costs. Policy implications are also discussed.

PMID- 10345915
TI  - Business planning health-check questionnaire: a survey of first, second, third
      and fourth wave NHS Trusts.
AB  - This paper reports the results of primary research which was carried out in July
      1995 with respect to business planning within first, second, third and fourth
      wave National Health Service (NHS) Trusts. The purpose of the research was to
      examine current practice in these Trusts in three areas--namely, the levels of
      responsibility for business planning in general, the business planning processes
      applied by these Trusts, and the tools and techniques used by business planning
      managers in the compilation of business plans. The research, based on a 37.5%
      response rate, concludes that, as a general rule, business planning in first,
      second, third and fourth wave NHS Trusts tends to be a board-level activity,
      where senior managers have a job title which reflects this function. Secondly,
      the research shows that by far the greatest challenge for Trusts lies in the
      external marketplace. In areas such as patient needs forecasting, competitive
      (Trust) intelligence, purchaser and general practice fundholder requirements,
      data are difficult to acquire. Finally, the evidence suggests that there is a
      significant gap between what is regarded as business planning practice in the NHS
      and what is actually applied as best practice. The report concludes that business
      planning in the NHS Trusts sampled appears to be an art rather than a science,
      and that many assumptions made by business planning managers are founded on
      qualitative information rather than on specific, measurable data derived from the
      external and internal market.

PMID- 10345916
TI  - Service quality attributes of maternity care services: the prospective consumer's
      perspective.
AB  - The application of the repertory grid technique made it possible to capture the
      mental categorization by which maternity care services are judged.
      Conceptualization of the expectation standard, defined as estimates of
      anticipated performance, led to the identification of 14 attributes. These
      include: reliability, responsiveness, competence, access, courtesy,
      communication, credibility, security, relationship, tangibles, control, cost,
      naturalness and quality. The definitions made use of the prospective consumer's
      own verbal labels. In addition, it was found that maternity care services were
      not perceived as one continuous process. Three distinct categorizations were
      identified, that is: before, during, and after the birth of the baby. This
      suggests that prospective consumers employ the service quality attributes,
      according to one of the above.

PMID- 10345917
TI  - Validity of three measures of severity of AIDS for use in health services
      research studies.
AB  - Policy makers and hospital managers often use severity adjustments as a control
      for patient mix differences when evaluating outcomes of care. Unfortunately, few
      indices are carefully examined and therefore the evaluations based on these
      methods of severity adjustment are suspect. This paper examines the accuracy of
      three indices for measuring the severity of illness of AIDS patients. We examine
      the Diagnosis-Based Severity Index (DBSI), a modified version of DBSI referred to
      as MDBSI and the Composite Laboratory Index (CLI) in predicting survival of AIDS
      patients at one medical centre. We analysed the correlation between indices and
      months of survival. We also examined the percentage of variance in survival
      months explained by each index separately and together. Finally, we used survival
      analysis to examine whether DBSI classifies patients in groups with distinct
      patterns of survival. Only patients who had died were included in the analysis so
      that information on the patients' full course of illness was available. Of the 91
      patients abstracted, 81 cases had date of AIDS, date of death, and the CLI. These
      81 cases were the focus of the analysis. Both CLI and DBSI were predictive of
      months of survival but were not correlated to each other. Predictions of months
      of survival were improved if both indices were used together rather than
      separately. Survival analysis confirmed that patients classified by DBSI had
      distinctly different survival patterns. Each index measures different aspects of
      the severity of the patient's condition and when possible both indices should be
      used together. When laboratory data are not available, e.g. in Medicaid
      administrative files, the use of DBSI may be reasonable.

PMID- 10345918
TI  - Change in stress outcomes following an industrial dispute in the ambulance
      service: a longitudinal study.
AB  - A longitudinal study to assess change in the symptoms of strain following an
      industrial dispute was carried out in a North of England ambulance service. A
      cohort of ambulance staff was surveyed over three stages: during the dispute;
      during the process of reorganizing the service; and during the implementation of
      a new operating structure. Dependent variables included measure of job
      satisfaction and mental and physical health. Independent variables included
      measures of the type A behaviour pattern, locus of control, source of perceived
      pressure and coping techniques. The results failed to support the main hypothesis
      as the symptoms of strain measured did not show any reduction after the dispute.
      Job dissatisfaction increased in the aftermath of the dispute and remained poor
      during the implementation of change. Symptoms of mental and physical ill-health
      showed no reduction following the dispute but symptoms of mental ill-health
      increased as organizational change was implemented. The high level of
      'externality' shown by ambulance staff partially accounted for both these
      increases. It is proposed that the manner in which the aftermath of the dispute
      and ensuing organizational change were managed gave an increasingly limited scope
      for influence.

PMID- 10345919
TI  - The role of Scottish area health boards in audit and clinical effectiveness.

PMID- 10345920
TI  - Water: friend and foe.
AB  - With a basic knowledge of the origin and transport of moisture, psychometrics,
      and the use of properly calibrated diagnostic tools, an EM can not only determine
      the origin of many moisture problems (and indoor air quality complaints), but
      also aid infection control efforts by minimizing microbial growth. In future
      issues of HHMM, CHEM will introduce the EM to flood and moisture mitigation
      procedures, as well as training courses and outside contracting services that
      should be used as an integral portion of a healthcare facility's emergency
      preparedness program.

PMID- 10345921
TI  - Poisonous plastics? Some cling wraps, children's toys and even IV bags may be
      carrying--and shedding--toxic chemicals.

PMID- 10345922
TI  - How to build a body part.

PMID- 10345923
TI  - The invisible uninsured. Congress fiddles while rising numbers of Americans lose
      their access to medical care.

PMID- 10345924
TI  - Home of the gray.
AB  - Generations: In 30 years, there will be almost 70 million retirees in America-
      more grandparents than grandchildren. The Senior Boom is coming, and it will
      transform our homes, our schools, our politics, our families, our lives and our
      deaths. And not just for the older people. For everybody.

PMID- 10345925
TI  - Do scopes spread sickness?

PMID- 10345926
TI  - What are they hiding? HMOs are getting more secretive about quality.

PMID- 10345927
TI  - The What Works Awards--1998.

PMID- 10345928
TI  - HotList. Y2K products and services.

PMID- 10345929
TI  - Telemedicine continues to wrestle wicked problems: reimbursement, licensure, and
      bandwidth rules (or is it compliance?).

PMID- 10345930
TI  - How to do HIMSS.

PMID- 10345931
TI  - IT system handles 3500 calls per day, with 20 second answer time. Kaiser
      Permanente takes the fast track to improving quality and increasing satisfaction.

PMID- 10345932
TI  - Health Management Technology 1999 market source guide.

PMID- 10345933
TI  - Changing the public-private mix: an assessment of the health reforms in Greece.
AB  - The 1983 health reform in Greece was a major political event in the social policy
      agenda. The main objective of the reform was the institution of a National Health
      System and the expansion of the health sector, improved equity, and the
      assumption of full responsibility for health services delivery by the state. An
      assessment of the results 10 years after full implementation of the reform shows
      that despite the expansion of the public sector, the public-private mix in
      financing and delivery has changed in favour of the private sector, making the
      Greek health system the most 'privatised' among the EU countries. The main
      reasons why the health reform failed to meet its objectives was the restrictive
      enforcement of full-time and exclusive hospital employment for doctors, the
      virtual ban on private hospital expansion, the much faster introduction and
      diffusion of new health technology by the private sector, and poor management,
      planning and control in the public sector. A new health reform voted into law in
      the summer of 1997 shows promise of redressing some of the shortcomings of the
      1983 reform.

PMID- 10345934
TI  - Curiosity, imagination, compassion, science and ethics: do curiosity and
      imagination serve a central function?
AB  - Curiosity and imagination have been neglected in epistemology. This paper argues
      that the role of curiosity and imagination is central to the way we think,
      regardless of whether it is thinking about problems of ethics or problems of
      science. In our ever more materialistic society, curiosity and reason are either
      discouraged or narrowly channeled. I shall argue that the role of curiosity and
      imagination for both science and ethics is so important that nurturing them can
      be seen as an ethical obligation and suppressing them as ethically problematic.

PMID- 10345935
TI  - Effective clinical policies in a district general hospital.
AB  - Effective clinical practice in a hospital needs current knowledge together with
      the skills and right attitude; these should be applied continuously. Failure of
      this system can be due to ignorance or arrogance. We attempted to correct these
      deficiencies by formulating a set of policies which were enforced from 1962 to
      1983. The policies related to the following: intensive care (including asthma,
      nutrition and organ donation), drug prescribing and resuscitation. We believe
      that these rules improved patient care and the standards of training; the
      prescribing policy also saved money.

PMID- 10345936
TI  - Rules in the clinical setting: pros and cons.

PMID- 10345937
TI  - Measurement of anticonvulsant adherence behaviour in the community using a
      Medication Events Monitoring System (MEMS)
AB  - The Medication Event Monitoring System (MEMS) is a relatively new device designed
      to overcome some of the disadvantages of traditional adherence-measuring
      techniques. MEMS has also been found useful in tracking adherence behaviour
      without the need to visit patients frequently. In this study each patient was
      given a pre-filled, labelled MEMS bottle and cap. Patients were monitored for 24
      weeks. For patients specifically studied, there were periods when drug levels may
      have been low and some exhibited erratic medication-taking behaviour. It is
      concluded that MEMS can measure adherence behaviour objectively, and so might be
      used to improve prescribing decisions, identify drug wastage and improve carer
      support. Further research is needed before the routine use of electronic
      medication monitoring can be recommended.

PMID- 10345938
TI  - Policy issues implied by technologies measuring patient adherence to prescribed
      drug therapies.

PMID- 10345939
TI  - MEMS: a technological solution to a social problem?

PMID- 10345940
TI  - Medication event monitoring systems, health resources and trust.

PMID- 10345941
TI  - What is primary care? Developments in Britain since the 1960s.
AB  - Since 1994, health policy in the UK has focused explicitly on making the NHS
      'primary care-led'. However, the meaning of primary is contested by different
      health professions and by policy-makers. This paper charts the major points of
      debate since the 1960s and suggests that there are limitations as to what general
      practice can be expected to deliver in respect of primary care.

PMID- 10345942
TI  - What is 'primary' about primary health care?

PMID- 10345943
TI  - Primary health care: definitions, users and uses.

PMID- 10345944
TI  - Questioning values.

PMID- 10345945
TI  - Report to HCFA to suggest refinements to RUGS III; permanent changes unlikely
      this year.

PMID- 10345946
TI  - MedPAC to recommend changes to SNF PPS, development of tracking system.

PMID- 10345947
TI  - How to manage group therapy minutes to improve rehab's efficiency under PPS.

PMID- 10345948
TI  - Restrictive SNF admission policies could place providers at risk, experts warn.

PMID- 10345949
TI  - AHCA sourcebook reports slowing in growth of new subacute programs.

PMID- 10345950
TI  - How to please medically complex subacute patients: the six key drivers of
      satisfaction.

PMID- 10345951
TI  - Thinking in three dimensions about 3-D in radiology.

PMID- 10345952
TI  - Decisions and service: seeking X.

PMID- 10345953
TI  - Roentgen's image: what's in a name?

PMID- 10345954
TI  - Team building.

PMID- 10345955
TI  - Breast cancer screening in an aging population.

PMID- 10345956
TI  - Nonpatient food service. How to make it work.

PMID- 10345957
TI  - How to achieve food service excellence. Part 4: Take risks, be tenacious, and
      keep the passion kindled.

PMID- 10345958
TI  - Will you be bitten by the millennium bug?

PMID- 10345959
TI  - Most challenging Joint Commission standards.

PMID- 10345960
TI  - Abuse and neglect in long-term care. A litigation boom threatens the industry.

PMID- 10345961
TI  - Avoiding legal hassles. Proper documentation is key when a resident's condition
      changes.

PMID- 10345962
TI  - Pleasing to the eye.

PMID- 10345963
TI  - Computer simulation. One way to solve operational problems.

PMID- 10345964
TI  - Obstacles to early discharge after cardiac surgery.
AB  - CONTEXT: Cardiovascular disease and cardiac surgery, in particular, are
      associated with a large expenditure of healthcare resources. Identifying the
      factors that affect length of stay for patients hospitalized for cardiac surgery
      and ways to safely and effectively shorten stays could have significant impact on
      healthcare costs. OBJECTIVE: To identify obstacles to and the effects of early
      discharge on outcome after cardiac surgery. STUDY DESIGN: A prospective approach
      using a protocol consisting of modifying anesthesia, limiting the use of
      postoperative narcotics, early extubation, and early mobilization, with a goal of
      discharge at < 5 days. PATIENTS AND METHODS: The study group consisted of 422
      consecutive patients (age range 15-89 years, 65% males): coronary artery bypass
      graft (CABG) (n = 290), valve procedures (n = 54), and CABG + valve procedures (n
      = 78). The discharge criteria included hemodynamic stability, normal bowel
      function, independence in activities of daily living, absence of fever, and no
      incision problems. RESULTS: Predictors of prolonged postoperative stay were
      prolonged intensive care unit stay (P < 0.0001), postoperative atrial
      fibrillation (P = 0.0006), preoperative congestive heart failure (P = 0.002),
      combined CABG and valve procedure (P = 0.005), prolonged ventilator support (P =
      0.01), increasing age (P = 0.012), history of peripheral vascular disease (P =
      0.02), and female gender (P = 0.025). The 30-day readmission rate for the early
      discharge group was 7.8% vs 16.2% for the late discharge group (P = 0.01). The
      mortality rate for the entire group was 3.3%.

PMID- 10345965
TI  - A community hospital-based congestive heart failure program: impact on length of
      stay, admission and readmission rates, and cost.
AB  - OBJECTIVE: To do an analysis of patients with a primary diagnosis of congestive
      heart failure at discharge before (n = 407) and after (n = 347) the
      implementation of a comprehensive inpatient and outpatient congestive heart
      failure program consistent with the guidelines of the Agency for Health Care
      Policy and Research. STUDY DESIGN: A retrospective analysis of the impact of the
      congestive heart failure program on length of stay, admission and readmission
      rates, and costs to both patient and provider. The program, which used a
      multidisciplinary team approach, included an intensive education program focusing
      on diet, compliance, and symptom recognition, as well as the use of outpatient
      infusions. It also incorporated aggressive pharmacologic treatment for patients
      with advanced congestive heart failure. RESULTS: Our analysis revealed
      significant decreases in length of stay, admission and readmission rates, and
      costs to the patient and provider (P < or = .05). The mean cost per admission
      decreased 17% ($1118), and a substantial 77% ($718,468) net reduction in
      nonreimbursed (lost) hospital revenue was noted. CONCLUSION: A multidisciplinary,
      comprehensive congestive heart failure program can improve patient care in a
      community-hospital setting while significantly reducing costs to both the patient
      and the institution.

PMID- 10345966
TI  - Integrating healthcare for older populations.
AB  - The complex array of needs posed by older adults has frequently produced
      fragmentation of care in traditional fee-for-service systems. Integration of care
      components in newer health systems will maximize patient benefits and
      organizational efficiency. This article outlines the major issues involved in
      integration of care for older populations. A health system must integrate its
      care of older adults in many ways: among providers, both in primary care and
      specialty services; with community-based sources of care; and across sites of
      care (clinic, hospital, emergency department, and nursing home). Integrating
      reimbursement structures for various services will serve to create a client
      oriented system, as opposed to a finance-centered system, thereby enhancing
      coordination of care. The extent to which two experimental comprehensive systems,
      PACE (Program of All-inclusive Care of the Elderly) and SHMO II (Social Health
      Maintenance Organization), have achieved clinical and financial integration are
      discussed in detail. Healthcare organizations are encouraged to create integrated
      models of care and to study the effects of integration on patient outcomes.

PMID- 10345967
TI  - Antibiotic therapy of Helicobacter pylori infection reduces healthcare
      expenditures related to duodenal ulcer.
AB  - OBJECTIVE: To test whether eradication of Helicobacter pylori saves costs in the
      treatment of duodenal ulcer disease, compared with conventional antisecretory
      therapy. STUDY DESIGN: A prospective, double-blind clinical trial was conducted
      at 132 sites in the United States. PATIENTS AND METHODS: Adult patients with
      active duodenal ulcer and confirmed H pylori infection were randomized to receive
      treatment with clarithromycin plus omeprazole, omeprazole alone, or ranitidine
      alone. Utilization of ulcer-related healthcare resources was documented during 1
      year following therapy. Costs were calculated by multiplying the number of health
      resources utilized by the cost of each resource. Resource costs were obtained
      from a database containing actual average costs spent by managed care
      organizations on outpatient and inpatient treatment. RESULTS: Of the 819 patients
      enrolled, 727 completed the study: 243 received clarithromycin plus omeprazole,
      248 omeprazole alone, and 236 ranitidine alone. Ulcer-related health resource
      utilization and total ulcer-related healthcare costs were decreased after
      treatment with clarithromycin plus omeprazole, compared to treatment with
      omeprazole or ranitidine alone. In multivariate linear regression analyses, type
      of treatment was found to be a significant predictor of total costs. Specific
      costs associated with endoscopic examinations, clinic visits, and medications
      were also significantly reduced by treatment with clarithromycin plus omeprazole
      as compared to other treatment forms. CONCLUSIONS: In a managed care environment,
      therapy with clarithromycin and omeprazole to eradicate H pylori in patients with
      duodenal ulcer disease would result in significant cost savings secondary to a
      reduction in the utilization of healthcare resources.

PMID- 10345968
TI  - Safety and efficacy of metformin in a restricted formulary.
AB  - OBJECTIVE: To assess the efficacy and safety of metformin (MET) in the Veterans'
      Administration Northern California Health Care System during the period from June
      1995 through April 1996 when its use required approval by Endocrinology. STUDY
      DESIGN: A retrospective review of patient charts and computerized pharmacy and
      laboratory records. Patients served as their own historical controls. PATIENTS
      AND METHODS: Patients receiving MET (n = 251) were identified from the pharmacy
      database. On-line laboratory data, including the intermediate outcome variable
      HbA1c, were retrieved by computer for the interval 4 months prior to the initial
      prescription to May 1996. Clinical data including weight and blood pressure were
      obtained from chart review. RESULTS: Of 228 patients whose charts were available
      for review, 29 reported side effects, and 12 discontinued use due to these side
      effects. No patients were identified with lactic acidosis. Both baseline and
      treatment data on HbA1c were available on 164 patients. Mean HbA1c (%) data
      (unpaired), expressed as mean +/- SE, were as follows: between 4 months
      pretreatment and 1 month pretreatment, 9.41 +/- 0.19 (n = 103 tests); between 1
      month pretreatment and baseline, 9.41 +/- 0.19 (n = 110 tests); 3 months of
      treatment, 8.79 +/- 0.16 (n = 157 tests, P < 0.05); 6 months of treatment, 8.30
      +/- 0.17 (n = 79 tests, P < 0.0001); 9 months of treatment, 8.72 +/- 0.24 (n = 70
      tests, P < 0.05), compared to pretreatment values. Similar analysis of unpaired
      weight and blood pressure data in 152 patients did not reveal any reduction in
      these clinical parameters over this treatment period. Serum lipids were unchanged
      on treatment (by paired analysis), but the number of tests was limited.
      CONCLUSION: In this setting, MET provided sustained beneficial effects on
      glycemic control and was well tolerated. Any effects on weight, blood pressure,
      and serum lipids were not demonstrable in this analysis. We conclude that MET can
      substantially improve outcome of diabetes care.

PMID- 10345969
TI  - The cost effectiveness of patient-applied versus provider-administered
      intervention strategies for the treatment of external genital warts.
AB  - OBJECTIVE: External genital warts are one of the fastest growing sexually
      transmitted diseases in the United States today. Two forms of therapy are
      available: provider-administered and patient-applied. In the most widely used
      provider-administered ablative therapies, sustained clearance rates range from
      18.5% to 40.1%. With nonablative, patient-applied therapies, which are typically
      more acceptable to patients, sustained clearance rates range from 19.6% with
      podofilox gel to 44.0% with imiquimod cream. The purpose of this study, given the
      range of therapies available, their cost differences, and clinical trial-reported
      differences in rates of sustained clearance, is to determine which therapy
      modalities, from the providers' perspective, are the most cost effective and
      which are likely to be the most acceptable to the patient population. STUDY
      DESIGN: We consider the cost effectiveness of the two patient-applied therapies
      as first-line therapy followed by provider-administered ablative treatment as
      second-line therapy. A decision-analytic model framework is developed, with data
      drawn both from clinical trials and from previously published studies. RESULTS:
      When considering a two-stage therapy model, with an average sustained clearance
      rate of 30% assumed for provider-administered ablative therapies, estimated costs
      per sustained cleared patient are $1265 for patients initially treated with
      imiquimod and $1304 for patients initially treated with podofilox gel.
      CONCLUSIONS: Initial treatment with imiquimod is the preferred intervention
      option as it yields a 39% greater sustained clearance rate than podofilox gel
      while being 3% less costly per successful outcome.

PMID- 10345970
TI  - Medical nutrition therapy: a powerful tool in disease management.

PMID- 10345971
TI  - Maintenance drug therapy of chronic obstructive pulmonary disease.

PMID- 10345972
TI  - Health economics and sexual dysfunction. Based on a presentation by Cyril F.
      Chang, PhD.
AB  - Erectile dysfunction (ED) and the results of its treatment are two separate
      issues, centering on how outcomes of the disorder affect the economy and the
      impact its treatment has on quality of life. The treatment of ED has been an $800
      million-a-year business in the United States alone. The recent introduction of
      the drug sildenafil raises the possibility that revenues from its sale could reap
      billions of dollars for the pharmaceutical industry, with much of that cost being
      borne by the managed care industry. The introduction of sildenatil raises new
      cost-effectiveness concerns about all available treatment options. Both the
      National Institutes of Health and the American Urological Association have
      identified the need for better studies whose outcomes could be used to analyze
      the problem of ED.

PMID- 10345973
TI  - Managed care and sexual dysfunction. Based on a presentation by William Parham,
      MD.
AB  - The availability of managed care benefits for the treatment of sexual dysfunction
      is inextricably linked with cost. An atypically low increase of 4.4% in aggregate
      healthcare expenditures in 1995-1996 stands in sharp contrast to outlays of more
      than 11% between 1966 and 1993. Between 1993 and 1996, that increase hovered at
      about 5%, the result largely of the growth of managed care and low levels of
      general inflation. However, despite relative containment of overall healthcare
      expenditures, those related to pharmaceuticals have risen more than 9.2%
      annually, an increase that reflects the managed care industry's failure to
      restrain drug costs. In deciding whether it will cover a particular treatment,
      the managed care industry applies three sets of criteria relating to efficacy,
      medical necessity, and appropriateness. Managed care companies are expected to
      counter runaway pharmacy costs for sildenafil by excluding it from coverage,
      imposing significant limitations, or requiring higher copayments.

PMID- 10345975
TI  - 1998 Georgia General Assembly. Budget success highlights banner year for
      hospitals and health systems.

PMID- 10345974
TI  - Advisory opinion casts doubt on percentage management fees.

PMID- 10345976
TI  - GHAREF (Georgia Hospital Association Research and Education Foundation) CARE
      (Collaborative Approach to Resource Effectiveness) Program.

PMID- 10345977
TI  - Hospitals woefully unprepared for risk contracting.

PMID- 10345978
TI  - California market a rough ride for risk contractors, data show.
AB  - Data Insight: California encompasses a variety of markets, but capitation is a
      common thread that runs through most. This snapshot of two provider groups' PMPM
      rates illustrates that financial results can differ dramatically.

PMID- 10345981
TI  - Providers not rushing onto PSO bandwagon.
AB  - The 1997 Balanced Budget Amendment gave providers a vehicle to market their own
      insurance products and contract directly for Medicare risk. But only one PSO has
      been approved to operate in the Medicare+Choice program, and significant
      operational barriers may prevent others from joining the fray.

PMID- 10345979
TI  - Health status data begins slow march into risk contracting arena.
AB  - A Wisconsin employer health care purchasing cooperative has become one of the
      first to compile data on employee health status that may give them a big
      advantage in negotiating capitated arrangements in the future.

PMID- 10345980
TI  - Will Congress, state legislatures follow Texas' lead this year?
AB  - The first lawsuit to cite Texas' pioneering HMO liability law was filed in
      October, and that could spark interest during the 1999 sessions of state
      legislatures and the new U.S. Congress.

PMID- 10345982
TI  - Managed care tools becoming a chief U.S. export.

PMID- 10345983
TI  - Coordinating patient care improves quality of care, efficiency. Interview by
      Therese Droste.

PMID- 10345984
TI  - Difficulties of radiology risk may require third-party manager.

PMID- 10345985
TI  - Consulting patients yields better healthcare guidelines.

PMID- 10345986
TI  - Increased direct-to-consumer advertising driving pharmaceutical costs, trends.

PMID- 10345987
TI  - Engaging physicians in improving satisfaction requires communication.

PMID- 10345988
TI  - American MCOs need local partners to succeed in overseas markets.

PMID- 10345990
TI  - Healthcare media advertising tracking.

PMID- 10345989
TI  - "Thinking retail" in healthcare: new approaches for business growth.

PMID- 10345992
TI  - Addressing voluntary disenrollment.

PMID- 10345991
TI  - Downsizing is out, growth is in at Connecticut's Middlesex Hospital. Interview by
      David O. Weber.

PMID- 10345994
TI  - Mass customization at Group Health Co-op.

PMID- 10345993
TI  - Concentration, co-opetition, consumerism ... and seven more "C's". Trends that
      will shape healthcare strategy in 1998.

PMID- 10345995
TI  - Redesigning primary care via member profiles.

PMID- 10345996
TI  - When a strong niche player reconfigures the local marketplace: a case example.

PMID- 10345997
TI  - Alternative medicine's potent attraction for boomers and seniors.
AB  - Ever since Harvard's David Eisenberg, MD, published his groundbreaking findings
      in the New England Journal of Medicine in 1993 (for example, that there were more
      visits to complementary or alternative medicine practitioners in 1990 than to all
      general practitioners and family practice physicians combined; and 83 million
      adults were spending about $11 billion on alternative or complementary medicine),
      interest in the marketplace implications has grown. Anne Alexander, editor of
      Prevention magazine, and Leah Kliger, principal of The Lakes Group, Lake Stevens,
      WA, provided some new information at The Alliance For Healthcare Strategy and
      Marketing's Annual Conference in March.

PMID- 10345998
TI  - Measuring the true value of a healthcare organization's brand.

PMID- 10345999
TI  - Marketing and finance issues in provider-sponsored Medicare HMOs.

PMID- 10346000
TI  - Competing on quality. Market competition will ultimately be determined by
      performance, not price.

PMID- 10346001
TI  - Your physician strategy: defining your approach.

PMID- 10346002
TI  - A new generation of report cards is forcing health plans and providers to strive
      for better grades.

PMID- 10346003
TI  - Database marketing pinpoints segments to cross-sell, re-sell, up-sell.

PMID- 10346004
TI  - Beating the new, aggressive, diverse niche players at their own game.

PMID- 10346005
TI  - Leaders lead and followers follow. Effective branding strategies depend on
      relative position in the marketplace.

PMID- 10346006
TI  - Consumer reaction to healthcare advertising.
AB  - How do consumers view healthcare advertising? This question, along with many
      others, was addressed in a national survey conducted by Market Strategies for The
      Alliance For Healthcare Strategy And Marketing, and presented during The
      Alliance's annual advertising and promotion conference last June.

PMID- 10346007
TI  - Women's service lines as robust distribution channel: five models.

PMID- 10346008
TI  - PSO vs. HMO: some pros and cons of entering the Medicare-risk market.

PMID- 10346009
TI  - Comparing satisfaction research methodologies.

PMID- 10346010
TI  - Global fees and creative marketing fill empty U.S. beds with well-insured (or
      wealthy) foreigners.

PMID- 10346011
TI  - Orphaned public hospital competes for patients.

PMID- 10346012
TI  - Integrated system or focused factory. Which strategy is best for your
      organization?

PMID- 10346013
TI  - Open access responds to consumers' desire for perceived "safety valve".

PMID- 10346014
TI  - Driven by the market.

PMID- 10346015
TI  - Strategic issues for diverse focused factories.

PMID- 10346016
TI  - Accreditation: year 2000 compatible.
AB  - Procedure pricing will not provide the competitive advantage in 2000. The
      ambulatory care organization must demonstrate its commitment to quality care and
      outcomes. Only through achieving an accreditation status can an organization
      truly demonstrate their commitment to their customers.

PMID- 10346017
TI  - A new look for tomorrow's health facilities.
AB  - Leland Kaiser, American healthcare futurist, said "the hospital is a human
      invention and as such can be reinvented at any time." In the future, our
      healthcare model will be reinvented to support a proactive healing environment
      based on providing patient, family and staff comfort. Facilities must be
      functionally planned as well as attractively designed with an aesthetic appeal
      and therapeutic environment. Tomorrow's health facility types will be created
      superseding the traditional inpatient and outpatient-reoriented hospitals. These
      new facilities will incorporate changing technologies, demographics and serve
      continually changing modes of operation.

PMID- 10346018
TI  - Gardens in the ambulatory care environment.

PMID- 10346019
TI  - The introduction of computer-based technology into ambulatory care practice:
      seeking future benefits.

PMID- 10346020
TI  - HCFA announces a prospective payment system for outpatient services.

PMID- 10346021
TI  - Integrative medicine and ambulatory care: strategic issues.

PMID- 10346022
TI  - Achieving success for freestanding ambulatory care centers: detailed planning.
AB  - This is the second in a series of three articles on achieving success for
      freestanding ambulatory care centers. This article focuses on detail planning,
      defining the scope of service and facility program, and conducting feasibility
      analyses for a new freestanding center. The first article, published in the Fall
      1998 issue, provided a framework for making the initial decision to invest in an
      ambulatory center. In the spring of 1999, a companion article, the last of the
      series, will offer practical advice regarding the start-up and operation of a
      freestanding center.

PMID- 10346023
TI  - A vision for ambulatory care in the 21st century.
AB  - The 1990's have been a remarkable decade for ambulatory care providers.
      Ambulatory care services have flourished in an era of rapidly increasing demands
      and seemingly limitless potential. Will the first decade of the next millennium
      continue this trend or is something new on the horizon? Ambulatory care's future
      prospects need to be evaluated within the context of the overall health care
      delivery environment of the future. At this time, three alternative "futures"
      seem plausible for the next decade. Managed care dominates. This scenario appears
      most likely at present with managed care poised to make significant inroads into
      Medicaid and Medicare populations. National health insurance is instituted. Some
      believe that this is a logical reaction to the excesses of the current
      competitive marketplace and is possible following the presidential election of
      2004. Slow evolution of current system. This scenario may be viewed as the status
      quo alternative and is likely in the absence of a crisis or a better, generally
      agreed upon way in which to improve health care delivery.

PMID- 10346024
TI  - Managing hidden transition points.

PMID- 10346025
TI  - Why 2k? Millenium issues in EMS.

PMID- 10346026
TI  - EMS Magazine Website review.

PMID- 10346027
TI  - Rethinking human resources: an agenda for the millennium.
AB  - Health care reforms require fundamental changes to the ways in which the health
      workforce is planned, managed and developed within national health systems. While
      issues involved in such transition remain complex, their importance and the need
      to address them in a proactive manner are vital for reforms to achieve their key
      policy objectives. For a start, the analysis of human resources in the context of
      health sector appraisal studies will need to improve in depth, scope and quality
      by incorporating functional, institutional and policy dimensions.

PMID- 10346028
TI  - Zimbabwe's hospital referral system: does it work?
AB  - BACKGROUND: Anecdotal evidence has suggested inefficiency in the pyramidal health
      care referral system established in Zimbabwe in 1980, as part of its primary
      health care (PHC) model. AIM: To assess the functioning of the pyramidal referral
      system in two rural districts surrounding Harare, Zimbabwe, with regard to two
      common indicator conditions: pneumonia in children and malaria in adults.
      METHODS: For a three-month period, all complete inpatient records with discharge
      diagnoses of pneumonia or malaria from three hospitals representing different
      levels of care were analyzed (n = 227). Data were collected on demographic and
      patient care variables. The appropriateness of admissions and referrals was
      determined by an assessment of the severity of illness and 'intensiveness' of
      care required. Data were analyzed for differences among the three hospitals and
      between the two indicator conditions. Per night inpatient bed costs for each
      hospital were also calculated. RESULTS: For pneumonia in children, 56.8% of
      patients admitted at the secondary level, 53.8% of patients at the tertiary level
      and 57.8% of patients at the quaternary level were of mild severity. For malaria
      in adults, 74.0% of patients seen at the secondary level, 81.5% of patients at
      the tertiary level and 54.3% at the quaternary level were of mild severity. For
      pneumonia, were no differences in severity between the three hospitals whereas
      for malaria significant case-mix differences among the hospitals were found. Most
      patients attending the highest level referral facility were inappropriate
      admissions who could have been treated at a lower level of care. The majority of
      patients at all the hospitals studied had used that hospital as their first or
      second point of contact with the health services. There were large variations in
      the inpatient per night bed costs between the three hospitals. CONCLUSIONS: Using
      the indicator diseases of pneumonia in children and malaria in adults, this study
      concluded that this network did not meet design expectations as the central level
      referral hospital cared for a similar case-mix of patients as the district level,
      but at six times the cost. The appropriateness of admissions and referrals could
      be improved by developing or strengthening intermediate level facilities, by
      changing mechanisms of access to specialist facilities and by training health
      professionals in community settings.

PMID- 10346029
TI  - Household health expenditures in Nepal: implications for health care financing
      reform.
AB  - His Majesty's Government of Nepal has embarked on an ambitious social welfare
      programme of increasing the accessibility of primary education and health care
      services in rural communities. The implications on the financing of health care
      services are substantial, as the number of health posts has increased twelve-fold
      from 1992 to 1996, from 200 to 2597. To strengthen health care financing,
      government policy-makers are considering a number of financing strategies that
      are likely to have a substantial impact on household health care expenditures.
      However, more needs to be known about the role of households in the current
      structure of the health economy before the government designs and implements
      policies that affect household welfare. This paper uses the Nepal Living
      Standards Survey, a rich, nationally-representative sample of households from
      1996, to investigate level and distribution of household out-of-pocket health
      expenditures. Utilization and expenditures for different types of providers are
      presented by urban/rural status and by socioeconomic status. In addition, the
      sources of health sector funds are analyzed by contrasting household out-of
      pocket expenditures with expenditures by the government and donors. The results
      indicate that households spend about 5.5% of total household expenditures on
      health care and that households account for 74% of the total level of funds used
      to finance the health economy. In addition, rural households are found to spend
      more on health care than urban households, after controlling for income status.
      Distributing health care expenditures by type of care utilized indicates that the
      wealthy, as well as the poor, rely heavily on services provided by the public
      sector. The results of this analysis are used to discuss the feasibility of
      implementing alternative health care financing policies.

PMID- 10346030
TI  - Cost of school-based drug treatment in Tanzania. The Partnership for Child
      Development.
AB  - It has been argued that targeting delivery of anthelmintics to school-children by
      taking advantage of the existing education infrastructure and administrative
      system can be one of the most cost-effective approaches in minimizing the
      intensity of infections with both schistosomiasis and major intestinal nematodes
      in many developing countries. The study was conducted in January 1997, shortly
      after the completion of the drug intervention programme. This paper provides an
      analysis of the costs of providing age-targeted treatment of school-children for
      urinary schistosomiasis using praziquantel and for intestinal nematodes using
      albendazole as an integral part of the School Health Programme in Tanga Region,
      Tanzania. The analysis shows that the total financial cost of the intervention
      programme in 1996 prices was US$54 252.28 (exchange rate: TSH 573 = US$1). Of
      this amount, the cost of drugs constitutes 80.6%, while the delivery cost appears
      relatively low, representing just below 20%. Even when the opportunity cost of
      unpaid days of labour input is included, the cost of drugs still remains the
      highest cost component of the intervention (55.8%). In the current
      epidemiological and logistic setting of Tanzania, the financial cost per child
      treated using praziquantel, which involved prior screening at the school level,
      was US$0.79, while treatment using albendazole was as low as US$0.23, of which
      US$0.20 was drug purchase cost. It is concluded that the base cost of delivering
      a universal, standard, school-based health intervention such as albendazole can
      be as low as US$0.03 per child tested, but even a very slight increase in the
      complexity of delivery can have a very significant impact on the cost of
      intervention.

PMID- 10346031
TI  - The costs of hospital services: a case study of Evangelical Lutheran Church
      hospitals in Tanzania.
AB  - The health care systems of many developing countries are facing a severe crisis.
      Problems of financing services leads to high patient fees which make institutions
      of Western health care unaffordable for the majority of the rural poor. The
      conflict between sustainability and affordability of the official health care
      system challenges both local decision-makers and health management consultants.
      Decisions must be made soon so that the existing health care systems can survive.
      However, these decisions must be based on sound data, especially on the costs of
      health care services. The existing accounting systems of most hospitals in
      developing countries do not provide decision-makers with these data. Costs are
      generally underestimated. The leadership of the 16 hospitals of the Evangelical
      Lutheran Church in Tanzania is currently analyzing how the existing health care
      services should be restructured. Therefore, reliable estimates of the costs of
      hospitals services are required. A survey on 'Costing of health services of the
      Evang. Luth. Church in Tanzania' was prepared, which summarizes the results of
      seven months of field investigations in Lutheran hospitals. The major findings
      are that the costs of providing adequate services are much higher than expected.
      The most important factors determining these costs are the administrative
      efficiency of the hospital and the scope of services offered. The paper closes
      with some recommendations on how to improve the services in order to make them
      both affordable for the rural poor and financially sustainable for the Church. It
      is concluded that even the best improvement of technical efficiency will not
      safeguard the survival of the hospital-based health care services of the Lutheran
      Church in Tanzania. These findings call for a reallocation of health care
      resources to lower levels of the health care pyramid.

PMID- 10346032
TI  - Ecological and geographic characteristics predict nutritional status of
      communities: rapid assessment for poor villages.
AB  - The quality of poverty alleviation programmes relies heavily on appropriate
      targeting and priority setting. Major problems in assessing poverty include
      identification of the indicators of poverty and the methods used for its
      assessment. Nutritional status, expressed by anthropometric indices, has been
      proposed as a poverty indicator because of its validity, objectivity, reliability
      and feasibility. This study was conducted to explore the application of remote
      sensing to poverty mapping based on nutritional status at the community level.
      Relationships between the nutritional status within a community and the
      ecological characteristics of the community were investigated. Multiple linear
      regression tests were executed, and the resultant equations were tested for their
      validity in predicting communities with poor nutritional status. Among
      geographical and ecological indicators used, distance to the nearest market, main
      soil type, rice field area, and perennial cultivation area were found to be most
      useful predictors for the ranking of the communities by nutritional status. Among
      non-ecological determinants, food consumption, health service status and living
      conditions were also found as predictors. The highest correlation was found if
      total population was also taken into account in the regression model (R2 = 0.69;
      p < 0.0001). In the assessment of the sensitivity and specificity of the eight
      models studied, 'undernutrition' was defined as a condition where a community
      belongs in the first quartile for nutritional status (highest prevalence of
      undernutrition), and the baseline nutritional survey was considered as a standard
      method for final diagnosis. Most models which included only ecological factors in
      the equations had lower sensitivity and specificity than models which included
      all determinant factors in the equations. All models which took into account the
      total population had higher sensitivity and specificity than those that did not
      take total population into account. The best model of those that took into
      account only the geographical and ecological characteristics of the community's
      living environment had similar sensitivity and specificity (80% and 94.1%,
      respectively) as the models that considered non-geographical and non-ecological
      variables in addition to geographical and ecological variables. In the case of
      West Sumatra, only four ecological and geographic characteristics were sufficient
      to predict poverty in village. Since these characteristics could be surveyed by
      remote sensing, it may well be possible to use remote sensing for a rapid method
      for poverty mapping.

PMID- 10346033
TI  - The hidden cost of 'free' maternity care in Dhaka, Bangladesh.
AB  - We studied the cost and affordability of 'free' maternity services at government
      facilities in Dhaka, Bangladesh, to assess whether economic factors may
      contribute to low utilization. We conducted a questionnaire survey and in-depth
      interviews among 220 post-partum mothers and their husbands, selected from four
      government maternity facilities (three referral hospitals and one Mother and
      Child Health hospital) in Dhaka. Mothers with serious complications were
      excluded. Information was collected on the costs of maternity care, household
      income, the sources of finance used to cover the costs, and the family's
      willingness to pay for maternity services. The mean cost for normal delivery was
      1275 taka (US$31.9) and for caesarean section 4703 taka (US$117.5). Average
      monthly household income was 4933 taka (US$123). Twenty-one per cent of families
      were spending 51-100% of monthly income, and 27% of families 2-8 times their
      monthly income for maternity care. Overall, 51% of the families (and 74% of those
      having a caesarean delivery) did not have enough money to pay; of these, 79% had
      to borrow from a money lender or relative. Surprisingly, 72% of the families said
      they were willing to pay a government-levied user charge, though this was less
      popular among low-income families (61%). 'Free' maternity care in Bangladesh
      involves considerable hidden costs which may be a major contributor to low
      utilization of maternity services, especially among low-income groups. To
      increase utilization of safer motherhood services, policy-makers might consider
      introducing fixed user charges with clear exemption guidelines, or greater
      subsidies for existing services, especially caesarean section.

PMID- 10346035
TI  - Study of a patient referral system in the Republic of Honduras.
AB  - The first nationwide study on a patient referral system was conducted in
      Honduras. It covered all 25 public hospitals (six National, five Regional and 14
      Area Hospitals) and 24 major health centres. Based on 46,739 reviews of patient
      records, 226 'received referral' and 1072 'sent referral' cases were analyzed by
      age and sex of the patient, diagnosis on referral, institution from or to which
      the case was referred, use of proper referral form, and reception of reply for
      referrals. At the same time, the study team supervised the function of the
      registry and management of patient records at each institution. The average
      referral rate by the level of health facility was 15.8% at National, 4.0% at
      Regional, 2.8% at Area Hospitals, and 0.8% at health centres. The referral rate
      was observed to be higher when institutional managers emphasized the importance
      of the referral system. Only 1.4% of referrals received a reply from upper level
      institutions. The most common cases for referral were neurological at National,
      obstetric at Regional and respiratory cases at Area Hospitals. The use rate of
      the standard referral form was 70 to 80% at hospitals and 60% at health centres.
      There was no norm to duplicate referral letters for record keeping. The patient
      referral system has not developed satisfactorily in Honduras. The main problems
      were: 1) low referral rate at all levels of institution, 2) evident by-pass
      phenomenon at intermediate hospitals, 3) inadequate health information system for
      patient referral, and 4) misunderstanding of the terminology of referral by
      health personnel. The following recommendations were made: guarantee of essential
      health services at peripheral institutions, development of an effective
      information system for patient referral, facilitation of frequent reply for
      referrals, elaboration of referral case discussion between institutions, patient
      education on proper use of health facilities, and restructuring the health
      service network in the two major cities.

PMID- 10346034
TI  - Knowledge, perceptions and behaviour of mothers toward intestinal helminths in
      Upper Egypt: implications for control.
AB  - Operational research was conducted in Qena Governorate, Upper Egypt, to gather
      the information needed to design an integrated control programme for intestinal
      helminths in the area. To this aim, qualitative and quantitative techniques were
      used on a sample representative of the entire governorate. Mothers were
      questioned about their knowledge and perception of intestinal helminths, their
      hygienic habits and health-seeking behaviour. At the same time, a coprological
      survey was conducted on all the children 2 to 12 years of age living in the
      selected households (n = 2657) to provide baseline data on the prevalence of
      infection with these parasites. The survey results showed that intestinal
      helminth infections were more prevalent in rural areas and in three of the 12
      Governorate districts. Almost all the respondents considered worms harmful and
      were aware of the need for treatment. More than adequate knowledge was present on
      ways to prevent infection. Good hygienic practices were associated with a low
      prevalence of infection in the household. Practical recommendations were
      formulated to design a helminth control programme tailored to the local situation
      and to prioritize allocation of resources. Passive case detection appeared to be
      appropriate to the level of infection in Qena (< 15%). The intervention should
      target areas and districts where prevalence of infection was higher, and all
      children below 12 years of age. Health education, besides encouraging mothers to
      refer their children to the health units for treatment, should focus on improving
      hygienic behaviour. While schools might be the best channel to contact children,
      the use of informal channels of communication, such as television, should be
      promoted to reach the mostly illiterate mothers. The research highlights the
      importance of gathering information on mothers' perceptions and behaviour in the
      design and implementation of a community-based intestinal helminths control
      programme.

PMID- 10346036
TI  - The development of a quality information system: a case study of Mexico.
AB  - One of the primary obstacles in the implementation of continuous quality
      improvement (CQI) programmes in developing countries is the lack of timely and
      appropriate information for decentralized decision-making. The integrated quality
      information system (QIS) described herein demonstrates Mexico's unique effort to
      package four separate, yet mutually reinforcing, tools for the generation and use
      of quality-related information at all levels of the Mexican national health care
      system. The QIS is one element of the continuous quality improvement programme
      administered by the Secretariat of Health in Mexico. Mexico's QIS was designed to
      be flexible and capable of adapting to local needs, while at the same time
      allowing for the standardization of health care quality assurance indicators, and
      subsequent ability to measure and compare the quality performance of health
      facilities nationwide. The flexibility of the system extends to permit the
      optimal use of available data by health care managers at all levels of the health
      care system, as well as the generation of new information in important areas
      often neglected in more traditional information systems. Mexico's QIS consists of
      four integrated components: 1) a set of client and provider surveys, to assess
      specific issues in the quality of health services delivered; 2) client and
      provider national satisfaction surveys; 3) a sentinel health events strategy; and
      4) a national Comparative Performance Evaluation System, for use by the
      Secretariate of Health for the quality assessment of state and provincial health
      care services (internal benchmarking). The QIS represents another step in
      Mexico's ongoing effort to use data for effective decision-making in the
      planning, monitoring and evaluation of services delivered by the national health
      care system. The design and application of Mexico's QIS provides a model for
      decentralized decision-making that could prove useful for developing countries,
      where the effective use of quality indicators is often limited. Further, the
      system could serve as a mechanism for motivating positive change in the way
      information is collected and used in the process of ensuring high quality health
      care service delivery.

PMID- 10346037
TI  - The genogram: a new research tool to document patterns of decision-making,
      conflict and vulnerability within households.

PMID- 10346038
TI  - New infant security system combines technology, training, patient care.

PMID- 10346040
TI  - Security from a multi-hospital perspective: what can you expect?

PMID- 10346039
TI  - An interview with: Butch Cappel on canine patrols in hospital settings.

PMID- 10346041
TI  - Reducing hospital parking area crime: strategies that work.
AB  - For hospitals, crime in parking garages and lots--ranging from assaults and
      murder to car theft and car break-ins--is reported second only to Emergency
      Department areas in the number of incidents. And, in recent reviews of lawsuits
      against hospitals for negligent or inadequate security, parking areas rank first
      in incidents that generate such actions. In our most recent special report on
      dealing with hospital parking area crime (see the June 1997 issue), we focused on
      the use of camera surveillance and improved lighting to reduce such crime. In
      this report, which will also cover recent developments in those strategies, we
      will focus on two Omaha, NE, hospitals which stress deployment of manpower and
      education of employees to achieve results.

PMID- 10346042
TI  - What information must be disclosed and by whom?

PMID- 10346043
TI  - New rule to increase organ donation promulgated.

PMID- 10346044
TI  - South Carolina court finds hospital subject to nondelegable duty in providing
      emergency care. Simmons v. Tuomey Regional Medical Center.

PMID- 10346045
TI  - PTCA catheters become less costly.

PMID- 10346046
TI  - Survey bares price woes, challenges of technology.

PMID- 10346047
TI  - Purchasing managers see better times ahead in 1999.

PMID- 10346048
TI  - Service, quality are as important as price.

PMID- 10346049
TI  - Public sector employer evaluation of health plans in the United States.
AB  - Recently, public employers have experimented with different types of health plans
      including Indemnity, Health Maintenance Organization (HMO) and Preferred Provider
      Organization (PPO) plans. This study examines factors that are related to
      municipal employer satisfaction with each type of plan. The data are drawn from
      the International City/County Management Association (ICMA) of municipal
      healthcare practices in 3301 US cities. Many more cities than anticipated used
      only indemnity plans, although there was widespread experimentation with managed
      care plans. Jurisdictions that offered only one type of plan showed highest
      satisfaction levels with HMOs, followed by PPOs and indemnity plans. In
      jurisdictions that offered multiple plans, patterns of satisfaction varied with
      the types of plans involved. Three factors were found to be correlated with
      employer plan satisfaction. As employee complaints and cost to the jurisdiction
      increased, plan satisfaction decreased. As the number of services offered by a
      plan increased, plan satisfaction also increased. While most municipalities
      contracted for health plans as individual employers, a small proportion
      contracted as part of a consortium: there was no statistically significant
      difference in satisfaction levels between the two arrangements.

PMID- 10346050
TI  - Access to obstetrics care for rural Alabama population.
AB  - The delivery of health care in rural areas is a problem throughout the United
      States. The health of an individual warrants consideration near conception, as
      the health of a mother affects the health of an unborn child. This article
      evaluates the status of obstetrics care in rural Alabama and offers possible
      alternatives to the current delivery of care.

PMID- 10346052
TI  - Towards an evidence based health care management.
AB  - Inspired by the development of Evidence Based Medicine, this article introduces a
      new approach for health care management called Evidence Based Management. This
      approach promises to improve the practice of health care management, at the same
      time as it may stimulate research on the organization and management of health
      care. Evidence Based Management means that health care managers should learn to
      search for and critically appraise evidence from management research as a basis
      for their practice. This will require some new managerial skills that should be
      included in the education and training of health care managers. It will also
      require a new orientation for research on health care management. There will be a
      demand for more applied research, and also for research with a more positivist
      orientation.

PMID- 10346051
TI  - Redistributive effects of Swedish health care finance.
AB  - This paper investigates the redistributive effects of the Swedish health care
      financing system in 1980 and 1990 for four different financial sources: county
      council taxes, payroll taxes, direct payments and state grants. The
      redistributive effects are decomposed into vertical, horizontal and 'reranking'
      segments for each of the four financial sources. The data used are based on
      probability samples of the Swedish population, from the Level of Living Survey
      (LNU) from 1981 and 1991. The paper concludes that the Swedish health care
      financing system is weakly progressive, although direct payments are regressive.
      There is some horizontal inequity and 'reranking', which mainly comes from the
      county council taxes, since those tax rates vary for each county council. The
      implication is that, to some extent, people with equal incomes are treated
      unequally.

PMID- 10346053
TI  - How evidence-based medicine will change the way you practice. Panel discussion.

PMID- 10346054
TI  - Recruiting doctors who'll stay.

PMID- 10346055
TI  - Will your HMO pull you into a malpractice suit?

PMID- 10346056
TI  - Dr. Stalter's amazing one-man medicine show.

PMID- 10346057
TI  - We're a group, but we feel like soloists.

PMID- 10346058
TI  - Managed care. Even higher cost can't turn employers away from PPOs.

PMID- 10346059
TI  - The future of managed care: whose prediction should you believe?

PMID- 10346060
TI  - Wrestling with the managed care octopus. Cut your losses by verifying patients'
      coverage.

PMID- 10346061
TI  - A new embezzlement twist: charge it!

PMID- 10346062
TI  - When elderly parents can't manage alone.

PMID- 10346063
TI  - Ultrashort laser pulse bioeffects and safety.
AB  - Recent studies of retinal damage due to ultrashort laser pulses have shown that
      less energy is required for retinal damage for pulses shorter than 1 ns than that
      for longer pulses. It has also been shown that more energy is required for near
      infrared (NIR) wavelengths than in the visible because the light focuses behind
      the retina, requiring more energy to produce a damaging fluence on the retina. We
      review the progress made in determining the trends in retinal damage from laser
      pulses of 1 ns to 100 fs in the visible and NIR wavelength regimes. We have
      determined the most likely damage mechanism(s) operative in this pulse width
      regime.

PMID- 10346064
TI  - A panorama of cardiac risk.

PMID- 10346066
TI  - Dejavu and something new: more POC work ahead.

PMID- 10346065
TI  - Fears collide as genetic testing moves forward.

PMID- 10346067
TI  - How regulatory agencies are addressing genetic testing.

PMID- 10346068
TI  - Transplanting hematopoietic progenitor cells.

PMID- 10346070
TI  - Coagulation analysis at the point of care.

PMID- 10346069
TI  - Home-use PT devices a blessing for some.

PMID- 10346071
TI  - Sampling procedures and survey methodologies for the 1996 survey with comparisons
      to earlier national roadside surveys.
AB  - This article describes the multistage sampling system employed in the 1996
      national roadside survey and compares it to the sampling methods employed in the
      two prior surveys in 1973 and 1986. Also described are the data collection
      procedures at the selected sites, the breath-test devices used to collect blood
      alcohol concentration (BAC) data, and the methods used to impute BAC values where
      breath-test measures were not obtained. Overall, almost twice as many (6,298 in
      1996 compared to 3,698 in 1973 and 3,043 in 1986) drivers were interviewed in the
      most recent national survey as in the previous efforts. The procedures
      implemented in the three surveys are sufficiently similar to permit comparison of
      these surveys conducted at 10-year intervals.

PMID- 10346072
TI  - A school-based social competency promotion demonstration.
AB  - A comprehensive, school-based, instructional and social competency promotion
      program to prevent problem behavior was attempted in a troubled middle school.
      The program included components aimed at increasing social competencies as well
      as components to increase social bonding and school success. The evaluation of
      the 5-year effort showed that it was ineffective. The program never reached the
      expected levels of implementation, and no dependable effects on youth behaviors
      or attitudes were observed. The results are interpreted within the context of
      what is known about the quality of implementation and the organizational climate
      within which the demonstration was attempted.

PMID- 10346073
TI  - Sequential assignment and treatment-as-usual. Alternatives to standard
      experimental designs in field studies of treatment efficacy.
AB  - Psychosocial treatment research studies encounter obstacles to random assignment
      (RA). Used together, two procedures offer an alternative to the standard RA
      design. First, sequential assignment (SA) may create less opposition from
      administration, staff, and clients. SA operates on the principle that limited bed
      availability, a common treatment consideration in the field, determines
      assignment of clients to conditions. Second, treatment-as-usual (TAU) represents
      an alternative type of control condition. Some clients on the waiting list will,
      before a slot opens up and they enter an experimental condition, be absorbed into
      the existing treatment system, in which the amount and type of treatment they
      receive can vary widely. Substituting SA and TAU for the standard RA design may
      introduce methodological impurities including certain limited biases.

PMID- 10346074
TI  - A targeted approach to diabetes planning and marketing.

PMID- 10346076
TI  - ABC tool: a method for identifying and weighting criteria for quality.

PMID- 10346075
TI  - FDA predicts medical device trends.

PMID- 10346077
TI  - Information systems in the rehabilitation setting: the multidisciplinary
      approach.
AB  - Very few inpatient rehabilitation facilities have implemented computerized
      patient information systems. HEALTHSOUTH Harmarville Rehabilitation Hospital has
      been able to successfully take advantage of its size and standing in the
      rehabilitation community to develop applications that provide clinicians with up
      to-date patient information in a usable and easy to access format at a very
      reasonable cost. These systems, designed by multidisciplinary teams of
      clinicians, data users, and programmers, include a Nutrition and Diet Record, a
      Computerized Education Record, Case Management Tracking and Documentation, On
      line Functional Outcomes Documentation and Patient Activity Calendar/Charge Entry
      applications.

PMID- 10346078
TI  - Social, legislative, and clinical influences on defining disability: implications
      for information management.
AB  - Making a clear distinction between illness and disability, as well as between
      organic, individual, and social components of disability, has important
      implications for clinical practice, research, development of social policy, and
      equalization of opportunity for people with disabilities. The influence of social
      and legislative change arising from social movements of people with disabilities,
      and advancements in rehabilitation medicine and assistive technology, have
      resulted in major changes in understanding all these components of disability.
      The role of information management professionals in clarifying and applying these
      concepts, as well as providing clear, accurate, and complete data, is of critical
      importance in efforts to prevent, remediate, and offset the social consequences
      of all aspects of disability.

PMID- 10346079
TI  - Observational data collection using computer and manual methods: which informs
      best?
AB  - Computer and manual systems were used simultaneously to record observations of
      nursing home residents with dementia during a study designed to improve their
      dressing performance. This article differentiates the overlapping and unique
      features of the two data collection systems and discusses the clinical and
      research utility of each system. Although the computer system was more suited to
      clinical research and the manual system to clinical practice, when used in tandem
      each system provided data about the residents' performance that could be used for
      both clinical research and clinical practice, and complemented or expanded upon
      data generated by the other system.

PMID- 10346080
TI  - Disabilities, opportunities, and other resources on the information highway: a
      case study (DOOR Online).
AB  - DOOR Online began as a collaborative effort between a number of agencies and
      people from the disabled community in Colorado. The shared goal was to develop an
      accessible, searchable resource listing for people with disabilities, their
      families, and community supports. DOOR Online, the result of this effort, is a
      database of local, state, and national resources that can be accessed directly
      through the Internet or the statewide library network.

PMID- 10346081
TI  - The Balanced Budget Act of 1997: bringing HIM and the rehabilitation therapies
      closer together.
AB  - This article examines the effect of the Balanced Budget Act of 1997 on current
      treatment and reimbursement practices in rehabilitation services. Specifically,
      we focus on the integration of HIM and therapy skills and practices in providing
      quality patient care. In this article we present two models that represent
      possible scenarios defining the interaction between the HIM and rehabilitation
      professionals that could occur as a result of this legislation.

PMID- 10346082
TI  - Interdependence: a model for community-based health information management
      systems.
AB  - When a person becomes ill or injured, it is the health care professional's role
      to restore patients to their preexisting condition. However, when injuries or
      illness render the individual disabled, it has been my experience that the health
      care system continues treatment based on what has been regarded as the Medical
      Model. This Medical Model, however, may not be appropriate for enabling community
      independence of the individual disabled. An alternative method I have found to be
      more appropriate in meeting the community participation needs of the individual
      is examined in this article. The Interdependent Model promotes community
      acceptance and personal empowerment of the individual. This paradigm is
      capacities-driven rather than deficit-driven. In an exciting and important way,
      we have found that it repositions the health care professional's perspective of
      the doctor-patient relationship.

PMID- 10346083
TI  - Application of grounded theory to content definition: a case study.
AB  - Successful implementation of a clinical information system requires clinician
      involvement throughout the process of content definition and system development
      to ensure acceptance of the automated care process. In these times of downsizing,
      however, clinicians are not always able to participate fully in the dontent
      definition phase of system development and often become frustrated with their
      inability to obtain the patient information they need from the system. The
      qualitative research principles of grounded theory afford clinicians the
      opportunity to participate in content definition for information systems. This
      article presents a case study of the application of grounded theory to develop
      systematically the content definition for a clinical information system in
      preparation for implementation on four medical-surgical units.

PMID- 10346084
TI  - Telemedicine and the role of the health information manager.
AB  - Telemedicine involves the use of rapidly evolving technology that carries
      enormous promise to improve the current level of medical care. In order to
      achieve these expectations, some barriers beyond its technological development
      must be overcome. These are primarily legal and regulatory issues that must be
      resolved by the current stakeholders. These barriers arise from the fact that a
      newly developing telemedicine technology changes the way clinical care is
      delivered to the population and documented.

PMID- 10346085
TI  - Telemedical record documentation.
AB  - Telemedicine is rapidly evolving into a viable method of delivering health care.
      As programs become more active, healthcare organizations must examine policies
      and procedures to assure they meet the needs of the changing complexities of
      healthcare delivery. Telemedicine, or providing health care from a distance,
      brings with it a new dimension that complicates a number of unresolved issues.
      Reimbursement and telemedicolegal concerns particularly bring into focus the need
      for quality documentation for telemedicine. A proposed telemedical record model
      provides guidelines to ensure consistent, accurate, timely, and nonduplicative
      documentation of teleconsultations in any telehealth scenario.

PMID- 10346086
TI  - Who's really raising drug prices?

PMID- 10346087
TI  - The real truth about the female.

PMID- 10346088
TI  - What to look for in a TPA.

PMID- 10346089
TI  - The new direction in disability management. When it works.

PMID- 10346090
TI  - Defusing workplace violence.

PMID- 10346091
TI  - Tracking and treating Hep C infection.

PMID- 10346092
TI  - The bucks behind the wellness boom.

PMID- 10346093
TI  - Empire State plays catch up.

PMID- 10346094
TI  - Data watch. The benefits of leadership.

PMID- 10346095
TI  - As voters pass pot measures, grass grows under plans' feet.

PMID- 10346096
TI  - Mental Health Parity: a year later, are we there?

PMID- 10346097
TI  - Shrinking managed care savings may give physicians greater voice.

PMID- 10346098
TI  - 'Nothing to fear but ...' A conversation with economist Paul Ginsburg, Ph.D..
      Interview by Peter F. Wehrwein.

PMID- 10346099
TI  - Disenfranchised doctors need new skills to compete.

PMID- 10346100
TI  - Kevorkian or quality? What end-of-life care could be.

PMID- 10346102
TI  - Managed care outlook. Customization of benefits: will diversity continue?

PMID- 10346101
TI  - Technically prohibited contracts may still be ok under Stark II law.

PMID- 10346103
TI  - Consensus eludes Medicare Commission as deadline for recommendations nears.

PMID- 10346104
TI  - Managed care reform: how Texas pulled off what Washington can't.

PMID- 10346105
TI  - Compensation monitor. Medical directors paid too little?

PMID- 10346106
TI  - Health care report cards: are you paying attention?

PMID- 10346107
TI  - The short, unhappy lives of too many DM programs.

PMID- 10346108
TI  - HMOs, employers happier with their PBMs.

PMID- 10346109
TI  - Recovering from the PPM debacle. Interview by Patrick Mullen.

PMID- 10346110
TI  - It's time to end the productivity bonus!

PMID- 10346111
TI  - It's OK to ignore referral bans in certain cases, HCFA indicates.

PMID- 10346112
TI  - Selling supplements in the office means grappling with tough issues.

PMID- 10346113
TI  - Managed care outlook. HMO penetration tops 70% in largest HMO markets.

PMID- 10346114
TI  - Technology strikes back. As the clock ticks to 2000, behavioral organizations
      find plenty of problems beyond the obvious.

PMID- 10346115
TI  - Crossing county lines. County-based behavioral health systems take diverse
      approaches to managed care.

PMID- 10346116
TI  - Addiction treatment, redefine thyself. Agencies try not to lose their souls as
      they cope with managed care realities.

PMID- 10346117
TI  - Public substance abuse and managed behavioral healthcare. American Managed
      Behavioral Healthcare Association and National Association of State Alcohol and
      Drug Abuse Directors, Inc.
AB  - In the interest of establishing a dialogue between state policy makers and
      commercial managed behavioral healthcare organizations, the American Managed
      Behavioral Healthcare Association (AMBHA) and the National Association of State
      Alcohol and Drug Abuse Directors (NASADAD) met to facilitate collaborative
      efforts around the use of managed care strategies in public substance abuse
      systems. Although diverse in their respective opinions on numerous issues, state
      substance abuse directors and AMBHA representatives identified several areas of
      agreement on which to build future dialogues. The provision of addictions
      treatment is complicated by the multiple priorities established by purchasers.
      Clinically sound service necessity criteria must be constructed in ways that
      acknowledge this complexity. Uniform clinical necessity criteria are needed and
      must be applied in ways that facilitate, rather than inhibit, consistent access
      to care. Benefits plan designers must ensure a balanced relationship among
      benefits, outcomes and price and must hold care managers accountable for
      performance and results. Participants agreed that open and fair competition is in
      the public interest and that this competition should be structured to preserve
      the values that protect vulnerable populations. Because public providers have
      developed significant expertise in offering a broad array of effective treatment
      and support services, they should be incorporated into both public and private
      systems of care. State substance abuse authorities can assist providers in
      developing the capacity to participate in managed systems by supporting training,
      conducting managed care readiness assessments and adopting uniform treatment
      guidelines. More uniform performance and outcomes measures would help the field
      demonstrate its value and these systems should be based on streamlined data
      collection and timely incorporation of data into quality-improvement efforts. The
      addictions treatment community, like other components of the healthcare system,
      can benefit from the adoption of quality-improvement programs that are data
      driven and outcome-oriented and that document the positive results achieved by
      both public and private providers.

PMID- 10346118
TI  - Psychotherapy under construction. Can telepsychiatric and online services mirror
      the traditional counseling experience?

PMID- 10346119
TI  - Dialogue. The ABCs of buying behavioral software.

PMID- 10346120
TI  - Is anyone out there? Public-sector approaches to recruitment, contracting and
      retention in behavioral health information technology.

PMID- 10346121
TI  - Information services and the art of communication: the real challenge of Y2K.

PMID- 10346122
TI  - Behavioral health takes on new complexion at work.

PMID- 10346123
TI  - Focusing on results. How outcome based management can point groups in the right
      direction.

PMID- 10346124
TI  - Negotiating the technology maze.

PMID- 10346125
TI  - The future of Medicare partial-hospitalization services: what providers and
      payors must consider.

PMID- 10346126
TI  - Data security: the time to begin is now.

PMID- 10346127
TI  - Choosing the right hardware.

PMID- 10346128
TI  - The renewed interest in PACS.

PMID- 10346130
TI  - Computers that think.

PMID- 10346131
TI  - National intranet takes shape in England.

PMID- 10346129
TI  - New HL7 standard strives to achieve plug-and-play.

PMID- 10346132
TI  - Winning physician support for electronic records.

PMID- 10346133
TI  - The next step in PCs?

PMID- 10346134
TI  - You've got mail.

PMID- 10346135
TI  - Managed care. Using a database to improve care.

PMID- 10346136
TI  - Will Congress pass privacy legislation?

PMID- 10346137
TI  - A slow migration. Because their members perceive no major benefits from the
      Internet, group purchasing alliances are conducting only small projects.

PMID- 10346138
TI  - HCFA's CIO has a full agenda. Interview by Joseph Goedert.

PMID- 10346139
TI  - Crafting a national strategy.

PMID- 10346140
TI  - What's the CEO's role? Why more chief executives are playing pivotal roles in
      I.T. strategic planning.

PMID- 10346141
TI  - Selecting the right consultant.

PMID- 10346142
TI  - A time for reflection: providers rethink plan ownership.
AB  - Even as recently as a year ago, the buzz in the healthcare provider community
      continued to be largely positive regarding the development and evolution of
      provider-sponsored health plans. But recent market shifts and setbacks are
      forcing a rethinking of the provider-sponsored plan concept. While a small number
      of such plans in various markets across the U.S. continue to do well, many others
      are floundering, being sold, or closed down outright. In this article, provider
      sponsored plan executives discuss their experiences, and they and industry
      observers approach questions of whether miscalculations have taken place and
      continue to take place in this rapidly changing arena of peril and opportunity.
      In particular, much attention has focused on Medicare provider-sponsored
      organization (PSO) development under the Balanced Budget Act. But, as industry
      observers and executives agree, the issues around all kinds of provider-sponsored
      managed care are now on the table for discussion as never before.

PMID- 10346143
TI  - The grass wasn't greener: hospital-physician partnering in the post-PPMC world.
AB  - With the crash of a number of leading PPMCs nationwide, it's time for hospital,
      health system, and physician executives to reconsider what partnering will mean
      going into the future. The author argues that the new dynamics of the marketplace
      offer a whole range of opportunities through which savvy hospital system and
      physician group leaders can find common ground.

PMID- 10346144
TI  - Patient dumping. Interview by Elise Nakhnikian.

PMID- 10346145
TI  - Adding rehab to adult day services.

PMID- 10346146
TI  - Defining the market. Study provides detailed but preliminary customer profile.

PMID- 10346147
TI  - A game of survival by numbers.

PMID- 10346148
TI  - Citizen Swan. Interview by Bruce Balestier.

PMID- 10346149
TI  - From welfare to health care.

PMID- 10346150
TI  - Close to home. Home and community-based services gain ground.

PMID- 10346151
TI  - Informal dispute resolution: should you or shouldn't you?

PMID- 10346152
TI  - There and back again, safely. Don't let patient transfers lead to drug errors.

PMID- 10346153
TI  - Contemporary Long-Term Care's 1999 source book. The guide to long-term care
      products and services.

PMID- 10346154
TI  - Capitation nation. Developing a strategy is the key to success.

PMID- 10346155
TI  - Assisted living bonds are no taxing matter.

PMID- 10346156
TI  - Enforcement heats up as HCFA and Congress spar.

PMID- 10346157
TI  - Through their eyes. Research suggests that personalizing dementia care can help
      counter behavioral problems.

PMID- 10346158
TI  - A changing population. The "average" long-term care resident looks much as she
      has for decades. But a lot is changing just under the surface.

PMID- 10346159
TI  - Surfing the Web beats pounding the pavement.

PMID- 10346160
TI  - Are assisted living residents tenants or licensees?

PMID- 10346161
TI  - Tapping private equity to finance your dream.

PMID- 10346162
TI  - The Eden alternative. Interview by Martin K. Bayne.

PMID- 10346163
TI  - How to achieve excellence, Part 2. Selecting the right employees.

PMID- 10346164
TI  - Who's regulating the global food market? Codex helps to protect health and
      facilitate international trade.

PMID- 10346165
TI  - Pre-employment inquiries. What you can and cannot ask job applicants.

PMID- 10346166
TI  - Improving the quality of pureed diets. The art and science of producing thickened
      foods.

PMID- 10346167
TI  - The "twinkie" tax. Opponents are angry, advocates believe it can curb obesity.

PMID- 10346168
TI  - Energy density. A key component in weight management.

PMID- 10346169
TI  - How to achieve excellence, Part 3. Share your vision, stretch your boundaries,
      and embrace change.

PMID- 10346170
TI  - Weight loss: still a big issue in long-term care.

PMID- 10346171
TI  - Tips for dealing with weight loss. Problems, goals, and approaches for food and
      nutrition services.

PMID- 10346172
TI  - Overcoming the "trayline blues".

PMID- 10346173
TI  - Billing for enteral tube feedings. A 12-step process for implementation.

PMID- 10346174
TI  - The merits of nutrition intervention.

PMID- 10346175
TI  - Putting your best foot forward.

PMID- 10346176
TI  - Decide to go on-line for the health of your business and your patients.
AB  - Health care providers have an opportunity to help consumers fill their voracious
      appetite for health information by providing resources on the World Wide Web. Web
      sites can encourage patients to get more involved in their own care, attract new
      patients, and make existing patients feel more connected. Successful Web sites
      are updated frequently and provide interactive elements that allow patients to
      ask questions or to find others with similar illnesses.

PMID- 10346177
TI  - Two health care providers conquer the Web.

PMID- 10346178
TI  - Web site offers database of national guidelines.
AB  - The National Guideline Clearinghouse (www.guideline.gov) features evidence-based
      clinical practice guidelines for a variety of diseases and conditions on a
      searchable Web site. The guidelines must meet certain criteria to be included and
      are presented with standardized abstracts and tables that allow for comparison of
      guidelines on similar topics. Officials say the easy access and improved
      credibility should lead to more widespread use of clinical practice guidelines.

PMID- 10346179
TI  - It's time to beef up your information security.

PMID- 10346180
TI  - Survey shows hospitals are keeping costs down.
AB  - For the third year in a row, the American Hospital Association's annual survey of
      more than 5,000 hospitals found little or no growth in hospital costs. The
      average length of stay for patients continued to drop, declining to an all-time
      low of 6.1 days. About 23% of hospitals were involved in developing an HMO
      insurance product independently or through a joint venture in 1997, up from 19%
      of hospitals in 1994.

PMID- 10346181
TI  - Atlanta to host regional summit on patient/provider relationship. Eye on patients
      -what care is right?

PMID- 10346182
TI  - FTC advisory opinion instructive on market share analysis for physician networks.

PMID- 10346183
TI  - Communications.

PMID- 10346184
TI  - HMOs address patients' complaints.

PMID- 10346185
TI  - Upper respiratory tract infections.
AB  - The routine, easiest-to-treat URI PTEs utilized 1.1 office visits during the
      course of a PTE. This patient group also received 0.05 tests, 0.66 laboratory and
      pathology services, and 0.05 medical/surgical procedures during the course of a
      PTE averaging 9.6 days in length. The major cost driver for URI PTEs was
      physician visits. Approximately 62% of URI PTEs produced a claim for prescription
      drug therapy. Overall, URI patients were treated with 1.3 prescriptions per PTE.
      Thirty-two percent of all PTEs received one-drug group and 17.5% received two
      drug group treatments. Amoxicillin was the most commonly used drug for these
      patients.

PMID- 10346186
TI  - Stats & facts. The introduction of the Medicare prospective payment system.

PMID- 10346187
TI  - A conversation with David Lansky PhD.

PMID- 10346188
TI  - The effect of managed care on community pharmacy reimbursement.

PMID- 10346189
TI  - Estimating a reasonable reimbursement for community pharmacies in third-party
      programs.
AB  - The purpose of this study was to estimate the level of reimbursement necessary to
      provide community pharmacies with a reasonable profit on prescriptions dispensed
      through third-party prescription programs. Data were gathered by means of a
      literature review and a survey of community pharmacies in Virginia. Results
      indicated that an average reimbursement of average wholesale price less 15% plus
      a $6.95 dispensing fee was needed to provide pharmacies with a reasonable profit.
      This is much higher than the reimbursements currently provided in most third
      party prescription programs.

PMID- 10346190
TI  - Turning data into information.

PMID- 10346191
TI  - Dissemination of an evidence-based intervention manual to improve managed care
      mammography rates.
AB  - After collaborating with the Centers for Disease Control and Prevention to
      develop an evidence-based mammography intervention manual, the dissemination of
      the manual in a managed care setting was assessed. Using qualitative methods (in
      depth interviews), factors were examined that motivated use of the manual by the
      quality improvement units of eight Prudential HealthCare health plans. Seven of
      the plans implemented more intensive interventions after having received the
      manual than in the previous year. Factors that facilitated use of the manual and
      implementation of recommendations included: internal motivation, support of
      senior level management, adequate resources (time, personnel, and funds) to
      support interventions, and the organization and content of the manual itself.

PMID- 10346192
TI  - Antibacterial management of acute and chronic sinusitis.
AB  - Sinusitis is a common disorder in both children and adults. It is responsible for
      significant absenteeism from school and work. Up to 10% of upper respiratory
      infections in children are complicated by acute sinusitis. Since antibacterial
      therapy is most often empirically chosen to treat the disorder, knowledge of the
      typical etiologic agents as well as awareness of the antibacterial susceptibility
      profiles in a given community are of paramount importance. The need for
      consistently bactericidal antibacterials, the recognition of the importance of
      nontypable Hemophilus influenzae unresponsive to first-generation cephalosporins,
      tetracyline-resistant Gram-positive cocci, and the increasing emergence of beta
      lactamase-positive respiratory pathogens such as H. influenzae and Moraxella
      catarrhalis, now mandate the use of newer therapeutic agents for acute and
      chronic sinusitis.

PMID- 10346193
TI  - Marketplace. Health benefit cuts for retirees loom at hundreds of companies.

PMID- 10346194
TI  - Perspectives. Need for access to new drugs creates big challenge for state ADAP
      programs (AIDS Drug Assistance Programs); better coordination with Medicaid
      urged.

PMID- 10346195
TI  - Perspectives. Breaux panel offers 'new definition of solvency'; passes torch to
      Senate.

PMID- 10346196
TI  - Service recovery doesn't mean showering unhappy patients with gifts.

PMID- 10346197
TI  - ED managers can reduce legal risks of complaints.

PMID- 10346198
TI  - Can 'shapes' improve staff relationships?

PMID- 10346199
TI  - New dictation system cuts report turnaround for ED.

PMID- 10346200
TI  - Know benefits, pitfalls of satisfaction measures.

PMID- 10346201
TI  - Visual triggers promote continuity in care.

PMID- 10346202
TI  - Creativity catches on with ED staff.

PMID- 10346203
TI  - Spoken menus, palm-top computers please patients, nutrition staff.

PMID- 10346204
TI  - Live music can be comfort to the terminally ill.

PMID- 10346205
TI  - Create healing environment without music therapist.

PMID- 10346206
TI  - ED slashes treatment time for heart attack drugs.

PMID- 10346207
TI  - Detect and manage crises in outpatient setting. A phone line, electricity--you're
      in business.

PMID- 10346208
TI  - Web site offers database of national guidelines.

PMID- 10346209
TI  - Survey shows hospitals are keeping costs down.

PMID- 10346210
TI  - Clinton administration's budget slashes providers again. Proposals draw lukewarm
      Congressional response.

PMID- 10346211
TI  - Norwood kicks off patient protection battle.

PMID- 10346212
TI  - Medicare Commission still trying to bridge gaps as deadline nears. Premium
      support, prescription drugs present problems.

PMID- 10346213
TI  - A conversation with ... Phil Gramm. Republican Senator from Texas.

PMID- 10346214
TI  - Making health care accessible, affordable for all.

PMID- 10346215
TI  - The Y2K issue at HCFA: problems and solutions.

PMID- 10346216
TI  - Keep it simple to gain provider support for DM.

PMID- 10346217
TI  - Early intervention prevents pneumonia in high-risk populations.

PMID- 10346218
TI  - Data, cooperation lend cohesiveness to carve-out pacts.

PMID- 10346219
TI  - Collaboration helps N.E. hospitals improve cardiac surgery.

PMID- 10346220
TI  - Specifics add value, usability to patient satisfaction surveys.

PMID- 10346221
TI  - Foundation takes 'go-slow' approach in global cap contracts in Northeast.

PMID- 10346222
TI  - Hospital uses IT to gain competitive edge in tight market.

PMID- 10346223
TI  - Worksite health promotion programs: renewed interest among employers?

PMID- 10346224
TI  - Same-day appointments create capacity, increase access.

PMID- 10346225
TI  - AMA urges physician office compliance plans: what should you do now?

PMID- 10346226
TI  - Independent physicians, unions & "messengers": negotiating the labor and
      antitrust laws.

PMID- 10346227
TI  - OIG advisory opinions recognize health care market realities.

PMID- 10346228
TI  - Excess benefit transaction regulations: room for improvement.

PMID- 10346229
TI  - MSO loses tax-exempt status.

PMID- 10346230
TI  - Understanding the impact of Federal Trade Commission v. Tenet Healthcare
      Corporation.

PMID- 10346231
TI  - Proposed regulations on taxation of excess benefit transactions.

PMID- 10346232
TI  - OIG issues provider self-disclosure protocol.

PMID- 10346233
TI  - Provider networks: withstanding antitrust inquiry.

PMID- 10346234
TI  - Extension of practice ambulatory surgery centers.

PMID- 10346235
TI  - A primer on the IRS private letter ruling process.

PMID- 10346236
TI  - Transforming and repositioning healthcare for the boomers.

PMID- 10346237
TI  - 1999 introduces the virtual audience ... and Y2K fallout.

PMID- 10346238
TI  - Healthcare "intentions": seeing demand as consumers do.

PMID- 10346239
TI  - Anti-kickback laws and hospitalists: is there any recourse?

PMID- 10346240
TI  - Practice profile. University of Massachusetts Medical Center, Department of
      Medicine, Nurse Practitioner Attending Collaborative Service (NPACS).

PMID- 10346241
TI  - Quality of care and the hospitalist: Part 3. Hospitalists and variation in
      healthcare.

PMID- 10346242
TI  - Practice profile. Inpatient Care Group.

PMID- 10346243
TI  - A model hospitalist training program.

PMID- 10346245
TI  - Georgia raises Medicaid rates, but still ranks near bottom.

PMID- 10346244
TI  - Meet these standards for greater efficiency, satisfaction.

PMID- 10346247
TI  - HMOs try new tactics to stand out in the marketplace.

PMID- 10346246
TI  - Do financial incentives stifle doctor satisfaction?

PMID- 10346248
TI  - Reports show the power of comparative analysis technology.

PMID- 10346249
TI  - Three factors of fund-raising motivation.

PMID- 10346250
TI  - Donor management database use and evaluation.

PMID- 10346251
TI  - Achieving success: assessing the role of and building a business case for
      technology in healthcare.
AB  - As the healthcare market continues to evolve, technology will play an
      increasingly important role in an integrated delivery system's ability to provide
      high-quality, cost-effective care. Healthcare leaders must be proactive and
      forward thinking about their technology investments. The financial investment for
      technology innovation can be significant. Therefore, it is important that
      healthcare executives deliberately design the role of technology and develop a
      consistent method for evaluating, identifying, and prioritizing technology
      investments. The article begins by describing technology's role in a healthcare
      organization as a window to the organization, a key driver of business strategy,
      and a high-performance enabler, and it develops a seven-step process for building
      a business case to ensure that an organization's technology investments are wise,
      well-reasoned, and will provide value to its customers. In addition, the article
      discusses the importance of combining people and process reengineering with new
      technology to exponentially increase the value to an organization. Healthcare
      leaders must understand the multiple roles of technology and consistently develop
      a business case when making technology investment decisions. Organizations driven
      by such an understanding will have a robust infrastructure of enabling technology
      designed to integrate people and process elements with technology to achieve the
      goals and initiatives of the organization. These organizations will lead the
      healthcare industry into the next millennium.

PMID- 10346252
TI  - Dimensions of technology in healthcare.

PMID- 10346253
TI  - Can information technology heal healthcare?

PMID- 10346254
TI  - The coming of the information age to healthcare.

PMID- 10346255
TI  - The 1997 IAHSS survey--crime in hospitals.
AB  - As useful as the IAHSS crime surveys conducted between 1987 and 1996 have been in
      demonstrating to JCAHO, AHA, and others about the nature and scope of crime in
      healthcare facilities, problems in data compilation that have caused concern
      about the survey format have resulted in a number of changes in the 1997 survey.
      Readers are cautioned that what seems to be a drop in crime in some of the
      categories in the 1997 survey may well be the result of changes in definition of
      these categories. More years of data will have to be accumulated before valid
      comparisons can be made.

PMID- 10346256
TI  - Code Pink: one hospital's infant abduction plan.
AB  - The author discusses the ways to protect against an infant or child abduction,
      which is a devastating problem for a healthcare facility. He presents his own
      hospital's "Code Pink" plan and describes a drill that was conducted to test the
      plan and uncover mistakes.

PMID- 10346257
TI  - Closing the door on wanderers.
AB  - The author discusses how the three types of patient movement (wanderer) control
      systems--a standalone door system; a remote annunciation system; and a computer
      controlled, centrally monitored system--can be used to better protect patients
      from harm and medical facilities from lawsuits.

PMID- 10346258
TI  - Sexual harassment: what every security manager needs to know.
AB  - Security directors are responsible for protecting against sexual harassment and
      ultimately may be civilly liable for any violations, says the author. His goals
      here are to highlight an often-overlooked topic, provide the reader with a basic
      understanding of sexual harassment, give a background of its growth since 1991,
      help security managers identify and prevent sexual harassment, and provide
      resources for further investigation.

PMID- 10346259
TI  - The 1996 IAHSS crime survey.
AB  - The 1996 IAHSS crime survey, whose publication was delayed because of data
      compilation problems, is the last to be conducted under the old computer program.
      Data for this survey have been re-entered and tables from the survey for
      individual categories are presented for review.

PMID- 10346260
TI  - The waiting room: a potential time bomb?
AB  - The waiting room can be a potential time bomb if not handled properly, says the
      author. Communication with patients about waiting time and being aware of and
      dealing with potential problems are the key to preventing violence.

PMID- 10346261
TI  - Hot spot: planning, design and construction is the right remedy for ED dangers.
AB  - The article presents some special planning and design tactics that can improve
      your hospital's security for the site areas adjacent to or serving the emergency
      department. EDs designed and built to embody the principles provided, say the
      authors, will achieve a good balance between the level of openness needed to
      treat patients and the level of security needed to protect patients, visitors,
      and staff.

PMID- 10346262
TI  - Redesigning your safety committee to a cross-functional team approach.

PMID- 10346263
TI  - Rating game: tips on how to assess your safety program.
AB  - The author offers tips on measuring the effectiveness of your healthcare
      facility's safety program--from establishing objectives to developing programs to
      meet them. He provides an 11-step process to develop a performance standard.
      Through these standards, he says, healthcare managers can showcase the
      improvements that have been implemented.

PMID- 10346264
TI  - Emergency and disaster preparedness in the healthcare setting: elements of a
      viable response.

PMID- 10346265
TI  - Curbing needlestick injuries. National Institute for Occupational Safety and
      Health.
AB  - According to NIOSH, organizational controls are vital in a prevention strategy to
      curb needlestick injuries to healthcare workers. These include worker training,
      eliminating unnecessary sharps, and placing disposal containers where sharps are
      used. The material presented in this article was excerpted from NIOSH's new
      guide, "Selecting, Evaluating, and Using Sharps Disposal Containers."

PMID- 10346266
TI  - HazMat training: first responder chemical spill response team.

PMID- 10346267
TI  - The role of crime prevention education in healthcare security.
AB  - The author describes the crime prevention education program developed at his
      medical center. This program, which he has coordinated, has increased staff
      awareness and inspired community involvement. As a result, he says, the facility
      is safer--with fewer staff injuries from assaults.

PMID- 10346268
TI  - Administering a healthy dose of security.
AB  - The article describes how a hospital located in a poor, crime-ridden section of a
      large city has made the most of in-house resources and public-private liaisons to
      improve security at its 113-acre campus. Details on the facility's double-pronged
      approach--tight internal security and strong external liaisons with businesses,
      law enforcement, and community groups--are provided.

PMID- 10346269
TI  - Hospitals threaten to pull plug on ORYX, demand more say in JCAHO decisions.

PMID- 10346270
TI  - What to do about ORYX? Improve priority areas.

PMID- 10346271
TI  - ORYX: 'there has to be a better way to do this'.

PMID- 10346273
TI  - Do 'consumers' trust health care providers?

PMID- 10346272
TI  - From interview to instrument: how to develop a PS (patient satisfaction) survey.

PMID- 10346274
TI  - Hospitals are keeping costs low, says survey.

PMID- 10346275
TI  - Medical staff competency: how much is enough? Part I.

PMID- 10346276
TI  - Patient confidentiality. Open and shut case.

PMID- 10346277
TI  - Scottish strategy. Knox sideways. Interview by Peter Mitchell.

PMID- 10346278
TI  - Clinical language. Tagging along.

PMID- 10346279
TI  - Telemedicine. Telly addicts?

PMID- 10346280
TI  - The pilgrim's progress.

PMID- 10346281
TI  - Volunteers. Cup final.

PMID- 10346282
TI  - Open space. The servician vision.

PMID- 10346283
TI  - First person. Siren voices.

PMID- 10346284
TI  - Regulation of health-related technologies in Germany.
AB  - Against the background of a financial crisis and supposed inefficiencies due to
      inappropriate use or the use of ineffective technologies in the German health
      care system, increasing awareness of the role of coverage decisions and the use
      of health technologies has stimulated interest in the regulation of health
      technologies. A systematic analysis of the decision processes at the levels of
      licensing/market admission, coverage by statutory health insurance and steering
      of diffusion and usage reveals considerable inconsistencies in different health
      care sectors. With regard to different types of technology, an explicit licensing
      procedure conforming to international standards is required for drugs and medical
      devices. Concerning coverage decisions, the ambulatory sector appears to be much
      more regulated than the in-hospital sector. This applies also to diffusion and
      usage of technologies. However, steering of usage of health related technologies
      is generally weak in Germany since only non-binding guidelines are in place.

PMID- 10346285
TI  - The care and course of diabetes: differences according to level of education.
AB  - OBJECTIVE: The objective of this study was to describe socioeconomic differences
      in the utilisation of health services among persons with diabetes and to link
      these differences with socioeconomic differences in the course of diabetes.
      RESEARCH DESIGN AND METHODS: A 2-year follow-up study (1991-1993) was done with
      data from a population-based survey in The Netherlands (city of Eindhoven and
      surroundings). Those reporting diabetes who also reported treatment with a diet,
      oral antidiabetics or insulin and who completed questionnaires in the years 1991
      and 1993 (n = 173) were included in the analysis. Main outcome measures were: (1)
      the odds ratios according to level of education of utilisation of 11 types of
      service or medical checks in 1991, relevant for diabetes; and (2) odds ratios
      according to level of education of the difference between 1991 and 1993 in the
      prevalence of symptoms of diabetic complications. RESULTS: Controlling for
      severity of diabetes, contact rates with the general practitioner were
      significantly (P < 0.05) higher among those with primary education, compared to
      those with an educational level of intermediate vocational training or higher.
      Rates of checks by a specialist, influenza vaccination and many other checks were
      statistically significantly lower among those with a low educational level,
      although the group with the lowest educational level did not always show the
      lowest rates. Of symptoms indicating diabetes complications, the prevalence of
      pain in the legs and visual impairments developed more unfavourably among those
      with primary education. The prevalence of all symptoms together developed more
      unfavourably among those with primary education. A direct contribution of uptake
      of checks and services to the differential course of diabetes by education could
      not be demonstrated. CONCLUSIONS: People with diabetes with a low level of
      education have lower utilisation rates of checks and services relevant for
      diabetes care, and a worse outcome in terms of complications.

PMID- 10346286
TI  - Research into the use of health economics in decision making in the United
      Kingdom--Phase II. Is health economics 'for good or evil'?
AB  - The purpose of this phased research project is to better understand the role of
      health economic arguments in the decision making process of healthcare providers
      and purchasers in the United Kingdom. Phase I of the research was directed at
      General Practitioners (GPs); in phase II we broadened the scope of the research
      to include different agents who influence resource allocation and the wider
      health care environment. The objective of phase II was to determine the relevance
      and appeal of diverse health economic measures to different decision makers. This
      phase of qualitative research involved 34 decision makers in 17 duo interviews.
      The study has provided a rich source of qualitative evidence on the role of
      health economics in decision making. The main conclusions to emerge are;
      different individuals seek different outcomes; health economic studies should
      report actionable conclusions; and any cost savings must be applicable. To
      succeed, economists need to demonstrate a better understanding of the contracting
      and budgetary processes of the National Health Service. Opinions of the value of
      health economic evaluations varied widely, however most respondents believed it
      would become increasingly influential in the prioritisation process in the
      National Health Service of the future.

PMID- 10346287
TI  - Contracting-out health care services: a conceptual framework.
AB  - Contracting-out has become increasingly prominent in the health-care sector. It
      has been used in activities ranging from 'internal market' arrangements in which
      providers compete for funding from government payers to purchases of medical and
      non-medical inputs by service providers. While contracting-out arrangements for
      non-medical services have been widely adopted with apparent success, the
      contracting-out of medical services has met with criticism. Specifically,
      prominent 'market failures' have been identified which allegedly make contracting
      out inefficient and even potentially disruptive to health care delivery. This
      paper presents and discusses a systematic framework for policymakers to identify
      and assess potential problems in contracting-out health care services, as well as
      some generic approaches to mitigating these potential problems. A key to the
      framework is the notion that conditions contributing to potential market failure
      problems can often be mitigated by policymakers, and that the strategic choices
      of policymakers in the 'first stage' of the contracting process should include an
      analysis of how the contracting-out environment can be changed to mitigate
      potential market failure problems.

PMID- 10346288
TI  - The management and policy challenges of the globalisation effect of informatics
      and telemedicine.
AB  - Managers and policy makers face new and as yet unrecognised challenges-
      particularly loss of control--through the application of new information
      technologies in healthcare. Whilst informatics and telemedicine are important
      developments, the potential for adverse organisational and societal effects
      should be recognised and anticipated. Health organisations are frequently seen as
      circumscribed networks, and these in turn form local alliances with related
      organisations. Information technologies are frequently construed as relating to
      operational systems within organisations, not least electronic patient record
      systems and diagnostic systems. These can then be linked to new generation health
      business systems, to provide accurate management information at low additional
      cost. However, this pair of assumptions is now seriously flawed, due to the
      effects of the latest developments in health informatics and telemedicine. In
      particular, telecommunications and Internet technologies render ineffectual
      previous external barriers of distance and national boundaries, whilst within the
      organisation the combination of knowledge bases with information technologies
      creates tendencies towards internal autonomy. Organisational and national policy
      control of health care face direct and radical challenges through perverse
      effects of otherwise beneficial developments, and early action is needed.

PMID- 10346289
TI  - Facility profile. Cafe caters to the eye and the needs of everyone.

PMID- 10346290
TI  - Building blocks. Single-source vs. design-bid-build: the facts on both sides of
      the hot controversy.

PMID- 10346291
TI  - The human touch. Long-term health care design gets personal.

PMID- 10346292
TI  - Guiding light. CAD/CAFM hits the Web.

PMID- 10346293
TI  - Clean team dream. Software is the ticket.

PMID- 10346294
TI  - Taking sides. Tough times, tough issues. Be glad ASHE's in your corner.

PMID- 10346295
TI  - "It's just like somebody's turned on a light": an NVQ (National Vocational
      Qualification) success story from the voluntary sector.
AB  - This paper reports the findings of an original piece of case study research
      conducted in a voluntary sector organisation engaged in the provision of care in
      the community. The organisation caters for three client groups: the elderly;
      people with learning disabilities; and people suffering from mental ill health.
      The aim is to promote a good quality of life through personal dignity,
      individuality and self-determination; and to provide a high standard of nursing
      care and social support within a homely environment. The organisation employs
      both professionally qualified nurses, i.e. Registered General and Registered
      Mental Nurses (RGNs and RMNs), and non-professionally qualified staff, i.e.
      care/support workers, in order to achieve those aims. The circumstances leading
      to the decision to introduce the NVQ in Care is examined, as is the level of
      success with regard to how candidates, their assessors and their managers
      perceived enhancements in candidates' work performance.

PMID- 10346296
TI  - The logic of job-sharing in the provision and delivery of health care.
AB  - By definition the practice of job-sharing starts from the premiss that there is a
      full-time job to be shared by those who want to balance their work with other
      commitments. In a public sector institution, such as the National Health Service
      (NHS), where most employees are female, it seems logical to believe that a job
      sharing policy would be able to promote equal opportunities, to increase employee
      job satisfaction and to reduce labour costs. Hence, this paper attempts to
      discuss the advantages and disadvantages of having a job-sharing policy, and to
      analyse the reasons for the limited number of job-sharers in the NHS despite the
      apparent benefits of job-sharing to both the employees and the employer. This
      study was carried out in 15 NHS Trusts in northern England and Scotland, by the
      use of questionnaires and interviews, and found that most NHS managers did not
      see the practice of job-sharing as a major cost-saving opportunity or as a
      working pattern that would enhance employee satisfaction and commitment. They saw
      job-sharing as just a routine equal opportunities request which did not deserve
      such managerial attention or long-term strategic thinking. It is argued in this
      paper that job-sharing is a potentially useful option against a background of
      demographic and other social and economic changes which require the development
      and use of long-term strategic policies. Therefore it is concluded that, in the
      NHS, there is a need for a more active and creative approach to job-sharing
      rather than the reactive and passive approach that has dominated the practice so
      far.

PMID- 10346297
TI  - The changing context of employment in the NHS: some legal implications of changes
      to employment contracts.
AB  - The NHS has undergone and continues to undergo rapid change. As a result of this,
      the duties and responsibilities of employees will also change. Managers within
      the NHS have a responsibility to ensure that appropriate contracts of employment
      are held by employees and that, where required, variations in these contracts are
      documented. This paper uses the example of the changing role of the Executive
      Nurse Director to highlight the importance of this need. It concludes by warning
      that failure to consider both the legal duties placed on employers when
      implementing contractual variations and the legal implications of adopting an
      unlawful method of variation, might lead to large legal bills and a demand on
      managerial time dealing with any legal claim against the employer.

PMID- 10346298
TI  - The third way: a new approach to management education in health care.
AB  - This article describes a number of significant changes taking place within the
      management education and development sphere within the National Health Service.
      It also highlights a number of important developments within the higher education
      world. At the confluence of these changes, it is possible to identify a new
      alternative to more conventional in-house management training and the pursuit of
      postgraduate management qualifications. An example of this "third way" in action
      is offered through the description of an in-house accredited management
      development programme run within an NHS Trust.

PMID- 10346299
TI  - The secret of good conversation--investing in success.
AB  - Organisations are created by conversations. They are key in all decisions.
      Negative conversations are familiar and a big investment in failure. We can learn
      to have positive and creative conversations and to make them even more effective
      by understanding differences and "talking each other's language". There are two
      models for successful conversations which the author uses in organisation and
      team development: The Mobius Model (Stockton, 1996) and the Myers-Briggs Type
      Indicator (MBTI). The Mobius maps the six stages of effective conversations and
      enables teams to identify strengths and gaps in how they work. The MBTI provides
      a logical framework of personality difference which increases mutual
      understanding, supports the different stages of Mobius conversations, and enables
      people to identify and respond positively to others who are unlike themselves.
      The impact of learning these models can be--and frequently is--dramatically
      improved outcomes.

PMID- 10346300
TI  - Are people really the major asset for modern competitiveness?

PMID- 10346301
TI  - Skills required for healthy commissioning.
AB  - There can be no doubt that literature regarding healthcare commissioning is on
      the increase. In particular, documentation is continuously emerging on the
      innovative models which have been designed and implemented to secure effective
      healthcare for the future. However, the literature tends to focus on the
      processes that have been designed rather than any required changes in human
      skills and outlook. While this article examines some of the organisational issues
      surrounding healthcare commissioning, it also covers the changes and demands
      required of the personnel practising within the purchasing arms of the National
      Health Service.

PMID- 10346302
TI  - Overcoming cultural barriers to change.
AB  - This article is a case study which focuses on organisational and cultural change
      associated with the incorporation of a college which provided pre- and post
      registration nursing and midwifery education into a much larger institution
      within the university sector. Among the issues addressed is whether
      transformational change, such as that represented by incorporation or merger, can
      be used by managers to successfully refashion the culture of the organisation,
      making more effective than traditional or discipline-based management structures.
      It examines the barriers to change and the various considerations that arose in
      determining the fit of managerial styles and assesses the outcomes of the process
      of change.

PMID- 10346303
TI  - Europe supports UK government in putting quality at the heart of health care.
AB  - The new government drive for quality to be at the heart of health care is
      discussed, following which an insight into the membership and remit of the new
      European Health-Care Working Group is given. The article also provides a brief
      description of the European Foundation for Quality Management model and the
      benefits associated with applying self-assessment as a tool for attaining
      business excellence. Finally, the first stages of the work proposed by the
      European Health-Care Working Group is highlighted along with the potential effect
      on health care within the UK.

PMID- 10346304
TI  - Integration into higher education: personal perceptions and reflections.
AB  - Integration of midwifery and nurse education into higher education was completed
      in 1996. This article highlights issues which emerged prior to, during and post
      integration. It focuses on the process itself, student support, status, titles
      and employment contracts of lecturers and examines these issues in relation to
      one model of change. The personal perceptions and reflections of the authors are
      based on their own experiences of integration in two institutions. The authors
      conclude that although lecturers are still "juggling" with their roles as
      lecturers in higher education, change should be embraced and viewed positively,
      and all opportunities for research, collaboration and professional development
      should be grasped.

PMID- 10346305
TI  - Developing postgraduate medical education for trusts: a secret to long-term
      success.
AB  - The delivery of effective postgraduate education for doctors in trusts is
      becoming vital to secure the individual services of trusts. Increasingly,
      training requirements are impacting on the location of clinical services that NHS
      trusts provide. Failure to understand the benefits and drawbacks of providing
      postgraduate education could affect the long-term strategic direction of trusts.
      The paper seeks to identify the case for investment, the need to address key
      deliverables to secure effective postgraduate education and the need for
      clinicians and managers to evaluate the effectiveness of such training for their
      organisations.

PMID- 10346306
TI  - Human resource management in the health-care industry.
AB  - It has been said that managing change is a synonym for managing people through
      change. No other industry has experienced more change in the past ten years than
      the health-care industry. In order to regulate all this change, managers in
      health-care organizations must identify new ways to deal with the changes. The
      issues are as old as time: job satisfaction, cultural conflict, and compensation.
      This paper addresses each of these key issues with the following examples. A new
      nursing paradigm that was implemented at a hospital has significantly increased
      job satisfaction. This paper also takes a look at ways to manage cultural
      conflict in a diversified workforce. Finally, the results of a team approach to
      compensation are studied.

PMID- 10346307
TI  - Protecting the whistleblower: preventing retaliation following a report of
      patient abuse in health-care institutions.
AB  - Health-care providers throughout the United States face litigation and the threat
      of litigation on a daily basis due to claims of patient abuse. Hidden within the
      costs associated with defending patient abuse claims are the wrongful termination
      filings made by employees who claim they were retaliated against for their
      whistleblowing activity. The purpose of this paper is to demonstrate why an
      employer would resort to retaliatory acts in the shadow of a patient abuse filing
      and to discuss what steps are currently taken to prove and investigate the
      validity of a retaliation claim. Included within the body of this paper are court
      decisions on the topics of whistleblowing protection and violation of public
      policy. These examples are illustrated so that recommendations can be provided
      that assist the employer in avoiding a wrongful discharge claim and help to
      conclude that retaliation against the whistleblower is a costly mistake even with
      the employment at-will principle as a defense.

PMID- 10346308
TI  - Managing human resources in healthcare: learning from world class practices--Part
      I.
AB  - This paper, which is presented in two parts, is intended to demonstrate that
      practices related to the area of human resources management, adopted by model
      organisations that have dominated their markets consistently, can lend themselves
      very well to the healthcare sector, which is primarily a "people-oriented"
      sector. As change in a modern business context is set to continue in an
      unrelenting way, most organisations will be presented with the challenge of
      developing the necessary skills and areas of expertise to enable them to cope
      with the demands on them, master technological opportunities at their disposal,
      learn how to exploit modern management concepts and optimise value to all the
      stakeholders they intend to serve. This paper draws from best practices using the
      experiences of quality recognised organisations and many admired names through
      pioneering human resource policies and practices and through clear demonstrations
      on the benefits of relying on people as the major "asset". Part I of this article
      addresses the importance of human resources as revealed through models of
      management for organisational excellence. In particular, the paper refers to the
      criteria for excellence in relation to people management using the following
      prestigious and integrative management models: Deming Prize (Japan); European
      Quality Award Model (Europe); and Malcolm Baldrige National Quality Award (USA).
      In addition, this paper illustrates several case studies using organisations
      known for their pioneering approaches to people management and which led them to
      win very prestigious quality awards and various international accolades. The
      paper concludes by reinforcing the point that human resource management in a
      healthcare context has to be viewed as an integrated set of processes and
      practices which need to be adhered to from an integrated perspective in order to
      optimise individuals' performance levels and so that the human potential can be
      exploited fully.

PMID- 10346309
TI  - Managing human resources in healthcare: learning from world class practices--Part
      II.
AB  - This is part II of an analysis of world class practices adopted by model
      organisations known for their excellence in terms of people management and their
      superior competitiveness based on harnessing the potential of their employees.
      This paper continues by addressing best practices adhered to by organisations
      using the NASA framework, such as Rockwell Space Systems Divisions. In addition
      and quite comprehensively, the paper examines the personnel function and how it
      is managed in Japan. Finally, the paper describes two cases of model
      organisations and the human resource practices adopted and concludes by drawing
      some useful pointers that professionals who are in a healthcare setting and who
      are concerned with human resources can learn from.

PMID- 10346310
TI  - New developments in a consolidating health care industry.
AB  - The current health care industry has recently seen a great deal of consolidation
      in the form of mergers and acquisitions. These mergers and acquisitions
      invariably result in a loss of jobs. This paper focuses on two strategies that
      health care companies use to reduce workforce under these circumstances.
      Specifically, the paper will focus on the mergers between SmithKline Beckman and
      Beecham plc in the late 1980s, FHP Health Care and TakeCare Health Plans, and
      PacifiCare's recent acquisition of FHP Health-care. It will compare and contrast
      theory, strategy and practices of these six companies as they endeavoured to
      merge or acquire each other.

PMID- 10346311
TI  - Team briefing--helping to rediscover the road to Utopia.
AB  - The BDC has implemented several team briefing schemes into various NHS
      organisations over the last seven years. Evaluation over the last three years has
      highlighted several problems with the team briefing system. The article explores
      these and suggests ways of overcoming the problems with clear, definable actions.
      It highlights that the basic team briefing model is sound but that organisations
      need to consider their commitment and whether the culture is compatible or not
      with some reinforcement of certain processes which includes training team
      briefers and having effective feedback as part of the process. The article
      concludes that team briefing is a useful tool, which can help organisations
      communicate effectively with their employees.

PMID- 10346312
TI  - Using the business excellence model to effectively manage change within clinical
      support services.
AB  - This article describes the journey of managing the change from seven separate
      health providing units to one overall team providing a range of services. To
      facilitate the change the Malcolm Baldrige National Quality Award self-assessment
      model was used. The benefits and limitations of the model are described as are
      the activities undertaken to achieve a goal of delivering quality care within a
      customer driven rather than service driven focus. Finally the learning gained
      from the change is shared in an attempt to help others undertaking a similar
      journey.

PMID- 10346313
TI  - Building human resources capability in health care: a global analysis of best
      practice--Part I.
AB  - This paper is one of a series of three, covering very comprehensively human
      resource practices in a global and generic context. The series of papers presents
      practices which are directly of relevance to the health-care context, and which
      are based on proven, effective and pioneering approaches. The first paper covers
      practices based on British and European experiences, gathered from world-class
      organisations that have either been finalists or went on to win prestigious
      quality awards such as the British and European Quality Awards. The benchmarking
      analysis presented in this paper is based on the sub-criteria prescribed by the
      European Quality Awards Model, which include: how people resources are planned
      and improved; how the skills and capabilities of people are preserved and
      developed through recruitment, training and career progression; how people and
      teams agree targets and continuously review performance; how the involvement of
      everyone in continuous improvement is prompted and people empowered to take
      appropriate action; how effective top-down and bottom-up communication is
      achieved.

PMID- 10346314
TI  - Building human resources capability in health care: a global analysis of best
      practice--Part II.
AB  - This paper is the second from a series of three, addressing human resource
      practices using best practice examples. The analysis covered is based on the
      experiences of organisations that have won the Malcolm Baldrige National Quality
      Award (MBNQA) in the USA. The subcriteria covered in this benchmarking
      comparative analysis covers the following areas: human resource planning and
      management; employee involvement; employee education and training; employee
      performance and recognition; employee wellbeing and satisfaction. The paper
      concludes by reflecting on the likely implications for health-care professionals
      working in the human resource field.

PMID- 10346315
TI  - Chaos and complexity--the future for health care HRM.
AB  - The need to understand chaos and complexity in organisations has particular
      importance for health which is bedevilled by the complexity of organisations and
      the sometimes chaotic nature of its core activities. This article seeks to
      explore these issues in the context of one of the key functions which is expected
      to hold together this diversity: Human Resource Management (HRM). An exploration
      of the nature of HRM in health care as it has evolved indicates that in order for
      it to have a pivotal role for the future it will need to rethink this role in the
      changing paradigm which is now emerging; in so doing it could develop as the
      organisational intelligence for health care in the future facilitating
      organisational learning and creativity.

PMID- 10346316
TI  - Human resource management in the health care industry.
AB  - Human resource management practices with special reference to the latest
      developments of the 1990s such as environmental effects and managing diversity,
      were investigated. The purpose of the study was to unveil how the health care
      industry can benefit from these new concepts, as well as to describe how the
      traditional health care facilities can adapt these new ideas. Specific examples
      were provided to illustrate this point. In compilation of this report, both
      primary and secondary research was used. As primary research, many reputable
      individuals in the health care industry were consulted, and asked to comment on
      the rough draft of this report. Secondary sources included many journal articles,
      original researches and books that were written on this technical subject. It can
      be concluded from this research, that the health care industry should adapt the
      latest methods to compete and survive, such as use more marketing tools to
      attract human resource management personnel from other industries, promote
      diversity at the work place, promote from within the company, and cross-train
      personnel whenever possible. Health care industry has generally lagged behind
      other industries in securing high-performance individuals and marketing
      personnel; however, with the development of health maintenance organizations,
      this trend is changing.

PMID- 10346317
TI  - Measuring resilience in health care provider organizations.
AB  - Health care providers offer an ideal setting to study the effectiveness of
      resilient behavior. The notion of a resilient organization is an emerging concept
      for understanding and coping with the modern-day pace of change and associated
      work stress. Resilience is the ability of an individual or organization to
      expeditiously design and implement positive adaptive behaviors matched to the
      immediate situation, while enduring minimal stress. This paper reports on the
      development and testing of several scales designed to measure aspects of
      resilience in the health care provider industry. Six factors explaining over half
      the instrument variance were found, including: goal-directed solution seeking;
      avoidance; critical understanding; role dependence; source reliance; and resource
      access. Results are discussed and future research is outlined.

PMID- 10346318
TI  - Occupational determinants of work attitudes and organizational attachment.
AB  - The "work attitudes-turnover" linkage was compared among four medical-sector
      occupational groups. In a sample of 707 employees, drawn from eight variously
      sized medical-sector sites, intended and actual turnover behavior is predicted.
      Combining a cross-sectional and longitudinal analysis, and using two logistic
      regression models, the direct effect of work attitudes on intended and actual
      turnover was assessed. The "work attitudes-turnover" was shown to be
      occupationally-dependent.

PMID- 10346319
TI  - Organisational behaviour in health care--the research agenda.

PMID- 10346320
TI  - Building human resources capability in health care: a global analysis of best
      practice--Part III.
AB  - This is the last part of a series of three papers which discussed very
      comprehensively best practice applications in human resource management by
      drawing special inferences to the healthcare context. It emerged from parts I and
      II that high performing organisations plan and intend to build sustainable
      capability through a systematic consideration of the human element as the key
      asset and through a continuous process of training, developing, empowering and
      engaging people in all aspects of organisational excellence. Part III brings this
      debate to a close by demonstrating what brings about organisational excellence
      and proposes a road map for effective human resource development and management,
      based on world class standards. Healthcare human resource professionals can now
      rise to the challenge and plan ahead for building organisational capability and
      sustainable performance.

PMID- 10346321
TI  - Developing our leaders in the future.
AB  - The role of the chief executive in a transformed organisation is an extremely
      challenging one. The development of vision, building a commitment to it and
      communicating it constantly are key skills for a chief executive. However, the
      need to build and empower the stakeholders within and outside the organisation to
      support the changes required to deliver the vision requires leaders who can
      connect with a wide range of people and build alliances and partnerships to
      secure organisational success. A passion for understanding human intervention and
      behaviour is needed to encourage, cajole and drive teams and individuals to own
      and commit to change and a new direction. This requires leaders who have
      imagination and creativity--who seek connections and thread them together to
      create order out of incoherence. These skills are not taught in schools or
      textbooks, but are probably innate. They are what separate leaders from the rest.
      These skills need to be developed. A movement towards encouraging
      experimentation, career transfers and more individuality is needed if capable
      leaders of the future are to appear.

PMID- 10346322
TI  - Systematic analysis and controlling of health care organisations lead to
      numerical health care improvements.
AB  - The EFQM model for organisational excellence is used in the health care sector as
      a tool to diagnose and assess the starting position for the effective QM
      programme. Feedback reports cover the fields of acute medical care,
      rehabilitation and ambulant care and contain strengths areas for improvement.
      Building on the EFQM feedback reports, the Modular Concept for Quality in Health
      Care ("Heidelberg Model") improves QM both holistically and specifically by
      implementing so-called "Modules for Excellence". The implementation process
      follows principles of project management covering medical, nursing and managing
      issues and the performance is periodically evaluated against targets. QM projects
      that are designed in the dichotomic way follow three goals. Organisational
      diagnosis and therapy lead to numerical health care improvements in "Prevention
      of nosocomial infections" and "Optimising out-patient treatment". Different
      assessment approaches lead to a diagnosing feedback report for QM in health care.
      The Modular Concept for Quality in Health Care ("Heidelberg Model") clusters,
      priorities, implements and evaluates the organisation's key areas for
      improvement.

PMID- 10346323
TI  - Substance abuse and dependence in physicians: detection and treatment.
AB  - Substance abuse continues to increase and permeate all sectors of US society
      including the medical profession. This article details the importance of testing
      everyone associated with health care organizations, including physicians, as a
      means of protecting patient welfare, increasing quality of care, and reducing
      negligence lawsuits, as well as providing treatment and recovery opportunities
      for those with addictions.

PMID- 10346324
TI  - Ready for take-off: realising the potential of the education and training
      consortia.
AB  - Education consortia are now over 18 months old and can be seen as a "hybrid"
      between a top-down resource allocation system and a bottom-up workforce planning
      system. The strengths and weaknesses of the developing system are identified, as
      is emerging good practice in consortia operations. A model for consortia working
      which emphasises strategic working is proposed.

PMID- 10346325
TI  - A feedforward and feedback framework for analysing an organisation's resources,
      capabilities and development needs.
AB  - The success of an organisation is measured by the progress its people make
      towards its goals and objectives. But, most organisations today operate in fast
      changing and competitive environments. In turn, these unpredictable conditions
      impact on the organisation's internal operations. As a result, established skills
      and competences can become obsolete. Strong and appropriate competences can
      enhance an organisation's performance. Strategic managers then need to ensure
      that their organisational skills and competences remain of an appropriate mix and
      measure. They need to continuously develop and/or renew the skills and
      capabilities of their workforce. Identifying what skills need renewing is not
      easy but very necessary. Identifying them quickly is harder still. An easy to
      follow framework that can be adapted at the various levels within the
      organisation's structure could prove useful as a consistent and relatively speedy
      format for analysing the organisation's resources, capabilities and development
      needs. This paper supports the use of such a framework.

PMID- 10346326
TI  - Primary care groups will have to be good at this, and that and the other.
AB  - Functions of primary care groups (PCG) should be considered ahead of structures
      and those forming PCGs need to see the links between the key health and social
      policy initiatives. Early influence by PCGs will shape the design and local
      implementation of health action zones, health improvement programmes and
      performance frameworks. The Green Paper "Our Healthier Nation" and its successor
      are central to the emerging role of PCGs. Partnership work between GPs, practice
      staff, trusts, local authorities and health authorities needs emphasis.
      Recognition of what people and existing organisations can contribute needs to be
      given. Leadership themes of good primary care operations, health development and
      clinical leadership or their equivalents need time and space to emerge.

PMID- 10346327
TI  - Educating health educators: a survey of hospital staff completing a certificate
      in health education course.
AB  - Health care professionals (nurses, a midwife, a physiotherapist and an
      occupational therapist) working in a large NHS Trust hospital who had completed
      the Certificate in Health Education with the support of their employer, were
      interviewed. The study objectives were to seek their views on the quality of the
      course, to determine the extent to which participants were able to apply their
      new found knowledge and skills in the care they provided to patients and the
      level of support received to allow them to do this. Barriers that prevented staff
      from routinely applying health education in their work were identified. The
      findings indicated that the majority found the course content to be good and
      relevant to their clinical work but they identified lack of time due to the
      pressure of routine clinical work as the main barrier to the promotion of health
      education in their clinical area.

PMID- 10346328
TI  - Delivering effective health care through teamwork: the role of pharmaceutical
      care management.
AB  - In recent years, there has been significant interest in the application of
      continuous quality improvement (CQI) and total quality management (TQM), and
      patient-focused care (PFC) in health care organisations around the globe. The
      hospital industry has substantially embraced the concepts of CQI and TQM with the
      belief that these concepts and programmes will lead to an improvement in both the
      quality and efficiency with which health services are delivered. The objective of
      this article is to achieve better outcomes in health care services with fewer
      resources by studying the implementation of patient-focused care in the health
      care provision context and particularly in the area of pharmaceutical care
      management as an integrated process in the delivery of health care in a hospital
      setting. The changes in health care provision have in many instances meant that
      the provision of pharmaceutical services needed re-assessing.

PMID- 10346329
TI  - Charting the developments in the NHS.
AB  - In this paper, key changes taking in the development of the UK health sector from
      the 1940s to the mid-1990s are briefly sketched. The changes originating from a
      variety of socio-economic and political circumstances have largely been
      responsible for the current shape and position of the NHS. In a forthcoming
      paper, we will review the status of the NHS under the new Labour Government and
      examine implications of new changes for the future of the NHS.

PMID- 10346331
TI  - Reintroducing the EMS Efficiency Act.

PMID- 10346330
TI  - Developing consultant care on delivery suite.
AB  - The need to develop a consultant presence on the delivery suite has never been
      greater given the emerging quality agenda that is occurring within the
      speciality. This is identifying a clear impetus for changing consultant practice
      and also meeting the needs of women more effectively. The article describes these
      trends, the impetus for change and identifies practically how such a change was
      achieved within the largest women's hospital in the UK. It defines the basis for
      building a vision for an improved future and the practical use of management and
      transformational leadership skills to change consultant behaviour and attitudes
      with a clear set of outcomes that were achieved.

PMID- 10346332
TI  - When good isn't enough.

PMID- 10346333
TI  - EMS in America's most populous cities.

PMID- 10346334
TI  - Tax consequences for EMS personnel.

PMID- 10346335
TI  - Joint Commission on Accreditation of Healthcare Organizations. 1998-99
      Comprehensive Accreditation Manual for Ambulatory Care, Management of the
      Environment of Care chapter. (Revisions appear in italics and become effective
      Jan. 1, 1998.).

PMID- 10346336
TI  - Joint Commission on Accreditation of Healthcare Organizations. 1998-99
      Comprehensive Accreditation Manual for Long-term Care, Management of the
      Environment of Care chapter. (Revisions appear in italics and become effective
      Jan. 1, 1998.).

PMID- 10346337
TI  - Joint Commission on Accreditation of Healthcare Organizations. 1997-98
      Comprehensive Accreditation Manual for Behavioral Health Care, Management of the
      Environment of Care chapter. (Revisions appear in italics and become effective
      Jan. 1, 1998.).

PMID- 10346338
TI  - Joint Commission on Accreditation of Healthcare Organizations. Comprehensive
      Accreditation Manual for Hospitals: the Official Handbook, Management of the
      Environment of Care chapter. (Revisions appear in italics and become effective
      Jan. 1, 1998.).

PMID- 10346339
TI  - Medical record statistics form for hospital surveys modified.

PMID- 10346340
TI  - Revisions made in management of information chapters in CAMAC and CAMH.
      Comprehensive Accreditation Manual for Ambulatory Care and Comprehensive
      Accreditation Manual for Hospitals.

PMID- 10346341
TI  - Revisions made to network standards for clinical privileges.

PMID- 10346342
TI  - Standards addressing inspection, testing, maintenance of fire protection and
      detection equipment revised.

PMID- 10346343
TI  - Environment of Care standards addressing performance improvement requirements
      revised.

PMID- 10346344
TI  - New standards seek to protect integrity of clinical decision making.

PMID- 10346345
TI  - Quality oversight: a modest proposal.
AB  - This is the first segment of an excerpted statement on health care quality that
      Joint Commission President Dennis S. O'Leary, MD, presented before the Senate
      Labor and Human Resource Committee on May 20, 1997. The second segment of this
      testimony will appear as the President's Column in the March/April 1997 issue of
      Perspectives. His testimony commented on the proposed Federal Health Care
      Quality, Consumer Information and Protection Act that would expand the role of
      the Agency for Health Care Policy and Research to include the review of
      performance measures, development of risk adjustment methodologies, and creation
      of data element dictionaries and standardized data collection methodologies.

PMID- 10346346
TI  - Special report--ORYX: the next evolution in accreditation. Joint Commission
      introduces new requirements to integrate performance measurement into
      accreditation process.

PMID- 10346347
TI  - Corrections to the 1997-98 Comprehensive Accreditation Manual for Home Care
      (CAMHC).

PMID- 10346348
TI  - Standards for evaluating licensed independent practitioners revised.

PMID- 10346349
TI  - Long-term care standards for medical record authentication revised.

PMID- 10346350
TI  - The value of health insurance: the access motive.
AB  - Why do people purchase health insurance? Many economists would answer that it
      permits purchasers to avoid risk of financial loss. This note suggests that
      health insurance is also demanded because it represents a mechanism for gaining
      access to health care that would otherwise be unaffordable. For example, although
      a US$300,000 procedure is unaffordable to a person with US$50,000 in net worth,
      access is possible through insurance because the annual premium is only a
      fraction of the procedure's cost. The value of insurance for coverage of
      unaffordable care is derived from the value of the medical care that insurance
      makes accessible.

PMID- 10346351
TI  - Modeling risk using generalized linear models.
AB  - Traditionally, linear regression has been the technique of choice for predicting
      medical risk. This paper presents a new approach to modeling the second part of
      two-part models utilizing extensions of the generalized linear model. The primary
      method of estimation for this model is maximum likelihood. This method as well as
      the generalizations quasi-likelihood and extended quasi-likelihood are discussed.
      An example using medical expense data from Washington State employees is used to
      illustrate the methods. The model includes demographic variables as well as an
      Ambulatory. Care Group variable to account for prior health status.

PMID- 10346352
TI  - Health problems as determinants of retirement: are self-rated measures
      endogenous?
AB  - We explore alternative measures of unobserved health status in order to identify
      effects of mental and physical capacity for work on older men's retirement.
      Traditional self-ratings of poor health are tested against more objectively
      measured instruments. Using the Health and Retirement Study (HRS), we find that
      health problems influence retirement plans more strongly than do economic
      variables. Specifically, men in poor overall health expected to retire one to two
      years earlier, an effect that persists after correcting for potential endogeneity
      of self-rated health problems. The effects of detailed health problems are also
      examined in depth.

PMID- 10346353
TI  - Medical savings accounts: microsimulation results from a model with adverse
      selection.
AB  - This paper examines medical savings accounts combined with high-deductible
      catastrophic health plans (MSA/CHPs), exploring the possible consequences of
      making tax preferred MSA/CHPs available to the entire employment-related health
      insurance market. The paper uses microsimulation methods to examine the
      equilibrium effects of MSA/CHPs on health care and non-health care expenditures,
      tax revenues, insurance premiums, and exposure to risk. If MSA/CHPs are offered
      alongside comprehensive plans, biased MSA/CHP enrollment can lead to premium
      spirals that drive out comprehensive coverage. Our estimates also raise concerns
      about equity, insofar as those who stand to lose the most tend to be poorer and
      in families with infant children.

PMID- 10346354
TI  - Consumer information and competition between nonprofit and for-profit nursing
      homes.
AB  - This paper develops implications of Arrow's hypothesis that nonprofit
      organizations are prevalent in health care because of quality uncertainty. The
      model analyzes the ability of nonprofits to mitigate market failures created by
      asymmetric information in an environment characterized by potential competition
      from both explicitly for-profit firms and for-profits in disguise (profit
      motivated firms who obtain nonprofit status in order to exploit the perceived
      trustworthiness of the nonprofit sector). Under certain conditions, it is shown
      that nonprofit status can serve as a credible signal of quality and that
      nonprofits can decrease the underprovision of quality both by providing high
      quality services and indirectly via a spillover effect on quality in the for
      profit sector. Applicability to long-term care and implications for empirical
      research and policy towards nonprofits in health care are discussed.

PMID- 10346355
TI  - The effects of short-term variation in abortion funding on pregnancy outcomes.
AB  - The appropriations for North Carolina's abortion fund have proven inadequate
      during five of the years between 1980 and 1994. This on-again, off-again funding
      pattern provides a natural experiment for estimating the short-run effect of
      changes in the cost of abortions on the number of abortions to indigent women.
      Using an unusually detailed dataset, we estimate the effects of funding
      termination on the monthly abortion and birth rates. Overall, approximately one
      third of pregnancies that would have resulted in an abortion, had state funds
      been available, are instead carried to term.

PMID- 10346356
TI  - Integrated laboratory networks: ideas that work--and some that don't.

PMID- 10346358
TI  - A foundation for PT (proficiency test) success.

PMID- 10346357
TI  - Achieving excellent customer service through education, competency assessment,
      and accountability.

PMID- 10346359
TI  - Breaux plan might drop means-testing.

PMID- 10346360
TI  - Barely breaking even. Industry-sponsored report projects hospitals will post
      minuscule margins on Medicare in '99.

PMID- 10346361
TI  - Who will take biggest payment hits?

PMID- 10346362
TI  - Novant moves for market share in N.C.

PMID- 10346363
TI  - Catholic deals with non-Catholics grow.

PMID- 10346364
TI  - The top 100 cardiac programs. HCIA study shows midsized cities can hold their own
      when it comes to cardiac care.

PMID- 10346365
TI  - JCAHO gives consumers new hotline.

PMID- 10346366
TI  - Feds to seniors: we want you for new army.

PMID- 10346367
TI  - No compromise. Managed-care industry girds for separate battles on patient
      protection, reimbursement.

PMID- 10346368
TI  - No safety in numbers for N.Y. hospitals. Announcement that hospitals achieved
      'record profits' followed by Medicaid payment cuts.

PMID- 10346369
TI  - Bond insurers put the squeeze on strapped hospitals. Credit enhancers pressure
      some facilities to pay off their debt by merging--or else.
AB  - Struggling hospitals are making their bond insures nervous. So the credit
      enhancers are getting tough with strapped facilities. Find a deep-pocketed
      partner or we'll call your bonds, is the message some hospitals are getting.
      Hospital CEO Edward Solvabile (left) knows that story firsthand.

PMID- 10346370
TI  - Volunteer caregivers a valuable commodity.

PMID- 10346371
TI  - Multispecialty clinic in Michigan to close.

PMID- 10346372
TI  - SSM gears up for Baldrige award.

PMID- 10346373
TI  - Cedars-Sinai settles 'dumping' charges.

PMID- 10346374
TI  - Chicago hospitals targeted. Federal government joins whistleblower suit alleging
      upcoding.

PMID- 10346375
TI  - Can't shake the blues. Nation's Blues plans gain market share but post another
      year of billion-dollar losses on operations.

PMID- 10346376
TI  - Calif. hospitals' report slams HMO practices.

PMID- 10346377
TI  - Five hospitals win performance 'trifecta'.

PMID- 10346378
TI  - Return to status quo for Medicare.

PMID- 10346379
TI  - Another big shoe drops. Cleveland's Primary Health Systems seeks bankruptcy
      protection, abandoning for-profit status.

PMID- 10346381
TI  - Kan. docs shed money-losing HMOs.

PMID- 10346380
TI  - Better, not bigger. Construction costs soar on wings of patient demand,
      construction & design survey finds.
AB  - Even though the number of construction projects remained flat in 1998, overall
      spending jumped 29% to nearly $15 billion, according to this year's Construction
      & Design Survey. Outpatient facilities remained in strong demand, increasing 17%
      compared with last year's survey.

PMID- 10346382
TI  - Hospice lengths of stay dwindling.

PMID- 10346383
TI  - Convenience in store. Hospital links strengthen medical supply chain.

PMID- 10346384
TI  - HMOs do credit to hospital owners.

PMID- 10346385
TI  - Getting doctors on board goal of incentive programs.

PMID- 10346386
TI  - Make use of lead time to prepare for APC payment.

PMID- 10346387
TI  - Data are groundwork for MD incentives.

PMID- 10346388
TI  - OR roundtable. Managers' tips on OR scheduling.

PMID- 10346389
TI  - OR benchmarks. 'Best performer' demonstrates savings.

PMID- 10346390
TI  - Top 100 hospitals. Big isn't really better, study shows.

PMID- 10346391
TI  - JCAHO: questions OR managers ask.

PMID- 10346392
TI  - Why worry about water quality?

PMID- 10346393
TI  - Coding: make or break for APCs.

PMID- 10346394
TI  - Clinton to continue fight against healthcare fraud.

PMID- 10346395
TI  - Could your facility's billing for prisoner medical care be considered fraud?

PMID- 10346396
TI  - Stroke busters. New treatments in the fight against 'brain attacks'.

PMID- 10346397
TI  - How global aging will challenge the world's economic well-being.

PMID- 10346398
TI  - Rewiring the brain. How a bright idea became an innovative medical device.

PMID- 10346399
TI  - Casting a cold eye on 'death with dignity'. Oregon studies year 1 of a benchmark
      law.

PMID- 10346400
TI  - Missing the signals. Doctors misdiagnose child-abuse injuries.

PMID- 10346402
TI  - Anti-personnel landmines: the next bold step...

PMID- 10346401
TI  - III Nordic Congress of Emergency and Disaster Medicine. Kuopio, Finland, 24-27
      June 1998. Abstracts.

PMID- 10346403
TI  - Mortality and morbidity among Rwandan refugees repatriated from Zaire, November,
      1996.
AB  - INTRODUCTION: Following renewed ethnic violence at the end of September 1996,
      conflict between Tutsi rebels and the Zairian army spread to North Kivu, Zaire
      where approximately 700,000 Rwandan Hutu refugees resided following the 1994
      genocide. After a major rebel offensive against the camps' militia groups on 15
      November, a massive movement of refugees towards Rwanda through Goma town, the
      capital of North Kivu, began. Massive population movements such as this are
      likely to be associated with substantial mortality and morbidity. OBJECTIVE: To
      study patterns of mortality, morbidity, and health care associated with the
      Rwandan refugee population repatriation during November 1996. METHODS: This study
      observed the functioning of the health-care facilities in the Gisenyi District in
      Rwanda and the Goma District in Zaire, and surveyed mortality and morbidity among
      Rwandan refugees returning from Zaire to Rwanda. Patterns of mortality,
      morbidity, and health care were measured mainly by mortality and health centre
      consultation rates. RESULTS: Between 15 and 21 November 1996, 553,000 refugees
      returned to Rwanda and 4,530 (8.2/1,000 refugees) consultations took place at the
      border dispensary (watery diarrhea, 63%; bloody diarrhea, 1%). There were 129
      (0.2/1,000) surgical admissions (72% soft tissue trauma) to the Gisenyi hospital
      in the subsequent two weeks. The average number of consultations from the 13
      health centres during the same period was 500/day. Overall, the recorded death
      rate was 0.5/10,000 (all associated with diarrhea). A total of 3,586 bodies were
      identified in the refugee camps and surrounding areas of Goma, almost all the
      result of trauma. Many had died in the weeks before the exodus. Health centres
      were overwhelmed and many of the deficiencies in provision of health care
      identified in 1994 again were evident. CONCLUSIONS: Non-violent death rates were
      low, a reflection of the population's health status prior to migration and
      immunity acquired from the 1994 cholera outbreak. Health facilities were over
      stretched, principally because of depleted numbers of local, health-care workers
      associated with the 1994 genocide. Health-care facilities running parallel to the
      existing health-care system functioned most effectively.

PMID- 10346404
TI  - Triage, transportation, and destination decisions by out-of-hospital emergency
      care providers.
AB  - INTRODUCTION: The effectiveness of a tiered emergency medical services system
      often hinges upon the ability of initial care providers with little or no formal
      training to identify emergent patient needs and determine the best means to meet
      those needs. OBJECTIVES: To determine if out-of-hospital emergency care providers
      consistently make appropriate triage, transportation, and destination decisions;
      and to determine if experience and training have an effect on these decisions.
      METHODS: A survey consisting of 14 patient-care scenarios was administered to
      certified and non-certified out-of-hospital emergency-care providers (n = 311)
      from 20 randomly selected EMS agencies. These agencies were part of EMS systems
      that utilize one, two, and three tiered responses by ambulance and fire-based
      commercial, municipal, and volunteer agencies. Participants were asked to select
      the most appropriate mode of transport and destination facility using the
      assumption that they had responded to each scenario in a basic life support
      ambulance. Answers included transporting the patient to various receiving
      facilities or requesting a more advanced-level unit to respond to the scene.
      Transport times to receiving facilities and estimated times of arrival for
      advanced-level units were provided with each choice. Eight emergency physicians
      unanimously had agreed upon the most appropriate answer for each scenario. A two
      tailed t-test was used to compare the scores of the certified and non-certified
      groups; and Spearman's Correlation Coefficients were used to test the effects of
      experience and training. RESULTS: Non-certified providers (n = 108) had a mean
      score of 32.6% or 4.6 (SD = 1.84) correct answers; certified providers (n = 203)
      had a mean score of 41.1% or 5.76 (SD = 2.12) correct answers (p < 0.000001).
      Spearman's Correlation Coefficients were: 1) individual provider level--(0.3978);
      2) agency provider level--(0.2741); 3) hours worked per week--(0.2505); 4) years
      in EMS--(-0.0821); 5) commercial or volunteer provider--(0.2398); 6) agency call
      volume--(0.2012); 7) agency location--(0.0685), and 8) transporting versus non
      transporting agency--(0.2523). CONCLUSIONS: A need exists for further education
      of out-of-hospital emergency care providers with respect to triage,
      transportation, and destination decisions. Provider experience and level of
      certification do not appear to affect these critical patient-care decisions.

PMID- 10346405
TI  - Perceived preparedness for a mass casualty disaster in the United States: a
      survey.
AB  - INTRODUCTION: A mass casualty disaster (MCD) never has occurred in the United
      States, but such an event remains a fearful possibility. The purpose of this
      study was to establish baseline information concerning the perceptions relative
      to the capabilities of the United States to respond to a MCD of persons most
      likely to involved in the responses to such an event when it does occur. METHODS:
      A survey was constructed in 1995 to query the perceptions of persons in authority
      in federal, state, and local agencies who would participate in the medical
      responses to a MCD. Participants were asked to select the most likely scenario, a
      hurricane or earthquake, that could generate 30,000 casualties within their
      respective region. The survey requested respondent's perceptions as to the timing
      of the federal responses and the quality and sufficiency of these responses. The
      survey also sought information about the availability of plans to meet such a
      catastrophe in the region, and the frequency with which such plans have been
      exercised. Responses were grouped by phase of the responses and whether the
      respondents were employed by federal, state, or local agencies. Descriptive
      statistics were used to summarize the data. When appropriate, a one-tailed t-test
      was used to compare the responses of the groups. A p-value = 0.05 was considered
      statistically significant. RESULTS: A total of 104 surveys were distributed of
      which 88 were completed and returned (85%). Both the federal and state
      respondents had considerable experienced in this area. Overall, the federal
      respondents were more optimistic about the availability, utility, and timely
      arrival of federal resources to assist regions in meeting the medical needs. In
      each of the three phases of MCD responses evaluated (medical response, patient
      evacuation, and definitive care), there was concern that there were insufficient
      resources to meet the requirements. States and local respondents perceived that
      initially, they will be on their own for field rescue, life-supporting first-aid,
      and casualty evacuation. Respondents acknowledged that a combination of local,
      state, federal, and private resources eventually would be needed to meet the huge
      demand. Only 31% federal and 26% state/local respondents believed that there will
      be sufficient combined local, state, federal, and private resources to meet the
      requirements for the evacuation of casualties to definitive care facilities
      outside of the region, and another 50% acknowledged the resources would only
      partially meet these requirements. Sixty-eight percent of state/local respondents
      believed that there would be insufficient local, state, federal, and private
      definitive care resources to meet the requirements for definitive care.
      CONCLUSIONS: While three years have elapsed since the survey was conducted and
      there have been some improvements in preparedness and responses, concerns center
      around the perceived lack of resource capability or lack of ability to get the
      resources to the MCD scene in time to meet requirements. Such perceptions by
      experienced professionals warrant further review by those at all levels of
      government responsible for planning and responding to mass casualty disasters.

PMID- 10346406
TI  - Prehospital treatment of severe hypoglycaemia: a comparison of intramuscular
      glucagon and intravenous glucose.
AB  - INTRODUCTION: By introducing an intensified insulin treatment regime to patients
      with insulin-dependent diabetes mellitus (IDDM), the frequency of long-term
      complications that the patient will experience has been shown to decrease. The
      price is an increase in the frequency of severe and mild hypoglycaemic events.
      Therefore, constant monitoring of these patients is necessary. HYPOTHESIS: This
      study compares the time until full recovery of IDDM patients with severe
      hypoglycaemia after treatment with either intravenous glucose or intramuscular
      glucagon. METHODS: 14 patients with IDDM with severe hypoglycaemia requiring
      treatment by the medical staff was randomised to treatment either with 50 ml of
      50% glucose intravenously or intramuscular 1 mg glucagon. The time to recovery
      was recorded. Plasma glucose was measured at fixed intervals to achieve a
      glycaemia profile. Demographic data were acquired through patient interviews
      following recovery. RESULTS: Recovery time between the two groups was
      significantly different statistically. Recovery time ranged for 1 to 3 minutes
      for those receiving glucose intravenously and 8 to 21 minutes for those receiving
      intramuscular glucagon. Characteristic glycaemia profiles were identified and
      differences were present between the two groups with a greater fluctuating
      pattern for the glucose group compared to the steadily increasing pattern seen
      after glucagon treatment. Alcohol was believed to be involved in 8 out of the 14
      cases, and thereby, is the major confounding factor in this study. CONCLUSION:
      Intramuscularly administered glucagon is a safe and reliable alternative to
      intravenous glucose infusion. The fluctuating glycemia pattern seen after glucose
      treatment indicates a low risk for secondary hypoglycaemia. However, further
      studies are necessary to support this assertion.

PMID- 10346407
TI  - Predicting survival from out-of-hospital cardiac arrest.
AB  - OBJECTIVE: To determine the effect of a return of spontaneous circulation (RO SC)
      on survival to hospital discharge as compared to other established predictors of
      survival. METHODS: A retrospective case review of all out-of-hospital primary
      cardiac arrests from 01 January, 1992 to 31 December 1994 was conducted. The
      relative values of age, race, gender, presenting cardiac rhythm, witnessed event,
      initiation of CPR by bystanders, response time intervals, and return of
      spontaneous circulation (ROSC) in an Utstein-template database were tested as
      predictors of survival of patients who had suffered a cardiac arrest in the out
      of-hospital setting. The ROSC was defined as return of spontaneous circulation
      prior to and present upon arrival at the emergency department. Predictors were
      evaluated for statistical significance using a logistic regression analysis (p <
      0.05). Odds ratios (OR) and 95% confidence intervals (CI) with positive and
      negative predictive values (PPV, NPV) were calculated. RESULTS: Of 832 patients
      with primary cardiac arrest, 153 (18.4%) had ROSC and 67 (8.1%) survived to
      hospital discharge. Comparing survivors to nonsurvivors, the mean values for age
      were 64 to 67 years, with 59.7% to 36.1% being witnessed, 35.8% to 23.9% having
      bystander CPR initiated, 88.1% to 48.4% having ventricular fibrillation (V-fib)
      and 82.1% to 64.0% having ROSC. An initial electrocardiographic rhythm of V-fib
      (p = 0.009; OR = 2.2; CI = 1.2-3.9), and ROSC (p < 0.0001; OR = 5.2; CI = 3.6
      7.5) are statistically significant predictors of survival to hospital discharge.
      The PPV was 13.8% for V-fib and 35.9% for ROSC, and the NPV was 98.0% for V-fib
      and 98.2% for ROSC. CONCLUSION: Presenting V-fib and out-of-hospital ROSC are
      significant predictors of survival from cardiac arrest. Failure to obtain ROSC in
      the out-of-hospital setting strongly suggests consideration for terminating
      resuscitation efforts.

PMID- 10346408
TI  - The role of tactical emergency medical support in hostage and crisis
      negotiations.
AB  - The use of tactical medics by members of hostage and crisis negotiations teams
      has not been examined in the literature or in the field. Usually, negotiations
      teams are deployed within the confines of the established inner perimeter along
      with the tactical team and tactical medics. While the likelihood of injuries or
      performance degrading medical problems for negotiators is less than that expected
      for Special Weapons and Tactics (SWAT) team members, they may occur and need
      attention. Additionally, there are other roles that tactical medical personnel
      can play that are specific to the needs of police negotiators. This article will
      examine these possible roles.

PMID- 10346409
TI  - Risk factors, prevention and prophylaxis of dog bites for disaster response
      personnel in the United States.
AB  - It commonly is rumored that in large scale disasters, packs of dogs present a
      human health hazard because of dog bites. However, it is likely that factors
      other than pack behavior comprise greater risk factors for dog bites in disaster
      response personnel. Important risk factors include: 1) the density of the human
      population, which in turn, determines the number of dogs at a disaster site; 2)
      territorial behavior of dogs at their site of residence, which determines the
      frequency with which dogs may bite; and 3) whether rabies is present at endemic
      or epidemic levels within the area in which the disaster is occurring, which
      determines the likelihood of fatal outcomes. Persons bitten by a dog should seek
      medical attention as contraction of rabies may result in a fatal outcome from a
      dog bite. It is recommended that disaster response personnel obtain pre-exposure
      vaccination against rabies. Vaccinated or not, they immediately should seek post
      exposure treatment for rabies following potential exposure.

PMID- 10346410
TI  - Principles of disaster management. Lesson 2: Program planning.
AB  - Many of the problems that develop in disaster management can be avoided with good
      program planning. Assessment following a disaster is essential. Needs assessment
      is essential in the early phases of a disaster and situation assessments become
      more important as the disaster process continues. Both are dynamic and continuous
      processes. Program planning requires setting policies, goals, and objectives with
      the end result of selection of strategies to accomplish the mission.
      Implementation of the strategies requires identification of funding sources,
      allocation of the resources, development management, and monitoring of the
      progress. Together, these elements should result in a balanced and successful
      program.

PMID- 10346411
TI  - Coming together--the time is now!

PMID- 10346412
TI  - Are mental health services losing out in the US under managed care?
AB  - Managed care in its various forms has become a dominating force in US healthcare.
      For people who have long term serious mental illnesses, this trend has had
      undesirable consequences. In the US, states that have adopted managed-care
      systems such as New Mexico, Tennessee and Texas have been harder hit than states
      that have not chosen managed care. Funds available for services have been
      reduced, hospital bed days have been shortened, formularies have been limited and
      number of treatment sessions reduced. A basic problem is that for-profit managed
      care is more interested in profits than in quality of services.

PMID- 10346413
TI  - Thrombolysis, stroke units and other strategies for reducing acute stroke costs.
AB  - Stroke is the leading cause of long term disability and the third leading cause
      of death in the US. Nearly $US40.9 billion (1997 values) are spent each year on
      direct and indirect stroke-related costs in the US alone. Length of hospital
      stay, hospital overheads and nursing-related and rehabilitation costs account for
      the majority of stroke-related expenditures. Intravenous recombinant tissue
      plasminogen activator (rt-PA) therapy for patients presenting within 3 hours from
      onset of ischaemic stroke was shown to improve outcome at 3 months by the
      National Institute of Neurological Disease and Stroke (NINDS) investigators using
      a dosage of 0.9 mg/kg. When the NINDS rt-PA Stroke Study results were examined
      using a Markov model, savings of $US4 to $US5 million (1996 values) per 1000
      patients treated with rt-PA were projected. These savings were predicted to
      result from decreases in length of hospital stay, inpatient rehabilitation and
      nursing home costs, increases in the number of patients discharged directly to
      home and improvements in quality-adjusted life-years. Furthermore, a recent meta
      analysis has documented that the institution of stroke units, consisting of
      multidisciplinary specialised stroke teams, also decreased length of hospital
      stay, death and dependency. Because only a minority of patients who have a stroke
      are currently eligible for thrombolysis, implementation of specialised and
      standardised stroke care may further enhance cost benefits and improve patient
      outcomes.

PMID- 10346414
TI  - A review of quality of life in Alzheimer's disease. Part 2: Issues in assessing
      drug effects.
AB  - There are numerous methods available for assessing patients with Alzheimer's
      disease (AD) or other forms of dementia. Quality-of-life (QOL) assessment is
      unique among these methods. The subjective nature of quality of life provides
      healthcare professionals with the opportunity of incorporating the value systems
      of patients and their carers into their assessments. A systematic review was
      carried out to assess the published data (and some unpublished data) on QOL
      assessment tools and instruments that claim to measure quality of life in
      dementia. A number of measures or methods used in the literature for assessing
      the quality of life of patients with dementing illnesses were identified. It was
      decided to present the resultant review in 2 parts that correspond to the 2 main
      groups into which the instruments were categorised. The first (part 1), looked at
      measures used to assess the impact of disease as well as instruments at a
      developmental or testing stage. The second (part 2), includes instruments that
      claim to measure quality of life in studies documenting the impact of a drug in
      this therapeutic area. This second group consists mainly of instruments
      identified as being used to assess quality of life during clinical trials in
      dementia/AD. As in part 1, this part of the review was unable to identify any
      validated methods of assessing the quality of life of both patients with dementia
      and their carers at the same time. The ideal instrument must show that it can
      reliably, reproducibly and comprehensively assess quality of life for both
      patients with dementia and their carers. It should also demonstrate that it can
      measure quality of life effectively using a practical administration technique
      that does not place any unnecessary burden on either informal carers, other
      healthcare workers involved or the patient themselves. In addition, any measure
      intended for use in assessing the impact of drug treatment on quality of life
      must demonstrate sensitivity to change, also known as responsiveness. All these
      criteria are even more important when measuring quality of life as an outcome
      during clinical trials of a new antidementia drug, because the data generated are
      likely to influence decisions made by regulatory bodies about whether to grant
      licences that are required by pharmaceutical companies to market their products.
      Further cross-sectional and longitudinal research is required to ensure that the
      available instruments possess the essential psychometric criteria that must be
      demonstrated prior to their utilisation in clinical trials of any compound
      developed for use in dementia/AD. Ongoing conceptual research may still be useful
      in exploring new ways of assessing quality of life in this important therapeutic
      area.

PMID- 10346415
TI  - Insomnia, health-related quality of life and healthcare resource consumption. A
      study of managed-care organisation enrollees.
AB  - OBJECTIVE: Insomnia is a prevalent sleep complaint which has been reported to be
      greatly associated with reduced health-related quality of life (HR-QOL) and
      increased healthcare resource use. This study documents the prevalence of
      insomnia, and its impact on patients' HR-QOL and healthcare resource use in
      managed-care settings in the US. DESIGN AND SETTING: A multi-site survey of 5
      American Medical Group Association (AMGA) clinics was conducted. Each clinic
      mailed questionnaires to 1100 randomly selected individuals enrolled in its
      healthcare system and distributed questionnaires to 400 individuals during a
      clinic visit and prior to seeing a physician. The questionnaire was a form of the
      Health Status Questionnaire with the well-validated Medical Outcomes Study 36
      Item Short Form (SF-36) Health Survey, a 3-question depression screen, a sleep
      questionnaire, demographic variables, and questions about medical encounters and
      prescription and over-the-counter (OTC) drug use. MAIN OUTCOME MEASURES AND
      RESULTS: Approximately one-third of managed-care enrollees in this study reported
      insomnia with daytime dysfunction. Individuals with insomnia reported lower HR
      QOL scores and increased healthcare resource use compared with individuals with
      no insomnia. After controlling for demographic variable and comorbid conditions,
      the negative association of insomnia remained significant on all HR-QOL scores,
      emergency room visits, calls to the physician and OTC drug use. CONCLUSIONS:
      Insomnia is significantly associated with reduced HR-QOL and increased healthcare
      resource use in enrollees of managed-care organisations.

PMID- 10346417
TI  - Cost-effectiveness analysis of ramipril in heart failure after myocardial
      infarction. Economic evaluation of the Acute Infarction Ramipril Efficacy (AIRE)
      study for Germany from the perspective of Statutory Health Insurance.
AB  - OBJECTIVE: Data from the Acute Infarction Ramipril Efficacy (AIRE) study were
      used in a cost-effectiveness analysis to determine the incremental cost per life
      year gained (LYG) when the ACE inhibitor ramipril was added to conventional
      treatment in patients with heart failure after acute myocardial infarction. In
      the AIRE trial, the addition of ramipril significantly lowered rates of total
      mortality and rehospitalisation due to heart failure. DESIGN AND SETTING: The
      cost-effectiveness analysis was conducted from the perspective of the Statutory
      Health Insurance (SHI) provider in Germany. A modelling approach was used which
      was based on secondary analysis of existing data, and costs were those incurred
      by SHI (i.e. expenses of SHI). In the base-case analysis, average case-related
      expenses of SHI were applied and LYG were quantified by the method of Kaplan and
      Meier. MAIN OUTCOME MEASURES AND RESULTS: The incremental cost-effectiveness
      ratios of ramipril varied between 2500 and 8300 deutschmarks (DM) per LYG (1993
      values for inpatient and 1995 values for outpatient treatment; DM1 approximately
      $US0.70), according to the treatment periods of 3.8 years and 1 year,
      respectively. In the sensitivity analysis, the robustness of the model and its
      results was shown when the extent of influence of different model variables on
      the base-case results was investigated. First, survival probability and LYG were
      estimated according to the Weibull method. Second, the dependency of the target
      variable (i.e. incremental cost per LYG) on random variables was described in a
      simulation. Third, the influence of the model variables on the target variable
      was quantified using a deterministic model. The variance of the target variable
      was broad and the hospitalisation impact of adding ramipril to conventional
      treatment was an independent variable with much greater influence on the target
      variable than the parameter of clinical effectiveness, i.e. the number of LYG.
      CONCLUSION: Results of this evaluation showed that ramipril has a favourable
      incremental cost-effectiveness ratio for the treatment of heart failure in post
      myocardial infarction patients and can be considered an economical therapeutic
      agent from the perspective of SHI (third-party payer) in Germany.

PMID- 10346416
TI  - The use and cost of HIV service provision in England in 1996. National
      Prospective Monitoring System (NPMS) Steering Group and NPMS Working Party on
      Costs.
AB  - OBJECTIVE: The aim of the study was to measure the use and estimate the cost of
      HIV service provision in England. DESIGN AND SETTING: Standardised activity and
      case-severity data were collected prospectively in 10 English HIV clinics (5
      London and 5 non-London sites) for the periods 1 January 1996 to 30 June 1996 and
      1 July 1996 to 31 December 1996 and linked to unit cost data. In total, 5440
      patients with HIV infection attended during the first 6 months and 5708 during
      the second 6 months in 1996. MAIN OUTCOME MEASURES AND RESULTS: The mean number
      of inpatient days per patient-year for patients with AIDS was 19.7 [95%
      confidence interval (CI): 13.7 to 25.7] for January to June and 20.8 (95% CI:
      15.3 to 26.4) for July to December 1996. The mean number of outpatient visits for
      asymptomatic patients with HIV infection was 14.8 (95% CI: 11.9 to 17.6) and 13.3
      (95% CI: 10.8 to 15.7) for the respective periods and 16.1 (95% CI: 13.21 to
      18.97) and 15.7 (95% CI: 11.2 to 20.2), respectively, for patients with
      symptomatic non-AIDS (i.e. symptomatic patients with HIV infection but without
      AIDS-defining conditions). Substantial centre-to-centre variation was observed,
      suggesting that many clinics can continue the shift from an inpatient- to an
      outpatient-based service. Cost estimates per patient-year for HIV service
      provision for 1996 varied from 4695 Pounds (95% CI: 3769 Pounds to 5648 Pounds)
      for asymptomatic patients, to 7605 Pounds (95% CI: 6273 Pounds to 8909 Pounds)
      for symptomatic non-AIDS patients to 20,358 Pounds (95% CI: 17,681 Pounds to
      23,206 Pounds) for patients with AIDS. CONCLUSIONS: Different combinations of
      antiretroviral therapy affect the cost estimates of HIV service provision
      differently. Anticipated reduction in inpatient-related activity through the
      increased use of combination antiretroviral therapy will further shift service
      provision from an inpatient- to outpatient-based service and reduce costs per
      patient-year. The extent and duration of such effects are currently unknown. The
      long term effects of combination treatment on the morbidity and mortality
      patterns of individuals infected with HIV are also currently unknown, as are
      their implications on the use and cost of HIV service provision. Multicentre
      databases like the National Prospective Monitoring System (NPMS) will provide
      healthcare professionals with information to improve existing services and
      anticipate the impact of new developments.

PMID- 10346418
TI  - Cost-effectiveness analysis of formoterol versus salmeterol in patients with
      asthma.
AB  - OBJECTIVE: The aim of this study was to determine the relative economic
      consequences of treating asthmatics with twice daily dry powder formoterol 12
      micrograms as compared with salmeterol 50 micrograms from a societal perspective.
      DESIGN AND SETTING: A randomised, 6-month, open-label study including 482
      patients with asthma was conducted in Italy, Spain, France, Switzerland, the UK
      and Sweden. Medical costs included the costs of medications, physician services,
      emergency room visits, hospital admissions and lung function and other tests.
      Travel costs and costs of production loss were also calculated. Unit prices were
      estimated from external sources. To pool the costs of the 6 countries, European
      currencies were converted to US dollars using 1995 exchange rates. Outcome
      measures were the number of episode-free days (EFDs) and the number of patients
      reaching a clinically relevant improvement in quality of life as measured using
      the St. Georges Respiratory Questionnaire. MAIN OUTCOME MEASURES AND RESULTS:
      There were no significant differences between the 2 treatment arms in the
      frequency of emergency room visits, hospital admissions, use of rescue medication
      or contacts with general practitioners (GPs), specialists or nurses. Median
      medical costs over 6 months were $US828 per patient with formoterol and $US850
      with salmeterol. This difference was not statistically significant. In both
      groups, about 60% of all days were episode-free. Average costs per EFD were about
      $US9 for both treatments. The average cost per patient reaching a clinically
      relevant improvement in quality of life was between $US1300 and $US1400.
      Incremental cost-effectiveness ratios were not calculated because both costs and
      outcomes were not significantly different. Asthma-related absenteeism ranged
      between 3 days and 6 months per patient in both groups. CONCLUSIONS: There was no
      evidence to suggest that either treatment was more cost effective than the other.

PMID- 10346419
TI  - Fosphenytoin. Pharmacoeconomic implications of therapy.
AB  - Advantages and disadvantages of Fosphenytoin. Advantages. More rapid intravenous
      administration than phenytoin and no need for an in-line filter. May be
      administered by intramuscular injection. Lower potential for local tissue and
      cardiac toxicity than phenytoin. Associated with less pain and phlebitis at the
      injection site, fewer reductions in infusion rate and fewer changes of
      administration site because of injection site complications than phenytoin.
      Benefits in terms of ease of administration and improved tolerability vs
      phenytoin have pharmacoeconomic implications which may translate into an overall
      cost advantage. Disadvantages. Approximately 10-fold higher acquisition cost vs
      phenytoin. Fosphenytoin is a parenterally administered prodrug of phenytoin, used
      in the treatment of patients with seizures. Advantages of fosphenytoin over
      phenytoin include more rapid intravenous administration, no need for an
      intravenous filter, and a lower potential for local tissue and cardiac toxicity.
      Unlike phenytoin, fosphenytoin may also be administered by intramuscular
      injection. Pharmacoeconomic data from a small study of patients with acute
      seizures in a US emergency department showed an overall cost advantage of
      fosphenytoin over phenytoin, despite a considerably greater acquisition cost of
      fosphenytoin. The main cost drivers for phenytoin therapy were treatment costs
      associated with adverse events. In view of the limited pharmacoeconomic data
      currently available, it is in the interests of individual institutions to conduct
      their own formal pharmacoeconomic studies applying local cost data and patterns
      of clinical practise to determine whether fosphenytoin should replace phenytoin
      on their formularly list.

PMID- 10346421
TI  - A short term cost-effectiveness model for oral antidiabetic medicines in Europe.

PMID- 10346420
TI  - Cyclosporin microemulsion (Neoral). A pharmacoeconomic review of its use compared
      with standard cyclosporin in renal and hepatic transplantation.
AB  - Cyclosporin microemulsion (Neoral) is a self-emulsifying preconcentrate of
      cyclosporin which is more rapidly and consistently absorbed than the original oil
      based formulation of cyclosporin (standard formulation; Sandimmun, Sandimmune).
      This superior pharmacokinetic profile suggests that cyclosporin microemulsion may
      be associated with improved therapeutic and economic outcomes compared with the
      standard formulation. Clinical studies comparing the 2 formulations of
      cyclosporin (using the recommended 1:1 dosage conversion factor) in de novo or
      stable renal and de novo liver transplant patients have demonstrated that
      cyclosporin microemulsion is as efficacious as the standard formulation. Rates of
      acute and chronic graft rejection are generally unaffected by the formulation of
      cyclosporin, although a trend toward fewer rejection episodes in cyclosporin
      microemulsion recipients was noted in several randomised studies (reaching
      statistical significance in 4 studies). Most transplant recipients experience
      adverse events during cyclosporin therapy, and with higher and more reliable
      maximum blood concentrations achieved by cyclosporin microemulsion, there is a
      potential risk of more drug-related adverse events. However, most studies have
      suggested that the frequency of drug-related adverse events (including
      nephrotoxicity) is not affected by the formulation of cyclosporin. Analyses of
      healthcare resource utilisation and associated costs in renal and liver
      transplant patients in Canadian and European studies have suggested that the cost
      of using cyclosporin microemulsion may be lower than the cost of using the
      standard formulation. Lower resource consumption among cyclosporin microemulsion
      recipients in several studies led to slightly (but not statistically
      significantly) lower overall healthcare costs in this group. The cost of
      cyclosporin itself was not included in most of these analyses; however, because
      the 2 formulations of cyclosporin are used in similar dosages and have similar
      acquisition costs, this was probably not an important factor in determining
      relative costs. A single cost analysis comparing cyclosporin microemulsion and
      tacrolimus suggested that the 2 drugs were associated with similar overall costs.
      The available economic data on the use of cyclosporin microemulsion are subject
      to a number of important limitations. In particular, only partial results and
      study methodology have been reported for most analyses. Several studies were
      based on small patient groups (< 25) and short periods of follow-up (3 months),
      although some economic studies included larger patient groups receiving treatment
      for up to 1 year. Moreover, all of the analyses published to date were 'protocol
      driven' studies, and hence may not reflect resource use in usual clinical
      practice. CONCLUSION: In de novo and stable renal and de novo liver transplant
      recipients, cyclosporin microemulsion is as effective and well tolerated as the
      standard formulation of cyclosporin. Economic analyses comparing the 2
      formulations indicate a consistent, although small and not statistically
      significant, reduction in overall healthcare costs associated with use of
      cyclosporin microemulsion.

PMID- 10346422
TI  - Common errors and controversies in pharmacoeconomic analyses.

PMID- 10346423
TI  - Impact of dyslipidaemia. Lessons from clinical trials.
AB  - Coronary heart disease (CHD) is a major cause of morbidity and mortality in
      Western countries, and is associated with significant healthcare costs.
      Epidemiological studies have shown that elevated cholesterol levels, particularly
      elevated low density lipoprotein (LDL) cholesterol, are a major established risk
      factor for the development of CHD. There is a large amount of clinical data
      available to indicate that lowering total or LDL-cholesterol levels reduces the
      risk of cardiovascular events and mortality. The most recent cholesterol
      treatment guidelines from the US and Europe recommend intensive treatment
      (usually pharmacological) for patients at highest risk for CHD. Results from a
      number of landmark primary and secondary prevention studies are in support of
      these guidelines and also suggest that the lower the level of LDL-cholesterol
      achieved with treatment, the better clinical benefit attained. Thus, these
      findings indicate that even more aggressive lipid lowering than that recommended
      by available treatment guidelines may be warranted. Finding and treating all
      individuals at risk for CHD would be expected to increase the overall treatment
      costs of hypercholesterolaemia because many patients may not otherwise be
      treated; however, targeting high risk patients, rather than treating all patients
      or treating inappropriately, would be expected to reduce other healthcare costs
      and the indirect costs of lost productivity due to cardiovascular morbidity and
      mortality. Studies with the HMG-CoA reductase inhibitors, which show that these
      drugs substantially lower LDL-cholesterol, are the most convincing since they
      have consistently shown reductions in cardiovascular morbidity and mortality. As
      a result, statins are now well-established agents for the treatment of
      dyslipidaemia.

PMID- 10346424
TI  - Resource utilisation in the management of dyslipidaemia.
AB  - In Western countries, cardiovascular disease accounts for substantial morbidity
      and mortality. In the US, where medical costs and intervention rates are the
      highest in the world, the direct and indirect costs of cardiovascular disease and
      stroke have been estimated at $US274 billion (1998 dollars), with the costs of
      hospitalisation ($US119.9 billion) and lost productivity because of early
      mortality ($US77.9 billion) representing the largest proportions of this amount.
      Dyslipidaemia is an important risk factor for coronary heart disease (CHD), a
      condition which accounts for $US39.3 billion and $US37.9 billion (1998 dollars)
      in hospitalisation/nursing home costs and lost productivity, respectively,
      annually in the US. Similarly, the UK National Health Service spends more than
      500 million pounds sterling annually on the treatment of CHD. Numerous studies
      have shown the benefit of lowering cholesterol levels in terms of decreasing CHD
      associated morbidity and mortality; however, drug therapy costs for dyslipidaemia
      can be high. US and European treatment guidelines for dyslipidaemia recommend
      aggressive treatment for those at highest CHD event risk. Because of the high
      prevalence of dyslipidaemia in Western countries, these recommendations impact on
      a substantial proportion of the population and have increased the use of
      cholesterol-lowering medications. In a limited number of economic studies using
      clinical data from large prevention trials, the cost of drug therapy was nearly
      offset by the reduction in costs associated with hospitalisation and
      revascularisation procedures. Therefore, it appears that the strategy of
      identifying and treating individuals at highest risk for CHD, although expensive
      in terms of drug costs, would be expected to reduce the substantial direct and
      indirect costs associated with this condition.

PMID- 10346425
TI  - The cost of treating dyslipidaemia using National Cholesterol Education Program
      (NCEP) guidelines.
AB  - Coronary heart disease (CHD) is a major cause of death in industrialised
      countries and places a large burden on society in terms of healthcare resources
      and lost productivity. US National Cholesterol Education Program (NCEP)
      guidelines recommend aggressive lipid-modifying therapy for individuals at
      highest risk for CHD. It has been estimated that more than 50 million individuals
      in the US (more than one-third of the total population) are candidates for some
      form of dietary and/or pharmacological intervention to modify their lipid
      profiles. Most individuals who receive lipid-lowering drug therapy do not meet
      target goals set by the NCEP; thus, there is a large potential for increased use
      of drug therapy. Pharmacoeconomic analyses applying NCEP guidelines are sparse;
      however, available data (using direct costs) suggest that secondary prevention is
      more cost effective than primary prevention, but that costs associated with
      primary prevention are generally in line with those of accepted medical
      interventions. Cost-effectiveness ratios for secondary prevention improved when
      indirect costs were assessed in one study. A recent randomised prospective 54
      week comparative study of statins in 662 patients with hypercholesterolaemia
      concurrently measured medical outcomes and economic data. Atorvastatin-treated
      patients were significantly more likely to achieve NCEP goals (overall and at the
      initial dosage), and to achieve these goals more quickly than patients treated
      with fluvastatin, lovastatin and simvastatin. The mean cost to reach NCEP goals
      was consequently lowest for atorvastatin. Results from pharmacoeconomic studies
      of primary and secondary prevention are therefore in support of NCEP treatment
      guidelines for hypercholesterolaemia.

PMID- 10346426
TI  - Clinical positioning of HMG-CoA reductase inhibitors in lipid management
      protocols.
AB  - Drug treatment of dyslipidaemia has progressed dramatically over the past decade.
      Of the available drugs, HMG-CoA reductase inhibitors (statins) have emerged as
      very effective and important treatments for dyslipidaemia. These agents potently
      reduce low density lipoprotein (LDL) cholesterol levels (the main lipid target in
      management protocols and treatment guidelines) and have produced significant
      reductions in coronary heart disease (CHD) related morbidity and mortality, as
      well as overall mortality, in large intervention studies. They have also been
      shown to reduce progression and increase regression of coronary atherosclerosis.
      Statins are generally well tolerated and are thus associated with high patient
      compliance in comparison with the other classes of medications used for
      dyslipidaemia. There are minimal studies to date with these agents in patients
      with elevated triglycerides, either with or without accompanying elevated
      cholesterol levels. Preliminary results with statins in patients with
      hypertriglyceridaemia are promising, with reductions in triglycerides of 26 and
      46%, respectively, having been reported following treatment with simvastatin and
      atorvastatin. Therefore, statins can be considered first-line drugs in many
      patients with elevated total and/or LDL-cholesterol levels according to treatment
      guidelines.

PMID- 10346428
TI  - Spotlight--consumer informatics.

PMID- 10346429
TI  - The universal desktop. Stepping stone technology or CPR alternative?

PMID- 10346427
TI  - Life line. Consumer informatics has gone beyond patient education on the Web.

PMID- 10346430
TI  - Can we talk? Voice recognition technology is speaking to evaluation and
      management documentation.

PMID- 10346431
TI  - Restore the faith. Want to find out what's wrong with your IS department? Just
      ask!

PMID- 10346432
TI  - Don't rock the boat. Y2K tips offer a life preserver to late starters.

PMID- 10346433
TI  - The Y2001 solution: getting beyond survival.

PMID- 10346434
TI  - How do you measure up? Start using benchmarking tactics as a yardstick for
      success.

PMID- 10346435
TI  - Enterprisewide systems: fact or fiction? Industry survey uncovers CIOs' hot
      buttons.

PMID- 10346436
TI  - Night of the living data. Data warehousing uncovers information buried in legacy
      systems.

PMID- 10346437
TI  - Heart link. Real-time cardiac telemedicine helps keep small Utah community
      hospital open. Allen Memorial Hospital.

PMID- 10346438
TI  - Building an IT utility.

PMID- 10346439
TI  - Outsourcing IT. On the grow or a flash in the pan?

PMID- 10346440
TI  - Dead-bolt your data. Sensitive patient records are too important to be left
      unguarded.

PMID- 10346441
TI  - Great Britain: changing healthcare by changing IT.

PMID- 10346442
TI  - Setting up camp ... overseas. If you're thinking about a foray abroad, IT
      implementation in Latin America and elsewhere offer constructive lessons.

PMID- 10346443
TI  - Erase the paper chase.

PMID- 10346444
TI  - More than money. Forget what you knew about recruiting and retaining IT
      employees.

PMID- 10346445
TI  - 9 hot technology trends.

PMID- 10346446
TI  - Responding to search warrants.

PMID- 10346447
TI  - The sky is falling. AAMT's dues are not too high; wages are too low!

PMID- 10346448
TI  - Are you planning to fail? The importance of preparing a business plan.

PMID- 10346449
TI  - 1996 Employer of the Year: TransQuick, Inc.

PMID- 10346450
TI  - Going to the well. An appeal for dictation.

PMID- 10346451
TI  - Health Level Seven (HL7) and AMIA (American Medical Informatics Association)
      update. A review of issues and activities of HL7 and AMIA.

PMID- 10346452
TI  - Who do they call?

PMID- 10346453
TI  - A 24-hour roadmap to the quality improvement process.

PMID- 10346454
TI  - Activity-based costing: a more accurate alternative.

PMID- 10346455
TI  - Making the right choices: VHA study benchmarks best practices in outsourcing.

PMID- 10346456
TI  - Linking it all together: computer system streamlines the peri-operative
      continuum.

PMID- 10346457
TI  - The effect of public accountability on hospital performance: trends in rates for
      cesarean sections and vaginal births after cesarean section in Cleveland, Ohio.
AB  - The article reports a study that was designed to identify whether hospitals in
      the Cleveland, Ohio area have responded to public concern about improving their
      cesarean section and vaginal birth after cesarean section (VBAC) rates. A 14-item
      survey based on the Joint Commission on Accreditation of Healthcare
      Organizations' 1997 Codman Quality Award was administered to 20 hospitals.
      Respondents self-scored the survey based on a 5-point Likert scale. Three
      hospitals provided a detailed description of their efforts. Results showed that
      all hospitals are at various stages of the process to improve their cesarean
      section and VBAC rates. From this, it is proposed that public accountability
      encourages quality improvement.

PMID- 10346458
TI  - Measurement of mammography rates for quality improvement.
AB  - To determine the best source of high-quality data related to mammography rates, a
      study was undertaken to compare chart audit and claims data from the Health Care
      Financing Administration's Ambulatory Quality Improvement Project. Because claims
      data captured a higher percentage of mammograms than chart audit data in this
      study, quality improvement projects should consider utilizing claims data only to
      ascertain mammography rates.

PMID- 10346459
TI  - Evaluation of a local cooperative project to improve postoperative pain
      management in Wisconsin hospitals.
AB  - The effectiveness of a local collaborative quality improvement project in
      improving the management of postoperative pain for Wisconsin Medicare patients
      was assessed. Six quality indicators were evaluated on the basis of baseline data
      from 714 subjects at 15 collaborating hospitals and follow-up data from 406
      subjects from the same 15 hospitals. After efforts to improve postoperative pain
      management, there was statistically significant improvement in all six quality
      indicators.

PMID- 10346460
TI  - Institutionwide pain management improvement through the use of evidence-based
      content, strategies, resources, and outcomes.
AB  - The Agency for Health Care Policy and Research pain guidelines and implementation
      theories were used in this improvement initiative to ensure that evidence-based
      pain management reached every provider and patient in a large tertiary care
      hospital. Implementation strategies, products, and outcome measures are described
      for use in the clinical setting. Critical success factors and implementation
      barriers are also addressed.

PMID- 10346461
TI  - The member satisfaction survey as a measure of health plan accountability.
AB  - In its 1996 study of St. Louis area health maintenance organization members,
      Gateway Purchasers for Health closely analyzed member responses to the National
      Committee for Quality Assurance's annual member health care survey. The analysis
      of specific questions regarding overall satisfaction levels and member health
      status afforded insight into the factors that contribute to an individual's
      reported satisfaction with health care services and into variations by subgroups
      within the population. Ultimately, consumer information that allows choice of a
      health plan that best suits specific needs and preferences will drive
      accountability, quality, and value in the health care market.

PMID- 10346463
TI  - Interview with Miles J. Zaremski, Esq.

PMID- 10346462
TI  - Performance improvement: the organization's quest.
AB  - In today's health care marketplace, quality has become an expectation.
      Stakeholders are demanding quality clinical outcomes, and accrediting bodies are
      requiring clinical performance data. The Roosevelt Institute's quest was to
      define and quantify quality outcomes, develop an organizational culture of
      performance improvement, and ensure customer satisfaction. Several of the
      organization's leaders volunteered to work as a team to develop a specific
      performance improvement approach tailored to the organization. To date, over 200
      employees have received an orientation to the model and its philosophy and nine
      problem action and process improvement teams have been formed.

PMID- 10346464
TI  - No green light yet. A long-awaited report supports medical marijuana. So now
      what?

PMID- 10346465
TI  - The only world they known. The government is closing the only mainland U.S.
      leprosy hospital--whether the residents want it to or not.

PMID- 10346466
TI  - Outsmarting an illness. Choosing your own specialists is not the key to good
      care.

PMID- 10346467
TI  - Information management systems: the "real world" in 1999.

PMID- 10346469
TI  - What works. Print manager does in minutes what once took hours.

PMID- 10346468
TI  - What works. Computerized records reduce paperwork, improve productivity.

PMID- 10346470
TI  - What works. Web-enabled Telemedicine project developed to monitor the health of
      Mt. Everest climbers.

PMID- 10346472
TI  - Working with wireless: more than a matter of convenience.

PMID- 10346471
TI  - For pharmaceutical companies, a data warehouse can be just what the doctor
      ordered.

PMID- 10346473
TI  - The search for managed care systems.

PMID- 10346474
TI  - What do healthcare organizations want from a consultant?

PMID- 10346475
TI  - The CHIME/HMT CIO roundtable: enterprise integration.

PMID- 10346476
TI  - 1999 and beyond: IT's impact on the business of healthcare in the new millennium.

PMID- 10346477
TI  - HotList: managed care systems.

PMID- 10346478
TI  - Healthcare information decisions aren't that simple; or are they?

PMID- 10346479
TI  - The rescue doctrine in medical malpractice and product liability actions: so much
      for heroes.

PMID- 10346480
TI  - Preferred provider organizations: "Top 10" trends for PPOs in the new millennium.

PMID- 10346481
TI  - Danger signs?! Lines are blurring between HMO and PPO models.

PMID- 10346482
TI  - Top 10 trends for preferred provider organizations: 1999-2003.

PMID- 10346483
TI  - Identify best practices to improve patient flow in your ED.

PMID- 10346484
TI  - Use of teddy bear nebulizers might make ED visits less stressful.

PMID- 10346485
TI  - Orientation of new physicians helps ensure smooth transition.

PMID- 10346486
TI  - ED compliance: billing processes receive more attention.

PMID- 10346487
TI  - HCFA updates, clarifies ambulance coverage requirements.

PMID- 10346488
TI  - Fiscal 2000 budget proposal seeks to increase spending on nursing home survey and
      certification, impose user fees.

PMID- 10346489
TI  - CARF proposes set of quality indicators for rehab programs.

PMID- 10346490
TI  - Provider appeals create backlog, point to flawed survey process.

PMID- 10346491
TI  - Lawmakers press HCFA on nontherapy ancillaries, DeParle agrees to hold town
      meeting.

PMID- 10346492
TI  - Government asks Supreme Court to decide if SNFs can challenge Medicare
      regulations. Illinois Council on Long Term Care Inc. v. Shalala.

PMID- 10346493
TI  - AHCA considers litigation over PPS assessment and payment concerns.

PMID- 10346494
TI  - Comparison of patient charts to MDS, claims data imperative under PPS.

PMID- 10346495
TI  - SNF chains report on impact of PPS: few good, many bad, some worse.

PMID- 10346496
TI  - Five minutes with Regina Herzlinger. Interview by Elise Nakhnikian.

PMID- 10346497
TI  - Training, timeliness, and teamwork.

PMID- 10346498
TI  - How low can we go? Affordability is a great idea, but it's more talk than action.

PMID- 10346499
TI  - Get me out! Resident outings are hard to arrange, but they're well worth the
      effort.

PMID- 10346500
TI  - Balancing act. How to make the most of your rehab minutes under the PPS.

PMID- 10346501
TI  - Who pays for long-term care? Form follows funding in long-term care as new
      payment systems emerge and old ones evolve.

PMID- 10346502
TI  - Nursing home-hospice relationships under scrutiny.

PMID- 10346503
TI  - Seniors in cyberspace. More facilities are setting up computer labs for
      residents.

PMID- 10346504
TI  - Mental health's impact on payment under PPS.

PMID- 10346505
TI  - The case for tiered pricing. How to stay flexible and fair--and financially
      viable.

PMID- 10346506
TI  - Playing for keeps. For a lasting relationship, apply matchmaking techniques when
      hiring.

PMID- 10346508
TI  - To better position your facility, create a Web site.

PMID- 10346507
TI  - The future of aging.
AB  - In 1984, the John D. and Catherine T. MacArthur Foundation funded a long-term
      research program that brought together 16 scientists from various disciplines to
      study what factors contribute to successful physical and mental aging. Last year,
      two of those scientists published Successful Aging, in which they discuss the
      study's generally encouraging findings. In the sections excerpted below, they
      share some sometimes surprising insights into how people age in America.

PMID- 10346509
TI  - Creating enforceable negotiated risk agreements.

PMID- 10346510
TI  - A new gold standard. Pending drugs could slow progression of Parkinson's.

PMID- 10346511
TI  - Cross-sectional comparison of live and interactive voice recognition
      administration of the SF-12 health status survey.
AB  - OBJECTIVE: To compare interactive voice recognition (IVR) and live telephone
      methods for administering the SF-12 health status survey (SF-12). STUDY DESIGN:
      Patients with low back pain received either IVR or live interviews in a cross
      sectional design with partial randomization. The interviews consisted of the SF
      12 and some additional questions specific to low back pain. PATIENTS AND METHODS:
      Complete findings were obtainable from 229 patients. Summary scales were compared
      by using multivariate analysis of variance with mean comparisons for continuously
      scored items. Response frequencies for categorically scored items were compared
      by using the chi-square test. RESULTS: The 2 methods produced similar results on
      the Physical Component Summary scale but not the Mental Component Summary scale.
      Compared with patients who had a live telephone interview, the patients using IVR
      acknowledged significantly greater overall mental interference, greater general
      emotional concerns, and poorer mood and overall health. CONCLUSIONS: Because IVR
      eliminates the demand characteristics of responding to a personal interviewer, it
      may be a desirable way to evaluate sensitive topics. It also may reduce costs of
      data entry, labor, and measurement error.

PMID- 10346512
TI  - Health status and satisfaction with pharmacy services.
AB  - OBJECTIVE: To evaluate the relationship between self-reported health status and
      satisfaction with pharmacy services. STUDY DESIGN: Secondary analysis of data
      previously collected via a computer-assisted telephone interview system. PATIENTS
      AND METHODS: Survey respondents were enrollees in a large managed care
      organization who were recent patrons of either traditional or mail pharmacy
      services. Satisfaction data were gathered using an existing satisfaction with
      pharmacy services survey. Health status was measured using the Medical Outcome
      Study's Short-Form 12-Item Health Survey. The relationships between satisfaction
      with pharmacy services and health status were analyzed using structural equation
      modeling. RESULTS: A significant positive relationship between mental health
      status and satisfaction with pharmacy services was hypothesized and confirmed.
      The correlations between mental health status and satisfaction, however, were not
      strong (r = .10 to .18). No relationship between physical health status and
      satisfaction with pharmacy services was observed. Similar results were observed
      in patrons of both traditional and mail pharmacy services. CONCLUSION: This
      investigation offers evidence that satisfaction with healthcare services is more
      closely related to mental health status than to physical health status. This has
      important implications for case-mix adjustments in the measurement of
      satisfaction with care.

PMID- 10346513
TI  - Quality and cost of healthcare: a cross-national comparison of American and Dutch
      attitudes.
AB  - OBJECTIVE: To compare attitudes of consumers in America and Holland toward the
      quality and cost of healthcare. STUDY DESIGN: Data were derived from one American
      (n = 466) and two Dutch (n = 260, n = 1629) surveys. PATIENTS AND METHODS:
      Questionnaires were completed by respondents. Pairwise comparisons requiring
      respondents to compare statements with one another were used to assess
      preferences for quality of care. Respondents were asked to "indicate the extent
      to which each of the factors listed plays a role in placing demands on the
      American (Dutch) healthcare system." Factors included the public's tendency to
      consume, high technology, defensive medicine, decrease in informal care, increase
      in standard diagnostic procedures, and medicalization. RESULTS: Americans
      reported comparatively greater concern with empathy, whereas the Dutch were more
      interested in the continuity of care. Effectiveness, knowledge, information, and
      patient-physician relationships were ranked higher in both nations than waiting
      time, autonomy, and efficiency. Respondents in both countries attributed the
      increase in healthcare cost primarily to the high cost of technology. Compared
      with their Dutch peers, Americans were less likely to attribute increases in the
      cost of healthcare to the public tendency to consume and to the decrease in
      informal care and were more likely to implicate defensive medicine and an
      increase in diagnostic procedures. CONCLUSIONS: As both nations experience
      pressures to reduce costs while maintaining and augmenting the quality of
      healthcare, planners and government officials should tailor their approaches to
      each nation's problems within the context of their public perspectives.
      Replication of such studies should help assess the impact of changing societal
      values on healthcare delivery.

PMID- 10346514
TI  - Critical pathways for postoperative care after simple congenital heart surgery.
AB  - OBJECTIVE: To evaluate the clinical, financial, and parent/patient satisfaction
      impact of critical pathways on the postoperative care of pediatric cardiothoracic
      patients with simple congenital heart lesions. STUDY DESIGN: Critical pathways
      were developed by pediatric intensive care nurses and implemented under the
      direction of pediatric cardiothoracic surgeons. PATIENTS AND METHODS: Critical
      pathways were used during a 12-month study on 46 postoperative patients with
      simple repair of atrial septal defect (ASD), coarctation of the aorta (CoA), and
      patent ductus arteriosus (PDA). Using the study criteria, a control group of 58
      patients was chosen from 1993. Prospective and control group data collected
      included postoperative intubation time, total laboratory tests, arterial blood
      gas utilization, morphine utilization, time in the pediatric intensive care unit,
      total hospital stay, total hospital charges, total hospital cost, and
      complications. Variances from the critical pathway and satisfaction data were
      also recorded for study patients. RESULTS: Resource utilization was reduced after
      implementation of critical pathways. Significant reductions were seen in total
      hours in the pediatric intensive care unit, total number of laboratory tests,
      postoperative intubation times, arterial blood gas utilization, morphine
      utilization, length of hospitalization (ASD, 4.9 to 3.1 days; CoA, 5.2 to 3.2
      days; and PDA, 4.1 to 1.4 days; all P < 0.05), total hospital charges (ASD,
      $16,633 to $13,627; CoA, $14,292 to $8319; and PDA, $8249 to $4216; all P <
      0.05), and total hospital costs. There was no increase in respiratory
      complications or other complications. Patients and families were generally
      satisfied with their hospital experience, including analgesia and length of
      hospitalization. CONCLUSIONS: Implementation of critical pathways reduced
      resource utilization and costs after repair of three simple congenital heart
      lesions, without obvious complications or patient dissatisfaction.

PMID- 10346515
TI  - Pharmacoeconomic and health outcome comparison of lithium and divalproex in a VA
      geriatric nursing home population: influence of drug-related morbidity on total
      cost of treatment.
AB  - OBJECTIVE: Clinicians use mood stabilizers for treating agitation in older
      patients, but limited information is available regarding side effects and costs
      in clinical practice. Total costs of treatment were assessed for a subset of
      geriatric patients receiving either lithium carbonate or divalproex sodium for
      agitation. STUDY DESIGN: Retrospective cohort examination of the medical records
      of 72 patients, 55 years of age or older, in a Veterans Administration long-term,
      skilled nursing care facility, with a diagnosis of dementia or bipolar affective
      disorder or both. PATIENTS AND METHODS: Patients treated with lithium or
      divalproex during the previous 4 years (1994-1997) were evaluated. Quantitative
      information was collected and compared regarding routine care, including cost of
      treatment and laboratory monitoring; and occurrence of adverse events and
      associated diagnostic and treatment measurements. RESULTS: Routine care costs for
      the 2 groups were similar. The lower annual acquisition cost per patient-year for
      lithium ($15 vs $339 for divalproex) was offset by higher laboratory monitoring
      costs associated with its administration ($278 vs $53 for divalproex). Examining
      the adverse events showed that the lithium group had more medication-related
      adverse events (32 total) than the divalproex group (10 total) and more severe
      occurrences, including 6 cases requiring medical intensive care unit (MICU)
      hospitalization. The total mean cost of treating drug-related mild-to-moderate
      morbidity was $3472 for lithium and $672 for divalproex. An additional cost per
      admission of $12,910 ($77,462 for all 6 cases) increased total morbidity-related
      expenditures in the lithium group to $80,934. CONCLUSIONS: Treating geriatric
      patients with lithium requires careful monitoring because of side effects.
      Staffing and resource limitations of a skilled nursing care facility may
      compromise optimal lithium monitoring in elderly patients. The collected data
      indicated that divalproex does not result in as many as or as severe adverse
      events and is, therefore, a safer treatment. The use of lithium was not only more
      expensive (on average $2875 more per patient) than treatment with divalproex but,
      more importantly, it was associated with poorer patient outcomes.

PMID- 10346516
TI  - A new physician's guide to evaluating managed care opportunities.
AB  - AUDIENCE: This article is designed for new physicians and administrators who
      evaluate and negotiate as providers with managed care organizations. GOALS: To
      provide a review of the major issues impacting on medical practices as they
      develop contractual relationships with managed care organizations. OBJECTIVES: 1.
      To review the four major types of health maintenance organizations, providing
      some general detail about the financial policies of each. 2. To outline how
      utilization review and quality assurance policies can affect individual physician
      practice. 3. To discuss risk-sharing arrangements employed by managed care
      organizations, including their financial and clinical impact, and to outline the
      issues a new physician should consider when evaluating a contract.

PMID- 10346517
TI  - Technology assessment and the drug use process.
AB  - This activity is designed for pharmacists, physicians, physician assistants,
      nurses, and other healthcare team members, payers for health services, and
      healthcare executives. OBJECTIVES: Upon completion of this activity, the
      participant should be able to: 1. Describe the rationale behind, the development
      of, and the advantages arising from the formulary process, and discuss the health
      professionals involved in the creation of formularies. 2. Describe the impact of
      new drug development and technology on the drug use process. 3. Discuss the
      functions of the pharmacy and therapeutics committee. 4. Describe the impact of
      consumers on the drug use process.

PMID- 10346518
TI  - Taking a disease management approach to migraine. Based on a presentation by
      William Parham III, MD.
AB  - Migraine, like many other common and costly chronic diseases, may be amenable to
      the disease management model of healthcare delivery. The disease management
      approach has improved clinical and economic outcomes in conditions such as
      asthma, diabetes, congestive heart failure, and arthritis. The critical elements
      needed for a successful migraine disease management program are: 1)
      identification of highest-acuity patients, 2) extensive patient education, and 3)
      implementation of clear evidence-based guidelines for the diagnosis and
      management of patients. Transition from the current emergency-driven system of
      severe migraine treatment will require additional training and incentives for
      primary providers, specialists, and nurses. Both pharmacologic and
      nonpharmacologic treatments may play a role in attaining the best outcomes in
      carefully selected patients.

PMID- 10346519
TI  - The economics of migraine. Based on a presentation by Stuart O. Schweitzer, PhD.
AB  - Migraine headaches produce an enormous financial burden on society, primarily
      because of their high incidence among people in the middle of their careers.
      Migraine-related indirect costs, which constitute more than three quarters of the
      total economic burden of this disease, include both lost work time and diminished
      work capacity. Direct costs of migraine, which run into the billions of dollars,
      are attributable mainly to clinic and emergency room visits but also to drug
      treatments and alternative care. Several studies have documented the efficacy of
      pharmaceutical agents versus placebo, but good comparative studies and economic
      studies are rare. Development of rational prescribing guidelines and
      reimbursement policies will depend on analysis of such studies.

PMID- 10346520
TI  - Migraine in managed care. Based on a presentation by Delores Bowman, RN, BSN,
      CRM.
AB  - Migraine, one of the most common conditions reported by health plan members,
      receives inadequate attention in most managed care settings. The lack of a
      consistent and concerted approach to the management of patients with the most
      severe and intractable varieties of migraine is particularly obvious. Studies in
      our plan population have documented that the availability of effective new
      pharmacologic antimigraine agents could reduce both sick days and hospital
      visits. Development of new guidelines for management of migraine patients,
      including a formulary indicating the availability of agents that have been
      documented to be effective, will be a critical step in educating physicians as to
      the proper management of patients with migraine. Such guidelines should also
      provide specific criteria for referral. Studies that document positive outcomes
      of new migraine protocols will provide a basis for employer-driven expansion of
      migraine-related healthcare coverage.

PMID- 10346521
TI  - Developing marketing strategies for the new millennium.

PMID- 10346522
TI  - It's a jumble out there.

PMID- 10346523
TI  - The four market models. The competitive battlefield gets defined.

PMID- 10346524
TI  - Risk management strategies for assisted living facilities.

PMID- 10346525
TI  - Manage like a coach not a cop.

PMID- 10346526
TI  - The dynamics of workplace violence.

PMID- 10346527
TI  - National report calls for more teeth in implementing enforcement remedies.

PMID- 10346528
TI  - Surviving Hurricane Georges: a cautionary tale.

PMID- 10346529
TI  - Want to increase cash flow? Revamp patient accounts.

PMID- 10346530
TI  - New process results in dramatic improvement for heart attack patients, lower
      hospital costs.
AB  - Ohio hospital reduces admissions for complicated heart attack, thanks to PRO's
      benchmark project. Cuyahoga Falls General Hospital was surprised when redesigning
      the way patients are identified as candidates for TPA and other thrombolytic drug
      therapies resulted in fewer admissions for complicated heart attack. Learn how
      the revamped system easily can be employed at other hospitals.

PMID- 10346531
TI  - Revamped preadmission process removes bottlenecks, boosts number of outpatient
      surgeries.
AB  - Partnering with outside organizations to reengineer a hospital function can be
      tricky if it's not well executed. MedCenter Hospital in Marion, OH, played its
      cards right and got an outside physician clinic to be a key player in helping a
      task force redesign the preadmission process for the hospital's outpatient
      surgeries. The new and improved system boosted the number of monthly outpatient
      surgeries, resulting in increased revenue for the hospital.

PMID- 10346532
TI  - AHA survey reveals hospitals continue to keep costs low.
AB  - DATA BENCHMARKS: Good news on the hospital cost front for 1997: Hospitals and
      health systems continued their three-year pace of keeping costs down, according
      to the American Hospital Association's annual survey of more than 5,000 hospitals
      and health systems. Find out what the survey results revealed.

PMID- 10346533
TI  - Senior community blazes trail as Medicare risk provider.

PMID- 10346534
TI  - Repeated ER visits, admissions of frail seniors signal need for social case
      management.
AB  - Seeing repeated ER visits and hospital admissions by your Medicare risk seniors?
      Try using social workers to case manage them. Two IPAs in California reveal how
      using a social work case management model can help reduce utilization--possibly
      up to 50%.

PMID- 10346535
TI  - Rural providers have tough row to hoe if they jump into Medicaid risk too
      quickly.
AB  - Learn some lessons in rural managed Medicaid from a provider-owned plan. Upper
      Peninsula Health Plan, based in Marquette, MI, discovered that introducing
      managed care to providers through their own rural Medicaid plan is full of
      surprises. Find out what to expect--and what to avoid--from a plan that's
      learning the hard way.

PMID- 10346536
TI  - Medicare benchmark data on hospital inpatient charges.
AB  - Data File: Here's some benchmark data on Medicare lengths of stay and average
      hospital charges from the Louisville, KY-based Data Advantage Corp. Providers can
      use the data to help determine their competitiveness and better assess discounts
      sought by Medicare risk plans.

PMID- 10346537
TI  - Employers, health plans, docs join fight against HBP (high blood pressure).

PMID- 10346538
TI  - Help hypertensive patients regain control over their BP.

PMID- 10346539
TI  - Major study ties modifiable risk factors to health costs.
AB  - Two health care companies are taking disease management into their own hands and
      using health risk appraisal and education as a one-two prevention punch against
      rising costs.

PMID- 10346540
TI  - Roadmap teams improve care for over-65 population.
AB  - Defining where the health care train stops and starts for an elderly population
      can be a unique challenge. Find out how one initiative defines senior care needs
      according to a structured roadmap of care.

PMID- 10346541
TI  - Will your disease management program pass muster with Joint Commission reviewers?
AB  - Health plans and integrated networks increasingly want the "gold star" of
      accreditation. Find out how a Joint Commission seal of approval can enhance
      quality--and how the on-site review team evaluates your health promotion and
      disease prevention efforts.

PMID- 10346542
TI  - Distribution of health handbook leads to reduction in ER visits.
AB  - In the upper Northwest, whole communities are using the demand management
      guidebook and other tools developed by Healthwise Communities Project, and
      emergency department utilization appears to be dropping as a result.

PMID- 10346543
TI  - Marketplace. Cooling hospital labor tensions: a Kaiser case study from
      California.

PMID- 10346544
TI  - Perspectives. States eye tobacco settlement money: public health bonanza or free
      for-all?

PMID- 10346545
TI  - Hospitalists are conduits for evidence-based care.

PMID- 10346546
TI  - GP IIb/IIIa inhibitors: an evidence-based approach to their use.

PMID- 10346547
TI  - A randomized trial of the use of patient self-assessment data to improve
      community practices.
AB  - OBJECTIVE: Because of time constraints in the office environment, problems of
      concern to elderly patients may not be raised during clinic visits. To facilitate
      communication about geriatric health problems, we examined the impact of a
      strategy that used patient self-assessment data to improve community practices.
      DESIGN: Twenty-two primary care practices were randomized to participate in the
      intervention strategy (intervention practices) or to provide usual care (usual
      care practices). SETTING: Primary care practices in 16 towns in New Hampshire
      (total, 45 physicians). PATIENTS: 1651 patients 70 years of age or older.
      INTERVENTION: All patients received a mailed survey that asked about their health
      problems and about how well these problems were being addressed by their
      physicians. In the intervention practices, these data were used to generate a
      customized letter that directed the patient to specific sections in an 80-page
      modified version of the National Institute on Aging's Age Pages and were
      summarized and communicated to the patient's physician. MAIN OUTCOME MEASURE:
      Change from baseline in patients' overall assessment of health care. RESULTS: In
      8 of 11 intervention practices, patients felt that their care had improved over
      the 2-year study period. This improvement occurred in only 1 of 11 usual care
      practices (P = 0.003). Patients in intervention practices reported receiving
      significantly more help with physical function, fall prevention, and assistance
      for memory problems. Self-assessed health status did not differ in the two
      groups. CONCLUSION: A standard, easy-to-implement strategy to improve the quality
      of provider--patient interactions can improve the satisfaction of older patients
      cared for in community practices.

PMID- 10346548
TI  - How ready are health plans for Medicare?
AB  - CONTEXT: The Medicare program is encouraging its beneficiaries to enroll in
      capitated health plans. OBJECTIVE: To determine how prepared these plans are to
      handle chronically ill and frail elderly persons. DESIGN: Telephone survey of 28
      health plans that together serve about one fourth of all enrollees of the
      Medicare Risk program. MEASURES: The degree of readiness (high, intermediate, or
      low) of health plans in seven domains that experts believe are important to the
      management of an elderly population. RESULTS: None of the 28 health plans had
      high readiness scores for all seven domains. The two domains for which the plans
      were most prepared were risk assessment and member self-care. The plans were
      least prepared for the domains of cooperative team care and geriatric
      consultations. CONCLUSIONS: Many plans do not offer the programs that experts
      believe are important for Medicare enrollees. They may hesitate to adopt
      strategies that lack data on effectiveness.

PMID- 10346550
TI  - Capitation among Medicare beneficiaries.
AB  - CONTEXT: The Medicare program has promoted capitation as a way to contain costs.
      About 15% of Medicare beneficiaries nationwide are currently under capitation,
      but tremendous regional variation exists. PRACTICE PATTERN EXAMINED: The
      proportion of Medicare beneficiaries who have enrolled in risk-contract plans in
      individual states and in the 25 largest metropolitan areas in the United States.
      DATA SOURCE: Health Care Financing Administration data files. RESULTS: Medicare
      beneficiaries are most likely to be under capitation in Arizona (38%) and
      California (37%). Eight other states have capitation rates greater than 20%:
      Colorado, Florida, Rhode Island, Oregon, Washington, Pennsylvania, Massachusetts,
      and Nevada. Thirty states, largely in the Great Plains area and the southern
      United States, have capitation rates less than 10%. Four major metropolitan areas
      have market penetration rates greater than 40%: San Bernardino, California; San
      Diego, California; Phoenix, Arizona; and Miami, Florida. Little penetration
      exists outside of metropolitan areas. CONCLUSION: Capitation in Medicare is a
      regional and predominantly an urban phenomenon.

PMID- 10346549
TI  - Use of an automated pharmacy system and patient registries to recruit HMO
      enrollees for an influenza campaign.
AB  - OBJECTIVE: To develop methods to identify, recruit, and vaccinate HMO enrollees
      at increased risk for influenza-related complications as part of a comprehensive
      influenza campaign. SETTING: Group Health Cooperative (GHC) is a large,
      membership-governed, managed care organization that serves 395,000 members in the
      Puget Sound area. APPROACH: An automated pharmacy system and patient data
      registries were used to identify enrollees with chronic illness. Enrollees with
      chronic illness and all enrollees 65 years of age and older were considered "high
      risk" enrollees to be recruited for vaccination. Postcard reminders coupled with
      a publicity and education campaign were used to recruit high-risk enrollees to
      special influenza clinics. RESULTS: Our approach identified 2.5% of children
      (persons < 18 years of age) and 10.5% of adults (persons 18 to 65 years of age)
      as chronically ill and thus at high risk for influenza-related complications.
      Most high-risk children were identified through prescriptions for steroids,
      autonomic inhalers, or both or because they were enrolled in the asthma registry.
      Most high-risk adults were identified because of prescriptions for steroids,
      insulin, or oral hypoglycemic agents; because they had received pneumococcal
      vaccine; or because they were enrolled in the diabetes registry. Influenza
      coverage rates for all seniors (persons > or = 65 years of age) increased from
      34% in 1984 to more than 72% in the 1996-1997 campaign year. Coverage rates were
      much lower for high-risk children (36%) and adults (46%). CONCLUSIONS: Influenza
      coverage rates can still be substantially improved for adults younger than 65
      years of age and children at high risk for influenza-related complications.

PMID- 10346551
TI  - Efficacy versus effectiveness of carotid endarterectomy.
AB  - CONTEXT: Several well-known clinical trials have demonstrated that the value of
      carotid endarterectomy depends on preoperative symptoms and the degree of carotid
      artery stenosis. The benefit of surgery also depends on how the results of these
      clinical trials (defining the efficacy of carotid endarterectomy) are applied to
      actual clinical practice (the effectiveness of the procedure), where surgical
      risks are greater. COUNT: The number of carotid endarterectomies needed to
      prevent one major stroke or death--that is, the number needed to treat (NNT).
      CALCULATION: Reciprocal of the difference between the 5-year cumulative incidence
      of major stroke or death with medical therapy and the 5-year cumulative incidence
      of major stroke or death with carotid endarterectomy. DATA SOURCES: Efficacy was
      calculated with data from the North American Symptomatic Carotid Endarterectomy
      Trials and the Asymptomatic Carotid Atherosclerosis Study. In calculating
      effectiveness, we accounted for increased surgical mortality rates reported in
      population-based studies. RESULTS: For symptomatic patients, the NNT predicted by
      the effectiveness model differed little from that estimated by the efficacy model
      (10 versus 9 for severe carotid stenosis and 29 versus 23 for moderate carotid
      stenosis). However, the NNT predicted by the effectiveness model was
      substantially higher than that predicted by the efficacy model for patients with
      asymptomatic severe stenosis (63 versus 38). CONCLUSIONS: In symptomatic
      patients, carotid endarterectomy is both efficacious and effective for severe and
      (to a lesser extent) moderate carotid stenosis. However, in asymptomatic
      patients, the benefits observed in published trials may overestimate those likely
      to be achieved in clinical practice.

PMID- 10346553
TI  - Simple strategies, complex issues.

PMID- 10346552
TI  - When should this patient be seen again?
AB  - CONTEXT: The decision about when to ask a patient to return to the clinic for his
      or her next visit is common to all outpatient encounters in longitudinal care. It
      directly affects provider workloads and has a potentially great impact on health
      care costs and outcomes. GENERAL QUESTION: What are the effects of lengthening or
      shortening revisit intervals (the recommended period between one visit and the
      next) on health status and health care costs? SPECIFIC RESEARCH CHALLENGE: How
      can we change the average revisit interval while preserving provider input for
      individual patients? PROPOSED APPROACH: Patients could be randomly assigned to
      either short or long revisit intervals. So that provider input would be
      preserved, providers would select from among three discrete categories of revisit
      intervals: near-term (1 to 2 months); intermediate-term (2 to 4 months); and long
      term (4 to 8 months). On the basis of randomization, patients would receive
      appointments at either the lower or the upper bound of the category selected.
      POTENTIAL DIFFICULTIES: Because blinding would be almost impossible, providers
      might "game" randomization at subsequent visits. ALTERNATE APPROACHES: A
      comparison of shorter and longer revisit intervals might be achieved with less
      direct approaches. In one such approach, patients would be randomly assigned to
      1) having an appointment made immediately after the initial visit or 2) calling
      back for an appointment according to the interval recommended by the provider. In
      another approach, patient panel size would be held constant and providers would
      be randomly assigned to either an increased or a reduced number of clinic
      sessions.

PMID- 10346554
TI  - Managed Medicare at the crossroads.

PMID- 10346555
TI  - Seven guidelines for approaching the new growth mandate.

PMID- 10346556
TI  - Bringing in market share and revenue growth through the front door.

PMID- 10346557
TI  - Practice profile. Temple University Children's Medical Center (TUCMC), Department
      of Pediatrics, Temple Pediatric Hospitalists (TPH).

PMID- 10346558
TI  - Hospitalists.

PMID- 10346559
TI  - Practice profile. Riverside Critical Care Physicians (RCCP)--Columbus, Ohio.

PMID- 10346560
TI  - Hospitalists and the practice of inpatient medicine: results of the UCSF-NAIP
      survey.

PMID- 10346561
TI  - Integrating care across settings: hospitalists and the computer-based patient
      record.

PMID- 10346562
TI  - Reflections on the practice of acute Irish hospital medicine.

PMID- 10346563
TI  - Practice profile. Inpatient practice. Department of Internal Medicine, Mayo
      Medical Center, Rochester, Minnesota.

PMID- 10346565
TI  - Practice profile. Inpatient practice. Cabarrus Medical Associates.

PMID- 10346564
TI  - The art and science of the handoff: how hospitalists share data.

PMID- 10346566
TI  - Improving outpatient appointment access--lessons learned.

PMID- 10346567
TI  - Reengineering home care: moving from functional fixes to process improvements.

PMID- 10346568
TI  - Integrating primary care and specialty physicians in the operations of ambulatory
      satellite facilities.

PMID- 10346569
TI  - Measuring outcomes of care for home care patients.

PMID- 10346570
TI  - Electronic medical records and the future.

PMID- 10346571
TI  - The evolution of an ambulatory clinical information system.

PMID- 10346573
TI  - The need for compliance programs in the home care industry.

PMID- 10346572
TI  - Outcome assessment: aggregate outcome management across the continuum of care.

PMID- 10346574
TI  - Acute care and long term care partner to provide better services for seniors.
AB  - Many seniors have the same common problem, they have experienced the frustration
      of having to go to several different facilities, making more than one trip, to
      access appropriate medical, rehabilitation, behavioral, and/or long term health
      care services. The seemingly simple task of obtaining a medical evaluation can
      often require not only a physical examination, but also a visit to a laboratory
      to have blood drawn, vision and/or hearing testing, a physical or rehabilitation
      therapy assessment and more. This series of events can be particularly difficult
      for seniors. Seniors may require assistance of a friend or family member and can
      be compounded when mental health issues are involved as well.

PMID- 10346575
TI  - The changing face or Bayfront Medical Center.

PMID- 10346576
TI  - Physician benchmarking: a collaborative, comparative approach.

PMID- 10346577
TI  - Oncology: practice guidelines and outcomes measurement.

PMID- 10346578
TI  - Home care medical directors: optional or medical necessity?

PMID- 10346579
TI  - A strategy for transforming daily data into organizational information through
      the efficient use of synergistic resources.
AB  - Benefits of this strategy include the promotion of innovation and growth among
      the team members while increasing the staff's capabilities through enhanced
      communication between colleagues with different perspectives. More work will be
      done with less resource thus reducing cost. Knowledge within the organization
      will grow and intellectual capital as embodied in the personal skills,
      experience, and brainpower of employees will increase.

PMID- 10346580
TI  - Developing comparative data tools: elements for success.
AB  - Planning the development of comparative data tools is very similar to planning
      any major project. However, it takes some preliminary work to define the data
      elements that will be collected in order to ensure longitudinal success of the
      overall project. INTELLIMED has used the elements outlined above to successfully
      plan and distribute comparative data products. The elements are meant to promote
      the development of a plan that is simple to evaluate progress against and easy to
      follow.

PMID- 10346581
TI  - Putting the clinical appropriateness factor in utilization management.

PMID- 10346582
TI  - Turning around failed practice acquisitions: MSO to the rescue.

PMID- 10346583
TI  - Making primary care accessible.

PMID- 10346584
TI  - Achieving success for freestanding ambulatory care centers: investment decision
      making.
AB  - This is the first installment in a series of three articles for Ambulatory
      Outreach on the topic of ambulatory center development. This article provides a
      framework for making decisions for investing in freestanding centers. The second
      article, to be published in the 1998 winter issue, will define the tasks and
      approaches required to effectively plan freestanding centers' strategies,
      operations and facilities. The last article, to be published in spring of 1999,
      will provide practical advice regarding start-up and operation of ambulatory care
      centers. Real-life examples of health care organizations facing these challenges
      will be highlighted throughout the series.

PMID- 10346585
TI  - ORYX: the next evolution in accreditation.

PMID- 10346586
TI  - Complex ambulatory settings demand scheduling systems.
AB  - Practice management systems are becoming more and more complex, as they are asked
      to integrate all aspects of patient and resource management. Although patient
      scheduling is a standard expectation in any ambulatory environment, facilities
      and equipment resource scheduling are additional functionalities of scheduling
      systems. Because these functions were not typically managed in manual patient
      scheduling, often the result was resource mismanagement, along with a potential
      negative impact on utilization, patient flow and provider productivity. As
      ambulatory organizations have become more seasoned users of practice management
      software, the value of resource scheduling has become apparent. Appointment
      scheduling within a fully integrated practice management system is recognized as
      an enhancement of scheduling itself and provides additional tools to manage other
      information needs. Scheduling, as one component of patient information
      management, provides additional tools in these areas.

PMID- 10346587
TI  - Basics of eligibility and Joint Commission home care accreditation.

PMID- 10346588
TI  - A reengineering success story: process improvement in emergency department x-ray
      cycle time, leading to breakthrough performance in the ED ambulatory care (Fast
      Track) process.
AB  - This article describes the journey of a multidisciplinary reengineering team,
      which worked to reduce a critical, high-leverage process in an emergency
      department setting. The process selected was emergency department radiology
      services. This process was selected on a rational basis. The team knew tht 60
      percent of our emergency department patients were truly ambulatory, and that most
      could be seen in a "fast track" process as part of our emergency department's
      core mission. However, we knew from customer satisfaction data, that patients
      would like to be "in and out" of emergency department Fast Track in less than an
      hour. Over half of our Fast Track patients require x-rays. For most, this was
      their sole reason for seeking emergency care. Our state, at the start of the
      project, included an average x-ray cycle time of over 60 minutes. The associated
      Fast-Track cycle time was over 90 minutes median. It was clear to the emergency
      department leadership, as well as to members of the Fast-Track management team,
      that a cycle time of 30 minutes or less for x-ray service was needed as a
      necessary condition to an hour or less Fast Track cycle time. It was also felt
      that a more rapid x-ray cycle time would allow for more rapid turn over of ED
      rooms, leading to a virtual greater capacity to the ED. It was hoped that this
      would lead to a reduction in the time from arrival to treatment by the emergency
      physician for all patients.

PMID- 10346589
TI  - Knowledge is power: comparative analysis software is a powerful tool for
      healthcare.

PMID- 10346590
TI  - Seamless integration of planned chemotherapy admissions from an ambulatory
      setting at Brigham and Women's Hospital.

PMID- 10346591
TI  - Benchmarking strategies for improving organizational performance.

PMID- 10346592
TI  - Reality check: using stimulation modeling to plan and sell change.
AB  - As anyone who has worked with a computer knows, technology doesn't always solve
      problems. But when it comes to planning for health care institutions, operation
      simulation modeling can help executives make better decisions and create more
      efficient operations--by bringing more information, issues and communication
      power to the table.

PMID- 10346593
TI  - A paradigm leap.

PMID- 10346594
TI  - Strengthening ambulatory care through product and organizational development.

PMID- 10346595
TI  - The role of physician house calls in comprehensive ambulatory care.

PMID- 10346596
TI  - Network formation: lessons learned.

PMID- 10346597
TI  - SACP & INTELLIMED International Corp. Set the stage for developing comparative
      data tools.

PMID- 10346598
TI  - Satellite clinics enhance reach and reputation: it's all about customer service
      in West Bend, Wisconsin.

PMID- 10346599
TI  - Improving access to primary care.

PMID- 10346600
TI  - Ambulatory care visits to physician offices, hospital outpatient departments, and
      emergency departments: United States, 1996.

PMID- 10346601
TI  - Asthma Education Project: "the asthma warriors".

PMID- 10346602
TI  - Cancer Information Teleservice.

PMID- 10346603
TI  - Bringing health benefits communications into the 21st century.
AB  - Most companies are in a far more complex benefits environment than they were even
      a few years ago, and communicating in that environment is a continuing challenge.
      By utilizing technology, employers can give employees the up-to-date,
      comprehensive information they need to be informed health care consumers. A
      company Web site may be an effective way to furnish much of the necessary
      information.

PMID- 10346604
TI  - Penalties, incentives and wellness programs after HIPAA.
AB  - In the aftermath of the Health Insurance Portability and Accountability Act of
      1996 (HIPAA), employers need to carefully examine their wellness programs and in
      particular the incentives or penalties they have installed to encourage employees
      to adopt healthy lifestyles. Employers should look at the reasons they offer
      discounts, exclusions and wellness programs and assess how effective these
      measures are. They may want to replace them with "positive" approaches such as
      health fairs and education programs.

PMID- 10346605
TI  - Beware the slippery slope!

PMID- 10346606
TI  - Looking good, feeling fit, staying strong: self-care in EMS.

PMID- 10346607
TI  - Back injuries in EMS.

PMID- 10346608
TI  - Volunteerism: a family affair.

PMID- 10346609
TI  - Patient-care documentation.

PMID- 10346610
TI  - Flying high: the role of helicopters in EMS.

PMID- 10346611
TI  - A reimbursement conundrum.

PMID- 10346612
TI  - On the outside moving in: will the alternative medicine integration movement
      shape U.S. healthcare?

PMID- 10346613
TI  - Dossey's odyssey: a conversation with Larry Dossey. Interview by Joe Flower.

PMID- 10346614
TI  - The revolution in medical education: complementary medicine joins the curriculum.

PMID- 10346615
TI  - Providing alternatives in your health system.

PMID- 10346616
TI  - Life with the new roommate: alternative medicine moves in with conventional
      medicine.

PMID- 10346617
TI  - Bearing witness to the evolution of contemporary medicine: the Institute for
      Health and Healing at California Pacific Medical Center, San Francisco.

PMID- 10346618
TI  - Three predictable crises in the health system and what to do about them.

PMID- 10346619
TI  - Getting technical.

PMID- 10346620
TI  - Are HMOs really a dying breed?

PMID- 10346621
TI  - Stop me before I kill again.

PMID- 10346622
TI  - When the patient changed her mind. Schreiber v. Physicians Ins. Co.

PMID- 10346623
TI  - Third Circuit Court of Appeals wrestles with ADA "being regarded as" language
      issues. Deane v. Pocono Medical Center.

PMID- 10346624
TI  - Court orders removal of report from National Practitioner Data Bank. Simpkins v.
      Shalala.

PMID- 10346625
TI  - Foley price hikes linked to contracts.

PMID- 10346626
TI  - IDNs still value GPOs--but on their own terms.

PMID- 10346627
TI  - Supply prices expected to hold steady.

PMID- 10346628
TI  - Energy: a new frontier in risk sharing.

PMID- 10346630
TI  - The toxic sock barrier.

PMID- 10346629
TI  - Pediatric legal dilemmas.

PMID- 10346631
TI  - Stress reactions. Understand and accept their appearance.

PMID- 10346632
TI  - About kids. Better integration of the care of children into EMS.

PMID- 10346634
TI  - Just deep pockets, or bids for control? In W.Pa., insurer, system, doctors square
      off over AHERF bid.

PMID- 10346635
TI  - Just deep pockets, or bids for control? Hospital system plays banker in health
      plan's bid to buy HMO.

PMID- 10346633
TI  - EMS hero commits suicide.

PMID- 10346636
TI  - Firms link on sophisticated data network.

PMID- 10346637
TI  - Rethink the doc-organization relationship.

PMID- 10346638
TI  - Disease management can be good for what ails patients and insurers.
AB  - Patients who suffer from chronic diseases consume the vast majority of healthcare
      resources, presenting a huge challenge to managed care. Many insurers and
      providers that manage risk are using disease management to diagnose conditions
      early and coordinate treatment over time.

PMID- 10346640
TI  - Managed care hurts research funds: study.

PMID- 10346639
TI  - Information, please. Survey shows health plans can build customer loyalty by
      providing large doses of information.

PMID- 10346641
TI  - Ranking the networks. Chicago's Advocate tops on analysis of performance,
      integration, physician participation.

PMID- 10346642
TI  - Making room in the pool. New York Business Group on Health creating buying
      organization for small businesses.

PMID- 10346643
TI  - Times get tougher for N.J. hospitals. Facilities try to stem large deficits,
      while state appoints advisory group to help avert crisis.

PMID- 10346644
TI  - Medicare managed care risk adjustment phase-in begins.

PMID- 10346645
TI  - Analyzing physician coding patterns can enhance revenues and compliance.

PMID- 10346646
TI  - Performance appraisal reviews: face to face with employees.

PMID- 10346647
TI  - A refresher course for management 101.

PMID- 10346648
TI  - Developing an orientation program.
AB  - When the local area experienced tremendous growth and change, the radiology
      department at Maury Hospital in Columbia, Tennessee looked seriously at its
      orientation process in preparation for hiring additional personnel. It was an
      appropriate time for the department to review its orientation process and to
      develop a manual to serve as both a tool for supervisors and an ongoing reference
      for new employees. To gather information for the manual, supervisors were asked
      to identify information they considered vital for new employees to know
      concerning the daily operations of the department, its policies and procedures,
      the organizational structure of the hospital, and hospital and departmental
      computer systems. That information became the basis of the orientation manual,
      and provided an introduction to the hospital and radiology department; the
      structure of the organization; an overview of the radiology department; personnel
      information; operating procedures and computer systems; and various policies and
      procedures. With the manual complete, the radiology department concentrated on an
      orientation process that would meet the needs of supervisors who said they had
      trouble remembering the many details necessary to teach new employees. A pre
      orientation checklist was developed, which contained the many details supervisors
      must handle between the time an employee is hired and arrives for work. The next
      step was the creation of a checklist for use by the supervisor during a new
      employee's first week on the job. A final step in the hospital's orientation
      program is to have each new employee evaluate the entire orientation process.
      That information is then used to update and revise the manual.

PMID- 10346649
TI  - Beyond culture and regular staff meetings.
AB  - Joining the radiology department of a New York City hospital, I learned that if I
      fostered employees' self-respect and self-reliance, they would do a good job. I
      believed the staff would achieve maximum performance levels when I understood the
      culture of the department and could work with staff members beyond regular staff
      meetings. More than anything else, understanding the department culture
      influenced my style of management. To keep the lines of communication open,
      department supervisors and attending radiologists meet biweekly with the chairman
      of radiology to discuss current and anticipated problems. Often, these meetings
      are charged with new ideas and excitement. An in-services program to educate and
      motivate employees on the job was another ongoing process, with radiologists and
      radiology administration working together. In-service presentations emphasized
      learning by using actual cases. Believing a seminar's effectiveness can be
      measured by its relevance to staff members, I gave a seminar on financial
      techniques and explained stocks, bonds, mutual funds, IRAs, 403B, 401K and
      multiple retirement options. Technical and clerical staffs are unionized so
      management and union delegates now meet to identify mutual concerns under the
      hospital-initiated labor management meetings. To meet additional goals, my
      department closely monitors the QI of the most important aspects of care-waiting
      times, turnaround times of radiology reports and satisfaction of both physicians
      and patients. In the creative atmosphere I brought to the hospital, I was able to
      teach staff members to reach for goals they had considered beyond them.

PMID- 10346650
TI  - Marketing on a shoestring.
AB  - Marketing includes the many steps taken to sell a product or service from its
      conception to its purchase or use. In healthcare, three cost-effective audiences
      to target are referring physicians and their staffs, local HMOs and PPOs,
      facility employees and patients. The potential users of such services--your
      target audience--should be made aware of new offerings such as the addition of
      special procedures, a new piece of equipment, or perhaps a new physician with
      special capabilities. To ensure a productive effort, a marketing attempt must
      follow two cardinal rules: first, the product or service offered must be of high
      quality and, second, the marketing effort must be carried out consistently. An
      effective marketing campaign should create an impression within the community
      about the facility by emphasizing those aspects of the department or facility
      that make it unique. Are its hours of operation adequate? Do its personnel
      project a professional attitude and demeanor? Does it have a specialty that makes
      it unique within the healthcare community? The most powerful marketing tool of
      all is word of mouth, which is based on the judgments clients make after visiting
      the facility-department or facility employees smile and greet visitors, they are
      polite and helpful on the telephone, their attitudes are professional, and so
      forth. Such impressions are worth millions in goodwill and can be used as a
      marketing tool. Last, an actual case study from my hospital explains how we
      determined the need for and marketed an open MRI system.

PMID- 10346651
TI  - The final rule: what administrators must know by April 28.
AB  - On April 28, 1999, the Final Rule of the Mammography Quality Standards Act (MQSA)
      goes into effect. The Final Rule remains basically the same, with the addition of
      a few new specifications and modifications. The Quality Standards are divided
      into two parts. To obtain and maintain compliance with the standards, facilities
      must be most familiar with sections 900.10 through 900.12 in Subpart B. A policy
      on reinstatement, added to the section on requirements for certification,
      outlines the conditions facilities must meet to have their certification
      reinstated. The requirements for mammography personnel, equipment and general
      quality assurance standards are listed in section 900.12, (a) through (j). A new
      requirement is that mammography technologists must have 40 hours of direct
      instruction, eight of which must include training in each modality they will use
      to perform examinations. All mammography personnel must have a minimum of eight
      hours training before working independently in a new modality. The Final Rule
      makes it clear that mammography facilities are responsible for communicating test
      results to patients. Under the Final Rule, responsibility for a facility's
      quality assurance program now belongs to the lead-interpreting physician, a
      position facilities are now required to have. Facility cleanliness and infection
      control standards have been added to the section on QA requirements. The Final
      Rule establishes that facilities must establish and implement an infection
      control program, as well as a documented procedure for resolving consumer
      complaints.

PMID- 10346652
TI  - Corporate compliance: framework and implementation.
AB  - The federal government has created numerous programs to combat fraud and abuse.
      The government now encourages healthcare facilities to have a corporate
      compliance program (CCP), a plan that reduces the chances that the facility will
      violate laws or regulations. A CCP is an organization-wide program comprised of a
      code of conduct and written policies, internal monitoring and auditing standards,
      employee training, feedback mechanisms and other features, all designed to
      prevent and detect violations of governmental laws, regulations and policies. It
      is a system or method ensuring that employees understand and will comply with
      laws that apply to what they do every day. Seven factors, based on federal
      sentencing guidelines, provide the framework for developing a CCP. First, a
      facility must establish rules that are reasonably capable of reducing criminal
      conduct. Second, high-level personnel must oversee the compliance effort. Third,
      a facility must use due care in delegating authority in the compliance
      initiative. Fourth, standards must be communicated effectively to employees, and
      fifth, a facility must take reasonable steps to achieve compliance. Sixth,
      standards must be enforced consistently across the organization and last,
      standards must be modified or changed for reported concerns, to ensure they are
      not repeated. PROMINA Health System, Inc. in Atlanta, Ga., designed a program to
      meet federal guidelines. It started with a self-assessment to define its areas or
      risk. Next, it created the internal structure and assigned organizational
      responsibility for running the CCP. PROMINA then developed standards of business
      and professional conduct, established vehicles of communication and trained
      employees on the standards. Finally, it continues to develop evidence of the
      program's effectiveness by monitoring and documenting its compliance activities.

PMID- 10346653
TI  - Negotiating computer systems and software purchases.

PMID- 10346654
TI  - Up against an immovable deadline.

PMID- 10346655
TI  - R U Y2K OK?

PMID- 10346657
TI  - Gender differences in social influence on physical activity at different stages
      of exercise adoption.
AB  - The belief that significant others (referents) felt the subjects should exercise
      (normative beliefs) was the strongest in subjects in the maintenance stage and
      weakest for subjects in the inactive stage. This pattern occurred in all the
      referent groups and for both male and female subjects. Women's normative beliefs
      were stronger than men's for all the stages and referent groups. For men,
      motivation to comply with referents was strongest in the maintenance stage and
      weakest in the inactive stage. This pattern was not as clearly visible in female
      subjects. Inactive women had higher motivation to comply then did men for all
      conditions and referent groups, but this motivation was most pronounced in the
      inactive stage.

PMID- 10346656
TI  - The impact of including incentives and competition in a workplace smoking
      cessation program on quit rates.
AB  - PURPOSE: To determine the effectiveness of a multicomponent smoking cessation
      program supplemented by incentives and team competition. DESIGN: A quasi
      experimental design was employed to compare the effectiveness of three different
      smoking cessation programs, each assigned to separate worksite. SETTING: The
      study was conducted from 1990 to 1991 at three aerospace industry worksites in
      California. SUBJECTS: All employees who were current, regular tobacco users were
      eligible to participate in the program offered at their site. INTERVENTION: The
      multicomponent program included a self-help package, telephone counseling, and
      other elements. The incentive-competition program included the multicomponent
      program plus cash incentives and team competition for the first 5 months of the
      program. The traditional program offered a standard smoking cessation program.
      MEASURES: Self-reported questionnaires and carbon monoxide tests of tobacco use
      or abstinence were used over a 12-month period. RESULTS: The incentive
      competition program had an abstinence rate of 41% at 6 months (n = 68), which was
      significantly better than the multicomponent program (23%, n = 81) or the
      traditional program (8%, n = 36). At 12 months, the quit rates for the incentive
      and multicomponent-programs were statistically indistinguishable (37% vs. 30%),
      but remained higher than the traditional program (11%). Chi-square tests, t
      tests, and logistic regression were used to compare smoking abstinence across the
      three programs. CONCLUSIONS: Offering a multicomponent program with telephone
      counseling may be just as effective for long-term smoking cessation as such a
      program plus incentives and competition, and more effective than a traditional
      program.

PMID- 10346658
TI  - Buena Alimentacion, Buena Salud: a preventive nutrition intervention in Caribbean
      Latinos with type 2 diabetes.
AB  - A culturally sensitive 3-month intervention was provided to 18 Caribbean Latino
      men and women with non-insulin-dependent (type 2) diabetes mellitus. Compared to
      the randomly assigned control group, the intervention group showed statistically
      significant decreases in total calories, fat calories, percent of calories from
      fat, saturated fat calories, and percent of calories from saturated fat The
      intervention group showed increases in calories from carbohydrates and in the
      percent of calories from fiber.

PMID- 10346659
TI  - Estimated economic costs of obesity to U.S. business.
AB  - OBJECTIVE: To estimate the economic costs of obesity to U.S. business. METHODS:
      Standard epidemiologic methods for risk attribution and techniques for
      ascertaining cost of illness were used to estimate obesity-attributable
      expenditures on selected employee benefits, including health, life, and
      disability insurance and paid sick leave by private-sector firms in the U.S. in
      1994. Data were obtained from a variety of secondary sources, including the
      National Health Interview Survey, reports from the Bureau of Labor Statistics and
      other federal agencies, and the published literature. Attention was focused on
      employees between the ages of 25 and 64 years who were classified according to
      body mass index (BMI) as "nonobese" (BMI < 25 kg/m2), "mildly obese" (BMI = 25
      28.9 kg/m2), or "moderately to severely obese" (BMI > or = 29 kg/m2). RESULTS:
      The cost of obesity to U.S. business in 1994 was estimated to total $12.7
      billion, including $2.6 billion as a result of mild obesity and $10.1 billion due
      to moderate to severe obesity. Health insurance expenditures constituted $7.7
      billion of the total amount, representing 43% of all spending by U.S. business on
      coronary heart disease, hypertension, type 2 diabetes, hypercholesterolemia,
      stroke, gallbladder disease, osteoarthritis of the knee, and endometrial cancer.
      Obesity-attributable business expenditures on paid sick leave, life insurance,
      and disability insurance amounted to $2.4 billion, $1.8 billion, and $800
      million, respectively. CONCLUSIONS: The health-related economic cost of obesity
      to U.S. business is substantial, representing approximately 5% of total medical
      care costs. Further research is needed to determine the cost-effectiveness of
      worksite weight management programs and of other efforts to reduce the prevalence
      of obesity in the U.S. workforce.

PMID- 10346660
TI  - The effects of a single bout of strength training on ambulatory blood pressure
      levels in 24 mildly hypertensive men.
AB  - Twenty-four mildly hypertensive sedentary men were randomly assigned to one or
      two control conditions of health education or a treatment of a single bout of
      strength training. The men were rotated through the conditions until each man had
      participated in the treatment and both control conditions. Blood pressure was
      measured every 15 minutes for the 24-hour period following participation in each
      condition using an ambulatory blood pressure monitoring system. Compared to the
      control conditions, systolic blood pressure and blood pressure load were reduced
      for at least 1 hour after exercise, and diastolic blood pressure and blood
      pressure load were reduced for at least 3 minutes and 1 hour, respectively, after
      exercise.

PMID- 10346661
TI  - Family members' influence on decision making about food: differences in
      perception and relationship with healthy eating.
AB  - PURPOSE: This study provides insight into decision making about food choices in
      the family and its relationship with (un)healthy eating, by including the
      responses of four members of the family as a sampling unit. SETTING: The study
      was conducted through four medical centers, visited by 69 classes from 19
      different schools in Belgium. SUBJECTS: Ninety-two family quartets, including
      both parents and two adolescents between 12 and 18 years old, completed
      questionnaires independently. MEASURES: Four previously investigated measures of
      decision-making power (30 items on a seven-point scale) were administered, along
      with a short food choice questionnaire and demographic variables. RESULTS:
      Results indicate that the influence of fathers but more especially that of
      children is important in food decisions. Moreover, the relative influence of each
      family member is dependent on the kind of product or product group considered.
      Differences in perceptions between the four family members show the importance of
      considering the responses of all the people involved in family decision making.
      Finally, it is clear that in families where adolescents have more power, food
      choices are less healthy. CONCLUSIONS: Our main conclusion is the rejection of
      the "gatekeeper hypothesis" as an artifact of biased measurement. A
      multidimensional approach to the issue of influence in food decision making in
      the family is potentially richer and leads to different conclusions. The
      necessity of the involvement of the entire family for the introduction and
      adoption of healthy eating is emphasized.

PMID- 10346662
TI  - A review of the health impact of smoking control at the workplace.
AB  - PURPOSE: To summarize and provide a critical review of worksite health promotion
      program evaluations published between 1968 and 1994 that addressed the health
      impact of worksite smoking cessation programs and smoking policies. METHODS: A
      comprehensive literature search conducted under the auspices of the Centers for
      Disease Control and Prevention identified 53 smoking cessation program evaluation
      reports, of which 41 covered worksite single-topic cessation programs. Nine
      additional reports were located through manual search of citations from published
      reports and reviews. These 50 reports covered 52 original data-based studies of
      cessation programs. The search produced 19 reports for tobacco policy
      evaluations, of which 12 addressed health impact. An additional 17 reports were
      located by the authors. These 29 reports covered 29 studies of policy impact.
      SUMMARY OF IMPORTANT FINDINGS: Smoking cessation group programs were found to be
      more effective than minimal treatment programs, although less intensive
      treatment, when combined with high participation rates, can influence the total
      population. Tobacco policies were found to reduce cigarette consumption at work
      and worksite environmental tobacco smoke (ETS) exposure. CONCLUSIONS: The
      literature is rated suggestive for group and incentive interventions; indicative
      for minimal interventions, competitions, and medical interventions; and
      acceptable for the testing of incremental effects. Because of the lack of
      experimental control, the smoking policy literature is rated as weak, although
      there is strong consistency in results for reduced cigarette consumption and
      decreased exposure to ETS at work.

PMID- 10346663
TI  - Hygroscopic behavior of nebulized aerosols: not as important as we thought?

PMID- 10346664
TI  - Safety of inhaled proteins for therapeutic use.
AB  - The use of the inhalation route for delivery of inhaled proteins has received
      increasing attention recently. The purpose of this article is to review the
      available information related to the safety aspects of inhaled proteins. The
      review focuses primarily on possible toxicity to the respiratory tract, because
      usually one is either considering an agent to treat the lung or an agent for
      which the systemic toxicity has been investigated following subcutaneous (s.c.)
      administration in its clinical use as a therapeutic agent. Some background is
      provided on mechanisms of absorption and reasons why inhalation delivery is
      considered for many proteins. Available data are summarized from clinical trials
      of proteins and protein-like biomolecules, generally showing minimal, if any,
      adverse respiratory effects. The results of the animal toxicology studies that
      have been published are presented. In general, the observed lung toxicity has
      been relatively low, and it has been difficult to interpret in cases where the
      animal protein differs considerably from the human protein. Discussion is
      presented on the possibility of adverse immune reactions, suggesting that this is
      not likely to be any greater issue than it is for subcutaneously injected
      materials. Although the safety information is relatively sparse at present, the
      available data suggest that the inhalation route can be an attractive route to
      consider for many therapeutic proteins.

PMID- 10346665
TI  - Estimating the type of hygroscopic behavior exhibited by aqueous droplets.
AB  - A method that allows hygroscopic aerosol behavior to be classified into three
      types based on the values of the two nondimensional parameters gamma and zeta is
      presented. Both parameters can be estimated relatively simply, allowing
      prediction of the type of behavior a hygroscopic aerosol is likely to exhibit.
      The parameter gamma is the ratio of the mass of droplets per unit volume divided
      by the mass of vapor per unit volume that must be exchanged between the droplets
      and the surrounding air in order to reach equilibrium. The parameter zeta is a
      measure of the importance of hygroscopic size changes if the aerosol were to be
      treated as a single droplet. Under many circumstances, zeta is large enough that
      aerosol behavior is determined solely by gamma. In this case, hygroscopic size
      changes are negligible if gamma is greater than approximately 3. In contrast, if
      gamma is less than approximately 0.1, hygroscopic size changes are significant
      but can be treated using a classical one-way coupled approach. For other values
      of gamma, hygroscopic size changes require a two-way coupled treatment to predict
      accurately. Values of gamma and zeta are estimated for several hygroscopic
      aerosols whose behavior is given in the literature, and it is found that these
      aerosols to classify into the above categories according to gamma and zeta.

PMID- 10346666
TI  - Influence of flow rate on aerosol particle size distributions from pressurized
      and breath-actuated inhalers.
AB  - Particle size distribution of delivered aerosols and the total mass of drug
      delivered from the inhaler are important determinants of pulmonary deposition and
      response to inhalation therapy. Inhalation flow rate may vary between patients
      and from dose to dose. The Andersen Sampler (AS) cascade impactor operated at
      flow rates of 30 and 55 L/min and the Marple-Miller Impactor (MMI) operated at
      flow rates of 30, 55, and 80 L/min were used in this study to investigate the
      influence of airflow rate on the particle size distributions of inhalation
      products. Total mass of drug delivered from the inhaler, fine particle mass, fine
      particle fraction, percentage of nonrespirable particles, and amount of
      formulation retained within the inhaler were determined by ultraviolet
      spectrophotometry for several commercial bronchodilator products purchased in the
      marketplace, including a pressurized metered-dose inhaler (pMDI), breath-actuated
      pressurized inhaler (BAMDI), and three dry powder inhalers (DPIs), two containing
      salbutamol sulphate and the other containing terbutaline sulphate. Varying the
      flow rate through the cascade impactor produced no significant change in
      performance of the pressurized inhalers. Increasing the flow rate produced a
      greater mass of drug delivered and an increase in respirable particle mass and
      fraction from all DPIs tested.

PMID- 10346667
TI  - Alveolar deposition of fibers in rodents and humans.
AB  - Alveolar deposition fractions (respirability) of inhaled fibers in rats,
      hamsters, and humans were calculated based on previously developed deposition
      models. Because of differences in airway size and ventilation condition, humans
      were found to have a greater deposition fraction than rodents. Nevertheless, the
      deposition curve (alveolar deposition fraction vs fiber aerodynamic diameter) for
      all species has a similar shape which exhibits two peak deposition values.
      Increasing the aspect ratio or decreasing the mass density of the fiber shifts
      the deposition curve to lower aerodynamic diameters and reduces the values of
      peak deposition. For fiber aerodynamic diameters greater than 3.5 microns and
      aspect ratios greater than 10, rodents were found to have no alveolar deposition,
      whereas the human deposition remains appreciable.

PMID- 10346668
TI  - But first, call your drug company: the doctor-patient relationship is being
      replaced by a drug marketer-patient bond.

PMID- 10346669
TI  - The application of the patent laws to the drug approval process.

PMID- 10346670
TI  - The cosmetic/drug dilemma: FDA regulation of alpha-hydroxy acids.

PMID- 10346671
TI  - Should combat troops be given the option of refusing investigational drug
      treatment?

PMID- 10346672
TI  - Overview of FDA regulation of human cellular and tissue-based products.

PMID- 10346673
TI  - The regulation of human tissue in the United States: a regulatory and legislative
      analysis.

PMID- 10346674
TI  - He's all heart . . . and a little pig too: a look at the FDA draft xenotransplant
      guideline.

PMID- 10346675
TI  - Biobusiness on campus: commercialization of university-developed biomedical
      technologies.

PMID- 10346676
TI  - FDA software policy and regulation of medical device software.

PMID- 10346677
TI  - FDA regulation of telemedicine devices.

PMID- 10346678
TI  - Implementation of the Food Quality Protection Act.

PMID- 10346679
TI  - Update on issues before the Codex Alimentarius.

PMID- 10346680
TI  - The Organic Foods Production Act of 1990 and its impending regulations: a big
      zero for organic food?

PMID- 10346681
TI  - Off-label promotion: is FDA's final guidance on industry-supported scientific and
      educational programs enforceable?

PMID- 10346682
TI  - Surfing the Net in shallow waters: product liability concerns and advertising on
      the Internet.

PMID- 10346683
TI  - The new Restatement (Third) of Torts--shelter from the product liability storm
      for pharmaceutical companies and medical device manufacturers?

PMID- 10346684
TI  - About-face: how FDA changed its mind, took on the tobacco companies in their own
      back yard, and won.

PMID- 10346685
TI  - Food and Drug Administration Modernization Act of 1997: medical device
      provisions.

PMID- 10346686
TI  - Medtronic v. Lohr: for want of a word, the patient was almost lost--fixing the
      mischief caused in Cipollone by dividing the preemption stream.

PMID- 10346687
TI  - FDA's efforts to improve access to agency records.

PMID- 10346688
TI  - FDA's consideration of Codex Alimentarius standards in light of international
      trade agreements.

PMID- 10346689
TI  - Update on FSIS initiatives.

PMID- 10346690
TI  - Ethical issues in the patenting of medical procedures. American Medical
      Association, Council on Ethical and Judicial Affairs.

PMID- 10346691
TI  - Xenotransplantation: ethics and economics.

PMID- 10346692
TI  - Early parental loss, recent life events, and changes in health among older
      adults.
AB  - The purpose of this study is to see whether older adults who lost a parent early
      in life are more vulnerable to the effects of recent stressful events than
      elderly people who were raised in an intact home. Data from a nationwide
      longitudinal survey of older adults provide support for this view.  The findings
      indicate that the combined effects of early parental loss and recent stressful
      events are associated with a decline over time in global self-rated health, as
      well as the number of chronic and acute conditions.  In contrast, significant
      effects failed to emerge with functional disability.  This study contributes to
      the literature by suggesting that only certain kinds of recent events (i.e.,
      stressors arising in highly valued roles) act in concert with early parental loss
      to compromise health in late life.

PMID- 10346693
TI  - Predictors of mobility and basic ADL difficulty among adults aged 70 years and
      older.
AB  - We use data from the 1993-1995 Assets and Health Dynamics of the Oldest-Old
      survey to estimate predictors of onset of mobility difficulty, onset of basic
      activity of daily living (ADL) difficulty, and improvement to no mobility
      difficulty.  Onset of mobility difficulty occurred among 20% of those with no
      difficulty at baseline (n = 2,857) and was most likely among those 85 years of
      age or over, women, those with a body-mass index of 30 or over, and those who
      reported lung disease, arthritis, frequent pain, and poor memory.  For those with
      mobility difficulty at baseline (n = 1,871), improvement occurred among 24% and
      onset of basic ADL difficulty occurred among 25%.  Improvement was more likely
      among those with difficulty in just one mobility item at baseline, and onset of
      ADL difficulty was most common among those with difficulty in three or more
      mobility items at baseline.

PMID- 10346694
TI  - The conceptualization and effect of control beliefs on exercise attendance in the
      elderly.
AB  - The purpose of the study was to compare the relative merits of two approaches to
      the measurement of perceived behavioral control for the prediction of attendance
      in an exercise program in an elderly population.  The first approach was to
      conceptualize perceived behavioral control in the traditional manner outlined by
      Ajzen (1987).  The second approach was to conceptualize control beliefs as two
      distinct constructs: scheduling self-efficacy and perceived barriers to exercise.
      Participants (N = 157, average age = 68 years +/-7.87, 74% female) were
      volunteers from elderly exercise classes.  Participants were asked to complete
      questionnaires assessing the constructs at Weeks 5 and 9 of a 16-week exercise
      program.  Attendance was monitored and used as the dependent variable.  Results
      revealed that in an active elderly sample, (a) scheduling self-efficacy is a
      superior conceptualization for control beliefs than perceived behavioral control,
      (b) neither attitude nor subjective norm predict intention or attendance in an
      exercise program, and (c) perceived barriers to exercise are not related to
      exercise intention or attendance.

PMID- 10346695
TI  - Aging, health, and the "electronic church".
AB  - We tested whether elders substitute religious media use for church attendance
      when health declines (using multidimensional disengagement theory) with data from
      a multiracial, population-based sample in the Bible Belt (N = 2,971).  In
      adjusted models, 3-year declines in functional status were significantly
      associated with concurrent reduction in frequency of church attendance but not
      with any change in rates of religious media (TV/radio) use.  Age-related declines
      in church attendance were substantively explained by declining functional
      ability. Changes in religious media use were independent of age and less
      sensitive to declining functional status or service attendance than to cultural
      heritage such as race, socioeconomic status, and rural upbringing.  Our data do
      not support the hypothesis that elders with deteriorating health substitute
      increased engagement with religious media as their participation in
      organizational religious activities is reduced.  However, applicability of the
      substitution hypothesis to other dimensions of nonorganizational religiousness
      (e.g., prayer) awaits similar scrutiny.

PMID- 10346696
TI  - Religious denomination and depression in older Dutch citizens: patterns and
      models.
AB  - This study describes the distribution of depressive symptoms in older Dutch
      citizens (N = 3,020) across religious denominations.  Reformed Calvinists had the
      lowest depressive scores (CES-D); Protestants from liberal denominations the
      highest; Roman Catholics, Dutch Reformed, and nonchurch members were in between.
      Two types of explanatory mechanisms are examined: (a) social integration and (b)
      positive self-perceptions, which both help to prevent depression.  Alternatively,
      strict Calvinist doctrines are hypothesized to enforce negative self-perceptions,
      facilitating depression.  For 2,509 respondents, complete data were available on
      social integration and self-perceptions, as well as on the parental religious
      denomination. Explanatory effects were tested using hierarchic regression models.
      The negative association between Calvinist background and depressive symptoms was
      partly explained by size of social network, and between Roman Catholic background
      and depressive symptoms by self-esteem. Leaving church had a positive association
      with depressive symptoms. This depressogenic effect remained after controlling
      for explanatory variables.

PMID- 10346697
TI  - Religion, health, and psychological well-being in older adults: findings from
      three national surveys.
AB  - This study examines the impact of religious involvement on health status and
      psychological well-being using data on older adults from three national
      probability surveys: the Myth and Reality of Aging (N = 2,797), the Quality of
      American Life (N = 1,209), and Americans' Changing Lives (N = 1,669) studies. 
      Constructs are measured by single items and indices that vary across data sets. 
      A proposed theoretical model specifies direct effects of religiosity on health
      and well-being and indirect effects on well-being through health. Analyses
      consist of structural-equation modeling of confirmed measurement models using
      weighted least squares estimation in LISREL 8.03.  The model is analyzed first as
      specified and is then rerun controlling for the effects of six exogenous
      constructs: age, gender, race, marital status, education, and geographical
      region.  Findings reveal excellent overall fit in all three samples and the
      presence of statistically significant religious effects, notably positive net
      effects of organizational religiosity, in all three samples.  These results build
      on those of prior studies based mostly on samples limited regionally or
      methodologically or to particular racial or ethnic groups. This study also
      underscores the value of replicated secondary data analysis as a strategy for
      gerontologists seeking to confirm or examine a given structural model.  Finally,
      an agenda is proposed for future research in this area.

PMID- 10346698
TI  - Rituals and the grieving process.
AB  - Cultural and psychotherapeutic rituals are designed to aid the bereaved in grief
      resolution.  This paper examines the function of funeral and bereavement rituals
      in contemporary Western society and considers the relationship between rituals
      and complicated and disenfranchised grief.  A new model for the use of rituals in
      psychotherapy with the bereaved that emphasizes intrapsychic and psychosocial
      processes is described.  Rituals are presented as vehicles for transformation and
      connection as well as the more commonly recognized transition.

PMID- 10346699
TI  - Personal meanings of death in relation to fear of death.
AB  - This study assessed death meanings and death fears held by 2 age groups of
      adults, related the death meanings to fear of death, and determined whether death
      meanings and fear of death depended on age and gender.  Study participants were
      265 college students (aged 19 to 55).  Factor analysis of participant responses
      to 30 death-meaning items identified 3 dimensions of death meanings: Extinction,
      Afterlife, and Legacy.  Hierarchical regression analyses determined the combined
      effect of the 3 death-meaning dimensions on each of 8 Leming Fear of Death Scale
      (LFDS) subscales, after effects of gender and age group were accounted for. 
      Younger respondents and women had greater fear of death on certain subscales. 
      Extinction was a significant predictor (p less than .05) of 7 LFDS subscores,
      Afterlife predicted 4 subscores, and legacy predicted 2 subscores.

PMID- 10346700
TI  - "This is not death, it is something safer": a psychodynamic approach to Sylvia
      Plath.
AB  - An attempt is made to illustrate the chronic suicidality and the separation
      individuation conflict in the life and work of Sylvia Plath.  Explanations of
      female suicidality in prevailing suicidality research are primarily influenced by
      male fantasms and gender role cliches.  Plath's work, however, not only enables
      insight into her individual fate, but also offers a differentiated perception of
      suicidality among women.  It becomes apparent that the texts in question are
      centered on specific conflict areas, in the sense of the formation of female
      identity and subjectivity, which affect current discussion on imagined concepts
      of femininity, and which are closely interwoven with the problems of female
      suicidality.

PMID- 10346702
TI  - The Stark laws: conquering physician conflicts of interest?

PMID- 10346701
TI  - Single- versus multi-item scales in measuring death anxiety.
AB  - The author investigated the reliability and concurrent validity of a Likert-type
      single-item test asking for a self-rating of death anxiety in two Arabic
      countries: Egypt and Kuwait.  A total of 1,439 participants were divided into 9
      male and female subsamples and were tested by a single item of death anxiety,
      along with three psychometric multi-item instruments (i.e., Templer's Death
      Anxiety Scale, Thorson and Powell's Revised Death Anxiety Scale, and the Arabic
      Scale of Death Anxiety).  The single- and multi-item scales had high
      reliabilities.  All of the thirteen correlations between the single-item and the
      multi-item scales of death anxiety among men and women were statistically
      significant (p less than .001) and positive.  They ranged from .30 to .66, with a
      median of .51.  It was concluded that single-item assessment can be reliable
      across time (test-retest = .82) and that it correlates moderately with multi-item
      instruments.

PMID- 10346703
TI  - Penetrating the walls of drug-resistant bacteria: a statutory prescription to
      combat antibiotic misuse.

PMID- 10346704
TI  - Remarks by the Commissioner of Food and Drugs.

PMID- 10346705
TI  - The Lohr decision: FDA perspective and position.

PMID- 10346706
TI  - Preparing America's food safety system for the twenty-first century--who is
      responsible for what when it comes to meeting the food safety challenges of the
      consumer-driven global economy?

PMID- 10346707
TI  - What every food manufacturer needs to know: realizing the impact of globalization
      on national food regulation.

PMID- 10346708
TI  - A legal assessment of FDA's new HACCP regulations.

PMID- 10346709
TI  - The food label and the right-to-know.

PMID- 10346710
TI  - New challenges for medical product promotion and its regulation.

PMID- 10346711
TI  - Enforcement of the current good manufacturing practices for solid oral dosage
      forms after United States v. Barr Laboratories.

PMID- 10346712
TI  - A whole new world?: pharmaceutical responses to the managed care revolution.

PMID- 10346713
TI  - Commentary on payment and reimbursement issues affecting the marketing of drugs,
      medical devices, and biologics, with emphasis on the anti-kickback statute and
      Stark II.

PMID- 10346714
TI  - The need for balancing the regulation of pharmaceutical trademarks between the
      Food and Drug Administration and the Patent and Trademark Office.

PMID- 10346715
TI  - Execution of a criminal search warrant by FDA--effective preparation and
      response.

PMID- 10346716
TI  - An interpretive guide to chairing an FDA advisory committee.

PMID- 10346717
TI  - Products liability implications of reprocessing and reuse of single-use medical
      devices.

PMID- 10346718
TI  - Black box warnings in prescription drug labeling: results of a survey of 206
      drugs.

PMID- 10346719
TI  - Dietary supplements: background for dialogue between the industry and the medical
      profession.

PMID- 10346720
TI  - So you want to market a food and to make health-related claims--how far can you
      go?  What rules of law will govern the claims you want to make?

PMID- 10346721
TI  - Civil and criminal liability associated with food recalls.

PMID- 10346722
TI  - FDA at war: securing the food that secured victory.

PMID- 10346723
TI  - ORA's role at FDA headquarters and in the field for product recalls.

PMID- 10346724
TI  - Corporate compliance programs: a shield against criminal liability.

PMID- 10346725
TI  - A plan that establishes a framework for achieving mutual recognition of good
      manufacturing practices inspections.

PMID- 10346726
TI  - The impact of international trade agreements on U.S. food safety and labeling
      standards.

PMID- 10346727
TI  - The marketing of foodstuffs in France.

PMID- 10346728
TI  - FDA regulation of genetic testing: institutional reluctance and public
      guardianship.

PMID- 10346729
TI  - Is it just a cold?

PMID- 10346730
TI  - Filling the geriatric gap: is the health system prepared for an aging population?

PMID- 10346731
TI  - Comparing parent loss with sibling loss.
AB  - The death of a loved one is a traumatic loss for children, but little attention
      has been paid to how children's responses vary according to who died--a parent or
      a sibling.  This article reports the findings of a comparison between children's
      responses to parent and sibling loss.  Two samples of bereaved children were
      combined for the project, which compared children's scores on the Achenbach Child
      Behavior Checklist.  Findings indicated that there were no significant
      differences between the two loss groups in the total number of problems, in any
      of the syndrome scales, or in the percentage of children at risk.  However, when
      the two loss groups were considered by gender, differences appeared--boys were
      more impacted by the loss of a parent than by the loss of a sibling and girls
      were most affected by the loss of a sibling, particularly a sister.  Possible
      explanations for these differences are discussed.

PMID- 10346732
TI  - Adults view their childhood bereavement experiences.
AB  - This study sought to determine if depression is an inevitable outcome of
      childhood bereavement experiences, as the Freudians believed, or if children can
      experience healthy mourning, as Bowlby predicted.  In an application of Q
      methodology, 43 adults parentally bereaved as children sorted statements about
      childhood bereavement experiences and outcomes in adulthood.  Debriefing
      interviews followed.  Four distinct types of experience emerged through factor
      analysis: appreciation, frustration, enmeshment, and ambivalence. Depression was
      not found to be an inevitable outcome, and Bowlby's prediction that certain
      positive family factors can influence a child toward healthy mourning during
      childhood were corroborated.  Salient factors contributing to healthy childhood
      mourning included positive relationships between the child and both parents,
      ample emotional and psychological support from the surviving parent, and open and
      honest communication with the child about the death and its impact on the family.

PMID- 10346733
TI  - Concept of death in a sample of Israeli kibbutz children.
AB  - The study of children's concept of death and factors that affect its acquisition
      continue to evolve.  In this study, the concept of death of 22 Israeli children
      (aged 5-12 years), were assessed using vignettes. Participants' understanding of
      finality, universality, inevitability, and total concept of death were explored
      using the Concept of Death Assessment (CODA).  The child's developmental level
      was assessed using an interactive developmental tool based on a
      Piagetian/constructivist framework (R. B. Sund, 1976).  Development was scored as
      a continuous, rather than as a dichotomous variable.  In this sample, age was the
      only significant predictor of concept of death (p less than .01).  Children had
      an accurate concept of death as young as 6 years, however, it was not possible to
      determine an upper age limit by which children had an accurate concept of death. 
      The mean developmental score was 64.8% +/-18.7.  Still, 45% of this sample had an
      accurate concept of death, and 95.5% had an accurate understanding of finality. 
      Environmental factors unique to an Israeli sample that might affect concept
      acquisition are explored.  Questions remain about the interrelationship of
      development and concept acquisition.

PMID- 10346735
TI  - Service through research.

PMID- 10346736
TI  - The TEC experience.

PMID- 10346734
TI  - Are teachers of children and young adolescents responsive to suicide prevention
      training modules?  Yes.
AB  - Both before and after a 1-hour suicide prevention training module, 75 elementary
      teachers-in-training read a 4-sentence vignette about a suicidal student ("Pat"),
      then completed 8 questions about their responses.  Compared with pretraining, at
      post-training these teachers were more likely to say that they would send or
      escort Pat to the counselor's office, use written or verbal no-suicide
      agreements, call Pat's parents, believe Pat to be serious rather than simply
      seeking attention, and feel comfortable handling a similar situation. Increased
      proactive attitudes after one hour of training imply that teachers would benefit
      from periodic suicide awareness and prevention training modules.

PMID- 10346737
TI  - The Cochrane Collaboration.

PMID- 10346738
TI  - Electron beam computed tomography (clinical assessment).

PMID- 10346739
TI  - High-dose chemotherapy with autologous stem-cell support for epithelial ovarian
      cancer.

PMID- 10346741
TI  - Fetal surgery for prenatally diagnosed malformations.

PMID- 10346742
TI  - Part I: bilateral urinary tract obstruction.

PMID- 10346740
TI  - High-dose chemotherapy with autologous stem-cell support in the treatment of high
      risk, primary breast cancer.

PMID- 10346743
TI  - Part II: congenital diaphragmatic hernia.

PMID- 10346744
TI  - Part III: pulmonary lesions--congenital cystic adenomatoid malformation (CCAM) or
      extralobar pulmonary sequestration (EPS).

PMID- 10346745
TI  - Single or tandem high-dose chemoradiotherapy with autologous stem-cell support
      (HDC/AUSCS) for resistant multiple myeloma.

PMID- 10346746
TI  - Transmyocardial revascularization for the treatment of coronary artery disease.

PMID- 10346747
TI  - Transurethral radiofrequency needle ablation of the prostate.

PMID- 10346748
TI  - Special report: stereotactic radiosurgery for intracranial lesions by gamma beam,
      linear accelerator, and proton beam methods.

PMID- 10346749
TI  - When doctors might kill their patients: foreseeing is not necessarily the same as
      intending.

PMID- 10346750
TI  - The moral character of clinicians or the best interests of patients?

PMID- 10346751
TI  - Foodborne viral infections.

PMID- 10346752
TI  - Public health, civil liberties, and tuberculosis.

PMID- 10346754
TI  - WHO agrees measures to stop global spread of tobacco use.

PMID- 10346755
TI  - Dutch launch plan to combat legionnaires' disease.

PMID- 10346753
TI  - Better blood transfusion.

PMID- 10346756
TI  - In brief 

PMID- 10346758
TI  - Hungary passes non-smokers' rights bill.

PMID- 10346757
TI  - Explanations shift attitudes to animal experiments.

PMID- 10346759
TI  - Bristol inquiry reveals lack of data on service quality.

PMID- 10346760
TI  - European union considers new plan to help refugees.

PMID- 10346761
TI  - High dose chemotherapy offers little benefit in breast cancer.

PMID- 10346762
TI  - Time to devolve the BMJ? 

PMID- 10346763
TI  - Trial of steroids for treating head injury begins.

PMID- 10346764
TI  - Chief medical officer clears genetically modified foods.

PMID- 10346765
TI  - Kent private finance initiative scheme will not save money 

PMID- 10346766
TI  - US drug trials expand outside academic centres.

PMID- 10346767
TI  - EU says growth hormones pose health risk.

PMID- 10346768
TI  - Cancer in children of nuclear industry employees: report on children aged under
      25 years from nuclear industry family study.
AB  - OBJECTIVE: To determine whether children of men and women occupationally exposed
      to ionising radiation are at increased risk of developing leukaemia or other
      cancers before their 25th birthday. DESIGN: Cohort study of children of nuclear
      industry employees. SETTING: Nuclear establishments operated by the Atomic Energy
      Authority, Atomic Weapons Establishment, and British Nuclear Fuels. SUBJECTS: 39
      557 children of male employees and 8883 children of female employees. MAIN
      OUTCOME MEASURES: Cancer incidence in offspring reported by parents. Employment
      and radiation monitoring data (including annual external dose) supplied by the
      nuclear authorities. RESULTS: 111 cancers were reported, of which 28 were
      leukaemia. The estimated standardised incidence ratios for children of male and
      female employees who were born in 1965 or later were 98 (95% confidence interval
      73 to 129) and 96 (50 to 168) for all malignancies and 109 (61 to 180) and 95 (20
      to 277) for leukaemia. The leukaemia rate in children whose fathers had
      accumulated a preconceptual dose of >/=100 mSv was 5.8 times that in children
      conceived before their fathers' employment in the nuclear industry (95%
      confidence interval 1.3 to 24.8) but this was based on only three exposed cases.
      Two of these cases were included in the west Cumbrian ("Gardner") case-control
      study. No significant trends were found between increasing dose and leukaemia.
      CONCLUSIONS: Cancer in young people is rare, and our results are based on small
      numbers of events. Overall, the findings suggest that the incidence of cancer and
      leukaemia among children of nuclear industry employees is similar to that in the
      general population. The possibility that exposure of fathers to relatively high
      doses of ionising radiation before their child's conception might be related to
      an increased risk of leukaemia in their offspring could not be disproved, but
      this result was based on only three cases, two of which have been previously
      reported. High conceptual doses are rare, and even if the occupational
      association were causal, the number of leukaemias involved would be small; in
      this study of over 46 000 children, fewer than three leukaemias could potentially
      be attributed to such an exposure.

PMID- 10346769
TI  - Sequential randomised and double blind trial of promethazine prophylaxis against
      early anaphylactic reactions to antivenom for bothrops snake bites.
AB  - OBJECTIVE: To investigate the efficacy of the H1 antihistamine promethazine
      against early anaphylactic reactions to antivenom. DESIGN: Sequential randomised,
      double blind, placebo controlled trial. SETTING: Public hospital in a venom
      research institute, Sao Paulo, Brazil. PARTICIPANTS: 101 patients requiring
      antivenom treatment after being bitten by bothrops snakes. INTERVENTION:
      Intramuscular injection of promethazine (25 mg for adults and 0.5/kg for
      children) or placebo given 15-20 min before starting intravenous infusion of
      antivenom. MAIN OUTCOME MEASURES: Incidence and severity of anaphylactic
      reactions occurring within 24 hours after antivenom. RESULTS: Reactions occurred
      in 12 of 49 patients treated with promethazine (24%) and in 13 of 52 given
      placebo (25%); most were mild or moderate. Continuous sequential analysis
      indicated that the study could be interrupted at the 22nd untied pair, without
      preference for promethazine or placebo. CONCLUSION: Prophylaxis with promethazine
      does not prevent early reactions. Patients should be observed carefully during
      antivenom infusion and the subsequent few hours.

PMID- 10346770
TI  - The nuclear industry family study: linkage of occupational exposures to
      reproduction and child health.

PMID- 10346772
TI  - Spitting of blood 

PMID- 10346771
TI  - Incidence of non-specific abdominal pain in children during school term:
      population survey based on discharge diagnoses.

PMID- 10346773
TI  - Advising parents of asthmatic children on passive smoking: randomised controlled
      trial.
AB  - OBJECTIVE: To investigate whether parents of asthmatic children would stop
      smoking or alter their smoking habits to protect their children from
      environmental tobacco smoke. DESIGN: Randomised controlled trial. SETTING:
      Tayside and Fife, Scotland. PARTICIPANTS: 501 families with an asthmatic child
      aged 2-12 years living with a parent who smoked. INTERVENTION: Parents were told
      about the impact of passive smoking on asthma and were advised to stop smoking or
      change their smoking habits to protect their child's health. MAIN OUTCOME
      MEASURES: Salivary cotinine concentrations in children, and changes in reported
      smoking habits of the parents 1 year after the intervention. RESULTS: At the
      second visit, about 1 year after the baseline visit, a small decrease in salivary
      cotinine concentrations was found in both groups of children: the mean decrease
      in the intervention group (0.70 ng/ml) was slightly smaller than that of the
      control group (0.88 ng/ml), but the net difference of 0.19 ng/ml had a wide 95%
      confidence interval (-0.86 to 0.48). Overall, 98% of parents in both groups still
      smoked at follow up. However, there was a non-significant tendency for parents in
      the intervention group to report smoking more at follow up and to having a
      reduced desire to stop smoking. CONCLUSIONS: A brief intervention to advise
      parents of asthmatic children about the risks from passive smoking was
      ineffective in reducing their children's exposure to environmental tobacco smoke.
      The intervention may have made some parents less inclined to stop smoking. If a
      clinician believes that a child's health is being affected by parental smoking,
      the parent's smoking needs to be addressed as a separate issue from the child's
      health.

PMID- 10346774
TI  - More than reason 

PMID- 10346775
TI  - Evidence based cardiology: psychosocial factors in the aetiology and prognosis of
      coronary heart disease. Systematic review of prospective cohort studies.

PMID- 10346776
TI  - Studying for the MRCP-was it worth while? 

PMID- 10346777
TI  - ABC of intensive care: organisation of intensive care.

PMID- 10346778
TI  - Why heart disease mortality is low in France: the time lag explanation.

PMID- 10346779
TI  - Not playing with a full DEC: why development and evaluation committee methods for
      appraising new drugs may be inadequate.

PMID- 10346780
TI  - Left ventricular dysfunction among elderly patients in general practice.
      Electrocardiograms are useful in these patients...

PMID- 10346781
TI  - Evidence exists for some advertising claims made on the internet.

PMID- 10346782
TI  - Clinical trials in primary care. Costs of research should not be borne by service
      practitioners.

PMID- 10346783
TI  - Migraine and stroke in young women. Authors' results suggest that all types of
      migraine are contraindications to oral contraceptives.

PMID- 10346784
TI  - Authors may have underestimated number of young doctors still working in NHS.

PMID- 10346785
TI  - Hereditary haemochromatosis should be more widely known about.

PMID- 10346786
TI  - Vaccines and their real or perceived adverse effects. Authors' conclusions are at
      odds with investigators'.

PMID- 10346787
TI  - Neurogenetic determinism and the new euphenics. Psychosocial and ethical issues
      in psychiatric genetics require constructive debate.

PMID- 10346788
TI  - Scanning during pregnancy is often for doctors' benefit rather than parents'.

PMID- 10346789
TI  - Radiosurgery for brain tumours. Editorial was wrong to denigrate radiosurgery so
      strongly.

PMID- 10346790
TI  - Presumed consent. If this is introduced, people will have to have all relevant
      information.

PMID- 10346791
TI  - Speaking sign language from birth can make deaf children confident.

PMID- 10346792
TI  - Assisted suicide law in Oregon.

PMID- 10346793
TI  - Airline passenger dies after being sedated. Death may have been due to positional
      asphyxia...

PMID- 10346794
TI  - George duncan stewart beechey 

PMID- 10346795
TI  - GPs oppose MPs' proposals on removing patients from lists 

PMID- 10346796
TI  - Informing patients: An assessment of the quality of patient information materials

PMID- 10346797
TI  - Should health screening be private? 

PMID- 10346798
TI  - Mobiles on the brain 

PMID- 10346799
TI  - Making a mess of sex 

PMID- 10346800
TI  - Website of the week 

PMID- 10346801
TI  - Anything else, sir? 

PMID- 10346803
TI  - Insight through argument 

PMID- 10346802
TI  - Basic science 

PMID- 10346805
TI  - Promethazine does not reduce reactions to bothrops antivenom 

PMID- 10346804
TI  - Cancer risk is not raised in children of nuclear workers 

PMID- 10346806
TI  - Brief advice to parents does not protect asthmatic children from passive smoking 

PMID- 10346807
TI  - Behavioural factors are important in non-specific abdominal pain 

PMID- 10346809
TI  - Methods of appraising new drugs may be inadequate 

PMID- 10346808
TI  - Time lag may explain the french paradox 

PMID- 10346810
TI  - Stress signaling from the lumen of the endoplasmic reticulum: coordination of
      gene transcriptional and translational controls.

PMID- 10346811
TI  - Phosphorylated RNA polymerase II stimulates pre-mRNA splicing.
AB  - RNA polymerase II (RNAP II) is responsible for transcription of mRNA precursors
      in eukaryotic cells. Recent studies, however, have suggested that RNAP II also
      participates in subsequent RNA processing reactions through interactions between
      the carboxy-terminal domain (CTD) of the RNAP II largest subunit and processing
      factors. Using reconstituted in vitro splicing assays, we show that RNAP II
      functions directly in pre-mRNA splicing by influencing very early steps in
      assembly of the spliceosome. We demonstrate that the phosphorylation status of
      the CTD dramatically affects activity: Hyperphosphorylated RNAP IIO strongly
      activates splicing, whereas hypophosphorylated RNAP IIA can inhibit the reaction.

PMID- 10346812
TI  - Loss of transcription factor IRF-1 affects tumor susceptibility in mice carrying
      the Ha-ras transgene or nullizygosity for p53.
AB  - The transcription factor IRF-1 has been implicated in tumor suppression: IRF-1
      suppresses cell transformation and mediates apoptosis in vitro. Here we show that
      the loss of IRF-1 alleles per se has no effect on spontaneous tumor development
      in the mouse but dramatically exacerbates previous tumor predispositions caused
      by the c-Ha-ras transgene or by nullizygosity for p53. Grossly altered tumor
      spectrum, as compared to p53-null mice, was also observed in mice lacking both
      IRF-1 and p53, and cells from these mice show significantly higher mutation rate.
      Our results suggest that IRF-1 is a new member of the tumor susceptibility genes.

PMID- 10346813
TI  - Critical role for Atm in suppressing V(D)J recombination-driven thymic lymphoma.
AB  - Chromosome translocations involving T cell receptor (TCR) loci have been found in
      tumors from Ataxia telangiectasia (AT) patients and in mouse Atm-/- thymoma,
      suggesting the involvement of V(D)J recombination in these malignancies. By
      introducing a RAG-1 deficiency into Atm-/- mice in the presence of a TCR
      transgene, we show that V(D)J recombination is critical for thymoma development
      in these mice. Therefore, aberrant V(D)J recombination, normally suppressed by
      Atm, facilitates tumorigenic events leading to cancer. Because V(D)J
      recombination is dispensable for lymphomagenesis upon p53 deficiency, this study
      also indicates that Atm and p53 function by distinct mechanisms in suppressing
      thymoma.

PMID- 10346814
TI  - GalR mutants defective in repressosome formation.
AB  - Transcription repression of the galactose operon of Escherichia coli requires (1)
      the binding of the GalR repressor to tandem operators flanking the promoters, (2)
      the binding of histone-like protein, HU, to a site between the GalR-binding
      sites, and (3) negatively supercoiled DNA. Under these conditions, protein
      protein interactions mediate the formation of a nucleoprotein complex in the form
      of a DNA loop, which we have termed a repressosome. To analyze the structure of
      the repressosome, we have screened and isolated galR mutants in which single
      amino acid substitutions in GalR lead to defects in loop formation while the
      protein's operator-binding activity is retained. The mutant proteins were
      purified and their properties confirmed in vitro. We verified that in the case of
      the two stronger mutations, the proteins had secondary structures that were
      identical to that of wild-type GalR as reflected by circular dichroism
      spectroscopy. Homology-based modeling of GalR by use of the crystal structures of
      PurR and LacI has enabled us to place the three sites of mutation in a structural
      context. They occur in the carboxy-terminal subdomain of the GalR core, are
      surface exposed, and, therefore, may be involved in protein-protein interactions.
      On the basis of our model of GalR and its structural alignment with LacI and
      PurR, we have identified additional residues, the substitution of which leads to
      a specific defect in repression by looping. The effects of the mutations are the
      same in the presence of HMG-17, a eukaryotic protein unrelated to HU, which can
      also mediate GalR-dependent repression of the gal promoter. This observation
      suggests that the mutations define sites of GalR-GalR interaction rather than HU
      GalR interaction in the repressosome.

PMID- 10346815
TI  - Crystal structure of the human Pax6 paired domain-DNA complex reveals specific
      roles for the linker region and carboxy-terminal subdomain in DNA binding.
AB  - Pax6, a transcription factor containing the bipartite paired DNA-binding domain,
      has critical roles in development of the eye, nose, pancreas, and central nervous
      system. The 2.5 A structure of the human Pax6 paired domain with its optimal 26
      bp site reveals extensive DNA contacts from the amino-terminal subdomain, the
      linker region, and the carboxy-terminal subdomain. The Pax6 structure not only
      confirms the docking arrangement of the amino-terminal subdomain as seen in
      cocrystals of the Drosophila Prd Pax protein, but also reveals some interesting
      differences in this region and helps explain the sequence specificity of paired
      domain-DNA recognition. In addition, this structure gives the first detailed
      information about how the paired linker region and carboxy-terminal subdomain
      contact DNA. The extended linker makes minor groove contacts over an 8-bp region,
      and the carboxy-terminal helix-turn-helix unit makes base contacts in the major
      groove. The structure and docking arrangement of the carboxy-terminal subdomain
      of Pax6 is remarkably similar to that of the amino-terminal subdomain, and there
      is an approximate twofold symmetry axis relating the polypeptide backbones of
      these two helix-turn-helix units. Our structure of the Pax6 paired domain-DNA
      complex provides a framework for understanding paired domain-DNA interactions,
      for analyzing mutations that map in the linker and carboxy-terminal regions of
      the paired domain, and for modeling protein-protein interactions of the Pax
      family proteins.

PMID- 10346816
TI  - Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the
      Mre11/Rad50 complex.
AB  - The Nijmegen breakage syndrome gene product (Nbs1) was shown recently to
      associate in vivo with the Mre11 and Rad50 proteins, which play pivotal roles in
      eukaryotic DNA double-strand break repair, meiotic recombination, and telomere
      maintenance. We show in this work that the triple complex of recombinant Nbs1,
      Mre11, and Rad50 proteins binds cooperatively to DNA and forms a distinct protein
      DNA species. The Mre11/Rad50/Nbs1 complex displays several enzymatic activities
      that are not seen without Nbs1, including partial unwinding of a DNA duplex and
      efficient cleavage of fully paired hairpins. Unwinding and hairpin cleavage are
      both increased by the presence of ATP. On nonhairpin DNA ends, ATP controls a
      switch in endonuclease specificity that allows Mre11/Rad50/Nbs1 to cleave a 3'
      protruding strand at a double-/single-strand transition. Mutational analysis
      demonstrates that Rad50 is responsible for ATP binding by the complex, but the
      ATP-dependent activities are expressed only with Nbs1 present.

PMID- 10346817
TI  - Assembly of functionally active Drosophila origin recognition complex from
      recombinant proteins.
AB  - In eukaryotes the sites for the initiation of chromosomal DNA replication are
      believed to be determined in part by the binding of a heteromeric origin
      recognition complex (ORC) to DNA. We have cloned the genes encoding the subunits
      of the Drosophila ORC. Each of the genes is unique and can be mapped to discrete
      chromosomal locations implying that the pattern and developmental regulation of
      origin usage in Drosophila is not regulated solely by a large family of different
      ORC proteins. The six-subunit ORC can be reconstituted with recombinant proteins
      into a complex that restores DNA replication in ORC-depleted Drosophila or
      Xenopus egg extracts.

PMID- 10346818
TI  - Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is
      sufficient for JNK and IKK activation and target gene induction via an amino
      terminal effector domain.
AB  - Interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) stimulate
      transcription factors AP-1 and NF-kappaB through activation of the MAP kinases
      JNK and p38 and the IkappaB kinase (IKK), respectively. The TNF-alpha and IL-1
      signals are transduced through TRAF2 and TRAF6, respectively. Overexpressed TRAF2
      or TRAF6 activate JNK, p38, or IKK in the absence of extracellular stimulation.
      By replacing the carboxy-terminal TRAF domain of TRAF2 and TRAF6 with repeats of
      the immunophilin FKBP12, we demonstrate that their effector domains are composed
      of their amino-terminal Zn and RING fingers. Oligomerization of the TRAF2
      effector domain results in specific binding to MEKK1, a protein kinase capable of
      JNK, p38, and IKK activation, and induction of TNF-alpha and IL-1 responsive
      genes. TNF-alpha also enhances the binding of native TRAF2 to MEKK1 and
      stimulates the kinase activity of the latter. Thus, TNF-alpha and IL-1 signaling
      is based on oligomerization of TRAF2 and TRAF6 leading to activation of effector
      kinases.

PMID- 10346819
TI  - Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis
      coli protein involved in tumorigenesis and development.
AB  - The adenomatous polyposis coli (APC) gene is considered as the true gatekeeper of
      colonic epithelial proliferation: It is mutated in the majority of colorectal
      tumors, and mutations occur at early stages of tumor development in mouse and
      man. These mutant proteins lack most of the seven 20-amino-acid repeats and all
      SAMP motifs that have been associated with down-regulation of intracellular beta
      catenin levels. In addition, they lack the carboxy-terminal domains that bind to
      DLG, EB1, and microtubulin. APC also appears to be essential in development
      because homozygosity for mouse Apc mutations invariably results in early
      embryonic lethality. Here, we describe the generation of a mouse model carrying a
      targeted mutation at codon 1638 of the mouse Apc gene, Apc1638T, resulting in a
      truncated Apc protein encompassing three of the seven 20 amino acid repeats and
      one SAMP motif, but missing all of the carboxy-terminal domains thought to be
      associated with tumorigenesis. Surprisingly, homozygosity for the Apc1638T
      mutation is compatible with postnatal life. However, homozygous mutant animals
      are characterized by growth retardation, a reduced postnatal viability on the B6
      genetic background, the absence of preputial glands, and the formation of nipple
      associated cysts. Most importantly, Apc1638T/1638T animals that survive to
      adulthood are tumor free. Although the full complement of Apc1638T is sufficient
      for proper beta-catenin signaling, dosage reductions of the truncated protein
      result in increasingly severe defects in beta-catenin regulation. The SAMP motif
      retained in Apc1638T also appears to be important for this function as shown by
      analysis of the Apc1572T protein in which its targeted deletion results in a
      further reduction in the ability of properly controlling beta-catenin/Tcf
      signaling. These results indicate that the association with DLG, EB1, and
      microtubulin is less critical for the maintenance of homeostasis by APC than has
      been suggested previously, and that proper beta-catenin regulation by APC appears
      to be required for normal embryonic development and tumor suppression.

PMID- 10346820
TI  - IKK1-deficient mice exhibit abnormal development of skin and skeleton.
AB  - IkappaB kinases (IKKs) IKK1 and IKK2 are two putative IkappaBalpha kinases
      involved in NF-kappaB activation. To examine the in vivo functions of IKK1, we
      generated IKK1-deficient mice. The mutant mice are perinatally lethal and exhibit
      a wide range of developmental defects. Newborn mutant mice have shiny, taut, and
      sticky skin without whiskers. Histological analysis shows thicker epidermis,
      which is unable to differentiate. Limbs and tail are wrapped inside the skin and
      do not extend properly out of the body trunk. Skeleton staining reveals a cleft
      secondary palate, split sternebra 6, and deformed incisors. NF-kappaB activation
      mediated by TNFalpha and IL-1 is diminished in IKK1-deficient mouse embryonic
      fibroblast (MEF) cells. The IKK complex in the absence of IKK1 is capable of
      phosphorylating IkappaBalpha and IkappaBbeta in vitro. Our results support a role
      for IKK1 in NF-kappaB activation and uncover its involvement in skin and skeleton
      development. We conclude further that the two related kinases IKK1 and IKK2 have
      distinct functions and can not be substituted for each other's functions.

PMID- 10346821
TI  - Mice devoid of all known thyroid hormone receptors are viable but exhibit
      disorders of the pituitary-thyroid axis, growth, and bone maturation.
AB  - Thyroid hormone (T3) has widespread functions in development and homeostasis,
      although the receptor pathways by which this diversity arises are unclear.
      Deletion of the T3 receptors TRalpha1 or TRbeta individually reveals only a small
      proportion of the phenotypes that arise in hypothyroidism, implying that
      additional pathways must exist. Here, we demonstrate that mice lacking both
      TRalpha1 and TRbeta (TRalpha1(-/-)beta-/-) display a novel array of phenotypes
      not found in single receptor-deficient mice, including an extremely hyperactive
      pituitary-thyroid axis, poor female fertility and retarded growth and bone
      maturation. These results establish that major T3 actions are mediated by common
      pathways in which TRalpha1 and TRbeta cooperate with or substitute for each
      other. Thus, varying the balance of use of TRalpha1 and TRbeta individually or in
      combination facilitates control of an extended spectrum of T3 actions. There was
      no evidence for any previously unidentified T3 receptors in TRalpha1(-/-)beta-/-
      mouse tissues. Compared to the debilitating symptoms of severe hypothyroidism,
      the milder overall phenotype of TRalpha1(-/-)beta-/- mice, lacking all known T3
      receptors, indicates divergent consequences for hormone versus receptor
      deficiency. These distinctions suggest that T3-independent actions of T3
      receptors, demonstrated previously in vitro, may be a significant function in
      vivo.

PMID- 10346822
TI  - Polarity determination in the Drosophila eye: a novel role for unpaired and
      JAK/STAT signaling.
AB  - The JAK/STAT signaling pathway is required for many processes including cytokine
      signaling, hematopoiesis, gliagenesis, and Drosophila segmentation. In this
      report we present evidence demonstrating that the JAK/STAT pathway is also
      central to the establishment of planar polarity during Drosophila eye
      development. We show that a localized source of the pathway ligand, Unpaired, is
      present at the midline of the developing eye, which is capable of activating the
      JAK/STAT pathway over long distances. A gradient of JAK/STAT activity across the
      DV axis of the eye regulates ommatidial polarity via an unidentified second
      signal. Additionally, localized Unpaired influences the position of the equator
      via repression of mirror.

PMID- 10346823
TI  - Limb-length inequality: assessment and treatment options.
AB  - Assessment and treatment of limb-length inequality, particularly in the growing
      child, is a challenging task. Evaluation of the discrepancy requires an
      understanding of the significance of the disparity, as well as the natural
      history of the disorder, before formulation of a treatment plan. In the immature
      patient, consistent longitudinal data are essential to avoid pitfalls in the
      projection of ultimate length difference. Therapeutic options range from no
      treatment or use of a simple shoe lift to a surgical shortening or lengthening
      procedure. The current indication for lengthening is a disparity exceeding 5 to 6
      cm. Epiphysiodesis or femoral shortening is useful for smaller discrepancies or
      for residual differences following a contralateral lengthening. Lengthening is
      done with a circular or cantilever external fixator, which may be combined with
      an intramedullary rod.

PMID- 10346824
TI  - Approach to the polytraumatized patient with musculoskeletal injuries.
AB  - The management of the multiply injured patient is a challenge for even
      experienced clinicians. Because many community hospitals lack a dedicated trauma
      team, it is often the orthopaedic surgeon who will direct treatment. Therefore,
      the orthopaedic surgeon must have an understanding of established guidelines for
      the evaluation, resuscitation, and care of the severely injured patient. Initial
      evaluation encompasses assessment and intervention for airway, breathing,
      circulation, disability (neurologic injury), and environmental and exposure
      considerations. Resuscitation requires not only administration of fluids, blood,
      and blood products but also emergent management of pelvic trauma and
      stabilization of long-bone fractures. Judicious early use of anterior pelvic
      external fixation can be lifesaving in many cases. The secondary survey, which is
      often neglected, must incorporate a thorough physical evaluation. Although the
      method of fracture stabilization is still controversial, most clinicians agree
      that early fixation offers many benefits, including early mobilization, improved
      pulmonary toilet, decreased cardiovascular risk, and improved psychological well
      being. Without an understanding of the complexities of the multiply injured
      patient, delays in the diagnosis and treatment of a patient's injuries are likely
      to adversely affect outcome.

PMID- 10346825
TI  - Acute management of spinal cord injury.
AB  - Demographic trends in the occurrence of injury and improvements in the early
      management of spinal trauma are changing the long-term profile of patients with
      spinal cord injuries. More patients are surviving the initial injury, and
      proportionately fewer patients are sustaining complete injuries. While preventive
      efforts to reduce the overall incidence of spinal cord injury are important, a
      number of steps can be taken to minimize secondary injury once the initial trauma
      has occurred. Recent efforts have focused on understanding the biochemical basis
      of secondary injury and developing pharmacologic agents to intervene in the
      progression of neurologic deterioration. The Third National Acute Spinal Cord
      Injury Study investigators concluded that methylprednisolone improves neurologic
      recovery after acute spinal cord injury and recommended that patients who receive
      methylprednisolone within 3 hours of injury should be maintained on the treatment
      regimen for 24 hours. When methylprednisolone therapy is initiated 3 to 8 hours
      after injury, it should continue for 48 hours. In addition to the adoption of the
      guidelines of that study, rapid reduction and stabilization of injuries causing
      spinal cord compression are critical steps in optimizing patients' long-term
      neurologic and functional outcomes.

PMID- 10346826
TI  - Painful conditions of the acromioclavicular joint.
AB  - The acromioclavicular (AC) joint may be affected by a number of pathologic
      processes, most commonly osteoarthritis, posttraumatic arthritis, and distal
      clavicle osteolysis. The correct diagnosis of a problem can usually be deduced
      from a thorough history, physical examination, and radiologic evaluation.
      Asymptomatic AC joint degeneration is frequent and does not always correlate with
      the presence of symptoms. Selective lidocaine injection enhances diagnostic
      accuracy and may correlate with surgical outcome. Nonoperative treatment is
      helpful for most patients, although those with osteolysis may have to modify
      their activities. In appropriately selected patients, open or arthroscopic distal
      clavicle resection is necessary to relieve symptoms. Recent biomechanical and
      clinical data emphasize the importance of capsular preservation and minimization
      of bone resection; however, the optimal amount of distal clavicle resection
      remains elusive. Patients with AC joint instability have poor results after
      distal clavicle resection.

PMID- 10346827
TI  - Revision anterior cruciate ligament reconstruction surgery.
AB  - Revision anterior cruciate ligament (ACL) reconstruction is indicated for
      selected patients with recurrent instability after a failed primary procedure.
      The cause of the failure must be carefully identified to avoid pitfalls that may
      cause the revision to fail as well. Associated instability patterns must be
      recognized and corrected to achieve a successful result. The choice of graft, the
      problem of retained hardware, and tunnel placement are the major challenges of
      revision ACL reconstruction. The patient must have reasonable expectations and
      understand that the primary goal of surgery is restoration of the ability to
      perform activities of daily living, rather than a return to competitive
      athletics. The results of revision ACL reconstructions are not as good as those
      after primary reconstructions; however, the procedure appears to be beneficial
      for most patients.

PMID- 10346828
TI  - Distal biceps tendon injuries: diagnosis and management.
AB  - Rupture of the distal biceps tendon occurs most commonly in the dominant
      extremity of men between 40 and 60 years of age when an unexpected extension
      force is applied to the flexed arm. Although previously thought to be an uncommon
      injury, distal biceps tendon ruptures are being reported with increasing
      frequency. The rupture typically occurs at the tendon insertion into the radial
      tuberosity in an area of preexisting tendon degeneration. The diagnosis is made
      on the basis of a history of a painful, tearing sensation in the antecubital
      region. Physical examination demonstrates a palpable and visible deformity of the
      distal biceps muscle belly with weakness in flexion and supination. The ability
      to palpate the tendon in the antecubital fossa may indicate partial tearing of
      the biceps tendon. Plain radiographs may show hypertrophic bone formation at the
      radial tuberosity. Magnetic resonance imaging is generally not required to
      diagnose a complete rupture but may be useful in the case of a partial rupture.
      Early surgical reattachment to the radial tuberosity is recommended for optimal
      results. A modified two-incision technique is the most widely used method of
      repair, but anterior single-incision techniques may be equally effective provided
      the radial nerve is protected. The patient with a chronic rupture may benefit
      from surgical reattachment, but proximal retraction and scarring of the muscle
      belly can make tendon mobilization difficult, and inadequate length of the distal
      biceps tendon may necessitate tendon augmentation. Postoperative rehabilitation
      must emphasize protected return of motion for the first 8 weeks after repair.
      Formal strengthening may begin as early as 8 weeks, with a return to unrestricted
      activities, including lifting, by 5 months.

PMID- 10346829
TI  - A church-sponsored medical mission to Panama: one ED nurse's experience.

PMID- 10346830
TI  - President's message. ComCARE because we care.

PMID- 10346831
TI  - The power to bring about change.

PMID- 10346833
TI  - ENA emergency nursing text wins 1998 AJN award

PMID- 10346834
TI  - Y2K: more on "What you don't know CAN hurt you"

PMID- 10346832
TI  - Are we effectively managing acute pain in the ED trauma patient?

PMID- 10346835
TI  - How do emergency departments cope with admitted patients who cannot go to the
      floor?

PMID- 10346836
TI  - Projectile lawn mower injuries in children: two case reports.

PMID- 10346837
TI  - A prospective study of ED pain management practices and the patient's
      perspective.
AB  - OBJECTIVE: This study was conducted to describe the prevalence of pain in the
      emergency department and to identify factors that may contribute to its
      treatment. METHODS: Interviews were conducted with 203 patients who entered the
      emergency department during the study period. Patients were interviewed regarding
      various aspects of their pain. Medical records were reviewed to determine what
      treatments were provided. RESULTS: One hundred sixty of the 203 patients came to
      the emergency department with a chief complaint related to pain, indicating a
      prevalence rate of 78%. Approximately 58% of all patients received either
      medication or an intervention. An average of 74 minutes elapsed from the time of
      arrival in the emergency department to the time of treatment with pharmacologic
      agents. Various independent variables were examined to determine their ability to
      predict the treatment of pain. Chest pain was most often treated with medication,
      and abdominal pain was least often treated with medication. Despite high pain
      ratings, only 15% of the sample received an opioid. DISCUSSION: This study
      revealed a very high prevalence of pain among patients in the emergency
      department and showed that, overall, pain was poorly treated. The findings
      suggest that chest pain is the only type of pain routinely relieved in the
      emergency department. An anecdotal finding was that 31 patients said they would
      refuse pain medications if such medications were offered. Twenty-five patients
      reported fear of addiction as their reason for this refusal.

PMID- 10346838
TI  - Adding medications in the emergency department: effect on knowledge of
      medications in older adults.
AB  - INTRODUCTION: Older adults constitute 20% of the ED population. Of older patients
      discharged from the emergency department, 40% receive at least one new medication
      to add to their already complex medication regimen. The purpose of this study was
      to determine the effect of increasing medication complexity on knowledge of newly
      prescribed medications for older adults discharged from the emergency department.
      METHODS: The complexity of self-administered medications after ED treatment was
      measured with the Medication Complexity Index to determine its potential
      influence on the patient's knowledge of medication. The Knowledge of Medication
      Subtest, a measure of the effectiveness of medication teaching, was administered
      by telephone interview 48 to 72 hours after ED discharge. RESULTS: Sixty rural ED
      patients ranging in age from 60 to 98 years completed the study. Higher
      medication complexity after the addition of medications in the emergency
      department was associated with less knowledge of their medications (r = 0.37, P
      =. 004). DISCUSSION: The increase in medication complexity that results from ED
      therapeutic intervention may decrease knowledge of medications. A heightened
      emphasis should be placed on effective medication teaching, counseling, and
      follow-up for older adult ED patients.

PMID- 10346839
TI  - ED nurse practitioners' employment by a physician group versus hospital: pros and
      cons.

PMID- 10346840
TI  - ED customer satisfaction survival skills: one hospital's experience.

PMID- 10346841
TI  - An organization-wide approach to improving ED patient satisfaction: one community
      teaching hospital's experience.

PMID- 10346842
TI  - CEN review questions

PMID- 10346843
TI  - Family violence screening: opportunities in prehospital settings.

PMID- 10346845
TI  - From the feds

PMID- 10346844
TI  - A mother's care: Do we include the family when the situation is critical?

PMID- 10346846
TI  - Our special patients moving their care online!

PMID- 10346847
TI  - Ohio ENA and ACEP chapters collaborate to adapt stimuli material for nursing
      continuing education.

PMID- 10346848
TI  - The use of nursing's credential letters.

PMID- 10346849
TI  - The danger of kissing toads: fire-bellied toad exposure and assessment parameters
      in children.

PMID- 10346850
TI  - Triage: how long does it take? how long should it take?

PMID- 10346851
TI  - Female offenders of sexual assault.

PMID- 10346852
TI  - Providing follow-up to prehospital care providers.

PMID- 10346853
TI  - A 67-year-old man with back pain, pale feet, and hypertension.

PMID- 10346854
TI  - Choosing the road less traveled. Interview by Marlene Jezierski.

PMID- 10346855
TI  - Brick by brick.

PMID- 10346856
TI  - More on responding to patients outside an emergency department

PMID- 10346857
TI  - Automatic external defibrillators on commercial airplanes.

PMID- 10346858
TI  - More on music therapy with children during invasive procedures.

PMID- 10346859
TI  - Molecular chaperone-like activity of hydrogel nanoparticles of hydrophobized
      pullulan: thermal stabilization with refolding of carbonic anhydrase B.
AB  - We have been studying the formation of hydrogel nanoparticles by the self
      aggregation of hydrophobized polysaccharide and the effective complexation
      between these nanoparticles as a host and various globular soluble proteins as a
      guest. This paper describes a new finding that refolding of the heat-denatured
      enzyme effectively occurs with the nanoparticles and beta-cyclodextrin according
      to a mechanism similar to that of a molecular chaperone. In particular, the
      irreversible aggregation of carbonic anhydrase B (CAB) upon heating was
      completely prevented by complexation between the heat-denatured enzyme and
      hydrogel nanoparticles formed by the self-aggregation of cholesteryl group
      bearing pullulan (CHP). The complexed CAB was released by dissociation of the
      self-aggregate upon the addition of beta-cyclodextrin. The released CAB refolded
      to the native form, and almost 100% recovery of the activity was achieved. The
      thermal stability of CAB was drastically improved by capture of the unfolded form
      which was then released to undergo refolding.

PMID- 10346860
TI  - Synthesis of novel europium-labeled estradiol derivatives for time-resolved
      fluoroimmunoassays.
AB  - The O-(5-carboxypentyl)-, O-(4-aminobutyl)-, O-(6-aminohexyl)oximes of 2- and 4
      formylestradiol as well as the 4-carboxyethylthioether derivative of estradiol
      were synthesized. These estradiol derivatives were characterized using IR-, 1H-,
      and 13C NMR spectroscopy. All synthesized estradiol derivatives were labeled with
      europium chelates. These "tracers" were purified and tested in a competitive time
      resolved fluoroimmunoassay with monoclonal antibody (SSI 57-2) raised against the
      6-O-(carboxymethyl)oxime-bovine serum albumin derivative of estradiol. All the
      tested europium-labeled estradiol-4-derivatives were bound by the antibody,
      whereas tracers linked via position 2 were not recognized by this antibody. It
      was observed that tracers conjugated via C-4 gave more sensitive standard curves
      than tracers conjugated via C-6. Especially, the estradiol-4-thioether derivative
      was found to be highly useful in time-resolved fluoroimmunoassays of estradiol
      while using this antibody.

PMID- 10346861
TI  - Toward an in vitro test for the diagnosis of allergy to penicillins. Synthesis,
      characterization, and use of beta-lactam and beta-lactam metabolite poly-L
      lysines which recognize human IgE antibodies.
AB  - Conjugates of poly-L-lysine (PLL) containing a penicillin or a penicilloyl
      residue were prepared and characterized by 1H NMR and by size-exclusion (SE)
      HPLC. These conjugates were used in a radio allergo sorbent tests (RAST) test for
      the determination of allergy toward beta-lactams. The chemiometric evaluation of
      the data indicates that allergy to amoxycillin is different from allergy to the
      other beta-lactams tested. Furthermore, careful chemical characterization of the
      conjugates appears to be crucial to obtain meaningful information from the RAST
      data.

PMID- 10346863
TI  - New use of cyanosilane coupling agent for direct binding of antibodies to silica
      supports. Physicochemical characterization of molecularly bioengineered layers.
AB  - A simple protocol to fix biological species to silica-based surfaces (silica
      microbeads and glass slides), using a bifunctional silane reagent (3-cyanopropyl
      dimethyl chlorosilane), is presented. This silane reagent was used without
      further derivatization. This system led to strong, but not covalent, linkage of
      antibodies through their glycosylated regions (OH groups) to solid supports. The
      use of a microsized sample revealed that the coupling process depends not only on
      physicochemical interactions but also on steric phenomena, and in this case, it
      was shown that a molecule acting as a spacer was required for more efficient cell
      fixation. Here, monoclonal mouse antibodies against the CD45 molecule expressed
      on rat lymphocytes (MAR anti CD45 Ab) were linked to lymphocytes, and as spacers,
      sheep anti-mouse antibodies (SAM Ab) were immobilized on silica surfaces,
      allowing the cells to stick to the floating hollow silica microbeads by simple
      incubation. Under such conditions, a single microbead can fix several cells. The
      potential of this hollow, low-density support is in ultrasound applications, for
      the destruction by cavitation phenomena of cells selectively fixed onto such a
      support. Such a study can serve as a basic model for various microbiosystems
      involving cell manipulation.

PMID- 10346862
TI  - Closo-dodecaborate(2-) as a linker for iodination of macromolecules. Aspects on
      conjugation chemistry and biodistribution.
AB  - Boron-containing compounds like closo-dodecaborate(2-) are in theory suitable for
      radioactive labeling with halogens. The boron-halogen bond is stronger than
      carbon-halogen bond and is not likely to be recognized by deiodinating enzymes in
      vivo. Peptides and proteins may be conjugated with various closo-dodecaborate(2-)
      containing ligands, and thereafter, the conjugate can be iodinated. Since closo
      dodecaborate(2-) is more avidly iodinated than tyrosine in moderately acidic
      media, such conjugates may be directly labeled on the boron part with
      radioisotopes of iodine using the standard Chloramine-T procedure. Mercapto
      undecahydro-closo-dodecaborate(2-) (BSH) was reacted with the double bond of
      allyldextran to form a boronated dextran compound of the molecular size of about
      70 kDa. This compound, in the text denoted as Dx-BS, and cesium dodecahydro-closo
      dodecaborate(2-) were labeled using iodine-125. The two compounds were
      administered to rats in order to study their in vivo stability. The results
      indicate that iodinated Dx-BS is stable for about 20 h in vivo. The degradation
      rate, as indicated by thyroid uptake, was found low. [125I]Iodo-closo
      dodecaborate(2-), which is a possible degradation product of [125I]Dx-BS-I, was
      rapidly excreted in urine without significant accumulation in any organ.

PMID- 10346864
TI  - Recognition of novel amphiphiles with many pendent mannose residues by Con A.
AB  - Novel amphiphiles which carry many mannose residues as side chains were prepared
      by telomerization of N-methacryloylaminopropyl D-mannopyranoside (alpha:beta =
      20:1), N-methacryloylaminohexyl D-mannopyranoside (alpha:beta = 20:1), or 3-(2
      methacryloylaminoethylthio)propyl D-mannopyranoside (alpha:beta = 4:1) using a
      lipophilic radical initiator. The mannose-carrying amphiphiles incorporated in
      liposomes were recognized by a lectin from Canavalia ensiformis (Con A), which
      was proven by the increase in turbidity of the liposome suspension after mixing
      with Con A. The interaction between sugar residues on the liposome surface and
      the lectin was largely affected by the degree of polymerization (DP) and the
      surface density of the amphiphile in the liposomes. The distance between the
      sugar residues and the polymer main chain did not affect the specific recognition
      by the lectin significantly in the liposome system, whereas it appreciably
      affected the recognition in the water-soluble polymer system. The association
      constants (Ka) of the amphiphiles (DP approximately 18) with Con A (0.3-2.2 x
      10(6) M-1 at 25 degrees C) were much larger than that of alpha-methyl D
      mannopyranoside (8.2 x 10(3) M-1) due to the "cluster effect ". The positive
      entropy change (20-52 J/mol K) for the binding of Con A to mannose residues on
      the liposome surface showed that the recognition in the liposome system was
      largely promoted by the release of water molecules from both the sugar residues
      on the liposome surface and the binding site of Con A.

PMID- 10346865
TI  - Polymeric gadolinium chelate magnetic resonance imaging contrast agents: design,
      synthesis, and properties.
AB  - We have synthesized and evaluated five series of polymeric gadolinium chelates
      which are of interest as potential MRI blood pool contrast agents. The polymers
      were designed so that important physical properties including molecular weight,
      relaxivity, metal content, viscosity, and chelate stability could be varied. We
      have shown that, by selecting polymers of the appropriate MW, extended blood pool
      retention can be achieved. In addition, relaxivity can be manipulated by changing
      the polymer rigidity, metal content affected by monomer selection, viscosity by
      polymer shape, and chelate stability by chelator selection.

PMID- 10346866
TI  - Ternary conjugates of guanosine monophosphate as initiator nucleotides for the
      enzymatic synthesis of 5'-modified RNAs.
AB  - We give a detailed account on the enzymatic synthesis of RNA conjugates by T7 RNA
      polymerase using modified initiator nucleotides during transcription. Following
      two different routes, ternary conjugates of guanosine-5'-monophosphate,
      poly(ethylene glycol), and anthracene were synthesized via phosphoramidite
      intermediates and characterized by a variety of spectroscopic techniques. Up to a
      degree of polymerization nPEG of about 17, these conjugates were efficiently
      incorporated into RNA by T7 RNA polymerase at the 5'-termini, thereby giving
      access to RNA conjugates required for biochemical studies as well as for the
      exploration of the catalytic potential of ribonucleic acids. The resulting
      conjugates are intact and functional.

PMID- 10346867
TI  - Synthesis of CpFe(CO)(L) complexes of hydantoin anions (Cp = eta5-C5H5, L = CO,
      PPh3), and the use of the 5,5-diphenylhydantoin anion complexes as tracers in the
      nonisotopic immunoassay CMIA of this antiepileptic drug.
AB  - As part of our ongoing development of the CMIA nonisotopic immunoassay method, in
      which the tracers are metal carbonyl complexes and detection is by Fourier
      transform infrared spectroscopy, we examined the potential use as tracers of the
      complexes CpFe(CO)2(5,5-diphenylhydantoin) 2d and CpFe(CO)(PPh3)(5, 5
      diphenylhydantoin) 3. The present study involved the synthesis of a series of
      hydantoin complexes (2a-2d), in particular that of the derivative of 5,5
      diphenylhydantoin 2d. The structure of 2d was confirmed by X-ray crystallography.
      The infrared analysis, establishing the position and intensity of the
      characteristic metal-carbonyl peaks of complexes 2d and 3 in the 1850-2200 cm-1
      region, shows that measurement of the absorbance values of these characteristic
      peaks will permit quantitative analysis in the picomole range, the norm for
      routine use in immunoassay and thus suitable for use as CMIA tracers. Cross
      reaction rates of these tracers with anti-DPH specific antibodies show that 2d
      and 3 are both recognized by anti-DPH antibodies (cross-reaction rates 43 and
      20%, respectively). In developing a CMIA of DPH with these tracers, it was found
      that 3, with a single, intense band at 1977 cm-1, had very promising IR
      characteristics for use in multiassay CMIA, but probably owing to its relatively
      weak affinity for the antibodies, it was not possible to develop a CMIA for DPH
      using this tracer. Complex 2d, however, showed better recognition by the
      antibodies, and using this complex as a tracer, it was possible to develop a
      particularly sensitive monoassay of DPH by the CMIA method.

PMID- 10346868
TI  - Intracellular metabolic fate of radioactivity after injection of technetium-99m
      labeled hydrazino nicotinamide derivatized proteins.
AB  - Hydrazino nicotinate (HYNIC) has been shown to produce technetium-99m (99mTc)
      labeled proteins and peptides of high stability with high specific activities.
      However, persistent localization of radioactivity was observed in nontarget
      tissues such as the liver and kidney after administration of [99mTc]HYNIC-labeled
      proteins and peptides, which compromises the diagnostic accuracy of the
      radiopharmaceuticals. Since lysosomes are the principal sites of intracellular
      catabolism of proteins and peptides, 99mTc-HYNIC-labeled galactosyl
      neoglycoalbumin (NGA) was prepared using tricine as a co-ligand to investigate
      the fate of the radiolabel after lysosomal proteolysis in hepatocytes. When
      injected into mice, over 90% of the injected radioactivity was accumulated in the
      liver after 10 min injection. At 24 h postinjection, ca. 40% of the injected
      radioactivity still remained in liver lysosomes. Size-exclusion HPLC analyses of
      liver homogenates at 24 h postinjection showed a broad radioactivity peak ranging
      from molecular masses of 0.5-50 kDa. RP-HPLC analyses of liver homogenates
      suggested the presence of multiple radiolabeled species. However, most of the
      radioactivity migrated to lower molecular weight fractions on size-exclusion HPLC
      after treatment of the liver homogenates with sodium triphenylphosphine-3
      monosulfonate (TPPMS). The TPPMS-treated liver homogenates showed a major peak at
      a retention time similar to that of [[99mTc](HYNIC-lysine)(tricine)(TPPMS)] on RP
      HPLC. Similar results were obtained with urine and fecal samples. These findings
      suggested that the chemical bonding between 99mTc and HYNIC remains stable in the
      lysosomes and following excretion from the body. The persistent localization of
      radioactivity in the liver could be attributed to the slow elimination rate of
      the final radiometabolite, [[99mTc](HYNIC-lysine)(tricine)2], from lysosomes, and
      subsequent dissociation of one of the tricine co-ligands in the low pH
      environment of the lysosomes in the absence of excess co-ligands, followed by
      binding proteins present in the organelles. The findings in this study also
      suggested that the development of appropriate co-ligands capable of preserving
      stable bonding with the Tc center is essential to reduce the residence time of
      radioactivity in nontarget tissues after administration of [99mTc]HYNIC-labeled
      proteins and peptides.

PMID- 10346869
TI  - Temperature control of biotin binding and release with A streptavidin-poly(N
      isopropylacrylamide) site-specific conjugate.
AB  - The many laboratory and diagnostic applications utilizing streptavidin as a
      molecular adaptor rely on its high affinity and essentially irreversible
      interaction with biotin. However, there are many situations where recovery of the
      biotinylated molecules is desirable. We have previously shown that poly(N
      isopropylacrylamide) (PNIPAAm), a temperature-sensitive polymer, can reversibly
      block biotin association as the polymer's conformation changes at its lower
      critical solution temperature (LCST). Here, we have constructed a streptavidin
      PNIPAAm conjugate which is able to bind biotin at room temperature or lower and
      release bound biotin at 37 degrees C. The conjugate can repeatedly bind and
      release biotin as temperature is cycled through the LCST. A genetically
      engineered streptavidin mutant, E116C, which has only one cysteine residue, was
      conjugated site specifically via the sulfhydryl groups with a PNIPAAm that has
      pendent sulfhydryl-reactive vinyl sulfone groups. The conjugation site is near
      the tryptophan 120 residue, which forms a van der Waals contact with biotin that
      is important in generating the large binding free energy. The temperature-induced
      conformational change of the polymer at position 116 may lead to structural
      changes in the region of tryptophan 120 that are responsible for the reversible
      binding between biotin and the conjugated streptavidin.

PMID- 10346870
TI  - Hemolytic activity of pH-responsive polymer-streptavidin bioconjugates.
AB  - Drug delivery systems that increase the rate and/or quantity of drug release to
      the cytoplasm are needed to enhance cytosolic delivery and to circumvent
      nonproductive cell trafficking routes. We have previously demonstrated that
      poly(2-ethylacrylic acid) (PEAAc) has pH-dependent hemolytic properties, and more
      recently, we have found that poly(2-propylacrylic acid) (PPAAc) displays even
      greater pH-responsive hemolytic activity than PEAAc at the acidic pHs of the
      early endosome. Thus, these polymers could potentially serve as endosomal
      releasing agents in immunotoxin therapies. In this paper, we have investigated
      whether the pH-dependent membrane disruptive activity of PPAAc is retained after
      binding to a protein. We did this by measuring the hemolytic activity of PPAAc
      streptavidin model complexes with different protein to polymer stoichiometries.
      Biotin was conjugated to amine-terminated PPAAc, which was subsequently bound to
      streptavidin by biotin complexation. The ability of these samples to disrupt red
      blood cell membranes was investigated for a range of polymer concentrations, a
      range of pH values, and two polymer-to-streptavidin ratios of 3:1 and 1:1. The
      results demonstrate that (a) the PPAAc-streptavidin complex retains the ability
      to lyse the RBC lipid bilayers at low pHs, such as those existing in endosomes,
      and (b) the hemolytic ability of the PPAAc-streptavidin complex is similar to
      that of the free PPAAc.

PMID- 10346871
TI  - Efficient gene transfer by histidylated polylysine/pDNA complexes.
AB  - Plasmid/polylysine complexes, which are used to transfect mammalian cells,
      increase the uptake of DNA, but plasmid molecules are sequestered into vesicles
      where they cannot escape to reach the nuclear machinery. However, the
      transfection efficiency increases when membrane-disrupting reagents such as
      chloroquine or fusogenic peptides, are used to disrupt endosomal membranes and to
      favor the delivery of plasmid into the cytosol. We designed a cationic polymer
      that forms complexes with a plasmid DNA (pDNA) and mediates the transfection of
      various cell lines in the absence of chloroquine or fusogenic peptides. This
      polymer is a polylysine (average degree of polymerization of 190) partially
      substituted with histidyl residues which become cationic upon protonation of the
      imidazole groups at pH below 6.0. The transfection efficiency was optimal with a
      polylysine having 38 +/- 5% of the epsilon-amino groups substituted with histidyl
      residues; it was not significantly impaired in the presence of serum in the
      culture medium. The transfection was drastically inhibited in the presence of
      bafilomycin A1, indicating that the protonation of the imidazole groups in the
      endosome lumen might favor the delivery of pDNA into the cytosol.

PMID- 10346872
TI  - Temperature sensitization of liposomes using copolymers of N-isopropylacrylamide.
AB  - To obtain liposomes which release the contents in response to ambient
      temperature, liposomes modified with copolymers of N-isopropylacrylamide with
      varying lower critical solution temperatures have been designed. Poly(N
      isopropylacrylamide-co-acrylamide)s with various compositions were synthesized by
      free-radical copolymerization. The lower critical solution temperature of the
      polymer increased with increasing acrylamide content in the polymer. Poly(N
      isopropylacrylamide-co-acrylamide-co-N, N-didodecylacrylamide)s were also
      prepared via the same method as the thermosensitive polymers having anchor groups
      to the liposome membrane. Calcein-loaded dioleoylphosphatidylethanolamine/egg
      yolk phosphatidylcholine (6:4, w/w) liposomes were coated with these polymers by
      incubating the liposomes with aqueous solutions of the polymers. The liposomes
      hardly released the contents below the lower critical solution temperature of the
      polymer, but the release was greatly enhanced above that temperature. The
      liposomes were also made from a mixture of the same lipids and the polymer. The
      liposome revealed a more drastic release property than the liposomes prepared by
      the incubation with the polymer solution, because the polymer chains were bound
      on both surfaces of the membrane. The close relationship between lower critical
      solution temperatures of the polymers and temperature regions where enhancement
      of the release from the polymer-fixed liposomes demonstrates that the release was
      triggered by alteration of the polymers from a hydrophilic state to a hydrophobic
      state occurring at their lower critical solution temperatures.

PMID- 10346873
TI  - Electrostatic interactions of redox cations with surface-immobilized and solution
      DNA.
AB  - Association constants for ruthenium(III) hexaamine and cobalt(III) tris(2,2'
      bipyridine) with solution and surface-immobilized DNA were determined. The
      interaction of the cationic redox molecules with calf thymus DNA was monitored
      via normal pulse voltammetry with analysis of the mass-transfer limited current
      assuming a discrete binding-site model. Single-stranded DNA was immobilized on
      gold via self-assembly of a 5' hexanethiol linker. Double-stranded surface
      immobilized DNA was produced by hybridization of a complementary target to
      surface-immobilized single strands. The interaction between the metal complexes
      and surface-immobilized DNA was determined using chronocoulometry to construct
      adsorption isotherms. The measured binding constants for the cationic redox
      molecules with solution, surface-immobilized single-stranded, and double-stranded
      DNA are well-correlated, even as a function of ionic strength. The agreement
      between the determined association constants for the surface-immobilized and
      solution DNA indicates the potential utility of DNA-derivatized electrodes for
      examination of small molecule interactions with nucleic acids.

PMID- 10346874
TI  - Site-specific modification of a single-chain antibody using a novel glyoxylyl
      based labeling reagent.
AB  - A novel, highly specific protein modification approach is described. By using
      conventional molecular cloning techniques, a protein can be constructed and
      expressed such that the N-terminal residue is replaced by cysteine. Its 1,2
      aminothiol structure reacts very specifically with a glyoxylyl group at pH 7 or
      below, forming a relatively stable thiazolidine bridge. Therefore, a glyoxylyl
      based labeling agent (e.g., radioactive tags, fluorescent probes, biotin) can be
      used to specifically modify a protein at its N-terminus. To highlight this novel
      approach, a recombinant anti-insulin single chain antibody (scFv) was
      specifically biotinylated at its N-terminus even in the presence of other
      proteins in the total cell lysate. The glyoxylyl-biotinylated scFv retained
      binding activity similar to unmodified scFv.

PMID- 10346875
TI  - Preparation, 99mTc-labeling, and in vitro characterization of HYNIC and N3S
      modified RC-160 and [Tyr3]octreotide.
AB  - The synthesis of conjugates of two somatostatin analogues, RC-160 and
      [Tyr3]octreotide with different bifunctional chelators for labeling with Tc-99m,
      is described. Conjugates with hydrazinonicotinamide (HYNIC) and two N3S compounds
      (benzoyl MAG3 and a N3S adipate derivative) were prepared on a small scale with
      high purity allowing evaluation of different bifunctional chelators on the same
      peptide without extensive peptide synthesis. High in vitro stability and retained
      binding affinity was found for all conjugates except for the N3S adipate. Peptide
      conjugates could be labeled at high specific activities (>1 Ci/micromol) with
      99mTc, and different coligands were explored for the HYNIC conjugates. The
      resulting radiolabeled complexes were highly stable and showed binding affinity
      to somatostatin receptors in the nanomolar range. Varying labeling yield,
      stability, lipophilicity, and isomerism were found for different coligands used
      for labeling HYNIC conjugates, with lower lipophilicity, higher stability, and
      fewer coordination isomers for EDDA and tricine/nicotinic acid as ternary
      coligand compared to tricine. In particular, HYNIC complexes showed promising
      results for further in vivo evaluation.

PMID- 10346876
TI  - Recognition of hairpin-containing single-stranded DNA by oligonucleotides
      containing internal acridine derivatives.
AB  - Oligodeoxynucleotides with an internal intercalating agent have been targeted to
      single-stranded sequences containing hairpin structures. The oligonucleotide
      binds to nonadjacent single-stranded sequences on both sides of the hairpin
      structure in such a way as to form a three-way junction. The acridine derivative
      is inserted at a position that allows it to interact with the three-way junction.
      The melting temperature (Tm) of complexes formed between the hairpin-containing
      target and oligonucleotides containing one internal acridine derivative was
      higher than that obtained with the same target and an unmodified oligonucleotide
      (DeltaTm = +13 degrees C). The internal acridine provided the oligonucleotide
      with a higher affinity than covalent attachment to the 5' end. Oligonucleotides
      could also be designed to recognize a hairpin-containing single-stranded nucleic
      acid by formation of Watson-Crick hydrogen bonds with a single-stranded part and
      Hoogsteen hydrogen bonds with the stem of the hairpin. An internal acridine
      derivative was introduced at the junction between the two domains, the double
      helix domain with Watson-Crick base pairs and the triple helix domain involving
      Hoogsteen base triplets in the major groove of the hairpin stem. Oligonucleotides
      with an internal acridine or an acridine at their 5' end have similar binding
      affinities for the stem-loop-containing target. The bis-modified oligonucleotide
      containing two acridines, one at the 5' end and one at an internal site, did not
      exhibit a higher affinity than the oligonucleotides with only one intercalating
      agent. The design of oligonucleotides with an internal intercalating agent might
      be of interest to control gene expression through recognition of secondary
      structures in single-stranded targets.

PMID- 10346878
TI  - NMR studies of the metal-loading kinetics and acid-base chemistry of DOTA and
      butylamide-DOTA.
AB  - The conjugation of a chelating agent to a protein via a covalent linkage has been
      previously reported to change the metal-binding characteristics of the chelator.
      A fundamental understanding of these binding changes would enable design of a new
      generation of metal-chelating agents for biological applications. To assess the
      effect of conjugation on the commonly used chelating agent 1 4,7, 10
      tetraaazacyclododecane-N,N',N'',N'''-tetraaacetic acid (DOTA), we synthesized a
      model protein conjugate, 1,4, 7-tris(carboxymethyl)-10-(butylaminocarboxymethyl)
      1,4,7, 10-tetraaazacyclododecane (BD) and explored the metal-binding
      characteristics via NMR. The extent of ionization of the carboxylic acid groups
      and the two protonated macrocycle nitrogens of DOTA and BD were determined as a
      function of pH by chemical shift changes in proximal carbon-bonded protons. In
      addition to the expected sensitivity of the chemical shifts to titration of
      proximate acidic groups, BD resonances from carbon-bonded protons 10-17 bonds
      distant from the deprotonation site also shifted significantly, indicating the
      presence of conformational changes. Furthermore, increased shielding of the amide
      and alkyl proton signals upon deprotonation of the carboxylic acid groups
      indicates the presence of pH-dependent hydrogen-bonded BD isoforms. On the basis
      of these NMR data, we propose new structures for the doubly protonated forms of
      DOTA and BD. To measure metal loading, the yttrium-loading rates (type I to type
      II) of DOTA and BD were determined by following the intensity of type I and type
      II proton signals as a function of time. The yttrium-loading rates of BD are
      approximately one-half those of DOTA at pHs between 4.6 and 6.5 and 37 degrees C.
      The loading rates measured as a function of pH indicate that while both the
      doubly protonated and singly protonated forms of DOTA are reactive to metal
      loading, only the singly protonated form of BD is reactive.

PMID- 10346877
TI  - Chemical modification to reduce renal uptake of disulfide-bonded variable region
      fragment of anti-Tac monoclonal antibody labeled with 99mTc.
AB  - The anti-Tac disulfide-bonded variable region fragment (dsFv) is a genetically
      engineered, 25 kDa, murine monoclonal antibody fragment that recognizes the alpha
      subunit of the interleukin-2 receptor (IL-2Ralpha). The dsFv radiolabeled with
      the tetrafluorophenyl ester (TFP) of [99mTc]mercaptoacetyltriglycine ([99mTc]MAG3
      TFP) showed rapid tumor uptake and fast blood clearance in mice, resulting in
      high tumor-to-nontumor background ratios. However, its high renal uptake was a
      problem. In this study, we tested the effect of lowering the isoelectric point
      (pI) of dsFv to <9.3 on renal and tumor uptake. To lower the pI, dsFv was
      acylated simultaneously with both [99mTc]MAG3-TFP and TFP-glycolate. The
      acylation of dsFv decreased its pI and its immunoreactivity inversely
      proportional to the molar ratio of TFP-glycolate to dsFv, whereas the conjugation
      of [99mTc]MAG3-TFP alone did not. When biodistribution studies were performed in
      nude mice, the effect of the lowered pI was reflected primarily in decreased
      kidney uptake and whole-body retention, with its highest effect seen at the
      earliest time point (15 min) after injection. In tumor-bearing nude mice,
      glycolated [99mTc]MAG3-dsFv with a pI range of 4.9 to 6.5 accumulated selectively
      into IL-2 receptor-positive SP2/Tac tumor similar to that of the control
      [125I]dsFv labeled by the Iodo-Gen method, whereas its renal uptake was 25% of
      [125I]dsFv at 15 min. At 90 min, the ratios of tumor to receptor-negative SP2/0
      tumor, liver, kidney, stomach, and blood had peaked at 10.9, 8.5, 0.3, 5.0, and
      6.2, respectively, for the glycolated [99mTc]MAG3-dsFv. The corresponding ratios
      for [125I]dsFv were 3.7, 5.0, 0.1, 1.5, and 2.1, respectively.

PMID- 10346879
TI  - A synthetic cysteine oxidase based on a ferrocene-cyclodextrin conjugate.
AB  - We report a novel synthetic cysteine oxidase consisting of a ferrocene-beta
      cyclodextrin conjugate in which the ferrocene moiety is bound to the secondary
      hydroxyl side of the cyclodextrin cavity through an ethylenediamine linker.
      Cysteine oxidation occurs after the ferrocene group is electrochemically oxidized
      to the ferricinium form, and this generates a voltammetric electrocatalytic wave,
      the magnitude of which is related to the rate constant for cysteine oxidation.
      Comparison of cysteine oxidation rates for the primary and secondary beta
      cyclodextrin derivatives (105 and 1470 M-1 s-1, respectively) shows that the
      secondary derivatives are more effective synthetic enzymes. Substrate selectivity
      of the secondary derivative is demonstrated by comparison of oxidation rates for
      cysteine (1470 M-1 s-1) and glutathione (260 M-1 s-1) at pH 7.0. The rate
      constant for cysteine oxidation was 3-fold higher at pH 8.0. With a constant
      synthetic enzyme concentration, electrocatalytic limiting currents increased
      linearly with increasing cysteine concentration to a maximum at 6 mM cysteine;
      above this concentration, the current decreased significantly. These and other
      results suggest that product inhibition of the catalytic cycle occurs as a result
      of cystine binding more strongly to the cyclodextrin than cysteine.

PMID- 10346880
TI  - An N2S2 bifunctional chelator for technetium-99m and rhenium: complexation,
      conjugation, and epimerization to a single isomer.
AB  - A bifunctional chelator 6 was prepared bearing an N2S2 core for binding rhenium
      or technetium and a carboxylic acid group for conjugation to amino groups of
      biomolecules. Complexation of 6 with rhenium(V) resulted in two kinetic isomers,
      anti-7 and syn-7, being formed in approximately equal amounts. Epimerization with
      0.5 M NaOH yields a single isomer anti-7, as determined by NMR spectroscopy and
      single-crystal X-ray analysis. The 99mTc complex was prepared at the tracer level
      by reaction of the ligand with 99mTcO4-, tin(II) chloride and sodium gluconate
      giving a mixture of two isomers, but showing a preference for the anti isomer.
      Chelation in the presence of 1 M NaOH results in anti-8 being formed as the sole
      product. The bifunctional ability of the ligand was explored by amide formation
      with (S)-alpha-phenethylamine, either by direct DCC coupling or through the N
      hydroxy succinimidyl ester 9 intermediate. The deprotected bioconjugate 11 was
      complexed with rhenium, yielding similar amounts of two isomeric rhenium
      complexes, anti-12 and syn-12, which were isolated and characterized by NMR
      spectroscopy. Treatment of the kinetic mixture of anti-12 and syn-12 with 1 M
      NaOH resulted in quantitative conversion to a single rhenium complex anti-12.
      With technetium-99m in 0.1 M sodium acetate, bioconjugate 11 yielded both
      technetium-99m complexes anti-13 and syn-13, in a 2:1 ratio, respectively. In
      contrast, complexation in the presence of 1 M NaOH gave only one technetium-99m
      complex, assigned the structure anti-13.

PMID- 10346882
TI  - Technetium-99m-labeled medium-chain fatty acid analogues metabolized by beta
      oxidation: radiopharmaceutical for assessing liver function.
AB  - External imaging of energy production activity of living cells with 99mTc-labeled
      compounds is a challenging task requiring good design of 99mTc
      radiopharmaceuticals. On the basis of our recent findings that 11C- and 123I
      labeled medium-chain fatty acids are useful for measuring beta-oxidation activity
      of hepatocytes, we focused on development of 99mTc-labeled medium-chain fatty
      acid analogues that reflect beta-oxidation activity of the liver. In the present
      study, monoamine-monoamide dithiol (MAMA) ligand and triamido thiol (MAG) ligand
      were chosen as chelating groups because of the stability and size of their
      complexes with 99mTc and their ease of synthesis. Each ligand was attached to the
      omega-position of hexanoic acid (MAMA-HA and MAG-HA, respectively). In
      biodistribution studies, [99mTc]MAMA-HA showed high initial accumulation in the
      liver followed by clearance of the radioactivity in the urine. Analysis of the
      urine revealed [99mTc]MAMA-BA as the sole radiometabolite. Furthermore, when
      [99mTc]MAMA-HA was incubated with living liver slices, generation of [99mTc]MAMA
      BA was observed. However, [99mTc]MAMA-HA remained intact when the compound was
      incubated with liver slices in the presence of 2-bromooctanoate, an inhibitor of
      beta-oxidation. The findings in this study indicated that [99mTc]MAMA-HA was
      metabolized by beta-oxidation after incorporation into the liver. On the other
      hand, poor hepatic accumulation was observed after administration of [99mTc]MAG
      HA.

PMID- 10346881
TI  - Multivalent thioether-peptide conjugates: B cell tolerance of an anti-peptide
      immune response.
AB  - Antibodies which bind beta2-glycoprotein I (beta2GPI) are associated with
      antiphospholipid syndrome. Synthetic peptide mimotopes have been discovered which
      compete with beta2GPI for binding to selected anti-beta2GPI. A thiol-containing
      linker was attached to the N-terminus of two cyclic thioether peptide mimotopes,
      peptides 1a and 1b. The resulting peptides, with linker attached, were reacted
      with two different haloacetylated platforms to prepare four tetravalent peptide
      platform conjugates to be tested as B cell toleragens. The linker-containing
      peptides were reacted with maleimide-derivatized keyhole limpet hemocyanin (KLH)
      to provide peptide-KLH conjugates. Peptides 1a and 1b were also modified by
      acylation with 3-(4'-hydroxyphenyl)propionic acid N-hydroxysuccinimidyl ester.
      The resulting hydroxyphenyl peptides were radioiodinated and used to measure anti
      peptide antibody levels. The KLH conjugates were used to immunize mice to
      generate an anti-peptide immune response. The immunized mice were treated with
      the conjugates or saline solution and boosted with the appropriate peptide-KLH
      conjugate. Three of the four conjugates suppressed the formation of anti-peptide
      antibody. The stabilities of the conjugates in mouse serum were measured, and the
      relative stabilities did not correlate with ability to suppress antibody
      formation.

PMID- 10346883
TI  - Purified protein derivative (PPD) as an immunogen carrier elicits high antigen
      specificity to haptens.
AB  - The effectiveness of the carrier protein in eliciting antigen-specific antibodies
      was investigated. The effect of the carrier protein was independent of the
      conjugation chemistry involved. Keyhole limpet hemocyanin (KLH), purified protein
      derivative (PPD), and ovalbumin (OVA) were used as carrier proteins in the
      immunization of mice. Three antigens were studied: LY170881 (a small drug
      molecule), 4-[1'-cyanobenz(f)isoindolyl]butyric acid (CBI-butyric acid), and a
      seven residue peptide GPGRGPG (KLE1). The serum antibody response to the antigen
      or antigen:BSA conjugate was superior in the case where the PPD:antigen
      conjugates were used as the immunogen when compared to KLH and OVA. The
      specificity of the antibodies to the respective antigens vs cross-reactivity with
      the carrier protein was investigated. PPD-coupled antigen immunized mice
      generated a higher percentage of antigen-specific hybridomas compared to the
      other carrier proteins. These findings confirmed PPD as the best carrier molecule
      for the production of both polyclonal and monoclonal antibodies.

PMID- 10346885
TI  - Proximity of a Tat peptide to the HIV-1 TAR RNA loop region determined by site
      specific photo-cross-linking.
AB  - Transcriptional regulation in human immunodeficiency virus type 1 (HIV-1)
      requires specific interactions of Tat protein with the trans-activation
      responsive region (TAR) RNA, a 59-base stem-loop structure located at the 5'-ends
      of all HIV-1 mRNAs. We have used a site-specific cross-linking method based on 4
      thio-uracil (4-thioU) photochemistry to determine the interactions of a Tat
      peptide, Tat(38-72), with the loop region of TAR RNA under physiological
      conditions. A TAR RNA construct with a single 4-thioU residue at positions U31 in
      the loop sequence was synthesized by chemical methods. Upon UV irradiation, 4
      thioU at U31 formed a covalent cross-link with the Tat peptide. We did not
      observe any RNA-RNA cross-link formation. Competition experiments revealed that a
      specific RNA-protein complex formation was necessary for the RNA-protein cross
      linking reaction. Our results demonstrate that, during RNA-protein recognition,
      the Tat peptide is located in close proximity to O4 of U31 in the TAR RNA loop
      sequence.

PMID- 10346884
TI  - Epidermal growth factor radiopharmaceuticals: 111In chelation, conjugation to a
      blood-brain barrier delivery vector via a biotin-polyethylene linker,
      pharmacokinetics, and in vivo imaging of experimental brain tumors.
AB  - Epidermal growth factor (EGF) is a potential peptide radiopharmaceutical for
      detection of brain tumors, because many human gliomas overexpress the EGF
      receptor (EGFR). The transport of EGF to the brain, however, is restricted by the
      blood-brain barrier (BBB). The purpose of the present study was to develop a
      vector-mediated brain delivery system for radiolabeled EGF. Human EGF was
      monobiotinylated with NHS-PEG3400-biotin, where NHS is N-hydroxysuccinimide and
      PEG3400 is poly(ethylene glycol) of 3400 Da molecular mass. EGF-PEG3400-biotin
      was radiolabeled with either 125I or 111In through the metal chelator,
      diethylenetriaminepentaacetic acid (DTPA). The radiolabeled EGF was then
      conjugated to a BBB delivery vector comprised of a complex of the OX26 monoclonal
      antibody (MAb) to the rat transferrin receptor, which was coupled to streptavidin
      (SA). Following intravenous injection in rats, the 125I conjugate was rapidly
      degraded in vivo, while the 111In conjugate was metabolically stable. The brain
      delivery of [111In]DTPA-EGF-PEG3400-biotin was enabled by conjugation with
      OX26/SA and was optimized by co-injection of unlabeled EGF to saturate EGF
      receptors in the liver. The specific binding of the [111In]DTPA-EGF-PEG3400
      biotin conjugated to OX26/SA to the EGF receptor was confirmed in C6 rat glioma
      cells, which had been transfected with a gene encoding for the human EGF receptor
      under the regulation of a dexamethasone-inducible promoter. In vivo studies of C6
      EGFR experimental tumors in Fischer 344 rats demonstrated successful brain
      imaging only when the peptide radiopharmaceutical was conjugated to the BBB
      delivery system, although the C6-EGFR tumors did not express EGFR in vivo. In
      conclusion, these studies describe the molecular formulation of a peptide
      radiopharmaceutical that can be used for imaging brain tumors behind the BBB.

PMID- 10346887
TI  - 5-[3-(E)-(4-azido-2,3,5,6-tetrafluorobenzamido)propenyl-1]-2'-deoxy- uridine-5'
      triphosphate substitutes for thymidine-5'-triphosphate in the polymerase chain
      reaction.
AB  - The DNA targets may be labeled and simultaneously amplified in the polymerase
      chain reaction (PCR) using a pair of respective primers after elongation with
      nucleoside-5'-triphosphates carrying photoreactive groups. The amplified DNA may
      be subsequently photoactivated by irradiation above 300 nm, resulting in photo
      cross-linking of the strands. For this goal 5-[3-(E)-(4-azido-2,3,5,6
      tetrafluorobenzamido)propenyl-1]-, 5-{N-[N'-(4-azido-2,3,5, 6-tetrafluorobenzoyl)
      3-aminopropionyl]aminomethyl}-, and 5-{N-[N'-(2-nitro-5-azidobenzoyl)-3
      aminopropionyl]aminomethyl}-2'-de oxyuridine-5'-triphosphate (VII, VIa, and VIb)
      derivatives have been synthesized. It was found that VII is capable of
      efficiently elongating DNA primers with both Klenow fragment DNA polymerase I and
      Thermus aquaticus DNA polymerase. Thereto, it turned out to provide quantitative
      incorporation in DNA as revealed by the formation of the full-length amplificate
      by PCR in the presence of this photoreactive analogue without any dilution with
      natural dTTP. On the contrary, it was found, that incorporation of VIa and VIb do
      not permit further DNA replication.

PMID- 10346886
TI  - Accelerated clearance of polyethylene glycol-modified proteins by anti
      polyethylene glycol IgM.
AB  - Tumor therapy by the preferential activation of a prodrug at tumor cells targeted
      with an antibody-enzyme conjugate may allow improved treatment efficacy with
      reduced side effects. We examined antibody-mediated clearance of poly(ethylene
      glycol)-modified beta-glucuronidase (betaG-sPEG) as a method to reduce serum
      concentrations of enzyme and minimize systemic prodrug activation. Enzyme-linked
      immunosorbent assay and immunoblot analysis of two monoclonal antibodies
      generated by immunization of BALB/c mice with an antibody-betaG-sPEG conjugate
      showed that mAb 1E8 (IgG1) bound betaG and betaG-sPEG whereas mAb AGP3 (IgM)
      bound poly(ethylene glycol). Neither antibody affected the betaG activity. mAb
      1E8 and AGP3 were modified with 36 and 208 galactose residues (1E8-36G and AGP3
      208G) with retention of 72 and 48% antigen-binding activity, respectively, to
      target immune complexes to the asialoglycoprotein receptor on liver cells. mAb
      1E8 and AGP3 cleared betaG-PEG from the circulation of mice as effectively as 1E8
      36G and AGP3-208G, respectively. mAb AGP3, however, cleared betaG-sPEG more
      completely and rapidly than 1E8, reducing the serum concentration of betaG-sPEG
      by 38-fold in 8 h. AGP3 also reduced the concentration of an antibody-betaG-sPEG
      conjugate in blood by 280-fold in 2 h and 940-fold in 24 h. AGP3-mediated
      clearance did not produce obvious damage to liver, spleen, or kidney tissues. In
      addition, AGP3 clearance of betaG-sPEG before administration of BHAMG, a
      glucuronide prodrug of p-hydroxyaniline mustard, prevented toxicity associated
      with systemic activation of the prodrug based on mouse weight and blood cell
      numbers. AGP3 should be generally useful for accelerating the clearance of PEG
      modified proteins as well as for improving the tumor/blood ratios of antibody
      betaG-PEG conjugates for glucuronide prodrug therapy of cancer.

PMID- 10346888
TI  - Direct observation of fibrinogen-heparinoid complexes formation using surface
      plasmon resonance.
AB  - We analyzed the binding of heparinoid or heparin with fibrinogen by real-time
      measurement using surface plasmon resonance technology. Poly(glucosyloxyethyl
      methacrylate) sulfate [poly(GEMA) sulfate] and dextran sulfate were used as
      heparinoids. The binding ability of each sulfated polymer was estimated by having
      each polymer-containing buffer interact with the sensor chip surfaces that had
      immobilized fibrinogen. Dextran sulfate and poly(GEMA) sulfate showed high
      affinity to the fibrinogen in this experiment, while the heparin did not. All of
      the dextran sulfates were desorbed from its surface, while about 30% of the
      poly(GEMA) sulfate remained on the immobilized fibrinogen upon the addition of
      NaCl to the buffer which was done in order to analyze the desorption of
      poly(GEMA) sulfate or dextran sulfate from the surface of the fibrinogen. These
      data show that the type of binding between fibrinogen-poly(GEMA) sulfate was
      different from that of dextran sulfate, indicating that the interaction between
      fibrinogen and poly(GEMA) sulfate was caused not only by an electrostatic but
      also by a hydrophobic force. These results suggest that the interaction mechanism
      of heparinoids with fibrinogen was different from that of heparin.

PMID- 10346889
TI  - Chemoenzymatic synthesis of 3'-O-(carboxyalkyl)fluorescein labels.
AB  - A general and versatile method is described for the synthesis of fluorescent
      labels. Coupling of the 3'-phenol of fluorescein methyl ester with hydroxyalkyl
      benzyl esters, followed by benzyl ester hydrolysis, provided a series of
      fluorescein carboxyalkyl ethers. Use of the Mitsunobu reaction allowed for the
      introduction of linkers of different lengths onto the 3'-phenol of fluorescein.
      Chemoenzymatic benzyl ester hydrolysis was achieved with LPL-80 lipase, providing
      pH-independent labels useful for the preparation of fluorescent conjugates.

PMID- 10346890
TI  - Synthesis of novel cationic poly(ethylene glycol) containing lipids.
AB  - In this paper, the synthesis of novel divalent cationic lipids with poly(ethylene
      glycol) segments is described. The lipids consist of an unsaturated double-chain
      hydrophobic moiety based on 3, 4-dihydroxy benzoic acid, attached to a
      hydrophilic poly(ethylene glycol) spacer which contains a divalent cationic end
      group. As poly(ethylene glycol) spacers monodisperse triethylene glycol and
      telechelic poly(ethylene glycol)s with an average degree of polymerization of 9,
      23, and 45 were used. The divalent cationic end group was attached by coupling a
      protected dibasic amino acid to the PEG spacer and following cleavage of the
      protecting groups. These novel class of cationic lipids is of particular interest
      for nonviral gene delivery applications.

PMID- 10346891
TI  - Ligand-induced conformational changes in lactose repressor: a phosphorescence and
      ODMR study of single-tryptophan mutants.
AB  - Phosphorescence and optically detected magnetic resonance (ODMR) measurements are
      reported on four single-tryptophan mutants of lac repressor protein from
      Escherichia coli: H74W/Wless, W201Y, Y273W/Wless, and F293W/Wless, where Wless
      represents a protein background containing the double mutation W201Y/W220Y. The
      single-tryptophan residues are located in the protein core region, either in the
      monomer-monomer interface of the tetrameric protein or in the region of the
      inducer binding cleft. Inducer binding elicits large changes in the energy (0,0
      band wavelength shifts) and zero-field splitting energies (ZFS) of the triplet
      states for each of the mutant proteins except W201Y which exhibits more modest
      effects. F293W/Wless exists in two distinguishable conformations, only one of
      which appears to be sensitive to the presence of inducer. These effects of
      inducer binding can be attributed to a conformational change that alters specific
      polar interactions that occur at each affected tryptophan site. Changes in the
      tryptophan triplet state indicator depend on the existence of specific polar
      interactions that are altered by local atomic relocations.

PMID- 10346892
TI  - Molecular recognition between a new pentacyclic acridinium salt and DNA sequences
      investigated by optical spectroscopic techniques, proton nuclear magnetic
      resonance spectroscopy, and molecular modeling.
AB  - A pentacyclic acridine, 1H-2,3-dihydroindolizino[7,6,5-kl]acridinium chloride
      (1), related in structure to tetra- and pentacyclic marine natural products, has
      previously been shown to induce apoptosis in breast and non-small-cell lung tumor
      cell lines and shows significant differences in biological potency and antitumor
      profile from other intercalating agents based on the acridine framework. We
      report on the molecular recognition of the acridinium salt with DNA, quantified
      by optical spectroscopic methods, and have compared these results with the
      clinical agent amsacrine (m-AMSA). The results point to an intercalative
      association between 1 and G-C-rich sequences of DNA. We have synthesized a
      hexamer duplex d(ACGCGT)2, presenting two potential 5'-CpG recipient sites, and
      have investigated in detail by NMR and molecular modeling methods the
      orientational preferences of 1, particularly with regard to the pyrrolidine ring
      system. On the basis of the intermolecular nuclear Overhauser effect (NOE) data,
      four possible intercalation models were considered; no single model produced a
      significantly better fit than any of the others. The best fit to the experimental
      data was obtained by considering a dynamic equilibrium between the different
      intercalated orientations with the drug maximizing pi-overlap with the G-C base
      pairs at the intercalation site. We found little evidence for any degree of
      groove specificity imparted by the pyrrolidine ring. If these simulations have
      biological relevance they suggest that, at most, the agent induces only a
      transitory hot spot in the DNA which, evidently, is sufficient to be sensed by
      damage-recognition mechanisms of the cell.

PMID- 10346893
TI  - Kinetic and thermodynamic analysis of 9-cis-retinoic acid binding to retinoid X
      receptor alpha.
AB  - The interaction of retinoid X receptor alpha with 9-cis-retinoic acid was studied
      using stopped-flow fluorescence spectroscopy. Transient kinetic analyses of this
      interaction suggest a two-step binding mechanism involving a rapid, enthalpically
      driven pre-equilibrium followed by a slower, entropically driven reaction that
      may arise from a conformational change within the ligand binding domain of the
      receptor. The assignment of this kinetic mechanism was supported by agreement
      between the overall equilibrium constant, Kov, derived from kinetic studies with
      that determined by equilibrium fluorescence titrations. Although these analyses
      do not preclude ligand-induced alteration in the oligomerization state of the
      receptor in solution, the simplest model that can be applied to these data
      involves the stoichiometric interaction of 9-cis-retinoic acid with retinoid X
      receptor alpha monomers.

PMID- 10346894
TI  - Effects of chirality at Tyr13 on the structure-activity relationships of omega
      conotoxins from Conus magus.
AB  - The effects of chirality inversions of Tyr13 on the structure-activity
      relationships of omega-conotoxins MVIIA and MVIIC were examined using a
      combination of 2D 1H NMR spectroscopy and radioligand binding studies specific
      for N-type ([125I]GVIA) and P/Q-type ([125I]MVIIC) voltage-sensitive calcium
      channels (VSCCs). A comparison of the Halpha secondary shifts suggests that the
      structural scaffolds of MVIIA and MVIIC are little altered by the L- to D-
      inversion of Tyr13; however, the conformations of several residues in loop 2
      (residues 9-14) are significantly altered. The experimentally determined 3D
      structure of [D-Y13]MVIIA indicates that the positions of key residues in this
      loop which are involved in the binding of MVIIA to the N-type VSCC (Tyr13, Arg10,
      and Leu11) are so changed as to render the peptide unrecognizable by its cognate
      ion channel. The large reduction in potency observed for MVIIA and MVIIC at both
      N-type and P/Q-type VSCCs is likely to stem from the change in conformation and
      orientation of loop 2.

PMID- 10346895
TI  - Global conformational changes control the reactivity of methane monooxygenase.
AB  - We present here X-ray scattering data that yield new structural information on
      the multicomponent enzyme methane monooxygenase and its components: a hydroxylase
      dimer, and two copies each of a reductase and regulatory protein B. Upon
      formation of the enzyme complex, the hydroxylase undergoes a dramatic
      conformational change that is observed in the scattering data as a fundamental
      change in shape of the scattering particle such that one dimension is narrowed
      (by 25% or 24 A) while the longest dimension increases (by 20% or 25 A). These
      changes also are reflected in a 13% increase in radius of gyration upon complex
      formation. Both the reductase and protein B are required for inducing the
      conformational change. We have modeled the scattering data for the complex by
      systematically modifying the crystal structure of the hydroxylase and using
      ellipsoids to represent the reductase and protein B components. Our model
      indicates that protein B plays a role in optimizing the interaction between the
      active centers of the reductase and hydroxylase components, thus, facilitating
      electron transfer between them. In addition, the model suggests reasons why the
      hydroxylase exists as a dimer and that a possible role for the outlying gamma
      subunit may be to stabilize the complex through its interaction with the other
      components. We further show that proteolysis of protein B to form the inactive B'
      results in a conformational change and B' does not bind to the hydroxylase. The
      truncation thus could represent a regulatory mechanism for controlling the enzyme
      activity.

PMID- 10346896
TI  - Contribution of a buried hydrogen bond to lambda repressor folding kinetics.
AB  - A hydrogen bond between the buried residues Asp 14 and Ser 77 in monomeric lambda
      repressor has been removed by mutation of these residues to alanine. Double
      mutant cycles show that the interaction stabilizes the native state of the
      protein by 1.5 kcal/mol. Removal of the interaction affects mainly the unfolding
      rates and not the folding rates, suggesting that this hydrogen bond is not
      substantially formed in the rate-limiting steps in the folding pathways of the
      protein. Mutations in two versions of lambda6-85, wild type and the faster
      folding G46A/G48A (WT), show similar effects. Diffusion-collision correctly
      predicts the behavior of WT but not of wild type. Our analysis suggests that
      folding of helix 3 is a crucial slow step along the various folding pathways and
      generally occurs before the formation of the 14-77 hydrogen bond. Experiments
      removing tertiary interactions, combined with experiments altering helical
      stability and diffusion-collision calculations, provide a strategy to unravel the
      folding mechanisms of small helical proteins.

PMID- 10346897
TI  - Different types of maize histone deacetylases are distinguished by a highly
      complex substrate and site specificity.
AB  - Enzymes involved in histone acetylation have been identified as important
      transcriptional regulators. Maize embryos contain three histone deacetylase
      families: RPD3-type deacetylases (HD1-B), nucleolar phosphoproteins of the HD2
      family, and a third form unrelated to RPD3 and HD2 (HD1-A). Here we first report
      on the specificity of deacetylases for core histones, acetylated histone H4
      subspecies, and acetylated H4-lysine residues. HD1-A, HD1-B, and HD2 deacetylate
      all four core histones, although with different specificity. However, experiments
      with histones from different sources (hyperacetylated MELC and chicken histones)
      using antibodies specific for individually acetylated H4-lysine sites indicate
      that the enzymes recognize highly distinct acetylation patterns. Only RPD3-type
      deacetylase HD1-B is able to deacetylate the specific H4 di-acetylation pattern
      (position 12 and 5) introduced by the purified cytoplasmic histone
      acetyltransferase B after incubation with pure nonacetylated H4 subspecies. HD1-A
      and HD2 exist as phosphorylated forms. Dephosphorylation has dramatic, but
      opposite effects; whereas HD2 loses enzymatic activity upon dephosphorylation,
      HD1-A is activated with a change of specificity against acetylated H4 subspecies.
      The data suggest that different types of deacetylases interact with different and
      highly specific acetylation patterns on nucleosomes.

PMID- 10346898
TI  - Binding-dependent disorder-order transition in PKI alpha: a fluorescence
      anisotropy study.
AB  - The conformational flexibility of peptidyl ligands may be an essential element of
      many peptide-macromolecular interactions. Consequently, the alpha-carbonyl
      backbone flexibility of the 8 kDa protein kinase inhibitor (PKI alpha) peptide of
      cAMP-dependent protein kinase (cAPK) free in solution and bound to cAPK was
      assessed by time-resolved fluorescence anisotropy. Specifically, three full
      length, single-site PKI alpha mutants (V3C, S28C, and S59C) were prepared, and
      fluorescein iodoacetamide (FI) was selectively conjugated to the side chains of
      each substituted cysteine. The time-resolved anisotropy decay profiles of the
      labeled mutants were well fit to a model-free nonassociative biexponential
      equation. Free in solution, the three labeled proteins had very similar
      anisotropy decays arising primarily from local alpha-carbonyl backbone movements.
      Only a small fraction of the anisotropy decay was associated with slower, whole
      body tumbling, confirming that PKI alpha is highly disordered at all three
      locations. Complexation of the mutants with the catalytic (C) subunit of cAPK
      decreased the rate of whole-body tumbling for all three mutants. The effects on
      the rapid decay processes, however, were dependent upon the site of conjugation.
      The anisotropy decay profiles of both FI-V3C- and FI-S28C-PKI alpha were
      associated with significantly reduced contributions from the fast decay
      processes, while that of FI-S59C-PKI alpha was largely unaffected by binding to
      the C-subunit. The results suggest that the cAPK-binding domain of PKI alpha
      extends from the its N-terminus to residues beyond Ser28 but does not include the
      segment around Ser59, which is still part of a highly flexible domain when bound
      to the C-subunit.

PMID- 10346899
TI  - DNA modifications by a novel bifunctional trinuclear platinum phase I anticancer
      agent.
AB  - The DNA-binding profile of a novel, trinuclear platinum Phase I clinical agent
      (BBR3464) is summarized. The structure of BBR3464 is best described as two trans
      [PtCl(NH3)2] units linked by a tetra-amine [trans-Pt(NH3)2{H2N(CH2)6NH2}2]2+
      unit. The +4 charge of BBR3464, the presence of at least two Pt coordination
      units capable of binding to DNA, and the consequences of such DNA binding are
      remarkable departures from the cisplatin structural paradigm. The chemical and
      biological features argue that the drug should be considered the first clinical
      representative of an entirely new structural class of DNA-modifying anticancer
      agents. The high charge on BBR3464 facilitates rapid binding to DNA with a t1/2
      of approximately 40 min, significantly faster than the neutral cisplatin. The
      melting temperature of DNA adducted by BBR3464 increased at low ionic strength
      but decreased in high salt for the same rb. This unusual behavior is in contrast
      to that of cisplatin. BBR3464 produces an unwinding angle of 14 degrees in
      negatively supercoiled pSP73 plasmid DNA, indicative of bifunctional DNA binding.
      Quantitation of interstrand DNA-DNA cross-linking in plasmid pSP73 DNA linearized
      by EcoRI indicated approximately 20% of the DNA to be interstrand cross-linked.
      While this is significantly higher than the value for cisplatin, it is,
      interestingly, lower than that for dinuclear platinum compounds such as [{trans
      PtCl(NH3)2}2H2N(CH2)6NH2]2+ (BBR3005) where interstrand cross-linking efficiency
      may be as high as 70-90%. Either the presence of charge in the linker backbone or
      the increased distance between platinating moieties may contribute to this
      relatively decreased ability of BBR3464 to induce DNA interstrand cross-linking.
      Fluorescence experiments with ethidium bromide were consistent with the formation
      of long-range delocalized lesions on DNA produced by BBR3464. The sequence
      preference for BBR3464 on plasmid DNA was determined to the exact base pair by
      assaying extension of the polynucleotide by VentR(exo+) DNA polymerase. Strong
      sequence preference for single dG or d(GG) sites was suggested. The presence of
      relatively few blocks on DNA in comparison to either cisplatin or BBR3005 was
      indicative of high sequence selectivity. The following appropriate sequence where
      stop sites occur was chosen: [sequence: see text] molecular modeling on 1,4
      interstrand (G'30 to G33) and 1,5 intrastrand (G33 to G29) cross-links further
      confirmed the similarity in energy between the two forms of cross-link. Finally,
      immunochemical analysis confirmed the unique nature of the DNA adducts formed by
      BBR3464. This analysis showed that antibodies raised to cisplatin-adducted DNA
      did not recognize DNA modified by BBR3464. In contrast, DNA modified by BBR3464
      inhibited the binding of antibodies raised to transplatin-adducted DNA. Thus, the
      bifunctional binding of BBR3464 contains few similarities to that of cisplatin
      but may have a subset of adducts recognized as being similar to the transplatinum
      species. In summary, the results point to a unique profile of DNA binding for
      BBR3464, strengthening the original hypothesis that modification of DNA binding
      in manners distinct from that of cisplatin will also lead to a distinct and
      unique profile of antitumor activity.

PMID- 10346900
TI  - Modified-peptide inhibitors of amyloid beta-peptide polymerization.
AB  - Cellular toxicity resulting from nucleation-dependent polymerization of amyloid
      beta-peptide (Abeta) is considered to be a major and possibly the primary
      component of Alzheimer's disease (AD). Inhibition of Abeta polymerization has
      thus been identified as a target for the development of therapeutic agents for
      the treatment of AD. The intrinsic affinity of Abeta for itself suggested that
      Abeta-specific interactions could be adapted to the development of compounds that
      would bind to Abeta and prevent it from polymerizing. Abeta-derived peptides of
      fifteen residues were found to be inhibitory of Abeta polymerization. The
      activity of these peptides was subsequently enhanced through modification of
      their amino termini with specific organic reagents. Additional series of
      compounds prepared to probe structural requirements for activity allowed
      reduction of the size of the inhibitors and optimization of the Abeta-derived
      peptide portion to afford a lead compound, cholyl-Leu-Val-Phe-Phe-Ala-OH (PPI
      368), with potent polymerization inhibitory activity but limited biochemical
      stability. The corresponding all-D-amino acyl analogue peptide acid (PPI-433) and
      amide (PPI-457) retained inhibitory activity and were both stable in monkey
      cerebrospinal fluid for 24 h.

PMID- 10346901
TI  - Reaction and binding of oligodeoxynucleotides containing analogues of O6
      methylguanine with wild-type and mutant human O6-alkylguanine-DNA
      alkyltransferase.
AB  - O6-Alkylguanine-DNA alkyltransferase (AGT) repairs DNA by transferring the methyl
      group from the 6-position of guanine to a cysteine residue on the protein. We
      previously found that the Escherichia coli Ada protein makes critical
      interactions with O6-methylguanine (O6mG) at the N1- and O6-positions. Human AGT
      has a different specificity than the bacterial protein. We reacted hAGT with
      double-stranded pentadecadeoxynucleotides containing analogues of O6mG. The
      second-order rate constants were in the following order (x10(-)5 M-1 s-1): O6mG
      (1.4), O6-methylhypoxanthine (1.6) > Se6-methyl-6-selenoguanine (0.1) > S6-methyl
      6-thioguanine (S6mG) (0.02) >> S6-methyl-6-thiohypoxanthine (S6mH), O6-methyl-1
      deazaguanine (O6m1DG), O6-methyl-3-deazaguanine (O6m3DG), and O6-methyl-7
      deazaguanine (O6m7DG) (all <0.0001). Electrophoretic mobility shift assays were
      carried out to determine the binding affinity to hAGT. Oligodeoxynucleotides
      containing O6mG, S6mG and O6m3DG bound to AGT in the presence of competitor DNA
      with Kd values from 5 to 20 microM, while those containing G, S6mH, O6m1DG, and
      O6m7DG did not (Kd > 200 microM). These results indicate that the 1-, N2-, and 7-
      positions of O6mG are critical in binding to hAGT, while the 3- and O6-positions
      are involved in methyl transfer. These results suggest that the active site of
      ada AGT is more flexible than hAGT and may be the reason ada AGT reacts with O4mT
      faster than hAGT.

PMID- 10346902
TI  - Association of terminal complement proteins in solution and modulation by
      suramin.
AB  - The association of terminal complement proteins was investigated by analytical
      ultracentrifugation and multi-angle laser light scattering. Native C8 and C9
      formed a heterodimer in solution of physiological ionic strength with a free
      energy change DeltaG degrees of -8.3 kcal/mol and a dissociation constant Kd of
      0.6 microM (at 20 degrees C) that was ionic strength- and temperature-dependent.
      A van't Hoff plot of the change in Kd was linear between 10 and 37 degrees C and
      yielded values of DeltaH degrees = -12.9 kcal/mol and DeltaS degrees = -15.9 cal
      mol-1 deg-1, suggesting that electrostatic forces play a prominent role in the
      interaction of C8 with C9. Native C8 also formed a heterodimer with C5, and low
      concentrations of polyionic ligands such as protamine and suramin inhibited the
      interaction. Suramin induced high-affinity trimerization of C8 (Kd = 0.10 microM
      at 20 degrees C) and dimerization of C9 (Kd = 0.86 microM at 20 degrees C).
      Suramin-induced C8 oligomerization may be the primary reason for the drug's
      ability to prevent complement-mediated hemolysis. Analysis of sedimentation
      equilibria and also of the fluorescence enhancement of suramin when bound to
      protein provided evidence for two suramin-binding sites on each C9 and three on
      each C8 in the oligomers. Oligomerization could be reversed by high suramin
      concentrations, but 8-aminonaphthalene-1,3,6- trisulfonate (ANTS2- ), which
      mimics half a suramin molecule, could not compete with suramin binding and
      oligomerization suggesting that the drug also binds nonionically to the proteins.

PMID- 10346903
TI  - Separate oligosaccharide determinants mediate interactions of the low-molecular
      weight salivary mucin with neutrophils and bacteria.
AB  - The low-molecular-weight human salivary mucin (MG2) coats oral surfaces, where it
      is in a prime location for governing cell adhesion. Since oligosaccharides form
      many of the interactive facets on mucin molecules, we examined MG2 glycosylation
      as it relates to the molecule's adhesive functions. Our previous study of MG2
      oligosaccharide structures showed that the termini predominantly carry T, sialyl
      T, Lewisx (Lex), sialyl Lex (sLex), lactosamine, and sialyl lactosamine
      determinants [Prakobphol, A., et al. (1998) Biochemistry 37, 4916-4927]. In
      addition, we showed that sLex determinants confer L-selectin ligand activity to
      this molecule. Here we studied adhesive interactions between MG2 and cells that
      traffic in the oral cavity: neutrophils and bacteria. Under flow conditions,
      neutrophils tethered to MG2-coated surfaces at forces between 1.25 and 2 dyn/cm2,
      i.e., comparable to the shear stress generated at the tooth surface by salivary
      flow ( approximately 0.8 dyn/cm2). MG2 was also found in association with
      neutrophils isolated from the oral cavity, evidence that the cells interact with
      this mucin in vivo. Since MG2 serves as an adhesion receptor for bacteria, the
      MG2 saccharides that serve this function were also identified. Seven of 18 oral
      bacteria strains that were tested adhered to MG2. Importantly, six of these seven
      strains adhered via T antigen, sialyl-T antigen, and/or lactosamine sequences. No
      adherence to Lex and sLex epitopes was detected in all the strains that were
      tested. Together, these results suggest that distinct subsets of MG2 saccharides
      function as ligands for neutrophil L-selectin and receptors for bacterial
      adhesion, a finding with interesting implications for both oral health and mucin
      function.

PMID- 10346904
TI  - Aspartate-132 in cytochrome c oxidase from Rhodobacter sphaeroides is involved in
      a two-step proton transfer during oxo-ferryl formation.
AB  - The aspartate-132 in subunit I (D(I-132)) of cytochrome c oxidase from
      Rhodobacter sphaeroides is located on the cytoplasmic surface of the protein at
      the entry point of a proton-transfer pathway used for both substrate and pumped
      protons (D-pathway). Replacement of D(I-132) by its nonprotonatable analogue
      asparagine (DN(I-132)) has been shown to result in a reduced overall activity of
      the enzyme and impaired proton pumping. The results from this study show that
      during oxidation of the fully reduced enzyme the reaction was inhibited after
      formation of the oxo-ferryl (F) intermediate (tau congruent with 120
      microseconds). In contrast to the wild-type enzyme, in the mutant enzyme
      formation of this intermediate was not associated with proton uptake from
      solution, which is the reason the DN(I-132) enzyme does not pump protons. The
      proton needed to form F was presumably taken from a protonatable group in the D
      pathway (e.g., E(I-286)), which indicates that in the wild-type enzyme the proton
      transfer during F formation takes place in two steps: proton transfer from the
      group in the pathway is followed by faster reprotonation from the bulk solution,
      through D(I-132). Unlike the wild-type enzyme, in which F formation is coupled to
      internal electron transfer from CuA to heme a, in the DN(I-132) enzyme this
      electron transfer was uncoupled from formation of the F intermediate, which
      presumably is due to the impaired charge-compensating proton uptake from
      solution. In the presence of arachidonic acid which has been shown to stimulate
      the turnover activity of the DN(I-132) enzyme (Fetter et al. (1996) FEBS Lett.
      393, 155), proton uptake with a time constant of approximately 2 ms was observed.
      However, no proton uptake associated with formation of F (tau congruent with 120
      micros) was observed, which indicates that arachidonic acid can replace the role
      of D(I-132), but it cannot transfer protons as fast as the Asp. The results from
      this study show that D(I-132) is crucial for efficient transfer of protons into
      the enzyme and that in the DN(I-132) mutant enzyme there is a "kinetic barrier"
      for proton transfer into the D-pathway.

PMID- 10346905
TI  - The reaction center-LH1 antenna complex of Rhodobacter sphaeroides contains one
      PufX molecule which is involved in dimerization of this complex.
AB  - The PufX membrane protein is essential for photosynthetic growth of Rhodobacter
      sphaeroides wild-type cells. PufX is associated with the reaction center-light
      harvesting 1 (RC-LH1) core complex and plays a key role in lateral
      ubiquinone/ubiquinol transfer. We have determined the PufX/RC stoichiometry by
      quantitative Western blot analysis and RC photobleaching. Independent of copy
      number effects and growth conditions, one PufX molecule per RC was observed in
      native membranes as well as in detergent-solubilized RC-LH1 complexes which had
      been purified over sucrose gradients. Surprisingly, two gradient bands with
      significantly different sedimentation coefficients were found to have a similar
      subunit composition, as judged by absorption spectroscopy and protein gel
      electrophoresis. Gel filtration chromatography and electron microscopy revealed
      that these membrane complexes represent a monomeric and a dimeric form of the RC
      LH1 complex. Since PufX is strictly required for the isolation of dimeric core
      complexes, we suggest that PufX has a central structural role in forming dimeric
      RC-LH1 complexes, thus allowing efficient ubiquinone/ubiquinol exchange through
      the LH1 ring surrounding the RC.

PMID- 10346906
TI  - Role of configurational gating in intracomplex electron transfer from cytochrome
      c to the radical cation in cytochrome c peroxidase.
AB  - Electron transfer within complexes of cytochrome c (Cc) and cytochrome c
      peroxidase (CcP) was studied to determine whether the reactions are gated by
      fluctuations in configuration. Electron transfer in the physiological complex of
      yeast Cc (yCc) and CcP was studied using the Ru-39-Cc derivative, in which the
      H39C/C102T variant of yeast iso-1-cytochrome c is labeled at the single cysteine
      residue on the back surface with trisbipyridylruthenium(II). Laser excitation of
      the 1:1 Ru-39-Cc-CcP compound I complex at low ionic strength results in rapid
      electron transfer from RuII to heme c FeIII, followed by electron transfer from
      heme c FeII to the Trp-191 indolyl radical cation with a rate constant keta of 2
      x 10(6) s-1 at 20 degrees C. keta is not changed by increasing the viscosity up
      to 40 cP with glycerol and is independent of temperature. These results suggest
      that this reaction is not gated by fluctuations in the configuration of the
      complex, but may represent the elementary electron transfer step. The value of
      keta is consistent with the efficient pathway for electron transfer in the
      crystalline yCc-CcP complex, which has a distance of 16 A between the edge of
      heme c and the Trp-191 indole [Pelletier, H., and Kraut, J. (1992) Science 258,
      1748-1755]. Electron transfer in the complex of horse Cc (hCc) and CcP was
      examined using Ru-27-Cc, in which hCc is labeled with trisbipyridylruthenium(II)
      at Lys-27. Laser excitation of the Ru-27-Cc-CcP complex results in electron
      transfer from RuII to heme c FeII with a rate constant k1 of 2.3 x 10(7) s-1,
      followed by oxidation of the Trp-191 indole to a radical cation by RuIII with a
      rate constant k3 of 7 x 10(6) s-1. The cycle is completed by electron transfer
      from heme c FeII to the Trp-191 radical cation with a rate constant k4 of 6.1 x
      10(4) s-1. The rate constant k4 decreases to 3.4 x 10(3) s-1 as the viscosity is
      increased to 84 cP, but the rate constants k1 and k3 remain the same. The results
      are consistent with a gating mechanism in which the Ru-27-Cc-CcP complex
      undergoes fluctuations between a major state A with the configuration of the hCc
      CcP crystalline complex and a minor state B with the configuration of the yCc-CcP
      complex. The hCc-CcP complex, state A, has an inefficient pathway for electron
      transfer from heme c to the Trp-191 indolyl radical cation with a distance of
      20.5 A and a predicted value of 5 x 10(2) s-1 for k4A. The observed rate constant
      k4 is thus gated by the rate constant ka for conversion of state A to state B,
      where the rate of electron transfer k4B is expected to be 2 x 10(6) s-1. The
      temperature dependence of k4 provides activation parameters that are consistent
      with the proposed gating mechanism. These studies provide evidence that
      configurational gating does not control electron transfer in the physiological
      yCc-CcP complex, but is required in the nonphysiological hCc-CcP complex.

PMID- 10346907
TI  - Functional roles of aspartic acid residues at the cytoplasmic surface of
      bacteriorhodopsin.
AB  - The functions of the four aspartic acid residues in interhelical loops at the
      cytoplasmic surface of bacteriorhodopsin, Asp-36, Asp-38, Asp-102, and Asp-104,
      were investigated by studying single and multiple aspartic acid to asparagine
      mutants. The same mutants were examined also with the additional D96N residue
      replacement. The kinetics of the M and N intermediates of the photochemical
      cycles of these recombinant proteins were affected only in a minor, although self
      consistent, way. When residue 38 is an aspartate and anionic, it makes the
      internal proton exchange between the retinal Schiff base and Asp-96 about 3 times
      more rapid, and events associated with the reisomerization of retinal to all
      trans about 3 times slower. Asp-36 has the opposite effect on these processes,
      but to a smaller extent. Asp-102 and Asp-104 have even less or none of these
      effects. Of the four aspartates, only Asp-36 could play a direct role in proton
      uptake at the cytoplasmic surface. In the 13 bacterioopsin sequences now
      available, only this surface aspartate is conserved.

PMID- 10346908
TI  - Temperature and pH dependence of the metarhodopsin I-metarhodopsin II equilibrium
      and the binding of metarhodopsin II to G protein in rod disk membranes.
AB  - The equilibria between metarhodopsins I and II (MI and MII) and the binding of
      MII to retinal G protein (G) were investigated, using the dual wavelength
      absorbance response of rod disk membrane (RDM) suspensions to a series of small
      bleaches, together with a nonlinear least-squares fitting procedure that
      decouples the two reactions. This method has been subjected to a variety of
      theoretical and experimental tests that establish its validity. The two
      equilibrium constants, the amount of active G protein (that can bind to and
      stabilize MII) and the fraction bleached by the flash, have been determined
      without a priori assumptions about these values, at temperatures between 0 and 15
      degrees C and pHs from 6.2 to 8.2. Binding of G to MII in normal RDM exhibits 1:1
      stoichiometry (not cooperative), relatively weak, 2-4 x 10(4) M-1 affinity on the
      membrane, with a pH dependence maximal at pH 7.6, and a low thermal coefficient.
      The reported amount of active G remained constant even when its binding constant
      was reduced more than 10-fold at low pH. The method can readily be applied to the
      binding of MII to other proteins or polypeptides that stabilize its conformation
      as MII. It appears capable of determining many of the essential physical
      constants of G protein coupled receptor interaction with immediate signaling
      partners and the effect of perturbation of environmental parameters on these
      constants.

PMID- 10346909
TI  - The interaction between rac1 and its guanine nucleotide dissociation inhibitor
      (GDI), monitored by a single fluorescent coumarin attached to GDI.
AB  - The interaction of rac with guanine nucleotide dissociation inhibitor protein
      (rhoGDI) is described, using GDI fluorescently labeled on its single cysteine
      with N-[2-(1-maleimidyl)ethyl]-7-diethylaminocoumarin-3-carboxamide (MDCC). The
      labeled GDI shows a 70% decrease in fluorescence emission on binding
      geranylgeranylated rac1.GDP and has an affinity for rac1 within a factor of 2 of
      the unlabeled GDI. The labeled GDI was used to determine the kinetic mechanism of
      the interaction by measuring the association and dissociation in real time. The
      kinetics are interpreted in terms of a two-step mechanism: binding of rac to GDI
      and then a conformational change of the complex with an overall dissociation
      constant of 0.4 nM. The conformational change has a rate constant of 7.3 s-1 (pH
      7.5, 30 degrees C), and the reverse has a rate constant of 1.4 x 10(-)3 s-1. To
      overcome difficulties inherent in using and manipulating lipid-modified rac, we
      also used a combination of unmodified rac1, expressed in Escherichia coli and
      produced with C-terminal truncation (thus lacking the cysteine that is the site
      of lipid attachment), and farnesylated C-terminal peptide. This combination can
      mimic geranylgeranylated rac1, producing a complex with the coumarin-labeled GDI,
      and was used to examine the relative importance of different regions of rac1 in
      interaction with GDI.

PMID- 10346910
TI  - The membrane lipid environment modulates drug interactions with the P
      glycoprotein multidrug transporter.
AB  - The P-glycoprotein multidrug transporter functions as an ATP-driven efflux pump
      for a large number of structurally unrelated hydrophobic compounds. Substrates
      are believed to gain access to the transporter after partitioning into the
      membrane, rather than from the extracellular aqueous phase. The binding of drug
      substrates to P-glycoprotein may thus be modulated by the properties of the lipid
      bilayer. The interactions with P-glycoprotein of two drugs (vinblastine and
      daunorubicin) and a chemosensitizer (verapamil) were characterized by quenching
      of purified fluorescently labeled protein in the presence of various
      phospholipids. Biphasic quench curves were observed for vinblastine and
      verapamil, suggesting that more than one molecule of these compounds may bind to
      the transporter simultaneously. All three drugs bound to P-glycoprotein with
      substantially higher affinity in egg phosphatidylcholine (PC), compared to brain
      phosphatidylserine (PS) and egg phosphatidylethanolamine (PE). The nature of the
      lipid acyl chains also modulated binding, with affinity decreasing in the order
      egg PC > dimyristoyl-PC (DMPC) > dipalmitoyl-PC (DPPC). Following reconstitution
      of the transporter into DMPC, all three compounds bound to P-glycoprotein with 2
      4-fold higher affinity in gel phase lipid relative to liquid-crystalline phase
      lipid. The P-glycoprotein ATPase stimulation/inhibition profiles for the drugs
      were also altered in different lipids, in a manner consistent with the observed
      changes in binding affinity. The ability of the drugs to partition into bilayers
      of phosphatidylcholines was determined. All of the drugs partitioned much better
      into egg PC relative to DMPC and DPPC. The binding affinity increased (i.e., the
      value of Kd decreased) as the drug-lipid partition coefficient increased,
      supporting the proposal that the effective concentration of the drug substrate in
      the membrane is important for interaction with the transporter. These results
      provide support for the vacuum cleaner model of P-glycoprotein action.

PMID- 10346911
TI  - Molecular characterization of the human neuropeptide Y Y2-receptor.
AB  - Five neuropeptide Y receptors, the Y1-, Y2-, Y4-, Y5- and y6-subtypes, have been
      cloned, which belong to the rhodopsin-like G-protein-coupled, 7-transmembrane
      helix-spanning receptors and bind the 36-mer neuromodulator NPY (neuropeptide Y)
      with nanomolar affinity. In this study, the Y2-receptor subtype expressed in a
      human neuroblastoma cell line (SMS-KAN) and in transfected Chinese hamster ovary
      cells (CHO-hY2) was characterized on the protein level by using photoaffinity
      labeling and antireceptor antibodies. Two photoactivatable analogues of NPY were
      synthesized, in which a Tyr residue was substituted by the photoreactive amino
      acid 4-(3-trifluoromethyl)-3H-diazirin-3-ylphenylalanine ((Tmd)Phe), [Nalpha
      biotinyl-Ahx2,(Tmd)Phe36]NPY (Tmd36), and the Y2-receptor subtype selective
      [Nalpha-biotinyl-Ahx2,Ahx5-24,(Tmd)Phe27]N PY (Tmd27). Both analogues were
      labeled with [3H]succinimidyl-propionate at Lys4 and bind to the Y2-receptor with
      affinity similar to that of the native ligand. A synthetic fragment of the second
      (E2) extracellular loop was used to generate subtype selective antireceptor
      antibodies against the Y2-receptor. Photoaffinity labeling of the receptor
      followed by SDS-PAGE and detection of bound radioactivity and SDS-PAGE of
      solubilized receptors and subsequent Western blotting revealed the same molecular
      masses. Two proteins correspondingly have been detected for each cell line with
      molecular masses of 58 +/- 4 and 50 +/- 4 kDa, respectively.

PMID- 10346912
TI  - Enhancement of the endopeptidase activity of botulinum neurotoxin by its
      associated proteins and dithiothreitol.
AB  - Botulinum neurotoxins type A (BoNT/A), the most toxic substance known to man, is
      produced by Clostridium botulinum type A as a complex with a group of neurotoxin
      associated proteins (NAPs), possibly through a polycistronic expression of a
      clustered group of genes. The botulinum neurotoxin complex is the only known
      example of a protein complex where a group of proteins (NAPs) protect another
      protein (BoNT) against acidity and proteases of the GI tract. We now report that
      NAPs also potentiate the Zn2+ endopeptidase activity of BoNT/A in both in vitro
      and in vivo assays against its known intracellular target protein, 25 kDa
      synaptosomal associated protein (SNAP-25). While BoNT/A exhibited no protease
      activity prior to reduction with dithiothreitol (DTT), the BoNT/A complex
      exhibited a high protease activity even in its nonreduced form. Our results
      suggest that the bacterial production of NAPs along with BoNT is designed for the
      NAPs to play an accessory role in the neurotoxin function, in contrast to their
      previously known limited role in protecting the neurotoxin in the GI tract and in
      the external environment. Structural features of BoNT/A change considerably upon
      disulfide reduction, as revealed by near-UV circular dichroism spectroscopy.
      BoNT/A in the reduced form adopts a more flexible structure than in the unreduced
      form, as also indicated by large differences in DeltaH values (155 vs 248 kJ mol
      1) of temperature-induced unfolding of BoNT/A.

PMID- 10346913
TI  - Troponin I inhibitory peptide (96-115) has an extended conformation when bound to
      skeletal muscle troponin C.
AB  - We have utilized CD and NMR spectroscopy to study the conformation of the
      troponin I (TnI) inhibitory peptide [TnI(96-115)] free in solution and when bound
      to troponin C (TnC). Analysis of the CD spectrum of the free peptide in aqueous
      solution indicates it is only approximately 3% helix. Upon complex formation with
      TnC, there is no change in total helix content compared to the sum of the free
      components. The NMR data support a predominantly extended conformation for the
      free peptide. TnI(96-115) bound to TnC was selectively observed by NMR using
      deuterated TnC (dTnC). For the 1:1 ratio of TnI(96-115) to dTnC used, 95% of the
      peptide was bound to dTnC. The chemical shifts of the TnC-bound peptide
      resonances are similar to those of the free peptide, indicating that the change
      in peptide conformation as a consequence of binding to TnC is small. For the TnC
      bound TnI(96-115) peptide, the ratios of sequential Halpha-HN to intraresidue HN
      Halpha NOE cross-peak volumes support a predominantly extended conformation,
      possibly kinked at Gly104. The results presented here are in agreement with
      sequence analysis predictions for TnI(96-115) as a free peptide or within the
      intact TnI sequence. The predominantly extended structure for the 96-115
      inhibitory sequence segment of TnI with a kink at Gly104 may facilitate its
      binding alternately to actin or TnC in response to the Ca2+ signals that control
      thick and thin filament interactions during the contractile cycle.

PMID- 10346914
TI  - A model describing the inactivation of factor Va by APC: bond cleavage, fragment
      dissociation, and product inhibition.
AB  - The inactivation of factor Va is a complex process which includes bond cleavage
      (at three sites) and dissociation of the A2N.A2C peptides, with intermediate
      activity in each species. Quantitation of the functional consequences of each
      step in the reaction has allowed for understanding of the presentation of disease
      in individuals possessing the factor V polymorphism factor VLEIDEN. APC cleavage
      of membrane-bound bovine factor Va (Arg306, Arg505, Arg662) leads to the
      dissociation of fragments of the A2 domain, residues 307-713 (A2N.A2C + A2C
      peptide), leaving behind the membrane-bound A1.LC species. Evaluation of the
      dissociation process by light scattering yields invariant mass loss estimates as
      a function of APC concentration. The rate constant for A2 fragment dissociation
      varies with [APC], reaching a maximal value of k = 0.028 s-1, the unimolecular
      rate constant for A2 domain fragment dissociation. The APC binding site resides
      in the factor Va light chain (LC) (Kd = 7 nM), suggesting that the membrane-bound
      LC.A1 product would act to sequester APC. This inhibitory interaction (LC.A1.APC)
      is demonstrated to exist with either purified factor Va LC or the products of
      factor Va inactivation. Utilizing these experimental data and the reported rates
      of bond cleavage, binding constants, and product activity values for factor Va
      partial inactivation products, a model is developed which describes factor Va
      inactivation and accounts for the defect in factor VLEIDEN. The model accurately
      predicts the rates of inactivation of factor Va and factor VaLEIDEN, and the
      effect of product inhibition. Modeled reaction progress diagrams and activity
      profiles (from either factor Va or factor VaLEIDEN) are coincident with
      experimentally derived data, providing a mechanistic and kinetic explanation for
      all steps in the inactivation of normal factor Va and the pathology associated
      with factor VLEIDEN.

PMID- 10346915
TI  - Biochemical and electrochemical characterization of quinohemoprotein amine
      dehydrogenase from Paracoccus denitrificans.
AB  - A new quinohemoprotein amine dehydrogenase from Paracoccus denitrificans IFO
      12442 was isolated and characterized in views of biochemistry and
      electrochemistry. This enzyme exists in periplasm and catalyzes the oxidative
      deamination of primary aliphatic and aromatic amines. n-Butylamine or benzylamine
      as a carbon and energy source strongly induces the expression of the enzyme.
      Carbonyl reagents inhibit the enzyme activity irreversibly. This enzyme is a
      heterodimer constituted of alpha and beta subunits with the molecular mass of
      59.5 and 36.5 kDa, respectively. UV-vis and EPR spectroscopy, and the quinone
      dependent redox cycling and heme-dependent peroxidative stains of SDS-PAGE bands
      revealed that the alpha subunit contains one quinonoid cofactor and one heme c
      per molecule, while the beta subunit has no prosthetic group. The redox potential
      of the heme c moiety was determined to be 0.192 V vs NHE at pH 7.0 by a mediator
      assisted continuous-flow column electrolytic spectroelectrochemical technique.
      The analysis of the substrate titration curve allowed the evaluation of the redox
      potential of the quinone/semiquinone and semiquinone/quinol redox couples as 0.19
      and 0.11 V, respectively.

PMID- 10346916
TI  - Interaction of bacteriophage lambda protein phosphatase with Mn(II): evidence for
      the formation of a [Mn(II)]2 cluster.
AB  - The interaction of bacteriophage lambda protein phosphatase with Mn2+ was studied
      using biochemical techniques and electron paramagnetic resonance spectrometry.
      Reconstitution of bacteriophage lambda protein phosphatase in the presence of
      excess MnCl2 followed by rapid desalting over a gel filtration column resulted in
      the retention of approximately 1 equiv of Mn2+ ion bound to the protein. This was
      determined by metal analyses and low-temperature EPR spectrometry, the latter of
      which provided evidence of a mononuclear high-spin Mn2+ ion in a ligand
      environment of oxygen and nitrogen atoms. The Mn2+-reconstituted enzyme exhibited
      negligible phosphatase activity in the absence of added MnCl2. The EPR spectrum
      of the mononuclear species disappeared upon the addition of a second equivalent
      of Mn2+ and was replaced by a spectrum attributed to an exchange-coupled (Mn2+)2
      cluster. EPR spectra of the dinuclear (Mn2+)2 cluster were characterized by the
      presence of multiline features with a hyperfine splitting of 39 G. Temperature
      dependent studies indicated that these features arose from an excited state.
      Titrations of the apoprotein with MnCl2 provided evidence of one Mn2+ binding
      site with a micromolar affinity and at least one additional Mn2+ site with a 100
      fold lower affinity. The dependence of the phosphatase activity on Mn2+
      concentration indicates that full enzyme activity probably requires occupation of
      both Mn2+ sites. These results are discussed in the context of divalent metal ion
      activation of this enzyme and possible roles for Mn2+ activation of other
      serine/threonine protein phosphatases.

PMID- 10346917
TI  - Mechanistic implications from crystalline complexes of wild-type and mutant
      adenylosuccinate synthetases from Escherichia coli.
AB  - Asp13 and His41 are essential residues of adenylosuccinate synthetase, putatively
      catalyzing the formation of adenylosuccinate from an intermediate of 6-phosphoryl
      IMP. Wild-type adenylosuccinate synthetase and three mutant synthetases (Arg143 -
      > Leu, Lys16 --> Gln, and Arg303 --> Leu) from Eschericha coli have been
      crystallized in the presence of IMP, hadacidin (an analogue of L-aspartate),
      Mg2+, and GTP. The active site of each complex contains 6-phosphoryl-IMP, Mg2+,
      GDP, and hadacidin, except for the Arg303 --> Leu mutant, which does not bind
      hadacidin. In response to the formation of 6-phosphoryl-IMP, Asp13 enters the
      inner coordination sphere of the active site Mg2+. His41 hydrogen bonds with 6
      phosphoryl-IMP, except in the Arg303 --> Leu complex, where it remains bound to
      the guanine nucleotide. Hence, recognition of the active site Mg2+ by Asp13
      evidently occurs after the formation of 6-phosphoryl-IMP, but recognition of the
      intermediate by His41 may require the association of L-aspartate with the active
      site. Structures reported here support a mechanism in which Asp13 and His41 act
      as the catalytic base and acid, respectively, in the formation of 6-phosphoryl
      IMP, and then act together as catalytic acids in the subsequent formation of
      adenylosuccinate.

PMID- 10346918
TI  - C-1027-induced alterations in Epstein-Barr viral DNA replication in latently
      infected cultured human Raji cells: relationship to DNA damage.
AB  - This study is the first detailing drug-induced changes in EBV DNA replication
      intermediates (RIs). Both EBV replication inhibition and damage induction were
      studied in latently infected human Raji cells treated with the enediyne DNA
      strand-scission agent C-1027. Analysis of RIs on two-dimensional agarose gels
      revealed a rapid loss in the EBV bubble arc. When elongation of nascent chains
      was blocked by aphidicolin, this loss was inhibited, suggesting that C-1027
      induced disappearance of RIs was related to maturation of preformed replication
      molecules in the absence of initiation of new RIs. C-1027 damage to EBV DNA was
      limited at concentrations where loss of the bubble arc was nearly complete, and
      none was detected within the replicating origin (ori P)-containing fragment,
      indicating that replication inhibition occurred in trans. By contrast, the non
      nuclear mitochondrial genome was insensitive to replication inhibition but highly
      sensitive to damage induced by C-1027. C-1027-induced trans inhibition of nuclear
      but not mitochondrial DNA replication is consistent with a cell cycle checkpoint
      response to a DNA-damaging agent. EBV replication and Raji cell growth were
      inhibited at equivalent C-1027 doses.

PMID- 10346919
TI  - Stopped-flow kinetic analysis of the ligand-induced coil-helix transition in
      glutathione S-transferase A1-1: evidence for a persistent denatured state.
AB  - Structural studies have suggested that the glutathione S-transferase (GST) A1-1
      isozyme contains a dynamic C-terminus which undergoes a ligand-dependent disorder
      order transition and sequesters substrates within the active site. Here, the
      contribution of the C-terminus to the kinetics and thermodynamics of ligand
      binding and dissociation has been determined. Steady-state turnover rates of the
      wild type (WT) and a C-terminal truncated (Delta209-222) rGST A1-1 with
      ethacrynic acid (EA) were measured in the presence of variable concentrations of
      viscogen. The results indicate that a physical step involving segmental protein
      motion is at least partially rate limiting at temperatures between 10 and 40
      degrees C for WT. Dissociation rates of the glutathione-ethacrynic acid product
      conjugate (GS-EA), determined by stopped-flow fluorescence, correspond to the
      steady-state turnover rates. In contrast, the chemical step governs the turnover
      reaction by Delta209-222, suggesting that the slow rate of product release for WT
      is controlled by the dynamics of the C-terminal coil-helix transition. In
      addition, the association reaction of WT rGST A1-1 with GS-EA established that
      the binding was biphasic and included ligand docking followed by slow
      isomerization of the enzyme-ligand complex. In contrast, binding of GS-EA to
      Delta209-222 was a monophasic, bimolecular reaction. These results indicate that
      the binding of GS-EA to WT rGST A1-1 proceeds via an induced fit mechanism, with
      a slow conformational step that corresponds to the coil-helix transition.
      However, the biphasic dissociation kinetics for the wild type, and the recovered
      kinetic parameters, suggest that a significant fraction of the [GST.GS-EA]
      complex ( approximately 15%) retains a persistent disordered state at
      equilibrium.

PMID- 10346920
TI  - 4-[[2-(1-Methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A): a
      novel cognitive enhancer with selectivity for neuronal nicotinic acetylcholine
      receptors.

PMID- 10346921
TI  - Design, synthesis, and in vitro activity of catamphiphilic reverters of multidrug
      resistance: discovery of a selective, highly efficacious chemosensitizer with
      potency in the nanomolar range.
AB  - On the basis of the results obtained in previous research, three series of
      compounds (A-C), derived from verapamil, were designed and synthesized to obtain
      drugs able to revert multidrug resistance (MDR), an acquired resistance that
      frequently impairs cancer chemotherapy. The ability of the obtained compounds to
      revert MDR was evaluated on anthracycline-resistant erythroleukemia K 562 cells,
      measuring the uptake of THP-adriamycin (pirarubicin) by continuous
      spectrofluorometric monitoring of the decrease of the fluorescence signal of the
      anthracycline at 590 nm (lambdaex = 480 nm), after incubation with cells.
      Cardiovascular activity, which is responsible for unwanted side effects, was also
      evaluated. The results obtained show that many of the compounds studied are
      potent reverters of MDR and are endowed with reduced cardiovascular activity. One
      of the compounds (7, MM36) presents a pharmacological profile (unprecedented
      nanomolar potency, high reversal of MDR, low cardiovascular activity) that makes
      it a promising drug candidate to treat MDR and a useful tool for studying P
      glycoprotein.

PMID- 10346922
TI  - Novel arylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides as inhibitors of
      platelet aggregation. 1. Synthesis and pharmacological evaluation.
AB  - A series of N-1-substituted derivatives of pyrazino[2,3-c][1,2, 6]thiadiazine 2,2
      dioxides bearing aryl groups at the pyrazino moiety have been prepared. The
      synthesis involves ring formation between the diaminothiadiazine and suitable
      dicarbonyl compounds and subsequent introduction of the substituent at N-1. The
      compounds have been tested in vitro, as inhibitors of rabbit and human platelet
      aggregation, and ex vivo against rat platelet aggregation induced by arachidonic
      acid, ADP, collagen, U46619, and I-BOP. The results obtained indicate that some
      pyrazino[2,3-c][1,2, 6]thiadiazine derivatives show significant platelet
      aggregation inhibition similar to other antithrombotic agents and that the
      antiplatelet properties may be mediated by interference with the arachidonic acid
      pathway.

PMID- 10346923
TI  - Solution conformation of a potent cyclic analogue of tuftsin: low- temperature
      nuclear magnetic resonance study in a cryoprotective mixture.
AB  - Tuftsin, a linear tetrapeptide (Thr-Lys-Pro-Arg), corresponding to the sequence
      289-292 of the heavy chain of leukokinin, has been the object of intensive SAR
      studies during the past 30 years, owing to its numerous biological activities and
      to the possibility of generating a novel anticancer drug. A cyclic tuftsin
      analogue, c-[T-K-P-R-G], has biological activity 50 times higher than that of the
      parent linear peptide. Here we present a conformational study of c-[T-K-P-R-G]
      based on NMR data in a cryoprotective DMSO/water mixture. The preferred
      conformation is a type VIa turn centered on the K-P residues. The orientation of
      the side chains of the two basic residues (K and R) may represent the essential
      feature of the bioactive conformation of tuftsin. A possible role of tuftsin as a
      DNA binding motif is suggested by the similarity of the bioactive conformation of
      c-[T-K-P-R-G] and of the beta-turn conformation proposed by Suzuki for the [T,S]
      P-K-R motif.

PMID- 10346924
TI  - An effort to understand the molecular basis of hypertension through the study of
      conformational analysis of losartan and sarmesin using a combination of nuclear
      magnetic resonance spectroscopy and theoretical calculations.
AB  - Losartan is the first recently approved drug against hypertension disease that
      competes with the biological action of angiotensin II (AII) at the AT1 receptor.
      Its design was based on the mimicry of the C-terminal segment of AII. Due to the
      biological significance of Losartan, its structure elucidation and conformational
      properties are reported as determined by NMR spectroscopy and computational
      analysis. In addition, molecular modeling of the peptide Sarmesin
      [Sar1Tyr(OMe)4AII], a competitive antagonist of AII, was also developed based on
      NMR and computational analysis data. Sarmesin's C-terminal was used as a template
      for superimposition with specific molecular features of interest in the structure
      of Losartan such as the conformation of biphenyltetrazole, the n-butyl chain, and
      the orientation of hydroxymethylimidazole relative to the biphenyl template. The
      major conclusions derived from this study are the following: (a) Sarmesin, like
      the AII superagonist [Sar1]AII, adopts a conformation which keeps in close
      proximity the key amino acids Sar1 (or Arg2)-Tyr(OMe)4-His6-Phe8. (b) Losartan
      favors a low-energy conformation in which imidazole and tetrazole rings are
      placed in the opposite site relative to the spacer phenyl ring plane; the
      hydroxymethyl group is placed away from the spacer phenyl ring, the alkyl chain
      is oriented above the spacer phenyl ring, and the two phenyl rings deviate
      approximately 60 degrees from being coplanar. (c) Overlay of the C-terminal
      region of Sarmesin with Losartan using equivalent groups revealed an excellent
      match. (d) Interestingly, the matching between enantiomeric structures of
      Losartan was not equivalent, proposing that the chirality of this molecule is
      significant in order to exert its biological activity. These findings open a new
      avenue for synthetic chemists to design and synthesize peptidomimetic drugs based
      on the C-terminal segment of the proposed model of Sarmesin. The new candidate
      drug molecules are not restricted to structurally resemble Losartan as the design
      is hitherto focused.

PMID- 10346925
TI  - Homology modeling of gelatinase catalytic domains and docking simulations of
      novel sulfonamide inhibitors.
AB  - Three-dimensional models for the catalytic domain of gelatinases (MMP-9 and -2)
      have been constructed based on the X-ray crystal structure of MMP-3.
      Conformations of the loop segment which forms the bottom half of the S1' subsite
      but shows conformational diversity among the crystal structures of other MMPs
      have been explored by simulated annealing of each gelatinase model complexed with
      two highly potent "probe" inhibitors. Representative catalytic domain models have
      been selected for each gelatinase from the set of generated conformations based
      on shape complementarity of the loop to the probe inhibitors. The single model
      selected for MMP-9 was utilized to explain the structure-activity relationship of
      our novel sulfonamide inhibitors. Molecular dynamics (MD) simulations of the
      complex models revealed important features of the binding mechanism of our
      inhibitors: (i) the ligand carboxylate group coordinating to the catalytic zinc
      ion and hydrogen bonding to the Glu219 side chain, (ii) one of the sulfonyl
      oxygens forming hydrogen bonds with the main chain NHs (Leu181 and Ala182), (iii)
      the sulfonyl substituent making extensive hydrophobic contact with the S1'
      subsite. The gauche conformation exclusively adopted by the sulfonamide C-N-S-C
      torsion plays an important role in achieving the third binding feature by
      properly directing the substituent into the S1' subsite. Improvement of the
      inhibitory activity according to straight elongation of the sulfonyl substituent
      was attributed to an increase of the hydrophobic contact between the substituent
      and the S1' subsite. Structural modifications which alter the straight shape of
      the substituent lead to deterioration of the activity. On the other hand, the two
      candidate models selected for MMP-2 differ in the bottom shape of the S1'
      subsite: one with a channel-like subsite and the other with a pocket-like subsite
      resembling that of the MMP-9 model. The bottom shape was experimentally probed by
      chemical synthesis of inhibitors having elongated sulfonyl substituents whose
      terminal alkyl groups were shown by MD simulations to protrude from the S1'
      subsite bottom into the solvent. Gelatinase assays of these inhibitors showed
      that elongation of the substituent significantly reduces activity against MMP-9
      while retaining activity against MMP-2, consequently increasing the selectivity
      between MMP-2 and -9. The results confirm that MMP-9 has a pocket-like S1'
      subsite with a floorboard and MMP-2 has a channel-like S1' subsite.

PMID- 10346926
TI  - Molecular hashkeys: a novel method for molecular characterization and its
      application for predicting important pharmaceutical properties of molecules.
AB  - We define a novel numerical molecular representation, called the molecular
      hashkey, that captures sufficient information about a molecule to predict
      pharmaceutically interesting properties directly from three-dimensional molecular
      structure. The molecular hashkey represents molecular surface properties as a
      linear array of pairwise surface-based comparisons of the target molecule against
      a common 'basis-set' of molecules. Hashkey-measured molecular similarity
      correlates well with direct methods of measuring molecular surface similarity.
      Using a simple machine-learning technique with the molecular hashkeys, we show
      that it is possible to accurately predict the octanol-water partition
      coefficient, log P. Using more sophisticated learning techniques, we show that an
      accurate model of intestinal absorption for a set of drugs can be constructed
      using the same hashkeys used in the aforementioned experiments. Once a set of
      molecular hashkeys is calculated, its use in the training and testing of property
      based models is very fast. Further, the required amount of data for model
      construction is very small. Neural network-based hashkey models trained on data
      sets as small as 30 molecules yield statistically significant prediction of
      molecular properties. The lack of a requirement for large data sets lends itself
      well to the prediction of pharmaceutically relevant molecular parameters for
      which data generation is expensive and slow. Molecular hashkeys coupled with
      machine-learning techniques can yield models that predict key pharmacological
      aspects of biologically important molecules and should therefore be important in
      the design of effective therapeutics.

PMID- 10346927
TI  - Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa
      inhibitors.
AB  - A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa,
      a serine protease strategically located in the coagulation cascade. The evolution
      from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine
      compounds with a pyridine heterocycle as the core scaffold has been achieved. The
      most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM.
      The selectivity of 6h against bovine trypsin and human thrombin was greater than
      90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa
      are made based on the crystal structures of 6h by itself and of 6h bound to
      bovine trypsin.

PMID- 10346928
TI  - Ligands for the tyrosine kinase p56lck SH2 domain: discovery of potent dipeptide
      derivatives with monocharged, nonhydrolyzable phosphate replacements.
AB  - p56lck is a member of the src family of tyrosine kinases. Through modular binding
      units called SH2 domains, p56lck promotes phosphotyrosine-dependent protein
      protein interactions and plays a critical role in signal transduction events that
      lead to T-cell activation. Starting from the phosphorylated dipeptide (2), a high
      affinity ligand for the p56lck SH2 domain, we have designed novel dipeptides that
      contain monocharged, nonhydrolyzable phosphate group replacements and bind to the
      protein with KD's in the low micromolar range. Replacement of the phosphate group
      in phosphotyrosine-containing sequences by a (R/S)-hydroxyacetic (compound 8) or
      an oxamic acid (compound 10) moiety leads to hydrolytically stable, monocharged
      ligands, with 83- and 233-fold decreases in potency, respectively. This loss in
      binding affinity can be partially compensated for by incorporating large
      lipophilic groups at the inhibitor N-terminus. These groups provide up to 13-fold
      increases in potency depending on the nature of the phosphate replacement. The
      discovery of potent (2-3 microM), hydrolytically stable dipeptide derivatives,
      bearing only two charges at physiological pH, represents a significant step
      toward the discovery of compounds with cellular activity and the development of
      novel therapeutics for conditions associated with undesired T-cell proliferation.

PMID- 10346929
TI  - Extension of the polyanionic cosalane pharmacophore as a strategy for increasing
      anti-HIV potency.
AB  - The anti-HIV agent cosalane inhibits both the binding of gp120 to CD4 as well as
      an undefined postattachment event prior to reverse transcription. Several
      cosalane analogues having an extended polyanionic "pharmacophore" were designed
      based on a hypothetical model of the binding of cosalane to CD4. The analogues
      were synthesized, and a number of them displayed anti-HIV activity. One of the
      new analogues was found to possess enhanced potency as an anti-HIV agent relative
      to cosalane itself. Although the new analogues inhibited both HIV-1 and HIV-2,
      they were more potent as inhibitors of HIV-1 than HIV-2. Mechanism of action
      studies indicated that the most potent of the new analogues inhibited fusion of
      the viral envelope with the cell membrane at lower concentrations than it
      inhibited attachment, suggesting inhibition of fusion as the primary mechanism of
      action.

PMID- 10346930
TI  - The role of waters in docking strategies with incremental flexibility for
      carbohydrate derivatives: heat-labile enterotoxin, a multivalent test case.
AB  - Molecular docking studies of carbohydrate derivatives in protein binding sites
      are often challenging because of water-mediated interactions and the inherent
      flexibility of the many terminal hydroxyl groups. Using the recognition process
      between heat-labile enterotoxin from Escherichia coli and ganglioside GM1 as a
      paradigm, we developed a modeling protocol that includes incremental
      conformational flexibility of the ligand and predicted water interactions. The
      strategy employs a modified version of the Monte Carlo docking program AUTODOCK
      and water affinity potentials calculated with GRID. After calibration of the
      protocol on the basis of the known binding modes of galactose and lactose to the
      toxin, blind predictions were made for the binding modes of four galactose
      derivatives: lactulose, melibionic acid, thiodigalactoside, and m-nitrophenyl
      alpha-galactoside. Subsequent crystal structure determinations have demonstrated
      that our docking strategy can predict the correct binding modes of carbohydrate
      derivatives within 1.0 A from experiment. In addition, it is shown that repeating
      the docking simulations in each of the seemingly identical binding sites of the
      multivalent toxin increases the chance of finding the correct binding mode.

PMID- 10346931
TI  - Structure-activity relationship of small-sized HIV protease inhibitors containing
      allophenylnorstatine.
AB  - We designed and synthesized a new class of peptidomimetic human immunodeficiency
      virus (HIV) protease inhibitors containing a unique unnatural amino acid,
      allophenylnorstatine [Apns; (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid],
      with a hydroxymethylcarbonyl (HMC) isostere as the active moiety. A systematic
      evaluation of structure-activity relationships for HIV protease inhibition, anti
      HIV activities, and pharmacokinetic profiles has led to the delineation of a set
      of structural charateristics that appear to afford an orally available HIV
      protease inhibitor. Optimum structures, exemplified by 21f (JE-2147),
      incorporated 3-hydroxy-2-methylbenzoyl groups as the P2 ligand, (R)-5,5-dimethyl
      1,3-thiazolidine-4-carbonyl (Dmt) residue at the P1' site, and 2
      methylbenzylcarboxamide group as the P2' ligand. The present study demonstrated
      that JE-2147 has potent antiviral activities in vitro and exhibits good oral
      bioavailability and plasma pharmacokinetic profiles in two species of laboratory
      animals.

PMID- 10346932
TI  - Tyrosine kinase inhibitors. 15. 4-(Phenylamino)quinazoline and 4
      (phenylamino)pyrido[d]pyrimidine acrylamides as irreversible inhibitors of the
      ATP binding site of the epidermal growth factor receptor.
AB  - A series of 6- and 7-acrylamide derivatives of the 4-(phenylamino)quinazoline and
      -pyridopyrimidine classes of epidermal growth factor receptor (EGFR) inhibitors
      were prepared from the corresponding amino compounds by reaction with either
      acryloyl chloride/base or acrylic acid/1-(3-dimethylaminopropyl)-3
      ethylcarbodiimide hydrochloride. All of the 6-acrylamides, but only the parent
      quinazoline 7-acrylamide, were irreversible inhibitors of the isolated enzyme,
      confirming that the former are better-positioned, when bound to the enzyme, to
      react with the critical cysteine-773. Quinazoline, pyrido[3,4-d]pyrimidine, and
      pyrido[3,2-d]pyrimidine 6-acrylamides were all irreversible inhibitors and showed
      similar high potencies in the enzyme assay (likely due to titration of the
      available enzyme). However the pyrido[3,2-d]pyrimidine analogues were 2-6-fold
      less potent than the others in a cellular autophosphorylation assay for EGFR in
      A431 cells. The quinazolines were generally less potent overall toward inhibition
      of heregulin-stimulated autophosphorylation of erbB2 (in MDA-MB-453-cells),
      whereas the pyridopyrimidines were equipotent. Selected compounds were evaluated
      in A431 epidermoid and H125 non-small-cell lung cancer human tumor xenografts.
      The compounds showed better activity when given orally than intraperitoneally.
      All showed significant tumor growth inhibition (stasis) over a dose range. The
      poor aqueous solubility of the compounds was a drawback, requiring formulation as
      fine particulate emulsions.

PMID- 10346933
TI  - Synthesis, mode of action, and biological activities of rebeccamycin bromo
      derivatives.
AB  - Bromo analogues of the natural metabolite rebeccamycin with and without a methyl
      substituent on the imide nitrogen were synthesized. The effects of the drugs on
      protein kinase C, the binding to DNA, and the effect on topoisomerase I were
      determined. The drugs' uptake and their antiproliferative activities against P388
      leukemia cells sensitive and resistant to camptothecin, their antimicrobial
      activity against a Gram-positive bacterium (B. cereus), and their anti-HIV-1
      activity were measured and compared to those of the chlorinated and dechlorinated
      analogues. Dibrominated imide 5 shows a remarkable activity against topoisomerase
      I, affecting both the kinase and DNA cleavage activity of the enzyme. The marked
      cytotoxic potency of this compound depends essentially on its capacity to inhibit
      topoisomerase I.

PMID- 10346934
TI  - A new method for rapidly generating inhibitors of glyoxalase I inside tumor cells
      using S-(N-aryl-N-hydroxycarbamoyl)ethylsulfoxides.
AB  - The enediol analogue S-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione is a
      powerful mechanism-based competitive inhibitor of the anticancer target enzyme
      glyoxalase I. Nevertheless, this compound exhibits limited toxicity toward tumor
      cells in vitro because it does not readily diffuse across cell membranes. We
      describe an efficient method for indirectly delivering the enzyme inhibitor into
      murine leukemia L1210 cells via acyl interchange between intracellular
      glutathione and the cell-permeable prodrug S-(N-p-chlorophenyl-N
      hydroxycarbamoyl)ethylsulfoxide. The second-order rate constant for the acyl
      interchange reaction in a cell-free system is 1.84 mM-1 min-1 (100 mM potassium
      phosphate buffer, 5% ethanol, pH 7.5, 25 degrees C). Incubation of L1210 cells
      with the sulfoxide in vitro results in a rapid increase in the intracellular
      concentration of the glyoxalase I inhibitor (kapp = 1. 41 +/- 0.03 min-1 (37
      degrees C)) and inhibition of cell growth (GI50 = 0.5 +/- 0.1 microM). This
      represents an improvement in both efficiency and potency over the dialkyl ester
      prodrug strategy in which the inhibitor is indirectly delivered into tumor cells
      as the [glycyl,glutamyl] diethyl or dicyclopentyl esters. The fact that pi
      glutathione transferase catalyzes the acyl-interchange reaction between GSH and
      the sulfoxide suggests that the sulfoxide, or related compounds, might exhibit
      greater selective toxicity toward tumor cells that overexpress the transferase.

PMID- 10346935
TI  - Studies on the monoamine oxidase-B-catalyzed biotransformation of 4-azaaryl-1
      methyl-1,2,3,6-tetrahydropyridine derivatives.
AB  - The substrate properties of a series of 1-methyl-4-phenyl-1,2,3, 6
      tetrahydropyridinyl (MPTP) analogues in which the C-4 phenyl group has been
      replaced with various 4-azaaryl moieties have been examined in an effort to
      evaluate the contribution of electronic, polar, and steric parameters to the MAO
      B-catalyzed oxidation of this type of cyclic tertiary allylamine to the
      corresponding dihydropyridinium metabolite. No significant correlation could be
      found with the calculated energy of the C-H bond undergoing cleavage. A general
      trend, however, was observed between the magnitude of the log P value with the
      magnitude of kcat/Km. The results indicate that the placement of a polar nitrogen
      atom in the space occupied by the phenyl group of MPTP leads to a dramatic
      decrease in substrate properties. Enhanced substrate properties, however, were
      observed when benzoazaarenes replaced the corresponding five-membered azaarenes.
      These results are consistent with our previously published molecular model of the
      active site of MAO-B.

PMID- 10346936
TI  - Syntheses of biotinylated alpha-galactosylceramides and their effects on the
      immune system and CD1 molecules.
AB  - A representative alpha-galactosylceramide (alpha-GalCer), KRN7000, has strong
      immunostimulatory and antitumor activity. Recent studies demonstrated that
      KRN7000-pulsed antigen-presenting cells (APC) can activate natural killer T (NKT)
      cells, a novel T-cell lineage, and CD1d molecules on APC play an important role
      in the activation of NKT cells. However, it remains unclear whether alpha-GalCers
      actually bind to CD1d molecules. To address this question, we synthesized three
      kinds of biotinylated alpha-GalCer and a biotinylated beta-GalCer and found that
      the biotinylated alpha-GalCers significantly stimulate the proliferation of
      murine spleen cells, but the biotinylated beta-GalCer does not and that all
      biotinylated compounds bind to CD1d molecules.

PMID- 10346937
TI  - Synthesis and evaluation of new sulfur-containing L-arginine-derived inhibitors
      of nitric oxide synthase.
AB  - A series of compounds (7, 8, 10-17, 23) containing new functional groups derived
      by the combination of the substrate, intermediate, product, and known inhibitors
      of nitric oxide synthase (NOS) were prepared and evaluated against NOS. While
      none of the compounds assayed acted as a nitric oxide-producing substrate, the
      sulfur-containing arginine derivatives 10-12 were competitive inhibitors of iNOS
      with Ki's of 202, 7, and 58 microM, respectively. Compound 11 demonstrated the
      greatest potency against NOS-mediated citrulline formation for each of the three
      isoforms with IC50's of 6. 7, 19.7, and 13 microM for nNOS, eNOS, and iNOS,
      respectively. Compounds 10-12 each demonstrated a slight selectivity for
      inhibition of the neuronal isoform compared to the endothelial and inducible
      isoforms. These compounds also influenced the NADPH oxidase activity and heme
      iron spin state in a manner similar to structurally related compounds. Compound
      10, a thiocarbonyl-containing compound, decreased the NADPH oxidase activity of
      the enzyme (EC50 = 190 microM) and shifted the heme iron spin state toward a low
      spin configuration, similar to that of L-thiocitrulline. Compounds 11 and 12, S
      alkylthiocitrulline derivatives, decreased the NADPH oxidase activity of the
      enzyme (EC50 = 6.6 and 180 microM, respectively) and shifted the heme iron spin
      state toward a high-spin configuration, similar to that of L-S
      methylisothiocitrulline. Carbonyl-containing amino acid (7, 8, 23) and non-amino
      acid (13-17) analogues did not interact well with the enzyme.

PMID- 10346938
TI  - 3-Amino-5-phenoxythiophenes: syntheses and structure-function studies of a novel
      class of inhibitors of cellular L-triiodothyronine uptake.
AB  - A series of substituted 3-amino-5-phenoxythiophenes was synthesized starting from
      malodinitrile and carbon disulfide. The resulting dicyanoketenedithiolate reacts
      via Thorpe-Dieckmann cyclization with halogen methanes bearing electron
      withdrawing groups to give thiophene-2-thiolates, which can be transformed into 3
      amino-5-(methylsulfonyl)thiophene-4-carbonitriles. Replacement of the
      methylsulfonyl groups by substituted phenolates provides the substituted 3-amino
      5-phenoxythiophenes. Some of the derivatives show a considerable inhibitory
      potency for the L-T3 uptake in inhibition studies on human HepG2 hepatoma cells
      with maximum values of about 60% at a dose of 10(-5) M for the most potent 2
      benzoyl derivatives. The structure of the phenoxythiophenes fits well into a
      general concept derived for other classes of L-T3 uptake inhibitors, which
      postulates an angular and perpendicular orientation of the ring systems in these
      compounds as a prerequisite for an inhibitory potency. Docking studies for the
      phenoxythiophenes with transthyretin as a receptor model show their preferred
      attack at the L-T4/L-T3 binding channel.

PMID- 10346939
TI  - Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase
      for Alzheimer's disease.
AB  - Four novel analogues (8-11) of cymserine (2) were synthesized by methods similar
      to those recently developed for the total syntheses of N8-norphenserine (Yu, Q.
      S.; et al. J. Med. Chem. 1997, 40, 2895-2901) and N1,N8-bisnorphenserine (Yu, Q.
      S.; et al. J. Med. Chem. 1998, 41, 2371-2379). As our structure-activity studies
      predicted, these compounds are highly potent and selective inhibitors of human
      butyrylcholinesterase (BChE) and will test the novel hypothesis that BChE
      inhibitors are useful in the treatment of Alzheimer's disease. In a similar
      manner, the same modifications that provided BChE selectivity were applied to the
      acetylcholinesterase (AChE)-selective inhibitor, tolserine (5), to provide the
      novel tolserine analogues 12-15. As predicted, these modifications altered the
      AChE-selective action of tolserine (5) to favor a lack of cholinesterase enzyme
      subtype selectivity.

PMID- 10346940
TI  - New steroidal alkaloids from the roots of buxus sempervirens 
AB  - Phytochemical studies on an EtOH-soluble extract of the roots of Buxus
      sempervirens of Turkish origin have resulted in the isolation of three new
      steroidal alkaloids, (+)-semperviraminol (1), (+)-buxamine F (2), and (+)-17
      oxocycloprotobuxine (3), along with two known steroidal alkaloids, (+)
      buxoxybenzamine (4) and (+)-buxapapillinine (5). The structures of 1-3 were
      elucidated with the aid of spectroscopic studies. Compounds 4 and 5 exhibited
      phytotoxic activity against Lemna minor.

PMID- 10346941
TI  - Application of lipase-catalyzed regioselective esterification in the preparation
      of digitonin derivatives.
AB  - The oligosaccharide chain of the monodesmosidic haemolytic saponin digitonin (1)
      undergoes an efficient and regioselective acylation in organic solvent by use of
      Novozym 435 (lipase B from Candida antarctica supported on acrylic resin) in the
      presence of an activated ester. With vinyl acetate, acetylation occurs at C-6 OH
      of glucose(II) and C-4 OH of xylose to afford the previously unreported diacetyl
      derivative 2 and the monoacetyl derivatives 3 and 4. With vinyl laurate only the
      monolauryl derivative 5 is formed. The structures of these acylated digitonins
      have been established using modern 2D NMR techniques, which allowed complete
      assignments of all proton resonances. The hemolytic activity of derivatives 2-5
      is significantly reduced compared to that of digitonin.

PMID- 10346942
TI  - Antifungal jujubogenin saponins from Colubrina retusa.
AB  - Antifungal assay-guided isolation of the 95% ethanol extract of the stems of
      Colubrina retusa yielded jujubogenin 3-O-alpha-L-arabinofuranosyl(1-->2)-[beta-D
      glucopyranosyl (1-->3)]-alpha-L-arabinopyranoside (1), which showed modest growth
      inhibitory effects against Candida albicans, Cryptococcus neoformans, and
      Aspergillus fumigatus (MICs, 50 microg/mL). In addition, two new minor saponins,
      jujubogenin 3-O-alpha-L-arabinofuranosyl(1-->2)-[2-O-(trans, cis)p-coumaroyl-beta
      D-glucopyranosyl(1-->3)]-alpha-L-arabinopy ranosi de (2), and jujubogenin 3-O-(5
      O-malonyl)-alpha-L-arabinofuranosyl (1-->2)-[beta-D-glucopyranosyl(1-->3)]-alpha
      L-arabinopyranoside (3), were obtained. Saponin 2 was marginally active against
      only C. neoformans, with a MIC of 50 microg/mL, while 3 was inactive. NMR
      spectroscopy was used extensively for the structure determination of these
      compounds. The previously reported ambiguity of the NMR assignments of
      jujubogenin saponins for carbons -26 to -29 was clarified by a comprehensive
      analysis of the NMR spectra of 1.

PMID- 10346943
TI  - Antifungal metabolites from the marine sponge Pachastrissa sp.: new bengamide and
      bengazole derivatives.
AB  - This paper reports the studies of components of an undescribed sponge in the
      genus Pachastrissa sp., collected along the Djibouti coast. The extract showed
      activity against Candida albicans. Six new bengazoles (1-6) and a new bengamide,
      named bengamide L (16), in addition to the known bengazoles (7-11), bengamides A
      (12), B (13), E (14), and F (15), and a lactone (17) are described in this paper.
      All structures were determined on the basis of spectroscopic studies.

PMID- 10346944
TI  - Biotransformation of the trichoderma metabolite 6-n-pentyl-2H-pyran-2-one (6PAP)
      by selected fungal isolates 
AB  - A variety of fungi were tested for their ability to transform the antifungal
      Trichoderma metabolite 6-n-pentyl-2H-pyran-2-one (6PAP) (1). Three Penicillium
      isolates, a Sclerotinia isolate, and a Fusarium isolate were all able to rapidly
      metabolize 1 and gave mixtures of isomers of monohydroxylated 1 and, in some
      cases, products resulting from further oxidation to carboxylic acids. Among these
      products were four previously unidentified metabolites (6, 7, 8, and 9) which
      were isolated and characterized by NMR spectroscopy. Sphaeropsis sapinea,
      Ophiostoma quercus, Ophiostoma piceae, a Verticillium sp., and two additional
      Fusarium isolates were unable to metabolize 1 efficiently.

PMID- 10346945
TI  - Novel seco-prezizaane sesquiterpenes from north american illicium species 
AB  - Three novel seco-prezizaane sesquiterpenes (1-3) were isolated from leaves of
      Illicium parviflorum (swamp star anise, yellow star anise), a species occurring
      endemically in central Florida. Compound 1, named cycloparvifloralone, possesses
      a hitherto unknown ring system with a cagelike acetal/hemiketal structure.
      Lactones 2 (cycloparviflorolide) and 3 (parviflorolide) which were obtained as an
      inseparable mixture, coexist in a hemiketal/keto equilibrium. It could be shown
      that a 4,7-hemiketal (4) occurs in an analogous fashion to pseudoanisatin 5, a
      known constituent of other Illicium species. From the fruits of
      Illiciumfloridanum the novel ortholactone 6 was isolated. The structures of the
      new compounds were elucidated by interpretation of their 1D and 2D homo- and
      heteronuclear NMR spectroscopic data. The modes of cyclization observed in 1, 2,
      4, and 6 have not been described previously, and a biogenetic sequence is
      proposed for these compounds and further seco-prezizaane sesquiterpenes.

PMID- 10346946
TI  - Amathaspiramides A-F, novel brominated alkaloids from the marine bryozoan amathia
      wilsoni 
AB  - A series of six new dibrominated alkaloids, amathaspiramides A-F (1-6), have been
      isolated from a New Zealand collection of the marine bryozoan Amathia wilsoni. An
      X-ray crystallographic structural determination of amathaspiramide F (6) revealed
      it to be an epimer of amathaspiramide C (3). These data, in addition to the
      results of NOESY NMR experiments were used to infer the absolute configuration of
      the amathaspiramides.

PMID- 10346947
TI  - Sesquiterpenes from lippia integrifolia essential Oil 
AB  - Four sesquiterpenes (1-4) with the africanane skeleton [of which only 5
      africanene (1) has been previously reported] and the new asteriscane derivative
      asterisca-3(15),6-diene (5) were isolated from the essential oil of Lippia
      integrifolia. A further new compound, african-2(6)-ene (7), was obtained as a
      semisynthetic product by derivatization of isoafricanol (6). The structures of
      the new compounds were assigned on the basis of spectroscopic data,
      enantioselective gas chromatography, and by chemical correlations.

PMID- 10346948
TI  - Sesquiterpene esters from Celastrus orbiculatus and their structure-activity
      relationship on the modulation of multidrug resistance.
AB  - Six new (1-6) and three known (7-9) sesquiterpene esters were isolated from the
      roots of Celastrus orbiculatus. The structures of the new compounds were
      elucidated as 1beta-acetoxy-6alpha-furoyloxy-9alpha-benzoyl oxydihydro-beta
      agarofur an (1), 1beta-acetoxy-6alpha-benzoyloxy-9alpha-furoyloxydih ydro-beta
      agarofur an (2), 1beta-acetoxy-6alpha, 9alpha-difuroyloxydihydro-beta-agarofuran
      (3), 1beta, 2beta-diacetoxy-6alpha-furoyloxy-9alpha-benzo yloxydihydro-beta
      agarof uran (4), 1beta-acetoxy-2beta, 6alpha-difuroyloxy-9alpha-benzoyloxydihydro
      beta -agarofuran (5), and 1beta-acetoxy-2beta,6alpha, 9alpha-tribenzoyloxydihydro
      beta-agarofuran (6). Compounds 4, 5, and 7-9 were shown to be more active than
      verapamil in reversing vinblastine resistance in multidrug-resistant KB-V1 cells.

PMID- 10346949
TI  - Isolation of diterpenoid alkaloids from herb and flowers of aconitum napellus
      ssp. vulgare and electrospray ion trap multiple MS study of these alkaloids 
AB  - Chemical investigation of herb and flowers of Aconitum napellus L. ssp. vulgare
      led to the isolation of 12 diterpenoid alkaloids. Their chemical structures were
      identified on the basis of NMR and MS and of their complete ion trap multiple
      fragmentation mass spectrometry study.

PMID- 10346952
TI  - Carboxylic acid microbial metabolites of the natural benzoquinone, maesanin 
AB  - Maesanin (1) is a naturally occurring bioactive benzoquinone isolated from the
      fruits of Maesa lanceolata (Myrsinaceae). Three carboxylic acid metabolites of
      maesanin were isolated in the course of a prospective microbial transformation
      study. The first metabolite, 2, was produced by Lipomyces lipofer ATCC 10742 and
      was characterized as (Z)-15-(2'-hydroxy-5'-methoxy-3', 6'-dioxocyclohexa-1',4'
      dienyl)pentadec-5-enoic acid. Metabolites 3 and 4 were produced by Rhodotorula
      rubra ATCC 20129 and were characterized as 6-(2'-hydroxy-5'-methoxy-3',6'
      dioxocyclohexa-1', 4'-dienyl)hexanoic acid and 4-(2'-hydroxy-5'-methoxy-3', 6'
      dioxocyclohexa-1',4'-dienyl)butanoic acid, respectively.

PMID- 10346950
TI  - Geranins A and B, new antiprotozoal A-type proanthocyanidins from Geranium
      niveum.
AB  - Bioassay-guided fractionation of the antiprotozoal extract of Geranium niveum led
      to the isolation of two new A-type proanthocyanidins, epi-afzelechin-(4beta-->8,
      2beta-->O-->7)-afzelechin (1) and epi-catechin-(4beta-->8, 2beta-->O-->7)
      afzelechin (2). Compounds 1 and 2 were given the trivial names of geranins A and
      B, respectively. In addition, five known compounds, mahuannin B (3), reynoutrin
      (4), hyperin (5), methyl gallate (6), and 3-beta-caffeoyl-12-oleanen-28-oic acid
      (7), were obtained. The structures of the new proanthocyanidins were elucidated
      by spectroscopic and chemical methods as well as CD measurements. Compounds 1, 2,
      and 4-7 were tested against axenically grown trophozoites of Giardia lamblia and
      Entamoeba histolytica.

PMID- 10346951
TI  - A new bistetrahydrofuran acetogenin from the roots of Annona salzmanii.
AB  - A new bistetrahydrofuran acetogenin, salzmanin (1), was isolated from the MeOH
      extract of Annona salzmanii, in addition to the known compounds, squamocin,
      almunequin, bullatalicin, and annonacin. The structure of 1 was elucidated by
      spectroscopic methods, including LSIMS-MS technique, and confirmed by a chemical
      transformation. The cytotoxic activity of 1 and squamocin was investigated.

PMID- 10346953
TI  - Silenosides A-C, triterpenoid saponins from Silene vulgaris.
AB  - Three new triterpenoid saponins named silenosides A-C (1-3) were obtained from
      the roots of Silene vulgaris. Their structures were elucidated by spectral and
      chemical methods as beta-D-galactopyranosyl(1-->2)-beta-D-glucuronopyranosyl
      3beta- hydrox y-23-oxoolean-12-en-28-oic acid 28-O-beta-D-xylopyranosyl(1-->3)
      beta-D-xylopyranosyl(1-->4)-alpha-L- rhamnopyranosyl(1-->2)-beta-D
      fucopyranoside; 3-O-beta-D-galactopyranosyl(1-->2)-beta-D-glucuronopyranosyl
      3beta , 16alpha-dihydroxy-23-oxoolean-12-en-28-oic acid 28-O-beta-D
      xylopyranosyl(1-->4)-[beta-D-glucopyranosyl(1-->2)]-alpha -L-rhamnopyranosyl(1-
      >2)-beta-D-fucopyranoside; and 3-O-alpha-L-arabinopyranosyl(1-->3)-[beta-D
      galactopyranosyl(1-->2 )]- beta-D-glucuronopyranosyl-3beta, 16alpha-dihydroxy-23
      oxoolean-12-en-28-oic acid 28-O-beta-D-xylopyranosyl(1-->4)-[beta-D
      glucopyranosyl(1-->2)]-alpha -L-rhamnopyranosyl(1-->2)-beta-D-fucopyranoside,
      respectively.

PMID- 10346955
TI  - Microbial transformation of sesquiterpene lactones by the fungi cunninghamella
      echinulata and rhizopus oryzae 
AB  - Incubations of the fungi Cunninghamella echinulata and Rhizopus oryzae with the
      sesquiterpene lactones (+)-costunolide (1), (+)-cnicin (2), (+)-salonitenolide
      (3), (-)-dehydrocostuslactone (4), (-)-lychnopholide (5), and (-)-eremantholide C
      (6) were perfomed. Incubation of 1 with C. echinulata afforded Delta11(13)
      dihydrogenation and Delta1(10)-epoxidation products (7-10). C. echinulata also
      hydrolyzed the side chain of 2, and transformed 4 into (+)-11alpha,13
      dihydrodehydrocostuslactone (12), a new natural product. R. oryzae converted 4
      into both Delta11(13)-dihydrogenation and Delta10(14)-epoxidation products (16
      and 17). Both fungi transformed 5 into (-)-16-(1-methyl-1
      propenyl)eremantholanolide (13), providing experimental evidence for the
      biosynthesis of the eremantholide hemiketal unit. Compounds 3 and 6 were not
      metabolized by either fungus under the test conditions.

PMID- 10346954
TI  - Components of the ether-insoluble resin glycoside fraction from the seed of
      Cuscuta australis.
AB  - An ether-insoluble resin glycoside fraction was obtained from the seeds of
      Cuscuta australis. Identification and characterization of alkaline hydrolysis
      products by means of GC, FABMS, and 1H, 13C, and 2D NMR revealed the material to
      be composed of three new glycosidic acids, cuscutic acids A1-A3 (1-3);
      triglycosides with (11S)-jalapinolic or (11S)-convolvulinolic acid as the
      aglycon; and acetic, isobutyric, (2S)-2-methylbutyric, tiglic, and (2R,3R)-nilic
      acids. The resin glycoside is considered to be a complex mixture of glycosidic
      ester-type oligomers (up to heptamers) with a core consisting of a number of the
      above cuscutic acids each acylated with one or two carboxylic acid moieties.

PMID- 10346956
TI  - New verticillin and glisoprenin analogues from gliocladium catenulatum, a
      mycoparasite of aspergillus flavus sclerotia 
AB  - Four new compounds (1-4) have been isolated from solid-substrate fermentation
      cultures of the sclerotial mycoparasite Gliocladium catenulatum. The structures
      of verticillins D (1), E (2), and F (3) were assigned on the basis of MS and NMR
      data and chemical derivatization. The structure of glisoprenin F (4) was assigned
      by analysis of MS and NMR results, and comparison of its spectral data to those
      of the known compound glisoprenin D (6).

PMID- 10346957
TI  - Three novel constituents from curculigo capitulata and revision of C-2
      stereochemistry in nyasicoside 
AB  - Continuing study of the constituents of the rhizomes of Curculigo capitulata
      provided three novel compounds, including two norlignan glucosides,
      curcapicycloside (2) and (1S,2R)-O-methylnyasicoside (3), and a phenanthrofuran,
      curcapital (9). The former two compounds were characterized as their tetra-O
      methyl derivatives. Compound 2 possesses a glucosyl-fused skeleton with 1R,2R
      configuration. Biogenetic consideration led to a revision of the previously
      assigned 2S configuration of nyasicoside (1) to 2R, which was confirmed by NOE
      studies of the acetonide of its tetra-O-methyl derivative. The 2R configuration
      in tetra-O-methyl-1-O-methyl curculigine (7a) and isocurculigine (8a) was also
      established by chemical correlation of the former with (1R, 2R)-tetra-O-methyl-1
      O-methylnyasicoside (10a). Curcapital (9) represents the first natural product
      having a phenanthro[9,10, b]furan skeleton.

PMID- 10346958
TI  - Four new triterpenoidal saponins acylated with one monoterpenic acid from
      Gleditsia sinensis.
AB  - Four new oleanane-type triterpenoidal glycosides, named gleditsiosides A-D (1-4),
      were isolated from the anomalous fruits of Gleditsia sinensis. Using modern NMR
      techniques, including DQF-COSY, HETCOR, HOHAHA, HMBC, and ROESY experiments and
      MS analysis as well as chemical methods, their structures were determined as 3-O
      beta-D-xylopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1-->6)- bet a-D
      glucopyranosyl oleanolic acid 28-O-beta-D-xylopyranosyl-(1-->3)-beta-D
      xylopyranosyl-(1-->4)-alpha- L-rhamnopyranosyl-(1-->2)-[(6S,2E)-6-hydroxy-2,6
      dimethyl-2, 7-octadienoyl-(1-->6)]-beta-D-glucopyranosyl ester (1); 3-O-beta-D
      xylopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1-->6)- bet a-D-glucopyranosyl
      oleanolic acid 28-O-beta-D-xylopyranosyl-(1-->3)-beta-D-xylopyranosyl-(1-->4)
      alpha- L-rhamnopyranosyl-(1-->2)-[(2E)-2-hydroxylmethyl-6-hydroxy-6-methy l-2 ,7
      octadienoyl-(1-->6)]-beta-D-glucopyranosyl ester (2); 3-O-beta-D-xylopyranosyl-(1
      ->2)-alpha-L-arabinopyranosyl-(1-->6)- bet a-D-glucopyranosyl echinocystic acid
      28-O-beta-D-xylopyranosyl-(1-->3)-beta-D-xylopyranosyl-(1-->4)-[beta- D
      galactopyranosyl-(1-->2)]-alpha-L-rhamnopyranosyl-(1-->2)-[(2E)-2-h ydroxylmethyl
      6-hydroxy-6-methyl-2, 7-octadienoyl-(1-->6)]-beta-D-glucopyranosyl ester (3); and
      3-O-beta-D-xylopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1-->6)- bet a-D
      glucopyranosyl echinocystic acid 28-O-beta-D-xylopyranosyl-(1-->3)-beta-D
      xylopyranosyl-(1-->4)-[beta- D-galactopyranosyl-(1-->2)]-alpha-L-rhamnopyranosyl
      (1-->2)-[(6S, 2E)-6-hydroxy-2,6-dimethyl-2, 7-octadienoyl-(1-->6)]-beta-D
      glucopyranosyl ester (4).

PMID- 10346959
TI  - New naphthopyranone glycosides from Paepalanthus vellozioides and Paepalanthus
      latipes.
AB  - Three new compounds-3, 4-dihydro-10-hydroxy-7-methoxy-3-(R)-methyl-1H-3,4
      dihydronaphtho- ]2, 3c]-pyran-1-one-9-O-beta-D-glucopyranoside (1), 3, 4-dihydro
      10-hydroxy-7-methoxy-3-(R)-methyl-1H-3,4-dihydronaphtho- [2, 3c]-pyran-1-one-9-O
      beta-D-glucopyranosyl-(1-->6)-glucopyranoside (2), and 3,4-dihydro-10-dihydroxy-7
      methoxy-3-(R)-methyl-1H-3, 4-dihydronaphtho-[2,3c]-pyran-1-one-9-O-beta-D
      allopyranosyl (1-->6)glucopyranoside (3)-were isolated from the leaves of
      Paepalanthus vellozioides and Paepalanthus latipes and characterized by
      spectrometric methods, mainly electrospray mass spectrometry and 1D and 2D NMR
      experiments. These unusual glycosylated dihydronaphthopyranones may serve as
      taxonomic markers of the genus Paepalanthus, since these compounds were not
      detected in other genera belonging to the Eriocaulaceae family.

PMID- 10346962
TI  - New furanocembranoid diterpenes from the soft coral sinularia maxima 
AB  - The soft coral Sinularia maxima yielded five terpenoids and one sterol, including
      two new furanocembranoid diterpenoids (1 and 2). The structures of these new
      compounds were determined by the interpretation of their spectral data.

PMID- 10346960
TI  - A new antibiotic nortriterpene quinone methide from Maytenus catingarum.
AB  - 15alpha-Hydroxy-21-keto-pristimerine (1), a new nortriterpene quinone methide was
      isolated from the root bark of Maytenus catingarum along with other well-known
      related compounds, including pristimerine (2), tingenone, and 20alpha-hydroxy
      tingenone. The structure of 1 was determined by means of 1H and 13C NMR
      spectroscopy, including homonuclear and heteronuclear correlations. Compound 1
      showed antibiotic activity against Gram-positive bacteria.

PMID- 10346961
TI  - Prenylagaramides A and B, new cyclic peptides from two strains of oscillatoria
      agardhii 
AB  - Prenylagaramides A (1) and B (2), two new cyclic peptides, were isolated from the
      cultured cyanobacteria Oscillatoria agardhii (NIES-205) and O. agardhii (NIES
      596), respectively. The structures of 1 and 2, which both contain a rare O
      prenyltyrosine (Ptyr) unit, were established as cyclo(-Ptyr1-Gly2-Thr3-Gly4-Glu5
      Phe6-Phe7-Asn8-Pro9-) and cyclo(-Ptyr1-Leu2-Tyr3-Pro4-Ile5-Asn6-Pro7-),
      respectively, by spectroscopic analysis and chemical degradation.

PMID- 10346963
TI  - A beta-carboline alkaloid from the soft coral lignopsis spongiosum 
AB  - From an EtOH extract of Lignopsis spongiosum, a new beta-carboline alkaloid, 2
      methyl-9H-pyrido[3,4b]indole-3-carboxylic acid (1), was isolated and
      characterized by spectral methods.

PMID- 10346964
TI  - Glucosidation of betulinic acid by Cunninghamella species.
AB  - Microbial transformation of the antimelanoma agent betulinic acid (1) was
      studied. Preparative scale biotransformation with resting-cell suspensions of
      Cunninghamella species NRRL 5695 resulted in the production of a fungal
      metabolite of 1, which has been characterized as 28-O-beta-D-glucopyranosyl 3beta
      hydroxy-lup-20(29)-en-28-oate (2) based on spectral and enzymic data. The in
      vitro cytotoxicity assay of metabolite 2 revealed no activity against several
      human melanoma cell lines.

PMID- 10346965
TI  - Two bioactive pentacyclic triterpene esters from the root bark of Hibiscus
      syriacus.
AB  - Two new triterpene caffeates have been isolated from the root bark of Hibiscus
      syriacus. Their structures were established through various spectral studies as
      3beta,23,28-trihydroxy-12-oleanene 23-caffeate (1) and 3beta,23,28-trihydroxy-12
      oleanene 3beta-caffeate (2). Compounds 1 and 2 showed lipid peroxidation
      inhibitory activity and significant cytotoxicity against a panel of human cancer
      cell lines.

PMID- 10346966
TI  - Two auronols from Pseudolarix amabilis.
AB  - Two new auronols, amaronols A (1) and B (2), were isolated from the bark of
      Pseudolarix amabilis, along with pseudolaric acid B (3), pseudolaric acid C (4),
      demethoxydeacetoxy-pseudolaric acid B (5), pseudolaric acid B-beta-D-glucoside
      (6), pseudolaric acid A-beta-D-glucoside (7), and myricetin (8). The structures
      of amaronols A and B were established by spectral data interpretation as 2,4,6
      trihydroxy-2-[(3',4',5'-trihydroxyphenyl) methyl]-3(2H)-benzofuranone and 2,4,6
      trihydroxy-2-[(3', 5'-dihydroxy-4'-methoxyphenyl) methyl]-3(2H)-benzofuranone,
      respectively. Antimicrobial testing results of the eight compounds indicated that
      only pseudolaric acid B was active against Candida albicans (MIC, 3.125
      microg/mL; MFC, 6.25 microg/mL), while myricetin was marginally active against
      Trichophyton mentagrophytes (MIC, 50 microg/mL).

PMID- 10346967
TI  - Furohyperforin, a prenylated phloroglucinol from st. John's wort
      (Hypericumperforatum) 
AB  - Furohyperforin, an oxygenated analogue of the prenylated phloroglucinol
      hyperforin, was isolated from the aerial parts of Hypericum perforatum. Its
      structure was elucidated as 2 on the basis of extensive NMR investigations.

PMID- 10346968
TI  - A cyclitol derivative as a replication inhibitor from the marine sponge Petrosia
      sp.
AB  - A bioactive cyclitol derivative (1) was isolated from the marine sponge Petrosia
      sp. The chemical structure of 1 was determined as (2S)-1-O-(2',3',4',5'
      tetrahydroxycyclopentyl)-3-O-(10' '-methylhexadecyl)glycerol. Compound 1
      inhibited DNA replication in vitro at the level of initiation.

PMID- 10346969
TI  - Evidence for de novo biosynthesis of the polyketide fragment of diaulusterol A by
      the northeastern pacific dorid nudibranch diaulula sandiegensis 
AB  - Stable isotope incorporation experiments using sodium [1, 2-13C2]acetate have
      demonstrated that the 3-hydroxybutyrate substituent of diaulusterol A (1) is
      biosynthesized de novo by the dorid nudibranch Diaulula sandiegensis. There was
      no evidence for acetate incorporation into the steroid portion of 1, nor were
      radiolabeled mevalonate or cholesterol incorporated.

PMID- 10346970
TI  - A new 1,2-dihydroisoquinoline from the sponge petrosia similis 
AB  - A new 1,2-dihydroisoquinoline (1) and a known isoquinolinequinone (2) have been
      isolated from the sponge Petrosia similis and characterized by the study of
      spectral data.

PMID- 10346971
TI  - Diterpenoids from isodon eriocalyx 
AB  - Three new diterpenoids, eriocalyxins C-E (1-3), were isolated from Isodon
      eriocalyx. Their structures were elucidated as 6beta-hydroxy-15beta-acetoxy
      3alpha,20-epoxy-16beta, 17-epoxy-ent-kaur-1,7-dione (1), 1alpha,7beta-dihydroxy
      6beta, 15beta-diacetoxy-7,20-epoxy-ent-kaur-16-ene (2), and 15beta-acetoxy-1,6
      dioxo-6,7-seco-ent-kaur-2,16-dien-7,20-olide (3), respectively, by means of
      spectroscopic methods, including one- and two-dimensional NMR techniques.

PMID- 10346972
TI  - An unusual novel C29 steroid from the soft coral lobophytum crassum1 
AB  - A new sterol, 23,24(S)-dimethylcholest-5,22-dien-3beta,7alpha-diol (1), has been
      isolated from the soft coral Lobophytum crassum and characterized by
      interpretation of spectral data.

PMID- 10346973
TI  - Unguisins A and B: new cyclic peptides from the marine-derived fungus emericella
      unguis 
AB  - Unguisin A (1) and B (2), the first cyclic heptapeptides containing GABA in the
      ring, were isolated from a marine-derived strain of Emericella unguis. The
      chemical structures of 1 and 2 were elucidated by extensive 2D NMR techniques,
      and the stereochemistry of the individual amino acids was determined using
      Marfey's method.

PMID- 10346974
TI  - Semisynthesis of 3-beta-hydroxyartemisinin 
AB  - 3-beta-Hydroxyartemisinin (5) was synthesized from 3-beta
      hydroxydihydroartemisinic acid (7c) via singlet oxygen oxidation followed by air
      (triplet oxygen) oxidation. Compound 7c was synthesized in two steps from
      dihydroartemisinic acid, 7a.

PMID- 10346975
TI  - Trypargine alkaloids from a previously undescribed Eudistoma sp. ascidian.
AB  - The MeOH extract of an undescribed Eudistoma sp. ascidian was found to contain
      the known beta-carboline trypargine (3); the two novel trypargine derivatives
      trypargimine (4) and 1-carboxytrypargine (5); and 3',5'-dibromo-4'
      methoxyphenethylamine (6). The structures of the novel trypargine derivatives
      were elucidated through the use of mass spectrometry and NMR. The trypargine
      isolated in this study was found to be nearly racemic in contrast to the
      previously described isolate which was chiroptically pure. Other previously
      described compounds detected in the MeOH extract include 4
      hydroxyphenylacetamide, tryptamine, 1,3,7-trimethylguanine, and
      tetrahydropentoxyline (7).

PMID- 10346976
TI  - Isolation of norditerpenoid alkaloids from flowers of aconitum lycoctonum 
AB  - The structures of two new lycoctonine-type alkaloids having an acetoxy group at C
      6, 6-O-acetyldemethylenedelcorine (1) and 6-O-acetyl-14-O-methyldelphinifoline
      (2), isolated from the flowers of Aconitum lycoctonum, were determined by
      spectroscopic analysis. In addition, 14-O-methyldelphinifoline (4), gigactonine
      (5), and lycoctonine (6) were obtained.

PMID- 10346977
TI  - Iridal-type triterpenoids with ichthyotoxic activity from belamcanda chinensis 

PMID- 10346978
TI  - Identification and characterization of SIGIRR, a molecule representing a novel
      subtype of the IL-1R superfamily.
AB  - A novel member of the interleukin 1 receptor (IL-1R) superfamily, SIGIRR (single
      Ig IL-1R-related molecule) was identified in mouse and human. Although it shows
      the typical conserved motifs that characterize the IL-1R and Toll superfamily, it
      is structurally and functionally distinct from both. SIGIRR has only one Ig
      domain in its extracellular portion whereas the IL-1R family contains three Ig
      folds. An unusually long cytoplasmic domain is reminiscent of the structure of
      drosophila Toll, yet the SIGIRR peptide sequence is more closely related to IL
      1RI. The human SIGIRR gene maps to 11p15. 5 and thus is not located in the same
      cluster on chromosome 2 that is known to contain four members of the IL-1R
      family. It failed to bind to the known IL-1-family members and, when co-expressed
      with the IL-1RI, had no effect on the binding of IL-1 and on subsequent nuclear
      factor kappaB (NFkappaB) activation. A chimera, in which the SIGIRR intracellular
      domain was fused to the IL-1R extracellular domain, did not activate NFkappaB
      unlike similar fusion proteins of other IL-1R related molecules. We conclude that
      the SIGIRR protein represents a novel subtype of the IL-1R superfamily.

PMID- 10346979
TI  - Interleukin 1beta increases arginine accumulation and activates the citrulline-NO
      cycle in rat pancreatic beta cells.
AB  - Nitric oxide (NO) may contribute to pancreatic beta cell damage during the
      development of type 1 diabetes. Its formation can be triggered by cytokines which
      induce the expression of the inducible form of nitric oxide synthase (iNOS) in
      pancreatic islets. In the iNOS-catalyzed reaction, arginine is converted into
      citrulline and NO. Cellular NO formation may be regulated by the availability of
      arginine. Arginine can be provided extracellularly, entering the cell mainly
      through the cationic amino acid transporter system y+CAT, and intracellularly, by
      protein degradation or synthesis from citrulline (the citrulline-NO cycle). This
      study demonstrates for the first time that the citrulline-NO cycle is induced in
      FACS-purified rat beta cells exposed to interleukin-1beta(IL-1beta) and that
      extracellular arginine or citrulline is required for NO production by beta cells.
      Moreover, the accumulation of arginine was higher in IL-1beta-treated beta cells
      than in control cells.beta cells expressed mRNAs for the two y+CAT transporters
      CAT-2A and CAT-2B with no change in transporter expression after exposure to IL
      1beta. It is concluded that the activation of the citrulline-NO cycle and an
      increase in arginine accumulation may be adaptive responses in cytokine-exposed
      beta-cells to assure an adequate arginine supply for continuous NO production in
      the presence of low extracellular arginine levels which may prevail during
      insulitis.

PMID- 10346980
TI  - Synergism between lipopolysaccharide and interferon gamma in the regulation of
      lipoprotein lipase in macrophages.
AB  - The regulation of macrophage lipoprotein lipase (LPL) by cytokines is potentially
      of crucial importance in the pathogenesis of atherosclerosis and in septic shock.
      The effect of combinations of lipopolysaccharide (LPS) and cytokines on the
      expression of LPL in macrophages was studied using the murine J774.2 cell line.
      The suppression of heparin-releasable LPL activity produced by combinations of
      LPS and interleukin 1 (IL-1), IL-11 or tumour necrosis factor alpha(TNF-alpha)
      was substantially less than that expected from the simple additive action of the
      corresponding two effectors. By contrast, co-exposure of the cells to LPS and
      interferon gamma(IFN-gamma) resulted in a more than additive, synergistic,
      suppression of LPL activity which was, additionally, also observed when the rat
      alveolar macrophage NR8383 cell line was studied. This synergistic action was
      also observed when J774.2 macrophages were exposed initially to IFN-gamma
      (priming), washed and then treated with LPS. A comparison of the LPL activity and
      mRNA levels produced by the synergistic action of LPS and IFN-gamma and the
      priming action of IFN-gamma indicated that a combination of mRNA metabolism
      (transcription or RNA stability), translation and post-translational mechanisms
      were responsible for the observed changes in LPL activity. These data, therefore,
      suggest that combinations of LPS and cytokines may be more important than the
      presence or absence of any given single effector in the modulation of LPL
      function during infection.

PMID- 10346981
TI  - Effect of ultrasound on the production of IL-8, basic FGF and VEGF.
AB  - Therapeutic angiogenesis is the controlled induction or stimulation of new blood
      vessel formation to reduce unfavourable tissue effects caused by local hypoxia
      and to enhance tissue repair. The effects of ultrasound on wound healing, chronic
      ulcers, fracture healing and osteoradionecrosis may be explained by the
      enhancement of angiogenesis. The aim of this study was to identify which
      cytokines and angiogenesis factors are induced by ultrasound in vitro. Two
      ultrasound machines were evaluated, a "traditional" (1 MHz, pulsed 1:4, tested at
      four intensities), and a "long wave" machine (45 kHz, continuous, also tested at
      four intensities). The ultrasound was applied to human mandibular osteoblasts,
      gingival fibroblasts and peripheral blood mononuclear cells (monocytes). The
      following cytokines and angiogenesis factors were assayed by ELISA techniques:
      interleukin-1beta(IL-1beta), IL-6, tumour necrosis factor alpha (TNF-alpha), IL
      8, fibroblast growth factor (bFGF) and vascular endothelial growth factor
      (VEGF).A slight stimulation of IL-1beta was noted in all cell types. There was no
      difference in the IL-6 and TNF-alpha levels. The angiogenesis-related cytokines,
      IL-8 and bFGF, were significantly stimulated in osteoblasts, and VEGF was
      significantly stimulated in all cell types. Both ultrasound machines produced
      similar results, and the optimum intensities were 0.1 and 0. 4 W/cm2 (SATA) with
      1 MHz ultrasound, and 15 and 30 mW/cm2 (SATA) with 45 kHz ultrasound.The results
      show that therapeutic ultrasound stimulates the production of angiogenic factors
      such as IL-8, bFGF and VEGF. This may be one of the mechanisms through which
      therapeutic ultrasound induces angiogenesis and healing.

PMID- 10346982
TI  - Chemokine production by human megakaryocytes derived from CD34-positive cord
      blood cells.
AB  - To clarify the roles of megakaryocytes and platelets in the responses associated
      with infection and inflammation, we examined the effects of interleukin (IL) 1,
      the common mediator of the inflammatory process, on the development and secretory
      functions of megakaryocytes generated from CD34(+)cord blood cells under
      stimulation with thrombopoietin (TPO). The addition of IL-1alpha did not
      influence the generation, endomitosis or expression of surface makers of
      megakaryocytes, compared with TPO alone. However, IL-1alphaenhanced the ability
      of megakaryocytes to produce IL-8 and growth-regulating oncogene-alpha(GRO-alpha)
      in the presence of TPO. In contrast, the production of regulated on activation
      with normal T cell expressed and secreted (RANTES), platelet factor 4 (PF4) and
      beta-thromboglobulin (beta-TG) were not potentiated. A flow cytometric analysis
      and a reverse transcription-polymerase chain reaction analysis revealed IL-1
      receptor type I (IL-1RI) expression of megakaryocytes generated by TPO. Moreover,
      the addition of an anti-IL-1RI monoclonal antibody significantly decreased the
      TPO plus IL-1alpha-induced secretion of IL-8 by the cultured megakaryocytes to
      the level attained by TPO alone. These results suggest that the production of IL
      8 and GRO-alpha (but not RANTES), PF4 and beta-TG, by megakaryocytes is
      potentiated by signalling through IL-1RI with the aid of TPO. Thus,
      megakaryocytes and platelets may play an important role in the development of
      inflammation via chemokine release.

PMID- 10346983
TI  - Relations between IL-3-induced proliferation and in vitro cytokine secretion of
      bone marrow cells from AML patients.
AB  - The influence of IL-3 on the bone marrow cells of 53 patients with acute myeloid
      leukaemia (AML) was investigated after 72 h suspension in cultures by analysing
      the proliferation of blasts and the secretion of cytokines. The titres of IL
      1beta IL-6, TNF-alpha and IL-3 were measured in the supernatants of these
      cultures with ELISA tests. Comparing the percentage of cells in S-phases of
      control cultures and cultures with IL-3, the leukaemias were divided into two
      growth pattern groups: IL-3-insensitive (n=19) and IL-3-sensitive (n=34)
      leukaemias. The IL-3-insensitive AML cells show a greater ability for autonomous
      growth, first by the increase of S-phase in the control culture compared with the
      S-phase in vivo (P=0.0486) and second, by the higher constitutive secretion
      (control culture) of IL-1beta P =0.0004), IL-6 ( P =0.0395) and TNF-alpha
      P=0.0005). The IL-3-induced secondary cytokine secretion is also different in the
      two growth pattern groups. Whereas in the IL-3-insensitive AML cells a moderate
      increase of IL-1beta (1.48-fold increase) was present, in the IL-3-sensitive AML
      cells a 4.72-fold increase of IL-1beta 2.71-fold increase of IL-6 and 11.81-fold
      increase of the TNF-alpha titre could be detected. Overall, the data show an
      inverse correlation between the ability of AML cells to respond to IL-3 with
      increase of an S-phase and the constitutive secretion of IL-1beta, II-6 and TNF
      alpha. A further effect of IL-3 is the induction of secondary cytokine secretion
      in the bone marrow of IL-3-sensitive growing AML cells.

PMID- 10346984
TI  - Dehydroepiandrosterone restores immune function following trauma-haemorrhage by a
      direct effect on T lymphocytes.
AB  - Although a profound depression in immune function occurs following injury, the
      mechanism responsible for this is not fully understood. Furthermore, steroid
      hormones are known to be important mediators in the regulation of immune
      function. Although dehydroepiandrosterone (DHEA), the most plentiful steroid
      hormone, has been shown to stimulate immune function in normal animals, it is
      unknown whether DHEA has any salutary or detrimental effects on immune responses
      after trauma and haemorrhage. To study this, male mice were subjected to trauma,
      haemorrhage and resuscitation, following which they received either DHEA or
      vehicle subcutaneously. DHEA administration restored the normally depressed
      splenocyte proliferation as well as interleukin 2, interleukin 3, and interferon
      gamma elaboration following trauma and haemorrhage. In an attempt to determine
      the mechanisms mediating this effect, T cells were stimulated in vitro in the
      presence of DHEA and a variety of hormone antagonists. The stimulatory effect of
      DHEA on splenocyte proliferation was unaltered by the testosterone receptor
      antagonist flutamide, while the oestrogen antagonist tamoxifen completely
      abrogated its effect. In addition, DHEA administration normalized the elevated
      serum corticosterone level typically seen following injury. These results
      indicate, therefore, that DHEA improves splenocyte function after trauma and
      haemorrhage by directly stimulating T cells and also by preventing a rise in
      serum corticosterone.

PMID- 10346985
TI  - Quantification of human interleukin 18 mRNA expression by competitive reverse
      transcriptase polymerase chain reaction.
AB  - Interleukin 18 (IL-18) is a recently identified cytokine, originally called
      interferon gamma inducing factor, due to its capacity to induce interferon gamma
      production in Th1 type cells. IL-18 is expressed by a wide variety of cell types
      including mononuclear phagocytes, osteoblasts, keratinocytes and adrenal cortex
      cells. To quantify human IL-18 mRNA expression in small-scale cell samples the
      authors developed a competitive reverse transcriptase polymerase chain reaction
      using a competitive template as an internal standard. This assay was demonstrated
      as a valid, sensitive and precise tool to quantify human IL-18 mRNA expression.
      IL-18 mRNA expression of primary peripheral blood monocytes, CD4(+)T cells,
      CD8(+)T cells, B cells and NK cells was assessed by competitive RT-PCR. Basal IL
      18 expression could be detected in all types of peripheral blood mononuclear
      cells (PBMC). The kinetics of IL-18 mRNA expression in PBMC from healthy donors
      was defined in vitro after monocyte-specific (lipopolysaccharide LPS), T-cell
      specific (anti-CD3) and polyclonal-unspecific stimulation (phytohaemagglutinin
      PHA). Only LPS led to a strong increase of IL-18 mRNA expression peaking after 2
      h. These results indicate that IL-18 is expressed constitutionally by all major
      PBMC subtypes. However, only monocyte specific stimulation resulted in a
      significant induction of IL-18 mRNA expression suggesting activated monocytes
      e.g. in inflammation as the main source of IL-18 expression.

PMID- 10346986
TI  - A quantitative focus assay for titration of retroviruses that encode human
      granulocyte-macrophage colony-stimulating factor (GM-CSF).
AB  - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a haematopoietic
      growth factor that regulates proliferation, differentiation, and effector
      functions of monocyte-macrophages and granulocytic cells. Because of the ability
      of this cytokine to enhance immune functions of antigen-presenting cells,
      retroviruses encoding GM-CSF have been used to transduce GM-CSF into murine and
      human tumour cells as part of autologous tumour vaccine strategies. We have
      previously shown that NIH 3T3 cells engineered to express functional human GM-CSF
      receptors (hGMR-NIH 3T3), become fully transformed when these cells are incubated
      in the presence but not in the absence of human GM-CSF. In this study we have
      used these hGM-CSF conditional transformants to devise a sensitive focus assay to
      titrate retroviruses encoding hGM-CSF, using MFG-hGM-CSF/Psi-CRIP as our model
      virus. This helper-free amphotropic retrovirus, which has been frequently used to
      transduce hGM-CSF into tumour cells, was quite transforming in our indicator cell
      line, exhibiting virus titres well above 10(5)FFU/ml. The transformation-based
      assay described here allows rapid determination of the titre of hGM-CSF-viruses,
      and may serve as a model for development of quantitative assays for other
      cytokine-encoding viruses of clinical importance.

PMID- 10346987
TI  - Building a network of research in children's environmental health.

PMID- 10346988
TI  - Etiology and pathogenesis of airway disease in children and adults from rural
      communities.
AB  - Asthma is the most common chronic disease of childhood and affects nearly 5
      million children. The prevalence and severity of childhood asthma have continued
      to increase over the past decade despite major advances in the recognition and
      treatment of this condition. A comparison of urban and rural children suggests
      that the etiology of airway disease is multifactorial and that unique exposures
      and genetic factors contribute to the development of asthma in both settings. The
      most important environmental exposure that distinguishes the rural environment
      and is known to cause asthma is the organic dusts. However, animal-derived
      proteins, common allergens, and low concentrations of irritants also contribute
      to the development of airway disease in children and adults living in rural
      communities. A fundamental unanswered question regarding asthma is why only a
      minority of children who wheeze at an early age develop persistent airway disease
      that continues throughout their life. Although genetic factors are important in
      the development of asthma, recurrent airway inflammation, presumably mediated by
      environmental exposures, may result in persistent airway hyperresponsiveness and
      the development of chronic airway disease. Increasing evidence indicates that
      control of the acute inflammatory response substantially improves airflow and
      reduces chronic airway remodeling. Reducing exposure to agricultural dusts and
      treatment with anti-inflammatory medication is indicated in most cases of
      childhood asthma. In addition, children with asthma from rural (in comparison to
      urban) America face multiple barriers that adversely affect their health e.g.,
      more poverty, geographic barriers to health care, less health insurance, and
      poorer access to health care providers. These unique problems must be considered
      in developing interventions that effectively reduce the morbidity and mortality
      of asthma in children from rural communities.

PMID- 10346989
TI  - A theoretical basis for investigating ambient air pollution and children's
      respiratory health.
AB  - Acute respiratory health effects in children from exposure at current ambient
      levels of ozone are well documented; however, evidence for acute effects from
      other criteria pollutants such as nitrogen dioxide and respirable particles is
      inconsistent. Whether chronic effects result from long-term exposure to any of
      these pollutants during childhood is an important unresolved question.
      Establishing whether acute or chronic effects result from childhood exposure and
      identifying sensitive subgroups may require integration of biologic mechanisms of
      lung defenses, injury, and response into the study design and statistical models
      used in analyses. This review explores the theoretical basis for explaining such
      adverse effects in light of our contemporary understanding of mechanisms of lung
      injury and response at the cellular and molecular levels. The rapidly evolving
      understanding of the effects of air pollution on cellular and molecular levels
      presents an opportunity to develop and refine innovative biologically based
      hypotheses about the effects of childhood exposure. We hypothesize that children
      with low fruit and vegetable intake, low antioxidant levels, high polyunsaturated
      fat intake, or who have inherited certain alleles for genes involved in lung
      defenses and immune response regulation may be at increased risk for adverse
      effects. Because responses to air pollutants of interest are complex and involve
      a number of pathophysiologic processes, the magnitude of main effects of dietary
      factors, genes, and gene-environment interactions may be modest for individuals;
      however, each may make an important contribution to the population burden of
      preventable respiratory diseases.

PMID- 10346990
TI  - Exposures of children to organophosphate pesticides and their potential adverse
      health effects.
AB  - Recent studies show that young children can be exposed to pesticides during
      normal oral exploration of their environment and their level of dermal contact
      with floors and other surfaces. Children living in agricultural areas may be
      exposed to higher pesticide levels than other children because of pesticides
      tracked into their homes by household members, by pesticide drift, by breast milk
      from their farmworker mother, or by playing in nearby fields. Nevertheless, few
      studies have assessed the extent of children's pesticide exposure, and no studies
      have examined whether there are adverse health effects of chronic exposure. There
      is substantial toxicologic evidence that repeated low-level exposure to
      organophosphate (OP) pesticides may affect neurodevelopment and growth in
      developing animals. For example, animal studies have reported neurobehavorial
      effects such as impairment on maze performance, locomotion, and balance in
      neonates exposed (italic)in utero(/italic) and during early postnatal life.
      Possible mechanisms for these effects include inhibition of brain
      acetylcholinesterase, downregulation of muscarinic receptors, decreased brain DNA
      synthesis, and reduced brain weight in offspring. Research findings also suggest
      that it is biologically plausible that OP exposure may be related to respiratory
      disease in children through dysregulation of the autonomic nervous system. The
      University of California Berkeley Center for Children's Environmental Health
      Research is working to build a community-university partnership to study the
      environmental health of rural children. This Center for the Health Assessment of
      Mothers and Children of Salinas, or CHAMACOS in Monterey County, California, will
      assess (italic)in utero(/italic) and postnatal OP pesticide exposure and the
      relationship of exposure to neurodevelopment, growth, and symptoms of respiratory
      illness in children. The ultimate goal of the center is to translate research
      findings into a reduction of children's exposure to pesticides and other
      environmental agents, and thereby reduce the incidence of environmentally related
      disease.

PMID- 10346991
TI  - Pesticides and inner-city children: exposures, risks, and prevention.
AB  - Six million children live in poverty in America's inner cities. These children
      are at high risk of exposure to pesticides that are used extensively in urban
      schools, homes, and day-care centers for control of roaches, rats, and other
      vermin. The organophosphate insecticide chlorpyrifos and certain pyrethroids are
      the registered pesticides most heavily applied in cities. Illegal street
      pesticides are also in use, including tres pasitos (a carbamate), tiza china, and
      methyl parathion. In New York State in 1997, the heaviest use of pesticides in
      all counties statewide was in the urban boroughs of Manhattan and Brooklyn.
      Children are highly vulnerable to pesticides. Because of their play close to the
      ground, their hand-to-mouth behavior, and their unique dietary patterns, children
      absorb more pesticides from their environment than adults. The long persistence
      of semivolatile pesticides such as chlorpyrifos on rugs, furniture, stuffed toys,
      and other absorbent surfaces within closed apartments further enhances urban
      children's exposures. Compounding these risks of heavy exposures are children's
      decreased ability to detoxify and excrete pesticides and the rapid growth,
      development, and differentiation of their vital organ systems. These
      developmental immaturities create early windows of great vulnerability. Recent
      experimental data suggest, for example, that chlorpyrifos may be a developmental
      neurotoxicant and that exposure in utero may cause biochemical and functional
      aberrations in fetal neurons as well as deficits in the number of neurons.
      Certain pyrethroids exert hormonal activity that may alter early neurologic and
      reproductive development. Assays currently used for assessment of the toxicity of
      pesticides are insensitive and cannot accurately predict effects to children
      exposed in utero or in early postnatal life. Protection of American children, and
      particularly of inner-city children, against the developmental hazards of
      pesticides requires a comprehensive strategy that monitors patterns of pesticide
      use on a continuing basis, assesses children's actual exposures to pesticides,
      uses state-of-the-art developmental toxicity testing, and establishes societal
      targets for reduction of pesticide use.

PMID- 10346992
TI  - The environment and asthma in U.S. inner cities.
AB  - The prevalence and severity of asthma has increased in the last 20 years, and the
      greatest increase has been seen among children and young adults living in U.S.
      inner cities. The reasons for this increase are obviously complex, but include
      environmental exposures to allergens and pollutants, changing patterns of
      medication, and the psychosocial stresses of living in poor inner-city
      neighborhoods. This paper presents an overview of environmental, immunologic, and
      genetic factors associated with asthma morbidity and mortality. This overview can
      be used to provide a framework for designing an interdisciplinary research
      program to address the complexities of asthma etiology and exacerbation. The
      strongest epidemiologic association has been found between asthma morbidity and
      the exposure of immunologically sensitive asthmatic patients to airborne
      allergens. Our current understanding of the process of sensitization suggests
      that there is a strong genetic predisposition to form IgE to allergenic proteins
      on airborne particles. Much of this work has been conducted with animal models,
      but in a number of instances, specific confirmation has been reported in humans.
      Sensitized individuals respond to inhaled exposure with immediate mast-cell
      dependent inflammation that may be augmented by pollutant particles, especially
      diesel exhaust particles. Relatively little is known about the methods of
      assessing exposure to airborne pollutants, especially biologically active
      particulates. However, to examine the relationship of morbidity in genetically
      predisposed individuals, it will be important to determine the most relevant
      method of making this assessment.

PMID- 10346994
TI  - Indoor mold and Children's health
AB  - Reactive airways disease in children is increasing in many countries around the
      world. The clinical diagnosis of asthma or reactive airways disease includes a
      variable airflow and an increased sensitivity in the airways. This condition can
      develop after an augmented reaction to a specific agent (allergen) and may cause
      a life-threatening situation within a very short period of exposure. It can also
      develop after a long-term exposure to irritating agents that cause an
      inflammation in the airways in the absence of an allergen. (paragraph) Several
      environmental agents have been shown to be associated with the increased
      incidence of childhood asthma. They include allergens, cat dander, outdoor as
      well as indoor air pollution, cooking fumes, and infections. There is, however,
      increasing evidence that mold growth indoors in damp buildings is an important
      risk factor. About 30 investigations from various countries around the world have
      demonstrated a close relationship between living in damp homes or homes with mold
      growth, and the extent of adverse respiratory symptoms in children. Some studies
      show a relation between dampness/mold and objective measures of lung function.
      Apart from airways symptoms, some studies demonstrate the presence of general
      symptoms that include fatigue and headache and symptoms from the central nervous
      system. At excessive exposures, an increased risk for hemorraghic pneumonia and
      death among infants has been reported. (paragraph) The described effects may have
      important consequences for children in the early years of life. A child's immune
      system is developing from birth to adolescence and requires a natural,
      physiologic stimulation with antigens as well as inflammatory agents. Any
      disturbances of this normal maturing process will increase the risk for abnormal
      reactions to inhaled antigens and inflammagenic agents in the environment.
      (paragraph) The knowledge about health risks due to mold exposure is not
      widespread and health authorities in some countries may not be aware of the
      serious reactions mold exposure can provoke in some children. Individual
      physicians may have difficulty handling the patients because of the lack of
      recognition of the relationship between the often complex symptoms and the indoor
      environment (paragraph) The workshop was organized to develop a basis for risk
      assessment and formulation of recommendations, particularly for diagnostic
      purposes and prevention, and to formulate priorities for future research. The
      participants were all active researchers with current experience in child health,
      molds, and respiratory disease. They were engaged in free and intensive
      discussions on a scientific basis throughout the duration of the 3-day workshop
      (paragraph) This monograph contains peer-reviewed papers based on individual
      presentations at the workshop as well as the workshop conclusions. They are
      offered to the public health community, administrators, research agencies,
      physicians, particularly pediatricians, nurses and health workers as information
      and encouragement to engage themselves in this health problem of importance for
      the next generation in our population. (paragraph) Acknowledgments: The workshop
      received financial support from the U.S. Environmental Protection Agency, the
      National Center for Environmental Assessment at the U.S. EPA, the Vardal
      Foundation (Sweden), Astra Corp (Sweden), the Committee on Organic Dusts,
      International Commission on Occupational Health. The printing of this document
      was made possible by a grant from the Center for Indoor Air Research (U.S.).
      Yvonne Peterson, research secretary, provided excellent and invaluable assistance
      in the organization and publication efforts.

PMID- 10346995
TI  - Introduction and summary: workshop on children's health and indoor mold exposure.
AB  - To evaluate the health consequences for children of indoor exposure to molds, an
      international workshop was organized with 15 scientists from eight countries. The
      participants agreed that exposure to molds may constitute a health threat to
      children resulting in respiratory symptoms in both the upper and lower airways,
      an increased incidence of infections, and skin symptoms. Allergy, either to molds
      or to other indoor agents, also presents a health risk. At very high exposure
      levels to specific molds, nose bleeding, hemoptysis, and pulmonary hemorrhage
      have been documented. Pediatricians and allergists need to obtain information
      about mold and dampness in the home environment when examining children with
      chronic respiratory symptoms, recurrent infections, or persistent fatigue and
      headache. Measurement techniques are available to determine exposure. Most
      important, the source of dampness must be eliminated and the indoor environment
      must be thoroughly cleaned of molds.

PMID- 10346996
TI  - Potential role of environmental factors in the etiology and pathogenesis of
      atopy: a working model.
AB  - Sensitization to inhalant allergens commonly commences in utero, and most
      children are born with weak T helper-2 (Th2)-polarized T-cell immunity to these
      agents. During early life, these responses are normally deviated toward the Th1
      cytokine profile. However, in atopics this immune deviation process fails,
      leading instead to consolidation of allergen-specific Th2 immunity and its
      eventual active expression in the airways. Both the induction and expression of
      Th2 immunity can be modulated by environmental agents that affect the cytokine
      milieu in the airway mucosa and/or the draining lymph nodes. Because of the known
      effects of the mold cell wall component (1-->3)-ss-d-glucan on monocyte cytokine
      secretion, exposure to molds during childhood may be a significant etiologic
      factor in allergic respiratory disease in general.

PMID- 10346993
TI  - Molecular epidemiologic research on the effects of environmental pollutants on
      the fetus.
AB  - Evidence shows that fetuses and infants are more affected than adults by a
      variety of environmental toxicants because of differential exposure, physiologic
      immaturity, and a longer lifetime over which disease initiated in early life can
      develop. In this article we review data on the effects of in utero exposure to
      common environmental contaminants, including polycyclic aromatic hydrocarbons
      (PAH), particulate matter and environmental tobacco smoke (ETS). We then
      summarize results from our molecular epidemiologic study to assess risks from in
      utero exposures to ambient air pollution and ETS. This research study, conducted
      in Poland, used biomarkers to measure the internal and bioeffective dose of
      toxicants and individual susceptibility factors. The study included 160 mothers
      and 160 newborns. Ambient air pollution was significantly associated (p= 0.05)
      with the amount of PAH bound to DNA (PAH-DNA adducts) in both maternal and infant
      cord white blood cells (WBC). Newborns with elevated PAH-DNA adducts (greater
      than the median) had significantly decreased birth weight (p= 0.05), birth length
      (p= 0.02), and head circumference (p= 0.0005) compared to the newborns with lower
      adducts (n= 135). Maternal and infant cotinine levels were increased by active
      and passive cigarette smoke exposure of the mother (p= 0.01). An inverse
      correlation was seen between newborn plasma cotinine (nanograms per milliliter)
      and birth weight (p= 0.0001) and length (p= 0.003). Adducts were elevated in
      placental tissue and WBC of newborns who were heterozygous or homozygous for the
      cytochrome P4501A1 MspI restriction fragment length polymorphism (RFLP) compared
      to newborns without the RFLP. Levels of PAH-DNA and cotinine were higher in
      newborns than mothers. These results document that there is significant
      transplacental transfer of PAH and ETS constituents from mother to fetus; that
      PAH-DNA adduct levels in maternal and newborn WBC were increased with
      environmental exposure to PAH from ambient pollution; and that the fetus is more
      sensitive to genetic damage than the mother. The study also provided the first
      molecular evidence that transplacental PAH exposure to the fetus is compromising
      fetal development. If confirmed, these findings could have significant public
      health implications since a number of studies have found that reduction of head
      circumference at birth correlates with lower intelligence quotient as well as
      poorer cognitive functioning and school performance in childhood.

PMID- 10346997
TI  - Clinical experience and results of a Sentinel Health Investigation related to
      indoor fungal exposure.
AB  - This is a review of exposure conditions, clinical presentation, and morbidity of
      children and adults with indoor fungal exposure such as toxic Stachybotrys
      chartarum. Indoor exposure was characterized using different methods including
      microscopic, culture, cytotoxicity screening tests, and chemical analyses.
      Clinical case histories and physical and laboratory findings are presented of
      children (age < 18 years, n = 22; mean age 9 years; 60% females) and adults (age
      >18 years, n = 125; mean age 39 years, 67% females) who consulted an
      environmental health specialty clinic. In the pediatric patients' exposure
      history, widespread fungal contamination of water-damaged building materials with
      known toxic or allergic fungi was identified. Primarily disorders of the
      respiratory system, skin, mucous membranes, and central nervous system were
      reported. Some enumeration and functional laboratory abnormalities, mainly of the
      lymphatic blood cells, were observed, although no statistically significant
      differences were found. IgE or IgG fungi-specific antibodies, used as exposure
      markers, were positive in less than 25% of all tested cases. In an evaluation of
      a symptomatic girl 11 years of age (sentinel case investigation) living in an
      apartment with verified toxigenic fungi (i.e., S. chartarum), several health
      indicators showed improvement after exposure cessation.

PMID- 10346998
TI  - Overview of investigations into pulmonary hemorrhage among infants in Cleveland,
      Ohio.
AB  - Idiopathic pulmonary hemorrhage was diagnosed in 37 infants in the Cleveland,
      Ohio, area between 1993 and 1998. This rare disorder has been related to 12
      deaths, including 7 originally thought to be sudden infant death syndrome. Thirty
      of the infants were African American, all of whom lived in a limited geographic
      area of eastern metropolitan Cleveland, an area of older housing stock. An
      investigation led by the Centers for Disease Control and Prevention has found an
      association with household exposure to a toxigenic mold, Stachybotrys chartarum,
      and other fungi. The rapidly growing lungs of young infants appear to be
      especially vulnerable to the toxins made by toxigenic molds. Environmental
      tobacco smoke was frequently present in the infants' homes and may be a trigger
      precipitating the acute bleeding. Stachybotrys, although not thought to be a
      common mold, is known to have a wide geographic distribution. An additional 101
      cases of acute, idiopathic pulmonary hemorrhage have been reported in infants in
      the United States over the past 5 years. In this overview, the investigations are
      summarized, the clinical profile is described, the toxicity of S. chartarum is
      discussed, and pathophysiologic concepts are presented.

PMID- 10346999
TI  - Indoor air-related effects and airborne (1 --> 3)-beta-D-glucan.
AB  - In studies on the relation between indoor mold exposure and symptoms/disease, the
      exposure should be described in terms of biomass and not viability. This paper
      reviews field studies in which (1--> 3)-ss-d-glucan was measured as a marker of
      biomass and was related to the extent of symptoms and measures of inflammation
      among exposed subjects. Increased levels of (1-->3)-ss-d-glucan were related to
      an increased extent of symptoms and markers of inflammation. The data suggest
      that (1-->3)-ss-d-glucan can be used as a risk marker in indoor environments.

PMID- 10347000
TI  - Microfungal contamination of damp buildings--examples of risk constructions and
      risk materials.
AB  - To elucidate problems with microfungal infestation in indoor environments, a
      multidisciplinary collaborative pilot study, supported by a grant from the Danish
      Ministry of Housing and Urban Affairs, was performed on 72 mold-infected building
      materials from 23 buildings. Water leakage through roofs, rising damp, and
      defective plumbing installations were the main reasons for water damage with
      subsequent infestation of molds. From a score system assessing the
      bioavailability of the building materials, products most vulnerable to mold
      attacks were water damaged, aged organic materials containing cellulose, such as
      wooden materials, jute, wallpaper, and cardboard. The microfungal genera most
      frequently encountered were Penicillium (68%), Aspergillus (56%), Chaetomium
      (22%), Ulocladium, (21%), Stachybotrys (19%) and Cladosporium (15%). Penicillium
      chrysogenum, Aspergillus versicolor, and Stachybotrys chartarum were the most
      frequently occurring species. Under field conditions, several trichothecenes were
      detected in each of three commonly used building materials, heavily contaminated
      with S. chartarum. Under experimental conditions, four out of five isolates of S.
      chartarum produced satratoxin H and G when growing on new and old, very humid
      gypsum boards. A. versicolor produced the carcinogenic mycotoxin sterigmatocystin
      and 5-methoxysterigmatocystin under the same conditions.

PMID- 10347001
TI  - The Health Protection Act, national guidelines for indoor air quality and
      development of the national indoor air programs in Finland.
AB  - This article presents the current handling of disease related to moldy buildings
      in Finland as an example of an integrated health strategy. It describes the role
      of the Finnish Health Protection Act for indoor environments and how cases of
      indoor air problems are dealt with by local, regional, and national authorities.

PMID- 10347003
TI  - Relationship between acid tolerance, cytoplasmic pH, and ATP and H+-ATPase levels
      in chemostat cultures of Lactococcus lactis.
AB  - The acid tolerance response (ATR) of chemostat cultures of Lactococcus lactis
      subsp. cremoris NCDO 712 was dependent on the dilution rate and on the
      extracellular pH (pHo). A decrease in either the dilution rate or the pHo led to
      a decrease in the cytoplasmic pH (pHi) of the cells, and similar levels of acid
      tolerance were observed at any specific pHi irrespective of whether the pHi
      resulted from manipulation of the growth rate, manipulation of the pHo, or both.
      Acid tolerance was also induced by sudden additions of acid to chemostat cultures
      growing at a pHo of 7.0, and this induction was completely inhibited by
      chloramphenicol. The end products of glucose fermentation depended on the growth
      rate and the environmental pHo of the cultures, but neither the spectrum of end
      products nor the total rate of acid production correlated with a specific pHi.
      The rate of ATP formation was not correlated with pHi, but a good correlation
      between the cellular level of H+-ATPase and pHi was observed. Moreover, an
      inverse correlation between the cytoplasmic levels of ATP and pHi was
      established. Each pHi below 6. 6 was characterized by unique levels of ATR, H+
      ATPase, and ATP. High levels of H+-ATPase also coincided with high levels of acid
      tolerance of cells in batch cultures induced with sublethal levels of acid. We
      concluded that H+-ATPase is one of the ATR proteins induced by acid pHi through
      growth at an acid pHo or a slow growth rate.

PMID- 10347002
TI  - The pediocin AcH precursor is biologically active.
AB  - The properties of the pediocin AcH precursor, prepediocin AcH, have been studied
      to gain insight into how producer cells may protect themselves from the activity
      of intracellular prebacteriocins. The native 62-amino-acid precursor and the 44
      amino-acid mature species were expressed in Escherichia coli host strains that
      lack the leader peptide processing enzyme, PapD. Both forms inhibited the growth
      of the test bacterium Listeria innocua Lin11, indicating that the native
      precursor is biologically active. The two species also were synthesized in the
      context of maltose-binding protein chimeric proteins to facilitate the
      measurement of their relative specific activities. The chimeric form of the
      precursor was approximately 80% as active as the chimeric mature species. Of
      relevance to cell protection and pediocin AcH production, it was determined that
      the precursor is strongly susceptible to inactivation by reducing agents and to
      degradation by chymotrypsin and endogenous E. coli proteases. Taken together, the
      results indicate that the activity of prepediocin AcH may have to be controlled
      prior to secretion to prevent toxicity to the host. Perhaps producer cells avoid
      membrane damage by maintaining the precursor in a reduced inactive state or by
      degrading molecules whose secretion is delayed.

PMID- 10347004
TI  - Two-component transcriptional regulation of N-acyl-homoserine lactone production
      in Pseudomonas aureofaciens.
AB  - Production of phenazine antibiotics by the biological control bacterium
      Pseudomonas aureofaciens 30-84 is regulated in part by the PhzI/PhzR N-acyl
      homoserine lactone (AHL) response system (L. S. Pierson III, V. D. Keppenne, and
      D. W. Wood, J. Bacteriol. 176:3966-3974, 1994; D. W. Wood and L. S. Pierson III,
      Gene 168:49-53, 1996). Two mutants, 30-84W and 30-84.A2, were isolated and were
      found to be deficient in the production of phenazine, protease, hydrogen cyanide
      (HCN), and the AHL signal N-hexanoyl-homoserine lactone. These mutants were not
      complemented by phzI, phzR, or the phenazine biosynthetic genes (phzFABCD) (L. S.
      Pierson III, T. Gaffney, S. Lam, and F. Gong, FEMS Microbiol. Lett. 134:299-307,
      1995). A 2.2-kb region of the 30-84 chromosome which fully restored production of
      all of these compounds in strain 30-84W was identified. Nucleotide sequence
      analysis of this region revealed a single open reading frame encoding a predicted
      213-amino-acid protein which is very similar to the global response regulator
      GacA. Strain 30-84.A2 was not complemented by gacA or any cosmid from a genomic
      library of strain 30-84 but was complemented by gacS (formerly lemA) homologs
      from Pseudomonas fluorescens Pf-5 (N. Corbel and J. E. Loper, J. Bacteriol.
      177:6230-6236, 1995) and Pseudomonas syringae pv. syringae B728a (E. M. Hrabek
      and D. K. Willis, J. Bacteriol. 174:3011-3020, 1992). Transcription of phzR was
      not altered in either mutant; however, phzI transcription was eliminated in
      strains 30-84W and 30-84.A2. These results indicated that the GacS/GacA two
      component signal transduction system of P. aureofaciens 30-84 controls the
      production of AHL required for phenazine production by mediating the
      transcription of phzI. Addition of exogenous AHL did not complement either mutant
      for phenazine production, indicating that the GacS/GacA global regulatory system
      controls phenazine production at multiple levels. Our results reveal for the
      first time a mechanism by which a two-component regulatory system and an AHL
      mediated regulatory system interact.

PMID- 10347005
TI  - Characterization of two subsurface H2-utilizing bacteria, Desulfomicrobium
      hypogeium sp. nov. and Acetobacterium psammolithicum sp. nov., and their
      ecological roles.
AB  - We examined the relative roles of acetogenic and sulfate-reducing bacteria in H2
      consumption in a previously characterized subsurface sandstone ecosystem.
      Enrichment cultures originally inoculated with ground sandstone material obtained
      from a Cretaceous formation in central New Mexico were grown with hydrogen in a
      mineral medium supplemented with 0.02% yeast extract. Sulfate reduction and
      acetogenesis occurred in these cultures, and the two most abundant organisms
      carrying out the reactions were isolated. Based on 16S rRNA analysis data and on
      substrate utilization patterns, these organisms were named Desulfomicrobium
      hypogeium sp. nov. and Acetobacterium psammolithicum sp. nov. The steady-state H2
      concentrations measured in sandstone-sediment slurries (threshold concentration,
      5 nM), in pure cultures of sulfate reducers (threshold concentration, 2 nM), and
      in pure cultures of acetogens (threshold concentrations 195 to 414 nM) suggest
      that sulfate reduction is the dominant terminal electron-accepting process in the
      ecosystem examined. In an experiment in which direct competition for H2 between
      D. hypogeium and A. psammolithicum was examined, sulfate reduction was the
      dominant process.

PMID- 10347006
TI  - Methods for detection of Anticarsia gemmatalis nucleopolyhedrovirus DNA in soil.
AB  - Two methods, phenol-ether and magnetic capture-hybridization (MCH), were
      developed and compared with regard to their sensitivities and abilities to
      extract the DNA of the insect baculovirus Anticarsia gemmatalis
      nucleopolyhedrovirus (AgMNPV) from soil and to produce DNA amplifiable by PCR.
      Laboratory experiments were performed with 0. 25 g of autoclaved soil inoculated
      with different viral concentrations to optimize both methods of baculovirus DNA
      extraction and to determine their sensitivities. Both procedures produced
      amplifiable DNA; however, the MCH method was 100-fold more sensitive than the
      phenol-ether procedure. The removal of PCR inhibitors from the soil appeared to
      be complete when MCH was used as the viral DNA isolation method, because
      undiluted aliquots of the DNA preparations could be amplified by PCR. The phenol
      ether procedure probably did not completely remove PCR inhibitors from the soil,
      since PCR products were observed only when the AgMNPV DNA preparations were
      diluted 10- or 100-fold. AgMNPV DNA was detected in field-collected soil samples
      from 15 to 180 days after virus application when the MCH procedure to isolate DNA
      was coupled with PCR amplification of the polyhedrin region.

PMID- 10347007
TI  - Reductive dechlorination of tetrachloroethene to cis-1, 2-dichloroethene by a
      thermophilic anaerobic enrichment culture.
AB  - Thermophilic anaerobic biodegradation of tetrachloroethene (PCE) was investigated
      with various inocula from geothermal and nongeothermal areas. Only polluted
      harbor sediment resulted in a stable enrichment culture that converted PCE via
      trichloroethene to cis-1, 2-dichloroethene at the optimum temperature of 60 to 65
      degrees C. After several transfers, methanogens were eliminated from the culture.
      Dechlorination was supported by lactate, pyruvate, fructose, fumarate, and malate
      as electron donor but not by H2, formate, or acetate. Fumarate and L-malate led
      to the highest dechlorination rate. In the absence of PCE, fumarate was fermented
      to acetate, H2, CO2, and succinate. With PCE, less H2 was formed, suggesting that
      PCE competed for the reducing equivalents leading to H2. PCE dechlorination,
      apparently, was not outcompeted by fumarate as electron acceptor. At the optimum
      dissolved PCE concentration of approximately 60 microM, a high dechlorination
      rate of 1.1 micromol h-1 mg-1 (dry weight) was found, which indicates that the
      dechlorination is not a cometabolic activity. Microscopic analysis of the
      fumarate-grown culture showed the dominance of a long thin rod. Molecular
      analysis, however, indicated the presence of two dominant species, both belonging
      to the low-G+C gram positives. The highest similarity was found with the genus
      Dehalobacter (90%), represented by the halorespiring organism Dehalobacter
      restrictus, and with the genus Desulfotomaculum (86%).

PMID- 10347008
TI  - Chemoselective nitro group reduction and reductive dechlorination initiate
      degradation of 2-chloro-5-nitrophenol by Ralstonia eutropha JMP134.
AB  - Ralstonia eutropha JMP134 utilizes 2-chloro-5-nitrophenol as a sole source of
      nitrogen, carbon, and energy. The initial steps for degradation of 2-chloro-5
      nitrophenol are analogous to those of 3-nitrophenol degradation in R. eutropha
      JMP134. 2-Chloro-5-nitrophenol is initially reduced to 2-chloro-5
      hydroxylaminophenol, which is subject to an enzymatic Bamberger rearrangement
      yielding 2-amino-5-chlorohydroquinone. The chlorine of 2-amino-5
      chlorohydroquinone is removed by a reductive mechanism, and aminohydroquinone is
      formed. 2-Chloro-5-nitrophenol and 3-nitrophenol induce the expression of 3
      nitrophenol nitroreductase, of 3-hydroxylaminophenol mutase, and of the
      dechlorinating activity. 3-Nitrophenol nitroreductase catalyzes chemoselective
      reduction of aromatic nitro groups to hydroxylamino groups in the presence of
      NADPH. 3-Nitrophenol nitroreductase is active with a variety of mono-, di-, and
      trinitroaromatic compounds, demonstrating a relaxed substrate specificity of the
      enzyme. Nitrosobenzene serves as a substrate for the enzyme and is converted
      faster than nitrobenzene.

PMID- 10347009
TI  - An alkane-responsive expression system for the production of fine chemicals 
AB  - Membrane-located monooxygenase systems, such as the Pseudomonas putida mt-2
      derived xylene oxygenase, are attractive for challenging transformations of
      apolar compounds, including enantiospecific epoxidations, but are difficult to
      synthesize at levels that are useful for application to biotechnological
      processes. In order to construct efficient biocatalysis strains, we utilized the
      alkane-responsive regulatory system of the OCT plasmid-located alk genes of
      Pseudomonas oleovorans GPo1, a very attractive system for recombinant
      biotransformation processes. Determination of the nucleotide sequence of alkS,
      whose activated gene product positively regulates the transcription of the
      structural genes alkBFGHJKL, on a 3.7-kb SalI-HpaI OCT plasmid fragment was
      completed, and the N-terminal amino acid sequence of an AlkS-LacZ fusion protein
      was found to be consistent with the predicted DNA sequence. The alkS gene and the
      alkBp promoter were assembled into a convenient alkane-responsive genetic
      expression cassette which allowed expression of the xylene oxygenase genes in a
      recombinant Escherichia coli strain at a specific activity of 91 U per g (dry
      weight) of cells when styrene was the substrate. This biocatalyst was used to
      produce (S)-styrene oxide in two-liquid-phase cultures. Volumetric productivities
      of more than 2 g of styrene oxide per h per liter of aqueous phase were obtained;
      these values represented a fivefold improvement compared with previous results.

PMID- 10347010
TI  - Expression of the Escherichia coli pntA and pntB genes, encoding nicotinamide
      nucleotide transhydrogenase, in Saccharomyces cerevisiae and its effect on
      product formation during anaerobic glucose fermentation.
AB  - We studied the physiological effect of the interconversion between the NAD(H) and
      NADP(H) coenzyme systems in recombinant Saccharomyces cerevisiae expressing the
      membrane-bound transhydrogenase from Escherichia coli. Our objective was to
      determine if the membrane-bound transhydrogenase could work in reoxidation of
      NADH to NAD+ in S. cerevisiae and thereby reduce glycerol formation during
      anaerobic fermentation. Membranes isolated from the recombinant strains exhibited
      reduction of 3-acetylpyridine-NAD+ by NADPH and by NADH in the presence of NADP+,
      which demonstrated that an active enzyme was present. Unlike the situation in E.
      coli, however, most of the transhydrogenase activity was not present in the yeast
      plasma membrane; rather, the enzyme appeared to remain localized in the membrane
      of the endoplasmic reticulum. During anaerobic glucose fermentation we observed
      an increase in the formation of 2-oxoglutarate, glycerol, and acetic acid in a
      strain expressing a high level of transhydrogenase, which indicated that
      increased NADPH consumption and NADH production occurred. The intracellular
      concentrations of NADH, NAD+, NADPH, and NADP+ were measured in cells expressing
      transhydrogenase. The reduction of the NADPH pool indicated that the
      transhydrogenase transferred reducing equivalents from NADPH to NAD+.

PMID- 10347011
TI  - Effect of temperature on structure and function of the methanogenic archaeal
      community in an anoxic rice field soil.
AB  - Soil temperatures in Italian rice fields typically range between about 15 and 30
      degrees C. A change in the incubation temperature of anoxic methanogenic soil
      slurry from 30 degrees C to 15 degrees C typically resulted in a decrease in the
      CH4 production rate, a decrease in the steady-state H2 partial pressure, and a
      transient accumulation of acetate. Previous experiments have shown that these
      changes were due to an alteration of the carbon and electron flow in the
      methanogenic degradation pathway of organic matter caused by the temperature
      shift (K. J. Chin and R. Conrad, FEMS Microbiol. Ecol. 18:85-102, 1995). To
      investigate how temperature affects the structure of the methanogenic archaeal
      community, total DNA was extracted from soil slurries incubated at 30 and 15
      degrees C. The archaeal small-subunit (SSU) rRNA-encoding genes (rDNA) of these
      environmental DNA samples were amplified by PCR with an archaeal-specific primer
      system and used for the generation of clone libraries. Representative rDNA clones
      (n = 90) were characterized by terminal restriction fragment length polymorphism
      (T-RFLP) and sequence analysis. T-RFLP analysis produced for the clones
      terminally labeled fragments with a characteristic length of mostly 185, 284, or
      392 bp. Sequence analysis allowed determination of the phylogenetic affiliation
      of the individual clones with their characteristic T-RFLP fragment lengths and
      showed that the archaeal community of the anoxic rice soil slurry was dominated
      by members of the families Methanosarcinaceae (185 bp) and Methanosaetaceae (284
      bp), the kingdom Crenarchaeota (185 or 284 bp), and a novel, deeply branching
      lineage of the (probably methanogenic) kingdom Euryarchaeota (392 bp) that has
      recently been detected on rice roots (R. Grosskopf, S. Stubner, and W. Liesack,
      Appl. Environ. Microbiol. 64:4983-4989, 1998). The structure of the archaeal
      community changed when the temperature was shifted from 30 degrees C to 15
      degrees C. Before the temperature shift, the clones (n = 30) retrieved from the
      community were dominated by Crenarchaeota (70%), "novel Euryarchaeota" (23%), and
      Methanosarcinacaeae (7%). Further incubation at 30 degrees C (n = 30 clones)
      resulted in a relative increase in members of the Methanosarcinaceae (77%),
      whereas further incubation at 15 degrees C (n = 30 clones) resulted in a much
      more diverse community consisting of 33% Methanosarcinaceae, 23% Crenarchaeota,
      20% Methanosaetaceae, and 17% novel Euryarchaeota. The appearance of
      Methanosaetaceae at 15 degrees C was conspicuous. These results demonstrate that
      the structure of the archaeal community in anoxic rice field soil changed with
      time and incubation temperature.

PMID- 10347012
TI  - Measurement of monosaccharides and conversion of glucose to acetate in anoxic
      rice field soil 
AB  - Degradation of glucose has been implicated in acetate production in rice field
      soil, but the abundance of glucose, the temporal change of glucose turnover, and
      the relationship between glucose and acetate catabolism are not well understood.
      We therefore measured the pool sizes of glucose and acetate in rice field soil
      and investigated the turnover of [U-14C]glucose and [2-14C]acetate. Acetate
      accumulated up to about 2 mM during days 5 to 10 after flooding of the soil.
      Subsequently, methanogenesis started and the acetate concentration decreased to
      about 100 to 200 &mgr;M. Glucose always made up >50% of the total monosaccharides
      detected. Glucose concentrations decreased during the first 10 days from 90
      &mgr;M initially to about 3 &mgr;M after 40 days of incubation. With the
      exception at day 0 when glucose consumption was slow, the glucose turnover time
      was in the range of minutes, while the acetate turnover time was in the range of
      hours. Anaerobic degradation of [U-14C]glucose released [14C]acetate and 14CO2 as
      the main products, with [14C]acetate being released faster than 14CO2. The
      products of [2-14C]acetate metabolism, on the other hand, were 14CO2 during the
      reduction phase of soil incubation (days 0 to 15) and 14CH4 during the
      methanogenic phase (after day 15). Except during the accumulation period of
      acetate (days 5 to 10), approximately 50 to 80% of the acetate consumed was
      produced from glucose catabolism. However, during the accumulation period of
      acetate, the rate of acetate production from glucose greatly exceeded that of
      acetate consumption. Under steady-state conditions, up to 67% of the CH4 was
      produced from acetate, of which up to 56% was produced from glucose degradation.

PMID- 10347013
TI  - Quantitative immunofluorescence of regulated eps gene expression in single cells
      of Ralstonia solanacearum.
AB  - Ralstonia solanacearum, a phytopathogenic bacterium, uses an environmentally
      sensitive and complex regulatory network to control expression of multiple
      virulence genes. Part of this network is an unusual autoregulatory system that
      produces and senses 3-hydroxypalmitic acid methyl ester. In culture, this
      autoregulatory system ensures that expression of virulence genes, such as those
      of the eps operon encoding biosynthesis of the acidic extracellular
      polysaccharide, occurs only at high cell density (>10(7) cells/ml). To determine
      if regulation follows a similar pattern within tomato plants, we first developed
      a quantitative immunofluorescence (QIF) method that measures the relative amount
      of a target protein within individual bacterial cells. For R. solanacearum, QIF
      was used to determine the amount of beta-galactosidase protein within wild-type
      cells containing a stable eps-lacZ reporter allele. When cultured cells were
      examined to test the method, QIF accurately detected both low and high levels of
      eps gene expression. QIF analysis of R. solanacearum cells recovered from stems
      of infected tomato plants showed that expression of eps during pathogenesis was
      similar to that in culture. These results suggest that there are no special
      signals or conditions within plants that override or short-circuit the regulatory
      processes observed in R. solanacearum in culture. Because QIF is a robust,
      relatively simple procedure that uses generally accessible equipment, it should
      be useful in many situations where gene expression in single bacterial cells must
      be determined.

PMID- 10347014
TI  - Transcriptional control of ADH genes in the xylose-fermenting yeast Pichia
      stipitis.
AB  - We studied the expression of the genes encoding group I alcohol dehydrogenases
      (PsADH1 and PsADH2) in the xylose-fermenting yeast Pichia stipitis CBS 6054. The
      cells expressed PsADH1 approximately 10 times higher under oxygen-limited
      conditions than under fully aerobic conditions when cultivated on xylose.
      Transcripts of PsADH2 were not detectable under either aeration condition. We
      used a PsADH1::lacZ fusion to monitor PsADH1 expression and found that expression
      increased as oxygen decreased. The level of PsADH1 transcript was repressed about
      10-fold in cells grown in the presence of heme under oxygen-limited conditions.
      Concomitantly with the induction of PsADH1, PsCYC1 expression was repressed.
      These results indicate that oxygen availability regulates PsADH1 expression and
      that regulation may be mediated by heme. The regulation of PsADH2 expression was
      also examined in other genetic backgrounds. Disruption of PsADH1 dramatically
      increased PsADH2 expression on nonfermentable carbon sources under fully aerobic
      conditions, indicating that the expression of PsADH2 is subject to feedback
      regulation under these conditions.

PMID- 10347015
TI  - High-resolution genotyping of Campylobacter strains isolated from poultry and
      humans with amplified fragment length polymorphism fingerprinting.
AB  - For epidemiological studies of Campylobacter infections, molecular typing methods
      that can differentiate campylobacters at the strain level are needed. In this
      study we used a recently developed genotyping method, amplified fragment length
      polymorphism (AFLP), which is based on selective amplification of restriction
      fragments of chromosomal DNA, for genetic typing of Campylobacter jejuni and
      Campylobacter coli strains derived from humans and poultry. We developed an
      automated AFLP fingerprinting method in which restriction endonucleases HindIII
      and HhaI were used in combination with one set of selective PCR primers. This
      method resulted in evenly distributed band patterns for amplified fragments
      ranging from 50 to 500 bp long. The discriminatory power of AFLP was assessed
      with a C. jejuni strain, an isogenic flagellin mutant, and distinct C. jejuni
      strains having known pulsed-field gel electrophoresis and fla PCR-restriction
      fragment length polymorphism genotypes. Unrelated C. jejuni strains produced
      heterogeneous patterns, whereas genetically related strains produced similar AFLP
      patterns. Twenty-five Campylobacter strains obtained from poultry farms in The
      Netherlands grouped in three C. jejuni clusters that were separate from a C. coli
      cluster. The band patterns of 10 C. jejuni strains isolated from humans were
      heterogeneous, and most of these strains grouped with poultry strains. Our
      results show that AFLP analysis can distinguish genetically unrelated strains
      from genetically related strains of Campylobacter species. However, desirable
      genetically related strains can be differentiated by using other genotyping
      methods. We concluded that automated AFLP analysis is an attractive tool which
      can be used as a primary method for subtyping large numbers of Campylobacter
      strains and is extremely useful for epidemiological investigations.

PMID- 10347016
TI  - Earthworm egg capsules as vectors for the environmental introduction of
      biodegradative bacteria.
AB  - Earthworm egg capsules (cocoons) may acquire bacteria from the environment in
      which they are produced. We found that Ralstonia eutropha (pJP4) can be recovered
      from Eisenia fetida cocoons formed in soil inoculated with this bacterium.
      Plasmid pJP4 contains the genes necessary for 2,4-dichlorophenoxyacetic acid (2,4
      D) and 2, 4-dichlorophenol (2,4-DCP) degradation. In this study we determined
      that the presence of R. eutropha (pJP4) within the developing earthworm cocoon
      can influence the degradation and toxicity of 2,4-D and 2,4-DCP, respectively.
      The addition of cocoons containing R. eutropha (pJP4) at either low or high
      densities (10(2) or 10(5) CFU per cocoon, respectively) initiated degradation of
      2,4-D in nonsterile soil microcosms. Loss of 2,4-D was observed within the first
      week of incubation, and respiking the soil with 2,4-D showed depletion within 24
      h. Microbial analysis of the soil revealed the presence of approximately 10(4)
      CFU R. eutropha (pJP4) g-1 of soil. The toxicity of 2,4-DCP to developing
      earthworms was tested by using cocoons with or without R. eutropha (pJP4).
      Results showed that cocoons containing R. eutropha (pJP4) were able to tolerate
      higher levels of 2,4-DCP. Our results indicate that the biodegradation of 2, 4
      DCP by R. eutropha (pJP4) within the cocoons may be the mechanism contributing to
      toxicity reduction. These results suggest that the microbiota may influence the
      survival of developing earthworms exposed to toxic chemicals. In addition,
      cocoons can be used as inoculants for the introduction into the environment of
      beneficial bacteria, such as strains with biodegradative capabilities.

PMID- 10347017
TI  - Overexpression of the Saccharomyces cerevisiae mannosylphosphodolichol synthase
      encoding gene in Trichoderma reesei results in an increased level of protein
      secretion and abnormal cell ultrastructure.
AB  - Production of extracellular proteins plays an important role in the physiology of
      Trichoderma reesei and has potential industrial application. To improve the
      efficiency of protein secretion, we overexpressed in T. reesei the DPM1 gene of
      Saccharomyces cerevisiae, encoding mannosylphosphodolichol (MPD) synthase, under
      homologous, constitutively acting expression signals. Four stable transformants,
      each with different copy numbers of tandemly integrated DPM1, exhibited roughly
      double the activity of MPD synthase in the respective endoplasmic reticulum
      membrane fraction. On a dry-weight basis, they secreted up to sevenfold-higher
      concentrations of extracellular proteins during growth on lactose, a carbon
      source promoting formation of cellulases. Northern blot analysis showed that the
      relative level of the transcript of cbh1, which encodes the major cellulase
      (cellobiohydrolase I [CBH I]), did not increase in the transformants. On the
      other hand, the amount of secreted CBH I and, in all but one of the
      transformants, intracellular CBH I was elevated. Our results suggest that
      posttranscriptional processes are responsible for the increase in CBH I
      production. The carbohydrate contents of the extracellular proteins were
      comparable in the wild type and in the transformants, and no hyperglycosylation
      was detected. Electron microscopy of the DPM1-amplified strains revealed
      amorphous structure of the cell wall and over three times as many mitochondria as
      in the control. Our data indicate that molecular manipulation of glycan
      biosynthesis in Trichoderma can result in improved protein secretion.

PMID- 10347018
TI  - Multiple epoxide hydrolases in Alternaria alternata f. sp. lycopersici and their
      relationship to medium composition and host-specific toxin production.
AB  - The production of Alternaria alternata f. sp. lycopersici host-specific toxins
      (AAL toxins) and epoxide hydrolase (EH) activity were studied during the growth
      of this plant-pathogenic fungus in stationary liquid cultures. Media containing
      pectin as the primary carbon source displayed peaks of EH activity at day 4 and
      at day 12. When pectin was replaced by glucose, there was a single peak of EH
      activity at day 6. Partial characterization of the EH activities suggests the
      presence of three biochemically distinguishable EH activities. Two of them have a
      molecular mass of 25 kDa and a pI of 4.9, while the other has a molecular mass of
      20 kDa and a pI of 4.7. Each of the EH activities can be distinguished by
      substrate preference and sensitivity to inhibitors. The EH activities present at
      day 6 (glucose) or day 12 (pectin) are concomitant with AAL toxin production.

PMID- 10347019
TI  - Lethality of a heat- and phosphate-catalyzed glucose by-product to Escherichia
      coli O157:H7 and partial protection conferred by the rpoS regulon.
AB  - A by-product of glucose produced during sterilization (121 degrees C, 15 lb/in2,
      15 min) at neutral pH and in the presence of phosphate (i.e., phosphate-buffered
      saline) was bactericidal to Escherichia coli O157:H7 (ATCC 43895). Other six
      carbon (fructose and galactose) and five-carbon (arabinose, ribose, and xylose)
      reducing sugars also produced a toxic by-product under the same conditions.
      Fructose and the five-carbon sugars yielded the most bactericidal activity.
      Glucose concentrations of 1% (wt/vol) resulted in a 99.9% decline in the CFU of
      stationary-phase cells per milliliter in 2 days at 25 degrees C. An rpoS mutant
      (pRR10::rpoS) of strain 43895 (FRIK 816-3) was significantly (P < 0.001) more
      sensitive to the glucose-phosphate by-product than the parent strain, as glucose
      concentrations from 0.05 to 0.25% resulted in a 2- to 3-log10 reduction in CFU
      per milliliter in 2 days at 25 degrees C. Likewise, log-phase cells of the wild
      type strain, 43895, were significantly more sensitive (P < 0.001) to the glucose
      phosphate by-product than were stationary-phase cells, which is consistent with
      the stability of rpoS and the regulation of rpoS-regulated genes. The
      bactericidal effect of the glucose-phosphate by-product was reduced when strains
      ATCC 43895 and FRIK 816-3 were incubated at a low temperature (4 degrees C).
      Also, growth in glucose-free medium (i.e., nutrient broth) did not alleviate the
      sensitivity to the glucose-phosphate by-product and excludes the possibility of
      substrate-accelerated death as the cause of the bactericidal effect observed. The
      glucose-phosphate by-product was also bactericidal to Salmonella typhimurium,
      Shigella dysenteriae, and a Klebsiella sp. Attempts to identify the glucose
      phosphate by-product were unsuccessful. These studies demonstrate the production
      of a glucose-phosphate by-product bactericidal to E. coli O157:H7 and the
      protective effects afforded by rpoS-regulated gene products. Additionally, the
      detection of sublethally injured bacteria may be compromised by the presence of
      this by-product in recovery media.

PMID- 10347020
TI  - Vertical distribution of methanogens in the anoxic sediment of Rotsee
      (Switzerland).
AB  - Anoxic sediments from Rotsee (Switzerland) were analyzed for the presence and
      diversity of methanogens by using molecular tools and for methanogenic activity
      by using radiotracer techniques, in addition to the measurement of chemical
      profiles. After PCR-assisted sequence retrieval of the 16S rRNA genes (16S rDNA)
      from the anoxic sediment of Rotsee, cloning, and sequencing, a phylogenetic
      analysis identified two clusters of sequences and four separated clones. The
      sequences in cluster 1 grouped with those of Methanosaeta spp., whereas the
      sequences in cluster 2 comprised the methanogenic endosymbiont of Plagiopyla
      nasuta. Discriminative oligonucleotide probes were constructed against both
      clusters and two of the separated clones. These probes were used subsequently for
      the analysis of indigenous methanogens in a core of the sediment, in addition to
      domain-specific probes against members of the domains Bacteria and Archaea and
      the fluorescent stain 4', 6-diamidino-2-phenylindole (DAPI), by fluorescent in
      situ hybridization. After DAPI staining, the highest microbial density was
      obtained in the upper sediment layer; this density decreased with depth from
      (1.01 +/- 0.25) x 10(10) to (2.62 +/- 0.58) x 10(10) cells per g of sediment (dry
      weight). This zone corresponded to that of highest metabolic activity, as
      indicated by the ammonia, alkalinity, and pH profiles, whereas the methane
      profile was constant. Probes Eub338 and Arch915 detected on average 16 and 6% of
      the DAPI-stained cells as members of the domains Bacteria and Archaea,
      respectively. Probe Rotcl1 identified on average 4% of the DAPI-stained cells as
      Methanosaeta spp., which were present throughout the whole core. In contrast,
      probe Rotcl2 identified only 0.7% of the DAPI-stained cells as relatives of the
      methanogenic endosymbiont of P. nasuta, which was present exclusively in the
      upper 2 cm of the sediment. Probes Rotp13 and Rotp17 did not detect any cells.
      The spatial distribution of the two methanogenic populations corresponded well to
      the methane production rates determined by incubation with either [14C]acetate or
      [14C]bicarbonate. Methanogenesis from acetate accounted for almost all of the
      total methane production, which concurs with the predominance of acetoclastic
      Methanosaeta spp. that represented on average 91% of the archaeal population.
      Significant hydrogenotrophic methanogenesis was found only in the organically
      enriched upper 2 cm of the sediment, where the probably hydrogenotrophic
      relatives of the methanogenic endosymbiont of P. nasuta, accounting on average
      for 7% of the archaeal population, were also detected.

PMID- 10347021
TI  - Flow cytometric analysis of 5-cyano-2,3-ditolyl tetrazolium chloride activity of
      marine bacterioplankton in dilution cultures.
AB  - The respiratory activity of marine bacteria is an important indication of the
      ecological functioning of these organisms in marine ecosystems. The redox dye 5
      cyano-2,3-ditolyl tetrazolium chloride (CTC) is reduced intracellularly in
      respiring cells to an insoluble, fluorescent precipitate. This product is
      detectable and quantifiable by flow cytometry in individual cells. We describe
      here an evaluation of flow cytometry for measuring CTC activity in natural
      assemblages of marine bacteria growing in dilution cultures. We found that more
      CTC-positive cells are detected by flow cytometry than by visual epifluorescence
      microscopy. Samples can be stored refrigerated or frozen in liquid nitrogen for
      at least 4 weeks without a significant loss of total cells, CTC-positive cells,
      or CTC fluorescence. Cytometry still may not detect all active cells, however,
      since the dimmest fluorescing cells are not clearly separated from background
      noise. Reduction of CTC is very fast in most active cells, and the number of
      active cells reaches 80% of the maximum number within 2 to 10 min. The proportion
      of active cells is correlated with the growth rate, while the amount of
      fluorescence per cell varies inversely with the growth rate. The CTC reduction
      kinetics in assemblages bubbled with nitrogen and in assemblages bubbled with air
      to vary the oxygen availability were the same, suggesting that CTC can
      effectively compete with oxygen for reducing power. A nonbubbled control,
      however, contained more CTC-positive cells, and the amount of fluorescence per
      cell was greater. Activity may have been reduced by bubble-induced turbulence.
      Addition of an artificial reducing agent, sodium dithionite, after CTC incubation
      and fixation resulted in a greater number of positive cells but did not
      "activate" a majority of the cells. This indicated that some of the negative
      cells actually transported CTC across their cell membranes but did not reduce it
      to a detectable level. Automated analysis by flow cytometry allows workers to
      study single-cell variability in marine bacterioplankton activity and changes in
      activity on a small temporal or spatial scale.

PMID- 10347022
TI  - A morphological and molecular perspective of Trichoderma viride: is it one or two
      species?
AB  - Trichoderma (Ascomycetes, Hypocreales) strains that have warted conidia are
      traditionally identified as T. viride, the type species of Trichoderma. However,
      two morphologically distinct types of conidial warts (I and II) have been found.
      Because each type corresponds to a unique mitochondrial DNA pattern, it has been
      questioned whether T. viride comprises more than one species. Combined molecular
      data (sequences of the internal transcribed spacer 1 [ITS-1] and ITS-2 regions
      and of part of the 28S rRNA gene along with results of restriction fragment
      length polymorphism analysis of the endochitinase gene and PCR fingerprinting),
      morphology, physiology, and colony characteristics distinguish type I and type II
      as different species. Type I corresponds to "true" T. viride, the anamorph of
      Hypocrea rufa. Type II represents a new species, T. asperellum, which is, in
      terms of molecular characteristics, close to the neotype of T. hamatum.

PMID- 10347023
TI  - Environmental factors modulating antibiotic and siderophore biosynthesis by
      Pseudomonas fluorescens biocontrol strains.
AB  - Understanding the environmental factors that regulate the biosynthesis of
      antimicrobial compounds by disease-suppressive strains of Pseudomonas fluorescens
      is an essential step toward improving the level and reliability of their
      biocontrol activity. We used liquid culture assays to identify several minerals
      and carbon sources which had a differential influence on the production of the
      antibiotics 2,4-diacetylphloroglucinol (PHL), pyoluteorin (PLT), and pyrrolnitrin
      and the siderophores salicylic acid and pyochelin by the model strain CHA0, which
      was isolated from a natural disease-suppressive soil in Switzerland. Production
      of PHL was stimulated by Zn2+, NH4Mo2+, and glucose; the precursor compound mono
      acetylphloroglucinol was stimulated by the same factors as PHL. Production of PLT
      was stimulated by Zn2+, Co2+, and glycerol but was repressed by glucose.
      Pyrrolnitrin production was increased by fructose, mannitol, and a mixture of
      Zn2+ and NH4Mo2+. Pyochelin production was increased by Co2+, fructose, mannitol,
      and glucose. Interestingly, production of its precursor salicylic acid was
      increased by different factors, i.e., NH4Mo2+, glycerol, and glucose. The mixture
      of Zn2+ and NH4Mo2+ with fructose, mannitol, or glycerol further enhanced the
      production of PHL and PLT compared with either the minerals or the carbon sources
      used alone, but it did not improve siderophore production. Extending fermentation
      time from 2 to 5 days increased the accumulation of PLT, pyrrolnitrin, and
      pyochelin but not of PHL. When findings with CHA0 were extended to an
      ecologically and genetically diverse collection of 41 P. fluorescens biocontrol
      strains, the effect of certain factors was strain dependent, while others had a
      general effect. Stimulation of PHL by Zn2+ and glucose was strain dependent,
      whereas PLT production by all strains that can produce this compound was
      stimulated by Zn2+ and transiently repressed by glucose. Inorganic phosphate
      reduced PHL production by CHA0 and seven other strains tested but to various
      degrees. Production of PLT but not pyrrolnitrin by CHA0 was also reduced by 100
      mM phosphate. The use of 1/10-strength nutrient broth-yeast extract, compared
      with standard nutrient broth-yeast extract, amended with glucose and/or glycerol
      resulted in dramatically increased accumulations of PHL (but not PLT), pyochelin,
      and salicylic acid, indicating that the ratio of carbon source to nutrient
      concentration played a key role in the metabolic flow. The results of this study
      (i) provide insight into the biosynthetic regulation of antimicrobial compounds,
      (ii) limit the number of factors for intensive study in situ, and (iii) indicate
      factors that can be manipulated to improve bacterial inoculants.

PMID- 10347024
TI  - Enhancement of expression and apparent secretion of Erwinia chrysanthemi
      endoglucanase (encoded by celZ) in Escherichia coli B.
AB  - Escherichia coli B has been engineered as a biocatalyst for the conversion of
      lignocellulose into ethanol. Previous research has demonstrated that derivatives
      of E. coli B can produce high levels of Erwinia chrysanthemi endoglucanase
      (encoded by celZ) as a periplasmic product and that this enzyme can function with
      commercial fungal cellulase to increase ethanol production. In this study, we
      have demonstrated two methods that improve celZ expression in E. coli B.
      Initially, with a low-copy-number vector, two E. coli glycolytic gene promoters
      (gap and eno) were tested and found to be less effective than the original celZ
      promoter. By screening 18,000 random fragments of Zymomonas mobilis DNA, a
      surrogate promoter was identified which increased celZ expression up to sixfold.
      With this promoter, large polar inclusion bodies were clearly evident in the
      periplasmic space. Sequencing revealed that the most active surrogate promoter is
      derived from five Sau3A1 fragments, one of which was previously sequenced in Z.
      mobilis. Visual inspection indicated that this DNA fragment contains at least
      five putative promoter regions, two of which were confirmed by primer extension
      analysis. Addition of the out genes from E. chrysanthemi EC16 caused a further
      increase in the production of active enzyme and facilitated secretion or release
      of over half of the activity into the extracellular environment. With the most
      active construct, of a total of 13,000 IU of active enzyme per liter of culture,
      7,800 IU was in the supernatant. The total active endoglucanase was estimated to
      represent 4 to 6% of cellular protein.

PMID- 10347025
TI  - A pyruvated mannose-specific xanthan lyase involved in xanthan degradation by
      Paenibacillus alginolyticus XL-1.
AB  - The xanthan-degrading bacterium Paenibacillus alginolyticus XL-1, isolated from
      soil, degrades approximately 28% of the xanthan molecule and appears to leave the
      backbone intact. Several xanthan-degrading enzymes were excreted during growth on
      xanthan, including xanthan lyase. Xanthan lyase production was induced by xanthan
      and inhibited by glucose and low-molecular-weight enzymatic degradation products
      from xanthan. A xanthan lyase with a molecular mass of 85 kDa and a pI of 7.9 was
      purified and characterized. The enzyme is specific for pyruvated mannosyl side
      chain residues and optimally active at pH 6.0 and 55 degrees C.

PMID- 10347027
TI  - Inhibition of nitrifiers and methanotrophs from an agricultural humisol by
      allylsulfide and its implications for environmental studies.
AB  - Allylsulfide, an inhibitor of ammonia monooxygenase, was tested to determine its
      ability to inhibit nitrification and methane oxidation in pure cultures, in
      agricultural humisol enrichment cultures, and in humisol slurries. We confirmed
      that allylsulfide is a differential inhibitor of cultures of nitrifiers and
      methanotrophs at concentrations of 1 and 200 microM, respectively, which result
      in 50% inhibition. However, although a nitrifying enrichment culture added to
      sterilized humisol was inhibited 50% by 4 microM allylsulfide, 500 microM
      allylsulfide was necessary for 50% inhibition of the endogenous nitrifying
      activity in nonsterile humisol. We concluded that native nitrifiers were
      protected, possibly by being in colonial aggregates or sheltered
      microenvironments.

PMID- 10347026
TI  - Differential expression of three alpha-galactosidase genes and a single beta
      galactosidase gene from Aspergillus niger.
AB  - A gene encoding a third alpha-galactosidase (AglB) from Aspergillus niger has
      been cloned and sequenced. The gene consists of an open reading frame of 1,750 bp
      containing six introns. The gene encodes a protein of 443 amino acids which
      contains a eukaryotic signal sequence of 16 amino acids and seven putative N
      glycosylation sites. The mature protein has a calculated molecular mass of 48,835
      Da and a predicted pI of 4.6. An alignment of the AglB amino acid sequence with
      those of other alpha-galactosidases revealed that it belongs to a subfamily of
      alpha-galactosidases that also includes A. niger AglA. A. niger AglC belongs to a
      different subfamily that consists mainly of prokaryotic alpha-galactosidases. The
      expression of aglA, aglB, aglC, and lacA, the latter of which encodes an A. niger
      beta-galactosidase, has been studied by using a number of monomeric, oligomeric,
      and polymeric compounds as growth substrates. Expression of aglA is only detected
      on galactose and galactose-containing oligomers and polymers. The aglB gene is
      expressed on all of the carbon sources tested, including glucose. Elevated
      expression was observed on xylan, which could be assigned to regulation via XlnR,
      the xylanolytic transcriptional activator. Expression of aglC was only observed
      on glucose, fructose, and combinations of glucose with xylose and galactose. High
      expression of lacA was detected on arabinose, xylose, xylan, and pectin. Similar
      to aglB, the expression on xylose and xylan can be assigned to regulation via
      XlnR. All four genes have distinct expression patterns which seem to mirror the
      natural substrates of the encoded proteins.

PMID- 10347028
TI  - Monooxygenase-mediated 1,2-dichloroethane degradation by Pseudomonas sp. strain
      DCA1.
AB  - A bacterial strain, designated Pseudomonas sp. strain DCA1, was isolated from a
      1,2-dichloroethane (DCA)-degrading biofilm. Strain DCA1 utilizes DCA as the sole
      carbon and energy source and does not require additional organic nutrients, such
      as vitamins, for optimal growth. The affinity of strain DCA1 for DCA is very
      high, with a Km value below the detection limit of 0.5 microM. Instead of a
      hydrolytic dehalogenation, as in other DCA utilizers, the first step in DCA
      degradation in strain DCA1 is an oxidation reaction. Oxygen and NAD(P)H are
      required for this initial step. Propene was converted to 1,2-epoxypropane by DCA
      grown cells and competitively inhibited DCA degradation. We concluded that a
      monooxygenase is responsible for the first step in DCA degradation in strain
      DCA1. Oxidation of DCA probably results in the formation of the unstable
      intermediate 1,2-dichloroethanol, which spontaneously releases chloride, yielding
      chloroacetaldehyde. The DCA degradation pathway in strain DCA1 proceeds from
      chloroacetaldehyde via chloroacetic acid and presumably glycolic acid, which is
      similar to degradation routes observed in other DCA-utilizing bacteria.

PMID- 10347029
TI  - Maintenance energy demand and starvation recovery dynamics of Nitrosomonas
      europaea and Nitrobacter winogradskyi cultivated in a retentostat with complete
      biomass retention.
AB  - Nitrosomonas europaea and Nitrobacter winogradskyi (strain "Engel") were grown in
      ammonia-limited and nitrite-limited conditions, respectively, in a retentostat
      with complete biomass retention at 25 degrees C and pH 8. Fitting the retentostat
      biomass and oxygen consumption data of N. europaea and N. winogradskyi to the
      linear equation for substrate utilization resulted in up to eight-times-lower
      maintenance requirements compared to the maintenance energy demand (m) calculated
      from chemostat experiments. Independent of the growth rate at different stages of
      such a retention culture, the maximum specific oxygen consumption rate measured
      by mass spectrometric analysis of inlet and outlet gas oxygen content always
      amounted to approximately 45 micromol of O2 mg-1 of biomass-C x h-1 for both N.
      europaea and N. winogradskyi. When bacteria were starved for different time
      periods (up to 3 months), the spontaneous respiratory activity after an ammonia
      or nitrite pulse decreased with increasing duration of the previous starvation
      time period, but the observed decrease was many times faster for N. winogradskyi
      than for N. europaea. Likewise, the velocity of resuscitation decreased with
      extended time periods of starvation. The increase in oxygen consumption rates
      during resuscitation referred to the reviving population only, since in parallel
      no significant increase in the cell concentrations was detectable. N. europaea
      more readily recovers from starvation than N. winogradskyi, explaining the
      occasionally observed nitrite accumulation in the environment after ammonia
      becomes available. From chloramphenicol (100 microg x ml-1) inhibition
      experiments with N. winogradskyi, it has been concluded that energy-starved cells
      must have a lower protein turnover rate than nonstarved cells. As pointed out by
      Stein and Arp (L. Y. Stein and D. J. Arp, Appl. Environ. Microbiol. 64:1514-1521,
      1998), nitrifying bacteria in soil have to cope with extremely low nutrient
      concentrations. Therefore, a chemostat is probably not a suitable tool for
      studying their physiological properties during a long-lasting nutrient shortage.
      In comparison with chemostats, retentostats offer a more realistic approach with
      respect to substrate provision and availability.

PMID- 10347031
TI  - Structures and properties of gellan polymers produced by sphingomonas
      paucimobilis ATCC 31461 from lactose compared with those produced from glucose
      and from cheese whey 
AB  - The dairy industry produces large quantities of whey as a by-product of cheese
      production and is increasingly looking for new ways to utilize this waste
      product. Gellan gum is reliably produced by Sphingomonas paucimobilis in growth
      media containing lactose, a significant component of cheese whey, as a carbon
      source. We studied and compared polysaccharide biosynthesis by S. paucimobilis
      ATCC 31461 in media containing glucose, lactose (5 to 30 g/liter), and sweet
      cheese whey. We found that altering the growth medium can markedly affect the
      polysaccharide yield, acyl substitution level, polymer rheological properties,
      and susceptibility to degradation. Depression of gellan production from lactose
      compared with gellan production from glucose (approximately 30%) did not appear
      to occur at the level of synthesis of sugar nucleotides, which are the donors of
      monomers used for biosynthesis of the repetitive tetrasaccharide unit of gellan.
      The lactose-derived biopolymer had the highest total acyl content; the glucose-
      and whey-derived gellans had similar total acyl contents but differed markedly in
      their acetate and glycerate levels. Rheological studies revealed how the
      functionality of a gellan polysaccharide is affected by changes in the acyl
      substitution.

PMID- 10347030
TI  - Detritus-dependent development of the microbial community in an experimental
      system: qualitative analysis by denaturing gradient gel electrophoresis.
AB  - Correlations between the biomass of phytoplankton and the biomass of bacteria and
      between the biomass of bacteria and the biomass of protozoans suggest that there
      is coupling between these compartments of the "microbial loop." To investigate
      this coupling on the species level, bacteria and protozoans from untreated lake
      water inocula were allowed to grow on detritus of the green alga Ankistrodesmus
      falcatus or the cyanobacterium Oscillatoria limnetica in continuous-flow systems
      for 1 month. Denaturing gradient gel electrophoresis (DGGE) of the 16S and 18S
      rRNA genes was used to monitor the development of the bacterial community
      structure and the eukaryotic community structure, respectively. Nonmetric
      multidimensional scaling of the DGGE profiles revealed the changes in the
      microbial community structure. This analysis showed that significantly different
      bacterial communities developed on the green algal detritus and on the
      cyanobacterial detritus. Although similar results were obtained for the
      eukaryotic communities, the differences were not significant. Hence, our findings
      indicate that the origin of detritus can affect the structure of at least the
      bacterial community. A phylogenetic analysis of 20 18S ribosomal DNA clones that
      were isolated from the continuous cultures revealed that many sequences were
      related to the sequences of bacterivorous protozoans (members of the Ciliophora,
      Rhizopoda, Amoeba, and Kinetoplastida). One clone grouped in a recently
      established clade whose previously described members are all parasites. The
      affiliations of about 20% of the clones could not be determined.

PMID- 10347033
TI  - Hyperproduction of tryptophan by Corynebacterium glutamicum with the modified
      pentose phosphate pathway.
AB  - A classically derived tryptophan-producing Corynebacterium glutamicum strain was
      recently significantly improved both by plasmid-mediated amplification of the
      genes for the rate-limiting enzymes in the terminal pathways and by construction
      of a plasmid stabilization system so that it produced more tryptophan. This
      engineered strain, KY9218 carrying pKW9901, produced 50 g of tryptophan per liter
      from sucrose after 80 h in fed-batch cultivation without antibiotic pressure.
      Analysis of carbon balances showed that at the late stage of the fermentation,
      tryptophan yield decreased with a concomitant increase in CO2 yield, suggesting a
      transition in the distribution of carbon flow from aromatic biosynthesis toward
      the tricarboxylic acid cycle via glycolysis. To circumvent this transition by
      increasing the supply of erythrose 4-phosphate, a direct precursor of aromatic
      biosynthesis, the transketolase gene of C. glutamicum was coamplified in the
      engineered strain by using low- and high-copy-number plasmids which were
      compatible with the resident plasmid pKW9901. The presence of the gene in low
      copy numbers contributed to improvement of tryptophan yield, especially at the
      late stage, and led to accumulation of more tryptophan (57 g/liter) than did its
      absence, while high-copy-number amplification of the gene resulted in a
      tryptophan production level even lower than that resulting from the absence of
      the gene due to reduced growth and sugar consumption. In order to assemble all
      the cloned genes onto a low-copy-number plasmid, the high-copy-number origin of
      pKW9901 was replaced with the low-copy-number one, generating low-copy-number
      plasmid pSW9911, and the transketolase gene was inserted to yield pIK9960. The
      pSW9911-carrying producer showed almost the same fermentation profiles as the
      pKW9901 carrier in fed-batch cultivation without antibiotic pressure. Under the
      same culture conditions, however, the pIK9960 carrier achieved a final tryptophan
      titer of 58 g/liter, which represented a 15% enhancement over the titers achieved
      by the pKW9901 and pSW9911 carriers.

PMID- 10347032
TI  - Occurrence of nontuberculous mycobacteria in environmental samples.
AB  - Nontuberculous mycobacteria (NTM) are a major cause of opportunistic infection in
      immunocompromised hosts. Because there is no evidence of person-to-person
      transmission and NTM have been found in drinking water, the environment is
      considered a likely source of infection. In this study the widespread occurrence
      of NTM was examined in drinking water, bottled water, and ice samples. A total of
      139 samples were examined for NTM by a membrane filtration culture technique
      followed by PCR amplification and 16S rRNA sequence determination to identify the
      isolates. NTM were not detected in bottled water or cisterns but were detected in
      54% of the ice samples and 35% of the public drinking-water samples from 21
      states. The most frequently occurring isolate was M. mucogenicum (formerly
      referred to as an M. chelonae-like organism).

PMID- 10347034
TI  - Aggregation of bacillus thuringiensis Cry1A toxins upon binding to target insect
      larval midgut vesicles 
AB  - During sporulation, Bacillus thuringiensis produces crystalline inclusions
      comprised of a mixture of delta-endotoxins. Following ingestion by insect larvae,
      these inclusion proteins are solubilized, and the protoxins are converted to
      toxins. These bind specifically to receptors on the surfaces of midgut apical
      cells and are then incorporated into the membrane to form ion channels. The steps
      required for toxin insertion into the membrane and possible oligomerization to
      form a channel have been examined. When bound to vesicles from the midguts of
      Manduca sexta larvae, the Cry1Ac toxin was largely resistant to digestion with
      protease K. Only about 60 amino acids were removed from the Cry1Ac amino
      terminus, which included primarily helix alpha1. Following incubation of the
      Cry1Ab or Cry1Ac toxins with vesicles, the preparations were solubilized by
      relatively mild conditions, and the toxin antigens were analyzed by
      immunoblotting. In both cases, most of the toxin formed a large, antigenic
      aggregate of ca. 200 kDa. These toxin aggregates did not include the toxin
      receptor aminopeptidase N, but interactions with other vesicle components were
      not excluded. No oligomerization occurred when inactive toxins with mutations in
      amphipathic helices (alpha5) and known to insert into the membrane were tested.
      Active toxins with other mutations in this helix did form oligomers. There was
      one exception; a very active helix alpha5 mutant toxin bound very well to
      membranes, but no oligomers were detected. Toxins with mutations in the loop
      connecting helices alpha2 and alpha3, which affected the irreversible binding to
      vesicles, also did not oligomerize. There was a greater extent of oligomerization
      of the Cry1Ac toxin with vesicles from the Heliothis virescens midgut than with
      those from the M. sexta midgut, which correlated with observed differences in
      toxicity. Tight binding of virtually the entire toxin molecule to the membrane
      and the subsequent oligomerization are both important steps in toxicity.

PMID- 10347035
TI  - The carboxy-terminal portion of the aflatoxin pathway regulatory protein AFLR of
      Aspergillus parasiticus activates GAL1::lacZ gene expression in Saccharomyces
      cerevisiae.
AB  - AFLR, a DNA-binding protein of 444 amino acids, transactivates the expression of
      aflatoxin biosynthesis genes in Aspergillus parasiticus and Aspergillus flavus,
      as well as the sterigmatocystin synthesis genes in Aspergillus nidulans. We show
      here by fusion of various aflR coding regions to the GAL4 DNA-binding coding
      region that the AFLR carboxyl terminus contained a region that activated
      GAL1::lacZ gene expression in Saccharomyces cerevisiae and that the AFLR internal
      region was required for the activation activity. Compared to the AFLR carboxy
      terminal fusion protein (AFLRC), a mutant AFLRC retained approximately 75% of the
      activation activity after deletion of three acidic amino acids, Asp365, Glu366,
      and Glu367, in a previously identified acidic stretch. Removal of the carboxy
      terminal amino acid, Glu444, did not affect the activation activity.
      Substitutions of acidic Glu423, Asp439, or Asp436/Asp439 with basic amino acids,
      Lys and His, resulted in 10- to 15-fold-lower activation activities. Strikingly,
      the Asp436His mutation abolished the activation activity. Substitutions of basic
      His428 and His442 with acidic Asp resulted in 20 and 40% decreases in the
      activation activities, respectively. Simultaneous substitutions of Arg427,
      Arg429, and Arg431 with Leu also significantly decreased the activation activity;
      the decrease was approximately 50-fold. Results suggest that the AFLR carboxy
      terminal region is involved in transcription activation and that total acidity in
      this region is not a major determinant of AFLR's activation ability in S.
      cerevisiae.

PMID- 10347036
TI  - Role of pfkA and general carbohydrate catabolism in seed colonization by
      Enterobacter cloacae.
AB  - Enterobacter cloacae A-11 is a transposon mutant of strain 501R3 that was
      deficient in cucumber spermosphere colonization and in the utilization of certain
      carbohydrates (D. P. Roberts, C. J. Sheets, and J. S. Hartung, Can. J. Microbiol.
      38:1128-1134, 1992). In vitro growth of strain A-11 was reduced or deficient on
      most carbohydrates that supported growth of strain 501R3 but was unaffected on
      fructose, glycerol, and all amino acids and organic acids tested. Colonization by
      strain A-11 was significantly reduced (P </= 0.05) for cucumber and radish seeds
      compared to that of strain 501R3, but colonization of pea, soybean, sunflower,
      and sweet corn seeds was not reduced. Pea seeds released several orders of
      magnitude more total carbohydrates and amino acids than cucumber and radish seeds
      and approximately 4,000-fold more fructose. Fructose was the only carbohydrate
      detected in the seed exudates which supported wild-type levels of in vitro growth
      of strain A-11. Soybean, sunflower, and sweet corn seeds also released
      significantly greater amounts of fructose and total carbohydrates and amino acids
      than cucumber or radish seeds. The exogenous addition of fructose to cucumber and
      radish seeds at quantities similar to the total quantity of carbohydrates
      released from pea seeds over 96 h increased the populations of strain A-11 to
      levels comparable to those of strain 501R3 in sterile sand. Molecular
      characterization of strain A-11 indicated that the mini-Tn5 kanamycin transposon
      was inserted in a region of the genome with significant homology to pfkA, which
      encodes phosphofructo kinase. A comparison of strain A-11 with Escherichia coli
      DF456, a known pfkA mutant, indicated that the nutritional loss phenotypes were
      identical. Furthermore, the pfkA homolog cloned from E. cloacae 501R3
      complemented the nutritional loss phenotypes of both E. coli DF456 and E. cloacae
      A-11 and restored colonization by strain A-11 to near wild-type levels. These
      genetic and biochemical restoration experiments provide strong evidence that the
      quantities of reduced carbon sources found in seed exudates and the ability of
      microbes to use these compounds play important roles in the colonization of the
      spermosphere.

PMID- 10347037
TI  - Microbial system for polysaccharide depolymerization: enzymatic route for xanthan
      depolymerization by Bacillus sp. strain GL1.
AB  - An enzymatic route for the depolymerization of a heteropolysaccharide (xanthan)
      in Bacillus sp. strain GL1, which was closely related to Brevibacillus
      thermoruber, was determined by analyzing the structures of xanthan
      depolymerization products. The bacterium produces extracellular xanthan lyase
      catalyzing the cleavage of the glycosidic bond between pyruvylated mannosyl and
      glucuronyl residues in xanthan side chains (W. Hashimoto et al., Appl. Environ.
      Microbiol. 64:3765-3768, 1998). The modified xanthan after the lyase reaction was
      then depolymerized by extracellular beta-D-glucanase to a tetrasaccharide,
      without the terminal mannosyl residue of the side chain in a pentasaccharide, a
      repeating unit of xanthan. The tetrasaccharide was taken into cells and converted
      to a trisaccharide (unsaturated glucuronyl-acetylated mannosyl-glucose) by beta-D
      glucosidase. The trisaccharide was then converted to the unsaturated glucuronic
      acid and a disaccharide (mannosyl-glucose) by unsaturated glucuronyl hydrolase.
      Finally, the disaccharide was hydrolyzed to mannose and glucose by alpha-D
      mannosidase. This is the first complete report on xanthan depolymerization by
      bacteria. Novel beta-D-glucanase, one of the five enzymes involved in the
      depolymerization route, was purified from the culture fluid. This enzyme was a
      homodimer with a subunit molecular mass of 173 kDa and was most active at pH 6.0
      and 45 degrees C. The enzyme specifically acted on xanthan after treatment with
      xanthan lyase and released the tetrasaccharide.

PMID- 10347038
TI  - Microbial control of the culture of Artemia juveniles through preemptive
      colonization by selected bacterial strains.
AB  - The use of juvenile Artemia as feed in aquaculture and in the pet shop industry
      has been getting more attention during the last decade. In this study, the use of
      selected bacterial strains to improve the nutritional value of dry food for
      Artemia juveniles and to obtain control of the associated microbial community was
      examined. Nine bacterial strains were selected based on their positive effects on
      survival and/or growth of Artemia juveniles under monoxenic culture conditions,
      while other strains caused no significant effect, significantly lower rates of
      survival and/or growth, or even total mortality of the Artemia. The nine selected
      strains were used to preemptively colonize the culture water of Artemia
      juveniles. Xenic culture of Artemia under suboptimal conditions yielded better
      survival and/or growth rates when they were grown in the preemptively colonized
      culture medium than when grown in autoclaved seawater. The preemptive
      colonization of the culture water had a drastic influence on the microbial
      communities that developed in the culture water or that were associated with the
      Artemia, as determined with Biolog GN community-level physiological profiles.
      Chemotaxonomical characterization based on fatty acid methyl ester analysis of
      bacterial isolates recovered from the culture tanks was performed, and a
      comparison with the initially introduced strains was made. Finally, several modes
      of action for the beneficial effect of the bacterial strains are proposed.

PMID- 10347039
TI  - Use of antibacterial agents To elucidate the etiology of juvenile oyster disease
      (JOD) in Crassostrea virginica and numerical dominance of an alpha
      proteobacterium in JOD-affected animals.
AB  - Since 1988, juvenile oyster disease (JOD) has resulted in high seasonal losses of
      cultured Eastern oysters (Crassostrea virginica) in the Northeast. Although the
      cause of JOD remains unknown, most evidence is consistent with either a bacterial
      or a protistan etiology. For the purpose of discerning between these hypotheses,
      the antibacterial antibiotics norfloxacin and sulfadimethoxine-ormetoprim (Romet
      B) were tested for the ability to delay the onset of JOD mortality and/or reduce
      the JOD mortality of cultured juvenile C. virginica. Hatchery-produced C.
      virginica seed were exposed in triplicate groups of 3,000 animals each to either
      norfloxacin, sulfadimethoxine-ormetoprim, or filter-sterilized seawater (FSSW)
      and deployed in floating trays on the Damariscotta River of Maine on 17 July
      1997. Each week thereafter, a subset of animals from each group was reexposed to
      the assigned treatment. Repeated immersion in either a sulfadimethoxine
      ormetoprim or a norfloxacin solution resulted in a delay in the onset of JOD
      mortality in treated animals and reduced weekly mortality rates. Weekly
      treatments with either norfloxacin or sulfadimethoxine-ormetoprim also resulted
      in a statistically significant reduction in cumulative mortality (55 and 67%
      respectively) compared to animals treated weekly with FSSW (81%) or those that
      had received only a single treatment with either norfloxacin, sulfadimethoxine
      ormetoprim, or FSSW (77, 84, and 82%, respectively). Bacteriological analyses
      revealed a numerically dominant bacterium in those animals with obvious signs of
      JOD. Sequence analysis of the 16S rRNA gene from these bacteria indicates that
      they are a previously undescribed species of marine alpha-proteobacteria.

PMID- 10347040
TI  - Generation of a superoxide dismutase (SOD)-deficient mutant of Campylobacter
      coli: evidence for the significance of SOD in Campylobacter survival and
      colonization.
AB  - The microaerophilic nature of Campylobacter species implies an inherent
      sensitivity towards oxygen and its reduction products, particularly the
      superoxide anion. The deleterious effects of exposure to superoxide radicals are
      counteracted by the activity of superoxide dismutase (SOD). We have shown
      previously that Campylobacter coli possesses an iron cofactored SOD. The sodB
      gene of C. coli UA585 was insertionally inactivated by the site-specific
      insertion of a tetO cassette. Organisms harboring the inactivated gene failed to
      produce a biologically functional form of the enzyme. While the ability of this
      mutant to grow in aerobic conditions was unchanged relative to the parental
      strain, its survival was severely compromised when nongrowing cells were exposed
      to air. Accordingly, the SOD-deficient mutant was unable to survive for prolonged
      periods in model foods. Furthermore, inactivation of the sodB gene decreased the
      colonization potential in an experimental infection of 1-day-old chicks. In
      contrast, strain CK100, which is deficient in catalase activity, showed the same
      survival and colonization characteristics as the parental strain. These results
      indicate that SOD, but not catalase, is an important determinant in the ability
      of C. coli to survive aerobically and for optimal colonization within the chicken
      gut.

PMID- 10347041
TI  - Degradation of chlorobenzenes at nanomolar concentrations by Burkholderia sp.
      strain PS14 in liquid cultures and in soil.
AB  - The utilization of 1,2,4,5-tetrachloro-, 1,2,4-trichloro-, the three isomeric
      dichlorobenzenes and fructose as the sole carbon and energy sources at nanomolar
      concentrations was studied in batch experiments with Burkholderia sp. strain
      PS14. In liquid culture, all chlorobenzenes were metabolized within 1 h from
      their initial concentration of 500 nM to below their detection limits of 0.5 nM
      for 1,2,4,5-tetrachloro- and 1,2,4-trichlorobenzene and 7.5 nM for the three
      dichlorobenzene isomers, with 63% mineralization of the tetra- and
      trichloroisomers. Fructose at the same initial concentration was, in contrast,
      metabolized over a 4-h incubation period down to a residual concentration of
      approximately 125 nM with 38% mineralization during this time. In soil
      microcosms, Burkholderia sp. strain PS14 metabolized tetrachlorobenzene present
      at 64.8 ppb and trichlorobenzene present at 54.4 ppb over a 72-h incubation
      period to below the detection limits of 0.108 and 0.09 ppb, respectively, with
      approximately 80% mineralization. A high sorptive capacity of Burkholderia sp.
      strain PS14 for 1,2,4, 5-tetrachlorobenzene was found at very low cell density.
      The results demonstrate that Burkholderia sp. strain PS14 exhibits a very high
      affinity for chlorobenzenes at nanomolar concentrations.

PMID- 10347042
TI  - Chitinases from uncultured marine microorganisms.
AB  - Our understanding of the degradation of organic matter will benefit from a
      greater appreciation for the genes encoding enzymes involved in the hydrolysis of
      biopolymers such as chitin, one of the most abundant polymers in nature. To
      isolate representative and abundant chitinase genes from uncultivated marine
      bacteria, we constructed libraries of genomic DNA isolated from coastal and
      estuarine waters. The libraries were screened for genes encoding proteins that
      hydrolyze a fluorogenic analogue of chitin, 4-methylumbelliferyl beta-D-N,N'
      diacetylchitobioside (MUF-diNAG). The abundance of clones capable of MUF-diNAG
      hydrolysis was higher in the library constructed with DNA from the estuary than
      in that constructed with DNA from coastal waters, although the abundance of
      positive clones was also dependent on the method used to screen the library.
      Plaque assays revealed nine MUF-diNAG-positive clones of 75,000 screened for the
      estuarine sample and two clones of 750,000 for the coastal sample. A microtiter
      plate assay revealed approximately 1 positive clone for every 500 clones screened
      in the coastal library. The number of clones detected with the plaque assay was
      consistent with estimates of the portion of culturable bacteria that degrade
      chitin. Our results suggest that culture-dependent methods do not greatly
      underestimate the portion of marine bacterial communities capable of chitin
      degradation.

PMID- 10347043
TI  - Deletions in the gibberellin biosynthesis gene cluster of Gibberella fujikuroi by
      restriction enzyme-mediated integration and conventional transformation-mediated
      mutagenesis.
AB  - We induced mutants of Gibberella fujikuroi deficient in gibberellin (GA)
      biosynthesis by transformation-mediated mutagenesis with the vector pAN7-1. We
      recovered 24 GA-defective mutants in one of nine transformation experiments
      performed without the addition of a restriction enzyme. Each mutant had a similar
      Southern blot pattern, suggesting the integration of the vector into the same
      site. The addition of a restriction enzyme by restriction enzyme-mediated
      integration (REMI) significantly increased the transformation rate and the rate
      of single-copy integration events. Of 1,600 REMI transformants, two produced no
      GAs. Both mutants had multiple copies of the vector pAN7-1 and one had a Southern
      blot pattern similar to those of the 24 conventionally transformed GA-deficient
      mutants. Biochemical analysis of the two REMI mutants confirmed that they cannot
      produce ent-kaurene, the first specific intermediate of the GA pathway. Feeding
      the radioactively labelled precursors ent-kaurene and GA12-aldehyde followed by
      high-performance liquid chromatography and gas chromatography-mass spectrometry
      analysis showed that neither of these intermediates was converted to GAs in the
      mutants. Southern blot analysis and pulsed-field gel electrophoresis of the
      transformants using the bifunctional ent-copalyl diphosphate/ent-kaurene synthase
      gene (cps/ks) and the flanking regions as probes revealed a large deletion in the
      GA-deficient REMI transformants and in the GA-deficient transformants obtained by
      conventional insertional transformation. We conclude that transformation
      procedures with and without the addition of restriction enzymes can lead to
      insertion-mediated mutations and to deletions and chromosome translocations.

PMID- 10347044
TI  - Cellobiose transport by mixed ruminal bacteria from a Cow.
AB  - The transport of cellobiose in mixed ruminal bacteria harvested from a holstein
      cow fed an Italian ryegrass hay was determined in the presence of nojirimycin-1
      sulfate, which almost inhibited cellobiase activity. The kinetic parameters of
      cellobiose uptake were 14 microM for the Km and 10 nmol/min/mg of protein for the
      Vmax. Extracellular and cell-associated cellobiases were detected in the rumen,
      with both showing higher Vmax values and lower affinities than those determined
      for cellobiose transport. The proportion of cellobiose that was directly
      transported before it was extracellularly degraded into glucose increased as the
      cellobiose concentration decreased, reaching more than 20% at the actually
      observed levels of cellobiose in the rumen, which were less than 0.02 mM. The
      inhibitor experiment showed that cellobiose was incorporated into the cells
      mainly by the phosphoenolpyruvate phosphotransferase system and partially by an
      ATP-dependent and proton-motive-force-independent active transport system. This
      finding was also supported by determinations of phosphoenolpyruvate
      phosphotransferase-dependent NADH oxidation with cellobiose and the effects of
      artificial potentials on cellobiose transport. Cellobiose uptake was sensitive to
      a decrease in pH (especially below 6.0), and it was weakly but significantly
      inhibited in the presence of glucose.

PMID- 10347045
TI  - Purification and characterization of a keratinolytic serine proteinase from
      Streptomyces albidoflavus.
AB  - Streptomyces strain K1-02, which was identified as a strain of Streptomyces
      albidoflavus, secreted at least six extracellular proteases when it was cultured
      on feather meal-based medium. The major keratinolytic serine proteinase was
      purified to homogeneity by a two-step procedure. This enzyme had a molecular
      weight of 18,000 and was optimally active at pH values ranging from 6 to 9.5 and
      at temperatures ranging from 40 to 70 degrees C. Its sensitivity to protease
      inhibitors, its specificity on synthetic substrates, and its remarkably high
      level of NH2-terminal sequence homology with Streptomyces griseus protease B
      (SGPB) showed that the new enzyme, designated SAKase, was homologous to SGPB. We
      tested the activity of SAKase with soluble and fibrous substrates (elastin,
      keratin, and type I collagen) and found that it was very specific for keratinous
      substrates compared to SGPB and proteinase K.

PMID- 10347046
TI  - Temperature dependence of inorganic nitrogen uptake: reduced affinity for nitrate
      at suboptimal temperatures in both algae and bacteria.
AB  - Nitrate utilization and ammonium utilization were studied by using three algal
      isolates, six bacterial isolates, and a range of temperatures in chemostat and
      batch cultures. We quantified affinities for both substrates by determining
      specific affinities (specific affinity = maximum growth rate/half-saturation
      constant) based on estimates of kinetic parameters obtained from chemostat
      experiments. At suboptimal temperatures, the residual concentrations of nitrate
      in batch cultures and the steady-state concentrations of nitrate in chemostat
      cultures both increased. The specific affinity for nitrate was strongly dependent
      on temperature (Q10 approximately 3, where Q10 is the proportional change with a
      10 degrees C temperature increase) and consistently decreased at temperatures
      below the optimum temperature. In contrast, the steady-state concentrations of
      ammonium remained relatively constant over the same temperature range, and the
      specific affinity for ammonium exhibited no clear temperature dependence. This is
      the first time that a consistent effect of low temperature on affinity for
      nitrate has been identified for psychrophilic, mesophilic, and thermophilic
      bacteria and algae. The different responses of nitrate uptake and ammonium uptake
      to temperature imply that there is increasing dependence on ammonium as an
      inorganic nitrogen source at low temperatures.

PMID- 10347047
TI  - Niche-partitioning of Prochlorococcus populations in a stratified water column in
      the eastern North Atlantic Ocean.
AB  - The in situ community structure of Prochlorococcus populations in the eastern
      North Atlantic Ocean was examined by analysis of Prochlorococcus 16S rDNA
      sequences with three independent approaches: cloning and sequencing,
      hybridization to specific oligonucleotide probes, and denaturing gradient gel
      electrophoresis (DGGE). The hybridization of high-light (HL) and low-light (LL)
      Prochlorococcus genotype-specific probes to two depth profiles of PCR-amplified
      16S rDNA sequences revealed that in these two stratified water columns, an
      obvious niche-partitioning of Prochlorococcus genotypes occurred. In each water
      column a shift from the HL to the LL genotype was observed, a transition
      correlating with the depth of the surface mixed layer (SML). Only the HL genotype
      was found in the SML in each water column, whereas the LL genotype was
      distributed below the SML. The range of in situ irradiance to which each genotype
      was subjected within these distinct niches was consistent with growth irradiance
      studies of cultured HL- and LL-adapted Prochlorococcus strains. DGGE analysis and
      the sequencing of Prochlorococcus 16S rDNA clones were in full agreement with the
      genotype-specific oligonucleotide probe hybridization data. These observations of
      a partitioning of Prochlorococcus genotypes in a stratified water column provide
      a genetic basis for the dim and bright Prochlorococcus populations observed in
      flow cytometric signatures in several oceanic provinces.

PMID- 10347048
TI  - Vibrios associated with Litopenaeus vannamei larvae, postlarvae, broodstock, and
      hatchery probionts.
AB  - Several bacteriological surveys were performed from 1994 to 1996 at different
      Litopenaeus vannamei hatcheries (in Ecuador) and shrimp farms (in Mexico).
      Samples were taken from routine productions of healthy and diseased L. vannamei
      larvae, postlarvae, and their culture environment and from healthy and diseased
      juveniles and broodstock. In Ecuador, the dominant bacterial flora associated
      with shrimp larvae showing symptoms of zoea 2 syndrome, mysis mold syndrome, and
      bolitas syndrome has been determined. Strains were characterized by Biolog
      metabolic fingerprinting and identified by comparison to a database of 850 Vibrio
      type and reference strains. A selection of strains was further genotypically fine
      typed by AFLP. Vibrio alginolyticus is predominantly present in all larval stages
      and is associated with healthy nauplius and zoea stages. AFLP genetic
      fingerprinting shows high genetic heterogeneity among V. alginolyticus strains,
      and the results suggest that putative probiotic and pathogenic strains each have
      specific genotypes. V. alginolyticus was found to be associated with larvae with
      the zoea 2 syndrome and the mysis mold syndrome, while different Vibrio species
      (V. alginolyticus and V. harveyi) are associated with the bolitas syndrome. V.
      harveyi is associated with diseased postlarvae, juveniles, and broodstock. The
      identities of the strains identified as V. harveyi by the Biolog system could not
      be unambiguously confirmed by AFLP genomic fingerprinting. Vibrio strain STD3-988
      and one unidentified strain (STD3-959) are suspected pathogens of only juvenile
      and adult stages. V. parahaemolyticus, Photobacterium damselae, and V. mimicus
      are associated with juvenile and adult stages.

PMID- 10347049
TI  - Mannan-degrading enzymes from Cellulomonas fimi.
AB  - The genes man26a and man2A from Cellulomonas fimi encode mannanase 26A (Man26A)
      and beta-mannosidase 2A (Man2A), respectively. Mature Man26A is a secreted,
      modular protein of 951 amino acids, comprising a catalytic module in family 26 of
      glycosyl hydrolases, an S-layer homology module, and two modules of unknown
      function. Exposure of Man26A produced by Escherichia coli to C. fimi protease
      generates active fragments of the enzyme that correspond to polypeptides with
      mannanase activity produced by C. fimi during growth on mannans, indicating that
      it may be the only mannanase produced by the organism. A significant fraction of
      the Man26A produced by C. fimi remains cell associated. Man2A is an intracellular
      enzyme comprising a catalytic module in a subfamily of family 2 of the glycosyl
      hydrolases that at present contains only mammalian beta-mannosidases.

PMID- 10347051
TI  - Analysis of fungal diversity in the wheat rhizosphere by sequencing of cloned PCR
      amplified genes encoding 18S rRNA and temperature gradient gel electrophoresis.
AB  - Like bacteria, fungi play an important role in the soil ecosystem. As only a
      small fraction of the fungi present in soil can be cultured, conventional
      microbiological techniques yield only limited information on the composition and
      dynamics of fungal communities in soil. DNA-based methods do not depend on the
      culturability of microorganisms, and therefore they offer an attractive
      alternative for the study of complex fungal community structures. For this
      purpose, we designed various PCR primers that allow the specific amplification of
      fungal 18S-ribosomal-DNA (rDNA) sequences, even in the presence of nonfungal 18S
      rDNA. DNA was extracted from the wheat rhizosphere, and 18S rDNA gene banks were
      constructed in Escherichia coli by cloning PCR products generated with primer
      pairs EF4-EF3 (1. 4 kb) and EF4-fung5 (0.5 kb). Fragments of 0.5 kb from the
      cloned inserts were sequenced and compared to known rDNA sequences. Sequences
      from all major fungal taxa were amplified by using both primer pairs. As
      predicted by computer analysis, primer pair EF4-EF3 appeared slightly biased to
      amplify Basidiomycota and Zygomycota, whereas EF4-fung5 amplified mainly
      Ascomycota. The 61 clones that were sequenced matched the sequences of 24
      different species in the Ribosomal Database Project (RDP) database. Similarity
      values ranged from 0.676 to 1. Temperature gradient gel electrophoresis (TGGE)
      analysis of the fungal community in the wheat rhizosphere of a microcosm
      experiment was carried out after amplification of total DNA with both primer
      pairs. This resulted in reproducible, distinctive fingerprints, confirming the
      difference in amplification specificity. Clear banding patterns were obtained
      with soil and rhizosphere samples by using both primer sets in combination. By
      comparing the electrophoretic mobility of community fingerprint bands to that of
      the bands obtained with separate clones, some could be tentatively identified.
      While 18S-rDNA sequences do not always provide the taxonomic resolution to
      identify fungal species and strains, they do provide information on the diversity
      and dynamics of groups of related species in environmental samples with
      sufficient resolution to produce discrete bands which can be separated by TGGE.
      This combination of 18S-rDNA PCR amplification and TGGE community analysis should
      allow study of the diversity, composition, and dynamics of the fungal community
      in bulk soil and in the rhizosphere.

PMID- 10347050
TI  - Characterization of Pseudomonas aeruginosa bacteriophage UNL-1, a bacterial virus
      with a novel UV-A-inducible DNA damage reactivation phenotype.
AB  - UNL-1, a lytic virus of Pseudomonas aeruginosa, was observed to express a novel
      inducible DNA damage reactivation activity in UV-A-irradiated P. aeruginosa host
      cells. The expression of bacteriophage reactivation was quantified in hosts
      exposed to either UV-C or UV-A radiation. While reactivation of UV-C-damaged UNL
      1 was not inducible in UV-C-irradiated host cells, an approximately 13-fold
      induction was observed in UV-A-irradiated host cells. When host cells were
      exposed to sunlight, reactivation of damaged UNL-1 virus increased eightfold. The
      UV-A induction of UNL-1 DNA damage reactivation was supported in hosts lacking
      recA gene function. This report is the first description of a recA-independent,
      UV-inducible virus DNA damage repair system. Our findings suggest that a
      combination of both host and virus DNA repair processes contribute to the
      persistence and sustained replication of some bacterial viruses in aquatic
      environments.

PMID- 10347052
TI  - Characterization of a Pseudomonas putida allylic alcohol dehydrogenase induced by
      growth on 2-methyl-3-buten-2-ol.
AB  - We have been working to develop an enzymatic assay for the alcohol 2-methyl-3
      buten-2-ol (232-MB), which is produced and emitted by certain pines. To this end
      we have isolated the soil bacterium Pseudomonas putida MB-1, which uses 232-MB as
      a sole carbon source. Strain MB-1 contains inducible 3-methyl-2-buten-1-ol (321
      MB) and 3-methyl-2-buten-1-al dehydrogenases, suggesting that 232-MB is
      metabolized by isomerization to 321-MB followed by oxidation. 321-MB
      dehydrogenase was purified to near-homogeneity and found to be a tetramer (151
      kDa) with a subunit mass of 37,700 Da. It catalyzes NAD+-dependent, reversible
      oxidation of 321-MB to 3-methyl-2-buten-1-al. The optimum pH for the oxidation
      reaction was 10.0, while that for the reduction reaction was 5.4. 321-MB
      dehydrogenase oxidized a wide variety of aliphatic and aromatic alcohols but
      exhibited the highest catalytic specificity with allylic or benzylic substrates,
      including 321-MB, 3-chloro-2-buten-1-ol, and 3-aminobenzyl alcohol. The N
      terminal sequence of the enzyme contained a region of 64% identity with the TOL
      plasmid-encoded benzyl alcohol dehydrogenase of P. putida. The latter enzyme and
      the chromosomally encoded benzyl alcohol dehydrogenase of Acinetobacter
      calcoaceticus were also found to catalyze 321-MB oxidation. These findings
      suggest that 321-MB dehydrogenase and other bacterial benzyl alcohol
      dehydrogenases are broad-specificity allylic and benzylic alcohol dehydrogenases
      that, in conjunction with a 232-MB isomerase, might be useful in an enzyme-linked
      assay for 232-MB.

PMID- 10347053
TI  - Effect of organic solvents on the yield of solvent-tolerant Pseudomonas putida
      S12.
AB  - Solvent-tolerant microorganisms are useful in biotransformations with whole cells
      in two-phase solvent-water systems. The results presented here describe the
      effects that organic solvents have on the growth of these organisms. The maximal
      growth rate of Pseudomonas putida S12, 0.8 h-1, was not affected by toluene in
      batch cultures, but in chemostat cultures the solvent decreased the maximal
      growth rate by nearly 50%. Toluene, ethylbenzene, propylbenzene, xylene, hexane,
      and cyclohexane reduced the biomass yield, and this effect depended on the
      concentration of the solvent in the bacterial membrane and not on its chemical
      structure. The dose response to solvents in terms of yield was linear up to an
      approximately 200 mM concentration of solvent in the bacterial membrane, both in
      the wild type and in a mutant lacking an active efflux system for toluene. Above
      this critical concentration the yield of the wild type remained constant at 0.2 g
      of protein/g of glucose with increasing concentrations of toluene. The reduction
      of the yield in the presence of solvents is due to a maintenance higher by a
      factor of three or four as well as to a decrease of the maximum growth yield by
      33%. Therefore, energy-consuming adaptation processes as well as the uncoupling
      effect of the solvents reduce the yield of the tolerant cells.

PMID- 10347054
TI  - Characterization of the binding protein-dependent cellobiose and cellotriose
      transport system of the cellulose degrader Streptomyces reticuli.
AB  - Streptomyces reticuli has an inducible ATP-dependent uptake system specific for
      cellobiose and cellotriose. By reversed genetics a gene cluster encoding
      components of a binding protein-dependent cellobiose and cellotriose ABC
      transporter was cloned and sequenced. The deduced gene products comprise a
      regulatory protein (CebR), a cellobiose binding lipoprotein (CebE), two integral
      membrane proteins (CebF and CebG), and the NH2-terminal part of an intracellular
      beta-glucosidase (BglC). The gene for the ATP binding protein MsiK is not linked
      to the ceb operon. We have shown earlier that MsiK is part of two different ABC
      transport systems, one for maltose and one for cellobiose and cellotriose, in S.
      reticuli and Streptomyces lividans. Transcription of polycistronic cebEFG and
      bglC mRNAs is induced by cellobiose, whereas the cebR gene is transcribed
      independently. Immunological experiments showed that CebE is synthesized during
      growth with cellobiose and that MsiK is produced in the presence of several
      sugars at high or moderate levels. The described ABC transporter is the first one
      of its kind and is the only specific cellobiose/cellotriose uptake system of S.
      reticuli, since insertional inactivation of the cebE gene prevents high-affinity
      uptake of cellobiose.

PMID- 10347056
TI  - PCR comparison of Mycobacterium avium isolates obtained from patients and foods.
AB  - Mycobacterium avium is a cause of disseminated disease in AIDS patients. A need
      for a better understanding of possible sources and routes of transmission of this
      organism has arisen. This study utilized a PCR typing method designed to amplify
      DNA segments located between the insertion sequences IS1245 and IS1311 to compare
      levels of relatedness of M. avium isolates found in patients and foods. Twenty
      five of 121 food samples yielded 29 mycobacterial isolates, of which 12 were M.
      avium. Twelve food and 103 clinical M. avium isolates were tested. A clinical
      isolate was found to be identical to a food isolate, and close relationships were
      found between two patient isolates and two food isolates. Relatedness between
      food isolates and patient isolates suggests the possibility that food is a
      potential source of M. avium infection. This study demonstrates a rapid,
      inexpensive method for typing M. avium, possibly replacing pulsed-field gel
      electrophoresis.

PMID- 10347055
TI  - cis/trans isomerase of unsaturated fatty acids of Pseudomonas putida P8: evidence
      for a heme protein of the cytochrome c type.
AB  - From a pool of 600 temperature-sensitive transposon mutants of Pseudomonas putida
      P8, 1 strain was isolated that carries a mini-Tn5 insertion within the cytochrome
      c operon. As a result, genes involved in the attachment of heme to cytochrome c
      type proteins are turned off. Accordingly, cytochrome c could not be detected
      spectrophotometrically. The mutant also exhibited a remarkable reduction of cis
      trans isomerization capability for unsaturated fatty acids. Consistent with the
      genetic and physiological data is the detection of a cytochrome c-type heme
      binding motif close to the N terminus of the predicted polypeptide of the
      cis/trans isomerase (cti) gene (CVACH; conserved amino acids in italics). The
      functional significance of this motif was proven by site-directed mutagenesis. A
      possible mechanism of heme-catalyzed cis-trans isomerization of unsaturated fatty
      acids is discussed.

PMID- 10347057
TI  - Comparison of fungal laccases and redox mediators in oxidation of a nonphenolic
      lignin model compound.
AB  - Several fungal laccases have been compared for the oxidation of a nonphenolic
      lignin dimer, 1-(3, 4-dimethoxyphenyl)-2-(2-methoxyphenoxy)propan-1,3-diol (I),
      and a phenolic lignin model compound, phenol red, in the presence of the redox
      mediators 1-hydroxybenzotriazole (1-HBT) or violuric acid. The oxidation rates of
      dimer I by the laccases were in the following order: Trametes villosa laccase
      (TvL) > Pycnoporus cinnabarinus laccase (PcL) > Botrytis cinerea laccase (BcL) >
      Myceliophthora thermophila laccase (MtL) in the presence of either 1-HBT or
      violuric acid. The order is the same if the laccases are used at the same molar
      concentration or added to the same activity (with ABTS [2, 2'-azinobis (3
      ethylbenzothiazoline-6-sulfonic acid)] as a substrate). During the oxidation of
      dimer I, both 1-HBT and violuric acid were to some extent consumed. Their
      consumption rates also follow the above order of laccases, i.e., TvL > PcL > BcL
      > MtL. Violuric acid allowed TvL and PcL to oxidize dimer I much faster than 1
      HBT, while BcL and violuric acid oxidized dimer I more slowly than BcL and 1-HBT.
      The oxidation rate of dimer I is dependent upon both kcat and the stability of
      the laccase. Both 1-HBT and violuric acid inactivated the laccases, violuric acid
      to a greater extent than 1-HBT. The presence of dimer I or phenol red in the
      reaction mixture slowed down this inactivation. The inactivation is mainly due to
      the reaction of the redox mediator free radical with the laccases. We did not
      find any relationship between the carbohydrate content of the laccases and their
      inactivation. When the redox potential of the laccases is in the range of 750 to
      800 mV, i.e., above that of the redox mediator, it does not affect kcat and the
      oxidation rate of dimer I.

PMID- 10347059
TI  - PCR-based genotyping of epidemic and preepidemic Trichoderma isolates associated
      with green mold of Agaricus bisporus.
AB  - We used randomly amplified polymorphic DNA (RAPD)-PCR to estimate genetic
      variation among isolates of Trichoderma associated with green mold on the
      cultivated mushroom Agaricus bisporus. Of 83 isolates examined, 66 were sampled
      during the recent green mold epidemic, while the remaining 17 isolates were
      collected just prior to the epidemic and date back to the 1950s. Trichoderma
      harzianum biotype 4 was identified by RAPD analysis as the cause of almost 90% of
      the epidemic-related episodes of green mold occurring in the major commercial
      mushroom-growing region in North America. Biotype 4 was more closely allied to T.
      harzianum biotype 2, the predominant pathogenic genotype in Europe, than to the
      less pathogenic biotype 1 and Trichoderma atroviride (formerly T. harzianum
      biotype 3). No variation in the RAPD patterns was observed among the isolates
      within biotype 2 or 4, suggesting that the two pathogenic biotypes were
      populations containing single clones. Considerable genetic variation, however,
      was noted among isolates of biotype 1 and T. atroviride from Europe. Biotype 4
      was not represented by the preepidemic isolates of Trichoderma as determined by
      RAPD markers and PCR amplification of an arbitrary DNA sequence unique to the
      genomes of biotypes 2 and 4. Our findings suggest that the onset of the green
      mold epidemic in North America resulted from the recent introduction of a highly
      virulent genotype of the pathogen into cultivated mushrooms.

PMID- 10347058
TI  - Effects of larval mosquitoes (Aedes triseriatus) and stemflow on microbial
      community dynamics in container habitats.
AB  - The dynamics of the microbial food sources for Aedes triseriatus larvae in
      microcosms were found to be strongly influenced by larval presence. The total
      abundance of bacteria in water samples generally increased in response to larvae,
      including populations of cultivable, facultatively anaerobic bacteria.
      Additionally, a portion of the community shifted from Pseudomonaceae to
      Enterobacteriaceae. Bacterial abundance on leaf material was significantly
      reduced in the presence of actively feeding larvae. Principle-component analysis
      of whole community fatty acid methyl ester (FAME) profiles showed that larvae
      changed the microbial community structure in both the water column and the leaf
      material. Cyclopropyl FAMEs, typically associated with bacteria, were reduced in
      microcosms containing larvae; however, other bacterial fatty acids showed no
      consistent response. Long-chain polyunsaturated fatty acids characteristic of
      microeukaryotes (protozoans and meiofauna) declined in abundance when larvae were
      present, indicating that larval feeding reduced the densities of these
      microorganisms. However, presumed fungal lipid markers either increased or were
      unchanged in response to larvae. Larval presence also affected microbial nitrogen
      metabolism through modification of the physiochemical conditions or by grazing on
      populations of bacteria involved in nitrification-denitrification. Stemflow
      primarily influenced inorganic ion and organic compound concentrations in the
      microcosms and had less-pronounced effects on microbial community parameters than
      did larval presence. Stemflow treatments diluted concentrations of all inorganic
      ions (chloride, sulfate, and ammonium) and organic compounds (total dissolved
      organic carbon, soluble carbohydrates, and total protein) measured, with the
      exceptions of nitrite and nitrate. Stemflow addition did not measurably affect
      larval biomass in the microcosms but did enhance development rates and early
      emergence patterns of adults.

PMID- 10347060
TI  - Nitrous oxide production and methane oxidation by different ammonia-oxidizing
      bacteria.
AB  - Ammonia-oxidizing bacteria (AOB) are thought to contribute significantly to N2O
      production and methane oxidation in soils. Most of our knowledge derives from
      experiments with Nitrosomonas europaea, which appears to be of minor importance
      in most soils compared to Nitrosospira spp. We have conducted a comparative study
      of levels of aerobic N2O production in six phylogenetically different
      Nitrosospira strains newly isolated from soils and in two N. europaea and
      Nitrosospira multiformis type strains. The fraction of oxidized ammonium released
      as N2O during aerobic growth was remarkably constant (0.07 to 0.1%) for all the
      Nitrosospira strains, irrespective of the substrate supply (urea versus
      ammonium), the pH, or substrate limitation. N. europaea and Nitrosospira
      multiformis released similar fractions of N2O when they were supplied with ample
      amounts of substrates, but the fractions rose sharply (to 1 to 5%) when they were
      restricted by a low pH or substrate limitation. Phosphate buffer (versus HEPES)
      doubled the N2O release for all types of AOB. No detectable oxidation of
      atmospheric methane was detected. Calculations based on detection limits as well
      as data in the literature on CH4 oxidation by AOB bacteria prove that none of the
      tested strains contribute significantly to the oxidation of atmospheric CH4 in
      soils.

PMID- 10347061
TI  - Mapping of sugar and amino acid availability in soil around roots with bacterial
      sensors of sucrose and tryptophan 
AB  - We developed a technique to map the availability of sugars and amino acids along
      live roots in an intact soil-root matrix with native microbial soil flora and
      fauna present. It will allow us to study interactions between root exudates and
      soil microorganisms at the fine spatial scale necessary to evaluate mechanisms of
      nitrogen cycling in the rhizosphere. Erwinia herbicola 299R harboring a
      promoterless ice nucleation reporter gene, driven by either of two nutrient
      responsive promoters, was used as a biosensor. Strain 299RTice exhibits
      tryptophan-dependent ice nucleation activity, while strain 299R(p61RYice)
      expresses ice nucleation activity proportional to sucrose concentration in its
      environment. Both biosensors exhibited up to 100-fold differences in ice
      nucleation activity in response to varying substrate abundance in culture. The
      biosensors were introduced into the rhizosphere of the annual grass Avena barbata
      and, as a control, into bulk soil. Neither strain exhibited significant ice
      nucleation activity in the bulk soil. Both tryptophan and sucrose were detected
      in the rhizosphere, but they showed different spatial patterns. Tryptophan was
      apparently most abundant in soil around roots 12 to 16 cm from the tip, while
      sucrose was most abundant in soil near the root tip. The largest numbers of
      bacteria (determined by acridine orange staining and direct microscopy) occurred
      near root sections with the highest apparent sucrose or tryptophan exudation.
      High sucrose availability at the root tip is consistent with leakage of
      photosynthate from immature, rapidly growing root tissues, while tryptophan loss
      from older root sections may result from lateral root perforation of the root
      epidermis.

PMID- 10347062
TI  - Reduction of technetium by Desulfovibrio desulfuricans: biocatalyst
      characterization and use in a flowthrough bioreactor.
AB  - Resting cells of Desulfovibrio desulfuricans coupled the oxidation of a range of
      electron donors to Tc(VII) reduction. The reduced technetium was precipitated as
      an insoluble low-valence oxide. The optimum electron donor for the
      biotransformation was hydrogen, although rapid rates of reduction were also
      supported when formate or pyruvate was supplied to the cells. Technetium
      reduction was less efficient when the growth substrates lactate and ethanol were
      supplied as electron donors, while glycerol, succinate, acetate, and methanol
      supported negligible reduction. Enzyme activity was stable for several weeks and
      was insensitive to oxygen. Transmission electron microscopy showed that the
      radionuclide was precipitated at the periphery of the cell. Cells poisoned with
      Cu(II), which is selective for periplasmic but not cytoplasmic hydrogenases, were
      unable to reduce Tc(VII), a result consistent with the involvement of a
      periplasmic hydrogenase in Tc(VII) reduction. Resting cells, immobilized in a
      flowthrough membrane bioreactor and supplied with Tc(VII)-supplemented solution,
      accumulated substantial quantities of the radionuclide when formate was supplied
      as the electron donor, indicating the potential of this organism as a biocatalyst
      to treat Tc-contaminated wastewaters.

PMID- 10347063
TI  - Enhancement of solubilization and biodegradation of polyaromatic hydrocarbons by
      the bioemulsifier alasan.
AB  - Alasan, a high-molecular-weight bioemulsifier complex of an anionic
      polysaccharide and proteins that is produced by Acinetobacter radioresistens KA53
      (S. Navon-Venezia, Z. Zosim, A. Gottlieb, R. Legmann, S. Carmeli, E. Z. Ron, and
      E. Rosenberg, Appl. Environ. Microbiol. 61:3240-3244, 1995), enhanced the aqueous
      solubility and biodegradation rates of polyaromatic hydrocarbons (PAHs). In the
      presence of 500 microg of alasan ml-1, the apparent aqueous solubilities of
      phenanthrene, fluoranthene, and pyrene were increased 6.6-, 25.7-, and 19.8-fold,
      respectively. Physicochemical characterization of the solubilization activity
      suggested that alasan solubilizes PAHs by a physical interaction, most likely of
      a hydrophobic nature, and that this interaction is slowly reversible. Moreover,
      the increase in apparent aqueous solubility of PAHs does not depend on the
      conformation of alasan and is not affected by the formation of multimolecular
      aggregates of alasan above its saturation concentration. The presence of alasan
      more than doubled the rate of [14C]fluoranthene mineralization and significantly
      increased the rate of [14C]phenanthrene mineralization by Sphingomonas
      paucimobilis EPA505. The results suggest that alasan-enhanced solubility of
      hydrophobic compounds has potential applications in bioremediation.

PMID- 10347064
TI  - Development of a self-cloning system for Actinomadura verrucosospora and
      identification of polyketide synthase genes essential for production of the
      angucyclic antibiotic pradimicin.
AB  - A self-cloning system for Actinomadura verrucosospora, a producer of the
      angucyclic antibiotic pradimicin A (PRM A), has been developed. The system is
      based on reproducible and reliable protoplasting and regeneration conditions for
      A. verrucosospora and a novel plasmid vector that consists of a replicon from a
      newly found Actinomadura plasmid and a selectable marker cloned from the
      Actinomadura strain. The system has an efficiency of more than 10(5)
      CFU/microgram of DNA. Using this system, we have cloned and identified the
      polyketide synthase (PKS) genes essential for PRM A biosynthesis from A.
      verrucosospora. Nucleotide sequence analysis of the 3.5-kb SalI-SphI fragment
      showed that ketosynthase subunits (open reading frame 1 [ORF1] and ORF2) of the
      essential PKS genes have strong similarities (59 to 89%) to those for angucyclic
      antibiotic biosynthesis.

PMID- 10347065
TI  - The quiescent-cell expression system for protein synthesis in Escherichia coli.
AB  - The quiescent-cell expression system is a radical alternative to conventional
      fermentation for protein overproduction in Escherichia coli. It is dependent on
      the controlled overexpression of a small RNA called Rcd in hns mutant strains to
      generate nongrowing, quiescent cells which are not nutrient limited. Quiescent
      cells no longer produce biomass and have their metabolic resources channelled
      toward the expression of plasmid-based genes. The biosynthetic capacity of the
      system is demonstrated by its ability to express chloramphenicol
      acetyltransferase to more than 40% of total cell protein. Quiescent cells may
      provide an ideal environment for the expression of toxic as well as benign
      proteins.

PMID- 10347066
TI  - Increase in alfalfa nodulation, nitrogen fixation, and plant growth by specific
      DNA amplification in Sinorhizobium meliloti.
AB  - To improve symbiotic nitrogen fixation on alfalfa plants, Sinorhizobium meliloti
      strains containing different average copy numbers of a symbiotic DNA region were
      constructed by specific DNA amplification (SDA). A DNA fragment containing a
      regulatory gene (nodD1), the common nodulation genes (nodABC), and an operon
      essential for nitrogen fixation (nifN) from the nod regulon region of the
      symbiotic plasmid pSyma of S. meliloti was cloned into a plasmid unable to
      replicate in this organism. The plasmid then was integrated into the homologous
      DNA region of S. meliloti strains 41 and 1021, which resulted in a duplication of
      the symbiotic region. Sinorhizobium derivatives carrying further amplification
      were selected by growing the bacteria in increased concentrations of an
      antibiotic marker present in the integrated vector. Derivatives of strain 41
      containing averages of 3 and 6 copies and a derivative of strain 1021 containing
      an average of 2.5 copies of the symbiotic region were obtained. In addition, the
      same region was introduced into both strains as a multicopy plasmid, yielding
      derivatives with an average of seven copies per cell. Nodulation, nitrogenase
      activity, plant nitrogen content, and plant growth were analyzed in alfalfa
      plants inoculated with the different strains. The copy number of the symbiotic
      region was critical in determining the plant phenotype. In the case of the
      strains with a moderate increase in copy number, symbiotic properties were
      improved significantly. The inoculation of alfalfa with these strains resulted in
      an enhancement of plant growth.

PMID- 10347067
TI  - Molecular analysis of Pseudomonas aeruginosa: epidemiological investigation of
      mastitis outbreaks in Irish dairy herds.
AB  - Pseudomonas aeruginosa is a pathogen in both humans and animals. This bacterium,
      most often associated with respiratory infections in cystic fibrosis patients,
      was found to be the causative agent in bovine mastitis outbreaks among 11 Irish
      dairy herds. Epidemiological findings suggested that the infection was spread to
      all herds by teat wipes that had been contaminated with this organism. Two
      molecular-typing strategies were used in an attempt to determine the genomic
      relationship(s), if any, of the P. aeruginosa strains isolated from the various
      herds and to verify whether the same strain was responsible for each outbreak.
      Thirty-six isolates from the mastitis outbreaks were tested and compared to
      fourteen clinical isolates from Cork University Hospital. With one exception, all
      outbreak-linked strains produced identical patterns when ribotyped with ClaI and
      PvuII enzymes. Eight of the clinical isolates gave the same ClaI ribotype pattern
      as the mastitis-causing strains. However, PvuII proved more discriminatory, with
      only the outbreak isolates producing identical patterns. Similar results were
      obtained with RW3A-primed DNA amplification fingerprinting, with all outbreak
      isolates except one displaying the same fingerprint array. The clinical strains
      produced several fingerprint patterns, all of which were different from those of
      the mastitis-causing isolates. Fine-resolution DNA fingerprinting with a
      fluorescence-labelled RW3A primer also identified a number of low-molecular
      weight polymorphisms that would have remained undetected by conventional methods.
      These data support the view that the same P. aeruginosa strain was responsible
      for the mastitis outbreaks in all 11 herds.

PMID- 10347068
TI  - Modulation of lipid metabolism and spiramycin biosynthesis in Streptomyces
      ambofaciens unstable mutants.
AB  - Streptomyces ambofaciens is prone to genetic instability involving genomic
      rearrangements at the extremities of the chromosomal DNA. An amplified DNA
      sequence (ADS205), including an open reading frame (orfPS), is responsible for
      the reversible loss of spiramycin production in the mutant strain NSA205
      (ADS205(+) Spi-). The product of orfPS is homologous to polyketide synthase
      systems (PKSs) involved in the biosynthesis of erythromycin and rapamycin and is
      overexpressed in strain NSA205 compared with the parental strain RP181110. As
      PKSs and fatty acid synthase systems have the same precursors, we tested the
      possibility that overexpression of orfPS also affects lipid metabolism in strain
      NSA205. This report focuses on comparative analysis of lipids in strain RP181110,
      the mutant strain NSA205, and a derivative, NSA228 (ADS205(-) Spi+). NSA205
      showed a dramatically depressed lipid content consisting predominantly of
      phospholipids and triacylglycerols. This lipid content was globally restored in
      strain NSA228, which had lost ADS205. Furthermore, strains RP181110 and NSA205
      presented similar phospholipid and triacylglycerol compositions. No abnormal
      fatty acids were detected in NSA205.

PMID- 10347069
TI  - Interactions of saprophytic yeasts with a nor mutant of Aspergillus flavus.
AB  - The nor mutant of Aspergillus flavus has a defective norsolorinic acid reductase,
      and thus the aflatoxin biosynthetic pathway is blocked, resulting in the
      accumulation of norsolorinic acid, a bright red-orange pigment. We developed a
      visual agar plate assay to monitor yeast strains for their ability to inhibit
      aflatoxin production by visually scoring the accumulation of this pigment of the
      nor mutant. We identified yeast strains that reduced the red-orange pigment
      accumulation in the nor mutant. These yeasts also reduced aflatoxin accumulation
      by a toxigenic strain of A. flavus. These yeasts may be useful for reducing
      aflatoxin contamination of food commodities.

PMID- 10347070
TI  - Piriformospora indica, a cultivable plant-growth-promoting root endophyte 
AB  - Piriformospora indica (Hymenomycetes, Basidiomycota) is a newly described
      cultivable endophyte that colonizes roots. Inoculation with the fungus and
      application of fungal culture filtrate promotes plant growth and biomass
      production. Due to its ease of culture, this fungus provides a model organism for
      the study of beneficial plant-microbe interactions and a new tool for improving
      plant production systems.

PMID- 10347071
TI  - High-level production of heterologous protein by engineered yeasts grown in
      cottage cheese whey.
AB  - Cottage cheese whey is a cheese industry by-product still rich in proteins and
      lactose. Its recycling is seldom cost-effective. In this work we show that the
      lactose-utilizing yeast Kluyveromyces lactis, engineered for production of
      recombinant human lysozyme, can be grown in cottage cheese whey, resulting in
      high-level production of the heterologous protein (125 microg/ml).

PMID- 10347072
TI  - Occurrence, diversity, and pathogenicity of halophilic Vibrio spp. and non-O1
      Vibrio cholerae from estuarine waters along the Italian Adriatic coast.
AB  - The occurrence, diversity, and pathogenicity of Vibrio spp. were investigated in
      two estuaries along the Italian Adriatic coast. Vibrio alginolyticus was the
      predominant species, followed by Vibrio parahaemolyticus, non-O1 Vibrio cholerae,
      and Vibrio vulnificus. By using a biochemical fingerprinting method, all isolates
      were grouped into nine phenotypes with similarity levels of 75 to 97.5%. The
      production of toxins capable of causing cytoskeleton-dependent changes was
      detected in a large number of Vibrio strains. These findings indicate a
      significant presence of potentially pathogenic Vibrio strains along the Adriatic
      coast.

PMID- 10347073
TI  - BACTOX, a rapid bioassay that uses protozoa to assess the toxicity of bacteria.
AB  - A new type of toxicity test based on the protozoan Tetrahymena pyriformis has
      been developed to assess the overall toxicity of bacterial strains given as prey.
      This simple and rapid test is able to detect toxicant-producing bacteria, which
      may present a biohazard. It can also be used for the risk assessment of microbes
      designed for deliberate release.

PMID- 10347074
TI  - Iron-oxidizing bacteria are associated with ferric hydroxide precipitates (Fe
      plaque) on the roots of wetland plants 
AB  - The presence of Fe-oxidizing bacteria in the rhizosphere of four different
      species of wetland plants was investigated in a diverse wetland environment that
      had Fe(II) concentrations ranging from tens to hundreds of micromoles per liter
      and a pH range of 3.5 to 6.8. Enrichments for neutrophilic, putatively
      lithotrophic Fe-oxidizing bacteria were successful on roots from all four
      species; acidophilic Fe-oxidizing bacteria were enriched only on roots from
      plants whose root systems were exposed to soil solutions with a pH of <4. In
      Sagittaria australis there was a positive correlation (P < 0.01) between cell
      numbers and the total amount of Fe present; the same correlation was not found
      for Leersia oryzoides. These results present the first evidence for culturable Fe
      oxidizing bacteria associated with Fe-plaque in the rhizosphere.

PMID- 10347075
TI  - Removal of endotoxin during purification of poly(3-hydroxybutyrate) from gram
      negative bacteria.
AB  - Poly(3-hydroxybutyrate) (PHB) was produced by cultivating several gram-negative
      bacteria, including Ralstonia eutropha, Alcaligenes latus, and recombinant
      Escherichia coli. PHB was recovered from these bacteria by two different methods,
      and the endotoxin levels were determined. When PHB was recovered by the
      chloroform extraction method, the endotoxin level was less than 10 endotoxin
      units (EU) per g of PHB irrespective of the bacterial strains employed and the
      PHB content in the cell. The NaOH digestion method, which was particularly
      effective for the recovery of PHB from recombinant E. coli, was also examined for
      endotoxin removal. The endotoxin level present in PHB recovered by 0.2 N NaOH
      digestion for 1 h at 30 degrees C was higher than 10(4) EU/g of PHB. Increasing
      the digestion time or NaOH concentration reduced the endotoxin level to less than
      1 EU/g of PHB. It was concluded that PHB with a low endotoxin level, which can be
      used for various biomedical applications, could be produced by chloroform
      extraction. Furthermore, PHB with a much lower endotoxin level could be produced
      from recombinant E. coli by simple NaOH digestion.

PMID- 10347076
TI  - Influence of temperature and growth phase on expression of a 104-kilodalton
      Listeria adhesion protein in Listeria monocytogenes.
AB  - Interaction of Listeria monocytogenes with mammalian intestinal cells is believed
      to be an important first step in Listeria pathogenesis. Transposon (Tn916)
      mutagenesis provided strong evidence that a 104-kDa surface protein, designated
      the Listeria adhesion protein (LAP), was involved in adherence of L.
      monocytogenes to a human enterocyte-like Caco-2 cell line (V. Pandiripally, D.
      Westbrook, G. Sunki, and A. Bhunia, J. Med. Microbiol. 48:117-124, 1999). In this
      study, expression of LAP in L. monocytogenes at various growth temperatures (25,
      37, and 42 degrees C) and in various growth phases was determined by performing
      an enzyme-linked immunoassay (ELISA) and Western blotting with a specific
      monoclonal antibody (monoclonal antibody H7). The ELISA and Western blot results
      indicated that there was a significant increase in LAP expression over time only
      at 37 and 42 degrees C and that the level of LAP expression was low during the
      exponential phase and high during the stationary phase. In contrast, there were
      not significant differences in LAP expression between the exponential and
      stationary phases at 25 degrees C. Examination of the adhesion of L.
      monocytogenes cells from exponential-phase (12-h) or stationary-phase (24-h)
      cultures grown at 37 degrees C to Caco-2 cells revealed that there were not
      significant differences in adhesion. Although expression of L. monocytogenes LAP
      was different at different growth temperatures and in different growth phases,
      enhanced expression did not result in increased adhesion, possibly because only a
      few LAP molecules were sufficient to initiate binding to Caco-2 cells.

PMID- 10347078
TI  - Virus passage through track-etch membranes modified by salinity and a nonionic
      surfactant.
AB  - Why do viruses sometimes not pass through larger pores in track-etch filters?
      Increasing the salinity (0.8 to 160 mM Na+) decreased phiX174 and PRD1 passage
      through track-etch polycarbonate membranes (sodium dodecyl sulfate coated but not
      polyvinylpyrrolidone coated) and PRD1 passage through polyester membranes.
      Undiminished passage when 0.1% Tween 80 was added implied that nonionic virus
      adsorption occurred and indicated that high levels of salinity decreased virus
      passage by decreasing electrostatic repulsion that prevented adsorption.

PMID- 10347077
TI  - Multiple antibiotic resistance patterns of Escherichia coli isolates from swine
      farms.
AB  - Antibiotic resistance of Escherichia coli from sows and pigs was determined to
      compare patterns between pigs of various ages and degrees of antibiotic use.
      Resistance patterns differed between farm types and pigs of differing ages,
      indicating that pig age and degree of antibiotic use affect resistance of fecal
      E. coli.

PMID- 10347079
TI  - Response of pathogenic Vibrio species to high hydrostatic pressure.
AB  - Vibrio parahaemolyticus ATCC 17802, Vibrio vulnificus ATCC 27562, Vibrio cholerae
      O:1 ATCC 14035, Vibrio cholerae non-O:1 ATCC 14547, Vibrio hollisae ATCC 33564,
      and Vibrio mimicus ATCC 33653 were treated with 200 to 300 MPa for 5 to 15 min at
      25 degrees C. High hydrostatic pressure inactivated all strains of pathogenic
      Vibrio without triggering a viable but nonculturable (VBNC) state; however, cells
      already existing in a VBNC state appeared to possess greater pressure resistance.

PMID- 10347080
TI  - Mechanism of alanine hyperproduction by arthrobacter oxydans HAP-1: metabolic
      shift to fermentation under nongrowth aerobic conditions 
AB  - Arthrobacter oxydans HAP-1 hyperproduces DL-alanine in a non-growth-associated
      manner. We found that decreased activities of pyruvate dehydrogenase and of the
      enzyme catalyzing NADH oxidation in the stationary phase are paralleled by a
      shift of pyruvate metabolism to alanine synthesis by L-alanine dehydrogenase. We
      propose that this enzyme functions as an electron sink even under aerobic
      conditions.

PMID- 10347081
TI  - Optimization of simultaneous chemical and biological mineralization of
      perchloroethylene.
AB  - Optimization of the simultaneous chemical and biological mineralization of
      perchloroethylene (PCE) by modified Fenton's reagent and Xanthobacter flavus was
      investigated by using a central composite rotatable experimental design.
      Concentrations of PCE, hydrogen peroxide, and ferrous iron and the microbial cell
      number were set as variables. Percent mineralization of PCE to CO2 was
      investigated as a response. A second-order, quadratic response surface model was
      generated and fit the data adequately, with a correlation coefficient of 0.72.
      Analysis of the results showed that the PCE concentration had no significant
      effect within the tested boundaries of the model, while the other variables,
      hydrogen peroxide and iron concentrations and cell number, were significant at
      alpha = 0.05 for the mineralization of PCE. The 14C radiotracer studies showed
      that the simultaneous chemical and biological reactions increased the extent of
      mineralization of PCE by more than 10% over stand-alone Fenton reactions.

PMID- 10347083
TI  - A new biocatalyst for production of optically pure aryl epoxides by styrene
      monooxygenase from Pseudomonas fluorescens ST.
AB  - We developed a biocatalyst by cloning the styrene monooxygenase genes (styA and
      styB) from Pseudomonas fluorescens ST responsible for the oxidation of styrene to
      its corresponding epoxide. Recombinant Escherichia coli was able to oxidize
      different aryl vinyl and aryl ethenyl compounds to their corresponding optically
      pure epoxides. The results of bioconversions indicate the broad substrate
      preference of styrene monooxygenase and its potential for the production of
      several fine chemicals.

PMID- 10347082
TI  - Characterization of the meta-cleavage compound hydrolase gene involved in
      degradation of the lignin-related biphenyl structure by Sphingomonas paucimobilis
      SYK-6.
AB  - Sphingomonas paucimobilis SYK-6 has the ability to transform a lignin-related
      biphenyl compound, 2,2'-dihydroxy-3,3'-dimethoxy-5, 5'-dicarboxybiphenyl (DDVA),
      to 5-carboxyvanillic acid (5CVA) via 2, 2',3-trihydroxy-3'-methoxy-5,5'
      dicarboxybiphenyl (OH-DDVA). In the 4.9-kb HindIII fragment containing the OH
      DDVA meta-cleavage dioxygenase gene (ligZ), we found a novel hydrolase gene
      (ligY) responsible for the conversion of the meta-cleavage compound of OH-DDVA to
      5CVA. Incorporation of 18O from H218O into 5CVA indicated there was a hydrolytic
      conversion of the OH-DDVA meta-cleavage compound to 5CVA. LigY exhibited
      hydrolase activity only toward the meta-cleavage compound of OH-DDVA, suggesting
      its restricted substrate specificity.

PMID- 10347084
TI  - Conjugal transfer but not quorum-dependent tra gene induction of pTiC58 requires
      a solid surface.
AB  - Donors of Agrobacterium tumefaciens harboring a transfer-constitutive derivative
      of the nopaline-type Ti plasmid pTiC58 transferred this element at frequencies 3
      to 4 orders of magnitude higher in matings conducted on solid surfaces than in
      those conducted in liquid medium. However, as measured with a lacZ reporter
      fusion, the tra genes of the wild-type Ti plasmid were inducible by opines to
      indistinguishable levels on solid and in liquid medium. Donors induced in liquid
      transferred the Ti plasmid at high frequency when mated with recipients on solid
      medium. We conclude that while formation of stable mating pairs and subsequent
      transfer of the Ti plasmid is dependent on a solid stratum, the regulatory system
      can activate tra gene expression to equivalent levels in liquid and on solid
      surfaces.

PMID- 10347085
TI  - High-efficiency transformation of Rhizobium leguminosarum by electroporation.
AB  - Electrotransformation of Rhizobium leguminosarum was successfully carried out
      with a 15.1-kb plasmid, pMP154 (Cmr), containing a nodABC-lacZ fusion by
      electroporation. The maximum transformation efficiency, 10(8)
      transformants/microg of DNA, was achieved at a field strength of 14 kV/cm with a
      pulse of 7.3 ms (186 Omega). The number of transformants was found to increase
      with increasing cell density, with no sign of saturation. In relation to DNA
      dosage, the maximum transformation efficiency (5.8 x 10(8) transformants/microg
      of DNA) was obtained with 0.5 microg of DNA/ml of cell suspension, and a further
      increase in the DNA concentration resulted in a decline in transformation
      efficiency.

PMID- 10347086
TI  - Cardiac myosin binding protein C.
AB  - Myosin binding protein C (MyBP-C) is one of a group of myosin binding proteins
      that are present in the myofibrils of all striated muscle. The protein is found
      at 43-nm repeats along 7 to 9 transverse lines in a portion of the A band where
      crossbridges are found (C zone). MyBP-C contains myosin and titin binding sites
      at the C terminus of the molecule in all 3 of the isoforms (slow skeletal, fast
      skeletal, and cardiac). The cardiac isoform also includes a series of residues
      that contain 3 phosphorylatable sites and an additional immunoglobulin module at
      the N terminus that are not present in skeletal isoforms. The following 2 major
      functions of MyBP-C have been suggested: (1) a role in the formation of the
      sarcomeric myofibril as a result of binding to myosin and titin and (2) in the
      case of the cardiac isoform, regulation of contraction through phosphorylation.
      The first is supported by the demonstrated effect of MyBP-C on the packing of
      myosin in the thick filament, the coincidence of appearance of sarcomeres and
      MyBP-C during myofibrillogenesis, and the defective formation of sarcomeres when
      the titin and/or myosin binding sites of MyBP-C are missing. The second is
      supported by the specific phosphorylation sites in cardiac MyBP-C, the presence
      in the thick filament of an enzyme specific for MyBP-C phosphorylation, the
      alteration of thick filament structure by MyBP-C phosphorylation, and the
      accompaniment of MyBP-C phosphorylation with all major physiological mechanisms
      of modulation of inotropy in the heart.

PMID- 10347087
TI  - Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes.
AB  - This study was designed to determine whether mechanical stretch activates the
      Janus kinase (JAK)/signal transducers and activators of transcription (STAT)
      pathway in cardiomyocytes and, if so, by what mechanism. Neonatal rat/murine
      cardiomyocytes were cultured on malleable silicone dishes and were stretched by
      20%. Mechanical stretch induced rapid phosphorylation of JAK1, JAK2, Tyk2, STAT1,
      STAT3, and glycoprotein 130 as early as 2 minutes and peaked at 5 to 15 minutes.
      It also caused gel mobility shift of sis-inducing element, which was supershifted
      by preincubation with anti-STAT3 antibody. Preincubation with CV11974 (AT1
      blocker) partially inhibited the phosphorylation of STAT1, but not that of STAT3.
      Preincubation with TAK044 (endothelin-1-type A/B-receptor blocker) did not
      attenuate this pathway. RX435 (anti-glycoprotein 130 blocking antibody) inhibited
      the phosphorylation of STAT3 and partially inhibited that of STAT1.
      Phosphorylation of STAT1 and STAT3 was strongly inhibited by HOE642 (Na+/H+
      exchanger inhibitor) and BAPTA-AM (intracellular calcium chelator), but not by
      gadolinium (stretch-activated ion channel inhibitor), EGTA (extracellular Ca2+
      chelator), or KN62 (Ca2+/calmodulin kinase II inhibitor). Chelerythrine (protein
      kinase C inhibitor) partially inhibited the phosphorylation of STAT1 and STAT3.
      Mechanical stretch also augmented the mRNA expression of cardiotrophin-1,
      interleukin-6, and leukemia inhibitory factor at 60 to 120 minutes. These results
      indicated that the JAK/STAT pathway was activated by mechanical stretch, and that
      this activation was partially dependent on autocrine/paracrine-secreted
      angiotensin II and was mainly dependent on the interleukin-6 family of cytokines
      but was independent of endothelin-1. Moreover, certain levels of intracellular
      Ca2+ were necessary for stretch-induced activation of this pathway, and protein
      kinase C was also partially involved in this activation.

PMID- 10347088
TI  - Adenylate kinase-catalyzed phosphotransfer in the myocardium : increased
      contribution in heart failure.
AB  - Although the downregulation of creatine kinase activity has been associated with
      heart failure, creatine kinase-deficient transgenic hearts have a preserved
      contractile function. This suggests the existence of alternative phosphotransfer
      pathways in the myocardium, the identity of which is still unknown. In this
      study, we examined the contribution of adenylate kinase-catalyzed phosphotransfer
      to myocardial energetics. In the isolated mitochondria/actomyosin system, which
      possesses endogenous adenylate kinase activity in both compartments, substrates
      for adenylate kinase promoted the rate and amplitude of actomyosin contraction
      that was further enhanced by purified adenylate kinase. Inhibition of adenylate
      kinase activity diminished both actomyosin contraction and mitochondrial
      respiration, which indicated reduced energy flow between mitochondria and
      myofibrils. In intact myocardium, the net adenylate kinase-catalyzed
      phosphotransfer rate was 10% of the total ATP turnover rate as measured by 18O
      phosphoryl labeling in conjunction with gas chromatography and mass spectrometry.
      In pacing-induced failing heart, adenylate kinase-catalyzed phosphotransfer
      increased by 134% and contributed 21% to the total ATP turnover. Concomitantly,
      the contribution by creatine kinase dropped from 89% in normal hearts to 40% in
      failing hearts. These phosphotransfer changes were associated with reduced levels
      of metabolically active ATP but maintained overall ATP turnover rate. Thus, this
      study provides evidence that adenylate kinase facilitates the transfer of high
      energy phosphoryls and signal communication between mitochondria and actomyosin
      in cardiac muscle, with an increased contribution to cellular phosphotransfer in
      heart failure. This phosphotransfer function renders adenylate kinase an
      important component for optimal myocardial bioenergetics and a compensatory
      mechanism in response to impaired intracellular energy flux in the failing heart.

PMID- 10347089
TI  - Hetero-domain interactions as a mechanism for the regulation of connexin
      channels.
AB  - Previous studies have shown that chemical regulation of connexin43 (Cx43) depends
      on the presence of the carboxyl terminal (CT) domain. A particle-receptor (or
      "ball-and-chain") model has been proposed to explain the mechanism of gating. We
      tested whether the CT region behaved as a functional domain for other members of
      the connexin family. The pH sensitivity of wild-type and Ct-truncated connexins
      was quantified by use of electrophysiological and optical techniques and the
      Xenopus oocyte system. The CT domain of Cx45 had no role in pH regulation,
      although a partial role was shown for Cx37 and Cx50. A prominent effect was
      observed for Cx40 and Cx43. In addition, we found that the CT domain of Cx40 that
      was expressed as a separate fragment rescued the pH sensitivity of the truncated
      Cx40 (Cx40tr), which was in agreement with a particle-receptor model. Because
      Cx40 and Cx43 often colocalize and possibly heteromerize, we tested the pH
      sensitivity of Cx40tr when coexpressed with the CT domain of Cx43 (hetero-domain
      interactions). We found that the CT domain of Cx43 enhanced the pH sensitivity of
      Cx40tr; similarly, the CT domain of Cx40 restored the pH sensitivity of the
      truncated Cx43. In addition, the CT domain of Cx43 granted insulin sensitivity to
      the otherwise insulin-insensitive Cx26 or Cx32 channels. These data show that the
      particle-receptor model is preserved in Cx40 and the regulatory domain of one
      connexin can specifically interact with a channel formed by another connexin.
      Hetero-domain interactions could be critical for the regulation of heteromeric
      channels.

PMID- 10347090
TI  - Role of protein kinase C in mitochondrial KATP channel-mediated protection
      against Ca2+ overload injury in rat myocardium.
AB  - Growing evidence exists that ATP-sensitive mitochondrial potassium channels
      (MitoKATP channel) are a major contributor to the cardiac protection against
      ischemia. Given the importance of mitochondria in the cardiac cell, we tested
      whether the potent and specific opener of the MitoKATP channel diazoxide
      attenuates the lethal injury associated with Ca2+overload. The specific aims of
      this study were to test whether protection by diazoxide is mediated by MitoKATP
      channels; whether diazoxide mimics the effects of Ca2+ preconditioning; and
      whether diazoxide reduces Ca2+ paradox (PD) injury via protein kinase C (PKC)
      signaling pathways. Langendorff-perfused rat hearts were subjected to the Ca2+ PD
      (10 minutes of Ca2+ depletion followed by 10 minutes of Ca2+ repletion). The
      effects of the MitoKATP channel and other interventions on functional,
      biochemical, and pathological changes in hearts subjected to Ca2+ PD were
      assessed. In hearts treated with 80 micromol/L diazoxide, left ventricular end
      diastolic pressure and coronary flow were significantly preserved after Ca2+ PD;
      peak lactate dehydrogenase release was also significantly decreased, although ATP
      content was less depleted. The cellular structures were well preserved, including
      mitochondria and intercalated disks in diazoxide-treated hearts compared with
      nontreated Ca2+ PD hearts. The salutary effects of diazoxide on the Ca2+ PD
      injury were similar to those in hearts that underwent Ca2+ preconditioning or
      pretreatment with phorbol 12-myristate 13-acetate before Ca2+ PD. The addition of
      sodium 5-hydroxydecanoate, a specific MitoKATP channel inhibitor, or
      chelerythrine chloride, a PKC inhibitor, during diazoxide pretreatment completely
      abolished the beneficial effects of diazoxide on the Ca2+ PD. Blockade of Ca2+
      entry during diazoxide treatment by inhibiting L-type Ca2+ channel with verapamil
      or nifedipine also completely reversed the beneficial effects of diazoxide on the
      Ca2+ PD. PKC-delta was translocated to the mitochondria, intercalated disks, and
      nuclei of myocytes in diazoxide-pretreated hearts, and PKC-alpha and PKC-epsilon
      were translocated to sarcolemma and intercalated disks, respectively. This study
      suggests that the effect of the MitoKATP channel is mediated by PKC-mediated
      signaling pathway.

PMID- 10347091
TI  - EVEC, a novel epidermal growth factor-like repeat-containing protein upregulated
      in embryonic and diseased adult vasculature.
AB  - A hallmark of vascular lesions is the phenotypic modulation of vascular smooth
      muscle cells (VSMCs) from a quiescent, contractile state to a more primitive,
      proliferative phenotype with a more fetal pattern of gene expression. Using
      subtraction hybridization to identify genes that may regulate this transition, we
      cloned a novel gene named EVEC, an acronym for its expression in the embryonic
      vasculature and the presence of Ca2+ binding epidermal growth factor-like repeats
      contained in the predicted protein structure. Although these repeats are
      characteristic of the extracellular matrix proteins, fibrillin, fibulin, and the
      latent transforming growth factor-beta binding proteins, EVEC most closely
      resembles the H411 and T16/S1-5 gene products, the latter of which are believed
      to regulate DNA synthesis in quiescent fibroblasts. Using in situ hybridization,
      we demonstrated that EVEC is expressed predominantly in the VSMCs of developing
      arteries in E11.5 through E16.5 mouse embryos. Lower levels of expression are
      also observed in endothelial cells, perichondrium, intestine, and mesenchyme of
      the face and kidney. EVEC mRNA expression is dramatically downregulated in adult
      arteries, except in the uterus, where cyclic angiogenesis continues; however,
      EVEC expression is reactivated in 2 independent rodent models of vascular injury.
      EVEC mRNA is observed in cellular elements of atherosclerotic plaques of LDL
      receptor-deficient, human apolipoprotein B transgenic mice and in VSMCs of the
      media and neointima of balloon-injured rat carotid arteries. These data suggest
      that EVEC may play an important role in the regulation of vascular growth and
      maturation during development and in lesions of injured vessels.

PMID- 10347092
TI  - Role of the Ets transcription factors in the regulation of the vascular-specific
      Tie2 gene.
AB  - The Tie2 gene encodes a vascular endothelium-specific receptor tyrosine kinase
      that is required for normal vascular development and is also upregulated during
      angiogenesis. The regulatory regions of the Tie2 gene that are required for
      endothelium-specific gene expression in vivo have been identified. However, the
      transcription factors required for Tie2 gene expression remain largely unknown.
      We have identified highly conserved binding sites for Ets transcription factors
      in the Tie2 promoter. Mutations in 2 particular binding sites lead to a 50%
      reduction in the endothelium-specific activity of the promoter. We have compared
      the ability of several members of the Ets family to transactivate the Tie2
      promoter. Our results demonstrate that 1 of 3 distinct isoforms of the novel Ets
      transcription factor NERF, NERF2, is expressed in endothelial cells and can
      strongly transactivate the regulatory regions of the Tie2 gene in comparison to
      other Ets factors, which have little or no effect. NERF2 can bind to the Tie2
      promoter Ets sites in electrophoretic mobility shift assays. These studies
      support a role for Ets factors in the regulation of vascular-specific gene
      expression and suggest that the novel Ets factor NERF2 may be a critical
      transcription factor in specifying the expression of the Tie2 gene in vascular
      endothelial cells.

PMID- 10347093
TI  - Rho and Rho kinase mediate thrombin-stimulated vascular smooth muscle cell DNA
      synthesis and migration.
AB  - Aberrant regulation of smooth muscle cell proliferation and migration is
      associated with the pathophysiology of vascular disorders such as hypertension,
      atherosclerosis, restenosis, and graft rejection. To elucidate molecular
      mechanisms that regulate proliferation and migration of vascular smooth muscle
      cells, we determined whether signaling through the small G protein Rho is
      involved in thrombin- and phenylephrine-stimulated proliferation and migration of
      rat aortic smooth muscle cells (RASMCs). Thrombin and the thrombin peptide
      SFLLRNP stimulated DNA synthesis of RASMCs as measured by [3H]thymidine
      incorporation. Both ligands also increased cell migration as measured by the
      Boyden chamber method. L-Phenylephrine failed to induce either of these responses
      but increased inositol phosphate accumulation and mitogen-activated protein
      kinase activation in these cells, which indicated that the cells were responsive
      to alpha1-adrenergic stimulation. The C3 exoenzyme, which ADP-ribosylates and
      inactivates Rho, fully inhibited both thrombin-stimulated proliferation and
      migration but had no effect on inositol phosphate accumulation. In addition, Y
      27632, an inhibitor of the Rho effector p160ROCK/Rho kinase, decreased thrombin
      stimulated DNA synthesis and migration. To directly examine Rho activation, Rho
      [35S]GTPgammaS binding was measured. The addition of the thrombin peptide
      SFLLRNP, but not phenylephrine, to RASMC lysates resulted in a significant
      increase in Rho-[35S]GTPgammaS binding. Thrombin and SFLLRNP, but not
      phenylephrine, also increased membrane-associated Rho in intact RASMCs,
      consistent with selective activation of Rho by thrombin. These results indicate
      that thrombin activates Rho in RASMCs and establish Rho as a critical mediator of
      thrombin receptor effects on DNA synthesis and cell migration in these cells.

PMID- 10347095
TI  - Chemiluminescent detection of oxidants in vascular tissue. Lucigenin but not
      coelenterazine enhances superoxide formation.
AB  - Lucigenin-amplified chemiluminescence has frequently been used to assess the
      formation of superoxide in vascular tissues. However, the ability of lucigenin to
      undergo redox cycling in purified enzyme-substrate mixtures has raised questions
      concerning the use of lucigenin as an appropriate probe for the measurement of
      superoxide production. Addition of lucigenin to reaction mixtures of xanthine
      oxidase plus NADH resulted in increased oxygen consumption, as well as superoxide
      dismutase-inhibitable reduction of cytochrome c, indicative of enhanced rates of
      superoxide formation. Additionally, it was revealed that lucigenin stimulated
      oxidant formation by both cultured bovine aortic endothelial cells and isolated
      rings from rat aorta. Lucigenin treatment resulted in enhanced hydrogen peroxide
      release from endothelial cells, whereas exposure to lucigenin resulted in
      inhibition of endothelium-dependent relaxation in isolated aortic rings that was
      superoxide dismutase inhibitable. In contrast, the chemiluminescent probe
      coelenterazine had no significant effect on xanthine oxidase-dependent oxygen
      consumption, endothelial cell hydrogen peroxide release, or endothelium-dependent
      relaxation. Study of enzyme and vascular systems indicated that coelenterazine
      chemiluminescence is a sensitive marker for detecting both superoxide and
      peroxynitrite.

PMID- 10347094
TI  - Vascular endothelial growth factor induces activation and subcellular
      translocation of focal adhesion kinase (p125FAK) in cultured rat cardiac
      myocytes.
AB  - Vascular endothelial growth factor (VEGF) has been proposed to be among the
      candidate factors with the most potential to play a role in ischemia-induced
      collateral vessel formation. Recently, we found that VEGF activated the mitogen
      activated protein kinase cascade in cultured rat cardiac myocytes. To elucidate
      how VEGF affects adhesive interaction of cardiac myocytes with the extracellular
      matrix (ECM), one of the important cell functions, we investigated the molecular
      mechanism of activation of focal adhesion-related proteins, especially focal
      adhesion kinase (p125(FAK)), in cultured rat cardiac myocytes. We found that the
      2 VEGF receptors, KDR/Flk-1 and Flt-1, were expressed in cardiac myocytes and
      that KDR/Flk-1 was significantly tyrosine phosphorylated on VEGF stimulation.
      VEGF induced tyrosine phosphorylation and activation of p125(FAK) as well as
      tyrosine phosphorylation of paxillin; this was accompanied by subcellular
      translocation of p125(FAK) from perinuclear sites to the focal adhesions. This
      VEGF-induced activation of p125(FAK) was inhibited partially by the tyrosine
      kinase inhibitors genistein and tyrphostin. Activation of p125(FAK) was
      accompanied by its increased association with adapter proteins GRB2, Shc, and
      nonreceptor type tyrosine kinase p60(c-src). Furthermore, we confirmed that VEGF
      induced a significant increase in adhesive interaction between cardiac myocytes
      and ECM using an electric cell-substrate impedance sensor. These results strongly
      suggest that p125(FAK) is one of the most important components in VEGF-induced
      signaling in cardiac myocytes, playing a critical role in adhesive interaction
      between cardiac myocytes and ECM.

PMID- 10347096
TI  - Soluble transforming growth factor-beta type II receptor inhibits negative
      remodeling, fibroblast transdifferentiation, and intimal lesion formation but not
      endothelial growth.
AB  - Using the rat balloon catheter denudation model, we examined the role of
      transforming growth factor-beta (TGF-beta) isoforms in vascular repair processes.
      By en face in situ hybridization, proliferating and quiescent smooth muscle cells
      in denuded vessels expressed high levels of mRNA for TGF-beta1, TGF-beta2, TGF
      beta3, and lower levels of TGF-beta receptor II (TGF-betaRII) mRNA. Compared with
      normal endothelium, TGF-beta1 and TGF-beta2, as well as TGF-betaRII, mRNA were
      upregulated in endothelium at the wound edge. Injected recombinant soluble TGF
      betaRII (TGF-betaR:Fc) localized preferentially to the adventitia and developing
      neointima in the injured carotid artery, causing a reduction in intimal lesion
      formation (up to 65%) and an increase in lumen area (up to 88%). The gain in
      lumen area was largely due to inhibition of negative remodeling, which coincided
      with reduced adventitial fibrosis and collagen deposition. Four days after
      injury, TGF-betaR:Fc treatment almost completely inhibited the induction of
      smooth muscle alpha-actin expression in adventitial cells. In the vessel wall,
      TGF-betaR:Fc caused a marked reduction in mRNA levels for collagens type I and
      III. TGF-betaR:Fc had no effect on endothelial proliferation as determined by
      reendothelialization of the denuded rat aorta. Together, these findings identify
      the TGF-beta isoforms as major factors mediating adventitial fibrosis and
      negative remodeling after vascular injury, a major cause of restenosis after
      angioplasty.

PMID- 10347097
TI  - Regression of hypertrophied rat pulmonary arteries in organ culture is associated
      with suppression of proteolytic activity, inhibition of tenascin-C, and smooth
      muscle cell apoptosis.
AB  - Increased elastase activity and deposition of the matrix glycoprotein tenascin-C
      (TN), codistributing with proliferating smooth muscle cells (SMCs), are features
      of pulmonary vascular disease. In pulmonary artery (PA) SMC cultures, TN is
      regulated by matrix metalloproteinases (MMPs) and mechanical stress. On attached
      collagen gels, MMPs upregulate TN, leading to SMC proliferation, whereas on
      floating collagen, reduced MMPs suppress TN and induce SMC apoptosis. We now
      investigate the response of SMCs in the whole vessel by comparing attached and
      floating conditions using either normal PAs derived from juvenile pigs or normal
      or hypertrophied rat PAs that were embedded in collagen gels for 8 days. Normal
      porcine PAs in attached collagen gels were characterized by increasing activity
      of MMP-2 and MMP-9 assessed by zymography and TN deposition detected by Western
      immunoblotting and densitometric analysis of immunoreactivity. PAs on floating
      collagen showed reduced activity of both MMPs and deposition of TN. Tenascin-rich
      foci were associated with proliferating cell nuclear antigen immunoreactivity,
      and TN-poor areas with apoptosis, by terminal deoxynucleotidyl transferase
      mediated nick end labeling assay, but no difference in wall thickness was
      observed. Although normal rat PAs were similar to piglet vessels, hypertrophied
      rat PAs showed an amplified response. Increased elastase, MMP-2, TN, and elastin
      deposition, as well as SMC proliferating cell nuclear antigen positivity,
      correlated with progressive medial thickening on attached collagen, whereas
      reduced MMP-2, elastase, TN, and induction of SMC apoptosis accompanied
      regression of the thickened media on floating collagen. In showing that
      hypertrophied SMCs in the intact vessel can be made to apoptose and that
      resorption of extracellular matrix can be achieved by inhibition of elastase and
      MMPs, our study suggests novel strategies to reverse vascular disease.

PMID- 10347098
TI  - The definition of cell type.

PMID- 10347099
TI  - The risk of surgery in patients with liver disease.

PMID- 10347100
TI  - Expression of delta F508 cystic fibrosis transmembrane conductance regulator
      protein and related chloride transport properties in the gallbladder epithelium
      from cystic fibrosis patients.
AB  - Cystic fibrosis transmembrane conductance regulator (CFTR), the cystic fibrosis
      (CF) gene product, functions as an adenosine 3', 5'-cyclic monophosphate (cAMP)
      regulated chloride channel in the apical membrane of biliary epithelial cells,
      including gallbladder epithelial cells. It has been shown that triangle upF508,
      the most common CF mutation, impedes CFTR trafficking to the apical surface of
      epithelial cells. To elucidate the mechanisms of CF biliary disease, we examined
      structural features, CFTR expression, and chloride transport properties in
      gallbladder epithelial cells from nine triangle upF508 homozygous liver
      transplant recipients. Three CF patients had microgallbladders, characterized by
      severe histological abnormalities. Microgallbladder epithelial cells displayed
      aberrant immunolocalization of CFTR and of other normally apical proteins in the
      lateral domain of their plasma membrane and in their cytoplasm. This pattern was
      mimicked by chronic cholecystitis in non-CF patients. In the 6 remaining CF
      patients, CFTR was predominantly apical in the gallbladder epithelium, consistent
      with the detection of a fully glycosylated form by Western blot. In CF as
      compared with non-CF gallbladder epithelial cells in primary culture, chloride
      efflux was lower in response to cAMP and tended to be higher in response to
      exogenous adenosine 5'-triphosphate (ATP). The CF cells exhibited a residual cAMP
      dependent chloride secretion that was inversely correlated with ATP-induced
      chloride secretion, and almost completely blunted in the cells derived from
      microgallbladders. Our results suggest that epithelial structural alterations
      aggravate triangle upF508 CFTR mislocalization in the gallbladder epithelium. The
      associated decrease in residual cAMP-dependent chloride secretion may contribute
      to biliary damage despite the up-regulation of alternative chloride transport
      pathways.

PMID- 10347101
TI  - Association of clonally expanded T cells with the syndrome of primary biliary
      cirrhosis and limited scleroderma.
AB  - Clinical features of the CREST (calcinosis cutis, Raynaud's syndrome, esophageal
      dysmotility, sclerodactyly, and telangiectasias) syndrome are sometimes exhibited
      in patients with primary biliary cirrhosis (PBC), but the postulated autoimmune
      mechanisms behind these conditions are poorly understood. Clonally expanded T
      cells may play an important role in disease pathogenesis. In this study,
      overrepresentation of one T-cell receptor beta chain variable region, TCRBV3, was
      documented in patients with PBC and/or CREST. Overrepresentation of the TCRBV3
      gene mRNA was demonstrated by semiquantitative reverse-transcriptase polymerase
      chain reaction (RT-PCR). T cells expressing TCRBV3 were analyzed by flow
      cytometry, were primarily CD8(+), and contained activated cells as assessed by
      expression of CD69. Clonally expanded T cells within this population were
      documented by both complementarity determining region 3 (CDR3) length
      polymorphism analysis and sequencing of T-cell receptor CDR3 cDNA. TCRBV3(+)
      clonal expansions were stable when followed for up to 5 years. The results of
      this study demonstrate that the T-cell repertoire of patients with PBC and CREST
      is characterized by expanded clonal populations of CD8(+) TCRBV3(+) T cells.
      These clonal expansions provide evidence that stimulation of clonal populations
      of CD8(+) T cells is associated with the clinical syndrome of PBC with CREST.

PMID- 10347102
TI  - The relative role of the Child-Pugh classification and the Mayo natural history
      model in the assessment of survival in patients with primary sclerosing
      cholangitis.
AB  - The Child-Pugh classification is a simple, convenient prognostic measure in
      patients with liver cirrhosis. We investigated the relative role of the Child
      Pugh classification and the Mayo model in the assessment of survival in patients
      with primary sclerosing cholangitis (PSC). Of the 173 patients described in the
      original Mayo PSC natural history model, 147 patients had sufficient information
      in the medical record to allow computation of the Child-Pugh score. We used our
      most recent modification of the Mayo model to compute the risk score, based on
      patient's age, serum levels of bilirubin, albumin, and aspartate aminotransferase
      and history of variceal bleeding. Using the risk score (R), patients were divided
      into the low- (R < 0), intermediate- (0 </= R < 2), and high-risk (R >/= 2)
      groups. Kaplan-Meier estimates and proportional hazards analysis were used to
      evaluate the two prognostic models. Although there was a statistically
      significant correlation between the Child-Pugh and Mayo risk scores, two-thirds
      of the patients had a Child-Pugh score of 5 or 6 and a relatively wide range of
      risk scores (-1.1-4.3). The probability of survival for 7 years in patients in
      the low-, intermediate-, and high-risk groups was 92%, 74%, and 40% for Child
      Pugh class A (n = 96) and 100%, 62%, and 28% for Child-Pugh class B patients (n =
      44), respectively. There were only a small number (n = 7) of Child-Pugh class C
      patients. In our age-adjusted multivariate analysis, each unit increase in the
      Mayo risk score was associated with a 2.5-fold increase in the risk of death (95%
      confidence interval: 1.8-3.4, P <.01), whereas Child-Pugh classification had no
      significant impact on survival (Child-Pugh B vs. A: risk ratio = 1.1 [95%
      confidence interval: 0.6-2.0]; Child-Pugh C versus A: risk ratio = 0.6 [95%
      confidence interval: 0. 2-1.8]). In contrast to the Child-Pugh classification,
      which was developed for advanced liver cirrhosis, the Mayo model provides valid
      survival information, particularly in patients early in the course of PSC.

PMID- 10347103
TI  - Biliary bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid.
AB  - Bile acid composition in fasting duodenal bile was assessed at entry and at 2
      years in patients with primary biliary cirrhosis (PBC) enrolled in a randomized,
      double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) (10-12
      mg/kg/d) taken as a single bedtime dose. Specimens were analyzed by a high
      pressure liquid chromatography method that had been validated against gas
      chromatography. Percent composition in bile (mean +/- SD) for 98 patients at
      entry for cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA), lithocholic
      (LCA), and ursodeoxycholic (UDCA) acids, respectively, were 57.4 +/- 18.6, 31.5
      +/- 15.5, 8.0 +/- 9.3, 0.3 +/- 1.0, and 0.6 +/- 0.9. Values for CA were
      increased, whereas those for CDCA, DCA, LCA, and UDCA were decreased when
      compared with values in normal persons. Bile acid composition of the major bile
      acids did not change after 2 years on placebo medication. By contrast, in
      patients receiving UDCA for 2 years, bile became enriched with UDCA on average to
      40.1%, and significant decreases were noted for CA (to 32.2%) and CDCA (to
      19.5%). No change in percent composition was observed for DCA and LCA. Percent
      composition at entry and changes in composition after 2 years on UDCA were
      similar in patients with varying severity of PBC. In patients whose bile was not
      enriched in UDCA (entry and placebo-treated specimens), CA, CDCA, DCA, and the
      small amount of UDCA found in some of these specimens were conjugated to a
      greater extent with glycine (52%-64%) than with taurine (36%-48%). Treatment with
      UDCA caused the proportion of all endogenous bile acids conjugated with glycine
      to increase to 69% to 78%, while the proportion conjugated with taurine (22%-31%)
      fell (P <.05). Administered UDCA was also conjugated predominantly with glycine
      (87%).

PMID- 10347104
TI  - Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic
      patients with gastrointestinal bleeding: a meta-analysis.
AB  - In cirrhotic patients with gastrointestinal bleeding, antibiotic prophylaxis
      decreases the incidence of infections but most randomized trials have not shown
      an increase in survival. The aim of this meta-analysis was to assess the efficacy
      of antibiotic prophylaxis in the prevention of infections and its effect on
      survival rate in cirrhotic patients with gastrointestinal bleeding. Four end
      points were assessed: infection, bacteremia and/or spontaneous bacterial
      peritonitis (SBP), incidence of SBP, and death. For each end point, heterogeneity
      and treatment efficacy were assessed by Der Simonian and Peto methods. Five
      trials including 534 patients, 264 treated with antibiotic prophylaxis for 4 to
      10 days and 270 without, were identified. Mean follow-up was 12 days. Antibiotic
      prophylaxis significantly increased the mean percentage of patients free of
      infection (32% mean improvement rate, 95% confidence interval [CI]: 22-42, P
      <.001), bacteremia and/or SBP (19% mean improvement rate, 95% CI: 11-26, P
      <.001), and SBP (7% mean improvement rate, 95% CI: 2.1-12.6, P =.006). Antibiotic
      prophylaxis also significantly increased the mean survival rate (9. 1% mean
      improvement rate, 95 % CI: 2.9-15.3, P =.004), without significant heterogeneity.
      In cirrhotic patients with gastrointestinal bleeding, short-term antibiotic
      prophylaxis significantly increases the mean percentage of patients free of
      infection and significantly increases short-term survival rate.

PMID- 10347105
TI  - Clinical features and survivial of cirrhotic patients with subclinical cognitive
      alterations detected by the number connection test and computerized psychometric
      tests.
AB  - The prevalence and the clinical implications of subclinical cognitive alterations
      in cirrhotic patients have not been well defined as yet. Therefore, we performed
      a study to assess the clinical features and the survival of cirrhotic patients
      with cognitive alterations detected by the number connection test (NCT) and a set
      of computerized psychometric tests (Scan, Choice1, and Choice2) measuring the
      reaction times and the percentage of errors in performing specific tasks. Ninety
      four cirrhotic patients (aged 58 +/- 9 years) without overt hepatic
      encephalopathy and 80 controls (aged 53 +/- 15 years) were consecutively
      enrolled. The median follow-up in cirrhotic patients was 426 days (lower quartile
      = 213 days; upper quartile = 718 days). Results of the NCT, Scan test, and
      Choice2 test were significantly worse in cirrhotic patients, whereas Choice1 did
      not differ significantly from the controls. In cirrhotic patients, the prevalence
      of altered psychometric tests was 21% (CI95% = 14%-31%) by NCT, 23% (CI95% =15%
      33%) by Scan test, and 20% (CI95% =16%-30%) by Choice2 test. The alterations of
      NCT, Scan, and Choice2 were found to be related to the severity of liver disease,
      independently of its etiology. Increased risk of death was found to be associated
      with altered Scan test (hazard ratio = 2.4; CI95% =1. 1-5.3), or altered Choice2
      test (hazard ratio = 2.8; CI95% = 1.2-6. 3). Multivariate regression showed that
      Scan and Choice2 tests had prognostic value on survival, in addition to Child
      Pugh classes in the first year of follow-up.

PMID- 10347106
TI  - Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary
      cirrhosis. The UDCA-PBC Study Group.
AB  - Ursodeoxycholic acid (UDCA) treatment has been shown to increase survival without
      orthotopic liver transplantation (OLT) in patients with primary biliary cirrhosis
      (PBC) at 4 years. Whether this beneficial effect was maintained over the long
      term remained to be established. In a large cohort of UDCA-treated patients with
      PBC, we aimed to determine the 10-year outcome of these patients using two
      endpoints: (1) survival without OLT, and (2) survival. The cohort was comprised
      of 225 patients with PBC treated with UDCA (13-15 mg/kg/d) monitored from the
      beginning of treatment until time of last follow-up, OLT, or death. Because of
      the absence of a control group, survival without OLT was compared with survival
      predicted by the Mayo model (first 7 years), and observed 10-year survival with
      an estimation of survival of a standardized control cohort of the French
      population. Observed survival without OLT of UDCA-treated patients was
      significantly higher (P <.04) than survival predicted by the Mayo model. Observed
      survival was significantly lower (P <. 01) than survival predicted from the
      French population. Observed survival of noncirrhotic patients was not different
      (P >.9) from that of the French control population but survival of cirrhotic
      patients was significantly lower (P <.0001). Twenty-two patients died; 13
      patients died of hepatic causes and 4 patients died after OLT. In conclusion,
      survival without OLT among patients treated with UDCA for PBC is higher than that
      of untreated patients, as predicted by the Mayo model. Ten-year survival among
      UDCA-treated patients is slightly lower than that of an age- and sex-matched
      general population, the difference mainly being explained by mortality among
      cirrhotic patients.

PMID- 10347107
TI  - Increased heme oxygenase-1 gene expression in liver cells and splanchnic organs
      from portal hypertensive rats.
AB  - Heme oxygenase (HO) catalyzes the conversion of heme into biliverdin, iron, and
      carbon monoxide (CO). Two isoforms of HO have been identified: the inducible HO-1
      and the constitutive HO-2. CO, like nitric oxide, is an endogenous vasodilator
      that could contribute to modulation of systemic and local vascular tone. The aim
      of the present study was to determine the expression of HO isoforms in liver
      cells and splanchnic organs from portal hypertensive (PH) and sham-operated (SO)
      rats. Liver cells (hepatocytes, Kupffer and stellate cells), and splanchnic
      organs (liver, mesentery, intestine, colon, and spleen) were isolated from PH and
      SO rats. Expression of HO mRNA and protein was assessed by reverse-transcription
      polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. In SO
      rats, HO-1 mRNA expression was only detected in spleen. In contrast, in PH rats,
      HO-1 mRNA was expressed in hepatocytes, Kupffer cells, and in all the splanchnic
      organs studied. Moreover, levels of HO-1 protein in splanchnic organs were
      significantly higher in PH rats than in SO animals. In addition, HO-2 expression
      was observed in all liver cell types and splanchnic organs studied from both PH
      and SO rats. These results indicate that HO-2 is expressed in parenchymal and
      nonparenchymal liver cells, as well as splanchnic organs, of both PH and SO rats.
      In addition, HO-1 is up-regulated in hepatocytes and splanchnic organs of PH
      rats, compared with SO animals, suggesting a possible pathophysiological role of
      HO-1 in chronic portal hypertension.

PMID- 10347108
TI  - Development of a new, simple rat model of early alcohol-induced liver injury
      based on sensitization of Kupffer cells.
AB  - The continuous intragastric in vivo enteral feeding model in the rat developed by
      Tsukamoto and French has been very useful; however, it requires surgical
      expertise. Recently, we found that Kupffer cells isolated from rats treated only
      once with ethanol were sensitized to endotoxin 24 hours later. Accordingly, these
      experiments were designed to determine if a new, simple animal model of ethanol
      hepatotoxicity could be developed based on Kupffer cell sensitization. Female
      Wistar rats were given ethanol (5 g/kg body weight) once every 24 hours
      intragastrically. Livers were stained with hematoxylin-eosin to assess steatosis,
      inflammation, and necrosis, and tissue triglycerides, serum transaminases, and
      plasma endotoxin were measured. Kupffer cells were isolated 0 to 24 hours after
      one intragastric dose of ethanol daily, and intracellular Ca2+ ([Ca2+]i) was
      measured using fura-2, while tumor necrosis factor alpha (TNF-alpha) was measured
      by enzyme-linked immunosorbent assay. CD14 was evaluated by Western and Northern
      analysis. Ethanol caused steatosis, necrosis, and inflammation in only a few
      weeks, and after 8 weeks, serum aspartate transaminase (AST) levels were doubled.
      Values were similar to levels achieved in the enteral feeding model.
      Triglycerides were also increased significantly by ethanol as expected, and
      endotoxin levels were increased to 70 to 80 pg/mL. This latter increase was
      prevented (<20 pg/mL) by antibiotics implicating endotoxin. In isolated Kupffer
      cells from untreated control rats, [Ca2+]i increased to 82 +/- 7 nmol/L after
      addition of lipopolysaccharide (LPS) (100 ng/mL), and levels were elevated about
      twofold by ethanol given 24 hours earlier (174 +/- 15 nmol/L). In addition, TNF
      alpha production by Kupffer cells was increased fourfold in cells isolated from
      rats treated with ethanol 24 hours earlier. Sterilization of the gut with
      antibiotics blocked all effects of ethanol on [Ca2+]i and TNF-alpha release
      completely. Moreover, 4 weeks after ethanol, CD14 in Kupffer cells was elevated
      about twofold. A new, simple chronic model of ethanol hepatotoxicity has been
      developed here based on sensitization of Kupffer cells to endotoxin.

PMID- 10347109
TI  - Reversal of type 1 hepatorenal syndrome with the administration of midodrine and
      octreotide.
AB  - The aim of the study was to verify the effects of the administration of an
      inhibitor of the release of endogenous vasodilators together with a
      vasoconstrictor agent in patients with hepatorenal syndrome (HRS). This new
      medical perspective was compared with a traditional medical approach for HRS,
      such as the infusion of nonpressor doses of dopamine to produce renal
      vasodilation. Thirteen patients with type 1 HRS were enrolled in the study. Five
      of them were treated with the oral administration of midodrine and the parenteral
      administration of octreotide. In addition, the patients received 50 to 100 mL of
      20% human albumin solution daily for 20 days. Midodrine and octreotide were dosed
      to obtain a stable increase of at least 15 mm Hg of mean arterial pressure. Eight
      patients were treated with the intravenous administration of nonpressor doses of
      dopamine (2-4 micrograms/kg/min) and the same daily amount of albumin. After 20
      days of treatment with midodrine and octreotide, an impressive improvement in
      renal plasma flow (RPF), glomerular filtration rate, and urinary sodium excretion
      was observed in patients. This was accompanied by a significant reduction in
      plasma renin activity, plasma vasopressin, and plasma glucagon. No side effects
      were observed. Three patients were discharged from the hospital. One of them
      successfully underwent liver transplantation. One of the two remaining patients
      is still alive after 472 days with a preserved renal function, and the other died
      from terminal liver failure after 76 days. One of the two patients who were not
      discharged from the hospital successfully underwent liver transplantation, and
      the other died from pneumonia after 29 days. Seven out of eight patients who were
      treated with dopamine experienced a progressive deterioration in renal function
      and died during the first 12 days. Only one patient recovered renal function and
      underwent liver transplantation. In conclusion, the long-term administration of
      midodrine and octreotide seems to be an effective and safe treatment of type 1
      HRS in patients with cirrhosis.

PMID- 10347110
TI  - Autonomic and peripheral (sensorimotor) neuropathy in chronic liver disease: a
      clinical and electrophysiologic study.
AB  - Peripheral neuropathy has been reported in association with chronic liver
      disease. However, the precise incidence, severity and characteristics of
      neuropathy, and the relationship of neuropathy to different etiologies of liver
      disease have not been defined. In this study, 58 patients with advanced liver
      disease were evaluated in detail for the presence of neuropathy. Peripheral
      (sensorimotor) neuropathy was found in 71% and autonomic neuropathy was found in
      48% of the patients. Although the majority of patients were asymptomatic,
      neurological examination showed distal sensory loss to pain, or vibration or
      distal loss of reflexes in 17 patients (29%). Sensory neuropathy was seen more
      commonly than motor axonal polyneuropathy on nerve conduction studies.
      Quantitative sensory testing was frequently abnormal (62%) and cooling thresholds
      were more affected than vibration thresholds. Overall, the pattern of neuropathy
      in patients with liver disease conformed to the pattern expected in "dying back"
      or length-dependent neuropathy. The neuropathy was most severe in patients with
      advanced hepatic decompensation. Comparison of causes of liver disease showed no
      significant differences in the severity of neuropathy among the different
      etiologies. In conclusion, axonal sensory-motor polyneuropathy and autonomic
      neuropathy are commonly seen in patients with end-stage liver disease of
      different causes.

PMID- 10347111
TI  - High prevalence of multinodular hepatocellular carcinoma in patients with
      cirrhosis attributable to multiple risk factors.
AB  - To see whether or not there is an association between the cause of cirrhosis and
      the number of hepatocellular carcinoma (HCC) nodules, we analyzed 178 consecutive
      patients in whom HCC was detected during a prospective screening by abdominal
      ultrasound (US). The relevant information was obtained from the database of the
      screening programs operating at four hospitals in the Milan area. One hundred
      twenty-nine (72%) patients had a single tumor nodule detected by US and 49 (28%)
      patients had multinodular disease. Ninety-eight (55%) patients had normal serum
      values of alpha-fetoprotein (AFP). Tumor staging with biphasic computed
      tomography (CT) scan or hepatic arteriography with lipiodol revealed that 101
      (57%) patients had single tumor nodules and 77 (43%) patients had more than one
      HCC nodule. After staging, multinodular HCC was more common in patients with
      multiple risk factors than in the hepatitis C virus (HCV) carriers (56% vs. 38%,
      P =.05). Interestingly, single tumors were as common in the 126 patients
      undergoing 6-month interval screening as in the 52 patients who were studied at
      yearly intervals. The former patients, however, had more small tumors than the
      latter ones (91% vs. 74%, P =.04). The 22 patients who were alcohol abusers had
      normal levels of serum AFP more often than the hepatitis B virus (HBV) or HCV
      carriers or those with multiple risk factors (86% vs. 57%, P <.04; vs. 47%, P
      <.002; vs. 52%, P <.006, respectively). We concluded that multinodular HCC was
      underdetected by real time US; it prevailed among patients with multiple risk
      factors. In these patients, screening with US exams every 6 months may be
      inadequate for early detection of liver cancer.

PMID- 10347112
TI  - Interferon alfa receptor expression and growth inhibition by interferon alfa in
      human liver cancer cell lines.
AB  - Type I interferon (IFN) receptor consists of two chains (Hu-IFN-alphaR1 and Hu
      IFN-alphaR2), and Hu-IFN-alphaR2 takes a soluble (Hu-IFN-alphaR2a), short (Hu-IFN
      alphaR2b), or long (Hu-IFN-alphaR2c) form. We examined the expression of type I
      IFN receptor, the growth-suppression effect of IFN-alpha, and their relationship
      in 13 liver cancer cell lines. With reverse-transcription polymerase chain
      reaction (RT-PCR) analysis, the expressions of Hu-IFN-alphaR1, Hu-IFN-alphaR2a,
      and Hu-IFN-alphaR2c were confirmed in all cell lines, and that of Hu-IFN-alphaR2b
      in 12 cell lines. All cell lines expressed mRNAs of a transcriptional activator,
      interferon regulatory factor (IRF)-1, and its antagonistic repressor (IRF-2).
      Flow cytometry revealed weak expression of Hu-IFN-alphaR2 on the cell surface in
      12 cell lines. The soluble-form protein of Hu-IFN-alphaR2 was detected at varying
      levels in culture supernatants of all cell lines with enzyme-linked immunosorbent
      assay (ELISA). Cell proliferation was suppressed in proportion to the dose of
      human natural IFN-alpha at 96 hours of culture, but it was not clearly related to
      the expression of Hu-IFN-alphaR2 protein on the cell surface. Investigations on
      the morphology, DNA, and cell cycle presented four growth suppression patterns as
      a result of IFN-alpha: 1) induction of apoptosis and blockage of cell cycle at
      the S phase (9 cell lines); 2) blockage at the S phase (2 cell lines); 3)
      induction of apoptosis and blockage at the G2/M phase (1 cell line); and 4)
      blockage at the G1 phase (1 cell line). There was no evidence showing that
      changes in the expressions of Bcl-2, Bcl-xL, Bak, and Bax lead directly to IFN
      alpha-mediated apoptosis. Our findings demonstrated that IFN-alpha would express
      growth-suppression effects at varying degrees by inducing inhibition of cell
      cycle progression with or without apoptosis, regardless of the expression level
      of Hu-IFN-alphaR2 protein on the cell surface.

PMID- 10347113
TI  - Failure to detect genetic alteration of the mannose-6-phosphate/insulin-like
      growth factor 2 receptor (M6P/IGF2R) gene in hepatocellular carcinomas in Japan.
AB  - The mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R)
      suppresses cell growth through binding to the insulin-like growth factor 2 (IGF2)
      and latent complex of the transforming growth factor-beta (TGF-beta). Recently,
      it was reported in the United States that loss of heterozygosity (LOH) and
      mutations in exons 27, 28, and 31 of the M6P/IGF2R gene are frequent in
      hepatocellular carcinomas (HCCs) and adenomas. In view of the possible importance
      of this finding, especially for differential diagnosis of small hepatic lesions,
      we analyzed 43 primary HCCs, 2 adenomatous hyperplasias (AHs), and 3 regenerative
      nodules (RNs) developing in 42 Japanese patients in Japan for LOH using the
      polymorphic locus and for mutations by both single strand conformation
      polymorphism (SSCP) and direct sequencing methods. In the LOH study, 21 out of 22
      informative HCCs and all of the informative AHs and RNs showed no allelic loss.
      In mutational studies of exons 27, 28, and 31, no mutations were detected either
      by SSCP or direct sequencing analysis in any of the 48 lesions. Thus inactivation
      of the M6P/IGF2R gene because of genetic alteration does not appear to be
      essential for hepatocarcinogenesis in Japan.

PMID- 10347114
TI  - Small hyperechoic nodules in chronic liver diseases include hepatocellular
      carcinomas with low cyclin D1 and Ki-67 expression.
AB  - In spite of the importance of periodic screening for hepatocellular carcinoma
      (HCC) by ultrasonography (US) in patients with underlying liver disease, the
      clinicopathological characteristics of hyperechoic nodules have not been clearly
      evaluated. The aim of this study was to characterize the pathological and
      proliferating features of small hyperechoic nodules. Tissue specimens of 55
      hyperechoic and 107 hypoechoic nodules less than 20 mm in diameter in patients
      with chronic liver disease were obtained by echo-guided needle biopsy and
      examined histopathologically. Of these, 42 (76%) hyperechoic and 56 (52%)
      hypoechoic nodules were diagnosed as HCC, and 82% of hyperechoic HCCs contained
      fatty change and/or clear cell change. In addition, immunohistochemical staining
      using cyclin D1, p53, and Ki-67 was examined. A high-level expression of cyclin
      D1 was found in only 5% of hyperechoic HCCs, in contrast to 38% of hypoechoic
      HCCs (P <.02). The labeling index of Ki-67 in hyperechoic HCCs was lower than in
      hypoechoic HCCs (4.2% vs. 8.9%; P <.003). However, there was no difference on p53
      staining between them. Retrospective follow-up study revealed that hyperechoic
      nodules showed slow growth (doubling time, median: 1,403 days) initially, and
      came to show rapid growth (doubling time, median: 56 days). From these results,
      small hyperechoic nodules in chronic liver diseases are worth notice as
      candidates for well-differentiated HCC with low cyclin D1 and Ki-67 expression.

PMID- 10347115
TI  - Role of transforming growth factor beta type II receptor in hepatic fibrosis:
      studies of human chronic hepatitis C and experimental fibrosis in rats.
AB  - Transforming growth factor beta (TGF-beta) is an antiproliferative and
      profibrogenic cytokine that signals through a receptor consisting of type I and
      type II (TbetaRII) components. We have examined changes in the expression of
      TbetaRII during liver injury, correlating this with the antiproliferative and
      profibrogenic effects of TGF-beta1. The experimental material consisted of biopsy
      samples of liver from patients with chronic hepatitis C and rats in which liver
      injury was induced by ligation of the common bile duct. Stellate cells were
      isolated from normal or injured rat liver and studied as fresh isolates. In the
      biopsy samples from patients, mRNAs for TGF-beta1 and TbetaRII were measured
      using competitive reverse polymerase chain reaction (PCR). TGF-beta1 mRNA was
      significantly increased in chronic hepatitis C relative to healthy controls (P
      =.03), while TbetaRII mRNA was significantly decreased (P =.001). In the rat
      model, 5 days after bile duct ligation during increased TGF-beta expression, mRNA
      for TbetaRII in stellate cells was 40% of that in stellate cells from control
      livers. This coincided with increased expression of collagen I mRNA and
      proliferation of stellate cells. The reciprocal relationship between expression
      of TGF-beta and the type II receptor suggest ligand-mediated receptor down
      regulation. The decreased level of TbetaRII appears to be permissive for
      proliferation while supporting ongoing fibrogenesis. We conclude that modulation
      of this receptor may be critical to the progression of wound repair in liver.

PMID- 10347116
TI  - Hepatic thrombopoietin mRNA levels in acute and chronic liver failure of
      childhood.
AB  - The liver is the main production site of the hormone thrombopoietin (TPO), the
      major regulator of megakaryopoiesis. To investigate the role of an impaired TPO
      gene expression in the pathogenesis of thrombocytopenia in pediatric patients
      suffering from liver failure, we measured hepatic TPO mRNA in children with acute
      or chronic end-stage liver disease undergoing orthotopic liver transplantation.
      Tissue samples for RNA extraction were obtained from 12 children with compensated
      cirrhosis (CC), 22 children with decompensated cirrhosis (DC), and 9 children
      with acute liver failure (ALF). TPO mRNA was quantitated by competitive
      polymerase chain reaction (PCR), following reverse transcription (RT).
      Furthermore, in 9 children with ALF, serum TPO levels were measured by enzyme
      linked immunosorbent assay before and 10 to 14 days after liver transplantation.
      The hepatic TPO mRNA concentration was highest in children with CC (median, 50.9
      amol/micrograms RNA). This value was significantly reduced in children with DC
      (30.2 amol/micrograms RNA) or ALF (13.8 amol/micrograms RNA). Children with ALF
      (139 cells/nL) or DC (200 cells/nL) had lower platelet counts than children with
      CC (368 cells/nL). The serum TPO concentration increased from a median of 156
      pg/mL in patients with ALF to 547 pg/mL after liver transplantation. These
      results show that the thrombocytopenia in children with liver failure is
      associated with reduced hepatic TPO mRNA levels. It remains to be investigated
      whether the serum TPO level and platelet counts are markers for the severity of
      liver damage that may serve as a prognostic indicator.

PMID- 10347117
TI  - Insulin and insulin-like growth factor-1 stimulate proliferation and type I
      collagen accumulation by human hepatic stellate cells: differential effects on
      signal transduction pathways.
AB  - Insulin and insulin-like growth factor (IGF-1) are mitogenic for fibroblasts and
      smooth muscle cells. IGF-1 increases in inflamed and fibrotic tissues and induces
      proliferation of rat hepatic stellate cells (HSC). This study evaluates the
      potential roles of these hormones in the development of liver fibrosis. Insulin
      and IGF-1 receptor expression was evaluated by immunohistochemistry in both
      cultured human HSC and human liver tissue. Phosphorylation of both 70-kd S6
      kinase and extracellular-regulated kinase (ERK), cell proliferation, type I
      collagen gene expression, and accumulation in HSC culture media were evaluated by
      Western blot, immunohistochemistry for bromodeoxyuridine (BrdU), Northern blot,
      and enzyme-linked immunosorbent assay, respectively. Insulin and IGF-1 receptors
      were detected in HSC in vitro and in liver sections from patients with chronic
      active hepatitis. Insulin and IGF-1 induced 70-kd S6 kinase phosphorylation in
      HSC, whereas IGF-1 only induced ERK phosphorylation. Insulin and IGF-1 stimulated
      HSC proliferation in a dose-dependent fashion, with IGF-1 being four to five
      times more potent than insulin. Cell exposure to specific inhibitors showed that
      both phosphatidylinositol 3-kinase (PI3-K) and ERK are involved in IGF-1-induced
      mitogenesis, whereas insulin stimulated mitogenesis through a PI3-K-dependent ERK
      independent pathway. IGF-1 increased type I collagen gene expression and
      accumulation in HSC culture media through a PI3-K- and ERK-dependent mechanism.
      In conclusion, insulin and IGF-1, which stimulate HSC mitogenesis and collagen
      synthesis, may act in concert to promote liver fibrosis in vivo by a differential
      activation of PI3-K- and ERK1-dependent pathways.

PMID- 10347118
TI  - Prevention of lethal acute hepatic failure by antimacrophage migration inhibitory
      factor antibody in mice treated with bacille Calmette-Guerin and
      lipopolysaccharide.
AB  - During the past few years, the biological functions of macrophage migration
      inhibitory factor (MIF) have been extensively re-evaluated. This has been found
      to be protein involved in broad-spectrum pathophysiological states as an
      inflammatory cytokine, pituitary-derived hormone, and glucocorticoid-induced
      immunomodulator. In this study, we investigated the involvement of this cytokine
      in the pathogenesis of lethal liver injury. Injecting a small dose of
      lipopolysaccharide (LPS) into bacille Calmette-Guerin (BCG)-primed Jcl:ICR mice
      caused a lethal hepatic injury mimicking fulminant hepatitis, in which 8 of 11
      mice died within 48 hours (27% survival rate). Massive necrosis of parenchymal
      hepatocytes with marked mononuclear cell infiltration was observed by
      histological examination. Immunohistochemical analysis showed that most of the
      infiltrating mononuclear cells were Kupffer cells, macrophages, and, to a lesser
      extent, T cells. In parallel, serum aminotransferase and tumor necrosis factor
      alpha (TNF-alpha) levels were increased. When an anti-MIF polyclonal antibody
      (0.3 mg IgG fraction/mouse) was intraperitoneally injected into mice primed with
      BCG, it protected them from acute hepatic failure (90% survival rate) with
      concomitant improvement of histological features. Injection of the antibody also
      suppressed the up-regulation of TNF-alpha and T-cell infiltration induced by LPS.
      Taken together, these results suggested that treatment with the anti-MIF antibody
      suppresses the endotoxin-induced fatal hepatic failure by regulating production
      of inflammatory cytokines and T-cell infiltration.

PMID- 10347119
TI  - In vitro migratory potential of rat quiescent hepatic stellate cells and its
      augmentation by cell activation.
AB  - In liver injury, hepatic stellate cells are considered to depart from the
      sinusoidal wall and accumulate in the necrotic lesion through migration and
      proliferation. In this study, we investigated the migratory capacity of quiescent
      stellate cells in vitro and analyzed the relationship with proliferative
      response. Freshly isolated stellate cells that were seeded in the upper chamber
      of Cell Culture Insert (Becton Dickenson, Franklin Lakes, NJ) started to migrate
      to the lower chamber at 1 day and increased in migration index to 19% at 2 days.
      Cells in the lower chamber were stretched in shape with many lipid droplets and
      showed quiescent properties, i.e., negative expression of alpha-smooth muscle
      actin (alpha-SMA) or platelet-derived growth factor receptor-beta (PDGFR-beta).
      Migratory capacity in quiescent cells was also shown in the Matrigel-coated
      insert. Matrix metalloproteinase-2 (MMP-2) messenger RNA expression was low just
      after isolation, but was enhanced as migration became prominent. Migrating cells
      further showed higher proliferative activity than resting ones. The presence of
      PDGF/BB and Kupffer cells accelerated stellate cell migration by the chemotactic
      mechanism and concurrently augmented proliferation, whereas that of dexamethasone
      and interferon-gamma (IFN-gamma) attenuated migration as a result of general
      suppression effects. Compared with quiescent ones, alpha-SMA and PDGFR-beta
      positive activated stellate cells obtained by 14-day culture exhibited more rapid
      and prominent migration, being regulated by mediators in a similar manner as
      described previously. These data indicate that quiescent stellate cells undergo
      migration, which is linked to proliferation and enhanced by PDGF/BB and Kupffer
      cells, suggesting the involvement of this function in the initial phase of
      development of postnecrotic fibrosis.

PMID- 10347120
TI  - Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase
      expressed by stellate cells at the tissue remodelling interface in human
      cirrhosis.
AB  - Fibroblast activation protein (FAP) is a cell surface-bound protease of the
      prolyl oligopeptidase gene family expressed at sites of tissue remodelling. This
      study aimed to delineate the expression of FAP in cirrhotic human liver and
      examine its biochemical activities. Seventeen cirrhotic and 8 normal liver
      samples were examined by immunohistochemistry and reverse-transcriptase
      polymerase chain reaction (RT-PCR). Hepatic stellate cells (HSC) were isolated
      and immunostained. Recombinant FAP and immunopurified, natural FAP were analyzed
      for protease activities and similarities to dipeptidyl peptidase IV (DPPIV), a
      structurally related enzyme. FAP-specific messenger RNA and immunoreactivity were
      detected in cirrhotic, but not normal, livers. FAP immunoreactivity was most
      intense on perisinusoidal cells of the periseptal regions within regenerative
      nodules (15 of 15 cases); this pattern coincides with the tissue remodelling
      interface. In addition, human FAP was expressed by cells within the fibrous septa
      (10 of 15 cases). Cell morphology, location, and colocalization with glial
      fibrillary acidic protein (GFAP) indicated that FAP is present on HSC in vivo.
      Similarly, isolated HSC expressed FAP in vitro. Both natural FAP from cirrhotic
      liver and recombinant FAP were shown to have gelatinase and dipeptidyl peptidase
      activities. FAP is a cell-bound, dual-specificity dipeptidyl peptidase and
      gelatinase expressed by activated HSC at the tissue remodelling interface in
      human cirrhosis. FAP may contribute to the HSC-induced extracellular matrix (ECM)
      changes of cirrhosis.

PMID- 10347121
TI  - Characterization of a reproducible rat model of hepatic veno-occlusive disease.
AB  - Lack of a reproducible animal model has hampered progress in understanding
      hepatic veno-occlusive disease (HVOD). This article characterizes a reproducible
      model of HVOD. Rats gavaged with monocrotaline, 160 mg/kg, were killed between
      days 1 and 10. Sections were evaluated by light microscopy with a standardized
      scoring system, by immunoperoxidase staining with ED-1 (monocytes, macrophages)
      and ED-2 (Kupffer cells) antibodies, and by transmission (TEM) and scanning
      electron microscopy (SEM). On days 1 and 2, the earliest manifestations were
      progressive injury to the sinusoidal wall with loss of sinusoidal lining cells,
      sinusoidal hemorrhage, and mild damage to central vein (CV) endothelium. On days
      3 through 5 ("early HVOD"), there was centrilobular coagulative necrosis, severe
      injury to sinusoids, severe sinusoidal hemorrhage, and severe CV endothelial
      damage; inflammation with ED-1-positive cells was most marked on these days. Days
      6 and 7 ("late HVOD") were characterized by subendothelial and advential fibrosis
      of CVs, damage of the CV endothelium with subendothelial hemorrhage, and some
      restoration of the sinusoidal wall. Between days 8 and 10, sections showed
      interindividual variation ranging from mild, residual fibrosis to severe, late
      HVOD. From days 1 through 10, ED-2-positive cells were decreased in number, and
      the number of ED-1-positive cells was increased. Sinusoidal damage is the
      earliest change in HVOD. Coagulative necrosis follows sinusoidal injury and
      resolves with improvement in sinusoidal endothelial cell (SEC) morphology.
      Moderate-to-severe CV fibrosis occurs after reappearance of sinusoidal lining
      cells and resolution of hepatocyte necrosis. The inflammatory response within the
      lobule and CVs is a result of recruitment of monocytes, whereas Kupffer cells are
      decreased in number.

PMID- 10347122
TI  - Formation of 4-hydroxynonenal adducts with cytochrome c oxidase in rats following
      short-term ethanol intake.
AB  - This study addresses the role of the lipid peroxidation product, 4-hydroxynonenal
      (HNE), in ethanol-related damage of cytochrome c oxidase (COX) in vivo. It
      utilizes an animal model with acute ethanol exposure in which HNE levels in liver
      mitochondria are strikingly increased. Pregnant female Sprague-Dawley rats were
      administered 5 doses of ethanol (4 gm/kg, po at 12-hour intervals) beginning on
      day 17 of gestation and were sacrificed on day 19. Controls were pair-fed and
      received dextrose isocaloric to ethanol. Mitochondria were isolated from maternal
      and fetal livers and COX activities were measured spectrophotometrically.
      Compared with the pair-fed controls, COX activity was decreased with exposure to
      ethanol by 25% in maternal rats and 43% in fetal rats (P<.05). Western Blot with
      an HNE-Histidine antibody showed enhanced formation of HNE adducts with COX from
      ethanol-exposed rats, which was more pronounced in fetal than in adult livers.
      The HNE adducts were mainly with subunit IV of COX. The cause and effect
      relationship between HNE adduct formation and COX inhibition was examined in
      vitro by incubating purified COX with HNE. COX inhibition was accompanied by
      concentration-dependent HNE adduct formation that was consistent with those found
      in in vivo ethanol-exposed samples. These results suggest that the ethanol
      related decreases in COX activity found in liver mitochondria could be
      attributable to HNE adduct formation with the enzyme complex. This could be an
      important mechanism by which modification of proteins occur in in vivo oxidative
      stress.

PMID- 10347124
TI  - Dietary iron overload and induced lipid peroxidation are associated with impaired
      plasma lipid transport and hepatic sterol metabolism in rats.
AB  - Although hemochromatosis is characterized by dramatic morphological and
      functional alterations in the liver, little is known about the effects of an
      excess of iron on lipid metabolism. Therefore, we determined the effect of
      chronic iron overload on plasma lipid profile and lipoprotein composition, as
      well as on hepatic cholesterol metabolism and biliary sterol output. Rats
      administered a diet enriched with 3% iron carbonyl for 12 weeks displayed a 30
      fold increase in iron (P <.0001) and a 5-fold rise in malondialdehyde (P <.001)
      in the liver. When compared with pair-fed controls, iron-overload rats showed a
      significant increase in triglycerides (P <.005), free cholesterol (P <.006),
      cholesteryl ester (P <.007), and high-density lipoprotein (HDL)-cholesterol (P <.
      003). Triglyceride and cholesteryl ester enrichment, protein depletion, size
      increase, and apolipoprotein composition alterations characterized the very low
      density lipoprotein (VLDL) and HDL particles of iron-overload rats. Assessment of
      the activity of intracellular key enzymes for cholesterol homeostasis in these
      rats disclosed a reduction in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
      reductase (66%, P <.005) and cholesterol 7alpha-hydroxylase (58%, P <.0004) with
      an increment of acyl-CoA: cholesterol acyltransferase (62%, P <.002). The lack of
      optimal enzymatic activity may be a result of marked membrane lipid peroxidation
      that brings about fluidity drop (P <.029) in microsomes of iron-overload rats
      (5.00 +/- 0.013) versus controls (8.20 +/- 0. 03), reflected by polarization. A
      decline of the pool size of cholesterol and bile acids was noted in iron-overload
      rats during a 6-hour bile drainage. Our results show that experimental iron
      overload causes marked perturbations in plasma lipid transport and hepatobiliary
      sterol metabolism. Given the positive correlation of malondialdehyde with most of
      the altered parameters, iron-catalyzed lipid peroxidation may well be one of the
      involved mechanisms.

PMID- 10347123
TI  - The roles of intrahepatic Valpha14(+) NK1.1(+) T cells for liver injury induced
      by Salmonella infection in mice.
AB  - To investigate the roles of intrahepatic T cells in liver injury after Salmonella
      infection, we examined serum alanine transaminase (ALT), histopathology, and
      bacterial numbers in liver after infection with Salmonella choleraesuis strain
      31N-1 in mice genetically lacking TCRalpha beta+, CD4(+), CD8(+), or NK1.1(+)T
      cells with C57BL/6 background. In control (+/+) mice, serum ALT reached a peak
      level by day 7 after an intraperitoneal inoculation of 2 x 10(6) CFU Salmonella
      choleraesuis 31N-1. In TCR-beta-/- mice, liver injury, as assessed by serum ALT
      level and histological examination, was significantly suppressed on day 7 after
      Salmonella infection but the numbers of bacteria in liver did not differ from
      those in normal mice, suggesting that alpha beta T cells are responsible for
      liver injury induced by Salmonella infection. To further determine which subsets
      in alpha beta T cells are important for the liver injury, we compared serum ALT
      level in mice genetically lacking CD4, CD8, beta2-microglobulin (beta2m, IAbeta,
      or Jalpha281 after Salmonella infection. In CD4(-/-) mice, serum ALT was
      significantly lower in comparison with control mice, but there was no difference
      in serum ALT levels in CD8(-/-) and IAbeta-/- mice from that in control mice.
      Notably, serum ALT levels and pathological lesions in liver were significantly
      decreased in beta2m-/- or Jalpha281(-/-) mice, which lacked in NK1.1(+) T cells
      bearing TCR Valpha14-Jalpha281 specific for beta2m-associated CD1d, following
      Salmonella infection. Taken together, it is suggested that alpha beta T cells
      bearing NK1.1 and CD4 may be main effector cells for liver injury after
      Salmonella infection.

PMID- 10347125
TI  - Increased circulating leptin in alcoholic cirrhosis: relation to release and
      disposal.
AB  - Leptin is a cytokine peptide that decreases appetite and thereby food intake and
      increases energy expenditure. It is produced in fat cells, but recent animal
      experiments have shown expression of leptin in modified stellate hepatic cells.
      Because a change in circulating leptin in cirrhosis could be caused by an altered
      production rate, altered disposal rate, or both, the present study was undertaken
      to identify regions of leptin overflow into the blood stream and regions of
      leptin extraction. Patients with alcoholic cirrhosis (n = 16) and control
      patients without liver disease (n = 12) were studied during catheterization with
      elective blood sampling from different vascular beds. Blood samples for leptin
      determination (radioimmunoassay) were taken simultaneously from artery/hepatic
      vein, artery/renal vein, artery/iliac vein, and artery/cubital vein. Patients
      with cirrhosis had significantly increased circulating leptin (7.3 vs. control
      2.6 ng/mL, P <.002) that correlated directly to ascitic-free body mass index (r =
      0.71, P <.005). A significant renal extraction ratio of leptin was observed in
      control patients (0. 16) and in patients with cirrhosis (0.07), but the latter
      value was significantly lower than in the control patients (-44%, P <.05) and
      inversely correlated to serum creatinine (r = -0.60, P <.05). A significant, but
      equal, hepatosplanchnic extraction of leptin was observed in cirrhotic patients
      and control patients (0.08 vs. 0.07). In patients with cirrhosis a significant
      cubital venous-arterial difference in leptin was observed, but not in control
      patients. The iliac venous/arterial leptin ratio was significantly above 1.0 in
      both groups and of similar size (1.16 vs. 1.15), but a higher difference in
      concentration was found in the cirrhotic patients (+33%, P <.05). The spillover
      rates of leptin in cirrhotic patients may be even higher than estimated from the
      increased systemic veno-arterial gradients. In conclusion, the elevated
      circulating leptin in patients with cirrhosis is most likely caused by a
      combination of decreased renal extraction and increased release from subcutaneous
      abdominal, femoral, gluteal, retroperitoneal pelvic, and upper limb fat tissue
      areas. The hepatosplanchnic bed drained through hepatic veins could not be
      identified as a source of increased circulating leptin in cirrhosis, but a
      contribution by the portosystemic collateral flow cannot be excluded.

PMID- 10347126
TI  - Enhancement of mdr2 gene transcription mediates the biliary transfer of
      phosphatidylcholine supplied by an increased biosynthesis in the pravastatin
      treated rat.
AB  - An increase of biliary lipid secretion is known to occur in the rat under
      sustained administration of statin-type 3-hydroxy-3-methylglutaryl (HMG) coenzyme
      A (CoA) reductase inhibitors. The present study has addressed critical mechanisms
      of hepatic lipid synthesis and phosphatidylcholine (PC) biliary transport in the
      rat fed with a 0.075% pravastatin diet for 3 weeks. After treatment, biliary
      secretion of PC and cholesterol increased to 233% and 249% of controls, while
      that of bile salts was unchanged. Activity of cytidylyltransferase (CT), a major
      regulatory enzyme in the CDP-choline pathway of PC synthesis, was raised in both
      microsomal and cytosolic fractions (226% and 150% of controls), and there was an
      increase to 187% in the mass of active enzyme as determined by Western blot of
      microsomal protein using an antibody specific to CT. Cytosolic activity of
      choline kinase, another enzyme of the CDP-choline pathway, also increased to 175%
      of controls. In addition, there was an over eightfold increase in the HMG CoA
      reductase activity and mRNA. Thus, an increased PC and cholesterol synthetic
      supply to hepatocytes appeared as a basic mechanism for the biliary
      hypersecretion of these lipids. Notwithstanding the increased synthesis, hepatic
      PC content was unchanged, suggesting an enhanced transfer of this lipid into
      bile. Indeed, there was a sevenfold increase of multidrug resistance gene 2
      (mdr2) gene mRNA coding for a main PC canalicular translocase. Thus,
      hypersecretion of biliary PC in the model studied can be explained by an up
      regulation of mdr2 gene transcription and its P-glycoprotein product mediating
      the biliary transfer of PC supplied by an increased biosynthesis.

PMID- 10347127
TI  - Regulation of hepatic transport systems involved in bile secretion during liver
      regeneration in rats.
AB  - We investigated the expression of hepatic transport systems involved in bile
      secretion during liver regeneration after partial hepatectomy (PH) in rats.
      Initial studies showed maximal BrdU incorporation 24 hours after PH. Therefore,
      transporter expression and bile secretion were analyzed in detail at this time.
      The mRNA levels of the multidrug resistance genes mdr1a and mrp1 slightly
      increased, whereas mdr1b mRNA levels showed an extensive increase after PH. The
      mRNA levels of the conjugate transporter, mrp2, decreased slightly, whereas mrp2
      protein levels did not change. Bilirubin secretion did not change, but the
      biliary glutathione secretion markedly decreased and the hepatic GSH content
      increased. The messenger RNA levels of the bile salt uptake transporters ntcp,
      oatp1, and oatp2 and the bile salt exporter, bsep/spgp, all decreased with ntcp
      showing the most prominent decrease. Protein levels of ntcp dramatically
      decreased whereas oatp2 only slightly decreased. Oatp1 protein expression
      slightly increased and bsep/spgp protein levels did not change. Decreased levels
      of bile salt uptake systems were associated with a 10-fold increase in the plasma
      bile salt concentration, yet, bile flow and bile salt secretion were increased
      when expressed per gram liver and unaffected when expressed on the basis of body
      weight. In conclusion, during the initial phase of rat liver regeneration ntcp is
      down-regulated whereas other transporter proteins involved in bile secretion are
      only slightly affected. Despite increased serum bile salt levels the remnant
      liver is not cholestatic: bile flow is maintained by uptake of bile salts
      probably via oatp isoforms and their secretion via bsep/spgp.

PMID- 10347128
TI  - Bile acids modulate the interferon signalling pathway.
AB  - We have previously shown that cholestasis and bile acids inhibit 2', 5'
      oligoadenylate synthetase (OAS) activity in the liver and in primary hepatocyte
      cultures. Here, we assessed the influence of bile acids on interferon (IFN)
      pathway activation in three hepatoma cell lines. In HepG2 cells, bile acids (100
      200 micromol/L) inhibited IFN-induced 2',5' OAS activity to an extent depending
      on their surface activity index. In Western blot analysis, IFN-induced expression
      of two major antiviral proteins, MxA and OAS p100, was reduced by 54% +/- 8% and
      44% +/- 12%, respectively, when cells were preincubated for 4 hours with 100
      micromol/L chenodeoxycholic acid (CDCA). In the same conditions, CDCA did not
      modify the IFN-induced signal transducers and activators of transcription (STAT)s
      tyrosine phosphorylation. In contrast, it reduced IFN-induced MxA promoter
      activity by 60%. The inhibitory effect of CDCA was not mediated by a 4beta
      phorbol 12beta-myristate 13alpha-acetate (PMA)-sensitive protein kinase C (PKC)
      dependent pathway. Finally, using CHO cells stably expressing a functional human
      bile acid carrier (Na+-dependent taurocholate cotransporting polypeptide [NTCP]),
      we found that bile acid inhibition of the IFN pathway occurred in the range of
      more physiological concentrations (12-50 micromol/L). In summary, our results
      provide strong evidence that bile acids inhibit the induction of proteins
      involved in the antiviral activity of IFN. This might partly explain the lack of
      responsiveness to IFN therapy in some patients with advanced chronic viral liver
      diseases.

PMID- 10347129
TI  - The "early-sorting" endocytic compartment of rat hepatocytes is involved in the
      intracellular pathway of caveolin-1 (VIP-21).
AB  - The sinusoidal plasma membrane of the hepatocyte is organized into functional and
      structural microdomains whose origin, maintenance, and functioning are closely
      related with the endocytic compartment. Three different subcellular fractions,
      from rat liver, containing caveolin-1, the structural protein of caveolae, were
      morphologically and biochemically characterized. A caveolae-enriched plasma
      membrane fraction (CEF), contains large membrane structures surrounding attached
      internal plasmalemmal vesicles; the receptor-recycling compartment (RRC),
      contains tubules and vesicles with similar morphology to the internal vesicles
      observed by electron microscopy in CEF; and finally, caveolin-1 was also detected
      in early-sorting endosomes (CURL, compartment of uncoupling receptors and
      ligands). In this study, we show that following an intravenous administration of
      retinol-binding protein (RBP), there was a redistribution of caveolin-1 from the
      plasma membrane (CEF) to intracellular endocytic compartments (RRC and early
      sorting endosomes). Thus, these results indicate that, in the hepatocyte,
      caveolae are dynamic structures actively interacting with the endocytic
      compartment.

PMID- 10347130
TI  - Genetic aberrations detected by comparative genomic hybridization in
      hepatocellular carcinomas: their relationship to clinicopathological features.
AB  - To elucidate cytogenetic alterations underlying human hepatocellular carcinomas
      (HCCs), we used a comparative genomic hybridization (CGH) method to analyze 41
      cases of hepatocellular carcinoma (HCC) including 15 well differentiated HCCs, 14
      moderately differentiated HCCs, and 12 poorly differentiated HCCs. Of these, 27
      patients were chronically infected with hepatitis C virus (HCV), and the
      remaining patients were positive for hepatitis B virus (HBV). The most common
      sites of increase in DNA copy number were 1q (78% of the cases) and 8q (66%) with
      minimal overlapping regions at 1q24-25 and 8q24, respectively. Frequent decreases
      in copy number were observed at 17p (51%), 16q (46%), 13q13-14 (37%), 4q13-22
      (32%), 8p (29%), and 10q (17%). In 6 cases (15%), an amplification was found in
      the region of 11q13. A gain of 8q24 was significantly associated with well
      differentiated HCCs (P<.05), whereas a loss of 13q13-14 and amplification of
      11q13 were linked to moderately and poorly differentiated HCCs (P<.01). These
      observations suggest that a gain of 8q24 is an early event and that a loss of
      13q13-14 and amplification of 11q13 are a late event in the course of liver
      carcinogenesis. A gain of 10q (7/41) was detected exclusively in cases with HCV
      infection. In contrast, an amplification of 11q13 was preferentially found in HBV
      positive HCCs. These findings raise the hypothesis that, although many genetic
      alterations are basically common to both HCV-positive and HBV-positive tumors,
      the process of carcinogenesis may be to some extent different between these two
      types of tumors.

PMID- 10347131
TI  - Biphasic clearance kinetics of hepatitis B virus from patients during adefovir
      dipivoxil therapy.
AB  - In a recent phase II clinical study, 13 chronic hepatitis B-infected patients
      treated daily with 30 mg adefovir dipivoxil for 12 weeks displayed a median 4.1
      log10 decrease in plasma hepatitis B virus (HBV)-DNA levels. The decline of viral
      load during therapy displayed a biphasic kinetic profile that was modeled to
      determine the efficacy of inhibition of viral production, as well as kinetic
      constants for the clearance of free virus and the loss of infected cells. Viral
      production was suppressed with an efficacy of 0.993 +/- 0.008, indicating that
      only 0.7% of viral production persisted during therapy. The initial, faster phase
      of viral load decline reflects the clearance of HBV particles from plasma with a
      half-life of 1.1 +/- 0.3 days, translating to a 48% daily turnover of the free
      virus. The second, slower phase of viral load decline closely mirrors the rate
      limiting process of infected cell loss, with a half-life of 18 +/- 7 days. The
      duration of therapy required to completely eliminate the virus from plasma or
      suppress it to levels sufficient to induce seroconversion is a function of the
      half-life of the free virus, the half-life of infected cells, and the efficacy of
      inhibition of virus production from infected cells. These quantitative analyses
      provide a more detailed picture of the dynamics of HBV infection and therapy, and
      can be used to compare the efficacy of various doses and inhibitors of HBV
      replication for the treatment of HBV infections.

PMID- 10347132
TI  - Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial
      of interferon alfa-2b versus no treatment.
AB  - To examine the effects of interferon (IFN) therapy on clinical, biochemical, and
      histological features in patients with compensated hepatitis C virus (HCV)
      related cirrhosis, we have conducted a randomized, controlled trial of IFN
      therapy versus observation. Eight centers included a total of 99 patients with
      biopsy-proven cirrhosis. IFN-alpha2b, 3 million units three times per week, or no
      antiviral therapy was given for 48 weeks. Twenty-three patients dropped out. End
      of-treatment biochemical response was not observed in any of the 39 controls but
      was observed in 6 of the 47 treated patients (P <.02); sustained biochemical
      response was obtained in only 2 treated patients. Controls and treated patients
      did not significantly differ with regard to the changes in serum level of
      albumin, bilirubin, alpha-fetoprotein, in plasma prothrombin, in histological
      activity, or liver collagen content. During trial or follow-up (160 +/- 57
      weeks), hepatocellular carcinoma developed in 9 controls and 5 treated patients
      (NS); decompensation of cirrhosis occurred in 5 controls and 7 treated patients.
      Seven controls and 10 treated patients died. In conclusion, in patients with
      compensated HCV-related cirrhosis, a 48-week course of IFN therapy is safe and is
      able to induce end-of-treatment biochemical response in a significant proportion
      of patients. However, a 48-week course of IFN therapy usually fails to achieve
      sustained response and, within the limit of this study, did not significantly
      improve the 3-year outcome. Therefore, a longer course of IFN therapy or
      combination therapy with ribavirin should be evaluated in patients with HCV
      related cirrhosis.

PMID- 10347133
TI  - Three cases of severe subfulminant hepatitis in heart-transplanted patients after
      nosocomial transmission of a mutant hepatitis B virus.
AB  - Fulminant and severe viral hepatitis are frequently associated with mutant
      hepatitis B virus (HBV) strains. In this study, the genetic background of a viral
      strain causing severe subfulminant outcome in heart-transplanted patients was
      studied and compared with viral hepatitis B strains that were not linked to
      severe liver disease in the same setting. A total of 46 patients infected
      nosocomially with HBV genotype A were studied. Five different viral strains were
      detected, infecting 3, 9, 5, 24, and 5 patients, respectively. Only one viral
      strain was found to be associated with the subfulminant outcome and 3 patient
      deaths as a consequence of severe liver disease. The remaining 43 patients with
      posttransplantation HBV infection did not show this fatal outcome. Instead,
      symptoms of hepatitis were generally mild or clinically undiagnosed. Comparison
      of this virus genome with the four other strains showed an accumulation of
      mutations in the basic core promoter, a region that influences viral replication,
      but also in hepatitis B X protein (HBX) (7 mutant motifs), core (10 mutant
      motifs), the preS1 region (5 mutant motifs), and the HBpolymerase open reading
      frame (17 motifs). Some of these variations, such as those in the core region,
      were located on the tip of the protruding spike of the viral capsid (codons 60 to
      90), also known in part as an important HLA class II-restricted epitope region.
      These mutations might therefore influence the immune-mediated response. The viral
      strain causing subfulminant hepatitis was, in addition, the only strain with a
      preCore stop codon mutation and, thus, hepatitis B e antigen (HBeAg) expression
      was never observed. The combination of these specific viral factors is thought to
      be responsible for the fatal outcome in these immune-suppressed heart-transplant
      recipients.

PMID- 10347134
TI  - Effects of iron loading on pathogenicity in hepatitis C virus-infected
      chimpanzees.
AB  - Elevated iron levels have been associated with raised serum alanine transaminase
      (ALT) levels in hepatitis C virus (HCV)-infected humans. However, it is not clear
      if HCV infection causes increased iron accumulation by the liver or if the
      severity of HCV infection is actually worsened by higher iron levels in the host.
      To better understand the relationship between iron and persistent HCV infections,
      we examined the effect of excess dietary iron on disease severity in HCV-infected
      chimpanzees. Iron was supplemented in the diets of four HCV-infected and two
      uninfected chimpanzees for 29 weeks to achieve iron loading. Iron loading was
      confirmed by increases in serum iron levels, percentages of transferrin
      saturation, ferritin levels, elevations in hepatic iron concentration (HIC), and
      by histological examination. The majority of HCV-infected chimpanzees had higher
      iron levels before iron feeding than the uninfected animals. Although various
      degrees of iron loading occurred in all chimpanzees, HCV-infected animals
      exhibited increased loading in comparison with uninfected animals. The effects of
      iron loading on HCV disease expression was determined by comparing disease
      parameters during an extended baseline period before iron loading with the period
      during iron loading and immediately following iron loading. Iron loading did not
      influence the viral load, but did exacerbate liver injury in HCV-infected
      chimpanzees, as evidenced by elevated ALT and histological changes. Because all
      chimpanzees on high iron diets experienced iron loading, but pathological effects
      were only observed in HCV-infected chimpanzees, HCV infection appears to increase
      the susceptibility of the liver to injury following iron loading. These results
      confirm and extend previous observations made in human populations and serve to
      further validate the chimpanzee model of chronic hepatitis C.

PMID- 10347135
TI  - Hepatitis C virus infection and bone marrow transplantation: a cohort study with
      10-year follow-up.
AB  - Before the introduction of routine blood donor screening in 1991, marrow
      transplant recipients were at significant transfusion-associated risk for
      infection with hepatitis C virus (HCV). We followed a cohort of 355 patients
      undergoing transplant in Seattle during 1987 to 1988 to determine (1) the impact
      of pretransplant HCV infection on the occurrence and severity of venocclusive
      disease (VOD); (2) the impact of HCV infection on liver dysfunction, other than
      VOD, occurring between 21 and 60 days after transplantation; and (3) the natural
      history of post-transplant HCV liver disease with a 10-year follow-up. HCV-RNA
      status was determined on serum stored before transplant and at day 100 post
      transplant. Sixty-two (17%) patients were HCV-RNA positive before transplant, and
      113 (32%) were HCV-RNA positive by day 100 post-transplant (or before death).
      Severe VOD developed in 22 of 46 (48%) evaluable patients with pretransplant HCV
      infection and in 150 of 229 (14%) evaluable patients without HCV (P <.0001). In
      multivariable analysis of risk factors for developing VOD, pretransplant HCV
      infection associated with elevated serum aspartate transaminase (AST) levels
      predicted the development of severe VOD (relative risk, 9.6; P =.0001). The
      presence of HCV with normal AST levels before transplant was not a risk factor
      for severe VOD. Between 21 and 60 days after transplant, HCV-RNA positive
      patients had higher AST levels (median 101 U/L), but similar alkaline phosphatase
      and total bilirubin levels compared with HCV-negative patients, suggesting that
      cholestatic liver disease (particularly graft-versus-host disease [GVHD]) was not
      related to HCV infection. An acute flare of hepatitis (AST >10 times the upper
      limit of normal) developed at a mean of 136 +/- 58 days in 31% of HCV-positive
      patients; no patients developed fulminant hepatitis. Between 5 and 10 years after
      transplant, 57% of HCV-positive and 6% of HCV-negative patients had mild to
      moderate elevations of AST (P <. 0001), but HCV infection was not associated with
      excess mortality between 3 and 10 years after bone marrow transplantation. In
      summary, HCV infection with elevated AST levels is a significant risk factor for
      severe VOD after marrow transplant. However, the decision to proceed to
      transplantation in HCV-positive patients must balance the absolute risk of death
      from VOD against the risks of the underlying disease. In long-term survivors, HCV
      infection is not associated with excess mortality over 10 years of follow-up.

PMID- 10347136
TI  - Interferon alfa subtypes and levels of type I interferons in the liver and
      peripheral mononuclear cells in patients with chronic hepatitis C and controls.
AB  - Viral infections stimulate the transcription of interferon type I, which includes
      IFN-alfa (IFN-alpha) (13 subtypes) and IFN-beta (a single substance). Hepatitis C
      virus (HCV) infection is remarkable by its ability to evade host antiviral
      defenses; however, there is little information as to whether endogenous IFN is
      activated or not in this disease. Additionally, despite the fact that the various
      IFN-alpha subtypes may differ in biological activity, there are no data
      concerning the IFN-alpha subtypes specifically expressed in normal and diseased
      liver tissue. Thus, we have analyzed the IFN-alpha subtypes and the mRNA levels
      of type I IFNs in samples of normal liver tissue and in liver from patients with
      chronic hepatitis C. Similar studies were performed in peripheral blood
      mononuclear cells (PBMC) from patients and controls. After amplification and
      cloning of IFN-alpha cDNA, we observed that 98 of the 100 clones from normal
      liver tissue corresponded to the IFN-alpha5 subtype. However, in livers with
      chronic hepatitis C and in PBMC from controls and patients, a variety of
      subtypes, in addition to IFN-alpha5, were detected, suggesting a participation of
      infiltrating leukocytes in the production of IFN-alpha in livers with chronic
      hepatitis C. As compared with controls, patients with chronic hepatitis C showed
      a significant increase in IFN-beta mRNA in both the liver and PBMC, while IFN
      alpha mRNA was significantly increased in PBMC but markedly reduced in liver
      tissue. In conclusion, IFN-alpha5 is the sole IFN-alpha subtype expressed in
      normal liver tissue. The hepatic levels of IFN-alpha are reduced in chronic
      hepatitis C, an event that may favor viral persistence.

PMID- 10347137
TI  - The role of TT virus infection in acute viral hepatitis.
AB  - Recently, transfusion-transmitted virus (TTV) was discovered to be a potential
      causative agent for non-A-E hepatitis. Little is known about the relation between
      TTV and the clinical courses of various types of acute viral hepatitis. One
      hundred twenty-five patients with acute viral hepatitis who were admitted to the
      Chiba University Hospital between 1984 and 1998 and 100 persons with normal liver
      function tests were tested for the presence of TTV in their sera. Serum samples
      were tested for TTV DNA and genotype by polymerase chain reaction (PCR). TTV DNA
      was detected in 15 of 35 patients (43%) with non-A-E hepatitis, 14 of 33 patients
      (42%) with hepatitis C, 8 of 28 patients (29%) with hepatitis A, 7 of 29 patients
      (24%) with hepatitis B, and 37 of 100 subjects with normal liver function tests
      (37%). The detection rate did not differ statistically between non-A-E hepatitis
      and hepatitis A, B, C, or controls. The distribution of TTV genotypes was similar
      in non-A-E, A, B, C types, and controls. The clinical characteristics of the
      acute illnesses were similar for patients with or without TTV in hepatitis non-A
      E, A, B, or C. Although TTV was detected frequently in non-A-E acute hepatitis,
      no etiologic role for TTV could be established.

PMID- 10347138
TI  - Transforming growth factor-beta signaling and cirrhosis.

PMID- 10347139
TI  - Another form of familial intrahepatic cholestasis, another new gene.

PMID- 10347140
TI  - Regulation of bile acid transport: beyond molecular cloning.

PMID- 10347141
TI  - Single-molecule enzymology.

PMID- 10347142
TI  - Feedback regulation of beta-arrestin1 function by extracellular signal-regulated
      kinases.
AB  - The functions of beta-arrestin1 to facilitate clathrin-mediated endocytosis of
      the beta2-adrenergic receptor and to promote agonist-induced activation of
      extracellular signal-regulated kinases (ERK) are regulated by its
      phosphorylation/dephosphorylation at Ser-412. Cytoplasmic beta-arrestin1 is
      almost stoichiometrically phosphorylated at Ser-412. Dephosphorylation of beta
      arrestin1 at the plasma membrane is required for targeting a signaling complex
      that includes the agonist-occupied receptors to the clathrin-coated pits. Here we
      demonstrate that beta-arrestin1 phosphorylation and function are modulated by an
      ERK-dependent negative feedback mechanism. ERK1 and ERK2 phosphorylate beta
      arrestin1 at Ser-412 in vitro. Inhibition of ERK activity by a dominant-negative
      MEK1 mutant significantly attenuates beta-arrestin1 phosphorylation, thereby
      increasing the concentration of dephosphorylated beta-arrestin1. Under such
      conditions, beta-arrestin1-mediated beta2-adrenergic receptor internalization is
      enhanced as is its ability to bind clathrin. In contrast, if ERK-mediated
      phosphorylation is increased by transfection of a constitutively active MEK1
      mutant, receptor internalization is inhibited. Our results suggest that
      dephosphorylated beta-arrestin1 mediates endocytosis-dependent ERK activation.
      Following activation, ERKs phosphorylate beta-arrestin1, thereby exerting an
      inhibitory feedback control of its function.

PMID- 10347143
TI  - Requirement of DNA polymerase activity of yeast Rad30 protein for its biological
      function.
AB  - The RAD30 gene of Saccharomyces cerevisiae encodes a DNA polymerase, Poleta. The
      Rad30 protein shares homology with the yeast Rev1 and the Escherichia coli DinB
      and UmuC proteins. Although these proteins contain several highly conserved
      motifs, only Rad30 has been shown to possess a DNA polymerase activity. To
      determine whether the DNA polymerase activity of Rad30 was essential for its
      biological function, we made a mutation in the highly conserved SIDE sequence in
      Rad30, in which the aspartate and glutamate residues have each been changed to
      alanine. The mutant Rad30 protein lacks the DNA polymerase activity, and the
      mutant gene does not complement the rad30Delta mutation. These findings indicate
      that DNA polymerase activity is indispensable for the biological function of
      RAD30.

PMID- 10347145
TI  - Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on
      serine 253 through a Wortmannin-sensitive pathway.
AB  - In the nematode Caenorhabditis elegans, mutations of the insulin/insulin-like
      growth factor-1 receptor homologue Daf-2 gene cause developmental arrest at the
      dauer stage. The effect of Daf-2 mutations is counteracted by mutations in the
      Daf-16 gene, suggesting that Daf-16 is required for signaling by Daf-2. Daf-16
      encodes a forkhead transcription factor. Based on sequence similarity, the FKHR
      genes are the likeliest mammalian Daf-16 homologues. FKHR proteins contain
      potential sites for phosphorylation by the serine/threonine kinase Akt. Because
      Akt is phosphorylated in response to insulin and has been implicated in a variety
      of insulin effects, we investigated whether insulin affects phosphorylation of
      FKHR. Insulin stimulated phosphorylation of endogenous FKHR and of a recombinant
      c-Myc/FKHR fusion protein transiently expressed in murine SV40-transformed
      hepatocytes. The effect of insulin was inhibited by wortmannin treatment,
      suggesting that PI 3-kinase activity is required for FKHR phosphorylation.
      Mutation of serine 253, located in a consensus Akt phosphorylation site at the
      carboxyl-terminal end of the forkhead domain, abolished the effect of insulin on
      FKHR phosphorylation. In contrast, mutation of two additional Akt phosphorylation
      sites, at amino acids threonine 24 or serine 316, did not abolish insulin-induced
      phosphorylation. These data indicate that FKHR may represent a distal effector of
      insulin action.

PMID- 10347144
TI  - Identification and characterization of a novel cytokine, THANK, a TNF homologue
      that activates apoptosis, nuclear factor-kappaB, and c-Jun NH2-terminal kinase.
AB  - By using the amino acid sequence motif of tumor necrosis factor (TNF), we
      searched the expressed sequence tag data base and identified a novel full-length
      cDNA encoding 285 amino acid residues and named it THANK. THANK is a type II
      transmembrane protein with 15-20% overall amino acid sequence homology to TNF, LT
      alpha, FasL, and LIGHT, all members of the TNF family. The mRNA for THANK was
      expressed at high levels by peripheral blood leukocytes, lymph node, spleen, and
      thymus and at low levels by small intestine, pancreas, placenta, and lungs. THANK
      was also prominently expressed in hematopoietic cell lines. The recombinant
      purified protein expressed in the baculovirus system had an approximate molecular
      size 20 kDa with amino-terminal sequence of AVQGP. Treatment of human myeloid
      U937 cells with purified THANK activated nuclear transcription factor-kappaB (NF
      kappaB) consisting of p50 and p65. Activation was time- and dose-dependent,
      beginning with as little as a 1 pM amount of the cytokines and as early as 15
      min. Under the same conditions, THANK also activated c-jun NH2-terminal kinase
      (JNK) in U937 cells. THANK also strongly suppressed the growth of tumor cell
      lines and activated caspase-3. Although THANK had all the activities and potency
      of TNF, it did not bind to the TNF receptors. Thus our results indicate that
      THANK is a novel cytokine that belongs to the TNF family and activates apoptosis,
      NF-kappaB, and JNK through a distinct receptor.

PMID- 10347146
TI  - Functional interaction between the N- and C-terminal halves of human hexokinase
      II.
AB  - Mammalian hexokinases (HKs) I-III are composed of two highly homologous
      approximately 50-kDa halves. Studies of HKI indicate that the C-terminal half of
      the molecule is active and is sensitive to inhibition by glucose 6-phosphate
      (G6P), whereas the N-terminal half binds G6P but is devoid of catalytic activity.
      In contrast, both the N- and C-terminal halves of HKII (N-HKII and C-HKII,
      respectively) are catalytically active, and when expressed as discrete proteins
      both are inhibited by G6P. However, C-HKII has a significantly higher Ki for G6P
      (KiG6P) than N-HKII. We here address the question of whether the high KiG6P of
      the C-terminal half (C-half) of HKII is decreased by interaction with the N
      terminal half (N-half) in the context of the intact enzyme. A chimeric protein
      consisting of the N-half of HKI and the C-half of HKII was prepared. Because the
      N-half of HKI is unable to phosphorylate glucose, the catalytic activity of this
      chimeric enzyme depends entirely on the C-HKII component. The KiG6P of this
      chimeric enzyme is similar to that of HKI and is significantly lower than that of
      C-HKII. When a conserved amino acid (Asp209) required for glucose binding is
      mutated in the N-half of this chimeric protein, a significantly higher KiG6P
      (similar to that of C-HKII) is observed. However, mutation of a second conserved
      amino acid (Ser155), also involved in catalysis but not required for glucose
      binding, does not increase the KiG6P of the chimeric enzyme. This resembles the
      behavior of HKII, in which a D209A mutation results in an increase in the KiG6P
      of the enzyme, whereas a S155A mutation does not. These results suggest an
      interaction in which glucose binding by the N-half causes the activity of the C
      half to be regulated by significantly lower concentrations of G6P.

PMID- 10347147
TI  - Endogenous proteins controlling amyloid beta-peptide polymerization. Possible
      implications for beta-amyloid formation in the central nervous system and in
      peripheral tissues.
AB  - We report that certain plasma proteins, at physiological concentrations, are
      potent inhibitors of amyloid beta-peptide (Abeta) polymerization. These proteins
      are also present in cerebrospinal fluid, but at low concentrations having little
      or no effect on Abeta. Thirteen proteins representing more than 90% of the
      protein content in plasma and cerebrospinal fluid were studied. Quantitatively,
      albumin was the most important protein, representing 60% of the total amyloid
      inhibitory activity, followed by alpha1-antitrypsin and immunoglobulins A and G.
      Albumin suppressed amyloid formation by binding to the oligomeric or polymeric
      Abeta, blocking a further addition of peptide. This effect was also observed when
      the incorporation of labeled Abeta into genuine beta-amyloid in tissue section
      was studied. The Abeta and the anti-diabetic drug tolbutamide apparently bind to
      the same site on albumin. Tolbutamide displaces Abeta from albumin, increasing
      its free concentration and enhancing amyloid formation. The present results
      suggest that several endogenous proteins are negative regulators of amyloid
      formation. Plasma contains at least 300 times more amyloid inhibitory activity
      than cerebrospinal fluid. These findings may provide one explanation as to why
      beta-amyloid deposits are not found in peripheral tissues but are only found in
      the central nervous system. Moreover, the data suggest that some drugs that
      display an affinity for albumin may enhance beta-amyloid formation and promote
      the development of Alzheimer's disease.

PMID- 10347148
TI  - The 67-kDa laminin-binding protein is involved in shear stress-dependent
      endothelial nitric-oxide synthase expression.
AB  - It has been suggested that the mechanical forces acting on endothelial cells may
      be sensed in part by cell-matrix connections. We therefore studied the role of
      different matrix proteins, in particular laminin I, on a shear stress-dependent
      endothelial response, namely nitric-oxide synthase (eNOS) expression. Primary
      porcine aortic endothelial cells were seeded onto glass plates either noncoated
      (NC cells) or precoated with fibronectin (FN cells), laminin (LN cells), or
      collagen I (CN cells). Western blots were used to detect differences in the final
      matrix composition of these cells. A shear stress of 16 dyn/cm2 was applied for 6
      h. Only LN cells showed detectable amounts of laminin I in their underlying
      matrix when they reached confluence. They reacted with a 2-fold increase of eNOS
      expression (n = 16, p < 0.001) to the exposure of shear stress, which went along
      with enhanced eNOS protein and NO release. In contrast, neither FN cells (n = 9)
      nor NC cells (n = 13) showed a significant increase of eNOS expression under
      shear stress. The increase in CN cells was borderline (1.4-fold; n = 9, p < 0.05)
      and was not associated with an increase of eNOS protein. The shear-induced
      increase in eNOS expression of LN cells was abolished by the peptide YIGSR, which
      blocks the cellular binding to laminin I via a 67-kDa laminin-binding protein,
      whereas a control peptide (YIGSK) had no effect. The induction of eNOS expression
      by shear stress is stimulated by an interaction of endothelial cells with laminin
      which is, at least in part, mediated by a 67-kDa laminin-binding protein.

PMID- 10347149
TI  - Zinc coordination and substrate catalysis within the neuropeptide processing
      enzyme endopeptidase EC 3.4.24.15. Identification of active site histidine and
      glutamate residues.
AB  - Endopeptidase EC 3.4.24.15 (EP24.15) is a zinc metalloendopeptidase that is
      broadly distributed within the brain, pituitary, and gonads. Its substrate
      specificity includes a number of physiologically important neuropeptides such as
      neurotensin, bradykinin, and gonadotropin-releasing hormone, the principal
      regulatory peptide for reproduction. In studying the structure and function of
      EP24.15, we have employed in vitro mutagenesis and subsequent protein expression
      to genetically dissect the enzyme and allow us to glean insight into the
      mechanism of substrate binding and catalysis. Comparison of the sequence of
      EP24.15 with bacterial homologues previously solved by x-ray crystallography and
      used as models for mammalian metalloendopeptidases, indicates conserved residues.
      The active site of EP24.15 exhibits an HEXXH motif, a common feature of zinc
      metalloenzymes. Mutations have confirmed the importance, for binding and
      catalysis, of the residues (His473, Glu474, and His477) within this motif. A
      third putative metal ligand, presumed to coordinate directly to the active site
      zinc ion in concert with His473 and His477, has been identified as Glu502.
      Conservative alterations to these residues drastically reduces enzymatic activity
      against both a putative physiological substrate and a synthetic quenched
      fluorescent substrate as well as binding of the specific active site-directed
      inhibitor, N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate, the
      binding of which we have shown to be dependent upon the presence, and possibly
      coordination, of the active site zinc ion. These studies contribute to a more
      complete understanding of the catalytic mechanism of EP24.15 and will aid in
      rational design of inhibitors and pharmacological agents for this class of
      enzymes.

PMID- 10347150
TI  - Role of multiple CytR binding sites on cooperativity, competition, and induction
      at the Escherichia coli udp promoter.
AB  - The CytR repressor fulfills dual roles as both a repressor of transcription from
      promoters of the Escherichia coli CytR regulon and a co-activator in some
      circumstances. Transcription is repressed by a three-protein complex (cAMP
      receptor protein (CRP)-CytR-CRP) that is stabilized by cooperative interactions
      between CRP and CytR. However, cooperativity also means that CytR can recruit CRP
      and, by doing so, can act as a co-activator. The central role of cooperativity in
      regulation is highlighted by the fact that binding of the inducer, cytidine, to
      CytR is coupled to CytR-CRP cooperativity; this underlies the mechanism for
      induction. Similar interactions at the different promoters of the CytR regulon
      coordinate expression of the transport proteins and enzymes required for
      nucleoside catabolism but also provide differential expression of these genes. A
      fundamental question in both prokaryotic and eukaryotic gene regulation is how
      combinatorial mechanisms of this sort regulate differential expression. Recently,
      we showed that CytR binds specifically to multiple sites in the E. coli deoP
      promoter, thereby providing competition for CRP binding to CRP operator site 1
      (CRP1) and CRP2 as well as cooperativity. The effect of the competition at this
      promoter is to negate the role of CytR in recruiting CRP. Here, we have used
      quantitative footprint and mobility shift analysis to investigate CRP and CytR
      binding to the E. coli udp promoter. Here too, we find that CytR both cooperates
      and competes for CRP binding. However, consistent with both the distribution of
      CytR recognition motifs in the sequence of the promoter and the regulation of the
      promoter, the competition is limited to CRP2. When cytidine binds to CytR, the
      effect on cooperativity is very different at the udp promoter than at the deoP2
      promoter. Cooperativity with CRP at CRP1 is nearly eliminated, but the effect on
      CytR-CRP2 cooperativity is negligible. These results are discussed in relation to
      the current structural model of CytR in which the core, inducer-binding domain is
      tethered to the helix-turn-helix, DNA-binding domain via flexible peptide
      linkers.

PMID- 10347151
TI  - Flux of the L-serine metabolism in rat liver. The predominant contribution of
      serine dehydratase.
AB  - L-Serine metabolism in rat liver was investigated, focusing on the relative
      contributions of the three pathways, one initiated by L-serine dehydratase (SDH),
      another by serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT), and the
      other involving serine hydroxymethyltransferase and the mitochondrial glycine
      cleavage enzyme system (GCS). Because serine hydroxymethyltransferase is
      responsible for the interconversion between serine and glycine, SDH, SPT/AGT, and
      GCS were considered to be the metabolic exits of the serine-glycine pool. In
      vitro, flux through SDH was predominant in both 24-h starved and glucagon-treated
      rats. Flux through SPT/AGT was enhanced by glucagon administration, but even
      after the induction, its contribution under quasi-physiological conditions (1 mM
      L-serine and 0.25 mM pyruvate) was about (1)/(10) of that through SDH. Flux
      through GCS accounted for only several percent of the amount of L-serine
      metabolized. Relative contributions of SDH and SPT/AGT to gluconeogenesis from L
      serine were evaluated in vivo based on the principle that 3H at the 3 position of
      L-serine is mostly removed in the SDH pathway, whereas it is largely retained in
      the SPT/AGT pathway. The results showed that SPT/AGT contributed only 10-20% even
      after the enhancement of its activity by glucagon. These results suggested that
      SDH is the major metabolic exit of L-serine in rat liver.

PMID- 10347152
TI  - Flux of the L-serine metabolism in rabbit, human, and dog livers. Substantial
      contributions of both mitochondrial and peroxisomal
      serine:pyruvate/alanine:glyoxylate aminotransferase.
AB  - L-Serine metabolism in rabbit, dog, and human livers was investigated, focusing
      on the relative contributions of the three pathways, one initiated by serine
      dehydratase, another by serine:pyruvate/alanine:glyoxylate aminotransferase
      (SPT/AGT), and the other involving serine hydroxymethyltransferase and the
      mitochondrial glycine cleavage enzyme system (GCS). Under quasi-physiological in
      vitro conditions (1 mM L-serine and 0.25 mM pyruvate), flux through serine
      dehydratase accounted for only traces, and that through SPT/AGT substantially
      contributed no matter whether the enzyme was located in peroxisomes (rabbit and
      human) or largely in mitochondria (dog). As for flux through serine
      hydroxymethyltransferase and GCS, the conversion of serine to glycine occurred
      fairly rapidly, followed by GCS-mediated slow decarboxylation of the accumulated
      glycine. The flux through GCS was relatively high in the dog and low in the
      rabbit, and only in the dog was it comparable with that through SPT/AGT. An in
      vivo experiment with L-[3-3H,14C]serine as the substrate indicated that in rabbit
      liver, gluconeogenesis from L-serine proceeds mainly via hydroxypyruvate. Because
      an important role in the conversion of glyoxylate to glycine has been assigned to
      peroxisomal SPT/AGT from the studies on primary hyperoxaluria type 1, these
      results suggest that SPT/AGT in this organelle plays dual roles in the metabolism
      of glyoxylate and serine.

PMID- 10347153
TI  - A novel mammalian lithium-sensitive enzyme with a dual enzymatic activity, 3'
      phosphoadenosine 5'-phosphate phosphatase and inositol-polyphosphate 1
      phosphatase.
AB  - We report the molecular cloning in Rattus norvegicus of a novel mammalian enzyme
      (RnPIP), which shows both 3'-phosphoadenosine 5'-phosphate (PAP) phosphatase and
      inositol-polyphosphate 1-phosphatase activities. This enzyme is the first PAP
      phosphatase characterized at the molecular level in mammals, and it represents
      the first member of a novel family of dual specificity enzymes. The phosphatase
      activity is strictly dependent on Mg2+, and it is inhibited by Ca2+ and Li+ ions.
      Lithium chloride inhibits the hydrolysis of both PAP and inositol-1,4
      bisphosphate at submillimolar concentration; therefore, it is possible that the
      inhibition of the human homologue of RnPIP by lithium ions is related to the
      pharmacological action of lithium. We propose that the PAP phosphatase activity
      of RnPIP is crucial for the function of enzymes sensitive to inhibition by PAP,
      such as sulfotransferase and RNA processing enzymes. Finally, an unexpected
      connection between PAP and inositol-1,4-bisphosphate metabolism emerges from this
      work.

PMID- 10347154
TI  - Yap1 and Skn7 control two specialized oxidative stress response regulons in
      yeast.
AB  - Yap1 and Skn7 are two yeast transcriptional regulators that co-operate to
      activate thioredoxin (TRX2) and thioredoxin reductase (TRR1) in response to redox
      stress signals. Although they are both important for resistance to H2O2, only
      Yap1 is important for cadmium resistance, whereas Skn7 has a negative effect upon
      this response. The respective roles of Yap1 and Skn7 in the induction of defense
      genes by H2O2 were analyzed by two-dimensional gel electrophoresis. Yap1 controls
      a large oxidative stress response regulon of at least 32 proteins. Fifteen of
      these proteins also require the presence of Skn7 for their induction by H2O2.
      Although about half of the Yap1 target genes do not contain a consensus Yap1
      recognition motif, the control of one such gene, TSA1, involves the binding of
      Yap1 and Skn7 to its promoter in vitro. The co-operative control of the oxidative
      stress response by Yap1 and Skn7 delineates two gene subsets. Remarkably, these
      two gene subsets separate antioxidant scavenging enzymes from the metabolic
      pathways regenerating the main cellular reducing power, glutathione and NADPH.
      Such a specialization may explain, at least in part, the dissociated function of
      Yap1 and Skn7 in H2O2 and cadmium resistance.

PMID- 10347155
TI  - Activation of neuronal nitric-oxide synthase by the 5-methyl analog of
      tetrahydrobiopterin. Functional evidence against reductive oxygen activation by
      the pterin cofactor.
AB  - Tetrahydrobiopterin ((6R)-5,6,7,8-tetrahydro-L-biopterin (H4biopterin)) is an
      essential cofactor of nitric-oxide synthases (NOSs), but its role in enzyme
      function is not known. Binding of the pterin affects the electronic structure of
      the prosthetic heme group in the oxygenase domain and results in a pronounced
      stabilization of the active homodimeric structure of the protein. However, these
      allosteric effects are also produced by the potent pterin antagonist of NOS, 4
      amino-H4biopterin, suggesting that the natural cofactor has an additional, as yet
      unknown catalytic function. Here we show that the 5-methyl analog of H4biopterin,
      which does not react with O2, is a functionally active pterin cofactor of
      neuronal NOS. Activation of the H4biopterin-free enzyme occurred in a biphasic
      manner with half-maximally effective concentrations of approximately 0.2 microM
      and 10 mM 5-methyl-H4biopterin. Thus, the affinity of the 5-methyl compound was 3
      orders of magnitude lower than that of the natural cofactor, allowing the direct
      demonstration of the functional anticooperativity of the two pterin binding sites
      of dimeric NOS. In contrast to H4biopterin, which inactivates nitric oxide (NO)
      through nonenzymatic superoxide formation, up to 1 mM of the 5-methyl derivative
      did not consume O2 and had no effect on NO steady-state concentrations measured
      electrochemically with a Clark-type NO electrode. Therefore, reconstitution with
      5-methyl-H4biopterin allowed, for the first time, the detection of enzymatic NO
      formation in the absence of superoxide or NO scavengers. These results
      unequivocally identify free NO as a NOS product and indicate that reductive O2
      activation by the pterin cofactor is not essential to NO biosynthesis.

PMID- 10347156
TI  - Pseudo-native motifs in the noncovalent heme-apocytochrome c complex. Evidence
      from antibody binding studies by enzyme-linked immunosorbent assay and
      microcalorimetry.
AB  - When beef heart apocytochrome c is unfolded, it folds upon noncovalent heme
      binding (Dumont, M. E., Corin, A. F., and Campbell, G.A. (1994) Biochemistry, 33,
      7368-7378). Here, the conformation of the heme-apocytochrome noncovalent complex
      is compared with that of holocytochrome c. A purification method was designed for
      obtaining in large amounts apocytochrome c that was shown by amino acid analysis
      and mass spectroscopy to be chemically intact. The apoprotein and its noncovalent
      complex were characterized by absorption, fluorescence, circular dichroism, and
      sedimentation velocity, confirming previous reports. Sedimentation-diffusion
      equilibrium showed that the apoprotein and its noncovalent complex with heme were
      monomeric. Surprisingly, whereas apocytochrome c was quite soluble, the
      noncovalent complex slowly formed heavy aggregates, thus precluding experiments
      at the concentrations needed for structural studies. Two monoclonal antibodies
      that bind strongly to distinct antigenic sites on native holocytochrome were used
      to probe the noncovalent complex conformation. For both antibodies, the affinity
      for the noncovalent complex was only about 5-10-fold smaller than that for native
      holocytochrome c, and about 50-100-fold larger than that for apocytochrome c.
      These results indicate that the noncovalent complex, although not entirely
      native, carries some pseudo-native structural motifs.

PMID- 10347157
TI  - Co-translational assembly of the D1 protein into photosystem II.
AB  - Assembly of multi-subunit membrane protein complexes is poorly understood. In
      this study, we present direct evidence that the D1 protein, a multiple membrane
      spanning protein, assembles co-translationally into the large membrane-bound
      complex, photosystem II. During pulse-chase studies in intact chloroplasts,
      incorporation of the D1 protein occurred without transient accumulation of free
      labeled protein in the thylakoid membrane, and photosystem II subcomplexes
      contained nascent D1 intermediates of 17, 22, and 25 kDa. These N-terminal D1
      intermediates could be co-immunoprecipitated with antiserum directed against the
      D2 protein, suggesting co-translational assembly of the D1 protein into PS II
      complexes. Further evidence for a co-translational assembly of the D1 protein
      into photosystem II was obtained by analyzing ribosome nascent chain complexes
      liberated from the thylakoid membrane after a short pulse labeling. Radiolabeled
      D1 intermediates could be immunoprecipitated under nondenaturing conditions with
      antisera raised against the D1 and D2 protein as well as CP47. However, when the
      ribosome pellets were solubilized with SDS, the interaction of these
      intermediates with CP47 was completely lost, but strong interaction of a 25-kDa
      D1 intermediate with the D2 protein still remained. Taken together, our results
      indicate that during the repair of photosystem II, the assembly of the newly
      synthesized D1 protein into photosystem II occurs co-translationally involving
      direct interaction of the nascent D1 chains with the D2 protein.

PMID- 10347158
TI  - Characterization of the transcriptional activator CBF1 from Arabidopsis thaliana.
      Evidence for cold denaturation in regions outside of the DNA binding domain.
AB  - A transcriptional activator, CBF1, from Arabidopsis thaliana, which has the AP2
      domain for DNA binding and regulates the cold acclimation response, was
      overexpressed in Escherichia coli, purified, and characterized. Analyses of the
      interaction between CBF1 and the C-repeat/dehydration-responsive element by
      fluorescence measurement showed that CBF1 binds to C-repeat/dehydration
      responsive element as a monomer irrespective of the temperature. CD spectra of
      the intact and truncated CBF1 proteins (1-213, 41-213, 41-157, and 41-146) were
      measured to examine the temperature-dependent changes of the secondary structure
      of CBF1. The results suggested that the CBF1 protein has regions exhibiting
      reversible cold denaturation in the range between 30 and -5 degrees C and also
      has a region exhibiting thermal denaturation between 40 and 60 degrees C. This
      cold denaturation occurred in both the N-terminal and acidic regions. The thermal
      denaturation occurred in the region encompassing the AP2 domain. The difference
      between the retention time of CBF1 at 4 degrees C and that at 25 degrees C in gel
      filtration, and the decrease of the sedimentation coefficient, s20,w, caused by
      the temperature change from 25 to 3 degrees C, strongly suggested that the cold
      denaturation was accompanied by the extension of the molecule. The possible cold
      denaturation observed here might be a physiologically important structural
      response of CBF1 to cold stress.

PMID- 10347160
TI  - Activation of the p38 mitogen-activated protein kinase pathway by Epstein-Barr
      virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin
      8 production.
AB  - The Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) is a pleiotropic
      protein the activities of which include effects on gene expression and cell
      transformation, growth, and death. LMP1 has been shown to induce nuclear factor
      (NF)-kappaB and c-Jun NH2-terminal kinase/AP-1 activities in target cells, and in
      this study we demonstrate that LMP1 also engages the p38 mitogen-activated
      protein kinase cascade, leading to activation of the transcription factor ATF2.
      Mutational analysis of the LMP1 cytoplasmic COOH terminus revealed that p38
      activation occurs from both the tumor necrosis factor receptor-associated factor
      (TRAF)-interacting, membrane-proximal COOH-terminal activating region (CTAR)1
      domain (amino acids 186-231) and the extreme tumor necrosis factor receptor
      associated death domain (TRADD) binding CTAR2 region (amino acids 351-386).
      Because LMP1 also engages signaling on the NF-kappaB axis through CTAR1 and
      CTAR2, we have examined whether these two pathways are overlapping or
      independent. We have found that inhibition of p38 by the highly specific
      inhibitor SB203580 did not affect NF-kappaB binding activity. Conversely,
      although the metabolic inhibitor D609 blocked NF-kappaB activation, it did not
      impair the ability of LMP1 to signal on the p38 axis, suggesting that these two
      LMP1-mediated pathways are primarily independent. Divergence of signals must,
      however, occur downstream of TRAF2 as a dominant negative TRAF2 mutant that
      blocks LMP1-induced NF-kappaB activation also inhibited p38 signaling. In
      addition, we have found that p38 inhibition significantly impaired LMP1-mediated
      interleukin-6 and -8 expression. Thus, p38 may play a significant cooperative
      role in regulating at least some of the pleiotropic activities of LMP1.

PMID- 10347159
TI  - Identification of amino acid residues critical for aggregation of human CC
      chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES.
      Characterization of active disaggregated chemokine variants.
AB  - Human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and
      RANTES (regulated on activation normal T cell expressed) self-associate to form
      high-molecular mass aggregates. To explore the biological significance of
      chemokine aggregation, nonaggregating variants were sought. The phenotypes of 105
      hMIP-1alpha variants generated by systematic mutagenesis and expression in yeast
      were determined. hMIP-1alpha residues Asp26 and Glu66 were critical to the self
      association process. Substitution at either residue resulted in the formation of
      essentially homogenous tetramers at 0.5 mg/ml. Substitution of identical or
      analogous residues in homologous positions in both hMIP-1beta and RANTES
      demonstrated that they were also critical to aggregation. Our analysis suggests
      that a single charged residue at either position 26 or 66 is insufficient to
      support extensive aggregation and that two charged residues must be present.
      Solution of the three-dimensional NMR structure of hMIP-1alpha has enabled
      comparison of these residues in hMIP-1beta and RANTES. Aggregated and
      disaggregated forms of hMIP-1alpha, hMIP-1beta, and RANTES generally have
      equivalent G-protein-coupled receptor-mediated biological potencies. We have
      therefore generated novel reagents to evaluate the role of hMIP-1alpha, hMIP
      1beta, and RANTES aggregation in vitro and in vivo. The disaggregated chemokines
      retained their human immunodeficiency virus (HIV) inhibitory activities.
      Surprisingly, high concentrations of RANTES, but not disaggregated RANTES
      variants, enhanced infection of cells by both M- and T-tropic HIV
      isolates/strains. This observation has important implications for potential
      therapeutic uses of chemokines implying that disaggregated forms may be necessary
      for safe clinical investigation.

PMID- 10347161
TI  - The transcriptional inhibitors, actinomycin D and alpha-amanitin, activate the
      HIV-1 promoter and favor phosphorylation of the RNA polymerase II C-terminal
      domain.
AB  - Actinomycin D and alpha-amanitin are commonly used to inhibit transcription.
      Unexpectedly, however, the transcription of the human immunodeficiency virus (HIV
      1) long terminal repeats (LTR) is shown to be activated at the level of
      elongation, in human and murine cells exposed to these drugs, whereas the Rous
      sarcoma virus LTR, the human cytomegalovirus immediate early gene (CMV), and the
      HSP70 promoters are repressed. Activation of the HIV LTR is independent of the
      NFkappaB and TAR sequences and coincides with an enhanced average phosphorylation
      of the C-terminal domain (CTD) from the largest subunit of RNA polymerase II.
      Both the HIV-1 LTR activation and the bulk CTD phosphorylation enhancement are
      prevented by several CTD kinase inhibitors, including 5, 6-dichloro-1-beta-D
      ribofuranosylbenzimidazole. The efficacies of the various compounds to block CTD
      phosphorylation and transcription in vivo correlate with their capacities to
      inhibit the CDK9/PITALRE kinase in vitro. Hence, the positive transcription
      elongation factor, P-TEFb, is likely to contribute to the average CTD
      phosphorylation in vivo and to the activation of the HIV-1 LTR induced by
      actinomycin D.

PMID- 10347162
TI  - Porins OmpC and PhoE of Escherichia coli as specific cell-surface targets of
      human lactoferrin. Binding characteristics and biological effects.
AB  - The binding of lactoferrin, an iron-binding glycoprotein found in secretions and
      leukocytes, to the outer membrane of Gram-negative bacteria is a prerequisite to
      exert its bactericidal activity. It was proposed that porins, in addition to
      lipopolysaccharides, are responsible for this binding. We studied the
      interactions of human lactoferrin with the three major porins of Escherichia coli
      OmpC, OmpF, and PhoE. Binding experiments were performed on both purified porins
      and porin-deficient E. coli K12 isogenic mutants. We determined that lactoferrin
      binds to the purified native OmpC or PhoE trimer with molar ratios of 1.9 +/- 0.4
      and 1.8 +/- 0.3 and Kd values of 39 +/- 18 and 103 +/- 15 nM, respectively, but
      not to OmpF. Furthermore, preferential binding of lactoferrin was observed on
      strains that express either OmpC or PhoE. It was also demonstrated that residues
      1-5, 28-34, and 39-42 of lactoferrin interact with porins. Based on sequence
      comparisons, the involvement of lactoferrin amino acid residues and porin loops
      in the interactions is discussed. The relationships between binding and
      antibacterial activity of the protein were studied using E. coli mutants and
      planar lipid bilayers. Electrophysiological studies revealed that lactoferrin can
      act as a blocking agent for OmpC but not for PhoE or OmpF. However, a total
      inhibition of the growth was only observed for the PhoE-expressing strain
      (minimal inhibitory concentration of lactoferrin was 2.4 mg/ml). These data
      support the proposal that the antibacterial activity of lactoferrin may depend,
      at least in part, on its ability to bind to porins, thus modifying the stability
      and/or the permeability of the bacterial outer membrane.

PMID- 10347163
TI  - A mutation in the MSH6 subunit of the Saccharomyces cerevisiae MSH2-MSH6 complex
      disrupts mismatch recognition.
AB  - In yeast, MSH2 interacts with MSH6 to repair base pair mismatches and single
      nucleotide insertion/deletion mismatches and with MSH3 to recognize small loop
      insertion/deletion mismatches. We identified a msh6 mutation (msh6-F337A) that
      when overexpressed in wild type strains conferred a defect in both MSH2-MSH6- and
      MSH2-MSH3-dependent mismatch repair pathways. Genetic analysis suggested that
      this phenotype was due to msh6-F337A sequestering MSH2 and preventing it from
      interacting with MSH3 and MSH6. In UV cross-linking, filter binding, and gel
      retardation assays, the MSH2-msh6-F337A complex displayed a mismatch recognition
      defect. These observations, in conjunction with ATPase and dissociation rate
      analysis, suggested that MSH2-msh6-F337A formed an unproductive complex that was
      unable to stably bind to mismatch DNA.

PMID- 10347164
TI  - A potential role for Elf-1 in CD4 promoter function.
AB  - The control of CD4 gene expression is believed to be linked directly to the
      signaling events that mediate T cell development and is directly dependent on the
      CD4 promoter. We have previously determined that this promoter contains four
      factor-binding sites important for its function. One of these sites, referred to
      as the P4 site, contains an Ets consensus recognition sequence. Using functional
      and biochemical analyses, we determine that Elf-1 binds to this site and
      specifically activates the CD4 promoter, indicating that Elf-1 is playing an
      important role in CD4 promoter function. In addition, a second nuclear factor
      binds to this region. Although there are consensus recognition sites for other
      factors, we demonstrate that none of these factors binds to the P4 site, nor do
      other known members of the Ets family. Thus, a novel transcription factor may
      bind to the CD4 promoter and help mediate its function.

PMID- 10347165
TI  - In vitro unfolding/refolding of wild type phage P22 scaffolding protein reveals
      capsid-binding domain.
AB  - The scaffolding proteins of double-stranded DNA viruses are required for the
      polymerization of capsid subunits into properly sized closed shells but are
      absent from the mature virions. Phage P22 scaffolding subunits are elongated 33
      kDa molecules that copolymerize with coat subunits into icosahedral precursor
      shells and subsequently exit from the precursor shell through channels in the
      procapsid lattice to participate in further rounds of polymerization and
      dissociation. Purified scaffolding subunits could be refolded in vitro after
      denaturation by high temperature or guanidine hydrochloride solutions. The lack
      of coincidence of fluorescence and circular dichroism signals indicated the
      presence of at least one partially folded intermediate, suggesting that the
      protein consisted of multiple domains. Proteolytic fragments containing the C
      terminus were competent for copolymerization with capsid subunits into procapsid
      shells in vitro, whereas the N terminus was not needed for this function.
      Proteolysis of partially denatured scaffolding subunits indicated that it was the
      capsid-binding C-terminal domain that unfolded at low temperatures and
      guanidinium concentrations. The minimal stability of the coat-binding domain may
      reflect its role in the conformational switching needed for icosahedral shell
      assembly.

PMID- 10347166
TI  - Folding and stability of mutant scaffolding proteins defective in P22 capsid
      assembly.
AB  - Bacteriophage P22 scaffolding subunits are elongated molecules that interact
      through their C termini with coat subunits to direct icosahedral capsid assembly.
      The soluble state of the subunit exhibits a partially folded intermediate during
      equilibrium unfolding experiments, whose C-terminal domain is unfolded (Greene,
      B., and King, J. (1999) J. Biol. Chem. 274, 16135-16140). Four mutant scaffolding
      proteins exhibiting temperature-sensitive defects in different stages of particle
      assembly were purified. The purified mutant proteins adopted a similar
      conformation to wild type, but all were destabilized with respect to wild type.
      Analysis of the thermal melting transitions showed that the mutants S242F and
      Y214W further destabilized the C-terminal domain, whereas substitutions near the
      N terminus either destabilized a different domain or affected interactions
      between domains. Two mutant proteins carried an additional cysteine residue,
      which formed disulfide cross-links but did not affect the denaturation
      transition. These mutants differed both from temperature-sensitive folding
      mutants found in other P22 structural proteins and from the thermolabile
      temperature-sensitive mutants described for T4 lysozyme. The results suggest that
      the defects in these mutants are due to destabilization of domains affecting the
      weak subunit-subunit interactions important in the assembly and function of the
      virus precursor shell.

PMID- 10347167
TI  - Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome
      proliferator-activated receptor gamma.
AB  - In an effort to understand transcriptional regulation by the peroxisome
      proliferator-activated receptor gamma (PPARgamma), we have investigated its
      potential interaction with coregulators and have identified ARA70 as a ligand
      enhanced coactivator. ARA70 was initially described as a coactivator for the
      androgen receptor (AR) and is expressed in a range of tissues including adipose
      tissue (Yeh, S., and Chang, C. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 5517
      5521). Here we show that ARA70 and PPARgamma specifically interact by
      coimmunoprecipitation and in a mammalian two-hybrid assay. PPARgamma and ARA70
      interact in the absence of the PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin
      J2, although the addition of exogenous ligand enhances this interaction.
      Similarly, in transient transfection of DU145 cells, cotransfection of PPARgamma
      and ARA70 induces transcription from reporter constructs driven by either three
      copies of an isolated PPAR response element or the natural promoter of the
      adipocyte fatty acid-binding protein 2 in the absence of exogenous 15-deoxy
      Delta12,14-prostaglandin J2. However, this PPARgamma-ARA70 transactivation is
      enhanced by the addition of ligand. Thus, ARA70 can function as a ligand-enhanced
      coactivator of PPARgamma. Finally, we show that AR can squelch PPARgamma-ARA70
      transactivation, which suggests that cross-talk may occur between PPARgamma- and
      AR-mediated responses in adipocytes.

PMID- 10347168
TI  - The ATPase mechanism of ArsA, the catalytic subunit of the arsenite pump.
AB  - The ArsA ATPase is the catalytic subunit of a novel arsenite pump, with two
      nucleotide-binding consensus sequences in the N- and C-terminal halves of the
      protein. The single tryptophan-containing Trp159 ArsA was used to elucidate the
      elementary steps of the ATPase mechanism by fluorescence stopped-flow
      experiments. The binding and hydrolysis of MgATP is a multistep process with a
      minimal kinetic mechanism (Mechanism 1). A notable feature of the reaction is
      that MgATP binding induces a slow transient increase in fluorescence of ArsA,
      which is independent of the ATP concentration, indicative of the build-up of a
      pre-steady state intermediate. This finding, coupled with a phosphate burst,
      implies that the steady-state intermediate builds up subsequent to product
      release. We propose that the rate-limiting step is an isomerization between
      different conformational forms of ArsA. kcat is faster than the phosphate burst,
      indicating that both nucleotide binding sites of ArsA are catalytic. Consistent
      with this interpretation, approximately 2 mol of phosphate are released per mole
      of ArsA during the phosphate burst.

PMID- 10347169
TI  - Comparison of the peroxidase reaction kinetics of prostaglandin H synthase-1 and 
      2.
AB  - Prostaglandin H synthase isoforms 1 and 2 (PGHS-1 and -2) each have a peroxidase
      activity and also a cyclooxygenase activity that requires initiation by
      hydroperoxide. The hydroperoxide initiator requirement for PGHS-2 cyclooxygenase
      is about 10-fold lower than for PGHS-1 cyclooxygenase, and this difference may
      contribute to the distinct control of cellular prostanoid synthesis by the two
      isoforms. We compared the kinetics of the initial peroxidase steps in PGHS-1 and 
      2 to quantify mechanistic differences between the isoforms that might contribute
      to the difference in cyclooxygenase initiation efficiency. The kinetics of
      formation of Intermediate I (an Fe(IV) species with a porphyrin free radical) and
      Intermediate II (an Fe(IV) species with a tyrosyl free radical, thought to be the
      crucial oxidant in cyclooxygenase catalysis) were monitored at 4 degrees c by
      stopped flow spectrophotometry with several hydroperoxides as substrate. With 15
      hydroperoxyeicosatetraenoic acid, the rate constant for Intermediate I formation
      (k1) was 2.3 x 10(7) M-1 s-1 for PGHS-1 and 2.5 x 10(7) M-1 s-1 for PGHS-2,
      indicating that the isoforms have similar initial reactivity with this lipid
      hydroperoxide. For PGHS-1, the rate of conversion of Intermediate I to
      Intermediate II (k2) became the limiting factor when the hydroperoxide level was
      increased, indicating a rate constant of 10(2)-10(3) s-1 for the generation of
      the active cyclooxygenase species. For PGHS-2, however, the transition between
      Intermediates I and II was not rate-limiting even at the highest hydroperoxide
      concentrations tested, indicating that the k2 value for PGHS-2 was much greater
      than that for PGHS-1. Computer modelling predicted that faster formation of the
      active cyclooxygenase species (Intermediate II) or increased stability of the
      active species increases the resistance of the cyclooxygenase to inhibition by
      the intracellular hydroperoxide scavenger, glutathione peroxidase. Kinetic
      differences between the PGHS isoforms in forming or stabilizing the active
      cyclooxygenase species can thus contribute to the difference in the regulation of
      their cellular activities.

PMID- 10347170
TI  - Ca2+/calmodulin-dependent kinase II phosphorylates the epidermal growth factor
      receptor on multiple sites in the cytoplasmic tail and serine 744 within the
      kinase domain to regulate signal generation.
AB  - Down-regulation of receptor tyrosine kinase activity plays an essential role in
      coordinating and controlling cellular growth/differentiation. Ca2+/calmodulin
      dependent kinase II (CaM kinase II)-mediated phosphorylation of threonine 1172 in
      the cytoplasmic tail of HER2/c-erbB2 can modulate tyrosine kinase activity and
      consensus phosphorylation sites are also found at serines 1046/1047 in the
      structurally related epidermal growth factor receptor (EGFR). We show that
      serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is
      a preference for serine 1047, which resides within the consensus -R-X-X-S-. In
      addition, we have identified major phosphorylation sites at serine 1142 and
      serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines
      1046/1047 in full-length EGFR enhanced both fibroblast transformation and
      tyrosine autokinase activity that was significantly potentiated by additional
      mutation of serines 1057 and 1142. A single CaM kinase II site was also
      identified at serine 744 within sub-kinase domain III, and autokinase activity
      was significantly affected by mutation of this serine to an aspartic acid making
      this site appear constitutively phosphorylated. We have addressed the mechanism
      by which CaM kinase II phosphorylation of the EGFR might regulate receptor
      autokinase activity and show that this modification can hinder association of the
      cytoplasmic tail with the kinase domain to prevent an enzyme-substrate
      interaction. We postulate that the location and greater number of CaM kinase II
      phosphorylation sites in the EGFR compared with HER-2/c-erbB2, leading to
      differential regulation of autokinase activity, contributes to differences in the
      strength of downstream signaling events and may explain the higher relative
      transforming potential of HER-2/cerbB2.

PMID- 10347171
TI  - Evidence for a 3'-5' decay pathway for c-myc mRNA in mammalian cells.
AB  - Many mRNAs in mammalian cells decay via a sequential pathway involving rapid
      conversion of polyadenylated molecules to a poly(A)-deficient state followed by
      rapid degradation of the poly(A)-deficient molecules. However, the rapidity of
      this latter step(s) has precluded further analyses of the decay pathways
      involved. Decay intermediates derived from degradation of poly(A)-deficient
      molecules could offer clues regarding decay pathways, but these intermediates
      have not been readily detected. Cell-free mRNA decay systems have proven useful
      in analyses of decay pathways because decay intermediates are rather stable in
      vitro. Cell-free systems indicate that many mRNAs decay by a sequential 3'-5'
      pathway because 3'-terminal decay intermediates form following deadenylation.
      However, if 3'-terminal, in vitro decay intermediates reflect a biologically
      significant aspect of mRNA turnover, then similar intermediates should be present
      in cells. Here, I have compared the in vivo and in vitro decay of mRNA encoded by
      the c-myc proto-oncogene. Its decay both in vivo and in vitro occurs by rapid
      removal of the poly(A) tract and generation of a 3'-terminal decay intermediate.
      These data strongly suggest that a 3'-5' pathway contributes to turnover of c-myc
      mRNA in cells. It is likely that 3'-5' decay represents a major turnover pathway
      in mammalian cells.

PMID- 10347172
TI  - Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled
      receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling.
AB  - Frizzled related proteins (FRPs) comprise a family of secreted molecules that
      contain an N-terminal cysteine-rich domain (CRD) highly similar to the CRDs of
      the frizzled family of membrane-anchored Wnt receptors. FRPs have been shown to
      interact with Wnt proteins and antagonize Wnt signaling in a Xenopus
      developmental model. We demonstrated that FRP antagonizes the Wnt-induced
      increase in uncomplexed beta-catenin in both transient cotransfection and stable
      transformation models, where Wnt-induced morphological alterations are inhibited
      as well. We showed further that FRP inhibits Wnt signaling in a paracrine mode
      using a T-cell factor luciferase reporter to measure Wnt function. Investigation
      of the mechanisms responsible for FRP inhibition revealed that FRP forms
      complexes with WNT-1 or WNT-2 through its CRD domain. Transfection analysis with
      FRPs containing different tags revealed that FRP itself forms complexes and that
      this ability is conferred by its CRD domain. Finally, we demonstrated by
      cotransfection that FRP forms complexes with a prototype frizzled. All of these
      findings are consistent with a model by which FRP inhibits Wnt signaling through
      interactions with Wnt and/or formation of nonfunctional complexes with the
      frizzled receptor.

PMID- 10347173
TI  - Titrating the effects of mitochondrial complex I impairment in the cell
      physiology.
AB  - The mitochondrial oxidative phosphorylation system consists of five multimeric
      enzymes (complexes I-V). NADH dehydrogenase or complex I (CI) is affected in most
      of the mitochondrial diseases and in some neurodegenerative disorders. We have
      studied the physiological consequences of a partial CI inhibition at the cellular
      level. We used a genetic model (40% CI-inhibited human-ape xenomitochondrial
      cybrids) and a drug-induced model (0-100% CI-inhibited cells using different
      concentrations of rotenone). We observed a quantitative correlation between the
      level of CI impairment and cell respiration, cell growth, free radical
      production, lipid peroxidation, mitochondrial membrane potential, and apoptosis.
      We showed that cell death was quantitatively associated with free radical
      production rather than with a decrease in respiratory chain function. The results
      obtained with human xenomitochondrial cybrid cells were compatible with those
      observed in rotenone-induced 40% CI-inhibited cells. At high concentrations (5-6
      fold higher than the concentration necessary for 100% CI inhibition), rotenone
      showed a second toxic effect at the level of microtubule assembly, which also led
      to apoptosis. The correlation found among all the parameters studied helped
      clarify the physiological consequences of partial CI inhibitions at the cellular
      level.

PMID- 10347174
TI  - Differential regulation of direct repeat 3 vitamin D3 and direct repeat 4 thyroid
      hormone signaling pathways by the human TR4 orphan receptor.
AB  - In situ hybridization analysis demonstrated that abundant testicular orphan
      receptor (TR4) transcripts were detected in kidney, intestine, and bone, which
      are vitamin D3 target organs. Cell transfection studies also demonstrated that
      the expression of the vitamin D3 target gene, 25-hydroxyvitamin D3 24
      hydroxylase, can be repressed by TR4 through high affinity binding (Kd = 1.32 nM)
      to the direct repeat 3 vitamin D3 receptor response element (DR3VDRE). This TR4
      mediated repression of DR3VDRE is in contrast to our earlier report that TR4
      could induce thyroid hormone target genes containing a direct repeat 4 thyroid
      hormone response element (DR4T3RE). Electrophoretic mobility shift assay using
      several TR4 monoclonal antibodies when combined with either TR4-DR3VDRE or TR4
      DR4T3RE showed a distinct supershifted pattern, and proteolytic analysis further
      demonstrated distinct digested peptides with either TR4-DR3VDRE or TR4-DR4T3RE.
      These results may therefore suggest that TR4 can adapt to different conformations
      once bound to DR3VDRE or DR4T3RE. The consequence of these different
      conformations of TR4-DR3VDRE and TR4-DR4T3RE may allow each of them to recruit
      different coregulators. The differential repression of TR4-mediated DR3VDRE and
      DR4T3RE transactivation by the receptor interacting protein 140, a TR4
      coregulator, further strengthens our hypothesis that the specificity of gene
      regulation by TR4 can be modulated by protein-DNA and protein-protein
      interactions.

PMID- 10347176
TI  - The energy transduction mechanism of Na,K-ATPase studied with iron-catalyzed
      oxidative cleavage.
AB  - This paper extends our recent report on specific iron-catalyzed oxidative
      cleavages of renal Na,K-ATPase and effects of E1 left arrow over right arrow E2
      conformational transitions (Goldshleger, R. , and Karlish, S. J. D. (1997) Proc.
      Natl. Acad. Sci. U. S. A. 94, 9596-9601). The experiments indicate that only
      peptide bonds close to a bound Fe2+ ion are cleaved, and provide evidence on
      proximity of the different cleavage positions in the native enzyme. A sequence
      HFIH near trans-membrane segment M3 appears to be involved in Fe2+ binding.
      Previously we hypothesized that E2 and E1 conformations are characterized by
      formation or relaxation of interactions within the alpha subunit at or near
      highly conserved sequences, TGES in the minor cytoplasmic loop and CSDK, MVTGD,
      and VNDSPALKK in the major cytoplasmic loop. This concept has been tested by
      examining iron-catalyzed cleavage in both non-phosphorylated and phosphorylated
      conformations and effects of phosphate, vanadate, and ouabain. The results imply
      that both E1 left arrow over right arrow E2 and E1P left arrow over right arrow
      E2P transitions are indeed associated with formation and relaxation of
      interactions between cytoplasmic domains, comprising the minor loop plus N
      terminal tail leading into M1 and major loop, respectively. Furthermore, it
      appears that either non-covalently or covalently bound phosphate bind near CSDK
      and MVTGD, and Mg2+ ions may bind to residues within TGES and VNDSPALKK and to
      bound phosphate. Thus cytoplasmic domain interactions seem to occur within or
      near the active site. We discuss the relationship between structural changes in
      the cytoplasmic domain and movements of trans-membrane segments that lead to
      cation transport. Presumably conformation-dependent formation and relaxation of
      domain interactions underlie energy transduction in all P-type pumps.

PMID- 10347175
TI  - SLP-76 and Vav function in separate, but overlapping pathways to augment
      interleukin-2 promoter activity.
AB  - SLP-76 and Vav, two hematopoietic cell specific molecules, are critical for T
      cell development and activation. Following T cell antigen receptor stimulation,
      SLP-76 and Vav both undergo tyrosine phosphorylation and associate with each
      other via the SH2 domain of Vav and phosphorylated tyrosines of SLP-76.
      Furthermore, SLP-76 and Vav have a synergistic effect on interleukin (IL)-2
      promoter activity in T cells. In this report, we show that two tyrosines, Tyr-113
      and Tyr-128, of SLP-76 are required for its binding to Vav, both in vitro and in
      intact cells. Surprisingly, we find also that the interaction between SLP-76 and
      Vav is not required for their cooperation in augmenting IL-2 promoter activity,
      as the two molecules appear to function in different signaling pathways upstream
      of IL-2 gene expression. Overexpression of SLP-76 in the Jurkat T cell line
      potentiates the activities of both nuclear factor of activated T cells and AP-1
      transcription factors. In contrast, overexpression of Vav leads to enhanced
      nuclear factor of activated T cells activity without affecting AP-1.
      Additionally, overexpression of Vav, but not SLP-76, augments CD28-induced IL-2
      promoter activity. These findings suggest that the synergy between SLP-76 and Vav
      in regulating IL-2 gene expression reflects the cooperation between different
      signaling pathways.

PMID- 10347178
TI  - Naturally occurring CCR5 extracellular and transmembrane domain variants affect
      HIV-1 Co-receptor and ligand binding function.
AB  - Analysis of CCR5 variants in human immunodeficiency virus, type 1 (HIV-1), high
      risk cohorts led to the identification of multiple single amino acid
      substitutions in the amino-terminal third of the HIV-1 co-receptor CCR5
      suggesting the possibility of protective and permissive genotypes; unfortunately,
      the low frequency of these mutations did not led to correlation with function.
      Therefore, we used analytical methods to assess the functional and structural
      significance of six of these variant receptors in vitro. These studies showed
      three categories of effects on CCR5 function. 1) Mutations in the first
      extracellular domain of CCR5 severely reduce specific ligand binding and
      chemokine-induced chemotaxis. 2) An extracellular domain variant, A29S, when co
      expressed with CD4, supported HIV-1 infection whereas the others do not. 3) The
      transmembrane region variants of CCR5 support monotropic HIV-1 infection that is
      blocked by addition of some receptor agonists. Mutations in the first and second
      transmembrane domains increase RANTES (regulated on activation normal T-cell
      expressed) binding affinity but did not affect MIP1beta binding affinity
      presumably based on differences in ligand-receptor interaction sites.
      Furthermore, the CCR5 transmembrane mutants do not respond to RANTES with the
      classical bell-shaped chemotactic response curve, suggesting that they are
      resistant to RANTES-induced desensitization. These data demonstrate that single
      amino acid changes in the extracellular domains of CCR5 can have profound effects
      on both HIV-1 co-receptor and specific ligand-induced functions, whereas
      mutations in the transmembrane domain only affect the response to chemokine
      ligands.

PMID- 10347177
TI  - Inhibition of glucocorticoid receptor nucleocytoplasmic shuttling by okadaic acid
      requires intact cytoskeleton.
AB  - It has been shown previously that glucocorticoid receptors (GRs) that have
      undergone hormone-dependent translocation to the nucleus and have subsequently
      exited the nucleus upon hormone withdrawal are unable to recycle into the nucleus
      if cells are treated during hormone withdrawal with okadaic acid, a cell
      permeable inhibitor of certain serine/threonine protein phosphatases. Using a
      green fluorescent protein (GFP) GR chimera (GFP-GR), we report here that okadaic
      acid inhibition of steroid-dependent receptor recycling to the nucleus is
      abrogated in cells treated for 1 h with colcemid to eliminate microtubule
      networks prior to steroid addition. After withdrawal of colcemid, normal
      cytoskeletal architecture is restored and okadaic acid inhibition of steroid
      dependent GFP-GR nuclear recycling is restored. When okadaic acid is present
      during hormone withdrawal, GR that is recycled to the cytoplasm becomes complexed
      with hsp90 and binds steroid, but it does not undergo the normal agonist
      dependent dissociation from hsp90 upon retreatment with steroid. However, when
      the cytoskeleton is disrupted by colcemid, the GR in okadaic acid-treated cells
      recycles from the cytoplasm to the nucleus in an agonist-dependent manner without
      dissociating from hsp90. This suggests that under physiological conditions where
      the cytoskeleton is intact, a dephosphorylation event is required for loss of
      high affinity binding to hsp90 that is required for receptor translocation
      through the cytoplasm to the nucleus along cytoskeletal tracts.

PMID- 10347179
TI  - Nitrogen dioxide induces cis-trans-isomerization of arachidonic acid within
      cellular phospholipids. Detection of trans-arachidonic acids in vivo.
AB  - Oxygen free radicals oxidize arachidonic acid to a complex mixture of metabolites
      termed isoeicosanoids that share structural similarity to enzymatically derived
      eicosanoids. However, little is known about oxidations of arachidonic acid
      mediated by reactive radical nitrogen oxides. We have studied the reaction of
      arachidonic acid with NO2, a free radical generated by nitric oxide and nitrite
      oxidations. A major group of products appeared to be a mixture of arachidonic
      acid isomers having one trans-bond and three cis-double bonds. We have termed
      these new products trans-arachidonic acids. These isomers were
      chromatographically distinct from arachidonic acid and produced mass spectra that
      were nearly identical with mass spectra of arachidonic acid. The lack of
      ultraviolet absorbance above 205 nm and the similarity of mass spectra of
      dimethyloxazoline derivatives suggested that the trans-bond was not conjugated
      with any of the cis-bonds, and the C=C bonds were located at carbons 5, 8, 11,
      and 14. Further identification was based on comparison of chromatographic
      properties with synthetic standards and revealed that NO2 generated 14-trans
      eicosatetraenoic acid and a mixture containing 11-trans-, 8-trans-, and 5-trans
      eicosatetraenoic acids. Exposure of human platelets to submicromolar levels of
      NO2 resulted in a dose-dependent formation of 14-trans-eicosatetraenoic acid and
      other isomers within platelet glycerophospholipids. Using a sensitive isotopic
      dilution assay we detected trans-arachidonic acids in human plasma (50.3 +/- 10
      ng/ml) and urine (122 +/- 50 pg/ml). We proposed a mechanism of arachidonic acid
      isomerization that involves a reversible attachment of NO2 to a double bond with
      formation of a nitroarachidonyl radical. Thus, free radical processes mediated by
      NO2 lead to generation of trans-arachidonic acid isomers, including biologically
      active 14-trans-eicosatetraenoic acid, within membrane phospholipids from which
      they can be released and excreted into urine.

PMID- 10347180
TI  - Physical and functional interactions of neuronal growth suppressor necdin with
      p53.
AB  - Necdin is expressed in virtually all postmitotic neurons, and ectopic expression
      of this protein suppresses cell proliferation. Necdin, like the retinoblastoma
      protein, interacts with cell cycle promoting proteins such as simian virus 40
      large T antigen, adenovirus E1A, and the transcription factor E2F1. Here we
      demonstrate that necdin interacts with the tumor suppressor protein p53 as well.
      The yeast two-hybrid and in vitro binding analyses revealed that necdin bound to
      a narrow region (amino acids 35-62) located between the MDM2-binding site and the
      proline-rich region in the amino-terminal domain of p53. The electrophoretic
      mobility shift assay showed that necdin supershifted a complex between p53 and
      its binding DNA, implying that the p53-necdin complex is competent for DNA
      binding. In p53-deficient osteosarcoma SAOS-2 cells, necdin markedly suppressed
      p53-dependent activation of the p21/WAF promoter. Necdin and p53 inhibited cell
      growth in an additive manner as assessed by the colony formation of SAOS-2 cells,
      suggesting that necdin does not affect p53-mediated growth suppression. On the
      other hand, necdin inhibited p53-induced apoptosis of osteosarcoma U2OS cells.
      Thus, necdin can be a growth suppressor that targets p53 and modulates its
      biological functions in postmitotic neurons.

PMID- 10347181
TI  - Protease trafficking in two primitive eukaryotes is mediated by a prodomain
      protein motif.
AB  - Trypanosome protozoa, an early lineage of eukaryotic cells, have proteases
      homologous to mammalian lysosomal cathepsins, but the precursor proteins lack
      mannose 6-phosphate. Utilizing green fluorescent protein as a reporter, we
      demonstrate that the carbohydrate-free prodomain of a trypanosome cathepsin L is
      necessary and sufficient for directing green fluorescent protein to the
      lysosome/endosome compartment. A proper prodomain/catalytic domain processing
      site sequence is also required to free the mature protease for delivery to the
      lysosome/endosome compartment. A nine-amino acid prodomain loop motif, implicated
      in prodomain-receptor interactions in mammalian cells, is conserved in the
      protozoa. Site-directed mutagenesis now confirms the importance of this loop to
      protease trafficking and suggests that a protein motif targeting signal for
      lysosomal proteases arose early in eukaryotic cell evolution.

PMID- 10347182
TI  - Substance P-induced trafficking of beta-arrestins. The role of beta-arrestins in
      endocytosis of the neurokinin-1 receptor.
AB  - Agonist-induced redistribution of G-protein-coupled receptors (GPCRs) and beta
      arrestins determines the subsequent cellular responsiveness to agonists and is
      important for signal transduction. We examined substance P (SP)-induced
      trafficking of beta-arrestin1 and the neurokinin-1 receptor (NK1R) in KNRK cells
      in real time using green fluorescent protein. Green fluorescent protein did not
      alter function or localization of the NK1R or beta-arrestin1. SP induced (a)
      striking and rapid (<1 min) translocation of beta-arrestin1 from the cytosol to
      the plasma membrane, which preceded NK1R endocytosis; (b) redistribution of the
      NK1R and beta-arrestin1 into the same endosomes containing SP and the transferrin
      receptor (2-10 min); (c) prolonged colocalization of the NK1R and beta-arrestin1
      in endosomes (>60 min); (d) gradual resumption of the steady state distribution
      of the NK1R at the plasma membrane and beta-arrestin1 in the cytosol (4-6 h). SP
      stimulated a similar redistribution of immunoreactive beta-arrestin1 and beta
      arrestin2. In contrast, SP did not affect Galphaq/11 distribution, which remained
      at the plasma membrane. Expression of the dominant negative beta-arrestin319-418
      inhibited SP-induced endocytosis of the NK1R. Thus, SP induces rapid
      translocation of beta-arrestins to the plasma membrane, where they participate in
      NK1R endocytosis. beta-Arrestins colocalize with the NK1R in endosomes until the
      NK1R recycles and beta-arrestins return to the cytosol.

PMID- 10347183
TI  - Topological and functional analysis of the human reduced folate carrier by
      hemagglutinin epitope insertion.
AB  - The membrane topology of the human reduced folate carrier protein (591 amino
      acids) was assessed by single insertions of the hemagglutinin epitope into nine
      sites of the protein. Reduced folate carrier-deficient Chinese hamster ovary
      cells expressing each of these constructs were probed with anti-hemagglutinin
      epitope monoclonal antibodies to assess whether the insertion was exposed to the
      external environment or to the cytoplasm. The results are consistent with the 12
      transmembrane topology predicted for this protein. The hemagglutinin epitope
      insertion mutants were also tested for their effects on the function of the
      reduced folate carrier. For these studies, each of the constructs had a carboxyl
      terminal fusion of the enhanced green fluorescent protein to monitor and
      quantitate expression. Insertions into the external loop between transmembrane
      regions 7 and 8 (Pro-297), the cytoplasmic loop between transmembrane regions 6
      and 7 (Ser-225), and near the cytoplasmic amino and carboxyl termini (Pro-20 and
      Gly-492, respectively) had minor effects on methotrexate binding and uptake. The
      insertion into the cytoplasmic loop between transmembrane regions 10 and 11 (Gln
      385) greatly reduced both binding and uptake of methotrexate, whereas the
      insertion into the external loop between transmembrane regions 11 and 12 (Pro
      427) selectively interfered with uptake but not binding.

PMID- 10347184
TI  - Putative reaction intermediates in Crm1-mediated nuclear protein export.
AB  - We discovered several novel interactions between proteins involved in Crm1
      mediated nuclear export of the nuclear export signal containing human
      immunodeficiency virus type 1 protein Rev. First, a Rev/Crm1/RanGTP complex
      (where Ran is Ras-related nuclear protein) reacts with some nucleoporins (Nup42
      and Nup159) but not others (NSP1, Nup116, and Nup1), forming a Nup/Crm1/RanGTP
      complex and concomitantly releasing Rev. Second, RanBP1 (or homologous proteins)
      can displace Nup and form a ternary RanBP1/RanGTP/Crm1 complex that can be
      disassembled by RanGAP via GTP hydrolysis. Third, and most surprisingly,
      RanBP1/RanGTP/Crm1 can be disassembled without GTP hydrolysis by the nucleotide
      exchange factor RanGEF. Recycling of a Ran/RanGEF complex by GTP and Mg2+ is
      stimulated by both Crm1 and Rev, allowing reformation of a Rev/Crm1/RanGTP
      complex. Based on these reactions we propose a model for Crm1-mediated export.

PMID- 10347185
TI  - beta-arrestins regulate interleukin-8-induced CXCR1 internalization.
AB  - The functional role of neutrophils during acute inflammatory responses is
      regulated by two high affinity interleukin-8 receptors (CXCR1 and CXCR2) that are
      rapidly desensitized and internalized upon binding their cognate chemokine
      ligands. The efficient re-expression of CXCR1 on the surface of neutrophils
      following agonist-induced internalization suggests that CXCR1 surface receptor
      turnover may involve regulatory pathways and intracellular factors similar to
      those regulating beta2-adrenergic receptor internalization and re-expression. To
      examine the internalization pathway utilized by ligand-activated CXCR1, a CXCR1
      GFP construct was transiently expressed in two different cell lines, HEK 293 and
      RBL-2H3 cells. While interleukin-8 stimulation promoted CXCR1 sequestration in
      RBL-2H3 cells, receptor internalization in HEK 293 cells required co-expression
      of G protein-coupled receptor kinase 2 and beta-arrestin proteins. The importance
      of beta-arrestins in CXCR1 internalization was confirmed by the ability of a
      dominant negative beta-arrestin 1-V53D mutant to block internalization of CXCR1
      in RBL-2H3 cells. A role for dynamin was also demonstrated by the lack of CXCR1
      internalization in dynamin I-K44A dominant negative mutant-transfected RBL-2H3
      cells. Agonist-promoted co-localization of transferrin and CXCR1-GFP in endosomes
      of RBL-2H3 cells confirmed that receptor internalization occurs via clathrin
      coated vesicles. Our data provides a direct link between agonist-induced
      internalization of CXCR1 and a requirement for G protein-coupled receptor kinase
      2, beta-arrestins, and dynamin during this process.

PMID- 10347186
TI  - The carbamoyl-phosphate synthetase of Pyrococcus furiosus is enzymologically and
      structurally a carbamate kinase.
AB  - The hyperthermophiles Pyrococcus furiosus and Pyrococcus abyssi make pyrimidines
      and arginine from carbamoyl phosphate (CP) synthesized by an enzyme that differs
      from other carbamoyl-phosphate synthetases and that resembles carbamate kinase
      (CK) in polypeptide mass, amino acid sequence, and oligomeric organization. This
      enzyme was reported to use ammonia, bicarbonate, and two ATP molecules as
      carbamoyl-phosphate synthetases to make CP and to exhibit bicarbonatedependent
      ATPase activity. We have reexamined these findings using the enzyme of P.
      furiosus expressed in Escherichia coli from the corresponding gene cloned in a
      plasmid. We show that the enzyme uses chemically made carbamate rather than
      ammonia and bicarbonate and catalyzes a reaction with the stoichiometry and
      equilibrium that are typical for CK. Furthermore, the enzyme catalyzes actively
      full reversion of the CK reaction and exhibits little bicarbonate-dependent
      ATPase. In addition, it cross-reacts with antibodies raised against CK from
      Enterococcus faecium, and its three-dimensional structure, judged by x-ray
      crystallography of enzyme crystals, is very similar to that of CK. Thus, the
      enzyme is, in all respects other than its function in vivo, a CK. Because in
      other organisms the function of CK is to make ATP from ADP and CP derived from
      arginine catabolism, this is the first example of using CK for making rather than
      using CP. The reasons for this use and the adaptation of the enzyme to this new
      function are discussed.

PMID- 10347187
TI  - Activity of the human centrosomal kinase, Nek2, depends on an unusual leucine
      zipper dimerization motif.
AB  - Nek2 is a human cell cycle-regulated kinase that is structurally related to the
      mitotic regulator, NIMA, of Aspergillus nidulans. Localization studies have shown
      that Nek2 is a core component of the centrosome, the microtubule organizing
      center of the cell, and functional approaches suggest a possible role for Nek2 in
      centrosome separation at the G2/M transition. Here, we have investigated the
      importance of an unusual leucine zipper coiled-coil motif present in the C
      terminal noncatalytic domain of the Nek2 kinase. Glycerol gradient centrifugation
      indicated that endogenous Nek2 is present in HeLa cells as a salt-resistant 6 S
      complex, the predicted size of a Nek2 homodimer. Recombinant Nek2 overexpressed
      in insect cells also formed a 6 S complex, whereas a Nek2 mutant specifically
      lacking the leucine zipper motif was monomeric. Using yeast two-hybrid
      interaction analyses and coprecipitation assays, we found that Nek2 can indeed
      form homodimers both in vivo and in vitro and that this dimerization specifically
      required the leucine zipper motif. Moreover, deletion of the leucine zipper
      prevented a trans-autophosphorylation reaction on the C-terminal domain of Nek2
      and strongly reduced Nek2 kinase activity on exogenous substrates. Finally, we
      emphasize that the Nek2 leucine zipper described here differs from classical
      leucine zippers in that it exhibits a radically different arrangement of
      hydrophobic and charged amino acids. Thus, this study reveals not only an
      important mechanism for the regulation of the Nek2 kinase but, furthermore,
      highlights an unusual organization of a leucine zipper dimerization motif.

PMID- 10347188
TI  - Molecular cloning and characterization of a mouse homolog of bacterial ClpX, a
      novel mammalian class II member of the Hsp100/Clp chaperone family.
AB  - In this paper, we present the molecular cloning and characterization of a murine
      homolog of the Escherichia coli chaperone ClpX. Murine ClpX shares 38% amino acid
      sequence identity with the E. coli homolog and is a novel member of the
      Hsp100/Clp family of molecular chaperones. ClpX localizes to human chromosome
      15q22.2-22.3 and in mouse is expressed tissue-specifically as one transcript of
      approximately 2.9 kilobases (kb) predominantly within the liver and as two
      isoforms of approximately 2.6 and approximately 2.9 kb within the testes.
      Purified recombinant ClpX displays intrinsic ATPase activity, with a Km of
      approximately 25 microM and a Vmax of approximately 660 pmol min-1 microgram-1,
      which is active over a broad range of pH, temperature, ethanol, and salt
      parameters. Substitution of lysine 300 with alanine in the ATPase domain P-loop
      abolishes both ATP hydrolysis and binding. Recombinant ClpX can also interact
      with its putative partner protease subunit ClpP in overexpression experiments in
      293T cells. Subcellular studies by confocal laser scanning microscopy localized
      murine ClpX green fluorescent protein fusions to the mitochondria. Deletion of
      the N-terminal mitochondrial targeting sequence abolished mitochondrial
      compartmentalization. Our results thus suggest that murine ClpX acts as a tissue
      specific mammalian mitochondrial chaperone that may play a role in mitochondrial
      protein homeostasis.

PMID- 10347189
TI  - Phe310 in transmembrane VI of the alpha1B-adrenergic receptor is a key switch
      residue involved in activation and catecholamine ring aromatic bonding.
AB  - Pharmacophore mapping of adrenergic receptors indicates that the phenyl ring of
      catecholamine agonists is involved in receptor binding and activation. Here we
      evaluated Phe310, Phe311, and Phe303 in transmembrane VI (TMVI), as well as
      Tyr348 in TMVII of the alpha1B-adrenergic receptor (alpha1B-AR), which have been
      implicated in a catechol-ring interaction. Neither catecholamine docking studies
      nor mutagenesis studies of Phe311, Phe303, or Tyr348 supported a role for these
      residues in catechol-ring binding. By contrast, docking studies indicated that
      the Phe310 side chain is well positioned to interact with the catechol-ring, and
      substituted cysteine accessibility method studies revealed that the side chain of
      the 310, but not 311 residue, is both solvent accessible and directed into the
      agonist-binding pocket. Also, saturation mutagenesis of both Phe310 and Phe311
      revealed for the former, but not for the latter, a direct relationship between
      side chain volume and agonist affinity, and that aromaticity is essential for
      wild-type agonist binding, and for both wild-type agonist potency and efficacy.
      Moreover, studies of Phe310 mutants combined with a previously described
      constitutively active alpha1B-AR mutant, A293E, indicated that although not
      required for spontaneous receptor isomerization from the basal state, R, to a
      partially activated conformation R', interaction of Phe310 with catecholamine
      agonists is essential for isomerization from R' to the fully activated state, R.

PMID- 10347190
TI  - Role for the third intracellular loop in cell surface stabilization of the
      alpha2A-adrenergic receptor.
AB  - Previous studies have shown that alpha2A-adrenergic receptor (alpha2A-AR)
      retention at the basolateral surface of polarized MDCKII cells involves its third
      intracellular (3i loop). The present studies examining mutant alpha2A-ARs
      possessing short deletions of the 3i loop indicate that no single region can
      completely account for the accelerated surface turnover of the Delta3ialpha2A-AR,
      suggesting that the entire 3i loop is involved in basolateral retention. Both
      wild-type and Delta3i loop alpha2A-ARs are extracted from polarized Madin-Darby
      canine kidney (MDCK) cells with 0.2% Triton X-100 and with a similar
      concentration/response profile, suggesting that Triton X-100-resistant
      interactions of the alpha2A-AR with cytoskeletal proteins are not involved in
      receptor retention on the basolateral surface. The indistinguishable basolateral
      t(1)/(2) for either the wild-type or nonsense 3i loop alpha2A-AR suggests that
      the stabilizing properties of the alpha2A-AR 3i loop are not uniquely dependent
      on a specific sequence of amino acids. The accelerated turnover of Delta3i
      alpha2A-AR cannot be attributed to alteration in agonist-elicited alpha2A-AR
      redistribution, because alpha2A-ARs are not down-regulated in response to
      agonist. Taken together, the present studies show that stabilization of the
      alpha2A-AR on the basolateral surface of MDCKII cells involves multiple
      mechanisms, with the third intracellular loop playing a central role in
      regulating these processes.

PMID- 10347191
TI  - The solution structure of FADD death domain. Structural basis of death domain
      interactions of Fas and FADD.
AB  - A signal of Fas-mediated apoptosis is transferred through an adaptor protein Fas
      associated death domain protein (FADD) by interactions between the death domains
      of Fas and FADD. To understand the signal transduction mechanism of Fas-mediated
      apoptosis, we solved the solution structure of a murine FADD death domain. It
      consists of six helices arranged in a similar fold to the other death domains.
      The interactions between the death domains of Fas and FADD analyzed by site
      directed mutagenesis indicate that charged residues in helices alpha2 and alpha3
      are involved in death domain interactions, and the interacting helices appear to
      interact in anti-parallel pattern, alpha2 of FADD with alpha3 of Fas and vice
      versa.

PMID- 10347192
TI  - Autophosphorylation, phosphotransfer, and DNA-binding properties of the RegB/RegA
      two-component regulatory system in Rhodobacter capsulatus.
AB  - In the purple, photosynthetic bacterium, Rhodobacter capsulatus, the RegB/RegA
      two-component system is required for activation of several anaerobic processes,
      such as synthesis of the photosynthetic apparatus and assimilation of CO2 and N2.
      It is believed that RegB is an integral membrane histidine kinase that monitors
      the external environment. Under anaerobic growth conditions, it transduces a
      signal through phosphorylation of the response regulator, RegA, which then
      induces target gene expression. We used an in vitro assay to characterize the
      phosphorylation of wild-type RegA and a mutant variant (RegA*) that is
      responsible for abnormally high photosynthesis gene expression under both aerobic
      and anaerobic growth conditions. Phosphorylation assays indicate that
      phosphorylated RegA* (RegA* approximately P) is much more stable than RegA
      approximately P, indicating that it may be locked in a conformation that is
      resistant to dephosphorylation. DNase I footprint assays also indicate that
      unphosphorylated RegA* has a much higher affinity for specific DNA binding sites
      than the wild-type protein. Phosphorylation of RegA* increases DNA binding 2. 5
      fold, whereas phosphorylation of RegA increases DNA binding more than 16-fold.
      Collectively, these results support the hypothesis that RegA* is a constitutively
      active variant that does not require phosphorylation to assume a structural
      conformation required to bind DNA.

PMID- 10347194
TI  - Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride
      cotransporter gene family.
AB  - The K+-Cl- cotransporters (KCCs) belong to the gene family of electroneutral
      cation-chloride cotransporters, which also includes two bumetanide-sensitive Na+
      K+-2Cl- cotransporters and a thiazide-sensitive Na+-Cl- cotransporter. We have
      cloned cDNAs encoding mouse KCC3, human KCC3, and human KCC4, three new members
      of this gene family. The KCC3 and KCC4 cDNAs predict proteins of 1083 and 1150
      amino acids, respectively. The KCC3 and KCC4 proteins are 65-71% identical to the
      previously characterized transporters KCC1 and KCC2, with which they share a
      predicted membrane topology. The four KCC proteins differ at amino acid residues
      within key transmembrane domains and in the distribution of putative
      phosphorylation sites within the amino- and carboxyl-terminal cytoplasmic
      domains. The expression of mouse KCC3 in Xenopus laevis oocytes reveals the
      expected functional characteristics of a K+Cl- cotransporter: Cl--dependent
      uptake of 86Rb+ which is strongly activated by cell swelling and weakly sensitive
      to furosemide. A direct functional comparison of mouse KCC3 to rabbit KCC1
      indicates that KCC3 has a much greater volume sensitivity. The human KCC3 and
      KCC4 genes are located on chromosomes 5p15 and 15q14, respectively. Although
      widely expressed, KCC3 transcripts are the most abundant in heart and kidney, and
      KCC4 is expressed in muscle, brain, lung, heart, and kidney. The unexpected
      molecular heterogeneity of K+-Cl- cotransport has implications for the physiology
      and pathophysiology of a number of tissues.

PMID- 10347193
TI  - Akt mediates cytoprotection of endothelial cells by vascular endothelial growth
      factor in an anchorage-dependent manner.
AB  - Regulation of endothelial cell apoptosis is a critical modulator of normal and
      pathological angiogenesis. In this study, we examined the role of the protein
      kinase Akt/PKB in endothelial cell survival in response to growth factor and
      matrix attachment signals. Vascular endothelial growth factor(VEGF)-induced
      cytoprotection of endothelial cell monolayers correlated with the wortmannin
      sensitive induction of Akt activity. Transfection of an adenovirus expressing a
      dominant-negative Akt mutant decreased endothelial cell viability in the presence
      of VEGF. Conversely, adenoviral transduction of wild-type Akt facilitated the
      cell survival effects of VEGF, whereas transduction of constitutively active Akt
      conferred endothelial cell survival in the absence of VEGF. Constitutively active
      Akt also conferred survival to endothelial cells in suspension culture, whereas
      stimulation with VEGF did not. In suspension cultures, VEGF stimulation was
      unable to activate Akt, and Akt protein levels were repressed in cells undergoing
      anoikis. These data suggest that cross-talk between growth factor- and anchorage
      dependent signaling pathways are essential for Akt activation and endothelial
      cell survival.

PMID- 10347195
TI  - Structure/function of the beta-barrel domain of F1-ATPase in the yeast
      Saccharomyces cerevisiae.
AB  - The first 90 amino acids of the alpha- and beta-subunits of mitochondrial F1
      ATPase are folded into beta-barrel domains and were postulated to be important
      for stabilizing the enzyme (Abrahams, J. P., Leslie, A. G., Lutter, R., and
      Walker, J. E. (1994) Nature 370, 621-628). The role of the domains was studied by
      making chimeric enzymes, replacing the domains from the yeast Saccharomyces
      cerevisiae enzyme with the corresponding domains from the enzyme of the
      thermophilic bacterium Bacillus PS3. The enzymes containing the chimeric alpha-,
      beta-, or alpha- and beta-subunits were not functional. However, gain-of-function
      mutations were obtained from the strain containing the enzyme with the chimeric
      PS3/yeast beta-subunit. The gain-of-function mutations were all in codons
      encoding the beta-barrel domain of the beta-subunit, and the residues appear to
      map out a region of subunit-subunit interactions. Gain-of-function mutations were
      also obtained that provided functional expression of the chimeric PS3/yeast alpha
      and beta-subunits together. Biochemical analysis of this active chimeric enzyme
      indicated that it was not significantly more thermostable or labile than the wild
      type. The results of this study indicate that the beta-barrel domains form
      critical contacts (distinct from those between the alpha- and beta-subunits) that
      are important for the assembly of the ATP synthase.

PMID- 10347196
TI  - Identification of a novel SNF2/SWI2 protein family member, SRCAP, which interacts
      with CREB-binding protein.
AB  - The ability of cAMP response-element binding protein (CREB)-binding protein (CBP)
      to function as a co-activator for a number of transcription factors appears to be
      mediated by its ability to act as a histone acetyltransferase and through its
      interaction with a number of other proteins (general transcription factors,
      histone acetyltransferases, and other co-activators). Here we report that CBP
      also interacts with a novel ATPase termed Snf2-Related CBP Activator Protein
      (SRCAP). Consistent with this activity, SRCAP contains the conserved ATPase
      domain found within members of the Snf2 family. Transfection experiments
      demonstrate that SRCAP is able to activate transcription when expressed as a Gal
      SRCAP chimera and that SRCAP also enhances the ability of CBP to activate
      transcription. The adenoviral protein E1A was found to disrupt interaction
      between SRCAP and CBP possibly representing a mechanism for E1A-mediated
      transcriptional repression.

PMID- 10347197
TI  - Activation mechanisms of the urokinase-type plasminogen activator promoter by
      hepatocyte growth factor/scatter factor.
AB  - Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effector
      inducing invasion and metastasis of tumor cells that express the Met tyrosine
      kinase receptor. One of the effectors of HGF/SF is the urokinase-type plasminogen
      activator, a serine protease that facilitates tumor progression and metastasis by
      controlling the synthesis of the extracellular matrix degrading plasmin.
      Stimulation of NIH 3T3 cells that were stably transfected with the human Met
      receptor (NIH 3T3-Methum) with HGF/SF induced a trans-activation of the urokinase
      promoter and urokinase secretion. Induction of the urokinase promoter by HGF/SF
      via the Met receptor was blocked by co-expression of a dominant-negative Grb2 and
      Sos1 expression construct. Further, the expression of the catalytically inactive
      mutants of Ha-Ras, RhoA, c-Raf, and Erk2 or addition of the Mek1-specific
      inhibitor PD 098059 abrogated the stimulation of the urokinase promoter by
      HGF/SF. A sequence residing between -2109 and -1870 base pairs (bp) was critical
      for stimulation of the urokinase gene by HGF/SF. Mobility shift assays with
      oligonucleotides spanning an AP-1 site at -1880 bp or a combined PEA3/AP-1 site
      at -1967 bp showed binding of nuclear factors from NIH 3T3-Methum cells.
      Expression of an expression plasmid that inhibits DNA binding of AP-1 proteins (A
      Fos) abrogated inducible and basal activation of the urokinase promoter. Nuclear
      extract from unstimulated NIH 3T3-Methum cells contained more JunD and showed a
      stronger JunD supershift with the AP-1 oligonucleotides, compared with HGF/SF
      stimulated cells. Consistent with the levels of JunD expression being
      functionally important for basal expression of the urokinase promoter, we found
      that overexpression of wild type JunD inhibited the induction of the urokinase
      promoter by HGF/SF. These data suggest that the induction of urokinase by HGF/SF
      is regulated by a Grb2/Sos1/Ha-Ras/c-Raf/RhoA/Mek1/Erk2/c-++ +Jun-dependent
      mitogen-activated protein kinase pathway.

PMID- 10347198
TI  - p75 neurotrophin receptor-mediated neuronal death is promoted by Bcl-2 and
      prevented by Bcl-xL.
AB  - The p75 neurotrophin receptor (p75NTR) has been shown to mediate neuronal death
      through an unknown pathway. We microinjected p75NTR expression plasmids into
      sensory neurons in the presence of growth factors and assessed the effect of the
      expressed proteins on cell survival. We show that, unlike other members of the
      TNFR family, p75NTR signals death through a unique caspase-dependent death
      pathway that does not involve the "death domain" and is differentially regulated
      by Bcl-2 family members: the anti-apoptotic molecule Bcl-2 both promoted, and was
      required for, p75NTR killing, whereas killing was inhibited by its homologue Bcl
      xL. These results demonstrate that Bcl-2, through distinct molecular mechanisms,
      either promotes or inhibits neuronal death depending on the nature of the death
      stimulus.

PMID- 10347199
TI  - Antagonistic action of novel 1alpha,25-dihydroxyvitamin D3-26, 23-lactone analogs
      on differentiation of human leukemia cells (HL-60) induced by 1alpha,25
      dihydroxyvitamin D3.
AB  - We examined the effects of two novel 1alpha,25-dihydroxyvitamin D3-26,23-lactone
      (1alpha,25-lactone) analogues on human promyelocytic leukemia cell (HL-60)
      differentiation using the evaluation system of the vitamin D nuclear receptor
      (VDR)/vitamin D-responsive element (DRE)-mediated genomic action stimulated by
      1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and its analogues. We found that
      the 1alpha,25-lactone analogues (23S)-25-dehydro-1alpha-hydroxyvitamin-D3-26,23
      lactone (TEI-9647), and (23R)-25-dehydro-1alpha-hydroxyvitamin-D3-26,23-lactone
      (TEI-9648) bound much more strongly to the VDR than the natural (23S, 25R)
      1alpha,25(OH)2D3-26,23-lactone, but did not induce cell differentiation even at
      high concentrations (10(-6) M). Intriguingly, the differentiation of HL-60 cells
      induced by 1alpha,25(OH)2D3 was inhibited by either TEI-9647 or TEI-9648 but not
      by the natural lactone. In contrast, retinoic acid or 12-O-tetradecanoylphorbol
      13-acetate-induced HL-60 cell differentiation was not blocked by TEI-9647 or TEI
      9648. In separate studies, TEI-9647 (10(-7) M) was found to be an effective
      antagonist of both 1alpha,25(OH)2D3 (10(-8) M) mediated induction of p21(WAF1,
      CIP1) in HL-60 cells and activation of the luciferase reporter assay in COS-7
      cells transfected with cDNA containing the DRE of the rat 25(OH)D3-24-hydroxylase
      gene and cDNA of the human VDR. Collectively the results strongly suggest that
      our novel 1alpha,25-lactone analogues, TEI-9647 and TEI-9648, are specific
      antagonists of 1alpha, 25(OH)2D3 action, specifically VDR/DRE-mediated genomic
      action. As such, they represent the first examples of antagonists, which act on
      the nuclear VDR.

PMID- 10347200
TI  - Functional significance of the conserved residues in the flexible hinge region of
      the myosin motor domain.
AB  - Analysis of the three-dimensional crystal structure of the Dictyostelium myosin
      motor domain revealed that the myosin head is required to bend at residues Ile
      455 and Gly-457 to produce the conformation changes observed in the ternary
      complexes that resemble the pre- and post-hydrolysis states (Fisher, A. J.,
      Smith, C. A., Thoden, J. B., Smith, R., Sutoh, K., Holden, H. M., and Rayment, I.
      (1995) Biochemistry 34, 8960-8972). Asp-454, Ile-455, and Gly-457 of smooth
      muscle myosin were substituted by Ala, Met, and Ala, respectively, and the
      mechano-enzymatic activities were determined to study the role of these residues
      in myosin motor function. Whereas the basal steady-state Mg2+-ATPase activity of
      D454A was higher than that of the wild type, the rate of the hydrolytic step is
      reduced approximately 2,000-fold and becomes rate-limiting. M-ATP rather than M
      ADP-P is the predominant steady-state intermediate, and the initial Pi burst and
      the ATP-induced enhancement of intrinsic tryptophan fluorescence are absent in
      D454A. D454A binds actin in the absence of ATP but is not dissociated from actin
      by ATP. Moreover, actin inhibits rather than activates the ATPase activity;
      consequently, D454A does not support actin translocating activity. I455M has
      normal actin-activated ATPase activity, Pi burst, and ATP-induced enhancement of
      intrinsic tryptophan fluorescence, suggesting that the enzymatic properties are
      normal. However, the actin translocating activity was completely inhibited. This
      suggests that the side chain at Ile-455 is critical for myosin motor activity but
      not for relatively normal enzymatic function, which indicates an apparent
      uncoupling between enzymatic activity and motile function. Although G457A has
      normal ATP-dependent actin dissociation, ATP hydrolytic step is reduced by
      approximately 10(5)-fold in the presence or absence of actin; consequently, G457A
      does not have actin translocating activity. These results indicate the importance
      of these conserved residues at the hinge region for normal myosin motor function.

PMID- 10347201
TI  - Oncogenic ras causes resistance to the growth inhibitor insulin-like growth
      factor binding protein-3 (IGFBP-3) in breast cancer cells.
AB  - Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits proliferation and
      promotes apoptosis in normal and malignant cells. In MCF-10A human mammary
      epithelial cells, 30 ng/ml human plasma-derived IGFBP-3 inhibited DNA synthesis
      to 70% of control. This inhibition appeared IGF-independent, since neither an IGF
      receptor antibody nor IGFBP-6 inhibited DNA synthesis. Malignant transformation
      of MCF-10A cells by transfection with Ha-ras oncogene abolished the inhibitory
      effect of IGFBP-3, concomitant with an increase in IGFBP-3 secretion and cell
      association of approximately 60 and 300%, respectively. When mitogen-activated
      protein (MAP) kinase activation was partially inhibited using PD 98059, IGFBP-3
      sensitivity in ras-transfected cells was restored, with a significant inhibitory
      effect at 10 ng/ml IGFBP-3. PD 98059 had no effect on IGFBP-3 secretion or cell
      association by ras-transfected or parent MCF-10A cells. Hs578T, a tumor-derived
      breast cancer cell line that expresses activated Ha-ras, similarly has a high
      level of secreted and cell-associated IGFBP-3. In the absence of PD 98059, DNA
      synthesis by Hs578T cells was reduced to 70% of control by 1000 ng/ml IGFBP-3. PD
      98059 increased sensitivity to IGFBP-3, so that this level of inhibition was
      achieved with 100 ng/ml IGFBP-3. These results suggest that MAP kinase activation
      by oncogenic ras expression causes IGFBP-3 resistance, a possible factor in the
      dysregulation of breast cancer cell growth.

PMID- 10347202
TI  - Two novel Kruppel-associated box-containing zinc-finger proteins, KRAZ1 and
      KRAZ2, repress transcription through functional interaction with the corepressor
      KAP-1 (TIF1beta/KRIP-1).
AB  - We have isolated two novel Kruppel-like zinc finger proteins containing the
      evolutionarily conserved Kruppel-associated box (KRAB), KRAZ1 and KRAZ2, and
      demonstrated that they repress transcription when heterologously targeted to DNA.
      Their repression activity appeared to be mediated by the putative corepressor KAP
      1 (KRAB-associated protein-1), because KRAZ1/2 bind to KAP-1, but KRAB mutants of
      KRAZ1/2 that are unable to interact with KAP-1 lack repression activity, and KAP
      1 has intrinsic repressor activity and potentiates KRAZ1/2-mediated repression.
      We dissected the KAP-1 protein into a KRAB-interacting domain and a region
      necessary for repression. Using a mammalian two-hybrid assay, we further
      demonstrated that KAP-1 deletions lacking repression activity fused to the VP16
      transactivation domain strongly activated transcription when coexpressed with
      KRAZ1. In contrast, VP16-KAP-1 fusions retaining repression activity resulted in
      repression. These results provide the first evidence that KAP-1 functionally
      interacts with KRAB in mammalian cells and seems to exert repressor activity in
      the DNA-bound KRAB-KAP-1 complex, and they further support the hypothesis that
      KAP-1 functions as a corepressor for the large class of KRAB-containing zinc
      finger proteins.

PMID- 10347203
TI  - Activated G protein-coupled receptor induces tyrosine phosphorylation of STAT3
      and agonist-selective serine phosphorylation via sustained stimulation of mitogen
      activated protein kinase. Resultant effects on cell proliferation.
AB  - The peptide hormone somatostatin exhibits antiproliferative activity by
      interacting with the G protein-coupled sst2 or sst5 receptor types. We show here
      that somatostatin at the human recombinant sst4 receptor induced a concentration
      dependent increase in proliferation (EC50 20 nM) with a maximal response 5-fold
      greater than that produced by its synthetic analog, L-362,855. Analysis of the
      phosphorylation status of extracellular signal-regulated kinase (ERK)1 and ERK2
      showed temporal differences in the changes evoked by the agonists.
      Phosphorylation induced by somatostatin (100 nM) peaked 10 min after the
      application and produced a response that continued for at least 4 h. In contrast,
      L-362,855 (1 microM) showed transient phosphorylation that had declined to basal
      levels by 1 h. However, both agonists induced rapid and sustained tyrosine
      phosphorylation of signal transducer and activator of transcription 3 (STAT3)
      which was pertussis toxin-insensitive. Serine phosphorylation of STAT3 was only
      apparent after somatostatin treatment and was abolished by pertussis toxin or PD
      98059, together with the associated increases in proliferation. Mitogen-activated
      protein/ERK kinase-1 inhibition also decreased the time interval over which
      somatostatin-induced ERK phosphorylation was observed (<2 h). We conclude that
      the difference in the magnitude of the proliferative response evoked by the two
      agonists at the sst4 receptor can be accounted for by their differential ability
      to phosphorylate STAT3 on serine residues and supports the concept that selective
      signaling can be achieved through pharmacological diversity.

PMID- 10347204
TI  - RNA polymerase-specific nucleosome disruption by transcription in vivo.
AB  - The nucleosomal chromatin structure within genes is disrupted upon transcription
      by RNA polymerase II. To determine whether this disruption is caused by
      transcription per se as opposed to the RNA polymerase source, we engineered the
      yeast chromosomal HSP82 gene to be exclusively transcribed by bacteriophage T7
      RNA polymerase in vivo. Interestingly, we found that a fraction of the T7
      generated transcripts were 3' end processed and polyadenylated at or near the 3'
      ends of the hsp82 and the immediately downstream CIN2 genes. Surprisingly, the
      nucleosomal structure of the T7-transcribed hsp82 gene remained intact, in marked
      contrast to the disrupted structure generated by much weaker, basal level
      transcription of the wild type gene by RNA polymerase II under non-heat shock
      conditions. Therefore, disruption of chromatin structure by transcription is
      dependent on the RNA polymerase source. We propose that the observed RNA
      polymerase dependence for transcription-induced nucleosome disruption may be
      related either to the differential recruitment of chromatin remodeling complexes,
      the rates of histone octamer translocation and nucleosome reformation during
      polymerase traversal, and/or the degree of transient torsional stress generated
      by the elongating polymerase.

PMID- 10347205
TI  - Analysis of functional domains of the host cell factor involved in VP16 complex
      formation.
AB  - We present biochemical analyses of the regions of the host cell factor (HCF)
      involved in VP16 complex formation and in the association between the N- and C
      terminal domains of HCF itself. We show that the kelch repeat region of HCF
      (residues 1-380) is sufficient for VP16 complex formation, but that residues C
      terminal to the repeats (positions 381-450) interfere with this activity.
      However, these latter residues are required for the interaction between the N-
      and C-terminal regions of HCF. The extreme C-terminal region of HCF,
      corresponding to an area of strong conservation with a Caenorhabditis elegans
      homologue, is sufficient for interaction with the N-terminal region. These
      results are discussed with respect to possible differences in the roles of HCF in
      VP16 activity versus its normal cellular function.

PMID- 10347206
TI  - Stimulation of cAMP synthesis by Gi-coupled receptors upon ablation of distinct
      Galphai protein expression. Gi subtype specificity of the 5-HT1A receptor.
AB  - The three Galphai subunits were independently depleted from rat pituitary GH4C1
      cells by stable transfection of each Galphai antisense rat cDNA construct.
      Depletion of any Galphai subunit eliminated receptor-induced inhibition of basal
      cAMP production, indicating that all Galphai subunits are required for this
      response. By contrast, receptor-mediated inhibition of vasoactive intestinal
      peptide (VIP)-stimulated cAMP production was blocked by selective depletions for
      responses induced by the transfected serotonin 1A (5-HT1A) (Galphai2 or Galphai3)
      or endogenous muscarinic-M4 (Galphai1 or Galphai2) receptors. Strikingly,
      receptor activation in Galphai1-depleted clones (for the 5-HT1A receptor) or
      Galphai3-depleted clones (for the muscarinic receptor) induced a pertussis toxin
      sensitive increase in basal cAMP production, whereas the inhibitory action on VIP
      stimulated cAMP synthesis remained. Finally, in Galphai2-depleted clones,
      activation of 5-HT1A receptors increased VIP-stimulated cAMP synthesis. Thus, 5
      HT1A and muscarinic M4 receptor may couple dominantly to Galphai1 and Galphai3,
      respectively, to inhibit cAMP production. Upon removal of these Galphai subunits
      to reduce inhibitory coupling, stimulatory receptor coupling is revealed that may
      involve Gbetagamma-induced activation of adenylyl cyclase II, a Gi-stimulated
      cyclase that is predominantly expressed in GH4C1 cells. Thus Gi-coupled receptor
      activation involves integration of both inhibitory and stimulatory outputs that
      can be modulated by specific changes in alphai subunit expression level.

PMID- 10347207
TI  - Brain-derived neurotrophic factor promotes survival and chemoprotection of human
      neuroblastoma cells.
AB  - Brain-derived neurotrophic factor (BDNF) promotes neuronal survival and
      protection against neuronal damage. We addressed whether BDNF might promote
      survival and chemoprotection in neuroblastoma (NB) using a drug-sensitive human
      NB cell line. All-trans-retinoic acid (ATRA) induces a striking phenotypic
      differentiation of NB1643 cells, and exogenous BDNF treatment promotes survival
      of these differentiated cells. ATRA induces TRKB expression, and exogenous BDNF
      stimulates both autophosphorylation of TRKB and induction of the immediate early
      gene, FOS, in these cells. BDNF mRNA is expressed in NB1643 cells. Because the
      time course of TRKB induction closely parallels phenotypic differentiation of
      these cells, it seems probable that ATRA induces differentiation of NB1643 cells
      by establishing an autocrine loop involving BDNF and TRKB. Exogenous BDNF
      treatment resulted in a further increase in neurite outgrowth, which again
      suggests that an autocrine loop is involved in differentiation of NB1643 cells in
      response to ATRA. We then tested whether BDNF might afford drug resistance in NB
      and found that BDNF does indeed protect in this NB model against cisplatin, a DNA
      damaging agent actually used in the treatment of NB.

PMID- 10347208
TI  - The N-terminal POZ domain of GAGA mediates the formation of oligomers that bind
      DNA with high affinity and specificity.
AB  - The Drosophila GAGA factor self-oligomerizes both in vivo and in vitro. GAGA
      oligomerization depends on the presence of the N-terminal POZ domain and the
      formation of dimers, tetramers, and oligomers of high stoichiometry is observed
      in vitro. GAGA oligomers bind DNA with high affinity and specificity. As a
      consequence of its multimeric character, the interaction of GAGA with DNA
      fragments carrying several GAGA binding sites is multivalent and of higher
      affinity than its interaction with fragments containing single short sites. A
      single GAGA oligomer is capable of binding adjacent GAGA binding sites spaced by
      as many as 20 base pairs. GAGA oligomers are functionally active, being
      transcriptionally competent in vitro. GAGA-dependent transcription activation
      depends strongly on the number of GAGA binding sites present in the promoter. The
      POZ domain is not necessary for in vitro transcription but, in its absence, no
      synergism is observed on increasing the number of binding sites contained within
      the promoter. These results are discussed in view of the distribution of GAGA
      binding sites that, most frequently, form clusters of relatively short sites
      spaced by small variable distances.

PMID- 10347209
TI  - Protein kinase C-beta activates tyrosinase by phosphorylating serine residues in
      its cytoplasmic domain.
AB  - We have previously shown that protein kinase C-beta (PKC-beta) is required for
      activation of tyrosinase (Park, H. Y., Russakovsky, V., Ohno, S., and Gilchrest,
      B. A. (1993) J. Biol. Chem. 268, 11742-11749), the rate-limiting enzyme in
      melanogenesis. We now examine its mechanism of activation in human melanocytes.
      In vivo phosphorylation experiments revealed that tyrosinase is phosphorylated
      through the PKC-dependent pathway and that introduction of PKC-beta into
      nonpigmented human melanoma cells lacking PKC-beta lead to the phosphorylation
      and activation of tyrosinase. Preincubation of intact melanosomes with purified
      active PKC-beta in vitro increased tyrosinase activity 3-fold. By immunoelectron
      microscopy, PKC-beta but not PKC-alpha was closely associated with tyrosinase on
      the outer surface of melanosomes. Western blot analysis confirmed the association
      of PKC-beta with melanosomes. Only the cytoplasmic (extra-melanosomal) domain of
      tyrosinase, which contains two serines but no threonines, was phosphorylated by
      the serine/threonine kinase PKC-beta. These two serines at positions 505 and 509
      both are present in the C-terminal peptide generated by trypsin digestion of
      tyrosinase. Co-migration experiments comparing synthetic peptide standards of all
      three possible phosphorylated tryptic peptides, a diphosphopeptide and two
      monophosphopeptides, to tyrosinase-phosphorylated in intact melanocytes by PKC
      beta and then subjected to trypsin digestion revealed that both serine residues
      are phosphorylated by PKC-beta. We conclude that PKC-beta activates tyrosinase
      directly by phosphorylating serine residues at positions 505 and 509 in the
      cytoplasmic domain of this melanosome-associated protein.

PMID- 10347210
TI  - A cell-free assay for glycosylphosphatidylinositol anchoring in African
      trypanosomes. Demonstration of a transamidation reaction mechanism.
AB  - We established an in vitro assay for the addition of glycosyl
      phosphatidylinositol (GPI) anchors to proteins using procyclic trypanosomes
      engineered to express GPI-anchored variant surface glycoprotein (VSG). The assay
      is based on the premise that small nucleophiles, such as hydrazine, can
      substitute for the GPI moiety and effect displacement of the membrane anchor of a
      GPI-anchored protein or pro-protein causing release of the protein into the
      aqueous medium. Cell membranes containing pulse-radiolabeled VSG were incubated
      with hydrazine, and the VSG released from the membranes was measured by carbonate
      extraction, immunoprecipitation, and SDS-polyacrylamide gel
      electrophoresis/fluorography. Release of VSG was time- and temperature-dependent,
      was stimulated by hydrazine, and occurred only for VSG molecules situated in
      early compartments of the secretory pathway. No nucleophile-induced VSG release
      was seen in membranes prepared from cells expressing a VSG variant with a
      conventional transmembrane anchor (i.e. a nonfunctional GPI signal sequence). Pro
      VSG was shown to be a substrate in the reaction by assaying membranes prepared
      from cells treated with mannosamine, a GPI biosynthesis inhibitor. When a
      biotinylated derivative of hydrazine was used instead of hydrazine, the released
      VSG could be precipitated with streptavidin-agarose, indicating that the biotin
      moiety was covalently incorporated into the protein. Hydrazine was shown to block
      the C terminus of the released VSG hydrazide because the released material,
      unlike a truncated form of VSG lacking a GPI signal sequence, was not susceptible
      to proteolysis by carboxypeptidases. These results firmly establish that the
      released material in our assay is VSG hydrazide and strengthen the proof that GPI
      anchoring proceeds via a transamidation reaction mechanism. The reaction could be
      inhibited with sulfhydryl alkylating reagents, suggesting that the transamidase
      enzyme contains a functionally important sulfhydryl residue.

PMID- 10347211
TI  - Cloning and characterization of a human genotoxic and endoplasmic reticulum
      stress-inducible cDNA that encodes translation initiation factor
      1(eIF1(A121/SUI1)).
AB  - We report the cloning and characterization of a DNA damage-inducible (DDI)
      transcript DDI A121. The full-length human DDI A121 cDNA contains an open reading
      frame of 113 amino acids, corresponding to a protein of 12.7 kDa. The deduced
      amino acid sequence of A121 shows high homology to the yeast translation
      initiation factor (eIF) sui1 and also exhibits perfect identity to the partial
      sequence of recently purified human eIF1. Expression of human A121 corrected the
      mutant sui1 phenotype in yeast, demonstrating that human A121 encodes a bona fide
      translation initiation factor that is equivalent to yeast sui1p. The mammalian
      A121/SUI1 gene exhibits two transcripts (1.35 kilobases and 0.65 kilobases)
      containing a common coding region but differing in their 3'-untranslated region.
      The long and short A121/SUI1 mRNAs are differentially regulated by genotoxic and
      endoplasmic reticulum stress. The genotoxic stress induction of A121/SUI1 mRNA is
      conserved in both humans and rodents and occurs in a p53-independent manner. Our
      identification of a stress-inducible cDNA that encodes eIF1 suggests that
      modulation of translation initiation appears to occur during cellular stress and
      may represent an important adaptive response to genotoxic as well as endoplasmic
      reticulum stress.

PMID- 10347212
TI  - Glycated phosphatidylethanolamine promotes macrophage uptake of low density
      lipoprotein and accumulation of cholesteryl esters and triacylglycerols.
AB  - Non-enzymatic glycation of low density lipoprotein (LDL) has been suggested to be
      responsible for the increase in susceptibility to atherogenesis of diabetic
      individuals. Although the association of lipid glycation with this process has
      been investigated, the effect of specific lipid glycation products on LDL
      metabolism has not been addressed. This study reports that glucosylated
      phosphatidylethanolamine (Glc-PtdEtn), the major LDL lipid glycation product,
      promotes LDL uptake and cholesteryl ester (CE) and triacylglycerol (TG)
      accumulation by THP-1 macrophages. Incubation of THP-1 macrophages at a
      concentration of 100 micrograms/ml protein LDL specifically enriched (10 nmol/mg
      LDL protein) with synthetically prepared Glc-PtdEtn resulted in a significant
      increase in CE and TG accumulation when compared with LDL enriched in non
      glucosylated PtdEtn. After a 24-h incubation with LDL containing Glc-PtdEtn, the
      macrophages contained 2-fold higher CE (10.11 +/- 1.54 micrograms/mg cell
      protein) and TG (285.32 +/- 4.38 micrograms/mg cell protein) compared with LDL
      specifically enriched in non-glucosylated PtdEtn (CE, 3.97 +/- 0.95, p < 0.01 and
      TG, 185.57 +/- 3.58 micrograms/mg cell protein, p < 0.01). The corresponding
      values obtained with LDL containing glycated protein and lipid were similar to
      those of LDL containing Glc-PtdEtn (CE, 11.9 +/- 1.35 and TG, 280.78 +/- 3.98
      micrograms/mg cell protein). The accumulation of both neutral lipids was further
      significantly increased by incubating the macrophages with Glc-PtdEtn LDL exposed
      to copper oxidation. By utilizing the fluorescent probe, 1,1'-dioctadecyl-3,3,3',
      3'-tetramethylindocarbocyanine perchlorate (DiI), a 1.6-fold increase was seen in
      Glc-PtdEtn + LDL uptake when compared with control LDL. Competition studies
      revealed that acetylated LDL is not a good competitor for DiI Glc-PtdEtn LDL (5
      6% inhibition), whereas glycated LDL gave an 80% inhibition, and LDL + Glc-PtdEtn
      gave 93% inhibition of uptake by macrophages. These results indicate that
      glucosylation of PtdEtn in LDL accounts for the entire effect of LDL glycation on
      macrophage uptake and CE and TG accumulation and, therefore, the increased
      atherogenic potential of LDL in hyperglycemia.

PMID- 10347213
TI  - A nuclear export signal prevents Saccharomyces cerevisiae Hsp70 Ssb1p from
      stimulating nuclear localization signal-directed nuclear transport.
AB  - Hsp70 has been implicated in nuclear localization signal (NLS)-directed nuclear
      transport. Saccharomyces cerevisiae contains distinct SSA and SSB gene families
      of cytosolic Hsp70s. The nucleocytoplasmic localization of Ssa1p and Ssb1p was
      investigated using green fluorescent protein (GFP) fusions. Whereas GFP-Ssa1p
      localized both to the nucleus and cytoplasm, GFP-Ssb1p appeared only in the
      cytosol. The C-terminal domain of Ssb1p contains a leucine-rich nuclear export
      signal (NES) that is necessary and sufficient to direct nuclear export. The
      accumulation of GFP-Ssb1p in the nuclei of xpo1-1 cells suggests that Ssb1p
      shuttles across the nuclear envelope. Elevated levels of SSA1 but not SSB1
      suppressed the NLS-GFP nuclear localization defects of nup188-Delta cells.
      Studies with Ssa1p/Ssb1p chimeras revealed that the Ssb1p NES is sufficient and
      necessary to inhibit the function of Ssa- or Ssb-type Hsp70s in nuclear
      transport. Thus, NES-less Ssb1p stimulates nuclear transport in nup188-Delta
      cells and NES-containing Ssa1p does not. We conclude that the differential
      function of Ssa1p and Ssb1p in nuclear transport is due to the NES-directed
      export of the Ssb1p and not to functional differences in their ATPase or peptide
      binding domains.

PMID- 10347214
TI  - Species barrier to RNA recognition overcome with nonspecific RNA binding domains.
AB  - We show here that nonspecific RNA-protein interactions can significantly enhance
      the biological activity of an essential RNA. protein complex. Bacterial
      glutaminyl-tRNA synthetase poorly aminoacylates yeast tRNA and, as a consequence,
      cannot rescue a knockout allele of the gene for the yeast homologue. In contrast
      to the bacterial protein, the yeast enzyme has an extra appended domain at the N
      terminus. Previously, we showed that fusion of this yeast-specific domain to the
      bacterial protein enabled it to function as a yeast enzyme in vivo and in vitro.
      We suggested that the novel yeast-specific domain contributed to RNA interactions
      in a way that compensated for the poor fit between the yeast tRNA and bacterial
      enzyme. Here we establish that the novel appended domain by itself binds
      nonspecifically to different RNA structures. In addition, we show that fusion of
      an unrelated yeast protein, Arc1p, to the bacterial enzyme also converts it into
      a functional yeast enzyme in vivo and in vitro. A small C-terminal segment of
      Arc1p is necessary and sufficient for this conversion. This segment was shown by
      others to have nonspecific tRNA binding properties. Thus, nonspecific RNA binding
      interactions in general can compensate for barriers to formation of a specific
      and essential RNA.protein complex.

PMID- 10347215
TI  - Interleukin-10 receptor signaling through the JAK-STAT pathway. Requirement for
      two distinct receptor-derived signals for anti-inflammatory action.
AB  - Interleukin-10 (IL-10) is a cytokine that has pleiotropic effects on a variety of
      different cell types. Although many of the biologic responses induced by IL-10
      are also induced by other cytokines, such as IL-6, IL-10 is relatively unique in
      its ability to potently inhibit production of pro-inflammatory cytokines in
      macrophages. In this study, we have used gain-of-function and loss-of-function
      genetic approaches to define the intracellular components involved in the
      different biologic actions of IL-10. Herein, we demonstrate that the ability of
      IL-10 to inhibit tumor necrosis factor alpha (TNFalpha) production in
      lipopolysaccharide-stimulated macrophages requires the presence of Stat3, Jak1,
      and two distinct regions of the IL-10 receptor intracellular domain. Macrophages
      deficient in Stat3 or Jak1 were unable to inhibit lipopolysaccharide-induced
      TNFalpha production following treatment with murine IL-10. Structure-function
      analysis of the intracellular domain of the IL-10 receptor alpha chain showed
      that whereas two redundant Stat3 recruitment sites (427YQKQ430 and 477YLKQ480)
      were required for all IL-10-dependent effects on either B cells or macrophages,
      expression of IL-10-dependent anti-inflammatory function required the presence on
      the intracellular domain of the IL-10 receptor of a carboxyl-terminal sequence
      containing at least one functionally critical serine. These results thus
      demonstrate that IL-10-induced inhibition of TNFalpha production requires two
      distinct regions of the IL-10 receptor intracellular domain and thereby establish
      a distinctive molecular basis for the developmental versus the anti-inflammatory
      actions of IL-10.

PMID- 10347216
TI  - Distribution of binding sequences for the mitochondrial import receptors Tom20,
      Tom22, and Tom70 in a presequence-carrying preprotein and a non-cleavable
      preprotein.
AB  - Preproteins destined for mitochondria either are synthesized with amino-terminal
      signal sequences, termed presequences, or possess internal targeting information
      within the protein. The preprotein translocase of the outer mitochondrial
      membrane (designated Tom) contains specific import receptors. The cytosolic
      domains of three import receptors, Tom20, Tom22, and Tom70, have been shown to
      interact with preproteins. Little is known about the internal targeting
      information in preproteins and the distribution of binding sequences for the
      three import receptors. We have studied the binding of the purified cytosolic
      domains of Tom20, Tom22, and Tom70 to cellulose-bound peptide scans derived from
      a presequence-carrying cleavable preprotein, cytochrome c oxidase subunit IV, and
      a non-cleavable preprotein with internal targeting information, the phosphate
      carrier. All three receptor domains are able to bind efficiently to linear 13-mer
      peptides, yet with different specificity. Tom20 preferentially binds to
      presequence segments of subunit IV. Tom22 binds to segments corresponding to the
      carboxyl-terminal part of the presequence and the amino-terminal part of the
      mature protein. Tom70 does not bind efficiently to any region of subunit IV. In
      contrast, Tom70 and Tom20 bind to multiple segments within the phosphate carrier,
      yet the amino-terminal region is excluded. Both charged and uncharged peptides
      derived from the phosphate carrier show specific binding properties for Tom70 and
      Tom20, indicating that charge is not a critical determinant of internal targeting
      sequences. This feature contrasts with the crucial role of positively charged
      amino acids in presequences. Our results demonstrate that linear peptide segments
      of preproteins can serve as binding sites for all three receptors with
      differential specificity and imply different mechanisms for translocation of
      cleavable and non-cleavable preproteins.

PMID- 10347217
TI  - Oligomerization is required for p53 to be efficiently ubiquitinated by MDM2.
AB  - Wild-type p53 is degraded in part through the ubiquitin proteolysis pathway.
      Recent studies indicate that MDM2 can bind p53 and promote its rapid degradation
      although the molecular basis for this degradation has not been clarified. This
      report demonstrates that MDM2 can promote the ubiquitination of wild-type p53 and
      cancer-derived p53 mutants in transiently transfected cells. Deletion mutants
      that disrupted the oligomerization domain of p53 displayed low binding affinity
      for MDM2 and were poor substrates for ubiquitination. However, efficient MDM2
      binding and ubiquitination were restored when an oligomerization-deficient p53
      mutant was fused to the dimerization domain from another protein. These results
      indicate that oligomerization is required for p53 to efficiently bind and be
      ubiquitinated by MDM2. p53 ubiquitination was inhibited in cells exposed to UV
      radiation, and this inhibition coincided with a decrease in MDM2 protein levels
      and p53.MDM2 complex formation. In contrast, p53 dimerization was unaffected
      following UV treatment. These results suggest that UV radiation may stabilize p53
      by blocking the ubiquitination and degradation of p53 mediated by MDM2.

PMID- 10347218
TI  - The HMG-I(Y) A.T-hook peptide motif confers DNA-binding specificity to a
      structured chimeric protein.
AB  - Chromosomal translocations involving genes coding for members of the HMG-I(Y)
      family of "high mobility group" non-histone chromatin proteins (HMG-I, HMG-Y, and
      HMG-IC) have been observed in numerous types of human tumors. Many of these gene
      rearrangements result in the creation of chimeric proteins in which the DNA
      binding domains of the HMG-I(Y) proteins, the so-called A.T-hook motifs, have
      been fused to heterologous peptide sequences. Although little is known about
      either the structure or biophysical properties of these naturally occurring
      fusion proteins, the suggestion has been made that such chimeras have probably
      assumed an altered in vivo DNA-binding specificity due to the presence of the A.T
      hook motifs. To investigate this possibility, we performed in vitro "domain-swap"
      experiments using a model protein fusion system in which a single A. T-hook
      peptide was exchanged for a corresponding length peptide in the well
      characterized "B-box" DNA-binding domain of the HMG-1 non-histone chromatin
      protein. Here we report that chimeric A. T-hook/B-box hybrids exhibit in vitro
      DNA-binding characteristics resembling those of wild type HMG-I(Y) protein,
      rather than the HMG-1 protein. These results strongly suggest that the chimeric
      fusion proteins produced in human tumors as a result of HMG-I(Y) gene chromosomal
      translocations also retain A.T-hook-imparted DNA-binding properties in vivo.

PMID- 10347219
TI  - Inversion of the intracellular Na+/K+ ratio blocks apoptosis in vascular smooth
      muscle at a site upstream of caspase-3.
AB  - Long term elevation of the intracellular Na+/K+ ratio inhibits macromolecule
      synthesis and proliferation in the majority of cell types studied so far,
      including vascular smooth muscle cells (VSMC). We report here that inhibition of
      the Na+,K+ pump in VSMC by ouabain or a 1-h preincubation in K+-depleted medium
      attenuated apoptosis triggered by serum withdrawal, staurosporine, or okadaic
      acid. In the absence of ouabain, both DNA degradation and Caspase-3 activation in
      VSMC undergoing apoptosis were insensitive to modification of the extracellular
      Na+/K+ ratio as well as to hyperosmotic cell shrinkage. In contrast, protection
      of VSMC from apoptosis by ouabain was abolished under equimolar substitution of
      Na+o with K+o, showing that the antiapoptotic action of Na+,K+ pump inhibition
      was caused by inversion of the intracellular Na+/K+ ratio. Unlike VSMC, the same
      level of increment of the [Na+]i/[K+]i ratio caused by a 2-h preincubation of
      Jurkat cells with ouabain did not affect chromatin cleavage and Caspase-3
      activity triggered by treatment with Fas ligand, staurosporine, or hyperosmotic
      shrinkage. Thus, our results show for the first time that similar to cell
      proliferation, maintenance of a physiologically low intracellular Na+/K+ ratio is
      required for progression of VSMC apoptosis.

PMID- 10347220
TI  - Characterization of human, Schizosaccharomyces pombe, and Candida albicans mRNA
      cap methyltransferases and complete replacement of the yeast capping apparatus by
      mammalian enzymes.
AB  - Human and fission yeast cDNAs encoding mRNA (guanine-N7) methyltransferase were
      identified based on similarity of the human (Hcm1p; 476 amino acids) and
      Schizosaccharomyces pombe (Pcm1p; 389 amino acids) polypeptides to the cap
      methyltransferase of Saccharomyces cerevisiae (Abd1p). Expression of PCM1 or HCM1
      in S. cerevisiae complemented the lethal phenotype resulting from deletion of the
      ABD1 gene, as did expression of the NH2-terminal deletion mutants PCM1(94-389)
      and HCM1(121-476). The CCM1 gene encoding Candida albicans cap methyltransferase
      (Ccm1p; 474 amino acids) was isolated from a C. albicans genomic library by
      selection for complementation of the conditional growth phenotype of S.
      cerevisiae abd1-ts mutants. Human cap methyltransferase was expressed in
      bacteria, purified, and characterized. Recombinant Hcm1p catalyzed quantitative S
      adenosylmethionine-dependent conversion of GpppA-capped poly(A) to m7GpppA-capped
      poly(A). We identified by alanine-scanning mutagenesis eight amino acids (Asp
      203, Gly-207, Asp-211, Asp-227, Arg-239, Tyr-289, Phe-291, and Phe-354) that are
      essential for human cap methyltransferase function in vivo. All eight residues
      are conserved in other cellular cap methyltransferases. Five of the mutant human
      proteins (D203A, R239A, Y289A, F291A, and F354A) were expressed in bacteria and
      found to be defective in cap methylation in vitro. Concordance of mutational
      effects on Hcm1p, Abd1p, and vaccinia capping enzyme underscores a conserved
      structural basis for cap methylation in DNA viruses, yeast, and metazoans. This
      is in contrast to the structural and mechanistic divergence of the RNA
      triphosphatase components of the yeast and metazoan capping systems.
      Nevertheless, we demonstrate that the entire three-component yeast capping
      apparatus, consisting of RNA 5'-triphosphatase (Cet1p), RNA guanylyltransferase
      (Ceg1p), and Abd1p could be replaced in vivo by the two-component mammalian
      apparatus consisting of a bifunctional triphosphatase-guanylyltransferase Mce1p
      and the methyltransferase Hcm1(121-476)p. Isogenic yeast strains with fungal
      versus mammalian capping systems should facilitate rational screens for
      antifungal drugs that target cap formation in vivo.

PMID- 10347221
TI  - Site-directed mutagenesis of putative substrate-binding residues reveals a
      mechanism controlling the different stereospecificities of two tropinone
      reductases.
AB  - Two tropinone reductases (TRs) constitute a key branch point in the biosynthetic
      pathway of tropane alkaloids, which are mainly produced in several solanaceous
      plants. The two TRs share 64% identical amino acid residues and reduce the 3
      carbonyl group of a common substrate, tropinone, but they produce distinct
      alcohol products with different stereospecific configurations. Previous x-ray
      crystallographic analysis has revealed their highly conserved overall folding,
      and the modeling of tropinone within the putative substrate-binding sites has
      suggested that the different stereospecificities may be determined solely by the
      different binding orientations of tropinone to the enzymes. In this study, we
      have constructed various mutant TRs, in which putative substrate-binding residues
      from one TR were substituted with those found in the corresponding positions of
      the other TR. Substitution of five amino acid residues resulted in an almost
      complete reversal of stereospecificity, indicating that the different
      stereospecificities are indeed determined by the binding orientation of
      tropinone. Detailed kinetic analysis of the mutant enzymes has shown that TR
      stereospecificity is determined by varying the contributions from electrostatic
      and hydrophobic interactions and that the present TR structures represent highly
      evolved forms, in which strict stereospecificities and rapid turnover are
      accomplished together.

PMID- 10347222
TI  - Cloning, tissue distribution, genomic organization, and functional
      characterization of NBC3, a new member of the sodium bicarbonate cotransporter
      family.
AB  - Previous functional studies have demonstrated that muscle intracellular pH
      regulation is mediated by sodium-coupled bicarbonate transport, Na+/H+ exchange,
      and Cl-/bicarbonate exchange. We report the cloning, sequence analysis, tissue
      distribution, genomic organization, and functional analysis of a new member of
      the sodium bicarbonate cotransporter (NBC) family, NBC3, from human skeletal
      muscle. mNBC3 encodes a 1214-residue polypeptide with 12 putative membrane
      spanning domains. The approximately 7.8-kilobase transcript is expressed uniquely
      in skeletal muscle and heart. The NBC3 gene (SLC4A7) spans approximately 80 kb
      and is composed of 25 coding exons and 24 introns that are flanked by typical
      splice donor and acceptor sequences. Expression of mNBC3 cRNA in Xenopus laevis
      oocytes demonstrated that the protein encodes a novel stilbene-insensitive 5-(N
      ethyl-N-isopropyl)-amiloride-inhibitable sodium bicarbonate cotransporter.

PMID- 10347223
TI  - Effects of tetracycline and spectinomycin on the tertiary structure of ribosomal
      RNA in the Escherichia coli 30 S ribosomal subunit.
AB  - Structural analysis of the 16 S rRNA in the 30 S subunit and 70 S ribosome in the
      presence of ribosome-specific antibiotics was performed to determine whether they
      produced rRNA structural changes that might provide further insight to their
      action. An UV cross-linking procedure that determines the pattern and frequency
      of intramolecular 16 S RNA cross-links was used to detect differences reflecting
      structural changes. Tetracycline and spectinomycin have specific effects detected
      by this assay. The presence of tetracycline inhibits the cross-link C967xC1400
      completely, increases the frequency of cross-link C1402x1501 twofold, and
      decreases the cross-link G894xU244 by one-half without affecting other cross
      links. Spectinomycin reduces the frequency of the cross-link C934xU1345 by 60%
      without affecting cross-linking at other sites. The structural changes occur at
      concentrations at which the antibiotics exert their inhibitory effects. For
      spectinomycin, the apparent binding site and the affected cross-linking site are
      distant in the secondary structure but are close in tertiary structure in several
      recent models, indicating a localized effect. For tetracycline, the apparent
      binding sites are significantly separated in both the secondary and the three
      dimensional structures, suggesting a more regional effect.

PMID- 10347224
TI  - CCAAT/enhancer-binding protein delta regulates mammary epithelial cell G0 growth
      arrest and apoptosis.
AB  - CCAAT/enhancer-binding proteins (C/EBPs) are a highly conserved family of DNA
      binding proteins that regulate cell-specific growth, differentiation, and
      apoptosis. Here, we show that induction of C/EBPdelta gene expression during G0
      growth arrest is a general property of mammary-derived cell lines. C/EBPdelta is
      not induced during G0 growth arrest in 3T3 or IEC18 cells. C/EBPdelta induction
      is G0-specific in mouse mammary epithelial cells; C/EBPdelta gene expression is
      not induced by growth arrest in the G1, S, or G2 phase of the cell cycle.
      C/EBPdelta antisense-expressing cells (AS1 cells) maintain elevated cyclin D1 and
      phosphorylated retinoblastoma protein levels and exhibit delayed G0 growth arrest
      and apoptosis in response to serum and growth factor withdrawal. Conversely,
      C/EBPdelta-overexpressing cells exhibited a rapid decline in cyclin D1 and
      phosphorylated retinoblastoma protein levels, a rapid increase in the cyclin
      dependent kinase inhibitor p27, and accelerated G0 growth arrest and apoptosis in
      response to serum and growth factor withdrawal. When C/EBPdelta levels were
      rescued in AS1 cells by transfection with a C/EBPdelta "sense" construct, normal
      G0 growth arrest and apoptosis were restored. These results demonstrate that
      C/EBPdelta plays a key role in the regulation of G0 growth arrest and apoptosis
      in mammary epithelial cells.

PMID- 10347225
TI  - Human PIR1 of the protein-tyrosine phosphatase superfamily has RNA 5'
      triphosphatase and diphosphatase activities.
AB  - A human cDNA was isolated encoding a protein with significant sequence similarity
      (41% identity) to the BVP RNA 5'-phosphatase from the Autographa californica
      nuclear polyhedrosis virus. This protein is a member of the protein-tyrosine
      phosphatase (PTP) superfamily and is identical to PIR1, shown by Yuan et al.
      (Yuan, Y., Da-Ming, L., and Sun, H. (1998) J. Biol. Chem. 272, 20347-20353) to be
      a nuclear protein that can associate with RNA or ribonucleoprotein complexes. We
      demonstrate that PIR1 removes two phosphates from the 5'-triphosphate end of RNA,
      but not from mononucleotide triphosphates. The specific activity of PIR1 with RNA
      is several orders of magnitude greater than that with the best protein substrates
      examined, suggesting that RNA is its physiological substrate. A 120-amino acid
      segment C-terminal to the PTP domain is not required for RNA phosphatase
      activity. We propose that PIR1 and its closest homologs, which include the
      metazoan mRNA capping enzymes, constitute a subgroup of the PTP family that use
      RNA as a substrate.

PMID- 10347226
TI  - Role of isoprenoid lipids on the heterotrimeric G protein gamma subunit in
      determining effector activation.
AB  - Post-translational prenylation of heterotrimeric G protein gamma subunits is
      essential for high affinity alpha-beta gamma and alpha-beta gamma-receptor
      interactions, suggesting that the prenyl group is an important domain in the beta
      gamma dimer. To determine the role of the prenyl modification in the interaction
      of beta gamma dimers with effectors, the CAAX (where A indicates alipathic amino
      acid) motifs in the gamma1, gamma2, and gamma11 subunits were altered to direct
      modification with different prenyl groups. Six recombinant beta gamma dimers were
      overexpressed in baculovirus-infected Sf9 insect cells, purified, and examined
      for their ability to stimulate three phospholipase C-beta isozymes and type II
      adenylyl cyclase. The native beta1 gamma2 dimer (gamma subunit modified with
      geranylgeranyl) is more potent and effective in activating phospholipase C-beta
      than either the beta1 gamma1 (farnesyl) or the beta1 gamma11 (farnesyl) dimers.
      However, farnesyl modification of the gamma subunit in the beta1 gamma2 dimer
      (beta1 gamma2-L71S) caused a decrement in its ability to activate phospholipase C
      beta. In contrast, both the beta1 gamma1-S74L (geranylgeranyl) and the beta1
      gamma11-S73L (geranylgeranyl) dimers were more active than the native forms. The
      beta1 gamma2 dimer activates type II adenylyl cyclase about 12-fold; however,
      neither the beta1 gamma1 nor the beta1 gamma11 dimers activate the enzyme. As was
      the case with phospholipase C-beta, the beta1gamma2-L71S dimer was less able to
      activate adenylyl cyclase than the native beta1 gamma2 dimer. Interestingly,
      neither the beta1 gamma1-S74L nor the beta1 gamma11-S73L dimers stimulated
      adenylyl cyclase. The results suggest that both the amino acid sequence of the
      gamma subunit and its prenyl group play a role in determining the activity of the
      beta gamma-effector complex.

PMID- 10347228
TI  - Characterization of the translation-dependent step during iron-regulated decay of
      transferrin receptor mRNA.
AB  - Iron regulates the stability of the mRNA encoding the transferrin receptor (TfR).
      When iron is scarce, iron regulatory proteins (IRPs) stabilize TfR mRNA by
      binding to the 3'-untranslated region. High levels of iron induce degradation of
      TfR mRNA; the translation inhibitor cycloheximide prevents this. To distinguish
      between cotranslational mRNA decay and a trans effect of translation inhibitors,
      we designed a reporter system exploiting the properties of the selectable marker
      gene thymidine kinase (TK). The 3'-untranslated region of human transferrin
      receptor, which contains all elements necessary for iron-dependent regulation of
      mRNA stability, was fused to the TK cDNA. In stably transfected mouse
      fibroblasts, the expression of the reporter gene was perfectly regulated by iron.
      Introduction of stop codons in the TK coding sequence or insertion of stable stem
      loop structures in the leader sequence did not affect on the iron-dependent
      regulation of the reporter mRNA. This implies that global translation inhibitors
      stabilize TfR mRNA in trans. Cycloheximide prevented the destabilization of TfR
      mRNA only in the presence of active IRPs. Inhibition of IRP inactivation by
      cycloheximide or by the specific proteasome inhibitor MG132 correlated with the
      stabilization of TfR mRNA. These observations suggest that inhibition of
      translation by cycloheximide interferes with the rate-limiting step of iron
      induced TfR mRNA decay in a trans-acting mechanism by blocking IRP inactivation.

PMID- 10347227
TI  - MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the p38 and
      c-Jun NH2-terminal kinases.
AB  - Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase
      kinase kinase 3 (MEKK3) activates the c-Jun NH2-terminal kinase (JNK) pathway,
      although no substrates for MEKK3 have been identified. We have examined the
      regulation by MEKK3 of MAPK kinase 7 (MKK7) and MKK6, two novel MAPK kinases
      specific for JNK and p38, respectively. Coexpression of MKK7 with MEKK3 in COS-7
      cells enhanced MKK7 autophosphorylation and its ability to activate recombinant
      JNK1 in vitro. MKK6 autophosphorylation and in vitro activation of p38alpha were
      also observed following coexpression of MKK6 with MEKK3. MEKK2, a closely related
      homologue of MEKK3, also activated MKK7 and MKK6 in COS-7 cells. Importantly,
      immunoprecipitates of either MEKK3 or MEKK2 directly activated recombinant MKK7
      and MKK6 in vitro. These data identify MEKK3 as a MAPK kinase kinase specific for
      MKK7 and MKK6 in the JNK and p38 pathways. We have also examined whether MEKK3 or
      MEKK2 activates p38 in intact cells using MAPK-activated protein kinase-2
      (MAPKAPK2) as an affinity ligand and substrate. Anisomycin, sorbitol, or the
      expression of MEKK3 in HEK293 cells enhanced MAPKAPK2 phosphorylation, whereas
      MEKK2 was less effective. Furthermore, MAPKAPK2 phosphorylation induced by MEKK3
      or cellular stress was abolished by the p38 inhibitor SB-203580, suggesting that
      MEKK3 is coupled to p38 activation in intact cells.

PMID- 10347229
TI  - Cbl-mediated negative regulation of platelet-derived growth factor receptor
      dependent cell proliferation. A critical role for Cbl tyrosine kinase-binding
      domain.
AB  - The Cbl proto-oncogene product has emerged as a novel negative regulator of
      receptor and non-receptor tyrosine kinases. Our previous observations that Cbl
      overexpression in NIH3T3 cells enhanced the ubiquitination and degradation of the
      platelet-derived growth factor receptor-alpha (PDGFRalpha) and that the
      expression of oncogenic Cbl mutants up-regulated the PDGFRalpha signaling
      machinery strongly suggested that Cbl negatively regulates PDGFRalpha signaling.
      Here, we show that, similar to PDGFRalpha, selective stimulation of PDGFRbeta
      induces Cbl phosphorylation, and its physical association with the receptor.
      Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the
      ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as
      observed with PDGFRalpha. We show that Cbl-dependent negative regulation of
      PDGFRalpha and beta results in a reduction of PDGF-induced cell proliferation and
      protection against apoptosis. A point mutation (G306E) that inactivates the
      tyrosine kinase binding domain in the N-terminal transforming region of Cbl
      compromised the PDGF-inducible tyrosine phosphorylation of Cbl although this
      mutant could still associate with the PDGFR. More importantly, the G306E mutation
      abrogated the ability of Cbl to enhance the ligand-induced ubiquitination and
      degradation of the PDGFR and to inhibit the PDGF-dependent cell proliferation and
      protection from apoptosis. These results demonstrate that Cbl can negatively
      regulate PDGFR-dependent biological responses and that this function requires the
      conserved tyrosine kinase binding domain of Cbl.

PMID- 10347230
TI  - Use of a disulfide cross-linking strategy to study muscarinic receptor structure
      and mechanisms of activation.
AB  - To gain insight into the molecular architecture of the cytoplasmic surface of G
      protein-coupled receptors, we have developed a disulfide cross-linking strategy
      using the m3 muscarinic receptor as a model system. To facilitate the
      interpretation of disulfide cross-linking data, we initially generated a mutant
      m3 muscarinic receptor (referred to as m3'(3C)-Xa) in which most native Cys
      residues had been deleted or substituted with Ala or Ser (remaining Cys residues
      Cys-140, Cys-220, and Cys-532) and in which the central portion of the third
      intracellular loop had been replaced with a factor Xa cleavage site. Radioligand
      binding and second messenger assays showed that the m3'(3C)-Xa mutant receptor
      was fully functional. In the next step, pairs of Cys residues were reintroduced
      into the m3'(3C)-Xa construct, thus generating 10 double Cys mutant receptors.
      All 10 mutant receptors contained a Cys residue at position 169 at the beginning
      of the second intracellular loop and a second Cys within the C-terminal portion
      of the third intracellular loop, at positions 484-493. Radioligand binding
      studies and phosphatidylinositol assays indicated that all double Cys mutant
      receptors were properly folded. Membrane lysates prepared from COS-7 cells
      transfected with the different mutant receptor constructs were incubated with
      factor Xa protease and the oxidizing agent Cu(II)-(1,10-phenanthroline)3, and the
      formation of intramolecular disulfide bonds between juxtaposed Cys residues was
      monitored by using a combined immunoprecipitation/immunoblotting strategy. To our
      surprise, efficient disulfide cross-linking was observed with 8 of the 10 double
      Cys mutant receptors studied (Cys-169/Cys-484 to Cys-491), suggesting that the
      intracellular m3 receptor surface is characterized by pronounced backbone
      fluctuations. Moreover, [35S]guanosine 5'-3-O-(thio)triphosphate binding assays
      indicated that the formation of intramolecular disulfide cross-links prevented or
      strongly inhibited receptor-mediated G protein activation, suggesting that the
      highly dynamic character of the cytoplasmic receptor surface is a prerequisite
      for efficient receptor-G protein interactions. This is the first study using a
      disulfide mapping strategy to examine the three-dimensional structure of a
      hormone-activated G protein-coupled receptor.

PMID- 10347231
TI  - The ubiquitin-proteasome pathway and serine kinase activity modulate adenomatous
      polyposis coli protein-mediated regulation of beta-catenin-lymphocyte enhancer
      binding factor signaling.
AB  - The tumor suppressor function of the adenomatous polyposis coli protein (APC)
      depends, in part, on its ability to bind and regulate the multifunctional
      protein, beta-catenin. beta-Catenin binds the high mobility group box
      transcription factors, lymphocyte enhancer-binding factor (LEF) and T-cell
      factor, to directly regulate gene transcription. Using LEF reporter assays we
      find that APC-mediated down-regulation of beta-catenin-LEF signaling is reversed
      by proteasomal inhibitors in a dose-dependent manner. APC down-regulates
      signaling induced by wild type beta-catenin but not by the non-ubiquitinatable
      S37A mutant, beta-catenin. Bisindoylmaleimide-type protein kinase C inhibitors,
      which prevent beta-catenin ubiquitination, decrease the ability of APC to down
      regulate beta-catenin-LEF signaling. All these effects on LEF signaling are
      paralleled by changes in beta-catenin protein levels. Lithium, an inhibitor of
      glycogen synthase kinase-3beta, does not alter the ability of APC to down
      regulate beta-catenin protein and beta-catenin-LEF signaling in the colon cancer
      cells that were tested. These results point to a role for beta-catenin
      ubiquitination, proteasomal degradation, and potentially a serine kinase other
      than glycogen synthase kinase-3beta in the tumor-suppressive actions of APC.

PMID- 10347232
TI  - WD repeats of the p48 subunit of chicken chromatin assembly factor-1 required for
      in vitro interaction with chicken histone deacetylase-2.
AB  - Chromatin assembly factor-1 (CAF-1) is essential for chromatin assembly in
      eukaryotes, and comprises three subunits of 150 kDa (p150), 60 kDa (p60), and 48
      kDa (p48). We cloned and sequenced cDNA encoding the small subunit of the chicken
      CAF-1, chCAF-1p48. It consists of 425 amino acid residues including a putative
      initiation Met, possesses seven WD repeat motifs, and contains only one amino
      acid change relative to the human and mouse CAF-1p48s. The immunoprecipitation
      experiment followed by Western blotting revealed that chCAF-1p48 interacts with
      chicken histone deacetylases (chHDAC-1 and -2) in vivo. The glutathione S
      transferase pulldown affinity assay revealed the in vitro interaction of chCAF
      1p48 with chHDAC-1, -2, and -3. We showed that the p48 subunit tightly binds to
      two regions of chHDAC-2, located between amino acid residues 82-180 and 245-314,
      respectively. We also established that two N-terminal, two C-terminal, or one N
      terminal and one C-terminal WD repeat motif of chCAF-1p48 are required for this
      interaction, using deletion mutants of the respective regions. These results
      suggest that chCAF-1p48 is involved in many aspects of DNA-utilizing processes,
      through alterations in the chromatin structure based on both the acetylation and
      deacetylation of core histones.

PMID- 10347233
TI  - Relaxation of transcription-induced negative supercoiling is an essential
      function of Escherichia coli DNA topoisomerase I.
AB  - It has been suggested that the essential function of DNA topoisomerase I in
      Escherichia coli is to prevent chromosomal DNA from reaching an unacceptably high
      level of global negative supercoiling. However, other in vivo studies have shown
      that DNA topoisomerase I is very effective in removing local negative
      supercoiling generated during transcription elongation. To determine whether
      topoisomerase I is essential for controlling global or local DNA supercoiling, we
      have prepared a set of topA null mutant strains in combination with different
      plasmid DNAs. Although we found a correlation between the severity of the growth
      defect with both transcription-induced and global supercoiling, near to complete
      growth inhibition correlated only with transcription-induced supercoiling. This
      result strongly suggests that the major function of DNA topoisomerase I is to
      relax local negative supercoiling generated during transcription elongation.

PMID- 10347234
TI  - Escherichia coli DNA topoisomerase I inhibits R-loop formation by relaxing
      transcription-induced negative supercoiling.
AB  - It has recently been shown that RNase H overproduction can partially compensate
      for the growth defect due to the absence of DNA topoisomerase I in Escherichia
      coli (Drolet, M., Phoenix, P., Menzel, R., Masse, E., Liu, L. F., and Crouch, R.
      J. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 3526-3530). This result has
      suggested a model in which inhibitory R-loops occur during transcription in topA
      mutants. Results presented in this report further support this notion and
      demonstrate that transcription-induced supercoiling is involved in R-loop
      formation. First, we show that stable R-loop formation during in vitro
      transcription with E. coli RNA polymerase only occurs in the presence of DNA
      gyrase. Second, extensive R-loop formation in vivo, revealed by the production of
      RNase H-sensitive hypernegatively supercoiled plasmid DNAs, is observed under
      conditions where topA mutants fail to grow. Furthermore, we have demonstrated
      that the coupling of transcription and translation in bacteria is an efficient
      way of preventing R-loop formation.

PMID- 10347235
TI  - Rho as a mediator of G protein-coupled receptor signaling.

PMID- 10347236
TI  - A regulatory domain (R1-R2) in the amino terminus of the N-methyl-D-aspartate
      receptor: effects of spermine, protons, and ifenprodil, and structural similarity
      to bacterial leucine/isoleucine/valine binding protein.
AB  - There are complex interactions between spermine, protons, and ifenprodil at N
      methyl-D-aspartate receptors. Spermine stimulation may involve relief of proton
      inhibition, whereas ifenprodil inhibition may involve an increase in proton
      inhibition. We studied mutations at acidic residues in the NR1 subunit using
      voltage-clamp recording of NR1/NR2B receptors expressed in Xenopus oocytes.
      Mutations at residues near the site of the exon-5 insert, including E181 and
      E185, reduced spermine stimulation and proton inhibition. Mutation NR1(D130N)
      reduced sensitivity to ifenprodil by more than 500-fold, but had little effect on
      sensitivity to spermine and pH. Mutations at six other residues in this region of
      the NR1 subunit reduced the potency and, in some cases, the maximum effect of
      ifenprodil. These mutants did not affect sensitivity to pH, glutamate, glycine,
      or other hallmark properties of N-methyl-D-aspartate channels such as Mg2+ block
      and Ba2+ permeability. Residues in this region presumably form part of the
      ifenprodil-binding site. To model this region of NR1 we compared the predicted
      secondary structure of NR1 (residues 19-400) with the known structures of 1,400
      proteins. This region of NR1 is most similar to bacterial
      leucine/isoleucine/valine binding protein, a globular amino acid binding protein
      containing two lobes, similar to the downstream S1-S2 region of glutamate
      receptors. We propose that the tertiary structure of NR1(22-375) is similar to
      leucine/isoleucine/valine binding protein, containing two "regulatory" domains,
      which we term R1 and R2. This region, which contains the binding sites for
      spermine and ifenprodil, may influence the downstream S1 and S2 domains that
      constitute the glycine binding pocket.

PMID- 10347238
TI  - Effect of mutations within the peripheral anionic site on the stability of
      acetylcholinesterase.
AB  - Torpedo acetylcholinesterase is irreversibly inactivated by modifying a buried
      free cysteine, Cys231, with sulfhydryl reagents. The stability of the enzyme, as
      monitored by measuring the rate of inactivation, was reduced by mutating a
      leucine, Leu282, to a smaller amino acid residue. Leu282 is located within the
      "peripheral" anionic site, at the entrance to the active-site gorge. Thus, loss
      of activity was due to the increased reactivity of Cys231. This was paralleled by
      an increased susceptibility to thermal denaturation, which was shown to be due to
      a large decrease in the activation enthalpy. Similar results were obtained when
      either of two other residues in contact with Leu282 in Torpedo
      acetylcholinesterase, Trp279 and Ser291, was replaced by an amino acid with a
      smaller side chain. We studied the effects of various ligands specific for either
      the active or peripheral sites on both thermal inactivation and on inactivation
      by 4,4'-dithiodipyridine. The wild-type and mutated enzymes could be either
      protected or sensitized. In some cases, opposite effects of the same ligand were
      observed for chemical modification and thermal denaturation. The mutated residues
      are within a conserved loop, W279-S291, at the top of the active-site gorge, that
      contributes to the peripheral anionic site. Theoretical analysis showed that
      Torpedo acetylcholinesterase consists of two structural domains, each comprising
      one contiguous polypeptide segment. The W279-S291 loop, located in the first
      domain, makes multiple contacts with the second domain across the active-site
      gorge. We postulate that the mutations to residues with smaller side chains
      destabilize the conserved loop, thus disrupting cross-gorge interactions and,
      ultimately, the entire structure.

PMID- 10347237
TI  - Activation and Ca2+ permeation of stably transfected alpha3/beta4 neuronal
      nicotinic acetylcholine receptor.
AB  - The alpha3/beta4 rat neuronal nicotinic acetylcholine receptor, stably
      transfected in human embryonic kidney cells, was examined using the whole-cell
      clamp technique and 2-dimensional confocal imaging. Application of agonists
      (nicotine, cytisine, epibatidine) activated a large (100-200 pA/pF) inwardly
      rectifying monovalent current, with little current at voltages between 0 and +40
      mV. Rapid application of nicotine and cytisine indicated EC50 values of congruent
      with22 and congruent with64 microM, respectively, and suggested second order
      binding kinetics (Hill coefficient approximately 2). The time constant of
      desensitization (decay) of nicotine-activated current was concentration-dependent
      (typically approximately 10 s at 30 microM versus approximately 1.0 s at 100-1000
      microM), but not voltage-dependent and was significantly smaller than the
      approximately 200 s reported for the alpha3/beta4 receptor expressed in Xenopus
      oocytes. Nicotine-activated current was rapidly and reversibly blocked by
      coapplication of mecamylamine and d-tubocurarine. At -80 mV holding potentials,
      the current was also suppressed by approximately 25% either upon complete removal
      or elevation of Ca2+ to 10 mM. Total replacement of Na+ by Ca2+ also completely
      blocked the current. On the other hand, evidence for permeation of Ca2+ was
      indicated by increased inward current at -40 mV upon elevation of Ca2+ from 2 to
      10 mM, as well as a rise in the cytosolic Ca2+ proportional to the current
      carried by the receptor. These findings are consistent with the idea that Ca2+,
      in addition to its channel-permeating properties, may also regulate the receptor
      from an extracellular site. Our results suggest that the alpha3/beta4 neuronal
      nicotinic acetylcholine receptor, when stably expressed in human embryonic kidney
      293 cells, has desensitization kinetics and Ca2+ regulatory mechanisms somewhat
      different from those described for the receptor expressed in Xenopus oocytes.

PMID- 10347239
TI  - Residues in transmembrane domains I and II determine gamma-aminobutyric acid type
      AA receptor subtype-selective antagonism by furosemide.
AB  - GABAA receptors in cerebellar granule cells are unique in expressing a subtype
      containing the alpha6 subunit. This receptor subtype has high affinity for GABA
      and produces a degree of tonic inhibition on cerebellar granule cells, modulating
      the firing of these cells via spillover of GABA from GABAergic synapses. This
      receptor subtype also has selective affinity for the diuretic furosemide over
      receptors containing other alpha-subunits. Furosemide exhibits approximately 100
      fold selectivity for alpha6-containing receptors over alpha1-containing
      receptors. By making alpha1/alpha6 chimeras we have identified a transmembrane
      region (209-279) responsible for the high furosemide sensitivity of
      alpha6beta3gamma2s receptors. Within the alpha1 transmembrane region, a single
      amino acid was identified that when mutated from threonine to isoleucine,
      increased furosemide sensitivity by 20-fold. We demonstrate the beta-subunit
      selectivity of furosemide to be due to asparagine 265 in the beta2 and beta3
      transmembrane-domain II similar to that observed with potentiation by the
      anticonvulsant loreclezole. We also show that Ile in transmembrane-domain I
      accounts for the increased GABA sensitivity observed at alpha6beta3gamma2s
      compared with alpha1beta3gamma2s receptors, but did not affect direct activation
      by pentobarbital or potentiation by the benzodiazepine flunitrazepam. Location of
      these residues within transmembrane domains leads to speculation that they may be
      involved in the channel-gating mechanism conferring increased receptor activation
      by GABA, in addition to conferring furosemide sensitivity.

PMID- 10347240
TI  - Pharmacological and histochemical distinctions between molecularly defined
      sarcolemmal KATP channels and native cardiac mitochondrial KATP channels.
AB  - A variety of direct and indirect techniques have revealed the existence of ATP
      sensitive potassium (KATP) channels in the inner membranes of mitochondria. The
      molecular identity of these mitochondrial KATP (mitoKATP) channels remains
      unclear. We used a pharmacological approach to distinguish mitoKATP channels from
      classical, molecularly defined cardiac sarcolemmal KATP (surfaceKATP) channels
      encoded by the sulfonylurea receptor SUR2A and the pore-forming subunit Kir6.2.
      SUR2A and Kir6.2 were expressed in human embryonic kidney (HEK)293 cells, and
      their activities were measured by patch-clamp recordings of membrane current.
      SurfaceKATP channels are activated potently by 100 microM pinacidil but only
      weakly by 100 microM diazoxide; in addition, they are blocked by 10 microM
      glibenclamide, but are insensitive to 500 microM 5-hydroxydecanoate. This
      pharmacology, which was confirmed with patch-clamp recordings in intact rabbit
      ventricular myocytes, contrasts with that of mitoKATP channels as indexed by
      flavoprotein oxidation. MitoKATP channels in myocytes are activated equally by
      100 microM diazoxide and 100 microM pinacidil. In contrast to its lack of effect
      on surfaceKATP channels, 5-hydroxydecanoate is an effective blocker of mitoKATP
      channels. Glibenclamide's effects on mitoKATP channels are difficult to assess,
      because it independently activates flavoprotein fluorescence, consistent with a
      previously described primary uncoupling effect. Confocal imaging of the
      subcellular distribution of expressed fluorescent Kir6.2 in HEK cells and in
      myocytes revealed no targeting of mitochondrial membranes. The differences in
      drug sensitivity and subcellular localization indicate that mitoKATP channels are
      distinct from surface KATP channels at a molecular level.

PMID- 10347241
TI  - Detection of nitrosyl hemoglobin in venous blood in the treatment of sickle cell
      anemia with hydroxyurea.
AB  - The clinical efficacy of hydroxyurea (HU) in the treatment of sickle cell anemia
      has mainly been attributed to increased levels of fetal hemoglobin (HbF), which
      reduces the tendency for sickle hemoglobin to polymerize, thereby reducing the
      frequency of the vaso-occlusive phenomena associated with the disease. However,
      benefits from HU treatment in patients have been reported in advance of increased
      HbF levels. Thus, it has been suggested that other hydroxyurea-dependent
      mechanisms may, in part, account for its clinical efficacy. We have previously
      demonstrated that HU is metabolized in rats to release nitric oxide and,
      therefore, postulated the same to occur in humans. However, to our knowledge,
      evidence of nitric oxide production from HU metabolism in humans has yet to be
      demonstrated. Here we report that oral administration of HU for the treatment of
      sickle cell anemia produced detectable nitrosyl hemoglobin. The nitrosyl
      hemoglobin complex could be detected as early as 30 min after administration and
      persisted up to 4 h. Our observations support the hypothesis that the ability of
      HU to ease the vaso-occlusive phenomena may, in part, be attributed to
      vasodilation and/or decreased platelet activation induced by HU-derived nitric
      oxide well in advance of increased HbF levels.

PMID- 10347242
TI  - Agonist and potentiation actions of n-octanol on gamma-aminobutyric acid type A
      receptors.
AB  - The n-octanol effects on the gamma-aminobutyric acid type A (GABAA) receptor were
      studied in human embryonic kidney 293 cells transfected with alpha1, beta2, and
      gamma2S subunit cDNAs. GABA-evoked currents had an EC50 of 13.3 +/- 1.7 microM
      and a Hill coefficient (nH) of 1.4 +/- 0.1. n-Octanol was also capable of evoking
      a small current with an EC50 of 1000 microM and an nH of 2. In addition, n
      octanol modulated GABA-induced currents in a concentration-dependent manner.
      Coapplications of n-octanol increased peak currents evoked by 3 microM GABA with
      an EC50 of 190 microM and an nH of 1.8. The extent of potentiation decreased with
      increasing GABA concentrations and no potentiation was observed when n-octanol
      was coapplied with 1000 microM GABA. One-minute preapplication of 1000 microM n
      octanol slightly potentiated 3 microM GABA-induced current, whereas it suppressed
      300 microM GABA-induced current to 16% of the control, suggesting that 84% of the
      receptors underwent desensitization. Two models were used to explain n-octanol
      agonistic and potentiating actions on the alpha1beta2gamma2S GABAA receptor: n
      octanol binds to multiple sites to exert multiple actions, or n-octanol acts as a
      partial agonist to manifest these actions. The partial agonist model is unique
      because it is a simpler model to explain n-octanol actions on the GABAA receptor.

PMID- 10347243
TI  - Bombesin receptors inhibit G protein-coupled inwardly rectifying K+ channels
      expressed in Xenopus oocytes through a protein kinase C-dependent pathway.
AB  - Although activation of G protein-coupled inward rectifying K+ (GIRK) channels by
      Gi/Go-coupled receptors has been shown to be important in postsynaptic inhibition
      in the central nervous system, there is also evidence to suggest that inhibition
      of GIRK channels by Gq-coupled receptors is involved in postsynaptic excitation.
      In the present study we addressed whether the Gq-coupled receptors of the
      bombesin family can couple to GIRK channels and examined the mechanism by which
      this process occurs. Different combinations of GIRK channel subunits (Kir3.1,
      Kir3.2, and Kir3.4) and bombesin receptors (BB1 and BB2) were expressed in
      Xenopus oocytes. In all combinations tested GIRK currents were reversibly
      inhibited upon application of the bombesin-related peptides, neuromedin B or
      gastrin-releasing peptide in a concentration-dependent manner. Incubation of
      oocytes in the phospholipase C inhibitor U73122 or the protein kinase C (PKC)
      inhibitors chelerythrine and staurosporine significantly reduced the inhibition
      of GIRK currents by neuromedin B, whereas the Ca2+ chelator, BAPTA-AM had no
      effect. The involvement of PKC was further demonstrated by direct inhibition of
      GIRK currents by the phorbol esters, phorbol-12,13-dibutyrate and phorbol-12
      myristate-13-acetate. In contrast, the inactive phorbol ester 4alpha-phorbol and
      protein kinase A activators, forskolin and 8-bromo cAMP did not inhibit GIRK
      currents. At the single-channel level, direct activation of PKC using phorbol
      ester phorbol-12, 13-dibutyrate caused a dramatic reduction in open probability
      of GIRK channels due to an increase in duration of the interburst interval.

PMID- 10347244
TI  - Relationship between internalization and mRNA decay in down-regulation of
      recombinant type 1 angiotensin II receptor (AT1) expression in smooth muscle
      cells.
AB  - In vascular smooth muscle cells, the hormone angiotensin II is thought to cause
      internalization of the seven-transmembrane domain type 1 angiotensin II receptor
      (AT1-R) but it also suppresses expression of the receptor mRNA. As for similarly
      regulated members of this gene superfamily, the relative roles of these processes
      in receptor down-regulation are not well understood. In this study a recombinant
      AT1-R mRNA was synthesized in A7r5 vascular smooth muscle cells from a
      tetracycline-suppressible promoter using a retroviral vector system. Angiotensin
      II induces a profound internalization of the cell surface AT1-R protein but has
      no effect on steady-state AT1-R mRNA levels. Shortly after either bolus or
      prolonged dosing with angiotensin II, cell surface AT1-R expression recovers,
      indicating the existence of a significant restorative externalization pathway.
      The extent of this recovery is attenuated markedly when transcription of the
      recombinant AT1-R gene is suppressed by cotreatment of the cells with
      anhydrotetracycline. Although agonist-stimulated internalization appears to
      contribute directly to a loss of AT1-R protein, these observations provide direct
      evidence that a reduction in AT1-R mRNA content plays a significant role in
      sustained AT1-R down-regulation.

PMID- 10347245
TI  - Molecular determinants of (+)-tubocurarine binding at recombinant 5
      hydroxytryptamine3A receptor subunits.
AB  - The 5-hydroxytryptamine type 3 (5-HT3) receptor is a transmitter-gated ion
      channel mediating neuronal excitation. The receptor native to neurons, or as a
      homopentameric assembly of 5-HT3A receptor subunits, displays a species-dependent
      pharmacology exemplified by a 1800-fold difference in the potency of (+)
      tubocurarine [(+)-Tc] as an antagonist of the current response mediated by mouse
      and human receptor orthologs. Here, we attempt to identify amino acid residues
      involved in binding (+)-Tc by use of chimeric and mutant 5-HT3A subunits of mouse
      and human expressed in Xenopus laevis oocytes. Replacement of the entire
      extracellular N-terminal domain of the mouse 5-HT3A (m5-HT3A) subunit by that of
      the human ortholog and vice versa exchanged the differential potency of (+)-Tc,
      demonstrating the ligand binding site to be contained wholly within this region.
      Mutagenesis of multiple amino acid residues within a putative binding domain that
      exchanged nonconserved residues between mouse and human receptors shifted the
      apparent affinity of (+)-Tc in a reciprocal manner. The magnitude of the shift
      increased with the number of residues (3, 5, or 7) exchanged, with septuple
      mutations of m5-HT3A and human 5-HT3A subunits producing a 161-fold decrease and
      53-fold increase in the apparent affinity of (+)-Tc, respectively. The effect of
      point mutations was generally modest, the exception being m5-HT3A D206E, which
      produced a 9-fold decrease in apparent affinity. We conclude that multiple amino
      acids within a binding loop of human and mouse 5-HT3A subunits influence the
      potency of (+)-Tc.

PMID- 10347246
TI  - Nontransportable inhibitors attenuate reversal of glutamate uptake in
      synaptosomes following a metabolic insult.
AB  - Na+-dependent, high-affinity glutamate transporters in the central nervous system
      are generally credited with regulating extracellular levels of L-glutamate and
      maintaining concentrations below those that would induce excitotoxic injury.
      Under pathological conditions, however, it has been suggested that these same
      transporters may contribute to excitotoxic injury by serving as sites of efflux
      for cellular L-glutamate. In this study, we examine the efflux of [3H]D-aspartate
      from synaptosomes in response to both alternative substrates (i.e.,
      heteroexchange), such as L-glutamate, and a metabolic insult (5 mM potassium
      cyanide and 1 mM iodoacetate). Exposure of synaptosomes containing [3H]D
      aspartate to either L-glutamate or metabolic inhibitors increased the efflux of
      the radiolabeled substrate to over 200% of control values. Two previously
      identified competitive transport inhibitors (L-trans-2, 3-pyrrolidine
      dicarboxylate and dihydrokainate) failed to stimulate [3H]D-aspartate efflux but
      did inhibit glutamate-mediated heteroexchange, consistent with the action of
      nontransportable inhibitors. These compounds also attenuated the efflux of [3H]D
      aspartate from synaptosomes exposed to the metabolic inhibitors. These results
      add further strength to the model of central nervous system injury-induced efflux
      of L-glutamate through its high-affinity transporters and identify a novel
      strategy to attenuate this process.

PMID- 10347247
TI  - Mechanism of inhibition of a poxvirus topoisomerase by the marine natural product
      sansalvamide A.
AB  - At present no antiviral agents are available for treatment of infection by the
      pathogenic poxvirus molluscum contagiosum virus (MCV). Here we report the
      identification and characterization of an inhibitor active against the virus
      encoded type-1 topoisomerase, an enzyme likely to be required for MCV
      replication. We screened a library of marine extracts and natural products from
      microorganisms using MCV topoisomerase assays in vitro. The cyclic depsipeptide
      sansalvamide A was found to inhibit topoisomerase-catalyzed DNA relaxation.
      Sansalvamide A was inactive against two other DNA-modifying enzymes tested as a
      counterscreen. Assays of discrete steps in the topoisomerase reaction cycle
      revealed that sansalvamide A inhibited DNA binding and thereby covalent complex
      formation, but not resealing of a DNA nick in a preformed covalent complex.
      Sansalvamide A also inhibits DNA binding by the isolated catalytic domain,
      thereby specifying the part of the protein sensitive to sansalvamide A. These
      data specify the mechanism by which sansalvamide A inhibits MCV topoisomerase.
      Cyclic depsipeptides related to sansalvamide A represent a potentially promising
      chemical family for development of anti-MCV agents.

PMID- 10347248
TI  - The amino terminus of receptor activity modifying proteins is a critical
      determinant of glycosylation state and ligand binding of calcitonin receptor-like
      receptor.
AB  - The calcitonin receptor-like receptor (CRLR) can function as either a receptor
      for calcitonin gene-related peptide (CGRP) or for adrenomedullin (ADM), depending
      upon the coexpression of a novel family of single transmembrane proteins, which
      we have called receptor activity modifying proteins or RAMPs. RAMPs 1, 2, and 3
      transport CRLR to the plasma membrane with similar efficiencies, however RAMP1
      presents CRLR as a terminally glycosylated, mature glycoprotein and a CGRP
      receptor, whereas RAMPs 2 and 3 present CRLR as an immature, core glycosylated
      ADM receptor. Characterization of the RAMP2/CRLR and RAMP3/CRLR receptors in
      HEK293T cells by radioligand binding (125I-ADM as radioligand), functional assay
      (cAMP measurement), or biochemical analysis (SDS-polyacrylamide gel
      electrophoresis) revealed them to be indistinguishable, even though RAMPs 2 and 3
      share only 30% identity. Chimeric proteins were created with the transmembrane
      and cytosolic portions of RAMP1 associated with the amino terminus of RAMP2
      (RAMP2/1) and vice versa (RAMP1/2). Coexpression of RAMP2/1 with CRLR formed a
      core glycosylated ADM receptor, whereas the RAMP1/2 chimera generated both core
      glycosylated and mature forms of CRLR and enabled both ADM and CGRP receptor
      binding. Hence, the glycosylation state of CRLR appears to correlate with its
      pharmacology.

PMID- 10347249
TI  - Stoichiometry of sulfonylurea-induced ATP-sensitive potassium channel closure.
AB  - Hypoglycemic sulfonylureas (e.g., glibenclamide, glipizide, and tolbutamide)
      exert their stimulatory effect on excitatory cells by closure of ATP-sensitive
      potassium (KATP) channels. These channels are heteromultimers composed with a 4:4
      stoichiometry of an inwardly rectifying K+ channel (KIR) subunit 6.x plus a
      sulfonylurea receptor (SUR). SUR1/KIR6.2 reconstitutes the neuronal/pancreatic
      beta-cell channel, whereas SUR2A/KIR6.2 and SUR2B/KIR6.1 (or KIR6.2) are proposed
      to reconstitute the cardiac and the vascular smooth muscle-type KATP channels,
      respectively. SUR2A and SUR2B are splice variants of a single gene differing only
      in their C-terminal 42 amino acids. Affinities of sulfonylureas for rat SUR2A,
      rat or human SUR2B, and a SUR2 chimera containing the C-terminal 42 amino acids
      of SUR1 did not differ significantly, implying that the C terminus does not form
      part of the binding pocket. Consistent with these findings, reconstituted
      SUR2A/KIR6.2 and SUR2B/KIR6.2 channels revealed similar sensitivities for
      glibenclamide and tolbutamide. Dissociation constants of sulfonylureas for SUR2A
      and SUR2B were 10- to 400-fold higher than for SUR1, however, amazingly the
      benzoic acid derivative meglitinide did not show lower affinity for SUR2
      isoforms. Potencies of glibenclamide, glipizide, tolbutamide, and meglitinide to
      inhibit activity of SUR1/KIR6.2 and SUR2B/KIR6.2 channels were 3- to 6-fold
      higher than binding affinities of these drugs with concentration-inhibition
      relations being significantly steeper (Hill coefficients 1.23-1.32) than binding
      curves (Hill coefficients 0.93-1.06). The data establish that the C terminus of
      SURs does not affect sulfonylurea affinity and sensitivity. We conclude that
      occupation of one of the four SUR sites per channel complex is sufficient to
      induce KATP channel closure.

PMID- 10347250
TI  - Differential regulation of peptide alpha-amidation by dexamethasone and
      disulfiram.
AB  - alpha-Amidation is essential for the function of many peptides in intercellular
      communication. This C-terminal modification is mediated in a two-step process by
      the hydroxylase and lyase activities of the bifunctional enzyme, peptidylglycine
      alpha-amidating monooxygenase (PAM). The first step, catalyzed by peptidylglycine
      alpha-hydroxylating monooxygenase (PHM; EC 1.14.17. 3), is rate limiting in the
      process, and therefore subject to regulation. Dexamethasone and disulfiram
      (tetraethylthiuram disulfide; Antabuse) were used as in vivo treatments to study
      the regulation of PHM expression and activity in cardiac atrium. Our findings
      show that both dexamethasone and disulfiram treatment increase the activity of
      PHM in atrial tissue but that they do so by distinctly different mechanisms.
      Dexamethasone elevated tissue levels of PAM mRNA and protein concurrently,
      suggesting that glucocorticoids regulate PAM expression at the level of gene
      transcription. In contrast, disulfiram treatment, which depletes stores of alpha
      amidated peptides, increased the specific activity of PHM without affecting the
      level of PAM expression. The catalytic efficiency of PHM was enhanced by raising
      the Vmax of the enzyme. Importantly, this increase in Vmax was retained through
      purification to homogeneity, indicating that either a covalent modification or a
      stable conformational change had occurred in the protein. These novel findings
      demonstrate that the rate-limiting enzyme in the bioactivation of peptide
      messengers is differentially regulated by transcriptional and post
      transcriptional mechanisms in vivo. It is proposed that regulation of PHM's
      expression and catalytic efficiency serve as coordinated physiologic mechanisms
      for maintaining appropriate levels of alpha-amidating activity under changing
      conditions in vivo.

PMID- 10347251
TI  - Selective recognition of vitamin D receptor conformations mediates promoter
      selectivity of vitamin D analogs.
AB  - The transcription factor VDR is the nuclear receptor for 1alpha, 25
      dihydroxyvitamin D3 (VD) and the mediator of all genomic actions of the nuclear
      hormone and its synthetic analogs. The sharp biological profile of the model VD
      analog 1(S), 3(R)-dihydroxy-20(R)-(5'-ethyl-5'-hydroxy-hepta-1'(E), 3'(E)-dien-1'
      yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (EB1089) (i.e., its high
      antiproliferative effect combined with low calcemic actions) has been correlated
      with the selectivity of EB1089 to activate heterodimeric complexes of VDR with
      its partner retinoid X receptor (RXR) on VD response elements (VDREs). These
      VDREs are formed by an inverted palindromic arrangement of two hexameric core
      binding motifs spaced by nine nucleotides (IP9) rather than VDREs that are formed
      by direct repeats with three intervening nucleotides (DR3). In this report,
      ligand-dependent gel-shift assays were used for a comparison of the ability of VD
      and EB1089 to stabilize VDR-RXR heterodimers on these two VDRE types. The gel
      shift assays revealed EB1089 to be more sensitive for complexes on IP9-type VDREs
      than on DR3-type VDREs. In addition, a gel-shift clipping method was established
      to identify and compare complexes of ligand-stabilized VDR-RXR heterodimers on
      different VDREs. On each VDRE, two complexes could be discriminated that seemed
      to contain different functional conformations of the VDR and allowed a more
      differential view on DNA-complexed VDR-RXR heterodimers. The VDR-RXR conformation
      (which was more ligand-sensitive) gained through EB1089 a higher affinity (7
      fold) for DNA binding and a more sensitive (9-fold) activation of an IP9-type
      VDRE than of a DR3-type VDRE, whereas with the natural hormone VD, no VDRE-type
      preference could be observed. This indicates that promoter selectivity of VDR
      ligands is based on their property to selectively increase affinity for VDREs and
      very sensitively stabilize VDR conformations in VDR-RXR-VDRE complexes.

PMID- 10347252
TI  - Overexpression of p21(waf1) decreases G2-M arrest and apoptosis induced by
      paclitaxel in human sarcoma cells lacking both p53 and functional Rb protein.
AB  - We examined the effect of overexpression of p21(waf1) on cytotoxicity of
      paclitaxel, a microtubule stabilizer, using a tetracycline-inducible expression
      system in human sarcoma cells (SaOs-2) that lack both functional retinoblastoma
      protein and p53. Under normal growth conditions, p21(waf1) is not detectable in
      SaOs-2 cells. Upon p21(waf1) induction by tetracycline withdrawal, we observed a
      reduced apoptotic response to paclitaxel with a 3- to 6-fold increase in IC50
      values compared with that of cells not induced by p21(waf1). We also observed a 5
      fold increase in the IC50 value when cytotoxicity to vincristine, another
      microtubule-disrupting agent, was assessed, whereas we observed a marked decrease
      in the IC50 value after p21(waf1) induction in response to etoposide, a
      topoisomerase II inhibitor. After treatment with paclitaxel, less accumulation of
      G2-M was observed in p21(waf1)-induced cells compared with non-p21(waf1)-induced
      cells (57% versus 74%). p21(waf1) induction also inhibited the increased cyclin
      B1-associated kinase activity induced by paclitaxel. Overexpression of p21(waf1)
      in SaOs-2 cells lacking both p53 and functional retinoblastoma protein may
      decrease the G2-M arrest induced by paclitaxel due to suppression of the S-G2
      checkpoint, resulting in a decreased apoptotic response of cells to paclitaxel.

PMID- 10347253
TI  - Inhibition of cyclic AMP response element-binding protein/cyclic AMP response
      element-mediated transcription by the immunosuppressive drugs cyclosporin A and
      FK506 depends on the promoter context.
AB  - The immunosuppressants cyclosporin A and FK506 (tacrolimus) can block the
      phosphatase calcineurin, thereby inhibiting gene transcription directed by the
      cyclic AMP (cAMP)- and calcium-responsive transcription factor, cAMP response
      element (CRE)-binding protein, and its binding site, CRE, in various cell lines.
      This action is a novel molecular mechanism of cyclosporin A and FK506 action.
      Because inhibition of CREB/CRE-directed transcription by cyclosporin A and FK506
      has previously been observed by using synthetic minienhancers, reporter fusion
      genes were constructed to examine the effect of cyclosporin A and FK506 on the
      transcriptional activity of CRE-containing natural promoters. In transient
      transfection experiments, cyclosporin A and FK506 inhibited the transcriptional
      activation by cAMP and the membrane depolarization of three CRE-containing
      promoters. However, cyclosporin A and FK506 failed to inhibit the activation by
      cAMP of another promoter, the rat insulin I gene promoter. The lack of
      cyclosporin A/FK506 sensitivity is not intrinsic to the insulin CRE because
      cyclosporin A and FK506 inhibited the activation by cAMP of the insulin CRE when
      isolated and used as a synthetic minienhancer. Rather, cyclosporin A/FK506
      resistance may be conferred by specific promoter interactions because a
      mutational analysis of the insulin promoter revealed that inside this promoter,
      CRE activity depends on an adjacent control element. These data show that
      cyclosporin A and FK506 can inhibit CRE activity when the CRE resides in its
      natural promoter. However, the cyclosporin A/FK506 sensitivity depends on the
      specific promoter context. The results suggest that cyclosporin A and FK506 may
      alter target tissue function through the regulation of a subset of CRE-containing
      genes.

PMID- 10347254
TI  - Cloning and functional expression of the human histamine H3 receptor.
AB  - Histamine regulates neurotransmitter release in the central and peripheral
      nervous systems through H3 presynaptic receptors. The existence of the histamine
      H3 receptor was demonstrated pharmacologically 15 years ago, yet despite
      intensive efforts, its molecular identity has remained elusive. As part of a
      directed effort to discover novel G protein-coupled receptors through homology
      searching of expressed sequence tag databases, we identified a partial clone
      (GPCR97) that had significant homology to biogenic amine receptors. The GPCR97
      clone was used to probe a human thalamus library, which resulted in the isolation
      of a full-length clone encoding a putative G protein-coupled receptor. Homology
      analysis showed the highest similarity to M2 muscarinic acetylcholine receptors
      and overall low homology to all other biogenic amine receptors. Transfection of
      GPCR97 into a variety of cell lines conferred an ability to inhibit forskolin
      stimulated cAMP formation in response to histamine, but not to acetylcholine or
      any other biogenic amine. Subsequent analysis revealed a pharmacological profile
      practically indistinguishable from that for the histamine H3 receptor. In situ
      hybridization in rat brain revealed high levels of mRNA in all neuronal systems
      (such as the cerebral cortex, the thalamus, and the caudate nucleus) previously
      associated with H3 receptor function. Its widespread and abundant neuronal
      expression in the brain highlights the significance of histamine as a general
      neurotransmitter modulator. The availability of the human H3 receptor cDNA should
      greatly aid in the development of chemical and biological reagents, allowing a
      greater appreciation of the role of histamine in brain function.

PMID- 10347255
TI  - Endovascular treatment of aortoiliac aneurysms: made-to-measure stent-grafts
      increase feasibility.
AB  - We describe here our preliminary experience with use of a range of made-to
      measure stent-grafts made from commercially available components. From January
      1996 to June 1998, 94 aortoiliac aneurysms (AIA) were treated with stent-grafts
      that were made to measure using Z autoexpandable stainless steel stents connected
      with polyester sutures and covered with commercially available polyester vascular
      prostheses. These stent-grafts were implanted through 18 to 24 (typically 20) Fr
      commercially available introducers via a surgical remote access. Made-to-measure
      tubular, bifurcated, tapered, and/or blind stents combined with extraanatomic
      bypass designs increased the rate of endovascular treatment (ET) of AIA in this
      series. This rate was further increased through the use of uncovered proximal or
      distal stents when dealing with short or tortuous necks near major collaterals
      and through use of hybrid, partly surgical designs, one with stented and the
      other with stentless ends, the latter allowing for a surgically made anastomosis.
      The results of our experience with these techniques show that use of made to
      measure stent-grafts greatly increases the feasibility of the ET of AIA among
      unselected patients while offering enough efficiency and safety to deserve
      further investigation.

PMID- 10347257
TI  - Stenting for atherosclerotic occlusive disease of the subclavian artery.
AB  - The purpose of this study was to evaluate the results of stenting subclavian
      artery pathologic lesions. Between July 1991 and December 1995, 69 patients (36
      males: mean age 67 years, range 34-87 years) underwent intraluminal balloon
      dilatations followed by stent implantations in 70 subclavian arteries to treat
      primary atherosclerotic stenoses > 70%. Twenty-three patients (34%) were treated
      for vertebrobasilar insufficiency (VBI), 25 patients (36%) were treated for upper
      limb ischemia (ULI), and 10 patients (15%) were treated for both VBI and ULI.
      Other indications included symptomatic subclavian steal phenomenon (SSS),
      protection of dialysis arteriovenous fistula, coronary steal syndrome, protection
      of axilloaxillary bypass, distal embolization, and protection of left internal
      mammary artery (LIMA)-coronary bypass. Fifty-three cases (78%) were treated for
      stenosis and 17 cases (22%) for total occlusion of the origin of the subclavian
      artery. The results of this series indicate that stenting of subclavian artery
      stenosis appears safe and feasible with good short and mid-term patency,
      improving at those intervals the initial disappointing reports of balloon
      angioplasty alone. However, its long-term durability is at present unknown.

PMID- 10347256
TI  - Endovascular stent-grafts for aneurysms of the femoral and popliteal arteries.
AB  - Our objective was to investigate the preliminary use of endovascular stent-grafts
      for the treatment of femoropopliteal artery aneurysm. Ten patients with an
      aneurysm of the femoropopliteal artery referred for endovascular treatment were
      investigated. The series consisted of patients with a true aneurysm of the
      superficial femoral artery (n = 2); a true aneurysm of the popliteal artery (n =
      4); an aneurysmal dilatation of a Biograft bypass (n = 2); a false aneurysm of
      the superficial femoral aneurysm (n = 1); and a false aneurysm of a composite
      bypass (n = 1). In 8 of the 10 patients the stent-graft was composed of one or
      more Palmaz stents sutured to an ePTFE tube graft; in the other 2 patients a
      venous covering was used in combination with Palmaz stents. The procedure was
      guided by angiography and intravascular ultrasound. The results of our
      investigation showed that endovascular stent-grafting of aneurysms of the
      femoropopliteal artery is a feasible but experimental technique that should be
      restricted to a selected group of patients.

PMID- 10347258
TI  - Cryopreserved arterial homografts: preliminary results in infrageniculate
      arterial reconstructions.
AB  - The aim of this report is to present our preliminary experience using
      cryopreserved arterial homografts in below-knee revascularization. We carried out
      a retrospective study at the Public Health Hospital of the Servicio Galego da
      Saude (SERGAS) from October 1995 to March 1997 in which cryopreserved arterial
      homografts were used for revascularization of 17 lower limbs in 16 patients. The
      clinical indications were limb-threatening ischemia in 15 lower extremities (7
      with rest pain and 8 with ischemic ulcers or gangrene), and large aneurysms of
      femoropopliteal arteries in 2. In addition, 75% of the patients had undergone
      previous surgical procedures for revascularization on the involved extremity. No
      patient had a suitable greater saphenous vein in the ipsilateral extremity and
      all patients required a below-knee arterial reconstruction procedure. There was
      just one runoff vessel in 11 of 17 extremities (65%). A histological exam was
      performed in four patients who died (1 case) or had homograft-related
      complications (3 cases). The results of this study indicated that cryopreserved
      arterial homografts could be a promising alternative when below-knee
      revascularization is required in patients lacking suitable greater saphenous
      vein, especially in those with limited life expectancy, but despite early
      acceptable results, many aspects must be clarified. Close follow-up is mandatory.

PMID- 10347259
TI  - Experience of supraclavicular exploration and decompression for treatment of
      thoracic outlet syndrome.
AB  - The purpose of this study was to assess the symptomatic outcome of patients with
      thoracic outlet syndrome who underwent decompression of the thoracic outlet. In
      our unit we prefer the supraclavicular approach, performing anterior scalenectomy
      with excision of fibrous bands or cervical ribs if present. Operative details
      were gained by theater logbook and case note review. Over a 6-year period, 31
      patients (37 limbs) underwent thoracic outlet decompression. Of the 37 affected
      limbs, the indications for surgery were a combination of both neurological and
      vascular symptoms in 24 patients (65%), neurological symptoms in 24 (65%), and 4
      patients (11%) had vascular symptoms alone. All patients were assessed for
      postoperative outcome either at out-patient clinics or by personal contact. From
      the results of this study we concluded that supraclavicular scalenectomy and
      cervical rib excision with selective first rib excision is a safe and effective
      procedure for most patients with thoracic outlet syndrome.

PMID- 10347261
TI  - Use of ipsilateral greater saphenous vein as a valved transplant in management of
      post-thrombotic deep venous insufficiency: long-term results.
AB  - Incompetence of the deep venous valve is a common feature of post-thrombotic deep
      venous insufficiency. Various surgical techniques have been proposed to treat
      reflux. In this study we describe long-term results of a novel transposition
      technique using the ipsilateral greater saphenous vein. From 1984 to 1994 we used
      this procedure to treat 16 patients including 10 men and 6 women with a mean age
      of 56 years (range: 25 to 76 years). In all 16 cases the indication for surgery
      was incapacitating pain associated with recurring ulceration in 9 patients. From
      the results of using this technique we conclude that transposition using the
      ipsilateral greater saphenous vein is safe and effective with good mid-term
      results, especially for pain. For ulcers the primary success rate was 55% but
      this increased to 84% with proper surveillance and treatment of secondary
      insufficiency of the superficial venous system.

PMID- 10347260
TI  - The predictive value of intraoperative duplex for early vein graft patency in
      lower extremity revascularization.
AB  - This study was undertaken to evaluate the ability of intraoperative duplex
      scanning during infrainguinal vein bypass to identify technical abnormalities and
      to determine the relation between intraoperative scan result and early primary
      graft patency. We retrospectively reviewed of 78 consecutive intraoperative
      duplex scans for infrainguinal vein bypass that were performed between October
      1993 and October 1996 during the course of infrainguinal vein bypass. Duplex
      scans were classified as normal or abnormal based on B-mode image and/or Doppler
      velocity spectra. Grafts were grouped according to duplex findings and
      intraoperative action: group I, normal intraoperative scan; group II, abnormal
      intraoperative scan, revised; group III, abnormal intraoperative scan, not
      revised. The relationship of intraoperative duplex scan findings to
      intraoperative graft revision to 1-month and 6-month primary graft patency by
      life table was analyzed. The analysis demonstrates that the results of
      intraoperative duplex scans can be used to identify grafts at low risk for early
      postoperative graft failure (groups I and II), and those at high risk for early
      postoperative graft failure (group III).

PMID- 10347262
TI  - Prosthetic reinforcement of varicose saphenous vein grafts for infrainguinal
      bypass.
AB  - Use of varicose saphenous veins for infrainguinal bypass is often contraindicated
      because of the risk of immediate rupture or long-term aneurysm. In this report we
      describe four cases in which prosthetic reinforcement allowed successful
      femoropopliteal bypass grafting using highly varicose saphenous veins while
      preserving normal endothelium. No thrombosis or any other complication was
      observed after a mean follow-up of 41 months.

PMID- 10347263
TI  - Ultrastructural analogies between intimal alterations in veins from diabetic
      patients and animals with STZ-induced diabetes.
AB  - The aim of this study was to document similarities and differences between veins
      from human diabetic patients and an experimentally induced diabetic animal model.
      The saphenous vein and posterior tibial vein from diabetic patients and the
      femoral vein from rats were studied. An increase in the extracellular matrix with
      migration of smooth muscle cells and endothelial alterations were observed in the
      intima of all specimens. These findings demonstrate that there is a high degree
      of similarity between the pathological changes in the venous wall during human
      diabetes mellitus and streptozotocin (STZ) induced-diabetes. This finding
      validates STZ induced-diabetes in rats as a model for further experimental study
      to clarify the fate of the diabetic venous wall when used as a graft.

PMID- 10347264
TI  - Aortic thrombosis associated with cocaine use: report of two cases.
AB  - Cocaine use has been associated with many vascular complications which may
      involve the carotid, coronary, and renal vascular beds. Cocaine may also cause
      venous thrombosis. This report describes a new entity of cocaine-induced aortic
      thrombosis. On the basis of clinical findings and response to treatment, a
      therapeutic algorithm is presented.

PMID- 10347265
TI  - Mycosis fungoides masquerading as an ischemic foot.
AB  - This case is of a man with bilateral lower-extremity ischemia and a solitary
      nonhealing ulcerated lesion of the right great toe. After revascularization with
      an aortobifemoral bypass, his right ABI increased from 0.5 to approximately 0.75,
      but the ulcerated toe lesion did not show signs of healing and instead progressed
      to a deeper ulceration exposing bone. Because of presumptive osteomyelitis, we
      performed a great toe amputation, and immunohistochemical analysis of the lesion
      revealed late plaque stage mycosis fungoides (MF). We present this case to alert
      the vascular surgeon to this diagnostic possibility when confronted with an
      apparent ischemic lesion and to describe what made this particular lesion
      suspicious for MF. To the best of our knowledge, this is the first case of MF
      presenting solely as an ischemic lesion.

PMID- 10347266
TI  - The hemodynamics of steal syndrome and its treatment.
AB  - A 61-year-old man developed steal syndrome after creation of a transposed basilic
      vein arteriovenous fistula (AVF) resulting in rest pain and ischemic ulcers in
      the fingertips. Our initial surgically created stenosis reduced the diameter by
      32% and the area by 56%, and increased the radial artery pressure from 52 to 78
      mmHg, with relief of symptoms. Within 3 weeks his symptoms reappeared. Repeat
      measurements did not explain his return of symptoms. A second area of stenosis
      was created in the AVF, with a diameter reduction of 75%, and an area reduction
      of 94%. His symptoms resolved, and his ulcers healed. The hemodynamics of the AVF
      and the steal syndrome were evaluated by duplex imaging and Doppler pressure
      assessment. A greater stenosis increased the radial artery pressure from 78 to
      140 mmHg while maintaining flow through the AVF. Rather than increasing the
      degree of stenosis at the first site, we created a second area of stenosis.
      Hemodynamically, this would be additive to the first without the risk of creating
      a high-grade stenosis that could thrombose the AVF. Increasing the resistance in
      the AVF will decrease flow in the AVF and, ultimately, increase flow to the hand.

PMID- 10347267
TI  - Clinical and experimental demonstration of complete healing of porous Dacron
      patch grafts used for closure of the arteriotomy after carotid endarterectomy.
AB  - A clinical porous Dacron patch graft used for closure after carotid
      endarterectomy was explanted 24 hr postmortem during autopsy. There had been no
      TIAs or stroke postoperatively, and the cause of death was congestive heart
      failure. The graft had been implanted for 25 months. The specimen had a very
      clean surface, was completely incorporated by full-wall tissue ingrowth, and the
      flow surface was covered with well-organized neointima containing endothelial
      cells and smooth muscle cells, as confirmed by immunological studies. For
      comparison, animal experiments were performed. In both the clinical and
      experimental specimens the carotid patches were patent without neointimal
      compromise of the lumen, and their healing patterns were similar, with
      endothelium on the flow surface.

PMID- 10347268
TI  - Deep venous thrombosis and pulmonary embolism: diagnosis, prophylaxis, and
      treatment.

PMID- 10347269
TI  - Animal models in syndromes of accelerated arteriosclerosis.

PMID- 10347270
TI  - Autogenous valve reconstruction technique for post-thrombotic reflux.
AB  - Post-thrombotic reflux in deep veins of the lower extremities cannot be treated
      by in situ valvuloplasty because of valve degeneration. The outcome of
      transplantation and transposition of segments with valves is controversial. From
      feasibility tests in animals and fresh human cadavers we have developed an
      autogenous valve reconstruction technique. The valve is fashioned from the
      proximal end of the greater saphenous vein that is left attached to the femoral
      vein, invaginated, and fixed to the venous wall. This technique provides a
      competent bicuspid valve. In a series of 19 patients operated on in 1995 we
      performed 20 valve reconstruction procedures at the level of the femorosaphenous
      junction by invagination of a fragment from the proximal end of the greater
      saphenous vein in the common femoral vein. Mean follow-up time was 10 months. No
      complications were observed. All femoral veins were patent and competent except
      one in which mild reflux was observed because of insufficient valve size. Further
      follow-up is needed to confirm the efficacy of this simple, new technique.

PMID- 10347271
TI  - Endoscopic subfascial perforating vein ligation: its complementary role in the
      surgical management of chronic venous insufficiency.
AB  - Endoscopic methods have proven as efficacious as previous open surgical
      techniques for ligation of calf perforating veins. The reduced incidence of wound
      complications favors the minimally invasive approach regardless of the technique
      used. Since isolated disease of the calf perforating veins is rare, most of these
      procedures are performed in conjunction with superficial venous ablation. These
      advanced procedures are indicated for patients with skin and subcutaneous
      manifestations of CVI (CEAP classes 4, 5, and 6). Although the contribution of
      perforator ligation to the hemodynamic and clinical result is unclear, clinical
      symptoms and hemodynamics have significantly improved when performed as
      described.

PMID- 10347272
TI  - : new challenges to the autopsy in the united states 

PMID- 10347273
TI  - Parvovirus B19: twenty-five years in perspective.

PMID- 10347274
TI  - Respiratory syncytial virus infects the Bonnet monkey, Macaca radiata.
AB  - The Bonnet monkey model of respiratory syncytial virus (RSV) infection may be a
      useful nonhuman primate model for studying RSV disease in humans because Bonnet
      monkeys can predictably be infected to obtain an orderly sequence of morphologic,
      cytologic, virologic, serologic, and inflammatory changes related to time of
      infection. Young feral Bonnet monkeys, Macaca radiata, were infected
      endotracheally with 10(6) plaque-forming units (pfu) of the Long strain of RSV.
      RSV was recovered from the animals' lungs at necropsy on days 3, 5, and 7 with
      the highest viral titer obtained on day 3 (1.1 and 5.2 x 10(3) pfu/g of tissue in
      the upper and lower lobes, respectively). RSV antigen and F protein mRNA were
      detected 3-5 days after infection in alveolar macrophages and in the epithelium
      of bronchi, terminal bronchioles, and alveoli. Histologic analysis of RSV
      infected lungs at necropsy revealed progressive bronchiolar mucosal and
      submucosal inflammation, periarterial mononuclear interstitial inflammation, and
      focal alveolitis, with a maximal response at 7 days after infection. Cell counts
      in bronchoalveolar lavage (BAL) increased with time with neutrophils and
      macrophages predominating on day 3 (6.47 and 5.85 x 10(5)/mm3, respectively) and
      lymphocytes predominating on day 9 (4.18 x 10(5)/mm3). Serum-neutralizing
      antibody appeared on day 5 and IgG antibody to RSV was detected on day 9. This
      sequence of morphologic, cytologic, virologic, serologic, and inflammatory change
      following RSV infection creates a useful model in the study of experimentally
      induced RSV disease with a potential for testing future vaccine-induced
      alterations in RSV disease response.

PMID- 10347275
TI  - Sudden death due to ventricular septal defect.
AB  - Ventricular septal defects (VSD) are usually considered non-life-threatening,
      usually closing spontaneously or causing symptoms of congestive heart failure,
      which can be surgically treated in time to save the patient's life. Despite the
      usually benign clinical course of VSD, serious arrhythmias occur in 16-31% of
      patients. Sudden death accounted for one-third of all deaths in a series of
      medically managed patients and occurred in 4.2% of patients in a study of VSD and
      arrhythmias. Cardiac hypertrophy is the common denominator in all cases reported
      in detail of VSD-associated sudden death. We have encountered four cases of
      sudden unexpected death from VSD in infants ranging in age from 1 week to 3 and
      (1/2) months. In each case there was cardiomegaly and in one case there was
      pulmonary arteriolar medial thickening, with extension of smooth muscle into
      small intralobular vessels. In half of our cases the attending physician was sued
      for malpractice. We believe that VSD in infants and young children are
      potentially life-threatening malformations which warrant careful clinical follow
      up.

PMID- 10347276
TI  - Testicular changes in newborn rats exposed to phototherapy.
AB  - In this study we investigated the long-term effects of 72-h continuous
      phototherapy on the reproductive system of newborn rats. The animals' weight,
      fertilization rates, and number of newborn and histopathological changes in the
      gonads in a normal group not exposed to phototherapy and in the test animals were
      compared. At the age of 24 weeks there were no significant differences between
      the two groups, apart from the histology of the testicles of the male rats who
      were exposed to the phototherapy. The study group showed a significantly reduced
      diameter of the seminiferous tubules when compared to the controls (P < 0.001).
      It can be postulated that phototherapy may cause histological degenerative
      changes in the structure of the rat's testes, even though there were no changes
      in fertilization rates. Further studies are necessary to reveal the effects of
      phototherapy on humans and to determine the effects, if any, on fertility.

PMID- 10347278
TI  - Congenital intraspinal lipomas: histological analysis of 234 cases and review of
      the literature.
AB  - The clinical, radiologic, and pathologic data from a series of 234 patients
      hospitalized in the Pediatric Neurosurgical Department of the Necker-Enfants
      Malades Hospital, Paris, for congenital intraspinal lipomas and operated on from
      1976 to 1995 were examined. Histological studies showed that these lesions may be
      simple lipomas, similar to those developing elsewhere in the body, or they may be
      more complex forms including in addition to the lipomatous component a variety of
      unusual ectopic tissues of ectodermal, mesodermal, and/or endodermal origin.
      These complex forms indica te the malformative nature of these tumors. When they
      contain elements that are truly foreign to the region, the possibility of
      teratoma with a tumoral potential should be considered. Data found in the
      literature and from Necker-Enfants Malades Hospital are discussed.

PMID- 10347277
TI  - Fatal hepatic short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency:
      clinical, biochemical, and pathological studies on three subjects with this
      recently identified disorder of mitochondrial beta-oxidation.
AB  - This report describes the clinical, biochemical, and pathological findings in
      three infants with hepatic short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase
      (SCHAD) deficiency, a recently recognized disorder of the mitochondrial oxidation
      of straight-chain fatty acids. Candidate subjects were identified from an ongoing
      study of infant deaths. SCHAD analysis was performed on previously frozen liver
      and skeletal muscle on subjects with a characteristic urine organic acid profile.
      Autopsy findings were correlated with the biochemical abnormalities. Enzyme
      analysis in liver revealed marked deficiency in SCHAD with residual activities of
      3-11%. All subjects had normal activity in skeletal muscle. However, Western blot
      analysis of SCHAD revealed an identical truncated protein in both liver and
      muscle from one patient, suggesting that SCHAD is similar in liver and muscle and
      that the normal activity in muscle may be due to other enzymes with C4 activity.
      Autopsy findings revealed marked steatosis and a muscle pattern consistent with
      spinal muscular atrophy in one patient. Lipid storage was less pronounced in one
      patient and not detected in the third patient who had a well-documented history
      of recurrent hypoglycemia. This is the initial pathological characterization of
      this enzyme defect, and our observations suggest that SCHAD deficiency is a very
      severe disorder contributing to early infant death.

PMID- 10347279
TI  - Infantile liver giant cells: immunohistological study of their proliferative
      state and possible mechanisms of formation.
AB  - The mechanism of liver giant cell formation is not clarified. Some authors
      consider the giant cells regenerative, others, degenerative. Paraffin sections of
      10 archival cases of idiopathic neonatal hepatitis (INH), 8 of extrahepatic
      biliary atresia (EHBA), and 5 normal liver samples were immunostained with two
      well-characterized cell proliferation markers: anti-PCNA monoclonal antibody
      (MAb) (clone PC-10) and MAb MIB-1, which detects Ki-67, a nuclear proliferation
      related antigen. In addition, polyclonal antibody to carcinoembryonic antigen
      (CEA) was used to identify remnants of canalicular, therefore hepatocytic,
      membranes in giant cells. Quantitative analysis of immunostaining was done by
      estimating PCNA and Ki-67 indices separately in giant cells and in nongiant
      hepatocytes. In normal samples, mean PCNA and Ki-67 indices were 1. 22% and
      0.74%, respectively. In the cases of INH and EHBA, only a small minority of giant
      cells showed PCNA or Ki-67 staining limited to occasional peripherally located
      nuclei. PCNA and Ki-67 indices were significantly higher in the non-giant cell
      compartment. CEA staining was seen only in rare giant cells as centrally located
      canalicular remnants bordered by polarized nuclei, suggesting that they had been
      formed from rosettes through dissolution of cell membranes. Other giant cells
      shared CEA-labeled canalicular membranes with mononuclear hepatocytes in
      rosettes. These findings indicate that the giant cells in INH and EHBA are not
      regenerative cells, they are not formed by amitotic division of nuclei in
      syncytia, and that fusion of rosette-forming hepatocytes is a possible mechanism
      of their formation.

PMID- 10347280
TI  - Hemophagocytic syndrome presenting as acute hepatic failure in two infants:
      clinical overlap with neonatal hemochromatosis.
AB  - Two patients with hemophagocytic lymphohistiocytosis who presented with acute
      liver failure are reported. Both presented with fever, hepatosplenomegaly,
      markedly elevated liver function tests, abnormal coagulation profiles, and an
      increase in serum ferritin. Both infants were diagnosed with neonatal
      hemochromatosis based on a clinical picture of hepatic insufficiency with
      hyperferritinemia and were referred for liver transplantation. The first patient
      died of liver failure and septicemia before transplantation. Review of autopsy
      material revealed a hepatitis-like pattern and extensive infiltration of liver
      and other organs including bone marrow by histiocytes, some of which were
      hemophagocytic. The second patient underwent liver transplantation but died 44
      days thereafter from progressive hemophagocytic lymphohistiocytosis. Examination
      of the resected liver demonstrated a hepatitis-like pattern, proliferation of
      histiocytes, and hemophagocytosis, and the bone marrow revealed hemophagocytic
      histiocytosis. Hemophagocytosis recurred in the allograft. Hepatic manifestations
      are common in hemophagocytic lymphohistiocytosis and overt hepatic failure may
      occur, but initial presentation as fulminant hepatic failure is not well
      recognized. Elevated serum ferritin can make the distinction from neonatal
      hemochromatosis and other forms of neonatal liver failure difficult.
      Hemophagocytic lymphohistiocytosis should be considered in the differential
      diagnosis of neonatal liver disease, especially when it is accompanied by
      cytopenias.

PMID- 10347281
TI  - Heterotopic pancreas as lead point in intussusception: new variant of
      vitellointestinal tract malformation.
AB  - Two cases of intussusception are reported with heterotopic pancreatic tissue
      attached to and draining into the ileum. The first patient, a boy aged 16 months,
      presented with ileoileal intussusception. The diagnosis was confirmed on
      ultrasound scan. Laparotomy and resection were performed. A 12-mm nodule of
      heterotopic pancreatic tissue was identified in the ileal serosa at the apex of
      the intussusceptum, fully formed with acinar tissue, islets, and draining duct.
      The second patient, also a boy aged 16 months, presented with obstructed
      ileocolic intussusception in which the lead point at surgery resembled a Meckel's
      diverticulum. Histopathology revealed a similar 10-mm nodule of fully formed
      pancreatic tissue in the ileal serosal tissues, with some acinar tissue extending
      through the wall of the intestine alongside ductal structures. In both cases
      there was ectopic gastric mucosa either in the distal part of the draining duct
      or in the small intestine itself at the opening. Heterotopic pancreas is a rare
      cause of intussusception. We propose that this lesion is of vitellointestinal
      tract origin, conceptually similar to a Meckel's diverticulum but without a
      diverticulum as such. Heterotopic pancreatic tissue occurring alone is more
      common in the proximal small intestine, duodenum, and stomach than in the ileum,
      and it is often asymptomatic.

PMID- 10347282
TI  - Hematogones as an internal control in flow cytometric analysis of suspected acute
      lymphoblastic leukemia.
AB  - Hematogones are benign immature B cells that commonly populate the bone marrow of
      children. Their presence has been noted to interfere with the flow-cytometric
      analysis of cases of suspected acute lymphoblastic leukemia (ALL) because their
      immunophenotype (positive for CD19, CD10, CD34, and terminal deoxynucleotidyl
      transferase) is similar to that of pre-B cell lymphoblasts. Here we report a case
      in which the presence of a discrete population of hematogones, characterized by
      low-intensity CD10 cell-surface staining compared with pre-B cell lymphoblasts,
      actually aided in the recognition of early relapsed ALL and disease progression
      over a 4-day period. We also review our experience with flow-cytometric
      immunophenotyping in pediatric cases of suspected leukemia to evaluate the
      frequency of this occurrence.

PMID- 10347283
TI  - p53 and Ki-67 proliferating cell nuclear antigen in benign and malignant
      peripheral nerve sheath tumors in children.
AB  - Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon soft tissue
      tumors. In children with neurofibromatosis 1 (NF1), a MPNST often arises in a pre
      existing neurofibroma, or may represent an initial manifestation without other
      obvious stigmata of the disease. The development of MPNSTs may be associated with
      instability of the p53 tumor suppressor gene since it is the most frequent
      genetic abnormality in soft tissue sarcomas. To assess the presence of p53
      accumulation in MPNSTs and its correlation with clinical and pathologic features,
      we studied 12 neurofibromas (NFs), including 4 tumors with cellular features (one
      congenital) and 10 MPNSTs. Six MPNSTs were associated with NF1, all of which
      developed within a plexiform neurofibroma. Cell proliferation evaluated with an
      antibody to Ki-67 and nuclear p53 staining were both detected by
      immunohistochemistry. We found p53 positivity in 60% of MPNSTs. All NFs except
      the congenital tumor were p53 immunonegative (P < 0.01). Rare p53-positive nuclei
      were detected in the transitional zone in two of six MPNSTs arising in plexiform
      NFs. Ki-67 distinguished the NFs from MPNSTs (P < 0.005). Half of the NF1
      patients with p53-positive MPNSTs developed recurrence or metastases or developed
      a second malignancy within 2 years of diagnosis, whereas patients with p53
      positive sporadic MPNSTs were free of disease 1 to 7 years later. We found p53
      accumulation more frequently in NF1-associated MPNSTs. p53 mutations may be an
      additional biologic factor to account for the poor prognosis in these tumors.

PMID- 10347285
TI  - Abstracts from the 44th annual meeting of the paediatric pathology society,
      lorient, france, september 17-19, 1998 

PMID- 10347284
TI  - Takayasu's arteritis coexisting with Wegener's granulomatosis in a teenager with
      renal insufficiency: case report.
AB  - A case of Wegener's granulomatosis (WG) coexisting with Takayasu's arteritis (TA)
      in a 12-year-old girl is presented. She presented with fulminant and severe renal
      insufficiency due to crescentic glomerulonephritis. At autopsy, aortic lesions of
      Takayasu's arteritis coexisted with pulmonary and renal findings of WG, and the
      patient's serum at autopsy had an elevated level of antineutrophil cytoplasmic
      antibodies (ANCA). Both forms of vasculitis have been thought to be triggered by
      infectious agents and it is postulated that this occurrence accounts for the
      coexistence of the two forms of vasculitis in this case.

PMID- 10347287
TI  - Laparoscopic bariatric surgery.

PMID- 10347288
TI  - Laparoscopic gastric banding for morbid obesity. Surgical outcome in 335 cases.
AB  - BACKGROUND: Morbid obesity occurs in 2-5% of the population of Europe, Australia,
      and the United States and is becoming more common. Open surgical techniques, such
      as vertical banded gastroplasty and other divisional procedures in the stomach,
      have led to long-term weight reduction as well as an amelioration of the
      attendant medical problems in approximately two-thirds of patients. MATERIALS AND
      METHODS: A total of 335 patients with a median age of 41 years underwent gastric
      banding. We emphasized the need for long-term maintenance and follow-up. The
      indications for surgery comprised a body mass index >35, a stated desire to
      undergo the procedure, and a full understanding of all possible complications.
      RESULTS: All patients have needed band adjustments of 1-4 ml over the course of
      their follow-up. No patient had increased his or her weight during the follow-up,
      and only three patients have not enjoyed sustained weight loss. CONCLUSIONS:
      Laparoscopic gastric banding has much to recommend it. Certainly in the short
      term, its results in terms of effectiveness of weight loss are at least as good
      as those of any open procedure. Longer follow-up will show whether this weight
      loss is maintainable. The procedure is technically demanding, and the major
      prerequisite of satisfactory performance of this surgery is laparoscopic
      experience.

PMID- 10347289
TI  - Laparoscopic gastric reduction surgery. Preliminary results of a randomized,
      prospective trial of laparoscopic vs open vertical banded gastroplasty.
AB  - BACKGROUND: The purpose of the current study was to present the preliminary
      results of a randomized prospective trial comparing laparoscopic and open
      vertical banded gastroplasty (Mason's procedure). METHODS: From April 1995 to
      April 1996, 68 patients (9 men and 59 women, mean age, 36 years; ranges, 17-60
      years) affected from morbid obesity (mean body weight, 123 kg; range, 89-188 kg;
      mean body mass index (BMI), 43 kg/m2; range, 37-66 kg/m2) were enrolled in a
      prospective trial and randomly assigned to a laparoscopic (group A) or open
      (group B) Mason's gastroplasty. There was no statistically significant difference
      between the two groups in terms of patient epidemiologic data. The significance
      level among the data was assessed by means of Fisher's exact test. RESULTS: The
      success of laparoscopic gastroplasty was 88.2% (30/34). The intervention was
      significantly longer in the laparoscopic group (150 min vs. 60 min; p = 0.001).
      No mortality was recorded in the overall population. Intraoperative complications
      included only one case of gastric bleeding in group A (2.9% vs. 0%; p value not
      significant [NS]). Early major complications ranged as high as 6.6% and 7.8%,
      respectively, in groups A and B (p = NS), and included one case of peritonitis
      and one case of pneumonia in group A, and two cases of peritonitis and one
      pulmonary embolism in group B. Early minor postoperative complications consisted
      of wound infections only, observed in one group A patient (3.3%) and four group B
      patients (10. 8%, p = 0.04). At longer follow-up, incisional hernias occurred in
      15.8% (6/38) of patients surgically treated with a conventional approach compared
      with none among those successfully surgically treated with laparoscopic access (p
      = 0.04). No statistically significant difference was observed between the two
      groups regarding the efficacy of the procedure, in terms of decrease in
      percentage of excess body weight, mean body weight, or mean BMI. CONCLUSIONS: The
      preliminary results of current study show that the laparoscopic Mason procedure
      is a time-consuming and technically demanding operation, as effective as its
      traditional counterpart, but carrying a statistically significant decrease in the
      incidence of wound infections and incisional hernias.

PMID- 10347290
TI  - Effect of spleen size on splenectomy outcome. A comparison of open and
      laparoscopic surgery.
AB  - BACKGROUND: Laparoscopic splenectomy (LS) is gaining acceptance as an alternative
      to open splenectomy (OS). However, splenomegaly presents an obstacle to LS, and
      massive splenomegaly has been considered a contraindication. Analyses comparing
      the procedure with the open approach are lacking. The purpose of this study was
      to analyze the effect of spleen size on operative and immediate clinical outcome
      in a series of 105 LS compared with a series of 81 cases surgically treated by an
      open approach. METHODS: Between January 1990 and November 1998, 186 patients
      underwent a splenectomy for a wide range of splenic disorders. Of these patients,
      105 were treated by laparoscopy (group I, LS; data prospectively recorded) and 81
      were treated by an open approach (group II, OS analyzed retrospectively).
      Patients also were classified into three groups according to spleen weight: group
      A, <400 g; group B, 400-1000 g; and group C, >1000 g. Age, gender, operative
      time, perioperative transfusion, spleen weight, conversion rate, mode of spleen
      retrieval (bag or accessory incision), postoperative analgesia, length of stay,
      and morbidity were recorded in both main groups. RESULTS: Operative time was
      significantly longer for LS than for OS. However, LS morbidity, mortality, and
      postoperative stay were all lower at similar spleen weights. Spleens weighing
      more than 3,200 g required conversion to open surgery in all cases. When LS
      outcome for hematologic malignant diagnosis was compared with LS outcome for a
      benign diagnosis, malignancy did not increase conversion rate, morbidity, and
      transfusion, even though malignant spleens were larger and accessory incisions
      were required more frequently. Postoperative hospital stay was significantly
      longer in malignant than in benign diagnosis (5 +/- 2.4 days vs. 4 +/- 2.3 days;
      p < 0. 05). CONCLUSIONS: In patients with enlarged spleens, LS is feasible and
      followed by lower morbidity, transfusion rate, and shorter hospital stay than
      when the open approach is used. For the treatment of this subset of patients, who
      usually present with more severe hematologic diseases related to greater
      morbidity, LS presents potential advantages.

PMID- 10347291
TI  - Laparoscopic splenectomy for treatment of patients with idiopathic
      thrombocytopenic purpura. Comparison with open splenectomy.
AB  - BACKGROUND: Laparoscopic splenectomy (LS) is one of the advanced laparoscopic
      procedures that benefit most from minimally invasive surgery. This study was
      undertaken to compare the operating time, blood loss, length of hospital stay,
      and platelet count response for patients with idiopathic thrombocytopenic purpura
      (ITP) undergoing open splenectomy (OS) versus LS. METHODS: We performed OS in 20
      cases before 1992 and LS in 14 cases after 1993 for the treatment of ITP.
      RESULTS: The operating time was significantly shorter for OS than for LS (126 +/-
      52 min versus 203 +/- 83 min, p < 0.01). Blood loss was less for OS than for LS
      (321 +/- 264 ml versus 524 +/- 648 ml, p = 0.287). None of the patients who
      underwent LS were converted to open surgery. Accessory spleens were found in four
      OS patients (20.0%) and four LS patients (28.6%). The postoperative hospital stay
      was significantly longer for OS patients than for LS patients (15.2 +/- 5.8 days
      versus 8.9 +/- 2.9 days, p < 0.0005). No significant difference was noted in the
      long-term results of splenectomy. CONCLUSIONS: Compared with OS, LS required more
      operating time, had the potential to cause greater blood loss, had a comparable
      incidence of accessory spleen and response rate, and appeared to shorten the
      postoperative stay.

PMID- 10347292
TI  - Laparoscopic resection of sigmoid diverticulitis. Results of a multicenter study.
      Laparoscopic Colorectal Surgery Study Group.
AB  - BACKGROUND: In the large bowel, resection of the sigmoid colon is the most
      commonly performed laparoscopic intervention because large bowel lesions often
      are located in this part of the bowel and the procedure technically is the most
      favorable one. A number of publications involving case series or the results of
      highly experienced individual surgeons already have confirmed the feasibility of
      laparoscopic resection in cases of diverticulitis. The aim of the present
      prospective multicentric investigation was to check the results obtained by a
      large number of surgeons performing laparoscopic resection of the sigmoid colon
      for diverticulitis in various stages of severity. RESULTS: Between January 8,
      1995 and January 1, 1998, the Laparoscopic Colorectal Surgery Study Group
      recruited 1,118 patients to the prospective multicenter study. Diverticulitis of
      the sigmoid colon, which accounted for 304 cases, was the most common indication
      for laparoscopic intervention. In most of these patients undergoing laparoscopic
      surgery (81.9%), the diverticulitis manifested as acute phlegmonous
      peridiverticulitis, recurrent attacks of inflammation, or stenosis. Complicated
      forms of diverticulitis in Hinchey stages I to IV and late complications of
      chronic diverticular disease with fistula formation and bleeding accounted for
      only 18.1% of the cases. For the overall group, the conversion rate was 7.2%.
      Patients with less severe diverticulitis (i.e., those presenting with
      peridiverticulitis, stenosis, or recurrent attacks of inflammation) had a
      conversion rate of 4.8% and the rate for complicated cases was 18.2%. Regarding
      laparoscopically completed interventions, 3 of 282 patients died (1.1%). In the
      group of patients with peridiverticulitis, stenosis, or recurrent attacks of
      inflammation the overall complication rate was 14.8%. The group with perforated
      diverticulitis in Hinchey stages I to IV or those with fistula and bleeding, the
      corresponding rate was 28.9%, and after conversion it was 31.8%. CONCLUSIONS:
      Laparoscopic colorectal interventions in sigmoid diverticulitis are, for the most
      part, carried out as elective procedures for peridiverticulitis, stenosis, or
      recurrent attacks of inflammation. The conversion, complication, and mortality
      rates associated with these interventions are acceptable. Laparoscopic procedures
      in Hinchey stages I to IV sigmoid diverticulitis and in the presence of fistula
      and bleeding are more likely to be associated with complications, and should be
      carried out only by highly experienced laparoscopic surgeons.

PMID- 10347293
TI  - Comparison of immunologic and physiologic effects of CO2 pneumoperitoneum at room
      and body temperatures.
AB  - BACKGROUND: Prolonged and complex laparoscopic procedures expose patients to
      large volumes of cool insufflation gas. The aim of this study was to compare the
      effects of a conventional room temperature carbon dioxide (CO2) pneumoperitoneum
      with those of a body temperature pneumoperitoneum. METHODS: Patients were
      randomized to undergo laparoscopic cholecystectomy with a CO2 pneumoperitoneum
      warmed to either body temperature (n = 15) or room temperature (n = 15). The
      physiologic and immunologic effects of warming the gas were examined by measuring
      peroperative core and intraperitoneal temperatures, peritoneal fluid cytokine
      concentrations, and postoperative pain. RESULTS: The mean duration of surgery was
      32 min in both groups. Core temperature was reduced in the room temperature group
      (mean, 0.42 degrees C; p < 0.05). No reduction in temperature occurred when the
      gas was warmed. Greater levels of cytokines were detected in peritoneal fluid
      from the room temperature insufflation group tumor necrosis factor alpha (TNF
      alpha): mean, 10.9 pg/ml vs. 0.42, p < 0.05; interleukin 1 beta (IL-1beta): mean,
      44.8 pg/ml vs. 15.5, p < 0.05; and IL-6: mean, 60.4 ng/ml vs. 47.2. There was no
      difference in postoperative pain scores or analgesia consumption between the two
      groups. CONCLUSIONS: The authors conclude that intraoperative cooling can be
      prevented by warming the insufflation gas, even in short laparoscopic procedures.
      In addition, warming the insufflation gas leads to a reduced postoperative
      intraperitoneal cytokine response.

PMID- 10347294
TI  - Does botulinum toxin injection make esophagomyotomy a more difficult operation?
AB  - BACKGROUND: Some patients with achalasia treated by botulinum toxin injection
      still require an esophagomyotomy. In this study, we analyzed the impact of
      botulinum toxin injection on the technical aspects and outcome of
      esophagomyotomy. METHODS: We studied 57 patients, with a mean age of 46 years
      (range, 12-97) who were treated between January 1995 and March 1998 by
      esophagomyotomy performed via minimally invasive techniques by one team.
      Operative reports, videotapes, and clinical outcome were analyzed to define the
      technical difficulties, perforations, and outcome. RESULTS: Fifteen of the 57
      patients had received one or more injections of botulinum toxin (botox group)
      preoperatively. Difficulties in dissection of the submucosal plane were
      encountered in eight of the 15 cases (53.3%), and a mucosal laceration
      (perforation) occurred in two cases (13.3%). Forty-two of the 57 patients had not
      received any injections (non-botox group). In three patients (7%), difficulties
      in identifying or following the submucosal plane were encountered, although 29
      patients had one or more previous dilations, and perforation occurred in one case
      (2.4%). All mucosal injuries were repaired laparoscopically, and the patients
      recovered without obvious sequelae. Dysphagia improved significantly after the
      operation in both groups (botox group, from preoperative score of 3. 8 to a
      postoperative score of 0.7; non-botox, from a score of 3.4 preoperatively to 0.5
      postoperatively). Regurgitation also improved in both groups (botox, 2.7
      preoperatively, 0.92 postoperatively; non-botox group, 2.0 preoperatively, 0.56
      postoperatively). CONCLUSIONS: Injection of botulinum toxin significantly
      increases the technical difficulties and thus the potential risk of
      esophagomyotomy. The immediate results were equally good for both groups in our
      series, but the long-term sequelae of repeated injections are unknown.
      Laparoscopic Heller myotomy is a safe and effective procedure even after
      unsuccessful treatment with botulinum toxin.

PMID- 10347295
TI  - A prospective randomized controlled trial of sclerotherapy vs ligation in the
      prophylactic treatment of high-risk esophageal varices.
AB  - BACKGROUND: Endoscopic ligation (EVL) and endoscopic sclerotherapy (EIS) are both
      effective in the treatment of bleeding esophageal varices, but the efficacy of
      the two techniques in the prophylaxis of first variceal bleeding has not been
      investigated. The aim of this study was to investigate the frequency of first
      variceal bleeding, the recurrence of varices, and survival after treatment with
      the two techniques, as compared to a nontreated control group. METHODS: A total
      of 157 patients with liver cirrhosis and advanced esophageal varices with no
      previous history of upper gastrointestinal bleeding were randomly assigned to
      either an EIS group (n = 55), an EVL group (n = 52), or a nontreated control
      group (n = 50). After the eradication of esophageal varices in the EIS and in EVL
      groups and in all control patients, the endoscopic examination was performed at 3
      month intervals. RESULTS: There were no significant differences between EIS and
      EVL in the eradication rate of esophageal varices (85% in the EIS group versus
      81% in the EVL group). The mean number of sessions required to obtain eradication
      was lower in the EVL group than in the EIS group (4.8 +/- 1.8 versus 6.2 +/- 2.0;
      p = 0.0003), but the recurrence of esophageal varices was higher in the EVL group
      (31% versus 11%; p = 0.01). Total mortality was significantly lower in the EIS
      patients than in the controls (20% versus 38%; p = 0.04). It was also lower, but
      not significantly, in the EVL patients than in the controls (23% versus 38%; p =
      0.10). A significant decrease in variceal bleeding was observed both in
      sclerotherapy cases (20%) and controls (54%; p = 0.0005) and in ligation cases
      and controls (29%; p = 0.01). No significant difference in bleeding episodes was
      observed between the sclerotherapy and ligation cases (p = 0.29). No serious
      complications were observed either in the EIS or EVL groups. CONCLUSIONS: EIS and
      EVL are similarly effective in the prevention of first variceal bleeding. The
      choice between EIS and EVL depends on the skill of the endoscopic unit. For
      highly experienced surgeons facing no complications, sclerotherapy seems to be
      preferable; for all others, it is technically easier to perform ligation.

PMID- 10347296
TI  - Missed lipoma of the spermatic cord. A pitfall of transabdominal preperitoneal
      laparoscopic hernia repair.
AB  - BACKGROUND: Missed lipoma of the spermatic cord is a pitfall unique to the
      transabdominal preperitoneal (TAPP) laparoscopic hernia repair. This problem
      occurs when a palpable inguinal mass is noted preoperatively, but no identifiable
      hernia defect is found at time of laparoscopy and the procedure is terminated.
      METHODS: Our group encountered six patients without intraperitoneal defects that
      had large cord lipomas on preperitoneal exploration. Two of these patients had
      undergone previous intraabdominal laparoscopy for a proposed TAPP repair, which
      was aborted when no defect was seen. RESULTS: Both patients were referred for
      continued symptomatic groin masses, which were subsequently treated by lipoma
      resection in conjunction with inguinal floor repair. CONCLUSIONS: When patients
      present with a groin mass, exploration of the preperitoneal space and cord
      structures is indicated during TAPP repair, even in the presence of a normal
      appearing abdominal floor. Abandoning a transabdominal approach without
      exploration of the preperitoneal structures may lead to a failure to identify
      symptomatic and/or palpable cord lipomas.

PMID- 10347297
TI  - The feasibility of laparoscopic extraperitoneal hernia repair under local
      anesthesia.
AB  - BACKGROUND: Laparoscopic preperitoneal herniorrhaphy has the advantage of being a
      minimally invasive procedure with a recurrence rate comparable to open
      preperitoneal repair. However, surgeons have been reluctant to adopt this
      procedure because it requires general anesthesia. METHODS: In this report, we
      describe the technique used in the laparoscopic repair of inguinal hernias under
      local anesthesia using the preperitoneal approach. We also report our results
      with 10 inguinal hernias repaired using the same technique. RESULTS: Ten patients
      underwent their primary inguinal hernia repairs under local anesthesia. None were
      converted to general anesthesia. Four patients received a small amount of
      intravenous sedation. Three patients had bilateral hernias. There were five
      direct and eight indirect hernias. The average operative time was 47 min. The
      average lidocaine usage was 28 cc. All patients were discharged within a few
      hours of the surgery. There were no complications. Follow-up has ranged from 1 to
      6 months. There has been no recurrences to date. CONCLUSIONS: The extraperitoneal
      laparoscopic repair of inguinal hernia is feasible under local anesthesia. This
      technique adds a new treatment option in the management of bilateral inguinal
      hernias, particularly in the population where general anesthesia is
      contraindicated or even for patients who are reluctant to receive general or
      epidural anesthesia.

PMID- 10347298
TI  - Methods for improving performance under reverse alignment conditions during
      endoscopic surgery.
AB  - BACKGROUND: There are times during endoscopic procedures when the surgeon has to
      operate ahead of the camera/telescope assembly. As a result, the image displayed
      on the monitor will be an inverted mirror image of the operative field (reverse
      alignment). The present study addresses the extent of these difficulties and
      suggests some techniques that may be used to overcome the problem. METHODS: Eight
      specialist registrars participated in experiments involving the execution of a
      simulated dissection task under 12 different imaging conditions. These conditions
      included normal alignment, reverse alignment, total or partial digital correction
      of reverse alignment (about the horizontal and vertical axes independently and
      together), and a simple rotation of the camera through 180 degrees. Normal,
      reverse, and corrected reverse alignment were also tested with optical axes of 45
      degrees and 60 degrees. The endpoints were the task execution and the errors
      rate. RESULTS: A marked deterioration in execution time was observed when the
      surgeons worked under reverse alignment rather than under normal viewing (p =
      0.036). Significant improvement in execution-time errors rate was found when both
      the horizontal and vertical axes were digitally corrected simultaneously (p =
      0.27) and when the camera was rotated 180 degrees with respect to the telescope
      during reverse alignment (p = 0.28). CONCLUSIONS: The effect on performance
      produced by reverse alignment of the endoscope and instruments can be overcome by
      means of digital electronic processing, or simply by turning the camera through
      180 degrees.

PMID- 10347299
TI  - Laparoscopically assisted intestinal resection in 88 patients with Crohn's
      disease.
AB  - BACKGROUND: Experience with 94 resections in 88 patients with Crohn's disease
      using advanced laparoscopic techniques is reported. Records of patients who
      underwent intestinal resection for Crohn's disease between August, 1993 and
      November, 1998 were reviewed. Indications, operative findings, clinicopathologic,
      and postoperative data were recorded. METHODS: In this study, the mean age was 37
      years (range, 16-70 years), and 55% of the participants were women. Indications
      for surgery included obstruction (64 cases), pain (22 cases), peritonitis (1
      case) and abscess (1 case). Seventy patients underwent ileocolic resection, 28 of
      whom had a previous history of one or two ileocolic resections. Eight of these
      patients had additional procedures including tubal ligation (1), sigmoidectomy
      (1), cholecystectomy (3 cases), and enterectomy (3 cases). Small bowel resection
      (13 cases), right hemicolectomy (3 cases), subtotal colectomy (3 cases), anterior
      rectal resection (2 cases), and sigmoid resection (3 cases) were performed in the
      remaining patients. All but one procedure were completed laparoscopically with
      extracorporeal anastomosis. The average length of intestine resected was 33 cm
      (range, 10-92 cm). Forty-one patients had 58 fistulae between ileum, jejunum,
      mesentery, colon, abdominal wall, skin, or bladder. Mean blood loss was 168 ml
      (range, 30-800 ml) and mean operative time was 183 min (range, 96-400 min).
      RESULTS: More than 85% of the patients were tolerating a liquid diet on the first
      postoperative day. Average length of hospital stay was 4.2 days (range, 3-11
      days). Complications included anastomotic leak necessitating reoperation,
      stricture requiring endoscopic dilation, hemorrhage treated expectantly, urinary
      tract infection, pulmonary embolus, line sepsis, and early postoperative
      intestinal obstruction (7 cases) requiring reoperation in three cases.
      CONCLUSIONS: Experience with both advanced laparoscopic techniques and
      conventional surgery for inflammatory bowel disease allowed successful
      laparoscopic management of patients with complicated Crohn's disease.

PMID- 10347300
TI  - Laparoscopic Heller's cardiomyotomy in achalasia. Is intraoperative endoscopy
      useful, and why?
AB  - BACKGROUND: Inappropriate length of the myotomy incision along the stomach, the
      most common technical fault during Heller's cardiomyotomy, is related to the
      difficulty of identifying the gastro-esophageal junction, in particular during
      laparoscopic surgery. The goal of this study was to evaluate the contribution of
      endoscopy to gastro-esophageal junction identification during laparoscopic
      Heller's cardiomyotomy. METHODS: In a group of 19 patients with intraoperative
      endoscopy with laparoscopic Heller's cardiomyotomy, surgical and endoscopic
      criteria for gastro-esophageal junction identification have been assessed. Then
      postoperative results of this group were compared with those of another group of
      16 patients previously operated on without intraoperative endoscopy. RESULTS:
      Endoscopic and laparoscopic criteria for gastro-esophageal junction
      identification were discordant in 11 patients (11/19, 58%). The cardia was in all
      these cases at a more distal site with endoscopic criteria. Complications
      ascribable to suboptimal technique were more frequent in the group without
      intraoperative endoscopy (7/16 patients) than in the other group (2/19 patients).
      CONCLUSIONS: Endoscopy during laparoscopic Heller's cardiomyotomy is of great
      assistance in identifying the cardia, and thereby could improve surgical
      outcomes.

PMID- 10347301
TI  - Laparoscopic surgery in a 0.5-t interventional magnetic resonance unit.
AB  - BACKGROUND: Intraoperative imaging using magnetic resonance imaging (MRI) is now
      possible in interventional MR (IMR) units. Magnetic resonance imaging has
      potential advantages over other methods used to guide surgery. These advantages
      include visualization of structures deep to the two-dimensional endoscopic image
      and clarification of surgical anatomy. This study investigates the feasibility of
      laparoscopic surgery with intraoperative imaging within an IMR unit. METHODS: The
      procedures were performed in a 0. 5-T General Electric IMR scanner. Surgical
      ergonomics and intraoperative imaging were investigated by performing 10
      laparoscopic cholecystectomies on porcine livers in a simulator using magnet-safe
      laparoscopic instruments and an ultrasonic scalpel for dissection. Intraoperative
      MR cholangiography (MRC) was performed using T2-weighted fast-spin-echo (FSE) and
      single-shot fast-spin-echo (ssFSE) techniques with maximal intensity projection
      (MIP) reconstruction. Two laparoscopic cholecystectomies then were performed on
      human patients with intraoperative MRC using similar techniques. RESULTS: The
      simulated procedures allowed the development of surgical techniques appropriate
      to this environment. Both FSE and ssFSE produced reasonable quality
      intraoperative images. Both patient procedures were performed without
      complication. The FSE imaging was of poor quality. However, ssFSE produced
      intraoperative images of the gallbladder with partial visualization of the
      extrahepatic biliary tree. CONCLUSIONS: Laparoscopic surgery in an IMR unit is
      technically possible. Currently, intraoperative MRC is difficult, and FSE imaging
      is very subject to movement artifact. However, the faster ssFSE, with further
      development, may be a useful technique for intraoperative imaging of the biliary
      tree during MR-guided surgery.

PMID- 10347302
TI  - Characteristic alterations of the peritoneum after carbon dioxide
      pneumoperitoneum.
AB  - OBJECTIVE: Any route of entry into the abdomen contributes to alterations of the
      intraperitoneal organs with different clinical consequences. Characteristic
      alterations of the peritoneum after CO2 pneumoperitoneum used in laparoscopic
      surgery is examined. METHODS: A CO2 pneumoperitoneum with an intraperitoneal
      pressure of 6 mmHg was applied for 30 min in 32 nude mice. In the course of 4
      days, the animals were killed and the peritoneal surface of the abdominal wall
      was studied by means of scanning electron microscopy. RESULTS: Already 2 h after
      release of the pneumoperitoneum, mesothelial cells were bulging up. The
      intercellular clefts thereby increased in size, and the underlying basal lamina
      became visible. This reaction peaked after 12 h. Subsequently, peritoneal
      macrophages and lymphocytes filled all gaps, thereby recovering the basal lamina.
      CONCLUSION: The morphologic integrity of the peritoneum is temporarily disturbed
      by a CO2 pneumoperitoneum.

PMID- 10347303
TI  - Laparoscopic removal of an Angelchik prosthesis.
AB  - The use of Angelchik prosthetic rings for the surgical treatment of
      gastroesophageal reflux disease has been associated with frequent complications,
      including dysphagia and migration, erosion, or disruption of the ring. Although
      reports of the laparoscopic insertion of Angelchik rings have been published,
      there have been no descriptions of the laparoscopic removal of rings inserted at
      open laparotomy. Our group recently removed an Angelchik ring laparoscopically in
      an 80-year-old woman with progressive, refractory dysphagia and esophageal
      narrowing due to an Angelchik ring originally placed in 1981 via an upper midline
      incision at open operation. Upper endoscopy and dilatation had failed to provide
      symptom relief. An extensive adhesiolysis was performed laparoscopically, and the
      Angelchik ring was dissected free from the proximal stomach, diaphragm, and
      liver. The fibrous pseudocapsule enclosing the ring was divided, and the
      prosthesis was removed from around the esophagus and abdominal cavity.
      Intraoperative upper endoscopy confirmed resolution of the esophageal stricture.
      There were no intraoperative complications, and the patient was discharged home
      on the 3rd postoperative day tolerating a regular diet. Postoperatively, she
      experienced resolution of her dysphagia and complained only of mild reflux
      symptoms, which were easily controlled with famotidine and antireflux
      precautions. This case suggests that laparoscopic removal of Angelchik prosthetic
      rings is feasible for surgeons familiar with advanced laparoscopic procedures of
      the esophageal hiatus and should be considered for symptomatic patients, even if
      the ring was inserted via an open operation.

PMID- 10347304
TI  - Combined endoscopic and surgical management of Mirizzi syndrome.
AB  - Mirizzi syndrome is a form of obstructive jaundice caused by a stone impacted in
      the gallbladder neck or the cystic duct that impinges on the common hepatic duct
      with or without a cholecystocholedochal fistula. This syndrome is a rare
      complication of cholelithiasis that accounts for 0.1% of all patients with
      gallstone disease. Preoperative recognition is necessary to prevent injury to the
      common duct during surgery. We present a patient with a preoperative diagnosis of
      type I Mirizzi syndrome that was confirmed and drained by endoscopic retrograde
      cholangiography (ERC), followed by subtotal cholecystectomy. A review of the
      literature covering its clinical presentation, diagnosis, and surgical treatment
      is also presented.

PMID- 10347305
TI  - Experimental study on heat production by a 23.5-kHz ultrasonically activated
      device for endoscopic surgery.
AB  - An experimental study was carried out to evaluate heat production by an
      ultrasonically activated device (USAD) using an animal model. In an anesthetized
      living pig, the gastroepiploic and mesenteric vessels were coagulated and cut by
      an USAD at a power level of 70% (n = 8) or 100% (n = 8). During the division, the
      time-discrete temperature change on the surface of the animal tissue adjacent to
      the blade was measured by thermography. To compare the USAD with conventional
      electrocautery (EC), a full-thickness incision of the gastric wall was performed
      by each device, and the temperature change was measured. With the USAD, the
      temperature increased gradually and remained below 150 degrees C during the
      entire activating time at both power levels. By contrast, with EC at 30 W, the
      temperature increased rapidly and exceeded 350 degrees C within only a few
      seconds. The area above 60 degrees C reached a final width of 10 mm for the USAD,
      as compared with 22 mm for EC. Microscopically, thermal alterations such as
      carbonization and vaporization were much more severe and extensive in the
      adjacent tissue when using EC rather than the USAD. With the USAD, heat
      production is much slower and more limited than with conventional EC; thus, the
      USAD causes fewer thermal alterations in adjacent tissue. USAD should be
      preferred for tissue coagulation and cutting during endscopic surgery.

PMID- 10347306
TI  - A combined laparoscopic-endoscopic method of assessment to prevent the
      complications of short esophagus.
AB  - As antireflux surgery has been used increasingly for gastroesophageal reflux
      disease (GERD), a need has arisen for an accurate method to assess esophageal
      length. There are a number of preoperative tests that can help surgeons to
      establish the presence of a short esophagus, but intraoperative assessment after
      esophageal mobilization is the standard method. In this era of laparoscopic
      surgery, the surgeon mobilizes the esophagus extensively from the abdomen and
      then determines if mobilization is sufficient. We report an intraoperative
      technique that combines laparoscopic with endoscopic methods to determine the
      position of the gastroesophageal junction. Because two physicians are required,
      there is additional operating room time, resulting in increased costs. However,
      these costs are offset by the assurance that the complications of the short
      esophagus can be avoided. With experience, modifications were made, resulting in
      the technique described herein.

PMID- 10347307
TI  - Ports, don't slip out!

PMID- 10347308
TI  - Needle pneumoperitoneum. An alternative technique.

PMID- 10347309
TI  - Experimental antireflux surgery.

PMID- 10347311
TI  - Magnetic resonance virtual endoscopy of the common bile duct stones.

PMID- 10347312
TI  - News and notices 

PMID- 10347313
TI  - Improving outcomes of percutaneous coronary intervention.

PMID- 10347314
TI  - Diagnostic testing for coronary heart disease in women: new information generates
      new questions.

PMID- 10347315
TI  - Understanding true risk: evaluating troponins in the emergency setting.

PMID- 10347316
TI  - Mining gold standards from ivory towers: quality of care in academic medical
      centers.

PMID- 10347317
TI  - Growth hormone therapy in patients with congestive heart failure: need for
      further research.

PMID- 10347318
TI  - Intravenous therapy for atrial fibrillation: more choices, more questions, more
      trials.

PMID- 10347319
TI  - Diagnostic accuracy of ST changes detected by exercise testing and ambulatory
      electrocardiographic monitoring in apparently healthy individuals.

PMID- 10347320
TI  - Practical application of three-dimensional echocardiography in evaluation of
      atrial septal defects.

PMID- 10347321
TI  - ST-segment elevation after myocardial infarction: what does it mean and when is
      it useful?

PMID- 10347322
TI  - What kind of coronary revascularization does the average American really want?

PMID- 10347323
TI  - Infarct size: thrombolysis versus PTCA.

PMID- 10347324
TI  - Reuse of coronary catheters: old questions, new environment.

PMID- 10347325
TI  - Trends in clinical and economic outcomes of coronary angioplasty from 1992 to
      1995: a population-based analysis.
AB  - BACKGROUND: The impact of recent developments in coronary angioplasty on the
      broad spectrum of patients treated in routine practice is largely undefined.
      Analysis of population-based data can provide insight into trends in clinical
      outcomes and associated costs of coronary angioplasty procedures. METHODS AND
      RESULTS: With the use of a comprehensive hospital discharge database covering
      more than 11 million Canadians, we analyzed 12,748 first-time angioplasty
      procedures performed from 1992 to 1995 inclusive. Patient demographics and major
      adverse events were recorded. With the use of forward linkage, readmissions
      within 12 months were classified according to procedure performed and/or most
      responsible diagnosis. The proportion of patients readmitted, the number of
      readmissions per index procedure, and diagnosis-specific readmission costs were
      compared by calendar year. Over the 4-year study period, there was a 21% increase
      in the annual volume of index procedures. There were no statistically significant
      differences between 1992 and 1995 in sex distribution, mean age, comorbid
      conditions, length of stay, or need for coronary bypass surgery related to the
      index procedure. The all-cause readmission rate declined from 51.6% to 47.2%
      between 1992 and 1995 (P <.001), primarily because of a decline in the admission
      rate for repeat revascularization from 24.8% to 19.6% (P <.001). The 12-month
      readmission cost declined by $435 (1994 Canadian dollars) per patient.
      CONCLUSIONS: The clinical outcomes of coronary angioplasty in a broad cohort of
      patients have improved in recent years. Although readmissions within 1 year of an
      angioplasty procedure remain common, the number related to repeat
      revascularization has declined, with an associated decline in downstream costs.

PMID- 10347326
TI  - Diagnosis of suspected coronary artery disease in women: a cost-effectiveness
      analysis.
AB  - BACKGROUND: The optimal strategy for the diagnosis of coronary artery disease
      (CAD) in women is not well defined. We compared the cost-effectiveness of several
      strategies for diagnosing CAD in women with chest pain. METHODS: We performed
      decision and cost-effectiveness analyses with simulations of 55-year-old
      ambulatory women with chest pain. With a Markov model, simulations of patients
      underwent exercise electrocardiography, exercise testing with thallium
      scintigraphy, exercise echocardiography, angiography, or no workup. RESULTS:
      Diagnosis with angiography cost less than $17, 000 per quality-adjusted life-year
      compared with exercise echocardiography if the patient had definite angina and
      less than $76,000 per life-year if she had probable angina. If she had
      nonspecific chest pain, diagnosis with exercise echocardiography increased life
      years compared with no testing. CONCLUSIONS: Cost-effectiveness of first-line
      diagnostic strategy for diagnosis of CAD in women varies mostly according to
      pretest probability of CAD. Diagnosis of coronary artery disease with angiography
      is cost-effective in 55-year-old women with definite angina. In 55-year-old women
      with probable angina, diagnosis with angiography would increase quality-adjusted
      life-years but significantly increase costs. Use of exercise echocardiography as
      a first-line diagnosis for CAD is cost effective in 55-year-old women with
      probable angina and nonspecific chest pain.

PMID- 10347327
TI  - Quality of care for patients hospitalized with heart failure at academic medical
      centers.
AB  - BACKGROUND: The purpose of this study was to determine the standard of care
      provided by academic medical centers for the management of congestive heart
      failure (CHF). METHODS AND RESULTS: The standard of care was estimated by
      assessing adherence to the treatment guidelines published by the US Agency for
      Health Care Policy and Research among 522 patients hospitalized at 7 university
      hospitals with a diagnosis of CHF. Data were abstracted by retrospective chart
      review. Of the 522 patients analyzed, 435 (83%) had a left ventricular ejection
      fraction (LVEF) measured or documented. Among these patients, 192 were considered
      "ideal" candidates for angiotensin-converting enzyme (ACE) inhibitor therapy (ie,
      with systolic dysfunction [LVEF <40%] and no contraindications to ACE
      inhibitors). In this cohort of "ideal" candidates, 138 (72%) were receiving ACE
      inhibitors at hospital discharge, including 60 (44%) who were prescribed doses
      recommended in large clinical trials. Compliance with patient education
      guidelines was assessed in all 487 patients who were alive at the time of
      discharge. Of these patients, 365 (75%) received dietary counseling, 404 (83%)
      were educated about exercise, 54 (11%) were instructed to follow daily weights,
      and 468 (96%) were counseled regarding medication compliance. Among the 87
      smokers who were alive at time of discharge, 8 (9%) had documented advice to quit
      smoking. CONCLUSIONS: This study indicates that academic medical centers
      performed fairly well on the assessment of LVEF, the prescription of ACE
      inhibitors at discharge, and on education regarding diet, exercise, and
      compliance with medications. However, the results suggest opportunities for
      improvement in ACE inhibitor dosing and patient education regarding the
      importance of monitoring daily weights and smoking cessation.

PMID- 10347329
TI  - CA 125 and its relation to cardiac function.
AB  - BACKGROUND: CA 125, known as a marker for ovarian cancer with hypothetical but
      hitherto uncharacterized biologic functions, was reported to be elevated in some
      not-well-defined benign conditions. There are no reports on fluctuations of CA
      125 related to cardiac function, especially the failing heart and neurohumoral
      factors such as norepinephrine or atrial natriuretic peptid/e. METHODS AND
      RESULTS: CA 125 blood levels were determined in patients with heart failure
      before and after heart transplantation (HTx). In 71 patients, parallel
      determinations of norepinephrine, atrial natriuretic peptide, pulmonary capillary
      wedge pressure, and right atrial filling pressure were done. CA 125 levels also
      were prospectively studied in patients with heart failure with stabilization (n =
      25) or worsening of the clinical status (n = 9) and after HTx (n = 25). Parallel
      determinations of the tumor markers CEA, CA 199, CA 153, TPS, and TPA were also
      done. The results were grouped according to the clinical status (New York Heart
      Association class) of the patients. CA 125 was significantly correlated with
      neurohormones and filling pressures. Follow-up investigations revealed a decrease
      of CA 125 levels after HTx (401 +/- 259 U/L vs 33 +/- 22 U/L, P <.001, n = 25) or
      stabilization (429 +/- 188 U/L vs 78 +/- 35 U/L, P <.001, n = 25) and an increase
      during worsening of heart failure (42 +/- 25 U/L vs 89 +/- 32 U/L, P <.01, n =
      9). In 4 patients after HTx, unexpected death was preceded by rising CA 125
      levels. CEA, CA 199, CA 153, TPS, or TPA did not correlate with heart failure
      status or clinical events. CONCLUSIONS: CA 125 is a marker of the clinical and
      hemodynamic status and the course of patients with heart failure before and after
      heart transplantation. The determination of CA 125 serum levels may be an
      additional tool in the management of these patients. In patients with cancer,
      these "nonspecific" changes must be considered when CA 125 levels are determined.
      Whether CA 125 has a specific biologic role in heart failure deserves further
      studies.

PMID- 10347328
TI  - Endocrine predictors of acute hemodynamic effects of growth hormone in congestive
      heart failure.
AB  - BACKGROUND: The aim of our study was to assess whether there could be any
      clinical and/or endocrine (spontaneous growth hormone [GH] secretion rate,
      baseline insulin-like growth factor-1 [IGF-1]) predictors and/or determinants of
      the acute effects of continuous intravenous infusion of recombinant human GH on
      hemodynamic parameters in 12 patients with dilated cardiomyopathy and congestive
      heart failure (CHF). METHODS AND RESULTS: The study involved 12 male patients
      with chronic CHF (ischemic in 8 patients and idiopathic in 4). Ten patients were
      in New York Heart Association functional class III or IV and 2 in class II. The
      first 24 hours were considered the control period; in fact, during the following
      24 hours, all the patients underwent intravenous constant pump infusion of
      recombinant human GH. Blood samples for GH assay were taken every 20 minutes
      during the first night of the study (from 10 PM to 6 AM). Moreover, blood samples
      for GH assay were also taken during exogenous GH infusion. Blood samples for IGF
      1 assays were taken at 8 AM of each of the 3 days of the study. Pulmonary artery
      pressure (PAP) and capillary wedge (PCWP) pressure, cardiac index, and arterial
      blood pressure were measured 30 minutes after right heart catheterization
      (baseline 1), at the end of the control period (baseline 2), and every 4 hours
      during GH infusion. A negative correlation has been found between mean nocturnal
      GH levels and baseline IGF-1 levels (r = -0.47, P =.124) and between mean
      nocturnal GH levels and both postinfusion absolute (r = -0.67, P <.05) and delta
      (postinfusion-preinfusion) (r = -0.58; P < 005) IGF-1 levels. No significant
      correlations have been found between several parameters of liver function
      (albumin, bilirubin, and pseudocholinesterase) and mean nocturnal GH. However,
      baseline IGF-1 levels showed a negative significant correlation (r = -0.76, P
      <.01) with total bilirubin and a positive correlation (r = 0.72, P <.01) with
      pseudocholinesterase. Baseline IGF-1 levels showed a significant negative
      correlation with baseline mean PAP (r = -0.68, P <.05) and PCWP (r = -0.70, P
      <.05) and a positive correlation with baseline cardiac index (r = 0.71, P <.05).
      Baseline IGF-1 levels also showed a significant negative correlation with
      absolute mean PAP (r = -0.63, P <.05) and mean PCWP (r = -0.67, P <.05) after GH
      infusion. After GH infusion, IGF-1 levels also negatively correlated with post-GH
      infusion mean PAP (r = -0.50, P =.09) and mean PCWP (r = -0.66, P <.05). The
      positive correlation between either baseline or postinfusion IGF-1 and the
      postinfusion cardiac index (r = 0.40 and 0.43, respectively) did not reach
      statistical significance. CONCLUSIONS: GH has acute functional effects on the
      heart in patients with CHF, including both an increase in myocardial
      contractility and a decrease in vascular resistances, and among patients with
      CHF, those with low baseline IGF-1 are likely to have fewer beneficial effects
      from GH infusion.

PMID- 10347330
TI  - A neural link to explain the "muscle hypothesis" of exercise intolerance in
      chronic heart failure.
AB  - BACKGROUND: In chronic heart failure the cause of exercise limitation is still
      unclear: ergoreceptors, muscle afferents sensitive to exercise metabolites, are
      proposed as a neural link between muscular abnormalities and the limited exercise
      responses in this syndrome. METHODS: In 92 stable patients with heart failure (34
      in New York Heart Association class I, 27 in class II, and 31 in class III) and
      28 age-matched normal controls, we assessed exercise tolerance (maximal upright
      bicycle) and ergoreflex activity (2 dynamic hand grips: one control and one
      followed by 3 minutes of local circulatory occlusion to isolate the ergoreflex
      component by metabolite trapping). RESULTS: Patients, with respect to the
      controls, showed reduced exercise tolerance (peak VO2: 20 vs 33 mL/kg/min),
      increased ergoreflex effects on ventilation (9 vs 4 L/min), systolic pressure (37
      vs 13 mm Hg), and leg vascular resistance (45 vs 22 units) (all P <.005); with
      the progression of the symptoms, a progressive increase in ergoreflex
      contribution to the ventilatory response to exercise was observed. The indexes of
      exercise limitation during arm and leg exercise (ie, peak VO 2, V/VCO2 slope)
      correlated highly with the ergoreflex contribution to ventilatory response during
      handgrip test ( r </= 0.7, P <.0001) but weakly with left ventricular ejection
      fraction (r </= 0.5). CONCLUSION: In chronic heart failure, the overactivity of
      the ergoreflex is related to a degree of functional limitation and appears,
      through direct ventilatory and cardiovascular responses, to contribute to the
      abnormal responses to exercise, explaining the "muscle hypothesis."

PMID- 10347331
TI  - Effect of long-term beta-blockade on aortic root compliance in patients with
      Marfan syndrome.
AB  - BACKGROUND: This study was undertaken to assess the effect of long-term beta
      blockade on the aortic root stiffness index and distensibility in patients with
      Marfan syndrome. METHODS: Aortic root stiffness index and distensibility were
      calculated according to the formulas of Stefanadis and Hirai, respectively, with
      2-dimensional guided M-mode echocardiogram before and after an average of 26
      months of atenolol administration. RESULTS: Twenty-three asymptomatic patients
      were studied (11 men and 12 women, aged 31 +/- 14.2 years). The follow-up was 4
      +/- 2.2 years. The dose of atenolol was individualized (mean 43.5 +/- 21.6 mg/d).
      Heart rate decreased from 79 +/- 9 beats/min to 64 +/- 9 beats/min (P =. 01), and
      systolic blood pressure decreased from 124 +/- 13 mm Hg to 114 +/- 2 mm Hg (P
      =.01). Distensibility increased from 1.85 +/- 0. 70 x 10(-6) cm2/dynes-1 to 2.21
      +/- 0.76 x 10-6 cm2/dynes-1 (P =.02), and the stiffness index decreased from 9.68
      +/- 3.78 to 8.85 +/- 3. 15 ( P =.2). Two groups of responses to treatment were
      identified. Compared with baseline values 15 (65%) patients who responded to
      treatment had increased distensibility and decreased stiffness index of the
      aortic root (P =.05). Eight patients (35%) who did not respond to treatment had
      no significant change. Body weight >91 kg and baseline end-diastolic aortic root
      diameter >40 mm were significantly associated with no response (P =.05). Two
      patients in the nonresponding group had echocardiographic progression of aortic
      insufficiency. CONCLUSIONS: There was a heterogeneous response in the aortic root
      elastic properties after long-term treatment with atenolol in asymptomatic
      patients with Marfan syndrome. Stiffness index and distensibility are more likely
      to respond when the baseline end-diastolic aortic root diameter is <40 mm.

PMID- 10347332
TI  - Efficacy and safety of intravenously administered dofetilide in acute termination
      of atrial fibrillation and flutter: a multicenter, randomized, double-blind,
      placebo-controlled trial. Danish Dofetilide in Atrial Fibrillation and Flutter
      Study Group.
AB  - BACKGROUND: This study was designed to assess the efficacy and safety of
      intravenous dofetilide in acute termination of atrial fibrillation (AF) and
      flutter (AFL). Dofetilide, an investigational class III antiarrhythmic agent,
      selectively inhibits the rapid component of the delayed rectifier potassium
      current, thus prolonging the effective refractory period and duration of the
      action potential. Dofetilide can be administered intravenously and has a rapid
      onset of electrophysiologic action. METHODS AND RESULTS: Ninety-six patients with
      AF (n = 79) or AFL (n = 17) with a median arrhythmia duration of 62 days (range 1
      to 180) were randomized to placebo (n = 30) or 8 micrograms/kg IV dofetilide (n =
      66) over 30 minutes. Conversion was defined as termination of the atrial
      arrhythmia within 3 hours from the start of infusion. The conversion rate was
      30.3% after dofetilide and 3.3% after placebo (P <.006). Conversion rate was
      higher in AFL than in AF: 64% versus 24% (P =. 012). In nonconverters, there was
      no statistically significant difference between the change in heart rate among
      the dofetilide-treated compared with the placebo-treated patients (P =. 42).
      Torsade de pointes ventricular tachycardia developed in 2 patients (3%). In both
      patients, drug infusion was discontinued before the event because of prolongation
      of the QT interval. CONCLUSIONS: Intravenous dofetilide is effective in acute
      termination of AF and AFL of medium duration, with a particularly high efficacy
      rate in AFL. A small but serious risk of proarrhythmia must be anticipated.

PMID- 10347333
TI  - ST-segment deviation during 24-hour ambulatory electrocardiographic monitoring
      and exercise stress test in healthy male subjects 51 to 75 years of age: the
      Copenhagen City Heart Study.
AB  - BACKGROUND: Although ST-segment deviation has been evaluated and used during many
      years both on continuous electrocardiographic Holter monitoring and during
      exercise stress testing, considerable controversy still remains concerning the
      prevalence and diagnostic significance of fortuitously discovered ST-segment
      deviation in asymptomatic healthy persons. METHODS AND RESULTS: The occurrence of
      ST-segment deviation was studied in a population of 63 clinically healthy male
      subjects 51 to 75 years of age, with the use of 24-hour Holter monitoring and
      exercise stress testing. The subjects were recruited from the Copenhagen City
      Heart Study and were without cardiovascular risk factors, chronic diseases, or
      medication and without cardiovascular events during 5 to 12 years before and 3 to
      5 years after admission. The specificity, that is, the probability of displaying
      a negative test result in healthy subjects without disease, was 1.0 when using as
      criterion for significant ST-segment deviation a horizontal or descending ST
      segment depression of >0.20 mV or ST-segment elevation >/=0.15 mV during Holter
      monitoring, and acceptable, for example, 0.95, when using as criterion a
      horizontal or descending ST-segment depression of >/=0.15 mV during Holter
      monitoring or at the exercise test, respectively. Furthermore, the specificity
      was 0.95 when a horizontal or downsloping ST-segment depression of 0.1 mV was
      displayed in both the Holter and exercise electrocardiographic recording system.
      CONCLUSIONS: Thus in asymptomatic persons, the usual criterion for significant ST
      segment depression of 0.1 mV can be applied when occurring in both
      electrocardiographic recording systems. However, if one test alone is used, the
      criterion of significant ST-segment depression should be 0.15 mV. Absence of ST
      segment deviation during Holter monitoring and exercise stress testing, indicated
      with a specificity of 1.0 or 0.95 according to choice of criterion, implies that
      the person is in a healthy state.

PMID- 10347334
TI  - Secundum atrial septal defect is a dynamic three-dimensional entity.
AB  - BACKGROUND: The aim of this study was to evaluate the diagnostic relevance of 3
      dimensional (3D) echocardiography in the assessment of secundum atrial septum
      defect (ASD2). METHODS AND RESULTS: Twenty-three patients (age 2 to 58 years)
      with an ASD2 were studied by transthoracic (n = 9) or transesophageal (n = 14)
      echocardiography for the acquisition of a 3D data set before undergoing surgical
      repair. Qualitative (location, shape, and structure) and quantitative (largest
      and smallest anteroposterior and superoinferior diameters) characteristics were
      analyzed and compared with surgical findings. Intraobserver and interobserver
      variability were assessed. The gross anatomy of the ASD2, shown by the 3D images,
      was confirmed by the surgeon in 21 of 23 patients, but the presence of membranous
      or fenestrated remnants of the valvula foramina ovalis in the defect was not
      optimally visualized in 7 patients. Three-dimensional echocardiography revealed
      changes in diameter and shape of the ASD2 during the cardiac cycle. The measured
      largest and smallest anteroposterior diameters and their intraobserver and
      interobserver agreement were 274 +/- 12 mm, r = 0. 95 (P <.001), r = 0.92 (P
      <.001), and 194 +/- 9 mm, r = 0.96 (P <. 001), r = 0.94 (P <.001), respectively.
      The measured largest and smallest superoinferior diameter and their intraobserver
      and interobserver agreement were 304 +/- 26 mm, r = 0.90 (P <.001), r = 0.97 (P
      <.001), and 204 +/- 10 mm, r = 0.83 (P <.001), r = 0.84 ( P <.001), respectively.
      The correlation coefficient between 2D and 3D echocardiography for the largest
      anteroposterior and superoinferior diameter was r = 0.69 (P <.001) and r = 0.68
      (P =.05), respectively. The correlation coefficient between the measurements from
      3D reconstructions and direct surgical measurements was r = 0.20 (P = not
      significant) and r = 0.57 (P <.05), whereas between 2D and surgery was r = 0.50
      (P <.05) and r = 0.26 (P = not significant). CONCLUSIONS: ASD2 has a complex
      morphology. Three-dimensional echocardiography provides better qualitative and
      quantitative information on its dynamic geometry, location, and extension as
      compared with standard 2D echocardiography and might be useful for device
      selection during catheter-based closure of ASD2.

PMID- 10347335
TI  - Transesophageal echocardiography and unexplained cerebral ischemia: a multicenter
      follow-up study. The STEPS Investigators. Significance of Transesophageal
      Echocardiography in the Prevention of Recurrent Stroke.
AB  - BACKGROUND: Transesophageal echocardiography (TEE) continues to play a prominent
      role in the evaluation of patients with unexplained cerebral ischemia. The STEPS
      Study Group (Significance of Transesophageal Echocardiography in the Prevention
      of Recurrent Stroke) was established to further examine the clinical significance
      of TEE findings in patients with suspected cardiac source of embolus and to
      assess the impact of these findings with respect to specific therapy and the
      prevention of recurrent events. METHODS: A total of 242 patients from 15
      institutions within the United States underwent TEE study for evaluation of
      unexplained cerebral ischemia. Over a 1-year period, detailed follow-up was
      obtained with respect to recurrent stroke, transient ischemia attacks, or
      documented embolic events as well as detailed information concerning
      nonrandomized antithrombotic therapy. RESULTS: Recurrent stroke occurred in 17 of
      132 (13%) of the patients in the aspirin group versus 5 of 110 (5%) of the
      patients receiving warfarin therapy (P <.02). This decrease in cerebral ischemic
      events in the warfarin group was noted, despite the higher prevalence of atrial
      fibrillation and impaired ventricular function in the warfarin group. The
      selection of antithrombotic therapy appears, at least in part, to have been
      influenced by the TEE findings. Among patients receiving aspirin, a higher
      recurrent stroke rate was noted in those with left ventricular enlargement and
      atherosclerotic aortic plaque. CONCLUSION: Abnormalities are commonly found by
      TEE in patients with unexplained cerebral ischemia. Patients with left
      ventricular enlargement and demonstrable aortic plaque on TEE study are at
      increased risk for recurrent stroke when receiving aspirin therapy alone. Empiric
      therapy with systemic anticoagulation may be indicated in patients with stroke
      unexplained by carotid atherosclerotic disease.

PMID- 10347336
TI  - Embolic risk based on aortic atherosclerotic morphologic features and aortic
      spontaneous echocardiographic contrast.
AB  - BACKGROUND: Different aortic atherosclerotic plaque morphologic features may have
      varying embolic potentials. Spontaneous echocardiographic contrast (SEC) in the
      aorta, as in the left atrium, has been associated with an increased risk of
      embolic events and often occurs with complex aortic atherosclerosis. Thus an
      evaluation of their isolated and combined association with embolic events was
      undertaken. METHODS: We retrospectively studied all patients who underwent
      biplane or multiplane transesophageal echocardiography meeting the following
      inclusion and exclusion criteria: age >/=55 years and no other cardiac pathologic
      condition known to be associated with embolic events other than aortic
      atherosclerosis or aortic SEC. The 105 patients meeting the criteria were divided
      into those with aortic atherosclerosis and/or aortic SEC (the study group) and
      those without these aortic pathologic conditions (the comparison group). Complex
      aortic atherosclerosis was defined as mobile, ulcerated, or protuberant (> 4 mm).
      SEC was defined as a pulsatile, swirling echo pattern within the aortic lumen.
      Embolic events included strokes, transient ischemic attacks, or peripheral
      emboli. RESULTS: The 61 study patients and 44 comparison patients did not
      significantly differ with respect to the reason for referral, age, or sex.
      Embolic events occurred in 35 patients. Those with ulcerated or mobile plaques
      had a greater prevalence of embolic events (odds ratio 4.50; 95% confidence
      interval, 1.30-15.5; P <.05). The highest embolic event rate was seen in patients
      with any complex atherosclerosis and concomitant SEC (odds ratio 9.00; 95%
      confidence interval, 2.06-39.3; P <.01). Patients with SEC alone or protuberant
      plaques alone did not have a higher event rate (odds ratio 1.71 and 0.60; 95%
      confidence interval, 0.57-5.17 and 0.15-2. 47, respectively). CONCLUSIONS:
      Embolic events were associated with the presence of ulcerated or mobile aortic
      plaques. In addition, the combination of aortic SEC and any complex
      atherosclerosis had the highest embolic association.

PMID- 10347337
TI  - Differential effects of enalapril and nitrendipine on the fibrinolytic system in
      essential hypertension.
AB  - BACKGROUND: Impaired fibrinolysis is associated with thromboembolic complications
      in hypertensive patients. It has been reported that cardiovascular morbidity and
      mortality rates are high even after lowering the elevated blood pressure with
      antihypertensive drugs. The aim of this study was to assess the effect of
      clinically used dosages of enalapril and nitrendipine on the fibrinolytic system.
      METHODS: Tissue plasminogen activator antigen (tPA) and tissue plasminogen
      activator inhibitor-1 (PAI-1) activity were measured in 20 normotensive male
      subjects and 46 male patients with mild essential hypertension divided into 2
      groups (22 patients treated with 5 to 10 mg enalapril once a day and 24 treated
      with 5 to 10 mg nitrendipine once a day) before and 3 months after drug
      administration. Plasma renin activity and norepinephrine concentration were also
      measured. RESULTS: There were no significant differences in basal characteristics
      between the 2 hypertensive groups. In both hypertensive groups, blood pressure
      was significantly reduced to a similar level after drug treatment. In the 2
      hypertensive groups, plasma renin activity significantly increased after drug
      treatment; however, there were no significant changes in norepinephrine
      concentration. Before drug treatment, the 2 hypertensive groups had significantly
      higher tPA and higher PAI-1 activity than the normotensive subjects. In the
      enalapril group, there was no significant change in tPA although PAI-1 activity
      significantly decreased after drug treatment. In the nitrendipine group, there
      was no significant change in tPA although PAI-1 activity significantly increased
      after drug treatment. CONCLUSION: Thus enalapril improved impaired fibrinolysis
      but nitrendipine further aggravated fibrinolysis in essential hypertension.
      Considering the effect of antihypertensive drugs on the fibrinolytic system, more
      effective and beneficial treatment of hypertensives, especially at a high risk
      for thrombus formation might be selected.

PMID- 10347338
TI  - An open-label preliminary trial of sertraline for treatment of major depression
      after acute myocardial infarction (the SADHAT Trial). Sertraline Anti-Depressant
      Heart Attack Trial.
AB  - BACKGROUND: Depression occurs frequently in patients with acute myocardial
      infarction and is associated with increased mortality rates. It is not known
      whether serotonin reuptake inhibitors would be safe and effective for patients
      with depression after myocardial infarction and whether such treatment would
      reduce mortality rates. METHODS AND RESULTS: We conducted a multicenter, open
      label, pilot study of sertraline treatment in patients with major depressive
      disorder identified 5 to 30 days after admission for acute myocardial infarction.
      Outcome measures included cardiovascular and hemostatic function, adverse events,
      and mood ratings. Twenty-six patients were enrolled in the study. During
      treatment there were no significant changes in heart rate, blood pressure,
      cardiac conduction, or left ventricular ejection fraction, and there was a trend
      toward reduced ventricular ectopic activity. There were no changes in coagulation
      measures. Bleeding time increased in 12 patients, decreased in 4 patients, and
      was unchanged in 2 patients. Three (12%) patients withdrew from treatment
      prematurely because of adverse events. Significant improvements in mood ratings
      occurred over the course of treatment. CONCLUSIONS: Sertraline treatment was
      associated with clinical improvement and was well tolerated in >85% of the
      patients in this open-label treatment trial for patients with major depression
      after myocardial infarction. These results encourage further controlled trials to
      establish the effects of treatment for this high-risk population.

PMID- 10347339
TI  - ST-segment elevation on Q leads at rest and during exercise: relation with
      myocardial viability and left ventricular remodeling within the first 6 months
      after infarction.
AB  - BACKGROUND: Resting ST-segment elevation on Q leads after an acute myocardial
      infarction has been related to a greater infarct size. Otherwise, the relation
      between exercise-induced ST-segment elevation and myocardial viability is
      controversial. We investigated the relation between ST-segment elevation on Q
      leads at rest and during exercise and regional dysfunction and its evolution,
      contractile reserve, left ventricular dilation, and coronary patency. METHODS AND
      RESULTS: Exercise testing and cardiac catheterization were performed at the first
      week after infarction in 51 patients. The study group was divided according to
      the existence (in 2 or more Q leads; n = 36) or not (n = 15) of resting ST
      segment elevation and according to the existence (n = 28) or not (n = 23) of
      exercise-induced ST-segment elevation. Left ventricular end-diastolic and end
      systolic volumes (mL/m2), regional wall motion (SD/chord), contractile reserve
      (wall motion percentage improvement with low-dose dobutamine), and coronary
      patency in the culprit artery were analyzed. Cardiac catheterization was repeated
      at the sixth month in 35 patients; systolic recovery (wall motion percentage
      improvement), left ventricular volumes, and coronary patency were again
      evaluated. Patients with resting ST-segment elevation showed poorer wall motion
      (2.1 +/- 0.8 SD/chord vs 1.2 +/- 1 SD/chord, P =.002), lesser contractile reserve
      (17% [0% to 39%] vs 41% [4% to 92%], P =.04), greater end-systolic volume (32 +/-
      15 mL/m2 vs 23 +/- 11 mL/m2, P =.04), and higher percentage of occlusion (36% vs
      7%, P =.04) than did patients without ST-segment elevation. Likewise, patients
      with exercise-induced ST-segment elevation showed lesser contractile reserve (8%
      [0% to 40%] vs 35% [12% to 86%], P =.03) than did patients without exercise
      induced ST-segment elevation. The only independent predictors of contractile
      reserve were wall motion <2 SD/chord (odds ratio [OR] 7.1, confidence interval
      [CI] 6.3 to 7.9, P =.01) and the absence of exercise-induced ST-segment elevation
      (OR 5.7, CI 4.9 to 6.5, P =. 02). There were no significant differences between
      patients with and those without ST-segment elevation (at rest or during exercise)
      in systolic recovery or left ventricular volumes at the sixth month. CONCLUSIONS:
      ST-segment elevation on Q leads at rest is related to a poorer systolic function
      (more severe regional dysfunction, greater end-systolic volume, and less response
      to dobutamine). ST-segment elevation during exercise is independently related to
      a lesser contractile reserve. ST-segment elevation (at rest or during exercise)
      is not related to the evolution of volumes or regional dysfunction during the
      first 6 months after infarction.

PMID- 10347340
TI  - Chlamydia pneumoniae infection and atherosclerotic coronary disease.
AB  - BACKGROUND: Previous works have suggested an association between Chlamydia
      pneumoniae infection and coronary heart disease. We evaluated the prevalence of
      C. pneumoniae infection in patients with acute myocardial infarction (AMI) and
      coronary heart disease (CHD). METHODS AND RESULTS: Ninety-eight patients with
      AMI, 80 patients with CHD, and 50 control subjects matched for age and sex were
      investigated. Immunoglobulin (Ig)M, IgG, and IgA antibodies to C pneumoniae were
      measured by the microimmunofluorescence test. IgM antibodies were not found; IgG
      positivity was found in 58.2% of the AMI group, 60.0% of the CHD group, and 38%
      of the control group, whereas for IgA, positivity was found in 33.7%, 43.7%, and
      22% of cases in AMI, CHD, and control groups, respectively. Titers indicating
      reinfection were found in AMI and CHD groups in 6.1% and 10%, respectively,
      whereas titers indicating chronic infection were found in 14% of the AMI group
      and 25% of the CHD group. A significant correlation was found between chronic C
      pneumoniae infection and dyslipidemias in the AMI and CHD groups (P =.003; P =.
      0006). CONCLUSIONS: The results suggest that chronic C pneumoniae infection may
      be associated with the development of atherosclerotic coronary disease. In our
      next step, we will test whether antichlamydial antibiotics may help to reduce the
      risk of atherosclerotic disease.

PMID- 10347341
TI  - Recent aspirin use is associated with smaller myocardial infarct size and lower
      likelihood of Q-wave infarction.
AB  - BACKGROUND: Controversy exists about the effect of recent aspirin use on infarct
      size and the likelihood of Q-wave infarction in patients who sustain myocardial
      infarction. METHODS: We performed face-to-face interviews and chart reviews on
      3665 patients with acute myocardial infarction for the Determinants of Myocardial
      Infarction Onset Study. For the 2206 patients who did not receive thrombolytic
      therapy, we assessed aspirin use, peak creatine kinase levels (in 1043 patients),
      and electrocardiographic interpretations (in 1447 patients). RESULTS: Of the
      initial 1043 patients, 317 (30. 3%) subjects reported aspirin use in the 4 days
      before their infarction. The mean +/- SD peak creatine kinase level for aspirin
      users was 701 +/- 570 IU/mL versus 851 +/- 727 IU/mL for nonusers, an 18%
      difference (95% confidence interval [CI], 8% to 26%; P <.001). After adjustment
      for confounding factors, the difference was 12% (95% CI, 2% to 21%; P =.03).
      Similarly, 38.9% of the aspirin users and 48.7% of the nonusers sustained a Q
      wave infarction, an odds ratio of 0.67 (95% CI, 0.54 to 0.83, P <.001). The
      adjusted odds ratio was 0.77 (95% CI, 0.61 to 0.97, P =.03). CONCLUSIONS: Recent
      aspirin use was associated with smaller infarct size and fewer Q-wave infarctions
      among this population of early survivors of acute myocardial infarction who did
      not receive thrombolytic therapy.

PMID- 10347342
TI  - Hemodynamic effects of new intra-aortic balloon counterpulsation timing methods
      in patients: a multicenter evaluation.
AB  - BACKGROUND: To test whether later intra-aortic balloon pump (IABP) deflation
      approaching or simultaneous with left ventricular ejection would improve
      hemodynamics and myocardial efficiency with the use of new balloon deflation
      methods, 4 IABP timing techniques were evaluated in 43 patients. METHODS AND
      RESULTS: Later balloon deflation produced significantly greater percentage
      changes in mean aortic pressure (6% vs 1%), systolic pressure time index (-27% vs
      -20%), diastolic pressure time index (35% vs 19%), and the systolic pressure-time
      index/diastolic pressure-time index ratio (97% vs 51%), respectively. However,
      these changes increased peak systolic pressure (-15% vs -11%). Cardiac output and
      stroke volume indexes were not significantly altered over the 4 settings.
      CONCLUSIONS: These data suggest that systemic hemodynamics and myocardial
      efficiency may be improved by later balloon deflation approaching left
      ventricular ejection in comparison to conventional IABP timing.

PMID- 10347343
TI  - Cardiac troponin T as a marker for myocardial ischemia in patients seen at the
      emergency department for acute chest pain.
AB  - BACKGROUND: Identification of patients with acute chest pain at high risk for
      cardiovascular complications is a common and difficult challenge for clinicians
      and must be based initially on data from the history, physical examination,
      electrocardiogram, and chest radiograph. Some data suggest that elevations in
      cardiac troponin T (cTnT) may be useful for detection of less severe degrees of
      myocardial injury that may occur in some patients with unstable angina. Therefore
      we designed a prospective follow-up study to assess the diagnostic performance
      and prognostic value of cTnT in a population of patients presenting to the
      emergency department with acute chest pain. METHODS: The patient population
      included all 1477 admitted patients aged 30 years or more who presented to the
      emergency department of an urban teaching hospital from October 1992, through
      February 1994, with a chief symptom of acute chest pain not explained by trauma
      or chest radiograph abnormalities. The 1303 patients (88%) who had 2 or more
      measurements of cTnT during the first 24 hours after presentation comprised the
      final study population. Sensitivity, specificity, positive predictive value,
      negative predictive value, and receiver operator characteristics curve (ROC) were
      determined for cTnT and creatine kinase-MB (CK-MB) (measured using activity and
      mass assays) data from the first 24 hours after admission for the outcomes of
      acute myocardial infarction (AMI) and major cardiac events during the first 72
      hours of hospitalization. RESULTS: The sensitivity and specificity of cTnT
      (threshold of 0.1 ng/mL) for detecting AMI during the first 24 hours after
      presentation were 99% and 86%, respectively. The CK-MB activity and mass assays
      had diagnostic performance for detecting AMI similar to cTnT. Among patients who
      did not meet study criteria for AMI, cTnT was elevated during the first 24 hours
      in 31% of patients who had major complications, compared with a 17% rate for the
      CK-MB activity assay and a 3% rate for the CK-MB mass assay. In these patients,
      the cTnT assay had superior diagnostic performance compared with the CK-MB mass
      assay as a marker for cardiac complications as assessed with ROC analysis (P
      <.0004). CONCLUSIONS: In a heterogeneous population of patients seen in the
      emergency department with acute chest pain, cTnT was similar to CK-MB (activity
      and mass assays) for detection of AMI and superior to the CK-MB mass assay as a
      marker for major cardiac events early in the hospital course among those who were
      ruled out for an AMI. Further study is required to determine how this assay can
      be used to provide more appropriate, cost-effective care.

PMID- 10347344
TI  - Kinetics of tumor necrosis factor alpha in plasma and the cardioprotective effect
      of a monoclonal antibody to tumor necrosis factor alpha in acute myocardial
      infarction.
AB  - BACKGROUND: Inflammation plays a critical role in acute myocardial infarction
      (AMI) and tumor necrosis factor alpha (TNF-alpha) is a potent inflammatory
      trigger. This study was designed to examine the kinetics of TNF-alpha in plasma
      in patients with AMI and the potential benefit of inhibition of TNF-alpha
      monoclonal antibody in AMI. METHODS AND RESULTS: TNF-alpha levels in plasma were
      measured in 42 patients with AMI. TNF-alpha levels were elevated at 4 hours after
      onset of chest pain and declined to control values at 48 hours. TNF-alpha levels
      were higher in patients with Killip III and IV than in those with Killip I and II
      (P <.01). To examine the pathogenic role of TNF-alpha, New Zealand White rabbits
      were treated with buffer or a TNF-alpha monoclonal antibody before left anterior
      descending artery (LAD) ligation. Treatment with the TNF-alpha monoclonal
      antibody decreased area of necrosis, number of circulating endothelial cells, and
      lipid peroxidation product malonaldehyde bis(dimethyl acetal). There was a
      significant correlation of TNF-alpha levels with peak CK-MB in AMI patients, and
      area of necrosis, MDA, and circulating endothelial cells in rabbits (all P <.05).
      CONCLUSIONS: TNF-alpha release early in the course of AMI contributes to
      myocardial injury and dysfunction. Treatment with the monoclonal antibody against
      TNF-alpha can be cardioprotective, particularly in the setting of heart failure
      in patients with AMI.

PMID- 10347345
TI  - Patient preferences in coronary revascularization.
AB  - BACKGROUND: This study was performed to assess patient preferences for
      consequences of 3 coronary revascularization procedures: angioplasty,
      conventional coronary bypass surgery, and minimally invasive coronary bypass
      surgery. METHOD: A nationwide sample of 3 types of respondents was recruited:
      respondents with no heart disease (n = 89), respondents with heart disease who
      had not undergone cardiac surgery (n = 97), and respondents with heart disease
      who had undergone cardiac surgery (n = 118). RESULTS: Sixty-two percent ranked
      the risk of repeat revascularization as the most important concern, followed by
      postprocedure pain (22%), time to recovery of physical functioning (8%), time in
      hospital (4%), and body appearance (4%). Respondents preferred angioplasty to
      conventional and minimally invasive cardiac surgery if the 3-year risk of repeat
      revascularization with angioplasty were to decline to less than 28% and 21%,
      respectively. CONCLUSION: These data suggest that patient preference should
      influence individual and policy recommendations when choosing among coronary
      revascularization procedures.

PMID- 10347346
TI  - Diagnosis, incidence, and clinical significance of early postoperative ischemia
      after transmyocardial laser revascularization.
AB  - BACKGROUND: Clinical improvement after transmyocardial laser revascularization
      (TMR) is typically delayed, and patients therefore remain at risk for ischemic
      events after the procedure. The purpose of this study was to define the range of
      creatine phosphokinase (CPK) and CPK-MB enzyme elevation after TMR and to assess
      the incidence of early postoperative ischemic events. METHODS: Twenty-one
      patients undergoing isolated TMR were evaluated for 48 hours after surgery with
      serial CPK and CPK-MB enzymes and 12-lead electrocardiograms for evidence of
      myocardial ischemia or injury. Clinically evident postoperative ischemic events
      including angina pectoris, myocardial infarction (MI), and cardiac death were
      recorded as well. RESULTS: Eleven patients (52.4%) had ischemic
      electrocardiographic changes in the first 48 hours after TMR. Ischemia was
      clinically silent in 7 (63.6%) of these 11 patients. Cardiac death occurred in 1
      patient (4.8%) as a result of acute MI. Nonfatal MI occurred in an additional 4
      patients (19.0%). Of the 5 patients with MI, 4 had angina pectoris versus no
      angina in the 16 patients without MI (P =.02). All patients had elevated CPK and
      CPK-MB levels after TMR: however, peak CPK (P =.02) and CPK-MB (P =. 005) levels
      were significantly higher for patients suffering postoperative MI compared with
      those without MI. CONCLUSIONS: Transient ischemia occurs frequently after TMR and
      is clinically silent in the majority of patients. Patients with postoperative MI
      are more likely to have symptomatic ischemia as well as significant cardiac
      enzyme elevation. The combination of 12-lead electrocardiogram and cardiac
      enzymes appears to have significant merit for the diagnosis of myocardial
      ischemia and infarction after TMR. These studies should be obtained in all
      patients undergoing TMR for the first 48 hours after surgery.

PMID- 10347347
TI  - Limitation of myocardial infarct size after primary angioplasty: is a higher
      patency the only mechanism?
AB  - BACKGROUND: Several studies demonstrate a better outcome after primary
      angioplasty compared with thrombolysis. The mechanism is assumed to be a higher
      rate of open infarct-related vessels. METHODS AND RESULTS: We conducted a
      randomized trial of primary coronary angioplasty compared with thrombolysis. A
      total of 401 patients with acute myocardial infarction were randomly assigned to
      either primary angioplasty or thrombolytic therapy. Radionuclide left ventricular
      ejection fraction was performed before hospital discharge. Infarct size was
      estimated by measurement of serial lactate dehydrogenase activity (LDH Q72).
      Separate analyses were performed in patients with an open infarct-related vessel,
      either after thrombolysis or angioplasty. Baseline characteristics were
      comparable between the 2 treatment groups. Of the 197 patients treated with
      angioplasty, 176 (89%) had an open infarct-related vessel compared with 126 (62%)
      of the 204 patients treated with thrombolysis (P <.001). In patients with an open
      infarct-related vessel, those treated with primary angioplasty had a lower enzyme
      release compared with those treated with thrombolysis: LDH Q72 949 (748) and 1200
      (1117), respectively (P <.05). Compared with angioplasty, patients treated with
      thrombolysis had a lower left ventricular ejection fraction. In the subgroup of
      patients with an open infarct-related vessel, after thrombolysis or angioplasty,
      patients treated with thrombolysis still had a lower ejection fraction (47% vs
      50%, P <.05). Multivariate analysis, adjusting for differences in several
      clinical variables, did not change these results. Patients with an open infarct
      related vessel and thrombolysis had a higher risk of an ejection fraction <40%
      compared with patients treated with primary angioplasty (relative risk 1.9, 95%
      confidence interval 1.0 to 2.7). CONCLUSIONS: Despite successful thrombolysis,
      with sustained patency of the infarct-related vessel, primary angioplasty remains
      superior to thrombolytic therapy with regard to left ventricular function and
      enzymatic infarct size. This may be caused by adverse effects of fibrinolytics on
      infarcted myocardium.

PMID- 10347348
TI  - Reuse of angioplasty catheters and risk of Creutzfeldt-Jakob disease.
AB  - BACKGROUND: In 1996, the Quebec Ministry of Health and Social Services, concerned
      that reuse of devices contaminated with blood or blood products could cause the
      transmission of Creutzfeldt-Jakob disease (CJD), discontinued its practice of
      reusing angioplasty catheters despite the significant cost savings reuse had
      afforded the health care system for several years. The objective of this study
      was to establish whether the medical literature provides documentation of any
      cases in which CJD was transmitted by reused percutaneous transluminal coronary
      angioplasty (PTCA) equipment. METHODS AND RESULTS: A Medline search was performed
      to identify previous studies that examined this issue. Key words for the search
      included PTCA, CJD, and material and equipment reuse. A substantial amount of
      effort has been spent on the study of PTCA catheter reuse in relation to the risk
      of infection, toxicity, and catheter breakage as well as cost. In Quebec, studies
      by the Conseil d'Evaluation des Technologies de la Sante investigated the
      effectiveness of cleaning and sterilizing PTCA equipment and considered the
      possibility that reuse of single-use catheters, hemodialyzers, and cardiac
      pacemakers could spread CJD. A number of other studies found evidence that
      iatrogenic transmission was responsible for several cases of CJD by direct
      implantation in or adjacent to the central nervous system during neurosurgery.
      CJD was also transmitted to human beings by injection of pituitary growth hormone
      and to mice through cerebral inoculation of contaminated blood and urine.
      However, there were no documented cases of CJD occurring as a complication of
      PTCA equipment reuse. CONCLUSIONS: The current literature indicates that there
      are no known cases of CJD attributable to the reuse of PTCA devices contaminated
      by blood or to the transfusion of blood or blood products. This practice is
      associated with a very low risk of CJD transmission. With the considerable cost
      savings made possible by reuse of PTCA equipment, reimplementation of this
      practice should be considered by health delivery systems, provided that stringent
      methods of cleaning and sterilization are observed.

PMID- 10347349
TI  - Methodologic drift in the assessment of TIMI grade 3 flow and its implications
      with respect to the reporting of angiographic trial results. The TIMI Study
      Group.
AB  - BACKGROUND: The Thrombolysis in Myocardial Infarction (TIMI) Study Group
      originally defined TIMI grade 3 flow (complete perfusion) as antegrade flow into
      the bed distal to the obstruction that occurs as promptly as antegrade flow into
      the bed proximal to the obstruction. Recently, several groups have defined TIMI
      grade 3 flow as opacification of the coronary artery within 3 cardiac cycles.
      METHODS AND RESULTS: On the basis of heart rate data at the time of the cardiac
      catheterization and the time for dye to go down the artery (TIMI frame count/30 =
      seconds), we estimated the number of patients who would meet the 3 cardiac cycle
      criterion and compared this with the number of patients with TIMI grade 3 flow by
      using the original definition in 1157 patients from 3 recent TIMI trials (10 A,
      10B, and 14). In 74 patients without acute myocardial infarction and normal
      coronary arteries, the fraction of a cardiac cycle required for dye to traverse
      the artery was a mean of 0.93 +/- 0.34 cardiac cycles (n = 74) (median 0.80,
      minimum 0.44, maximum 2.1, none >3.0 cycles). The mean heart rate at 90 minutes
      after thrombolysis in the TIMI 14 trial was 79.6 +/- 16.8 beats/min (n = 194),
      and the duration of 3 cardiac cycles was a mean of 2.36 seconds, or a TIMI frame
      count of 70.8 frames. In all trials, the rate of TIMI grade 3 flow was 57.3% (n =
      663/1157) with the original definition and 66.8% (n = 743/1113) with the <3
      cardiac cycle definition (P <.001). CONCLUSIONS: A duration of 3 cardiac cycles
      for dye to traverse the artery lies approximately 6 SD above that observed in
      normal coronary arteries. A 3 cardiac cycle definition of TIMI grade 3 flow
      results in rates of normal perfusion that are approximately 10% higher than if
      the original definition of TIMI grade 3 flow is applied. Application of this
      simple correction factor may help place data reported with the 3 cardiac cycle
      definition of TIMI grade 3 flow in context.

PMID- 10347350
TI  - Comparison of the right and left ventricle as a systemic ventricle during
      exercise in patients with congenital heart disease.
AB  - BACKGROUND: Few studies have investigated the clinical advantages of surgical
      correction with the morphologic left ventricle (MLV) instead of the morphologic
      right ventricle as a systemic ventricle (SV) in patients with congenital heart
      disease. METHODS: Twenty-four healthy control subjects (group A1), 6 patients
      with isolated congenitally corrected transposition of the great arteries (TGA)
      (group A2), 16 patients with TGA who had undergone an arterial switch operation
      (group B1), 18 patients with TGA who had undergone a venous switch operation
      (group B2), 9 patients with atrioventricular and ventriculoarterial discordance
      who had undergone a double switch operation (group C1), and 6 patients with
      atrioventricular and ventriculoarterial discordance who had undergone a
      conventional external conduit operation from the MLV to the pulmonary artery
      (group C2), performed treadmill exercise testing. Their heart rate (HR), oxygen
      uptake (VO2), and oxygen pulse (O2 pulse), which reflects individual stroke
      volume, were measured, and contractile function was assessed by echocardiography.
      RESULTS: The peak HR for the patients after a definitive operation were
      significantly lower than that in group A1 and was correlated with peak VO2 (r
      =.67, P <.0001). The peak VO2 and peak O2 pulse for the groups A2 and B2 were
      significantly lower than those for the groups A1 and B1, respectively. The peak
      O2 pulse data were strongly correlated with those of peak VO 2 (r = 0.91, P
      <.0001). The left ventricular ejection fraction was significantly lower in groups
      B1 and C1 than in group A1 and was correlated with peak VO 2 (r =.50, P <.01). No
      significant differences in VO2, HR, and O 2 pulse at peak exercise were observed
      between groups C1 and C2. CONCLUSIONS: Chronotropic incompetence and an impaired
      response of the stroke volume of the MRV during exercise are partly responsible
      for the reduced exercise capacity in groups A2 and B2 compared with groups with
      the MLV as an SV, and the SV function at rest is also related to exercise
      capacity. Superiority of the double-switch operation compared with the
      conventional conduit operation was not observed. A longer-term follow-up is
      necessary before the advantages of these 2 operations can be compared.

PMID- 10347351
TI  - Eagle's syndrome associated with temporomandibular disorder: a clinical report.

PMID- 10347352
TI  - Clinically relevant approach to failure testing of all-ceramic restorations.
AB  - STATEMENT OF PROBLEM: One common test of single-unit restorations involves
      applying loads to clinically realistic specimens through spherical indenters, or
      equivalently, loading curved incisal edges against flat compression platens. As
      knowledge has become available regarding clinical failure mechanisms and the
      behavior of in vitro tests, it is possible to constructively question the
      clinical validity of such failure testing and to move toward developing more
      relevant test methods. PURPOSE: This article reviewed characteristics of the
      traditional load-to-failure test, contrasted these with characteristics of
      clinical failure for all-ceramic restorations, and sought to explain the
      discrepancies. Literature regarding intraoral conditions was reviewed to develop
      an understanding of how laboratory testing could be revised. Variables considered
      to be important in simulating clinical conditions were described, along with
      their recent laboratory evaluation. CONCLUSIONS: Traditional fracture tests of
      single unit all-ceramic prostheses are inappropriate, because they do not create
      failure mechanisms seen in retrieved clinical specimens. Validated tests are
      needed to elucidate the role(s) that cement systems, bonding, occlusion, and even
      metal copings play in the success of fixed prostheses and to make meaningful
      comparisons possible among novel ceramic and metal substructures. Research over
      the past 6 years has shown that crack systems mimicking clinical failure can be
      produced in all-ceramic restorations under appropriate conditions.

PMID- 10347353
TI  - Survival of Dicor glass-ceramic dental restorations over 14 years. Part II:
      effect of thickness of Dicor material and design of tooth preparation.
AB  - STATEMENT OF PROBLEM: The influence of different restorative design features on
      the long-term survival of Dicor glass-ceramic restorations is not well
      understood. PURPOSE: This study examined the relationship of different types of
      restorations and methods of preparation with the survival of Dicor glass-ceramic
      restorations functioning in vivo. MATERIAL AND METHODS: A total of 1444 Dicor
      glass-ceramic restorations were placed on the teeth of 417 adults. Failure was
      defined as a restoration that required remake because of material fracture.
      Survival of restorations of different types and with different methods of
      preparation was described by using Kaplan Meier survivor functions. Statistical
      significance between restoration type and preparation method was determined with
      the log rank test. RESULTS: Probability of survival of a typical partial coverage
      restoration was 92% at 11.3 years. There was no statistically significant
      difference between the survival of inlay or onlay restorations. For the 91 cores
      used for pulpless teeth, none failed over a total cumulative monitoring period of
      419 years. There was no significant difference in survival of acid-etched Dicor
      restorations that were placed on shoulder or chamfer preparations. Thickness
      measured at the midpoint of the labial, lingual, mesial, distal, and midocclusal
      surfaces did not relate to risk of failure. CONCLUSIONS: The majority of Dicor
      glass-ceramic partial coverage inlay and onlay restorations and cores survived
      over time. Survival of restorations with either chamfer or shoulder preparations
      did not differ whether the restoration was acid-etched. Thickness of the
      restoration measured at the midaxial point of each surface did not relate to
      survival.

PMID- 10347354
TI  - Retention of adhesive cement on the tooth surface after crown cementation.
AB  - STATEMENT OF PROBLEM: Adhesive cements increase crown retention, but it is
      unknown if traces of cement remain undetected on the tooth surface after clinical
      removal of excess cement, which could exacerbate plaque retention. PURPOSE: This
      study measured the surface area, volume, mean depth, and maximum depth of a resin
      composite and a compomer luting cement left adherent on the tooth surface after
      removal of excess cement, as judged clinically. METHODS AND MATERIAL: Four groups
      of specimens (n = 48) were prepared for full coverage crowns: group AC bonding
      alloy with chamfer finish line, group G gold alloy with chamfer finish line,
      group PC porcelain with a chamfer finish line, and group PS porcelain with a
      shoulder finish line. Two profiles of the mesial and distal surfaces of the teeth
      were carried out: (1) tooth with crown seated but not cemented and (2) tooth with
      the crown cemented in place. Two cements and 2 methods of cement removal were
      studied. RESULTS: A 4-way analysis of variance for cement, crown type, method of
      removal, and tooth surface morphology showed that significantly greater volumes
      and mean depth, but not surface areas, of resin composite cement remained
      adherent than compomer cement (P<.05). Among crown types, significant differences
      were found for cement volume (group G>AC, G>PC, G>PS), cement surface area (group
      AC>PC, G>PC, G>PS), and maximum cement depth (group G>AC). There was no
      significant difference between the 2 methods of cement removal. Significantly
      larger surface areas and maximum depths of cement were retained on the
      anatomically grooved mesial surface of the maxillary first premolars than on the
      ungrooved distal surface. CONCLUSION: Subclinical cement retention occurred after
      crown cementation, which was influenced by cement, crown type, and tooth surface
      morphology but not method of cement removal.

PMID- 10347355
TI  - Effects of three bonding systems on the torsional resistance of titanium
      reinforced composite cores supported by two post designs.
AB  - STATEMENT OF PROBLEM: There are no studies that have investigated the effects of
      bonding agents on the resistance to torque of a composite core supported by a
      prefabricated post. PURPOSE: This study investigated the ability of bonding
      agents to resist rational forces applied to titanium-reinforced composite cores
      supported by 2 post designs. MATERIAL AND METHODS: Two post designs (AccessPost
      and ParaPost dowels) with titanium-reinforced core material and 4 bonding
      conditions (AllBond-2, ScotchBond Multi-Purpose, Tenure A&B, and without a
      bonding agent) were studied. A total of 80 specimens in 8 experimental groups
      were prepared and subjected to clockwise torsional forces until failure. RESULTS:
      Torsional values ranged from 53.31 in. x oz (ParaPost/ScotchBond Multi-Purpose)
      to 72.31 in. x oz (AccessPost/ScotchBond Multi-Purpose). Two-way of analysis of
      variance failed to demonstrate a significant difference among posts or type of
      bonding system. CONCLUSION: The use of a multistep bonding agent had no
      significant effect on the torsional resistance of a core supported by a passive
      endodontic post.

PMID- 10347356
TI  - New telescopic crown design for removable partial dentures.
AB  - STATEMENT OF PROBLEM: Special technical skills and experiences are required to
      fabricate a telescopic crown to provide adequate retention with precise
      frictional retention ("conus friction force") between coping and telescope. It is
      also difficult to control clinically alterations of retentive forces after
      prolonged usage. PURPOSE: This study examined an innovative telescopic crown
      system for removable partial dentures that can be fabricated without special
      technical skill or experience and readily adjusted retentive forces. The
      retention of telescopic crowns was investigated after repeated
      insertion/separation tests. MATERIAL AND METHODS: Ten telescopic crowns were
      constructed to evaluate retentive forces. Each telescopic crown was adjusted to
      provide a retentive force of approximately 9.8 N. Each telescopic crown was then
      subjected to 10,000 insertion/separation cycles, and retentive force of each
      telescopic crown was recorded initially and after every 1,000 cycles. The
      retentive force of each telescopic crown was re-adjusted after these measurements
      to provide a retentive force of approximately 9.8 N. The retentive force was
      recorded a second time after each 1,000 insertion/separation cycles up to 10,000
      cycles. RESULTS: Retention of the telescopic crowns gradually diminished,
      depending on the number of insertion/separation cycles. The mean retentive force
      after 10,000 insertion/separation cycles was over 2 N. All 10 telescopic crowns
      were re-adjusted to exert a retentive force of 9.8 N after the initial 10,000
      cycles, and the retentive force also diminished on the second 10,000 cycles.
      CONCLUSIONS: Reduction of retention was dependent on insertion/separation cycles.
      This new telescopic crown with reduced retention could be easily readjusted.
      Readjusted retentive forces were at least equivalent to the initial retention.

PMID- 10347357
TI  - Longitudinal peri-implant clinical responses in anterior mandibles of female
      patients: a preliminary report.
AB  - STATEMENT OF PROBLEM: There is a need for specific documentation that successful
      osseointegration related to Branemark implants can be maintained, despite an
      apparent clinically vulnerable peri-implant soft tissue status. PURPOSE: This
      study monitored longitudinal peri-implant clinical responses in the mandible and
      sought to question whether a relatively deep mucogingival pocket will give rise
      to a greater loss of peri-implant bone than a shallow pocket. METHODS AND
      MATERIAL: Subjects, 8 women patients (mean age 62 years), were treated with
      Branemark mandibular osseointegrated implant-supported prostheses. Four of these
      subjects had limited (average <3.5 mm) and 4 had unlimited (average > or =3.5 mm)
      peri-implant pocket probing depths and constituted the control and test
      subgroups, respectively. Longitudinal changes in peri-implant PAL and
      radiographic bone support were assessed. RESULTS: Overall probing attachment
      levels (PALs) of the peri-implant mucogingival complex showed little change. The
      PAL loss was only minimally significant within the control subjects, and not
      significant for test subjects. The difference in these mucogingival responses
      between test and control subjects was significant (P = .04). There was no
      significant overall longitudinal change in peri-implant bone levels. The
      longitudinal change of peri-implant bone level was not significant within or
      between the control and test subjects.

PMID- 10347358
TI  - Photoelastic stress analysis of load transfer to implants and natural teeth
      comparing rigid and semirigid connectors.
AB  - STATEMENT OF PROBLEM: Controversy exists regarding the connection of implants to
      natural teeth. PURPOSE: This simulation study measured photoelastically the
      biologic behavior of implants. Stress transfer patterns with variable implant
      support and simulated natural teeth through rigid and nonrigid connection were
      examined under simulated functional loads. MATERIAL AND METHODS: A photoelastic
      model of a human left mandible edentulous distal to first premolar was fabricated
      having 2 screw type implants (3.75x13 mm) embedded within the edentulous area.
      Two fixed prosthetic restorations were fabricated with either a nonsplinted
      proximal contact or a soldered proximal contact, and cast precision dowel
      attachment between implant areas and simulated tooth. Simulated vertical occlusal
      loads were applied at fixed locations on the restorations. Stresses, which
      developed in the supporting structure, were monitored photoelastically and
      recorded photographically. RESULTS: The rigid connector in the 1 implant
      situation caused only slightly higher stresses in the supporting structure than
      the nonrigid connector. The distally loaded 1 and 2 implant-supported restoration
      produced the highest apical stresses, which occurred at the distal implant. The
      rigid connector demonstrated the greatest stress transfer in the 2 implant
      supported restoration. CONCLUSIONS: Lower stresses apical to the tooth or implant
      occurred with forces applied further from the supporting abutment. Although the
      least stress was observed when using a nonrigid connector, the rigid connector in
      particular situations caused only slightly higher stresses in the supporting
      structure. The rigid connector demonstrated more widespread stress transfer in
      the 2 implant-supported restoration. Recommendations for selection of connector
      design should be based on sound clinical periodontal health of a tooth and the
      support provided by implants.

PMID- 10347359
TI  - Development of a synthetic bolus using silicone elastomer for the study of
      masticatory efficiency.
AB  - STATEMENT OF PROBLEM: Masticatory efficiency has been proposed as an outcome
      measure for prosthetic rehabilitation. However, no standardized method is
      available for this type of assessment. PURPOSE: This study developed a normalized
      synthetic test food with reproducible physical and rheologic properties. MATERIAL
      AND METHODS: Two silicone putties of different hardness were studied. The texture
      of each putty varied by the addition of silicone oil. Rheologic characteristics
      of 7 samples were compared with the same properties of 5 natural food substances.
      RESULTS: Seven varieties of synthetic bolus were produced, each of which were of
      a different hardness, modulus of elasticity, and tensile strength. The natural
      food substances demonstrated great rheologic variability. The synthetic bolus
      samples exhibited a texture profile approaching that of natural foods. The
      principal difference between the 2 groups tested was that of the homogeneity of
      the silicone samples. CONCLUSION: None of the samples reproduced all the
      rheologic properties of the natural food substances; however, the results showed
      that their characteristics were sufficiently similar for the silicone samples to
      be suggested as a reproducible alternative for the testing of masticatory
      efficiency.

PMID- 10347361
TI  - Accelerated toxicity testing of casting alloys and reduction of intraoral release
      of elements.
AB  - STATEMENT OF PROBLEM: Short-term (72-168 hours) in vitro testing of dental
      casting alloys for cytotoxicity may not reflect in vivo biocompatibility. An
      accelerated test for evaluation of dental casting alloy cytotoxicity could help
      screen newly developed alloys more rapidly and accurately. PURPOSE: This study
      evaluated a method of accelerating alloy cytotoxicity by short-term conditioning
      of alloys. Cytotoxicity and mass release of these conditioned alloys were
      compared with alloys conditioned for 10 months or unconditioned alloys. The
      hypothesis was that a short-term conditioning procedure could be developed that
      would give cytotoxicity and mass release values similar to alloys exposed to a
      biologic solution for 10 months. MATERIAL AND METHODS: Dental casting alloys were
      conditioned in either saline, cell-culture medium, or a saline/bovine serum
      albumin (BSA) solution for 168 hours before standard in vitro cytotoxicity
      testing. Eight types of casting alloys with a range of nobilities (98% to 0%)
      were tested (n = 6). Controls were Teflon (Tf). Conditioned alloys were placed in
      direct contact with Balb/c fibroblasts for 72 hours, and cell viability was
      measured by succinic dehydrogenase activity (MTT method) relative to Tf controls.
      Elements released into the conditioning solutions were measured by atomic
      absorption spectroscopy. The cytotoxicities of conditioned alloys and total mass
      released were compared with unconditioned alloys (0 month) and alloys that were
      exposed to cell culture medium for 10 months. ANOVA and Tukey multiple comparison
      intervals (alpha =. 05) were used to compare mass released and cytotoxicity.
      RESULTS: Conditioning for 168 hours altered the cytotoxicity of the alloys. The
      saline/BSA conditioning solution reduced cytotoxicity of the alloys compared with
      unconditioned alloys, except for the Ni-Cr alloy. Other conditioning solutions
      were not as uniform in their effects, some increasing toxicity, others decreasing
      it. Overall, the saline/BSA solution was the most effective at changing alloy
      cytotoxicity from the unconditioned (0 month) toward the 10-month values. Mass
      loss during saline/BSA conditioning most closely approximated 10-month loss for
      most alloys. CONCLUSION: Conditioning of casting alloys appeared to be a useful
      method for predicting long-term cytotoxicity with a short-term in vitro test, but
      all conditioning solutions were not equivalent.

PMID- 10347362
TI  - Finite element stress analysis on the effect of splinting in fixed partial
      dentures.
AB  - STATEMENT OF PROBLEM: Long-span fixed partial dentures usually require splinting
      of multiple abutments to overcome mechanical problems associated with the long
      edentulous span. Most information and indications for the use of multiple
      splinted abutments have been empirically derived. PURPOSE: This study analyzed
      the stress levels in the teeth and supporting structures of a fixed prosthesis
      and ascertained how the addition of multiple abutments in a fixed prosthesis
      modifies the stresses and their deflection. MATERIAL AND METHODS: The finite
      element method was used to analyze mechanical behaviors of a prosthesis and its
      supporting structures when a fixed prosthesis with several designs replaced a
      mandibular second premolar and a first molar. Variations of the standard finite
      element model were made by changing the number of splinted teeth and the level of
      bone support. RESULTS: A reduction of stress and deflection was observed in the
      supporting structures when a fixed partial denture was fabricated and teeth were
      splinted together. Increasing the number of splinted abutments did not reveal a
      proportional reduction of stress in the periodontium. Stress concentrations were
      seen in the connectors of prosthesis and in the cervical dentin area near the
      edentulous ridge. CONCLUSION: Increasing the number of the splinted abutment did
      not compensate for the mechanical problems of a long-span fixed partial denture
      sufficiently.

PMID- 10347360
TI  - Effect of noble metal conditioners on bonding between prosthetic composite
      material and silver-palladium-copper-gold alloy.
AB  - STATEMENT OF PROBLEM: Mechanical retentive devices and the application of
      complicated surface preparation have been indispensable for bonding composite
      material to the metal substructure of restorations. PURPOSE: This study evaluated
      the priming effects of 4 metal conditioners on bonding between a prosthetic
      veneering material and a silver-palladium-based casting alloy. MATERIAL AND
      METHODS: Four primers designed for conditioning noble metal alloys (Alloy Primer,
      Metaltite, Metal Primer II, and V-Primer) were assessed (all materials contain
      organic sulfur compounds). Cast disk specimens made of silver-palladium-copper
      gold alloy (Castwell M.C.12) were primed with 1 of the 4 primers, and bonded with
      a light-activated prosthetic composite material (Axis). Shear testing was
      performed before and after thermocycling for evaluation of bond durability.
      RESULTS: All primed groups showed improved 24-hour bond strengths compared with
      the unprimed group. After thermocycling, 3 groups primed with the Metal Primer
      II, Alloy Primer, and Metaltite agents exhibited the highest bond strength.
      CONCLUSION: Use of 1-liquid metal conditioners containing sulfur compounds was a
      simple and useful method for improving bonding between the alloy and the
      composite material tested.

PMID- 10347363
TI  - Provisionalization for a single cementable dental implant restoration.
AB  - This article presents a procedure for refining margins of provisional implant
      crowns. This procedure uses an analog of the implant and abutment. This procedure
      allows functional and esthetic considerations such as emergence profiles,
      symmetry, diastemas, embrasures, size, contours, position, angulation, and
      relation to other teeth to be evaluated.

PMID- 10347364
TI  - Modified fixed partial dentures for orthognathic surgery patients.

PMID- 10347365
TI  - Adapting the ITI torque driver for use with other implant systems.

PMID- 10347366
TI  - Health, HIV infection, human rights, and injecting drug use.

PMID- 10347367
TI  - Arms Against Illness: Crack Cocaine and Drug Policy in the United States.
AB  - The emergence of crack cocaine use in the United States during the mid-1980s was
      one of the most significant public health problems of that era. Crack use
      contributed to a series of sexually transmitted disease epidemics, to epidemic
      increases in violent injuries and homicides, and to significant increases in the
      incidence and prevalence of cocaine addiction. Despite these threats to health
      and safety, a national public health campaign to counter crack-related morbidity
      and mortality was never mounted. To the contrary, the strongest response to the
      crack epidemic has come from the police and the courts. As a result, crack
      related crimes have accounted for dramatic increases in the numbers of
      adolescents and adults imprisoned in the United States. Scarce attention to the
      public health dimensions of these policies, let alone the human rights
      implications, has been catastrophic for affected individuals and communities.

PMID- 10347368
TI  - Human rights and AIDS in South Africa: from right margin to left margin.

PMID- 10347369
TI  - Burma and Cambodia: Human Rights, Social Disruption, and the Spread of HIV/AIDS.
AB  - The debate around the issues raised by HIV/AIDS and human rights has largely
      focused on the protection from rights violations of individuals or groups
      affected by the disease. The relationship between political and social conditions
      where human rights abuses are frequent and the spread of HIV infection has been
      less studied. Two countries in Southeast Asia, Burma and Cambodia, are currently
      undergoing serious and uncontrolled epidemics of HIV; both are marked by
      political cultures of state violence and corruption, chronic civil war and
      insurgency, and widespread human rights violations. This article attempts to
      investigate associations between rapid HIV spread and political and social
      crises, using Burma and Cambodia as case studies. The climate and context of
      rights abuses are seen as significant factors of national vulnerability to the
      epidemic spread of HIV/AIDS.

PMID- 10347370
TI  - AIDS, Not Hearing Aids: Exploring the Link Between the Deaf Community and
      HIV/AIDS.
AB  - This article will address the reasons that the messages brought by massive
      HIV/AIDS prevention campaigns in several countries literally fell on deaf ears
      within the Deaf community, and how this in turn made it possible for Deaf
      people's health and human rights to be violated. Then it will show how the Deaf
      community has gradually geared up to protect itself against the spread of the HIV
      virus. Attention is given to the importance and meaning of "effective
      communication" and the role of Sign Language interpreters. Finally,
      recommendations are offered towards better protection of Deaf people's health and
      human rights.

PMID- 10347371
TI  - HIV/AIDS and human rights: continued commitment in the second decade.

PMID- 10347373
TI  - Human rights approaches to an expanded response to address women's vulnerability
      to HIV/AIDS.
AB  - Research from around the world has revealed how gender-related sociocultural
      norms and economic realities contribute to women's vulnerability to HIV
      infection, and how gender-related discrimination contributes to their
      vulnerability to the impact of AIDS. As the global response to the epidemic
      enters its second decade, the need for an expanded response to address the
      societal determinants of women's vulnerability to HIV/AIDS is widely accepted.
      However, public health has been ill-equipped to address the broader context of
      vulnerability. This paper analyzes the research on gender and vulnerability,
      including five key policy and programmatic responses that have emerged from the
      research, through the lens of human rights. Each recommendation will be presented
      in terms of the promotion and protection of enumerated rights under four human
      rights treaties, the realization of which can support the objectives of an
      expanded response to reduce women's vulnerability to HIV and the impact of AIDS.

PMID- 10347374
TI  - HIV vaccine research and human rights: examples from three countries planning
      efficacy trials.
AB  - The protection of human rights will be critical to the success of HIV vaccine
      trials throughout the world. A vaccine for HIV remains our best hope to control
      the global epidemic. In order to launch and sustain useful and successful human
      trials of HIV vaccines, a partnership between scientists, governments,
      pharmaceutical companies, and affected communities is essential. This article
      provides a review of some of the key issues relevant to human rights in the
      design, testing, and dissemination of HIV vaccines. The article gives specific
      examples from three countries -- Brazil, Thailand, and the United States -- which
      may initiate large-scale trials in the near future.

PMID- 10347375
TI  - Children confronting HIV/AIDS: charting the confluence of rights and health.
AB  - From a child rights perspective, HIV/AIDS serves to illuminate how cultural norms
      and legal precepts facilitate or constrain the protection of the child from HIV
      infection and from its individual and collective impacts. Recognition of human
      rights in the design, implementation, and evaluation of governmental policy can
      point the way toward actions which are not only necessary but, in public health
      terms, most effective. This article summarizes the three situations -- children
      infected, affected, and vulnerable -- and three levels of governmental obliations
      -- to respect, protect, and fulfill rights -- which should be considered when
      identifying children's specific needs and rights in the context of HIV/AIDS. The
      article then proposes a method to analyze systematically the confluence between
      HIV/AIDS and children's rights, creating opportunities for a synergy between
      those involved in HIV/AIDS prevention, care, and research, and others engaged to
      the promotion and protection of the rights of the child.

PMID- 10347376
TI  - UNAIDS: human rights, ethics, and law.

PMID- 10347377
TI  - The highest priority: making use of UN conference documents to remind governments
      of their commitments to HIV/AIDS.

PMID- 10347378
TI  - AIDS and human rights: where do we go from here?

PMID- 10347380
TI  - Fifty Years of Synergy Between Health and Rights.

PMID- 10347379
TI  - Celebrating the Fiftieth Anniversary of the Universal Declaration of Human
      Rights.

PMID- 10347381
TI  - The Universal Declaration of Human Rights: Hope and History.

PMID- 10347382
TI  - Antioxidant and antiinflammatory activities of anthocyanins and their aglycon,
      cyanidin, from tart cherries 

PMID- 10347383
TI  - Resuscitation endpoints in trauma.
AB  - Shock is defined as inadequate perfusion of tissues with oxygen and nutrients to
      support cellular function. Resuscitation from shock can therefore only be
      complete when all evidence of oxygen debt, anaerobic metabolism, and tissue
      acidosis has been eliminated. All of the diagnostic and therapeutic maneuvers
      performed by trauma nurses today, whether basic or advanced, whether performed in
      the field, emergency department, operating room, or intensive care unit, can be
      traced directly or indirectly to this goal. Resuscitation in trauma is now viewed
      across the continuum of physiologic insult and response that occurs after
      hemorrhage or tissue injury. Resuscitation endpoints (i.e., variables or
      parameters) must be viewed across the continuum of shock because the
      effectiveness of endpoints varies with the phase of resuscitation. The optimal
      resuscitation endpoint in trauma is controversial, remains elusive, and is one of
      the most published topics in modern medical literature. This article presents the
      current understanding of the resuscitation endpoints in trauma.

PMID- 10347384
TI  - Right heart volumetric monitoring: measuring preload in the critically injured
      patient.
AB  - Accurate assessment of preload status is a major concern in the resuscitation of
      the critically injured patient. Of the three physiologic determinants of stroke
      volume, preload is the variable that is most frequently influenced by an insult
      or intervention or both in the trauma patient. In the critically injured patient,
      clinicians focus on the preload status to restore and maintain intravascular
      volume in attempts to optimize cardiac output and oxygen delivery. Until
      recently, efforts to measure and optimize ventricular preload have focused on
      intracardiac filling pressures (central venous pressure and pulmonary artery
      occlusion pressure). The purpose of this review is to discuss the application of
      volumetric measurements that provide a more accurate means of determining
      recruitable ventricular preload in the critically injured patient.

PMID- 10347385
TI  - Resuscitation of the multitrauma patient with head injury.
AB  - Head injury remains the leading cause of death from trauma. The definitive method
      for eliminating preventable death from traumatic brain injury remains elusive.
      New research underscores the danger of inadequate or inappropriate support of
      oxygenation, ventilation, and perfusion to cerebral tissues. The belief that
      sensitivity to hypotension makes the patient with head injury fundamentally
      different is critical to nursing strategies. The conventional concept that fluid
      restriction decreases cerebral edema in patients with head injury must be weighed
      against mounting evidence that aggressive hemodynamic support decreases the
      incidence of subsequent organ system failure and secondary brain injury. New
      evidence has triggered a scrutiny of conventional interventions. A search for
      optimal treatments based on prospective randomized trials will continue.
      Development of neuroprotective drugs and use of hypertonic saline may be on the
      horizon. In an effort to ensure optimal outcome, contemporary trauma nursing must
      embrace new concepts, shed outmoded therapy, and ensure compliance with the basic
      tenets of critical care for the multitrauma patient with head injury.

PMID- 10347386
TI  - Initial resuscitation after burn injury: therapies, strategies, and
      controversies.
AB  - Thermal injury disrupts normal hemostasis and sets off a cascade of events:
      cellular alterations and release of inflammatory mediators cause hypovolemic and
      cellular shock. Fluid resuscitation in burn injuries has been in use for more
      than a century, and much research has been devoted to development of
      resuscitation formulas and appropriate choice of fluid. Parameters for adequate
      monitoring of resuscitation are greatly debated. Current research efforts focus
      on minimizing burn edema through mediator modulation and on development of
      definitive endpoints of resuscitation monitoring.

PMID- 10347388
TI  - Massive transfusion in trauma.
AB  - The critically injured trauma patient in severe hemorrhagic shock presents a
      complex and arduous challenge to even the most experienced trauma staff. Lives
      are at stake as trauma teams feverishly pour massive amounts of blood into
      severely injured patients attempting to replace entire blood volumes several
      times over. Prompt identification of patients at risk for hemorrhage and
      establishment of massive transfusion protocols can provide guidance in managing
      the transfusion needs of the exsanguinating patient. These state-of-the-art
      protocols address component therapy, endpoints to transfusion and complications
      related to massive transfusions. Other treatments, such as autotransfusion and
      blood substitutes, are promising adjunctive therapies that may in the near future
      help to improve outcomes in patients who require massive blood transfusions. This
      article reviews the current standard of care for the trauma patient requiring
      massive transfusion.

PMID- 10347387
TI  - Limited volume resuscitation in penetrating thoracoabdominal trauma.
AB  - Trauma is the leading cause of death in young adults. Development of trauma
      centers in urban settings including emergency medical services has contributed
      greatly to the improved quality of trauma patient care. Based on animal
      experiments performed 3 decades ago, the traditional management of hypovolemic
      hemorrhagic shock includes adequate circulatory volume with aggressive initial
      infusion of crystalloid solution. However, in several recent animal studies,
      investigators have found that aggressive treatment with fluids before control of
      bleeding results in a higher mortality rate, especially if blood pressure is
      elevated. This notion has been supported by findings in a recent prospective,
      randomized study involving patients with penetrating injuries to the torso. This
      article discusses briefly the pathophysiology of shock and hemostasis and the
      current literature on fluid resuscitation, with emphasis on limited volume
      resuscitation in patients with penetrating thoracoabdominal injuries.

PMID- 10347389
TI  - The trauma triad of death: hypothermia, acidosis, and coagulopathy.
AB  - With the organization of trauma systems, the development of trauma centers, the
      application of standardized methods of resuscitation, and improvements in modern
      blood banking techniques, the ability to aggressively resuscitate patients in
      extremis has evolved. The concept of the "golden hour" has translated into
      unprecedented speed and efficiency of trauma resuscitation with the ultimate goal
      of short injury-to-incision times. As the shift in care of patients in extremis
      has continued to move from the street to the emergency department and beyond, the
      focus of trauma resuscitation has shifted to the operating room and ultimately to
      the intensive care unit. The "new" golden hour may well be the time in the
      operating room before the patient reaches the physiologic limit, defined as the
      onset of the triad: hypothermia, acidosis and coagulopathy. Critical care nurses
      must understand this triad, because it forms the basis and underlying logic on
      which the damage control philosophy has been built. This article explores the
      pathogenesis and treatment of acidosis, hypothermia, and coagulopathy as it
      applies to the exsanguinating trauma patient.

PMID- 10347390
TI  - Damage control surgery.
AB  - The triad of hypothermia, acidosis, and coagulopathy during initial operative and
      resuscitation efforts has been recognized as a significant cause of death in
      patients with traumatic injuries. A staged surgical approach with a brief initial
      laparotomy, subsequent intensive care unit resuscitation, and a planned
      reoperation is an emerging technique used in trauma surgery, with application to
      a variety of other surgical challenges. Successful damage control therapy
      requires a coordinated multidisciplinary team effort by a trauma team experienced
      in the process of damage control operations, intensive care unit priorities, and
      potential complications of this innovative surgical approach.

PMID- 10347391
TI  - Intraabdominal hypertension and abdominal compartment syndrome in trauma:
      pathophysiology and interventions.
AB  - Intraabdominal hypertension and abdominal compartment syndrome are increasingly
      recognized as potential complications in patients who have significant
      intraabdominal trauma. Intraabdominal hypertension and abdominal compartment
      syndrome affect all body systems, most notably the cardiac, respiratory, renal,
      and neurologic systems. This complication also affects blood flow to various
      intraabdominal organs and may play a significant role in the sepsis and multiple
      organ failure syndrome seen in many trauma patients. Nursing knowledge of the
      risk factors and clinical signs of intraabdominal hypertension and abdominal
      compartment syndrome can reduce the morbidity and mortality associated with this
      syndrome.

PMID- 10347392
TI  - Temperature management in trauma patients across the continuum of care: the TEMP
      Group. Temperature Evaluation and Management Project.
AB  - Hypothermia is a potentially preventable consequence of injury in the trauma
      patient. The physiologic aftermath of hypothermia is such that it is regarded as
      one of the three components in the trauma triad of death. A multidisciplinary
      group at a Level I trauma center was formed to originate an innovative team
      approach to managing temperature in trauma patients. This article describes this
      unique project to combat a preventable cause of significant morbidity and
      mortality.

PMID- 10347393
TI  - Application of trauma concepts in the medical-surgical client.
AB  - Concepts related to fluid administration, hemodynamic monitoring, bladder
      pressure monitoring, acid-base status, and temperature management are applicable
      in all clients, not just those with traumatic injury. Two case studies are
      illustrated showing how trauma care concepts are also relevant to the acutely ill
      client. Nurses are challenged to identify how the content presented in this
      symposium can be used for all clients.

PMID- 10347394
TI  - Continuing education for advanced practice nurses.
AB  - Continuing education (CE) enables the advanced practice nurse (APN) to be
      apprised of practice issues and meet recertification requirements. Opportunities
      for obtaining CE program credits for APNs have expanded, yet uncertainty exists
      regarding specific program requirements for obtaining state and national
      certification. To obtain accurate information related to state requirements for
      CE for APNs, all 50 state boards of nursing were contacted by telephone in July
      1998. Responses were received from all 50 states by telephone or facsimile
      transmission. This article outlines information related to CE for APNs including
      state renewal and national recertification requirements. Factors to consider when
      deciding on CE offerings in advanced practice nursing are also discussed.

PMID- 10347395
TI  - Worksite cholesterol and nutrition: an intervention project in Colorado.
AB  - The study purpose was to determine whether group intervention or an individual
      self help program proved to be more effective at lowering heart disease risk
      factors among employees in different worksites. Eight worksites and 502 employees
      in the Denver metropolitan area were selected for the project, with four
      randomized to Usual Care and four to the Special Intervention. Most worksites had
      < 200 employees. Employees were randomly assigned to either a control group
      receiving usual nutrition education or one of two special intervention groups in
      which employees selected to attend group nutrition education classes or complete
      an individual self paced nutrition education program. Results indicated that
      offering a choice of methods for the special nutrition education intervention was
      valuable, and both approaches modified behavior and certain physiological
      outcomes. Results suggested that enhanced nutrition education efforts in
      worksites may be effective and will realize greater benefits than a pamphlet or
      brief discussion following a worksite screening.

PMID- 10347396
TI  - Modifications to standard guidelines and changes in blood pressure readings: use
      of an automatic blood pressure device.
AB  - The purpose of the study was to determine what effect modifications to American
      Heart Association (AHA) guidelines produce when taking blood pressures with an
      automatic device. Eight blood pressure measurements were taken at least 2 minutes
      apart; two with standard AHA guidelines and six with modifications. Findings of
      this study suggest that elevation of the arm can have a significant effect on
      both the systolic and diastolic blood pressure. Two modifications, talking and
      placing the arm beside the trunk, raised the diastolic pressure. However, some
      modifications did not have a statistically significant effect. Techniques used to
      take blood pressures with an automatic device can have a significant effect on
      the readings.

PMID- 10347397
TI  - New hypertension guidelines: commentary.

PMID- 10347398
TI  - The effects of vibration on hands and arms: clinical brief.
AB  - 1. Prevention and early intervention are crucial for reducing unhealthy outcomes
      from exposures to vibration hazards. 2. Greater awareness by the worker of the
      interactions among stressors, heavy tools, awkward and forceful movements, cold
      temperatures, smoking, and other factors specific to the situation are essential.
      3. Reviewing regular tool maintenance with the worker which stresses the
      recording of lubrication, rebalancing, calibration, and applicable support is
      important. 4. Health and safety committees and purchasing agents need to be
      supplied with vibration particulars of tools in advance of their purchase. This
      serves two purposes,--facilitating employee problem prevention and alerting
      equipment manufacturers to potential workplace exposure hazards.

PMID- 10347399
TI  - Returning to work through job accommodation: a case study.
AB  - 1. As more people live longer and more active lives the likelihood of
      experiencing a disability during one's career increases. Although the
      unemployment rate among people with disabilities is high, workers with
      disabilities are becoming more common. 2. Effective job accommodation costs only
      a small fraction of the hundreds of thousands of dollars that would otherwise be
      paid out in disability benefits and insurance premiums, or wasted in litigation.
      3. Job accommodation planning should begin as early as possible in the disability
      process and include the active involvement of the individual with the disability
      and appropriate clinicians, as well as the supervisor and coworkers. 4.
      Successful accommodation is the result of teamwork, The occupational health
      professional is often the coordinator of a number of internal and external
      resources in the job accommodation process. Tools are available for sharing
      information among all those involved in the accommodation process, without
      compromise of confidential medical or business information.

PMID- 10347400
TI  - Internet security.

PMID- 10347401
TI  - Health impact of worksite health promotion programs.

PMID- 10347402
TI  - New body to replace UKCC and national boards.

PMID- 10347403
TI  - National strategy for carers: the way forward?

PMID- 10347404
TI  - Acute surgical wound care. 3: Fitting the dressing to the wound.
AB  - The third article in this series on surgical wound care discusses the types of
      dressings currently available, and selection of the correct dressing for a
      particular wound type. There is an abundance of information on the types of
      dressings available. Wound management for the individual patient must be decided
      using best evidence and taking into account patients' increased involvement in
      their care, new technology and the push to mobilize early, leading to early
      discharge from hospital. The nurse needs to have a good knowledge of the types of
      dressings available, the properties of individual dressings and a sound
      understanding of wound healing, in order to make an informed decision on wound
      management. General factors such as safety, comfort, pain management and
      convenience must be borne in mind when deciding which dressing is the best for
      individual patients, given that dressings now have to be cost-effective as well
      as clinically effective.

PMID- 10347405
TI  - Pressure sore formation in the operating theatre: 1.
AB  - While theatre nurses strive to master increasingly sophisticated equipment and
      techniques they must also endeavour to ensure that the quality of fundamental
      nursing care has positive outcomes for the patient. According to Land (1995),
      pressure area care is such a fundamental nursing activity that many health
      professionals do not recognize the importance of keeping abreast of new
      developments. A review of the literature concerning pressure sore formation
      suggests that, far from being a ward-based problem, all surgical patients
      experience a critical period during which they are most susceptible to pressure
      injury--the time spent on the operating table. This article, the first of two
      parts, outlines the pathophysiology of pressure sores and the contributory
      factors present within the operating theatre. The second part suggests nursing
      interventions to reduce the incidence of pressure sore formation during the
      perioperative phase.

PMID- 10347406
TI  - A practical guide to assessing nursing students in clinical practice.
AB  - Preregistration student nurses and qualified nurses undertaking clinical
      programmes of study spend a substantial proportion of their courses in practice
      settings where they are contributing to patient care. Much of the accountability
      for assessing the clinical competence of learners lies with the nursing team with
      whom a student is working. Assessment is a significant responsibility and one
      which many professionals find complex, and hence challenging and time consuming
      (Rowntree, 1987). Making effective use of the time available for assessment is an
      important component of student learning, and is essential in order to determine
      competence to practice. This article seeks to offer practical guidance on how to
      tackle the assessment of nursing students in clinical practice so that the
      process is both rigorous and manageable.

PMID- 10347407
TI  - Indeterminate detention for 'innocent' psychopaths.

PMID- 10347408
TI  - Psychosis and medication: strategies for improving adherence.
AB  - The development of traditional anti-psychotic medication has led to improvements
      in the care of mentally ill people. These medications have been the mainstay of
      drug treatment for schizophrenia for many years. In recent years, however, the
      advent of so-called 'atypical' anti-psychotics has enabled patients to be treated
      without experiencing the range of severe side-effects associated with traditional
      medicines. Ensuring mentally ill patients take prescribed treatment is seen as an
      important element of the work of mental health nurses. Adopting approaches which
      are non-adversarial may provide better outcomes than straightforward advice
      giving. A combination of psycho-education and a technique known as brief
      motivational interviewing could provide a useful starting point for nurses.
      Whether such approaches will be supported given recent declarations on policy
      intentions remains to be seen.

PMID- 10347409
TI  - What are personality disorders and are they treatable?
AB  - The recently published report of the Fallon inquiry (Fallon et al, 1999) has
      reopened the debate on how best to treat people with personality disorders.
      Currently, the treatment varies depending on whether patients are in an NHS
      setting or inpatient psychotherapeutic unit, a special hospital or the penal
      system. Personality disorder is prevalent in approximately 10% of the population
      and some evidence suggests a 50% prevalence rate for all psychiatric patients. It
      is a heterogeneous disorder that is often misunderstood by professionals. There
      is some consensus within the literature about what constitutes effective
      treatment. Treatment includes behavioural therapy, cognitive behavioural therapy,
      psychopharmacological treatment, the development of a therapeutic programme
      including offence-focused work, addressing substance misuse, interpersonal
      training and a triumvirate/collegiate method of team nursing, where nurses share
      the responsibility for patients.

PMID- 10347410
TI  - Current treatment of impotence: Viagra and other options.
AB  - This article looks at the current treatment of impotence and recent developments
      in the pharmacological treatment of erectile dysfunction. Sildenafil (Viagra)
      threatens to become the most costly drug treatment within the NHS, but its value
      may be overestimated and its effectiveness under-researched. This oral treatment
      has received a lot of recent press attention and is perhaps overshadowing the
      value of established treatment regimens. Pharmacological treatment may also fail
      to tackle the important psychological problems often associated with this
      distressing condition.

PMID- 10347412
TI  - Multidisciplinary teamwork.

PMID- 10347411
TI  - Review of the statutory bodies: five into one may go.

PMID- 10347413
TI  - An interview with a chair. Interview by Paul Wicker.

PMID- 10347414
TI  - The Chris Gill column. Crisis? What crisis?

PMID- 10347416
TI  - Towards 2000: a new age in DVT prophylaxis.

PMID- 10347415
TI  - Deep vein thrombosis: a risky business.

PMID- 10347417
TI  - Laparoscopic surgery.

PMID- 10347418
TI  - Reflecting on practical knowledge and critical knowledge. Part 6.

PMID- 10347419
TI  - 3M/NATN Award. Central pump store project--Yoevil District Hospital.

PMID- 10347420
TI  - Finding meaning and art in work.

PMID- 10347421
TI  - The conscious business culture.

PMID- 10347422
TI  - One hospital's employee 'soul care' strategy.

PMID- 10347423
TI  - 'The soul of a corporation'. Interview by Pat Jakobsen.

PMID- 10347424
TI  - Rejoicing, renewal for a bedside nurse.

PMID- 10347425
TI  - What a psych nurse remembers while driving home at midnight.

PMID- 10347426
TI  - Homeless parents' perceptions of parenting stress.
AB  - PURPOSE: To describe homeless parents' perceptions of parenting stress as
      potential indicators of needs for support in parenting roles. SAMPLE: Forty-seven
      homeless parents (30 mothers, 17 fathers). METHODS: Subjects completed the
      Parenting Stress Index to measure perceived parenting stress in the areas of
      child domain, parent domain, and life stress. FINDINGS: Homeless mothers and
      homeless fathers both identified the child domain as the most frequent source of
      stress. T tests showed a significant difference between groups only in the parent
      domain subscale of competence. CONCLUSIONS: Findings from this study indicate the
      need to include parenting stress questions in an initial nursing or health
      assessment.

PMID- 10347427
TI  - Childhood memories about food: the Successful Dieters Project.
AB  - PURPOSE: The Successful Dieters Project explored and described the
      characteristics of dieters. This paper reports the results of a content analysis
      of one question about childhood memories surrounding food. METHODS: All subjects
      were interviewed once with an intensive interview guide, were weighed, and were
      measured for height and waist-hip ratios. SUBJECTS: Subjects (N = 162) were 76
      men and 86 women, who ranged in age from 21 to 84 years. FINDINGS: Gender and
      weight history differences were noted in the areas of food rules, the age at
      which dieting to control weight began, family food rules, positive versus
      negative memories, and the use of food as a reward or punishment. Parental
      experience with food deprivation was a strong force in shaping children's
      attitudes toward food. CONCLUSIONS: Childhood memories about food appear to
      contribute to differences among the obese, the always-normal-weight, and the
      successful dieter. Further research into this area of investigation is warranted.

PMID- 10347428
TI  - Adolescent suicide as a public health threat.
AB  - TOPIC: Adolescent suicide patterns. PURPOSE: To raise awareness of the
      seriousness of adolescent suicidal behavior by reviewing international research
      on adolescent suicide and evaluating the prospects for identification and
      intervention. SOURCES: Published literature. CONCLUSIONS: Adolescent suicide
      research is complicated and often contradictory, but it does provide some insight
      into prevalence, risk factors, screening tools, and interventions. For
      completers, the problem may be intractable. But a few broad-based identification
      and prevention efforts show promise, and psychotherapy is a proven success. Even
      if suicide rates remain high, treatment of attempters should prevent further self
      harm and reduce the completion rate, and thus should be funded.

PMID- 10347429
TI  - Kaleidoscope of excellence. An interview with Edilma L. Yearwood, PhD, RN, CS.
      Interview by Linda M. Finke.

PMID- 10347430
TI  - Pharmacotherapy in children and adolescents with pervasive developmental
      disorders.
AB  - Children with autism and the related PDDs may benefit from serotonin reuptake
      inhibitors such as clomipramine, fluoxetine, fluvoxamine, and sertraline for
      targeting repetitive thoughts and behaviors, anxiety, and depressed mood. To
      date, however, there are few controlled studies of these agents in children with
      PDD, so definitive evidence is lacking. Despite preliminary results in favor of
      naltrexone, neuroleptic medication appears to be effective for reducing
      aggression, self-injurious behavior, agitation, and stereotypies. The primary
      drawback with traditional neuroleptics is risk of short- and long-term side
      effects. The newer atypical neuroleptics have the potential for benefit with
      fewer extrapyramidal side effects, but more study is needed to establish their
      efficacy and safety. Children on neuroleptic medications should be started at the
      lowest possible dose, with gradual increases until clinical benefit is observed.
      The likelihood of untoward side effects is increased if the medication dose is
      increased rapidly. Baseline measurement of target behaviors can be aided by using
      standardized scales. The presence of abnormal movements should be assessed before
      initiating treatment and at regular intervals during the course of treatment-
      including after medication withdrawal. Weight gain is emerging as a recurrent
      side effect with the atypical neuroleptics. Thus, weight should be monitored, and
      the family should be advised about a diet baseline. As with all treatments of
      children with severe behavioral difficulties, pharmacotherapy should be
      instituted in the context of an integrated treatment plan.

PMID- 10347431
TI  - Alzheimer's disease. Focusing on the individual.

PMID- 10347432
TI  - Communicating with individuals with dementia. The impaired person's perspective.
AB  - 1 To better meet needs of individuals with dementia, caregivers should focus on
      receiving and interpreting verbal and nonverbal messages conveyed by the
      afflicted individuals. 2 Prior research has focused on enhancing communication
      from caregivers to individuals with dementia; however, the content and meaning of
      communication received from individuals with dementia remains largely unexplored.
      3 This study demonstrates that individuals with dementia are able to transmit
      meaningful communication and this communication can be interpreted by others,
      making client-centered interventions possible with this population. 4 If care
      models based on communication interpretation techniques can be built, perhaps the
      needs of individuals with dementia can be better met, tensions reduced,
      problematic behaviors decreased, and quality of life enhanced.

PMID- 10347433
TI  - Family visitation on special care units.
AB  - 1 With placement of a family member with Alzheimer's disease on a SCU, the family
      does not relinquish the caregiving role, rather they take on different roles in
      relation to the residents. 2 Family visitation of the residents on the SCU is an
      integral part of family involvement in care of individuals with Alzheimer's
      disease, as well as SCU functioning. 3 Within the context of changing
      relationships with the residents, family members visited the residents as a sense
      of duty to "be faithful," to monitor care by "being their eyes and ears," and to
      foster a sense of family through ongoing relationships and family rituals. 4
      Nurses have critical roles in promoting physical, emotional, and interactive
      environments which foster family visitation on SCUs.

PMID- 10347434
TI  - When traditional care falls short. Caring for people with atypical presentations
      of cortical dementia.
AB  - 1 People with chronic dementias receive care and support with programs designed
      for people with Alzheimer's disease, meaning a significant minority of patients
      will not benefit as a result of atypical or unusual presentations of cortical
      decline. 2 When patients have atypical presentations of dementia, nurses must
      recognize the unusual symptoms, assess care needs, and develop appropriate
      management strategies. 3 For patients with chronic dementia, individualized care
      planning includes knowledge of: 1) the patient's culture; 2) their past habits,
      activities, and preferences; 3) their remaining abilities; 4) the regions of the
      brain affected, histopathology, and size of the affected area; 5) the usual
      trajectory for the disease type; and 6) external demands. 4 Conducting research
      on assessment and care of people with atypical presentations of dementia is very
      difficult because of their rare nature and lack of recognition by health
      practitioners who may diagnose the patients with Alzheimer's disease.

PMID- 10347435
TI  - Assessing patients in the early stages of irreversible dementia. The relevance of
      patient perspectives.
AB  - 1 Individuals with Alzheimer's dementia are able to describe their personal
      responses to the disease, including how the disease has affected their
      perceptions of self. 2 Individual-centered variables, other than those related to
      the disease, are associated with quality of life outcomes in individuals with
      Alzheimer's dementia, including the individuals' personality, age, and education
      level. 3 The importance of maintenance of social activities and past pleasant
      activities is shown by the relationships among these variables and quality of
      life outcomes in individuals with dementia. 4 The quality of the relationship
      between caregivers and individuals with dementia, including the role-stress
      experiences by the caregivers, is moderately to strongly associated with the
      individuals' level of depression, psychological well-being, and productive
      behaviors.

PMID- 10347436
TI  - Measurement of inappropriate behavior associated with dementia.
AB  - Inappropriate behaviors in dementia affect caregivers, causing depression,
      burden, stress, and affecting caregivers' social life, morale, and somatic
      health. These behaviors also may signal that the elderly individuals with
      dementia are distressed and because of a combination of inappropriate behaviors
      and loss of communication skills, these individuals may not receive adequate
      assessment or treatment. This article discusses the assessment of behavior
      problems in elderly individuals suffering from dementia. The following issues are
      addressed: the need for assessment; difficulties in assessment of inappropriate
      behaviors; approaches to the assessment of behavior problems, including caregiver
      ratings, observational methods, and technological devices; and issues in the
      clinical use of assessments.

PMID- 10347437
TI  - To what extent are dementia (all types) and depression diagnosed and treated in
      nursing facilities?

PMID- 10347438
TI  - A holistic view of nursing concepts and theories in practice.
AB  - This article offers an alternative view to Hall's statements concerning concepts
      and theories in nursing practice. This article also represents an example of how
      journal articles can be forums for ongoing dialogue about the complex matters
      related to developing nursing knowledge. New ideas are presented by which the
      concept of self-transcendence, developmental theory, and theory in general are
      viewed from a holistic perspective rather than the perspectives offered in Hall's
      article. In contrast to Hall's claims about theory and about developmental theory
      in particular, theory is discussed as integral to holistic nursing practice.

PMID- 10347439
TI  - Imaging ourselves: nurses' metaphors of practice.
AB  - Metaphors are vivid, expressive tools popularly used in everyday conversations.
      The familiarity of metaphors combined with their capacity for generating meaning
      make the metaphor a powerful heuristic device for effecting nursing discoveries
      and pedagogical shifts. Exploring nursing metaphors can provide opportunities to
      develop new understandings of nursing and challenge metaphorical images that may
      be constraining and/or obscuring significant elements of holistic nursing
      practice. A research study that examined the metaphorical images of practicing
      nurses uncovered a wide variety of images. The thematic analysis of the
      metaphorical descriptions illuminated four major themes: (a) the character of
      nursing work, (b) power and empowerment, (c) nursing as a growth process, and (d)
      the relational nature of nursing. Nurses' metaphorical images provide a window
      into the complexities and ambiguities within nursing practice. The images
      highlight the significance of social and organizational constraints that
      influence how nurses take up their practice, the ways in which nurses feel unable
      to practice holistically, and the struggles nurses encounter when they try.

PMID- 10347440
TI  - Does your care plan tell my story? Documenting aspects of personhood in long-term
      care.
AB  - Learning about aspects of one's personhood allows the nurse to know the
      individual as a person and to individualize the care provided. A pilot project
      was conducted on a supportive residential care unit to explore why health records
      in long-term care rarely reveal who the person is. Five nurse participants
      generated a list of features of an individual's personhood that they felt should
      be known by members of the team. They subsequently gathered that information from
      a variety of sources, with documentation in a designated location provided on the
      plan of care. They were thus able to overcome some of the previously encountered
      barriers to collecting and documenting the personhood data reflecting their
      knowledge of the individual as a person. Although nurses were successful in
      learning who the persons were, changes in approach to care as a result of the new
      knowledge have not been measured.

PMID- 10347441
TI  - The use of the qualitative research interview to uncover the essence of community
      psychiatric nursing: methodological reflections.
AB  - During the last decade in the Nordic countries, the qualitative research
      interview (QRI) has become a fruitful method for the study of how people
      experience their life-world, especially in social and professional contexts. The
      essential features and structural components of the QRI have been well developed,
      and various aspects of the interpretation of interview texts have been analyzed
      and theoretically assessed from the hermeneutic-phenomenological point of view.
      The validity, reliability, and fruitfulness of the method also have been
      constructively scrutinized. The present study, which examines the choice of
      appropriate QRI strategy and technique as illustrated with concrete examples,
      focuses on the specific area of psychiatric nurses' professional thoughts and
      experiences in community psychiatric nursing. This scientific article seeks to
      stimulate and illuminate the right use of QRI.

PMID- 10347442
TI  - Pow-wowing: the Pennsylvania Dutch way to heal.
AB  - Since ancient times, Germanic tribes from the Palatine valley relied on faith
      healers, brauchers, when health problems developed. Several hundred years ago,
      brauchers immigrated to the New World with various Germanic religious sects.
      Cooperative, instructional meetings, or pow wows, between Native American
      medicine men and newly immigrated brauchers allowed the newcomers to learn about
      herbs and remedies indigenous to North America. The brauchers, now known as pow
      wowers, practice within Pennsylvania Dutch communities across the country,
      especially in the Lancaster, Pennsylvania region. A review of the literature
      explores the history and development of the Pennsylvania Dutch practice of pow
      wowing.

PMID- 10347443
TI  - The children of toxic families: what can be done.

PMID- 10347444
TI  - Giving voice to childbearing teens: views on sexuality and the reality of being a
      young parent.
AB  - Interpretive phenomenology was the qualitative research approach used to explore
      the lived experience of teenage mothers in regard to their sexuality and
      associated development, decision making, relationships, and hopes for the future.
      Several interviews were conducted with each of nine low-income, African-American
      teen mothers over the course of several months. This paper presents narrative
      exemplars from the lives of these teenage mothers gathered during interviews in
      the school nurse's office. Exemplars were: Sand Castles: the unreliability of
      support systems; Tough Boys, Soft Hearts: feeling less powerless with a strong
      male; Erosion of Trust: the deterioration of trusted kin networks; and Staying
      the Course: the intergenerational nature of adolescent pregnancy. Intervention
      and prevention implications for school nurses and other school professionals are
      suggested based on the findings.

PMID- 10347445
TI  - School relocation and stress in teens.
AB  - Geographical relocation, with transfer to a new school, is a life transition
      experienced by many adolescents. The normal developmental tasks of adolescence
      may complicate the transition for relocated teens, particularly those with
      inadequate coping skills. This 2-year study, conducted in an upper-middle-income
      suburban community in the Northeast, with highly mobile students, compared the
      effects of relocation on 43 teens with matched non-relocated controls. While
      statistical significance was found in differences between the relocated and non
      relocated groups, the relocated teens were only mildly anxious. There were no
      significant differences between the groups for depression, hostility, life
      events, or coping. Implications for schools and school nursing regarding health
      promotion interventions with relocated adolescents are discussed.

PMID- 10347446
TI  - Prevention of smoking among adolescent girls: health promotion strategies for
      nurses.
AB  - Adolescent girls experience a range of interpersonal pressures that affect their
      health and development. Their identities are linked to where they live, what they
      believe, how they learn, and how they view themselves. Efforts to influence the
      behavior of adolescent girls must address and draw from this full range of
      experiences. Cigarette smoking is associated with multiple social and personal
      risks, and the prevalence is rising in this population. School nurses can combine
      concepts from the Health Beliefs Model and Social Learning Theory to reach out to
      and teach adolescent girls the risks of smoking and develop health-promoting
      behaviors.

PMID- 10347447
TI  - Nursing interventions used in school nursing practice.
AB  - School nurses need to define clearly their practice and identify the
      interventions they provide to students, families, and school employees. The
      purpose of this research was to identify which nursing interventions listed in
      Nursing Interventions Classification (NIC) are used by school nurses. Of the 174
      surveys mailed to school nurses, 78 usable surveys were returned, representing a
      45% return rate. Of the 433 NIC interventions, 114 were used by school nurses at
      least monthly, with 32 of these 114 interventions identified as being used at
      least once a week.

PMID- 10347448
TI  - The use of standardized language in individualized healthcare plans.
AB  - The specialty of school nursing can benefit from the use of standardized language
      to communicate what school nurses do and to articulate their value during times
      of budget cuts and reduction of services. The use of a standardized language in
      IHPs is helpful in communicating with other health professionals and the
      educational team. The use of NANDA, NIC, and NOC assists school nurses in using a
      common language to describe what they do to meet student outcome goals. Linkages
      among NANDA, NIC, and NOC facilitate careful selection of appropriate
      interventions and outcomes. The diagnoses, interventions, and outcomes are coded
      and written in a manner that can be entered into computerized information systems
      -information needed for potential reimbursement. It also is essential that this
      information is entered into data bases that will tangibly demonstrate the
      contribution of school nurses to the health of the children they serve.

PMID- 10347449
TI  - Preparing for a crisis: crisis team development.
AB  - Emergency preparedness in the school setting necessitates the formation and
      development of a Crisis Team that will be prepared to assume critical roles in
      the event of a crisis. This paper discusses the school Crisis Team, including
      member identification and responsibilities, and the relationship of the Crisis
      Team to the school crisis plan and policies.

PMID- 10347451
TI  - Playing the waiting game.

PMID- 10347450
TI  - The insidious effects of racism.

PMID- 10347452
TI  - Racism in the NHS.

PMID- 10347453
TI  - Protecting the public.

PMID- 10347455
TI  - Offering a hand of hope.

PMID- 10347454
TI  - Testing times.

PMID- 10347456
TI  - Counsel in confidence.

PMID- 10347457
TI  - State of emergency.

PMID- 10347458
TI  - Give up on no smoking.

PMID- 10347459
TI  - Talking cure.

PMID- 10347460
TI  - Shift the balance.

PMID- 10347461
TI  - A digest of research funding and training opportunities.
AB  - Access to research funding information is a significant barrier to the
      development of research ideas and the involvement of nurses in research. Nancy
      Lester and Christine Parker-Jones describe a new database intended to overcome
      this barrier.

PMID- 10347462
TI  - The religious and spiritual needs of mental health clients.
AB  - This research study demonstrates the necessity for mental health nurses and
      allied clinical staff to be conscious that their clients may have spiritual and
      religious needs. A comprehensive assessment of these religious and spiritual
      needs should be standard practice, and multidisciplinary liaison and utilisation
      of chaplaincy resources are essential.

PMID- 10347463
TI  - Pneumoconiosis: a study of its effect on miners' health in South Wales 1900-1980.
AB  - Since its discovery in the late 19th century, pneumoconiosis has shaped the lives
      of thousands of miners. In some ways it became inextricably linked to the South
      Wales coal field and was a major public health threat to the men who worked in
      those mines. The disease was caused by the conditions of work and worsened the
      situation of many who were already living in poverty. This historical research
      account traces the miners' plight and touches on some of the public health issues
      raised by the disease.

PMID- 10347464
TI  - Environmental effects on health.
AB  - Patients with a cancer or respiratory disease and parents of children with a
      congenital abnormality often ask nurses: 'What caused this? Was it pollution or
      my job, or something I've done?' Often there is no clear answer. Media coverage-
      of such issues as Sellafield and childhood leukaemias, mobile phones and brain
      cancers, or waste sites and congenital abnormalities--may prompt a rash of
      questions from anxious patients. This article discusses environmental issues so
      that nurses are in a position to answer some of these questions.

PMID- 10347465
TI  - Sharing bad news.

PMID- 10347467
TI  - H grade nurses: focusing on patient care.

PMID- 10347468
TI  - Coming soon: nurse consultants.

PMID- 10347466
TI  - Taking advice.

PMID- 10347469
TI  - A few home truths.

PMID- 10347470
TI  - Facing inequality.

PMID- 10347471
TI  - Egg donation. A gift of love.

PMID- 10347472
TI  - Bumpy ride but on course.

PMID- 10347473
TI  - How healthcare professionals can become disability aware.

PMID- 10347474
TI  - Working together.

PMID- 10347476
TI  - Save the elephant.

PMID- 10347475
TI  - Think global.

PMID- 10347477
TI  - Ties that bind.

PMID- 10347478
TI  - Primary care groups.
AB  - From April 1, 1999 all general practices in England will become members of local
      primary care groups (PCGs). This report from the King's Fund outlines what PCGs
      are and how they will work.

PMID- 10347479
TI  - Historical research: process, problems and pitfalls.
AB  - Nurse researchers have developed a range of approaches to increase knowledge. In
      this article, the increasingly influential approach of historical research is
      described to illustrate the processes and skills involved, and stimulate interest
      in the study of nursing history. The authors describe the process in the context
      of a study reported in Nursing Standard (vol 13, no 26) of the impact of
      pneumoconiosis on miners in South Wales (Howells 1997, Howells and Rees 1999).

PMID- 10347480
TI  - Referencing academic assignments.
AB  - External examiners often identify inaccurate referencing as a weakness in scripts
      submitted for assessment. This article explores the main aspects of referencing,
      and offers a protocol for referencing founded on the Harvard (name-date) system.

PMID- 10347481
TI  - Equal care for all.
AB  - Fifty years after the NHS was launched to offer health care for all, there are
      still many inequalities, particularly for clients from ethnic minorities. This
      article discusses these inequalities in the light of an increase in stoma
      formation and bowel disease in Walsall's Asian community. The author recommends a
      number of proactive measures that trusts and nurses can use to improve uptake of
      services by ethnic minority patients.

PMID- 10347482
TI  - Coronary heart disease: the Indian Asian diet.
AB  - This article explores the link between the high incidence of coronary heart
      disease in Indian Asian people and their dietary habits.

PMID- 10347483
TI  - Nutrition in Crohn's disease.
AB  - This article discusses ways in which nurses can help to advise patients who have
      Crohn's disease about their nutritional requirements.

PMID- 10347484
TI  - Preparing your CV.

PMID- 10347485
TI  - Developments in children's nursing.

PMID- 10347486
TI  - Critical thinking: extending the boundaries.

PMID- 10347487
TI  - The results are in!--1997 Canadian Association of Critical Care Nurses Survey.

PMID- 10347488
TI  - Certification communique.

PMID- 10347489
TI  - With shortages critical, more nurses becoming certified.

PMID- 10347491
TI  - Communication needs of patients receiving mechanical ventilation: a pilot study.
AB  - Patients experiencing mechanical ventilation are unable to speak while being
      dependent on others for their physical needs. The purpose of this work is to
      describe the communication needs of individuals who are mechanically ventilated.
      This article reports the findings of a pilot study to assess communication needs
      of ventilated patients and to compare patients' perceptions of their needs with
      their nurses' perceptions of their needs. Twenty-seven nurse-patient comparisons
      were generated. The only statistically significant correlation was observed for
      the needs concerning social stimulation. Nurses and patients did not agree on the
      patients' communication needs in areas of information-seeking, information
      sharing or request for assistance. Further research is needed to verify these
      findings.

PMID- 10347492
TI  - The use of restraints in critical care.
AB  - A restraint is any physical or chemical measure used to limit activity or to
      control an individual's behaviour. Restraints may include locked rooms, locked
      chairs, mummy bags, jackets, vests, wristlets, anklets, belts, mitts, joint
      splints, or pharmacological agents. Clinical experience indicates that there is a
      high prevalence of restraint use in critical care areas. The use of restraints
      has become an important issue for health care professionals and is just beginning
      to be considered by critical care nurses. This article is intended to provide
      Canadian critical care nurses with a summary of the literature related to the use
      of restraints.

PMID- 10347493
TI  - Do physical restraints prevent patients from removing invasive therapeutic
      devices?
AB  - Many critical care nurses have cared for patients who have removed invasive
      therapeutic devices such as endotracheal tubes or intravenous lines despite
      secure physical restraints. Recently medical and nursing authors have begun to
      question the effectiveness and appropriateness of physical restraints. Through a
      literature review, this article explores the question: "Do physical restraints
      prevent patients from removing invasive therapeutic devices?" and identifies some
      alternatives to restraints that may be appropriate for use in critical care
      areas.

PMID- 10347494
TI  - Canadian critical care nurses and advance directives.
AB  - This article describes the findings from a survey which was conducted during the
      Canadian Association of Critical Care Nurses (CACCN) September 1997 national
      conference. The survey was intended to identify Canadian critical care nurses'
      experience, knowledge, and opinions of advance directives. Major findings
      included that 80% of those surveyed had cared for at least one patient who had an
      advance directive, 89% were in favour of advance directives, 54% were familiar
      with their provincial legislation relating to advance directives, and 34% could
      correctly differentiate between an instructional and a proxy directive. The
      findings from this study suggest that while the majority of respondent Canadian
      critical care nurses have had some experience with advance directives, most
      require further education in order to use advance directives effectively in their
      daily practice.

PMID- 10347495
TI  - Determining the potential need for a bereavement follow-up program: how well are
      family and health care workers' needs currently being met?
AB  - The purpose of the study was to determine the need for a bereavement follow-up
      program for either the families of patients dying in a critical care unit or the
      health care workers who care for these patients. Two questionnaires, the first a
      telephone administered questionnaire to all consenting family members of patients
      dying in the critical care unit, and the second a self-administered questionnaire
      administered to all health care workers in the critical care unit, were developed
      and piloted for content validity and clarity. The data was analyzed using
      descriptive statistics. Family members of 42 patients who died in the critical
      care unit were interviewed (54% response rate). During the critical care unit
      stay most family members obtained support from family and friends. While 70%
      listed health care workers as a source of support, 50% were satisfied with the
      support from staff. After a family member had died, 40% of those interviewed did
      not identify a specific source for support and 48% were interested in obtaining
      information on community resources available for aid in the bereavement process.
      The results from 117 (79% response rate) health care workers revealed that 30%
      were either uncomfortable or only somewhat comfortable with the dying process and
      the support available for them to deal with the death of their patients. The
      authors identified a need for bereavement follow-up programs for both the
      families of patients who die in the critical care unit and for the health care
      workers who care for these patients.

PMID- 10347496
TI  - Living at home on a ventilator.
AB  - This study was undertaken to explore the perspectives of patients living at home
      on a ventilator. Understanding their perspectives could be helpful for planning
      education programs to prepare them for discharge as well as supporting them once
      they are at home. Analysis of audiotaped interviews with eight individuals
      revealed themes concerning skill in managing equipment, need for organization and
      planning, variations in necessary assistance, experiencing an emotional roller
      coaster, struggles with changing lifestyle, holding a positive attitude, the
      ventilator as an extension of self and preferences for the home environment.

PMID- 10347497
TI  - Workload measurement for resource nurses in the critical care unit: a pilot
      study.
AB  - Faced with financial and staffing pressures, the resource nurses in a large
      pediatric critical care unit asked, "How do we spend our time at work?" When a
      literature review showed no evidence of an applicable type of survey, a workload
      measurement tool was developed and the workload measured over a six-week period.
      Large amounts of time were shown to be spent on tasks or jobs that could be
      delegated to someone who was not a nurse. This study provided documentation to
      support the hiring of a staffing secretary and a pharmacy technician. An
      increased need to be available to offer educational and professional growth and
      developmental support to colleagues was also identified.

PMID- 10347498
TI  - Positioning and intracranial hypertension: implications of the new critical
      pathway for nursing practice.
AB  - Evidence based practice in nursing requires careful scrutiny of research studies
      to determine if there is support to continue existing protocols or if a change in
      clinical practice is warranted. Current nursing practice in critical care
      includes the routine elevation of the head of the bed (HOB) to 30 degrees or 45
      degrees for patients with cerebral edema. Intracranial hypertension is a common
      complication of cerebral edema. New guidelines for medical management of
      intracranial hypertension have been developed and presented in a critical
      pathway. Positioning of patients with intracranial hypertension must be re
      evaluated in light of the changing goals of medical management outlined in the
      critical pathway. The author of this article will critically appraise the
      research examining the impact of elevating the HOB on patients with intracranial
      hypertension within the context of the critical pathway parameters.
      Recommendations for positioning, in keeping with the new critical pathway for
      intracranial hypertension, will be suggested. Future research directions will be
      identified.

PMID- 10347499
TI  - An assessment of a sedative algorithm for sleep in an intensive care unit.
AB  - The difficulty for intensive care unit (ICU) patients to obtain frequent and
      extensive sleep has been well-documented. This project assessed the benefit of an
      algorithm of pharmacological assistance (lorazepam and methotrimeprazine) on
      sedation level and sleep duration in the ICU. The setting was a 15-bed closed ICU
      dealing with medical and surgical patients in a tertiary care, teaching hospital.
      Desired and actual levels of sedation for individual patients were determined
      hourly by the bedside nurse. Medications could be administered to facilitate
      achieving the desired level of sedation. Our results should no difference
      occurred in the achievement of the target sedation or duration of sleep with the
      implementation of the sedation algorithm. The amount of additional medication
      required during the night did change with the implementation of the sedation
      algorithm. A reduction in the amount of diazepam, morphine, and additional
      methotrimeprazine was noted. Efforts to change nursing practice will be required
      to improve the quality and quantity of sleep in ICU patients. This clinical
      evaluation demonstrates that the implementation of an algorithm for medication
      use is not effective alone in obtaining the desired level and duration of sleep
      in ICU patients. Nursing practice should continue to look at non-pharmacological
      factors, such as environmental noise, patient interruptions, and patient care
      practice to determine strategies in addition to medications which would aid the
      critically ill patient in achieving adequate sleep.

PMID- 10347500
TI  - Reducing emotional conflict during the organ donor process.
AB  - It is widely recognized that nurses support and play a paramount role in the
      organ donor process. Nurses are faced with conflict as they deal with a grieving
      family while at the same time providing aggressive medical treatment to a
      clinically dead patient. Nurses' attitudes regarding the organ donor process will
      affect the process and families either positively or negatively. The organ donor
      coordinator in our hospital and the transplant community support the nurse, who
      in turn supports the family before, during and after the process. The family
      needs, emotional conflict and difficult decisions will be identified as perceived
      by a critical care nurse who was a member of an organ donor family.

PMID- 10347501
TI  - Bridging the gap.

PMID- 10347502
TI  - Canadian critical care nurses and physical restraints.
AB  - While physical restraints are frequently used in Canadian critical care units, a
      limited number of studies related to this practice have been conducted. In this
      article, the author describes the findings from a survey about physical
      restraints which was completed by nurses who attended a 1998 conference of the
      Manitoba chapter of the Canadian Association of Critical Care Nurses. The purpose
      of the study was to identify Canadian critical care nurses' knowledge, practice,
      and attitudes related to the use of physical restraints. Major findings included
      a mean score of 77% in knowledge of restraints, a lack of uniform restraint
      practices, and the fact that many nurses experience negative emotions related to
      the use of restraints. Participants typically used wrist restraints to prevent
      injury or removal of invasive therapeutic devices. The most commonly suggested
      alternatives for restraints included constant observation or medications. The
      results of this survey suggest that critical care nurses require further
      education in order to improve their knowledge and to standardize nursing practice
      protocols related to the use of restraints. Further research to identify
      appropriate restraint alternatives, specifically for critical care, is required.

PMID- 10347503
TI  - Striving to recapture our previous life: the experience of families with
      critically ill children.
AB  - The aim of this practice-based phenomenological study was to examine the
      experience of families with a critically ill child. Ten families were studied for
      a minimum of four months and a maximum of five years following the onset of a
      child's critical illness. 'Striving to recapture our previous life' was the
      central (systemic) phenomenon that characterized the overall struggles of these
      families. A number of specific phenomena were identified that related to the
      particular experiences of parents, siblings, and critically ill children. The
      findings of this study raise significant implications for the development of
      support strategies for these families.

PMID- 10347504
TI  - Do-not-resuscitate patients in critical care: moral and ethical considerations.
AB  - In this article the author describes moral and ethical dilemmas presented by the
      "do-not-resuscitate" (DNR) patient in the critical care unit. The author defines
      the term DNR, and discovers implementation of the concept is not universally
      consistent among health care facilities. From the literature review, the author
      identifies characteristics, care requirements, economic cost, suitability of
      treatment, patient/family preferences, and health care professionals' values and
      beliefs as six important factors encompassing care and treatment of DNR patients
      in critical care. Recommendations for critical care professional practice,
      emphasizing the importance of communication, education, research, the development
      of specialized care units, and advance personal directives, is presented.

PMID- 10347505
TI  - Don't be immune to your patients' economic concerns.

PMID- 10347506
TI  - The emotional face of harm.
AB  - Nonmaleficence refers to the maxim Primum non nocere, "Above all, do no harm."
      Nonmaleficence is an important ethical principle, especially in the face of
      advanced technology and other superordinary or extraordinary therapeutic
      interventions available to patients today. Chronic illness poses challenges in
      balancing the benefits with the burdens of therapeutic intervention. A discussion
      of nonmaleficence as a principle to consider in chronic conditions is presented.

PMID- 10347507
TI  - Exploring wound care in Japan.

PMID- 10347508
TI  - Treating stage IV pressure ulcers with negative pressure therapy: a case report.
AB  - Decubitus ulcers remain a significant healthcare concern today, especially in the
      elderly and immobile population. Following the observation of three Stage IV
      decubitus ulcers refractory to standard medical and surgical therapy for 10
      months, a new vacuum-assisted closure device (V.A.C.) was initiated to speed
      wound healing. The V.A.C. was initiated in August 1996. The three Stage IV ulcers
      were located on the patient's right ischium, left ischium, and sacrum. On
      initiation, they measured 7 1/2 cm x 2 1/2 cm x 2 1/2 cm, 8 cm x 3 1/2 cm x 2 1/2
      cm, and 3 1/2 cm x 2 cm x 2 cm respectively. The treatment consisted of insertion
      of sterile sponge into the wound bed connected to the negative pressure device by
      suction hose. The device operated at a negative pressure of 125 mm Hg with a 5
      minute-on 2-minute-off-cycle. Dressing changes were performed every 48 hours
      during the treatment period. Successful closure of the sacral ulcer occurred in
      October 1996. The ischial ulcers were small enough to be taken off V.A.C. therapy
      in early November 1996. While we are encouraged by the results of this study,
      further additional clinical studies are warranted.

PMID- 10347509
TI  - Successfully managing incontinence-related irritant dermatitis across the
      lifespan.
AB  - The management of irritant dermatitis caused by incontinence is not always an
      easy patient care problem to solve. A brief review of the literature demonstrated
      that irritant dermatitis from body fluids is either not an issue in the
      healthcare arena or that only a few individuals have recognized it as a
      healthcare concern. Many products are used to treat this type of dermatitis, yet
      this can be a very challenging problem for the clinician and painful problem for
      the patient. It is imperative for healthcare providers to be aware of the effects
      of stool and urine on the skin, how products interact with body waste, and how to
      manage this problem properly.

PMID- 10347510
TI  - Self-perceptions about having an ostomy: a postoperative analysis.
AB  - The aim of this study is to identify the self-perceptions of patients at
      different postoperative phases and settings. The case study involves two ostomy
      patients: a young woman with a temporary ileostomy, and an older man with a
      permanent colostomy. Both patients were interviewed while still in the hospital
      on the third, fifth, and seventh postoperative days, and on the second day of the
      first and third months after discharge. Four major factors were identified after
      the patients were analyzed: social support, health and life expectations,
      physical suffering, and self-care. Family support predominated the social support
      category for both patients. The results showed that the patients' perceptions
      about having an ostomy were not influenced by the type of ostomy (i.e., whether
      the ostomy was temporary or permanent in the in-hospital phase). However, these
      results/perceptions, primarily those related to health and life expectancy and
      self-care, changed early in the study. We believe it is important for the
      healthcare team to know the perceptions patients have about their ostomies and
      themselves postoperatively. This, in turn, may contribute to systematic and
      personalized care based on specific patients' demands that vary at different
      stages of treatment and, most certainly, in different cultures.

PMID- 10347511
TI  - The importance of growth factors in wound healing.
AB  - For the last decade it has been acknowledged that growth factors are essential
      for regulating the cellular events involved in the formation of granulation
      tissue and in wound healing. Growth factors attract cells into the wound,
      stimulate their proliferation, and have a profound influence on extracellular
      matrix deposition. Studies have demonstrated that several growth factors are
      promising for cases of impaired healing. This paper is a review of the literature
      concerning growth factors and focuses on their role in and effect on soft tissue
      wound healing.

PMID- 10347512
TI  - Product safety and business interests: a delicate balance.

PMID- 10347513
TI  - The dollars and sense of patient teaching.

PMID- 10347514
TI  - The meaning of "otherness" in healthcare planning.
AB  - Otherness holds special meaning in healthcare planning. When clinicians assign
      the quality of "otherness" to a patient or a patient group, they may justify
      inadequate care by blaming the patient for the numerous management difficulties
      he or she presents. This response suggests that as a culture we need to be aware
      of the moral dimensions of otherness and recognize how this influences care. A
      case study is offered to illustrate the numerous barriers otherness poses in
      healthcare planning.

PMID- 10347515
TI  - Exploring wound care in Germany.

PMID- 10347516
TI  - Molnlycke Health Care.

PMID- 10347517
TI  - Recommendations to change the FDA classification of various wound dressings.

PMID- 10347518
TI  - A comparative study of an alternating air mattress for the prevention of pressure
      ulcers in surgical patients.
AB  - Research indicates that 8.5% of all patients undergoing surgical procedures for
      more than 3 hours develop pressure ulcers. In some types of surgery, incidence
      rates in excess of 25% have been reported. An 11-month study was conducted on the
      safety and efficacy of an experimental alternating air device in comparison with
      a tertiary care facility's conventional practice. A series of 217 patients
      undergoing surgical procedures scheduled for a minimum of 3 hours were enrolled.
      No ulcers developed in the experimental group and 11 ulcers developed in seven
      patients in the control group (8.75% incidence rate). Of the 11 ulcers, one was
      Stage I, four were Stage II, and six were unstageable secondary to eschar. The
      difference between the groups is significant at the P = 0.005 level. Individuals
      who developed ulcers had a length of stay approximately 7 days longer than the
      hospital average for comparable patients who did not develop ulcers.

PMID- 10347519
TI  - Protein-calorie malnutrition and involuntary weight loss: the role of aggressive
      nutritional intervention in wound healing.
AB  - Protein-calorie malnutrition and involuntary weight loss continue to be prevalent
      among hospitalized and long-term care patients, particularly the elderly. Studies
      on nutritional intervention have established a correlation between nutritional
      status, body weight, and rate of wound healing. Nutritional intervention,
      however, must be provided early enough to prevent a catabolic-induced decline in
      lean muscle mass, which can further impair wound healing. Chronic, nonhealing
      wounds are particularly difficult to treat and contribute to significant
      morbidity, mortality, and hospitalizations. More aggressive nutritional
      management and a greater understanding of the role of nutrition and weight gain
      in wound healing can result in more effective patient care. This article
      discusses the role of protein-calorie malnutrition and involuntary weight loss in
      hindering the wound-healing process, and the need to establish an optimal
      anabolic environment for weight gain and improved wound healing.

PMID- 10347521
TI  - Substance-use assessment.

PMID- 10347520
TI  - The ethics of using contingency management to reduce pressure ulcers: data from
      an exploratory study.
AB  - Although there is a widely held argument that pressure ulcers are preventable,
      they continue to cause major healthcare and financial problems. The blame for
      pressure ulcers has typically focused on the patient's self-neglect or self
      destructiveness. However, more recently, there has been a call for a paradigm
      shift from the current "paternalistic" medical model to one that includes the
      patient as a participant in his or her own care. Contingency management, a
      procedure well known in behaviorism, is presented as one such possibility.
      Controversy about the use of monetary reward, as well as discussion of initial
      efficacy in a current study, are discussed.

PMID- 10347522
TI  - Nutritional status: a priority of care.

PMID- 10347523
TI  - Acute pain teams make a difference.

PMID- 10347524
TI  - Dilemmas in the ethics of health-care research.
AB  - Evidence-based practice is now widely accepted as the most appropriate basis of
      patient care. Humans should only be used as research subjects with their full
      consent and in their best interests. Ethics committees play a pivotal role in
      maintaining the balance between scientific advances and ethical research.

PMID- 10347525
TI  - Substance-use assessment for hospital inpatients.
AB  - Many patients are not assessed for substance use and few are assessed
      comprehensively. Nurses are more likely than doctors to take a comprehensive
      substance-use history. A substance-use history assessment tool can be used
      hospital-wide.

PMID- 10347526
TI  - An audit of measuring equipment in elderly care.
AB  - Accurate monitoring of weight and height is a vital element of nutritional
      assessment. Specialist equipment may be required for older patients. Accuracy
      depends upon calibration and maintenance of equipment.

PMID- 10347527
TI  - The needs of neurology patients after discharge.
AB  - Patients discharged from neurosciences units and their carers often express a
      range of needs. Patients' needs relate to the illness and its physical effects.
      Carers experience mainly psychosocial effects. Needs can be met through planning
      and co-operation between the statutory and voluntary sectors and the use of
      liaison nurses.

PMID- 10347528
TI  - An assessment of urethral catheter valves.
AB  - Catheter valves have rarely been compared with conventional urinary drainage
      systems. Valves may only be suitable for certain patients. Patients should be
      counselled on the use and choice or combination of systems.

PMID- 10347530
TI  - Contamination in moving and handling equipment.
AB  - There is a risk of cross contamination when using moving and handling equipment
      in hospitals. Launderable equipment should be designated for single-patient use
      only and hard surfaces should be cleaned between patient use. Guidelines on the
      cleaning, decontamination and storage of moving and handling equipment should be
      made available to all users.

PMID- 10347529
TI  - Intermittent subcutaneous opioids: using an algorithm.
AB  - Nurses and patients prefer the administration of injections via an indwelling
      subcutaneous cannula. Patients undergoing intermediate and minor surgery need
      improved pain relief. The algorithm provides a safe and acceptable mechanism for
      administering subcutaneous opioids more frequently.

PMID- 10347531
TI  - Managing dysphagia in palliative care.
AB  - Dysphagia is a common problem in patients with advanced cancer. The nursing
      management of this condition must pay equal attention to the various physical and
      psychological signs and symptoms to promote patient well-being and comfort.

PMID- 10347532
TI  - Alginates and hydrofibre dressings.
AB  - Alginates are versatile dressings able to support moist wound healing. They can
      absorb large amounts of wound exudate. Although similar to alginates, hydrofibre
      dressings are hydrocolloids.

PMID- 10347533
TI  - Rheumatology. Part 4: Psychosocial issues.
AB  - Arthritis can affect physical, psychological, social, sexual and role function.
      Nurses need to enter into a therapeutic relationship with patients to address
      coping strategies. Care must be placed within the context of the patient's and
      family's life for it to be meaningful and relevant.

PMID- 10347534
TI  - Caring for older people.

PMID- 10347535
TI  - Value in SCI health care: achieving a practice equilibrium.

PMID- 10347536
TI  - President's message. Thinking outside the box: a vision for the future.

PMID- 10347537
TI  - In the long run. Achieving normalcy following spinal cord injury.

PMID- 10347538
TI  - Refusal of treatment: an ethical dilemma.
AB  - When a patient with a new spinal cord injury (SCI) refuses all care, the
      treatment team struggles with an ethical dilemma. The issues of patients' rights
      and autonomy are in conflict with the concepts of beneficence and nonmaleficence.
      Thomasma (1978) recommended a model useful in addressing situations in which
      values are in conflict. This model for an ethical workup is applied
      retrospectively to review a specific clinical case. The need to recognize and
      respect as many ethical principles as possible is identified as useful in
      reaching some acceptable resolution of an ethical dilemma.

PMID- 10347540
TI  - Therapeutic touch.

PMID- 10347539
TI  - Pilot evaluation of a nurse-administered carepath for successful colonoscopy for
      persons with spinal cord injury.
AB  - Due to ongoing improvements in medical care, the life expectancy of persons with
      spinal cord injury (SCI) continues to improve and approach that of the able
      bodied population. As the SCI population ages, cancer would be expected to
      increase as a cause of death. When a patient presents with occult fecal blood and
      anemia, colonscopy to the cecum is often pursued. It has been our experience that
      80 percent of patients are found to have inadequate bowel preps resulting in
      suboptimal colonoscopy when the prep is attempted at home. Because of this, we
      developed a nurse-administered carepath necessitating a 48-hour admission for
      bowel prep and colonoscopy. The bowel prep consists of magnesium citrate,
      polyethylene glycol-electrolyte solution, and sodium phosphate/biphosphate
      enemas. Throughout hospitalization, the patient receives a clear liquid diet.
      Eighteen patients have been placed on the carepath. At the time of colonoscopy,
      all 18 were noted to have received an acceptable bowel prep allowing
      vizualization to the cecum. A description of the carepath and its benefits is
      presented.

PMID- 10347541
TI  - Innovation in pediatric ventilatory support: application of BiPAP at British
      Columbia's Children's Hospital.

PMID- 10347542
TI  - Spinal cord injury resources on the Web.

PMID- 10347543
TI  - The art of balancing an unequal life.

PMID- 10347544
TI  - Exploring male fertility options after spinal cord injury: the role of the nurse
      clinician.
AB  - Male sexual function and fertility are important areas that need to be addressed
      for men undergoing spinal cord injury (SCI) rehabilitation. Rehabilitation nurses
      need to understand what fertility after SCI involves. Significant advances in the
      areas of sperm retrieval and advanced reproductive technologies have made
      biological parenthood for many men with SCI a viable option. This article reviews
      the various sperm retrieval techniques and advanced reproductive technologies
      available today. It also describes the unique role of a nurse clinician working
      in a fertility clinic designed specifically to address the fertility concerns of
      men and their partners after SCI.

PMID- 10347545
TI  - Elucidation of the mechanism of homozygous deletion of 3p12-13 in the U2020 cell
      line reveals the unexpected involvement of other chromosomes.
AB  - Homozygous deletions in tumor cells have been useful in the localization and
      validation of tumor suppressor genes. We have described a homozygous deletion in
      a lung cancer cell line (U2020) which is located within the most proximal of the
      three regions on the short arm of chromosome 3 believed to be lost in lung cancer
      development. Construction of a YAC contig map indicates that the deletion spans
      around 8 Mb, but no large deletion was apparent on conventional cytogenetic
      analysis of the cell line. To investigate this paradox, whole chromosome, arm
      specific, and regional paints have been used. This analysis has revealed that
      genetic loss has occurred by complex rearrangements of chromosomes 3, rather than
      simple interstitial deletion. These studies emphasize the power of molecular
      cytogenetics to disclose unsuspected tumor-specific translocations within the
      extremely complex karyotypes characteristic of solid tumors.

PMID- 10347546
TI  - Interphasic analysis of aneuploidy in cancer cell lines using primed in situ
      labeling.
AB  - The primed in situ (PRINS) labeling technique has been adapted to chromosomal
      screening of interphasic tumoral cells. A panel of ten chromosome-specific alpha
      satellite DNA primers was used to evaluate numerical chromosome abnormalities in
      two colon cancer cell lines (Caco-2 and HT-29) and in three of their
      subpopulations (PF11, TC7, and HT29-MTX). In each cell line, the copy number
      distribution for different chromosomes showed different patterns. The observation
      of significant variations in the chromosome constitutions between subpopulations
      derived from the same original tumor suggests the common occurrence of chromosome
      copy number heterogeneity in tumoral cell lines. This study demonstrates that the
      PRINS procedure offers a simple and reliable method for in situ chromosomal
      screening, which could be efficiently used for karyotypic analysis of tumoral
      cells.

PMID- 10347547
TI  - Frequent alterations of evolutionarily conserved regions of chromosome 1 in human
      malignant melanoma.
AB  - Recurring alterations of chromosome 1 represent the most frequent site of
      structural chromosome abnormalities across all human solid tumors, including
      human cutaneous malignant melanoma. In melanoma, breakpoints involving chromosome
      1 appear to accumulate most frequently at the paracentromeric regions, and
      secondly, to cluster within 1p36. Of interest, these three band regions (1p11-12,
      1q21, and 1p36) were simultaneously recognized by a single YAC clone which was
      isolated from sequences mapping to 1q21. This observation indicates the common
      and highly conserved nature of sequences residing within these three bands.
      Because of this finding, we have examined the possible association of these
      recurring sites of rearrangements of chromosome 1 in malignant melanoma. To
      elucidate genomic alterations in these regions, we have analyzed melanoma samples
      simultaneously by fluorescence in situ hybridization (FISH) using both the YAC
      clone encoding 1p11, 1q21, and 1p36 homologous sequences, and an alpha-satellite
      probe for the chromosome 1 centromere. Twelve of 20 (60%) randomly selected
      melanoma cell lines showed detectable rearrangements in one or more of the
      chromosome 1 band regions. These results provide support for the notion that the
      homology between these regions is associated with chromosomal instability, and
      possibly, is of biologic relevance in malignant melanoma.

PMID- 10347548
TI  - Cytogenetic analysis and RAS mutations in primary myelodysplastic syndromes.
AB  - Cytogenetic analysis was performed in 60 patients with primary myelodysplastic
      syndromes--diagnosed, treated, and followed in our department. In 41 cases, the
      presence of the NRAS mutation was also evaluated. The aim of this study was to
      evaluate the prognostic value of chromosomal abnormalities and NRAS mutation. The
      median age of the patients was 67 years (18-88 years), and the French-American
      British classification was as follows: refractory anemia 26, refractory anemia
      with ring sideroblasts 4, refractory anemia with excess of blast cells 15,
      refractory anemia with excess of blast cells in transformation 3, and chronic
      myelomonocytic leukemia 12. Survival analysis was performed for the patients with
      a normal (n = 35), an abnormal (n = 25) karyotype and with a single (n = 15) or
      multiple (n = 10) cytogenetic abnormalities. Abnormal karyotypes were detected in
      25 of the 60 patients (41.6%). Fifteen of these patients had a single and 10 had
      two or more lesions. The median survival of the patients with a normal (33.1
      months) and with an abnormal (36.5 months) karyotype was not significantly
      different. Patients with multiple lesions had a reduced median survival compared
      with patients with single anomalies (19.2 versus 39.7 months, p = 0.5). Patients
      with an abnormal karyotype progressed to acute leukemia more frequently compared
      with patients without lesions (36 versus 28.6%, p = 0.5). NRAS mutation was
      detected in 2 of 10 CMMoL patients studied and in none of the 31 patients with
      other types of myelodysplastic syndrome. Marrow blasts more than 10%
      significantly affected survival.

PMID- 10347549
TI  - A rare chimeric TLS/FUS-CHOP transcript in a patient with multiple liposarcomas:
      a case report.
AB  - Myxoid liposarcomas harbor a unique and specific t(12;16)(q13,p11) chromosomal
      translocation. The breakpoint has recently been identified, and involvement of
      the TLS/FUS gene on chromosome 16 and the CHOP gene on chromosome 12 was
      demonstrated. We report a case of a 45-year-old woman who developed multiple
      malignant lipomatous tumors of unknown origin and myxoid/round cell histology at
      different locations. To examine the diagnostic potential of this translocation
      and to develop a hypothesis on the origin of the tumors, we used cytogenetic and
      molecular cytogenetic methods (reverse transcription polymerase chain reaction,
      RT-PCR). We identified a chimeric RNA transcript in the second recurrence in the
      thigh/groin, as well as in another tumor in the mediastinum, which has an
      additional sequence of 33 bp, known as fusion transcript type III. Cytogenetic
      analysis of another tumor in retroperitoneal space revealed a rare type of
      unbalanced translocation der(16)t(12;16). We hypothesize that these tumors are
      metastases rather than multicentric tumors. The detection of the chimeric message
      in the present case is not only useful for differential diagnosis, but also for
      analyzing the origin of multiple neoplasms.

PMID- 10347550
TI  - Loss of chromosome 13 is the most frequent genomic imbalance in malignant fibrous
      histiocytomas. A comparative genomic hybridization analysis of a series of 30
      cases.
AB  - Regional chromosome localizations of DNA copy number imbalances were studied by
      comparative genomic hybridization in 30 malignant fibrous histiocytomas: 13
      primary tumors (2 myxoid, 9 storiform pleomorphic, and 2 with more
      undifferentiated phenotype) and 17 local recurrences (2 myxoid, 11 storiform
      pleomorphic, and 4 with more undifferentiated phenotype). Abnormal comparative
      genomic hybridization (CGH) profiles were observed in 25 tumors (83%). The most
      frequent gains (ratio > 1.2) corresponded, by order of frequency, to entire Xp,
      and bands 1q21, 19q13.1, 19p13, 5p13-p14, 1p31, 17p, 18p, 20q, 1p35, 17q23, and
      22q12. High levels of gains (ratio > 1.5) were recurrently detected for Xp (10
      cases), and in bands 1q21-q22 (8 cases), 3q27 (4 cases), 5p13-p14 (3 cases),
      13q32-q34 (3 cases), 15q22-q26 (3 cases), and 17p11-p12 (3 cases). Losses of
      13q12-q14 or 13q21 were observed in a large proportion of tumors (17 cases),
      suggesting that a gene localized in this region could act as a tumor suppressor
      gene. Losses of 11q23, 2q32, 11p13, 10p, 1q4, 9p2, 16q12, 4q3, 10q25, 3p23, 2p24,
      and 12p were also recurrently observed. Taken together, these results provide an
      overview of chromosome imbalances present in MFH, which could be of use for
      diagnostic purposes. They point to various chromosome regions which may harbor
      genes important for malignant fibrous histiocytomas (MFH) oncogenesis and
      progression.

PMID- 10347551
TI  - Complex variant 15;17 translocations in acute promyelocytic leukemia. A case
      report and review of three-way translocations.
AB  - Complex variant 15;17 translocations are increasingly recognized in acute
      promyelocytic leukemia (APL). We report a novel three-way translocation in APL
      involving chromosomes 15, 17, and X in the form of t(X;17;15)(q13;q12;q21).
      Southern blot analysis showed retinoic acid receptor alpha (RARA) gene
      rearrangement at intron 2. Clinical and morphologic findings are typical of APL,
      and a complete remission was attained with a course of conventional chemotherapy.
      A review of three-way complex variants of 15;17 translocation in the literature
      reveals 21 published cases in addition to ours. PML/RARA fusion was observed in
      all 8 cases in which molecular genetic analysis had been performed. More cases
      need to be analyzed to determine if clustering to particular chromosomal bands
      occurs in variant translocations, and whether APL cases harboring complex 15;17
      variants differ clinically from those with classical 15;17 translocation.

PMID- 10347552
TI  - Multiple polysomies in breast carcinomas: preferential gain of chromosomes 1, 5,
      6, 7, 12, 16, 17, 18, and 19.
AB  - Chromosome G-banding analysis of metaphase cells from 16 primary breast
      carcinomas revealed the presence of multiple polysomies in near-diploid as well
      as in polyploid cells. Chromosome 17 was preferentially gained in 7 tumors,
      followed in frequency by chromosomes 1, 12, and 19 (5 tumors each), and
      chromosomes 5, 6, 7, 16, and 18 (4 tumors each). Eleven of the 16 carcinomas had,
      apart from the clones exhibiting the numerical gains, other unrelated clones.
      Nine of these 11 cases had clones with structural chromosome aberrations, 5 of
      which had structural aberrations involving the short arm of chromosome 3. The
      biologic significance, if any, of this seemingly nonrandom coexistence of
      multiple polysomies with structural aberrations of 3p is at present not known.
      The pattern of numerical chromosome aberrations observed in the present study is
      comparable to previous results from fluorescence in situ hybridization (FISH)
      studies, with the use of centromeric probes on interphase cells. However, unlike
      FISH studies, which have been focused on chromosomes 1, 3, 7, 8, 11, 16, and 17,
      the cytogenetic results reveal that other chromosomes also may be nonrandomly
      gained as part of multiple polysomies in breast carcinomas. In addition, the
      tumors with multiple polysomies were generally of high histologic grade and with
      metastasis to axillary lymph nodes, suggesting that multiple wholechromosome
      gains may be a pathway of genetic evolution or progression or both in some breast
      carcinomas.

PMID- 10347553
TI  - T-cell prolymphocytic leukemia with a novel translocation (6;11)(q21;q23).
AB  - T-cell prolymphocytic leukemia (T-PLL) is an uncommon chronic lymphoproliferative
      disorder characterized by lymphadenopathy, splenomegaly, and lymphocytosis. The
      leukemic cells have the appearance of prolymphocytes and usually an
      immunophenotype of T-helper cells (CD3+ CD4+ CD8-). Inv(14q), del(11q), i(8q),
      and rearranged Xq28 are the commonest nonrandom chromosomal abnormalities in T
      PLL. Recently, it has been shown that the ataxia-telangiectasia mutated (ATM)
      gene located at 11q23 is often deleted in T-PLL, suggesting a tumor suppressor
      role of the ATM gene on tumorigenesis of T-PLL. We report a case of T-PLL with
      t(6;11)(q21;q23) as the sole chromosomal abnormality and suggest that the
      cytogenetically identified translocation also implicates the ATM gene.

PMID- 10347554
TI  - Seven novel mutations in the APC gene of Portuguese families with familial
      adenomatous polyposis: correlation with phenotype.
AB  - Germ-line mutations in the adenomatous polyposis coli (APC) gene are responsible
      for familial adenomatous polyposis (FAP). In the present study, we have used the
      protein truncation test to screen for mutations in exon 15 and exons 1-14 of the
      APC gene and denaturing gradient gel electrophoresis to analyze exons 1-14. We
      have studied nine unrelated FAP kindreds, eight with the classical phenotype and
      one with an atypical phenotype, with several family members exhibiting fewer than
      50 colonic polyps. The combined use of these two methodologies allowed the
      identification of seven novel mutations, with two unrelated families sharing the
      same mutation. All mutations were chain terminating: six resulted from small
      deletions, one from a small insertion, and one was a point mutation, resulting in
      a premature stop codon. Seven mutations were located in exon 15 of the APC gene,
      one was in exon 10, and the remaining one, which corresponded to the kindred with
      an atypical phenotype, was located in exon 4.

PMID- 10347555
TI  - Four cases of follicular lymphoma with t(14;18)(q32;q21) and t(3;4)(q27;p13) with
      LAZ3 (BCL6) rearrangement.
AB  - We report four cases of follicular lymphoma with both t(14;18)(q32;q21) and the
      newly characterized t(3;4)(q27;p13). Molecular investigation confirmed LAZ3
      (BCL6) rearrangement for all patients. The 3q27 aberrations have been rarely
      described in low-grade lymphomas and may represent secondary events whose
      implication remains to be elucidated.

PMID- 10347556
TI  - Loss of heterozygosity of 14q32 in colorectal carcinoma.
AB  - Previous allelotyping studies on colorectal carcinoma suggest that loss of
      heterozygosity (LOH) on chromosome 14q may be a common genetic alteration in this
      tumor type. The purpose of this study was to determine precise frequency of LOH
      at 14q32 region in colorectal carcinomas and to define a minimal region of LOH.
      LOH at 14q32 in 66 primary colorectal carcinomas were analyzed by polymerase
      chain reaction-based deletion mapping using six highly polymorphic
      microsatellites. The average rate of informative data was 68.2% in all cases of
      colorectal carcinoma analyzed. The average rate of LOH at 14q32 was 44.1%, with
      the highest frequency of 50.0% at D14S267 locus in the informative cases. The
      minimal region of LOH was defined by markers D14S65 and D14S250 at 14q32. The
      present data provide useful information for the isolation of tumor suppressor
      genes from this region.

PMID- 10347557
TI  - A translocation breakpoint at chromosome band 12q13 associated with B-cell
      chronic lymphocytic leukemia.
AB  - Low-grade B-cell lymphoproliferative disorders are frequently associated with an
      extra copy of chromosome 12. This well-documented acquired anomaly is one of the
      most specific numerical chromosome alterations to occur in human hematological
      malignancies. We have cytogenetically characterized bone marrow and peripheral
      blood cells from a patient with B-cell chronic lymphocytic leukemia (CLL) having
      a unique acquired translocation involving chromosomes 6 and 12, t(6;12)
      (p21.3;q13), which implicates band 12q13 as the site of the gene(s) important in
      this lymphoproliferative B-cell disorder. Aneuploidy, in the form of trisomy of
      chromosome 12, is not a requirement for neoplastic transformation in B-cell CLL,
      but gene rearrangement (present case) or nondisjunctional acquisition of
      additional copies of defective genes on chromosome 12 at band q13 may be involved
      in the genesis or progression of this disorder.

PMID- 10347558
TI  - Solitary fibrous tumor of the pleura: a cytogenetic study.
AB  - A solitary fibrous tumor of the pleura was studied. Its karyotype was
      46,XY,t(6;17) (p11.2;q23),ins(9;12)(q22;q15q24.1),inv(16)(p13.1q24). The
      rearrangement of 12q13-15 was also described in a subset of hemangiopericytomas
      of soft tissue and meninges. Because both types of tumors are morphologically and
      immunophenotypically quite similar, and because some of them share rearrangement
      of 12q13-15, the possibility of their histogenetical relatedness should be
      considered.

PMID- 10347559
TI  - Cytogenetic investigation of canine lipomas.
AB  - Akin to humans, lipomas are common in the dog as well; however, until now there
      were no reports of cytogenetic investigations on these tumors in the canine. We
      report our results of cytogenetic investigations on a series of ten canine
      lipomas. Clonal aberrations were observed in seven cases. In one case a trisomy
      27 was evident; in another case a trisomy 13 was present in addition to a marker
      chromosome. A third lipoma showed a fusion of chromosomes 2 and 13. These cases
      showed one derivative chromosome each (der(X), der(7), and der(4)), and one case
      had two derivative chromosomes (der(X) plus der(4)). In the two cases with
      derivative chromosomes 4, the same region (4q31) was affected. It is tempting to
      speculate that this region might harbor a gene associated with tumor development.
      The results are compared to the cytogenetic situation in human lipomas.

PMID- 10347560
TI  - Acute myeloblastic leukemia (M0) with an unusual chromosomal abnormality:
      translocation (1;14)(p13;q32).
AB  - We describe a case of acute myeloblastic leukemia, French-American-British
      subclassification of M0 (AML-M0), with an unusual chromosomal abnormality. The
      diagnosis of AML-M0 was made morphologically, cytochemically, and
      immunophenotypically. At the time of diagnosis, cytogenetic studies were
      performed, revealing a translocation involving chromosomes 1 and 14--specifically
      t(1;14)(p13;q32). The patient responded to high-dose ARA-C. In our survey of the
      literature, we were unable to find a reported case of AML-M0 with this
      chromosomal translocation.

PMID- 10347561
TI  - Pleomorphic adenomas of the salivary glands: absence of HMGIY rearrangements.
AB  - Rearrangements of chromosome region 12q14-15 affecting the HMGIC gene are a
      frequent finding in benign solid tumors. Another non-random chromosomal
      alteration observed in subgroups of several of the tumor entities with 12q14-15
      changes are rearrangements of 6p21 resulting in alterations of the HMGIY gene,
      which have so far not been documented in pleomorphic adenomas of the salivary
      glands. In our series of 335 pleomorphic adenomas, karyotypic changes affecting
      chromosomal region 6p21-23 were observed in five tumors all showing either a
      simple or complex t(6;8)(p21-p23;q12). Molecular cytogenetic studies of two of
      these tumors revealed that the 6p-breakpoint of this translocation maps distal to
      HMGIY, not affecting the gene or its closer vicinity. The results strongly
      suggest that pleomorphic adenomas are the only exception to the rule that
      entities of benign tumors with HMGIC rearrangements also have subtypes with HMGIY
      rearrangements. The difference from the other tumors is discussed in terms of
      tissue specificity of both HMG protein genes.

PMID- 10347562
TI  - Chromosome instability in elastofibroma.

PMID- 10347563
TI  - Trisomy 13 in a Philadelphia negative chromosome and BCR-ABL negative
      myeloproliferative disorder.

PMID- 10347564
TI  - Sensitivity and specificity of methods of classification of leprosy without use
      of skin-smear examination.

PMID- 10347565
TI  - Incidence of nerve damage in leprosy patients treated with MDT.
AB  - The incidence rates of sensory and motor impairments during and after multidrug
      therapy (MDT) are reported for a prospective cohort of patients who had no nerve
      damage at registration (N = 1621). Sensory and motor loss increased with age and
      both were high among multibacillary patients as compared with paucibacillary
      patients. The lateral popliteal (common peroneal) and posterior tibial nerves
      seem to be most affected for sensory loss; whereas the posterior tibial and ulnar
      nerves are mainly responsible for motor loss. No significant difference by gender
      was found. Implications for prevention of disability (POD) activities are
      discussed and suitable recommendations made.

PMID- 10347566
TI  - Monitoring the elimination of leprosy in Brazil.
AB  - A decreasing trend in the prevalence rate of leprosy was reached in Brazil only
      after the introduction of the World Health Organization multidrug therapy
      (WHO/MDT) program in 1990. This paper analyzes leprosy morbidity indicators and
      the prevalence rate, and their utilization in monitoring the progress of leprosy
      elimination in Brazil. Since these indicators are modified by changes in health
      service procedures, comparing prevalence rates from different endemic countries
      or current prevalence rates with old ones from the same endemic region needs
      careful attention. The current official prevalence rate of 6.72/10,000
      inhabitants in Brazil could be considered high when compared with rates from
      other countries, but it is important to remember that defaulters and patients
      being treated with old regimens are kept on the active registers in Brazil, while
      in most other endemic countries they are not.

PMID- 10347567
TI  - Susceptibility to Mycobacterium leprae of ALY (alymphoplasia) mice and IFN-gamma
      induction in the culture supernatant of spleen cells.
AB  - The aly/aly (alymphoplasia) mice from a mutation of a colony of the C57BL/6J
      mouse strain, which has a systemic absence of lymph nodes and Peyer's patches,
      are deficient in both T- and B-cell-mediated immune functions. We have undertaken
      a comparison of susceptibility to Mycobacterium leprae of ALY (aly/aly, aly/+)
      mice with C57BL/6J mice. The aly/aly mouse was found to have an excellent high
      susceptibility to M. leprae with no distinction between female and male. The
      aly/+ mouse also was more susceptible to M. leprae at an earlier stage than the
      C57BL/6J mouse. Therefore, we examined and compared the cytokine gene expression
      and gamma interferon (IFN-gamma) induction in the splenocytes of ALY mice. The
      expression of interleukin 4 (IL-4), IL-10 and IL-12 mRNA was weakly stimulated
      with ML-lysate in inoculated aly/aly mice but IL-2, IL-6, IGIF/IL-18 and IFN
      gamma mRNA were not observed. None of the cytokine genes used appeared, except
      the mRNA for IL-1-alpha, when uninfected cultured spleen cells were stimulated
      with ML-lysate. Also, IFN-gamma production was not induced. However, the
      appearance of these cytokine genes was observed when stimulated with concanavalin
      A (ConA), and IFN-gamma production was also induced in the culture supernatant by
      aly/+ and even aly/aly mice stimulated with ConA. To examine the reason why IFN
      gamma cannot be produced by splenocytes of ALY mice inoculated with M. leprae, we
      detected cytokine gene expression and IFN-gamma induction in the presence of
      recombinant murine IL-12 or IGIF/IL-18. IL-2 mRNA expression was detected in all
      of the mice tested in the presence of IL-12 but not in aly/aly mice under IGIF/IL
      18, and iNOS mRNA expression was not observed in aly/aly mice under IL-12 or
      IGIF/IL-18. IL-4 and IL-10 mRNA were detected by aly/aly mice only by exposure to
      IGIF/IL-18. In culture, the supernatant with ML antigens of the aly/aly mice did
      not produce IFN-gamma in spite of the presence of IL-12 and IGIF/IL-18, while IFN
      gamma was weakly induced in aly/+ mice stimulated with ML-lysate and in the
      presence of IGIF/IL-18. Nevertheless, IFN-gamma production was observed in
      splenocytes of the aly/aly mice stimulated with ConA and also with IGIF/IL-18
      plus anti-CD3 antibody. Our results suggest that ALY mice might be showing a high
      susceptibility to M. leprae because of deficient priming for activation of T
      cells with the leprosy bacilli infection. Moreover, it is possible that the
      phagocytic activities of the macrophages of ALY mice are also impaired.

PMID- 10347568
TI  - Anti-neutrophil cytoplasmic antibodies (ANCA) in the clinical forms of leprosy.
AB  - Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies against enzymes
      present in primary granules of neutrophils and lysosomes of monocytes detected in
      systemic vasculitis and in other diseases, including infections. ANCA are markers
      of active Wegener granulomatosis, which presents some anatomo-pathologic and
      immune response features similar to those of leprosy. Thus, we raised the
      hypothesis that ANCA may be present in leprosy as markers specifically linked to
      the presence of vasculitis. The aim of this study was to determine the presence
      of ANCA in leprosy and its correlation with the clinical forms of the disease.
      Sera from 60 normal individuals and from 59 patients with different clinical
      forms of leprosy were studied. The patients were also allocated into reactional
      and nonreactional groups. By indirect immunofluorescence, ANCA were positive, an
      atypical pattern (A-ANCA), in 28.8% of the patient sera. A-ANCA predominated,
      although not significantly (p > 0.05), in the reactional groups 37.9% vs 20.0%),
      and in those at the lepromatous pole (41.6% vs 20.0%). There was no correlation
      between ANCA positivity and either disease duration, disease activity, or
      therapeutic regimen (p > 0.05). An interesting finding was the correlation
      between ANCA and gender: 94.1% of ANCA-positive patients were males (p < 0.01), a
      feature that so far has not been reported in ANCA-related diseases and for which
      there is no explanation at the moment. By ELISA, the sera of the lepromatous
      leprosy patients did not show activity against either PR3, MPO, HLE, the most
      common ANCA antigens. Because A-ANCA are nonspecific, this finding requires
      further investigation for the determination of the responsible antigen(s). In
      conclusion, A-ANCA are present in 28.8% of leprosy patients but are not related
      to vasculitis in the erythema nodosum leprosum reaction and are not a marker of a
      specific clinical form.

PMID- 10347569
TI  - Bone scintigraphy in leprosy.

PMID- 10347570
TI  - Cellular immune responses of healthy and Mycobacterium leprae-inoculated
      armadillos (Dasypus novemcinctus)

PMID- 10347571
TI  - Achievements and prospects on leprosy prevention and control in China.

PMID- 10347572
TI  - Taking home lessons from the 15th International Leprosy Congress.

PMID- 10347574
TI  - Report of workshop on defining the disease and antibacterial therapy.

PMID- 10347575
TI  - Report of workshop on early case detection.

PMID- 10347577
TI  - Report of workshop on prevention of disability.

PMID- 10347576
TI  - Report of workshop on organization of leprosy services under low-endemic
      conditions.

PMID- 10347578
TI  - Report of workshop on changing community perceptions and ensuring community
      involvement.

PMID- 10347579
TI  - Report of workshop on social and economic integration.

PMID- 10347580
TI  - Report of workshop on global need and opportunities for rehabilitation.

PMID- 10347581
TI  - Report of workshop on people affected by leprosy as working partners.

PMID- 10347582
TI  - Causative organism and host response early diagnosis of leprosy.

PMID- 10347583
TI  - Vaccine trials against leprosy.

PMID- 10347584
TI  - The Mycobacterium leprae genome project.

PMID- 10347585
TI  - Potential application of molecular biology to leprosy research.

PMID- 10347586
TI  - Report of workshop on new tools for diagnosis and epidemiology.

PMID- 10347587
TI  - Report of workshop on chemotherapy.

PMID- 10347588
TI  - Report of workshop on epidemiology/transmission/vaccines.

PMID- 10347589
TI  - Report of workshop on pathogenesis and lessons from leprosy.

PMID- 10347590
TI  - Report of workshop on nerve damage and reactions.

PMID- 10347591
TI  - Drugs for depression and anxiety.

PMID- 10347592
TI  - [The anthropic principle in biology and radiobiology].
AB  - In accordance with the anthropic principle of the Universe the physical constants
      of fundamental particles of matter and the laws of their counteraction are those
      that an appearance of man and mind becomes possible and necessary. It is
      suggested to add some biological constants to the set of fundamental constants.
      With reparation of DNA as an example it was shown how a cell ran some parameters
      of Watson-Crick double helix. It was pointed that the concept of the anthropic
      principle of the Universe in its full body including biological constants is a
      key to developing of a unified theory of evolution of the Universe within the
      limits of scientific creationism.

PMID- 10347593
TI  - [Globular model of interphase chromosome and intrachromosomal exchange
      aberrations].
AB  - A globular folding model formerly proposed for large-scale interphase
      chromatin/chromosome organization is investigated here by computer simulation.
      Large-scale structure of interphase chromosome is suggested to be determined by
      volumetric interactions between chromosome subunits resulting in folding of
      subunit chain in a globular state. Structure unit of interphase chromosome is
      considered as a spherical structure consisting of a cluster of compact chromatin
      domains. These structure units/domain clusters were termed as a superdomains to
      emphasize their supradomain organization. Globular state of superdomain chain
      with excluded volume as well as phase transitions between condensed (globular)
      and decondensed (coiled) states are studied by dynamic Monte-Carlo approach.
      Globular model is supported by confocal microscopy data. It extends current view
      on interphase chromosome as a random Gauss polymer chain. Radiation-induced
      intrachromosome exchange aberrations (intrachanges) are modeled on the basis of
      the contact hypothesis. It implies that intrachanges result from radiation damage
      of chromatin mainly in contacted subunits. Computer modeling of chromosome
      structure provides a wealth of information about proximity effects and results in
      prediction of pattern of intrachromosome contacts. Calculated intrachange
      frequencies agree well with experimental data. Globular model suggests a physical
      mechanism for conformational changes of large-scale chromosome structure similar
      to phase transitions in polymer systems. These rearrangements of structure
      organization of chromosomes in the nuclei following irradiation could be
      mechanistically linked to the complex chromosome aberrations formation as well as
      to alteration of gene expression due to position variegation effect.

PMID- 10347594
TI  - [Morphological changes in lungs during chest irradiation].
AB  - Morphological characteristics of the lung are presented for rats and hamsters
      with esophageal and lung damages following chest exposure to 10-100 Gy. A four
      month post-exposure follow-up revealed changes in the lung tissue in all cases.
      Depending on radiation dose, lung damages differed in genesis and time of
      development. These were either extensive secondary suppurative inflammation in
      the bronchi and alveolar parenchyma, to the point of empyemas, or radiation
      injuries proper of alveolar and bronchial epithelia, being degenerative and
      atrophic in nature. In four months after exposure to 18-42 Gy, the hamsters
      exhibited a pathological process, i.e. a basis for pulmonary fibrosis and
      cardiopulmonary insufficiency to be developed.

PMID- 10347596
TI  - [Universal character of induction of cytogenetic aberrations by low intensity
      radiation, and estimation of genetic risk].
AB  - The analysis of contemporary state of the problem in quantitative estimation of
      cytogenetic effects within the low dose range is given. Experimentally derived
      modern data led to a conclusion that the relationship between radiation induced
      cytogenetic damage and dose within the low dose range is non-linear and universal
      (concerning test-objects) in nature. Consequences of the received results for
      biological dosimetry and the estimation of genetic and carcinogenic risk of low
      dose exposure are discussed.

PMID- 10347595
TI  - [New aspects of of the effects of low intensity radiation].
AB  - In paper the new aspects of action regularity of ionizing radiation of low
      intensity on the biophysical and biochemical characteristics of bio-objects and
      populations are considered. From the point of view of breaking the connection
      between occurrence of damages and work of systems of restoration at low intensity
      irradiation, are described the dose dependence of different types--from threshold
      up to extreme and a plateau curve, differing among themselves only by a parity of
      these processes. The features of action of low intensity irradiation on bio
      objects and populations--change of structure of a population, sensitivity to
      action of external stimulus, force of connections between the elements of
      regulatory systems--allow to consider the low intensity irradiation as the factor
      capable to cause unpredictable transition of quasistationary systems in new
      status.

PMID- 10347597
TI  - [Relationship between structural characteristics of eukaryotic DNA and its
      sensitivity to the effect of low intensity ionizing radiation].
AB  - Analysis of literature and own experimental data as well as the up-to-date
      conception of heterogeneous damage of cell genome allows the author to conclude
      that there are some sensitive regions in DNA, which are the sites of DNA
      attachment to nuclear matrix. The role of conformational changes in chromatin is
      considered in formation of long-term consequences of low-dose irradiation of
      mammalian and human.

PMID- 10347599
TI  - [Radioadaptive response in human cells with different DNA repair activity].
AB  - Some experimental and literature data revealed the independency of the protection
      systems at the adaptive response (AR) and DNA repair. AR and DNA repair compared
      in some systems: 1) normal and repair-deficient human cells, 2) lymphocytes from
      children living in the regions with increased level of radiation, 3) formation of
      AR in the experiments with chloride cadmium which induced inrepairable damage of
      DNA.

PMID- 10347598
TI  - [Current aspects of radiobiology of Drosophila melanogaster. Apoptosis and
      aging].
AB  - The mechanisms of post radiation life span alteration are reviewed and discussed.
      The mechanisms underlying radiation induced organism aging and death are not well
      understood and under great interest. What is the cause of radiation-induced
      "aging"? What are the mechanisms leading to senescence and death? Recent
      achievements in molecular biology and genetics suggest that cell senescence is
      determined by telomeres reduction (Biokhimiya, 1997). This mechanism seems to
      play an important role in aging. However the aging in postmitotic organisms (for
      example Drosophila melanogaster) can not be explained by telomeres reduction
      mechanism. It is suggested that radiation induced life span alteration can be
      explained by deregulation of apoptosis in multicellular organisms.

PMID- 10347600
TI  - [Laser correlation spectroscopy of blood plasma for diagnosis of postradiation
      sequels].
AB  - The method of laser correlation spectroscopy (LCS) of biological fluids, permit
      to detect fractional composition of biological fluids (in this case--blood
      plasma). This method have been used to study the late effects of radiation in
      experimental investigations on animals (irradiation in doses that induce the high
      frequency of malignant tumors) and on the people living in the zone of Ural
      Radiation Trace. LCS spectra analysis show the proportion of separate ingredients
      in the blood plasma in the very bright range of molecular dimensions (d = 1-10000
      nm) and for this analysis the special way of classification (semiotic
      classification) have been proposed. Multicomponent spectra, represented as a
      histogram (the abscess--diameters of light-scattering particles, ordinate--their
      per cent in the light-scattering of the whole sample) divide on the separate a
      priori marked zones with the appropriate means of diameters light-scattering
      subcomponent. In dependence on the increasing, or decreasing of enclosing in the
      light-scattering separated subcomponent the program of classification refer this
      histogram to separate cluster. Each cluster on the basis of preliminary
      investigations of different pathologic states related to the definite sign
      reflecting the type of homeostatic alterations (intoxication, allergic,
      dystrophic, catabolic and their combinations). The detection of the direction of
      homeostatic alteration and its degree is the main purpose of the semiotic
      classification of LC-spectra. In this paper it was shown that this way of
      diagnostic of the nature of homeostatic alterations in the blood plasma is more
      informative in the evaluation of the weightiness of pathologic state of organism
      in the comparison with the complexes of laboratory methods, usually used. The
      method can register immunoglobulin relations, changes in concentrations of
      lipoproteids and cholesterol and fractional composition of immunocompetent blood
      cells. The model experiments on animals irradiated in the doses that induce the
      high frequency of malignant tumors in 12 months thereafter (50 per cent of
      irradiated rats) have been conducted. With the help of LCS blood plasma it is
      possible to show the differences in direction of homeostatic changes in animals
      with and without oncological disease in a long period of time before
      pathomorphological registration of tumors. At last when 764 individuals living in
      the Zone of Ural radiation trace have been inspected by the LCS blood plasma it
      was shown: a. individuals without pathological diagnosis (in the range of 100-150
      cz cumulating doses) the radiation action doesn't modify the homeostasis system
      in practice; b. in individuals with preoncological, oncological, autoimmune and
      metabolical diseases the modification of homeostasis system in these doses range
      is noticed. The direction of this modification depend on the nature of
      pathological process. The methodical simplicity of LCS investigations, rapidity
      and automatism of analysis together with informative sensitivity of this method
      testify to perspectives use of LCS blood plasma for the decision of the problem
      of biodosimetry of irradiation of experimental animals and for monitoring of late
      effects after low dose irradiation.

PMID- 10347601
TI  - [Mechanism of radiobiological effects of low intensity nonionizing
      electromagnetic radiation].
AB  - The results of the research of the biological effects of the non-ionizing
      electromagnetic radiation were studied from the position of "thermal" and
      "unthermal" mechanisms. The special attention was spared to analysing the
      information characterising the high sensitiveness of the human and animals
      organism to the very-low intensity electromagnetic fields.

PMID- 10347602
TI  - [Secondary biogenic radiation of human body].
AB  - It was shown that tissues of alive healthy hyman organism (hands, surface of
      breast, hair) permanently emitted secondary biogenous radiation (SBR), which was
      registered with biological detectors. The hypothesis was suggested that natural
      background radiation permanently excited biopolymers (proteins, nucleic acids) in
      condensed state and induced electromagnetic field of SBR which is vitally
      important for human organism. The field partly extends beyond the organism, where
      it is registered with sensitive biological detectors.

PMID- 10347603
TI  - [Molecular mechanisms of major radiobiological sequels of the effect of ionizing
      radiation on mammals].
AB  - The modern knowledge about the molecular bases of reproductive cell death,
      apoptosis, necrosis and disturbance of the cell reproduction, the main causes of
      radiation sickness and radiation death of mammals and men was considered. It was
      marked, that these deterministic effects of ionizing radiation as the stochastic
      effects (mutagenesis and carcinogenesis) have an common molecular basis that most
      full opened up by study of apoptosis and including in complex genetical and
      biochemical phenomena of DNA repair.

PMID- 10347604
TI  - [Role of emotional stress in development of somatic injuries in liquidators of
      the Chernobyl power plant accident irradiated with small doses].
AB  - In the light of modern beliefs about emotional stress are considered available in
      the literature given on changing a picture of health beside persons, taken part
      in liquidations of consequences of damage on Chernobil atomic stations. Results
      of psychological, psychophysiological and endocrinological examinations point to
      that beside significant numbers of liquidators of damage was developed chronic
      emotional stress. Expected presence of feedforward between the emotional stress
      and development beside liquidators of psychic frustrations, cardiovascular
      pathology, peptic ulcer of stomach and duodenum. Is discussed problem of
      combining action on the organism of ionizing radiating in small doses and long
      emotional stress.

PMID- 10347605
TI  - [Radiation-induced adaptive response in children and effect of external and
      internal factors].
AB  - 434 children 3-13 old age and 4 adult people 20-40 old age have been investigated
      by the use of micronucleus (MN) assay and cytokinetical block by cytochalasin B
      on the ability to the adaptive response (AR). The frequency of lymphocytes with
      MN was scored in 1000 binucleated cells after irradiation in challenge dose of 1
      Gy and together in adaptive (0.05 Gy) and challenge doses. The significance of
      differences have been determined by chi 2 criteria. It was shown that definite AR
      was determined in approximately 20 percent of "normal" children, when in adult
      population--in approximately 50 percent cases. The part of children with AR
      decreases in the groups of children with defects of development, with mentally
      deficiencies, with hard heredity (the parents are the chronic alcoholics), with
      the high pressure of genotoxic agents. It was discovered that in about the half
      of the children there is opposite effect observed-irradiation in adaptive dose
      induce the increasing of radiosensitivity; this effect is insignificantly
      expressed in adult people. The problems of genetic determination of AR, influence
      of different factors, the significance of AR as the phenomen of protection from
      extremal action have been discussed.

PMID- 10347606
TI  - [Small doses and synergistic interaction of environmental factors].
AB  - Methodology approach demonstrating a principle importance of mutual increase of
      damaging action of physical and chemical environmental factors at low doses and
      intensities was described. A generalize conceptual basis of synergism was
      suggested which was appropriate both for combined action of ionizing radiation
      with other agents and for combined action of any other harmful environmental
      factors. The main idea of the concept described here is in the formation of
      additional effective damages under combined action due to interaction of
      sublesions induced by every agent and which are not effective under separate
      action of each agent employed. Mathematical presentation of this concept allowed
      to make some new non-trivial conclusions. It was shown theoretically the
      existence of optimal ratio of damages induced by acting agents under which the
      highest synergism must be obtained. The effect of synergistic interaction has to
      be dependent on intensities of agents: the less intensity of one agent used, the
      small intensity of another factor must be applied for the greatest synergistic
      effect expression. The test of these consequences was performed for a number of
      experiments described in this paper. The results presented here have of principle
      importance for interpretation of the higher effectiveness of low dose and dose
      rate of ionizing radiation observed in some cases.

PMID- 10347607
TI  - [Biological effects of low level ionizing radiation (the threshold of effects and
      radiosensitivity/radioreactivity of biological structures with different level of
      organization)].
AB  - There have been analysed the data as own as taken from the literature concerning
      the action of low level radiation (LLR) on different structure level in a
      mammalian organism. There have been compared the types of various structures
      early reactions regarding an acute or prolonged exposure depending on the test
      type and the studied structure organization level. The data analysis has shown it
      should differentiate the damaging and irritating action of LLR. The former
      reveals the radiosensitivity and the latter does the radioreactivity of the
      structure studied. The damaging radiation action has an threshold and the latter
      increases in the way from molecular to whole body level. It is supposed the
      irritating LLR action is realized through the involvement of organism and cell
      regulative systems. The existence of a threshold in the case is unknown so far.

PMID- 10347608
TI  - [Novel biophysical and biological aspects of mechanisms of effects of low doses
      of ionizing radiation (low LET) on eukaryotic cells].
AB  - Novel biophysical and biological aspects of eukaryotic cell response to low doses
      of low-LET radiation are considered in the present paper. The model of universal
      nuclear target in eukaryotic cells is proposed. The target is considered as a
      spherical volume homogeneously filled of DNA with adjacent water layer. Thickness
      of water layer equals to diffusion length of hydroxil radicals hitting DNA. Two
      subregions are proposed of the cellular membrane with different ability to
      respond to low doses of ionizing radiation. An original mechanism of repair of
      DNA double strand breaks (dsb) is described. This mechanism suggests directional
      conformational movement of separate locuses of homological chromosomes through
      narrow tube ("throat") between specialised nuclear regions. The fluxes of nuclear
      liquid induce a force which is responsible for highly elastic chromosome
      deformation and chromosome movement resulting in proximity of homological
      chromosomes in the throat. Close proximity is required for DNA dsb repair. All of
      DNA dsbs have to be repaired in low doses range owing to high genomic stability
      of eukaryotic cells. However, it has been hypothesized an existence of a small
      subpopulation of cells with unstable genome named as cells of evolutionary or/and
      ontogenetical reserve (ER or/and OR). Genomic instability is induced in these
      cells by epigenetic program. This program results in DNA damage mainly in
      chromosomal "hot spots". As a result new genetic variants are originated. The
      ability of cell population in vivo to eliminate or not eliminate Er/OR cells
      determinates individual sensitivity of organism and hence health consequences to
      low dose radiation exposure.

PMID- 10347609
TI  - [Radiochemistry of polysaccharides (review)].
AB  - Data on the radiolysis of polysaccharides (in the form of aqueous solutions in
      liquid or frozen states, and native "dry" preparations) is surveyed to explore
      the possibility of participation of free radicals in formation of ruptures in
      macromolecules, low-molecular products of polysaccharides decomposition,
      carbonyl, carboxyl, and peroxide groups in the macromolecules. The reaction
      schemes for principal transformation pathways of polysaccharides free radicals
      account for ultimate molecular products of the radiolysis. Effects of the
      adsorbed structured water on formation and conversions of free radicals, of
      postradiation polymer decomposition, and radiation protection of polysaccharides
      are discussed.

PMID- 10347610
TI  - [Genetic effects in populations of plants growing in the zone of Kyshtym and
      Chernobyl accidents].
AB  - Studies to analyze the genetic processes in natural populations of plants were
      started on the territory of the East-Ural Radioactive Trace (EURT) in 1962 and in
      the zone of the Chernobyl accident in May 1986. The main directions of the
      genetic studies in both radioactive areas were similar: 1) study of the mutation
      process intensity depending on the dose and dose rate and analysis of dose-effect
      relationships for different genetic changes (point mutations, chromosome
      aberrations in mitosis and meiosis) in irradiated plant populations; 2) study of
      the mutation process dynamics in generations of chronically (prolongly)
      irradiated populations of plants; 3) analysis of microevolutionary processes in
      irradiated plant populations. The report presents an analysis of observed dose
      effect relationships under the action of radiation on populations of Arabidopsis
      thaliana, Pinus sylvestris and a number of other plant species. Analysis of the
      mutation processes dynamics in 8 Arabidopsis populations growing in the zone of
      the Chernobyl catastrophe has demonstrated that the level of the embryo lethal
      mutations 10 years after the accident in the irradiated populations significantly
      exceeds the control level. The following phenomena observed in chronically
      irradiated populations have also been considered: increased radioresistance of
      irradiated populations (radioadaptation), the appearance of abnormal karyotypes
      and selective markers upon chronic irradiation. The authors call attention to the
      high importance of monitoring of genetic processes in irradiated plant
      populations for understanding of the action of radiation on human populations.

PMID- 10347611
TI  - [Extrapolation of dose-effect relationships for cytogenetic aberrations from high
      to low doses].
AB  - It is known, that extrapolation of dose response curve for cytogenic lesions,
      based on the linear non-threshold concept is not correct due to anomalies in the
      low dose region, among them the dose intervals of the so-called "low dose
      effects" (LDE) and "plato"-effect. As a rule they are attributed to assumed
      heterogeneity of cell populations or to existence of several repair systems.
      Analysing the data on modification the cytogenetic lesions we concluded, that in
      the whole low-dose range functions one on the same repair system, but it
      "switches on" only at sufficient reorganization of chromatin (accompanied by
      expression of before "silent" genes), caused by radiation-induced increase of the
      membranes permeability. In the dose interval of LDE this occurs only in vary
      narrow diapason of dose rate (approximately(1-30) cGy/min for many cell kinds);
      in the "plato" dose interval--in its beginning. By the assessment of cancerogenic
      risk the linear non threshold concept can be used only for dose dependence,
      obtained when repair is absent or inhibited.

PMID- 10347612
TI  - [Radiation and immunity. Interference of ionizing radiation with key immune
      processes].
AB  - Recent evidences of the interference of ionizing radiation into the intimate
      immune processes are presented in the review. gamma-irradiation induces some
      events in V-gene rearrangement in T cells. Low-dose irradiation can result in the
      thymocyte differentiation and activation. Immediately after irradiation stromal
      thymic cell activity are stimulated and in the later stages it is depressed.
      Irradiation induces an expression of some functionally important molecules on a
      surface of the cells of immune system and thus influences the processes of cell
      interaction, costimulation, adhesion and transvascular migration. It is shown
      that many events of the signal transduction pathways resulting in radiation
      induced and activation-induced apoptosis of lymphocyte are general. This data
      evidence that the possibility of the choice between the death and activation
      exists for the cells which are undergone to action of ionizing radiation.

PMID- 10347613
TI  - Participation of M1 receptors in NO pathway in cat ileum.
AB  - Electrical field stimulation (EFS) elicited two types of responses from
      longitudinal muscle strips of the distal cat ileum: contraction at switching on
      the stimulation (in 62% of the strips) and inhibition of the phasic contractions
      at switching on the stimulation followed by contraction in 38% of the strips. In
      all strips the muscarinic acetylcholine subtype M1-receptor agonist (4-Hydroxy-2
      butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride (McN-A-343) increased
      the tone and amplitude of the spontaneous contractions. On this background EFS
      elicited an inhibition of the phasic contractions at switching on the stimulation
      followed by contraction. Blockade of nitric oxide (NO)-synthase by Nw-nitro-L
      arginine (L-NNA) transformed the inhibitory response into contraction and this
      transformation was partly overcome by L-arginine. The results suggest that
      presynaptically situated M1 receptors are involved in the NO pathway.

PMID- 10347614
TI  - Perceptual grouping of strip dot patterns.
AB  - Grouping of one-dimensional (strip) dot patterns was investigated, using an
      adjustment procedure to evaluate the distance (adjusted gap) at which two
      patterns appear to merge in a single strip. The size of the patterns had only a
      scaling effect on the adjusted gap. The adjusted gap and the variance of the
      estimates were influenced by the number of dots and the regularity (similarity,
      symmetry) of the patterns in the pair. Models of proximal grouping failed to
      account for the results obtained. A two-stage process implying determination of
      dot location and evaluation of inter-dot separation by means of "eclectic units"
      (Morgan, Hole & Glennerster, 1990) was considered to explain the findings.

PMID- 10347615
TI  - Non-invasive registration of the aboral and oral spreading of the gastroduodenal
      peristaltic activity (experimental and clinical investigations).
AB  - The electrical activity of the stomach and the upper part of the small intestine
      of healthy volunteers and patients with nausea and vomiting was recorded non
      invasively on an original electrogastrograph. Two kinds of waves were
      distinguished according to their amplitude: low-amplitude waves, corresponding to
      the period of quiescence of migrating myoelectrical complex (MMC) and about twice
      higher in amplitude waves, characterising the periods of activity of MMC
      (peristaltic activity). There was also some difference between the low- and high
      amplitude waves from the small intestine. Sequence of high-amplitude waves
      recorded from the stomach was followed usually by sequence of high-amplitude
      waves from the small intestine, presenting the aboral spreading of an activity
      period of MMC from the stomach to the small intestine. In some patients however,
      high-amplitude waves were led off first from the duodenal record and after that
      high-amplitude waves appeared in the gastric record. This suggests an oral
      spreading of the peristaltic activity (antiperistalsis). Experimental model of
      antiperistalsis was performed on dogs with chronically implanted electrodes on
      the gastric and duodenal muscle wall. Carbachol 5 micrograms/kg i.m. evoked
      bursts of spike potentials first with duodenal slow waves and after that with the
      gastric slow potentials. The antiperistaltic spreading of the spike activity in
      dog corresponded to the appearance of high-amplitude waves first in the record of
      the human small intestine, followed by sequence of high-amplitude waves in the
      stomach. Thus, the non-invasive recording of the electrical activity of the
      stomach and small intestines gives reliable information about the direction of
      the spreading of the peristaltic activity.

PMID- 10347616
TI  - Behavioral changes as a result of dotarizine or flunarizine influence on
      dopaminergic neurotransmission in the striatum.
AB  - In experiments on rats, we studied the changes in stereotypy induced by
      apomorphine (2.5 mg/kg i.p.) or amphetamine (2 mg/kg i.p.) and in haloperidol (1
      mg/kg i.p.) catalepsy in rats treated with dotarizine (25 mg/kg orally),
      flunarizine (25 mg/kg) or vehicle for 10 days. Dotarizine did not induce any
      significant changes in the intensity and duration of apomorphine- or amphetamine
      induced stereotypy nor in haloperidol-induced catalepsy. The flunarizine-induced
      changes in the behavioral effects of apomorphine, amphetamine and haloperidol
      suggest the decrease of striatal dopaminergic neurotransmission, whereby the risk
      of occurrence of extrapyramidal side effects of the drug when used in clinical
      practice. Dotarizine is not associated with such a risk.

PMID- 10347617
TI  - Influence of aluminium on erythropoiesis, iron metabolism and some functional
      characteristics of erythrocytes in rats.
AB  - The increased aluminium (Al) levels in serum of patients with chronic renal
      failure on hemodialysis are associated with impaired erythropoiesis and iron
      metabolism. The long term Al loading of rats (20 to 90 days) has similar effect.
      Data are still lacking about the effects after short-term aluminium treatment.
      The 7 day's treatment with Al2(SO4)3 in a dose 67.5 mg/kg b. w., i. m. m.
      significantly decreased hemoglobin, hematocrit, incorporation of 59Fe in newly
      formed erythrocytes and increased reticulocytes in absolute and relative counts.
      We observed a mild degree hypochromic, ferropenic, microcytic anemia and
      polychromazia in the available macrocytes. The immature erythroblasts were
      predominant forms in the erythroblastogram while the number of mature
      erythroblasts was decreased. Index of maturation of erythroblasts was lower,
      indicating inhibited erythroblast maturation. Plasma iron, TIBC, transferrin
      saturation and 59Fe absorption in the experimental group were significantly
      decreased. Spontaneous and mechanical hemolysis of erythrocytes were lower while
      erythrocyte deformability was increased. Obviously, Al treatment inhibits
      erythropoiesis and iron metabolism, probably hinders hemoglobin synthesis and
      erythroid cell maturation but does not affect the studied functional
      characteristics of mature erythrocytes negatively.

PMID- 10347618
TI  - Effects of nordihydroguaiaretic acid and indomethacin on the viability and
      functional activities of normal and carbon tetrachioride-injured rat hepatocytes
      cultured alone and with Kupffer cells.
AB  - In order to study the contribution of eicosanoids to the regulation of the
      functions of normal and carbon tetrachloride (CCl4)-injured liver cells, primary
      cultures of hepatocytes (HC) either alone or in coculture with Kupffer cells (KC)
      were exposed for 4 and 24 h to lipoxygenase inhibitor (nordihydroguaiaretic acid
      NDGA) or cyclooxygenase inhibitor (indomethacin-IND) in the presence and in the
      absence of CCl4. Treatment with CCl4 resulted in increased ALT release and a
      decreased mitochondrial respiration (MR) in HC and their cocultures with KC. The
      addition of NDGA decreased ALT levels and increased MR in control and CCL4
      injured cells. Urea production (UP) was not significantly affected by NDGA. In
      contrast, addition of IND) decreased UP by HC (4 h), and did not alter ALT
      release and MR in control and CCl4-treated cells. These results indicate that
      arachidonic acid metabolites are involved in the regulation of HC flinctions.
      There is also evidence that a protective action of lipoxygenase inhibitors on
      CCl4-injured liver is mediated, at least partly, by their direct effects on HC
      and KC, in particular by increasing the mitochondrial respiration.

PMID- 10347620
TI  - Altered response characteristics of cat visual neurons after systemic
      administration of the dihydropyridine calcium antagonist nimodipine.
AB  - Nimodipine, a cerebrovasotropic dihydropyridine calcium antagonist, has gained
      increasing interest in geriatric research during last years and is discussed with
      regard to its possible involvement in restoration and preservation of brain
      plasticity. Single unit responses were recorded by microelectrodes in the visual
      cortex of anaesthetized adult cats. Receptive fields were stimulated with light
      bars moved forward and backward or flashed On/Off. Neuronal activity was recorded
      before and 5 and 30 min after i.v. administration of 0.1 mg/kg nimodipine. On the
      basis of penstimulus-time-histograms (PSTH) the response was analysed. There was
      a marked variability of the response after stimulation with both stationary and
      moving bars. Median firing rate was reduced 5 min after injection following On
      stimulation but generally rose 30 min both after stimulation with light bars
      flashed On or Off Following stimulation with moving light bars about 60% of
      neurons showed decreased firing rates and 40% of neurons increased firing rates
      after injection of the calcium antagonist. The latency following On/Off
      stimulation was rather constant, whereas the median latency following stimulation
      with moving light bars increased by about 15O ms after administration of
      nimodipine. In conclusion, nimodipine alters neuronal response characteristics in
      the visual cortex of the cat.

PMID- 10347619
TI  - Effects of bombesin on the canine gallbladder motility: in vivo and in vitro
      experiments.
AB  - The effects of bombesin (BM) on the canine gallbladder motility was studied under
      two different experimental conditions: (i) in conscious dogs with a balloon
      chronically implanted into the gallbladder lumen where intragallbladder pressure
      was recorded in mm Hg by means of a pressure transducer, and (ii) in smooth
      muscle preparations isolated from different regions of the gallbladder where the
      contractions were recorded isometrically by means of mechanoelectrical
      transducers. Similar to CCK8 bolus injection of. BM i.v. increased the
      gallbladder pressure in a dose-dependent manner. The response was characterized
      by a slow increase of the tone and a gradual restoration (in 4 to 8 min) of the
      background activity. The threshold dose and the maximum dose were 30 ng/kg and
      100 ng/kg for BM and 1 ng/kg and 10 ng/kg for CCK8, respectively. Both atropin
      (10 to 50 micrograms/kg) and hexamethonium (0.5 to 3 mg/kg) injected i.v. 5 to 10
      min before BM strongly reduced or even abolished the gallbladder response to BM.
      Somatostatin (1 to 2 micrograms/kg) and VIP (0.5 to 1 microgram/kg) injected 3 to
      5 min before BM also exerted a strong inhibitory effect on the canine gallbladder
      response to BM. However BM (up to 10(-6) M) had no effect on the spontaneous or
      electrically-induced contractions of the canine gallbladder smooth muscle
      preparations. The results suggest the involvement of prejunctional cholinergic-,
      somatostatinergic- and VIP-ergic pathways in the bombesin-induced increase of the
      gallbladder pressure of conscious dogs.

PMID- 10347621
TI  - alpha-Tocopherol and reduced glutathione deficiency and decreased deformability
      of erythrocytes after thermal skin injury.
AB  - Burns are followed by oxidative changes in red blood cells, probably as a result
      of ischemia/reperfusion which takes place in the microvasculature of the injured
      tissues. This leads to a marked decrease in the erythrocyte deformability, one of
      the most prominent factors for haemorheological disorders in the early post-burn
      period. We found that at the 24 th hour after burn skin injury of rats, the
      decrease in erythrocyte deformability was accompanied by an increase of
      fluorescent product levels in red blood cells. The erythrocyte systems for
      antioxidative protection fail to control the oxidative burst after burning. This
      was due to the decreased concentration of vitamin E (a-tocopherol) and reduced
      glutathione (GSH) and the increased oxidized glutathione (GSSG) in red blood
      cells. Both alpha-tocopherol and GSH-deficiency potentiate the susceptibility of
      red blood cells to oxidative membrane injury, and decrease the deformability of
      thermally affected erythrocytes. Treatment with alpha-tocopherol (20 ml/kg b.m.,
      immediately after thermal skin injury) prevented the vitamin E reduction and
      peroxidative membrane damage of erythrocytes and improved their deformability.
      These results provided strong evidence that the decreased erythrocyte
      deformability is partly related with alpha-tocopherol deficiency and oxidative
      membrane damage of red blood cells in the early post burn period.

PMID- 10347623
TI  - [Interferon beta-1b now also for the secondary progressive form of multiple
      sclerosis?].
AB  - Recently, a placebo-controlled multicentre randomised clinical trial was
      published on the efficacy of interferon beta-Ib in the treatment of secondary
      progressive multiple sclerosis. The study was stopped after the interim analysis
      because evidence of efficacy was already clear. However, the results appear to be
      considerably less convincing. The decision to prematurely stop the clinical trial
      was based more on an overestimate of the p-values than on the clinical relevance
      of the treatment effects. The efficacy of interferon should be investigated in
      relation to other treatment options, such as immunoglobulin, copolymer I,
      azathioprine and methotrexate.

PMID- 10347622
TI  - [Obstetric problems followed by stroke].
AB  - Obstetrical problems sometimes portend manifestations of atherosclerosis, as
      illustrated by two case reports. The first patient had the combination of
      hyperhomocysteinaemia due to chronic vitamin deficiencies in the diet, and
      smoking. The second was also a smoker and had a genetically determined mild
      hyperhomocysteinaemia, aggravated by chronic vitamin deficiencies resulting from
      poor dietary habits; she also had an increased folic acid requirement because of
      use of anti-epileptic drugs in combination with a familial predisposition for
      premature atherosclerotic manifestations. The first patient had four pregnancies,
      two of which ended in intrauterine foetal death due to placental infarction, and
      one in the birth of a dysmature boy. The second patient's four pregnancies ended
      twice in abortion and twice in the birth of a dysmature child; in one of the
      latter cases placental infarction was observed. Both women subsequently suffered
      cerebrovascular accidents while in addition, older cerebral infarctions were
      found to be present. Women with recurrent abortion, pre-eclampsia, placental
      infarction, placental detachment and foetal growth retardation should be
      examined, even if other risk factors are also present, for (mild)
      hyperhomocysteinaemia, and treated for it with vitamin suppletion (folic acid,
      vitamins B6 and B12), even although admittedly more research is necessary to make
      certain that such treatment has a preventive effect on the manifestations of this
      disorder.

PMID- 10347624
TI  - [The need for 'postmarketing surveillance'].
AB  - Postmarketing surveillance of medicines includes two activities:
      pharmacovigilance and pharmaco-epidemiology. Despite the importance of
      postmarketing surveillance, too few surveillance studies are performed. The
      studies carried out by the pharmaceutical industry predominantly consist of
      'seeding trials': offering prescribing physicians financial rewards if they
      prescribe a particular product, thus trying to change the prescription habits.
      The results of such trials are scientifically worthless. These activities cast a
      shadow on sincere postmarketing surveillance. A recent nationwide cohort study by
      the Inspectorate for Health Care on mortality in users of ibopamine demonstrates
      that Dutch medical doctors and pharmacists are very co-operative if further
      studying of a particular adverse reaction is warranted.

PMID- 10347625
TI  - [The practice of systematic reviews. III. Evaluation of methodological quality of
      research studies].
AB  - The methodological quality of the primary studies included in a systematic review
      may influence its results and final conclusions. Methodological quality may be
      defined in various ways. Partially because of this there are many different
      assessment lists. The most important dimension of quality is internal validity,
      defined as the confidence that the design, performance and report of a trial
      prevent or reduce systematic errors (bias) in the outcomes. For only a limited
      number of internal validity items a relationship with bias has been proven in
      empirical studies: concealment of randomisation and blinding of patients and
      outcome assessors. Preferably, quality should be assessed by at least 2 assessors
      independently. There is no consensus whether assessment should be done blinded
      for authors, journal, results and conclusions. Internal validity can be
      incorporated into statistical pooling in various ways: as a selection criterion,
      to be used as weight or to hierarchically order studies in a presentation. Well
      designed comparative studies are needed to provide clearer guidelines for
      methodological assessment in the future.

PMID- 10347626
TI  - [Paget's disease of the bones: diagnosis and treatment].
AB  - Paget's disease of bone affects one or more bones and is characterized by
      increased bone turnover (remodelling) with hypertrophy and abnormal bone
      structure with diminished strength leading to deformity and fracture. The cause
      of the disease is not known, possibly is a slow virus infection. For diagnosis
      and follow-up the conventional bone markers, serum alkaline phosphatase and urine
      hydroxyproline, are still useful. Paget's disease cannot be cured, but it may be
      suppressed. Specific drug treatment aims at reducing the increased bone
      remodelling. New and potent biphosphonates enable early and more effective
      treatment of Paget's disease than in the past and better prevention of late
      complications of the disease.

PMID- 10347627
TI  - [Ventilator-associated pneumonia; controversies with respect to diagnosis,
      pathogenesis, therapy and prevention].
AB  - Ventilator-associated pneumonia (VAP) is the most frequent nosocomial infection
      among intensive care patients; it is associated with increased morbidity and
      mortality. VAP is always preceded by colonization of the upper respiratory tract
      with potentially pathogenic micro-organisms. Oropharyngeal colonization is
      pivotal in the pathogenesis of VAP, while gastric and intestinal colonization
      appear to be less important than generally believed. The diagnosis is difficult
      and usually relies on a combination of clinical, microbiological and radiographic
      criteria. This combination of criteria may have a high sensitivity for VAP, but
      specificity is low. As a result, many patients receive antibiotics unnecessarily.
      Bronchoscopic sampling of lower airways can increase specificity, but whether
      these relatively expensive techniques are cost-effective remains to be
      established. The best antibiotic therapy for VAP is unknown. General infection
      control measures remain the cornerstone of infection prevention in each intensive
      care unit (ICU). Selective digestive decontamination (SDD) was associated with a
      reduction in the incidence of VAP, but mortality rates remained largely
      unaffected, and selection of antibiotic-resistant pathogens remains a potential
      disadvantage. Routine SDD in ICU is discouraged. Decontamination of the
      oropharynx appears to be equally effective.

PMID- 10347628
TI  - [High-dose chemotherapy with stem cell support for solid tumors in adults].
AB  - High-dose chemotherapy for advanced solid malignancies has been the subject of
      many clinical studies. The replacement of autologous bone marrow transplantation
      by peripheral blood haematopoietic progenitor cell transplantation and other
      advances in supportive care have led to a considerable reduction of therapy
      related mortality and morbidity. In certain rare disorders, such as germ cell
      tumours or pediatric sarcomas in adults, high-dose therapy is currently
      considered the therapeutic standard. It is likely that a subgroup of patients
      with high-risk or disseminated breast cancer can also benefit in terms of
      survival from this treatment modality, but final proof from randomized studies
      remains to be generated. On theoretical grounds, high-dose chemotherapy could
      also be effective in small cell lung cancer and ovarian cancer, and randomized
      studies to answer this question are in progress. Many investigators concur that
      high-dose chemotherapy often leads to dramatic cytoreduction in solid tumours,
      but only rarely achieves cure. Novel therapeutic modalities are required to
      control the residual microscopic disease.

PMID- 10347629
TI  - [Peroperative parathyroid hormone assay: assurance of successful surgical
      treatment of primary hyperparathyroidism].
AB  - OBJECTIVE: To study the reliability and applicability of a rapid parathormone
      (PTH) test as predictor of successful surgical treatment of primary
      hyperparathyroidism. DESIGN: Prospective. METHOD: All 35 consecutive patients
      undergoing surgery for primary hyperparathyroidism in the University Hospital
      Utrecht, the Netherlands, in august 1997-august 1998, were tested just prior to
      surgery, and immediately following adenomectomy. The rapid PTH test consisted of
      a modification of the computerized immunometric detection by chemoluminescence.
      The decrease of serum PTH as estimated with the rapid test was correlated with
      surgical findings as well as postoperative serum calcium levels. In the first 25
      patients (group A) the reliability of the test was investigated. In the next 10
      patients (group B) the PTH test results were allowed to have implications for
      surgical management, i.e. an insufficient (< 50%) decrease of serum PTH following
      adenomectomy resulted in immediate re-exploration. RESULTS: The 35 patients, 22
      women and 13 men, had a median age of 58 years (range: 22-80). The results
      obtained with our rapid PTH test correlated fully with both conventional PTH
      measurement techniques and postoperative serum calcium levels. In group A 21/25
      patients showed adequate (> 50%) decrease of their serum PTH levels; the 4
      patients without such decrease were the ones displaying persistent postoperative
      hypercalcaemia. In group B 9/10 patients had adequate PTH decrease immediately
      following adenomectomy, while in one patient this was only attained after further
      exploration and excision of a second adenoma. No false-positive or false-negative
      measurements were encountered. CONCLUSION: The rapid PTH test used is a reliable
      predictor of successful adenomectomy for primary hyperparathyroidism, also in
      minimally invasive surgery.

PMID- 10347630
TI  - [Chlamydia pneumonia and atherosclerosis].

PMID- 10347631
TI  - [Chlamydia pneumonia and atherosclerosis].

PMID- 10347632
TI  - [Chlamydia pneumonia and atherosclerosis].

PMID- 10347633
TI  - [The report 'Late termination of pregnancy: caution and assessment' by the
      consultant group Late Termination of Pregnancy].

PMID- 10347634
TI  - [The place of long-acting beta 2 adrenergic agonists in the treatment of asthma
      and chronic obstructive pulmonary disease].

PMID- 10347635
TI  - [Towards an accreditation system for the Dutch hospitals].

PMID- 10347636
TI  - [Immunology in medical practice. XVIII [correction of XVII]. Children with
      recurrent airway problems: asthma is not always the cause.
AB  - Three children, two boys aged 16 and 11 years and a girl aged 16 years, with
      symptoms resembling asthma had been treated for years with inhaled
      corticosteroids and beta 2-sympathicomimetics without satisfactory results. It
      was found that the antibody production after vaccination with 23-valent
      pneumococcal vaccine was impaired. The symptoms diminished during maintenance
      treatment with antibiotics in two children and with intravenous immunoglobulins
      in one. In patients with recurrent respiratory problems, but no specific history
      of asthma, immunological investigation is warranted, especially in patients whose
      'asthma' is accompanied by respiratory infections. When treated for their
      immunodeficiency these patients show remarkable improvement and the need for
      steroids often disappears.

PMID- 10347637
TI  - [Primary prevention remains expensive, notwithstanding the consensus on lowering
      serum cholesterol levels].
AB  - Recently guidelines for cholesterol lowering therapy by means of 'statines' (HMG
      CoA reductase inhibitors) were published by the National Organization of Quality
      Assurance in Hospitals. The part about primary prevention of cardiovascular
      disease is based on absolute risks for coronary heart disease as calculated by
      the Framingham Heart Study risk functions and on a cost-effectiveness analysis.
      However, the function predicts risk of disease such as silent infarction and
      angina pectoris. The incidence thus produced is higher than any observed clinical
      incidence. Absolute risk increases exponentially with age, but remaining life
      expectancy, and thus benefit, decreases. Therefore, decisions about treatment
      levels are based on arbitrary assumptions. The function is ultimately only used
      to advise treatment to the smoker, while the better choice is always to stop
      smoking. The effectiveness is overestimated by using a long time horizon of
      treatment of 25 years in the cost-effectiveness analysis. Primary prevention of
      coronary heart disease according to the new guidelines is still very expensive.

PMID- 10347638
TI  - [Practice guidelines to physicians and their economic aspects; merits and
      drawbacks].
AB  - In drawing up policy recommendations to physicians, two crucial problems arise:
      to what extent can research findings be extrapolated to everyday practice? And:
      may or must economic arguments be considered in drawing up the policy
      recommendation? In the revised consensus 'Cholesterol', the proposals on
      secondary prevention are based on justifiable extrapolation of available data,
      but this is not true of those on primary prevention. Use of economic arguments in
      a policy recommendation to physicians is not acceptable, because it gives rise to
      a situation in which the treating physician constantly has to weigh economic
      interests against the patient's interests, so that the patient may begin to doubt
      if the physician is constantly any exclusively acting as the representative of
      his or her interests.

PMID- 10347639
TI  - [Treatment with inhalation corticosteroids: useful or useless in chronic
      obstructive pulmonary disease (COPD)?].
AB  - The effects of inhaled corticosteroids on lung function in chronic obstructive
      pulmonary disease (COPD) are small, particularly when compared with the effects
      in asthma. While there appears to be a positive effect on lung function, this is
      limited to the first few months of use. The clinical relevance of this is a minor
      delay in reaching a low (disabling) lung function level. Of more importance is
      probably the effect on the quality of life, the functional status (e.g. the 6
      minute walking distance) and the number of exacerbations. In more severe COPD
      patients a clear gain in quality of life and decrease in exacerbations has been
      shown. So far, we must conclude that the use of inhaled corticosteroids in COPD
      may be useful. As soon as it is clear what other parameters than lung function
      make an adequate evaluation of a drug therapy possible, this interim conclusion
      can be given a firmer basis.

PMID- 10347640
TI  - [Retinal detachments and retinal surgery].
AB  - The incidence of retinal detachment is approximately 1:10,000. Most retinal
      detachments occur between the ages of 50 and 65 years. A rhegmatogenous retinal
      detachment starts with a tear in the peripheral retina. Through this retinal tear
      liquefied vitreous may enter the subretinal space, resulting in a retinal
      detachment with progressive visual loss. In 50% prodromal light flashes are
      observed. Laser coagulation around a tear without subretinal fluid can make
      surgical intervention unnecessary in approximately 96% of cases. When subretinal
      fluid is present, conventional scleral buckling surgery is successful in 80-90%
      of the cases. In more complex retinal detachments or in re-detachment cases, a
      trans pars plana vitrectomy is indicated. Anatomical success can be achieved in
      approximately 96% of cases, sometimes after several operations. Functional
      success depends on preoperative pathology and duration of the detachment. Eyes
      with retinal detachment of the macula and with larger and complex defects have
      poorer visual prognosis.

PMID- 10347641
TI  - [The practice of systematic reviews. IV. Pooling results from separate studies].
AB  - Meta-analysis comprises the analysis of the data gathered in a systematic review.
      Meta-analysis can be defined as the combination of pooling results of similar
      studies into one overall estimate of the effect on the one hand and the
      exploration of sources of heterogeneity between studies on the other. A general
      statistical model is available for pooling the estimates of various types of
      effect parameters. Pooling enables the estimation of the effect of an
      intervention or exposure as precisely as possible (with narrow confidence
      intervals) which allows detection of minor effects. The Mantel-Haenszel method is
      also an excellent method for pooling effect parameters of dichotomous outcomes.
      Pooling provides an efficient means of summarizing the available knowledge.

PMID- 10347642
TI  - [Clinical thinking and decision-making in practice. A patient with episodes of
      flushing].
AB  - A 74-year-old woman had an 8-year history of spells consisting of facial flushing
      and swelling, itching and erythema of the hands, rhinorrhoea and gastrointestinal
      complaints. The ultimate diagnosis was systemic mastocytosis without urticaria
      pigmentosa. In the clinical decision process the treating physicians used
      clinical axioms to try to establish a diagnosis, but these axioms were sometimes
      used inappropriately. In particular, spells accompanied by flushing
      inappropriately elicited a possible diagnosis of phenochromocytoma. Generalised
      mastocytosis can occur in the absence of urticaria pigmentosa and is probably an
      underestimated cause of spell-like complaints.

PMID- 10347643
TI  - [Patients with fatigue in family practice: prevalence and treatment].
AB  - OBJECTIVE: To gain insight into the prevalence and treatment of severe fatigue in
      general practice. DESIGN: Secondary data analysis. METHOD: By means of an episode
      oriented morbidity registration by 54 GPs throughout the Netherlands over the
      period 1985-1994 it was established how often in the course of one year 'fatigue'
      was listed as the reason for consultation, what diagnoses were then made, how
      long episodes of care because of 'fatigue' lasted and what interventions took
      place (n = 93,297). Of the patients with a care episode because of 'fatigue'
      lasting at least 6 months, age, sex, comorbidity and consumption of care were
      established; for this purpose use was also made of a file containing data on 4
      years in succession (n = 9630). RESULTS: Per annum, 92 per 1000 listed patients
      consulted the GP because of fatigue. Somatic or psychic diagnoses were made in
      27.7 per 1000 patients listed. The episode of care lasted 4 weeks at most in 86%
      and at least 6 months in approximately 4%. The GPs' management of patients with
      'fatigue' included physical examination in 63% and blood testing in 34%,
      conversation in 35%, prescription of medication in 24% and referral to a
      specialist in 3%. Of the 97 patients with fatigue lasting longer than 6 months,
      61% had a chronic disease or psychic problems. CONCLUSION: Fatigue is frequently
      encountered in general practice, but the estimate that one per 1000 listed
      patients meets the criteria of the chronic fatigue syndrome looks a little high.
      It appears that GPs, in accordance with recommendations, mostly adopt a policy of
      wait and see.

PMID- 10347644
TI  - [Nosocomial transmission of hepatitis C virus in a Dutch dialysis center].
AB  - OBJECTIVE: To describe the transmission of hepatitis C virus (HCV) in a dialysis
      centre in the Netherlands, to analyse risk factors and to redefine additional
      preventive measures. DESIGN: Descriptive. METHODS: The data of patients attending
      the dialysis centre of the Deventer Hospital, the Netherlands, who had
      participated in a national prospective survey on the epidemiology of HCV among
      Dutch dialysis patients, were examined. In addition, patients who developed signs
      of hepatic failure in the ensuing year were included in this study. To diagnose
      an HCV-infection serology as well as polymerase chain reaction were used.
      Genotyping and sequence analysis were used to assess phylogenetic relations.
      Infection control practices were audited. RESULTS: In the dialysis centre a
      cluster of four almost identical HCV isolates genotype 2a was found. Within a
      period of one year another cluster of four HCV-infected dialysis patients was
      detected in the same centre. These four isolates were almost identical to a fifth
      isolate, genotype 2b, found in the earlier study from another patient dialysing
      in the same unit. It was observed that possibly contaminating procedures were not
      strictly separated. Some of the shared medical equipment was not sterilised but
      only cleaned. Also blood-contaminated gloves might have played a role in the
      transmission of HCV. CONCLUSION: Nosocomial transmission plays an important role
      in the epidemiology of HCV in dialysis patients. Shared medical equipment and
      blood-contaminated gloves may constitute a potential route of transmission. There
      is a need for stringent implementation and regular auditing of infection control
      measures.

PMID- 10347645
TI  - [Interferon beta-1b now also for the relapsing progressive form of multiple
      sclerosis?].

PMID- 10347646
TI  - [Drug therapy in Parkinson's disease].

PMID- 10347648
TI  - [Physical diagnostics--auscultation of fetal heart sounds].

PMID- 10347649
TI  - [Epidemic caused by a multiresistant Acinetobacter baumanii infection; MRSA
      incognito].

PMID- 10347650
TI  - [Pulmonary damage after radiotherapy for breast cancer].
AB  - Radiation therapy for breast cancer can cause pulmonary damage. This was
      diagnosed in two patients aged 75 and 57 years respectively. They had different
      types of radiation pneumonitis. The first patient presented with a so-called
      bronchiolitis obliterans organizing pneumonia (BOOP), four months after radiation
      therapy. Characteristic in BOOP are the bilateral and migrating lung infiltrates
      that are distributed predominantly in the middle and lower lung zones. The second
      patient developed a pneumonitis that classically was confined to the area of
      irradiation four months after radiation therapy. The two types of radiation
      pneumonitis can be treated successfully with corticosteroids. If symptomatic
      radiation pneumonitis is diagnosed early it can be treated well and than has a
      good prognosis.

PMID- 10347651
TI  - [A return of endemic malaria to the Netherlands is highly unlikely].
AB  - The Netherlands has been free from malaria since the early 1960, due to a
      combination of factors: active search and treatment of patients and parasite
      carriers, targeted use of insecticides, changes in farming and in housing of man
      and cattle, pollution of surface water with phosphates and the fact that surface
      waters became fresher. These factors reduced the mosquito population that is
      dependent on brackish water. The Dutch malaria mosquito cannot transmit the
      parasite of tropical malaria. The mosquito population could possibly increase due
      to measures to 'develop nature' but the number of parasite carriers, the acute
      disease manifestations, the quality and organization of the health care system
      make it extremely unlikely that local transmission will occur. Fears that malaria
      may become endemic and that the population in the western parts of the country
      will have to apply malaria chemoprophylaxis in the near future, are unfounded.

PMID- 10347652
TI  - [Interaction between breast cancer, psychosocial stress and the immune response].
AB  - Awareness of the interactive relation between psychosocial stressors,
      neuroendocrine and immunological processes, and tumour progression in patients
      with breast cancer appears to be important for clinicians. However, it is not
      established yet how the available knowledge can be applied therapeutically.
      Hormonal factors play a part in the carcinogenesis of breast cancer. Growth of
      the breast tumour is influenced by endocrine hormones. Antioestrogen therapy is
      effective in the treatment of breast cancer. Several components of the immune
      system are related to the course of disease in breast cancer patients.
      Psychosocial stressors influence neuroendocrine (corticotrophin-releasing hormone
      (CRH), cortisol, oestrogen) and immunological functions. Psychosocial stressors
      may be linked to recurrence or survival. Certain coping mechanisms (even those of
      a negative nature) and the social network of the patient may have prognostic
      values. Since recurrence of the disease is still possible many years after
      curative surgery, multifactorial effects on the course of disease are likely.

PMID- 10347653
TI  - [The practice of systematic reviews. V. Heterogeneity between studies and
      subgroup analysis].
AB  - Meta-analysis comprises the analysis of the data of similar studies gathered in a
      systematic review. If the results of the studies differ (strongly), this is
      called heterogeneity. Possible causes of heterogeneity are: a wrong choice of
      type of measure of treatment effect, differences of methodological quality
      between studies, or real differences between studies. Heterogeneity between
      studies can be assessed by thorough examination of the differences between study
      characteristics in combination with a visual inspection of the degree of overlap
      of the confidence intervals of the estimates of effect of the different studies.
      By applying the random effects model for pooling, (non-systematic) heterogeneity
      between studies can be addressed. In case of heterogeneity between studies,
      sources of heterogeneity should be explored by means of subgroup analysis
      according to strict, present criteria. Subgroup analysis should address subgroups
      of patients within studies.

PMID- 10347654
TI  - [Physical diagnostics--tendon reflexes].
AB  - Clinical examination of the tendon reflexes is helpful in localising lesions in
      the nervous system, which is an important step in the diagnosis of neurological
      disorders. The large intra- and interindividual variations of reflex amplitudes
      make interpretation difficult. Published interobserver agreement studies provide
      conflicting results. The diagnostic specificity of unequivocally abnormal
      reflexes is moderate to good (70-95%, decreasing with increasing age), but the
      sensitivity is lower (50-70%), both for peripheral and for central lesions. This
      implies that the finding of a clearly abnormal reflex pattern is often helpful,
      but the finding of normal reflexes usually does not exclude a neurological
      lesion.

PMID- 10347655
TI  - [General knowledge of the performance of Mantoux-test procedure deemed
      inadequate].
AB  - OBJECTIVE: To investigate whether health care professionals have sufficient
      knowledge of the Mantoux test procedure. DESIGN: Descriptive. METHODS: The
      hospital pharmacy records of the Medisch Spectrum Twente, a large teaching
      hospital in Enschede (1034 beds), the Netherlands, were reviewed to determine
      which departments had performed Mantoux tests in 1996. The municipal health
      service and the industrial/occupational medicine department of the hospital were
      included in the investigation. Knowledge of the Mantoux test procedure was
      assessed in 44 randomly chosen health care professionals by means of a multiple
      choice questionnaire. They were also asked how often they had performed Mantoux
      tests in 1996 and whether they thought themselves able to perform the total
      Mantoux test procedure correctly. RESULTS: The frequency of setting and/or
      reading the Mantoux test was generally low and varied per department. Ninety
      three percent of the 44 subjects under investigation presumed themselves able to
      perform the Mantoux test correctly. From the questionnaire forty percent knew how
      to set a Mantoux test, while 15 of the 33 persons (45%) who had read a Mantoux
      reaction knew how to do this correctly. Nine of these 33 (27%) had sufficient
      knowledge to execute the whole Mantoux test procedure correctly. The knowledge of
      the correct Mantoux test procedure was significantly better among those who
      performed the Mantoux test more often. CONCLUSION: The theoretical knowledge
      regarding the Mantoux test is insufficient, especially among those health care
      professionals who rarely perform the test. It appears advisable to have the
      Mantoux tests performed by a few well-trained professionals.

PMID- 10347656
TI  - [Specificity of the Mantoux-reaction to the new tuberculin RT23 in relation to
      that of previously used PPD-RIVM; a comparative study in hospital staff].
AB  - OBJECTIVE: In the Netherlands, an increase in prevalence of tuberculin positivity
      has been noted since the replacement of the Dutch PPD-RIVM preparation by RT23.
      This investigation was carried out to assess the specificity of RT23 compared
      with PPD-RIVM. DESIGN: Comparative. METHOD: In 90 hospital workers simultaneous
      tuberculin tests were performed in both forearms with RT23 (Statens Serum
      Institut, Copenhagen, Denmark; lot number 13751; 2 tuberculin units) and PPD-RIVM
      (Rijksinstituut voor Volksgezondheid en Milieu, Bilthoven, the Netherlands; lot
      number 76B; 1 IU), respectively. Sensitivity to atypical mycobacteria
      (Mycobacterium scrophulaceum, M. avium and M. kansasii) was assessed where
      differences were > 3 mm. RESULTS: In two of 73 non-vaccinated subjects, reactions
      to RT23 were 11 and 15 mm larger than to PPD-RIVM; both showed sensitivity to M.
      scrophulaceum and M. avium. Five of nine BCG vaccinated subjects showed
      differences of five to eight mm; in four of these, the reaction to RT23 was
      larger. Repeat testing in one showed no cross-reactions. The specificity of RT23
      compared with PPD-RIVM was 96% (cut-off at 10 mm diameter). CONCLUSIONS: In a low
      tuberculosis risk population, tuberculin testing with RT23 yields more positive
      results than PPD-RIVM. This is probably due to stronger cross-reactivity with
      atypical mycobacteria of RT23. Decisions on isoniazide prophylaxis should take
      into account an increased false-positivity rate with RT23.

PMID- 10347657
TI  - [Microsurgery, a 'small' surgical revolution in the medical history of the 20th
      century].
AB  - Microsurgery in the twentieth century enabled surgeons to operate on very fine
      structures, which was impossible before the advent of the microscope. Since 1860
      loupe magnification was employed in rare cases. In 1921 Nylen from Sweden
      transformed an ordinary laboratory microscope into an operation microscope for
      ear interventions. The eye specialists were the second group of doctors who
      employed the microscope in the operating theatre during the years 40-50 of this
      century. Since 1953 Zeiss in Germany has produced highly professional operation
      microscopes. In the sixties experimental laboratory studies were taken up to
      develop microsurgical techniques, microinstruments and suture material. Both
      plastic and reconstructive surgeons and neurosurgeons continued to develop
      microsurgery and indeed transformed their disciplines a great deal. Microsurgery
      is here to stay and still experiments are going on with video-assisted systems in
      order to further miniaturize the instruments for magnification and to gain a more
      comfortable working position for the surgeon.

PMID- 10347658
TI  - [Defibrillation with an automatic external defibrillator outside the hospital: a
      life-saving, but restricted treatment?].

PMID- 10347659
TI  - [Distressed or relieved? Psychological sequelae of breast cancer screening in
      Netherlands].

PMID- 10347660
TI  - [Practice guidelines for physicians and related economic considerations].

PMID- 10347661
TI  - [Physician-assisted suicide of a patient suffering from a psycho-organic
      disorder].
AB  - A 71-year-old man suffering from vascular dementia since four years asked for
      physician-assisted suicide. In the Netherlands physician-assisted suicide, which
      is forbidden by law, remains an intricate dilemma in medical practice. As far as
      it concerns untreatable terminal patients who decide to put an end to their lives
      in agreement with and assisted by their physician, procedures are well defined.
      The present case may be used as an example in the development of a protocol for
      physician-assisted suicide in patients who are not terminal in the short term,
      but who suffer unbearably with no prospect of remission. After the protocol
      securing various formal and medical consequences was run through, the patient was
      assisted by handling him a high-dose solution of a barbiturate which he drank
      himself. The procedure incorporates several second and third opinions. First, the
      chief psychiatrist of the psychiatric hospital assesses the request. Second, a
      committee consisting of a number of independent professionals form a second
      opinion. They have no direct responsibility in the treatment of the patient. The
      patient also may consult an independent consultant psychiatrist with specific
      knowledge in the domain of his disorder for a third opinion. This procedure was
      found legally as well as medically sound, and was approved by the public
      prosecutor after consultation with the Dutch forum of Procurators-General.

PMID- 10347662
TI  - [Comments on a case of physician-assisted suicide of a patient with an organic
      psychiatric disorder].
AB  - Well-documented case histories concerning the role of physicians in assisted
      suicide are rarely published in medical journals even in the Netherlands; this
      applies in particular if the patient's suffering is mainly due to a psychiatric
      disorder. In this issue physician-assisted suicide is described in a patient
      suffering from a psycho-organic disorder. The case illustrates the problems the
      attending physician encountered in his decision-making process against the
      background of the actual professional views and the legal regulations in the
      Netherlands. When the doctor's considerations as well as his actions are
      discussed with reference to the official criteria and regulations, the conclusion
      is that notwithstanding some minor procedural inconsistencies, he acted in
      accordance with the accepted medical, ethical, and legal standards in this
      country.

PMID- 10347663
TI  - [More consideration to dietary protein in the nutrition of chronically ill adults
      with tendency to weight loss].
AB  - Weight loss is an independent risk factor for mortality in chronically ill weight
      losing patients. Hunger strikers and chronically ill patients die after a weight
      loss of about 40%; weight loss is strongly correlated with loss of lean body
      mass. Lean body mass is determined by protein synthesis and protein breakdown.
      Increased supply of amino acids diminishes loss of lean body mass. It is
      advisable to increase the protein content of the diet of chronically ill weight
      losing patients to the level that maximally stimulates protein synthesis, i.e.
      1.5 g protein/kg/day.

PMID- 10347664
TI  - [Clinical significance of extra vitamin supplements and enriched food products].
AB  - Consumers increasingly use vitamin supplements. Also, since June 1996, foodstuffs
      enriched with vitamins are available on the Dutch market. These sources of extra
      vitamins may be useful for groups at risk for marginal vitamin deficiencies.
      These risk groups include the chronically ill (e.g. diabetics), people using
      medicaments, older people and pregnant women. Extra vitamins from low-dose
      supplements or enriched foodstuffs may also constitute a valuable and safe
      supplement to the diet of children, smokers, people eating unbalanced, people on
      slimming diets, vegetarians and people engaged in intensive sports. According to
      the advisory group Nutrition of the Health Council, addition of vitamins to
      foodstuffs causes no risks of any importance for public health, apart from
      vitamins A and D and of the trace elements selenium, copper and zinc.
      Consequently, these should only be added to reconstituted foodstuffs or in a
      substitution product, not in enriched foodstuffs.

PMID- 10347665
TI  - [No consensus on the definition, diagnosis and treatment of habitual abortion in
      the Netherlands].
AB  - OBJECTIVE: To review the current policy in diagnosis and treatment of recurrent
      miscarriage in the Netherlands. DESIGN: Cross-sectional survey. METHOD: A printed
      questionnaire was sent in 1996 to all 125 departments of gynaecology in the
      Netherlands with questions about definition, investigation and therapy of
      recurrent miscarriage. RESULTS: The response rate was 90% (n = 112). Twenty-nine
      per cent of the respondents defined recurrent miscarriage as having two or more
      abortions and 71% as three or more abortions. In 42% of the departments a
      diagnostic protocol for recurrent miscarriage was present. Diagnostic
      investigations most frequently performed were vaginal ultrasound (79%), parental
      chromosome analysis (78%), thyroid-stimulating hormone (72%), lupus anticoagulant
      (69%), blood glucose (65%), hysterosalpingography (56%) and anticardiolipin
      antibodies (IgG, IgM) (56%). Therapy most frequently applied was prescription of
      folic acid (53%). CONCLUSION: The definition of recurrent miscarriage differed.
      Uncertainty about a rational diagnostic approach was evident from the large
      number of tests requested by 20-50% of the respondents. Some diagnostic tests
      like immunological investigation and search for infectious factors were not
      followed by a therapeutical intervention.

PMID- 10347666
TI  - [Utilization of middle ear ventilatory tubes for children, ages 0-12 years, in
      the Netherlands during 1990-1994].
AB  - OBJECTIVE: To explore the incidence of treatment with ventilation tubes in the
      Netherlands in children from birth to 12 years of age in the period from 1990 to
      1994. DESIGN: Secondary data analysis. METHODS: Data on bilateral treatment with
      ventilation tubes in 1990-1994 in the Netherlands were obtained from the National
      Medical Register of SIG Health Care Information. Incidence rates of the treatment
      in children aged 0-12 years were calculated using population estimates issued by
      the National Department of Statistics. RESULTS: Whereas from 1990 to 1992 the
      total number of bilateral inserted tubes increased from 39.923 to 51.615, a
      decrease to 48.635 was observed in 1994. The average incidence rate of treatment
      with ventilation tubes was 1.97% (range: 0.12%-5.08%) in children from birth to
      12 years. Peak incidences were found around 2 years and 6 years of age.
      Prevalence rates of otitis media with effusion as found in the literature were
      higher, especially during infancy.

PMID- 10347668
TI  - [A child with puzzling complaints--does he have a disease?].

PMID- 10347667
TI  - [Physician-assisted suicide for a patient with a psychiatric disorder: guidelines
      for psychiatrists. Dutch Association of Psychiatry].
AB  - In September 1998, the Dutch Association of Psychiatry published guidelines for
      the psychiatrist concerning cases of psychiatric patients requesting assistance
      with suicide. Assistance with suicide is restricted to a psychiatrist in his role
      as a treating physician of a patient with a psychiatric disorder. Requests for
      assisted suicide should primarily be considered as requests for help with life.
      Individual psychiatrists have no moral or legal obligation to assist in suicide.
      The guidelines require that the request is voluntary, explicit and well
      considered, the desire for death long-lasting and the suffering unbearable and
      hopeless. In addition an independent psychiatrist should be consulted as well as
      former treating physicians, general practitioner, family members and other people
      involved. If a somatic specialist or a general practitioner is asked to assist in
      suicide consultation of two psychiatrists is required. The guidelines offer
      psychiatrists a framework for taking great care when their patients request
      assisted suicide and will certainly play a part in the legal control of assisted
      suicide.

PMID- 10347669
TI  - [Palliative care of cancer patients with refractory ulcerating malignant skin
      tumors and skin metastases].

PMID- 10347670
TI  - Injury control research and wilderness medicine: a babe dangling in the woods.

PMID- 10347671
TI  - Climbing harness fit in kidney transplant recipients.
AB  - OBJECTIVE: The superficial location of renal transplants places them at risk for
      traumatic damage. Significant injuries have been reported from automobile seat
      belts, for example. This study was designed to assess the potential for direct
      transplant injury from the use of climbing harnesses. METHODS: Ten patients with
      kidney transplants were fitted with a variety of climbing harnesses after the
      locations of their grafts were defined. RESULTS: With the exception of two
      harnesses in a single patient, all devices came into contact with all
      transplants. CONCLUSION: Sports requiring the use of climbing harnesses (eg, rock
      climbing, rappelling, and challenge course participation) may be unsafe for
      recipients of kidney transplants.

PMID- 10347672
TI  - Mojave rattlesnake (Crotalus scutulatus scutulatus) identification.
AB  - Mojave rattlesnake (Crotalus scutulatus scutulatus) identification has important
      diagnostic and therapeutic implications. Envenomation by certain populations of
      Mojave rattlesnakes may cause a different clinical presentation than that caused
      by other rattlesnakes. Specifically, Mojave rattlesnake envenomation may cause
      fewer local effects and more neurologic effects (including respiratory
      difficulty) than are typically seen after bites from other types of rattlesnake.
      Thus, it is useful for clinicians to distinguish the Mojave rattlesnake from
      other rattlesnakes in order to prevent underestimation of severe envenomation
      because of the lack of local tissue injury. Patients suspected to have been
      bitten by Mojave rattlesnakes may need more aggressive treatment with antivenin
      as well as more intensive supportive care. In addition, patients suspected to
      have been bitten by Mojave rattlesnakes should be closely monitored for an
      extended observation period, as venom effects may be delayed or prolonged. Mojave
      rattlesnakes may be particularly difficult to distinguish from Western
      Diamondback rattlesnakes (Crotalus atrox) because of their similarity in
      appearance and overlapping ranges. The purpose of this report is to provide
      clinicians with key characteristics which may assist in distinguishing Mojave
      rattlesnakes from Western Diamondback and other rattlesnakes.

PMID- 10347673
TI  - The use of a modified Dakin's solution (sodium hypochlorite) in the treatment of
      Vibrio vulnificus infection.
AB  - We report the first clinical use of a modified Dakin's solution (0.025% sodium
      hypochlorite [NaOCl]) to halt the progress of severe cutaneous Vibrio vulnificus
      infection in a critically ill patient. The regimen used arose from an initial in
      vitro study designed to examine the sensitivity of Vibrio species to topical
      antimicrobial agents. Twenty-eight wound isolates were tested against the
      following eight topical preparations: silver sulfadiazine (Silvadene),
      nitrofurazone, mupirocin ointment (Bactroban), polymyxin B/bacitracin, mafenide
      acetate (Sulfamylon), nystatin/Silvadene, nystatin/polymyxin B/bacitracin, and
      0.025% NaOCl solution. The results showed that V vulnificus, along with the other
      18 Vibrio species tested, was most sensitive to the modified NaOCl solution.

PMID- 10347674
TI  - Wilderness first responder: recommended minimum course topics. Wilderness Medical
      Society Curriculum Committee.

PMID- 10347675
TI  - Clinical update on emergency medical care in the wilderness.

PMID- 10347676
TI  - Images. Chilblains (pernio).

PMID- 10347677
TI  - Review of Ross malaria paper--a commentary.

PMID- 10347678
TI  - On some peculiar pigmented cells found in two mosquitos fed on malarial blood.
      1897.

PMID- 10347679
TI  - Robert Marshall, Part I: Preserver of wilderness.

PMID- 10347680
TI  - Teaching wilderness emergency care.

PMID- 10347681
TI  - Snakebite scenario.

PMID- 10347683
TI  - [Evaluation of propranolol response by catheterization and Doppler
      ultrasonography in patients with cirrhosis].
AB  - AIMS: To analyze the changes in portal pressure, blood flow and resistance after
      propranolol administration, and to assess the predictive value of the variations
      of Doppler Duplex Ultrasonography (DDU) measurements according to the response of
      the hepatic venous pressure gradient (HVPG). PATIENTS & METHODS: 30 cirrhotic
      patients were studied. Assessment of systemic hemodynamics and HVPG were
      performed in baseline and after intravenous propranolol administration (0.15
      mg/kg). Patients who showed a decrease > or = 20% &/or < 12 mm/Hg in HVPG were
      considered responders. The DDU study was performed in blind conditions, in
      baseline and after propranolol. Measurement of blood flow of the portal vein,
      splenic vein and femoral artery were performed. Portal resistance was calculated
      as HVPG/portal blood flow. RESULTS: All patients were beta blocked and 14 (47%)
      were responders. There were no significant differences in systemic or splachnic
      hemodynamic baseline data between responders and non responders. Femoral blood
      flow decreased in both groups. Splenic and portal blood flow decreased
      significantly only in responders. No significant difference was found in the
      variation of portal resistance between responders and non responders; when these
      changes were considered individually, a great variability was found in both
      groups. A decrease > or = 15% in splenic blood flow showed a positive predictive
      value of 88%, a lack of a similar decrease in portal blood flow showed a negative
      predictive value of 86%. CONCLUSIONS: The decrease in portal blood flow was the
      main factor in determining the response to propranolol.

PMID- 10347682
TI  - [MMP-2 expression (type IV collagenase) in gastric cancer].
AB  - The protein MMP-2 (type IV collagenase) belongs to the family of
      metalloproteinases. Its function is related to cellular matrix degradation
      including basement membrane type IV collagen. Its presence in the neoplastic
      cells might enhance its capacity for dissemination. To find out some of its
      clinico-pathological and immunohistochemical behavior, 98 adenocarcinomas of the
      stomach were immunohistochemically studied, in search for MMP-2 in neoplastic
      cells. The results showed a correlation between MMP-2 with parietal depth of
      infiltration (p = 0.03) and with metastases in regional lymph nodes (p = 0.05).
      On the other hand, no correlation was found with sex, gastric localization, size
      of the tumor, histological type or grade neither with expression of MIB-1, c-erbB
      2 nor p53 proteins, recurrence nor 5 year survival or no recurrency.

PMID- 10347684
TI  - [Ecoendoscopy in the assessment of esophageal neoplasms].
AB  - OBJECTIVE: To asses the diagnostic accuracy of endoscopic ultrasonography (EUS)
      for the local and regional staging of esophageal cancer, and its possible
      alteration resulting from the performance of preoperative chemoradiation.
      METHODS: Prospective study of 85 consecutive patients with esophageal cancer
      evaluated by EUS and operated between January 1992 and December 1995. 28 of these
      patients had received previous induction therapy. In all cases, EUS examination
      was performed by the same physician not informed about the results of previous
      morphological explorations. Histopathological analysis of all specimens was
      performed by the same pathologist, not informed about the results of the EUS.
      Data were collected by another independent observer. RESULTS: EUS examination
      resulted in incomplete staging in 8 patients (9.5%) with severe stenosis
      precluding endoscope passage. The accuracy, specificity and sensibility of EUS in
      detecting the depth of esophageal involvement (T0-2 vs T3-4) were 82.3%, 78% and
      86% respectively, and 72%, 70% and 73% respectively for the lymph node
      metastasis. The overall accuracy of EUS in identifying the preoperative stage was
      67% with a clear-cut alteration when patients had received induction therapy (61%
      vs 72%). On the other hand, 7(64%) of the 11 patients thought to have a complete
      response at endosonography had no residual tumor. CONCLUSION: EUS provides
      precise information for the preoperative identification of locally advanced
      esophageal tumor, even after induction therapy. The latter alters the diagnostic
      accuracy of EUS, although complete responders could be identified in two-thirds
      os cases.

PMID- 10347685
TI  - [Intestinal tuberculosis and AIDS. Case report and literature review].
AB  - We describe a patient with HIV-1 infection and disseminated tuberculosis
      complicated with intestinal localization. The authors describe the clinical and
      radiological findings and the histological and microbiological diagnosis
      corroboration of the intestinal biopsy. The incidence of tuberculosis has been
      increasing during the last decade. The resurgence of tuberculosis, secondary to
      AIDS pandemic, mandates that the clinician be aware of the wide spectrum of
      presentation of intestinal tuberculosis.

PMID- 10347686
TI  - [Gastric xanthogranuloma (inflammatory malignant fibrohistiocytoma). Case report
      and literature review].
AB  - A case of xanthogranuloma of the stomach as cause of clinical signs of gastric
      cancer is reported. Review of the literature is also included.

PMID- 10347687
TI  - [Gastric neoplasms. Prognosis: poor with a likelihood of relapse].

PMID- 10347688
TI  - [Beta-blockers and portal hypertension: in search of the ideal].

PMID- 10347689
TI  - [Psychosexual features of people with permanent colostomy].

PMID- 10347690
TI  - [Programs and politics on growth deficit (consequences of a line of research
      carried out in Chile)].
AB  - This communication offers suggestions for programs and policies in relation to
      stunting within the infant population. The proposal is based on current social
      strategies and the results of research carried out on Chilean school children.
      These results indicate that height deficit is concentrated in sectors of the
      population belonging to low socio-economic levels, and the risk factors are
      related to the small stature of their parents with a record of undernutrition,
      small size at birth and low per capita income. This deficit begins early,
      occurring mainly before the child's second birthday and as a consequence is
      reflected in below average performance at school of those children living in
      areas of social vulnerability. Suggestions offered take into account the
      orientation that should be considered for social policies, the selection of
      beneficiaries, program contents and management and problems that need to be
      overcome. Among these, the following issues are highlighted:--That the social
      welfare programs designed to combat stunting in the infant population should
      have, as a priority objective, the aim of benefiting sectors of the population
      most at need. It is vital to include in these programs: adequate pre-natal care
      of women with a high risk profile of giving birth to a child with intrauterine
      growth retardation; promotion of child growth; food supplementation and/or
      fortification, and improvement of physical fitness.--The government should play a
      leading role in the promotion and management of these programs, in the regulation
      of private sector involvement, as well as promoting local community
      participation.--Warnings are given about the inadequacies of present government
      social welfare policies related to infant nutrition, and the lack of research
      carried out into the effectiveness of current programs. In relation to future
      aims, we would like to see more emphasis put into the integration of
      international and regional intervention programs aimed at combating infant
      undernutrition. This would include sharing resources and collecting information
      related to the problem. Finally, all these actions should be aligned and focused
      on the principal aim; allowing children to reach their full growth potential.

PMID- 10347691
TI  - Effects of dietary polyunsaturated fatty acids on rat brain plasma membrane fatty
      acid composition.
AB  - The effects of four different diets on phospholipid fatty acid composition of rat
      brain plasma membranes were evaluated. Rats were given a semisynthetic diet in
      which lipids were supplied by 5% peanut oil (n-3 PUFA deficient diet), cod liver
      oil (n-6 PUFA deficient diet), partially hydrogenated palm oil (total PUFA
      deficient diet) or a mixture of peanut and rapeseed oil (control group). Animals
      fed the total PUFA deficient diet had significantly lower body and brain weights
      than the control group (p < 0.05). Lower brain cholesterol and phospholipids also
      were observed in animals fed the total PUFA deficient diet, whereas the brain of
      animals fed the n-6 PUFA deficient diet had higher levels of these lipid
      components than the control group (p < 0.05). Phosphatidylcholine and
      phosphatidylethanolamine were mutually replaced in animals fed the n-6 and n-3
      PUFA deficient diets, so that the sum of these two membrane constituents was
      maintained around 77% of total phospholipids. Brain phospholipid fatty acid
      composition was significantly modified by the diets studied. Thus, despite being
      a highly protected organ, the fatty acid composition of the brain can be
      extensively modulated by dietary lipids.

PMID- 10347692
TI  - Effects of dietary polyunsaturated fatty acids on adenylate cyclase,
      5'nucleotidase and Na+K(+)-ATPase activities in rat brain-plasma membrane.
AB  - The incidence of polyunsaturated fatty acids (PUFA) in human nutrition is now
      generally accepted. As essential membrane components, PUFA may act as enzyme
      activity modulators. In this study, four different diets, in which PUFA type was
      the only modifying factor, were evaluated on 5'nucleotidase, adenylate cyclase
      and Na+/K+ATPase activities in rat brain plasma membranes. Animals fed the total
      PUFA deficient diet exhibited significant lower body weight and lower brain
      weight than did the control group. The specific activities of 5'nucleotidase and
      Na+/K+ATPase in brain plasma membrane were slightly modified by dietary PUFA. The
      catalytic unit of adenylate cyclase in total PUFA deficient animals presented
      augmented enzyme activity and animals receiving diets deficient in n-6 PUFA
      showed reduced activity in relation to the control animals. Our results showed
      that the epinephrine receptors, in the case of adenylate cyclase are not modified
      by dietary PUFA, but rather the catalytic unit seems to be altered by dietary
      PUFA. These results can be partially explained by the fluidity that PUFA confers
      to membranes facilitating the proximity of enzyme-substrate. The physiological
      consequences of dietary PUFA incidence on enzyme activity needs further study.

PMID- 10347693
TI  - [The cholesterol-lowering effect of black beans (Phaseolus vulgaris, L.) without
      hulls in hypercholesterolemic rats].
AB  - The cholesterol-lowering property of beans has been shown in several studies. The
      propose of the present work was to investigate the effect of black beans
      (Phaseolus vulgaris, L.) without hulls on blood cholesterol of
      hypercholesterolemic rats. Four groups of 8 male rats, Wistar strain, initial
      body weight of 200 g were kept at +/- 25 degrees C in a light-dark cycle of 12 h,
      for 28 days. The group Standard received a basal casein diet. Group Control
      received the basal diet added of 1% cholesterol plus 0.1% cholic acid. The group
      BB received a diet similar to the Control, substituted by 30% black beans, on dry
      weight. The group SBB received black beans without hulls, equivalent to 30% of
      whole beans. The addition of cholesterol and cholic acid raised blood cholesterol
      levels of rats on Control diet by 58%, in relation to the Standard. BB diet
      reduced blood cholesterol by 15% (non-significant-NS) and SBB diet reduced (p <
      0.05) by 35%, in relation to the Control diet. The levels of HDL-cholesterol were
      reduced (p < 0.05) by both bean diets. SBB diet promoted a higher excretion of
      fecal cholesterol, compared to the Control. This suggests that beans without
      hulls promote a higher cholesterol output and that the whole beans, although had
      lowered blood cholesterol (NS), kept it in the enterohepatic circulation. The
      hypocholesterolemic compounds of beans seem to be located in the inner part of
      the grain. Further studies are necessary to identify these compounds and to
      elucidate their mechanisms of action.

PMID- 10347695
TI  - [Nutritional evaluation of protein quality of cassava leaf combined with casein
      by plastein reaction].
AB  - The present work was conducted to obtain a proteic product and to evaluate its
      biological value in order to be used for human and/or domestic animal
      consumption. Thus, it were used cassava leaves as a non conventional source of
      protein. It was produced a freeze-dried, fat-free and colourless proteic isolated
      from those leaves (CLPI). This was mixed with casein and after the mixture as
      enzymatically hydrolyzed and resynthesized (Plastein reaction) to obtain a
      precipitated (PP) and a soluble plastein (SP) fractions. The protein contents
      observed were 64.39% (PS), 61.36% (PP) and 51.97% (CLPI). Trypsin inhibitor
      activities values showed a 41% reduction in the PP fraction suggesting that the
      heat treatment used to inactivated the enzyme also inactiveted partially the
      inhibitor or the reduction was due to the casein dilution. The amino acid
      composition of the frations obtained showed values close to the standards
      established. It can be concluded:--the utilization of non-conventional source
      should be stimulated when the proteins from those sources have an amino acidic
      profile that allow them to be used as an amino acid supplementation in food with
      low level of essential amino acids;--the fractions obtained by the plastein
      reaction showed satisfactory protein contents and their amino acid profiles were
      comparable with the FAO/OMS/UNU (1985) recommendations;--the plastein reaction
      can be utilized in food processing, after industrial scale adaptation remove
      compounds responsible to bitter taste, fetidness and to discolour protein
      products.

PMID- 10347694
TI  - [The cholesterol-lowering effect of black, carioquinha and red beans (Phaseolus
      vulgaris, L.) in hypercholesterolemic rats].
AB  - The propose of the present work was to investigate the cholesterol-lowering
      effect of black carioquinha and red beans (Phaseolus vulgaris, L.), widely
      consumed in Brazil, in hypercholesterolemic rats. Five groups of 8 male rats,
      Wistar strain, initial body weight of 200 g were kept at 25 degrees in a light
      dark cycle of 12 h, for 28 days. The group Standard received a basal casein diet.
      Group Control was formulated by the addition of 1% cholesterol to the basal diet
      to produce hypercholesterolemia in the rats. The other groups received similar
      diets to the Control, substituted by 30% black (BB), carioquinha (CB) or red (RB)
      beans, on dry-weight. The addition of 1% cholesterol promoted an increase of 49%
      in the levels of total blood cholesterol on Control group, compared with the
      Standard. The bean diets reduced total blood cholesterol (non-significant): BB
      reduced 16%, RB 12% and CB 11%, in relation to the Control. The addition of
      cholesterol to the diets promoted lipid deposition in the rat livers, even in
      those fed the bean diets. It seems that the reduction of cholesterol in blood is
      followed by its retention in the rat livers.

PMID- 10347696
TI  - [Effect of raw and cooked nopal (Opuntia ficus indica) ingestion on growth and
      profile of total cholesterol, lipoproteins, and blood glucose in rats].
AB  - Two different concentrations (approx. 6 and 12%) and two presentations (raw and
      cooked) of dehydrated nopal were fed to laboratory rats and growth and serum
      total cholesterol, lipoprotein profile and glucose determined. Samples of raw and
      cooked nopal were chemically characterized for moisture, protein, ash, crude
      fiber, ether extract, total dietary fiber, reducing sugars, amino acids, minerals
      and gross energy. Cooking slightly affected some of the nutrients analyzed. After
      one month feeding, blood was withdrawn via intracardiac puncture and serum
      glucose, total cholesterol, HDL, LDL, and VLDL were determined. Rats fed 12%
      nopal had lower weight gains (P < 0.05) when compared with counterparts fed 6%
      nopal or the control diet. Consumption of nopal did not affect (P > 0.05)
      glucose, total cholesterol and HDL cholesterol levels. However, rats fed raw
      nopal at the 12% concentration level had a 34% reduction in LDL cholesterol
      levels; thus, it was concluded that raw nopal had a potentially beneficial effect
      for hypercholesterolemic individuals.

PMID- 10347697
TI  - [Chemical-nutritional evaluation of Sorghum saccharatum var. sugar drip. A
      supplementation study with lactoserum proteins].
AB  - The chemical-nutritional composition and some indexes of biological quality of
      sorghum (Sorghum saccharum, var. sugar drip) unwashed whole flour were studied.
      The culture and selection of sorghum were assayed in the "San Roque" Experimental
      Station of the Agriculture Department, Undersecretary of Agricultural Affairs,
      San Luis, Argentina. The obtained protein content was 7.5% (Nx6.25). The values
      for net protein utilization (NPU); true digestibility (tD); net protein ratio
      (NPR) and and relative net protein ratio (RNPR) were 12.4 +/- 0.6, 22.0 +/- 0.2,
      0.8 +/- 0.1 and 24%, respectively. Deficient nitrogen utilization constitutes a
      limitation for the use of sorghum. However, considering its abundance and low
      cost, sorghum could become a profitable feeding resource if conveniently
      supplemented without increasing costs. Sorghum flour was supplemented with
      protein recovered from ricotta serum (50:50), discarded as industrial waste, in
      order to compensate for lysine and threonine deficiency in this cereal. Studies
      performed on this mixture gave RNPR values of 85.7%. This might permit us to
      infer that despite its low biological value, sorghum can be used as food
      resource, potentially for poultry, with adequate supplementation.

PMID- 10347698
TI  - [Effect of cooking on the chemical and nutritional value of the Pithecellobium
      flexicaule (Bent) seed].
AB  - The leguminous P. flexicaule grows at the Northeast of Mexico. People living at
      this region traditionally consume the seeds (unripe cooked or toasted mature).
      Three localities samples of mature seeds were analyzed. The main results were:
      Protein (Nx6.25) 35.3%, lipids 25% and total dietary fiber (TDF) 13.2%. After a
      toasted treatment during 10 minutes (80-90 degrees C), the true protein
      digestibility increased from 79.3-91.8%, the phytate content and protein
      inhibitors decreased up to 35 an 96% respectively. Tannin concentration increased
      from 12.4 to 236 mg eq. cathequine/100 g, probably because during the treatment
      they passed from the shell to the cotyledons. Unripe seeds gave; protein 12.7%,
      lipids 6.6%, TDF 3.5%. When the unripe seeds in their sheath were boiling, the
      true protein digestibility was 85.8% (same value of the raw seeds), phytate
      content was reduced 68.4% and tannin concentration rose from 4.9 to 226 mg. Due
      to these results, the seeds free of the shell and sheaths were boiling, this time
      the tannin and phytate concentration were reduced 73.5 and 88.6% respectively,
      the true protein digestibility was 94.5%. The sulphur containing amino acids were
      the limit, as in other leguminous, the protein digestibility corrected amino acid
      score was 50.6% (unripe seeds), similar to that of pinto beans.

PMID- 10347699
TI  - Enzymatic determination of soluble and insoluble dietary fiber in rice and wheat
      bran.
AB  - The information about dietary fiber presents controversies in many research areas
      such as in nomenclature, related illnesses, recommended quantities and
      terminology, mainly because of lack of analytical data. Different needs and
      interests for the dietary fiber composition of foods and forages have led to a
      proliferation of methods for its analysis. This research, a further adaptation of
      the enzymatic method of Asp et al. (1983) for its application is proposed for
      rice and wheat bran, byproducts of agroindustries in the southern region of Rio
      Grande do Sul (Brazil). The inclusion of Amyloglucosidase in the proposed
      methodology contributed to the decrease in the content of residual starch at the
      end of the experiment, like Prosky et al (1992). To increase the efficiency of
      the enzyme system in this type of samples, other changes were made with respect
      to incubation time and proteolytic enzyme concentration. In the final adaptation,
      a decrease of 51.33% of the starch content was observed in rice bran (RB) and of
      52.93% in wheat bran (WB). This decrease was also verified in the model system
      (MS) (52.08%), which demonstrates the adequacy of the proposed adaptation. With
      respect to the residual protein, it was verified that the measures adopted
      provoked a reduction of 42.15% (RB), 52.19% (WB) and 42.11% (MS) as compared to
      the original method. Then the proposed conditions has been shown to be efficient
      in decreasing the level of interference (indigestible starch and protein) in the
      quantification of dietary fiber in rice and wheat bran.

PMID- 10347700
TI  - [Amino acid composition evaluation of Pleurotus spp. cultivated in banana
      leaves].
AB  - The protein quality of edible mushrooms besides being species/strain specific,
      could also vary with the growth substrate. The aim of this work was to determine
      the amino acid composition of the protein from edible mushrooms--Pleurotus sp.
      "Florida" (L1), P. ostreatoroseus (L2) and P. sajor-caju (L3), cultivated on
      banana leaves (BL) single and, mixed with sugar cane bagasse (BLSCB). Total amino
      acids, cystine and tryptophan were evaluated; the chemical score index and PDCAAS
      -"protein digestibility-correct amino acid scoring" were calculated. From both
      substrates, the studied species contain all essential amino acids; in decreasing
      order, the amino acids in great amounts were glutamic acid, aspartic acid,
      leucine and lysine. The L1 chemical score was 90.4, with limitation in sulfur and
      aromatic amino acids when from BL substrate; and, from BLSC substrate the
      chemical score was 88.7 with limitation in aromatics only. The L2 and L3 was 100,
      0, independent of cultivation substrate. The calculated PDCAAS value, considering
      90% of recommended digestibility, varied between 80.0-96%. The L1 proteins were
      limiting in sulfur and aromatic amino acids and had the lowest value of PDCAAS
      (approximately 80.0) in both substrates; the L3 proteins were limiting in
      aromatic, sulfur and tryptophan, dependent of cultivation substrate; the L2
      proteins had the greatest value of PDCAAS (approximately 96%) and were limiting
      in aromatic and/or sulfur amino acids, dependent of cultivation substrate.
      Considering the conditions of this study, the protein of the studied species is
      incomplete, although of high biological value, comparable to meet.

PMID- 10347701
TI  - [Nutritional improvement of French type bread].
AB  - In Argentina there is an increasing production of soybean and consequently of
      oil, it gives a very important amount of proteins of good quality. Also dairy
      industry produces an useful protein: whey protein concentrate (WPC). The
      objective of this work is to improve the nutritional value of French bread adding
      soy flour and whey proteins to the mixture. Physics, sensory and nutritional
      evaluation were made with statistic treatment by variance analysis, Duncan
      multiple range test. Soy flour and WPC had an opposite behavior with the water
      absorption, while the first show an increasing the second produce a decreasing of
      the absorption values. About the alveographics values they produce a similar
      effect which is a stretching of the dough. In bread manufacture the product
      quality was reduced when soy flour and WPC were individually used but this
      deleterious effect was less important when they were used together in the recipe.
      Nutritional parameters were improved specially when the soy flour that was used
      had low heat treatment (PDI 61).

PMID- 10347703
TI  - [Chemical composition of three Mexican strains of mushrooms (Pleurotus
      ostratus)].
AB  - The chemical composition of three Mexican strains of Pleurotus ostreatus (INIREB
      8, CDBB-H-896 and CDBB-H-897), were determined. The mushrooms were cultivated on
      wheat straw in a greenhouse (22-28 degrees C temperature and 80 +/- 5% of
      relative humidity). Fruits bodies of P. ostreatus contained (all values are
      expressed in g/100 g dry wt.), protein (N x 6.25): 24.64 +/- 0.21-28.50 +/- 0.26;
      lipids: 1.10 +/- 0.16-1.85 +/- 0.22; mineral matter: 7.66 +/- 0.23-8.79 +/- 0.25;
      dietary fibre: 32.14 +/- 0.14-36.81 +/- 0.40; and available carbohydrates: 26.33
      +/- 1.04-30.46 +/- 0.21. They contain vitamins (mg/100 g dry wt): riboflavin:
      3.31-3.7, thiamin: 1.92-1.96, niacin: 35.98-36.56 and ascorbic acid: 28-35. The
      main fatty acid was linoleic (0.70-1.19 g/100 g dry wt), it was also reported a
      low calcium and phosphorus content. Concluding the Pleurotus ostreatus could be a
      source of some of the complex B vitamins, dietary fiber, protein and linoleic
      acid.

PMID- 10347702
TI  - Fatty acid composition of beef, pork, and poultry fresh cuts, and some of their
      processed products.
AB  - Numerous researchers have shown that dietary fats and oils may affect blood lipid
      levels and the development of cardiovascular diseases, but consumers are
      receiving mixed messages about the percentage of fat they should consume in their
      diets, and they can make proper food choices only when they have the right
      information. Fatty acid profiles of the meat food products in the Venezuelan diet
      were determined. Methyl esters were analyzed by gas chromatography on a PT 10%
      Silar-10C on Gas-Chrom Q 100/120 mesh column. Beef cuts presented a predominant
      presence of oleic acid (36.21%), palmitic (25.67%) and stearic (20.97). Oleic and
      palmitic acids are present in pork meat at 42.83 and 24.15% respectively; with
      lesser quantities of stearic and higher amounts of linoleic acid than beef.
      Poultry products showed a high content of linoleic (19.54%) and low content of
      stearic (8.22%) acids. Pork, poultry products, and beef liver presented a
      considerable amount of linoleic acid 11.85%, 19.54%, and 12.09%, respectively.

PMID- 10347704
TI  - [Epidemiology, clinical features and clinical course of Crohn's disease].

PMID- 10347705
TI  - [Epidemiology, clinical features and clinical course of Crohn's disease: a study
      of 60 cases].
AB  - The authors present their experience with the follow-up of 60 cases of Crohn's
      disease, from 1970 until 1998, in the city of Juiz de Fora, Minas Gerais state, a
      county of the Southeast region of Brazil, and analyse the epidemiology of disease
      to improve the understanding of its behaviour in the country. The incidence rates
      increased greatly in the last 28 years. In the group studied 53.3% were men, 90%
      white, 71.7% non-smokers, 93.3% non-alcoholics, and all, but two, lived in urban
      area; 58.3% had their symptoms started at the age between 11 and 30 years and 30%
      were in the second decade of life. Relatives with Crohn's disease were seen in
      6.7%, and the most common symptoms observed at the beginning of disease were:
      abdominal pain (78.3%), diarrhea (68.3%), weight loss (26.7%) and small bowel
      obstruction or localized peritonitis (15%). The ileum was involved in 90% and
      five cases (8.3%) with lesions restricted to the colon were observed. Two
      patients died because they were non-responders despite any therapy schedule and
      had sepsis after surgery. The effect of several substances used in the treatment
      is described, being prednisone the most effective in controlling the active
      disease. Other drugs as aminosalicilates, metronidazol and immunomodulators are
      also considered to avoid the side-effects of long-term use of steroides. Comments
      are made about the clinical evolution, surgeries and response to many treatments
      adopted. The authors conclude that Crohn's disease is increasing its incidence
      rate in Brazil and probably in South America formerly considered as a region of
      low frequency.

PMID- 10347706
TI  - Role of lysosomes on human ulcerogenic gastropathies. Effect of zinc ion on the
      lysosomal stability.
AB  - Numerous conditions are involved in the equilibrium between protective and
      aggressive factors for gastric mucosa injuring. Among them the lysosomal membrane
      stability plays a very important role in the inflammatory process. Zinc ion is a
      well-known lysosomal membrane stabilizer. When given orally to animals or even to
      humans it protects gastric mucosa against erosive lesions induced by a variety of
      experimental conditions. Compared with the control group (8.45 +/- 1.49 mU/mg)
      the lysosomes isolated from samples of gastric mucosa obtained from patients
      suffering of erosive gastropathies, showed a great liability on their membranes
      (18.37 +/- 4.52 mU/mg). When these patients were treated orally with zinc sulfate
      (100 mg of zinc element, twice a day, for two weeks) the lysosomes isolated from
      their gastric mucosa showed a strong reduction on enzymatic activity (5.49 +/-
      1.02 mU/mg), probably due to increasing on the membrane stability. Based on these
      experimental findings we propose the use of zinc ion as an important adjuvant in
      treatment of erosive gastropathies.

PMID- 10347707
TI  - [Relationship between 24 h ambulatory esophageal pHmetry and upper digestive
      endoscopy in reflux esophagitis patients].
AB  - The reflux gastroesophageal patients can be divided in three patterns, according
      with ambulatorial esophageal 24 h-pHmetry: orthostatic, which the reflux episodes
      occur when the patients are upright; supine, which the reflux episodes occur when
      the patients are sleeping; combined, when the reflux episodes are both observed
      in upright or lay down position. There are presented 56 patients with endoscopic
      reflux esophagitis who are divided according to the patterns of reflux by 24 h
      pHmetry. The results are similar to those of international reports. Complicated
      esophagitis is more common in the combined refluxers following by supine
      refluxers. In the orthostatic refluxers were not observed complicated
      esophagitis. The 24 h-pHmetry is an useful tool for clinical use and prognosis in
      the gastroesophageal reflux disease.

PMID- 10347709
TI  - Patients with inflammatory bowel disease: their response to information leaflets
      about medical therapy in particular azathioprine.
AB  - Thirty-eight patients with inflammatory bowel disease who had been treated with
      azathioprine were asked to complete an anonymous questionnaire about information
      they had received on the drug. Twenty responded of which 16 recalled having had
      information on azathioprine. Recall of the content on an information leaflet was
      poor with up to 25% of patients failing to recall warnings about side effects.
      Documentation of this advice on the clinical notes was also poor with this
      happening in only one case. This failure to both recall and record information
      must increase the chances of successful litigation.

PMID- 10347708
TI  - Esophageal dysplasia and chronic esophagitis: detection at upper gastrointestinal
      tract endoscopy.
AB  - Cancer of the esophagus becomes symptomatic at an advanced phase with a late
      diagnosis, when the tumor is already incurable. Early diagnosis has been shown to
      improve the survival rates. Conventional esophagoscopy is largely available but
      its sensitivity to detect early cancer or precancerous lesions remains
      controversial. In this study we tested the sensitivity of conventional
      esophagoscopy to identify suspicious areas and compared to histopathology of
      endoscopic biopsies to detect dysplasia and chronic esophagitis in a population
      at risk for cancer in southern Brazil. Adult males scheduled to have outpatient
      endoscopy were examined by two experienced endoscopists and any small (< 5 mm)
      plaque, nodule, erosion, hyperemia and or friable areas of the mucosa were
      biopsied and looked for the presence of early cancer or precancerous lesions.
      Normal appearing mucosa at the middle third of the esophagus was also biopsied
      and results compared for sensitivity, specificity, positive and negative
      predictive value. Of the 89 individuals with satisfactory biopsies, 3 had
      dysplasias, 29 moderate or severe chronic esophagitis and 57 normal findings at
      the histopathological study. We found no early cancer. We found two large,
      vegetating lesions confirmed to be advanced squamous cell carcinoma but they were
      excluded from analysis. To detect dysplasia or moderate/severe chronic
      esophagitis conventional esophagoscopy had a sensitivity of 40.6%, specificity of
      78.9%, positive predictive value of 52% and negative predictive value of 70.3.
      CONCLUSIONS: In this study, conventional esophagoscopy had a low sensitivity to
      detect dysplasias and/or chronic esophagitis and techniques to improve endoscopic
      identification of these lesions in individuals at risk for cancer are much
      needed.

PMID- 10347710
TI  - [Primary sclerosing cholangitis in children and adolescents].
AB  - Primary sclerosing cholangitis is a disease usually with a poor prognosis with a
      mean survival of 10-12 years, starting from the time of diagnosis. Among the
      different populations studied, males predominate in a ratio 2:1 with ages ranging
      from 20-78 (mean 42 years). This article describes four patients with this
      syndrome, a child of eight and three adolescents, thirteen and fourteen years
      old. It is possibly of autoimmune etiology, characterized by stenosis, dilatation
      and fibrosis involving the intrahepatic and extrahepatic biliary tree. We
      analyzed laboratory assays, clinical, immunological, laboratory assays,
      histological and cholangiographic aspects. In conclusion, in this age group
      perhaps of the small population sample there was no sex predominance, and 50%
      progressed without jaundice and without hepatomegaly. The serum levels of gamma
      glutamyltransferases and especially alkaline phosphatase were elevated compared
      to aminotransferases without increase of the serum auto antibodies. Only one
      patients displayed the typical histological appearance of primary sclerosing
      cholangitis. The diagnosis in al was confirmed by typical cholangiographic signs,
      restricted only to the intrahepatic biliary tree, identified in all those
      included in this study.

PMID- 10347711
TI  - [Use of botulin toxin in the treatment of diffuse esophageal spasm. A case
      report].
AB  - The diffuse esophageal spasm distinguishes from others esophageal disturbs by the
      symptoms severity and bad results to conservative treatment. This situation
      requires formal indication to surgical treatment or dilation. In high risk
      patients this situation becomes a big problem, due to the lack of another
      therapeutic option. In a patient with this problem we use an endoscopic injection
      of botulin toxin in cardia with good results in three months follow-up. Despite
      this short period of observation we believe that the infiltration with botulin
      toxin in cardia constitutes a valid therapeutic option in treatment of diffuse
      esophageal spasm.

PMID- 10347712
TI  - Gastric emptying of liquids in rats with acute renal insufficiency.
AB  - The gastric emptying of watery meals was studied in 112 male Wistar rats. The
      meals utilized were saline and glucose-saline solutions whose emptying was
      assessed 10 and 30 minutes after administration. A liquid 5% glucose meal and a
      0.25 M sodium bicarbonate meal were assessed after 30 minutes and a commercial
      meal was assessed after 60 minutes. For each study time eight control animals and
      eight animals bilaterally nephrectomized 48 hours before the gastric emptying
      tests were used. The meals were labeled with red phenol and the gastric residue
      was determined by standard methodology. A blood sample to determine serum
      creatine and blood gases analysis was obtained from 22 animals of the control
      group and the same number of nephrectomized animals. At the time of the gastric
      emptying tests, the nephrectomized animals had significantly higher levels of
      creatinine and moderate metabolic acidosis. Results for the saline meal showed
      that at 10 minutes there was a significant delay in emptying in animals with
      renal insufficiency. Results for the glucose-saline meal were similar to the
      saline alone group, except that they did not differ significantly between the
      control group and the nephrectomized groups. There was a significant delay in the
      emptying of all the other meals in the animals with renal insufficiency. These
      data suggest that uremia does not lead to serious disturbances in gastric
      motility, but that it does interfere with the mechanisms controlling gastric
      emptying.

PMID- 10347713
TI  - [Immunohistochemical study of colonic mucosa macrophages in children with Crohn's
      disease and ulcerative colitis].
AB  - In this research the histological characteristics of the macrophages on the
      colonic mucosa in Crohn's disease and ulcerative colitis were quantified and
      analysed. Twelve Crohn's disease, 19 ulcerative colitis and 10 specimen of the
      rectal mucosa, representing the control group according to the followed model,
      were studied: I period (PI) = pre-treatment, II period (PII) = up two years of
      evolution and III period (PIII) = more than two years of evolution. The
      macrophages were identified in a colonic mucosa by the monoclonal CD68 through
      the immunoperoxidase method. The macrophages quantification was done by chromatic
      computer images analysis, that express the area (mm2) used by the CD68 positive
      cells, in percentage. The percentage of the area used by the macrophages was
      increased in both diseases, in all the studied periods, when compared with the
      control group, but without statistic significance. The macrophages' distribution
      inside the control group mucosa was subepithelial, while in the illness group, it
      reached all the mucosa that was concentrated on the basis of ulcers and all long
      the fissures. On the Crohn's disease the CD68 positive cells facilited the
      identification of the microgranulomas, sometimes unnoticed in the hematoxiline
      eosine. Although there was no difference between patients and control group in
      the macrophages area, the difference in the distribution could suggest the
      macrophages' participation on the injure in both diseases although they do not
      permit a differential diagnosis because of the variety of the values. The CD68
      did not identify the different functional status of the macrophages, but their
      position in the mucosa suggest that, in terms of fissures and ulcers, their
      mainly function should be the phagocitosis and in the other cases, they have been
      the cells that should show the antigens and that recruit the other inflammatory
      cells.

PMID- 10347714
TI  - [Esophageal intra-abdominal ultrasonographic in children with gastroesophageal
      reflux: correlation between endoscopic and histopathologic data].
AB  - Gastroesophageal reflux disease has been very often in children and one of its
      most critical complications is the peptic esophagitis disease. The diagnosis of
      peptic esophagitis is obtained based on the endoscopic changes and the histologic
      features. The pressure reduction of the lower esophageal sphincter is one of the
      elements of the esophagitis pathogenesis. The pressure is related with the length
      of the esophageal abdominal segment, which can be measured by ultrasonography.
      The research presented in this paper aims to relate ultrasonographic measurements
      of esophageal abdominal segment length with endoscopic changes and with
      esophageal biopsy obtained from children with gastroesophagel reflux disease. We
      submitted 16 children with gastroesophagel reflux disease, between 10 and 156
      months old (median 63.5 months old), to endoscopy and to esophageal biopsy. We
      verified the following results from endoscopy and biopsy: six of the 16 patients
      had endoscopic peptic esophagitis and, in five of these (six patients), the same
      diagnosis was confirmed by biopsy. Ten of the 16 patients had normal endoscopy,
      but the biopsy of four of these 10 patients showed histologic changes compatible
      with esophagitis. We observed no relationship between endoscopy and biopsy, when
      all degrees of histologic change were used to diagnose esophagitis. However, we
      found high relationship when the mild histologic changes were considered as only
      a consequence of the reflux. We verified the following results from
      ultrasonography: five of the six patients with endoscopic peptic esophagitis and
      all patients with esophagitis determined by biopsy (excluding those with mild
      histologic changes) had reduced esophageal abdominal segment length. In
      conclusion, we have found relationship between endoscopic changes and histologic
      features in the diagnosis of esophagitis and correlation between the reduced
      esophageal abdominal segment length and the presence of esophagitis.

PMID- 10347715
TI  - Clinical and molecular studies in five Brazilian cases of Friedreich ataxia.
AB  - Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is caused
      in 94% of cases by homozygous expansions of an unstable GAA repeat localised in
      intron 1 of the X25 gene. We have investigated this mutation in five Brazilian
      patients: four with typical FRDA findings and one patient with atypical
      manifestations, who was considered to have some other form of cerebellar ataxia
      with retained reflexes. The GAA expansion was detected in all these patients. The
      confirmation of FRDA diagnosis in the atypical case may be pointing out, as in
      other reports, that clinical spectrum of Friedreich's ataxia is broader than
      previously recognised and includes cases with intact tendon reflexes.

PMID- 10347716
TI  - Myasthenia gravis and thymoma. Evaluation of 41 patients.
AB  - We evaluated the epidemiological, clinical, laboratory and therapeutical aspects
      of 41 patients with thymomatous myasthenia gravis. Thirty five patients (85.36%)
      were submitted to thymectomy. Follow-up ranged from two to 18 years. Diagnosis of
      thymoma was based upon clinical investigations and CT scan of the anterior
      mediastinum and in 11 patients supported by immunological tests of anti-striated
      muscle antibodies with a positive result in more than 80% of cases.
      Histopathologic examination of all thymomectomized patients confirmed the
      diagnosis of thymoma. There was a significant predominance of benign over
      malignant thymoma. Occurred higher prevalence of male patients and of patients
      over 40 years of age. The therapeutical strategy to control myasthenic clinical
      findings was the same as that for non-thymomatous myasthenia gravis. The
      corticosteroids associated to cytotoxic drugs were less often used. Radiotherapy
      of the anterior mediastinum was more often used in patients having invasive
      tumors submitted to surgery or not. With regard to survival and control of
      myasthenia gravis, especially in younger patients and in those submitted to early
      surgery, results of treatment were surprisingly favorable.

PMID- 10347717
TI  - Sleep habits in Native Brazilian Bororo children.
AB  - Sleep behavior patterns in childhood are influenced by familial, cultural and
      environmental factors. In understanding sleep in Native Brazilian Bororo
      children, one should consider the influence of their culture on the child's
      sleep. This research analyzes sleep habits of Native Bororo children from the
      Meruri village, located in an Indian Reservation in the state of Mato Grosso.
      Fourty four children (24 M; 20 F) were evaluated; ages ranged from one month to
      10 years, with a mean age of 4.9 years. Sleep characteristics were assessed by
      means of a standard questionnaire applied to the mothers. Cosleeping--sleeping
      together with family members--was a remarkable finding, in every child 0-2 year
      old and in 81.5% in the 2-10 years group. The second characteristic was sleeping
      with many people in the same room. There was an average of 5.1 people per room in
      the younger group and 3.9 people in the older group.

PMID- 10347718
TI  - Sustained long-term improvement with clozapine in schizophrenia.
AB  - The present paper reports the long-term use of clozapine in a prospective sample
      of 46 chronic schizophrenics. In six months, 21 subjects had been excluded for a
      number of reasons. In four of them the reasons for exclusion were related to lack
      of response or adverse effects. The median daily clozapine dose was 400 mg in the
      remaining 25 patients. As a whole, there were remarkable improvements in core
      dimensions of psychopathology, global cognitive status, and level of functioning.
      We confirmed that clozapine is effective in a subgroup of schizophrenics with the
      severest forms of the disease. If tolerated after the first few months it leads
      to progressive gains in several domains of behavior. Clozapine should be tried in
      every patient with schizophrenia in whom positive symptoms, disorganization, or
      bizarre behavior are a matter of incapacitation despite efforts to keep them
      under control with other drugs.

PMID- 10347719
TI  - [Evaluation scale of autistic behavior. Validity and reliability of a scale for
      autistic behavior detection].
AB  - This study aimed to translate, to adapt and to validate the scale of autistic
      traits (ATA) developed by Ballabriga et al. in Barcelona, by the analysis of 31
      patients with mental deficiency and 30 patients with autism, according to the DSM
      IV criteria. The "cut off point" found was 15 (p = 0.05); the reliability
      coefficient was 0.27; the construct validity showed low agreement (kappa = 0.04)
      and the internal validity was 100%, with all evaluated patients having their
      clinical diagnosis confirmed through the scale application. The correlation index
      was 0.42, showing that it is specific for autism. The scale presents
      discrimination capacity and internal consistency, and the Cronbach's alpha was
      0.71. We consider that achieved results show that the scale is reliable to be
      used in our population.

PMID- 10347720
TI  - [Quality of life of patients after epilepsy surgery].
AB  - Drug resistant epilepsy impairs patients' quality of life making social
      interaction more difficult. Surgical treatment is an option for seizure control
      in medically refractory patients. We evaluated pre-operative and post-operative
      quality of life using a standardized questionnaire based on the QOLIE-10. The
      questionnaire included ten questions dealing with psychosocial and drug's side
      effects and was applied before surgery and eight months post-operatively. The
      studied sample comprised twelve consecutive adult patients with epilepsy treated
      surgically who were seizure free. Differences were found between the pre
      operative and post-operative periods in 70% of the questions, with a better post
      operative profile. Successful epilepsy surgery has a great impact in the quality
      of life of these patients.

PMID- 10347721
TI  - [Quality of life in childhood epilepsy].
AB  - Epilepsy is a chronic disorder in which onset occurs primarily during childhood
      and adolescence. Traditionally, treatment of childhood epilepsy emphasizes
      neurologic aspects over psychological factors. The attention to the seizure
      control in the clinical setting will not address the full range of quality of
      life problems of childhood epilepsy. Many of the psychosocial difficulties that
      plague adults with epilepsy develop from the complications associated with this
      early onset. Children with epilepsy have a high prevalence of behavior problems
      and learning problems. Assessing quality of life in pediatric epilepsy is
      especially important because children are in critical periods of development
      during which many cognitive and social skills are being learned. This study
      presents a simplified inventory of quality of life, with cultural, personal,
      social and relationship aspects. This investigation makes possible to the
      professional knowledge about children and a best direction of their conducts.

PMID- 10347722
TI  - [Simplified inventory of quality of life in childhood epilepsy: initial results].
AB  - PURPOSE: To check how parents realize the quality of life of their epileptic
      children and if the relationship is controlled by their beliefs about epilepsy.
      METHODS: It has been applied 21 protocols of "Simplified inventory of quality of
      life in childhood epilepsy" to parents of children aged between 6-14 years old
      with benign childhood epilepsy. RESULTS: It was observed that 86% of parents
      reported beliefs about epilepsy. The majority of parents evaluated their
      children's quality of life as very good, but reported difficulties to deal with
      them. Behaviors of overprotection (62%) and feelings of worry, fear and
      insecurity (90%) were observed. The children were evaluated as irritated (52%),
      dependents (38%), overwroughts and inquiets (38%). About school, 33% are in
      special schools and have difficulties of academic and relationship. CONCLUSION:
      It was verified a lot of beliefs and acknowledgement seem to control parent's
      behavior on the way of dealing with epileptic children producing inadequate
      behaviors, in spite of realizing the quality of life of their children as been
      very good.

PMID- 10347723
TI  - [IQ in hydrocephalus and myelomeningocele. Implications of surgical treatment].
AB  - Myelomeningocele occurs in 0.4 for 1000 neonates and is associated with
      hydrocephalus in 85-90%, and reports on cognition are sparsely found in
      literature. Forty five children with treated hydrocephalus and myelomeningocele
      were studied in regard of IQ, and statistically correlated to functional motor
      level, age of the first shunt, number of revisions of shunt, infection of the
      shunt and circumference of the head. The medium age was of 7.5 years (3-15
      years), 16 males and 29 females. Three (6.6%) had a IQ score > 110, 11 (24.4%)
      had a score between 100-110, 8 between 85-100 (17.7%), 16 (35.5%) between 85-100
      (17.7%) and 7 (15.5%) between 50-70. IQ directly correlated with motor level,
      having better cognitive results the children with minor functional motor
      disabilities. Cognition was best in children operated until the seven day of life
      (t 0.0099), with progressive worse results in children operated after the first
      month of life, no significance was observed in children operated in the period 7
      to 31 days (t 0.1013). Worse results were observed in the group of patients with
      infection of shunts (t 0.0146). Results were progressively worse with
      reoperations. The best results in relation of the circumference of the head were
      seen with children in the medium range (t 0.0115); intermediate results were seen
      in patients between the medium range and-1SD (t 0.00130) and medium range and
      +1SD. The worse results were seen in patients at the extremes of > 1SD (t 0.0269)
      and < ISD (t 0.0042). According to cognitive results the surgical treatment of
      hydrocephalus have to be done until the first month of life, avoiding
      reoperations and infections that have unfavorable impact in IQ.

PMID- 10347724
TI  - [Multiple sclerosis. Clinical survey of 50 patients followed at the Ambulatory of
      Neurology UNIFESP-EPM].
AB  - Multiple sclerosis, seems to be a rare disease however in the population herein
      studied it is similar to the one described by others, in Brazil and abroad. We
      studied 50 patients classified according Poser's criteria that were followed at
      the Department of Neurology UNIFESP-EPM from 1983 to 1995. The clinical findings
      of these 50 patients were similar to those described in other series. We found a
      high prevalence among female young patients who presented relapsing-remitting
      evolution. The most common symptoms were those related to pyramidal and
      cerebellar dysfunctions. The EDSS score seems to be worse in patients with
      specific cerebellar and pyramidal signs, higher number of relapses and longer
      time of disease but it is not related to the number of white matter lesions found
      at MRI.

PMID- 10347725
TI  - [Lesion of the Lissauer tract and of the posterior horn of the gray substance of
      the spinal cord and the electrical stimulation of the central nervous system for
      the treatment of brachial plexus avulsion pain].
AB  - We analyze the effectiveness of the treatment of 10 patients of brachial plexus
      avulsion pain. Seven underwent dorsal root entry zone lesions (DREZ), 3, dorsal
      column stimulation (DCS) and, 2 thalamic stimulation (TS). DCS resulted in
      immediate improvement of pain in 50% of the patients. After a long term follow up
      period, just 25% of the patients were still better. TS resulted the in temporary
      improvement of 2 patients. Both had full recurrence few months after the
      operation. Immediate improvement of the symptoms occurred in all patients treated
      by DREZ. After a long term follow up period, excellent results were observed in
      71.4% of the patients and good results in the remainder. The complication rate
      was higher among DREZ patients. It is concluded that DREZ is a better procedure
      for treatment of brachial plexus avulsion pain than DCS and TS (p = 0.0046);
      however, DCS and TS are safer.

PMID- 10347726
TI  - [Intracranial arachnoid cysts. Neuroendoscopic treatment].
AB  - The author reports the techniques and results of seven patients with intracranial
      arachnoid cysts treated surgically, all of them through neuroendoscopic approach.
      Two carriers of supraselar cysts had undergone several shunt surgeries, and
      another carrier of a temporal cyst undergone external drainage to treat an
      associated subdural higroma. Only in this case the endoscopic approach has not
      resulted in control of the symptoms of the patient. The follow up period extended
      from one to nine years.

PMID- 10347727
TI  - [Fixation of cervical spine with interspinous wiring and autologous bone
      grafting].
AB  - Thirty-two patients with acute cervical spine trauma were treated at Municipal
      Hospital Instituto Dr. Jose Frota, in Fortaleza, Ceara, Brazil, from January 1996
      to May 1997. We performed posterior spinal stabilization with interspinous wiring
      and autologous bone grafting when the patients with cervical spine trauma
      presented dislocations and rupture of the posterior ligamentous complex. The
      results in the period of one year according to Frankel's functional scale
      indicate that among the patients with some degree of neurological lesion in the
      entrance, 11 improved, 1 worsened and 1 died of respiratory tract infection.
      There was not worsening in none of the 12 patients that presented absence of
      neurological lesion in the admission. Our data emphasize that the method is
      effective, safe and accessible.

PMID- 10347728
TI  - [Subclinical apoplexy in pituitary tumors].
AB  - Acute pituitary apoplexy is a rare event, even in patients with pituitary
      macroadenomas. On the other hand, the presence of necrotic/hemorrhagic areas,
      especially in macroadenomas, seems to be more common than earlier reported in the
      CT period. After the introduction of MR in the presurgical workup of these
      patients, these apopleptic areas have been more easily diagnosed preoperatively.
      Forty consecutive patients with pituitary macroadenomas were studied with high
      resolution 1.5 T T1 coronal, sagittal and axial slices over the sellar region.
      Special attention was paid in the detection of necrotic, cystic and hemorrhagic
      areas within these tumors. Ten patients had hemorrhagic/necrotic areas within
      their tumors, without any sign or symptom of acute apoplexy. These areas varied
      from small (2 mm) to very large (30 mm) ones. Seven patients had non-secreting
      tumors, 2 GH and 1 prolactin secreting tumors, which is the same profile of
      secretory pattern for the whole series (40 patients). The clinical picture
      included (other than that caused by endocrine secretion) slowly progressive (but
      not acute) visual loss (n = 8) and headache (n = 3). After surgical decompression
      of the surrounding structures and visual apparatus, which was facilitated by the
      presence of the necrotic areas, there was visual improvement in 6 patients and
      headache resolution in 2. The presence of asymptomatic apopletic areas in these
      macroadenomas and their absence in microadenomas as can be seen in the literature
      suggest that they are related more to the size of the tumor than to its endocrine
      secretion pattern. This is in agreement with a vascular insufficiency hypothesis
      in the pathogenesis of these lesions.

PMID- 10347730
TI  - Cerebrovascular disease in neonates. Evaluation of four cases.
AB  - The clinical and neurological study in four neonates infants with cerebral
      infarction are reported. The purpose of this study is to call attention for the
      clinical course, cranial ultrasound, computed tomography and laboratories tests,
      in order to evaluate the neurological sequelae. A careful evaluation has be taken
      in order to determine the significance of clinical and laboratory tests for
      syndromic, topographic and etiologic diagnosis after one year ambulatorial follow
      up.

PMID- 10347729
TI  - [Brain aging. The problem of differential diagnosis between normal and
      pathologic].
AB  - The author reports three cases of pseudodementia and discuss the difficulties in
      establishing limits between normality and illness in the elderly. The mental and
      neuropathological changes that accompany the normal ageing of the brain are
      similar to those of early Alzheimer's dementia (AD). These similarities often
      lead to difficulties in the differential diagnosis, hence the search for
      consensus criteria. The decline of working and secondary memory is greater than
      that of primary and tertiary memory, as is found in AD. On the other hand, tests
      of delayed recall of 10 to 15 unrelated words, logical memory, categorical
      thinking, visuo-motor-spatial skills, and Boston Naming Test have been pointed
      out as the most discriminative. Neuroimaging findings of atrophy or hypoperfusion
      in the entorhinal-hippocampal or temporo-parietal regions are suggestive of DA,
      but they can be lacking in the early stages of this disease. In the conclusion,
      the author suggests the diagnostic process should be based on a comprehensive
      neuropsychological and behavioral evaluation (including a survey of the subject's
      premorbid level of cognitive and socio-occupational functioning), supplemented by
      neuroimaging and laboratory tests. If inconclusive, the whole evaluation can be
      repeated after 4 to 6 months, to check the consistency of the findings.

PMID- 10347731
TI  - Association of misoprostol, Moebius syndrome and congenital central alveolar
      hypoventilation. Case report.
AB  - We report a case showing the association of Moebius syndrome, the use of
      misoprostol during pregnancy and the development of central congenital alveolar
      hypoventilation. Pathophysiological aspects of these three diseases are discussed
      and also the unfavorable prognosis of this association.

PMID- 10347732
TI  - Pineal metastasis as first clinical manifestation of colorectal adenocarcinoma.
      Case report.
AB  - Cerebral metastases from colorectal adenocarcinomas occur in 8% of the cases.
      Diagnosis is usually made when primary disease and widespread metastases are
      already known. We report the case of a patient with single metastases in the
      pineal region as the first clinical manifestation of a colorectal adenocarcinoma.
      A 48-year-old female with Parinaud's syndrome for 15 days prior her admission was
      evaluated in our clinic. She had no symptoms or signs of colorectal disease. MRI
      examination revealed an heterogeneous lesion with peritumoral gadolinium
      enhancement, located in the pineal region. The tumor was radically resected
      through an infratentorial/supracerebellar approach. Histology showed metastatic
      carcinoma and immunohistochemical examination showed gastrointestinal tract
      adenocarcinoma. Metastases to the pineal region are extremely rare and should be
      considered in the differential diagnosis of tumors of this region.

PMID- 10347733
TI  - [Acoustic neuroma in children without association with neurofibromatosis. Report
      of 2 cases].
AB  - Acoustic schwannoma is the most common tumor of the cerebellopontine angle in
      adults and is rarely found in children without neurofibromatosis. In the
      literature there are 18 children under the age of 16 with such tumor. Two female
      patients with age of 9 and 15 years old with acoustic schwannoma without
      neurofibromatosis are related. Progressive deafness followed by signs and
      symptoms of a posterior fossa tumor were the initial complaint of both, as well
      as of the other related cases and in adulthood.

PMID- 10347734
TI  - [Paraplegia as initial manifestation of tethered spinal cord. Case report].
AB  - Tethered spinal cord (TSC) is a rare disorder; it occurs when the conus medularis
      is anchored to the base of the vertebral canal by thickened filum terminale
      cysts, lipoma and spinal dysraphia. This disorder may cause paraplegia, sensory
      and sphincter disturbance. We report a twenty-two months-old girl presenting with
      paraplegia. TSC diagnostic was confirmed by myelotomography. The patient was
      submitted to surgical relief of tethered filum terminale.

PMID- 10347735
TI  - [Cockayne syndrome. Case report].
AB  - We describe a girl with Cockayne syndrome (CS), the diagnostic criteria and the
      complications of this syndrome. The required criteria for the diagnosis include:
      prenatal poor growth failure, congenital structural eye anomalies, cataracts,
      pigmentary retinopathy, severe neurologic dysfunction from birth, sensorineural
      hearing loss, cutaneous photosensitivity and dental caries. CS is a rare
      autosomal recessive and biochemical disorder.

PMID- 10347736
TI  - [Migraine with aphasia. Report of a family].
AB  - We describe a Brazilian family in which one female patient and her three
      daughters present a clinical course compatible with migraine, preceded by
      language disorders (aphasia), without paresis. Several aspects related to
      genetics of migraine are reviewed. We conclude that further genetical studies are
      necessary to establish if these cases are different sources of well-known
      migraine subtypes as the familial hemiplegic migraine.

PMID- 10347737
TI  - [Greater occipital neuralgia associated with occipital osteolytic lesion. Case
      report].
AB  - The anatomic distribution of the greater occipital nerve during its path permits
      a close relationship with muscular structures, tendons, vessels and bones. The
      rupture of this relationship can origin its irritation and headache. We describe
      an uncommon association between an osteolytic lesion on occipital bone and
      greater occipital nerve. The patient, female 50, has been presenting headache for
      two years on the right occipital region spreading to the hemicranic and
      ipsilateral supraorbital region. The symptoms started spontaneously or by
      pressure on the trapezius tendon. The pain lasted about 30 minutes, compressive,
      mild intensity, with no autonomic symptoms and no improvement after the
      infiltration in the greater occipital nerve. The total improvement of the
      symptoms after releasing the nerve has allowed us to associate this lesion to the
      presence of algic symptoms.

PMID- 10347738
TI  - [Organic somatoform disorder. Case report].
AB  - Based on the neuropsychological and imagenological evaluation of a frontal
      damaged patient with a somatoform disorder, we study the differential diagnosis
      of this condition compared to that of other patients: temporal or parietal
      damaged ones, schizophrenics, melancholics, obsessives, hypochondriacs and
      dismorphophobics.

PMID- 10347739
TI  - [RSI--repetitive strain injury. A questionable and harmful concept].
AB  - The hypothesis that repetitive movements and postures cause musculoskeletal
      injury is not supported by scientific data. The sensory and pain symptoms are
      better explained as of psychological and psychosocial nature, such as job
      dissatisfaction or disajustment, with financial gains objectives. The repetitive
      strain injury concept is iatrogenic and costly to society, and must be abandoned.

PMID- 10347740
TI  - [Guidelines for recording/analyzing quantitative EEG and evoked potentials. Part
      II: Clinical aspects].
AB  - Digital EEG (DEEG) and quantitative EEG (QEEG) are recently developed tools
      present in many clinical situations. Besides showing didactic and research
      utility, they may also have a clinical role. Although a considerable amount of
      scientific literature has been published related to QEEG, many controversies
      still subsist regarding its clinical utilization. Clinical applications are: 1.
      DEEG is already an established substitute for conventional EEG, representing a
      clear technical advance. 2. Certain QEEG techniques are an established addition
      to DEEG for: 2a) screening for epileptic spikes or seizures in long-term
      recordings; 2b) Operation room and intensive care unit EEG monitoring. 3. Certain
      QEEG techniques are considered possible useful additions to DEEG: 3a) topographic
      voltage and dipole analysis in epilepsy evaluations; 3b) frequency analysis in
      cerebrovascular disease and dementia, mostly when other tests have been
      inconclusive. 4. QEEG remains investigational for clinical use in postconcussion
      syndrome, learning disability, attention disorders, schizophrenia, depression,
      alcoholism and drug abuse. EEG brain mapping and other QEEG techniques should be
      clinically used only by physicians highly skilled in clinical EEG interpretation
      and as an adjunct to traditional EEG work.

PMID- 10347741
TI  - [Stereotaxic thalamotomy and pallidotomy in the treatment of Parkinson disease].

PMID- 10347742
TI  - Intelligence and genetic markers in Chilean children.
AB  - Genetic markers and total intelligence quotient (IQ) assessed by WISC (Wechsler
      Intelligence Scale for Children) were studied in children of both sexes from
      Santiago, Chile. Heterozygous boys for phosphoglucomutase 1 (PGM) and
      heterozygous girls for haptoglobin (Hp) had lower IQ than homozygotes. For ABO
      system, B girls had lower and B boys had higher IQ than children with other ABO
      phenotypes. These differences were highly significant with the two tailed t'-test
      (Student's t-test with the Welch-Satterthwaite correction for degrees of
      freedom), and most of them remained significant after the correction for multiple
      comparisons. Girls had greater variance of IQ than boys. Relationships between
      homozygotes and heterozygotes were found in two independent studies. Thus, the
      genetic relationship found here seems likely to be a true biotic effect.

PMID- 10347743
TI  - In memoriam Professor Enrique Egana, MD (1912-1997).
AB  - Enrique Egana-Barahona. Born Santiago, Chile, 10 March 1912. Deceased Santiago,
      Chile, 23 November 1997. MD, University of Chile, 1936. Rockefeller Foundation
      Fellow at Harvard University Medical School, 1940-1944. Professor of
      Pathophysiology, 1963; Director, Institute of Experimental Medicine, Faculty of
      medicine, University of Chile. Author of a Textbook on General Pathophysiology
      (1963) and of many scientific articles in Chilean and American medical journals.
      Strong supporter of evidence-based medicine as well as of medical education by
      involving students in short research projects.

PMID- 10347744
TI  - How do calcium channels transport calcium ions?
AB  - Calcium channel activity is crucial for many fundamental physiological processes
      ranging from the heart beat to synaptic transmission. The channel-forming
      protein, of about 2000 amino acids, comprises four domains internally homologous
      to each other. Voltage-dependent Ca2+ channels are the most selective ion
      channels known. Under physiological conditions, they prefer Ca2+ over Na+ by a
      ratio of about 1000:1. To explain at the same time the exquisite ion selectivity
      and the large Ca2+ ion turnover rate of Ca2+ channels (approximately 3 x 10(6)
      ions/s), two kind models have been proposed. In one, the conduction pathway
      possesses two high-affinity binding sites. When two Ca2+ ions are bound to each
      site, the mutual repulsion between them speeds the exit rate for the ions,
      causing greater ion permeation through the pore. The second model hypothesizes
      the existence of a single site having a charged structure able to attract
      multiple, interacting ions, simultaneously. Recent studies that combine
      mutagenesis and electrophysiology show that the high-affinity binding site is
      formed by a ring of glutamate residues located in the pore forming region of the
      Ca2+ channel. As proposed in the second class of models, the results suggest that
      four glutamate residues, one glutamate donated by each repeat, combine to form a
      single high-affinity site. In this review the different conduction models for
      Ca2+ channels are discussed and confronted with structural data.

PMID- 10347745
TI  - Kinins mediate the inhibition of atrial natriuretic peptide diuretic effect
      induced by pepsanurin.
AB  - Pepsanurin is a peptidic fraction resulting from pepsin digestion of plasma
      globulins, that inhibits ANP renal excretory actions. We studied whether kinin
      like peptides mediate the anti-ANP effect by testing if pepsanurin: 1) was
      blocked by the kinin B2 receptor antagonist HOE-140, 2) was produced from
      kininogen, and 3) was mimicked by bradykinin. Anti-ANP activity was assessed in
      anesthetized female rats by comparing the excretory response to two ANP boluses
      (0.5 microgram i.v.) given before and after i.p. injection of test samples.
      Pepsanurin from human or rat plasma (1-5 mL/kg), and bradykinin (5-20
      micrograms/kg), dose-relatedly inhibited ANP-induced water, sodium, potassium and
      cyclic GMP urinary excretion, without affecting arterial blood pressure. The same
      effect was exerted by pepsin hydrolysates of purified kininogen, whereas
      hydrolysates of kininogen-free plasma had no effect. HOE-140 (5 micrograms, i.v.)
      did not alter baseline, or ANP-induced excretion, but blocked the anti-ANP
      effects of pepsanurin. Histamine (15 micrograms/kg) plus seroalbumin hydrolysates
      did not affect ANP response, despite inducing larger peritoneal fluid
      accumulation as compared with pepsanurin or bradykinin. We concluded that kinins
      cleaved from kininogen mediate the anti-ANP effects of pepsanurin by activation
      of kinin B2 receptors, independently of changes in systemic arterial pressure or
      peritoneal fluid sequestration.

PMID- 10347746
TI  - Immunolocalization of cytochrome P450 side chain cleavage, 17-alpha-hydroxylase
      and aromatase in the ovary of vespertilionid bat (Scotophilus heathi) during
      different phases of ovulatory delay.
AB  - Immunocytochemical localization of steroidogenic enzymes, cytochrome P450 side
      chain cleavage, 17-alpha-hydroxylase and aromatase, was performed in the ovaries
      of Scotophilus heathi during reproductive cycle, with reference to the period of
      delayed ovulation. Moderate immunoreactivity of side chain cleavage enzyme and 17
      alpha-hydroxylase was observed mainly in thecal cells and interstitial cells of
      the ovarian stroma during quiescence. Thecal cells positive for 17-alpha
      hydroxylase were found even around the primary follicles. The peak
      immunoreactivity for all the three enzymes was observed during recrudescence. It
      coincided with high circulating steroid levels during this period. In the stroma,
      immunoreactivity for side chain cleavage and 17-alpha-hydroxylase was so
      extensive that it almost occupied the entire interfollicular area of the ovary.
      Aromatase immunoreactivity declined, but side chain cleavage enzyme and 17-alpha
      hydroxylase remained extensive during the period of delayed ovulation. This
      suggests a high androgen and low estrogen synthesis during the period of delayed
      ovulation. There was a marked decline in 17-alpha-hydroxylase and an increase in
      aromatase immunoreactivity during the preovulatory period, suggesting a decrease
      in androgen and increase in estrogen synthesis. The results suggest thecal cells
      and interstitial cells of the stroma as the major site of steroidogenesis in the
      ovary of S. heathi. Over production of androgen is attributed to the extensive
      development of 17-alpha-hydroxylase positive interstitial cells in the ovarian
      stroma, and this may be responsible for delayed ovulation in Scotophilus heathi.

PMID- 10347747
TI  - Effect of detergents and lipids on transducin photoactivation by rhodopsin.
AB  - Rhodopsin samples, isolated using four different extraction procedures, were used
      to investigate the photodependent activation of the GTPase activity of
      transducin. A complete inhibition of transducin light-dependent GTP hydrolytic
      activity was observed when rhodopsin purified in the presence of 1% digitonin,
      following rod outer segment (ROS) solubilization with 1% 3-[(3-cholamidopropyl)
      dimethylammonio]-1-propane-sulfonate (CHAPS), was used for its activation [0 pmol
      of inorganic phosphate (Pi) released/min/pmol of rhodopsin]. Rhodopsin, isolated
      in the presence of 1% digitonin following ROS solubilization with 1% digitonin,
      was capable of stimulating slightly transducin GTPase activity, with an initial
      rate of 1 pmol of GTP hydrolyzed/min/pmol of rhodopsin. However, rhodopsin
      purified in the presence of 0.2% n-dodecyl-beta-D-maltoside (DM), following ROS
      solubilization with either 1% CHAPS or 1% DM, stimulated the enzymatic activity
      of transducin in a light-dependent manner, with an initial rate of 5 pmol of Pi
      released/min/pmol of rhodopsin. Addition of 0.075% egg phosphatidylcholine (PC)
      to the four different solubilized rhodopsin samples significantly enhanced light
      stimulated GTP hydrolysis by transducin, with initial rates increasing from 0 to
      1, 1 to 2, and 5 to 30 pmol of Pi released/min/pmol of rhodopsin, respectively.
      Furthermore, DM-solubilized rhodopsin induced the hydrolysis of the maximum
      amount of GTP by transducin at 0.0075% PC, while digitonin-solubilized rhodopsin
      only stimulated the GTPase activity of transducin to a similar value, when the
      amount of the photoreceptor protein was increased 4-fold and 0.15% PC was added
      to the assay mixture. These results suggest that the effective photoactivation of
      transducin by rhodopsin requires phospholipids, which seem to be differentially
      eliminated with the detergent extraction procedure utilized during ROS membranes
      solubilization and photopigment isolation.

PMID- 10347748
TI  - The challenge of vector development in gene therapy.
AB  - Gene therapy is the treatment of diseases based on the transfer of genetic
      information. Agents that carry or deliver DNA to target cells are called vectors
      (Latin vector: carrier, deliverer). Ideally, a vector should accommodate an
      unlimited amount of inserted DNA, lack the ability of autonomous replication of
      its own DNA, be easily manufactured, and be available in concentrated form.
      Secondly, it should have the ability to target specific cell types or to limit
      its gene expression to specific cell types, and to achieve sustained gene
      expression in the long term or in a controlled fashion. Finally, it should not be
      toxic or immunogenic. Such a vector does not exist and none of the DNA delivery
      systems so far available for in vivo gene transfer is perfect with respect to any
      of these points. Gene therapy and the means to promote it depend heavily on the
      development and improvement of new gene vector systems.

PMID- 10347749
TI  - Main features of DNA-based immunization vectors.
AB  - DNA-based immunization has initiated a new era of vaccine research. One of the
      main goals of gene vaccine development is the control of the levels of expression
      in vivo for efficient immunization. Modifying the vector to modulate expression
      or immunogenicity is of critical importance for the improvement of DNA vaccines.
      The most frequently used vectors for genetic immunization are plasmids. In this
      article, we review some of the main elements relevant to their design such as
      strong promoter/enhancer region, introns, genes encoding antigens of interest
      from the pathogen (how to choose and modify them), polyadenylation termination
      sequence, origin of replication for plasmid production in Escherichia coli,
      antibiotic resistance gene as selectable marker, convenient cloning sites, and
      the presence of immunostimulatory sequences (ISS) that can be added to the
      plasmid to enhance adjuvanticity and to activate the immune system. In this
      review, the specific modifications that can increase overall expression as well
      as the potential of DNA-based vaccination are also discussed.

PMID- 10347750
TI  - Regulation of transgene expression in genetic immunization.
AB  - The use of mammalian gene expression vectors has become increasingly important
      for genetic immunization and gene therapy as well as basic research. Essential
      for the success of these vectors in genetic immunization is the proper choice of
      a promoter linked to the antigen of interest. Many genetic immunization vectors
      use promoter elements from pathogenic viruses including SV40 and CMV. Lymphokines
      produced by the immune response to proteins expressed by these vectors could
      inhibit further transcription initiation by viral promoters. Our objective was to
      determine the effect of IFN-gamma on transgene expression driven by viral SV40 or
      CMV promoter/enhancer and the mammalian promoter/enhancer for the major
      histocompatibility complex class I (MHC I) gene. We transfected the luciferase
      gene driven by these three promoters into 14 cell lines of many tissues and
      several species. Luciferase assays of transfected cells untreated or treated with
      IFN-gamma indicated that although the viral promoters could drive luciferase
      production in all cell lines tested to higher or lower levels than the MHC I
      promoter, treatment with IFN-gamma inhibited transgene expression in most of the
      cell lines and amplification of the MHC I promoter-driven transgene expression in
      all cell lines. These data indicate that the SV40 and CMV promoter/enhancers may
      not be a suitable choice for gene delivery especially for genetic immunization or
      cancer cytokine gene therapy. The MHC I promoter/enhancer, on the other hand, may
      be an ideal transgene promoter for applications involving the immune system.

PMID- 10347751
TI  - Liposomes as a gene delivery system.
AB  - Gene therapy is an active field that has progressed rapidly into clinical trials
      in a relatively short time. The key to success for any gene therapy strategy is
      to design a vector able to serve as a safe and efficient gene delivery vehicle.
      This has encouraged the development of nonviral DNA-mediated gene transfer
      techniques such as liposomes. Many liposome-based DNA delivery systems have been
      described, including molecular components for targeting given cell surface
      receptors or for escaping from the lysosomal compartment. Another recent
      technology using cationic lipids has been evaluated and has generated substantial
      interest in this approach to gene transfer.

PMID- 10347753
TI  - Liposomes: from biophysics to the design of peptide vaccines.
AB  - Liposomes (lipid-based vesicles) have been widely studied as drug delivery
      systems due to their relative safety, their structural versatility concerning
      size, composition and bilayer fluidity, and their ability to incorporate almost
      any molecule regardless of its structure. Liposomes are successful in inducing
      potent in vivo immunity to incorporated antigens and are now being employed in
      numerous immunization procedures. This is a brief overview of the structural,
      biophysical and pharmacological properties of liposomes and of the current
      strategies in the design of liposomes as vaccine delivery systems.

PMID- 10347752
TI  - Poly-DL-lactide-co-glycolide microspheres as a controlled release antigen
      delivery system.
AB  - Successful vaccine application means maximum protection with minimal number of
      administrations. A rational development of vaccines involves studies of the
      nature of the antigen as well as of the adjuvant to be used to improve the immune
      responses. This has provided the impetus for studies to design the degradable
      devices and for different approaches to antigen delivery by different routes of
      administration. The development of controlled release systems based on polymeric
      devices that permit a sustained or pulsed release of encapsulated antigens has
      attracted much interest. Polymeric delivery systems consist of polymers that
      release their content continuously in a controlled manner over a period of time.
      The development of a biocompatible delivery system for parenteral administration
      offers several advantages in terms of immunoadjuvanticity over other compounds.
      It was found that, in contrast to other carriers, microspheres are more stable,
      thus permitting administration by the oral or parenteral route. In the present
      study, we describe the main characteristics and potentialities of this new
      immunoadjuvant for oral and parenteral administration.

PMID- 10347754
TI  - Heterologous protein secretion in Lactococcus lactis: a novel antigen delivery
      system.
AB  - Lactic acid bacteria (LAB) are Gram-positive bacteria and are generally regarded
      as safe (GRAS) organisms. Therefore, LAB could be used for heterologous protein
      secretion and they are good potential candidates as antigen delivery vehicles. To
      develop such live vaccines, a better control of protein secretion is required. We
      developed an efficient secretion system in the model LAB, Lactococcus lactis.
      Staphylococcal nuclease (Nuc) was used as the reporter protein. We first observed
      that the quantity of secreted Nuc correlated with the copy number of the cloning
      vector. The nuc gene was cloned on a high-copy number cloning vector and no
      perturbation of the metabolism of the secreting strain was observed. Replacement
      of nuc native promoter by a strong lactococcal one led to a significant increase
      of nuc expression. Secretion efficiency (SE) of Nuc in L. lactis was low, i.e.,
      only 60% of the synthesized Nuc was secreted. Insertion of a synthetic propeptide
      between the signal peptide and the mature moiety of Nuc increased the SE of Nuc.
      On the basis of these results, we developed a secretion system and we applied it
      to the construction of an L. lactis strain which secretes a bovine coronavirus
      (BCV) epitopeprotein fusion (BCV-Nuc). BCV-Nuc was recognized by both anti-BCV
      and anti-Nuc antibodies. Secretion of this antigenic fusion is the first step
      towards the development of a novel antigen delivery system based on LAB-secreting
      strains.

PMID- 10347755
TI  - MHC-restricted antigen presentation and recognition: constraints on gene,
      recombinant and peptide vaccines in humans.
AB  - The target of any immunization is to activate and expand lymphocyte clones with
      the desired recognition specificity and the necessary effector functions. In
      gene, recombinant and peptide vaccines, the immunogen is a single protein or a
      small assembly of epitopes from antigenic proteins. Since most immune responses
      against protein and peptide antigens are T-cell dependent, the molecular target
      of such vaccines is to generate at least 50-100 complexes between MHC molecule
      and the antigenic peptide per antigen-presenting cell, sensitizing a T cell
      population of appropriate clonal size and effector characteristics. Thus, the
      immunobiology of antigen recognition by T cells must be taken into account when
      designing new generation peptide- or gene-based vaccines. Since T cell
      recognition is MHC-restricted, and given the wide polymorphism of the different
      MHC molecules, distinct epitopes may be recognized by different individuals in
      the population. Therefore, the issue of whether immunization will be effective in
      inducing a protective immune response, covering the entire target population,
      becomes an important question. Many pathogens have evolved molecular mechanisms
      to escape recognition by the immune system by variation of antigenic protein
      sequences. In this short review, we will discuss the several concepts related to
      selection of amino acid sequences to be included in DNA and peptide vaccines.

PMID- 10347756
TI  - Immunological properties of gene vaccines delivered by different routes.
AB  - Gene vaccines represent a new and promising approach to control infectious
      diseases, inducing a protective immune response in the appropriate host. Several
      routes and methods of genetic immunization have been shown to induce antibody
      production as well as T helper (Th) cell and cytotoxic T lymphocyte activation.
      However, few studies have compared the nature of the immune responses generated
      by different gene vaccination delivery systems. In the present study we reviewed
      some aspects of immunity induced by gene immunization and compared the immune
      responses produced by intramuscular (i.m.) DNA injection to gene gun-mediated DNA
      transfer into the skin of BALB/c mice. Using a reporter gene coding for beta
      galactosidase, we have demonstrated that i.m. injection raised a predominantly
      Th1 response with mostly IgG2a anti-beta gal produced, while gene gun
      immunization induced a mixed Th1/Th2 profile with a balanced production of IgG2a
      and IgG1 subclasses. Distinct types of immune responses were generated by
      different methods of gene delivery. These findings have important implications
      for genetic vaccine design. Firstly, a combination between these two systems may
      create optimal conditions for the induction of a broad-based immune response.
      Alternatively, a particular gene vaccine delivery method might be used according
      to the immune response required for host protection. Here, we describe the
      characteristics of the immune response induced by gene vaccination and the
      properties of DNA involved in this process.

PMID- 10347757
TI  - DNA vaccines for viral diseases.
AB  - DNA plasmids encoding foreign proteins may be used as immunogens by direct
      intramuscular injection alone, or with various adjuvants and excipients, or by
      delivery of DNA-coated gold particles to the epidermis through biolistic
      immunization. Antibody, helper T lymphocyte, and cytotoxic T lymphocyte (CTL)
      responses have been induced in laboratory and domesticated animals by these
      methods. In a number of animal models, immune responses induced by DNA
      vaccination have been shown to be protective against challenge with various
      infectious agents. Immunization by injection of plasmids encoding foreign
      proteins has been used successfully as a research tool. This review summarizes
      the types of DNA vaccine vectors in common use, the immune responses and
      protective responses that have been obtained in animal models, the safety
      considerations pertinent to the evaluation of DNA vaccines in humans and the very
      limited information that is available from early clinical studies.

PMID- 10347758
TI  - New vaccine strategies against enterotoxigenic Escherichia coli. I: DNA vaccines
      against the CFA/I fimbrial adhesin.
AB  - Stimulation of the mammalian immune system by administration of plasmid DNA has
      been shown to be an important approach for vaccine development against several
      pathogens. In the present study we investigated the use of DNA vaccines to induce
      immune responses against an enteric bacterial pathogen, enterotoxigenic
      Escherichia coli (ETEC). Three plasmid vectors encoding colonization factor
      antigen 1 (CFA/I), an ETEC fimbrial adhesin, were constructed. Eukaryotic cells
      transfected with each of these plasmids expressed the heterologous antigen in
      different compartments: bound to the cytoplasmic membrane (pRECFA), accumulated
      in the cytoplasm (pPolyCFA) or secreted to the outside medium (pBLCFA). BALB/c
      mice were intramuscularly (i.m.) inoculated with purified plasmid DNA and the
      systemic, cellular and secreted CFA/I-specific immune responses were analyzed.
      The results showed that all three DNA vaccine formulations could elicit CFA/I
      specific immune responses. Moreover, cellular location of the plasmid-encoded
      CFA/I seems to have an important role in the induced immune response. Taken
      together, these results indicate that DNA vaccines also represent a promising
      approach against enteric bacterial pathogens.

PMID- 10347759
TI  - DNA encoding individual mycobacterial antigens protects mice against
      tuberculosis.
AB  - Over the last few years, some of our experiments in which mycobacterial antigens
      were presented to the immune system as if they were viral antigens have had a
      significant impact on our understanding of protective immunity against
      tuberculosis. They have also markedly enhanced the prospects for new vaccines. We
      now know that individual mycobacterial protein antigens can confer protection
      equal to that from live BCG vaccine in mice. A critical determinant of the
      outcome of immunization appears to be the degree to which antigen-specific
      cytotoxic T cells are generated by the immune response. Our most recent studies
      indicate that DNA vaccination is an effective way to establish long-lasting
      cytotoxic T cell memory and protection against tuberculosis.

PMID- 10347760
TI  - Trans-sialidase delivered as a naked DNA vaccine elicits an immunological
      response similar to a Trypanosoma cruzi infection.
AB  - Trypanosoma cruzi. the protozoan parasite that causes Chagas' disease, does not
      synthesize sialic acid, but expresses a trans-sialidase (TS) that catalyzes the
      transfer of sialic acid from host glycoconjugates to the parasite surface. Here,
      we review studies that characterize the immune response to the catalytic domain
      of the enzyme in humans during Chagas' disease or in mice following immunization
      with the TS gene. In both cases, there are antibodies that strongly inhibit the
      enzymatic activity and generation of interferon-gamma-producing T cells.

PMID- 10347761
TI  - New vaccine strategies against enterotoxigenic Escherichia coli. II: Enhanced
      systemic and secreted antibody responses against the CFA/I fimbriae by priming
      with DNA and boosting with a live recombinant Salmonella vaccine.
AB  - The induction of systemic (IgG) and mucosal (IgA) antibody responses against the
      colonization factor I antigen (CFA/I) of enterotoxigenic Escherichia coli (ETEC)
      was evaluated in mice primed with an intramuscularly delivered CFA/I-encoding DNA
      vaccine followed by two oral immunizations with a live recombinant Salmonella
      typhimurium vaccine strain expressing the ETEC antigen. The booster effect
      induced by the oral immunization was detected two weeks and one year after the
      administration of the DNA vaccine. The DNA-primed/Salmonella-boosted vaccination
      regime showed a synergistic effect on the induced CFA/I-specific systemic and
      secreted antibody levels which could not be attained by either immunization
      strategy alone. These results suggest that the combined use of DNA vaccines and
      recombinant Salmonella vaccine strains can be a useful immunization strategy
      against enteric pathogens.

PMID- 10347762
TI  - Carbon monoxide: from toxin to endogenous modulator of cardiovascular functions.
AB  - Carbon monoxide (CO) is a pollutant commonly recognized for its toxicological
      attributes, including CNS and cardiovascular effects. But CO is also formed
      endogenously in mammalian tissues. Endogenously formed CO normally arises from
      heme degradation in a reaction catalyzed by heme oxygenase. While inhibitors of
      endogenous CO production can raise arterial pressure, heme loading can enhance CO
      production and lead to vasodepression. Both central and peripheral tissues
      possess heme oxygenases and generate CO from heme, but the inability of heme
      substrate to cross the blood brain barrier suggests the CNS heme-heme oxygenase
      CO system may be independent of the periphery. In the CNS, CO apparently acts in
      the nucleus tractus solitarii (NTS) promoting changes in glutamatergic
      neurotransmission and lowering blood pressure. At the periphery, the heme-heme
      oxygenase-CO system can affect cardiovascular functions in a two-fold manner;
      specifically: 1) heme-derived CO generated within vascular smooth muscle (VSM)
      can promote vasodilation, but 2) its actions on the endothelium apparently can
      promote vasoconstriction. Thus, it seems reasonable that the CNS-, VSM- and
      endothelial-dependent actions of the heme-heme oxygenase-CO system may all affect
      cardiac output and vascular resistance, and subsequently blood pressure.

PMID- 10347763
TI  - Metabolic fate of glutamine in lymphocytes, macrophages and neutrophils.
AB  - Eric Newsholme's laboratory was the first to show glutamine utilization by
      lymphocytes and macrophages. Recently, we have found that neutrophils also
      utilize glutamine. This amino acid has been shown to play a role in lymphocyte
      proliferation, cytokine production by lymphocytes and macrophages and
      phagocytosis and superoxide production by macrophages and neutrophils. Knowledge
      of the metabolic fate of glutamine in these cells is important for the
      understanding of the role and function of this amino acid in the maintenance of
      the proliferative, phagocytic and secretory capacities of these cells. Glutamine
      and glucose are poorly oxidized by these cells and might produce important
      precursors for DNA, RNA, protein and lipid synthesis. The high rate of glutamine
      utilization and its importance in such cells have raised the question as to the
      source of this glutamine, which, according to current evidence, appears to be
      muscle.

PMID- 10347765
TI  - Expression of the Mycobacterium bovis P36 gene in Mycobacterium smegmatis and the
      baculovirus/insect cell system.
AB  - In the present study we evaluated different systems for the expression of
      mycobacterial antigen P36 secreted by Mycobacterium bovis. P36 was detected by
      Western blot using a specific antiserum. The P36 gene was initially expressed in
      E. coli, under the control of the T7 promoter, but severe proteolysis prevented
      its purification. We then tried to express P36 in M. smegmatis and insect cells.
      For M. smegmatis, we used three different plasmid vectors differing in copy
      number and in the presence of a promoter for expression of heterologous proteins.
      P36 was detected in the cell extract and culture supernatant in both expression
      systems and was recognized by sera from M. bovis-infected cattle. To compare the
      expression level and compartmentalization, the MPB70 antigen was also expressed.
      The highest production was reached in insect cell supernatants. In conclusion, M.
      smegmatis and especially the baculovirus expression system are good choices for
      the production of proteins from pathogenic mycobacteria for the development of
      mycobacterial vaccines and diagnostic reagents.

PMID- 10347764
TI  - Effect of dimethylsulfoxide on sphingomyelinase activity and cholesterol
      metabolism in Niemann-Pick type C fibroblasts.
AB  - Niemann-Pick type C (NPC) fibroblasts present a large concentration of
      cholesterol in their cytoplasm due to a still unidentified deficiency in
      cholesterol metabolism. The influence of dimethylsulfoxide (DMSO) on the amount
      of intracellular cholesterol was measured in 8 cultures of normal fibroblasts and
      in 7 fibroblast cultures from NPC patients. DMSO was added to the fibroblast
      cultures at three different concentrations (1, 2 and 4%, v/v) and the cultures
      were incubated for 24 h. Sphingomyelinase activity was significantly increased in
      both groups of cells only when incubated with 2% DMSO (59.4 +/- 9.1 and 77.0 +/-
      9.1 nmol h-1 mg protein-1, controls without and with 2% DMSO, respectively: 47.7
      +/- 5.2 and 55.8 +/- 4.1 nmol h-1 mg protein-1. NPC without and with 2% DMSO,
      respectively). However, none of the DMSO concentrations used altered the amount
      of cholesterol in the cytoplasm of NPC cells (0.704 +/- 0.049, 0.659 +/- 0.041,
      0.688 +/- 0.063 and 0.733 +/- 0.088 mg/mg protein, without DMSO, 1% DMSO, 2% DMSO
      and 4% DMSO, respectively). This finding suggests that sphingomyelinase
      deficiency is a secondary defect in NPC and shows that DMSO failed to remove the
      stored cholesterol. These data do not support the use of DMSO in the treatment of
      NPC patients.

PMID- 10347766
TI  - Modulation of staphylokinase-dependent plasminogen activation by mono- and
      divalent ions.
AB  - The effect of several ions (Cl-, Na+, K+, Ca2+) on the rate of plasminogen (Pg)
      activation by recombinant staphylokinase (rSTA) is reported. Both monovalent and
      divalent ions affect the rate at which Pg is activated by rSTA, in a
      concentration-dependent manner (range 0-100 mM). In almost all cases, a decrease
      of the initial velocity of activation was observed. Cl- showed the most striking
      inhibitory effect at low concentrations (64% at 10 mM). However, in the presence
      of a fibrin surface, this inhibition was attenuated to 38%. Surprisingly, 10 mM
      Ca2+ enhanced the Pg activation rate 21% when a polymerized fibrin matrix was
      present. These data support the idea that ions can modulate the rate of Pg
      activation through a mechanism that may be associated with changes in the
      molecular conformation of the zymogen. This effect is strongly dependent on the
      presence of a fibrin clot.

PMID- 10347767
TI  - A polymerase chain reaction-based assay to identify genotype F of hepatitis B
      virus.
AB  - We have developed a polymerase chain reaction (PCR) assay which distinguishes
      genotype F from the other genotypes of hepatitis B virus (HBV). The method was
      used to characterize HBV strains isolated in urban areas of the Brazilian Amazon.
      DNA was amplified in 54 of a total of 78 HBsAg-positive serum samples, using
      universal, non-genotype-specific primers. Only 4 (7.4%) were identified as
      genotype F by our genotype-specific PCR assay. This proportion is notably lower
      than that previously reported in Argentina, Venezuela, Peru, and Central America.

PMID- 10347768
TI  - A liver metalloendopeptidase which degrades the circulating hypotensive peptide
      hormones bradykinin and atrial natriuretic peptide.
AB  - A new metalloendopeptidase was purified to apparent homogeneity from a homogenate
      of normal human liver using successive steps of chromatography on DEAE-cellulose,
      hydroxyapatite and Sephacryl S-200. The purified enzyme hydrolyzed the Pro7-Phe8
      bond of bradykinin and the Ser25-Tyr26 bond of atrial natriuretic peptide. No
      cleavage was produced in other peptide hormones such as vasopressin, oxytocin or
      Met- and Leu-enkephalin. This enzyme activity was inhibited by 1 mM divalent
      cation chelators such as EDTA, EGTA and o-phenanthroline and was insensitive to 1
      microM phosphoramidon and captopril, specific inhibitors of neutral endopeptidase
      (EC 3.4.24.11) and angiotensin-converting enzyme (EC 3.4.15.1), respectively.
      With M(r) 85 kDa the enzyme exhibits optimal activity at pH 7.5. The high
      affinity of this endopeptidase for bradykinin (Km = 10 microM) and for atrial
      natriuretic peptide (Km = 5 microM) suggests that it may play a physiological
      role in the inactivation of these circulating hypotensive peptide hormones.

PMID- 10347769
TI  - Detection of point mutations by non-isotopic single strand conformation
      polymorphism.
AB  - We have developed a procedure for nonradioactive single strand conformation
      polymorphism analysis and applied it to the detection of point mutations in the
      human tumor suppressor gene p53. The protocol does not require any particular
      facilities or equipment, such as radioactive handling, large gel units for
      sequencing, or a semiautomated electrophoresis system. This technique consists of
      amplification of DNA fragments by PCR with specific oligonucleotide primers,
      denaturation, and electrophoresis on small neutral polyacrylamide gels, followed
      by silver staining. The sensitivity of this procedure is comparable to other
      described techniques and the method is easy to perform and applicable to a
      variety of tissue specimens.

PMID- 10347770
TI  - Peritoneal fluid modulates the sperm acrosomal exocytosis induced by N
      acetylglucosaminyl neoglycoprotein.
AB  - The effect of peritoneal fluid (PF) on the human sperm acrosome reaction (AR) was
      tested. Sperm was pre-incubated with PF and the AR was induced by calcium
      ionophore A23187 and a neoglycoprotein bearing N-acetylglycosamine residues
      (NGP). The AR induced by calcium ionophore was inhibited 40% by PF from controls
      (PFc) and 50% by PF from the endometriosis (PFe) group, but not by PF from
      infertile patients without endometriosis (PFi). No significant differences were
      found in the spontaneous AR. When the AR was induced by NGP, pre-incubation with
      PFc reduced (60%) the percentage of AR, while PFe and PFi caused no significant
      differences. The average rates of acrosome reactions obtained in control. NGP-
      and ionophore-treated sperm showed that NGP-induced exocytosis differed
      significantly between the PFc (11%) and PFe/PFi groups (17%), and the ionophore
      induced AR was higher for PFi (33%) than PFc/PFe (25%). The incidence of the NGP
      induced AR was reduced in the first hour of pre-incubation with PFc and remained
      nearly constant throughout 4 h of incubation. The present data indicate that PF
      possesses a protective factor which prevents premature AR.

PMID- 10347771
TI  - Specific insulin and proinsulin in normal glucose tolerant first-degree relatives
      of NIDDM patients.
AB  - In order to identify early abnormalities in non-insulin-dependent diabetes
      mellitus (NIDDM) we determined insulin (using an assay that does not cross-react
      with proinsulin) and proinsulin concentrations. The proinsulin/insulin ratio was
      used as an indicator of abnormal beta-cell function. The ratio of the first 30
      min increase in insulin to glucose concentrations following the oral glucose
      tolerance test (OGTT; I30-0/G30-0) was taken as an indicator of insulin
      secretion. Insulin resistance (R) was evaluated by the homeostasis model
      assessment (HOMA) method. True insulin and proinsulin were measured during a 75-g
      OGTT in 35 individuals: 20 with normal glucose tolerance (NGT) and without
      diabetes among their first-degree relatives (FDR) served as controls, and 15 with
      NGT who were FDR of patients with NIDDM. The FDR group presented higher insulin
      (414 pmol/l vs 195 pmol/l; P = 0.04) and proinsulin levels (19.6 pmol/l vs 12.3
      pmol/l; P = 0.03) post-glucose load than the control group. When these groups
      were stratified according to BMI, the obese FDR (N = 8) showed higher fasting and
      post-glucose insulin levels than the obese NGT (N = 9) (fasting: 64.8 pmol/l vs
      7.8 pmol/l: P = 0.04, and 60 min post-glucose: 480.6 pmol/l vs 192 pmol/l: P =
      0.01). Also, values for HOMA (R) were higher in the obese FDR compared to obese
      NGT (2.53 vs 0.30; P = 0.075). These results show that FDR of NIDDM patients have
      true hyperinsulinemia (which is not a consequence of cross-reactivity with
      proinsulin) and hyperproinsulinemia and no dysfunction of a qualitative nature in
      beta-cells.

PMID- 10347772
TI  - Pituitary glycoprotein hormone a-subunit secretion by cirrhotic patients.
AB  - Secretion of the alpha-subunit of pituitary glycoprotein hormones usually follows
      the secretion of intact gonadotropins and is increased in gonadal failure and
      decreased in isolated gonadotropin deficiency. The aim of the present study was
      to determine the levels of the alpha-subunit in the serum of patients with
      cirrhosis of the liver and to compare the results obtained for eugonadal
      cirrhotic patients with those obtained for cirrhotic patients with
      hypogonadotropic hypogonadism. Forty-seven of 63 patients with cirrhosis (74.6%)
      presented hypogonadism (which was central in 45 cases and primary in 2), 7 were
      eugonadal, and 9 women were in normal menopause. The serum alpha-subunit was
      measured by the fluorimetric method using monoclonal antibodies. Cross-reactivity
      with LH, TSH, FSH and hCG was 6.5, 1.2, 4.3 and 1.1%, respectively, with an intra
      assay coefficient of variation (CV) of less than 5% and an interassay CV of 5%,
      and sensitivity limit of 4 ng/l. The serum alpha-subunit concentration ranged
      from 36 to 6253 ng/l, with a median of 273 ng/l. The median was 251 ng/l for
      patients with central hypogonadism and 198 ng/l for eugonadal patients. The
      correlation between the alpha-subunit and basal LH levels was significant both in
      the total sample (r = 0.48, P < 0.01) and in the cirrhotic patients with central
      hypogonadism (r = 0.33, P = 0.02). Among men with central hypogonadism there was
      a negative correlation between alpha-subunit levels and total testosterone levels
      (r = -0.54, P < 0.01) as well as free testosterone levels (r = -0.53, P < 0.01).
      In conclusion, although the alpha-subunit levels are correlated with LH levels,
      at present they cannot be used as markers for hypogonadism in patients with
      cirrhosis of the liver.

PMID- 10347773
TI  - Differential in vitro pathogenicity of predatory fungi of the genus
      Monacrosporium for phytonematodes, free-living nematodes and parasitic nematodes
      of cattle.
AB  - In vitro tests were carried out on the pathogenicity of nine isolates of the
      predatory fungi of the genus Monacrosporium (5 M. sinense isolates, 3 M.
      appendiculatum and 1 M. thaumasium isolate) for a phytonematode (second stage
      juveniles from Meloidogyne incognita, race 3), a free-living nematode
      (Panagrellus spp), and two gastrointestinal parasitic nematodes of cattle
      (infective larvae of Cooperia punctata and Haemonchus placei). A suspension
      containing 2,000 nematodes from each species was added to Petri dishes containing
      fungi and grown on 2% water-agar medium at 25 degrees C in the dark for up to 7
      days. The dishes were examined every other day for 7 days and predation-free
      nematodes were counted. The results showed that the free-living nematodes,
      Panagrellus spp. were the most susceptible (P < 0.05), followed by the
      phytonematode M. incognita, while the controls were > or = 98.5% viable. However,
      a variable susceptibility of the nematodes to different fungi was observed. This
      indicates that the use of predatory fungi for the environmental control of
      nematodes will be limited by the multiplicity of nematodes in the environment and
      their differential susceptibility to fungal isolates of the same genus.

PMID- 10347774
TI  - The carotid body of the spontaneous insulin-dependent diabetic rat.
AB  - The carotid bodies from adult spontaneous insulin-dependent diabetic rats (strain
      BB/S) were perfusion-fixed at normal arterial blood pressure with 3% phosphate
      buffered glutaraldehyde and compared with the organs from control rats (strain
      BB/Sc) prepared in the same way. Serial 5-micron sections were cut, stained, and
      using an interactive image analysis system, were analysed to determine the
      volumes of the carotid body and its vascular and extravascular compartments.
      There was no evidence of systemic arterial disease in the carotid stem arteries
      in either group of animals, and the microvasculature of the organs appeared
      normal by light microscopy. The volume of the carotid body was unchanged 3 months
      after the onset of diabetes but was increased at 6 months. The total vascular
      volume of the organ was unchanged, but the volume of the small vessels (5-12
      microns) was increased. In the control group the small vessels comprised 5% of
      the total volume of the carotid body, or about 44% of the vascular compartment.
      The percentage of small vessels increased at 3 months in the diabetic group, but
      had returned to normal at 6 months. The extravascular volume followed the same
      pattern as the total carotid body volume and so did not change appreciably when
      expressed as a percentage of the total volume of the organ. The increase in size
      of the carotid body in diabetic rats is due, therefore, to an augmented
      extravascular volume. In one diabetic specimen the carotid sinus nerve showed
      signs of diabetic neuropathy, axonal swelling and intramyelinic oedema. The
      clinical implications of these results are discussed.

PMID- 10347775
TI  - Postnatal development of rats exposed to fluoxetine or venlafaxine during the
      third week of pregnancy.
AB  - The aim of the present study was to compare the toxic effects of fluoxetine (F)
      (8 and 16 mg/kg) and venlafaxine (V) (40 and 80 mg/kg) administered during the
      third week of pregnancy on early development of rats. Both antidepressants were
      administered by gavage on pregnancy days 15 to 20 to groups of 10 to 12 animals
      each. Duration of gestation, food and water consumtion, number of live pups and
      birth weight were recorded. Litters were culled to six pups at birth (day 1) and
      followed for growth until weaning (day 25). On day 60, a male and a female from
      each litter were injected with the 5-HT1 agonist, 5-methoxy-N,N
      dimethyltryptamine (6 mg/kg, i.p.) and the serotonergic syndrome was graded.
      Fluoxetine but not venlafaxine reduced the duration of pregnancy when compared to
      the control (C) group (F = 21.1 days and C = 21.6 days, mean, P < 0.02: maximum =
      22 days and minimum = 21 days in both groups). The highest doses of both
      fluoxetine, 16 mg/kg (F16), and venlafaxine, 80 mg/kg (V80), reduced the food
      intake of pregnant rats, resulting in different rates of body weight gain during
      treatment (from pregnancy day 15 to day 20): F16 = 29.0 g, V80 = 28.7 g vs C =
      39.5 g (median). Birth weight was influenced by treatment and sex (P < 0.05; two
      way ANOVA). Both doses of fluoxetine or venlafaxine reduced the body weight of
      litters; however, the body weight of litters from treated dams was equal to the
      weight of control litters by the time of weaning. At weaning there was no
      significant difference in weight between sexes. There was no difference among
      groups in number of live pups at birth, stillbirths, mortality during the
      lactation period or in the manifestation of serotonergic syndrome in adult rats.
      The occurrence of low birth weight among pups born to dams which did not show
      reduced food ingestion or reduction of body weight gain during treatment with
      lower doses of fluoxetine or venlafaxine suggests that these drugs may have a
      deleterious effect on prenatal development when administered during pregnancy. In
      addition, fluoxetine slightly but significantly affected the duration of
      pregnancy (about half a day), an effect not observed in the venlafaxine treated
      groups.

PMID- 10347776
TI  - Behavioral profiles displayed by rats in an elevated asymmetric plus-maze:
      effects of diazepam.
AB  - When rats are exposed to unknown environments where novelty and fear-inducing
      characteristics are present (conflictive environments), some specific behaviors
      are induced and exploration is apparently modulated by fear. In our laboratory, a
      new type of plus-maze was designed as a model of conflictive exploration. The
      maze is composed of four arms with different geometrical characteristics,
      differing from each other by the presence or absence of walls. The degree of
      asymmetry was as follows: NW, no wall arm; SW, a single high wall present; HL, a
      low and a high wall present, and HH, two high walls present. The four arms were
      arranged at 90 degrees angles and the apparatus was called the elevated
      asymmetric plus-maze (APM). The purpose of the present study was to assess the
      behavioral profile of rats exposed for a single time to the APM with or without
      treatment with benzodiazepine. Increasing doses of diazepam were injected
      intraperitoneally in several groups of male, 90-day-old Holtzman rats. Distilled
      water was injected in control animals. Thirty minutes after treatment all rats
      were exposed singly to a 5-min test in the APM. Diazepam induced a biphasic
      modification of exploration in the NW and SW arms. The increase in the
      exploration score was evident at low doses of diazepam (0.25-1.0 mg/kg body
      weight) and the decrease in exploration was found with the higher doses of
      diazepam (2.0-3.0 mg/kg body weight). Non-exploratory behaviors (permanency) were
      not affected by benzodiazepine treatment. In the HL arm, exploration was not
      modified but permanency was increased in a dose-dependent manner. In the HH arm,
      exploration and permanency were not affected. Results are compatible with the
      idea that exploration-processing mechanisms in conflictive environments are
      modulated by fear-processing mechanisms of the brain.

PMID- 10347777
TI  - Effect of thyroparathyroidectomy on urinary acidification in diabetic rats.
AB  - In previous studies we have shown stimulation of renal acid excretion in the
      proximal tubules of rats with diabetes of short duration, with no important
      alterations in glomerular hemodynamics; on the other hand, in
      thyroparathyroidectomized rats (TPTX model), a significant decrease in renal acid
      excretion, glomerular filtration rate (GFR) and renal plasma flow (RPF) was
      detected. Since important changes in the parathyroid hormone-vitamin D-Ca axis
      are observed in the diabetic state, the present study was undertaken to
      investigate the renal repercussions of thyroparathyroidectomy in rats previously
      made diabetic by streptozotocin (45 mg/kg). Four to 6 days after the induction of
      diabetes (DM), a group of rats were thyroparathyroidectomized (DM + TPTX). Renal
      functional parameters were evaluated by measuring the inulin and sodium para
      aminohippurate clearance on the tenth day. The decrease in the GFR and RPF
      observed in TPTX was not reversed by diabetes since the same alterations were
      observed in DM + TPTX. Net acid (NA) excretion was unchanged in DM (6.19 +/-
      0.54), decreased in TPTX (3.76 +/- 0.25) and returned to normal levels in DM +
      TPTX (5.54 +/- 0.72) when compared to the control group (6.34 +/- 0.14 mumol min
      1 kg-1). The results suggest that PTH plays an important vasodilator role
      regarding glomerular hemodynamics, since in its absence the impairment in GFR and
      RPF was not reversed by the diabetic state. However, with respect to acid
      excretion, the presence of diabetes was able to overcome the negative stimulus
      represented by TPTX.

PMID- 10347778
TI  - Evaluation of electromyographic activity and heart rate responses to isometric
      exercise. The role played by muscular mass and type.
AB  - The purpose of the present study was to examine the relationship between the
      electromyographic (EMG) activity and heart rate (HR) responses induced by
      isometric exercise performed by knee extension (KE) and flexion (KF) in men.
      Fifteen healthy male subjects, 21 +/- 1.3 years (mean +/- SD), were submitted to
      KE and KF isometric exercise tests at 100% of maximal voluntary contraction
      (MVC). The exercises were performed with one leg (right or left) and with two
      legs simultaneously, for 10 s in the sitting position with the hip and knee
      flexed at 90 degrees. EMG activity (root mean square values) and HR (beats/min)
      were recorded simultaneously both at rest and throughout the sustained
      contraction. The HR responses to isometric exercise in KE and KF were similar
      when performed with one and two legs. However, the HR increase was always
      significantly higher in KE than KF (P < 0.05), whereas the EMG activity was
      higher in KE than in KF (P < 0.05), regardless of the muscle mass (one or two
      legs) involved in the effort. The correlation coefficients between HR response
      and the EMG activity during KE (r = 0.33, P > 0.05) and KF (r = 0.15, P > 0.05)
      contractions were not significant. These results suggest that the predominant
      mechanism responsible for the larger increase in HR response to KE as compared to
      KF in our study could be dependent on qualitative and quantitative differences in
      the fiber type composition found in each muscle group. This mechanism seems to
      demand a higher activation of motor units with a corresponding increase in
      central command to the cardiovascular centers that modulate HR control.

PMID- 10347779
TI  - Staircase in mammalian muscle without light chain phosphorylation.
AB  - In disuse atrophied skeletal muscle, the staircase response is virtually absent
      and light chain phosphorylation does not occur. The purpose of the present study
      was to determine if staircase could be restored in atrophied muscle with
      continued absence of myosin light chain phosphorylation, by reducing what appears
      to be an otherwise enhanced calcium release. Control (untreated) and sham
      operated female Sprague-Dawley rats were compared with animals after 2 weeks of
      complete inactivity induced by tetrodotoxin (TTX) application to the left sciatic
      nerve. In situ isometric contractile responses of rat gastrocnemius muscle were
      analyzed before and after administration of dantrolene sodium (DS), a drug which
      is known to inhibit Ca2+ release in skeletal muscle. Twitch active force (AF) was
      attenuated by DS from 2.2 +/- 0.2 N, 2.7 +/- 0.1 N and 2.4 +/- 0.2 N to 0.77 +/-
      0.2 N, 1.05 +/- 0.1 N and 1.01 +/- 0.2 N in TTX (N = 5), sham (N = 11) and
      control (N = 7) muscles, respectively. Following dantrolene treatment, 10 s of 10
      Hz stimulation increased AF to 1.32 +/- 0.2 N, 1.52 +/- 0.1 N and 1.45 +/- 0.2 N
      for the TTX, sham and control groups, respectively, demonstrating a positive
      staircase response. Regulatory light chain (R-LC) phosphorylation was lower for
      TTX-treated (5.5 +/- 5.5%) than for control (26.1 +/- 5.3%) and sham (20.0 +/-
      5%) groups. There was no significant change from resting levels for any of the
      groups after DS treatment (P = 0.88). This study shows that treatment with
      dantrolene permits staircase in atrophied muscle as well as control muscle, by a
      mechanism which appears to be independent of R-LC phosphorylation.

PMID- 10347780
TI  - Cyanobacterial toxins in Portugal: effects on aquatic animals and risk for human
      health.
AB  - Toxic cyanobacteria are common in Portuguese freshwaters and the most common
      toxins are microcystins. The occurrence of microcystin-LR (MCYST-LR) has been
      reported since 1990 and a significant number of water reservoirs that are used
      for drinking water attain high levels of this toxin. Aquatic animals that live in
      eutrophic freshwater ecosystems may be killed by microcystins but in many cases
      the toxicity is sublethal and so the animals can survive long enough to
      accumulate the toxins and transfer them along the food chain. Among these, edible
      mollusks, fish and crayfish are especially important because they are harvested
      and sold for human consumption. Mussels that live in estuarine waters and rivers
      where toxic blooms occur may accumulate toxins without many significant acute
      toxic effects. In this study data are presented in order to understand the
      dynamics of the accumulation and depuration of MCYST-LR in mussels. The toxin is
      readily accumulated and persists in the shellfish for several days after contact.
      In the crayfish the toxin is accumulated mainly in the gut but is also cleared
      very slowly. In carps, although the levels of the toxins found in naturally
      caught specimens were not very high, some toxin was found in the muscle and not
      only in the viscera. This raises the problem of the toxin accumulation by fish
      and possible transfer through the food chain. The data gathered from these
      experiments and from naturally caught specimens are analyzed in terms of risk for
      human consumption. The occurrence of microcystins in tap water and the incidence
      of toxic cyanobacteria in fresh water beaches in Portugal are reported. The
      Portuguese National Monitoring Program of cyanobacteria is mentioned and its
      implications are discussed.

PMID- 10347781
TI  - The photodynamic and non-photodynamic actions of porphyrins.
AB  - Porphyrias are a family of inherited diseases, each associated with a partial
      defect in one of the enzymes of the heme biosynthetic pathway. In six of the
      eight porphyrias described, the main clinical manifestation is skin
      photosensitivity brought about by the action of light on porphyrins, which are
      deposited in the upper epidermal layer of the skin. Porphyrins absorb light
      energy intensively in the UV region, and to a lesser extent in the long visible
      bands, resulting in transitions to excited electronic states. The excited
      porphyrin may react directly with biological structures (type I reactions) or
      with molecular oxygen, generating excited singlet oxygen (type II reactions).
      Besides this well-known photodynamic action of porphyrins, a novel light
      independent effect of porphyrins has been described. Irradiation of enzymes in
      the presence of porphyrins mainly induces type I reactions, although type II
      reactions could also occur, further increasing the direct non-photodynamic effect
      of porphyrins on proteins and macro-molecules. Conformational changes of protein
      structure are induced by porphyrins in the dark or under UV light, resulting in
      reduced enzyme activity and increased proteolytic susceptibility. The effect of
      porphyrins depends not only on their physico-chemical properties but also on the
      specific site on the protein on which they act. Porphyrin action alters the
      functionality of the enzymes of the heme biosynthetic pathway exacerbating the
      metabolic deficiencies in porphyrias. Light energy absorption by porphyrins
      results in the generation of oxygen reactive species, overcoming the protective
      cellular mechanisms and leading to molecular, cell and tissue damage, thus
      amplifying the porphyric picture.

PMID- 10347782
TI  - Characterization of six rat strains (Rattus norvegicus) by mitochondrial DNA
      restriction fragment length polymorphism.
AB  - Restriction fragment length polymorphism (RFLP) was used to examine the extent of
      mtDNA polymorphism among six strains of rats (Rattus norvegicus)--Wistar, Wistar
      Munich, Brown Norway, Wistar Kyoto, SHR and SHR-SP. A survey of 26 restriction
      enzymes has revealed a low level of genetic divergence among strains. The sites
      of cleavage by EcoRI, NcoI and XmnI were shown to be polymorphic. The use of
      these three enzymes allows the 6 strains to be classified into 4 haplotypes and
      identifies specific markers for each one. The percentage of sequence divergence
      among all pairs of haplotypes ranged from 0.035 to 0.33%, which is the result of
      a severe population constriction undergone by the strains. These haplotypes are
      easily demonstrable and therefore RFLP analysis can be employed for genetic
      monitoring of rats within animal facilities or among different laboratories.

PMID- 10347783
TI  - Sex-dependent differences in the activities of acetylsalicylic acid-esterases in
      mouse kidneys.
AB  - Acetylsalicylic acid (ASA), the most used drug worldwide, is hydrolyzed to
      salicylic acid and acetate by esterases present in tissues of several species
      including humans. Sex differences in drug metabolism by rodent liver are
      documented in the literature. In this paper we report a difference in the
      activities of the esterases (ASA-esterase I and II) in the kidneys of male and
      female mice. In this species there is no difference between males and females in
      liver ASA-esterases (ASA-esterase I: males 38.5 +/- 7.9 (N = 5) and females 31.6
      +/- 7.6 (N = 5) nmol of salicylic acid formed min-1 mg protein-1, P > 0.05; ASA
      esterase II: males 77.3 +/- 17.4 (N = 5) and females 61.4 +/- 15.1 (N = 5) nmol
      of salicylic acid formed min-1 mg protein-1, P > 0.05). However, in the kidneys
      males presented a much higher enzyme activity than females (ASA-esterase I: males
      25.2 +/- 6.3 (N = 5) and females 6.8 +/- 0.6 (N = 5) nmol of salicylic acid
      formed min-1 mg protein-1, P < 0.0002; ASA-esterase II: males 79.8 +/- 10.1 (N =
      5) and females 13.0 +/- 1.1 (N = 5) nmol of salicylic acid formed min-1 mg
      protein-1, P < 0.0001). The difference between sexes observed in mouse kidneys
      could serve as a model to study the molecular basis of this sex difference and
      also to determine the possible involvement of pituitary and gonadal hormones in
      this difference in ASA-esterase activities since these hormones control the sex
      differences in rodent liver enzyme activity.

PMID- 10347784
TI  - Distribution of HCV genotypes among different exposure categories in Brazil.
AB  - Hepatitis C virus (HCV) infection is widespread and responsible for more than 60%
      of chronic hepatitis cases. HCV presents a genetic variability which has led to
      viral classification into at least 6 genotypes and a series of subtypes. These
      variants present characteristic geographical distribution, but their association
      with different responses to treatment with interferon and severity of disease
      still remains controversial. The aim of this study was to investigate the
      patterns of distribution of HCV genotypes among different exposure categories in
      Brazil. Two hundred and fifty anti-HCV positive samples were submitted to HCV-RNA
      detection by RT-PCR and their genotype was determined by restriction fragment
      length polymorphism (RFLP) analysis. In addition, the genotype/subtype of 60
      samples was also determined by a reverse hybridization assay. HCV 1 was the most
      prevalent (72.0%), followed by type 3 (25.3%), HCV 2 (2.0%) and HCV 4 (0.7%). The
      HCV genotype distribution varied among the different exposure categories, with
      HCV 1 being more frequent among blood donors, hemophiliacs and hemodialysis
      patients. A high frequency of HCV 3 was observed in cirrhotic patients, blood
      donors from the South of Brazil and injecting drug users (IDUs). The general
      distribution of the HCV genotype in Brazil is similar to that in other regions of
      the world.

PMID- 10347785
TI  - Analysis of p53 expression and proliferative assessment using PCNA in localized
      prostate carcinoma.
AB  - The surgical specimens from 51 men submitted to radical prostatectomy for
      localized prostate cancer were examined by immunohistochemistry using
      proliferation cell nuclear antigen (PCNA) monoclonal antibody to evaluate the
      proliferative index (PI). The relationship between PI, biological variables and
      p53 protein expression was evaluated by immunohistochemistry. PI was low in
      invasive localized prostate carcinoma (mean, 12.4%) and the incidence of PCNA
      positive cells was significantly higher in tumors with p53 expression (P =
      0.0226). There was no statistical difference in PCNA values when biological
      parameters such as Gleason score, tumor volume, extraprostatic involvement,
      seminal vesicle infiltration or lymph node metastasis were considered. We
      conclude that proliferative activity is usually low in prostate carcinoma but is
      correlated with p53 immune staining, indicating that p53 is important in cell
      cycle control in this neoplasm.

PMID- 10347786
TI  - Dialysis, time and death: comparisons of two consecutive decades among patients
      treated at the same Brazilian dialysis center.
AB  - The survival of hemodialysis patients is likely to be influenced not only by well
      known risk factors like age and comorbidity, but also by changes in dialysis
      technology and practices accumulated along time. We compared the survival curves,
      dialysis routines and some risk factors of two groups of patients admitted to a
      Brazilian maintenance hemodialysis program during two consecutive decades: March
      1977 to December 1986 (group 1, N = 162) and January 1987 to June 1997 (group 2,
      N = 237). The median treatment time was 22 months (range 1-198). Survival curves
      were constructed using the Kaplan-Meier method and compared using the log-rank
      method. The Cox proportional hazard regression model was used to investigate the
      more important variables associated with outcome. The most important changes in
      dialysis routine and in patient care during the total period of observation were
      the progressive increase in the dose of dialysis delivered, the prohibition of
      potassium-free dialysate, the use of bicarbonate as a buffer and the upgrading of
      the dialysis equipment. There were no significant differences between the
      survival curves of the two groups. Survival rates at 1, 5 and 10 years were 84,
      53 and 29%, respectively, for group 1 and 77, 42 and 21% for group 2. Patients in
      group 1 were younger (45.5 +/- 15.2 vs 52.2 +/- 15.9 years, P < 0.001) and had a
      lower prevalence of diabetes (11.1 vs 27.4%, P < 0.001) and of cardiovascular
      disease (9.3 vs 20.7%, P < 0.001). According to the Cox multivariate model, only
      age (hazard ratio (HR) 1.04, confidence interval (CI) 1.03-1.05, P < 0.001) and
      diabetes (HR 2.55, CI 1.82-3.58, P < 0.001) were independent predictors of
      mortality for the whole group. Patients of group 2 had a lower prevalence of
      sudden death (19.1 vs 9.7%, P < 0.001). After adjusting for age, diabetes and
      other mortality risk factors, the risk of death was 17% lower in group 2,
      although this difference was not statistically significant. We conclude that the
      negative effects of advanced age and of higher frequency of comorbidity on the
      survival of group 2 patients were probably offset by improvements in patient care
      and in the quality and dose of dialysis delivered, so that the survival curves
      did not undergo significant changes along time.

PMID- 10347787
TI  - Electrocardiographic changes during low-dose, short-term therapy of cutaneous
      leishmaniasis with the pentavalent antimonial meglumine.
AB  - The pentavalent antimonial (Sb5+) meglumine is the drug of choice for the
      treatment of cutaneous leishmaniasis (CL) in Brazil. Although the cardiotoxicity
      of high-dose, long-term Sb5+ therapy is well known, the use of low-dose, short
      term meglumine has been considered to be safe and relatively free from
      significant cardiac effects. In order to investigate the cardiotoxicity of low
      dose, short-term therapy with meglumine in cutaneous leishmaniasis, 62 CL
      patients treated with meglumine were studied. A standard ECG was obtained before
      and immediately after the first cycle of treatment (15 mg Sb5+ kg-1 day-1). The
      electrocardiographic interpretation was carried out blindly by two investigators
      using the Minnesota Code. There were no significant differences in qualitative
      ECG variables before and after meglumine treatment. However, the corrected QT
      interval was clearly prolonged after antimonial therapy (420.0 vs 429.3 ms, P <
      10(-6)). QTc augmentation exceeded 40 ms in 12 patients, 7 of whom developed
      marked QTc interval enlargement (500 ms) after meglumine therapy. This previously
      unrecognized cardiac toxicity induced by short-term, low-dose antimonial therapy
      has potentially important clinical implications. Since sudden death has been
      related to QTc prolongation over 500 ms induced by high-dose antimonial therapy,
      routine electrocardiographic monitoring is probably indicated even in CL patients
      treated with short-term, low-dose meglumine schedules. Until further studies are
      conducted to establish the interactions between pentavalent antimonials and other
      drugs, special care is recommended when using meglumine in combination with other
      medications, in particular with drugs that also increase the QTc interval.

PMID- 10347788
TI  - Lack of a relationship between serum ferritin levels and coronary atherosclerosis
      evaluated by coronary arteriography.
AB  - Many clinical and epidemiological studies have demonstrated the relationship
      between serum ferritin and ischemic heart disease. In the present study we
      evaluated the relationship between coronary heart disease (CHD) and serum
      ferritin levels in patients submitted to coronary arteriography. We evaluated 307
      patients (210 (68.7%) males; median age: 60 years) who were submitted to coronary
      angiography, measurement of serum ferritin and identification of clinical events
      of ischemic heart disease. Serum ferritin is reported as quartiles. Ninety-six
      patients (31.27%) had normal coronary angiography (group 1) and 211 (68.73%) had
      coronary heart disease (group 2). Of the patients with CHD, 61 (28.9%) had serum
      ferritin levels higher than 194 ng/ml (4th quartile), as opposed to only 14
      (14.58%) of those without CHD (P = 0.0067). In the 2nd quartile, 39 patients
      (18.48%) had CHD, while 35 patients (36.46%) had normal coronary arteries (P =
      0.00064). Multivariate analysis of the data showed that the difference between
      groups was not statistically significant (P = 0.33). We conclude that there is no
      independent relationship between coronary heart disease and increased levels of
      serum ferritin.

PMID- 10347789
TI  - The influence of septal lesions on sodium and water retention induced by Walker
      256 tumor.
AB  - In the course of studies on the effects of septal area lesions on
      neuroimmunomodulation and Walker 256 tumor development, it was observed that
      tumor-induced sodium and water retention was less marked in lesioned than in non
      lesioned rats. In the present study possible mechanisms involved in this
      phenomenon were investigated. The experiments were performed in septal-lesioned
      (LW; N = 15) and sham-operated (SW; N = 7) 8-week-old male Wistar rats, which
      received multifocal simultaneous subcutaneous (sc) inoculations of Walker 256
      tumor cells about 30 days after the stereotaxic surgery. Control groups (no
      tumor, sham-operated food-restricted (SFR), N = 7) and lesioned food-restricted
      (LFR, N = 10) were subjected to a feeding pattern similar to that observed in
      tumor-bearing animals. Multifocal inoculation of Walker 256 tumor rapidly induces
      anorexia, which is paradoxically accompanied by an increase in body weight, as a
      result of renal Na+ and fluid retention. These effects of the tumor were also
      seen in LW rats, although the rise in fractional sodium balance during the early
      clinical period was significantly smaller than in SW rats (day 4: SW = 47.6 +/-
      6.4% and LW = 13.8 +/- 5.2%; day 5: SW = 57.5 +/- 3.5% and LW = 25.7 +/- 4.8%;
      day 6: SW = 54.4 +/- 3.8% and LW = 32.1 +/- 4.4%; P < 0.05), suggesting a
      temporary reduction in tumor-induced sodium retention. In contrast, urine output
      was significantly reduced in SW rats and increased in LW rats (LW up to -0.85 and
      SW up to 4.5 ml/100 g body weight), with no change in osmolar excretion. These
      temporary changes in the tumor's effects on LW rats may reflect a "reversal" of
      the secondary central antidiuretic response induced by the tumor (from
      antidiuretic to diuretic).

PMID- 10347790
TI  - A laboratory cage for foster nursing newborn mice.
AB  - We describe a cage to be used for foster nursing in order to guarantee that
      original mother's colostrum is not ingested by the newborn mice. A common (30.5
      cm x 19.5 cm x 12.0 cm) mouse cage was fitted with a wire net tray with a mesh (1
      cm x 1 cm), which divides the cage into an upper and a lower compartment. Mice
      born to females placed in the upper compartment pass through the mesh and fall
      into the lower compartment, where another lactating female with one or two of its
      own pups are. Of a total of 28 newborn mice of C3H/Hc and Swiss strains, 23 were
      successfully fostered. Important observations are presented to show that this is
      a valuable alternative for foster studies without great suffering on the part of
      the female.

PMID- 10347791
TI  - The role of natural killer cells in the early period of infection in murine
      cutaneous leishmaniasis.
AB  - In order to study the role of natural killer (NK) cells during the early period
      of Leishmania infection, BALB/c mice were selectively and permanently depleted of
      NK cells by injection with 90Sr and subsequently infected with Leishmania
      (Leishmania) amazonensis (HSJD-1 strain). 90Sr is known to selectively deplete NK
      cells, leaving an intact T- and B-cell compartment and preserving the ability to
      produce both interferon alpha and IL-2. This method of depletion has advantages
      when compared with depletion using anti-NK cell monoclonal antibodies because the
      effect is permanent and neither activates complement nor provokes massive cell
      death. In the present study, after one month of treatment with 90Sr, the
      depletion of NK cells was shown by a more than ten-fold reduction in the
      cytotoxic activity of these cells: 2 x 10(6) spleen cells from NK-depleted
      animals were required to reach the same specific lysis of target cells effected
      by 0.15 x 10(6) spleen cells from normal control animals. The histopathology of
      the skin lesion at 7 days after Leishmania infection showed more parasites in the
      NK cell-depleted group. This observation further strengthens a direct role of NK
      cells during the early period of Leishmania infection.

PMID- 10347793
TI  - Anxiogenic-like effect of acute and chronic fluoxetine on rats tested on the
      elevated plus-maze.
AB  - The selective serotonin reuptake inhibitor fluoxetine (FLX) is widely prescribed
      for depression and anxiety-related disorders. On the other hand, enhanced
      serotonergic transmission is known to be classically related to anxiety. In this
      study, the effects of acute (5.0 mg/kg) and chronic (5.0 mg/kg, 22 days) FLX were
      investigated in both food-deprived and non-deprived rats tested in the elevated
      plus-maze. Significant main effects of the three factors (drug, food condition
      and administration regimen) were observed, but no interaction between them. The
      administration of either acute or chronic FLX resulted in an anxiogenic effect,
      as detected by a significant reduction in the percentage of time spent in the
      open arms and in the percentage of open arm entries. Food deprivation yielded an
      anxiolytic-like profile, probably related to changes in locomotor activity. The
      administration regimen resulted in an anxiolytic profile in chronically treated
      rats, as would be expected after 22 days of regular handling. The anxiogenic
      action of acute FLX is consistent with both its neurochemical and clinical
      profile. The discrepancy between the anxiogenic profile of chronic FLX and its
      therapeutic uses is discussed in terms of possible differences between the type
      of anxiety that is measured in the plus-maze and the types of human anxiety that
      are alleviated by fluoxetine.

PMID- 10347792
TI  - Electron microscopy of glial cells of the central nervous system in the crab
      Ucides cordatus.
AB  - Invertebrate glial cells show a variety of morphologies depending on species and
      location. They have been classified according to relatively general morphological
      or functional criteria and also to their location. The present study was carried
      out to characterize the organization of glial cells and their processes in the
      zona fasciculata and in the protocerebral tract of the crab Ucides cordatus. We
      performed routine and cytochemical procedures for electron microscopy analysis.
      Semithin sections were observed at the light microscope. The Thiery procedure
      indicated the presence of carbohydrates, particularly glycogen, in tissue and in
      cells. To better visualize the axonal ensheathment at the ultrastructural level,
      we employed a method to enhance the unsaturated fatty acids present in membranes.
      Our results showed that there are at least two types of glial cells in these
      nervous structures, a light one and a dark one. Most of the dark cell processes
      have been mentioned in the literature as extracellular matrix, but since they
      presented an enveloping membrane, glycogen and mitochondria--intact and with
      different degrees of disruption--they were considered to be glial cells in the
      present study. We assume that they correspond to the perincurial cells on the
      basis of their location. The light cells must correspond to the periaxonal cells.
      Some characteristics of the axons such as their organization, ensheathment and
      subcellular structures are also described.

PMID- 10347794
TI  - Effect of repeated restraint stress on memory in different tasks.
AB  - The present study investigated the effect of repeated stress applied to female
      rats on memory evaluated by three behavioral tasks: two-way shuttle avoidance,
      inhibitory avoidance and habituation to an open field. Repeated stress had
      different effects on rat behavior when different tasks were considered. In the
      two-way active avoidance test the stressed animals presented memory of the task,
      but their memory scores were impaired when compared to all other groups. In the
      habituation to the open field, only the control group showed a significant
      difference in the number of rearings between training and testing sessions, which
      is interpreted as an adequate memory of the task. In the handled and chronically
      stressed animals, on the other hand, no memory was observed, suggesting that even
      a very mild repeated stress would be enough to alter habituation to this task.
      The performance in the inhibitory avoidance task presented no significant
      differences between groups. The findings suggest that repeated restraint stress
      might induce cognitive impairments that are dependent on the task and on stress
      intensity.

PMID- 10347795
TI  - Increased training prevents the impairing effect of intra-amygdala infusion of
      the non-NMDA receptor antagonist CNQX on inhibitory avoidance expression.
AB  - Intra-amygdala infusion of the non-N-methyl-D-aspartate (NMDA) receptor
      antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) prior to testing impairs
      inhibitory avoidance retention test performance. Increased training attenuates
      the impairing effects of amygdala lesions and intra-amygdala infusions of CNQX.
      The objective of the present study was to determine the effects of additional
      training on the impairing effects of intra-amygdala CNQX on expression of the
      inhibitory avoidance task. Adult female Wistar rats bilaterally implanted with
      cannulae into the border between the central and the basolateral nuclei of the
      amygdala were submitted to a single session or to three training sessions (0.2
      mA, 24-h interval between sessions) in a step-down inhibitory avoidance task. A
      retention test session was held 48 h after the last training. Ten minutes prior
      to the retention test session, the animals received a 0.5-microliter infusion of
      CNQX (0.5 microgram) or its vehicle (25% dimethylsulfoxide in saline). The CNQX
      infusion impaired, but did not block, retention test performance in animals
      submitted to a single training session. Additional training prevented the
      impairing effect of CNQX. The results suggest that amygdaloid non-NMDA receptors
      may not be critical for memory expression in animals given increased training.

PMID- 10347796
TI  - Differential effects of isoproterenol on the activity of angiotensin-converting
      enzyme in the rat heart and aorta.
AB  - The excessive stimulation of beta-adrenergic receptors in the heart induces
      myocardial hypertrophy. There are several experimental data suggesting that this
      hypertrophy may also depend, at least partially, on the increase of local
      production of angiotensin II secondary to the activation of the cardiac renin
      angiotensin system. In this study we investigated the effects of isoproterenol on
      the activity of angiotensin-converting enzyme (ACE) in the heart and also in the
      aorta and plasma. Male Wistar rats weighing 250 to 305 g were treated with a dose
      of (+/-)-isoproterenol (0.3 mg kg-1 day-1, N = 8) sufficient to produce cardiac
      hypertrophy without deleterious effects on the pumping capacity of the heart.
      Control rats (N = 7) were treated with vehicle (corn oil). The animals were
      killed one week later. ACE activity was determined in vitro in the four cardiac
      chambers, aorta and plasma by a fluorimetric assay. A significant hypertrophy was
      observed in both ventricular chambers. ACE activity in the atria remained
      constant after isoproterenol treatment. There was a significant increase (P <
      0.05) of ACE activity in the right ventricle (6.9 +/- 0.9 to 8.2 +/- 0.6 nmol His
      Leu g-1 min-1) and in the left ventricle (6.4 +/- 1.1 to 8.9 +/- 0.8 nmol His-Leu
      g-1 min-1). In the aorta, however, ACE activity decreased (P < 0.01) after
      isoproterenol (41 +/- 3 to 27 +/- 2 nmol His-Leu g-1 min-1) while it remained
      unchanged in the plasma. These data suggest that ACE expression in the heart can
      be increased by stimulation of beta-adrenoceptors. However, this effect is not
      observed on other local renin-angiotensin systems, such as the aorta. Our data
      also suggest that the increased sympathetic discharge and the elevated plasma
      concentration of catecholamines may contribute to the upregulation of ACE
      expression in the heart after myocardial infarction and heart failure.

PMID- 10347797
TI  - Comparison of three methods for the determination of baroreflex sensitivity in
      conscious rats.
AB  - Baroreflex sensitivity was studied in the same group of conscious rats using
      vasoactive drugs (phenylephrine and sodium nitroprusside) administered by three
      different approaches: 1) bolus injection, 2) steady-state (blood pressure (BP)
      changes produced in steps), 3) ramp infusion (30 s, brief infusion). The heart
      rate (HR) responses were evaluated by the mean index (mean ratio of all HR
      changes and mean arterial pressure (MAP) changes), by linear regression and by
      the logistic method (maximum gain of the sigmoid curve by a logistic function).
      The experiments were performed on three consecutive days. Basal MAP and resting
      HR were similar on all days of the study. Bradycardic responses evaluated by the
      mean index (-1.5 +/- 0.2, -2.1 +/- 0.2 and -1.6 +/- 0.2 bpm/mmHg) and linear
      regression (-1.8 +/- 0.3, -1.4 +/- 0.3 and -1.7 +/- 0.2 bpm/mmHg) were similar
      for all three approaches used to change blood pressure. The tachycardic responses
      to decreases of MAP were similar when evaluated by linear regression (-3.9 +/-
      0.8, -2.1 +/- 0.7 and -3.8 +/- 0.4 bpm/mmHg). However, the tachycardic mean index
      (-3.1 +/- 0.4, -6.6 +/- 1 and -3.6 +/- 0.5 bpm/mmHg) was higher when assessed by
      the steady-state method. The average gain evaluated by logistic function (-3.5 +/
      0.6, -7.6 +/- 1.3 and -3.8 +/- 0.4 bpm/mmHg) was similar to the reflex
      tachycardic values, but different from the bradycardic values. Since different
      ways to change BP may alter the afferent baroreceptor function, the MAP changes
      obtained during short periods of time (up to 30 s: bolus and ramp infusion) are
      more appropriate to prevent the acute resetting. Assessment of the baroreflex
      sensitivity by mean index and linear regression permits a separate analysis of
      gain for reflex bradycardia and reflex tachycardia. Although two values of
      baroreflex sensitivity cannot be evaluated by a single symmetric logistic
      function, this method has the advantage of better comparing the baroreflex
      sensitivity of animals with different basal blood pressures.

PMID- 10347798
TI  - Bi-directional actions of estrogen on the renin-angiotensin system.
AB  - Estrogen stimulates the renin-angiotensin system by augmenting both tissue and
      circulating levels of angiotensinogen and renin. We show, however, that
      angiotensin converting enzyme (ACE) activity in the circulation and in tissues is
      reduced in two animal models of postmenopausal chronic hormone replacement. We
      observed a reduction of ACE activity in association with a significant increase
      in plasma angiotensin I (Ang I) and hyperreninemia in ovariectomized monkeys
      treated with Premarin (conjugated equine estrogen) replacement for 30 months.
      Plasma angiotensin II (Ang II) levels were not increased in monkeys treated with
      estrogen, suggesting that the decrease in ACE curtailed the formation of the
      peptide. The Ang II/Ang I ratio, an in vivo index of ACE activity, was
      significantly reduced by estrogen treatment, further supporting the biochemical
      significance of estrogen's inhibition of ACE. In ovariectomized transgenic
      hypertensive (mRen2)27 rats submitted to estrogen replacement treatment for 3
      weeks, ACE activity in plasma and tissue (aorta and kidney) and circulating Ang
      II levels were reduced, whereas circulating levels of angiotensin-(1-7) (Ang-(1
      7)) were increased. Ang-(1-7), the N-terminal fragment of Ang II, is a novel
      vasodilator and antihypertensive peptide. Thus, the net balance of these effects
      of estrogen on the reninangiotensin vasoconstrictor/vasodilator system is to
      promote the anti-hypertensive effect.

PMID- 10347799
TI  - Galectins: a key intersection between glycobiology and immunology.
AB  - Galectins are a family of evolutionarily conserved animal lectins, widely
      distributed from lower invertebrates to mammals. They share sequence and
      structure similarities in the carbohydrate recognition domain and specificity for
      polylactosamine-enriched glycoconjugates. In the last few years significant
      experimental data have been accumulated concerning their participation in
      different biological processes requiring carbohydrate recognition such as cell
      adhesion, cell growth regulation, inflammation, immunomodulation, apoptosis and
      metastasis. In the present review we will discuss some exciting questions and
      advances in galectin research, highlighting the significance of these proteins in
      immunological processes and their implications in biomedical research, disease
      diagnosis and clinical intervention. Designing novel therapeutic strategies based
      on carbohydrate recognition will provide answers for the treatment of autoimmune
      disorders, inflammatory processes, allergic reactions and tumor spreading.

PMID- 10347800
TI  - Apoptosis in parasites and parasite-induced apoptosis in the host immune system:
      a new approach to parasitic diseases.
AB  - Apoptosis, a form of programmed cell death (PCD), has been described as essential
      for normal organogenesis and tissue development, as well as for the proper
      function of cell-renewal systems in adult organisms. Apoptosis is also pivotal in
      the pathogenesis of several different diseases. In this paper we discuss, from
      two different points of view, the role of apoptosis in parasitic diseases. The
      description of apoptotic death in three different species of heteroxenic
      trypanosomatids is reviewed, and considerations on the phylogenesis of apoptosis
      and on the eventual role of PCD on their mechanism of pathogenesis are made. From
      a different perspective, an increasing body of evidence is making clear that
      regulation of host cell apoptosis is an important factor on the definition of a
      host-pathogen interaction. As an example, the molecular mechanisms by which
      Trypanosoma cruzi is able to induce apoptosis in immunocompetent cells, in a
      murine model of Chagas' disease, and the consequences of this phenomenon on the
      outcome of the experimental disease are discussed.

PMID- 10347802
TI  - Inspiratory flow-volume curve in snoring patients with and without obstructive
      sleep apnea.
AB  - We analyzed the flow-volume curves of 50 patients with complaints of snoring and
      daytime sleepiness in treatment at the Pneumology Unit of the University Hospital
      of Brasilia. The total group was divided into snorers without obstructive sleep
      apnea (OSA) (N = 19) and snorers with OSA (N = 31); the patients with OSA were
      subdivided into two groups according to the apnea/hypopnea index (AHI): AHI <
      20/h (N = 14) and AHI > 20/h (N = 17). The control group (N = 10) consisted of
      nonsmoking subjects without complaints of snoring, daytime sleepiness or
      pulmonary diseases. The population studied (control and patients) consisted of
      males of similar age, height and body mass index (BMI); spirometric data were
      also similar in the four groups. There was no significative difference in the
      ratio of forced expiratory and inspiratory flows (FEF50%/FIF50%) in any group:
      control. 0.89; snorers, 1.11; snorers with OSA (AHI < 20/h), 1.42, and snorers
      with OSA (AHI > 20/h), 1.64. The FIF at 50% of vital capacity (FIF50%) of snoring
      patients with or without OSA was lower than the FIF50% of the control group (P <
      0.05): snorers 4.30 l/s; snorers with OSA (AHI < 20/h) 3.69 l/s; snorers with OSA
      (AHI > 20/h) 3.17 l/s and control group 5.48 l/s. The FIF50% of patients with
      severe OSA (AHI > 20/h) was lower than the FIF50% of snorers without OSA (P <
      0.05): 3.17 l/s and 4.30 l/s, respectively. We conclude that 1) the FEF50%/FIF50%
      ratio is not useful for predicting OSA, and 2) FIF50% is decreased in snoring
      patients with and without OSA, suggesting that these patients have increased
      upper airway resistance (UAR).

PMID- 10347801
TI  - Detection and analysis of apoptosis in peripheral blood cells from breast cancer
      patients.
AB  - Apoptosis is a well-known specific process of cell death that normally occurs in
      physiological situations such as tissue or organ development and involution.
      During tumor growth there is a balance between proliferation and cell death which
      involves apoptotic mechanisms. In the present study genomic DNAs from 120 breast
      tumor biopsies were analyzed by agarose gel electrophoresis and none of them
      presented the fragmentation pattern characteristic of the apoptosis process.
      However, 33% of the 105 breast cancer patients clearly showed the apoptotic
      pattern when DNA from blood cells was analyzed. None of the DNAs from healthy
      volunteer blood cells showed any trace of apoptosis. Since the breast cancer
      patients were not receiving chemo- or hormone therapy, the possible relationship
      between blood cortisol levels and the apoptotic pattern found in patient blood
      cells was investigated. Using a chemoluminescence immunodetection assay, similar
      cortisol levels were observed in breast cancer patient sera presenting or not
      apoptotic blood cells and in healthy volunteer sera. Analysis of the clinical
      data obtained from 60 of these patients showed that patients bearing tumors of
      smaller size (under 20 mm) were more susceptible to the apoptotic effect in blood
      cells. According to the Elston grade, it was observed that 7 of 12 patients with
      grade III tumors (58%) presented apoptotic peripheral blood cells, in contrast to
      10 of 48 patients with grade I and grade II tumors. These observations may
      reflect the immunosuppression characteristic of some breast cancer patients,
      which may contribute to tumor growth. Therefore, further studies are necessary to
      elucidate the factor(s) involved in such massive blood cell death.

PMID- 10347803
TI  - Reduced bone mineral density in men after heart transplantation.
AB  - Heart transplantation is associated with rapid bone loss and an increased
      prevalence and incidence of fractures. The aim of the present study was to
      compare the bone mineral density (BMD) of 30 heart transplant (HT) recipients to
      that of 31 chronic heart failure (CHF) patients waiting for transplantation and
      to determine their biochemical markers of bone resorption and hormone levels. The
      BMD of lumbar spine and proximal femur was determined by dual-energy X-ray
      absorptiometry. Anteroposterior and lateral radiographs of the thoracic and
      lumbar spine were also obtained. The mean age of the two groups did not differ
      significantly. Mean time of transplantation was 25.4 +/- 21.1 months (6 to 88
      months). Except for the albumin levels, which were significantly higher, and
      magnesium levels, which were significantly lower in HT patients when compared to
      CHF patients, all other biochemical parameters and hormone levels were within the
      normal range and similar in the two groups. Both groups had lower BMD of the
      spine and proximal femur compared to young healthy adults. However, the mean BMD
      of HT patients was significantly lower than in CHF patients at all sites studied.
      Bone mass did not correlate with time after transplantation or cumulative dose of
      cyclosporine A. There was a negative correlation between BMD and the cumulative
      dose of prednisone. These data suggest that bone loss occurs in HT patients
      mainly due to the use of corticosteroids and that in 30% of the patients it can
      be present before transplantation. It seems that cyclosporine A may also play a
      role in this loss.

PMID- 10347804
TI  - Urinary secretory IgA after nutritional rehabilitation.
AB  - We studied the secretory IgA (sIgA) response of the mucosal urinary tract of
      malnourished children before and after nutritional rehabilitation. sIgA
      concentration (mg/l) was determined by ELISA in 187 children aged 3 months to 5
      years. The children, who frequented a day care center, were divided into four
      groups, according to nutritional status: 57 were eutrophic, 49 were undergrown,
      57 were moderately malnourished and 24 were severely malnourished. In addition,
      dip slide (Urotube, Roche) and dip-stick (Combur 9-Boehringer) tests showed that
      children had no bacteriuria or any other urinary abnormalities. Plasma albumin
      concentration (g/dl) was significantly lower (P < 0.005) in the severely
      malnourished group (mean 3.0 +/- 0.3 SD) than in the eutrophic group (mean 4.0 +/
      0.5 SD). When each nutritional state was analyzed, no significant differences in
      the sIgA were found between the 0 [symbol: see text]1 and 1 [symbol: see text]5
      year age range. In the moderately and severely malnourished groups, sIgA (0.36
      and 0.45, respectively) was significantly lower than in the eutrophic (0.69) and
      undergrown (0.75) groups. Ninety-five children were included in the 8-month
      follow-up study; 30 children were excluded from the follow-up because 4 had
      bacteriuria, 11 had leukocyturia, 8 had proteinuria and 7 had hematuria. Among
      the malnourished children, 40% showed nutritional improvement (P < 0.05) and
      significantly increased sIgA as compared to reference values for the eutrophic
      and undergrown groups. These data suggest that malnourished children have a
      significantly lower urinary sIgA than eutrophic children. After nutritional
      rehabilitation, they develop local immunity with a significant increase in sIgA.

PMID- 10347805
TI  - Specific insulin and proinsulin secretion in glucokinase-deficient individuals.
AB  - Glucokinase (GCK) is an enzyme that regulates insulin secretion, keeping glucose
      levels within a narrow range. Mutations in the glucokinase gene cause a rare form
      of diabetes called maturity-onset diabetes of the young (MODY). An early onset
      (less than 25 years), autosomal dominant inheritance and low insulin secretion
      stimulated by glucose characterize MODY patients. Specific insulin and proinsulin
      were measured in serum by immunofluorimetric assays (IFMA) during a 75-g oral
      glucose tolerance test (OGTT). Two kindreds (SA and LZ) were studied and compared
      to non-diabetic unrelated individuals (control group 1) matched for age and body
      mass index (BMI). In one kindred, some of these subjects were also obese (BMI >
      26 kg/m2), and other family members also presented with obesity and/or late-onset
      NIDDM. The MODY patients were also compared to a group of five of their first
      degree relatives with obesity and/or late-onset NIDDM. The proinsulin profile was
      different in members of the two MODY kindreds. Fasting proinsulin and the
      proinsulin/insulin ratio were similar in MODY members of kindred LZ and subjects
      from control group 1, but were significantly lower than in MODY members of
      kindred SA (P < 0.02 and P < 0.01, for proinsulin and proinsulin/insulin ratio,
      respectively). Moreover, MODY members of family SA had higher levels of
      proinsulin and proinsulin/insulin ratio, although not significantly different,
      when compared to their first-degree relatives and to subjects from control group
      2. In conclusion, we observed variable degrees of proinsulin levels and
      proinsulin/insulin ratio in MODY members of two different kindreds. The higher
      values of these parameters found in MODY and non-MODY members of kindered SA is
      probably related to the obesity and late-onset NIDDM background present in this
      family.

PMID- 10347806
TI  - Effect of toxin-g from Tityus serrulatus scorpion venom on gastric emptying in
      rats.
AB  - The effect of toxin-gamma from Tityus serrulatus scorpion venom on the gastric
      emptying of liquids was studied in 176 young adult male Wistar rats (2-3 months
      of age) divided into subgroups of 8 animals each. Toxin-gamma was injected i.v.
      at doses of 25, 37.5, 50 or 100 micrograms/kg and the effect on gastric emptying
      was assessed 30 min and 8 h later. A time-course study was also performed by
      injecting 50 micrograms of toxin-gamma/kg and measuring the effect on gastric
      emptying at times 0.25, 0.5, 1, 2, 4, 8, 24 and 48 h post-venom. Each envenomed
      animal was paired with its saline control and all received a saline test meal
      solution containing phenol red (60 micrograms/ml) as a marker. Ten minutes after
      administering the test meal by gavage the animals were sacrificed and gastric
      retention was determined by measuring the residual marker concentration of the
      test meal. A significant delay in gastric emptying, at 30 min and 8 h post-venom,
      was observed only after 50 and 100 micrograms of toxin-gamma/kg compared to
      control values. The responses to these two doses were significantly different
      after 8 h post-venom. Toxin-gamma (50 micrograms/kg) significantly delayed the
      gastric emptying of liquids at all times studied, with a peak response at 4 h
      after toxin administration compared to control values. These results indicate
      that the i.v. injection of toxin-gamma may induce a rapid, intense and sustained
      inhibition of gastric emptying 0.25 to 48 h after envenomation.

PMID- 10347807
TI  - Synthesis of fructans by fructosyltransferase from the tuberous roots of Viguiera
      discolor (Asteraceae).
AB  - Sucrose:sucrose fructosyltransferase (SST) and fructan:fructan fructosyl
      transferase (FFT) activities from crude extracts of tuberous roots of Viguiera
      discolor growing in a preserved area of cerrado were analyzed in 1995-1996. SST
      activity was characterized by the synthesis of 1-kestose from sucrose and FFT
      activity by the production of nystose from 1-kestose. The highest fructan
      synthesizing activity was observed during early dormancy (autumn), when both (SST
      and FFT) activities were high. The increase in synthetic activity seemed to start
      during the fruiting phase in the summer, when SST activity was higher than in
      spring. During winter and at the beginning of sprouting, both activities
      declined. The in vitro synthesis of high molecular mass fructans from sucrose by
      enzymatic preparations from tuberous roots collected in summer showed that long
      incubations of up to 288 h produced consistently longer polymers which resembled
      those found in vivo with respect to chromatographic profiles.

PMID- 10347808
TI  - Immunization by subcutaneous implants of polyester-polyurethane sponges coupled
      with antigen.
AB  - A new protocol is described for immunization of outbred Swiss mice. The procedure
      is based on subcutaneous implantation of antigen-coupled polyester-polyurethane
      sponges cut into disks of 10 mm in diameter vs 2 mm in thickness. Antigen
      coupling was performed by overnight incubation of the sponge with a solution of
      ovalbumin (Ova) (2 mg/ml) diluted in sodium carbonate buffer, pH 9.6. The amount
      of ovalbumin that was taken up by the sponge was between 71.4 to 82.5 micrograms.
      This was estimated by comparing the Ova absorbance at 280 nm in coating buffer
      solutions before and after incubation. To compare the efficiency of the proposed
      method, experimental groups immunized with the antigen in the presence of
      adjuvants (10 micrograms in Al(OH)3 or 100 micrograms in complete Freund's
      adjuvant (CFA)) were run in parallel. The data obtained after the 3rd week of
      immunization indicate that both cellular and humoral immune responses were
      achieved. These were assayed by antigen-induced footpad swelling and ELISA
      (specific antibodies), respectively. The levels of both immune responses elicited
      were similar to the responses observed in mice immunized with ovalbumin in the
      presence of Al(OH)3. The method might represent an advantage when immunizing with
      pathogenic antigens. Preliminary experiments have suggested that the antigen
      remains immobilized or bound to the sponge for a long period of time, since there
      is an increment on the cell population inside the sponges after boosting the
      animals. If so, the undesirable effects of immunization would be reduced.

PMID- 10347809
TI  - Reactivity of anti-thyroid antibodies to thyroglobulin tryptic fragments:
      comparison of autoimmune and non-autoimmune thyroid diseases.
AB  - Studies concerning the antigenicity of thyroglobulin fragments allow the
      characterization of the epitopes but do not consider the role of heavier
      antigenic fragments that could result in vivo from the action of endoproteases.
      Here we assess the relative importance of the fragments obtained from
      thyroglobulin by limited proteolysis with trypsin and compare by immunoblotting
      their reactivity to serum from patients with autoimmune (Graves' disease and
      Hashimoto's thyroiditis) and non-autoimmune (subacute thyroiditis) disease. The
      results showed no difference in frequency of recognition of any peptide by sera
      from patients with autoimmune thyroiditis. In contrast, sera from patients with
      subacute thyroiditis reacted more frequently with a peptide of 80 kDa. These
      results suggest the presence of antibody subpopulations directed at fragments
      produced in vivo by enzymatic cleavage of thyroglobulin. This fragment and
      antibodies to it may represent markers for subacute thyroiditis.

PMID- 10347810
TI  - Experimental anxiety and the reinforcing effects of ethanol in rats.
AB  - In order to examine the relationship between anxiety and reinforcing effects of
      alcohol, drug-naive male Wistar rats weighing 250-300 g were classified as
      "anxious" and "non-anxious" in the elevated plusmaze test. A conditioned place
      preference test was then used to investigate the reinforcing effects of ethanol
      (EtOH) on these animals. On 2 alternate days, groups of "anxious", "non-anxious"
      and "normal" rats received intraperitoneal (i.p.) injections of EtOH (0.5, 1.0 or
      1.5 g/kg) immediately before a 15-min confinement to the white compartment. On
      the 2 intervening days the same rats received i.p. injections of saline before
      confinement to the opposite compartment. On day 5, a 15-min free-choice test was
      carried out with no injections. Rats classified as "anxious" showed a
      significant, though not dose-dependent preference for all doses of ethanol
      compared to saline-treated animals. These data demonstrate that rats regarded as
      "anxious" are more sensitive to the reinforcing effects of EtOH than "non
      anxious" and "normal" Wistar rats and emphasize the relevance of the basal levels
      of anxiety of rats when trying to detect the reinforcing effects of EtOH.

PMID- 10347811
TI  - The study of genetic polymorphisms related to serotonin in Alzheimer's disease: a
      new perspective in a heterogenic disorder.
AB  - Genetic and environmental factors have been implicated in the development of
      Alzheimer's disease (AD), the most common form of dementia in the elderly.
      Mutations in 3 genes mapped on chromosomes 21, 14 and 1 are related to the rare
      early onset forms of AD while the epsilon 4 allele of the apolipoprotein E (APOE)
      gene (on chromosome 19) is the major susceptibility locus for the most common
      late onset AD (LOAD). Serotonin (5-hydroxytryptamine or 5-HT) is a key
      neurotransmitter implicated in the control of mood, sleep, appetite and a variety
      of traits and behaviors. Recently, a polymorphism in the transcriptional control
      region upstream of the 5-HT transporter (5-HTT) gene has been studied in several
      psychiatric diseases and personality traits. It has been demonstrated that the
      short variant(s) of this 5-HTT gene-linked polymorphic region (5-HTTLPR) is
      associated with a different transcriptional efficiency of the 5-HTT gene promoter
      resulting in decreased 5-HTT expression and 5-HT uptake in lymphocytes. An
      increased frequency of this 5-HTTLPR short variant polymorphism in LOAD was
      recently reported. In addition, another common polymorphic variation in the 5
      HT2A and 5-HT2C serotonin receptor genes previously analyzed in schizophrenic
      patients was associated with auditory and visual hallucinations in AD. These
      observations suggest that the involvement of the serotonin pathway might provide
      an explanation for some aspects of the affective symptoms commonly observed in AD
      patients. In summary, research on genetic polymorphisms related to AD and
      involved in receptors, transporter proteins and the enzymatic machinery of
      serotonin might enhance our understanding of this devastating neurodegenerative
      disorder.

PMID- 10347812
TI  - Electro-oscillographic correlation between dorsal raphe nucleus, neocortex and
      hippocampus during wakefulness before and after serotoninergic inactivation.
AB  - Theta rhythm in many brain structures characterizes wakefulness and
      desynchronized sleep in most subprimate mammalian brains. In close relation to
      behaviors, theta frequency and voltage undergo a fine modulation which may
      involve mobilization of dorsal raphe nucleus efferent pathways. In the present
      study we analyzed frequency modulation (through instantaneous frequency
      variation) of theta waves occurring in three cortical areas, in hippocampal CA1
      and in the dorsal raphe nucleus of Wistar rats during normal wakefulness and
      after injection of the 5-HT1a receptor agonist 8-OH-DPAT into the dorsal raphe.
      We demonstrated that in attentive states the variation of theta frequency among
      the above structures is highly congruent, whereas after 8-OH-DPAT injection,
      although regular signals are present, the variation is much more complex and
      shows no relation to behaviors. Such functional uncoupling after blockade
      demonstrates the influence of dorsal raphe nucleus efferent serotoninergic fibers
      on the organization of alertness, as evaluated by electro-oscillographic
      analysis.

PMID- 10347813
TI  - Induction of apoptosis in cancer cells by tumor necrosis factor and
      butyrolactone, an inhibitor of cyclin-dependent kinases.
AB  - Induction of apoptosis by tumor necrosis factor (TNF) is modulated by changes in
      the expression and activity of several cell cycle regulatory proteins. We
      examined the effects of TNF (1-100 ng/ml) and butyrolactone I (100 microM), a
      specific inhibitor of cyclin-dependent kinases (CDK) with high selectivity for
      CDK-1 and CDK-2, on three different cancer cell lines: WEHI, L929 and HeLa S3.
      Both compounds blocked cell growth, but only TNF induced the common events of
      apoptosis, i.e., chromatin condensation and ladder pattern of DNA fragmentation
      in these cell lines. The TNF-induced apoptosis events were increased in the
      presence of butyrolactone. In vitro phosphorylation assays for exogenous histone
      H1 and endogenous retinoblastoma protein (pRb) in the total cell lysates showed
      that treatment with both TNF and butyrolactone inhibited the histone H1 kinase
      (WEHI, L929 and HeLa) and pRb kinase (WEHI) activities of CDKs, as compared with
      the controls. The role of proteases in the TNF and butyrolactone-induced
      apoptosis was evaluated by comparing the number and expression of polypeptides in
      the cell lysates by gel electrophoresis. TNF and butyrolactone treatment caused
      the disappearance of several cellular protein bands in the region between 40-200
      kDa, and the 110-90- and 50-kDa proteins were identified as the major substrates,
      whose degradation was remarkably increased by the treatments. Interestingly, the
      loss of several cellular protein bands was associated with the marked
      accumulation of two proteins apparently of 60 and 70 kDa, which may be cleavage
      products of one or more proteins. These findings link the decrease of cyclin
      dependent kinase activities to the increase of protease activities within the
      growth arrest and apoptosis pathways induced by TNF.

PMID- 10347814
TI  - DL-methionine supplementation of rice-and-bean diets affects gamma
      glutamyltranspeptidase activity and glutathione content in livers of growing
      rats.
AB  - Gamma-glutamyltranspeptidase (GGT-EC 2.3.2.2) activity and glutathione (GSH)
      content were measured in livers of female weanling Wistar rats (N = 5-18),
      submitted to rice-and-bean diets (13 and 6% w/w protein), both supplemented or
      not with DL-methionine (0.5 and 0.23 g/100 g dry diet, respectively). After 28
      days, the rats on the rice-and-bean diets showed significantly higher levels
      (four times higher) of liver GGT activity and a concomitant 50% lower
      concentration of liver GSH in comparison with control groups feeding on casein.
      The addition of DL-methionine to rice-and-bean diets significantly increased the
      liver GSH content, which reached levels 50% higher than those found in animals on
      casein diets. The increase in GSH was accompanied by a decrease in liver GGT
      activity, which did not reach levels as low as those observed in the control
      groups. No significant correlation could be established between GGT and GSH
      changes under the present experimental conditions. Linear correlation analysis
      only revealed that in animals submitted to unsupplemented rice-and-bean diets GSH
      concentration was positively associated (P < 0.05) with weight gain, food intake
      and food efficiency. GGT, however, was negatively correlated (P < 0.05) with food
      intake only, and exclusively for supplemented rice-and-bean diets. The high
      levels of GGT activity observed in the present study for rats receiving a rice
      and-bean mixture could be a result of the poor quality of these diets associated
      with their deficiency in sulfur amino acids. The results also suggest that diet
      supplementation with methionine could be important in the reduction of the
      deleterious effects of GSH depletion by restoring the intracellular concentration
      of this tripeptide.

PMID- 10347815
TI  - Axotomy increases NADPH-diaphorase activity in the dorsal root ganglia and lumbar
      spinal cord of the turtle Trachemys dorbigni.
AB  - Seven days after transection of the sciatic nerve NADPH-diaphorase activity
      increased in the small and medium neurons of the dorsal root ganglia of the
      turtle. However, this increase was observed only in medium neurons for up to 90
      days. At this time a bilateral increase of NADPH-diaphorase staining was observed
      in all areas and neuronal types of the dorsal horn, and in positive motoneurons
      in the lumbar spinal cord, ipsilateral to the lesion. A similar increase was also
      demonstrable in spinal glial and endothelial cells. These findings are discussed
      in relation to the role of nitric oxide in hyperalgesia and neuronal regeneration
      or degeneration.

PMID- 10347816
TI  - [Eimeria species (Eucoccidida: Eimeriidae) found in the cotton rat Sigmodon
      hispidus in Costa Rica].
AB  - Cotton rats (Sigmodon hispidus) were collected from Ojo de Agua, Alajuela (N =
      74) and Canas, Guanacaste (N = 29). Feces had 31 E. sigmodontis, nine E.
      tuskegeensis, eight E. roperi, three E. webbae and two Eimeria sp. This is the
      first report of these coccidian parasites for Costa Rica.

PMID- 10347817
TI  - Theletrum lamothei sp. nov. (Digenea), parasite of Echidna nocturna from
      Cuajiniquil, Guanacaste, and other digenes of marine fishes from Costa Rica.
AB  - A new species of Theletrum is described from the intestine of two palenose
      morays, Echidna nocturna, collected in Cuajiniquil, Guanacaste Province, Costa
      Rica. The new species differs from the type species, T. fustiforme Linton, 1910
      by having a subspherical pars prostatica, a subspherical seminal vesicle
      extending anteriorly to the anterior border of the acetabulum, by the presence of
      a poorly developed hermaphroditic sac, and by having a larger body size. We also
      report eight additional species of digeneans parasitizing marine fishes in
      several localities along the Atlantic and Pacific coast of Costa Rica: Bianium
      simonei, Didymozoinae (metacercariae), Ectenurus virgulus, Hypocreadium
      myohelicatum, Lecithochirium microstomum, Pseudolecithaster sp., Stephanostomum
      casum, and Tergestia laticollis. In addition, we present an updated list of
      helminth parasites of marine fish from Costa Rica and discuss the importance of
      including parasites as an integral part of biodiversity inventories.

PMID- 10347818
TI  - Levels of natural resistance to Boophilus microplus (Acari: Ixodidae) in Carora
      breed bulls.
AB  - Boophilus microplus infestation is one of the most serious limitations to cattle
      industry in tropical regions, even though bovines show natural resistance to
      ticks. This resistance was evaluated in Cross-bred Carora Bulls (CCB) a
      tropicalized dairy breed from Venezuela. Seven CCB were experimentally infested
      with B. microplus larvae, "Mozo" strain, they were considered tick-naive because
      they had never been infested with ticks. The mean inoculum size applied on each
      bull was 6,477 larvae. After life cycle was completed adult female body weight
      (BW), egg mass weight (EW), egg hatching rate (%EH), and reproductive index (RI)
      were recorded. Results revealed a high variability in the levels of resistance to
      B. microplus. Thus, one animal showed greater resistance (Dunnett, p < 0.05) for
      the analyzed parameters in contrast with three non-resistant bulls. The others
      had moderate resistance. The trait "resistance" should be included together with
      other traits often used in genetic selection of cattle.

PMID- 10347819
TI  - [Annual follow-up of the gastrointestinal parasitosis of white-tailed deer
      Odocoileus virginianus (Artiodactyla: Cervidae) in captivity in Yucatan, Mexico].
AB  - Gastrointestinal parasites, and egg and oocyst output in the faeces of captive
      white-tailed deer (Odocoileus virginianus yucatanensis) were recorded in Yucatan,
      Mexico. Feces were obtained from from January through December 1995 (ten samples
      every two weeks per place). Samples were processed by flotation and the McMaster
      techniques. Faecal cultures for L3 larvae were made by the Corticelli-Lai
      technique. Oocysts in faeces were cultured in 2% potassium dicromate. Seven
      genera were determined (Haemonchus spp., Cooperia spp, Isospora spp., Eimeria
      spp., Trichuris spp., Strongyloides spp. and Moniezia spp.) which represent five
      orders. The most frequent genera were Haemonchus, Isospora and Eimeria. The genus
      Isospora is reported for the first time in deer of this region, although it was
      not possible to explain the source of this parasite. The frequency and level of
      faecal egg and oocyst outputs were variable during the year and increased during
      the rainy season. There was a positive correlation between relative humidity,
      environmental temperature and rainfall with the coccidia and strongylida orders.
      In the central zone of Yucatan the meteorological conditions during the rainy
      season are favourable for the development of gastrointestinal parasitism which
      enable an increased risk of infection for deer.

PMID- 10347820
TI  - [The relation of Helicobacter pylori with dysplasia and stomach neoplasms in
      Costa Rica].
AB  - Occurrence of the bacterium Helicobacter pylori was compared for two Costa Rican
      sites with contrasting levels of gastric cancer incidence, Poas (incidence
      15.13%) and Puriscal (83.53%). A sample of 185 adults of similar age and sex
      proportions was studied in each site, using both H. pylori antiserum tests and
      gastroscopy to collect two biopsies per case. No clear association between H.
      pylori and gastric cancer was found.

PMID- 10347821
TI  - [Expression of reverse transcriptase coded by LINE-1 mobile element in human
      genome using the baculovirus system].

PMID- 10347822
TI  - [Cold paralysis of the respiratory center and restoration of its function in
      homeothermic animals without rewarming].

PMID- 10347823
TI  - [Morphological characteristics of human m. vastus lateralis in supportless
      environment].

PMID- 10347824
TI  - [Seasonal changes in the size of testis and vocalization in pikas as a
      confirmation of hormonal control for acoustic behavior in mammals].

PMID- 10347825
TI  - [Systematic and taxonomic rank of voles based on histochemical characteristics of
      skin glands in Micsotus oeconomus and Miscotus limnophilus].

PMID- 10347826
TI  - [Imidazole compounds simulated active center of ribonuclease A. Synthesis and RNA
      cleaving activity].

PMID- 10347827
TI  - [Regeneration of rat gastrocnemius muscle after X-ray radiation, mechanical
      trauma and prolonged infrared laser irradiation].

PMID- 10347828
TI  - [Lipopolysaccharide from photosynthetic bacteria blocks Ca2+ response of human
      neutrophils induced by endotoxins from Shigella flexneri and its Re-mutant].

PMID- 10347829
TI  - [Use of trecrezan for increasing the reproduction ability of mammals and the
      viability of their offspring].

PMID- 10347830
TI  - [Neuroprotective effect of targeted microelectric stimulation in acute
      cerebrovascular circulation disorders].

PMID- 10347831
TI  - [The comparison of the development of the auditory and vestibular structures in
      thoothed whales--beluga (Cetacea: Odontoceti-Delphinapterus leucas)].

PMID- 10347832
TI  - Systematic reviews of trials and other studies.

PMID- 10347833
TI  - The role of the formed elements of the blood in host defense.

PMID- 10347834
TI  - Myocardial protection for cardiac surgery: classical views and new trends.

PMID- 10347835
TI  - The pathophysiology and management of perioperative pulmonary hypertension with
      specific emphasis on the period following cardiac surgery.
AB  - Pulmonary hypertension, right ventricular dysfunction, and RV failure are common
      occurrences following CPB. The endothelium is now recognized as an important
      organ and is central to the pathophysiology and management of this condition.
      Current progress has arisen from the development of newer methods and the
      refinement of older methods attempting to protect the endothelium. Modern methods
      attempting to preserve endothelial function (thereby preventing pulmonary
      vasoconstriction and RV dysfunction) include new pharmacological inhibitors of
      the inflammatory response to CPB, improved myocardial protection using substrate
      enhanced cardioplegia, improved cardioplegia delivery techniques combined with
      monitoring by myocardial contrast TEE, and new minimally invasive surgical
      techniques not requiring extracorporeal support. Progress in therapeutic methods
      attempting to reverse pulmonary hypertension, RV dysfunction, and support of the
      failing right ventricle include the application of nitric oxide, prostacyclin,
      other pulmonary selective vasodilators, and improved ventricular assist devices
      that provide support to the right ventricle until recovery of the myocardium
      occurs or serve as a bridge to transplantation.

PMID- 10347836
TI  - The role of the gut in major surgical postoperative morbidity.
AB  - Gut mucosal hypoperfusion has been termed the motor of multiple organ failure.
      While a large proportion of high-risk surgery proceeds unremarkably, the insult
      to the inflammatory system during perioperative periods of regional hypoperfusion
      may manifest themselves over the subsequent few days, leading to microvascular
      thrombi, organ dysfunction, and failure. Several approaches have been made to
      prevent this, including systemic optimization of the cardiovascular system and
      specific targeting of the splanchnic circulation with monitoring techniques such
      as tonometry or metabolic markers of hepatic function to guide fluid and drug
      therapies. It is believed that in a proportion of patients such methods are not
      likely to suffice and gut mucosal hypoperfusion is probable. If these patients
      can be identified preoperatively, then recently developed techniques used
      prophylactically such as immunonutrition, passive and active immunization,
      specific antimediator agents, or nonspecific anti-inflammatory agents may help
      minimize the number of patients progressing to multiple organ dysfunction and
      failure. Techniques that may help us identify at-risk patients may include in
      depth cardiovascular assessment, possibly with echocardiography or a noninvasive
      cardiac output monitor such as the suprasternal adaptation of the ODM esophageal
      Doppler. The measurement of baseline endotoxin immune status (EndoCAb) may select
      those patients in advance who are most at-risk from gut mucosal hypoperfusion,
      thus allowing a more rational use of tonometry. Conventional risk scoring systems
      used in conjunction with knowledge of the type of surgery to be undertaken and
      whether large fluid shifts are likely along with the less conventional techniques
      discussed above may enable perioperative therapy to be closer to optimal.

PMID- 10347837
TI  - Renal preservation in the perioperative period.

PMID- 10347838
TI  - [Functional analysis of a novel cell adhesion molecule, gicerin].
AB  - Recent studies identified a novel cell adhesion molecule, gicerin, that exists on
      the surface of developing neurons. Determination of the amino acid sequence
      revealed that this molecule has five immunoglobulin-like structures in its
      extracellular domain and a short cytoplasmic tail. Gicerin binds in a homophilic
      manner and also displays heterophilic binding activity to NOF (Neurite Outgrowth
      Factor), which belongs to the laminin family extracellular matrix molecule. We
      clarified that there are two subtypes of gicerin that differ only in the
      cytoplasmic domain. S-gicerin, which has smaller tail, has stronger activity in
      cell aggregation or NOF binding. This suggests a physiological difference in the
      activity of each subtype. In the nervous system, gicerin is expressed during its
      developmental stage when neurons migrate or extend neurites to form a neural
      network. Gicerin promotes neurite extension from embryonic neurons by both
      homophilic adhesion and heterophilic adhesion to NOF. These data suggest that
      gicerin participates in the formation of neural tissues. Gicerin is also
      expressed in other tissues such as the kidney and trachea. In these tissues,
      gicerin expression is also observed during the regeneration process and in tumors
      in addition to being present during the developmental stage. We believe that
      gicerin plays an important role in the histogenesis of the nervous system as well
      as other tissues.

PMID- 10347839
TI  - [Effects of propiverine hydrochloride (propiverine) on isolated rat and dog
      urinary bladder].
AB  - Propiverine is a drug for the treatment of incontinence and pollakiuria. The
      effects of propiverine on isolated rat and dog urinary bladder were investigated.
      At doses of 10(-6)-3 x 10(-5) M, propiverine caused both a rightward shift and
      inhibition of the maximum response in the acetylcholine (ACh) dose-response
      curve. The pA2 values for rat and dog urinary bladder were 5.97 and 6.62,
      respectively. At doses of 10(-5)-10(-5) M, propiverine also dose-dependently
      inhibited KCl (100 mM)-induced contractions. The IC50 values for rat and dog
      urinary bladder were 3.9 x 10(-6) M and 3.8 x 10(-6) M, respectively. The pA2
      value and the IC50 value of terodiline for rat urinary bladder were 6.08 and 6.6
      x 10(-6) M, respectively. In contrast, the pA2 value and the IC50 value of
      oxybutynin for rat urinary bladder were 7.69 and 4.5 x 10(-6) M, respectively,
      suggesting that oxybutynin exerts an anti-muscarinic effect at doses at which no
      discernible anti-KCl effect was observed, whereas propiverine and terodiline
      exerted both effects at the same doses. The inhibitory effect of drugs on the
      contraction induced by electrical field stimulation was tested. At a dose of 10(
      7) g/ml, tetrodotoxin inhibited the contraction of rat and dog urinary bladder by
      76.6% and 92.6%, respectively. Propiverine and verapamil dose-dependently
      inhibited the contractile response induced by electrical field stimulation at
      doses of 10(-5) M or more and 3 x 10(-6) M or more, respectively. At these
      concentrations, a marked anti-KCl effect of the drugs on smooth muscle was
      observed. On the other hand, atropine caused no inhibition of the contractile
      response in rat urinary bladder at a dose of 3 x 10(-5) M, and it inhibited the
      contraction in dog urinary bladder by 14.9% at a dose of 10(-5) M. These findings
      suggest that although propiverine exhibits both anti-muscarinic and anti-KCl
      effects in isolated rat and dog urinary bladder, the inhibitory effects of
      propiverine on the atropine-resistant part of contraction may be mainly due to
      its anti-KCl effect.

PMID- 10347841
TI  - [Histological study on healing of cryocautery-induced rat gastric ulcer treated
      with T-593].
AB  - The effect of T-593, a novel anti-ulcer agent, on the healing of cryocautery
      induced rat gastric ulcer was investigated histologically in comparison with that
      of famotidine. Seven days after ulceration, T-593 (30 mg/kg) or famotidine (30
      mg/kg) was orally administered twice daily for 8 weeks. Two, 4 and 8 weeks after
      the start of administration, the ulcer size was measured by a stereoscopic
      microscope, and the gastric mucosa was observed histologically. The thickness of
      the regenerated mucosa, the density and the arrangement of gastric glands, the
      degree of inflammatory-cell infiltration in the submucosal tissue and the number
      of microvessels in the submucosal tissue were quantified. In macroscopical
      evaluation, T-593 and famotidine significantly accelerated ulcer healing, and the
      time courses of the ulcer index were similar in both cases. In histological
      evaluation of healed ulcers, T-593 normalized the thickness of regenerated mucosa
      and reduced the degree of inflammatory-cell infiltration and the number of
      microvessels in the submucosal tissue, while famotidine had no effect. In
      conclusion, T-593 possesses accelerating effects not only on the restoration of
      regenerated mucosa but also on the maturation of submucosal tissue. Therefore, T
      593 improves the quality of ulcer healing.

PMID- 10347840
TI  - [Effects of propiverine hydrochloride (propiverine) on the muscarinic receptor
      binding affinity in guinea pig tissues and on salivation in conscious dogs].
AB  - Propiverine is a drug for the treatment of incontinence and pollakiuria. Such
      micturitional disorders are principally caused by a hyperactive bladder. The
      effects of propiverine, its active metabolite, 1-methyl-4-piperidyl benzilate N
      oxide (DPr-P-4 (N-->O)), oxybutynin and terodiline on muscarinic receptors in
      guinea pig urinary bladder, salivary glands, cerebral cortex, ileal longitudinal
      muscle and heart were compared. Both propiverine and DPr-P-4 (N-->O)
      competitively inhibited specific binding of 3H-quinuclidinyl benzilate (3H-QNB)
      to membrane fractions of these tissues. Oxybutynin, terodiline, pirenzepine and
      atropine also competitively inhibited the binding of 3H-QNB. The order of these
      drugs in terms of their affinity for muscarinic receptors was as follows:
      atropine > oxybutynin > pirenzepine, DPr-P-4 (N-->O), terodiline > propiverine.
      Propiverine and DPr-P-4 (N-->O) had no selectivity for muscarinic receptors in
      these tissues, the same as atropine. In contrast, pirenzepine, a M1-selective
      drug, had 10.1 times greater affinity for muscarinic receptors in the cerebral
      cortex than in urinary bladder, and the affinity of oxybutynin for muscarinic
      receptors in salivary glands and in cerebral cortex was 10.9 times and 13.9 times
      higher, respectively, than in urinary bladder. The affinity of terodiline for
      muscarinic receptors in the cerebral cortex was 4.4 times higher than in urinary
      bladder. In this study, the effect of propiverine and oxybutynin on pilocarpine
      (1 mg/kg, s.c.)-induced salivation in conscious dogs was also compared.
      Propiverine (5 mg/kg, i.v.) had no effect on pilocarpine-induced salivation,
      whereas oxybutynin (0.1 mg-0.5 mg/kg, i.v.) inhibited it significantly and dose
      dependently. The ID50 values (95% confidence limits) for propiverine and
      oxybutynin during the 20 min after intravenous administration were 6.88 mg/kg
      (4.71-15.67) and 0.154 mg/kg (0.115-0.205), respectively. These findings suggest
      that although propiverine, its active metabolite DPr-P-4 (N-->O), oxybutynin and
      terodiline competitively inhibit the binding of 3H-QNB to muscarinic receptors,
      the affinity of these drugs for the muscarinic receptors of these tissues is very
      different and that propiverine has less effect on salivation than oxybutynin.

PMID- 10347842
TI  - [Hemostatic effect of a novel sheeted fibrin adhesive agent, TO-193, on
      experimental incision models].
AB  - TO-193 (TachoComb) is a new fibrin adhesive agent that consists of a collagen
      sheet coated with fibrin glue. We compared the hemostatic effect of TO-193 in
      several experimental models with Beriplast P as a fibrin adhesive agent, Avitene
      and Novacol as a microfibrillar collagen hemostat, and a sponge-like collagen
      sheet as the constitutional parts of TO-193. In the in vitro bleeding model in
      which blood leaks out through cotton cloth, the pressure of TO-193 when blood
      leakage was observed was higher than those of Beriplast P, Avitene, Novacol and
      the collagen sheet, indicating that TO-193 possessed a strong adhesive effect on
      the bleeding surface. On the kidney resection surface, TO-193 showed a more
      potent adhesive effect than those of Beriplast P and the collagen sheet,
      suggesting that TO-193 has a potent hemostatic effect. In the liver resection, TO
      193 significantly reduced the bleeding volume compared with that of Novacol in
      normal rats. Furthermore, the bleeding volume of TO-193 was about half that of
      Beriplast P and equivalent to that of Novacol even in anticoagulant-treated rats.
      From these data, it is expected that TO-193 would be a valuable hemostatic agent
      for clinical use since TO-193 possesses a potent adhesive ability on the bleeding
      resection surface and would certainly stop bleeding in both patients with normal
      coagulation and those with a low blood coagulation condition.

PMID- 10347843
TI  - [Interaction of warfarin and vitamin K2 on arterial thrombotic tendency using a
      rat aorta loop model].
AB  - Vitamin K2(K2), a therapeutic agent osteoporosis, is prohibited for patients with
      thrombosis who are receiving warfarin (WF). However, because some aged patients
      with thrombosis have osteoporosis, some patients treated with WF may be
      administered K2 concomitantly. We investigated here the interaction between K2
      and WF on thrombosis in a rat aorta loop model. Administration of WF at 0.58,
      0.82 and 1.16 mg/l in drinking water for 7 days decreased the thrombotic rate and
      increased the death rate, dose-dependently. Therefore in the following study,
      0.80 mg/l of WF was used. After 2 days of WF-treatment, 1.5, 14 and 145 mg/kg of
      K2 was administered for 5 days. The blood coagulation time was markedly prolonged
      by WF treatment for 7 days and this effect was completely inhibited by all doses
      of K2. WF treatment significantly decreased the cumulative thrombotic rate for 5
      days. Administration of 1.5 and 14 mg/kg of K2 did not influence the WF effect on
      thrombosis. The thrombotic rate in the 145 mg/kg K2 group was lower than that in
      the WF-control group, but similar to that in the WF-untreated group. These
      findings suggest that high dose of K2 reduces the effect of WF on thrombosis but
      does not enhance the occurrence of thrombosis more than that without WF
      treatment.

PMID- 10347844
TI  - [Surgical treatment of intractable epilepsies: experimental approach].

PMID- 10347845
TI  - [Intraoperative electrophysiological monitoring for functional preservation of
      the cauda equina during lumbosacral surgery].
AB  - Adequate electrophysiological techniques to monitor function of the cauda equina
      have been proposed for surgery in patients with lumbosacral lipoma or
      myeloschisis. Motor fibers were identified by electrical stimulation in the
      operating field with bipolar rectangular impulses of 200 mu sec duration at 2 Hz
      under 5 mA and compound muscle action potentials (CMAPs) recorded from the leg
      and anal muscles. By recording CMAPs from the tibialis anterior, the biceps
      femoris, the gastrocnemius, and the external anal sphincter muscles, all of the
      roots from the fourth lumbar to the fourth sacral segment were continuously
      monitored. To spare recording channels, recordings were obtained from the right
      versus the left side. In our institute, 5 patients have undergone lumbosacral
      surgery while using this monitoring system, and the results indicated that there
      was no postoperative neurological exacerbation in any of the cases. According to
      a combination of the CMAPs produced by stimulation, the segment of the stimulated
      motor root could be identified electrophysiologically. Monitoring of
      somatosensory evoked potentials was not performed because this would have
      required too much time and would have prolonged surgery. However, some sensory
      fibers, which appeared to be posterior roots of the cauda equina on
      intraoperative inspection, could be identified indirectly with CMAPs recording
      because of current spreading from the stimulation to motor fibers.

PMID- 10347846
TI  - [Use of Ommaya CSF reservoir for refractory chronic subdural hematoma].
AB  - Ten patients with refractory chronic subdural hematoma were the subjects of this
      paper. All patients had severe diseases influencing the clinical course of
      chronic subdural hematoma, such as cerebral infarction, liver cirrhosis,
      thrombocytopenia, severe parkinsonism, severe heart disease, and spino-cerebellar
      degeneration. They were first treated in a usual manner; irrigation and drainage
      of the hematoma cavity. After recurrence of the hematoma, an Ommaya CSF reservoir
      was put into place and whenever the volume of the hematoma increased the
      reservoir was punctured. Postoperatively, 7 patients returned to the same
      conditions as they had before the onset. However, one patient died of myocardial
      infarction and 2 patients with parkinsonism could not maintain the condition they
      had before the onset of their disease, resulting in their partially dependent
      state. Complications were minor bleeding in one patient and an occlusion of the
      reservoir in another patient. By using this method reoperation was unnecessary,
      and the patients were able to move early in the post-operative period. This
      method was suitable for refractory chronic subdural hematoma with severe disease
      influencing its clinical course.

PMID- 10347847
TI  - [Combined chronic subdural and acute epidural hematoma secondary to metastatic
      hepatocellular cancer: case report].
AB  - We report a case of combined chronic subdural and acute epidural hematoma caused
      by metastatic hepatocellular cancer of the dura mater. A 44-year-old woman, who
      had been under treatment for hepatic cancer for one year, presented with right
      hemiparesis. MRI revealed a chronic subdural hematoma on the left fronto-parietal
      region with subgaleal and epidural metastasis. The patient was found comatose 7
      days later. A huge epidural hematoma in the left parietal region was disclosed
      with CT scan. She died of hepatic failure despite the evacuation of the hematoma.
      This is the first reported case with a combined subdural and epidural hematoma
      secondary to metastatic brain tumor of the dura mater.

PMID- 10347848
TI  - [A case of neurocysticercosis with multiple intraparenchymal and intraventricular
      cysts].
AB  - Neurocysticercosis is a rare disease, and no association with intraventricular
      cysts has been reported in Japan. We report a case of neurocysticercosis that
      presented the unique symptom of a fourth ventricular cyst. A 55-year-old man with
      a 7 year history of neurocysticercosis and hydrocephalus developed a positional
      headache and vomiting 3 months after an L-P shunt, and was admitted to our
      hospital. MRI showed multiple intraparenchymal cysts, ventricular enlargement and
      an intraventricular cyst in the fourth ventricle. The cyst and the cysticercus in
      the fourth ventricle were totally removed via the suboccipital approach.
      Histological examination showed characteristics of cysticercus. Two weeks after
      this surgery, V-P shunt with neuroendoscopical observation of the ventricle was
      performed. A small cyst was detected in the right lateral ventricle. The symptoms
      disappeared after surgery. Following surgery, a therapeutic course of albendazole
      was administered at a daily dose of 600 mg for 30 days. MRI after administration
      of the anticysticercal drug revealed reduction in the size of the cysts.

PMID- 10347849
TI  - [Bilateral distal anterior cerebral artery aneurysm associated with supreme
      anterior cerebral artery: case report].
AB  - A 67-year-old woman presented with bilateral distal anterior cerebral artery
      aneurysms manifesting as consciousness disturbance. Computed tomography revealed
      subarachnoid hemorrhage in the interhemispheric fissure, right sylvian fissure,
      and a hematoma in the right frontal lobe and lateral ventricles. Angiography
      showed bilateral symmetrical aneurysms located on the pericallosal artery at the
      bifurcation of the callosomarginal artery. The operation was performed on the day
      the patient was admitted. The aneurysms were clipped via the interhemispheric
      approach, and the hematoma was aspirated. Operative view demonstrated rupture of
      the left aneurysm, and supreme anterior cerebral aneurysm. Postoperative
      angiography showed disappearance of the aneurysms and an intact bilateral
      anterior cerebral artery. The patient was discharged with mild organic mental
      syndrome. However, a few days later, she was admitted again with a high fever and
      died of complications due to sepsis. Pathological view showed clipped aneurysms
      and the connection of the bilateral distal anterior cerebral artery with the so
      called supreme anterior communicating artery.

PMID- 10347850
TI  - [Metastatic calvarial tumor: report of 3 cases].
AB  - We report 3 cases of calvarial tumor metastasized from the following
      malignancies: squamous cell carcinoma of the lung, hepatocellular carcinoma, and
      clear cell carcinoma of the kidney. All three patients presented with a painful
      mass as the initial symptom. Although each tumor was successfully extirpated, out
      come was not satisfactory because of the malignant nature of the primary sources.
      The main purpose of treatment of metastatic calvarial tumors was thought to be
      relief of pain and cosmetic reasons. Metastatic calvarial tumors may reach
      considerable size as reported here. We stressed that meticulous care should be
      paid to repair of the dura and reconstruction of subcutaneous soft tissues, since
      scalp necrosis or cerebrospinal fluid retention may occur following preoperative
      embolization of feeding arteries and extensive removal of subcutaneous tissues
      invaded by tumor.

PMID- 10347851
TI  - [Open surgery for pontine hemorrhage: experience in 3 cases].
AB  - Experience in three pontine hemorrhage cases which were treated by open surgery
      is recorded here. They were operated on by trans-fourth ventricular, subtemporal
      transtentorial on retromastoid suboccipital approaches. The neurological symptom
      improved noticeably in one case who was operated on through the retromastoid
      suboccipital approach seven days after the onset. The pontine hemorrhage can even
      be cured with open surgery which is performed in the early stage and through the
      operative approach.

PMID- 10347853
TI  - [Stenting for dissecting restenosis of the subclavian artery after balloon
      angioplasty: a case report].
AB  - A 51-year-old male presenting with dizziness and arm claudication was admitted to
      our hospital. The angiogram showed severe stenosis of the left subclavian artery
      accompanied by to and fro motion of left vertebral artery flow. He was treated at
      first by percutaneous transluminal angioplasty (PTA) resulting in satisfactory
      dilatation of the stenosis and transient amelioration of the symptoms. However,
      the symptoms recurred five months later and the angiogram revealed restenosis
      with subintimal dissection. We chose stent implantation as the second treatment,
      and, hemodynamically, it produced a good result. As some reports have suggested,
      because of the therapeutic limitation of surgery or PTA, stenting could be a good
      alternative for the treatment of such disease, since it is less invasive and safe
      even in patients with a wide range of systemic atherosclerosis.

PMID- 10347852
TI  - [Choroid plexus metastasis of renal cell carcinoma causing intraventricular
      hemorrhage: a case report].
AB  - We report a rare case of choroid plexus metastasis of renal cell carcinoma
      causing intraventricular hemorrhage. A 75-year-old female was admitted to our
      hospital for SAH. Preoperative examination evoked suspicion of an anterior
      communicating aneurysm as a cause of SAH. Furthermore, there were lesions on the
      tuberculum sellae and in the left trigone of the lateral ventricle, which were
      enhanced by Gd-DTPA on MRI. The patient was operated on via the pterional
      approach on December 3, 1996, but no aneurysm was found. She underwent total
      removal of the tuberculum sellae mass, which was postoperatively proved to be a
      meningioma by histological examination. The intraventricular tumor was supposed
      to be a meningioma, but it was not treated surgically. Two months later, the
      patient presented hematuria and was diagnosed as having a right renal cancer and
      underwent right nephrectomy on March 18, 1997. However, postoperatively,
      disturbance of consciousness continued. A CT scan revealed intraventricular
      hemorrhage around the tumor in the trigone of the lateral ventricle on March 21.
      An emergency operation for tumor and clot removal succeeded in improving the
      patient's condition. Histological examination of the tumor revealed clear-cell
      type renal cell carcinoma. Solitary choroidal plexus metastasis from renal cell
      carcinoma is quite rare: only 5 cases have been reported. But only our case was
      accompanied by intraventricular hemorrhage. Renal cell carcinomas are divided
      into two types: a slowly progressive type and a rapidly progressive type. Four
      cases among the reported 5 cases were the slowly progressive type, and our case
      was regarded as being of the same type.

PMID- 10347854
TI  - [Surgical removal of large cavernous angioma in the pontomedullary junction: a
      case report].
AB  - Recent advances in neuroradiology have enabled us to approach cavernous angioma
      in the brain stem. A case of large cavernous angioma, which was located in the
      pontomedullary junction, was removed surgically. A 24-year-old female was
      admitted with occipitalgia, dizziness, nausea, gait disturbance. On neurologic
      examination, the patient had right hemiparesis, slight right facial palsy and
      paresthesia, right hemiparesthesia, dysphagia. T1 weighted Gd enhanced MRI
      revealed a mixed intensity lesion. These findings were thought to be consistent
      with a cavernous angioma. Follow up MRI findings demonstrated progressive
      increase in cavernous angioma. Vertebral angiograms showed a mass sign and a
      venous angioma in the midline of the pontomedullary junction. Therefore, the
      operation was performed in an attempt to remove the cavernous angioma through the
      midline of the fouth ventricle. The operation was performed under monitoring of
      electromyogram of facial muscle and external ocular muscle. The cavernous angioma
      was removed totally, and addition neurogical deficits were minimal.

PMID- 10347855
TI  - [A case of symptomatic interhemispheric arachnoid cyst in the elderly].
AB  - The incidence of interhemispheric cyst is rare. There have been only 12 cases
      reported in adults since the advent of CT. We encountered a case of an
      interhemispheric arachnoid cyst in a 54-year-old patient who had developed
      paraparesis. Excision of the cystic wall produced a satisfactory result. The CT
      and MRI scans were not contributory to histological differentiation of the
      lesions. According to the literature, however, it is highly likely that these
      patients are suffering from an arachnoid cyst, when the interhemispheric cyst
      without agenesis of the corpus callosum occurs in adults.

PMID- 10347856
TI  - [Lymphoplasmacyte-rich meningioma: a report of three cases and a review of the
      literature].
AB  - We report three patients (a 36-year-old man, a 41-year-old woman, and a 22-year
      old man) with lymphoplasmacyte-rich meningioma who manifested characteristics on
      radiological and blood examinations. Two were hospitalized with gradual
      deterioration of hemiparesis and one with general convulsive seizure.
      Radiological examination revealed typical meningiomas of convexity in two and
      that of falx in one. Two of the patients showed large perifocal edema. Anemia was
      found in one patient and an elevated level in the zinc sulfate turbidity test was
      noted in all cases. Abnormal findings in laboratory examination improved quickly,
      whereas perifocal edema remained for six months after tumor removal. The tumors
      were histologically confirmed to be meningioma with massive infiltrates of plasma
      cells and lymphocytes. Seventeen cases of lymphoplasmacyte-rich meningioma that
      have been reported to date including our three cases were reviewed.

PMID- 10347857
TI  - Multiple imputation: a primer.
AB  - In recent years, multiple imputation has emerged as a convenient and flexible
      paradigm for analysing data with missing values. Essential features of multiple
      imputation are reviewed, with answers to frequently asked questions about using
      the method in practice.

PMID- 10347858
TI  - Applications of multiple imputation in medical studies: from AIDS to NHANES.
AB  - Rubin's multiple imputation is a three-step method for handling complex missing
      data, or more generally, incomplete-data problems, which arise frequently in
      medical studies. At the first step, m (> 1) completed-data sets are created by
      imputing the unobserved data m times using m independent draws from an imputation
      model, which is constructed to reasonably approximate the true distributional
      relationship between the unobserved data and the available information, and thus
      reduce potentially very serious nonresponse bias due to systematic difference
      between the observed data and the unobserved ones. At the second step, m complete
      data analyses are performed by treating each completed-data set as a real
      complete-data set, and thus standard complete-data procedures and software can be
      utilized directly. At the third step, the results from the m complete-data
      analyses are combined in a simple, appropriate way to obtain the so-called
      repeated-imputation inference, which properly takes into account the uncertainty
      in the imputed values. This paper reviews three applications of Rubin's method
      that are directly relevant for medical studies. The first is about estimating the
      reporting delay in acquired immune deficiency syndrome (AIDS) surveillance
      systems for the purpose of estimating survival time after AIDS diagnosis. The
      second focuses on the issue of missing data and noncompliance in randomized
      experiments, where a school choice experiment is used as an illustration. The
      third looks at handling nonresponse in United States National Health and
      Nutrition Examination Surveys (NHANES). The emphasis of our review is on the
      building of imputation models (i.e. the first step), which is the most
      fundamental aspect of the method.

PMID- 10347860
TI  - Parametric models for incomplete continuous and categorical longitudinal data.
AB  - This paper reviews models for incomplete continuous and categorical longitudinal
      data. In terms of Rubin's classification of missing value processes we are
      specifically concerned with the problem of nonrandom missingness. A distinction
      is drawn between the classes of selection and pattern-mixture models and, using
      several examples, these approaches are compared and contrasted. The central roles
      of identifiability and sensitivity are emphasized throughout.

PMID- 10347859
TI  - Maximum likelihood analysis of generalized linear models with missing covariates.
AB  - Missing data is a common occurrence in most medical research data collection
      enterprises. There is an extensive literature concerning missing data, much of
      which has focused on missing outcomes. Covariates in regression models are often
      missing, particularly if information is being collected from multiple sources.
      The method of weights is an implementation of the EM algorithm for general
      maximum-likelihood analysis of regression models, including generalized linear
      models (GLMs) with incomplete covariates. In this paper, we will describe the
      method of weights in detail, illustrate its application with several examples,
      discuss its advantages and limitations, and review extensions and applications of
      the method.

PMID- 10347861
TI  - Genetic analysis of Aspergillus nidulans unstable transformants obtained by the
      biolistic process.
AB  - Mitotically unstable Aspergillus nidulans argB+ transformants obtained by the
      biolistic process were studied in the present work. Hybridization signals from
      undigested DNA and pulsed-field chromosomal bands of the transformants suggested
      the introduced plasmid occurred as free concatenated molecules. Fifteen vigorous
      growth sectors released from the transformants were analysed in order to
      understand the mechanisms involved in their formation. All sectors showed the
      integration of exogenous genes into the fungal genome by homologous or
      heterologous recombinant events.

PMID- 10347863
TI  - Esterase activity and release of ethyl esters of medium-chain fatty acids by
      Saccharomyces cerevisiae during anaerobic growth.
AB  - During anaerobic fermentation, Saccharomyces cerevisiae releases large amounts of
      medium-chain fatty acids (MCFAs) and related ethyl esters which are very
      important for aromatic quality of fermented beverages. The physiological function
      of ester synthesis is not yet understood. As MCFAs are toxic, their conversion to
      esters has been proposed to be a detoxification mechanism. Esterases possess
      ester synthesizing ability. Throughout an anaerobic fermentation of a lipid-free
      synthetic medium carried out with a S. cerevisiae strain selected for wine
      making, we have monitored MCFA and ethyl ester production and, at the same time,
      measured growth and esterasic activity of intact cells. Because no correlation
      was found between the concentration of each fatty acid and its ethyl ester, there
      is no evidence that ester synthesis reduces the toxicity of MCFAs. Esterasic
      activity did not show any correlation with ester synthesis, but it was related to
      the release of MCFAs. A model is proposed in which ester synthesis is a
      consequence of the arrest of lipid biosynthesis resulting from a lack of oxygen.
      Under these conditions, an excess of acyl coenzyme A is produced, and acyl esters
      are formed as secondary products of reactions aimed at recovering free coenzyme
      A.

PMID- 10347864
TI  - Interactions between gut-associated lymphoid tissue and colonization levels of
      indigenous, segmented, filamentous bacteria in the small intestine of mice.
AB  - Unlike most other indigenous bacteria, segmented filamentous bacteria (SFB) are
      potent activators of the mucosal immune system. SFB are strongly anchored to the
      epithelial cells of the small intestine where they have a preference for mucosal
      lymphoid epithelium. Since SFB are only present in high numbers shortly after
      weaning, it was investigated whether an SFB-induced immune reaction results in
      the removal of these bacteria from the small intestine. A correlation was found
      between age and colonization levels in the small intestines of SFB monoassociated
      Swiss mice. Five-week-old athymic BALB/c (nu/nu) mice showed lower colonization
      levels than their heterozygous littermates, but the opposite was found at the age
      of 12 weeks. However, SFB inoculation of germfree Swiss mice resulted in higher
      colonization levels in 5-week-old mice when compared with 4-month-old mice. We
      conclude that SFB colonization levels in the small intestine are likely
      influenced by the activity of the mucosal immune system. However, an additional
      age-dependent factor that modulates SFB colonization levels cannot be excluded.

PMID- 10347865
TI  - Computer-assisted restriction endonuclease analysis of plasmid DNA in field
      strains of Salmonella enteritidis.
AB  - Computer-assisted restriction endonuclease analysis of plasmid DNA in field
      strains of Salmonella enterica serovar Enteritidis (S. enteritidis) is described.
      The procedure consists of plasmid DNA purification, its digestion with
      restriction endonuclease TaqI, electrophoresis, charge-coupled device camera
      scanning of the gels, and an analysis of the restriction patterns with the
      software Gel Manager. The system allowed us to analyse, in detail, results of
      plasmid profiling in more than 600 field strains of S. enteritidis. In addition
      to plasmid-free and virulence plasmid only containing strains, 15 additional
      plasmid types were detected. All the images and detailed protocols are available
      at the Web site http://www.clark.cz/vri/salmon.htm.

PMID- 10347866
TI  - pGR71 plasmid promotor sequence temporally regulated in Bacillus subtilis.
AB  - pGR71, a composite of plasmids pUB110 and pBR322, replicates in Escherichia coli
      and in Bacillus subtilis. It carries the chloramphenicol resistance gene (cat)
      from Tn9, which is not transcribed in either host by lack of a promoter. The cat
      gene is preceded by a Shine-Dalgarno sequence functional in E. coli but not in B.
      subtilis. Deleted pGR71 plasmids were obtained in B. subtilis when cloning
      foreign viral DNA upstream of this cat sequence, as well as by BAL31 exonuclease
      deletions extending upstream from the cat into the pUB110 moiety. These mutant
      plasmids expressed chloramphenicol acetyltransferase (CAT), conferring on B.
      subtilis resistance to high chloramphenicol concentrations. CAT expression peaked
      at the early postexponential phas of B. subtilis growth. The transcription
      initiation site of cat, determined by primer extension, was located downstream of
      a putative promoter sequence within the pUB110 moiety. N-terminal amino acid
      sequencing showed that native CAT was produced by these mutant plasmids. The cat
      ribosome-binding site, functional in E. coli, was repositioned within the pUB110
      moiety and had consequently an extended homology with B. subtilis 16S rRNA,
      explaining the production of native enzyme.

PMID- 10347867
TI  - The serodiagnosis of infections caused by Verocytotoxin-producing Escherichia
      coli.
AB  - Patients with haemolytic uraemic syndrome (HUS) and haemorrhagic colitis (HC)
      produce serum antibodies to the lipopolysaccharides (LPS) of Escherichia coli
      O157 and certain other E. coli serogroups. Patients may also make salivary
      antibodies to the LPS of E. coli O157. Serological tests based on these
      antibodies can be used to provide evidence of infection in the absence of
      culturable VTEC or the toxins they produce. Serum antibodies to LPS persist for
      several months following onset of disease, enabling both current and
      retrospective serological testing. The LPS of E. coli O157 shares epitopes with
      strains of Brucella abortus, Yersinia enterocolitica O9, Vibrio cholerae O1
      Inaba, group N Salmonella and certain strains of Citrobacter freundii and E.
      hermanni. Serological tests for serum antibodies to E. coli O157 should be
      evaluated in the light of these cross-reactions. Serological tests to supply
      evidence of infection with E. coli O157 have been shown to provide a valuable
      adjunct to bacteriological procedures for detecting culturable VTEC and VT. The
      use of well characterized LPS antigens in association with the techniques of
      ELISA and immunoblotting provide valuable procedures for detecting evidence of
      infection with E. coli O157 and possibly other VTEC.

PMID- 10347868
TI  - Characterization of plasmids that encode streptomycin-resistance in bacterial
      epiphytes of apple.
AB  - Streptomycin resistance in strains of Pseudomonas syringae pv. papulans, Pantoea
      agglomerans and a yellow-pigmented, non-fluorescent Pseudomonas sp. (Py),
      isolated from apple orchards in New York and Washington states, is predominantly
      associated with strA-strB genes carried on conjugal plasmids (R plasmids). None
      of 128 resistant Erwinia amylovora strains from the eastern and western USA
      hybridized with a strA-strB probe, SMP3. Resistant Py strains transfered R
      plasmids to Ps. syringae pv. papulans and to Py in vitro at frequencies of 10(-1)
      10(-2) per recipient cell whereas Ps. syringae pv. papulans transferred its
      plasmids at frequencies of 10(-2) to below detectable levels. Transfer of R
      plasmids to P. agglomerans was not detected and resistant P. agglomerans did not
      transfer their R plasmids to any recipients. R plasmids were found to be highly
      diverse as measured by DNA fingerprint analysis. Transfer-deficient transposon
      mutants of R plasmid pCPP519 were generated, and 3.9 kb EcoRI and 3.0 kb SmaI
      fragments that hybridized with a Tn5 probe were cloned and sequenced. The deduced
      amino acid sequences of the 3.9 kb fragment were similar to proteins involved in
      replication, nicking at oriT, and piliation in other bacteria.

PMID- 10347869
TI  - Transcriptional analysis of the nitrile-degrading operon from Rhodococcus sp.
      ACV2 and high level production of recombinant amidase with an Escherichia coli-T7
      expression system.
AB  - Northern blotting analysis with RNA probes derived from amidase and nitrile
      hydratase genes from Rhodococcus sp. ACV2 revealed that both genes are part of
      the same operon. RNase protection mapping and sequence analysis indicated that
      the operon is probably under the control of a sigma 70-like promoter located
      upstream from the amidase gene. Plasmids were constructed with the cloned genes
      under tac and lac promoter control. Expression of amdA was demonstrated in
      Escherichia coli. In another construction, the amdA gene was inserted under the
      control of the bacteriophage T7 promoter. Large amounts of recombinant amidase
      (at least 20% of total proteins) in a soluble and active form were obtained with
      the E. coli-T7 expression system by lowering the growth temperature to 29 degrees
      C, without IPTG induction. The ratio of amidase activity of strain ACV2 to E.
      coli was approximately 1:3. Purification of the recombinant amidase was carried
      out in one chromatographic step, giving an enzyme preparation that could be used
      directly in a biotechnological process.

PMID- 10347870
TI  - Use of pulsed field gel electrophoresis as an epidemiological tool for analysis
      of sporadic associated strains of Salmonella typhi isolated in Taiwan.
AB  - In order to characterize the subtypes of Salmonella typhi which cause sporadic
      disease in Taiwan, 55 isolates of Salm. typhi obtained from unrelated patients of
      sporadic cases during 1992-96 were subjected to chromosomal DNA digestion and
      pulsed field gel electrophoresis (PFGE). When DNAs of these 55 Salm. typhi
      strains were digested with XbaI, 41 PFGE patterns were observed. Strains sharing
      the same XbaI digestion pattern could not be further discriminated by PFGE
      analysis using SpeI and NotI as digestion enzymes. Thus, considerable genetic
      diversity exists among the Salm. typhi isolates. Although strains of the same
      patterns were mainly isolated during the same time, recirculation of certain
      infectious strains could be possible. When 12 antibiotics, i.e. ampicillin,
      trimethoprim/sulfamethoxazole, erythromycin, norfloxacin, tetracycline,
      sulphonamide, streptomycin, neomycin, chloramphenicol, kanamycin, cefoperazone
      and gentamycin were used to test the antibiotic susceptibility for these
      Salmonella isolates, only three antibiogram patterns were obtained and 49 of the
      55 Salm. typhi isolates were found to belong to one pattern. Phage typing and
      plasmid profiles were also poor in discriminating these strains. Thus, PFGE alone
      may be used as a powerful tool for analysis of sporadic associated Salm. typhi
      strains.

PMID- 10347871
TI  - Selective agars for the isolation of Streptococcus iniae from Japanese flounder,
      Paralichthys olivaceus, and its cultural environment.
AB  - Two kinds of selective agar were developed for the isolation of Streptococcus
      iniae, the causal agent of streptococcosis, from Japanese flounder (Paralichthys
      olivaceus) and from culture tanks in flounder farms. The selective agars were
      heart infusion agar with added thallium acetate and oxlinic acid (TAOA), and
      colistin sulphate and oxolinic acid (CSOA). For samples containing various
      bacterial flora, selective agars were supplemented with defibrinated horse blood
      in order to distinguish beta-haemolytic colonies of Strep. iniae. Streptococcus
      iniae was quantitatively isolated from the brain and kidney of diseased flounders
      in pure culture. Two-thirds of isolates picked up from selective blood agars
      inoculated with intestinal samples were identified as Strep. iniae. The bacterial
      colony numbers of deposits and water from culture tanks on selective blood agars
      were about 10-10(5) times smaller than those on control heart infusion agar;
      Strep. iniae was isolated from few deposit and water samples.

PMID- 10347873
TI  - Application of laser scanning for the rapid and automated detection of bacteria
      in water samples.
AB  - It is widely accepted that the heterotrophic plate count method may not support
      the growth of all viable bacteria which may be present within a water sample and
      that alternative procedures using 'viability markers' may yield additional
      information. In this study, ChemChrome B (CB), which is converted to a
      fluorescent product by esterase activity, was used to stain viable bacteria
      (captured by membrane filtration) from potable water samples. The labelled
      bacteria from each sample were subsequently enumerated using a novel laser
      scanning instrument (ChemScan). Analysis of 107 potable water samples using this
      procedure demonstrated the presence of a significantly greater number of bacteria
      than were detected by culture (z-test, P < 0.05). The mean number of bacteria
      isolated by culture on R2A agar incubated at 22 degrees C for 7 d was only 25.2%
      of the total number of viable bacteria detected using the CB/ChemScan viability
      assay. Further analysis of 81 water samples using a 5-cyano-2,3,4-tolyl
      tetrazolium chloride (CTC) viability assay also demonstrated the presence of many
      viable bacteria which were not capable of growth under the culture conditions
      employed in this study. However, the results indicate that ChemChrome B has the
      ability to stain a significantly greater number of heterotrophs than CTC (z-test,
      P < 0.05). In contrast, six potable waters were identified in which the CTC
      viability assay resulted in counts greater than those obtained using CB. The
      ChemScan instrument was successfully used for rapid and accurate enumeration of
      labelled micro-organisms, allowing information on the total viable microbial load
      of a water sample to be determined within 1 h. Furthermore, the ChemScan system
      has the potential for use in detecting specific organisms labelled with
      fluorescently-labelled antibodies or nucleic acid probes.

PMID- 10347874
TI  - Characterization by numerical taxonomy and ribotyping of Vibrio splendidus biovar
      I and Vibrio scophthalmi strains associated with turbot cultures.
AB  - Twelve Vibrio strains were examined phenotypically in 91 biochemical characters
      and genotypically by ribotyping. Ten were isolated from sea water and two from
      diseased turbot (Scophthalmus maximus). All isolates originated from one
      experimental system located in Ria de Vigo (Galicia, north-west Spain). Different
      type strains were used for comparative purposes. The taxonomic position was
      analysed with the NTSYST-pc and similarities among strains were calculated by the
      Simple Matching coefficient (SSM). rRNA gene restriction patterns were performed
      with the HindIII enzyme. The SSM coefficient separated the 12 Vibrio strains into
      two groups which included strains that showed a SSM coefficient quite similar to
      V. splendidus biovar 1 (ATCC 33125) and V. scophthalmi (CECT 4638). None of 91
      phenotypical characters were specific in distinguishing both species. The
      ribotyping confirmed the taxonomic classification of strains. The pathogenicity
      of each strain was evaluated; 10 environmental strains were avirulent and two,
      isolated from diseased turbot, were virulent. Different biotypes and ribotypes
      were found among the avirulent isolates. This work showed ribotyping to be a
      valuable tool for identification and confirmed the necessity of extending the
      ribotype database within closely related Vibrio species in order to clarify the
      taxonomic position.

PMID- 10347875
TI  - A mathematical model for toxin accumulation by killer yeasts based on the yeast
      population growth.
AB  - The accumulation of toxin by killer yeast populations is modelled starting from a
      mechanistic approach that explains the toxin production in terms of yeast
      population growth, and takes into account the environmental inactivation of the
      toxin. A modified Richard's general equation for limited growth is used to define
      the function that describes the toxin produced in relation to the yeast biomass
      increase. The relationship between the rates of cell and toxin production is
      explicitly shown, and the implications of the resulting proportionality factor
      are discussed. The model parameters have been adjusted and the model has been
      validated using experimental data of growth and toxin accumulation from cultures
      of Pichia membranaefaciens in two different media. The differences between both
      types of cultures are analysed on the basis of parameter estimates and the
      predicted rate of toxin production per cell. The results support the hypothesis
      that biomass production and toxin synthesis are controlled in different ways;
      they also suggest that the composition of the medium could have a distinct effect
      on toxin synthesis. Model assumptions are discussed in comparison with a previous
      model for killer-sensitive interaction of Saccharomyces cerevisiae strains.

PMID- 10347876
TI  - Stable expression of the Lactobacillus casei bacteriophage A2 repressor blocks
      phage propagation during milk fermentation.
AB  - A general strategy was applied to implement resistance against temperate
      bacteriophages that infect food fermentation starters through cloning and
      expression of the phage repressor. Lactobacillus casei ATCC 393 and phage A2 were
      used to demonstrate its feasibility as milk fermentation is drastically inhibited
      when the strain is infected by this phage. The engineered strain Lact. casei
      EM40::cI, which has the A2 repressor gene (cI) integrated into the genome, was
      completely resistant and able to ferment milk whether phage was present or not.
      In addition, viable phages were eliminated from the milk, probably through
      adsorption to the cell wall. Finally, the integration of cI in the genome
      resulted in a stable resistance phenotype, being unnecessary selective pressure
      during milk fermentation.

PMID- 10347877
TI  - Tolerance and biodegradation of m-toluate by Scots pine, a mycorrhizal fungus and
      fluorescent pseudomonads individually and under associative conditions.
AB  - The tolerance to, and degradation of m-toluate by Scots pine (Pinus sylvestris),
      a symbiotic mycorrhizal fungus (Suillus bovinus) and Pseudomonas fluorescens
      strains, with or without m-toluate-degrading capacity, was determined
      individually and in all symbiotic/associative plant-microbe combinations. Fungal
      survival on medium with m-toluate was increased in co-culture with the
      degradative bacterial strains on agar plates (up to 0.02%, w/v). When fungi were
      grown in mycorrhizal association with Scots pine seedlings in test-tube
      microcosms containing expanded clay pellets and growth media, the fungus was able
      to withstand m-toluate concentrations up to 2.0%, w/v in all treatments. The
      seedling tolerance remained unaltered regardless of the presence or absence of
      mycorrhizal fungi or biodegradative bacteria. Reduction in m-toluate levels was
      only detected in treatments inoculated with bacterial strains harbouring TOL
      catabolic plasmids. The plant and fungus, alone or in mycorrhizal symbiosis, were
      unable to cleave m-toluate. The presence of easily available plant-derived carbon
      sources did not impede m-toluate degradation by the bacteria in the
      mycorrhizosphere.

PMID- 10347878
TI  - Disinfection of hospital waste sludge using hypochlorite and chlorine dioxide.
AB  - Hypochlorite and chlorine dioxide were used to disinfect hospital waste-water
      sludge. Their abilities to inactivate pathogenic micro-organisms were compared.
      Reductions in indigenous coliform organisms and Pseudomonas aeruginosa were
      estimated. The results indicate that hypochlorite is a better disinfectant than
      chlorine dioxide for coliforms. Higher disinfection efficiency was obtained by
      treating a lower concentration of sludge. In addition, a higher agitation speed
      gave a higher disinfection efficiency with hypochlorite. The disinfection
      efficiencies of both disinfectants were higher against settled sludge than
      against thickened sludge. Therefore, it is recommended that disinfection should
      be performed on settled sludge rather than in a thickening tank.

PMID- 10347879
TI  - Enumeration and characterization of bacteria in mineral water by improved direct
      viable count method.
AB  - Fifteen strains from two emergent mineral waters were isolated and tentatively
      identified with API 20NE and BIOLOG GN systems. These strains were screened for
      their sensitivities to seven replication-inhibiting antibiotics of the
      (fluoro)quinolone group (nalidixic and pipemidic acid, flumequine, norfloxacin,
      ofloxacin, pefloxacin and ciprofloxacin). It was shown that the direct viable
      count (DVC) procedure could be improved by using certain antibiotic cocktails,
      which were active against the isolates. Geometric bacterial features were
      successfully determined with image analysis and adapted software (ICONIX, Perfect
      Image). Elongations were significant and allowed rapid discrimination of
      antibiotic inhibited and non-inhibited strains. Particular isolates in a mixed
      culture were characterized and enumerated after only 14 h exposure with the
      appropriate antibiotic cocktail. This method can also be applied to other
      communities, such as mixed cultures in bio-fermentors or in food with known
      microflora.

PMID- 10347880
TI  - Adaptation of Pseudomonas aeruginosa ATCC 15442 to didecyldimethylammonium
      bromide induces changes in membrane fatty acid composition and in resistance of
      cells.
AB  - The role of membrane fatty acid composition in the resistance of Pseudomonas
      aeruginosa ATCC 15442 to the bactericidal activity of didecyldimethyl ammonium
      bromide (DDAB) was investigated. In this study, the strain was sub-cultured in a
      medium with increasing DDAB concentrations. After adaptation, Ps. aeruginosa was
      able to grow until the DDAB concentration in the medium was about five times
      greater than the Minimal Inhibitory Concentration. Resistance of cells to the
      bactericidal activity of DDAB also increased gradually during adaptation. This
      resistance was dependent on the presence of the biocide, as it quickly decreased
      when the cells were transferred to medium without biocide. Adapted cells showed
      changes in membrane fatty acid composition. The modifications mainly affected
      lauric, beta-hydroxylauric and palmitic acids, and they underlined the
      implication of the membranes in the cell response to the presence of the biocide.
      Simple linear regression analysis showed that the membrane fatty acid composition
      of Ps. aeruginosa played an important part in the resistance mechanisms of cells
      to the bactericidal activity of DDAB.

PMID- 10347881
TI  - The effect of pH and culture system on the attachment of plasmid-bearing and
      plasmid-cured Yersinia enterocolitica to a polycarbonate membrane in a surface
      adhesion immunofluorescent technique.
AB  - A rapid surface adhesion based immunofluorescence technique was used to isolate
      and detect Yersinia enterocolitica from inoculated enriched culture systems. The
      pathogen was isolated by surface adhesion to a polycarbonate membrane which was
      mounted on a glass slide and immersed in the enriched culture for 15 min. The
      pathogen was detected using a fluorescent labelled (FITC) monoclonal antibody
      which was specific for Y. enterocolitica serotype O:3 and then viewed using
      fluorescent microscopy. The effect of culture type (broth, meat homogenate and
      minced meat) and pH (5.00, 7.00, 9.00 and 11.00) on the adhesion of plasmid
      bearing and plasmid-cured Y. enterocolitica to the polycarbonate membrane in this
      technique was determined. The pH had a significant effect (P < 0.05) in broth and
      meat homogenate cultures, with enhanced attachment of Y. enterocolitica (P+ and P
      ) at pH 9.00 than at pH 5, 7 or 11. Culture type was also important, with
      differences observed in the numbers of Yersinia adhering to membranes immersed in
      broth, meat homogenate and minced beef. Differences in attachment were noted
      between plasmid-bearing and plasmid-cured Y. enterocolitica isolated from similar
      cultural environments. The reasons for these observed differences, and their
      implications for the surface adhesion immunofluorescent rapid method, are
      discussed.

PMID- 10347882
TI  - Comparative toxicity of four microcystins of different hydrophobicities to the
      protozoan, Tetrahymena pyriformis.
AB  - Microcystins (MC) are a group of over 60 cyclic heptapeptide hepatotoxins
      produced by cyanobacteria. The 1-octanol/water partition coefficients (log P) of
      MC-LR, -LY, -LW and -LF have been estimated by HPLC to be 2.16, 2.92, 3.46 and
      3.56, respectively. Their in vivo toxicities to Tetrahymena pyriformis was also
      investigated. Twenty-four hour LC50 values followed the order MC-LR > -LY > -LW
      approximately -LF. The LC50 values of MC-LR and -LY were significantly reduced in
      the presence of 1% (v/v) dimethylsulphoxide, although no significant effect
      occurred with MC-LW or -LF. Tetrahymena pyriformis respiration rates were
      inhibited by MC-LR in both a time- and dose-dependent manner. Increasing log P of
      the MC used caused a significantly greater inhibition of respiration. Population
      growth rate and maximum culture density were inhibited by all MC variants in
      proportion to log P. Positive correlations between all toxicological endpoints
      and log P occurred, with the most hydrophobic toxin, MC-LF, being 1.4 to 3.5
      times more toxic than MC-LR. MC-LW had a similar toxicity to MC-LF, while MC-LY
      toxicity was intermediate between that of MC-LR and -LF. Implications of this
      positive relationship between in vivo toxicity and hydrophobicity for the
      toxicity of MC to aquatic organisms, and the potential for using log P as a
      descriptor in a quantitative structure-activity relationship for MC, are
      discussed.

PMID- 10347883
TI  - Chlorination and ozonation of waste-water: comparative analysis of efficacy
      through the effect on Escherichia coli membranes.
AB  - The effect of chlorine and ozone on Escherichia coli cells resuspended in waste
      water was compared. Selected chlorination and ozonation conditions produced a
      similar decrease in culturability (2-2.5 log). Under these conditions,
      differences in membrane permeability and cell surface hydrophobicity, depending
      on the disinfectant tested, were detected. After ozonation, while no changes in
      cell surface hydrophobicity were observed, approximately 95.5% of cells showed
      altered membrane permeability. The effect of chlorine was not linked to changes
      in membrane permeability. After chlorination, E. coli cells showed a tendancy to
      aggregate. The possibility that aggregation of cells could interfere with
      conventional colony counts is discussed. The degree of toxicity (Microtox assay)
      was unrelated to the effect on cellular activity.

PMID- 10347884
TI  - Analysis of urine samples containing cardiovascular drugs by micellar liquid
      chromatography with fluorimetric detection.
AB  - A simple direct injection chromatographic procedure with fluorimetric detection
      is successfully applied to the determination of mixtures of 4 diuretics
      (amiloride, bendroflumethiazide, piretanide, and triamterene) and 6 beta-blockers
      (acebutolol, atenolol, labetalol, metoprolol, nadolol, and propranolol), which
      are usually administered in combinations for the treatment of hypertension, in
      urine samples. The procedure makes use of C18 columns and micellar mobile phases
      of sodium dodecyl sulphate (SDS), propanol, and phosphate buffer at pH 3. The
      adequate resolution of most drugs is obtained with a chemometrics approach where
      the retention is modeled as a first step using the retention factors in only 5
      mobile phases. Afterward, an optimization criterion that takes into account the
      position and shape of the chromatographic peaks is applied. A mobile phase of
      0.11M SDS--8% propanol could resolve mixtures of 8 drugs and was adequate for the
      analysis of the combinations of diuretic and beta-blocker usually prescribed.
      However, a mobile phase of larger elution strength, such as 0.15M SDS--15%
      propanol, is preferred for the analysis of mixtures of amiloride-metoprolol,
      amiloride-labetalol, and triameterene-propranolol. The method is sensitive enough
      for the routine analysis of diuretics and beta-blockers at therapeutic urine
      levels with limits of detection in the 0.5-28-ng/mL range. Urinary excretion
      studies show that the detection of most drugs is possible up to 24-72 h after
      their ingestion.

PMID- 10347885
TI  - Shiga toxin-producing Escherichia coli in sheep and pre-slaughter lambs in
      eastern Australia.
AB  - Sheep and lambs from 14 farms in southern Queensland and one from central New
      South Wales were surveyed to determine the prevalence of Shiga toxin-producing
      Escherichia coli (STEC). STEC, isolated from 45% of 144 sheep faeces collected on
      the farms and 36% of 72 lamb faeces from abattoir yards, were tested for the
      presence of genes encoding virulence factors. Most (64%) of the 117 STEC isolates
      contained Shiga toxin 1 and 2 genes, 22% contained those encoding Shiga toxin 1,
      and 14% contained genes encoding Shiga toxin 2. The genes encoding the E. coli
      attaching and effacing factor were present in 2.6% of STEC and 26% contained the
      enterohaemolysin gene. The isolates that contained the E. coli attaching and
      effacing gene were serotype O157:H. This study has shown that STEC are widely
      distributed in eastern Australian sheep and lambs and are shed in their faeces
      prior to slaughter. Thus, there is potential for contamination of carcasses and
      entry of STEC into the human food chain.

PMID- 10347886
TI  - Synergistic effect of heat and sodium lactate on the thermal resistance of
      Yersinia enterocolitica and Listeria monocytogenes in minced beef.
AB  - The effect of sodium lactate (NaL) (0, 2.4 or 4.8%), in heating and recovery
      media, on Yersinia enterocolitica and Listeria monocytogenes numbers recovered
      from minced beef heated at 55 degrees C, was examined. Survivors were enumerated
      on selective media at pH 5.7/7.4 (Y. enterocolitica) or pH 5.7/7.2 (L.
      monocytogenes). Recovery of the organisms depended on the pH and NaL levels in
      the recovery medium. The heat resistance of Y. enterocolitica (P < 0.001) and L.
      monocytogenes (P < 0.01) decreased as the concentration of NaL in the minced beef
      increased from 0 to 2.4% or 4.8%. The thermal destruction of pathogens in foods
      processed using mild temperatures may be enhanced by the addition of 2.4% NaL.

PMID- 10347888
TI  - Bacterial surface display of an anti-pollutant antibody fragment.
AB  - A peptidoglycan-associated lipoprotein (PAL) fused to an antibody fragment (scFv)
      specific to the herbicide and environmental pollutant atrazine, has been
      successfully targeted to the cell surface of Escherichia coli. Anti-atrazine
      binding could be observed via an atrazine-alkaline phosphatase conjugate. Cells
      containing the PAL fusion grew with little cellular toxicity when compared with
      the control. In contrast, expression of anti-atrazine antibody fragments alone
      caused the cells to lyse after 4 h. The surface display of anti-pollutant
      antibodies may have a future role in the bioremediation of contaminated water or
      the development of pollutant-specific, whole-cell biosensors.

PMID- 10347890
TI  - Isolation, partial purification and characterization of a bacteriocin produced by
      a newly isolated Bacillus subtilis strain.
AB  - A wild type micro-organism producing antibacterial substances has been isolated
      from a Chinese fermented soybean seasoning and identified as Bacillus subtilis. A
      crude antibacterial preparation (CABP) was obtained by ammonium sulphate
      precipitation. Isoelectric focusing assay revealed at least four antimicrobial
      components in the CABP. However, in SDS-PAGE analysis, only one peptide band
      displayed antimicrobial activity against pathogenic Bacillus cereus and Listeria
      monocytogenes. This inhibitory peptide had a molecular weight of approximately
      3.4 kDa and a pI value of approximately 4.7. Results of this study suggest that
      at least one antimicrobial substance produced by this wild type strain of B.
      subtilis may be a new bacteriocin. Its sensitivity to gastric peptidases and
      activity against the food-borne pathogens make this bacteriocin potentially
      useful as an antimicrobial agent in foods.

PMID- 10347889
TI  - Lacticin 3147 displays activity in buffer against gram-positive bacterial
      pathogens which appear insensitive in standard plate assays.
AB  - Lacticin 3147 is a broad-spectrum bacteriocin produced by Lactococcus lactis
      subsp. lactis DPC3147, which has been shown to be active against a range of food
      borne bacteria. The reported inhibitory range for lacticin is extended to include
      methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus
      faecalis, penicillin-resistant Pneumococcus, Propionibacterium acne and
      Streptococcus mutans. This extended host range is not obvious from traditional
      agar plate-based methods, but reductions in bacterial cell numbers by up to 6
      log10 cfu ml-1 was observed after 2 h in time-kill curve studies conducted in
      broth, suggesting that the bacteriocin may have potential as a therapeutic agent
      in the treatment of human infections.

PMID- 10347891
TI  - Presence of peptidase activities in different varieties of cheese.
AB  - Lactic acid bacteria (LAB) counts, PepX activity towards H-Phe-Pro-beta NA, and
      aminopeptidase activity towards H-Arg-beta NA. HCl, H-Lys-beta NA, H-Leu-beta NA,
      H-Pro-beta NA, H-Glu-beta NA derivatives have been evaluated in 32 commercial
      samples of cheese, one processed cheese, and one yoghurt. The presence of
      intracellular exo-peptidase activities in cheese extracts free from bacterial
      cells was detected, even after 1 year of ripening. An inverse ratio between the
      presence of viable lactic microflora and peptidase activity in the cheese
      extracts was observed. The importance of LAB starter exo-peptidases in the
      degradation of casein oligopeptides, and the key role of autolysis in the release
      of peptidases in the cheese, are discussed.

PMID- 10347892
TI  - Nisin and ALTA 2341 inhibit the growth of Listeria monocytogenes on smoked salmon
      packaged under vacuum or 100% CO2.
AB  - The effects of nisin and ALTA 2341 on the growth of Listeria monocytogenes were
      assessed on smoked salmon packaged under vacuum or 100% CO2. Smoked salmon slices
      (pH 6.3) were inoculated with a cocktail of seven L. monocytogenes isolates at a
      level of approximately 2.5 log10 colony forming units (cfu) g-1. After
      inoculation, the surface of the smoked salmon slices was treated with either
      nisin (400 or 1250 IU g-1) or ALTA 2341 (0.1 or 1%). The smoked salmon was
      packaged and stored at 4 degrees C (28 d) or 10 degrees C (9 d). On untreated
      vacuum-packaged smoked salmon, L. monocytogenes grew by 3.8 log10 cfu g-1 at 4
      degrees C and 5.1 log10 cfu g-1 at 10 degrees C. Growth was reduced on nisin- and
      ALTA 2341-treated vacuum-packaged smoked salmon. On the nisin-treated samples, L.
      monocytogenes increased by 2.5 (400 IU g-1) and 1.5 (1250 IU g-1) log10 cfu g-1
      at 4 degrees C, and by 4.3 (400 IU g-1) and 2.7 (1250 IU g-1) log10 cfu g-1 at 10
      degrees C. With the ALTA 2341-treated samples, L. monocytogenes increased by 2.8
      (0.1%) or 1.6 (1.0%) log10 cfu g-1 at 4 degrees C, and 3.3 (0.1%) or 3.6 (1.0%)
      log10 cfu g-1 at 10 degrees C. The growth of L. monocytogenes was retarded by
      packaging the smoked salmon in 100% CO2. On untreated smoked salmon, only a 0.8
      log10 cycle increase was observed at 10 degrees C. Under all the other conditions
      tested with 100% CO2, L. monocytogenes was detected but growth was prevented.

PMID- 10347894
TI  - Osmotic stress on dilution of acid injured Escherichia coli O157:H7.
AB  - To determine surviving numbers of Escherichia coli from cultures or food systems,
      dilution with 0.1% peptone is regularly used. Higher numbers of survivors could
      be obtained from an acid-treated culture if 0.5 mol l-1 sucrose was added to the
      0.1% peptone. Sorbitol, glucose or sodium chloride, but not glycerol, could be
      used in place of sucrose. Using electron microscopy distinct differences could be
      seen between acid-treated and untreated cells. The osmolarity of the diluents
      ranged from 5 to 500 mosmol kg-1 H2O for the 0.5 mol l-1 sugar or glycerol
      solutions, to about 1000 mosmol kg-1 H2O for the salt solution. Maximum recovery
      diluent has an osmolarity of about 300 mosmol kg-1 H2O and resulted in recovery
      of similar numbers of injured cells as a 0.5 mol l-1 solution of sugar in 0.1%
      peptone. Taking into account the observed damage to acid-treated cells and the
      differences in osmolarity of the diluents, it is likely that dilution in 0.1%
      peptone imposed additional stress on the acid-injured cells which caused further
      cell damage. Dilution in a more osmotically stable solution alleviated this
      osmotic stress.

PMID- 10347895
TI  - Improved cytotoxicity assay for Bacillus cereus diarrhoeal enterotoxin.
AB  - An improved McCoy cell cytotoxicity assay for Bacillus cereus diarrhoeal toxin,
      which includes a staining procedure in addition to visual examination, was
      developed and the method was compared with two commercially available kits (Oxoid
      BCET-RPLA and Tecra BDE-VIA). A total of 71 strains of 15 different Bacillus,
      Brevibacillus and Paenibacillus species, including 16 strains of B. cereus from
      outbreaks of food-borne illness, were evaluated for toxin production. Eleven of
      the outbreak strains exhibited cytotoxicity, including all six B. cereus strains
      associated with diarrhoeal illness. Several other isolates of B. cereus, and its
      relatives B. anthracis, B. mycoides and B. thuringiensis, exhibited similar
      cytotoxicity. The other species showed no cytotoxicity, with the exception of
      certain B. subtilis strains. The cytotoxicity assay was more sensitive than the
      Oxoid kit and unlike the Tecra kit, did not give false positive results with
      supernatant fluids heat-treated to destroy the toxin.

PMID- 10347897
TI  - Abundance and distribution of bacteria carrying sltII gene in natural river
      water.
AB  - Direct in situ PCR with HNPP/Fast Red TR was used to enumerate bacteria carrying
      the sltII gene in river water. By direct in situ PCR with a sltII-specific EVS
      primer, 10(2)-10(5) cells ml-1 of bacteria carrying the sltII gene were detected
      from all sampling sites, except the site nearest to the source of the river,
      while 10(2)-10(4) cells ml-1 of Escherichia coli O157:H7 were detected using a
      direct fluorescent antibody staining method. These results indicate that such
      bacteria are commonly distributed in natural river water. Direct in situ PCR with
      HNPP/Fast Red TR is a useful tool for detecting cells carrying specific genes,
      such as verotoxin-producing bacteria in natural environments.

PMID- 10347898
TI  - Bacterial loss from biofilms exposed to free chlorine.
AB  - Previous studies have demonstrated the increased resistance of biofilm bacteria
      to biocides when compared with freely suspended planktonic cells, but there have
      been few investigations of sloughing and losses from biofilms in response to
      biocide activity. A model biofilm system was used to demonstrate that the loss of
      sloughed bacteria (including Escherichia coli as a pathogen indicator organism)
      from actively growing biofilm reached levels of 10(6)-10(7) CFU ml-1 of eluted
      medium. The sloughing response was examined in response to a range of free
      chlorine concentrations from 0.6 to 5.0 mg l-1. While chlorine treatment greatly
      reduced bacterial sloughing, significant bacterial loss into the planktonic phase
      still occurred with free chlorine concentrations below 3.0 mg l-1, indicating
      active growth and sloughing of biofilm organisms. Exposure of the biofilm to
      higher levels of free chlorine resulted in inhibition of bacterial loss, though
      biocide removal was accompanied by a rapid, almost immediate, recovery of
      sloughing ability. This work demonstrates the endurance and speed of biofilm
      recovery upon quenching of chlorine residuals, highlighting a potentially
      significant public health risk from biofilm recovery and the sloughing of
      pathogenic organisms associated with the biofilm.

PMID- 10347900
TI  - Location of haemagglutinin in bacterial cells of Fusobacterium necrophorum subsp.
      necrophorum.
AB  - The location of haemagglutinin (HA) of Fusobacterium necrophorum subsp.
      necrophorum VPI 2891 strain was investigated by immunofluorescence, confocal
      laser scan microscopy and immunoelectron microscopy. The immunofluorescence study
      demonstrated the fluorescence specific for the HA on the bacterial cells and
      confocal laser scan microscopy indicated similar fluorescence around the cross
      section of the bacterial cell. The immunoelectron microscopic study also revealed
      that the protein A-gold conjugates were located around the bacterial surfaces.
      These findings suggest that HA is one of the components of the cell surfaces of
      F. necrophorum subsp, necrophorum.

PMID- 10347899
TI  - Epstein-Barr virus and oral squamous cell carcinoma in patients without HIV
      infection: viral detection by polymerase chain reaction.
AB  - In order to test the hypothesis that Epstein-Barr virus (EBV) may be a cofactor
      for oral squamous cell carcinoma (OSCC) the authors evaluated tumour cells from
      OSCC of 108 patients without HIV infection, for the presence of EBV DNA by
      polymerase chain reaction. The sequences of oligonucleotides used in the
      amplification and hybridization included a set for the DNA polymerase region. The
      amplification was detected using an ELISA assay with peroxidase. EBV DNA was
      detected in 17.59% of the tumours. Inhibition studies showed that the ability to
      detect EBV DNA was not affected by the pathological material, suggesting that the
      negative PCR results in these samples were not caused by PCR inhibitors in the
      biopsy. Results revealed that 63.1% of the tumours (12 cases) were DNA positive
      affecting the lateral margin of the tongue, and were statistically significant (p
      < 0.001; chi 2). In the pool of tumours with EBV DNA only 26.3% (5 of 19 cases)
      were well differentiated OSCCs whereas the remaining 73.7% (14 of 19 cases) were
      moderately and poorly differentiated OSCCs, with a statistical significance of p
      = 0.08; chi 2. This study suggests a relationship between OSCC and EBV.

PMID- 10347901
TI  - Mitogenic activity of the outer membrane of Treponema denticola.
AB  - The outer membrane (OM) was isolated by detergent extraction from Treponema
      denticola ATCC 35405, ATCC 33521 and ATCC 35404, representing serovars a, b and
      c, respectively, as well as from two fresh isolates of T. denticola. Strict
      precautions were undertaken against the introduction of contaminant
      lipopolysaccharide when the OM was isolated. The OM was active in mitogenic
      stimulation of C3H/HeOuJ mouse spleen cultures, but to a somewhat lesser extent
      than purified lipopolysaccharide (LPS) from Escherichia coli 055:B5. Polymyxin B
      only partially inhibited the response. Unheated OM abrogated mitogenic activity
      of E. coli LPS, but heated preparations enhanced the mitogenic activity of E.
      coli LPS, suggesting the presence of a heat-labile cytolytic factor associated
      with T. denticola OM in addition to a putative lipopolysaccharide and/or heat
      stable lipoprotein.

PMID- 10347902
TI  - Carbamic acid: molecular structure and IR spectra.
AB  - Infrared absorption spectra of mixed H2O, NH3 and 12CO2/13CO2 ices subjected to 1
      MeV proton irradiation were investigated. The results of analyses of the spectra
      suggest formation of carbamic acid at low temperatures. The stability of this
      compound in the solid phase is attributed to intermolecular hydrogen bonding of
      the zwitter-ion (NH3+ COO-) structure.

PMID- 10347903
TI  - Observations on photochemical fluorescence enhancement of the terbium(III)
      sparfloxacin system.
AB  - Fluorescence of terbium(III) was sensitized when excited in the presence of
      sparfloxacin (SPFX) in the aqueous solution because a Tb(III)-SPFX complex was
      formed. The sensitized fluorescence was further enhanced when this system was
      exposed to 365 nm ultraviolet light. By the spectral properties and contrast
      experiments, it is proved that irradiation makes this system undergo
      photochemical reactions and a new terbium complex which is more favorable to the
      intramolecular energy transfer is formed. The mechanism of photochemical
      fluorescence enhancement of the Tb(III)-SPFX system is discussed and a new
      sensitive and selective photochemical fluorimetry for the determination of SPFX
      is established. Under the optimum conditions, the linear range is 1.0-50 x 10(-7)
      M for SPFX, the detection limit is 3.0 x 10(-9) M and the R.S.D. for 5.0 x 10(-7)
      M SPFX is 1.3% (n = 9). Without any pretreatment the recovery of SPFX in human
      urine was determined with satisfaction.

PMID- 10347904
TI  - [Basic life support in adults by a single rescuer. International Liaison
      Committee on Resuscitation].

PMID- 10347905
TI  - [Universal algorithm for advanced life support].

PMID- 10347906
TI  - [Early defibrillation].

PMID- 10347907
TI  - [Life support in pediatrics].

PMID- 10347908
TI  - [Special situations in resuscitation].

PMID- 10347909
TI  - Chronic coronary artery disease.

PMID- 10347910
TI  - Rational utilization of diagnostic tests in cardiology.

PMID- 10347911
TI  - Neoplastic pericardial disease. Analysis of 26 patients.
AB  - PURPOSE: To characterize patients with neoplastic pericardial disease diagnosed
      by clinical presentation, complementary test findings, and the histological type
      of tumor. METHODS: Twenty-six patients with neoplastic pericardial disease were
      retrospectively analyzed. RESULTS: Clinical manifestations and abnormalities in
      chest roentgenograms and electrocardiograms were frequent, but were not specific.
      Most patients underwent surgery. There was a high positivity of the pericardial
      biopsy when associated with the cytological analysis of the pericardial liquid
      used to determine the histological type of the tumor, particularly when the
      procedure was performed with the aid of pericardioscopy. CONCLUSION: The correct
      diagnosis of neoplastic pericardial disease involves suspicious but nonspecific
      findings during clinical examination and in screen tests. The suspicious findings
      must be confirmed through more invasive diagnostic approaches, in particular
      pericardioscopy with biopsy and cytological study.

PMID- 10347912
TI  - Percutaneous closure of atrial septal defects. The role of transesophageal
      echocardiography.
AB  - PURPOSE: Evaluation of the role of transesophageal echocardiography in
      percutaneous closure of atrial septal defects (ASD) with the Amplatzer septal
      occluder. METHODS: Patients were selected for percutaneous closure of ASD by
      transesophageal echocardiography (TEE), which was also used to monitor the
      procedure, helping to select the appropriate size of the Amplatzer device, to
      verify its position, and to access the immediate results of the procedure. During
      the follow-up, TEE was used to evaluate the presence and magnitude of residual
      shunt (RS), device position, and right cardiac chamber diameters. RESULTS: Twenty
      two (40%) of a total of 55 studied patients were selected. Thirteen underwent
      Amplatzer device implantation, eight are still waiting for it, and one preferred
      the conventional surgical treatment. All procedures were successful, which was
      mainly due to proper patient selection. Six (23%) patients acutely developed RS,
      which spontaneously disappeared at the three-month follow-up examination in three
      patients. There was a significant reduction in the right ventricle diastolic
      diameter, from 27 mm (average) to 24 mm and 20 mm, one and three months after the
      procedure, respectively (p < 0.0076). CONCLUSION: With the aid of TEE,
      percutaneous closure of ASD can be successfully, safely, and effectively
      performed.

PMID- 10347913
TI  - Relapsing pulmonary embolism in a patient with a spinal cord-injury.

PMID- 10347914
TI  - Tetralogy of Fallot and aortic coarctation. A rare association.

PMID- 10347915
TI  - Cardiovascular changes and cardiac morbidity of menopause. Effects of hormone
      replacement therapy.

PMID- 10347916
TI  - The no reflow phenomenon in the coronary arteries.

PMID- 10347917
TI  - [Basic step sequence in the development of research protocols].

PMID- 10347918
TI  - [Quantification of mitral prosthesis failure by different methods of evaluation
      by transesophageal echocardiography].
AB  - PURPOSE: To evaluate the different methods for grading mitral regurgitation (MR)
      by transesophageal echocardiography (TEE) in patients with clinical suspicion of
      mitral prosthesis dysfunction. METHODS: Cardiac catheterization (Cath) was
      performed in 15 patients for grading the severity of prosthetic MR, divided in
      two groups based on the presence or absence of severe MR. Prosthetic MR was
      quantified by TEE using methods commonly used for MR of native valves: subjective
      assessment by color Doppler, objective assessment based on absolute jet area and
      on its relative area (jet area/left atrial area) and assessment based on the
      presence of systolic flow reversal in pulmonary vein. RESULTS: Prosthetic MR was
      mostly transprosthetic (14 patients) and eccentric (11 patients). There was
      significant correlation (p < 0.05) between Cath and TEE for identification of
      severe MR based on subjective assessment and on the presence of systolic flow
      reversal in pulmonary vein. Identification based on absolute (jet area > 7 cm2)
      and relative (jet area > 35% of left atrial area) jet areas did not reveal
      significant correlation with the angiographic grade and showed clear
      underestimation by TEE when the last method was used. However, there was good
      correlation (p < 0.05) if relative jet areas > 30% were considered as cut point.
      CONCLUSION: TEE correctly identified angiographic severe mitral prosthesis
      regurgitation, mainly by the presence of systolic flow reversal in pulmonary vein
      and subjective assessment. The estimation of severity of the prosthetic MR by
      absolute or relative jet area seems to be limited and should be used with caution
      due to eccentricity of the regurgitant jet, frequently seen in mitral prosthesis
      dysfunction.

PMID- 10347919
TI  - [Myocardial revascularization surgery via a left minithoracotomy].
AB  - PURPOSE: There is, today, a global tendency towards a surgical approach
      privileging very small incisions, the so-called minimally invasive intervention,
      which results in a less aggressive action. The introduction of this new technique
      makes it possible to dissect the left internal thoracic artery (LITA) and to
      perform in the anastomosis with the anterior interventricular artery (AIA)
      through a left minithoracotomy. METHODS: From May of 1996 to october of 1997, 11
      patients with ischemic heart disease and a single proximal lesion of the AIA were
      submitted to a myocardial revascularization (MR). The surgical approach consisted
      of a left anterolateral thoracotomy through the 4th left intercostal space, of
      approximately 10 cm, and in the last 6 cases, resection of part of the cartilage
      of the 4th and 5th ribs, dissection of the LITA, as well as opening and repair of
      the pericardium adjacent to the AIA was done. All patients received a single
      bypass to the AIA with a graft of the LITA, without extracorporeal circulation.
      RESULTS: The patients' age varied between 46 and 76 years (mean = 58.55). Ten
      patients (90.90%) were males and 1 (9.09%) was a female. Hospital stay ranged
      from 4 to 8 days, with the average of 5.2 days. None of the patients presented
      any electrocardiographic change in the immediate post-operatory period. During
      the control period one patient developed a clot in the distal LITA, with
      important compromise of the flow. In another patient the stenosis was at the
      level of the anastomosis. Both were successfully submitted to angioplasty. There
      were no deaths in the groups studied. CONCLUSION: The absence of deaths suggests
      to us that MR surgery carried out with this minimally invasive technique, in
      selected groups and is an excellent alternative to the revascularization of the
      AIA.

PMID- 10347920
TI  - [Pacemaker with sensor of contractility regulated by autonomic nervous system
      variations in chronic Chagas cardiomyopathy].
AB  - PURPOSE: To analyse the performance of the artificial cardiac stimulation with
      the VVIR pacemaker whose sensor is adjusted by the variations of the autonomic
      nervous system in Chagas disease patients with deficiency of the conduction
      system. METHODS: Forty-seven Chagas disease patients have been studied, 28 male
      between 24 and 68 years old, 36 patients had complete AV block, 8 had 2nd degree
      AV block and the other 3 had sinusnode disease. The patients were in class I (4),
      II (15), III (16) and IV (12) according to the NYHA. A 12-month-follow-up with
      constant clinical evaluations was carried out after pacemaker implantation.
      Patients were divided in 2 different groups according to the HR at rest--group 1:
      > 65 beats per minute (bpm) and group 2: < or = 65 bpm, for a comparative study
      considering: 1) HR at stress test after the implantation; 2) arterial blood
      pressure at rest after the implantation and, 3) evaluation of the identified
      electrodes such as TIR-60-UP and others. RESULTS: The group 1 had greater HR at
      rest, and a smaller variation of values at stress than group 2. This shows that
      with this type of stimulation system it is possible to control each patient
      separately. The values of blood pressure at rest and during stress were not
      different between groups. According to the factors analysed the TIR-60-UP
      electrode had the same performance as the others. CONCLUSION: The VVIR pacemaker
      with the sensor adjusted by the ANS variations has provided the Chagas patients
      with a restoration of their physiological mechanisms. 74% of them had the
      improvement of either one or 2 functional classes.

PMID- 10347921
TI  - [Diagnosis wi transesophageal echocardiography and clinical course of 35 patients
      with flail mitral valve].
AB  - PURPOSE: To describe transesophageal echocardiographic findings in patients
      presenting with flail mitral valve and to obtain their clinical follow-up.
      METHODS: From January/93 to March/97, 1675 patients were submitted to
      transesophageal echocardiogram at our institution; 35 of them were diagnosed as
      having flail mitral valve and their clinical follow-up was obtained. RESULTS:
      Thirty-five patients with the diagnosis of flail mitral valve were studied. Mean
      age was 65 +/- 15 years (12-87) and 27 (77%) were male. The posterior leaflet was
      involved in 25 (71%) patients. Ruptured chrodae tendineae was present in all but
      one patient in whom flail mitral valve was due to a very elongated and redundant
      chordae. The etiology was prolapse and/or mixomatous degeneration in 16 patients,
      degenerative in 10, ischemic in 5, rheumatic in 4 and endocarditis in 3. Mitral
      regurgitation was severe in 25 (71%) patients and moderate in 10 (29%). The mean
      follow-up was 375 +/- 395 days (1 to 1380). Nineteen patients were followed
      clinically and 16 were submitted to surgery (transesophageal echocardiogram
      findings were confirmed in all 16). Overall mortality was high (34%). Among the
      survivors, 17 are in NYHA class I and 6 in class II. CONCLUSION: The diagnosis of
      flail mitral valve by transesophageal echocardiography is accurate, allowing for
      the definition of its mechanism and etiology, as well as the evaluation of
      hemodynamic compromise. The observed high mortality at the time of diagnosis may
      be related to the severity of the disease causing the flail mitral valve.
      Although non-operated survivors are doing well, the observed low functional class
      in these patients may be related to the short period of follow-up.

PMID- 10347922
TI  - [Overall experience with percutaneous occlusion of patent ductus arteriosus].
AB  - PURPOSE: To evaluate the overall experience of our institution with percutaneous
      occlusion of the patent ductus arteriosus. METHODS: Since December/92, 150
      patients underwent 178 procedures (85-Rashkind technique; 87-Gianturco coils; 6
      Duct Occlud). Median age was 6.5 years (1 to 57). Mean minimum ductal diameter
      was 3.05 +/- 1.24 mm (1 to 8). Clinical and echocardiographic evaluations were
      performed periodically. RESULTS: Adequate implantation was achieved in 143
      (95.3%) patients. Prevalence of immediate residual shunting was 52.1%, falling to
      15.9% during follow-up. This figure decreased to 5.2% after new additional
      procedures. Umbrella and coil embolization occurred in 1 and 12 procedures,
      respectively. Hemolysis and mild stenosis of left pulmonary artery were observed
      in one patient each. There was no mortality. CONCLUSION: This therapeutic
      modality is safe and efficacious with good follow-up results.

PMID- 10347923
TI  - [Significance of alcohol abstinence in alcoholic cardiomyopathy with moderate
      left ventricular dysfunction].
AB  - PURPOSE: To evaluate the role of a 12 month alcohol abstinence period in patients
      with moderate left ventricular dysfunction treated with anticongestive therapy.
      METHODS: Prospective observational study with 20 patients with alcoholic
      cardiomyopathy (ACM), 9 (45%) in functional class (FC) II and 11 (55%) in FC III,
      16 (80%) men, mostly black (55%), from 35 to 56 (x = 45) years old, heavy alcohol
      users (> 80 g ethanol for 51 to 112 (x = 88) months. At the beginning, all agreed
      to participate with psychotherapy and clinical evaluation. After 12 months, they
      were divided in G-I, formed by those who remained abstemious and G-II of non
      abstemious. RESULTS: After 12 months, among the 11 (55%) who remained in
      psychotherapy, 8 were in G-I, among those who did not 9 (45%), only 2 (22.22%)
      remained abstemious (G-I). At the end of the evaluation period, both groups had
      the same number of patients. Comparing them, we observed: a) lower mean systolic
      and diastolic left ventricular diameters in G-I; b) more hospitalizations in G-II
      (3); c) more patients with stable or better clinical evaluation in G-I.
      CONCLUSION: Despite the initial will, only 50% reached abstinence. When it was
      reached, patients had a better evolution in left ventricular systolic diameter
      and abstinence should always be tried even in the presence of moderate left
      ventricular dysfunction.

PMID- 10347924
TI  - [Heart rate response and its variability during different phases of maximal
      graded exercise].
AB  - PURPOSE: Heart rate variability (HRV) has been studied at rest as a non-invasive
      tool for the assessment of cardiac autonomic control and, its attenuation is
      related to cardiovascular risk. However, during exercise, when important neural
      changes take place, HRV behaviour is not well established. The aim of this
      investigation was to study the heart rate (HR) and HRV responses during the
      different metabolic phases of maximal graded exercise in young men. METHODS:
      Seventeen men (age 28 +/- 6 years) were submitted to a graded cardiopulmonary
      exercise test in a cycloergometer (30W/3 min). To study HR and HRV (standard
      deviation), the electrocardiographic signal was amplified and acquired beat-to
      beat in a computer at a frequency of 125 Hz (AT/Codas). RESULTS: The HR increases
      concomitantly to the increase in exercise intensity. The HRV was significantly
      lower than rest values after exercise intensities of 60% of peak exercise oxygen
      uptake, 45-60% of maximal power and, after anaerobic threshold intensity.
      CONCLUSION: This results suggest that HRV measured by standard deviation of HR
      decreases during exercise phases when HR increment is determined mainly due to
      vagal withdrawal.

PMID- 10347925
TI  - [Absence of right atrioventricular connection. Morphological and clinical
      presentation when the dominant ventricle is morphologically right].
AB  - Absent right atrioventricular connection, with the left atrium connected to a
      dominant left-sided morphologically right ventricle is a rare situation. We
      report five cases with these anatomical features, with emphasis on the
      morphological and clinical aspects. Although this combination of lesions is very
      uncommon, the sequential segmental analysis can easily provide an accurate
      description of the anomaly.

PMID- 10347926
TI  - [Anatomoclinical correlation (case n. 6/98--Instituto Dante Pazzanese de
      Cardiologia-Sao Paulo)].

PMID- 10347927
TI  - [Heart failure in the elderly. Differences and similarities with the young].

PMID- 10347929
TI  - [The impact HMG-CoA reductase inhibitors in the modification of the natural
      history of coronary artery disease]

PMID- 10347928
TI  - [Dyslipidemia in children and adolescents. Therapeutic bases].

PMID- 10347930
TI  - [Heart failure in Brazil].

PMID- 10347931
TI  - [In search of new paradigms for the management of heart failure].

PMID- 10347932
TI  - [Essential items in biostatistics].

PMID- 10347933
TI  - [Home blood pressure measurement and ambulatory blood pressure measurement versus
      office blood pressure measurement].
AB  - PURPOSE: To compare both home blood pressure measurement (HBPM) and ambulatory
      blood pressure monitoring (ABPM) with office blood pressure measurement (OBP);
      and also to compare the correlation between HBPM and OBP with LVMI (left
      ventricular mass index). METHODS: Protocol 1--68 hypertensive patients (58 +/- 12
      years, 37 females): a) self recorded blood pressure at home in the 7 days; b)
      recorded the ABPM during 24 hours; and c) the physician recorded blood pressure
      in the office. Protocol 2-41 hypertensive patients underwent the HBPM, OBP, and
      BI-dimensional echocardiogram. RESULTS: Protocol 1--OBP (153 +/- 24/96 +/- 13
      mmHg) was higher (p < 0.05) than HBPM (133 +/- 18/84 +/- 12 mmHg) and ABPM (137
      +/- 17/87 +/- 12 mmHg); Protocol 2--LVMI correlated better with HBPM (r =
      0.39/0.49, p < 0.05, systolic and diastolic, respectively) than OBP (r = 0.02/
      0.22, p > 0.05, systolic and diastolic, respectively). CONCLUSION: This study
      showed that HBPM has a better correlation with LVMI than OBP.

PMID- 10347934
TI  - [Difference of hospital mortality of acute myocardial infarction between men and
      women treated with primary angioplasty].
AB  - PURPOSE: To compare the in-hospital case-fatality rate of men and women submitted
      to percutaneous transluminal coronary angioplasty (PTCA) as a strategy of
      reperfusion in acute myocardial infarction (MI). METHODS: A retrospective cohort
      study based on information abstracted from medical records of MI patients
      admitted to a hospital where PTCA is used as the preferred method for early
      myocardial reperfusion. A total of 83 patients, 35 (42%) women and 48 (58%) men,
      who met the criteria for early myocardial reperfusion was included in the
      analysis. RESULTS: The mean age of women was higher than that of men (66 +/- 10
      vs 58 +/- 11 years; p < 0.001). The women also had a higher frequency of diabetes
      mellitus (37.1% vs 6.4%; p < 0.001). Despite these differences in age and in the
      frequency of diabetes mellitus, the percentage of patients in whom the PTCA was
      considered successful was similar between men (83.3%) and women (82.3%). The case
      fatality rate was also similar between men and women; 14.6% and 14.3%,
      respectively. CONCLUSION: The possibility that the excess risk of death in women
      with MI may be reduced and even eliminated with the use of PTCA, supports to the
      need for the development of a clinical trial to assess this question.

PMID- 10347935
TI  - [Coronary intervention at a general hospital in the State of Piaui, Brazil].
AB  - PURPOSE: To evaluate retrospectively success and complication rates of coronary
      interventions performed in a general hospital with no digital equipment in the
      State of Piaui with a small annual number of procedures. METHODS: From August/91
      to January/98, 122 patients underwent 146 procedures using a fluoroscope with
      camera and TV monitor of 525 lines. The variables analyzed included the initial
      success of procedures (residual stenosis less than fifty percent and TIMI III
      flow) and more serious complications (acute occlusion, infarcts, emergency
      surgeries and death). The clinical data and the morphological characteristics of
      the lesions (ACC/AHA Task Force) were also analyzed. RESULTS: Eighty five percent
      of the patients presented with an acute ischemic syndrome (acute myocardial
      infarction, post infarction angina, rest angina), 5% were in cardiogenic shock
      and 88% had type B lesions. The initial success rate was 93% while the more
      serious complications occurred in 3.5% of the cases. CONCLUSION: In spite of the
      small annual procedural volume and the use of conventional equipment, the initial
      success rate in our institution was excellent in a diverse and complex patient
      population while the complication rates were similar to that of the literature.

PMID- 10347936
TI  - [High resolution electrocardiogram in frequency domain. Use of statistical
      techniques of spectral correlation for identification of patients with sustained
      monomorphic ventricular tachycardia].
AB  - PURPOSE: To evaluate the diagnostic accuracy of monomorphic ventricular
      tachycardia (MVT), in patients with structural heart diseases and episodes of
      sustained MVT, using the signal-averaged ECG (SAECG) in the time (TD) and the
      frequency domain (FD) with statistical techniques of spectral correlation.
      METHODS: Twenty seven patients with at least one episode of sustained MVT, 30
      patients with structural heart diseases and no evidence of ventricular
      arrhythmias and 80 subjects with no evidence of heart disease have been studied.
      SAECG was performed in all patients with the following parameters: duration of
      the filtered QRS, RMS 40 and LAS40 in TD and the mean and the standard deviation
      of both signal energy intersegmentar spectral correlation and energy frequency
      edge track in FD. RESULTS: The sensitivity(S) and positive predict value (PPV) of
      the SAECG in TD, in FD and combined analysis of both domains were: S = 59.3%,
      63.0%, 81.5% and PPV = 80.0%, 81.0%, 84.6%, respectively. CONCLUSION: The
      combined analysis of SAECG in TD and in FD improves the diagnostic accuracy in
      patients with S sustained MVT.

PMID- 10347937
TI  - [Efficacy and tolerance of the bisoprolol/hydrochlorothiazide combination in
      arterial hypertension].
AB  - PURPOSE: Multicenter, open and non-controlled study to evaluated the efficacy and
      the tolerability of a low-dose combination of two anti-hypertensive agents: a
      cardioselective beta-blocker, bisoprolol (2.5 and 5.0 mg) with 6.25 mg of
      hydrochlorothiazide. METHODS: One hundred and six patients in the stage I and
      stage II of the systemic hypertension (mild to moderate) were given the
      bisoprolol/hydrochlorothiazide combination once daily and the diastolic and
      systolic blood pressures were monitored during the 8-week trial. RESULTS: The
      bisoprolol/hydrochlorothiazide combination reduced the initial mean values of
      systolic and diastolic blood pressures, respectively, from the 157.4 mmHg and
      98.8 mmHg to 137.3 mmHg and 87.4 mmHg. At the end of the treatment period, 61% of
      the patients normalized blood pressure values (< 90 mmHg) and 22.9% of them had
      responded to the treatment, resulting in a total response rate (normalized +
      responsive) of 83.9% of cases. Adverse events were described only in 18.9% of the
      patients and dizziness and headache were the most common. There were no
      clinically significant changes on plasma levels of potassium, uric acid, glucose,
      or in the lipid profile. CONCLUSION: The combination of low dosages of bisoprolol
      and hydrochlorothiazide may be considered an effective, well tolerated and
      rational alternative for the initial treatment of the patients with mild to
      moderate hypertension.

PMID- 10347938
TI  - [Intracardiac mass in suspected case of Wegener's granulomatosis].
AB  - Although Wegener's granulomatosis is known for almost 65 years, the disease is
      still a dilemma for physicians. This is probably due to its different clinical
      presentations or to the lack of diagnostic methods. The laboratorial diagnosis is
      supported on the presence of antineutrophil cytoplasmic antibodies (ANCA-c) and
      on histological analysis of tissues from affected organs. This paper describes a
      case report of a patient whose clinical history presented all protean aspects of
      the disease, including cardiac involvement such as myocarditis, pericarditis and,
      surprisingly, intracardiac mass.

PMID- 10347939
TI  - [Coronary sinus atrial septal defect, ventricular septal defect and absence of
      left superior vena cava].
AB  - We report a rare case of a 21 month old child with a coronary sinus atrial septal
      defect associated with perimembranous ventricular septal defect and no left
      superior vena cava. The diagnosis was made by transthoracic echocardiogram and
      confirmed by angiography. The patient was operated on uneventfully, both defects
      were closed with bovine pericardial patches and the flow from the coronary veins
      was directed towards the left atrium. An echocardiogram revealed complete closure
      of both defects.

PMID- 10347940
TI  - [Anatomoclinical correlation (case 5/98--Instituto do Coracao do Hospital das
      Clinicas--FMUSP)].

PMID- 10347941
TI  - [Partial left ventriculectomy. Forgotten paradigms].

PMID- 10347942
TI  - [Troponin as myocardial cell injury marker].

PMID- 10347943
TI  - [Heart failure].

PMID- 10347944
TI  - [Treatment of chronic Chagas' disease. Is the etiological treatment effective?].

PMID- 10347945
TI  - [Aortic coarctation. From simple diagnosis to unpredictable complications].

PMID- 10347946
TI  - [Evidence based cardiology--IV. Main research strategies and recommendation
      levels in cardiology].

PMID- 10347947
TI  - [High blood pressure among bank employees in Rio de Janeiro. Life-style and
      treatment].
AB  - PURPOSE: This study estimates the frequency of treatment of high blood pressure
      and compares life-styles among hypertensives and non-hypertensives. METHODS:
      Cross-sectional study in a systematic sample of 1183 employees in a government
      owned bank in the State of Rio de Janeiro, through a self-administered
      questionnaire. Direct measurements of arterial pressure, weight and height were
      also taken in a sub-sample. Those who had been informed more than once as having
      high blood pressure, by a health professional, were classified as hypertensives.
      RESULTS: There were no important differences among hypertensives and non
      hypertensives with respect to the prevalence of smoking, alcohol and physical
      activities. Dieting was more frequent among overweight/obese hypertensives than
      overweight/obese non-hypertensives. Only 44.7% were under treatment. Subjects
      with high level of education were more likely to be treated as were those who
      quit smoking, presented overweight/obesity or family history of cerebrovascular
      diseases. CONCLUSION: Access to information and health care was not sufficient to
      guarantee high blood pressure treatment or a healthy life-style which contributes
      to hypertension control.

PMID- 10347948
TI  - [Hemodynamic evaluation and clinical outcome of children with severe dilated
      cardiomyopathy eligible for heart transplantation].
AB  - PURPOSE: To evaluate hemodynamic parameters and clinical outcome of children with
      severe cardiomyopathy who are candidates for heart transplantation. METHODS:
      Twenty four children aged from 4 months to 10 years and 8 months (mean 3.7 +/-
      2.5 years) from February 1992 to May 1996, were submitted to hemodynamic study
      and the following parameters were measured: cardiac output, mean pulmonary artery
      pressure (MPAP) and capillary wedge pressure. The pulmonary vascular resistance
      index (PVRI) and transpulmonary pressure gradient (TGP) were calculated. RESULTS:
      Ten (41.6%) children were transplanted (group A), 5 (20.8%) are still waiting
      heart transplantation (group B) and 9 (37.6%) died (group C). The mean age of the
      B and C group were significantly different. The PVRI, MPAP and TPG were
      significant lower in group A than group C (p = 0.01; p = 0.044 and p = 0.023
      respectively). CONCLUSION: The profile of the hemodynamic parameters of children
      with severe dilated cardiomyopathy was compatible with the clinical findings. The
      age was the only difference comparing groups B and C. PVRI, MPAP and TPG were
      significant factors between group A and C. The older the patient, the worse was
      the prognosis.

PMID- 10347949
TI  - [Risk factors for acute myocardial infarction in Brazil. FRICAS Study].
AB  - PURPOSE: To determine risk factors related to acute myocardial infarction (AMI)
      in Brazil. METHODS: Five hundred ninety one patients were selected in 20 medical
      centers in Brazil, between January/94 and March/95. Two-hundred-ninety-nine
      patients were cases, and 292 controls with a variety of acute diseases not
      related to the suspected or known risk factors for acute myocardial infarction.
      All data were collected through a structured questionnaire filled by the
      patients. The evaluation of the variables was done through univariate analysis
      with a significance level of 5%. RESULTS: The factors related to acute myocardial
      infarction were respectively to cases and controls: Hypercholesterolemia--210.93
      +/- 46.74 mg/dl and 185.71 +/- 45.45 mg/dl, (p = 0.000); smoking--41.69% and
      27.20% (p = 0.000); hypertension--52.35% and 20.88% (p = 0.000); diabetes--19.70%
      and 9.93% (p = 0.001); family history--related to the patient's father in 42.14%
      and 33.22% (p = 0.025) and to the mother in 42.14% and 30.82% (p = 0.007);
      socioeconomic level--88.99% and 60.20% owned house (p = 0.002); 44.45% and 33.21%
      owned car (p = 0.010); physical activity--56.83% and 48.28% had the habit of
      walking in the year prior to study entry (p = 0.029); diet--38.79% and 28.42%
      consumed canned food (p = 0.013). The mean weight was 72.50 +/- 26.89 kg and 69
      +/- 12.26 kg (p = 0.0271). The mean height was 166.56 +/- 8.81 cm and 166.66 +/-
      8.47 cm. CONCLUSION: This study confirmed the importance of hypercholesterolemia,
      hypertension, diabetes mellitus, overweight and family history as risk factors
      for acute myocardial infarction. There was a significant relation between
      socioeconomic level and the prevalence of acute myocardial infarction.

PMID- 10347950
TI  - [Myocardial morphometric study in protein-energy malnourished adults].
AB  - PURPOSE: To compare cardiac muscle cells width and cardiomyocyte lipofuscin
      pigment presence between malnourished and non-malnourished necropsied adults.
      METHODS: Out of 315 necropsy protocols of adults randomly chosen, those with
      edema, ascitis, systemic arterial hypertension, chronic liver disease, and heart
      disease were excluded. Malnutrition was defined by body mass index (BMI) < 17
      kg/m2. Cardiomyocytes morphometry study and lipofuscin pigment counts were
      performed. RESULTS: Malnourished (n = 8) and controls (n = 4), respectively,
      showed statistical differences in relation to BMI (14.86 +/- 1.13 vs 22.02 +/-
      0.9 kg/m2), heart weight/body weight ratio (0.68 +/- 0.09 vs 0.54 +/- 0.07%),
      cardiomyocytes width (10.91 +/- 0.77 vs 12.90 +/- 1.82 microns) and lipofuscin
      pigment presence (39.1 vs 54.4%). CONCLUSION: When compared with controls,
      necropsied malnourished adults showed decreased myocardial fibers diameters and
      lower lipofuscin pigment presence. These findings might reflect altered
      metabolism, and would be associated with harmful clinical effects in terminally
      ill patients.

PMID- 10347951
TI  - [Morpho-functional cardiac evaluation in young normotensive children of
      hypertensive patients. A prospective Doppler-echocardiographic study].
AB  - PURPOSE: Evaluate functional and/or structural cardiac changes in young
      normotensive subjects with a family history of hypertension. METHODS: Prospective
      study was performed with 62 normotensive persons, ages 15 to 30 years, divided in
      32 children of hypertensive patients (group 1) and 30 children of normotensive
      persons (group 2) comparable in blood pressure, body surface area, heart rate,
      age and sex. After clinical examination, all underwent Doppler-echocardiogram to
      evaluate cardiac structure and left ventricular (LV) systolic and diastolic
      function. RESULTS: Systolic LV fractional shortening was increased in group 1
      when compared with group 2 (38.03 +/- 4.95% and 34.7 +/- 4.48%, respectively--p <
      0.01). Mitral deceleration time (DT) ranged from 85 to 160 ms--mean values 116.47
      +/- 16.99 ms--in group 1 and from 100 to 220 ms--mean values 126.73 +/- 26.66 ms-
      in group 2 (p < 0.05). A correlation between LV mass and left atrium (LA)
      diameter was noted in group 1 (r-0.514, p < 0.01). CONCLUSION: Children of
      hypertensive patients show increased LV function, similar to what occurs in early
      hypertension and in borderline hypertension, even when there is no evidence of LV
      hypertrophy or high blood pressure. Mitral DT (shorten in group 1) was the only
      diastolic parameter that differed in the groups. The correlation between LV mass
      and LA dimension suggests that LA size could be related to functional and
      hemodynamic LV changes.

PMID- 10347952
TI  - [Evaluation of fragmented potentials in right bundle branch block without
      structural myocardium abnormalities. Study made by signal-averaged
      electrocardiogram on time and frequency domain].
AB  - PURPOSE: To evaluate if the presence of right bundle branch block (RBBB), without
      structural myocardial abnormalities (SMA) can generate fragmented potentials (FP)
      and spectral turbulence on signal-averaged electrocardiogram (SAECG). METHODS:
      Twelve children with atrial septal defect (ASD) and incomplete right bundle
      branch block (IRBBB without SMA (group I) were compared to 17 children with post
      operative tetralogy of Fallot (TF) with CRBBB, all with SMA, 5 with ventricular
      premature beats and 2 with sustained ventricular tachycardia (group II). All had
      SAECG on time (TD) and frequency domain (FD) with 5 variables analysed. RESULTS:
      All patients of group I had normal variables, in contrast with group II which
      presented abnormal variables suggesting FP and ST. CONCLUSION: In ASD without
      SMA, the isolated IRBBB did not generate FP and ST.

PMID- 10347953
TI  - [Use of digitalis in elderly patients admitted to a geriatric unit at a general
      hospital].
AB  - PURPOSE: To determine the prevalence of digoxin use as well as its indications in
      elderly patients at the time of admission to a geriatric unit of a general
      hospital. METHODS: One hundred and thirty elderly patients aged 65 and over (mean
      age = 80 +/- 9 years), 100 women and 30 men were consecutively investigated. Each
      patient was submitted to a thorough clinical investigation, laboratory work-up,
      chest X-ray, electrocardiogram and doppler echocardiogram. The use of digoxin was
      considered appropriate, questionable or inappropriate. RESULTS: At the time of
      admission to the geriatric unit 27.6% of the patients were receiving digoxin. The
      indication was considered appropriate in 36.1%, questionable in 11.1% and
      inappropriate in 52.7%. CONCLUSION: We found a high prevalence of digoxin use in
      elderly patients admitted to a geriatric unit of a general hospital. In most
      cases its indications were considered inappropriate or questionable. Due to the
      increased risk of digitalis intoxication in this age group the drug should be
      prescribed under more strict indications.

PMID- 10347954
TI  - [Trends in cholesterol levels in the adult population of Sao Jose do Rio Preto].
AB  - PURPOSE: To develop a survey about risk factors for atherosclerosis in a > or =
      20-year-old population from Sao Jose do Rio Preto, and compare the results with
      those obtained in a similar survey in 1991. METHODS: Quantitative survey with
      sample stratified by sex and age. The individuals (a total of 646, 303 men) where
      contacted in outpatient facilities from the Health Secretary and other populated
      sites, distributed by geographic zone and social class of different
      neighborhoods. The standard error of the survey was 4%, and the confidence
      interval was 95%. RESULTS: A) Mean HDL-cholesterol (only in 1997): male gender
      43.7 +/- 15 mg/dL, female gender 49.6 +/- 13.5 mg/dL (p < 0.001, 95% CI 3.7 a
      8.1). B) Mean total cholesterol in 1991 vs 1997: for the global population 192.5
      +/- 48.9 mg/dL vs 190.5 +/- 42.5 mg/dL (p = NS); for men 187.6 +/- 53.3 mg/dL vs
      190.5 +/- 42.5 mg/dL (p = NS); for women 196.8 +/- 40 mg/dL vs 187.6 +/- 37.8
      mg/dL (p = 0.008, 95% CI 2.4 a 15.9). C) By regression analysis, the variables
      that correlated significantly with cholesterol levels, in both surveys, were: age
      (p < 0.001), systolic (p < 0.001) and diastolic (p < 0.001) arterial pressure,
      diet (p < 0.001). Female gender showed correlation only in the 1991 survey (p =
      0.011), and sedentarism only in 1997 (p = 0.014). CONCLUSION: The mean
      cholesterol levels in the adult population of Sao Jose do Rio Preto are very
      favorable and, in female gender, showed a significant decrease in the 1997
      survey, relatively to the 1991 survey.

PMID- 10347956
TI  - [Captopril combined with hydrochlorothiazide in mild and moderate hypertension. A
      Brazilian multicenter study].
AB  - PURPOSE: To evaluate the effectiveness and tolerance of the association of
      captopril 50 mg and hydrochlorithiazide 25 mg in hypertensive patients with
      diastolic pressure between 95 and 115 mmHg. METHODS: An open, multicenter and non
      comparative study was performed. After 2 weeks of placebo, the patients received
      1/2 tablet of drug association. Patients were evaluated after 4, 8 and 12 weeks,
      and those who had diastolic pressure > 90 mmHg after 8 weeks of therapy received
      1 tablet/day. RESULTS: The results of 433 patients were analyzed: 47 +/- 10 years
      old, 30% female, 76% white. Initial systolic and diastolic pressures were 156 +/-
      16 and 103 +/- 11 mmHg and after 14 days of placebo were 156 +/- 15 and 103 +/- 9
      mmHg (p > 0.05). Systolic/diastolic pressure after 4, 8 and 12 weeks of treatment
      reduced progressively (p < 0.05) to 143 +/- 14/95 +/- 11, 140 +/- 13/91 +/- 9 and
      134 +/- 11/86 +/- 8 mmHg. Blood pressure control was observed in 45, 67 and 88%
      (p < 0.05) of patients after 4, 8 and 12 weeks. Cough was the most important
      symptom, registered in 7% of patients under placebo and 12% in patients under
      treatment. The tolerance was considered good for 98% of patients. CONCLUSION: The
      association of captopril with hydrochlorothiazide is effective with good
      tolerance, being indicated as a once a day monotherapy for mild and moderate
      hypertension.

PMID- 10347955
TI  - [Type I atrial flutter radiofrequency ablation. Importance of bidirectional block
      of isthmus between the inferior vena cava and of tricuspid valve ring].
AB  - PURPOSE: To determine the clinical importance of a bi-directional line of block
      demonstration in the inferior vena cava-tricuspid annulus isthmus as an end-point
      for radiofrequency (RF) atrial flutter (FL) ablation. METHODS: Forty consecutive
      patients (51 +/- 11 years) with type I FL were divided in 2 groups: GI (30
      patients) anatomic, non-electrophysiologic isthmus ablation technique
      (interruption and non-induction FL criteria); and GII (10 patients) anatomic with
      electrophysiologic evaluation of bi-directional isthmus conduction. The isthmus
      activation was analyzed before and after anatomic RF ablation with a cateter
      exploring each side of the line of block, depending on the conduction evaluation
      (anterograde or retrograde). RESULTS: FL was interrupted and not reinduced in 26/
      30 (86.6%) GI patients and in 10 (100%) GII patients (p = 0.5558). During follow
      up FL recurred in 30% of the patients in both groups. In GII, 6 patients with bi
      directional block remained assymptomatic, whereas 3 patients with unidirectional
      block presented recurrence (p = 0.012). CONCLUSION: Electrophysiologic
      demonstration of bidirectional line of block in the isthmus is related to long
      term success and should be the criterion for interruption of type I atrial FL RF
      ablation.

PMID- 10347957
TI  - [Giant left atrial myxoma].
AB  - A 65 year-old man with dilated cardiomyopathy and long history of high blood
      pressure and a previous cerebral vascular accident had a giant left atrial myxoma
      as an echocardiographic finding.

PMID- 10347958
TI  - [Ergospirometry. Cardiopulmonary exercise test, methodology and interpretation].

PMID- 10347959
TI  - [Glycoprotein (GP) IIb/IIIa platelet inhibitors in acute ischemic syndrome and
      percutaneous coronary intervention].

PMID- 10347960
TI  - [Clinical features and diagnosis of mucocutaneous leishmaniasis in patients of an
      endemic area in Salta].
AB  - A total of 39 patients with a clinical diagnosis of mucocutaneous leishmaniasis,
      in an endemic area for leishmaniasis in Salta, Argentina, were examined between
      June 1990 and December 1992. Of these cases, 87% (34/39) presented the cutaneous
      simple form, 10.3% the cutaneous multiple form and 2.6% the mucosal form. Lesions
      were more frequently located in legs and arms (71.8%), followed by trunk and
      multiple location (10.3%). Of the patients, 43% were housewives, students or
      children, suggesting that the infection could be contracted in the domestic or
      peridomestic environment. Of 39 patients diagnosed, in 22 (56.4%) the parasite
      was found. Direct microscopy (smear) permitted a diagnosis in 13 (59.4%) of these
      22 patients. Among these, 5 (22.7%) had positive diagnosis by culture, and 9
      (40.9%) by inoculation in hamsters. Ten parasite isolates (45.4%) were obtained.
      The smear is recommended as a diagnostic method for epidemiological surveillance
      due to the sensibility demonstrated herein and its easy application in the
      endemic area. The time of clinical evolution, from the appearance of the lesion
      up to the detection of the patient by Sanitary Agents, was approximately 90 days.
      This would be related to the frequency of the visits, usually every 3 months.
      Only one of 30 treated patients had a relapse at 6 months, due to non fulfillment
      of the treatment.

PMID- 10347961
TI  - [Inhaled corticosteroids and asthma education].
AB  - Thirty asthmatic patients were evaluated to assess the association of therapy
      with inhalatory corticosteroids and an educational program, EDUCASMA. Spirometric
      evaluation with Flow-Volume loop (MEDICAL GRAPHIC CPF-S), ambulatory FEP (mini
      WRIGHT meters) was performed. In regard of initial symptoms patients were
      qualified as moderate or severe. After two weeks of a screening period, they were
      randomized into 2 groups: a) beclomethasone; b) budesonide; respective doses in
      according to the initial status. During the study period (8 wks) they visited the
      medical Staff six or more times. In each visit the patients received clinical
      evaluation (i.e. clinical scoring), spirometry (i.e. FEV1), and FEP ambulatory
      revision. FEP x (mean), FEP delta, FEV1, and clinical scores values were matched
      at the start and at the end of the follow-up period. Non-parametric statistics
      were applied (Wilcoxon test) and significative changes were defined (p < 0.05).
      CONCLUSIONS: 1) inhalatory corticosteroids therapy associated with a previous
      educational program could achieve early improvements of clinical scores; 2) in
      moderate asthma ambulatory FEP showed objective changes both in beclomethasone
      and budesonide treatments. It appears to indicate increasing changes very close
      to the clinical improvement; 3) the short period of our observation and the
      inflammatory condition of airways in severe asthma, could be explained as
      probable factors for the minor differences in the FEV1 evaluation; 4) no
      differences between budesonide and beclomethasone treatment were found.

PMID- 10347962
TI  - [Malignant pleural mesotheliomas].
AB  - An increase in incidence of malignant pleural mesotheliomas has been noted
      recently. In order to assess our own experience, we reviewed all medical records
      and biopsies of patients who were seen with this diagnosis in Hospital Maria
      Ferrer between January 1986 and December 1997. Clinical data of 17 patients were
      analyzed. Mean age was 59 years, 76% were male. Industrial or environmental
      exposure to asbestos was established in 9 patients (53%). Most common symptoms at
      presentation were dyspnea (88%) and chest pain (65%). Pleural thickening with or
      without effusion was the usual finding in chest X rays and CAT scans. Biochemical
      analysis of pleural fluids was consistent with exudate. Diagnosis was performed
      by thoracotomy (47%), needle biopsy (23.5%) and videothoracoscopy (29.5%).
      Histological samples were available for review in 16 of the 17 patients: they
      were epithelial (10), sarcomatoid (2) and mixed tumors (4). Treatment reflected
      varying approaches. Palliative methods (pleurodesis, chemotherapy and
      radiotherapy) were preferred at the beginning while more aggressive interventions
      are performed nowadays. Pleuroneumonectomy alone or in combination with other
      therapies was carried out in 5 patients with no operative mortality although some
      complications occurred such as empyema, bronchopleural fistula and severe chest
      pain. Survival rate for all groups was 10.5 +/- 5.9 months. However, the mean
      survival of patients who underwent surgery was 17.5 +/- 2.1 months (p < 0.04)
      with an associated improvement in quality of life. Therefore, we consider that
      surgery associated with other therapies offers at present, the best therapeutic
      option for this bad prognosis condition.

PMID- 10347963
TI  - [Non invasive ventilation in acute respiratory insufficiency: an alternative].
AB  - Effectiveness of non invasive positive pressure ventilation (NIPPV) was
      prospectively evaluated in 22 selected patients with acute respiratory failure,
      meeting criteria for orotracheal intubation and conventional mechanical
      ventilation. Patients were divided in two groups: group A (17 patients) with
      initial PaCO2 above 45 mm Hg and group B (5 patients) with initial PaCO2 below 45
      mmHg. NIPPV was administered with 2 levels of pressure either by nasal or facial
      mask. Respiratory rate (RR), arterial blood pH, PaCO2 and PaO2/FiO2 were
      registered pretreatment, 1 hour and 24 hours after NIPPV. Statistical analysis
      was performed by ANOVA test, p < 0.05 was considered significant. RESULTS: In
      group A there was a reduction in RR (X +/- DS) from 31.2 +/- 8.2 to 24.7 +/- 8.2
      at one hour (h) (p = 0.02) and to 23.4 +/- 6.5 at 24 hs (p = 0.01), pH change
      from 7.33 +/- 0.07 to 7.37 +/- 0.07 at one hour (p = 0.13) and to 7.40 +/- 0.07
      at 24 hs (p = 0.01), a PaCO2 change from 69.5 +/- 19.6 to 57.8 +/- 16.9 at one
      hour (p = 0.06) and to 54 +/- 13 at 24 hs (p = 0.02), and PaO2/FiO2 change from
      187.3 +/- 60.2 to 223.9 +/- 6.5 at one hour (p = 0.12) and to 245.8 +/- 75 at 24
      hs (p = 0.03). In group B there was a change in RR from 33 +/- 16.3 to 26.6 +/-
      12.5 at one hour (p = 0.46) and to 21.3 +/- 4.2 at 24 hs (p = 0.27), PaO2/FiO2
      change from 113.4 +/- 31 to 137.8 +/- 57.2 at one hour (p = 0.44) and to 208.7 +/
      51.2 at 24 hs (p = 0.03). Only two patients in group A and one in group B were
      converted to conventional ARM. CONCLUSION: 1) NIPPV is a therapeutic alternative
      for selective patients with acute respiratory insufficiency and may reduce known
      morbidity of conventional mechanical ventilation. 2) In the group with
      hypercapnic acute respiratory failure the improvement in respiratory function
      begins with an immediate reduction in RR. Significant improvement in arterial
      blood gases usually occurs within 24 hours of NIPPV.

PMID- 10347965
TI  - [Exercise training in chronic obstructive pulmonary disease. Comparative study of
      aerobic training of lower limbs vs. combination with upper limbs].
AB  - A prospective, randomized and controlled study has been performed in 28 patients
      with severe COPD. A group of 14 has been trained with their lower limbs (LL),
      while another similar group of 14 patients was also trained with their upper
      limbs (UL). Results showed improvement in both groups in the endurance test for
      LL, dyspnea scale, efficiency and muscular working capacity. A considerable
      improvement was observed in the oxygen uptake at the anerobic threshold (VO2AT)
      which suggests a training effect, expressed through an improvement in exercise
      tolerance. Only the group who trained UL showed a remarkable improvement in the
      dyspnea scale, endurance test and maximal static mouth pressure, showing a better
      intrinsic working capacity and participation of the UL muscles producing those
      manoeuvres. At the end of training, quality of life was significantly increased
      and the hospitalization rate was lower in both groups. According to these
      findings, it is suggested that patients with severe COPD included in training
      programmes add UL exercises to the LL usually carried out.

PMID- 10347966
TI  - [Comparative study of glycosylated hemoglobin with oral glucose tolerance test in
      a selected population].
AB  - A series of 405 consecutive oral glucose tolerance tests was analyzed in
      comparison with simultaneous glycosylated hemoglobin (HbA1c) measurements, in
      order to ascertain the possible utility of HbA1c as an alternative method for
      diagnosis and screening in populations suspected or at increased risk of
      presenting diabetes mellitus. The study group consisted of 158 male and 247
      nonpregnant female patients aged 3 to 84 years (median 61.5 and 56 years,
      respectively) referred by their physicians for diagnostic purposes. Tolerance
      test was performed according to usual methods and HbA1c was measured with the
      2000 DC immunoassay. Results showed a good correlation between HbA1c and fasting
      or 2 hour glucose levels. Using WHO diagnostic criteria, HbA1c maximal normal
      level of 5.4% showed a sensitivity of 0.96 in distinguishing between non
      diabetics and those at increased risk, for screening purposes. With HbA1c levels
      of 6.0 or 6.3%, specificity for a correct diagnosis of diabetes was high (0.94 or
      0.97) making this a suitable level for diagnostic confirmation. With the new ADA
      criteria for fasting plasma glucose, the results were similar. We suggest that
      HbA1c measurement with highly accurate methods might be considered a valid
      alternative for diagnosis and screening in populations suspected or at increased
      risk of presenting diabetes mellitus.

PMID- 10347964
TI  - [Leucocyte tartrate-resistant acid phosphatase as marker for the transition of
      monocyte to macrophage].
AB  - The presence of the 5 degrees isoenzyme of leukocyte tratrate-resistant acid
      phosphatase (FATRE) was investigated in human peripheral blood monocytes in 32
      samples: 26 normal, 4 thrombocytopenia, 1 anemia and 1 hairy cell leukemia. The
      Cobe Spectra Version 4 cell separador was used for 3 samples while the others
      were obtained by centrifugation with or without latex particles in order to study
      macrophages and monocytes, respectively. Using a Sigma Kit for both total acid
      phosphatase and FATRE reactions, the presence of two monocyte populations was
      detected, one slightly positive and the other negative for FATRE. Upon the
      addition of latex particles, the monocytes were transformed into intensely FATRE
      positive macrophages. It can be concluded that FATRE must play an important role
      in macrophage function and consequently in human cell immunity.

PMID- 10347967
TI  - Acid fast filaments in stool samples from an AIDS patient.
AB  - The presence of filamentous bacteria morphologically similar to Nocardia in a
      fresh stool sample from an AIDS patient with pulmonary nocardiosis is here
      reported. The material was submitted to our laboratory for a parasitologic
      examination and was stained by the Kinyoun method, revealing numerous delicate,
      irregularly stained, branching acid-fast filaments. Nocardia asteroides had been
      isolated from sputum samples of this patient. The patient was a 32 year-old HIV+
      female admitted to our center on June 1997 because of productive cough, right
      sided thoracic pain and weight loss. Chest X rays showed the presence of right
      superior lobe excavated pneumonia. This was the first time we had observed
      filamentous bacteria similar to Nocardia in a stool sample submitted to
      parasitologic examination. For similar cases, and when its presence was not
      detected in other specimens collected from the same patient, intestinal endoscopy
      and biopsy should be performed for eventual lesions and smear examination
      repeated with Kinyoun stain and cultures for Nocardia.

PMID- 10347968
TI  - [Cardiac primary lymphoma].
AB  - The primary cardiac lymphoma is extremely rare. A case is presented of a 60 year
      old female patient with non-Hodgkin lymphoma of probable primary cardiac
      localization and with subsequent extension to peripheral lymph nodes. She had had
      a febrile syndrome for 8 months. Two two-dimensional echocardiograms gave
      negative results. Due to a syncope with atrial fibrillation, a transesophageal
      echocardiogram was carried out, which showed tumors in both atria, interatrial
      septum and right ventricle. The later appearance of right preauricular lymph
      nodes and left supraclavicular nodes led to a biopsy which confirmed a diagnosis
      of diffuse non-Hodgkin lymphoma with large immunoblastic cells. The patient died
      15 months after the first symptoms, having undergone 6 chemotherapy cycles. The
      autopsy showed remission of the macroscopic lesions but presence of microscopic
      lesions in the cardiac chambers with histology and phenotypic markers identical
      to the ones found in the lymph nodes.

PMID- 10347969
TI  - [Rhabdomyolysis associated with disseminated gonococcal infection in an elderly
      woman].
AB  - Disseminated Gonococcal Infection (DGI) is very unusual in elderly patients and
      its association with Rhabdomyolysis (RML) has not been published for which reason
      we are presenting a case of RML secondary to DGI in an elderly women. We presume
      that the muscle damage was directly related with the gonococcal infection through
      toxin generation and release of endogenous mediators from mononuclear phagocytes
      and neutrophils and/or with ischemic injury due to altered tissue perfusion
      evidenced in this case by the presence of hypotension, oliguria and acidosis. We
      suggest that DGI be added to the RML infectious etiologies and considered in the
      initial differential diagnosis of all patients with polyarthritis and RML in
      order to facilitate an optimal treatment.

PMID- 10347970
TI  - [Hypopituitarism and shock in an 88 year old woman].

PMID- 10347971
TI  - [Kidney revascularization and function recovery in patients in dialysis].
AB  - The available literature was reviewed to analyze the indications and results of
      the surgical restoration of flow to ischemic kidneys in dialyzed patients with
      ischemic nephropathy. Only 57 were found, a small number compared with the
      estimated percentage (5 to 15%) of ischemic insufficiency in dialyzed patients.
      Atherosclerosis was the main cause of ischemia and most patients were over the
      seventh decade of life. Common clinical findings were uncontrolled hypertension
      and/or acute cardiac failure, symptomatic atherosclerotic disease in other areas
      and rapid deterioration of renal function. Kidneys recovered after variable
      periods of ischemia (days to 13 months of dialysis, mean 30.5 days), with small
      size, 9, 8 or even 7 cm, absent nephrograms of flat flow curves in isotopic
      studies or without distal arteries and/or collaterals in the angiogram. Total
      arterial occlusion was more frequent than stenosis. After surgery the patients
      recovered immediately (35%) or required transitory dialysis (52%); in a few
      (12.2%) function was not restored. Hypertension improved or was cured in almost
      all patients. The good results persisted during long periods. A better knowledge
      of the disease, early detection and treatment, will improve the quality of life
      and survival of patients with ischemic nephropathy.

PMID- 10347972
TI  - [Life-sustaining therapy and dignified death. Myths and realities].
AB  - The use of a variety of diagnostic and therapeutic procedures made available by
      modern technology for critical patients have given rise to forms of death which
      are incompatible with a person's dignity in cases in which the inevitable
      occurrence of death is inexplicably delayed. The search for the multiple factors
      influencing this phenomenon, related to the development and progress of medicine,
      leads to the investigation of four aspects deemed essential in their
      determination: imperative technology, sanctity of life, omnipotence of medicine
      and the lack of a unique medical decision. Apart from the availability of high
      technology, there is an increasing requirement of the patient's full autonomy
      with respect to the decisions involving the end of his life, which include the
      debated right to die. In the struggle towards death with dignity in a context
      where practical decisions are required, the following are taken into account:
      refusal of treatment, irreversibility of clinical diagnosis and palliative
      support, and withholding and withdrawal of life-sustaining therapy.

PMID- 10347973
TI  - [Physician harassment].

PMID- 10347974
TI  - [Follicular dendritic cell sarcoma in lymph node].

PMID- 10347975
TI  - [Follicular dendritic cell sarcoma in lymph node].

PMID- 10347976
TI  - Case for free access to fundamental data.

PMID- 10347977
TI  - Thrombomodulin and coronary heart disease.

PMID- 10347978
TI  - Therapeutic vaccines for preventing AIDS: their use with HAART.

PMID- 10347979
TI  - Why might infertile couples have problem pregnancies?

PMID- 10347980
TI  - Mismatched transplants for refractory lymphoma?

PMID- 10347981
TI  - Where we are now with rhDNase.

PMID- 10347982
TI  - Post-stroke depression, not to be underestimated.

PMID- 10347983
TI  - Acronymania.

PMID- 10347984
TI  - Soluble thrombomodulin as a predictor of incident coronary heart disease and
      symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in
      Communities (ARIC) Study: a case-cohort study.
AB  - BACKGROUND: Small amounts of soluble thrombomodulin in plasma are thought to
      reflect endothelial damage. In a case-cohort study, we examined whether soluble
      thrombomodulin is a predictor of incident coronary heart disease and carotid
      artery atherosclerosis. METHODS: The study population consisted of 14,170 black
      and white participants from the Atherosclerosis Risk in Communities (ARIC) study,
      who did not have cardiovascular disease at the start of the study and who we
      followed up for 6 years. After appropriate exclusions, we analysed 258 cases of
      incident coronary heart disease and 449 cases of carotid atherosclerosis. A
      stratified random sample of 753 individuals from the ARIC cohort was used as the
      comparison group. We used EIA to measure soluble thrombomodulin in plasma samples
      from both groups. For the analysis, we used quintiles of soluble thrombomodulin
      concentrations (< 24.7, 24.8-30.6, 30.7-40.2, 40.3-55.2, and > or = 55.3 ng/mL).
      FINDINGS: Soluble thrombomodulin showed a strong, graded, inverse association
      with incident coronary heart disease (p=0.005). The adjusted rate ratio of the
      highest quintile of soluble thrombomodulin compared with the lowest quintile was
      0.29 (95% CI 0.15-0.57). The association with carotid atherosclerosis, however,
      tended to be positive, especially among white participants (odds ratio 2.94 [1.15
      7.51] for highest vs lowest quintile). The relation of soluble thrombomodulin to
      incident coronary heart disease and carotid atherosclerosis was dependent on
      factor VIII coagulant activity (p=0.06 and 0.003, respectively). INTERPRETATION:
      The prospective association of soluble thrombomodulin with incident coronary
      heart disease differs from its cross-sectional association with carotid
      atherosclerosis. In healthy people, plasma concentrations of soluble
      thrombomodulin may reflect endothelial expression of thrombomodulin. High
      concentration of soluble thrombomodulin may be associated with decreased risk of
      coronary heart disease.

PMID- 10347985
TI  - Therapeutic immunisation with recombinant gp160 in HIV-1 infection: a randomised
      double-blind placebo-controlled trial. Nordic VAC-04 Study Group.
AB  - BACKGROUND: The immune system's ability to scavenge and destroy detrimental HIV-1
      products has an important effect on virion production and the course of
      infection. In earlier trials of therapeutic immunisation with envelope protein
      recombinant gp160 (rgp160) we observed a transient positive effect on CD4
      lymphocyte counts. This randomised placebo-controlled study investigated whether
      our preliminary findings represented a potential for a more benign clinical
      course. METHODS: 835 HIV-seropositive patients from 20 centres in Sweden, Norway,
      and Finland with CD4-cell counts above 200/microL were randomly assigned to
      receive 160 microg rgp160 or placebo (alum adjuvant alone) every 3 months for 3
      years after an induction period, as well as optimum available treatment. Analyses
      were by intention to treat. FINDINGS: 63 of 416 vaccine-group patients and 61 of
      419 placebo-group patients reached a primary clinical endpoint (AIDS-defining
      event or death); the time to first clinical endpoint did not differ between the
      groups (p=0.864). Significantly fewer vaccine-group patients than placebo-group
      patients reached the primary immunological endpoint of a decrease of more than
      30% from baseline CD4-cell count (157 vs 189, p=0.03). A higher proportion of the
      vaccine group had CD4-cell counts higher than baseline at 6 months (167 vs 133,
      p=0.014). HIV-1-specific T-cell immune reactivity was induced in all vaccine
      recipients studied. No severe adverse events associated with the vaccine were
      noted during the study. There were significantly fewer deaths among the vaccine
      recipients than among the placebo-group patients at 2 years, but not at the end
      of the study. INTERPRETATION: Therapeutic immunisations with rgp160 have a modest
      effect on CD4-cell counts, but this treatment alone did not lead to clinical
      benefit when given in addition to best clinical practice at the time of the
      trial. Immunisation in conjunction with antiretroviral therapy was also
      effective, which strongly suggests that a combination with highly active therapy
      would improve the total effect.

PMID- 10347986
TI  - Risk of breast cancer in women with palpable breast cysts: a prospective study.
      Edinburgh Breast Group.
AB  - BACKGROUND: 7% of women in the western world develop palpable breast cysts.
      Studies of the relation between cysts and breast cancer have conflicting results.
      There are two clearly defined types of cyst. We investigated whether one cyst
      type is associated with a higher rate of breast-cancer development than the
      other. METHODS: We studied 1374 women with palpable breast cysts presenting
      between 1981 and 1987, who had cysts aspirated between 1981 and 1989. Cysts were
      classified as type I if the sodium/potassium (Na+/K+) ratio in the cyst fluid was
      less than 3, or type II if the Na+/K+ ratio was 3 or more. Data on incidence of
      breast cancer were available until January, 1995, and we compared them with the
      expected numbers of cancers calculated from age-specific breast-cancer incidence
      in Scotland in 1988. FINDINGS: 65 cancers developed during follow-up. The overall
      standardised incidence rate of breast cancer in patients with palpable cysts was
      2.81 (95% CI 2.17-3.59). The relative incidence rate was increased for all cyst
      types. The standardised incidence rate of developing breast cancer among women
      younger than 45 years was highest at 5.94 (2.97-10.63), with a significant trend
      for decreasing relative incidence rate with age (p<0.05). Women older than 54
      years had a standardised incidence rate of 1.73 (0.86-3.10). The standardised
      incidence rate of breast cancer was highest in the first year after aspiration
      (7.02 [3.73-12.00]) but the risk was still raised after 5 years (2.68 [1.84
      3.76]). INTERPRETATION: Women with breast cysts are at an increased risk of
      breast cancer, especially at younger ages. The type of cyst did not alter the
      associated relative incidence rate of breast-cancer development.

PMID- 10347987
TI  - Assessment of separate contributions to perinatal mortality of infertility
      history and treatment: a case-control analysis.
AB  - BACKGROUND: Few studies have described the perinatal risks associated with
      infertility, other than for infertility treated by in-vitro fertilisation or
      gamete intrafallopian transfer. The aim of this analysis was to estimate the
      risks of perinatal death associated with treated and untreated infertility.
      METHODS: A population-based case-control study of perinatal deaths was carried
      out in Leicestershire Health District over the period 1990-94, during which
      60,922 babies were delivered. Of these, 567 perinatal deaths were associated with
      542 women. 972 mothers were randomly selected as controls. Medical, obstetric,
      and social data were collected for cases and controls from the medical notes and
      interviews with the women. The relative risks of perinatal death associated with
      treated and untreated infertility before the index pregnancy were estimated as
      odds ratios by means of unconditional logistic regression analysis. FINDINGS: 65
      (10%) of cases and 34 (3.5%) of the controls had infertility before the index
      pregnancy. History of infertility in the index pregnancy, irrespective of
      treatment, increased the risk of perinatal death (odds ratio 2.9 [95% CI 1.8
      4.5]). The population attributable risk fraction for perinatal death related to
      infertility was 6.2% (3.4-9.0). 45 (54%) of the deaths, even in the untreated
      group, were associated with immaturity. Compared with women without infertility,
      women with untreated infertility were at increased risk of perinatal death (3.3
      [1.6-6.8]). The risk of perinatal death associated with multiple births did not
      explain this finding. Similarly, treated infertility also increased the risk of
      perinatal death (2.7 [1.5-4.7]); the risks associated with multiple births
      explained some, but not all, of this excess. In Leicestershire, the overall
      underlying risk of a mother experiencing at least one perinatal death over the
      study was 9.0 per 1000 women. For women who experience infertility, this risk
      increases by about 18 per 1000 (6-30). INTERPRETATION: Counselling for women
      before any form of infertility treatment should include discussion of the risks
      of perinatal death. Our results would benefit from confirmation. However, we
      advocate that at antenatal booking a history of infertility, irrespective of
      treatment, should be sought, because these women have a significantly increased
      risk of perinatal death, particularly associated with prematurity.

PMID- 10347988
TI  - Occupational asthma in Europe and other industrialised areas: a population-based
      study. European Community Respiratory Health Survey Study Group.
AB  - BACKGROUND: There are no large population-based studies on occupational asthma,
      and few estimates of the proportion of asthma attributed to occupation, even
      though asthma is the most common occupational respiratory disorder in
      industrialised countries. METHODS: We assessed data on 15,637 people aged 20-44,
      randomly selected from the general population of 26 areas in 12 industrialised
      countries. Asthma was assessed by methacholine challenge test and by
      questionnaire data on respiratory symptoms and use of medication. Occupation was
      defined by job-titles and a job exposure matrix was constructed. FINDINGS:
      Highest risk of asthma, defined as bronchial hyperresponsiveness and reported
      asthma symptoms or medication, was shown for farmers (odds ratio 2.62 [95% CI
      1.29-5.35]), painters (2.34 [1.04-5.28]), plastic workers (2.20 [0.59-8.29]),
      cleaners (1.97 [1.33-2.92]), spray painters (1.96 [0.72-5.34]), and agricultural
      workers (1.79 [1.02-3.16]). Similar risks were shown for asthma defined as
      reported asthma symptoms or medication. The most consistent results across
      countries were shown for farmers and cleaners. Excess asthma risk was associated
      with high exposure to biological dusts, mineral dusts, and gases and fumes. The
      proportion of asthma among young adults attributed to occupation was 5%-10%.
      INTERPRETATION: The prevalence of occupational asthma in women and in specific
      occupations has been underestimated. Given a mean prevalence of asthma of about
      5%, about 0.2%-0.5% of young adults become asthmatics or have their asthma
      exacerbated because of their occupations.

PMID- 10347989
TI  - Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non
      myeloablative therapy and HLA-mismatched bone-marrow transplantation.
AB  - BACKGROUND: HLA-mismatched donor bone-marrow transplantation after standard
      myeloablative conditioning therapy for haematological malignant disorders has
      been limited by severe graft-versus-host disease (GVHD) and graft failure. We
      tested a new approach to find out whether lymphohaemopoietic graft-versus-host
      reactions could occur without excessive GVHD in mixed haemopoietic chimeras
      produced across HLA barriers with non-myeloablative conditioning. METHODS: Five
      patients with refractory non-Hodgkin lymphoma underwent bone-marrow
      transplantation from haploidentical related donors sharing at least one HLA A, B,
      or DR allele on the mismatched haplotype. Conditioning included cyclophosphamide
      and thymic irradiation before transplantation, and antithymocyte globulin before
      and after transplantation. The only other GVHD prophylaxis was cyclosporin.
      FINDINGS: Four of five patients were evaluable and showed engraftment. Mixed
      haemopoietic chimerism was established, with a predominance of donor lymphoid
      tissue and varying degrees of myeloid chimerism. Two patients were in GVHD-free
      states of complete and partial clinical remission at 460 and 103 days after bone
      marrow transplantation. INTERPRETATION: Mixed chimerism can be induced in adult
      recipients of HLA-mismatched bone-marrow transplantation by a non-myeloablative
      conditioning regimen. The antilymphoma responses seen in two patients suggest
      that allogeneic bone-marrow transplantation without myeloablative conditioning
      might have potent immunotherapeutic benefits.

PMID- 10347990
TI  - A midlife crisis.

PMID- 10347991
TI  - Oral health of elderly occupants in residential homes.

PMID- 10347992
TI  - Tacrolimus in refractory polymyositis with interstitial lung disease.

PMID- 10347993
TI  - A new splitting technique for liver grafts.

PMID- 10347994
TI  - Atorvastatin-induced acute hepatitis with absence of cross-toxicity with
      simvastatin.

PMID- 10347995
TI  - Riluzole for levodopa-induced dyskinesias in advanced Parkinson's disease.

PMID- 10347996
TI  - Laparoscopically assisted abdominal aortic aneurysm repair.

PMID- 10347997
TI  - Prevalence of Werner's syndrome heterozygotes in Japan.

PMID- 10347998
TI  - Iodine deficiency in France.

PMID- 10347999
TI  - Ready-to-use therapeutic food for treatment of marasmus.

PMID- 10348000
TI  - Wernicke's encephalopathy induced by magnesium depletion.

PMID- 10348001
TI  - British Medical Association enters GM-crop affray.

PMID- 10348002
TI  - Arterial chemotherapy improves survival after hepatic metastases.

PMID- 10348003
TI  - Neurosurgeons wake up to awake-brain surgery.

PMID- 10348004
TI  - When institutional review boards fail the system.

PMID- 10348005
TI  - Brundtland sets out the challenges for WHO.

PMID- 10348006
TI  - Lichen sclerosus.
AB  - Lichen sclerosis is a chronic inflammatory skin disease that causes substantial
      discomfort and morbidity, most commonly in adult women, but also in men and
      children. Any skin site may be affected (and, rarely, the oral mucosa) but lichen
      sclerosus is most common in the anogenital area, where it causes intractable
      itching and soreness. In children, the disorder may be confused with changes seen
      in sexual abuse. Progression to destructive scarring is common. There is
      increased risk of developing vulval cancer, and there are links with penile
      cancer. Patients should be kept under long-term review. Lichen sclerosus can
      occur without symptoms, and the exact prevalence is uncertain. It occurs most
      commonly in women at times of low sex hormone output. The underlying cause is
      unknown, but there seems to be a genetic susceptibility and a link with
      autoimmune mechanisms. The wart virus and the spirochaete borrelia have been
      suggested but not substantiated as infective triggers. The Koebner phenomenon is
      known to occur (lichen sclerosus occurs in skin already scarred or damaged), so
      trauma, injury, and sexual abuse have been suggested as possible triggers of
      symptoms in genetically predisposed people. The treatment of choice for
      anogenital lichen sclerosus is potent topical corticosteroid ointment for a
      limited time. Circumcision may be indicated in men, and surgery may be considered
      in women, to relieve effects of scarring or to treat coexisting carcinoma.
      Current research aims to identify a treatable cause of lichen sclerosus, to
      identify patients at risk of scarring and of malignant disorders, and to find
      target pathways for therapeutic intervention.

PMID- 10348007
TI  - Assessment of patients' reporting of pain: an integrated perspective.
AB  - A common assumption about pain is that it always results from the presence of
      underlying organic pathology. In the absence of objective pathology, an
      individual's report of pain may be ascribed to psychological causes. There is a
      wide variation in patient's experience of pain and organic factors alone cannot
      explain individual differences in patients' reports. Assessment of patients who
      report pain requires attention to psychosocial, behavioural, and organic factors.
      We describe a comprehensive approach to the assessment of psychological and
      behavioural variables that affect patients' reports of pain. We counter the
      duality of the somatogenic versus psychogenic perspective and suggest a more
      integrated assessment that encompasses not only the severity of pain and related
      physical pathology but also the person who is reporting the presence of pain.

PMID- 10348009
TI  - CAPPP trial. Captopril Prevention Project.

PMID- 10348008
TI  - The fetal insulin hypothesis: an alternative explanation of the association of
      low birthweight with diabetes and vascular disease.
AB  - Low birthweight is associated with insulin resistance, hypertension, coronary
      artery disease, and non-insulin-dependent diabetes (NIDDM). A suggested
      explanation for this association is intrauterine programming in response to
      maternal malnutrition. We propose, however, that genetically determined insulin
      resistance results in impaired insulin-mediated growth in the fetus as well as
      insulin resistance in adult life. Low birthweight, measures of insulin resistance
      in life, and ultimately glucose intolerance, diabetes, and hypertension could all
      be phenotypes of the same insulin-resistant genotype. There is evidence to
      support this hypothesis. Insulin secreted by the fetal pancreas in response to
      maternal glucose concentrations is a key growth factor. Monogenic diseases that
      impair sensing of glucose, lower insulin secretion, or increase insulin
      resistance are associated with impaired fetal growth. Polygenic influences
      resulting in insulin resistance in the normal population are therefore likely to
      result in lower birthweight. Abnormal vascular development during fetal life and
      early childhood, as a result of genetic insulin resistance, could also explain
      the increased risk of hypertension and vascular disease. The predisposition to
      NIDDM and vascular disease is likely to be the result of both genetic and fetal
      environmental factors.

PMID- 10348010
TI  - CAPPP trial. Captopril Prevention Project.

PMID- 10348011
TI  - CAPPP trial. Captopril Prevention Project.

PMID- 10348012
TI  - CAPPP trial. Captopril Prevention Project.

PMID- 10348013
TI  - CAPPP trial. Captopril Prevention Project.

PMID- 10348014
TI  - CAPPP trial. Captopril Prevention Project.

PMID- 10348015
TI  - Buccal midazolam and rectal diazepam for epilepsy.

PMID- 10348016
TI  - Buccal midazolam and rectal diazepam for epilepsy.

PMID- 10348018
TI  - Interleukin-6 concentrations in neonatal sepsis.

PMID- 10348017
TI  - Buccal midazolam and rectal diazepam for epilepsy.

PMID- 10348019
TI  - Routine PCR screening of blood.

PMID- 10348020
TI  - Circadian variation in thrombotic risk factors in haemorrhagic cardiovascular
      events.

PMID- 10348021
TI  - "Hard boiled egg" in the peritoneal cavity.

PMID- 10348022
TI  - Epidural analgesia and risk of caesarean section.

PMID- 10348023
TI  - Bezafibrate for tamoxifen-induced non-alcoholic steatohepatitis.

PMID- 10348024
TI  - Sexual dysfunction with protease inhibitors.

PMID- 10348025
TI  - Religion and medicine.

PMID- 10348026
TI  - Religion and medicine.

PMID- 10348027
TI  - Religion and medicine.

PMID- 10348028
TI  - Religion and medicine.

PMID- 10348029
TI  - A propos premieres in medicine.

PMID- 10348032
TI  - The Nobel chronicles. 1955: Axel Hugo Theodor Theorell (1903-82).

PMID- 10348034
TI  - The Thames.

PMID- 10348035
TI  - Asterriquinones produced by Aspergillus candidus inhibit binding of the Grb-2
      adapter to phosphorylated EGF receptor tyrosine kinase.
AB  - Five new asterriquinone analogs (2-4, 6, 7), together with previously identified
      neoasterriquinone (1) and isoasterriquinone (5), were isolated from a
      fermentation broth of the fungus Aspergillus candidus and purified by HSCCC (high
      speed counter current chromatography) followed by HPLC. The structures were
      determined by 1D and 2D NMR and MS/MS techniques. All seven showed inhibitory
      activity against the binding of a recombinant protein containing the SH2 protein
      domain of Grb-2 to the tyrosine phosphorylated form of the EGF receptor tyrosine
      kinase. Some of these asterriquinones exhibited specific inhibition of Grb-2
      binding compared to Grb-7 and PLC-gamma.

PMID- 10348036
TI  - A novel fungal metabolite NG-061 enhances and mimics neurotrophic effect of nerve
      growth factor (NGF) on neurite outgrowth in PC12 cells.
AB  - During the course of our screening program for low molecular natural products
      with their ability to potentiate and/or mimic neurotrophic effect of NGF, a novel
      fungal metabolite, phenylacetic acid hydrazide derivative NG-061 was isolated
      from the fermentation broth of Penicillium minioluteum F-4627. NG-061 enhanced
      and mimicked neurotrophic effect of NGF on neurite outgrowth in a rat
      pheochromocytoma cell line PC12.

PMID- 10348037
TI  - Structure of NG-061, a novel potentiator of nerve growth factor (NGF) isolated
      from Penicillium minioluteum F-4627.
AB  - The structure of NG-061, a new potentiator of nerve growth factor (NGF) isolated
      from Penicillium minioluteum F-4627, was determined by spectroscopic analysis and
      X-ray diffraction method to be phenylacetic acid 2-(2-methoxy-4-oxocyclohexa-2,4
      dienylidene)-hydrazide.

PMID- 10348038
TI  - RP-1551s, a family of azaphilones produced by Penicillium sp., inhibit the
      binding of PDGF to the extracellular domain of its receptor.
AB  - Nine azaphilones designated RP-1551-1, -2, -3, -4, -5, -6, -7, -M1, and -M2 were
      isolated from the culture broth of Penicillium sp. SPC-21609 as inhibitors of
      PDGF binding to its receptor. RP-1551s inhibit the binding of PDGF AA to the
      extracellular domain of PDGF alpha-receptor with IC50 values ranging from 0.1 to
      2 microM without affecting PDGF BB binding to the extracellular domain of PDGF
      beta-receptor. PDGF binding was not restored after the PDGF alpha-receptor
      extracellular domain was washed in an attempt to remove the RP-1551-1 bound to
      the receptor. This result suggests that RP-1551-1 may irreversibly interact with
      the PDGF alpha-receptor. Since many azaphilone compounds possess high reactivity
      with an amino group, RP-1551-1 may prevent PDGF AA binding by reacting with amino
      groups on the alpha-receptor extracellular domain.

PMID- 10348039
TI  - Glucolipsin A and B, two new glucokinase activators produced by Streptomyces
      purpurogeniscleroticus and Nocardia vaccinii.
AB  - During the screening of the natural products for their ability to increase the
      activity of glucokinase by relieving inhibition by long chain fatty acyl CoA
      esters (FAC), two novel compounds, glucolipsin A (1) and B (2) were isolated from
      the butanol extracts of Streptomyces purpurogeniscleroticus WC71634 and Nocardia
      vaccinii WC65712, respectively. The structures of these two compounds were
      established by spectroscopic methods and chemical degradation. Glucolipsin A (1)
      and B (2) relieved the inhibition of glucokinase by FAC with RC50 values of 5.4
      and 4.6 microM.

PMID- 10348040
TI  - Novel naphthoquinones from a Streptomyces sp.
AB  - Cdc25A assay-guided fractionation of a fermentation broth derived from a
      Streptomyces sp. resulted in the isolation of four novel naphthoquinones 1-4.
      Structures of these compounds were deduced by NMR and mass spectrometry. Two of
      them, 3 and 4, incorporate a modified cysteine residue which is observed for the
      first time in this class of natural products. Naphthoquinones 1-4 showed weak
      activity against cdc25A phosphatase.

PMID- 10348041
TI  - Gilvusmycin, a new antitumor antibiotic related to CC-1065.
AB  - A new antitumor antibiotic gilvusmycin was isolated from the culture broth of
      Streptomyces sp. QM16. The structure of gilvusmycin was related to CC-1065 and
      determined by NMR spectral analysis. Gilvusmycin exhibited antitumor activity
      against murine leukemia P388 in vivo.

PMID- 10348042
TI  - Lactonamycin, a new antimicrobial antibiotic produced by Streptomyces
      rishiriensis MJ773-88K4. I. Taxonomy, fermentation, isolation, physico-chemical
      properties and biological activities.
AB  - Lactonamycin (1) was isolated from a culture broth of Streptomyces rishiriensis
      MJ773-88K4. Antibiotic 1 exhibited antimicrobial activities against Gram-positive
      bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and
      vancomycin-resistant Enterococcus (VRE).

PMID- 10348043
TI  - Lactonamycin, a new antimicrobial antibiotic produced by Streptomyces
      rishiriensis MJ773-88K4. II. Structure determination.
AB  - The absolute structure of a new antibiotic lactonamycin is described. The NMR
      studies deduced one of four possible structures for the aglycon attached by a
      rhodinose through glycosidic bond. The stereochemistry of the sugar obtained by
      an acid hydrolysis was determined to be L-form by measuring optical rotation. The
      stereochemistry of the aglycon was determined by X-ray crystallographic analysis.

PMID- 10348044
TI  - New types of liposidomycins produced by Streptomyces that inhibit bacterial
      peptidoglycan synthesis. Structure elucidation of fatty acid components by tandem
      mass spectrometry.
AB  - The structures of the fatty acid components of various new liposidomycins were
      determined using tandem mass spectrometry; the negative FAB/MS/MS/MS technique
      for liposidomycins with a 3-methylglutaric acid moiety and the negative FAB/MS/MS
      technique for liposidomycins without a 3-methylglutaric acid moiey. This
      structural information was obtained by analysis of peaks due to charge-remote
      fragmentations for 3-hydroxycarboxylate anions or carboxylate anions which were
      generated from liposidomycin molecules in a mass spectrometer. The MS/MS/MS
      technique that can exclude the matrix-derived and/or interfering ions showed
      higher sensitivity than the MS/MS technique.

PMID- 10348045
TI  - Molecular analysis of tlrB, an antibiotic-resistance gene from tylosin-producing
      Streptomyces fradiae, and discovery of a novel resistance mechanism.
AB  - The tlrB gene, which confers inducible resistance to a range of macrolide
      antibiotics including biosynthetic precursors of tylosin, was isolated and
      sequenced. In the genome of Streptomyces fradiae, it lies between pbp, which
      encodes a putative penicillin-binding protein, and tylN, encoding a
      glycosyltransferase involved in tylosin biosynthesis. The TlrB protein was
      produced in E. coli as a fusion to MalE. The fusion protein, but not MalE alone,
      inactivates macrolides in the presence of S-adenosyl-methionine (SAM) but the
      modified product(s) has not been characterised.

PMID- 10348046
TI  - Inhibition of nitric oxide synthase induction by 15-deoxyspergualin in a cultured
      macrophage cell line, J774A.1 [correction of J744A.1] activated with IFN-gamma
      and LPS.
AB  - Immunosuppressant 15-deoxyspergualin (DSG) inhibited induction of inducible
      nitric oxide synthase (iNOS) following stimulation with IFN-gamma and LPS in a
      cultured macrophage cell line, J774A.1 [corrected]. By DSG treatment NO2-
      accumulation in the medium was blocked, and cellular iNOS protein level decreased
      as shown by Western blotting. DSG didn't have any direct effect on iNOS activity.
      DSG was not used as a substrate of NOS in in vitro enzyme systems, and it was too
      weak an inhibitor of iNOS and cNOS to cause the inhibition of accumulation of NO2
      . DSG did not scavenge NO spontaneously generated from NOR. Structure-activity
      relationships of analogs and decomposed elements showed that there is correlation
      between the inhibition of iNOS induction and immunosuppressive activity.

PMID- 10348047
TI  - Mulundocandin, an echinocandin-like lipopeptide antifungal agent: biological
      activities in vitro.
AB  - Mulundocandin (MCN) is an antifungal lipopeptide which belongs to the
      echinocandin class of antimycotic agents. MCN exhibited good in vitro activity
      against Candida albicans and C. glabrata isolates with MIC ranges of 0.5-4.0
      microg/ml and 2.0-4.0 microg/ml, respectively. MCN also exhibited some activity
      against C. tropicalis isolates (MIC range 1.0-8.0 microg/ml). However, MCN was
      poorly active against other non-albicans isolates and was inactive against
      Cryptococcus neoformans, Aspergillus species and Trichophyton. MCN appeared to
      exert its antifungal activity through preferential inhibition of germ tube
      formation (MIC-HY 0.015-0.03 microg/ml) and was typically less active on the
      yeast form (MIC 0.5-4.0 microg/ml). In kill-curve experiments 99.9% reductions in
      cell viability were observed following 8 hours exposure to MCN at 4 x MIC and 8 x
      MIC and after 5 hours exposure to 16 x MIC.

PMID- 10348048
TI  - Aspirochlorine: a highly selective and potent inhibitor of fungal protein
      synthesis.
AB  - Aspirochlorine, a compound belonging to the gliotoxin family of compounds,
      exhibits antifungal and antibacterial activity but its mechanism of action
      remains unknown. In this study we show that aspirochlorine inhibits the
      pathogenic fungus Candida albicans by acting on fungal protein synthesis. The
      compound selectively inhibits cell-free protein synthesis when using a C.
      albicans system, but does not inhibit this synthesis in vitro when tested with
      bacterial and mammalian systems. Moreover, in intact C. albicans cells,
      aspirochlorine inhibits protein synthesis but does not inhibit chitin, DNA or
      glucan synthesis though at high concentrations some inhibition of RNA synthesis
      is observed. By contrast, in intact Bacillus subtilis cells, aspirochlorine did
      not inhibit protein, DNA, or cell wall synthesis though it significantly
      inhibited RNA synthesis. Furthermore, using heterologous systems (mammalian
      ribosomes and C. albicans cytosolic factors) the data suggest that the inhibitory
      action of aspirochlorine is not exerted through a direct interaction with C.
      albicans EF-1 or EF-2.

PMID- 10348051
TI  - De-N-methylpamamycin-593A and B, new pamamycin derivatives isolated from
      Streptomyces alboniger.

PMID- 10348049
TI  - Chemical modification of antibiotic eremomycin at the asparagine side chain.
AB  - AA3-Carboxyeremomycin 2, obtained by selective hydrolysis of antibiotic
      eremomycin was used as a starting compound for the eremomycin chemical
      modifications at the asparagine side chain to be transformed into eremomycin AA3,
      AA7 bis-amides (3a-c). Bis-benzylamide 3b displayed an activity (8 microg/ml)
      against an E. faecium VanA strain.

PMID- 10348050
TI  - Kitamycins, new antimycin antibiotics produced by Streptomyces sp.

PMID- 10348052
TI  - 9-Hydroxyoudemansin A, a novel antifungal (E)-beta-methoxyacrylate from a Mycena
      species.

PMID- 10348053
TI  - Inactivation of fusidic acid by pathogenic Nocardia.

PMID- 10348055
TI  - Synthesis of 1-monoglycerides having C11-20 branched chain fatty acids and their
      hemolysis effects.

PMID- 10348054
TI  - Skeletal structure of neocopiamycin B from Streptomyces hygroscopicus var.
      crystallogenes.

PMID- 10348056
TI  - A facile synthesis of D-galactose-type gem-diamine 1-N-iminosugar: a new family
      of galactosidase inhibitor.

PMID- 10348057
TI  - Attempting to avoid antibiotic resistance: lessons for the primary care
      physician. Introduction.

PMID- 10348058
TI  - Methicillin-resistant Staphylococcus aureus: long-term care concerns.
AB  - Colonization of residents of long-term care facilities with methicillin-resistant
      Staphylococcus aureus (MRSA) is an important healthcare concern. MRSA
      colonization is prevalent; in two of the most common sites of colonization, nares
      and wounds, colonization rates range from 8% to 53%, and 30% to 82%,
      respectively. With such a large number of patients harboring the organism, it is
      imperative that long-term care facilities are knowledgeable regarding the overall
      significance of MRSA, are aware of MRSA infection rates at their facilities, and
      have established a threshold above which outbreak precautions will be instituted.
      More importantly, facilities must ensure that appropriate precautions (e.g., hand
      washing, glove changes, gowns) are utilized to prevent transmission of MRSA to
      noncolonized residents. If these basic measures are taken, MRSA-colonized
      residents of long-term facilities should be able to be fully integrated into the
      everyday activities within the long-term care environment. In the event of an
      outbreak of MRSA infection, stricter isolation of colonized and infected
      residents is warranted, and such isolation should be discontinued as soon as the
      chain of transmission has been disrupted. Systemic antibiotics should be avoided
      in asymptomatic colonized patients; topical antibiotics like mupirocin should be
      reserved for short-term administration in outbreak situations.

PMID- 10348059
TI  - Control of methicillin-resistant Staphylococcus aureus in the hospital setting.
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of
      nosocomial infections. Healthcare professionals in the United States should
      develop programs to prevent transmission of this organism within their
      institutions. Aggressive control efforts are justified for several reasons: (1)
      the incidence of nosocomial MRSA reflects the general effectiveness of infection
      control practice; (2) MRSA do not replace susceptible strains but instead
      increase the overall rate of nosocomial S. aureus infections; (3) MRSA infections
      cause substantial morbidity and mortality; (4) serious MRSA infections must be
      treated with vancomycin. Thus, in hospitals with high rates of MRSA, use of this
      antimicrobial agent increases, which in turn may increase the risk for selecting
      vancomycin-resistant enterococci. Hospitals have used numerous different
      approaches to control nosocomial spread of MRSA. Staff should choose a control
      method based on the prevalence of MRSA in their institution and in their
      referring facilities, the rate of nosocomial transmission of MRSA in their
      hospital, the risk factors present in their patient population, the reservoirs
      and modes of transmission specific to their hospital, and their resources. Any
      MRSA control plan must stress adherence to basic infection control measures, such
      as hand washing and contact isolation precautions. In addition, decolonization of
      patients and staff, control of antimicrobial use, surveillance cultures, and
      molecular typing may be helpful adjuncts.

PMID- 10348060
TI  - Drug-resistant Streptococcus pneumoniae: rational antibiotic choices.
AB  - Increasingly, Streptococcus pneumoniae with reduced susceptibility to penicillin
      is becoming a healthcare concern, not only because of the high prevalence of
      infections caused by this pathogen but also because of the rate at which
      resistance has progressed. The incidence of penicillin resistance in strains of
      S. pneumoniae approaches 40% in some areas of the United States, and the
      incidence of high-level resistance has increased by 60-fold during the past 10
      years. With the exception of meningitis and otitis media, there is no conclusive
      evidence that the acquisition of resistance by S. pneumoniae to beta-lactam
      antibiotics incurs greater morbidity and mortality in infections caused by this
      pathogen. However, if the current trends of resistance patterns continue, one can
      expect the morbidity and mortality to increase. The mechanism of beta-lactam
      resistance of S. pneumoniae involves genetic mutations which alter penicillin
      binding protein structure, resulting in a decreased affinity for all beta-lactam
      antibiotics. In the treatment of infections caused by S. pneumoniae, it should
      not be assumed that nonsusceptibility to beta-lactam antibiotics correlates with
      clinical ineffectiveness of these agents. On the contrary, the recommended
      therapy for nonmeningeal pneumococcal infections (e.g., pneumonia, sepsis, acute
      otitis media) includes a beta-lactam antibiotic: penicillin G, amoxicillin,
      amoxicillin/clavulanate, cefuroxime, cefotaxime, or ceftriaxone. Recommended
      therapy for meningitis is cefotaxime or ceftriaxone, with the addition of
      vancomycin until susceptibility is known. These agents are recommended because of
      their ability to achieve serum/tissue concentrations greater than the minimum
      inhibitory concentrations (MICs) of these agents against penicillin-susceptible,
      penicillin-intermediate, and most penicillin-resistant strains (e.g., penicillin
      G, cefotaxime, ceftriaxone, amoxicillin, amoxicillin/clavulanate, and
      cefuroxime), or their ability to provide adequate concentrations in cerebrospinal
      fluid (e.g., cefotaxime, ceftriaxone).

PMID- 10348061
TI  - The threat of vancomycin resistance.
AB  - Vancomycin, produced in 1958, an essential antibiotic in the modern age, often is
      reserved for use in patients who are gravely ill or for infections caused by
      organisms resistant to penicillin, cephalosporin, or other antibiotics. Bacterial
      resistance to vancomycin has caused great concern among many healthcare
      professionals. First reported in 1986 in Europe and in 1988 in the United States,
      vancomycin-resistant enterococci (VRE) have become a major cause of nosocomial
      infections. During this time, scattered reports of clinical infections caused by
      vancomycin-resistant coagulase-negative staphylococci also were reported.
      Recently, enterococci that require vancomycin in media for growth, vancomycin
      dependent enterococci (VDE), have been reported to cause clinically significant
      infections. Vancomycin or other glycopeptide intermediately resistant
      Staphylococcus aureus (VISA/GISA) also has emerged. The mechanisms of resistance
      to vancomycin for VRE, and probably for VISA/GISA, relate to the acquired ability
      of these organisms to circumvent the vancomycin-mediated disruption of bacterial
      cell wall synthesis. Risk factors that lead to VRE colonization or infection
      include prior antibiotic therapy, prolonged hospitalization, hospitalization in
      an intensive care unit, concomitant serious medical and surgical illnesses,
      exposure to equipment contaminated with VRE, and exposure to patients with VRE.
      Patients colonized or infected with VRE, healthcare workers with contaminated
      hands, and environmental surfaces in healthcare facilities are major reservoirs
      of VRE. Risk factors for VDE and VISA/GISA are less well understood, although
      both organisms emerge in patients receiving vancomycin or other glycopeptide
      antibiotics. Infection and antibiotic control procedures for both organisms,
      including restriction of vancomycin use, optimization of the antibiotic
      formulary, education of hospital personnel, early detection and reporting of
      vancomycin resistance, isolation of colonized patients, and appropriate cleansing
      of the environment are used to prevent the spread of these organisms in
      healthcare settings.

PMID- 10348063
TI  - Reducing patient anxiety about positive screening tests.

PMID- 10348062
TI  - A focus on acute sinusitis in adults: changes in disease management.
AB  - Sinusitis is a prevalent and costly disease that affects >14% of the population
      and accounts for >$2 billion in yearly healthcare costs. It is one of the most
      common conditions treated by primary care physicians. The multiple host and
      environmental factors that contribute to the pathogenesis of the disease and the
      lack of clear guidelines for diagnosis and treatment pose a challenge to
      effective management of the problem. The diagnosis of uncomplicated cases rests
      mainly on the history and clinical examination; attempts have been made to
      identify the most useful clinical predictors of acute bacterial sinusitis.
      Microbiologic and imaging studies are rarely performed during the initial
      assessment and are usually reserved for recurrent or refractory disease.
      Treatment involves drainage of the congested sinuses and elimination of
      pathogenic organisms. Although antimicrobial therapy hastens the resolution of
      symptoms of acute sinusitis, the need for antimicrobial therapy remains
      questionable, and its judicious use is challenged by the increase in antibiotic
      resistant Haemophilus influenzae and Streptococcus pneumoniae, the organisms most
      commonly implicated in acute sinusitis. A lack of resolution or frequent
      recurrence of sinusitis warrants evaluation by a specialist.

PMID- 10348064
TI  - Gomco circumcision.

PMID- 10348065
TI  - Gomco circumcision.

PMID- 10348066
TI  - Gomco circumcision.

PMID- 10348067
TI  - Gomco circumcision.

PMID- 10348068
TI  - Gomco circumcision.

PMID- 10348069
TI  - Aseptic meningitis in the newborn and young infant.
AB  - When a toxic newborn or young infant presents with fever and lethargy or
      irritability, it is important to consider the diagnosis of meningitis even if the
      classic localizing signs and symptoms are absent. Cerebrospinal fluid should be
      obtained (unless lumbar puncture is clinically contraindicated) to enable initial
      therapy to be planned. Initial results of cerebrospinal fluid testing may not
      conclusively differentiate between aseptic and bacterial meningitis, and
      antimicrobial therapy for all likely organisms should be instituted until
      definitive culture results are available. Comprehensive therapy, including
      antibacterial and antiviral agents, should continue until a cause is identified
      and more specific therapy is initiated, an etiology is excluded or the patient
      improves considerably and the course of antimicrobial therapy is completed. Group
      B streptococcus is the most common bacterial etiologic agent in cases of
      meningitis that occur during the first month after birth. Etiologies of aseptic
      meningitis include viral infection, partially treated bacterial meningitis,
      congenital infections, drug reactions, postvaccination complications, systemic
      diseases and malignancy. Long-term sequelae of meningitis include neuromuscular
      impairments, learning disabilities and hearing loss. Prompt diagnosis and
      treatment are essential to improved outcome.

PMID- 10348070
TI  - Shoulder instability in young athletes.
AB  - The term "shoulder instability" constitutes a spectrum of disorders that includes
      dislocation, subluxation and laxity. Anterior instability is the most common form
      of glenohumeral instability and may be associated with nerve injury. The
      diagnosis of anterior, posterior or multidirectional instability is based on a
      thorough history and physical examination that includes specific provocative
      maneuvers. The load-and-shift test, the relocation test, the drawer test, the
      sulcus test and the anterior apprehension test are useful for assessment of the
      shoulder. Radiographic studies should include special views to delineate specific
      lesions, such as a Bankart lesion and a Hill-Sachs defect. Early surgical
      intervention may be a consideration, especially in younger patients. Recent
      studies suggest that surgical intervention after the first dislocation may reduce
      the rate of recurrence. Rehabilitation is accomplished in four phases, beginning
      with rest and pain control and proceeding to isometric and isotonic exercises.
      The goal is for the patient to reach 90 percent strength in the injured shoulder
      compared with the uninjured shoulder.

PMID- 10348071
TI  - HPV testing in the evaluation of the minimally abnormal Papanicolaou smear.
AB  - Minor cytologic abnormalities of the cervix, such as atypical squamous cells of
      undetermined significance (ASCUS), are vastly more common than high-grade
      squamous intraepithelial lesions or invasive cancer. Current guidelines for the
      management of ASCUS include repeating the Papanicolaou (Pap) smear at specific
      intervals, referring all patients for colposcopy or using an adjunctive test such
      as hybrid capture human papillomavirus (HPV) testing or cervicography. The
      usefulness of the Pap smear is limited by its considerable false-negative rate
      and its dependence on clinician and laboratory performance. Colposcopy is a
      highly sensitive procedure, but many patients with ASCUS have normal colposcopic
      findings. The hybrid capture test not only measures quantitative HPV load but
      also detects both oncogenic and nononcogenic HPV types, thereby increasing the
      probability that serious cervical disease is not missed. Hybrid capture sampling
      is simple to perform, and positive results are strongly associated with cervical
      dysplasia. HPV testing in women with ASCUS can be used as an adjunctive test to
      identify those with HPV-associated disease; it can also serve as a quality
      assurance measure. Together, repeat Pap smears and HPV testing should identify
      most patients with underlying cervical dysplasia. Combined testing may also
      minimize the number of unnecessary colposcopic examinations in women who have no
      disease.

PMID- 10348072
TI  - Elder mistreatment.
AB  - Elder mistreatment is a widespread problem in our society that is often under
      recognized by physicians. As a result of growing public outcry over the past 20
      years, all states now have abuse laws that are specific to older adults; most
      states have mandated reporting by all health care professionals. The term
      "mistreatment" includes physical abuse and neglect, psychologic abuse, financial
      exploitation and violation of rights. Poor health, physical or cognitive
      impairment, alcohol abuse and a history of domestic violence are some of the risk
      factors for elder mistreatment. Diagnosis of elder mistreatment depends on
      acquiring a detailed history from the patient and the caregiver. It also involves
      performing a comprehensive physical examination. Only through awareness, a
      healthy suspicion and the performing of certain procedures are physicians able to
      detect elder mistreatment. Once it is suspected, elder mistreatment should be
      reported to adult protective services.

PMID- 10348073
TI  - Cutaneous T-cell lymphoma presenting as benign dermatoses.
AB  - Cutaneous T-cell lymphoma, also known as mycosis fungoides, is a malignancy of
      the T helper (CD4+) cells. Diagnosis is difficult early in the course of this
      disease because it mimics several benign skin disorders, including eczema,
      psoriasis and contact dermatitis. Cutaneous T-cell lymphoma is also difficult to
      identify histologically, and multiple biopsies may be necessary to confirm the
      diagnosis. Treatment may require a combination of topical and systemic agents.
      Patients with limited skin disease have a good prognosis, but the prognosis is
      less hopeful in those with extracutaneous involvement. As the disease progresses,
      the normal T-cell population is eliminated, and the patient becomes significantly
      immunosuppressed. Infection is the primary cause of mortality in patients with
      cutaneous T-cell lymphoma.

PMID- 10348074
TI  - School problems and the family physician.
AB  - Children with school problems pose a challenge for the family physician. A
      multidisciplinary team of professionals can most appropriately assess and manage
      complex learning problems, which are often the cause of poor school performance.
      The family physician's primary role in this process is to identify or exclude
      medical causes of learning difficulties. An understanding of the complicated
      nature of school problems, the methods used to assess, diagnose and treat them,
      and the resources available to support the child and family are essential to
      successful management. Various references and resources are helpful for a more in
      depth study of specific school problems.

PMID- 10348075
TI  - Stroke: part II. Management of acute ischemic stroke.
AB  - Optimal treatment of the patient who has sustained an acute ischemic stroke
      requires rapid assessment and early intervention. The leisurely approach to acute
      stroke management sometimes taken in the past should be replaced by an approach
      that treats stroke as a true medical emergency. Thrombolysis with tissue
      plasminogen activator has been labeled for the treatment of acute ischemic
      stroke, but it must be given within three hours of stroke onset. However,
      fibrinolytic therapy can be given safely to only a fraction of patients with
      acute stroke, and more broadly applicable therapies are needed. Recent evidence
      does not support the routine use of heparin in patients with acute stroke, and
      early use of aspirin offers only modest benefit. Neuroprotective therapies
      designed to interfere with cytotoxic events initiated by ischemia are undergoing
      clinical trials that should be completed within the next year. At present, only
      tissue plasminogen activator has been labeled for acute stroke treatment;
      however, other agents are on the horizon, and much can be done supportively to
      improve neurologic outcome. Because of the unique susceptibility of neurons to
      ischemia, minutes count. Thus, hospitals providing care for patients with acute
      stroke should organize clinical protocols and pathways for effective
      implementation of therapies.

PMID- 10348076
TI  - Treatment of type 2 diabetes mellitus.
AB  - Type 2 diabetes mellitus (formerly called non-insulin-dependent diabetes) causes
      abnormal carbohydrate, lipid and protein metabolism associated with insulin
      resistance and impaired insulin secretion. Insulin resistance is a major
      contributor to progression of the disease and to complications of diabetes. Type
      2 diabetes is a common and underdiagnosed condition that poses treatment
      challenges to family practitioners. The introduction of new oral agents within
      the past three years has expanded the range of possible combination regimens
      available for treating type 2 diabetes. Despite the choice of pharmacologic
      agents, physicians must stress the nonpharmacologic approaches of diet
      modification, weight control and regular exercise. Pharmacologic approaches must
      be based on patient characteristics, level of glucose control and cost
      considerations. Combinations of different oral agents may be useful for
      controlling hyperglycemia before insulin therapy becomes necessary. A stepped
      care approach to drug therapy may provide the most rational, cost-efficient
      approach to management of this disease. Pharmaco-economic analyses of clinical
      trials are needed to determine cost-effective treatment strategies for management
      of type 2 diabetes.

PMID- 10348077
TI  - HIV patients receiving HAART therapy can still transmit the virus. Highly active
      antiretroviral chemotherapy.

PMID- 10348078
TI  - AHA assesses the impact of genotyping on diagnosis of genetic cardiac disease.
      American Heart Association.

PMID- 10348079
TI  - AAP updates its recommendations on circumcision. American Academy of Pediatrics.

PMID- 10348080
TI  - Does vaginismus exist? A critical review of the literature.
AB  - The basic strategies and methods for assessing and treating vaginismus were
      proposed by the early 20th century and have not essentially changed. Etiological
      theories have changed over time but are not supported by controlled empirical
      studies. This critical review of the literature disputes the widely held belief
      that vaginismus is an easily diagnosed and easily treated sexual dysfunction. We
      propose a reconceptualization of vaginismus as either an aversion/phobia of
      vaginal penetration or a genital pain disorder.

PMID- 10348081
TI  - Oral contraceptive use: implications for cognitive and emotional functioning.
AB  - This study investigated the role of oral contraception use versus nonuse as a
      moderator variable differentially influencing cognitive-emotional processes.
      Seventy-six healthy women (29 users and 47 nonusers; 18 to 48 years old),
      completed the State-Trait Anger Expression Inventory, the Clinical Analysis
      Questionnaire, the Rotter Scale of locus of control, the Daily Hassles Scale, and
      a Repertory Grid. A subsample (N = 33) also volunteered for a blood draw.
      Hormonal levels of progesterone and estrogen mostly were unrelated to cognitive
      and emotional measures, and contraindicated the "chemical suppression"
      proposition. Alternatively, when cognitive-emotional functioning was examined
      separately for users and nonusers, cognitive factors including the appraisal of
      stress, loci of control, and self-integration were implicated with specific
      patterns of negative affect and much more so for users than for nonusers. For the
      most part, oral contraceptive use versus nonuse seemed to influence the saliency
      rather than the nature of cognitive-emotional patterns. Discussion focused on
      oral contraceptive use as a moderator variable and the need for longitudinal
      research to clarify the evolving, biopsychosocial influence of hormonal
      regulatory treatment.

PMID- 10348082
TI  - Thought disorder and psychosocial functioning in schizophrenia: the concurrent
      and predictive relationships.
AB  - Recent findings have linked impairments in social performance among individuals
      with schizophrenia to deficits in cognition. However, one component of cognition,
      thought disorder (TD), has received little attention in its association with
      social functioning. The current investigation examined the cross-sectional and
      predictive relationships between bizarre-idiosyncratic thought and psychosocial
      functioning throughout the early course of schizophrenia and compared these
      relationships to those observed among individuals with affective disorders (i.e.,
      bipolar disorder, manic type, and major depression without psychotic features).
      Participants were assessed on TD, work, and social functioning using standardized
      procedures across three follow-ups over an 8-year period. The cross-sectional
      relationships between TD and impairment in work performance were generally
      significant. TD also significantly predicted subsequent work functioning years
      later. Less support was found for the relationship between TD and social
      functioning. Finally, the relationship between TD and work performance appeared
      to be more consistent over time for the subjects with schizophrenia compared to
      those with affective disorders. The results suggest that techniques which
      minimize TD may have implications for occupational functioning among persons with
      chronic psychiatric disorders.

PMID- 10348083
TI  - The Objective Behavioral Index: a measure for assessing treatment response of
      patients with severe personality disorders.
AB  - A measure that captures the frequency and intensity of experienced dysfunctional
      behaviors as well as the use of mental health services was developed and tested
      as part of a treatment controlled trial of patients with borderline personality
      disorder. The Objective Behavioral Index (OBI) was completed by 136 subjects with
      the diagnosis of borderline personality disorder before random assignment to
      treatment and by 35 subjects at each follow-up point. With one exception, the OBI
      subindexes (Dysfunctional Behaviors and Service Utilization) were not
      intercorrelated nor were they associated with any of the other patient status
      measures. Both of the OBI subindexes were sensitive to change after a course of
      psychotherapy. The OBI measurement system is easy to use and provides important
      information about behavioral dysfunction and service utilization. Also, contrary
      to expectations, service utilization is not associated with patient symptomatic
      and behavioral status.

PMID- 10348084
TI  - Clinical correlates of self-mutilation in a sample of general psychiatric
      patients.
AB  - The aims of this study were to examine whether certain axis I disorders
      characterized by impulsive aggression were associated with self-mutilative
      behavior and to evaluate the clinical correlates of self-mutilation in a sample
      of general psychiatric outpatients. Two hundred fifty-six outpatients were
      administered diagnostic interviews for axis I and axis II disorders. In addition,
      questionnaires that measured self-mutilative acts within the last 3 months,
      dissociation, and childhood abuse were completed. This study found that axis I
      disorders of substance abuse, posttraumatic stress disorder, and intermittent
      explosive disorder were significantly related to self-mutilative behavior,
      independent of borderline personality disorder and antisocial personality
      disorder. Also, a higher level of dissociation was related to self-mutilation,
      controlling for borderline personality disorder and childhood abuse. Outpatients
      with certain axis I disorders and those who dissociate may represent a sizable
      group of patients who are at risk for self-mutilative behavior.

PMID- 10348085
TI  - Postconcussive symptoms and posttraumatic stress disorder after mild traumatic
      brain injury.
AB  - Postconcussive symptoms after mild traumatic brain injury (MTBI) may be
      exacerbated by anxiety associated with posttraumatic stress. The aim of this
      study was to investigate the relationship between postconcussive symptoms and
      posttraumatic stress disorder (PTSD) in an MTBI population. Survivors of motor
      vehicle accidents who either sustained an MTBI (N = 46) or no TBI (N = 59) were
      assessed 6 months posttrauma for PTSD and postconcussive symptoms. Postconcussive
      symptoms were more evident in MTBI patients with PTSD than those without PTSD,
      and in MTBI patients than non-TBI patients. Further, postconcussive symptoms were
      significantly correlated with PTSD symptoms. These findings indicate that
      postconcussive symptoms may be mediated by an interaction of neurological and
      psychological factors after MTBI.

PMID- 10348086
TI  - Traumatic experiences, posttraumatic stress disorder, and dissociative symptoms
      in a group of refugees from former Yugoslavia.

PMID- 10348087
TI  - An evaluation of a computer assisted telephone interview for screening for mental
      disorders among primary care patients.

PMID- 10348088
TI  - Cardiovascular responses to a pet snake.

PMID- 10348089
TI  - Borderline personality disorder and bipolar mood disorder: two distinct disorders
      or a continuum?

PMID- 10348090
TI  - Relationship of psychiatric experience and interrater reliability in assessment
      of negative symptoms.

PMID- 10348093
TI  - Safety issues concerning the use of disulfiram in treating alcohol dependence.
AB  - Disulfiram is known to cause hepatitis, which is sometimes fatal. The best
      estimate of the frequency of disulfiram-induced fatal hepatitis is 1 case in
      30,000 patients treated/year. Its appears to be more common in patients given
      disulfiram for the treatment of nickel sensitivity. Frequent blood testing for
      liver function is probably not necessary, but patients taking disulfiram should
      be in regular contact with a physician. There are rare reports of psychosis and
      confusional states in conjunction with disulfiram treatment and peripheral
      neuropathy and optic neuritis have been reported; these effects are dose-related.
      Psychiatric complications appear to be more common with the use of disulfiram in
      India than in Western countries. Of the less serious adverse effects, tiredness,
      headache and sleepiness are the most common. Deaths from the disulfiram-alcohol
      (ethanol) interaction have not been reported in recent years, possibly because
      the dosages used are lower than those used 40 years ago, and patients with
      cardiac disease are now excluded from treatment. There is no evidence to suggest
      that disulfiram causes cancer. Of note, there are drug interactions with
      compounds that utilise the cytochrome P450 enzyme system. Disulfiram can be
      viewed as a drug with a moderate record of adverse effects. Alcohol dependence,
      for which it can be a helpful treatment, is associated with a high morbidity and
      mortality.

PMID- 10348091
TI  - Comparative tolerability of second generation antihistamines.
AB  - Second generation histamine H1 receptor antagonists, the so-called 'nonsedating'
      antihistamines, have high potency and additional antiallergic properties as well
      as H1 antagonism and are associated with fewer adverse effects compared with the
      first generation antihistamines. A number of drugs in this class are approved for
      use: acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine,
      loratadine, mizolastine and terfenadine. All of them have a more favourable risk
      benefit ratio with regard to the CNS adverse effects. Even those second
      generation antihistamines that are not actually 'nonsedating' are less impairing
      than their predecessors, but not one of them is entirely devoid of CNS activity.
      Under certain circumstances some antihistamines may affect cardiac repolarisation
      resulting in cardiovascular adverse effects. Serious cardiovascular effects have
      been reported with terfenadine and astemizole when they are used in high dosages
      or when they are given to 'at risk' patients. Animal models indicate that there
      might be a potential risk of cardiovascular adverse effects with other
      antihistamines as well. However, up to now there is no clinical evidence for this
      assumption, despite some confusing reports. Likewise there has been much
      discussion about a link between these agents and carcinogenicity. However, there
      is no evidence that any of the second generation antihistamines increase the risk
      of tumour growth in humans. Small children, elderly patients and persons with
      chronic renal or liver impairment are special groups in which the individual
      adverse effects of the second generation antihistamines must be kept in mind. The
      dosage for an individual has to be modified with respect to their metabolic
      situation. Despite the fact that some of the second generation antihistamines are
      listed in the US Food and Drug Administration pregnancy risk classification as
      class B, the use of second generation antihistamines should be avoided during
      pregnancy and they should never be administered to nursing mothers. Taking into
      account their negligible CNS activity, the low incidence of cardiovascular
      adverse effects, their lack of anticholinergic effects and other benefits, this
      class of antiallergic drugs represents a definite advance in therapy.

PMID- 10348094
TI  - Cyclosporin-induced hypertension: incidence, pathogenesis and management.
AB  - Blood pressure increases soon after administration of immunosuppressive regimens
      using cyclosporin. Characteristic vascular changes lead to systemic and renal
      vasoconstriction. Changes in blood pressure are commonly associated with
      disturbed circadian regulation and may promote the rapid development of target
      organ injury, including intracranial haemorrhage, left ventricular hypertrophy
      and microangiopathic haemolysis. The mechanisms underlying this disorder are
      complex and include altered vascular endothelial function. Vasodilators such as
      prostacyclin and nitric oxide are suppressed, whereas vasoconstrictors, including
      endothelin, are increased. Changes in the kidney include vasoconstriction,
      reduced glomerular filtration and sodium retention. Effective therapy depends
      upon rigorous blood pressure control by administration of vasodilating agents,
      with attention to potential interactions with cyclosporin.

PMID- 10348092
TI  - A risk and benefit assessment of treatment for AIDS-related Kaposi's sarcoma.
AB  - Kaposi's sarcoma is the most common malignancy observed in patients with HIV-1
      infection, and causes considerable morbidity and, when the lungs are involved,
      mortality. Therapy should be based on an evaluation of prognostic factors, in
      particular the extent and rate of tumour growth, patient symptoms, immune system
      condition and concurrent complications of AIDS. Nevertheless, considering the
      palliative role of Kaposi's sarcoma therapy, the potential benefits of therapy
      must be weighed against the high risk of adverse effects. Therefore, quality of
      life assessment is an integral component of therapeutic decisions. Localised
      Kaposi's sarcoma cutaneous tumours have been successfully treated with surgical
      excision, laser therapy, liquid nitrogen cryotherapy and radiotherapy. In
      patients with moderately extensive cutaneous or mucosal disease and CD4+ cell
      counts of > or =200/ml, immunotherapy and antiretroviral drugs are indicated.
      Preliminary results indicate that antiretroviral therapy might be effective and
      well tolerated in the treatment of less advanced Kaposi's sarcoma. In patients
      with aggressive and extensive mucocutaneous disease or with visceral
      manifestations of Kaposi's sarcoma, systemic cytotoxic therapy is indicated.
      However, the optimal treatment has yet to be found. The combination of
      doxorubicin, bleomycin and vincristine (ABV) has produced high overall response
      rates and is indicated as first-line treatment for patients with life-threatening
      or visceral disease. In patients who are leucopenic and require chemotherapy,
      single or dual agents associated with lower myelotoxicity [i.e. bleomycin,
      vincristine/vinblastine or a combination of bleomycin and vincristine/vinblastine
      (BV)] are most widely used. Other effective cytotoxic regimens are liposomal
      anthracyclines, paclitaxel and vinorelbine. To date, 3 randomised trials have
      compared these drugs to ABV and BV. In a large phase III study, the efficacy of
      liposomal daunorubicin was comparable with that of ABV. In 2 phase III studies,
      liposomal doxorubicin was compared with ABV and BV regimens and was found to be
      significantly more effective in producing objective responses. Therefore,
      liposomal doxorubicin, although more myelosuppressive than the BV regimen, is now
      considered by many physicians as the first-line therapy in patients with advanced
      stage Kaposi's sarcoma. Paclitaxel and vinorelbine have potential in Kaposi's
      sarcoma, but additional studies are needed to evaluate different schedules and to
      compare their activity with that of the reference regimens. Institution or
      continuation of both effective antiretroviral therapy and prophylaxis of
      opportunistic infections should be recommended to all patients receiving systemic
      cytotoxic therapies. However, attention must be paid to the cross-toxicity and
      possible pharmacokinetic interactions between antiretrovirals and
      antineoplastics.

PMID- 10348095
TI  - The treatment of advanced prostate cancer with ketoconazole: safety issues.
AB  - The definition of hormone refractory prostate cancer is changing. It has become
      clear that patients with advanced prostate cancer whose disease has progressed
      following treatment with luteinising hormone releasing hormone agonists and
      antiandrogens can respond to additional hormonal manoeuvres. Ketoconazole is an
      imidazole antifungal and the antiandrogen effects of this agent have been known
      about for over 15 years. Initial concerns about the excessive adverse effects
      associated with this agent appear to have been overstated. Recent studies have
      demonstrated that treatment with ketoconazole can produce a significant response
      in a majority of patients with advanced prostate cancer and that the agent has a
      reasonable toxicity profile. The most common adverse effect is gastrointestinal
      intolerance, followed by fatigue, liver function abnormalities and skin changes;
      the agent is also associated with a variety of rarer adverse effects. The most
      serious potential adverse effects of the drug can be ameliorated by simple
      measures.

PMID- 10348096
TI  - Treating depression in patients with ischaemic heart disease: which agents are
      best to use and to avoid?
AB  - There are a number of dimensions to the complex relationship between
      cardiovascular disease and affective disorders including: (i) patients with
      depression are at an increased risk of dying from sudden cardiovascular death
      compared with the general population; (ii) patients with depression over the
      course of a lifetime have a higher rate of symptomatic and fatal ischaemic heart
      disease compared with a control group without depression; and, (iii) patients
      after either a myocardial or a cerebrovascular infarction who are depressed have
      a higher mortality rate than their medically comparable nondepressed
      counterparts. The deleterious impact of depression on the prognosis of cardiac
      disease and the suggestion that treatment of depression may reduce cardiac
      mortality has led clinicians to seek safe and effective treatment for patients
      with comorbid depression and ischaemic disease. Though they are robustly
      effective, the tricyclic antidepressants are type 1A antiarrhythmic agents and
      presumably carry the same risk in patients with ischaemic disease as treatment
      with other type 1 antiarrhythmics such as moricizine. Short term studies of the
      safety of other antidepressant agents, specifically amfebutamone (bupropion) and
      the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs)
      fluoxetine, paroxetine and sertraline, suggest that these medications have a
      benign cardiovascular profile in patients with depression and pre-existing
      cardiac disease. However, given the methodological limitations of study design
      and the relatively small number of patients included, it is premature to conclude
      that SSRIs are a 'safe' treatment in patients with heart disease. Thus,
      clinicians must still make treatment decisions on a case by case basis,
      considering the type and severity of depression and cardiovascular disease, as
      well as what is known about the cardiovascular effects and therapeutic profile of
      the different classes of antidepressant medications.

PMID- 10348097
TI  - Infectivity and cross-immunity studies of Theileria lestoquardi and Theileria
      annulata in sheep and cattle: I. In vivo responses.
AB  - In a series of experiments, sporozoite stabilates of a Theileria lestoquardi
      (Lahr) and a T. annulata (Ankara) stock prepared from Hyalomma anatolicum
      anatolicum ticks, were used to examine the infectivity of both parasite species
      for sheep and cattle and to study the development of cross-immunity between these
      parasite species. In the first experiment sheep and cattle were inoculated with
      T. lestoquardi sporozoites. Surviving animals and naive sheep and cattle were, in
      the second experiment, inoculated with T. annulata. In the third experiment,
      naive sheep and sheep previously infected with T. annulata, were inoculated with
      T. lestoquardi. The following responses to inoculations were monitored: clinical
      and haematological signs of infection, appearance of parasitic stages of the
      parasites in lymph node biopsies and in peripheral blood and serological response
      to T. lestoquardi and T. annulata schizont antigens. While T. lestoquardi readily
      infected sheep and caused severe disease, it did not infect cattle. On the other
      hand, T. annulata infected both cattle and sheep. However, whereas cattle became
      severely affected, infected sheep showed mild clinical symptoms only and
      piroplasms did not develop. Despite their different behaviour in the host species
      examined, cross-immunity studies suggested that the parasite species are very
      closely related. Experiments in sheep indicated that T. lestoquardi infection
      protected against subsequent T. annulata infection. On the other hand, recovery
      from T. annulata infection did not prevent infection by sporozoites of T.
      lestoquardi, resulting in the establishment of schizonts and their subsequent
      development into piroplasms, although it protected against the major clinical
      effects of T. lestoquardi infection.

PMID- 10348098
TI  - Infectivity and cross-immunity studies of Theileria lestoquardi and Theileria
      annulata in sheep and cattle: II. In vitro studies.
AB  - In the studies previously reported, the tick-borne protozoan parasites Theileria
      lestoquardi and Theileria annulata were shown to differ in their capacity to
      infect sheep and cattle. In the studies presented here, these findings were
      further supported. In vitro infectivity of T. lestoquardi and T. annulata
      sporozoites for peripheral blood mononuclear cells of sheep and cattle were
      determined by analysis of cell cultures for cell proliferation, the detection of
      parasites in Giemsa-stained cytospin smears and the establishment of continuously
      growing schizont-infected cell lines. In the same way, the development of
      schizont-infected cells into continuously growing cell lines was studied with
      material isolated ex vivo from the sheep and cattle undergoing primary infections
      described elsewhere. Comparisons were also made between development of ex vivo
      cell lines from animals undergoing primary infections with those of the animals
      undergoing challenge infection with the other parasite species. Theileria species
      specific primers were used in a PCR to determine the identity of the parasites in
      the cell lines. These in vitro studies confirmed earlier observations that T.
      lestoquardi was unable to infect cattle, whereas infection of all sheep with T.
      annulata was proven. Moreover, earlier indications of the development of partial
      cross-immunity in sheep of T. annulata to T. lestoquardi and vice versa were
      strengthened. These findings may thus have consequences for the understanding of
      the epidemiology of T. lestoquardi infections of sheep. On the other hand. since
      piroplasms were not demonstrated in sheep infected with T. annulata, such sheep
      will not be infective to ticks and will consequently be unlikely to play a role
      in the maintenance and transmission of T. annulata to cattle.

PMID- 10348099
TI  - Determination of the activity of pyrimethamine, trimethoprim, sulfonamides, and
      combinations of pyrimethamine and sulfonamides against Sarcocystis neurona in
      cell cultures.
AB  - Equine protozoal myeloencephalitis (EPM) is a neurologic syndrome in horses from
      the Americas and is usually caused by infection with the apicomplexan parasite,
      Sarcocystis neurona. The activities of pyrimethamine, trimethoprim,
      sulfachloropyridazine, sulfadiazine, sulfadimethoxine, sulfamethoxazole,
      sulfamethazine, and sulfathiazole were examined against developing S. neurona
      merozoites in bovine turbinate cell cultures. A microtiter plate host cell lesion
      based assay was used to determine the effects of agents on developing merozoites.
      A cell culture flask assay was used to determine if selective concentrations of
      the agents killed or only inhibited development of S. neurona. Pyrimethamine was
      coccidiocidal at 1.0 microg/ml and trimethoprim was coccidiocidal at 5.0
      microg/ml. None of the sulfonamides had activity when used alone at 50.0 or 100.0
      microg/ml. Combinations of sulfonamides (5.0 or 10.0 microg/ml) with 0.1
      microg/ml pyrimethamine demonstrated improved activity.

PMID- 10348100
TI  - Infectivity of feline enteroepithelial stages of Toxoplasma gondii isolated by
      Percoll-density gradient centrifugation.
AB  - The infectivity of the feline enteroepithelial stages of Toxoplasma gondii
      isolated by Percoll-density gradient centrifugation was examined by the trypan
      blue dye exclusion method by assaying their penetration into feline fibroblast
      cells in vitro and by inoculation of the intestinal mucosa of cats. A large
      population of the parasites showed trypan blue dye exclusion activity. When
      feline fibroblast cells were inoculated with feline enteroepithelial stage
      parasites, no intracellular parasites were found 18 h post-inoculation. Kittens
      inoculated intraduodenally with 2 x 10(6) feline enteroepithelial stage parasites
      shed oocysts between 2 and 8 days post-inoculation. These results indicate that
      the isolated feline enteroepithelial stage parasites display infectivity towards
      enterocytes of cats and are capable of gametogenesis.

PMID- 10348101
TI  - Nematophagous fungi in fresh feces of cattle in the Mata region of Minas Gerais
      state, Brazil.
AB  - The capacity to survive gut passage is one of the desirable characteristics for
      nematophagous fungi to be considered potential biological control agents of
      gastrointestinal nematodes of livestock. From April 1995 to April 1996, a pool of
      10 cow fecal samples and 10 individual samples of feces from heifers, which were
      raised under partial (cows) or total (heifers) confinement in the Mata Region of
      Minas Gerais State, Brazil, were examined monthly for the presence of
      nematophagous fungi. A total of 10 isolates was found in the survey. Eight
      isolates were recovered from the pooled samples of cow feces and two from the
      individual samples of heifers. Fungi were present in the cow feces during the dry
      months of August (two isolates of Arthrobotrys oligospora and one Monacrosporium
      eudermatum) and September (one isolate of Harposporium lilliputanum and one of M.
      gephyropagum). Fungi were also recovered at the beginning and middle of the rainy
      season: one isolate of A. musiformis in October, and one isolate of M.
      gampsosporum and one unidentified fungus which produced septate hyphae and
      adhesive buds in December. In the individual samples collected from heifers,
      fungi were present only in the months of September (end of dry season) and March
      (end of rainy season). One isolate each of H. lilliputanum and A. oligospora were
      found, respectively. Additional studies to further characterize these isolates
      should be encouraged.

PMID- 10348102
TI  - Concurrent Ascaris suum and Oesophagostomum dentatum infections in pigs.
AB  - The aim of this study was to examine interactions between Ascaris suum and
      Oesophagostomum dentatum infections in pigs with regard to population dynamics of
      the worms such as recovery, location and length; and host reactions such as
      weight gain, pathological changes in the liver and immune response. Seventy-two
      helminth-naive pigs were allocated into four groups. Group A was inoculated twice
      weekly with 10000 O. dentatum larvae for 8 weeks and subsequently challenge
      infected with 1000 A. suum eggs, while Group B was infected with only 1000 A.
      suum eggs; Group C was inoculated twice weekly with 500 A. suum eggs for 8 weeks
      and subsequently challenge-infected with 5000 O. dentatum larvae, whereas Group D
      was given only 5000 O. dentatum larvae. All trickle infections continued until
      slaughter. Twelve pigs from Group A and B were slaughtered 10 days post challenge
      infection (p.c.i.) and the remaining 12 pigs from the each of the four groups
      were slaughtered 28 days p.c.i.. No clinical signs of parasitism were observed.
      The total worm burdens and the distributions of the challenge infection species
      were not influenced by previous primary trickle-infections with the heterologous
      species. Until day 10 p.c.i. the ELISA response between A. suum antigen and sera
      from the O. dentatum trickle infected pigs (Group A) pigs were significantly
      higher compared to the uninfected Group B. This was correlated with a
      significantly higher number of white spots on the liver surface both on Day 10
      and 28 p.c.i. in Group A compared to Group B. The mean length of the adult O.
      dentatum worms was significantly reduced in the A. suum trickle infected group
      compared to the control group. These results indicate low level of interaction
      between the two parasite species investigated.

PMID- 10348103
TI  - Persistent activity of doramectin and ivermectin against Ascaris suum in
      experimentally infected pigs.
AB  - A study was conducted to investigate the persistent nematocidal activity of two
      avermectins against experimentally-induced infections of Ascaris suum in swine.
      Seventy-two nematode-free cross-bred pigs of similar bodyweight were randomly
      allotted to nine treatment groups of eight pigs each. Eight of the groups were
      treated with injectable solutions containing 300 microg of doramectin/kg (IM) or
      300 microg of ivermectin/kg (SC) either 0 (same day), 7, 14, or 21 days prior to
      an oral challenge of 50000 embryonated A. suum eggs. The ninth group (control)
      was challenged in parallel without any avermectin treatment. At 41 or 42 days
      after challenge, pigs were euthanatized and adult and larval stages of A. suum
      were collected from the gastrointestinal tract of each pig and counted. Both
      avermectins significantly (P < 0.0002) reduced nematode counts when given on the
      day of challenge (0 days prior), and the efficacy was 100% and 97.5% for
      doramectin and ivermectin, respectively. Doramectin given 7 days prior to
      challenge significantly (P < 0.0001) reduced nematode counts, and the efficacy
      was 98.4%. For all other avermectin-treatment groups, nematode counts were not
      significantly reduced compared to those in control pigs. These data indicated
      that anthelmintic activity of ivermectin against A. suum persisted for less than
      7 days and the activity of doramectin persisted for more than 7, but less than 14
      days.

PMID- 10348104
TI  - Prevalence and clustering of louse infestation in Queensland sheep flocks.
AB  - Information provided by wool growers in Queensland, Australia between 1995 and
      1997 was used to assess the prevalence and spatial distribution of louse
      (Bovicola ovis) infestation in sheep flocks. The estimated prevalence of louse
      infested flocks was 40% (95% confidence interval, 35-46%). Although the
      prevalence of infestation was higher in western regions (41-50%) compared to the
      south region of Queensland (31%), the difference was not statistically
      significant (P > 0.05). Significant (P = 0.02) clustering of infested flocks was
      detected in the south region where two foci were apparent. We conclude that
      Queensland sheep flocks have a moderate prevalence of louse infestation, and that
      clustering of infestation is not strong. The control of lice is an industry-wide
      issue that needs to be addressed by most wool growers in Queensland.

PMID- 10348105
TI  - Repetitive abortion in Neospora-infected ewes.
AB  - Pregnant ewes inoculated with cultured Neospora caninum tachyzoites in 1995,
      1996, or 1995 and 1996 aborted or delivered weak or clinically normal lambs in
      1996. Nine of 11 ewes in the study had previously produced infected lambs or
      fetuses after being experimentally infected in 1995. Fetuses and lambs produced
      in 1996 showed histologic lesions and zoites indicative of Neospora. Serologic
      responses and production of infected fetuses/lambs indicated systemic neosporosis
      in the ewes during gestation, although tachyzoites could not be cultured from
      maternal tissues. The repetitive infection of fetuses, and resulting clinical and
      histopathologic findings in the present study are similar to those reported in
      naturally infected cattle, adding to the already established similarities of
      neosporosis between sheep and cattle.

PMID- 10348106
TI  - Gamekeeper's thumb.

PMID- 10348107
TI  - Venous thrombosis after THA.

PMID- 10348108
TI  - Do you just want to feel better or get better?

PMID- 10348109
TI  - Deep infection and fracture healing in immediate and delayed locked
      intramedullary nailing for open femoral fractures.
AB  - Fifty-nine patients with 61 open femoral fractures were treated with immediate
      locked intramedullary (IM) nailing (group 1; n=15), delayed IM nailing following
      nonoperative treatment (group 2; n=42), and delayed IM nailing following external
      fixation (group 3; n=7). Sixteen fractures were Gustilo type I, 28 were type II,
      7 were type IIIA, 6 were type IIIB, and 4 were type IIIC open fractures. Four
      (6.6%) deep infections occurred. Significant differences existed in the deep
      infection rate (DIR) between types I and II and all type III fractures (2.3% for
      types I and II versus 17.6% for type III). The deep infection rate did not differ
      significantly among the nailing groups (13.3%, 2.6%, and 15.3% for groups 1, 2,
      and 3, respectively), nor did the deep infection rate correlate with the degree
      of fracture comminution, the existence of polytrauma or polyskeletal trauma, or
      preexistence of superficial or pin-site infections. Seven (11.7%) of these
      fractures resulted in nonunion, excluding one secondary amputation; the nonunion
      rate correlated with fracture location. There were no significant differences in
      the mean fracture healing times between any of the nailing groups. These results
      suggest that IM nailing for the treatment of type III open femoral fractures
      should be considered carefully, regardless of whether it is performed immediately
      or delayed.

PMID- 10348110
TI  - Vascularized iliac bone graft for displaced femoral neck fractures in young
      adults.
AB  - From November 1989 to September 1994, a total of 26 patients (18 men and 8 women)
      with acute displaced femoral neck fractures were treated with closed reduction
      and Knowles pinning combined with vascularized iliac bone grafting. Mean patient
      age was 37.5 years (range: 24-48 years). The mean time interval from injury to
      surgery was 3.6 days (range: 1-10 days). One patient experienced loss of the
      reduction at 6 weeks postoperatively and subsequently went on to hip replacement.
      Mean follow-up for the remaining 25 patients was 56.2 months (range: 20-78
      months). All fractures united within 4 months. The average union time was 3.3
      months. Plain radiographs confirmed the presence of avascular necrosis in 2
      patients during the final follow-up; 1 of these patients developed systemic lupus
      erythematous 1 year after the fracture and had been treated with high doses of
      corticosteroid. Functional and radiographic results were satisfactory in the
      remaining patients.

PMID- 10348111
TI  - Walking boot design: a gait analysis study.
AB  - This study investigated the effect of various short-leg walking boot designs on
      walking. Four commercially available walking boots and a synthetic walking cast
      were tested using three-dimensional gait analysis to determine their effect on a
      normal individual's gait pattern. Temporal-spatial parameters and lower limb
      kinematics and kinetics were analyzed for 10 normal subjects. The synthetic
      walking cast was the most different when compared with the shoe condition with
      respect to the all parameters tested. The Bledsoe walking boot was the only boot
      that was not significantly different from the shoe condition for all parameters
      tested.

PMID- 10348112
TI  - Humeral fracture following shoulder arthroplasty.
AB  - Fracture of the humeral shaft after total or hemiarthroplasty of the shoulder
      occurs infrequently but has serious consequences. This article reports on five
      patients with ipsilateral humeral fractures following shoulder hemiarthroplasty
      who were treated either conservatively or surgically. Fractures in the three
      patients treated conservatively healed on average by 7 months. The results were
      satisfactory in one patient and unsatisfactory in two patients. Both of these
      patients complained of pain and limitation of shoulder motion. Fractures in the
      two patients treated by open reduction and Mennen plate fixation healed on
      average by 2 months, resulting in a better outcome for these patients treated
      surgically.

PMID- 10348113
TI  - Use of the fork plate for internal fixation of periprosthetic fractures and
      osteotomies in connection with total knee replacement.
AB  - Six cases of periprosthetic fractures of the distal femur following total knee
      arthroplasty were treated with a newly developed fork plate. Instead of the blade
      of the condylar plate, this implant features two prongs that are adaptable in
      length. Because of the space between the prongs, the distal femoral fragment
      surrounds the anchorage pegs of the prosthesis and can be gripped near the joint
      line. The average patient age was 74 years. Follow-up ranged between 2 and 54
      months. All patients were mobilized immediately postoperatively. Full weight
      bearing and bone consolidation was achieved by 9 weeks postoperatively.

PMID- 10348114
TI  - Clinical utility of demineralized bone matrix for osseous defects, arthrodesis,
      and reconstruction: impact of processing techniques and study methodology.
AB  - The findings of studies on DBM in the surgical management of osseous defects,
      arthrodeses, and reconstructive procedures have been promising. In general, DBM
      grafts have supported healing in a timely fashion without complication and with a
      diminished need to harvest bone from a secondary operative site. Nonetheless,
      controlled prospective trials are needed to confirm the comparative effectiveness
      of DBM and to quantitate the benefits of avoiding secondary site autologous bone
      harvesting. Notwithstanding the known deleterious effects of certain processing
      steps, current commercial demineralization processes vary widely and use
      ancillary procedures aimed at attenuating potential residual antigens and
      pathogens. While some of these procedures may improve or facilitate graft
      performance (eg, lipid and lipoprotein removal with detergents), others may be
      deleterious (eg, sterilization with radiation or ethylene oxide) (Table 1).
      Therefore, it is important that DBM be processed using methods that consistently
      establish conditions known to preserve DBM's documented osteoinductive potential
      and that authors appropriately identify processing methods known to have effects
      on graft performance.

PMID- 10348115
TI  - Simultaneous ipsilateral pertrochanteric and subcapital fractures.

PMID- 10348116
TI  - Surface hemangiomas presenting as bone lesions.

PMID- 10348117
TI  - Displaced pathological patella fracture due to gout.

PMID- 10348118
TI  - Radiologic case study. Meniscal ossicle.

PMID- 10348119
TI  - How good are experienced interventional cardiologists in predicting the risk and
      difficulty of a coronary angioplasty procedure? A prospective study to optimize
      surgical standby.
AB  - The prediction of the risk of a percutaneous transluminal coronary angioplasty
      has either been based on coronary lesion morphology or on clinical parameters,
      but a combined angiographic and clinical risk assessment system has not yet been
      evaluated prospectively. Five experienced interventionalists categorized 7,144
      patients with 10,081 stenoses (1.4 lesion/patient) for both the risk and the
      difficulty of the procedure. Risk categories are as follows: 1 = low risk; 2 =
      intermediate risk; 3 = high risk. This division was made for percutaneous
      transluminal coronary angioplasty planning purposes. Category 1 patients denotes
      those in whom surgical standby is not required; category 2 patients, surgical
      standby not required but available within 1 hr; category 3 patients, surgical
      standby required. Difficulty categories are as follows: 1 = easy lesion; 2 =
      moderately difficult lesion; 3 = difficult lesion. Success was defined as a
      reduction of the degree of stenosis to less than 50%, without acute myocardial
      infarction, emergency redilatation, emergency bypass grafting, or death within 1
      week. The procedure was not successful in difficulty category 1 in 1.6%, in
      category 2 in 3.5%, and in category 3 in 9.9%. Complications occurred in risk
      category 1 in 3.5%, in category 2 in 5.2%, and in category 3 in 12.4%. All
      differences were statistically significant (P < 0.05). Experienced cardiologists
      can well predict the risk and success of a coronary angioplasty procedure. This
      helps to optimize surgical standby, although even in the lowest-risk category
      complications can occur.

PMID- 10348120
TI  - Risky business.

PMID- 10348121
TI  - Impact of residual plaque burden on clinical outcomes of coronary interventions.
AB  - In this study, we summarize the role of residual plaque burden, as determined by
      intravascular ultrasound, on the development of restenosis following percutaneus
      coronary interventions. Several clinical trials have shown that the amount of
      residual plaque is a consistent and independent predictor of subsequent
      restenosis. The impact of residual plaque burden on late lumen loss is
      particularly augmented by negative vessel remodeling that is commonly seen after
      balloon angioplasty and atherectomy. However, early evidence suggests that the
      importance of plaque burden also applies in the context of stenting. The
      cotreatment of debulking may further improve the long-term outcome of stenting by
      maximizing an acute lumen gain with less vessel stretching, preventing stent edge
      problems and possibly reducing the cell source involved in the intimal
      hyperplastic process. Evaluation of residual plaque burden with on-line
      intravascular ultrasound could lead to definitive therapies via risk
      stratification of the treated segments.

PMID- 10348122
TI  - "Doctor, where did the plaque go?".

PMID- 10348123
TI  - Simultaneous intracoronary ultrasound and Doppler flow studies distinguish flow
      mediated from receptor-mediated endothelial responses.
AB  - Abnormalities in vascular endothelial function, which occur early in
      atherosclerosis, may play an etiologic role in the development of the disease or
      represent a marker for the extent of atherosclerosis. Endothelial dysfunction,
      usually characterized by demonstration of decreased endothelium-dependent
      vasorelaxation, may be a sensitive and specific method to detect vascular disease
      in its earliest stages. In this context, separation of abnormalities in receptor
      mediated and flow-mediated endothelium-dependent vasodilatory responses may allow
      for the most accurate characterization of endothelial dysfunction. In 35 patients
      undergoing routine annual cardiac catheterization after heart transplantation,
      changes in epicardial lumen area and coronary blood flow in response to
      intracoronary administration of adenosine, acetylcholine, and nitroglycerin were
      measured simultaneously using an intravascular ultrasound (IVUS) catheter
      positioned over a Doppler flow wire in the left anterior descending coronary
      artery. The combination of these techniques allowed for distinction between
      receptor-mediated and flow-mediated endothelium-dependent vascular responses.
      Peak flow with the endothelium-independent resistance vessel dilator adenosine
      occurred at 18+/-2 sec; the maximal lumen area response occurred later, at 43+/
      11 sec (P < 0.001). Acetylcholine, an endothelium-dependent small- and large
      vessel vasodilator, caused an immediate increase in both flow and lumen area, but
      a second peak of dilation was observed, and maximal area occurred 46 sec after
      maximal flow (54+/-14 vs. 100+/-26 sec, P < 0.001). Simultaneous IVUS and Doppler
      flow measurements after infusion of vasoactive agents allows for distinction
      between and evaluation of the relative contribution of agonist-mediated and flow
      mediated responses, which may offer important and unique insights into coronary
      endothelial function.

PMID- 10348124
TI  - Better tools for approaching endothelial function: intracoronary ultrasound
      imaging and flow.

PMID- 10348125
TI  - Prognostic significance of myocardial enzyme release after coronary
      interventions.
AB  - Mild to moderate periprocedural elevation in CK with concurrent CK MB elevation
      result in increased subsequent myocardial infarction and mortality. However the
      potential risks that percutaneous revascularization interventions pose must be
      evaluated in light the risks of alternative procedures and the risks of continued
      medical management. Prospective clinical trials examining the relationship of
      periprocedural enzyme elevations to long term prognosis will need to address this
      issue.

PMID- 10348126
TI  - Creatine kinase leaks, myocardial necrosis, and prognosis after percutaneous
      coronary interventions.

PMID- 10348128
TI  - Rotational atherectomy: new technology, improved technique, and better results.

PMID- 10348127
TI  - Rotational atherectomy: improved procedural outcome with evolution of technique
      and equipment. Single-center results of first 1,000 patients.
AB  - We present our single-center experience of rotational atherectomy (RA) in the
      first 1,000 consecutive patients divided arbitrarily into three different time
      periods corresponding to significant changes in technique or equipment for RA.
      Period I (August 1994 to April 1995; 172 cases) is characterized by early
      experience, longer ablation, and frequent use of intra-aortic balloon pump;
      period II (May 1995 to January 1996; 254 cases) is characterized by short
      ablation runs (20-30 sec) and use of rotaflush; period III (February 1996 to
      February 1997; 574 cases) is characterized by ReoPro use, neosynephrine boluses
      to avoid hypotension, and rota floppy wire and flexible shaft burrs. The
      procedural success rate has improved and complication rates have progressively
      declined over these three time periods. The incidence of lesion complexity (long
      and type C lesions) and patients with unstable rest angina have increased over
      these time periods of RA. Therefore, modification in procedural techniques and
      equipment over time have made RA a safe technique despite its use in very complex
      lesion subsets.

PMID- 10348129
TI  - Effects of increasing balloon pressure on mechanism and results of balloon
      angioplasty for treatment of restenosis after Palmaz-Schatz stent implantation:
      an angiographic and intravascular ultrasound study.
AB  - Repeat balloon angioplasty is a widely used therapeutic option for in-stent
      restenosis, but the optimal balloon inflation pressure has not yet been
      determined. We used angiography and intravascular ultrasound imaging to assess
      the mechanism and results of lumen enlargement at various inflation pressures.
      Thirteen consecutive patients with restenosis post-Palmaz-Schatz stent
      implantation were submitted to a four-step balloon angioplasty using increasing
      balloon pressure of 2, 4, 8, and >12 atm. As a global result, the lumen size was
      only 80% of that observed at stent implantation. Significant changes in
      angiographic minimal lumen diameter, minimal lumen cross-sectional area, and
      lumen volume were observed after each step except after the highest-pressure
      inflation. At low inflation pressure (<8 atm), the decrease in neointimal tissue
      and the stent over expansion explained the lumen enlargement, whereas after
      further high inflation pressure (>8 atm), only additional stent over expansion
      was observed. These results suggest that only moderate balloon inflation pressure
      (up to 12 atm) is needed for angioplasty of post-Palmaz-Schatz stent restenotic
      lesions.

PMID- 10348130
TI  - Evaluation of coronary artery bypass grafts using helical scan computed
      tomography.
AB  - The patency of coronary artery bypass grafts was evaluated by helical computed
      tomographic (CT) scan. One hundred forty patients who received an enhanced chest
      CT scan and a coronary angiography after bypass surgery were studied before
      discharge at the Fukui Cardiovascular Center. Among them was a total of 398
      grafts and 436 anastomoses. For the evaluation of 248 vein grafts, the CT scan
      showed a 99.5% correct positive ratio and an overall accuracy of 96.4%. In 122
      internal thoracic arteries tested, an overall accuracy of 64.7% was obtained. In
      gastroepiploic artery tests the overall accuracy was 33.3% and in radial artery
      tests it was 45.5%. Thirty-seven venous sequential anastomoses in 34 grafts and 1
      internal thoracic artery sequential anastomosis were also evaluated. In the
      venous sequential anastomosis, the CT scan showed a 73.0% of accuracy overall.
      This study showed that the helical CT scan was useful to evaluate graft patency
      following bypass surgery.

PMID- 10348131
TI  - Value of intravascular ultrasound in the assessment of coronary pseudostenosis
      during coronary interventions.
AB  - Coronary pseudostenosis (PS) are increasingly visualized during coronary
      interventions. In many patients PS are readily recognized by a characteristic
      angiographic pattern, but in other cases the diagnosis remains difficult. The
      value of intravascular ultrasound (IVUS) in the study of PS remains unknown. In
      this study, IVUS was used to assess the morphologic appearance of the vessel wall
      in 10 consecutive patients showing images of PS during coronary interventions.
      Mean age of the group was 60+/-12 years and two patients were female. IVUS was
      performed with a motorized pullback system to assess lumen, plaque, and total
      vessel cross-sectional areas. Measurements were performed both at the site of PS
      and at the distal reference segment. PS were always located on angled coronary
      segments. In one patient no lumen narrowing was detected with IVUS at the site of
      PS. In the remaining nine patients, however, a very localized elliptic-shaped
      lumen narrowing was demonstrated. As compared with the distal reference segment,
      coronary lumen (6.3+/-2.2 vs. 12.7+/-4.8 mm2, P < 0.001) and total vessel area
      (11.9+/-3.3 vs. 16.1+/-6.1 mm2, P < 0.05) were smaller at the site of PS. Severe
      lumen asymmetry was also documented at this site. In addition, a characteristic
      image of a flattened, three-layered wall, overlying a hypoechogenic space, was
      visualized in five patients. This unique pattern was considered the correlate of
      a partial coronary intussusception. PS induced some resistance to the advancement
      of catheters in two patients and temporary flow impairment in two additional
      patients. However, in every case, the image of PS disappeared once the guidewire
      was removed. Thus, at sites with PS, IVUS allows ruling out severe
      atherosclerosis and coronary dissections. In addition, IVUS also provides
      important diagnostic clues, including the image of intussusception, for making
      the correct diagnosis of this benign entity.

PMID- 10348132
TI  - Stenting of coronary artery stenosis in Kawasaki disease.
AB  - Coronary artery lesions can develop in Kawaski disease as a major complication,
      and result in aneurysm formation and stenosis. Reported is the evolution of
      important coronary artery stenosis in a pediatric patient managed with an
      endovascular stent.

PMID- 10348133
TI  - Coronary arterial stenosis after Kawasaki disease: role of catheter intervention.

PMID- 10348135
TI  - Placement of an intracoronary stent via translumbar puncture.
AB  - Translumbar puncture for access to the central arterial tree has been used for
      aortography and for selective coronary angiography in selected patients where
      conventional peripheral access is not possible. A single case report of coronary
      angioplasty through this access technique is available in the literature. We
      report a case of coronary stent placement using the translumbar approach to
      access the coronary arteries.

PMID- 10348134
TI  - Vessel-sparing technique for coil occlusion of the very small patent ductus
      arteriosus.
AB  - A technique is described for coil occlusion of the small patent ductus arteriosus
      through a 4 French arterial catheter. The need for a 5 French sheath and catheter
      to stabilize the 3 French size delivery catheter system is obviated. The method
      is proposed as a way to minimize arterial vascular injury in the small patient
      undergoing transcatheter occlusion of the small ductus.

PMID- 10348136
TI  - Placement of an intracoronary stent via translumbar puncture.

PMID- 10348137
TI  - Unexpanded, irretrievable stent in the proximal right coronary artery: successful
      management with stent graft implantation.
AB  - Stent loss and failure of retrieval are rare; nevertheless, complications have to
      be taken into account during percutaneous coronary intervention. Here we report a
      case of an unexpanded, irretrievable Palmaz-Schatz stent in the proximal right
      coronary artery near to the ostium and the successful management by implanting a
      synthetic stent graft.

PMID- 10348138
TI  - New approach to the diagnosis of patent ductus arteriosus during catheterization.
AB  - The diagnosis of patent ductus arteriosus (PDA) usually requires catheterization,
      as does percutaneous treatment of the disorder. To obtain pressure gradients, a
      catheter can be passed in either direction through the PDA, from the pulmonary
      artery to the aorta or via the more common route of aorta to pulmonary artery.
      Several types of catheters have been used, but to date there have been no reports
      showing the use of a left internal mammary artery (LIMA) angiographic catheter
      for this purpose. We report successful passage of this catheter from the aorta
      across a PDA to the pulmonary artery in 15 adult patients who were observed to
      have no complications.

PMID- 10348139
TI  - Combined use of Orgaran and Reopro during coronary angioplasty in patients unable
      to receive heparin.
AB  - Orgaran, a heparinoid, has been used successfully in patients with heparin
      induced thrombocytopenia. We report three cases in which Orgaran was combined
      with the glycoprotein IIbIIa receptor antagonist Reopro during coronary
      angioplasty. Orgaran was given as a single intravenous bolus of 1500 anti-factor
      Xa units. No ischemic or hemorrhagic complications occurred during or following
      the procedure.

PMID- 10348140
TI  - Options to heparin anticoagulation for cardiac interventions.

PMID- 10348141
TI  - Reduction in ischemic vascular complications with a hydrophilic-coated intra
      aortic balloon catheter.
AB  - Hydrophilic coatings improve the handling characteristics of angioplasty
      equipment, but until recently this technology has not been available for intra
      aortic balloon (IAB) catheters. To determine whether a new hydrophilic coating is
      associated with a reduction in IAB-related complications, we prospectively
      evaluated 188 patients undergoing insertion of this new IAB catheter.
      Complications related to IAB insertion were recorded and compared to data from
      682 patients previously treated with an uncoated IAB catheter of the same shaft
      diameter and balloon size. By multivariate analysis the hydrophilic-coated IAB
      catheter was associated with a 72% reduction in ischemic vascular complications
      (relative risk 0.28, 95% CI 0.08-0.96, P= 0.04). There were also trends toward
      reductions in IAB rupture and the need for vascular surgical repair for bleeding
      or ischemia. While further investigation is warranted, hydrophilic coatings that
      reduce the coefficient of friction during IAB catheter insertion may also reduce
      subsequent ischemic vascular complications.

PMID- 10348142
TI  - Intracoronary stent placement proximal to a myocardial bridge: immediate and long
      term results.
AB  - The intracoronary stent placement in a lesion proximal to a myocardial bridge is
      of special importance and is considered to be a challenge for the interventional
      cardiologist. In this study 4 cases of stent implantation proximal to a coronary
      bridged segment are described. In all cases complications were observed after the
      procedure. The patients remained free of symptoms and the exercise TI201 test was
      negative for ischemia 8.5+/-2.6 months later. Although there is skepticism
      because of the abnormal coronary flow pattern, the endothelial dysfunction and
      the subsequent thrombogenicity, the stent placement proximal to a myocardial
      bridge was safe and with favorable long term results in all 4 cases. However,
      further studies in large populations are necessary.

PMID- 10348143
TI  - Fluoroscopic and fluorographic cameras.
AB  - Cameras and display devices transfer images from the image intensifier to the
      observer's eye. Cinefilm cameras and video cameras are used together for the
      performance of cardiac angiography. The state of the art is evolving toward
      digital video-based systems. This tutorial introduces underlying technology.

PMID- 10348144
TI  - Assessing coronary artery stenosis severity: in vitro validation of the concept
      of fractional flow reserve.
AB  - Fractional flow reserve (FFR) is an index to assess the functional obstruction of
      an isolated coronary artery stenosis. It can be measured using only pressure
      measurements proximal (Pa) and distal (Pd) to the stenosis: FFR = P(d)/P(a). We
      studied the relation of pressure and flow-derived measurements of FFR in a
      pulsatile, hydraulic model of a coronary artery under physiological aorta
      pressure (80-110 mm Hg) and coronary flow (140-260 ml/min) conditions.
      Measurements were done at baseline and for several stenosis levels obtained with
      an external occluder. We found good correlations (r2 > 0.95) between pressure and
      flow-derived FFR, irrespective of isolated changes in myocardial resistance or
      aortic perfusion pressure. The basic assumption, i.e., that myocardial resistance
      is constant, was identified as most crucial in the validity of the concept of
      pressure-derived FFR. The agreement between our data and published animal and
      human studies indicates that this is most probably the case in hyperaemic
      conditions.

PMID- 10348145
TI  - Radial force of coronary stents: a comparative analysis.
AB  - High radial force has become an essential feature of new coronary stents. These
      stents are expected to exhibit sufficient radial force and minimum radial recoil
      when deployed in atheromatous lesions of various morphologies. The aim of this
      study was to compare the radial force of 17 coronary stents in vitro
      (Anglodynamics, ACS Multilink, AVE Micro II and GFX, Bard XT, Biocompatibles PC,
      Cook GR II, Cordis Crossflex, Hexacath Freedom, Johnson & Johnson PS 153'PS 154,
      and Crown, Medtronic Wiktor and BeStent BEL-15, Saint-Come SC 1616, Scimed Nir 7
      and 9). Two in vitro mechanical tests were performed to assess the stent radial
      force. The first test measured the deformation of coronary stents in a V-stand by
      using a deformation controlled by a dynamometer based on a longitudinal
      generatrix. The precision was of 1 micron. This comparative test highlighted the
      appreciable variation in behavior of the range of tested stents in terms of
      resistance to local compression. The line graphs obtained show a very small (and
      in some cases nonexistent) purely elastic behavior area in the stents, with this
      result reflecting a small (<0.4 Newtons) range of forces applied to all stents.
      Above this value, the stents did not return to their size before compression and
      the line graph remains approximately linear for a long period. It was therefore
      possible to distinguish between two families of stents on the basis of the
      presence or absence of this elastic area. In the second test, the stent was
      deployed in a 3.0-mm elastic tube and a pressure gradient created between the
      interior and exterior of the tube. The precision was of 50 microns. A typical
      line graph of the pressure-diameter relationship was recognizable for a given
      stent. No difference in behavior between the different coronary stents was noted
      up to 0.3 x 10(5) Pa; subsequently, after 0.3 x 10(5) Pa, sizable deformation
      differences were visible between the least resistant stent, the BeStent BEL-15,
      and the most resistant stent, the Crossflex.

PMID- 10348146
TI  - Multiplex PCR--a rapid screening method for detection of gene rearrangements in
      childhood acute lymphoblastic leukemia.
AB  - Chromosomal rearrangements in childhood acute lymphoblastic leukemia (ALL) play
      an important role in the identification of clinical relevant subgroups. For rapid
      and easy detection of the clinically most important gene rearrangements, a nested
      multiplex reverse transcriptase polymerase chain reaction (multiplex PCR) was
      developed. This multiplex PCR enables the detection of M-BCR/ABL, m-BCR/ABL, TEL/
      AML1, and MLL/AF4 fusion transcripts in one PCR reaction. However, the existence
      of splicing variants and different breakpoints on the DNA level hampers the
      discrimination of the rearrangements by their fragment size on an agarose gel.
      Therefore, one of the internal primers of each translocation (ABL-2, TEL-2, AF4
      2) was labeled with a characteristic fluorescent dye, and an automatic
      fluorescence-based DNA fragment analysis was performed. The sensitivity of this
      multiplex PCR is in the same range as that of the corresponding single PCR
      reaction and allows a fast screening for the detection of therapy-relevant
      rearrangements, with a high turnover of samples.

PMID- 10348148
TI  - The soluble form of interleukin-6 receptor modulates cell proliferation by acute
      myeloblastic leukemia blast cells.
AB  - As interleukin-6 (IL-6) has been shown to have diverse effects on blast cell
      growth in acute myeloblastic leukemia (AML), and as a soluble (s) form of IL-6
      receptor (IL-6R) agonizes IL-6 effects in many cell types, we investigated
      whether sIL-6R was able to modulate clonogenic blast cell growth in AML. The
      proliferation responses of eight autonomously growing AML cell lines and eight
      primary AML blast cell samples were compared with their IL-6 and sIL-6R
      expression. Only three of the 16 AML samples were influenced by IL-6, two of them
      being stimulated and one inhibited by it. The sIL-6R-induced responses were more
      frequent, however, and, in contrast to those by IL-6, always stimulatory:
      clonogenic cell growth in six of the 16 AML samples was stimulated by sIL-6R
      treatment. All the cell lines and four of the seven primary blast cell samples
      analyzed expressed IL-6, and the expression was associated with unresponsiveness
      to exogenous IL-6. sIL-6R was also frequently expressed by AML cells: only one of
      the samples was negative for it. However, there was no correlation between sIL-6R
      expression and the responsiveness of cells to exogenous sIL-6R. The work
      presented here shows that sIL-6R is able to stimulate blast cell growth in AML.
      As AML blast cells are provided by exogenous IL-6 and sIL-6R in a bone marrow
      environment, and as many of them also express IL-6 and sIL-6R themselves in
      vitro, it is possible that signaling through the IL-6/sIL-6R system plays a role
      in maintaining their growth also in vivo.

PMID- 10348147
TI  - Effects of interleukin 3, interleukin 7, and B-cell growth factor on
      proliferation and drug resistance in vitro in childhood acute lymphoblastic
      leukemia.
AB  - Growth factors have been reported to enhance the cytotoxicity of anticancer
      agents. In our study we investigated the capacities of interleukin 3 (IL-3),
      interleukin 7 (IL-7), low-molecular-weight B-cell growth factor (lmw-BCGF), and
      IL-3 + 7 to induce proliferation and to modulate the drug resistance of childhood
      acute lymphoblastic leukemia (ALL) cells. Proliferation was assessed with the
      methyl-thiazole-tetrazolium (MTT) assay and other parameters. Cellular resistance
      to cytarabine, thioguanine, and prednisolone was measured using the MTT assay. In
      19 samples containing >90% leukemic cells the proliferative response and the
      modulation of drug resistance was markedly heterogeneous between patient samples
      and between growth factors. All growth factors were able to stimulate
      proliferation significantly after 5 days of culture. lmw-BCGF was the most potent
      growth factor in this respect. Cytotoxicity of cytarabine and thioguanine was
      significantly increased by IL-7, that of thioguanine by IL-3 as well. IL-7
      enhanced the cytotoxicity of thioguanine significantly more than IL-3 and lmw
      BCGF and that of cytarabine more than IL-3. Cytotoxicity of prednisolone was not
      significantly influenced by any growth factor. In individual cases, growth
      factors reduced the cytotoxicity of the drugs. IL-3 + 7 did not add activity to
      the most potent single growth factor in both proliferation and drug resistance
      measurements. This study shows that IL-3, IL-7, and lmw-BCGF generally induce and
      occasionally inhibit proliferation of ALL cells. Furthermore, they may either
      increase or decrease cytotoxicity of anticancer drugs. This heterogeneous
      response to growth factors concerning induction of proliferation and modulation
      of drug resistance should be taken into account in their clinical use.

PMID- 10348149
TI  - Generation of dendritic cells from patients with chronic myelogenous leukemia.
AB  - Dendritic cells (DCs) are professional antigen-presenting cells (APCs)
      specialized to internalize, process, and present antigen. They have the capacity
      to stimulate the primary immune response of resting T-cells. We generated DCs
      from the adherent cell fraction of peripheral blood, as well as from purified
      CD34+ cells from CML patients. Characterizing DCs from ten CML patients by flow
      cytometry, we found that these cells are highly positive for HLA-DR, CD1a, CD23,
      and CD80 and negative for CD14, CD15, and CD16. The yield of DCs ranged from 19.5
      to 68%. In addition, we used a functional test of FITC-dextran uptake to verify
      that early DCs take up large particles (0.5-3 microm) by macropinocytosis while
      monocytes do not. FITC-dextran uptake was detected by flow cytometry, showing
      that DCs had accumulated these fluorescent particles. Electron-microscopic
      analysis showed no major morphological differences between normal and CML-derived
      DCs. Furthermore, cultured DCs were isolated by FAC sorting for CD1a and HLA-DR
      expression. In these highly purified cells the Ph chromosome was detected by
      interphase fluorescence in situ hybridization (FISH) and by fluorescence
      immunophenotyping and interphase cytogenetics as a tool for the investigation of
      neoplasms (FICTION); 30-85% of DCs generated were Ph-chromosome positive. It
      might therefore be possible not only to prime T-cells with bcr/abl-specific
      synthetic peptides, but also to stimulate T-cells directly with Ph-positive DCs.
      Use of DCs might serve as a novel therapeutic approach in CML patients, due to
      their ability to induce highly specific T-cell responses in an autologous system.

PMID- 10348150
TI  - Hydroxyurea-induced acute interstitial pneumonitis in a patient with essential
      thrombocythemia.
AB  - Hydroxyurea is a drug widely used to control myeloproliferative disorders, due in
      part to its relative lack of severe side effects. We present a case of acute
      interstitial pneumonitis in a patient who was treated with hydroxyurea for
      essential thrombocythemia. The clinical course suggests that the interstitial
      pneumonitis was induced by hydroxyurea. This is the first case of hydroxyurea
      induced acute interstitial pneumonitis reported in the literature.

PMID- 10348151
TI  - Effect of high-dose melphalan and peripheral blood stem cell transplantation on
      renal function in patients with multiple myeloma and renal insufficiency: a case
      report and review of the literature.
AB  - Multiple myeloma with IgG-lambda monoclonal gammopathy and severe renal
      impairment with light-chain deposit disease was diagnosed in a 51-year-old man.
      Following conventional therapy with VAD (vincristine, adriamycin, dexamethasone)
      a partial remission was achieved. Peripheral blood stem cells (PBSC) were then
      collected following mobilization with cyclophosphamide and recombinant human
      granulocyte colony-stimulating factor and enriched for CD34-positive cells by
      immunoaffinity column. Fourteen months after diagnosis high-dose melphalan was
      given, followed by infusion of CD34-positive PBSC. Aside from mild oral mucositis
      and trigonitis, high-dose therapy was tolerated well. After he underwent PBSC
      transplantation his renal function improved, and the patient has been in in
      continuous complete remission for 1 year. Thus, high-dose chemotherapy can be
      safely administered to patients with multiple myeloma and severe renal
      impairment. Our findings confirm previous reports summarized in the current
      presentation.

PMID- 10348152
TI  - Splenectomy induced complete remission in a patient with multicentric Castleman's
      disease and autoimmune hemolytic anemia.
AB  - Castleman's disease (CD) is a rare disorder of the lymphoid tissue in which the
      clinical manifestations often mimic a malignant lymphoma. Despite the absence of
      monoclonality of the lymphoid proliferation, the multicentric variant of the
      disease (MCD) is characterized by severe symptoms and poor prognosis. Etiologic,
      pathogenetic, and therapeutic aspects of MCD are still uncertain. We report the
      case of a 57-year-old patient affected by MCD complicated by severe
      immunohemolytic anemia. Whereas the clinical and laboratory response to steroids
      and chemotherapeutic agents was only partial, splenectomy induced a complete
      remission of hemolysis and disappearance of the constitutional symptoms and of
      all generalized lymphadenopathies.

PMID- 10348153
TI  - Impaired response of granulocyte-committed progenitor cells to stem cell factor
      and granulocyte colony-stimulating factor in human cyclic neutropenia.
AB  - Although cyclic neutropenia (CN) has been the subject of extensive studies due to
      its striking clinical picture, the abnormality of hematopoietic progenitor cells
      in patients with CN has been poorly defined. We studied the sensitivity of
      progenitor cells of a CN patient to colony-stimulating factors (CSF) including G
      CSF, interleukin-3 (IL-3), and stem cell factor (SCF). Peripheral blood
      progenitor cells of the patient required a significantly higher dose of G-CSF to
      give rise to colonies than those of normal controls. While the presence of SCF
      enhanced the number of G-CSF-induced colonies regardless of the concentration of
      G-CSF in normal controls, this synergistic effect of SCF was limited to the high
      concentration of G-CSF in the patient, indicating that the abnormality in
      hematopoiesis in CN involved more immature progenitor cells responsive to SCF.

PMID- 10348154
TI  - Late epileptic seizures after cerebral infarction.
AB  - OBJECTIVES: To determine the profile of late epileptic seizures following
      cerebral infarcts and the predictive clinical and radiological factors associated
      with their development. METHODS: We compared 86 patients who developed late
      seizures after cerebral infarction with 285 similar patients who did not develop
      seizures for at least 1 year after their stroke. Patients who had seizures only
      at the onset of the stroke were excluded. Odds' ratios were used for statistical
      analysis. RESULTS: Simple partial, and mainly motor seizures, with or without
      secondary generalization, accounted for 80% of the classifiable seizures but it
      was not possible to determine the seizure type in half of the cases. Factors that
      appeared to be predictive of seizure development were the presence of large
      cortical infarcts and the presence of apparently preserved cerebral tissue within
      the infarcted area. Seizures were rare in patients with lacunar infarction but
      the presence of associated leukoaraiosis increased the risk. The risk was also
      increased in patients with other medical problems known to lower seizure
      threshold, such as renal failure.

PMID- 10348155
TI  - Fracture risk is increased in epilepsy.
AB  - OBJECTIVES: To study fracture rates and risk factors for fractures in non
      institutionalized patients with epilepsy. MATERIAL AND METHODS: Historical follow
      up. Self-administered questionnaires were issued to 755 patients with epilepsy
      (ICD 10: G40.0 to G40.9) and 1000 randomly selected controls from the background
      population. RESULTS: A total of 345 patients (median age: 45, range 17-80 years)
      and 654 control subjects (median age: 43, range 19-93 years) returned the
      questionnaire. Before epilepsy was diagnosed there was no difference in overall
      fracture rate between patients and controls (RR = 1.0, 95% CI: 0.8-1.3). After
      the diagnosis the overall fracture rate was significantly higher in the patients
      (RR = 2.0, 95% CI: 1.6-2.5). Fractures of the spine, forearms, femurs, lower
      legs, and feet and toes were significantly increased. Fractures related to
      seizures accounted for 33.9% (95% CI: 25.3-43.5%) of all fractures. After
      elimination of seizure related fractures the increase in fracture frequency was
      only borderline significant: RR = 1.3 (95% CI: 1.0-1.7, P = 0.042). No difference
      in fracture energy between patients and controls was observed (low energy
      fractures: 1.7/1.4%, medium energy fractures: 59.8/52.0%, and high energy
      fractures: 38.3/46.6%). Use of phenytoin (OR = 2.4, 95% CI: 1.1-5.4) and a family
      fracture history (OR = 2.4, 95% CI: 1.3-4.6) was associated with an increased
      fracture risk. CONCLUSIONS: Fractures were more common in epileptics than in
      controls especially among users of phenytoin. Most of the increase in fracture
      frequency was related to seizures and not to low bone biomechanical competence.

PMID- 10348156
TI  - Electroencephalography in dogs with epilepsy: similarities between human and
      canine findings.
AB  - OBJECTIVES: To investigate the diagnostic value of electroencephalography (EEG)
      in dogs with epilepsy, applying human criteria for EEG abnormalities observed
      with this disorder. MATERIAL AND METHODS: Twenty-six dogs with a clinically
      established diagnosis of epilepsy were investigated with electroencephalography
      (EEG) in order to evaluate the diagnostic yield of EEG in canine epilepsy.
      RESULTS: Of 23 dogs with evaluable EEGs 15 (65%) demonstrated abnormal activity.
      The most common abnormalities were focal low frequency patterns without spikes
      (48%), followed by focal epileptiform activity (22%) and generalized epileptiform
      activity (17%). The distribution between focal and generalized activity were 73%
      and 27%, respectively. Consistency were demonstrated between the clinical- and
      the EEG-diagnosis in 13 dogs (87%). A relationship was demonstrated between the
      number of abnormal EEGs and the proximity of a seizure to the EEG examination.
      CONCLUSION: A marked consistency was demonstrated between the clinical diagnosis
      of seizure type and the type of abnormalities observed in the EEG, thus
      indicating that EEG is a valuable diagnostic aid in confirming the diagnosis of
      epilepsy in dogs. EEG findings in dogs with epilepsy and humans with this
      disorder were markedly similar.

PMID- 10348157
TI  - Patient outcome after endovascular treatment of intracranial aneurysms with
      reference to microsurgical clipping.
AB  - OBJECTIVES: Endovascular treatment of intracranial aneurysms with Guglielmi
      detachable coils (GDC) has found growing acceptance worldwide, and partially
      replaced conventional microsurgery. In this study clinical and angiographical
      results of embolization are reviewed. In addition, long-term neuropsychological
      patient outcome with reference to surgery is assessed. Indications for screening
      and follow-up of the patients as limitations and recent achievements of aneurysm
      embolization are discussed. MATERIAL AND METHODS: Angiographical and clinical
      follow-up of the first 44 patients with 48 GDC-coiled aneurysms are reviewed.
      Postprocedural clinical, emotional and social (CES) outcome on disability scale
      as scored from postal questionnaire data is presented and compared to 106
      currently operated patients. RESULTS: In 75% of the embolized aneurysms
      successful occlusion was achieved, procedural mortality was 2.3% and morbidity
      18.2%. Clinical status of all 15 patients with unruptured aneurysms preserved. Of
      the surviving 29 patients with ruptured aneurysms 12 improved and the rest
      preserved their clinical status. In 91% of the embolized patients and in 85% of
      the operated patients CES outcome was categorized as good or excellent. The
      difference was statistically nonsignificant. CONCLUSION: Embolization with GDC is
      a feasible, effective and safe mini-invasive method in small aneurysms with a
      small neck. However, intentional parent artery occlusion, novel endovascular
      techniques and embolic agents or supplementary surgery may be necessary in
      selected cases. Neuropsychological long-term outcome of the patients treated for
      an intracranial aneurysm does not differ much between GDC embolization and
      microsurgical clipping.

PMID- 10348158
TI  - Analysis of sensory function in Charcot-Marie-Tooth disease.
AB  - Ten patients each with Charcot-Marie-Tooth disease type 1 (CMT1), demyelinating
      form, and CMT2, axonal form, were subjected to analysis of sensory function
      including sensory screening and quantitative determination of thermal, thermal
      pain and vibratory thresholds in hands and feet. The threshold values were
      compared with data from age- and sex-matched control groups. All patients had a
      symmetrical sensory dysfunction, which was most prominent in the lower
      extremities. Temperature was the modality most often affected on screening and on
      quantitative determination of thresholds in both CMT1 and CMT2 patients. Mean
      thermal thresholds were significantly increased in both hands and feet in CMT1 as
      well as in CMT2 patients when compared with controls. There was no statistically
      significant difference between thermal thresholds in the CMT1 and CMT2 patients.
      Mean thermal pain thresholds were significantly increased in the feet of the CMT2
      patients when compared with the controls and they were significantly higher in
      the hands of the CMT2 than in the CMT1 patients. Vibratory thresholds (VT) were
      abnormal in all CMT1 patients and in a majority of the CMT2 patients. Mean VT was
      significantly increased in hands and feet of both CMT1 and CMT2 patients when
      compared with the controls and the mean VT was significantly higher in the feet
      of the CMT1 than in the CMT2 patients. The difference with an increased heat pain
      threshold in the CMT2 patients and an increased VT in the CMT1 patients is
      suggested to be due to demyelination in CMT1 leading to affection of sensory
      function mediated by myelinated nerve fibres and to axonal disturbance in CMT2
      with affection of sensory function mediated by small diameter myelinated and
      unmyelinated C-fibres.

PMID- 10348159
TI  - Bromocriptine test in the evaluation of patients with syncope of unknown
      aetiology. A case-control study.
AB  - The aim of the present study was to evaluate, through a case-control study, the
      specificity of the upright tilt test with bromocriptine as a marker of neurally
      mediated syncope of unknown aetiology. We have compared upright tilt test with
      bromocriptine (2.5 mg p.o.) in patients with syncope of unknown aetiology and
      controls. A total of 23 patients and controls matched by age and sex had upright
      tilt test with bromocriptine. The upright tilt test procedure consisted of 10 min
      in supine position, 10 min of 60 degree head-up tilt and a further 10 min with
      the subject supine; this procedure was performed in baseline condition and 60,
      120, 180 and 240 min after the administration of bromocriptine. The protocol end
      points were the development of syncope or presyncope in association with
      hypotension with or without bradycardia. A positive response to bromocriptine
      test was found in 78% (95% CI, 61% to 95%) of patients and in 13% (95% CI, 0% to
      26%) of controls (P<0.001). No significant differences were detectable among
      patients and controls showing a positive response to the test. Bromocriptine test
      seems to be a useful alternative tool for the diagnosis of neuromediated syncope
      also suggesting that dopaminergic supersensitivity may, at various and to varying
      degrees, play a role in the pathogenesis of syncopal episodes.

PMID- 10348160
TI  - Clinical and neurophysiological abnormalities before and after reconstruction of
      the anterior cruciate ligament of the knee.
AB  - OBJECTIVES: We aimed to study knee proprioception and somatosensory evoked
      potentials (SEPs) to stimulation of the common peroneal nerve (CPN) in 7 patients
      with lesion of the anterior cruciate ligament (ACL) before and after ACL
      reconstruction. MATERIALS AND METHODS: We recorded the spinal N14 and scalp P27
      potentials in 5 patients, while in the remaining 2 patients we calculated scalp
      SEP maps by 20 electrodes. The knee proprioception was tested by comparing the
      sensitivity to movement of both the knees. RESULTS: Before surgery, all patients
      showed decreased knee position sense and lack of the cortical P27 potential on
      the side of the ACL lesion. Arthroscopic reconstruction of the ligament improved
      neither the knee proprioception nor the somatosensory central conduction.
      CONCLUSION: We suggest that the loss of the knee mechanoreceptors can be followed
      by modifications of the central nervous system, which are not compensated by
      other nervous structures.

PMID- 10348161
TI  - Cardiac sympathetic denervation in early stages of amyotrophic lateral sclerosis
      demonstrated by 123I-MIBG-SPECT.
AB  - Involvement of the autonomic cardiac nervous system in early stages of
      amyotrophic lateral sclerosis (ALS) was evaluated in 40 patients. I-123
      metaiodobenzylguanidine-single photon emission computed tomography (MIBG-SPECT)
      and heart rate variability (HRV) yielded information about sympathetic and
      parasympathetic innervation of the heart. MIBG-SPECT is a sensitive diagnostic
      method for demonstration of early cardiac sympathetic denervation. Both
      sympathetic and parasympathetic dysfunction was observed in 16 (40%) out of 40
      patients. Mean cardiac MIBG uptake as demonstrated by the heart/mediastinum ratio
      was significantly reduced in all ALS patients in comparison with controls
      (P<0.01). The global MIBG-SPECT score was clearly abnormal in 29% and slightly
      abnormal in 22% of patients. HRV was diminished in 6 of 38 patients, 4 of whom
      having an abnormal MIBG-SPECT score as well. The presented results indicate that
      ALS patients with mild to moderate impairment may have evidence of postganglionic
      sympathetic adrenergic cardiac or cardiovagal denervation. To our knowledge, this
      is the first study indicating possible postganglionic sympathetic denervation in
      ALS. The original concept of ALS as an isolated degeneration of motor neurons
      seems to extend to a more widespread understanding of the disease which possibly
      represents different entities.

PMID- 10348162
TI  - Serum levels of beta-carotene, alpha-carotene, and vitamin A in patients with
      amyotrophic lateral sclerosis.
AB  - To elucidate whether serum alpha and beta-carotene and retinol levels are related
      with the risk for amyotrophic lateral sclerosis (ALS), we compared serum levels
      of alpha-carotene, beta-carotene, and retinol (vitamin A), measured by HPLC, in
      40 patients with amyotrophic lateral sclerosis (ALS) and 87 matched controls
      using an isocratic high performance liquid chromatography technique. The mean
      serum alpha and beta-carotene, and retinol levels did not differ significantly
      between the 2 study groups. These values were not influenced by the clinical form
      (spinal vs bulbar) of ALS, and they did not correlate with age, age at onset, and
      duration of the disease. These results suggest that serum alpha and beta-carotene
      and retinol concentrations are unrelated with the risk for ALS.

PMID- 10348163
TI  - Acquired dural fistulae in benign intracranial hypertension: a short case report.
AB  - Venous sinus thrombosis has been regarded as a known cause of intracranial
      hypertension. We report a case of long-standing raised intracranial hypertension
      (ICT) that presented with deteriorating vision in both eyes. Magnetic resonance
      (MR) imaging of the brain and cerebral angiography showed blockage of superior
      saggital sinus and sigmoid sinuses with bilateral dural arteriovenous fistulae
      (DAVF) formation.

PMID- 10348164
TI  - A non-familial Huntington's disease patient with grumose degeneration in the
      dentate nucleus.
AB  - We report a non-familial Huntington's disease (HD) patient presenting with
      increased levels of protein and IgG in his cerebrospinal fluid (CSF),
      antineuronal antibody in his serum and CSF, Purkinje cell and granule cell
      degeneration in the cerebellum, and grumose degeneration in the dentate nucleus,
      in addition to typical HD findings. This patient showed an expanded CAG repeat in
      the HD gene, and provides new information on the clinical and neuropathologic
      varieties of HD.

PMID- 10348165
TI  - Measurement of S-nitrosoalbumin by gas chromatography-mass spectrometry. I.
      Preparation, purification, isolation, characterization and metabolism of S
      [15N]nitrosoalbumin in human blood in vitro.
AB  - S-Nitrosoalbumin (SNALB) and S-[15N]nitrosoalbumin (S[15N]ALB) were prepared by
      various methods, purified and isolated by a novel selective extraction procedure
      using HiTrapBlue Sepharose affinity columns and characterized by various
      techniques including SDS-PAGE electrophoresis, UV-Vis spectroscopy and gas
      chromatography-mass spectrometry (GC-MS). S-Nitrosylation of albumin in freshly
      obtained human plasma by unlabeled and 15N-labeled butylnitrite at neutral pH
      revealed the purest preparations. For GC-MS analysis, SNALB and S[15N]ALB were
      treated with HgCl2 to obtain nitrite and [15N]nitrite, respectively, which were
      then analysed as their pentafluorobenzyl derivatives. S[15N]ALB preparations were
      standardized by GC-MS using nitrite as internal standard. S[15N]ALB was prepared
      and isolated at concentrations of 188+/-43 microM (mean +/- SD, n = 8) at a final
      yield of about 45%, an isotopic purity of 98%, and SDS-PAGE electrophoretic
      purity of 90%. 15N-Labeled SNALB was used to study its metabolism in human blood.
      The half-life of S[15N]ALB (25 microM) in human heparinized blood in vitro was
      determined by GC-MS as 5.5 h. The GC-MS method described here could be useful for
      the quantitative determination of SNALB in human plasma using S[15N]ALB as an
      internal standard.

PMID- 10348166
TI  - Measurement of S-nitrosoalbumin by gas chromatography-mass spectrometry. II.
      Quantitative determination of S-nitrosoalbumin in human plasma using S
      [15N]nitrosoalbumin as internal standard.
AB  - A gas chromatographic-mass spectrometric method for the quantitative
      determination of S-nitrosoalbumin (SNALB) in human plasma is described. The
      method is based on selective extraction of SNALB and its 15N-labeled SNALB analog
      (S15NALB) used as internal standard on HiTrapBlue Sepharose affinity columns,
      Hg2+ -catalysed conversion of the S-nitroso groups to nitrite and [15N]nitrite,
      respectively, followed by their derivatization to the pentafluorobenzyl
      derivatives and quantification by GC-MS. Mean recovery of SNALB and S15NALB from
      plasma was 45%. Mean precision and accuracy within the range 0-10 microM was 95%
      and 99%, respectively. The limit of quantitation was determined as 100 nM at a
      precision of 93.8% and an accuracy of 94.8%. Considerable improvement of method
      sensitivity is possible by eliminating nitrite present in the elution buffer. The
      limit of detection was 0.2 nM corresponding to 67 amol of S15NALB. In 0.4-ml
      aliquots of plasma samples from healthy humans, endogenous SNALB was determined
      at concentrations of 181+/-150 nM (mean +/- SD, n = 23). External addition of
      SNALB to these plasma samples at 2 microM and 5 microM serving as quality control
      samples resulted in quantitative recovery of SNALB. Our results show that SNALB
      occurs in human plasma at concentrations at least one-order of magnitude smaller
      than those reported in the literature from measurements using chemiluminescence.

PMID- 10348167
TI  - Composition of the peptide fraction in human blood plasma: database of
      circulating human peptides.
AB  - A database was established from human hemofiltrate (HF) that consisted of a mass
      database and a sequence database, with the aim of analyzing the composition of
      the peptide fraction in human blood. To establish a mass database, all 480
      fractions of a peptide bank generated from HF were analyzed by MALDI-TOF mass
      spectrometry. Using this method, over 20000 molecular masses representing native,
      circulating peptides were detected. Estimation of repeatedly detected masses
      suggests that approximately 5000 different peptides were recorded. More than 95%
      of the detected masses are smaller than 15000, indicating that HF predominantly
      contains peptides. The sequence database contains over 340 entries from 75
      different protein and peptide precursors. 55% of the entries are fragments from
      plasma proteins (fibrinogen A 13%, albumin 10%, beta2-microglobulin 8.5%,
      cystatin C 7%, and fibrinogen B 6%). Seven percent of the entries represent
      peptide hormones, growth factors and cytokines. Thirty-three percent belong to
      protein families such as complement factors, enzymes, enzyme inhibitors and
      transport proteins. Five percent represent novel peptides of which some show
      homology to known peptide and protein families. The coexistence of processed
      peptide fragments, biologically active peptides and peptide precursors suggests
      that HF reflects the peptide composition of plasma. Interestingly, protein
      modules such as EGF domains (meprin Aalpha-fragments), somatomedin-B domains
      (vitronectin fragments), thyroglobulin domains (insulin like growth factor
      binding proteins), and Kazal-type inhibitor domains were identified. Alignment of
      sequenced fragments to their precursor proteins and the analysis of their
      cleavage sites revealed that there are different processing pathways of plasma
      proteins in vivo.

PMID- 10348168
TI  - Size-exclusion chromatography performed in capillaries. Studies by liquid
      chromatography-mass spectrometry.
AB  - Miniaturization of the chromatographic column led to increased sensitivity and
      shortened time of analysis. In our work we applied 300 microm I.D. capillaries
      packed with a novel stationary phase Superdex Peptide for the size-exclusion
      chromatography, capable of separating molecules within the mass range of 0.1-7
      kDa. Here we proved that such capillary columns can operate effectively at high
      sensitivity. Several peptide mixtures were efficiently chromatographed and
      analyzed on line with electrospray ionization mass spectrometry as a detection
      technique. A CNBr peptide map, derived from human globin alpha subunit, was
      effectively separated using this method. These fragments are difficult to elute
      from the reversed-phase column at low pH, therefore, such approach can be
      considered as a complementary to other separation techniques, in particular for
      analyzing hydrophobic components and complex mixtures.

PMID- 10348169
TI  - Various forms of mouse lactoferrins: purification and characterization.
AB  - This work was conducted to study the microheterogeneity of mouse lactoferrin
      (LF). Two forms, LF1 and LF2, could be purified from uterine luminal fluid by ion
      exchange HPLC on a Protein PAK SP 5PW column. Another form, LF3, was purified
      from the epididymis homogenate by affinity chromatography on a column of Protein
      A-Sepharose coupled with the purified LF2 antibody that was prepared to give no
      crossreaction with serum albumin. Both LF1 and LF2 showed a Mr 74000 band while
      LF3 gave a Mr 70000 band on reducing SDS-PAGE. All of them were reduced to a Mr
      68000 band after they had been digested with N-glycosidase F. The data from
      automated Edman degradation confirmed the completely identical 19 amino acid
      sequences in the N-terminal regions of these three LFs, except the lack of N
      terminal Lys-Ala of LF2/LF3 in LF1. LF in tissue homogenates was immunodetected
      by Western blot procedure using the purified LF2 antibody. Different amounts of
      LF with a molecular mass of the 70000 or 74000 were distributed in the non-sexual
      organs such as kidney, spleen, lung, heart and liver and the sexual glands
      including epididymis, vagina, uterus, ovary and prostate. No LF was detected in
      stomach, intestine, testis and seminal vesicle.

PMID- 10348170
TI  - Identification and determination of succinyladenosine in human cerebrospinal
      fluid.
AB  - Succinyladenosine (S-Ado) is a biochemical marker of adenylosuccinase deficiency-
      the genetic defect of purine de novo synthesis. S-Ado has been previously
      reported as normally undetectable in cerebrospinal fluid (CSF) of children not
      suffering from this defect. In present study, we employed solid-phase extraction
      and thin-layer chromatography for isolation of a compound with spectral and
      chromatographic characteristics identical to S-Ado from human CSF. The high
      performance liquid chromatography-negative-ion electrospray ionization mass
      spectrometry analysis confirmed that the isolated compound is S-Ado. We
      established the reference values of S-Ado in CSF of children (1.1+/-0.4
      micromol/l; mean +/- S.D; n = 26) by means of reversed-phase HPLC method on a C18
      column with UV detection.

PMID- 10348171
TI  - Separation and identification of corticosterone metabolites by liquid
      chromatography--electrospray ionization mass spectrometry.
AB  - High-performance liquid chromatography coupled to atmospheric pressure ionization
      electrospray ionization mass spectrometry (API-ESI-MS) was investigated for the
      analysis of corticosterone metabolites; their characterization was obtained by
      combining the separation on Zorbax Eclipse XDB C18 column (eluted with a methanol
      water-acetic acid gradient) with identification using positive ion mode API-ESI
      MS and selected ion analysis. The applicability of this method was verified by
      monitoring the activity of steroid converting enzymes (20beta-hydroxysteroid
      dehydrogenase and 11beta-hydroxysteroid dehydrogenase) in avian intestines.

PMID- 10348172
TI  - Determination of bile acids in human faecal samples using supercritical fluid
      extraction and high-performance liquid chromatography.
AB  - A supercritical fluid extraction (SFE) method for the extraction of bile acids
      from faeces is described. HPLC with pulsed amperometric detection was used to
      examine and confirm the recovery of bile acids. The analytes were extracted
      within a period of 75 min using supercritical carbon dioxide at a pressure of
      34.5 MPa and a temperature of 90 degrees C. In developing this method the
      following parameters were investigated: temperature, pressure, and extraction
      time. Two alternative methods of sample preparation were also investigated with a
      view to reducing the overall analysis time. The method was validated for the
      major primary and secondary bile acids found in faeces. It was found that the
      overall mean +/- SD recoveries were 102.1+/-7.92%, 111.6+/-9.91%, 112.1+/-9.92%
      and 113.7+/-9.92% for dry samples and 108.5+/-15.77%, 110.0+/-7.22%, 115.9+/
      11.11% and 106.6+/-9.16% for wet samples with respect to cholic, deoxycholic,
      chenodeoxycholic and lithocholic acid. The SFE is an alternative to the
      traditional methods available. The extraction is relatively easy to conduct and
      does not utilise as much glassware, solvents or time.

PMID- 10348173
TI  - Rapid mass spectrometric analysis for ascorbate and related organic acids in
      small volumes of plasma for use in pediatric subjects.
AB  - A gas chromatographic-mass spectrometric isotope dilution method was developed
      for analysis of ascorbate on 10 microl samples of plasma. This assay was
      reproducible (standard deviation of less than 4%) and gave values for plasma
      ascorbate content within 8% of our previously published gas chromatographic-mass
      spectrometric method. Non-specific sample preparation allowed other analytes to
      be determined on the same sample by adjusting data acquisition parameters and
      adding the appropriate internal standard. Analysis on 28 subjects fell within the
      expected range for plasma ascorbate 68+/-29 microm (11.9+/-5.0 microg/ml) and
      established a normal range for plasma threonate of 28.1+/-2.4 microm (3.8+/-0.4
      microg/ml).

PMID- 10348174
TI  - Determination of urinary 2-thiazolidinethione-4-carboxylic acid after exposure to
      alkylene bisdithiocarbamates using gas chromatography-mass spectrometry.
AB  - This is a newly developed method which permits the quantitative determination of
      2-thiazolidinethione-4-carboxylic acid (TTCA, an established biomarker of
      exposure to CS2) as a metabolite of alkylene bisdithiocarbamates (ABDCs) in human
      urine. After separation of TTCA from the urinary matrix using liquid-liquid
      extraction the analyte was converted into its diethyl derivative. Separation and
      quantitative analysis was carried out by capillary gas chromatography and mass
      selective detection in single ion monitoring mode. 4-(4-Chloro-2
      methylphenoxy)butanoic acid (MCPBA) served as internal standard. The detection
      limit was 0.7 microg/l in urine. The relative standard deviation of the within
      series imprecision was 4.3% at a concentration of 13 microg/l. The relative
      recovery was within the range of 86 to 98%. In order to determine the suitability
      of TTCA for biological monitoring after exposure to ABDCs, we analysed 87 24-h
      urine samples from occupationally exposed workers. The results were compared with
      the levels of TTCA excreted in urine by 50 control persons without known exposure
      to dithiocarbamates or CS2. This collective of unexposed persons also provided
      TTCA reference values for the general population. The urinary TTCA concentrations
      of the exposed persons were in the range from 0.8 microg/g creatinine to 515
      microg/g creatinine. Unexposed persons excreted TTCA in concentrations from below
      the detection limit to 182 microg/g creatinine. The median concentration found in
      exposed persons (27 microg/g) was nearly 2.5 times higher than in non-exposed
      persons (11 microg/g). The difference between the exposed and unexposed
      collective was highly significant. Assessment of an individual's exposure by
      determining the level of TTCA in urine nevertheless was not possible. This was
      due to the relatively wide range of concentrations and because the ranges of both
      collectives overlapped.

PMID- 10348175
TI  - High-performance liquid chromatography of methotrexate for environmental
      monitoring of surface contamination in hospital departments and assessment of
      occupational exposure.
AB  - In the frame of applicative research in occupational hygiene of hospital
      workplaces, we investigate hospital indoor contamination as a consequence of the
      use of antineoplastic drugs (ANDs), with the purpose of assessing exposure of
      medical and nursing personnel to potentially harmful doses of ANDs, and
      ultimately of yielding advice on safe operating procedures for manipulation of
      ANDs in hospitals and in house-care of cancer patients. Among the large number of
      currently employed ANDs, methotrexate (MTX) has been selected as a tracer of
      surface contamination, on the basis of its wide use in therapy, its ease of
      measurement and of its chemical properties relevant to persistence and transport
      in the indoor environment. MTX is a polyelectrolyte, with a high water, but lower
      organic solvent solubility, a negligible vapour pressure and a high chemical
      robustness to environmental stress, thus allowing to measure surface-to-surface
      carryover (e.g. from spillage or glove fingerprint) and indoor contamination due
      to aerosol transport (e.g. from syringe manipulation procedures). Monitoring of
      MTX in environmental samples such as swab washings of surfaces and objects
      requires an analytical method with characteristics of sensitivity,
      reproducibility, precision, analytical speed, ease of automation and robustness.
      We have therefore developed an analytical procedure which employs simple short
      column RP-HPLC with UV detection, automated sample injection and a close analogue
      internal standard for improved precision and solid-phase extraction (SPE) for
      sample concentration. Our method has proven suitable for detecting traces of MTX
      on a wide variety of surfaces and objects, with a limit of quantification in the
      range of 50 microg/dm3 for direct injection of unconcentrated washings,
      corresponding to the possible detection of surface contamination as low as 1
      microg/m3 and a limit of detection in the range of 10 ng/m2 for samples as large
      as 100 dm3 concentrated by SPE. We present preliminary results from a recent
      hospital case-study, assessing the contamination level of furniture and equipment
      in drug preparation areas. Spillage fractions as high as 5% of the employed mass
      (70-260 mg/day) are measured on the polythene-backed paper disposable hood cover
      sheet; traces of MTX in the microgram range can also be measured on floor
      surfaces, furniture and handles, even at a distance from the preparation hoods.

PMID- 10348176
TI  - Determination of ethyl glucuronide, a minor metabolite of ethanol, in human serum
      by liquid chromatography-electrospray ionization mass spectrometry.
AB  - A rapid and sensitive determination procedure using liquid chromatography
      electrospray ionization mass spectrometry (LC-ESI-MS) has been developed for the
      determination of ethyl glucuronide (EtG) in human serum. Samples were
      precipitated with methanol, centrifuged and the supernatant was evaporated to
      dryness followed by reconstitution with distilled water. As mobile phase 30 mM
      ammonium acetate-acetonitrile (30:70, v/v) was utilized. The base peak observed
      at m/z 221 was the [M-H]- ion of EtG, which was detectable in satisfactory sense.
      The detection limit was 0.03 microg/ml in the selected ion monitoring mode. A
      calibration graph constructed for EtG in serum gave good linearity over the range
      from 0.1 to 25 microg/ml. This paper also presents the application of this LC-ESI
      MS procedure to the analysis of authentic serum samples.

PMID- 10348177
TI  - Immunoaffinity extraction of morphine, morphine-3-glucuronide and morphine-6
      glucuronide from blood of heroin victims for simultaneous high-performance liquid
      chromatographic determination.
AB  - The development of an immunoaffinity-based extraction method for the
      determination of morphine and its glucuronides in human blood is described. For
      the preparation of an immunoadsorber, specific antisera (polyclonal, host:
      rabbit) against morphine, morphine-3-glucuronide and morphine-6-glucuronide were
      coupled to 1,1'-carbonyldiimidazole-activated tris-acrylgel and used for
      immunoaffinity extraction of morphine and its glucuronides from coronary blood.
      The resulting extracts were analysed by HPLC with native fluorescence detection.
      The mean recoveries from spiked blood samples were 71%, 76% and 88% for morphine,
      morphine-3-glucuronide and morphine-6-glucuronide, respectively. The limit of
      detection was 3 ng/g blood and the limit of quantitation was 10 ng/g blood for
      all three analytes. The results of the analysis of coronary blood samples from 23
      fatalities due to heroin are presented.

PMID- 10348178
TI  - Supercritical fluid extraction of methyltestosterone, nortestosterone and
      testosterone at low ppb levels from fortified bovine urine.
AB  - A multi-residue supercritical fluid extraction (SFE) method is proposed for the
      isolation of nortestosterone, testosterone and methyltestosterone from bovine
      urine. Prior to SFE, bovine urine was hydrolyzed and then fortified with the
      three steroids at 100 ng/ml and 50 ng/ml each for HPLC analysis and 25 ng/ml and
      12.5 ng/ml each for GC-MS analysis. The samples then were mixed with an adsorbent
      material, placed in an SFE extraction vessel prepacked with a 3-ml SPE column
      containing neutral alumina and the testosterones were extracted from the urine
      matrix using unmodified supercritical CO2 at 27.2 MPa and 40 degrees C. The
      steroids were retained in-line on the neutral alumina sorbent in the SPE column
      while co-extracted artifactial material was trapped off-line after CO2
      decompression. After SFE, the SPE column was removed from the extraction vessel,
      and the trapped steroids were eluted from the neutral alumina sorbent with 3 ml
      of a methanol-water mixture. Eluates were used directly without post-SFE clean-up
      either for HPLC analysis (detection limit 50 ng/ml) or for GC-MS analysis
      (detection limit 5 ng/ml after steroid derivatization). The multi-residue SFE
      recoveries (n=6) for nortestosterone, testosterone and methyltestosterone from
      hydrolyzed bovine urine by GC-MS analysis were 90.8+/-6%, 93.9+/-3% and 92.5+/
      5%, respectively for each steroid at the 12.5 ng fortification level.

PMID- 10348179
TI  - Determination of clenbuterol residues in bovine hair by using diphasic dialysis
      and gas chromatography-mass spectrometry.
AB  - A method for the determination of clenbuterol (4-amino-3,5-dichloro-alpha[(tert.
      butylamino)methyl]-benzyl alcohol hydrochloride) in hair of living cows has been
      developed. Hair samples were digested in an alkaline medium. The diphasic
      dialysis technique is a semi-permeable membrane technology developed for the
      direct extraction of relatively low-molecular-mass analytes such as clenbuterol.
      In this case, we used sodium citrate buffer to homogenize the digested hair,
      dichloromethane was used as the extraction solvent at 37 degrees C, and stirring
      was applied at 150 rpm for 4 h. The analysis was carried out using gas
      chromatography-mass spectrometry. The calibration curve for clenbuterol in hair
      was linear in the range from 12.5 to 400 ng g(-1). The detection limit of
      clenbuterol was 5 ng g(-1) and the quantification limit was 12.5 ng g(-1), in
      hair. A good inter-day reproducibility was obtained (R.S.D. = 7.08%). The
      repeatability and intra-day reproducibility (50 ng g(-1) of hair, n = 10) show
      R.S.D.s of 7.1 and 9.5%, respectively.

PMID- 10348180
TI  - Excretion study of the beta2-agonist reproterol in human urine.
AB  - An excretion study of the beta2-agonist 7-[3-[(beta-3,5
      trihydroxyphenethyl)amino]-propyl]theophylline (reproterol) in human urine, which
      is reportedly misused by athletes and horses as a doping agent, is presented. The
      study was performed after an oral administration of 20 mg of reproterol
      hydrochloride. The collected urine samples were prepared using the standard
      anabolic steroid extraction procedure and analyzed by gas chromatography coupled
      with quadrupole mass spectrometry and, also, with high-resolution mass
      spectrometry (HRMS). The main reproterol metabolite was found, whereas unchanged
      reproterol was not detected. The structure of the main metabolite was confirmed
      by an accurate HRMS measurement of diagnostic ions. Finally, an excretion urine
      profile of the main metabolite is presented. The mass spectrum of another
      possible unidentified reproterol metabolite is also reported.

PMID- 10348181
TI  - Multiresidue analysis of beta2-agonist in human and calf urine using multimodal
      solid-phase extraction and high-performance liquid chromatography with
      electrochemical detection.
AB  - Various beta2-agonists are used as illegal growth promoters in man and in
      animals. We developed a multiresidue procedure for the analysis of four beta
      agonists in human and calf urine. The sample was pre-extracted with an Extrelut
      column at alkaline pH. The beta-agonists were eluted with a mixture of tert.
      butylmethyl ether and hexane. Then the extract was further cleaned with a mixed
      mode SPE column, or with a combination of immunoaffinity chromatography (IAC) and
      the mixed mode SPE column. The IAC column contained antibodies against
      salbutamol, which were suitable for multiresidue extractions. The extract was
      then brought onto a mixed mode SPE column at an acidic pH. The column was washed
      with 70% methanol in water. Thereafter, the beta-agonists were eluted with
      ammoniated ethanol-hexane. The extract was analysed with an HPLC method with
      electrochemical detection. The beta-agonists were separated on a reversed-phase
      column using a mobile phase buffered at pH 5.5 and containing an ion-pair
      reagent. Recoveries were higher when the IAC procedure was not performed (90-105%
      vs. 65-75%), but the extracts were cleaner when the latter step was included.
      Detection limits in human and calf urine were in the low ng/ml range. The study
      indicated that beta2-agonists can be analysed in human and calf urine without the
      selectivity of a mass spectrometer, but that comprehensive clean-up is required
      to avoid the interference of urine matrix components.

PMID- 10348182
TI  - Isolation and identification of the C6-hydroxy and C20-hydroxy metabolites and
      glucuronide conjugate of methylprednisolone by preparative high-performance
      liquid chromatography from urine of patients receiving high-dose pulse therapy.
AB  - In the present study metabolites of methylprednisolone were detected using
      gradient elution high-performance liquid chromatography. Separation was performed
      by a Cp Spherisorb ODS 5 microm (250 mmx4.6 mm I.D.) column, connected to a guard
      column, packed with pellicular reversed phase. The mobile phase was a mixture of
      acetonitrile and 1% acetic acid in water. At t = 0, this phase consisted of 2%
      acetonitrile and 98% acetic acid 1% in water (v/v). During the following 35 min
      the phase changed linearly until it attained a composition of acetonitrile-buffer
      (50:50, v/v). At 40 min (t = 40) the mobile phase was changed over 5 min to the
      initial composition, followed by equilibration during 2 min. The flow-rate was
      1.5 ml/min. UV detection was achieved at 248 nm. We have isolated the respective
      compounds with the most abundant concentration and suggested their chemical
      structure based on NMR, IR, UV, MS, retention behaviour and melting points. The
      c/, stereochemistry could not be solved in this study. The overall picture of the
      metabolic pathways of methylprednisolone is apparently simple: reduction of the
      C20 carbonyl group and further oxidation of the C20-C21 side chain (into C21-COOH
      and C20-COOH), in competition with or additional to the oxidation at the C6
      position.

PMID- 10348183
TI  - Application of a semipermeable surface column for the determination of
      amoxicillin in human blood serum.
AB  - A high-performance liquid chromatography column-switching system for the
      automated determination of amoxicillin in human serum was developed as a more
      efficient alternative for the already existing systems with off-line sample
      pretreatment. The column-switching system consists of a semipermeable surface
      (SPS) column and an analytical reversed-phase (RP) C18 column. After
      centrifuging, pure serum samples were injected into the column-switching system.
      Clean-up, with regard to removal of proteins, was performed on the SPS column.
      The fraction containing amoxicillin was concentrated on the analytical RP-C18
      column. Finally, chromatography and detection were performed with the RP-C18
      column using UV detection at 234 nm. The total analysis time was 15 min. The
      method has proven to be reliable and to be more time- and resource-efficient
      compared to previously used methods with off-line sample clean-up. It is now used
      in bioavailability studies for the development of new amoxicillin formulations.

PMID- 10348184
TI  - Simultaneous determination of enrofloxacin and ciprofloxacin in animal biological
      fluids by high-performance liquid chromatography. Application in pharmacokinetic
      studies in pig and rabbit.
AB  - A simple and rapid high-performance liquid chromatographic method for the
      simultaneous determination of enrofloxacin and ciprofloxacin has been developed
      in pig and rabbit samples. Solid-phase extraction was applied from samples on a
      C18 cartridge using a mixture of methanol-hydrochloric acid (98:2, v/v).
      Analytical separation was performed on a C18 column with UV detection at 277 nm
      under gradient conditions. The mobile phase was a mixture of orthophosphoric
      acidtriethylamine-acetonitrile. The method has been validated for both molecules
      in pig and rabbit plasma and adapted for rabbit tissue-cage fluid (TCF). The
      assay is specific and reproducible within the both drugs and mean recoveries for
      ciprofloxacin and enrofloxacin, respectively, were 92+/-6% and 90+/-5% for pig
      plasma over the range used. Mean recoveries for enrofloxacin were 108+/-9% and
      102+/-7% for rabbit plasma and TCF, respectively, over the range used. The
      suitability of the assay for pharmacokinetic studies was determined by measuring
      enrofloxacin and ciprofloxacin concentrations either in pig plasma after
      administration of a single intravenous 5 mg/kg dose of enrofloxacin or in rabbit
      plasma and TCF during a 24 h infusion of enrofloxacin at a rate of 1.25 mg/kg per
      hour.

PMID- 10348185
TI  - Simultaneous determination of local anesthetics including ester-type anesthetics
      in human plasma and urine by gas chromatography-mass spectrometry with solid
      phase extraction.
AB  - The present study describes the simultaneous determination of seven different
      kinds of local anesthetics and one metabolite by GC-MS with solid-state
      extraction: Mepivacaine, propitocaine, lidocaine, procaine (an ester-type local
      anesthetics), cocaine, tetracaine (an ester-type local anesthetics), dibucaine
      (Dib) and monoethylglycinexylidide (a metabolite of lidocaine) were clearly
      separated from each other and simultaneously determined by GC-MS using a DB-1
      open tubular column. Their recoveries ranged from 73-95% at the target
      concentrations of 1.00, 10.0 and 100 microg/ml in plasma, urine and water.
      Coefficients of variation of the recoveries ranged from 2.3-13.1% at these
      concentrations. The quantitation limits of the method were approximately 100
      ng/ml for monoethylglycinexylidide, propitocaine, procaine, cocaine, tetracaine
      and dibucaine, and 50 ng/ml for lidocaine and mepivacaine. This method was
      applied to specimens of patients who had been treated with drip infusion of
      lidocaine, and revealed that simultaneous determination of lidocaine and
      monoethylglycinexylidide in the blood and urine was possible.

PMID- 10348186
TI  - High-performance liquid chromatographic method for simultaneous determination of
      [1-methyl-14C]caffeine and its eight major metabolites in rat urine.
AB  - A selective and sensitive reversed-phase liquid chromatographic method was
      developed for the simultaneous analysis of [1-Me-14C]caffeine and its eight major
      radiolabelled metabolites in rat urine. The separation of the complex mixture of
      caffeine metabolites was achieved by gradient elution with a dual solvent system
      using an endcapped C18 reversed-phase column, which in contrast to commonly used
      C18 reversed-phase columns also allows the separation of the two isomers of 6
      amino-5-(N-formylmethylamino)-1,3-dimethyluracil (1,3,7-DAU), a caffeine
      metabolite of quantitative importance predominantly occurring in rat. As caffeine
      is metabolised primarily by members of the cytochrome P450 1A (CYP1A) subfamiliy,
      determination of the pattern of caffeine metabolites in rat urine enables
      analysis of activities of this important enzyme subfamily in vivo. Since CYP1A is
      suggested to be involved in the detoxification of bilirubin, the assay may be
      applied to search for untoxic inducers of CYP1A which might be of pharmacological
      interest in the treatment of hyperbilirubinaemia.

PMID- 10348187
TI  - Determination of olanzapine in human breast milk by high-performance liquid
      chromatography with electrochemical detection.
AB  - A reversed-phase high-performance liquid chromatographic-electrochemical assay
      was developed and validated for the quantification of olanzapine in human breast
      milk. The assay involved a solid-phase extraction (SPE) of olanzapine and its
      internal standard on a Bond Elut Certify LRC mixed-mode cartridge. After
      conditioning of the SPE cartridge, human milk (1 ml) was passed through the
      cartridge. The cartridge was washed with five separate washing steps to remove
      endogenous compounds, and the analytes were eluted with ethyl acetate-ammonium
      hydroxide (98:2, v/v) solution. The eluate was evaporated to dryness (gentle
      stream of nitrogen at 40 degrees C), and the residue was dissolved in mobile
      phase. The extract was injected onto a YMC basic column (150 mmx4.6 mm I.D., 5
      microm particle size) at a flow-rate of 1 ml/min. A mixture of 75 mM phosphate
      buffer, pH 7.0-acetonitrile-methanol (48:26:26, v/v/v) was used as the mobile
      phase. Standard curves with a lower limit of quantitation of 0.25 ng/ml of
      olanzapine were linear (r2> or =0.9992) over a range of 0.25-100 ng/ml. Based on
      the analysis of quality control (QC) samples, the average inter-day accuracy (RE)
      was 99.0% with an average precision (CV) of 6.64% over the entire range. The
      stability of olanzapine in human milk was established after three freeze-thaw
      heat cycles and storage at -70 degrees C for 10 months. The validated method was
      used to measure olanzapine concentrations in human milk during a clinical trial.

PMID- 10348188
TI  - Determination of propafenone and its main metabolite 5-hydroxypropafenone in
      human serum with direct injection into a column-switching chromatographic system.
AB  - Column-switching chromatographic systems using conventional reversed-phase
      Separon SGX C18 and restricted access media LiChrospher ADS RP-18 precolumns were
      applied for the determination of propafenone and its main metabolite 5
      hydroxypropafenone in human serum samples. The LiChrospher ADS RP-18 precolumn
      has been found to be more suitable for the sample clean-up. Serum samples were
      directly injected into the chromatographic system. Proteins and other endogenous
      compounds were removed by washing with 10% 2-propanol in water and the analytes
      separated on the Gromsil ODS AB analytical column. The chromatograms were
      detected at 246 nm. The method validation confirms the suitability of the column
      switching system for the quantitation of propafenone and its metabolite. The
      presented assay shows good linearity with high correlation coefficients (0.992
      0.999), high recoveries (96.6+/-6.1-103.5+/-5.8) and excellent values of the
      repeatabilities (1.23-4.5%). The limits of quantitation are 25-40 ng/ml for the
      injection volume of 50 microl. The complete analysis including the precolumn
      reconditioning and the sample clean-up requires 26 min, the sample throughput is
      approximately four samples in an hour.

PMID- 10348189
TI  - Determination of concentrations of flecainide in human serum by high-performance
      liquid chromatography on a fluorocarbon-bonded silica gel column.
AB  - An optimized method for the determination of flecainide in serum is presented.
      Extraction using a solid-phase C18 column and chromatography on a stabilized
      fluorocarbon-bonded silica gel column effectively separate flecainide from an
      internal standard (a positional isomer of flecainide). The HPLC apparatus and
      conditions were as follows: analytical column, Fluofix 120N; sample solvent, 20
      microl; column temperature, 40 degrees C; detector, Shimadzu RF-5000 fluorescence
      spectrophotometer (excitation wavelength = 300 nm, emission wavelength = 370 nm);
      mobile phase, 0.06% phosphoric acid containing 0.1% tetra-n-butyl ammonium
      bromide-acetonitrile (75:25, v/v); flow-rate, 1.0 ml/min. The standard curves for
      flecainide were linear in the concentration range examined (10-2000 ng/ml). The
      regression equation was y = 0.08+0.0078x (r = 0.9998). The minimum detectable
      amount of flecainide was approximately 5 ng/ml. In the within-day study, the
      precision coefficients of variation were 2.66, 2.18, 2.54, 2.72, 2.88, 2.24, and
      3.29% for the 10, 50, 100, 200, 500, 1000, and 1500 ng/ml standards,
      respectively. The absolute recovery rates of flecainide at each concentrations
      were 94-100%. The method described provides analytical sensitivity, specificity
      and reproducibility suitable for both biomedical research and therapeutic drug
      monitoring.

PMID- 10348190
TI  - Complete two-dimensional separation for analysis of acidic compounds in plasma
      using column-switching reversed-phase liquid chromatography.
AB  - A complete two-dimensional separation technique for the determination of acidic
      compounds in plasma was developed by using column-switching reversed-phase liquid
      chromatography. This technique was based on solute peak enrichment at the top of
      the second column during heart-cutting and an ion-pair chromatographic separation
      in the second column using tetrabutylammonium ion, where different separation
      modes in the first and second columns and solute peak enrichment at the top of
      the second column during heart-cutting were achieved coincidentally. Retention
      behaviors of two solutes, zidovudine-beta-D-glucuronide (AZT-beta-D-Gluc) and
      probenecid, in the first and second column and solute peak enrichment at the top
      of the second column were investigated for establishment of the system. Different
      retention behaviors of the solutes in the first and second column, which were
      evaluated by changes in capacity factor versus acetonitrile concentration in the
      mobile phases, and peak enrichment could be accomplished by using ion-pair
      chromatography in the second column. System suitability was confirmed by
      assessing the number of theoretical plates (N) of the second column for the
      solutes after heart-cutting. The N values in the second column after column
      switching were almost same as those in the case that the solutes were directly
      injected onto the second column. These results indicate that complete two
      dimensional separation should be achieved by using this system. Furthermore, this
      technique was applied to method development for the determination of AZT-beta-D
      Gluc and probenecid in rat plasma. The peaks of each analyte in the plasma
      extract obtained by deproteinization were well separated from those of endogenous
      substances, and easy determination of the analytes could be accomplished at the
      ng/ml level only by changing the acetonitrile concentration in the mobile phases.

PMID- 10348191
TI  - Purification of a highly modified RNA-aptamer. Effect of complete denaturation
      during chromatography on product recovery and specific activity.
AB  - To evaluate RNA-aptamers as potential drug candidates, efficient and scaleable
      purification protocols are needed. Because aptamers are highly structured and
      rigid molecules, denaturation during the purification process is a critical
      aspect to obtain a pure and active product. A two-step chromatographic procedure
      was developed to purify a synthetic anti-VEGF aptamer at the preparative scale. A
      reversed-phase chromatographic step was optimized with a highly hydrophobic ion
      pairing reagent, followed by ion-exchange chromatography in which heat and a
      chaotropic salt were used. Because of the presence of 2'-modified ribose,
      denaturation conditions had to be optimized in both chromatographic steps to
      achieve a fully active molecule.

PMID- 10348192
TI  - Development and validation of a high-performance liquid chromatographic assay
      using solid-phase extraction for the novel antitumor agent pancratistatin in
      human plasma.
AB  - The stability of the experimental anti-tumour agent pancratistatin in human
      plasma has been investigated. A solid-phase extraction technique and an HPLC
      assay with external standards have been developed and validated. Extraction was
      performed using C18 cartridges and HPLC, analysis was performed on a 15 cm
      Hypersil BDS column using isocratic elution with 13% acetonitrile and aqueous
      solution of 1% (w/v) acetic acid. The lower limit of quantification for
      pancratistatin in 5% DMF-95% water was found to be 0.58 ng/ml (+/-10.58%) and 2.3
      ng/ml (+/-9.2%) following extraction from human plasma. Mean recovery of 89.4%
      (+/-4.73%) was obtained over the concentration range 0.0023-9.45 microg/ml for a
      five day validation study. Pancratistatin was stable at room temperature in light
      or dark for at least 15 days, in the refrigerator at 4 degrees C for at least 16
      days and in the freezer at -20 degrees C or -80 degrees C for at least 28 days.
      Under all conditions monitored, % recovery of pancratistatin from human plasma
      was greater than 95% and no evidence of degradation had occurred. There also was
      no loss of pancratistatin after three cycles of freezing and thawing.

PMID- 10348194
TI  - Determination of (E)-5-(2-bromovinyl)-2'-deoxyuridine in plasma and urine by
      capillary electrophoresis.
AB  - (E)-5-(2-Bromovinyl)-2'-deoxyuridine is an antiviral drug used for treatment of
      infections with Herpes simplex virus type 1 as well as Varicella zoster virus.
      Two fast methods for the determination of the drug and its metabolite in plasma
      and urine by capillary electrophoresis have been developed. The plasma method can
      be used for measurement of total as well as unbound drug and metabolite. Plasma
      and urine samples are prepared for measuring by liquid/liquid extraction
      resulting in a limit of quantification of 40 ng/ml for total and 10 ng/ml for
      free BVdU in plasma and 170 ng/ml in urine. Inter- as well as intra-day precision
      were found to be better than 10% and both methods have been used for drug
      monitoring of patients.

PMID- 10348193
TI  - Bioanalysis of thiocoraline, a new marine antitumoral depsipeptide, in plasma by
      high-performance liquid chromatography and fluorescence detection.
AB  - A sensitive bioanalytical assay for thicoraline, an investigational marine
      anticancer agent, in plasma, based on reversed-phase liquid chromatography and
      fluorescence detection, is reported. The proteins in the sample are precipitated
      by the addition of acetonitrile. After centrifugation, the supernatant is
      injected directly into the chromatograph. The analyte is quantified by
      fluorescence detection with excitation and emission at 365 and 540 nm,
      respectively. The method has been validated in the 1-100 ng/ml range, 1 ng/ml
      being the lower limit of quantification. Precision and accuracy both meet the
      current requirements for a bio-analytical assay and are <15% at 1 ng/ml and < or
      =5% in the 5-100 ng/ml range. Plasma samples can be stored for at least 4 months
      at -80 degrees C. Finally, the usefulness of this method for pharmacological
      research was shown in a pilot study of the pharmacokinetics of thiocoraline in
      rats.

PMID- 10348195
TI  - Development and validation of a bioanalytical assay for (E)-5-(2-bromovinyl)
      2'deoxyuridine in plasma by capillary zone electrophoresis.
AB  - A capillary zone electrophoretic method for the quantification of (E)-5-(2
      bromovinyl)-2'-deoxyuridine in plasma has been developed and validated.
      Separation was performed with a 25 mmol/l borate buffer, pH 9.0, after an initial
      rinsing step with sodium hydroxide. The rinsing step was necessary for
      reproducible analyses of aqueous samples and plasma extracts obtained by C18
      solid-phase extraction after deproteination with perchloric acid. No
      interferences with plasma compounds were observed. The calibration graph was
      linear over the range of 30 to 3000 ng/ml using 5-fluorouracil as external
      standard. The limit of quantification was 24 ng/ml. The CZE method is fast,
      reproducible, linear and is therefore a good alternative for the already
      established HPLC methods.

PMID- 10348196
TI  - Analysis of (+)-catechin, (-)-epicatechin and their 3'- and 4'-O-methylated
      analogs. A comparison of sensitive methods.
AB  - (+)-Catechin and (-)-epicatechin are found in many foods and may have important
      effects on human health. These compounds, like many other catechols, are thought
      to be converted to methylated metabolites after ingestion. This paper describes
      the synthesis of the 3'- and 4'-methyl ethers and their unambiguous
      identification. These products, along with catechin, epicatechin and an internal
      standard, (+)-taxifolin, were separated using RP-HPLC with ultraviolet,
      electrochemical and fluorescence detection. The trimethylsilylated derivatives of
      the seven compounds were also separated by GC with mass spectrometric detection.
      The limits of detection and selectivity of the analytical methods were compared
      with respect to their application in complex matrices such as human plasma.

PMID- 10348198
TI  - Purification of cytochrome P-450 from adult pig testis by hydroxylapatite and
      deoxycorticosterone affinity column chromatography.
AB  - Adult testicular cytochrome P-450 was purified by a two-step procedure utilizing
      hydroxylapatite and deoxycorticosterone affinity column chromatography.
      Cytochrome P-450 was determined to have an isoelectric point of 6.5 on analytical
      isoelectric focusing. The purified cytochrome P-450 was found to be homogeneous
      and its molecular mass was estimated to be 52000 on polyacrylamide gel
      electrophoresis in the presence of sodium dodecyl sulfate. The carbon monoxide
      difference spectrum with a peak at 448 nm exhibited the absorption spectrum of a
      typical cytochrome P-450. A 1000-fold purification was achieved with a yield of
      5%.

PMID- 10348197
TI  - Simultaneous determination of gamma-aminobutyric acid and glutamic acid in the
      brain of 3-mercaptopropionic acid-treated rats using liquid chromatography
      atmospheric pressure chemical ionization mass spectrometry.
AB  - The measurement of gamma-aminobutyric acid (GABA) and glutamic acid (Glu) in the
      whole brain and in various regions of the brain in 3-mercaptopropionic acid (3
      MPA)-treated rats has been developed using liquid chromatography-mass
      spectrometry with an atmospheric pressure ionization interface system. The
      recoveries of these compounds were 94.90+/-4.18% for GABA, 95.60+/-2.86% for Glu
      after ion-exchange treatment. The detection limits for GABA and Glu were 2.5+/
      0.3 microg/ml and 5.0+/-0.8 microg/ml, respectively, when 20 microl sample were
      injected. GABA concentration in the whole brain decreased gradually to 5 min and
      reached 63% of normal value after administration of 3-MPA, and the concentration
      increased gradually thereafter until 60 min. Conversely, the concentration of Glu
      in the whole brain increased gradually to 10 min and reached 154% of normal
      value, and after that decreased gradually and reached almost normal level at 60
      min after administration of 3-MPA. GABA concentration in various regions of brain
      decreased to 5 min in all regions after administration of 3-MPA, and reached
      normal levels at 60 min as in the whole brain. This method was found to be useful
      for studies of metabolism of GABA and Glu in biological samples.

PMID- 10348199
TI  - Automated high-performance liquid chromatographic method with precolumn reduction
      for the determination of ubiquinol and ubiquinone in human plasma.
AB  - We developed a gradient HPLC method with automated precolumn reduction for direct
      electrochemical detection of ubiquinol-10 (CoQ10H2) and total coenzyme Q10 (TQ10)
      in human plasma. The concentration of ubiquinone-10 (CoQ10) was calculated by
      subtraction of CoQ10H2 from TQ10. Preparation of reducing agent and precolumn
      reduction was performed by a programmable auto-injector. The two mobile phases
      used were: A, 100% of methanol containing 50 mM sodium perchlorate and 10 mM
      perchloric acid; and B, a mixture of ethanol and tert.-butanol (80:20, v/v).
      Sample preparation was simply a deproteinisation process with 10-fold ethanol. A
      good linear relationship was obtained for CoQ10H2 concentration from 0.1 to 3
      micromol/l. The detection limit was 2.5 nmol/l with an injection volume of 20
      microl. The analytical recovery and reproduciblity were generally >90%. To
      validate the method, 18 freshly collected plasma samples of normal healthy
      subjects were analysed. The mean ratio of CoQ10H2/CoQ10 was 93:7. The proposed
      method is sensitive, reliable and can be used for clinical investigation.

PMID- 10348200
TI  - High-performance liquid chromatographic method for determination of vanillin and
      vanillic acid in human plasma, red blood cells and urine.
AB  - A simple high-performance liquid chromatographic method was developed for the
      determination of vanillin and its vanillic acid metabolite in human plasma, red
      blood cells and urine. The mobile phase consisted of aqueous acetic acid (1%,
      v/v)-acetonitrile (85:15, v/v), pH 2.9 and was used with an octadecylsilane
      analytical column and ultraviolet absorbance detection. The plasma method
      demonstrated linearity from 2 to 100 microg/ml and the urine method was linear
      from 2 to 40 microg/ml. The method had a detection limit of 1 microg/ml for
      vanillin and vanillic acid using 5 microl of prepared plasma, red blood cells or
      urine. The method was utilized in a study evaluating the pharmacokinetic and
      pharmacodynamic effects of vanillin in patients undergoing treatment for sickle
      cell anemia.

PMID- 10348201
TI  - High-performance liquid chromatographic determination of pholedrine in human
      serum using ion-pair extraction and amperometric detection.
AB  - The method for the quantitation of pholedrine in human serum involves extraction
      of the sample with benzene utilizing an ion-pairing reagent, bis(2
      ethylhexyl)phosphoric acid, and re-extraction into diluted phosphoric acid.
      Analysis is carried out on a ODS reversed-phase column with heptanesulfonate as
      the ion-pairing reagent. The procedure allows quantitation at the lower nanogram
      level and is useful for pharmacokinetic investigations.

PMID- 10348202
TI  - High-performance liquid chromatographic determination of 1,3-diethyl-2
      thiobarbituric acid--malonaldehyde adduct in fish meat.
AB  - The reaction conditions of 1,3-diethyl-2-thiobarbituric acid (DETBA)
      malonaldehyde (MA) adduct formation were examined in order to analyze MA in fish
      tissue by high-performance liquid chromatography. A reaction mixture containing 4
      mM butyl hydroxytoluene was heated at 100 degrees C for 150 min and the DETBA-MA
      adduct formed was separated by a Inertsil ODS column for 20 min. The detection
      limit was 5 pmol.

PMID- 10348203
TI  - Minimally invasive techniques in neurosurgery: the transoral transpharyngeal
      approach to the brain.
AB  - In 30 cases, an analysis of the transoral transpharyngeal approach to the ventral
      brain stem was made. All preparations were performed in situ using microscopic
      and endoscopic methods. Modern imaging techniques and computer-assisted approach
      planning were also applied and discussed. To show the subarachnoidal cisterns and
      receive a realistic impression of the tissue, the preparation was performed 26
      times in non-fixed cases. To use currently available equipment safely, it is
      important to take anatomical details into account when determining the size and
      type of the clivus window to be used. Preparation of the preclival tissue is the
      most difficult step. It requires a precise approach plan to ensure safe closure.
      This selective approach gives the best access to the lower ventral brainstem,
      without any of the problems associated with other approaches to the same region.
      The transoral transpharyngeal approach is described here within the context of
      minimally invasive techniques, in particular endoscopy, modern imaging methods,
      and computer-assisted approach planning.

PMID- 10348204
TI  - Orbital and cerebral cavernomas: comparison of clinical, neuroimaging, and
      neuropathological features.
AB  - Our results with 15 orbital cavernomas showed that there are important
      differences in comparison with cerebral cavernomas: in contrast all orbital
      cavernomas were embedded by a lilac hard and compact capsule. Clinical symptoms
      were characterized by the growth of the orbital cavernomas. There were no signs
      of hemorrhage, which is typical for cerebral cavernomas. The latter showed in
      contrast to orbital cavernomas a degenerated collagenous tissue forming the
      vessel walls. The capsule of the orbital cavernomas can be proved by magnetic
      resonance imaging (MRI). Because of its tendency to lead to irreversible loss of
      visual acuity, we recommend early surgery after the onset of symptoms.

PMID- 10348205
TI  - Posterior fossa epidural hematomas: observations on a series of 73 cases.
AB  - The posterior fossa is an uncommon site for epidural hematomas. Clinical progress
      is silent and slow, but the deterioration is sudden and quick to become fatal if
      not promptly treated. Early recognition is therefore extremely important. The
      recommended treatment for posterior fossa epidural hematoma is surgical
      evacuation soon after the diagnosis, since the posterior fossa contains vital
      structures. However, conservative management under close clinical and
      radiological supervision can be applied in patients without mass effect. In our
      study, a review of 73 cases with posterior fossa epidural hematoma among a total
      number of 737 patients with epidural hematoma is presented, and a new
      neuroradiological classification is proposed in order to determine the
      appropriate type of treatment. In this series, 14 patients were treated
      conservatively, while 59 required surgery. The conservatively treated 9 pediatric
      and 5 adult patients, and 51 of the 59 surgically treated cases, in other words a
      total of 65 of the 73 patients, showed excellent recovery; 4 patients treated
      surgically had a moderate disability, and 4 patients died (overall mortality
      5.4%). The critical factors influencing outcome were the neuroradiological class,
      the level of consciousness just before the operation, and the other systemic
      and/or intracranial traumatic lesions. In this study, the critical observation
      was that the neuroradiological findings were earlier, more reliable and
      predictive than the clinical findings. Therefore, based upon the obliteration of
      perimesencephalic cisterns and/or displacement of the fourth ventricle, a new
      neuroradiological classification was designed for decision-making in management.

PMID- 10348206
TI  - Functional imaging in periventricular nodular heterotopia with the use of FDG-PET
      and HMPAO-SPECT.
AB  - We analyzed the interictal [18F]fluoro-2-deoxy-D-glucose positron emission
      tomography (FGD-PET) and single photon emission computed tomography with
      technetium-99m-hexamethyl-propyleneamine oxime (HMPAO-SPECT) in two epileptic
      patients with periventricular nodular heterotopia (PNH). In both cases, we found
      both the glucose metabolism and the perfusion of PNH to be almost identical to
      those of the normal cerebral cortex. The metabolic activity and perfusion in the
      heterotopic gray matter in a subependymal white matter area probably represent
      the glucose metabolism and perfusion of the abnormally located gray matter rather
      than a subclinical ictal phenomenon. FDG-PET and HMPAO-SPECT were thus found to
      be a useful complement to magnetic resonance imaging in the evaluation of PNH.

PMID- 10348207
TI  - Orthopedic and neurosurgical treatment of severe kyphosis in myelomeningocele.
AB  - Kyphosis in myelomeningocele is characterized by a complex pattern of problems
      during development and therapy. On the one hand, decompensation of upright
      posture leads to loss of sitting ability and social integration; on the other
      hand, accompanying malformations and trophic alterations threaten the physical
      integrity and performance. Neurologic function, cerebrospinal fluid (CSF)
      circulation, skeletal deformity and the urinary transport system need to be kept
      in mind and need to be treated with cooperation between the different
      specialties. Especially during serious surgical interventions such as spinal
      surgery, neither the nervous system nor the kidneys must be ignored. Sixteen
      patients underwent kyphectomy in the Orthopedic Department of the University of
      Mainz between 1993 and 1997, all of them supervised by the Neurosurgical
      Department. In 13 cases, transversal myelotomy was performed. No insufficiency of
      CSF circulation was seen; neither were there any CSF fistulae. Particular
      problems arose from the skin and soft tissue above the gibbus, the lack of
      muscles and the regeneration deficiency caused by trophic disorders. Therefore, a
      significantly higher complication rate was found than with other correctional
      operations.

PMID- 10348208
TI  - A new subtype of meningioma.
AB  - Three patients with small meningiomas presented with diffuse cerebral edema that
      was out of proportion to the size of tumors. All lesions were small and no brain
      invasion or unusual tumor vascularity or dural sinus involvement was noted in any
      of the three cases. Tumor material was subjected to conventional and
      immunohistochemical stains. All three tumors showed benign meningothelial
      components, prominent formation of hyaline inclusions (pseudopsammoma bodies),
      and striking vascular mural proliferation of small dark cells. All patients have
      remained asymptomatic without any evidence of tumor recurrence after a follow-up
      of 4-6 years. These tumors showed proliferation of pericytes in blood vessel
      walls and, therefore, represent a new subtype of meningothelial meningioma. In
      the study presented here, the location, size, histotype, and clinical findings
      that may influence the development of peritumoral brain edema are discussed in
      detail.

PMID- 10348209
TI  - Brain metastasis of Merkel cell carcinoma. Case report and review of the
      literature.
AB  - Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumor that
      is locally aggressive and has potential for metastatic spread. However, brain
      metastases are rare, and therapy for such tumors has never reported. The authors
      present a 48-year-old woman with MCC of the left elbow and a right cerebellar
      metastasis. After the right cerebellar mass was totally resected, radiation
      treatment and chemotherapy were performed. Eight cases of brain metastasis have
      been reported in the literature, but only 5 have been presented in sufficient
      detail for analysis. Therapy for brain metastases has always been palliative
      whole-brain irradiation and chemotherapy except for our patient, who underwent
      total removal of the tumor and survived for 11 months without neurological
      deficit. Except in the case of 1 with a particularly radiosensitive MCC, the
      patients with brain metastases died within 9 months after detection of the brain
      lesions. If possible, aggressive excision of brain metastases as well as of the
      primary lesion should be done.

PMID- 10348210
TI  - Solid cerebral echinococcosis mimicking a primary brain tumor.
AB  - Solitary brain affection is rare in echinococcosis. We report the case of a 35
      year-old woman presenting with symptomatic grand-mal epilepsy due to a right
      frontal, partially cystic space-occupying lesion. Pre-operative computed
      tomography and magnetic resonance imaging (MRI) suggested a cystic astrocytoma.
      However, histological examination yielded the diagnosis of a 'chitinoma', a rare
      subtype of solid cerebral hydatid disease (echinococcosis). It mimicked a primary
      brain tumor and, therefore, posed a diagnostic problem. We present the--to our
      knowledge--first MRI scans in a case of a histologically proven chitinoma.

PMID- 10348211
TI  - Variable attachment for the Mayfield head rest to fit on a Halo ring in the
      surgery of cervical spine injuries.
AB  - A small device is described helping to attach a Mayfield head rest to a patient
      who is already in a Halo device for a cervical spine injury. This makes it very
      easy to position the patient prior to anesthesia for performing cervical spine
      surgery.

PMID- 10348212
TI  - Effects of air pollution and smoking on chronic obstructive pulmonary disease and
      bronchial asthma.
AB  - Although both tobacco smoking and air pollution are believed to be environmental
      factors affecting the prevalence of chronic obstructive pulmonary disease (COPD)
      and bronchial asthma, the mechanisms by which they induce/aggravate these
      diseases are still not known in detail. While smoking has been demonstrated to
      cause and aggravate COPD and bronchial asthma, the influence of air pollution,
      suspected to have hazardous environmental effects since the historical episodes
      of severe air pollution such as the London Smog, on the prevalence of airway
      diseases remains unclear. This is due, in part, to changes over time in the
      nature of the air pollutants concerned. There have been no consistent findings on
      the effects on airway diseases of air pollutants at levels currently observed in
      developed countries. It is believed that cessation of smoking is the most
      important factor in preventing the development of COPD.

PMID- 10348213
TI  - Progressive multifocal leukoencephalopathy in a patient with acquired
      immunodeficiency syndrome (AIDS) manifesting Gerstmann's syndrome.
AB  - We reported a case of acquired immunodeficiency syndrome (AIDS) via multiple
      blood transfusions, who manifested progressive multifocal leukoencephalopathy
      (PML) about 18 months after the development of AIDS. PML initiated with right
      hemiparesis, dysphasia, and Gerstmann's syndrome and resulted in death within 2
      months after the onset. Neuroimaging examinations revealed white matter lesions
      mainly in the left posterior parietal lobe. The cortical gray matter also showed
      abnormal signal intensity. Peripheral CD4+ lymphocyte count was 81/microl.
      Routine cerebrospinal fluid (CSF) examinations were negative. CSF antibodies
      against herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein
      Barr virus as well as serum antibody against toxoplasma gondii were negative.
      Though autopsy or biopsy of the brain was not performed, JC virus genomes were
      detected in the CSF sample by a polymerase chain reaction, and their sequencing
      showed unique alterations of the regulatory regions, characteristic to PML-type
      JC virus.

PMID- 10348214
TI  - Erythroid accelerating activity of rat serum in early stage of drug induced
      hemolysis.
AB  - An increase in the number of erythroblasts can be seen to some extent in the bone
      marrow of rats in the early stage of experimentally induced hemolytic anemia
      prior to any elevation in the plasma erythropoietin (Epo) level. This observation
      suggests that there is another erythroid stimulating factor present other than
      Epo. We studied the enhancing effect of serum, taken sequentially during
      experimentally induced hemolysis in rats, on erythroid proliferation,
      differentiation and maturation in vitro. Single intraperitoneal injection of 60
      mg/kg of acetylphenylhydrazine (APH) induced self-limited hemolytic anemia in
      rats, in which the hematocrit dropped rapidly with a nadir at day 4 after APH
      injection, followed by a gradual increase with return to normal level by day 8.
      Serum obtained consecutively every day after APH injection from day 1 to day 7
      was applied to an in vitro culturing system of erythroid progenitors. Addition of
      day 1 serum, in which an elevation of Epo level had not occurred, to a
      conventional methyl-cellulose culture of rat bone marrow mononuclear cells (BM
      MNCs) resulted in a significant increase in the number of colonies derived from
      colony forming unit erythroid, but not in burst forming unit erythroid. This
      erythropoietic activity of the serum was particularly evident in the presence of
      Epo. In the liquid culture of BM-MNCs, day 1 serum also showed some enhancing
      effect on erythroblast formation. We were able to see significant differences in
      these erythroid enhancing activities induced by serum drawn on day 1 in
      comparison to the serum drawn on subsequent days. These results suggest that an
      unknown erythroid enhancing factor besides Epo stimulates erythropoiesis in the
      early stage of hemolytic anemia or sudden hypoxia before there is a measurable
      rise in the serum Epo level. We propose that this factor be termed erythroid
      accelerating factor (EAF).

PMID- 10348215
TI  - Significant changes in volume of seminal vesicles as determined by transrectal
      sonography in relation to age and benign prostatic hyperplasia.
AB  - We evaluated the changes in volume of the seminal vesicles as determined by
      transrectal sonography in terms of the possible relationship with aging, lower
      urinary tract symptoms and benign prostatic hyperplasia (BPH) in community based
      populations in Japan. In 641 men (55-86 year, mean 67) on a mass screening
      program for prostatic diseases, the maximum horizontal area of the seminal
      vesicles (MHA) was compared with age, American Urological Association (AUA)
      symptom index scores and transrectal ultrasonic parameters of the prostate
      including prostatic volume, transition zone (TZ) volume, TZ index and presumed
      circle area ratio (PCAR). Simple regression analyses demonstrated that MHA
      correlated significantly with age, prostatic volume, TZ volume, TZ index and
      PCAR, but not with AUA symptom index scores. Multiple regression analysis
      revealed age, prostatic volume and PCAR to be independent determinants of MHA.
      There was a difference in MHA between subjects with BPH (7.1+/-2.5 cm2) and those
      with a normal prostate (5.6+/-2.1 cm2) with a statistical significance. In the
      morphological evaluation of the seminal vesicles, the significant influence of
      age and BPH has to be taken into account.

PMID- 10348216
TI  - Effect of melatonin on cadmium-induced hepatotoxicity in male Sprague-Dawley
      rats.
AB  - Effect of melatonin on toxicity of cadmium (Cd) was studied in male SD rats co
      administered daily Cd (1 mg/kg b.w., s.c.) with melatonin (10 mg/kg b.w., i.p.)
      for 15 days. Cd alone injection decreased GSH concentrations in the liver and RBC
      by 35% and 43% compared with those in saline-treatment group, but not in the
      kidney and whole brain. The activity of GSSG-reductase was significantly
      decreased in the liver of Cd alone injected rats, while melatonin given in
      combination with Cd failed to prevent the Cd-induced decreased activity of
      hepatic GSSG-reductase. However, the hepatic GSH concentration decreased by Cd
      alone was restored by melatonin treatment, and the melatonin also ameliorated Cd
      induced histopathological changes in the liver. Therefore, data indicate that
      melatonin restores the reduction of hepatic GSH level induced with Cd regardless
      of GSSG-reductase activity, and suggests that melatonin may ameliorate Cd-induced
      hepatotoxicity.

PMID- 10348218
TI  - Gametocytogenesis-stimulating interventions may provide clinical benefit in
      falciparum malaria.

PMID- 10348217
TI  - A case of aldosterone-producing adenoma with severe postoperative hyperkalemia.
AB  - It is known that some patients with primary aldosteronism show postoperative
      hyperkalemia, which is due to inability of the adrenal gland to secrete
      sufficient amounts of aldosterone. However, hyperkalemia is generally neither
      severe nor prolonged, in which replacement therapy with mineralocorticoid is
      seldom necessary. We report a case of a 46-year-old woman with an aldosterone
      producing adenoma associated with severe postoperative hyperkalemia. After
      unilateral adrenalectomy, the patient showed episodes of severe hyperkalemia for
      four months, which required not only cation-exchange resin, but also
      mineralocorticoid replacement. Plasma aldosterone concentration (PAC) was low,
      although PAC was increased after rapid ACTH test. Histological examination
      indicated the presence of adrenocortical tumor and paradoxical hyperplasia of
      zona glomerulosa in the adjacent adrenal. Immunohistochemistry demonstrated that
      the enzymes involved in aldosterone synthesis, such as cholesterol side chain
      cleavage (P-450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), and 21
      hydroxylase (P-450c21), or the enzyme involved in glucocorticoid synthesis,
      11beta-hydroxylase (P-450c11beta), were expressed in the tumor, but they were
      completely absent in zona glomerulosa of the adjacent adrenal. These findings
      were consistent with the patterns of primary aldosteronism. Serum potassium level
      was gradually decreased with concomitant increase in PAC. These results suggest
      that severe postoperative hyperkalemia of the present case was attributable to
      severe suppression of aldosterone synthesis in the adjacent and contralateral
      adrenal, which resulted in slow recovery of aldosterone secretion. It is
      plausible that aldosterone synthesis of adjacent and contralateral adrenal glands
      is severely impaired in some cases with primary aldosteronism, as glucocorticoid
      synthesis in Cushing syndrome.

PMID- 10348219
TI  - Adaptation of the agent of the human monocyte ehrlichiosis (Ehrlichia
      chaffeensis) to HL60.

PMID- 10348220
TI  - Possible establishment of chloroquine-resistant P. falciparum in Saudi Arabia.

PMID- 10348221
TI  - Short report: outbreak of cutaneous leishmaniasis in a nonimmune population of
      soldiers in Wadi Araba, Jordan.

PMID- 10348222
TI  - Association between asymptomatic cystic echinococcosis and some types of rural
      water supplies.

PMID- 10348223
TI  - A randomized, double-blind, placebo-controlled field trial to determine the
      efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of
      malaria in Zambia.
AB  - Malaria poses a major health risk to people who are exposed to infection in
      malaria-endemic areas. A randomized, double-blind, placebo-controlled study was
      conducted to determine the efficacy and safety of Malarone (250 mg of
      atovaquone/100 mg of proguanil hydrochloride per tablet) for the chemoprophylaxis
      of Plasmodium falciparum malaria in Zambia. Adult volunteers received a three-day
      treatment course of Malarone to eliminate pre-existing parasitemia and were then
      immediately randomized to treatment with either one Malarone tablet daily (n =
      136), or one placebo tablet daily (n = 138) for at least 10 weeks. Malaria blood
      smears were prepared on a weekly basis and a failure of chemoprophylaxis was
      defined as any subject who had a positive blood smear, or who withdrew from the
      study due to a treatment-related adverse event. The prophylaxis success rates in
      the Malarone and placebo groups were 98% and 63%, respectively (P < 0.001). The
      most commonly reported adverse events with at least a possible causal
      relationship to study medication were headache and abdominal pain, which occurred
      with a higher incidence in the placebo group. No subjects were withdrawn from the
      study due to a treatment-related adverse event. Thus, Malarone appears to have an
      excellent safety and efficacy profile for the chemoprophylaxis of P. falciparum
      infection.

PMID- 10348224
TI  - Efficacy and safety of atovaquone/proguanil compared with mefloquine for
      treatment of acute Plasmodium falciparum malaria in Thailand.
AB  - The increasing frequency of therapeutic failures in falciparum malaria
      underscores the need for novel, rapidly effective antimalarial drugs or drug
      combinations. Atovaquone and proguanil are blood schizonticides that demonstrate
      synergistic activity against multi-drug-resistant Plasmodium falciparum in vitro.
      In an open-label, randomized, controlled clinical trial conducted in Thailand,
      adult patients with acute P. falciparum malaria were randomly assigned to
      treatment with atovaquone and proguanil/hydrochloride (1,000 mg and 400 mg,
      respectively, administered orally at 24-hr intervals for three doses) or
      mefloquine (750 mg administered orally, followed 6 hr later by an additional 500
      mg dose). Efficacy was assessed by cure rate (the percentage of patients in whom
      parasitemia was eliminated and did not recur during 28 days of follow-up),
      parasite clearance time (PCT), and fever clearance time (FCT). Safety was
      assessed by sequential clinical and laboratory assessments for 28 days.
      Atovaquone/proguanil was significantly more effective than mefloquine (cure rate
      100% [79 of 79] vs. 86% [68 of 79]; P < 0.002). The atovaquone/proguanil and
      mefloquine treatments did not differ with respect to PCT (mean = 65 hr versus 74
      hr) or FCT (mean = 59 hr versus 51 hr). Adverse events were generally typical of
      malaria symptoms and each occurred in < 10% of the patients in either group, with
      the exception of increased vomiting found in the atovaquone/proguanil group.
      Transient elevations of liver enzyme levels occurred more frequently in patients
      treated with atovaquone/proguanil than with mefloquine, but the differences were
      not significant and values returned to normal by day 28 in most patients. The
      combination of atovaquone and proguanil was well tolerated and more effective
      than mefloquine in the treatment of acute uncomplicated multidrug-resistant
      falciparum malaria in Thailand.

PMID- 10348225
TI  - Malarone (atovaquone and proguanil hydrochloride): a review of its clinical
      development for treatment of malaria. Malarone Clinical Trials Study Group.
AB  - The continuing spread of drug-resistant malaria emphasizes the need for new
      antimalarial drugs. Atovaquone is a broad-spectrum antiprotozoal drug with a
      novel mechanism of action, via inhibition of parasite mitochondrial electron
      transport, and a favorable safety profile. Early studies with atovaquone alone
      for treatment of malaria demonstrated good initial control of parasitemia but an
      unacceptable rate of recrudescent parasitemia. Parasites isolated during
      recrudescence after treatment with atovaquone alone were resistant to atovaquone
      in vitro. The combination of atovaquone and proguanil is synergistic in vitro,
      and clinical studies demonstrated enhanced efficacy of the combination compared
      to either drug alone for treatment of malaria. Malarone, a fixed-dose combination
      of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, is available in
      many countries for treatment of acute, uncomplicated malaria caused by Plasmodium
      falciparum. At the recommended dose (in adults, four tablets once a day for three
      days), the overall cure rate was > 98% in more than 500 patients with falciparum
      malaria. In four randomized, controlled clinical trials, treatment with
      atovaquone and proguanil hydrochloride was significantly more effective than
      mefloquine (Thailand), amodiaquine (Gabon), chloroquine (Peru and the
      Philippines) or chloroquine plus pyrimethamine/sulfadoxine (Philippines). In
      clinical trials where the comparator drug was highly effective, treatment with
      atovaquone and proguanil hydrochloride was equally effective. Parasites isolated
      during recrudescence after treatment with the combination of atovaquone and
      proguanil were not resistant to atovaquone in vitro. The most commonly reported
      adverse events in clinical trials (abdominal pain, anorexia, nausea, vomiting,
      diarrhea and coughing) occurred with similar frequency in patients treated with a
      comparator drug. Malarone is a safe and effective new agent for treatment of
      malaria.

PMID- 10348226
TI  - In vivo responses to antimalarials by Plasmodium falciparum and Plasmodium vivax
      from isolated Gag Island off northwest Irian Jaya, Indonesia.
AB  - There is renewed interest in the rich nickel and cobalt deposits of Pulau Gag, an
      isolated but malarious island off the northwest coast of Irian Jaya. In
      preparation for an expanded workforce, an environmental assessment of malaria
      risk was made, focusing upon malaria prevalence in the small indigenous
      population, and the in vivo sensitivity of Plasmodium falciparum and P. vivax to
      chloroquine (CQ) and sulfadoxine/pyrimethamine (S/P), the respective first- and
      second-line drugs for uncomplicated malaria in Indonesia. During April-June 1997,
      mildly symptomatic or asymptomatic malaria infections were found in 24% of 456
      native residents. Infections by P. falciparum accounted for 60% of the cases.
      Respective day 28 cure rates for CQ (10 mg base/kg on days 0 and 1; 5 mg/kg on
      day 2) in children and adults were 14% and 55% (P < 0.005). Type RII and RIII
      resistance characterized only 5% of the CQ failures. Re-treatment of 36 P.
      falciparum CQ treatment failures with S/P (25 mg/kg and 1.25 mg/kg, respectively)
      demonstrated rapid clearance and complete sensitivity during the 28-day follow-up
      period. More than 97% of the P. vivax malaria cases treated with CQ cleared
      parasitemia within 48 hr. Three cases of P. vivax malaria recurred between days
      21 and 28, but against low drug levels in the blood. The low frequency of RII and
      RIII P. falciparum resistance to CQ, the complete sensitivity of this species to
      S/P, and the absence of CQ resistance by P. vivax are in contrast to in vivo and
      in vitro test results from sites on mainland Irian Jaya.

PMID- 10348227
TI  - Adverse effects in patients with acute falciparum malaria treated with
      artemisinin derivatives.
AB  - In prospective studies of acute uncomplicated, multidrug-resistant falciparum
      malaria on the western border of Thailand, the oral artemisinin derivatives were
      used alone in the treatment of 836 patients (artesunate 630, artemether 206),
      were combined with mefloquine (15-25 mg base/kg) in 2,826 patients, and
      mefloquine alone was used in 1,303 patients. The combined regimens of mefloquine
      plus an artemisinin derivative were associated with more side effects than those
      with an artemisinin derivative alone; acute nausea (31% versus 16%), vomiting
      (24% versus 11%), anorexia (51% versus 34%), and dizziness (47% versus 15%) (P <
      0.001). Oral artesunate and artemether alone were very well tolerated. There was
      no difference in the incidence of possible adverse effects between the two drugs,
      and no evidence that either derivative caused allergic reactions, neurologic or
      psychiatric reactions, or cardiovascular or dermatologic toxicity. Blackwater
      fever occurred in three patients treated with mefloquine plus artesunate
      regimens. Oral artesunate and artemether are safe and well tolerated antimalarial
      drugs.

PMID- 10348228
TI  - Evidence for an improvement in cognitive function following treatment of
      Schistosoma japonicum infection in Chinese primary schoolchildren.
AB  - A double-blind, placebo-controlled, treatment trial was conducted in Sichuan,
      China to investigate the unique and combined effects on the cognitive function
      (working memory) of children after treating geohelminth infections with
      albendazole and treating Schistosoma japonicum infection with praziquantel. One
      hundred eighty-one children 5-16 years of age participated. At baseline, the
      praziquantel and placebo groups were similar in all background characteristics.
      Three months after praziquantel treatment, there was a significant reduction in
      the prevalence and intensity of S. japonicum infection. There were significant
      age group by praziquantel treatment interaction effects in three of the five
      cognitive tests, Fluency, Picture Search, and Free Recall, with effects being
      strongest in the youngest children (5-7 years old). Exploratory analysis within
      the youngest children showed a significant positive main effect of treatment on
      Fluency (P < 0.001), after controlling for sex, anthropometric, and parasitic and
      iron status. There was also a treatment by height-for-age interaction (P = 0.03)
      and a treatment by iron status interaction (P = 0.024) on Fluency. There was a
      treatment by S. japonicum intensity interaction (P < 0.001) on Free Recall, but
      the main effect of treatment on Picture Search was not significant (P = 0.058).
      Younger children and those who are physically the most vulnerable are likely to
      benefit the most from the treatment of S. japonicum infection in terms of
      improved performance on tests of working memory.

PMID- 10348229
TI  - Geographic information systems and the environmental risk of schistosomiasis in
      Bahia, Brazil.
AB  - A geographic information system was constructed using maps of regional
      environmental features, Schistosoma mansoni prevalence in 30 representative
      municipalities, and snail distribution in Bahia, Brazil to study the spatial and
      temporal dynamics of infection and to identify environmental factors that
      influence the distribution of schistosomiasis. Results indicate that population
      density and the duration of annual dry period are the most important determinants
      of prevalence of schistosomiasis in the areas selected for study. Maximum
      rainfall, total precipitation during three consecutive months, annual maximum or
      minimum temperatures, and diurnal temperature difference were not shown to be
      significant factors influencing S. mansoni prevalence in local populations or
      distribution of snail hosts. Prevalence of the disease was highest in the coastal
      areas of the state. Higher prevalence tended to occur in areas with latossolo
      soil type and transitional vegetation.

PMID- 10348230
TI  - Agranulocytosis in Bangkok, Thailand: a predominantly drug-induced disease with
      an unusually low incidence. Aplastic Anemia Study Group.
AB  - Agranulocytosis, a syndrome characterized by a marked reduction in circulating
      granulocytes, is strongly associated with medical drug use in Europe and the
      United States. Unregulated use of common pharmaceutical agents in developing
      countries has been suspected of causing large numbers of cases of agranulocytosis
      and deaths, especially among children. To elucidate the incidence and etiology of
      agranulocytosis in Thailand, a population-based case-control study of symptomatic
      agranulocytosis that resulted in hospital admission was conducted in Bangkok from
      1990 to 1994. An attempt was also made to study the disease in Khonkaen (in
      northeastern Thailand) and Songkla (in southern Thailand), but there were
      insufficient cases in the latter regions, and the analysis was confined to
      subjects from Bangkok. In that region, the overall incidence of agranulocytosis
      was 0.8 per million per year; there were no deaths. As expected, the incidence
      was higher in females (0.9 per million), and it increased with age (4.3 per
      million beyond age 60). Among 25 cases and 529 controls the relative risk
      estimate for a combined category of all suspect drugs was 9.2 (95% confidence
      interval = 3.9-21), and the proportion of cases that could be attributed to drug
      use was 68%. For individual drugs and drug classes the data were sparse; within
      these limitations, the strongest association appeared to be with antithyroid
      drugs. One case and three controls were exposed to dipyrone, a drug known to
      cause agranulocytosis; with such scanty data the risk could not be evaluated.
      Exposure to pesticides or solvents was not associated with an increased risk.
      This is the first formal epidemiologic study of agranulocytosis in a developing
      country. As in the West, most cases are attributable to medical drug use.
      However, the incidence of agranulocytosis in Bangkok, and apparently, in Thailand
      as a whole, is unusually low, and the disease does not pose a public health risk.

PMID- 10348231
TI  - Epidemic and endemic seroprevalence of antibodies to Cryptosporidium and Giardia
      in residents of three communities with different drinking water supplies.
AB  - This study was carried out to compare cryptosporidiosis and giardiasis
      seroprevalence rates in residents of three communities. Community (Com 1) uses
      drinking water from deep wells, community 2 (Com 2) uses surface water from a
      protected watershed, and community 3 (Com 3) uses surface water frequently
      containing Cryptosporidium oocysts and Giardia cysts. Unfiltered drinking water
      from each community was collected at the tap and tested for Cryptosporidium
      oocysts and Giardia cysts during the 12 months in which sera were collected for
      testing. No oocysts or cysts were detected in the water from the Com 1 deep
      wells; oocysts and cysts were detected intermittently in the drinking water from
      the other two communities. A waterborne outbreak of cryptosporidiosis occurred in
      a municipality adjacent to Com 3 six months into this 12-month study. Sera from
      residents of each of the communities were collected proportionately by month and
      by population size. Coded sera were tested for IgG to Cryptosporidium using a
      previously developed Western blotting method. The presence or absence of bands at
      15-17 kD and/or 27 kD was recorded for the 1,944 sera tested. Definite bands at
      15-17 kD and/or 27 kD were detected in 981 (50.5%) of the sera. A total of 33.2%
      of sera from Com 1 (community using deep wells) were positive using the same
      criteria compared with 53.5% (Com 2) and 52.5% (Com 3) of sera from the two
      communities using surface drinking water. Both bands (15-17 kD plus 27 kD) were
      detected in 582 sera (29.9%) from the three communities: 14.1% of sera from Com 1
      compared with 32.7% from Com 2 and 31.5% from Com 3. These findings are
      consistent with a lower risk of exposure to Cryptosporidium from drinking water
      obtained from deep well sources. However, analysis of results by calendar quarter
      showed a significant (P < 0.001) increase in the number of Com 3 positive sera
      (compared with Com 1) following the waterborne outbreak. Without this outbreak
      related observation, a significant overall difference in seropositivity would not
      have been seen. We also observed that in sera from the community affected by the
      outbreak, the presence on immunoblots of both Cryptosporidium bands appeared to
      be the best indicator of recent infection. Seroprevalence rates using an ELISA to
      detect IgG to Giardia were estimated using the same sera. Overall 30.3% (590 of
      1,944) of sera were positive by the ELISA. A total of 19.1% of sera from Com 1,
      34.7% from Com 2 and 16.0% from Com 3 were seropositive. Rates for both Com 3 and
      Com 1 did not change significantly over time. In Com 2, rates decreased
      significantly (P < 0.001) during the last half of the study period (third and
      fourth calendar quarters). The reasons for the decrease in seroprevalence in Com
      2 sera are presently not known. These studies show intriguing associations
      between seroprevalence, outbreak-related laboratory serologic data, and patterns
      of parasite contamination of drinking water. Further studies are required to
      validate the serologic approach to risk assessment of waterborne parasitic
      infections at a community level.

PMID- 10348232
TI  - Cyclospora cayetanensis infections in Haiti: a common occurrence in the absence
      of watery diarrhea.
AB  - Stool samples from a population-based cohort of mothers and children living in
      Leogane, Haiti were tested for Cyclospora cayetanensis from January 1997 through
      January 1998. Data on gastrointestinal symptoms were also collected. During the
      winter months of January to March, the infection was detected in 15-20% of the
      persons sampled. Most infections did not appear to be causing diarrhea and most
      infected persons had few oocysts detectable in concentrates of stool. The
      infection appears to have marked seasonality, with highest rates during the
      driest and coolest time of the year. It may be that in this tropical setting,
      high summer temperature is the critical environmental factor that influences the
      seasonality of infection. This study demonstrates that Cyclospora infections in
      Haiti are common in the general population.

PMID- 10348233
TI  - Serologic IgG response to urease in Helicobacter pylori-infected persons from
      Mexico.
AB  - Helicobacter pylori urease is required to counteract acidity during colonization
      of the stomach, and has been suggested as a major immunodominant antigen. The aim
      of this study was to determine the anti-urease response in a representative
      national serologic survey in Mexico. The population surveyed included persons 1
      90 years of age from all socioeconomic levels and geographic zones of the
      country. Helicobacter pylori status was determined by ELISA serology. The IgG
      anti-urease was studied by ELISA using a recombinant apoenzyme. We found that
      2,930 of the 7,720 infected patients (38%) were seropositive for IgG urease. The
      rate of IgG anti-urease positivity increased with age; in children < 10 years old
      it was < 20% and in persons > 40 years old it was > 50%. Age and a region with a
      high level of development were risk factors for seropositivity, whereas gender,
      educational level, crowding, and socioeconomic level were not associated with
      seropositivity. In conclusion, in natural infection with H. pylori, the response
      to urease is poor, mainly during the first years of infection. This inconsistent
      immune response to the enzyme may favor persistence of infection. A vaccine
      eliciting a consistent anti-urease response might overcome immune evasion and
      enhance clearance of bacteria after exposure.

PMID- 10348234
TI  - Bartonella henselae and Bartonella clarridgeiae infection in domestic cats from
      The Philippines.
AB  - One hundred seven domestic cats from The Philippines were serologically tested to
      establish the prevalence of Bartonella infection. A subset of 31 of these cats
      also had whole blood collected to tentatively isolate Bartonella strains.
      Bartonella henselae and B. clarridgeiae were isolated from 19 (61%) of these
      cats. Bartonella henselae type I was isolated from 17 (89%) of the 19 culture
      positive cats. Six cats (31%) were infected with B. clarridgeiae, of which four
      were coinfected with B. henselae. Sixty-eight percent (73 of 107) and 65% (70 of
      107) of the cats had antibodies to B. henselae and B. clarridgeiae, respectively,
      detected by an immunofluorescence antibody (IFA) test at a titer > or = 1:64.
      When tested by enzyme immunoassay (EIA), 67 cats (62.6%) had antibodies to B.
      henselae and 71 cats (66.4%) had antibodies to B. clarridgeiae. Compared with the
      IFA test, the B. henselae EIA had a sensitivity of 90.4% and a specificity of
      97%, with positive and negative predictive values of 98.5% and 82.5%,
      respectively. Similarly, the B. clarridgeiae EIA had a sensitivity of 97% and a
      specificity of 92% specificity, with positive and negative predictive values of
      95.8% and 94.4%, respectively. The presence of antibodies to Bartonella was
      strongly associated with flea infestation. Domestic cats represent a large
      reservoir of Bartonella infection in the Philippines.

PMID- 10348235
TI  - Longitudinal study of infection with Borrelia burgdorferi in a population of
      Peromyscus leucopus at a Lyme disease-enzootic site in Maryland.
AB  - The maintenance of Borrelia burgdorferi in a population of Peromyscus leucopus
      was investigated from 202 mark and recapture mice and 61 mice that were removed
      from a site in Baltimore County, Maryland. Borrelia burgdorferi infection was
      detected by culture and polymerase chain reaction (PCR) of ear tissue, and
      exposure to the spirochete was quantified by serology. Overall prevalence of B.
      burgdorferi, as determined by culture and PCR of ear tissue at first capture, was
      25% in the longitudinal sample and 42% in the cross-sectional sample.
      Significantly more juvenile mice were captured in the longitudinal sample (18%)
      than in the cross-sectional sample (0%). Among 36 captured juvenile mice, only
      one was infected with B. burgdorferi; this contributed to a significant trend for
      infection with B. burgdorferi with age. Recovery from infection with B.
      burgdorferi was not detected among 77 mice followed for an average of 160 days.
      The incidence rate of infection with B. burgdorferi was 10 times greater in mice
      captured during two periods of high risk of exposure to nymphal Ixodes scapularis
      ticks compared with a period of low risk. Maintenance of B. burgdorferi in this
      population was dependent on indirect transmission of the organism from infected
      ticks to susceptible mice and development of chronic infection with the
      spirochete, which had no measurable effect on the survival of infected mice.

PMID- 10348236
TI  - Leptospirosis and Ebola virus infection in five gold-panning villages in
      northeastern Gabon.
AB  - An exhaustive epidemiologic and serologic survey was carried out in five gold
      panning villages situated in northeastern Gabon to estimate the degree of
      exposure of to leptospirosis and Ebola virus. The seroprevalence was 15.7% for
      leptospirosis and 10.2% for Ebola virus. Sixty years after the last
      seroepidemiologic survey of leptospirosis in Gabon, this study demonstrates the
      persistence of this infection among the endemic population and the need to
      consider it as a potential cause of hemorrhagic fever in Gabon. There was no
      significant statistical correlation between the serologic status of populations
      exposed to both infectious agents, indicating the lack of common risk factors for
      these diseases.

PMID- 10348237
TI  - Hepatitis B surface antigen disappearance and hepatitis B surface antigen
      subtype: a prospective, long-term, follow-up study of Japanese residents of
      Okinawa, Japan with chronic hepatitis B virus infection.
AB  - To determine the natural course of hepatitis B surface antigen (HBsAg)
      disappearance in chronic hepatitis B virus (HBV) infection and the factors
      related to its disappearance, 946 HBsAg carriers in Okinawa, Japan were
      prospectively followed for up to 19 years (mean = 9.2 years). The disappearance
      of HBsAg, as determined by radioimmunoassay (RIA), was observed in 62 (6.6%) and
      the overall annual disappearance rate was 0.79%/year. Its disappearance was more
      frequent in 60 (7.4%) of 815 serum samples negative for hepatitis B e antigen
      (HBeAg) by RIA at entry compared with only two (1.5%) of 131 serum samples that
      were HBeAg positive by RIA at entry (P < 0.05). Stepwise logistic regression
      analysis showed that age and HBsAg subtype were significantly associated with
      HBsAg disappearance (both P < 0.05), and that carriers with subtype adr (odds
      ratio = 2.87) had an increased probability of clearing HBsAg compared with
      carriers with subtype adw. Conversely, HBeAg disappearance was earlier in those
      with the adw subtype than in those with adr. Hepatitis B virus DNA was not
      detected by the polymerase chain reaction after HBsAg disappearance in any of the
      62 from whom it had disappeared. The HBsAg titer, as measured by reverse passive
      hemagglutination, was related to the time to its disappearance; the higher the
      titer, the longer the time to disappearance. These findings suggest that HBeAg
      negativity, a more advanced age, and low titers of HBsAg are favorable factors
      for HBsAg disappearance in the natural course of chronic HBV infection. Moreover,
      HBsAg subtype adr was a predictive factor for HBsAg disappearance, whereas
      subtype adw was predictive of early HBeAg disappearance.

PMID- 10348238
TI  - Prevalence of antibody to human T cell lymphotropic virus types 1/2 among
      aboriginal groups inhabiting northern Argentina and the Amazon region of Peru.
AB  - We carried out a seroepidemiologic survey to define the prevalence of human T
      cell lymphotropic virus types 1/2 (HTLV-1/2) infections among aboriginal
      populations from isolated regions of northern Argentina and the Amazon region of
      Peru. Antibodies against HTLV were measured with agglutination tests and
      confirmed with by an immunofluorescence assay (IFA) and Western blotting. Five
      (6.94%) of 72 samples from the Tobas Indians in Argentina were positive by the
      IFA; two samples were typed as HTLV-1 (2.78%), two as HTLV-2 (2.78%), and one
      (1.39%) could not be typed because it had similar antibody titers against both
      viruses. No positive samples were found among 84 Andinos Punenos and 47 Matacos
      Wichis Indians. Seroprevalences of 2.50% (1 of 40) and 1.43% (1 of 70) for HTLV-1
      were observed among Wayku and San Francisco communities in the Amazon region of
      Peru, and seroprevalences of 4.54% (1 of 22) and 2.38% (1 of 42) for HTLV-2 were
      observed among Boca Colorada and Galilea communities. No serologic evidence of
      human immunodeficiency virus (HIV) infection was found among the Indians tested.
      These results indicated the presence of HTLV-1 and HTLV-2 in the indigenous
      populations of Argentina and Peru. Moreover, the lack of HIV infection indicates
      that the virus has probably not yet been introduced into these populations.

PMID- 10348239
TI  - Geographic distribution of Venezuelan equine encephalitis virus subtype IE
      genotypes in Central America and Mexico.
AB  - Phylogenetic analysis of 20 strains of Venezuelan equine encephalitis (VEE) virus
      subtype IE isolated from 1961 to 1996 in Mexico and throughout Central America
      showed that VEE virus subtype IE was monophyletic with respect to other VEE virus
      subtypes. Nonetheless, there were at least three distinct geographically
      separated VEE virus IE genotypes: northwestern Panama, Pacific coast
      (Mexico/Guatemala), and Gulf/Caribbean coast (Mexico/Belize). Strains from the
      Caribbean coast of Guatemala, Honduras, and Nicaragua may cluster with the
      Gulf/Caribbean genotype, but additional isolates from the region between
      Guatemala and Panama will be required to firmly establish their phylogenetic
      position. Viruses associated with two separate equine epizootics in Mexico in the
      1990s were phylogenetically related to nonepizootic viruses from neighboring
      Guatemala and may represent the emergence or re-emergence of equine-virulent VEE
      virus subtype IE in Middle America.

PMID- 10348240
TI  - Longitudinal cohort study of the epidemiology of malaria infections in an area of
      intense malaria transmission I. Description of study site, general methodology,
      and study population.
AB  - A large-scale longitudinal cohort project was initiated in western Kenya in June
      1992. The primary purpose of the project was to study Plasmodium falciparum
      malaria in a highly endemic area using a comprehensive and multidisciplinary
      approach, which included epidemiology, entomology, and immunology. Between June
      1992 and July 1994, pregnant women living in 15 rural villages were identified
      during a monthly census and 1,164 were enrolled. The women were followed-up
      throughout their pregnancy and they, along with their newborn infants and direct
      siblings of the infants' less than 15 years of age, were monitored over time. As
      of May 1995, 1,017 infants had been born to these women. This paper presents the
      design and general methodology used in this study and describes the initial
      experience with intense monitoring of a large population over a prolonged period.

PMID- 10348241
TI  - Longitudinal cohort study of the epidemiology of malaria infections in an area of
      intense malaria transmission II. Descriptive epidemiology of malaria infection
      and disease among children.
AB  - A large-scale longitudinal cohort project was initiated in western Kenya in June
      1992. Between June 1992 and July 1994, 1,848 children less than 15 years of age
      were monitored prospectively for a mean of 236 days. During this period, 12,035
      blood smears were examined for malaria and only 34% were found to be negative.
      Parasite prevalence (all species) decreased with age (from a high of 83% among
      children 1-4 years old to 60% among children 10-14 years old). Even more dramatic
      decreases were noted in the prevalence of high density falciparum infection (from
      37% among children 12-23 months old to < 1% among 10-14-year-old children) and in
      clinical malaria (20% to 0.3% in the same age groups). Children < 1 year of age
      accounted for 55% of all cases of anemia detected. Anemia was consistently
      associated with high density infection in children < 10 years of age (20% to 210%
      increased risk relative to aparasitemic children). These results demonstrate the
      relationship between high-density malaria infection and two clinical
      manifestations of malarial illness.

PMID- 10348242
TI  - Cytogenetic evidence for a species complex within Anopheles pseudopunctipennis
      theobald (Diptera: Culicidae).
AB  - Anopheles pseudopunctipennis was collected from Acapulco, Mexico and Sallee
      River, Grenada, West Indies and used in cross-mating experiments. Larvae from the
      cross, Mexico female X Grenada male, died in the third instar. However, adult
      progeny were obtained from the reciprocal cross Grenada female x Mexico male.
      These hybrid males had testes with apparently normal appearance but some without
      viable sperm. Polytene chromosomes obtained from hybrid females exhibited
      extensive asynapsis of the X chromosomes. Previously undescribed fixed inversion
      differences between the two populations were noted on the X chromosome. It is
      concluded that the two populations belong to different species. The Grenada
      population is designated An. pseudopunctipennis species C, since it is the third
      taxon recognized in this species complex.

PMID- 10348243
TI  - Gender-related efficacy difference to an extended duration formulation of topical
      N,N-diethyl-m-toluamide (DEET).
AB  - A clinical trial (n = 120, 60 males and 60 females) was conducted to assess the
      efficacy of an extended duration tropical insect/arthropod repellent (EDTIAR)
      topical formulation of N,N-diethyl-m-toluamide (DEET). The amount of EDTIAR (mean
      +/- confidence interval), applied by participants in accordance with label
      directions, was not significantly different between females (3.66 +/- 0.32
      mg/cm2) and males (3.45 +/- 0.33 mg/cm2). There also was no significant
      difference in the number of Anopheles stephensi mosquitoes biting the control arm
      of females or males at 0, 3, 6, 9, and 12 hr. While gender had no effect on
      feeding, the time of day did effect mosquito feeding with fewer mosquitoes
      feeding in the afternoon than in the morning or evening. The percent protective
      efficacy at 0, 3, 6, 9, and 12 hr was 100.0, 99.3, 92.8, 79.7 and 66.3 for
      females, and 100.0, 100.0, 97.6, 91.9, and 77.5 for males. These data are
      inconsistent with the EDTIAR label claim that the repellent provides 95% or
      greater protection against mosquitoes for 12 hr or more under normal use
      conditions. The results of a multivariate regression analysis indicated that 1)
      protection decreased linearly as time after application of repellent increased (P
      < 0.001), 2) individuals who applied higher doses of repellent were better
      protected against mosquito bites (P < 0.001), 3) females experienced
      significantly less protection over time than did males (P = 0.005), and 4) the
      estradiol concentration in the blood had no effect on efficacy of the repellent
      (P = 0.110).

PMID- 10348244
TI  - Relationships between several markers of extracellular matrix turn-over and
      ultrasonography in human Schistosomiasis mansoni.
AB  - We measured the concentrations of several serum and urinary fibrosis markers,
      which are metabolites of extracellular matrix, in schistosomiasis patients to
      investigate their relationship with the ultrasonographic scoring system and with
      parasitologic data. This study was conducted in patients with various stages of
      the disease evaluated by ultrasonography (intestinal disease with no organ
      involvement, with minor hepatosplenic involvement and with severe disease) and in
      endemic controls. The level of hyaluronan, which were increased in infected
      patients compared with controls (P < 0.01), was the only fibrosis marker that
      correlated with the ultrasonographic score (P = 0.003) and is thus a potential
      serum marker of schistosomiasis-associated morbidity. Urinary free pyridinoline
      levels were lower (P < 0.001) in infected patients with fibrosis (score > or = 1)
      than in nonfibrotic patients. A two-year follow-up of the patients treated with
      praziquantel showed that type I collagen and hyaluronan decreased during the
      first year post-treatment, whereas free pyridinolines peaked after 12 months and
      decreased thereafter.

PMID- 10348245
TI  - Reactivation of neurocysticercosis: case report.
AB  - A 37-year-old woman with a known history of longstanding neurocysticercosis
      presented with a three-day history of new onset headache. Several years prior to
      her current presentation, she had undergone cysticidal treatment and was assumed
      to be cured of active disease. Computed tomography and magnetic resonance imaging
      studies done three months prior to presentation showed multiple intracerebral
      calcified lesions consistent with resolved neurocysticercosis. Physical and
      laboratory findings were noncontributory. Imaging studies showed the same
      previously calcified lesions, but they were now surrounded by large amounts of
      edema. This case represents a unique report of reactivation of neurocysticercosis
      and raises interesting questions about the natural history of this infection.

PMID- 10348246
TI  - Role of eicosanoids in the pathogenesis of murine cerebral malaria.
AB  - Because microvascular damage is a common feature of cerebral malaria, we have
      examined the role eicosanoid metabolites (prostaglandins and leukotrienes) in
      experimental cerebral malaria. Eighty ICR mice were infected with Plasmodium
      berghei ANKA, with 40 uninfected mice as controls. Half of the infected mice were
      treated on days 4 and 5 with aspirin, a prostaglandin synthesis inhibitor.
      Infected mice started to die of cerebral malaria on day 6, and by day 17, all
      infected mice died. In contrast, all infected mice treated with aspirin died by
      day 12. Infected mice had increased phospholipase A2 mRNA expression in the
      spleen and cyclooxygenase 1 (COX1) and COX2 expression in the brain. At the peak
      of cerebral malaria, infected mice had higher serum leukotriene B4 levels than
      control mice, and aspirin-treated infected mice had higher serum leukotriene B4
      levels than untreated infected mice. These results suggest that prostaglandins
      are protective whereas leukotrienes are detrimental in cerebral malaria.

PMID- 10348247
TI  - Cellular responses to Plasmodium falciparum major surface antigens and their
      relationship to human activities associated with malaria transmission.
AB  - In Brazil, two types of activities have led to the worsening of malarial
      transmission in the Amazon region: prospecting/mining and agricultural
      settlements. In the present study, we analyze the cellular response of 52 of
      these individuals (14 gold-miners and 38 farmers) living within the same endemic
      area. Two Plasmodium falciparum major surface antigens (recombinant proteins)
      were used for cellular proliferative assays: circumsporozoite protein and
      merozoite surface protein-1. The frequency of these cellular responses were
      significantly higher among the miners (57-64%) than the farmers (10-20%) when
      either recombinant protein was used. Our data suggest that a higher exposure to
      malaria of the gold-miners contributed to their higher in vitro cellular response
      compared with the farmers. These findings point the way to further studies
      evaluating the influence of risk factors associated with the life styles of
      different social groups and the immune responses to these antigens.

PMID- 10348248
TI  - Increased frequency of Th2-type cytokine-producing T cells in microfilaremic
      loiasis.
AB  - The frequency of cytokine-producing peripheral blood mononuclear cells was
      assessed in 28 subjects with microfilaremic loiasis and in 14 amicrofilaremic
      individuals. In addition, a subgroup of seven microfilaremic individuals
      coinfected with Plasmodium malariae was evaluated. By using flow cytometry for
      the intracellular detection of cytokines, a more pronounced T helper (Th)2 cell
      type response with the expansion of interleukin (IL)-4, IL-10, and IL-13
      expressing CD4+ cells in the microfilaremic compared with the amicrofilaremic
      group was noted. Expression of IL-5 was equivalent in both groups as was the
      frequency of Th2-type cytokines expressing CD8+ cells and of Th1-type cytokines
      (interferon [IFN]-gamma, IL-2, IFN-gamma/IL-2) producing CD4+ and CD8+ cells. Th0
      type cytokine-expressing cells, represented by IL-4/IFN-gamma, IL-10/IFN-gamma,
      and IL-13/IFN-gamma, were equally distributed within groups. Coinfection of P.
      malariae did not significantly alter the cytokine expression compared with
      microfilaremic individuals without P. malariae infections. By identifying a large
      panel of cytokine-producing T cell subpopulations, a Th2-driven immune response
      in microfilaremic Loa loa patients was noted.

PMID- 10348249
TI  - A genus- and species-specific nested polymerase chain reaction malaria detection
      assay for epidemiologic studies.
AB  - A nested polymerase chain reaction (PCR) assay that uses Plasmodium genus
      specific primers for the initial PCR (nest 1) amplification and either genus- or
      species-specific primers for the nest 2 amplifications was tested on laboratory
      and field samples. With in vitro cultured Plasmodium falciparum-infected blood
      samples, it was capable of detecting six parasites/microl of blood using DNA
      prepared from 25-microl blood spots on filter paper. The assay was evaluated on
      fingerprick blood samples collected on filter paper from 129 individuals living
      in a malaria-endemic area in Malaysia. Malaria prevalence by genus-specific
      nested PCR was 35.6% (46 of 129) compared with 28.7% (37 of 129) by microscopy.
      The nested PCR detected seven more malaria samples than microscopy in the first
      round of microscopic examination, malaria in three microscopically negative
      samples, six double infections identified as single infections by microscopy and
      one triple infection identified as a double infection by microscopy. The nested
      PCR assay described is a sensitive technique for collecting accurate malaria
      epidemiologic data. When coupled with simple blood spot sampling, it is
      particularly useful for screening communities in remote regions of the world.

PMID- 10348250
TI  - Rapid serologic diagnosis of dengue virus infection using a commercial capture
      ELISA that distinguishes primary and secondary infections.
AB  - A commercial capture ELISA for specific IgM and IgG antibodies produced during
      dengue infection (PanBio Dengue Duo) showed excellent sensitivity (99%, n = 78)
      using sera collected at hospital discharge compared with established ELISA and
      hemagglutination inhibition (HAI) assays. Furthermore, the ELISA was able to
      diagnose 79% of the dengue cases using sera collected at hospital admission. The
      ELISA also showed high specificity (92%) in paired sera from patients without
      flavivirus infection (n = 26), although 45% of the patients with Japanese
      encephalitis (n = 20) showed elevation of IgG but not IgM. The IgG capture ELISA
      showed good correlation with the HAI assay (r = 0.83, P < 0.0001), and IgG levels
      could be used to distinguish between primary and secondary infection, with 100%
      of primary infections and 96% of secondary infections being correctly classified.
      This ELISA should prove useful in the clinical diagnosis of dengue infections.

PMID- 10348251
TI  - Population genetics and phylogenetic analysis of Colorado Borrelia burgdorferi.
AB  - Borrelia burgdorferi is transmitted in an enzootic cycle in Colorado between the
      tick Ixodes spinipalpis and the woodrat Neotoma mexicana. The genetic
      relationship of Colorado isolates to other B. burgdorferi isolates is unknown nor
      have relationships among various Colorado isolates been determined. Portions of
      the flagellin (fla), 66-kD protein, and outer surface protein A (ospA) genes were
      amplified from 71 Colorado isolates, screened for genetic variability using
      single strand conformation polymorphism analysis, and unique alleles were
      sequenced. Colorado isolates were most similar to tick isolates from California
      and New York isolate 25015. Genetic distances among Colorado ospA sequences were
      the same or higher than distances among other isolates whereas distances among
      fla sequences tended to be the same or lower. The index of association (I(A)) was
      calculated among all loci as a measure of clonality. The I(A) among Colorado
      isolates was similar to I(A) previously estimated among other United States
      isolates.

PMID- 10348252
TI  - Genetic variation among isolates of western equine encephalomyelitis virus from
      California.
AB  - The mechanism for long-term maintenance of western equine encephalomyelitis (WEE)
      virus in California was investigated by studying genetic variation in the E2
      portion of the genome of 55 strains of WEE virus isolated since 1938 from
      different locations in California. Four major lineages were evident: virus
      strains isolated from the Central Valley since 1993 and Los Angeles in 1991
      formed lineage A; southern California strains isolated since 1978 and isolates
      from the Central Valley from 1978 to 1987 formed lineage B; northern California
      isolates from 1968 to 1971 formed lineage C; and early isolates from 1938 to 1961
      formed a fourth lineage, D. The separation of strains from north and south of the
      Tehachapi and San Bernardino Mountains (i.e., the Central Valley and southern
      California, respectively) since 1991 indicates that there has been little recent
      movement of virus between the two regions and recent strains from these two
      locations appear to be evolving independently. However, within the Central Valley
      and within southern California, virus appears to circulate freely, perhaps by
      movement of birds or mosquito vectors. Although the current virus lineage in the
      Central Valley may have been introduced from an unknown source in 1991,
      introduction and establishment of new viral genotypes from outside California do
      not seem to occur regularly. It appears most likely that virus is maintained in
      separate geographic areas of California through local persistence in enzootic
      foci.

PMID- 10348253
TI  - Hepatocellular carcinoma in Egyptians with and without a history of hepatitis B
      virus infection: association with hepatitis C virus (HCV) infection but not with
      (HCV) RNA level.
AB  - The aim of this study was to analyze the association of hepatocellular carcinoma
      (HCC) with hepatitis C virus (HCV) in Egypt, using hepatitis B virus (HBV) and
      hepatitis E virus (HEV) as virus controls. In addition, the association of HCC
      with HCV RNA levels among persons seropositive for HCV was analyzed. We compared
      131 patients with proven HCC, 247 with bladder cancer, and 466 healthy hospital
      employees. Age, sex, and place of residence were recorded to study confounding
      factors. Among the healthy controls, 16% were seropositive for HCV, 21% for HBV,
      and 31% for HEV. When healthy controls were age-matched with HCC patients, the
      latter were significantly (P < 0.001) more often HCV seropositive (67%) than were
      the controls (30%). The seropositivity for HBV and HEV did not differ
      significantly in frequency between the two groups. The seropositivity for HCV was
      also significantly (P < 0.001) more often found in HCC patients (76%) than in BC
      patients (47%), with seroprevalences for HBV and HEV not differing significantly
      in these age-matched groups. In HBV-negative HCC and bladder cancer patients,
      seroprevalence for HCV was significantly (P = 0.002) higher in HCC patients (68%)
      than in bladder cancer patients (36%). This difference was even more pronounced
      (P < 0.001) in HBV-positive HCC and bladder cancer patients (78% versus 52%,
      respectively). Of HCV-seropositive individuals, 49% were HCV RNA positive by
      branched DNA assay, and of these, 96% were infected by HCV genotype 4. No
      correlation between HCV RNA load and seropositivity of HBV or age or disease
      state was found. Infection with HCV and HCV-HBV double infection, but not HBV or
      HEV infection alone, is strongly correlated with HCC in Egypt.

PMID- 10348254
TI  - Recent developments and emerging options: the role of amifostine as a broad
      spectrum cytoprotective agent.

PMID- 10348255
TI  - The preclinical basis for broad-spectrum selective cytoprotection of normal
      tissues from cytotoxic therapies by amifostine.
AB  - Administered before cytotoxic chemotherapy or radiation, the aminothiol,
      amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West
      Conshohocken, PA), provides broad-spectrum cytoprotection of various normal
      tissues without attenuating antitumor response. The basis for the selectivity of
      action resides in the anabolism of amifostine at the normal tissue site by
      membrane-bound alkaline phosphatase. Dephosphorylation to the free thiol, WR
      1065, is followed by rapid uptake into normal tissues. In contrast, uptake into
      tumor tissue is slow to negligible. Pretreatment with amifostine provides
      protection of normal tissues from the cytotoxic effects of alkylating agents,
      organoplatinums, anthracyclines, taxanes, and radiation. Additionally, the
      mutagenic and carcinogenic effects of these modalities are also attenuated.
      Preclinical studies show significant protection of marrow progenitor cells.
      Synergistic effects in marrow recovery are noted with the sequential use of
      amifostine and granulocyte colony-stimulating factor. Protection of kidneys and
      neural tissues from cisplatin toxicity has been shown, as well as protection of
      the heart, intestinal crypt cells, and pulmonary tissues from chemotherapy and
      radiation, and vasculoconnective and musculoconnective tissue in an irradiated
      field. Comparative in vitro and in vivo studies using murine and human tumor
      xenografts show no protection of antitumor effects of these same therapies
      despite the protection of normal organs. The unique preclinical profile of
      amifostine serves as the basis for the clinical development program for this new
      broad-spectrum cytoprotective agent.

PMID- 10348256
TI  - Chemopreventive doses of amifostine confer no cytoprotection to tumor nodules
      growing in the lungs of mice treated with cyclophosphamide.
AB  - In addition to the cytoprotective benefits of amifostine (Ethyol; Alza
      Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) to normal
      cells, it also prevents the induction of somatic mutations that can lead to
      therapy-induced second cancers. The mutagenic effects of cyclophosphamide, an
      agent that is known to be mutagenic to normal cells, were determined in mouse
      splenocytes using a mutational assay system. Cyclophosphamide 100 mg/kg increased
      mutant frequencies 10-fold. In contrast, amifostine 100 mg/kg, whether
      administered 30 minutes before or 2 hours after cyclophosphamide administration,
      resulted in eightfold lowered mutant frequencies. To address potential
      cytoprotective effects on tumors exposed to this dose, amifostine was
      administered to tumor-bearing mice either 30 minutes before or 2 hours after the
      administration of cyclophosphamide. Cyclophosphamide (range, 10 to 100 mg/kg) was
      administered intraperitoneally into mice 4 days following the injection of 3.5 x
      10(5) viable fibrosarcoma (FSa) cells. At this time, microcolonies of FSa tumors
      containing 50 to 200 cells were present in the lung. The number of FSa lung
      nodules formed at the end of 14 days in control animals was compared with that of
      animals treated with cyclophosphamide +/- amifostine. No cytoprotection of murine
      FSa tumors by amifostine was observed across the entire cyclophosphamide dose
      range tested, regardless of time of administration, demonstrating the utility of
      amifostine as a chemopreventive drug under conditions that do not allow
      cytoprotection for tumor cells.

PMID- 10348257
TI  - Amifostine modulation of bleomycin-induced lung injury in rodents.
AB  - Bleomycin is an effective anticancer agent whose treatment is limited by severe
      and potentially fatal pulmonary toxicity. This toxicity, characterized by
      alveolar inflammation and proliferative fibrosis, is mediated by active oxygen
      species and may result in disruption of the balance between type 2 pneumocyte
      apoptosis and fibroblast proliferation. The chemoprotectant activity of
      amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West
      Conshohocken, PA) is attributed, in part, to the scavenging of active oxygen
      species. Therefore, it was of interest to study the effects of amifostine on
      ameliorating the pulmonary toxicities associated with bleomycin in animals.
      Studies in hamsters and mice demonstrate that pretreatment with amifostine
      reduces the pulmonary toxicity induced by bleomycin administration. The results
      of these preclinical studies suggest that amifostine may be clinically beneficial
      in reducing the severe pulmonary toxicity associated with bleomycin.

PMID- 10348258
TI  - Pharmacokinetics of amifostine: effects of dose and method of administration.
AB  - Findings of pharmacokinetic studies of amifostine (Ethyol; Alza Pharmaceuticals,
      Palo Alto, CA/US Bioscience, West Conshohocken, PA) in animal models and in human
      cancer patients support the hypothesis that amifostine pharmacokinetics are
      nonlinear. The nonlinear pharmacokinetic behavior of amifostine suggests that
      administration of doses higher than 740 mg/m2 does not increase the amount of
      drug available due to urinary excretion of the excess parent drug and its
      metabolites. Although the intravenous formulation of amifostine is the only one
      currently used in the treatment of cancer patients, there is growing interest in
      the investigation of subcutaneous administration as a practical alternative. A
      pilot pharmacokinetic evaluation of subcutaneous administration of amifostine in
      12 healthy male volunteers compared the relative bioavailability of 500 mg of
      amifostine administered subcutaneously with that of 200 mg/m2 given
      intravenously.

PMID- 10348259
TI  - Protection by amifostine of cyclophosphamide-induced myelosuppression.
AB  - The dose and schedule of administration of chemotherapeutic agents are often
      dictated by their bone marrow toxicity. Cumulative bone marrow damage may be
      associated with chronic exposure to chemotherapeutic agents such as alkylating
      agents. Amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience,
      West Conshohocken, PA), a cytoprotective agent, protects bone marrow from this
      type of cumulative toxicity. Three well-controlled clinical trials have shown
      that amifostine can ameliorate cumulative bone marrow toxicity and the acute and
      chronic neutropenic and/or thrombocytopenic effects of cyclophosphamide. In a
      pivotal phase III study of cisplatin/cyclophosphamide with or without amifostine,
      amifostine treatment reduced course-by-course cumulative bone marrow damage when
      compared with the course-by-course cumulative myelosuppression experienced by
      those treated with cisplatin/cyclophosphamide alone. Despite this clinically
      significant cytoprotection, amifostine treatment did not adversely affect
      pathologically proven complete response, overall objective response rates, or
      survival duration associated with cisplatin/cyclophosphamide chemotherapy.

PMID- 10348260
TI  - Approaches to managing carboplatin-induced thrombocytopenia: focus on the role of
      amifostine.
AB  - Thrombocytopenia is a significant problem for patients receiving prolonged or
      aggressive chemotherapy for malignancy. For carboplatin, it is the predominant
      dose-limiting toxicity and it is cumulative in nature. A number of agents have
      been evaluated for efficacy in reducing the problem of thrombocytopenia. Some
      have proved valueless and have been discarded. Others (eg, recombinant
      thrombopoietin) are under current study, and one (interleukin-11 or oprelvekin)
      is now commercially available. In addition, the currently available
      cytoprotectant, amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US
      Bioscience, West Conshohocken, PA), has been shown to reduce the severity and
      duration of thrombocytopenia caused by carboplatin. Because of the short half
      life of amifostine relative to that of carboplatin, multiple doses of amifostine
      have been administered in conjunction with carboplatin. The optimal dosing
      regimen with amifostine and carboplatin needs to be further evaluated in clinical
      studies. Future trials will also expand these observations to carboplatin
      containing combination chemotherapy regimens and will further define the role of
      amifostine as a multilineage bone marrow protectant. The ability of amifostine to
      demonstrate multilineage bone marrow protection differentiates it from currently
      available growth factors and fulfills a medical need, including reducing the need
      for platelet transfusions and maintaining the desired chemotherapy dose
      intensity.

PMID- 10348261
TI  - Carboplatin and paclitaxel in non-small cell lung cancer: the role of amifostine.
AB  - Lung cancer remains the leading cause of cancer deaths in industrialized
      countries. Efforts toward the development of new cytotoxic drugs and more active
      combination regimens for non-small cell lung cancer (NSCLC) are ongoing.
      Nevertheless, specific targeting of malignant cells poses a major challenge;
      toxicities of normal tissues continue to be dose limiting. Cytoprotective agents,
      such as amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience,
      West Conshohocken, PA), that can shield normal tissues from cytotoxic effects are
      now the subject of intense clinical investigation. Amifostine has been shown to
      selectively protect normal tissues when used in combination with a large number
      of chemotherapeutic agents, including cisplatin, carboplatin, and paclitaxel. The
      addition of amifostine to paclitaxel or carboplatin has been shown to reduce the
      dose-limiting toxicities associated with each chemotherapeutic agent. However,
      now the combination regimen of carboplatin/paclitaxel is commonly used in NSCLC.
      To improve the tolerance of this regimen, a large, phase III, multicenter,
      randomized trial has been initiated that compares carboplatin/paclitaxel with or
      without amifostine in patients with locally advanced and metastatic NSCLC. The
      main objective is to evaluate the impact of amifostine on myelotoxicity and
      neurotoxicity. The addition of cytoprotective agents such as amifostine to other
      active NSCLC regimens may also reduce overall toxicity and improve the
      therapeutic index.

PMID- 10348262
TI  - Use of amifostine in hematologic malignancies, myelodysplastic syndrome, and
      acute leukemia.
AB  - The phosphorylated thiol amine, amifostine (Ethyol; Alza Pharmaceuticals, Palo
      Alto, CA/US Bioscience, West Conshohocken, PA), is a cytoprotective agent for
      cisplatin-based chemotherapy. Recent investigations have given rise to new
      potential applications of amifostine in hematologic malignancies. Amifostine
      appears to exert a sustained mitogenic effect in primitive hematopoietic
      progenitors that results in a significant increase in colony-forming capacity.
      Amifostine also retards cell loss and delays commitment to apoptosis initiated by
      cytokine deprivation, suggesting that amifostine has trophic effects similar to
      the hematopoietic cytokines. The abilities to prolong progenitor survival and to
      delay apoptosis under conditions of cellular stress make amifostine an attractive
      agent for investigation in bone marrow failure states. Amifostine promotes more
      effective hematopoiesis in patients with myelodysplastic syndrome, although
      additional investigation is needed to further define the optimal dose and
      schedule of administration. Furthermore, amifostine may selectively enhance the
      cytotoxicity of chemotherapeutic agents in leukemia progenitors. When the
      sensitivity of leukemic and normal progenitors to mafosfamide was evaluated with
      and without amifostine pretreatment, amifostine effectively protected normal
      myeloid and erythroid progenitors while increasing leukemic cell kill. Thus,
      amifostine represents a unique agent with promising potential for therapeutic
      application in hematologic malignancies. Further investigation is needed to
      define its role in clinical practice.

PMID- 10348263
TI  - Ex vivo manipulation of hematopoietic stem cells for transplantation: the
      potential role of amifostine.
AB  - High-dose chemotherapy with autologous stem cell transplantation is an
      increasingly used procedure in oncohematologic diseases and represents a
      promising strategy in selected patients with solid tumors. In autologous stem
      cell transplantation, the risk of reinfusion of clonogenic tumor cells is a
      remarkable biologic obstacle that can be at least partly overcome by ex vivo
      graft purging to reduce residual tumor. Mafosfamide and 4
      hydroxyperoxycyclophosphamide, active metabolites of cyclophosphamide, are the
      most widely used pharmacologic agents for ex vivo bone marrow purging. However,
      in addition to killing tumor cells, they are toxic to normal bone marrow as
      measured by reduced colony-forming unit granulocyte-macrophage (CFU-GM). Thus,
      the therapeutic index of these alkylating agents is narrow, and parameters for
      dose selection must include toxicity to normal bone marrow progenitor cells that
      can delay bone marrow engraftment and increase risk of infections, bleeding
      complications, hospitalization, and the need for a costly transplantation
      procedure. Amifostine (WR-2771, Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US
      Bioscience, West Conshohocken, PA) selectively protects human CFU-GM progenitor
      cells from the cytotoxicities of active metabolites of cyclophosphamide without
      altering its cytotoxic effect on malignant cells. This has been demonstrated both
      in preclinical and clinical studies in patients with breast cancer, malignant
      lymphomas, and acute leukemia. Amifostine use during the ex vivo procedure
      significantly shortened the time to bone marrow engraftment with decreased
      incidence of infections and need for red blood cell transfusions.

PMID- 10348264
TI  - Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin:
      laboratory and clinical aspects.
AB  - Cisplatin, a heavy metal complex, is one of the most active drugs used in the
      treatment of a variety of cancers. One of the major limitations to the
      maximization of its therapeutic potential is nephrotoxicity. Several preclinical
      studies have shown that pretreatment of mice or rats with amifostine (WR-2721,
      Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA)
      protected against nephrotoxicity induced by both single and repeated doses of
      cisplatin without affecting the antitumor effects of cisplatin. The preclinical
      evidence of amifostine's protective effects led to phase I-III clinical studies.
      A phase III trial was conducted in 242 women with stage III/IV ovarian cancer
      receiving six cycles of cyclophosphamide/cisplatin (CP) +/- amifostine.
      Consistent with the cumulative nature of cisplatin-induced nephrotoxicity, by
      cycles 5 and 6, a significantly greater proportion of patients in the control arm
      compared with patients in the amifostine-treated arm were not eligible to receive
      cisplatin as scheduled because their serum creatinine levels had failed to return
      to < or = 1.5 mg/dL. Amifostine pretreatment did not affect the antitumor effects
      of CP as assessed by response determined at second-look surgery or overall
      survival. Phase II trials support these findings. To date, amifostine is the only
      available therapy that can ameliorate the cumulative nephrotoxic effects of
      cisplatin without reducing antitumor efficacy.

PMID- 10348265
TI  - Neurologic protection by amifostine.
AB  - Amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West
      Conshohocken, PA) is a thiophosphate cytoprotectant agent with the potential to
      abrogate many chemotherapy-induced toxicities. In preclinical studies, amifostine
      protected against the cytotoxic effects of alkylating agents, platinum analogs,
      and radiation therapy in normal tissues, but preserved antineoplastic activity of
      these therapeutic modalities in tumor tissue. Most normal tissues were protected,
      including bone marrow, kidney, lung, and peripheral nerves. Recently, the
      protective effects of amifostine were confirmed by clinical studies, including a
      randomized trial demonstrating protection from cisplatin-induced
      myelosuppression, nephrotoxicity, and neurotoxicity. Many common chemotherapeutic
      agents, such as cisplatin, paclitaxel, and vinca alkaloids, cause dose-limiting
      neurotoxicity. Therefore, a neurologic protectant may help to reduce toxicity to
      patients, improve the tolerability of combination therapy with multiple
      neurotoxic agents, or allow investigators to intensify chemotherapy dose. This
      report reviews the potential role of amifostine as a neuroprotectant. Future
      clinical trials may expand the use of amifostine to abrogate neurotoxicity from
      multiple agents and combinations and compare amifostine with other
      neuroprotective agents.

PMID- 10348266
TI  - Radioprotective effects of amifostine.
AB  - Effective radiotherapy for patients with cancer should include maximal tumor cell
      killing with minimal injury to normal tissue. However, current radiation doses
      that can be delivered without causing severe damage to surrounding normal tissues
      are often insufficient to eradicate a tumor. Recently, a number of agents have
      been developed to protect normal tissue from the harmful effects of antitumor
      therapies. The aminothiol amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto,
      CA/US Bioscience, West Conshohocken, PA) has been the subject of extensive
      research as a prospective protector. While this drug has been approved for use to
      reduce toxicities associated with cisplatin, several studies also have
      demonstrated that amifostine protects normal tissues from both acute and late
      radiation damage without protecting the tumor. Consequently, higher radiation
      doses could be used with less than or equal risk to surrounding normal tissues.
      This report reviews the physicochemical basis of radiation therapy on biologic
      tissues and the mechanisms responsible for the cytoprotective effects of
      amifostine. The increasing body of biochemical, preclinical, and clinical data
      could justify the use of protectors such as amifostine with radiotherapy to
      provide improved therapeutic efficacy and quality of life for the patient.

PMID- 10348267
TI  - Amifostine and combined-modality therapeutic approaches.
AB  - Recent interest has focused on the use of amifostine (Ethyol; Alza
      Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) as a
      possible multiorgan combined-modality protector. Amifostine has been shown to
      selectively protect normal tissues from the cytotoxic and mutagenic effects of
      alkylating and platinum-based chemotherapy and ionizing radiation. There are a
      number of approaches to ameliorating therapy-related toxicities, including the
      use of individual agents that target specific toxicities. However, amifostine is
      unique in that it possesses a broad range of tissue-protective effects.
      Amifostine has been studied in clinical trials comprising patients with lung
      cancer, head and neck cancer, and cancer of the cervix. Results of these trials
      show that amifostine can be safely administered to patients receiving
      chemotherapy and radiation therapy. These trials also demonstrate that amifostine
      has the potential to be a broad-spectrum cytoprotectant of normal tissues from
      the toxicities of radiation, as well as certain forms of chemotherapy. The
      selective cytoprotective effects of amifostine allow for the use of higher doses
      of cytotoxic therapy. Theoretically, this could improve therapeutic outcome in
      patients with cancer.

PMID- 10348268
TI  - Pharmacoeconomics of amifostine in ovarian cancer.
AB  - Physicians are frequently pressured to make therapeutic decisions within a cost
      effective framework to demonstrate value to managed care. Because cancer is a
      chronic disease, health care costs are known to be expensive and physicians must
      use their resources as efficiently as possible. Historically, economic analyses
      in oncology have emphasized survival as their clinical end point. Today, both
      government groups and professional organizations are moving toward making quality
      of life the clinical end point in determining the economics of chemotherapy. This
      report evaluates the cost and efficacy of amifostine (Ethyol; Alza
      Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) use in the
      treatment of advanced ovarian cancer using two pharmacoeconomic analyses. A cost
      utility analysis performed in the United States indicated that inclusion of
      amifostine therapy had both a favorable clinical and cost-utility profile
      compared with other medical therapies. A second cost-benefit analysis, conducted
      in Canada, suggested that use of amifostine in patients with advanced ovarian
      cancer would be cost saving. Amifostine is a novel agent that protects against
      both chemotherapy- and radiotherapy-induced toxicities, such as nephrotoxicity,
      neutropenia, thrombocytopenia, peripheral neuropathy, mucositis, and xerostomia.
      These toxicities are disturbing to both patients and physicians alike. The
      results of these studies support the use of amifostine as a valuable resource
      both economically and clinically.

PMID- 10348269
TI  - Dosing considerations with amifostine: a review of the literature and clinical
      experience.
AB  - Numerous dosing regimens have been used in the clinical development of amifostine
      (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken,
      PA). Whereas the current recommended dose of amifostine is 910 mg/m2 administered
      intravenously as a 15-minute infusion 30 minutes before chemotherapy, other
      studies have demonstrated cytoprotection with lower doses, suggesting that the
      optimal biologic dose may indeed be lower. Amifostine doses that protect against
      the toxicities associated with daily fractionated radiotherapy are also lower,
      with a dose range of 200 to 340 mg/m2 per fraction commonly reported in the
      literature. The toxicities most commonly associated with amifostine, namely,
      hypotension and nausea and vomiting, are dose related. They can be reduced using
      adequate prophylactic measures and can be effectively managed if they occur.
      Hypocalcemia and allergic reactions also can be lessened or averted with
      precautionary measures. Thus, although amifostine is generally well tolerated at
      the current recommended doses, clinical studies of variations in the approved
      dosing regimen would be useful in further defining the optimal amifostine dose
      for chemoprotection, for radioprotection, and for inducing hematopoiesis in
      patients with refractory myelodysplastic syndromes.

PMID- 10348270
TI  - Future directions in non-small cell lung cancer.
AB  - Although chemotherapeutic regimens remain limited in activity against non-small
      cell lung cancer, some novel cytotoxic agents and radiotherapy techniques, alone
      or in combination, have shown promising advances. Numerous clinical trials have
      demonstrated increases in overall response rates, and some agents have shown
      additive or synergistic effects against tumor tissue. The cytoprotectant
      amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West
      Conshohocken, PA) is being assessed for its protection of normal tissue against
      the toxic effects of chemotherapy and radiotherapy and for its potential role in
      enhancing the efficacy of these modalities. Protection from dose-limiting
      toxicities may allow dose escalation and improve the therapeutic index. Current
      and future investigations of novel agents and modalities, with or without
      cytoprotectants, should lead to better prognosis and prolonged survival rates.

PMID- 10348271
TI  - Future directions in gynecologic cancer.
AB  - Cisplatin is one of the most commonly used chemotherapeutic agents to treat
      gynecologic cancers. However, many patients treated with platinum therapy
      experience significant toxicities, including neurotoxicity, ototoxicity, and/or
      nephrotoxicity. Clinical trials have documented the role of amifostine as a
      cytoprotectant against cisplatin-induced toxicities in patients with advanced
      ovarian cancer. In these trials, the incidence and severity of many dose-limiting
      toxicities was reduced significantly by the concomitant administration of
      amifostine. The management of advanced ovarian, cervical, and endometrial cancers
      provides many opportunities for future applications of amifostine. Several
      studies that are being initiated in the United States involve maintaining
      platinum dose intensity, reducing toxicities, and developing chemotherapeutic
      combinations that would otherwise have to be avoided without the use of a
      cytoprotective agent such as amifostine.

PMID- 10348272
TI  - Future development of amifostine as a radioprotectant.
AB  - Animal data and clinical trials document the efficacy of amifostine (WR-2721,
      Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA)
      in decreasing the effects of radiation on normal tissues without decreasing the
      cytotoxic effects on malignant tumors. The selection of the optimal dose may
      depend on the intensity of the regimen to be administered as well as on the
      normal tissues to be protected. Also of important consideration is the question
      of how to sequence amifostine infusion. The optimal amifostine schedule during
      the course of the combined-modality treatment may require shortening the duration
      of chemotherapy infusion or giving amifostine in two split doses (before and
      after chemotherapy). Wide application of amifostine in once-daily/multiple-daily
      fractionated radiotherapy regimens may be facilitated by the availability of
      other, nonintravenous delivery routes, which are being explored. Although efforts
      are currently directed at amifostine-mediated modification of acute or late
      mucosal reactions associated with radiation therapy, there are many other
      radiation-induced toxicities. Further randomized studies are necessary to
      document the effects of amifostine on nonmucosal damage. Amifostine has the
      potential to protect a broad range of normal tissues from the toxicities of
      radiation and from certain forms of chemotherapy.

PMID- 10348273
TI  - Predicting and overcoming the radioresistance of individual tumors.

PMID- 10348274
TI  - Observation versus early stereotactic radiotherapy of acoustic neuroma: what are
      you waiting for?

PMID- 10348275
TI  - A comprehensive review of prostate cancer brachytherapy: defining an optimal
      technique.
AB  - PURPOSE: A comprehensive review of prostate cancer brachytherapy literature was
      performed to determine if an optimal method of implantation could be identified,
      and to compare and contrast techniques currently in use. METHODS AND MATERIALS: A
      MEDLINE search was conducted to obtain all articles in the English language on
      prostate cancer brachytherapy from 1985 through 1998. Articles were reviewed and
      grouped to determine the primary technique of implantation, the method or
      philosophy of source placement and/or dose specification, the technique to
      evaluate implant quality, overall treatment results (based upon pretreatment
      prostate specific antigen, (PSA), and biochemical control) and clinical,
      pathological or biochemical outcome based upon implant quality. RESULTS: A total
      of 178 articles were identified in the MEDLINE database. Of these, 53 studies
      discussed evaluable techniques of implantation and were used for this analysis.
      Of these studies, 52% used preoperative ultrasound to determine the target volume
      to be implanted, 16% used preoperative computerized tomography (CT) scans, and
      18% placed seeds with an open surgical technique. An additional 11% of studies
      placed seeds or needles under ultrasound guidance using interactive real-time
      dosimetry. The number and distribution of radioactive sources to be implanted or
      the method used to prescribe dose was determined using nomograms in 27% of
      studies, a least squares optimization technique in 11%, or not stated in 35%. In
      the remaining 26%, sources were described as either uniformly, differentially, or
      peripherally placed in the gland. To evaluate implant quality, 28% of studies
      calculated some type of dose-volume histogram, 21% calculated the matched
      peripheral dose, 19% the minimum peripheral dose, 14% used some type of CT-based
      qualitative review and, in 18% of studies, no implant quality evaluation was
      mentioned. Six studies correlated outcome with implant dose. One study showed an
      association of implant dose with the achievement of a PSA nadir < or = 0.5. Two
      studies showed an improvement in biochemical control with a D90 (dose to 90% of
      the prostate volume) of 120 to 140 Gy or higher, and 2 additional studies found
      an association of clinical outcome with implant dose. One study correlated
      implant quality with biopsy results. Of the articles, 33 discussed evaluable
      treatment results, but only 16 reported findings based upon pretreatment PSA and
      biochemical control. Three- to 5-year biochemical control rates ranged from 48%
      to 100% for pretreatment PSAs < or = 4, 55% to 90% for PSAs between 4 and 10, 30%
      to 89% for PSAs > 10, < or = 20 and < 10% to 100% for PSAs > 20. Due to
      substantial differences in patient selection criteria (e.g., median Gleason
      score, clinical stage, pretreatment PSA), number of patients treated, median
      follow-up, definitions of biochemical control, and time points for analysis, no
      single technique consistently produced superior results. CONCLUSIONS: Our
      comprehensive review of prostate cancer brachytherapy literature failed to
      identify an optimal treatment approach when studies were analyzed for treatment
      outcome based upon pretreatment PSA and biochemical control. Although several
      well-designed studies showed an improvement in outcome with total dose or implant
      quality, the numerous techniques for implantation and the varied and inconsistent
      methods to specify dose or evaluate implant quality suggest that standardized
      protocols should be developed to objectively evaluate this treatment approach.
      These protocols have recently been suggested and, when implemented, should
      significantly improve the reporting of treatment data and, ultimately, the
      efficacy of prostate brachytherapy.

PMID- 10348276
TI  - Randomized trials on radioactive iodine ablation of thyroid remnants for thyroid
      carcinoma--a critique.
AB  - PURPOSE: The dose of radioactive iodine ((131)I) required to ablate thyroid
      remnants following surgery for differentiated thyroid carcinoma is controversial.
      Typical administered activities range from less than 30 mCi up to 100 mCi,
      reflecting local practice and regulations governing allowable outpatient doses.
      This review examines the available randomized trials designed to assess the
      optimal ablative dose in this setting. METHODS AND MATERIALS: The authors
      identified three such trials published in 1987, 1991, and 1996, and critically
      reviewed them from a scientific and statistical point of view. RESULTS: Two of
      these studies were small and lacked adequate statistical power to answer the
      question, and the third was very poorly conducted. CONCLUSION: In our opinion,
      the appropriate dose of (131)I for ablation of thyroid remnants remains
      undetermined.

PMID- 10348277
TI  - Psychoeducational group increases vaginal dilation for younger women and reduces
      sexual fears for women of all ages with gynecological carcinoma treated with
      radiotherapy.
AB  - PURPOSE: The association between radiotherapy for gynecological carcinoma and
      sexual dysfunction is well established. Regular vaginal dilation is widely
      recommended to these women as a way for them to maintain vaginal health and good
      sexual functioning. However, the compliance rate with this recommendation is low.
      The purpose of this study was to test the effectiveness of a group
      psychoeducational program based on the "information-motivation-behavioral skills"
      model of behavior change in increasing the rate of compliance. METHODS AND
      MATERIALS: Thirty-two women with Stage I or II cervical or endometrial carcinoma
      who were being treated with radiotherapy were randomized and received either the
      experimental group program or the control intervention that consisted of written
      information and brief counseling. Outcome measures included global sexual health,
      knowledge about sexuality and cancer, fears about sexuality after cancer, and
      vaginal dilation compliance. RESULTS: Younger women attending the experimental
      program (44.4%) were significantly more likely to follow recommendations for
      vaginal dilation than those who received the control intervention (5.6%). Women,
      regardless of age, who received the experimental intervention reported less fear
      about sex after cancer treatment. The older women who received the experimental
      intervention gained more sexual knowledge. There was no evidence that the
      experimental intervention improved global sexual health. CONCLUSIONS: This is the
      first controlled study to provide evidence of an intervention's effectiveness 1.
      in increasing women's vaginal dilation following radiotherapy for gynecological
      carcinoma and 2. in reducing their fears about sex after cancer. Most women,
      particularly younger women, are unlikely to follow the recommendation to dilate
      unless they are given assistance in overcoming their fears and taught behavioral
      skills.

PMID- 10348278
TI  - A high ratio of apoptosis to proliferation correlates with improved survival
      after radiotherapy for cervical adenocarcinoma.
AB  - PURPOSE: A retrospective study was made of the role of apoptosis in determining
      radiotherapy outcome in 39 adenocarcinoma of the cervix. A comparison was also
      made of the detection of apoptosis by morphology and the TdT dUtp nick end
      labeling (TUNEL) assay. METHODS AND MATERIALS: The level of apoptosis was
      assessed in paraffin-embedded sections by cell morphology, the TUNEL assay, and a
      combination of the two. A total of 2,000 cells were counted per section, to
      obtain apoptotic (AI) and mitotic (MI) indices. RESULTS: Patients with a high AI
      had a higher survival rate than those with a low AI, however, the difference was
      not significant. Using a ratio of apoptosis to proliferation indices, patients
      with an AI:MI > median had significantly better survival than those with AI:MI <
      median. This was true where the AI was quantified by morphology alone (p = 0.030)
      or in combination with the TUNEL assay (p = 0.008). Where the AI was quantified
      by a combination of morphology and TUNEL, the 5-year survival rates for women
      with AI:MI greater or less than the median were 81% and 25%, respectively.
      CONCLUSION: A high ratio of AI:MI in adenocarcinoma of the cervix indicates a
      good prognosis. A combination of the TUNEL assay and morphology provided the best
      discrimination between outcome groups.

PMID- 10348279
TI  - Irradiation with or without misonidazole for patients with stages IIIB and IVA
      carcinoma of the cervix: final results of RTOG 80-05. Radiation Therapy Oncology
      Group.
AB  - PURPOSE: The purpose of this study was to evaluate tumor response, progression
      free survival, local tumor control, patterns of relapse, and toxicity in patients
      with Stages IIIb and IVa squamous cell carcinoma of the uterine cervix treated
      with irradiation or irradiation and misonidazole. This is a report of the final
      results of the study. METHODS: This study was a prospective randomized Phase III
      trial performed by the Radiation Therapy Oncology Group (RTOG). Between August
      1980 and November 1984, 120 patients with Stages IIIb and IVa squamous cell
      carcinoma of the cervix were randomized to receive either standard irradiation or
      standard irradiation and misonidazole. Irradiation consisted of 46 Gy to the
      pelvis plus a 10 Gy parametrial boost followed by intracavitary brachytherapy or
      external irradiation boost to the primary tumor. Misonidazole was administered at
      400 mg/m2 daily, 2-4 h before irradiation. Patients in the 2 treatment groups
      were evenly distributed by stage, Karnofsky Performance Status, and positive para
      aortic lymph nodes. RESULTS: Sixty-one patients were treated with irradiation
      alone, and 59 patients received irradiation and misonidazole. Complete response
      in the pelvis occurred in 44 (75%) of those treated with irradiation and in 38
      (64%) of those treated with irradiation and misonidazole. The progression-free
      survivals were 22% at 5 years for the control group, and 29% at 5 years for the
      misonidazole group. At the time of last follow-up, 18 patients in the control arm
      were free of disease, and in the experimental arm, 19 were free of disease. The
      patterns of failure for those treated with irradiation alone were local-only in 9
      patients, distant-only in 8 patients, and local and distant in 11 patients. The
      patterns of failure for those receiving irradiation and misonidazole were local
      only in 3 patients, distant-only in 8 patients, and local and distant in 8
      patients. The maximum toxicity experienced per patient was grade 3 in 18%, grade
      4 in 8%, and no grade 5 toxicity for those treated with irradiation alone
      compared to 8%, 2%, and 2%, respectively, for the experimental arm. CONCLUSION:
      There were no statistically significant differences in pelvic response, disease
      free survivals, patterns of failure, or toxicity for the irradiation alone group
      or for the irradiation and misonidazole group as administered in this study for
      patients with Stages IIIb and IVa squamous cell carcinoma of the uterine cervix.

PMID- 10348280
TI  - Accelerated hyperfractionated radiotherapy for locally advanced cervix cancer.
AB  - PURPOSE: A phase II trial was designed to evaluate the toxicity and outcome of
      patients with locally advanced cervix cancer treated with accelerated
      hyperfractionated radiotherapy (AHFX). METHODS AND MATERIALS: In this prospective
      trial, AHFX doses of 1.25 Gy were administered twice daily at least 6 hours apart
      to a total pelvic dose of 57.5 Gy. A booster dose was then administered via
      either low-dose rate brachytherapy or external beam therapy to a smaller volume.
      All patients were accrued and treated at Peter MacCallum Cancer Institute (PMCI)
      between 1986 until April 1991. RESULTS: Sixty-one eligible patients were enrolled
      in this protocol; 2 (3.2%) had Stage IIB; 42 (68.9%) had Stage III; 8 (13.1%) had
      Stage IV and 9 (14.8%) had recurrent cervical cancer. Fifty-two patients (85%)
      completed the planned external beam without a treatment break. Thirty patients
      had acute toxicity that required regular medication. One patient died of acute
      treatment related toxicity. Fifty-five patients received booster therapy: 45 with
      intrauterine brachytherapy, 6 with interstitial brachtherapy, and 4 with external
      beam. The median follow-up of surviving patients was 6 years. Overall 5-year
      survival is 27% and 5-year relapse free survival is 36%. Nineteen patients died
      with pelvic disease and the actuarial local control rate was 66%. There were 8
      severe late complications observed in 7 patients. Seven required surgical
      intervention (an actuarial rate of 27%). Five patients also required total hip
      replacement. CONCLUSIONS: The local control rate was favorable compared with
      other series that have used standard fractionation, although overall survival
      remained similar. The severe late complication rate was high for this protocol
      and higher than similar protocols reported in the literature.

PMID- 10348281
TI  - Evaluating the effect of rectal distension and rectal movement on prostate gland
      position using cine MRI.
AB  - PURPOSE: To evaluate the dynamic interrelationship between rectal distension and
      rectal movements, and to determine the effect of rectal movement on the position
      of the prostatic gland using cine magnetic resonance imaging (MRI). METHODS AND
      MATERIALS: Fifty-five patients with biopsy-proven or suspected prostate cancer
      were examined in the axial plane using repeated spoiled gradient-echo sequences
      every 10 seconds for 7 minutes. Twenty-four patients received bowel relaxants
      before imaging. Images were analyzed for the degree of rectal distension, for the
      incidence, magnitude, and number of rectal and prostate movements. RESULTS:
      Rectal movements were seen in 28 (51%) patients overall, in 10 (42%) of those
      receiving bowel relaxants and in 18 (58%) not receiving bowel relaxants. The
      incidence of rectal movements correlated with the degree of rectal distension (p
      = 0.0005), but the magnitude of rectal movements did not correlate with the
      degree of rectal distension. Eighty-six rectal movements resulting in 33 anterior
      posterior (AP) prostate movements were seen. The magnitude of rectal movements
      correlated well with degree of prostate movements (p < 0.001). Prostate movements
      in the AP direction were seen in 16 (29%) patients, and in 9 (16%) patients the
      movement was greater than 5 mm. The median prostate AP displacement was anterior
      by 4.2 (-5 to +14 mm). CONCLUSIONS: Cine MRI is able to demonstrate near real
      time rectal and associated prostate movements. Rectal movements are related to
      rectal distension and result in significant displacements of the prostate gland
      over a time period similar to that used for daily fractionated radiotherapy
      treatments. Delivery of radiotherapy needs to take into account these organ
      movements.

PMID- 10348282
TI  - The effects of sequential versus concurrent chemotherapy and radiotherapy on
      survival and toxicity in patients with newly diagnosed high-grade astrocytoma.
AB  - PURPOSE: To determine the effects of sequential versus concurrent administration
      of cranial radiotherapy and cisplatin/carmustine (BCNU) chemotherapy on survival
      and toxicity in newly diagnosed high-grade astrocytomas. METHODS AND MATERIALS:
      From 1988 to 1996, 101 patients were treated on 2 therapeutic protocols for
      malignant glioma that used the identical chemotherapy regimen but differed in the
      timing of cranial radiotherapy. The eligibility criteria for the 2 protocols were
      identical. In the first protocol (1988-1991, 52 patients), cisplatin 120 mg/BCNU
      120 mg i.v. over 72 h, was given for 3 monthly cycles prior to cranial
      radiotherapy. After a response rate of 42%, with a median survival of 13 months
      was achieved with this sequential regimen, a successor protocol (1992-1996, 49
      patients) was developed in which cranial radiotherapy began concurrently with the
      start of the identical chemotherapy regimen. Chemotherapy was delayed but not
      discontinued if prolonged grade III/IV hematologic toxicity was experienced, but
      protocol therapy was discontinued if disease progression or thromboembolic events
      occurred. Survival outcome and hematologic toxicity were compared for the
      patients treated on these protocols. RESULTS: Seventy-seven percent of
      sequentially-treated patients and 68% of concurrently-treated patients completed
      all planned therapy. Kaplan-Meier survival was similar to concurrent or
      sequential administration of chemotherapy and radiotherapy (median 12.8 months
      vs. 13.8 months, respectively). Hematologic toxicity was significantly less in
      sequentially- versus concurrently-treated patients, with median nadir per cycle
      (2.9 vs. 1.8 x 10(3)/mm3) (p < 0.001), and incidence of grade 3/4 leukopenia 40%
      versus 77% (p = 0.002). There was also an increase in platelet transfusion
      requirements in concurrently-treated patients, but no significant worsening of
      anemia. We postulate that the worsened leukopenia results from the effects of
      concurrent radiotherapy on circulating stem cells. CONCLUSION: Concurrent
      radiotherapy with this regimen of cisplatin and BCNU chemotherapy did not improve
      survival, but did increase hematologic toxicity. Therefore, we do not recommend
      further testing of the concurrent regimen, whereas the sequential regimen is
      currently under evaluation in a Phase III trial of the Eastern Cooperative
      Oncology Group and the Southwest Oncology Group. In addition, these studies
      demonstrate that relatively small radiotherapy fields can deliver a dose to
      circulating stem cells sufficient to worsen the hematologic toxicity of
      concurrent myelosuppressive chemotherapy, a phenomena which should be considered
      in the design of combined modality protocols for other body sites.

PMID- 10348283
TI  - Comparison between observation policy and fractionated stereotactic radiotherapy
      (SRT) as an initial management for vestibular schwannoma.
AB  - PURPOSE: To compare the use of an observation policy with that of stereotactic
      radiotherapy (SRT) for treatment of vestibular schwannoma. METHODS AND MATERIALS:
      The study group consisted of 27 patients who underwent observation as an initial
      treatment (observation group) and 50 who received SRT (SRT group). The mean
      follow-up period was 35 months and 31 months, respectively. Stereotactic
      radiotherapy consisted of small-field fractionated radiotherapy (36-44 Gy in 20
      22 fractions over 6 weeks) with or without a subsequent 4-Gy single irradiation
      boost. RESULTS: Actuarial tumor control rate of the SRT group was significantly
      better than that of the observation group (p < 0.0001). The mean growth was 3.87
      mm/year in the observation group and -0.75 mm/year in the SRT group (p < 0.0001).
      Eleven patients (41 %) in the observation group and 1 (2 %) in the SRT group
      received salvage therapy (p < 0.001). There was no difference in the actuarial
      Gardner and Robertson's class preservation curves for 5 years after the initial
      presentation. CONCLUSION: Stereotactic radiotherapy using a fractionated schedule
      provides a better tumor control rate and a similar rate of deterioration for
      hearing levels compared to an observation policy. Initial SRT may be a reasonable
      alternative to a wait-and-see policy.

PMID- 10348284
TI  - The optimal dose of radiation in Hodgkin's disease: an analysis of clinical and
      treatment factors affecting in-field disease control.
AB  - PURPOSE: The purpose of this study is to analyze the effect of radiation dose, as
      well as other clinical and therapeutic factors, on in-field disease control.
      PATIENTS AND MATERIALS: The study population comprised 232 patients with Stage I
      and II Hodgkin's disease (HD) treated with curative intent at the University of
      Florida with radiotherapy (RT) alone (169 patients) or chemotherapy and
      radiotherapy (CMT) (63 patients). Sites of involvement and radiation doses were
      prospectively recorded and correlated with sites of disease recurrence. RESULTS:
      Freedom from relapse and absolute survival rates at 10 years were as follows: 76%
      and 77%, entire group; 76% and 80%, RT group; 79% and 70%, CMT group; 85% and
      78%, Stage I; and 71% and 77%, Stage II. Treatment failure occurred in 50
      patients (22%) including in-field failure in 22 patients (9%). In-field failure
      was rare in electively treated sites. Multivariate analysis of clinical factors
      (tumor size, number of sites involved, B-symptoms, gender, histology, age, and
      site of involvement) and treatment factors (use of chemotherapy, number of cycles
      of chemotherapy, radiation dose, radiation treatment volume, and radiation
      treatment time) showed only tumor size (p = 0.0001) to be significantly
      correlated with in-field disease control. In RT patients, the in-field failure
      rate according to tumor size was as follows: 0% for < or = 3 cm; 4% for > 3 cm
      and < or = 6 cm; 23% for > 6 cm and < or = 9 cm; and 36% for > 9 cm. In CMT
      patients, the in-field failure rate was as follows: 0% for < or = 3 cm; 0% for >
      3 and < or = 6 cm; 5% for > 6 cm and < or = 9 cm; and 26% for > 9 cm. In-field
      recurrence was not a predominant pattern of failure in RT patients with small
      tumors (< or = 6 cm); thus, the difference in in-field control in tumors < or = 6
      cm between doses < or = 35 Gy (6%) and doses > or = 36 Gy (0%) was not
      statistically significant. In larger tumors (> 6 cm), in-field recurrence was a
      predominant pattern of failure; the in-field failure rate in RT patients with
      tumors > 6 cm of 30% for doses < or = 35 Gy was not significantly different from
      25% for doses > 35 Gy. In moderately bulky tumors (> 6 cm and < or = 9 cm), the
      addition of chemotherapy did appear to increase in-field disease control; the in
      field failure rate was 23% with RT and 5% with CMT (p = 0.07). CONCLUSION: Our
      data do not demonstrate statistically significant evidence of increasing tumor
      control in HD with doses > 30 Gy. The data do show that increasing tumor size is
      associated with increased rates of in-field failure, and the addition of
      chemotherapy may improve in-field disease control in tumors > 6 cm. In-field
      recurrence in large tumors remains a predominant pattern of failure, however, and
      the role of radiation doses higher than 30-35 Gy in this high-risk subset
      warrants further study.

PMID- 10348285
TI  - The impact of radiotherapy dose and other treatment-related and clinical factors
      on in-field control in stage I and II non-Hodgkin's lymphoma.
AB  - PURPOSE/OBJECTIVE: To assess local (in-field) disease control, identify potential
      prognostic factors, and elucidate the optimal radiotherapy dose in various
      clinical settings of Stage I and II non-Hodgkin's lymphoma (non-CNS). MATERIALS &
      METHODS: A total of 285 consecutive patients with Stage I and II non-Hodgkin's
      lymphoma were treated with curative intent, including 159 with radiotherapy (RT)
      alone and 126 with combined-modality therapy (CMT). Of these, 72 patients had low
      grade lymphomas (LGL), 92 had intermediate or high-grade lymphomas (I/HGL), and
      21 had unclassified lymphomas. Clinical and treatment variables with potential
      prognostic significance for in-field disease control, freedom from relapse (FFR),
      and absolute survival (AS) were evaluated by univariate and multivariate
      analyses. RESULTS: The 5-, 10-, and 20-year actuarial AS rates were 73%, 46%, and
      33% for patients with LGL and 64%, 44%, and 18% for patients with I/HGL,
      respectively. The 5-, 10-, and 20-year actuarial FFR rates were 62%, 59%, and 49%
      for patients with LGL and 66%, 57%, and 57% for patients with I/HGL,
      respectively. Significant prognostic factors identified by the multivariate
      analysis were age, tumor size, and histology for AS; tumor size and treatment for
      FFR; and only tumor size for in-field disease control. There were 95 total
      failures, with only 12 occurring infield. Most failures (65%) were in contiguous
      unirradiated sites. All 4 in-field failures in patients with LGL occurred after
      RT doses < 30 Gy, although none occurred in 10 patients with small-volume LGL of
      the orbit treated with doses < 30 Gy. The 8 in-field failures in patients with
      I/HGL were distributed evenly throughout the RT dose range; 5 occurred in
      patients treated with CMT, all with tumors > 6 cm, and 4 with less than a
      complete response (CR) to chemotherapy. CONCLUSION: Our analysis suggests that
      the overwhelming problem in the treatment of non-Hodgkin's lymphoma is not in
      field failure but, rather, failure in contiguous unirradiated sites. A dose of 20
      25 Gy may be sufficient for small-volume LGL of the orbit. A dose of 30 Gy is
      sufficient for LGL in general, as well as for patients with nonbulky (< or = 6
      cm) I/HGL treated with CMT who have a CR. However, patients with I/HGL treated
      with CMT for tumors > 6 cm and/or without a CR may benefit from doses > or = 40
      Gy.

PMID- 10348286
TI  - Radiation therapy for consolidation of metastatic or recurrent sarcomas in
      children treated with intensive chemotherapy and stem cell rescue. A feasibility
      study.
AB  - PURPOSE: To assess the role of consolidative radiation therapy (CRT) in
      conjunction with myeloablative therapy with or without total body irradiation
      (TBI) in children and young adults with metastatic or recurrent sarcoma. METHODS
      AND MATERIALS: Twenty-one pediatric sarcoma patients with metastatic (10) or
      recurrent (11) disease were entered on a prospective feasibility study of
      intensive myeloablative therapy with or without TBI. Median patient age was 17.8
      years (range, 9.4-24.7 years). Primary histologies included Ewing's (12), PNET
      (3), and other soft tissue sarcomas (6). Twenty patients received induction
      chemotherapy. Myeloablative therapy consisted of TBI in 11 patients with either
      high dose melphalan/etoposide (9) or high dose cytoxan/thiotepa (2). TBI
      consisted of 12 Gy in 2 Gy fractions delivered twice daily over 3 days. Ten
      patients received high dose chemotherapy alone, either with
      thiotepa/carboplatinum/etoposide (8) or cytoxan/carboplatinum (2). Myeloablative
      therapy was followed by autologous stem cell rescue (ASCR) 24 to 48 hours after
      completing chemotherapy. Fourteen patients (67%) received CRT either prior to (5)
      or following (9) myeloablative therapy. Median CRT dose was 37.2 Gy (range, 20
      60). Fifty-one disease sites were present prior to myeloablative therapy. Twelve
      (24%) were bulky (> 8 cm) and 18 (35%) underwent surgical debulking. The median
      follow-up of surviving patients was 15 months (range, 8-20) with 25% of patients
      having been followed for more than 20 months. RESULTS: The 3-year actuarial
      disease-free (DFS) and overall survival (OS) rates for the entire group were 36%
      and 27%, respectively. Following myeloablative treatment, responses were: 11
      complete, 6 partial, 1 stable, and 3 progressive disease. Sixteen patients (71%)
      have relapsed. The most common site of relapse was the lung (13). Of the 51
      disease sites present prior to myeloablative therapy, 36 sites (71%) were
      amenable to CRT. Nonamenable sites were: multiple lung metastases (13) and bone
      marrow (2). Twenty-six amenable sites (51%) received CRT either prior to (14) or
      following (12) ASCR. Amenable sites treated with CRT had a better 3-year
      actuarial local control (80 vs 37%) (p = 0.0065) than amenable sites not treated
      with CRT. Factors associated with improved disease-free survival (DFS) in
      univariate analysis were induction chemotherapy response (p = 0.002) and extent
      of surgical resection (p = 0.045). There was a trend toward improved DFS on
      univariate analysis with the use of TBI as part of myeloablative therapy (p =
      0.07). The one factor associated with improved OS on univariate analysis was
      induction chemotherapy response (p = 0.007). Multivariate analysis revealed that
      induction chemotherapy response is the only factor that remains significant for
      DFS (p = 0.032) as well as for OS (p = 0.017). Patients with complete response to
      induction therapy had 40% probability of survival versus all other patients who
      had 10% survival (p = 0.05). CONCLUSION: Consolidative radiotherapy is feasible
      in primary metastatic or recurrent pediatric sarcoma patients treated with
      myeloablative therapy with or without TBI. CRT to sites amenable to irradiation
      provided an improved 3-year actuarial local control than that seen in sites
      amenable to CRT that did not undergo radiotherapy. There was a trend for improved
      DFS with the use of TBI. Improved DFS and OS can be predicted by response to
      induction therapy. This intensive regimen may improve the cure rate of advanced
      pediatric sarcomas in select patients.

PMID- 10348287
TI  - Significance and management of computed tomography detected pulmonary nodules: a
      report from the National Wilms Tumor Study Group.
AB  - PURPOSE: To define the optimal treatment for children with Wilms tumor who have
      pulmonary nodules identified on chest computed tomography (CT) scan, but have a
      negative chest radiograph, we evaluated the outcome of all such patients
      randomized or followed on National Wilms Tumor Study (NWTS)-3 and -4. PATIENTS
      AND METHODS: We estimated the event-free and overall survival percentages of 53
      patients with favorable histology tumors and pulmonary densities identified only
      by CT scan (CT-only) who were treated as Stage IV with intensive doxorubicin
      containing chemotherapy and whole-lung irradiation, and compared these to the
      event-free and overall survival percentages of 37 CT-only patients who were
      treated less aggressively based on the extent of locoregional disease with 2 or 3
      drugs, and without whole-lung irradiation. RESULTS: The 4-year event-free and
      overall survival percentages of the 53 patients with CT-only nodules and
      favorable histology Wilms tumor who were treated as Stage IV were 89% and 91%,
      respectively. The 4-year event-free and overall survival percentages for the 37
      patients with CT-only nodules and favorable histology who were treated according
      to the extent of locoregional disease were 80% and 85%, respectively. The
      differences observed between the 2 groups were not statistically significant.
      Among the patients who received whole-lung irradiation, there were fewer
      pulmonary relapses, but more deaths attributable to lung toxicity. CONCLUSIONS:
      The current data raise the possibility that children with Wilms tumor and CT-only
      pulmonary nodules who receive whole lung irradiation have fewer pulmonary
      relapses, but a greater number of deaths due to treatment toxicity. The role of
      whole lung irradiation in the treatment of this group of patients cannot be
      definitively determined based on the present data. Prolonged follow-up of this
      group of patients is necessary to accurately estimate the frequency of late,
      treatment-related mortality.

PMID- 10348288
TI  - Anesthesia for pediatric external beam radiation therapy.
AB  - BACKGROUND: For very young patients, anesthesia is often required for
      radiotherapy. This results in multiple exposures to anesthetic agents over a
      short period of time. We report a consecutive series of children anesthetized for
      external beam radiation therapy (EBRT). METHODS: Five hundred twelve children <
      or = 16 years old received EBRT from January 1983 to February 1996. Patient
      demographics, diagnosis, anesthesia techniques, monitoring, airway management,
      complications, and outcome were recorded for the patients requiring anesthesia.
      RESULTS: One hundred twenty-three of the 512 children (24%) required 141 courses
      of EBRT with anesthesia. Anesthetized patients ranged in age from 20 days to 11
      years (mean 2.6 +/- 1.8 ). The frequency of a child receiving EBRT and requiring
      anesthesia by age cohort was: < or = 1 year (96%), 1-2 years (93%), 2-3 years
      (80%), 3-4 years (51%), 4-5 years (36%), 5-6 years (13%), 6-7 years (11%), and 7
      16 years (0.7%). Diagnoses included: primary CNS tumor (28%), retinoblastoma
      (27%), neuroblastoma (20%), acute leukemia (9%), rhabdomyosarcoma (6%), and
      Wilms' tumor (4%). Sixty-three percent of the patients had been exposed to
      chemotherapy prior to EBRT. The mean number of anesthesia sessions per patient
      was 22 +/- 16. Seventy-eight percent of the treatment courses were once daily and
      22% were twice daily. Anesthesia techniques included: short-acting barbiturate
      induction + inhalation maintenance (21%), inhalation only (20%), ketamine (19%),
      propofol only (12%), propofol induction + inhalation maintenance (7%), ketamine
      induction + inhalation maintenance (6%), ketamine or short-acting barbiturate
      induction + inhalation maintenance (6%). Monitoring techniques included: EKG
      (95%), O2 saturation (93%), fraction of inspired O2 (57%), and end-tidal CO2
      (55%). Sixty-four percent of patients had central venous access. Eleven of the 74
      children with a central line developed sepsis (15%): 6 of the 11 were
      anesthetized with propofol (55%), 4 with a short-acting barbiturate induction
      plus inhalation maintenance (36%), and 1 with inhalation alone (9%). Eight of the
      11 (73%) received prior chemotherapy. CONCLUSION: Anesthesia was generally
      necessary at < or = 3 years, and rarely required at > 5 years of age. Sepsis
      associated with frequent use of the central venous access line was seen in 15% of
      the patients with these lines.

PMID- 10348289
TI  - 18F-deoxyglucose positron emission tomography (FDG-PET) for the planning of
      radiotherapy in lung cancer: high impact in patients with atelectasis.
AB  - PURPOSE: 18F-deoxyglucose positron emission tomography (FDG-PET) is increasingly
      applied in the staging of lung cancer (LC). This study analyzes the potential
      contribution of PET in radiotherapy planning for LC with special respect to tumor
      associated atelectasis. METHODS AND MATERIALS: Thirty-four patients with
      histologically confirmed LC, who had been examined by PET during pretreatment
      staging, were included. All were irradiated after CT-based therapy planning with
      anterior/posterior (AP) portals encompassing the primary tumor and the
      mediastinum (CT portals, CP). The result of the PET examination was unknown in
      treatment planning. In retrospect, a PET portal (PP) was delineated and compared
      with the CP. RESULTS: In 12/34 cases, the shape and/or size of the portals were
      changed, primarily (n = 10) the size of the fields was reduced. The median area
      of CP was 182 cm2 versus 167 cm2 of PP. Seventeen of 34 patients had dys- or
      atelectasis caused by a central primary tumor. In these cases, differences
      between CP and PP were significantly more frequent than in the other patients
      (8/17 vs. 3/17, p = 0.03). CONCLUSION: In this retrospective analysis, the
      information provided by FDG-PET would have contributed to a substantial reduction
      of the size of radiotherapy portals. This applies particularly for patients with
      tumor-associated dys- or atelectasis.

PMID- 10348290
TI  - Late retinal complications of radiation therapy for nasal and paranasal
      malignancies: relationship between irradiated-dose area and severity.
AB  - PURPOSE: Radiation-induced cataract, once a notorious ocular complication of
      radiation therapy, is no longer considered a severe complication, because visual
      acuity can be restored by surgical treatment without significant complications.
      Late retinal complications of retinopathy and glaucoma, for which there is no
      effective method of treatment, have become serious complications of radiotherapy
      of the head and neck. We retrospectively investigated the risk of late retinal
      complications of radiotherapy for nasal and paranasal malignancies according to
      the radiation dose and area of the retina irradiated. METHODS AND MATERIALS:
      Between October 1982 and May 1996, 43 eyes of 25 patients were exposed to
      fractionated external-beam irradiation for treatment of advanced nasal and
      paranasal cancer. None of the patients had tumor invasion into the eyes. The
      patients were followed ophthalmologically for a minimum of 2 years (range 2.0-11,
      mean 4.5, median 3.3). The radiation dose and area of the retina irradiated were
      estimated from the dose distribution figures calculated using the portal films
      and CT scan. RESULTS: Major late adverse effects of radiotherapy were observed in
      the retina in 9 of 43 eyes (in 8/25 patients). Radiation retinopathy was observed
      in 7 eyes, and the cumulative incidence was 25%. The median interval before the
      onset of symptoms attributable to retinopathy was 32 months (range 16-60).
      Neovascular glaucoma developed in 3 of the 43 eyes, with a cumulative incidence
      of 7%. The median period to the onset of symptoms attributable to glaucoma was 22
      months (range 16-26). Obstruction of the central retinal artery was observed in 1
      eye. The irradiation doses to the retinas that developed late complications
      ranged between 54-75 Gy (mean 61, median 61). No patients who received less than
      50 Gy developed retinal complications. The retina in 21 eyes was exposed to a
      dose of 50 Gy or more. In 13 of the 21 eyes, 60% or more of the retina was
      irradiated, and 8 of the eyes (62%) in this group (> or = 50 Gy, > or = 60%)
      developed severe retinal complications, whereas such complications only developed
      in 1 of the 8 eyes (13%) in the other group (> or = 50 Gy, > or = 60%). The
      results suggest that the radiation dose and area irradiated are the most
      important factors in the development of severe complications. CONCLUSION:
      Radiation-induced retinopathy and glaucoma are more serious late complications
      than cataracts, which are easily treated with surgery. We investigated the risk
      of late retinal complications of radiotherapy, and our findings suggested that
      the radiation dose and area irradiated are the most important factors in the
      development of severe complications. We recommend that the radiation dose and
      area of the retina irradiated be minimized in patients at risk of eye
      complications, and the patients should be closely followed by periodic
      ophthalmologic testing after treatment.

PMID- 10348291
TI  - Palliative radiotherapy for recurrent and metastatic malignant melanoma:
      prognostic factors for tumor response and long-term outcome: a 20-year
      experience.
AB  - PURPOSE: Radiotherapy is used as a "last resort" for patients with advanced
      cutaneous malignant melanoma. We have analyzed our 20-year clinical experience
      with respect to different endpoints and prognostic factors in patients with
      locally advanced, recurrent, or metastatic malignant melanoma. METHODS: From 1977
      to 1995, 2,917 consecutive patients were entered in the melanoma registry of our
      hospital. Radiotherapy was indicated in 121 patients (56 females, 65 males) for
      palliative reasons in advanced malignant melanoma stages UICC IIB/III/IV. The
      histology of the primary lesion was nodular in 51 patients, superficial spreading
      in 35, acral-lentiginous in 8, and lentigo maligna melanoma in 4 patients. Eleven
      patients had primary or recurrent lesions which were either not eligible for
      surgery or had residual disease (R2) after resection of a primary or recurrent
      lesion (UICC IIB); 57 patients had lymph node (n = 33) or in-transit metastases
      (n = 24) (UICC III), and 53 had distant organ metastases (7 M1a; 46 M1b) (UICC
      IV). Time from first diagnosis to on-study radiotherapy averaged 19 (median: 18;
      range: 3-186) months. In most cases, conventional RT was applied with 2-6 Gy
      single fractions up to a median total radiation dose of 48 (mean: 45; range: 20
      66) Gy. RESULTS: At 3 months follow-up, complete response (CR) was achieved in 7
      (64%) and overall response [complete (CR) and partial response (PR)] in all
      (100%) UICC IIB patients, in 25 (44%) and 44 (77%) of 57 UICC III patients, and
      in 9 (17%) and 26 (49%) of 53 UICC IV patients. Tumor progression during
      radiotherapy occurred in 25 (21%) patients. Patients with CR survived longer
      (median: 40 months) than those without CR (median 10 months) (p < 0.01). At last
      follow-up (Dec 31, 1996), 26 patients were still alive: 6 (55%) UICC IIB, 17
      (30%) UICC III, and 3 (6%) UICC IV patients (p < 0.01). Univariate analysis
      revealed the following prognostic factors for complete response and long-term
      survival: UICC stage (p < 0.001), primary location in the head and neck region,
      total radiation dose above 40 Gy (all p < 0.05), while age, gender, and histology
      had no impact. In multivariate analysis, UICC stage was the only independent
      prognostic factor (p < 0.001). CONCLUSION: External beam radiotherapy can provide
      long-term local control and effective palliation in malignant melanoma UICC
      stages IIB-IV. The current UICC staging system is an excellent prognostic factor
      for initial and long-term tumor response in metastatic melanoma. Therefore,
      prospective randomized trials using external radiotherapy with or without
      adjuvant therapy for advanced malignant melanoma are justified.

PMID- 10348292
TI  - Radiation-induced emesis: a prospective observational multicenter Italian trial.
      The Italian Group for Antiemetic Research in Radiotherapy.
AB  - PURPOSE: A prospective observational multicenter trial was carried out to assess
      the incidence, pattern, and prognostic factors of radiation-induced emesis (RIE),
      and evaluate the use of antiemetic drugs in radiation oncology clinical practice.
      METHODS AND MATERIALS: Fifty-one Italian radiation oncology centers took part in
      this trial. The accrual lasted 2 consecutive weeks, only patients starting
      radiotherapy in this period were enrolled. Exclusion criteria were age under 18
      years, and concomitant chemotherapy. Evaluation was based on diary cards filled
      in daily by patients during radiotherapy and 1 week after stopping it. Diary
      cards recorded the intensity of nausea and any episode of vomiting and retching.
      Prophylactic and symptomatic antiemetic drug prescriptions were also registered.
      RESULTS: Nine hundred thirty-four patients entered the trial, and 914 were
      evaluable. Irradiated sites were: breast in 211 patients, pelvis in 210 patients,
      head and neck in 136 patients, thorax in 129 patients, brain in 52 patients,
      upper abdomen in 42 patients, skin and/or extremities in 37 patients, and other
      sites in 97 patients. Vomiting and nausea occurred in 17.1% and 37.3% of
      patients, respectively, and 38.7 % patients had both vomiting and nausea. At
      multifactorial analysis, the only patient-related risk factor that was
      statistically significant was represented by previous experience with cancer
      chemotherapy. Moreover, two radiotherapy (RT)-related factors were significant
      risk factors for RIE, the irradiated site and field size. In fact, a
      statistically significant higher percentage of RIE was registered in upper
      abdomen RT and RT fields > 400 cm2. Although nonstatistically significant,
      patients receiving RT to the thorax and head and neck presented a higher
      incidence of RIE. Only a minority (14%) of patients receiving RT were given an
      antiemetic drug, and the prescriptions were more often symptomatic than
      prophylactic (9% vs. 5%, respectively). Different compounds and a wide range of
      doses and schedules were used; however, there is some evidence from our data that
      in spite of antiemetic prophylaxis, 46% of patients had vomiting, and 58% had
      nausea. The majority (93%) of the prophylactic group received oral 5
      hydroxytriptamine receptor (5-HT3) antagonist (8 mg/day, 7 days/week). In the
      symptomatic group, 54% and 41% patients received 5-HT3 antagonists and
      metoclopramide, respectively. At multivariate analysis, no patient- or RT-related
      risk factor for RIE was found to influence significantly the prophylactic or
      symptomatic use of antiemetics. CONCLUSION: Our study provided useful data on
      epidemiology and characteristics of RIE. Previous chemotherapy, field size, and
      irradiated site (upper abdomen) were the only significant prognostic factors of
      RIE. A remarkable incidence of RIE was found in patients submitted to thoracic
      and head and neck RT. With this background of knowledge, it will be possible to
      better plan further studies on this important problem. Moreover, the low rate of
      antiemetics use and the wide variety of doses and schedules employed suggest the
      need to reinforce the "evidence based" approach to identify the best antiemetic
      approach to RIE.

PMID- 10348293
TI  - Hiring of radiation oncologists by physician groups in 1997.
AB  - PURPOSE: To determine the hiring activities of physician groups with respect to
      radiation oncologists. METHODS AND MATERIALS: A survey was mailed to a
      stratified, random sample of 589 groups in the fall of 1997. A total of 448
      surveys were returned from groups with more than one radiation oncologist or
      diagnostic radiologist. The response rate was 76%. Responses were weighted to
      represent the total population of approximately 3286 practices in the United
      States that have multiple radiation oncologists or diagnostic radiologists.
      Eighty-seven responding groups had radiation oncologists and are the basis of
      reported data. Findings were compared to results of similar, previous surveys.
      RESULTS: In the 12 months prior to the survey, groups sought to hire 289 (SE =
      76) radiation oncologists, about the same as in 1996 but well above 1994 and
      1995. Almost all the 289 jobs were full-time positions; 70% were to fill
      expansion positions, 10% were replacements for physicians who had left the
      profession, and the remaining 20% were replacements for physicians who had moved
      to other radiation oncology positions. During the year, an additional 83 (SE =
      36) positions were vacated that groups did not seek to refill. Private,
      nonacademic groups offered 26% of their full-time positions on a non-partnership
      track basis. Seventy-one percent of available positions were in groups that
      preferred recently trained radiation oncologists to those with 10-20 years
      experience. Groups succeeded in hiring 220 (SE = 65) radiation oncologists, 76%
      of those sought. CONCLUSIONS: In 1997, the number of positions available
      apparently was approximately equal to the number needed, which is the number of
      graduates plus the number of experienced radiation oncologists moving to new
      jobs. However, because our sample was small, there might have been a considerable
      disparity.

PMID- 10348294
TI  - Fibrocellular tissue responses to endovascular and external beam irradiation in
      the porcine model of restenosis.
AB  - PURPOSE: Endovascular radiation has reduced postangioplasty restenosis in
      preclinical and early clinical studies. External radiation treatment may have
      advantages over endovascular therapy. We examined vascular and perivascular
      tissue responses to endovascular and external irradiation in pig coronary
      arteries. METHODS AND MATERIALS: Ninety-one animals received endovascular or
      external radiation following balloon injury and were sacrificed at 14, 30, or 180
      days. Injured segments of coronary vessels including perivascular and myocardial
      tissues were evaluated with histochemistry. RESULTS: Endovascular radiation was
      associated with delayed arterial wound healing as late as 6 months, evidenced by
      paucity of smooth muscle alpha-actin in neointimal cells compared to control.
      External treatment was associated with increased collagen in neointima and
      adventitia, and focal interstitial necrosis in adjacent myocardium. CONCLUSIONS:
      These investigations showed whole-heart 14 Gy external radiation treatment
      following coronary injury exacerbated certain aspects of arterial healing. In
      addition focal myocardial necrosis and fibrosis was observed following external
      but not endovascular irradiation. Endovascular radiation has some advantages over
      external irradiation; however the persistence of a synthetic smooth muscle cell
      phenotype in the neointima at 6 months suggests ionizing radiation in general may
      have profound effects on vessel architecture over the long term.

PMID- 10348295
TI  - The effect of external electron beam on neointima in rat carotid artery injury
      model.
AB  - PURPOSE: Endovascular irradiation with either a gamma or a beta source has shown
      to reduce neointimal proliferation. However, the effect of external-beam
      radiation on neointimal hyperplasia is controversial. The objective of this study
      was to determine the effect of external-beam irradiation with different doses on
      neointimal hyperplasia in the rat carotid artery injury model. METHODS AND
      MATERIALS: Twenty-seven Sprague-Dawley rats underwent endothelial denudation
      injury by 2F Fogarty balloons on carotid artery. Immediately after the injury,
      rats were irradiated externally using 6-MeV electrons. Rats were grouped
      according to the radiation doses, 0 Gy as controls (n = 5), 5 Gy (n = 5), 10 Gy
      (n = 5), 15 Gy (n = 6), and 20 Gy (n = 6). Then, rats were sacrificed after 2
      weeks and the carotid arteries were perfusion-fixed in paraformaldehyde. External
      elastic lamina (EEL) area, lumen area, maximal intimal thickness (MIT), and
      intimal area (IA) of the injured segments were measured on the basis of
      histomorphometry. RESULTS: In EEL and lumen area, there was no statistically
      significant difference between the irradiated groups and the controls. In MIT and
      IA, low-dose radiation (5 Gy and 10 Gy) did not induce any significant reduction.
      High-dose radiation (15 Gy and 20 Gy), however, reduced MIT and IA significantly.
      CONCLUSION: External electron beam reduced the intimal area, and the inhibition
      of neointimal proliferation was dependent upon radiation doses. This study
      suggests that the minimal effective dose for the inhibition of neointimal
      hyperplasia following denudation injury in the rat carotid model is between 10 Gy
      and 15 Gy.

PMID- 10348296
TI  - Characterization and validation of noninvasive oxygen tension measurements in
      human glioma xenografts by 19F-MR relaxometry.
AB  - PURPOSE: The aim of this study was to characterize and to validate noninvasive
      19F-magnetic resonance relaxometry for the measurement of oxygen tensions in
      human glioma xenografts in nude mice. The following three questions were
      addressed: 1. When perfluorocarbon compounds (PFCs) are administrated
      intravenously, which tumor regions are assessed by 19F-MR relaxometry? 2. Are
      oxygen tension as detected by 19F-MR relaxometry (pO2/relaxo) comparable to
      Eppendorf O2-electrode measurements (pO2/electrode)? 3. Can 19F-MR relaxometry be
      used to detect oxygen tension changes in tumor tissue during carbogen breathing?
      METHODS AND MATERIALS: Slice-selective 19F-MR relaxometry was carried out with
      perfluoro-15-crown-5-ether as oxygen sensor. The PFC was injected i.v. 3 days
      before the 19F-MR experiments. Two datasets were acquired before and two after
      the start of carbogen breathing. The distribution of PFCs and necrotic areas were
      analyzed in 19F-Spin Echo (SE) density MR images and T2-weighted 1H-SE MR images,
      respectively. One day after the MR investigations, oxygen tensions were measured
      by oxygen electrodes in the same slice along two perpendicular tracks. These
      measurements were followed by (immuno)histochemical analysis of the 2D
      distribution of perfused microvessels, hypoxic cells, necrotic areas, and
      macrophages. RESULTS: The PFCs mainly became sequestered in perfused regions at
      the tumor periphery; thus, 19F-MR relaxometry probed mean oxygen tensions in
      these regions throughout the selected MR slice. In perfused regions of the tumor,
      mean PO2/relaxo values were comparable to mean PO2/electrode values, and varied
      from 0.03 to 9 mmHg. Median pO2/electrode values of both tracks were lower than
      mean pO2/relaxo values, because low pO2 electrode values that originate from
      hypoxic and necrotic areas were also included in calculations of median
      pO2/electrode values. After 8-min carbogen breathing, the average PO2/relaxo
      increase was 3.3 +/- 0.8 (SEM) mmHg and 2.1 +/- 0.6 (SEM) after 14 min breathing.
      CONCLUSIONS: We have demonstrated that PFCs mainly became sequestered in perfused
      regions of the tumor. Here, mean PO2/relaxo values were comparable to mean
      PO2electrode values. In these areas, carbogen breathing was found to increase the
      PO2/relaxo values significantly.

PMID- 10348297
TI  - Radiation enhancement by 9-aminocamptothecin: the effect of fractionation and
      timing of administration.
AB  - PURPOSE: The camptothecins (CPTs) are potent radiation sensitizers in vivo but
      the optimal schedule of administration is unknown. In this article, the effects
      of irradiation combined with 9-aminocamptothecin (9AC) on a mouse mammary cancer
      and the gastrointestinal tract were compared for single and fractionated
      treatment. We also examined the circadian dependency for cytotoxicity, radiation
      sensitization, and acute toxicity after single doses of 9AC given at six
      different times over 24 h. MATERIALS AND METHODS: 9AC was administered
      intramuscularly to C3Hf/Kam mice with and without an 8 mm mouse mammary carcinoma
      (MCa-4). Acute toxicity was assessed by examination of body weight loss,
      peripheral blood counts, clinical assessment of diarrhea, and survival. Radiation
      sensitization was assessed using the tumor regrowth delay model. RESULTS:
      Regrowth delay of MCa-4 tumor after a single treatment of 15 Gy is comparable to
      28 Gy given in 14 fractions (absolute regrowth delays of 7.1 days and 6.6 days,
      respectively). With 9AC alone, comparable tumor regrowth was obtained with a
      total dose of 4 mg/kg given intramuscularly repeated twice weekly (1 mg/kg doses
      X 4), or as a single injection of 4 mg/kg (2.9 days and 3.8 days, respectively).
      9-AC and irradiation together in single doses of 15 Gy and 4 mg/kg resulted in
      little radiation sensitization compared to the repeated 9AC schedule combined
      with fractionated irradiation [Dose Modifying Factors (DMF) of 1.12 vs. 2.8,
      respectively]. Acute normal tissue toxicity after single or fractionated 9AC
      treatment was assessed at six times over a 24-h period (6 A.M., 10 A.M., 2 P.M.,
      6 P.M., 10 P.M., and 2 A.M.) and was highest at 2 A.M. after either single or
      multiple doses. A single dose of 9AC administered with single fraction
      irradiation could be escalated by 33% when given at the best-tolerated time.
      CONCLUSION: The frequency and timing of CPT administration with irradiation are
      important factors to be considered in the design of clinical protocols. CPTs are
      S-phase inhibitors that are better tolerated by the mouse when given during the
      rest phase when intestinal mucosal proliferation is relatively low. A modest
      increase in CPT dosage was possible by choosing the best tolerated time to
      administer the radiation sensitizer. This concept could potentially be evaluated
      in clinical trials with this class of agents.

PMID- 10348298
TI  - A model to accumulate fractionated dose in a deforming organ.
AB  - PURPOSE: Measurements of internal organ motion have demonstrated that daily organ
      deformation exists throughout the course of radiation treatment. However, a
      method of constructing the resultant dose delivered to the organ volume remains a
      difficult challenge. In this study, a model to quantify internal organ motion and
      a method to construct a cumulative dose in a deforming organ are introduced.
      METHODS AND MATERIALS: A biomechanical model of an elastic body is used to
      quantify patient organ motion in the process of radiation therapy. Intertreatment
      displacements of volume elements in an organ of interest is calculated by
      applying an finite element method with boundary conditions, obtained from
      multiple daily computed tomography (CT) measurements. Therefore, by incorporating
      also the measurements of daily setup error, daily dose delivered to a deforming
      organ can be accumulated by tracking the position of volume elements in the
      organ. Furthermore, distribution of patient-specific organ motion is also
      predicted during the early phase of treatment delivery using the daily
      measurements, and the cumulative dose distribution in the organ can then be
      estimated. This dose distribution will be updated whenever a new measurement
      becomes available, and used to reoptimize the ongoing treatment. RESULTS: An
      integrated process to accumulate dosage in a daily deforming organ was
      implemented. In this process, intertreatment organ motion and setup error were
      systematically quantified, and incorporated in the calculation of the cumulative
      dose. An example of the rectal wall motion in a prostate treatment was applied to
      test the model. The displacements of volume elements in the rectal wall, as well
      as the resultant doses, were calculated. CONCLUSION: This study is intended to
      provide a systematic framework to incorporate daily patient-specific organ motion
      and setup error in the reconstruction of the cumulative dose distribution in an
      organ of interest. The realistic dose distribution in an organ of interest gives
      the true dose-volume relationship, and may play an important role in the
      evaluation of the dose response of human organs. Dose reconstruction during the
      course of treatment delivery can also be used as an important feedback for the
      online optimization of individual treatment plans.

PMID- 10348299
TI  - p53 mutation decreased radiosensitivity in rat yolk sac tumor cell lines.
AB  - PURPOSE: We reported that two established rat yolk sac tumor cell lines differ in
      their radiosensitivity by 1.7 fold, and the variation is most likely manifested
      by the differences seen in their apoptotic response. We investigated the
      relationship between radiosensitivity and p53 in these cell lines. METHODS AND
      MATERIALS: We assessed the status of p53 in cell lines by polymerase chain
      reaction-single strand conformation polymorphism (PCR-SSCP) and sequence
      analysis, and also analyzed protein expression of p53, p21, and bax as a function
      of time after irradiation to determine the signal transduction for p53 by
      immunoblotting. RESULTS: A band shift was observed only in exon 7 for the
      radioresistant NMT-1R cells and no band shift was detected for the radiosensitive
      NMT-1 cells. A band shift was confirmed also at the mRNA level. Exon 7 of p53 DNA
      showed a three base substitution of DNA at codon 267 to 268. Expression of p53,
      p21, and bax proteins in NMT-1R cells did not change after 10 Gy irradiation;
      however, in NMT-1 cells, the expression of these proteins was increased from 1-12
      h after irradiation. CONCLUSION: A loss of p53 function by radiation-induced
      mutation of p53 decreased the radiosensitivity in these cell lines.

PMID- 10348300
TI  - Radiosensitivity of human normal and tumoral thyroid cells using fluorescence in
      situ hybridization and clonogenic survival assay.
AB  - PURPOSE: By using cell survival as a reference, we evaluated the radiosensitivity
      of human normal and tumoral thyroid cells using of radiation-induced
      translocations. METHODS AND MATERIALS: Tissue samples were obtained from patients
      undergoing thyroidectomy. Cell cultures were established, irradiated with 60Co,
      and metaphases painted using commercial whole-chromosome 4 hybridization probe
      and pancentromeric probe. The clonogenic survival was assessed by conventional
      colony forming assay. RESULTS: After irradiation, normal cultured thyroid cells
      yielded a higher number of translocations than cultures derived from adenomas or
      thyroid carcinoma. The colony forming assay demonstrated, by way of the mean
      inactivation dose, a higher survival of thyroid carcinoma and adenoma cells than
      of normal thyroid cells. This difference between tumoral and nontumoral cells is
      significant in each method (p = 0.0001), and cannot be explained by apoptosis in
      irradiated malignant cells. Correlation of the results obtained by both methods
      is shown by comparing the survival fraction at 2 Gy (SF2) and the percentage of
      chromosome 4 translocations at 2 Gy. CONCLUSION: These results indicate that the
      yield of radiation-induced translocations serves as a good and rapid prediction
      of the intrinsic radiosensitivity of thyroid cells, and that this test could be
      applied to other tumors.

PMID- 10348301
TI  - Volumetric visualization of head and neck CT data for treatment planning.
AB  - PURPOSE: To demonstrate the utility of volume rendering, an alternative
      visualization technique to surface rendering, in the practice of CT based
      radiotherapy planning for the head and neck. METHODS AND MATERIALS: Rendo-avs, a
      volume visualization tool developed at the University of Chicago, was used to
      volume render head and neck CT scans from two cases. Rendo-avs is a volume
      rendering tool operating within the graphical user interface environment of AVS
      (Application Visualization System). Users adjust the opacity of various tissues
      by defining the opacity transfer function (OTF), a function which preclassifies
      voxels by opacity prior to rendering. By defining the opacity map (OTF), the user
      selectively enhances and suppresses structures of various intensity. Additional
      graphics tools are available within the AVS network, allowing for the
      manipulation of perspective, field of view, data orientation. Users may draw
      directly on volume rendered images, create a partial surface, and thereby
      correlate objects in the 3D scene to points on original axial slices. Information
      in volume rendered images is mapped into the original CT slices via a Z buffer,
      which contains the depth information (Z coordinate) for each pixel in the
      rendered view. Locally developed software was used to project conventionally
      designed GTV contours onto volume rendered images. RESULTS: The lymph nodes,
      salivary glands, vessels, and airway are visualized in detail without prior
      manual segmentation. Volume rendering can be used to explore the finer anatomic
      structures that appear on consecutive axial slices as "points." Rendo-avs allowed
      for acceptable interactivity, with a processing time of approximately 5 seconds
      per 256 x 256 pixel output image. CONCLUSIONS: Volume rendering is a useful
      alternative to surface rendering, offering high-quality visualization, 3D
      anatomic delineation, and time savings to the user, due to the elimination of
      manual segmentation as a preprocessing step. Volume rendered images can be merged
      with conventional treatment planning images to add anatomic information to the
      treatment planning process.

PMID- 10348302
TI  - Technology assessment of multileaf collimation: a North American users survey.
AB  - PURPOSE: The American Association of Physicists in Medicine (AAPM) initiated an
      Assessment of Technology Subcommittee (ATS) to help the radiotherapy community
      evaluate emerging technologies. The ATS decided to first address multileaf
      collimation (MLC) by means of a North American users survey. The survey attempted
      to address issues such as MLC utility, efficacy, cost-effectiveness, and customer
      satisfaction. METHODS AND MATERIALS: The survey was designed with 38 questions,
      with cross-tabulation set up to decipher a particular clinic's perception of MLC.
      The surveys were coded according to MLC types, which were narrowed to four:
      Elekta, Siemens, Varian 52-leaf, and Varian 80-leaf. A 40% return rate was
      desired. RESULTS: A 44% (108 of 250) return was achieved. On an MLC machine,
      76.5% of photon patients are being treated with MLC. The main reasons for not
      using MLC were stair stepping, field size limitation, and physician objection.
      The most common sites in which MLC is being used are lung, pelvis, and prostate.
      The least used sites are head & neck and mantle fields. Of the facilities, 31%
      claimed an increase in number of patients being treated since MLC was installed,
      and 44% claimed an increase in the number of fields. Though the staffing for
      block cutting has decreased, therapist staffing has not. However, 91% of the
      facilities claimed a decreased workload for the therapists, despite the increase
      in daily treated patients and fields. Of the facilities that justified MLC
      purchase for more daily patients, 63% are actually treating more patients. Only
      26% of the facilities that justified an MLC purchase for intensity-modulated
      radiotherapy (IMRT) are currently using it for that purpose. The satisfaction
      rating (1 = low to 5 = high) for department groups averaged 4.0. Therapists
      ranked MLC as 4.6. CONCLUSIONS: Our survey shows that most users have
      successfully introduced MLC into the clinic as a block replacement. Most have
      found MLC to be cost-effective and efficient. The use of MLC for IMRT has
      progressed slower, but users anticipate escalated use.

PMID- 10348303
TI  - Comparison of computer workstation with light box for detecting setup errors from
      portal images.
AB  - PURPOSE: Observer studies were conducted to test the hypothesis that radiation
      oncologists using a computer workstation for portal image analysis can detect
      setup errors at least as accurately as when following standard clinical practice
      of inspecting portal films on a light box. METHODS AND MATERIALS: In a controlled
      observer study, nine radiation oncologists used a computer workstation, called
      PortFolio, to detect setup errors in 40 realistic digitally reconstructed portal
      radiograph (DRPR) images. PortFolio is a prototype workstation for radiation
      oncologists to display and inspect digital portal images for setup errors.
      PortFolio includes tools for image enhancement; alignment of crosshairs, field
      edges, and anatomic structures on reference and acquired images; measurement of
      distances and angles; and viewing registered images superimposed on one another.
      The test DRPRs contained known in-plane translation or rotation errors in the
      placement of the fields over target regions in the pelvis and head. Test images
      used in the study were also printed on film for observers to view on a light box
      and interpret using standard clinical practice. The mean accuracy for error
      detection for each approach was measured and the results were compared using
      repeated measures analysis of variance (ANOVA) with the Geisser-Greenhouse test
      statistic. RESULTS: The results indicate that radiation oncologists participating
      in this study could detect and quantify in-plane rotation and translation errors
      more accurately with PortFolio compared to standard clinical practice.
      CONCLUSIONS: Based on the results of this limited study, it is reasonable to
      conclude that workstations similar to PortFolio can be used efficaciously in
      clinical practice.

PMID- 10348304
TI  - Potential role of various dosimetric quality indicators in prostate
      brachytherapy.
AB  - PURPOSE: Postoperative CT-based dosimetric analysis provides detailed information
      regarding the coverage and uniformity of an implant, but the assessment of
      implant quality remains an unanswered and controversial issue. There is no
      disagreement that a good implant should cover the target volume with an adequate
      dose, but there is no consensus as to what represents an adequate dose. MATERIALS
      AND METHODS: The American Brachytherapy Society has recently proposed that
      prostate brachytherapy quality be measured in terms of the following parameters:
      D90, V100, and V150 where D90 is defined as the minimal dose covering 90% of the
      prostate volume and V100 and V150 are defined as the percent volume of the
      prostate receiving at least 100% or 150% of the prescribed minimal peripheral
      dose (mPD), respectively. We report detailed day 0 dosimetric evaluation for 60
      consecutive prostate brachytherapy patients implanted via a standard
      transperineal ultrasound guided approach in terms of D90, D100, V90, V100, and
      V150 and also the maximal and average rectal and urethral dose. RESULTS:
      Dosimetric evaluation resulted in a V100 greater than 80% of the prostate volume
      and a D90 greater than 90% of the mPD in the entire patient population. There was
      a statistically significant difference between the quality scores of 125I
      implants and 103Pd implants with the 125I mean V100 and D90 at 95.3% volume and
      109.9% mPD, respectively, vs. 103Pd at 91.8% volume and 103.7% mPD. Likewise, the
      rectal and urethral doses as a fraction of mPD were significantly lower in 103Pd
      than in 125I implants. This occurred despite the fact that palladium implants
      were typically preplanned with significantly better coverage and hotter V150 than
      iodine implants. We consider V150 to be an important parameter for determining
      dose homogeneity although the clinical utility of dose homogeneity remains
      unknown. The mean V150 was 45.6 +/- 9.6% volume. There was no additional
      dosimetric utility from a determination of V90 while D100 was found to be overly
      sensitive to steep dose gradients at the periphery of the prostate. CONCLUSIONS:
      This report represents the first detailed postimplant day 0 dosimetric evaluation
      comparing ABS recommended quality parameters used to evaluate prostate
      brachytherapy. At the present time, no long-term clinical outcomes are available
      because of short follow-up. As PSA based follow-up data becomes available,
      however, this report may help define what represents an adequate implant.

PMID- 10348305
TI  - Effect of metal reconstruction plates on cobalt-60 dose distribution: a
      predictive formula and clinical implications.
AB  - PURPOSE: We sought to create a predictive formula for the dose perturbations
      caused by head and neck reconstruction plates in the delivery of postoperative
      radiotherapy with 60Co beams. MATERIALS AND METHODS: The dose perturbation
      effects of Vitallium and Titanium reconstruction plates and flat metal plates of
      aluminum (13Al), stainless steel (26Fe), tin (50Sn) and lead (82Pb) irradiated
      with a 60Co beam were measured in polystyrene phantoms using a film dosimetry
      system. We then used these results to create formulas to predict the effect of a
      metal reconstruction plate dependent upon its effective atomic number. RESULTS:
      Percentage dose increases secondary to back scattering were 10% at 1 mm in front
      of the Vitallium plate and 40% at the plate while the percentage dose decrease
      was 29% at the plate and 10% 1 mm behind the plate. For the Titanium plate, the
      percentage dose increase was 5% at 1 mm in front the plate and 25% at the plate
      while the percentage dose decrease was 20% at the plate and 5% 1 mm behind the
      plate. For flat plates the percentage dose increases and decreases, respectively,
      at the plate surfaces were: 13Al (8%, 6%), 26Fe (35%, 16%), 50Sn (60%, 24%), and
      82Pb (85%, 13%). A second order polynomial predicting the back scatter and
      shadowing effects was created, Y = a + bZ + cZ2, where Z is the effective atomic
      number of the plate while a, b, and c are the following constants: for back
      scatter a = 0.854 +/- 0.082, b = 0.0212 +/- 0.0044, c = -0.00011 +/- 0.00004 and
      for shadowing a = 1.108 +/- 0.021, b = -0.0141 +/- 0.0011, c = 0.00014 +/-
      0.00001. CONCLUSIONS: It is possible to predict the effect of a metal
      reconstruction plate upon the delivered postoperative radiotherapy dose. The dose
      perturbations around the plate only exist for a few millimeters, but this is
      substantially greater than the thickness of a normal tissue or tumor cell.
      Perhaps a coating of a low effective atomic number, biologically inert, substance
      might allow for greater dose homogeneity and decrease the risks of plate failure
      or tumor recurrence.

PMID- 10348306
TI  - Stereolithographic modelling as an aid to orbital brachytherapy.
AB  - PURPOSE: This paper describes the technique of stereolithographic biomodelling
      and its application to a patient who was treated using orbital brachytherapy.
      METHODS AND MATERIALS: The process uses a moving laser beam, directed by a
      computer, to draw cross-sections of the model onto the surface of photo-curable
      liquid plastic. Using a stereolithographic apparatus (SLA), solid or surface data
      is sliced by software into very thin cross-sections. A helium cadmium (HeCd)
      laser then generates a small intense spot of ultraviolet (UV) light that is moved
      across the top of a vat of liquid photo monomer by a computerised optical
      scanning system. The laser polymerises the liquid into a solid where it touches,
      precisely printing each cross-section. A vertical elevator lowers the newly
      formed layer, and a recoating and levelling system establishes the next layer's
      thickness. Successive cross-sections (0.25 mm thick), each one adhering to the
      one below, are built one on top of the other, to form the part from the bottom
      up. The biomodel allowed the implant to be planned in detail prior to the
      surgery. The accurate placement of brachytherapy catheters was assured, and the
      dosimetry could be determined and optimised prior to the definitive procedure.
      CONCLUSIONS: Stereolithography is a useful technique in the area of orbital
      brachytherapy. It allows the implant to to be carried out with greater accuracy
      and confidence. For the patient, it minimises the risk to the eye and provides
      them with a greater understanding of the procedure.

PMID- 10348307
TI  - Total body irradiation.

PMID- 10348308
TI  - Regarding two papers from the same group on radiotherapy for macular
      degeneration.

PMID- 10348309
TI  - Concerning Roberts and Hendry IJROBP 1998;41:689-699.

PMID- 10348310
TI  - Glucose loading precipitates acute encephalopathy in thiamin-deficient rats.
AB  - A rat model of glucose-precipitated Wernicke's encephalopathy (WE) has been
      developed in which glucose loading (10 g/kg, i.p.) of ataxic thiamin-deficient
      (TD) rats induced episodes of gross neurological dysfunction and sometimes death.
      The acute effects of a glucose load on the neurological state of thiamin-replete
      control and TD rats were assessed by scoring of clinical observations and
      performance measured on a moving belt (MB) apparatus at 30 min intervals for 2 hr
      after the challenge. Glucose loading or saline treatment (2.5 mL, i.p.) had no
      significant behavioural or clinical consequences when administered to controls or
      rats fed TD diet for <21 days. Glucose loading of ataxic rats fed TD diet for 28
      35 days precipitated episodes of gross ataxia and signs of advanced neurological
      dysfunction (e.g. loss of righting reflex and hyperexcitability) leading to
      significant increases in the Ataxia (p<0.05) and Advanced Sign (p<0.05) scores
      within 2 hr after the challenge. Simultaneously, the performance of these animals
      on the MB decreased 10-fold. Regular glucose challenges significantly increased
      the rate of progression of disease in TD rats when compared with untreated TD
      rats. This model may be useful for the further investigation of the pathogenesis
      of WE at the molecular level.

PMID- 10348312
TI  - Energy metabolism and NAD-NADH redox state in brain slices in response to
      glutamate exposure and ischemia.
AB  - A comparative study of the effects of excitotoxic levels of glutamate with
      ischemia on the cerebral energy metabolism and [NAD]/[NADH] ratio was carried out
      in adult rat brain slices. Glutamate moderately decreased the high energy
      phosphates and intracellular pH whereas ischemia showed a pronounced decrease in
      the high energy phosphates and intracellular pH. The [NAD]/[NADH] ratio increased
      continuously during glutamate exposure whereas an initial reduction and
      subsequent oxidation occurred during ischemia. Uptake of glutamate prevailed
      throughout the glutamate exposure to brain slices signifying favorable glial
      energy levels while efflux occurred during ischemia indicating complete neuronal
      and glial depolarization. A net synthesis of glutamate was also observed during
      ischemia. A small but significant increase in lactate may be a result of
      increased glycolysis during glutamate exposure, on the other hand a large
      increase in lactate during ischemia suggests a total failure of oxidative
      metabolism. Our results show that glutamate exposure to brain slices causes a
      mild energetic stress and an increase in [NAD]/[NADH] ratio whereas predominant
      inhibition of phosphate metabolites and dual effect on NAD/NADH redox state was
      observed during ischemia. It is suggested that the NAD/NADH redox state together
      with phosphate metabolites and intracellular pH of the periinfarct region could
      provide vital evidence about the possible involvement of glutamate.

PMID- 10348311
TI  - Increases in [3H]FK-506 and [3H]L-N(G)-nitro-arginine binding in the rat brain
      after nigrostriatal dopaminergic denervation.
AB  - Receptor autoradiographic technique was studied to investigate sequential changes
      in FK-506 binding proteins, nitric oxide synthase and dopamine uptake sites in
      the brain 1 week to 8 weeks after unilateral 6-hydroxydopamine injection of the
      medial forebrain bundle in rats. [3H]FK-506, [3H]L-N(G)-nitro-arginine and
      [3H]mazindol were used to label FK-506 binding proteins (immunophilin), nitric
      oxide synthase and dopamine uptake sites, respectively. [3H]FK-506 binding showed
      about 13-25% increase in the ipsilateral striatum from 2 to 8 weeks after
      degeneration of nigrostriatal pathway. However, no significant change in [3H]FK
      506 binding was observed in the ipsilateral substantia nigra during the
      postlesion periods. In the contralateral side, [3H]FK-506 binding also showed
      about 13-25% increase in the striatum from 2 to 8 weeks postlesion. The
      substantia nigra showed a 21% increase in [3H]FK-506 binding only 2 weeks after
      the lesioning. On the other hand, [3H]L-N(G)-nitro-arginine binding showed about
      21-31% increase in the parietal cortex and striatum 1 week or 2 weeks postlesion.
      In the contralateral side, a 21% increase in [3H]L-N(G)-nitro-arginine binding
      was found in the dorsolateral striatum only 1 week postlesion. In contrast,
      degeneration of nigrostriatal pathway caused a conspicuous loss of [3H]mazindol
      binding in the ipsilateral striatum (87-96%), substantia nigra (36-73%) and
      ventral tegmental area (91-100%) during the postlesion periods. In the
      contralateral side, no significant changes in [3H]mazindol binding were observed
      in these areas up to 8 weeks after the postlesion. The present study demonstrates
      that unilateral injection of 6-hydroxydopamine into the medial forebrain bundle
      of rats can cause a significant increase in [3H]FK-506 and [3H]L-N(G)-nitro
      arginine bindings in the brains. In contrast, a marked reduction in [3H]mazindol
      binding is observed in the brains after the lesioning, indicating severe damage
      to nigrostriatal dopaminergic pathway. These results suggest that immunophilin
      and nitric oxide synthase may play some role in the pathogenesis of
      neurodegenerative disorders such as Parkinson's disease.

PMID- 10348313
TI  - A proton magnetic resonance spectroscopy study of the striatum and cerebral
      cortex in Parkinson's disease.
AB  - Animal studies have suggested an increased striatal glutamate activity in
      Parkinson's disease models, although this has not been substantiated in magnetic
      resonance spectroscopy studies in patients. Our initial aim was to assess
      glutamate and glutamine levels in the striatum of patients with idiopathic
      Parkinson's disease, using multivoxel proton magnetic resonance spectroscopy
      techniques. Since data were collected from other areas of the brain without a
      priori selection, information on the cortex was also obtained. Twelve healthy
      volunteers, seven dyskinetic and five non-dyskinetic patients were studied. Peak
      area ratios of choline-containing compounds (Cho), glutamine and glutamate (Glx)
      and N-acetyl moieties including N-acetylaspartate (NAx), relative to creatine
      (Cr) were calculated. Spectra were analysed from the corpus striatum, the
      occipital cortex and the temporo-parietal cortex. The median Glx/Cr ratio was
      unaltered in the striatal spectra of Parkinson's disease patients compared to
      healthy controls. However, the more severely affected patients had significantly
      reduced NAx/Cr ratios in spectra localised to the temporo-parietal cortex,
      compared to healthy controls. Furthermore, the entire patient population had
      significantly reduced Cho/Cr ratios in spectra from the temporo-parietal cortex,
      compared to the reference population. We found no evidence of increased striatal
      glutamate in either dyskinetic or non-dyskinetic Parkinson's disease. However,
      the low NAx/Cr and Cho/Cr ratios in the temporo-parietal cortex may indicate the
      presence of subclinical cortical dysfunction.

PMID- 10348315
TI  - Normal ascorbic acid in cerebrospinal fluid of patients with infantile neuronal
      ceroid-lipofuscinosis.
AB  - Neuronal ceroid-lipofuscinoses (NCL) are a group of neurodegenerative disorders.
      There is much evidence for a role of peroxidation processes in the pathogenesis
      of NCL, although this would certainly be indirect. Reduced total antioxidant
      activity of cerebrospinal fluid (CSF) has been reported in NCL. Since ascorbic
      acid represents a major antioxidant in CSF, we have now determined this parameter
      in CSF of two patients with the infantile form of NCL (Santavuori-Haltia
      disease). However, the ascorbic acid values obtained (103.6 and 181.3 microM) are
      comparable with control values from the literature as well as with those measured
      in groups of children with neurologic/psychiatric diseases other than NCL (mean
      +/- standard deviation: 137.1+/-41.3 microM), with suspected (but excluded)
      meningitis (124.1+/-34.0 microM) and acute lymphoblastic leukemia (131.7+/-17.0
      microM). Our results indicate that CSF ascorbic acid concentrations are not
      affected by peroxidation processes in infantile NCL, but reveal a sharply
      decreased ascorbic acid concentration in one of the non-NCL patients, possibly
      associated with his convulsions and/or his anticonvulsant therapy.

PMID- 10348314
TI  - Bone marrow transplantation does not ameliorate the neurologic symptoms in mice
      deficient in hypoxanthine guanine phosphoribosyl transferase (HPRT).
AB  - The use of bone marrow transplantation (BMT) for the treatment of genetic
      diseases with neurologic involvement has yielded mixed results. We have employed
      a mouse model of Lesch-Nyhan disease (LND) to assess the efficacy of BMT in
      ameliorating the neurologic manifestations of the disease. Adult HPRT-deficient
      mice exhibit a measurable decrease in striatal dopamine levels and a
      hypersensitivity to amphetamine. Marrow-ablated adult HPRT-deficient mice were
      transplanted with marrow from congenic HPRT-expressing mice. BMT altered neither
      the neurochemical nor the behavioral phenotypes in either HPRT-positive or HPRT
      deficient mice. Barring any important species differences, these results suggest
      that BMT in its present form may not be an effective therapy for Lesch-Nyhan
      syndrome.

PMID- 10348316
TI  - Emission tomography contribution to clinical neurology.
AB  - The role of functional neuroimaging techniques in furthering the understanding of
      pathophysiological mechanisms of neurological diseases and in the assessment of
      neurological patients is increasingly important. Here, we review data mainly from
      emission tomography techniques, namely positron emission tomography (PET) and
      single photon emission computerized tomography (SPECT), that have helped
      elucidate the pathophysiology of a number of neurological diseases and have
      suggested strategies in the treatment of neurological patients. We also suggest
      possible future developments of functional neuroimaging applied to clinical
      populations and briefly touch on the emerging role of functional magnetic
      resonance imaging (fMRI) in clinical neurology and neurosurgery.

PMID- 10348317
TI  - P3a and P3b from typical auditory and visual stimuli.
AB  - OBJECTIVE: Target/standard discrimination difficulty was manipulated
      systematically to assess how this variable affects target and nontarget P300
      scalp distributions for both auditory and visual stimuli. DESIGN AND METHODS: A 3
      stimulus paradigm (target, standard, nontarget) was employed in which subjects (n
      = 16) responded only to an infrequently occurring target stimulus. The perceptual
      discrimination difficulty between the target and more frequently occurring
      standard stimuli was varied as Easy or Difficult in different conditions, while
      holding the nontarget stimulus properties constant. RESULTS: When target/standard
      discrimination was Easy, P300 amplitude was larger for the target than the
      nontarget across all electrode sites, and both demonstrated parietal maximums. In
      contrast, when target/standard discrimination was Difficult, target amplitude
      (P3b) was larger parietally and occurred later than nontarget components, whereas
      nontarget amplitude (P3a) was larger and earlier than the target P300 over the
      frontal electrode sites. Similar outcomes across task conditions were obtained
      for both auditory and visual stimuli. CONCLUSIONS: The findings suggest that
      target/standard discrimination difficulty, rather than stimulus novelty,
      determines P3a generation for both auditory and visual stimulus modalities.

PMID- 10348318
TI  - The dimensional complexity of the P3 event-related potential: area-specific and
      task-dependent features.
AB  - Appropriate methods are needed for the study of the non-linear properties of the
      nervous system. The correlation dimension, as expressed by the effective point
      correlation dimension (PD2eff), was used in this study for the analysis of the
      dimensional complexity of event-related potentials. The ERPs were recorded at Fz,
      Cz and Pz in an auditory oddball paradigm in which 'easy' and 'difficult' sensory
      discrimination tasks were applied. The PD2eff was calculated from each EEG epoch
      used in the process of ERP averaging. The PD2eff significantly decreased during
      the ERPs in which the P3-component appeared, and this reduction showed area
      specific and task-specific patterns. The area-specific PD2eff changes indicated
      distinctive functional features of the frontal areas in this task. The magnitude
      of the PD2eff change was found to depend on the degree of task difficulty.
      Implications of the findings related to theories on the functional significance
      of the P3-wave in information processing are discussed.

PMID- 10348319
TI  - Relationship of sleep interictal epileptiform discharges to sigma activity (12-16
      Hz) in benign epilepsy of childhood with rolandic spikes.
AB  - OBJECTIVE: The activation of interictal epileptic discharges (IEDs) by NREM sleep
      is a well-known phenomenon in benign epilepsy of childhood with rolandic spikes
      (BECRS). The activating properties of NREM sleep on IEDs have been attributed to
      increased synchronization within thalamocortical neurons. During NREM sleep two
      synchronizing mechanisms lead to the appearance of spindles and delta waves on
      the EEG. Spectral analysis technique is a suitable method that can be used to
      quantitatively describe the dynamics of delta (slow wave activity (SWA) 0.5-4.0
      Hz) and sigma activity (12.0-16.0 Hz) during sleep. METHODS: In order to define
      more accurately the relationship between synchronizing mechanisms (spindles and
      delta activities) and IEDs during sleep in BECRS, we have performed overnight
      continuous EEG polysomnography studies in 9 patients (mean age 7.4 +/- 2.5
      years). The temporal series of SWA and sigma values, derived from spectral
      analysis, have been obtained from a spike-free derivation lead. The IEDs count
      has been performed on the most active lead. Relationships between sigma and SWA
      and time series of IEDs were tested by means of correlation techniques after data
      normalization. RESULTS: Our results revealed a significant higher correlation
      between IEDs and sigma activity with respect to SWA in all the subjects, in total
      sleep time. The same analysis limited to NREM sleep highlights the better
      correlation between sigma and IEDs. CONCLUSIONS: Data suggest that during sleep
      of BECRS patients, IEDs are more sensitive to the promoting action of the spindle
      generating mechanism than to the SWA-producing one.

PMID- 10348320
TI  - Functional MRI of human primary somatosensory and motor cortex during median
      nerve stimulation.
AB  - OBJECTIVES: Somatosensory evoked potential (SEP) studies suggested that some
      early cortical SEP components may be generated in the primary motor cortex (M1)
      rather than the primary somatosensory cortex (S1). METHODS: We now used
      functional magnetic resonance imaging (fMRI) to study activation of S1 and M1 by
      electrical median nerve stimulation in healthy volunteers. RESULTS: The hand
      areas of both S1 and M1 showed significant activation (correlation coefficients
      >0.45) in 7 of 9 subjects (activated volume S1 > M1). For comparison, a
      sequential finger opposition task significantly activated S1 in 7 and M1 in all 9
      subjects (activated volume M1 > S1). CONCLUSIONS: These data show that the
      electrical stimuli used for SEP recording lead to a functional activation of S1
      as well as M1.

PMID- 10348321
TI  - 'Oddball' event-related potentials and information processing during REM and non
      REM sleep.
AB  - Auditory stimuli consisting of the subject's own name and an irrelevant word,
      counterbalanced in probabilities, were presented to 15 male subjects in the awake
      state and during natural sleep. Potentials recorded to these stimuli, as well as
      to clicks presented during sleep in a preceding night, were recorded and
      compared. Principal component analysis (PCA) was conducted on evoked potentials
      to distinguish temporally overlapping components, and ANOVA was applied on the
      eigenvector coefficients. During non-REM sleep a parietal P450, more prominent in
      stage 2, was observed in addition to the prominent waveform of a K-complex, which
      was also recorded in response to clicks and consisted of N350, N550 and P1000.
      During REM sleep, a fronto-central negativity which resembled non-REM N350, a
      parietal positivity at about 450 ms and a large N700 were detected. ANOVA on PCA
      coefficients showed a significant effect of verbal-stimulus type
      (name/irrelevant) on an eigenvector, which included all the components observed
      during stage 2 sleep. Coefficients during REM sleep showed a significant effect
      of stimulus probability on an eigenvector consisting of a prominent P450,
      suggesting a resemblance to the awake P300 component. This could not be
      demonstrated during non-REM sleep. The results indicate continued evaluation of
      auditory input salience during sleep, which diminishes during deep sleep, and is
      replaced by evaluation of stimulus context in a train of stimuli during REM
      sleep.

PMID- 10348322
TI  - Auditory steady-state responses to click trains from the rat temporal cortex.
AB  - In order to investigate the mechanisms underlying the generation of steady-state
      responses (SSRs), auditory evoked potentials elicited by click trains presented
      at several stimulation rates (30, 40, 50, 60 Hz) were recorded in 7 awake rats by
      means of epidural electrodes placed over the temporal cortex. Mean amplitude-rate
      function calculated on the recorded responses appeared almost flat and showed the
      maximum value at 50 Hz, while mean phases showed a linear increase when
      increasing the stimulation rate. In each rat, predictions of the recorded
      responses at 30, 40, 50 and 60 Hz were synthesized by superimposing middle
      latency auditory evoked potentials (MAEPs) at suitable time intervals at each
      rate. Mean amplitudes calculated on the predicted curves decreased linearly when
      increasing the stimulation rate and appeared higher in comparison to those
      obtained from the recorded SSRs. Predicted phases showed a linear increase when
      increasing the stimulation rate and were leading with respect to corresponding
      phase values calculated for recorded SSRs. Our findings indicate that the MAEP
      superimposition mechanism does not adequately predict the generation of temporal
      recorded SSRs in rats. This was explained by admitting that phenomena related to
      the recovery cycle and, to a lesser extent, to rate-dependent facilitating
      effects come into play.

PMID- 10348323
TI  - Visual evoked potential interhemispheric transfer time in different frequency
      bands.
AB  - OBJECTIVE: Visual evoked potentials (VEP) have been used to estimate
      interhemispheric transfer time (IHTT). However, the complex wave of VEP is most
      probably formed by different generators of neural populations that act through
      different frequency channels. If the main peaks of VEP are established by
      different types of generators, which can also be connected to each other by a
      different type of callosal fibres, we would be able to estimate a wide range of
      various IHTT by measuring the latency between time-locked peaks of narrow band
      pass filtered VEP. This research aimed to test this hypothesis. METHODS: Nine
      right-handed men were presented with a reversal of a checkerboard pattern as
      stimuli at RVF or LVF, and EEG was recorded at O1, O2, P3, P4. The grand-averaged
      VEPs were transformed to the frequency domain by means of the fast Fourier
      transform to obtain the amplitude frequency characteristics. Band-pass filters
      were chosen adequately, according to tuning frequencies indicated by clear peaks
      in the amplitude frequency characteristics. The chosen band pass filters (4-8 Hz,
      8-15 Hz, 15-20 Hz, 20-32 Hz) were applied to the VEP of the subjects, and 4
      different components of VEPs for each VEP were obtained. The latency of P100 and
      N160 of unfiltered VEP was measured. In the band-pass digital filter applied
      VEPs, positive and negative peaks, which are consistent with P100 and N160, were
      measured for each subject. Latency differences between hemispheres for digitally
      unfiltered and filtered VEPs were computed to estimate IHTT. RESULTS: In the
      different frequency bands, different IHTTs were estimated, ranging from 3 ms to
      30 ms. Approximately 16 ms for theta band, 11 ms for alpha band, 6 ms for 15-20
      Hz and 3 ms for 20-32 Hz bands were found. CONCLUSIONS: Our findings support the
      hypothesis which states that unfiltered VEPs provide us with only a rough
      estimation of IHTT. Also, they are consistent with anatomical findings that
      describe callosal fibres of varying dimensions, predicting various velocities
      between hemispheres.

PMID- 10348324
TI  - A mixed D1 and D2 antagonist does not replay pattern electroretinogram
      alterations observed with a selective D2 antagonist in normal humans:
      relationship with Parkinson's disease pattern electroretinogram alterations.
AB  - The human retina produces a tuned response to stimuli of increasing spatial
      frequency reversed at a steady state. The peak amplitude response, at medium
      spatial frequencies, is decreased in Parkinson's disease and in normal subjects
      (n = 18) treated with a D2 dopaminergic antagonist (l-sulpiride). Here, we report
      that a mixed D1-D2 receptor antagonist (haloperidol) in normal subjects (n = 18)
      does not produce an amplitude decrease of medium spatial frequencies (SFs)
      responses but it decreases low-frequency response. It could argued that the
      increased dopamine release produced by the presynaptic D2 antagonistic action of
      haloperidol is subsequently counteracted at postsynaptic level by its D1
      antagonistic effect, producing a net counterbalance at medium SFs. These data
      suggest that the two dopamine receptors may play different roles in the retinal
      function and in the origin of visual alterations in Parkinson's disease.

PMID- 10348325
TI  - Edge detection and surface 'filling in' as shown by texture visual evoked
      potentials.
AB  - OBJECTIVES: We designed a stimulation paradigm that was designed to ascertain
      whether specific components of the texture visual evoked potentials were
      attributable to edge detection or to surface 'filling-in' processes. METHODS: The
      stimuli were textures of parallel line elements, which were either uniform (all
      horizontal or vertical lines) or segregated (checkerboards in which texture line
      elements of neighbor checks were oriented orthogonally). A sequence of 4 stimuli,
      two uniform followed by two segregated stimuli, was repeated cyclically.
      Accordingly, segregation could appear from a uniform display; it could also be
      maintained, with the checkerboard illusory margin location unchanged but with
      alteration in the orientation of all line elements. Each stimulus was presented
      for 487 ms and instantly replaced by the following one. RESULTS: Segregation
      related components for segregation-appearance (Sa) and for segregation
      maintenance (Sm) conditions were obtained separately by subtraction. In both
      conditions, a negative component was obtained with a peak latency of about 140
      150 ms. However, the onset of Sa was earlier than that of Sm, whereas the
      respective offsets were almost identical. CONCLUSIONS: We hypothesize that the
      segregation component in VEPs is composed of two subcomponents: an early part,
      which is related to the segregation of edges, and a final part, which is related
      to the 'filling-in' of the homogeneous texture surface within the boundary
      defined by these edges.

PMID- 10348326
TI  - Localization of the optic tract by using subcortical visual evoked potentials
      (VEPs) in cats.
AB  - OBJECTIVES: This study was aimed to clarify the relationship between the
      amplitudes of visual evoked near field potentials and distance from the optic
      tract, and to determine the adequate filter settings to record these potentials
      from the optic tract separately from the far field potentials. METHODS: The
      visual evoked near field potentials from the optic tract were consecutively
      recorded through intracerebral electrodes in 6 cats' brains. Different filter
      settings were tried and the amplitudes of visual evoked potentials (VEPs) were
      compared with the distance from the optic tract. RESULTS: The filter settings of
      100 Hz to 1 kHz were the best to obtain only the near field potentials separately
      from the far field potentials. Histological sections revealed that the potentials
      of the surface of the optic tract showed sudden increase of amplitude, above the
      50% of the maximum VEPs amplitudes. CONCLUSIONS: The optic tract can be
      identified using these methods. These results can be applied to localize the
      optic tract during such an operative procedure as postero-ventral pallidotomy.

PMID- 10348327
TI  - Visual evoked potentials in school children: a comparative study of transient and
      steady-state methods with pattern reversal and flash stimulation.
AB  - OBJECTIVE: Flash visual evoked potentials (VEPs) are commonly used in pediatrics,
      because children are sometimes uncooperative. We performed a comparative study of
      transient and steady-state VEPs with pattern reversal (PR) and flash (light
      emitting diode, LED) stimulation. METHODS: We recorded VEPs in 15 boys and 17
      girls (aged 6-12 years) using 4 different stimulus conditions. The latency and
      amplitude of transient VEPs (T-VEPs) were measured. Steady-state VEPs (S-VEPs)
      were Fourier analyzed, and both the phase and amplitude of the major components
      were obtained. RESULTS: The mean P100 latency of LED T-VEPs was longer and had a
      greater variability than that of PR T-VEPs. The LED T-VEPs had an amplitude of
      about double that of PR T-VEPs. The first harmonic response in the LED and second
      harmonic in PR were the major components of S-VEPs. The phases of PR and LED S
      VEPs had narrow angular dispersions and amplitudes showed marked intersubject
      variability. Sex and age had no significant effect on both T-VEPs and S-VEPs.
      CONCLUSIONS: Reproducible VEPs with 4 stimulus conditions can be obtained in
      school children. T-VEPs and S-VEPs are clinically useful because these methods
      provide complementary information.

PMID- 10348328
TI  - Asynchronous and asymmetric burst-suppression in a patient with a corpus callosum
      lesion.
AB  - INTRODUCTION: Burst suppression is seen in the electroencephalograms of patients
      receiving high doses of pentobarbital. In such circumstances, burst suppression
      is characterized by bilaterally synchronous and symmetric bursts of electrical
      activity followed by intervals of attenuation. METHODS: We report on a case of
      asymmetric and asynchronous pentobarbital-induced burst suppression that occurred
      after a corpus callosum lesion sustained during trauma. CONCLUSIONS: To our
      knowledge, this is the first such reported human case of asymmetric and
      asynchronous pentobarbital-induced burst suppression. These findings suggest that
      the corpus callosum may be involved in the synchronization of the burst
      suppression pattern.

PMID- 10348329
TI  - Accuracy of EEG dipole source localization using implanted sources in the human
      brain.
AB  - OBJECTIVES: The location of electrical sources in the brain can be estimated by
      calculating inverse solutions in which the location, amplitude and orientation of
      the electrical sources are fitted to the scalp EEG. To assess localization
      accuracy of the moving dipole inverse solution algorithm (ISA), we studied two
      patients who had depth electrodes implanted for presurgical planning of epilepsy
      surgery. METHODS: Artificial dipoles were created by connecting a single sine
      wave pulse generator to different pairs of electrodes in multiple orientations
      and depths. Surface EEG recordings of the resulting pulses were evaluated with
      the ISA using a 4-shell spherical head model and plotted on the subjects' MRI.
      Dipole localization errors were evaluated with respect to the number of averaged
      pulses, different electrode montages and different dipole locations and
      orientations. RESULTS: Dipoles located at 40-57 mm from the scalp surface had
      localization errors that were greater than those located at 62-85 mm.
      Localization accuracy improved with increasing numbers of pulses and recording
      electrodes. Results with a standard 10-20 array of 21 electrodes showed an
      average localization error of 17 mm, whereas 41 electrodes improved this to 13
      mm. Mean angular errors were 31 and 30 degrees, respectively. CONCLUSIONS: The
      ISA was able to differentiate between tangential and radial dipoles. We conclude
      that our implementation of the ISA is a useful and sound method for localizing
      electrical activity in the brain.

PMID- 10348330
TI  - Spectral modulation of cortical connections measured by EEG coherence in humans.
AB  - OBJECTIVE: Description of coherence patterns of cortical EEG. METHODS: EEG
      recordings were collected from 9 subdural electrode grids implanted in 6 patients
      undergoing EEG monitoring for refractory epilepsy. RESULTS: Coherence decreased
      with increasing inter-electrode distance and exhibited considerable variability
      at the same inter-electrode distances. Analysis of variance demonstrated that
      both spatial and temporal factors contributed significantly (P < 0.01) to this
      variability. The spatial factor contributed the largest portion (up to 90%) of
      the variability, and was modulated by frequency and inter-electrode distance.
      CONCLUSION: The finding that the mean frequency modulation was consistent over
      time for the same pair of electrodes and was different between different pairs of
      electrodes indicated a spatial-spectral pattern of cortical synchrony. The
      connections (pairs of electrodes) could be accordingly predicted from their
      spatial-spectral pattern, which suggested that the spatial heterogeneity of
      neuronal synchrony was expressed not only by the degree of synchrony, but also by
      distinct spectral channels of synchrony. A model based on neuronal connection and
      activation is proposed to account for the observations.

PMID- 10348331
TI  - Cortical potentials preceding voluntary finger movement in patients with focal
      cerebellar lesion.
AB  - OBJECTIVE: To elucidate influences of the dentate nucleus on the generation of
      the related cortical potentials (MRCPs) preceding voluntary movement,
      Bereitschaftspotential (BP) and negative slope (NS). DESIGN AND METHODS: MRCPs
      preceding self-paced voluntary finger movement were recorded in 5 cases with
      localized cerebellar lesions due to stroke or tumor. Comparing 3 of them
      involving the dentate nucleus and 2 others sparing it, as judged from CT or MRI
      findings. RESULTS: BP and NS preceding voluntary finger movement ipsilateral to
      the lesion were absent or markedly reduced in amplitude in those 3 cases with the
      dentate nucleus lesion, whereas those negative components were present in the 2
      cases with no evidence of dentate lesion. CONCLUSION: The dentate nucleus has a
      facilitatory effect on the generation of BP and NS.

PMID- 10348332
TI  - Intracortical recordings of early pain-related CO2-laser evoked potentials in the
      human second somatosensory (SII) area.
AB  - We studied responses of the parieto-frontal opercular cortex to CO2-laser
      stimulation of A delta fiber endings, as recorded by intra-cortical electrodes
      during stereotactic-EEG (SEEG) presurgical assessment of patients with drug
      resistant temporal lobe epilepsy. After CO2-laser stimulation of the skin at the
      dorsum of the hand, we consistently recorded in the upper bank of the sylvian
      fissure contralateral to stimulation, a negative response at a latency of 135 +/-
      18 ms (N140), followed by a positivity peaking around 171 +/- 22 ms (P170). The
      stereotactic coordinates in the Talairach's atlas of the electrode contacts
      recording these early responses covered the pre- and post-rolandic part of the
      upper bank of the sylvian fissure (-27 < y < +12 mm; 31 < x < 57 mm; 4 < z < 23
      mm), corresponding to the accepted localization of the SII area in man, possibly
      including the upper part of the insular cortex. The spatial distribution of these
      early contralateral responses in the SII-insular cortex fits wit that of the
      modeled sources of scalp CO2-laser evoked potentials (LEPs) and with PET data
      from pain activation studies. Moreover, this study showed the likely existence of
      dipolar sources radial to the scalp surface in SII, which are overlooked in
      magnetic recordings. Early responses also occurred in the SII area ipsilateral to
      stimulation peaking 15 ms later than in contralateral SII, suggesting a callosal
      transmission of nociceptive inputs between the two SII areas. Other pain
      responsive areas such as the anterior cingulate gyrus, the amygdala and the
      orbitofrontal cortex did not show early LEPs in the 200 ms post-stimulus. These
      findings suggest that activation of SII area contralateral to stimulation,
      possibly through direct thalamocortical projections, represents the first step in
      the cortical processing of peripheral A delta fiber pain inputs.

PMID- 10348333
TI  - Parallel processing of sensory inputs: an evoked potentials study in Parkinsonian
      patients implanted with thalamic stimulators.
AB  - In two drug-resistant Parkinsonian subjects, who underwent thalamic chronic
      stimulation for extrapyramidal symptoms relief, median nerve somatosensory evoked
      potentials (SEPs) were recorded before and at different times following the
      thalamic lead implant. In both subjects, a transient obliteration of post
      rolandic SEPs components was detected; pre-rolandic waves' amplitude was
      preserved or showed a tendency to increase after the beginning of chronic
      stimulation. Parietal waves' amplitude totally recovered pre-surgical values
      after 1 month. Latency of both pre- and post-central components remained stable.
      The 'dissociate behaviour' of the examined waves following the thalamic implant
      reinforces the hypothesis that short-latency sensory inputs are processed by
      separate and independent routes which are functionally segregated at subcortical
      level.

PMID- 10348334
TI  - Facilitation of rhythmic events in progressive myoclonus epilepsy: a transcranial
      magnetic stimulation study.
AB  - Twelve subjects with progressive myoclonus epilepsy (PME) were studied with
      transcranial magnetic stimulation (TMS), using single and paired magnetic stimuli
      at different interstimulus intervals (ISIs), and polygraphic recording. Motor
      threshold (T) and silent period (SP) were normal. Paired TMS showed a loss of
      inhibition at 100-150 ms ISI and a marked facilitation at 50 ms ISI of
      conditioned motor evoked potential (MEP). Polygraphic analysis showed 20 Hz
      oscillatory activity over the sensorimotor area coupled to contralateral
      myoclonic jerks. These findings suggest a condition of increased supraspinal
      excitability and support the evidence of a cortical rhythm in the range of 20 Hz.
      No direct evidence exists that these findings are mediated by the same
      intracortical pathway. Furthermore, the normal SP and T suggest that the abnormal
      excitability is not a constant feature but is evident during rhythmic events.

PMID- 10348335
TI  - Peak gamma latency correlated with reaction time in a conventional oddball
      paradigm.
AB  - OBJECTIVE: To determine whether a relationship existed across trials between
      evoked gamma and reaction time in a conventional cognitive ERP paradigm. METHODS:
      Auditory oddball data in 40 normal subjects was examined. A moving Welch window
      and short time FFT were employed to elucidate the time course of gamma (29 to 45
      Hz) activity in each single-trial target ERP. The time point with maximum total
      gamma amplitude (across all sites) was identified automatically, and the
      associated amplitude, power and latency of this peak was determined. Spearman's
      rank correlation was employed to examine the relationship of these measures with
      reaction time. RESULTS: A highly significant and robust correlation between peak
      gamma latency and reaction time was found (P = 0.000001). Further frequency
      analysis revealed that this relationship was primarily confined to the 37 to 41
      Hz band. This narrow band finding, coupled with the fact that the finding
      remained after exclusion of possibly EMG contaminated epochs, indicated that the
      effect was not due to EMG contamination. No relationship between peak gamma
      amplitude or power and reaction time was found. CONCLUSIONS: Peak evoked gamma
      latency was correlated with reaction time and seems likely to have functional
      significance in relation to stimulus processing.

PMID- 10348336
TI  - Intracellular contribution to extracellularly recorded waveforms: the 'membrane
      rent' hypothesis.
AB  - OBJECTIVE: This investigation uses simulation studies to account for single
      muscle fiber waveforms with complex configurations as arising from the
      simultaneous recording of a partial intracellular discharge and its associated
      extracellular manifestation by way of an electrode-induced 'rent' or tear in the
      sarcolemma. METHODS: Published material on intracellular action potentials from
      healthy and 7 day denervated rat skeletal muscle was used as the basis for
      calculations. A single muscle fiber computer simulation capable of formulating a
      cut or crush termination effect used the modeled action potentials to generate
      extracellular waveforms at different locations along the muscle fiber. These
      extracellular waveforms were then summated with a varied fraction of the
      intracellular action potential to yield a combined potential. These simulated
      waveforms were then compared to previously recorded single muscle fiber
      discharges in order to establish if a combined waveform could reproduce the
      clinically recorded potentials' configuration. RESULTS: It was not possible to
      simulate any of the previously detected innervated single muscle fiber discharges
      by combining the action potential's intracellular and extracellular
      configurations. However, 12 of the 14 clinically observed complex waveforms
      documented in denervated tissue could be simulated with morphologies similar to
      the clinical potentials. CONCLUSIONS: Presumed single muscle fiber discharges
      with complex configurations may result from the needle electrode simultaneously
      recording the action potential's intracellular and extracellular waveforms
      secondary to a 'rent' in the sarcolemma. This explanation may in part account for
      some of the complex appearing potentials detected in denervated tissue, but this
      'rent' hypothesis is likely not the explanation for potentials observed in
      innervated muscle tissue. The apparent success of the 'rent' hypothesis in
      denervated tissue may be a result of the denervated action potential's unique
      morphology rather than an actual tear in the sarcolemma. Further investigations
      are necessary to determine if it is possible for a needle electromyographic
      electrode to actually record in part the intracellular action potential without
      disrupting the fiber.

PMID- 10348337
TI  - Frequency domain EEG source localization of ictal epileptiform activity in
      patients with partial complex epilepsy of temporal lobe origin.
AB  - The aim of this study was to investigate whether EEG source localization in the
      frequency domain, using the FFT dipole approximation (Lehmann, D. and Michel,
      C.M. Electroenceph. clin. Neurophysiol., 1990, 76: 271-276), would be useful for
      quantifying the frequency content of epileptic seizure activity. Between one and
      7 extracranially recorded seizures were analyzed in each of 7 patients with
      mesolimbic epilepsy, who were seizure-free after temporal lobe resection. The
      full scalp frequency spectrum for the first 4 s after seizure onset, as well as
      for subsequent periods, was determined. Power peaks in the spectra were
      identified, and an instant dipole fit was performed for the frequencies
      corresponding to these peaks. Ictal frequencies, ranging between 3.5 and 8.5 Hz,
      showed a variable degree of stability over time in the different patients. For a
      particular frequency, dipole results were similar during the different phases of
      seizure development. In patients with more than one prominent frequency, dipole
      results for the different frequencies were similar. Dipole results were also
      similar between patients. We conclude that dipole localization of dominant
      frequencies, as obtained from full scalp FFT analysis, gives quite reproducible
      results for seizures originating in the mesial temporal area. The method may
      become a useful tool for the pre-surgical identification of patients with
      mesolimbic epilepsy.

PMID- 10348338
TI  - Somatosensory evoked high-frequency oscillation in Parkinson's disease and
      myoclonus epilepsy.
AB  - AIM: A high-frequency oscillation in the range of 600-900 Hz has been shown to be
      a component of the somatosensory evoked potential (SEP) in humans. In the present
      communication, we studied these oscillation potentials in two neurological
      disorders. SUBJECTS AND METHODS: Subjects were 20 healthy volunteers, 17 patients
      with Parkinson's disease (PD) and 3 with myoclonus epilepsy (ME). Median nerve
      SEPs were recorded using filters set at 0.5 and 3000 Hz. Several peaks of
      oscillation were obtained by digitally filtering raw SEPs from 500 to 1000 Hz,
      and their amplitudes and onset latencies were measured. RESULTS: In normal
      subjects, several oscillation potentials were observed at the latency of 0 to 8
      ms after the onset of N20. In PD patients, the oscillation potentials at normal
      latencies were significantly larger than those of normal subjects. Moreover, in 7
      of 17 PD patients, they were extremely enlarged (>mean +/- 3 SD of normal
      values). In contrast, in patients with ME, abnormally enlarged oscillation
      potentials were seen at longer latencies (7-14 ms) in spite of normal-sized early
      oscillation potentials. Magnetoencephalographic analyses showed that any
      oscillation potentials originated from the primary sensory cortex. CONCLUSIONS:
      There are at least two mechanisms for producing the oscillation potentials of
      SEP. Those around N20 have some relation with the basal ganglia function and are
      enlarged in PD patients, the others around P25-N33 are enhanced in ME patients.

PMID- 10348339
TI  - Visual motion direction evoked potentials are direction specifically influenced
      by concurrent vestibular stimulation.
AB  - We investigated the influence of vestibular stimulation on visual motion
      direction perception using electrophysiological recordings. Visual motion
      direction evoked potentials decreased in area during the rotation of subjects
      about their vertical z-axis, when visual and vestibular motion directions were
      incongruous (visual and vestibular stimulation in the same directions). Visual
      pattern onset evoked potentials, however, remained unaffected by vestibular
      stimulation. For rotations about the interaural y-axis, decreased area of visual
      direction evoked potentials was found for both congruous and incongruous
      combinations of visual and vestibular stimulation. The results are in accordance
      with previous psychophysically obtained data and discussed in terms of postnatal
      development and neurophysiological optimization processes. An interaction model
      focused on reciprocal inhibition of the middle temporal visual (MT) area and the
      medial superior temporal (MST) area is presented.

PMID- 10348340
TI  - Human T-cell leukemia virus type 1 Tax protein induces the expression of STAT1
      and STAT5 genes in T-cells.
AB  - Human T-cell leukemia virus type 1 (HTLV-1) Tax transforms normal T-cells in the
      presence of interleukin (IL)-2 in vitro. STAT is a family of transcription
      factors that play a pivotal role in cytokine-induced functions of a various type
      of cells. We investigated the involvement of STATs in the transformation of T
      cells by HTLV-1. HTLV-1-transformed T-cell lines expressed higher amounts of
      STAT1, STAT3 and STAT5 RNA and proteins than virus-negative T cells. The
      expression of STAT1 and STAT5 in a human T-cell line was induced by Tax. IL-2
      induced the DNA binding activity of STAT3 and STAT5 of a HTLV-1-transformed cell
      line and then stimulated its proliferation. In contrast, IL-2 did neither in a
      cell line lacking STAT3 and STAT5. The expression of STAT1, STAT3 and STAT5 mRNAs
      were also induced by a T-cell mitogen in normal human peripheral blood
      mononuclear cells. Our results suggest that the induction of STAT1 and STAT5 by
      Tax enhances cytokine-induced functions of virus-infected T-cells, hence the
      induction may play a role in IL-2-dependent transformation steps of T-cells by
      HTLV-1.

PMID- 10348341
TI  - Mutator phenotype of BCR--ABL transfected Ba/F3 cell lines and its association
      with enhanced expression of DNA polymerase beta.
AB  - Chronic myelogenous leukemia (CML) is characterized by the Philadelphia
      chromosome resulting from the translocation t(9-22) producing the chimeric 190
      and 210 kDa BCR-ABL fusion proteins. Evolution of the CML to the more agressive
      acute myelogenous leukemia (AML) is accompanied by increased cellular
      proliferation and genomic instability at the cytogenetic level. We hypothezised
      that genomic instability at the nucleotide level and spontaneous error in DNA
      replication may also contribute to the evolution of CML to AML. Murine Ba/F3 cell
      line was transfected with the p190 and p210-encoding BCR-ABL oncogenes, and
      spontaneous mutation frequency at the Na-K-ATPase and the hypoxanthine guanine
      phosphoribosyl transferase (HPRT) loci were measured. A significant 3-5-fold
      increase in mutation frequency for the transfected cells relative to the
      untransfected control cells was found. Furthermore, we observed that BCR-ABL
      transfection induced an overexpression of DNA polymerase beta, the most
      inaccurate of the mammalian DNA polymerases, as well as an increase in its
      activity, suggesting that inaccuracy of DNA replication may account for the
      observed mutator phenotype. These data suggest that the Philadelphia abnormality
      confers a mutator phenotype and may have implications for the potential role of
      DNA polymerase beta in this process.

PMID- 10348342
TI  - Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor
      tyrosine kinase.
AB  - The ErbB/HER family of receptor tyrosine kinases consists of four receptors that
      bind a large number of growth factor ligands sharing an epidermal growth factor-
      (EGF)-like motif. Whereas ErbB-1 binds seven different ligands whose prototype is
      EGF, the three families of neuregulins (NRGs) activate ErbB-3 and/or ErbB-4. Here
      we characterize a fourth neuregulin, NRG-4, that acts through ErbB-4. The
      predicted pro-NRG-4 is a transmembrane protein carrying a unique EGF-like motif
      and a short cytoplasmic domain. A synthetic peptide encompassing the full-length
      EGF-like domain can induce growth of interleukin-dependent cells ectopically
      expressing ErbB-4, but not cells expressing the other three ErbB proteins or
      their combinations. Consistent with specificity to ErbB-4, NRG-4 can displace an
      ErbB-4-bound NRG-1 and can activate signaling downstream of this receptor.
      Expression of NRG-4 mRNA was detected in the adult pancreas and weakly in muscle;
      other tissues displayed no detectable NRG-4 mRNA. The primary structure and the
      pattern of expression of NRG-4, together with the strict specificity of this
      growth factor to ErbB-4, suggest a physiological role distinct from that of the
      known ErbB ligands.

PMID- 10348343
TI  - The double-stranded RNA activated protein kinase PKR physically associates with
      the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in
      vitro.
AB  - The tumor suppressor p53 is a multifunctional protein that plays a critical role
      in modulating cellular responses upon DNA damage or other stresses. These
      functions of p53 are regulated both by protein-protein interactions and
      phosphorylation. The double-stranded RNA activated protein kinase PKR is a
      serine/threonine kinase that modulates protein synthesis through the
      phosphorylation of translation initiation factor eIF-2alpha. PKR is an interferon
      (IFN)-inducible protein that is thought to mediate the anti-viral and anti
      proliferative effects of IFN via its capacity to inhibit protein synthesis. Here
      we report that PKR physically associates with p53. The interaction of PKR with
      p53 is enhanced by IFNs and upon conditions that p53 acquires a wild type
      conformation. PKR/p53 complex formation in vitro requires the N-terminal
      regulatory domain of PKR and the last 30 amino acids of the C-terminus of human
      p53. In addition, p53 may function as a substrate of PKR since phosphorylation of
      human p53 on serine392 is induced by activated PKR in vitro. These novel findings
      raise the possibility of a functional interaction between PKR and p53 in vivo,
      which may account, at least in part, for the ability of each protein to regulate
      gene expression at both the transcriptional and the translational levels.

PMID- 10348344
TI  - HuD, a neuronal-specific RNA-binding protein, is a putative regulator of N-myc
      pre-mRNA processing/stability in malignant human neuroblasts.
AB  - N-myc gene copy numbers and transcription rates are similar in N (neuroblastic,
      tumorigenic) and S (non-neuronal, non-tumorigenic) neuroblastoma cells with
      chromosomally integrated amplified N-myc genes. However, N cells show
      significantly higher N-myc mRNA levels than S cells. Therefore, post
      transcriptional control of N-myc gene expression must differ between these cell
      types. Since no differences in N-myc mRNA half-life were found between N and S
      cells from two cell lines, steady-state levels of N-myc pre-mRNA processing
      intermediates were analysed. Results suggest that the differences in N-myc
      expression arise primarily at the nuclear post-transcriptional level. The
      neuronal-specific RNA-binding Hu proteins are present in cytoplasmic and nuclear
      fractions of N cells and one of them, HuD, binds specifically to both exonic and
      intronic N-myc RNA sequences. In sense and antisense HuD-transfected N cells,
      there are coordinate changes in HuD and N-myc expression levels. Thus, we propose
      that HuD plays a role in the nuclear processing/stability of N-myc pre-mRNA in N
      type neuroblastoma cells.

PMID- 10348345
TI  - cDNA expression array reveals heterogeneous gene expression profiles in three
      glioblastoma cell lines.
AB  - Tumor cell lines are an indispensable tool for cancer research. However, among
      cell lines of the same pathological group, heterogeneity has been detected in
      gene expression, gene mutation, and cellular response to various treatments. In
      this study, we systematically investigated the extent of heterogeneity of gene
      expression in three glioblastoma cell lines using cDNA array technology in which
      the expression of 588 cellular genes is studied simultaneously. Comparison of the
      expression profiles revealed substantial qualitative and quantitative
      heterogeneity. Among the 588 genes, 197 genes were expressed in all three lines
      and 56 genes were not expressed in any of the three lines; total of 222 genes
      were expressed in only two of the three cell lines, and 113 genes were expressed
      in only one of the three cell lines. These results provide molecular evidence
      that cell lines of the same pathological origin can be highly heterogeneous.

PMID- 10348346
TI  - p19ARF prevents G1 cyclin-dependent kinase activation by interacting with MDM2
      and activating p53 in mouse fibroblasts.
AB  - p19ARF encoded by the INK4a tumor suppressor gene locus functions upstream of p53
      to induce cell cycle arrest. p19ARF can interact with MDM2 and p53 in cells
      ectopically overexpressing these three components, but the biochemical cascades
      from p19ARF to cell cycle arrest has not been fully elucidated. In this study, we
      generated stably transfected NIH3T3 cells that express exogenous p19ARF under the
      control of a heavy metal-inducible metalothionine promoter. Cells arrested in G1
      by ectopically expressed p19ARF contained considerably reduced G1 cyclin
      dependent kinase (cdk2 and cdk4) activities. The expression of cyclin A (a
      regulatory subunit of cdk2) markedly decreased, while cyclin D1, the major cdk4
      partner in fibroblasts, expressed at a slightly higher level and formed complexes
      with cdk2 and cdk6 in addition to cdk4. Induction of p19ARF activated p53 by
      increasing its stability, and allowed the expression of p21Cip1, which bound to
      all of the cyclin D1-cdk complexes (cyclin D1-cdk2, -cdk4, and -cdk6) thereby
      inhibiting their kinase activities. p19ARF formed complexes with several cellular
      proteins including mouse MDM2. The majority of MDM2 was found in the complex with
      p19ARF, while no p53 was detected in association with p19ARF. Thus, we propose
      that p19ARF neutralizes MDM2 by sequestration from p53, which results in
      activation of p53, inhibition of G1 cyclin-cdk activities, and G1 arrest.

PMID- 10348348
TI  - SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with
      the human Polycomb group complex.
AB  - Chromosome translocation t(X;18)(p11.2;q11.2) is unique to synovial sarcomas and
      results in an 'in frame' fusion of the SYT gene with the SSX1 or closely-related
      SSX2 gene. Wild-type SYT and SSX proteins, and the SYT-SSX chimaeric proteins,
      can modulate transcription in gene reporter assays. To help elucidate the role of
      these proteins in cell function and neoplasia we have performed immunolabelling
      experiments to determine their subcellular localization in three cell types.
      Transient expression of epitope-tagged proteins produced distinctive nuclear
      staining patterns. The punctate staining of SYT and SYT-SSX proteins showed some
      similarities. We immunolabelled a series of endogenous nuclear antigens and
      excluded the SYT and SYT-SSX focal staining from association with these domains
      (e.g. sites of active transcription, snRNPs). In further experiments we
      immunolabelled the Polycomb group (PcG) proteins RING1 or BMI-1 and showed that
      SSX and SYT-SSX proteins, but not SYT, co-localized with these markers.
      Consistent with this we show that SSX and SYT-SSX associate with chromatin, and
      also associate with condensed chromatin at metaphase. Noteably, SSX produced a
      dense signal over the surface of metaphase chromosomes whereas SYT-SSX produced
      discrete focal staining. Our data indicate that SSX and SYT-SSX proteins are
      recruited to nuclear domains occupied by PcG complexes, and this provides us with
      a new insight into the possible function of wild-type SSX and the mechanism by
      which the aberrant SYT-SSX protein might disrupt fundamental mechanisms
      controlling cell division and cell fate.

PMID- 10348347
TI  - Expression of human p53 requires synergistic activation of transcription from the
      p53 promoter by AP-1, NF-kappaB and Myc/Max.
AB  - Transcriptional control of p53 expression participates in the generation of
      appropriate levels of active p53 in response to mitogenic stimulation. This
      prompted us to study the role of a putative AP-1 and a NF-kappaB motif in the
      human p53 promoter for transcriptional regulation. We show that mutation of the
      AP-1 or the NF-kappaB motif abolishes transcription from the human p53 promoter
      in HeLa, HepG2 and adenovirus type 5 E1-transformed 293 cells. In comparison,
      mutation of the previously characterized Myc/Max/USF binding site in the human
      p53 promoter reduces the transcription rate fivefold. The AP-1 motif in the human
      p53 promoter binds c-Fos and c-Jun and the NF-kappaB motif binds p50(NF-kappaB)
      and p65RelA. The cooperative nature of transcriptional activation by these
      factors was documented by repression of c-fos or NF-kappaB1 translation:
      Pretreatment of the cells with a c-fos or p50(NF-kappaB1) antisense
      oligonucleotide suppresses transcription from the human p53 promoter completely.
      In addition, we show that (a) the level of endogenous p53 mRNA and (b)
      transcription from the strictly p53-dependent human mdm2 promoter are reduced in
      the presence of c-fos, c-jun, p50(NF-kappaB1), p65RelA or c-myc antisense
      oligonucleotides, underscoring the importance of these transcription factors for
      the expression of functional p53.

PMID- 10348349
TI  - Induction of apoptosis and G2/M cell cycle arrest by DCC.
AB  - The Deleted in Colorectal Cancer gene (DCC) encodes a cell surface receptor that
      belongs to the Ig superfamily. Inactivation of the DCC gene has been implicated
      in human tumor progression. However, little is known about the biological
      function of the DCC protein. In the present study, we demonstrated that
      expression of DCC activated caspase-3 and programmed cell death, or induced G2/M
      cell cycle arrest in tumor cells. In some cell lines, apoptosis was evident
      within 24 h of DCC expression. Timing of the appearance of apoptotic cells
      coincided with that of the cleavage of poly (ADP-ribose) polymerase, a substrate
      of caspase-3. Expression of the apoptosis inhibitory gene Bcl-2 was not able to
      abrogate the DCC-induced apoptosis. In the G2/M cycle arrest cells, cdk1 activity
      was inhibited. Our results suggest that the DCC protein may transduce signals
      resulting in activation of caspases or inhibition of Cdk1. These data provide a
      possible mechanism by which DCC suppresses tumorigenesis.

PMID- 10348350
TI  - FGF8 over-expression in prostate cancer is associated with decreased patient
      survival and persists in androgen independent disease.
AB  - Identification of prostate cancers at high risk of progression is difficult and a
      better understanding of how peptide growth factors influence cellular function
      might be useful. Fibroblast growth factors (FGFs) have been implicated in
      prostate cancer development. FGF8 was identified in the Shionogi mouse mammary
      carcinoma SC-3 cell line as an androgen-induced mitogen. We tested if FGF8 was
      over-expressed in human prostate cancer and if its expression correlated with
      clinical data and outcome. One hundred and six cases of prostate cancer and ten
      cases of BPH were examined. In situ hybridization was employed to detect FGF8
      mRNA expression, which was identified within the malignant prostatic epithelium
      in 85/106 (80.2%) cases. Increased expression of FGF8 correlated significantly
      with higher Gleason scores (P=0.0004) and advanced tumour stage (P=0.0016). Using
      immunohistochemistry, we confirmed over-expression of the FGF8b isoform. Men with
      tumours which expressed high levels of FGF8 had worse survival (P=0.034),
      although FGF8 mRNA was not able to provide additional prognostic information in a
      multivariate analysis. Additionally, FGF8 expression was shown to persist in
      androgen independent prostate cancer. Using a range of normal adult tissues, FGF8
      expression was restricted to neurones and the germinal epithelium in addition to
      the prostate. In vitro studies demonstrated that in the presence of neutralizing
      antibody to FGF8b there was significant inhibition of prostate cancer cell
      growth, confirming the biological significance of FGF8 in prostate
      carcinogenesis.

PMID- 10348351
TI  - The retinoblastoma susceptibility gene product/Sp1 signalling pathway is
      modulated by Ca2+/calmodulin kinases II and IV activity.
AB  - To investigate the possible link between Ca2+ signalling and cell cycle control
      we analysed Ca2+/calmodulin kinases (CamK) interaction with the retinoblastoma
      susceptibility gene product/SP1 pathway. CamK II and IV activate c-fos
      transcription through a short promoter region (-99 to -53) containing the
      retinoblastoma control element (RCE) and a cAMP response element (CRE) related
      sequences. Deletion analysis revealed that the RCE is a major CamK responsive
      element and is sufficient to confer CamK and Ca2+ regulation to a minimal
      promoter. Direct interactions between SP1 and RCE were confirmed by gel shift
      experiments. Using transient transfection experiments, we show that CamK
      dependent transcription is regulated by the retinoblastoma (Rb) susceptibility
      gene product and the p107 Rb related protein. However, the stimulatory effects of
      CamKs and Rb on c-fos are blocked by overexpression of both proteins. These
      effects appear to be directly mediated by SP1 as shown by the use of a Gal4/SP1
      fusion proteins. In conclusion, CamK II and IV, two major Ca2+-dependent
      intracellular effectors, may represent a molecular link between this second
      messenger transduction pathway and effectors that control cell cycle progression
      through Rb/SP1 signalling pathway.

PMID- 10348352
TI  - Cell cycle dependent subcellular distribution of Cdc25B subtypes.
AB  - The dual specificity phosphatase and oncogene Cdc25B has been implicated in the
      G2/M cell cycle checkpoint, but the mode by which it is regulated remains poorly
      understood. Regional subcellular redistribution of proteins represents a unique
      potential regulatory mechanism. Thus, we examined in live cells the subcellular
      localization characteristics of Cdc25B2 and Cdc25B3 fused to green fluorescent
      protein. Cdc25B2 partitioned primarily in the cytoplasm during G1 and
      progressively migrated to the nucleus as cells transited from S to G2/M phase. In
      contrast, Cdc25B3 maintained a homogeneously staining diffuse phenotype
      irrespective of cell cycle phase. Treatment of the Cdc25B2-green fluorescent
      protein stable transfectants with vanadate inhibited the cell cycle dependency of
      intracellular distribution, while okadaic acid had little effect except in G1,
      suggesting regulation by at least one phosphorylation-dependent pathway. The DNA
      topoisomerase II poison and DNA damaging agent, etoposide, inhibited nuclear
      localization of Cdc25B2 in S phase, possibly by invoking a sequestration cascade.
      Thus, differences in the spatial distribution of Cdc25B subtypes exist within
      cells and the 41 amino acid insert in the N-terminus of the Cdc25B3 splice
      variant encodes an important inhibitory determinant for such regulation. The
      subcellular redistribution of Cdc25B2 could be functionally important for G2/M
      checkpoint regulation.

PMID- 10348353
TI  - Altered expression of the MYCN oncogene modulates MRP gene expression and
      response to cytotoxic drugs in neuroblastoma cells.
AB  - We have recently shown a close correlation between expression of the Multidrug
      Resistance-associated Protein (MRP) gene and the MYCN oncogene and provided
      evidence that high MRP expression is a powerful independent predictor of poor
      outcome in neuroblastoma (Norris et al., New Engl. J. Med., 334, 231-238, 1996).
      The effect of MYCN down-regulation on MRP expression and response to cytotoxic
      drugs was investigated in NBL-S neuroblastoma cells transfected with MYCN
      antisense RNA constructs. Concomitant with MYCN down-regulation, the level of MRP
      expression was decreased in the NBAS-4 and NBAS-5 antisense transfectants. These
      cells demonstrated significantly increased sensitivity to the high affinity MRP
      substrates vincristine, doxorubicin, sodium arsenate and potassium antimony
      tartrate, but not to the poor MRP substrates, taxol or cisplatin. Similarly,
      transfection of full-length MYCN cDNA into SH-EP neuroblastoma cells resulted in
      increased MRP expression and significantly increased resistance specifically to
      MRP substrates. The results provide evidence for the MYCN oncogene influencing
      cytotoxic drug response via regulation of MRP gene expression. Our data also
      provide a link between the malignant and chemoresistant phenotypes of this
      childhood malignancy.

PMID- 10348354
TI  - Specific accumulation of Rho-associated kinase at the cleavage furrow during
      cytokinesis: cleavage furrow-specific phosphorylation of intermediate filaments.
AB  - The small GTPase Rho and one of its targets, Rho-associated kinase (Rho-kinase),
      are implicated in a wide spectrum of cellular functions, including cytoskeletal
      rearrangements, transcriptional activation and smooth muscle contraction. Since
      Rho also plays an essential role in cytokinesis, Rho-kinase may possibly mediate
      some biological aspects of cytokinesis. Here, using a series of monoclonal
      antibodies that can specifically recognize distinct phosphorylated sites on glial
      fibrillary acidic protein (GFAP) and vimentin, phosphorylation sites by Rho
      kinase in vitro were revealed to be identical to in vivo phosphorylation sites on
      these intermediate filament (IF) proteins at the cleavage furrow in dividing
      cells. We then found, by preparing two types of anti-Rho-kinase antibodies, that
      Rho-kinase accumulated highly and circumferentially at the cleavage furrow in
      various cell lines. This subcellular distribution during cytokinesis was very
      similar to that of ezrin/radixin/moesin (ERM) proteins and Ser19-phosphorylated
      myosin light chain. These results raise the possibility that Rho-kinase might be
      involved in the formation of the contractile ring by modulating these F-actin
      binding proteins during cytokinesis and in the phosphorylation and regulation of
      IF proteins at the cleavage furrow.

PMID- 10348355
TI  - Immunolocalization of gelatinase-A (matrix metalloproteinase-2) in damaged human
      temporomandibular joint discs.
AB  - The fibrous tissue of the articular disc of the dysfunctional temporomandibular
      joint undergoes deep and variable structural modifications. Here the concurrence
      of morphological changes and the expression of matrix metalloproteinase-2 (MMP-2)
      in damaged discs from individuals suffering joint dysfunction was investigated.
      Microscopic, ultrastructural and immunocytochemical investigations were made on
      variously damaged articular discs and on one control sample. Disaggregation of
      collagen fibres, an increase in cellular components and calcification of large
      areas of tissue were observed in the damaged discs. These modifications were
      accompanied by a positive immunoreaction pattern for MMP-2. Fibroblast-,
      chondroblast- and osteoblast-like cells displayed a positive cytoplasmic
      reaction. In samples displaying evidence of synovial hyperplasia, some cells of
      the synovial protrusions were MMP-2 immunoreactive. No MMP-2 staining was
      observed in the control sample. These findings demonstrate that structural
      modifications of the articular disc could be specific responses to changes in the
      function of the temporomandibular joint. Variations in extrinsic stimuli may
      activate intrinsic factors, such as MMPs, that induce structural modifications in
      the discal tissue.

PMID- 10348356
TI  - Salivary and serum soluble interleukin-2 receptor in primary Sjogren's syndrome.
AB  - Salivary and serum concentrations of soluble interleukin-2 receptor (sIL-2R) were
      studied in a group of patients with Sjogren's syndrome and a group suffering from
      dry mouth. Salivary sIL-2R levels was significantly higher (57.9+/-15.1 vs 16.7+/
      4.7 pg/ml) (p < 0.05) in the group of 26 patients with Sjogren's syndrome than in
      the dry-mouth group. Both the salivary and the serum sIL-2R of normal controls
      were below the level of detection. No significantly statistical differences were
      noted between the concentrations of serum sIL-2R in either abnormal groups. No
      correlations were found between salivary or serum sIL-2R and the erythrocyte
      sedimentation rate, C-reactive protein, the presence of various autoantibodies or
      the focus score from lip biopsies in the group of patients with Sjogren's
      syndrome. The results show that, although the salivary sIL-2R does not actually
      reflect the extent of inflammation, it might have an important role in the
      diagnosis of Sjogren's syndrome.

PMID- 10348357
TI  - Autofluorescence in human dentine in relation to age, tooth type and temperature
      measured by nanosecond time-resolved fluorescence microscopy.
AB  - Stationary and dynamic characteristics of autofluorescence in human dentine were
      examined with a nanosecond time-resolved fluorescence microphotometer. With
      ageing, the intensity of the fluorescence increased whereas the decay time
      decreased. There were no differences in fluorescence intensity, decay time or
      spectral profile among tooth types taken from the same individuals or from
      individuals of the same age. Fluorescence intensity was enhanced after the
      application of heat (37 and 50 degrees C), but remained unchanged when specimens
      were kept at 4 degrees C. These results suggest that the increase in fluorescence
      intensity was partially due to a temperature-dependent physicochemical mechanism.

PMID- 10348358
TI  - Effect of intravenous infusion of an alpha-adrenergic blocking agent on the
      haemodynamic changes in human masseter muscle induced by cold pressor
      stimulation.
AB  - This study evaluated the effect of intravenous infusion of a non-selective alpha
      adrenergic blocking agent on masseter muscle haemodynamics induced by 4 degrees C
      cold pressor stimulation (CPS) of the right foot and ankle, which reportedly
      evokes a rapidly increasing sympathetic nerve activity in human skeletal muscle.
      Nine healthy non-smoking males (mean age 23.7+/-2.1 year) with no history of
      chronic muscle pain or migraine participated. The haemoglobin (Hb) concentration
      in the right masseter was continuously recorded by non-invasive, near-infrared
      spectroscopy. Heart rate and blood pressure were also recorded. The experiment
      involved the following sequence: (1) a placebo (physiological saline) with a CPS
      trial; (2) a 30-sec maximal voluntary clenching (MVC)-only trial; and (3) an
      alpha-adrenergic blocking agent with a CPS trial. The saline and drug trials each
      involved continuous recording for 1 min before, 2 min during and 5 min after the
      CPS. Physiological saline (20 ml) or phentolamine mesylate (20 ml) were infused
      at the rate of 2 ml/min. This infusion was begun 15 min before baseline recording
      and participants were not aware which solution (saline or phentolamine) was being
      infused. For the MVC trial, each participant performed a 30-sec MVC of his jaw
      closing muscles followed by a 15-min rest between each trial. The individual Hb
      data were adjusted so that the baseline at the beginning of the experiment was
      equal to zero and all data were normalized as a percentage of the individual's
      highest absolute Hb change seen after the MVC. The mean baseline Hb
      concentrations 1 min before CPS were significantly higher in the alpha-blocker
      trial (83.6%) than in the placebo saline trial (P < 0.001). The change in mean Hb
      concentration from baseline during CPS in the alpha-blocker trial was
      significantly less than in the placebo trial (P = 0.006). Mean heart rate before
      CPS was also significantly higher in the alpha-blocker trial (85.2 beats/min)
      than in the placebo trial (69.6 beats/min) (P < 0.001). There were no significant
      differences in the mean systolic and diastolic blood pressures between the
      placebo and alpha-blocker trials in any time period. The results suggest that non
      selective alpha-adrenoceptor blockade increases the blood volume in the masseter
      muscle. This change might be due to a combination of peripheral vasodilation and
      an increase in cardiac output.

PMID- 10348359
TI  - Adaptation of guinea-pig superficial masseter muscle to an increase in occlusal
      vertical dimension.
AB  - To study the effect of increased occlusal vertical dimension on the fibre
      phenotypes of the superficial masseter muscle, the composition of myosin heavy
      chains (MHC), myosin light-chains (MLC) and tropomyosin was investigated by
      sodium dodecyl sulphate-polyacrylamide gel electrophoresis and two-dimensional
      gel electrophoresis in conjunction with densitometric analysis in normal
      (control) and bite-opened (5.7 mm increase in the vertical dimension for 1 week)
      guinea-pigs. The superficial masseter contained two fast-type MHC isoforms, II-1
      and II-2, in both the bite-opened and control groups; their relative content
      (mean+/-SD, n = 7) was 47.8+/-2.9% and 52.2+/-2.9%, in the bite-opened and 44.4+/
      3.0% and 55.6+3.0% in control preparations, indicating no significant (p>0.05)
      changes in MHC composition in association with the bite opening. On the other
      hand, significant differences in MLC and tropomyosin composition were found
      between the two preparations. Although the MLC consisted of three components,
      LC1f, LC2f and LC3f, in both preparations, their relative content (mean+/-SD, n =
      7) was 37.1+/-2.4%, 49.6+/-1.6% and 13.2+/-3.2%, respectively, in the bite-opened
      and 28.1+/-3.1%, 50.9+/-1.6% and 21.0+/-3.5% in the control preparations,
      indicating that the bite opening induced a significant (p < 0.0001) increase in
      the relative content of LC1f at the expense of that of LC3f. Although the
      tropomyosin consisted of two components, TM-alpha and TM-beta, in both
      preparations, their relative content (mean+/-SD, n = 7) was 91.8%+/-1.9% and
      8.2+/-1.9%, respectively, in the bite-opened and 95.9+/-0.7% and 4.1+/-0.7% in
      the control preparations, showing a significant (p < 0.001) increase in the
      relative content of TM-beta in relation to the bite opening. These results
      indicate that in guinea-pigs an increase in occlusal vertical dimension for 1
      week changes the composition of MLC and tropomyosin, with no significant change
      in MHC, in the masseter muscle. These changes might be required to meet altered
      functional demands.

PMID- 10348360
TI  - Induction of apoptosis in human gingival fibroblasts by a Porphyromonas
      gingivalis protease preparation.
AB  - Proteases produced by Porphyromonas gingivalis are believed to contribute to the
      pathogenesis of periodontal diseases. Here the cytotoxic effects of a purified
      preparation of a P. gingivalis protease with trypsin-like specificity were tested
      on human gingival fibroblasts in vitro. The active protease induced apoptotic
      cell death in the fibroblasts, as indicated by DNA fragmentation and the
      expression of 7A6 antigen. Thus, the production of proteases by periodontopathic
      bacteria could be an important factor in the induction of apoptosis of host cells
      in the aetiology of periodontal diseases.

PMID- 10348361
TI  - Metabolic indicators of hydration status in the prediction of parotid salivary
      gland function.
AB  - Salivary glands require body fluids for normal function. It has been suggested
      that decreased levels of hydration (dehydration) may cause diminished salivary
      output, but it is not known whether salivary flow rates are related to biological
      measures of hydration status. The purpose of this study was to determine whether
      reduced parotid salivary flow rates, as a result of dehydration, can be assessed
      through physiological markers of hydration status. Twenty-four healthy and
      unmedicated adults abstained from eating and drinking for 24 h and then underwent
      intravenous rehydration to replace all lost weight. Unstimulated (UPFR) and 2%
      citric acid-stimulated (SPFR) parotid flow rates, body weight, and markers of
      hydration status (haematocrit, haemoglobin, serum sodium, plasma protein,
      creatinine, serum and urine osmolality) were assessed at baseline, at the
      completion of the 24-h dehydration period, and 1 h after rehydration had been
      completed. Correlation coefficients (r) and coefficients of determination (r2)
      were obtained between: (a) UPFR and each metabolic variable at each time point,
      (b) the change in UPFR and the corresponding change in each metabolic variable
      due to dehydration and rehydration, and (c) the percentage change in UPFR and the
      corresponding percentage change of each metabolic variable due to dehydration and
      rehydration. These tests were then repeated for SPFR. There were several isolated
      significant correlations but no consistent trends between salivary flow rates and
      metabolic markers of hydration status. These findings suggest that metabolic
      indicators of hydration status are not accurate predictors of parotid salivary
      flow rates.

PMID- 10348362
TI  - Differences in the pattern of lanthanum diffusion into predentine and dentine in
      mouse incisors and molars.
AB  - Lanthanum nitrate was either perfused intravascularly or segments of mouse tooth
      were immersed in a fixative solution containing the tracer. The tracer deposits
      were examined in young (8-day-old) and older (8-week-old) mouse incisors and
      molars, demineralized or undemineralized. Lanthanum passed the distal junctional
      complex of odontoblasts and appeared in the predentine of incisors as large
      electron-dense stellate aggregates, 40-70 nm in diameter, and in molars as round,
      20-40 nm dots. In dentine, tracer deposits were detected at three locations. Near
      the predentine dentine junction, the tracer densely stained a band 0.5-2.5 microm
      in width, also termed metadentine; in the inner circumpulpal dentine, the
      staining was weaker or lacking in an area extending 5-7 microm from the
      predentine-dentine junction; in outer circumpulpal dentine, lateral diffusion had
      occurred in porosities of intertubular dentine. Lanthanum impregnated the walls
      of dentine tubules and a peritubular-like dentine. In contrast, the mantle
      dentine was never stained. These differences in the pattern of diffusion prove
      that lanthanum staining is age-dependent and varies between mouse incisors and
      molars, independently of tissue processing. Architectural properties and driving
      flux are involved in the transport and localization of lanthanum in predentine
      and dentine.

PMID- 10348363
TI  - Stimulation of proliferation and differentiation of dog dental pulp cells in
      serum-free culture medium by insulin-like growth factor.
AB  - Insulin, insulin-like growth factors (IGF) I and II are considered to play an
      important part in the growth and differentiation of dental pulp cells. The
      present study examined the effects of these factors on pulp cells in serum-free
      culture conditions. The DNA content and alkaline phosphatase (ALPase) activity of
      dog pulp cells increased when they were cultured in a serum-free medium
      supplemented with transferrin, yolk lipoprotein and basic fibrobrast growth
      factor (TYF medium). The pulp cells produced type I collagen but not type III,
      suggesting that they might proliferate and differentiate into odontoblast-like
      cells in a serum-free culture. Both IGF-I and IGF-II enhanced the ALPase activity
      of pulp cells cultured in TYF medium to an equivalent level, but a higher
      concentration of IGF-II was necessary to produce a similar effect on DNA
      synthesis to that of IGF-I. Insulin dose-dependently enhanced DNA synthesis and
      increased ALPase activity, but its effects were weaker than those of the IGFs.
      These findings suggest that IGF-I might have a primary role in the growth and
      differentiation of pulp cells.

PMID- 10348364
TI  - Histochemical localization of hyaluronan and versican in the rat molar dental
      pulp.
AB  - The distribution of hyaluronan and versican in the dental pulp of the young rat
      was mapped histochemically. The pattern of staining showed considerable variation
      between different teeth and different specimens. The most common pattern was a
      strong reaction for hyaluronan and a weak reaction for versican in the
      subodontoblastic region, with the reverse deeper in the pulp. This was not an
      entirely consistent pattern and there was considerable regional variation in the
      staining intensity for both molecules. The localization of these molecules at
      similar sites could thus indicate related roles in the connective tissue matrix
      rather than any chemical bonding between them.

PMID- 10348365
TI  - Stimulating activity of Chinese medicinal herbs on human lymphocytes in vitro.
AB  - The effects of eight kinds of Chinese medicinal herbs (CMH) on human lymphocytes
      was studied in vitro. The extract of Cinnamomum cassia presl markedly stimulated
      human lymphocytes to proliferate. Codonopsis pilosula, Oldenlandia diffusa and
      Rhizoma typhonii weakly stimulated. These extracts enhanced cytotoxic T
      lymphocyte (CTL) activity, but failed to enhance natural killer (NK)-cell
      activity. The extracts of these CMHs have stimulatory effect on immunoglobulin
      (Ig) production by B-cells and interleukin(IL)-1 production by monocytes. These
      activities of Cinnamomun cassia presl extract are associated with glycoproteins,
      whose molecular weight was about 100 KDa. These results suggest that CMH extracts
      have a stimulating activity on human lymphocytes and these abilities could be
      used clinically for the treatment of diseases such as cancer.

PMID- 10348366
TI  - Atiprimod (SK&F 106615), a novel macrophage targeting agent, enhances alveolar
      macrophage candidacidal activity and is not immunosuppressive in Candida-infected
      mice.
AB  - Azaspiranes are novel macrophage-targeting agents with activity in preclinical
      animal models of autoimmune disease and transplantation. The purpose of this work
      was to determine the effects of atiprimod (SK&F 106615), an azaspirane being
      developed for the treatment of rheumatoid arthritis, on rat pulmonary alveolar
      macrophage (AM) function and immunocompetance in Candida-infected mice. AM from
      rats treated with 20 mg/kg/day of atiprimod for 15 days demonstrated enhanced
      killing of Candida albicans ex vivo. Concentration-dependent increases in
      candidacidal activity were also observed as early as one hour after exposure in
      vitro in AM from untreated normal rats. Treatment of AM with atiprimod in vitro
      did not increase particulate-stimulated superoxide production or phagocytosis of
      Candida but decreased their ability to concentrate acridine orange, indicating an
      increase in lysosomal pH. Increased candidacidal activity was inhibited by
      superoxide dismutase and catalase, suggesting a role for reactive oxygen
      intermediates (ROI). Atiprimod also increased free radical-mediated killing of
      Candida in the presence of H2O2, iron and iodide in a cell-free system. These
      findings indicated that treatment with atiprimod increased the candidacidal
      activity of rat AM in a free radical-dependent manner. The data also suggested
      that atiprimod did not increase ROI production by AM, but rather increased the
      efficiency of radical-mediated killing. This increase may be caused by
      cyclization of atiprimod, facilitating electron transfer and peroxidation of
      lipid membranes. In vivo studies in Candida-infected CBA mice showed that
      atiprimod (10 mg/kg/day), did not compromise immune function in the infected mice
      and could be differentiated from prototypical immunosuppressive compounds used
      for treatment of autoimmune diseases.

PMID- 10348367
TI  - Effect of multiparity on T-cell proliferation response to mitogen stimulation in
      elderly women.
AB  - The purpose of the present study was to investigate whether multiparity in women
      prevents some age-related changes in their cell function, as is known for age and
      sex. 49 women from the same village, free of acute inflammation or neoplastic
      diseases, were selected and divided into the following three groups: nulliparous
      1935 years old, nulliparous 65 92 years old and multiparous (3-9 pregnancies) 65
      88 years old. The response of their blood-lymphocytes to phytohaemagglutinin-P
      was estimated by thymidine uptake, number of mitoses and number of sister
      chromatid exchanges. The stimulation index, mitotic index and proliferative rate
      in the aging nulliparous women were significantly lower than in the younger
      nulliparous women, but the latter group (young nulliparous) did not differ in
      their lymphocyte parameters assayed, from the values in the aging multiparous
      women breast-feeding their newborn. It is concluded that when the proliferative
      capacity to mitogen in elderly multiparous women (after 3-9 pregnancies) is
      related to breast feeding, it is similar to the proliferative capacity in young
      women. We suggest therefore, that breast feeding is beneficial not only to the
      newborns, but also to their mothers.

PMID- 10348368
TI  - Increased replication of Sendai virus in morphine-treated epithelial cells:
      evidence for the involvement of the intracellular levels of glutathione.
AB  - This paper shows that morphine increases Sendai virus replication in cultured
      epithelial cells. The effect was maximal when it was added before viral
      infection. Morphine also reduced the intracellular level of glutathione, namely,
      the oxidative and most abundant cell thiol. Altered intracellular redox status
      has recently been proposed as a factor influencing viral infection. Support for
      this view was provided by our data showing that inhibition of de novo glutathione
      synthesis, using L-buthionine sulfoximine, increased virus replication. These
      findings provide the first evidence that morphine increases the susceptibility to
      virus infection by altering the intracellular levels of glutathione.

PMID- 10348369
TI  - Effects of hyaluronan on models of immediate and delayed hypersensitivity in the
      rat.
AB  - Others have previously shown that superoxide dismutase conjugated with hyaluronan
      (HA) retains enzymic activity but is non-immunogenic. Whether HA could be widely
      used to prevent sensitisation to protein/polypeptide therapeutics is not known.
      In this study we investigated the effects of HA on bovine serum albumin (BSA) and
      methylated BSA pleural reactions in sensitised rats (active Arthus and delayed
      hypersensitivity reactions respectively) and on a reverse passive Arthus reaction
      in which rats received an intravenous injection of rabbit immunoglobulin and
      intrapleural challenge with goat anti rabbit immunoglobulin. HA suppressed the
      active Arthus and delayed hypersensitivity models when administered at the time
      of sensitisation but only the delayed hypersensitivity model at the time of
      intrapleural challenge. HA did not modulate the reverse passive Arthus reaction.
      The results show no evidence that simple mixing of HA with antigens masks
      antigenic determinants. However, HA appeared to have suppressive effects on both
      antibody and cell-mediated immune reactions. Therefore it may not be necessary to
      conjugate protein/polypeptide therapeutics to HA in order to prevent immune
      sensitisation.

PMID- 10348370
TI  - Proteosome delivery of a protective 9B-antigen against Schistosoma mansoni.
AB  - We have previously characterized a stage specific, partially protective protein
      denoted 9B-antigen. This antigen is of 450 kDa in its native form but upon SDS
      PAGE in reducing conditions it exhibits two subunits of 30 kDa and 45 kDa. The 9B
      antigen is localized at the surface of schistosomula and persists at the surface
      of lung schistosomula. The 9B-antigen is also localized in internal organs of a
      vital function in the parasite such as flame cells and cytoplasmic tubes.
      Infected individuals or mice vaccinated with irradiated cercariae recognize the
      9B-antigen. We have previously shown that when injected with complete Freunds
      adjuvant, the 9B-antigen can induce 40% protection against challenge infection.
      In this study we have used a more effective delivery system for this antigen. The
      9B-antigen was coupled to proteosomes derived from meningoccocal outer membrane
      proteins. Vaccination of mice with this complex increased the protection level to
      60%. Sera from these vaccinated mice induced high levels of complement mediated
      cytotoxicity of the parasite. Since the proteosomes are approved for human use,
      these results are promising towards the development of a vaccine against
      schistosomiasis.

PMID- 10348371
TI  - Inhibitory effects of indomethacin on interleukin-1 and nitric oxide production
      in rat microglia in vitro.
AB  - Indomethacin, as a nonsteroidal antiinflammatory drug, is reported to be
      effective in some degree in the prevention and treatment of Alzheimer's disease
      (AD). Effects of indomethacin on proinflammatory cytokines interleukin-1 (IL-1),
      tumor necrosis factor alpha and nitric oxide (NO) on rat microglia in vitro were
      investigated. The biological activities of IL-1 were assayed by thymocyte
      proliferation assay and the activities of TNG-alpha, by L929 cytotoxicity assay.
      NO concentration was represented by nitrite and determined by Griess reaction.
      Indomethacin inhibited IL-1 and NO production by rat microglia stimulated at the
      concentration of 0.1-10 micromol/l. However, it did not show any inhibitory
      effect on TNF-alpha production by resting and LPS-stimulated rat microglia. The
      results suggest that the mechanism by which indomethacin might be beneficial in
      treatment of AD might be due to the inhibition IL-1 and NO production from
      microglia.

PMID- 10348372
TI  - The interaction of immunomodulatory muramyl dipeptide with peripheral 5-HT
      receptors: overview of the current state.
AB  - Immunomodulator muramyl dipeptide (MDP) exerts also pronounced
      neuropharmacological activities which are probably mediated by an interaction
      with 5-HT receptors. Some of these effects are considered as undesirable by its
      clinical use. More precise information concerning MDP effects on 5-HT receptors
      with respect to their many subtypes could result from studies using isolated
      organs in vitro. Earlier conducted studies of this type provided data that are
      concisely overviewed and reinterpreted here from the view of current 5-HT
      receptor classification. Since new 5-HT receptor types have emerged recently, new
      studies are under way. The results might contribute to the development of novel
      immunomodulatory drugs devoid of adverse effects.

PMID- 10348373
TI  - Internal representation in neural networks used for classification of patient
      anaesthetic states and dosage.
AB  - In this study we aimed to explore the ability of artificial neural networks (ANN)
      to classify patient anaesthetic states and dosage. Surgical data obtained under
      different states of anaesthesia and dose levels were modelled via this approach.
      It is shown that inferential parameters can be used to determine the patient
      anaesthetic states and drug dosage. In addition to demonstrating the capability
      of ANN for classification we were interested in the internal representations that
      are developed automatically by networks while they are learning their processing
      task. An unsupervised learning procedure of clustering via which the classes are
      inferred from the data and a supervised learning technique of discrimination via
      which to construct a classification of the known categories were applied to
      analyse the performance of the ANN. Discriminant analysis (DA) was also utilised
      to optimise the network architecture.

PMID- 10348375
TI  - Graphical simulation of early development of the cerebral cortex.
AB  - Much experimental data exists concerning the development of the cerebral cortex.
      There is a need for a common vehicle to integrate this data and to allow the
      testing of hypotheses concerning development. Computer simulation and
      visualization are powerful mechanisms for hypothesis testing. Our long-term goal
      is to create a robust, extensible, portable tool for simulation and visualization
      of cortical development to serve both research and educational purposes. This
      paper describes a simulation program, SimCortex, which models the early stages of
      development of the cerebral cortex of the mouse. Version 1.0 of SimCortex models
      the proliferation of progenitor cells in the pseudostratified ventricular
      epithelium (PVE), the generation of young neurons and their migration into the
      cortical plate, which is the forerunner of cell layers II through VI of the adult
      cortex. We present an overview of the design and implementation of SimCortex,
      sample output of the system and a comparison of our results with experimental
      data. We conclude with a brief overview of proposed future enhancements of the
      system.

PMID- 10348374
TI  - Dynamic monitoring and control of patient anaesthetic and dose levels: time
      delay, moving-average neural networks, and principal components analysis.
AB  - The goal of this study was to examine the capabilities of neural network models
      for dynamic monitoring and control of patient anaesthetic and dose levels. The
      network models that we considered are split into two basic groups: static
      networks and dynamic networks. Static networks are characterised by equations
      that are memoryless. On the other hand, dynamic networks are systems with memory.
      Additionally, principal components analysis was used to introduce a further
      improvement to network design by reducing the dimensionality of the encoded
      temporal information. Principal components analysis was applied as both pre
      processing and post-processing techniques. In the first instance it was used to
      reduce the dimensionality of the data to more manageable intrinsic information.
      In the second instance it was employed to understand how the hidden layers
      separate the data, in order to optimise the network architecture.

PMID- 10348376
TI  - An integrated logistics support system for training crew medical officers in
      advanced cardiac life support management.
AB  - The purpose of this paper is to present an approach for the development of an
      integrated logistics support system for training space flight crew medical
      officers in advanced cardiac life support (ACLS). The most practical approach to
      deal with this problem has been determined to be the training of one or more of
      the crew members on the mission as crew medical officers (CMO's). If this
      approach is taken, there are a number of problems that must be addressed. The
      basic approach presented in this paper is to develop a performance quality index
      for ACLS tasks and use this index to monitor and control the performance of crew
      members throughout their tenure as CMO's. The control tool of the system is based
      on an integrated learning and forgetting model used to forecast CMO performance
      level at a given point during flight training. The model represents an aid for
      trainers in determining a training regime and maintaining the performance
      standards. A performance evaluator and trainer is also developed to help in the
      establishment of trainee performance level during training or retraining. All of
      these tools were evaluated using either expert opinion questionnaires or
      experimental results. In conclusion, the results presented provide the tools
      required for an integrated logistics support system for training ACLS personnel.

PMID- 10348377
TI  - Building quantitative stereology data files with scion image, a public domain
      image processing and analysis software.
AB  - Two-dimensional data obtained from a histological cross-section of a tissue can
      be utilized to obtain three-dimensional information by the methods of
      quantitative stereology. The resulting quantitative information is useful in both
      experimental studies and whole-animal investigations for regulatory and safety
      purposes. Quantitative stereologic analysis requires considerable data collection
      and calculation and is thus practical only through the use of computer hardware
      and software. We have previously reported the development of a program, STEREO,
      which compiles data from carcinogenesis experiments, recording information from
      tissue sections for the estimation of the number of altered hepatic foci (AHF)
      per liver and the volume fraction of AHF in liver on a three-dimensional basis.
      The data file itself was built by measuring tissue and focal transections through
      a slide-reading process that involved the manual use of a digitizer. In order to
      increase the speed and efficiency of the analytical process, we have integrated
      the STEREO program with a public domain software, Scion Image. This software
      integration involves two portions: the building macros and the interface. Macros
      for quantitative stereology used in Scion Image were written to customize and
      simplify the measurement and to generate data needed for building each of the
      data files. An interface program, BuildFi.exe, was developed to receive data
      generated from Scion Image and to align sequential tissue plots from up to four
      serial sections stained with different markers. As a result, the user can store
      data on a disk in the format of the STEREO data files. By combining STEREO with
      Scion Image, the slide-reading process is simplified and can be performed
      automatically. It has proven to be more objective, time saving, and efficient
      than all earlier versions.

PMID- 10348378
TI  - A longitudinal analysis of maternal abuse potential and developmental delays in
      children of adolescent mothers.
AB  - OBJECTIVE: This project was designed to examine the impact of adolescent mothers'
      abuse potential on the development of preschool children. The specific aims were
      to demonstrate relationships between maternal abuse potential and developmental
      problems in preschool children, to examine these relationships across time, and
      to determine whether maternal abuse potential predicted developmental delays
      after controlling for problematic parenting orientations. METHOD: Using a
      longitudinal design, we examined 146 first time mothers and their children.
      Maternal abuse potential was assessed when children were 1, 3, and 5 years old;
      problematic parenting orientation was assessed when the children were 6 months
      old; and child development (i.e., IQ, adaptive behavior, and behavior problems)
      was assessed at ages 3 and 5. RESULTS: Regression analyses revealed significant
      relationships between maternal abuse potential and a variety of developmental
      problems. Path analyses revealed unidirectional relationships between abuse
      potential predicting IQ and adaptive behaviors. Further analyses indicated that
      maternal abuse potential at 1 and 3 years predicted intelligence and adaptive
      behavior at ages 3 and 5, even when problematic parenting orientation was
      controlled. In contrast, children's behavioral problems at ages 3 and 5 was
      better accounted for by problematic parenting orientation than by abuse
      potential. CONCLUSIONS: The results of this study revealed that developmental
      delays in children of adolescent are related to abuse potential. Two pathways
      were found for predicting developmental delays: One pathway linked child abuse
      potential with IQ and adaptive functioning: the other pathway showed that
      problematic parenting orientation accounted for the development of emotional and
      behavioral problems.

PMID- 10348379
TI  - Influence of negative childhood experiences on psychological functioning, social
      support, and parenting for mothers recovering from addiction.
AB  - OBJECTIVE: This study was conducted with mothers recovering from drug and alcohol
      addiction and had three aims: first, to understand the range of negative
      childhood events these mothers experienced; second, to understand their current
      level of distress and their parenting experiences; and third, to examine the
      relationships between negative childhood events and parenting experiences.
      METHOD: Forty-six mothers participated in a cross-sectional exploratory study and
      completed a range of self-report measures, including the Child Abuse & Trauma
      Scale, Social Support Inventory, CES-D, Parenting Stress Index, and the Parenting
      Scale. RESULTS: When compared to norming samples these mothers reported
      significantly higher levels of aversive childhood experiences, psychological
      distress, parenting stress and use of problematic parenting behaviors along with
      lower levels of social support. Higher levels of neglect and growing up in a
      negative home environment were significantly correlated with lower levels of
      social support from the family, higher levels of distress and parenting stress,
      and greater use of problematic parenting behaviors. CONCLUSION: For this sample
      there is a greater incidence of aversive childhood experiences and greater
      problems with maternal functioning. Mothers recovering from addiction have an
      additional need for clinical attention towards issues of recovery from childhood
      abuse and responding to parenting difficulties with their own children.

PMID- 10348380
TI  - Evaluating the success of Sweden's corporal punishment ban.
AB  - OBJECTIVE: In 1979, Sweden became the first nation to explicitly prohibit all
      forms of corporal punishment of children by all caretakers in an effort to: (1)
      alter public attitudes toward this practice; (2) increase early identification of
      children at risk for abuse; and (3) promote earlier and more supportive
      intervention to families. The aim of this study was to examine trends over recent
      decades in these areas to assess the degree to which these goals have been met.
      METHOD: Primary data were collected from official Swedish sources for the
      following variables: public support for corporal punishment, reporting of child
      physical assault, child abuse mortality, prosecution rates, and intervention by
      the social authorities. Lines of best fit were generated and Cox and Stuart tests
      for trend were conducted. RESULTS: Public support for corporal punishment has
      declined, identification of children at risk has increased, child abuse mortality
      is rare, prosecution rates have remained steady, and social service intervention
      has become increasingly supportive and preventive. CONCLUSIONS: The Swedish ban
      has been highly successful in accomplishing its goals.

PMID- 10348381
TI  - Improving child welfare through a children's ombudsman.
AB  - OBJECTIVE: This report examines the changes in a child welfare system created by
      establishing an ombudsman's office to investigate complaints regarding children
      in the foster care, adoption, and child protection systems. METHOD: Serving as a
      complaint office, the Michigan Office of Children's Ombudsman investigated 443
      cases involving 820 children during its first 18 months of operation. Information
      was collected regarding the nature of abuse and system concerns identified in
      child protective services, foster care, or adoption agencies from across our
      state. Information was also collected regarding changes in agency practices or
      procedures or legislation resulting from case investigation. RESULTS: The
      Children's Ombudsman in Michigan identified 209 cases in which "administrative
      acts" of child protective services, foster care, or adoption agencies led to real
      or potential harm to children. Through investigation of these complaints, a
      number of areas of concern in the child welfare system were identified, resulting
      in changes in case management, investigation, or service provision. CONCLUSIONS:
      A children's ombudsman can improve the child welfare system through complaint
      investigation and identification of system-wide deficiencies on a state-wide
      level.

PMID- 10348383
TI  - Treatment effects with an adolescent abuse survivor's group.
AB  - OBJECTIVE: The goal of the study was to demonstrate the efficacy of a structured
      group therapy intervention in reducing the negative emotional and behavioral
      sequelae of adolescent girls' who are survivors of sexual abuse. It was
      hypothesized teens would show an increase in adaptive behaviors and knowledge of
      positive coping strategies. METHOD: A 7-session structured group treatment
      protocol based on Solution Focused and Ericksonian interventions was used. Forty
      one teens between the ages of 13 and 18 years old participated in the groups.
      Each group session included a didactic presentation. an art activity and
      development of a positive associational cue. Pre- and post-test assessment was
      done using the Solution Focused Recovery Scale, a measure of adaptive
      functioning; and the Skill Mastery Test, designed to evaluate teens knowledge of
      the concepts and strategies taught throughout the group. RESULTS: Overall, there
      was a significant change in pre- to post- measurements of adaptive functioning as
      assessed by the Recovery Scale. At this time, no statistically significant pre-
      to post- changes were evident for scores on the Skill Mastery Test. However,
      there was a trend toward improvement on visual inspection of the Skill Mastery
      scores. CONCLUSIONS: This study demonstrates emphasizing competence and skill
      development in the treatment of adolescent abuse survivors can aid teens in
      improving their daily functioning and positive recovery behaviors. In addition,
      early findings regarding the efficacy of this intervention suggest theory driven
      research methodology can be applied in a clinical setting with standardized
      treatment protocols.

PMID- 10348382
TI  - The treatment histories and service involvement of physically and sexually
      abusive families: description, correspondence, and clinical correlates.
AB  - OBJECTIVE: This study examines the treatment histories, and the service needs,
      concerns, and involvement of cases referred to Child Protective Services (CPS)
      following an allegation of child physical or sexual abuse in an effort to
      document their services experiences. METHOD: Standardized clinical assessments
      were conducted with child victims and their caregivers at intake and at a second
      assessment following an initial service about 4 to 8 months later (M = 6 mos.).
      Group differences due to informant type and abuse allegation were examined at
      each assessment and across time. RESULTS: Thirty percent of the caregivers and
      children had a past history of psychiatric hospitalization. Reports from both
      informants at intake identified a range of perceived service needs, treatment
      goals, and obstacles to service participation. At the post-service assessment,
      children and their caregivers reported high rates of family (54%, 51%) and parent
      counseling (50%, 51%), and lower rates for child treatment (13%, 18%). Some
      significant differences between the two abuse subgroups were found in their
      patterns of service involvement and in their ratings of service goals and
      obstacles. Four variables predicted overall family service use at intake: child
      is Caucasian, low child anxiety, high parental distress, and parental abuse
      history as a child. CONCLUSIONS: These findings extend initial descriptions of
      the service involvement of CPS families and bear implications for both practice
      and research on the delivery of services in CPS.

PMID- 10348384
TI  - Inappropriate child rearing practices as perceived by Jewish immmigrant parents
      from the former Soviet Union.
AB  - OBJECTIVES: First to explore what Jewish immigrant parents from the Former Soviet
      Union consider to be appropriate and inappropriate child rearing practices, and
      second what are their help seeking preferences in situations of children at risk.
      METHOD: Interviews with 273 immigrant parents were conducted in Israel. A semi
      structured questionnaire included seven vignettes which related to three areas of
      parental behaviors: Lack of provision of child's needs, corporal punishment and
      psychological punishment. In addition, open-ended questions were included about
      the participants' personal beliefs regarding the use of physical punishment
      towards children. RESULTS: Suggest a concrete and practical approach towards
      child rearing practices, support for the utilization of certain types of corporal
      and psychological punishment, consideration of the gender of the child might be a
      factor in the approach towards corporal punishment. a perception of children as
      self sufficient at a fairly young age and a tendency not to cooperate with
      outsiders in situations of children at risk. CONCLUSIONS: Even though Jewish
      immigrants from the Former Soviet Union might be in a new country for several
      years, their background may still have a significant role in their child rearing
      practices and help seeking patterns. Awareness of their perceptions could provide
      information which is significant for the accurate assessment of situations of
      abuse and neglect among the immigrants and for defining appropriate treatment
      objectives and means for achieving change.

PMID- 10348385
TI  - Female genital mutilation: the penultimate gender abuse.
AB  - OBJECTIVE: The five goals established for the development of this article were
      to: (1) provide an historical overview of the practice, (2) describe the
      procedure and its sequelae in realistic terms, (3) explore cultural
      justifications for the continuation of this action, (4) evaluate inherent
      moral/ethical/legal issues and, (5) focus worldwide professional attention on a
      gender-specific child atrocity. METHOD: A review of the past and current
      historical, popular and professional literature was undertaken to determine the
      precursors, magnitude, settings, rationale, and moral-ethical-legal-treatment
      issues associated with this mutilating procedure. RESULTS: Four forms of female
      genital mutilation were identified. These are: (1) sunna (removal of the prepuce
      of the clitoris); (2) clitoridectomy (removal of the prepuce and the clitoris);
      (3) excision (removal of the prepuce, clitoris, upper labia minora and perhaps
      the labia majora); and, (4) infibulation (removal of the prepuce, clitoris, labia
      minora, and labia majora). The "surgery" is performed most frequently by
      untrained midwives who use sharp rocks, razor blades, kitchen knives, broken
      glass, or even their teeth. As a rule, no anesthetics, antiseptics, analgesics or
      antibiotics are available to victims. Consequently, these females typically
      suffer from massive short-term and long-term physical, emotional, sexual and
      obstetrical sequelae. CONCLUSIONS: The justifications tendered by proponents do
      not withstand moral-legal-ethical scrutiny. Female genital mutilation is a
      violation of human rights and an atrocity perpetrated against helpless
      individuals who are unable to provide informed consent and who must therefore be
      protected through education and legislation.

PMID- 10348386
TI  - Child sexual abuse in Hong Kong: double victimization?

PMID- 10348387
TI  - Outcome measurement and rehabilitation.

PMID- 10348388
TI  - Rivermead Mobility Index: a brief review of research to date.
AB  - OBJECTIVE: To determine the extent of use of the Rivermead Mobility Index (RMI)
      in published research and document findings relevant to the RMI in that research.
      DESIGN: Literature search and document analysis. RESULTS: Eight research articles
      in which the RMI was used were found. The RMI was described as reliable,
      correlated with other published scales, and responsive to changes over time.
      CONCLUSIONS: The RMI possesses characteristics desirable in a measurement scale.
      It warrants broader application.

PMID- 10348389
TI  - The effectiveness of predischarge home assessment visits: a systematic review.
AB  - OBJECTIVE: To evaluate the effectiveness of predischarge home assessment visits
      for elderly patients. DESIGN: Systematic review. METHODS: A computer-aided search
      was conducted using the databases of Medline and Cinahl. Any studies
      investigating predischarge home assessment visits were included in the analysis.
      RESULTS: No randomized controlled trials were found. Only five studies (two
      retrospective surveys, three observational surveys) were identified. In four of
      these, a possible benefit for home visiting was suggested. CONCLUSIONS: Little
      evidence exists for the effectiveness of predischarge home assessment visits.
      Further research is needed to establish their value.

PMID- 10348390
TI  - A randomized controlled trial of day hospital and day centre therapy.
AB  - OBJECTIVE: To compare the outcome of day hospital to day centre rehabilitation.
      DESIGN: Single blind randomized controlled trial with home assessments at
      baseline (twice), six weeks and three months. SETTING: Mainly rural health
      district. Day hospital and social services day centres in market towns. SUBJECTS:
      One hundred and five physically disabled older patients living at home referred
      for day hospital rehabilitation or maintenance before discharge from hospital
      (66) or referred as outpatients (39). INTERVENTIONS: Day hospital treatment or
      day centre rehabilitation by a physiotherapist and two health support workers.
      MAIN OUTCOME MEASURES: Barthel Index, Philadelphia Geriatric Morale Scale and
      Caregiver Strain Index. RESULTS: More day centre (23/55) than day hospital
      patients (6/50) (p <0.001) withdrew from allocated treatment by choice or because
      of operational difficulties. Both groups improved significantly in functional
      ability and reduction of care-giver strain by three months but there was no
      significant difference between groups. The mean improvement in Barthel Index
      (standard error) for day hospital = +1.5 (0.41) (n = 34) and day centres = +1.5
      (0.48) (n = 38). The mean difference (95% confidence interval) between day
      hospital and day centre was 0 (-1.28, +1.28). Likewise the mean Philadelphia
      Geriatric Morale Scale improvement for day hospital +1.8 (0.66) (n = 35) and day
      centres was +0.9 (0.63) (n = 38). The mean difference was -0.88 (-2.7, +0.95).
      The mean reduction in Caregiver Strain for day hospital was -1.45 (0.5) (n = 23)
      and day centre was -1.59 (0.47) (n = 27). The difference was -0.14 (1.52, +1.24).
      (These analyses are all on an intention-to-treat basis.) CONCLUSION: Whilst the
      improvement in functional ability and care-giver strain was similar in both
      groups, day centre rehabilitation was less popular and had practical
      difficulties. If these difficulties can be overcome the model should be tested
      elsewhere.

PMID- 10348392
TI  - Predictors of outcome of rehabilitation of elderly stroke patients in a geriatric
      ward.
AB  - PURPOSE: To identify predictors of outcome after 12 months in elderly stroke
      patients rehabilitated in a geriatric ward. DESIGN: Prospective with evaluation
      in the subacute phase and after 12 months. SETTING: Geriatric ward and outpatient
      clinic. SUBJECTS: All stroke patients admitted from the acute unit to a geriatric
      ward for rehabilitation during a 16-month period (n = 171). MAIN OUTCOME
      MEASURES: Place of living, mortality and social functioning (Frenchay Activities
      Index) 12 months following stroke. RESULTS: Age, urinary incontinence and
      cognitive function were significantly associated with place of living (home
      versus nursing home) 12 months post stroke in bivariate analyses. However, using
      multivariate logistic regression analyses, only age (p = 0.005) and urinary
      incontinence at baseline (p = 0.028) remained independent predictors of place of
      living. Mortality during the first year was significantly predicted by urinary
      incontinence and gender (men doing worse), whereas the Barthel Activities of
      Daily Living (ADL) Index sumscore was the only significant independent predictor
      of social activities. CONCLUSION: Urinary incontinence at baseline seems to be a
      most important predictor of outcome 12 months post stroke in geriatric patients.
      However, with regard to social activities (Frenchay Activities Index), functional
      impairment in the initial phase as reflected by the Barthel ADL Index supersedes
      other predictors.

PMID- 10348391
TI  - Effect of a physiotherapist-led training programme on attitudes of nurses caring
      for patients after stroke.
AB  - BACKGROUND: A multidisciplinary project team developed a five-month
      physiotherapist-led training programme designed to enhance nurses' rehabilitation
      skills. AIMS: Investigation of the effects of the training programme on nurses
      attitudes to patients with stroke. METHOD: An attitude questionnaire was
      completed by the participating nurses before and after the training programme. In
      a complementary qualitative evaluation the nurses' expectations and views of the
      training programme were explored. RESULTS: Analysis of the attitude questionnaire
      indicated that the programme was successful in positively influencing the nurses'
      attitudes (median of the change in score 2, p = 0.005). The qualitative
      interviews reflected a similar outcome. CONCLUSIONS: Quantitative and qualitative
      evaluation indicates that the training programme had some effect in changing
      nurses' attitudes to treating patients after a stroke. Such a training programme
      could be a useful contribution to post-stroke care.

PMID- 10348393
TI  - Psychological correlates of outcome following rehabilitation from stroke.
AB  - OBJECTIVES: To confirm, in a new sample, the value of our previously described
      procedure for identifying abnormal illness behaviour (AIB) in stroke
      rehabilitation patients, and to examine the relative effects of AIB, depression,
      family functioning, knowledge of stroke, and expectations of rehabilitation on
      long-term rehabilitation outcome. DESIGN: A longitudinal design, with assessments
      on admission to and discharge from rehabilitation, and six and twelve months
      after discharge. SETTING: The study was undertaken in the rehabilitation unit at
      Repatriation General Hospital, in Adelaide, South Australia. SUBJECTS: Sixty
      twelve-month stroke survivors, residing in a family environment, who had
      undergone an inpatient rehabilitation programme. MAIN OUTCOME MEASURES: AIB was
      assessed using the Illness Behaviour Questionnaire, depression with the Zung Self
      Rating Depression Scale, family functioning with the McMaster Family Assessment
      Device, stroke knowledge with the Stroke Care Information Test, and expectations
      of rehabilitation with an open-ended question. Functional outcome was assessed
      with the competence and performance assessments of the Australian ADL Index, and
      lifestyle activities with the Frenchay Activities Index. RESULTS: Using our
      previously derived AIB classification rule, AIB cases scored poorly on
      functional, social and psychological indicators. Further, cluster analysis of
      discharge data replicated the rule for identifying patients with AIB. AIB was a
      strong predictor of functional competence and performance at rehabilitation
      discharge and both six and twelve months later, while depression was associated
      with an inactive lifestyle at both six and twelve months. Greater stroke
      knowledge and clearer expectations of rehabilitation were associated with better
      functional outcome at discharge. Family functioning was strongly associated with
      lifestyle activities and ADL performance at both six and twelve months.
      CONCLUSIONS: The procedure for identifying AIB in this rehabilitation environment
      appears to be robust. AIB was a key determinant of long-term functional
      disability, while depression was associated with poorer social functioning.
      Family functioning was an important determinant of social activities, and of the
      activities the patient actually does, rather than those the patient is capable of
      carrying out. Good stroke knowledge and clear expectations of rehabilitation were
      important determinants of rehabilitation success, and should be fostered to
      ensure a good rehabilitation outcome. Psychological factors are crucial in
      determining long-term outcomes after rehabilitation from stroke.

PMID- 10348394
TI  - Sensitivity of Shah, Vanclay and Cooper's modified Barthel Index.
AB  - OBJECTIVE: To investigate whether Shah, Vanclay and Cooper's modification of the
      Barthel Index improved its sensitivity to change. DESIGN: Correlational study.
      SETTING: School of Occupational Therapy at Auckland Institute of Technology,
      Auckland, New Zealand. SUBJECTS: One hundred subjects requiring rehabilitation
      following a stroke. MAIN OUTCOME MEASURES: Change in function which was measured
      using Shah, Vanclay and Cooper's (1989) modified Barthel Index and walking speed
      over 10 metres. RESULTS: Five statistical analyses were undertaken, none of which
      demonstrated clear superiority of one measure over the other. CONCLUSIONS: The
      study did not indicate the modified Barthel Index to be more sensitive to change
      than the 20-point Barthel Index for this population. The statistical analysis
      strategies utilized are recommended for similar studies.

PMID- 10348395
TI  - Joint reposition sense in subjects with unilateral osteoarthritis of the knee.
AB  - OBJECTIVE: To identify the sensory deficit of partial weight-bearing joint
      repositioning sense in subjects with unilateral osteoarthritis (OA) of the knee.
      The methodology was developed to incorporate measures made easily in a clinical
      setting. In OA, local degenerative changes can affect the function of sensory
      receptors and mechanoreceptors. As a result, appreciation of limb position as
      well as function may be compromised. Because proprioceptive sense plays an
      important role in reflex muscle contraction and stabilization of the joint,
      functional stability and joint integrity may be at risk if proprioception is
      impaired. DESIGN: Twenty subjects with unilateral OA of the knee were age-matched
      with 20 controls for the purpose of this study. The difference in degrees between
      a target angle of knee flexion and a reposition angle was measured during a
      partial weight-bearing test. A Dualer (electronic dual inclinometer) was used to
      measure the joint reposition sense (JRS) of the knee. Both sides were tested with
      six repetitions on each side. A mixed-model ANOVA was applied to the data for
      analysis. RESULTS: Comparison of the JRS between groups revealed a significant
      difference, with OA subjects having higher JRS error (JRSE) (p <0.001) than
      controls. There was no significant difference in JRSE for either side, regardless
      of group. CONCLUSIONS: Subjects with unilateral OA of the knee demonstrated
      poorer performance on both legs in a partial weight-bearing reposition test than
      did control subjects.

PMID- 10348396
TI  - Repeatability of goniometer measurements of the knee in patients wearing an
      Ilizarov external fixator: a clinic-based study.
AB  - OBJECTIVE: To examine the intra-tester and inter-tester reliability of three
      different methods of measurement of knee range of motion in patients undergoing
      limb reconstruction with the Ilizarov external fixator. DESIGN: Twenty-five
      patients had the passive range of motion of their knee measured by 13
      physiotherapists who were experienced in the use of goniometry. The testers were
      assigned into random pairs, each tester measured three or four patients who were
      allocated to them using the three different methods. These were: (1) a universal
      goniometer aligned against anatomical landmarks, (2) a universal goniometer
      aligned against the Ilizarov frame and (3) a modified universal goniometer.
      SETTING: Orthopaedic limb reconstruction outpatient clinics. SUBJECTS: Twenty
      five patients undergoing limb reconstruction using an Ilizarov external fixator
      on both the femur and tibia. RESULTS: Comparison of the three different
      goniometry methods showed that using a modified goniometer there was enhanced
      reliability compared with other methods. This method demonstrated good
      repeatability for both intra-tester and inter-tester measurements. CONCLUSIONS:
      When serial measurements of knee range of motion are taken in patients wearing an
      Ilizarov external fixator the modified model of goniometer should be used.

PMID- 10348397
TI  - The Short Orientation-Memory-Concentration Test: a study of its reliability and
      validity.
AB  - OBJECTIVE: To establish the limits of intra-observer test-retest reliability of
      the Short Orientation-Memory-Concentration Test (SOMC), and to investigate the
      relationship of performance on the SOMC with a test of verbal memory. DESIGN:
      Each patient was assessed twice by the same assessor over an interval of 3-7
      days. SETTING: Two specialist rehabilitation units concerned with patients with
      severe and/or complex disability arising from neurological disease. SUBJECTS:
      Thirty-eight patients aged 17-63 years, 25 being men, with a variety of
      neurological diseases. The Barthel Activities of Daily Living Index score ranged
      from 0 to 20, median 10.5. MEASURES: The Short Orientation-Memory-Concentration
      Test, the Barthel Activities of Daily Living Index and the paragraph recall
      subtest of the Rivermead Behavioural Memory Test (RBMT). RESULTS: There was a
      slight but statistically significant (p <0.01) improvement in the score of 2
      points (out of 28) between the two test occasions, but this was not related to
      the interval between testing or to the mean score of the two tests. The scores
      differed by as much as +10 to -8, but most patients (n = 35; 92%) showed a
      difference between -2 and +6 points. The SOMC scores were correlated with the
      RBMT paragraph recall immediate and delayed scores (r = 0.74) but the scatterplot
      showed considerable variation. CONCLUSION: If used by the same observer, changes
      in the SOMC score are likely to reflect a real difference if it increases by more
      than 6 points or decreases by more than 2 points. The SOMC does seem to reflect
      verbal memory.

PMID- 10348398
TI  - Walking speed on parquetry and carpet after stroke: effect of surface and retest
      reliability.
AB  - OBJECTIVE: At the transition stage from rehabilitation to home this study aimed
      to (1) investigate the effect of floor surface (carpet and parquetry) on walking
      speed; (2) investigate whether there was a difference between these surfaces as
      stroke patients voluntarily increased from comfortable to fast pace; (3)
      investigate whether walking speed on parquetry was a predictor of walking speed
      on carpet at the two paces; (4) investigate whether walking speed at a
      comfortable pace was a predictor of walking speed at a fast pace on the two
      surfaces; and (5) quantify systematic and random error in repeated measurements
      for fast-paced walking trials. DESIGN: Subjects walked 10 metres at comfortable
      and fast paces on carpet and parquetry on two consecutive days. SETTING:
      Inpatient rehabilitation centre. SUBJECTS: Twenty-four stroke patients. MAIN
      OUTCOME MEASURE: Walking speed. RESULTS: Two-way analysis of variance confirmed
      that patients walked more slowly on carpet than parquetry (F(1,23) = 5.3, p
      <0.05) at both paces; the interaction effect was not significant (p >0.05).
      Walking speed on parquetry was a strong predictor of walking speed on carpet at a
      comfortable (r = 0.92), and fast pace (r = 0.97). Walking speed at comfortable
      pace was a moderately strong predictor of walking speed at fast pace on parquetry
      (r = 0.84), and on carpet (r = 0.88). Random error in repeated measurements was
      higher when walking fast on carpet (7.21 m/min) and parquetry (8.32 m/min) than
      when walking at a comfortable pace on carpet (4.63 m/min) and parquetry (3.48
      m/min). Systematic error was negligible (p <0.05). CONCLUSION: Carpet surface was
      more challenging than parquetry surface, as evidenced by the systematic decrease
      in walking speed. This may have been due to lack of familiarity. Relative to the
      wide range of scores in the group, stroke patients showed consistency of walking
      speed across both surfaces. Likewise, stroke patients retained their relative
      position in the group as they changed from a comfortable to a fast walking pace.
      The difference in random error between comfortable and fast-paced trials
      highlights the need to quantify error in the repeated measurement situation
      according to specific test conditions.

PMID- 10348399
TI  - Introduction: The future of psychotherapy training: psychodynamic, experiential,
      and eclectic perspectives.
AB  - What does the future hold with regard to psychotherapy training? We posed that
      question to experts representing three important therapeutic approaches:
      Psychodynamic, Experiential, and Eclectic. In what follows we introduce this
      special section, provide our rationale for putting it together, and briefly
      highlight some interesting, substantive points made in the subsequent papers.

PMID- 10348400
TI  - Recommendations for the future of training in brief dynamic psychotherapy.
AB  - The results of 2 large surveys (of practitioners and graduate school/internship
      training directors) indicate that there is a considerable amount of brief therapy
      being conducted by psychodynamically trained therapists. However, their training
      in this specialization does not appear to be adequate. Eleven recommendations
      (e.g., addressing therapists' attitudes toward brief therapy, studying training
      processes and outcomes, using videotapes for teaching and supervision) are set
      forth to foster improvements in such training. We conclude that it is critical
      that the sizeable number of psychodynamic therapists conducting brief therapy
      receive continuing in-depth training in this challenging and demanding field.

PMID- 10348401
TI  - An unabashedly unrealistic wish list for the education and training of
      psychotherapists.
AB  - Proposals for the education and training of psychotherapists are offered in a
      spirit of constructive good faith, yet they are unabashedly unrealistic in
      departing from some common canons of education and training. Seven principles are
      proposed as a suggested starting point for further discussion of the education
      and training of psychotherapists.

PMID- 10348402
TI  - Manualizing flexibility: the training of eclectic therapists.
AB  - Manualized training has become the standard for psychotherapy research and is
      rapidly becoming adopted in clinical and counseling psychology training programs.
      However, it is still unclear whether manualization improves outcomes, and there
      is evidence that manualized training reduces nonspecific therapist qualities and
      attenuates clinical judgment. Prescriptive and integrative models of
      psychotherapy are designed to increase therapist flexibility. This article
      describes some current and anticipated efforts to teach therapists to flexibly
      use therapeutic procedures without losing some of the advantages of
      manualization.

PMID- 10348403
TI  - Clinical training: challenges for a new millennium.
AB  - It is a challenging and intimidating task to comment on the thoughts of several
      prominent leaders in the field of psychotherapy research and training. For many
      years I have turned to their scholarly writings for guidance, insight, and
      understanding. I have also urged my students to read their articles and books, to
      attend their presentations, and to listen carefully to the reports of these
      experts about the state of psychotherapy. In the present context Drs. Watkins and
      Guarnaccia have invited this impressive group of experts to offer their views on
      the direction in which psychotherapy training is moving and the particular
      implications of these trends for psychotherapy educators and training programs.
      To paraphrase the once popular television commercials about an American
      investment company, "When Levenson, Strupp, Mahrer, Boulet, and Beutler talk,
      people listen." When thinkers of this stature share their wisdom, I listen
      carefully, and I urge my colleagues who are involved in psychotherapy training to
      do the same. In my brief comments, I will discuss some of the challenges that we
      educators face and attempt to offer some recommendations that are based, in part,
      on the views of these contributors.

PMID- 10348404
TI  - Chronic fatigue syndrome: assessing symptoms and activity level.
AB  - Current approaches to the diagnosis and assessment of Chronic Fatigue Syndrome
      (CFS) rely primarily on scales that measure only the occurrence of various
      symptoms related to CFS. Such approaches do not provide information on either the
      severity of symptoms or on fluctuations in symptom severity and activity level
      that occur over time. As a result, these measures do not reflect the complexities
      and the interrelations among symptoms. By obscuring the fluctuating nature of CFS
      and its high variability, current assessment procedures may prevent health care
      professionals from understanding the complexities of this disease. The present
      study provides two CFS case studies to illustrate the advantages of using self
      reporting rating scales in combination with a device used to measure the
      frequency and intensity of activity. The implications of this assessment system,
      which captures the symptom dynamics and variability involved in CFS, are
      discussed.

PMID- 10348405
TI  - Noverbal communication and alliance in therapy: the body formation coding system.
AB  - Body formations of therapist and couple during therapy sessions mainly function
      to signal their degree of readiness to interact or their degree of engagement in
      the therapeutic process, which is one contextual display of their affective
      communication. For this study, we developed the Body Formation Coding System
      (BFCS), a 4-category instrument to assess engagement at the triadic level. This
      article presents the BFSC method as well as a first validation on a sample of 14
      triads. The results show that (a) triads vary according to their degree of
      triadic engagement; (b) engagement is related to the degree of therapeutic
      alliance; and (c) when the alliance is sufficient, a triadic invariant of
      engagement emerges. This means that partners regulate and coordinate their
      behaviors to maintain a stable level of engagement, whatever changes in their
      conversational organization. Finally, it discusses the potential of this method
      for describing the interactive aspects of the therapeutic alliance.

PMID- 10348406
TI  - The effects of violent media on adolescent inkblot responses: implications for
      clinical and forensic assessments.
AB  - Two experiments were conducted to assess the degree to which violent media
      stimulate violent fantasy as depicted on inkblot responses. In Experiment I, 41
      gifted high school students were exposed to a bucolic or violent film clip and
      then were asked to produce inkblot responses. In Experiment II, a second sample
      of 43 additional students were exposed to a verbal description of the bucolic or
      violent scene to assess whether the "hot" or "cooler" media (McLuhan, 1964) had
      different effects on the inkblot responses. In both experiments, the media
      exposure led to increased levels of violent responses, and in both cases males
      produced more violent responses. There was no sex by media interaction effect.
      Implications for clinical and forensic assessments are presented.

PMID- 10348407
TI  - Development and evaluation of problem frequency scales from version 3 of the
      computerized assessment system for psychotherapy evaluation and research
      (CASPER).
AB  - A comprehensive analysis of interview items on the Computerized Assessment System
      for Psychotherapy Evaluation and Research (CASPER) was conducted using derivation
      (N = 1,168) and cross-validation samples (N = 1,158) from a university counseling
      center and an outpatient training clinic sample (N = 355). Nine scales were
      identified that demonstrated acceptable internal consistency and
      unidimensionality. Confirmatory factor analyses of 6 of these scales supported
      the presence of 6 factors, but indicated that several were highly
      intercorrelated. These findings were consistent across all 3 samples. Analyses
      relating these 6 scales to comparable scales on the Brief Symptom Inventory (BSI)
      obtained for the training clinic sample indicated a high degree of correspondence
      across instruments. In addition, significant correlations were found between
      global measures obtained from CASPER and the BSI.

PMID- 10348408
TI  - Power of univariate and multivariate analyses of repeated measurements in
      controlled clinical trials.
AB  - The power of univariate and multivariate tests of significance is compared in
      relation to linear and nonlinear patterns of treatment effects in a repeated
      measurement design. Bonferroni correction was used to control the experiment-wise
      error rate in combining results from univariate tests of significance
      accomplished separately on average level, linear, quadratic, and cubic trend
      components. Multivariate tests on these same components of the overall treatment
      effect, as well as a multivariate test for between-groups difference on the
      original repeated measurements, were also evaluated for power against the same
      representative patterns of treatment effects. Results emphasize the advantage of
      parsimony that is achieved by transforming multiple repeated measurements into a
      reduced set of mean ngful composite variables representing average levels and
      rates of change. The Bonferroni correction applied to the separate univariate
      tests provided experiment-wise protection against Type I error, produced slightly
      greater experiment-wise power than a multivariate test applied to the same
      components of the data patterns, and provided substantially greater power than a
      multivariate test on the complete set of original repeated measurements. The
      separate univariate tests provide interpretive advantage regarding locus of the
      treatment effects.

PMID- 10348409
TI  - Mental health outcomes in dually diagnosed individuals with mental retardation
      assessed with the MMPI-168(L): case studies.
AB  - Recently it has been shown that oral administration of the MMPI-168(L), with
      simplified explanations of the items provided when needed, can reveal information
      related to personality and psychopathology in many individuals with mental
      retardation. The results of repeated administrations of the inventory to 7
      clients residing in an institutional setting over a period exceeding 3 years in
      some cases are presented here. It is argued that results obtained by repeated
      administration the MMPI-168(L) can reveal information concerning changes in
      mental health status for many individuals with mental retardation.

PMID- 10348410
TI  - A model of parental representations, second individuation, and psychological
      adjustment in late adolescence.
AB  - This study examined the role that mental representations and the second
      individuation process play in adjustment during late adolescence. Participants
      between the ages of 18 and 22 were used to test a theoretical model exploring the
      various relationships among the following latent variables: Parental
      Representations, Psychological Differentiation, Psychological Dependence,
      Positive Adjustment, and Maladjustment. The results indicated that the quality of
      parental representations facilitates the second individuation process, which in
      turn facilitates psychological adjustment in late adolescence. Furthermore, the
      results indicated that the second individuation process mediates the influence
      that the quality of parental representations have on psychological adjustment in
      late adolescence. These findings are discussed in light of previous research in
      this area, and clinical implications and suggestions for future research are
      offered.

PMID- 10348412
TI  - Predictive validity of WAIS-R VIQ-PIQ splits in persons with major depression.
AB  - We selected a sample of patients with depression (N = 70) and used Bayesian
      analyses to examine the diagnostic predictive validity of the Wechsler Adult
      Intelligence Scale-Revised Verbal IQ (VIQ) minus Performance IQ (PIQ) difference
      score for depression. The patients showed average VIQ-PIQ differences in the
      expected direction (i.e., VIQ > PIQ). However, based on sensitivity, specificity,
      and positive predictive value statistics, we concluded that the VIQ-PIQ split has
      very low predictive validity in persons with depression.

PMID- 10348411
TI  - Is diagnostic judgment influenced by a bias to see pathology?
AB  - The clinical judgment literature suggests that clinicians are biased to see
      psychopathology. The social cognition literature shows that people can be biased
      to search for information relevant only to the hypothesis under test and to
      ignore information relevant to the alternative. In light of these biases, we
      asked practicing clinicians (N = 106 respondents) in three conditions to read 1
      of 9 biographical essays. The conditions called for the clinicians to judge the
      writer of the essay as (a) psychologically healthy or not, (b) psychologically
      healthy or unhealthy, or (c) experiencing psychopathology or not The latter
      condition was expected to produce the highest frequency of negative judgments.
      The opposite result was obtained. To determine if this was due to the extreme
      wording in the "psychopathology" condition, 30 additional practicing clinicians
      assessed whether the writer of the essay was psychologically unhealthy or not. A
      comparison of these data with those from the two less extreme conditions showed
      no bias. The results were interpreted as an appropriate level of conservativism
      in clinical judgment with respect to the extreme diagnosis implied by the term
      psychopathology.

PMID- 10348413
TI  - Redefining the analytical approach to pharmacoeconomics.

PMID- 10348414
TI  - Bayesian estimation of cost-effectiveness ratios from clinical trials.
AB  - Estimation of the incremental cost-effectiveness ratio (ICER) is difficult for
      several reasons: treatments that decrease both cost and effectiveness and
      treatments that increase both cost and effectiveness can yield identical values
      of the ICER; the ICER is a discontinuous function of the mean difference in
      effectiveness; and the standard estimate of the ICER is a ratio. To address these
      difficulties, we have developed a Bayesian methodology that involves computing
      posterior probabilities for the four quadrants and separate interval estimates of
      ICER for the quadrants of interest. We compute these quantities by simulating
      draws from the posterior distribution of the cost and effectiveness parameters
      and tabulating the appropriate posterior probabilities and quantiles. We
      demonstrate the method by re-analysing three previously published clinical
      trials.

PMID- 10348415
TI  - Sample size and power issues in estimating incremental cost-effectiveness ratios
      from clinical trials data.
AB  - It is becoming increasingly more common for a randomized controlled trial of a
      new therapy to include a prospective economic evaluation. The advantage of such
      trial-based cost-effectiveness is that conventional principles of statistical
      inference can be used to quantify uncertainty in the estimate of the incremental
      cost-effectiveness ratio (ICER). Numerous articles in the recent literature have
      outlined and compared various approaches for determining confidence intervals for
      the ICER. In this paper we address the issue of power and sample size in trial
      based cost-effectiveness analysis. Our approach is to determine the required
      sample size to ensure that the resulting confidence interval is narrow enough to
      distinguish between two regions in the cost-effectiveness plane: one in which the
      new therapy is considered to be cost-effective and one in which it is not. As a
      result, for a given sample size, the cost-effectiveness plane is divided into two
      regions, separated by an ellipse centred at the origin, such that the sample size
      is adequate only if the truth lies on or outside the ellipse.

PMID- 10348416
TI  - At what price significance? The effect of price estimates on statistical
      inference in economic evaluation.
AB  - Because data on resource utilization are now collected in many comparative trials
      of health interventions, statistical analysis of between-group differences in
      mean costs has become common. Statistical analyses of costs are generally
      performed conditional on a set of resource prices (or unit costs), thereby
      suppressing any uncertainty associated with those price estimates. Results
      presented here demonstrate that varying price estimates can have a non-negligible
      effect on statistical inference regarding between-group cost differences.
      Depending on the relative prices used in an analysis, between-group differences
      in total costs per patient may be either statistically significant or
      insignificant, regardless of whether differences in utilization of the underlying
      resources are statistically significant. These results highlight the importance
      of recognizing that evaluations based on patient-level economic data may be
      sensitive to assumptions regarding the values of unobserved variables, such as
      the relative prices of resources. Traditional methods of sensitivity analysis
      remain a valuable tool for analysing the implications of uncertainty around
      estimates of those unobserved variables.

PMID- 10348417
TI  - Will the real elasticity of substitution 'in Norwegian dentistry' please stand
      up?
AB  - The non-homothetic production cost structure in Norwegian private dentistry
      involves more than two factor inputs. Consequently, this paper implements
      separately for solo and group practices-three conceptually different measures of
      factor substitutions to infer the precise nature of input associations using
      translog cost model estimates based on 1993 data. We calculate own- and cross
      price elasticities of factor demands, pairwise elasticities of substitution and
      their approximate S.E.s. We find that: (1) dentists and dental assistants cannot
      be consistently aggregated as one homogeneous labour input; (2) input demands are
      inelastic; (3) the theoretically restrictive Allen-Uzawa and the less restrictive
      shadow and Morishima elasticities of substitution are not equivalent; (4)
      dentists and auxiliary dental personnel relate as significant substitutes in solo
      practices and as significant complements in group practices; (5) 'supplies'
      (e.g., dental materials) in the aggregate are substitutes for the two types of
      dentistry labour; and (6) there appears to be a wider scope for factor
      substitutions in group rather than solo practices. Due to inelastic factor
      demands, opportunities for cost controls are limited despite some tendencies for
      factor interchange. Finally, future researchers of production costs involving
      more than two inputs should investigate the less restrictive, alternative
      measures of factor substitutions.

PMID- 10348418
TI  - Price competition and hospital cost growth in the United States (1989-1994).
AB  - In recent years, most health care markets in the United States (US) have
      experienced rapid penetration by health maintenance organizations (HMOs) and
      preferred provider organizations (PPOs). During this same period, the US has also
      experienced slowing health care costs. Using a national database, we demonstrate
      that HMOs and PPOs have significantly restrained cost growth among hospitals
      located in competitive hospital markets, but not so in the case of hospitals
      located in relatively concentrated markets. In relative terms, we estimate that
      HMOs have contained cost growth more effectively than PPOs.

PMID- 10348419
TI  - Annuitizing the human capital investment costs of health service professionals.
AB  - When evaluating initiatives that make innovative uses of staff it is important to
      consider the long-term cost consequences of training an appropriately qualified
      workforce. In order to incorporate the costs of qualifying professionals we need
      both the costs themselves and an appropriate method of annuitizing these costs.
      This paper focuses on the latter and describes an approach to estimating the
      expected working life of health service professionals and a method of
      annuitization that takes into consideration patterns of employment over time.
      Analyses of the census and Labour Force Survey result in estimates of expected
      working lives of between 19 and 22 years for nurses and 26 and 29 years for
      doctors. The implications of different assumptions about the distribution of
      these years for the equivalent annual cost are identified.

PMID- 10348420
TI  - A Bayesian approach to stochastic cost-effectiveness analysis.
AB  - The aim of this paper is to briefly outline a Bayesian approach to cost
      effectiveness analysis (CEA). Historically, frequentists have been cautious of
      Bayesian methodology, which is often held as synonymous with a subjective
      approach to statistical analysis. In this paper, the potential overlap between
      Bayesian and frequentist approaches to CEA is explored--the focus being on the
      empirical and uninformative prior-based approaches to Bayesian methods rather
      than the use of subjective beliefs. This approach emphasizes the advantage of a
      Bayesian interpretation for decision-making while retaining the robustness of the
      frequentist approach. In particular the use of cost-effectiveness acceptability
      curves is examined. A traditional frequentist approach is equivalent to a
      Bayesian approach assuming no prior information, while where there is pre
      existing information available from which to construct a prior distribution, an
      empirical Bayes approach is equivalent to a frequentist approach based on pooling
      the available data. Cost-effectiveness acceptability curves directly address the
      decision-making problem in CEA. Although it is argued that their interpretation
      as the probability that an intervention is cost-effective given the data requires
      a Bayesian interpretation, this should generate no misgivings for the
      frequentist.

PMID- 10348421
TI  - A Bayesian approach to sensitivity analysis.
AB  - Sensitivity analysis has traditionally been applied to decision models to
      quantify the stability of a preferred alternative to parametric variation. In the
      health literature, sensitivity measures have traditionally been based upon
      distance metrics, payoff variations, and probability measures. We advocate a new
      approach based on information value and argue that such an approach is better
      suited to address the decision-maker's real concerns. We provide an example
      comparing conventional sensitivity analysis to one based on information value.
      This article is a US government work and is in the public domain in the United
      States.

PMID- 10348422
TI  - Bayesian approaches to the value of information: implications for the regulation
      of new pharmaceuticals.
AB  - The current regulation of new pharmaceuticals is inefficient because it demands
      arbitrary amounts of information, the type of information demanded is not
      relevant to decision-makers and the same standards of evidence are applied across
      different technologies. Bayesian decision theory and an analysis of the value of
      both perfect and sample information is used to consider the efficient regulation
      of new pharmaceuticals. This type of analysis can be used to decide whether the
      evidence in an economic study provides 'sufficient substantiation' for an
      economic claim, and assesses whether evidence can be regarded as 'competent and
      reliable'.

PMID- 10348423
TI  - Acute reduction in ankle/brachial index following smoking in chronic smokers with
      peripheral arterial occlusive disease.
AB  - The ankle-brachial systolic pressure index (ABI), a noninvasive measure of
      peripheral arterial occlusive disease (PAOD) severity, is considered a marker of
      atherosclerosis and an independent predictor of mortality. However, it is not
      known whether factors other than PAOD severity, such as cigarette smoking, have
      an effect on ABI measurement. Therefore, the authors examined the acute effects
      of cigarette smoking on ABI and the peripheral circulation in 10 older (63 +/- 10
      years) chronic smokers (39 +/- 37 pack-years) with PAOD (ABI=0.64 +/- 0.14). The
      patients were instructed to refrain from smoking and from consuming caffeine
      containing beverages for at least 12 hours before the tests. The patients were
      randomly assigned to 2 days of testing consisting of a nonsmoking and a smoking
      day. Resting heart rate, blood pressure, ABI, and calf blood flow by
      plethysmography were obtained on both testing days. The smoking day consisted of
      smoking two filter cigarettes over a period of 10 minutes before the measurement
      of ABI and calf blood flow. The ABI on the smoking day (0.55 +/- 0.11) was lower
      (p=0.008) than on the nonsmoking day (0.64 +/- 0.14) owing to a lower (p=0.020)
      ankle systolic blood pressure (81 +/- 28 vs 93 +/- 28 mmHg). Brachial systolic
      blood pressures, heart rate, and calf blood flow were not altered by smoking
      (p>0.05). These results demonstrate that the acute effect of cigarette smoking
      lowers the ABI in chronic smokers with intermittent claudication, thereby
      yielding evidence of a transient deleterious effect of cigarette smoking on the
      peripheral circulation in chronic smokers.

PMID- 10348425
TI  - Relation of occupation to presence or absence of coronary artery disease: an
      angiographic study.
AB  - To determine the relation of occupation to the presence or absence of coronary
      artery disease (CAD) and cardiovascular risk factors, the authors compared the
      occupations of a series of 116 consecutive patients who underwent coronary
      angiography and were found to have normal or near-normal coronary arteries (< 30%
      stenosis of all major coronary arteries) with those of a series of 116 patients
      with moderate to severe CAD (> or = 60% stenosis of one or more major coronary
      artery). The usual lifetime occupational status of each study participant was
      classified as sedentary, intermediate, or strenuous. The presence of the usual
      cardiovascular risk factors in the patients was also recorded. There was no
      significant difference in the frequency of the three occupational categories
      between the two groups (those with or without CAD) when subjects of all ages were
      considered or when subjects less than 40 years or more than 60 years old were
      considered. However, the results indicate that among 40-60-year-old individuals
      CAD occurred significantly more frequently in those engaged in strenuous
      occupations than in those engaged in sedentary occupations. Cardiovascular risk
      factors occurred significantly more frequently in patients with CAD than in those
      with normal coronary arteries and in those engaged in strenuous occupations
      compared with those in sedentary occupations.

PMID- 10348424
TI  - The exercise pressor reflex and changes in radial arterial pressure and heart
      rate during walking in patients with arteriosclerosis obliterans.
AB  - Little is known about the time course and extent of the changes in radial
      arterial pressure and heart rate taking place in patients with arteriosclerosis
      obliterans during walking, as well their subtending mechanisms. For this reason
      the authors measured these variables in 23 patients with arteriosclerosis
      obliterans and in nine normal subjects (control group), during treadmill walking
      and several tests. In the patients a rapid and marked increase in radial arterial
      pressure was recorded during walking, whereas the same parameter either fell
      abruptly or persisted at elevated levels during recovery. This pattern markedly
      differed from that recorded in normal subjects, and it was mainly brought about
      by the activation of the exercise pressor reflex. The following findings
      suggested that the exercise pressor reflex was activated: the conditions required
      for activation of the reflex were present in our patients; the pressure changes
      observed during walking tightly paralleled the changes due to this reflex
      activation; the hypertensive response to walking was enhanced by increases in
      severity of disease and in walking speed and duration; the reflex activity
      persisted during recovery; and the pressure pattern during walking was reproduced
      by walking with arrested blood circulation to a lower limb. On the contrary, the
      behavior of heart rate was similar in patients and normal subjects both during
      walking and recovery because it was not influenced by the exercise pressor
      reflex.

PMID- 10348426
TI  - Elective intracoronary Micro-Stent II implantation without quantitative coronary
      angiography or intravascular ultrasound guidance and without subsequent
      anticoagulation: short- and long-term results.
AB  - Intracoronary stenting has been shown to reduce acute closure and restenosis rate
      in patients treated with coronary angioplasty. The use of high inflation
      pressures and intravascular ultrasound guidance allowed the substitution of
      anticoagulants with antiplatelet agents but increased the cost. The aim of this
      study was to investigate the effectiveness, safety, and long-term outcome of the
      elective implantation of a relatively new type of stent (Micro-Stent II), without
      the use of quantitative coronary angiography or intravascular ultrasound guidance
      and without subsequent anticoagulation. The study included 361 patients who
      underwent elective microstent implantation. Stent expansion was performed at 8
      atm followed by higher inflation pressure at 14-20 atm. Heparin was given
      intraarterially only once immediately after the arterial sheath insertion.
      Ticlopidine was started at least 48 hours before the procedure and continued for
      1 month while aspirin was continued indefinitely. All patients were followed up
      for 12.9 +/- 3.6 months. Short term outcome (first month): Stent implantation was
      successfully achieved in 361 of 366 patients (98.6%). Seven patients (1.9%) were
      excluded from the study and received anticoagulants because of a suboptimal
      result. In total, 423 stents were implanted. There was no subacute thrombosis,
      but acute vessel closure occurred in one patient (0.3%). Non-Q wave myocardial
      infarction occurred in six patients (1.7%), Q wave myocardial infarction occurred
      in one patient (0.3%), and only one death (0.3%) of nonischemic origin was
      reported. No major peripheral vascular complications were observed. Late results:
      Q or non-Q wave infarction occurred in 13 patients (3.6%), 26 patients (7.2%)
      underwent a repeat angioplasty, eight patients (2.2%) underwent coronary artery
      bypass grafting, and four patients (1.1%) died. Overall, 284 patients (78.7%)
      were free of symptoms, while 77 (21.3%) had recurrent coronary ischemia. In
      conclusion, Micro-Stent II implantation without quantitative coronary angiography
      or intravascular ultrasound guidance and without anticoagulation was found to be
      effective, safe, and with good long-term outcome.

PMID- 10348427
TI  - Dendritic cells in venous pathologies.
AB  - Dendritic cells are potent antigen-presenting cells responsible for the
      activation of T-lymphocytes in various immune responses. Their role in the
      initiation of immune reactions in allergies, autoimmune diseases, tumors,
      transplantation, and, more recently, in atherosclerosis has been well
      established, but their involvement in venous pathologies has not been previously
      investigated. The aim of this study was to determine whether dendritic cells are
      present in veins affected by varicosity and thrombophlebitis. Three groups of
      veins obtained at operation were studied: (1) varicose veins of the great
      saphenous vein from patients who were undergoing vein stripping for primary
      varicosity; (2) segments of the great saphenous vein from patients with
      varicosity complicated by thrombophlebitis; and (3) great saphenous veins without
      varicosity or thrombophlebitis from patients who were undergoing femoropopliteal
      bypass grafting. The specimens were fixed in 10% neutral buffered formalin and
      embedded in paraffin, and the sections were stained with antibodies to S-100 (to
      identify dendritic cells), CD3 (T-lymphocytes), CD68 (macrophages), von
      Willebrand factor (endothelial cells), alpha-smooth muscle actin (smooth muscle
      cells), and CD15 (mast cells) by use of avidin-biotin complex (ABC)
      immunoperoxidase technique. Immunohistochemical examination showed that no S-100
      positive dendritic cells were present in normal saphenous veins. In contrast, S
      100-positive cells with dendritic cell morphology were detected in the intima and
      media of veins with varicosity and thrombophlebitis, where they represented a
      minor cell population. S-100-positive dendritic cells were located between smooth
      muscle cells as well as around areas of neovascularization where they colocalized
      with T-lymphocytes. The present work suggests that dendritic cells might be
      involved in pathological processes in veins affected by varicosity and
      thrombophlebitis. The authors speculate that dendritic cells may be involved in
      the inflammatory mechanisms in these veins through their interaction with T
      lymphocytes.

PMID- 10348428
TI  - Circulating cytokines and complements in chronic heart failure.
AB  - Elevated levels of cytokines and complements have been reported in patients with
      advanced heart failure, but the exact clinical significance remains unclear.
      Therefore, assessments correlated with hemodynamic and clinical variables may
      provide important insight into the actions of cytokines and complements in
      chronic heart failure. The authors evaluated the clinical significance of
      cytokines and complements. The study included 60 subjects (50 men, 10 women); 34
      had idiopathic dilated cardiomyopathy (DCM) and 26 had ischemic heart disease
      (IHD). Tumor necrosis factor alpha and interleukin-2 receptor concentrations in
      chronic heart failure were greater than in control subjects (20.0 +/- 0.4 vs 18.0
      +/- 0.5 pg/mL, p<0.05 and 817.23 +/- 63.50 vs 642.75 +/- 27.31 pg/mL, p<0.05,
      respectively). There was no significant difference between DCM and IHD patients
      in circulating levels of the cytokines and the components complements (p=NS).
      Additionally, although functional classes III and IV heart failure patients
      showed a tendency to increase the levels of the cytokines and the component
      complements, these differences were not statistically significant (p=NS).
      Similarly, correlation analysis showed that the levels of the circulating
      cytokines and the component complements had independent value for mortality.
      These results suggest that humoral and cellular immunity abnormalities may play
      an important role in the pathogenesis of heart failure and dilated
      cardiomyopathy.

PMID- 10348429
TI  - Apical hypokinesis in a patient with hypertrophic cardiomyopathy and myocardial
      bridging: reversal with beta-blockade--a case report.
AB  - A 42-year-old man presented with effort angina pectoris of 20 minutes' duration.
      Hypertrophic obstructive cardiomyopathy, severe myocardial bridging involving the
      midleft anterior descending coronary artery, and apical hypokinesis were
      identified. Regional wall motion normalized following the initiation of beta
      blockade.

PMID- 10348430
TI  - Bifurcating aneurysm of the left main coronary artery involving left anterior
      descending and left circumflex arteries--a case report.
AB  - Coronary artery aneurysm is a rare coronary abnormality, usually diagnosed
      incidentally by coronary angiography. Major causes of coronary aneurysms include
      coronary ectasia, Kawasaki disease, and atherosclerosis. Most of the discrete
      coronary aneurysms are of atherosclerotic origin. The incidence of
      atherosclerotic coronary aneurysms is about 0.2%, and the left main coronary
      artery is the least frequently involved artery. Only a few cases of left main
      coronary artery aneurysm have been reported in the literature, and a left main
      coronary artery aneurysm involving the proximal segments of the left anterior
      descending and the left circumflex arteries has not been reported previously. The
      authors describe this finding in a man who presented with worsening exertional
      angina pectoris. Coronary angiography demonstrated an aneurysm of the distal left
      main coronary artery extending into the proximal segments of the left anterior
      descending and the left circumflex arteries. In addition, a significant flow
      limiting atherosclerotic lesion was present in the proximal portion of the left
      anterior descending artery distal to the aneurysm.

PMID- 10348431
TI  - Takayasu's arteritis accompanied with massive pericardial effusion--a case
      report.
AB  - A 40-year-old woman who had been treated for Takayasu's arteritis was admitted to
      the hospital with fever, fatigue, malaise, and severe chest pain. Computed
      tomography of the chest demonstrated massive pericardial effusion and bilateral
      pleural effusion. In laboratory data, the C-reactive protein was high at 22.0
      mg/dL, and erythrocyte sedimentation rate was also high at 80 mm/hr. The
      diagnosis was pericarditis with a recurrence of the systemic inflammatory process
      of Takayasu's arteritis. The patient was treated with methylprednisolone pulse
      therapy. Her massive pericardial effusion disappeared without pericardiocentesis.

PMID- 10348432
TI  - Cerebral venous thrombosis in patients with nephrotic syndrome--case reports.
AB  - The authors describe two cases of cerebral venous thrombosis (CVT) in patients
      with nephrotic syndrome. The main clinical features of CVT were persistent
      headache, hemiparesis, and seizure, and the diagnosis was based on magnetic
      resonance imaging and magnetic resonance angiography. Both showed acquired
      deficiency of free protein S. The neurologic symptoms remained stationary in the
      first patient, who received no anticoagulation therapy, but resolved rapidly in
      the second, treated with intravenous heparin and supplemented with fresh frozen
      plasma. CVT should be suspected in patients with nephrotic syndrome who present
      with symptoms of intracranial hypertension or any focal neurologic deficit.

PMID- 10348433
TI  - Acquisition of human multislice MR images at 8 Tesla.
AB  - PURPOSE: The purpose of this work was to acquire high quality multislice MR
      images from the human brain at 8 Tesla (T). METHOD: Initial images were acquired
      with an 8 T/80 cm magnet designed and manufactured by Magnex Scientific
      (Abingdon, England). Images were acquired using volume RF coils operating at 340
      MHz. A torque-free head gradient insert was utilized to spatially encode the
      spins. Images were acquired from the human head using gradient-recalled echo
      pulse sequences. RESULTS: Ultra high frequency (UHF) MR images have been obtained
      from the human head that display both excellent signal/noise ratio and image
      quality. The power required to obtain the 8 T images was much less than expected
      based on the trend obtained at lower fields. CONCLUSION: In this work, we have
      demonstrated that it is possible to obtain high quality multislice images from
      the human brain at 8 T. These images display the phenomenal potential for imaging
      at UHF and reveal that none of the stumbling blocks advanced by the MR community
      for an 8 T project (RF penetration, dielectric effects, specific absorption rate
      problems, RF power requirements) proved to be a limitation.

PMID- 10348434
TI  - Contrast-enhanced time-resolved MR angiography of spinal vascular malformations.
AB  - PURPOSE: The purpose of this work was to assess the potential and limitations of
      a contrast-enhanced time-resolved MR angiography technique for evaluation of
      spinal vascular malformations. METHOD: Two patients with intramedullary
      arteriovenous (AV) malformations and three patients with dural AV fistula
      underwent four serial acquisitions, every 17-20 s, of 20-32 coronal 1.5- to 2-mm
      thick partitions with a fast 3D SPGR sequence after injection of 0.2-0.3 mmol/kg
      paramagnetic contrast agent. This was followed by coronal 3D and sagittal or
      coronal 2D phase contrast (PC) MR angiography. RESULTS: No spinal vessels were
      visualized in the first (baseline) series. In patients with intramedullary AV
      malformations, the arterial feeders, nidus, and perimedullary draining veins were
      visualized in the second (early) series. In the third (intermediate) series, the
      arterial feeder vanished, whereas the intercostal and lumbar veins appeared. In
      patients with dural AV fistula, abnormal intraspinal vessel appeared in the third
      series and persisted, although less conspicuous, in the fourth (late) series.
      Contrast-enhanced time-resolved MR angiography demonstrated the venous components
      of the lesion with better conspicuity than 3D PC MR angiography, whereas it was
      inferior for visualization of arterial feeders. Moreover, indirect identification
      of the level of the dural AV fistula was possible only on the phase display of
      the 2D PC MR angiography. CONCLUSION: Contrast-enhanced time-resolved MR
      angiography is a useful complement to PC MR angiography for the evaluation of
      spinal vascular malformation.

PMID- 10348435
TI  - Vascular suppression technique in MRI using Gd-DTPA: improving image quality of
      MR myelography.
AB  - PURPOSE: To delete signals of juxta-thecal venous structures on MR myelograms, we
      evaluated the potential of Gd-DTPA as a negative contrast material in experiments
      and actual MR myelograms. METHOD: We measured the signals of Gd-DTPA solutions of
      various concentrations on T2-weighted turbo-SE and turbo-STIR images. The
      experiments revealed that 0.83 mmol/L Gd-DTPA worked as a negative contrast
      material in turbo-STIR. Subsequently, we obtained turbo-STIR myelograms of 31
      patients who complained of lumbago or sciatica before and after intravenous
      administration of 0.15 mmol/kg Gd-DTPA, which was presumed to provide the optimal
      plasma density in vivo. RESULTS: On postcontrast MR myelograms, the venous
      signals around the thecal sac decreased remarkably in almost all the cases as
      compared with precontrast images. In these cases, the nerve roots could be
      observed clearly. CONCLUSION: Gd-DTPA can work as a negative contrast material in
      turbo-STIR sequences. This characteristic should be used to improve the image
      quality of MR myelography using turbo-STIR.

PMID- 10348436
TI  - Idiopathic localized hydromyelia: dilatation of the central canal of the spinal
      cord of probable congenital origin.
AB  - Three adult patients are reported with asymptomatic localized widening of the
      central canal of the spinal cord. These patients were followed for a period of 24
      years by imaging and/or clinical history and physical examination without
      evidence of signs or symptoms related to the spinal cord. This condition probably
      represents persistence into adult life of a fetal configuration of the central
      canal of the spinal cord. This process may be termed "idiopathic localized
      hydromyelia" to distinguish it from syringomyelia secondary to such causes as
      Chiari malformation, trauma, infection, or neoplasm.

PMID- 10348437
TI  - "The disappearing lens": failure of CT to image the lens in traumatic intumescent
      cataract.
AB  - The CT scans of three patients whose eyes were lacerated by trauma failed to
      demonstrate the lens. A slit-lamp examination of those eyes clearly indicated
      that the lenses were present behind the iris but that they were swollen and
      opaque (intumescent cataract). Apparently, a shift of water into the injured lens
      had reduced the expected hyperdense CT image of the lens to a level that it was
      no longer discernible.

PMID- 10348438
TI  - Cavernous hemangioma of the intracranial optic pathways: CT and MRI.
AB  - PURPOSE: The purpose of this work was to describe the CT and MR findings in three
      patients with cavernous hemangioma (CH) of the intracranial optic pathways.
      METHOD: CT and MR studies of three patients with CH of the optic chiasm were
      reviewed. All patients underwent MRI of the chiasmal area, with coronal T2- and
      T1-weighted studies as well as gadolinium-enhanced coronal and sagittal T1
      weighted studies. RESULTS: The patients (mean age, 40 years) presented with
      chiasmal apoplexy (two cases) and progressive decrease of visual acuity (one
      case). In all cases, MRI showed regular enlargement of the optic chiasm, with
      extension to the optic nerve in one case and to the left optic tract in one case.
      The chiasmatic dimension was 2.5-3 cm in two cases and 1-1.5 cm in the other
      case. In all cases, MRI revealed an acute (isointense signal on T1-weighted and
      hypointense signal on T2-weighted sequences) or subacute (hyperintense signal on
      T1 - and T2-weighted sequences) hemorrhage with, adjacent to it, an area with
      signals of blood of different ages, highly suggestive of CH. CT showed, in
      chiasmatic CHs, a suprasellar mass spontaneously denser than adjacent brain
      parenchyma. In two cases, microcalcifications were associated. In two cases, CT
      and MRI revealed slight heterogeneous enhancement after contrast agent
      administration. In one case, no enhancement was observed. Two patients underwent
      surgery by frontopterional craniotomy. The optic chiasms were swollen with an
      intrinsic bluish mass. The cerebrospinal fluid was not xanthochromic. Microscope
      examination confirmed the diagnosis of CH. After 12 months, the operated patients
      had improved visual acuity and visual field but did not completely recover. The
      nonoperated patient (because of spontaneous rapid recovery of visual acuity) was
      followed clinically and on MRI over 18 months. CONCLUSION: CH in the optic chiasm
      must be suspected in the presence of an acute chiasmatic syndrome. MRI is the
      best imaging modality, showing either an acute or a subacute chiasmatic
      hemorrhage or the typical pattern of CH with heterogeneous alternation of foci of
      blood of different ages, with a central focus of methemoglobin, a peripheral rim
      of hemosiderin, adjacent foci of acute or subacute hemorrhage, and slight or no
      enhancement after gadolinium administration.

PMID- 10348439
TI  - The Lacrimo-Auriculo-Dento-Digital (LADD) syndrome: temporal bone CT findings.
AB  - The temporal bone CT examination of a 16-year-old female patient with the LADD
      syndrome or Levy-Hollister syndrome showed multiple bilateral middle as well as
      inner ear malformations. Ossicular chain anomalies were seen, especially of the
      incus and stapes. The oval window was very narrow to absent. Both cochleas were
      hypoplastic and showed modiolar deficiency. A common cavity between the vestibule
      and lateral semicircular canal was bilaterally present.

PMID- 10348440
TI  - Positron emission tomography in a case of intracranial hemangiopericytoma.
AB  - Due to the low prevalence of hemangiopericytomas (HPCs), data on the
      biophysiological characteristics of this tumor are rare. Positron emission
      tomography (PET) demonstrated a sixfold increased uptake of [11C]methionine and
      hyperperfusion in the HPC, whereas glucose utilization was decreased in this
      area. This low glucose utilization is in contrast to the high [11C]methionine
      uptake and the malignancy of these tumors. The characteristics of HPCs in PET
      described herein for the first time offer additional diagnostic criteria and may
      help especially to differentiate these tumors from meningiomas.

PMID- 10348441
TI  - Spiral CT of acute pulmonary thromboembolism: evaluation of pleuroparenchymal
      abnormalities.
AB  - PURPOSE: The goal of this work was to identify and categorize the spectrum of
      pulmonary parenchymal and pleural abnormalities identified by CT in patients with
      acute pulmonary thromboembolism (PE). METHOD: A review of interpretations from
      4,715 consecutive contrast-enhanced thoracic CT studies identified 41
      examinations in which the diagnosis of PE was reported. Thirty-four studies were
      available for review, and two radiologists confirmed intraluminal defects in 31
      patients. The number of emboli were counted and localized using bronchopulmonary
      nomenclature. Associated parenchymal and pleural abnormalities were tabulated.
      RESULTS: Of the 31 patients, 13 underwent confirmatory or correlative studies
      including angiography, radionuclide study, or autopsy. In addition, deep venous
      thrombosis was confirmed by ultrasound or MRI in 13 patients. An average of 7.5
      emboli per patient was detected. Pleuroparenchymal findings were as follows: Nine
      patients (29%) had no acute pulmonary parenchymal or pleural abnormality. In the
      remaining 22 patients, pleural effusion was the most common abnormality, found in
      14 of 31 (45%). Ten patients (32%) had peripheral wedge-shaped parenchymal
      opacities suggestive of pulmonary infarction. Normally enhancing lobar
      atelectasis was seen in nine patients (29%). Six patients (19%) demonstrated
      heterogeneous parenchymal enhancement within nonaerated lung, two of whom had
      pathologically proven pulmonary infarct. Thirteen of 31 patients underwent high
      resolution CT; a typical mosaic perfusion pattern was seen in only 1 patient.
      CONCLUSION: Twenty-nine percent of patients with acute PE had no acute lung
      parenchymal abnormality on CT; thus, the absence of parenchymal abnormality on CT
      does not exclude PE. High resolution CT mosaic perfusion was not a common feature
      of acute pulmonary embolism. Regions of decreased enhancement within nonaerated
      lung, seen in 19%, may prove to be an indicator of pulmonary infarction; however,
      this is a nonspecific finding.

PMID- 10348442
TI  - Comparison of high resolution CT findings of sarcoidosis, lymphoma, and
      lymphangitic carcinoma: is there any difference of involved interstitium?
AB  - PURPOSE: The purpose of this study was to determine distinguishing features of
      three diseases that are distributed along the lymphatics. METHOD: CT scans of 40
      patients with lymphangitic carcinomatosis, 41 with sarcoidosis, and 44 with
      malignant lymphoma were retrospectively reviewed. We evaluated the degree of
      involvement of the interlobular septa, bronchovascular structures, subpleural
      interstitium, and other CT findings. RESULTS: The number of thickened
      interlobular septa and the extent of involvement of the subpleural interstitium
      in lymphangitic carcinomatosis were higher than those in sarcoidosis and
      malignant lymphoma (p<0.0001). Nodules of >1 cm in diameter were more often seen
      in malignant lymphoma (41.0%) than in the other two diseases (p < 0.001).
      Bilateral distribution was more common in sarcoidosis (100%) than in the others
      (p<0.001). CONCLUSION: The major difference among lymphangitic carcinomatosis,
      sarcoidosis, and malignant lymphoma is the greater involvement of the
      interlobular septa and subpleural interstitium in lymphangitic carcinomatosis
      than in either sarcoidosis or malignant lymphoma.

PMID- 10348443
TI  - Optimized scanning conditions of high resolution CT in the follow-up of pulmonary
      emphysema.
AB  - PURPOSE: To address the optimal scanning condition of high resolution
      computerized tomography from the perspective of minimizing exposed dose. METHOD:
      The influence of the electric current, the slice number, and the slice thickness
      on precise percent ratio of the low attenuation area to whole lung field (LAA%)
      of chronic obstructive pulmonary disease patients was examined. The standard
      conditions were 250 mA, 3 slices, 2 mm slice thickness, and a varied parameter.
      RESULTS: In cases showing an LAA% less than 30, LAA% obtained by < or =150 mA
      were significantly larger than those by 250 mA. The mean LAA% with 3 and 10
      slices were well correlated and the correlation with lung function was similar.
      The correlation of LAA% with lung function was approximately the same between the
      2 and 5 mm slice thicknesses. CONCLUSION: The electrical current must be > or
      =200 mA, and 3 slices and 2 mm slice thickness are appropriate.

PMID- 10348444
TI  - A comparison of methods for enhancing the detection of areas of decreased
      attenuation on CT caused by airways disease.
AB  - PURPOSE: The purpose of this work was to investigate thin section CT image
      enhancement of subtle areas of decreased attenuation of the lung parenchyma in
      suspected airways disease. METHOD: Forty-seven consecutive patients with chronic
      sputum production underwent pulmonary function tests and high resolution CT
      (HRCT). Single section inspiratory (INSP), expiratory (EXP), and minimum
      intensity projection (MINIP) images through the lower lobes were acquired. A
      histogram stretch was applied to the INSP and MINIP images, generating two
      further image formats. The five image types were compared for the extent of
      decreased attenuation, observer confidence, and correlations with pulmonary
      function tests. RESULTS: Interobserver variation was lowest with MINIP images
      (mean weighted K: MINIP 0.70, INSP sections 0.65, other image formats < or
      =0.48). Observers were most confident with EXP and MINIP images. EXP sections
      identified more disease than MINIP images (p<0.001). Correlations with pulmonary
      function tests were similar for each image format. CONCLUSION: The HRCT changes
      of small airways disease are enhanced with image postprocessing. MINIP images are
      associated with increased observer confidence and agreement as compared with HRCT
      alone.

PMID- 10348445
TI  - Measurement of in vivo myocardial microcirculatory function with electron beam
      CT.
AB  - PURPOSE: The purpose of this work was to examine the capability of electron beam
      CT (EBCT) to characterize responses of recruitable (capillaries and small
      arterioles) compared with nonrecruitable (small to large arterioles) myocardial
      microvessels to vasoactive substances. METHOD: Myocardial perfusion (F) and total
      intramyocardial blood volume (BV) of the anterior cardiac wall were quantitated
      in 36 pigs, using EBCT and intravenous contrast agent injections, before and
      after intracoronary administration of either NG-monomethyl-L-arginine (L-NMMA),
      nitroglycerin, adenosine, or saline. Plotting the relationship of BV and F
      provided values for the recruitable and nonrecruitable microvascular transit
      times and BV allotment. RESULTS: Nitroglycerin increased nonrecruitable BV by
      84.5+/-7.4%, whereas adenosine increased both recruitable and nonrecruitable
      microvascular BV (47.1+/-18.9 and 66.0+/-10.9%, respectively). L-NMMA led to a
      25.1% decrease only in the recruitable BV. In the control group, no changes were
      observed. CONCLUSION: Characteristic responses of different-size myocardial
      microvessels may be inferred with EBCT, which provides a unique opportunity to
      portray intramyocardial microcirculatory function noninvasively.

PMID- 10348446
TI  - Spectrum of neurogenic tumors in the thorax: CT and pathologic findings.
AB  - Neurilemomas and neurofibromas appear as round soft tissue masses at CT. Variable
      enhancement with either homogeneity or heterogeneity is seen in neurilemomas.
      Attenuation of the tumors on enhanced CT depends on histology: the extent of
      Antoni A or B tissue and the amount of myxoid or cystic degeneration or
      hemorrhage. Neurofibromas are usually homogeneous low attenuation lesions on
      unenhanced CT. They show homogeneous enhancement or early central blush on
      enhanced scan. The extent of enhancement depends on the proportions of tumor
      components: nerve sheath cells, collagen bundles, and areas of myxoid
      degeneration. Malignant nerve sheath tumors show variable attenuation. Bony
      destruction, pleural effusion, and metastatic pulmonary nodules may also occur.
      Ganglioneuromas appear as oblong homogeneous low attenuation lesions on both
      enhanced and unenhanced CT. This low attenuation is due to their pathologic
      components, with an abundant amount of myxoid matrices and a relatively small
      amount of ganglion cells. Neuroblastomas appear as aggressive soft tissue lesions
      with calcification. Ganglioneuroblastomas may appear with features in between
      those of ganglioneuromas and neuroblastomas. The typical location of the
      posterior mediastinum or the aortopulmonary window and high enhancement with
      administration of contrast medium at CT suggest the diagnosis of paragangliomas.

PMID- 10348447
TI  - Assessment of breast tissue changes on hormonal replacement therapy using MRI: a
      pilot study.
AB  - PURPOSE: The purpose of this study was to investigate, using MRI, the potential
      morphologic effects of hormonal replacement therapy (HRT) on breast tissue in
      post-menopausal women. METHOD: Five subjects were enrolled who were treated
      subsequently with both estrogen (2 mg/day) and a combination of estrogen (2
      mg/day) and progestagen (1 mg/day). T1-weighted (TR 11 ms, TE 4.65 ms, flip angle
      35 degrees, two excitations) 3D MR scans were acquired on a 1.5 T whole-body
      scanner before therapy and after each regimen. With use of a segmentation
      algorithm and histogram evaluation, parenchymal tissue/fat ratios were calculated
      over targeted volumes and changes were assessed. RESULTS: An increase in these
      ratios was observed in two subjects after receiving the combined therapy,
      indicating a change in parenchymal pattern, whereas no obvious changes were
      detected in any of the subjects during the estrogen-based therapy. CONCLUSION:
      MRI is able to detect and quantitate changes in breast parenchyma during HRT.

PMID- 10348448
TI  - Male breast myofibroblastoma and MR findings.
AB  - Myofibroblastoma of the breast is a rare benign tumor seen predominantly in men
      in the sixth to seventh decades of life. We present a case of breast
      myofibroblastoma in a man and describe the mammographic, sonographic, and MR
      findings.

PMID- 10348449
TI  - CT of nonneoplastic diseases of the small bowel: spectrum of disease.
AB  - This article reviews the CT imaging features of a variety of nonneoplastic
      conditions that affect the small bowel and stresses important distinctive
      patterns that may help distinguish specific entities. Various inflammatory
      conditions (Crohn disease, radiation enteritis, graft versus host disease, celiac
      disease, Whipple disease, eosinophilic gastroenteritis, Behcet disease) as well
      as infiltrative disorders (amyloidosis, lymphangiectasia) and infectious diseases
      (Mycobacterium avium intracellulare, cytomegalovirus, cryptosporidiosis) are
      reviewed, with key differential points emphasized. In addition, miscellaneous
      conditions such as ischemia, small bowel diverticulitis, and small bowel
      hemorrhage are discussed.

PMID- 10348450
TI  - CT and MRI of pelvic varices in women.
AB  - Pelvic varices in women consist of tortuous and dilated parauterine and ovarian
      veins and have a characteristic appearance at CT and MRI. Imaging is critical in
      the evaluation of pelvic varices, both to prevent confusion with other conditions
      and because pelvic varices may be secondary to serious underlying pathology.
      Additionally, primary pelvic varices are associated with the pelvic pain
      syndrome, and patients with the pelvic pain syndrome may benefit from therapeutic
      venous embolization. Secondary pelvic varices are rarely associated with pelvic
      pain.

PMID- 10348452
TI  - CT and ultrasound features of metanephric adenoma in adults with pathologic
      correlation.
AB  - PURPOSE: The purpose of this work was to correlate the CT, ultrasound, and
      pathologic features of metanephric adenoma, a rare benign renal tumor in adults.
      METHOD: Retrospective review of medical records (1990-1997) revealed three adult
      female patients who had both preoperative imaging and nephrectomy with pathologic
      diagnosis of metanephric adenoma performed at our institution. CT (n = 3) and
      ultrasound (n = 2) features were reviewed in consensus by two radiologists and
      correlated with pathologic findings. RESULTS: In all three cases, the metanephric
      adenoma was of increased attenuation relative to adjacent renal parenchyma on
      unenhanced CT scans. No septa or calcifications were seen. Ultrasound images
      showed both tumors to be hyperechoic with enhanced through-transmission.
      CONCLUSION: The CT and ultrasound findings correlate with the pathologic features
      of a high nuclear-to-cytoplasmic ratio and psammomatous calcifications. In the
      adult population, it is unlikely that metanephric adenoma can be prospectively
      differentiated from renal cell carcinoma based on imaging features.

PMID- 10348451
TI  - Three-dimensional imaging of liver tumors using helical CT during intravenous
      injection of contrast medium.
AB  - PURPOSE: The goal of this work was to determine whether 3D reconstruction of
      images from CT during intravenous injection of contrast medium, performed in
      tandem with advanced rendering algorithms, could accurately depict major anatomic
      structures and hepatic tumors. METHOD: Thirty-one patients (22 with
      hepatocellular carcinoma, 8 with metastatic lesions, and 1 with intrahepatic
      cholangiocarcinoma) underwent CT imaging. Twenty-three of the 31 patients
      underwent needle biopsy or surgery, yielding a histologic diagnosis. The
      remaining eight patients were diagnosed from imaging findings and laboratory
      data. We compared the ability of maximum intensity projection (MIP) and volume
      rendered technique (VRT) images to depict the hepatic veins and intrahepatic
      portal veins. RESULTS: Both MIP and VRT depicted the course of vessels up to the
      second or third branches. The techniques did not significantly differ. In this
      regard, in most cases, visualization of the liver surface and tumor was excellent
      with VRT images. CONCLUSION: Volume-rendered 3D-CT images during intravenous
      injection without the MIP technique produced 3D images of high quality with
      excellent visualization of tumors and their relationships to vital structures.

PMID- 10348453
TI  - Hemosiderin deposition on the renal cortex by mechanical hemolysis due to
      malfunctioning prosthetic cardiac valve: report of MR findings in two cases.
AB  - We present two cases of mechanical hemolysis due to malfunctioning prosthetic
      cardiac valves in which MRI was characteristic. The signal intensity of the renal
      cortex was much lower than that of the medulla on T2-weighted images due to
      deposition of hemosiderin in proximal convoluted tubules by intravascular
      hemolysis. These MR findings are identical to those in paroxysmal nocturnal
      hemoglobinuria.

PMID- 10348454
TI  - Clinical significance of increased density in the proximal femoral marrow
      detected by visual inspection on abdominopelvic postcontrast CT examination.
AB  - PURPOSE: The purpose of this study was to ascertain the clinical significance of
      increased density of the proximal femoral diaphyseal marrow when incidentally
      detected on postcontrast abdominopelvic CT examinations. METHOD: The proximal
      femoral marrow of 63 patients was classified as normal or abnormal based on
      visual inspection by three attending radiologists. Abnormal density was defined
      as attenuation greater than that of adjacent musculature. The attenuation of the
      marrow was also measured. All patient medical records were reviewed for pertinent
      laboratory and clinical data. RESULTS: Increased marrow density had a low
      sensitivity for anemia (28%) but a high specificity and positive predictive value
      (100%) for anemia. Three of these patients had unilaterally increased attenuation
      associated with local pathology. Visual inspection was adequate for identifying
      abnormalities in instances of underlying malignancy. CONCLUSION: Increased
      density of the proximal femoral diaphysis is a highly specific finding for a
      marrow replacement process. Anemia was the most common clinical diagnosis in our
      series of patients with abnormal marrow density. Although the sensitivity for
      increased bone marrow attenuation is low, the extremely high specificity and
      positive predictive value of this finding for marrow reconversion and/or
      replacement suggest that even if detected incidentally, it should not be
      disregarded and, in the absence of a preexisting causative diagnosis, warrants
      further evaluation. The specific pattern of marrow abnormality may be helpful in
      differentiating localized processes from other processes that may affect
      hematopoietic function in a more widespread or global distribution. In
      particular, visual inspection of marrow density was more specific for identifying
      asymmetric marrow density in localized processes than was a quantitative measure
      of difference between the two femurs (>20 HU).

PMID- 10348455
TI  - MRI of tuberculous pyomyositis.
AB  - PURPOSE: The purpose of this article is to describe the findings of MRI in
      tuberculous pyomyositis (PM). METHOD: The MR images of four proven cases of
      tuberculous PM were retrospectively reviewed and analyzed with clinical and
      laboratory findings. The location, signal intensity on T1- and T2-weighted spin
      echo images, presence of abscess, signal intensity of peripheral rim, patterns of
      contrast enhancement, and associated findings were evaluated. RESULTS: On MR
      images, all cases demonstrated low signal intensity on T1-weighted images and
      high signal intensity on T2-weighted images in a single muscle. Abscess was seen
      in all cases. Peripheral rim showed subtle hyperintensity on T1-weighted images
      and hypointensity on T2-weighted images. After gadolinium infusion, peripheral
      rim enhancement was observed in all cases. Cellulitis was associated in one case.
      The patients clinically presented with a palpable mass of long duration.
      CONCLUSION: Tuberculous PM shows characteristic findings of a well demarcated
      abscess with rim enhancement at MRI and can be distinguished from other soft
      tissue masses.

PMID- 10348456
TI  - Intramuscular solitary fibrous tumor: a clinicopathological case study.
AB  - We present a case of extrapleural solitary fibrous tumor arising within the
      muscle, an unusual and hitherto-undescribed tumor lesion. A 42-year-old woman
      presented a painless mass in her left thigh. The lesion was depicted as an
      intramuscular mass that enhanced on both CT and MRI, showing quite rich tumor
      vascularity. The histological features of the tumor were spindle cell
      proliferation with various histological patterns, typical fibrocollagenous
      background, and positive immunoreactivity for CD-34.

PMID- 10348458
TI  - Mathematical analysis of arterial enhancement and optimization of bolus geometry
      for CT angiography using the discrete fourier transform.
AB  - PURPOSE: The goal of this work was to develop a clinically applicable
      mathematical algorithm to analyze and optimize individual arterial enhancement in
      CT angiography (CTA). METHOD: Assuming a time-invariant linear system, the
      discrete Fourier transform was used to calculate the transfer function of the
      system ("patient function") from the arterial time-attenuation response to a test
      bolus. The patient function was subsequently used to predict aortic enhancement
      in five select patients and to calculate optimized biphasic injection protocols
      in two of these patients undergoing CTA of the abdominal aorta. RESULTS: Arterial
      time-attenuation curves were accurately predicted in all patients. Optimized
      biphasic contrast agent injection protocols resulted in uniform aortic
      enhancement at the predefined level over the entire scanning period in both
      subjects despite markedly different contrast agent volumes and injection rates
      used. CONCLUSION: Fourier analysis of the time-attenuation response to a test
      bolus is a simple and feasible approach to optimize arterial enhancement in CTA.

PMID- 10348457
TI  - Treatment of baseline drifts in fMRI time series analysis.
AB  - PURPOSE: Gradual drifting of baseline signal intensity is common in functional
      MRI (fMRI) time course data. Methods for dealing with this effect are studied.
      METHOD: Simulations and fMRI data are used to study three statistical models that
      account for baseline drift. A method is proposed in which the time course data
      are linear least-squares fit to a reference function that includes the slope of
      the baseline drift as a free parameter. RESULTS: It is shown that the least
      squares method is equivalent to cross-correlation with Gram-Schmidt
      orthogonalization. Additionally, it is shown that certain paradigm designs
      improve the sensitivity of statistical tests when using any of the drift
      correction methods commonly employed. The least-squares method results in a
      variety of useful parameters such as activation amplitude, with a well
      characterized error. CONCLUSION: Very simple techniques can effectively account
      for observed drifts. It is important to design paradigms that are symmetric about
      the midpoint of the time series. In calculating confidence levels, a proper
      statistical model that accounts for baseline drifts is necessary to ensure
      accurate confidence level assessment.

PMID- 10348459
TI  - Aunt Minnie's Corner. Adrenal myelolipoma.

PMID- 10348460
TI  - Catatonia: re-awakening to a forgotten disorder.

PMID- 10348461
TI  - Pathophysiology of chorea and bradykinesia in Huntington's disease.
AB  - This article reviews the neurophysiological abnormalities described in
      Huntington's disease. Among the typical features of choreic movements are
      variable and random patterns of electromyographic (EMG) activity, including
      cocontraction of agonist and antagonist muscles. Studies of premotor potentials
      show that choreic movements are not preceded by a Bereitschaftspotential,
      therefore demonstrating that choreic movement is involuntary. Early cortical
      median-nerve somatosensory-evoked potentials have reduced amplitudes and the
      reduction correlates with reduced glucose consumption in the caudate nucleus.
      Long-latency stretch reflexes evoked in the small hand muscles are depressed.
      These findings may reflect failed thalamocortical relay of sensory information.
      In Huntington's disease, the R2 response of the blink reflex has prolonged
      latencies, diminished amplitudes, and greater habituation than normal. These
      abnormalities correlate with the severity of chorea in the face. Patients with
      Huntington's disease perform simple voluntary movements more slowly than normal
      subjects and with an abnormal triphasic EMG pattern. Bradykinesia is also present
      during their performance of simultaneous and sequential movements. Eye movements
      show abnormalities similar to those seen in arm movements. In Huntington's
      disease, arm movement execution is associated with reduced PET activation of
      cortical frontal areas. Studies using transcranial magnetic stimulation show that
      patients with Huntington's disease have normal corticospinal conduction but some
      patients have a prolonged cortical silent period. Bradykinesia results from
      degeneration of the basal ganglia output to the supplementary motor areas
      concerned with the initiation and maintenance of sequential movements. The
      coexisting hyperkinetic and hypokinetic movement disorders in patients with
      Huntington's disease probably reflect the involvement of direct and indirect
      pathways in the basal ganglia-thalamus-cortical motor circuit.

PMID- 10348462
TI  - Catatonia as a psychomotor syndrome: a rating scale and extrapyramidal motor
      symptoms.
AB  - BACKGROUND: Catatonia was first described by Kahlbaum as a psychomotor disease
      with motor, behavioral, and affective symptoms. In keeping with this concept, we
      developed a rating scale for catatonia (Northoff Catatonia Scale [NCS]) with
      three different categories of symptoms (i.e., motor, behavioral, affective).
      Furthermore, the question of the relationship among catatonic symptoms,
      extrapyramidal motor symptoms, and neuroleptics was addressed in the present
      study. METHOD: 34 acute catatonic patients and 68 age-, sex-, diagnosis-, and
      medication-matched psychiatric control subjects were investigated on days 0, 1,
      3, 7, and 21 with the NCS, with other already validated catatonia rating scales
      by Rosebush, Bush (BFCRS), and Rogers (MRS), as well as with scales for
      hypokinetic (SEPS) and dyskinetic (AIMS) extrapyramidal motor features. Validity
      and reliability of the new scale, factor analysis, correlational analysis, and
      differences between catatonic patients and psychiatric control subjects were
      statistically calculated. RESULTS: NCS showed high validity (i.e., significant
      positive correlations [p <0.0001] with the other scales, significant differences
      between catatonic and control subjects), high intra-and interrater reliabilities
      (r = 0.80-0.96), and high affective subscores. Factor analysis revealed four
      factors best characterized as affective, hypoactive, hyperactive, and behavioral.
      Catatonic scores in NCS correlated significantly with AIMS on day 0 and SEPS on
      days 7 and 21. There were no significant differences in catatonic (i.e., NCS,
      MRS, BFCRS) and extrapyramidal (i.e., AIMS, SEPS) scores between neuroleptically
      treated and untreated catatonic subjects. CONCLUSIONS: The following conclusions
      were drawn: (1) the NCS has to be considered as a valid and reliable rating
      instrument for catatonia; (2) catatonia can be characterized by psychomotor
      symptoms encompassing motor, affective, and behavioral alterations; and (3)
      extrapyramidal hyperkinesias like dyskinesias are apparently closely related to
      catatonic symptoms which, in general, seem to be relatively independent of
      previous neuroleptic medication.

PMID- 10348463
TI  - Alpha-synuclein expression in substantia nigra and cortex in Parkinson's disease.
AB  - Mutations in the human alpha-synuclein gene have been identified in several
      families of European descent with early-onset Parkinson's disease (PD). We
      sequenced the complete alpha-synuclein cDNA from substantia nigra and cortex from
      nine patients with PD and eight control subjects. No mutations were found. We
      then analyzed alpha-synuclein mRNA levels using a ribonuclease protection assay.
      Two major protected bands of alpha-synuclein mRNA, possibly representing two
      splice variants of the gene, were observed. Alpha-synuclein mRNA was
      significantly diminished in the substantia nigra of patients with PD compared
      with control subjects but not in the cortex. Our findings suggest that decreased
      synuclein mRNA may be an early alteration in the SN in PD, and imply that
      decreased levels of the protein may play a role in the pathogenesis of sporadic
      cases of the disease.

PMID- 10348464
TI  - Bradykinesia and impairment of EEG desynchronization in Parkinson's disease.
AB  - It has been suggested that the basal ganglia control the release of cortical
      elements from low-frequency rhythmic idling activity during voluntary movement.
      This hypothesis was tested by recording the local idling rhythms of the motor
      cortex, the alpha and beta rhythms, in 12 untreated and treated patients with
      Parkinson's disease as they moved a wrist. Recordings were made after overnight
      withdrawal of medication and again 1 hr after levodopa. The treatment-related
      attenuation of the alpha and beta rhythms picked up over the cortical motor areas
      contralateral to the active arm correlated with the improvement in size and speed
      of movement effected by levodopa. The distribution and degree of attenuation
      depended on the complexity of the task. These results demonstrate for the first
      time a specific effect of levodopa on the organization of motor cortical activity
      in the frequency domain, an effect that correlates with improvements in
      bradykinesia.

PMID- 10348465
TI  - Phosphorus magnetic resonance spectroscopy in multiple system atrophy and
      Parkinson's disease.
AB  - We performed in vivo phosphorus magnetic resonance spectroscopy on the occipital
      lobes of 15 patients with multiple system atrophy (MSA; eight with
      olivopontocerebellar atrophy [OPCA] and seven with the striatonigral degeneration
      variant [SND]), 13 patients with idiopathic Parkinson's disease (PD), and 16 age
      matched healthy subjects. The MSA group showed significantly reduced
      phosphocreatine (PCr), increased inorganic phosphate (Pi), and unchanged
      cytosolic free [Mg2+], and pH. We did not find any significant difference between
      the OPCA and SND variants. However, patients with PD showed significantly
      increased content of Pi, decreased cytosolic free [Mg2+], and unchanged [PCr] and
      pH. Comparing the MSA and PD groups, [PCr] was significantly lower in MSA than in
      PD, whereas cytosolic free [Mg2+] was significantly lower in PD. Despite a
      certain degree of overlap of [PCr] and [Mg2+] values between the two groups, by
      considering both variables at the same time it was possible to classify correctly
      93% of cases by discriminant analysis. We conclude that phosphorus magnetic
      resonance spectroscopy discloses abnormal phosphate metabolite and ion contents
      in both MSA and PD, respectively, and may provide noninvasive diagnostic help to
      differentiate MSA from PD.

PMID- 10348466
TI  - Effect of treatment with L-dopa/carbidopa or L-selegiline on striatal dopamine
      transporter SPECT imaging with [123I]beta-CIT.
AB  - The effect of subchronic treatment with L-dopa/carbidopa or L-selegiline on
      striatal dopamine transporters (DAT) was examined in patients with idiopathic
      Parkinson's disease with SPECT (single photon emission computed tomography) using
      [123I]beta-CIT (2beta-carbomethoxy-3beta-[4-iodophenyl]tropane) as the
      radiotracer. Patients who were not currently being treated with these medications
      were given either 750 mg L-dopa/carbidopa per day (n = 8) or 10 mg L-selegiline
      per day (n = 8). [123I]beta-CIT imaging was performed three times in each
      patient: at baseline before treatment, while on medication and after 4-6 weeks of
      drug treatment, and following withdrawal from medication (approximately 1 week
      for L-dopa/carbidopa and 9 weeks for L-selegiline). Comparison of scans 2 and 3
      provided a measure of drug occupancy of the [123I]beta-CIT binding site;
      comparison of scans 1 and 2 provided a measure of both up- or downregulation of
      DAT levels and drug occupancy following subchronic drug treatment. DAT levels
      were assessed from an image acquired approximately 22 hours after radiotracer
      injection as a ratio of regional brain activities: (striatum -
      occipital)/occipital. Striatal DAT levels were not significantly different when
      any two of the three scans were compared for both drug treatments. These results
      suggest that typical clinical doses of L-dopa/carbidopa and L-selegiline do not
      induce significant occupancy of the [123I]beta-CIT binding site and that 4-6
      weeks of treatment causes no significant modulation of DAT levels. These results
      support the validity of measuring DAT levels with [123I]beta-CIT without the need
      to withdraw patients from medication treatment.

PMID- 10348467
TI  - Camptocormia (bent spine) in patients with Parkinson's disease--characterization
      and possible pathogenesis of an unusual phenomenon.
AB  - Camptocormia is characterized by severe forward flexion of the thoracolumbar
      spine which increases while walking and disappears in the recumbent position. We
      describe for the first time eight patients with presumed idiopathic Parkinson's
      disease (mean age 66+/-5 yrs; mean symptom duration 13.1+/-5.1 yrs) who developed
      camptocormia. This impressive abnormal posture emerged 4-14 years from disease
      onset, and in some patients stooped posture was the prominent symptom at
      diagnosis. There was no clear correlation between camptocormia and levodopa
      treatment. In some patients the camptocormic posture improved, and in others it
      was unchanged or even aggravated following levodopa administration. Three
      patients reported worsening of this symptom during "off" periods and also with
      fatigue. The pathogenesis of this phenomenon is unknown but might represent
      either a rare type of dystonia or an extreme form of rigidity.

PMID- 10348468
TI  - Clinical rating of dyskinesias in Parkinson's disease: use and reliability of a
      new rating scale.
AB  - Drug-induced dyskinesias (DID) manifested as hyperkinetic and/or dystonic
      movements or postures are common problems in Parkinson's disease (PD). Novel
      therapeutic interventions may offer possibilities to counteract these common
      adverse effects of an otherwise necessary treatment. To be able to evaluate the
      effects of such interventions on DID, reliable and relevant clinical assessment
      tools are needed. We tested the inter- and intrarater reliability of a new
      clinical dyskinesia rating scale consisting of separate ratings of different body
      parts, including lateralization and separate ratings of dystonia and
      hyperkinesias. Interrater reliability was tested both with and without a defined
      scoring code and clarification of the dystonia section. The nondefined version
      was also tested for intrarater reliability. Thirteen raters independently
      reviewed 23 videotape sequences showing PD patients performing standardized motor
      tests. Inter- and intrarater agreement was significant in all evaluations, and no
      differences were detected when comparing ratings performed with the defined and
      nondefined version of the scale. The rationale for, and the role and use of, the
      present scale are addressed.

PMID- 10348469
TI  - Validity of family history data on essential tremor.
AB  - BACKGROUND: In family studies of essential tremor (ET), valid data on the
      presence of ET in relatives of probands with ET is important. The family history
      method uses information obtained by interviewing probands with ET to identify ET
      in their relatives. The validation of this method by direct examination of the
      relatives has not been performed. OBJECTIVE: To determine the validity of family
      history data on ET in families in which the proband has ET. METHODS: ET cases
      (probands) and their respective relatives were enrolled in a genetic study of ET
      in Washington Heights-Inwood, New York. Each underwent a tremor interview and
      videotaped examination. Two neurologists rated the severity of tremor and
      assigned diagnoses (ET versus normal). Probands were asked to identify their
      relatives who had ET. The validity of the probands' responses was tested against
      the neurologists' diagnoses. RESULTS: There were 206 subjects: 46 ET cases and
      160 relatives. Twelve (7.5%) of 160 relatives were diagnosed with ET (four
      definite ET and eight probable ET). Probands with ET reported that two of these
      12 had tremor (sensitivity of probands' report = 16.7%). Six of the 12 affected
      relatives (50.0%) reported their own tremor. The probands reported that one of
      136 of their unaffected relatives had tremor (specificity of probands' report =
      99.3%). CONCLUSIONS: For family studies of ET, information on reportedly
      unaffected relatives is of limited use given the low sensitivity of family
      history data. The neurologic examination remains the only valid means of
      ascertaining cases of ET among relatives.

PMID- 10348470
TI  - A comparison of different bedside tests for essential tremor.
AB  - OBJECTIVE: To compare the performance of different bedside tests for essential
      tremor (ET). BACKGROUND: Numerous tests (for example, writing, arm extension) may
      be used to elicit tremor in patients with ET. In large epidemiological surveys in
      which many patients must be evaluated efficiently, knowledge about the relative
      performance of these tests would be useful. METHODS: 154 subjects (42 with ET and
      112 control subjects) were part of a community-based family study of ET in
      northern Manhattan, New York. Subjects underwent a tremor interview and a
      videotaped tremor examination which included six different tests for ET. Each of
      the six tests was performed with both the dominant and the nondominant arms. Two
      neurologists reviewed the videotaped examination and rated the severity of tremor
      during each test. Tremor ratings were 0 (none), +1 (mild), +2 (moderate), and +3
      (severe). RESULTS: Among ET cases, there was considerable variation in the
      performance of each bedside test. With some tests (nondominant arm extension), as
      few as 48.8% of the ratings were >+2 and 29.8% of the ratings were 0 (no tremor).
      With other tests (finger-to-nose maneuver using nondominant arm), as many as
      88.1% of the ratings were >+2 and only 2.4% were 0. Among the control subjects,
      there was also considerable variation in the performance of each test. Using some
      tests (finger-to-nose maneuver using nondominant arm), as many as 26.3% of the
      ratings were >+2, 72.8% were >+1 tremor, and only 27.2% of the ratings were 0.
      CONCLUSIONS: The performance of the tests varied considerably. In settings in
      which only one or two tests must be selected to screen a population, tests that
      are most likely to be abnormal in an ET case (finger-to-nose maneuver) could be
      used. In settings in which it is also desirable to exclude normal subjects, tests
      such as sustained arm extension, pouring water, or drawing a spiral could be
      used. Data regarding the performance of bedside tests for diagnosing ET are
      central to the design of research strategies for the clinical evaluation of
      patients with ET.

PMID- 10348471
TI  - Acute and chronic effects of clozapine in essential tremor.
AB  - Patients with essential tremor (ET) may not respond to commonly used drugs.
      Clozapine, an atypical neuroleptic drug, has been reported to improve postural
      Parkinson's disease tremor clinically resembling ET. The effects of a single dose
      of 12.5 mg clozapine and placebo were evaluated in a randomized, double-blind,
      crossover study in 15 drug-resistant patients with ET. Patient responders with
      more than 50% improvement after a single dose of clozapine subsequently received
      the drug (39+/-9 mg up to 50 mg) unblinded for a period of 15.8+/-7.7 months.
      Tremor was effectively reduced by a single dose of clozapine in 13 of 15 patients
      (p <0.01). Sedation was the only side effect reported during the clozapine test;
      however, the time course of sedation and of the antitremor effect were not
      coincident. A significant reduction of tremor was reported with chronic clozapine
      treatment (p <0.01) with no tolerance to drug antitremor effect, whereas sedation
      markedly decreased after 6-7 weeks of therapy. No clozapine-induced hematologic
      side effects were observed in our cohort of patients during long-term treatment.
      Our results suggest that in selected drug-resistant ET cases, clozapine should be
      considered before resorting to neurosurgical options.

PMID- 10348472
TI  - Evidence for an abnormal cortical sensory processing in dystonia: selective
      enhancement of lower limb P37-N50 somatosensory evoked potential.
AB  - We evaluated brain stem P30, contralateral frontal N37, and the vertex
      ipsilateral central P37, N50 somatosensory evoked potentials (SEPs) obtained in
      response to stimulation of the tibial nerve in 10 patients with idiopathic
      dystonia. Results were compared with those obtained in 10 healthy subjects
      matched for age and sex. The amplitude of the brain stem P30 potential and of the
      contralateral frontal N37 response in dystonic patients was not significantly
      different from that recorded in normal subjects. The vertex- ipsilateral central
      P37-N50 complex, which is thought to originate in the pre-rolandic cortex, was
      significantly enhanced in patients compared with the control group. These results
      suggest the enhancement of the vertex-ipsilateral central P37-N50 complex might
      reflect an abnormal response to somatosensory inputs of a precentral cortex which
      is excessively activated because of a disorder of the basal ganglia. Such
      inefficient sensory processing in motor areas might contribute to motor
      impairment in dystonia.

PMID- 10348473
TI  - GPi firing rate modification during beginning-of-dose motor deterioration
      following acute administration of apomorphine.
AB  - We present a patient with clinically evident beginning-of-dose motor
      deterioration who had undergone posteroventral pallidotomy. This patient
      underwent an intrasurgical apomorphine test followed by single cell recording of
      the internal globus pallidus (GPi) to determine changes in GPi firing rate during
      the occurrence of such phenomenon. A significant increase in GPi firing rate
      coincident with worsening of patient disabilities prior to improvement was found.
      This finding suggests that beginning-of-dose motor deterioration may be mediated
      by enhanced thalamic inhibition.

PMID- 10348474
TI  - Quetiapine for the treatment of drug-induced psychosis in Parkinson's disease.
AB  - Quetiapine is an atypical antipsychotic with clozapine-like pharmacology but
      without associated agranulocytosis. We report our complete experience with
      quetiapine for the treatment of drug-induced psychosis (DIP) in Parkinson's
      disease (PD). Thirty-five patients with PD and DIP aged 75 years (range, 58-89)
      with a mean PD duration of 8.4 years on an average of 427 mg levodopa per day
      received a mean dose of 40.6 mg quetiapine daily. Twenty of 24 neuroleptic-naive
      patients reported marked improvement of psychosis without a decline in motor
      function as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS
      motor). Ten patients had a baseline and 4-week follow-up assessment using the
      Mini-Mental Status Examination (MMSE) and Brief Psychiatric Rating Scale (BPRS).
      The improvement in BPRS score (32.6 versus 22.8) was clinically and statistically
      significant (p = 0.024). Three of 24 were unable to tolerate quetiapine because
      of orthostatic hypotension, headache, nausea, and persistence of hallucinations.
      One patient died of an unrelated cause. We also tried to switch 11
      psychiatrically stable patients on clozapine (eight) and olanzapine (three). Five
      patients made this transition without a loss of effect as measured on BPRS and
      MMSE. Six did not (five on clozapine, one on olanzapine) because of confusion,
      erratic behavior, and increased hallucinations. No crossover failure had worsened
      PD except for increased tremor in one. Quetiapine is useful and well-tolerated as
      a first drug to treat DIP in PD but must be used cautiously to replace other
      atypical antipsychotic drugs.

PMID- 10348475
TI  - Dystonia as a presenting feature of the 3243 mitochondrial DNA mutation.
AB  - A variety of neurologic phenotypes have been described in patients with
      mitochondrial disorders. We report a 32-year-old man in whom dystonia was the
      salient and presenting feature of a mitochondrial DNA mutation. He presented at
      age 23 with writer's cramp and progressed over 5 years to exhibit dystonia in
      facial muscles and lower limbs. He also has exercise intolerance, mild, bilateral
      ptosis, proximal muscle weakness, and sensorineural hearing loss. Molecular
      genetic analysis of blood, urine, and muscle biopsy demonstrated the presence of
      a heteroplasmic point mutation at nucleotide position 3243. The 3243 mtDNA
      mutation has pleomorphic manifestations, and dystonia should be added to the list
      of associated clinical features.

PMID- 10348476
TI  - Atypical and typical cranial dystonia following dental procedures.
AB  - It is generally recognized that focal dystonia of the limbs or cervical region
      and blepharospasm sometimes follow, and in these cases may be caused or triggered
      by, peripheral injury. However, the association between peripheral injury and
      lower cranial dystonia is rare. We report eight cases who developed cranial
      dystonia within hours to months following a dental procedure. One group of five
      cases, all women, developed atypical dystonia associated with painful
      paresthesias at the site of dystonia. Two of these five cases had fixed jaw
      deviating dystonia, whereas the remaining three had additional tremor and spread
      of their dystonia to involve the tongue in all three, and the lips and neck in
      two cases. These five patients are reminiscent of cases of limb causalgia
      dystonia syndrome, which occurs after minor peripheral trauma and can spread. The
      remaining three cases developed more typical cranial dystonia following the
      dental procedure. There was no family history of dystonia or prior use of
      neuroleptics in any of the patients. The close association in time and location
      of the procedure and onset of symptoms suggests that the onset of the dystonia
      may have been caused by the dental intervention, but whether there is a causal
      relationship between the dental intervention and the development of the
      dyskinesias requires further epidemiologic studies.

PMID- 10348477
TI  - Hemichorea and hemiballism associated with contralateral hemiparesis and
      ipsilateral basal ganglia lesions.
AB  - We report on two patients with unilateral hyperkinetic movement disorders
      associated with contralateral hemiparesis and ipsilateral basal ganglia lesions.
      The first patient, a 47-year-old woman, had a low-grade astrocytoma located in
      the right basal ganglia extending into the subthalamic area and the cerebral
      peduncle. She presented with left hemiparesis, right hemichorea, and intermittent
      right-sided tremor at rest. The second patient, a 85-year-old woman, had
      hypertensive hemorrhage to the right posterior basal ganglia, the posterior limb
      of the internal capsule, the lateral thalamus, and the subthalamic region with
      accompanying intraventricular bleeding. She developed right-sided transient
      hemichorea-hemiballism. A videotape illustration of one of the patients is
      provided. The literature on the rare occurrence of ipsilateral hemichorea
      hemiballism is discussed and possible pathomechanisms are reviewed. We postulate
      that hemiparesis contralateral to basal ganglia lesions might have a conditioning
      effect on the appearance of ipsilateral dyskinetic movement disorders.

PMID- 10348478
TI  - Advantages of a modified scoring method for the Rush Video-Based Tic Rating
      Scale.
AB  - Previously, we published a video-based objective rating scale of tics that met
      reliability and validity criteria for measurement of five domains of tic
      disability. In the original form, the scale's metric properties did not permit
      internal comparison of each of the five domains of impairment and did not provide
      a total score for use as a primary outcome measure. In this study, we retained
      the original scale and videotape protocol but tested whether a modified scoring
      system corrected these limitations. The new scoring method rated assigned tic
      data to ratings of 0-4 on five disability categories: number of body areas,
      frequency of motor tics, frequency of phonic tics, severity of motor tics, and
      severity of phonic tics. The sums of these ratings yielded a total score of
      overall tic disability (0-20). In a series of 31 patients with Gilles de la
      Tourette syndrome, we assessed Spearman correlation coefficients for the old and
      new scoring systems as well as the correlation of the new ratings with the
      objectively derived sections of the Yale Global Tic Severity Scale (YGTSS),
      another valid and reliable scale used in clinical practice and research. For each
      domain, the rank order for the scores on the original scale was well retained in
      the new scores. Likewise, for each domain, ranking with the new scoring system
      correlated well with scores on the comparable objective item from the YGTSS. The
      new total score accurately captured the rank order of the combined five domains
      from the original scale and correlated well with the total objective motor plus
      phonic tic score from the YGTSS and the YGTSS Tourette Syndrome Overall
      Impairment Rating. These data demonstrate that the modified videotape-based
      scoring system retains the essential information gathered in the original Rush
      scale. The modification provides comparisons among the five assessed domains and
      a total objectively based disability score that can be used as a single outcome
      measure for assessing tic disability.

PMID- 10348479
TI  - Melatonin as a therapy in REM sleep behavior disorder patients: an open-labeled
      pilot study on the possible influence of melatonin on REM-sleep regulation.
AB  - REM sleep behavior disorder (RBD) is clinically impressive by virtue of its
      vigorous sleep behaviors usually accompanying vivid, striking dreams. The main
      feature of the disorder, REM sleep without muscle atonia, has been shown in a
      variety of diseases; therefore, the disorder might possibly be underestimated. In
      an open-labeled trial, we treated six consecutive RBD patients over a 6-week
      period with 3 mg melatonin given within 30 minutes before bedtime. There was a
      dramatic clinical improvement in five of the six patients within a week which
      extended beyond the end of treatment for weeks or months. A second polysomnogram
      performed 6 weeks after the beginning of treatment showed a significant tendency
      toward normalization of the percentage of REM sleep, a significant reduction of
      30-second epochs, scored as REM sleep without muscle atonia, a significant
      reduction of stage-shifts in REM, and a significant reduction in epochs
      considered as movement time in REM. All other sleep parameters were not changed
      consistently. We hypothesize that internal desynchrony might be a part of the
      underlying pathophysiology in RBD. Our data might give first evidence to the
      hypothesis that exogenous melatonin, administered to patients with internal
      desynchrony at the time of the maximal rise of melatonin secretion, might
      increase the overall amplitude of the circadian pacemaker by reentraining the
      suprachiasmatic nucleus and thereby restore circadian driven rhythms, one of them
      being the circadian modulation of REM sleep.

PMID- 10348480
TI  - A posttraumatic thalamic lesion associated with contralateral action myoclonus.

PMID- 10348481
TI  - No increase of synthesis of (R)salsolinol in Parkinson's disease.

PMID- 10348482
TI  - Transient benefit of amantadine in Parkinson's disease: the facts about the myth.

PMID- 10348483
TI  - The NMDA antagonist budipine can alleviate levodopa-induced motor fluctuations.

PMID- 10348484
TI  - Parkinsonism from methanol poisoning: benefit from treatment with anti-Parkinson
      drugs.

PMID- 10348485
TI  - Central pontine and extrapontine myelinolysis presenting with parkinsonism in a
      patient with cystic fibrosis.

PMID- 10348486
TI  - Severe akinetic syndrome resulting from a bilateral basal ganglia lesion
      following bone marrow transplantation.

PMID- 10348487
TI  - An unusual jaw tremor with characteristics of primary orthostatic tremor.

PMID- 10348488
TI  - Primary antiphospholipid syndrome presenting as a corticobasal degeneration
      syndrome.

PMID- 10348489
TI  - Successful treatment of hemichorea with olanzapine.

PMID- 10348490
TI  - Cinnarizine-induced parkinsonism: ten years later.

PMID- 10348491
TI  - Protease inhibitors enhance levodopa effects in Parkinson's disease.

PMID- 10348492
TI  - Decrease in akinesia seems to result from chronic electrical stimulation in the
      external (GPe) rather than internal (Gpi) pallidum.

PMID- 10348493
TI  - Isoproterenol decreases leptin expression in adipose tissue of obese humans.
AB  - OBJECTIVE: We investigated the effects of the non-selective beta-adrenergic
      agonist, isoproterenol (Iso), on leptin expression in human adipose tissue.
      RESEARCH METHODS AND PROCEDURES: Subcutaneous (SQ) and omental adipose (OM)
      tissue taken during surgery from 12 morbidly obese subjects (10 women and 2 men)
      were cultured for up to 24 hours with insulin (7 nM) and/or dexamethasone (25
      nM), a synthetic glucocorticoid, in the presence or absence of isoproterenol (10
      microM). Adipose tissue was also acutely incubated for 3 hours in media alone
      with or without isoproterenol. Leptin secretion and leptin mRNA abundance were
      measured. RESULTS: Iso acutely decreased leptin release by approximately 30% (vs.
      no hormone controls) in fragments of OM and SQ adipose tissue. In 24-hour
      culture, addition of Iso (in the presence of insulin) resulted in lower leptin
      accumulation in the medium (-20-30%) and leptin mRNA levels (-40-50%) from both
      tissue depots. Culture with insulin and dexamethasone increased leptin expression
      vs. insulin alone. Addition of Iso with insulin and dexamethasone decreased media
      leptin (-40-60%) and leptin mRNA levels were lower (-65%) in Iso-treated adipose
      tissue from both depots after 24 hours. Iso effects were not detectable after 5
      hours of culture. DISCUSSION: We conclude that stimulation of beta-adrenergic
      receptors may modulate leptin expression in human adipose tissue by two
      mechanisms: an acute effect on leptin release and a longer-term antagonism of
      stimulatory effects of insulin and dexamethasone on leptin mRNA expression. These
      mechanisms may contribute to the decline in serum leptin that occurs during
      fasting.

PMID- 10348494
TI  - Collection and interpretation of plasma leptin concentration data in humans.
AB  - OBJECTIVE: To reassess the relationship between body fat and plasma leptin
      concentrations when a) replicate measures of leptin are made; b) energy intake is
      controlled at isoenergetic levels before the study; and c) body fat and percent
      body fat are measured with dual energy X-ray absorptiometry (DXA). RESEARCH
      METHODS AND PROCEDURES: Two separate studies were conducted. In the first study,
      four plasma samples were collected for measurement of leptin over 30 minutes on a
      single day in 43 lean and obese men and women. For the second study, plasma
      samples were collected on four consecutive days from a group of 50 lean and obese
      men and women. Percent body fat (and body fat mass) was related to log
      transformed mean plasma leptin concentrations using linear regression analysis;
      multiple linear regression analysis was used to determine whether there was an
      effect of gender on this relationship, and the analysis of Choi was used to
      examine whether percent body fat or body fat mass better predicts plasma leptin
      concentrations. RESULTS: For the first study, percent body fat was highly
      correlated (r=0.96, p<0.0001) with log-transformed mean leptin concentrations. No
      difference in the relationship between leptin and percent body fat in men and
      women was detected. The second study confirmed this observation; the relationship
      between ln leptin and percent body fat was virtually identical (r=0.93, p<0.001).
      Analysis of the pooled data suggests that percent body fat is a better predictor
      of plasma leptin concentration than body fat mass. The use of multiple (as
      opposed to a single) leptin measurements did not significantly improve the
      leptin/body fat relationship. DISCUSSION: When robust body composition techniques
      and diet control measures are taken into consideration, the relationship between
      ln plasma leptin concentrations and percent body fat is not different in men and
      women.

PMID- 10348495
TI  - Segregation analysis of body mass index in a large sample selected for obesity:
      the Swedish Obese Subjects study.
AB  - OBJECTIVE: To investigate a major gene hypothesis for body mass index (BMI) in a
      large sample of probands (n = 2580, ages 37-57 years) who were selected for
      obesity (BMI> or =34 kg/m2 for males and > or =38 kg/m2 for females), along with
      their spouses and first-degree relatives (n = 11,204 family members). The
      probands were recruited as part of an intervention trial assessing whether
      mortality and morbidity were improved after surgical intervention for obesity as
      part of the Swedish Obese Subjects (SOS) study. METHODS AND PROCEDURES: The
      current analyses were based on BMI measures obtained before intervention.
      Segregation analysis was carried out using the mixed model implementation in PAP
      (Pedigree Analysis Package), which allowed for ascertainment correction and for
      genotype-dependent effects of covariates (sex and age) in both the major gene
      component and the multifactorial (i.e., polygenic and familial environment)
      component. RESULTS: Both a major effect and a multifactorial effect were
      significant. The percentage of the total variance accounted for by the
      multifactorial effect was 17%-24% (increasing as a function of age), and by the
      major effect, 8%-34% (decreasing as a function of age). Although tests on the
      transmission probabilities (taus) were not compatible with Mendelian expectations
      of 1, 1/2, and 0, the equal taus model was rejected (i.e., the effect is
      transmitted in families) and the point estimates (0.96, 0.60, and 0.17) compared
      favorably to Mendelian expectations. The major effect was transmitted in a
      codominant fashion, consistent with a gene-environment interaction. DISCUSSION:
      These results suggest both multifactorial and major effect etiologies for BMI in
      these families of extremely obese probands. Before 20 years of age, the major
      effect dominates the BMI expression, but after age 20, multifactorial effects
      account for the most variance. Although the major effect is transmitted in these
      families, the pattern does not appear to be consistent with a simple Mendelian
      trait. The possibility of additional major loci (i.e., epistasis) and gene by
      environment interactions may explain these findings.

PMID- 10348496
TI  - The use of anthropometric and dual-energy X-ray absorptiometry (DXA) measures to
      estimate total abdominal and abdominal visceral fat in men and women.
AB  - OBJECTIVE: A single-slice computed tomography (CT) scan provides a criterion
      measure of total abdominal fat (TAF) and abdominal visceral fat (AVF), but this
      procedure is often prohibitive due to radiation exposure, cost, and
      accessibility. In the present study, the utility of anthropometric measures and
      estimates of trunk and abdominal fat mass by dual-energy X-ray absorptiometry
      (DXA) to predict CT measures of TAF and AVF (cross-sectional area, cm2) was
      assessed. RESEARCH METHODS AND PROCEDURES: CT measures of abdominal fat (at the
      level of the L4-L5 inter-vertebral space), DXA scans, and anthropometric measures
      were obtained in 76 Caucasian adults ages 20-80 years. RESULTS: Results
      demonstrated that abdominal sagittal diameter measured by anthropometry is an
      excellent predictor of sagittal diameter measured from a CT image (r=0.88 and
      0.94; Total Error [TE]=4.1 and 3.1 cm, for men and women, respectively). In both
      men and women, waist circumference and abdominal sagittal diameter were the
      anthropometric measures most strongly associated with TAF (r=0.87 to 0.93;
      Standard Error of Estimate (SEE)=60.7 to 75.4 cm2) and AVF (r=0.84 to 0.93;
      SEE=0.7 to 30.0 cm2). The least predictive anthropometric measure of TAF or AVF
      was the commonly used waist-to-hip ratio (WHR). DXA estimates of trunk and
      abdominal fat mass were strongly associated with TAF (r=.94 to 0.97; SEE=36.9 to
      50.9 cm2) and AVF (r=0.86 to 0.90; SEE=4.9 to 27.7 cm2). DISCUSSION: The present
      results suggest that waist circumference and/or abdominal sagittal diameter are
      better predictors of TAF and AVF than the more commonly used WHR. DXA trunk fat
      and abdominal fat appear to be slightly better predictors of TAF but not AVF
      compared to these anthropometric measures. Thus DXA does not offer a significant
      advantage over anthropometry for estimation of AVF.

PMID- 10348497
TI  - Association of total and central adiposity measures with fasting insulin in a
      biracial population of young adults with normal glucose tolerance: the CARDIA
      study.
AB  - OBJECTIVE: To determine the association of computed tomography (CT)-measured
      visceral adipose tissue (AT) and other measures of adiposity with fasting insulin
      in a biracial (African American and Caucasian) study population of young adults.
      RESEARCH METHODS AND PROCEDURES: The study population consisted of 251 young
      adults with normal glucose tolerance (NGT), ages 28-40 years, who were volunteers
      from the Birmingham, Alabama, and Oakland, California centers of the Coronary
      Artery Risk Development in Young Adults (CARDIA) study. RESULTS: In regression
      models with total adiposity measures (body mass index or dual-energy X-ray
      absorptiometry-measured percent fat), visceral AT (measured as a cross-sectional
      area in cm2) was generally a stronger predictor of insulin than overall adiposity
      in all race/gender groups (partial correlation coefficients ranging from 0.31 to
      0.47) except for black men, in whom the associations were nonsignificant. Partial
      correlation coefficients between waist circumference and insulin, controlling for
      percent fat, were nearly identical to those between visceral AT and insulin in
      women and in white men. Analyses performed on 2060 NGT CARDIA subjects who were
      not in this study of visceral AT showed significant correlations of waist
      circumference with insulin in all race/gender groups, including black men, and
      that black men in the visceral AT study group were significantly leaner than
      other black male CARDIA subjects. DISCUSSION: We conclude that visceral AT was
      associated with fasting insulin in NGT participants in three of the four
      race/gender groups (black men excepted) and that waist circumference was a good
      surrogate for visceral AT in examining associations of central adiposity with
      fasting insulin.

PMID- 10348498
TI  - Components of total energy expenditure in healthy young women are not affected
      after 14 days of feeding with medium-versus long-chain triglycerides.
AB  - OBJECTIVE: To examine the effect of consumption of medium-chain triglycerides
      (MCT) vs. long-chain triglycerides (LCT) on total energy expenditure (TEE) and
      its components in young women during the second week of a 2-week feeding period.
      RESEARCH METHODS AND PROCEDURES: Twelve healthy lean women (age: 22.7+/-0.7
      years, body mass index [BMI]: 21.5+/-0.8 kg/m2) were fed weight maintenance diets
      containing 15% of energy as protein, 45% as carbohydrate, and 40% as fat, 80% of
      which was treatment fat, for 2 weeks in a randomized cross-over design separated
      by a 2-week washout period. Dietary fat was composed of triglycerides containing
      either 26% medium-chain fatty acids (MCFA) and 74% long-chain fatty acids (LCFA),
      or 2% MCFA and 98% LCFA. Free-living TEE was measured from day 7 to 14 on each
      dietary treatment using doubly labeled water (DLW). Basal metabolic rate (BMR)
      and thermic effect of food (TEF) were measured on days 7 and 14 using respiratory
      gas exchange analysis (RGE) for 30 minutes and 330 minutes, respectively.
      Activity-induced energy expenditure (AIEE) was derived as the difference between
      TEE and the sum of BMR and TEF. RESULTS: The average TEE while consuming the MCT
      diet (2246+/-98 kcal/day) did not differ from that of the LCT diet (2186+/-138
      kcal/day. BMR was significantly higher on the MCT diet on day 7 (1219+/-38
      kcal/day vs. 1179+/-42 kcal/day), but not on day 14; there was no effect of diet
      on TEF. There were no differences in BMR, TEF, or AIEE between diets when
      expressed as percentages of TEE. On average, BMR, TEF, and AIEE represented
      54.6%, 8.2%, and 37.2%, respectively, of TEE. DISCUSSION: Results suggest that
      between day 7 and day 14 feeding of MCT vs. LCT at these levels, TEE is not
      affected and that increases seen in energy expenditure following MCT feeding may
      be of short duration. Thus, compensatory mechanisms may exist which blunt the
      effect of MCT on energy components over the longer term.

PMID- 10348499
TI  - A comparison of body size evaluations of obesity surgery patients and general
      population adults.
AB  - OBJECTIVE: To compare post-operative obesity surgery patients and general
      population adults in their assessments of a wide range of body sizes. RESEARCH
      METHODS AND PROCEDURES: Obesity surgery patients (n = 274) and general population
      adults (n = 326) rated ideal and socially acceptable body sizes in separate
      arrays of babies, children, young adults, and middle-aged and older adults. Nine
      line figure drawings ranging from very thin to very obese were rated for each
      array. RESULTS: Both groups selected the same ideal body size for all arrays
      except for babies. Both groups rejected obese and very thin body sizes as
      socially acceptable. However, the obesity surgery patients were more restrictive
      than general population adults in their ratings of socially acceptable body
      sizes. Current obesity status did not impact ratings for the patient or general
      population subjects. In the patient sample, time since surgery did not influence
      body size evaluations. DISCUSSION: The study of body size ratings limited only to
      the "ideal" size may be misleading because it may mask subtle but meaningful
      differences between groups. The consistent difference in more restrictive ratings
      of obesity surgery patients compared to general population adults may be due to
      patients' greater psychological investment in endorsing the societal ideal body
      size. It may also be due to patients' status as peripheral group members of the
      normal weight community. The inability of some patients to maintain their post
      operative weight loss may be particularly problematic for those who have defined
      "socially acceptable" body size most narrowly.

PMID- 10348500
TI  - Changes in self-efficacy and decisional balance for exercise among obese women in
      a weight management program.
AB  - OBJECTIVE: To assess changes in eating and exercise self-efficacy and decisional
      balance for exercise in an obese population enrolled in a multi-disciplinary
      weight management program. RESEARCH METHOD AND PROCEDURES: Thirty-two obese women
      were assessed at entry and after 12 weeks of treatment. RESULTS: Participants
      showed 15% mean weight loss after 12 weeks of treatment. Mean minutes of self
      reported exercise increased by 229%. Participants demonstrated significant
      improvements in self-efficacy for both eating and exercise and health parameters
      but not in decisional balance for exercise adoption. DISCUSSION: These results
      may have implications for the practitioner in that self-efficacy changes occur
      during successful weight loss, but decisional balance for exercise may not change
      until individuals enter maintenance. These results imply that practitioners may
      be advised to shift from confidence building to relapse prevention early on in
      treatment, and that focusing on strengthening the pros of exercise and reducing
      the cons of exercise may need to remain constant during treatment.

PMID- 10348501
TI  - The presence of the "fa" gene in heterozygous (FA/fa) lean female rats, effects
      on body weight, body fat and serum leptin.
AB  - OBJECTIVE: In previous studies, suckling lean heterozygous (FA/fa) pups had
      higher body fat levels in comparison to lean homozygous (FA/FA) pups. However, in
      older male rats fed either low- or high-fat diets, we found no effects of the
      "fa" gene in heterozygous lean rats compared to homozygous lean rats. Other
      studies have reported effects of the "fa" gene on aspects of insulin metabolism
      for lean heterozygous female rats compared to their homozygous counterparts. In
      the present study, the effect of the "fa" gene on body weight and body fat in
      lean female rats was investigated. RESEARCH METHODS AND PROCEDURES: Homozygous
      lean female rats were obtained by mating homozygous lean male and female rats.
      Heterozygous lean female rats were obtained by mating homozygous obese male rats
      with heterozygous lean female rats. Following weaning, rats were maintained on a
      standard laboratory diet until 10 weeks of age when they were killed after an
      overnight fast. RESULTS: Body weight (p<0.03) and inguinal (p = 0.01) and
      combined retroperitoneal+parametrial (p = 0.06) fat pad weights were heavier in
      heterozygous lean compared to homozygous lean female rats. Combined fat pad-to
      body weight ratio (p = 0.05) and fat cell sizes (p = 0.06) were also higher in
      the heterozygous lean compared to homozygous lean rats. No differences in serum
      triacylglycerol, cholesterol, glucose, or insulin concentrations were found
      between the two groups, but serum leptin levels were significantly higher
      (p<0.004) in heterozygous lean rats. DISCUSSION: These results indicate that
      effects of the "fa" gene are present during the postweaning period in lean female
      rats. Implications for increased body fat and leptin with respect to sexual
      maturation and fertility are discussed.

PMID- 10348502
TI  - Dermatoses in 156 obese adults.
AB  - BACKGROUND: Skin diseases are mentioned as a frequent finding in the obese
      patient. However, to our knowledge no study has been done on this subject.
      OBJECTIVE: To determine the prevalence of skin diseases associated with different
      obesity grades and if any dermatosis can be considered an obesity marker.
      MATERIALS AND METHODS: A cross-sectional study of 156 obese patients who were
      110% to 293% overweight were included. Complete medical history and
      dermatological examination were done. RESULTS: In the 126 female and 30 male
      obese patients, grades I to V, with a body mass index (BMI) of 27-51, cutaneous
      findings with statistical significance for linear trend were: plantar
      hyperkeratosis 54 patients p = 0.00001; acanthosis nigricans 46 patients p =
      0.00005; striae 67 patients p = 0.03; skin tags 69 patients p = 0.01; keratosis
      pilaris 33 patients p = 0.007. Patients with plantar hyperkeratosis were
      distributed in the obesity groups as follows: grade I = 3 patients; grade II = 7
      patients; grade III = 8 patients; grade IV = 17 patients; and grade V = 19
      patients. Of the 76 diabetic patients, 26 had acanthosis nigricans, 38 had skin
      tags, and 27 had plantar hyperkeratosis. DISCUSSION: Plantar hyperkeratosis
      should be considered as a cutaneous stigma of severe obesity. This is probably a
      result of pressure directly related to the excess weight.

PMID- 10348503
TI  - Conference report--obesity: new directions, June 27-29, 1998, Charleston, South
      Carolina.

PMID- 10348504
TI  - Valvular heart disease in fenfluramine- phentermine-treated patients: a
      comparison with control patients.

PMID- 10348505
TI  - Radiology--a dental specialty awaiting its just recognition.

PMID- 10348506
TI  - Toluidine blue--viewpoints.

PMID- 10348507
TI  - Toluidine blue--viewpoints.

PMID- 10348508
TI  - Propofol anesthesia for outpatient oral and maxillofacial surgery.
AB  - Propofol is a sedative-hypnotic intravenous anesthetic agent that has gained wide
      use in outpatient oral and maxillofacial surgery since its clinical introduction
      in 1985. Propofol has several therapeutic advantages that make it an excellent
      choice for use in all phases of general anesthesia and conscious sedation. It is
      associated with minimal side effects, a controllable anesthetic state, and rapid
      recovery. This review of propofol discusses its pharmacologic character,
      administration, and side effects and presents anesthetic drug interaction
      information and comparisons.

PMID- 10348509
TI  - Levels of human defensin-1, an antimicrobial peptide, in saliva of patients with
      oral inflammation.
AB  - OBJECTIVE: The purpose of this study was to investigate the presence of an
      antimicrobial peptide, human defensin-1, in the saliva of patients with oral
      inflammation. STUDY DESIGN: Whole saliva samples were collected from patients
      with oral inflammation and from healthy volunteers. Human defensin-1 in saliva
      was isolated and purified by reversed-phase high-performance liquid
      chromatography. The amino acid sequence and molecular weight of defensin-1 were
      determined. The concentration of defensin-1 in saliva was quantified by high
      performance liquid chromatography. Serum C-reactive protein concentration was
      measured by particle-enhanced turbidimetric immunoassay. RESULTS: The salivary
      defensin-1 concentration was significantly higher in patients with oral
      inflammation than in healthy volunteers; furthermore, in patients with oral
      inflammation, the concentration was significantly higher before treatment than
      after treatment. In the patients with oral inflammation, there was a strong
      positive correlation between salivary defensin-1 concentration and serum C
      reactive protein concentration. CONCLUSIONS: The findings suggest that defensin-1
      in saliva may be a convenient marker of inflammation associated with oral
      disease.

PMID- 10348510
TI  - Effect of local application of the antimicrobial peptide IB-367 on the incidence
      and severity of oral mucositis in hamsters.
AB  - OBJECTIVE: The purpose of this animal study was to determine whether IB-367, an
      antimicrobial peptide, is able to ameliorate oral mucositis by reducing
      microflora densities on the mucosal surfaces of the mouth. STUDY DESIGN: Oral
      mucositis was induced in hamsters by intraperitoneal injection of 5-fluorouracil
      followed by superficial abrasion of the buccal mucosa. A test formulation was
      applied topically to the buccal mucosa 5 or 6 times per day starting 6 to 8 hours
      before abrasion. RESULTS: Mucositis scores were significantly lower (P < .05) in
      hamsters given formulations containing 0.5 or 2.0 mg/mL of IB-367 than in placebo
      treated controls. Treatment with IB-367 produced a more than 100-fold reduction
      in oral microflora densities. In a second experiment, treatment of hamsters with
      a formulation containing IB-367 at 0.12, 0.5 or 2.0 mg/mL resulted in a dose
      dependent reduction in mucositis severity. CONCLUSION: The results indicate that
      reduction of local microflora densities through use of IB-367 may improve
      clinical outcomes in patients at risk for the development of oral mucositis.

PMID- 10348511
TI  - Irrigating solution and pressure effects on tooth sectioning with surgical burs.
AB  - OBJECTIVE: The purpose of this study was to determine the influence of the
      applied load on the handpiece, type of cooling agent, and type of tooth on
      surgical tooth dissection with a tapered crosscut fissure bur. STUDY DESIGN:
      Cutting studies were performed at handpiece loadings of 295 and 590 g through use
      of an oral surgery straight handpiece, tapered crosscut fissure burs, and an
      established cutting regimen. Extracted molars were dissected under irrigation
      with water, 0.9% saline solution, and lactated Ringer's solution at constant flow
      rates of 15 and 25 mL/min. Cutting efficiencies were analyzed by 1-way analysis
      of variance and Scheffe tests. RESULTS: No difference in cutting efficiency was
      found at low loads under irrigation with water or saline solution, but under
      irrigation with lactated Ringer's solution, a higher cutting efficiency was found
      (P < .05). There was no difference in cutting efficiency for lactated Ringer's
      solution and saline solution at high loads, but both cut more efficiently than
      water (P < .01). CONCLUSIONS: Saline solution is a useful coolant/irrigant for
      the dissection of teeth under most conditions, but lactated Ringer's solution
      might be beneficial with respect to cutting efficiency when lower handpiece loads
      are required.

PMID- 10348512
TI  - Anesthetic efficacy of the mylohyoid nerve block and combination inferior
      alveolar nerve block/mylohyoid nerve block.
AB  - OBJECTIVE: The purpose of this study was to measure the degree of anesthesia
      obtained with the mylohyoid nerve block and the combination mylohyoid nerve
      block/conventional inferior alveolar nerve (IAN) block in mandibular teeth. STUDY
      DESIGN: With the use of a repeated-measures design, 30 subjects randomly received
      each of 3 combinations of injections at 3 separate appointments. The combinations
      were as follows: mylohyoid nerve block (1.8 mL of 2% lidocaine with 1:100,000
      epinephrine) + IAN block (3.6 mL of 2% lidocaine with 1:100,000 epinephrine);
      mock mylohyoid nerve block + IAN block (3.6 mL of 2% lidocaine with 1:100,000
      epinephrine); mylohyoid nerve block (1.8 mL of 2% lidocaine with 1:100,000
      epinephrine) + mock IAN block. The mylohyoid injections were aided by the use of
      a peripheral nerve stimulator. Mandibular anterior and posterior teeth were
      blindly tested with a pulp tester at 4-minute cycles for 60 minutes
      postinjection. Anesthesia was considered successful when 2 consecutive 80
      readings were obtained. RESULTS: One hundred percent of the subjects had lip
      numbness with the mylohyoid nerve block + IAN block and mock mylohyoid nerve
      block + IAN block techniques. For these 2 techniques, anesthetic success rates
      were higher in posterior teeth (73% to 93%) than in anterior teeth (33% to 60%).
      There were no significant differences (P > .05) between the 2 techniques. The
      mylohyoid nerve block + mock IAN block technique resulted in a very low success
      rate (0% to 17%) and was significantly different (P < .05) from the mylohyoid
      nerve block + IAN block technique. CONCLUSIONS: The results of this study suggest
      that the mylohyoid nerve block does not by itself predictably provide pulpal
      anesthesia in mandibular teeth and does not significantly enhance pulpal
      anesthesia when administered in combination with the IAN block.

PMID- 10348513
TI  - Oxypentifylline in the management of recurrent aphthous oral ulcers: an open
      clinical trial.
AB  - OBJECTIVE: The purpose of this study was to determine the efficacy of
      oxypentifylline in the treatment of recurrent oral aphthous ulcers and to compare
      the results with those of previous studies. STUDY DESIGN: A 6-week open trial and
      a patient survey regarding pain were conducted at the Oral and Maxillofacial
      Surgery Unit, City General Hospital, Carlisle. Twenty-four patients (11 male and
      13 female) were selected from sequential referrals involving complaints of
      recurrent oral ulcers. A 2-week pretrial period was used to record data
      pertaining to the occurrence, duration, and pain associated with ulcers. A 4-week
      period of treatment with oxypentifylline (400 mg administered orally 3 times
      daily) was followed by an assessment of improvement at the end of 6 weeks.
      RESULTS: The results were comparable to those of previous studies, with positive
      responses seen in 63.6% of male patients and 61.5% of female patients. However,
      recurrence of ulcers was noted in all patients once the drug was discontinued.
      This was attributed to the small size of the patient sample studied and to the
      relatively short duration of treatment. No significant side effects were noted.
      CONCLUSIONS: Double-blind, controlled studies are indicated for a definitive
      assessment of the efficacy of oxypentifylline in the management of recurrent oral
      aphthous ulcers. The encouraging results of this study support the suggestion
      that the use of oxypentifylline be considered in refractory cases of recurrent
      oral aphthous ulcers.

PMID- 10348514
TI  - Primary sialoangiectasia--a diagnostic pitfall in Sjogren's syndrome: case
      report.
AB  - A case of primary sialoangiectasia, which in this case was initially misdiagnosed
      as Sjogren's syndrome, is described. Other diseases, including HIV infection,
      psoriatic arthritis, and acute parotitis, may cause glandular changes similar to
      the changes found in the syndrome. Therefore, sialography must be combined with
      other methods of assessment of the oral cavity when suspicion is high for
      Sjogren's syndrome. Properly applied, sialography provides essential information
      regarding the severity of glandular damage and the progression of the disease.

PMID- 10348515
TI  - Longstanding trigeminal sensory neuropathy of nontraumatic cause.
AB  - OBJECTIVE: Trigeminal sensory neuropathy is an uncommon but often significant
      orofacial symptom. There are few detailed descriptions of the problem in the
      dental literature. The aim of this study was to evaluate the clinical
      presentation and management of a cohort of patients presenting with
      anesthesia/paresthesia affecting one or more divisions of the trigeminal nerve
      unrelated to any identifiable traumatic cause. STUDY DESIGN: Nine patients with
      trigeminal neuropathy were examined. Each patient underwent a standard protocol
      of examination and hematologic, serologic, radiologic, and histopathologic
      investigations, as appropriate. RESULTS: Trigeminal neuropathy was found to be
      secondary to distant malignancy in 4 patients and to connective tissue disease in
      2 patients. In each of 3 other patients, there was no obvious cause for the
      neuropathy. Patients with malignancy as the cause of their neuropathy tended to
      have involvement of more than one division of the trigeminal nerve and/or other
      neurologic features. CONCLUSIONS: Trigeminal sensory neuropathy may herald
      underlying distant malignancy or connective tissue disease. Anesthesia and
      paresthesia of the orofacial region are therefore serious clinical symptoms that
      must be carefully investigated before a diagnosis of idiopathic disease is made.

PMID- 10348516
TI  - Trigeminal sensory neuropathy: a study of 35 cases.
AB  - OBJECTIVE: Trigeminal sensory neuropathy includes a wide variety of conditions
      sharing a common symptom described as sensory disturbance of the face--usually
      numbness. STUDY DESIGN: This 10-year retrospective study included 35 patients
      referred for investigation of trigeminal sensory neuropathy. RESULTS: The most
      common causes of trigeminal sensory neuropathy were nonneoplastic cerebral
      disorders, mainly represented by multiple sclerosis and idiopathic trigeminal
      sensory neuropathy. Furthermore, when only mandibular trigeminal sensory
      neuropathy was considered, metastatic neoplasia was the most frequent cause,
      often afflicting men over the age of 60 years. CONCLUSIONS: This overview will
      orient clinicians in their diagnosis when they are faced with patients consulting
      for trigeminal sensory neuropathy.

PMID- 10348517
TI  - Referral patterns, lesion prevalence, and patient care parameters in a clinical
      oral pathology practice.
AB  - OBJECTIVE: The purpose of this study was to determine the following parameters in
      a referral-based private practice oral and maxillofacial pathology clinic: (1)
      sources of clinical referrals; (2) types of problems referred; and (3) clinical
      effectiveness of treatment. STUDY DESIGN: Clinical charts were reviewed for a
      cohort of 362 patients seen over a 2 1/2-year period (1993-1995). From these
      charts, we determined the source of referral and the final diagnosis for each
      patient. In addition, 50 patients were randomly selected and surveyed by
      telephone; each was asked a series of questions to determine the following: (1)
      the number of health care practitioners previously seen with regard to the
      patient's condition; (2) the length of time that the condition had been present
      before the patient came to the oral and maxillofacial pathology clinic; (3) the
      costs associated with medications and office visits that had been incurred before
      the patient came to the oral and maxillofacial pathology clinic; (4) the costs
      associated with medications and office visits that were incurred at the oral and
      maxillofacial pathology clinic; and (5) the patient's level of satisfaction with
      the oral and maxillofacial pathology clinic. RESULTS: Fifty-five percent of the
      referrals came from dentists, and 45% came from physicians. The 3 problems most
      commonly seen were candidiasis (12%), burning mouth syndrome (10%), and lichen
      planus (8%). For the 50 patients who were interviewed, the mean number of health
      care practitioners seen previously was 2.2 (range, 1-9). The mean time from
      initial symptoms to evaluation by an oral pathologist was 15 months. The mean
      approximate cost of medications and office visits before evaluation by an oral
      pathologist was $350 (range, $30-$4,000; median, $100); this compared with a cost
      of $94 (range, $50-$300; median, $70) for the patient visit and medications
      associated with the oral pathology appointment. The difference was statistically
      significant (P < or = .001). CONCLUSIONS: This preliminary study suggests that
      the clinical evaluation of oral lesions by an oral pathologist appears to be cost
      effective and should be an integral part of a comprehensive health management
      system. These results should be corroborated by similar multicenter studies.

PMID- 10348519
TI  - Salivary gland aplasia with cleft lip and palate: a case report and review of the
      literature.
AB  - We report the case of a patient with lifelong symptoms of xerostomia and a
      repaired bilateral cleft lip and palate. The clinical evaluation demonstrated
      aplasia of the major salivary glands. A review of the literature pertaining to
      salivary gland aplasia is presented, along with a summary of the data regarding
      patient gender, defect sites, hereditary background, and combined manifestations.
      The diagnostic methods, possible pathogenesis, and management are also discussed.

PMID- 10348518
TI  - Solitary fibrous tumor of the oral cavity: an uncommon location for a ubiquitous
      neoplasm.
AB  - Solitary fibrous tumor is an uncommon soft tissue tumor initially reported in the
      pleura but recently described in other sites of the body. To date, only 5
      examples of oral solitary fibrous tumor have been reported. Here, we describe 2
      additional cases of this tumor in the oral cavity. The tumors were composed of
      small to medium-sized spindle cells with bland cytologic features; these cells
      were haphazardly arranged in highly cellular sheets or ill-formed fascicles as
      well as in hypocellular areas with hyalinized blood vessels. Both tumors
      contained blood vessels with a hemangiopericytomalike appearance and expressed
      vimentin, CD34, and CD99. One case was also strongly positive for bcl-2. The
      diagnosis of solitary fibrous tumor may be difficult inasmuch as it shares a
      number of histologic features with other soft tissue tumors. Awareness of its
      occurrence in the oral cavity is important so that confusion with other spindle
      cell neoplasms can be avoided.

PMID- 10348520
TI  - Autosomal dominant osteosclerosis: report of a kindred.
AB  - Autosomal dominant osteosclerosis (ADO), a rare inherited craniotubular bone
      disorder, is a generalized hyperostosis that manifests itself as increased
      cortical thickening of the skull, mandible, metacarpals, metatarsals, long bones,
      vertebral bodies, ribs, and clavicles. Jaw abnormalities, which clinically
      resemble the widening and deepening of the mandible seen in cherubism, begin in
      childhood and have been reported to stabilize after puberty. Teeth and alveolar
      bone are normal. ADO must be distinguished from Van Buchem's disease, which is
      characterized by elevated serum alkaline phosphatase, neurologic complications,
      exopthalmos, periosteal excrescences, and an autosomal recessive pattern of
      inheritance, as well as from other craniotubular bone disorders such as
      osteopetrosis. We present clinical and radiographic documentation of members of a
      kindred representing 4 generations affected with ADO. At initial examination of
      the proband, a differential diagnosis included cherubism, fibrous dysplasia,
      osteopetrosis, and Paget's disease. Radiographic examination revealed extensive
      radiopacity of the inferior border and basal bone of the mandible. The proband's
      clavicles and humerus were also affected. All family members examined were
      similarly affected and had mandibular and palatal tori. Authors of a previously
      published report on the dental and dentoalveolar management of patients with
      craniotubular bone disorders have recommended prophylactic antibiotics to
      minimize risk of osteomyelitis in all such cases. The members of our kindred
      received extensive dental treatment before diagnosis, including extractions of
      severely carious teeth, preprosthetic dentoalveolar surgery, and endodontic
      therapy; there was no incidence of osteomyelitis or postsurgical complications.
      Therefore, the use of prophylactic antibiotics may not be warranted in patients
      with ADO who have otherwise normal medical histories.

PMID- 10348521
TI  - Subepithelial nerve plexus (with ganglion cells) associated with taste buds.
AB  - OBJECTIVE: The purpose of this investigation was to confirm the presence of
      subepithelial nerve plexuses associated with taste buds in the human tongue and
      to study the histomorphologic features of each plexus. STUDY DESIGN: Through use
      of a light microscope, several hundred microslides representing biopsies of the
      human tongue were reviewed so that the histomorphologic character of
      subepithelial nerve plexuses could be detected and studied. Tissue sections were
      stained with hematoxylin-erythrosin, Bodian, and Masson's trichrome, as well as
      with immunohistochemical stains for neuron-specific enolase and S-100 protein.
      RESULTS: Twelve examples of the subepithelial nerve plexus, many with mature
      ganglion cells, were selected for microscopic evaluation. The plexuses were quite
      small, ranging from 1 to 3 millimeters in diameter. With one exception, each
      plexus was an incidental finding in a biopsy of a definitive soft tissue lesion,
      such as fibroma, papilloma, granular cell tumor, lymphoepithelial cyst, lingual
      tonsil, or foliate papilla. Ganglion cells, 1 to 5 in number and confirmed by
      neuron-specific enolase and S-100 protein, were observed in 9 of the cases.
      CONCLUSIONS: The subepithelial (subgemmal) nerve plexus is a tortuous neural
      proliferation associated with the taste buds of the human tongue, with ganglion
      cells and intergemmal/intragemmal branches. When hyperplastic, it should be
      recognized as such and not diagnosed as a neoplastic process--eg, a
      ganglioneuroma, neurofibroma, syndrome-associated neuroma, or traumatic neuroma.

PMID- 10348522
TI  - Symmetric lipomatosis of the tongue: report of a case and review of the
      literature.
AB  - Lipomatosis of the tongue is an extremely rare condition. To date, only 5 cases
      have been reported in the literature. An additional example, confirmed by biopsy,
      is presented. This appears to represent only the second instance of a nonoriental
      person who has been described with this condition.

PMID- 10348523
TI  - Laser Doppler flowmetry: an aid in differential diagnosis of apical
      radiolucencies.
AB  - The case of a patient having 2 teeth with associated apical radiolucencies that
      responded to conventional pulp tests is presented. A decision was made to
      reexamine the patient at intervals rather than perform root canal treatment.
      During a recall visit, use of an available laser Doppler flowmeter allowed
      detection of blood flow within the affected teeth. A diagnosis of periapical
      cemental dysplasia (cementoma) was made.

PMID- 10348524
TI  - Persistent periapical radiolucencies of root-filled human teeth, failed
      endodontic treatments, and periapical scars.
AB  - OBJECTIVE: This report describes 6 cases that demonstrate persistent periapical
      radiolucent lesions after conventional root canal treatment. STUDY DESIGN: Six
      teeth that had conventional root canal treatment or re-treatment with
      nonresolving periapical radiolucencies underwent periapical surgery. Biopsies
      were obtained and analyzed descriptively by correlative light and transmission
      electron microscopy for general features and microbial findings. RESULTS: Three
      findings were identified: periapical lesions with persisting infection in the
      apical root canal system (2 cases); a cyst (1 case); and periapical healing by
      scar tissue formation (2 cases). CONCLUSIONS: These results confirm previous
      observations that associated factors in the failure of endodontic treatment
      include persistent intraradicular infection and periapical cysts. In addition,
      unresolved periapical radiolucencies may occasionally be due to healing by scar
      tissue, which may be mistaken as a sign of failed endodontic treatment.

PMID- 10348525
TI  - Dens invaginatus in the maxillary lateral incisor: treatment of 3 cases.
AB  - Nonsurgical treatment of 3 maxillary lateral incisors with dens invaginatus is
      reported. Invaginated teeth present technical difficulties with respect to their
      management because of complicated canal morphology. In the first case reported,
      apical abscess with incomplete root formation was found at the time of
      examination. Calcium hydroxide apexification provided favorable conditions for
      root closure and obturation. The other 2 cases were treated by conventional root
      canal treatment. Follow-up examinations showed successful clinical results, with
      osseous healing evident radiographically.

PMID- 10348527
TI  - Image quality assessment: a timely look.

PMID- 10348526
TI  - The value of coronal computer tomograms in fractures of the mandibular condylar
      process.
AB  - OBJECTIVE: A prospective investigation designed to compare the diagnostic
      accuracy of conventional panoramic and posteroanterior mandibular radiographs
      with that of coronal computed tomography scans in cases of fracture of the
      mandibular condylar process was conducted. STUDY DESIGN: In all, 182 patients
      with a total of 249 fractures (some unilateral and some bilateral) of the
      mandibular condyle received conventional radiographs and coronal computed
      tomography scans as diagnostic procedures. The ability of these procedures to
      detect and correctly classify these fractures was determined, and their
      importance for therapeutic decision-making is described. RESULTS: All clinically
      identified fractures were detected by means of both conventional and computed
      tomography imaging. However, only computed tomography scanning could correctly
      classify high condylar neck fractures. CONCLUSIONS: Especially in cases of high
      condylar neck fracture, coronal computed tomography scans were more useful than
      conventional radiographs in the determination of type of condylar fracture so
      that a correct treatment decision could be made.

PMID- 10348529
TI  - Reperfusion therapy for every infarction with ST segment elevation.

PMID- 10348528
TI  - Comparison of primary angioplasty with conservative therapy in patients with
      acute myocardial infarction and contraindications for thrombolytic therapy.
      Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) Study Group.
AB  - The benefit of primary angioplasty in patients with acute myocardial infarction
      (AMI) and contraindications for thrombolysis compared to a conservative regimen
      is still unclear. Out of 5,869 patients with AMI registered by the MITRA trial,
      337 (5.7%) patients had at least one strong contraindication for thrombolytic
      therapy. Out of these 337 patients 46 (13.6%) were treated with primary
      angioplasty and 276 (86.4%) were treated conservatively. Patients treated
      conservatively were older (70 years vs. 60 years; P=0.001), had a higher rate of
      a history with chronic heart failure (14.8% vs. 4.4%; P=0.053), a higher heart
      rate at admission (86 beats/min vs. 74 beats/min; P=0.001), and a higher
      prevalence of diabetes mellitus (27.1% vs. 12.8%; P=0.056). Patients treated with
      primary angioplasty received more often aspirin (91.3% vs. 74.6%; P=0.012), beta
      blockers (60.9% vs. 46.1%; P = 0.062), angiotensin converting enzyme (ACE)
      inhibitors (71.7% vs. 44%; P=0.001), and the so-called optimal adjunctive
      medication (54.4% vs. 32.3%; P=0.004). Hospital mortality was significantly lower
      in patients who received primary angioplasty (univariate: 2.2% vs. 24.7%;
      P=0.001; multivariate: OR=0.46; P=0.0230). In patients with AMI and
      contraindications for thrombolytic therapy, primary angioplasty was associated
      with a significantly lower mortality compared to conservative treatment.
      Therefore, hospitals without the facilities to perform primary angioplasty should
      try to refer such patients to centers with the facilities for such a service, if
      this is possible in an acceptable time.

PMID- 10348530
TI  - Stepwise intravascular ultrasound (IVUS) guidance of high-pressure coronary
      stenting does not result in an improved acute or long-term outcome: a randomized
      comparison to "final-look" IVUS assessment.
AB  - The objective of this study was to evaluate the potential benefit of stepwise
      intravascular ultrasound (IVUS)-guided coronary stent deployment compared to
      angiographic stent implantation with final IVUS assessment only. Acute procedural
      success and 6-month angiographic follow-up were compared in both groups.
      Intravascular ultrasound was performed using a 20- or 30-MHz mechanically rotated
      catheter in 85 patients who were prospectively randomized to group A (n=42; IVUS
      guided) and group B (n=43; angiography +/- final IVUS assessment). There was no
      difference in the number of stents implanted (1.5+/-0.9 stents/lesion in group A
      and 1.3+/-0.6 stents/lesion in group B), the duration of the procedure, or the
      amount of contrast medium used. Defined criteria of optimal stent deployment
      (stent apposition, stent symmetry, complete coverage of dissections, >90% in
      stent lumen area/reference lumen area) were achieved in 54.2% in group A and
      56.6% in group B (NS). Angiographic follow-up was 87.1% at 6+/-2 months, and
      clinical follow-up was 100% at 8+/-1 months. There was no significant difference
      in restenosis rate (33.3% vs. 34.9%) applying a binary >50% diameter stenosis
      criterion for both groups. There was no significant difference in minimal in
      stent lumen area at both baseline (7.91+/-2.64 mm2 vs. 7.76+/-2.21 mm2) and
      follow-up (5.84+/-2 mm2 vs. 5.52+/-1.87 mm2). With regard to immediate procedural
      lumen gain and rate of restenosis, multiple IVUS examinations during the
      procedure showed no advantage compared to final IVUS assessment only.

PMID- 10348531
TI  - Is IVUS-lite acceptable?

PMID- 10348532
TI  - Catheter-based techniques for closure of coronary fistulae.
AB  - This study details different methodologies of percutaneous closure of
      arteriosystemic and arteriovenous coronary fistula. Seven patients underwent
      transcatheter intervention of 10 fistulas, with 7 fistulas successfully closed: 6
      with embolic coil devices and 1 with a covered stent obstructing the fistula
      ostium. The major complication encountered was one death as a result of device
      recoil into a major epicardial vessel. Percutaneous transcatheter closure of
      coronary fistulas appears to be simple, facile, and effective. However, device
      recoil into an undesired arterial segment, while irritating in a noncoronary
      arterial tree, may be catastrophic when occurring in an epicardial coronary
      artery.

PMID- 10348533
TI  - Management of coronary artery fistulas: percutaneous transcatheter embolization
      versus surgical closure.

PMID- 10348534
TI  - A prospective study of elective stenting in unprotected left main coronary
      disease.
AB  - The standard treatment of left main coronary artery (LMCA) disease has been
      bypass surgery (CABG). Recent reports suggested that stenting of LMCA disease
      might be feasible. From January 1995 to April 1998, we carried out a prospective
      study of elective stenting of unprotected LMCA disease to evaluate its immediate
      and long-term results. Of 61 consecutive patients with unprotected LMCA disease,
      6 were excluded. Acute procedural success was 100% for the remaining 55 patients,
      without any complications such as stent thrombosis, myocardial infarction, CABG,
      or death. During a mean follow-up of 16.1+/-9.6 months, 11 patients (20%) had
      symptomatic recurrence, between 2 to 6 months after their procedure. Seven
      patients underwent CABG, two had repeat intervention, one continued with medical
      therapy, and one died before planned angiography. There was no late sudden death.
      Forty-four patients (80%) remained asymptomatic. We conclude that elective
      stenting may be a safe alternative to CABG in unprotected LMCA disease.

PMID- 10348535
TI  - Left main angioplasty goes "main" stream.

PMID- 10348536
TI  - A randomized comparison of trapidil (triazolopyrimidine), a platelet-derived
      growth factor antagonist, versus aspirin in prevention of angiographic restenosis
      after coronary artery Palmaz-Schatz stent implantation.
AB  - The aim of the study is to assess the safety of trapidil in the setting of
      coronary stenting and to evaluate its efficacy in reducing angiographic in-stent
      restenosis. One hundred eighteen patients undergoing Palmaz-Schatz stent
      implantation were randomly assigned to receive antiplatelet therapy using either
      aspirin (325 mg/d) or trapidil (400 mg/d), in combination with ticlopidine (500
      mg) for the first month. At entry, both groups were comparable with regard to
      clinical, angiographic, and procedural characteristics. At 6-month angiographic
      follow-up, >50% restenosis occurred in 15 of 52 lesions (28.8%) of the aspirin
      group and in 14 of 47 lesions (29.8%) of the trapidil group (P=not significant,
      NS). At 6-month clinical follow-up, there was no difference in the two groups in
      the rate of adverse events (2.0% vs. 2.1%, P=NS), medication side effects (4.0%
      vs. 4.2%, P=NS), and peripheral vascular complications (4.0% vs. 4.2%, P=NS). In
      conclusion, treatment with trapidil seems to be associated with a similar
      incidence of stent restenosis and adverse cardiac events as compared to aspirin
      and could be a valuable alternative to aspirin in the setting of coronary
      stenting.

PMID- 10348537
TI  - Immediate and late outcomes of subclavian artery stenting.
AB  - Stenting for subclavian artery occlusive disease is being increasingly utilized.
      To determine the immediate and late outcome of subclavian artery stenting, we
      studied 38 consecutive patients in whom the procedure was attempted. Technical
      and clinical success was achieved in 35 patients without complications. Failures
      occurred only in completely occluded arteries. Late clinical success was
      demonstrated in 31 patients. Three patients had recurrent symptoms. Two had
      angiographic restenosis within 4 months of the procedure; both were successfully
      redilated. The third patient had a new lesion, which was successfully stented.
      One patient died from lung cancer 10 months after the procedure. We conclude that
      stenting for subclavian artery occlusive disease has favorable immediate and late
      clinical outcomes and may be considered as a primary therapy.

PMID- 10348538
TI  - Influence of the ratio between radial artery inner diameter and sheath outer
      diameter on radial artery flow after transradial coronary intervention.
AB  - To test the feasibility of using guiding catheters equal to or greater than 7 Fr
      in transradial coronary intervention (TRI), we measured the inner diameter of the
      radial artery (RA) and its flow using two-dimensional ultrasound and Doppler
      examinations before and after TRI in 250 Japanese patients. The incidence of
      severe flow reduction of the RA after TRI was 6.8% on average (7.2%, 4.7%, and
      8.3% in patients with 6, 7, and 8 Fr sheaths used, respectively), which increased
      from 4.0% to 13.0% (P=0.0113) if the ratio of the RA inner diameter/sheath outer
      diameter was less than 1.0. The frequency of this ratio (> or = 1.0) for 7 and 8
      Fr sheaths was 71.5% and 44.9% in male patients and 40.3 and 24.0% in female
      patients, respectively. We conclude that the use of guiding catheters equal to or
      greater than 7 Fr in the radial artery is feasible in selected patients.

PMID- 10348539
TI  - Blade and balloon atrial septostomy for left heart decompression in patients with
      severe ventricular dysfunction on extracorporeal membrane oxygenation.
AB  - Extracorporeal membrane oxygenation (ECMO) is used as circulatory support or
      bridge to transplantation in patients with severe left ventricular (LV)
      dysfunction. Left heart decompression is needed to reduce pulmonary edema,
      prevent pulmonary hemorrhage, and reduce ventricular distention that may aid in
      recovery of function. We reviewed our experience from November 1993 to December
      1997 with 10 patients having severe LV dysfunction (7 myocarditis, 3 dilated
      cardiomyopathy) who required circulatory support with ECMO and who underwent left
      heart decompression with blade and balloon atrial septostomy (BBAS). Patients
      ranged in age from 1 to 24 years (median, 3 years). Indications for BBAS included
      left atrial/left ventricular distension (10), pulmonary edema/hemorrhage (9), or
      severe mitral regurgitation (2). BBAS was performed electively in eight patients
      and urgently in two patients. BBAS was performed while on ECMO in seven patients
      and pre-ECMO in three. A femoral venous approach was used in all patients. ECMO
      patients were fully heparinized. Transseptal puncture was required in nine
      patients while one patient had a patent foramen ovale. Blade septostomy was
      performed in all patients. Enlargement of the defect was then performed by
      stationary balloon dilation in nine and Rashkind balloon atrial septostomy in
      one. Balloon diameters ranged from 10 to 20 mm. Sequential balloon inflations
      were performed in some patients. Adequacy of the atrial septal defect (ASD) was
      confirmed by pressure measurement and echocardiography. Adequate left heart
      decompression was achieved in all patients. Pulmonary edema improved in nine of
      nine patients. Left atrial mean pressure fell from a mean of 30.5 mm Hg, (range,
      12-50 mm Hg) to 16 mm Hg (range, 9-24 mm Hg). Left atrial to right atrial
      pressure gradient fell from a mean of 20 mm Hg pre-BBAS to 3 mm Hg post-BBAS.
      ASDs ranged in size from 2.5 to 8 mm (mean, 5.9 mm). Complications included
      needle perforation of the left atrium without hemodynamic compromise (one),
      ventricular fibrillation requiring defibrillation (one), and hypotension
      following BBAS which responded to volume infusion (two). Duration of ECMO ranged
      from 41 hr to 704 hr (mean, 294 hr). Seven patients survived and four patients
      had recovery of normal LV function. Of those who recovered, two had no ASD at
      follow-up while two ASDs are patent 14 days and 3 months post-BBAS. Three
      patients underwent successful cardiac transplantation. Three patients died, all
      of whom had multisystem organ failure with or without sepsis. A patent ASD was
      noted at transplant (three) or autopsy (two). No patient required a second BBAS.
      BBAS alleviates severe left atrial hypertension and pulmonary edema. In addition,
      BBAS avoids the potential bleeding complications of surgical left heart
      decompression. Stationary balloon dilation of the atrial septum is an effective
      alternative to Rashkind balloon septostomy in older patients. BBAS achieves left
      heart decompression that may permit recovery of LV function or allow extended
      ECMO support as a bridge to transplant.

PMID- 10348540
TI  - Percutaneous translumbar cardiac catheterization and central venous line
      insertion: an alternative approach in children with congenital heart disease.
AB  - Children with congenital heart disease present major problems with venous access,
      eliminating conventional routes for cardiac catheterization. Although the
      transhepatic approach has recently gained popularity, we describe here an
      alternative approach using percutaneous translumbar approach for cardiac
      catheterization and/or in-dwelling central line insertion in three children with
      congenital heart disease. Diagnostic hemodynamic studies, transcatheter delivery
      of an intravascular stent for left pulmonary artery (LPA) stenosis, and chronic
      central venous line insertion were performed using this technique. Disadvantages
      include interventionalist's unfamiliarity with technique, awkward patient
      positioning, technically more difficult than transhepatic, and potential injury
      to kidney and bowel. Advantages include avoidance of vascular-rich hepatic
      parenchyma, thus reducing risk of hemorrhage; providing an alternative where
      transhepatic entry may be contraindicated; avoidance of bile duct, portal vein,
      and hepatic artery injury; and providing another alternative for not only
      transvenous, but also transarterial access that may be required for intravascular
      aortic stent delivery. The interventional radiologist should be utilized as a
      valuable resource to the cardiologist to help teach and supervise this technique
      in selected infants and children with limited vascular access.

PMID- 10348541
TI  - Choice of venous access for cardiac catheterization in patients with congenital
      heart disease.

PMID- 10348542
TI  - A comparison of arterial versus venous-activated clotting time in patients with
      congenital heart disease undergoing cardiac catheterization.
AB  - Studies in adult patients undergoing percutaneous coronary angioplasty have
      demonstrated differences in measured activated clotting time (ACT) in venous vs.
      arterial blood samples. Ninety-two patients with congenital heart disease
      undergoing cardiac catheterization were prospectively evaluated to compare venous
      vs. arterial ACT values in monitoring heparin effect in this population.
      Simultaneous venous and arterial ACT samples were drawn at baseline, 10 min, 60
      min, and every 30 min thereafter until each case was finished. ACT values were
      determined simultaneously with a dual-chambered Hemochron 801 instrument. At
      baseline and throughout the study up to 90 min, venous and arterial ACT values
      were not significantly different. They were also no different in the subgroup of
      cyanotic patients. Therefore, venous and arterial ACT values can be safely used
      alternatively to guide heparin dosing during cardiac catheterization in patients
      with congenital heart disease without the risk of undercoagulation.

PMID- 10348543
TI  - Bedside transseptal balloon dilation atrial septostomy for decompression of the
      left heart during extracorporeal membrane oxygenation.
AB  - A 10-year-old male presented with severe heart failure secondary to myocarditis.
      Venoarterial extracorporeal membrane oxygenation was instituted. He developed
      severe left heart distention with acute pulmonary hemorrhage. Balloon dilation of
      the atrial septum to decompress the left atrium was performed at the bedside with
      transesophageal echocardiographic guidance.

PMID- 10348544
TI  - Severe agitation and hyperventilation after contrast media application during
      coronary angiography.
AB  - Severe agitation developed in two patients 20 min and 120 min after cardiac
      catheterization, clearing again within 24 hr. Neurotoxicity of contrast media may
      be the cause for this clinically dramatic, not previously reported side effect of
      coronary angiography.

PMID- 10348545
TI  - Balloon entrapment during side-branch angioplasty through a stent.
AB  - Entrapment of the distal tip of a balloon catheter occurred during attempted
      passage between the struts of a stent into a side branch. Traction on the balloon
      resulted in fracture of the catheter shaft requiring extraction with percutaneous
      retrieval forceps.

PMID- 10348546
TI  - Retrograde embolization during saphenous vein graft angioplasty.
AB  - Angioplasty of degenerated saphenous vein grafts is not infrequently complicated
      by distal embolization of atheromatous debris. We describe an uncommon case in
      which balloon angioplasty of an old vein graft to a second diagonal branch of the
      left anterior descending coronary artery was followed by distal embolization.
      However, the embolization occurred in a retrograde fashion distal to the
      anastomotic site, resulting in occlusion of the upstream first diagonal branch.
      The reasons for its occurrence are discussed, together with suggestions for its
      recognition.

PMID- 10348547
TI  - Unruptured congenital aneurysm of the sinus of Valsalva presenting with pulmonary
      stenosis.
AB  - Congenital aneurysm of the sinus of Valsalva is a rare cardiovascular anomaly. It
      is usually silent until rupture occurs. The natural history of unruptured
      aneurysm of the sinus of Valsalva is still not clear, and the therapeutic
      strategy is uncertain. Here we reported a case of unruptured aneurysm of the
      sinus of Valsalva which was correctly diagnosed before invasive diagnostic
      procedures. A 30-year-old female noted mild palpitation and dyspnea for 1 month.
      Physically, a grade 3/6 systolic ejection murmur at upper left sternal border was
      detected. Echocardiography revealed dilatation and irregular protrusion of the
      right sinus of Valsalva encroaching on right ventricular outflow tract to cause
      obstruction. With these findings, unruptured aneurysm of the sinus of Valsalva
      with pulmonary stenosis was diagnosed. Cardiac catheterization and angiography
      confirmed the diagnosis. The aneurysm was repaired with a Dacron patch with good
      results. It is concluded that sinus of Valsalva aneurysm can be diagnosed by
      echocardiography before its rupture so as to render a proper management for this
      potentially life-threatening anomaly.

PMID- 10348548
TI  - Successful closure of coronary-bronchial artery fistula with vein graft-coated
      stent.
AB  - A coronary-bronchial fistula and aneurysmal dilatation of the proximal part of
      the fistula was successfully closed using an autologous vein graft-coated stent
      (Palmaz-Schatz stent). This is the first report that demonstrates the feasibility
      of the vein-coated stent for the treatment of congenital disease.

PMID- 10348549
TI  - Functional assessment of internal mammary artery bypass grafts: case reports and
      review of the literature.
AB  - The utility of intra-arterial Doppler flow in assessing internal mammary artery
      (IMA) bypass grafts has infrequently been reported. Two patients are described in
      which Doppler evaluation of the IMA graft provided valuable diagnostic
      information prior to intervention. Also provided is a review of the available
      literature concerning evaluation of pathology in IMA grafts.

PMID- 10348550
TI  - Use of stents to treat kinks causing obstruction in a left internal mammary
      artery graft.
AB  - Left internal mammary arteries (LIMA) are used routinely as grafts to the left
      anterior descending coronary artery (LAD) in selected patients undergoing
      coronary artery bypass graft (CABG) surgery because of better long-term patency
      rates. Pathology other than fibrointimal hyperplasia, accelerated
      atherosclerosis, or thrombus can sometimes cause obstructive lesions in such
      grafts. This report illustrates a kink in a LIMA graft to the LAD causing an
      obstructive lesion shortly after surgery and describes the subsequent management
      of this lesion with intracoronary stents.

PMID- 10348552
TI  - X-ray image intensifier.
AB  - The X-ray image intensifier converts an X-ray image into a bright visible light
      image. This enables image recording as well as viewing without dark adaptation.
      This tutorial describes the construction and function of the image intensifier
      tube and its associated optics.

PMID- 10348551
TI  - Percutaneous revascularization modalities in heart transplant recipients.
AB  - Accelerated allograft vasculopathy significantly limits the survival of heart
      transplant recipients. The prevalence of allograft coronary artery disease is as
      high as 18% by 1 year and 50% by 5 years following heart transplant. Heart
      failure and sudden cardiac death are the two most common clinical presentations.
      In heart transplant recipients with severe, discrete focal allograft vascular
      disease, percutaneous balloon angioplasty is a viable palliative option. However,
      its application is limited by a significant restenosis rate and progression of
      allograft disease in nontreated segments. Diffuse disease with tapering of
      vessels may be approached by debulking devices. Emerging revascularization
      modalities for focal stenoses and some of the diffuse tapering vessels include
      coronary stents, rotational atherectomy, various wavelength lasers, and, to a
      lesser extent, directional atherectomy. Conceivably, stents will reduce
      restenosis rates related to focal, discrete plaques; yet it is unknown whether
      they will be efficacious in short- and long-term treatment of diffusely diseased
      segments affected by allograft disease. Accurate assessment of clinical outcomes
      and long-term evaluation is imperative prior to acceptance of these devices as
      fundamental interventional tools for treatment of allograft coronary artery
      disease.

PMID- 10348553
TI  - No-touch technique for reducing aortic wall trauma during renal artery stenting.
AB  - Cholesterol embolism, a serious but infrequent complication of renal artery
      stenting, may be avoided by minimizing contact between the guide catheter and the
      atherosclerotic aorta. In this report, we illustrate the "no-touch" technique for
      stenting renal arteries. By placing a second 0.035-inch J-wire within the guide
      catheter during cannulation of the renal artery to prevent the tip of the guide
      from rubbing the aortic wall, we minimize the contact between the guide catheter
      and atherosclerotic plaques and reduce the potential for intimal disruption and
      cholesterol embolization.

PMID- 10348554
TI  - First clinical experience with the premounted balloon-expandable serpentine
      stent: acute angiographic and intermediate-term clinical results.
AB  - The beStent-Artist coronary stent is a newly developed, stainless steel coronary
      stent with a serpentine tubular design and terminal stent markers, premounted on
      a semicompliant balloon. During this pilot evaluation we aimed to test the acute
      clinical and angiographic results, short-term (30 days) and 6-month clinical
      results. A total of 57 stents were used to treat 43 lesions in 40 patients.
      Deployment strategy included predilatation, stent deployment, balloon
      repositioning to match the distal end of the balloon to the distal stent marker,
      and subsequent 12-14 atm postdilatation. There were two cases of stent
      dislodgment, but no procedural complications. In four cases, stent recrossing
      with another balloon was necessary. In two of these cases, distal dissections
      were observed and treated with another stent. The minimal lumen diameter (MLD)
      increased from 0.84+/0.52 mm at baseline to 2.7+/-0.62 mm at the end of the
      procedure (a corresponding decrease in diameter stenosis from 78.6 > 16.4 to
      18.2+/-10.7%). The acute gain was 1.89+/-0.61mm. No adverse events occurred by 30
      days. During six months, 7/40 (18.5%) of patients required target vessel
      revascularization due to in-stent restenosis. In summary, the premounted beStent
      Artist can be delivered and deployed with favorable immediate results and high
      success rate with favorable long-term recurrent event rates.

PMID- 10348555
TI  - Left main coronary artery stenosis after percutaneous transluminal coronary
      angioplasty: importance of remaining "minimally invasive".

PMID- 10348556
TI  - Primary stenting in acute myocardial infarction: a 30-day follow up study.
AB  - Primary coronary stenting is being increasingly used in patients undergoing
      primary coronary angioplasty for acute myocardial infarction. In this prospective
      study we evaluated our experience of direct angioplasty in 68 patients with acute
      myocardial infarction of whom 57 received intracoronary stents using high
      pressure deployment (> or =12 atmospheres) with adjunct aspirin and ticlopidine
      therapy without coumadin. All patients underwent pre-discharge follow-up
      angiography. Stent implantation was successful in all patients. Stent thrombosis
      was not seen in any patient. However, TIMI grade 3 flow was obtained in only 51
      patients (89.6%) with evidence of slow flow present in remaining six patients.
      Follow-up angiograms showed no stent thrombosis but five out of the six patients
      (83%) with slow-flow phenomenon persisted to have slow flow. These patients had
      lower left ventricular ejection fraction as compared to patients with TIMI 3 flow
      at follow-up angiography (27.5 +/- 10.2% vs. 42.1 +/- 15.2%, P < .001) and a high
      mortality (two out of six) within 30 days. Primary stenting is safe and feasible
      in the majority of patients with good short-term outcomes, but persistent slow
      flow phenomenon with adverse clinical outcome is seen in a small but significant
      number of patients.

PMID- 10348557
TI  - Routine use of stents in acute myocardial infarction.

PMID- 10348558
TI  - Stent thrombosis: incidence and related factors in the R.I.S.E. Registry(Registro
      Impianto Stent Endocoronarico)
AB  - Although stent thrombosis has been greatly reduced by adequate stent expansion
      with high-pressure balloon inflations and by the use of antiplatelet drugs, this
      event is still frightening, as it may lead to acute myocardial ischemia resulting
      in acute myocardial infarction or sudden death. Therefore, the definition of
      factors associated with stent thrombosis may provide a better understanding of
      the mechanisms underlying this phenomenon and may permit us to define therapeutic
      strategies to further reduce its occurrence. The purpose of this study was to
      assess factors responsible for the occurrence of stent thrombosis after coronary
      stent implantation in 939 consecutive patients enrolled in the Registro Impianto
      Stent Endocoronarico (R.I.S.E. Study Group). Consecutive patients undergoing
      coronary stent implantation at 16 medical centers in Italy were prospectively
      enrolled in the registry. Clinical data, and qualitative and quantitative
      angiographic findings were obtained from data collected in case report forms at
      each investigator site. The study group consisted of 781 men and 158 women with a
      mean age of 59 yr: 1,392 stents were implanted in 1,006 lesions and expanded at a
      maximal inflation pressure of 14.7 +/- 3 atm. The great majority of patients
      (92%) received only antiplatelet drugs after coronary stenting. During
      hospitalization there were 45 major ischemic complications in 39 patients (4.2%):
      13 events were related to acute or subacute thrombosis (1.4%). Another stent
      thrombotic event occurred in the first month of follow-up. On multivariate
      logistic regression analysis, stent thrombosis was related to the following
      factors: unplanned stenting (OR 3.46, 95% CI 1.65-7.23), unstable angina (OR
      3.37, 95% CI 1.11-10.14) and maximal inflation pressure (OR 0.83, 95% CI 0.75
      0.93). In conclusion, this registry shows that in an unselected population of
      patients undergoing coronary stenting, stent thrombosis occurs in less than 2% of
      patients and is significantly related to unplanned stent implantation, unstable
      angina, and maximal inflation pressure. The incidence of this phenomenon is
      likely to be further reduced by the use of new potent antiplatelet drugs, such as
      platelet glycoprotein IIb/IIIa antagonists.

PMID- 10348559
TI  - Toward the elimination of stent thrombosis.

PMID- 10348560
TI  - Revised guidelines for the performance of peripheral vascular intervention.

PMID- 10348561
TI  - Lessons learned from the review of cardiac catheterization laboratories: a report
      from the Laboratory Survey Committee of the Society for Cardiac Angiography and
      Interventions.
AB  - The Laboratory Survey Committee of the Society for Cardiac Angiography and
      Interventions was created as a resource for physicians and administrators to
      provide comprehensive independent outside review services for cardiac
      catheterization laboratories. Since 1989, when the committee began its work,
      surveys of 23 catheterization laboratories have been completed. Our review of
      this experience identified several recurring problems among the laboratories. The
      purpose of this paper is to summarize our experience and highlight the lessons we
      learned in the hope that this information will benefit many other laboratories.

PMID- 10348562
TI  - Utility of standby cardiopulmonary support for elective coronary interventions.
AB  - At our institution, elective coronary interventions are performed without formal
      surgical backup. Instead, a policy of "standby cardiopulmonary support" (CPS),
      and "next-available operating room" is used. Standby CPS requires a perfusionist
      dedicated to the catheterization laboratory with immediate access to CPS
      apparatus. Between January 1989 and June 1994 we performed 2,850 elective
      coronary interventions. Eleven patients (0.4%) required emergency CPS. None of
      these patients fell into a high-risk category for PTCA (i.e., sole circulation,
      ejection fraction <20%, unprotected left main). Eight of these (73%) had
      completion of their coronary intervention while on CPS in the catheterization
      laboratory. Three patients were sustained on CPS until an operating room became
      available. All patients required blood transfusions and sustained non-Q-wave
      myocardial infarctions. Two late in-hospital deaths occurred. Nine patients (82%)
      were successfully discharged. Standby CPS provides hemodynamic support for
      patients who sustain a potentially catastrophic event during coronary
      intervention. Our data suggest that this modality should not be limited to high
      risk patients.

PMID- 10348563
TI  - Cardiopulmonary support for cath lab catastrophes.

PMID- 10348564
TI  - Transradial coronary intervention in Japanese patients.
AB  - The objectives of this study was to test the feasibility and safety of
      transradial coronary intervention (TRI) in Japanese patients. We compared the
      results of TRI in 1,791 lesions (1,360 patients) between November 1995 and
      December 1997 with those of transfemoral coronary intervention (TFI) in 966
      lesions (793 patients) between April and October 1995. We also examined the
      radial artery pulse in 294 patients 1-2 weeks after TRI by palpation and Doppler
      examination. Arterial puncture, coronary artery cannulation, lesion, and patient
      success rates were similar in both groups. No significant difference was noted in
      the major complication rate. Local complications were significantly lower in the
      TRI group (0.3% vs. 3.3%, P < 0.001). Doppler studies of the radial artery were
      performed in 294 patients chosen at random. In the first 234 patients, the sheath
      was pulled out 3 hr after the procedure, and in the last 60 patients, immediately
      after the procedure; radial artery occlusion rates were 5% and 0%, respectively.
      In conclusion, TRI seems safe and feasible in Japanese patients.

PMID- 10348565
TI  - Transcatheter closure of ventricular septal defects using the Rashkind device:
      initial experience.
AB  - We report our initial experience with transcatheter closure of ventricular septal
      defects (VSD) using the Rashkind device. Transcatheter closure of 25 VSDs was
      attempted in 16 patients with a median age of 2 (range 0.1-4) years and a median
      weight of 11 (range 4.1-19) kg. The location of the VSDs was apical in 14,
      midmuscular in 8, and anterior muscular in 3. Five patients had complex heart
      lesions, 10 patients had associated defects, including perimembranous VSD, atrial
      septal defect, patent ductus arteriosus, and coarctation of aorta. The remaining
      patient had isolated multiple muscular VSDs. The surgical repair of VSDs was a
      high-risk option in all the patients. Of the 25 attempted closures, 22 devices
      were placed successfully. Nine patients had a single device, four patients had
      two devices each and one patient had a total of five devices placed. In two
      patients attempts to close three VSDs were associated with major problems/death.
      Fourteen patients have been followed up for at least 1 year and all are doing
      well. Five patients, who otherwise remain asymptomatic, have a trace residual
      shunt. The fluoroscopy time ranged from 51 to 205 min (median 110) and the
      procedure time 120 to 300 min (median 200). The transcatheter closure of VSDs
      acts as a palliation as well as a definitive therapeutic modality in some
      patients with surgically inaccessible VSDs. Deployment of multiple devices in a
      patient is feasible. Increased experience may diminish the initial rate of
      complications.

PMID- 10348566
TI  - Transcatheter closure of ventricular septal defects: are we there yet?

PMID- 10348567
TI  - A new technique for sizing of atrial septal defects.
AB  - This article evaluates a new compliant balloon catheter for sizing of Atrial
      Septal Defects (ASDs) in vitro and in vivo using X-ray and echo measurements. A
      phantom consisting of a plastic plate with 17 circular holes varying from 8 to 30
      mm was used to determine the accuracy of the measurements. The catheter has a 7
      Fr shaft with a double lumen. The balloon is made from a 0.002" plastic membrane.
      Four platinum marker bands on the shaft of the catheter allow radiographic
      measurements. The balloon catheter was placed through various holes of the
      phantom and inflated with 38% contrast medium. X-ray measurement by video and
      cine recording were performed and compared with the true measurement of the
      model. The study was carried out in a double blind fashion. For echo
      measurements, the plastic model was immersed in a water bath. The balloon was
      inflated with water and measured in a long-axis view. The actual diameters were
      compared with the measurements obtained by video, cine, and echo recordings. One
      young pig with a surgically created ASD was used for in vivo measurement. The
      balloon catheter was passed through the ASD over an exchange wire, inflated with
      diluted contrast medium until a waist was observed, which was measured by video
      and cine techniques. The animal was euthanized, and the defect was measured by a
      tapered measuring probe. The difference between the actual size and measurements
      obtained by video recordings was 0.54 +/- 0.30 mm, by cine 0.62 +/- 0.20 mm, and
      by echo measurements 0.60 +/- 0.43 mm. All measurements were less than 1 mm in
      error except for four measurements (<1.5 mm). A strong correlation was present
      between each two groups (r = 0.99, P < 0.0001). In the in vivo study, the size of
      the video and cine recordings (14.2 and 13.9 mm, respectively) were very closer
      to the actual size (14 mm) as measured by a probe in the postmortem specimen. The
      new balloon catheter provides a more rapid and precise determination of the
      stretched diameter of atrial septal defects. It eliminates the error of pulling a
      catheter through the communication. This new technique should be of benefit to
      all investigators using septal occlusion devices and will facilitate the
      selection of the properly sized Amplatzer septal occluder.

PMID- 10348568
TI  - Measurement of the stretched diameters of atrial septal defects.

PMID- 10348569
TI  - Right coronary artery occlusion as a complication of accessory pathway ablation
      in a 12-year-old treated with stenting.
AB  - We describe a complication of radiofrequency ablation of a posteroseptal pathway
      that resulted in acute occlusion of a distal right coronary artery in a pediatric
      patient. The complication was treated with coronary stenting after unsuccessful
      angioplasty.

PMID- 10348570
TI  - Utility of cardiac catheterization in pediatric cardiac patients on ECMO.
AB  - Cardiac catheterization has been utilized rarely in children on extracorporeal
      membrane oxygenation (ECMO). We performed a retrospective review of 15 children
      with congenital heart disease who had undergone catheterization while on ECMO
      from December 1990-December 1995. The procedures, including four interventions,
      were successful in all patients with adequate evaluation of clinical questions.
      Unexpected diagnostic information of clinical importance was obtained in 40%, and
      clinical management of patients was significantly altered in 73%. All patients
      tolerated the procedure and transport well. The only significant complication was
      a retroperitoneal hemorrhage in one patient after approximately 12 hr. Although
      no patients died at catheterization, overall survival was poor, with 50% weaning
      from ECMO, 29% surviving to discharge, and 14% surviving at follow-up. We
      conclude that diagnostic and interventional catheterization may be performed in
      patients on ECMO with acceptable morbidity and mortality; however, long-term
      survival in this population is poor.

PMID- 10348571
TI  - Intravascular ultrasound imaging before and after balloon angioplasty for
      pulmonary artery stenosis.
AB  - Previous reports regarding intravascular ultrasound (IVUS) imaging of the
      pulmonary arteries in children and its application to balloon pulmonary
      angioplasty are limited. This study was designed to compare findings of IVUS
      imaging and those of angiography of the pulmonary artery before and after the
      balloon angioplasty procedure. Thirty patients had significant pulmonary artery
      stenosis and underwent balloon angioplasty. In all, of 34 branch pulmonary
      arteries were dilated. All patients underwent both angiography and IVUS imaging
      at the time of balloon angioplasty. The mean age at balloon angioplasty was 5.7
      +/- 4.0 yr. One echo-dense layer on IVUS was detected in 9% of the 34 stenotic
      vessels, and a two- or three-layered vascular wall pattern in 91%. The thickness
      of intima-medial layer (inner and middle layers) was greater than normal in 91%
      of stenotic vessels. After balloon angioplasty, intimal flaps and aneurysm were
      observed at 29 and 28 locations, respectively. Of these locations, the intimal
      flaps were detected by angiography in 44% and by IVUS in 100%; the aneurysm was
      detected by angiography in 61% and by IVUS in 93%. Media rupture was observed at
      26 locations, and the change was detected only by IVUS. The present study
      suggests that intimal and medial changes in the pulmonary artery can be detected
      more precisely by IVUS than by angiography.

PMID- 10348572
TI  - Rotational atherectomy for left anterior descending artery septal perforator
      stenosis.
AB  - Stenosis in large septal perforators can result in significant clinical ischemia.
      The distribution of the septal arteries is as large as many more commonly treated
      branch vessels. The interventricular septal blood supply has been ignored as a
      target for revascularization due to its inaccessibility for surgical
      revascularization, and the elastic recoil associated with balloon angioplasty in
      this location. Rotational atherectomy is a new therapeutic option for
      revascularization in this previously difficult location. The septal perforator
      ostium is the most common site of lesions and is functionally a branch ostial
      stenosis. We describe four cases in which rotational atherectomy was performed in
      patients with reversible ischemia due to septal artery stenosis. The acute
      angiographic results were stable, without evidence for immediate recoil. By
      debulking, facilitated angioplasty can yield stable acute results in this
      location. The small size of most septal branches and their angulated origin make
      rotational atherectomy challenging, and cases must be selected carefully. This
      previously ignored lesion location can be considered for revascularization in
      patients with suitable lesion and vessel morphology.

PMID- 10348573
TI  - Rotational atherectomy for the septal perforator: drilling into a deep frontier.

PMID- 10348574
TI  - Revascularization of a thrombosed, previously stented aorto-renal graft using
      combined directional atherectomy and AngioJet thrombectomy.
AB  - We report an interesting case with bilateral PTFE aorto-renal grafts of which one
      graft underwent balloon angioplasty and stenting for proximal stenosis. Combined
      debulking by AngioJet thrombectomy and Simpsons directional atherectomy was
      performed within the stent following reocclusion of the graft 9 months later.

PMID- 10348575
TI  - Rescue PTCA complicated by pulmonary artery rupture after tPA and abciximab.
AB  - Since the introduction of pulmonary artery catheterization for hemodynamic
      monitoring, several complications associated with its use have been described.
      Pulmonary artery rupture is an infrequent complication of flow-directed pulmonary
      artery catheters. We report a case of pulmonary artery rupture complicating
      rescue PTCA in the presence of systemic platelet inhibition with abciximab
      (Reopro), anticoagulation, and thrombolytic therapy. With the increasing use of
      these medications in patients undergoing acute coronary interventions,
      particularly those patients requiring hemodynamic monitoring, this uncommon but
      potentially fatal complication may be seen more frequently.

PMID- 10348576
TI  - X-ray generation and control.
AB  - This article has focused on those aspects of X-ray generation that are of
      immediate concern to clinicians. Generators and tubes result from more than a
      century of basic technology, engineering design, and manufacturing know-how. How
      are the rotating anode bearings lubricated? Most tubes use ball bearings. They
      are exposed to temperatures ranging up to several hundred degrees Centigrade.
      They are expected to provide a reasonable lifetime while supporting the static
      and gyroscopic loads imposed by a heavy anode running at 10,000 rpm. This all
      happens in a vacuum. The answer is the use of silver alloy balls. Modern systems
      use many feedback circuits for precise control of X-ray output. Spatial,
      spectral, and temporal beam shaping are all active development areas. The goal is
      image optimization with minimum radiation risk to the patient. In exchange, the
      operator needs to tell the system something about the clinical requirements
      needed to manage the patient on the table. Other examples of the interaction of
      technical means and clinical requirements will be discussed in future articles.

PMID- 10348577
TI  - Use of vibrational angioplasty for the treatment of chronic total coronary
      occlusions: preliminary results.
AB  - The aim of the study was to investigate the feasibility and clinical safety of
      vibrational angioplasty in the treatment of chronic total coronary occlusions and
      evaluate the clinical and angiographic factors that are predictive of the
      procedural success and complications of the procedure. Seventy-eight patients
      with chronic total occlusions (>3 months) resistant to conventional techniques
      were treated by vibrational angioplasty using a variety of conventional
      guidewires. Lesions were successfully crossed in 67 (85.9%) cases and antegrade
      flow was achieved in 59 (75.5%). Major complications (myocardial infarction and
      tamponade) occurred in two (2.5%) patients, but no fatalities ensued.
      Angiographically detectable dissections were seen in 23 (29.5%) patients but only
      resulted in vessel compromise and reclosure in 5 cases. Multiple stepwise
      logistic regression analysis identified the duration (<6 months, P = 0.008) and
      the length of the occlusion (<15 mm, P = 0.03) as independent predictors of final
      success and the age of the patient (<55 years, P = 0.006) as the only independent
      predictor of procedural complications. Vibrational angioplasty is a safe
      technique useful in the treatment of chronic coronary occlusive disease. Patients
      in whom the procedure is likely to prove most successful may be easily identified
      by clinical and angiographic features (duration and length of occlusion).

PMID- 10348578
TI  - Good vibrations.

PMID- 10348579
TI  - Adjunctive abciximab improves outcomes during recanalization of totally occluded
      saphenous vein grafts using transluminal extraction atherectomy.
AB  - Degenerative disease of aortocoronary saphenous vein grafts is a major cause of
      late morbidity and mortality in patients after coronary bypass surgery. We
      previously described a technique for recanalization of totally occluded grafts
      using extraction atherectomy (TEC) as a primary modality. While success was
      comparable to overnight urokinase, distal embolization, no-reflow, and non-Q
      myocardial infarction were common. Recently, abciximab has been used adjunctively
      in angioplasty and stenting with a reduced incidence of periprocedural
      complications. In order to determine whether abciximab can reduce the incidence
      of distal embolization, no-reflow, and myocardial infarction during TEC in
      totally occluded saphenous vein grafts, we compared patients treated with
      adjunctive abciximab with control subjects not receiving the drug. Male patients
      with previous coronary bypass surgery, class III-IV angina, and totally occluded
      saphenous vein grafts serving a vascular territory with ischemia not approachable
      by standard catheter-based techniques underwent TEC with or without adjunctive
      abciximab. Recanalization of the graft was achieved in 8/10 (80%) of subjects
      without abciximab, but complete success was achieved in only 5/10 (50%). In
      contrast, all procedures in the abciximab group were completely successful,
      without embolization or no-reflow. Our results suggest that TEC with adjunctive
      abciximab may be a highly effective approach for management of totally occluded
      saphenous vein grafts.

PMID- 10348580
TI  - Use of the Perclose device in the brachial artery after coronary intervention.

PMID- 10348581
TI  - Obliteration of a coronary artery aneurysm with a PTFE-covered stent: endoluminal
      graft for coronary disease revisited.
AB  - This is the first reported use of the JOSTENT stent graft for aneurysm disease in
      native coronaries. Consideration can be given to using this
      polytetrafluoroethylene (PTFE)-covered stent in situations such as dissections
      and restenosis in saphenous vein grafts or in long native coronary arteries
      without side branches, though further investigation is warranted.

PMID- 10348582
TI  - Re Manjunath et al. Balloon mitral valvuloplasty.

PMID- 10348583
TI  - Gastroepiploic bypass graft stenting.

PMID- 10348584
TI  - Re Sandoval et al. Thromboembolic stroke complicating balloon angioplasty of a
      vein graft.

PMID- 10348585
TI  - Iatrogenic brain attack: treatment and/or prevention?

PMID- 10348586
TI  - Coronary stenting without predilatation: a clinical routine with Jomed Delivery
      System.

PMID- 10348587
TI  - The days of multiple tooth identification systems are numbered.

PMID- 10348588
TI  - Load fatigue of five restoration modalities in structurally compromised
      premolars.
AB  - Twenty-five freshly extracted maxillary first premolars were divided equally
      among five modalities for rebuilding structurally compromised premolars. These
      modalities were: (A) buccal stainless steel Parapost/amalgam core, (B) palatal
      stainless steel parapost/amalgam core, (C) two stainless steel Paraposts/amalgam
      core, (D) two regular Link Plus TMS single-shear Minim pins/amalgam core, and (E)
      palatal cast gold post and core. Load fatigue was used as the testing protocol,
      using a 5.2-kg load applied at 72 cycles per minute. Each tooth was prepared with
      a 1.0-mm ferrule, and an upper limit of 250,000 load cycles was set for the
      testing. Two failures were exhibited, (1) preliminary failure which involved a
      crack in the luting cement layer, and (2) catastrophic failure wherein the core
      and crown separated from the root section. Statistical analysis using Kruskal
      Wallis test showed three subsets (P < or = .05). The subset with the highest
      number of load cycles to failure contained the palatal stainless steel
      post/amalgam core, two stainless steel Paraposts/amalgam core, and palatal cast
      gold post and core.

PMID- 10348589
TI  - Fundamental studies of maxillofacial materials: Part 1. Differential scanning
      calorimetric analyses of a heat-polymerized silicone.
AB  - Differential scanning calorimetry was used to evaluate the effects of
      polymerizing conditions and the addition of pigments for a heat-activated
      maxillofacial silicone (MDX 4-4515). Unpigmented specimens were examined in the
      starting condition and after polymerizing at 100 degrees C for 1 hour, 4 hours,
      and 20 hours, and specimens of four different pigmented silicones processed 1
      hour at 100 degrees C were also included. The DSC scanning was performed from 
      150 degrees C to 200 degrees C at 10 degrees C per minute, and a strong melting
      recrystallization peak at approximately -40 degrees C was found for all eight
      specimen groups (N = 5). Modulated differential scanning calorimetry resolved
      this peak into separate melting and recrystallization peaks, and confirmed the
      existence of a very weak glass transition peak in this silicone at approximately 
      125 degrees C. The mechanical properties of the MDX 4-4515 silicone appear to be
      dominated by melting and recrystallization, rather than the glass transition, and
      differences may exist in the viscoelastic and creep behavior for the unpigmented
      and pigmented materials.

PMID- 10348590
TI  - Element release and cytotoxicity of Pd-Cu binary alloys.
AB  - The release of elements from a series of palladium-copper alloys into cell
      culture medium was measured using atomic absorption spectroscopy. The effect of
      the alloys on the succinyl dehydrogenase activity of Balb/c 3T3 fibroblasts was
      also measured. Palladium inhibited the release of Cu in alloys up to 70 atomic
      weight percent Cu. Below 70 at. % Cu, Cu release was < 0.8 micrograms/cm2 at 72
      hours. Palladium release was lower from pure Pd (0.08 micrograms/cm2) at 72 hours
      than from Pd-Cu alloys containing > 70 at. % Cu, where it increased to 1.2
      micrograms/cm2. The cytotoxicity of the alloys correlated closely with the
      release of Cu, becoming markedly cytotoxic above 70 at. % Cu, when Cu release was
      greater than 2.2 micrograms/cm2.

PMID- 10348591
TI  - Tensile bond strength of two ceramic and three resin composite inlay materials
      placed using a resin luting agent.
AB  - The tensile bond strength of inlay materials to dentin was evaluated. Five
      materials, two direct resin composite inlay products, one hybrid resin composite,
      a preformed ceramic block, and a conventional porcelain material were bonded to
      bovine dentin and bonded together using a dual-polymerizing resin luting agent.
      Specimens were tested with and without thermocycling. Some bar-to-bar bonding
      groups fractured through the bar. Significantly higher (P < .05) bar-to-bar bonds
      were recorded than the bar-dentin bonds, irrespective of the inlay materials.
      VitaDur N showed the lowest bar-to-bar failure values (7.6 MPa) compared to the
      four other inlay materials (14.4 MPa to 22.2 MPa), but had the highest dentin
      bond strength (4.5 MPa). Unexpectedly, thermal loading increased the bond
      strength to bovine dentin, although this was only statistically significant for
      VitaDur N. The dentin bond strength of Charisma (1.4 MPa) was inferior (P < .02)
      to all other materials (2.6 MPa to 4.5 MPa) when thermocycled before testing.

PMID- 10348592
TI  - Relative flexural strength of six new ceramic materials.
AB  - The flexural strength of six recently introduced dental ceramic materials was
      measured using a three-point-bend test. Conventional feldspathic porcelain and
      soda-lime glass were used as controls. All six of the new materials had
      significantly greater breaking strength than the controls. The alumina-based
      crystalline-reinforced materials exhibited the highest breaking strengths. The
      silica-based crystalline-reinforced materials resulted in ceramic materials with
      more moderate strength but still with significantly greater strength than the
      controls. Scanning electron microscopic analysis of the fractured surfaces
      indicated crack deflection appeared to be the principal strengthening mechanism
      in the highly crystalline materials.

PMID- 10348593
TI  - The effect of load angulation on fracture resistance of teeth restored with cast
      post and cores and crowns.
AB  - The purpose of this study was to determine if loading post-restored teeth at
      different angles would affect their fracture resistance. Thirty maxillary central
      incisors were treated endodontically to within 5.0 mm of the apex. Standardized
      cast post and cores were fabricated using plastic #4 Parapost patterns. Post and
      cores were cemented using zinc phosphate cement, followed by crowns of average
      dimensions. Ten teeth each were loaded at 110, 130, and 150 degrees to the long
      axis of the tooth. Mean failure loads were: 110 degrees = 372.4 N +/- 140.8 (SD);
      130 degrees = 597.6 N +/- 138.5 (SD); 150 degrees = 1274.3 N +/- 429.9 (SD).
      There were significant differences in fracture resistance between teeth tested at
      the following angles: 110 degrees versus 150 degrees (P < .0001), and 130 degrees
      versus 150 degrees (P < .0001), but not for 110 degrees versus 130 degrees (P =
      .2016). Mean failure loads increased as load angle approached parallelism to the
      long axis of the teeth. Significant differences in fracture resistance of post
      restored teeth can occur as a result of load angle.

PMID- 10348594
TI  - Use of CAD/CAM system to fabricate dental prostheses. Part 1: CAD for a clinical
      crown restoration.
AB  - The development of a computer-aided design system for a clinical crown
      restoration is reported. Initially, the shape of the standard crown was deformed
      and adapted on the die depending on the shape of the margin. Then, the measured
      occlusal record data were taken in the computer graphics, and the adapted crown
      was adjusted with these data to obtain the centric occlusion. The occlusal data
      were replaced with data obtained using a functionally generated path record and
      the occlusal interferences eliminated. The ends of the adapted crown were
      connected with the margin. Thus, the entire crown was efficiently designed using
      the computer program developed.

PMID- 10348595
TI  - Monitoring the polymerization process of acrylic resins.
AB  - Four groups of autopolymerizing acrylic resins used for various purposes in
      current dental practice were investigated by monitoring their temperature changes
      during the polymerization process. Resins were compared in terms of
      characteristic parameters (such as the time interval needed to reach mechanical
      stability and the maximum temperature generated during the polymerization
      process) and interpretations were made of such temporal temperature profiles.

PMID- 10348596
TI  - Strength and mode of failure of single implant all-ceramic abutment restorations
      under static load.
AB  - The strength and mode of failure of three different designs of custom-made all
      ceramic implant abutments fabricated by milling of In-Ceram sintered ceramic
      blocks were compared with the conventional CeraOne system under static load. Four
      test groups were formed with different locations of abutment screws. In three
      test groups, In-Ceram crowns were fabricated for placement on the all-ceramic
      abutments, and in one test group, a veneer porcelain was fired directly on the
      abutment; crowns in the control group were fabricated using the CeraOne system.
      Ten-mm-long Branemark implants were placed into a brass block that allowed
      loading at a 30-degree angle to the long axis. The test group in which the veneer
      porcelain was fired directly on the all-ceramic abutments was the weakest, and it
      showed fractures at a mean value of 236 N. The fracture strength of the three
      other test groups was dependent on the extension of the crown margin relative to
      the location of the screw head. The test group that had the screw on the top
      compressing the entire ceramic abutment showed a mean value of 422 N that was
      similar to the results that were achieved with the CeraOne system (427 N). The
      weakest link in the all-ceramic single implant restorations was the abutment
      screw in which the bending began at approximately 190 N.

PMID- 10348597
TI  - Treatment outcomes in implant therapy: the influence of surgical and
      prosthodontic experience.
AB  - In this retrospective study reviewing 30 months of treatment, 53 partially or
      completely edentulous patients were provided with implant-supported restorations.
      The restorative aspects of the therapy were undertaken by an experienced
      prosthodontist who had just begun involvement with implant rehabilitation
      techniques. Patients were treated in two centres, 21 in a major teaching
      institution (Group A) and 32 in a private practice (Group B). In Group A, the
      implants were placed by experienced oral and maxillofacial surgeons just
      beginning involvement in implant techniques. The implants of the Group B patients
      were placed by surgeons with a minimum of 2 years implant experience. It appeared
      that the surgeon's experience had a major impact on the failure probability of
      unloaded implants. Loading conditions and the design of the prosthesis may be the
      decisive determinants for the probability of success with loaded implants. The
      hazards of extensive cantilevered extensions were demonstrated. The results
      suggest that those entering implant prosthodontics should not expect their early
      work to match the results obtained from established centres.

PMID- 10348598
TI  - Lithium ion strengthening of dental porcelain.
AB  - The effects of experimental lithium-containing ion exchange pastes on dental
      porcelain were compared with a commercial ion strengthening paste. Maximum
      biaxial flexure strength using the experimental pastes was obtained by firing
      lithium paste containing 200 g per L lithium sulphate dihydrate for 45 minutes at
      750 degrees C onto the surface of the porcelain. However, the commercial paste
      produced the greatest strengthening overall.

PMID- 10348599
TI  - Surface conditions and viscoelastic properties of the denture liner Permaflex.
AB  - This in vitro study evaluated the viscoelastic properties of Permaflex compared
      to other soft lining materials. The surface condition of this material was also
      investigated under both laboratory and simulated clinical conditions and with and
      without the application of a varnish. The tests provided practical instructions
      for the use of Permaflex, which showed good adaptive properties to stress and
      surface condition initially and after adjustment.

PMID- 10348600
TI  - [Collagenous colitis and lymphocytic colitis: not such an infrequent diagnosis].

PMID- 10348602
TI  - Chiral stationary phases in HPLC for the stereoselective determination of
      methadone.
AB  - An extensive study of the behavior of three chiral stationary phases (CSP) is
      presented for the stereoselective determination of methadone. The following
      chromatographic columns were selected: a cellulose, Chiralcel OJ; a modified
      cyclodextrin. Cyclobond I 2000 RSP, and a protein, Chiral-AGP. Retention factors,
      enantioselectivity, efficiency, and resolution were tested by modifying the
      composition of the mobile phase as well as the temperature. The mechanism for the
      chiral recognition of methadone on each support was discussed. Optimal
      chromatographic parameters were obtained for the three supports tested, and
      methadone enantiomers were separated in less than 20 minutes. The cellulose-based
      column gave the best resolution, but this CSP was not adapted to clinical
      analyses of methadone. Under optimized conditions, the cyclodextrin- and protein
      based columns allowed an excellent separation of methadone enantiomers, but no
      interference with the primary metabolite was found only with Chiral-AGP.

PMID- 10348601
TI  - [Chronic hepatitis C, autoimmunity and interferon alfa treatment].

PMID- 10348603
TI  - The influence of Morton Kramer in research on mental health and aging.

PMID- 10348605
TI  - Development. Web alert.

PMID- 10348604
TI  - 25th International Symposium on Growth Hormone and Growth Factors in
      Endocrinology and Metabolism and the 3rd International Workshop on Growth Hormone
      Insensitivity. Istanbul, Turkey, 24-27 April 1998. Proceedings and Abstracts.

PMID- 10348606
TI  - JAMA editor sacked.

PMID- 10348607
TI  - The generation of plastid mutants in vitro.

PMID- 10348608
TI  - New horizons in health. Proceedings of the XVIth World Conference on Health
      Promotion and Health Education. San Juan, Puerto Rico, June 1998.

PMID- 10348609
TI  - Spring meeting of the UK Branch of the World's Poultry Science Association.
      Scarborough, March 1998. Proceedings.

PMID- 10348610
TI  - A statement on the use of sildenafil in the management of sexual dysfunction in
      patients with cardiovascular disease. Heart and Stroke Foundation of Canada.
      Canadian Cardiovascular Society.

PMID- 10348611
TI  - Chiral genetics: Chiroscience Group, plc.

PMID- 10348612
TI  - The neurobiology of opiate reinforcement.
AB  - This article provides a basic introduction into two commonly used behavioral
      paradigms used for the assessment of the reinforcing and rewarding effects of
      drugs in experimental animals. Behavioral as well as neurochemical data regarding
      the neural basis of opiate reward are then critically reviewed in order to
      evaluate the neuroanatomical and neurochemical substrates mediating the primary
      and conditioned reinforcing effects of opiates as well as current hypotheses of
      drug-induced reward and aversion.

PMID- 10348613
TI  - Stress and brain angiotensin II receptors.
AB  - Angiotensin II (ANG II) has been recognized recently as one of the stress
      hormones that participate in various stress-induced responses, including
      sympathetic (pressor, tachycardiac, and hyperthermic) and neuroendocrine
      responses. Brain ANG II receptors have been identified in many brain regions
      involved in the stress responses. During stress-exposure, ANG II increases in the
      plasma and in the brain. Central administration of ANG II induces stress
      responses, whereas central blockade of ANG II receptors results in the inhibition
      of the sympathetic and neuroendocrine responses to stress. All these findings
      indicate that ANG II and its receptors contribute to the development of various
      sympathetic and neuroendocrine responses during stress exposure. This review
      focuses on the role of brain ANG II receptors in the stress-induced responses.

PMID- 10348614
TI  - Serotonin 5-HT2A receptors: molecular biology and mechanisms of regulation.
AB  - Serotonin 5-HT2A receptors are essential for a large number of physiological
      functions in the central nervous system and periphery. This review article
      summarizes our current knowledge of the molecular biology and mechanisms of
      regulation of 5-HT2A receptors. The mode of drug binding using data derived from
      molecular modeling and site-directed mutagenesis is described. The cellular and
      subcellular localization of 5-HT2A receptors is described, and the concentration
      of 5-HT2A receptors on apical dendrites of pyramidal neurons is emphasized.
      Various modes of regulation of 5-HT2A receptors are also summarized, including
      transcriptional, post-translational and mRNA editing processes. Finally, an
      integrated model of 5-HT2A receptor regulation that involves various protein
      kinases (protein kinase C, G-protein receptor kinases), arrestins, clathrin
      coated vesicles, endosomes and lysosomes. The relevance of these pathways for
      antidepressant and antipsychotic drug actions is emphasized.

PMID- 10348615
TI  - Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in
      rodents.
AB  - This review discusses efforts to develop rodent models for the study of
      neurobiological mechanisms underlying chronic alcohol drinking, alcoholism, and
      abnormal alcohol-seeking behavior. Selective breeding has produced stable lines
      of rats that reliably exhibit high and (for comparison purposes) low voluntary
      alcohol consumption. In addition, animal models of chronic ethanol self
      administration have been developed in rodents, who do not have a genetic
      predisposition for high alcohol-seeking behavior, to explore environmental
      influences in ethanol drinking and the effects of physical dependence on alcohol
      self-administration. The selectively bred high-preference animals reliably self
      administer ethanol by free-choice drinking and operantly respond for oral ethanol
      in amounts that produce pharmacologically meaningful blood alcohol concentrations
      (50 to 200 mg% and higher). In addition, the alcohol-preferring rats will self
      administer ethanol by intragastric infusion. With chronic free-choice drinking,
      the high alcohol-preferring rats develop tolerance to the high-dose effects of
      ethanol and show signs of physical dependence after the withdrawal of alcohol.
      Compared with nonpreferring animals, the alcohol-preferring rats are less
      sensitive to the sedative-hypnotic effects of ethanol and develop tolerance more
      quickly to high-dose ethanol. Nonselected common stock rats can be trained to
      chronically self-administer ethanol following its initial presentation in a
      palatable sucrose or saccharin solution, and the gradual replacement of the
      sucrose or saccharin with ethanol (the sucrose/saccharin-fade technique).
      Moreover, rats that are trained in this manner and then made dependent by ethanol
      vapor inhalation or liquid diet increase their ethanol self-administration during
      the withdrawal period. Both the selectively bred rats and common-stock rats
      demonstrate "relapse" and an alcohol deprivation effect following 2 or more weeks
      of abstinence. Systemic administration of agents that (1) increase synaptic
      levels of serotonin (5-HT) or dopamine (DA); (2) activate 5-HT1A, 5-HT2, D2, D3,
      or GABA(A) receptors; or (3) block opioid and 5-HT3 receptors decrease ethanol
      intake in most animal models. Neurochemical, neuroanatomical, and
      neuropharmacological studies indicate innate differences exist between the high
      alcohol-consuming and low alcohol-consuming rodents in various CNS limbic
      structures. In addition, reduced mesolimbic DA and 5-HT function have been
      observed during alcohol withdrawal in common stock rats. Depending on the animal
      model under study, abnormalities in the mesolimbic dopamine pathway, and/or the
      serotonin, opioid, and GABA systems that regulate this pathway may underlie
      vulnerability to the abnormal alcohol-seeking behavior in the genetic animal
      models.

PMID- 10348616
TI  - My doctor says I have sick sinus syndrome. I was recently hospitalized because of
      runs of rapid heart rates. When they gave medications to make my heart slow down,
      it went too slowly. Finally, they put a pacemaker in me and now I take pills
      every day. Is all this necessary?

PMID- 10348618
TI  - TBI Model System Grants.
AB  - The Traumatic Brain Injury (TBI) Model Systems Program has been funded by the
      National Institute on Disability and Rehabilitation Research (NIDRR) since 1987.
      Until recently, this program has consisted of four center s that conducted
      priority-focused research on specific aspects of TBI and analyzed data on the
      basis of a uniform, comprehensive national database. In 1997, $5 million in
      additional funding was allocated for the expansion of this program. In October
      1998, after a competitive renewal process, a total of 12 new centers were
      awarded, bringing the total TBI Model Systems to 17. In addition to the creation
      of new centers, funding was provided for specific collaborative research projects
      and increased resources for the TBI National Data Center. Below are the abstracts
      for both the newly funded systems and the existing systems.

PMID- 10348619
TI  - TBI State Demonstration Grants.
AB  - In 1996, Congress enacted Public law 104-66, the Traumatic Brain Injury (TBI)
      Act, to provide for the conduct of expanded studies and the establishment of
      innovative programs with respect to TBI. As part of the Act, the Health Resources
      and Services Administration (HRSA), Maternal and Child Health Bureau and other
      services regarding persons with TBI and their families. Currently, the TBI State
      Demonstration Grant Program includes two categories of grants: Planning and
      Implementation. Planning Grants are available to states that wish to develop the
      core components necessary to improve the overall infrastructure of a coordinating
      agency and designated staff, the completion of a comprehensive needs/resource
      assessment, and the development of a statewide action plan. Those states that can
      successfully demonstrate core capacity are eligible for grants in the
      implementation category. Implementation grants provide resources to implement
      statewide systems and models that will improve and enhance access to
      comprehensive and coordinated services for individuals with TBI and their
      families.

PMID- 10348620
TI  - Heme-mediated oxygen activation in biology: cytochrome c oxidase and nitric oxide
      synthase.
AB  - Major advances have been made in our understanding of cytochrome c oxidase owing
      to continued crystallographic work on important intermediates. This, together
      with a wealth of data derived from selective mutations and sophisticated
      spectroscopic probes, has provided significant new insights into oxidase dioxygen
      chemistry and proton pumping activities. Recent advances have also been made for
      nitric oxide synthase, owing to the crystal structure determination of the heme
      domain for two of three nitric oxide synthase isoforms.

PMID- 10348622
TI  - Are you making illegal referrals?

PMID- 10348621
TI  - Inorganic nitrogen metabolism in bacteria.
AB  - Enzymatic reactions involving inorganic nitrogen species provide a rich variety
      of systems with which to study biological chemistry. In many cases, catalysis
      involves redox chemistry and takes place at metal centres. Recent structures and
      new spectroscopic data have rapidly advanced our knowledge of nitrogen cycle
      enzymology, particularly in the areas of nitrogen fixation, hydroxylamine
      oxidation and nitrite reduction. In the case of the nitrate reductases and nitric
      oxide reductase, models for structure and catalysis can be designed, based on new
      structural information that is now available for closely related enzymes. The
      past two years have also seen significant progress in our understanding of the
      enzymology of some 'new' reactions of the nitrogen cycle, for example anaerobic
      ammona oxidation and heterotrophic nitrification.

PMID- 10348623
TI  - Improving Prognosis in Type 1 Diabetes. Proceedings from an Official Satellite
      Symposium of the 16th International Diabetes Federation Congress. Helsinki,
      Finland, 19-20 July 1997.

PMID- 10348624
TI  - Neonatal Society Meeting. June 1998 and November 1998. Abstracts.

PMID- 10348625
TI  - International study finds breast milk free of significant lead contamination.

PMID- 10348626
TI  - Response: Keeping abreast of new science.

PMID- 10348627
TI  - Killer environment.

PMID- 10348628
TI  - Annual review of the environment.

PMID- 10348629
TI  - The source of sick buildings.

PMID- 10348630
TI  - BCTP sounds its battle cry.

PMID- 10348632
TI  - Proceedings of the 1st Balkan Congress of Medicine and Dentistry for Students and
      Young Doctors. Plovdiv, Bulgaria, October 1997.

PMID- 10348631
TI  - Radically new research.

PMID- 10348633
TI  - Proceedings of the International Symposium of Multi-Disciplinary Therapy for
      Hepatocellular Carcinoma. March 22, 1997.

PMID- 10348634
TI  - Festschrift in memoriam of Wallace H. Clark, Jr., MD (1924-1997).

PMID- 10348635
TI  - Spontaneous mutations in SELH/Bc mice due to insertions of early transposons:
      molecular characterization of null alleles at the nude and albino loci.

PMID- 10348636
TI  - Keratocan (Kera), a corneal keratan sulfate proteoglycan, maps to the distal end
      of mouse chromosome 10.

PMID- 10348637
TI  - Localization of p27 beta 4 binding protein gene (ITGB4BP) to human chromosome
      region 20q11.2.

PMID- 10348638
TI  - Developmental genomics and its relation to aging.

PMID- 10348639
TI  - Children with bipolar disorder.

PMID- 10348640
TI  - Adolescents and religion: a view from the millenium.

PMID- 10348641
TI  - Religious development in adolescence.

PMID- 10348642
TI  - Facial diplegia with paraesthesias: facial nerve enhancement in three dimensional
      MRI.

PMID- 10348643
TI  - Restless legs syndrome associated with spinal cord lesions.

PMID- 10348644
TI  - Coma in thrombotic thrombocytopenic purpura.

PMID- 10348645
TI  - Anaphylactoid reaction to methyl prednisolone developing after starting treatment
      with interferon beta-1b.

PMID- 10348646
TI  - Posstreptococcal neuropathy.

PMID- 10348647
TI  - A sensory level on the trunk and sparing the face from vertebral artery
      dissection: how much more subtle can we get?

PMID- 10348648
TI  - Sudden unexpected death: a rare event in a large community based prospective
      cohort with newly diagnosed epilepsy and high remission rates.

PMID- 10348649
TI  - Opportunities for improving the quality of care in malignant cerebral glioma.

PMID- 10348650
TI  - MRI in vertebral artery dissection.

PMID- 10348651
TI  - Clinical usefulness of MRI in multisystem atrophy.

PMID- 10348653
TI  - Neurology and the gastrointestinal system.

PMID- 10348652
TI  - A dubious therapy for patients with multiple sclerosis.

PMID- 10348654
TI  - Memorial Symposium for Irene Guggenmoos-Holzmann.

PMID- 10348655
TI  - Precision of Cavalieri sections and slices with local errors.
AB  - Cavalieri sections--and more recently Cavalieri slices, especially in combination
      with non-invasive scanning--are widely used to estimate volumes. Physical
      Cavalieri slices are also increasingly used to estimate neuron numbers via the
      optical fractionator. In either case, the prediction of the error variance is
      important to assess optimal sample sizes. The error variance consists of two
      components, one due to the variation among the true contents of sections or
      slices, and the other due to local or 'nugget' errors. The latter may arise for
      instance estimating section areas by point counting discrete particles in slices
      or disectors. In this paper, a fairly comprehensive set of prediction formulae is
      presented to separate both variance components.

PMID- 10348656
TI  - The efficiency of systematic sampling in stereology--reconsidered.
AB  - In the present paper, we summarize and further develop recent reseach in the
      estimation of the variance of sterelogical estimators based on systematic
      sampling. In particular, it is emphasized that the relevant estimation procedure
      depends on the sampling density. The validity of the variance estimation is
      examined in a collection of data sets, obtained by systematic sampling. Practical
      recommendations are also provided in a separate section.

PMID- 10348657
TI  - Nerve growth factor inhibits apoptosis induced by tumor necrosis factor in PC12
      cells.
AB  - Tumor necrosis factor-alpha (TNFalpha) may play a role in at least some of the
      neuronal death that occurs following brain insults or in neurodegenerative
      diseases. It is therefore important to characterize the mechanism underlying
      apoptosis induced by TNFalpha in neuronal cells and to identify factors capable
      of protecting neurons from this death. In the present study, we characterized the
      apoptotic effect of TNFalpha in PC12 cells, a model system commonly used for
      studying neuronal apoptosis, and examined the role of Bcl-2 and caspases in this
      process. We show that TNFalpha induces apoptosis in both naive and primed PC12
      cells. The TNFalpha-induced apoptosis was inhibited by nerve growth factor (NGF)
      but not by insulin. These findings suggest that the apoptotic effect of TNFalpha
      can be inhibited by trophic factors and that the survival-promoting effect of NGF
      is mediated by a specific pathway not shared by all tyrosine kinase receptors.
      The effect of Bcl-2 on TNFalpha-induced apoptosis was examined in PC12 cells
      overexpressing Bcl-2. These cells were resistant to TNFalpha-induced apoptosis,
      suggesting that the apoptotic effect of TNFalpha in PC12 cells is mediated via a
      pathway controlled by Bcl-2. Examination of the role of caspase-3 like activity
      in TNFalpha-induced apoptosis showed that caspase-3-like proteases are activated,
      and their substrate, poly (ADP-ribose) polymerase, is cleaved following TNFalpha
      treatment. In addition, the broad-spectrum inhibitor of caspases,
      benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), was found to
      inhibit the TNFalpha-induced apoptosis of PC12 cells. These results suggest that
      caspases are activated following TNFalpha treatment and are needed for TNFalpha
      induced apoptosis in PC12 cells.

PMID- 10348658
TI  - Downregulation of glycogen synthase kinase-3beta (GSK-3beta) protein expression
      during neuroblastoma IMR-32 cell differentiation.
AB  - Glycogen synthase kinase-3gamma (GSK-3beta) is a multifunctional protein kinase
      that phosphorylates a variety of substrates including the neuronal-specific
      microtubule-associated protein tau. Here we report that the down-regulation of
      the GSK-3beta protein is an early event in the course of the differentiation of
      human neuroblastoma IMR-32 cells. This decline in GSK-3beta is accompanied by a
      significant decrease in the phosphorylation state of tau protein. A noteworthy
      increase in tau protein expression also takes place later during the
      differentiation of IMR-32 cells. The augmented expression and diminished
      phosphorylation of tau protein in differentiated IMR-32 cells can be correlated
      with increments in the assembly of microtubules and in the association of tau
      with microtubules. These results suggest a contribution of a decrease in GSK
      3beta to molecular events leading to neuroblastoma cell differentiation. Among
      these, tau protein dephosphorylation might favor microtubule stabilization within
      neurites.

PMID- 10348660
TI  - Atypical PKC zeta is activated by ceramide, resulting in coactivation of NF
      kappaB/JNK kinase and cell survival.
AB  - Both protein kinase C (PKC) and ceramide play a critical role in cell signaling,
      but the relationship between PKC and ceramide is unclear. Low concentrations of
      ceramide were observed to transiently stimulate PKC zeta activity in vitro and in
      vivo, whereas high doses of ceramide lead to inhibition of PKC zeta. Inhibition
      of activity was accompanied by enhanced binding of the negative regulator, Par4
      to PKC zeta. Treatment of PC12 cells with low doses of ceramide promoted survival
      in serum-free media and activation of nuclear factor-KB, whereas higher doses
      (>2.5 microM) resulted in cell death. Overexpression of either aPKC isoform, PKC
      zeta or iota, resulted in enhanced survival of PC12 cells at high doses of
      ceramide and in ceramide-stimulated Jun N-terminal kinase (JNK), without any
      apparent effect on mitogen-activated kinase. These findings support a role for
      ceramide-induced PKC zeta activity in the control of cell survival signaling via
      a pathway that also activates JNK kinase.

PMID- 10348659
TI  - Phasic synaptic remodeling of the rat arcuate nucleus during the estrous cycle
      depends on insulin-like growth factor-I receptor activation.
AB  - Insulin-like growth factor-I (IGF-I) has trophic and plastic effects on neurons
      and glial cells and modulates neuroendocrine events by acting at the level of the
      hypothalamus. IGF-I and estrogen signaling interact to regulate in vitro
      hypothalamic neuronal survival and differentiation. In vivo, IGF-I levels
      fluctuate in the rat hypothalamic arcuate nucleus during the estrous cycle in
      parallel with a phasic remodeling of synaptic contacts and glial cell processes.
      Both the fluctuation of IGF-I levels and the synaptic and glial changes are
      induced by estrogen. The possible role of IGF-I in the regulation of arcuate
      nucleus synaptic plasticity has been assessed in the present study by
      intracerebroventricular administration to cycling female rats of a specific IGF-I
      receptor antagonist. In agreement with previous findings, the number of synaptic
      inputs to arcuate neuronal somas in control rats showed a significant decrease
      between the morning of proestrus and the morning of estrus. This decline in
      synaptic inputs and the accompanying increase in glial ensheathing of neuronal
      somas were blocked by the IGF-I receptor antagonist. In contrast, the IGF-I
      receptor antagonist did not affect the basal number of synapses or the morphology
      of synaptic terminals or length of the synaptic contacts. These findings indicate
      that IGF-I receptor activation may be involved in the phasic remodeling of
      arcuate nucleus synapses during the estrous cycle. Res.

PMID- 10348661
TI  - Delayed oligodendrocyte degeneration induced by brief exposure to hydrogen
      peroxide.
AB  - An in vitro model system of cultured oligodendrocytes was used to determine the
      susceptibility of these cells to oxidative stress induced by 15 min exposure to
      millimolar concentrations of hydrogen peroxide (H2O2). Following the exposure,
      the cells were incubated in normal growth medium, and analyzed at different time
      points. Although no cell loss was observed during the exposure period, there was
      a progressive depletion of adherent cells during the postexposure period as seen
      from either the number of recoverable nuclei, or from total RNA content of the
      cultures. Both the rate and the extent of cell deletion was directly dependent on
      H2O2 concentration. Cell death was preceded by structural alterations in the
      nuclear envelope resulting in "fragile" nuclei which disintegrated during
      isolation. Northern blot analysis showed that the expression of myelin-specific
      genes was rapidly downregulated in H2O2-treated cells. On the other hand, the
      expression of antiapoptotic gene, bcl-2 featured massive but transient
      upregulation. Oligodendrocyte degeneration also featured genomic DNA degradation
      into high molecular weight fragments, which are likely to represent cleaved
      chromosomal loops. The results demonstrate vulnerability of oligodendrocytes to
      oxidative stress that induces rapid degeneration and ultimately leads to delayed
      cell death. This feature is highly relevant to oligodendrocyte damage and
      depletion following ischemic, traumatic, or inflammatory insults to the central
      nervous system (CNS).

PMID- 10348662
TI  - Noradrenaline inhibits glutamate release in the rat bed nucleus of the stria
      terminalis: in vivo microdialysis studies.
AB  - The microdialysis technique was used to simultaneously study the in vivo
      extracellular levels of noradrenaline, glutamate, and gamma aminobutyric acid
      (GABA) in the bed nucleus of the stria terminalis in order to assess the
      regulation that noradrenaline may exert upon the release of amino acid
      neurotransmitters. Perfusion through the probe with UK14304, a selective alpha2
      adrenergic agonist, produced a significant decrease of noradrenaline and
      glutamate extracellular levels. Perfusion through the probe with RX821002, a
      selective alpha2-adrenergic antagonist, produced a significant increase of
      noradrenaline and glutamate basal extracellular levels. Perfusion with prazosine,
      a selective alpha1-adrenergic antagonist, produced a significant decrease of
      noradrenaline basal extracellular levels without affecting glutamate levels.
      Under the same conditions, GABA basal extracellular levels were not changed in
      the presence of any of the alpha-adrenergic ligands studied. The perfusion of
      high potassium through the probe induced a significant Ca++dependent release of
      the three neurotransmitters; however, extracellular noradrenaline returned to
      normal levels even though potassium was still present. In addition, it was
      observed that alpha-adrenergic receptor ligands exerted differential effects upon
      K+-induced release of noradrenaline and glutamate. Perfusion with the
      nonselective alpha-adrenergic antagonist, phenoxybenzamine, presented a biphasic
      effect upon K+-induced release of noradrenaline; a significant decrease during
      the first 5 min of stimulation followed by a significant increase in the next 5
      min of stimulation. Perfusion with RX821002 produced a significant increase in K+
      induced release of noradrenaline that returned to normal basal values before the
      end of the stimulation period. In contrast, local perfusion with prazosine caused
      a significant decrease of K+-induced noradrenaline release. In the case of
      glutamate, perfusion through the probe with phenoxybenzamine produced a
      significant increase in K+-induced release of glutamate. In addition, RX821002
      and prazosine produced a significant increase in K+-induced release of glutamate.
      Perfusion through the probe with UK14304 produced a significant decrease of both
      noradrenaline and glutamate K+-induced release. The present results show that
      noradrenaline in the bed nucleus of stria terminalis exerts a significant
      inhibition over its own release through alpha2-adrenergic receptors and over
      glutamate release mainly through alpha2-adrenergic receptors. Thus, the results
      suggest that noradrenaline in the bed nucleus of the stria terminalis maintains
      an inhibitory tone over the information flow mediated by glutamate.

PMID- 10348663
TI  - Immunohistochemical localization of the INsP4 receptor GTPase-activating protein
      GAP1IP4BP in the rat brain.
AB  - The distribution of GAP1(IP4BP), a GTPase-activating protein showing high
      affinity and stereospecificity for inositol 1,3,4,5-tetrakisphosphate (InsP4),
      was investigated by Western blot and immunohistochemistry of rodent brain with
      polyclonal antibodies generated against the carboxy-terminus of the cloned
      protein. GAP1(IP4BP)-like immunoreactivity was found throughout the brain, most
      notably in the pyriform cortex, neocortex, hippocampus, striatum, and cerebellar
      cortex. However, the most striking immunolabeling was consistently localized to
      area CA1 of the hippocampus and the central, medial, and intercalated nuclei of
      the amygdala. Western blot analysis of the corresponding brain regions
      corroborated these immunohistochemical observations. The regionally specific
      expression of GAP1(IP4BP) provides the prerequisite neuroanatomical substrate
      toward elucidating the functional role of InsP4 and GAP1(IP4BP) in the central
      nervous system.

PMID- 10348664
TI  - Oxidative stress oppositely modulates protein tyrosine phosphorylation stimulated
      by muscarinic G protein-coupled and epidermal growth factor receptors.
AB  - This study's goals were to more fully define the activation of protein tyrosine
      phosphorylation stimulated by muscarinic receptors, to test if this signaling
      process is affected by oxidative stress induced by H2O2, and to compare the
      effects of H2O2 on protein tyrosine phosphorylation activated by epidermal growth
      factor (EGF) receptors. Experiments used human neuroblastoma SH-SY5Y cells which
      express endogenous M3 muscarinic and EGF receptors. Carbachol induced time
      dependent increases in phosphotyrosine immunoreactivity of several protein bands,
      which were quantitated, and immunoprecipitation was used to identify the adhesion
      related proteins focal adhesion kinase, p130Cas/HEF1, and paxillin, and three shc
      adapter proteins. Carbachol-induced tyrosine phosphorylation of the adhesion
      related proteins was mediated by muscarinic receptors, and was inhibited by a src
      family kinase inhibitor, PP1. That carbachol can activate src family kinases was
      indicated further by the finding that carbachol induced an increase in tyrosine
      phosphorylation of p120-src substrate, which was inhibited by PP1. Oxidative
      stress induced by H2O2 concentration dependently inhibited carbachol-induced
      tyrosine phosphorylation of each of the adhesion-related proteins. EGF increased
      the phosphotyrosine immunoreactivity of 180- and 116-kDa proteins, identified as
      the EGF receptor and Cbl, respectively. In contrast to the results with
      carbachol, H2O2 potentiated EGF-induced tyrosine phosphorylation. These results
      demonstrate that muscarinic receptor activation induces previously unrecognized
      increases in tyrosine phosphorylation, and that this signaling process is
      impaired by H2O2, whereas protein tyrosine phosphorylation stimulated by EGF is
      increased by H2O2. Thus, oxidative stress can oppositely modulate protein
      tyrosine phosphorylation induced by activation of G protein-coupled and growth
      factor receptors in the same cells.

PMID- 10348665
TI  - N8-acetyl spermidine protects rat cerebellar granule cells from low K+-induced
      apoptosis.
AB  - The endogenous polyamines have been extensively studied with respect to their
      role in cellular death mechanisms, although the results are contradictory. In
      contrast, their primary metabolites, the N-acetyl polyamines, have not been much
      studied. It has been hypothesized that the N-acetyl metabolites may play a role
      in cellular death mechanisms, and some of the variability between different
      reports may be due to altered polyamine metabolic capacities. Using primary
      cultures of rat cerebellar granule cells, the effects of N-acetyl metabolites
      have been examined on basal, cytosine beta-D-arabinofuranoside (Ara-C)-induced
      and low K+-induced apoptosis. None of the compounds affected either basal or Ara
      C-induced apoptosis at low doses. At higher doses, all compounds were toxic. Two
      compounds, N8-acetyl spermidine and N1-acetyl spermine, were found to protect
      cells from low K+-induced apoptosis, which has been shown to be p53-independent.
      In contrast, the parent polyamines were devoid of protective activity at subtoxic
      doses. This represents the first time that an antiapoptotic effect of N-acetyl
      polyamines has been demonstrated. These results raise the possibility that these
      compounds may act as endogenous neuroprotectants. The lack of effect on basal
      apoptosis provides evidence of at least two forms of p53-independent apoptosis
      that can be regulated independently.

PMID- 10348666
TI  - Induction of neuronal nitric oxide synthase by methylmercury in the cerebellum.
AB  - A free radical, nitric oxide (NO), besides being a messenger molecule in the
      brain, becomes a neurotoxin if overproduced. We recently reported that
      methylmercury (MeHg) induces neuronal NO synthase (nNOS) in Purkinje cells. In
      the present study, we examined the distribution and the mechanism of nNOS
      induction by MeHg. Subcutaneous administration of MeHg chloride to mice, 10
      mg/kg/day for 9 days, increased calcium-dependent NOS activity to 60% more than
      the controls only in the cerebellum but not in other brain regions. The Western
      blots showed a comparable increase in nNOS protein in the cerebellum. A N-methyl
      D-aspartate (NMDA) receptor antagonist, MK-801, did not block, but rather
      enhanced, the increase in the nNOS activity. Another NMDA antagonist, 3-(2
      carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), did not affect the nNOS
      activity. The Western blots of protein kinase C (PKC), which is an important
      cofactor regulating nNOS, did not change after the administration of MeHg. These
      results show that MeHg induces biologically active nNOS selectively in the
      cerebellum. The induction is independent of PKC and is not reduced by the
      blockade of the NMDA receptor.

PMID- 10348667
TI  - Effect of NGF treatment on outcome measures in a rat model of middle cerebral
      artery occlusion.
AB  - Ischemic insults to the brain result in a time-dependent increase in neuronal
      death that is responsible for some of the functional deficits associated with
      stroke. Our working hypothesis is that ischemia results in a prompt depletion of
      high energy phosphate species resulting in decreased pH and glutathione levels in
      brain in a temporal and spatial pattern that disrupts nerve growth factor
      homeostasis and increases neuronal apoptosis. Here we show hemispheric depletion
      of active phosphate species after ischemia. Also, we observed that the striatum
      is an early target for oxidative stress that is followed by energy metabolic
      impairment and altered neurotrophin levels that were detected by noninvasive
      magnetic resonance imaging (MRI) measurements of cytotoxicity and conventional
      biochemical determinations of apoptosis, glutathione, and nerve growth factor
      (NGF) protein levels in a pattern distinct from that observed in the hippocampus.
      Furthermore, early assessment of intracellular pH by 31P-magnetic resonance
      spectroscopy (31P-MRS) was a predictor of later infarct development as determined
      by MRI. We also show that pretreatment with pharmacological doses of NGF did not
      have overall significant beneficial consequences on irreversible ischemia in an
      intraluminal unilateral irreversible model of stroke in rat brain.

PMID- 10348668
TI  - Isolation and culture of human neuromicrovascular endothelial cells for the study
      of angiogenesis in vitro.
AB  - Neovascularization in the adult central nervous system occurs as a response to
      several pathophysiological conditions such as ischemia, wound repair, or
      neoplasia. Endothelial cells from different blood vessel types, different organs,
      and different species are heterogeneous; therefore, the appropriate cell type
      should be used to study specific aspects of vascular pathology. We have developed
      a method to isolate human cerebral microvascular endothelial cells (CMECs) from
      small, freshly obtained specimens of normal brain adherent to human arteriovenous
      malformations (AVMs). The isolation procedure involves enzymatic digestions and
      gradient centrifugations, yielding over 95% pure primary cultures. Alternative
      isolation methods using magnetic beads, panning, or cloning were not superior
      with regard to cell purity or yield. CMECs were identified by their
      immunoreactivity for vWF, CD34, EN4, binding of Ulex europeus lectin, and uptake
      of DiI-Ac-LDL. They displayed ultrastructural features characteristic of blood
      brain barrier endothelial cells and expressed GLUT-1. CMECs were subcultured;
      however, prolonged culture led to reduced culture purity. Vascular endothelial
      growth factor, basic fibroblast growth factor and hepatocyte growth
      factor/scatter factor stimulated the directional motility of CMECs, with dose
      response profiles similar to human umbilical vein endothelial cells (HUVECs). In
      contrast, to stimulate proliferation, lower concentrations of growth factors
      tended to be necessary for CMECs than for the large vessel endothelial cells.
      CMECs formed capillary tube-like structures in an in vitro angiogenesis assay
      using matrigel. This study expands the spectrum of available tissue sources for
      the isolation of human neuromicrovascular endothelial cells, which are essential
      for the in vitro study of blood-brain barrier function and cerebral angiogenesis.

PMID- 10348669
TI  - Neutral glycolipid and ganglioside composition of type-1 and type-2 astrocytes
      from rat cerebral hemisphere.
AB  - We reported previously that the major gangliosides in primary mixed-type
      astrocyte cultures are GM3 and GD3. To obtain more information regarding the
      exact distribution of glycosphingolipids in different types of astrocytes, we
      established a line of type-1 astrocytes that are characterized by a Ran-2
      positive, broad flat morphology, and by the absence of binding to A2B5
      antibodies. We also purified O-2A progenitor cells by immunopanning and cultured
      them in the presence of 10% newborn calf serum. They differentiated into type-2
      astrocytes that were identified by immunostaining for each of GD3, A2B5, and
      GFAP. Using these cell cultures, we demonstrate that the major gangliosides were
      GM3 in type-1 astrocytes and GM3 and GD3 in type-2 astrocytes. In addition, a set
      of neutral glycolipids was identified based on the HP-TLC migration properties of
      CMH, CDH, CTH, and Glob, but the component distribution of these glycolipids is
      related to that of glycolipids of astrocytes. A marked increase in the expression
      of CTH and Glob was shown in type-2 astrocytes. The amount of neutral glycolipid
      sugar was higher in the type-2 astrocytes than in the type-1 astrocytes. These
      results suggest that the increase in the total glycosphingolipid content and the
      change in the neutral glycolipid composition produced by type-2 astrocytes may be
      related to their biological functions and the cellular compositions.

PMID- 10348670
TI  - Developmental expression of the neurotransmitter transporter GAT3.
AB  - Neurotransmitter transporters are involved in termination of the synaptic
      neurotransmission and they also play a key role in neuroregulation and brain
      development. In this report, we describe the developmental distribution of the y
      aminobutyric acid transporter GAT3 which transports gamma-aminobutyric acid
      (GABA) and beta-alanine in a sodium chloride-dependent manner. GAT3 was localized
      to the meninges in developmental stages where two other GABA transporters, GAT1
      and GAT4, were adjacently expressed. In later developmental stages, only GAT3
      remained in this area. The expression of GAT3 in the peripheral embryonic tissues
      was confined to the liver, to a layer of cells under the skin, to the mouse
      kidney, and to hipoccampal blood vessels only in late developmental stages. The
      developmental distribution of GAT3 suggests involvement in central nervous system
      (CNS) maturation.

PMID- 10348671
TI  - Proceedings of the XIX Symposium of the International Association for Comparative
      Research on Leukemia and Related Diseases (IACRLRD). Mannheim/Heidelberg,
      Germany, 12-18 July 1997.

PMID- 10348673
TI  - Both sides now.

PMID- 10348672
TI  - Diagnostic strategy in deep-vein thrombosis.

PMID- 10348674
TI  - 1998 Mutation Research Award for Scientific Excellence. Dr. Thomas Kunkel.

PMID- 10348675
TI  - Expediting publication to inform political debates.

PMID- 10348676
TI  - Expediting publication to inform clinical debates.

PMID- 10348677
TI  - Expediting publication to inform political debates.

PMID- 10348678
TI  - Expediting publication to inform political debates.

PMID- 10348679
TI  - Expediting publication to inform political debates.

PMID- 10348680
TI  - Expediting publication to inform political debates.

PMID- 10348681
TI  - Control of HIV despite the discontinuation of antiretroviral therapy.

PMID- 10348682
TI  - Treatment of esophageal cancer.

PMID- 10348683
TI  - Treatment of esophageal cancer.

PMID- 10348684
TI  - Treatment of esophageal cancer.

PMID- 10348685
TI  - Treatment of esophageal cancer.

PMID- 10348686
TI  - Tumorigenic potential of apparently tumor-free lymph nodes.

PMID- 10348687
TI  - Creutzfeldt-Jakob disease.

PMID- 10348688
TI  - Creutzfeldt-Jakob disease.

PMID- 10348689
TI  - Creutzfeldt-Jakob disease.

PMID- 10348690
TI  - Disclosure statements regarding hormonal treatment of prostate cancer.

PMID- 10348691
TI  - Disclosure statements regarding hormonal treatment of prostate cancer.

PMID- 10348692
TI  - Excessive blood drawing for laboratory tests.

PMID- 10348693
TI  - Cortical plasticity: the representation of experience. Proceedings from the 6th
      annual Neuropharmacology Conference. Berlin, Germany, 24-26 June 1998.

PMID- 10348694
TI  - Dentists in a bubble.

PMID- 10348695
TI  - Molecular and cellular aspects of exocytosis. Proceedings of a symposium. Milan,
      Italy, 24-25 June 1998.

PMID- 10348696
TI  - The Electronic Plant Gene Register.

PMID- 10348697
TI  - Confidentiality of social work records in the computer age.
AB  - Computers have brought social, cultural, and economic benefits. They also are
      challenging social workers to preserve a basic tenet of the profession-
      confidentiality. Electronic record systems and rapid changes in communication
      over the Internet are outpacing the profession's ability to ensure privacy. This
      article discusses ideas of information protection and makes recommendations to
      minimize violations of privacy.

PMID- 10348698
TI  - The new confidentiality for the 21st century in a managed care environment.
AB  - As society becomes more dependent on technology to store and obtain information
      quickly and effectively, there has been increasing concern in the social work
      community about protecting privacy and maintaining confidentiality, especially in
      a managed care environment. The concept of confidentiality is very different in a
      technologically advanced environment. This article reviews relevant social work,
      legal, and other professional literature on confidentiality, technology, and
      managed care. A three-level topology of client problems and behaviors is
      delineated and illustrated through practice examples, which demonstrate the
      different types of information that can be computer stored and retrieved and
      electronically transmitted. The articles discussed the levels of security,
      including log-on procedures, firewalls, and encryption, which can be used at each
      level to protect sensitive information, and presents guidelines to help
      professionals protect and promote confidentiality within the constraints of
      technology and managed care.

PMID- 10348699
TI  - The biology of P-selectin glycoprotein ligand-1: its role as a selectin
      counterreceptor in leukocyte-endothelial and leukocyte-platelet interaction.
AB  - Cell-cell interactions mediating leukocyte trafficking, thrombogenesis and
      inflammation are crucial for the host defense mechanism. The selectin family of
      integral membrane proteins includes E-selectin, L-selectin and P-selectin.
      Selectins mediate tethering and rolling of leukocytes to the vessel wall at the
      site of inflammation. The counter-receptor for P-selectin and possibly the other
      selectins is P-selectin glycoprotein ligand-1 (PSGL-1). This review focuses on
      the properties and biology of PSGL- 1.

PMID- 10348700
TI  - Lipoprotein(a) levels and isoforms and fibrinolytic activity in postmenopause-
      influence of hormone replacement therapy.
AB  - Epidemiological studies suggest that hormone replacement therapy (HRT) decreases
      the risk of cardiovascular disease in postmenopausal women via several
      mechanisms, including modifications in the fibrinolytic system and lipoprotein(a)
      [Lp(a)] levels. The aim of this study was to examine the influence of the levels
      and isoforms of Lp(a) on fibrinolytic activity in 91 postmenopausal women in
      comparison with premenopause and analyze the effect of HRT on those parameters.
      In postmenopause, an increase in plasma Lp(a) and plasminogen activator inhibitor
      1 (PAI-1) levels was found. A significant inverse correlation was observed
      between Lp(a) or PAI-1 levels and plasmin generation. Plasma samples with low
      molecular weight (MW) apo(a) isoforms showed higher plasmin inhibition than
      plasmas with high MW apo(a) isoforms and similar levels of total Lp(a) and PAI-1.
      HRT induced a significant decrease in Lp(a) and PAI-1 levels and an increase in
      estradiol levels, as well as an increase in fibrinolytic activity. A significant
      correlation was found between the percentages of variation in Lp(a) levels and in
      plasmin generation and between the percentages of variation in PAI-1 levels and
      in the euglobulin lysis time under HRT. In conclusion, the increase in
      fibrinolytic activity observed in women under HRT could be explained by two
      independent mechanisms: (a) the decrease in PAI-1 and (b) the decrease in the
      inhibition of plasmin generation due to the decrease in Lp(a) levels.

PMID- 10348701
TI  - Evidence for two distinct G-protein-coupled ADP receptors mediating platelet
      activation.
AB  - The identity of the receptors mediating platelet activation by ADP remains
      elusive. To distinguish between platelet ADP receptor subtypes, the effects of
      antagonists on platelet responses and the cloned P2Y1 receptor, a putative
      platelet ADP receptor, have been investigated. 2-methylthio-AMP (2MeSAMP), an
      inhibitor of ADP-dependent platelet aggregation, antagonized ADP-mediated
      inhibition of adenylyl cyclase, competed with binding of [3H]2-methylthio-ADP and
      inhibited the stimulation of [35S]GTPgammaS binding. 2MeSAMP did not inhibit
      platelet shape change and was only a weak antagonist of intracellular calcium
      mobilization in platelets or in cells expressing the cloned human P2YI receptor.
      By contrast, the P2Y1 receptor antagonist adenosine 3',5'-diphosphate (A3P5P)
      inhibited ADP-induced platelet aggregation, completely abolished shape change,
      but did not antagonize ADP effects on cyclic AMP generation or [3H]2-methylthio
      ADP binding. However, A3P5P antagonized intracellular calcium mobilization in
      platelets and cells expressing the cloned P2Y1 receptor. Furthermore, using a
      specific monoclonal antibody and flow cytometry, P2Y1 receptor protein was
      detected on human platelets. These results support the existence of two G protein
      coupled ADP receptors mediating platelet aggregation, one of which is coupled to
      Gi proteins and blocked by 2MeSAMP, whereas the second receptor is similar or
      identical to P2Y1 and coupled to Gq.

PMID- 10348702
TI  - Platelet adhesion to collagen type I, collagen type IV, von Willebrand factor,
      fibronectin, laminin and fibrinogen: rapid kinetics under shear.
AB  - Extracellular matrix proteins in the blood vessel wall fulfill an essential role
      in haemostasis by promoting platelet adhesion at the site of vessel injury. We
      have combined a continuous-flow system with affinity chromatography to study
      platelet adhesion under conditions mimicking arterial flow and have examined the
      adhesion kinetics of unstimulated platelets to collagens type I and IV, von
      Willebrand factor (vWf), fibronectin, laminin and to fibrinogen. In the absence
      of red cells, in ACD-prepared plasma adhesion to collagens type I and IV or vWf
      was rapid, efficient (>50% in <1 s ) and independent of shear rates from 650 to
      3400 s(-1) with kinetics following an inverse exponential decay curve. We
      introduced a simple mathematical model in which this type of kinetics arises, and
      which may be more generally applicable to various adhesion processes under flow
      conditions. The model is characterized by the rate of platelet deposition on the
      adhesive surface being proportional to the number of platelets in the flow.
      Adhesion to fibronectin was independent of shear rate, but revealed a lag phase
      of approximately 1.5 s before significant adhesion began. Laminin and fibrinogen
      supported efficient adhesion at low shear rates (650-1000 s(-1)), but a lag phase
      of approximately 1.5 s was seen at high shear rates (1700-3400 s(-1)). Control
      proteins (albumin and gelatin) supported minimal adhesion. Nonspecific adhesion
      to poly-L-lysine differed from that to other substrate proteins in that the
      kinetics were linear. In conclusion, human platelets adhered specifically,
      rapidly (within seconds) and efficiently to several proteins under flow
      conditions and the kinetics of adhesion depended on the protein serving as
      substrate as well as on shear rate.

PMID- 10348703
TI  - Clustering of integrin alphaIIb-beta3 differently regulates tyrosine
      phosphorylation of pp72syk, PLCgamma2 and pp125FAK in concanavalin A-stimulated
      platelets.
AB  - Tyrosine phosphorylation of the non-receptor tyrosine kinases pp72syk and
      pp125FAK and of the gamma2 isoform of phospholipase C (PLCgamma2) in human
      platelets stimulated with the lectin Concanavalin A was investigated.
      Concanavalin A induced the rapid tyrosine phosphorylation of pp72syk and
      PLCgamma2 with a similar kinetics, while tyrosine phosphorylation of pp125FAK
      occurred in a later phase of platelet activation. When compared with other
      platelet agonists, Concanavalin A revealed to be at least as potent as collagen
      in inducing tyrosine phosphorylation of PLCgamma2 and pp125FAK, while tyrosine
      phosphorylation of pp72syk induced by the lectin was much stronger than that
      induced by thrombin or collagen. Concanavalin A-induced tyrosine phosphorylation
      of pp72syk, PLCgamma2 and pp125FAK was not dependent on platelet aggregation as
      it occurred normally even in the absence of sample stirring and when fibrinogen
      binding to integrin alphaIIb-beta3 was inhibited by the peptide RGDS. Tyrosine
      phosphorylation of pp72syk, PLCgamma2 and pp125FAK required the binding of the
      lectin to the platelet surface, but was not observed in platelets treated with
      succinyl-Concanavalin A, a derivative of the lectin that interacts with the same
      receptors but does not promote clustering of membrane glycoproteins. Moreover,
      the aggregation-independent tyrosine phosphorylation of pp125FAK and pp72syk
      induced by Concanavalin A required the expression of integrin alphaIIb-beta3 on
      the platelet surface as it was strongly inhibited in platelets from patients
      affected by Glanzmann thrombasthenia. By contrast, tyrosine phosphorylation of
      PLCalpha2 occurred normally also in thrombasthenic platelets stimulated with
      Concanavalin A. These results demonstrate that, even in the absence of
      aggregation, the clustering of integrin alphaIIb-beta3 induced by Concanavalin A
      on the platelet surface directly promotes tyrosine phosphorylation of pp72syk and
      pp125FAK and provide further evidence that the oligomerization of the fibrinogen
      receptor promoted by its natural ligand during platelet aggregation may be
      responsible for the tyrosine phosphorylation of these proteins induced by
      physiological agonists.

PMID- 10348704
TI  - Measurement of GPV released by activated platelets using a sensitive
      immunocapture ELISA--its use to follow platelet storage in transfusion.
AB  - Thrombin, the most potent platelet agonist, plays a central role in haemostasis
      and in the occurrence of thrombotic events. This agonist activates platelets by
      cleaving the PAR G-protein coupled receptors and by binding to glycoprotein (GP)
      Ib and also cleaves GPV at the platelet surface to liberate the soluble 69 kDa
      fragment GPVf1. Monoclonal antibodies (MoAbs) to GPV were developed as tools to
      study the mechanism of platelet GPV cleavage and measure release of GPV in
      pathological situations. Specificity of the MoAbs for GPV was confirmed by flow
      cytometry and immunoprecipitation of proteins from human platelets and Dami
      megakaryocytic cells. A sensitive immunocapture sandwich ELISA for soluble GPV
      was developed using two MoAbs recognizing different epitopes of GPV and purified
      platelet or recombinant GPV as reference protein. This ELISA was employed to
      determine the mean plasma concentration of GPV in 100 normal individuals (17.3
      ng/ml), to demonstrate the dose-dependent release of GPVf1 from washed platelets
      stimulated with thrombin and to follow the progressive release of GPVf1 during
      storage of therapeutic platelet concentrates. The present report describes a
      sensitive GPV ELISA of direct application to survey the processing and storage of
      platelet concentrates for transfusion and of potential value to monitor platelet
      activation in thrombotic states.

PMID- 10348705
TI  - Epinephrine promotes IL-8 production in human leukocytes via an effect on
      platelets.
AB  - Interleukin-8 (IL-8) is generally accepted to be an important mediator of a
      number of acute and chronic inflammatory diseases and is produced by monocytes
      upon stimulation by lipopolysaccharide (LPS). Epinephrine has been reported by
      several groups to suppress activation of monocytes in response to LPS, and the
      aim of the present study was to examine the effect of epinephrine on LPS induced
      IL-8 production using whole blood as a model system. Epinephrine increased LPS
      induced IL-8 production in a dose-dependent manner in the whole concentration
      range (0.001-100 microM) and 1 microM epinephrine increased IL-8 levels with
      125%. Epinephrine per se had no effect on IL-8 levels. The potentiating effect of
      epinephrine was mediated by blood platelets, since IL-8 levels in samples
      containing platelets and stimulated with LPS and epinephrine (1-100 microM) were
      significantly higher (p<0.05) than in control samples containing no platelets.
      This effect of platelets seemed to be due to platelet release products, since
      addition of 25 microL platelet lysate supernatant to whole blood increased LPS
      induced IL-8 production with 100% and a similar effect was observed in freshly
      isolated mononuclear cells resuspended in plasma. Upon addition of 50 microg/ml
      of the carboxyterminal peptide of platelet factor 4 (PF4(58-70)) to whole blood,
      LPS stimulated IL-8 levels were increased with 115%, whereas in mononuclear
      cells, 20 microg/ml PF4(58-70) enhanced IL-8 production with 40%. We demonstrate
      for the first time that epinephrine promotes LPS induced production of IL-8 in
      whole blood via an effect on blood platelets. This potentiating effect of
      platelets is shown to be due to platelet granule contents, and platelet factor 4
      (PF4) is suggested to be one of several platelet granule proteins promoting LPS
      induced IL-8 production in whole blood.

PMID- 10348707
TI  - Human atheromatous plaque extracts induce tissue factor activity (TFa) in
      monocytes and also express constitutive TFa.
AB  - Tissue factor activity (TFa) is a major activator of the coagulation cascade and
      may play a role in atheroma-induced thrombosis. Monocyte-macrophages (MO-MF)
      generate considerable quantities of TFa when stimulated by a variety of inducers.
      To test the hypothesis that MO could be induced by atheromatous plaque to
      generate TFa, plaque extracts obtained from patients with obstructive
      atheromatous disease were used. These extracts were also assayed for constitutive
      TFa. The constitutive activity was variable from extract to extract but could be
      very high, up to 250 U TFa. The TFa induced in MO could be also very high, up to
      200 U (i.e. 1/5 of the TFa of full strength rabbit brain thromboplastin). These
      findings point to a major role for MO-MF TFa in the induction or thrombosis by
      atheromatous plaque.

PMID- 10348706
TI  - The risk of early recurrent venous thromboembolism after oral anticoagulant
      therapy in patients with the G20210A transition in the prothrombin gene.
AB  - A G20210A transition in the prothrombin gene is a common risk factor of venous
      thrombosis. The risk of recurrent venous thromboembolism in carriers of the
      20210A allele is unknown and guidelines for secondary thromboprophylaxis in these
      patients are not available. In a prospective multicenter trial, 492 patients with
      a history of objectively documented venous thromboembolism were followed for a
      mean observation time of 24+/-16 months after discontinuation of oral
      anticoagulants. Forty-two patients (8.5%) were carriers of the 20210A allele.
      Three of the 42 patients with the G20210A mutation (7%) and 54 of 450 patients
      without the mutation (12%) experienced recurrent venous thrombosis. At 24 months,
      the probability of recurrence was 8% (95% CI 0-16.7) in patients with the
      mutation and was 12.2% (95% CI 8.8-15.6) in patients without the mutation. In
      conclusion, the risk of early recurrent venous thromboembolism is not higher in
      patients with the G20210A mutation than in those without the mutation. Therefore,
      long-term secondary thromboprophylaxis with oral anticoagulants in heterozygous
      carriers of the 20210A allele is not justified.

PMID- 10348708
TI  - Effects of heparin and related sulfated polysaccharides on tissue factor
      expression induced by mitogenic and non-mitogenic factors in human vascular
      smooth muscle cells.
AB  - Smooth muscle cells (SMCs) of the intima are generally quiescent and non
      proliferative. Their proliferation due to different stimulations occurs in
      myointimal hyperplasia and is regularly present in atherogenesis or after
      transluminal angioplasty leading to vascular occlusive stenosis. In the course of
      these pathologies, the Tissue Factor (TF) synthesis was upregulated and rapidly
      expressed at the membrane of the SMCs. Heparin is known to inhibit SMCs
      proliferation induced by FCS. We evaluated the inhibitory effect of heparin on
      the expression of TF induced by various mitogenic (FCS, PDGF-BB and EGF) and non
      mitogenic (bacterial LPS) agents. Inhibition by heparin of SMCs proliferation
      induced by the same agonists was also determined. Quiescent human vascular SMCs
      from normal adult arteries were treated for 1 h by heparin and related sulfated
      polysaccharides before stimulation by the agonists. All the agonists up-regulated
      the expression of TF antigen and activity. TF expression induced by the growth
      factors was inhibited by heparin (IC 50: 10-30 microg/ml), and other sulfated
      polysaccharides (IC 50: 1-5 microg/ml). SMCs proliferation, late activation of
      the extracellular signal-regulated kinases (ERK1/2), and PKC activity were
      inhibited by heparin (IC 50: 30-50 microg/ml) in SMCs stimulated by FCS but not
      in SMCs treated by PDGF or EGF. In contrast, heparin had no effect on LPS-induced
      TF expression nor on LPS-induced PKC activation. These results indicate that,
      besides its well known effect on SMC proliferation, heparin displays an
      inhibitory effect on cell mediated blood clotting processes through regulation of
      the TF expression.

PMID- 10348709
TI  - RPR120844, a novel, specific inhibitor of coagulation factor Xa inhibits venous
      thrombosis in the rabbit.
AB  - The in vivo antithrombotic activity of RPR 20844, a novel synthetic coagulation
      factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit
      thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous
      dose-response studies were performed and thrombus mass (TM), activated partial
      thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa
      activity and plasma drug levels (PDL) were determined. TM, measured at the end of
      a 50 min infusion, was significantly reduced (p<0.05 vs. saline-treated animals)
      by RPR120844 at 30 and 100 microg/kg/min. At doses of 10, 30 and 100
      microg/kg/min, APTT was prolonged by 2.1, 4.2 and 6.1-fold, and PT was prolonged
      by 1.4, 2.2 and 3.5-fold, respectively. PDL were determined by measuring anti-fXa
      activity using an amidolytic assay. Peak PDL were 0.8+/-0.3, 1.5+/-0.9 and 2.4+/
      0.6 microM, respectively. The drug effect was reversible with APTT, PT and PDL
      returning toward pretreatment values 30 min after termination of treatment. The
      results suggest that RPR 120844, or similar compounds, may provide an
      efficacious, yet easily reversible, means of inhibiting thrombus formation.

PMID- 10348711
TI  - Simultaneous genotyping for factor V Leiden and prothrombin G20210A variant by a
      multiplex PCR-SSCP assay on whole blood.

PMID- 10348710
TI  - The prevalence of the prothrombin 20210 G-->A mutation is not increased in
      angiographically confirmed coronary artery disease.

PMID- 10348712
TI  - The 20210 G to A prothrombin polymorphism and late complications in type 1
      diabetes mellitus.

PMID- 10348713
TI  - APC-resistance is a risk factor for postoperative thromboembolism in elective
      replacement of the hip or knee--a prospective study.
AB  - Postoperative venous thromboembolic complications are commonly seen after total
      replacement of the hip or knee. Recently, an inherited defect with resistance to
      the anticoagulant activity of activated protein C (APC-resistance) has been
      detected. APC-resistance seems to be a common risk factor, especially in Sweden,
      and it increases the propensity for venous thrombosis. This study assesses the
      prevalence of APC-resistance in a general population and its clinical
      significance for patients undergoing surgery associated with a high risk of
      thromboembolic complications. In a prospective cohort study, we analysed for APC
      resistance in 645 consecutive patients before elective replacement of the hip or
      knee at 3 hospitals in southern Sweden. Thromboprophylaxis with LMWH-heparin was
      given to all patients throughout the hospitalisation period. We recorded events
      of clinical thromboembolism for 3 months postoperatively. Venography,
      ultrasonography or pulmonary scintigraphy was requested by the clinicians
      according to the existing routines, i.e. only patients with symptoms of
      thromboembolism were examined. A thromboembolic complication was registered in 20
      (3.1%) patients. Fifty per cent of the venous thrombi had a proximal location.
      Only 0.3% of the patients had verified pulmonary embolism. APC-resistance was
      found in 14.1% of the patients, of whom 9.9% had experienced postoperative
      thromboembolism compared with 2.0% of the patients without APC-resistance
      (p<0.0007). We conclude that APC-resistance is a frequent risk factor for
      symptomatic postoperative deep venous thrombosis with an estimated relative risk
      of 5.0 (95% confidence interval: from 1.9 to 12.9) in elective replacement of the
      hip or knee.

PMID- 10348714
TI  - Prevention of deep vein thrombosis after hip replacement--comparison between two
      low-molecular heparins, tinzaparin and enoxaparin.
AB  - Consecutive patients undergoing total hip replacement in 43 centres were randomly
      assigned to receive blindly either enoxaparin (40 mg) or tinzaparin (4,500 anti
      Factor IU Xa), as once daily subcutaneous injections. The first injection was
      administered 12 h preoperatively. Efficacy was assessed by bilateral venography
      performed 12-14 days postoperatively. Efficacy and safety were blindly and
      centrally adjudicated. Among the 499 patients included, 440 had a venogram. The
      total incidence of DVTs was 44 (20.1%) of the 219 patients of the enoxaparin
      group and 48 (21.7%) of the 221 patients of the tinzaparin group. The upper limit
      of the 80% confidence interval of the difference between the two treatment groups
      was less than 5.0%. Therefore according to the protocol's specifications
      equivalence was shown. Proximal DVTs occurred in 10.5% of the enoxaparin group
      (23 patients) and in 9.5% (21 patients) of the tinzaparin group. No overt major
      bleeding was observed. One patient in the enoxaparin group developed severe
      thrombocytopenia and died. The LMWH tinzaparin appears clinically to be as
      effective and safe as enoxaparin in the prophylaxis of deep vein thrombosis after
      total hip replacement, at the doses used and under the conditions of this study.

PMID- 10348715
TI  - Recovery and half-life of von Willebrand factor-cleaving protease after plasma
      therapy in patients with thrombotic thrombocytopenic purpura.
AB  - Plasma exchange using fresh-frozen plasma (FFP) for replacement was given to two
      brothers during a relapse of thrombotic thrombocytopenic purpura (TTP). A
      constitutional deficiency of von Willebrand factor(vWF)-cleaving protease had
      been previously established in both patients. No inhibitor of vWF-cleaving
      protease was present in patients' plasmas. They received plasma exchange for four
      and three consecutive days, respectively. In both patients, the activity of vWF
      cleaving protease after the first plasmapheresis session was evaluated and was
      found to be virtually identical to anticipated activity calculated from predicted
      patient plasma volume and volume of exchanged plasma. Pathologic platelet counts
      and lactate dehydrogenase levels were normalized in both patients within 4-6
      days. The biologic half-life of vWF-cleaving protease was determined in these
      patients following the last plasma exchange. The respective half-lives of 3.3 and
      2.1 days represent the lowest known clearance rates of proteases in circulating
      human plasma. Another patient with relapsing TTP was treated with plasma exchange
      and/or plasma infusion for 10 consecutive days during the first relapse, 221-231
      days after the initial TTP event. Pharmacokinetic studies of vWF-cleaving
      protease were performed after plasma exchange on day 221 and after plasma
      infusion on day 231. High level of an IgG in patient plasma, capable of
      completely inhibiting protease activity in an equal volume of normal plasma, had
      been established prior to first plasmapheresis. There was no measurable protease
      activity at any time during plasma therapy. Following plasma exchange, the level
      of the inhibitor was transiently slightly depressed. After 10 days of plasma
      therapy, the concentration of the inhibitor in patient plasma was increased about
      5-fold. We suggest that, in contrast to protease deficient patients without
      circulating inhibitor, complementary therapy including immunosuppressive
      treatment, vincristine and/or splenectomy is indicated in patients with acquired
      inhibitors of vWF-cleaving protease. Testing for vWF-cleaving protease inhibitor
      may be useful in predicting the response to plasma exchange in patients with TTP.

PMID- 10348716
TI  - Crotalase, a fibrinogen-clotting snake venom enzyme: primary structure and
      evidence for a fibrinogen recognition exosite different from thrombin.
AB  - Crotalase, a fibrinogen-clotting enzyme isolated from the venom of Crotalus
      adamanteus, and its overlapping fragments were subjected to Edman degradation.
      The resulting amino acid sequence [see text] characteristic of a serine
      proteinase. Comparison with thrombin, the physiological fibrinogen-clotting
      enzyme, showed that thrombin's fibrinogen-recognition exosite (FRE) is poorly
      represented in crotalase. Hirudin, a FRE-dependent inhibitor, had no effect on
      crotalase. Spatial modeling of crotalase yielded a possible alternative
      fibrinogen-recognition site comprised of Arg 60F, Lys 85, Lys 87, and Arg 107
      (underlined in the sequence above). Crotalase also lacks thrombin's YPPW loop, as
      well as its functionally important ETW 146-148, and its heparin-binding site. The
      enzyme contains a single asparagine-linked glycosylation site, NFT, bearing
      neutral and amino sugars that account for 8.3% of the enzyme's total molecular
      weight of 29,027. The calculated absorbance of crotalase at 280 nm, 1%, cm(-1) is
      15.2.

PMID- 10348717
TI  - Beta2-glycoprotein I is proteolytically cleaved in vivo upon activation of
      fibrinolysis.
AB  - Beta2-glycoprotein I (beta2GPI) is a plasma glycoprotein with unknown
      physiological function(s). In in vitro experiments it has been demonstrated that
      beta2GPI has both anticoagulant properties, such as the inhibition of factor X
      and prothrombin activation and procoagulant properties, such as the inhibition of
      the anticoagulant activity of activated protein C. Besides this, beta2GPI bound
      to cardiolipin is recognized by antiphospholipid antibodies (aPL). In this study
      we demonstrate that beta2GPI is very sensitive for cleavage between Lys317 and
      Thr318 by plasmin, resulting in two immunologically different cleaved forms. In
      vitro experiments show that these plasmin cleaved forms of beta2GPI bind to
      negatively charged phospholipids with much lower affinity compared to intact
      beta2GPI. Similar to plasmin, trypsin and elastase can also induce this
      proteolytical cleavage in beta2GPI, whereas thrombin and factor Xa do not cleave
      beta2GPI. The in vivo occurrence of the proteolytical cleavage was demonstrated
      by the finding that in plasmas of patients with disseminated intravascular
      coagulation (DIC) and in plasmas of patients treated with streptokinase,
      significant amounts of cleaved beta2GPI (up to 12 microg/ml) are present. During
      the development of DIC, the increase in levels of cleaved beta2GPI is accompanied
      by a 70% decrease in the levels of intact beta2GPI, whereas in streptokinase
      treated patients levels of intact beta2GPI stay within the normal range. This
      study demonstrates for the first time that during in vivo activation of
      fibrinolysis beta2GPI is cleaved. which results in the formation of a form of
      beta2GPI with much lower affinity for negatively charged phospholipids. Plasmin
      is most likely responsible for this modification.

PMID- 10348719
TI  - Alzheimer's disease: the tacrine legacy.

PMID- 10348718
TI  - Monocyte plasminogen activator inhibitor 2 (PAI-2) inhibits u-PA-mediated fibrin
      clot lysis and is cross-linked to fibrin.
AB  - Plasminogen activator inhibitor 2 (PAI-2) is a major product of activated human
      monocytes. Here we show that monocytes inhibited u-PA- but not t-PA-mediated
      fibrinolysis, by secreting PAI-2 into an overlying fibrin clot. Extracts of
      arterial and venous human thrombi were found to contain active PAI-2. PAI-2 was
      cross-linked to fibrin in a reaction catalyzed by two major transglutaminases
      (TG), tissue TG and factor XIII. The activity of PAI-2 was not affected by such
      cross-linking. Cross-linking of PAI-2 to fibrin was inhibited by Tridegin, a
      specific inhibitor of TG, and also by EDTA and iodoacetamide. The use of
      competitive peptides mimicking the loop between helices C and D of PAI-2
      identified Gln 83 and 86 as residues important in cross-linking. This study
      defines a mechanism by which PAI-2 is localized to fibrin, where it acts as an
      effective inhibitor of u-PA-mediated fibrinolysis.

PMID- 10348720
TI  - Disclosing apoptosis in the CNS.

PMID- 10348721
TI  - 'Omnicompetent' graduates.

PMID- 10348722
TI  - [Dissertations defended at the end of 1998-the start of 1999].

PMID- 10348723
TI  - [The 140th anniversary of the Society of Naval Physicians in Kronshtadt].

PMID- 10348724
TI  - [The 45th anniversary of Totskoe Military Hospital].

PMID- 10348725
TI  - [The journal presents: P. F. Khveshchuk, Colonel in the Medical Service.
      Interview by L. L. Galin].

PMID- 10348726
TI  - Proceedings of the 1st World Congress on Vaccines and Immunization. Istanbul,
      Turkey, April 26-30, 1998.

PMID- 10348727
TI  - Proceedings of the 15th Conference of the Japan Neuroscience in Otolaryngology
      Meeting.

PMID- 10348729
TI  - [Genetic modulation in ophthalmology. The present and future].

PMID- 10348728
TI  - Proceedings of a satellite meeting of the European Human Genetic Society on
      Copper Transport and Its Disorders: Molecular and Cellular Aspects. Sestri
      Levante, Italy, May 21-25, 1997.

PMID- 10348730
TI  - Focal lesion in the splenium of the corpus callosum in epileptic patients:
      antiepileptic drug toxicity?

PMID- 10348731
TI  - XXVI Annual meeting of the Arbeitsgemeinschaft Dermatologische Forschung. Bonn,
      Germany, 18-20 February 1999. Abstracts.

PMID- 10348733
TI  - A younger age for the universe 
AB  - The age of the universe in the Big Bang model can be calculated from three
      parameters: Hubble's constant, h; the mass density of the universe, Omegam; and
      the cosmological constant, OmegaLambda. Recent observations of the cosmic
      microwave background and six other cosmological measurements reduce the
      uncertainty in these three parameters, yielding an age for the universe of 13.4
      +/- 1.6 billion years, which is a billion years younger than other recent age
      estimates. A different standard Big Bang model, which includes cold dark matter
      with a cosmological constant, provides a consistent and absolutely time
      calibrated evolutionary sequence for the universe.

PMID- 10348734
TI  - Supercurrents through single-walled carbon nanotubes 
AB  - Proximity-induced superconductivity in single-walled carbon nanotubes below 1
      kelvin, both in a single tube 1 nanometer in diameter and in crystalline ropes
      containing about 100 nanotubes, was observed. The samples were suspended between
      two superconducting electrodes, permitting structural study in a transmission
      electron microscope. When the resistance of the nanotube junction is sufficiently
      low, it becomes superconducting and can carry high supercurrents. The temperature
      and magnetic field dependence of the critical current of such junctions exhibits
      unusual features related to their strong one-dimensional character.

PMID- 10348732
TI  - The global topography of Mars and implications for surface evolution.
AB  - Elevations measured by the Mars Orbiter Laser Altimeter have yielded a high
      accuracy global map of the topography of Mars. Dominant features include the low
      northern hemisphere, the Tharsis province, and the Hellas impact basin. The
      northern hemisphere depression is primarily a long-wavelength effect that has
      been shaped by an internal mechanism. The topography of Tharsis consists of two
      broad rises. Material excavated from Hellas contributes to the high elevation of
      the southern hemisphere and to the scarp along the hemispheric boundary. The
      present topography has three major drainage centers, with the northern lowlands
      being the largest. The two polar cap volumes yield an upper limit of the present
      surface water inventory of 3.2 to 4.7 million cubic kilometers.

PMID- 10348735
TI  - A post-stishovite SiO2 polymorph in the meteorite Shergotty: implications for
      impact events.
AB  - Transmission electron microscopy and electron diffraction show that the martian
      meteorite Shergotty, a shocked achondrite, contains a dense orthorhombic SiO2
      phase similar to post-stishovite SiO2 with the alpha-PbO2 structure. If an SiO2
      mineral exists in Earth's lower mantle, it would probably occur in a post
      stishovite SiO2 structure. The presence of such a high-density polymorph in a
      shocked sample indicates that post-stishovite SiO2 structures may be used as
      indicators of extreme shock pressures.

PMID- 10348736
TI  - Temperatures on europa from galileo photopolarimeter-radiometer: nighttime
      thermal anomalies 
AB  - Galileo observations of Europa's thermal emission show low-latitude diurnal
      brightness temperatures in the range of 86 to 132 kelvin. Nighttime temperatures
      form an unexpected pattern, with high temperatures on the bright ejecta blanket
      of the crater Pwyll and an equatorial minimum in temperatures after sunset,
      uncorrelated with surface albedo or geology. The nighttime anomalies may be due
      to regional thermal inertia variations of an unknown origin, which are equivalent
      to a two- to threefold variation in thermal conductivity, or to endogenic heat
      fluxes locally reaching 1 watt per square meter. Endogenic heat flow at this high
      level, although consistent with some geological evidence, is theoretically
      unlikely.

PMID- 10348737
TI  - An aqueous channel for filamentous phage export.
AB  - Filamentous phage f1 exits its Escherichia coli host without killing the
      bacterial cell. It has been proposed that f1 is secreted through the outer
      membrane via a phage-encoded channel protein, pIV. A functional pIV mutant was
      isolated that allowed E. coli to grow on large maltodextrins and rendered E. coli
      sensitive to large hydrophilic antibiotics that normally do not penetrate the
      outer membrane. In planar lipid bilayers, both mutant and wild-type pIV formed
      highly conductive channels with similar permeability characteristics but
      different gating properties: the probability of the wild-type channel being open
      was much less than that of the mutant channel. The high conductivity of pIV
      channels suggests a large-diameter pore, thus implicating pIV as the outer
      membrane phage-conducting channel.

PMID- 10348738
TI  - Comparative genomics of BCG vaccines by whole-genome DNA microarray.
AB  - Bacille Calmette-Guerin (BCG) vaccines are live attenuated strains of
      Mycobacterium bovis administered to prevent tuberculosis. To better understand
      the differences between M. tuberculosis, M. bovis, and the various BCG daughter
      strains, their genomic compositions were studied by performing comparative
      hybridization experiments on a DNA microarray. Regions deleted from BCG vaccines
      relative to the virulent M. tuberculosis H37Rv reference strain were confirmed by
      sequencing across the missing segment of the H37Rv genome. Eleven regions
      (encompassing 91 open reading frames) of H37Rv were found that were absent from
      one or more virulent strains of M. bovis. Five additional regions representing 38
      open reading frames were present in M. bovis but absent from some or all BCG
      strains; this is evidence for the ongoing evolution of BCG strains since their
      original derivation. A precise understanding of the genetic differences between
      closely related Mycobacteria suggests rational approaches to the design of
      improved diagnostics and vaccines.

PMID- 10348739
TI  - Broadly protective vaccine for Staphylococcus aureus based on an in vivo
      expressed antigen.
AB  - Vaccines based on preferential expression of bacterial antigens during human
      infection have not been described. Staphylococcus aureus synthesized poly-N
      succinyl beta-1-6 glucosamine (PNSG) as a surface polysaccharide during human and
      animal infection, but few strains expressed PNSG in vitro. All S. aureus strains
      examined carried genes for PNSG synthesis. Immunization protected mice against
      kidney infections and death from strains that produced little PNSG in vitro.
      Nonimmune infected animals made antibody to PNSG, but serial in vitro cultures of
      kidney isolates yielded mostly cells that did not produce PNSG. PNSG is a
      candidate for use in a vaccine to protect against S. aureus infection.

PMID- 10348740
TI  - Spatiotemporal dynamics of inositol 1,4,5-trisphosphate that underlies complex
      Ca2+ mobilization patterns.
AB  - Inositol 1,4,5-trisphosphate (IP3) is a second messenger that elicits complex
      spatiotemporal patterns of calcium ion (Ca2+) mobilization and has essential
      roles in the regulation of many cellular functions. In Madin-Darby canine kidney
      epithelial cells, green fluorescent protein-tagged pleckstrin homology domain
      translocated from the plasma membrane to the cytoplasm in response to increased
      concentration of IP3. The detection of translocation enabled monitoring of IP3
      concentration changes within single cells and revealed spatiotemporal dynamics in
      the concentration of IP3 synchronous with Ca2+ oscillations and intracellular and
      intercellular IP3 waves that accompanied Ca2+ waves. Such changes in IP3
      concentration may be fundamental to Ca2+ signaling.

PMID- 10348741
TI  - Interactions of prefrontal cortex in relation to awareness in sensory learning.
AB  - In an associative learning paradigm, human subjects could be divided based on
      whether they were aware that one tone predicted a visual event and another did
      not. Only aware subjects acquired a differential behavioral response to the
      tones. Regional cerebral blood flow in left prefrontal cortex showed learning
      related changes only in aware subjects. Left prefrontal cortex also showed
      changes in functional connectivity with contralateral prefrontal cortex, sensory
      association cortices, and cerebellum. Several of the interacting areas correlated
      with aware subjects' behavior. These results suggest cerebral processes
      underlying awareness are mediated through interactions of large-scale
      neurocognitive systems.

PMID- 10348742
TI  - Defective angiogenesis in mice lacking endoglin.
AB  - Endoglin is a transforming growth factor-beta (TGF-beta) binding protein
      expressed on the surface of endothelial cells. Loss-of-function mutations in the
      human endoglin gene ENG cause hereditary hemorrhagic telangiectasia (HHT1), a
      disease characterized by vascular malformations. Here it is shown that by
      gestational day 11.5, mice lacking endoglin die from defective vascular
      development. However, in contrast to mice lacking TGF-beta, vasculogenesis was
      unaffected. Loss of endoglin caused poor vascular smooth muscle development and
      arrested endothelial remodeling. These results demonstrate that endoglin is
      essential for angiogenesis and suggest a pathogenic mechanism for HHT1.

PMID- 10348743
TI  - Equivalence in yield from marine reserves and traditional fisheries management 
AB  - Marine reserves have been proposed as a remedy for overfishing and declining
      marine biodiversity, but concern that reserves would inherently reduce yields has
      impeded their implementation. It was found that management of fisheries through
      reserves and management through effort control produce identical yields under a
      reasonable set of simplifying assumptions corresponding to a broad range of
      biological conditions. Indeed, for populations with sedentary adults
      (invertebrates and reef fishes), reserves have important advantages for
      sustainability, making marine reserves the preferred management approach.

PMID- 10348744
TI  - PKS1, a substrate phosphorylated by phytochrome that modulates light signaling in
      Arabidopsis.
AB  - Plants constantly monitor their light environment in order to grow and develop
      optimally, in part through use of the phytochromes, which sense red/far-red
      light. A phytochrome binding protein, PKS1 (phytochrome kinase substrate 1), was
      identified that is a substrate for light-regulated phytochrome kinase activity in
      vitro. In vivo experiments suggest that PKS1 is phosphorylated in a phytochrome
      dependent manner and negatively regulates phytochrome signaling. The data suggest
      that phytochromes signal by serine-threonine phosphorylation.

PMID- 10348745
TI  - Peptide antibiotics.

PMID- 10348746
TI  - Molecular investigation of the postantibiotic effects of clarithromycin and
      erythromycin on Staphylococcus aureus cells.
AB  - The kinetics of recovery after inhibition of growth by erythromycin and
      clarithromycin were examined in Staphylococcus aureus cells. After inhibition for
      one mass doubling by 0.5 microg of the antibiotics/ml, a postantibiotic effect
      (PAE) of 3 and 4 h duration was observed for the two drugs before growth resumed.
      Cell viability was reduced by 25% with erythromycin and 45% with clarithromycin
      compared with control cells. Erythromycin and clarithromycin treatment reduced
      the number of 50S ribosomal subunits to 24 and 13% of the number found in
      untreated cells. 30S subunit formation was not affected. Ninety minutes was
      required for resynthesis to give the control level of 50S particles. Protein
      synthesis rates were diminished for up to 4 h after the removal of the
      macrolides. This continuing inhibition of translation was the result of prolonged
      binding of the antibiotics to the 50S subunit as measured by 14C-erythromycin
      binding to ribosomes in treated cells. The limiting factors in recovery from
      macrolide inhibition in these cells, reflected as a PAE, are the time required
      for the synthesis of new 50S subunits and the slow loss of the antibiotics from
      ribosomes in inhibited cells.

PMID- 10348747
TI  - Intrapulmonary concentrations of pyrazinamide.
AB  - The objective of this study was to compare the steady-state plasma and
      intrapulmonary concentrations of orally administered pyrazinamide in normal
      volunteers and subjects with AIDS. Pyrazinamide was administered at 1 g once
      daily for 5 days to 40 adult volunteers (10 men with AIDS, 10 normal men, 10
      women with AIDS, and 10 normal women). Subjects with AIDS and with more than four
      stools per day were excluded. Blood was obtained prior to administration of the
      first dose, 2 h after the last dose, and at the completion of bronchoscopy and
      bronchoalveolar lavage, which were performed 4 h after the last dose.
      Standardized bronchoscopy was performed without systemic sedation. The volume of
      epithelial lining fluid (ELF) recovered was calculated by the urea dilution
      method. The total number of alveolar cells (AC) was counted in a hemocytometer,
      and differential cell counting was performed after cytocentrifugation.
      Pyrazinamide was measured by high-performance liquid chromatography. The presence
      of AIDS or gender had no significant effect on the concentrations of pyrazinamide
      in plasma. The concentrations of pyrazinamide in ELF and AC were lower in the
      subjects with AIDS than in the subjects without AIDS, but the difference was not
      significant. The concentrations in plasma (mean +/- standard deviation) were 25.1
      +/- 7.6 and 21.1 +/- 6.8 microg/ml at 2 and 4 h after the last dose,
      respectively, and were not significantly different from the concentration (17.4
      +/- 16.9 microg/ml) in AC. The concentration of pyrazinamide in ELF was high (431
      +/- 220 microg/ml) and was approximately 4 to 40 times the reported MIC for
      pyrazinamide-susceptible strains of Mycobacterium tuberculosis. The high
      concentration of pyrazinamide in ELF may contribute in part to the effectiveness
      of the drug in treating pulmonary tuberculosis.

PMID- 10348748
TI  - A mechanism for the synergistic antimalarial action of atovaquone and proguanil.
AB  - A combination of atovaquone and proguanil has been found to be quite effective in
      treating malaria, with little evidence of the emergence of resistance when
      atovaquone was used as a single agent. We have examined possible mechanisms for
      the synergy between these two drugs. While proguanil by itself had no effect on
      electron transport or mitochondrial membrane potential (DeltaPsim), it
      significantly enhanced the ability of atovaquone to collapse DeltaPsim when used
      in combination. This enhancement was observed at pharmacologically achievable
      doses. Proguanil acted as a biguanide rather than as its metabolite cycloguanil
      (a parasite dihydrofolate reductase [DHFR] inhibitor) to enhance the atovaquone
      effect; another DHFR inhibitor, pyrimethamine, also had no enhancing effect.
      Proguanil-mediated enhancement was specific for atovaquone, since the effects of
      other mitochondrial electron transport inhibitors, such as myxothiazole and
      antimycin, were not altered by inclusion of proguanil. Surprisingly, proguanil
      did not enhance the ability of atovaquone to inhibit mitochondrial electron
      transport in malaria parasites. These results suggest that proguanil in its
      prodrug form acts in synergy with atovaquone by lowering the effective
      concentration at which atovaquone collapses DeltaPsim in malaria parasites. This
      could explain the paradoxical success of the atovaquone-proguanil combination
      even in regions where proguanil alone is ineffective due to resistance. The
      results also suggest that the atovaquone-proguanil combination may act as a site
      specific uncoupler of parasite mitochondria in a selective manner.

PMID- 10348750
TI  - Antimicrobial activities of amine- and guanidine-functionalized cholic acid
      derivatives.
AB  - Compounds in a series of cholic acid derivatives, designed to mimic the
      activities of polymyxin B and its derivatives, act as both potent antibiotics and
      effective permeabilizers of the outer membranes of gram-negative bacteria. Some
      of these compounds rival polymyxin B in antibacterial activity against gram
      negative bacteria and are also very active against gram-positive organisms. Other
      compounds interact synergistically with hydrophobic antibiotics to inhibit
      bacterial growth.

PMID- 10348749
TI  - Use of a genetic approach to evaluate the consequences of inhibition of efflux
      pumps in Pseudomonas aeruginosa.
AB  - Drug efflux pumps in Pseudomonas aeruginosa were evaluated as potential targets
      for antibacterial therapy. The potential effects of pump inhibition on
      susceptibility to fluoroquinolone antibiotics were studied with isogenic strains
      that overexpress or lack individual efflux pumps and that have various
      combinations of efflux- and target-mediated mutations. Deletions in three efflux
      pump operons were constructed. As expected, deletion of the MexAB-OprM efflux
      pump decreased resistance to fluoroquinolones in the wild-type P. aeruginosa (16
      fold reduction for levofloxacin [LVX]) or in the strain that overexpressed mexAB
      oprM operon (64-fold reduction for LVX). In addition to that, resistance to LVX
      was significantly reduced even for the strains carrying target mutations (64-fold
      for strains for which LVX MICs were >4 microg/ml). We also studied the
      frequencies of emergence of LVX-resistant variants from different deletion
      mutants and the wild-type strain. Deletion of individual pumps or pairs of the
      pumps did not significantly affect the frequency of emergence of resistant
      variants (at 4x the MIC for the wild-type strain) compared to that for the wild
      type (10(-6) to 10(-7)). In the case of the strain with a triple deletion, the
      frequency of spontaneous mutants was undetectable (<10(-11)). In summary,
      inhibition of drug efflux pumps would (i) significantly decrease the level of
      intrinsic resistance, (ii) reverse acquired resistance, and (iii) result in a
      decreased frequency of emergence of P. aeruginosa strains highly resistant to
      fluoroquinolones in clinical settings.

PMID- 10348751
TI  - Characterization and nucleotide sequence of a Klebsiella oxytoca cryptic plasmid
      encoding a CMY-type beta-lactamase: confirmation that the plasmid-mediated
      cephamycinase originated from the Citrobacter freundii AmpC beta-lactamase.
AB  - Plasmid pTKH11, originally obtained by electroporation of a Klebsiella oxytoca
      plasmid preparation into Escherichia coli XAC, expressed a high level of an AmpC
      like beta-lactamase. The enzyme, designated CMY-5, conferred resistance to
      extended-spectrum beta-lactams in E. coli; nevertheless, the phenotype was
      cryptic in the K. oxytoca donor. Determination of the complete nucleotide
      sequence of pTKH11 revealed that the 8,193-bp plasmid encoded seven open reading
      frames, including that for the CMY-5 beta-lactamase (blaCMY-5). The blaCMY-5
      product was similar to the plasmidic CMY-2 beta-lactamase of K. pneumoniae and
      the chromosomal AmpC of Citrobacter freundii, with 99.7 and 97.0% identities,
      respectively; there was a substitution of phenylalanine in CMY-5 for isoleucine
      105 in CMY-2. blaCMY-5 was followed by the Blc and SugE genes of C. freundii, and
      this cluster exhibited a genetic organization identical to that of the ampC
      region on the chromosome of C. freundii; these results confirmed that C. freundii
      AmpC was the evolutionary origin of the plasmidic cephamycinases. In the K.
      oxytoca host, the copy number of pTKH11 was very low and the plasmid coexisted
      with plasmid pNBL63. Analysis of the replication regions of the two plasmids
      revealed 97% sequence similarity in the RNA I transcripts; this result implied
      that the two plasmids might be incompatible. Incompatibility of the two plasmids
      might explain the cryptic phenotype of blaCMY-5 in K. oxytoca through an
      exclusion effect on pTKH11 by resident plasmid pNBL63.

PMID- 10348752
TI  - Serine protease inhibitors block invasion of host cells by Toxoplasma gondii.
AB  - We investigated the effect of protease inhibitors on the asexual development of
      the protozoan parasite Toxoplasma gondii. Among the inhibitors tested only two
      irreversible serine protease inhibitors, 3,4-dichloroisocoumarin and 4-(2
      aminoethyl)-benzenesulfonyl fluoride, clearly prevented invasion of the host
      cells by specifically affecting parasite targets in a dose-dependent manner, with
      50% inhibitory concentrations between 1 and 5 and 50 and 100 microM,
      respectively. Neither compound significantly affected parasite morphology, basic
      metabolism, or gliding motility within the range of the experimental conditions
      in which inhibition of invasion was demonstrated. No partial invasion was
      observed, meaning that inhibition occurred at an early stage of the interaction.
      These results suggest that at least one serine protease of the parasite is
      involved in the invasive process of T. gondii.

PMID- 10348753
TI  - OXA-17, a further extended-spectrum variant of OXA-10 beta-lactamase, isolated
      from Pseudomonas aeruginosa.
AB  - Pseudomonas aeruginosa isolates 871 and 873 were isolated at Hacettepe University
      Hospital in Ankara and were highly resistant to ceftazidime (MIC, 128 microg/ml).
      Each produced three beta-lactamases, with pIs of 5.3, 6.1, and 7.9. The beta
      lactamase with a pI of 5.3 was previously shown to be PER-1 enzyme. The
      antibiograms of the isolates were not entirely explained by production of PER-1
      enzyme, insofar as ceftazidime resistance was incompletely reversed by
      clavulanate. The enzymes with pIs of 6.1 and 7.9 were therefore investigated. The
      enzyme with a pI of 6.1 proved to be a novel mutant of OXA-10, which we
      designated OXA-17, and had asparagine changed to serine at position 73 of the
      protein. When cloned into Escherichia coli XL1-blue, OXA-17 enzyme conferred
      greater resistance to cefotaxime, latamoxef, and cefepime than did OXA-10, but it
      had only a marginal (two- to fourfold) effect on the MIC of ceftazidime. This
      behavior contrasted with that of previous OXA-10 mutants, specifically OXA-11, 
      14, and -16, which predominately compromise ceftazidime. Extracted OXA-17 enzyme
      had relatively greater activity than OXA-10 against oxacillin, cloxacillin, and
      cefotaxime but, in terms of kcat/Km, it had lower catalytic efficiency against
      most beta-lactams. The enzyme with a pI of 7.9 was shown by gene sequencing to be
      OXA-2.

PMID- 10348754
TI  - Erythromycin-resistant Neisseria gonorrhoeae and oral commensal Neisseria spp.
      carry known rRNA methylase genes.
AB  - Two Neisseria gonorrhoeae isolates from Seattle and two isolates from Uruguay
      were resistant to erythromycin (MIC, 4 to 16 microg/ml) and had reduced
      susceptibility to azithromycin (MIC, 1 to 4 microg/ml) due to the presence of the
      self-mobile rRNA methylase gene(s) ermF or ermB and ermF. The two Seattle
      isolates and one isolate from Uruguay were multiresistant, carrying either the
      25.2-MDa tetM-containing plasmid (Seattle) or a beta-lactamase plasmid (Uruguay).
      Sixteen commensal Neisseria isolates (10 Neisseria perflava-N. sicca, 2 N. flava,
      and 4 N. mucosa) for which erythromycin MICs were 4 to 16 microg/ml were shown to
      carry one or more known rRNA methylase genes, including ermB, ermC, and/or ermF.
      Many of these isolates also were multiresistant and carried the tetM gene. This
      is the first time that a complete transposon or a complete conjugative transposon
      carrying an antibiotic resistance gene has been described for the genus
      Neisseria.

PMID- 10348755
TI  - ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human
      immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical
      Trials Group Protocol 260 Team.
AB  - ACTG 260 was an open-label, four-arm trial designed to study the safety and anti
      human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at
      three ranges of concentrations in plasma compared to those of control therapy
      with zidovudine or didanosine. Delavirdine doses were adjusted weekly until
      subjects were within their target trough concentration range (3 to 10, 11 to 30,
      or 31 to 50 microM). A total of 113 subjects were analyzed. At week 2, the mean
      HIV type 1 (HIV-1) RNA level declines among the subjects in the three delavirdine
      arms were similar (0.87, 1.08, and 1.02 log10 for the low, middle, and high
      target arms, respectively), but by week 8, the subjects in the pooled delavirdine
      arms showed only a 0.10 log10 reduction. In the subjects in the nucleoside arm,
      mean HIV-1 RNA level reductions at weeks 2 and 8 were 0.67 and 0.55 log10,
      respectively. Because viral suppression by delavirdine was not maintained, the
      trial was stopped early. Rash, which was usually self-limited, developed in 36%
      of subjects who received delavirdine. Delavirdine monotherapy has potent anti-HIV
      activity at 2 weeks, but its activity is time limited due to the rapid emergence
      of drug resistance.

PMID- 10348756
TI  - Emergence of antibiotic-resistant Pseudomonas aeruginosa: comparison of risks
      associated with different antipseudomonal agents.
AB  - Pseudomonas aeruginosa is a leading cause of nosocomial infections. The risk of
      emergence of antibiotic resistance may vary with different antibiotic treatments.
      To compare the risks of emergence of resistance associated with four
      antipseudomonal agents, ciprofloxacin, ceftazidime, imipenem, and piperacillin,
      we conducted a cohort study, assessing relative risks for emergence of resistant
      P. aeruginosa in patients treated with any of these drugs. A total of 271
      patients (followed for 3,810 days) with infections due to P. aeruginosa were
      treated with the study agents. Resistance emerged in 28 patients (10.2%).
      Adjusted hazard ratios for the emergence of resistance were as follows:
      ceftazidime, 0.7 (P = 0.4); ciprofloxacin, 0.8 (P = 0.6); imipenem, 2.8 (P =
      0.02); and piperacillin, 1.7 (P = 0.3). Hazard ratios for emergence of resistance
      to each individual agent associated with treatment with the same agent were as
      follows: ceftazidime, 0.8 (P = 0.7); ciprofloxacin, 9.2 (P = 0.04); imipenem, 44
      (P = 0.001); and piperacillin, 5.2 (P = 0.01). We concluded that there were
      evident differences among antibiotics in the likelihood that their use would
      allow emergence of resistance in P. aeruginosa. Ceftazidime was associated with
      the lowest risk, and imipenem had the highest risk.

PMID- 10348757
TI  - The trailing end point phenotype in antifungal susceptibility testing is pH
      dependent.
AB  - The interpretation of end points in azole antifungal drug susceptibility testing
      is problematic, in part due to incomplete growth inhibition of Candida species.
      Such trailing growth can cause the MICs of fluconazole for some isolates to be
      low (<1 microg/ml) after 24 h of growth but much higher (>64 microg/ml) after 48
      h. Isolates having this type of growth have been described as having a low-high
      phenotype. Although these isolates would be considered resistant by current
      National Committee of Clinical Laboratory Standards definitions, growing evidence
      suggests that they are susceptible in vivo. To further characterize these
      isolates in vitro, microdilution susceptibility testing comparing the complex
      defined medium RPMI 1640 to a defined minimal medium (yeast nitrogen broth) was
      performed. Isolates having trailing growth in MOPS (morpholinepropanesulfonic
      acid)-buffered RPMI 1640 (pH 7.0) were found to have clear end points in the
      minimal medium at its native pH of 4.5. The pH of the medium influenced the low
      high phenotype, as these same isolates trailed in minimal medium adjusted to a pH
      of >/=6.0 but did not trail in RPMI 1640 adjusted to a pH of </=5.0. This pH
      effect was independent of the medium buffering capacity, as trailing was
      decreased in both minimal medium and RPMI 1640 (pH 4.5) buffered in citrate.
      Adjustment in the pH of MOPS-buffered RPMI 1640 reduced trailing in multiple
      strains of Candida albicans without affecting the MICs for isolates having known
      susceptible (low-low) and resistant (high-high) phenotypes. Adjustment of the
      medium pH could be considered to eliminate trailing in azole drug susceptibility
      testing.

PMID- 10348758
TI  - Activities of beta-lactams and macrolides against Helicobacter pylori.
AB  - A continuous-culture system (chemostat) was used to study the activities of beta
      lactam antimicrobial agents, clarithromycin, and 14-OH-clarithromycin against
      slowly growing Helicobacter pylori NCTC 11637. H. pylori was grown to steady
      state before exposure to these antimicrobial agents at x8 the MIC. The
      bactericidal actions of combinations of amoxicillin and clarithromycin were also
      studied. Viable counts (numbers of CFU per milliliter) were determined at 2-h
      intervals for 12 h and at 20 h after the addition of antibiotics. The effects of
      pH changes (6.5 to 7.4) on the activities of amoxicillin, clarithromycin, and the
      combination of these against H. pylori NCTC 11637 were also studied. Viable
      counts following exposure to ampicillin, cefixime, ceftazidime, cefuroxime,
      cefotaxime, azlocillin, and piperacillin at 20 h showed bacteriostatic activity.
      Imipenem, meropenem, amoxicillin, clarithromycin, and 14-OH-clarithromycin
      reduced the viable counts by 3 log10 CFU/ml (>/=99.9% killing). Imipenem was the
      most rapidly bactericidal against H. pylori NCTC 11637. Results of the pH
      experiments showed that amoxicillin was bactericidal at pHs 6.5 to 7. 4.
      Clarithromycin was bactericidal at pH 7.0 to 7.4 but was bacteriostatic at pH
      6.5. The combination of amoxicillin and clarithromycin was bactericidal at pHs
      6.5 and 7.0. A batch culture (flask system) was also used to investigate 12
      strains of H. pylori for their susceptibilities to beta-lactams, clarithromycin,
      and/or 14-OH-clarithromycin in order to determine whether results from the
      chemostat model can be reproduced with batch cultures. Results of the chemostat
      time-kill kinetic study were reproducible in our batch culture flask system. The
      role of carbapenems in the eradication of H. pylori should be investigated.

PMID- 10348759
TI  - Use of microdilution panels with and without beta-lactamase inhibitors as a
      phenotypic test for beta-lactamase production among Escherichia coli, Klebsiella
      spp., Enterobacter spp., Citrobacter freundii, and Serratia marcescens.
AB  - Over the past decade, a number of new beta-lactamases have appeared in clinical
      isolates of Enterobacteriaceae that, unlike their predecessors, do not confer
      beta-lactam resistance that is readily detected in routine antibiotic
      susceptibility tests. Because optimal methodologies are needed to detect these
      important new beta-lactamases, a study was designed to evaluate the ability of a
      panel of various beta-lactam antibiotics tested alone and in combination with
      beta-lactamase inhibitors to discriminate between the production of extended
      spectrum beta-lactamases, AmpC beta-lactamases, high levels of K1 beta-lactamase,
      and other beta-lactamases in 141 isolates of Escherichia coli, Klebsiella
      pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter aerogenes,
      Citrobacter freundii, and Serratia marcescens possessing well-characterized beta
      lactamases. The microdilution panels studied contained aztreonam, cefpodoxime,
      ceftazidime, cefotaxime, and ceftriaxone, with and without 1, 2, and 4 microg of
      clavulanate per ml or 8 microg of sulbactam per ml and cefoxitin and cefotetan
      with and without 8 microg of sulbactam per ml. The results indicated that a
      minimum panel of five tests would provide maximum separation of extended-spectrum
      beta-lactamase high AmpC, high K1, and other beta-lactamase production in
      Enterobacteriaceae. These included cefpodoxime, cefpodoxime plus 4 microg of
      clavulanate per ml, ceftazidime, ceftriaxone, and ceftriaxone plus 8 microg of
      sulbactam per ml. Ceftriaxone plus 2 microg of clavulanate per ml could be
      substituted for cefpodoxime plus 4 microg of clavulanate per ml without altering
      the accuracy of the tests. This study indicated that tests with key beta-lactam
      drugs, alone and in combination with beta-lactamase inhibitors, could provide a
      convenient approach to the detection of a variety of beta-lactamases in members
      of the family Enterobacteriaceae.

PMID- 10348760
TI  - In vitro antifungal activity of nikkomycin Z in combination with fluconazole or
      itraconazole.
AB  - Nikkomycins are nucleoside-peptide antibiotics produced by Streptomyces species
      with antifungal activities through the inhibition of chitin synthesis. We
      investigated the antifungal activities of nikkomycin Z alone and in combination
      with fluconazole and itraconazole. Checkerboard synergy studies were carried out
      by a macrobroth dilution procedure with RPMI 1640 medium at pH 6.0. At least 10
      strains of the following fungi were tested: Candida albicans, other Candida spp.,
      Cryptococcus neoformans, Coccidioides immitis, Aspergillus spp., and dematiacious
      fungi (including Exophiala jeanselmei, Exophiala spinifera, Bipolaris spicifera,
      Wangiella dermatitidis, Ochroconis humicola, Phaeoannellomyces werneckii, and
      Cladophialophora bantiana), and 2 strains each of Fusarium, Scedosporium,
      Paecilomyces, Penicillium, and Trichoderma spp. A total of 110 isolates were
      examined. Inocula of fungal elements were standardized by hemacytometer counting
      or spectrophotometrically. MICs and minimum lethal concentrations (MLCs) were
      determined visually by comparison of growth in drug-treated tubes with growth in
      drug-free control tubes. Additive and synergistic interactions between nikkomycin
      and either fluconazole or itraconazole were observed against C. albicans, Candida
      parapsilosis, Cryptococcus neoformans, and Coccidioides immitis. Marked synergism
      was also observed between nikkomycin and itraconazole against Aspergillus
      fumigatus and Aspergillus flavus. No antagonistic interaction between the drugs
      was observed with any of the strains tested.

PMID- 10348761
TI  - In vivo efficacies of combinations of beta-lactams, beta-lactamase inhibitors,
      and rifampin against Acinetobacter baumannii in a mouse pneumonia model.
AB  - The effects of various regimens containing combinations of beta-lactams, beta
      lactam inhibitor(s), and rifampin were assessed in a recently described mouse
      model of Acinetobacter baumannii pneumonia (M. L. Joly-Guillou, M. Wolff, J. J.
      Pocidalo, F. Walker, and C. Carbon, Antimicrob. Agents Chemother. 41:345-351,
      1997). Two aspects of the therapeutic response were studied: the kinetics of the
      bactericidal effect (treatment was initiated 3 h after intratracheal inoculation,
      and bacterial counts were determined over a 24-h period) and survival (treatment
      was initiated 8 h after inoculation, and the cumulative mortality rate was
      assessed on day 5). Two clinical strains were used: a cephalosporinase-producing
      strain (SAN-94040) and a multiresistant strain (RCH-69). For SAN-94040 and RCH
      69, MICs and MBCs (milligrams per liter) were as follows: ticarcillin, 32, 64,
      256, and >256, respectively; ticarcillin-clavulanate, 32, 64, and 512, and >512,
      respectively; imipenem, 0.5, 0.5, 8, and 32, respectively; sulbactam, 0.5, 0.5,
      8, and 8, respectively; and rifampin, 8, 8, 4, and 4, respectively. Against SAN
      94040, four regimens, i.e., imipenem, sulbactam, imipenem-rifampin, and
      ticarcillin-clavulanate (at a 25/1 ratio)-sulbactam produced a true bactericidal
      effect (>/=3-log10 reduction of CFU/g of lung). The best survival rate (i.e.,
      93%) was obtained with the combination of ticarcillin-clavulanate-sulbactam, and
      regimens containing rifampin provided a survival rate of >/=65%. Against RCH-69,
      only regimens containing rifampin and the combination of imipenem-sulbactam had a
      true bactericidal effect. The best survival rates (>/=80%) were obtained with
      regimens containing rifampin and sulbactam. These results suggest that
      nonclassical combinations of beta-lactams, beta-lactamase inhibitors, and
      rifampin should be considered for the treatment of nosocomial pneumonia due to A.
      baumannii.

PMID- 10348762
TI  - Randomized, placebo-controlled, double-blind trial to evaluate the efficacy of
      mupirocin for eradicating carriage of methicillin-resistant Staphylococcus
      aureus.
AB  - Mupirocin has been widely used for the clearance of nasal methicillin-resistant
      Staphylococcus aureus (MRSA) carriage during outbreaks, but no placebo-controlled
      trial has evaluated its value for eradicating MRSA carriage at multiple body
      sites in settings where MRSA is not epidemic. In a 1,500-bed teaching hospital
      with endemic MRSA, 102 patients colonized with MRSA were randomized into a double
      blind, placebo-controlled trial and treated with either mupirocin (group M) or
      placebo (group P) applied to the anterior nares for 5 days; both groups used
      chlorhexidine soap for body washing. Follow-up screening, susceptibility testing,
      and genotyping were performed to evaluate treatment success, mupirocin or
      chlorhexidine resistance, and exogenous recolonization. At baseline, MRSA
      carriage was 60% in the nares, 38% in the groin, and 62% in other sites (skin
      lesions, urine). The MRSA eradication rate (all body sites) was 25% in group M
      (12 of 48 patients), compared to 18% in group P (9 of 50 patients; relative risk
      [RR], 0.72; 95% confidence interval [CI95], 0.33 to 1.55). At the end of follow
      up, 44% of patients (19 of 43) were free of nasal MRSA in group M, compared to
      23% (11 of 44) in group P (RR, 0.57; CI95, 0.31 to 1.04). Ten patients developed
      MRSA infections (three in group M and seven in group P). One mupirocin treatment
      failure was due to exogenous MRSA recolonization. No MRSA isolate showed
      chlorhexidine resistance or high-level mupirocin resistance; however, we observed
      an association (P = 0.003) between low-level mupirocin resistance at study entry
      (prevalence, 23%) and subsequent treatment failure in both study arms. These
      results suggest that nasal mupirocin is only marginally effective in the
      eradication of multisite MRSA carriage in a setting where MRSA is endemic.

PMID- 10348763
TI  - Amphotericin B in children with malignant disease: a comparison of the toxicities
      and pharmacokinetics of amphotericin B administered in dextrose versus lipid
      emulsion.
AB  - In a prospective, randomized clinical trial, the toxicity of 1 mg of amphotericin
      B (AmB) per kg of body weight per day infused in 5% dextrose was compared with
      that of AmB infused in lipid emulsion in children with malignant disease. In an
      analysis of 82 children who received a full course of 6 days or more of AmB (117
      courses), it was shown that there were significant increases in plasma urea and
      creatinine concentrations and in potassium requirement after 6 days of therapy
      with both AmB infused in dextrose and AmB infused in lipid emulsion, with there
      being no difference between the two methods of AmB administration. An intent-to
      treat comparison of the numbers of courses affected by acute toxicity (fever,
      rigors) and chronic toxicity (nephrotoxicity) also indicated that there was no
      significant difference between AmB infused in dextrose (78 courses) and AmB
      infused in lipid emulsion (84 courses). The pharmacokinetics of AmB were
      investigated in 20 children who received AmB in dextrose and 15 children who
      received AmB in lipid emulsion. Blood samples were collected up to 24 h after
      administration of the first dose, and the concentration of AmB in plasma was
      analyzed by a high-performance liquid chromatography assay. The clearance (CL) of
      AmB in dextrose (0.039 +/- 0.016 liter. h-1. kg-1) was significantly lower (P <
      0.005) than the CL of AmB in lipid emulsion (0.062 +/- 0. 024 liter. h-1. kg-1).
      The steady-state volume of distribution for AmB in dextrose (0.83 +/- 0.33 liter.
      kg-1) was also significantly lower (P < 0.005) than that for AmB in lipid
      emulsion (1.47 +/- 0.77 liter. kg-1). Although AmB in lipid emulsion is
      apparently cleared faster and distributes more widely than AmB in dextrose, this
      study did not reveal any significant advantage with respect to safety and
      tolerance in the administration of AmB in lipid emulsion compared to its
      administration in dextrose in children with malignant disease.

PMID- 10348764
TI  - Species differences in the proportion of plasma lipoprotein lipid carried by high
      density lipoproteins influence the distribution of free and liposomal nystatin in
      human, dog, and rat plasma.
AB  - The objective of this study was an interspecies comparison of free nystatin (NYS)
      and liposomal NYS (Nyotran) distribution in plasma. NYS and liposomal NYS at
      concentrations of 5, 10, and 20 microg of NYS/ml were incubated in human, dog,
      and rat plasma for 5, 60, and 180 min at 37 degrees C. Following these
      incubations, plasma samples were separated into their high-density lipoprotein
      (HDL), triglyceride-rich lipoprotein, low-density lipoprotein, and lipoprotein
      deficient plasma (LPDP) fractions by density-gradient ultracentrifugation, and
      each fraction was assayed for NYS by high-pressure liquid chromatography. Total
      plasma and lipoprotein cholesterol, triglyceride, and protein concentrations in
      each human, dog, or rat plasma sample were determined by enzymatic assays. When
      NYS and liposomal NYS were incubated in human, dog, or rat plasma, the majority
      of the NYS was recovered in the LPDP fraction. For the 5- and 60-min incubation
      times for all plasmas measured, a significantly greater percentage of NYS was
      recovered in the lipoprotein fraction (primarily HDL) following the incubation of
      liposomal NYS than following the incubation of NYS. There was a significant
      correlation between the lipoprotein lipid and protein profiles in human, dog, and
      rat plasmas and the distribution of NYS and liposomal NYS in plasma. In
      particular, differences in the proportion of plasma lipoprotein cholesterol,
      triglyceride, and apolar lipids (cholesteryl ester and triglycerides) carried by
      HDL influenced the distribution of NYS and liposomal NYS within plasmas of
      different species. These findings suggest that the distribution of NYS among
      plasma lipoproteins of different species is defined by the proportion of lipid
      carried by HDL, and this is possibly an important consideration when evaluating
      the pharmacokinetics, toxicities, and activities of these compounds following
      administration to different animal species.

PMID- 10348765
TI  - Characterization of novel antimicrobial peptoids.
AB  - Peptoids differ from peptides in that peptoids are composed of N-substituted
      rather than alpha-carbon-substituted glycine units. In this paper we report the
      in vitro and in vivo antibacterial activities of several antibacterial peptoids
      discovered by screening combinatorial chemistry libraries for bacterial growth
      inhibition. In vitro, the peptoid CHIR29498 and some of its analogues were active
      in the range of 3 to 12 microg/ml against a panel of gram-positive and gram
      negative bacteria which included isolates which were resistant to known
      antibiotics. Peptoid antimicrobial activity against Staphylococcus aureus was
      rapid, bactericidal, and independent of protein synthesis. beta-Galactosidase and
      propidium iodide leakage assays indicated that the membrane is the most likely
      target of activity. Positional isomers of an active peptoid were also active,
      consistent with a mode of action, such as membrane disruption, that does not
      require a specific fit between the molecule and its target. In vivo, CHIR29498
      protected S. aureus-infected mice in a simple infection model.

PMID- 10348766
TI  - In vitro activities of designed antimicrobial peptides against multidrug
      resistant cystic fibrosis pathogens.
AB  - The emergence of multidrug-resistant pathogens renders antibiotics ineffective in
      the treatment of lung infections in patients with cystic fibrosis (CF). Designed
      antimicrobial peptides (DAPs) are laboratory-synthesized peptide antibiotics that
      demonstrate a wide spectrum of antibacterial activity. Optimal conditions for
      susceptibility testing of these peptides have not yet been established. Medium
      composition is clearly a major factor influencing the results and
      reproducibilities of susceptibility tests. Using time-kill assays, we tested the
      effects of different media and buffers on the bactericidal activities of the
      peptides D2A21 and D4E1 on Staphylococcus aureus ATCC 29213 and Pseudomonas
      aeruginosa ATCC 27853. Each peptide at 1 and 5 microM was incubated with bacteria
      in the different media and buffers. Both peptides were most active in Tris-HCl
      buffer against S. aureus and P. aeruginosa. Among the more complex media tested,
      modified RPMI medium was the medium in which the peptides demonstrated the
      highest activity, while it supported the growth of the bacteria. The broth
      microdilution technique was used to test the activities of D2A21 and D4E1 in
      modified RPMI medium against multidrug-resistant pathogens from patients with CF.
      The MICs of DAPs for methicillin-resistant S. aureus ranged from 0.25 to 4
      microg/ml, those for multidrug-resistant P. aeruginosa ranged from 0.125 to 4
      microg/ml, those for Stenotrophomonas maltophilia ranged from 0.5 to 32
      microg/ml, and those for Burkholderia cepacia ranged from 32 to >/=64 microg/ml.
      When the activity of peptide D2A21 was compared with that of the tracheal
      antimicrobial peptide (TAP), D2A21 had greater potency than TAP against P.
      aeruginosa. In addition, no difference in the MICs of D2A21 was seen when it was
      tested in nutrient broth supplemented with NaCl at different concentrations.
      Thus, DAPs are a class of salt-insensitive antibiotics potentially useful in the
      treatment of CF patients harboring multidrug-resistant P. aeruginosa.

PMID- 10348767
TI  - Azithromycin versus ciprofloxacin for treatment of uncomplicated typhoid fever in
      a randomized trial in Egypt that included patients with multidrug resistance.
AB  - To compare clinical and bacteriological efficacies of azithromycin and
      ciprofloxacin for typhoid fever, 123 adults with fever and signs of uncomplicated
      typhoid fever were entered into a randomized trial. Cultures of blood were
      positive for Salmonella typhi in 59 patients and for S. paratyphi A in 3 cases;
      stool cultures were positive for S. typhi in 11 cases and for S. paratyphi A in 1
      case. Multiple-drug resistance (MDR; resistance to ampicillin, chloramphenicol,
      and trimethoprim-sulfamethoxazole) was present in isolates of 21 of 64 patients
      with positive cultures. Of these 64 patients, 36 received 1 g of azithromycin
      orally once on the first day, followed by 500 mg given orally once daily on the
      next 6 days; 28 patients received 500 mg of ciprofloxacin orally twice daily for
      7 days. Blood cultures were repeated on days 4 and 10 after the start of therapy,
      and stool cultures were done on days 4, 10, and 28 after the start of therapy.
      All patients in both groups improved during therapy and were cured. Defervescence
      (maximum daily temperatures of </=38 degrees C) occurred at the following times
      [mean +/- standard deviation (range)] after the start of therapy: 3.8 +/- 1.1 (2
      to 7) days with azithromycin and 3.3 +/- 1.0 (1 to 5) days with ciprofloxacin. No
      relapses were detected. Cultures of blood and stool during and after therapy were
      negative in all cases, except for one patient treated with azithromycin who had a
      positive blood culture on day 4. These results indicated that azithromycin and
      ciprofloxacin were similarly effective, both clinically and bacteriologically,
      against typhoid fever caused by both sensitive organisms and MDR S. typhi.

PMID- 10348768
TI  - Comparison of the toxicity of amphotericin B in 5% dextrose with that of
      amphotericin B in fat emulsion in a randomized trial with cancer patients.
AB  - A multicentric randomized trial was undertaken to compare the toxicity of
      amphotericin B in 5% dextrose with that of amphotericin B in a fat emulsion
      (Intralipid) in cancer patients. Group 1 (n = 33) received amphotericin B diluted
      in 5% dextrose with premedication consisting of promethazine plus an antipyretic.
      Group 2 (n = 28) received amphotericin B diluted in 20% Intralipid without
      premedication. Amphotericin B was infused daily at a dose of 1 mg/kg of body
      weight over a 1-h period to members of both groups for empirical antifungal
      therapy (in neutropenic patients) or for the treatment of documented fungal
      infections. The majority of patients (80%) received empirical amphotericin B
      treatment. The two groups were comparable with regard to age, gender, underlying
      disease, and the following baseline characteristics: use of other nephrotoxic
      drugs and serum levels of potassium and creatinine. The median cumulative doses
      of amphotericin B were 240 mg in group 1 and 245 mg in group 2 (P = 0.73). Acute
      adverse events occurred in 88% of patients in group 1 and in 71% of those in
      group 2 (P = 0.11). Forty percent of the infusions in group 1 were associated
      with fever, compared to 23% in group 2 (P < 0.0001). In addition, patients in
      group 2 required less meperidine for the control of acute adverse events (P =
      0.008), and fewer members of this group presented with hypokalemia (P = 0.004) or
      rigors (P < 0.0001). There was no difference in the proportions of patients with
      nephrotoxicity (P = 0.44). The success rates of empirical antifungal treatment
      were similar in the two groups (P = 0.9). Amphotericin B diluted in a lipid
      emulsion seems to be associated with a smaller number of acute adverse events and
      fewer cases of hypokalemia than amphotericin B diluted in 5% dextrose.

PMID- 10348769
TI  - Cloning and nucleotide sequence determination of the entire mec DNA of pre
      methicillin-resistant Staphylococcus aureus N315.
AB  - In methicillin-resistant Staphylococcus aureus, the methicillin resistance gene
      mecA is localized within a large chromosomal region which is absent in the
      methicillin-susceptible S. aureus chromosome. The region, designated mec DNA, is
      speculated to have originated from the genome of another bacterial species and
      become integrated into the chromosome of the S. aureus cell in the past. We
      report here cloning and determination of the structure of the entire mec DNA
      sequence from a Japanese S. aureus strain, N315. The mec DNA was found to be
      51,669 bp long, including terminal inverted repeats of 27 bp and a characteristic
      pair of direct repeat sequences of 15 bp each: one is situated in the right
      extremity of mec DNA, and the other is situated outside the mec DNA and abuts the
      left boundary of mec DNA. The integration site of mec DNA was found to be located
      in an open reading frame (ORF) of unknown function, designated orfX. Clusters of
      antibiotic resistance genes were noted in mec DNA carried by transposon Tn554 and
      an integrated copy of plasmid pUB110. Both the transposon and plasmid were
      integrated in the proximity of the mecA gene, the latter being flanked by a pair
      of insertion sequence IS431 elements. Many ORFs other than those encoding
      antibiotic resistance were considered nonfunctional because of the acquired
      mutations or partial deletions found in the ORFs. Two ORFs potentially encoding
      novel site-specific recombinases were found in mec DNA. However, there was no ORF
      that might encode mec DNA-specific transposase or integrase proteins, indicating
      that the mec DNA is not a transposon or a bacteriophage in nature.

PMID- 10348770
TI  - Outer membrane permeability barrier in Escherichia coli mutants that are
      defective in the late acyltransferases of lipid A biosynthesis.
AB  - The tight packing of six fatty acids in the lipid A constituent of
      lipopolysaccharide (LPS) has been proposed to contribute to the unusually low
      permeability of the outer membrane of gram-negative enteric bacteria to
      hydrophobic antibiotics. Here it is shown that the Escherichia coli msbB mutant,
      which elaborates defective, penta-acylated lipid A, is practically as resistant
      to a representative set of hydrophobic solutes (rifampin, fusidic acid,
      erythromycin, clindamycin, and azithromycin) as the parent-type control strain.
      The susceptibility index, i.e., the approximate ratio between the MIC for the
      msbB mutant and that for the parent-type control, was maximally 2.7-fold. In
      comparison, the rfa mutant defective in the deep core oligosaccharide part of LPS
      displayed indices ranging from 20 to 64. The lpxA and lpxD lipid A mutants had
      indices higher than 512. Furthermore, the msbB mutant was resistant to
      glycopeptides (vancomycin, teicoplanin), whereas the rfa, lpxA, and lpxD mutants
      were susceptible. The msbB htrB double mutant, which elaborates even-more
      defective, partially tetra-acylated lipid A, was still less susceptible than the
      rfa mutant. These findings indicate that hexa-acylated lipid A is not a
      prerequisite for the normal function of the outer membrane permeability barrier.

PMID- 10348771
TI  - In vitro susceptibilities of Candida and Cryptococcus neoformans isolates from
      blood cultures of neutropenic patients.
AB  - Fluconazole-resistant Candida albicans and intrinsically fluconazole-resistant
      Candida species have been reported as bloodstream isolates. However, an
      association between the isolation of fluconazole-resistant Candida from the
      bloodstream and patient risk factors for fungemia has not been established. The
      purpose of this study was to determine the prevalence of fluconazole resistance
      in bloodstream isolates of Candida species and Cryptococcus neoformans collected
      from patients with neutropenia, one of the most important risk factors for
      fungemia. MICs of voriconazole, fluconazole, itraconazole, ketoconazole,
      amphotericin B, and flucytosine were determined by the National Committee for
      Clinical Laboratory Standards M27-A method (1997). Voriconazole, on a per-weight
      basis, was the most active azole tested. Fluconazole resistance (MIC >/= 64
      microg/ml) was not identified in any of the C. albicans (n = 513), Candida
      parapsilosis (n = 78), Candida tropicalis (n = 62), or C. neoformans (n = 38)
      isolates tested.

PMID- 10348772
TI  - Piperacillin and tazobactam exhibit linear pharmacokinetics after multiple
      standard clinical doses.
AB  - A population pharmacokinetic (PK) analysis was conducted to determine if
      piperacillin and tazobactam exhibited linear or nonlinear PKs and if incremental
      changes in the daily dosage of piperacillin affected tazobactam PKs. Four dosage
      groups were evaluated after multiple dosing regimens. Concentrations of drug in
      plasma and amounts in urine were best fitted by using a linear two-compartment PK
      model. No significant difference between dosing groups was seen for any
      piperacillin or tazobactam PK parameters. Both drugs exhibited linear PKs when
      given at usual clinical doses. Tazobactam PKs did not appear to be affected by
      the different dosing regimens of piperacillin.

PMID- 10348773
TI  - Linezolid activity compared to those of selected macrolides and other agents
      against aerobic and anaerobic pathogens isolated from soft tissue bite infections
      in humans.
AB  - Linezolid was tested against 420 aerobes and anaerobes, including 148 Pasteurella
      isolates, by an agar dilution method. Linezolid was active against all
      Pasteurella multocida subsp. multocida and P. multocida subsp. septica isolates
      and most Pasteurella canis, Pasteurella dagmatis, and Pasteurella stomatis
      isolates. The MIC was </=2 microg/ml for staphylococci, streptococci, EF-4b,
      Weeksella zoohelcum, Fusobacterium nucleatum, other fusobacteria, Porphyromonas
      spp., Prevotella spp., peptostreptococci, and almost all Bacteroides tectum
      isolates.

PMID- 10348774
TI  - Activity of gatifloxacin compared to those of five other quinolones versus
      aerobic and anaerobic isolates from skin and soft tissue samples of human and
      animal bite wound infections.
AB  - The activity of gatifloxacin against 308 aerobes and 112 anaerobes isolated from
      bite wound infections was studied. Gatifloxacin was active at </=0.016 microg/ml
      against all 148 Pasteurella isolates (eight species and three subspecies) tested
      and all other aerobes tested, including Actinobacillus-Haemophilus spp.,
      Eikenella corrodens, Neisseria weaveri, Weeksella zoohelcum, staphylococci, and
      streptococci. Fusobacteria were sometimes resistant. Gatifloxacin MICs at which
      90% of the isolates were inhibited were 0. 125 microg/ml against Bacteroides
      tectum and Prevotella spp., 0.25 microg/ml against Porphyromonas spp., and 0.5
      microg/ml against peptostreptococci.

PMID- 10348775
TI  - Emergence in france of multiple clones of clinical Streptococcus pneumoniae
      isolates with high-level resistance to amoxicillin.
AB  - The genetic relatedness of French isolates of Streptococcus pneumoniae highly
      resistant to amoxicillin (MIC, >/=4 microg/ml, equal to or exceeding those of
      penicillin) was investigated by molecular fingerprinting. The results suggest
      that high-level resistance to amoxicillin has emerged within preexisting
      penicillin-resistant clones.

PMID- 10348776
TI  - Subpopulations of Helicobacter pylori are responsible for discrepancies in the
      outcome of nitroimidazole susceptibility testing.
AB  - Metronidazole susceptibility testing by E test was compared to that by disk
      diffusion for 263 Helicobacter pylori isolates and to that by breakpoint agar
      dilution for 90 H. pylori isolates. In 5% and 6% of the cases, respectively,
      results were discrepant. For each of 52 clinical isolates an E test was performed
      on 10 separate colonies. Subpopulations of resistant and susceptible bacteria
      were found in five cases. From three isolates, each colony was subcultured and
      tested up to 10 times. All but 1 of 292 tests showed the same result. We conclude
      that the E test is reliable and that subpopulations are responsible for
      discordant results.

PMID- 10348777
TI  - In vitro anti-human immunodeficiency virus activities of Z- and E
      methylenecyclopropane nucleoside analogues and their phosphoro-L-alaninate
      diesters.
AB  - Nucleoside analogues with a Z- or an E-methylenecyclopropane moiety were
      synthesized and examined for activity against human immunodeficiency virus type 1
      (HIV-1) in vitro. The addition of a methyl phenyl phosphoro-L-alaninate moiety to
      modestly active analogues resulted in potentiation of their anti-HIV-1 activity.
      Two such compounds, designated QYL-685 (with 2,6-diaminopurine) and QYL-609 (with
      adenine), were most potent against HIV-1 in vitro, with 50% inhibitory
      concentrations of 0.034 and 0.0026 microM, respectively, in MT-2 cell-based
      assays. Both compounds were active against zidovudine-resistant, didanosine
      resistant, and multi-dideoxynucleoside-resistant infectious clones in vitro.
      Further development of these analogues as potential therapies for HIV-1 infection
      is warranted.

PMID- 10348778
TI  - Effect of azithromycin plus rifampin versus that of azithromycin alone on the
      eradication of Chlamydia pneumoniae from lung tissue in experimental pneumonitis.
AB  - Azithromycin, doxycycline, and rifampin, alone or in combination, were tested in
      vitro against Chlamydia pneumoniae AR-39. The combination of azithromycin plus
      rifampin showed the strongest activity and produced higher rates of eradication
      of C. pneumoniae from lung tissues than azithromycin alone in experimental mouse
      pneumonitis.

PMID- 10348779
TI  - Effect of HSR-903, a new fluoroquinolone, on the concentration of theophylline in
      serum.
AB  - The effect of HSR-903, a new fluoroquinolone, on the concentration of
      theophylline in serum in healthy male volunteers was investigated. The
      concentration of theophylline in serum and the urinary excretion rates of
      theophylline on day 5 of concomitant dosing with HSR-903 tended to increase
      compared to those on day 4, when theophylline was given alone; however, the
      urinary excretion rates of 1-methyluric acid and 3-methylxanthine on day 5 of
      concomitant dosing with HSR-903 tended to decrease in comparison to those on day
      4, when theophylline was given alone.

PMID- 10348780
TI  - Rifampin and rifabutin resistance mechanism in Helicobacter pylori.
AB  - Eighty-one clinical isolates of Helicobacter pylori showed no resistance to
      rifampin (MIC range, 0.032 to 2 microg/ml; MIC at which 50% of isolates are
      inhibited [MIC50], 0.25 microg/ml). The MIC50 of rifabutin was 0.008 microg/ml (n
      = 16). All resistant laboratory mutants of H. pylori ATCC 43504 showed amino acid
      exchanges in codons 524 to 545 or codon 585 of the rpoB gene, corresponding to
      the gene sequences from Mycobacterium tuberculosis and Escherichia coli.

PMID- 10348781
TI  - Interstrain variation in the human cytomegalovirus DNA polymerase sequence and
      its effect on genotypic diagnosis of antiviral drug resistance. Adult AIDS
      Clinical Trials Group CMV Laboratories.
AB  - The polymerase (pol) coding sequence was determined for 40 independent clinical
      cytomegalovirus isolates sensitive to ganciclovir and foscarnet. Sequence
      alignments showed >98% interstrain homology and amino acid variation in only 4%
      of the 1, 237 codons. Almost all variation occurred outside of conserved
      functional domains where resistance mutations have been identified.

PMID- 10348782
TI  - Pharmacokinetics and pharmacodynamics of amoxicillin-sulbactam, a novel
      aminopenicillin-beta-lactamase inhibitor combination, against Escherichia coli.
AB  - We evaluated the pharmacokinetics of amoxicillin-sulbactam (AMX-SUL), a novel
      drug combination, and its pharmacodynamics against Escherichia coli in 12
      volunteers receiving a single oral dose (1, 000 mg). Peak serum bactericidal and
      urine inhibitory activities in most volunteers were observed against E. coli
      strains for which AMX-SUL MICs were low (2- to 4-mg/liter) (2 strains) and high
      (>/=16-mg/liter) (47 strains), respectively.

PMID- 10348784
TI  - Pharmacokinetics and inflammatory-fluid penetration of moxifloxacin following
      oral or intravenous administration.
AB  - A single 400-mg oral or intravenous (i.v.) dose of moxifloxacin was given to each
      of eight healthy male volunteers, and 6 weeks later the dose was administered by
      the other route. The concentrations of the drug in plasma, cantharidin-induced
      inflammatory fluid, and urine were measured over the subsequent 24 h. The mean
      maximum concentrations observed in plasma were 4.98 microg/ml after oral dosing
      and 5.09 microg/ml after i.v. dosing. The mean maximum concentrations attained in
      the inflammatory fluid were 2.62 and 3.23 microg/ml, respectively. The mean
      elimination half-lives from plasma were 8.32 and 8.17 h, respectively. The
      overall penetration into the inflammatory fluid was 103.4 and 104.2%. Over 24 h
      15% of the drug was recovered in the urine when administered by either route.

PMID- 10348783
TI  - Molecular characterization of multidrug resistance in Streptococcus mitis.
AB  - Antimicrobial resistance was characterized for 14 strains of Streptococcus mitis.
      HinfI restriction fragment length mapping of gyrA PCR amplicons from three
      ciprofloxacin-resistant isolates correlated with mutations associated with such
      resistance in other organisms. By using PCR, seven erythromycin-resistant strains
      were found to possess either the mef or ermB gene. Hybridization revealed tet(M)
      in seven tetracycline-resistant isolates.

PMID- 10348785
TI  - Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of
      fluoroquinolones in rats.
AB  - The in vivo convulsant activities in rats of five representative fluoroquinolones
      (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were
      compared. The experimental approach allowed distinction between the drugs'
      ability to reach the pharmacological receptors at the level of the central
      nervous system (pharmacokinetic contribution) and their ability to interact with
      these receptors (pharmacodynamic contribution). The presence of a methyl group on
      the piperazine moiety decreased the pharmacodynamic contribution to the
      convulsant activity by severalfold, and the ratios of concentrations of the FQs
      in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied
      from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the
      highest intrinsic convulsant activities had the lowest levels of diffusion in CSF
      and vice versa. This in vivo approach provides information complementary to that
      of in vitro experiments and should be recommended for early preclinical
      assessment of a new FQ's epileptogenic risk.

PMID- 10348786
TI  - Pharmacokinetics of azithromycin administered alone and with atovaquone in human
      immunodeficiency virus-infected children. The ACTG 254 Team.
AB  - To evaluate if atovaquone (ATQ) interacts pharmacokinetically with azithromycin
      (AZ) in human immunodeficiency virus-infected children, 10 subjects (ages, 4 to
      13 years) were randomized in a crossover study to receive AZ (5 mg/kg/day) alone
      (ALONE) or AZ (5 mg/kg/day) and ATQ (30 mg/kg/day) simultaneously (SIM) prior to
      receiving AZ and ATQ staggered by 12 h. Despite a lack of significant difference
      in the mean AZ pharmacokinetic parameters, the steady-state values of AZ's area
      under the concentration-time curve from 0 to 24 h and maximum concentration in
      serum were consistently lower (n = 7 of 7) for the SIM regimen than they were for
      the ALONE regimen. A larger study will be required to determine if ATQ affects AZ
      pharmacokinetics and efficacy in a clinically significant manner.

PMID- 10348787
TI  - In vitro antifungal susceptibilities of Scopulariopsis isolates.
AB  - MICs and minimum fungicidal concentrations of amphotericin B, miconazole,
      itraconazole, ketoconazole, fluconazole, and flucytosine against 17 isolates of
      Scopulariopsis spp. were determined by a broth microdilution method. All the
      isolates were resistant to itraconazole, fluconazole, and flucytosine, and
      amphotericin B, miconazole, and ketoconazole MICs were low for only a few.

PMID- 10348788
TI  - Nomenclature for new tetracycline resistance determinants.
AB  - Letters of the English alphabet have heretofore been used to name tetracycline
      resistance determinants. Since all 26 letters have now been used, a nomenclature
      employing numerals is recommended for future determinants, and one laboratory has
      offered to coordinate the assignment of numerals.

PMID- 10348789
TI  - In vitro activities of pyronaridine, alone and in combination with other
      antimalarial drugs, against Plasmodium falciparum.
AB  - The in vitro activities of pyronaridine, alone and in combination with
      established antimalarial drugs, were assessed by isotopic microtest. Pyronaridine
      was highly active against all Cameroonian isolates. A positive correlation was
      observed between the response to pyronaridine and that to chloroquine. Drug
      combination studies showed synergy between pyronaridine and primaquine, additive
      effects with 4-aminoquinolines, and weak antagonism with dihydroartemisinin,
      antifolates, or amino alcohols.

PMID- 10348790
TI  - The disposition of 14C-labeled tacrolimus after intravenous and oral
      administration in healthy human subjects.
AB  - Tacrolimus is a macrolide lactone with potent immunosuppressive properties. It
      has been shown in clinical studies to prevent allograft rejection. The
      pharmacokinetics of tacrolimus in healthy subjects and transplant patients has
      been described in earlier studies using immunoassay methods; however, detailed
      information on the absorption, distribution, metabolism, and excretion of
      tacrolimus using a radiolabeled drug is lacking. The objective of the present
      study was to characterize the disposition of tacrolimus after single i.v. (0.01
      mg/kg) and oral (0.05 mg/kg) administration of 14C-labeled drug in six healthy
      subjects. Tacrolimus was absorbed rapidly after oral dosing with a mean Cmax and
      Tmax of 42 ng/ml and 1 h, respectively. The oral bioavailability was about 20%.
      After i.v. and oral dosing, most of the administered dose was recovered in feces,
      suggesting that bile is the principal route of elimination. Urinary excretion
      accounted for less than 3% of total administered dose. In systemic circulation,
      unchanged parent compound accounted for nearly all the radioactivity; however,
      less than 0.5% of unchanged drug was detectable in feces and urine. The excretion
      of the metabolites was formation-rate-limited. The mean total body clearance at
      37.5 ml/min was equivalent to about 3% of the liver blood flow. Renal clearance
      was less than 1% of the total body clearance. The mean elimination half-life was
      44 h.

PMID- 10348791
TI  - Correlation of biliary excretion in sandwich-cultured rat hepatocytes and in vivo
      in rats.
AB  - The relationship between biliary excretion in sandwich-cultured rat hepatocytes
      and in vivo in rats was examined. The biliary excretion of seven model substrates
      in 96-h sandwich-cultured rat hepatocytes was determined by differential
      cumulative uptake of substrate in the monolayers preincubated in standard buffer
      (intact bile canaliculi) and Ca2+-free buffer (disrupted bile canaliculi).
      Biliary excretion in vivo was quantitated in bile duct-cannulated rats. The
      biliary excretion index of model substrates, equivalent to the percentage of
      retained substrate in the canalicular networks, was consistent with the
      percentage of the dose excreted in bile from in vivo experiments. The in vitro
      biliary clearance of inulin, salicylate, methotrexate, [D-pen2,5]enkephalin, and
      taurocholate, calculated as the ratio of the amount excreted into the bile
      canalicular networks and the area under the incubation medium concentration-time
      profile ( approximately 0, approximately 0, 4.1 +/- 1.0, 12.6 +/- 2.2, and 56. 2
      +/- 6.0 ml/min/kg, respectively), correlated with their intrinsic in vivo biliary
      clearance (0.04, 0, 17.3, 34.4, and 116.9 ml/min/kg, respectively; r2 = 0.99).
      The model compound 264W94 was not excreted in bile either in vivo or in vitro.
      The glucuronide conjugate of 2169W94, the O-demethylated metabolite of 264W94,
      was excreted into bile in vitro when 2169W94, but not 264W94, was incubated with
      the monolayers; 2169W94 glucuronide undergoes extensive biliary excretion after
      administration of 264W94 or 2169W94 in vivo. Biliary excretion in long-term
      sandwich-cultured rat hepatocytes correlates with in vivo biliary excretion. The
      study of biliary excretion of metabolites in the hepatocyte monolayers requires
      consideration of the status of metabolic activities.

PMID- 10348792
TI  - Comparative pharmacokinetics and tissue distribution of the d-enantiomers of para
      substituted methylphenidate analogs.
AB  - A comparative study of the plasma pharmacokinetics and tissue distribution of the
      d-threo enantiomers of methylphenidate (MPH), para-bromomethylphenidate (p-Br
      MPH), and para-methoxymethylphenidate (p-OCH3 MPH) was conducted in rats after
      i.p. administration of a 37 micromol/kg dose. The plasma kinetic data was fit to
      a two-compartment model with absorption and lag time as well as evaluated by
      noncompartmental methods. All three compounds attained maximal concentration
      within 10 min of injection. Calculated mean residence time and elimination half
      life values for d-p-Br MPH were significantly longer than those for d-MPH and d-p
      OCH3 MPH, and clearance of the bromo derivative was substantially lower than the
      latter two compounds. Tissue distribution studies of the three d-threo
      enantiomers revealed that para-substitution of d-MPH had a profound effect on the
      distribution pattern of these drugs. The highest concentration of drug was found
      in the kidney and lung for d-MPH, lung and liver for d-p-Br MPH, and lung and
      brain for d-p-OCH3 MPH. The bromo derivative was found in the highest
      concentration in the central nervous system at 30, 120, and 180 min whereas
      levels of d-MPH were twice as high as d-p-OCH3 MPH at 30 min but slightly lower
      than the latter at 120 min. Related studies on the lipophilicity, plasma protein
      binding, and resistance to plasma degradation of these compounds were also
      conducted. The combined data from these experiments along with the
      pharmacokinetics and central nervous system distribution of these drugs provide
      explanations for discrepancies between the in vivo and in vitro activity of these
      compounds described in previous work.

PMID- 10348794
TI  - Development of a substrate-activity based approach to identify the major human
      liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA
      expressed activities and liver microsomal P-450 profiles.
AB  - The contributions of specific human liver cytochrome P-450 (CYP) enzymes to the
      activation, via 4-hydroxylation, of the oxazaphosphorine anticancer prodrugs
      cyclophosphamide (CPA) and ifosfamide (IFA) were investigated. Analysis of a
      panel of 15 human P-450 cDNAs expressed in human lymphoblasts and/or baculovirus
      infected insect cells (Supersomes) demonstrated that CYPs 2A6, 2B6, 3A4, 3A5, and
      three CYP2C enzymes (2C9, 2C18, 2C19) exhibited significant oxazaphosphorine 4
      hydroxylase activity, with 2B6 and 3A4 displaying the highest activity toward CPA
      and IFA, respectively. CYP2B6 metabolized CPA at a approximately 16-fold higher
      in vitro intrinsic clearance (apparent Vmax/Km) than IFA, whereas 3A4
      demonstrated approximately 2-fold higher Vmax/Km toward IFA. A relative substrate
      activity factor (RSF)-based method was developed to calculate the contributions
      of individual P-450s to total human liver microsomal metabolism based on cDNA
      expressed P-450 activity data and measurements of the liver microsomal activity
      of each P-450 form. Using this method, excellent correlations were obtained when
      comparing measured versus predicted (calculated) microsomal 4-hydroxylase
      activities for both CPA (r = 0. 96, p <.001) and IFA (r = 0.90, p <.001) in a
      panel of 17 livers. The RSF method identified CYP2B6 as a major CPA 4-hydroxylase
      and CYP3A4 as the dominant IFA 4-hydroxylase in the majority of livers, with CYPs
      2C9 and 2A6 making more minor contributions. These predicted P-450 enzyme
      contributions were verified using an inhibitory monoclonal antibody for 2B6 and
      the P-450 form-specific chemical inhibitors troleandomycin for 3A4 and
      sulfaphenazole for 2C9, thus validating the RSF approach. Finally, Western blot
      analysis using anti-2B6 monoclonal antibody demonstrated the presence of 2B6
      protein at a readily detectable level in all but one of 17 livers. These data
      further establish the significance of human liver CYP2B6 for the activation of
      the clinically important cancer chemotherapeutic prodrug CPA.

PMID- 10348795
TI  - Molecular basis for hepatic detoxifying enzyme induction by 2-(allylthio)pyrazine
      in rats in comparison with oltipraz: effects on prooxidant production and DNA
      degradation.
AB  - The expression of hepatic microsomal epoxide hydrolase (mEH) and glutathione S
      transferases (GSTs) by 2-(allylthio)pyrazine (2-AP), an experimental
      chemopreventive agent, was investigated in rats. Northern blot analysis revealed
      that 2-AP caused increases in mEH, rGSTA2/3/5, and rGSTM1/2 mRNA levels. mEH and
      rGSTA2 proteins were also induced. Molecular basis of the enzyme induction by 2
      AP was studied in comparison with oltipraz (Olt). Rats exposed to buthionine
      sulfoximine, a GSH-depleting agent, before treatment with either 2-AP or Olt
      exhibited greater increases in the mRNA levels than the individual treatment.
      Conversely, increases of the mRNAs were prevented by cysteine treatment,
      indicating that metabolic intermediates or reactive oxygens produced from the
      agents could be reduced by cysteine. Gel shift analysis revealed that nuclear
      factor-kappaB, which is associated with the altered cellular redox state, was not
      activated by the agents. Effects of these agents on the breakage of phix-174 DNA
      were compared in vitro. 2-AP effectively reduced the conversion of supercoiled
      DNA to the open circular form induced by benzenetriol and prevented benzenetriol-
      and iron-catalyzed degradation of DNA, whereas Olt failed to prevent strand
      breakage of DNA. These results provided evidence that: 1) 2-AP was effective in
      elevating the hepatic mEH and GST gene expression in rats, which might be
      mediated with the production of reactive oxygen species; 2) nuclear factor-kappaB
      activation was not involved in the induction of the detoxifying enzymes by either
      2-AP or Olt in spite of their production of reactive oxygens in vivo; and 3) the
      antioxidant effect of 2-AP in vitro differed from that of Olt.

PMID- 10348793
TI  - Dihydropyrimidine dehydrogenase activity and fluorouracil pharmacokinetics with
      liver damage induced by bile duct ligation in rats.
AB  - Hepatic metabolism is the main determinant in the pharmacokinetics of 5
      fluorouracil (5-FU). Its disposition might be affected with liver dysfunction. In
      the present study, the influence of liver damage induced by bile duct ligation on
      dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in 5-FU catabolism,
      CYP2B, and 5-FU pharmacokinetics were compared in male Sprague-Dawley rats. After
      3 weeks of the ligation in two different groups of animals for in vitro and
      pharmacokinetic experiments, significant increases in serum bilirubin level and
      spleen weight were found in both groups. No significant differences were noted in
      bilirubin level or spleen weight of the bile duct ligation group between the two
      experiment groups. In the in vitro experiment, DPD activity and protein levels
      determined by Western blot analysis in the bile duct ligation group were slightly
      but significantly greater than those of a sham-operated group, whereas CYP2B
      activity and protein level were significantly reduced. These findings were
      supported by mRNA levels of CYP2B and DPD. When 40 mg/kg 5-FU was administered
      i.v. in the pharmacokinetic experiment, no significant differences in
      pharmacokinetic parameters were found between the bile duct ligation and sham
      operated groups. These results suggested that DPD activity and protein level were
      maintained and that 5-FU pharmacokinetics was not altered in the presence of
      liver damage accompanied by a significant reduction in CYP2B activity and protein
      level, supporting previous clinical studies showing that mild to moderate liver
      dysfunction does not affect 5-FU disposition.

PMID- 10348796
TI  - Comparative disposition of the nephrotoxicant N-(3, 5-dichlorophenyl)succinimide
      and the non-nephrotoxicant N-(3, 5-difluorophenyl)succinimide in Fischer 344
      rats.
AB  - Disposition of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide (NDPS) was
      compared with that of a nontoxic analog, N-(3, 5-difluorophenyl)succinimide
      (DFPS). Male Fischer 344 rats were administered 0.2 or 0.6 mmol/kg [14C]NDPS or
      [14C]DFPS (i.p. in corn oil). Plasma concentrations were determined from blood
      samples obtained through the carotid artery. Urine samples were analyzed for
      metabolite content by HPLC. Rats were sacrificed at 3 h (DFPS) or 6 h (NDPS) and
      tissue radiolabel content and covalent binding were determined. [14C]NDPS-derived
      plasma radioactivity levels were 6- to 21-fold higher and peaked later than those
      from [14C]DFPS. Six hours after dosing, NDPS was 40% eliminated in the urine
      compared with approximately 90% for DFPS. By 48 h, only 67% of the NDPS dose was
      eliminated in urine. In contrast, DFPS excretion was virtually complete within 24
      h. NDPS underwent oxidative metabolism to a slightly greater extent than DFPS.
      Distribution of [14C]NDPS-derived radioactivity into the kidneys was 3- to 6-fold
      higher than that into the liver or heart, and was more extensive than with
      [14C]DFPS. NDPS also covalently bound to plasma, renal, and hepatic proteins to a
      greater extent than DFPS. In summary, NDPS achieves higher tissue and plasma
      concentrations, covalently binds to a greater extent, and is eliminated more
      slowly than DFPS. Differences in the lipid solubility of NDPS metabolites and
      DFPS metabolites may help explain these results. The overall greater tissue
      exposure of NDPS and its metabolites may contribute to differential toxicity of
      these analogs.

PMID- 10348797
TI  - Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen
      and 3-hydroxytamoxifen (droloxifene) yielding tamoxifen catechol: involvement of
      catechols in covalent binding to hepatic proteins.
AB  - Earlier study suggested that 3,4-dihydroxytamoxifen (tam catechol), a tamoxifen
      metabolite, is proximate to the reactive intermediate that binds covalently to
      proteins and possibly to DNA (). The current study demonstrates that rat and
      human hepatic cytochrome P-450s (CYPs) catalyze tam catechol formation from
      tamoxifen (tam), 3-hydroxy-tam (Droloxifene), and 4-hydroxy-tam (4-OH-tam).
      Higher levels of catechol were formed from 4-OH-tam and 3-hydroxy-tam than from
      tam. Evidence that human hepatic CYP3A4 and 2D6 catalyze the formation of tam
      catechol from 4-OH-tam and supportive data that the catechol is proximate to the
      reactive intermediate, was obtained: 1) There was a good correlation (r = 0.82; p
      </=.0004) between steroidal 6beta-hydroxylase (CYP3A activity) and ortho
      hydroxylation of 4-OH-tam in human liver microsomes; 2) monospecific antibodies
      against CYP3A4 strongly inhibited catechol formation from 4-OH-tam and its
      covalent binding to proteins in human liver microsomes; 3) low levels of
      ketoconazole inhibited catechol tam accumulation and covalent binding of 4-OH-tam
      to human liver proteins; 4) among human P-450s expressed in insect cells
      (supersomes), only CYP3A4 and 2D6 noticeably catalyzed catechol formation, and
      cytochrome b5 markedly stimulated the CYP3A4 catalysis; and 5) human livers with
      high CYP3A and low or high CYP2D6 activity exhibited high catechol formation and
      those with low 3A and 2D6 activities formed only little catechol. These findings
      demonstrate that CYP3A4 and to a lesser extent 2D6 catalyze tam catechol
      formation and support the participation of tam catechol in covalent binding to
      proteins.

PMID- 10348798
TI  - Effect of PSC 833, a P-glycoprotein modulator, on the disposition of vincristine
      and digoxin in rats.
AB  - PSC 833 has been used to overcome the phenomenon of multidrug resistance by
      inhibiting the P-glycoprotein (P-gp)-mediated efflux of antitumor drugs from
      tumor cells. Because P-gp expressed in several normal tissues may affect the
      disposition of its substrates, we examined the dose-dependent effect of PSC 833
      on the disposition of vincristine (VCR) and digoxin (DGX) in rats. One-tenth
      milligram per kilogram PSC 833 was sufficient to significantly reduce the biliary
      excretion clearance of DGX from 3.0 ml/min/kg to 0.5 ml/min/kg, whereas 3 mg/kg
      PSC 833 was needed to significantly reduce the biliary excretion clearance of VCR
      from 36 ml/min/kg to 9 ml/min/kg. Three milligrams per kilogram PSC 833
      significantly reduced the renal clearance of VCR by 30% but did not affect that
      of DGX significantly. The tissue-to-plasma DGX concentration ratio in the brain
      at 6 h after administration (0.34 versus 1.64), but not that of VCR at 2 h (1.07
      versus 1.37), was significantly increased by PSC 833, 3 mg/kg. The differential
      effect of PSC 833 on the disposition of VCR and DGX may be ascribed to the
      different degree of contribution of P-gp to the disposition of these ligands.

PMID- 10348799
TI  - Effect of leptin on cytochrome P-450, conjugation, and antioxidant enzymes in the
      ob/ob mouse.
AB  - Leptin is a hormone that is secreted by adipocytes and regulates body weight
      through its effect on satiety and energy metabolism. The ob/ob mouse is deficient
      in this protein and is characterized by obesity and other metabolic disorders.
      This study investigated the alterations of several hepatic cytochrome P-450
      (CYP), conjugation, and antioxidant enzymes in lean and ob/ob mice and the role
      leptin plays in the modulation of these enzymes. Lean and ob/ob male mice were
      injected with leptin (100 microg) or PBS for 15 days. Liver microsomes from ob/ob
      mice, when compared with lean controls, displayed significantly reduced
      chlorzoxazone 6-hydroxylation activity (27%); however, 7alpha- and 16alpha-
      testosterone hydroxylation and pentoxyresorufin O-dealkylation activities were
      significantly higher (47%, 22%, and 39%, respectively). Leptin administration
      corrected alterations seen with all P-450 activities. Dealkylation of
      ethoxyresorufin and omega-hydroxylation of lauric acid activities from ob/ob and
      lean mice were not statistically different; however, leptin exposure
      significantly increased ethoxyresorufin activity in lean mice (14%) and decreased
      the activity in ob/ob mice (36%). UDP-glucuronosyl-transferase and glutathione S
      transferase activities were not altered. The antioxidant enzymes, catalase (11%)
      and glutathione peroxidase (26%), as well as glutathione reductase (17%), were
      lower in the ob/ob mice and leptin treatment corrected these alterations. The
      results of this study demonstrate alterations in constitutive expression of
      CYP2B, CYP2E, CYP2A, catalase, glutathione peroxidase, and glutathione reductase
      in ob/ob mice that were restored to lean control values following leptin
      treatment. Additionally, CYP3A activity was increased following leptin treatment
      in ob/ob mice. The mechanism for the observed alterations may be due to direct
      leptin effects or via indirect alterations in insulin, corticosterone, and/or
      growth hormone.

PMID- 10348800
TI  - Cardiovascular effect and simultaneous pharmacokinetic and pharmacodynamic
      modeling of pimobendan in healthy normal subjects.
AB  - Pimobendan is a new inotropic agent with vasodilator properties. We have reported
      the pharmacokinetics of enantiomers of pimobendan in healthy humans. The present
      report focuses on the pharmacodynamic effect of pimobendan and a simultaneous
      pharmacokinetic-pharmacodynamic modeling. Eight normal healthy volunteers were
      studied with oral administration of 7.5 mg and i.v. administration of 5 mg of
      racemic pimobendan. Concentrations of enantiomers of pimobendan were determined
      by high performance liquid chromatography. Cardiovascular effects of pimobendan
      were evaluated by echocardiography. Oral pimobendan significantly reduced 29.0%
      and 16.5% of the left ventricle end-systolic dimension (LVESD) and end-diastolic
      dimension, respectively. The mean velocity of circumferential fiber shortening,
      ejection fraction, and fractional shortening significantly increased 105.9%,
      29.8%, and 46% from their baseline values, respectively. The cardiovascular
      effects of i.v. pimobendan were similar but to a lesser extent. Plots of effect
      versus plasma concentration (Cp) showed counterclockwise hysteresis loops. A
      hypothetical effect compartment was established and incorporated into a sigmoid
      Emax model to describe the time courses of Cps of pimobendan and effects on
      LVESD. The maximal changes (Emax) in LVESD would be 2.60 +/- 0.51 cm and 2.30 +/-
      0.13 cm as estimated from plasma data of (+)- and (-)-pimobendan, respectively.
      The estimated effect-site concentrations corresponding with 50% of the maximal
      effect (Ce50) were 6.54 +/- 1.35 and 6.64 +/- 1.35 ng/ml for (+)- and (-)
      pimobendan, respectively. A simultaneous pharmacokinetic-pharmacodynamic model
      could be established to suppress the hysteresis loop and to predict the
      pharmacological effect based on Cp.

PMID- 10348801
TI  - Pharmacokinetic changes of a new carbapenem, DA-1131, after intravenous
      administration to spontaneously hypertensive rats and deoxycorticosterone acetate
      salt-induced hypertensive rats.
AB  - The pharmacokinetics of a new carbapenem, DA-1131, were compared after i.v.
      administration of the drug, 50 mg/kg, to spontaneously hypertensive rats (SHRs)
      at 16 weeks of age (an animal model for human primary hypertension) and at 6
      weeks of age (corresponding to the early phase of the development of
      hypertension, at which time blood pressure remains within the normotensive range)
      and their respective age-matched control normotensive Kyoto-Wistar rats (KW
      rats), and deoxycorticosterone acetate-salt-induced hypertensive rats at 16 weeks
      of age (an animal model for human secondary hypertension) and their age-matched
      control Sprague-Dawley rats. The total area under the plasma concentration-time
      curve from time zero to time infinity (AUC) (4720 versus 7070 microg x min/ml)
      was significantly smaller, and the nonrenal clearance (CLNR) (5.37 versus 3.57
      ml/min/kg) was significantly faster in 16-week-old SHRs than those in their
      control KW rats. Similar results were also obtained from 6-week-old SHRs in AUC
      (3800 versus 4680 microg x min/ml) and CLNR (7.73 versus 3.31 ml/min/kg).
      However, the values were reversed in 16-week-old deoxycorticosterone acetate-salt
      rats in AUC (5310 versus 3870 microg.min/ml) and CLNR (2.57 versus 4.90
      ml/min/kg). The significantly faster CLNR of DA-1131 in both 6- and 16-week-old
      SHRs could be supported at least partly by the results of the in vitro metabolism
      with kidney homogenate and considerably greater total renal dehydropeptidase-I
      activity. The data above indicated that the significantly faster CLNR of DA-1131
      in 16-week-old SHRs than that in their age-matched control KW rats was due to any
      hereditary characteristics of SHRs and was not due to the hypertensive state
      itself.

PMID- 10348802
TI  - Lack of single-dose disulfiram effects on cytochrome P-450 2C9, 2C19, 2D6, and
      3A4 activities: evidence for specificity toward P-450 2E1.
AB  - Disulfiram and its primary metabolite diethyldithiocarbamate are effective
      mechanism-based inhibitors of cytochrome P-450 2E1 (CYP2E1)1 in vitro. Single
      dose disulfiram diminishes CYP2E1 activity in vivo and has been used to identify
      CYP2E1 participation in human drug metabolism and prevent CYP2E1-mediated
      toxification. Specificity of single-dose disulfiram toward CYP2E1 in vivo,
      however, remains unknown. This investigation determined single-dose disulfiram
      effects on human CYP 2C9, 2C19, 2D6, and 3A4 activities in vivo. In four
      randomized crossover experiments, volunteers received isoform-selective probes
      (oral tolbutamide, mephenytoin, dextromethorphan, or i.v. midazolam) on two
      occasions, 10 h after oral disulfiram or after no pretreatment (controls). Plasma
      and/or urine parent and/or metabolite concentrations were measured by HPLC or gas
      chromatography-mass spectrometry. CYP2C9, 2C19, 2D6, and 3A4 activities were
      determined from the tolbutamide metabolic ratio, 4'-hydroxymephenytoin excretion,
      and dextromethorphan/dextrorphan ratios in urine and midazolam systemic
      clearance, respectively. Midazolam clearance (670 +/- 190 versus 700 +/- 240
      ml/min, disulfiram versus controls), dextromethorphan/dextrorphan metabolic ratio
      (0.013 +/- 0.033 versus 0.015 +/- 0.035), 4'-hydroxymephenytoin excretion (122 +/
      22 versus 128 +/- 25 micromol), and tolbutamide metabolite excretion (577 +/-
      157 versus 610 +/- 208 micromol) were not significantly altered by disulfiram
      pretreatment, although the tolbutamide metabolic ratio was slightly diminished
      after disulfiram (60 +/- 17 versus 81 +/- 40, p <.05). Results show that single
      dose disulfiram does not cause clinically significant inhibition of human CYP2C9,
      2C19, 2D6, and 3A4 activities in vivo. When single-dose disulfiram is used as an
      in vivo probe for P-450, inhibition of drug metabolism suggests selective
      involvement of CYP2E1. Single-dose disulfiram should not cause untoward drug
      interactions from inhibition of other P-450 isoforms.

PMID- 10348803
TI  - Panipenem, a carbapenem antibiotic, enhances the glucuronidation of intravenously
      administered valproic acid in rats.
AB  - Previously, a significant decrease in the trough plasma-concentration of valproic
      acid (VPA) owing to the concomitant administration of panipenem
      (PAPM)/betamipron, a carbapenem antibiotic, in epileptic patients was reported.
      To determine the site and mechanism of the drug interaction between VPA and PAPM,
      we performed in vivo and in vitro experiments using rats. A 30 mg/kg bolus dose
      of VPA was given i.v. to normal Sprague-Dawley rats, nephrectomized rats, and
      hepatectomized rats, with and without prior treatment of PAPM. PAPM treatment
      resulted in a significant reduction of biological half-life and a significant
      increase of total body clearance in normal rats. The effects of PAPM on the
      disposition kinetics of VPA were also observed in nephrectomized rats, whereas
      hepatectomy abolished the interaction completely. Thus, the site of interaction
      was identified as the liver. At steady state, PAPM treatment significantly
      increased total body clearance, the biliary excretion rate of VPA glucuronide,
      and the apparent metabolic clearance of VPA by glucuronidation, but did not
      affect the biliary excretion clearance of VPA glucuronide. Initial uptake
      velocity of VPA into rat hepatocytes proportionally increased as a function of
      VPA concentration added and was not affected by PAPM. The plasma-unbound fraction
      of VPA in vitro was not altered by PAPM. These data demonstrate that PAPM does
      not affect the uptake of VPA into the liver, the plasma-unbound fraction, and the
      excretion process of VPA glucuronide. Consequently, PAPM appears to enhance the
      rate of metabolism of VPA to VPA glucuronide in the liver.

PMID- 10348804
TI  - Deposition of [3H]cocaine, [3H]nicotine, and [3H]flunitrazepam in mouse hair
      melanosomes after systemic administration.
AB  - Microautoradiography was employed to show that association of drugs from the
      serum directly with forming hair pigment is a primary pathway of deposition into
      the hair. After systemic administration of [3H]flunitrazepam, [3H]nicotine, and
      [3H]cocaine, association of all three drugs with melanin in the forming hair was
      observed within minutes of dosage. Sebum was determined to be an insignificant
      deposition route for all three drugs. Pigmented mice had significantly higher
      concentrations of all three drugs than did nonpigmented mice. The results provide
      a better basis for ultimately using hair for reliable analysis of drug and
      environmental toxin exposure.

PMID- 10348805
TI  - Presystemic metabolism of albendazole: experimental evidence of an efflux process
      of albendazole sulfoxide to intestinal lumen.
AB  - Albendazole (ABZ) presystemic clearance was studied in rat by perfusion of a 25
      microM ABZ solution in isolated intestinal loops. Significant secretion of the
      active metabolite, ABZSO, into the lumen was observed. The metabolite was also
      present in mesenteric blood. After 30 min of intestinal perfusion, 64% of the ABZ
      dose had disappeared from lumen. The total amount of ABZSO measured was 0.341 +/-
      0.04 nmol/cm with 0.176 +/- 0.03 nmol/cm in mesenteric blood. The metabolite
      secretion to intestinal lumen was 0.165 +/- 0.05 nmol/cm. Intestinal
      sulfoxidation was induced by repeated administration of ABZ and ABZ
      coadministered with surfactants, especially polysorbate 80. The
      enantioselectivity of the in vitro intestinal sulfoxidation of ABZ showed that
      the relative contribution of P-450 and flavin-containing monooxygenase was quite
      similar, but after the induction by ABZ coadministered with polysorbate 80, the
      cytochrome P-450 system contribution was significantly increased. The appearance
      of ABZSO in mesenteric blood clearance was also increased under these conditions.

PMID- 10348806
TI  - Mechanism-based inactivation of rat liver cytochrome P-450 2B1 by 2-methoxy-5
      nitrobenzyl bromide.
AB  - Mechanism-based inactivators serve as probes of enzyme mechanism, function, and
      structure. Koshland's Reagent II (2-methoxy-5-nitrobenzyl bromide, KR-II) is a
      potential mechanism-based inactivator of enzymes that perform O-dealkylations.
      The major phenobarbital-inducible form of cytochrome P-450 in male rat liver
      microsomes, CYP2B1, is capable of catalyzing O-dealkylations. The interactions of
      KR-II with purified CYP2B1 in the reconstituted system containing P-450, NADPH:P
      450 oxidoreductase, and sonicated dilaurylphosphatidyl choline were studied. The
      benzphetamine N-demethylase activity of CYP2B1 was inactivated by KR-II in a time
      and NADPH-dependent manner, and the loss of activity followed pseudo-first-order
      kinetics. The inactivation also required KR-II, and the rate of activity loss was
      dependent on the concentration of KR-II in a saturable fashion. The inactivator
      concentration required for the half-maximal rate of inactivation (KI) was
      approximately 0.1 mM. The inactivation was not prevented by the addition of the
      nucleophiles dithiothreitol and glutathione, nor was it reversed by gel
      filtration. The present results demonstrate that KR-II is a mechanism-based
      inactivator of rat CYP2B1.

PMID- 10348807
TI  - The multiple indicator-dilution method for the study of enzyme heterogeneity in
      liver: theoretical basis.
AB  - The theoretical basis of the use of the multiple indicator dilution technique to
      account for the heterogeneous distribution (or zonation) of enzymes in the liver
      was explored. The microcirculation was assumed to consist of identical
      capillaries perfused in parallel, with enzymatic activities for drug metabolism
      being distributed uniformly over the upstream half (periportal or pp) or the
      downstream half (perivenous or pv) of the flow path, whereas all other
      transport/removal processes were assumed to be homogeneously distributed. Outflow
      dilution profiles for parent drug and metabolite were estimated by inversion of
      Laplace transforms or by a finite difference method. The areas under the curves
      for parent and metabolite, the mean transit times of parent (MTT) and metabolite
      (MTTM, mean time from injection of parent to exit of metabolite from organ), and
      their relative dispersions (CV2 or CVM2) were estimated from analytical
      expressions. When the influx-efflux ratio (or cellular-sinusoidal distribution
      ratio) for metabolite was equal to or smaller than that of the parent, the MTTM
      ranking was: pp < homogeneous < pv. The ranking was reversed when the influx
      efflux ratio for metabolite greatly exceeded that for the parent. The presence of
      elimination pathways for the metabolite reduced its MTTM and CVM2, more for pp
      than for homogeneous and pv cases. The theory can be applied to determine enzyme
      zonation in multiple indicator dilution studies with use of the area under the
      curve for the metabolite and MTTM during prograde (from portal vein to hepatic
      vein) and retrograde (from hepatic vein to portal vein) perfusion.

PMID- 10348808
TI  - Estimation of Ki in a competitive enzyme-inhibition model: comparisons among
      three methods of data analysis.
AB  - There are a variety of methods available to calculate the inhibition constant
      (Ki) that characterizes substrate inhibition by a competitive inhibitor.
      Linearized versions of the Michaelis-Menten equation (e.g., Lineweaver-Burk,
      Dixon, etc.) are frequently used, but they often produce substantial errors in
      parameter estimation. This study was conducted to compare three methods of
      analysis for the estimation of Ki: simultaneous nonlinear regression (SNLR);
      nonsimultaneous, nonlinear regression, "KM,app" method; and the Dixon method.
      Metabolite formation rates were simulated for a competitive inhibition model with
      random error (corresponding to 10% coefficient of variation). These rates were
      generated for a control (i.e., no inhibitor) and five inhibitor concentrations
      with six substrate concentrations per inhibitor and control. The KM/Ki ratios
      ranged from less than 0.1 to greater than 600. A total of 3 data sets for each of
      three KM/Ki ratios were generated (i.e., 108 rates/data set per KM/Ki ratio). The
      mean inhibition and control data were fit simultaneously (SNLR method) using the
      full competitive enzyme-inhibition equation. In the KM,app method, the mean
      inhibition and control data were fit separately to the Michaelis-Menten equation.
      The SNLR approach was the most robust, fastest, and easiest to implement. The
      KM,app method gave good estimates of Ki but was more time consuming. Both methods
      gave good recoveries of KM and VMAX values. The Dixon method gave widely ranging
      and inaccurate estimates of Ki. For reliable estimation of Ki values, the SNLR
      method is preferred.

PMID- 10348809
TI  - Translational research: what is it?

PMID- 10348810
TI  - Urocortin reduces food intake and gastric emptying in lean and ob/ob obese mice.
AB  - BACKGROUND & AIMS: Gastric emptying plays an important role in regulating food
      intake. This study was designed to investigate whether intraperitoneally injected
      urocortin reduces gastric emptying, feeding, and body weight in lean and ob/ob
      obese mice. METHODS: Food intake and body weight were measured after
      intraperitoneal injections of one of the following: urocortin, deamidated form of
      urocortin (urocortin OH), corticotropin-releasing factor (CRF), CRF6-33,
      cholecystokinin octapeptide (CCK-8), and leptin in 16-hour food-deprived animals.
      Gastric emptying was assessed 2, 4, or 8 hours after intraperitoneal injection.
      Repeated injections of urocortin were continued for 5 days in ob/ob mice.
      RESULTS: Urocortin (0.003-3 nmol) dose-dependently and potently decreased food
      intake and body weight gain in lean mice. The ranking order of potency was
      urocortin > urocortin OH >/= CRF > CCK-8 > CRF6-33 > leptin. Gastric emptying was
      also potently reduced by urocortin with a similar ranking order of potency of
      urocortin > CRF > urocortin OH > CCK-8. Simultaneous administration of urocortin
      and CRF receptor antagonist, alpha-helical CRF9-41, blocked the effects of
      urocortin. Urocortin reduced food intake and body weight gain, as well as the
      rate of gastric emptying, in ob/ob mice, which was significantly faster than that
      of lean mice. Five daily injections of urocortin significantly lowered body
      weight and improved glycemic control in ob/ob mice. CONCLUSIONS: The urocortin
      induced decrease in food intake and body weight in lean and ob/ob mice is closely
      related to gastric emptying and opens new possibilities for the treatment of
      obesity.

PMID- 10348811
TI  - Duodenogastroesophageal reflux and esophageal mucosal injury in mechanically
      ventilated patients.
AB  - BACKGROUND & AIMS: Esophagitis has been reported to be the most frequent cause of
      upper gastrointestinal bleeding in intensive care patients. The mechanisms
      causing esophagitis are unclear. The aim of this study was to measure esophageal
      acid and bile reflux and to examine the relationship between reflux and mucosal
      injury in mechanically ventilated patients. METHODS: Twenty-five critically ill,
      mechanically ventilated patients with nasogastric tubes were prospectively
      included for 24-hour esophageal pH and duodenogastroesophageal bile reflux
      studies (Bilitec 2000 system). All patients received acid-suppressive therapy for
      stress ulcer prophylaxis with ranitidine. On the day before the study, patients
      underwent esophageal endoscopy to determine the presence or absence of
      esophagitis. RESULTS: After approximately 5 days of mechanical ventilation, 12
      patients (48%) had erosive esophagitis, 2 patients had pathological acid reflux,
      and 12 patients had pathological bile reflux. The presence of esophagitis was
      significantly associated with pathological bile reflux (P = 0.017, Fisher exact
      test). The severity of esophagitis was significantly correlated with the volume
      of gastric residual volume and with increasing times of bile reflux. The latter
      was significantly correlated with the number of organ failures. CONCLUSIONS:
      Despite acid-suppressive therapy, esophagitis is a frequent finding in critically
      ill patients after less than a week of mechanical ventilation. In these patients,
      besides mechanical irritation by the nasogastric tube, chemical injury caused by
      duodenogastroesophageal reflux seems to have a major role in the pathogenesis of
      esophageal mucosal lesions.

PMID- 10348812
TI  - Chest pain in achalasia: patient characteristics and clinical course.
AB  - BACKGROUND & AIMS: In this prospective study, the prevalence of episodic pain in
      patients with achalasia was investigated, risk factors for its occurrence were
      determined, and its long-term clinical course was evaluated. METHODS: Over an 18
      year period, patients with newly diagnosed achalasia were followed up at 2-year
      intervals. At the first visit and after each treatment, all patients underwent
      manometric, endoscopic, and radiographic examinations. In addition, structured
      interviews were performed during each patient visit and at 2-year intervals.
      Potential risk factors for the presence or absence of chest pain were evaluated
      with the use of a logistic model. To determine the evolution of this symptom,
      Kaplan-Meier life-table analyses were performed. RESULTS: Among 101 patients with
      achalasia, 64 reported chest pain and 37 had never had this symptom. Neither
      manometric nor radiographic findings predicted the occurrence of retrosternal
      pain. However, patients with chest pain were significantly younger than those
      without, and they had a shorter duration of symptoms. Treatment with pneumatic
      dilatation or myotomy effectively diminished dysphagia but had little effect on
      the occurrence of retrosternal pain. However, over a course of several years,
      chest pain diminished in most patients and disappeared in a minority of them.
      CONCLUSIONS: Chest pain is a common symptom of achalasia and predominantly
      affects younger patients. Its cause remains unknown, and no treatment exists to
      effectively relieve this symptom. However, with advancing age, the frequency of
      chest pain will spontaneously diminish in most patients.

PMID- 10348813
TI  - Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti
      inflammatory drugs: a case-control study.
AB  - BACKGROUND & AIMS: Peptic ulcer complications related to use of nonsteroidal anti
      inflammatory drugs (NSAIDs) are among the most common serious adverse drug
      reactions. Whether Helicobacter pylori infection potentiates this
      gastrointestinal toxicity of NSAIDs is still unresolved. In this study, we
      investigated the role of H. pylori as a cause of bleeding peptic ulcer among
      NSAID users. METHODS: A case-control study of current users (n = 132) of NSAIDs
      (including acetylsalicylic acid), admitted because of bleeding peptic ulcer, was
      performed. Controls were 136 NSAID users without gastrointestinal complications.
      H. pylori was diagnosed by either increased levels of serum immunoglobulin G or
      by 13C-urea breath test. RESULTS: Fifty-eight (44%) case subjects had a bleeding
      gastric ulcer, 54 (41%) had a bleeding duodenal ulcer, 12 (9%) had both gastric
      and duodenal ulcers, and 8 (6%) had hemorrhagic gastritis. H. pylori was present
      in 75 (57%) cases compared with 59 (43%) controls. The adjusted odds ratio of
      bleeding peptic ulcer among NSAID users associated with H. pylori infection was
      1.81 (95% confidence interval, 1.02-3.21). H. pylori accounted for approximately
      24% of bleeding peptic ulcers among elderly NSAID users. CONCLUSIONS: NSAID users
      infected with H. pylori have an almost twofold increased risk of bleeding peptic
      ulcer compared with NSAID users without H. pylori.

PMID- 10348814
TI  - Mutations of RegIalpha are associated with enterochromaffin-like cell tumor
      development in patients with hypergastrinemia.
AB  - BACKGROUND & AIMS: The RegIalpha gene (Reg) encodes a secretory protein proposed
      to regulate islet beta-cell and gastric mucous cell growth. Reg is expressed in
      rat gastric enterochromaffin-like (ECL) cells. The aim of this study was to
      examine Reg expression in human corpus and to determine the identity of Reg in
      ECL cell carcinoid tumors in hypergastrinemic patients. METHODS: Reg messenger
      RNA (mRNA) abundance was quantified by Northern blot in extracts of gastric
      corpus from patients with and without ECL cell tumors and in AR4-2J cells
      stimulated by gastrin; cellular origins were determined by immunocytochemistry.
      Mutations of Reg were determined by reverse-transcription polymerase chain
      reaction, cloning, and sequencing, and the mutated protein was expressed in HIT
      T15 cells. RESULTS: Reg mRNA abundance was increased approximately threefold in
      the corpus of hypergastrinemic patients compared with controls, and was enriched
      in 3 of 7 ECL cell carcinoid tumors but not in non-endocrine cell gastric polyps.
      In AR4-2J cells, gastrin stimulated Reg mRNA abundance; this was eliminated by
      the gastrin/cholecystokinin B antagonist L-740,093 (10(-9) mol/L).
      Immunocytochemistry indicated that Reg was located in both chief cells and ECL
      cells in human corpus. Mutations of Reg were identified in 3 of 5 patients with
      ECL cell carcinoid tumors; in 2 cases, mutation of the initiator methionine
      residue led to exclusion of the protein from the secretory pathway. CONCLUSIONS:
      Gastrin regulates Reg mRNA abundance in human corpus. Mutations of Reg that
      prevent secretion are associated with ECL cell carcinoids, suggesting a function
      as an autocrine or paracrine tumor suppressor.

PMID- 10348815
TI  - Increased expression and cellular localization of inducible nitric oxide synthase
      and cyclooxygenase 2 in Helicobacter pylori gastritis.
AB  - BACKGROUND & AIMS: Inducible nitric oxide synthase (iNOS) and cyclooxygenase
      (COX)-2 are important regulators of mucosal inflammation and epithelial cell
      growth. To determine the role of iNOS and COX-2 in Helicobacter pylori-induced
      tissue injury, we compared their gene expression in H. pylori-induced gastritis
      with that in normal gastric mucosa and in non-H. pylori gastritis. METHODS: In 43
      patients, we assessed H. pylori infection status, histopathology, messenger RNA
      (mRNA) and protein expression, and cellular localization of iNOS and COX-2.
      RESULTS: By reverse-transcription polymerase chain reaction (RT-PCR), antral iNOS
      and COX-2 mRNA expression was absent to low in normal mucosa (n = 10),
      significantly increased in H. pylori-negative gastritis (n = 13), and even more
      markedly increased in H. pylori-positive gastritis (n = 20). Increased iNOS and
      COX-2 levels were confirmed by Northern and Western blot analysis and were both
      greater in the gastric antrum than in the gastric body of infected patients.
      Immunohistochemistry also showed increased expression of both genes in H. pylori
      gastritis: iNOS protein was detected in epithelium, endothelium, and lamina
      propria inflammatory cells, and COX-2 protein localized to mononuclear and
      fibroblast cells in the lamina propria. CONCLUSIONS: iNOS and COX-2 are induced
      in H. pylori-positive gastritis and thus may modulate the inflammation and
      alterations in epithelial cell growth that occur in this disease. Higher levels
      of iNOS and COX-2 in H. pylori-positive vs. -negative gastritis and in gastric
      antrum, where bacterial density is greatest, suggest that expression of these
      genes is a direct response to H. pylori infection.

PMID- 10348816
TI  - Helicobacter pylori-dependent ceramide production may mediate increased
      interleukin 8 expression in human gastric cancer cell lines.
AB  - BACKGROUND & AIMS: Helicobacter pylori adheres to gastric epithelial cells,
      activates nuclear factor kappaB (NF-kappaB), and stimulates interleukin (IL)-8
      production, but the responsible molecular mechanisms remain largely unknown.
      Because several studies have shown that sphingolipids are involved in a number of
      signaling pathways, including NF-kappaB activation, we investigated the possible
      role of sphingolipids in the regulation of IL-8 expression in Kato III and AGS
      cells. METHODS: IL-8 production in the conditioned media was quantified by enzyme
      immunoassay. Induction of messenger RNA (mRNA) was assessed by Northern blot
      analysis. Activation and binding activity of transcription factors were examined
      by luciferase assay and electrophoretic mobility shift assay, respectively.
      Intracellular levels of ceramide were quantified by diacylglycerol kinase assay.
      RESULTS: A cell-permeable ceramide analogue (C2-ceramide) increased IL-8
      expression with comparable mRNA induction. This effect was mimicked by
      sphingomyelinase, but not by phospholipase A2 or phospholipase C. C2-ceramide
      induced IL-8 gene transcription mainly through activation of NF-kappaB because
      mutation of the NF-kappaB-binding site completely abrogated the induction of
      luciferase activity. Direct contact of live H. pylori with epithelial cells
      increased the intracellular concentration of ceramide. CONCLUSIONS: The results
      suggest a novel role of the sphingomyelin-ceramide pathway, at least in part
      through NF-kappaB, in IL-8 production induced by H. pylori infection in gastric
      epithelial cells.

PMID- 10348817
TI  - Characterization of the inhibitory effect of boiled rice on intestinal chloride
      secretion in guinea pig crypt cells.
AB  - BACKGROUND & AIMS: When rice is incorporated into oral rehydration therapy for
      patients with secretory diarrhea, clinical outcomes improve. We have shown that a
      factor purified from boiled rice (RF) blocks the secretory response of intestinal
      crypt cells to adenosine 3',5'-cyclic monophosphate (cAMP). Now we report that
      the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel
      is the cellular target for this rice inhibitor. METHODS: We used RF, the same
      previously described extract prepared from boiled rice, to assess chloride
      channel activation in vitro, measuring (1) cell volume regulation of guinea pig
      intestinal crypt epithelial cell suspensions using standard Coulter counter
      technology, (2) transepithelial chloride current in monolayers of T84 cells
      mounted in Ussing chambers, and (3) whole-cell and single-channel currents using
      the patch-clamp technique in cells transfected to express CFTR. RESULTS: RF
      inhibited activation by cAMP of CFTR chloride channels in all experimental
      preparations; RF did not block volume-stimulated Cl- secretion, suggesting that
      its effect might be specific for CFTR chloride channels. RF inhibited
      transepithelial cAMP-stimulated Cl- current in T84 cells and inhibited forskolin
      (i.e., cAMP)-induced current in cells transfected with CFTR. Excised patch and
      single-channel patch-clamp recordings supported the view that the response was a
      direct effect on CFTR rather than on cAMP signal transduction. CONCLUSIONS: RF
      exerts a specific inhibitory effect on CFTR chloride channels, blocking
      activation from the luminal surface of the cell and reversing established
      activation. Many major diarrheal states are based on cAMP-induced CFTR
      activation, leading to excessive gut secretion; our findings could have clinical
      relevance.

PMID- 10348818
TI  - Gastric cancers of the microsatellite mutator phenotype display characteristic
      genetic and clinical features.
AB  - BACKGROUND & AIMS: Colon cancer of the microsatellite mutator phenotype (MMP)
      exhibits significant genotype differences from cancer without the MMP. Twenty
      nine MMP-positive gastric cancers were analyzed to clarify if these genotype
      differences were also associated with distinctive clinicopathologic features.
      METHODS: Alterations of p53, beta2-microglobulin (beta2M ), hMLH1, and hMSH2
      genes were analyzed by using polymerase chain reaction, single-strand
      conformational polymorphism, sequencing, microallelotyping, hypermethylation
      assays, and immunostaining. The results were contrasted with mutations in BAX,
      hMSH3, and hMSH6, genes target for the MMP. RESULTS: Tumors with the MMP had a
      significantly lower incidence of p53 gene mutations than the other tumors and
      often contained beta2M gene somatic mutations. Many tumors contained concomitant
      genetic and epigenetic alterations in DNA mismatch repair genes, hMLH1, hMSH2,
      hMSH3, and hMSH6. Gastric cancer of the MMP was associated with well/moderate
      differentiation, distal location, and better survival. CONCLUSIONS: Analysis of
      somatic alterations in microsatellite sequences and in cancer genes target for
      the MMP is useful for the classification of groups of gastric cancers with
      different prognosis. The results further support the concept that (gastric)
      cancer of the MMP represents a distinctive oncogenic pathway because the mutated
      cancer genes are usually different from those found in tumors without the MMP.

PMID- 10348819
TI  - Cell cycle block at G1-S or G2-M phase correlates with differentiation of Caco-2
      cells: effect of constitutive insulin-like growth factor II expression.
AB  - BACKGROUND & AIMS: We have previously shown that autocrine insulin-like growth
      factor (IGF)-II synthesis through IGF-I receptor stimulates proliferation and
      inhibits differentiation of Caco-2 cells. To demonstrate whether differentiation
      of Caco-2 cells is dependent on cell growth status, we analyzed the effect of
      cell cycle arrest on differentiation of wild-type and IGF-II-overexpressing
      cells. METHODS: Cells were treated with drugs that inhibit the progression either
      to S phase (l-b-D-arabinofuranosylcytosine or M phase (nocodazole). Cell
      differentiation was analyzed by assessing apolipoprotein A-1 and sucrase
      isomaltase expression. Cell proliferation and DNA content were assessed by
      thymidine incorporation and fluorescence-activated cell sorter analysis,
      respectively. Cell cycle regulatory molecules were analyzed by assessing p21 and
      retinoplasma protein (pRb) expression and pRb phosphorylation. RESULTS: Cell
      cycle block at G1-S phase was associated with increased expression of
      differentiation markers in both parental and IGF-II-transfected cells. On the
      contrary, cell cycle arrest at G2-M phase correlated with the expression of
      differentiation markers in parental but not in IGF-II-transfected cells.
      Constitutive IGF-II-expressing cells actively incorporated thymidine and showed
      an increase in the proportion of cells with >4N DNA ploidy in the presence of
      nocodazole. Nocodazole treatment of constitutive IGF-II-expressing cells
      stimulated p21 expression in the presence of hyperphosphorylated pRb.
      CONCLUSIONS: The data show that cell cycle arrest increases differentiation of
      Caco-2 cells. IGF-II-mediated proliferation may prevent cell differentiation
      through effects on control cell checkpoint proteins.

PMID- 10348820
TI  - Involvement of T3Ralpha- and beta-receptor subtypes in mediation of T3 functions
      during postnatal murine intestinal development.
AB  - BACKGROUND & AIMS: Thyroid hormones are implicated in intestinal development.
      Their effects are mediated by nuclear receptors, which are transcriptional
      regulators activated upon binding of triiodothyronine. The aim of this study was
      to define the involvement of the receptor subtypes during intestinal development.
      METHODS: We used strains of knockout mice lacking T3Ralpha, T3Rbeta, or both
      receptors, encoded by T3Ralpha and T3Rbeta genes. RESULTS: Morphological features
      and expression of digestive enzymes and of two intestinal regulators, Cdx-1 and
      Cdx-2, were compared in wild-type and T3Ralpha, T3Rbeta, and T3Ralphabeta
      knockout animals. T3Ralpha-/- mice had abnormal intestinal morphology, assessed
      by a decrease in the number of epithelial cells along the crypt-villus axis and a
      decrease in proliferating crypt cells. Expression of Cdx-1 and Cdx-2, and of the
      digestive enzymes, was down-regulated. These parameters can be partially reversed
      by T3 injection. A similar (jejunum) or more severe (ileum) phenotype was found
      in T3Ralphabeta double mutants. In contrast, no changes occurred in T3Rbeta mice.
      CONCLUSIONS: These data describe for the first time a direct effect of TH through
      the T3Ralpha-receptor subtypes on postnatal intestinal mucosa maturation. They
      also suggest that T3Rbeta receptors are dispensable but can partially substitute
      for T3Ralpha.

PMID- 10348822
TI  - Na+/HCO3- cotransport and expression of NBC1 and NBC2 in rabbit gastric parietal
      and mucous cells.
AB  - BACKGROUND & AIMS: The gastric epithelium protects itself against luminal acid by
      secreting HCO3--rich fluid into the mucous layer and by HCO3--dependent
      intracellular pH regulation, but the basolateral HCO3- uptake mechanisms are
      incompletely characterized. This study examined the expression and functional
      significance of the Na+/HCO3- cotransporters NBC1 and NBC2 in rabbit gastric
      epithelial cells. METHODS: Rabbit NBC1 and NBC2 complementary DNA fragments were
      cloned and sequenced, and cellular expression levels were assessed by
      semiquantitative polymerase chain reaction. Na+/HCO3- cotransport activity was
      measured fluorometrically in cultured rabbit parietal and mucous cells. RESULTS:
      NBC1 expression was 4.5-fold lower in the stomach than kidney cortex and 5.5-fold
      higher in mucous than parietal cells. NBC2 expression in the stomach was much
      lower than in the eye, approximately 4-fold lower than NBC1 expression in the
      stomach, and 2.5-fold higher in mucous than parietal cells. The Na+- and HCO3-
      dependent, dimethylamiloride-insensitive (which at 500 micromol/L completely
      inhibits all Na+/H+ exchanger isoforms) base influx rates were 4.6 +/- 0.02 and
      16.2 +/- 0.04 mmol/L/min in acidified parietal and mucous cells, respectively,
      and were not significantly different in the absence of Cl-. CONCLUSIONS: This
      study shows that NBC1 and NBC2 are expressed in rabbit stomach, with high levels
      in mucous cells where Na+/HCO3- cotransport is the major base-importing mechanism
      in the presence of CO2/HCO3-.

PMID- 10348821
TI  - Stimulation of cystic fibrosis transmembrane conductance regulator-dependent
      short-circuit currents across DeltaF508 murine intestines.
AB  - BACKGROUND & AIMS: The cystic fibrosis transmembrane conductance regulator (CFTR)
      can be activated by pharmacological manipulation of the protein kinase A pathway
      in cell lines. Our goals were to stimulate wild-type CFTR in murine intestines
      via isoform-specific phosphodiesterase inhibition or protein kinase A activation
      and to apply the optimal stimulus to activate chloride secretion from homozygous
      DeltaF508 jejunum. METHODS: The response of T84 cells and sections of murine
      intestine to various inhibitors and activators was examined by Ussing chamber
      experiments. RESULTS: Maximal chloride secretion can be activated in T84 cells
      with application of class III phosphodiesterase inhibitors and in wild-type
      murine intestines with class I or III phosphodiesterase inhibitors or with
      activators of type II protein kinase A. Chloride secretion can be stimulated from
      homozygous DeltaF508 murine jejunum using a mixture of inhibitors and activators.
      CONCLUSIONS: DeltaF508 CFTR can be activated to levels 4% of wild-type when the
      combination of protein kinase A type II activators and phosphodiesterase class I
      and III inhibitors are used in murine jejunum. This result suggests that partial
      CFTR-mediated electrolyte transport can be restored in DeltaF508 murine jejunum
      by application of specific pharmacological agents.

PMID- 10348823
TI  - A role for spinal nitric oxide in mediating visceral hyperalgesia in the rat.
AB  - BACKGROUND & AIMS: Intracolonic instillation of zymosan in rats produces
      hyperalgesia (i.e., facilitates the visceromotor response to colorectal
      distention) mediated by activity at spinal N-methyl-D-aspartate (NMDA) and non
      NMDA receptors. Nitric oxide (NO*) production often increases after NMDA receptor
      activation; NO* may then function as a further messenger. This study was designed
      to investigate the role of spinal NO* in this model of visceral hyperalgesia.
      METHODS: Zymosan or saline was given intracolonically, and the visceromotor
      response to noxious colorectal distention (80 mm Hg, 20 seconds) was measured 3
      hours afterward. RESULTS: There was a significant enhancement of the visceromotor
      response in zymosan-, but not saline-treated, rats. This hyperalgesia was dose
      dependently and reversibly attenuated by intrathecal administration of the
      nonselective NO* synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (100
      800 nmol) as well as by the selective neuronal NOS inhibitor ARL 17477 (30-600
      nmol). In support of these observations, there was a significant increase in the
      number of cells labeled for NADPH diaphorase or neuronal NOS in the lumbosacral
      spinal cord after intracolonic instillation of zymosan, but not saline.
      CONCLUSIONS: These data suggest that colonic inflammation induces the expression
      of neuronal NOS in the spinal cord and that increased production of spinal NO* is
      necessary for maintenance of zymosan-produced visceral hyperalgesia.

PMID- 10348824
TI  - A novel mutation of HFE explains the classical phenotype of genetic
      hemochromatosis in a C282Y heterozygote.
AB  - BACKGROUND & AIMS: Most patients with genetic hemochromatosis are homozygous for
      a single mutation of the HFE gene (C282Y). There is a second mutation, H63D, but
      its role in iron overload is less conclusive. The aim of this study was to
      investigate the basis of iron overload in a patient with classical
      hemochromatosis who was only heterozygous for C282Y and negative for H63D.
      METHODS: Genotype for the C282Y, H63D, and S65C mutations of HFE was determined
      in patient RFH, his family members, and 365 controls. The HFE gene was sequenced
      in patient RFH. Allele-specific reverse-transcription polymerase chain reaction
      was performed to investigate RNA splicing. Allele frequency was determined by
      allele-specific oligonucleotide hybridization. RESULTS: The patient is compound
      heterozygous for C282Y and a novel splice site mutation (IVS3 + 1G --> T). His
      sister has an identical genotype and elevated serum ferritin and transferrin
      saturation. The novel mutation functionally alters messenger RNA splicing,
      causing obligate skipping of exon 3. However, the IVS3 + 1G --> T mutation was
      found to be rare and was not detected in 630 control European chromosomes.
      CONCLUSIONS: IVS3 + 1G --> T in the compound heterozygous state with C282Y
      results in iron overload that can progress to a severe phenotype of classical
      hemochromatosis. The demonstration of IVS3 +1G --> T highlights the possibility
      of other rare HFE mutations, particularly in C282Y heterozygotes with iron
      overload.

PMID- 10348825
TI  - Nonalcoholic fatty liver disease: a spectrum of clinical and pathological
      severity.
AB  - BACKGROUND & AIMS: The spectrum of nonalcoholic fatty liver disease ranges from
      fatty liver alone to nonalcoholic steatohepatitis. Most previous studies have
      short follow-up and have not carefully delineated different histological types
      when determining clinical outcomes. The aim of this study was to compare clinical
      characteristics and outcomes of patients with different types of nonalcoholic
      fatty liver. METHODS: All liver biopsy specimens from 1979 to 1987 with fat
      accumulation were assessed for inflammation, ballooning degeneration, Mallory
      hyaline, and fibrosis. Biopsy specimens were also assessed for histological iron
      and hepatitis C RNA. Outcomes were cirrhosis, mortality, and liver-related
      mortality. RESULTS: Of 772 liver biopsy specimens, complete data were available
      in 132 patients. Fatty liver (type 1) did not differ from the other three types
      combined with respect to gender, race, age, or obesity. Cirrhosis was more common
      in the other types combined (22%) than fatty liver alone (4%; P </= 0.001).
      Overall mortality, histological iron, and hepatitis C did not differ between
      groups. Most of the liver-related deaths were in type 4. CONCLUSIONS: The outcome
      of cirrhosis and liver-related death is not uniform across the spectrum of
      nonalcoholic fatty liver. These poor outcomes are more frequent in patients in
      whom biopsies show ballooning degeneration and Mallory hyaline or fibrosis.

PMID- 10348826
TI  - Enterohepatic cycling of bilirubin: a putative mechanism for pigment gallstone
      formation in ileal Crohn's disease.
AB  - BACKGROUND & AIMS: Patients with ileal disease, bypass, or resection are at
      increased risk for developing gallstones. In ileectomized rats, bilirubin
      secretion rates into bile are elevated, most likely caused by increased colonic
      bile salt levels, which solubilize unconjugated bilirubin, prevent calcium
      complexing, and promote its absorption and enterohepatic cycling. The hypothesis
      that ileal disease or resection engenders the same pathophysiology in humans was
      tested. METHODS: Sterile gallbladder bile samples were obtained intraoperatively
      from 29 patients with Crohn's disease and 19 patients with ulcerative colitis.
      Bilirubin, total calcium, biliary lipids, beta-glucuronidase activities, and
      cholesterol saturation indices in bile were measured, and markers of hemolysis
      and ineffective erythropoiesis in blood were assessed. RESULTS: Bilirubin
      conjugates, unconjugated bilirubin, and total calcium levels were increased 3-10
      fold in bile of patients with ileal disease and/or resection compared with
      patients with Crohn's colitis or ulcerative colitis. Biliary bilirubin
      concentrations correlated positively with the anatomic length and duration of
      ileal disease. Endogenous biliary beta-glucuronidase activities were comparable
      in all groups, and both the hemogram and serum vitamin B12 levels were normal.
      CONCLUSIONS: This study establishes that increased bilirubin levels in bile of
      patients with Crohn's disease are caused by lack of functional ileum, supporting
      the hypothesis that enterohepatic cycling of bilirubin occurs.

PMID- 10348827
TI  - Induction of cytokine production in naive CD4(+) T cells by antigen-presenting
      murine liver sinusoidal endothelial cells but failure to induce differentiation
      toward Th1 cells.
AB  - BACKGROUND & AIMS: Murine liver sinusoidal endothelial cells (LSECs)
      constitutively express accessory molecules and can present antigen to memory Th1
      CD4(+) T cells. Using a T-cell receptor transgenic mouse line, we addressed the
      question whether LSECs can prime naive CD4(+) T cells. METHODS: Purified LSECs
      were investigated for their ability to induce activation and differentiation of
      naive CD4(+) T cells in comparison with bone marrow-derived antigen-presenting
      cells and macrovascular endothelial cells. Activation of T cells was determined
      by cytokine production. LSECs were further studied for expression of interleukin
      (IL)-12 by reverse-transcription polymerase chain reaction, and the unique
      phenotype of LSECs was determined by flow cytometry. RESULTS: We provide evidence
      that antigen-presenting LSECs can activate naive CD62Lhigh CD4(+) T cells.
      Activation of naive CD4(+) T cells by LSECs occurred in the absence of IL-12. In
      contrast, macrovascular endothelial cells from aorta could not activate naive
      CD4(+) T cells. The unique functional characteristics of microvascular LSECs
      together with a unique phenotype (CD4(+), CD11b+, CD11c+, CD80(+), CD86(+)) make
      these cells different from macrovascular endothelial cells. Furthermore, LSECs
      did not require in vitro maturation to activate naive CD4(+) T cells. Most
      importantly, LSECs failed to induce differentiation toward Th1 cells, whereas
      conventional antigen-presenting cell populations induced a Th1 phenotype in
      activated CD4(+) T cells. Upon restimulation, CD4(+) T cells, which were primed
      by antigen-presenting LSECs, expressed interferon gamma, IL-4, and IL-10, which
      is consistent with a Th0 phenotype. Exogenous cytokines (IL-1beta, IL-12, or IL
      18) present during T-cell priming by antigen-presenting LSECs could not induce a
      Th1 phenotype, but neutralization of endogenously produced IL-4 during T-cell
      priming led to a reduced expression of IL-4 and IL-10 by CD4(+) T cells upon
      restimulation. The addition of spleen cells to cocultures of LSECs and naive
      CD4(+) T cells during T-cell priming led to differentiation of T cells toward a
      Th1 phenotype. CONCLUSIONS: The ability of antigen-presenting LSECs to induce
      cytokine expression in naive CD4(+) T cells and their failure to induce
      differentiation toward a Th1 phenotype may contribute to the unique hepatic
      microenvironment that is known to promote tolerance.

PMID- 10348828
TI  - Transforming growth factor alpha activates Ha-Ras in human pancreatic cancer
      cells with Ki-ras mutations.
AB  - BACKGROUND & AIMS: The aim of this study was to identify signaling pathways that
      mediate cell proliferation in response to a Ras-activating growth factor,
      transforming growth factor (TGF)-alpha, in two pancreatic cancer cell lines with
      constitutively active Ki-Ras, MiaPaCa-2, and Panc-1. METHODS: ERK1/-2- and
      p90(rsk) activation were determined by immune complex kinase assays. AP-1 and E74
      activation were assessed in transient transfections using luciferase reporter
      plasmids. Ha-Ras activation was determined using a glutathione S-transferase
      fusion protein comprising the Ras-binding domain of Raf and by
      immunocytochemistry, growth by DNA synthesis and colony formation in softagar.
      RESULTS: TGF-alpha stimulated activation of ERK1/-2, which was dependent on MEK
      1, but independent of PKC activity. TGF-alpha-induced activation of an AP-1
      reporter plasmid also required MEK-1 and Ras activity. Using an E74 reporter
      plasmid, we demonstrate that TGF-alpha indeed activates Ras in both cell lines.
      In particular, TGF-alpha induced membrane translocation and activation of the Ras
      isoform Ha-Ras. Finally, TGF-alpha-stimulated DNA synthesis and clonal growth in
      soft agar were prevented by treatment of cells with a MEK-1 inhibitor or a Ras
      farnesyl transferase inhibitor. CONCLUSIONS: The Ha-Ras-ERK cascade plays an
      important role in TGF-alpha-induced growth of pancreatic cancer cells with
      activating Ki-ras mutations. Inhibitors of this cascade could constitute novel
      anticancer agents for pancreatic tumors.

PMID- 10348829
TI  - New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch
      syndrome) proposed by the International Collaborative group on HNPCC.

PMID- 10348830
TI  - Presentation of the Julius M. Friedenwald medal to Jerry S. Trier, M.D.

PMID- 10348831
TI  - American Gastroenterological Association medical position statement: guidelines
      for the evaluation and management of chronic diarrhea.
AB  - This document presents the official recommendations of the American
      Gastroenterological Association (AGA) on the Evaluation and Management of Chronic
      Diarrhea. It was approved by the Clinical Practice and Practice Economics
      Committee on September 27, 1998, and by the AGA Governing Board on November 8,
      1998.

PMID- 10348832
TI  - AGA technical review on the evaluation and management of chronic diarrhea.
AB  - This literature review and the recommendations therein were prepared for the
      American Gastroenterological Association Clinical Practice and Practice Economics
      Committee. The paper was approved by the committee on September 27, 1998.

PMID- 10348833
TI  - Of mice and men-the control of food intake and body weight.

PMID- 10348834
TI  - Is reg gene mutation involved in the development of enterochromaffin-like cell
      carcinoid tumors?

PMID- 10348835
TI  - Pigment gallstones in Crohn's disease.

PMID- 10348836
TI  - Why patients on long-term intravenous hyperalimentation are prone to infections.

PMID- 10348838
TI  - Lamivudine for chronic hepatitis B: the magic bullet or just another bright
      prospect?

PMID- 10348837
TI  - Escape from the Smad world by colon cancer.

PMID- 10348839
TI  - Extended lymphadenectomy for carcinoma of the head of the pancreas.

PMID- 10348840
TI  - Schiff's diseases of the liver 

PMID- 10348841
TI  - Anaerobic life-a centennial view.

PMID- 10348842
TI  - Cell cycle expression and transcriptional regulation of DNA topoisomerase IV
      genes in caulobacter.
AB  - DNA replication and differentiation are closely coupled during the Caulobacter
      crescentus cell cycle. We have previously shown that DNA topoisomerase IV (topo
      IV), which is encoded by the parE and parC genes, is required for chromosomal
      partitioning, cell division, and differentiation in this bacterium (D. Ward and
      A. Newton, Mol. Microbiol. 26:897-910, 1997). We have examined the cell cycle
      regulation of parE and parC and report here that transcription of these topo IV
      genes is induced during the swarmer-to-stalked-cell transition when cells prepare
      for initiation of DNA synthesis. The regulation of parE and parC expression is
      not strictly coordinated, however. The rate of parE transcription increases ca.
      20-fold during the G1-to-S-phase transition and in this respect, its pattern of
      regulation is similar to those of several other genes required for chromosome
      duplication. Transcription from the parC promoter, by contrast, is induced only
      two- to threefold during this cell cycle period. Steady-state ParE levels are
      also regulated, increasing ca. twofold from low levels in swarmer cells to a
      maximum immediately prior to cell division, while differences in ParC levels
      during the cell cycle could not be detected. These results suggest that topo IV
      activity may be regulated primarily through parE expression. The presumptive
      promoters of the topo IV genes display striking similarities to, as well as
      differences from, the consensus promoter recognized by the major Caulobacter
      sigma factor sigma73. We also present evidence that a conserved 8-mer sequence
      motif located in the spacers between the -10 and -35 elements of the parE and
      parC promoters is required for maximum levels of parE transcription, which raises
      the possibility that it may function as a positive regulatory element. The
      pattern of parE transcription and the parE and parC promoter architecture suggest
      that the topo IV genes belong to a specialized subset of cell cycle-regulated
      genes required for chromosome replication.

PMID- 10348843
TI  - Saccharomyces cerevisiae mid2p is a potential cell wall stress sensor and
      upstream activator of the PKC1-MPK1 cell integrity pathway.
AB  - The MID2 gene of Saccharomyces cerevisiae encodes a protein with structural
      features indicative of a plasma membrane-associated cell wall sensor. MID2 was
      isolated as a multicopy activator of the Skn7p transcription factor. Deletion of
      MID2 causes resistance to calcofluor white, diminished production of stress
      induced cell wall chitin under a variety of conditions, and changes in growth
      rate and viability in a number of different cell wall biosynthesis mutants.
      Overexpression of MID2 causes hyperaccumulation of chitin and increased
      sensitivity to calcofluor white. alpha-Factor hypersensitivity of mid2Delta
      mutants can be suppressed by overexpression of upstream elements of the cell
      integrity pathway, including PKC1, RHO1, WSC1, and WSC2. Mid2p and Wsc1p appear
      to have overlapping roles in maintaining cell integrity since mid2Delta wsc1Delta
      mutants are inviable on medium that does not contain osmotic support. A role for
      MID2 in the cell integrity pathway is further supported by the finding that MID2
      is required for induction of Mpk1p tyrosine phosphorylation during exposure to
      alpha-factor, calcofluor white, or high temperature. Our data are consistent with
      a role for Mid2p in sensing cell wall stress and in activation of a response that
      includes both increased chitin synthesis and the Mpk1p mitogen-activated protein
      kinase cell integrity pathway. In addition, we have identified an open reading
      frame, MTL1, which encodes a protein with both structural and functional
      similarity to Mid2p.

PMID- 10348844
TI  - Isolation and characterization of mutations in Bacillus subtilis that allow spore
      germination in the novel germinant D-alanine.
AB  - Bacillus subtilis spores break their metabolic dormancy through a process called
      germination. Spore germination is triggered by specific molecules called
      germinants, which are thought to act by binding to and stimulating spore
      receptors. Three homologous operons, gerA, gerB, and gerK, were previously
      proposed to encode germinant receptors because inactivating mutations in those
      genes confer a germinant-specific defect in germination. To more definitely
      identify genes that encode germinant receptors, we isolated mutants whose spores
      germinated in the novel germinant D-alanine, because such mutants would likely
      contain gain-of-function mutations in genes that encoded preexisting germinant
      receptors. Three independent mutants were isolated, and in each case the mutant
      phenotype was shown to result from a single dominant mutation in the gerB operon.
      Two of the mutations altered the gerBA gene, whereas the third affected the gerBB
      gene. These results suggest that gerBA and gerBB encode components of the
      germinant receptor. Furthermore, genetic interactions between the wild-type gerB
      and the mutant gerBA and gerBB alleles suggested that the germinant receptor
      might be a complex containing GerBA, GerBB, and probably other proteins. Thus, we
      propose that the gerB operon encodes at least two components of a multicomponent
      germinant receptor.

PMID- 10348845
TI  - Mutant forms of Salmonella typhimurium sigma54 defective in transcription
      initiation but not promoter binding activity.
AB  - Transcription initiation with sigma54-RNA polymerase holoenzyme (sigma54
      holoenzyme) has absolute requirements for an activator protein and ATP
      hydrolysis. sigma54's binding to core RNA polymerase and promoter DNA has been
      well studied, but little is known about its role in the subsequent steps of
      transcription initiation. Following random mutagenesis, we isolated eight mutant
      forms of Salmonella typhimurium sigma54 that were deficient in transcription
      initiation but still directed sigma54-holoenzyme to the promoter to form a closed
      complex. Four of these mutant proteins had amino acid substitutions in region I,
      which had been shown previously to be required for sigma54-holoenzyme to respond
      to the activator. From the remaining mutants, we identified four residues in
      region III which when altered affect the function of sigma54 at some point after
      closed-complex formation. These results suggest that in addition to its role in
      core and DNA binding, region III participates in one or more steps of
      transcription initiation that follow closed-complex formation.

PMID- 10348847
TI  - Conjugative mobilization of the rolling-circle plasmid pIP823 from Listeria
      monocytogenes BM4293 among gram-positive and gram-negative bacteria.
AB  - We determined the sequence and genetic organization of plasmid pIP823, which
      contains the dfrD gene; dfrD confers high-level trimethoprim resistance to
      Listeria monocytogenes BM4293 by synthesis of dihydrofolate reductase type S2.
      pIP823 possessed all the features of the pUB110/pC194 plasmid family, whose
      members replicate by the rolling-circle mechanism. The rep gene encoded a protein
      identical to RepU, the protein required for initiation of the replication of
      plasmids pTB913 from a thermophilic Bacillus sp. and pUB110 from Staphylococcus
      aureus. The mob gene encoded a protein with a high degree of amino acid identity
      with the Mob proteins involved in conjugative mobilization and interplasmidic
      recombination of pTB913 and pUB110. The host range of pIP823 was broad and
      included L. monocytogenes, Enterococcus faecalis, S. aureus, Bacillus subtilis,
      and Escherichia coli. In all these species, pIP823 replicated by generating
      single-stranded DNA and was stable. Conjugative mobilization of pIP823 was
      obtained by self-transferable plasmids between L. monocytogenes and E. faecalis,
      between L. monocytogenes and E. coli, and between strains of E. coli, and by the
      streptococcal conjugative transposon Tn1545 from L. monocytogenes to E. faecalis,
      and from L. monocytogenes and E. faecalis to E. coli. These data indicate that
      the gene flux observed in nature from gram-positive to gram-negative bacteria can
      occur by conjugative mobilization. Our results suggest that dissemination of
      trimethoprim resistance in Listeria spp. and acquisition of other antibiotic
      resistance determinants in this species can be anticipated.

PMID- 10348846
TI  - Maltose metabolism in the hyperthermophilic archaeon Thermococcus litoralis:
      purification and characterization of key enzymes.
AB  - Maltose metabolism was investigated in the hyperthermophilic archaeon
      Thermococcus litoralis. Maltose was degraded by the concerted action of 4-alpha
      glucanotransferase and maltodextrin phosphorylase (MalP). The first enzyme
      produced glucose and a series of maltodextrins that could be acted upon by MalP
      when the chain length of glucose residues was equal or higher than four, to
      produce glucose-1-phosphate. Phosphoglucomutase activity was also detected in T.
      litoralis cell extracts. Glucose derived from the action of 4-alpha
      glucanotransferase was subsequently metabolized via an Embden-Meyerhof pathway.
      The closely related organism Pyrococcus furiosus used a different metabolic
      strategy in which maltose was cleaved primarily by the action of an alpha
      glucosidase, a p-nitrophenyl-alpha-D-glucopyranoside (PNPG)-hydrolyzing enzyme,
      producing glucose from maltose. A PNPG-hydrolyzing activity was also detected in
      T. litoralis, but maltose was not a substrate for this enzyme. The two key
      enzymes in the pathway for maltose catabolism in T. litoralis were purified to
      homogeneity and characterized; they were constitutively synthesized, although
      phosphorylase expression was twofold induced by maltodextrins or maltose. The
      gene encoding MalP was obtained by complementation in Escherichia coli and
      sequenced (calculated molecular mass, 96,622 Da). The enzyme purified from the
      organism had a specific activity for maltoheptaose, at the temperature for
      maximal activity (98 degrees C), of 66 U/mg. A Km of 0.46 mM was determined with
      heptaose as the substrate at 60 degrees C. The deduced amino acid sequence had a
      high degree of identity with that of the putative enzyme from the
      hyperthermophilic archaeon Pyrococcus horikoshii OT3 (66%) and with sequences of
      the enzymes from the hyperthermophilic bacterium Thermotoga maritima (60%) and
      Mycobacterium tuberculosis (31%) but not with that of the enzyme from E. coli
      (13%). The consensus binding site for pyridoxal 5'-phosphate is conserved in the
      T. litoralis enzyme.

PMID- 10348848
TI  - Isolation and characterization of two cryptic plasmids in the ammonia-oxidizing
      bacterium Nitrosomonas sp. strain ENI-11.
AB  - Two plasmids were discovered in the ammonia-oxidizing bacterium Nitrosomonas sp.
      strain ENI-11, which was isolated from activated sludge. The plasmids, designated
      pAYS and pAYL, were relatively small, being approximately 1.9 kb long. They were
      cryptic plasmids, having no detectable plasmid-linked antibiotic resistance or
      heavy metal resistance markers. The complete nucleotide sequences of pAYS and
      pAYL were determined, and their physical maps were constructed. There existed two
      major open reading frames, ORF1 in pAYS and ORF2 in pAYL, each of which was more
      than 500 bp long. The predicted product of ORF2 was 28% identical to part of the
      replication protein of a Bacillus plasmid, pBAA1. However, no significant
      similarity to any known protein sequences was detected with the predicted product
      of ORF1. pAYS and pAYL had a highly homologous region, designated HHR, of 262 bp.
      The overall identity was 98% between the two nucleotide sequences. Interestingly,
      HHR-homologous sequences were also detected in the genomes of ENI-11 and the
      plasmidless strain Nitrosomonas europaea IFO14298. Deletion analysis of pAYS and
      pAYL indicated that HHR, together with either ORF1 or ORF2, was essential for
      plasmid maintenance in ENI-11. To our knowledge, pAYS and pAYL are the first
      plasmids found in the ammonia-oxidizing autotrophic bacteria.

PMID- 10348849
TI  - Metabolic imbalance and sporulation in an isocitrate dehydrogenase mutant of
      Bacillus subtilis.
AB  - A Bacillus subtilis mutant with a deletion in the citC gene, encoding isocitrate
      dehydrogenase, the third enzyme of the tricarboxylic acid branch of the Krebs
      cycle, exhibited reduced growth yield in broth medium and had greatly reduced
      ability to sporulate compared to the wild type due to a block at stage I, i.e., a
      failure to form the polar division septum. In early stationary phase, mutant
      cells accumulated intracellular and extracellular concentrations of citrate and
      isocitrate that were at least 15-fold higher than in wild-type cells. The growth
      and sporulation defects of the mutant could be partially bypassed by deletion of
      the major citrate synthase gene (citZ), by raising the pH of the medium, or by
      supplementation of the medium with certain divalent cations, suggesting that
      abnormal accumulation of citrate affects survival of stationary-phase cells and
      sporulation by lowering extracellular pH and chelating metal ions. While these
      genetic and environmental alterations were not sufficient to allow the majority
      of the mutant cell population to pass the stage I block (lack of asymmetric
      septum formation), introduction of the sof-1 mutant form of the Spo0A
      transcription factor, when coupled with a reduction in citrate synthesis,
      restored sporulation gene expression and spore formation nearly to wild-type
      levels. Thus, the primary factor inhibiting sporulation in a citC mutant is
      abnormally high accumulation of citrate, but relief of this metabolic defect is
      not by itself sufficient to restore competence for sporulation.

PMID- 10348850
TI  - Role of SpoVG in asymmetric septation in Bacillus subtilis.
AB  - Deletion of the citC gene, coding for isocitrate dehydrogenase, arrests
      sporulation of Bacillus subtilis at stage I after bipolar localization of the
      cell division protein FtsZ but before formation of the asymmetric septum. A
      spontaneous extragenic suppressor mutation that overcame the stage I block was
      found to map within the spoVG gene. The suppressing mutation and other spoVG loss
      of-function mutations enabled citC mutant cells to form asymmetric septa and to
      activate the forespore-specific sigma factor sigmaF. However, little induction of
      mother cell-specific, sigmaE-dependent sporulation genes was observed in a citC
      spoVG double mutant, indicating that there is an additional defect(s) in
      compartmentalized gene expression in the citC mutant. These other defects could
      be partially overcome by reducing the synthesis of citrate, by buffering the
      medium, or by adding excess MnCl2. Overexpression of the spoVG gene in wild-type
      cells significantly delayed sigmaF activation. Increased expression and stability
      of SpoVG in citC mutant cells may contribute to the citC mutant phenotype.
      Inactivation of the spoVG gene caused a population of otherwise wild-type cells
      to produce a small number of minicells during growth and caused sporulating cells
      to complete asymmetric septation more rapidly than normal. Unlike the case for
      inactivation of the cell division inhibitor gene minD, many of these minicells
      contained DNA and appeared only when the primary sporulation signal transduction
      pathway, the Spo0A phosphorelay, was active. These results suggest that SpoVG
      interferes with or is a negative regulator of the pathway leading to asymmetric
      septation.

PMID- 10348851
TI  - Transcriptional control of the iron-responsive fxbA gene by the mycobacterial
      regulator IdeR.
AB  - Exochelin is the primary extracellular siderophore of Mycobacterium smegmatis,
      and the iron-regulated fxbA gene encodes a putative formyltransferase, an
      essential enzyme in the exochelin biosynthetic pathway (E. H. Fiss, Y. Yu, and W.
      R. Jacobs, Jr., Mol. Microbiol. 14:557-569, 1994). We investigated the regulation
      of fxbA by the mycobacterial IdeR, a homolog of the Corynebacterium diphtheriae
      iron regulator DtxR (M. P. Schmitt, M. Predich, L. Doukhan, I. Smith, and R. K.
      Holmes, Infect. Immun. 63:4284-4289, 1995). Gel mobility shift experiments showed
      that IdeR binds to the fxbA regulatory region in the presence of divalent metals.
      DNase I footprinting assays indicated that IdeR binding protects a 28-bp region
      containing a palindromic sequence of the fxbA promoter that was identified in
      primer extension assays. fxbA regulation was measured in M. smegmatis wild-type
      and ideR mutant strains containing fxbA promoter-lacZ fusions. These experiments
      confirmed that fxbA expression is negatively regulated by iron and showed that
      inactivation of ideR results in iron-independent expression of fxbA. However, the
      levels of its expression in the ideR mutant were approximately 50% lower than
      those in the wild-type strain under iron limitation, indicating an undefined
      positive role of IdeR in the regulation of fxbA.

PMID- 10348852
TI  - Transcriptional regulation of the esp genes of enterohemorrhagic Escherichia
      coli.
AB  - We have determined that the genes encoding the secreted proteins EspA, EspD, and
      EspB of enterohemorrhagic Escherichia coli (EHEC) are organized in a single
      operon. The esp operon is controlled by a promoter located 94 bp upstream from
      the ATG start codon of the espA gene. The promoter is activated in the early
      logarithmic growth phase, upon bacterial contact with eukaryotic cells and in
      response to Ca2+, Mn2+, and HEPES. Transcription of the esp operon seems to be
      switched off in tightly attached bacteria. The activation process is regulated by
      osmolarity (induction at high osmolarities), modulated by temperature, and
      influenced by the degree of DNA supercoiling. Transcription is sigmaS dependent,
      and the H-NS protein contributes to its fine tuning. Identification of the
      factors involved in activation of the esp operon and the signals responsible for
      modulation may facilitate understanding of the underlying molecular events
      leading to sequential expression of virulence factors during natural infections
      caused by EHEC.

PMID- 10348853
TI  - Cloning and characterization of the genes encoding a cytochrome P450 (PipA)
      involved in piperidine and pyrrolidine utilization and its regulatory protein
      (PipR) in Mycobacterium smegmatis mc2155.
AB  - Transposon mutagenesis of Mycobacterium smegmatis mc2155 enabled the isolation of
      a mutant strain (called LGM1) altered in the regulation of piperidine and
      pyrrolidine utilization. The complete nucleotide sequence of the gene inactivated
      in mutant LGM1 was determined from the wild-type strain. This gene (pipR) encoded
      a member of the GntR family of bacterial regulatory proteins. An insertion
      element (IS1096), previously described for M. smegmatis, was detected downstream
      of the gene pipR. Three additional open reading frames were found downstream of
      IS1096. The first open reading frame (pipA) appeared to encode a protein
      identified as a cytochrome P450 enzyme. This gene is the first member of a new
      family, CYP151. By a gene replacement experiment, it was demonstrated that the
      cytochrome P450 pipA gene is required for piperidine and pyrrolidine utilization
      in M. smegmatis mc2155. Genes homologous to pipA were detected by hybridization
      in several, previously isolated, morpholine-degrading mycobacterial strains. A
      gene encoding a putative [3Fe-4S] ferredoxin (orf1) and a truncated gene encoding
      a putative glutamine synthetase (orf2') were found downstream of pipA.

PMID- 10348854
TI  - Organization and differential regulation of a cluster of lignin peroxidase genes
      of Phanerochaete chrysosporium.
AB  - The lignin peroxidases of Phanerochaete chrysosporium are encoded by a minimum of
      10 closely related genes. Physical and genetic mapping of a cluster of eight lip
      genes revealed six genes occurring in pairs and transcriptionally convergent,
      suggesting that portions of the lip family arose by gene duplication events. The
      completed sequence of lipG and lipJ, together with previously published
      sequences, allowed phylogenetic and intron/exon classifications, indicating two
      main branches within the lip family. Competitive reverse transcription-PCR was
      used to assess lip transcript levels in both carbon- and nitrogen-limited media.
      Transcript patterns showed differential regulation of lip genes in response to
      medium composition. No apparent correlation was observed between genomic
      organization and transcript levels. Both constitutive and upregulated
      transcripts, structurally unrelated to peroxidases, were identified within the
      lip cluster.

PMID- 10348855
TI  - Growth phase-regulated induction of Salmonella-induced macrophage apoptosis
      correlates with transient expression of SPI-1 genes.
AB  - Invasive Salmonella has been reported to induce apoptosis in a fraction of
      infected macrophages within 2 to 14 h from the time of infection by a mechanism
      involving the type III secretion machinery encoded by the Salmonella
      pathogenicity island 1 (SPI-1). Here, we show that bacteria in the transition
      from logarithmic to stationary phase cause 90% of the macrophages to undergo
      phagocytosis-independent, caspase-mediated apoptosis within 30 to 60 min of
      infection. The ability of Salmonella to induce this rapid apoptosis was growth
      phase regulated and cell type restricted, with epithelial cells being resistant.
      Apoptosis induction was also abrogated by disruption of the hilA gene (encoding a
      regulator of SPI-1 genes) and by the expression of a constitutively active PhoPQ.
      hilA itself and a subset of SPI-1 genes were transiently expressed during aerobic
      growth in liquid medium. Interestingly, however, hilA was found to be required
      only for the expression of the prgH gene, while sipB, invA, and invF were
      expressed in a hilA-independent manner. The expression of SPI-1 genes and the
      secretion of invasion-associated proteins correlated temporally with the
      induction of apoptosis and are likely to represent its molecular basis. Thus,
      growth phase transition regulates the expression and secretion of virulence
      determinants and represents the most efficient environmental cue for apoptosis
      induction reported to date.

PMID- 10348856
TI  - Mapping an interface of SecY (PrlA) and SecE (PrlG) by using synthetic phenotypes
      and in vivo cross-linking.
AB  - SecY and SecE are integral cytoplasmic membrane proteins that form an essential
      part of the protein translocation machinery in Escherichia coli. Sites of direct
      contact between these two proteins have been suggested by the allele-specific
      synthetic phenotypes exhibited by pairwise combinations of prlA and prlG signal
      sequence suppressor mutations in these genes. We have introduced cysteine
      residues within the first periplasmic loop of SecY and the second periplasmic
      loop of SecE, at a specific pair of positions identified by this genetic
      interaction. The expression of the cysteine mutant pair results in a dominant
      lethal phenotype that requires the presence of DsbA, which catalyzes the
      formation of disulfide bonds. A reducible SecY-SecE complex is also observed,
      demonstrating that these amino acids must be sufficiently proximal to form a
      disulfide bond. The use of cysteine-scanning mutagenesis enabled a second contact
      site to be discovered. Together, these two points of contact allow the modeling
      of a limited region of quaternary structure, establishing the first characterized
      site of interaction between these two proteins. This study proves that actual
      points of protein-protein contact can be identified by using synthetic
      phenotypes.

PMID- 10348857
TI  - Complex evolutionary patterns of tRNA Leu(UAA) group I introns in the
      cyanobacterial radiation [corrected].
AB  - Based on the findings that plastids and cyanobacteria have similar group I
      introns inserted into tRNAUAALeu genes, these introns have been suggested to be
      immobile and of ancient origin. In contrast, recent evidence suggests lateral
      transfer of cyanobacterial group I introns located in tRNAUAALeu genes. In light
      of these new findings, we have readdressed the evolution and lateral transfer of
      tRNAUAALeu group I introns in cyanobacteral radiation. We determined the presence
      of introns in 38 different strains, representing the major cyanobacterial
      lineages, and characterized the introns in 22 of the strains. Notably, two of
      these strains have two tRNAUAALeu genes, with each of these genes interrupted by
      introns, while three of the strains have both interrupted and uninterrupted
      genes. Two evolutionary distinct clusters of tRNA genes, with the genes
      interrupted by introns belonging to two distinct intron clusters, were
      identified. We also compared 16S rDNA and intron evolution for both closely and
      distantly related strains. The distribution of the introns in the clustered
      groups, as defined from 16S rDNA analysis, indicates relatively recent gain
      and/or loss of the introns in some of these lineages. The comparative analysis
      also suggests differences in the phylogenetic trees for 16S rDNA and the
      tRNAUAALeu group I introns. Taken together, our results show that the evolution
      of the intron is considerably more complex than previous studies found to be the
      case. We discuss, based on our results, evolutionary models involving lateral
      intron transfer and models involving differential loss of the intron.

PMID- 10348858
TI  - A functional 4-hydroxysalicylate/hydroxyquinol degradative pathway gene cluster
      is linked to the initial dibenzo-p-dioxin pathway genes in Sphingomonas sp.
      strain RW1.
AB  - The bacterium Sphingomonas sp. strain RW1 is able to use dibenzo-p-dioxin,
      dibenzofuran, and several hydroxylated derivatives as sole sources of carbon and
      energy. We have determined and analyzed the nucleic acid sequence of a 9,997-bp
      HindIII fragment downstream of cistrons dxnA1A2, which encode the dioxygenase
      component of the initial dioxygenase system of the corresponding catabolic
      pathways. This fragment contains 10 colinear open reading frames (ORFs),
      apparently organized in one compact operon. The enzymatic activities of some
      proteins encoded by these genes were analyzed in the strain RW1 and, after
      hyperexpression, in Escherichia coli. The first three ORFs of the locus,
      designated dxnC, ORF2, and fdx3, specify a protein with a low homology to
      bacterial siderophore receptors, a polypeptide representing no significant
      homology to known proteins, and a putative ferredoxin, respectively. dxnD encodes
      a 69-kDa phenol monooxygenase-like protein with activity for the turnover of 4
      hydroxysalicylate, and dxnE codes for a 37-kDa protein whose sequence and
      activity are similar to those of known maleylacetate reductases. The following
      gene, dxnF, encodes a 33-kDa intradiol dioxygenase which efficiently cleaves
      hydroxyquinol, yielding maleylacetate, the ketoform of 3-hydroxy-cis,cis
      muconate. The heteromeric protein encoded by dxnGH is a 3-oxoadipate succinyl
      coenzyme A (succinyl-CoA) transferase, whereas dxnI specifies a protein
      exhibiting marked homology to acetyl-CoA acetyltransferases (thiolases). The last
      ORF of the sequenced fragment codes for a putative transposase. DxnD, DxnF, DxnE,
      DxnGH, and DxnI (the activities of most of them have also been detected in strain
      RW1) thus form a complete 4-hydroxysalicylate/hydroxyquinol degradative pathway.
      A route for the mineralization of the growth substrates 3-hydroxydibenzofuran and
      2-hydroxydibenzo-p-dioxin in Sphingomonas sp. strain RW1 thus suggests itself.

PMID- 10348859
TI  - Cd(II)-responsive and constitutive mutants implicate a novel domain in MerR.
AB  - Expression of the Tn21 mercury resistance (mer) operon is controlled by a metal
      sensing repressor-activator, MerR. When present, MerR always binds to the same
      position on the DNA (the operator merO), repressing transcription of the
      structural genes merTPCAD in the absence of Hg(II) and inducing their
      transcription in the presence of Hg(II). Although it has two potential binding
      sites, the purified MerR homodimer binds only one Hg(II) ion, employing Cys82
      from one monomer and Cys117 and Cys126 from the other. When MerR binds Hg(II), it
      changes allosterically and also distorts the merO DNA to facilitate
      transcriptional initiation by sigma70 RNA polymerase. Wild-type MerR is highly
      specific for Hg(II) and is 100- and 1, 000-fold less responsive to the chemically
      related group 12 metals, Cd(II) and Zn(II), respectively. We sought merR mutants
      that respond to Cd(II) and obtained 11 Cd(II)-responsive and 5 constitutive
      mutants. The Cd(II)-responsive mutants, most of which had only single-residue
      replacements, were also repression deficient and still Hg(II) responsive but,
      like the wild type, were completely unresponsive to Zn(II). None of the Cd(II)
      responsive mutations occurred in the DNA binding domain or replaced any of the
      key Cys residues. Five Cd(II)-responsive single mutations lie in the antiparallel
      coiled-coil domain between Cys82 and Cys117 which constitutes the dimer
      interface. These mutations identify 10 new positions whose alteration
      significantly affect MerR's metal responsiveness or its repressor function. They
      give rise to specific predictions for how MerR distinguishes group 12 metals, and
      they refine our model of the novel domain structure of MerR. Secondary-structure
      predictions suggest that certain elements of this model also apply to other MerR
      family regulators.

PMID- 10348860
TI  - Cells of Escherichia coli contain a protein-tyrosine kinase, Wzc, and a
      phosphotyrosine-protein phosphatase, Wzb.
AB  - Two proteins of Escherichia coli, termed Wzc and Wzb, were analyzed for their
      capacity to participate in the reversible phosphorylation of proteins on
      tyrosine. First, Wzc was overproduced from its specific gene and purified to
      homogeneity by affinity chromatography. Upon incubation in the presence of
      radioactive ATP, it was found to effectively autophosphorylate. Two-dimensional
      analysis of its phosphoamino acid content revealed that it was modified
      exclusively at tyrosine. Second, Wzb was also overproduced from the corresponding
      gene and purified to homogeneity by affinity chromatography. It was shown to
      contain a phosphatase activity capable of cleaving the synthetic substrate p
      nitrophenyl phosphate into p-nitrophenol and free phosphate. In addition, it was
      assayed on individual phosphorylated amino acids and appeared to dephosphorylate
      specifically phosphotyrosine, with no effect on phosphoserine or
      phosphothreonine. Such specificity for phosphotyrosine was confirmed by the
      observation that Wzb was able to dephosphorylate previously autophosphorylated
      Wzc. Together, these data demonstrate, for the first time, that E. coli cells
      contain both a protein-tyrosine kinase and a phosphotyrosine-protein phosphatase.
      They also provide evidence that this phosphatase can utilize the kinase as an
      endogenous substrate, which suggests the occurrence of a regulatory mechanism
      connected with reversible protein phosphorylation on tyrosine. From comparative
      analysis of amino acid sequences, Wzc was found to be similar to a number of
      proteins present in other bacterial species which are all involved in the
      synthesis or export of exopolysaccharides. Since these polymers are considered
      important virulence factors, we suggest that reversible protein phosphorylation
      on tyrosine may be part of the cascade of reactions that determine the
      pathogenicity of bacteria.

PMID- 10348861
TI  - Regulation of alginate biosynthesis in Pseudomonas syringae pv. syringae.
AB  - Both Pseudomonas aeruginosa and the phytopathogen P. syringae produce the
      exopolysaccharide alginate. However, the environmental signals that trigger
      alginate gene expression in P. syringae are different from those in P. aeruginosa
      with copper being a major signal in P. syringae. In P. aeruginosa, the alternate
      sigma factor encoded by algT (sigma22) and the response regulator AlgR1 are
      required for transcription of algD, a gene which encodes a key enzyme in the
      alginate biosynthetic pathway. In the present study, we cloned and characterized
      the gene encoding AlgR1 from P. syringae. The deduced amino acid sequence of
      AlgR1 from P. syringae showed 86% identity to its P. aeruginosa counterpart.
      Sequence analysis of the region flanking algR1 in P. syringae revealed the
      presence of argH, algZ, and hemC in an arrangement virtually identical to that
      reported in P. aeruginosa. An algR1 mutant, P. syringae FF5.32, was defective in
      alginate production but could be complemented when algR1 was expressed in trans.
      The algD promoter region in P. syringae (PsalgD) was also characterized and shown
      to diverge significantly from the algD promoter in P. aeruginosa. Unlike P.
      aeruginosa, algR1 was not required for the transcription of algD in P. syringae,
      and PsalgD lacked the consensus sequence recognized by AlgR1. However, both the
      algD and algR1 upstream regions in P. syringae contained the consensus sequence
      recognized by sigma22, suggesting that algT is required for transcription of both
      genes.

PMID- 10348862
TI  - Regulation of hmp gene transcription in Mycobacterium tuberculosis: effects of
      oxygen limitation and nitrosative and oxidative stress.
AB  - The Mycobacterium tuberculosis hmp gene encodes a protein which is homologous to
      flavohemoglobin in Escherichia coli. Northern blotting analysis demonstrated that
      hmp transcription increased when a microaerophilic culture became oxygen limited
      as it entered stationary phase at 20 days. There was a fivefold increase of the
      hmp transcripts during early stationary phase compared with the value which was
      observed in the exponential growth phase. This induction of hmp transcription was
      not due to changes in the mRNA stability since the half-life of hmp mRNA was very
      short in a 20-day microaerophilic culture. No induction of hmp mRNA was observed
      during entry into stationary phase when the culture was continuously aerated. hmp
      transcription was induced after a short exposure of a late-exponential-phase
      culture to anaerobic conditions. These data indicate that oxygen limitation is
      the trigger for hmp gene transcription. In addition, when a microaerophilic
      culture entered into the stationary phase at 20 days, transcription of hmp
      increased to a small extent after exposure to S-nitrosoglutathione (a nitric
      oxide [NO] releaser) and sodium nitroprusside (an NO+ donor) and decreased after
      exposure to paraquat (a superoxide generator) and H2O2. In log phase (4 days) and
      late stationary phase (40 days), the transcription of hmp was unaffected by
      nitrosative and oxidative stress. Three primer extension products were observed.
      The -10 region is 100% identical to that of promoter T3 in mycobacteria and shows
      a strong similarity to the -10 sequence of hmp and rpoS promoters in E. coli.
      These observations of hmp mRNA induction in response to O2 limitation and
      nitrosative stress suggest that the hmp gene of M. tuberculosis may have a role
      in protection of the organism from NO killing under microaerophilic conditions.

PMID- 10348863
TI  - Genetic analysis of a chromosomal region containing vanA and vanB, genes required
      for conversion of either ferulate or vanillate to protocatechuate in
      Acinetobacter.
AB  - VanA and VanB form an oxygenative demethylase that converts vanillate to
      protocatechuate in microorganisms. Ferulate, an abundant phytochemical, had been
      shown to be metabolized through a vanillate intermediate in several Pseudomonas
      isolates, and biochemical evidence had indicated that vanillate also is an
      intermediate in ferulate catabolism by Acinetobacter. Genetic evidence supporting
      this conclusion was obtained by characterization of mutant Acinetobacter strains
      blocked in catabolism of both ferulate and vanillate. Cloned Acinetobacter vanA
      and vanB were shown to be members of a chromosomal segment remote from a
      supraoperonic cluster containing other genes required for completion of the
      catabolism of ferulate and its structural analogs, caffeate and coumarate,
      through protocatechuate. The nucleotide sequence of DNA containing vanA and vanB
      demonstrated the presence of genes that, on the basis of nucleotide sequence
      similarity, appeared to be associated with transport of aromatic compounds,
      metabolism of such compounds, or iron scavenging. Spontaneous deletion of 100 kb
      of DNA containing this segment does not impede the growth of cells with simple
      carbon sources other than vanillate or ferulate. Additional spontaneous mutations
      blocking vanA and vanB expression were shown to be mediated by IS1236, including
      insertion of the newly discovered composite transposon Tn5613. On the whole, vanA
      and vanB appear to be located within a nonessential genetic region that exhibits
      considerable genetic malleability in Acinetobacter. The overall organization of
      genes neighboring Acinetobacter vanA and vanB, including a putative
      transcriptional regulatory gene that is convergently transcribed and overlaps
      vanB, is conserved in Pseudomonas aeruginosa but has undergone radical
      rearrangement in other Pseudomonas species.

PMID- 10348865
TI  - cpmA, a gene involved in an output pathway of the cyanobacterial circadian
      system.
AB  - We generated random mutations in Synechococcus sp. strain PCC 7942 to look for
      genes of output pathways in the cyanobacterial circadian system. A derivative of
      transposon Tn5 was introduced into the chromosomes of reporter strains in which
      cyanobacterial promoters drive the Vibrio harveyi luxAB genes and produce an
      oscillation of bioluminescence as a function of circadian gene expression. Among
      low-amplitude mutants, one mutant, tnp6, had an insertion in a 780-bp open
      reading frame. The tnp6 mutation produced an altered circadian phasing phenotype
      in the expression rhythms of psbAI::luxAB, psbAII::luxAB, and kaiA::luxAB but had
      no or little effect on those of psbAIII::luxAB, purF::luxAB, kaiB::luxAB,
      rpoD2::luxAB, ndhD::luxAB, and conII::luxAB. This suggests that the interrupted
      gene in tnp6, named cpmA (circadian phase modifier), is part of a circadian
      output pathway that regulates the expression rhythms of psbAI, psbAII, and kaiA.

PMID- 10348864
TI  - The physiological contribution of Acinetobacter PcaK, a transport system that
      acts upon protocatechuate, can be masked by the overlapping specificity of VanK.
AB  - VanK is the fourth member of the ubiquitous major facilitator superfamily of
      transport proteins to be identified that, together with PcaK, BenK, and MucK,
      contributes to aromatic catabolism in Acinetobacter sp. strain ADP1. VanK and
      PcaK have overlapping specificity for p-hydroxybenzoate and, most clearly, for
      protocatechuate: inactivation of both proteins severely impairs growth with
      protocatechuate, and the activity of either protein alone can mask the phenotype
      associated with inactivation of its homolog. Furthermore, vanK pcaK double
      knockout mutants appear completely unable to grow in liquid culture with the
      hydroaromatic compound quinate, although such cells on plates convert quinate to
      protocatechuate, which then accumulates extracellularly and is readily visible as
      purple staining. This provides genetic evidence that quinate is converted to
      protocatechuate in the periplasm and is in line with the early argument that
      quinate catabolism should be physically separated from aromatic amino acid
      biosynthesis in the cytoplasm so as to avoid potential competition for
      intermediates common to both pathways. Previous studies of aromatic catabolism in
      Acinetobacter have taken advantage of the ability to select directly strains that
      contain a spontaneous mutation blocking the beta-ketoadipate pathway and
      preventing the toxic accumulation of carboxymuconate. By using this procedure,
      strains with a mutation in structural or regulatory genes blocking degradation of
      vanillate, p-hydroxybenzoate, or protocatechuate were selected. In this study,
      the overlapping specificity of the VanK and PcaK permeases was exploited to
      directly select strains with a mutation in either vanK or pcaK. Spontaneous
      mutations identified in vanK include a hot spot for frameshift mutation due to
      contraction of a G6 mononucleotide repeat as well as point mutations producing
      amino acid substitutions useful for analysis of VanK structure and function.
      Preliminary second-site suppression analysis using transformation-facilitated PCR
      mutagenesis in one VanK mutant gave results similar to those using LacY, the
      prototypic member of the major facilitator superfamily, consistent with the two
      proteins having a similar mechanism of action. The selection for transport
      mutants described here for Acinetobacter may also be applicable to Pseudomonas
      putida, where the PcaK permease has an additional role in chemotaxis.

PMID- 10348867
TI  - Role of genomic rearrangements in producing new ribotypes of Salmonella typhi.
AB  - Salmonella typhi is the only species of Salmonella which grows exclusively in
      humans, in whom it causes enteric typhoid fever. Strains of S. typhi show very
      little variation in electrophoretic types, restriction fragment length
      polymorphisms, cell envelope proteins, and intervening sequences, but the same
      strains are very heterogeneous for ribotypes which are detected with the
      restriction endonuclease PstI. In addition, the genome of S. typhi has been
      proven to undergo genomic rearrangement due to homologous recombination between
      the seven copies of rrn genes. The relationship between ribotype heterogeneity
      and genomic rearrangement was investigated. Strains of S. typhi which belong to
      23 different genome types were analyzed by ribotyping. A limited number of
      ribotypes were found within the same genome type group; e. g., most strains of
      genome type 3 belonged to only two different ribotypes, which result from
      recombination between rrnH and rrnG operons. Different genome type groups
      normally have different ribotypes. The size and identity of the PstI fragment
      containing each of the seven different rrn operons from S. typhi Ty2 were
      determined, and from these data, one can infer how genomic rearrangement forms
      new ribotypes. It is postulated that genomic rearrangement, rather than mutation,
      is largely responsible for producing the ribotype heterogeneity in S. typhi.

PMID- 10348866
TI  - Control of acid resistance in Escherichia coli.
AB  - Acid resistance (AR) in Escherichia coli is defined as the ability to withstand
      an acid challenge of pH 2.5 or less and is a trait generally restricted to
      stationary-phase cells. Earlier reports described three AR systems in E. coli. In
      the present study, the genetics and control of these three systems have been more
      clearly defined. Expression of the first AR system (designated the oxidative or
      glucose-repressed AR system) was previously shown to require the alternative
      sigma factor RpoS. Consistent with glucose repression, this system also proved to
      be dependent in many situations on the cyclic AMP receptor protein. The second AR
      system required the addition of arginine during pH 2.5 acid challenge, the
      structural gene for arginine decarboxylase (adiA), and the regulator cysB,
      confirming earlier reports. The third AR system required glutamate for protection
      at pH 2.5, one of two genes encoding glutamate decarboxylase (gadA or gadB), and
      the gene encoding the putative glutamate:gamma-aminobutyric acid antiporter
      (gadC). Only one of the two glutamate decarboxylases was needed for protection at
      pH 2.5. However, survival at pH 2 required both glutamate decarboxylase isozymes.
      Stationary phase and acid pH regulation of the gad genes proved separable.
      Stationary-phase induction of gadA and gadB required the alternative sigma factor
      sigmaS encoded by rpoS. However, acid induction of these enzymes, which was
      demonstrated to occur in exponential- and stationary-phase cells, proved to be
      sigmaS independent. Neither gad gene required the presence of volatile fatty
      acids for induction. The data also indicate that AR via the amino acid
      decarboxylase systems requires more than an inducible decarboxylase and
      antiporter. Another surprising finding was that the sigmaS-dependent oxidative
      system, originally thought to be acid induced, actually proved to be induced
      following entry into stationary phase regardless of the pH. However, an inhibitor
      produced at pH 8 somehow interferes with the activity of this system, giving the
      illusion of acid induction. The results also revealed that the AR system
      affording the most effective protection at pH 2 in complex medium (either Luria
      Bertani broth or brain heart infusion broth plus 0.4% glucose) is the glutamate
      dependent GAD system. Thus, E. coli possesses three overlapping acid survival
      systems whose various levels of control and differing requirements for activity
      ensure that at least one system will be available to protect the stationary-phase
      cell under naturally occurring acidic environments.

PMID- 10348868
TI  - Function of proline residues of MotA in torque generation by the flagellar motor
      of Escherichia coli.
AB  - Bacterial flagellar motors obtain energy for rotation from the membrane gradient
      of protons or, in some species, sodium ions. The molecular mechanism of flagellar
      rotation is not understood. MotA and MotB are integral membrane proteins that
      function in proton conduction and are believed to form the stator of the motor.
      Previous mutational studies identified two conserved proline residues in MotA
      (Pro 173 and Pro 222 in the protein from Escherichia coli) and a conserved
      aspartic acid residue in MotB (Asp 32) that are important for function. Asp 32 of
      MotB probably forms part of the proton path through the motor. To learn more
      about the roles of the conserved proline residues of MotA, we examined motor
      function in Pro 173 and Pro 222 mutants, making measurements of torque at high
      load, speed at low and intermediate loads, and solvent-isotope effects (D2O
      versus H2O). Proton conduction by wild-type and mutant MotA-MotB channels was
      also assayed, by a growth defect that occurs upon overexpression. Several
      different mutations of Pro 173 reduced the torque of the motor under high load,
      and a few prevented motor rotation but still allowed proton flow through the MotA
      MotB channels. These and other properties of the mutants suggest that Pro 173 has
      a pivotal role in coupling proton flow to motor rotation and is positioned in the
      channel near Asp 32 of MotB. Replacements of Pro 222 abolished function in all
      assays and were strongly dominant. Certain Pro 222 mutant proteins prevented
      swimming almost completely when expressed at moderate levels in wild-type cells.
      This dominance might be caused by rotor-stator jamming, because it was weaker
      when FliG carried a mutation believed to increase rotor-stator clearance. We
      propose a mechanism for torque generation, in which specific functions are
      suggested for the proline residues of MotA and Asp32 of MotB.

PMID- 10348870
TI  - Carbon-13 nuclear magnetic resonance study of metabolism of propionate by
      Escherichia coli.
AB  - We have evaluated the use of [1,2-13C2]propionate for the analysis of propionic
      acid metabolism, based on the ability to distinguish between the methylcitrate
      and methylmalonate pathways. Studies using propionate-adapted Escherichia coli
      MG1655 cells were performed. Preservation of the 13C-13C-12C carbon skeleton in
      labeled alanine and alanine-containing peptides involved in cell wall recycling
      is indicative of the direct formation of pyruvate from propionate via the
      methylcitrate cycle, the enzymes of which have recently been demonstrated in E.
      coli. Additionally, formation of 13C-labeled formate from pyruvate by the action
      of pyruvate-formate lyase is also consistent with the labeling of pyruvate C-1.
      Carboxylation of the labeled pyruvate leads to formation of [1,2
      13C2]oxaloacetate and to multiply labeled glutamate and succinate isotopomers,
      also consistent with the flux through the methylcitrate pathway, followed by the
      tricarboxylic acid (TCA) cycle. Additional labeling of TCA intermediates arises
      due to the formation of [1-13C]acetyl coenzyme A from the labeled pyruvate,
      formed via pyruvate-formate lyase. Labeling patterns in trehalose and glycine are
      also interpreted in terms of the above pathways. The information derived from the
      [1, 2-13C2]propionate label is contrasted with information which can be derived
      from singly or triply labeled propionate and shown to be more useful for
      distinguishing the different propionate utilization pathways via nuclear magnetic
      resonance analysis.

PMID- 10348869
TI  - Role of region C in regulation of the heat shock gene-specific sigma factor of
      Escherichia coli, sigma32.
AB  - Expression of heat shock genes is controlled in Escherichia coli by the
      antagonistic action of the sigma32 subunit of RNA polymerase and the DnaK
      chaperone system, which inactivates sigma32 by stress-dependent association and
      mediates sigma32 degradation by the FtsH protease. A stretch of 23 residues (R122
      to Q144) conserved among sigma32 homologs, termed region C, was proposed to play
      a role in sigma32 degradation, and peptide analysis identified two potential DnaK
      binding sites central and peripheral to region C. Region C is thus a prime
      candidate for mediating stress control of sigma32, a hypothesis that we tested in
      the present study. A peptide comprising the central DnaK binding site was an
      excellent substrate for FtsH, while a peptide comprising the peripheral DnaK
      binding site was a poor substrate. Replacement of a single hydrophobic residue in
      each DnaK binding site by negatively charged residues (I123D and F137E) strongly
      decreased the binding of the peptides to DnaK and the degradation by FtsH.
      However, introduction of these and additional region C alterations into the
      sigma32 protein did not affect sigma32 degradation in vivo and in vitro or DnaK
      binding in vitro. These findings do not support a role for region C in sigma32
      control by DnaK and FtsH. Instead, the sigma32 mutants had reduced affinities for
      RNA polymerase and decreased transcriptional activities in vitro and in vivo.
      Furthermore, cysteines inserted into region C allowed cysteine-specific cross
      linking of sigma32 to RNA polymerase. Region C thus confers on sigma32 a
      competitive advantage over other sigma factors to bind RNA polymerase and thereby
      contributes to the rapidity of the heat shock response.

PMID- 10348871
TI  - Early expression of the calmodulin gene, which precedes appressorium formation in
      Magnaporthe grisea, is inhibited by self-inhibitors and requires surface
      attachment.
AB  - Fungal conidia contain chemicals that inhibit germination and appressorium
      formation until they are well dispersed in a favorable environment. Recently,
      such self-inhibitors were found to be present on the conidia of Magnaporthe
      grisea, and plant surface waxes were found to relieve this self-inhibition. To
      determine whether the self-inhibitors suppress the expression of early genes
      involved in the germination and differentiation of conidia, the calmodulin gene
      was chosen as a representative early gene, because it was found to be expressed
      early in Colletotrichum gloeosporioides and Colletotrichum trifolii
      differentiation. After calmodulin cDNA and genomic DNA from M. grisea were
      cloned, the promoter of the calmodulin gene was fused to a reporter gene, that
      for green fluorescent protein (GFP), and transformed into the M. grisea genome.
      Confocal microscopic examination and quantitation of expression of GFP green
      fluorescence showed (i) that the expression of the calmodulin gene decreased
      significantly when self-inhibition of M. grisea appressorium formation occurred
      because of high conidial density or addition of exogenous self-inhibitors and
      (ii) that the expression level of this gene was restored when self-inhibition was
      relieved by the addition of plant surface waxes. The increase in fluorescence
      correlated with the percentage of conidia that formed appressoria. The induction
      of calmodulin was also confirmed by RNA blotting. Concanavalin A inhibited
      surface attachment of conidia, GFP expression, and appressorium formation without
      affecting germination. The high correlation between GFP expression and
      appressorium formation strongly suggests that calmodulin gene expression and
      appressorium formation require surface attachment.

PMID- 10348872
TI  - Characterization of colicin S4 and its receptor, OmpW, a minor protein of the
      Escherichia coli outer membrane.
AB  - Analysis of the nucleotide sequence of an Escherichia coli colicin S4 determinant
      revealed 76% identity to the pore-forming domain of the colicin A protein, 77%
      identity to the colicin A immunity protein, and 82% identity to the colicin A
      lysis protein. The N-terminal region, which is responsible for the Tol-dependent
      uptake of colicin S4, has 94% identity to the N-terminal region of colicin K. By
      contrast, the predicted receptor binding domain shows no sequence similarities to
      other colicins. Mutants that lacked the OmpW protein were resistant to colicin
      S4.

PMID- 10348873
TI  - Cloning of the glutamyl-tRNA synthetase (gltX) gene from Pseudomonas aeruginosa.
AB  - The glutamyl-tRNA synthetase (gltX) gene from Pseudomonas aeruginosa was
      identified. A plasmid containing a 2.3-kb insert complemented the temperature
      sensitive gltX mutation of Escherichia coli JP1449, and GltX activity was
      demonstrated. The inferred amino acid sequence of this gene showed 50.6% identity
      with GltX from Rhizobium meliloti.

PMID- 10348874
TI  - Importance of a 5' stem-loop for longevity of papA mRNA in Escherichia coli.
AB  - High-level expression of the major pilus subunit (PapA) of uropathogenic strains
      of Escherichia coli results in part from the unusually long lifetime of the mRNA
      that encodes this protein. Here we report that the longevity of papA mRNA derives
      in large measure from the protection afforded by its 5' untranslated region. This
      papA RNA segment can prolong the lifetime of an otherwise short-lived mRNA to
      which it is fused. In vivo alkylation studies indicate that, in its natural
      milieu, the papA message begins with a stem-loop structure. This stem-loop is
      important for the stabilizing effect of the papA 5' untranslated region, as
      evidenced by the significant acceleration in papA mRNA decay that results from
      its removal.

PMID- 10348875
TI  - Membrane topology of MntB, the transmembrane protein component of an ABC
      transporter system for manganese in the cyanobacterium Synechocystis sp. strain
      PCC 6803.
AB  - The structure of the membrane protein MntB, a component of a manganese
      transporter system in Synechocystis sp. strain PCC 6803, was examined with a
      series of fusions to the reporter proteins alkaline phosphatase and beta
      galactosidase. The results support a topological model for MntB consisting of
      nine transmembrane segments, with the amino terminus of the protein being in the
      periplasm and the carboxyl terminus being in the cytoplasm.

PMID- 10348876
TI  - Comparison of the heme iron utilization systems of pathogenic Vibrios.
AB  - Vibrio alginolyticus, Vibrio fluvialis, and Vibrio parahaemolyticus utilized heme
      and hemoglobin as iron sources and contained chromosomal DNA similar to several
      Vibrio cholerae heme iron utilization genes. A V. parahaemolyticus gene that
      performed the function of V. cholerae hutA was isolated. A portion of the tonB1
      locus of V. parahaemolyticus was sequenced and found to encode proteins similar
      in amino acid sequence to V. cholerae HutW, TonB1, and ExbB1. A recombinant
      plasmid containing the V. cholerae tonB1 and exbB1D1 genes complemented a V.
      alginolyticus heme utilization mutant. These data suggest that the heme iron
      utilization systems of the pathogenic vibrios tested, particularly V.
      parahaemolyticus and V. alginolyticus, are similar at the DNA level, the
      functional level, and, in the case of V. parahaemolyticus, the amino acid
      sequence or protein level to that of V. cholerae.

PMID- 10348877
TI  - Analysis of the 5' portion of the type 19A capsule locus identifies two classes
      of cpsC, cpsD, and cpsE genes in Streptococcus pneumoniae.
AB  - Analysis of the sequence data obtained from the 5' portion of the Streptococcus
      pneumoniae type 19A capsular polysaccharide biosynthesis locus (cps19a) revealed
      that the first seven genes are homologous to the first seven genes in the type
      19F (cps19f) locus. The former genes were designated cps19aA to -G and were 70 to
      90% identical to their cps19f counterparts. Southern hybridization analysis of
      the cps loci from various S. pneumoniae serotypes with probes specific for the
      cps19aC, cps19aD, and cps19aE genes indicated a hybridization pattern
      complementary to that previously reported for cps19fC, cps19fD, and cps19fE. That
      is, all serotypes tested contained high-stringency homologues of either the
      cps19aC to -E genes or the cps19fC to -E genes, but not both. On this basis S.
      pneumoniae cps loci can be divided into two distinct classes. Long-range PCR was
      used to amplify the cps regions between cpsB and aliA from a variety of
      pneumococcal serotypes. Direct sequencing of the 5' end of these PCR products,
      and phylogenetic analysis of the sequence data, confirmed the presence of the two
      distinct classes of cpsC. Whereas members within one class are greater than 95%
      identical to each other, the DNA sequence identity between the two classes is
      only approximately 70%.

PMID- 10348878
TI  - A role for the mannose-sensitive hemagglutinin in biofilm formation by Vibrio
      cholerae El Tor.
AB  - While much has been learned regarding the genetic basis of host-pathogen
      interactions, less is known about the molecular basis of a pathogen's survival in
      the environment. Biofilm formation on abiotic surfaces represents a survival
      strategy utilized by many microbes. Here it is shown that Vibrio cholerae El Tor
      does not use the virulence-associated toxin-coregulated pilus to form biofilms on
      borosilicate but rather uses the mannose-sensitive hemagglutinin (MSHA) pilus,
      which plays no role in pathogenicity. In contrast, attachment of V. cholerae to
      chitin is shown to be independent of the MSHA pilus, suggesting divergent
      pathways for biofilm formation on nutritive and nonnutritive abiotic surfaces.

PMID- 10348880
TI  - Inequity as Violence: Race, Health and Human Rights in the United States.

PMID- 10348879
TI  - Salmonella typhimurium IroN and FepA proteins mediate uptake of enterobactin but
      differ in their specificity for other siderophores.
AB  - Salmonella typhimurium possesses two outer membrane receptor proteins, IroN and
      FepA, which have been implicated in the uptake of enterobactin. To determine
      whether both receptors have identical substrate specificities, fepA and iroN
      mutants and a double mutant were characterized. While both receptors transported
      enterobactin, the uptake of corynebactin and myxochelin C was selectively
      mediated by IroN and FepA, respectively.

PMID- 10348883
TI  - Sexual Rights: Concepts and Action.

PMID- 10348881
TI  - The Prevention of Institutionalized Intergroup Violence.

PMID- 10348884
TI  - Activism for Sexual and Reproductive Rights: Progress and Challenges.

PMID- 10348885
TI  - Implementing Sexual and Reproductive Rights in Colombia.

PMID- 10348886
TI  - Strengthening Alliances for Sexual Health and Rights.

PMID- 10348887
TI  - Health and Human Rights: The Equity Issue.

PMID- 10348889
TI  - Promoting Child Health and the Convention on the Rights of the Child.

PMID- 10348888
TI  - Challenges of Global Health: How Can We Do Better?

PMID- 10348891
TI  - A Personal Perspective on Human Rights and Health.

PMID- 10348890
TI  - Women's Human Rights and Health in Developing Countries.

PMID- 10348892
TI  - Common Strategies for Health and Human Rights: From Theory to Practice.

PMID- 10348893
TI  - Report from the Conference Rapporteur.

PMID- 10348894
TI  - Health and Human Rights: If Not Now, When?

PMID- 10348895
TI  - A Call to Action on the 50th Anniversary of the Universal Declaration of Human
      Rights.

PMID- 10348897
TI  - Role of tyrosine 265 of alanine racemase from Bacillus stearothermophilus.
AB  - Tyrosine 265 (Y265) of Bacillus stearothermophilus is believed to serve as a
      catalytic base specific to the L-enantiomer of a substrate amino acid by removing
      (or returning) an alpha-hydrogen from (or to) the isomer on the basis of the X
      ray structure of the enzyme [Stamper, C.G., Morollo, A.A., and Ringe, D. (1998)
      Biochemistry 37, 10438-10443]. We found that the Y265-->Ala mutant (Y265A) enzyme
      is virtually inactive as a catalyst for alanine racemization. We examined the
      role of Y265 further with beta-chloroalanine as a substrate with the expectation
      that the Y265A mutant only catalyzes the alpha,beta-elimination of the D
      enantiomer of beta-chloroalanine. However, L-beta-chloroalanine also served as a
      substrate; this enantiomer was rather better as a substrate than its antipode.
      Moreover, the mutant enzyme was as equally active as the wild-type enzyme in the
      elimination reaction. These findings indicate that Y265 is essential for alanine
      racemization but not for beta-chloroalanine elimination.

PMID- 10348896
TI  - Crystallographic studies on a family B DNA polymerase from hyperthermophilic
      archaeon Pyrococcus kodakaraensis strain KOD1.
AB  - A hyperthermostable family B DNA polymerase from the hyperthermophilic archaeon,
      Pyrococcus kodakaraensis strain KOD1, has been crystallized by the hanging-drop
      vapor diffusion method at 293 K with 2-methyl-2,4-pentanediol as the precipitant.
      The diffraction pattern of a crystal extends to 3.0 A resolution, and two full
      sets of 3.0 A resolution diffraction data for native crystals were successfully
      collected at 290 K and 100 K upon exposure to synchrotron radiation at KEK-PF,
      Japan. The crystals belong to the space group, P212121, with unit-cell dimensions
      of a = 112.8, b = 115.4, and c = 75.4 A at 290 K, and a = 111.9, b = 112.4, and c
      = 73.9 at 100 K. Structural analysis by means of the multiple isomorphous
      replacement method is now in progress.

PMID- 10348898
TI  - Restoration to a quiescent and contractile phenotype from a proliferative
      phenotype of myofibroblast-like human aortic smooth muscle cells by culture on
      type IV collagen gels.
AB  - Aortic smooth muscle cells (A-SMC) undergo phenotypic transition to a synthetic
      and proliferative state and become fibroblast-like cells upon serial passage with
      culture on plastic dishes, especially in the presence of serum. Such fibroblast
      like cells (M-SMC) derived from A-SMC may correspond to the cells identified
      pathologically as myofibroblasts. We examined the effects of type IV collagen
      gels used as a culture substrate on the morphology and proliferation of M-SMC.
      The M-SMC underwent extreme elongation in shape when cultured on rigid type IV
      collagen gels, and eventually formed cell-to-cell junctions with the elongated
      processes. In contrast, M-SMC showed a spindle-like cell shape on dishes coated
      with a type IV collagen solution or type I collagen solution, or on type I
      collagen gels or fragile type IV collagen gels. Cell proliferation was totally
      repressed by culture on rigid type IV collagen gels for over 10 days, while the
      highest proliferative activity was seen for cells grown on dishes coated with
      type IV collagen solution. The expression of smooth muscle myosin heavy chains,
      specific markers for contractile A-SMC, was acquired by M-SMC cultured on rigid
      type IV collagen gels for 3 days, while M-SMC cultured on type IV collagen-coated
      dishes continued to show no expression. These results suggest that the quiescent
      and contractile phenotype of A-SMC might be restored in M-SMC by culture on rigid
      type IV collagen gels, even after they have become myofibroblastic.

PMID- 10348899
TI  - Characterization of heparin low-affinity phospholipase A1 present in brain and
      testicular tissue.
AB  - We identified a unique phospholipase A (PLA) with relatively low heparin
      affinity, which was distinguishable from the heparin-binding secretory PLA2s, in
      rat, mouse, and bovine brains and testes. The partially purified enzyme was Ca2+
      independent at neutral pH but Ca2+-dependent at alkaline pH. It predominantly
      hydrolyzed phosphatidic acid (PA) in the presence of Triton X-100 and
      phosphatidylethanolamine (PE) in its absence. When rat brain-derived endogenous
      phospholipids were used as a substrate, the enzyme released saturated fatty acids
      in marked preference to unsaturated ones. Consistent with this observation, the
      enzyme hydrolyzed sn-1 ester bonds in the substrates about 2,000 times more
      efficiently than sn-2 ones, thereby acting like PLA1. The enzyme also exhibited
      weak but significant sn-1 lysophospholipase activity. On the basis of its limited
      tissue distribution, substrate head group specificity and immunochemical
      properties, this enzyme appears to be identical to the recently cloned PA
      preferring PLA1.

PMID- 10348901
TI  - Identification and designing of the S3 site of aqualysin I, a thermophilic
      subtilisin-related serine protease.
AB  - Aqualysin I is a bacterial subtilisin-related alkaline serine protease,
      originating in Thermus aquaticus YT-1. Based on computational analysis, we
      predicted that two residues, Ser102 and Gly131, form the S3 site of aqualysin I,
      and we proved that this prediction by site-directed mutagenesis. To alter the P3
      specificity of the enzyme, we built a "wall" on the S3 site edge by introducing a
      bulky side chain at target sites. Six mutant proteins were prepared: S102H,
      S102K, S102E, G131H, G131K, and G131D. The mutant enzymes were examined with two
      kinetically typical peptides for aqualysin I, suc-X-Ala-Ala-pNA, where X is Ala
      or Phe. All mutations reduced the efficiency for the Phe-containing peptide,
      while they raised the k(cat) values for the Ala-containing peptide. Especially,
      the S102K mutant protein hydrolyzed the polyalanine peptide efficiently. The
      strategies we have adopted in this paper are applicable to all subtilisin-related
      enzymes.

PMID- 10348900
TI  - A novel crosslinking reagent and its application for the detection and isolation
      of heparin-binding protein(s) on the platelet surface.
AB  - A new hetero-bifunctional photo crosslinking reagent, 2-(4-azidoanilyl)-4-(4
      azabicyclo-[2,2, 2]hexylammonio)-6-morpholino-1,3,5-triazine chloride, was
      designed to detect and isolate heparin-binding protein(s) that may act as heparin
      receptor(s) on the platelet surface. In a preliminary study using ethanol as a
      model substrate, the reagent was shown to react with the alcoholic hydroxy group
      under mild conditions and its crosslinking photoreactivity was high. The reagent
      effectively formed similar covalent bonds with heparin, while preserving its
      anticoagulant anti-Xa activity. [3H]Heparin labeled with this reagent crosslinked
      to antithrombin III very specifically but not to ovalbumin, as analyzed by the
      Bio-imaging Analyzer System (BAS, Fuji Photo Film, Tokyo). Affinity crosslinking
      of [3H]heparin was then used to detect heparin-binding proteins on the surface of
      intact platelets. Several discrete protein bands were detected by the BAS-imaging
      of SDS-PAGE.

PMID- 10348902
TI  - Molecular cloning of Ca2+/calmodulin-dependent protein kinase phosphatase.
AB  - Calmodulin-dependent protein kinase (CaM-kinase) phosphatase dephosphorylates and
      concomitantly deactivates CaM-kinase II activated upon autophosphorylation, and
      CaM-kinases IV and I activated upon phosphorylation by CaM-kinase kinase [Ishida,
      I., Okuno, S., Kitani, T., Kameshita, I., and Fujisawa, H. (1998) Biochem.
      Biophys. Res. Commun. 253, 159-163], suggesting that CaM-kinase phosphatase plays
      important roles in the function of Ca2+ in the cell, because the three
      multifunctional CaM-kinases (CaM-kinases I, II, and IV) are thought to be the key
      enzymes in the Ca2+-signaling system. In the present study, cDNA for CaM-kinase
      phosphatase was cloned from a rat brain cDNA library. The coded protein consisted
      of 450 amino acids with a molecular weight of 49, 165. Western blot analysis
      showed the ubiquitous tissue distribution of CaM-kinase phosphatase.
      Immunocytochemical analysis revealed that CaM-kinase phosphatase is evenly
      distributed outside the nucleus in a cell.

PMID- 10348903
TI  - Biochemical analysis of a 5S rRNA-associated sub-particle from trypsinized
      eukaryotic ribosomes.
AB  - On limited trypsinization, eukaryotic ribosomes released sub-particles that
      comprised a 5S rRNA molecule and two peptides (a 32 kDa and a 14 kDa). By tryptic
      finger-printing and amino-terminal sequence analysis, these two peptides were
      determined to be derived from large subunit ribosomal protein L5 (rpL5). The 32
      kDa peptide represents the rpL5 protein minus the amino terminal eight residues
      and the carboxyl terminal ends (approximately 21 residues), whereas the 14 kDa
      peptide comprised near the amino-terminal region. The time course of ribosome
      trypsinization revealed that the two peptides were released kinetically. The
      indicated that the amino and carboxyl terminal ends of rpL5 were the first to be
      hydrolyzed, suggesting that the two ends of the rpL5 protein were exposed on the
      surface of ribosomes. Exposure of the carboxyl-terminal end was confirmed by use
      of an anti-L5c antibody raised against the carboxyl terminal region of rpL5. The
      kinetic data also revealed that the nearby amino terminal region of rpL5
      (represented by the 14 kDa peptide) was the last part of rpL5 to be hydrolyzed,
      which was considered to be the 5S rRNA binding site.

PMID- 10348904
TI  - Gene transfer mediated by YKS-220 cationic particles: convenient and efficient
      gene delivery reagent.
AB  - A monocationic lipid, YKS-220, with a symmetrical and biodegradable structure can
      be used as an effective gene transfer vector in a cationic particle form (not a
      cationic liposome form), and is obtained by diluting an ethanol solution of YKS
      220 and DOPE (1:5, molar ratio) with an aqueous medium. This preparation method
      is more convenient than that for cationic liposomes. YKS-220 cationic particles
      showed a heterogeneous large mean diameter of 4.4 microm. An obvious size change
      was not observed when plasmid DNA was added. The transfection activity of YKS-220
      cationic particles was comparable to those of YKS-220 liposomes and DOSPA
      liposomes (LipofectAMINE), and even higher than that of DOGS (TRNSFECTAM).
      Interestingly, the YKS-220 cationic particle/DNA complexes were resistant to the
      neutralizing effect of serum. All of these findings indicate that YKS-220
      cationic particles are a convenient and efficient gene delivery reagent.

PMID- 10348905
TI  - Monkey hepatocytes efficiently express tissue factor pathway inhibitor (TFPI), in
      contrast with human and rat hepatocytes.
AB  - It has been reported that tissue factor pathway inhibitor (TFPI), a Kunitz-type
      protease inhibitor that regulates the extrinsic blood coagulation pathway, is not
      expressed in human, bovine, rabbit, or rat liver. Here, we found that TFPI is
      efficiently expressed in Macaque monkey liver. Monkey hepatocytes were identified
      as the expression cells by Northern blot analysis. The hepatocytes were stained
      with anti-human TFPI antibody, as were endothelial cells of the small vessels. We
      isolated and sequenced the 5'-flanking 1.4 kb regions of monkey and human TFPI
      genes, and found them to show 92.6% identity in their nucleotide sequences. We
      measured their transcriptional activities using a luciferase reporter gene and
      showed that the activity of the monkey TFPI gene is higher than that of the human
      gene in monkey primary hepatocytes. Although the binding motif of hepatocyte
      nuclear factor-1 is present only in the monkey gene, the site does not seem to be
      involved in the transcriptional activity. Mutagenetic analyses revealed that the
      region from -138 to +28 in the monkey gene is important for the expression of
      TFPI in hepatocytes. The present study indicates that the expression of the
      monkey TFPI gene is regulated by different mechanisms from the human TFPI gene.

PMID- 10348906
TI  - Characterization of recombinant mouse epidermal-type transglutaminase (TGase 3):
      regulation of its activity by proteolysis and guanine nucleotides.
AB  - Epidermal-type TGase (TGase 3) is involved in the formation of the cornified cell
      envelope by cross-linking a variety of structural proteins in the epidermis.
      Unknown proteases activate this enzyme from the zymogen form by limited
      proteolysis during epidermal differentiation. It has been difficult to isolate
      sufficient quantities of native enzymes from tissues for biochemical studies of
      the properties of TGase 3. In this paper, we circumvented these problems by
      expressing recombinant full-length mouse TGase 3 in a baculovirus system, and
      purifying it to homogeneity by successive chromatography and HPLC. Treatment of
      the purified recombinant protein with dispase, a bacterial protease known to
      activate zymogens, produced activated TGase 3. The migration of TGase 3 zymogen
      in SDS-polyacrylamide gel electrophoresis was anomalous when the proTGase 3 was
      pre-incubated with calcium ion. GTP inhibited the enzymatic activity of
      recombinant TGase 3. Calpain, a calcium-dependent neutral protease, was a
      candidate protease, but had no effect on the activation of TGase 3 zymogen.

PMID- 10348907
TI  - Inhibitory effect of the catalytic domain of myosin light chain kinase on actin
      myosin interaction: insight into the mode of inhibition.
AB  - The catalytic domain of myosin light chain kinase (MLCK) not only exerts kinase
      activity to phosphorylate the 20 kDa light chain but also inhibits the actin
      myosin interaction. The site of action of this novel role of the domain has been
      suggested to be myosin [Okagaki et al. (1999) J. Biochem. 125, 619-626]. In this
      study, we have analyzed the amino acid sequences of MLCK and myosin that are
      involved in the inhibition. The ATP-binding peptide of Gly526-Lys548 of chicken
      gizzard MLCK exerted the inhibitory effect on the movement of actin filaments on
      a myosin-coated glass surface. However, the peptide that neighbors the sequence
      failed to inhibit the movement. The inhibition of the ATP-binding peptide was
      confirmed by measuring ATPase activities of the myosin. The inhibition by parent
      MLCK of the movement was relieved by the 20 kDa light chain, but not by the 17
      kDa myosin light chain. The peptide of the 20 kDa light chain sequence of Ser1
      Glu29 also relieved the inhibition. Thus, the interaction of the ATP-binding
      sequence with the 20 kDa light chain sequence should cause the inhibition of the
      actin-myosin interaction. Concerning the regulation of the inhibition, calmodulin
      relieved the inhibitory effect of MLCK on the movement of actin filaments. The
      calmodulin-binding peptide (Ala796 Ser815) prevented the relief, suggesting the
      involvement of this sequence. Thus, the mode of regulation by Ca2+ and calmodulin
      of the novel role of the catalytic domain is similar, but not identical, to the
      mode of regulation of the kinase activity of the domain.

PMID- 10348908
TI  - A fission yeast gene (prr1(+)) that encodes a response regulator implicated in
      oxidative stress response.
AB  - An inspection of the Schizosaccharomyces pombe genome database revealed that this
      eukaryotic microorganism possesses a gene that may encode a bacterial type of
      histidine-to-aspartate (His-Asp) phosphorelay component, namely, a response
      regulator. The predicted gene, named prr1(+) (S. pombe response regulator),
      encodes a protein that contains a typical phospho-accepting receiver domain,
      preceded by a mammalian heat shock factor (HSF)-like DNA-binding domain.
      Inactivation of this prr1(+) gene resulted in mutant cells defective in some
      aspects of stress responses, including sensitivity to oxidative stress, cold
      temperature, and heavy metal toxicity. It was also demonstrated that Prr1 is
      required for the transcription of some genes (e.g., trr1(+), ctt1(+)), which are
      induced by oxidative stress. These results suggest that a His-Asp phosphorelay
      system may be involved in a stress-activated signaling pathway in S. pombe.

PMID- 10348909
TI  - Expression of trypsin in human cancer cell lines and cancer tissues and its tight
      binding to soluble form of Alzheimer amyloid precursor protein in culture.
AB  - It was recently found that overexpression of the trypsin gene in tumor cells
      stimulates their growth in culture and in nude mice. In the present study,
      expression of trypsin in various human cancer cell lines and tissues was studied
      by gelatin zymography and immunoblotting before and after enterokinase treatment
      and by immunohistochemistry. The analyses showed that many stomach, colon, and
      breast cancer cell lines secreted trypsinogens-1 and/or -2, as well as an
      unidentified serine proteinase of about 70 kDa, into culture medium. Lung cancer
      cell lines secreted 18- and 19-kDa unidentified trypsin-like proteins. Stomach
      cancer cell lines frequently secreted active trypsin, suggesting that they
      produced an endogenous activator of trypsinogen, most likely enterokinase. Active
      trypsin formed a complex with a soluble form of Alzheimer amyloid precursor
      protein (sAPP), a Kunitz-type trypsin inhibitor, which was secreted by all cell
      lines tested. This indicated that sAPP is a primary inhibitor of secreted
      trypsin. Immunohistochemical analysis showed that trypsin(ogen) was frequently
      expressed at high levels in stomach and colon cancers, but scarcely in breast
      cancers. In the stomach cancers, the trypsin immunoreactivity was higher in the
      malignant, non-cohesive type than in the cohesive type. These results support the
      hypothesis that tumor-derived trypsin is involved in the malignant growth of
      tumor cells, especially stomach cancer cells.

PMID- 10348910
TI  - Purification and characterization of diacylglycerol lipase from human platelets.
AB  - Diacylglycerol lipase (DGL) was solubilized from human platelet microsomes with
      heptyl-beta-D-thioglucoside, and purified to homogeneity on SDS-PAGE using a
      combination of chromatographic and electrophoretic methods. The molecular mass of
      the purified DGL was estimated to be 33 kDa. Its apparent pI was pH 6.0, as
      determined by Immobiline isoelectro-focusing. The enzymatic activity of the
      partially purified DGL was investigated in the presence of a variety of
      inhibitors and reagents, as well as its pH and calcium dependence. Thiol reagents
      such as p-chloromercurubenzoic acid (pCMB), N-ethylmaleimide (NEM), and HgCl2
      inhibited the activity, while dithiothreitol (DTT) and reduced glutathione (GSH)
      enhanced it. In addition, the enzymatic activity was inhibited by two serine
      blockers, phenylmethylsulfonyl fluoride (PMSF) and diisopropyl fluorophosphate
      (DFP), and by a histidine modifying reagent, p-bromophenacyl bromide (pBPB).
      These results suggest that cysteine, serine and histidine residues are required
      for the enzymatic activity of DGL. DGL was optimally active in the pH range of 7
      8 and its activity did not change significantly in the presence of various
      calcium concentrations, even in the presence of 2 mM EGTA. This indicates that
      DGL can hydrolyze substrates with a basal cytosolic free Ca2+ level in the
      physiological pH range. A DGL inhibitor, RHC-80267, inhibited DGL activity in a
      dose-dependent manner with an IC50 (the concentration required for 50%
      inhibition) of about 5 microM. Unexpectedly, several phospholipase A2 (PLA2)
      inhibitors were potent inhibitors of DGL activity (IC50<5 microM), suggesting
      that the catalytic mechanisms of DGL and PLA2 may be similar. Finally, we show
      that DGL activity was inhibited by 2-monoacylglycerols (2-MGs), the reaction
      products of this enzyme. Among the three 2-MGs tested (2-arachidonoyl glycerol, 2
      stearoyl glycerol, and 2-oleoyl glycerol), 2-arachidonoyl glycerol was the most
      potent inhibitor.

PMID- 10348911
TI  - Sequence of the V. parahaemolyticus gene for cytoplasmic N, N'-diacetylchitobiase
      and homology with related enzymes.
AB  - The nucleotide sequence of the gene encoding the cytoplasmic N, N'
      diacetylchitobiase [EC 3.2.1.14] from Vibrio parahaemolyticus (ATCC #27969) has
      been determined. The deduced peptide sequence of this unusual beta-hexosaminidase
      surprisingly shows minimum evolutionary relationship to two other reported N, N'
      diacetylchitobiases from vibrios, except in highly conserved regions which are
      also homologous to lysosomal beta-hexosaminidases from eukaryotes including
      humans. In contrast, the two other beta-hexosaminidases from vibrios with
      reported sequences are much more closely related to each other. This novel 85 kDa
      cytoplasmic glycosyl hydrolase with restricted specificity participates in the
      high level utilization of chitin-derived 2-deoxy-2-acetamido-D-glucose (GlcNAc)
      by vibrios as one of two parallel pathways for the metabolism of N,N'
      diacetylchitobiose [Bassler, B.L., Yu, C., Lee, Y.C., and Roseman, S. (1991) J.
      Biol. Chem. 266, 24276-24286]. These pathways use chitin-binding proteins for the
      adherence of the bacterial chitinase to the substrate, and an extracellular
      chitinase and a periplasmic chitodextrinase to produce N,N'-diacetylchitobiose.
      The V. parahaemolyticus cytoplasmic N,N'-diacetyl-chitobiase reported herein
      appears to be a unique protein, lacking a signal sequence, and genetically
      distant from other known chitinoclastic beta-N,N'-diacetyl-hexosaminidases. This
      is consistent with its limited substrate specificity to small GlcNAc terminated
      oligosaccharides and its cytoplasmic rather than periplasmic localization.

PMID- 10348912
TI  - Genetic analysis of cytochrome b5 from arachidonic acid-producing fungus,
      Mortierella alpina 1S-4: cloning, RNA editing and expression of the gene in
      Escherichia coli, and purification and characterization of the gene product.
AB  - Information on the amino acid sequences of the internal peptide fragments of
      cytochrome b5 from Mortierella hygrophila was used to prepare synthetic
      oligonucleotides as primers for the polymerase chain reaction. A 100-base DNA
      fragment was thus amplified, by using a genomic gene from Mortierella alpina 1S-4
      as a template, which produced polyunsaturated fatty acids such as arachidonic
      acid. The amplified DNA fragment was used as the probe to clone both a 523-base
      cDNA fragment and a 2.1-kilobase SalI-NruI genomic fragment coding for the whole
      M. alpina 1S-4 cytochrome b5. On the basis of nucleotide sequences of both
      cytochrome b5 genomic gene and cDNA, the genomic cytochrome b5 gene was found to
      consist of four exons and three introns. A novel type of RNA editing, in which
      the cDNA included either guanine insertion or adenine-->guanine substitution at
      one base upstream of poly(A), was interestingly observed. The deduced amino acid
      sequence of M. alpina 1S-4 cytochrome b5 showed significant similarities with
      those of cytochrome b5s from other organisms such as rat, chicken, and yeast. The
      soluble form of the cytochrome b5 gene was expressed to 16% of the total soluble
      protein in Escherichia coli. The holo-cytochrome b5 accounted for 8% of the total
      cytochrome b5 in the transformants. The purified cytochrome b5 showed the
      oxidized and reduced absorbance spectra characteristic of fungal microsomal
      cytochrome b5.

PMID- 10348913
TI  - Retrovirus integration site Mintb encoding the mouse homolog of hnRNP U.
AB  - Retroviral genes are not usually expressed in mouse embryonal carcinoma (EC)
      cells, but they are readily expressed upon differentiation of these cells. We
      previously reported the isolation of EC cell lines that express a neomycin
      resistance (neo) gene introduced by a recombinant transducing Moloney murine
      leukemia virus from specific integration sites, Minta, Mintb, Mintc, or Mintd. In
      some of these clones, the entire 5' long terminal repeat (LTR) was deleted, and
      the neo gene was expressed by read-through transcription from upstream cellular
      promoters in a "promoter-trap" fashion. One such promoter ("promoter B" at the
      Mintb locus) was found in a CpG island, associated with an upstream enhancer
      ("enhancer B"). Although enhancer B caused expression of the neo gene in the
      transductant EC cell line, no endogenous transcription from promoter B was
      detected in the parental EC or NIH3T3 cells. In contrast, we found a strong
      counter-flow endogenous transcription unit ("R" for reverse), which apparently
      interfered with transcription from promoter B. Promoter R turned out to have a
      bidirectional activity in transfection assays. In normal tissues, promoter R
      activates gene R, which encodes an 800-residue protein that is highly homologous
      to the rat and human heterogeneous nuclear ribonucleoprotein U (hnRNP U).
      Northern and in situ hybridization analyses revealed that gene R was abundantly
      expressed in the testis, especially in the pachytene spermatocytes and round
      spermatids.

PMID- 10348915
TI  - Crystal structure of beta-amylase from Bacillus cereus var. mycoides at 2.2 A
      resolution.
AB  - The crystal structure of beta-amylase from Bacillus cereus var. mycoides was
      determined by the multiple isomorphous replacement method. The structure was
      refined to a final R-factor of 0.186 for 102,807 independent reflections with
      F/sigma(F) > or = 2.0 at 2.2 A resolution with root-mean-square deviations from
      ideality in bond lengths, and bond angles of 0.014 A and 3.00 degrees,
      respectively. The asymmetric unit comprises four molecules exhibiting a dimer-of
      dimers structure. The enzyme, however, acts as a monomer in solution. The beta
      amylase molecule folds into three domains; the first one is the N-terminal
      catalytic domain with a (beta/alpha)8 barrel, the second one is the excursion
      part from the first one, and the third one is the C-terminal domain with two
      almost anti-parallel beta-sheets. The active site cleft, including two putative
      catalytic residues (Glu172 and Glu367), is located on the carboxyl side of the
      central beta-sheet in the (beta/alpha)8 barrel, as in most amylases. The active
      site structure of the enzyme resembles that of soybean beta-amylase with slight
      differences. One calcium ion is bound per molecule far from the active site. The
      C-terminal domain has a fold similar to the raw starch binding domains of
      cyclodextrin glycosyltransferase and glucoamylase.

PMID- 10348914
TI  - Selection of an RNA molecule that specifically inhibits the protease activity of
      subtilisin.
AB  - RNA ligands (RNA aptamers) to a protease subtilisin were selected from pools of
      random RNA by SELEX (systematic evolution of ligands by exponential enrichment)
      and by use of a subtilisin-immobilized Sepharose column. After eight rounds of
      selection, RNA aptamers were isolated by cloning to a plasmid vector. We
      characterized one of the selected RNA molecules. This RNA aptamer displayed
      specific inhibition toward the subtilisin activity, even when the assay for
      subtilisin was performed using the chromogenic small peptide as substrate, and
      almost no inhibitory activity toward trypsin and chymotrypsin, although these
      enzymes are serine proteases similar to subtilisin. These findings indicate that
      this RNA can differentially recognize the surfaces of similar proteases. Kinetic
      analysis of the RNA aptamer revealed that the inhibition constant (Ki) toward
      subtilisin was 2.5 microM.

PMID- 10348916
TI  - Fourier-transform infrared studies on conformation changes in bd-type ubiquinol
      oxidase from Escherichia coli upon photoreduction of the redox metal centers.
AB  - Cytochrome bd is a two-subunit ubiquinol oxidase in the aerobic respiratory chain
      of Escherichia coli that does not belong to the heme-copper terminal oxidase
      superfamily. To explore unique protein structural changes associated with the
      reduction of the redox metal centers, we carried out Fourier-transform infrared
      and visible spectroscopic studies on cytochrome bd. For infrared measurements of
      a partially dehydrated thin sample solution, the air-oxidized enzyme was fully
      reduced by the intermolecular electron transfer of photo-excited riboflavin in
      the absence and presence of KCN, and redox difference spectra were calculated.
      Upon reduction, the bound cyanide was released from the heme b595-heme d
      binuclear center but remained in a protein pocket as a deprotonated form.
      Reduction of heme b558, heme b595, and heme d resulted in large changes in amide
      I and protonated carboxylic CO-stretching vibrations and also a small change in
      the cysteine SH-stretching vibration. The location of the redox metal centers and
      the effects of cyanide suggest that these protein structural changes occur at the
      heme-binding pockets near the protein surface. Systematic site-directed
      mutagenesis and time-resolved FTIR studies on cytochrome bd will facilitate an
      understanding of the unique molecular mechanisms for dioxygen reduction and
      delivery of chemical protons to the active center at the atomic level.

PMID- 10348917
TI  - Characterization of new fluorogenic substrates for the rapid and sensitive assay
      of cathepsin E and cathepsin D.
AB  - Cathepsin E and cathepsin D are two major intracellular aspartic proteinases
      implicated in the physiological and pathological degradation of intra- and
      extracellular proteins. In this study, we designed and constructed highly
      sensitive synthetic decapeptide substrates for assays of cathepsins E and D based
      on the known sequence specificities of their cleavage sites. These substrates
      contain a highly fluorescent (7-methoxycoumarin-4-yl)acetyl (MOCAc) moiety and a
      quenching 2,4-dinitrophenyl (Dnp) group. When the Phe-Phe bond is cleaved, the
      fluorescence at an excitation wavelength of 328 nm and emission wavelength of 393
      increases due to diminished quenching resulting from the separation of the
      fluorescent and quenching moieties. The first substrate, MOCAc-Gly-Lys-Pro-Ile
      Leu-Phe-Phe-Arg-Le u-Lys(Dnp)gamma-NH2, in which the Lys-Pro combination at
      positions P5 and P4 was designed for specific interaction with cathepsin E, is
      hydrolyzed equally well by cathepsins E and D (kcat/Km = 10.9 microM(-1) x s(-1)
      for cathepsin E and 15.6 microM(-1) x s(-1) for cathepsin D). A very acidic pH
      optimum o was obtained for both enzymes. The second substrate, MOCAc-Gly-Lys-Pro
      Ile-Ile-Phe-Phe-Arg-Le u-Lys(Dnp)gamma-NH2, in which the isoleucine residue at
      position P2 was meant to increase the specificity for cathepsin E, is also
      hydrolyzed equally by both enzymes (kcat/Km = 12.2 microM(-1) x s(-1) for
      cathepsin E and 16.3 microM(-1) x s(-1) for cathepsin D). The kcat/Km values for
      both substrates are greater than those for the best substrates for cathepsins E
      and D described so far. Unfortunately, each substrate shows little discrimination
      between cathepsin E and cathepsin D, suggesting that amino acids at positions far
      from the cleavage site are important for discrimination between the two enzymes.
      However, in combination with aspartic proteinase inhibitors, such as pepstatin A
      and Ascaris pepsin inhibitor, these substrates enable a rapid and sensitive
      determination of the precise levels of cathepsins E and D in crude cell extracts
      of various tissues and cells. Thus these substrates represent a potentially
      valuable tool for routine assays and for mechanistic studies on cathepsins E and
      D.

PMID- 10348918
TI  - The effect of carboxyl group modification on the chromophore regeneration of
      archaeopsin-1 and bacterioopsin.
AB  - Carboxyl group modification with DCCD and NCD-4 was employed to investigate the
      chemical environment of the side chains of archaeopsin-1 (aO-1) and bacterioopsin
      (bO). Some differences were observed between aO-1 and bO. Although DCCD or NCD-4
      did not modify aO-1 in bleached membrane, they modified bO in bleached membrane
      and in mixed DMPC/CHAPS/SDS micelles at neutral pH, thereby affecting the opsin
      shift and the photocycle of the regenerated chromophore. On the contrary, after
      solubilization with SDS, aO-1 and bO were modified by DCCD and NCD-4, which
      decreased the chromophore regeneration. In particular, the reaction of aO-1 in
      SDS with NCD-4 proceeded in a 1:1 ratio at neutral pH. The fluorescence and CD
      spectra indicated that the modified site was located in the hydrophobic,
      asymmetrical region. Lysyl-endopeptidase digestion of NCD-4 modified aO-1
      produced a fluorescent fragment and amino acid sequence analysis showed that
      Asp85 or Asp96 in helix C is a probable candidate for the modified residue at
      present. Kinetic CD measurements revealed that the introduction of N-acylurea at
      an Asp residue in helix C did not affect the formation of the transient
      intermediate but inhibited the side chain packing during refolding.

PMID- 10348919
TI  - Solution structure of the SH2 domain of Grb2/Ash complexed with EGF receptor
      derived phosphotyrosine-containing peptide.
AB  - 1H, 13C, and 15N NMR resonances of the SH2 domain of Grb2/Ash in both the free
      form and the form complexed with a phosphotyrosine-containing peptide derived
      from the EGF receptor were assigned by analysis of multi-dimensional, double- and
      triple-resonance NMR experiments. From the chemical shift changes of individual
      residues upon peptide binding, the binding site for the peptide was mapped on the
      structure of Grb2/Ash SH2. The peptide was not recognized by the groove formed by
      the BG and EF loops, suggesting that the EGFR peptide does not bind to Grb2/Ash
      SH2 in an extended conformation. This was supported by analysis of the binding
      affinity of mutants where residues on the BG and EF loops were changed to
      alanine. The present results are consistent with the recently reported structures
      of Grb2/Ash SH2 complexed with BCR-Abl and Shc-derived phosphotyrosine containing
      peptides, where the peptide forms a turn conformation. This shows that the
      specific conformation of the phosphotyrosine-containing sequence is required for
      the SH2 binding responsible for downstream signaling.

PMID- 10348920
TI  - Enhancement of transfection efficiency by protamine in DDAB lipid vesicle
      mediated gene transfer.
AB  - We have previously developed a simple gene transfection procedure mediated by
      cationic lipid vesicles for animal cells, in which a commercially available
      cationic surfactant, dimethyldioctadecyl ammonium bromide (DDAB), was used for
      making lipid vesicles. In the present study, we examined enhancement of
      transfection efficiency for this method by adding protamine to plasmid DNA
      solution before the formation of DNA/lipid vesicle complexes. Both free-base
      protamine and protamine sulfate provided enhanced transfection efficiency and
      expression level, but the optimal amount of the two protamines was different. The
      enhancement in transfection efficiency and expression level by protamines was
      observed in all the cell lines (COS-7, Hela, NIH3T3, MDCK, and BHK-21C13) and all
      the plasmids (pCMVbeta, pmiwZ, and pCH110) tested. The enhancement in both
      transfection efficiency and expression level was at most 20-fold compared with
      that using only DDAB lipid vesicles. Protamines seemed to protect DNA from
      degradation by DNase and promote DNA delivery into a nucleus.

PMID- 10348921
TI  - Transmembrane topology of the peroxin, Pex2p, an essential component for the
      peroxisome assembly.
AB  - The peroxisome biogenesis factor, peroxin Pex2p, is an integral membrane protein
      of peroxisomes [Tsukamoto, T., Miura, S., and Fujiki, Y. (1991) Nature 350, 77
      81]. As a step toward elucidating the structure and biological function of Pex2p,
      we determined the transmembrane topology of Pex2p by expressing epitope-tagged
      rat Pex2p in COS-7 cells. Pex2p tagged with myc at the C-terminus was detected as
      a punctate staining pattern, when the cells were permeabilized with 50 microg/ml
      of digitonin, under which conditions intra-peroxisomal proteins such as PTS1
      proteins are inaccessible to exogenous antibodies. N-terminally flag-tagged Pex2p
      was likewise detected upon the same treatment. These results strongly suggest
      that both the N- and C-terminal parts of Pex2p are exposed to the cytosol. The
      transmembrane orientation of Pex2p was also assessed by using rat liver
      peroxisomes and Pex2p region-specific antibodies. The two types of antibodies
      used, raised to the N- (amino acid residues 1-131) and C-terminal part (residues
      226 to the C-terminus), respectively, specifically recognized Pex2p and
      immunoprecipitated intact, whole peroxisomes. Pex2p was not recognized by the
      antibodies when the peroxisomes were treated with Proteinase K. Furthermore, in
      situ crosslinking studies involving bifunctional reagents revealed an apparently
      dimeric form of Pex2p. Therefore, Pex2p is anchored to the peroxisomal membrane
      by two membrane-spanning segments, with its N- and C-terminal regions exposed to
      the cytosol.

PMID- 10348922
TI  - Xenopus maintenance-type DNA methyltransferase is accumulated and translocated
      into germinal vesicles of oocytes.
AB  - In vertebrates, DNA methylation plays an important role in the regulation of gene
      expression and embryogenesis. DNA methyltransferase, which catalyzes the
      introduction of a methyl group at the 5th position of cytosine in the CpG
      sequence, is highly accumulated in mouse oocytes and is excluded from nuclei
      [Carlson et al. (1992) Genes Dev. 6, 2536-2541]. In this study, we examined the
      expression level and localization of Xenopus DNA methyltransferase in oocytes
      during oogenesis. The DNA methyltransferase protein was detectable in stage III
      oocytes and increased thereafter, until the oocytes had matured. The rate of DNA
      methyltransferase synthesis rapidly increased after stage IV oocytes. Different
      from in mouse oocytes, DNA methyltransferase was equally distributed in the
      nuclear and post-nuclear fractions, in stage VI oocytes. DNA methyltransferase
      translocated into nuclei was uniformly localized in the nuclear matrix, and the
      accumulated DNA methyltransferase in stage VI nuclei had DNA methylation
      activity.

PMID- 10348923
TI  - Characterization of mouse integrin alpha3 subunit gene.
AB  - Integrin alpha3beta1 (VLA-3) is an adhesion receptor for extracellular matrix
      proteins including various isoforms of laminin. We have isolated mouse genomic
      clones encoding the integrin alpha3 subunit and deduced the exon/intron
      organization. The mouse integrin alpha3 subunit gene is encoded by 26 exons
      spanning 40 kb. The exon/intron structure of the integrin alpha3 subunit gene
      resembles that of the integrin alpha6 subunit gene, but differs somewhat from
      those of other members of the integrin family. We have demonstrated that the
      cytoplasmic domain splicing variants of the alpha3 subunits (alpha3A and alpha3B)
      are generated by alternative exon usage. We also cloned the 5'-flanking region
      and performed a preliminary analysis of its promoter activity in various tumor
      cell lines with different degrees of integrin alpha3 expression. Following
      transfection, activity in the luciferase assay was found to be roughly correlated
      with the expression level of integrin alpha3 as measured by flow cytometry.
      Furthermore, the luciferase assay was performed with normal and SV-40- or polyoma
      virus-transformed fibroblasts. In mouse, human, and hamster fibroblasts, higher
      levels of luciferase expression were observed in transformed cells than in normal
      cells. This result is consistent with our previous finding that integrin alpha3
      expression at both the protein and mRNA levels is enhanced upon oncogenic
      transformation of fibroblasts by tumor viruses.

PMID- 10348924
TI  - Functional dissection of the promoter of the interphotoreceptor retinoid-binding
      protein gene: the cone-rod-homeobox element is essential for photoreceptor
      specific expression in vivo.
AB  - The essential control elements in the interphotoreceptor retinoid-binding protein
      gene (IRBP) promoter are located between -156 and +19. The -156/-109 sequence
      contains a retina-specific DNAse I footprint and shows a positive regulatory
      activity in transiently transfected retinoblastoma cells. The -105/-85 sequence
      is G/C rich, shows a non-tissue specific DNAse I hypersensitivity, and a negative
      regulatory activity in retinoblastoma cells. The -76/-42 sequence shows a retinal
      specific footprint and contains a "cone-rod-homeobox element" (CRXE) and a
      "photoreceptor conserved element" (PCE). IRBP promoter fragments with mutations
      in either CRXE, PCE or in both were linked to reporter genes and analyzed both by
      transient transfection and in transgenic mice. In retinoblastoma cells, the
      mutated CRXE-containing promoter shows a 60% repression of the CAT activity
      whereas the mutated PCE-containing promoter shows a 30% repression. In HeLa cells
      transfected with these promoters, co-transfection of a Crx expression vector with
      wild-type, but not with CRXE mutant promoter, activates CAT activity 20-fold over
      the background activity. Mutation of PCE alone or conversion of CRXE to PCE
      reduces this Crx-activated CAT activity to only 4-fold over the background
      activity. In the transgenic mouse experiments, none of the 12 lines with CRXE
      mutant promoter show significant expression of lacZ in the retina. In contrast, 9
      of the 17 transgenic lines with PCE mutant promoter show photoreceptor-specific
      lacZ expression. Thus the Crx interaction with CRXE is essential for the
      photoreceptor-specific activity of the IRBP promoter in vivo. This interaction
      does not appear to require PCE, but is enhanced when PCE is present.

PMID- 10348925
TI  - Expression and characterisation of the heavy chain of tetanus toxin:
      reconstitution of the fully-recombinant dichain protein in active form.
AB  - Tetanus toxin, composed of a disulphide-linked heavy (HC) and light (LC) chain,
      preferentially blocks the release of inhibitory neurotransmitters in the spinal
      cord by Zn2+-dependent proteolytic cleavage of synaptobrevin. This intoxication
      involves binding via HC to ecto-acceptors on peripheral nerve endings, followed
      by internalisation and retrograde transportation to its prime site of action in
      central neurons. To facilitate exploitation of the toxin's unique activities, HC
      was expressed at a high level in Escherichia coli as a fusion with maltose
      binding protein; after cleavage by thrombin, free HC was isolated and its
      identity confirmed by Western blotting and N-terminal microsequencing. The
      expressed and native HC gave very similar circular dichroism spectra, excluding
      any gross differences in their folded structures. Recombinant HC antagonised the
      neuromuscular paralysing activity of the native toxin, by competing for binding
      to neuronal ecto-acceptors. The HC was reconstituted with bacterially-expressed
      LC to create disulphide-bridged dichain toxin that blocked neuromuscular
      transmission. The fully-recombinant toxin produced spastic paralysis in mice
      characteristic of the blockade of central inhibitory synapses, revealing that it
      undergoes axonal transport to the spinal cord, like the native toxin but with a
      reduced efficacy. This first report of the large-scale production of recombinant
      tetanus toxin in active form should facilitate studies on the use of engineered
      innocuous forms of the toxin as neuronal transport vehicles.

PMID- 10348926
TI  - Pancolitis and genetic markers in the Spanish population.
AB  - BACKGROUND: although the etiology of ulcerative colitis disease remains an
      enigma, the importance of the major histocompatibility complex genes has been
      described, as in many other autoimmune diseases. AIM: we investigated the
      contribution of HLA-DRB1, DQA1 and DQB1 genes (HLA region) in patients with
      pancolitis. METHODS: we studied a total of 89 patients diagnosed as having
      ulcerative colitis (34 pancolitis and 55 left colitis) and 275 healthy control
      subjects. Complete information on sex, age, family history, age of onset,
      localization, complications, surgery and treatment was obtained from all
      patients. DNA was extracted from peripheral blood leukocytes and all individuals
      were HLA-DRB1 genotyped. RESULTS AND CONCLUSIONS: there was an association
      between pancolitis and the presence of DR4-Val86 (p = 0.009; OR = 3.3) and
      DRB1*0103 (p = 0.02; OR = 5.1) alleles. In patients with left colitis an
      association with DRB1*1501 (p = 0.03; OR = 1.9) and DRB1*0103 alleles (p = 0.03;
      OR = 3.8) was observed. We conclude that a strong association between DR4-Val86
      and pancolitis exists.

PMID- 10348927
TI  - Estimated incidence of inflammatory bowel disease in Argentina and Panama (1987
      1993).
AB  - AIM: to estimate the incidence of inflammatory bowel disease (IBD) in two areas
      from Panama and Argentina. METHOD: during a 7-year period from 1987 to 1993 we
      surveyed IBD in two well-defined communities from Panama (District of Colon) and
      Argentina (Partido General Pueyrredon). The mean annual incidence of IBD was
      estimated from hospital-based registries. Records from the General Records
      Department and the endoscopy, radiology and pathology services were reviewed at
      the Hospital MA Guerrero in Colon and at two other hospitals in Partido General
      Pueyrredon to identify suspected cases of IBD. Cases were confirmed using
      standard criteria, and disease incidence rates were calculated by dividing the
      number of cases in which a positive diagnosis could be established by the
      population served by each hospital. RESULTS: mean annual incidence of ulcerative
      colitis in Panama was 1.2/100 000 inhabitants/year, and no cases of Crohn's
      disease (CD) could be diagnosed. Mean annual incidence of IBD in Partido General
      Pueyrredon was 2.2/100 000 inhabitants/year, with only a single case of CD being
      identified. We argue that such figures could represent a good estimate of the
      incidence of IBD in each area, given the wide coverage of the population by the
      hospitals surveyed in each region. CONCLUSION: according to these results, the
      incidence rates of IBD seem to be much lower than those published for other
      "Hispanic" communities outside Latin America. Factors such as population
      structure, environment or genetic determinants might account for these
      differences.

PMID- 10348928
TI  - Magnetic resonance study of the pancreatic duct.
AB  - AIM: to prospectively determine the diagnostic accuracy of magnetic resonance
      cholangiopancreatography (MRCP) in the evaluation of the normal and diseased
      pancreatic duct. METHODS: patients seen during a 6-month period with a diagnosis
      of biliary tract or pancreatic disease underwent endoscopic retrograde
      cholangiopancreatography (ERCP) after a previous MRCP. The pancreatic duct was
      evaluated with both techniques in 37 patients. RESULTS: the pancreatic duct
      appeared normal in ERCP in 27 patients, and also appeared normal in MRCP in 25 of
      these patients (specificity 93%). ERCP showed moderate-severe pancreatic duct
      dilation in 8 patients, in whom the same diagnosis was reached with MRCP
      (sensitivity 100%). The causes of dilation were chronic pancreatitis (2
      patients), pancreatic cancer (3 patients) and ampullary tumor (2 patients); in 1
      patient the findings with both techniques were suggestive of neoplasm of the head
      of the pancreas or focal chronic pancreatitis. Pancreas divisum was diagnosed in
      2 patients by both methods, and the predominant dorsal duct as well as the
      ventral duct were visualized by MRCP. CONCLUSIONS: MRCP is an accurate technique
      for evaluating the normal or diseased pancreatic duct, and for determining the
      underlying disease.

PMID- 10348930
TI  - [Inaccurate diagnosis presumption of haemochromatosis in a patient with alpha-1
      antitrypsin deficiency].

PMID- 10348929
TI  - [Non-steroidal anti-inflammatory drugs and cyclooxygenase-2 selectivity in
      gastroenterology].
AB  - The discovery of, at least, two isoforms of the enzyme cyclooxygenase, named by
      the numbers 1 and 2, has updated our knowledge about the NSAID. This has led
      investigators to reconsider what we can expect from this kind of drugs. The two
      isoforms share enzymatic and structural properties, although they are regulated
      differently, at molecular level and can be distinguished from their functions,
      although an overlap of roles between them do exist. The main goal of the
      development of highly selective inhibitors is to improve gastric tolerability.
      The classical NSAID inhibit preferentially the isoform 1 of the cyclooxygenase,
      in vitro, which appears to be dangerous, according to gastrointestinal safety
      profile. The new compounds with high selectivity for the isoform 2 of the
      cyclooxygenase could be better tolerated at gastrointestinal level. Meanwhile
      these compounds also could have a potential use in several diseases such as
      colorectal cancer and neurodegenerative processes. The potential occurrence of
      side effects, perhaps related with renal function, should be noted. Finally large
      controlled clinical trials are needed to estimate the therapeutic advantages
      which can be offered by the new highly selective NSAID, and the potential
      consequences which can result from the isoform 2 of the cyclooxygenase prolonged
      inhibition

PMID- 10348932
TI  - [Bouveret's syndrome. Diagnosis and therapy].

PMID- 10348931
TI  - [Small bowel lymphoma associated to carcinoid of the duodenum and angiodysplasia
      of the colon].

PMID- 10348933
TI  - [Pneumatosis cystoides intestinalis due to ileo-colic anastomosis].

PMID- 10348934
TI  - Relationship Between Chronic Fatigue Syndrome and Neurally Mediated Hypotension.
AB  - Chronic fatigue syndrome is a chronic debilitating disease that afflicts 4/1000
      of the general population. The pathophysiologic basis for this condition is
      unknown, and no known consistently effective therapy has been identified. Recent
      studies have reported a link between the chronic fatigue syndrome and neurally
      mediated hypotension, a common abnormality of blood pressure regulation. In
      nonrandomized studies, treatment directed at neurally mediated hypotension has
      been effective in treating the symptoms of the chronic fatigue syndrome in two
      thirds of patients. Prospective randomized trials are now in progress.

PMID- 10348935
TI  - Dynamic Left Ventricular Outflow Obstruction in Hypertrophic Cardiomyopathy
      Revisited: Significance, Pathogenesis, and Treatment.
AB  - Systolic anterior motion of the mitral valve and mitral-septal contact is the
      usual cause of dynamic left ventricular outflow obstruction in hypertrophic
      cardiomyopathy. That true obstruction actually occurs is now established based on
      cardiac catheterization and echocardiographic evidence. A mid-systolic drop in
      left ventricular systolic ejection velocity because of obstruction has been
      demonstrated recently. Echocardiographic data indicate that systolic anterior
      motion of the mitral valve is initiated by flow drag; the mitral valve is swept
      toward the septum by the pushing force of flow. After mitral-septal contact,
      obstruction begets further obstruction as the pressure gradient pushes the mitral
      valve into the septum. Most symptomatic patients with obstruction can be treated
      successfully with negatively inotropic drugs. These medications reduce systolic
      anterior motion and obstruction by decreasing early left ventricular ejection
      acceleration, decreasing the early systolic pushing force on the protruding
      mitral leaflet. Patients who do not improve on medication generally benefit from
      surgery. Newer interventions to relieve obstruction, such as dual-chamber pacing
      and percutaneous transluminal septal myocardial ablation are under active
      investigation.

PMID- 10348937
TI  - Pacemaker Lead Removal: An Increasingly Complicated Skill.

PMID- 10348936
TI  - Percutaneous Pacemaker/ICD Lead Explantation: Current Status.
AB  - Several developments have led to an increase in the number of lead explantation
      procedures performed by a variety of health care providers. This brief review
      presents the current techniques available for explantation, as well as an
      examination of the current indications for the performance of these procedures.

PMID- 10348939
TI  - Current Echocardiography-Doppler Approaches to the Quantification of Valvular
      Regurgitation.
AB  - Echocardiography-Doppler methods frequently are used to assess patients with
      mitral and aortic valve disease. Quantitation of the regurgitant lesions remains
      an important part of the noninvasive exam. Recently, several newer quantitative
      methods have been developed that can be helpful to the clinician. This article
      reviews conventional volumetric techniques and recently validated hydrodynamic
      approaches to the assessment of mitral and aortic regurgitation. The derivation
      of formulas is discussed along with the value and limitations of each technique.

PMID- 10348938
TI  - Fetal Echocardiography: Who Needs It?
AB  - Fetal echocardiography is presently the definitive modality for diagnosing and
      evaluating fetal congenital heart disease (CHD). Fetal heart disease frequently
      occurs sporadically without a known risk factor; however, certain pregnancies
      carry a higher risk of the fetus having CHD. Various known factors place the
      pregnancy and fetus in a high-risk category. To understand "who needs a fetal
      echocardiogram," one must recognize and identify the risk factors. Referral
      indications for a fetal echocardiogram are based on these risk factors that
      include fetal chromosomal anomalies, fetal extracardiac defects, fetal
      arrhythmias, maternal teratogenic exposures, maternal metabolic risks, and
      various inherited syndromes. Referral indications are reviewed along with the
      associated risk of the fetus having a congenital cardiac abnormality. The
      anticipated cardiac defect based on the specific referral reason along with the
      associated frequency of CHD is also addressed. Reasons for performing a fetal
      echocardiogram, various modalities of imaging, and the benefits and limitations
      of a study are included. The question of who needs a fetal echocardiogram is
      closely enmeshed with recognition of the fetal, maternal, and familial risk
      factors.

PMID- 10348940
TI  - Social and Psychologic Aspects of Coronary Heart Disease in Women.
AB  - This literature review examines the association of social and psychologic
      characteristics among women with a) the risk of developing coronary heart disease
      and b) prognosis and recovery after disease has become manifest. Studies of
      psychosocial risk factors are often conflicting. These divergent findings can
      result from different study designs, the use of different measures and scales, or
      the study of different populations. This review attempts to draw conclusions from
      the existing literature and indicate where there are needs for additional
      research.

PMID- 10348941
TI  - Anticoagulation Issues in Atrial Fibrillation.
AB  - Despite the compelling evidence that antithrombotic therapy, particularly
      warfarin, is effective in preventing stroke in patients with nonvalvular atrial
      fibrillation, these agents remain underused. In addition, despite evidence
      demonstrating that strokes are prevented when the international normalized ratio
      is greater than 2 and that hemorrhagic complications are higher when the
      international normalized ratio is greater than 3 to 3.5, many patients have
      values that fall outside a therapeutic range. Clinical, transthoracic, and, now,
      transesophageal information is available to help stratify patients at high risk
      or low risk for stroke, including those patients undergoing cardioversion.

PMID- 10348942
TI  - Use of Echocardiography in Patients with Congestive Heart Failure.
AB  - Echocardiography is used widely to evaluate patients presenting with congestive
      heart failure (CHF). Because of its unique ability to evaluate left ventricular
      (LV) size and geometry, LV systolic and diastolic function, right ventricular
      size and function, heart valves, pericardium, and congenital abnormalities,
      echocardiography is valuable in establishing a specific cardiac diagnosis,
      guiding therapy, and assessing prognosis in CHF. Stress echocardiography can be
      useful in diagnosing underlying coronary artery disease or myocardial viability.
      Newer techniques such as contrast echocardiography and 3D reconstruction can
      improve the ability of echocardiography to accurately provide quantitative
      assessments of chamber sizes, geometry, and function. This review discusses the
      strengths and limitations of echocardiography in patients with CHF.

PMID- 10348943
TI  - The Conundrum of Cardiovascular Syndrome X.
AB  - Patients found to have normal or near-normal coronary angiograms at the time of
      cardiac catheterization often continue to have chest pain symptoms despite
      reassurances of a benign prognosis. Many groups have investigated the possibility
      of a dynamic abnormality in coronary flow responsiveness to stress, but with
      conflicting results. Furthermore, objective metabolic and hemodynamic evidence of
      myocardial ischemia during stress generally has been absent, even in those
      patients selected for an ischemic-appearing ST segment response to exercise
      (often designated as syndrome X). In recent years, several groups have noted an
      abnormal pain sensitivity during the performance of cardiac catheterization and
      during dobutamine infusion. Use of therapies effective in chronic pain syndrome
      management may be of symptom benefit to many.

PMID- 10348944
TI  - Current Management of the Infant and Child with Supraventricular Tachycardia.
AB  - In recent years, there have been new insights into the natural history of and the
      mechanisms responsible for supraventricular tachycardia in infants and children.
      Coupled with the advances in antiarrhythmic therapy and the development of
      radiofrequency ablation, there are now many therapeutic options for
      supraventricular tachycardia. This article provides an overview of the mechanisms
      of supraventricular tachycardia, as well as a framework in which to choose the
      appropriate treatment for the infant or child with tachycardia.

PMID- 10348945
TI  - Diastolic Dysfunction.
AB  - The pumping function of the left ventricle depends both on its ability to empty
      and its capacity to fill at a low pressure. Diastolic dysfunction occurs when
      filling of the left ventricle necessary to produce an adequate cardiac output
      requires an elevated pulmonary venous pressure. Diastolic dysfunction can be
      secondary to systolic dysfunction or occur with normal systolic function (primary
      diastolic dysfunction). Primary diastolic dysfunction most commonly results from
      systolic hypertension, left ventricular hypertrophy, and aging. Primary diastolic
      dysfunction is an important cause of heart failure, especially in elderly
      patients. Diastolic dysfunction can be recognized from the pattern of mitral
      valve flow velocity measured by Doppler echocardiography. Strategies to improve
      diastolic function include: control of systolic blood pressure, preservation of
      sinus rhythm, and avoidance of tachycardia.

PMID- 10348947
TI  - The Ten Most Commonly Asked Questions about Platelet Glycoprotein IIb/IIIa
      Receptor Antagonists.

PMID- 10348946
TI  - Exercise and Cardiac Rehabilitation in Women.
AB  - Most of the information available about the cardiovascular benefits of exercise
      has been derived from studies in men. However, improvements in risk factors,
      functional capacity, and all-cause mortality have been demonstrated in women.
      Unfortunately, women are less likely than men to participate in leisure-time
      physical activities and, therefore, become more inactive with age. Women are also
      less likely than men to enroll in cardiac rehabilitation programs, despite
      evidence regarding the significant value of participation. Providers and programs
      will have to address the concerns and barriers that women, who are generally of
      older age, perceive as preventing their participation. It seems clear that
      regular, physical activity for women has the potential to improve many facets of
      health over their lifetime.

PMID- 10348948
TI  - Unusual Forms of Ventricular Tachycardia.
AB  - An overview of four unusual types of ventricular tachycardia is presented:
      arrhythmogenic right ventricular dysplasia, bundle branch reentry, and idiopathic
      left and right ventricular tachycardias. In most patients with these
      tachycardias, severe structural heart disease is absent. The prognosis of
      patients is dependent on the clinical manifestations produced by the arrhythmia
      and the presence and type of structural heart disease. We describe their
      clinical, electrocardiographic, and electrophysiologic features. Based on the
      most common clinical courses and tachycardia mechanisms, current management
      options are discussed.

PMID- 10348949
TI  - Combination Drug Therapy in Patients with Heart Failure: Tenets of Rational
      Polypharmacy.
AB  - Combining drugs to treat patients with heart disease is common. It is important
      to assess this practice with respect to sound principles of therapeutics and
      review what has become a complicated and challenging practice, combining drugs to
      treat heart failure. The purpose of this review is to consider the philosophy of
      polypharmacy in heart failure and formulate specific recommendations regarding
      the creation of a rational pharmacologic approach to these patients.

PMID- 10348950
TI  - The Sixth Report of the Joint National Committee on Prevention, Detection,
      Evaluation, and Treatment of High Blood Pressure: What's New? What's Different?
AB  - Hypertension remains a major cause of cardiovascular morbidity and mortality in
      the United States. Disturbing trends have been reported recently and include
      declining rates of successful blood pressure control and increasing rates of
      stroke, congestive heart failure, and hypertension-associated end-stage renal
      disease. Recent clinical trials have demonstrated the potential benefits of more
      aggressive blood pressure control using specific antihypertensive agents in
      patients with both diabetic and nondiabetic renal disease. Additional studies
      have demonstrated the benefit of treating isolated systolic hypertension in the
      elderly and the potential for lifestyle modification to lower blood pressure. The
      Sixth Report of the Joint National Committee on Prevention, Detection,
      Evaluation, and Treatment of High Blood Pressure has been published recently and
      should serve as an important resource for busy practitioners caring for
      hypertensive patients. This article describes the significant additions and
      revisions that distinguish this Sixth Report from previous editions.

PMID- 10348951
TI  - Considerations in the Selection of Noninvasive Testing for the Diagnosis of
      Coronary Artery Disease.
AB  - In selecting a noninvasive test for the assessment of patients with suspected
      coronary artery disease, the clinician must choose from a growing number of
      methods that use various types of stress and markers of ischemia. Noninvasive
      testing is most valuable in patients with an intermediate pretest likelihood of
      disease based on clinical history and risk factors. In patients who are able to
      exercise, this form of stress is optimal, whereas pharmacologic stress testing
      can be performed in those who are unable to exercise adequately. Imaging studies,
      including two-dimensional echocardiography and nuclear scintigraphy, increase the
      accuracy of noninvasive tests in the diagnosis of coronary artery disease and are
      essential in pharmacologic stress studies. Ultimately, the selection of an
      appropriate test depends on multiple factors, which can be considered in a
      sequential fashion.

PMID- 10348952
TI  - Positron Emission Tomography for Assessment of Myocardial Perfusion and
      Viability.
AB  - The distinction between left ventricular (LV) dysfunction caused by fibrosis and
      that arising from viable (hibernating and/or stunned) myocardium has important
      implications for the management of patients with ischemic cardiomyopathy. In many
      of these patients, LV function can improve significantly, and even normalize,
      after revascularization. Positron emission tomography (PET) is the most accurate
      noninvasive imaging technique for detection of viable myocardium. Increased
      glucose uptake in dysfunctional segments with reduced blood flow at rest (PET
      mismatch) indicates the presence of viable myocardium, whereas a concordant
      reduction in blood flow and glucose uptake (PET match) indicates a myocardial
      scar. A PET mismatch pattern has a 79% average positive predictive value for
      predicting improved function after revascularization, whereas a PET match pattern
      has an 84% average negative predictive value for lack of such functional
      recovery. The greater the number of viable myocardial segments shown by PET, the
      greater the probability that revascularization will improve regional and global
      LV function and, consequently, improve heart failure symptoms and survival. In
      patients with PET mismatch, long-term survival is consistently poor with medical
      therapy but significantly improved by early referral to revascularization. This
      survival benefit is apparent in patients with and without angina. Conversely,
      long-term survival in patients without such PET mismatch is similar with medical
      therapy or revascularization, especially if minimal or no anginal symptoms are
      present. These observations suggest that noninvasive investigation of the amount
      of viable myocardium should be an important component of the diagnostic
      evaluation of patients with heart failure because of coronary artery disease.
      This approach will likely enhance the often difficult process of selecting
      patients with poor cardiac function in whom revascularization will likely improve
      both the quality and quantity of life.

PMID- 10348954
TI  - The Ten Most Commonly Asked Questions about Mitral Valve Prolapse.

PMID- 10348953
TI  - Inflammation, Chronic Ulcerated Plaques, and Unstable Coronary Syndromes.
AB  - Inflammation is a well-recognized component of active atherosclerotic disease,
      believed to play a major role in plaque ulceration and the development of acute
      coronary events. Although ulcerated plaque lesions underlie the development of
      acute coronary thrombosis and acute coronary disease, the ulceration may not be a
      sudden or recent event. Our studies, based on extensive histologic study of the
      coronary tree in patients who died of acute coronary disease, suggest that
      ulcerated plaques may exist as chronic, unrecognized lesions. Clinical studies
      indicate that ulcerated plaques may exist, silent and unrecognized, for weeks,
      months, or even years without resolving and reestablishing endothelial integrity.
      In addition, pathologic studies show that patients with acute coronary disease
      often have multiple, ubiquitous plaques in all stages of plaque development,
      which are not associated with luminal stenosis or thrombosis but are consistently
      associated with inflammation. Because inflammation is a marker of active
      atherosclerotic disease, and because ulcerated plaques are consistently
      associated with inflammation, ulcerated plaques appear to be a component of
      active inflammatory atherosclerotic disease. Ulcerated plaques, and the
      associated exposure of subendothelial collagen to flowing blood, are potentially
      unstable lesions until endothelial integrity is restored. Patients with unstable
      coronary syndromes may harbor unstable lesions, such as chronic ulcerated
      plaques, that play an important role in the pathogenesis of such syndromes.
      Recognition and treatment of ulcerated plaques before the onset of acute coronary
      events may prevent acute coronary syndromes by eliminating the pathologic
      substrate responsible for coronary thrombosis.

PMID- 10348955
TI  - Acquired QT Prolongation: Mechanisms and Implications.
AB  - QT interval prolongation can be caused by several drugs. Torsade de pointes (TdP)
      is a form of ventricular proarrhythmia associated with QT interval prolongation,
      and in some cases, the development of U waves. The mechanism of TdP is believed
      to be related to an abnormality of repolarization in the ventricular myocardium
      and the development of early afterdepolarizations. QT prolongation leading to TdP
      can be caused by antiarrhythmic drugs (primarily class IA and III drugs), as well
      as a variety of other drugs. These other classes of drugs include phenothiazines,
      tricyclic antidepressants, antihistamines, antibiotics, antifungal agents, and
      antianginals. The recognition of a patient profile at increased risk for the
      development of TdP can help the patient avoid this drug-related complication.
      Treatment of TdP depends on the correct identification of the problem and
      discontinuation of the agent causing TdP, as well as correction of metabolic
      abnormalities, increase in the resting heart rate, and infusion of magnesium.
      Prompt diagnosis and treatment of this condition are central to avoid poor
      outcome.

PMID- 10348956
TI  - Evolving Concepts about Aortic Stenosis.
AB  - Concepts about the management of aortic stenosis have evolved over the last
      several years. Concerns about the safety of exercise, positive inotropic drugs,
      and afterload reduction have been based on the expected exponential relationship
      of pressure and flow predicted by the Gorlin equation. However, in most patients,
      even those with severe stenosis, transvalvular pressure gradient increases much
      less than predicted with increases in cardiac output. Furthermore, data show that
      exercise testing usually can be performed safely and often provides helpful
      information about functional status and symptoms. In addition, positive inotropes
      and afterload-reducing drugs, when initiated cautiously, are often beneficial for
      these patients. Based on newly available data, physicians are encouraged to wait
      until symptoms develop before replacing the aortic valve in patients with severe
      stenosis. Patients with severe aortic stenosis but low transvalvular gradients
      because of left ventricular dysfunction should have functional testing with
      dobutamine or nitroprusside. If an increase in flow produces only a minimal
      increase in transvalvular velocity or pressure gradient, the patient is less
      likely to benefit from surgery. Risk for noncardiac surgery may not be as high as
      previously reported in most patients with aortic stenosis; again, functional
      testing can play an important role in their clinical assessment.

PMID- 10348957
TI  - Surgical Interventions for Patients with Nonischemic Dilated Cardiomyopathy.
AB  - Symptomatic congestive heart failure causes great suffering and is associated
      with high rates of morbidity and mortality. It is now a widespread epidemic and
      one of the most important public health problems in cardiovascular medicine.
      Great insight has occurred with respect to pharmacotherapeutic approaches to
      heart failure, yet symptomatic patients can still anticipate 5-year mortality
      rates of between 50% and 80%. Increased understanding of the pathophysiology of
      heart failure has resulted in clinicians focusing on the importance of
      revascularization strategies in patients with ischemic syndromes causing
      ventricular dysfunction. In patients without overt coronary artery disease,
      operative interventions can also play a significant role. Obviously, cardiac
      transplantation is the ultimate surgical intervention for treatment of any end
      stage cardiomyopathy, but this procedure, although extremely successful, still
      has limitations of immunosuppressive drug morbidity and inadequate donor organ
      availability. Several alternative procedures have been proposed, and include
      mitral valve reconstruction for cardiomyopathy-induced mitral regurgitation,
      partial left ventriculectomy or volume reduction surgery (sometimes called the
      Batista Procedure), and dynamic cardiomyoplasty. It is important to consider
      pathophysiologic concepts underlying these surgical procedures and study emerging
      experience to determine if these operative interventions subsequently can play a
      significant role in managing patients with dilated cardiomyopathy.

PMID- 10348958
TI  - Minimally Invasive Coronary Artery Bypass Grafting: A Review.
AB  - Minimally invasive coronary artery bypass grafting (CABG) without cardiopulmonary
      bypass is a useful option for selected patients with isolated, proximal stenoses
      of the left anterior descending (LAD) or right coronary artery (RCA), or with
      recurrent stenosis after conventional CABG (with cardiopulmonary bypass),
      angioplasty, or stenting, particularly in elderly patients and those with major
      comorbidities making cardiopulmonary bypass too risky. Benefits of minimally
      invasive CABG include a smaller skin incision, shorter operating time, fewer
      arrhythmias, less blood loss, a shorter hospital stay, and lower cost.
      Multivessel disease can be treated with a staged, hybrid approach integrating
      minimally invasive CABG and transcatheter interventions. As new mechanical
      stabilizing devices become available for local immobilization of the myocardium
      during operations on the beating heart, minimally invasive CABG can be extended
      to lesions involving coronary branches on the posterolateral surface of the heart
      that are difficult to access. Although minimally invasive CABG is an exciting
      alternative to transcatheter interventions or conventional CABG with
      cardiopulmonary bypass in selected cases, it is technically more challenging, and
      the long-term results are unknown. Therefore, indiscriminate widespread use is
      unjustified. Because of the high restenosis rate after transcatheter
      interventions, conventional CABG is still believed to offer a more durable
      treatment for coronary artery disease. With refinements and reduction in the
      stenosis rate, stenting can become increasingly competitive with minimally
      invasive CABG as a less invasive technique of myocardial revascularization. Some
      centers use port access and video assistance to aid minimally invasive
      procedures. Video-assisted robotic surgery is still in an experimental stage.

PMID- 10348959
TI  - Heart Retransplantation.
AB  - Retransplantation of the heart is not a widely performed procedure, and few
      centers have large series. The most common indication for heart retransplantation
      is transplant graft coronary artery disease, followed by acute rejection and
      primary graft dysfunction. The outcome after heart retransplantation is not as
      good as with primary transplantation; the one year actuarial survival rate is
      lower and there are more perioperative complications. The number of episodes of
      infection and rejection, however, is not increased. The outcome of heart
      retransplantation for transplant graft coronary artery disease is better than
      that of retransplantation for rejection or primary graft failure. However, it is
      still inferior to that of primary heart transplantation. Because of this and the
      critical shortage of donor hearts, it is suggested that heart retransplantation
      should be limited to carefully selected patients.

PMID- 10348960
TI  - The Sexual Dimorphism of High Blood Pressure.
AB  - There is a sexual dimorphism in blood pressure: men tend to have higher blood
      pressures than women with functional ovaries, whereas ovariectomy or menopause
      tends to abolish the sexual dimorphism and cause women to develop a "male"
      pattern of blood pressure. Synthetic estrogens and progestins, found in oral
      contraceptives, tend to elevate blood pressure, whereas naturally occurring
      estrogens, used in postmenopausal hormone replacement therapy, lower it or have
      no effect. Women are more likely than men to be aware of their hypertension, to
      be treated with antihypertensive drugs, and to have their blood pressure
      controlled. Antihypertensive therapy induces similar blood pressure reductions in
      men and women. However, men experience larger reductions in total cardiovascular
      risk with successful treatment of high blood pressure, because their absolute
      risk of coronary events at baseline is so much higher. Special considerations
      that can dictate antihypertensive treatment choices for women include increased
      vulnerability to the adverse effects of some drugs, including angiotensin
      converting enzyme inhibitor-induced cough, calcium channel blocker-induced edema,
      and minoxidil-induced hirsutism. Beta-adrenergic blockers tend to be less
      effective in women than in men, and diuretics are particularly useful in women
      because they protect against hip fracture. Angiotensin-converting enzyme
      inhibitors and angiotensin II receptor blockers are contraindicated during
      pregnancy or if pregnancy is planned because of the risk of fetal developmental
      abnormalities.

PMID- 10348961
TI  - Effect of recent randomized trials on current pacing practice.
AB  - The most common indication for a permanent pacemaker is symptomatic bradycardia.
      An atrial-based pacemaker (dual-chamber or atrial) usually is preferred, except
      in patients with chronic atrial fibrillation. Several prospective, randomized
      trials recently have been completed to evaluate new indications for permanent
      pacemakers. A dual-chamber pacemaker with an optimal atrioventricular interval
      can reduce the left ventricular outflow tract gradient by >50% in patients with
      hypertrophic cardiomyopathy. This has been associated with symptomatic
      improvement in the majority of patients, but an important placebo effect appears
      likely. Pacing also has been evaluated in patients with medically refractory
      dilated cardiomyopathy. Despite encouraging initial studies, routine implantation
      of a permanent pacemaker in dilated cardiomyopathy is not indicated. In patients
      with cardioinhibitory or mixed vasovagal syncope and carotid sinus
      hypersensitivity, implantation of a pacemaker markedly decreases syncopal
      episodes. Pacemaker therapy is clearly indicated in patients with atrial
      fibrillation associated with symptomatic bradycardia, and exciting new data on
      the use of pacing to prevent atrial fibrillation appear promising. The best
      pacing modality for this indication may be dual-site atrial pacing. Finally,
      permanent pacemakers play an important role in the treatment of symptomatic long
      QT syndrome, usually in combination with beta-blockers.

PMID- 10348962
TI  - Evaluation of low-risk patients with chest pain in the emergency department:
      value and limitations of recent methods.
AB  - More than 2 million patients are hospitalized annually in this country because of
      chest pain suggestive of myocardial ischemia. However, a coronary event is
      demonstrated in <20% of this population. It has been further shown that among
      patients presenting with acute chest pain, a very low-risk group, with <5%
      probability of a coronary event, can be identified by the initial clinical
      assessment. Recognition of this group could prevent many unnecessary hospital
      admissions, affording more appropriate patient care and improved cost
      effectiveness. To enhance identification and management of low-risk patients with
      chest pain, several diagnostic approaches are currently being investigated to
      determine their value in the early detection of myocardial ischemia to select
      those requiring admission. In addition to the initial history, these strategies
      include physical examination and electrocardiogram, new serum markers, early
      noninvasive cardiac imaging by echocardiography or myocardial scintigraphy, new
      electrocardiographic methods, and early exercise testing. Most of these methods
      have shown promise for stratifying patients presenting with chest pain into high
      risk and low-risk groups, thereby extending the initial clinical assessment in
      the critical decision of patient admission or discharge from the emergency
      department with early follow-up. This review presents the current status of these
      techniques with emphasis on our experience with immediate treadmill testing of
      selected patients in the emergency department. These methods are still in the
      developmental phase and their long-term utility will be determined by their
      safety, accuracy, cost, and specific institutional expertise.

PMID- 10348963
TI  - Evaluation of the low-risk patient with chest pain: is there incremental value
      over the clinical assessment of the patient with chest pain to doing a stress
      test in the emergency department?

PMID- 10348964
TI  - Carotid artery disease: natural history, diagnosis, and therapy.
AB  - Stroke remains a major complication of atherosclerotic cerebrovascular disease,
      with extracranial carotid occlusive disease accounting for nearly one-third of
      all events. Although historical symptoms and physical examination findings are
      important, objective testing with carotid duplex ultrasonography and magnetic
      resonance arteriography represent the foundation for therapeutic decision making.
      Contrast arteriography is playing a decreasing role in the evaluation of patients
      with carotid artery disease. Options for therapy, based on the presence or
      absence of symptoms and degree of stenosis, include antiplatelet therapy with
      cardiovascular risk factor modification, carotid endarterectomy, and more
      recently, endovascular therapy.

PMID- 10348965
TI  - Myocardial hibernation vs repetitive stunning in patients.
AB  - Myocardial hibernation is a state of persistently impaired left ventricular
      function in patients with coronary artery disease that was thought to be caused
      by a chronic reduction in resting myocardial blood flow in a segment subtended by
      a diseased coronary artery. However, recent studies using positron emission
      tomography have demonstrated that absolute myocardial blood flow (ml/min/g) to
      hibernating myocardium is within normal limits in most patients. If resting flow
      is not reduced, one must therefore suspect an alternative "trigger" for
      hibernation that is still a consequence of coronary artery disease and ischemia.
      We suspect that hibernating myocardium may be the result of repetitive myocardial
      stunning. Myocardial stunning is the reversible contractile dysfunction occurring
      after a period of myocardial ischemia that persists for a period of time despite
      the return of blood flow to normal. Myocardial stunning has been demonstrated in
      humans in the setting of thrombolysis, coronary angioplasty, coronary artery
      bypass surgery, and coronary artery spasm. Furthermore, stunning has been
      demonstrated after exercise in patients with coronary artery disease, and recent
      studies have provided evidence that repetitive episodes of exercise-induced
      ischemia can lead to cumulative and prolonged left ventricular dysfunction.

PMID- 10348966
TI  - The inherited long QT syndrome: from ion channel to bedside.
AB  - The inherited long QT syndrome is caused by mutations of at least 5 ion channel
      genes. Mutations of the cardiac sodium ion channel gene and 3 potassium channel
      genes have been identified to this time. A genetic locus on chromosome 4 has been
      identified, but no gene has been discovered as of yet. More than 120 mutations of
      the genes have been discovered. The majority of cases are inherited by autosomal
      dominant transmission. Syncope occurs in approximately two-thirds of gene
      carriers, with sudden death in 10% to 15% of untreated patients. The primary
      electrophysiologic disturbance is delayed recovery of the action potential,
      because of diverse physiologic perturbations dependent upon the specific ion
      channel and mutation. The delayed recovery predisposes individuals to the
      development of early afterdepolarizations and initiation of torsade de pointes
      arrhythmias. The torsade produces the syncope and sudden death. Patients with
      self-terminating torsade have syncope, whereas those whose torsade degenerates to
      ventricular fibrillation experience sudden death. The torsade maintenance appears
      to be because of complex reentry or repetitive triggered beats, both of which
      have been proposed as capable of explaining the unique and characteristic QRS
      morphology of torsade. It is proposed that the degree of dispersion of recovery
      at the time of torsade determines whether the torsade degenerates to ventricular
      fibrillation or self-terminates. The signs of long QT syndrome are prolongation
      of the QT interval on the electrocardiogram and abnormalities of T wave
      morphology. QTc values average 0.49 seconds and vary somewhat by genotype.
      Approximately 12% of long QT gene carriers have a normal QTc, < or =0. 44
      seconds. Thus, a normal QTc interval does not exclude long QT syndrome. T wave
      morphology is relatively characteristic for each genotype. Diagnosis is likely
      with a QTc > or =0.48 seconds in females and > or =0.47 seconds in males. Values
      between 0.41 and 0.46 seconds require additional evaluation, as the disorder can
      neither be excluded nor made with those QTc intervals. Diagnosis is enhanced by
      identification of T wave abnormalities consistent with long QT syndrome. The
      principal treatment is beta-blocker therapy. Appropriate dosing, with
      ascertainment of efficacy and compliance with administration, are the key
      elements in therapeutic success. Molecular physiology-based strategies are being
      considered, including the use of sodium channel blockers in LQT3 and potassium
      administration in LQT1 patients.

PMID- 10348967
TI  - Antioxidants and vitamins in your cardiac patient: are they helpful?
AB  - There is an intense interest in the use of antioxidants in the prevention and
      treatment of coronary artery disease (CAD). Oxidants or free radicals are
      necessary for human physiology, but excess of free radical formation and release
      can lead to vascular injury and lipid peroxidation. Some, but not all, studies
      show beneficial effect of exogenous antioxidants, primarily vitamin E, in
      patients with CAD. This article summarizes our current understanding of free
      radicals and their role in physiology and the role of antioxidants in disease
      prevention with special emphasis on the potential adverse effect of treatment of
      patients with large doses of antioxidants.

PMID- 10348968
TI  - Current perspectives on pacing therapy in cardiomyopathies.
AB  - Hypertrophic cardiomyopathy (HCM) is a complex disease that is sometimes
      difficult to control with medical therapy. Surgical treatment is highly effective
      but can be associated with significant morbidity and mortality. It has been
      suggested in uncontrolled studies that patients with obstructive HCM may improve
      symptomatically when treated with dual-chamber pacing. Several hypotheses have
      been suggested to explain this phenomenon, but the mechanism still remains
      unclear. Many recent randomized trials showed much less uniform effects on
      symptoms than previously reported. These results indicate the need for further
      comprehensive inquiry into the effects of pacing on HCM before it can be
      recommended for widespread use. The data on the benefit of pacing therapy in
      dilated cardiomyopathy are much more recent and limited. Initial optimistic
      reports have been only partially confirmed.

PMID- 10348969
TI  - Thrombolysis versus primary percutaneous transluminal coronary angioplasty for
      acute myocardial infarction.
AB  - For the patient with acute myocardial infarction (MI), both primary percutaneous
      transluminal coronary angioplasty (PTCA) and intravenous thrombolytic therapy are
      effective in restoring antegrade coronary blood flow, improving left ventricular
      systolic function, and reducing mortality. Primary PTCA is effective when
      performed quickly by experienced operators. It is the preferred therapy in the
      patient a) with a contraindication to thrombolytic therapy, b) aged 70 years or
      older, and c) in whom thrombolytic therapy is likely to be ineffective (ie, the
      patient with cardiogenic shock). Thrombolytic therapy is widely available and can
      be given quickly and easily. As a result, it remains the treatment of choice for
      most patients with acute MI. The goal of therapy for the patient with acute MI is
      the rapid and sustained restoration of coronary blood flow. For the individual
      patient, the better therapy-primary PTCA or thrombolytic therapy-is the one that
      can be given more safely and expeditiously.

PMID- 10348970
TI  - Clinical application of rest thallium-201/Stress technetium-99m sestamibi dual
      isotope myocardial perfusion single-photon emission computed tomography.
AB  - Stress radionuclide myocardial perfusion imaging is a commonly used modality to
      evaluate patients with known or suspected coronary artery disease. The dual
      isotope rest thallium-201/stress technetium-99m sestamibi gated single-photon
      emission computed tomography protocol has gained increasing popularity for these
      applications. By combining the use of thallium-201, the optimal radioisotope for
      assessment of viability, with technetium-99m, a radionuclide agent that permits
      optimal image resolution and simultaneous assessment of viability information,
      maximization of clinical information can be achieved. Recent publications have
      demonstrated the efficacy of this imaging approach for both the identification of
      the presence of coronary artery disease and risk stratification.

PMID- 10348971
TI  - Hypertrophic cardiomyopathy in children.
AB  - Hypertrophic cardiomyopathy is a congenital disease that may be manifested in
      infancy, childhood, adolescence, or young adulthood. It is heterogeneous both
      genotypically and phenotypically, and as such, it requires an individualized
      approach to medical management. The symptomatic patient can have progression of
      symptoms but can be treated with appropriate medical or surgical therapy. The
      symptomatic infant usually has a grave prognosis and should be given early
      consideration for heart transplantation. The future holds promise because
      genotyping may recognize pedigrees with more "malignant" courses that can be
      treated more aggressively to prevent sudden death. The greatest challenge lies
      with the primary care physician who must take careful measures to identify those
      asymptomatic patients who may be at risk for sudden death during athletic
      activities.

PMID- 10348972
TI  - Homocysteine: evidence for a causal relationship with cardiovascular disease.
AB  - Elevated plasma homocysteine levels are associated with vascular disease and
      thrombosis. Premature atherosclerosis and thromboembolism are seen in children
      who are homozygotes for defects in enzymes responsible for the metabolism of
      homocysteine. Adults with heterozygous defects have less marked elevations of
      homocysteine, and onset of atherosclerosis and vascular disease are delayed into
      the fourth and fifth decade of life. Homocysteine can damage vascular
      endothelium, cause proliferation of vascular smooth muscle, activate platelets,
      promote lipid peroxidation, and activate the coagulation cascade. Epidemiologic
      studies have linked elevations in plasma homocysteine with coronary artery
      disease, cerebrovascular disease, and thromboembolism. Folic acid, in combination
      with vitamins B6 and B12, can normalize homocysteine levels in most patients.
      Although randomized trials assessing the efficacy of homocysteine reduction have
      yet to be completed, treatment with vitamin supplementation should be considered
      in all patients at risk for vascular disease.

PMID- 10348973
TI  - Percutaneous mitral commissurotomy.
AB  - Rheumatic fever is the most common cause of acquired heart disease in children
      and young adults worldwide, mainly in developing countries, and is the reason
      that a large number of patients with mitral stenosis will require some modality
      of treatment during their life span. The early therapeutic approach for this
      condition was solely surgical, but since the early 1960s, several balloon
      catheter interventional techniques have emerged as alternatives to surgical
      treatment. In 1976 Inoue described a novel single-balloon device designed
      specifically for percutaneous transvenous mitral commissurotomy (PMC), and in
      1982 the first clinical application of Inoue's technique was successfully
      accomplished. Ever since several clinical trials established PMC as an effective
      and safe procedure for severe mitral stenosis in more than 30,000 patients
      worldwide, percutaneous balloon techniques have been considered the method of
      choice in selected patients (functional class >II, mitral valve area <1.5 cm2,
      and Wilkins' score <8) for several reasons. PMC is a nonsurgical method with
      results similar to those of surgical intervention, but without the unnecessary
      risks and complications of general anesthesia and extracorporeal circulation
      pump. Both PMC and surgical commissurotomy yield comparable acute and long-term
      results and similar restenosis rates. Moreover, PMC is the strategy of choice in
      symptomatic pregnant women with mitral stenosis, as well as in some cases with
      restenosis after a previous PMC. Patient selection and procedural technique are
      reviewed in detail.

PMID- 10348974
TI  - Women, myocardial infarction, and coronary revascularization: concordant and
      discordant clinical trial and registry data.
AB  - Contemporary data define the persisting less favorable outcome for women than men
      after myocardial infarction. An important contributor is likely lesser
      application of beneficial therapies. Current outcomes of percutaneous
      transluminal coronary angioplasty for women have improved, despite its use in
      older and sicker women, and are comparable with or better than those for men.
      Although most reports of coronary artery bypass graft surgery continue to
      document a doubled mortality for women compared with men, recent clinical trial
      data suggest that elective surgery with improved surgical and perioperative
      management may constitute determining factors for favorable outcomes.

PMID- 10348975
TI  - Association of Lutzomyia columbiana (Diptera: Psychodidae) with a leishmaniasis
      focus in Colombia due to species of the Leishmania mexicana complex.
AB  - In Colombia, Leishmania mexicana has a scattered geographical distribution and no
      sand fly vectors have been associated with its transmission. During the present
      study, the anthropophilic sand fly Lutzomyia columbiana was found to be the only
      species collected using diverse methods, in a small focus of Le. mexicana in the
      municipality of Samaniego, SW Colombia. Ecological data indicate that this sand
      fly species is present in both peri and intradomestic habitats, where it readily
      bites man. Further evidence comes from experimental infections of wild-caught Lu.
      columbiana with Le. mexicana after feeding on infected hamsters. Based on these
      results, it is suggested that this sand fly is the most likely vector in the
      study area, suggesting the existence of a previously unknown sand fly-parasite
      association.

PMID- 10348976
TI  - Presence of Panstrongylus rufotuberculatus (Champion, 1899) (Hemiptera:
      Reduviidae: Triatominae) in Argentina.
AB  - Panstrongylus rufotuberculatus is reported for the first time in Argentina. Four
      adults were attracted by the light of human dwellings in Calilegua National Park,
      Jujuy, at 1150 masl within the subtropical humid forest. The individuals were
      similar to those described in the literature. The epidemiological significance of
      this species is very low in the area, although deforestation might increase its
      role in the transmission of Trypanosoma cruzi.

PMID- 10348977
TI  - Distribution of sandflies (Diptera:Psychodidae) on tree-trunks in a non-flooded
      area of the Ducke Forest Reserve, Manaus, AM, Brazil.
AB  - Sandflies were collected in the base of tree-trunks in the seasons of high and
      least rainfall in the Ducke Forest Reserve, near Manaus in the State of Amazonas.
      Lutzomyia umbratilis was the most abundant sandfly species. Caryocar villosum,
      Chrysophyllum amazonicum, Dinizia excelsa, Eschweilera atropetiolata and Parkia
      multijuga were the tree species on which most sandflies were collected and
      relative abundance were related to trunk characteristics. Seasonal patterns of
      sandfly distribution in the forest were observed.

PMID- 10348978
TI  - Use of monoclonal antibodies for the identification of Leishmania spp. isolated
      from humans and wild rodents in the State of Campeche, Mexico.
AB  - The genus Leishmania includes 30 described species which infect a wide variety of
      mammalian hosts. The precise identification of leishmanial parasites at the
      species level is very important in order to determine whether an organism,
      causing the disease in a given area, is of the same biotype as that found in
      suspected mammalian reservoirs. The objectives of the present study were (1) to
      identify leishmanial parasites isolated from humans and wild rodents from the
      State of Campeche, an endemic focus of localized cutaneous leishmaniasis (LCL) in
      southern Mexico, using an indirect immunofluorescent assay (IFA) with monoclonal
      antibodies (Mabs); and (2) to determine if the parasites of the two types of
      hosts were of the same biotype. All the wild rodents (six Ototylomys phyllotis,
      eight Oryzomys melanotis, five Peromyscus yucatanicus and two Sigmodon hispidus)
      and 96% (24/25) of the human isolates were identified as Leishmania (L.) mexicana
      confirming that this specific LCL focus is a wild zoonosis. The presence of one
      human isolate of L. (Viannia) braziliensis in the State of Campeche, confirmed
      the importance of an accurate taxonomic identification at species level.

PMID- 10348979
TI  - Binema bonaerensis n. sp. (Oxyurida: Thelastomatidae) parasite of Neocurtilla
      claraziana Saussure (Orthoptera: Gryllotalpidae) in Argentina.
AB  - The nematode Binema bonaerensis n. sp. (Oxyurida: Thelastomatidae) is described
      from the intestine of the mole cricket of Neocurtilla claraziana Saussure
      (Orthoptera: Gryllotalpidae) from Buenos Aires Province, Argentina. It is
      distinguished mainly by having a conical tail; three sclerotized arches in the
      buccal cavity; an excretory pore immediately posterior to the base of the
      esophagus and the presence of five pairs of male genital papillae with one pair
      preanal and four pairs postanal.

PMID- 10348980
TI  - Restriction fragment length polymorphism of 195 bp repeated satellite DNA of
      Trypanosoma cruzi supports the existence of two phylogenetic groups.
AB  - The restriction fragment length polymorphism of the 195 bp repeated DNA sequence
      of Trypanosoma cruzi was analyzed among 23 T. cruzi stocks giving a reliable
      picture of the whole phylogenetic variability of the species. The profiles
      observed with the enzymes Hinf I and Hae III were linked together and supported
      the existence of two groups. Group 1 shows a 195 bp repeated unit (Hinf I) and
      high molecular weight DNA (Hae III), while group 2 presents a ladder profile for
      each enzyme, which is a characteristic of tandemly repeated DNA. The two groups,
      respectively, clustered stocks pertaining to the two principal lineages evidenced
      by isoenzyme and RAPD markers. The congruence among these three independent
      genomic markers corroborates the existence of two real phylogenetic lineages in
      T. cruzi. The specific monomorphic profiles for each major phylogenetic lineage
      suggest the existence of ancient sexuality and cryptic biological speciation.

PMID- 10348981
TI  - Genetic structure of Triatoma sordida (Hemiptera: Reduviidae) domestic
      populations from Bolivia: application on control interventions.
AB  - The genetic population of Triatoma sordida group 1, a secondary vector of Chagas
      disease in Bolivia, was studied by multi-locus enzyme electrophoresis. A total of
      253 nymphal and adult specimens collected from seven neighbouring localities in
      the Velasco Province, Department of Santa Cruz, were processed. The relatively
      low genetic variability was confirmed for this species (rate of polymorphism:
      0.20). The absence of genetic disequilibrium detected within the seven localities
      was demonstrated. A geographical structuration appears between localities with
      distances greater than 20 km apart. Although T. sordida presents a relatively
      reduced dispersive capacity, its panmictic unit is wider than compared with T.
      infestans. Genetic distances between T. sordida populations were correlated with
      geographic distance. Gene flow between geographic populations of T. sordida
      provides an efficient framework for effective vigilance and control protocols.

PMID- 10348982
TI  - Genomic classification and genetic relationships of a new variant of hepatitis A
      virus isolated in Cuba.

PMID- 10348983
TI  - Anomalies of Lutzomyia intermedia (Lutz & Neiva, 1912) (Diptera, Psychodidae,
      Phlebotominae).

PMID- 10348984
TI  - T cell response of asymptomatic Leishmania chagasi infected subjects to
      recombinant leishmania antigens.
AB  - In areas of Leishmania chagasi transmission the ability to control leishmania
      infection is associated with IFN-gamma production. In visceral leishmaniasis down
      regulation of T cell responses is mediated by interleukin-10 (IL-10). In this
      study we evaluated the lymphoproliferative response, IFN-gamma and IL-10
      production on lymphocyte cultures stimulated with recombinant leishmania antigens
      in subjects with asymptomatic L. chagasi infection. There was a statistically
      significant difference in the lymphoproliferative response of the subjects with
      asymptomatic infection as compared to patients with visceral leishmaniasis and
      healthy subjects with respect to crude antigens (p<0.01), gp-63 (p<0.05) and hsp
      70 (p<0. 01), as well as between asymptomatic L. chagasi infected subjects and
      patients with visceral leishmaniasis with respect to the response to all antigens
      tested. The IFN-gamma production observed in the group with asymptomatic
      infection with all the three recombinant antigens tested was higher (p<0.01) than
      that observed in patients with visceral leishmaniasis and in healthy subjects.
      Furthermore, in individuals with asymptomatic infection, IL-10 levels in cultures
      stimulated with recombinant antigens were very low. This study shows that
      lymphocytes from individuals with asymptomatic L. chagasi infection are able to
      recognize recombinant leishmania antigens with production of a cytokine that is
      associated with leishmania killing.

PMID- 10348985
TI  - Humoral immune response kinetics in Philander opossum and Didelphis marsupialis
      infected and immunized by Trypanosoma cruzi employing an immunofluorescence
      antibody test.
AB  - Philander opossum and Didelphis marsupialis considered the most ancient mammals
      and an evolutionary success, maintain parasitism by Trypanosoma cruzi without
      developing any apparent disease or important tissue lesion. In order to elucidate
      this well-balanced interaction, we decided to compare the humoral immune response
      kinetics of the two didelphids naturally and experimentally infected with T.
      cruzi and immunized by different schedules of parasite antigens, employing an
      indirect fluorescence antibody test (IFAT). Both didelphids responded with high
      serological titers to different immunization routes, while the earliest response
      occurred with the intradermic route. Serological titers of naturally infected P.
      opossum showed a significant individual variation, while those of D. marsupialis
      remained stable during the entire follow-up period. The serological titers of the
      experimentally infected animals varied according to the inoculated strain. Our
      data suggest that (1) IFAT was sensitive for follow-up of P. opossum in natural
      and experimental T. cruzi infections; (2) both P. opossum and D. marsupialis are
      able to mount an efficient humoral immune response as compared to placental
      mammals; (3) experimentally infected P. opossum and D. marsupialis present
      distinct patterns of infection, depending on the subpopulation of T. cruzi, (4)
      the differences observed in the humoral immune responses between P. opossum and
      D. marsupialis, probably, reflect distinct strategies selected by these animals
      during their coevolution with T. cruzi.

PMID- 10348986
TI  - Comparison between human immunodeficiency virus positive and negative patients
      with tuberculosis in Southern Brazil.
AB  - The objective of this study is to determine the different characteristics of
      human immunodeficiency virus (HIV) positive and negative patients treated for
      tuberculosis (TBC) in a tertiary hospital in Southern Brazil. We conducted a
      retrospective cohort study over a 5-year period, from January 1992 through
      December 1996. We reviewed medical charts of patients from our institution who
      received TBC treatment. We reviewed 167 medical charts of patients with confirmed
      TBC. HIV positivity was detected in 74 patients. There were statistically
      significant difference between HIV positive and negative patients in sex and age.
      HIV-infected patients showed significantly more signs of bacteremia than HIV
      negative patients. Extra-pulmonary TBC was present respectively in 13 (17.6%) and
      21 (22.6%) HIV positive and negative patients. There was a significant difference
      between chest radiograph presentation in HIV positive and negative patients.
      There were significantly lower hematocrit, hemoglobin, leukocyte and lymphocyte
      levels in HIV-positive compared to HIV-negative patients. Outcome was
      significantly different in the two groups with a death rate of 36.5% and 10.8% in
      HIV-positive and in HIV-negative patients. The difference between HIV positive
      and negative patients may have importance in the diagnosis, management and
      prognosis of patients with TBC.

PMID- 10348987
TI  - Adenosine deaminase and guanosine deaminase activities in sera of patients with
      viral hepatitis.
AB  - In order to investigate purin and primidin metabolism pathways in hepatitis,
      adenosine deaminase (ADA) and guanosine deaminase (GDA) activities in sera of
      patients with different types and manifestations of viral hepatitis disease (A,
      B, C, D, E, chronic, acute) were investigated and compared with the control group
      of healthy individuals. Hepatitis cases were classified with respect to their
      serological findings and clinics. When compared all the hepatitis cases with the
      controls, levels of aspartate aminotransferase, alanine aminotransferase, and
      alkaline phosphatase enzymes, as well as ADA and GDA, were significantly higher
      than the control group (p<0.01). Levels of ADA and GDA in hepatitis cases were
      determined as 26.07 11.98 IU/l and 2.37 1.91 IU/l, respectively. When compared
      their ADA and GDA levels amongst the classified hepatitis groups, there was no
      difference in ADA levels amongst cases (p>0.05). However, GDA levels in hepatitis
      A group were closed to the controls. Increase in serum ADA activities in
      hepatitis forms may be dependent on and reflect the increase in phagocytic
      activity of macrophages and maturation of T-lymphocytes, and may be valuable in
      monitoring in viral hepatitis cases.

PMID- 10348988
TI  - Increased pro-inflammatory cytokines (TNF-alpha and IL-6) and anti-inflammatory
      compounds (sTNFRp55 and sTNFRp75) in Brazilian patients during exanthematic
      dengue fever.
AB  - Pro-inflammatory cytokines, tumor necrosis factor (TNF-alpha), interleukin-6 (IL
      6) and interleukin-1beta (IL-1beta) as well as anti-inflammatory compounds,
      soluble TNF-Receptor p55 (sTNFRp55), sTNFRp75 and IL-1 receptor antagonist (sIL
      1Ra), were investigated in 34 Brazilian cases of dengue fever (DF) originated
      from a study of exanthematic virosis. The presence of pro-inflammatory cytokines
      was detected in sera from these patients by ELISA. TNF-alpha and IL-6 levels were
      significantly higher than control subjects in 32% and 52% patients, respectively.
      To our knowledge this was the first time a receptor antagonist and soluble
      receptors for cytokines were detected in sera obtained during exanthematic DF
      without hemorrhagic manifestations. Both sTNFRp55 and sTNFRp75 were consistently
      elevated in 42% and 84% patients, respectively. Most patients had IL-1beta levels
      not different from those of normal subjects, except for one case. Only 16%
      patients had altered levels of IL-1Ra. Previous studies in dengue hemorrhagic
      fever patients demonstrated production of these soluble factors; here we observed
      that they are found in absence of hemorrhagic manifestations. The possible role
      of these anti-inflammatory compounds in immune cell activation and in regulating
      cytokine-mediated pathogenesis during dengue infection is discussed.

PMID- 10348989
TI  - Detection of anti-pili antibodies of gonococcus using an enzyme-linked
      immunosorbent assay.

PMID- 10348990
TI  - Trypanosoma cruzi: correlations of biological aspects of the life cycle in mice
      and triatomines.
AB  - The infection pattern in Swiss mice and Triatomine bugs (Rhodnius neglectus) of
      eleven clones and the original stock of a Trypanosoma cruzi isolate, derived from
      a naturally infected Didelphis marsupialis, were biochemically and biologically
      characterized. The clones and the original isolate were in the same zymodeme (Z1)
      except that two clones were found to be in zymodeme 2 when tested with G6PDH.
      Although infective, neither the original isolate nor the clones were highly
      virulent for the mice and lesions were only observed in mice infected with the
      original stock and one of the clones (F8). All clones and the original isolate
      infected bugs well while only the original isolate and clones E2 and F3 yielded
      high metacyclogenesis rates. An observed correlation between absence of lesions
      in the mammal host and high metacyclogenesis rates in the invertebrate host
      suggest a evolutionary trade off i.e. a fitness increase in one trait which is
      accompanied by a fitness reduction in a different one. Our results suggest that
      in a species as heterogeneous as T. cruzi, a cooperation effect among the
      subpopulations should be considered.

PMID- 10348991
TI  - Development of Rhodnius prolixus (Hemiptera: Reduviidae) under constant and
      cyclic conditions of temperature and humidity.
AB  - Development of Rhodnius prolixus after eclosion until the adult stage was studied
      at constant temperatures (T), 15, 20, 25, 28, 35 C, and relative humidities (RH),
      75, 86 and 97%, and fluctuating (16/8 hr) temperatures, T I/II, 15/28 C, 20/25 C,
      25/28 C and 25/35 C, and relative humidities, RH I/II, 86/75% and 97/75%.
      Eclosion or molting were not observed at 15 C and 86 or 97% RH, respectively. At
      35 C and 75% RH only few insects molted. By alternating T I/II, 15/28 C and 25/35
      C, insects developed at high frequency. Cumulating the average lengths of the
      interphases within independent groups for each instar, R. prolixus reached the
      adult stage most rapidly (86.7 days) and at highest frequency per instar (mean:
      91.8%) at 28 C and 75% RH. Under fluctuating T I/II, development was completed
      within 100 days or less at 25/28 C and 25/35 C with high rates of hatch and
      molting. Development was slowest at fluctuating TI/II, 15/28 C and 20/25 C (>185
      days), and at constant 20 C (>300 days). Mortality was higher at constant 97% RH
      or fluctuating RH I, 97%, than at constant or fluctuating 86% RH. Refeeding was
      minimal at optimal conditions of T and RH for development. The most refeeding was
      observed at a constant 35 C.

PMID- 10348992
TI  - Screening of Asteraceae (Compositae) plant extracts for molluscicidal activity.

PMID- 10348993
TI  - Effects of non-susceptible hosts on the infection with Trypanosoma cruzi of the
      vector Triatoma infestans: an experimental model.
AB  - We tested experimentally the effects of the presence of non-susceptible hosts on
      the infection with Trypanosoma cruzi of the vector Triatoma infestans. The
      experiment consisted in two treatments: with chickens, including two chickens
      (non-susceptible hosts) and two infected guinea pigs (susceptible hosts), and
      without chickens, including only two infected guinea pigs. The hosts were held
      unrestrained in individual metal cages inside a closed tulle chamber. A total of
      200 uninfected T. infestans third instar nymphs were liberated in each replica,
      collected on day 14, and examined for infection and blood meal sources on day 32
      36. The additional presence of chickens relative to infected guinea pigs: (a)
      significantly modified the spatial distribution of bugs; (b) increased
      significantly the likelihoods of having a detectable blood meal on any host and
      molting to the next instar; (c) did not affect the bugs' probability of death by
      predation; and (d) decreased significantly the overall percentage of T. infestans
      infected with T. cruzi. The bugs collected from inside or close to the guinea
      pigs' cages showed a higher infection rate (71-88%) than those collected from the
      chickens' cages (22-32%). Mixed blood meals on chickens and guinea pigs were
      detected in 12-21% of bugs. Although the presence of chickens would decrease the
      overall percentage of infected bugs in short term experiments, the high rate of
      host change of T. infestans would make this difference fade out if longer
      exposure times had been provided.

PMID- 10348994
TI  - Effects of Polydispyrenia simulii (Microspora; Duboscqiidae) on development of
      the gonads of Simulium pertinax (Diptera; Simuliidae).
AB  - The effects of the infection caused by the microsporidium Polydispyrenia simulii
      in gonads of the simuliid Simulium pertinax were evaluated. This blackfly species
      is the main target of control programmes in southeastern Brazil. Infected and
      noninfected blackflies were reared from larval stage to adults using a laboratory
      rearing system. There was no significant difference between the oogenic
      development and dimensions of ovarian follicles of healthy females compared to
      those reared from infected larvae. Otherwise, there was a significant difference
      between the fecundity of healthy females and those reared from infected larvae.
      In males, there was an evident reduction of motility of spermatozoids of males
      reared from infected larvae. The results obtained suggest that the microsporidium
      P. simulii have an important effect on the natural population dynamics of S.
      pertinax.

PMID- 10348995
TI  - Partial lack of susceptibility to Schistosoma mansoni infection of Biomphalaria
      glabrata strains from Itanhomi (Minas Gerais, Brazil) after fourteen years of
      laboratory maintenance.

PMID- 10348996
TI  - The RCN's honesty about institutional racism.

PMID- 10348997
TI  - More nurse power.

PMID- 10348998
TI  - Mental health record can blight your career.

PMID- 10348999
TI  - Heading off tragedy.

PMID- 10349000
TI  - Right to supply.

PMID- 10349001
TI  - Cash Gordon?

PMID- 10349002
TI  - What is CHIMP?

PMID- 10349003
TI  - The government's inaction on long-term care.

PMID- 10349004
TI  - Here's to 1,000 brave innovators.

PMID- 10349006
TI  - Shifting gear.

PMID- 10349007
TI  - Think it over.

PMID- 10349005
TI  - Glad to be back.

PMID- 10349008
TI  - Time travel.

PMID- 10349009
TI  - Internet.

PMID- 10349010
TI  - So you want to be a ... chiropodist.

PMID- 10349011
TI  - Trust watch. Small is beautiful.

PMID- 10349012
TI  - Public relations.

PMID- 10349013
TI  - Removal of a vacuum drain.

PMID- 10349014
TI  - Community and district nurses have a pivotal role to play in improving the public
      health of the nation.

PMID- 10349015
TI  - Caring for carers coping with stroke.

PMID- 10349017
TI  - Nutrition on the ward.

PMID- 10349016
TI  - The health wheel: a tool for assessing carers' health needs.

PMID- 10349018
TI  - The weak link in the food chain.

PMID- 10349019
TI  - Beating bedtime blues.

PMID- 10349020
TI  - Eating into resources.

PMID- 10349021
TI  - Show a leg.

PMID- 10349022
TI  - Help is in the air.

PMID- 10349023
TI  - Sexuality, culture, and political economy: recent developments in anthropological
      and cross-cultural sex research.

PMID- 10349024
TI  - Neural plasticity and the development of sex differences.

PMID- 10349025
TI  - Understanding and promoting sexual and reproductive health behavior: theory and
      method.

PMID- 10349026
TI  - Whither menstrual synchrony?
AB  - The initial report of menstrual synchrony indicated that social interactions
      among groups of women could regulate their ovarian cycles. The initial focus on
      menstrual synchrony was just the beginning of a discovery process, not all facets
      of the whole phenomenon. Menstrual synchrony was similar to an archeologist
      finding a fossilized tooth, which demonstrated the existence of a prehistoric
      creature. Menstrual synchrony could have turned out to be like the chronodonts,
      prehistoric creatures for which we still have only their fossilized teeth as
      evidence for their existence. Fortunately, after almost 3 decades of work, we
      have excavated the site and been able to unearth more about the structure of this
      particular creature. It is social regulation of ovulation throughout the lifespan
      -a creature made up not only of menstrual synchrony, but various forms of the
      timing of spontaneous ovulatory cycles in adults. It also includes the social
      regulation of ovulation at other points during the reproductive lifespan:
      puberty, inter-birth intervals and reproductive senescence. Menstrual synchrony
      is but one indicator of the phenomenon; it is now clear that there is a great
      deal more to it than was seen at the time of the original report.

PMID- 10349028
TI  - The sexual revictimization of women and men sexually abused as children: a review
      of the literature.

PMID- 10349027
TI  - The Japanese quail as a model system for the investigation of steroid
      catecholamine interactions mediating appetitive and consummatory aspects of male
      sexual behavior.

PMID- 10349029
TI  - Sexuality and late modernity.

PMID- 10349030
TI  - Neurobiological correlates of child abuse.

PMID- 10349031
TI  - An fMRI study of Stroop word-color interference: evidence for cingulate
      subregions subserving multiple distributed attentional systems.
AB  - BACKGROUND: The goal of this study was to model the functional connectivity of
      the neural systems that subserve attention and impulse control. Proper
      performance of the Stroop Word-Color Interference Task requires both attention
      and impulse control. METHODS: Word-color interference was studied in 34 normal
      adult subjects using functional magnetic resonance imaging. RESULTS:
      Interregional correlation analyses suggested that the anterior cingulate is
      coupled functionally with multiple regions throughout the cerebrum. A factor
      analysis of the significant regional activations further emphasized this
      functional coupling. The cingulate or related mesial frontal cortices loaded on
      each of the seven factors identified in the factor analysis. Other regions that
      loaded significantly on these factors have been described previously as belonging
      to anatomically connected circuits believed to subserve sensory tuning, receptive
      language, vigilance, working memory, response selection, motor planning, and
      motor response functions. These seven factors appeared to be oriented
      topographically within the anterior cingulate, with sensory, working memory, and
      vigilance functions positioned more rostrally, and response selection, motor
      planning, and motor response positioned progressively more caudally. CONCLUSIONS:
      These findings support a parallel distributed processing model for word-color
      interference in which portions of the anterior cingulate cortex modify the
      strengths of multiple neural pathways used to read and name colors. Allocation of
      attentional resources is thought to modify pathway strengths by reducing cross
      talk between information processing modules that subserve the competing demands
      of reading and color naming. The functional topography of these neural systems
      observed within the cingulate argues for the presence of multiple attentional
      subsystems, each contributing to improved task performance. The topography also
      suggests a role for the cingulate in coordinating and integrating the activity of
      these multiple attentional subsystems.

PMID- 10349032
TI  - A.E. Bennett Research Award. Developmental traumatology. Part I: Biological
      stress systems.
AB  - BACKGROUND: This investigation examined the relationship between trauma,
      psychiatric symptoms and urinary free cortisol (UFC) and catecholamine
      (epinephrine [EPI], norepinephrine [NE], dopamine [DA]) excretion in prepubertal
      children with posttraumatic stress disorder (PTSD) secondary to past child
      maltreatment experiences (n = 18), compared to non-traumatized children with
      overanxious disorder (OAD) (n = 10) and healthy controls (n = 24). METHODS:
      Subjects underwent comprehensive psychiatric and clinical assessments and 24 hour
      urine collection for measurements of UFC and urinary catecholamine excretion.
      Biological and clinical measures were compared using analyses of variance.
      RESULTS: Maltreated subjects with PTSD excreted significantly greater
      concentrations of urinary DA and NE over 24 hours than OAD and control subjects
      and greater concentrations of 24 hour UFC than control subjects. Post hoc
      analysis revealed that maltreated subjects with PTSD excreted significantly
      greater concentrations of urinary EPI than OAD subjects. Childhood PTSD was
      associated with greater co-morbid psychopathology including depressive and
      dissociative symptoms, lower global assessment of functioning, and increased
      incidents of lifetime suicidal ideation and attempts. Urinary catecholamine and
      UFC concentrations showed positive correlations with duration of the PTSD trauma
      and severity of PTSD symptoms. CONCLUSIONS: These data suggest that maltreatment
      experiences are associated with alterations of biological stress systems in
      maltreated children with PTSD. An improved psychobiological understanding of
      trauma in childhood may eventually lead to better treatments of childhood PTSD.

PMID- 10349033
TI  - A.E. Bennett Research Award. Developmental traumatology. Part II: Brain
      development.
AB  - BACKGROUND: Previous investigations suggest that maltreated children with a
      diagnosis of posttraumatic stress disorder (PTSD) evidence alterations of
      biological stress systems. Increased levels of catecholaminergic
      neurotransmitters and steroid hormones during traumatic experiences in childhood
      could conceivably adversely affect brain development. METHODS: In this study, 44
      maltreated children and adolescents with PTSD and 61 matched controls underwent
      comprehensive psychiatric and neuropsychological assessments and an anatomical
      magnetic resonance imaging (MRI) brain scan. RESULTS: PTSD subjects had smaller
      intracranial and cerebral volumes than matched controls. The total midsagittal
      area of corpus callosum and middle and posterior regions remained smaller; while
      right, left, and total lateral ventricles were proportionally larger than
      controls, after adjustment for intracranial volume. Brain volume robustly and
      positively correlated with age of onset of PTSD trauma and negatively correlated
      with duration of abuse. Symptoms of intrusive thoughts, avoidance, hyperarousal
      or dissociation correlated positively with ventricular volume, and negatively
      with brain volume and total corpus callosum and regional measures. Significant
      gender by diagnosis effect revealed greater corpus callosum area reduction in
      maltreated males with PTSD and a trend for greater cerebral volume reduction than
      maltreated females with PTSD. The predicted decrease in hippocampal volume seen
      in adult PTSD was not seen in these subjects. CONCLUSIONS: These data suggest
      that the overwhelming stress of maltreatment experiences in childhood is
      associated with adverse brain development.

PMID- 10349034
TI  - New directions in treatment research of anorexia and bulimia nervosa.
AB  - Although considerable progress has been made in the understanding and treatment
      of anorexia and bulimia nervosa, a substantial proportion of people with these
      disorders have a limited response to treatment. Treatment strategies used in
      eating disorders have tended to be adopted from therapies that were devised to
      treat other psychiatric illnesses. Recent studies suggest that eating disorders
      are independently transmitted familial liabilities with a unique pathophysiology.
      These new findings raise the possibility that an improved understanding of the
      pathogenesis of eating disorders will generate more specific and effective
      psychotherapies and pharmacologic interventions.

PMID- 10349035
TI  - Salivary cortisol responses in prepubertal boys: the effects of parental
      substance abuse and association with drug use behavior during adolescence.
AB  - BACKGROUND: The purpose of this investigation was three-fold. First, we extended
      our original observation of decreased cortisol reactivity to an anticipated
      stressor in sons of fathers with a substance use disorder (SUD). Second, we
      examined the hypothesis that salivary cortisol underresponsivity in these high
      risk prepubertal boys is an adaptation to the stress associated with having a
      father with a current, rather than remitted, SUD. Third, we tested the hypothesis
      that prepubertal cortisol underreactivity might be associated with subsequent
      drug use behavior during adolescence. METHODS: Preadolescent salivary cortisol
      responses were examined in the context of risk-group status, paternal substance
      abuse offsets, and subsequent adolescent drug use behavior. RESULTS: The results
      confirmed a decreased salivary cortisol response to an anticipated stressor among
      sons of SUD fathers in our expanded sample. In addition, sons of fathers with a
      current SUD and boys whose fathers had a SUD offset from their 3rd to 6th
      birthdays had lower anticipatory stress cortisol levels compared with sons of
      control fathers. Finally, lower preadolescent anticipatory cortisol responses
      were associated with regular monthly cigarette smoking and regular monthly
      marijuana use during adolescence. CONCLUSIONS: Hyporeactivity as an adaptation to
      chronic stress may be salient to the intergenerational transmission of substance
      abuse liability.

PMID- 10349036
TI  - Serotonergic function in cocaine addicts: prolactin responses to sequential D,L
      fenfluramine challenges.
AB  - BACKGROUND: Preclinical studies have shown that cocaine produces alterations in
      serotonergic function but our knowledge of the serotonergic alterations due to
      cocaine abuse in humans is still fragmentary. We therefore assessed the central
      serotonergic responsivity of cocaine addicts and control subjects by
      neuroendocrine challenges with the serotonin releaser and reuptake inhibitor D,L
      fenfluramine (FEN). METHODS: Plasma prolactin levels following a 60 mg oral dose
      of FEN and placebo were studied in 25 hospitalized male cocaine addicts and 13
      healthy male subjects. Control subjects underwent one set of FEN/placebo
      challenges and cocaine addicts two sets of challenges, during the first and third
      weeks following cocaine discontinuation. Patients were divided into two subgroups
      as a function of presence (FH+) and absence (FH-) of a paternal history of
      substance abuse. The following comparisons were made: 1) Control subjects versus
      entire patient group and versus patient subgroups; 2) entire patient group and
      patient subgroups responses to first versus second challenges; 3) FH+ versus FH-
      patients' early responses and FH+ versus FH- patients' late responses. RESULTS:
      The prolactin responses to FEN increased significantly in the entire patient
      group as time following cocaine discontinuation increased. The FH+ patients had
      significantly blunted early responses by comparison with FH- patients and control
      subjects. There was a more pronounced rebound of the responses of FH+ patients by
      comparison with those of FH- patients. As a result, comparisons of the late
      responses of FH+ and FH- patients and of FH+ patients and control subjects became
      nonsignificant. CONCLUSIONS: Cocaine use appears to have an effect on the
      serotonergic mechanisms mediating prolactin release in humans. In the present
      study, this effect was more pronounced in a subgroup of patients with a paternal
      history of alcoholism or drug abuse. The greater blunting of the prolactin
      response observed within days of cocaine discontinuation followed by a greater
      rebound of this response 2 weeks later could indicate an increased vulnerability
      to the disruptive effects of cocaine in these patients.

PMID- 10349037
TI  - Reduced P50 auditory gating response in psychiatrically normal chronic marihuana
      users: a pilot study.
AB  - BACKGROUND: Neurophysiological studies of marihuana (THC) often contain
      uncontrolled confounds [psychiatric diagnoses, polydrug use, central nervous
      system (CNS)-relevant injury, etc.] that can alter electrophysiological measures.
      This P50 sensory gating report is part of a larger neurophysiological and
      neurocognitive investigation of chronic THC exposure using rigorously screened
      medically and psychiatrically normal individuals without concurrent use of non
      THC substances. METHODS: Following medical and psychiatric screening, including
      serial urine drug screens, technically adequate P50 paired auditory recovery
      tests were obtained on 19 chronic THC users and 14 control subjects. Fifty pairs
      of 80-dB auditory clicks (1 pair per 10 sec, 500-msec interclick separation) were
      delivered through earphones. The sensory gating measure was the ratio between the
      P50 amplitudes at the vertex elicited by the conditioning (first) and test
      (second) click. RESULTS: THC subjects had significantly higher sensory gating
      ratios (i.e., reduced suppression) than did control subjects. Among THC users,
      sensory gating ratios did not correlate with duration or frequency of THC use,
      although subjects with ratios above 40 had nearly twice the number of "joint
      years" of THC exposure than did those with lower ratios. CONCLUSIONS: Reduced P50
      suppression in the sensory gating paradigm may be a possible neurophysiological
      CNS sequela of long-term cumulative exposure to THC.

PMID- 10349038
TI  - Nocturnal and daytime panic attacks--comparison of sleep architecture, heart rate
      variability, and response to sodium lactate challenge.
AB  - BACKGROUND: The purpose of this study was to determine if nocturnal panic
      patients have greater autonomic dysregulation than patients with daytime panic.
      METHODS: Three groups were studied: patients who suffer from panic attacks during
      sleep (n = 12), those who suffer from daytime panic attacks only (n = 12), and
      control subjects (n = 12). Each subject underwent 24-hour holter monitoring for
      heart rate variability (HRV), an overnight sleep recording, and sodium lactate
      challenge during wakefulness. RESULTS: There was a marked subjective response to
      the sodium lactate challenge in the panic disorder (PD) patients but not in
      control subjects. Each group showed changes in HRV in response to sodium lactate
      challenge. The decrease in HRV measures was more marked in PD patients as a whole
      than in control subjects. During non-rapid eye movement (REM) sleep the value for
      total power (TP) was significantly higher in the nocturnal panic patients. The PD
      patients as a whole had higher values for TP and low-frequency (LF) power during
      REM sleep than control subjects. There were no significant differences between
      the two PD groups in sleep architecture. The PD patients as a whole had lower
      sleep efficiency and less stage 4 sleep than control subjects. CONCLUSIONS: These
      findings indicate that there are substantial differences between PD and control
      subjects in autonomic regulation and that there are small differences between
      patients with daytime panic attacks and those with sleep-related panic attacks.

PMID- 10349039
TI  - Landmark-based morphometric analysis of first-episode schizophrenia.
AB  - BACKGROUND: The goal of this investigation was to utilize landmark-based shape
      analysis and image averaging to determine the sites and extent of specific
      structural changes in first-episode schizophrenia. METHODS: Neuroanatomic
      structures identified on midsagittal magnetic resonance imaging (MRI) scans were
      compared between 20 patients with schizophrenia and 22 normal control subjects.
      The difference between averaged landmark configurations in the two groups was
      visualized as a shape deformation by a thin-plate spline and through averaged MRI
      images for both groups. RESULTS: A shape difference was found to be statistically
      significant; by inspection, it is contrast between differences in two closely
      abutting regions, involving primarily the posterior corpus callosum and upper
      brain stem--the "focus" is the relation between them. CONCLUSIONS: The findings
      are consistent with prior studies suggesting involvement in schizophrenia of the
      corpus callosum and the limbic structures contributing to the corpus callosum;
      the possibility of local pathology primarily involving the brain stem cannot be
      excluded. The methods of landmark-based shape analysis and image averaging
      utilized in this study can complement the "region-of-interest" method of
      investigating morphometric abnormalities by characterizing the spatial
      relationships among structural brain abnormalities in schizophrenia.

PMID- 10349040
TI  - The thalamus and the schizophrenia phenotype: failure to replicate reduced
      volume.
AB  - BACKGROUND: Thalamic abnormalities resulting in impaired attention and
      information processing may form a foundation for cognitive and perceptual
      disturbances in schizophrenia. Measurements of the thalamus in patients with
      schizophrenia have shown reductions relative to normal comparison subjects.
      METHODS: In the current project, magnetic resonance images of the brain were
      obtained in 10 male and 11 female subjects with paranoid-type schizophrenia, and
      15 male and 12 female normal comparison subjects. Total brain and bilateral
      thalamic volumes were calculated. RESULTS: There were no significant diagnosis,
      hemisphere, or gender differences in thalamic volumes. CONCLUSIONS: Structural
      thalamic abnormalities are not likely to universally and parsimoniously explain
      the schizophrenia phenotype. Abnormal thalamic size in patients with
      schizophrenia should be understood as reflecting one of several possible
      structural abnormalities contributing to production of the schizophrenia
      phenotype, but must be regarded with caution unless paired with functional
      studies.

PMID- 10349041
TI  - Modulation of language processing in schizophrenia: effects of context and
      haloperidol on the event-related potential.
AB  - BACKGROUND: Disturbances in language associations were among the first clinical
      symptoms reported for individuals described as schizophrenic (Bleuler 1911/1950).
      Currently, associative language disturbance is a diagnostic feature of
      schizophrenia (American Psychiatric Association 1994); however, the mechanisms
      that produce this symptom remain unknown. In the present study, two candidate
      psychological functions were examined: sensitivity to semantic context and
      expectancy (attention). METHODS: Visual event-related potentials were recorded
      during a lexical decision task in which semantic relationship and expectancy
      (relatedness proportions) were varied. Semantic priming processes were compared
      between 34 male normal control subjects tested once and 37 male schizophrenic
      inpatients evaluated during their participation in a double-blind haloperidol
      maintenance therapy and placebo replacement protocol. RESULTS: Schizophrenic
      patients failed to discriminate between associated and unassociated words, as
      measured by the amplitude of the N400 component (i.e., absence of the N400
      priming effect); however, the overall mean amplitude of N400 did not differ
      between patients and control subjects. In addition, patients and control subjects
      did not differ significantly in the amplitude of N400 elicited to associated
      words or to unassociated words. Finally, the effect of expectancy-based
      processing on the magnitude of the N400 priming effect did not differ between
      patients and control subjects. CONCLUSIONS: On the basis of these findings, a
      tentative hypothesis is suggested that schizophrenic patients are characterized
      by a pattern of indiscriminate or random spread of activation in their semantic
      network during the processing of single-word semantic contexts.

PMID- 10349042
TI  - Continuous-processing related ERPS in adult schizophrenia: continuity with
      childhood onset schizophrenia.
AB  - BACKGROUND: Previous work with schizophrenic children disclosed deficits on two
      continuous performance tests (CPTs) and ERP indices of reduced attentional
      resource allocation. METHODS: The two CPTs were administered to adult
      schizophrenics and matched control subjects. The simple CPT required only that
      the subject respond whenever the target digit was displayed. The complex version
      required a response whenever any digit was displayed on two successive trials.
      Event-related potentials (ERPs) were recorded during task performance. RESULTS:
      Schizophrenics had fewer hits on both CPT versions, showed a greater drop in
      performance from the simple to the complex CPT, and took longer to respond than
      controls. The processing negativity (Np) showed a greater amplitude increase from
      nontarget to target in normals than in schizophrenics, and the overlapping P2
      component was more negative in normals. P3 latency was longer in schizophrenics,
      but P3 amplitude did not differ. CONCLUSIONS: Group performance and processing
      negativity effects replicated those from an earlier study of schizophrenic and
      normal children administered the same versions of the CPT, suggesting similar
      abnormalities in the allocation and modulation of information processing
      resources.

PMID- 10349043
TI  - Evaluation of superior vermal Purkinje cell placement in mental illness.
AB  - BACKGROUND: A number of neuroimaging and neuropathological studies have reported
      abnormalities in the cerebellar vermis in schizophrenia and bipolar disorder. In
      an effort to further understand vermal abnormalities in mental illness, we have
      analyzed ectopic placement of Purkinje-like cells. METHODS: The superior
      cerebellar vermis was evaluated in 39 cases of severe mental illness
      [schizophrenia (n = 12), bipolar disease (n = 12), and depression (n = 15)]. We
      also examined 9 subjects with polysubstance abuse and 15 normal controls. All
      normally placed Purkinje cells and displaced Purkinje-like cells (i.e., in the
      internal granule layer and intrafoliar white matter) were counted in the same
      foliar field. The ratio of displaced Purkinje-like cells to total Purkinje cells
      and Purkinje cell density were calculated. RESULTS: No significant difference in
      the ratio of displaced to normally placed Purkinje cells or in Purkinje cell
      density between groups of subjects was found. CONCLUSIONS: Our study does not
      support a hypothesis of abnormalities of Purkinje cell migration or other events
      related to their displacement as a basis for the vermal abnormalities reported
      previously in schizophrenia and bipolar disorder.

PMID- 10349044
TI  - Does akathisia influence psychopathology in psychotic patients treated with
      clozapine?
AB  - BACKGROUND: Akathisia has been reported to predict more severe symptoms and
      poorer treatment response to typical neuroleptics among patients with
      schizophrenia. Akathisia has also been associated with symptom exacerbation. This
      study addressed four questions: 1) Does akathisia predict greater severity in
      global psychopathology? 2) Is this effect global or specific? 3) Does clozapine
      treatment alter this relationship? 4) Does severity of psychopathology covary
      with the level of akathisia? METHODS: Akathisia and clinical symptoms were
      examined in 33 "treatment refractory" schizophrenic patients treated with
      clozapine across 16 weeks. Weekly ratings were Barnes Akathisia Rating Scale,
      Abbreviated Dyskinesia Rating Scale, and Brief Psychiatric Rating Scale (BPRS).
      Patients were classified as "with" (n = 15) or "without" (n = 18) akathisia. Data
      analyses involved independent t-test comparisons of selected variables, between
      group multivariate analyses of variance across time for BPRS Total scores and
      Guy's five factors, and partial correlations to assess covariation between BPRS
      scores and level of akathisia. RESULTS: Akathisia predicted more severe global
      psychopathology, specific to the Activation (AC) and Thought Disturbance (TH)
      factors. These relationships did not change with clozapine treatment even when
      akathisia declined. Interestingly, level of akathisia did not covary with
      severity of psychopathology. CONCLUSIONS: In this sample, akathisia predicted
      more severe psychopathology, specific to AC and TH BPRS factor scores. Clozapine
      treatment did not alter this relationship. Although the presence of akathisia
      predicted more severe symptoms, the level of akathisia did not covary across time
      with severity of psychopathology, suggesting an "uncoupling" of these symptom
      domains.

PMID- 10349045
TI  - Characterization of human brain pharmacokinetics using a two-compartment model.
AB  - We developed a two-compartment pharmacokinetic model to systematically
      characterize 19F magnetic resonance spectroscopy (19F MRS) data on the
      concentration time course of psychotropic compounds measured in human brain.
      Using this model, brain volume of distribution and clearance were calculated for
      fluvoxamine as an index compound. Our interest in formalizing a multicompartment
      model was motivated by recent advances in the field of brain spectroscopy that
      allow the noninvasive characterization of brain uptake and elimination half-lives
      of fluorinated psychotropic compounds. Differences between central compartment
      single-dose and steady-state half-lives and the peripheral elimination half-life
      at steady state were used to formulate the model. Application of the model is
      illustrated using previously published data on the elimination half-lives of
      fluvoxamine from plasma and brain at steady state, along with the literature
      values for single-dose plasma elimination half-life. Applying the model, brain
      volume of distribution (1.12 L/kg +/- 0.2 SEM) and clearance (1.01 L/hour +/-
      0.12 SEM) were calculated for fluvoxamine. The bioavailability of fluvoxamine to
      the brain from plasma was 1.85 +/- 0.23 SEM. The underlying multicompartment
      pharmacokinetics of fluvoxamine were reflected by the difference between brain
      and plasma elimination half-lives from steady state. This method to derive
      pharmacokinetic parameters using 19F MRS measurements of drug concentration in
      brain can be applied to characterize the pharmacokinetics of other fluorinated
      psychotropic compounds.

PMID- 10349047
TI  - Welcome to Prescrire! Evidence-based reviews of drugs.

PMID- 10349046
TI  - Elevated pain threshold in anorexia nervosa subjects.
AB  - BACKGROUND: Conflicting data have been published regarding pain threshold in
      subjects with anorexia nervosa (AN), with some studies indicating elevated pain
      threshold and others indicating normal thresholds. Previous research has
      indicated the presence of elevated pain threshold in eating disorder subjects
      with binge-eating behavior. METHODS: In this study pressure pain detection
      thresholds (PDT) (assessed by a pressure analgesiometer) in binge-eating/purging
      and restricting subtypes of AN subjects were compared to control subjects.
      RESULTS: PDT was elevated in AN compared to control subjects at baseline. There
      was no difference in PDT between the subgroups of AN subjects. CONCLUSIONS: The
      etiology of elevated PDT in AN subjects is most likely different from the
      etiology of elevated PDT in bulimia nervosa subjects.

PMID- 10349048
TI  - Pursuit of science, New social factors.

PMID- 10349049
TI  - Another kick at the CAM.

PMID- 10349050
TI  - Physician supply to rural areas challenged.

PMID- 10349051
TI  - Health care problems of Quebec.

PMID- 10349052
TI  - Proper training in rural medicine.

PMID- 10349053
TI  - It's about the process.

PMID- 10349054
TI  - Decreasing physician burnout.

PMID- 10349055
TI  - Asking the right questions is important.

PMID- 10349056
TI  - Continuing drug therapy while breastfeeding. Part 2. Common misconceptions of
      physicians.
AB  - QUESTION: Is there any way to predict whether a drug taken by a mother is safe
      for a suckling baby, or is it just trial and error? One of my patients is
      receiving lithium for manic depression. She wishes to breastfeed, but clinically
      there is no way she can discontinue the drug. My sources say the drug is
      incompatible with breastfeeding. ANSWER: The amount of drug available to a baby
      through breastmilk is estimated as the percentage of maternal dose per kg
      ingested by the baby. Because infants' clearance rate of many drugs is slower
      than adults', however, the true level of the drug circulating in the infant's
      blood might be much higher. Because lithium can be measured in plasma, it is
      prudent to measure it in milk and to estimate the "baby dose." If a baby shows
      any adverse effects, lithium levels should be measured in its blood.

PMID- 10349057
TI  - Ophthaproblem. Optic nerve pit.

PMID- 10349058
TI  - Dermacase. Lichen Planus.

PMID- 10349059
TI  - Requests for screening tests. What if patients insist?

PMID- 10349060
TI  - Practice tips. Incorporating a rapid group A streptococcus assay with the sore
      throat score.

PMID- 10349061
TI  - Maternal risk factors. Alcohol use.

PMID- 10349062
TI  - Raloxifene: designer estrogen for preventing postmenopausal osteoporosis.

PMID- 10349063
TI  - Should we offer famciclovir to patients with new-onset herpes zoster?

PMID- 10349064
TI  - Carvedilol.
AB  - Carvedilol is the first beta-blocker to obtain approval for treatment of heart
      failure. Improvement in hemodynamic parameters was initially documented in three
      methodologically sound studies involving 156 patients. Follow up was limited to
      16 weeks. A placebo-controlled, double-blind trial involving 1094 patients showed
      beneficial effects on overall mortality of 4.6% in absolute terms after a median
      follow up of 6.5 months. This benefit was not found in another trial involving
      415 patients followed on average for 19 months. Results for symptom-based
      criteria conflict. When treatment is introduced very gradually, adverse effects
      (malaise) seem to be minor and infrequent. Carvedilol's place in the treatment of
      heart failure is not yet precisely documented.

PMID- 10349065
TI  - How patient outcomes are reported in drug advertisements.
AB  - OBJECTIVE: To examine how changes in outcomes are reported in drug advertisements
      in medical journals. QUALITY OF EVIDENCE: Advertisements from a convenience
      sample of 38 issues of Canadian Family Physician, Canadian Journal of
      Anaesthesia, Canadian Journal of Psychiatry, Canadian Medical Association
      Journal, and the New England Journal of Medicine. MAIN MESSAGE: Method of
      reporting changes in clinical outcomes (relative risk reduction [RRR], absolute
      risk reduction [ARR], number needed to treat [NNT]), name of product, and company
      marketing product were sought. In the 22 advertisements included in the analysis,
      11 reported results as RRRs; two reported results as RRRs, but readers could
      calculate ARRs or NNTs from figures given in the advertisement; and nine gave no
      measure of results, but readers could calculate RRRs, ARRs, or NNTs from figures
      given. CONCLUSIONS: Most companies report changes in outcomes as RRRs, and this
      bias could influence the way physicians prescribe. Changes to the rules governing
      journal advertising and increased emphasis on critical appraisal skills would
      help mitigate this bias.

PMID- 10349066
TI  - Do family physicians treat older patients with mental disorders differently from
      younger patients?
AB  - OBJECTIVE: To determine whether there are differences between family physicians'
      beliefs and treatment intentions regarding older patients with mental disorders
      and younger patients with similar disorders. Such differences might contribute to
      older adults' lower rates of mental health service use. DESIGN: Mailed survey.
      SETTING: Primary care practices in and around Kingston, Ont. PARTICIPANTS:
      Questionnaires were mailed to 294 general practitioners listed in the 42nd Annual
      Canadian Medical Directory. Of the 285 eligible physicians, 115 (40%) completed
      and returned questionnaires. MAIN OUTCOME MEASURES: Physicians' ratings of
      preparedness to identify and treat, likelihood of treating, likelihood of using
      each of five different treatment methods, likelihood of referral, preferences for
      six referral options, and treatment effectiveness with respect to hypothetical
      older and younger patients with panic disorder or dysthymia. RESULTS: Physicians
      reported being less prepared to identify and treat older patients than younger
      patients. In addition, physicians reported being significantly less likely to
      treat and to refer older patients than younger patients. Finally, physicians
      reported that both psychotherapy alone, and in combination with pharmacotherapy,
      were less effective for older patients than for younger patients. CONCLUSIONS: In
      addition to other possible reasons for older adults' low rates of mental health
      service use, this study suggests that family physicians' beliefs and treatment
      intentions could be contributing factors. Changes in medical education aimed at
      replacing inaccurate beliefs with accurate information regarding older patients
      might be one way to increase rates of use in this underserved age group, because
      family physicians play a key role in the mental health care of older adults.

PMID- 10349067
TI  - Bipolar disorder in old age.
AB  - OBJECTIVE: To review the classification, clinical characteristics, and
      epidemiology of bipolar disorders in old age with a special focus on neurologic
      comorbidity, high mortality, and management. QUALITY OF EVIDENCE: Most available
      data is gleaned from retrospective chart reviews and cohort studies. Treatment
      recommendations are based on evidence from younger populations and a few
      anecdotal case reports and series involving elderly people. MAIN MESSAGE: While
      relatively rare in the community setting, mania in old age frequently leads to
      hospitalization. It is associated with late-onset neurologic disorders
      (especially cerebrovascular disease) involving the right hemisphere and
      orbitofrontal cortex. Prognosis is relatively poor; morbidity and mortality rates
      are high. Management of bipolarity includes cautious use of mood stabilizers,
      especially lithium and divalproex. CONCLUSIONS: Mania in old age should trigger a
      careful assessment of underlying neurologic disease, especially cerebrovascular
      disease. Close clinical follow up is essential.

PMID- 10349068
TI  - Update in liver transplantation.
AB  - OBJECTIVE: To review recent developments in liver transplantation with particular
      emphasis on issues relevant to patient care before and after transplantation.
      QUALITY OF EVIDENCE: Preference was given to recent studies with well-designed
      cohort methods and large numbers of study subjects. Data on natural history are
      summarized from large databases in Canada and the United States. Due to the
      nature of the subjects involved, most treatment studies are open studies or
      consecutive series rather than randomized controlled trials. MAIN MESSAGE:
      Substantial advances in liver transplantation have established it as an effective
      treatment for most end-stage liver diseases, with 1-year survival rates higher
      than 85% in many centres. Early referral by family physicians and careful patient
      selection by transplant centres remain crucial to continued success. Managing
      these patients requires special care from family physicians because of post
      transplantation immunosuppression, increased risk of opportunistic infection, and
      transplantation-associated medical problems. Other unresolved issues include
      recurrence of disease (hepatitis B and C, and malignancy) and an ongoing shortage
      of organs. CONCLUSIONS: Liver transplantation is an effective form of therapy for
      end-stage liver disease, improving both patients' likelihood of survival and
      their quality of life. Because medical care of liver transplant patients is so
      complex, coordinated efforts between primary care physicians and transplant teams
      are crucial.

PMID- 10349069
TI  - [Physician-patient relations in family medicine].
AB  - PROBLEM ADDRESSED: In addition to clinical instruction, residents need "people"
      skills that will enable them to deal with all sorts of patients in difficult
      clinical situations. We planned a series of 12 seminars to teach these skills to
      first-year residents. OBJECTIVES OF PROGRAM: To ask relevant questions typical of
      the patient-centred approach; with empathy and respect, to encourage patients to
      express their emotions; to become more aware of one's own emotions and reactions
      in one's work as a physician; to negotiate with patients, taking into account
      both the patient's agenda and one's own. MAIN COMPONENTS OF PROGRAM: Clinical
      problems drawn from a list of situations likely to involve difficult contact with
      patients were used to achieve program objectives. Various teaching methods
      (discussion, brief presentation, practical demonstration, role play) were used
      during the four stages of skills development: information, demonstration,
      practice, and feedback. Various tools were used to test the program. CONCLUSION:
      Proper planning requires ongoing exploration of objectives, content, teaching
      methods, and evaluation. This discussion of the teaching principles applied in
      planning our seminars might inspire others to develop similar programs.

PMID- 10349070
TI  - New treatments for allergic rhinitis.
AB  - OBJECTIVE: To review new treatments for allergic rhinitis. QUALITY OF EVIDENCE:
      Most studies supporting the principles in this paper are double-blind, placebo
      controlled trials. Good evidence supports use of antihistamines, nasal steroid
      sprays, and immunotherapy. Fewer trials have been done on the new
      antileukotrienes. MAIN MESSAGE: Allergic rhinitis causes significant morbidity,
      which can be successfully treated. Newer antihistamines, developed to replace
      terfenadine and astemizole which have potential side effects, include loratadine,
      cetirizine, and the newest, fexofenadine. Intranasal steroid sprays are also
      effective, particularly for people with nasal stuffiness. One study showed some
      growth retardation in children using beclomethasone over a prolonged period (1
      year). The newer steroid sprays, such as fluticasone, budesonide, and mometasone
      furoate aqueous, however, have not been studied in the same way and are usually
      recommended for shorter periods. The newest group of medications showing real
      promise are the antileukotrienes, including zafirlukast and montelukast. Taken
      orally, these medications avoid the discomfort of nasal sprays and seem to have
      few side effects. Immunotherapy offers a new option: a short-course, preseasonal
      series of six to 11 injections that reduces the burden on patients for year-round
      therapy. Combinations of these therapies are also possible. CONCLUSIONS: With new
      medications and immunotherapy options, family physicians can offer effective
      treatment to patients with allergic rhinitis.

PMID- 10349073
TI  - Working together to process CPP disability claims.

PMID- 10349074
TI  - What doctors should known about disability claims in Quebec.

PMID- 10349075
TI  - Working in association with other physicians.

PMID- 10349076
TI  - Early ear problems and developmental problems at school age.
AB  - Retrospective history of middle ear disease was compared with developmental
      diagnosis in 507 consecutively referred school-age children. History of major ear
      problems was positively associated with discrepancies between the performance and
      verbal IQ on the WISC-R. History of major ear problems was positively associated
      with the presence of articulation disorders for children in the low social class,
      hyperactivity in the middle social class, and language problems in the high
      social class. A history of significant middle ear disease in early childhood
      should raise concerns for articulation difficulties and possible language
      problems in children presenting to clinicians with school problems.

PMID- 10349077
TI  - Dietary considerations in osteopenia in tube-fed nonambulatory children with
      cerebral palsy.
AB  - Children with nonambulatory cerebral palsy are frequently found to be osteopenic.
      We sought factors, in addition to immobility and anticonvulsant therapy, that may
      contribute to the osteopenia. A retrospective chart review of 19 children with
      nonambulatory cerebral palsy who received gastrostomy tube feedings of standard
      commercial formulas was performed. Less than 75% of the Recommended Daily
      Allowance (RDA) was administered to 95% of the children for calories, 58% for
      calcium, 68% for phosphorus, and 74% for vitamin D. Five of the 19 children
      sustained fractures without major trauma. This study suggests that inadequate
      intake of crucial vitamins and minerals may contribute to the severe osteopenia
      observed in many children with nonambulatory cerebral palsy. The nutritional
      needs of these children, including those for micronutrients, must be defined and
      appropriate supplementation given.

PMID- 10349078
TI  - Capillary refill time in the hands and feet of normal newborn infants.
AB  - We measured capillary refill time (CRT) in a convenience sample of 137 healthy
      newborns between 1 and 120 hours of age and 36-42 weeks gestation in the well
      baby nursery of a large community hospital. CRT was measured by applying moderate
      pressure to the dorsum of the right hand and right foot for 5 seconds. Pressure
      was released and the time for complete refilling of the blanched area noted. Each
      infant was studied only once. We also measured ambient temperature and the skin
      temperature of the dorsum of the hand and foot and tested interobserver
      agreement. Mean CRT was 4.23 +/- 1.47 s (SD) range 1.63-8.78 s) in the hand and
      4.64 +/- 1.41 s (range 2.15-9.94 s) in the foot (p = 0.0001) and did not change
      significantly in the first 72 hours. CRT decreased with increasing temperature.
      Environmental temperature, axillary temperature, and temperature of the hand and
      foot were all significantly and indirectly related to CRT, the strongest
      relationship existing between CRT and the skin temperature of the hand (r = 
      0.59, 95% CI -0.69, -0.47 p < 0.00001) and foot (r = -0.33, 95% CI -0.46, -0.16 p
      < 0.0001). With triplicate measurements, there was a statistically significant,
      but clinically moderate, order effect, CRT decreasing with each successive
      measurement (p < 0.0001). Interobserver agreement was fair, the correlation
      coefficient (r) ranged from 0.47 to 0.71. We conclude that CRT as measured in the
      hand or foot of a newborn infant in the first 5 days of life is a relatively
      subjective measurement with an endpoint that is not easy to define and a wide
      range of values in normal infants. It is influenced significantly by
      environmental, axillary, and skin temperatures. Since there is no accepted
      standard for measuring decreased perfusion in the newborn, it is impossible to
      document the clinical utility of CRT in this population. Further studies are
      necessary before CRT can be accepted as a useful measure of peripheral perfusion
      and circulatory status in the newborn infant.

PMID- 10349079
TI  - Children's and parents' visual perception of physicians.
AB  - The purpose of this study is to evaluate the child's and parents' visual
      perception of physicians. To do this, 50 children and their parents were asked
      which physician they preferred, when shown eight pairs of photographs. Four
      characteristics were tested twice, white coat versus no white coat, smile versus
      stern face, cartoon posters versus no posters, and standing versus stooping. We
      found that both children and parents preferred the smiling physician and the
      physician with cartoon posters on the wall. Surprisingly 54% of children
      preferred the physician in the white coat, whereas only 35% of parents preferred
      the white coat. Sixty-eight percent of children also preferred the standing
      physician compared with only 41% of parents. There was little correlation between
      the parent's and child's answers. The results did not differ significantly with
      age, gender, or number of hospitalizations. In conclusion our study did not
      confirm the popular belief that children are afraid of physicians in white coats,
      although children did strongly prefer physicians who smiled and those with
      cartoon posters on the wall.

PMID- 10349080
TI  - Managed care of children with special health care needs: the ABC Program.
AB  - Families of children voluntarily enrolled in a managed care program for children
      with special health care needs receiving SSI and Medicaid benefits and their case
      managers were surveyed regarding care satisfaction, quality, and access. Claims
      data were used to compare the cost and utilization of health care before and
      during program enrollment. Families rated health care quality improved in 43%,
      unchanged as "excellent" in 50% of cases. The care received was seen as more
      nearly complete and of higher quality when the provider was based in the hospital
      or the hospital's community clinics as compared with "private" community
      pediatricians. Hospitalization decreased, but no decrease in cost was
      demonstrated. A carefully planned and implemented managed care program can
      improve patient perception of quality among chronically ill children.

PMID- 10349082
TI  - RVUs, TVUs, AVUs, and IOUs = BCNU.

PMID- 10349081
TI  - Children with special health care needs and managed care.

PMID- 10349083
TI  - A girl with knee pain.

PMID- 10349084
TI  - The influence of Epstein-Barr virus seropositivity on the efficacy of intravenous
      immune globulin in children with immune thrombocytopenic purpura.

PMID- 10349085
TI  - Primary peritonitis associated with streptococcal toxic shock-like syndrome.

PMID- 10349086
TI  - Choosing pediatrics as a career: influences and trends.

PMID- 10349087
TI  - Phenylephrine hydrochloride nose drops in adjunctive treatment of respiratory
      syncytial virus infection.

PMID- 10349088
TI  - Ultrasound evaluation of the fetal heart: is it possible?
AB  - Ultrasound evaluation of the fetal heart can be performed. Knowledge of the
      embryology, anatomy, and function of the heart have led us to understand the
      pathophysiology of congenital heart disease. In this review we discuss the
      indications as well as some basic principles of fetal echocardiography.

PMID- 10349089
TI  - Neuropsychiatric systemic lupus erythematosus.
AB  - The systemic lupus erythematosus (SLE) patients with neuropsychiatric complaints
      requires a comprehensive and timely diagnostic approach. Despite the obvious
      difficulties in diagnosing neuropsychiatric SLE, the neurologic complications of
      SLE can be approached in a careful, logical manner with gratifying results.

PMID- 10349090
TI  - Menstrual irregularities associated with athletics and exercise.
AB  - For women and girls, and dangers of excessively rigorous exercise regimens can
      include disturbances in reproductive function and a negative impact on bone
      density. Assisting female patients in finding a balance between the benefits and
      potential dangers of exercise is an important role for health professionals.

PMID- 10349091
TI  - Behcet's disease: an update.
AB  - No diagnostic laboratory test or curative treatment yet exists for Behcet's
      disease. However, genetic studies have identified those most at risk, and newer
      molecular biologic investigations further elucidate the etiology and shed light
      on potential triggers. This article reviews current therapies.

PMID- 10349092
TI  - Diagnosis, etiology, and therapy of fibromyalgia.
AB  - Fibromyalgia is characterized by diffuse pain, multiple tender points, fatigue,
      and sleep disturbance. Its frequent concurrence with rheumatic diseases modifies
      the clinical picture of the "primary" disease. This article reviews new
      information about the etiopathogenesis and treatment of this syndrome.

PMID- 10349093
TI  - Management of Lyme arthritis.
AB  - Musculoskeletal complaints and findings can be features of Lyme disease and can
      occur following treatment. Only with a good understanding of the pathogenesis of
      these problems can further evaluation and a proper therapeutic scheme be
      developed.

PMID- 10349094
TI  - Current concepts on lung development.
AB  - Recent molecular genetic and embryonic organ culture studies have implicated
      several novel regulatory processes in the coordination of lung development.
      Failure of pulmonary initiation results from interruptions of the sonic
      hedgehog/patched/Gli and Nkx 2.1 signaling pathways. Sonic hedgehog null mutants
      and Gli2/Gli3 compound null mutants each exhibited failed tracheoesophageal
      septation. However, proximodistal epithelial differentiation is disrupted by
      compound Gli mutation, but is preserved in sonic hedgehog mutants. Null mutation
      of Nkx 2.1 also abrogates tracheoesophageal septation in association with thyroid
      and pituitary agenesis. Primary tracheal branching is regulated by fibroblast
      growth factor-10 signaling; in the murine fibroblast growth factor-10 null
      phenotype, the lung fails to separate from the foregut and morphogenesis is
      arrested distal to the trachea. Several genes in the fibroblast growth factor-10
      pathway have homologous roles in fruit fly tracheal organogenesis, and
      corresponding Drosophila mutations yield strikingly similar phenotypes. Recent
      data also indicate that airway branching can be regulated by vascular endothelial
      growth factor, suggesting mutual regulation of airway and vascular development.
      The bases of pulmonary left-right asymmetry and laterality have also been
      investigated. The transforming growth factor-beta superfamily members Lefty-1,
      Lefty-2, and nodal comprise a regulatory pathway whose function is required for
      the development of left-right asymmetry, whereas left-right laterality is
      dependent on regulation of dynein expression by the transcription factor
      hepatocyte nuclear factor-4. Terminal lung differentiation is modulated by yet
      another set of signals. Hoxa5 null mutants exhibit tracheal occlusion and
      surfactant protein deficiency, whereas fibroblast growth factor receptor-2 and -4
      compound null phenotypes include abrogated neonatal alveolization, perturbed
      alveolar myofibroblast differentiation, and persistent neonatal elastin
      deposition. These new contributions represent substantial advances toward a
      comprehensive molecular model of pulmonary development.

PMID- 10349095
TI  - New developments in fetal lung surgery.
AB  - After more than two decades of experimental and clinical work, fetal surgery has
      become a reasonable treatment modality for selected fetuses with life-threatening
      anomalies. We review the literature on anatomic anomalies of the fetal lung that
      are amenable to fetal surgical therapy. Ultrafast fetal magnetic resonance
      imaging has enhanced the accuracy of prenatal evaluation. Fetal lung masses
      associated with hydrops are nearly 100% fatal. These lesions can be resected in
      utero if they are predominantly solid or multicystic. Thoracoamniotic shunting
      may be effective in the setting of a single large predominant cyst. Fetuses
      diagnosed with left congenital diaphragmatic hernia before 26 weeks' gestation,
      who have liver herniation and a sonographic right lung-to-head circumference
      ratio of less than 1.0, may benefit from temporary fetal tracheal occlusion to
      enhance lung growth before birth.

PMID- 10349096
TI  - Current concepts on interstitial lung disease in children.
AB  - Pediatric interstitial lung disease comprises a diverse group of rare conditions
      characterized by an infiltrative process, abnormal gas exchange, and restrictive
      lung disease. Although the disorder is similar to its adult counterpart, its
      course is complicated by the continued need for lung growth and differentiation
      in infants and children. Knowledge about the pathogenesis, prognosis, and
      treatment of pediatric interstitial lung disease is limited. Investigators are
      focusing on defining the cellular mediators of the interstitial damage and
      describing the role of viral infections in and possible genetic predisposition to
      interstitial lung disease. Clinicians continue to define the various types of
      interstitial lung disease and to evaluate the roles of bronchoalveolar lavage,
      radiography, and biopsy in diagnosis. Together, investigators are working toward
      the development of specific, targeted therapy that will reduce the significant
      morbidity and mortality seen in pediatric interstitial lung disease.

PMID- 10349097
TI  - Pain management and weaning from narcotics and sedatives.
AB  - Over the last 10 years, there has been a fundamental change in physicians'
      attitudes toward analgesia and sedation in pediatrics. In this time, basic and
      clinical research have provided a wealth of information. In this paper we review
      important advances registered in the past year, including new molecular and
      physiological mechanisms of antinociception and sedation, behavioral and
      psychoemotional implications of pain, and advances in the clinical practice of
      pediatric analgesia and sedation. Fortunately, the attitude of physicians toward
      these matters has changed significantly and much more attention is now paid to
      the alleviation of pain and provision of adequate sedation. However, there
      remains, according to most estimates, incongruity between these advances and what
      is practiced clinically.

PMID- 10349098
TI  - Venous thromboembolic disease in the pediatric intensive care unit.
AB  - Long recognized to be a major source of morbidity in the adult population, venous
      thromboembolism is being increasingly recognized in the pediatric age group.
      Pediatric intensive care unit patients are exposed to multiple risk factors for
      venous thromboembolism. Prothrombotic tendencies may be inherited or acquired,
      secondary to either the underlying disease or selected therapeutic interventions.
      In children in whom venous thromboembolism is diagnosed, the most commonly
      identified risk factor is the presence of a central venous catheter. Many cases
      are not diagnosed until autopsy. Because current treatment recommendations are
      extrapolated from adult studies, further investigation is needed to define the
      optimal treatment and prophylaxis regimens in critically ill children.

PMID- 10349099
TI  - Long-term therapy for pulmonary hypertension in children.
AB  - This review recounts recent advances in the understanding and treatment of the
      processes that cause pulmonary hypertension in infancy and childhood. New
      discoveries have begun to unveil connections between the basic physiological
      mechanisms responsible for the regulation of pulmonary vascular tone and the
      abnormal responses of the pulmonary vasculature in a variety of disease
      conditions. These discoveries raise hope for new therapeutic interventions that
      may improve the high mortality and morbidity of both children and adults with
      pulmonary vascular disease. In the meantime, treatment efforts continue to be
      focused on the relief of pulmonary vasoconstriction with inhaled nitric oxide and
      intravenous prostacyclin in the short term and oral calcium channel blockers as
      the mainstay of long-term therapy. Lung transplantation often remains as the only
      viable option for continued survival when the pulmonary vascular disease is
      progressive.

PMID- 10349100
TI  - Hypoxic-ischemic brain injury: advancements in the understanding of mechanisms
      and potential avenues for therapy.
AB  - Hypoxic-ischemic brain injury occurs frequently in infancy and childhood. Events
      such as perinatal asphyxia, near drowning, respiratory arrest, and near sudden
      infant death syndrome cause significant mortality and morbidity. Despite current
      critical care practices, the outcomes from such injuries may be life-long
      neurologic deficits. This review discusses findings from laboratory
      investigations into such injuries--in particular the roles of excitotoxic amino
      acids, proteolytic enzymes, free radicals, nitric oxide, and leukocytes.
      Understanding of the two distinct forms of neuronal death, necrosis and
      apoptosis, provides additional insights into mechanisms of injury. The
      development of new therapies for hypoxic-ischemic brain injury depends on such
      understanding. To date, the results of preclinical therapeutic trials have not
      demonstrated a "magic bullet." Nevertheless, the understanding of injury
      mechanisms has uncovered potential avenues for new therapies, particularly
      combination therapies or single interventions that have multiple effects.
      Clinical trials, using these strategies, are planned or have been recently begun
      and offer hope for advancements in treatment.

PMID- 10349101
TI  - Metabolic response to neonatal surgery.
AB  - The energy and protein metabolism of newborn infants differs from that of older
      individuals. Although energy expenditure and protein turnover are higher in
      newborn infants than in adults, the metabolic response to surgery in neonates has
      not been fully characterized. Preliminary studies indicate that metabolic
      response to operative stress is different in infants and adults: infants have an
      increased metabolic rate postoperatively for only 6 to 12 hours and do not have
      increased protein catabolism. More studies are needed in "stressed" newborn
      infants to further characterize substrate use and the metabolism of single
      organs.

PMID- 10349102
TI  - Nutritional support of the pediatric surgical patient.
AB  - This review discusses the important developments in pediatric surgical nutrition
      over the past year. Sepsis and total parenteral nutrition-associated cholestasis
      remain complex problems for patients on total parenteral nutrition.
      Investigations suggest that total parenteral nutrition may compromise
      bactericidal activity, increasing the risk of sepsis. Sepsis possibly sensitizes
      the liver to cholestatic injury. Small volume enteral feeds may restore immune
      system function. Current research does not support an association between
      phytosterols in parenteral lipid solutions and total parenteral nutrition
      associated cholestasis. Methionine has been identified as a potential
      hepatotoxin. Ursodeoxycholic acid and S-adenosyl-L-methionine are the most
      promising treatments of total parenteral nutrition-associated cholestasis. Small
      bowel transplant is now a reasonable option for patients with irreversible
      intestinal failure. Patient and graft survival rates have improved with FK-506
      (Tacrolimus) immunosuppression. Isolated intestinal grafts have the best survival
      rate (92% at 1 year). Most surviving graft recipients are weaned off of total
      parenteral nutrition. The Cox Proportional Hazard model may help to identify
      candidates for small bowel transplant. This equation predicts the duration of
      dependence on total parenteral nutrition. Patients with irreversible intestinal
      failure can then be referred for early small bowel transplantation.

PMID- 10349103
TI  - Advances in ventilatory support of the pediatric surgical patient.
AB  - Severe respiratory failure in newborn and pediatric patients is associated with
      significant morbidity and mortality. Basic science laboratory investigation has
      led to advances both in our understanding of ventilator-induced lung injury and
      in optimizing the supportive use of conventional ventilation strategies. Over the
      past few years, progress has been made in alternative therapies for ventilating
      both children and adults with severe respiratory failure. This review focuses on
      recent laboratory and clinical data detailing the techniques of permissive
      hypercapnia, high frequency oscillatory ventilation, inhaled nitric oxide,
      intratracheal pulmonary ventilation, and liquid ventilation. Some of these
      modalities are becoming commonplace, and others may have much to offer the
      clinician if their benefit is clearly demonstrated in future clinical trials.

PMID- 10349104
TI  - Hematocolpos as an easily overlooked diagnosis.

PMID- 10349105
TI  - Therapeutics and toxicology.

PMID- 10349106
TI  - The role of iron therapy in childhood plumbism.
AB  - Iron deficiency and lead poisoning share common environmental risk factors and
      both are causes of neurocognitive toxicity. Despite their links
      epidemiologically, little is known of the effects of iron supplements on lead
      kinetics and toxicity. Nevertheless, iron is routinely prescribed in children
      with lead poisoning. Most of the existing data focus on the effects of
      preexisting iron deficiency on lead absorption. Animal studies demonstrate that
      iron-deficient animals have increased lead absorption. Lead-poisoned iron
      deficient animals treated with iron supplements have demonstrated decreased lead
      excretion, a factor that might exacerbate lead toxicity while mitigating the
      effects of iron deficiency. Iron supplements given to children with iron
      deficiency and lead poisoning have been demonstrated to improve developmental
      assessment scores, an effect that is independent of blood lead concentration,
      suggesting that it is solely due to reversal of iron deficiency. Improvements in
      developmental assessment scores and decreases in blood lead in iron-replete
      children with lead poisoning secondary to iron supplements have not been
      demonstrated in clinical studies. Given these factors, the use of iron
      supplements in lead poisoning should be individualized, and the supplements
      should be provided only to patients who are iron deficient or who continue to
      live in lead-exposed housing.

PMID- 10349107
TI  - Hyperbaric oxygen therapy in childhood carbon monoxide poisoning.
AB  - Hyperbaric oxygen therapy is the administration of 100% oxygen at pressures two
      to three times ambient pressure, and it significantly increases dissolved oxygen
      content. Although it has been used successfully to treat decompression illness
      and arterial air embolism, its role in the treatment of carbon monoxide poisoning
      remains somewhat controversial. Published evidence and guidelines for the use of
      hyperbaric oxygen therapy in carbon monoxide-poisoned infants and children are
      scarce compared with those available for carbon monoxide-poisoned adults. Because
      of their higher metabolic rates and developing nervous systems, infants and
      children may be more susceptible to the effects of carbon monoxide and also may
      warrant special considerations. This review focuses on the unique aspects of
      carbon monoxide poisoning and hyperbaric oxygen therapy in the fetus, the
      newborn, the infant, and the child. In addition, it discusses general indications
      for and special and practical considerations in the use of hyperbaric oxygen
      therapy in children.

PMID- 10349108
TI  - Treatment of mercury intoxication.
AB  - The element mercury exists as inorganic, elemental, or organic species. Routes of
      exposure and toxicity in humans vary according to the species of mercury
      involved. Treatment of mercury poisoning generally requires the use of sulfhydryl
      bond-containing chelation agents, including the parenterally administered
      dimercaprol and its oral congeners. These oral chelators, meso-2,3
      dimercaptosuccinic acid and sodium 2,3-dimercapto-1-propanesulfonate, have
      numerous advantages over dimercaprol, including less toxicity. Although
      dimercaprol is contraindicated in organic mercury exposures, meso-2,3
      dimercaptosuccinic acid and sodium 2,3-dimercapto-1-propanesulfonate may be used
      to chelate all species of mercury. Recent evidence suggests that their efficacy
      in organic mercury poisoning is uncertain.

PMID- 10349109
TI  - Novel therapies for ethylene glycol intoxication.
AB  - Ethylene glycol is a serious toxin that children frequently ingest. Diagnosis and
      treatment of this poisoning are challenging and frequently involve the use of
      novel therapies. In the past year, fomepizole (4-methylpyrazole) has been
      approved for use as an antidote in the treatment of ethylene glycol poisoning in
      adults, and the first article reporting the use of fomepizole in a pediatric
      ethylene glycol exposure was published. As a result, the therapy of ethylene
      glycol poisoning in children is likely to change from the traditional approach of
      ethanol administration coupled with hemodialysis to the administration of
      fomepizole with or without hemodialysis.

PMID- 10349110
TI  - Breast milk and breastfeeding in the 1990s.
AB  - The biology of human breast milk, and the policy of encouraging breastfeeding,
      continue to be the object of much scientific inquiry. The past year has seen
      several advances in these fields of nutrition, and this article reviews some of
      the most interesting and pertinent studies. Four general themes have been
      apparent in the recent literature: 1) the role of breastfeeding and breast milk
      in the incidence of infectious diseases; 2) the effect of breastfeeding on
      neurodevelopmental outcome; 3) the nutritional composition of breast milk; and 4)
      the determinants of breastfeeding among adolescents and ethnic minority mothers.
      Review of these studies will assist the office-based pediatrician in knowing the
      scientific rationale, and the best methodology, for the promotion of
      breastfeeding.

PMID- 10349111
TI  - [Bone marrow transplantation in chronic myeloid leukemia].
AB  - Chronic Myelogenous Leukemia (CML) is an oncohematological disease characterized
      by a clonal proliferation concerning the primitive hematopoietic cell. A typical
      cytogenetic alteration known as Philadelphia Chromosome (Ph1), a 9:22 chromosomic
      translocation which produces a hybrid gene BCR/ABL, is present in 95% of the
      patients. Nineteen CML patients (9 female and 10 male) underwent Bone Marrow
      Transplantation (BMT). Median age was 32 years (range 9 to 47); 15 of them were
      in chronic phase (CP), and 4 in accelerated phase (AP). At diagnosis, all
      patients were Ph1+, BCR/ABL+. The conditioning regimen consisted of busulphan and
      cyclophosphamide while patients in AP received etoposide as well. Seventeen
      patients received cyclosporine A, methotrexate and methylprednisone as
      prophylaxis for Graft Versus Host Disease (GVHD) while 2 patients received only
      the first two drugs. The 9.22 translocation was determined by means of RT-PCT
      technique using the primers NB1+, Abl3, B2A, CA3 and A2. The sensitivity of the
      method was 1 x 10(-6). Among the 19 patients who entered the protocol, 14 are
      alive and in clinical, hematological and cytogenetic remission (Ph1-) and 3
      patients died due to acute GVHD, 1 due to graft failure and 1 due to Hemolytic
      Uremic Syndrome. Of the 4 transplanted patients in AP, 3 are alive and in
      complete remission. The patients had a 74% survival, with a median follow-up of
      655 days. Complete hematopoietic chimerism was demonstrated in 16 patients, with
      the study of 3 loci, D1S80, APO B and D17S30. No relationship was found between
      post BMT hybrid BCR/ABL (RT.PCR) persistence and disease relapse; the presence of
      acute and/or chronic GVHD did not influence the BCR/ABL positivity. In our
      experience, BMT has proved to be the only therapeutic alternative for CML with
      complete clinical, hematological and cytogenetic remission and a mean survival of
      74%, comparable to the international experience.

PMID- 10349112
TI  - [Immunocytochemistry techniques for the diagnosis of hematologic neoplasms].
AB  - We studied 22 patients with hematological neoplasias which included: 12 patients
      with a diagnosis of Acute Myeloblastic Leukemia (AML) following the morphology
      and cytochemistry criteria established by FAB (French, American and British
      Committee), a Myeloblastic Leukemia secondary to MDS (Myelodysplastic Syndromes)
      and a biphenotypic acute leukemia where we established the relationship between
      the traditional peroxidase reaction with the anti-MPO by APAAP. We also carried
      out the nonspecific esterase reaction and determined the immunologic phenotype by
      FACS technology. The same procedure was used for the cellular analysis of the
      light chains kappa (kappa) and lambda (lambda) in 3 cases of hairy cell leukemia,
      one lymphoma and 4 cases of plasma cell neoplasia and reactive plasma cell
      disease. We conclude that immunocytochemical reactions must be used when
      morphology and traditional cytochemical reactions need to be confirmed in order
      to establish a correct diagnosis and this is specially important for B and T
      lymphomas. Their prognostic value is restricted and the results are useful as a
      complement to morphology, cytochemistry and immunological determinations.

PMID- 10349113
TI  - [Red cell distribution width (RDW): its use in the characterization of microcytic
      and hypochromic anemias].
AB  - With the widespread use of cell counters we have now acquired new red cell
      indices complementary of the old ones, like the HDW and RDW (Red Cell
      Distribution Width) which detect the heterogeneity of red cell size and
      anisocytosis in the blood smear. We studied 90 patients with the following
      results. 1) in the control group of healthy volunteers (n = 50) RDW results were
      (mean +/- ES) 13.90 +/- 0.10% and MCV (mean +/- ES) 90 +/- 5 fl; 2) the iron
      deficiency patients (IDA) (n = 20) gave a MCV of (mean +/- ES) 68.60 +/- 1.77
      fl., and RDW (mean +/- ES) 20.20 +/- 1.21%; 3) the beta-thalassemic patients (n =
      20) had an MCV of (mean +/- ES) 66.45 +/- 1.95 fl, and RDW (mean +/- ES) 17.08 +/
      0.40%. We compared the results of MCV between IDA and thalassemics and against
      the control group with the following results: control vs IDA and control vs
      thalassemic with significant differences with p < 0.01, and no significant
      difference when we compared IDA vs thalassemics. Then we compared the results of
      RDW between IDA and thalassemics and against the control group with the following
      results: control vs IDA and control vs thalassemic with significant differences
      with p < 0.001 and with significant differences when we compared IDA vs
      thalassemics p < 0.001. The statistical results were obtained with the one-way
      analysis of variance (ANOVA). The results show that RDW is a more sensitive
      indicator than MCV to establish the possible origin of microcytic hypochromic
      anemias and that both should be used together in early diagnosis.

PMID- 10349114
TI  - [Porphyric crisis: experience of 30 episodes].
AB  - The experience of 30 porphyric crisis is reviewed in 25 patients attended since
      1967: 21 patients had 1 crisis, 3 had 2, and 1 had 3 of these episodes. In all
      patients, porphyria was diagnosed in relation to one crisis, even though many of
      them had family histories and/or previous clinical symptoms of this disease.
      There was clear predominance (80%) of women, but they are also a majority among
      acute porphyrias. The most frequent symptoms were: abdominal pain, tachycardia,
      dark urine, neurological and psychiatric alterations and arterial hypertension.
      The neurological alterations required the use of a respirator in 9 crisis (33%),
      which was maintained in 2 patients during 4 months. In 6 crisis (20%) there were
      no neurological symptoms. Among laboratory tests, hyponatremia was notable for
      its frequency (53.4%) and intensity. Increase in urinary porphobilinogen, a
      requirement for diagnosis, between 15 and 130 times the normal value was
      observed. Septic complications, such as pneumonia, septicemia, and urinary
      infection, were frequent (50%). Factors suspicious of triggering crisis episodes
      were: drugs, usually more than 2, in 50% of the cases; pregnancy in 30% of the
      women and in a lesser proportion, intense exercise, and surgery. In 10 patients,
      crisis triggering factors were not identified or informed. The role of pregnancy,
      childbirth delivery or puerperium in causing a crisis is not clear, because the
      patients who had a crisis related to them had 15 other pregnancies without
      incidents; besides, in the pregnancy which was accompanied by a crisis, there was
      always one or more than one potentially triggering drug present. The first
      therapeutic step was oral and/or parenteral administration of an overload of
      carbohydrates and, if there was no response, intravenous infusion of hematin was
      prescribed. Four (13.3%) patients died even though they had received hematin, but
      it had been administered too late due to a delay in diagnosis. In surviving
      patients, there were no organic sequels of any kind.

PMID- 10349116
TI  - Senescent erythrocytes: modification of rheologic properties, antigenic
      expression and interaction with monocytes.
AB  - Human erythrocytes have a well-defined lifespan of 120 days. Their eventual
      removal from circulation is a complex process affected by many cellular
      parameters, making them susceptible to sequestration in the spleen and other
      organs. The purpose of this study was to investigate putative changes in
      rheologic properties, antigenic expression and interaction with monocytes of
      senescent erythrocytes (SE). SE and young erythrocyte (YE) fractions were
      obtained by differential centrifugation from 20 healthy donor blood samples.
      Membrane rheomechanic properties (by diffractometric method), ABO and MN antigens
      reactivity and erythrophagocytosis by peripheral monocytes were investigated in
      each fractions. SE showed a little decrease in the deformability index and an
      increase of both membrane elastic modulus and surface viscosity. The studies
      performed indicate a decreased expression in the antigens of both blood group
      systems studied (p < 0.01) and an increased rate of erythrophagocytosis by
      monocytes in SE compared to YE (p < 0.01). The significant modifications in the
      biomechanic properties of senescent red blood cell membrane and the loss of
      antigenic expression could lead to physiological phagocytosis.

PMID- 10349115
TI  - [PCR determination of an association between class II HLA and pemphigus
      vulgaris].
AB  - Pemphigus vulgaris (PV) is an autoimmune blistering disease affecting the skin
      and mucous membranes. It is characterized by the presence of an autoantibody
      directed against desmoglein 3, which causes acantholysis and blister formation.
      In this study, we examined the HLA antigens of 30 caucasian argentinian patients
      compared with 199 controls. We used the PCR-SSO method (Polymerase Chain Reaction
      Sequence Specific Oligonucleotide). We found that PV patients had significantly
      increased frequencies of HLA DR4 (RR = 3.80, P = 0.001) and HLA DR 14 (RR = 5.97,
      P = 0.0001). As in other populations, two associated alleles were found: the
      first was DR beta 1*0402 (RR = 44.70, P = 10.7) and DQ beta 1*0302 (RR = 71.82, P
      = 10(-7)) and the second was DR beta 1*1401 (RR = 117.94, P = 10(-7)) y DQ beta
      1*0503 (RR = 86.95, P = 10(-7)).

PMID- 10349117
TI  - Beneficial effects of diphenhydramine in dystonia.
AB  - The objective of this paper was to evaluate the efficacy of diphenhydramine
      hydrochloride (DPH) in dystonic patients. In 1995, Truong et al reported
      encouraging results in five patients with idiopathic torsion dystonia (ITD)
      treated with DPH, an H1 antagonist with sedative and anticholinergic properties.
      Five patients with generalized ITD, one with secondary generalized dystonia and
      one with idiopathic segmental dystonia were included in the prospective study.
      Initially the response to intravenous administration of DPH versus placebo in two
      sessions a week apart was evaluated. Two weeks later all patients started oral
      DPH in increasing doses (range 100-300 mg, mean 164 mg). The degree of dystonia
      was determined by a modified University of Columbia Scale evaluating the baseline
      score, after placebo and DPH I.V. administration then at one and six months after
      starting oral treatment. The results were analyzed by Friedman's test for
      repeated measurements. On comparing scores for baseline severity, I.V. placebo
      and I.V. DPH presented a highly significant correlation (12.09; p = 0.00) as well
      as comparing baseline score with oral DPH at one and 6 months, treatment (12.78;
      p = 0.00). Functional score results were 9.5 p = 0.01 and 8.4 p = 0.02 at one and
      6 months respectively. The most common side effects were somnolence and
      dizziness. It can be concluded that DPH proved effective in our patients with
      mild to moderate adverse effects not requiring drug withdrawal in any case.
      However, I.V. challenge was unable to predict the long-term response to oral
      medication perhaps due to the limited number of cases.

PMID- 10349118
TI  - [Risk factors for nosocomial bacterial infection in children: a case-control
      study].
AB  - With the objective to identify independent risk factors associated with the
      development of nosocomial bacteremia, we have performed a prospective,
      exploratory, case-control study. All non-neutropenic children with nosocomial
      bacteremia admitted during a seven-month period were eligible. All children non
      neutropenic without nosocomial bacteremia were eligible as controls. The
      incidence of bacteremia in the study population was 11.3/1000 admissions. Ninety
      one cases and ninety nine controls were analyzed. In 46% of patients clinical
      foci were detected. The catheter-related infection was the most frequently
      founded. Staphylococcus spp coagulase negative, Staphylococcus aureus and
      Klebsiella pneumoniae were the microorganisms more frequently isolated.
      Multivariate analysis identified five risk factors independently associated with
      nosocomial bacteremia: admission outside of Intensive Care Units (ICU) (OR: 8.14,
      2.60-25.5), previous antibiotic treatment (OR: 5.02, 2.18-11.5), invasive
      procedures (OR: 5.35, 1.70-16.8), without surgery (OR: 2.99, 1.37-6.52) and the
      presence of central venous lines (OR: 5.35, 2.13-12.4). Our data give strong
      support for the value of testing strict guidelines for limiting vascular catheter
      and antibiotic use, and limiting the invasive procedures.

PMID- 10349119
TI  - [Distribution of the genotypes of hepatitis C virus in intravenous drug addicts
      in Argentina].
AB  - Intravenous drug addiction (IVD) is an unfrequent risk factor in Argentina,
      representing less than 10% of patients (pts) with chronic HCV infection seen in
      our Unit. In order to study the genotypes (Gt) in IVD and compare them with a non
      drug addicted control population, 68 pts with a history of IVD were enrolled in
      this study and compared with 68 non drug addict (NDA) pts with chronic HCV, with
      similar age and gender distribution. In all pts a liver biopsy was performed.
      Genotyping was done by INNO LiPA (Innogenetics, Belgium). Mean age in both groups
      was 35 +/- 7.8 years and 50 were males. No difference was observed between both
      groups in the prevalence of Gt1a, Gt2a/c and in those with mixed infections. The
      prevalence of Gt1b in IVD was 19.1% and in NDA 38.2% (p = 0.0228). A highly
      significant difference was also observed in the prevalence of Gt3a, of 42.6% in
      IVD and only 11.8% in NDA (p = 0.0001). Gt1a was the second most frequent
      genotype in IVD pts (26.5%). Simultaneous HIV infection was present in 8 IVD pts
      (11.8%) and in none of NDA group. Liver biopsies showed a higher prevalence of
      mild chronic hepatitis in NDA (57.3%) than in IVD (32.4%) (p = 0.0058). Severe
      chronic hepatitis with advanced fibrosis or cirrhosis was more frequent in the
      Gt3 of the group with IVD when compared with Gt3 of the NDA group. It can be
      concluded that in accordance with other geographical areas, Gt3a is far more
      prevalent in intravenous drugs addicts than in the general population in
      Argentina where Gt1b is more frequent. Mild forms of chronic hepatitis are less
      frequent in IVD. In spite of the relatively small group with HCV co-infection
      with HIV, it seems important to note that 2/8 (25%) showed severe hepatitis C or
      cirrhosis.

PMID- 10349120
TI  - [Evaluation of two methods to avoid the nephropathy associated with radiologic
      contrast].
AB  - Our objective was to establish the efficacy of two methods to avoid contrast
      associated nephropathy (C.A.N). We studied in prospective and randomized form a
      sample of 75 patients of whom 25 were assigned to the CONTROL GROUP: without
      interventions; 25 to the Saline group: 0.45% saline solution I.V., 1.5 cc/kg/min,
      6 hours before and after the angiographic study and 25 to the Dopa group: equal
      procedure plus the aggregate of dopamine 2 micrograms/kg/min, 30 minutes before
      the study until the termination. The evaluation effected at patient's entry was
      considered T0, T1, 24 hs after the T2, 48 hs after. In T0 was registered: age,
      sex, pathological antecedents, drugs and plasmatic creatinine, and in T2
      creatinine. An increase of 25% of the plasmatic creatinine in T2 was considered
      as C.A.N. The latter was present in 13/25 (OR: 1) CONTROL GROUP patients, 7/25
      (OR 0.36), Salina group patients and in 5/25 (OR 0.23) Dopa group patients (p =
      0.01). No significant difference was registered in the urinary output nor in the
      plasmatic creatinine levels. It is concluded that hydration during six hours
      before and after the study with 0.45% saline solution and the same plan with the
      aggregate of dopamine are effective to prevent a C.A.N.

PMID- 10349121
TI  - [Diagnosis and treatment of spinal epidural abscess].
AB  - Spinal epidural I abscess is an uncommon disease. The medical literature
      emphasizes the importance of its timely recognition and treatment. Three patients
      admitted in our hospital are presented. None of them was diagnosed on ambulatory
      bases. All of them were admitted because of spinal ache and two of them also had
      fever. Magnetic resonance imaging yielded the correct diagnosis in all cases and
      was very effective in delineating the extent of the lesion. We used antimicrobial
      therapy directed against the bacteria identified by cultures as well as surgical
      drainage in all cases. The three patients had a good outcome and no neurologic
      sequela. Early recognition, proper microbiologic diagnosis and surgical drainage
      are the main criteria for the current management of spinal epidural abscess.

PMID- 10349122
TI  - [Cuban dominant cerebellar ataxia. Peripheral nerve conduction studies in
      patients and asymptomatic relatives].
AB  - A total of 59 relatives of patients suffering from Cuban Dominant Cerebellar
      Ataxia (SCA2) were studied, undergoing physical examination in order to evaluate
      them clinically as well as by studies of peripheral nerve conduction. Clinical
      manifestations were detected in 13 of these patients. In 11 other patients there
      were electrophysiological alterations without symptoms or signs. The main
      electrophysiological alterations detected were reduced amplitude of the sensitive
      potentials. This is an expression of an axonal lesion occurring at a
      presymptomatic stage.

PMID- 10349123
TI  - [Bronchiectasia in HIV-positive patients].
AB  - Between July 1995 and July 1997 we diagnosed bronchiectasis confirmed by CT scan
      chest in 25 (18 men and 7 women) out of 295 hospitalised patients with HIV
      infection who suffered from lower respiratory infection. Median age at time of
      diagnosis of bronchiectasis was 32 years old. The patients were mostly
      intravenous drug addicts. In all cases a previous pulmonary infection was
      revealed (Pneumocystis carinii pneumonia, tuberculosis, recurrent pneumonia) with
      impairment of immune status (CD4 media = 64.8 mm3). Presence of persistent or
      intermittent cough with purulent sputum, repeated low respiratory infection and
      abnormal chest radiograph were correlated to bronchiectasis by chest CT scan. We
      conclude, that there is a significant occurrence of bronchiectasis in patients
      with HIV infections and pulmonary disease, thus increasing morbidity and
      mortality in these patients and being the cause of repeated hospitalisations due
      to bacterial respiratory infections.

PMID- 10349124
TI  - [Self monitoring of capillary blood glucose. Evaluation of long-term results (3
      to 7 years)].
AB  - We analyzed data provided by 60 diabetic patients (DP) included in a Program (P)
      of Self Blood Glucose Monitoring (SBGM) which showed an initial adherence of at
      least 6 months. Total follow-up was 67,293 DP-days (110,504 capillary glycemias).
      Only 50% of DP's remained for > 3 years. Rates of drop-out (DO) peaked early (3th
      semester (S) and late (10th. S) mean +/- SE of daily SBGM reported in the
      preprogram period and during the 1st S on P-SBGM by the future DO was
      significantly higher (4.25 +/- 0.22) than those reported by their P-SBGM-mates
      who stayed in the program (3.11 +/- 0.29; p < 0.01). DO showed a higher % of
      capillary glycemias < 60 mg/dl (hypoglycemia) (5.34 +/- 1.49 vs 2.85 +/- 1.14; p
      < 0.01). During the 3rd S early DO showed significantly higher Glycosilated
      Hemoglobin (HbA1) levels (10.4 +/- 0.49%) than late DO (8.19 +/- 0.45%; p <
      0.01). HbA1's recorded by the late DO's just before leaving P-SBGM were
      significantly higher (10.14 +/- 0.61%) than those seen at 2nd/5th S (8.2 +/- 0.2;
      p < 0.01). However, HbA1's of 1-DO at time of abandoning P-SBGM were comparable
      to those shown by those DP's who remained (10.14 +/- 0.61 vs 9.46 +/- 0.27%).
      DP's performed daily SBGM's in 70% of possible days during 4 years and in only
      50% afterwards. Daily SBGM's was 3.3 +/- 1 during the first 3 years and 2.1 +/-
      0.8 thereafter. Compared to preprogram period, all DP's improved HbA1's (12.5 +/-
      0.31 vs 9.46 +/- 0.27; p < 0.001) and mean blood glucose (166 +/- 5.2 vs 146 +/-
      3.6; p < 0.01). DP's who reached a faster and more satisfactory degree of
      glycemic control in earlier stages of P-SBGM showed the highest rates of drop
      out. Early identification of such patients, as well as setting of feasable and
      individualy adjusted goals of glycemic control may improve current compliance of
      DP's on long term tight control.

PMID- 10349125
TI  - [Role of 3 beta hydroxysteroid dehydrogenase (3 beta HSD) in human adrenal
      androgen synthesis].
AB  - Adrenarche is the maturational increase of adrenal androgens that takes place in
      6-8 year old children. In order to study the role of 3 beta HSD in the regulation
      of the synthesis of human adrenal androgens, the abundance of 3 beta HSD mRNA
      (Dot Blot and semiquantitative RT-PCR) was measured in 11 human prepubertal and
      early pubertal adrenal tissues. Subjects were divided in 2 age groups (Gr): Gr1,
      < 8 years (y) old (n = 6, range 0.1-2.5) and Gr2, > or = 8 y old (n = 5, range
      8.0-13.0). Tissue from one adrenal tumor with Cushing's syndrome (TSC) and 2
      virilizing adrenal tumors (TV), as well as adrenal cells prepared from the TSC
      and from 1 TV were also studied. They were maintained in culture for 3 days in
      basal conditions (BC) and under ACTH and IGF-1 stimulation. mRNA in Gr1 was
      higher than in Gr2 (Dot blot: 4.65 +/- 2.70 and 0.28 +/- 0.27 AU, p = 0.006; RT
      PCR: 21.5 +/- 12.5 and 6.77 +/- 3.78 AU, p = 0.039, respectively). 3 beta HSD
      mRNA in TSC (8.74 +/- 1.74) was higher than in the 2 TVs (0.47 +/- 0.02 and 0.87
      +/- 0.08) p = 0.001. In TSC cells, basal mRNA (0.82 +/- 0.10) decreased under
      ACTH (0.55 +/- 0.06), p = 0.005, and increased under IGF-1 (2.36 +/- 0.07), p =
      0.006. No changes were observed in TV cells. On day 3, TV cells in BC secreted
      1170.0 +/- 210.0 and 335.0 +/- 29.0 pmol/10(6) cells in 24 hs of DHEAS and
      androstenedione, while TSC cells secreted 17.1 +/- 3.5 and 73.7 +/- 11.7,
      respectively. Values increased under ACTH in TV cells (2006.0 +/- 360.0 and 525.0
      +/- 76.0) and in TSC cells (29.8 +/- 5.4 and 366.8 +/- 129) p < 0.05, but they
      decreased under IGF-1 only in TSC cells (7.9 +/- 2.4 and 43.7 +/- 6.1) p < 0.05.
      These data support the hypothesis that human adrenarche could be secondary to a
      decrease of 3 beta HSD mRNA. Our finding that when 3 beta HSD mRNA decreases
      androgen secretion increases (ACTH) and when 3 beta HSD mRNA increases androgen
      secretion decreases (IGF-1), strongly suggests that 3 beta HSD has a modulatory
      role in adrenal androgen steroidogenesis.

PMID- 10349126
TI  - Chylothorax in hairy cell leukemia.
AB  - A case of postoperative left chylothorax in a 43-year-old black woman with hairy
      cell leukemia is reported. First submitted to pleural drainage, she was
      successfully treated with a combination of chemotherapy and elemental enteral
      diet enriched with medium-chain triglycerides.

PMID- 10349127
TI  - [Intestinal infarct caused by giant cell arteritis].
AB  - Arteritis of giant cells compromising extracranial and particularly intestinal
      tissues is not frequent. Therefore, it is common practice to make the diagnosis
      retrospectively after analyzing the surgical sample. A case is presented of an 83
      year old woman admitted to the Clinical Department with a clinical course of 3
      days of evolution characterized by fever and pain in the left hemiabdomen. Her
      personal medical history included multiple diverticulosis of colon,
      collecistectomy and appendicectomy. Laboratory tests showed that uremia was 0.75
      g/L (N.L to 0.45 g/L), V.E.S. 90 mm at the first hour, and the rest of the
      determinations were normal. The chest and abdomen rays as well as the abdomen and
      pelvis ecographies were normal. A diagnosis was reached as acute diverticulitis
      and the patient was treated with 400 mgr of ciprofloxacina and 2,000 mgr a day of
      metronidazol. She continued in a feverish state and with abdominal pain, so that
      an anexial tomography of abdomen was taken. It showed a widening of peritoneal
      fascias with scarce liquid in the left parietocolic dripping and Douglas septum.
      After 96 hours, surgery exploration was done and injuries in the left colon
      revealed compatibility with an infarct of the colon which had to be extirpated.
      Pathological examination revealed an infarct of colon due to a secondary arterial
      thrombosis characteristic of giant cell arteritis. After the diagnosis,
      immunological studies and biopsy of the left temporal artery were performed and
      reported as normal. The patient was treated with 40 mgr of prednisone a day
      improving rapidly.

PMID- 10349128
TI  - [Partial lecithin-cholesterol acyltransferase (LCAT) deficiency syndrome].
AB  - This syndrome is a pathological entity of low incidence which mainly affects high
      density lipoprotein (HDL) metabolism. We here show the first case reported in our
      country, observed in a 63-year-old woman who showed bilateral corneal opacity and
      eruptive xanthomas in both arms. The lipoprotein profile disclosed severe
      hypertriglyceridemia and normocholesterolemia, although the percentage of
      cholesteryl esters was low. Plasma levels of HDL-cholesterol and HDL major
      apolipoproteins, A-I and A-II, were markedly decreased. The patient also showed
      glucose intolerance and hematological alterations related to abnormal lipid
      composition of erythrocyte membranes. As evaluated by the exogen substrate
      method, LCAT activity proved to be 82% lower in the patient than in a control
      subject. It is noteworthy that the patient had experienced cardiac events and
      presented hypertension, neither of which has been commonly documented in partial
      LCAT deficiency syndromes.

PMID- 10349129
TI  - [Simultaneous pancreas-kidney transplantation].

PMID- 10349130
TI  - [Posterior interosseous nerve syndrome].

PMID- 10349131
TI  - [Heparin cofactor II, a thrombin inhibitor with a still not clarified physiologic
      role].
AB  - Heparin Cofactor II (HCII) is a glycoprotein in human plasma which inactivates
      thrombin rapidly in the presence of dermatan sulfate. Inhibition occurs by
      formation of a stable equimolar complex between HCII and thrombin. HCII
      association with thrombotic events has not always been observed, thus decreased
      HCII does not appear to be a strong risk factor for thromboembolic events.
      Reduced HCII levels have been detected in different clinical conditions, such as
      hepatic failure, disseminated intravascular coagulation, thalasemina, sickle cell
      anemia. Increased physiological levels have been found in pregnant women and oral
      contraception. In our laboratory, we measured HCII plasmatic levels in the normal
      Buenos Aires city population and in patients under different clinical conditions,
      such as sepsis, diabetis, burns, oral anticoagulation and in patients treated
      with heparin, hyperhomcysteinemia in whom septic and diabetic patients showed
      decreased values. HCII thrombin inhibition possibly takes place in extravascular
      sites where dermatan sulfate is present. HCII activity would be important in the
      regulation of wound healing, inflammation, or neuronal development.

PMID- 10349132
TI  - [If I were president of the CONICET].

PMID- 10349133
TI  - [In defense of the aminophylline].

PMID- 10349134
TI  - [The contribution of molecular biology to genetic arterial hypertension].

PMID- 10349135
TI  - [Posthyperventilation hypoxia].

PMID- 10349136
TI  - [Polycystic ovarian syndrome. GnRH pulse generator defect?].

PMID- 10349137
TI  - [Meta-analysis. Is it a statistical panacea?].

PMID- 10349138
TI  - [Babinsky? Babinski].

PMID- 10349139
TI  - Biology of nymphs of Rhodnius robustus Larrousse, 1927 (Hemiptera, Reduviidae),
      fed on pigeon or on Swiss mouse blood in laboratory conditions.
AB  - The duration of the life cycle of Rhodnius robustus Larrousse, 1927 as well as
      the mortality rate of each nymphal instar were studied comparing groups fed on
      pigeon or on mouse blood weekly or fortnightly. This species showed a better
      development and lower mortality rate when fed on swiss mouse. The intervals
      between feedings apparently did not have influence on the shortening of the
      cycle. We suggest that laboratory colonies and experiments with R. robustus are
      better maintained when these triatomines are fed on swiss mouse.

PMID- 10349140
TI  - [Culicidae mosquitoes as emerging vectors of diseases].
AB  - A review is presented of the relationships between the so-called emerging
      infectious diseases and what may be defined as emerging vectors. These include
      not only those that have recently appeared but also those that present remarkable
      behavioral changes. Specific factors leading to that emergence can be associated
      with the powerful human influence on the environment. So the man-made, i.e.
      anthropic environment, exercises a selective pressure inducing vector populations
      to adapt to new circumstances. These may arise from ecological, environmental, or
      demographic factors that increase contact with the new vector. With this in mind,
      data on anomalous Culicidae breeding places in the Americas are reported. An
      interpretation of these findings is offered in the light of epidemiological
      surveillance. The question is whether vector emergence or re-emergence may
      constitute an epidemiological problem. Thus it is suggested that plane for all
      inclusive surveillance be prepared.

PMID- 10349141
TI  - Influence of HIV positive status on sexual behavior among males.
AB  - OBJECTIVE: To compare HIV seronegative (HIV-) and HIV seropositive (HIV+) males
      in terms of sexual behavior with female and male partners of different types.
      METHOD: Cross-sectional study. From August 1994 to February 1995, a sample of 236
      respondents (150 HIV- and 86 HIV+) recruited from public health centers in the
      State of S. Paulo (Brazil), answered a questionnaire, including questions on
      demographic aspects, HIV and AIDS related knowledge, sexual orientation, use of
      alcohol and other drugs, sexual behavior with regular and casual female and male
      partners, and perceived risk of HIV infection. Sexual behavior with regular and
      casual female and male partners within the previous three months, was
      investigated. RESULTS: A lower proportion of HIV+ engaged in sexual contact with
      regular female partners (p < .01) and in vaginal intercourse with this type of
      partner (p < .01). A lower proportion of HIV+ engaged in overall sexual activity
      (p < .001) and reported lower frequency of penetrative sexual practices (p <
      .05). A high level of condom use with female and male partners was identified
      with no significant differences being found between the two serostatus groups.
      Some risky sexual behavior was identified, however, especially with regular
      partners, suggesting that some men were continuing to practice unsafe sex.
      CONCLUSIONS: The high level of condom use identified suggests that safer sex
      advice has been taken up. Condom use was not universal, however, and some men
      continue to place themselves at risk, especially with regular partners.
      Prevention programs should strive not only to encourage HIV- to practice safer
      sex, but also to encourage HIV+ to do so in order to prevent further transmission
      of the virus.

PMID- 10349142
TI  - Epidemiological aspects of centipede (Scolopendromorphae: Chilopoda) bites
      registered in greater S. Paulo, SP, Brazil.
AB  - INTRODUCTION: The lack of basic knowledge on venomous arthropods and the
      benignity of the clinical manifestations contribute to the centipede bite
      victims' not being taken to a treatment reference center, leading to
      underestimation of the number of cases and minimizing the possibility of a
      broader epidemiological view. An inventory of the centipede bite occurrences in
      Greater S. Paulo, Brazil, and the therapeutic methods employed, by the main
      Brazilian medical center for the notification of poisoning by venomous animals,
      is presented. METHOD: All patient cards of the period 1980-1989 have been checked
      as to place, month and time of occurrence; sex, age, affected part of the body,
      signs and symptoms have been observed, as well as the therapeutic methods
      employed. The centipedes that caused the accidents were identified at the
      Arthropods Laboratory. RESULTS: It was registered 216 accidents, with a 69%
      predominance of the Greater S. Paulo and in only 63% of the cases (136) was the
      agent brought in by the victim for identification. The genera most frequently
      represented were Cryptops (58%), Otostigmus (33%) and Scolopendra (4%). Of the
      136 cases, 87% showed erythema, edema, hemorrhage, burns, cephalalgia, and
      intense pain. There was a predominance of accidents in the warm rainy season, in
      the morning and for females between 21 and 60 years of age. Hands and feet were
      the parts of the body most affected. The benign evolution of the clinical picture
      (54%) made therapeutical treatment unnecessary. Only the victims of Scolopendra
      and Otostigmus (46%) were medicated with anesthetics (51%), analgesics (25%),
      antihistamines and cortisone (24%). CONCLUSION: The reproductive period of the
      centipedes, associated with their sinanthropic habits, contributes to the greater
      incidence of accidents in urban areas in the warm rainy season. Only patients
      bitten by Scolopendra and Otostigmus require therapeutical treatment.

PMID- 10349143
TI  - [Regional and interspecific variations in the morphology of insects of the
      Lutzomyia intermedia complex (Diptera, Psychodidae, Phlebotominae)].
AB  - INTRODUCTION: Lutzomyia intermedia s. s. and L. neivai, usually considered as
      belonging to just one species, constitute a complex of species. The measurements
      of several anatomical structures of specimens of both groups, from Brazil,
      Paraguay, Argentina and Bolivia were analysed. METHOD: Thirty-nine structures
      were measured in specimens of both sexes, using a graduated ocular, analysing
      comparisons by analyses of variance (ANOVA). RESULTS: A significant deviation in
      the proportions of females and males showing each palpal formula and the
      influence of the region of origin of the flies were verified. Labrum and maxilary
      palps were longer in females and Antennomere III was longer of males. Several
      significant differences in the measurements of wings were noted, most of them
      greater in females. The proportion of spermathecae with simple heads was
      significantly greater in L. neivai than in L. intermedia. Significant differences
      in the length of genital pump and filaments between the species were also noted.
      DISCUSSION: The variation in the palpal formulae in both sexes show the risk of
      the use of this formula for the association between specimens of the two sexes.
      The differences in the lengths of palps and labrum between the sexes could be
      related to female blood feeding. The possible biological significance of the
      sexual differential relation length/width of wings is commented on. The different
      proportions of females of the two species with each spermathecae head shape may
      help in identification. The differences in the lengths of genital pumps and
      filaments and the relation between them could help in the identification of
      males, which is still difficult.

PMID- 10349144
TI  - [Reliability of diagnoses on authorization forms for hospital admission].
AB  - OBJECTIVE: The reliability of the diagnoses given on forms authorizing Hospital
      Admittance (AIH), financed by the official Health System, was analysed during the
      period January through December, 1992, in Maringa-PR, Brazil. METHOD: A
      systematic method was used to sample 1,595 medical records of the admittances to
      8 general hospitals. The diagnoses registered in the medical records were
      compared to those registered in the corresponding AIH forms. The level of
      agreement on the main diagnoses was analysed by using the Kappa test. RESULTS:
      The results of the study show that the agreement for the five leading chapters of
      International Classification Disease-9 (ICD-9) has ranged from k = 0.79 to k =
      0.98. The agreement for the five leading groupings of diagnoses has ranged from k
      = 0.79 to k = 0.97. CONCLUSION: Some reasons for disagreement, such as miscoding
      and the hospital reimbursement system are discussed. It is also concluded that it
      may be possible to use the hospital admittance data of the Official Health
      System, according to the diagnostic chapters and groupings of the ICD-9, with
      some degree of confidence.

PMID- 10349145
TI  - [Cigarette smoking among bank employees].
AB  - OBJECTIVE: To describe the prevalence of cigarette smoking and its association
      with other risk factors for chronic diseases among active workers of
      communication and data processing centers of a Bank. METHODS: Cross-sectional
      study in a simple random sample of 647 active workers of the bank. The data were
      collected in the work environment, through self-administered questionnaires.
      RESULTS: The prevalence of cigarette smoking was 29.5% (95% Confidence Interval
      (CI): 27.5%-31.5%), 31.1% (95% CI: 26.2%-35.8%) among men and 27.8% (95% CI:
      22.6%-32.9%) among women. On average, males started smoking at the age of 17.6
      years and women at the age of 19.4. High prevalence of heavy smokers was observed
      among men and women (53% and 42%, respectively, smoked more than 20 cigarettes
      per day). Smokers were older, more likely to be divorced, separated and widowed,
      to have high blood pressure, to drink alcoholic beverages more often, and to
      exercise less often than to non-smokers. Those who gave up smoking were older,
      drank more alcoholic beverages, and were more often overweight. CONCLUSION: The
      considerable frequency of smoking and other risk factors for chronic diseases
      among those workers may be an indication of the need for new strategies for
      health interventions. Opportunities for preventive actions, which are more
      effective and less costly, may have been lost.

PMID- 10349147
TI  - [Predictive value of the "Clinical Risk Index for Babies" for the risk of
      neonatal death].
AB  - OBJECTIVE: Several indicators, mainly birthweight and gestational age, have been
      used to predict the mortality risk in neonatal intensive care units. In order to
      assess the potential value of CRIB in predicting neonatal mortality, the score
      was used over the first 12 hours of life of the newborns admitted to this unit,
      during the year of 1996. METHOD: The inclusion criteria consisted of all infants
      without inevitably lethal congenital malformations, birthweight below 1,500 g
      and/or gestational age less than 31 weeks. Newborn children who died within 12
      hours after delivery were excluded. The CRIB score covers birth weight,
      gestational age, the presence of congenital malformations (not inevitably lethal)
      and three indexes of physiological status during first 12 hours after birth
      maximum and minimum appropriate fraction of inspired oxygen and maximum (most
      acidotic) base excess. RESULTS: In a prospective cohort, seventy one newborn
      children were studied. The birthweight (average) was 1,119 +/- 275.6 g,
      gestational age 30 weeks 4/7 +/- 2 weeks 3/7; male (57%); Apgar 1(0) min. score <
      or = 3 (36.2%) and Apgar 5 degrees min. score < 5 (5.8%). The mortality rate was
      29.6% (gold standard). But mortality rate by birthweight less than 1,000 gr. or
      gestational age lower than 29 weeks was 60.0% and for the CRIB score above 10 was
      100%. DISCUSSION: The specificity and predictive positive values for CRIB score
      above 10 were greater than any other two parameters. The area under the receiver
      operating characteristic (ROC) curve for predicting death was significantly
      greater for CRIB than for birthweight alone. It was concluded that the CRIB score
      is a better predictive indicator for mortality than are birthweight and
      gestational age.

PMID- 10349146
TI  - [Factors associated with obesity among adolescents].
AB  - INTRODUCTION: Obesity during adolescence is considered a strong predictor of
      adult obesity. The present study assessed the overweight/obesity prevalence and
      associated factors in middle class adolescents of a school in the city of
      Niteroi, Rio de Janeiro, Brazil, and evaluated the correlation between body mass
      index with anthropometric measures of fatness. METHOD: The analysis covered 391
      students aged from 15 to 17 years. Adolescents had their weight, height, skinfold
      thickness and upper arm circumference measured at school. A food frequency
      questionnaire (list of 79 items) and a questionnaire including food habits,
      parents anthropometric characteristics, physical activity and other factors
      associated with obesity were filled out by the adolescents at school. RESULTS:
      The proportion of overweight individuals among boys (Body Mass Index (BMI)
      greater than the 90th percentile of the Brazilian population) was 23.9%, whereas
      the prevalence among girls was 7.2%. The fact of being on a slimming diet was a
      relevant factor for the prediction of BMI and was 7 times more frequent among
      girls than among boys. Among boys, being on a diet, absence of breakfast, and
      family body appearance were positively associated with BMI. Among girls these
      variables were also significantly associated, whereas age at menarche was
      negatively associated with BMI. Hours of watching TV/video/video-game was
      associated with BMI only among boys. The correlation coefficient between BMI and
      measures of fatness varied from 0.7 to 0.9 for boys, and from 0.8 to 0.90 for
      girls. CONCLUSIONS: BMI appears to be a good indicator of obesity among
      adolescents and showed that girls demonstrated an exaggerated preoccupation with
      body image and stereotyped slim body patterns.

PMID- 10349148
TI  - [Cost-effectiveness of interventions for end-stage renal disease].
AB  - OBJECTIVE: The study reports the cost-effectiveness results of end-stage renal
      disease (ESDR) patients in Mexico in terms of years of life gained and quality of
      life and the economic cost with regards to three treatment alternatives that
      could be considered mutually exclusive: continuous peritoneal ambulatory dialysis
      (CAPD), hemodialysis (HD) and renal transplant (RT). METHOD: The economic costs
      were calculated by using the average cost case-management methodology and
      further, the probable of life expectancy and the quality of life were cross
      sectionally assessed by means of the Quality Adjusted Life Years (QALY) measured
      by the Rosser Index. RESULTS: The results show that economic costs in US$ of the
      three treatment alternatives were: CAPD $5,643.07, HD $9,631.60, and RT
      $3,021.63. The probability of life expectancy for CAPD and RT for the first and
      third year were: 86.2% and 66.9%, and 89.9% and 79.6%, respectively. The QALY
      scores for patients were: CAPD 0.8794, HD 0.8640, and RT 0.9783. CONCLUSION: The
      intervention with the highest cost-effectiveness coefficient was the renal
      transplant (3,088.69), followed by the CAPD (6,416.95) and HD (11,147.68). A
      significant difference was found between the transplanted patients and patients
      undergoing dialysis. Finally, this study concluded that the RT offers the least
      expensive alternative and the greatest number of years of life gained as well as
      providing significant changes in the quality of life of ESRD patients.

PMID- 10349149
TI  - [Trypanosoma cruzi infection in blood donor candidates].
AB  - INTRODUCTION: Transmission of American trypanossomiasis by transfusion has been
      reduced by expansion of control measures of blood quality in Brazil. A research
      project was, therefore, undertaken to evaluate soropositivity for Trypanosoma
      cruzi infection on blood donors and to compare this rate with those found in 1958
      and 1975 in blood banks. METHOD: A transversal study was carried out on blood
      donors in Londrina, Parana, Brazil. ELISA and Immunofluorescence were the
      serological test techniques used in the diagnosis of Trypanosoma cruzi infection.
      RESULTS AND CONCLUSION: A serumprevalence rate of 1.3% was found with a tendency
      for positive serum findings for Trypanosoma cruzi infection on blood donors to
      decrease over Aime (1958, 1975, and 1995).

PMID- 10349151
TI  - [Prevalence and risk factors associated with syphilis in women].
AB  - INTRODUCTION: Although the incidence of syphilis is generally low, it remains an
      important global public health problem, given its interaction with other sexually
      transmitted diseases (STDs). It has been shown that syphilis, due to the genital
      ulcers it produces, is a co-factor for acquiring other STDs, principally those of
      viral origin such as herpes simples type 2, hepatitis B and HIV. Many female
      commercial sex workers (FCSW) in Mexico have been found to have acquired good
      levels of knowledge about STD prevention. Nevertheless, they constitute a
      heterogeneous group in terms of socio-economic level, health status and type of
      work site; these factors in turn appear to determine their attitudes, knowledge
      and behavior related to acquiring and transmitting STDs, including syphilis. This
      study, therefore, focused on the factors associated with Treponema pallidum
      infection in this group of women. METHOD: Based on a sample frame of sites where
      female commercial sex work takes place within Mexico City, a sample of 807 FCSWs
      was selected; after providing informed consent, they completed a structured
      questionnaire. A blood sample for identifying serologic markers for STDs was
      collected and analyzed according to a procedure manual for STD diagnosis.
      Treponema pallidum was diagnosed using the RPR (Bigaux Diagnostica) screening
      test, and FTA-ABS (Pasteur Diagnostics) for confirmation. RESULTS: The prevalence
      of syphilis in this sample of FCSWs was 6.4% (52/807), and was higher among women
      who worked at street sites than among those who worked in massage parlors. The
      age of the women interviewed ranged from 17 to 58 years, with a mean of 29.2
      years (SD 7.3 years); syphilis was more prevalent among women over 30 years of
      age. Age at first sexual intercourse ranged from 11 to 30 years, with a mean of
      16 years (SD 3.1 years), which is similar to that of the general female
      population in Mexico. Predictive factors for T. pallidum infection, determined
      adjusted logistic regression, included: tupe of by work site (bar and street
      sites); socio-economic level (middle and low); age (over 30 years); duration of
      involvement in sex work (> 5 years) and number of clients per week (> 10).
      CONCLUSION: In spite of some limitations regarding statistical precision, this
      study shows that FCSWs are heterogeneous in terms of risk of acquiring STDs,
      including syphilis; the principal differentiating factor was shown to be the type
      of work site. Given that it is not belonging to a risk group but rather
      participating in risky practices that leads to acquiring STDs, situations that
      facilitate riskier or safer practices (such as type of sex work site, for sex
      workers) should be taken into account when studying people's risk level. STD
      prevention campaigns must also consider these factors, in addition to focusing on
      FCSWs and their clients and personal partners, so that all involved assume their
      responsibility for safer sex.

PMID- 10349150
TI  - [Mortality descriptors in HIV inpatients].
AB  - OBJECTIVE: To assess the clinical-epidemiological descriptors of inpatient
      mortality in persons infected with the human immunodeficiency virus (HIV).
      METHOD: All adult HIV/AIDS patients hospitalized at a university hospital in
      1990, 1992 and 1994 were studied retrospectively. Descriptive statistics for all
      variables of interest were generated. Chi-square test and Fisher's exact test
      were performed to compare categorical variables. Means were compared using the
      Student t test. Stepwise logistic regression was used to identify the odds of
      dying associated with each risk factor. RESULTS: Two hundred and forty patients
      were included in the study. Between 1990 and 1994 the mean age rose from 35 to
      36.9 years, the male/female ratio decreased from 9.8 to 2.0, the non-white
      proportion increased from 18.5 to 41.3% and the mean time between detection of
      HIV infection and hospitalization rose from 0.7 to 2.5 years. In addition, length
      of stay dropped from 31.3 to 25.3 days and the proportion of patients being
      followed up in the outpatient clinic of the University Hospital increased from
      47.8 to 83.3%. Respiratory infections were the main cause of hospitalization
      (58.0%). Oral candidiasis (27.1%), tuberculosis (18.3%). Pneumocystis carinii
      pneumonia (15.4%) and toxoplasmic encephalitis (10.4%) were the most frequent
      opportunistic infections. Multivariate analysis showed that the factors
      associated with a worse outcome included the length of stay less than or equal to
      7 days (Odds Ratio [OR] = 3.88; p = 0.02) and no outpatient follow-up at the
      Hospital (OR = 3.29; p = 0.01). CONCLUSION: Identification of independent risk
      factors for death may help in the implementation of more efficient interventions
      directed towards inpatients with HIV/AIDS.

PMID- 10349152
TI  - [The building of a health center from the point of view of planners and doctors:
      a case study].
AB  - OBJECTIVE: The relationship between the structure of the health center and the
      population seeking comprehensive health care. METHOD: It was studied a health
      center of the county of S. Paulo (Brazil) in the period of 1989 to 1992. The
      speech of managers at three levels, regional, district and local, as well as the
      speech of physicians who were working at the Primary Health Care Units, was
      analysed. The concept of comprehensive care covers five dimensions: 1) the
      individual and not the illness itself as the primary aim; 2) the individual or
      group as a whole; 3) the intervention provided by other types of care; 4)
      different treatment for those who live in different situations; 5) the
      intervention in the general living conditions of the population. RESULTS: It was
      concluded that the relationship between the district structure and the seek for
      comprehensive care was dependent on the following: health planning, emphasizing a
      wider view of the real life situation of the population connected to the Primary
      Health Care Unit; the kind of interaction between different members of the staff;
      better organization of the work and of the reference and counter-reference
      networks and a good relationship with other health departments, thus making
      possible better comprehensive care. COMMENTS: Being a local care unit does not
      enable the health district to meet the challenge of being the "locus" of
      knowledge, work and power as between the population and the workers and among the
      different groups within these two sectors.

PMID- 10349153
TI  - [Comparison of epidemiological data on pulmonary tuberculosis in Sorocaba, Sao
      Paulo, Brazil, (1986-1996)].
AB  - Pulmonary tuberculosis is a serious public health problem in Brazil. Data were
      collected relating to the patients' health before diagnosis and also to the time
      lag between this diagnosis and the beginning of specific treatment over a period
      of three months. Fifty patients suffering from pulmonary tuberculosis were
      questioned about: symptomatology before diagnosis, lapse between the occurrence
      of the first symptoms and the beginning of treatment and relationship with AIDS.
      There had been no significant change in the time-lag between the time of
      discovery of new cases and the beginning of treatment, over the last ten years.

PMID- 10349154
TI  - [New findings of Anopheles mosquitoes in artificial containers].
AB  - New findings of Anopheles mosquitoes in artificial containers are reported. In
      one, a plastic container served as a breeding place for Anopheles bellator larvae
      and, in another, four instar larvae of An. albitarsis s.l. were found in an
      abandoned toilet basin. Reflections are offered as to the selective pressure
      represented by the production, of an ever increasing scale, of disposable
      objects.

PMID- 10349155
TI  - [Current situation of organ transplantation in Chile].
AB  - In Chile, the experience in organ transplantation began in the sixties with renal
      transplantation. Since then, a great progress has been made in terms of number of
      transplants, performance of extrarenal transplants (liver and to a lesser extent,
      heart), organ procurement and increasing the access of adult and pediatric
      patients to these complex and expensive procedures. Transplantation has become
      widely accepted as the therapy of choice for end stage organ failure and we have
      acquired considerable experience in the fields of renal and liver
      transplantation. These improvements have been the result of the great efforts
      made by transplant groups but the financial support provided by public health
      authorities has also contributed to the success. In the near future, organ
      transplantation will most likely continue to progress in our country, specially
      in the area of thoracic organs, but there still is a good deal of work to be
      done. In the forthcoming years, we will face the challenge of maintaining high
      quality levels with tremendous financial restrictions. We are optimistic that we
      will continue to improve our skills and experience as in the last decade and
      organ transplantation will become a widely available therapy with high standards
      of results.

PMID- 10349156
TI  - [Microalbuminuria, lipid changes and coronary heart disease in non-insulin
      dependent diabetics].
AB  - BACKGROUND: Microalbuminuria could be a possible coronary risk factor: AIM: To
      study the association between microalbuminuria, serum lipid levels and coronary
      heart disease in non-insulin-dependent diabetics. PATIENTS AND METHODS: We
      studied 104 non-insulin-dependent diabetics, who were separated in four groups
      according to the presence of microalbuminuria, defined as a 24 h albumin
      excretion of 30-300 mg/24 h and according the history of coronary artery disease.
      Total, HDL and LDL cholesterol, triglycerides, alpha, beta, prebeta lipoproteins,
      lipoprotein (a), apoproteins A and B were measured in all. RESULTS: Twenty
      patients with and 32 without coronary artery disease had normal albumin excretion
      and the same number of patients had a urinary albumin 30-300 mg/24 h. All four
      groups were comparable in terms of metabolic control, nutritional status, blood
      pressure and creatinine levels. Patients with coronary artery disease had higher
      urinary albumin excretion than patients without the disease 91 (32-173) and 34 (5
      97) mg/24 h respectively p < 0.01. Patients with coronary artery disease and
      microalbuminuria had higher triglycerides, beta, pre beta lipoproteins, Apo B,
      Lp(a) and lower Apo B and alpha lipoproteins. This group also had a higher
      frequency of abnormal pre beta and alpha lipoprotein levels, when compared with
      coronary patients with normal albumin excretion. In coronary patients there was a
      positive association between urinary albumin levels and triglycerides (r = 0.24),
      pre beta lipoproteins (r = 0.27) and Apo B (r = 0.3); there was also a negative
      association with HDL cholesterol (r = 0.25) and alpha lipoproteins (r = -0.41).
      CONCLUSIONS: In this group of non-insulin-dependent diabetics, an association
      among microalbuminuria, abnormal serum lipid levels and coronary artery disease
      was detected.

PMID- 10349157
TI  - [Direct molecular analysis of FMR-1 gene mutation in patients with fragile Xq
      syndrome and their families].
AB  - BACKGROUND: The unequivocal diagnosis of fragile Xq syndrome is based in the
      direct analysis of the underlying FMR-1 gene mutation, that consists in an
      increased number of trinucleotide CGG repetitions. AIM: To study families with
      fragile Xq syndrome, using the Southern technique for the analysis of the
      mutation. SUBJECTS AND METHODS: Fifteen individuals, pertaining to 6 families
      with fragile Xq syndrome, were studied. Clinical, cytogenetic and molecular
      analysis using Southern technique, were done. RESULTS: Five male individuals had
      a clinically evident syndrome, confirmed by cytogenetic analysis that showed
      fragility in 10 to 29% of studied cells. One subject with a clinical picture
      suggesting fragile Xq had a normal cytogenetic study. The other studied subjects
      were the mothers of the five subjects with the syndrome, that must be carriers,
      and four brothers. Molecular analysis showed that seven subjects (5 males) had a
      complete mutation, five (4 females) were carriers of a pre mutation and three (2
      males) did not have the mutation. CONCLUSIONS: The Southern technique allows to
      verify the normal condition of FRAXA locus, identify carriers and to detect
      complete mutations in fragile Xq syndrome.

PMID- 10349158
TI  - [Fragile X syndrome. Clinical analysis of 300 Chilean patients with unspecific
      mental retardation].
AB  - BACKGROUND: Fragile X syndrome is the most important cause of sex linked mental
      retardation and the second of chromosomal origin, after Down syndrome. AIM: To
      apply the modified Hagerman score to patients with mental retardation and to
      relate clinical findings with cytogenetic and molecular diagnosis. PATIENTS AND
      METHODS: The modified Hagerman score was applied to 214 male and 86 female
      patients with mental retardation. The clinical variables in non fragile X and
      fragile X cases, determined by molecular and cytogenetic methods, were compared.
      RESULTS: The score in 210 non fragile X males was 10.5 + 3.7 (range 3-23),
      compared to 21.4 + 2.1 (range 19 to 23) in the four fragile X patients. All
      fragile X patients had mental retardation, attention deficits, hyperactivity
      disorders, hand biting and poor visual contact. Hand biting, flapping and
      perserving speech were observed in a significantly higher number of fragile X
      males. Only one of 86 females had fragile X syndrome: Her most relevant findings
      were a long face and high forehead, an attention deficit, hyperactivity and poor
      visual contact. No clinical differences with other mentally retarded females were
      found. CONCLUSIONS: Approximately 5% of institutionalized males with mental
      retardation have a fragile X syndrome.

PMID- 10349159
TI  - [HLA haplotypes in families with type 1 diabetes].
AB  - BACKGROUND: Inherited susceptibility to type 1 diabetes is partially determined
      by HLA genes. HLA-DQA1 and DQB1 alleles have been chosen as the most sensitive
      susceptibility markers. Family studies are a good method to establish specific
      relationship between type 1 diabetes and specific haplotypes as risk markers for
      the disease. AIM: To analyse the role of class II HLA molecules and the
      distribution of haplotypes in the genetic predisposition to type 1 diabetes in
      Chilean families. MATERIAL AND METHODS: Twelve family groups constituted by 58
      individuals were studied. Fourteen children (10 male) less than 15 years old with
      diabetes and their family members were included. The allele and haplotype
      frequency of the population was determined in 74 unrelated healthy children.
      RESULTS: Risk haplotypes such as HLA-DR3/DQB1*0201/DQA1*0501 and HLA
      DQB10302/DQA1*0501 were more common among diabetic patients and comparable to the
      haplotypes described in other Caucasian populations. Meanwhile, protective
      haplotypes found in relatives without diabetes, such as HLA
      DR2/DQB1*0301/DQA1*0301 and HLA-DR8/DQB1*0402/DQA1*0301, were absent in children
      with diabetes. CONCLUSIONS: The general pattern of neutral or protective
      haplotypes, found with higher frequency in non diabetic individuals, indicates
      that their presence could confer protection against the disease, with a higher
      effect over those haplotypes associated to the disease.

PMID- 10349160
TI  - [Antimicrobial multiresistance of Shigella sp strains in a semi rural community
      of northern Santiago].
AB  - Appropriate antimicrobial therapy shortens the duration of Shigellosis and
      significantly reduces the risk of transmission. Shigella strains resistant to
      common antimicrobials have increased during the past years, determining the need
      for a periodic surveillance, to guide effective therapy. AIM: To report the
      results of a surveillance program in a rural community near Santiago (Colina),
      for Shigella infections. MATERIAL AND METHODS: Between 1995 and 1997, stool
      samples from 3,534 episodes of diarrhoea, that occurred in Colina, were obtained.
      Two hundred twenty six Shigella strains were isolated and studied for
      susceptibility to ampicilin (AM), amoxicillin/clavulanic acid (AMC),
      cotrimoxazole (STX), chloramphenicol (CAF), tetracycline (TET), furazolidine
      (FU), ciprofloxacine (CIPR), nalidixic acid (AC NAL), gentamycin (GENT) and
      cefotaxime (CFTX). RESULTS: Shigella flexnerii represented 134 of 226 Shigella
      strains isolated. All strains were susceptible to CIPR, AC NAL, GENT and CFTX.
      Yearly variation of resistance patterns to other antimicrobials were observed for
      these strains. Resistance to AM varied from 56 to 76%, to AMC from 25 to 56%, to
      STX from 21 to 47%, to CAF from 36 to 69%, to TET from 44 to 78% and to FU from 9
      to 18%. Overall resistance was higher during 1997. All 85 strains of S sonnei
      were susceptible to CIPR, AC NAL and CFTX. Resistance throughout the years varied
      from 56 to 88% for AM, from 0 to 28% for AMC, from 44 to 53% for STX, from 11 to
      40% for CAF, from 11 to 42% for TET and from 5 to 11% for FU. Overall resistance
      was also higher during 1997, except for AM and STX. Seven S hoydii strains were
      isolated, only during 1995. All seven were resistant to AM and TET and none were
      resistant to FU, CIPR, AC NAL and CFTX. Two strain was resistant to AMC, STX and
      CAF. CONCLUSIONS: Antimicrobial resistance patterns of Shigella sp isolated in
      Colina have increased from 1995 to 1997, specially for commonly used
      antimicrobials. Resistance remains low for furazolidine and all strains remain
      susceptible to quinolones.

PMID- 10349161
TI  - [Urinary tract malformations in newborns at the Clinical Maternity Hospital of
      the University of Chile].
AB  - BACKGROUND: The prevalence of urinary malformations at birth is steadily
      increasing, probably due to the availability of better diagnostic techniques.
      AIM: To assess the prevalence of renal agenesis, hidroureteronephrosis and
      polycystic kidney at birth in the obstetric wards of the University of Chile
      Clinical Hospital. PATIENTS AND METHODS: As a part of the Latin American
      Collaborative Study of Congenital Malformations, 54.039 consecutive births at the
      Maternity, between January 1982 and December 1997, were studied. RESULTS: Eighty
      three newborns had urinary tract malformations (15.3/10,000). Fourteen
      (2.6/10,000) had renal agenesis, 34 (6.3/10,000) had hidroureteronephrosis and 35
      (6.5/10,000) had polycystic kidney. Eleven percent of these children were
      stillbirths and 35% died in the first days of life. Fifty six percent were male,
      34% female and 10% had ambiguous sex. Mean birth weight was 2750 g, mean
      gestational age was 35.4 weeks and mean maternal age was 28 years old. Twenty
      three percent of mothers had a history of previous abortions, 8% had a history of
      stillbirths and 10% a history of metrorrhagia during the first trimester of
      pregnancy. Twenty five percent of children had a relative with a malformation and
      48 children had other associated malformations such as pulmonary hypoplasia,
      external malformations caused by extreme oligoamnios or internal malformations
      such as utereral, urinary bladder; uretral or external genitalia agenesis.
      CONCLUSIONS: The prevalence of urinary malformations in this hospital was higher
      than in other hospitals participating in the collaborative study. This difference
      could be due to an under registration of malformations in other hospitals.

PMID- 10349162
TI  - [Treatment results in 588 patients with multiple trauma].
AB  - BACKGROUND: Ten to fifteen million wounded and 700,000 deaths each year, around
      the world, are the consequences of accidents, according to the World Health
      Organization. In Chile 2,269 deaths occur each year due to accidents. The
      successful treatment of these patients requires a schematized initial management,
      that is taught in the Advanced Trauma Life Support Course. AIM: To review the
      results of trauma treatment using this model at Hospital del Trabajador in
      Santiago. PATIENTS AND METHODS: A retrospective review of patients with trauma
      treated between 1984 and 1994. The severity of trauma was classified according to
      the Injury Severity Score. RESULTS: Five hundred eighty eight patients (60
      female) aged 35.4 +/- 14 years old were treated in the period. Vehicular
      accidents accounted for 62% of trauma. The most frequently injured corporal
      segments were limbs and pelvis in 79%, head and neck in 66% and thorax in 44%.
      There were 2.45 lesions per patient. Mortality was 8% and, among survivors, 79%
      had a complete recovery and were reintegrated to their usual activities. Fifteen
      percent of patients were severely injured. Among these, mortality was 28% and 43%
      of survivors had some sequel. Head injuries had a predominant role in mortality
      and post traumatic disabilities. CONCLUSIONS: These results confirm the efficacy
      of Advanced Trauma Life Support system in the treatment of patients with multiple
      trauma.

PMID- 10349163
TI  - [Chlamydia pneumoniae in patients with acquired pneumonia in the Santiago of
      Chile community].
AB  - BACKGROUND: The prevalence of Chlamydia pneumoniae infection varies according to
      the population and geographic area studied. AIM: To evaluate the incidence of
      Chlamydia pneumoniae infection in Chilean subjects with community acquired
      pneumonia. PATIENTS AND METHODS: Between 1995 and 1997, patients with community
      acquired pneumonia attending two emergency rooms in Santiago, were studied. The
      diagnosis of Chlamydia pneumoniae infection was based on the detection of
      Chlamydia pneumoniae specific IgG antibody in samples from both the acute and
      convalescent phase, using an indirect microimmunofluorescent technique. Evidence
      of present infection was defined as seroconversion, a significant increase in the
      titer of the second sample and an initial titer equal or greater than 1/512.
      RESULTS: During the study period, 160 patients consulted and seven (six male),
      aged 54 +/- 27 years old, complied with the diagnostic criteria of present
      Chlamydia pneumoniae infection. These patients had no special clinical or
      radiological features. Five of seven patients improved without any specific
      treatment. CONCLUSIONS: Eight percent of this sample of patients with community
      acquired pneumonia had Chlamydia pneumoniae infection. This agent should be
      included in the design of empiric treatment schemes, although our results cast
      doubt on the pathogenic role of Chlamydia pneumoniae in pneumonia.

PMID- 10349164
TI  - [Late effects of radiofrequency fulguration: report of five cases].
AB  - Radiofrequency fulguration is the definitive treatment of several
      supraventricular and ventricular arrhythmias. During radiofrequency application,
      the conduction in a specific zone is interrupted as a consequence of cellular
      necrosis and edema. The disappearance of edema, minutes or hours after the
      procedure, allows the reappearance of conduction and arrhythmias. On the other
      hand, the definitive lesion is larger than the one caused acutely, due to the
      progression of the scar. We report five patients, in whom there was an apparent
      failure of the fulguration, since at the end of the procedure there was
      conduction in the fulgurated zone, the tachycardia was inducible or pre
      excitation and arrhythmias reappeared during the follow up. All five were
      subjected to a new electrophysiological study and in all, fulguration had been
      effective. We conclude that these late effects of fulguration are due to the slow
      progression of fibrosis, that continues days or weeks after the procedure.

PMID- 10349165
TI  - [Partial remission of hypercortisolism in Cushing disease after pituitary
      apoplexy. A case report].
AB  - ACTH secreting macroadenomas and pituitary apoplexy are unusual in Cushing
      disease. In the few cases reported in the literature, they have been found in
      long term hypercortisolism. We communicate a 43 yr old woman with a 4 year
      evolution Cushing syndrome, who developed sudden cephalea and oftalmoplejia. A
      Computed Tomography of the pituitary fossa disclosed a macroadenoma with
      intracapsular hemorrhage and suprasellar expansion. In the functional tests,
      serum cortisol was suppressed with dexamethasone in a dose of 1 and 8 mg and
      responded to the desmopressin stimulus. Nevertheless, cortisol levels were lower
      than those observed in Cushing syndrome of similar magnitude. The tumor was
      resected by transphenoidal surgery and immunohistochemistry to ACTH was positive.
      In this case, the laboratory results suggest a partial remission of the
      hypercortisolism after pituitary apoplexy.

PMID- 10349166
TI  - [Torsade de Pointes and demand endocavitary pacemaker. A case report].
AB  - We report a 81 years old female with a severe aortic insufficiency, treated with
      diuretics and antidepressants admitted due to recurrent syncopal episodes. During
      the first syncopal episode, an atrioventricular block was detected and an
      endocavitary demand pacemaker implanted. Two years later, she had a new syncope
      without evidences of pacemaker failure. The EKG during pacemaker rhythm showed a
      prolonged QT interval. During hospital monitoring, she presented a self limited
      polymorphic ventricular tachycardia (Torsade de Pointes). Consequently, the
      pacemaker was programmed at a greater frequency, and the QT interval shortened
      from 0.73 to 0.56 sec. Thereafter, the patient no longer had tachycardia or
      syncopal episodes, after one year of follow up.

PMID- 10349167
TI  - [Advances in the diagnosis and treatment of pancreatic carcinoma].
AB  - Pancreatic carcinoma has a dismal prognosis. In the last years, great efforts
      have been made to improve diagnosis and preoperative staging of potentially
      curable carcinomas. Actually, the diagnosis of fairly small tumours is possible.
      Chemoradiation therapy protocols prior to pancreatectomy, aiming to improve
      survival, are currently being held. This therapy allows radiation to be
      distributed into well oxygenated cells before surgical devascularization. This
      procedure can be done with acceptable morbidity and mortality rates. In selected
      cases of irresectable carcinoma, surgical palliation allows a better quality of
      life. Pancreatoduodenal resection, along with other traditional oncological
      therapies, will continue to be the therapy of choice for patients with carcinoma
      of the head of the pancreas, without local or regional metastases. However, an
      intensive search for new therapeutic strategies, specially in the field of
      molecular biology, is being carried out.

PMID- 10349168
TI  - [Newborn's heterozygocity for five blood groups and neonatal morbidity].

PMID- 10349169
TI  - [Sildenafil (viagra) at the time of warnings].
AB  - Sildenafil is the first orally administered available treatment for erectile
      dysfunction. It produces a selective vasodilatation of corpus carvernosum,
      mediated by the inhibition of phosphodiesterase 5, an enzyme that degrades GMPc.
      Its therapeutic efficacy has been demonstrated in organic as well as psychogenic
      or mixed erectile dysfunction. Most of its adverse effects, such as headache,
      flushing, gastroesophageal reflux and color vision disturbances, are related to
      the mechanism of action. Its interactions with other medications, can have severe
      adverse consequences. The concomitant use of sildenafil with drugs that release
      nitric oxide in their molecule, can produce severe hypotension. In patients with
      coronary heart disease or cardiac failure, this interaction can cause death.
      Sildenafil is metabolized in the liver through cytochrome P-450. This enzymatic
      system can be inhibited by cimetidine, ketoconazole or erythromycin. These drugs
      can increase plasma concentrations of sildenafil. We must identify the groups of
      patients that will have a better response to the drug and those in whom the drug
      will be useless. We must also know more about the security profile of the drug.
      With time, we will know the real role of sildenafil in the treatment of erectile
      dysfunction.

PMID- 10349170
TI  - [Unstable angina: invasive or conservative management?].
AB  - Acute coronary syndromes without ST segment elevation (Non-Q-Infarction and
      unstable angina) share a common pathophysiology, have no indication of
      thrombolysis, and should not routinely be catheterized on an emergency basis on
      admission. They should be put in bed rest, given anti-ischemic medications,
      aspirin and heparin. The small group of patients that do not stabilize with this
      medical regimen, should be catheterized, in order to have revascularization if
      they have the appropriate anatomy. There is nowadays a great controversy in the
      best management strategy for the larger group of patients that becomes stable
      after medical treatment installation. The invasive strategy proposes early,
      routine coronary angiography, and revascularization when anatomy is appropriate.
      The conservative strategy proposes continued medical treatment with invasive
      management only indicated by development of spontaneous or inducible ischemia.
      These two alternative strategies have been tested recently in large, prospective,
      randomized clinical trials: there is not a definitive answer, but the provisional
      guideline is that both are reasonably safe and effective.

PMID- 10349171
TI  - [Serum lipids and blood pressure levels in the +Mapuche population living in the
      Chilean region of Araucania].
AB  - BACKGROUND: Chilean aboriginal populations (Mapuche) predominantly live in the
      region of Araucania, in the southern part of the country. Their cardiovascular
      risk factors have not been systematically assessed. AIM: To study the prevalence
      of cardiovascular risk factors in the Mapuche population. SUBJECTS AND METHODS:
      Blood pressure, weight, height, dietary habits, fasting serum total cholesterol,
      HDL cholesterol and triglycerides were measured in 1.948 adults living in 28
      Mapuche communities. RESULTS: Thirteen percent of males and 16% of females had
      high blood pressure. Body mass index was 25.5 kg/m2 in males and 28.1 kg/m2 in
      females. Forty five percent of women and 24% of men were classified as obese.
      Mean serum total cholesterol was 186.7 +/- 9.6 mg/dl, HDL cholesterol was 58.7 +/
      30.7 mg/dl, total cholesterol/HDL cholesterol was 3.4 +/- 2 and triglycerides
      were 155.2 +/- 91.2 mg/dl. Twenty eight percent of males and 9.6% of females
      smoked. CONCLUSIONS: Mapuche individuals have higher levels of HDL cholesterol a
      better total cholesterol/HDL cholesterol ratio and lower frequency of smoking
      than non aboriginal Chileans subjects.

PMID- 10349172
TI  - [Chromosome anomaly and flow cytometry in gallbladder adenocarcinoma].

PMID- 10349173
TI  - [Association between Kidd blood group and congenital malformations].
AB  - BACKGROUND: Since the discovery of blood groups, an association between these
      genetic polymorphisms and pathological phenotypes has been searched, looking for
      factors involved in the pathogenesis of diseases or biological population
      mechanisms that maintain these polymorphisms. In previous reports, we have
      described some associations between erythrocytic genetic marker segregation and
      the presence of congenital malformations. AIM: To explore the association between
      Kidd blood group and congenital malformations. PATIENTS AND METHODS: One hundred
      twenty two malformed newborns and their mothers and 136 normal newborns, seen at
      the Clinical Hospital of the University of Chile, were studied. RESULTS: Kidd
      blood group segregation distortions were found among male malformed newborns,
      that were not present in normal newborns. Among mothers of both groups of
      newborns, a paucity of heterozygous for this system was found. CONCLUSIONS: The
      association found between a blood group and congenital malformations, allows to
      state that malformed children have a different genetic background, when compared
      to normal children.

PMID- 10349174
TI  - [Functional risk assessment of poor Chilean elders using an instrument validated
      in Canada].
AB  - BACKGROUND: Information about medical and social situation of elders is limited
      in Chile. AIM: To assess the functional risk of Chilean elders using an
      instrument validated in Canada. SUBJECTS AND METHODS: As part of a project aimed
      to help poor elders, 2,116 subjects living in Santiago, aged 65 to 99 years old
      (1,334 female, and 625 older than 75 years old), were interviewed. RESULTS:
      Thirty percent of these elders were using more than three medications and 13%
      lived alone. Visual problems were detected in 75%, memory problems were found in
      62%, 63% felt depressed, 46% had hearing problems, 42% suffered a fall during the
      last year, 35% had a health problem that forced them to stay at home, 32% did not
      count with help in a case of need, 33% referred some type of nutritional problem,
      26% needed help for daily living activities and 25% considered to have a worst
      health than counterparts of the same age. Among subjects older than 75 years old,
      the frequency of memory problems, auditory impairment, number of falls, health
      problems that precluded leaving the house, limitation for daily activities and
      the use of walking aids, was significantly higher. Although men and women had
      similar ages, men were in worst functional conditions, and had required more
      admissions to hospitals. There was a higher proportion of women living alone.
      Females also had a higher frequency of depression, memory disturbances, falls and
      use of more than three medications. CONCLUSIONS: Women elders tend to be in
      better functional conditions than men and people older than 75 years old have a
      higher functional risk. The applied instrument allowed a better focalization of
      our geriatric program.

PMID- 10349175
TI  - [Prognostic factors in acute bacterial meningitis in children. A case control
      study].
AB  - BACKGROUND: The prognosis of acute bacterial meningitis continues to be poor in
      our country. Previous studies suggest that the delay in diagnosis has an
      important prognostic value. AIM: To study the influence of diagnosis timing and
      the clinical conditions of children with acute bacterial meningitis on admission
      on death and incidence of gross sequelae. PATIENTS AND METHODS: Charts of
      children deceased or discharged with gross sequelae as consequence of an acute
      bacterial meningitis were selected. To each of these cases, 4 children with the
      same diagnosis but discharged in good conditions were selected as controls.
      Variables recorded were time and number of visits previous to the diagnosis,
      etiology of meningitis, neurological, respiratory, digestive and hemodynamic
      involvement on admission. RESULTS: Fifty seven cases and 224 controls were
      studied. Most cases were 12 months old or less (OR 4.1, 95% CI = 1.97-8.7).
      Diagnosis made on the first visit or within the first 24 hours of disease,
      improved prognosis (OR 0.25, 95% CI = 0.07-0.78). An age of less than 12 months
      and a diagnosis made after more than 12 hours of disease or after more than one
      consultation interacted multiplying their effect on a dismal prognosis. Coma on
      admission (OR 7.95% CI = 3-14.3) and S Pneumoniae etiology (OR 7, CI 95% = 3.4,
      14.3) were also associated with a bad prognosis. CONCLUSIONS: Early diagnosis of
      acute bacterial meningitis is protective for death or gross sequelae at
      discharge. Age, coma and S Pneumoniae etiology are the main factors associated
      with a poor prognosis.

PMID- 10349176
TI  - [Kinetic assessment of salivary secretory response to citric acid. Differences
      with pilocarpine].
AB  - BACKGROUND: Induction of salivation is becoming increasingly popular in the
      assessment of salivary gland status. Various mechanical or pharmacological
      procedures are empirically used to produce salivation. Oral stimulation by citric
      acid (AC) is by far the most used sialagogue procedure. AIM: To characterize the
      salivary secretory response to AC solutions applied to the dorsolateral tongue
      surfaces. SUBJECTS AND METHODS: Young healthy women from the upper levels of a
      medical career (n = 19) participated as volunteers. Salivary volume and UV
      absorbing organic material in saliva from single subjects were measured after
      various protocols of topical stimulation by AC. RESULTS: After a single
      stimulation by 1-8% AC the salivary flow rate peaked before 30 seconds and
      recovered the basal level earlier than 2 minutes. Repetitive stimulations at 30
      sec intervals kept the flow rate at a maximum. After suspending these
      stimulations, basal flow rate was recovered before 2 minutes. Repetitive AC
      stimulations at 8-min intervals produced a series of identical and independent
      secretory responses. The concentration of organic material in saliva remained
      unaltered after the various modes of stimulation. Thus, the profile of organic
      material secretion was always a direct expression of changes in salivary flow
      rate. In contrast to AC, the oral administration of the cholinergic agonist
      pilocarpine (PIL) produced a two-wave salivary response that as a whole lasted
      for about 30 minutes. In this case the volume and the amount of organic material
      were at least 10-fold the ones secreted in response to AC. CONCLUSIONS: AC
      provoked a rapid and short-lived salivary response that differs markedly from the
      one produced by other secretagogues, like pilocarpine.

PMID- 10349177
TI  - [Unstable angina: immediate and one-year results of transluminal coronary
      angioplasty treatment].
AB  - BACKGROUND: Unstable angina is characterized by angina at rest, angina of recent
      onset or accelerating angina. It is caused by a fissure or ulceration of an
      atheromatous plaque leading to thrombi formation and coronary spasm. AIM: To
      report the immediate and late results of coronary angioplasty in patients with
      unstable angina. PATIENTS AND METHODS: Eight hundred twenty eight patients were
      subjected to coronary arteriography between January 1994 and June 1996. Of these,
      242 were subjected to a transluminal coronary angioplasty, 245 patients were
      subjected to surgical revascularization and 341 patients were treated without
      revascularization. RESULTS: A total of 323 stenotic lesions (1.3 lesions per
      patient) were subjected to angioplasty. Angiographic success was obtained in 93%
      of patients. Angiographic success and lack of major complications such as death,
      infarction of the need for surgery, was obtained in 90% of patients. Five
      patients (2.1%) had a non fatal infarction and five required emergency surgery.
      Hospital mortality was 1.2%. During the year of follow up, 15% required a new
      revascularization, 3.3% had a non fatal infarction and 3.3% died. CONCLUSIONS:
      Coronary angioplasty had a 90% immediate success and 78% of patients were free of
      ischemic events after one year of follow up.

PMID- 10349178
TI  - [Treatment of idiopathic pulmonary fibrosis with colchicine].
AB  - BACKGROUND: Experimental and clinical evidences suggest that colchicine can be
      effective in the treatment of patients with idiopathic pulmonary fibrosis. AIM:
      To assess the effect of colchicine in the treatment of idiopathic pulmonary
      fibrosis. PATIENTS AND METHODS: Patients with clinically diagnosed idiopathic
      pulmonary fibrosis were treated with colchicine in doses of 0.5 to 1 mg/day,
      according to tolerance and followed for periods ranging from 7 to 40 months. The
      clinical and radiological score reported by Watters et al was used for the
      longitudinal assessment of patients. Maintenance or improvement in forced vital
      capacity and maintenance or decrease in alveolar arterial O2 gradient during
      follow up, were considered as positive therapeutic responses. RESULTS: Seventeen
      patients (10 male, aged 61 to 81 years old) were studied. Their basal score for
      dyspnea was 5.8 (over 20), for the chest X ray examination was 2.4 (over 3) and
      for CT scan was 2.8 (over 3). Basal FVC was 77% of predicted value (range 51
      108%), basal FEV, was 82% (range 59-117%) and FEV1/FVC was 0.82 (range 0.68
      0.95). PaO2 at rest was 78 mm Hg (ranges 63-97). Alveolar-arterial PO2 gradient
      was 16 mm Hg (range 5-31.6) at rest and 31 mm Hg (range 5.7-51.4) after exercise.
      Six patients (35%) had a positive response to therapy. CONCLUSIONS: The response
      rates of these patients to colchicine are at least similar to those obtained with
      steroids, but with less side effects.

PMID- 10349179
TI  - [Accessibility to the specific pharmacotherapy for Parkinson disease, in Santiago
      de Chile].
AB  - BACKGROUND: The high costs of adequate pharmacological treatment for Parkinson
      disease preclude the universal access of patients to this medication. AIM: To
      assess the accessibility to pharmacological treatment of Chilean patients with
      Parkinson disease. PATIENTS AND METHODS: An inquiry about socioeconomic
      stratification, medical controls, disease features and costs of pharmacological
      therapy, was applied to 95 patients (56 male, aged 32 to 89 years old) attending
      the Chilean League Against Parkinson Disease. RESULTS: Among studied patients,
      the disease had a mean duration of 7.9 +/- 6 years. There was a direct
      relationship between family income, the frequency of visits to physicians and the
      dose and cost of pharmacological therapy. CONCLUSIONS: The accessibility to
      pharmacological therapy among patients with Parkinson disease, depends on their
      socioeconomic level. Measures to correct this situation and improve the quality
      of life of these patients should be undertaken by health services.

PMID- 10349180
TI  - [Coronary stent placement for recurrent angina secondary to myocardial bridging].
AB  - Myocardial bridging of the epicardic coronary arteries is not an uncommon finding
      in angiographic or necropsic studies. Patients who have symptoms usually improve
      with medical treatment. However, in refractory patients a surgical myotomy of
      overlying myocardium and/or a coronary bypass may be needed. We report two
      patients with long myocardial bridges in the mid-left anterior descending
      coronary artery, who had recurrent angina refractory to conventional treatment.
      In both patients two consecutive coronary stents were successfully implanted. At
      five and six months follow-up they are asymptomatic and with good exercise
      tolerance.

PMID- 10349182
TI  - [Radical resective surgery for the management of rectosigmoidal endometriosis.
      Clinical case].
AB  - We report a 35 years old female with a profound rectosigmoidal endometriosis, who
      had been subjected to multiple laparoscopic procedures and open surgery due to
      infertility in the last five years. Main presenting symptoms were cyclic
      hematochezia during the menstrual periods associated to pelvic pain. Colonoscopy
      was inconclusive, barium enema showed a marked stenosis of the zone, appearing as
      an extrinsic compression. CAT scan showed a homogeneous, solid parauterine mass.
      During surgery, an inflammatory mass with multiple endometriotic foci was found.
      A low anterior resection with mechanical anastomosis was done, preserving the
      uterus and left adnexa. Two months later, the patient became pregnant and an
      elective cesarean section was done at 38 weeks of gestation, giving birth to a
      healthy newborn. Radical resective surgery for rectosigmoidal endometriosis is
      indicated in patients with intense and recurrent symptoms in whom hormonal
      treatment has failed and when a tumor cannot be discarded. The fertility rate,
      when adnexa and uterus are preserved, is 40% and symptomatic improvement is
      achieved in 85% of patients.

PMID- 10349181
TI  - [Pheochromocytoma and von Recklinghausen neurofibromatosis: postpartum crisis and
      renal artery thrombosis].
AB  - Pheochromocytoma is observed with higher frequency in patients with von
      Recklinghausen neurofibromatosis. We report a 36 years old female with von
      Recklinghausen neurofibromatosis who developed mild hypertension during the
      fourth month of pregnancy. A cesarean section was performed at 37 weeks of
      pregnancy. Thereafter, the patient presented severe hypertensive and hypotensive
      crises, sinus tachycardia and fever. No evidences of an infectious disease were
      found. Abdominal ultrasound examination showed a right adrenal mass of 7 x 5 cm.
      High levels of urinary cathecolamines confirmed the diagnosis of
      pheochromocytoma. After three weeks of prazosin therapy, the patient was
      operated. During the surgical procedure, an encapsulated pheochromocytoma was
      found and excised. A right renal atrophy and renal artery thrombosis were also
      found and a nephrectomy was done. Postoperative evolution was uneventful and the
      patient remains with normal blood pressure levels six months after the operation.

PMID- 10349183
TI  - [Medical treatment of obesity from a multi professional perspective].
AB  - Obesity is a serious condition affecting the physical and psychological well
      being of a large number of individuals. There are many therapeutic options for
      the disease and their judicious selection is critical. The best results are
      obtained with well-organised multi professional programs. The aims of the
      treatment must be defined balancing risks and benefits. Eating behaviour patterns
      must be considered for the proper selection of therapy. Diet is an essential
      therapeutic component and has to be individually prescribed for each patient.
      Pharmacological agents inhibit appetite, increase thermogenesis or inhibit
      gastrointestinal absorption of nutrients. As these medications have important
      side effects and complications, extreme care must be taken for their
      prescription.

PMID- 10349184
TI  - [Membrane receptors and their enzymatic mechanisms of action. Associated
      endocrine diseases].
AB  - The cell, as a functional unit of a living individual, has the capacity to
      recognize signals from the extracellular compartment and to respond to these
      signals in a specific, precise and characteristic way. This review analyzes some
      membrane receptor mediated processes, characterized by a complex chain of events
      from the external signal to the induction of specific genes. Additionally, some
      endocrine diseases associated with molecular defects in some of these stages are
      analyzed.

PMID- 10349185
TI  - [Autonomy accreditation of private Chilean universities (1994-1998)].
AB  - BACKGROUND: In 1995, a score to measure the quality of private universities in
      Chile, using excellency indicators as predictors of autonomy certification, was
      devised by the author. AIM: To compare this score with autonomy certification
      results of ensuing years, to assess the usefulness of excellency indicators.
      MATERIAL AND METHODS: During 1995, the records of 21 private universities in
      Santiago were studied. These universities were qualified using eight indicators
      of academic excellency. These results were compared with the Superior Education
      Council qualification results, obtained between 1996 and 1998. RESULTS: The
      scores obtained by universities ranged from 19 and 137 points. Universities with
      the better scores obtained autonomy and those with the worst scores were
      eliminated. There was a good concordance between the score obtained in 1995 and
      the fate of autonomy certification. CONCLUSION: The best predictors and
      indicators of academic excellency to certificate autonomy of private universities
      were the magnitude of indirect budget contributed by the state, the size of
      academic list of staff and the percentage of admitted students with scores over
      573 in the national academic aptitude tests.

PMID- 10349186
TI  - [Mortality among steel workers: retrospective study 1985-1994].
AB  - BACKGROUND: Some studies have reported an increased incidence of lung, kidney and
      colon cancer among steel workers, however this has not been an universal
      observation. AIM: To study the causes of death in a group of Chilean steel
      workers. SUBJECTS AND METHODS: Between January 1985 and December 1994, 4718 steel
      workers were followed. Their crude and standardized death rates, adjusted for age
      and diagnosis, were calculated. RESULTS: During the study period 153 deaths were
      registered (3.2%), 78 in active workers (2.7%), 68 in retired workers (5.9%) and
      7 in hired workers (1%). Main causes of death were liver cirrhosis (19%), gastric
      cancer (9.2%) and myocardial infarction (8.5%). Cirrhosis was the only cause with
      a significantly higher standardized adjusted rate (= 171). CONCLUSIONS: We did
      not find elevated standardized mortality rates for respiratory diseases, lung or
      kidney cancer in this group of steel workers. Thus, our results did not show a
      specific occupational risk among these workers.

PMID- 10349187
TI  - [A controlled trial with 2 anti-Neisseria B meningitidis vaccines and placebo in
      Chilean population].

PMID- 10349188
TI  - [The physician-patient relation and the schools of medicine].

PMID- 10349189
TI  - The impact of health care this century.

PMID- 10349190
TI  - Protective effects of different doses of inhaled fenoterol on methacholine
      induced bronchoconstriction in asthmatic children.
AB  - OBJECTIVE: To evaluate the protective effect of different doses of inhaled
      fenoterol (F) on bronchoconstriction induced by methacholine (M). DESIGN:
      Randomized double-blind study. SETTING: Referrence center. PARTICIPANTS: 9
      children (aged from 7 to 15 years old), with mild or moderate asthma and allergic
      to D. pteronyssinus. INTERVENTION: On the first day, the M concentration
      necessary to induce a 20% fall in the forced expiratory volume in the first
      second (FEV1; PC20FEV1) was determined using closed circuit inhalation (De
      Vilbiss 646). On subsequent days, the children inhaled a dose of F (25 or 50 or
      100 or 200 micrograms) through the same circuit and, after 15 minutes the FEV1
      was measured, becoming the basal value. Bronchoprovocation was then initiated
      using the concentration prior to the PC20FEV1 of the first day and continuing
      until there was a 20% fall in the FEV1. This concentration was the "new"
      PC20FEV1. RESULTS: F in a dose of 25 micrograms protected 2 of the 9 children, in
      a dose of 50 mg protected 4 of the 9 and in doses of 100 and 200 micrograms
      protected all children. We did not observe any relationship between the magnitude
      of the bronchodilation and bronchoprotection induced by the inhalation of F.
      CONCLUSIONS: Our results suggest that a dose of 100 micrograms of F is capable of
      inducing bronchoprotection in children with mild/moderate asthma.

PMID- 10349191
TI  - The value of unenhanced CT in the diagnosis of acute appendicitis.
AB  - OBJECTIVE: To establish the accuracy of unenhanced CT in the preoperative
      diagnosis of acute appendicitis. DESIGN: Accuracy study, prospective and blinded.
      SETTING: The University Hospital. PARTICIPANTS: 52 patients with clinical and
      laboratorial manifestations of acute appendicitis. CT diagnosis was made by:
      presence of an abnormal appendix, appendiceal calculi with pericecal phlegmon or
      alterations in the pericecal appendicular site and absence of signs that may lead
      to other diagnosis. MAIN OUTCOME MEASURES: Overall accuracy, comparing the
      tomographic aspects with the intra-operative findings and pathological reports
      ("gold standard"). RESULTS: Acute appendicitis was confirmed in 44 cases.
      Efficacy was 92%, sensitivity was 91%, specificity was 100%, positive predictive
      value was 100% and negative predictive value was 67%. CONCLUSIONS: Unenhanced CT
      presents a similar overall accuracy to that reported by other authors who studied
      enhanced CT diagnosis of acute appendicitis.

PMID- 10349192
TI  - Immunohistochemical study of basement membrane collagen IV in uterine cervix
      carcinoma.
AB  - CONTEXT: The integrity of basement membrane (BM) is damaged during the evolution
      of a benign or potentially malignant lesion into a malignant one, in which it may
      undergo several degrees of discontinuity as a necessary condition for the
      invasive process. Immunostaining for collagen IV, which is exclusively found in
      BM, has been used to evaluate its formation in neoplastic and benign lesions of
      several organs. OBJECTIVE: To investigate BM continuity pattern in squamous
      carcinoma "in situ" (CIS), microinvasive (MIC) and invasive (IC) squamous cell
      carcinoma of the uterine cervix, and to find out if BM expression could be useful
      in the diagnosis of early stromal invasion (MIC). DESIGN: Archival material
      between 1988 and 1993 was studied at the Pathological Anatomy Department-Unicamp.
      PROCEDURES: The selected cases, previously formalin fixed and paraffin embedded,
      were reviewed retrospectively by submitting them to immunohistochemical study via
      the avidin-biotin-peroxidase method using a monoclonal antibody anticollagen IV.
      RESULTS: In all, 17 cases of CIS, 16 of MIC and 21 of IC were evaluated. All IC
      cases showed evident BM discontinuity, either focal or diffuse. In the CIS group,
      a continuous BM pattern was predominant, being focally disrupted in only 2/17
      cases (11.8%). The MIC group showed an intermediate pattern, but with a clear
      tendency to BM discontinuity in 10/16 cases (62.5%). Inflammatory infiltrate, a
      variable also studied, cannot be considered responsible for BM discontinuity,
      since there was no statistical correlation between them. CONCLUSION: We conclude
      that immunostaining for collagen IV may contribute to the diagnosis of stromal
      invasion by BM discontinuity.

PMID- 10349193
TI  - Risk factors associated to fetal death.
AB  - OBJECTIVE: The purpose of this study was to investigate risk factors associated
      to fetal death in a Brazilian population. DESIGN: A case control study. SETTING:
      The Hospital Maternidade Leonor Mendes de Barros in Sao Paulo. PARTICIPANTS: 122
      pregnant women with diagnosis of fetal death and gestation age of 20 or more
      weeks and 244 controls of pregnant women who delivered liveborns. VARIABLES
      STUDIED: The fetal death (dependent variable), independent variable (the social
      demographic factors, clinical and obstetrical history, prenatal care indicators
      and pathological conditions). RESULTS: The risk factors associated to fetal death
      were abruptio placentae, syphilis, few prenatal care visits, one or more previous
      stillbirths, hospitalization during pregnancy, diabetes, age above or equal to 25
      years, hypertension during pregnancy, anemia and age below 20 years. CONCLUSIONS:
      Results of the current study might be useful to orientate a primary prevention
      health program, specially those concerning antenatal care.

PMID- 10349194
TI  - Metabolic assessment and enteral tube feeding usage in children with acute
      neurological diseases.
AB  - OBJECTIVE: To report on acquired experience of metabolic support for children
      with acute neurological diseases, emphasizing enteral tube feeding usage and
      metabolic assessment, and also to recommend policies aimed towards improving its
      implementation. DESIGN: Retrospective analysis. SETTING: Pediatric Intensive Care
      Unit of Hospital do Servidor Publico Estadual de Sao Paulo. SUBJECTS: 44 patients
      consecutively admitted to the Pediatric ICU over a period of 3 years who were
      given nutrition and metabolic support for at least 72 hours. Head trauma, CNS
      infections and craniotomy post-operative period following tumor exeresis were the
      main diagnoses. MEASUREMENTS: Records of protein-energy intake, nutrient supply
      route, nitrogen balance and length of therapy. RESULTS: From a total of 527 days
      of therapy, single parenteral nutrition was utilized for 34.3% and single enteral
      tube feeding for 79.1% of that period. 61.4% of the children were fed exclusively
      via enteral tube feeding, 9.1% via parenteral and 39.5% by both routes. The
      enteral tube feeding was introduced upon admission and transpyloric placement was
      successful in 90% of the cases. Feeding was started 48 hours after ICU admission.
      The caloric goal was achieved on the 7th day after admission, and thereafter
      parenteral nutrition was interrupted. The maximum energy supply was 104.2 +/-
      23.15 kcal/kg. The median length of therapy was 11 days (range 4-38). None of the
      patients on tube feeding developed GI tract bleeding, pneumonia or
      bronchoaspiration episodes and, of the 4 patients who were given exclusive TPN, 2
      developed peptic ulcer. The initial urinary urea nitrogen was 7.11 g/m2 and at
      discharge 6.44 g/m2. The protein supply increased from 1.49 g/kg to 3.65 g/kg (p
      < 0.01). The nitrogen balance increased from--7.05 to 2.2 g (p < 0.01).
      CONCLUSIONS: Children with acute neurological diseases are hypercatabolic and
      have high urinary nitrogen losses. The initial negative nitrogen balance can be
      increased by more aggressive feeding regimes than the usual ones. Early tube
      feeding was well tolerated, which permits the conclusion that it is a safe and
      effective method for nutrition support. Recommendations of basic rules for
      metabolic support are made.

PMID- 10349195
TI  - Microangiopathic complications in type 1 diabetes mellitus: differences in
      severity when isolated or associated with autoimmune polyendocrinopathies.
AB  - CONTEXT: The development and evolution of different chronic diabetic
      complications may present variations among the different types and conditions of
      this disease. OBJECTIVE: To evaluate the degree of microangiopathy in Type 1
      diabetes mellitus (DM1) associated with autoimmune polyendocrinopathies (OSAD) or
      isolated DM1 (iDM1). PATIENTS: OSAD (n = 17) and iDM1 (n = 13) were over 15 years
      old at diagnosis of DM and were matched for diabetes duration (13.9 +/- 8.2 and
      13.2 +/- 5.9 years respectively) and metabolic control (HbA1c: 6.4 +/- 1.9 and
      6.8 +/- 1.4%). MAIN OUTCOME MEASURES: Urinary albumin excretion (UAE; ELISA), the
      inversion of serum creatinine (1/C) level and indirect ophthalmoscopy. RESULTS:
      Although the prevalence of hypertension was similar in both groups, the OSAD had
      inferior levels of UAE (7.4 +/- 2.5 vs. 17.3 +/- 9.2 micrograms/min; p < 0.05).
      Nephropathy was detected in 12% of the OSAD (none of them macroproteinuric) and
      in 39% of the iDM1. The UAE in the iDM1 correlated negatively with 1/C values (r
      = -0.7, p < 0.005), but the same did not occur in the OSAD (r = 0.2, ns). Among
      patients with retinopathy, the severe form was found in 29% of the OSAD and in
      46% of the iDM1. CONCLUSIONS: OSAD was associated with a lower degree of
      microangiopathy, in spite of age at diagnosis, duration of diabetes and the
      metabolic control. In contrast with the iDM1, the increase in UAE of OSAD was not
      associated with reductions in GFR.

PMID- 10349196
TI  - Chediak-Higashi syndrome: presentation of seven cases.
AB  - CONTEXT: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease
      characterized by recurrent infections, giant cytoplasmic granules, and
      oculocutaneous albinism. OBJECTIVE: To describe clinical and laboratory findings
      from CHS patients. DESIGN: Case report. SETTING: The patients were admitted into
      the Allergy and Immunology Unit of the Instituto da Crianca, a tertiary public
      care institution. CASES REPORT: Seven patients had oculocutaneous albinism,
      recurrent infections and giant cytoplasmic granules in the leukocytes. One
      patient had low IgG levels and three showed impaired bactericidal activity of
      neutrophils. Six patients died of infectious complications during the accelerated
      phase. Therapy included ascorbic acid and antibiotics. Chemotherapy was used for
      the accelerated phase in two patients. Bone marrow transplantation (BMT) was
      proposed for one patient. DISCUSSION: The authors emphasize the need for early
      diagnosis and therapy of CHS. BMT should be indicated before the accelerated
      phase of the disease has developed.

PMID- 10349197
TI  - Spinal cord compression in beta-thalassemia: follow-up after radiotherapy.
AB  - CONTEXT: Spinal cord compression due to extramedullary hematopoiesis is a well
      described but rare syndrome encountered in several clinical hematologic
      disorders, including beta-thalassemia. CASE REPORT: We report the case of a
      patient with intermediate beta-thalassemia and crural paraparesis due to spinal
      cord compression by a paravertebral extramedullary mass. She was successfully
      treated with low-dose radiotherapy and transfusions. After splenectomy, she was
      regularly followed up for over four years without transfusion or recurrence of
      spinal cord compression. DISCUSSION: Extramedullary hematopoiesis should be
      investigated in patients with hematologic disorders and spinal cord symptoms. The
      rapid recognition and treatment with radiotherapy can dramatically alleviate
      symptoms.

PMID- 10349198
TI  - Esophageal ulcer and alendronate.
AB  - OBJECTIVE: To describe a case of esophageal ulcer associated with the use of
      alendronate. CASE REPORT: This is the fifth case ever described in the literature
      according to our bibliographic review. In our patient, the association between
      the drug and the esophageal lesions was masked by the presence of a hiatal
      hernia, potentially a cause of the esophageal lesion. The persistence of the
      lesions despite high doses of anti-reflux therapy called attention to the
      possibility of the relationship. The esophageal lesion healed soon after
      suspension of alendronate. DISCUSSION: The authors present a review of the
      literature and point to the need for diagnostic investigation, to suspend such a
      drug from patients who experience dyspeptic symptoms while using it.

PMID- 10349199
TI  - Hepatitis C virus and autoimmune manifestations.

PMID- 10349200
TI  - [Video-assisted extensive thymectomy in the treatment of autoimmune myasthenia].
AB  - In the surgical treatment of autoimmune myasthenia, complete thymectomy is
      considered indispensable to ensure maximum clinical results. From May 1995
      through June 1997, we carried out video-assisted extended thymectomy via sole
      left access in 16 patients. There were no deaths and no major complications. At
      the intermediate-term follow-up, remission and improvement rates were 19% and 56%
      respectively. These results were similar to those achieved on the last 16
      patients who had extended thymectomy via median sternotomy. We believe that the
      advantages of the video-assisted approach render it a reliable option for the
      surgical management of autoimmune myasthenia.

PMID- 10349201
TI  - Factors associated with autonomic nervous function in type 1 and type 2 diabetic
      subjects free of clinical manifestations of autonomic neuropathy.
AB  - Even though autonomic diabetic neuropathy is highly prevalent and a noted risk
      factor for cardiovascular morbidity and mortality, very little is known about
      factors associated with it. We carried out standard autonomic nervous system
      function tests by means of a computerized portable system on 55 diabetic patients
      (22 with type 1 diabetes, 33 with type 2 diabetes) who had no signs or symptoms
      of autonomic diabetic neuropathy and on 10 age- and sex-matched healthy control
      subjects. Test results of patients with type 1 diabetes did not differ
      significantly from those with type 2 diabetes. Of the clinical, metabolic, and
      anthropometric variables considered, only the duration of diabetes was inversely
      and independently correlated to deep breathing test scores (E:I ratio value of
      deep breathing 1.38-0.009. years of diabetes; R2 = 0.25). The duration of
      diabetes was inversely correlated to variations in orthostatic systolic blood
      pressure (r = -0.37, p < 0.01). The prevalence of diabetic retinopathy (score: 1
      = no; 2 = yes) was significantly higher in the diabetic group with lower deep
      breathing values (1.8 +/- 0.3 vs 1.0 +/- 0.0; p < 0.01). The prevalence of
      ischemic electrocardiographic alterations (score: 1 = no; 2 = yes) was
      significantly higher in the diabetic group with a poorer orthostatic systolic
      blood pressure response (1.4 +/- 0.1 vs 1.2 +/- 0.1; p < 0.01). This study
      suggests that 1) autonomic neuropathy is correlated to disease duration; 2) type
      of diabetes, present level of metabolic compensation, and anthropometric
      characteristics do not seem correlated to this complication; 3) diabetic
      retinopathy and ischemic cardiopathy may be correlated to autonomic neuropathy.

PMID- 10349202
TI  - [Prion diseases. The association of bovine spongiform encephalopathy with new
      variant of Creutzfeldt-Jakob disease].
AB  - This review summarizes current knowledge of prion diseases and investigates
      connections between the bovine spongiform encephalopathy epidemic, observed in
      Great Britain since 1986, and the new variant of human Creutzfeldt-Jakob disease,
      reported for the first time in 1996. Information from the international
      literature and results of the most recent experimental studies on prion diseases
      and transmissible spongiform encephalopathies are evaluated, and particular
      attention is focused on the possible transmission of the etiological agents of
      spongiform encephalopathy, the prions, from animals to humans. Epidemiological,
      clinical, and histopathological data and experimental results seem to confirm the
      suspected link between bovine spongiform encephalopathy and the new variant of
      Creutzfeldt-Jakob disease. In this context, transmission of prions from infected
      cattle to humans by oral intake seems not only possible but also very probable.

PMID- 10349203
TI  - [Colorectal cancer: prevention and screening].
AB  - At present, colorectal carcinoma is one of the few types of cancer for which it
      is possible to carry out both primary and secondary prevention. Primary
      prevention involves following a correct diet and maintaining a healthy lifestyle.
      Secondary prevention includes carrying out appropriate diagnostic examinations on
      subjects at risk for this type of cancer. Randomized trials, cohort and case
      control studies have demonstrated that mortality due to colorectal carcinoma
      decreases significantly when these screening tests are done. They include testing
      for fecal occult blood (if annual mortality reduction ranges from 25 to 33%),
      sigmoidoscopy (case-control studies have shown that this technique can reduce
      mortality by 60-80%), colonoscopy, and the double-contrast barium enema. Total
      effectiveness increases when these tests are used in combination. This review
      synthetically illustrates current knowledge of risk factors and the molecular
      genetics of colorectal cancer. It offers indications for primary prevention,
      investigates the effectiveness of each screening test used in secondary
      prevention, and presents the most highly accredited guidelines for surveillance
      of the at-risk population.

PMID- 10349204
TI  - [Anticoagulant therapy in patients with dilated cardiomyopathy].
AB  - Heart failure due to dilated cardiomyopathy is associated with a significant
      increase in risk of thromboembolism. The incidence can be estimated, on the
      average, at 2.0-2.5 events per 100 patients per year. At this time, in the
      absence of randomized trials, limited evidence exists to support the use of
      anticoagulant treatment for patients with heart failure due to dilated
      cardiomyopathy in sinus rhythm, even if these subjects appear to be at higher
      risk than those with ischemic cardiomyopathy and comparable degree of left
      ventricular dysfunction. Women with left ventricular ejection fraction < 25%
      constitute a remarkable exception to this rule, and anticoagulation is strongly
      indicated for them. Unless there are contraindications, anticoagulant treatment
      is mandatory for patients with heart failure and atrial fibrillation. As studies
      on preventive treatment in atrial fibrillation have indicated, a target
      International Normalized Ratio between 2.0 and 3.0 seems appropriate. Patients
      with intraventricular thrombi present a difficult therapeutic challenge inasmuch
      as no strong evidence exists that anticoagulant treatment significantly decreases
      the risk of embolization particularly in patients with flat thrombus. Therapy
      should thus probably be limited to patients with pedunculated or floating
      thrombus.

PMID- 10349205
TI  - [Pulmonary mucosa-associated lymphoid tissue lymphoma in a patient with
      myasthenia gravis].
AB  - Mucosa-associated lymphoid tissue lymphomas are a subgroup of non-Hodgkin's
      lymphoma. The lung is the most frequent non-gastrointestinal organ they affect.
      Pulmonary mucosa-associated lymphoid tissue lymphoma usually appears as a
      solitary mass often accidentally discovered on chest radiography. Diffuse,
      bilateral involvement is rare. The association of mucosa-associated lymphoid
      tissue lymphoma with autoimmune diseases has been reported, and a pathogenetic
      role has been suggested for the autoimmune process in its development. Optimum
      management has not yet been standardized. The case described here is a mucosa
      associated lymphoid tissue lymphoma with multiple, unusually large opacities
      involving both lungs. The patient, a 55-year-old woman, also suffered from
      myasthenia gravis, an autoimmune disease characterized by an autoaggressive
      process against the acetylcholine receptors. Whereas other autoimmune diseases
      such as rheumatoid arthritis, polymyositis, and fibrosing alveolitis have been
      correlated with mucosa-associated lymphoid tissue lymphoma, an association
      between this lymphoma and myasthenia gravis has not yet been reported. Complete
      resolution of the pulmonary opacities was obtained with cyclophosphamide
      treatment. It continues at 15 months after the suspension of therapy.

PMID- 10349207
TI  - Autoimmune thrombocytopenic purpura and dermatomyositis associated with chronic
      hepatitis C. A therapeutic dilemma.
AB  - We recently observed a patient with chronic C hepatitis who developed first
      autoimmune thrombocytopenic purpura and subsequently dermatomyositis. While the
      association could be coincidental, it is possible that hepatitis C virus could
      have induced autoantibodies or circulating immune complexes which contributed to
      both. Although concerns are sometimes raised about the use of corticosteroids and
      immunosuppressive therapy to control symptoms in hepatitis C virus infected
      patients with rheumatic or autoimmune diseases, corticosteroid and
      immunosuppressive therapies are considered appropriate in cases of chronic C
      hepatitis with rapidly progressive autoimmune diseases. Our case illustrates the
      paradox that, despite the continuing presence of a viremic form of chronic C
      hepatitis, clinical symptoms improved with combined immunosuppressive therapy,
      without deterioration of the hepatitis. Our results could be the consequence of
      the association of immunosuppressive therapy intensive enough to control the
      autoimmune thrombocytopenic purpura and dermatomyositis with alpha-interferon
      whose antiviral capacity may have been able to prevent re-exacerbation of the
      hepatitis.

PMID- 10349206
TI  - [Barbiturate withdrawal syndrome: a case associated with the abuse of a headache
      medication].
AB  - Barbiturates can produce psychological and physical dependence and produce a
      withdrawal syndrome on the second to fourth day after the drug is suspended.
      Symptoms include anxiety, restlessness, insomnia, rhythmic intention tremor,
      dizziness, seizures, and psychosis. If the syndrome is not recognized and
      correctly treated, hyperthermia, circulatory failure, and death may ensue.
      Although barbiturates are less frequently used nowadays, they are employed in
      combination with other drugs in many medications used for the treatment of
      headache. We report the case of a 54-year-old woman who developed a barbiturate
      abstinence syndrome when she suspended self-administration of a drug containing
      butalbital. The patient had been using barbiturates, 900 mg/die, for 2+ years for
      persistent headache. She was admitted to the hospital because of seizures,
      hallucinations and delirium not controlled by benzodiazepine and phenothiazine
      administration. Her symptoms resolved after parenteral phenobarbital
      administration.

PMID- 10349208
TI  - [Hyperthyroidism and cholestasis: a case report].
AB  - Intrahepatic cholestasis has rarely been observed in patients with thyrotoxicosis
      and generally occurs in association with coexistent congestive heart failure. We
      report the case of a 63-year-old man who was referred to our Institution because
      of jaundice and hyperthyroidism. During his hospital stay, his plasma bilirubin
      level reached 27.41 mg/dL. Clinical, biohumoral, and instrumental examinations
      excluded heart failure and autoimmune or viral hepatitis. After the start of
      therapy with methimazole, thyroid hormone and plasma bilirubin levels decreased
      progressively and simultaneously, eventually returning to normal. Plasma
      bilirubin values as high as the ones we recorded, in the absence of congestive
      heart failure or autoimmune chronic hepatitis, have not, to our knowledge, been
      previously reported.

PMID- 10349209
TI  - Tobacco reduction: a continued health promotion challenge.

PMID- 10349210
TI  - Youth smoking in Ontario 1981-1997: a cause for concern.

PMID- 10349211
TI  - Knowledge of Ontario's Tobacco Control Act in the community of Scarborough.

PMID- 10349212
TI  - Predictors of health risk behaviours among young adults: analysis of the National
      Population Health Survey.
AB  - This paper examines the individual and social determinants of physical
      inactivity, daily smoking, heavy drinking, and overall risk behaviour among 1,395
      Canadians aged 20-24 in the 1994 National Population Health Survey. Logistic
      regression was used to estimate models of risk behaviour using the following
      variables: sex, mastery, self-esteem, sense of coherence, chronic stress,
      psychological distress, social support, income adequacy, education, and main
      activity (working, looking for work, attending school, other). Results of the
      analysis indicate that the most consistent predictors were chronic stress and
      main activity. Thus, social context appears to be an important influence on risk
      related behaviour, and should be taken into account in approaches designed to
      promote health behaviours.

PMID- 10349213
TI  - The development of self-rated health during adolescence: an exploration of inter-
      and intra-cohort effects.
AB  - Self-rated health is a commonly used measure of physical health status. While the
      development of one's perception of self-rated health likely occurs during
      childhood and adolescence, its development has been largely unexplored. This
      study addresses this issue by examining the relationship between adolescent self
      rated health and personal (sex, age) and situation (family structure, family
      income) factors at five different time intervals to identify inter- and intra
      cohort effects as well as concomitant changes in adolescent health compromising
      behaviour, specifically substance use. Five waves between 1989 and 1997 of the
      biennial Ontario Student Drug Use Survey (OSDUS) by the Addiction Research
      Foundation (ARF) consisting of 19,512 cases were examined. The results indicate
      the presence of both inter- and intra-cohort effects on self-rated health. In
      addition, health-compromising behaviours had a varied effect on self-rated health
      across grade. This analysis confirms some previous findings but also presents
      contradictory evidence by identifying the complexity of relationships among these
      factors and self-rated health.

PMID- 10349214
TI  - The injury experience observed in two emergency departments in Kingston, Ontario
      during 'ice storm 98'.
AB  - OBJECTIVES: 1) To describe patterns of unintentional injury presenting for
      emergency medical care in Kingston, Ontario following the ice storm in January
      1998; and 2) to provide recommendations for prevention during such situations.
      METHODS: Unintentional injuries related to the ice storm that presented at the
      two emergency departments in Kingston, Ontario were identified and described.
      RESULTS: A total of 254 injuries were identified. Injuries peaked the day
      following the onset of the ice storm and again 4-6 days following the storm.
      Common sources of injury included slips and falls on the ice (56%), activities
      related to clearing brush or trees (15%), and unintentional carbon monoxide
      poisonings (9%). CONCLUSIONS: While the number of injuries that presented during
      the storm and its aftermath was not unusual, the distribution of injuries by type
      did reflect the irregular nature of environmental conditions. This analysis
      provides useful information for public officials to use reviewing disaster plans
      and to generate recommendations for managing future occurrences.

PMID- 10349215
TI  - [Public health professionals' perceptions regarding two dimensions of health
      promotion: the ecological approach and community participation].
AB  - The aim of this paper is to explore public health professionals' perceptions
      regarding two dimensions of the new health promotion movement: the ecological
      approach and the principle of community participation. Data were collected by
      focus-groups of public health professionals (n = 22) in one Public Health
      Directorate in Quebec. Results indicate a fair degree of integration of these two
      dimensions into the respondents' professional practice. However, limitations
      related to the work environment and to the theoretical underpinnings of these two
      components might impede the respondents' ability to integrate them into their
      practice.

PMID- 10349216
TI  - An analysis of the geographic variation in cancer incidence and its determinants
      in Ontario.
AB  - Cancer incidence data for the Ontario Public Health Units in 1980-91 were
      examined to investigate regional patterns and the existence of outlier values
      after adjustment for known risk factors. Candidate risk factors were derived from
      the Ontario Health Survey and the census. Weighted regressions were fit to the
      data, and the spatial pattern of the residuals was analyzed. The number of
      outlier data points with significant elevations or reductions in risk was close
      to that expected by chance. They were dispersed geographically, and occurred in a
      variety of cancer types. We conclude that, in general, most of the geographic
      variation in cancer risk can be associated with variation in known risk factors,
      and that there appear to be no broad regional effects remaining after adjustment
      for these factors. A few cancer sites provide limited evidence of regional
      effects that may warrant further investigation.

PMID- 10349217
TI  - Household food insecurity and hunger among families using food banks.
AB  - Over the past two decades, the demand for charitable food assistance has steadily
      grown, and a massive ad hoc system of food banks has become established in
      Canada. To assess the food insecurity and nutritional vulnerability of one
      subgroup of food bank users, interviews were conducted with a sample of 153 women
      in families using emergency food relief programs in Metropolitan Toronto. Ninety
      percent reported household incomes which were less than two thirds of the
      'poverty line', and 94% reported some degree of food insecurity over the previous
      12 months. Seventy percent reported some level of absolute food deprivation,
      despite using food banks. The findings highlight the limited capacity of ad hoc,
      charitable food assistance programs to respond to problems of household food
      insecurity which arise in the context of severe and chronic poverty.

PMID- 10349218
TI  - Factors influencing infant feeding practices of mothers in Vancouver.
AB  - This study describes factors influencing infant feeding choices of 434 mothers
      with 9-month-old infants in Vancouver. Consistent with Social Cognitive Theory,
      both internal personal and socio-environmental factors influence infant feeding
      choices. Mothers attributed the choice to breastfeed primarily to personal
      choice, whereas the choice to formula feed was attributed to socio-environmental
      factors. Among mothers who breastfed < 3 months, the choice to wean was primarily
      attributed to concern for baby's nutrition; compared to returning to work,
      concern about milk supply and concern for baby's nutrition among those who
      breastfed > or = 3 to < 6 months; and returning to work and personal choice among
      those who breastfed > or = 6 months. Among Caucasian mothers, the choice to wean
      was primarily attributed to returning to work, compared to concern for baby's
      nutrition among non-Caucasian mothers. Initiatives to facilitate further advances
      in breastfeeding promotion could address three areas: 1) prenatal intentions, 2)
      early postpartum concerns, and 3) later issues surrounding returning to work and
      infant nutrition.

PMID- 10349219
TI  - Time since immigration and excess body weight.
AB  - OBJECTIVES: To examine the relationship between time since immigration and excess
      body weight. METHODS: Secondary data analysis of a cross-sectional survey of
      19,600 Canadians. RESULTS: The prevalence of excess weight (BMI > 25) increases
      with time since immigration for both men and women. After controlling for
      birthplace, socio-demographic, lifestyle and health correlates, only female
      immigrants (less than five years) are significantly less likely to have BMI
      scores greater than 25 kg/m2 compared to those born in Canada. Stratified
      analyses, however, revealed similar findings for Asian men who had immigrated
      less than five years prior to the survey. DISCUSSION: Our results suggest that
      length of time since immigration is an important risk factor for excess weight.
      Further research with longitudinal data, more reliable measures of ethnicity and
      anthropometric measures of weight are required to confirm these initial findings.

PMID- 10349220
TI  - [The arrangement of hair salons: an efficient method to reduce risks].

PMID- 10349221
TI  - Morbidity and mortality related to human immunodeficiency virus in Canadian men
      and women, 1987-94.
AB  - OBJECTIVE: To assess the impact of HIV/AIDS on hospitalization and mortality
      patterns in Canada. METHODS: Hospitalizations and deaths due to HIV/AIDS were
      compared with select causes of morbidity and mortality among men and women across
      provinces, regions and select cities between 1987-94. Patterns of hospitalization
      and mortality were characterized by calculating age-specific, standardized rates,
      rate ratios and potential years of life lost before 65 years. RESULTS: A total of
      28,462 hospitalizations (26,153 in men and 2,309 in women) and 8,739 deaths
      (8,192 in men and 547 in women) were attributed to HIV/AIDS during the study
      period. Rates of HIV/AIDS hospitalization were highest for men in Ontario, Quebec
      and British Columbia, and in Montreal, Toronto and Vancouver; while among women
      they were highest in Quebec and in Montreal, Toronto and Vancouver. Mortality
      rates followed a pattern similar to the rates found for hospitalization.
      CONCLUSIONS: Our analysis reveals the considerable impact of HIV/AIDS on patterns
      of morbidity and mortality in Canada.

PMID- 10349222
TI  - Screening seniors for risk of functional decline: results of a survey in family
      practice.
AB  - OBJECTIVE: To measure functional status, determine risk of functional decline and
      assess consistency between responses and standardized instruments. DESIGN: A
      mailed survey which measured functional impairment, recent hospitalization and
      bereavement. A positive response on at least one of these factors indicated that
      the individual was "at risk" for functional decline. A random sample (n = 73) of
      "at risk" subjects (specifically, family practice patients aged 70 and older)
      were assessed by a nurse. RESULTS: The response rate was 89% (369/415), 59% of
      seniors were female and the mean age was 77.1 (SD = 5.5) years. Self-reported
      risk, based on activities of daily living (ADLs), was associated with impairment
      in at least one basic ADL (p < 0.0005) using a standardized instrument. The
      positive predictive value of the survey for ADL impairment was 65%. CONCLUSION:
      Response to a mailed survey was high and self-reported ADL risks were consistent
      with findings from standardized assessment tools.

PMID- 10349223
TI  - When to be skeptical of negative studies: pitfalls in evaluating occupational
      risks using population-based case-control studies.
AB  - This study investigated arsenic and lung cancer incidence in a community setting
      in the Montreal area. Job histories and sociodemographic factors were collected
      by interview from 857 lung cancer cases, 533 general population controls, and
      1,360 controls with other cancers. Chemist-hygienists assessed each subject's
      life-time occupational exposure to 294 substances. Logistic regressions yielded
      arsenic/lung cancer odds ratios of 1.1 (95% confidence interval = 0.60, 1.7)
      based on cancer controls, and 0.82 (95% confidence interval = 0.41, 1.6) based on
      population controls. Risk did not rise with increasing level or probability of
      exposure. Worksite studies consistently show lung carcinogenicity from arsenic.
      Since confounding from other chemicals was well controlled, the most likely
      explanation is substantially lower exposures than in previous studies. The lack
      of association in this study demonstrates the need for caution in interpreting
      negative findings from population-based case-control studies, particularly when
      exposures are low or rare, as well as the difficulty in generating hypotheses
      from such studies.

PMID- 10349224
TI  - Re: Donovan C. AIDS: focus on youth.

PMID- 10349226
TI  - [The hygienic evaluation of 1,2,4,5-tetramethylbenzene via inhalation body
      uptake].

PMID- 10349227
TI  - [The hygienic validation of the permissible loads of synthetic anionic surface
      active substances in the soil during irrigation].
AB  - Permissible concentrations of anionic surfactants for the soil of irrigated
      agricultural fields are experimentally grounded: these are as follows: 12 and 17
      kg/ha (5 and 7 mg/kg) for sod-podzolic soils and black earths, respectively. By
      calculation, approximate permissible concentrations were also determined for
      other soils: 7 kg/ha (3 mg/kg) for sandy soils, 20 kg/ha (8 mg/kg) for loamy
      soils, and 25 kg/ha (10 mg/kg) for clay soils.

PMID- 10349225
TI  - [The hygienic standardization of gamma-butyrolactone in the air of populated
      sites].

PMID- 10349228
TI  - [An experimental validation of the maximum permissible concentration of a mixture
      of mono- and bicyclic terpenoid alcohols in water].
AB  - The maximum permissible concentrations (MPC) of Viterol in water were
      established, which was equal to 0.14 mg/l. Its organoleptic and general sanitary
      thresholds were determined at the same level.

PMID- 10349229
TI  - [The evaluation of the working conditions and of the health status of workers in
      steam-flushing yards].

PMID- 10349230
TI  - [The psychological status of workers subjected to noise exposure].
AB  - Mental health was examined in workers from a reinforced concrete plant and a
      thermal electric power station who were exposed to intensive noise at work. Noise
      was shown to have an adverse effect on their body's function. Higher occupational
      doses were found to result in the asthenic syndrome, to impair psychic processes
      along with the most profound emotional and volitional changes.

PMID- 10349231
TI  - [The effect of their life style and ecological factors on the health status of
      pre-draft-age youth].
AB  - Assessing the health indices in 330 adolescents aged 14-17 years who live in
      different microdistricts of an oil-processing center has demonstrated that
      adolescents of today are taller than those of the 1980s. Their body weight and
      chest circumference are greater only in 14-16-year-old adolescents, the lung
      capacity (LC) is higher only in 14-year-olds. Normal physical development was
      observed in 47.8-71/9%. Asthenic and hypertensive responses of the cardiovascular
      system (CVS) to graded exercise were found in 9.7-19.6%. There are no differences
      in the mean increment and mean rate of growth as to height in adolescents of
      today and the 1980s. But there are differences in the increase in body weights
      and LC. The adolescents residing in the more polluted microdistricts show less
      increases in their growth (8.4 vs 10.8 cm), body weight (8.1 vs 14.7 kg, and
      resting chest circumference (5.1 vs 7.5 cm). Gradual exercise testing has
      revealed asthenic and hypertensive CVS responses in 20% (13.4% in a less polluted
      area). By physical development, as high as 41.3% of adolescents are referred to
      health group II, in the less polluted area, this health group has been
      established only in 14-year-old adolescents.

PMID- 10349232
TI  - [The assessment and prediction of the weight-height ratio in boys during sexual
      maturation].
AB  - Based on long-term follow-up findings, a variety of Rorer's indices (RI) and
      their individual variation at different stages of sexual maturation was analyzed
      in 173 boys. Centile scales for rating weight-height ratios (WHR) were developed.
      With group RI differences amounting to as high as 200%, the individual ones were
      no more than 25%, as confirmed by a high correlation in RI changes at different
      stages of maturation. The established relation of the pattern of RI dynamics to
      the level of sexual maturation and individual traits of the boys' constitution
      and maturation allows one to predict individual WHR dynamics. The findings are of
      interest for medical monitoring of young men undergoing preconscription military
      training, young sportsmen, for implementation of sanitary measures in male
      adolescents.

PMID- 10349233
TI  - [Environmental pollution and the status of the immune system in children].

PMID- 10349234
TI  - [A decrease in the motor activity of children under the influence of technogenic
      air pollution].
AB  - Among multiple and various functions of the body, motor activity is essential.
      But it is little studied in schoolchildren. The present study was undertaken to
      investigate the impact of industrial pollution of the ambient air on the motor
      activity in old schoolchildren. At school, the motor activity of 8th-, 10th-, and
      11th-form schoolchildren was found to decrease with age, the dynamics of its
      decrease was determined by not only sexual differences of pupils, but also by the
      technogenic ambient air pollutions.

PMID- 10349235
TI  - [Enterobiasis in preschool institutions].

PMID- 10349236
TI  - [A hygienic evaluation of textbooks for the senior grades].
AB  - Difficulty presented by text-books is a leading factor that forms relations in
      the pupil-school system. Text-books on algebra, chemistry, geometry, and Russian
      for secondary forms are most difficult in their component complexity and abstruse
      character. The difficulty of educational texts increases with the 5th to 8th
      forms.

PMID- 10349237
TI  - [Methodological principles for using agents for the mass prevention of the
      sequelae of human irradiation].
AB  - The means of mass prevention of radiation consequences are biologically active
      additives to food, usual diet components, etc., micronutrients, as well as some
      sorbents and radio protective agents, which show various actions: 1) those
      reducing absorption; 2) those accelerating radionuclide excretion; 3) those
      enhancing the body's resistance to radiation; 4) those contributing to the
      prevention (less risk) of late radiation-induced cancer. The paper formulates
      basic requirements for means of mass prevention and guidelines for their use in
      terms of benefits and risk.

PMID- 10349238
TI  - [The evaluation of the effect of chemical and radiation factors on the health of
      the population in an industrial city].
AB  - Kamensk-Ural'skiy, Sverdlovsk Province, is one of the Russian industrial cities
      and towns exposed to a combination of radiation and chemical pollutions. This is
      a large industrial center of the mid-Urals, where enterprises of ferrous and
      nonferrous metallurgy, power engineering. Intensive chemical and radiation
      pollutions of Kamensk-Ural'skiy have an adverse impact on its population's
      health, which is manifested by higher morbidity rates among both children and
      adolescents. Comparing its matched areas by using routine analytical methods has
      defined the contribution of radiation to increased morbidity in different age
      groups, which is caused by a combination of chemical and radiation pollutions of
      the environment. The incidence of concomitant diseases may be an important
      additional indicator of the impact of environmental pollution on human health.

PMID- 10349239
TI  - [Food fibers--blockers and decontaminants of the radionuclides cesium and
      strontium].
AB  - The Chernobyl accident and its resultant radioactive pollution of enormous areas
      led to long-term entrance of radionuclides into the human habitat. Among more
      than 200 radionuclides, the products of uranium fission in the reactor of the
      atomic power station, the isotopes of iodine, cesium, and strontium present the
      highest hazard. If iodine-131 virtually decayed by August, 1986, the long-lived
      isotopes of cesium and strontium will still stir the world public and scientists
      for many years. The authors' result show that new types of dietary cellulose and
      composite food additives based on alfalfa polymers have rather pronounced
      antiradioactive properties against Cs-137 and Sr-85. This makes it necessary to
      organize the manufacture of these food additives whose daily dose of 12-20 should
      be supplemented into human diet every day.

PMID- 10349240
TI  - [The ecological problems of railroad transport today].

PMID- 10349241
TI  - [The complex hygienic assessment of environmental status and its effect on the
      health of the population of a region].

PMID- 10349242
TI  - [The atomic volumes of chemical elements as indices of their acute toxicity].

PMID- 10349243
TI  - [The hygienic characteristics of the heavy metal pollution of the environment of
      an industrial region and the immune status of children].

PMID- 10349244
TI  - [The carcinogenic activity of the pesticide Kreokhin (Leptocide)].

PMID- 10349245
TI  - [The experience of winter field deratization in a focus of hemorrhagic fever with
      renal syndrome].

PMID- 10349246
TI  - [The effect of electromagnetic fields on health (a review)].

PMID- 10349247
TI  - [An analysis of the effect of social factors on morbidity dynamics in a period of
      economic instability].

PMID- 10349248
TI  - [Modern information support for the state epidemiological health service].

PMID- 10349249
TI  - [The procedures for the organization and management of comprehensive health and
      hygiene measures under extreme conditions].

PMID- 10349250
TI  - [The rationale for priority trends in reducing the regional expenditure risks in
      the social hygiene monitoring system].

PMID- 10349251
TI  - [The history of the health service of Vologda Province].

PMID- 10349252
TI  - [A modification to the method for the gas-chromatographic determination of butyl
      alcohol, acrylic acid and the butyl ester of acrylic acid in the atmosphere and
      in the air of a work area].

PMID- 10349253
TI  - [Analytical control of the phenol content of the air].

PMID- 10349254
TI  - [A method for the comparative biotesting of drinking water using bacterial
      indicator strains].

PMID- 10349256
TI  - Hypertension corner. Clinical significance of various blood pressure components.

PMID- 10349257
TI  - [Percutaneous renal angioplasty. Experience of the Radiodiagnostic Service of the
      Hotel-Dieu of France].
AB  - OBJECTIVE: We report on a series of 42 renal artery stenosis treated with
      percutaneous transluminal angioplasty (PTA). MATERIALS AND METHODS: From January
      1988 to June 1996, these 42 renal artery stenoses were found in 33 patients (17
      males and 16 females) who had a balloon dilation (with 3 stent deployment); 9 of
      these lesions were bilateral and 7 on a single kidney. Initially, 32 patients had
      a high blood pressure and 6 a progressive renal failure. Twenty-two patients
      presented an atheromatous pathology, 7 a fibromuscular dysplasia. One patient had
      a Takayasu arteritis, and 3 others a stenosis of the renal graft artery. RESULTS:
      We find a complete initial success in 86% of the patients, a partial success in
      14% without any catheterization failure. Global success rate of PTA is 90% at 29
      months mean follow-up. A benefit of PTA regarding blood pressure was found in
      84.4% of the patients. The renal function became normal in half the patients with
      renal insufficiency. CONCLUSION: PTA is an efficient treatment for renal artery
      stenosis. A satisfactory improvement of blood pressure and renal function is
      found in a high number of patients.

PMID- 10349258
TI  - Vein grafting of tunical incisions in the treatment of Peyronie's disease.
AB  - The effectiveness of vein grafting of tunical incisions of Peyronie's plaques in
      straightening the penis, with preservation of normal erectile function is
      evaluated. Eighteen patients with Peyronie's disease were surgically treated with
      a vein patch graft technique to correct their penile curvature. Transverse
      relaxing incisions were made on the tunica albuginea where a curvature was
      identified by an artificial erection. A vein graft from the saphenous vein was
      sewn into the defect created by relaxing incisions. If there was evidence of a
      residual curvature after the vein grafts were sewn in, a plication of the
      contralateral surface of the tunica albuginea was performed. The saphenous vein
      grafting alone was sufficient to straighten the penis 90 to 100% in 50% of
      patients. Of twelve patients who were potent preoperatively, one required
      postoperatively an occasional intracorporeal injection to maintain erection. Two
      of the impotent men regained their potency postoperatively. None of the patients
      lost sensation in the glans or shaft of the penis. Penile shortening was reported
      in three patients. No decrease in the penis rigidity was noted. Patients were
      discharged within 5 days of the procedure. There were no immediate complications.
      Fifteen of our sixteen followed patients resumed intercourse in eight weeks. We
      found that plaque incision in the venous grafting is much easier than the other
      incisional and excisional procedures described in the literature, and may lead to
      successful correction of penile deformity without compromising potency, penile
      length and sensitivity.

PMID- 10349260
TI  - Adapting guidelines to Lebanese clinical practice.

PMID- 10349259
TI  - Major congenital malformations presenting in the first 24 hours of life in 3865
      consecutive births in south of Beirut. Incidence and pattern.
AB  - 3865 consecutive newborns delivered between 2/1/91 and 7/31/93 were prospectively
      studied. All the neonates received a physical examination during the first 24
      hours of life. Major congenital anomalies (MCA) were found in 64 newborns at
      incidence of 16.5/1000 births. 61 patients with full description included 40 with
      single and 21 with multiple MCA. Out of the latter 2 had syndromal (Osteogenesis
      Imperfecta and Achondroplasia), 16 nonsyndromal and 3 sequence multiple (Pierre
      Robin, diaphragmatic hernia with dextrocardia and breech presentation sequence)
      malformations. Skeletal anomalies were leading among the group (46.29%), followed
      by genitourinary (GU) defects (12.14%) and neural tube fusion defects (NTFD)
      (11.21%). Incidence of low birth weight (LBW) was 6% among the studied group of
      newborns and 26.56% among the group with MCA. Incidence of MCA among the group of
      LBW was 7.32%. While 65.62% of cases were amenable to surgery the malformed
      infants formed 24.34% of all perinatal death suggesting that improved care given
      to these patients will appreciably participate in reducing perinatal mortality.
      Incidence of NTFD (3.10/1000 births) was higher than in many western and middle
      eastern reports suggesting the need for further testing for incidence and
      etiology. Among the malformed infants, the rate of low birth weight and the rate
      of parental first cousin consanguinity were significantly higher than
      corresponding rates among normal infants in a control group.

PMID- 10349261
TI  - Consensus conference. Colorectal cancer: prevention, screening and management.
AB  - We report in this section a series of consensus conferences organized and
      published by official and well known organizations. They are of general and
      public interest and can be used as clinical guidelines. We will be ready to
      report any consensus conference organized methodologically in Lebanon by medical
      societies or other scientific organizations.

PMID- 10349262
TI  - [Diabetes and pregnancy. Part II: obstetrical aspects].

PMID- 10349263
TI  - Assessment of AIDS knowledge, attitudes, behaviors and occupational risk of
      laboratory.

PMID- 10349264
TI  - [Laparoscopic adrenalectomy for pheochromocytoma. Case report and review of the
      literature].
AB  - Laparoscopic surgery has a wide application in general surgery. Since the first
      laparoscopic adrenalectomy, this approach has quickly been adopted, and
      increasing numbers are being reported. The small size of the adrenal gland, the
      benign nature of most adrenal tumors and the difficulty in reaching the organ via
      open means make resection of this gland particularly amenable to the laparoscopic
      approach. The potential benefits of this mini-invasive surgery include decreased
      operation blood loss, reduced narcotics requirements, shorter hospital stay and
      recovery time and minimize the parietal trauma. We report herein the first
      Lebanese case of laparoscopic adrenalectomy for pheochromocytoma with review of
      the literature.

PMID- 10349266
TI  - [Physicians held between two fires: between the exigencies of patients...and
      financial constraints].

PMID- 10349265
TI  - [Triple filling plasty in Clagett thoracostomy].
AB  - Clagett's thoracostomy is a widely used procedure in the initial treatment of
      postpneumonectomy empyema. We describe in this paper an original one-step
      operation of thoracic filling after empyema sterilization. The triple plasty
      includes an apical thoracoplasty limited to the first 3 ribs, a pedicle flap of
      the latissimus dorsi transferred inside the thoracic cavity, and an upper
      translation of the diaphragm to the 4th rib in order to reduce residual pleural
      space. Three patients were operated and followed up clinically (for 20, 29, and
      30 months), and radiologically with a MRI on the 12th month. Complete tissue
      healing and loss of all residual space was observed in all patients. We therefore
      recommend the use of this technique rather than thoracic wall coverage
      procedures.

PMID- 10349267
TI  - Hypertension corner. Wide pulse pressure: diagnostic, prognostic and therapeutic
      implications.

PMID- 10349268
TI  - Renal disease in Lebanese children and adolescents. Findings in 118 consecutive
      percutaneous renal biopsies.
AB  - One hundred and eighteen consecutive percutaneous renal biopsies performed on 104
      Lebanese children and adolescents at the American University of Beirut Medical
      Center over a period of six years were reviewed retrospectively. These patients
      represent the great majority of renal biopsies performed on Lebanese children and
      adolescents during that period. The kidney was localized with the help of an IVP
      or ultrasound and the procedure was performed without direct guidance. Adequate
      renal tissue was obtained in 112 biopsies with a success rate of 95.0%. The
      procedure appears to be safe in children. The renal diseases identified and their
      incidence is comparable to those reported in the literature. Acute nephropathy
      was seen in 9.6% of the patients, primary nephrosis in 45.0% and secondary
      glomerular disease in 14.6%. Tubulointerstitial disease, metabolic and hereditary
      diseases and end-stage renal diseases were found in 7.7%, 6.7%, and 5.8% of
      patients respectively. Some previously unreported conditions were identified.

PMID- 10349269
TI  - Prevalence, antimicrobial susceptibility and molecular characterization of
      Campylobacter isolates recovered from humans and poultry in Lebanon.
AB  - Recovery of Campylobacter was attempted from 281 consecutive non selected out
      patients diarrheic stools, 150 individual ceca collected from meat chicken
      breeder farms and 31 slaughtered marketed chicken obtained from shops in Lebanon.
      Campylobacter isolates were recovered from 2 (0.7%) human stool specimens, 34
      (22.7%) chicken ceca and 3 (9.7%) raw chicken carcasses. Speciation of these
      isolates revealed 2 C. jejuni from humans diarrheic stools, 16 C. coli, 10 C.
      jejuni, 3 C. fetus, 2 C. fennelliae (Helicobacter fennelliae, new taxon), 2 C.
      upsaliensis, 1 C. cryaerophila (Archobacter cryaerophilus, new taxon) from
      chicken ceca and 2 C. coli and 1 C. fennelliae (H. fennelliae) from raw chicken
      carcasses. Antimicrobial susceptibility testing of the different isolates against
      9 antimicrobial agents was performed using the E-test. Overall, most isolates
      showed high to moderate susceptibility to gentamicin (97%),
      amoxicillin/clavulanate (95%), clindamycin (77%), chloramphenicol (77%), and
      ampicillin (69%). Lower susceptibility were observed against tetracycline (49%),
      erythromycin (47%), ciprofloxacin (39%), and norfloxacin (36%). This overall
      susceptibility profile generally applied to C. coli and C. jejuni, as well,
      although C. coli mostly showed higher susceptibility than C. jejuni. beta
      lactamase production was detected in 59% of all the isolates, being higher in C.
      coli (72%) than C. jejuni (33%). Whole cell protein profile analysis of 18 C.
      coli and 12 C. jejuni by SDS-PAGE revealed 6 different patterns. In both species,
      major variations existed in the region between mol wt 45-60 and all protein
      profiles were dominated by the presence of 5 major bands of mol wt: 61 (doublet),
      45, 31 and an approximate 24. Differences in banding patterns within and between
      both species indicated diversity and heterogeneity of strains. This study shows
      that despite high prevalence and diversity of strains in chicken, Campylobacter
      in Lebanon is rare in human diarrheic stools compared to Salmonella (3.2%) and
      Shigella (1.4%).

PMID- 10349270
TI  - [Retrospective study of nine Lebanese families with fragile X syndrome and review
      of the literature].
AB  - The Fragile X syndrome is the most common inherited form of mental retardation.
      Despite its incidence, which is estimated at 1/4000 boys, only 9 families have
      been documented so far in Lebanon, of which 3 have been partially investigated.
      This syndrome therefore seems to be largely ignored by physicians. Although no
      treatment is yet available for the Fragile X syndrome, the diagnosis of the
      disorder in a child is essential in order to provide the family with genetic
      counselling. The most critical point is still to convince the family of the need
      for such an evaluation and relieve the parents of any feeling of guilt.

PMID- 10349271
TI  - Pesticides primer for the primary care physician.

PMID- 10349272
TI  - Health sector reform in Lebanon.

PMID- 10349273
TI  - Renal fibrohistiocytic sarcoma. Three cases and a review of the literature.
AB  - The purpose of this paper is to report three unpublished cases of so-called
      "renal malignant fibrous histiocytoma" which should be more appropriately called
      "renal fibrohistiocytic sarcoma", and to review and analyze the data concerning
      41 cases collected from the literature and our three new cases, making a total of
      44 cases. Our third case is very interesting; in addition to the fact that this
      condition is rare, this particular patient also had concomitant nonmalignant
      ascites and compression of the descending colon, both conditions being rarely
      associated with renal cancer. The average age of the patients was 58 years; in
      66% of the cases the tumor involved the left kidney; 57% of the patients were
      males; the average tumor size was 12 cm; nephrectomy was performed in 93% of the
      cases; the average survival was 16 months. In none of the cases was a
      preoperative diagnosis correctly made. It is concluded that a triad of symptoms
      and signs (renal pain, weight loss, and large tumor size) as well as a triad of
      imaging characteristics (areas of low density on the CT scan, hypoechoic areas on
      ultrasound, and hypovascularity on angiography) may hold the promise of a
      preoperative diagnosis. It is suggested that the tumor arises from the system of
      Gerota's fascia-renal capsule.

PMID- 10349274
TI  - [Allergic granulomatous angiitis in the Churg-Strauss syndrome. Two case
      reports].
AB  - The Churg-Strauss Syndrome (CSS) or allergic granulomatosis and angiitis is a
      relatively unusual disease. It is a subset of the group of systemic necrotizing
      vasculitis and the clinical manifestations involve multiple organ system. The CSS
      is characterized typically by three phases, asthma or atopic disease, peripheral
      eosinophilia and ultimately, vasculitis. The authors report two cases of CSS. The
      first patient presented allergic rhinitis and asthma for 19 years when she
      developed acute abdominal pain, mononeuritis of her right leg, pulmonary
      infiltrates and hypereosinophilia. The lung biopsy showed extravascular
      granulomas and eosinophilic infiltration. The second patient presented asthma for
      two years when she developed a mononeuritis of the left leg and then a
      hypereosinophilia with cutaneous eruption of hands and feet, and a myo
      pericarditis. In both cases, treatment with prednisolone produced a dramatic
      improvement in symptoms and eosinophilia.

PMID- 10349276
TI  - [Scleroderma and colonic adenocarcinoma. A fortuitous association].

PMID- 10349277
TI  - The effects of community and migrant health centers on rural communities.

PMID- 10349275
TI  - Instructive case report. A 26-year-old Indian woman with seizures and multiple
      intracranial mass lesions.
AB  - We describe the case of a 26-year-old Indian woman who presented to our
      institution with seizures and papilledema. Her diagnosis was originally thought
      to be neurocysticercosis, but later confirmed to be intracranial tuberculoma.
      Antituberculous therapy with isoniazid, rifampin, pyrazinamide and ethambutol was
      initiated. Improvement in the patient's neurological symptoms with diminution in
      size of the intracerebral lesions was observed. This case illustrates the
      difficulty in distinguishing intracranial tuberculoma from neurocysticercosis.
      Radiological features that distinguish these two diseases are described. Both
      diseases must be considered in regions endemic for tuberculosis and
      cysticercosis.

PMID- 10349278
TI  - Building a research agenda: responding to the needs of Community and Migrant
      Health Centers.
AB  - This article summarizes the results of an invitational conference designed to
      establish a research agenda for collaborative projects involving university-based
      health services researchers and staff (administrative and clinical) from
      Community and Migrant Health Centers (C/MHCs). More research related to C/MHCs
      needs to be developed, preferably by collaborative teams of researchers and C/MHC
      personnel. Specific research ideas are summarized, and five more detailed
      research proposals are presented. This is an especially important area that needs
      work, given the changes taking place in health care finance and the impacts of
      those changes on C/MHCs.

PMID- 10349279
TI  - Residential differences in attitudes about barriers to using community-based
      services among older adults.
AB  - Despite poorer health, rural elders tend to use fewer community-based services
      than their urban or suburban counterparts. Researchers have speculated that
      residential differences in the receipt of community-based services may be
      attributable to, among other factors, the attitudes of older adults toward such
      services. Twelve focus groups were conducted to explore residential variation in
      the attitudes of older adults toward the use of community-based services,
      specifically emphasizing perceived barriers to the use of services. While both
      rural and urban residents expressed overall satisfaction with the services that
      they had received in the past or currently receive and both groups noted
      insufficient community-based services, residential differences emerged in both
      the nature of the perceived barriers and the frequency in which they were
      mentioned. Rural elders more frequently highlighted barriers that diminished
      their use of community-based services. Such barriers included a lack of awareness
      of services, inadequate transportation, and perceived rigid program eligibility
      standards. Urban older adults mentioned far fewer and different barriers to the
      receipt of services, but those barriers seemed to be consistent with the
      community context in which they lived. While these findings support speculations
      that differences in attitudes may account for some of the residential variation
      in the use of community-based services that has been observed, the conclusion
      also can be drawn that, regardless of residence, older adults face substantial
      barriers to services, resulting in unmet needs.

PMID- 10349280
TI  - Clergy perspectives and practices regarding intimate violence: a rural view.
AB  - Intimate violence has been recognized as a major problem in the United States.
      The financial and social hardships of declining rural economies, the social
      isolation of distance and poor transportation, inadequate social services for
      families in crisis, and limited options for women who might otherwise leave
      abusive partners are risk factors for intimate violence in rural areas. Church
      based prevention programs are considered particularly useful in rural
      communities. If preventive health programs engage them properly, rural church
      members' overlapping social structures and their especially interconnected social
      circles can spread and support new ideas and practices. This study was conducted
      in four rural, predominately white, southern Illinois counties. The survey
      instrument used consisted of four subscales, measuring knowledge about, attitudes
      toward, and practices to prevent intimate violence as well as religious ideology.
      Overall, clergy knowledge and attitudes about intimate violence in this study did
      not necessarily translate into actual prevention practices against intimate
      violence. However, liberal clergy tend to employ prevention practices more often
      when compared with conservative clergy. Nevertheless, rural churches and their
      clergy seem to be promising sources for diffusion of intimate violence prevention
      information, attitudes and acceptable standards of behavior to rural communities.

PMID- 10349281
TI  - Physician and clinical integration among rural hospitals.
AB  - The pressures for closer alignment between physicians and hospitals in both rural
      and urban areas are increasing. This study empirically specifies independent
      dimensions of physician and clinical integration and compares the extent to which
      such activities are practiced between rural and urban hospitals and among rural
      hospitals in different organizational and market contexts. Results suggest that
      both rural and urban hospitals practice physician integration, although each
      emphasizes different types of strategies. Second, urban hospitals engage in
      clinical integration with greater frequency than their rural counterparts.
      Finally, physician integration approaches in rural hospitals are more common
      among larger rural hospitals, those proximate to urban facilities, those with
      system affiliations, and those not under public control.

PMID- 10349282
TI  - Networks and the fiscal performance of rural hospitals in Oklahoma: are they
      associated?
AB  - This paper uses regression analysis to explore the relation of network membership
      to the financial performance of rural hospitals in Oklahoma during fiscal year
      1995. After adjusting for the scope of service, as measured by the number of
      facilities or services offered by the hospital, indicators of fiscal status are
      (1) the cash receipts derived from net patient revenue; (2) the cash
      disbursements related to operating costs, net of interest and depreciation
      expense, labor costs and nonlabor costs; and (3) net cash flow, defined as the
      difference between cash receipts and disbursements. Controlling for the effects
      of the hospital's structural attributes, operating characteristics and market
      conditions, the results indicate that members of a network reported lower net
      operating costs, labor costs and nonlabor expenses per service than nonmembers.
      Hence, the analysis seems to suggest that the membership of rural hospitals in a
      network is associated with lower cash disbursements and an improved net cash
      flow, outcomes that may preserve their fiscal viability and the access of the
      population at risk to service.

PMID- 10349283
TI  - Physician visits in a farming-dependent county.
AB  - Physician visits in a farming-dependent county in the upper-Midwest were studied
      using a mail questionnaire. A 16 percent random sample of households yielded 426
      surveys (60 percent response rate). The dependent variable was the natural log
      (plus one) of the number of times the respondent had seen a physician in the
      prior 12 months. Predisposing, enabling, and medical need variables were tested
      as potential predictors of medical care usage. Self-rated health status proved to
      be an important predictor, as was a history of hospitalization and being married.
      However, health insurance coverage and family income were not associated with
      increased physician visits. Implications for modifying the conceptual model
      employed to analyze medical care utilization in similar populations are
      discussed.

PMID- 10349284
TI  - Physician practice characteristics and satisfaction: a rural-urban comparison of
      medical directors at U.S. Community and Migrant Health Centers.
AB  - For this study, the association between physician practice characteristics and
      satisfaction of medical directors at rural and urban Community and Migrant Health
      Centers (C/MHCs) was investigated. Data for this study came from a 1996 cross
      sectional survey of C/MHCs' medical directors. A total of 411 centers (68.3
      percent) responded to the survey, including 240 rural (67.4 percent) and 171
      urban (68.7 percent) C/MHCs. Factor analysis was used to synthesize physician
      practice characteristics related to overall satisfaction. The resulting factors
      were entered as new variables in a predictive logistic regression model of
      overall satisfaction. Growing up in an inner-city community was significantly
      associated with practicing in an urban center; whereas, growing up in a rural or
      frontier community was more likely to result in practicing in a rural center. The
      majority of medical directors (82.3 percent) were either somewhat satisfied or
      very satisfied with their work. Satisfaction with work was most significantly
      associated with overall level of satisfaction, followed by satisfaction with
      administration, peers and patients. Recruitment efforts are more likely to
      succeed when they target individuals with prior exposure to underserved areas.
      Improving the working conditions and interactions with administrators would help
      sustain the high level of satisfaction experienced by medical directors at
      C/MHCs.

PMID- 10349285
TI  - Hospital mergers and closures: survival of rural hospitals.
AB  - There are two major models to save financially failing rural hospitals: (1)
      expanding through an affiliation or merger with other hospitals to increase the
      utilization and diversity of services, or (2) downsizing by employing the limited
      service model and providing only emergency and primary care service with limited
      acute care. This study investigates hospital mergers and closures from 1990 to
      1992 using the American Hospital Association's (AHA's) data from the Annual
      Survey of U.S. Hospitals. The presence of potential scale and scope economies
      among merging and closing hospitals prior to the merger or closure suggests that
      rural hospitals are operating at a size level that has great potential for
      achieving scope and scale efficiencies through mergers.

PMID- 10349286
TI  - Orthoses in the treatment of rearfoot problems.
AB  - Orthotic management is helpful in the treatment of most orthopedic conditions
      involving the rearfoot, including plantar fasciitis, Achilles tendon disorders,
      posterior tibial tendon dysfunction, flatfoot, ankle sprains, and problems
      associated with diabetes, arthritis, and equinus disorders. A review of the
      effectiveness of orthoses in the treatment of these conditions is presented here.
      An in-depth analysis of the orthotic management of plantar fasciitis and a
      critical review of foot orthoses for the pronated foot are presented. Also
      discussed are the rationale and effectiveness of the tension night splint in the
      treatment of plantar fasciitis, orthotic devices for the different stages of
      posterior tibial tendon dysfunction, and the various categories of orthoses for
      off-loading the diabetic foot. The modern ankle brace, the effectiveness of
      prefabricated versus prescription foot orthoses, and recent developments in the
      ankle-foot orthosis are also reviewed.

PMID- 10349287
TI  - Biomechanics as a basis for management of intra-articular fractures of the
      calcaneus.
AB  - This article presents a critical examination of biomechanics studies in the
      literature that could shed light on or contribute to the development of methods
      of managing intra-articular calcaneal fractures. An appreciation and
      understanding of such studies is predicated on a sound knowledge of a number of
      germane topics: the anatomy of the normal calcaneus, the pathomechanics of the
      calcaneus, fracture-classification schemes, and fracture-management methods. The
      first part of this review presents overviews of these topics. The biomechanics
      studies are then reviewed in detail. The article concludes with a description of
      research areas that might close the gaps identified in these studies.

PMID- 10349288
TI  - Use of the ROC anchor in foot and ankle surgery. A retrospective study.
AB  - A retrospective study was conducted on the use of the ROC (Radial Osteo
      Compression) soft-tissue anchor in foot and ankle surgery. This article describes
      how the anchor is deployed, problematic aspects of using the anchor, and
      complications and success rates associated with the anchor in ankle
      stabilizations, posterior tibial tendon reconstruction, peroneus brevis tendon
      reconstruction after fracture of the base of the fifth metatarsal, and detachment
      and reattachment of the Achilles tendon. The ROC anchor consists of the anchor
      with nonabsorbable suture attached to the shaft, the deployment handle, and drill
      bits. The anchor and shaft are snapped into the deployment handle and inserted
      into the drill hole. Compression of the trigger deploys the anchor into the hole.
      The ROC anchor was found to be reliable, useful, and relatively easy to deploy,
      with outcomes similar to those of other soft-tissue anchors.

PMID- 10349289
TI  - Management of heel pain syndrome with acetic acid iontophoresis.
AB  - This study was undertaken to determine the effectiveness of acetic acid
      iontophoresis in the treatment of heel pain. Thirty-five patients with chronic
      heel pain were treated with acetic acid iontophoresis over a 4-year period.
      Ninety-four percent of patients had complete or substantial relief of heel pain
      after an average of 5.7 sessions of acetic acid iontophoresis over an average
      period of 2.8 weeks. Heel pain levels were rated from 0 to 10, with 10
      representing the most severe pain. Heel pain prior to iontophoresis treatment
      received an average rating of 7.5; by the end of therapy, the average rating had
      decreased to 1.8. At an average follow-up time of 27 months, heel pain levels
      averaged 0.64, indicating continued reduction in heel pain. Ninety-four percent
      of participants said that they would recommend acetic acid iontophoresis to
      someone with similar heel pain.

PMID- 10349290
TI  - Reevaluation of the relaxed calcaneal stance position. Reliability and normal
      values in children and adults.
AB  - Reliability and normal values for the relaxed calcaneal stance position were
      determined in a nonclinic population of healthy adults and children (88 adults
      and 124 children) ranging in age from 5 to 36 years. The mean relaxed calcaneal
      stance position for adults was 6.07 degrees valgus (SD 2.71 degrees) (range, 1
      degree varus to 14 degrees valgus). The mean relaxed calcaneal stance position
      for children was 5.6 degrees valgus (SD 2.9 degrees) (range, 6 degrees varus to
      12 degrees valgus). There was no significant difference between the relaxed
      calcaneal stance positions of adults and children. In children the relaxed
      calcaneal stance position did not correlate with age, height, or weight and did
      not decrease with age to the theoretical normal value of 0 degree +/- 2 degrees
      as postulated by Root et al. The relaxed calcaneal stance position was found to
      be a reliable measurement; however, the theoretical normal value of 0 degree +/-
      2 degrees was not found. The values reported in the present study correspond with
      the results of other empirical studies; thus the theoretical normal value for the
      relaxed calcaneal stance position of 0 degree +/- 2 degrees may be invalid.

PMID- 10349291
TI  - Planovalgus foot deformity revisited.

PMID- 10349292
TI  - Planovalgus foot deformity revisited.

PMID- 10349294
TI  - Brain activation and pupil response during covert performance of the Stroop Color
      Word task.
AB  - Patterns of brain activation associated with covert performance of the Stroop
      Color-Word task were studied in young, healthy, adult volunteers using blood
      oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI).
      Comparisons of the incongruous Stroop condition were made with both color naming
      and word reading baselines. Areas of the left and right anterior cingulate, the
      right precuneus, and the left pars opercularis displayed larger BOLD signal
      responses during the incongruous Stroop condition than during baseline
      conditions. Activation of BOLD signals in these areas was highly repeatable. In a
      second experiment, pupil diameter was used to assess cognitive load in 7
      individuals studied during overt and covert performance of both Stroop and color
      naming conditions. Cognitive load was similar in overt and covert response
      conditions. Results from the BOLD study indicate that brain regions participating
      in selective visual attention and in the selection of motor programs involved in
      speech were activated more by the Stroop task than by the baseline tasks. The
      neural substrate involved in the resolution of the perceptual and motor conflicts
      elicited by the Stroop Color-Word task does not appear to be a single brain
      region. Rather, a network of brain regions is implicated, with separate regions
      within this system supporting distinct functions.

PMID- 10349295
TI  - Timing and force control during a sequential tapping task in children with and
      without motor coordination problems.
AB  - In the present study a sequential tapping task was used to compare the planning
      and execution of finger tapping sequences in children with motor coordination
      problems (clumsy children) and control children. Fifteen children with
      significant movement problems were compared to 15 control children matched on
      age, sex, and Verbal IQ. The clumsy children took significantly longer to
      initiate the movement sequence (i.e., reaction time). During the execution of the
      sequence, the clumsy children left their finger on the tap plate for
      significantly longer for each tap than the control children. No significant
      differences were found between the groups for the time taken between the taps, or
      mean average force. Past research has indicated that the source of timing
      problems in clumsy children may lie in a central timing mechanism possibly the
      cerebellum, whereas the evidence from the present study indicates an impairment
      of the peripheral processes may be a more important contributor to timing
      deficits in clumsy children.

PMID- 10349293
TI  - Mini-Mental State Examination and Mattis Dementia Rating Scale performance
      differs in Hispanic and non-Hispanic Alzheimer's disease patients.
AB  - Little information exists regarding the performance of Spanish-speaking versus
      English-speaking patients with Alzheimer's disease (AD) on the Mini-Mental State
      Examination and the Mattis Dementia Rating Scale. In an attempt to identify
      culturally biased MMSE items or DRS subscales, we matched Spanish-speaking
      Hispanic and English-speaking non-Hispanic White community-dwelling AD patients
      by their MMSE scores and examined specific items within each scale. Our findings
      indicate that Hispanic AD patients perform significantly worse than non-Hispanics
      in terms of total DRS score, scores on the DRS subscales for Conceptualization
      and Memory, and on serial subtraction (or backward spelling item) of the MMSE.
      While mildly to moderately demented Hispanic and non-Hispanic patients obtained
      comparable scores on the DRS, severely impaired Spanish-speaking participants
      obtained considerably lower DRS scores than their English-speaking counterparts.
      The discrepancy in the DRS scores of the severely impaired Hispanic and non
      Hispanic examinees might reflect a cultural bias in the test or educational
      differences between the groups. Alternatively, the DRS may be more sensitive than
      the MMSE for detecting severe cognitive impairment in Hispanic patients.

PMID- 10349296
TI  - Object identification deficits in dementia of the Alzheimer type: combined
      effects of semantic and visual proximity.
AB  - Identification deficits in dementia of the Alzheimer Type (DAT) often target
      specific classes of objects, sparing others. Using line drawings to uncover the
      etiology of such category-specific deficits may be untenable because the
      underlying shape primitives used to differentiate one line drawing from another
      are unspecified, and object form is yoked to object meaning. We used computer
      generated stimuli with empirically specifiable properties in a paradigm that
      decoupled form and meaning. In Experiment 1 visually similar or distinct blobs
      were paired with semantically close or disparate labels, and participants
      attempted to learn these pairings. By having the same blobs stand for
      semantically close and disparate objects and looking at shape-label confusion
      rates for each type of set, form and meaning were independently assessed.
      Overall, visual similarity of shapes and semantic similarity of labels each
      exacerbated object confusions. For controls, the effects were small but
      significant. For DAT patients more substantial visual and semantic proximity
      effects were obtained. Experiment 2 demonstrated that even small changes in
      semantic proximity could effect significant changes in DAT task performance.
      Labeling 3 blobs with "lion," "tiger," and "leopard" significantly elevated DAT
      confusion rates compared to exactly the same blobs labeled with "lion," "tiger,"
      and "zebra." In conclusion both visual similarity and semantic proximity
      contributed to the identification errors of DAT patients.

PMID- 10349297
TI  - Test-retest reliability and practice effects of expanded Halstead-Reitan
      Neuropsychological Test Battery.
AB  - Test-retest reliabilities and practice effects of a broad range of
      neuropsychological measures were examined in 384 normal or neurologically stable
      adults. Median test-retest interval was 11 months (range 3-16 months). The
      reliability estimates for most of the measures are reasonably good, ranging from
      .70 to low .90s. An exception is the relatively poor reliabilities of most memory
      measures. For all test measures, the value on initial testing is a strong
      determinant of the value on the second examination. Practice effects are seen on
      most measures. The magnitude of the practice effects, however, varies as a
      function of type of measure, test-retest interval, age, and overall competency
      level of the participant. This study provides several types of retest information
      that may be useful for future research and clinical work: comparative
      reliabilities of the various measures, estimate of error variability associated
      with each administration, standard deviation of the change, and comparative
      magnitude of practice effects on various tests.

PMID- 10349298
TI  - Detecting significant change in neuropsychological test performance: a comparison
      of four models.
AB  - A major use of neuropsychological assessment is to measure changes in functioning
      over time; that is, to determine whether a difference in test performance
      indicates a real change in the individual or just chance variation. Using 7
      illustrative test measures and retest data from 384 neurologically stable adults,
      this paper compares different methods of predicting retest scores, and of
      determining whether observed changes in performance are unusual. The methods
      include the Reliable Change Index, with and without correction for practice
      effect, and models based upon simple and multiple regression. For all test
      variables, the most powerful predictor of follow-up performance was initial
      performance. Adding demographic variables and overall neuropsychological
      competence at baseline significantly but slightly improved prediction of all
      follow-up scores. The simple Reliable Change Index without correction for
      practice performed least well, with high error rates and large prediction
      intervals (confidence intervals). Overall prediction accuracy was similar for the
      other three methods; however, different models produce large differences in
      predicted scores for some individuals, especially those with extremes of initial
      test performance, overall competency, or demographics. All 5 measures from the
      Halstead-Reitan Battery had residual (observed--predicted score) variability that
      increased with poorer initial performance. Two variables showed significant
      nonnormality in the distribution of residuals. For accurate prediction with
      smallest prediction--confidence intervals, we recommend multiple regression
      models with attention to differential variability and nonnormality of residuals.

PMID- 10349299
TI  - [Inhibitors in calcium oxalate crystals].

PMID- 10349300
TI  - [In vivo scavenging effect of ethylcysteine on reactive oxygen species in human
      semen].
AB  - PURPOSE: The production of reactive oxygen species (ROS) is a normal
      physiological event in various organs including the testis. Overproduction of
      ROS, however, can be detrimental to sperm, being associated with male
      infertility. In vivo experiments using vitamin E (Vit. E), one of the major
      membrane protectants against ROS and lipid peroxidation, have shown its
      significant potential in treating ROS-associated male infertility. There has been
      no study that the scavenging drugs reduce the level of ROS in human semen.
      Previously we reported the in vitro scavenging effectiveness of ethylcysteine
      (EC) against ROS in human semen. The present study was performed in order to
      determine the effectiveness of the in vivo administration of EC as treatment for
      ROS-associated male infertility. PATIENTS AND METHODS: Ten cases of male
      infertility, with the exceptions of azoospermia and pyospermia, were chosen.
      Patients were divided randomly into two groups. Each group received either 600
      mg/day of EC (Group A) or Vit. E 600 mg/day (Group B) for 3 months. Then, after a
      1-month wash-out period, the patients were switched to another treatment.
      Conventional semen analysis, computerized motility assessment, measurement of ROS
      generation and sperm function assessment by triple stain were performed before
      and after administration of EC and Vit. E. The levels of EC and Vit. E were also
      assessed in patients' blood serum and seminal plasma before and after
      administration of EC and Vit. E. RESULTS: Sperm density and sperm motility did
      not improve but sperm function had a significant tendency toward improvement
      after administration of EC and Vit. E. ROS levels significantly decreased only
      after administration of EC After administration of EC and Vit. E, their levels
      significantly increased in patients' blood serum but were unchanged in patients'
      seminal plasma. CONCLUSION: Since our study showed that oral administration of EC
      produced results similar to those of Vit. E, we conclude that EC is an effective
      treatment agent for ROS-associated male infertility.

PMID- 10349301
TI  - [Histological characteristics and clinical significance of Japanese prostate
      cancer with low levels of prostate specific antigen of 4.0 ng/ml or lower].
AB  - PURPOSE: They set a normal limit of prostate specific antigen (PSA) to 4.0 ng/ml
      in Tandem R assay at most institutions. We investigated clinical and histological
      characteristics of prostate cancer based on whole mount step-section histology of
      radical prostatectomy specimens, and taking notice of Japanese prostate cancer
      whose levels of PSA are less than 4.0 ng/ml in normal levels. MATERIALS AND
      METHODS: One hundred and twenty-two patients underwent radical prostatectomy for
      clinically resectable prostate cancer at University Hospital from February 1992
      to April 1997. Clinicopathological findings were stratified according to the
      preoperative PSA levels in 111 patients without preoperative endocrine therapy.
      Immunohistochemical study for PSA was conducted in 7 randomly selected patients.
      RESULTS: Of the patients 22 (19.8%) had normal (4.0 ng/ml or lower) preoperative
      serum PSA. Mean tumor volume in this PSA range was 1.5 cm3 with one pT 0 case
      included. Pathologically organ confined, potentially curable disease (< pT 3) was
      found in 17 (77.3%) patients and extracapsular extension and seminal vesicle
      invasion in 5 (23.8%), respectively. No patients had positive pelvic lymph nodes.
      Well differentiated tumors of Gleason scores 2-4 were found in 9 (40.9%) of the
      patients, moderately differentiated tumors (Gleason scores 5, 6) in 5 (22.7%) and
      poorly differentiated histology (Gleason scores 7-10) in 7 (31.8%). Sixteen
      (72.7%) patients had clinically significant tumors (> 0.5 cm3, Gleason score > or
      = 7). All 7 patients had positive staining for PSA, but its intensity did not
      correlate with serum PSA levels. CONCLUSIONS: Many prostate cancers found in
      surgical specimens were clinically significant despite the low levels of PSA and
      potentially curable by definitive treatment. Age, co-morbidity and other
      clinicopathological variables as well as PSA levels should all be taken into
      account when treatment options are discussed.

PMID- 10349302
TI  - [Structural characteristics of osteopontin for calcium oxalate crystal].
AB  - BACKGROUND: I investigated which structural segment of osteopontin (OPN), a
      matrix component of urinary stones, is significantly related to the formation of
      urinary stones. METHODS: I prepared several kinds of OPNs under various
      conditions and compared the effects of these OPNs on calcium oxalate (CaOx)
      crystal using RI counts obtained by the seed crystal method and diluted urine
      method. Furthermore, I performed scanning electron microscopic (SEM) observation
      of CaOx crystals used in these experiments and evaluated the effects of OPN based
      on morphological changes in CaOx crystals. The following OPNs were used in this
      study: human recombinant OPN (rOPN), human native OPN (nOPN) purified from human
      milk, denatured OPN (dOPN) obtained by adding organic solvent during the course
      of nOPN purification, and asiaro OPN (aOPN) obtained by removing sialic acid
      after enzymatic digestion of nOPN. RESULTS: When the effects of OPNs (15
      micrograms/ml) were evaluated by the seed crystal method, the following
      inhibitory activities were observed: nOPN (82%), aOPN (56%), dOPN (49%) and rOPN
      (15%). When the effects of OPNs (150 micrograms/ml) were evaluated by the
      undiluted urine method, the following inhibitory activities were observed: nOPN
      (38%), aOPN (27%), dOPN (21%) and rOPN (0%). Furthermore, using nOPN, I performed
      SEM observation of CaOx crystals and found that nOPN mainly inhibited CaOx
      crystal aggregation. CONCLUSION: Since the inhibitory activity of nOPN was
      observed not only in the seed crystal method, but also in the undiluted urine
      method, it was suggested that nOPN may play an important role in the living body
      during the course of urinary stone formation. Moreover, the inhibitory activity
      of OPN was not due to its primary structure, but it was closely related to its
      higher-order structure and side chains including sialic acid. Furthermore, it was
      clarified that the inhibitory activity of OPN mainly resulted from inhibition of
      CaOx crystal aggregation rather than growth inhibition in these crystals.

PMID- 10349303
TI  - [Assessment of QOL and survival for patients undergoing radical cystectomy or
      bladder preservation for invasive bladder cancer].
AB  - PURPOSE: In this study, we have retrospectively compared patient backgrounds,
      prognosis and QOL (quality of life) in patients with invasive bladder cancer
      treated by radical cystectomy or by bladder preservation. PATIENTS AND METHODS:
      This study enrolled recent 30 cases from each institutions, totally 120 cases
      from four institutions. All patients were diagnosed with invasive bladder cancer
      in stage T 2 or T 3, N 0, M 0. The patients planned for preserving the bladder
      were treated with a combination of intra-arterial chemotherapy and radiation as
      an induction therapy. The questionnaire used to assess QOL was the EORTC QLQ-C 30
      (Japanese-language edition). RESULTS: Radical cystectomy was selected as the
      initial treatment in 60 cases (the planned radical cystectomy group). Bladder
      preservation was planned but the presence of residual tumors after induction
      therapy underwent radical cystectomy in 18 cases (the preservation-radical
      cystectomy group). Bladder preservation was achieved in 42 cases (the
      preservation group). In a comparison of background factors, histologically grade
      3 tumor and cases with histology other than transitional cell carcinoma, were
      significantly common in the planned radical cystectomy group. Because this study
      is not an randomized test, it is difficult to compare the outcomes between the
      patients treated by radical cystectomy or by bladder preservation. However, it is
      indicated that the candidates for bladder preservation therapy exist among the
      patients with T 2 or T 3, N 0, M 0 bladder cancer. Quality of life, as evaluated
      from global QL and from physical, cognitive, and emotional function, tended to be
      better in the patients with their bladder, although no difference was noted among
      the groups with regard to life role or social function. Symptoms such as sleep
      disturbance and diarrhea were common in the radical cystectomy groups, and
      financial impact, constipation, appetite loss, and dyspnea also tended to more
      frequently affect patients in these groups. CONCLUSION: Our results indicate that
      bladder preservation treatment using an induction therapy is one of option of the
      treatment for clinically T 2 or T 3, N 0, M 0 bladder cancer. We need a
      prospective randomized study with a long-term follow-up to elucidate true
      candidates for this treatment.

PMID- 10349304
TI  - [Urinary disturbance in olivopontocerebellar atrophy (OPCA)--changes during the
      progression of the disease].
AB  - PURPOSE: Among spinocerebellar degeneration, syndromes categorized as multiple
      system atrophy (MSA) are commonly associated with neurogenic bladder, and urinary
      disturbances change with the disease progression. Accordingly, the changes in the
      urodynamic findings during the progression of the disease have been studied in
      the case of Olivopontocerebellar atrophy (OPCA) and OPCA type of MSA. METHODS:
      Urodynamic study (UDS) was performed more than twice in eight patients (5 males,
      3 females, age 48-76, mean 55.0). The interval range between the first
      examination and follow up examination was 9-93 months (mean 42.4). UDS included
      cystogram, intravenous pyelography, residual urine volume, cystometry, urethral
      pressure profilometry, and external sphincter electromyography. RESULTS: The
      bladder was deformed in almost all patients with the progression of the disease,
      but the upper urinary tract was properly preserved. Residual urine volume tended
      to increase, and residual urine rate worsened significantly. The stable detrusor
      activity seemed to become overactive accompanied by detorusor hyperreflexia, and
      finally seemed to be acontractile. The normal sphincter activity seemed to become
      overactive accompanied by detrusor-sphincter dyssynergia, and finally complete
      relaxation could't be observed. CONCLUSION: These results suggest that urinary
      disturbance deteriorates together with other neuropathies as the disease
      progresses in OPCA. These patients should be continuously observed along with
      proper urinary management depending on the disease progression.

PMID- 10349305
TI  - [A case of drug induced urolithiasis composed of acetyl sulphapyridine associated
      with ulcerative colitis].
AB  - A 26-year-old female visited our hospital complaining left flank pain and
      macroscopic hematuria. She had been suffering ulcerative colitis and administered
      salazosulphapyridine and predonisolone from 17-year-old. Intravenous urography
      showed radiolucent multiple stones in the left renal pelvis. Three sessions of
      extracorporeal shock wave lithotripsy were performed after ureteral stenting.
      Although disintegration and discharge of the stones were satisfactory, bladder
      stone induced by ureteral stent was complicated. The extracted bladder stone
      showed a yellowish brown color and the surface was granular shape. Composition of
      the stone was acetyl sulphapyridine which was a metabolite of
      salazosulphapyridine. After maintenance of the urinary pH ranges between 6.5 and
      7.5 by medication of sodium bicarbonate, the patient remains free of stone for 3
      years. Drug induced urolithiasis originated from salazosulphapyridine is
      extremely rare. Satisfactory oral fluid intake and urinary alkalization are
      important for prevention of sulpha drugs calculi of urinary tract.

PMID- 10349306
TI  - [A case report of urinary tract infection and meningitis caused by methicillin
      resistant Staphylococcus aureus (MRSA) after transurethral resection of the
      prostate].
AB  - We present a case of meningitis that developed following a urinary tract
      infection caused by methicillin-resistant Staphylococcus aureus (MRSA) after
      transurethral resection of the prostate. The patient, a 69-year-old man with
      diabetes mellitis, underwent transurethral resection of the prostate following a
      diagnosis of benign prostatic hypertrophy. On the 4 th day after surgery, high
      fever occurred immediately after the removal of the indwelling urethral catheter.
      Cultures of urine and blood revealed MRSA. On the 6 th day after surgery, severe
      lumbago was evident and MRSA was isolated from cerebrospinal fluid. Separate
      administration of arbekacin or vancomycin, to which the isolated MRSA was
      sensitive, was not effective. Combined therapy with fosfomycin, vancomycin and
      human immunoglobulin effectively relieved the inflammation. Although it is
      generally reported that the pathogenicity of MRSA is low in the urinary tract,
      this case suggests that a urinary tract infection caused by MRSA can advance to
      sepsis and meningitis.

PMID- 10349307
TI  - [Evaluation of blood flow in transplanted kidney by flow profile].
AB  - BACKGROUND: The clinical usefulness of color Doppler method with flow profile for
      examination of blood flow in the transplanted kidney was evaluated. PROCEDURE: We
      measured blood flow in the transplanted kidney by flow profile in 14 renal
      recipients. RESULTS: Blood flow in the renal arteries in recipients with graft
      dysfunction was significantly lower than those in recipients with good graft
      function. There was significant correlation between blood flow in the renal
      arteries and graft function. In addition, in the segmental arteries, there was
      significant correlation between peak flow velocity and blood flow. But there was
      no significant correlation between index of resistance and blood flow in the
      transplanted kidney. CONCLUSIONS: Measurement of blood flow by flow profile may
      improve the examination capability of color Doppler ultrasonography of the
      transplanted kidney.

PMID- 10349308
TI  - [CT diagnosis of hyperdense intracranial neoplasms: review of the literature].
AB  - In contrast to typical astrocytic tumors that show hypodense areas on computed
      tomographic images, some intracranial tumors show hyperdense areas on CT images.
      The major reasons for hyperdensity on CT images are hypercellular lesions,
      intratumoral calcification, and intratumoral hemorrhage. Malignant lymphomas,
      germinomas, and medulloblastomas show homogeneous hyperdensity on CT images
      because of their hypercellularity. Tumorous lesions such as subependymal giant
      cell astrocytomas, oligodendrogliomas, ependymomas, central neurocytomas,
      craniopharyngiomas, and meningiomas often present with hyperdense calcified
      lesions on CT images. Intratumoral hemorrhage also causes hyperdensity on CT
      images, and is often associated with metastatic brain tumors, glioblastomas,
      pituitary adenomas, and rarely with any of the other intracranial tumors.
      Although magnetic resonance imaging is now the major diagnostic tool for diseases
      of the central nervous system, the first imaging studies for patients with
      neurologic symptoms are still CT scans. Hyperdense areas on CT images are a clue
      to making an accurate diagnosis of intracranial neoplasms.

PMID- 10349309
TI  - [Computed tomography of brain infarct with special reference to vascular
      territories and collateral pathways].
AB  - The essential approach to CT diagnosis is to evaluate precise radiological
      findings. However, in some cases, other additional information may play an
      important role in the detection of disease itself. In brain infarct, this can
      include clinical symptoms, the hemodynamics of cerebral circulation, and other
      factors. From this point of view, the normal vascular territories of the brain
      and collateral pathways in cerebral stenotic or occlusive vascular diseases are
      described, and representative cases are presented.

PMID- 10349310
TI  - [Diagnosis of breast cancer extent and enhancement patterns using 3D-dynamic MR
      imaging: correlation with intraductal component].
AB  - The usefulness of 3D-dynamic MR imaging with fat suppression and magnetization
      transfer contrast for assessing breast cancer extent and tumor profile was
      evaluated in 74 breasts with 67 malignant and 7 benign lesions. We classified
      breast cancer by the intraductal component of the main tumor. Five histological
      types were assigned: type 1 (DS 0) invasive carcinoma without intraductal
      component, type 2 (DS 1): intraductal component is less than 50% of whole tumor,
      type 3 (DS 2): intraductal component is nearly equal to 50%, type 4 (DS 3):
      intraductal component is more than 50%, type 5 (DS 4): pure DSIC or DCIS
      associated with microinvasive foci. Histologic results and preoperative MR
      imaging were analyzed regarding tumor size and enhancement pattern for the
      various tumor types (DS 0, 1, 2, 3 and 4). The three tumors occult to MR imaging
      were two DCIS and one Paget's disease. The other 64 breast cancers were detected
      on MR imaging. Tumor size measured with MR imaging correlated closely with
      histologic measurement in DS 0, 1 and 2, whereas less accuracy was noted in DS 3
      and 4. Rapid enhancement was frequently seen in DS 0, 1, 2 and 3. Peripheral
      enhancement was highly specific for breast cancer. However, peripheral
      enhancement was not found in all cases of DS 4. Linear and nodular enhancement
      was frequently seen in DS 3 and 4. MR imaging was useful in predicting the
      intraductal component.

PMID- 10349311
TI  - [Reexamination of hepatic falciform artery: angiographic study].
AB  - Supraumbilical skin complication during hepatic artery infusion chemotherapy or
      transcatheter arterial chemoembolization (TACE) for liver tumor has been reported
      by some authors. This complication is thought to be caused by the flow of
      chemotherapeutic, agent and embolus into the hepatic falciform artery (HFA). It
      is important for angiographers to be aware of the presence of HFA to prevent
      possible supraumbilical skin complication. The rate of visualization of the HFA
      on angiography has been considered to be only about 2%. In a retrospective study
      of celiac angiograms performed in 200 patients, we found an incidence of 32/200
      (16%). The proximal side of this artery may be tortuous. In all cases, the flow
      of the HFA is slower than that of the hepatic artery. The paraumbilical vein was
      visualized with the HFA in 18 cases. Chemotherapy or transcatheter arterial
      chemoembolization was performed in 10 patients, and there was no postprocedure
      supraumbilical skin complication.

PMID- 10349312
TI  - [Linac-based stereotactic radiosurgery for arteriovenous malformations (AVMs) in
      brain: estimation for efficacy of therapeutic response using angiography].
AB  - The purpose of this study was to determine whether it is possible to predict the
      efficacy of therapeutic response to linac-based stereotactic radiosurgery for
      AVMs on the basis of the stagnation rate in the nidus, which was defined as
      follows: [(pooling time of contrast material in the nidus of AVM)/ (intracranial
      circulation time)] x 100. Cerebral angiograms of twenty-five AVMs were
      retrospectively evaluated, and the stagnation rates in the nidus were calculated
      before and one year after stereotactic radiosurgery. Reduction rate was also
      calculated by using angiography, and we statistically evaluated the relationship
      between the stagnation rates in the nidus and the reduction rates. The stagnation
      rates in the nidus prior to linac-based stereotactic radiosurgery were positively
      correlated with the reduction ratios of AVMs after stereotactic radiosurgery (r =
      0.406, p = 0.0432). Our study suggested that a higher stagnation rate in the
      nidus of the AVM might be obliterated faster after linac-based stereotactic
      radiosurgery. Thus, calculation of the stagnation rate in the nidus before
      stereotactic radiosurgery is useful in predicting the efficacy of therapeutic
      response to linac-based stereotactic radiosurgery for AVMs.

PMID- 10349314
TI  - [Minimum intensity projection image and curved reformation image of the main
      pancreatic duct obtained by helical CT in patients with main pancreatic duct
      dilation].
AB  - Contrast enhanced CT was performed in seven patients with pancreatic disease
      (chronic pancreatitis, n = 3; pancreatic head cancer, n = 2; mucin-producing
      pancreatic tumor, n = 2) who showed dilation of the main pancreatic duct (MPD)
      Minimum intensity projection (Min-IP) images of the pancreas were obtained using
      multi-projection volume reconstruction (MPVR) software by selecting an oblique
      slab that contained the entire MPD. Curved reformation (CR) images were obtained
      using multiplanar reformation (MPR) software by tracing the MPD on the Min-IP
      image. Both Min-IP images and CR images clearly showed the dilated main
      pancreatic duct in all seven patients. In three of the seven, obstruction of the
      MPD in the pancreatic head and the cause of obstruction (tumor mass, n = 2;
      caliculus, n = 1) were also clearly seen. Min-IP and CR images seem to be useful
      for the diagnosis of pancreatic diseases.

PMID- 10349313
TI  - [Kinematic MRI using short TR single shot fast spin echo (SSFSE) in evaluating
      swallowing].
AB  - PURPOSE: To determine the utility of short TR single shot fast spin echo (SSFSE)
      MR imaging for evaluating swallowing. MATERIALS AND METHODS: Five healthy
      volunteers underwent kinematic MR imaging of swallowing with a 1.5T MR scanner
      using the short TR (300 ms) SSFSE sequence. Twenty phases of sagittal sections
      were acquired within 6 sec, where the temporal resolution was 300 ms. For oral
      contrast medium, we used prune yogurt juice with Fe added. RESULTS: The image
      contrast of short TR SSFSE was found to be somewhere like that of T1-weighted
      images. In all cases, both the buccal and pharyngeal stages of swallowing were
      successfully depicted. The Fe-added prune yogurt juice performed as a positive
      contrast medium and helped determine anatomical structures in the buccal stage.
      CONCLUSION: Short TR (300 ms) SSFSE was useful in evaluating swallowing. The
      combined use of Fe-added prune yogurt juice was helpful in enhancing the surface
      of the oropharynx.

PMID- 10349316
TI  - [Carotid atherosclerotic lesions in stroke patients with diabetes mellitus].
AB  - The aim of the study was to assess the incidence of atherosclerotic lesions on
      carotid arteries among diabetic subjects suffering from cerebrovascular accident.
      A further aim was to investigate the relationship between the severity of the
      carotid lesion, the stroke subtype and the fatal outcome. One hundred and sixty
      eight patients treated because of cerebrovascular accident at the Dept. of
      Neurology University Medical School of Debrecen were studied. The age of the
      patients, the duration of diabetes and hypertension were registrated. Base on
      duplex scanning carotid lesions were divided in 6 groups of severity (normal,
      intimal sclerosis, slight, moderately severe, severe stenosis and occlusion).
      Based on clinical signs and CT results stroke subtypes were divided into five
      groups (lacunar and non-lacunar infarctions, hemorrhages, normal CT and others).
      The relationship between severity of carotid lesions, stroke subtype and lethal
      outcome was assessed using statistical tests. Carotid stenosis of different
      severity was detected in 60% of the cases. Severity of stenosis was independent
      from duration of diabetes, but it was positively related to duration of
      hypertension (p = 0.016). In 1/3 of the patients lacunar strokes, in another 1/3
      non-lacunar strokes were observed. No significant relationship was found between
      severity of carotid stenosis, stroke subtype and lethal outcome of the patients
      (p = 0.53 and p = 0.26 respectively). Diabetic patients suffering from stroke
      have a higher incidence of carotid artery atherosclerotic lesions than diabetics
      without stroke. A special attention should be paid to the carotid duplex
      sonography in order to detect diabetic cerebral macroangiopathies in early,
      asymptomatic stage.

PMID- 10349315
TI  - [Family-centered obstetrics in Hungary].
AB  - The author has carried out a survey at hospitals in Hungary to examine how
      general family-centred obstetrics is, and to what extent obstetrics departments
      are able to meet the increasing demand for this exerted by society. In the course
      of the survey he focused on the characteristics of obstetrics departments, the
      preparation for delivery and maternity, open delivery-rooms, delivery with the
      partner, early mother-baby contact and rooming-in, and to what extent these
      operate. He describes the findings on the basis of data returned by 87 maternity
      departments, 81.3% of the total number of institutions in the country. The data
      reveals that 96.6% of wards have preparatory courses for delivery and maternity,
      98.8% of open-delivery rooms welcome the partner at the delivery, early mother
      baby contact is possible in 97.7% and 95.6% offer rooming-in. The study gives a
      comprehensive view of the present state of family-centred obstetrics offering an
      opportunity for everyone to re-evaluate their practices and to set up new
      objectives so that every mother and family can have easy access to family-centred
      obstetrics.

PMID- 10349317
TI  - [Skull base fractures in childhood. The role of CT in the accuracy of diagnosis].
AB  - The authors treated 51 patients suffering from basilar skull fractures between
      January 1995 and June 1997 following a newly initiated protocol. The
      effectiveness of recognizing these fractures increased to twice and a half after
      applying a complex (neurologic, otolaryngologic, ophthalmologic, X-ray and
      cranial CT) diagnostic examination. CT scans were performed at the slightest
      suspicion of basilar skull fracture since they provide far more information than
      the native skull X-ray. A close coherence was observed concerning clinical
      symptoms, potential complications and the manifested fractures, which helped to
      draw an exact therapeutical strategy and to prevent potential complications. The
      authors found X-ray gave satisfactory information only about fractures starting
      on the vault. In the studied period CT proved the basilar skull fracture in 40
      (78%) cases out of the total 51. X-ray did it in only 4 (8%) cases and raised the
      suspicion of the vault fracture spreading to the cranial floor in 20 (39%) cases.
      CT did not prove the clinically supposed basilar skull fractures in only 11 (22%)
      cases compared to 27 (53%) by X-ray. After having consultation with radiologists
      examination methods were always determined by the clinical picture and the
      available technical conditions (helical technique, multiplan or 3D
      reconstruction).

PMID- 10349318
TI  - [Therapeutic problems with HIV-infected tuberculous spondylitis patients in the
      South African Republic].
AB  - We can only hope, that the dual epidemic of tuberculosis and HIV disease is not
      going to affect the population of Europe and Hungary so badly and unexpectedly as
      it happened in sub-Saharan Africa. The spinal tuberculosis with or without
      paraplegia presents with increasing frequency and their management may differ
      from those without HIV infection. The success of antituberculotic drug therapy
      alone reduced the role of surgeons to a largely diagnostic one, however
      complications frequently require surgery.

PMID- 10349319
TI  - [Leukemic neutrophilic dermatosis].
AB  - A case of a 67 year-old female patient with acute myeloid leukemia is presented.
      As the first manifestation of the disease, the patient had symptoms of Sweet's
      syndrome, later signs of gangrenous pyoderma have developed. This transient form
      is termed as a "leukemic neutrophilic dermatosis". The authors focus on the
      important diagnostic and prognostic value of this entity.

PMID- 10349320
TI  - [Primary prevention of developmental abnormalities].

PMID- 10349321
TI  - [Analysis of the activity of neurologic intensive care units].
AB  - The authors analysed six-year activity of the intensive Care Unit of Department
      of Neurology, Medical University of Pecs (POTEI), and two-year activity of the
      Intensive Care Unit of Department of Neurology, Semmelweis University of
      Medicine, Budapest (SOTEI). Mortality at POTEI and SOTEI was 33.9% and 32.2%,
      respectively. Mean duration of stay of survivors at POTEI was 10 +/- 12.8 days,
      and 7 +/- 6.8 days at SOTEI; mean duration of care of the deceased patients at
      POTEI was 6.3 +/- 10.5 days, and 10 +/- 13.7 days at SOTEI. At POTEI 60.7%, at
      SOTEI 63% of the patients was admitted because of cerebrovascular insult.
      Mortality of patients with brain haemorrhage at POTEI and SOTEI was 53.4% and
      57.7% respectively. Mortality of the ischaemic group was 40.6% (POTEI) and 35.3%
      (SOTEI). In the group of intracranial tumours 44.4% mortality was recorded at
      POTEI and 47.6% at SOTEI. At POTEI 240 patients (15.9%), while at SOTEI 94
      patients (21%) were admitted to treat epileptic seizures. Among the 510 patients,
      who died within one month 284 patients (55.6%) were unconscious at admission.
      From those with coma due to severe structural lesion of the brain (brain
      ischaemia, bleeding, meningitis) only 15 patients survived. Among the 184
      patients, who were comatose and survived, the most frequent diagnosis was
      suicidal attempt with hypnotics (n = 67), metabolic encephalopathy (n = 19) and
      epilepsy (n = 12). At SOTEI among the 144 deceased patients 102 (70.8%) were
      unconscious at admission. Coma at admission proved to be a strong predictor of
      mortality. Mortality of the ventilated patients was 83% at POTEI and of those
      having subclavian catheter (n = 592) was 47.1%. In the acute phase of brain
      ischaemia at POTEI 39%, at SOTEI 10.7% of the patients received heparin. At SOTEI
      the cost of medication of patients who died after two weeks of care was 65.2%
      higher than that of the survived patients.

PMID- 10349322
TI  - [Hairy cell leukemia: authors' own experience (1977-1998)].
AB  - Hairy cell leukaemia (HCL) is a rare, clinically and haematologically well
      characterised entity. The prognosis of patients with hairy cell leukaemia has
      significantly improved due to the new therapeutic approaches. Development of
      diagnostic and therapeutic methods, together with the analysis of their own hairy
      cell leukaemia patients, is reviewed by the authors. Between 1977 and 1998 twenty
      five patients (16 male, 9 female) were treated. The malignant cells were usually
      analysed by morphological and cytochemical methods and recently flow cytometric
      analysis could be performed in eight patients. Splenectomy with lethal outcome in
      six patients was performed in 21 cases. Approximately one third of patients
      received interferon, while 2-chlorodeoxyadenosine was given only to three
      patients. Favourable experiences obtained by splenectomy and efficacy of
      interferon treatment are emphasised, but according to the literature and their
      own results administration of purine analogues can be highly recommended in the
      future.

PMID- 10349324
TI  - [Transbronchial catheterization: a method for outpatient angiographic
      examination].
AB  - The authors report on their own experiences with a not unknown, but not widely
      used catheter technique. On the basis of 607 transbrachial angiographies, they
      have established the possibilities and occasional dangers of this method. They
      conclude that the transbrachial technique is suitable not only for aortography,
      but also for selective angiography and vascular interventions. In cases involving
      cooperative patients, this method can furnish a basis for the angiography of
      outpatients.

PMID- 10349323
TI  - [Helicobacter pylori infection in diabetic patients].
AB  - The purpose of our research was to prove the occurrence of Helicobacter pylori
      infection in diabetic patients. Out of the 100 patients who were treated at the
      diabetological clinic, the antibody of Helicobacter pylori could be shown in 57
      patients. Through histological tests carried out in the course of upper
      panendoscopia of the patients having positive results of serological test,
      Helicobacter pylori infection could be actually proved in 39 cases. On the basis
      of the evaluated material of diabetic patients, the occurrence of Helicobacter
      pylori infection was not higher than that in of the average population. No
      connection has been found between the frequency of the infection, and type of
      diabetes or its duration. The eradicational treatment was successful with 85% of
      the patients.

PMID- 10349325
TI  - [History of the start and first decades of neurosurgery in Hungary].

PMID- 10349326
TI  - [The St. John Hospital is 100 years old].

PMID- 10349327
TI  - [Ophthalmologic implications in diabetes mellitus].

PMID- 10349331
TI  - [Possibilities of advanced education in phytotherapy].

PMID- 10349328
TI  - [Comment on the subject of cumulative incidence of pectus excavatum in the
      township of Tata in Hungary].

PMID- 10349332
TI  - [Therapy oriented neurology from repair to remedy].
AB  - In addition to the traditional preoccupation for accurate localization of
      lesions, a new trend in our discipline emphasizes therapeutic approaches to
      various neurological disorders. This review summarizes the result of multi-center
      trials that we personally participated during the past decade to present an
      overview of the current thought in the area of our interest. The disorders in
      question include dystonia, chronic inflammatory demeyelinating polyneuropathy,
      myoclonic epilepsy, diabetic polyneuropathy, amyotrophic lateral sclerosis, and
      experimental allergic neuritis. These results and other equally encouraging data
      suggest that we are not necessarily fighting a loosing battle in dealing with
      these incapacitating diseases, even though our effort often falls short of
      achieving a complete cure. In formulating a list of differential diagnosis, we
      must always entertain the possibility of remedy as the eventual goal of our
      clinical practice.

PMID- 10349333
TI  - [Analysis of neuronal connections in the basal ganglia].
AB  - Morphological features indicating occurrence of two types of extrasynaptic
      chemical transmission were observed within rat basal ganglia. (1) Striatonigral
      neurons containing substance P (SP) sent many axon collaterals equipped with
      axonal varicosities to the striatum: the varicosities displayed synaptophysin
      like immunoreactivity (-LI). However, only 15% of the varicosities appeared to be
      in close contact with structures showing SP receptor (SPR)-LI. Many of axon
      terminals of striatonigral neurons were confirmed electron microscopically not to
      be in synaptic contact with SPR-like immunoreactive structures within the
      striatum. SP released from the varicosities might, at least partly, diffuse to
      reach SPR at distance from the release sites. (2) Immunoreactivities for
      metabotropic glutamate receptors (mGluRs) 4 a, 7 a, 7 b and 8 were in axon
      terminals within the globus pallidus (external segment of the globus pallidus in
      primates). The immunoreactivities disappeared after destruction of the striatum,
      but not after destruction of the subthalamic nucleus. The immunoreactivity for
      mGluR 7 a was confirmed electron microscopically to be within axon terminals
      showing glutamic acid decarboxylase-LI. Glutamate released from glutamatergic
      subthalamopallidal neurons might partly spilled over from the synaptic sites to
      reach mGluRs on "nearby" axon terminals of GABAergic striatopallidal neurons.
      Functional significance of thalamostriatal and corticosubthalamic fibers was also
      discussed.

PMID- 10349334
TI  - [Recent advances in the studies on Alzheimer's diseases].
AB  - Recent progress on the molecular mechanisms on Alzheimer's disease has been made
      through discoveries of genes involved in the pathogenesis of Alzheimer's disease.
      Amyloid precursor protein (APP), presenilin I (PS 1) and presenilin II (PS 2)
      genes have been identified as the causative genes for early-onset familial
      Alzheimer's disease. Apolipoprotein E gene, which was originally identified as
      the gene for late-onset familial Alzheimer's disease, has now been established as
      a genetic risk factor for not only early-onset but also late-onset sporadic
      Alzheimer's disease. Recent studies suggest that mutations in APP, PS 1 or PS 2
      result in increased production of amyloid beta protein (A beta), a major
      constituent of senile plaques. Apolipoprotein E 4, which is a risk factor for
      Alzheimer's disease, has also been reported to be associated with increased
      density of senile plaques. Although these data suggest that accumulation of A
      beta is an essential step in the pathogenesis of Alzheimer's disease, it still
      remains to be elucidated whether such process is causative for Alzheimer's
      disease. Recently another gene on chromosome 12 has been suggested to be involved
      in the development of late-onset Alzheimer's disease, and identification of the
      gene on chromosome 12 may bring a new insight into the pathogenesis of
      Alzheimer's disease.

PMID- 10349335
TI  - [Recent progress in the research field on triplet repeat diseases].
AB  - At present, 8 inherited neurodegenerative disorders (e.g. Huntington disease,
      Machado-Joseph disease, etc.) are identified to be caused by the polyglutamine
      coding CAG triplet expansions in the responsible genes. These disorders commonly
      demonstrate dominant inheritance, if autosomal, and late onset of their
      manifestations. Interestingly, the longer expansions result in earlier onset and
      more severe clinical manifestations. Proteins containing expanded polyglutamine
      repeats appear to precipitate by self-aggregation, and as a result produce a core
      disease-related phenotype: neuronal cell death or degeneration. Given that
      polyglutamine aggregation might be central in neurodegeneration, the parameters
      that determine the feasibility of the polyglutamines to aggregate would determine
      the age of onset and the clinical severity. These parameters are postulated to be
      the concentration and the length of polyglutamines, which is supported by
      clinical and experimental observations. The stronger neuronal degenerations are
      always accompanied by the longer polyglutamine stretches and by the higher
      concentration of the expanded polyglutamines. In other neurodegenerative
      disorders, such as Alzheimer disease, prion disease, Parkinson disease and
      amyotrophic lateral sclerosis, precipitation of abnormal proteins is also now
      considered to play a key role. These observations might lead to the elucidation
      of universal mechanisms for neurodegeneration and to treatments effective for
      many neurodegenerative disorders.

PMID- 10349337
TI  - [Pathophysiology in muscle fiber necrosis and regeneration with a particular
      reference to regenerating process].
AB  - It is well known that muscle fiber is capable of regeneration after myonecrosis
      even in a case of muscular dystrophies. We first examined how and when the
      regulatory genes for myogenesis, MyoD and myogenin were expressed in
      experimentally induced myonecrosis. MyoD, a responsible gene for myoblast
      proliferation began to express at 18 hours and reached to the maximum level 48
      hours after necrosis. Myogenin known to play a role for myotube formation was
      most extensively expressed 72 hours after myonecrosis when the newly formed
      myotubes were recognizable, confirming that both genes were necessary for
      regenerating process. The MyoD and myogenin were also expressed in regenerating
      fibers in muscular dystrophies including dy mouse with progressive muscle
      weakness and mdx mouse with no apparent muscle symptom. The genes were more
      extensively expressed in mdx mouse, than dy mouse simply reflecting their
      respective regenerating activity.

PMID- 10349336
TI  - [Recent advance in neuroimmunology].
AB  - Many important reports have been published during these several years in Japan in
      the field of neuroimmunology. Serum vascular endothelial factor (VEGF) levels in
      Crow-Fukase (POEMS) syndrome were about 15 to 30 times than those in the control
      subjects and other neurological disorders. The overproduction of VEGF may be
      relevant to the pathogenesis of most of the manifestations including neuropathy.
      We speculate that VEGF may affect the blood nerve barrier by increasing
      microvascular hyperpermeability and thereby increasing endoneural pressure
      subsequent to edema. In Isaacs' syndrome, voltage-gated potassium channel (VGKC)
      were suppressed by anti-VGKC antibodies. The patch clamp study indicate that the
      pathophysiology of the suppression of VGKC seems to be due to the increased
      degradation of VGKC. By the recent nationwide survey, the total number of HTLV-I
      associated myelopathy (HAM) patients in Japan is now estimated as 1,432. A most
      likely pathological mechanism of HAM is that cytotoxic T lymphocytes attack the
      HTLV-I infected lymphocytes infiltrating the central nervous system, resulting a
      surrounding nervous tissue damage by bystander mechanism.

PMID- 10349338
TI  - [Recent advances in pathophysiology and treatment of acute ischemic stroke].
AB  - The pathophysiology of ischemic neuronal cell damage has been studied
      extensively. Intracellular calcium ions, excitatory amino acids, nitric oxide,
      oxygen free radicals, proteolysis, apoptosis, and so on play important roles.
      There are also gene expressions following cerebral ischemia, such as the
      immediately early gene, heat shock protein, cytokines, adhesion molecule, and
      growth factor, etc. In vessels of the ischemic brain, activation of platelets,
      leukocytes, the coagulation cascade, and fibrin generation occur and aggravate
      the cerebral microcirculatory disturbance. Treatment of acute ischemic stroke
      must be based on the clinical type (atherothrombotic, lacunar or cardioembolic)
      and the time after onset. Fibrinolysis by tissue plasminogen activator
      (intravenous administration) is approved in the USA for patients with cerebral
      infarction within 3 hours after onset. Efficacy of anticoagulant therapy using
      heparin was not verified by the International Stroke Trial (IST). In Japan
      selective anti-thrombin agent (argatroban) is used in patients with
      atherothrombotic cerebral infarction within 48 hours after onset. Results of IST
      and Chinese Acute Stroke Trial (CAST) showed aspirin within 48 hours after onset
      of cerebral infarction reduced recurrence of ischemic stroke during the acute
      stage and death within 6 months.

PMID- 10349339
TI  - [Chemical neuroanatomy of cholinergic neurons].
AB  - Acetylcholine (ACh), the first neurotransmitter to be discovered from the frog
      heart, is distributed widely in both the central and peripheral nervous systems.
      In the brain, for example, ACh plays important roles in several higher functions
      such as memory and learning. In peripheral organs, ACh has been shown to be a
      neurotransmitter in spinal motoneurons, all autonomic preganglionic neurons, all
      parasympathetic postganglionic neurons, and an exceptional sympathetic
      postganglionic neurons innervating the sweat gland. There has been, however, no
      good method to visualize ACh in tissues and organs. So far, immunohistochemistry
      for its synthetic enzyme choline acetyltransferase (ChAT: E. C. 2. 3. 1. 6) has
      been used as the most reliable marker for morphological studies of cholinergic
      neurons. Despite the fact that most antibodies against ChAT clearly stain central
      cholinergic systems, they have poor ability to detect peripheral cholinergic
      systems. We found that there are two types of ChAT expressed in the rat
      pterygopalatine ganglion. One is identical to the ChAT in the brain, and another
      (pChAT) lacks exons 6, 7, 8, and 9. The peripheral cholinergic system is now
      clearly demonstrated by immunohistochemistry using our antiserum raised against
      the recombinant pChAT.

PMID- 10349340
TI  - [Neuroimaging of motor disturbances].
AB  - High-field MRI has given us a great impact in the clinical diagnosis of various
      motor disturbances, because the structural abnormalities of the pyramidal tract,
      basal ganglia and cerebellum are easily observed with this technique. In case of
      lower motor neuron disease without clinical upper motor neuron sign, proton
      density-weighted image of the internal capsule and cerebral peduncle is useful
      for detecting the latent pyramidal tract degeneration. Differential diagnosis of
      parkinsonism is one of the most successful examples of the clinical use of high
      field MRI. Postero-lateral putaminal T2-hypointensity which has been reported to
      be diagnostic for multiple system atrophy (MSA) might be seen in the aged normal
      subjects, whereas the proton density weighted image of the normals revealed no
      abnormal change in signal intensity. In MSA, not only T2-weighted but also proton
      density image show marked hypointensity in posterior part of putamen. Proton
      density image of pons, moreover, reveals "four of dice sign" representing the
      degeneration of the pontine transverse fibers. Another pathological condition
      which could be differentiated from PD with MRI is PSP. Characteristic "humming
      bird sign" of the mid brain on the mid-sagittal section is thought to represent
      the atrophy of the rostro-dorsal mid-brain tegmentum, where the vertical gaze
      centers are located. MRI is also useful for differentiating the pathological
      processes of cerebellar atrophies. Cortical cerebellar atrophy with loss of
      Purkinje cells shows the disappearance of T2-hypointensity of dentate nucleus,
      while cerebellipetal atrophy like olivopontocerebellar atrophy causes T2
      hyperintensity of cerebellar white matter making dentate hypointensity more
      conspicuous. Degeneration of the dentate neucleus is revealed by the T2
      hyperintensity of dentate contour associated with atrophy of superior cerebellar
      peduncle at the level of rostral pons.

PMID- 10349341
TI  - [Atrophy and magnetization transfer ratio of the corpus callosum in patients with
      Alzheimer's disease].
AB  - We compared atrophy and magnetization transfer ratio (MTR) in the corpus callosum
      in patients with Alzheimer's disease and age-matched normal subjects. Fifteen
      patients with Alzheimer's disease and fourteen normal subjects received MRI. The
      corpus callosum was divided into three parts (anterior, middle, and posterior
      portions) on midsagittal slice, and their areas on T2-weighted reversed images
      and MTR on magnetization transfer contrast images in each portion were measured.
      The area and MTR decreased significantly in the posterior portion in patients
      with Alzheimer's disease. In the anterior portion, MTR decreased significantly,
      but although the area showed no significant change. In the middle portion, the
      area and MTR showed no significant change. MTR and the area was correlated in
      each portion in patients with Alzheimer's disease. The score of Hasegawa dementia
      scale-revised (HDS-R) and the area of the middle, posterior and total of corpus
      callosum were significantly related. The score of HDS-R and MTR in the anterior
      portion of corpus callosum were significantly related. The present study revealed
      decreases in MTR in the anterior portion of the corpus callosum of patients with
      Alzheimer's disease although the area showed no significant change, and this
      change suggests the increase in free water and/or the decrease in bound water in
      tissues, probably due to demyelination and axonal degeneration.

PMID- 10349342
TI  - [Effects of excitatory sulfur amino acids on glutamate transport in synaptosomes
      isolated from the rat cerebral cortex].
AB  - Transport of glutamate, the disturbance of which has been implicated in
      amyotrophic lateral sclerosis (ALS), may be influenced by various substances.
      Excitatory sulfur amino acids (SAAs) could be increased in ALS, because the
      elevation of taurine, the final product of the metabolic pathway of SAAs, has
      been reported in this intractable disease. I examined effects of excitatory SAAs
      on the transport of glutamate in synaptosomes. Synaptosome fractions were
      prepared by discontinuous density-gradient centrifugation from the rat cerebral
      cortex, and were incubated at 35 degrees C with varying concentrations of L-[3H]
      glutamate in the absence or presence of excitatory SAAs; cysteine sulfinic acid
      (CSA), cysteic acid (CA), homocysteine sulfinic acid (HCSA), homocysteic acid
      (HCA) and S-sulfocysteine (SC). Kinetic characterization of uptake confirmed the
      high-affinity nature of the transport system, the Michaelis constant (Km) for
      glutamate uptake being 10 microM. The nature of inhibition was competitive.
      Potent inhibition of transport was exhibited by CSA and CA, whereas substantially
      weaker inhibitory effects were exhibited by HCSA, and almost no effects by HCA or
      SC. Inhibition by excitatory SAAs, especially CSA and CA of the high-affinity
      glutamate transporter may be involved in the pathogenesis of ALS.

PMID- 10349343
TI  - [Apoptosis induced by excitatory sulfur amino acids in primary cultured rat
      immature cerebral neurons].
AB  - In the neural tissue of patients with amyotrophic lateral sclerosis (ALS), the
      elevation of taurine, the final product of the metabolic pathway of sulfur amino
      acids (SAAs), has been reported, suggesting that excitatory SAAs, the
      intermediates of this pathway, could also be increased. This study was undertaken
      to evaluate whether excitatory SAAs have the ability to inhibit cystine uptake.
      Since immature neurons have not yet expressed the receptor channels, they are not
      susceptible to excitotoxicity. Inhibition of cystine transport leads to a
      depletion of glutathione, and results in cell death due to oxidative stress. Cell
      cultures were obtained from the cerebral cortex of fetal Wistar rats.
      Cytotoxicity studies were performed 48 hours after plating by addition of the
      culture medium containing SAAs; cysteine sulfinic acid, cysteic acid,
      homocysteine sulfinic acid (HCSA), homocysteic acid (HCA) and S-sulfocysteine.
      Cell death was quantified by the release of the cytosolic enzyme lactate
      dehydrogenase, and single cell assessment of apoptosis was carried out by
      staining cells with acridine orange, DNA isolation and agarose gel
      electrophoresis were also performed. Protection of cycloheximide, a protein
      synthesis inhibitor, against non-receptor mediated excitatory SAA cytotoxicity
      was also assessed. HCA and HCSA showed cytotoxicity, the morphology and
      biochemistry of which were compatible to apoptosis. It will be a subject for
      future study to examine whether this mechanism of cell death is primarily present
      in ALS.

PMID- 10349344
TI  - [Clinico-MRI study of hemispheric disorder in long-term follow-up cases of
      multiple system atrophy].
AB  - Twelve cases of multiple system atrophy (MSA) were studied for clinical and MRI
      findings of the cerebral hemispheric involvement. The subjects consisted of five
      olivopontocerebellar atrophy (OPCA) type and seven striatonigral degeneration
      (SND) type. The age at onset was 56.7 +/- 8.0 (M +/- SD) years, duration of
      illness at the first MRI study 3.2 +/- 1.1 years, duration of illness at the last
      study 8.1 +/- 2.2 years, and the following up duration 4.9 +/- 2.0 years. The
      grasping phenomenon was observed in 70% of the cases examined, snout reflex in
      80%, slowness of verbal response in 88%, and decrease of spontaneous speech in
      100%. Three cases finally fell into the state of mutism. Three out of ten cases
      were categorized as dementia by HDS-R (Hasegawa Dementia Scale-Revised) test.
      Besides the progression of the pontocerebellar atrophy and putaminal changes, MRI
      study revealed progressive frontal lobe atrophy in most cases. At six years after
      the onset, SND type showed significantly higher incidence of conspicuous frontal
      lobe atrophy and dilatatation of the Sylvian fissure than OPCA type. Cerebral
      ventricular dilatation was common feature, and atrophy of the temporal and
      occipital lobes were observed in several cases. We indicated the possible
      involvement of the cerebral hemisphere, especially the frontal lobe, and higher
      nervous function in MSA.

PMID- 10349345
TI  - [A case of hereditary motor and sensory neuropathy with pyramidal tract sign,
      optic nerve atrophy and mental retardation].
AB  - The patient was a 61-year-old man who suffered from gait disturbance since
      childhood. He also had mental retardation. Gait disturbance was slowly
      progressive. His mother, sister, brother and son of his sister suffered from gait
      disturbance. On neurological examination, he showed mental retardation, optic
      nerve atrophy and neural deafness. He also showed severe muscle atrophy and
      weakness of bilateral lower limbs associated with pes cavus. Muscle tonus of
      lower limbs and patellar tendon reflex were increased bilaterally. Achilles
      tendon reflex was absent. Babinski and Chaddock signs were positive. Superficial
      and deep sensations were almost normal. There were no cerebellar signs. Blood
      chemistry was normal. On nerve conduction studies, motor nerve conduction
      velocity of the upper limbs was normal and that of the posterior tibial nerve was
      decreased; right 36.0m/sec, left 29.7m/sec. Sensory nerve conduction velocity of
      the median nerve was slightly decreased; right 36.5m/sec, left 45.2m/sec and
      sural nerve did not respond to electric stimuli. On sural nerve biopsy, the
      density of myelinated fibers was severely decreased. Onion bulb formation was not
      observed. We classified this case as hereditary motor and sensory neuropathy
      (HMSN) type II based on nerve conduction studies and findings from sural nerve
      biopsy. HMSN with pyramidal tract sign has been classified as type V and HMSN
      with optic nerve atrophy as type VI. This case had characteristic symptoms as
      type V and VI. Histopathological findings of HMSN type V and VI have not been
      established yet. This case might provide an important clue for classification of
      HMSN.

PMID- 10349346
TI  - [A case of multiple sclerosis associated with myelin associated glycoprotein
      neuropathy].
AB  - A 28-year-old woman had developed chronic, recurrent, visual disturbance
      (bilateral), and girdle sensation at Th 5-6. She was admitted to our hospital
      because of left visual disturbance, distal limb weakness on right side, and
      numbness of four extremities. The neurological examination revealed decreased
      visual acuity of the left eye with abnormality of the optic disk, moderate muscle
      weakness of the right upper and lower extremities, absent tendon reflexes and
      paresthesia on distal portions of the four limbs. Laboratory examinations
      disclosed the titration of anti-myelin associated glycoprotein (MAG) antibody
      (IgM) and CSF protein was elevated (104 mg/dl). Motor nerve conduction studies
      revealed conduction block in more than one nerve. The conduction velocities in
      the upper and lower extremities were all diminished. P100 latency was prolonged
      by flash visual evoked potential (VEP) studies. N13-N20 interpeak latency of
      somatosensory evoked potential (SEP) of median nerve was also prolonged. She was
      treated with steroid pulse therapy, followed by an oral dose of 30 mg/day of
      prednisolone. Her symptoms resolved completely three months later, and multifocal
      conduction block subsided on electrophysiological study. There are some cases of
      multiple sclerosis with multifocal conduction block, but such a case is very rare
      in Japan. We discussed the pathogenic mechanisms of these conditions, and we
      conclude that we must take notice of demyelinating neuropathy in multiple
      sclerosis and that nerve conduction studies are useful for detecting them.

PMID- 10349347
TI  - [An autopsy case of Degos' disease with ascending thoracic myelopathy].
AB  - Degos' disease is a rare multisystem vasculopathy of unknown etiology. We report
      a 44-year-old man who presented himself with gait and sensory disturbances mainly
      due to thoracic transverse myelopathy four years after the appearance of many
      characteristic umbilicated papules over the trunk and extremities. He did not
      complain of abdominal pain or discomfort. Laboratory, electrophysiological and
      imaging studies did not show any characteristic change, except for the increase
      of protein contents and cell counts in the cerebrospinal fluid. We tried
      methylprednisolone pulse-dose therapy (1,000 mg/day x 3 days) five times, but
      this patient's neurological condition worsened stepwise after it, although the
      appearance of new skin lesion was suppressed. Intravenous infusion of ozagrel
      sodium and cyclophosphamide (1,000 mg/day) were also ineffective, and this
      patient died of respiratory failure after showing oculomotor paresis and comatose
      state. Necropsy revealed Degos' disease-specific vasculopathy in the central
      nervous system and the gastrointestinal tract, where occlusions of small-sized
      arteries and veins due to the intimal thickening were evident. The tissue
      necrosis was macroscopically remarkable in the brainstem and the thoracic spinal
      cord. The efficacy of steroid therapy for this disease should be investigated
      more carefully.

PMID- 10349348
TI  - [A survival case of fulminant pneumococcal meningitis as overwhelming
      postsplenectomy infection (OPSI) syndrome].
AB  - A 39-year-old female, who had splenectomy for idiopathic thrombocytopenic purpura
      (ITP) in 1988, was admitted to our hospital with high fever, headache, and loss
      of consciousness on November 29,1997. Neck stiffness and Kernig's sign were
      present. Examination of cerebrospinal fluid showed pleocytosis up to 506
      cells/mm3 with 89% of polymorphonuclear cells and elevated protein to 1,135
      mg/dl, and absence of glucose, Streptococcus pneumoniae phagocytosis was detected
      in the fluid. We diagnosed her as having pneumococcal meningitis as overwhelming
      postsplenectomy infection (OPSI) syndrome. After administration of dexamethasone
      (8 mg/day), cefotaxime (4 g/day), and ampicillin (6 g/day), she survived without
      any complications. Splenectomized patients have been recognized as
      immunocompromized hosts, and carry high morbidity and mortality risk from
      fulminant bacterial infections. Therefore, emergency treatment is important to
      reduce high mortality in such infections. We present an adult case of OPSI
      syndrome which occurred as pneumococcal meningitis, and we would like to
      emphasize the importance of prompt use of corticosteroids and high dose of
      sensitive antibiotics before DIC may occur during the course of illness.

PMID- 10349349
TI  - [Effective nasal CPAP therapy for heavy snoring and paradoxical respiration
      during sleep in a case of multiple system atrophy].
AB  - A 64-year-old man with multiple system atrophy complained of daytime sleepiness,
      fatigue, and snoring. Neurological examination revealed severe autonomic failure,
      mild cerebellar ataxia and akinesia. Daytime blood gas analysis showed
      respiratory acidosis with hypoxia and hypercapnia. MR imaging of the brain showed
      atrophy of the pons, cerebellum and bilateral frontal lobes. Although paralysis
      of the vocal cord abduction was not found by laryngoscopy during daytime
      examination, polysomnography (PSG) showed heavy snoring with paradoxical
      respiration associated with severe desaturation during sleep as well as reduced
      slow wave sleep and REM sleep. He was diagnosed as having sleep-related upper
      airway obstructive breathing disorder probably due to Gerhardt syndrome.
      Tracheostomy was considered, but we performed nasal CPAP therapy during sleep
      because this therapy is non-invasive and would not impair his daily life. After
      nasal CPAP therapy, daytime sleepiness, fatigue, and snoring with desaturation
      improved, and PSG showed increased slow wave sleep. These results demonstrate
      that nasal CPAP therapy improves the quality of sleep and should be considered in
      patients with early stages of multiple system atrophy who exhibit sleep-related
      breathing disorders.

PMID- 10349350
TI  - [A case of chronic inorganic mercury poisoning with progressive intentional
      tremor and remarkably prolonged latency of P300].
AB  - A 59-year-old man showed slowly progressive intentional tremor for 40 years prior
      to first visit to us in 1996. He was exposed to mercury vapor for about 3 years
      (1956-1959) and the diagnosis of chronic inorganic mercury poisoning was made.
      Hasegawa dementia scale-revised (HDS-R), mini-mental state (MMS) examination and
      P300 examination were performed. HDS-R and MMS were within normal range but the
      latency of P300 was remarkably prolonged. His tremor was considered to be due to
      chronic inorganic poisoning because there were no other causes and the frequency
      of his tremor was 3-4 Hz. which was lower than that in essential tremor. The
      prolonged P300 latency was also considered to be due to the same cause because
      there were no other causes and the head MRI were normal. Chronic inorganic
      mercury poisoning has been reported to produce organic changes in the brain and
      P300 is considered to be useful to detect these changes.

PMID- 10349351
TI  - [A case of musicogenic epilepsy induced by listening to an American pop music].
AB  - This is the second report of musicogenic epilepsy in Japan. A 23-year-old woman
      was admitted to our hospital due to the musicogenic epilepsy. She had four
      generalized tonic clonic seizures at 18 and 19 years old. Since 19, she had had
      complex partial seizures lasting for about 20 seconds which was easily evoked by
      listening to an American pops particularly "Dreamlover" song by Mariah Carey.
      Brian MRI and interictal 99mTc HMPAO-SPECT showed no abnormalities. In the ictal
      EEG recording, three minutes after listening to the song, seizure activities were
      recorded from the right temporal region with 11Hz rhythmic epileptiform
      activities over the right temporal region and subsequent delta activities over
      the right hemisphere. The song that induced the seizure had a specific meaning
      that might evoke her emotion as had been pointed out in the previous reports.

PMID- 10349352
TI  - [An adult case of peripheral facial nerve palsy following acute cerebellitis
      associated with high antibody titers against varicella-zoster virus].
AB  - Here we report a case of acute cerebellitis, in which the patient developed right
      peripheral facial palsy during the recovery phase of cerebellar ataxia. A 67-year
      old man developed truncal and limb ataxia following a fever, general fatigue and
      anorexia. He was diagnosed to have acute cerebellitis. While the ataxia symptoms
      were improving without any treatment, right peripheral facial nerve palsy
      developed and an MRI revealed an enhancement of the right facial nerve proximal
      to the geniculate ganglion. After treatment with acyclovir and corticosteroids,
      his facial nerve palsy and ataxia both gradually improved. There has been no
      previous report of an adult case who developed peripheral facial nerve palsy
      during the recovery phase of acute cerebellitis. This case indicates that a wide
      spectrum of neurological complications may develop in association with a
      varicella-zoster virus infection.

PMID- 10349353
TI  - [Bilateral horizontal gaze palsy due to brainstem encephalitis].

PMID- 10349354
TI  - The perils of outperformance: sensitivity about being the target of a threatening
      upward comparison.
AB  - Outperforming others, although privately satisfying, can be a source of
      interpersonal strain. This article presents the framework of a major form of
      outperformance-related distress, which we label sensitivity about being the
      target of a threatening upward comparison (STTUC). To become STTUC, an individual
      must believe that another person is making an upward comparison against the self
      and feels threatened by the contrast in status. The outperformer must also
      experience concern about some facet of the other's response, and this concern may
      be focused on the other, the self, or the relationship. In addition to offering
      new predictions about outperformance-related distress, the STTUC framework unites
      many previously disconnected findings on topics such as fear of success, envy,
      self-presentation, and self-evaluation maintenance.

PMID- 10349356
TI  - Pain demands attention: a cognitive-affective model of the interruptive function
      of pain.
AB  - Pain interrupts and demands attention. The authors review evidence for how and
      why this interruption of attention is achieved. The interruptive function of pain
      depends on the relationship between pain-related characteristics (e.g., the
      threat value of pain) and the characteristics of the environmental demands (e.g.,
      emotional arousal). A model of the interruptive function of pain is developed
      that holds that pain is selected for action from within complex affective and
      motivational environments to urge escape. The implications of this model for
      research and therapy are outlined with an emphasis on the redefinition of chronic
      pain as chronic interruption.

PMID- 10349355
TI  - Reading skills in hyperlexia: a developmental perspective.
AB  - Hyperlexia is characterized by advanced word-recognition skills in individuals
      who otherwise have pronounced cognitive, social, and linguistic handicaps.
      Language, word recognition, and reading-comprehension skills are reviewed to
      clarify the nature and core deficits associated with the disorder. It is
      concluded that hyperlexia should be viewed as part of the normal variation in
      reading skills, which are themselves associated with individual differences in
      phonological, orthographic, and semantic processing, short-term memory, and print
      exposure. A compulsive preoccupation with reading may also be crucial to the
      development of a hyperlexic reading profile. A theoretical framework, based on
      recent connectionist models of reading development, is described. This
      perspective provides a satisfactory account for how individual differences in a
      number of different skills can lead to a variety of manifestations of reading
      behavior, including hyperlexia.

PMID- 10349357
TI  - Clinical cytology as cytology in the clinical setting.

PMID- 10349359
TI  - Triple test approach to inadequate fine needle aspiration biopsies of palpable
      breast lesions.
AB  - OBJECTIVE: To perform a retrospective study evaluating the triple test for
      inadequate fine needle aspiration (FNA) biopsies of palpable breast lesions with
      a two-year clinical follow-up. STUDY DESIGN: All aspirates were reviewed and
      assessed for cellular adequacy in a one-year period. Specimen adequacy was based
      on the most stringent criteria, the presence of six or more epithelial cell
      clusters composed of at least six cells each. In all cases, clinical and
      radiologic results were reviewed and compared with the histologic outcome.
      RESULTS: Aspirates from 61 of 263 (23%) patients with palpable breast lesions
      that yielded nondiagnostic results were examined. The study showed a misdirected
      FNA rate of 21% and a misinterpreted rate of 1.6%. The other 77% of cases had
      benign surgical biopsies and/or clinical follow-up. Three of 61 (4.9%) cases with
      nondiagnostic smears were found to have cancer; two were inadequate due to
      misdirected aspirates, and one was misinterpreted microscopically. All cancer
      cases underwent surgical removal of the mass as a result of clinical or
      radiologic suspicion. CONCLUSION: We recommend utilizing the three diagnostic
      parameters of cytology, clinical findings and radiology, the "triple test," to
      achieve the best diagnostic accuracy in breast FNAs and to enhance patient
      management.

PMID- 10349358
TI  - Fine needle aspiration cytology in the management of male breast masses. Nineteen
      years of experience.
AB  - OBJECTIVE: To determine the utility and accuracy of fine needle aspiration
      cytology (FNAC) as well as its sensitivity, specificity and predictive value in
      the diagnosis of male breast masses. STUDY DESIGN: Data on male breast FNAC done
      between 1978 and 1997 were retrieved from the records of the cytopathology
      laboratory. FNAC diagnoses were categorized as positive, negative, inconclusive
      or unsatisfactory. Cytohistologic correlation was done with data from
      histopathology records. Sensitivity, specificity, diagnostic accuracy and
      predictive values of FNAC were calculated using standard statistical methods.
      RESULTS: Five hundred seven of 13,175 patients undergoing breast FNAC were males.
      Of them, 393/507 had satisfactory aspirates. Of these, 70 were positive (13.8%),
      295 were negative (58%), and 29 were inconclusive (5.7%). A total of 114 FNACs
      (22.5%) were unsatisfactory. Histopathology was available in 97/507 cases. There
      were no false positive or false negative diagnoses. FNAC had a sensitivity,
      specificity and diagnostic accuracy of 100% for male breast lesions. CONCLUSION:
      This large study shows that FNAC is a very accurate tool for diagnosis of male
      breast lesions. It is highly sensitive and specific, with good cytohistologic
      correlation. FNAC should therefore be an integral part of the primary assessment
      of breast lumps in males.

PMID- 10349360
TI  - False negative rate of cervical cytologic smear screening as determined by rapid
      rescreening.
AB  - OBJECTIVE: To determine the reliability of the false negative rate (FNR) of
      cervical cytologic smear screening by rapid rescreening. STUDY DESIGN: A test set
      of 401 cases (311 originally diagnosed as negative, 74 as atypical squamous cells
      of undetermined significance [ASCUS], 14 as low grade squamous intraepithelial
      lesion [LSIL] and 2 as high grade squamous intraepithelial lesion [HSIL]) were
      rapidly (30 seconds each) rescreened by five cytotechnologists with no prior
      experience in rapid rescreening, and the FNRs of rapid rescreening and primary
      screening were determined. These results were compared with each other and with
      the FNR of primary screening as determined by routine rescreening of all cases
      with no time limit. RESULTS: All five observers detected a different group of
      abnormal cases; only 9% of all cases originally diagnosed as ASCUS or worse and
      43% of all cases diagnosed as LSIL or worse were detected by all five observers.
      Nevertheless, using ASCUS as the threshold for an abnormal result, the FNR of
      rapid rescreening fell into a relatively narrow range, 61-74% (mean, 68.2 +/-
      5.0); using LSIL as the threshold resulted in FNRs of rapid rescreening between
      25% and 38% (30.0 +/- 4.7). Each observer, using rapid rescreening, detected
      between one and three false negative cases; routine rescreening of all cases
      without a time limit detected five cases. The FNR of cervical cytologic smear
      screening, as determined by rapid rescreening, was 18.4 +/- 6.1% as compared with
      14.8% by routine rescreening without a time limit. CONCLUSION: The FNR of rapid
      rescreening is relatively reproducible even though the individual cases
      identified varied between reviewers. The FNR of rapid rescreening is similar to
      that of routine rescreening. Rapid prescreening may be the most logistically
      simple method to determine the true FNR of a laboratory.

PMID- 10349361
TI  - Atypical glandular cells of undetermined significance on cervical smears. A study
      with cytohistologic correlation.
AB  - OBJECTIVE: The incidence of endocervical adenocarcinoma has increased steadily
      over the past two decades. Since the Bethesda System was introduced, the
      diagnosis of atypical glandular cells of undetermined significance (AGUS) has
      also risen and now accounts for 0.46-1.83% of all cervical (Pap) smears. The
      purpose of this study was to evaluate the significance of a diagnosis of AGUS
      using cytohistologic correlation. STUDY DESIGN: A retrospective review of
      archival material from 1993 through 1996 identified 64 patients who had smears
      diagnosed as AGUS and had a subsequent surgical biopsy. The smears were reviewed
      and cytologic features analyzed and correlated with the histologic diagnosis.
      RESULTS: On biopsy, 3 (5%) of the 64 cases showed endocervical adenocarcinoma in
      situ (AIS) (1 case with invasive adenocarcinoma also), 14 (22%) had a benign
      glandular lesion (endocervical polyp, tubal metaplasia, microglandular
      hyperplasia, reactive changes), 35 (54%) had squamous intraepithelial lesion
      (SIL) (15 diagnosed on the original smear), and 12 (19%) had no abnormality.
      Among the cytologic criteria evaluated, feathering (P = .01), palisading (P <
      .001) and chromatin clearing (P = .002) were shown to have a significant
      association with the histopathologic diagnosis of AIS/adenocarcinoma. These
      features were also useful in distinguishing AIS/adenocarcinoma from SIL and
      benign glandular changes from AIS/adenocarcinoma but not benign/reactive
      glandular changes from SIL. CONCLUSION: A diagnosis of AGUS correlated with a
      clinically significant lesion in the majority of cases. Squamous dysplasia (SIL)
      was the most common lesion identified. The presence of feathering, nuclear
      palisading and chromatin clearing increased the likelihood of a histologic
      diagnosis of AIS/adenocarcinoma.

PMID- 10349362
TI  - Atypical squamous cells of undetermined significance in women over 55. Comparison
      with the general population and implications for management.
AB  - OBJECTIVE: To determine the significance of atypical squamous cells of
      undetermined significance (ASCUS) in patients 55 years or older. STUDY DESIGN:
      From January 1994, to January 1997, 8,175 cervicovaginal smears were obtained
      from patients 55 years or older (mean age, 64.8; range, 56-84) at University
      Hospitals of Cleveland. Ninety-six of these patients were diagnosed with ASCUS
      only or ASCUS with a qualifying statement on the smear. Patient records, follow
      up cervicovaginal smears and biopsies were reviewed for a period of one to four
      years following the diagnosis of ASCUS. RESULTS: The incidence of ASCUS only or
      ASCUS with a qualifying statement for patients 55 years or older was 1.8%. The
      ASCUS:SIL ratio was 2.6:1. An estrogen stimulation test was recommended in two
      cases. Women older than 55 with ASCUS were three times more likely to be
      receiving hormonal replacement therapy than similar-aged women with normal
      cervicovaginal smears. Follow-up cervicovaginal smears or biopsies were obtained
      on 93 (80 cervicovaginal smears, 13 biopsies). The results were the following:
      LSIL (13), squamous carcinoma in situ (1) and ASCUS (53); the remainder of the
      cases were normal. In the patients who received a second diagnosis of ASCUS,
      follow-up cervi covaginal smears or biopsies revealed low grade dysplasia in six.
      CONCLUSION: Although the incidence of ASCUS and the frequency of underlying
      dysplasia is lower in postmenopausal women than the general population, there is
      still a real risk that a postmenopausal woman with ASCUS has underlying
      intraepithelial neoplasia. Therefore, these patients should be managed as is the
      general population.

PMID- 10349363
TI  - Sensitivity studies of AutoPap System Location-Guided Screening of cervical
      vaginal cytologic smears.
AB  - OBJECTIVE: To present the results of a study that assessed the efficacy of a
      cervical cytology screening method utilizing the AutoPap System with Location
      Guided Screening (AutoPap LGS) software for detecting abnormal Papanicolaou smear
      slides. STUDY DESIGN: Two hundred cases of abnormal cervical and vaginal smears
      were selected from the recent archives of the Taipei Institute of Pathology. For
      each abnormal slide, a matched "within normal limit" slide was included in the
      study. The slides were processed on the AutoPap Primary Screening System to
      select slides for Review or No Review and identify areas of the Review slides for
      human review and diagnosis (AutoPap LGS). The effectiveness of AutoPap LGS for
      detecting abnormal Papanicolaou smear slides was evaluated at multiple No Review
      rates. RESULTS: The AutoPap LGS demonstrated statistically superior sensitivity
      over current laboratory practice for the identification of abnormal slides.
      Assessing the potential benefit of the AutoPap LGS using a projection method, it
      is expected that the AutoPap LGS would detect an additional 52 low grade squamous
      intraepithelial lesion and 13 high grade squamous intraepithelial lesion cases
      missed by current laboratory practice in a population of 2,860 cases. CONCLUSION:
      The effectiveness of AutoPap LGS was demonstrated by its statistically superior
      performance in the detection of missed abnormal slides as compared to current
      laboratory practice at the Taipei Institute of Pathology.

PMID- 10349364
TI  - Endocervical glandular neoplasia and its mimics in ThinPrep Pap tests. A
      descriptive study.
AB  - OBJECTIVE: To document the cytologic features of endocervical adenocarcinoma in
      situ (AIS) and invasive endocervical adenocarcinoma as observed in ThinPrep
      slides and to compare these features with those that have been described for
      conventional smears. STUDY DESIGN: Six cases of endocervical AIS and three cases
      of invasive adenocarcinoma were evaluated with respect to 3 low-power and 14 high
      power features. All cases were biopsy proven. Glandular "look-alikes" (tubal
      metaplasia, n = 3; florid repair, n = 3; sampling of lower uterine segment, n =
      1) were also examined. RESULTS: All cases of AIS contained dark groups and sheets
      at screening power. At higher power, nuclear detail was extremely well
      visualized. All cases had crowding, continuous depth of focus, variability of
      nuclear size and shape within groups, irregular nuclear membranes, uniformly
      stippled chromatin and at least occasional single atypical cells. Only one case
      lacked nucleoli. Traditional features (strips, feathering, rosettes and mitoses)
      were observed about as frequently as in conventional smears. Invasive lesions had
      many of the same features, with relatively more inflammation and lysed blood.
      Nonneoplastic look-alikes could be distinguished from neoplasms using traditional
      criteria. CONCLUSION: In this small study, AIS and invasive endocervical
      adenocarcinoma maintained the features previously described for conventional
      smears. Improved visualization of nuclear detail may allow the application of
      additional criteria, such as irregular nuclear membranes and the more consistent
      presence of nucleoli, for distinguishing glandular neoplasms from their look
      alikes.

PMID- 10349365
TI  - Do qualifiers of ASCUS distinguish between low- and high-risk patients?
AB  - OBJECTIVE: To evaluate the qualification of a Pap smear classified as atypical
      squamous cells of undetermined significance (ASCUS) favor reactive or neoplasia
      as recommended by the Bethesda System. STUDY DESIGN: The smears from 105
      concurrent patients with a cytologic diagnosis of ASCUS not otherwise qualified
      were reviewed and subclassified as ASCUS favor reactive, low grade squamous
      intraepithelial lesion (LSIL) or high grade squamous intraepithelial lesion
      (HSIL) based on the Bethesda System criteria. The cervical biopsy diagnoses were
      correlated. RESULTS: Of the 105 cases classified as ASCUS, 37 were subclassified
      as favor reactive, 51 as favor LSIL and 17 as favor HSIL on cytologic review. In
      the ASCUS favor reactive group, 19 (51%) had reactive changes on biopsy, 17 (46%)
      had cervical intraepithelial neoplasia (CIN) 1, and 1 (2%) had CIN 3. A total of
      48% patients had CIN. In the favor LSIL group, there was CIN 1 in 28 cases (55%),
      CIN 2 or 3 in 12 (23%) and benign changes in 11 (22%) on biopsy. Seventy-eight
      percent had CIN. In the 17 cases classified as ASCUS favor HSIL group, all had
      CIN. CONCLUSION: Of the total 105 cases of ASCUS, 71% had CIN, 29% had reactive
      changes on follow-up biopsies, and 48% of patients in the ASCUS favor reactive
      group had CIN. Qualifiers of ASCUS have questionable utility in patient
      management.

PMID- 10349366
TI  - Cytologic features based on the expression of E-cadherin and catenins in lung
      adenocarcinoma.
AB  - OBJECTIVE: To investigate the relationship between E-cadherin-associated cell-to
      cell adhesion and cytologic features in preoperative cytologic lung
      adenocarcinoma specimens. STUDY DESIGN: Evaluation of the relationship between
      cell-to-cell adhesion, formation of cellular clusters and frequency of single
      cells in 31 cases of primary lung adenocarcinoma, collected by brush and needle
      cytology preoperatively. RESULTS: Most cases with remarkable overlapping of cells
      in compact cellular clusters and a few solitary cells maintained cell-to-cell
      adhesion. Cellular clusters that had a slight tendency to overlap, a small cell
      to-cell adhesion area and a high frequency of solitary cells tended to lack E
      cadherin-associated cell-to-cell adhesion. CONCLUSION: Formation of cellular
      clusters and the appearance of solitary cancer cells are closely related to E
      cadherin-associated cell-to-cell adhesion. Therefore, it is highly likely that
      cytologic features may indicate malignant behavior, such as local invasion and
      lymph node metastasis, in primary lung adenocarcinoma.

PMID- 10349367
TI  - Fine needle aspiration cytodiagnosis of sialadenitis with crystalloids.
AB  - OBJECTIVE: To assess the utility of fine needle aspiration cytology in the
      diagnosis of sialadenitis with crystalloid formation in four patients that
      presented with a swelling of the parotid gland. STUDY DESIGN: The swelling was
      aspirated in all the cases using a 22-gauge needle, and aspirates were submitted
      as needle and syringe washings in a cytology fixative (30% ethyl alcohol in
      physiologic saline). From these washings filter preparations were made on
      Sartorius or Gelman filters (pore size, 3 microns) and stained by the
      Papanicolaou method. Additionally, cell block preparations were made from the
      aspirate. After processing, sections were cut and stained by hematoxylin-eosin,
      Prussian blue, alcian blue, mucicarmine, and Von Kossa and congo red stain. No
      air-dried smears were made, and no electron microscopic studies were done.
      RESULTS: Stained cytologic preparations and cell blocks showed numerous
      nonbirefringent crystalloids of varying sizes and shapes appearing as rectangles,
      needles, squares and rods mixed with neutrophils and rare multinucleated giant
      cells. No salivary gland components were seen, and all special staining was
      negative. CONCLUSION: Fine needle aspiration cytology not only provided an
      accurate diagnosis of sialadenitis with crystalloids but also resulted in
      adopting conservative management and avoiding unnecessary surgery.

PMID- 10349368
TI  - Optimal prefixation of cells to demonstrate apoptosis by the TUNEL method.
AB  - OBJECTIVE: To determine the optimal fixation method for cultured human ovarian
      cancer cell line SHIN-3 to document cisplatin-induced apoptosis by the terminal
      deoxynucleotidyl transferase-mediated biotinylated dUTP nick end-labeling (TUNEL)
      assay. STUDY DESIGN: Cisplatin-treated cancer cell suspensions were (1) fixed in
      4% buffered formalin for 10 minutes (BF group); (2) treated with 2% Carbowax in
      50% ethanol (CW) for 10 minutes and then fixed in 100% ethanol for one hour (CW +
      ET); or (3) treated with CW for 10 minutes and then fixed in 4% buffered formalin
      for one hour (CW + BF). Cell morphology, adhesion to the glass slides and TUNEL
      reactivity were compared among the three groups. The effects of prolonged
      prefixation of cell suspensions in CW and of the postfixation of cell smears in
      BF for one, three and seven days were also examined. RESULTS: CW + BF treatment
      yielded satisfactory cell morphology, minimum cell loss and an excellent TUNEL
      reaction. However, prolonged prefixation in CW resulted in cell shrinkage.
      CONCLUSION: CW + BF treatment can be widely recommended for use with cytologic
      preparations for the TUNEL assay.

PMID- 10349370
TI  - Cytomorphologic features of angiosarcoma on fine needle aspiration biopsy.
AB  - OBJECTIVE: To present the cytomorphologic features of angiosarcomas identified on
      fine needle aspiration biopsy, review the literature, and discuss the
      differential diagnosis and pitfalls involved in such cases. STUDY DESIGN: Fine
      needle aspirate smears from 11 cases (1 hepatic, 3 breast and 7 subcutaneous/soft
      tissue lesions of angiosarcomas from eight patients were reviewed. All cases had
      histologic confirmation of angiosarcoma. RESULTS: All aspirates were
      hypocellular, with predominantly single cells in a background of moderate to
      abundant amounts of blood. Nine cases had scattered inflammatory cells, primarily
      neutrophils, in the background. Six of the cases had rare small clusters of
      cells. The cells were oval, round or spindled, with eccentric, round to spindle
      shaped nuclei and moderate to abundant amounts of pale blue-gray, vacuolated
      cytoplasm. The cells ranged from two to nine times the size of the background red
      blood cells. In four cases, malignant cells demonstrated intracytoplasmic
      hemosiderin deposits. Small nucleoli were identified in five cases, large
      nucleoli in one case and hyperchromasia in seven cases. Mitotic figures,
      erythrophagocytosis, acinarlike or vascular structures, and necrosis were not
      identified in any of the studied cases. In four cases, a definitive diagnosis of
      angiosarcoma was rendered on the fine needle aspiration specimen. In three other
      cases, the differential diagnosis remained between angiosarcoma and radiation
      change. CONCLUSION: The presence of scarce single pleomorphic cells in a bloody
      background should raise the diagnostic possibility of angiosarcoma. A definitive
      diagnosis of angiosarcoma is often difficult to render due to the paucity of
      diagnostic cells unless intracytoplasmic hemosiderin deposits can be identified.
      Multiple aspirations are often needed in order to obtain diagnostic material. In
      the setting of radiotherapy, it may be impossible to distinguish angiosarcoma
      from radiation change, and biopsy should be recommended.

PMID- 10349371
TI  - Conjunctival impression cytology with transfer in the assessment of vitamin A
      status in Nigerian children.
AB  - OBJECTIVE: To determine vitamin A status by conjunctival impression cytology with
      transfer (CIC-T) and assess its ability to predict low and deficient serum
      retinol concentrations. STUDY DESIGN: CIC-T was performed on 128 healthy, well
      nourished and 230 malnourished children aged under 6 years by a 3-5-second
      application of cellulose acetate paper to each bulbar conjunctiva followed by
      transfer of the adhered cells onto glass slides. The slides were stained with
      Alcian green 2GX, and smears were classified as normal, borderline normal,
      borderline abnormal and deficient. Corresponding serum retinol levels were
      determined in each subject. RESULTS: The results showed that CIC-T is a simple
      procedure with a failure rate of 7.3% caused by tearing and agitation. The power
      of CIC-T to predict vitamin A status varied with both the CIC-T smear
      classification used and serum retinol concentration threshold. CIC-T smear
      classification as abnormal and normal appears to be the most robust and
      predictive of serum retinol, < 10 and > 10 < 20 micrograms/dL, respectively.
      CONCLUSION: The simplicity, sensitivity and specificity of CIC-T suggest that
      this procedure is a good screening tool for epidemiologic survey of vitamin A
      status.

PMID- 10349369
TI  - Fine needle aspiration biopsy of Hashimoto's thyroiditis. Sources of diagnostic
      error.
AB  - OBJECTIVE: To determine the accuracy of cytologic interpretation in the diagnosis
      of Hashimoto's thyroiditis (HT). STUDY DESIGN: At Ottawa Hospital from 1987 to
      1994, 1,638 fine needle aspiration biopsies (FNABs) from thyroid were performed.
      HT was suggested in 184 FNAB samples taken from 157 patients. Of the 184
      aspirates diagnosed with HT, 39 had corresponding surgical specimens taken from
      31 patients. A retrospective review of these FNABs and surgical pathology slides
      formed the basis of this study. RESULTS: In 27 (69%) aspirates, HT was diagnosed
      on both the FNAB and surgical specimens. In 10 of 27 FNABs an associated lesion
      was not sampled by FNAB. In four of these 10 aspirates some of the cellular
      features of HT were misinterpreted, and the possibility of an associated neoplasm
      could not be ruled out. This resulted in four false positive diagnoses. In 12
      (31%) FNABs from nine patients, the cytologic diagnosis of HT was not confirmed
      histologically. These cases included five Hurthle cell adenomas and one case each
      of follicular adenoma, nodular goiter, macrofollicular adenoma and malignant
      lymphoma. This resulted in five false negative diagnoses. CONCLUSION: These
      results support the value of FNAB in the diagnosis of HT. The presence of
      hyperplastic follicular cells on FNAB samples from HT may mimic a follicular
      neoplasm and result in a false positive interpretation. Adequate sampling of the
      thyroid is important, particularly when there is an associated lesion. The
      diagnosis of lymphocytic thyroiditis should not be made when only a few
      lymphocytes are present. Finally, pleomorphic Hurthle cells may be present in
      aspirates from Hurthle cell neoplasms and underdiagnosed as HT, especially when
      they are associated with a few lymphocytes.

PMID- 10349372
TI  - Fine needle aspiration cytology of primary non-Hodgkin's lymphoma of the tongue.
      A case report.
AB  - BACKGROUND: Fine needle aspiration cytology (FNAC) of extranodal non-Hodgkin's
      lymphoma of the tongue has rarely been described. CASE: A 47-year-old male was
      referred to the cytology laboratory for FNAC of a 3-cm-diameter swelling on the
      dorsum of the tongue, with a primary clinical diagnosis of soft tissue tumor.
      FNAC smears showed discrete, monomorphic, round to oval cells with scanty, deep
      blue cytoplasm. The nuclear margin was regular, with occasional prominent
      nucleoli and fine nuclear chromatin. The background showed many lymphoglandular
      bodies. The cells were strongly positive for leukocyte common antigen. A
      cytologic diagnosis of high grade non-Hodgkin's (NHL) was offered and
      subsequently confirmed by histopathology. CONCLUSION: Primary NHL of the tongue
      is relatively rare. As there are no characteristic clinical features of
      extranodal NHL of the tongue, FNAC may be useful for rapid diagnosis and
      management of such cases.

PMID- 10349373
TI  - Solitary fibrous tumor of the spinal cord. Report of a case with scrape cytology.
AB  - BACKGROUND: Solitary fibrous tumor is a rare spindle cell tumor and has been
      forced at a variety of sites. To the best of our knowledge, only two cases of
      solitary fibrous tumor arising in the spinal cord have been reported; no
      cytologic findings were documented. CASE: A 62-year-old male presented with a
      spinal cord tumor. A scrape smear of the resected tumor revealed naked, spindle
      shaped nuclei. Some nuclei were twisted or had long spindles. In the background,
      abundant, thin and thick collagen fibers were present. Immunohistochemically, the
      spindle cells were positive for CD34 and negative for S-100 protein and alpha
      smooth muscle actin. Histologic diagnosis of the tumor was benign solitary
      fibrous tumor. CONCLUSION: Our case indicates that solitary fibrous tumor can
      occur in the spinal cord and should be differentiated from other benign spindle
      cell tumors, such as meningioma and schwannoma. The key cytologic features of
      solitary fibrous tumor may be the presence of abundant thin and thick collagen
      fibers in scrape specimens.

PMID- 10349374
TI  - Fine needle aspiration cytology of Langerhans cell histiocytosis of the thyroid.
      A case report.
AB  - BACKGROUND: Langerhans cell histiocytosis (LCH) of the thyroid is a rare
      condition, and fine needle aspiration cytology (FNAC) of this entity has rarely
      been described. CASE: FNAC was done on a 3-cm-diameter thyroid swelling in the
      left lower lobe of the thyroid gland. Smears showed a large number of
      lymphocytes, eosinophils, thyroid follicular cells and discrete, large cells with
      prominent nuclear grooves. Mitotic activity was frequent. A cytologic diagnosis
      of LCH was offered. Subtotal thyroidectomy was performed, and the cytologic
      diagnosis was confirmed by histology. CONCLUSION: LCH of the thyroid has certain
      salient diagnostic features. The presence of histiocytes with prominent nuclear
      grooves, reactive lymphoid cells and eosinophils along with benign thyroid
      follicular cells should raise the suspicion of this rare entity on FNAC smears of
      the thyroid.

PMID- 10349375
TI  - Cytologic diagnosis of a solitary brain metastasis from papillary carcinoma of
      the thyroid. A case report.
AB  - BACKGROUND: Papillary carcinoma of the thyroid metastasizes to the brain in rare
      instances. In published series and case reports of metastatic papillary thyroid
      carcinoma, diagnosis of central nervous system (CNS) metastases has been
      determined by histologic methods. We present a case of papillary carcinoma
      metastatic to brain diagnosed by cytologic methods. CASE: A 43-year-old female,
      initially diagnosed at age 12 with papillary carcinoma of the thyroid metastatic
      to regional lymph nodes and lung, presented with head aches of increasing
      frequency and severity. A computed tomography scan confirmed a 1-cm nodule in the
      right inferior frontal lobe of the brain. For clinical reasons, the patient was
      followed with serial imaging for five years. At age 48 there was significant
      progression of the CNS disease, and the patient underwent stereotactic biopsy
      with drainage of cyst fluid. Cytologic examination of the cyst fluid and
      immunocytochemical studies confirmed the typical features of papillary thyroid
      carcinoma, including papillary clusters of cells with finely granular chromatin,
      micronucleoli, nuclear grooves and an associated psammoma body. CONCLUSION:
      Neurocytology is a useful technique in the examination of cystic lesions of the
      brain and may be the sole technique for determination of diagnosis.

PMID- 10349376
TI  - Tall cell variant of papillary carcinoma coexisting with chronic lymphocytic
      thyroiditis. A case report.
AB  - BACKGROUND: Recent studies have shown a correlation between lymphocytic
      thyroiditis and papillary carcinoma of the thyroid. It is thought that autoimmune
      thyroiditis could be a risk factor for the development of thyroid carcinoma,
      mainly for the papillary variant. CASE: A 59-year-old female presented with a
      history of enlargement in the neck and five months of dysphagia. Clinical
      examination showed generalized expansion and an increase in the hardness of the
      thyroid gland. Hormonal outline showed subclinical hypothyroidism with serum
      levels of TSH slightly elevated (5 micrograms/dL; range, 0.25-4). Thyroglobulin
      antibodies and thyroperoxidase titers were moderately positive. Given these
      results, a diagnosis of chronic thyroiditis was made. Thyroid ultrasound scan
      showed diffuse gland irregularity and the presence of a solitary nodule (2.3 cm
      in diameter) localized in the right lobe. Fine needle aspiration biopsy (FNAB) of
      the nodule was performed under ultrasound guidance. CONCLUSION: Although clinical
      and laboratory results supported the diagnosis of autoimmune thyroiditis only,
      FNAB of the nodular lesion provided evidence of a rare case of papillary
      carcinoma, tall cell variant, confirmed by histologic results.

PMID- 10349377
TI  - Intravenous pyogenic granuloma mimicking pleomorphic adenoma in a fine needle
      aspirate. A case report.
AB  - BACKGROUND: Intravenous pyogenic granuloma (IvPG) is a rare, benign lesion
      occurring usually as a subcutaneous mass in the neck or upper extremity. The
      cytologic features of IvPG have not been described before. CASE: A patient
      presented with a subcutaneous nodule on the lower border of the left parotid
      area. The clinical diagnosis was bronchial cleft cyst or lymphadenitis, and the
      fine needle aspiration diagnosis was pleomorphic adenoma. The tissue section,
      however, disclosed IvPG. CONCLUSION: Evaluation of subcutaneous nodules
      presenting cytologically as spindle cell lesions may be problematic, particularly
      in the neck and head region. Such lesions occurring in the parotid area may be
      interpreted as pleomorphic adenoma of the salivary gland.

PMID- 10349378
TI  - Fine needle aspiration cytology of a cervical lymph node lymphangioma in an
      adult. A case report.
AB  - BACKGROUND: Although the cytologic features of cervical cystic lesions are well
      established, no cytology reports on lymphangioma in adults have been published.
      CASE: A 60-year-old male presented with a slowly growing, upper laterocervical,
      painless enlargement. Fine needle aspiration (FNA) obtained 15 mL of yellowish
      fluid, consisting predominantly of a uniform population of small and round
      lymphocytes without mitosis or atypia and with some histiocytes intermingled with
      them. Some centrocytes and occasionally centroblasts and plasma cells could also
      be observed. Immunohistochemistry performed on cell block sections displayed
      polyclonal B lymphocytes mixed with T cells. The specimen showed a clearly
      circumscribed, 50-mm, cystic lesion with a multilocular appearance and abundant,
      yellowish liquid. Microscopic examination demonstrated cystic lymphangioma
      arising from the medullary portion of a lymph node. CONCLUSION: FNA cytology
      permits a suggested diagnosis of lymphangioma. This is one of the few reports of
      FNA cytology of lymphangioma and, to the best of our knowledge, this entity has
      not previously been found as a neck mass in an adult.

PMID- 10349379
TI  - Pancreatic metastasis of cardiac rhabdomyosarcoma diagnosed by fine needle
      aspiration. A case report.
AB  - BACKGROUND: Fine needle aspiration (FNA) is a valuable technique in the diagnosis
      of soft tissue tumors or their metastases. CASE REPORT: A rhabdomyosarcoma of the
      left atrium with metastasis to the pancreas was diagnosed by FNA in a 74-year-old
      female. The patient presented with dyspnea, weight loss and generalized weakness
      and was found to have a cardiac arrhythmia. Magnetic resonance imaging showed a 9
      cm mass in the left atrium and anterior mediastinum. Computed tomography (CT) of
      the abdomen revealed a 2.8-cm nodule within the head of the pancreas. The patient
      underwent CT-guided percutaneous aspiration biopsy of the pancreatic mass on the
      first hospital day and, on the second day, transvenous FNA biopsy of the
      intracardiac mass. The cytologic morphology and immunocytochemistry of the
      aspirated material from both sites established a diagnosis of cardiac
      rhabdomysarcoma with metastasis to the pancreas. CONCLUSION: This is the fifth
      reported case of rhabdomysarcoma metastatic to the pancreas and the first in
      which the diagnosis was made by FNA, thereby eliminating the need for open
      biopsy.

PMID- 10349380
TI  - Fine needle aspiration biopsy of well-differentiated liposarcoma of the neck in a
      young female. A case report.
AB  - BACKGROUND: Well-differentiated liposarcomas are low grade, nonmetastasizing,
      malignant neoplasms composed primarily of mature adipose tissue. They are
      uncommon in the head and neck. CASE: A 24-year-old female presented to the ears,
      nose and throat clinic for evaluation of a recent, rapidly growing neck mass on
      the right side. Fine needle aspiration (FNA) biopsy of the mass showed that the
      smears had fragments of connective tissue with a mixture of mature-appearing fat
      traversed by bands of fibrous collagen and vessels. Nuclei within the fat and
      fibrous bands were mildly irregular, hyperchromatic and enlarged, with one or two
      small nucleoli. Infrequently present but readily identified, lipoblasts were
      scattered throughout the aspirate smears. A diagnosis of "atypical lipomatous
      neoplasm" was rendered. Subsequently, the mass was surgically removed. On
      histologic examination, the tumor was a well-differentiated liposarcoma.
      CONCLUSION: FNA biopsy of well-differentiated liposarcomas in the head and neck
      can present difficulties in the classification and diagnosis of this neoplasm.

PMID- 10349381
TI  - Fine needle aspiration cytology of an intraductal papilloma originating in a
      sublingual gland. A case report.
AB  - BACKGROUND: Intraductal papilloma of the salivary gland is a very rare tumor;
      only eight cases have been reported to date. Only histopathology has been used to
      investigate this tumor to our knowledge. There has not been any reported case of
      this tumor in a sublingual gland. CASE: A 3-cm oral floor mass with a lanulalike
      lesion in a 72-year-old female was aspirated. The cytologic features included
      various cellular smears containing compact clusters of papillary, radial,
      palisading, trabecular, tubular and buddinglike projected patterns; monomorphic
      columnar cells with oval-to-spindle nuclei basally located; abundant, finely
      vacuolar cytoplasm; indistinct nucleoli; and no squamous differentiated cells. A
      sublingual glandectomy was performed. Cytology, histology, immunohistochemistry
      and electron microscopy were performed with standard methods. The intraductal
      papilloma seems to have arisen within an excretory duct and differentiated into
      acinar cells. CONCLUSION: The cytologic findings of intraductal papilloma are
      unique and may allow its specific diagnosis on fine needle aspiration.

PMID- 10349382
TI  - Fine needle aspiration cytology and core biopsy in the diagnosis of alveolar soft
      part sarcoma presenting with lung metastases. A case report.
AB  - BACKGROUND: Alveolar soft part sarcoma is a rare soft tissue tumor of uncertain
      origin usually affecting young adults. This neoplasm has early metastatic
      potential. Its cytologic features, particularly when presenting with metastases,
      have rarely been described. CASE: A 23-year-old male presented with shortness of
      breath and scapular pain. Routine chest roentgenograms revealed multiple lung
      nodules. Malignancy was established by percutaneous fluoroscopically guided fine
      needle aspiration on a lung nodule. Possible metastatic alveolar soft part
      sarcoma was suggested by cytology among few considerations in the differential
      diagnosis. Alveolar soft part sarcoma was confirmed by lung core biopsy and
      further supported by immunohistochemistry and electron microscopy. Tumor cells
      expressed muscle-specific actin and myoglobin, and contained diastase-resistant
      inclusions with periodic acid-Schiff stain. Ultrastructurally, peculiar,
      elongated intracytoplasmic crystalline bodies typical of this neoplasm were
      identified. A meticulous clinical search led to finding the primary tumor deeply
      located in the right posterior thigh. CONCLUSION: Aspiration cytology is a
      reliable, cost-efficient technique in the diagnostic workup of masses suspicious
      for malignancy.

PMID- 10349383
TI  - Poroid hidradenoma. Report of a case with cytologic findings on fine needle
      aspiration.
AB  - BACKGROUND: Fine needle aspiration cytology (FNAC) can be used for establishing a
      diagnosis of cutaneous lesions, especially in cases with cyst formation. Poroid
      hidradenoma is eccrine neoplasm with both solid and cystic components. CASE: A 77
      year-old female presented with a slightly elevated nodule in the skin on her left
      elbow. The tumor was well demarcated, 2.7 x 2.4 cm and soft, and overlying skin
      was slightly reddish. FNAC revealed two types of cell: one had abundant cytoplasm
      in which small to large, occasionally multinucleated nuclei with small but
      distinct nucleoli were evident. Chromatin was finely granular, and nuclear
      membrane was thin and almost smooth. Another type of cell had scanty cytoplasm
      and a round to oval nucleus with small but prominent nucleoli. Histologic
      diagnosis was poroid hidradenoma. CONCLUSION: FNAC can be useful for diagnosing
      intradermal cystic lesions before surgical resection.

PMID- 10349384
TI  - Sarcoma botryoides of the cervix. Report of a case with cytopathologic findings.
AB  - BACKGROUND: Cytologic findings of sarcoma botryoides were still equivocal because
      sarcoma botryoides of the uterine cervix is an extremely rare neoplasm, and few
      cases have been reported to date. CASE: A 17-year-old female was diagnosed with
      sarcoma botryoides of the uterine cervix. The entire vaginal canal was occupied
      with polypoid masses, which arose from the anterior lip of the uterine cervix,
      and the tumor was classified as group I (Intergroup Rhabdomyosarcoma Study).
      After wedge resection and six courses of combination chemotherapy, the tumor
      recurred in the same location of the cervix as the primary lesion. Touch smear of
      the polypoid mass formed loose clusters and also showed short spindle cells in a
      necrotic background. The nucleus of the tumor cells had a thin nuclear membrane,
      fine chromatin pattern and partly clear nucleolus, showing mild nuclear atypia.
      Immunohistochemically, some of the tumor cells showed positive staining for
      myoglobin and desmin. CONCLUSION: The cytologic findings of sarcoma botryoides of
      the female genital tract are typical features of nonepithelial malignant tumor.
      Immunohistochemical study is useful for the diagnosis of rhabdomyosarcoma.

PMID- 10349385
TI  - Idiopathic granulomatous mastitis. Report of a case diagnosed with fine needle
      aspiration cytology.
AB  - BACKGROUND: Idiopathic granulomatous mastitis (IGM) is a benign, inflammatory
      breast disease of unknown etiology. Although it is rare, it frequently presents
      in a manner similar to that of breast carcinoma. CASE: A 41-year-old female
      developed unilateral idiopathic granulomatous mastitis, diagnosed by fine needle
      aspiration cytology. The clinical presentation and mammographic findings were
      suspicious for carcinoma. Fine needle aspiration cytology showed granulomatous
      inflammation. Histopathologic examination revealed a noncaseating, granulomatous
      lesion. Further clinical, radiologic and laboratory investigations disclosed no
      etiology. Therefore, we considered the case to be idiopathic granulomatous
      mastitis. CONCLUSION: Cytologically it may be difficult to distinguish IGM from
      carcinoma of the breast. Typical cytologic findings of the lesion are helpful to
      rule out cancer. In the differential diagnosis, all known causes of granulomatous
      changes have to be excluded before a diagnosis of idiopathic granulomatous
      mastitis is made.

PMID- 10349386
TI  - Scrape cytology of elastofibroma. Report of a case with diagnostic cytologic
      features.
AB  - BACKGROUND: Elastofibroma is a benign, soft tissue tumor that occurs most
      frequently in the subscapular area in elderly people. To the best of our
      knowledge, in only two cases has the cytology been reported. The aim of this
      report is to describe the characteristic cytologic findings of elastofibroma and
      to discuss the usefulness of elastin stain in scrape smears. CASE: A 72-year-old
      female had bilateral masses in the lower subscapular area. Scrape smears from a
      cut surface of the resected masses revealed abundant, "wormlike" or "braidlike"
      material with central cores with Papanicolaou stain in an intraoperative
      consultation. Various-sized, petaloid or crystalloid globules were also present.
      Those elastic fibers were strongly positive for elastin stain in cytologic
      preparations. CONCLUSION: Elastofibroma can be diagnosed cytologically, and
      elastin-stained, scrape cytologic preparation is especially useful in such a
      case.

PMID- 10349387
TI  - Primary pleomorphic adenoma of the external auditory canal diagnosed by fine
      needle aspiration cytology. A case report.
AB  - BACKGROUND: Pleomorphic adenoma (PA) arising in the external auditory canal (EAC)
      is a very rare neoplasm, thought to be derived from ceruminous glands. CASE: A 43
      year-old male presented with a slowly growing mass in the right EAC. Clinical and
      radiologic examinations showed a well-circumscribed tumor limited to the EAC,
      without a connection to the parotid gland. Fine needle aspiration cytology (FNAC)
      revealed the typical cytologic findings of PA. The diagnosis was confirmed by
      histologic examination. CONCLUSION: This case illustrates that together with
      clinical and radiologic findings, primary PA of the EAC can confidently be
      diagnosed by FNAC.

PMID- 10349388
TI  - Fine needle aspiration of thoracic splenosis. A case report.
AB  - BACKGROUND: Thoracic splenosis is a rare event, and fine needle aspiration (FNA)
      of a pleural implant of splenic tissue can be a pitfall when previous anamnestic
      data are ignored. CASE: A 53-year-old male underwent FNA of a left thoracic
      subpleural nodule highly suggestive of a metastatic lesion. The presence of a
      population of small and medium-sized lymphocytes suggested the possibility of
      lymphoproliferative disease; frozen sections confirmed this possibility. The
      final diagnosis was normal splenic tissue. Twenty-five years earlier the patient
      sustained a gunshot wound in the left side of the upper abdomen followed by
      splenectomy and drainage of the left pleural cavity because of mild, concomitant
      hemothorax. CONCLUSION: A left pleural thoracic nodule in subjects with a
      previous history of traumatic rupture of the spleen must be considered highly
      suggestive of thoracic splenosis. Scintigraphy with Tc 99 m and magnetic
      resonance imaging are diagnostic, while FNA, especially in the absence of
      anamnestic data, can create a pitfall that can induce inappropriate removal of
      ectopic, normally functioning splenic tissue.

PMID- 10349389
TI  - Fine needle aspiration cytology of adenomatoid tumor. A case report.
AB  - BACKGROUND: Adenomatoid tumor is a benign neoplasm of the male and female genital
      tract. The epididymis is the most common site. CASE: A 25-year-old male presented
      with a swelling in the left side of the epididymis. Cytology showed monotonous
      cells arranged in sheets, cords and glandular patterns. The cell showed eccentric
      vesicular nuclei with fine chromatin and abundant, vacuolated cytoplasm.
      CONCLUSION: With the help of fine needle aspiration cytology, an accurate
      diagnosis of adenomatoid tumor is possible and can relieve anxiety and
      uncertainty in both the patient and physician.

PMID- 10349390
TI  - CD-30(Ki-1)-positive anaplastic large cell lymphoma in a pleural effusion. A case
      report with diagnosis by cytomorphologic and immunocytochemical studies.
AB  - BACKGROUND: Reports on cytodiagnosis of Ki-1-positive anaplastic large cell
      lymphoma (ALCL) are rare. This report describes one such case diagnosed by
      cytologic examination of a pleural effusion and confirmed by immunocytochemistry.
      CASE: An 87-year-old male presented with breathlessness, fever and a cough.
      Computed tomographic scan of the thorax showed a small, right, pleura-based
      nodule with infiltration of the immediate surroundings in addition to a massive,
      right-sided pleural effusion. Cytologic examination of pleural fluid revealed a
      heterogeneous population of cells comprising small mature lymphocytes, and
      numerous medium and large atypical lymphoid cells having frequent nuclear
      irregularity. Occasional very large cells resembling Reed-Sternberg cells or
      multinucleated cells with a horseshoe or wreathlike arrangement of nuclei
      (doughnut cells) were also present. Cytomorphology was suggestive of Ki-1
      anaplastic large cell lymphoma (ALCL). Immunocytochemistry revealed intense
      positivity for CD-30, positivity for LCA and EMA in a variable number of cells
      and a negative result for cytokeratin except for occasional cells. CONCLUSION:
      Cytologic examination of pleural fluid can serve as a useful tool for the initial
      diagnosis of Ki-1-positive ALCL.

PMID- 10349391
TI  - Fine needle aspiration of solid tumors in HIV-positive patients.

PMID- 10349392
TI  - Fine needle aspiration cytology in the diagnosis of muscular echinococcosis.

PMID- 10349393
TI  - Crystalloids in smears from thyroid nodular hyperplasia.

PMID- 10349394
TI  - Mucoepidermoid carcinoma of the parotid gland.

PMID- 10349395
TI  - Cytodiagnosis of microfilaria of the breast from a needle aspirate.

PMID- 10349396
TI  - False negative proportion: a complementary form of sensitivity.

PMID- 10349397
TI  - Giemsa staining for alveolar soft part sarcoma.

PMID- 10349398
TI  - Immunocytochemical staining using the cell suspension method to detect
      monoclonality of immunoglobulin in malignant lymphoma.

PMID- 10349399
TI  - Fine needle aspiration biopsy of primary leiomyosarcoma arising from a pulmonary
      vein.

PMID- 10349400
TI  - Parotid mucoepidermoid carcinoma metastatic to pleural fluid.

PMID- 10349401
TI  - Differential diagnosis of thymic lesions.

PMID- 10349402
TI  - Diagnosis of localized Leishmania lymphadenitis by fine needle aspiration
      cytology.

PMID- 10349403
TI  - Fine needle aspiration diagnosis of a breast fibroadenoma with multinucleated
      stromal giant cells.

PMID- 10349404
TI  - Papillary carcinoma arising in a thyroglossal duct cyst and diagnosed by fine
      needle aspiration cytology.

PMID- 10349405
TI  - Large cell neuroendocrine carcinoma of the parotid gland: fine needle aspiration,
      and light microscopic and ultrastructural study.

PMID- 10349406
TI  - Cystic endometriosis and related neoplasms arising from extragonadal
      endometriosis diagnosed by transvaginal fine needle aspiration biopsy.

PMID- 10349407
TI  - A clinician's guide to journal articles about prognosis.

PMID- 10349408
TI  - The history of circumcision.

PMID- 10349409
TI  - Religious circumcision: a Muslim view.

PMID- 10349410
TI  - Religious circumcision: a Jewish view.

PMID- 10349411
TI  - Jewish circumcision: an alternative perspective.

PMID- 10349412
TI  - Male circumcision: a South Korean perspective.

PMID- 10349413
TI  - The prepuce.

PMID- 10349415
TI  - Does circumcision influence sexually transmitted diseases?: a literature review.

PMID- 10349414
TI  - Medical indications for circumcision.

PMID- 10349416
TI  - Involuntary circumcision: the legal issues.

PMID- 10349417
TI  - A child's right to circumcision.

PMID- 10349418
TI  - The effect of male circumcision on the sexual enjoyment of the female partner.

PMID- 10349419
TI  - A preliminary poll of men circumcised in infancy or childhood.

PMID- 10349420
TI  - The psychological impact of circumcision.

PMID- 10349421
TI  - Female circumcision: the peril remains.

PMID- 10349422
TI  - Surgical methods of restoring the prepuce: a critical review.

PMID- 10349423
TI  - [Electronic repellents against mosquitoes: the propaganda and the reality].
AB  - A bibliographic review about the use of electroacoustic devices with a supposed
      repellent action on the females of different species of hematophagous mosquitoes
      is presented. 15 direct references and 2 indirect ones are given, in which it is
      concluded that these devices do not protect those who have them from the stings
      of mosquitoes. The names of 9 of the tested devices as well as of 16 of the main
      species of mosquitoes present in the field tests are mentioned. These tests have
      been carried out in very different ecological conditions from Alaska to
      Equatorial Africa. It is also stressed that the high intensity ultrasonic
      frequencies emitted by these devices produces a potentially harmful effect on
      man.

PMID- 10349424
TI  - [The determination of antibodies to the human immunodeficiency virus type 1 (HIV
      1) in samples of dried blood on filter paper].
AB  - The possibility of detecting HIV-1 antibodies by an immunoblotting kit is studied
      in a panel of 125 known specimens of dried blood spotted on filter paper and
      their corresponding serum samples. No differences were observed in the patterns
      of bands with both types of samples or in the sensitivity and specificity, where
      100% figures were attained, allowing to conclude that the blood specimen taken on
      filter paper may be used for the detection of HIV-1 antibodies by the DAVIH-BLOT
      system and may be kept at 4 degrees C during 30 weeks.

PMID- 10349425
TI  - [The biological characterization of HIV-1 isolated in patients with a rapid
      clinical evolution].
AB  - The biological characteristics of 11 HIV-1 strains isolated from patients with a
      fast clinical evolution to AIDS were studied. The viral isolates were classified
      according to their replication kinetics and cell tropism. Taking into account
      these criteria, it was observed that 8 of the isolated strains (72.7%) were of
      rapid high growth (RH) or slow low 3 (SL3) with preferential tropism to the
      lymphocytic stock, as it corresponds to AIDS patients. 3 (27.3%) had
      characteristics of slow low 1 (SL1). The cytopathogenicity of the strains was
      studied in the MT4 cellular line, and it was observed that most of them (72.7%)
      were syncytium-inducing strains (SI), which allowed to prove the in vivo and in
      vitro relation of the biological properties. It was not so in 3 of the cultures
      (27.3%) that behaved as non-syncytium inducers.

PMID- 10349426
TI  - [The intratypic characterization of the poliovirus by the polymerase chain
      reaction technic].
AB  - The polymerase chain reaction techniques was introduced for the intratypic
      characterization of Poliovirus. Primers were used only to promote the
      amplification of the Sabin vaccine strains proved by electrophoretic run of the
      amplified DNA products (Sabin 1-97 pb, Sabin 2-71 pb, Sabin 3-44 pb) and whose
      specificity was satisfactorily verified. 23 Cuban poliovirus strains isolated and
      identified at the Laboratory of Enterovirus of the "Pedro Kouri" Tropical
      Medicine Institute from 1993 to 1994 were studied by this technique. All of them
      were of the vaccine type. It was observed how the Sabin vaccine poliovirus may be
      the cause of viral meningoencephalitis as a milder neurological complication.
      This study provided one more evidence about the non circulation of the wild
      poliovirus in Cuba.

PMID- 10349427
TI  - [The immunoassay of IgM antibodies in samples clinically suspected of measles].
AB  - 60 matched sera clinically suspicious of measles that were received at the
      Diagnostic Laboratory of the "Pedro Kouri" Tropical Medicine Institute between
      January and May, 1996, coming from the seroepidemiological surveillance of the
      MPR vaccine were studied. The detection of measles and rubella hemagglutinant
      antibodies, as well as of IgM, was carried out with the Clark Laboratories INC.
      Measles IgM ELISA diagnostic kit. The positive cases were confirmed by the IgM
      indirect immunofluorescence and neutralization. 3 positive cases to measles and
      rubella, which were negative to measles IgM, were obtained by hemagglutination
      inhibition. Antibodies against Epstein Barr, cytomegalovirus and herpes simplex
      virus were also determined by indirect immunofluorescence (IIF) due to the
      capacity of these viruses to induces polyclonal responses. 6 positive cases,
      which were negative by IIF, were detected by means of the above mentioned
      diagnostic kit.

PMID- 10349428
TI  - [Esophageal candidiasis in AIDS patients. A clinical and microbiological study].
AB  - 18 AIDS patients who presented high gastrointestinal symptoms or lesions in the
      oral cavity suggestive of candidiasis were studied. Clinical data, specimen of
      the oral cavity, biopsies and esophageal brushing, as well as serum from all
      patients were obtained. Dysphagia was the main symptom observed in the esophageal
      candidiasis. Candida albicans was the most isolated species with a predominance
      of serotype A. The protein profiles of 12 strains belonging to this species were
      analyzed by the polyacrylamide gel electrophoresis, and it was found that their
      molecular weight patterns were identical, which indicates that the same strain is
      in the oral cavity and in the esophagus. The response of the anti-C. albicans
      antibodies was evaluated. The double immunodiffusion was not useful for the
      diagnosis of esophageal candidiasis.

PMID- 10349430
TI  - [A chromatographic analysis of the Mycobacterium tuberculosis strains isolated
      from an outbreak in HIV patients in Cuba].
AB  - A group of strains of Mycobacterium tuberculosis isolated from an outbreak in HIV
      infected patients was studied by chromatographic techniques. A group of strains
      of M. Tuberculosis from symptomatic respiratory patients (SR+ 14) and patterns
      strains from the laboratory collection were used as a reference aimed at making a
      qualitative comparison of the chromatographic patterns described by the strains
      isolated from patients. The chromatographic profiles of the strains isolated from
      patients (SR+) and fro HIV+ were obtained and compared by thin layer
      chromatography (TLC). Each of the present fatty acids was identified by using the
      gas chromatography technique (GC) coupled to mass spectrum analysis. All the
      studied strains were classified as Mycobacterium tuberculosis. According to the
      results attained, the usefulness of the chromatographic techniques as alternative
      techniques for the mycobacterial diagnosis is demonstrated.

PMID- 10349429
TI  - [The excretion pattern and protective capacity in rabbits orally immunized with
      attenuated strains of Vibrio cholerae O1 biotype El Tor].
AB  - In order to study the excretion patterns, colonization and protective capacity of
      live attenuated strains of Vibrio cholerae O1. El Tor, rabbits were immunized in
      New Zealand with these strains and their corresponding parental strains. 2 doses
      were administered by the model of oral inoculation in adult rabbits. Rabbits were
      rotated 2 weeks after the second dose by the model of ligated intestine with
      highly virulent strains of V. cholerae O1 Ogawa and Inaba serotypes and O139
      serogroup. It was proved that the genetically manipulated strains do not effect
      the excretion patterns when they are compared with their parental strains. It was
      observed in the challenge a decrease in the levels of colonization of virulent
      strains of both serotypes, not only among the rabbits immunized with the
      attenuated strains, but also among those immunized with the parental strains in
      comparison with control animals immunized with the strain of Escherichia coli K
      12, which means that there was certain degree of protection. In the case of the
      animals challenged with the O139 strain it was demonstrated that the protection
      is specific for each serogroup, since in this case there was no reduction of the
      colonization.

PMID- 10349431
TI  - [The effect of insecticide resistance on the demographic parameters of 3 strains
      of Culex quinquefasciatus (Diptera: Culicidae) under laboratory conditions].
AB  - The life tables of 3 strains of Culex quinquefasciatus were studied under
      laboratory conditions: Slab, susceptible to reference; Old Havana, treated with
      cypermethrin until its fourth generation; and Cotorro, from the field. It was
      found that the different levels of resistance to organophosphate insecticides and
      pyrethroids present in the Cotorro and Old Havana strains did not influence
      either on the duration of the period of development of the immature stages or in
      the sexual proportion of the emerged adults, but they had a favorable and
      directly proportional effect on the survival and longevity of the adults.
      However, they exerted a negative and inversely proportional influence on the
      reproduction and population growth of these strains. Useful data for the use and
      management of insecticides within the strategies of control of Culex
      quinquefasciatus, an important vector of lymphatic filariasis, are provided.

PMID- 10349432
TI  - [The selection of a strain of Culex quinquefasciatus resistant to
      lambdacyhalothrin and its spectrum of cross-resistance to other insecticides].
AB  - A field strain of Culex quinquefasciatus resistant to pyrethroid lambda
      cyhalothrin insecticide was selected to be used as a reference strain in the
      laboratory for conducting studies of biochemistry and genetics of resistance, to
      evaluate the utility of this insecticide for the control of mosquitoes in Cuba,
      and to determine the cross resistance to organophosphate insecticides,
      pyrethroids and a carbamate. A high resistance to lambdacyhalothrin was obtained
      after 6 generations of selective pressure. Lowe or no cross resistance to other
      pyrethroids (deltamethrin and cypermethrin), to a carbamate (propoxur) and to the
      organophosphate insecticides (clorpirifos and methyl-pyrimifos) was observed. A
      high cross resistance to malathion (organophosphate) was detected.

PMID- 10349433
TI  - [Resistance in a strain of Culex quinquefasciatus coming from Medellin,
      Colombia].
AB  - The levels of susceptibility and/or resistance to 5 organophosphate insecticides
      (malathion, methyl-pyrimifos, clorpirifos, temephos and fenthion), 4 pyrethroids
      (cypermethrin, deltamethrin, permethrin and lambda-cyhalothrin), and a carbamate
      (propoxur) were determined in order to know the state of resistance in a strain
      of Culex quinquefasciatus from a locality of the city of Medellin, Colombia.
      Resistance to all organophosphate insecticides, though with relatively lower
      values for methyloirimifos and fenthion, was observed. No resistance to lambda
      cyhalothrin and cypermethrin or to propoxur was found. These insecticides may be
      useful for the control of mosquitoes in Colombia. It was demonstrated by using
      the piperonil butoxide synergist that the oxidases of multiple function played an
      important role in the resistance to organophosphate insecticides and pyrethroids.
      The utilization of S.S.S. tributyl phosphotritiate revealed that the
      superproduction of unspecific esterases was a mechanism of resistance to
      organophosphate insecticides, except methyl-pirimifos and for perythroids, except
      lambda-cyhalothrin. This result should be taken into consideration for the
      strategies to be used to control Culex quinquefasciatus in Colombia. These two
      mechanism of resistance are not responsible for the resistance to propoxur. The
      electrophoretic analysis showed the presence of esterases B1, A6 and B6, which
      seem to have an important function in resistance.

PMID- 10349434
TI  - [The incidence of Culicidae in an urban area of Ciudad de La Habana during 1995].
AB  - In the present paper it is made an analysis of the incidence of culicides in the
      municipality of Marianao, Havana City, during 1995, after following the
      requirements of the National Program for the Eradication of Aedes aegypti. 6
      species of mosquitoes were found in the municipality, with a predominance of the
      Culex quinquefasciatus and Aedes mediovittatus species. 4 focuses of Aedes
      aegypti were detected during this period. It was found that the groups of
      deposits preferred by the culicides for their breeding in this municipality were
      other deposits, low tanks, artificial deposits and larva traps. The People's
      Councils 4 and 5 (Libertad and Pogolotti) had the highest number of focuses (967
      and 1,240, respectively, and therefore, they need more attention. It is analyzed
      the influence of the deficiencies of the public services, such as the collection
      of solid, wastes (garbage) and the existence of leakages and sewing overflows, on
      the proliferation of mosquitoes in the municipality.

PMID- 10349435
TI  - [The effect of 2 diets on the biological aspects of Blattella germanica
      (Dictyoptera: Blattellidae) under laboratory conditions].
AB  - It was conducted a study of 2 colonies of Blattella germanica (Dictyoptera:
      Blattellidae) kept since 1994 in the laboratory at 29 +/- 1 degrees C, 70-75% of
      relative humidity and with different foods: one on a diet without proteins,
      consisting in portions of potatoes (Solanum tuberosum, L.), ripe banana (Musa
      paradisiaca, L.) and a sugary solution 10%, and the other with a protein content
      of 20.45% composed of pulverized and dry laboratory food for rats and a source of
      water. 6 nymphal stages were found with both types of food. There were determined
      the times of interchanges and the time of nymphal development, which were much
      shorter among the nymphs fed with proteins. The longevity of each sex showed no
      significant differences in connection with the type of food used. The times of
      appearance and eclosion of the oothecae of each oothecal cycle were determined
      with both foods. It was found that the females deposited up to 5 oothecae during
      their lives with the 2 types of diet. The average of nymphs per ootheca among the
      females fed with proteins was much greater (t = 5.33; p < 0.001). The results of
      this study show that when the food for B. germanica contains proteins, its
      nymphal development is faster and its reproductive capacity increases, which
      means that protein is a necessary nutrient for the diet of this species.

PMID- 10349436
TI  - [The management of tuberculosis in the Republic of Cuba].
AB  - The essential aspects for the management of tuberculosis surveillance and control
      are described to propitiate their divulgation among to health professionals.
      Since 1970 there is an integrated program under way within the health services
      based on the localization of cases by the bacilloscopic examination and the
      sputum culture in symptomatic respiratory patients, the ambulatory controlled
      treatment, the investigation of the contacts of the notified cases, including the
      chemoprophylaxis with isoniacide, and the BCG vaccination to newborns. In 1995,
      the percentage of symptomatic patients detected at the general medicine offices
      was of 0.7%, whereas the percentage of the first bacilloscopy performed among the
      symptomatic individuals was of 78.6%, 99.5% of the detected contacts were
      investigated. 37.9% of the new cases were diagnosed at the primary health care
      level. After a decreasing trend maintained from 1979 to 1991, mortality has
      increased from 50 deaths (0.5 x 10(5)) in 1991 to 157 (1.4 x 10(5)) in 1995, and
      the incidence rose from 503 (4.7 x 10(5)) in 1991 to 1,574 (14.3 x 10(5)) in
      1994, and to 1,553 (14.0 x 10(5)) in 1995, which suggests that the increase
      observed during the last 6 years begins to stop. The primary resistance to
      tuberculostatics was of 3.5% in 1992-1995, and of 11.5% in 1996. A priority
      integrated program of surveillance and control adjusted to the present
      socioeconomic conditions of the country is still going on.

PMID- 10349437
TI  - [The reactogenicity and immunogenicity of the first Cuban vaccine against human
      leptospirosis].
AB  - A controlled double-blind trial was conducted with the participation of 80 adult
      volunteers of both sexes, who were randomly divided into groups of 40 individuals
      each one. The case-base study received the vaccine and the control group was
      administered placebo to know the safety, the behaviour of reactogenicity, and to
      star the immunogenicity studies of the first Cuban vaccine against human
      leptospirosis. The vaccine used in the case-base study was an inactivated and
      trivalent vaccine containing strains of Leptospira canicola, icterohaemorrhagiae
      and pomona, since they have the highest circulation in the country. The results
      obtained showed the inocuity of the vaccine as no adverse severe reactions were
      detected. The general symptomatology observed was low, where as febricula was the
      most common general symptom. It appeared during the first 3 days of observation
      and there were no significant differences between the 2 group. Only a mild pain
      at the site of the injection was reported as a local symptom, which was more
      frequent in the vaccinated group than in the control group (7.8 against 1.5%,
      respectively). The seroconversion obtained was of 29% by microagglutination, and
      of 34.2% by ELISA. The final results allowed to conclude that this vaccine is
      safe for human adults at the ages under study, and give the possibility to
      continue other studies in more advanced stages to complete the requirements for
      obtaining its license.

PMID- 10349438
TI  - [The identification of Cryptococcus neoformans var. neoformans in Cuban clinical
      isolates].
AB  - 50 strains of Cryptococcus neoformans of clinical origin were studied by using
      the canavanine-glycine-bromothymol blue (CGB) medium. 56% of the strains were
      isolated from AIDS patients, and 16% belonged to patients with kidney
      transplantation. 90% of the samples were obtained from the samples of
      cerebrospinal fluid, which corresponded to the classical form of presentation of
      cryptococcosis. All the strains were identified as C. neoformans var. neoformans,
      coinciding with previous reports made in Cuba. Knowing the varieties of C.
      neoformans, inferences can be drawn on the epidemiology, clinics and response to
      the treatment of cryptococcosis.

PMID- 10349439
TI  - [The standardization of the plaque reduction technic for differentiating a dengue
      infection from a yellow fever infection].
AB  - The plaque reduction neutralization assay was standardized to differentiate an
      infection caused by dengue from another infection produced by yellow fever. Serum
      samples from Cuban donors were used to this end. Information on previous
      vaccination against yellow fever was available. Samples from Costa Rican patients
      with a clinical picture of dengue and with no antecedents of vaccination against
      yellow fever were also utilized. The optimal plaque staining day was the fifth
      day and the smallest serum dilution capable of differentiating an infection
      resulting from dengue from another infection caused by yellow fever was of 1/5.
      According to the high specificity of the standardized technique, risk factor
      studies of dengue hemorrhagic fever could be made among individuals vaccinated
      against yellow fever, which is a present and important topic.

PMID- 10349440
TI  - [The incidence of adenoviruses in viral conjunctivitis].
AB  - A study about the incidence of Adenovirus on viral conjunctivitis was conducted.
      A sample design was made and samples of conjunctival exudate were taken from 150
      patients with diagnosis of apparently viral conjunctivitis at the "Ramon Pando
      Ferrer" Ophthalmological Hospital from July to December, 1994. Samples were
      inoculated in cell culture and the indirect immunofluorescence technique was
      applied to those with a cytopathogenic effect that suggested infection due to
      Adenovirus. Monoclonal antibodies were used against Adenovirus allowing to
      identify them as part of the Adenoviridae family. The hemagglutination technique
      was used with erythrocytes of monkeys and rats as an indicator system in order to
      group the isolates previously identified by the indirect immunofluorescence
      technique. Later on, it was made an analysis by restriction enzymes of the viral
      genome to enable typing. The results of this study showed an incidence of
      Adenovirus on viral conjunctivitis of 20%, with a confidence interval between 14
      and 26% and a reliability index of 95%. It was proved that serotype 37 caused
      conjunctivitis more frequently.

PMID- 10349441
TI  - [Herpesvirus detection in immunocompromised patients with meningoencephalitis by
      the polymerase chain reaction technic].
AB  - The multiple polymerase chain reaction technique was used to detect in a single
      assay tube the presence of herpes simplex virus (HSV), Cytomegalovirus (CMV).
      Epstein Barr virus (EBV), varicella zoster virus (VZV), and/or human herpes virus
      6 (HHV6). 50 cerebrospinal fluids from patients with AIDS and clinically
      suspected to have meningoencephalitis due to HSV were received and analyzed at
      the laboratories of Sexually Transmitted Diseases of the Virology Department of
      the "Pedro Kouri" Tropical Medicine Institute from 1993 to 1996. 4 of them were
      positive to HSV, 3 to CMV, 2 to VZV, and 1 to HHV6 for a positivity of 20%. The
      results of the PCR were correlated to the clinical findings presented by the
      patients at the time of the lumbar puncture. The introduction of this technique
      in the laboratory allows to have an easy, fast and useful tool for the diagnosis
      of meningoencephalitis due to herpesvirus.

PMID- 10349442
TI  - [The application of the polymerase chain reaction technic for the detection of
      human papillomavirus sequences].
AB  - The polymerase chain reaction technique was applied to detect sequences of human
      Papillomavirus (HPV) by controls of cellular lines of cervical cancer and of
      tissues obtained through biopsy with a HPV-positive clinical diagnosis. A set of
      consensus oligonucleotides, which are complementary to a highly conserved region
      within the open reading frame E1 of the viral genome of HPV affecting the
      cervical mucosa, was used. With these primers it was possible to amplify DNA
      sequences corresponding to HPV 6 and 11, considered in the low risk group, and to
      HPV 16, 18, 31 and 33, included in the high risk group. The study of the
      sensitivity of the amplification technique showed a level of detection of 3,5
      viral particles per each cellular diploid genome.

PMID- 10349443
TI  - [The susceptibility of Anopheles pseudopunctipennis larvae to parasitism by the
      nematode Romanomermis iyengari (Nematoda: Mermithidae), the state of Oaxaca,
      Mexico].
AB  - Mosquito larvae of the species Anopheles pseudopunctipennis Theobald 1901 were
      studied under laboratory and field conditions to evaluate the level of
      susceptibility to the parasitism of nematode Romanomermis iyengari Welch 1964.
      Doses of 5:1 and 10:1 and development stage II larvae collected in natural
      reservoirs were used for the laboratory assays. A dose of 1,000 preparasitic
      agents/m2 was applied to field trials. The results of the lab and field tests
      yielded high levels of infestation in larvae with values ranging from 90 to 100%
      and from 85 to 95%, respectively. A marked reduction of the larval densities was
      observed in the 5 treated reservoirs seven days later, which showed an elevated
      susceptibility of the anopheline species to mermithid parasitism.

PMID- 10349444
TI  - [The antimicrobial sensitivity and plasmid isolation in Plesiomonas
      shigelloides].
AB  - 30 strains of Plesiomonas shigelloides isolated from patients with acute
      diarrheal disease at different health centers of the country were studied. The
      were phenotypically characterized by conventional biochemical tests and the
      antimicrobial susceptibility to 11 drugs was determined by the Kirby Bauer's
      method. It was found that the strains of Plesiomonas shigelloides were sensitive
      to 7 and resistant to 6 of the investigated drugs. The presence of plasmids in 12
      of the 29 analyzed strains was determined and the diversity in their plasmidic
      patterns was proved.

PMID- 10349445
TI  - [The evaluation of the specific type of capsular polysaccharide of Cryptococcus
      neoformans as an immunogen and positive-control antigen].
AB  - The specific type of capsular polysaccharide of an autochthonous strain of
      Cryptococcus neoformans var. neoformans was obtained by using the method of
      selective precipitation with hexadimethrine bromide. The capsular polysaccharide
      was matched to lamb's erythrocytes and it was used as an immunogen in rabbits.
      Antibody titres of up to 1:32 were attained. Doble serial dilutions of the
      capsular polysaccharide were evaluated as positive control antigen by
      contraimmunoelectrophoresis, latex and ELISA techniques, showing biological
      activity.

PMID- 10349446
TI  - [The detection of antibodies, antigens and circulating immune complexes in acute
      and chronic fascioliasis. Preliminary results].
AB  - 24 patients with fascioliasis were studied. 19 of them were in the chronic stage
      and 5 in acute stage. The presence of antigens and of circulating immune
      complexes (CIC) was detected in 100% of the patients suffering from acute
      fascioliasis with less than 30 days of evolution of the clinical symptoms;
      whereas coproantigens were present in 100% of the chronic patients. In this group
      it was observed a considerable number of cases with elevated levels of
      antibodies. 43.7% of the cases with CIC were detected by using the precipitation
      technique with PEG and that of Clq deviation. A highly significant correlation
      was found between the eggs counting and the CIC levels by both techniques.
      Another important correlation was established between the eggs counting and the
      levels of coproantigens.

PMID- 10349447
TI  - Dermatitis causada por Hylesia metabus (Lepidoptera: Hemileucidae) en la region
      costera del Estado del Delta del Amacuro, Venezuela [Dermatitis caused by Hylesia
      metabus (Lepidoptera: Hemileucidae) in the costal region of the state of Delta
      Amacuro, Venezuela].
AB  - 2 cases of acute dermatitis caused by butterfly Hylesia metabus in an area that
      so far has not been considered as endemic for this species were presented. The
      dermatitis observed in these individuals may be described as very circumscribed,
      pruriginous, erythematous generalized protruding papules that may be compared
      with urticaria, and with a variable degree oedema. Monomorphic eruption
      consisting in small hard papules crowned by a little vesicle was also present.
      The lesions of these 2 patients evolved with intensely pruriginous papules for a
      week and after that they healed without dermatological sequelae.

PMID- 10349448
TI  - [A comparative study between different regimens for administering 2 doses of the
      Cuban anti-hepatitis B vaccine].
AB  - A controlled clinical trial, corresponding to stage 2, was conducted in a
      population of sound adult males aged 18-23 to evaluate the immunogenicity of 5
      schedules of Cuban vaccine against hepatitis B (Heberbiovac-HB [correction of
      Cheberbiovac-HB]). 5 groups were studied: I (control group 0, 1 and 6 months), II
      (0 and 2 months), III (0 and 4 months), IV (0 and 6 months), and V (0 and 8
      months). The results showed no significant differences as regards the percentage
      of seroprotection of any of the groups of 2 doses compared with the control of 3
      doses. It is concluded that between the first and the second dose there may be a
      period of time from 2 to 6 months with no need to reinitiate the schedule. This
      information will serve as a basis for a population based study to determine which
      schedule is the best to be used.

PMID- 10349449
TI  - [The serological diagnosis of HIV-1 in samples of dried blood on filter paper by
      the HIV-1 DAVIH Dot system].
AB  - Dried blood specimens spotted on filter paper were evaluated by the HIV-1 DAVIH
      Dot system from DAVIH Laboratories (Havana, Cuba). The samples used, 103 positive
      and 105 negative, were previously confirmed by DAVIH Blot from DAVIH
      Laboratories. In order to use the dried blood on filter paper some modifications
      were made to the original procedure regarding the times of incubation of the
      samples and conjugate, and the agitation in both stages. Relative sensitivity and
      specificity of 100 and 99.05%, respectively, were attained.

PMID- 10349450
TI  - [Apropos a case of filaria].

PMID- 10349451
TI  - [The emergence of epidemic neuropathy in 1992-1993].

PMID- 10349452
TI  - [The antigenic characteristics of the viruses isolated from the cerebrospinal
      fluid of patients with epidemic neuropathy].
AB  - During the epidemic of neuropathy occurred in Cuba from 1992 to 1994 viral agents
      antigenically related to the Coxsackie viruses were isolated from the
      cerebrospinal fluid of patients. To establish a function of these viruses in the
      etiopathogenesis of the disease, strains 47/93 IPK identified as Coxsackie A9 and
      the strain 44/93 of light cytopathic effect were selected to conduct a study of
      their antigenic characteristics by Western Blot. It was proved that there is an
      antigenic relationship between both strains and it was also demonstrated the
      absence of structural proteins in their native form among the agents of light
      cytopathic effect. According to these results, it is stated the possibility that
      persistence may be a mechanism through which these viruses take part in the
      etiopathogenesis of epidemic neuropathy in Cuba.

PMID- 10349453
TI  - [The nutritional-viral etiology of epidemic neuropathy. The Group for the Study
      of Epidemic Neuropathy].
AB  - Viral sequences of the cerebrospinal fluid were amplified by using
      oligonucleotides that are homologous to region 5' of the Enteroviruses. The
      results showed a great variability in the amplified sequences, suggesting the
      presence of enteroviral quasispecies with altered biological properties in the
      stressed individuals that may play an important role in the neurological damage.

PMID- 10349454
TI  - [Amino acids as biochemical markers in epidemic and endemic optic neuropathies].
AB  - It was studied the amino acids pattern in serum and cerebrospinal fluid of 12 and
      8 patients, respectively, suffering from optic epidemic neuropathy diagnosed
      between 1995 and 1997 (endemic period). The cerebrospinal fluid of 16 patients
      diagnosed during the epidemic (1992) was also studied. The analysis of amino
      acids in serum and cerebrospinal fluid was made by high resolution liquid
      chromatography with fluorescent detection, previous derivation with orthofthallic
      aldehyde. As in the previous study, no important deficiencies of the essential
      amino acids were observed in the serum of the studied patients. Lower
      concentrations of threonine, aspartic acid and taurine were found in the serum of
      patients with epidemic optic neuropathy diagnosed in the endemic period. Taurine
      plays an important role in the structure and function of photoreceptors of the
      retina. It is synthesized in the necessary amounts in man, so it must be supplied
      in the diet. As it is only present in food of animal origin, it is considered
      that the deficiency of taurine may contribute to the development of optic
      epidemic neuritis in our patients. Samples of cerebrospinal fluid were analyzed
      during the epidemic and endemic periods and it was observed an increase of the
      glutamic and aspartic acid in the epidemic period and of glutamic acid during the
      endemic. The excess of excitotoxic amino acids in the cerebrospinal fluid
      supports the previous neurocognitive studies that suggested the affection of the
      central nervous system in these patients.

PMID- 10349455
TI  - [The topographic diagnosis of the sympathetic nervous system lesions in Cuban
      epidemic neuropathy. The value of the sympathetic skin response].
AB  - The purpose of this study is to demonstrate from the electrophysiological point
      of view the existence of disorders of the autonomic nervous system (ANS) and to
      deepen in the probable topography of the lesions. The sympathetic skin response
      (SSR) was studied in 37 patients with Cuban epidemic neuropathy (CEN) and in 29
      sound individuals. The response to electrical stimulation with simultaneous
      registry in the 4 limbs was assessed. The latencies and amplitudes of the SSR
      registered in the lower limbs of patients were significantly different from those
      of the controls (p < 0.05). This difference between both groups was not observed
      in the upper limbs. These results are an objective and reproducible evidence of
      the injury of the ANS in the Cuban epidemic neuropathy. The highest intensity of
      affectation of the amplitudes of the SSR of lower limbs, with relative indemnity
      of those of the upper limbs, suggests a predominance of the axonal injury of the
      peripheral efferent branch towards the lower limbs that is congruent with the
      greatest affectation of the peripheral nerves in this localization.

PMID- 10349456
TI  - [New evidence of the antigenic relation between the viruses of epidemic
      neuropathy and the human nervous system. A study of the immune cellular response
      in patients with epidemic neuropathy and controls. A review of the topic].
AB  - A series of experiments was made at the Virology Department of the "Pedro Kouri"
      Institute of Tropical Medicine aimed at obtaining new evidences on the possible
      antigenic relations existing between the viruses isolated from patients with
      epidemic neuropathy and the structures of the human nervous system. According to
      the results it may be finally inferred that the persistence and/or autoimmunity
      may be considered as mechanisms through which the studied viruses participate in
      the etiopathogenesis of the epidemic neuropathy in Cuba. For future experiments
      it is very important to identify the possible viral epitopes involved in the
      molecular mimicry that are responsible for the probable autoimmune mechanisms or
      for the viral persistence.

PMID- 10349457
TI  - [The assessment of the nutritional status of patients with epidemic neuropathy in
      the year of its evolution. The biochemical indicators].
AB  - The nutritional status of a group of patients with epidemic neuropathy (EN) was
      reevaluated after a one-year follow-up to observe the changes occurred and to
      assess their relationship with the individual clinical evolution. 71 patients (40
      men and 31 women) were examined. 28 had optic epidemic neuropathy and 43 mixed
      epidemic neuropathy. Vitamins thiamine, niacin, A and E were determined and the
      values were compared with those of risk 21 days later. There was an improvement
      of these indicators after 21 days as a response to the treatment, and an increase
      one year later of the percentage of individuals deficient in or situated at the
      margin of thiamine and niacin, which reflects a nutritional unbalance without an
      apparent association with the clinical evolution that showed a trend towards the
      recovery of the patients. This disassociation between the clinics and the
      nutritional and vitamin status suggest that the pathogeny of the EN may be
      connected with non-nutritional factors. The deficiency found in the nutritional
      vitamin state could anticipate a worsening of the clinical picture and/or the
      appearance of clinical manifestations corresponding to deficiency diseases.

PMID- 10349458
TI  - [Epidemic neuropathy. An etiopathogenetic hypothesis].
AB  - An etiopathogenic hypothesis is explained taking into consideration the most
      significant results of the research performed on neuropathy as well as the latest
      knowledge about the infections produced by Enterovirus. The hypothesis allows to
      make a logical interpretation of these results; however, the new aspects included
      make it controversial in the light of the present knowledge to pathogeny by
      Enterovirus. Further research is needed to confirm this hypothesis.

PMID- 10349459
TI  - [A retrospective study of patients with epidemic optic neuropathy in a health
      area].
AB  - The sample of 104 patients who were diagnosed optic epidemic neuropathy at the
      health area of the "Rampa" Polyclinic in 1993 was reviewed. 50 of them were
      studied again. Visual acuity as well as the sensitivity to contrast by the Pelli
      Robson's method were explored. Ishihara's color-vision test was applied and an
      ophthalmological examination including fundus of the eye was made. All this was
      done by a group of experts who were searching temporary papillary paleness or
      lost of the bundles of papillomacular fibres, which are the diagnostic elements
      of the disease even in those cases that recover vision. 21 (42%) of the 50
      studied patients fulfilled the criteria established for these cases by the
      Ministry of Public Health concerning visual acuity and color vision to diagnose
      optic epidemic neuropathy, although only 14 (28%) were ratified as cases. The
      typical alterations of the fundus of the eye were described, confirming the
      diagnosis. Cases were classified according to the initial state of visual acuity
      and to evolution. 3 had had an affectation of the visual acuity of 0.1 or worse
      (severe), and only one patient had a mild affectation with 0.8 of vision. The
      rest ranged between 0.2 and 0.6. Only one patient had a serious sequela. The low
      percentage of cases ratified as optic epidemic neuropathy does not represent what
      happened in the whole country, but it may be considered as a pattern of what took
      place at those units with the same conditions during the peak of the epidemic.

PMID- 10349460
TI  - [The genomic characterization of the Cuban strain with a light cytopathic
      effect].
AB  - The genomic characterization of the strain of light cytopathic effect by
      nucleotide sequence is presented. It was possible to sequence 90% of the strain
      of light cytopathic effect. A close relationship with Coxsackie A9 was observed.
      The greatest mutations occurred in the region of the genome that codifies for the
      structural proteins. Therefore, it may be considered as a variant of Coxsackie A9
      never reported before.

PMID- 10349461
TI  - [The evolution of some food and nutrition indicators in Cuba starting from 1993].

PMID- 10349462
TI  - [The research and work of the Instituto de Neurologia y Neurocirugia on epidemic
      neuropathy from the 1st workshop in 1994 up to the date of the 2nd workshop in
      1998].

PMID- 10349463
TI  - Visual perception of human activity and gender in biological-motion displays by
      individuals with mental retardation.
AB  - By examining perception of biological-motion in three experiments, we
      investigated whether limitations in perceptual ability by individuals with mental
      retardation may extend to learning perceptual categories based on elements of
      actions. In two experiments individuals with mental retardation and age- and
      gender-matched controls reported gender and activity in randomly ordered point
      light displays. In Experiment 2 decision times were measured and in Experiment 3,
      the effect of training with feedback on discriminating gender was assessed.
      Individuals with mental retardation identified walking, running, and stair
      climbing without error but were less proficient in identifying throwing, had
      slower decision times for activity identification, and could not identify gender.
      For both groups feedback training improved gender identification in the short-
      and long-term. Improvements represented above-chance responding for the retarded
      group. Experimental outcomes are discussed in terms of capacity to classify
      perceptual stimuli as actions.

PMID- 10349464
TI  - Gender differences in the use of linguistic devices by youths with mental
      retardation: a preliminary analysis.
AB  - One potential influence on communication behavior that is often overlooked in the
      field of mental retardation is the effect of gender. Two recent studies reporting
      gender-related differences in social (Wilkinson & Romski, 1995) and semantic
      (Wilkinson & Murphy, 1998) aspects of communication have underscored the need to
      examine the role of gender in this population. The relative use by males and
      females with mental retardation of linguistic (grammatical) devices identified as
      characteristic of typical female speech (qualifying markers, question styles, and
      politeness terms) was examined. Females produced significantly more qualifying
      markers than did males, although neither question style nor politeness marking
      differentiated the two.

PMID- 10349465
TI  - Correlations among the Reiss Screen, the Adaptive Behavior Scale Part II, and the
      Aberrant Behavior Checklist.
AB  - Relations among instruments used in community mental health services for people
      with developmental disabilities were explored with 284 individuals. Correlation
      coefficients among the instrument subscales were interpreted in terms of
      statistical significance and effect size. Of the 157 coefficients, 44% were
      significant, p < .001, and 35% represented large effects, r > .50. Reiss Screen
      subscale scores correlated with Irritability, Lethargy, and Hyperactivity on the
      Aberrant Behavior Checklist (ABC) and with Social Behavior and Disturbing
      Interpersonal Behavior on the ABS Part II. Stepwise regression analyses
      predicting Reiss Screen scores from the ABS and ABC resulted in a significant
      regression, with an overall adjusted R2 of .67. Variance was largely accounted
      for by two ABS domains and two ABC subscales.

PMID- 10349466
TI  - Communication patterns of youth with mental retardation with and without their
      speech-output communication devices.
AB  - The communication skills of 13 youth with moderate or severe mental retardation
      were compared while they communicated with a "standard partner" with and without
      access to their communication devices. When participants employed the
      communication device, they were able to convey more appropriate information as
      well as clearer and more specific information to an unfamiliar adult partner than
      they were able to convey without the device. These findings highlight the
      distinct contributions the participants' use of an augmented communication device
      make to the overall communicative interaction.

PMID- 10349468
TI  - Recognition of facial emotional expressions from moving and static displays by
      individuals with mental retardation.
AB  - Moving and static videotaped and photographic displays of posed emotional
      expressions were presented to 12 adults with mental retardation and 12 without
      mental retardation to investigate the role of movement in the recognition of
      facial expressions of emotion. Participants chose the corresponding emotion
      portrayed by the displays from among six written and pictorial labels of the
      emotions. Results indicated that individuals with mental retardation were
      significantly poorer at identifying anger, fear, disgust, and surprise. Both
      groups performed significantly better on the moving as opposed to the static
      videotaped displays of the emotions sad and angry. Visual-perceptual limitations
      are likely contributors to the poorer performance of the group with mental
      retardation in recognizing moving and static facial expressions of emotion.

PMID- 10349467
TI  - Self-injurious behavior and Prader-Willi syndrome: behavioral forms and body
      locations.
AB  - With few exceptions (e.g., Lesch-Nyhan syndrome), the specific nature of self
      injury in relation to identified genetic syndromes associated with mental
      retardation is poorly understood. In the present study we surveyed the families
      of 62 persons with Prader-Willi syndrome to determine the prevalence,
      topographies, and specific body locations of self-injurious behavior. Self-injury
      was reported for 81% of the participants. Skin-picking was the most prevalent
      form, with the front of the legs and head being disproportionately targeted as
      preferred self-injury body sites. Individuals with the 15q11-q13 deletion injured
      significantly more body sites than did individuals with maternal disomy 15.
      Results are discussed in relation to previous self-injury body site findings and
      implications for the relevance of syndrome-specific behavioral phenotypes.

PMID- 10349469
TI  - Variability of stereotypic body-rocking in adults with mental retardation.
AB  - The variability of stereotypic body-rocking motions of adults with severe and
      profound mental retardation not on medication was examined through a kinematic
      analysis. A matched nonretarded group of adults was also examined in the
      production of preferred rates of body-rocking. The inter- and intra-individual
      variability of the body-rocking motions was, on average, higher for the
      individuals with mental retardation, although a few participants showed as low a
      variability as the least variable participants in the nonretarded group. These
      findings provide further evidence that the kinematic variability of stereotypies
      is not lower than that displayed by others engaged in similar movement activities
      and support the proposition that low variability of discrete kinematic variables
      may not be a defining feature of stereotypy.

PMID- 10349470
TI  - Sensitivity, functional analysis, and behavior genetics: a response to Freeman et
      al.
AB  - Freeman et al. (1998) asserted that sensitivity theory is circular, unsupported
      by empirical evidence, and represents an "either/or" decision in regard to
      applied behavior analysis. We reply by showing that sensitivities are objectively
      measured and that our theory permits testable predictions. Further, we briefly
      summarize the results of recent studies that support our theory, including
      investigations that link sensitivities to genes and challenging behavior.
      Finally, we reject the idea that sensitivity theory and functional analysis
      represent an "either/or" viewpoint and call again for research to integrate these
      approaches.

PMID- 10349471
TI  - [ERBB: an exemplary family].

PMID- 10349472
TI  - [Granular cell tumors of the skin of nonneural origin: report of 8 cases].
AB  - We report six cases of benign fibrous histiocytoma, one case of
      dermatomyofibroma, one case of cutaneous leiomyosarcoma with a granular cell
      component. Besides the clinical, histologic and immunohistochemical features of
      the primary lesion, these tumors do not express S100 protein in contrast to the
      classic granular cell tumor described by Abrikossoff. Such a component has no
      implication in prognosis, which remains related to the main lesion. Ignorance of
      this rare event can lead to misdiagnosis, requiring a total revision of the
      granular cell tumor entity.

PMID- 10349473
TI  - [Detection of respiratory syncytial virus using immunohistochemistry. Report of
      53 cases of sudden infant death].
AB  - We analyzed 53 cases of sudden infant death to detect immunohistochemical
      expression of respiratory syncytial virus on pulmonary sections. The virus was
      identified in 7 cases. The immunohistochemical staining was intracytoplasmic and
      mainly observed in bronchioles. Among these 7 cases, 6 showed severe pulmonary
      lesions which were assumed to be accountable for decrease. The inflammatory
      lesions related to respiratory syncytial virus were diffuse, located with the
      same intensity to either bronchi, bronchioles, alveoles and upper respiratory
      tract. The immunohistochemical staining was markedly heterogeneous, requiring
      numerous pulmonary samples.

PMID- 10349474
TI  - [Prognostic, therapeutic, exploratory tool for carcinogenesis: what is the role
      of ERBB-2 in breast cancer?].

PMID- 10349475
TI  - [Pulmonary endodermal tumor resembling fetal lung. Low grade adenocarcinoma of
      the fetal lung type].
AB  - Pulmonary endodermal tumor resembling fetal lung is a rare pulmonary neoplasm,
      classified either within the pulmonary blastomas spectrum or as a subtype of
      adenocarcinoma. We report a case revealed by a fever in a 24-year-old woman. The
      tumor measured 9 cm and extended into the lower right bronchus. The diagnosis was
      done on a biopsy performed during fiberoptic endoscopy. The patient was treated
      by lobectomy. She is well without disease 6 years after surgery. This type of
      predominantly epithelial tumor with neuroendocrine differentiation and a scanty
      non malignant stromal component should be identified in young women because of
      its favorable outcome after surgical resection. It must not be confused with
      ordinary adenocarcinoma nor metastatic adenocarcinoma, especially endometrioid
      type.

PMID- 10349476
TI  - [An unusual variant of urothelial carcinoma: the "nested variant of urothelial
      carcinoma." Report of two cases].
AB  - We report two cases of a poorly known variant of transitional cell carcinoma, the
      "nested variant of urothelial carcinoma". This tumor is composed of small islands
      or nests of transitional cells, presenting little atypia and mimicking von
      Brunn's nests. This low grade tumoral variant seems to behave as a high grade
      tumor of the same stage. Deep biopsies are necessary to display tumoral invasion,
      which allows the diagnosis. Importance of the knowledge of this entity is
      highlighted in order to avoid misdiagnoses that could delay appropriate therapy.

PMID- 10349477
TI  - [Breast-like carcinoma of the vulva].
AB  - Breast-like carcinomas of the vulva is a rare finding. Only 11 cases are reported
      in the literature. This article reports a painful tumor of the left vulvar labia
      in a 62 year-old woman. Excisional biopsy showed an infiltrating adenocarcinoma,
      histologically similar to a breast tumor with positive hormonal receptors. The
      origin of this tumor, ectopic mammary tissue or specific adnexal genito-anal
      gland, is discussed. From data of the literature, we offer guidelines for
      diagnosis, treatment and origin of this rare tumor.

PMID- 10349478
TI  - [Endocervical glial implant].
AB  - We report a new case of glial tissue in uterine cervix found in a 63 year-old
      woman with an abortion 30 years ago. The lesion, measuring 0.5 cm in diameter,
      showed a typical feature of mature glial tissue immunoreactive for the glial
      fibrillary acid protein. Hypothesis concerning its histogenesis (fetal graft,
      tumor, metaplasia) are discussed. Fetal implantation is likely as in the majority
      of published cases.

PMID- 10349479
TI  - [Congenital generalized dropsy and intrapericardial fetal teratoma. Report of a
      case of prenatal diagnosis].
AB  - Intrapericardial teratomas are rare tumors usually occurring in early infancy.
      Such a case was diagnosed in a 20 week old fetus, with a lethal outcome. About
      fifteen cases of intrapericardial teratoma have been reported in the fetal
      period. They are usually symptomatic, with a more or less severe pericardial
      effusion, sometimes complicated by cardiac compression and/or hydrops fetalis.
      Prognosis of the prenatally diagnosed pericardial teratomas is more related to
      the occurrence of hydrops fetalis than to the behavior of the tumor itself. The
      main interest of sonographic ante-natal diagnosis consists of the possible
      improvement of hemodynamic consequences through in utero pericardiocentesis.
      Macroscopic and microscopic features of this cardiac tumor are similar to those
      of extrapericardial teratomas. Most tumors discovered in fetal period are mature
      and histologically benign lesions. Only one case showed immature components. The
      coexistence of a malignant component (germ cell or non germ cell tumor) has been
      described in the postnatal and adulthood.

PMID- 10349480
TI  - [Cholesterol crystal embolisms in adenomatous polyposis coli].
AB  - Cholesterol crystal embolism is a serious complication of atherosclerosis
      responsible for renal, cutaneous and less often digestive manifestations. We
      report a case of cholesterol crystal embolization in an adenomatous colonic polyp
      with foci of adenocarcinoma in a patient with an abdominal aortic aneurysm taking
      anticoagulant therapy. This case shows that cholesterol crystal embolization may
      be diagnosed by microscopic examination of a colonic polyp.

PMID- 10349481
TI  - [Bone metastasis of a clear cell tumor].

PMID- 10349482
TI  - [An unusual prostatic carcinoma].

PMID- 10349483
TI  - [Chronic glomerular rejection of a renal graft].

PMID- 10349484
TI  - [An odontogenic mandibular tumor].

PMID- 10349485
TI  - [How to optimize lymph node dissection in colorectal cancers. A technique for
      simple and efficacious clarification].
AB  - Studies relating to the prognosis of colorectal carcinomas insist on the quality
      of mesocolic examination and on the frequency of metastases in minute lymph
      nodes. The aim of our study was to evaluate an easy, rapid and new clearance
      method recently described by Koren et al. Twenty-one surgical specimens for
      colorectal carcinomas have been investigated. After lymph node examination with
      the traditional method, the mesocolic fat was immersed in a clearing solution.
      After 6 hours, lymph nodes stood out as white chalky nodules, and were dissected.
      By the traditional method 182 lymph nodes were detected and 89 additional lymph
      nodes after clearing. In one case, the detection of a metastasis in lymph node
      after clearing allowed to upstage the tumour from Dukes B (N0) to Dukes C (N+).
      This easy and inexpensive method allows the detection of minute lymph nodes and
      helps to establish a more accurate staging.

PMID- 10349486
TI  - [Malignant granular cell tumors. Report of a case of anal localization].

PMID- 10349487
TI  - [Recommendations of the FNCLCC Sarcoma Group for pathologic management of soft
      tissue sarcoma in adults].

PMID- 10349488
TI  - Resonance behaviors and mirror neurons.
AB  - This article is subdivided into two parts. In the first part we review the
      properties of a particular class of premotor neurons, the "mirror" neurons. With
      this term we define neurons that discharge both when the monkey makes a
      particular action and when it observes another individual (monkey or human)
      making a similar action. The second part is an attempt to give a
      neurophysiological account of the mechanisms underlying behaviors where an
      individual reproduces, overtly or internally, movements or actions made by
      another individual. We will refer to these behaviors as "resonance behaviors". We
      distinguish two types of resonance behavior. The first type is characterized by
      imitation, immediate or with delay, of movements made by other individuals.
      Examples of resonance behavior of this type are the "imitative" behaviors
      observed in birds, young infants and patients with frontal lesions. The second
      type of resonance behavior is characterized by the occurrence, at the observation
      of an action, of a neural pattern, which, when internally generated, determines
      the making of the observed action. In this type of resonance behavior the
      observed action is, typically, not repeated (overtly). We argue that resonance
      behavior of the second type is at the basis of the understanding of actions made
      by others. At the end of the article we review evidence of mirror mechanisms in
      humans and discuss their anatomical localizations.

PMID- 10349489
TI  - Functional magnetic resonance imaging as a tool for investigating human cortical
      motor function.
AB  - Non-invasive functional magnetic resonance imaging (fMRI) mapping techniques
      sensitive to the local changes of blood flow, blood volume, and blood oxygenation
      which accompany neuronal activation have been widely used over the last few years
      to investigate the functional organization of human cortical motor systems, and
      specifically of the primary motor cortex. Validation studies have demonstrated a
      good correspondence between quantitative and topographic aspects of data acquired
      by fMRI and positron emission tomography. The spatial and temporal resolution
      affordable by fMRI has allowed to achieve new important information on the
      distributed representation of hand movements in multiple functional modules, and
      on the intensity and spatial extent of neural activation in the contralateral and
      ipsilateral primary motor cortex in relation to parametric and nonparametric
      aspects of movement and to the degree of handedness. Neural populations with
      different functional characteristics have been identified in anatomically defined
      regions, and the temporal aspects of the activation during voluntary movement
      tracked in different components of the motor system. Finally, this technique has
      proved useful to deepen our understanding of the neural basis of motor imagery,
      demonstrating increased activity in the primary motor cortex during mental
      representation of sequential finger movements.

PMID- 10349490
TI  - Intraoperative motor evoked potentials monitoring in spinal neurosurgery.
AB  - Neurological damage may follow even a technically accurate spinal surgery. The
      intraoperative monitoring of neurological functions put at risk by the operation
      is a method utilized to correctly identify the topography of neural structures
      and to avoid surgical insults. SEPs monitoring is 20 year old, and only recently
      direct motor tract monitoring has become possible. Transcranial electrical motor
      cortex stimulation with single pulses or with short trains of stimuli and
      recording of the evoked responses from the spinal epidural space (D-waves) and
      from limb muscles is a reliable and safe technique for monitoring corticospinal
      tract activity even under general anesthesia. The method has a solid theoretical
      experimental background. Its clinical application has demonstrated high
      sensitivity and specificity. Intraoperative MEPs monitoring is nowadays
      considered indispensable during spinal neurosurgery.

PMID- 10349492
TI  - Facilitation and interference components in the Simon effect.
AB  - In four experiments we investigated whether the Simon effect consists of both
      facilitation and interference. In Experiment 1 subjects had to press one of two
      lateralized keys in response to one of two stimuli (a rectangle or a square). The
      stimuli were presented at fixation or to the right or left of it. The stimulus
      response mappings could be corresponding (i.e., right key--rectangle or square on
      the right side), non-corresponding (i.e., right key--rectangle or square on the
      left side), or neutral (i.e., stimulus in the center). Results showed both
      facilitation and interference effects, but interference was three times greater
      than facilitation. To test whether the neutral position was favored by visual
      acuity, Experiments 2, 3 and 4 used slight different displays where visual acuity
      was the same at every stimulus position. Results indicated that the Simon effect
      is comprised of facilitation and interference components of the same magnitude.
      These findings were discussed with reference to dual-route models of the Simon
      effect.

PMID- 10349491
TI  - Possible recoding of visual space in covert orienting tasks.
AB  - Reaction time to lateralized light targets is longer if targets are preceded by
      light stimuli in the same visual hemifield compared to when they are preceded by
      light stimuli in the opposite visual hemifield. The effect is probably caused by
      interactions between implicit oculomotor tendencies and covert shifts of
      attention. We show here that a similar, but much smaller, ipsilateral RT
      inhibition can be observed when all stimuli are presented in a display completely
      lateralized to one hemifield, where ipsilateral and contralateral are defined
      with respect to the midpoint of the display. The persistence of ipsilateral
      inhibition with unilateral stimulus displays can be accounted for by a recoding
      of visual space predicated on the centering of covert attention on the display
      midpoint rather than on the fixation point. The recoding seems to affect the
      control of covert attention and perhaps oculomotor control as well.

PMID- 10349493
TI  - Hippocampal type 1 (movement-related) theta rhythm positively correlates with
      serotonergic activity.
AB  - To investigate the relationship between the hippocampal [symbol: see text]
      activity (or Rhythmical Slow Activity, RSA) and the hippocampal serotonergic
      activity during spontaneous behavior, simultaneous recordings of i) hippocampal
      EEG, ii) sleep-wake activity, and iii) hippocampal levels of the serotonin (5-HT)
      metabolite 5-hydroxyndolacetic acid (5-HIAA--measured by in vivo voltammetry and
      infrared telemetry) were performed. The results show that hippocampal type 1 RSA
      recorded during wakefulness and voluntary movements (such as walking), is
      positively correlated to hippocampal 5-HIAA levels. Since in the experimental
      conditions used in the study, 5-HIAA levels are a reliable index of 5-HT release,
      the results support the hypothesis that hippocampal type 1 RSA is generated by a
      serotonergic mechanism. In contrast, hippocampal type 2 RSA recorded during
      desynchronized sleep is negatively correlated with 5-HT release, suggesting a
      different neurochemical mechanism for its production. These results also show
      that, in the experimental condition of this study, hippocampal RSA power spectrum
      has a main peak frequency of 3.5 during wakefulness, and of 6.5 Hz during
      desynchronized sleep.

PMID- 10349494
TI  - Selective brain cooling is impaired in REM sleep.
AB  - There are systemic and selective mechanisms for brain cooling in mammals. The
      difference between the temperatures of the vertebral and the carotid blood
      perfusing the brain is determined by selective heat loss and is, therefore, a
      quantitative indicator of the intensity of selective brain cooling. Across the
      wake-sleep cycle systemic and selective brain cooling are affected by state
      dependent autonomic changes. In REM sleep selective brain cooling is impaired.

PMID- 10349495
TI  - Cerebral blood flow regulation in REM sleep: a model for flow-metabolism
      coupling.
AB  - The pattern of metabolic and circulatory changes occurring during REM sleep in
      the whole brain is also observed at a regional level in different instances of
      functional activation. This pattern is characterized by an increase in metabolic
      rate, blood flow, glucose and oxygen uptake, the increase in glucose uptake
      generally exceeding oxygen uptake. A model of interpretation is presented, based
      on the assumption that substantial limitation to oxygen diffusion exists in the
      brain. According to the model, microregions lying at mid-distance between
      capillaries may become hypoxic, depending on metabolic rate and blood-cell PO2
      difference. At increasing metabolic rates, O2 consumption in pericapillary
      microregions increases and the PO2 drop becomes steeper. As a consequence, in
      microregions far from capillaries a decrease in O2 availability occurs, in
      concomitance with the increase in metabolic rate, so that non-oxidative glucose
      metabolism develops locally. A similar spatial PO2 pattern forms in the case of
      arterial hypoxia, when capillary PO2, and then blood-cell PO2 difference, is
      reduced. The hypoxic microregions are the source of vasodilatatory messages, the
      consequent vasodilatation increasing average capillary PO2 and then favoring O2
      diffusion to the tissue. Oxygen thus appears to be a better candidate than
      glucose as a mediator of blood flow-metabolism coupling. This is supported by its
      higher extraction fraction and by the fact that, in physiologic conditions,
      arterial hypoxia (and not hypoglycemia) acts on cerebral blood flow. Moreover,
      the diffusion capacity of glucose in the brain is higher than that of oxygen, so
      that diffusion limitation is more likely to occur for oxygen. The present model
      allows consistent organization of the stereotyped changes in cerebral blood flow
      and glucose and oxygen uptake occurring both in REM sleep and in other instances
      of brain activation.

PMID- 10349496
TI  - Mechanisms of axonal plasticity.
AB  - GAP-43 plays an important role in axonal plasticity by guiding growth cones
      rather than supporting axonal elongation. In Purkinje cells that show no
      regenerative responses and no GAP-43 expression after axotomy, the simple
      addition of GAP-43 gene induces the formation of branched plexuses typical of
      sprouting growth. Purkinje cells can express some growth-associated proteins, but
      never GAP-43, when axotomy is made very close to cell body or when an antibody
      for the myelin-associated inhibitory molecules is applied to intact cells both in
      vivo and in vitro. Also in these conditions they are unable to show new axonal
      profiles even in a permissive environment that allows inferior olive cells to
      regenerate and reinnervate their target cells. We suggest that GAP-43 is a key
      molecule to initiate axon growth while other genes are necessary to develop a
      full regenerative program.

PMID- 10349497
TI  - Pheromone signalling in the mouse: role of urinary proteins and vomeronasal
      organ.
AB  - The lipocalin protein family is characterized in structure by a conserved
      hydrophobic pocket which can bind small volatile odorants. The Major Urinary
      Proteins (MUPs) are a class of lipocalins found in the urine of adult male mice
      which concentrate in the urine odorants which confer a characteristic odor. The
      behavioural as well as the endocrine effects of mouse urine and MUPs are briefly
      reviewed, suggesting a complex role is pheromonal communication. Some recent data
      on the molecular receptors of the vomeronasal organ further suggest a complex
      interaction with the MUP system.

PMID- 10349498
TI  - Is the "nonspecific" thalamus still "nonspecific"?
AB  - The classical concept of "nonspecific" thalamus, as distinguished from the
      principal thalamic nuclei (i.e. the primary sensory, motor and limbic relays) is
      here briefly revisited in the light of anatomical investigations performed in the
      last decades, and primarily those based on tract tracing techniques. Altogether
      these data pointed out that the so-called "nonspecific" thalamus is composed by a
      heterogeneous collection of nuclear masses, which display not only species
      differences, but also marked internuclear variations in their cytological and
      neurochemical features, connections, areal and laminar distribution upon the
      cortex, and functional properties. Thus, the "nonspecific" thalamus exerts a
      modulatory role on cortical activity, chiefly regulated at the intrathalamic
      level by the interplay between the thalamic reticular nucleus and the
      interneurons and projection neurons of the dorsal thalamus. However, each of the
      components that have been traditionally considered as "nonspecific" also
      subserves selective roles in the transfer of different kinds of information from
      the thalamus to the cerebral cortex and basal ganglia.

PMID- 10349499
TI  - Roman ruins in the basement of the Institute of Physiology of the University of
      Pisa.

PMID- 10349500
TI  - Pesticides and Parkinson's disease.
AB  - Epidemiological studies and case reports provide evidence for an association
      between Parkinson's disease and past exposure to pesticides. Susceptibility to
      the effects of pesticides and other putative neurotoxins depends on variability
      in xenobiotic metabolism possibly generated by genetic polymorphisms, aging and
      variation in exposure to environmental agents including pesticides. The simplest
      mechanistic hypothesis for the association of pesticides with Parkinson's disease
      is that pesticides or their metabolites are directly toxic to mitochondria,
      although modulation of xenobiotic metabolism by pesticides provides an adjunct or
      alternative hypothesis.

PMID- 10349501
TI  - Dopamine imaging markers and predictive mathematical models for progressive
      degeneration in Parkinson's disease.
AB  - We conducted PET imaging studies of modulation of dopamine transporter function
      and MRS studies of neurochemicals in idiopathic primate Parkinson's disease (PD)
      model induced by long-term, low-dose administration of MPTP. MR spectra showed
      striking similarities of the control spectrum of the primate and human striatum
      as well as MPTP-treated primate (six months after cessation of MPTP), and
      Parkinson's disease patient striatum (68 year old male; Hoehn-Yahr scale II; 510
      mg/d L-DOPA). The choline/creatine ratio was similar in the MPTP model and human
      parkinsonism, suggesting a possible glial abnormality. The progressive
      degeneration of dopamine re-uptake sites observed in our PD model can be
      expressed by a time dependent exponential equation N(t) = N0 exp (-(0.072 +/-
      0.016) t), where N0 represents intact entities (dopamine re-uptake sites before
      MPTP) and 0.072 per month is the rate of degeneration. When the signs of PD
      appear, N(t) is about 0.3-0.4 times N0. Interestingly, this biological
      degenerative phenomena has similar progression to that observed in cell survival
      theory. According to this theory and calculated degeneration rate, predictive
      models can be produced for regeneration and protective treatments.

PMID- 10349502
TI  - IL-1 beta, IL-2, IL-6 and TNF-alpha production by peripheral blood mononuclear
      cells from patients with Parkinson's disease.
AB  - The capacity of peripheral blood mononuclear cells (PBMC) from patients with
      treated Parkinson's disease (PD) to produce interleukin (IL) IL-1 beta IL-2, IL
      6, tumor necrosis factor (TNF)-alpha and the proliferative response to mitogens,
      was compared with that from cells from healthy subjects. The production of IL-2
      and the mitogen response were significantly lower in PD patients, whereas the
      secretion of IL-1 beta, IL-6 and TNF-alpha were significantly enhanced. To
      evaluate the role of levodopa in creating immunological alterations, PBMC of
      patients and controls were incubated with concentrations of the drug extrapolated
      from those used in clinical practice. Levodopa caused an inhibition of mitogen
      induced proliferation, stimulation of IL-6 and TNF-alpha production, whereas the
      secretion of IL-1 beta and IL-2 was not affected. The results of the study
      provide a further support for the interrelationship between the central nervous
      and immune system. In addition, the data indicate that the immunological
      alterations found in PD may be partially attributed to levodopa administration.

PMID- 10349503
TI  - Decreased phagocytic function in patients with Parkinson's disease.
AB  - To determine the phagocytic function of the peripheral blood polymorphonuclears
      from patients with treated and untreated Parkinson's disease (PD), these cells
      were incubated with latex particles and the number of phagocytes, as well as the
      number of particles engulfed by each individual cell, were counted. Cells of
      untreated PD patients were significantly less phagocytotic than those of matched
      subjects without neurological or immune disorders (24% vs. 45%, P < 0.001). In
      addition, phagocytes from PD patients engulfed less particles per cell than those
      of the controls (8.4 +/- 0.7 vs. 16.5 +/- 1.3, P < 0.001). There was no
      significant difference in both functions in untreated and treated PD. The results
      indicate that in addition to the known immune alterations in patients with PD,
      the ability of their peripheral blood phagocytic cells to engulf latex particles
      is impaired.

PMID- 10349504
TI  - Therapy of behavioral disorders in Parkinson's disease.
AB  - Behavioral disturbances in Parkinson's disease (PD) are a common source of
      disability to both patients and their families, but there is a considerable
      controversy regarding their frequency and their neuropathological and
      neurochemical bases. Since they are so common, the disorders associated with PD
      should be well recognized, and proper management by neurologists is required. The
      most frequent behavioral disturbances encountered in patients with PD are
      depression, anxiety, cognitive impairment and dementia. Also frequent are sleep
      disorders such as sleep fragmentation, REM sleep behavior disorder, insomnia and
      altered dreaming. The most troublesome situations come from drug-induced
      psychiatric states, such as delusional states, hallucinations, paranoid ideation,
      delirium, and confusion. The treatment of these behaviors is reviewed here.

PMID- 10349505
TI  - Non-small cell lung cancer: report on the 5th central European lung cancer
      conference.
AB  - Organized by the International Association for the Study of Lung Cancer (IASLC),
      the European Organization for Research and Treatment of Cancer (EORTC), the
      European Lung Cancer Working Party, and with the support of several learned Czech
      societies, the 5th central European lung cancer conference was held in Prague
      from September 13th to 16th. Over 500 participants from different disciplines
      (surgery, chemotherapy, radiotherapy, chest medicine) attended the meeting, which
      was once again shown to be an important forum for interchanges. The various
      specialists involved in the management of lung cancer patients were able to
      discuss recent progress, problems to be resolved, and prospects for the future.
      The present article is designed to report the main communications relating to the
      most frequent type of lung cancer, non-small cell lung cancer (NSCLC).

PMID- 10349506
TI  - Genetics of Parkinson's disease.
AB  - Here we review familial Parkinson's disease from clinical, as well as molecular
      genetic aspects. To date, two genes responsible for familial Parkinson's disease
      have been identified: one is the alpha-synuclein gene located in the long arm of
      chromosome 4, and the other is the parkin gene located in the long arm of
      chromosome 6. The mode of inheritance of the former is autosomal dominant and
      clinical features consist of levodopa-responsive parkinsonism; the age of onset
      is younger than that of the sporadic cases (in their 40s), and the progression is
      faster (average disease duration approximately nine years). The latter form is
      transmitted as an autosomal recessive, and clinical features consist of early
      onset (in their 20s), levodopa-responsive parkinsonism, and a slow progression of
      the disease. In addition, the tau gene has been shown to be the disease gene for
      familial frontotemporal dementia and parkinsonism linked to chromosome 17. There
      are many other clinical phenotypes of familial Parkinson's disease among which
      three forms have been mapped to certain chromosome loci: one is in the short arm
      of chromosome 2, the two other forms are in the different loci of the short arm
      of chromosome 4. All of them are transmitted as autosomal dominant traits
      manifesting levodopa responsive parkinsonism. There still exists however, other
      clinical phenotypes of chromosome loci which are not known. Molecular cloning of
      these familial Parkinson's disease genes and the elucidation of the functions of
      the proteins encoded will certainly contribute greatly to the investigation of
      the etiology and pathogenesis of more common sporadic form of Parkinson's
      disease.

PMID- 10349507
TI  - Pathophysiology of Parkinson's disease.
AB  - Parkinson's disease is a progressive disease with selective dopaminergic neuronal
      loss. The pathophysiology is at present better understood with plurifactorial
      etiology, including genetic predisposition and environmental toxic factors. The
      mechanisms of cell death are based upon oxidative stress and apoptosis. The
      heterogeneity of dopaminergic neuronal loss leads to etiopathogenic clues. In the
      same way, the model of functional organization of basal ganglia circuitry gives a
      basis for further experimental and therapeutic research.

PMID- 10349508
TI  - Plasma chitotriosidase activity in patients with beta-thalassemia.
AB  - Chitotriosidase, a macrophage marker, which is extremely increased in plasma of
      Gaucher patients, was measured in patients with beta-thalassemia, an
      haematological disorder characterized by the genetic defect of beta-globin chains
      synthesis resulting in unproductive erythropoiesis and enormous expansion of the
      reticuloendothelial system. Plasma chitotriosidase was increased to a variable
      extent in 13 of 70 patients with beta-thalassemia major treated with the intense
      transfusion regimen and iron chelation therapy. It was normal in 22 and slightly
      elevated in 3 subjects with beta-thalassemia intermedia which were not
      transfused. The highest levels of plasma chitotriosidase, as high as in Gaucher
      patients, were found in 7 (10%) of the beta-thalassemia major patients which also
      had the highest degree of iron overload as judged by their serum ferritin level
      (> 3000 ng/ml), high SGPT level and elevated urinary iron excretion. To our
      knowledge, beta-thalassemia is hitherto the only disorder in which an increase of
      plasma chitotriosidase, comparable to that seen in Gaucher disease, may occur.
      The increase of plasma chitotriosidase activity in beta-thalassemia patients with
      high iron overload, could be related to an iron mediated damage to the lysosomal
      apparatus. In addition, similarly to Gaucher disease, the increased
      chitotriosidase production in beta-thalassemia might reflect macrophage
      activation probably related to the intracellular iron overload, storage of
      erythrocytes membrane break-down products and oxidation of excess alpha
      hemoglobin subunits. Further studies are required to define the role of
      chitotriosidase evaluation to assess the efficacy of chelation therapy in
      reducing the macrophage activation due to intracellular iron overload in beta
      thalassemia.

PMID- 10349509
TI  - The role of calcium metabolism in human red blood cell ageing: a proposal.
AB  - The mechanisms of recognition, trapping and destruction of senescent human
      erythrocytes are not completely understood. Here we discuss some evidences
      supporting the idea that red cell ageing is closely related to a progressive
      increase in intracellular ionic Ca. This in turn, is the determining factor of a
      series of events such as Ca pump proteolysis and opening of the Ca-dependent K
      channel, that finally lead to the removal of old cells by macrophages at spleen
      level.

PMID- 10349510
TI  - The proteasome regulates caspase-dependent and caspase-independent protease
      cascades during apoptosis of MO7e hematopoietic progenitor cells.
AB  - Withdrawal of trophic support from growth factor-dependent MO7e human myeloid
      progenitor cells induces apoptosis characterized by DNA fragmentation and
      degradation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).
      Inhibitors of caspase (ICE) protease family members did not inhibit apoptosis or
      DNA fragmentation induced by factor withdrawal, but blocked degradation of DNA
      PKcs. Thus, caspase activity accounts for only a component of the apoptotic
      program in MO7e hematopoietic cells. The protease inhibitor TPCK, but not other
      protease inhibitors, blocked DNA fragmentation, but not degradation of DNA-PKcs
      during apoptosis of MO7e cells. Thus, caspase-independent and caspase-dependent
      protease cascades mediate distinct features of MO7e cell apoptosis. The
      proteasome inhibitors calpain inhibitor I and lactacystin promoted DNA
      fragmentation, degradation of DNA-PKcs and apoptosis of MO7e cells. The ability
      of lactacystin to promote DNA fragmentation was abrogated by TPCK, but not by
      caspase inhibitors, whereas the ability of lactacystin to promote degradation of
      DNA-PKcs was blocked by caspase inhibitors, but not by TPCK. Thus, caspase
      dependent and caspase-independent protease cascades are downstream of and
      regulated by the proteasome, which plays a central role in regulating the
      multiple protease cascades that induce apoptosis.

PMID- 10349512
TI  - Advantages of the CBA mouse in leukemogenesis research.
AB  - The objectives of this review are to: (a) demonstrate that the male CBA/Ca mouse
      has several characteristics that make it an excellent animal for the study of
      leukemogenesis, (b) show that several of the genetic abnormalities observed in
      the male CBA/Ca mouse during the development of radiation induced acute myeloid
      leukemia (AML) are syntenic with those frequently detected in patients with
      myeloid disorders such as myelodysplastic syndrome and AML, (c) illustrate that
      leukemia-related chromosomal lesions are the indicators for high risk
      individuals.

PMID- 10349511
TI  - Human hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase) encoded at 1p36:
      coding sequence and expression.
AB  - Using the published protein sequence from a rabbit microsomal glucose-6-phosphate
      dehydrogenase G6PD we have isolated and sequenced a cDNA clone coding for its
      human equivalent, which is also known as hexose-6-phosphate dehydrogenase (H6PD)
      and glucose dehydrogenase. The corresponding genomic sequence is in the databases
      enabling its localization to chromosome 1p36. The gene spans 37 kb and consists
      of 5 exons, the fifth of which codes for more than half of the 89 kDa protein.
      The first intron is a 10 kb insertion in the 5' untranslated sequence. The
      predicted mRNA has an exceptionally long (6.5 kb) 3' untranslated sequence. The
      predicted protein shows extensive homology with X-linked G6PD, suggesting the two
      genes share a common ancestor but no intron positions are conserved between the
      two genes suggesting the gene duplication was an ancient event. The C-terminal
      portion of the protein is not homologous with G6PD but shows limited homology
      with proteins of unknown function found throughout evolution and encoded next to
      G6PD in various micro-organisms. Intriguingly this C-terminal portion has some
      homology with the N-terminal sequence of Plasmodium falciparum G6PD.

PMID- 10349513
TI  - Targeted remodeling of human beta-globin promoter chromatin structure produces
      increased expression and decreased silencing.
AB  - The chromatin structure of the human beta-globin gene locus assumes a
      transcriptionally-active conformation in erythroid cells. One feature of this
      chromatin reorganization is the formation of DNase 1 hypersensitive sites in the
      regions of active globin gene promoters. This reorganization requires the globin
      locus control region and is associated with normal expression of the beta-like
      globin genes. To determine whether it is possible to artificially enhance the
      opening of the chromatin structure of a minimal beta-globin promoter, we placed a
      101bp, erythroid-specific DNase 1 hypersensitive site-forming element (HSFE)
      immediately upstream of the beta-globin promoter and gene. This element includes
      binding sites for NF-E2, AP-1, GATA-1 and Sp-1. Constructs were stably
      transfected into murine erythroleukemia cells and promoter chromatin structure
      and gene expression were analyzed. The HSFE induced an area of enhanced DNase 1
      hypersensitivity extending from the transcriptional start site to -300bp of the
      artificial promoter and significantly increased the proportion of beta-globin
      promoters in an open chromatin configuration. This remodeling of promoter
      chromatin structure resulted in 3-fold increases in beta-globin gene
      transcription and induction, and inhibited long-term beta-globin gene silencing.
      These results indicate that a relatively small cis-acting element is able to
      enhance remodeling of promoter chromatin structure resulting in increased beta
      globin gene expression.

PMID- 10349514
TI  - Alternate splicing produces a soluble form of the hereditary hemochromatosis
      protein HFE.
AB  - HFE is a non-typical MHC class 1-type protein that is mutated in hereditary
      hemochromatosis. The purpose of this study was to identify possible splice
      variants of HFE mRNA and investigate the regulation of these isoforms in duodenum
      and liver of patients with normal and altered iron stores. RT-PCR was performed
      using HFE specific primers and duodenal RNA obtained from patients with
      hemochromatosis, iron deficiency, secondary iron overload and normal controls.
      The reaction products were visualized by Southern blot and identified by DNA
      sequence analysis. Additional studies were performed on RNA isolated from liver
      and a range of human tissues. A truncated (soluble) form of HFE protein was
      identified that lacks the transmembrane domain and occurs as a result of
      alternative splicing. Soluble HFE was found predominantly in the duodenum,
      spleen, breast, skin and testicle. In hereditary hemochromatosis full length HFE
      was the predominant isoform present in the duodenum similar to iron deficiency.
      Alternate splicing produces soluble HFE that may have a unique function to
      regulate cellular iron transport.

PMID- 10349515
TI  - The role of c-myb during the maturation of murine CFU-E.
AB  - Proper expression of the c-myb proto-oncogene is essential for definitive, but
      not primitive erythropoiesis. To examine the role of c-myb during adult
      erythropoiesis, we incubated purified murine colony-forming units (CFU-E) with a
      c-myb-specific antisense oligodeoxynucleotide (AS-oligo) in order to diminish
      expression levels. By western blot analysis, c-myb expression was reduced during
      the first seven hours of AS-oligo treatment as compared to untreated cells. We
      then quantitated the amount of heme synthesized in CFU-E treated with c-myb AS
      oligo, a random sequence oligo or no oligo. No significant differences were seen
      in the amount of heme synthesized during 42 hours of erythroid culture with
      either high levels (1 U/mL) or physiological levels (20 mU/mL) of Epo. In
      contrast, CFU-E treated with an AS-oligo directed toward mRNA encoding the first
      enzyme of the heme biosynthetic pathway in erythroid cells (d-aminolevulinate
      synthase) demonstrated a 65% reduction in the amount of heme synthesized. We
      conclude that the major role of c-myb during hematopoiesis must be in progenitor
      cells antecedent to the CFU-E stage and may possibly involve the establishment of
      the genetic program directing the formation of red blood cells.

PMID- 10349516
TI  - Reframing special educational needs: shaping a shared agenda.

PMID- 10349517
TI  - The Perceived Illness Experience Scale (PIE): reliability and validity revisited.
AB  - This paper reports psychometric evaluation of the Perceived illness Experience
      Scale (PIE). This includes eight sub-scales developed to determine the impact of
      a chronic illness from the patient's perspective. The sample included 34 patients
      (mean age = 17 years) successfully treated by limb salvage procedures for a
      primary bone tumour. Patients also completed measures of well-being (the SF-36)
      and function. To determine the relationship between patient and proxy ratings,
      mothers also completed the PIE. Evidence of construct validity of the PIE was
      obtained from significant correlations between PIE and SF-36 scale scores. There
      were also significant correlations between function and three of the eight sub
      scales of PIE. Good correlations between patients' and mothers' ratings suggests
      that mothers can be useful proxy raters where patients are unable to provide data
      themselves. These data suggest that evaluations of patients following limb
      salvage surgery should not be limited to function measures alone, but need to
      include assessment of the perceived impact of treatment.

PMID- 10349518
TI  - A model for the assessment and management of children with multiple disabilities.
AB  - Children with multiple disabilities present complex management problems, both for
      their families and for the professionals involved in their care. For any one
      child, the list of functional and medical problems that need to be addressed is
      frequently reflected in an even longer list of involved professionals, leading to
      conflicting advice and problems in co-ordination of care. A hierarchical model
      for assessment and management is proposed, which highlights the interdependency
      of apparently different areas of functioning. The model aims to assist both
      parents and professionals in determining priorities, to improve interdisciplinary
      working, and to underpin staff training. Illustrative case studies indicate the
      importance of resolving issues in areas such as visual functioning, positioning
      and nutrition before integrated functions such as communication skills can be
      addressed successfully.

PMID- 10349519
TI  - A prospective study on quality of life and traumatic events in early life--a 30
      year follow-up.
AB  - AIM: To investigate the connection between early life trauma and the quality of
      life some 30 years later in Denmark. DESIGN: Prospective, longitudinal study with
      questionnaire-based follow-up survey. METHODS: In 'The Quality of Life Research
      Study of 10,000 Danes', a newly designed questionnaire was mailed in February
      1993 to 7222 persons from the Prospective Paediatric Cohort of persons born at
      the State University Hospital in Copenhagen (Rigshospitalet) between 1959 and
      1961. Response rate was 64% (4626 people between the ages 31-33). VARIABLES:
      Mother's attitude towards her pregnancy, child being placed in a children's home,
      mother using antipsychotic drugs indicating acute, mental illness, child adopted
      in the first year of life and quality of life of the child 31-33 years later.
      RESULTS: Of the early life traumas studied, only relatively weak connections to
      the quality of life in later life were found. CONCLUSIONS: These relatively weak
      findings suggest that the children that survive to adulthood are resilient to
      many adverse events in early life.

PMID- 10349520
TI  - Developing rational protocols for paediatric psychopharmacological prescribing.
AB  - The number of child psychiatrists, paediatricians and general practitioners
      prescribing psychotropic medication for children in the UK is increasing.
      Medication is being used not just to treat children of normal intelligence with
      hyperkinetic disorder or depression, but also to modify behavioural problems in
      children with developmental disorders and severe learning difficulties.
      Literature reviews highlight the lack of robust randomized controlled drug trials
      on which to base clinical practice and the authors have found no appropriate
      existing protocols to help develop a systematized approach. Against such a
      background the authors have developed a comprehensive set of protocols covering
      prescribing details for individual drugs, and also addressing issues such as
      informed consent, long-term monitoring and school liaison. All children referred
      to the authors' clinics go through a standardized decision-making process. This
      article describes both the protocols themselves and the philosophies that guided
      their development. The authors describe how such a system benefits the children,
      their families, general practitioners and schools, whilst also facilitating audit
      and research.

PMID- 10349521
TI  - The relationship between lifestyle, social characteristics and obesity in 3-year
      old Japanese children.
AB  - It has been observed that obese children receive genetic and environmental
      effects that are associated with them being overweight. With regard to the
      latter, lifestyles such as eating habits and physical activity have been focused
      on. In the present study, the social characteristics which would dominate their
      lifestyles were investigated as background variables. For this purpose, 9668
      Japanese children aged three years who were all born in Toyama prefecture, Japan,
      in 1998, served as birth cohort subjects. For the comparison between obese (Kaup
      Index; mass in kg/(height in m)2 > or = 18) and nonobese (Kaup index < 18)
      children, irregular snack intake, physical inactivity and reduced sleeping hours
      were chosen as statistically significant obesity-related lifestyle indicators for
      the children. For social characteristics, family construction (expanded family
      with grandparents/nonexpanded family), main caregiver (mother/other), attending a
      nursery school (yes/no) and mother's employment (full-time worker/other) were
      chosen. These were significantly associated with the obesity-related lifestyles
      mentioned above using multiple logistic regression analysis adjusted for other
      variables of social characteristics as well as for gender and birth month (July
      December/January-June). The two greatest population-attributable risk percentages
      were observed for mother as main caregiver (-36.5%) and attending a nursery
      school (-28.9%) for irregular snack intake. Therefore, these two social
      characteristics substantially reduced the number of children with irregular snack
      intake. On the other hand, the two social characteristics were reversed in
      children with reduced sleeping hours (population-attributable risk percentage of
      mother as main caregiver: 15.4%; attending a nursery school: 17%). In contrast
      with favourable effects on snack intake these social characteristics showed an
      adverse influence on the sleeping habits of children.

PMID- 10349522
TI  - Pediatric hospitals' and physician strategies for the 21st century.
AB  - Changes in market-driven health care economics are rapid and of great magnitude.
      This report describes a study of some of these changes in regard to children's
      health issues. We used a survey tool to assess long-range plans (next 10 years)
      and marketing strategies for major free-standing children's hospitals in
      different regions of the United States. We then used these assessments to draw
      conclusions about the impact of the plans and strategies on the practice of
      pediatric physicians and their workforce requirements. This may allow pediatric
      specialists and their programs to develop strategic plans and to take actions to
      contend with these market-driven economic changes. The tool was a questionnaire
      mailed to chief executive officers of 30 randomly chosen but geographically well
      distributed children's hospitals. Seventeen children's hospitals responded (57%),
      providing information concerning each hospital and its current medical economic
      environment. The data were analyzed and trends were then identified from their
      responses. All institutions in this study expected to have fewer physicians on
      staff in the future. These institutions plan: (1) to improve quality and (2) to
      reduce costs. Quality will be improved by utilizing Continuous Quality
      Improvement (CQI) and/or Benchmarking to Best Practices, both of which encourage
      physicians to follow standardized treatment protocols. Costs will be reduced by
      decreasing hospital staff size. Some children's hospitals have merged or will
      merge with larger, full-service adult hospitals, but most plan to remain
      autonomous. Many expect a continued decrease in revenues, and almost all expect
      to downsize both bed number and staff. Restructuring will reduce the number of
      specialists, particularly in the fields of hematology-oncology, psychiatry,
      endocrinology, nephrology, and cardiology, and will also reduce the number of
      surgical specialists. The administrators predicted that more nurse practitioners
      will be employed at these hospitals in the 21st century, serving the role of
      physician extenders, if not physician substitutes. To ensure their own survival,
      physicians must develop their own strategic plans as have the hospitals in which
      they practice. Optimally they should embrace those activities that parallel their
      hospital's efforts such as Quality Improvement (CQI, Benchmarking), cost
      containment, and practice mergers.

PMID- 10349523
TI  - Treatment of acute sinusitis in childhood with ceftibuten.
AB  - Acute sinusitis is a common childhood illness. If it is overlooked or
      undertreated, suppurative and intracranial complications may develop. Amoxicillin
      has traditionally been the antibiotic of choice for treatment of acute sinusitis.
      However, the efficacy of amoxicillin has been reduced because of the emergence of
      bacteria producing b-lactamase and altered penicillin-binding proteins. This
      study compares the effectiveness of 10, 15, and 20 days of ceftibuten therapy
      with 14 days of erythromycin-sulfisoxazole therapy in treating acute sinusitis.
      The results indicate that both treatment regimens are effective in treating acute
      sinusitis (96% clinical response for erythromycin-sulfisoxazole vs 92% for a 10-
      or 15-day course of ceftibuten vs 100% for a 20-day course of ceftibuten). Longer
      treatment periods may be more effective in resolving the acute illness.

PMID- 10349524
TI  - Follow-up imaging studies in children with splenic injuries.
AB  - We undertook a retrospective study of pediatric blunt splenic injuries treated
      nonoperatively at our institution from 1990 to 1995 (n = 72) to assess the impact
      of serial computed tomography (CT) scans on the outcome. Median number of studies
      per child was three. The result showed that the appearance of the splenic injury
      remained unchanged or improved in 95% of the imaging studies obtained (116 of
      122). Only one of five patients with an image suggesting a worsening splenic
      injury required operative intervention. There were no instances of missed
      injuries, delayed ruptures, or readmissions. We conclude that serial CT scans
      have limited follow-up value and should be used selectively.

PMID- 10349525
TI  - Delayed pubertal growth spurt and normal adult height attainment in boys
      receiving long-term alternate-day prednisone therapy.
AB  - Statural growth to age > or = 20 years was studied in 10 boys with
      glomerulonephritis who received alternate-day prednisone (mean 1.2 mg/kg) for at
      least 2 consecutive years during pubertal age. Peak growth velocity was delayed
      after age 15 years in six patients and it was less than 7 cm/year in five.
      However, after age 16, growth velocity was significantly (p = 0.02) higher than
      expected and allowed patients to ultimately reach their genetic height potential.

PMID- 10349526
TI  - Maternal fever and neonatal depression: preliminary observations.
AB  - The objectives of this study were to determine in term infants: (1) the
      importance of maternal fever (maternal temperature > 38 degrees C) as a risk
      factor for neonatal depression and (2) the clinical course of infants admitted to
      the Neonatal Intensive Care Unit (NICU) born to mothers with fever. For 2 years,
      59 (0.24%) of 25,000 term infants had a 5-minute Apgar score < or = 5 and 22
      (0.08%) infants were administered chest compressions with or without epinephrine
      as part of cardiopulmonary resuscitation (CPR) in the delivery room. The
      perinatal event most commonly associated with a 5-minute Apgar score < or = 5 was
      maternal fever in 19 infants (32%), with meconium + fetal heart rate (FTHR)
      abnormalities in 15 (25%), and FTHR abnormalities only in 13 (22%), additional
      associations (n = 13). By stepwise linear regression analysis, a 5-minute Apgar <
      or = 5 was related only to the initial infant temperature (p = 0.009, r = 0.33).
      Maternal fever noted in six infants (27%) was also commonly associated with CPR,
      as was the presence of meconium + FTHR abnormalities in seven (32%), and FTHR
      abnormalities only in four (18%). One hundred thirteen (7.5%) of the
      approximately 1,500 term infants born to mothers with maternal fever were
      admitted to the NICU. In addition to fever, the labor was complicated by meconium
      (in 16 infants), meconium + FTHR abnormalities (in 19 infants), and FTHR
      abnormalities only (in 11 infants). Resuscitative interventions in the delivery
      room included oxygen only in 43 infants, bag and mask ventilation in 38,
      continuous positive airway pressure in 10, intubation in 16, and CPR in six
      infants. Forty-nine infants (43%) had an initial temperature > 38 degrees C
      including 13 (11%) with an initial temperature > 39 degrees C. Twelve (10%)
      infants remained intubated on admission and five required ventilator support > 24
      hours. One blood culture was positive although all mothers were pretreated with
      antibiotics. One infant developed hypoxic ischemic encephalopathy including
      seizures. Maternal fever is the perinatal event most frequently associated with a
      5-minute Apgar score < or = 5 and a common association with the need for CPR.
      Clinicians attending the delivery of a mother with fever should anticipate the
      potential for neonatal depression; such awareness should facilitate appropriate
      preparation before delivery and potentially reduce the need for more intensive
      resuscitation.

PMID- 10349527
TI  - Correlation of serum cholylglycine level with hepatic dysfunction in children
      with sickle cell anemia.
AB  - Hepatic dysfunction occurs commonly in children with sickle cell disease (SCD).
      Although the etiology is multifactorial, cholestasis is a prominent feature.
      Serum cholylglycine (CG) has been found to be a very sensitive indicator of
      cholestasis. Our objective was to determine whether CG levels are elevated in
      children with SCD and whether they are predictive of hepatic dysfunction. Blood
      samples were obtained from 97 children with SCD. Liver function tests were done
      and serum CG concentrations were measured. Patients were followed up for 2 years.
      Thirty-eight percent of the patients had an elevated CG level. During the 2 years
      of follow-up, 16% of the children with a previously elevated CG level developed
      abnormal liver function test results or required a cholecystectomy as compared
      with 13% with a previously normal CG level (p = 0.92). We conclude that although
      CG level was elevated in 38% of the patients with SCD, it did not appear to
      predict liver dysfunction during the ensuring 2 years.

PMID- 10349528
TI  - How not to train pediatric residents.

PMID- 10349529
TI  - Bilateral spontaneous pneumothorax associated with Mycoplasma pneumoniae
      infection.

PMID- 10349530
TI  - Coexisting health problems in obese children and adolescents that might require
      special treatment considerations.

PMID- 10349531
TI  - Neonatologist attrition to general pediatrics.

PMID- 10349532
TI  - Growth hormone deficiency in a child with sarcoidosis.

PMID- 10349533
TI  - Necrosis related to the use of pulse oximetry in a very-low-birth-weight infant.

PMID- 10349534
TI  - Nonketotic hyperosmolar diabetic coma in an infant with Down syndrome.

PMID- 10349535
TI  - Styrofoam cup, ipratropium bromide, and anisocoria.

PMID- 10349536
TI  - Postpartum complications in the abdomen and pelvis: CT evaluation.
AB  - Postpartum patients rarely develop complications that require radiologic
      evaluation. When indicated, CT can provide a rapid and reliable examination of
      the major pelvic organs and enable diagnosis of a multitude of postpartum
      complications, including abscesses, endometritis, thrombophlebitis, as well as
      more serious and potentially life-threatening sequelae of toxemia, DIC, and HELLP
      syndrome. This pictorial essay illustrates the utility of CT in the postpartum
      patient and demonstrates the spectrum of complications evaluated with CT.

PMID- 10349537
TI  - MR of the thoracic aorta: a pulse sequence approach to discrete feature analysis.
AB  - Magnetic resonance (MR) imaging is a reliable tool for the depiction of the
      thoracic aorta. By combining traditional T1-weighted spin echo pulse sequences
      with newer MR angiography techniques, MR imaging can provide both the structural
      and functional information necessary to manage most thoracic aortic
      abnormalities. This article reviews the various MR pulse sequences germane to
      aortography, highlighting their technical considerations and clinical
      applications. Newer MR techniques for vascular imaging are also introduced.

PMID- 10349538
TI  - Sports-related cutaneous reactions: Part III. Sports identification marks.

PMID- 10349540
TI  - Successful treatment of porokeratosis with 585 nm pulsed dye laser irradiation.
AB  - Porokeratosis, a keratinization and fibroblast cutaneous disorder, is a
      progressive disease with limited treatment options. We describe a case of linear
      porokeratosis that responded favorably to a series of 585 nm pulsed dye laser
      treatments. In addition to its vascular specificity, the pulsed dye laser
      presumably produces a direct effect on collagen, as well as an indirect effect on
      histamine and mast cells that could account for the clinical changes seen in our
      patient.

PMID- 10349539
TI  - What's eating you? Pediculus humanus (head louse and body louse).
AB  - Head lice remain a common problem worldwide. As resistance to available
      therapeutic agents can emerge rapidly, there is a need for continued research to
      find new and better agents. Until better agents are available, clinicians may
      find that rotational therapy, using different agents, may help to slow the
      emergence of resistance. Physical modalities, such as mechanical nit and louse
      removal and occlusive agents to asphyxiate the lice, should not be ignored,
      especially in light of our limited therapeutic armamentarium. All therapeutic
      agents are doomed to failure if infestation is allowed to recur. Classmates,
      playmates, and family members of infested children should be inspected for head
      lice. Efforts should be directed at fomite control and nit removal. Louse
      infestation must be addressed as a community-wide problem. Body lice remain
      important vectors of disease. War, natural disaster, and poverty favor the spread
      of body lice. As we work to solve these seemingly eternal problems, we must
      develop better agents to treat infestation and prevent the spread of body lice.

PMID- 10349541
TI  - Subcutaneous Fusarium foot abscess in a renal transplant patient.
AB  - Fusarium species are ubiquitous plant and grain phytopathogens that rarely cause
      opportunistic infections in immunocompromised patients. While disseminated
      Fusarium infections are almost always fatal, localized infections may be
      responsive to a combination of systemic antibiotic therapy and surgical
      debridement. We present a diabetic renal transplant patient who developed a foot
      abscess due to Fusarium solani. Infection persisted despite aggressive surgical
      debridement and a 3-month course of intravenous liposomal amphotericin B.

PMID- 10349542
TI  - Pemphigus foliaceus and renal cell carcinoma.
AB  - It is possible to distinguish the various forms of pemphigus from one another
      using clinical, histologic, and immunologic criteria. Paraneoplastic pemphigus, a
      recently defined type that is severe and often fatal, is associated with an
      underlying malignancy. We present the second reported case of pemphigus
      associated with renal cell carcinoma. We do not believe that either case
      represents paraneoplastic pemphigus, which suggests the possibility of some other
      link between these two diseases.

PMID- 10349543
TI  - Malignant melanoma: a clinical review.
AB  - The incidence of cutaneous malignant melanoma is increasing at an alarming rate.
      It is projected that Americans born in the year 2000 will have a 1 in 75 lifetime
      risk of developing melanoma. Long-term survival for patients with metastatic
      disease is only 5% and approximately 15% of patients diagnosed with melanoma
      eventually die from their disease. Conversely, the prognosis for early disease is
      excellent and often simple surgical excision is curative. It is therefore crucial
      that the practicing physician becomes familiar with all of the clinical and
      histologic presentations in order to ensure an accurate and prompt diagnosis.
      This, in turn, should lead to earlier detection and a more favorable prognosis.

PMID- 10349544
TI  - Ocular melanoma.
AB  - The eye is the second most common site for primary melanoma after the skin. An
      ophthalmologic evaluation should be an integral aspect of melanoma screening that
      is often not even considered by nonophthalmologists. Delays or failures to make
      an accurate and early diagnosis can have grave consequences. Early recognition
      and diagnosis, before the tumor has progressed into an advanced process with a
      poor prognosis, can often result in complete cures through early interventional
      treatments. It is imperative that physicians adequately understand and
      appropriately examine or refer patients for appropriate screening for ocular
      melanoma as a routine practice in screening for melanoma. This article is
      intended to raise the clinical awareness of the practicing physician regarding
      this disease.

PMID- 10349545
TI  - Current therapy of cutaneous melanoma.
AB  - We review the current therapy for cutaneous malignant melanoma. Early surgical
      resection offers the best likelihood of cure. The initial staging of melanoma
      patients determines subsequent therapeutic decisions and follow-up care. The
      prognosis and appropriate therapy for each stage of melanoma are discussed. We
      review the controversy over lymph node dissection, and recent recommendations for
      the use of lymphoscintigraphy. Interferon-alpha continues to be the only Food and
      Drug Administration-approved adjuvant therapy for high-risk patients. In
      addition, the follow-up care of melanoma patients will be discussed.

PMID- 10349546
TI  - Colon carcinoma cutis: a case report.
AB  - The occurrence of cutaneous metastasis from colon cancer is rare especially when
      located on the extremities. Cutaneous metastasis typically signifies widespread
      disease and poor prognosis. Although uncommon, carcinoma cutis must be considered
      in any patient with a history of carcinoma who presents with a new skin eruption.
      Diagnostic biopsy is essential, inasmuch as the appearance of these lesions is
      not distinctive. We present a patient with known colon cancer and the new onset
      of papules on her right lower extremity.

PMID- 10349547
TI  - Temperature dependent characteristics of a recombinant infectious hematopoietic
      necrosis virus glycoprotein produced in insect cells.
AB  - A recombinant infectious hematopoietic necrosis virus (IHNV) glycoprotein (G
      protein) was produced in insect cells using a baculovirus vector (Autographa
      californica nuclear polyhedrosis virus). Characteristics of this protein were
      evaluated in relation to native viral G protein. A full-length (1.6 kb) cDNA copy
      of the glycoprotein gene of IHNV was inserted into the baculovirus vector under
      control of the polyhedrin promoter. High levels of G protein (approximately 0.5
      microgram/1 x 10(5) cells) were produced in Spodoptera frugiperda (Sf9) cells
      following recombinant baculovirus infection. Analysis of cell lysates by sodium
      dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot
      revealed a recombinant IHNV G of slightly higher mobility on the gel than the
      viral G protein. Differences in mobility were abrogated by endoglycosidase
      treatment. When the recombinant G protein was produced in insect cells at 20
      degrees C (RecGlow), immunostaining and cell fusion activity demonstrated surface
      localization of the protein. In contrast, when recombinant protein was produced
      at 27 degrees C (RecGhigh), G protein was sequestered within the cell, suggesting
      that at the 2 different temperatures processing differences may exist. Eleven
      monoclonal antibodies (MAbs) were tested by immunoblotting for reactivity to the
      recombinant G protein. All 11 MAbs reacted to the reduced proteins. Four MAbs
      recognized both RecGhigh and RecGlow under non-reducing conditions; however, 1
      neutralizing MAb (92A) recognized RecGlow but failed to react to RecGhigh under
      non-reducing conditions. This suggests that differences exist between RecGlow and
      RecGhigh which may have implications in the development of a properly folded
      recombinant G protein with the ability to elicit protective immunity in fish.

PMID- 10349549
TI  - Anti-immunoglobulin antisera used in an ELISA to detect antibodies in barramundi
      Lates calcarifer to Cryptocaryon irritans.
AB  - Immunoglobulins (Ig) in serum from barramundi vaccinated with bovine serum
      albumin (BSA) were purified by ammonium sulphate precipitation and affinity
      chromatography using BSA as the ligand. The BSA-binding activity of eluted
      putative Ig fractions was assessed by enzyme-linked immunosorbent assay (ELISA)
      before being pooled and characterised by sodium dodecyl sulphate polyacrylamide
      gel electrophoresis (SDS-PAGE). Double affinity purification did not improve the
      purity of the Ig preparation compared to single affinity purification. Barramundi
      Ig were injected into sheep to produce anti-Ig antisera which were assessed in an
      indirect ELISA as the secondary antibody to detect serum Ig in barramundi
      vaccinated with Cryptocaryon irritans theronts. Affinity-purified Ig induced a
      more specific reagent for use as secondary antibody in ELISA than did normal
      whole-barramundi sera. The heavy (H) chain of barramundi Ig had an apparent
      molecular weight of 70 kDa while that of the light (L) chain was 27 kDa in SDS
      PAGE studies. Under non-reducing conditions 2 putative populations of Ig were
      identified, at 768 and 210 kDa. The N-terminal sequence of the barramundi Ig H
      chain showed 78% homology with channel catfish Ictalurus punctatus Ig H chain
      sequence.

PMID- 10349548
TI  - Comparative study of viral encephalopathy and retinopathy in juvenile sea bass
      Dicentrarchus labrax infected in different ways.
AB  - The transmission of viral encephalopathy and retinopathy (VER) was investigated
      in juvenile sea bass (3 g) Dicentrarchus labrax by using cell culture supernatant
      (SSN-1 cell line) containing nodavirus. Five methods of infection were tested:
      intramuscular injection (IM), intraperitoneal injection (IP), oral infection,
      bath exposure and cohabitation of healthy fish with infected fish. Some
      differences were observed in time of disease onset and severity of symptoms
      depending on the mode of infection used. Clinical symptoms such as whirling
      swimming and lethargic or hyperactive behaviour were generally reproduced, except
      for fish infected via oral and IP infection. First mortalities occurred 3 d after
      IM and IP infection and 6 d after for the other modes of infection. Cumulative
      mortalities were also variable: 100% after IM infection, 10% after IP infection,
      32% for bath exposure, 43% after cohabitation and 24% via oral infection.
      Histopathologically, vacuolation was observed in the central nervous tissues and
      in the retina. The observed lesions were more or less severe depending on the
      mode of infection, the sampling time and the organs: lesions on the surviving
      fish (42 days post infection, d p.i.) seemed to be generally more conspicuous in
      the retina than in the brain of the same fish. In most cases, the presence of
      nodavirus was confirmed in the same samples of brain and retina by
      immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT
      PCR). The virus was not detected in other organs examined. The present results
      suggest that 2 forms of VER can be induced: IM injection leads to an acute form
      (severe nervous disorders with high and fast mortality) whereas oral infection,
      bath exposure and cohabitation induce a subacute form (less severe disorders and
      weak daily mortality). This experiment demonstrates experimentally induced
      horizontal transmission of VER in sea bass for the first time.

PMID- 10349550
TI  - Elevated temperature treatment as a novel method for decreasing p57 on the cell
      surface of Renibacterium salmoninarum.
AB  - Renibacterium salmoninarum is a Gram-positive diplo-bacillus and the causative
      agent of bacterial kidney disease, a prevalent disease of salmonid fish. Virulent
      isolates of R. salmoninarum have a hydrophobic cell surface and express the 57-58
      kDa protein (p57). Here we have investigated parameters which effect cell
      hydrophobicity and p57 degradation. Incubation of R. salmoninarum cells at 37
      degrees C for > 4 h decreased cell surface hydrophobicity as measured by the salt
      aggregation assay, and decreased the amount of cell associated p57. Incubation of
      cells at lower temperatures (22, 17, 4 or -20 degrees C) for up to 16 h did not
      reduce hydrophobicity or the amount of cell associated p57. Both the loss of cell
      surface hydrophobicity and the degradation of p57 were inhibited by pre
      incubation with the serine protease inhibitor phenylmethylsulfonyl fluoride
      (PMSF). Cell surface hydrophobicity was specifically reconstituted by incubation
      with extracellular protein (ECP) concentrated from culture supernatant and was
      correlated with the reassociation of p57 onto the bacterial cell surface as
      determined by western blot and total protein stain analyses. The ability of p57
      to reassociate suggests that the bacterial cell surface is not irreversibly
      modified by the 37 degrees C treatment and that p57 contributes to the
      hydrophobic nature of R. salmoninarum. In summary, we describe parameters
      effecting the removal of the p57 virulence factor and suggest the utility of this
      modification for generating a whole cell vaccine against bacterial kidney
      disease.

PMID- 10349551
TI  - Evaluation of a whole cell, p57- vaccine against Renibacterium salmoninarum.
AB  - A whole cell Renibacterium salmoninarum vaccine was developed using 37 degrees C
      heat treated cells that were subsequently formalin fixed; this treatment reduced
      bacterial hydrophobicity and cell associated p57. Coho salmon Oncorhynchus
      kisutch were immunized with the p57- vaccine by either a combination of
      intraperitoneal (i.p.) and intramuscular (i.m.) injections or per os. In the
      first experiment, i.p./i.m. vaccination of coho salmon with p57- cells in
      Freund's Incomplete Adjuvant (FIA) conferred a statistically significant increase
      in mean time to death after the salmon were i.p. challenged with 4.1 x 10(6)
      colony forming units (cfu) of R. salmoninarum. There was no significant
      difference in response between fish immunized with R. salmoninarum cell surface
      extract in FIA and those immunized with extracellular protein (ECP) concentrated
      from culture supernatant in FIA. The i.p. challenge dose resulted in complete
      mortality of all fish by Day 43. In a second experiment, fish were orally
      vaccinated with p57- R. salmoninarum cells encased in a pH protected, enteric
      coated antigen microsphere (ECAM). Fish were bath challenged with 4.2 x 10(6) cfu
      ml-1 on Day 0 and sampled at time points of 0 (pre-challenge), 50, 90, or 150 d
      immersion challenge. Vaccine efficacy was determined by monitoring the
      elaboration of p57 in the kidneys of vaccinated and control fish. Fish vaccinated
      orally demonstrated a significantly lower concentration of p57 (p < 0.01) at Day
      150 post challenge compared to fish receiving ECAMs alone. Fish receiving p57
      cells without ECAM coating also showed a significantly lower p57 level (p < 0.03)
      versus control. In contrast, fish injected intraperitoneally with the p57- cells
      or fish fed p57+ R. salmoninarum cells in ECAMs demonstrated no significant
      difference (p > 0.05) versus controls. In summary, these studies suggest the
      preliminary efficacy of 37 degrees C treatment of R. salmoninarum cells as an
      oral bacterial kidney disease vaccine.

PMID- 10349552
TI  - Development of a polymerase chain reaction diagnostic assay for Ceratomyxa
      shasta, a myxosporean parasite of salmonid fish.
AB  - A diagnostic procedure based on the polymerase chain reaction (PCR) was developed
      for the myxosporean parasite Ceratomyxa shasta. Three sets of oligonucleotide
      primers were designed to specifically amplify C. shasta ribosomal RNA genes and
      several parameters of the assay were tested and optimised. A simple protocol for
      the processing of fish tissue samples was also developed. In a single round, 20
      microliters volume reaction the optimised procedure allows the detection of 50 fg
      of purified C. shasta genomic DNA, or 0.01 spore from a seeded fish intestine
      sample. This protocol is considerably faster, cheaper and more reliable than any
      previous diagnostic procedure for a myxosporean parasite, and can be an
      invaluable tool for the monitoring of early and/or subclinical C. shasta
      infections in wild and cultured salmon populations.

PMID- 10349553
TI  - Immunogenicity of a recombinant infectious hematopoietic necrosis virus
      glycoprotein produced in insect cells.
AB  - A recombinant infectious hematopoietic necrosis virus (IHNV) glycoprotein (G
      protein), produced in Spodoptera frugiperda (Sf9) cells following infection with
      a baculovirus vector containing the full-length (1.6 kb) glycoprotein gene,
      provided very limited protection in rainbow trout Oncorhynchus mykiss challenged
      with IHNV. Fish were injected intraperitoneally (i.p.) with Sf9 cells grown at 20
      degrees C (RecGlow) or 27 degrees C (RecGhigh) expressing the glycoprotein gene.
      Various antigen (Ag) preparations were administered to adult rainbow trout or
      rainbow trout fry. Sera collected from adult fish were evaluated for IHNV
      neutralization activity by a complement-dependent neutralization assay. Anti-IHNV
      neutralizing activity was observed in sera, but the percent of fish responding
      was significantly lower (p < 0.05) in comparison to fish immunized with a low
      virulence strain of IHNV (LV-IHNV). A small number of fish immunized with RecGlow
      or RecGhigh possessed IHNV G protein specific antibodies (Abs) in their serum.
      Cumulative mortality (CM) of rainbow trout fry (mean weight, 1 g) vaccinated by
      i.p. injection of freeze/thawed Sf9 cells producing RecGlow was 18% in initial
      trials following IHNV challenge. This level of protection was significant (p <
      0.05) but was not long lasting, and neutralizing Abs were not detected in pooled
      serum samples. When trout fry (mean weight, 0.6 g) were vaccinated with
      supernatant collected from sonicated Sf9 cells, Sf9 cells producing RecGlow, or
      Sf9 cells producing RecGhigh, CM averaged 46%. Protection was enhanced over
      negative controls, but not the positive controls (2% CM), suggesting that in the
      first trial soluble cellular proteins may have provided some level of non
      specific protection, regardless of recombinant protein expression. Although some
      immunity was elicited in fish, and RecGlow provided short-term protection from
      IHNV, Ab-mediated protection could not be demonstrated. The results suggest that
      recombinant G proteins produced in insect cells lack the immunogenicity
      associated with vaccination of fish with an attenuated strain of IHNV.

PMID- 10349554
TI  - Effectiveness of a vaccine against red sea bream iridoviral disease in a field
      trial test.
AB  - Since 1990, red sea bream iridovirus (RSIV) has caused high mortalities in the
      summertime in cultured red sea bream Pagrus major in southwest Japan. To
      establish control measures for red sea bream iridoviral disease (RSIVD), the
      effectiveness of a formalin-killed viral vaccine was evaluated in a field trial.
      Two groups each consisting of 1000 juvenile red sea bream were either
      intraperitoneally inoculated with vaccine (vaccinated group) or were not
      vaccinated (non-vaccinated group). After vaccination, the fish were held for 1
      wk, then transferred to a marine net pen and observed for 12 wk. The cumulative
      mortalities caused by RSIVD in the vaccinated group or control group were 19.2
      and 68.5%, respectively. Additionally, the presence of virus antigen in the
      spleen was investigated and body weight was measured 6 and 12 wk post
      vaccination. In the vaccinated group, viral antigen was not detected. The
      increase in body weight of vaccinated fish was significantly (p < 0.05) greater
      than that of control fish. These results suggest that the vaccine against RSIVD
      was effective in 1 field trial.

PMID- 10349555
TI  - Design, development, and biopharmaceutical properties of buccoadhesive compacts
      of pentazocine.
AB  - Buccoadhesive compacts (BCs) of pentazocine (PZ) were prepared by the direct
      compression method using polymers like carbopol 974P (CP 974P) and hydroxypropyl
      methylcellulose (HPMC K4M) in ratios of 1:0 (batch B1), 1:1 (B2), 1:2 (B3), 1:4
      (B4), and 0:1 (B5). The compacts were evaluated for thickness uniformity, weight
      variation, drug content uniformity, and swelling index. Swelling was increased
      with an increase in HPMC K4M content in the compacts. An in vitro assembly was
      developed to measure and compare the bioadhesive strength of compacts. The
      maximum bioadhesive strength was observed in compacts formulated with a
      combination of CP 974P and HPMC K4M. The compacts were evaluated in vitro for 24
      hr in pH 6.6 phosphate buffer using a standardized dissolution apparatus. The
      data were evaluated by a simple power equation (Mt/M infinity = Ktn); it was
      observed that all the compacts followed non-Fickian release kinetics. Some of the
      buccoadhesive compacts were evaluated in vivo in rabbits. The compacts gave
      controlled blood level profiles with a twofold to threefold increase in area
      under-the-curve (AUC) values in comparison to oral administration of aqueous drug
      solution.

PMID- 10349556
TI  - Effects of hydrophilic excipients and compression pressure on physical properties
      and release behavior of aspirin-tableted microcapsules.
AB  - Aspirin ethylcellulose microcapsules were tableted by compression with or without
      excipients (lactose or polyvinylpyrrolidone [PVP]). The effects of the amount of
      the excipients and microcapsule size on the crushing strength and release rate of
      aspirin from tableted microcapsules were investigated. Tablets without excipients
      had a crushing strength that was independent of the applied pressure and
      microcapsule size. An increase in compression pressure from 15 to 60 MPa resulted
      in an increase in the crushing strength of tablets containing 20% or 40% w/w
      lactose, but the reverse results were obtained for the tableted microcapsules
      containing 20% or 40% w/w PVP. Results showed that the release rate of aspirin
      from microcapsules containing lactose or PVP was independent of the compression
      pressure with the exception of tablets containing 40% w/w lactose. In vitro
      release profiles of aspirin from tableted microcapsules containing lactose or PVP
      showed that increasing the concentration of the excipients resulted in an
      increase in the release rate of aspirin. Values of n were changed by the
      compression pressure and the added excipients.

PMID- 10349557
TI  - Topical oleo-hydrogel preparation of ketoprofen with enhanced skin permeability.
AB  - In an attempt to improve the skin penetration of ketoprofen, various transdermal
      formulations were prepared, and their in vitro skin permeability and in vivo
      percutaneous absorption were evaluated. In vitro permeation studies were
      performed using a modified Franz cell diffusion system in which permeation
      parameters such as cumulative amount at 8 hr Q8hr, steady-state flux Jss, or lag
      time tL were determined. In the in vivo percutaneous absorption study using the
      hairless mouse, maximum concentration Cmax and area under the curve at 24 hr
      AUC24h were measured. The optimal transdermal formulation (oleo-hydrogel
      formulation) of ketoprofen showed a Q8hr value of 227.20 micrograms/cm2, a Jss
      value of 29.61 micrograms/cm2/hr, and a tL value of 0.46 hr. The Q8hr and Jss
      values were about 10-fold (p < .01) higher than those (Q8hr = 19.61
      micrograms/cm2; Jss = 2.66 micrograms/cm2/hr) from the K-gel and about 3.5-fold
      (p < .01) than those (Q8hr = 60.00 micrograms/cm2; Jss = 7.99 micrograms/cm2/hr)
      of the K-plaster. In the in vivo percutaneous absorption, the Cmax (6.82
      micrograms/ml) and AUC24h (55.74 micrograms.hr/ml) values of the optimal
      formulation were significantly (p < .01) higher than those of K-gel and K
      plaster. The relative bioavailability of the oleo-hydrogel following transdermal
      administration in reference to oral administration was about 37%, and the Cmax
      value (4.73 micrograms/cm2) in the hypodermis following topical administration
      was much higher than those from the conventional products (Cmax of K-gel and K
      plaster were 0.92 +/- 0.19 microgram/cm2 and 1.27 +/- 0.37 microgram/cm2,
      respectively). These data demonstrate that the oleo-hydrogel formulation of
      ketoprofen was more beneficial than conventional products (K-gel and K-plaster)
      in enhancing transdermal permeation and skin absorption of ketoprofen.
      Furthermore, there was a good correlation between in vitro permeation parameters
      and in vivo percutaneous absorption parameters.

PMID- 10349558
TI  - Evaluation of microspheres containing cytokine neutralizing antibodies in
      endotoxemia.
AB  - Albumin microspheres are efficient carriers for delivering therapeutic agents to
      macrophages. In response to endotoxin, macrophages release tumor necrosis factor
      alpha (TNF alpha) and interleukin-1-beta (IL-1 beta). Blocking the effects of TNF
      alpha and IL-1 beta decreased lethality due to endotoxin-induced shock. In this
      study, we compared the efficacy of the microsphere form of TNF alpha and/or IL-1
      beta neutralizing antibodies (NAs) with the free form of TNF alpha and/or IL-1
      beta NA in preventing lethality due to endotoxemia and evaluated the duration of
      blockade by the microsphere form of TNF alpha and/or IL-1 beta NA on endotoxin
      induced cytokine release. The results indicate that the microsphere form of TNF
      alpha and/or IL-1 beta NA protected 80% of the rats from lethal endotoxemia,
      while none of the rats that received the free from of TNF beta and/or IL-1 beta
      NA survived longer than 48 hr. The microsphere form of TNF alpha and/or IL-1 beta
      NA attenuated endotoxin-induced cytokine release more potently than the free form
      of TNF alpha and/or IL-1 beta NA in vivo. In vitro, the microsphere form of TNF
      alpha and/or IL-1 beta NA blocked endotoxin-induced cytokine release for at least
      24 hr. Higher efficacy of the microsphere form of NA in reducing mortality and
      blocking cytokine release makes it more therapeutically advantageous than the
      free form of NA in the treatment of lethal endotoxemia.

PMID- 10349559
TI  - Using difference spectrophotometry to study the influence of different ions and
      buffer systems on drug protein binding.
AB  - Difference spectrophotometry was used to investigate the effect of different ions
      and buffer systems on the binding of the anti-inflammatory drug tenoxicam to
      human serum albumin (HSA). Chloride anions, as well as sodium cations, were found
      to decrease the binding affinity. The effect of chloride ions was greater on the
      primary binding constant K1, while sodium ions had a greater effect on the
      secondary binding constant K2. The number of binding sites n1 and n2 were not
      affected except at 0.12% HSA, for which the presence of sodium ions halved n2.
      Potassium ions significantly increased K1. The presence of potassium instead of
      sodium ions increased binding affinity at lower HSA concentrations. The number of
      binding sites n1 and n2 were fewer in presence of potassium than in the presence
      of sodium ions except at 0.12% HSA. The divalent calcium and magnesium cations
      increased the binding affinity of HSA to tenoxicam, with a greater effect on K1.
      The effect of magnesium ions on K1 occurred when the MgCl2 concentration was
      increased to 3 and 9 mM, with the former seeming to be a critical concentration.
      The number of primary binding sites n1 was not affected by calcium ions, but was
      halved by 1 mM MgCl2. Both calcium and magnesium cations decreased n2, which was
      halved when the concentration of either cation was increased to 9 mM. The effect
      of buffer systems on tenoxicam binding to HSA was dependent on HSA concentration.
      The value of K1 was higher in Sorensen's phosphate buffer than in Tris
      [tris(hydroxymethyl) aminomethane HCl] buffer when the HSA concentration was
      0.04% and 0.16%, while the reverse was observed at 0.08% and 0.12% HSA. The other
      binding parameters (K2, n1, and n2) were higher in Sorensen's phosphate than in
      Tris buffer. However; at certain HSA concentrations, the values of such
      parameters were comparable in both buffer systems.

PMID- 10349560
TI  - Relative hypoglycemia of rectal insulin suppositories containing deoxycholic
      acid, sodium taurocholate, polycarbophil, and their combinations in diabetic
      rabbits.
AB  - In this study, insulin suppositories containing 50 U insulin incorporated with 50
      mg of deoxycholic acid, sodium taurocholate, or both were placed in the rectum of
      alloxan-induced hyperglycemic rabbits. A large decrease in plasma glucose
      concentrations was observed, and the relative hypoglycemias were calculated to be
      38.0%, 34.9%, and 44.4%, respectively, compared with insulin subcutaneous (s.c.)
      injection (40 U). Insulin suppositories containing 50 mg polycarbophil alone or
      mixed with 50 mg deoxycholic acid produced relative hypoglycemia of 43.1% and
      42.2%, respectively. The most pronounced effect was observed with the addition of
      polycarbophil to the suppository formulation containing a combination of
      deoxycholic acid and sodium taurocholate, which produced a 56% relative
      hypoglycemia compared with subcutaneous injection. These suppository formulations
      could be very promising alternatives to the current insulin injections, being
      roughly half as efficacious as subcutaneous injection.

PMID- 10349561
TI  - Use of tablet tensile strength adjusted for surface area and mean
      interparticulate distance to evaluate dominating bonding mechanisms.
AB  - In this study, tablet tensile strength has been adjusted for tablet surface area
      and the average distance between particles in compacts of different materials.
      The aim of the study was to evaluate the feasibility of using this concept to
      assess the dominating interparticulate bonding mechanisms. Adjustment of the
      tensile strength for both tablet surface area and mean pore radius gave similar
      bonding strength values for materials bonding mainly by weak distance forces
      (crystalline lactose, sucrose, and microcrystalline cellulose) almost
      independently of compaction pressure. However, particle size and other factors
      may still affect the compensated strength values. The bond strength was much
      higher and more varied for materials bonding also with solid bridges (potassium
      chloride, sodium chloride, and possibly also sodium bicarbonate and amorphous
      lactose). For these materials, particle size and compaction pressure had a
      substantial effect on the bond strength. It is probably the formation of
      continuous bridges between adjacent particles that is important in these
      materials rather than the surface properties and the average distance between
      particles positioned at some distance from each other. Hence, adjusting the
      tensile strength of compacts does not necessarily reflect all the dominating
      factors responsible for interparticulate bonding. Nonetheless, adjustment for
      tablet surface area and mean pore radius allowed discrimination between different
      dominating interparticulate bonding mechanisms in these compacted materials.

PMID- 10349562
TI  - Investigation of prandial effects on hydrophilic matrix tablets.
AB  - The prolonged release of drug from hydrophilic matrix tablets can be greatly
      affected by administration in connection with the intake of food. Changes of the
      tablet erosion are one of the main components of this effect. The aim of the
      present study was to identify the postprandial factors responsible for changes in
      tablet erosion and to develop predictive in vitro tests. Two formulations, one
      sensitive and the other robust to prandial effects in vivo, were investigated in
      vitro (a) in a complex physiological media simulating fasting and fed conditions;
      (b) according to a factorial experimental design that included agitation and pH
      concentrations of salt, surface-active agent, and nonionic solute as factors; and
      (c) at varying agitation intensities in three different sets of dissolution
      apparatus. Of the studied factors, only increased agitation enhanced the erosion
      of tablets in accordance with the in vivo effects of a meal. The other factors
      retarded erosion or had only minor effects. The hydrodynamic mechanical stress
      was thus considered to be the main factor responsible for postprandial effects on
      tablet erosion. The influence of changes in agitation and the opportunity to
      discriminate between sensitive and robust formulations differed among the three
      sets of dissolution apparatus. The modified USP II apparatus, operated at speeds
      of 50 and 100 rpm, is proposed as a discriminatory test.

PMID- 10349563
TI  - Development of biodegradable drug delivery system to treat addiction.
AB  - Opiate addiction is a serious problem that has now spread worldwide to all levels
      of society. Buprenorphine has been used for several years for the treatment of
      opiate addiction. The objective of this project was to develop sustained-release
      biodegradable microcapsules for the parenteral delivery of buprenorphine.
      Biodegradable microcapsules of buprenorphine/poly(lactide-co-glycolide) were
      prepared using two main procedures based on an in-water drying process in a
      complex emulsion system. These procedures differ in the way the organic solvent
      was eliminated: evaporation or extraction. The effect of drug loading and the
      effect of partial saturation of the aqueous phase with the core material during
      the in-water solvent evaporation were also studied. The efficiency of
      encapsulation increased from 11% to 34% when the drug loading was decreased from
      20% to 5%. There was no significant change in the efficiency of encapsulation
      when the aqueous phase was partially saturated with buprenorphine. In changing
      the solvent removal process from evaporation to extraction, no significant change
      in the efficiency of encapsulation was observed. The microcapsules prepared by
      the solvent evaporation were smooth and spherical. However, the microcapsules
      prepared by the extraction of the organic solvent lost their surface smoothness
      and became slightly irregular and porous compared with the other batches. The
      average particle size of the microcapsules was between 14 and 49 microns. The
      cumulative drug release was between 2% and 4% within the first 24 hr. A sustained
      drug release continued over 45 days.

PMID- 10349564
TI  - Feasibility of an in vitro microbiological model as an alternative to the rabbit
      eye model.
AB  - Ocular inserts of gentamicin sulfate with polyvinyl alcohol (PVA) 1.5%, 2.0%, and
      2.5% and a combination of methyl cellulose 2% and Eudragit NE 30D 30%, 35%, and
      40% w/w of methyl cellulose were fabricated by a casting technique. The inserts
      were sterilized by gamma radiation at 25 kGy and tested for sterility. The
      microbiological efficacy of the ocular inserts against Staphylococcus aureus ATCC
      6538P and Pseudomonas aeruginosa NCIM 2200 was evaluated by developing an in
      vitro microbiological model and an in vivo noninvasive rabbit eye model.
      Parameters of the in vitro microbiological model were varied, and the results
      correlated with a noninvasive rabbit eye model. The in vitro model proved to be a
      viable alternative to the rabbit eye model in evaluating the microbiological
      efficacy of gentamicin sulfate ocular inserts.

PMID- 10349565
TI  - In vitro study of transdermal nicotine delivery: influence of rate-controlling
      membranes and adhesives.
AB  - The objective of this study was to evaluate the influence of a rate-controlling
      membrane and adhesive on the in vitro permeation of nicotine. The physicochemical
      properties of the adhesive, including adhesion and rheology (viscosity), were
      also detected. Higher permeability of nicotine was observed through a hydrophilic
      membrane than through a hydrophobic membrane. Natural rubber and silicone were
      used as the adhesive bases, respectively. The silicone adhesive showed the
      highest adhesion among all adhesive formulations. To increase the adhesion of
      natural rubber, a tackifier (polyisoprene) and a secondary tackifier (terpene
      polymer; Px 1150) were incorporated into the formulations to achieve acceptable
      adhesion. The nicotine permeation through silicone adhesive and three natural
      rubber adhesives with the secondary tackifier (2%, 4%, and 6% Px 1150) was close
      to that from a commercially available patch (Habitrol), although the loading
      amount of nicotine was not the same. A longer lag time during the in vitro
      permeation study of nicotine was required for the adhesives prepared in our
      laboratory than for the commercially available patch.

PMID- 10349566
TI  - Comparative tablet and rheological properties of new microcrystalline cellulose:
      direct compression and wet granulation methods.
AB  - The overall objective of this study was to compare the rheological properties and
      tablet characteristics of two new varieties of celluloses (Vivacel 101 and 102),
      recently produced and commercialized, with the classical varieties of celluloses
      (Avicel and Elcema). The results showed no significant differences in the
      rheological properties of Vivacel and Avicel, while significant differences were
      found between the two celluloses and Elcema. Furthermore, there were no
      statistically significant differences in the disintegration times and Td values
      of Vivacel and Avicel. In conclusion, it was found that these new celluloses
      offer all the known advantages of Avicel.

PMID- 10349567
TI  - Stability of pilocarpine ophthalmic solutions.
AB  - The stability of pilocarpine and pilocarpine-timolol eyedrop preparations
      available on the Argentine market was studied. A high-performance liquid
      chromatographic method that allows the estimation of pilocarpine in the presence
      of degradation products was used for the study according to the preestablished
      design. It was found that pilocarpine solutions are stable, while pilocarpine in
      association with timolol shows significant degradation.

PMID- 10349568
TI  - Search for related substances in market products containing enalapril maleate as
      the active principle.
AB  - This study's main object was the determination of substances, by means of high
      performance liquid chromatography (HPLC), that are related to enalapril maleate
      in medicinal tablets. The research was on products containing a 20 mg active
      principle with a 12-month delta t and on those batches near their expiration date
      with an enalapril maleate concentration of 10, 5, and 2.5 mg.

PMID- 10349569
TI  - Examination of the polymorphism of piroxicam in connection with the preparation
      of a new "soft-patch" type pharmaceutical dosage form.
AB  - The influence of different solvents (propylene glycol, glycerol, ethanol), as
      well as different technological procedures (melting, rapid and slow cooling), on
      the formation of polymorphous piroxicam modifications was examined in the course
      of the elaboration of a "soft-patch" type of semisolid pharmaceutical dosage
      form. The thermodynamical behavior, some physicochemical properties (such as
      melting point, dissolution rate), and infrared (IR) spectrum of the formed
      (needle and cubic) crystal modifications were studied, and the possibilities of
      their formation and their avoidance were examined.

PMID- 10349570
TI  - Skin cancer prevention: the problem, responses, and lessons learned.
AB  - Skin cancer is one of the most common forms of cancer and has rapidly increased
      during the past three decades in the United States. More than 1 million new cases
      of skin cancer are estimated to be diagnosed in the United States each year. The
      National Skin Cancer Prevention Education Program (NSCPEP) was launched by the
      Centers for Disease Control and Prevention (CDC) in 1994 as a national effort to
      address the Healthy People 2000 objectives for skin cancer prevention. The NSCPEP
      is a comprehensive, multidimensional public health approach that includes (1)
      primary prevention interventions; (2) coalition and partnership development; (3)
      health communications and education; and (4) surveillance, research, and
      evaluation. In 1994, through support from the CDC, state health departments in
      Arizona, California, Georgia, Hawaii, and Massachusetts initiated primary
      prevention intervention projects to conduct and evaluate skin cancer prevention
      education. This article discusses the comprehensive, multidimensional public
      health approach highlighting examples from the state demonstration projects.

PMID- 10349571
TI  - Skin cancer prevention for children: a critical review.
AB  - Increasing sun protection for children may reduce their risk for skin cancer, so
      many health authorities recommend comprehensive sun safety for children. Sun
      protection of children in North America and Europe is generally lower than
      desired and lower than in Australia. This article provides a critical review of
      evaluations on the effects of 24 sun protection programs for children under age
      14. Programs are classified based on the target population, setting, and
      features. Most programs improved sun safety knowledge, but changes in sun
      protection attitude and behaviors were smaller. Multiunit presentations were more
      effective than short-duration presentations. Peer education was effective but
      needs further evaluation. Some programs for parents have been shown to increase
      sun protection for children. Strategies to improve sun safety policies need
      further study. A few community-wide programs have effectively improved sun
      protection. Future research should address innovative strategies and issues of
      design and measurement. There is no gold standard for measuring sun protection
      behavior, but self-report, prospective diaries, and observational techniques show
      small positive correlations.

PMID- 10349572
TI  - Factors associated with skin cancer prevention practices in a multiethnic
      population.
AB  - A better understanding of factors influencing sun protection practices can
      improve the design and evaluation of skin cancer prevention programs. These data
      are from a cross-sectional survey of 756 parents with children in Grades 1
      through 3, and 176 recreation program staff members in a multiethnic population
      in Hawaii. Questionnaires asked about skin cancer prevention practices (sunscreen
      use, covering up, shade seeking), knowledge, benefits and barriers, policies, and
      staff norms for prevention. The most important correlates of children's
      prevention practices were their parents' sun protection habits. Multiple
      regression models--which included knowledge, beliefs, program policies, and
      covariates related to sun protection--explained a total of between 38% and 41% of
      the variance in children's sun safety habits, 22% to 25% of parents' habits, and
      24% of recreation staff members' sun safety habits. The models were less
      successful at predicting the use of hats, shirts, and shade seeking and a
      composite sun protection habits index. Parents and caregivers' knowledge,
      beliefs, and behaviors, as well as recreation program policies, are strong
      predictors of sun protection practices among children in Grades 1 to 3 in a
      multiethnic sample.

PMID- 10349573
TI  - Sun avoidance practices among non-Hispanic white Californians.
AB  - This study measures self-reported sun avoidance practices, use of protective
      clothing, and use of sunscreen among 4,749 non-Hispanic white adults living in
      households in California. Data are from the California Behavioral Risk Factor
      Survey, a population-based telephone survey of health behaviors and attitudes.
      The average respondent spent at least 15 minutes in the sun on 21.4 days out of
      the last 30 days. Regular use of protective clothing was reported by 30.7%,
      regular use of sunscreen by 22.2%, and regular sun avoidance by 17.1% of the
      respondents. Results varied by month, gender, skin tone, age, education, and
      presence of children in the household. Health strategies should target younger
      adults (especially men), households with children and adults with less than a
      high school education. Because of relatively low rates of sun avoidance behaviors
      overall, a general population campaign also is warranted.

PMID- 10349574
TI  - The Falmouth Safe Skin Project: evaluation of a community program to promote sun
      protection in youth.
AB  - A multidimensional community-based skin cancer prevention program was conducted
      in Falmouth, Massachusetts, combining community activism with publicity campaigns
      and behavioral interventions to improve sun protection knowledge; attitudes; and
      practices in parents, caregivers, and children. The program was associated with
      improvements in target outcomes, based on two telephone surveys of random samples
      of parents (n = 401, 404). After program implementation, fewer parents reported
      sunburning of their children, particularly among children 6 years old or younger
      (18.6% in 1994 vs. 3.2% in 1997), and more parents reported children using
      sunscreen, particularly continuous use at the beach (from 47.4% to 69.9% in
      younger children). Hat and shirt use did not increase. Improvements also were
      seen in parent role modeling of sun protection practices, parents' self-efficacy
      in protecting children from the sun, and sun protection knowledge. While these
      findings must be interpreted cautiously, they do suggest that this project was
      effective in promoting sun protection.

PMID- 10349575
TI  - Communicating about youth's sun exposure risk to soccer coaches and parents: a
      pilot study in Georgia.
AB  - Efforts to increase the sun-protective behaviors of children were extended to
      outdoor recreational sports and youth soccer settings in this study. The pretest
      results of a pilot survey of coaches (n = 12), parents (n = 50), and youths (n =
      61) on eight soccer teams in south Georgia were used to guide the development of
      a health education program for coaches. In the pilot programs, half the coaches
      were trained to be involved in soccer-playing youths' sun protection by acting as
      positive role models and promoting sun protection to youths and their parents.
      The pilot demonstrated coaches' willingness to participate in sun protection
      promotion to youth: Youths indicated that coaches and parents were more likely to
      tell youths to wear sunscreen after the training than before, and coaches
      perceived getting youths to wear sunscreen to be less difficult than before.

PMID- 10349577
TI  - Promoting sun protection in children: rationale and challenges.
AB  - This article outlines the epidemiological and educational arguments for promoting
      sun protection during childhood and highlights factors that may facilitate or
      hinder achievement of this behavioral outcome. A model describing behavioral
      factors in the causation of skin cancer is presented. Summary results from
      previous behavioral studies and interventions relating to primary prevention of
      skin cancer are described, and recent data on the cost-effectiveness of sun
      protection in Australia and its implications for health insurers are discussed.
      This article also includes a commentary on the demonstration projects promoting
      skin cancer prevention among children and their caregivers featured in this
      special issue of Health Education and Behavior.

PMID- 10349576
TI  - Evaluation of a three-year school-based intervention to increase adolescent sun
      protection.
AB  - The efficacy of a school-based intervention was evaluated using a randomized
      controlled trial in Australia. In consecutive grades (8, 9, and 10), students in
      the intervention group received components of a program that addressed issues
      related to the need to protect yourself from the sun, behavioral strategies
      related to using sun-protective measures, personal and social images of having a
      tan, the use of sun-safe clothing, and how to change their schools through forms
      of structural change. Pre- and postintervention measures among junior high school
      students showed greatest improvement in the intervention group's knowledge scores
      and minimal changes in sun protection behavior from Grade 8 to Grade 9, which
      were not maintained through Grade 10. Results of the study highlight some
      limitations of school-based interventions for changing sun protection behaviors.

PMID- 10349578
TI  - Social support, social adjustment, and recovery status in bulimia nervosa.
AB  - OBJECTIVE: To examine recovery status in bulimia nervosa (BN) and its relation to
      social support and social adjustment. METHOD: Using a cross-sectional design, we
      administered the modified Social Support Questionnaire and the Social Adjustment
      Scale-Self-Report (SAS-SR) to 40 women, each of whom was actively bulimic (ABN),
      was in remission from BN (RBN), or had no history of eating disturbance
      (comparison). RESULTS: In terms of social support, relative to RBN and comparison
      subjects, the ABN group had significantly fewer persons in their friendship and
      kinship networks available to provide emotional support, although the groups were
      equivalent in number of persons available to provide things and advice. Relative
      to the comparison group, both bulimic groups were significantly dissatisfied with
      the quality of emotional support provided by relatives. On the SAS-SR, women in
      the ABN group displayed the poorest overall social functioning. The RBN group was
      functioning significantly better than the ABN group, but significantly more
      poorly than the comparison group. DISCUSSION: Our results suggest that the social
      functioning of RBN women lies between ABN women and non-eating-disordered women,
      indicating both gains relative to the active phase and residual deficits.

PMID- 10349579
TI  - Effects of a body image curriculum for college students on improved body image.
AB  - OBJECTIVE: This study evaluated the effects of an undergraduate body image
      course, "Body Traps: Perspectives on Body Image," on decreasing body
      dissatisfaction, weight concern, and disordered eating behaviors. METHODS: Twenty
      four undergraduate females enrolled in the body image course. Measures of body
      image and disordered eating patterns were assessed at baseline and at
      postintervention. RESULTS: Subjects significantly decreased the frequency and
      severity of their body dissatisfaction and disordered eating. No changes in body
      mass index or global self-esteem were observed. DISCUSSION: This is the first
      investigation to demonstrate that a formal, academic course can result in the
      reduction of both attitudinal and behavioral eating disorder risk factors. Future
      controlled studies need to be undertaken to substantiate this effect.

PMID- 10349580
TI  - Suppressing thoughts about chocolate.
AB  - OBJECTIVE: Thought suppression frequently results in subsequent
      hyperaccessibility of the suppressed thoughts. This study investigated whether
      this effect transfers to behavior. Does suppressing thoughts result in a
      subsequent increase in the performance of behaviors related to those thoughts?
      METHODS: Twenty chocolate cravers and 22 noncravers were instructed to suppress
      chocolate-related thoughts in an articulated thoughts task or they were given no
      specific instructions. Participants then completed a computer-based task which
      yielded chocolate rewards. RESULTS: Both cravers and noncravers could suppress
      chocolate-related thoughts when instructed to do so. Both groups of participants
      showed greater performance, and hence earned more chocolate, in the suppression
      than control condition (p < .05). DISCUSSION: Behavioral control may follow many
      of the same ironic pathways traced by mental control.

PMID- 10349582
TI  - Hostility, dieting, and nutrition attitudes in overweight and weight-cycling men
      and women.
AB  - OBJECTIVE: Relationships were examined between hostility, weight status, weight
      cycling, dieting behaviors, and nutrition attitudes. METHOD: Data were derived
      from the RENO Diet-Heart Study (RDHS), a 5-year prospective natural history
      (descriptive) study of weight fluctuations, behavior patterns, and cardiovascular
      (CVD) risk factors. Overweight versus normal-weight and weight-cycling versus non
      weight-cycling men and women were compared on overt and covert hostility.
      RESULTS: Overweight subjects scored significantly higher than normal-weight
      individuals on covert but not overt hostility. Similarly, subjects with a history
      of weight fluctuation scored significantly higher on covert hostility than
      subjects without a history of weight cycling. Subjects who reported more
      hostility scored higher on measures of eating disinhibition, hunger, and dietary
      helplessness. DISCUSSION: The relationships among hostility, dieting behaviors,
      and nutrition attitudes could not be explained on the basis of general distress
      alone. The findings supported the hypothesis that the relationship between
      hostility and health is mediated by the association between hostility and health
      related behaviors.

PMID- 10349581
TI  - Role of leptin in women with eating disorders.
AB  - OBJECTIVE: This study investigated the role of leptin on eating behavior and
      reproductive function in eating disorders. METHOD: The subjects included 80
      eating-disordered women, having different fat mass, eating behavior, and
      endocrine abnormalities, and 26 control women. Plasma leptin, insulin,
      luteinizing hormone (LH), follicle-stimulating hormone (FSH), cortisol, insulin
      growth factor-1 (IGF-1), free T4 levels, percent body fat, eating behavior score,
      and menstrual status score were evaluated for each subject. RESULTS: In eating
      disordered patients, log of leptin levels were significantly correlated with body
      fat mass, eating behavior score, menstrual status score, and insulin, LH, and FSH
      levels. Stepwise regression analysis showed that fat mass and eating behavior
      score were significant determinants of leptin levels. Furthermore, in patients
      undergoing recovery, leptin levels were determined by fat mass and/or eating
      behavior. DISCUSSION: These results suggest that leptin may play some role in
      counteracting the abnormal eating behavior, reproductive function, and fat mass
      in these disorders.

PMID- 10349583
TI  - Body image, social comparison, and eating disturbance: a covariance structure
      modeling investigation.
AB  - OBJECTIVE: To evaluate the role of appearance-based social comparison processes
      as a possible mediational link between developmental factors (negative social
      feedback, i.e., teasing about appearance; biological status, i.e., early physical
      maturation) and levels of body dissatisfaction, eating disturbance, and global
      psychological functioning. METHOD: In this study of 173 female undergraduates,
      covariance structure modeling (CSM) was used to examine direct and mediational
      relationships among these variables. RESULTS: Appearance-based social comparison
      mediated the effect of appearance-related teasing on body image and eating
      disturbance; body image mediated the effect of teasing on eating disturbance;
      eating disturbance had a direct effect on overall psychological functioning.
      DISCUSSION: Implications for devising and testing other theoretical models are
      discussed.

PMID- 10349584
TI  - Validation of the flexible and rigid control dimensions of dietary restraint.
AB  - OBJECTIVE: Two subscales for the Eating Inventory (Three-Factor Eating
      Questionnaire) are developed and validated: Rigid and Flexible control of eating
      behavior. METHOD: Study I is an analysis of questionnaire data and a 7-day food
      diary of 54,517 participants in a computer-assisted weight reduction program.
      Study II is a study of 85 subjects used to develop a final item pool. Study III
      is a questionnaire survey of a random sample (N = 1,838) from the West German
      population aged 14 years and above used to validate the developed subscales.
      RESULTS: Rigid control is associated with higher scores of Disinhibition, with
      higher body mass index (BMI), and more frequent and more severe binge eating
      episodes. Flexible control is associated with lower Disinhibition, lower BMI,
      less frequent and less severe binge eating episodes, lower self-reported energy
      intake, and a higher probability of successful weight reduction during the 1-year
      weight reduction program. DISCUSSION: Rigid and flexible control represent
      distinct aspects of restraint having different relations to disturbed eating
      patterns and successful weight control.

PMID- 10349585
TI  - Evolving ideals of male body image as seen through action toys.
AB  - OBJECTIVE: We hypothesized that the physiques of male action toys--small plastic
      figures used by children in play--would provide some index of evolving American
      cultural ideals of male body image. METHOD: We obtained examples of the most
      popular American action toys manufactured over the last 30 years. We then
      measured the waist, chest, and bicep circumference of each figure and scaled
      these measurements using classical allometry to the height of an actual man (1.78
      m). RESULTS: We found that the figures have grown much more muscular over time,
      with many contemporary figures far exceeding the muscularity of even the largest
      human bodybuilders. DISCUSSION: Our observations appear to represent a "male
      analog" of earlier studies examining female dolls, such as Barbie. Together,
      these studies of children's toys suggest that cultural expectations may
      contribute to body image disorders in both sexes.

PMID- 10349586
TI  - Eating-disordered behaviors and personality characteristics of high school
      athletes and nonathletes.
AB  - OBJECTIVE: To assess whether high school athletes are at risk for an eating
      disorder, whether personality characteristics differentiate athletes from
      nonathletes, and whether high levels of perfectionism put athletes at risk.
      METHOD: 318 high school athletes were randomly matched to 360 nonathletes.
      Comparisons were made by means of the Eating Disorders Inventory (EDI), Restraint
      Scale, Risk Symptom Checklist, Multidimensional Personality Questionnaire (MPQ),
      and body mass index (BMI). RESULTS: Athletes did not have higher levels of
      disordered eating behaviors and attitudes than their nonathletic counterparts.
      Athletes had less negative views of life than nonathletes. However,
      perfectionistic tendencies may put some athletes at risk. DISCUSSION: High school
      athletes are not at greater risk for the development of an eating disorder than
      other students. Athlete's positive outlook on life and high self-efficacy may
      serve as protective factors. Alternatively, athletes may not be at risk until
      they train for one particular sport in a highly competitive environment.

PMID- 10349587
TI  - Marital status, marital satisfaction, and body image dissatisfaction.
AB  - OBJECTIVE: This study examined whether married individuals have comparable body
      image disturbance to nonmarried individuals and whether the quality of a marital
      relationship is significantly related to body image disturbance in a sample of
      dieters. METHOD: Measures of marital status, marital satisfaction, and body
      dissatisfaction were administered to a sample of 16,377 subjects who had tried to
      lose weight at least once within the previous 3 years. RESULTS: Marital status
      was not associated with increased body dissatisfaction. Marital satisfaction was
      significantly related to body dissatisfaction when controlling for age, body mass
      index, self-esteem, and gender. DISCUSSION: Body dissatisfaction occurs at
      comparable levels among married and single individuals and the study of marital
      functioning among eating-disordered individuals represents a large gap in the
      literature.

PMID- 10349588
TI  - Vegetarianism in young women: another means of weight control?
AB  - OBJECTIVE: To investigate the links between vegetarianism (meat avoidance) and
      weight control in young women. METHODS: Self-reported food habits (indicating
      meat avoidance and weight loss dieting) and dietary restraint (using the Dutch
      Eating Behavior Questionnaire [DEBQ]) were collected from 131 young adult women.
      Restraint scores and weight loss behavior were compared between vegetarians and
      nonvegetarians. In addition, reasons for meat avoidance were identified in the
      vegetarian subjects. RESULTS: Vegetarianism, broadly defined, was reported by
      34.3% of participants. Vegetarians had significantly higher dietary restraint,
      but did not differ in current dieting. DISCUSSION: The relationship between
      vegetarianism and weight control is complex. Vegetarianism may be best seen as a
      method for complicating the normalization of eating rather than a simple risk
      factor for eating disorders.

PMID- 10349589
TI  - Eating problems in female Japanese high school students: a prevalence study.
AB  - OBJECTIVES: This study was conducted to estimate the prevalence of eating
      problems and to identify factors associated with the eating problems among
      Japanese high school girls. METHODS: This study used a cross-sectional design.
      The study population was 3,032 female students attending three high schools in
      Fukushima, Japan. The 26-item version of the Eating Attitudes Test (EAT-26) was
      administered to assess eating problems. Inquiries were also made regarding
      possible risk factors for the eating problems. RESULTS: Of the 2,685 subjects,
      5.4% had a total EAT-26 score above the cutoff point (20 < or =). Logistic
      regression analysis demonstrated that older age, higher body mass index, a
      distorted body image, obsessive-compulsive tendency, and some familial issues
      were independently related to the eating problems. DISCUSSION: The prevalence of
      eating problems in the Japanese female population was low compared with reports
      from Western countries. In addition, distorted body image was suggested to have
      the greatest influence on eating problems.

PMID- 10349590
TI  - Mortality from eating disorders--a 5- to 10-year record linkage study.
AB  - PURPOSE: Previous research has found elevated mortality rates from anorexia
      nervosa (AN) and perhaps bulimia nervosa (BN). This study was performed using
      computerized record linkage to examine mortality rates in a cohort of patients
      with eating disorder (ED) diagnoses seen in an emergency room (ER) by a
      psychiatry service. METHODS: ER records were retrieved for 122 consecutive ED
      patients seen over a 5-year period from 1985 to 1990. Demographic data,
      identifiers including social security number and date of birth, and clinical
      information were recorded; record linkage to a computerized vital status
      database, MINNDEX, through 1995 was then performed. Death certificates were
      subsequently obtained and reviewed to identify cause of death. RESULTS: The
      average age at time of ER visit was 25.7 (SD 7.4); 91.8% were female, 8.2% male.
      The most common diagnosis was AN (44.3%); 34.4% were diagnosed with BN, and 21.3%
      with eating disorder not otherwise specified (EDNOS). Five subjects died in the 5
      to 10-year follow-up period (all female). One deceased subject carried a
      diagnosis of BN, the other 4 had AN. Three subjects with AN were listed on death
      certificates as having died of that illness; the fourth died of emphysema. The
      deceased subject with BN died of traumatic causes. The crude mortality rates were
      7.4% for AN and 2.4% for BN. The standardized mortality ratio for AN was 8.35.
      CONCLUSIONS: This study confirms and extends prior reports of high mortality
      rates in AN, using an epidemiologic database with high ascertainment rates. While
      the crude mortality rate for BN was also high, the small sample size makes it
      difficult to draw conclusions.

PMID- 10349591
TI  - Weight concern across the life-span: relationship to self-esteem and feminist
      identity.
AB  - OBJECTIVE: The aim of this study was to investigate the correlates of weight
      concern across the life-span. METHOD: Questionnaires assessing weight concern,
      self-esteem, and feminist attitudes were completed in their homes by 180 women
      aged between 18 and 60 years. RESULTS: It was found that there was a negative
      relationship between weight concern and self-esteem for 30 to 49-year-old women,
      but not for younger or older women. A similar pattern held for feminist
      attitudes. Among 30 to 49-year-old women, a strong feminist orientation related
      to a lesser concern with weight. DISCUSSION: It was concluded that the meaning
      and experience of body weight and size change across the life-span.

PMID- 10349592
TI  - Complete recovery from intractable bulimia nervosa by the surgical cure of
      primary hyperparathyroidism.
AB  - We document here the first case of bulimia nervosa associated with primary
      hyperparathyroidism. The binge eating and self-induced vomiting that occurred for
      more than 10 years disappeared completely after the surgical cure of primary
      hyperparathyroidism. Depressive and anxiety symptoms also improved dramatically.
      The possible influence of derangement in calcium metabolism on the
      neurobiochemical mechanism of bulimia nervosa is discussed.

PMID- 10349593
TI  - Licorice-induced hypokalemic myopathy and hypokalemic renal tubular damage in
      anorexia nervosa.
AB  - A patient with a history of anorexia nervosa developed licorice-induced
      hypokalemic myopathy. With potassium replacement, high CPK blood level and
      myopathic signs returned to normal. However, the patient manifested persistent
      hypokalemia and impaired renal function to concentrate and acidify the urine.
      Renal biopsy demonstrated intense degeneration and vacuolation of tubules with a
      normal glomerus which was consistent with hypokalemic nephropathy. Prolonged
      hypokalemia in anorexia nervosa is sometimes attributed to surreptitious purging
      or taking diuretics, but it is necessary to check the urine pH, the urine
      specific gravity, and the urine potassium level in order to find underlying renal
      damage even after hypokalemic myopathy is treated successfully.

PMID- 10349594
TI  - Characterization of melatonin-induced fos-like immunoreactivity in the
      hypothalamic suprachiasmatic nucleus of the rat.
AB  - The hypothalamic suprachiasmatic nucleus (SCN) is primarily responsible for the
      regulation of circadian rhythmicity. Melatonin, the pineal-derived neurohormone,
      modulates the rhythmic output of the SCN. Property timed exposure to melatonin is
      able to induce changes in rhythmic function and thereby entrain circadian rhythms
      of activity. c-fos is an immediate early gene that is transiently expressed in
      neurons in response to receptor activation. The ventrolateral portion of the SCN
      (vSCN) is activated in response to phase-shifting stimuli, an event which is
      marked by an increase in the expression of c-fos.

PMID- 10349595
TI  - Comparative affinities of adrenomedullin (AM) and calcitonin gene-related peptide
      (CGRP) for [125I] AM and [125I] CGRP specific binding sites in porcine tissues.
AB  - We have investigated the binding characteristics of rat [125I] adrenomedullin
      (AM) and human [125I] calcitonin gene-related peptide (CGRP) to membranes
      prepared from a number of porcine tissues including atrium, ventricle, lung,
      spleen, liver, renal cortex and medulla. These membranes displayed specific, high
      affinity binding for [125I] rat AM and [125I] human CGRP. Porcine lung displayed
      the highest density of binding sites for radiolabeled AM and CGRP followed by
      porcine renal cortex. Competition experiments performed with [125I] rat AM
      indicated that the rank order of potencies of various peptides for inhibiting
      [125I] rat AM binding to various tissues were rat AM > or = human AM > or = human
      AM(22-52) > h alpha CGRP > or = h alpha CGRP(8-37) >>>> sCT except spleen,
      atrium, renal cortex and renal medulla where rAM and hAM were 20-300 fold more
      potent than hAM (22-52). When the same experiments were performed using [125I] h
      alpha CGRP as the radioligand, the rank order potencies for various peptides were
      rAM = hAM > h alpha CGRP > h alpha CGRP(8-37) in most of the tissues except in
      spleen and liver where h alpha CGRP was the most potent ligand. In lung, h alpha
      CGRP was almost as potent as rAM and hAM in displacing [125I] h alpha CGRP
      binding. These data suggest the existence of distinct CGRP and AM specific
      binding sites in contrast to previous reports that showed that both peptides
      interact differently in rat tissues.

PMID- 10349596
TI  - Selective alkylation of rat urinary bladder muscarinic receptors with 4-DAMP
      mustard reveals a contractile function for the M2 muscarinic receptor.
AB  - Our previous data indicate that M3 muscarinic receptors mediate carbachol induced
      bladder contractions. The data presented here were obtained by selective
      alkylation of M3 receptors with 4-DAMP mustard and suggest that the M2 receptor
      subtype may be involved in inhibition of beta-adrenergic receptor induced
      relaxation, therefore, allowing recontraction. Alkylation resulted in 85% of M3
      receptors and 65% of M2 receptors unable to bind radioligand as demonstrated by
      subtype selective immunoprecipitation. Rat bladder strips subjected to our
      alkylation procedure contracted submaximally, and direct carbachol contractions
      were inhibited by antagonists with affinities consistent with M3 receptor
      mediated contraction. In contrast, the affinities of antagonists for inhibition
      of carbachol induced recontractions following isoproterenol stimulated relaxation
      in the presence of 90 mM KCl, indicated a contractile function for the M2
      receptor that was not observed in control strips. In conclusion, these studies
      demonstrate a possible role for the M2 subtype in bladder smooth muscle
      contraction.

PMID- 10349597
TI  - Beta 2-adrenoceptor agonist-induced down-regulation after short-term exposure.
AB  - We examined the effect of duration of beta 2-adrenergic receptor (beta 2AR)
      occupancy by isoproterenol on specific binding of 125I-lodocyanopindolol (125I
      ICYP) in membranes from rat L6 myoblasts. Ten minute exposure caused a time-and
      concentration-dependent maximal decrease in 125I-ICYP binding 24 hours after
      exposure equal to that following continuous exposure (p < 0.05). Low temperature,
      concanavalin A, H89 and ICl 118,551 blocked the decline in 125I-ICYP binding
      during the first hour following exposure probably representing receptor
      sequestration to a compartment or change to a form incapable of ligand binding.
      Compared to controls, receptor binding 4 and 24 hours following exposure was
      reduced 56 +/- 8.7% and 72 +/- 8.8%, respectively (p < 0.05), and was blocked by
      ICl 118,551 but not CGP12177. Isoproterenol-induced, but not forskolin
      stimulated, cAMP accumulation was reduced 35% 24 hours following exposure (p <
      0.05). 125I-ICYP binding in intact L6 cells 4 and 24 hours after exposure were
      respectively 56 +/- 8.9 and 61 +/- 13% of controls (p < 0.05). Following agonist
      exposure, CHO cell membranes expressing human beta 2ARs exhibited 125I-ICYP
      binding 85 +/- 2.0% and 6 +/- 2.8% of control values 4 and 24 hours, respectively
      (p < 0.05). A model predicting that full occupation of the beta 2AR activates
      receptor degradation explains our results that agonist-induced down-regulation of
      beta 2AR does not require continuous presence of the agonist.

PMID- 10349598
TI  - An efficient cyclic AMP assay for the functional evaluation of beta-adrenergic
      receptor ligands.
AB  - beta-Adrenoceptors are G-protein linked receptors that are positively coupled to
      adenylyl cyclase. We wanted to develop an alternative method to the detection of
      cAMP using radioimmunoassay for functional analysis of ligands for human beta
      adrenoceptors (ARs). Chinese hamster ovary cells that stably expressed the beta 2
      AR were transiently transfected with reporter plasmids containing the firefly
      luciferase gene under the transcriptional control of 6 or 12 cAMP response
      elements. The transiently transfected cells (electroporated at 150 volts, single
      pulse, 70 ms) were grown in 96-well microtiter plates (50,000 cells per well) for
      20 hours, exposed to various ligands for 4 hours, and the luciferase activity was
      assayed. Stimulation of beta-ARs in these transfected cells resulted in a greater
      than 25-fold induction of luciferase activity. This activity was maximally
      increased in response to 20 microM forskolin, 1 mM 3-isobutyl-1-methylxanthine,
      and 10-30 nM (-)-isoproterenol. Exposure of cells to (-)-isoproterenol elicited a
      concentration dependent luciferase response and these effects of (-)
      isoproterenol were blocked by propranolol (K(B) = 1.5 nM) and bupranolol (K(B) =
      1.9 nM). The concentration of (-)-isoproterenol exhibiting half maximal response
      was 0.35 nM. This assay offers an excellent alternative to traditional methods of
      cAMP measurement and has applications to elucidate cAMP mediated signaling
      pathways in cells.

PMID- 10349599
TI  - Activation of STAT1 alpha by phosphatase inhibitor vanadate in glomerular
      mesangial cells: involvement of tyrosine and serine phosphorylation.
AB  - Vanadate is an insulinomimetic agent that has potent inhibitory effect on
      tyrosine phosphatases. We have recently demonstrated that low concentration of
      vanadate stimulates phosphotyrosine-dependent signal transduction pathways
      leading to gene expression and DNA synthesis in mesangial cells. To further
      examine the mechanisms by which vanadate activates mesangial cell, we studied its
      effect on signal transducer and activators of transcription (STAT). Incubation of
      lysates from vanadate-stimulated mesangial cells with a specific high affinity
      sis-inducible DNA element (SIE) resulted in the formation of protein-DNA complex.
      Supershift analysis using monoclonal antibody against STAT1 alpha showed its
      exclusive presence in the DNA-protein complex. Incubation of cell lysate with
      antiphosphotyrosine antibody or with excess phosphotyrosine caused decrease in
      binding of STAT1 alpha to SIE probe indicating that tyrosine phosphorylation and
      dimerization of this transcription factor are necessary for its activation.
      Immunoprecipitation followed by immunecomplex kinase assay showed increased
      tyrosine kinase activity of Janus kinase 2 (JAK2) in vanadate-treated mesangial
      cells. The addition of a monoclonal antiphosphoserine antibody to lysates from
      vanadate-treated mesangial cells results in supershift of protein-DNA complex
      indicating the presence of serine phosphorylated STAT1 alpha in this complex.
      Treatment of lystates from vanadated-stimulated mesangial cells with serine
      phosphatase PP2A causes inhibition of DNA-protein interaction. Collectively, our
      data indicate that at least one mechanism of activation of mesangial cells during
      vanadate treatment is increased activation of STAT1 alpha by both tyrosine and
      serine phosphorylation.

PMID- 10349600
TI  - Play therapy and art therapy for substance abuse clients who have a history of
      incest victimization.
AB  - This article discusses the use of play therapy and art therapy treatment
      techniques for persons in substance abuse treatment who have a history of incest
      victimization. While substance abuse treatment focuses on substance abuse,
      neglecting to address issues related to past incest contact may increase the
      potential for relapse. This population displays unique characteristics that may
      prevent them from participating in, or benefitting from, traditional treatment
      modalities (which are highly dependent upon the verbal interactions between
      clients and therapists). Play therapy and art therapy are discussed in terms of
      history, rationale, and benefits to clients.

PMID- 10349601
TI  - Smoking intervention with adolescent substance abusers. Initial recommendations.
AB  - Recent increases in adolescent cigarette smoking have provided an impetus for
      developing effective youth smoking-cessation interventions. Adolescents treated
      for substance abuse are a particularly important target for tobacco use
      intervention given the high prevalence and persistence of smoking among this
      subgroup of youth. The few studies to date of adolescent smoking cessation have
      demonstrated little success in effecting change in tobacco use. In the absence of
      empirical evidence, recommendations for tobacco intervention with substance
      abusing adolescents are proposed based on information from several sources:
      studies of adolescent smoking cessation, adolescent developmental considerations,
      issues specific to substance abusers, motivational concerns, and adult smoking
      cessation techniques. An outline is provided of components to consider for
      inclusion in a substance-abusing adolescent smoking intervention. It is suggested
      that tobacco-focused interventions be incorporated as a routine part of treatment
      for adolescent substance abuse.

PMID- 10349602
TI  - Matching clients' needs with drug treatment services.
AB  - This paper reports results of a study that investigated whether matching drug
      treatment services with client needs improved outcomes for a sample of 171
      clients who participated in community-based drug treatment programs. Clients were
      initially assessed on multiple problem areas (alcohol use, drug use, medical,
      psychological, family/social, legal, employment, housing) and on areas of special
      needs or stated preferences for services (e.g., transportation, child care,
      language). A 6-month follow-up interview reassessed clients' problems/needs in
      all areas and collected information on the services received. The results showed
      that some services significantly improved client outcome for those who had
      expressed needs for such services. Notably, services meeting the need for
      vocational training, child care, transportation, and housing showed beneficial
      effects. A higher level of needs and services matching (defined either by the
      ratio of services received to services desired, or by the total level of met
      versus unmet needs in the eight problem areas) significantly predicted longer
      treatment retention.

PMID- 10349603
TI  - Clarifying the nature of therapeutic community treatment. The Survey of Essential
      Elements Questionnaire (SEEQ).
AB  - This study reports on the extent to which Therapeutic Community (TC) agencies
      share a common set of beliefs about the essential elements of TC treatment. The
      Survey of Essential Elements Questionnaire (SEEQ), a TC theory-based instrument,
      was used in a field survey of 59 directors of agencies identified as TCs through
      their membership in Therapeutic Communities of America (TCA). Results showed a
      high degree of concordance in the perceived importance of a common set of
      treatment elements identified as essential to the TC modality. Two clusters of TC
      oriented agencies, identified as Traditional and Modified, were determined based
      on beliefs in the importance of the elements. Results were seen as validating the
      TC formulation from which the SEEQ items were drawn. Implications on the
      potential use of the SEEQ as a means of codifying TC treatment for research,
      training, and quality assurance are discussed.

PMID- 10349605
TI  - Cognitive restructuring and the 12-step program of alcoholics anonymous.
AB  - Alcohol addiction affects many clients that enter the offices of traditional
      mental health professionals. Their recovery is impacted by what goes on inside
      the office, in treatment, as well as by involvement outside the office, in 12
      step programs as Alcoholics Anonymous (AA). This article examines alcoholism as a
      thought disorder and cognitive restructuring as an effective model of treatment.
      Cognitive restructuring occurs in therapy and in AA. It can, therefore, be the
      bridge that encourages understanding and cooperation between the two factors
      influencing recovery.

PMID- 10349604
TI  - Treatment of nicotine dependence in the chronic mentally ill.
AB  - Since rates of smoking cessation in psychiatric patients are low, the manner in
      which information on the importance of abstinence is presented and the scope of
      the treatment provided to psychiatric patients who have decided not to smoke are
      very important. This article will describe the development and implementation of
      a smoking-cessation group for chronic mentally ill patients. Components of the
      program are described and a detailed case example is provided. The smoking
      behavior of patients who participated in the first year of programming is
      reviewed, along with patient evaluation of program effectiveness. Our experience
      demonstrates the importance of psychoeducation for chronic psychiatric patients
      who tend not to have received formal education on the dangers of smoking and the
      possibility of addiction. Our findings indicate that patients are willing to
      learn more about smoking and the consequences of this behavior, even though many
      of them were not able to set quit dates. The provision of information through
      education groups increases the possibility of moving patients to the
      precontemplation stage.

PMID- 10349606
TI  - Revisiting the effectiveness of methadone treatment on crime reductions in the
      1990s.
AB  - This study examines the relationship between methadone treatment and the criminal
      activity of 126 individuals participating in treatment during the early 1990s.
      The primary question addressed is to what extent is methadone maintenance
      treatment associated with reductions in crime? Although prior studies in the
      1970s and early 1980s showed significant decreases in crime for individuals in
      treatment programs, criteria for remaining in this treatment modality have
      changed in recent years, particularly with the advent of acquired immune
      deficiency syndrome and the need to reduce intravenous drug use. A pre-post study
      design is employed spanning a 6-year time period of subject recruitment and
      follow-up (1987-1993). Uniform administrative records on arrests are used for the
      analyses. A multiple regression model is employed to explain the variance in the
      number of arrests 2 years following program admission, with prior criminal
      history, prior and current drug treatment, and current cocaine use employed as
      explanatory variables. Results indicate that treatment retention has only a
      slight, though significant, effect on reducing criminal activity during
      treatment. Two other factors that appear to increase arrest activity are the use
      of cocaine and prior criminal history. The fact that arrests did not decrease
      during a treatment period of 18 months on average requires more investigation in
      light of the increase in cocaine use in this population.

PMID- 10349607
TI  - An assessment of nicotine dependence among pregnant adolescents.
AB  - Studies have reported that between 28 and 62% of pregnant teenagers smoke
      (Cornelius, Taylor, Geva, & Day, 1995; Trollestrup, Frost, & Starzyk, 1992).
      Because smoking is prevalent among pregnant teenagers, the purpose of this
      research is to assess nicotine dependence in this high-risk group. This study
      analyzed baseline data from a sample of pregnant teen smokers who had volunteered
      to participate in a smoking cessation study (N = 94). Nicotine dependence was
      measured by adapting the Fagerstrom Tolerance Questionnaire (FTQ; Prokhorov,
      Pallonen, Fava, Ding, & Niaura, 1996), and by a 6-item withdrawal symptom scale.
      The overall FTQ score found among pregnant adolescents was 3.10 (SD = 2.3)
      compared to the mean overall FTQ score among vocational-technical students of
      4.27 (SD = 2.2) (Prokhorov et al., 1996). Duration of smoking in years was
      significantly correlated with the overall FTQ score (r = 0.43, p < .01). Quantity
      of smoking, as measured by average number of cigarettes smoked, significantly
      correlated with overall FTQ scores (r = 0.67, p < .01). Lighter smokers were more
      likely to have previously attempted to quit, however, among the quit attempters,
      those who smoked 10+ cigarettes per day reported greater severity of withdrawal
      symptoms than those who smoked less per day. Prenatal education and smoking
      cessation programs for pregnant teenagers, and pregnant women in general, need to
      consider that nicotine dependence is an important issue. Early pregnancy may be
      an opportune time to intervene among pregnant smokers; incentives may be
      necessary to attract those women who are the heaviest smokers, and possibly the
      most dependent on nicotine.

PMID- 10349608
TI  - An argument for choice. An alternative women's treatment program.
AB  - Current substance abuse treatment strategies tend to be relatively narrow and not
      empirically based. This is a result of a general failure on the part of
      practitioners to keep abreast of current research, which would direct them toward
      more effective models. Substance abuse treatment, usually based on a "one size
      fits all" philosophy, is often not particularly effective. Substance abuse
      research is often limited to the measurement of a single outcome--abstinence--and
      research on alternative models is scarce. This article argues for more flexible
      models of treatment that are based on research. A substance abuse treatment
      program that uses an empirically based model is described. The program
      incorporates broader outcomes research, which is yielding encouraging results.
      The suppositions that directed the research are discussed.

PMID- 10349609
TI  - The accumulation and histological effects of organometallic fungicides propineb
      and maneb in the livers of pregnant rats and their offspring.
AB  - Dithiocarbamate propineb and maneb are organometal fungicides, which are widely
      used for the control of diseases in plants. Female Wistar rats were exposed
      orally to 200 and 400 ppm propineb (Zn-containing dithiocarbamate) and 250 ppm
      maneb (Mn-containing dithiocarbamate), from the 6th day of gestation up to birth.
      We found that the body weights of both newborn litters and their fungicide
      treated mothers were lower than those of controls. Histological examination of
      the livers of fungicide-treated pregnant females and the offspring showed a
      variety of histopathological effects. Moreover, the analysis of Zn and Mn
      concentrations in the livers of pregnant females exposed to organometallic
      fungicides during pregnancy demonstrated that the metal concentrations in the
      liver were higher than those of controls. Similarly, the hepatic metal
      concentrations were significantly increased in the litters, indicating the
      transplacental passage of the organometallic fungicides.

PMID- 10349610
TI  - Mutagenicity tests of 4-phenyl-1,3-dithia-2-thioxo-cyclopent-4-ene.
AB  - The mutagenicity of 4-phenyl-1,3-dithia-2-thioxo-cyclopent-4-ene (DT827B) was
      examined in reverse mutation tests using Salmonella typhimurium and Escherichia
      coli, in the chromosomal aberration test with Chinese hamster ovary (CHO) cells,
      and in the micronucleus test using mice bone-marrow. In reverse mutation assay on
      DT827B according to Ames' method, DT827B was not mutagenic to S. typhimurium or
      E. coli when tested in dimethylsulfoxide to the limit of its solubility where
      precipitation occurred. In chromosomal aberration assay using CHO cells, DT827B
      was not clastogenic to induce structural chromosomal aberration but capable of
      inducing polyploidy. In micronucleus test, DT827B did not show micronucleus
      inducing potential at the maximum dose. In conclusion of the three mutagenicity
      studies, DT827B was considered to cause no mutagenicity under the conditions used
      in the present experiments except the increase in polyploidy, which probably is
      due to a toxic effect of the compound.

PMID- 10349612
TI  - Skin toxicity of propranolol in guinea pigs.
AB  - The skin toxicities of propranolol were studied in guinea pigs. In the primary
      and cumulative skin irritation studies, the skin reactions and the
      histopathological changes were observed in all animals treated with propranolol,
      and those tended to increase with the increase of propranolol dosage. The skin
      reactions increased with the application times of propranolol up to 7 days in the
      cumulative skin irritation study. In the skin sensitization, the phototoxicity
      and the skin photosensitization studies, no skin reactions were observed in any
      animals used in the studies. These results indicate that propranolol caused skin
      irritation, but was negative for skin sensitization, phototoxicity and skin
      photosensitization in guinea pigs.

PMID- 10349611
TI  - Mouse popliteal lymph node assay for assessment of allergic and autoimmunity
      inducing potentials of low-molecular-weight drugs.
AB  - In the present collaborative study, popliteal lymph node (PLN) responses to
      penicillin G (an allergenic chemical), D-penicillamine (an autoimmunity-inducing
      chemical), and barbital (a negative reference chemical) were investigated in
      three different mouse strains by ten pharmaceutical companies. Two inbred mouse
      strains (BALB/c and A/J) and one outbred strain (ICR) were subcutaneously
      injected with saline solutions containing penicillin G (1.25, 2.5 and 5
      mg/mouse), D-penicillamine (0.5, 1 and 2 mg/mouse), or barbital (2 mg/mouse) into
      one hind footpad and saline only was injected into the contralateral footpad. PLN
      cellularity indices were determined on day 7. In the three strains tested, the
      penicillin G and D-penicillamine injections resulted in approximately dose
      dependent responses. In contrast, barbital failed to generate a significant PLN
      reaction. In the typical data from one of the participating laboratories, the PLN
      responses of A/J, BALB/c, and ICR to penicillin G were high, intermediate and
      low, respectively, while their PLN responses to D-penicillamine were all high.
      Some variation in PLN cellularity indices was observed among the participating
      laboratories, but reproducibility of the popliteal lymph node assay (PLNA)
      evaluation was partly confirmed. Although the appropriate selection of mouse
      strains and drug dosage levels has to be considered, these results suggest that
      the PLNA may be an appropriate screening system for prediction of the allergic or
      autoimmunity-inducing potentials of low-molecular-weight drugs.

PMID- 10349613
TI  - Experimental infusion phlebitis: tolerance pH of peripheral vein.
AB  - This study aims to determine the pH that peripheral veins can tolerate.
      Intravenous nutrient solutions with different pHs (from 4.52 to 6.71) were
      infused into rabbit ear veins, and the veins were examined histopathologically.
      After 6-hr infusion at 10 mL/kg/hr, a commercial 2.72% amino acid/7.5% glucose
      solution with electrolytes (AG) caused obvious phlebitic changes, such as loss of
      venous endothelial cells, inflammatory cell infiltration, and perivascular edema,
      in all 6 rabbits because of its low pH (4.52) and high titratable acidity (22
      mEq/L). The phlebitis was reduced when the solution was neutralized with NaOH to
      pH 5.93, and was almost eliminated when the pH was neutralized to 6.49. After 8
      hr infusion at 15 mL/kg/hr, AG-adjusted pH to 6.30 caused slight phlebitic
      changes, but AG-adjusted pH to 6.71 scarcely caused any change. Furthermore, 24
      hr infusion of the pH 6.49 solution caused no histopathological changes in 3
      rabbits. These results suggest that the tolerance pH for the peripheral vein is
      about 6.5, and that an infusion solution does not cause phlebitis due to acidity
      if the pH is not lower than the tolerance pH.

PMID- 10349614
TI  - A quantitative comparison of induction and challenge concentrations inducing a
      50% positive response in three skin sensitization tests; the guinea pig
      maximization test, adjuvant and patch test and Buehler test.
AB  - The sensitivities of three skin sensitization tests such as the Guinea pig
      maximization test (GPMT), Adjuvant and patch test (APT) and Buehler test (BT),
      were quantitatively compared with reference to induction and challenge
      concentrations. Four chemical which had different physico-chemical properties
      (octanol-water partition coefficient (logP) and reactivity with NH2-group) were
      used in order to clarify the effect of the physico-chemical properties of
      chemicals on the sensitivity of the different methods. The induction
      concentrations inducing a 50% positive response (IC50) demonstrated extreme
      variation with the three methods. For example, the BT/GPMT ratio of IC50 values
      for 2,4-dinitrochlorobenzene was 33, whereas that for maleic anhydride was
      300,000. The results were thought to be caused by difference properties such as
      the logP and reactivity of chemicals. This correlation was confirmed by using 2
      dodecen-1-yl succinic anhydride, which had the same reactivity but higher logP
      than that of maleic anhydride. On the other hand, the challenge concentrations
      inducing 50% positive responses (CC50) were less affected by the methods and the
      BT/GPMT ratios for CC50 values were all within a 10-fold range. These results
      suggest that the sensitivity might be strongly different with reference to
      induction concentration, but not challenge concentration among the three methods.

PMID- 10349615
TI  - Influences of long-term administration of 24R, 25-dihydroxyvitamin D3, a vitamin
      D3 derivative, in rats.
AB  - In order to examine the influences by long-term feeding of 24R, 25
      dihydroxyvitamin D3[24R, 25(OH)2D3], an active form of vitamin D, Wistar rats (14
      week-old, male, 20 rats/group) were fed a powder diet containing 0 or 5 ppm 24R,
      25(OH)2D3 for 57 weeks. Final body weights and total food consumption were
      comparable between the groups. Urinary calcium levels were significantly (p <
      0.05 or 0.01) increased by the administration of 24R, 25(OH)2D3 at weeks 3, 22
      and 56, although the levels of serum calcium did not differ between the groups at
      the termination of week 57. In the 24R, 25(OH)2D3 group, weights of the adrenals
      and femurs were significantly (p < 0.01) increased. Histopathologically, this was
      found due to thickening of cortical bone in the femurs, and medullary hyperplasia
      and pheochromocytoma of the adrenals. Immunohistochemically, proliferating cell
      nuclear antigen (PCNA)-labeling indices for intact adrenal medulla, medullary
      hyperplasia and pheochromocytoma in the 24R, 25(OH)2D3 group were respectively
      1.82 +/- 1.21, 5.88 +/- 4.13 and 16, all higher than that for the adrenal medulla
      in the control group (0.87 +/- 0.67). These results indicate that 24R, 25(OH)2D3
      at a dose with which serum calcium is not chronically increased causes thickening
      of the cortex of the femur, and development of adrenal proliferative lesions,
      suggesting that rats may be too sensitive for results to be relevant to human
      risk assessment.

PMID- 10349616
TI  - Protein kinase A is involved in the induction of early mesodermal marker genes by
      activin.
AB  - In this study we have investigated the role of cAMP-dependent protein kinase A
      (PKA) in the induction of the early mesodermal marker genes goosecoid and no tail
      by activin in zebrafish embryos. We show that upon treatment with activin,
      zebrafish blastula cells exhibit a rapid and transient increase in PKA activity.
      In these cells, activin rapidly induces the expression of the immediate early
      response genes goosecoid and no tail. Stimulation and inhibition of PKA by
      activin, respectively, enhances and reduces the induction of goosecoid and no
      tail mRNA expression. Similar effects of PKA stimulation and inhibition on the
      induction by activin of a 1.8 kb zebrafish goosecoid promoter construct were
      observed. The induction by activin of a fragment of the zebrafish goosecoid
      promoter that mediates an immediate early response to activin is blocked by
      inhibition of PKA. Activation of PKA alone has no effect in these experiments.
      Finally, inhibition of PKA in whole embryos by overexpression of a dominant
      negative regulatory subunit of PKA reduces the expression of no tail and
      goosecoid, whereas the expression of even-skippedl remains unaltered.
      Overexpression of the catalytic subunit of PKA in embryos does not affect
      expression of goosecoid, no tail or even-skippedl. These data show that in
      dissociated blastulae, PKA is required, but not sufficient for activin signalling
      towards induction of goosecoid and no tail. In intact zebrafish embryos, PKA
      contributes to induction of goosecoid and no tail, although it is not required or
      sufficient.

PMID- 10349617
TI  - A mouse homologue of FAST-1 transduces TGF beta superfamily signals and is
      expressed during early embryogenesis.
AB  - The transcription factor FAST-1 has recently been shown to play a key role in the
      specification of mesoderm by TGF beta superfamily signals in the early Xenopus
      embryo. We have cloned Fast1, a mouse homologue of Xenopus FAST-1, and
      characterized its expression during embryogenesis and function in activin/TGF
      beta signal transduction. In vitro, Fast1 associates with Smads in response to an
      activin/TGF beta signal to form a complex that recognizes the Xenopus activin
      responsive element (ARE) targeted by Xenopus FAST-1. In intact cells,
      introduction of Fast1 confers activin/TGF beta regulation of an ARE-luciferase
      reporter. In embryos, Fast1 is expressed predominantly throughout the epiblast
      before gastrulation and declines as development progresses. We propose that mouse
      Fast1, like Xenopus FAST-1, mediates TGF beta superfamily signals specifying
      developmental fate during early embryogenesis.

PMID- 10349618
TI  - The role of the brachyury gene in heart development and left-right specification
      in the mouse.
AB  - The midline has a theoretical role in the development of left-right asymmetry,
      and this is supported by both genetic analyses and experimental manipulation of
      midline structures in vertebrates. The mouse brachyury (T) gene encodes a
      transcription factor which is expressed in the developing notochord and is
      required for its development. T/T mice lack a mature notochord and have a
      dorsalised neural tube. We have examined the hearts of T/T mice and have found
      consistent morphological abnormalities, resulting in ventrally displaced
      ventricular loops, and a 50% incidence of inverted heart situs. Three TGF-beta
      related genes, lefty-1, lefty-2 and nodal, are expressed asymmetrically in mouse
      embryos, and are implicated in the development of situs. We find that nodal,
      which is normally expressed around the node and in left lateral plate mesoderm in
      early somite embryos, is completely absent at this stage in T/T embryos. In
      contrast, lefty-1 and lefty-2, which are normally expressed in the left half of
      prospective floorplate and left lateral plate mesoderm, respectively, are both
      expressed in T/T embryos only in a broad patch of ventral cells in, and just
      rostral to, the node region. These results implicate the node as a source of
      instructive signals driving expression of nodal and lefty-2 in the left lateral
      plate mesoderm, and being required for normal looping and situs of the heart.

PMID- 10349619
TI  - Evidence for a novel Notch pathway required for muscle precursor selection in
      Drosophila.
AB  - The Notch pathway mediates cell fate choice in many species and developmental
      contexts. In the Drosophila mesoderm, phenotypic differences were observed when
      different components of the pathway were defective. To determine if these
      differences reflect variations in the signaling pathway or in the persistence of
      wild-type maternal products, we examined muscle precursors in embryos that lacked
      both maternally- and zygotically-derived gene products, called holonull embryos.
      Most holonull neurogenic embryos have the same number and arrangement of extra
      muscle precursors, but in Notch holonull embryos many additional cells also
      become muscle precursors. Thus Notch is active in cells where its known ligands
      and downstream effectors are not. These results indicate that Notch acts in two
      pathways to determine cell fates in mesoderm: the Delta-to-Notch-to-Suppressor of
      Hairless-to-Enhancer of split signaling pathway previously defined, and a second
      pathway that acts independently.

PMID- 10349620
TI  - Identification and developmental expression of a 5'-3' exoribonuclease from
      Drosophila melanogaster.
AB  - In multicellular organisms, very little is known about the role of mRNA stability
      in development, and few proteins involved in degradation pathways have been
      characterized. We have identified the Drosophila homologue of XRN1, which is the
      major cytoplasmic 5'-3' exoribonuclease in Saccharomyces cerevisiae. The protein
      sequence of this homologue (pacman) has 59% identity to S. cerevisiae XRN1 and
      67% identity to the mouse homologue (mXRN1p) in certain regions. Sequencing of
      this cDNA revealed that it includes a trinucleotide repeat (CAG)9 which encodes
      polyglutamine. By directly measuring pacman exoribonuclease activity in yeast, we
      demonstrate that pacman can complement the yeast XRN1 mutation. Northern blots
      show a single transcript of approximately 5.2 kb which is abundant only in 0-8-h
      embryos and in adult males and females. In situ hybridization analysis revealed
      that the pcm transcripts are maternally derived, and are expressed at high levels
      in nurse cells. During early embryonic syncytial nuclear divisions, pcm
      transcripts are homogenously distributed. pcm mRNA is expressed abundantly and
      ubiquitously throughout the embryo during gastrulation, with high levels in the
      germ band and head structures. After germ band retraction, pcm transcripts are
      present at much lower levels, in agreement with the Northern results. Our
      experiments provide the first example of an exoribonuclease which is
      differentially expressed throughout development.

PMID- 10349621
TI  - Distinct but overlapping expression patterns of two vertebrate slit homologs
      implies functional roles in CNS development and organogenesis.
AB  - The Drosophila slit gene (sli) encodes a secreted leucine-rich repeat-containing
      protein (slit) expressed by the midline glial cells and required for normal
      neural development. A putative human sli homolog, SLIT1, has previously been
      identified by EST database scanning. We have isolated a second human sli homolog,
      SLIT2, and its murine homolog Slit2. Both SLIT1 and SLIT2 proteins show
      approximately 40% amino acid identity to slit and 60% identity to each other. In
      mice, both genes are expressed during CNS development in the floor plate, roof
      plate and developing motor neurons. As floor plate represents the vertebrate
      equivalent to the midline glial cells, we predict a conservation of function for
      these vertebrate homologs. Each gene shows additional but distinct sites of
      expression outside the CNS suggesting a variety of functions for these proteins.

PMID- 10349622
TI  - An interplay between two EGF-receptor ligands, Vein and Spitz, is required for
      the formation of a subset of muscle precursors in Drosophila.
AB  - Activation of the Drosophila EGF-receptor (DER) is spatially and temporally
      controlled by the release of its various ligands. DER and its ligand Spitz
      mediate the formation of specific somatic muscle precursors. We show that a
      second DER ligand, Vein, complements the activity of Spitz in the development of
      various somatic muscle precursors. In vn mutant embryos, the DER-dependent muscle
      precursors do not form in some of the segments. This phenotype is significantly
      enhanced in embryos carrying only one copy of wild type spitz. Our analysis
      suggests that Vein activation of DER differs qualitatively from that of Spitz in
      that it does not lead to the expression of the inhibitory protein Argos, possibly
      leading to a continuous activation of the DER signaling pathway.

PMID- 10349623
TI  - Drosophila endoderm development requires a novel homeobox gene which is a target
      of Wingless and Dpp signalling.
AB  - We have identified and cloned a novel type of homeobox gene that is composed of
      two homeodomains and is expressed in the Drosophila endoderm. Mutant analysis
      reveals that its activity is required at the foregut/midgut boundary for the
      development of the proventriculus. This organ regulates food passage from the
      foregut into the midgut and forms by the infolding of ectoderm and endoderm
      derived tissues. The endodermal outer wall structure of the proventriculus is
      collapsed in the mutants leading to a failure of the ectodermal part to
      invaginate and build a functional multilayered organ. Lack-of-function and gain
      of-function experiments show that the expression of this homeobox gene in the
      proventriculus endoderm is induced in response to Wingless activity emanating
      from the ectoderm/endoderm boundary whereas its expression in the central midgut
      is controlled by Dpp and Wingless signalling emanating from the overlying
      visceral mesoderm.

PMID- 10349624
TI  - The development of the paired fins in the zebrafish (Danio rerio).
AB  - In the present study, we describe the structure and normal development of the
      zebrafish (Danio rerio) paired fins. Particularly, we focus on the structure of
      the apical epidermis and on endoskeletal morphogenesis. Endoskeletal development
      proceeds differently in the pectoral and pelvic fins. Whereas in both fins major
      parts of the endoskeletal girdle develop within the fin bud mesenchyme, the
      pattern of chondrogenic condensations observed in the pelvic fins directly
      reflects the adult endoskeletal pattern. In the pectoral fin, a morphogenetic
      detour is taken via a functional larval endoskeleton, the endoskeletal disc. It
      arises in the fin bud mesenchyme from a chondrogenic anlage common with the
      girdle. The disc chondrifies and represents the functional endoskeleton of the
      larval pectoral fin. The pectoral fin endoskeleton is expanded as well as
      restructured during larval stages in a process which involves decomposition of
      cartilage matrix in the endoskeletal disc. Our comparisons of apical fold
      morphology with reports on other teleosts and tetrapod apical ridges show them to
      be homologous on the structural level. Comparisons of endoskeletal development of
      the zebrafish with reports on teleosts, actinopterygians and chondrichthyans show
      that endoskeletal morphogenesis in the zebrafish pectoral fin follows a
      morphogenetic process which is wide-spread among actinopterygians.

PMID- 10349625
TI  - Expression of cyclin E or DP/E2F rescues the G1 arrest of trol mutant neuroblasts
      in the Drosophila larval central nervous system.
AB  - The trol locus of Drosophila regulates the timing of neuroblast proliferation. In
      trol mutants, quiescent neuroblasts fail to begin division. We have investigated
      this cell cycle arrest to examine trol function. Induced expression of cyclin E
      or DP/E2F in trol mutants results in normal levels of dividing neuroblasts, while
      cyclin B expression has no effect. cyclin E expression is lower in the trol
      mutant larval CNS as assayed by quantitative RT-PCR, suggesting that trol
      neuroblasts are arrested in G1 due to lack of Cyclin E. Neither cyclin E nor E2F
      expression can phenocopy ana mutations, indicating that arrest caused by lack of
      Trol is different from Ana-mediated arrest.

PMID- 10349626
TI  - Mab21, the mouse homolog of a C. elegans cell-fate specification gene,
      participates in cerebellar, midbrain and eye development.
AB  - A multitude of regulatory genes are involved in phylogenetically conserved
      developmental cascades required for the patterning, cell-type specification, and
      differentiation of specific central nervous system (CNS) structures. Here, we
      describe the distribution of a mouse transcript encoding a homolog of the C.
      elegans mab-21 gene. In the nematode tail, mab-21 is required for the short-range
      patterning and cell-fate determination events mediated by egl-5 and mab-18, two
      homeobox genes homologous to Abd-B and Pax6, respectively. In mouse midgestation
      embryogenesis, Mab21 is expressed at its highest levels in the rhombencephalon,
      cerebellum, midbrain, and prospective neural retina. Our data and the genetic
      interactions previously documented in the nematode suggest that Mab21 may
      represent a novel, important regulator of mammalian cerebellum and eye
      development.

PMID- 10349627
TI  - Anteroposterior patterning and organogenesis of Xenopus laevis require a correct
      dose of germ cell nuclear factor (xGCNF).
AB  - The germ cell nuclear factor of Xenopus laevis (xGCNF; NR6A1) is a nuclear orphan
      receptor that is predominantly expressed during neurula and late tailbud stages.
      As a strategy to analyze the role of xGCNF in embryogenesis, we have induced a
      gain of function by overexpression of full-length (fl) GCNF and a functional
      inhibition by a dominant-negative (dn) GCNF. Early events of embryogenesis
      including gastrulation and neurulation were not affected and the expression of
      several early mesodermal markers was normal. Yet specific defects were observed
      upon organogenesis. Ectopic posterior overexpression of the full-length xGCNF
      caused posterior defects and disturbed somite formation. In contrast, expression
      of dnGCNF interfered with differentiation of the neural tube and affected the
      differentiation of anterior structures, including the cement gland and the eyes.
      Embryos affected by dnGCNF were rescued by coexpression of flGCNF. After
      expression of dnGCNF, mRNA encoding the the retinoic acid receptor xRAR gamma 2
      was selectively suppressed anteriorly. From the distinct phenotypes obtained, we
      conclude that GCNF has an essential function in anteroposterior differentiation
      during organogenesis.

PMID- 10349628
TI  - Pax 4 and 6 regulate gastrointestinal endocrine cell development.
AB  - The mechanisms behind the cell-specific and compartmentalized expression of gut
      and pancreatic hormones is largely unknown. We hereby report that deletion of the
      Pax 4 gene virtually eliminates duodenal and jejunal hormone-secreting cells, as
      well as serotonin and somatostatin cells of the distal stomach, while deletion of
      the Pax 6 gene eliminates duodenal GIP cells as well as gastrin and somatostatin
      cells of the distal stomach. Thus, together, these two genes regulate the
      differentiation of all proximal gastrointestinal endocrine cells and reflect
      common pathways for pancreatic and gastrointestinal endocrine cell
      differentiation.

PMID- 10349629
TI  - A transcription unit at the ken and barbie gene locus encodes a novel Drosophila
      zinc finger protein.
AB  - We describe a novel Drosophila transcription unit, located in chromosome region
      60A. It encodes a zinc finger protein that is expressed in distinct spatial and
      temporal patterns during embryogenesis. Its initial expression occurs in a stripe
      at the anterior and the posterior trunk boundary, respectively. The two stripes
      are activated and spatially controlled by gap-gene activities. The P-element of
      the enhancer trap line l(2)02970 is inserted in the 5'-region of the transcript
      and causes a ken and barbie (ken) phenotype, associated with malformation of male
      genital structures.

PMID- 10349630
TI  - Developmental expression of the TGF beta s in the mouse cochlea.
AB  - Mice with targeted disruption of the TGF beta 2 gene display defects in
      epithelial-mesenchymal tissue interactions in several tissues including the
      developing cochlea. Specifically, the region of the spiral limbus and the
      overlying interdental cells, structures putatively involved in endolymphatic
      fluid homeostasis, display morphogenetic abnormalities. These findings prompted
      us to explore the pre-natal and post-natal expression of all three mammalian TGF
      beta genes in the developing mouse inner ear. TGF beta 2 mRNA expression was
      identified throughout the cochlear epithelium at all of the developmental stages
      examined. TGF beta 3 mRNA expression was identified in the mesenchymal tissues of
      the cochlea surrounding the otic epithelium. We found no evidence for
      compensation by the other two TGF beta isoforms in the cochleas of the TGF beta 2
      mutants.

PMID- 10349631
TI  - YAC transgenic analysis reveals Wilms' tumour 1 gene activity in the
      proliferating coelomic epithelium, developing diaphragm and limb.
AB  - Wilms' Tumour 1 gene (WT1) is required for the correct development of the
      urogenital system. To examine its regulation and expression, we created several
      transgenic mouse lines containing a beta-galactosidase reporter driven by the
      human WT1 promoter. A 5 kb promoter weakly recapitulated a subset of the
      endogenous Wt1 expression pattern. In contrast, 470 and 280 kb YAC transgenes
      reproduced the correct pattern with high activity and highlighted new expression
      sites. Wt1 is expressed in the septum transversum revealing how its mutation
      causes diaphragmatic defects. Wt1 expression in the limb demarcates a zone
      between chondrogenic and apoptotic domains. Finally, Wt1 is expressed in
      mesenchymal cells derived from the coelomic epithelium. Based upon these and
      further data we discuss a Wt1 role in epithelial<-->mesenchymal transitions.

PMID- 10349633
TI  - Characterization of Drosophila Presenilin and its colocalization with Notch
      during development.
AB  - Mutant Presenilin proteins cause early-onset familial Alzheimer's disease in
      humans and Caenorhabditis elegans Presenilins may facilitate Notch receptor
      signaling. We have isolated a Drosophila Presenilin homologue and determined the
      spatial and temporal distribution of the encoded protein as well as its
      localization relative to the fly Notch protein. In contrast to previous mRNA in
      situ studies, we find that Presenilin is widely expressed throughout oogenesis,
      embryogenesis, and imaginal development, and generally accumulates at comparable
      levels in neuronal and nonneuronal tissues. Double immunolabeling with Notch
      antibodies revealed that Presenilin and Notch are coexpressed in many tissues
      throughout Drosophila development and display partially overlapping subcellular
      localizations, supporting a possible functional link between Presenilin and
      Notch.

PMID- 10349632
TI  - Neurons derived in vitro from ES cells express homeoproteins characteristic of
      motoneurons and interneurons.
AB  - We have characterized different neuronal subpopulations derived from in vitro
      differentiation of embryonic stem (ES) cells using as markers the expression of
      several homeodomain transcription factors. Following treatment of embryo-like
      aggregates with retinoic acid (RA), Pax-6, a protein expressed by ventral central
      nervous system (CNS) progenitors is induced. In contrast, Pax-7 expressed in vivo
      by dorsal CNS progenitors, and erbB3, a gene expressed by neural crest cells and
      its derivatives, are almost undetectable. CNS neuronal subpopulations generated
      expressed combinations of markers characteristic of somatic motoneurons (Islet
      1/2, Lim-3, and HB-9), cranial motoneurons (Islet-1/2 and Phox2b) and
      interneurons (Lim-1/2 or EN1). Molecular characterization of neuron subtypes
      generated from ES cells should considerably facilitate the identification of new
      genes expressed by restricted neuronal cell lineages.

PMID- 10349634
TI  - Segmental expression of aggrecan in the non-segmented perinotochordal sheath
      underlies normal segmentation of the vertebral column.
AB  - The embryonic vertebral column is derived from the unsegmented axial mesenchyme
      surrounding the notochord, and its development and differentiation are influenced
      by the notochord. The role of cartilage in determining the ultimate pattern of
      the segmental skeleton has been well documented, but a gene whose segmental
      expression corresponds to the pattern of the developing skeleton has yet to be
      identified. We show that chick aggrecan is initially expressed within the entire
      length of the notochord, and as development proceeds, aggrecan expression becomes
      restricted to the surrounding perinotochordal sheath in a segmental pattern,
      mirroring the differentiated somite pattern.

PMID- 10349635
TI  - Preparation of cDNA from single cells and subcellular regions.
AB  - Phenotypic characterization of cells in conjunction with single-cell mRNA
      analysis, which yields information regarding expression of multiple genes in
      individual neurons, facilitates a detailed and comprehensive view of neuronal
      cell biology. More specifically, the aRNA amplification method has provided an
      approach to analyze mRNA levels in single cells that have been phenotypically
      characterized on the basis of electrophysiology, morphology, and/or protein
      expression. In this way, relative mRNA abundances can be directly assayed from a
      well-defined population of neurons. The concept of expression profiling led to
      the development of robotics methods for arraying thousands of cDNAs on
      microarrays. These cDNA arrays can be screened with labeled aRNA or cDNA to
      generate a molecular fingerprint of a specific cell type, disease state, or
      therapeutic efficacy. A broad view of how gene expression is altered in single
      neurons affected by a particular disease process may provide clues to
      pathogenetic disease mechanisms or avenues for therapeutic interventions. The use
      of mRNA profiles to produce diagnostics and therapeutics is called transcript
      aided drug design (TADD). When coupled with single-cell resolution, TADD promises
      to be an important tool in diagnosis of disease states, as well as provide a
      blueprint on which to develop therapeutic strategies. For example, mRNA
      abundances in an individual diseased cell may increase, decrease, or remain
      constant, and thus it is possible that a pharmaceutical alone or in combination
      with other drugs may be specifically designed to restore mRNA abundances to a
      normal state. Alternatively, if functional protein levels parallel the mRNA level
      changes, then drugs targeting the function of the proteins translated from these
      altered mRNAs may prove to be therapeutic. One promise of such an approach is
      that information about mRNA abundances that are altered in a diseased cell may
      provide new therapeutic indications for existing drugs. For example, if the
      abundance of mRNA for the beta-adrenergic receptor is altered as shown by the
      microarrays for a particular disease, already available adrenergic receptor
      agonists or antagonists that had not previously been used in this particular
      disease paradigm may prove to be therapeutically efficacious. The expression
      profile of a given cell is a measure of the potential for protein expression.
      Proteins are generally the functional entities within cells and differences in
      protein function often result in disease. The ability to monitor the coordinate
      changes in gene expression, in single phenotypically identified cells, that
      correlate with disease will provide unique insight into the expressed genetic
      variability of cells and will likely furnish unforeseen insight into the
      underlying cellular mechanisms that produce disease etiology.

PMID- 10349636
TI  - High-efficiency full-length cDNA cloning.

PMID- 10349637
TI  - Preparation and analysis of cDNA from a small number of hematopoietic cells.

PMID- 10349638
TI  - Optical mapping: an approach for fine mapping.

PMID- 10349639
TI  - Current status of computational gene finding: a perspective.

PMID- 10349640
TI  - Gene identification by exon amplification.

PMID- 10349641
TI  - Cosmid-based exon trapping.

PMID- 10349642
TI  - Direct cDNA selection using large genomic DNA targets.

PMID- 10349643
TI  - cDNA selection: an approach for isolation of chromosome-specific cDNAs.

PMID- 10349644
TI  - Saturation identification of coding sequences in genomic DNA.

PMID- 10349645
TI  - cDNA screening by array hybridization.

PMID- 10349646
TI  - DNA arrays for analysis of gene expression.

PMID- 10349647
TI  - Construction and analysis of arrayed cDNA libraries.
AB  - For any attempt to understand the biology of an organism the incorporation of a
      cDNA-based approach is unavoidable, because it is a major approach to studying
      gene function. The complete sequence of the genome alone is not sufficient to
      understand any organism; its gene regulation, expression, splice variation,
      posttranslational modifications, and protein-protein interactions all need to be
      addressed. Because the majority of vertebrate genes have probably been identified
      as ESTs the next stage of the Human Genome Project is attributing functional
      information to these sequences. In most cases hybridization-based approaches on
      arrayed pieces of DNA represent the most efficient way to study the expression
      level and splicing of a gene in a given tissue. Similar technology, now being
      applied at the protein level using protein expression libraries, high-density
      protein membranes, and antibody screening, should allow studies of protein
      localization and modifications. Coupled to these approaches is the use of
      technologies, which although lacking the highly parallel nature of hybridization,
      can potentially characterize large numbers of samples individually and with high
      accuracy. Automated gel-based DNA sequencing is an example of such a technique;
      protein sequencing and mass fingerprinting are further examples. In the case of
      mass spectroscopic analysis, the speed and sensitivity are vastly superior to
      that of gel-based approaches; however, the preparation of samples is more
      tedious. Our laboratory is developing a system to characterize DNA samples by
      mass spectrometry, allowing more rapid genotyping than is currently possible
      using gel-based technologies ([symbol: see text]. Gut, [symbol: see text]. Berlin
      and H. Lehrach, personal communication, 1998). Such technology would make
      information on gene polymorphisms widely accessible. Data generated using all of
      these techniques at the DNA and protein level will be connected by both protein
      expression libraries and database comparisons; finally, two hybrid library
      screens will identify many of the protein-protein interactions, linking genes
      together. In this way we will start to understand the interplay between genes on
      a global scale, both at the level of molecular interaction and the biological
      processes they regulate.

PMID- 10349649
TI  - READS: a method for display of 3'-end fragments of restriction enzyme-digested
      cDNAs for analysis of differential gene expression.

PMID- 10349648
TI  - Principles of differential display.

PMID- 10349650
TI  - A modified method for the display of 3'-end restriction fragments of cDNAs:
      molecular profiling of gene expression in neutrophils.

PMID- 10349651
TI  - Fluorescent differential display: a fast and reliable method for message display
      polymerase chain reaction.

PMID- 10349652
TI  - Identification of differentially expressed genes using RNA fingerprinting by
      arbitrarily primed polymerase chain reaction.

PMID- 10349653
TI  - cDNA representational difference analysis: a sensitive and flexible method for
      identification of differentially expressed genes.

PMID- 10349654
TI  - Suppression subtractive hybridization: a versatile method for identifying
      differentially expressed genes.
AB  - A new and highly effective method, termed suppression subtractive hybridization
      (SSH), has been developed for the generation of subtracted cDNA libraries. It is
      based primarily on a technique called suppression PCR, and combines normalization
      and subtraction in a single procedure. The normalization step equalizes the
      abundance of cDNAs within the target population and the subtraction step excludes
      the common sequences between the target and driver populations. As a result only
      one round of subtractive hybridization is needed and the subtracted library is
      normalized in terms of abundance of different cDNAs. It dramatically increases
      the probability of obtaining low-abundance differentially expressed cDNA and
      simplifies analysis of the subtracted library. The SSH technique is applicable to
      many molecular genetic and positional cloning studies for the identification of
      disease, developmental, tissue-specific, or other differentially expressed genes.
      This chapter provides detailed protocols for the generation of subtracted cDNA
      and differential screening of subtracted cDNA libraries. As a representative
      example we demonstrate the usefulness of the method by constructing a testis
      specific cDNA library as well as using the subtracted cDNA mixture as a
      hybridization probe. Finally, we discuss the characteristics of subtracted
      libraries, the nature and level of background nondifferentially expressed clones
      in the libraries, as well as a procedure for the rapid identification of truly
      differentially expressed cDNA clones.

PMID- 10349655
TI  - Reduced complexity probes for DNA arrays.

PMID- 10349656
TI  - Targeted display: a new technique for the analysis of differential gene
      expression.

PMID- 10349657
TI  - RNA polymerase III-based two-hybrid system.

PMID- 10349658
TI  - Screening for protein-protein interactions.
AB  - The assays described above can be used to screen for cellular proteins that can
      interact with a protein of interest, to screen for mutant proteins that retain
      the ability to bind to its partner, and to identify the domains and amino acids
      involved in known protein-protein interactions. Nonetheless, the biological
      significance of some of these interactions needs to be confirmed by appropriate
      cellular studies.

PMID- 10349659
TI  - Using the Lac repressor system to identify interacting proteins.
AB  - The present protocol describes a series of procedures to identify peptides
      interacting with PDZ domains. It is conceivable that the procedures can be
      applied to other purified protein modules or intact proteins without substantial
      modifications. With the deduced consensus combined with sequence information, it
      is possible to identify proteins present in the database with compatible
      sequences. If the expression of target protein and potential interacting
      candidate overlap temporally and spatially, biochemical and molecular experiments
      can be designed to study their physical and functional interactions.

PMID- 10349661
TI  - The signal sequence trap method.

PMID- 10349660
TI  - A genetic selection for isolating cDNA clones that encode signal peptides.

PMID- 10349662
TI  - Solid-phase differential display and bacterial expression systems in selection
      and functional analysis of cDNAs.
AB  - Differential gene expression can be expected during activation and
      differentiation of cells as well as during pathological conditions, such as
      cancer. A number of strategies have been described to identify and understand
      isolated differentially expressed genes. The differential display methodology has
      rapidly become a widely used technique to identify differentially expressed
      mRNAs. In this chapter we described a variant of the differential display method
      based on solid-phase technology. The solid-phase procedure offers an attractive
      alternative to solution-based differential display because minute amounts of
      sample can be analyzed in considerably less time than previously. The employed
      solid support, monodisperse super paramagnetic beads, which circumvents
      precipitation and centrifugations steps, has also allowed for optimization of the
      critical enzymatic and preparative steps in the differential display methodology.
      We also described how bacterial expression can be used as a means to elucidate
      gene function. An efficient dual-expression system was presented, together with a
      basic concept describing how parallel expression of selected portions of cDNAs
      can be used for production of cDNA-encoded proteins as parts of affinity-tagged
      fusion proteins. The fusion proteins are suitable both for the generation of
      antibodies reactive to the target cDNA-encoded protein and for the subsequent
      affinity enrichment of such antibodies. Affinity-enriched antibodies have proved
      to be valuable tools in various assays, including immunoblotting and
      immunocytochemical staining, and can thus be used to localize the target cDNA
      encoded protein to certain cells in a tissue section or even to a specific cell
      compartment or organelle within a cell. High-resolution localization of a cDNA
      encoded protein would provide valuable information toward the understanding of
      protein function.

PMID- 10349663
TI  - Transposon mutagenesis for the analysis of protein production, function, and
      localization.

PMID- 10349664
TI  - Maintaining "alternative" standards.

PMID- 10349665
TI  - Listening and referring.

PMID- 10349666
TI  - Emergency contraception.

PMID- 10349667
TI  - NP role recognition.

PMID- 10349668
TI  - Evaluating mild to moderate hypertension.
AB  - The 1997 recommendations for diagnosing, evaluating, and treating mild to
      moderate hypertension, made in the Sixth Report of the National Joint Committee
      on Prevention, Detection and treatment of High Blood Pressure,are reviewed in
      this article. Because drug therapy may actually increase the risk of morbidity
      and mortality for hypertensive patients at low risk for adverse cardiovascular
      outcomes, not all patients with borderline hypertension should be treated with
      pharmacotherapy. Treatment decisions should be based not only on blood pressure
      level but also on the presence of additional risk factors, the existence of
      clinical cardiovascular disease, and evidence of target organ damage. The
      reviewed national guidelines recommend a risk stratification approach to
      determining the appropriate therapy level for patients with hypertension. The
      newest hypertension classifications and recommendations for risk assessment,
      patient classification, the appropriate initial level of therapy, and follow-up
      are presented.

PMID- 10349669
TI  - Management of chronic stable angina.
AB  - Coronary artery disease (CAD) remains the number one cause of death and
      disability in men and women in the United States and all industrialized
      societies. The prevalence of CAD is increasing as the population ages. The
      predominant presenting symptom is angina, classified as chronic stable,
      microvascular, Prinzmetal's, or unstable. Chronic stable angina is the form most
      often encountered in the primary care setting. With appropriate management, long
      term prognosis is good. Because anginal thresholds vary, treatment must address
      individual patients' needs. Patients should be counseled throughout follow-up and
      educated about modifying risk factors and managing routine activities. Most
      patients can be treated pharmacologically with single or combination therapy
      including long-acting nitrates, beta-blockers, and calcium channel blockers.
      Consultation with a cardiologist during follow-up may also be warranted.

PMID- 10349671
TI  - Guidelines for the Department of Transportation physical examination.
AB  - Primary care providers commonly perform the mandatory Department of
      Transportation Federal Highway Administration physical examination for
      individuals who drive commercial motor vehicles. Although these examinations may
      be offered at the worksite or in occupational health clinics, many drivers prefer
      to have them performed in the primary care setting. Performing the examination
      and subsequently certifying the driver is a highly regulated process with
      potentially serious consequences for the driver, the examiner, and the public.
      This article discusses the regulations and recommendations for certification of
      commercial drivers and the problems commonly encountered in the clinical setting.

PMID- 10349670
TI  - Micronized progesterone: a new option for women's health care.
AB  - Although progestational agents have been widely used for gynecologic conditions,
      treatment options have usually been limited to synthetic agents with adverse
      effects and sparse patient acceptance. Recent Food and Drug Administration
      approval of oral micronized progesterone (MP) has introduced therapy with a safe,
      effective, well-tolerated drug. This article reviews therapeutic indications for
      MP as illustrated in five case studies. Issues of patient compliance,
      individualized treatment plans, and patient partnership to obtain the most
      beneficial outcomes are discussed.

PMID- 10349672
TI  - Increasing professional tension limits NP opportunities.

PMID- 10349673
TI  - Managing allergic rhinitis.

PMID- 10349675
TI  - Accurately interpreting PPD skin test results.

PMID- 10349674
TI  - Diagnosis and referral of Wilms' tumor.
AB  - Wilms' Tumor, also know as nephroblastoma, is a childhood renal tumor. The
      assessment and diagnosis of a Wilms' tumor is one of the many challenges faced in
      the primary care setting. This article presents a brief review of Wilms' tumor in
      the pediatric population and its occurrence in a case presentation.

PMID- 10349676
TI  - Mechanisms of response to ozone exposure: the role of mast cells in mice.
AB  - Acute and subacute exposure to ozone (O3) induces lung inflammation and
      hyperpermeability and causes epithelial injury of both upper (nasal) and lower
      airways. Mast cells are important regulatory cells in mice for each of these
      effects. Subacute and chronic O3 exposures cause epithelial injury and
      inflammation in terminal bronchioles and proximal alveoli. Little is known,
      however, about the mechanisms of injury. Because inflammatory processes may be
      linked to the pathogenesis of many airway diseases, it is critical to understand
      the underlying mechanisms that initiate and propagate these processes. We tested
      the hypothesis that mast cells mediate airway injury induced by chronic O3
      exposure by comparing regional airway inflammation and epithelial injury as well
      as ventilatory responses in genetically mast cell-deficient mice (WBB6F1
      KitW/KitW-v [KitW/KitW-v]) with those in (1) normal, mast cell-sufficient,
      congenic littermates (WBB6F1(-)+/+ [+/+]) and those in (2) KitW/KitW-v mice that
      were repleted with mast cells by bone marrow transplantation (BMT) from +/+
      donors (KitW/KitW-v-BMT). Thus, three (different) groups of mice were used. The
      following experimental protocol was utilized to test this hypothesis. Animals
      from each treatment group (n = 4-6/group) were exposed to 0.26 parts per million
      (ppm) O3 8 hours/day and 5 days/week for durations of 1, 3, 14, 30, and 90 days.
      Between 8-hour exposures, mice were exposed continuously to 0.06 ppm O3. Age
      matched mice were simultaneously exposed to filtered air (0.0 ppm O3) to serve as
      O3 controls. To evaluate reversibility of exposure-induced lesions, a set of mice
      from each genotypic group was exposed to air or O3 for 90 days and then placed in
      HEPA-filtered air for 35 days. After each period of exposure and after 35-day
      recovery, the nasal cavity and lungs of O3- and air-exposed mice from each group
      were evaluated for regional inflammation and permeability, epithelial
      proliferation, and ventilation pattern. Estimates of airway inflammation and
      hyperpermeability were obtained by analysis of cell differentials and total
      protein concentrations, respectively, in fluids obtained through use of
      bronchoalveolar lavage (BAL). Ozone exposure caused significantly greater
      increases in lung macrophages, epithelial cells, and polymorphonuclear leukocytes
      (PMNs) in mast cell-sufficient +/+ and KitW/KitW-v-BMT mice than in mast cell
      deficient KitW/KitW-v mice. Comparable ozone exposure also elicited increases in
      lung lymphocytes and in total protein, but there were no significant differences
      in these two genotypic groups. Cell and total-protein responses in BAL fluid
      returned to control levels (that is, air exposure only) in all three groups of
      mice after a 35-day recovery period. The effects of O3 exposure on cell
      proliferation in the nose and lung were evaluated in the genotypic groups by
      counting the number of cells that incorporated bromodeoxyuridine (BrdU, a
      thymidine analog) into DNA. In the centriacinar region of the lung, DNA synthesis
      was increased significantly in O3-exposed +/+ and KitW/KitW-v-BMT mice, but not
      in KitW/KitW-v mice, compared with DNA synthesis in air controls. Epithelial
      proliferation remained significantly elevated or even increased in +/+ and
      KitW/KitW-v-BMT mice after O3 exposure. Nasal responses to O3 were also evaluated
      in these three genotypic groups of mice, and there were slight, although
      statistically significant, O3-exposure effects on the transitional epithelium.
      However, there were no differences among the groups up to an exposure of 90 days
      in duration. After a 35-day recovery period, epithelial cell proliferation in +/+
      and KitW/KitW-v-BMT mice was greater than that in KitW/KitW-v mice. There were no
      significant exposure, genotype, or duration effects on baseline ventilation or
      responses to hypercapnic hypoxia in the three groups of mice exposed to air or
      O3. (ABSTRACT TRUNCATED)

PMID- 10349677
TI  - Long-term renal function in primary hypertension. An epidemiological and
      pathophysiological study.
AB  - The purpose of this study was to investigate the influence of birth factors on
      adult blood pressure and to study the long-term renal function and hemodynamic
      changes in primary hypertension. The investigations were performed in two
      population-based samples of men derived from two large screening investigations
      on blood pressure, a screening investigation of 49-year-old men and the Primary
      Prevention Study. Birth variables were studied in 430 subjects, born in 1926-27,
      who had participated in the screening investigation of 49-year-old men in
      Goteborg. The 14-year follow-up study of renal function and haemodynamics and
      urinary albumin excretion was performed in a stratified random sample of
      normotensive (n = 11) and hypertensive (n = 23) 49-year-old men. The effects of
      intensified blood pressure control (to a diastolic blood pressure, DBP < or = 85
      mmHg) on renal function, haemodynamics and urinary albumin excretion, achieved by
      addition of felodipine or ramipril to ongoing treatment with beta-blockade, were
      investigated in 28 hypertensives. To determine if treated primary hypertension
      can lead to end-stage renal disease, the development of serum creatinine levels
      during 20 years in 686 hypertensive men from the Primary Prevention Study,
      recruited from a random third of the male population aged 47-55 years at entry,
      was studied. The findings demonstrate that preterm birth (gestational age less
      than 38 weeks) seemed to increase the risk of hypertension in adult life. They
      also showed, that good long-term blood pressure control (DBP < or = 90 mmHg) in
      primary hypertension can protect the kidneys from abnormal progressive decline in
      glomerular filtration rate and arrest proteinuria but does not normalise the
      reduced renal blood flow or the increased renal vascular resistance seen in
      primary hypertension. On decreasing the DBP to < or = 85 mmHg, achieved by
      addition of felodipine to ongoing treatment with beta-blockade, renal blood flow
      increased and renal vascular resistance decreased to levels no longer
      significantly different from normal. Addition of ramipril to beta-blockade
      reduced blood pressure less and renal function and haemodynamics did not
      normalise, but the urinary albumin excretion was lowered. The median value for
      the urinary albumin excretion remained within the range of the urinary albumin
      excretion of the normotensives in both the felodipine and the ramipril-treated
      groups. In the Primary Prevention Study, none of the hypertensives developed a
      hypertensive end-stage renal disease and only a few patients showed a slight
      increase in serum creatinine level before the age of 70. Thus, white patients
      with non-malignant primary hypertension without underlying renal disease and with
      good blood pressure control do not appear to develop progressive decline in
      kidney function or hypertensive end-stage renal disease.

PMID- 10349678
TI  - Foreword: prospects of liver cell transplantation and liver-directed gene
      therapy.
AB  - The liver offers specific opportunities, as well as challenges, as a target for
      cell transplantation and gene therapy. Hepatocyte transplantation and hepatocyte
      directed gene therapy are mutually augmenting complementary strategies that are
      rapidly developing for the treatment of inherited and acquired disorders. Both
      non-viral and viral vectors are being rapidly improved for exploiting the
      advantages and overcoming the challenges of liver-directed gene therapy. Rapid
      development in these areas suggests that vectors that will be used a decade from
      now have not yet been developed. Nevertheless, hepatocyte transplantation already
      has been successful in ameliorating at least some inherited liver diseases, and
      it is safe to state that successful liver-directed gene therapy will be achieved
      during the early years of the new millennium. The nine articles in this issue of
      the Seminars review the promise and limitations of the current methods of
      hepatocyte transplantation and liver-directed gene therapy and attempt to provide
      a glimpse of the anticipated developments.

PMID- 10349679
TI  - Principles of therapeutic liver repopulation.
AB  - Recently, it has been shown in several animal models that more than 90% of host
      hepatocytes can be replaced by a small number of transplanted donor cells in a
      process we term therapeutic liver repopulation. This phenomenon is analogous to
      repopulation of the hematopoietic system after bone marrow transplantation. Liver
      repopulation occurs when transplanted cells have a growth advantage in the
      setting of damage to recipient liver cells. Here we review the current knowledge
      of this process and discuss the hopeful implications for treatment of liver
      diseases.

PMID- 10349680
TI  - Mechanisms of cell engraftment during liver repopulation with hepatocyte
      transplantation.
AB  - Hepatocyte transplantation has excited much interest among investigators for
      applications in cell therapy and studies of fundamental mechanisms concerning
      liver biology. Progress in these areas has been greatly facilitated by the
      development of novel animal models. An understanding of early events during
      engraftment of transplanted cells is essential for optimal repopulation of the
      liver. Insights into how transplanted cells integrate in the parenchyma of the
      liver with reconstitution of specific plasma membrane structures is critical in
      devising therapeutic strategies for specific disorders. Moreover, these insights
      are necessary for understanding mechanisms concerning regulation of cell
      proliferation and gene expression in transplanted hepatocytes. Finally, analysis
      of the safety of cell transplantation is necessary for clinical applications of
      liver repopulation with cell transplantation. This review highlights selected
      advances in related areas concerning liver repopulation.

PMID- 10349681
TI  - Retroviral vectors for liver-directed gene therapy.
AB  - Retroviruses are popular gene therapy vectors because they stably integrate the
      DNA copy of their genome into the host chromosome during their replication cycle.
      The widely used murine retroviral vector systems have two components: the
      transfer vector for the transgene carries all the cis-acting elements necessary
      for the replication and efficient integration of the viral DNA; and the packaging
      cell line produces all the trans-acting proteins necessary for both structural
      and catalytic functions of the virus. Advances in design of retroviral vectors
      have resulted in greater degree of biosafety, expanded host range, and increased
      stability of the virus particles. Retroviral vectors have been widely used in the
      ex vivo gene therapy protocols to correct the liver diseases in a wide variety of
      species. In a limited number of applications, in vivo gene therapy has been
      achieved after the liver cells have been stimulated to regenerate. One major
      limitation of murine retroviral vectors is their inability to infect nondividing
      cells. This problem has been overcome by deriving vectors from lentiviruses (a
      class of retroviruses) that have the ability to infect both dividing and
      nondividing cells. The lentiviral vectors are derived from human immunodeficiency
      virus type 1 (HIV-1). Initial studies using lentiviral vectors for gene delivery
      to the liver in vivo show promising results. A highly crippled version of
      lentivirus has been generated by using producer cells in which the trans-acting
      components are expressed by several different coding elements and vectors that
      incorporate features of self-inactivation. These improvements should ensure
      biosafety of lentiviruses and make them useful in efficient delivery of
      therapeutic genes to nondividing differentiated tissues such as the liver.

PMID- 10349682
TI  - Hepatocyte transplantation for the treatment of human disease.
AB  - A great deal of work with animal models indicates that hepatocytes transplanted
      into the liver or spleen survive, function, and participate in the normal
      regenerative process. Recent clinical studies suggest that hepatocyte
      transplantation may be useful for bridging patients to whole organ
      transplantation and for providing metabolic support during liver failure and for
      replacing whole organ transplantation in certain metabolic liver diseases. In
      specific situations where the rate of death of host hepatocytes is high, the
      transplanted cells can repopulate the native liver. Techniques have been
      established for the large scale isolation, culture and cryopreservation of human
      hepatocytes. Shortage of donor organs and the need for immunosuppression are two
      major hurdles to widespread application of this procedure, and current research
      in experimental animals is aimed at addressing these problems.

PMID- 10349683
TI  - Adenovirus-mediated gene therapy of liver diseases.
AB  - Recombinant adenoviruses can infect nondividing cells with high efficiency and
      are rapidly concentrated in the liver after systemic administration, making them
      attractive for use in liver-directed gene therapy. However, there are two hurdles
      to clinical application of these vectors. First, adenoviruses are episomal and
      have limited life spans within the cell. Second, host antiviral immune responses
      reduce the duration of vector persistence and preclude long-term transgene
      expression by repeated injection of the vector. Several strategies have been
      designed for abrogation of the specific antiadenoviral immune responses by
      modification of the host immune system or alteration of the vector. These
      strategies and the use of adenoviral vectors for the treatment of hereditary,
      infectious, and malignant diseases of the liver are discussed in this review.

PMID- 10349684
TI  - Hepatic gene therapy using adeno-associated virus vectors.
AB  - Recombinant adeno-associated virus vectors have been shown to safely transduce a
      number of tissues in preclinical animal studies. The level of gene transfer is
      sufficient to successfully treat a large number of medical disorders. Moreover,
      the long-term persistence of the vector sequences in animals makes it likely that
      this vector will be useful for genetic diseases requiring life-long therapy. This
      review outlines the biological principles of the vector, as well as its
      advantages and current limitations as it relates to use in hepatic gene therapy.

PMID- 10349685
TI  - Gene delivery to the liver using simian virus 40-derived vectors.
AB  - We describe here the development and testing of simian virus 40 (SV40)-derived
      vectors to deliver foreign genetic material to the liver. Based on current
      understanding of the biology of wild-type SV40, it should be possible to exploit
      several important attributes of this virus, including efficient replication and
      gene expression, almost universal infectivity, and low immunogenicity if large T
      antigen is deleted, to deliver DNA to the liver effectively. Our studies in
      cultured hepatocytes and in vivo, using both reporter constructs and transgenes
      of therapeutic interest, provide strong experimental support for this prediction.
      These successes indicate that SV40 may play an important role in gene delivery to
      the liver.

PMID- 10349686
TI  - Hepatocyte-directed gene delivery by receptor-mediated endocytosis.
AB  - The application of gene therapy to liver disease is contingent on the development
      of an effective gene delivery vehicle. Receptor-mediated endocytosis can be
      exploited as a means of selective and efficient targeting of gene therapy vectors
      to hepatocytes. DNA-binding conjugates have been directed to the liver by the
      attachment of asialoglycoproteins or other ligands for receptors expressed on
      hepatocytes. Recent studies suggest refinements in this approach through which
      high transduction rates in vitro may be reproduced in vivo. The intrinsic liver
      tropism of viral vectors and liposomes can be augmented by the addition of
      targeting features, as demonstrated in animal models. With further modification,
      such as the incorporation of hepatotropic elements of the hepatitis viruses or
      lipoproteins, the next generation of delivery systems may achieve efficient,
      persistent expression of therapeutic genes in a safe and cell type-specific
      manner.

PMID- 10349687
TI  - Gene repair using chimeric RNA/DNA oligonucleotides.
AB  - An experimental strategy has been developed for the site-specific alteration of
      genomic DNA. The approach is based on the observation that oligonucleotides
      containing complementary RNA/DNA hybrid regions are more active than duplex DNA
      in homologous pairing reactions in vitro. The chimeric molecules are designed
      with a homologous targeting sequence comprised of a DNA region flanked by blocks
      of 2'-O-methyl RNA residues (the chimeric strand), its complementary all-DNA
      strand, thymidine hairpin caps, a single-strand break, and a double-stranded
      clamp region. The oligonucleotide can align in perfect register with a genomic
      target except for the designed single base pair mismatch, which is recognized and
      corrected by harnessing the cell's endogenous DNA repair system. The mechanism of
      repair has been studied using mammalian cell-free extracts and bacterial systems
      and has revealed a mismatch correction pathway distinct from homologous
      recombination. The chimeric molecules have been demonstrated to be effective in
      the alteration of single nucleotides in episomal and genomic DNA in cell culture,
      as well as genomic DNA of cells in situ. This is a potentially powerful strategy
      for gene repair for the myriad hepatic genetic diseases caused by point
      mutations.

PMID- 10349688
TI  - New perspectives in the diagnosis of hepatitis C.
AB  - Since the identification and molecular characterization of the non-A, non-B
      hepatitis virus (HCV) in 1989, a variety of diagnostic tests based on the
      detection of hepatitis virus antibodies or HCV RNA in the serum have been
      developed and refined. The enzyme-linked immunosorbent assays (ELISAs) and the
      recombinant immunoblot assays (RIBAs) exhibit improved sensitivity and
      specificity for HCV antibodies compared with their predecessors, and the ELISA-3
      is at the forefront of HCV screening. Furthermore, the advent of molecular assays
      that employ quantitative reverse-transcriptase polymerase chain reaction to
      detect HCV RNA has allowed clinicians to track the natural history of HCV and to
      monitor the progress of therapy. A role for further refinement of an HCV
      diagnosis using tests to determine genotype, subtype, and quasispecies is
      explored. In addition, the role of liver biopsy and non-invasive markers of
      histologic status are placed into the context of patient prognosis. This article
      reviews the state-of-the-art tests and assays developed for the diagnosis and
      management of HCV infection.

PMID- 10349689
TI  - The clinical pharmacology of ribavirin.
AB  - This article summarizes pharmacokinetic studies of ribavirin in healthy volunteer
      and patient populations. Ribavirin is rapidly absorbed after oral administration
      (time to maximum concentration = 1.5 hours), followed by rapid distribution and
      prolonged elimination phases. Uptake from the proximal small bowel is active via
      concentrative N1 sodium-dependent nucleoside transporters. Ribavirin appears to
      be extensively absorbed; however, absolute bioavailability is approximately 50%,
      probably due to first-pass metabolism. Apparent volume of distribution is
      extensive (approximately 2,000 L) due to ribavirin's distribution into nonplasma
      (cellular) compartments, which occurs via es-nucleoside transporters. Ribavirin
      does not bind to plasma proteins. Upon multiple dosing there is extensive
      accumulation in plasma, and steady state is achieved by approximately 4 weeks.
      Because of slow elimination of ribavirin from nonplasma compartments, the
      multiple dose half-life is approximately 298 hours. The pharmacokinetic
      properties of ribavirin in special populations, the effect of food on ribavirin's
      pharmacokinetics, and the potential interactions between ribavirin and other
      agents are also reviewed.

PMID- 10349690
TI  - Use of high-dose interferon in the treatment of chronic hepatitis C.
AB  - High-dose interferon therapy is defined as any treatment regimen that provides
      more than 3 million Units (MU) of interferon three times weekly (TIW), or more
      than 9 MU on a weekly basis. Such treatment could be achieved with either a fixed
      dose of interferon administered daily (QD) or TIW, an induction regimen in which
      doses greater than 3 MU QD are administered for several weeks to months followed
      by a reduction in the dose or dosing frequency, or by escalation in the
      interferon dose. Each of these high-dose regimens appears to increase end-of
      treatment response. Unfortunately, sustained response and virologic "cure"
      following treatment with high-dose interferon appear no better than what could be
      achieved with standard-dose interferon therapy. Whether sustained response can be
      improved by utilizing ribavirin in combination with high-dose interferon remains
      to be determined.

PMID- 10349691
TI  - Standards of treatment in chronic hepatitis C.
AB  - Standards of treatment for patients who are infected with the hepatitis C virus
      have been developed from national and international consensus conferences, from
      extensive clinical experience with various regimens, from exhaustive literature
      reviews, and from opinion leaders in the general medical community. From 1987
      until very recently, the standard of treatment for non-A, non-B hepatitis, later
      defined as hepatitis C, had consisted of alpha interferon monotherapy
      administered for up to 18 to 24 months. Alpha interferon has been used in a
      variety of regimens with varying success for the initial treatment of chronic
      hepatitis C, for the retreatment of patients who have relapsed after responding
      to interferon, and for the retreatment of alpha interferon nonresponders.
      Treatment standards have evolved as new agents have become available for use in
      our treatment armamentarium. The current treatment standards, as well as
      recommendations for the treatment of specific HCV subgroups, are reviewed.

PMID- 10349692
TI  - Combination therapy with interferon alfa and ribavirin as retreatment of
      interferon relapse in chronic hepatitis C.
AB  - Interferon (IFN) results in normalization of the serum alanine aminotransferase
      (ALT), loss of detectable serum hepatitis C virus (HCV) RNA, and histologic
      improvement in approximately 40% of patients. However, regardless of the duration
      of initial therapy, most patients relapse within the first few months after the
      drug is stopped and only a small proportion have a sustained response.
      Retreatment of IFN relapsers with the combination of IFN and oral ribavirin for 6
      months results in end-of-treatment loss of detectable HCV RNA and normalization
      of the ALT level in over 80% of patients. Nearly half achieve a sustained viral
      negative response. Histologic improvement occurs in nearly two thirds of patients
      retreated with combination therapy and is most pronounced in those who lose serum
      HCV-RNA.

PMID- 10349693
TI  - Combination therapy with interferon plus ribavirin for the initial treatment of
      chronic hepatitis C.
AB  - The limited efficacy of alpha interferon (IFN) monotherapy for hepatitis C virus
      (HCV) infection has led to the investigation of alternative treatment approaches,
      including combining interferons with other antiviral agents. In several small,
      pilot studies, the combination of IFN plus ribavirin was significantly more
      effective than IFN monotherapy for the initial treatment of HCV. The encouraging
      results from these studies provided the rationale for conducting two (one US, one
      International) large, multicenter, randomized, placebo-controlled clinical trials
      of IFN plus ribavirin therapy for the initial treatment of HCV patients. Of
      patients receiving therapy [corrected] for 24 weeks, 31% (US) and 35%
      (International) achieved sustained virologic remission with interferon plus
      ribavirin [corrected], compared with only 6% (US) receiving interferon
      [corrected] plus placebo. Sustained virologic response rates were improved in
      patients treated for 48 weeks (interferon plus ribavirin, 38% [US]; 43%
      [International] compared to interferon plus placebo, 13% [US]; 19%
      [International]) [corrected]. Improvement was also observed in terms of
      biochemical and histologic end points in those receiving combination therapy.
      Pretreatment variables (HCV genotype, viral burden, stage of fibrosis) were less
      important as predictors of treatment outcome in patients receiving combination
      therapy. The safety profile of combination therapy reflected the individual
      safety profiles of IFN and ribavirin, without synergism. Combination therapy with
      IFN plus ribavirin was more effective than IFN monotherapy for the initial
      treatment of HCV in terms of virologic, biochemical, and histologic end points.
      The combination appears to be well tolerated with a predictable safety profile.

PMID- 10349694
TI  - Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C
      relapsed and treatment-naive patients.
AB  - The coadministration of ribavirin with recombinant interferon alfa-2b (rIFN-alpha
      2b) compared with rIFN-alpha 2b alone markedly enhanced sustained virologic
      response rates in relapsed and treatment-naive chronic hepatitis C patients. The
      potential for ribavirin to likewise exacerbate the adverse events associated with
      the alpha interferons is reviewed. The overall safety and tolerability of
      combination rIFN-alpha 2b/ribavirin therapy was evaluated in 2,089 patients
      treated in phase III clinical studies conducted in the United States and
      internationally. Serious adverse events were also evaluated on an interim basis
      in > 25,000 patients--a majority of whom were treated with combination therapy
      (open label)--treated worldwide in investigator-initiated studies. Patients in
      the phase III studies received 3 million International Units rIFN-alpha 2b three
      times per week by subcutaneous injection plus either ribavirin or placebo orally
      in divided daily doses of 1,000 or 1,200 mg for patients weighing < or = 75 or >
      75 kg, respectively. Adverse event frequency and severity and dose modifications
      were recorded throughout the 24-week (relapse) or 48-week (naive) treatment
      period and 24-week follow-up period. Clinically significant adverse events
      included anemia and depression. There was no evidence that the adverse effects of
      alpha interferon (e.g., fatigue, depression, neutropenia) were exacerbated by
      ribavirin. Severe adverse events were limited due to strict adherence to dose
      modification criteria; approximately 6% to 9% of patients discontinued
      combination therapy because of an adverse event. Clinically serious adverse
      events, dose reductions and discontinuations, and potential mechanisms of
      toxicity associated with rIFN-alpha 2b and ribavirin are examined.

PMID- 10349696
TI  - Activity of combination therapy with interferon alfa-2b plus ribavirin in chronic
      hepatitis C patients co-infected with HIV.
AB  - The hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) often co
      infect the same individuals because they share comparable routes of transmission.
      Co-infection with HIV in those patients infected with HCV influences the accuracy
      of HCV diagnostic testing, levels of HCV viremia, severity of liver
      histopathology, and rate of progression to cirrhosis. By contrast, the effect of
      HCV co-infection on HIV disease is unclear. Nevertheless, the combination therapy
      containing recombinant interferon alfa-2b (rIFN-alpha 2b) plus ribavirin has been
      shown to be efficacious in the treatment of chronic hepatitis C, whereas alpha
      interferon monotherapy has been shown to be efficacious in patients co-infected
      with HCV and HIV. It is therefore logical to propose and test the hypothesis that
      combination rIFN-alpha 2b/ribavirin therapy will also benefit patients who are co
      infected with HCV and HIV. A double-blind, placebo-controlled study is presently
      under way to investigate this hypothesis.

PMID- 10349695
TI  - Sustained virologic response is associated with improved health-related quality
      of life in relapsed chronic hepatitis C patients.
AB  - Although evidence of virologic elimination, normalization of serum alanine
      aminotransferase levels, and reduction in liver inflammation are the principal
      therapeutic outcome goals in chronic hepatitis C patients, improvement in health
      related quality of life (HQL) is also an important aspect of therapeutic outcome.
      In a recent report of chronic hepatitis C patients treated for 24 weeks with
      interferon, sustained virologic response (24 weeks post-treatment) was associated
      with improvement in HQL compared with nonresponse. We report on the relationship
      between sustained virologic response and Hepatitis Quality-of-Life Questionnaire
      (HQLQ) survey results of patients who relapsed after a previous course of
      interferon alfa who were subsequently treated with recombinant interferon alfa-2b
      (rIFN-alpha 2b) either alone or in combination with ribavirin. The HQLQ was
      administered at baseline, at treatment Weeks 12 and 24, and at follow-up Weeks 12
      and 24. All patients received rIFN-alpha 2b 3 million International Units by
      subcutaneous injection three times weekly plus either oral ribavirin (1,000 or
      1,200 mg) or placebo daily for 24 weeks. At baseline, patients scored lower than
      adjusted population norms in HQL. Relative to patients treated with rIFN-alpha 2b
      monotherapy, patients receiving combination therapy showed better HQL in 6 of 13
      domains. Furthermore, sustained virologic response in either treatment group was
      associated with improvement in the scores of both generic and hepatitis-specific
      HQL survey domains. These results indicate that successful therapeutic resolution
      of hepatitis C infection improves HQL as assessed by generic and hepatitis C
      specific measures of functional health and well-being. Furthermore, improvements
      in HQL outcome measures may predict reduced demand for health care resources and
      greater productivity in the workplace.

PMID- 10349697
TI  - The roles of amantadine, rimantadine, ursodeoxycholic acid, and NSAIDs, alone or
      in combination with alpha interferons, in the treatment of chronic hepatitis C.
AB  - Although alpha interferons are currently the standard treatments for chronic
      hepatitis C, they are effective in only 15% to 20% of patients. This low success
      rate has prompted research into new approaches for maximizing responses to alpha
      interferons. A variety of drugs have been investigated alone or in combination
      with alpha interferons. Of these agents, ribavirin is currently the most
      promising adjuvant, and the combination therapy of ribavirin plus recombinant
      interferon alfa-2b is reviewed in detail elsewhere in this issue (see Davis
      article, pp. 49-55; and McHutchison article, pp. 57-65). This article reviews the
      literature concerning studies of amantadine, rimantadine, ursodeoxycholic acid
      (UDCA), and nonsteroidal anti-inflammatory drugs (NSAIDs), which are the most
      commonly used alternatives to ribavirin. As of this writing, virologic response
      rates have been unsatisfactory when these agents are used as monotherapies.
      Furthermore, combining alpha interferons with either UDCA or NSAIDs does not
      appear to improve sustained virologic response rates. However, combination
      regimens composed of an alpha interferon plus amantadine, or an alpha interferon
      plus rimantadine, or triple therapy with either amantadine or rimantadine plus an
      alpha interferon and ribavirin, warrant further investigation.

PMID- 10349698
TI  - Future options for the management of hepatitis C.
AB  - Current therapy for hepatitis C virus (HCV) infection is believed to be based in
      part on the ability of interferons to directly inhibit intracellular HCV
      replication and prevent infection of uninfected hepatocytes, although the exact
      mechanisms by which this therapy exerts its effect remain unknown. There are
      several potential avenues open to development of new antiviral treatment
      strategies for HCV infection. These include extracellular neutralization of virus
      to prevent new infection, inhibition of viral entry and uncoating, impairment of
      intracellular replication by either inhibition of host or viral enzymes or by
      destruction of the viral genome, enhancement of the host immune response to HCV,
      or control of the hepatic inflammation that results in progressive liver injury.
      Although the potential of these therapeutic approaches have been demonstrated in
      vitro or have been used for the treatment of other infections, their use in man,
      and so their future and potential efficacy, require further investigation.

PMID- 10349699
TI  - Interactions in sheep between tall fescue ergot alkaloids and hepatotoxic carbon
      tetrachloride and Senecio pyrrolizidine alkaloids.
AB  - The interaction between ergot alkaloids in endophyte-infected (E+) tall fescue
      (Festuca arundinacea) seed and pyrrolizidine alkaloids (PA) in tansy ragwort (TR;
      Senecio jacobaea) when simultaneously fed to sheep was investigated. Because of
      the hepatogenic effects of prolactin (PRL), it was hypothesized that low serum
      PRL induced by ergot alkaloids would increase the susceptibility of sheep to
      hepatotoxicity induced by PA. Sheep are normally resistant to PA-induced
      hepatotoxicity. Twenty-four wether lambs weighing 34.1 +/- 2.3 kg were used after
      being randomly assigned to 1 of 6 treatments of 4 wethers each. The diets offered
      were a control basal diet containing endophyte-free (E-) tall fescue seed,
      control + carbon tetrachloride (CCL4), E+ tall fescue basal diet, E+2CCl4, E(
      )+TR, or E+2TR. The diets were composed of 50% alfalfa meal, 34.5% rolled barley,
      5% soybean meal, 4% cane molasses, 0.5% trace mineralized salt and 6% tall fescue
      (E- or E+) seed. In the 2 TR treatments 25% of the alfalfa was replaced by TR.
      Interaction between ergot alkaloids in E+ tall fescue and PA in TR was assessed
      by gamma glutamyl transferase (GGTP) activity and/or sulfobromophthalein (BSP)
      clearance rate, both of which measure liver function. Serum GGTP activity was
      measured on days 14 and 28; plasma BSP clearance was monitored on days 28 and 70
      by collection of blood at 4, 8 and 16 min after i.v. BSP injection. Serum PRL
      assays were performed on days 14, 70 and 84. Serum GGTP activity was elevated by
      CCl4 drenching on days 14 and 28. On day 28 TR feeding reduced GGTP activity, but
      there was no difference between the 2 TR treatments. There was no difference in
      the mean BSP half-times (t1/2) and % BSP retentions on day 28 among any of the 6
      treatments. On day 70, there was no difference in the t1/2 or % BSP retention 4
      min after BSP injection among any of the treatments. At 8 min after BSP
      injection, however, % BSP retention was significantly higher for the control
      +CCl4 than for the E+2CCl4 treatment. At 16 min after BSP injection, the E+
      treatment had a higher mean % BSP retention value than the E+2CCl4 treatment;
      there were no differences among the other treatments. Serum PRL levels were
      reduced by E+ or CCl4 on all 3 dates of PRL evaluation. The lack of interaction
      between ergot alkaloids in E+ tall fescue seed and PA in TR as assessed by GGTP
      activity and/or BSP clearance in sheep may imply that the target sites o the 2
      alkaloids are metabolically different. The low serum PRL with E+ did not increase
      susceptibility of sheep to CCl4 or PA.

PMID- 10349700
TI  - Alterations in bovine serum biochemistry profiles associated with prolonged
      consumption of endophyte-infected tall fescue.
AB  - Tall fescue (Festuca arundinacea) is a forage grass that is widely used in
      pastures in the eastern US for cattle, sheep and horses. The endophytic fungus
      Neotyphodium coenophialum is endemic in tall fescue pastures in the US. The
      turfgrass industry intentionally infects fescue cultivars with strains of the
      fungus to impart desirable growth and disease tolerance qualities to the plants.
      In contrast, ergot and pyrrolizidine alkaloid toxins produced by fungus-infected
      plants have been incriminated causally in bovine tall fescue toxicosis, a poorly
      defined syndrome of morbidity that occurs in cattle that consume endophyte
      infected tall fescue (E+TF). We compared the serum biochemistry profiles from
      cattle that grazed E+TF with those from control cattle that grazed on endophyte
      free tall fescue (E-TF). Cattle were bled on 7 dates from April 1 to August 30,
      1996 and on 5 dates from May 1 to July 30, 1997. Cattle that grazed E+TF retained
      rough winter haircoats and had lesser weight gains, typical of tall fescue
      toxicosis, compared to those grazing E-TF. They had decreased activities of
      alkaline phosphatase and alanine aminotransferase. Compared to controls, they had
      lower values for serum prolactin and globulin concentrations. The concentration
      of creatinine and the albumin/globulin ratio were increased in the cattle grazing
      E+TF. Isozyme determination of alkaline phosphatase indicated that the decrease
      in serum activity of cattle grazing E+TF was due to decreases in both intestinal
      and bone isozymes. Serum protein electrophoresis indicated that the decrease in
      serum globulin concentration was due to decreases in both alpha and gamma
      globulin fractions of this protein. The data collected in these experiments add
      to our understanding of the alterations that occur in the serum chemistry
      profiles when cattle consume E+TF for prolonged periods of time.

PMID- 10349701
TI  - Effect of chlorpyrifos on immune function in rats.
AB  - A commercial formulation of chlorpyrifos was evaluated for effects on selected
      immune system functions in male Fisher 344 rats. Chlorpyrifos in an olive oil
      vehicle was administered by oral gavage twice weekly for 28 d at a dose of 5.0
      mg/kg for each treatment. Body weight and organ/body weight ratios were
      unaffected by the chlorpyrifos. In contrast, chlorpyrifos impaired T-lymphocyte
      blastogenesis induced by concanavalin A (P = 0.03) and phytohemagglutinin (P =
      0.023), but did not alter B-lymphocyte blastogenesis induced by
      lipopolysaccharide/dextran (P = 0.082. Humoral immunity (anti-sheep red blood
      cell), a T-lymphocyte macrophage-dependent response, was also reduced (P = 0.019)
      when the antibody response was expressed/10(6) spleen cells, although the
      response expressed/spleen was unaffected (P = 0.32), reflecting increased
      lymphocyte production. The total splenic lymphocyte counts in the chlorpyrifos
      treated rats increased by 91% (P < 0.0001), therefore reducing the antibody
      response when expressed/10(6) spleen cells. Chlorpyrifos had no effect on
      macrophage phagocytosis (P = 0.27), but increased the relative percentage
      expression of CD5+ (P = 0.028) and CD8+ (P = 0.003). The presence of normal
      antibody and phagocytic responses in association with reduced T-lymphocyte
      blastogenesis and enhanced expression of specific cell surface antigens indicated
      that chlorpyrifos induced immune alterations associated with lymphocyte
      subpopulations.

PMID- 10349702
TI  - Suspected Vipera palaestinae envenomation in three cats.
AB  - Vipera palaestinae is the only venomous snake in Israel whose envenomation is
      clinically significant. It is found in most of the populated areas of the
      country. The venom of Vipera palaestinae has hemorrhagic and neurotoxic activity.
      Viper snake envenomation always demonstrates local effects with or without
      systemic effects. Cats are considered more resistant to snake bites than other
      animals. Although several case reports of snakebites in cats have been published,
      this is the first report which describes cases of cats suspected of being bitten
      by Vipera palaestinae. These cases differ in their severity and in their clinical
      presentation. Hemoconcentration occurred in 2 cases; and anemia, hypoproteinemia,
      hemolysis and the appearance of nucleated erythrocytes in another.
      Thrombocytopenia varied from mild to moderate to severe. These variations reflect
      the stage and severity of envenomation, and may be due to factors in the snake
      and/or victim and the time lapsed since the bite occurred.

PMID- 10349703
TI  - Copperhead envenomations: clinical profiles of three different subspecies.
AB  - Copperhead envenomation cases reported in the literature frequently lack
      identification of the subspecies of copperhead responsible for the envenomation.
      Whether subspecific identity would be useful in predicting possible different
      toxicity profiles may have clinical relevance. We report here the clinical
      profiles from envenomations involving 3 different subspecies of captive adult
      copperhead snakes--the southern copperhead (Agkistrodon contortrix contortrix),
      the northern copperhead (Agkistrodon contortrix mokasen), and the broad-banded
      copperhead (Agkistrodon contortrix laticinctus). The bites occurred in the north
      central region of the US where none of these subspecies are endemic and involved
      a professional and 2 amateur herpetologists. The victims were adult males with no
      previous history of venomous snake bite, and all bites were evidenced by fang
      puncture marks to their index finger or thumb. Envenomations from the broad
      banded and northern copperhead subspecies caused localized symptoms of pain,
      edema and ecchymosis. In addition to these symptoms, southern copperhead
      envenomation resulted in a more severe clinical toxicity profile as evidenced by
      propulsive emesis, diarrhea and hematuria. Whether these differences in observed
      clinical toxicity were the result of unique subspecific venom pharmacological
      actions is an interesting question. However, independent of the copperhead
      subspecies involved, conservative medical management was effective in each case.

PMID- 10349705
TI  - An assessment of exposure to mercury and mercuric chloride from handling treated
      herbarium plants.
AB  - A curator at a university herbarium reported headache, nausea and mucosal
      irritation after initiating a project to remount plant specimens treated with
      mercuric chloride. Workplace exposure assessment indicated potential for mercury
      compound ingestion through hand-to-mouth contact. Blood, hair and urine assays
      were negative.

PMID- 10349704
TI  - Recurrent convulsions and cardiac conduction disturbances after propafenone
      overdose.
AB  - Propafenone is a class Ic antiarrhythmic agent which also exhibits beta
      adrenergic and fast sodium channel blockade. We report a case of severe poisoning
      in a 24-y-old woman who suffered a seizure 1 h after the intentional ingestion of
      2.7 g propafenone, and had a recurrence of convulsion on arrival at the hospital.
      She also developed severe arrhythmia during her hospital course. She recovered
      uneventfully with supportive treatment.

PMID- 10349706
TI  - Accidental intranasal administration of phenol.
AB  - A 79-y-old man developed erythema and superficial sloughing of the turbinate
      following accidental intranasal administration of 89.2% phenol solution. Previous
      documented reports of phenol exposure include exposures via dermal and oral
      routes, but no reports of nasal phenol administration were found.

PMID- 10349707
TI  - Retrospective searching for poisonous plant vouchers.
AB  - Few published reports of plant poisoning, whether experimental or accidental,
      document vouchers. This can be rectified by retrospective location of vouchers
      through determination of a collaborating botanist or herbarium of deposit. An
      absolute voucher is referenced in the toxicology report. For a probable voucher
      the report does not identify an herbarium specimen, but the report and the
      specimen label or sheet agree on plant name, collector's name, collection date
      and place. A possible voucher is perhaps from the exposure lot, but was collected
      by the collaborating botanist at a somewhat earlier or later date than the
      exposure date. On the other hand, a supporting specimen was collected by the
      collaborating botanist but is not from the exposure lot. Vouchers and supporting
      specimens for some species of Asclepias tested for toxicity by CD Marsh and
      coworkers were found in the US National Herbarium at the Smithsonian Institution,
      Washington DC.

PMID- 10349708
TI  - Poisonous plant vouchers.
AB  - Every published report of plant poisoning, whether experimental or accidental,
      should document plant identification. The essential elements are: complete
      botanical Latin name including species, specific epithet and author(s); name of
      the collaborating botanist who identified the plant; and herbarium and collection
      number of a voucher specimen from the exposure lot. Additional information to aid
      identification might include plant photographs, drawings, and descriptions.

PMID- 10349709
TI  - Re-analysis of 2,4-D use and the occurrence of canine malignant lymphoma.
AB  - An independent scientific review panel had concerns involving study design,
      analysis and interpretation of results in a case-control study investigating the
      relationship between canine malignant lymphoma (CML) and the use of 2,4-D
      herbicide. To address these concerns, a re-analysis was done to examine 2,4-D use
      and its association with CML. This case-control study re-analyzed the data using
      the exposure definition used in the original study, re-analyzed the data using a
      redefinition of exposure, and conducted a dose-response analysis with the
      redefined exposure criteria. Our results agreed with the original author's
      analyses that no effects were found when stratifying by survey method and
      geographic region, and that there were no significant differences between
      separated and pooled control groups. However, we did not confirm a dose-response
      relationship between 2,4-D use and CML. Additionally, the occurrence of CML was
      not found significantly associated with the use of 2,4-D.

PMID- 10349710
TI  - Comparison of hepatic lesions in veal calves with concentrations of copper, iron
      and zinc in liver and kidney.
AB  - Veal calf producers in Indiana have reported condemnation of carcasses due to
      icterus as well as condemnation of livers because of yellow discoloration,
      hepatomegaly and fibrosis. This study assessed the degree of hepatic injury in
      affected veal calves and correlated it with copper, iron and zinc concentrations
      in the liver and kidney. Tissues examined histopathologically were from
      slaughtered and necropsied veal calves. Hepatic lesions were divided into
      histopathologic categories of severity (minimal, moderate, marked or severe)
      based upon the degree of fibrosis, biliary epithelial hyperplasia, and
      inflammation. Hepatic copper levels decreased as the severity of lesions
      increased. The clinical observations and morphologic changes suggested initial
      hepatic damage before 9 w-of-age. The affected calves either died of acute copper
      toxicosis or survived to develop hepatomegaly, hepatic discoloration and/or
      fibrosis at the time of slaughter.

PMID- 10349711
TI  - Seizures induced by theophylline and isoniazid in mice.
AB  - Isoniazid-induced seizures respond poorly to anticonvulsants but well to
      pyridoxine (Vitamin B6); theophylline produces difficult-to-treat seizures with
      substantial morbidity and mortality. Theophylline therapy depresses plasma
      pyridoxal-5'-phosphate (PLP), the active metabolite of pyridoxine, suggesting
      that theophylline-induced seizures might be amenable to treatment with
      pyridoxine. Our study established the dose-response relationship for convulsions
      due to isoniazid and theophylline in mice and determined if pyridoxine
      antagonized such seizures. Female CD-1 outbred mice weighing 25 to 30 g were
      used. Clonic seizures had clonic activity lasting 5 sec; tonic seizures had loss
      of the righting reflex with tonic hindlimb extension. Groups of 10 mice received
      single doses of 50, 100, 150, 200, 250 or 300 mg aminophylline/kg i.p. or 100,
      150, 200, 250, 300 or 350 mg isoniazid/kg i.p. and were observed for seizures or
      death. Pyridoxine or saline with aminophylline or isoniazid were administered
      simultaneously. The LD50 for aminophylline was 266 mg/kg; for isoniazid it was
      160 mg/kg. Doses of 150 mg aminophylline/kg or 100 mg isoniazid/kg did not induce
      seizures. Pyridoxine with aminophylline or isoniazid did not alter the frequency
      or time of onset of seizures or death. This was unexpected because pyridoxine
      antagonizes theophylline-induced seizures in mice and reverses isoniazid-induced
      seizures in humans. We found no evidence that PLP depletion in mice is a
      mechanism for seizures induced by isoniazid or aminophylline in a fashion similar
      to isoniazid in humans.

PMID- 10349712
TI  - Ionophore toxicosis.

PMID- 10349713
TI  - Metabolite formation and toxicity measurements in evaluating bioremediation of a
      jet-fuel-contaminated aquifer.
AB  - The metabolic capabilities of subsurface, jet-fuel-contaminated, aquifer
      microbial communities were characterized using an ecological approach to
      biotreatment assessment. A multifaceted experimental design was used that
      incorporated quantification of metabolite formation and toxicity screening along
      with the typical microbial activity measurements and pollutant degradation
      measurements used for assessing bioremediation potential. For select experiments,
      dissolved oxygen levels and pH in microcosm systems were also monitored. Results
      suggest that a sizable, metabolically active microbial community exists in both
      contaminated and uncontaminated areas of the study site. Time course metabolism
      analyses indicated that the microbial communities were capable of degrading all
      three test compounds (amino acids, decane, and toluene) without any apparent
      adaptation period. Measurements of mineralization, cellular uptake, and
      metabolite formation indicated that metabolite formation was the predominant fate
      of the target pollutants in the microcosms. The results of toxicity screening
      time courses indicated that under oxygen-limiting conditions, the potential for
      the accumulation of toxic, acidic metabolites that could adversely affect the
      rates and extent of bioremediation existed. The experimental results indicate
      that the microbial communities at the site possess the metabolic potential for in
      situ biodegradation of the jet fuel. Care must be taken in the design of an in
      situ biodegradation treatment system (for this site and perhaps other petroleum
      contaminated aquifers) to avoid the development of microaerophilic or oxygen
      depleted zones, which could result in possible self-poisoning owing to acidic
      metabolite accumulation.

PMID- 10349715
TI  - Isolation of an asporogenic (spoOA) protective antigen-producing strain of
      Bacillus anthracis.
AB  - We found that Congo red agar allows identification of sporulation-deficient
      Bacillus anthracis. Using Congo red agar, we isolated an asporogenic derivative
      of the protective antigen-producing strain B. anthracis delta Sterne-1(pPA102).
      Polymerase chain reaction and Southern hybridization analyses of DNA from the
      asporogenic mutant revealed that a deletion was present in spoOA, an essential
      gene for the initiation of sporulation. The deletion also encompassed the spoIVB
      homologue and a portion of the recN homologue. The avirulent spoOA strain delta
      Sterne-1(pPA102)CR4 is suitable for the safe production of protective antigen
      without endospore contamination of the vaccine production facility.

PMID- 10349716
TI  - Organic solvent-tolerant mutants of Pseudomonas aeruginosa display multiple
      antibiotic resistance.
AB  - Organic solvent-tolerant mutants of Pseudomonas aeruginosa selected in the
      presence of hexane exhibited increased resistance to a variety of structurally
      unrelated antimicrobial agents, including beta-lactams, fluoroquinolones,
      chloramphenicol, tetracycline, and novobiocin, a phenotype typical of nalB
      multidrug-resistant mutants. Western immunoblotting with antibodies specific to
      components of the three known multidrug efflux systems in P. aeruginosa
      demonstrated that the solvent-tolerant mutants displayed increased expression of
      the MexAB-OprM system and decreased expression of the MexEF-OprN system. Sequence
      analysis of mexR, the repressor gene of mexAB-oprM efflux operon, identified a
      nonsense mutation and a point mutation in the mexR genes of two solvent-tolerant
      mutants. These results emphasize the importance of the MexAB-OprM efflux system
      in organic solvent tolerance and the ability of environmental pollutants to
      select bacteria with a medically relevant antibiotic-resistant phenotype.

PMID- 10349714
TI  - Separation and characterization of trypsin and carboxypeptidase B-digested
      products of Met-Lys-human proinsulin.
AB  - Met-Lys-human proinsulin could be converted into insulin in vitro with the
      treatment of trypsin and carboxypeptidase B (CPB). Under less effective
      conditions, the enzymatic reaction does not proceed perfectly, and two main bands
      have been identified by native-polyacrylamide gel electrophoresis (PAGE)
      analysis. These two main products were thus separated and purified by DEAE
      Sephadex A25 chromatography in a Tris-isopropanol system with an NaCl gradient.
      The isopropanol and NaCl were removed by a second DEAE-Sephadex column. Native
      PAGE, mass spectrometric, and amino acid composition analyses indicate that one
      fraction of these two major products contains human insulin and desB30-insulin
      and that the other fraction is a mixture of human insulin analogs, which have one
      more basic amino acid than human insulin owing to the unsuitable amount of
      proteases, especially the lack of CPB. Furthermore, both receptor binding assay
      and radioimmunoassay have been utilized for the activity determination, and both
      fractions display almost full biological activity with porcine insulin as the
      standard. Present results provide further evidence for the quality control of
      recombinant human insulin production.

PMID- 10349717
TI  - Isolation and purification of a Campylobacter upsaliensis autolysin.
AB  - Autolytic activity in the soluble and sediment fractions of sonicates of the
      spiral and the coccoid form of Campylobacter upsaliensis could not be
      demonstrated by native (nondenaturing) polyacrylamide gel electrophoresis (PAGE).
      Autolysins were detected, however, by using denaturing sodium dodecyl sulfate
      (SDS)-PAGE gels containing either purified Escherichia coli peptidoglycan or
      whole cells of Micrococcus luteus (Micrococcus lysodeikticus) as the turbid
      substrate, with subsequent renaturation by treatment with Triton X-100 buffer. In
      renaturing gels that contained Escherichia coli peptidoglycan, 14 putative
      autolytic bands ranging from 200 to 12 kDa were detected. In similar gels
      containing whole cells of M. luteus, only a single band appeared with a molecular
      mass of 34 kDa. This band corresponded to one of the bands present in the gels
      containing Escherichia coli peptidoglycan. This common autolysin was isolated by
      adsorbing it from Campylobacter upsaliensis soluble fractions onto M. luteus
      cells and then subjecting these cells to renaturing SDS-PAGE in gels containing
      Escherichia coli peptidoglycan. The 34-kDa autolysin differed from a single 51
      kDa autolysin unique to the M. luteus cells, and when isolated from an SDS-PAGE
      gel, was pure when tested by isoelectric focusing. The N-terminal amino acid
      sequence analysis showed the first 15 amino acids of the 34-kDa autolysin to have
      67% identity to a part of antigenic protein PEB4 of Campylobacter jejuni. The
      purified autolysin was used to immunize rabbits and the antibodies produced
      precipitated autolytic activity from cell lysates. The specificity of the
      antibodies was shown by Western blotting: only a single specific band occurred,
      with a molecular mass of 34 kDa, and thus it seems unlikely that the 34-kDa
      autolysin was derived from any of the other autolysins that were detected.

PMID- 10349718
TI  - PKA from Saccharomyces cerevisiae can be activated by cyclic AMP and cyclic GMP.
AB  - Analysis of Saccharomyces cerevisiae genome revealed no sequence homologous to
      cyclic GMP (cGMP) dependent protein kinase from other organisms. Here we
      demonstrate that cyclic AMP (cAMP) dependent protein kinase purified from S.
      cerevisiae was almost equally activated by cAMP and cGMP in 3 x 10(-6) M
      concentrations of either nucleotide in the presence of Mg2+ ions. Interestingly,
      if Mn2+ ions were used instead of Mg2+, cGMP was only 30% as effective as cAMP in
      the activation of cAMP-dependent protein kinase. Analogs of cAMP such as 8-chloro
      cAMP and 3':5'-cyclic monophosphate of ribofuranosylbenzimidazole were as potent
      as cAMP in the enzyme activation, while N6,2'-O-dibutyryl-cAMP activated the
      enzyme to a lower extent. It was also found that yeast cAMP-dependent protein
      kinase can be activated by limited proteolytic digestion. The results presented
      were obtained with protamine and ribosomal protein S10 used as phosphorylation
      substrates.

PMID- 10349719
TI  - Cell extensions in PKC1 mutants of Saccharomyces cerevisiae.
AB  - To obtain information on cell wall synthesis and its relationship to morphology,
      we examined the induction of cell extensions of yeast upon the addition of
      isoamyl alcohol in osmotically fragile mutants that had mutations in genes
      related to the cell integrity pathway through activation of the mitogen-activated
      protein kinase cascade. We found that isoamyl alcohol induces cell extensions in
      pkc1 deletion mutants but not in mutants with mutations in genes positioned
      downstream or upstream of the PKC1 gene. These results suggest that Pkc1p
      functions not only in the integrity pathway but also in the induction. We
      characterized the elongated cells; many had two or more nuclei. We found no
      difference in cell surface structure between round and elongated cells from the
      results of chitin staining and cell wall extraction. Actin cytoskeleton was
      organized in elongated cells, as well as round cells. Cytochalasin D (0.08 mg/mL)
      inhibited the formation of actin cable but did not affect the induction of cell
      extensions.

PMID- 10349720
TI  - Polyclonal antibodies against fusaproliferin.
AB  - Fusaproliferin (FP), a toxic metabolite of the world-wide maize pathogens
      Fusarium proliferatum and Fusarium subglutinans, was recently found to be a
      natural contaminant of maize. Its toxic activity on haematopoietic human cell
      lines and its teratogenic effects on chicken embryos has been recently proved.
      Therefore a sensitive, rapid, and inexpensive screening test to detect FP in
      agricultural commodities is necessary to protect human health. FP-hemiglutarate
      conjugated to modified bovine serum albumin was synthesized, characterized, and
      used as an antigen for raising polyclonal antibodies by immunizing rabbits.
      Indirect and competitive ELISA and immunoblotting analyses were performed to
      determine antibody specificity towards the mycotoxin. The determination of 10
      micrograms of free FP/mL was achieved using antibodies purified by means of
      affinity chromatography on a FP-lysine-Sepharose column. This unsatisfactory
      detection limit is due to high background values; thus, this method is not
      competitive with traditional UV-HPLC methods.

PMID- 10349721
TI  - Brewing spoilage Lactobacilli detected using monoclonal antibodies to bacterial
      surface antigens.
AB  - A panel of thirteen monoclonal antibodies (Mabs) was assembled that reacts with
      surface antigens on eight of eleven Lactobacillus brewing spoilage organisms,
      including one or more of L. brevis, L. buchneri, L. casei-alactosus, L.
      plantarum, or unspeciated isolate(s). Immunoblotting was done to identify the
      antigens involved in Mab binding. Antigen stability in situ was tested by
      protease treatment and by surface antigen extraction of washed bacteria. Protease
      susceptibility of extracted surface antigens was also examined. In most cases,
      Lactobacillus surface antigens detected by the Mabs appear to be noncovalently
      bound proteins readily altered or removed from the bacterium by various
      environmental conditions. This research identifies brewing conditions that need
      to be tested to ascertain whether bacterial surface antigen-reactive Mabs can be
      used for the rapid, sensitive, and specific detection of Lactobacillus brewing
      spoilage organisms.

PMID- 10349722
TI  - Changes in fecal microflora induced by intubation of mice with Bacillus subtilis
      (natto) spores are dependent upon dietary components.
AB  - We examined changes in mouse fecal microflora after various dietary components
      and Bacillus subtilis (natto) spores were delivered by intubation. The
      administration of intact spores of Bacillus subtilis (natto) did not affect fecal
      Enterobacteriaceae and Enterococcus spp. in all three diet groups; on the other
      hand, it did affect fecal Bacteroidaceae and Lactobacillus spp., depending upon
      the diets fed. The administration of autoclaved spores did not alter fecal
      microflora. In vitro cultures of Lactobacillus murinus obtained from mouse feces,
      together with Bacillus subtilis (natto) under aerobic conditions as a mixed
      culture, revealed that the growth of L. murinus was enhanced by the addition of
      intact spores of Bacillus subtilis (natto). This enhancement of growth was
      displayed only in media containing either sucrose, glucose, maltose, or fructose
      but not in media containing cornstarch, soluble starch, or microcrystalline
      cellulose. From these results it was evident that some metabolites of Bacillus
      subtilis (natto) produced during germination and (or) outgrowth of spores of this
      strain, requiring monosaccharides or oligosaccharides, participated in the
      enhancement of the growth of L. murinus.

PMID- 10349723
TI  - The influence of bacterial inoculants on the microbial ecology of aerobic
      spoilage of barley silage.
AB  - The aerobic decomposition of barley silage treated with two inoculants (LacA and
      LacB) containing mixtures of Lactobacillus plantarum and Enterococcus faecium was
      investigated over a 28-day period. Initially, yeast and bacterial populations
      were larger in silage inoculated with LacA than in silage treated with LacB or
      water alone (control). Differences in the succession of yeasts in silage treated
      with LacA were observed relative to the other two treatments. From silage
      treatment with LacA, Issatchenkia orientalis was the most prevalent yeast taxon
      over all of the sample times, and the filamentous fungus Microascus brevicaulis
      was also frequently isolated at later sample dates (> or = 14 days). In contrast,
      Saccharomyces exiguus was the most prominent yeast recovered from silage treated
      with LacB and water alone on days 2 and 4, although it was supplanted by I.
      orientalis at later sample times. Successional trends of bacteria were similar
      for all three treatments. Lactobacillus spp. were initially the most prevalent
      bacteria isolated, followed by Bacillus spp. (primarily Bacillus pumilus).
      However, the onset of Bacillus spp. prominence was faster in LacA silage, and
      Klebsiella planticola was frequently recovered at later sample times (> or = 14
      days). More filamentous fungi were recovered from LacA silage on media containing
      carboxylmethylcellulose, pectin, or xylan. The most commonly isolated taxa were
      Absidia sp., Aspergillus flavus, Aspergillus fumigatus, Byssochlamys nivea,
      Monascus ruber, Penicillium brevicompactum, Pseudoallescheria boydii, and M.
      brevicaulis. The results of this study indicated that the two bacterial
      inoculants incorporated into barley at the time of ensilage affected the
      microbial ecology of silage decomposition following exposure to air. However,
      neither of the microbial inoculants effectively delayed aerobic spoilage of
      barley silage, and the rate of decomposition of silage treated with one of the
      inoculants (LacA) was actually enhanced.

PMID- 10349724
TI  - A basal-defined medium for the study of proteolytic activity of Serratia
      marcescens.
AB  - A simple defined basal medium is presented for the study of proteolytic activity,
      induction and repression, and protease purification with Serratia marcescens.
      Since the medium contains no protein, it does not interfere with or present
      artifact to protein assays, column chromatography, or electrophoresis. The medium
      consists of the basal salts and buffer medium of Bromke and Hammel (1979) plus a
      carbon-energy source such as glycerol, calcium chloride for the cation
      requirement for protease activity, and an amino acid, preferably leucine. Growth
      parameters and proteolytic activities are presented for unsupplemented medium and
      for the medium supplemented with each of 18 amino acids. Unsupplemented medium
      completes the logarithmic phase in 12.5 h of incubation and has a constitutive
      level of proteolytic activity. Supplementation with any amino acid, except
      cysteine and tryptophan, increases significantly the proteolytic activity, but
      has a varied effect on growth parameters.

PMID- 10349725
TI  - The replication cycle of tanapox virus in owl monkey kidney cells.
AB  - The growth kinetics of tanapox virus in owl monkey kidney cells was elucidated by
      single-step growth curves at multiplicities of 10, 1.0, and 0.1 plaque forming
      units (pfu) per cell at 37 and 33 degrees C. Virus replicated equally well at
      both temperatures and produced a cytopathic effect that was characterized by
      densely packed rounded cells with retrogressed monolayer and granular vacuolated
      cytoplasm. Single-step growth curves revealed that the eclipse period varied from
      24 h postinfection (hpi) at a multiplicity of infection of 10 pfu/cell to 48 hpi
      at 0.1 pfu/cell. The length of the latent period also varied from 36 hpi at 10
      pfu/cell to 48 hpi at 0.1 pfu/cell. The intracellular virus, extracellular virus,
      and total virus titers reached their maximums relatively early at 10 pfu/cell as
      compared with 0.1 pfu/cell. About 78% of the mature progeny virion is retained
      intracellularly at 10 pfu/cell at 96 hpi. We conclude that tanapox virus
      replication is similar to other poxviruses, but the replication cycle is longer
      when compared with vaccinia virus.

PMID- 10349727
TI  - Common fears: a comparison of adolescents' self-generated and fear survey
      schedule generated fears.
AB  - Investigations into normative fear in adolescence have indicated that the most
      common fears are consistently death-related and danger-related. Assessments have
      most commonly been made from self-reports on fear survey schedules. The aim of
      the present study, therefore, was to determine whether adolescents would provide
      responses comparable to those generated through the use of a fear survey schedule
      when asked to list their 3 greatest fears. A total of 439 adolescents aged 11 to
      18 years (237 girls, 201 boys, 1 sex not reported) listed their greatest fears;
      then they completed the 78-item Fear Survey Schedule for Children-II (E. Gullone
      & N. J. King, 1992). Consistent with past research, the 10 most common fears
      generated via the fear schedule related to death and danger. However, on the
      whole, the self-generated fears deviated from the death and danger theme, also
      including fear of failure, fear of animals, and fear of the unknown. A tendency
      toward global responses in self-generated fears appeared to encompass the
      majority of specific death-related fears included in the fear schedule, thus
      allowing for other predominant fears to be listed among the 3 most common.

PMID- 10349726
TI  - Successful part-whole perception in young children using multiple-choice tests.
AB  - In 3 experiments involving young children (N = 164), excellent perceptual
      integration of parts and wholes was revealed, unlike findings of earlier
      Piagetian studies (D. Elkind, R. R. Koegler, & E. Go, 1964). In Experiment 1, 5
      year-olds' performance in part-whole perception was raised nearly sixfold when a
      multiple-choice task was substituted for the Piagetian verbal task used earlier.
      Performing the multiple-choice first rather than second also raised verbal
      scores. Experiment 2, with 3- to 5-year-olds, tested whether the children could
      have been confusing "whole made of parts" with "whole and parts" stimuli. Equal
      performance was found with 2 versions of a multiple-choice task, including either
      a whole and parts or a whole and different parts picture, which contradicts the
      confusion hypothesis. In Experiment 3, with 2- to 4-year-olds, good part-whole
      perception was demonstrated through the use of a 2-alternative, forced-choice
      procedure. The lower age bounds for this type of performance are much earlier
      than hitherto proposed.

PMID- 10349728
TI  - Amelioration by glucose-6-phosphate and NADP of potato glycoalkaloid inhibition
      in cell, enzyme and liposome assays.
AB  - Lysis of human erythrocytes by 20 microM chaconine was reduced by 0.5 mM glucose
      6-phosphate (G6P) and NADP. Both compounds caused approximately 50% inhibition of
      haemolysis at 1 mM. Glucose, glucose-1-phosphate, rhamnose, galactose and
      galactose-6-phosphate were ineffective; NAD was effective, although not to the
      extent of NADP. Of the tested sugars, only G6P reduced solanine-induced
      haemolysis. G6P also reduced the synergistic haemolytic action of solanine and
      chaconine in combination. G6P and NADP at or above 5 mM antagonised chaconine
      induced betanin loss from excised red beet root discs; NADP was more effective
      than G6P. Disruption of PC/cholesterol liposomes by chaconine and inhibition of
      acetylcholinesterase by chaconine or solanine, were unaffected by up to 10 mM
      NADP or 50 mM G6P.

PMID- 10349729
TI  - Inhibitor studies of tabersonine metabolism in C. roseus hairy roots.
AB  - The conversion of tabersonine to lochnericine and horhammericine was investigated
      in C. roseus hairy root cultures. The accumulation of lochnericine and
      horhammericine, like tabersonine, was associated with growth. Through the use of
      oxygenase inhibitors, 1-aminobenzotriazole (ABT), clotrimazole (CLOT), and 2.5
      pyridinedicarboxylic acid (PCA), details of the metabolic pathway around
      tabersonine in hairy roots of C. roseus were elucidated. ABT specifically
      inhibited the formation of horhammericine, while CLOT inhibited the accumulation
      of lochnericine. Using jasmonic acid in combination with the inhibitors suggests
      an inducible P-450 enzyme responsible for the formation of horhammericine. The
      inhibitor study also revealed that both lochnericine and horhammericine are
      'turned over' in hairy root cultures.

PMID- 10349730
TI  - A diabetes switch?

PMID- 10349731
TI  - How the body tells left from right.

PMID- 10349732
TI  - Image-guided surgery.

PMID- 10349733
TI  - Biological warfare against crops.

PMID- 10349734
TI  - Chasing the ghost bat.

PMID- 10349735
TI  - Noroudemansin A, a new antifungal antibiotic from Pterula species 82168 and three
      semisynthetic derivatives.
AB  - A new antifungal (E)-beta-methoxyacrylate noroudemansin A (1), was isolated from
      cultures of Pterula sp. 82168. Its biological activities were investigated and
      compared with oudemansin A. The structure was elucidated by spectroscopic
      methods. Three semisynthetic noroudemansin A derivatives were synthesized from
      the natural product.

PMID- 10349736
TI  - Antibacterial activity of simple coumarins: structural requirements for
      biological activity.
AB  - The antibacterial activity of a series of simple coumarins was evaluated against
      8 microorganisms, including three Gram-positive (Staphylococcus aureus, beta
      hemolytic Streptococcus and Streptococcus pneumoniae) and five Gram-negative
      bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa,
      Proteus mirabilis and Haemophilus influenzae), using the microdilution broth
      method. The coumarins tested showed broad diversity regarding growth inhibitory
      activity with minimum inhibitory concentrations ranging from 0.9 to > 12.4
      microM. This study, presenting the first systematic analysis of structure
      activity relationships among this group of coumarins, revealed some interesting
      structural requirements. While coumarins with a methoxy function at C-7 and, if
      present, an OH group at either the C-6 or C-8 position are invariably effective
      against the spectrum of tested standard bacteria (Gram-negative microorganisms
      including the Gram-positive bacterium Staphylococcus aureus), the presence of an
      aromatic dimethoxy arrangement is apparently favourable against those
      microorganisms which require special growth factors (beta-hemolytic
      Streptococcus, Streptococcus pneumoniae and Haemophilus influenzae). A
      combination of these structural features, two methoxy functions and at least one
      additional phenolic group as reflected by the highly oxygenated coumarins,
      identify promising candidates with antibacterial broad-spectrum activity.

PMID- 10349737
TI  - Structure elucidation of a purple peptide found during the purification of a
      recombinant protein from Escherichia coli.
AB  - A purple substance (4) partially co-purified with a recombinant human B-type
      natriuretic peptide (hBNP), following an E. coli fermentation. The structure of
      the compound was elucidated by NMR, electrospray and FAB mass spectrometry. The
      chromophore is a 1,4-naphthoquinone condensed with the N-terminal cysteine of a
      heptapeptide by its NH2- and SH-groups to form a dihydro-thiazine ring. The
      peptide sequence was determined as Cys-Lys-Val-Leu-Arg-Arg-His by mass
      spectrometric techniques. CID and data base matching identified it as the C
      terminus of the 32-amino-acid recombinant peptide hBNP. This modification of an N
      terminal Cys may be a more general phenomenon with implications for the
      production of heterologous proteins by microorganisms.

PMID- 10349738
TI  - Effects of trehalose and ethanol on yeast cytosolic pyrophosphatase.
AB  - Trehalose has been described to protect several enzymes against destabilizing
      conditions. This sugar is naturally accumulated by yeast as a stress protectant.
      A common stress condition that yeast is normally submitted is the presence of
      ethanol, the by-product of fermentation process of several yeast. In this paper
      we show the effects of trehalose and ethanol, alone or together, on yeast
      pyrophosphatase, and the effects of these compounds on inhibition and unfolding
      of pyrophosphatase promoted by urea. We show that both trehalose and ethanol
      inhibit pyrophosphatase in a dose-dependent manner, and that the presence of
      ethanol does not modify the inhibition promoted by trehalose as well as the
      presence of trehalose does not modify the inhibition promoted by ethanol. The
      effects of trehalose on pyrophosphatase are completely reversible, but the
      inhibition caused by ethanol was only partially reversible. Incubation of
      pyrophosphatase with 10% (v/v) ethanol promoted an inhibition of 15%, and the
      control activity was completely recovered after removal of ethanol. On the other
      hand, when pyrophosphatase was incubated with 20% (v/v) ethanol an inhibition of
      40% of the control activity was observed which persisted after removal of
      ethanol. Ethanol also potentiates the inhibition of pyrophosphatase promoted by
      urea, and contributes for an irreversible inactivation and unfolding of
      pyrophosphatase in the presence of urea. Trehalose, that protects this enzyme
      against the inhibition and unfolding promoted by the chaotropic compound urea,
      was inefficient to protect against the effects of ethanol. Trehalose was also
      efficient to prevent an irreversible inactivation induced by urea.

PMID- 10349739
TI  - Comparative immunological and chemical analysis of lipids and carotenoids of the
      D1-peptide and of the light-harvesting-complex of photosystem II of Nicotiana
      tabacum.
AB  - The light-harvesting-complex (LHCP) was isolated from photosystem II of Nicotiana
      tabacum var. John William's Broadleaf by means of the detergent acetyl-beta-D
      glucopyranoside and fractionating centrifugation. The D1-peptide of photosystem
      II was isolated as a dimer with the molecular mass of 66 kDa from the chlorophyll
      deficient tobacco mutant N. tabacum Su/su by means of sodium dodecyl sulfate
      polyacrylamide gel electrophoresis. Both preparations were characterized by means
      of the Western blot procedure using monospecific antisera to the proteins of
      photosystem II and monospecific antisera to lipids with which the lipids bound to
      peptides were determined. In parallel to this, lipids bound to the isolated LHCP
      complex and to the isolated D1-peptide were determined by lipido-chemical
      methods. The extraction of the isolated core peptide D1 with a mixture of boiling
      methanol and chloroform and subsequent HPLC-chromatography showed that in the D1
      peptide isolated via SDS-polyacrylamide gel electrophoresis, monogalactolipids,
      phosphatidylglycerol and sulfolipid molecules are bound in the molar ratio
      1:3:17. By means of the immunological procedure of Western blotting we were able
      to show that the 66 kDa band of the isolated dimeric D1 reacts positively only
      with the antisera to monogalactolipid, sulfolipid, beta-carotene and
      violaxanthin. With the antiserum to digalactolipid and that to
      phosphatidylglycerol a positive reaction is only observed if the preparation used
      in the Western blot is not the isolated D1-peptide but a "total" photosystem II
      preparation. The lipid extraction of the LHCP-complex and the subsequent analysis
      by thin-layer chromatography led to the result that the isolated LHCP complex
      contained in bound form 3 molecules monogalactolipid, 1 molecule of
      digalactolipid, 1 molecule of phosphatidylglycerol and 1 molecule of lutein. Less
      than 1 molecule of sulfolipid, beta-carotene, neoxanthin and violaxanthin are
      found. In the Western blot analysis only the antiserum to monogalactolipid and
      phosphatidylglycerol and among the carotenoid antisera only the antisera to beta
      carotene, violaxanthin and to neoxanthin reacted. With the antisera to the
      digalactolipid, to the sulfolipid and the antisera to the xanthophylls, namely to
      lutein and neoxanthin, a positive reaction occurred only if the material used in
      the Western Blot was the "total" photosystem II-preparation. By gas
      chromatography of the fatty acids of the isolated peptide fractions it was shown
      that, compared to the lipids of photosystem II and of the thylakoid membrane, in
      lipids of the isolated D1-peptide and of the LHCP-complex the saturation degree
      of fatty acids is strongly increased. Whereas palmitic acid in chloroplast lipids
      makes up for only 11% of the fatty acids, this saturated fatty acid increases in
      the lipids of the LHCP to 20% and makes up for 74% of total fatty acids in the
      lipids of the D1-peptide. Linoleic and linolenic acids are completely absent and
      oleic acid makes up for 14% of total fatty acids. In contrast to the lipids of
      the thylakoid membrane, the lipids bound to proteins/peptides are characterized
      by a strongly saturated character.

PMID- 10349740
TI  - Grapevine protoplasts as a transient expression system for comparison of stilbene
      synthase genes containing cGMP-responsive promoter elements.
AB  - A method for preparing elicitor-responsive protoplasts from grapevine cells kept
      in suspension culture was established. The protoplasts were employed in order to
      perform transient gene expression experiments produced by externally added
      plasmids. Using the gene coding for bacterial beta-glucuronidase as the reporter
      gene, the transient expression under the control of various promoters of stilbene
      synthase genes were analyzed. The elicitor-responsiveness of promoters from
      grapevine genes and heterologous promoters were assayed: the grapevine stilbene
      synthase gene VST-1 and pine stilbene synthase genes PST-1, PST-2 and PST-3.
      Compared to the expression effected by the cauliflower mosaic virus 35S RNA
      promoter, the stilbene synthase promoters caused a 2-5-fold increase in GUS
      activity. Incubation of transformed protoplasts with fungal cell wall further
      stimulated the stilbene synthase promoters but not the 35S RNA-promoter. An even
      more pronounced differentiation between the promoters was observed when cGMP was
      included in the transient expression assays. Instead of treating transformed
      protoplasts with fungal cell wall we administered simultaneously cGMP and the
      plasmid to be tested. The cGMP-responsive increase was (a) specific concerning
      the nucleotide applied, (b) characteristic of grapevine protoplasts, and (c) not
      seen with shortened promoter-GUS constructs or GUS under the control of the 35S
      RNA-promoter. The highest cGMP-dependent response to stress was shown by the
      promoter of the grapevine stilbene synthase gene VST-1.

PMID- 10349741
TI  - Heterologous overexpression of membrane-anchored subunit II of spinach
      chloroplast ATP synthase and its detergent-free purification as a soluble
      protein.
AB  - Subunit II is one of the four nonidentical subunits of the membrane integral,
      proton-transporting moiety (CFo) of the chloroplast ATP synthase. In chloroplasts
      of spinach leaves, it is the only nuclear-encoded CFo subunit. It has been
      deduced that CFoII is not an additional subunit typical for photosynthetic
      organisms with no counterpart in E. coli, but equivalent to E. coli subunit b
      (Tiburzy, H.-J. and Berzborn, R. J. (1997), Z. Naturforsch. 52c, 789-798).
      Heterologous expression of subunit II was achieved by using the bacterial
      expression vector pT7-7. Recombinant subunit II (IIrec) does not integrate into
      the bacterial membrane nor does it precipitate into inclusion bodies. Gel
      filtration chromatography indicates that IIrec forms higher order aggregates. In
      three chromatographic steps approx. 10 mg of soluble IIrec of electrophoretic
      homogeneity are obtained from one liter of bacterial culture without using
      detergents. Thus, a eukaryotic membrane-anchored protein has been overexpressed
      in E. coli and has been purified in a soluble form.

PMID- 10349742
TI  - Theoretical description of the coding potential of diamino-5
      formamidopyrimidines.
AB  - The results of geometry optimisation of possible Watson-Crick-like pairs of 2,6
      diamino-4-oxy-5-formamidopyrimidine (fapy-adenine) or 4,6-diamino-5
      formamidopyrimidine (fapy-guanine) were presented. In the absence of the external
      field the fapy-adenine is able to form pairs with all four canonical nucleic acid
      bases. However, pairs with guanine, cytosine and thymine the most stable are.
      Thus, the potential miscoding abilities may be observed. In contrast, in the
      presence of the external field the mispairing abilities of fapy-adenine become
      insignificant since the most stable dimers are formed with thymine. The pairing
      properties of fapy-guanine are complex and depend on its tatomeric form. In the
      absence of an external field the 4-enol-6-keto-diamino tautomer of fapyG is able
      to form stable dimers with thymine and cytosine, while the 4,6-diketo-diamino
      tautomer forms the most stable pairs with cytosine and guanine. The presence of
      the water solvent does not significantly alter the pairing abilities of fapy
      guanine. However, pairs with thymine are at least as stable as the Watson-Crick
      GC pair. Thus, in polar conditions the mispairing potential of fapyG will be
      extended and may be enriched by potential GC-->AT transition.

PMID- 10349743
TI  - The anticancer drug adriamycin interacts with the human erythrocyte membrane.
AB  - Adriamycin is an aminoglycosidic anthracycline antibiotic widely used in the
      treatment of cancer. Increasing reports point to the involvement of cell
      membranes in its mechanism of action. The interaction of adriamycin with human
      erythrocytes was investigated in order to determine the membrane binding sites
      and the resultant structural perturbation. Electron microscopy revealed that red
      cells incubated with the therapeutical concentration of the drug in human plasma
      changed their discoid shape to both stomatocytes and echinocytes. According to
      the bilayer couple hypothesis, this means that adriamycin was incorporated into
      either the inner or outer leaflets of the erythrocyte membrane. To explain this
      unusual result, the drug was incubated with molecular models. One of them
      consisted of dimyristoylphosphatidylcholine (DMPC) and
      dimyristoylphosphatidylethanolamine (DMPE) multilayers, representative of
      phospholipid classes located in the outer and inner leaflets of the erythrocyte
      membrane, respectively. X-ray diffraction showed that adriamycin interaction
      perturbed the polar head and acyl chain regions of both lipids. Fluorescence
      spectroscopy on another model, consisting of DMPC large unilamellar vesicles
      (LUV), confirmed the X-ray results in that adriamycin fluidized its hydrophobic
      moiety. It is concluded that adriamycin incorporates into both erythrocyte
      leaflets affecting its membrane structure.

PMID- 10349744
TI  - Fluorescence studies on association of human translation initiation factor eIF4E
      with mRNA cap-analogues.
AB  - Binding of a long series of mono- and dinucleotide analogues of the 7
      methylguanosine containing 5'-mRNA-cap to human protein translation initiation
      factor eIF4E has been investigated by means of fluorescence. A new methodological
      approach in gathering and analysis of the fluorescence data provided us with very
      accurate values of the association equilibrium constant K and normalized, maximal
      quenching of the protein fluorescence delta Fmax, during titration of eIF4E by
      various cap-analogues. The results confirm participation of at least two
      conserved tryptophan residues of eIF4E in interaction with 7-methylguanine, as
      has been described recently for murine eIF4E, complexed with 7-methyl-GDP in
      crystal (Marcotrigiano et al., 1997, Cell 89, 951), and for yeast eIF4E,
      complexed with the same ligand in solution (Matsuo et al., 1997, Nature Struct.
      Biol. 4, 717). On the other hand binding by eIF4E of unmethylated guanine
      nucleotides and N2,N2,7-trimethylguanine containing nucleotides differ
      substantially from the way of binding of the regular mRNA-cap. Influence of the
      structural features of the cap-analogues, especially the type of the second
      nucleoside in the dinucleotide caps, on their association with eIF4E and
      biological activities in in vitro protein translation systems has been discussed
      in light of the known structures of the eIF4E-7-methyl-GDP complexes in crystal
      and solution.

PMID- 10349745
TI  - Mitogen-activated protein kinase and cell cycle progression during mouse egg
      activation induced by various stimuli.
AB  - A very sensitive method was established for detecting the activity of mitogen
      activated protein (MAP) kinase in mouse eggs, and used to follow temporal changes
      of this kinase during fertilization and spontaneous or chemically-induced
      parthenogenic activation. MAP kinase activity increased between 1 and 2.5 h post
      insemination, at which time the second polar body was emitted and sperm chromatin
      was dispersed; its activity decreased sharply at 8 h. when pronuclei were formed.
      Both calcium ionophore A23187 and ethanol simultaneously induced pronuclear
      formation and MAP kinase inactivation in aged eggs 8 h after incubation but less
      effectively in fresh eggs. The protein kinase inhibitor staurosporine induced
      pronuclear formation and MAP kinase inactivation more quickly than other
      treatments, with MAP kinase inactivation occurring slightly proceeding pronuclear
      formation. Okadaic acid, a specific inhibitor of protein phosphatase 1 and 2A,
      induced increase in MAP kinase activity, and overcame pronuclear formation
      induced by various stimuli. MAP kinase inactivation preceded pronuclear formation
      in eggs spontaneously activated by aging in vitro, perhaps due to cytoplasmic
      degeneration and thus delayed response of nuclear envelope precursors to MAP
      kinase inactivation. These data suggest that MAP kinase is a key protein kinase
      regulating the events of mouse egg activation. Increased MAP kinase activity is
      temporally correlated with the second polar body emission and sperm chromatin
      decondensation. Although different stimuli (including sperm) may initially act
      through different mechanisms, they finally inactivate MAP kinase, probably by
      allowing the action of protein phosphatase, and thus induces the transition to
      interphase.

PMID- 10349746
TI  - Impact of the media on vaccine uptake in British Columbia's grade 6 hepatitis B
      immunization program.

PMID- 10349747
TI  - [Anesthesia in France in 1996. Results of a study of the French Society of
      Anesthesia and Resuscitation].

PMID- 10349748
TI  - [Orthotopic liver transplantation from a living adult donor to an adult using the
      right hepatic lobe].
AB  - STUDY AIM: In children, living donor liver transplantation has been shown to be
      efficient in treating end-stage liver diseases when the left lateral segment is
      harvested. In adults, more liver mass is needed to provide adequate hepatic
      function. The aim of this study is to report 2 successful cases of living donor
      liver transplantation using a right hepatic lobe from adult. PATIENTS AND
      METHODS: In 2 sons, the right hepatic lobe was harvested without the middle
      hepatic vein for transplantation in their fathers who were suffering from end
      stage liver cirrhosis. Hepatectomy was done without vascular inflow occlusion
      after dissection of vascular and biliary structures, itself strictly restricted
      to the right side. In recipients, the graft was implanted orthotopically with
      preservation of the native inferior vena cava and after temporary porto-caval
      shunt. RESULTS: The duration of donors procedures was 7 h and 11 h 45 min; intra
      operative transfusions comprised of 700 mL from cell-saver in the first case, and
      1300 mL plus 1 autologous red blood cell unit in the second case. Graft weights
      were 770 g and 1100 g. None of the donors experienced liver failure and both were
      able to leave the hospital 9 days after the operation. In recipients, initial
      graft function was excellent in the first case and correct in the second case,
      despite the necessity to redo intra-operatively the hepatic vein anastomosis
      secondary to a twisting. Patients were discharged 20 and 40 days respectively
      following transplantation. CONCLUSION: Adult living donor liver transplantation
      using a right hepatic lobe is efficient and safe. This option could contribute to
      reducing the mortality of patients on the waiting list.

PMID- 10349749
TI  - [Klatskin tumor. A study of 15 resected cases].
AB  - STUDY AIM: Klatskin tumors are rare. Prognosis is still poor, and long term
      survival can be expected only after surgery, which is the treatment of choice.
      The aim of this study is to report the results of 15 resected cases and, by
      analysis of the literature, to emphasize the progress of the surgical treatment
      in hilar cholangiocarcinoma. PATIENTS AND METHODS: Between 1990 and 1998, 27
      patients affected by Klatskin tumor were observed. Eight women and seven men
      underwent surgical resection. The mean age was 59 years. Thirteen patients (48%)
      had curative resection (7 hilar resection (HR), 5 HR combined with partial
      hepatectomy (PH) and 1 HR + PH with portal vein resection). Two patients had
      palliative resection and surgical drainage. RESULTS: One in-hospital death
      occurred right after hepatectomy with portal vein resection (6.6%). Postoperative
      morbidity was 40%. Patients were regularly followed. Ten patients died and 5 were
      alive at the time of this study. The 1, 2 and 3-year survival after a curative
      resection was 84%, 54% and 34%. The median survival was 28.5 months. Lymph node
      involvement did not show a statistically significant difference on median
      survival between the positive group and the negative group (26.2 vs 29.8 months)
      because of the small number of patients. Survival after hilar resection at 1, 2,
      3, and 5 years was 100%, 57.1%, 28.6% and 0%. Four out of the 6 patients who
      underwent hilar resection combined with partial hepatectomy were still alive 1,
      23, 29, 38 months after resection. Hepatectomy increased mortality (16% vs 0%).
      Palliative biliary resection and surgical drainage were successfully performed in
      2 patients. CONCLUSION: Aggressive surgical treatment of Klatskin tumor can
      improve the survival of patients. Careful pre-operative management has to be
      carried out by a multidisciplinary approach including surgeons, hepatologists,
      radiologists and pathologists. Hepatic resection including the caudate lobe is
      often performed in order to obtain microscopic tumor-free margins and curative
      resection (R0). Biliary drainage and treatment of cholangitis is mandatory before
      surgery in order to improve the surgical outcome. Surgical treatment is
      characterized by high technical difficulties, and better results can be achieved
      by hepatobiliary surgical teams.

PMID- 10349751
TI  - [Results of laparoscopic treatment of perforated ulcers].
AB  - STUDY AIM: The aim of this retrospective survey was to evaluate the results of
      laparoscopic treatment in perforated peptic ulcer. PATIENTS AND METHODS: From
      1989 to 1998, 84 patients were operated on for perforated ulcer. Sixty nine
      patients, operated on with videolaparoscopy, were included in this study: 53 men
      and 12 women with a mean age of 45 +/- 16 years (19-85). Nine had a history of
      peptic ulcer disease and 12 received anti-inflammatory drugs. Perforation
      occurred in the duodenum (60 patients) and in the stomach (five patients).
      Laparoscopic treatment included peritoneal lavage and either a simple duodenal
      closure (51 patients), a closure with a highly selective vagotomy (one patient),
      an epiplooplasty (eight patients), or an excision-closure for the gastric ulcers
      (five patients). Drainage was associated in 38 patients (58%). RESULTS: A
      conversion into laparotomy was necessary in six patients. Among the 59 patients
      treated with laparoscopy, 56 were only managed laparoscopically, three had
      exploration and peritoneal lavage through laparoscopy, and underwent suture of
      the perforation through minilaparotomy. Mean operative time was 105 +/- 40
      minutes (30-240). Mean postoperative hospital stay was 8.2 +/- 4 days.
      Reoperation was performed in three patients for leakage (n = 2) and gall bladder
      perforation (n = 1). Complications were medically treated in three patients.
      There was no in-hospital mortality. CONCLUSION: Laparoscopic management in
      perforated peptic ulcer is successful in 90% of the patients. Results are good.
      There was no postoperative death in this series.

PMID- 10349750
TI  - [Adenocarcinoma in Barrett's esophagus. A study of 28 resected cases].
AB  - STUDY AIM: The aim of this retrospective study was to report a series of 28
      patients with adenocarcinoma (ADK) arising in Barrett's esophagus (BE), treated
      by esophagectomy. PATIENTS AND METHODS: From 1992 to 1998, 28 patients were
      operated on for ADK in BE. There were 27 men and one woman (mean age: 65 years)
      classified as ASA I (n = 2), ASA II (n = 15) and ASA III (n = 11). Eighteen
      patients had a long story of gastro-esophageal reflux disease which required
      surgical repair in five of them. Dysphagia was the main symptom (n = 19).
      Surgical procedures included 15 Ivor Lewis operations, nine esophagectomies
      without thoracotomy and four esophagogastrectomies by the left thoracic approach.
      RESULTS: Pathological examination of the specimens showed an EBO with
      adenocarcinoma (n = 27) and a high grade dysplasia (n = 1). Among five patients
      with a previously known BE, three under endoscopic surveillance had high grade
      dysplasia (n = 1) and limited T1 tumor (n = 2), while the other two patients
      without surveillance developed an invasive tumor (T3N1). There were three
      postoperative deaths (mortality rate: 10%), all arising from pulmonary failure.
      Median survival was 16.6 months. All patients resumed a normal diet. The
      actuarial survival rates were 63%, 42% and 15.2% respectively at 1, 2 and 4
      years. A multivariate analysis could identify 3 prognostic factors: ASA score
      previously known BE under surveillance, length of BE. CONCLUSION: Adenocarcinoma
      arising in BE is very often diagnosed too late. Patients with high risk BE
      require an endoscopic survey. High grade dysplasia detected in two successive
      examinations by two different pathologists may require prophylactic
      esophagectomy, but local endoscopic management presently under evaluation could
      be efficient in the future.

PMID- 10349752
TI  - [Laparoscopic splenorraphy using a resorbable prosthesis in splenic injuries.
      Apropos of 5 cases].
AB  - STUDY AIM: The aim of this retrospective study is to report five cases of
      laparoscopic splenorraphy with an absorbable perisplenic mesh for splenic injury.
      PATIENTS AND METHOD: From January 1996 to February 1998, three men and two women
      (mean age: 52 years) were included in this study. The splenic lesions were due to
      either a fall (n = 3), a traffic accident (n = 1), or pleural paracenthesis in a
      patient with mediastinitis after valvular replacement. Splenic injury was
      recognized by ultrasonography. The patients were operated as either emergency
      cases (n = 2), or within 24 hours (n = 3). The procedure included evacuation of
      the hemoperitineum, total liberation of the spleen, and splenic hemostasis with a
      perisplenic mesh which was used in open surgery. The mesh placed behind the
      spleen, covering its superior and inferior poles, was unrolled forwards and
      burses progressively tightened. RESULTS: There was no conversion, no mortality,
      no morbidity. In the four injured patients, the mean duration of surgery was 120
      minutes (70-180), without any blood transfusion, and the patients were discharged
      on d4 or 5. The fifth patient, after valvular replacement, was operated on with
      anticoagulation. The mean duration of surgery was 270 minutes. Four blood units
      were necessary. He was discharged at d26. CONCLUSION: This technique combines the
      advantages of the perisplenic mesh which is efficient and safe, with the
      advantages of laparoscopic surgery which simplifies the postoperative course. It
      can only be used in case of isolated splenic injury in patients with stable
      hemodynamic condition.

PMID- 10349753
TI  - [Inhibition of peritoneal bacterial adhesion using oligosaccharides. An
      experimental model of peritonitis in rats].
AB  - BACKGROUND: Peritoneal colonization is a crucial event in the pathogenesis of
      peritonitis and its local complications. Adherence to the serosal mesothelium is
      mediated in a number of microorganisms derived from the digestive tract
      (especially E. coli) by type-1 fimbriae which have an oligosaccharide
      specificity. PURPOSE: To evaluate the effect of repeated peritoneal washes with
      saline solution and oligosaccharides on E. coli peritoneal adherence in a rat
      peritonitis model. METHODS: Sixty rats were randomized in 3 groups of 20. E. coli
      was inoculated at a constant concentration of 10(8)/mL per 100 g of weight. Then,
      peritoneal washes were achieved daily during three consecutive days (D1, D2, D3),
      with saline solution in Group I (control group), Methyl alpha-D-Mannoside (MADM)
      in Group II, and p-Nitro-phenyl alpha-D-Mannoside (pNADM) in Group III.
      Peritoneal samples were obtained before and after lavage at D1, D2, and D3.
      Microbial recovery was expressed as cfu/mg of tissue, and converted into a
      percentage of the initial value. A 10% threshold defined efficiency of the wash
      (inhibition of adherence for 90% of bacteries). RESULTS: Compared with data from
      Group I, E. coli peritoneal adherence was significantly lower after washes in
      Group III (D1: p = 0.03; D2: p = 0.009; D3: p = 0.003). Repeated washes were more
      efficient in Group III than in Group II (D1: p = 0.1; D2: p = 0.5; D3: p =
      0.001). CONCLUSION: These results suggest that the addition of oligosaccharides,
      especially of pNADM, reduces the peritoneal adherence of E. coli when a
      peritoneal wash is performed for peritonitis.

PMID- 10349754
TI  - [Conservation of the left pancreas in rupture of the pancreatic isthmus. Apropos
      of 3 cases].
AB  - AIM OF THE STUDY: To report three cases of neck pancreatic disruption caused by
      blunt abdominal trauma and to emphasize the advantages of conservative surgery
      with internal drainage. PATIENTS AND RESULTS: In two cases, one with
      hemoperitoneum, and the other with intraperitoneal fluid collection with 1,323
      U/mL of amylase, laparotomy showed a complete disruption of the neck of the
      pancreas. The pancreatic head side was sutured whereas the left side was
      anastomosed to a Roux-en-Y jejunal loop. The clinical results were good at 8 and
      6 months after surgery, respectively. For the third patient, a pancreatic trauma
      (which was suspected on a CT. Scan), was not confirmed at laparotomy. In the
      postoperative course, the amount of fluid drainage was important and the
      endoscopic retrograde pancreatography (ERCP) showed a disruption of the neck of
      the pancreas. An endoprosthesis was placed into the duct of Wirsung. Three months
      later, the patient complained of pain, and a migration of the prosthesis was
      detected by X-ray examination. It was not possible to place another
      endoprosthesis because of a stenosis of the duct. A resection of the neck of the
      pancreas was performed, the cephalic side was sutured and the left side
      anastomosed to the posterior gastric wall. Eight months after surgery, the
      clinical result was good and glycemia was normal. CONCLUSION: In blunt abdominal
      trauma, if a pancreas injury is suspected upon clinical presentation an ERCP, or
      moreover a magnetic resonance imaging, is indicated. When there is no disruption
      of the Wirsung duct, a simple peritoneal drainage should suffice. In cases with
      partial disruption, an endoprosthesis may give good results. In patients with a
      complete disruption, as in the three cases reported, a suture of the head side of
      the pancreas, and an internal drainage of the left side with a Roux-en-Y jejunal
      loop (or more easily with the stomach), are indicated.

PMID- 10349755
TI  - [Laparoscopic cholecystectomy in acute cholecystitis].
AB  - PURPOSE: To determine the feasibility, operative risk and patients' benefit of
      laparoscopy in emergency cholecystectomy for acute calculous cholecystitis.
      PATIENTS AND METHODS: From January 1991 to December 1998, 234 patients with acute
      calculous cholecystitis were operated on by emergency laparoscopic
      cholecystectomy. There were 131 women and 103 men (mean age: 57 years), (Asa 2:
      48%, Asa 3: 10%). In seven patients, choledocolithiasis was detected by
      endoscopic ultrasonography and preoperatively treated by endoscopic
      sphincterotomy. The mean delay between in-hospital admission and cholecystectomy
      was 20 hours (2-160). Cholecystectomy was performed with primary approach of
      Calot's triangle. Intraoperative cholangiography, selectively performed (n = 70),
      detected choledocolithiasis in three patients. RESULTS: The mean duration of
      surgery was 149 minutes (62-313). The conversion rate was 13% and decreased
      through the years. The postoperative complication rate was 18%. Eight patients
      (3.4%) had an abdominal complication. One patient (0.4%) died of bile peritonitis
      after intraoperative undetected main bile duct injury. The mean postoperative
      hospital stay was 6.04 days. It was 3.5 days only, very old patients and those
      with severe associated disease being excluded. CONCLUSION: Laparoscopy appears to
      be a good approach for emergency cholecystectomy in patients with acute calculous
      cholecystitis.

PMID- 10349756
TI  - [Laparoscopic treatment of small intestine obstruction].
AB  - Laparoscopic surgery for small bowel obstruction is still under evaluation. A
      review of the literature retrieved over 200 published cases. Technically, the
      open laparoscopy procedure seems mandatory to avoid bowel injuries. Grasping the
      enlarged bowel and using monopolar cautery should be avoided. The surgeon should
      also be sure that at the end of the procedure adhesiolysis was correct.
      Evaluation of the results must also take into account that most studies were
      retrospective and included few patients. The cumulative effectiveness rate of
      laparoscopy was 60%. Failures were mainly due to multiple adhesions, iatrogenic
      perforations to the intestine, and colonic cancers not recognized before the
      procedure. There was no prospective study comparing laparoscopy with laparotomy.
      Finally, it is not proved at present that laparoscopy prevents the recurrence of
      adhesions after digestive surgery. Owing to the results of the literature,
      laparoscopic surgery for acute small bowel obstruction does not appear as based
      on fact.

PMID- 10349757
TI  - [Laparoscopy with a diagnostic aim in abdominal emergencies].
AB  - In acute abdominal syndromes when a surgical exploration is required by the
      presence of peritoneal symptoms, laparoscopy allows to recognize the lesions and
      to perform simultaneously the appropriate treatment in most cases. When the
      surgical indication is doubtful, mainly in case of acute appendicitis, sonography
      or scanography may confirm the diagnosis. In case of persisting doubt, diagnostic
      laparoscopy is justified and laparoscopic appendicectomy seems to be the best
      method when another pathology is not detected by laparoscopy. In abdominal
      wounds, laparoscopy is useful to confirm their intraperitoneal penetration,
      mainly in gunshot wounds, and to recognize a diaphragmatic wound which is often
      isolated and unknown. Laparoscopy often fails to detect all abdominal injuries.
      In blunt abdominal traumas, laparoscopy is not recommended at the first step. In
      conclusion, laparoscopy with diagnostic intent only is rarely indicated in
      abdominal emergencies and its use is not worth being extended. Diagnostic value
      of laparoscopy is closely linked to its therapeutic interest. Laparoscopy with
      both diagnostic and therapeutic intent has to be developed in most abdominal
      emergencies.

PMID- 10349758
TI  - [Magnetic resonance imaging in abdominal pathology].

PMID- 10349759
TI  - [History of the National Academy of Surgery].

PMID- 10349760
TI  - Artificial grammar learning by 1-year-olds leads to specific and abstract
      knowledge.
AB  - Four experiments used the head-turn preference procedure to assess whether
      infants could extract and remember information from auditory strings produced by
      a miniature artificial grammar. In all four experiments, infants generalized to
      new structure by discriminating new grammatical strings from ungrammatical ones
      after less than 2 min exposure to the grammar. Infants acquired specific
      information about the grammar as demonstrated by the ability to discriminate new
      grammatical strings from those with illegal endpoints (Experiment 1). Infants
      also discriminated new grammatical strings from those with string-internal
      pairwise violations (Experiments 2 and 3). Infants in Experiment 4 abstracted
      beyond specific word order as demonstrated by the ability to discriminate new
      strings produced by their training grammar from strings produced by another
      grammar despite a change in vocabulary between training and test. We discuss the
      implications of these findings for the study of language acquisition.

PMID- 10349761
TI  - Infants' ability to use object kind information for object individuation.
AB  - The present studies investigate infants reliance on object kind information in
      solving the problem of object individuation. Two experiments explored whether
      adults, 10- and 12-month-old infants could use their knowledge of ducks and cars
      to individuate an ambiguous array consisting of a toy duck perched on a toy car
      into two objects. A third experiment investigated whether 10-month-old infants
      could use their knowledge of cups and shoes to individuate an array consisting of
      a cup perched on a shoe into two objects. Ten-month-old infants failed to use
      object kind information alone to resolve the ambiguity with both pairs of
      objects. In contrast, infants this age succeeded in using spatiotemporal
      information to segment the array into two objects, i.e. they succeeded if shown
      that the duck moved independently relative to the car, or the cup relative to the
      shoe. Twelve-month-old infants, as well as adults, succeeded at object
      individuation on the basis of object kind information alone. These findings shed
      light on the developmental course of object individuation and provide converging
      evidence for the Object-first Hypothesis [Xu, F., Carey, S., 1996; Xu, F.,
      1997b]. Early on, infants may represent only one concept that provides criteria
      for individuation, namely physical object; kind concepts such as duck, car, cup,
      and shoe may be acquired later in the first year of life.

PMID- 10349762
TI  - Shape constancy and theory of mind: is there a link?
AB  - In three experiments, children aged between 4 and 7 years viewed a circular disc
      oriented at a slant. The disc was made of luminous material and situated in a
      darkened chamber. Children of all ages exaggerated the circularity of the disc
      when they knew that the object was really a circle (the circle task), and the
      effect was greatest in the younger members of the sample. Crucially, however, a
      group of children in Experiment 3 who viewed an identical shape that they knew
      emanated from an actual ellipse did not exaggerate circularity. In the second
      experiment, children tackled three standard theory of mind tasks in addition to
      the circle task mentioned above. A significant correlation emerged (even with age
      partialed) between the extent of exaggeration made by those who knew that the
      shape was a circle and ability to pass the theory of mind tests. It seems
      knowledge of reality contaminates judgements of appearance in the circle task.
      This might be the same bias that features in realist errors in theory of mind
      tasks.

PMID- 10349763
TI  - Active and passive scene recognition across views.
AB  - Recent evidence suggests that scene recognition across views is impaired when an
      array of objects rotates relative to a stationary observer, but not when the
      observer moves relative to a stationary display [Simons, D.J., Wang, R.F., 1998.
      Perceiving real-world viewpoint changes. Psychological Science 9, 315-320]. The
      experiments in this report examine whether the relatively poorer performance by
      stationary observers across view changes results from a lack of perceptual
      information for the rotation or from the lack of active control of the
      perspective change, both of which are present for viewpoint changes. Three
      experiments compared performance when observers passively experienced the view
      change and when they actively caused the change. Even with visual information and
      active control over the display rotation, change detection performance was still
      worse for orientation changes than for viewpoint changes. These findings suggest
      that observers can update a viewer-centered representation of a scene when they
      move to a different viewing position, but such updating does not occur during
      display rotations even with visual and motor information for the magnitude of the
      change. This experimental approach, using arrays of real objects rather than
      computer displays of isolated individual objects, can shed light on mechanisms
      that allow accurate recognition despite changes in the observer's position and
      orientation.

PMID- 10349764
TI  - Experimental evidence for a minimalist account of English resumptive pronouns.
AB  - In this article we provide evidence for a Minimalist account of English-type
      resumptive pronouns. Our findings provide empirical support for syntactic
      theories that, like Minimalist accounts, allow for competition among derivations.
      According to our account, resumptive pronouns are spell-outs of traces. For
      reasons of economy, the resumptive pronoun surfaces only when the derivation with
      the trace is precluded by syntactic principles. This account predicts that
      resumptive pronouns should only improve violations of constraints on
      representation, and not violations of constraints on movement. We tested this
      prediction by conducting an acceptability judgment task with 36 native speakers
      of English. The results bore out our prediction; subjects preferred the
      resumptive pronoun over the trace in cases where the trace itself was illicit,
      but not in cases where only the movement operation was illicit.

PMID- 10349765
TI  - The surface form x problem size interaction in cognitive arithmetic: evidence
      against an encoding locus.
AB  - Sixty-four university students received simple addition problems with operands
      presented as arabic digits (e.g. 2 + 3, 8 + 6) or as English number words (two +
      three, eight + six). Operands either were displayed simultaneously or
      sequentially with the left operand appearing 800 ms before the right operand.
      Consistent with previous findings, word problems were slower than digit problems
      and this word-format cost was larger for large- than small-number problems. The
      central question addressed by this experiment concerned whether this Format x
      Size interaction arises during problem encoding processes or in subsequent
      retrieval or production processes. In the simultaneous condition, both operands
      would contribute to format-related differences in encoding, whereas in the
      sequential condition encoding differences would arise only in connection with the
      second operand. Critically, however, the Format x Size interaction did not differ
      between the sequential and simultaneous conditions, although the experiment had
      ample power to detect such an effect. The results argue that the Format x Size
      interaction does not arise during encoding, but instead arises during calculation
      or production processes.

PMID- 10349767
TI  - [Treatment of sexually transmitted diseases and pelvic infections in gynecology].

PMID- 10349766
TI  - [Evaluation of follicular reserve].

PMID- 10349768
TI  - [Management of a low grade smear].

PMID- 10349769
TI  - [Should amniocentesis disappear?].

PMID- 10349770
TI  - [Amniocentesis at 12 or 15 weeks?].

PMID- 10349771
TI  - [Ocular complications of hormonal treatments: oral contraception and menopausal
      hormonal replacement therapy].
AB  - Numerous reports have described ocular complications of sex hormone preparations,
      particularly after the appearance of the oral contraceptive pill. The most
      serious complications are vascular occlusions such as central retinal vein or
      artery occlusion and acute ischemic optic neuropathy. In these cases, permanent
      visual loss may occur. Combined oral contraceptives have been reported to
      increase the incidence of these complications but it remains very low. It seems
      to lessen with the decrease in the estrogen dosage and the use of third
      generation progestins. Conversely, post-menopausal hormone replacement therapy
      seems to have a protective effect for retinal vascular complications. Other
      ocular involvements have been described with sex hormone preparations but remain
      not yet confirmed, such as the effect on cataract, lacrymal secretion, diabetic
      retinopathy, age-related macular degeneration.

PMID- 10349772
TI  - [Hysterectomies for benign pathology: is there a place for laparoscopic
      surgery?].
AB  - STUDY OBJECTIVE: To investigate the alternative routes for hysterectomy for
      benign disease and the appropriate role of laparoscopic surgery. DESIGN:
      Retrospective study of hysterectomies performed between August 1991 and July
      1997. SETTING: University hospital. PATIENTS: Hysterectomy for benign disease
      without prolapse, pelvic floor relaxation. INTERVENTION: 359 hysterectomies:
      vaginal (n = 211), laparoscopically-assisted vaginal (n = 56), and abdominal (n =
      92). MEASUREMENTS AND MAIN RESULTS: Uterine volume was the principal indication
      for laparotomy. Laparoscopy was required only in cases of adnexal disorders or
      when the vaginal access was limited or associated with extensive adhesions. The
      rate of laparotomies and laparoscopies dropped steadily over the six-year study
      period: during the last two years, 75% of all hysterectomies were vaginal, and
      90% of those for patients without a previous vaginal birth. CONCLUSION: With
      experienced surgeons, the number of cases in which there appears to be poor
      vaginal accessibility experience decreases, and indications for vaginal
      hysterectomies increase.

PMID- 10349773
TI  - [Therapeutic problems posed by sub-clinical breast cancers].
AB  - Screening has led to the earlier detection of non palpable ductal or lobular
      carcinoma in situ microinvasive carcinoma and invasive breast cancer 1 cm or less
      in size (minimal breast cancer). Formerly, most of these cancers were cured by
      mastectomy but the dramatic change in frequency has prompted interest in the role
      of conservation treatment. Minimal breast cancer is a heterogeneous group of
      lesions, no single approach will be appropriate for all form of these diseases
      and methods must be developed to determine the most appropriate treatment for
      each patient.

PMID- 10349774
TI  - [For or against peridural analgesia?: a psychological approach based on the
      parturient's needs].
AB  - The present study investigates why some women, before and during delivering,
      request peridural analgesia or, on the contrary, refuse it. On the basis of a
      literature review and of an empiricial study involving 57 women, a psychological
      differentiation is attempted to discriminate users from non-users of peridural
      analgesia. Pain perceptions, health locus of control, when internal (IHLC),
      family and couple adaptability appear to be discriminating factors. Our results
      indicate a higher chance locus of control (externality) in non-users then in
      users, as well as a more rigid couple functioning. The incidence of Internal
      Health Locus of Control of pain perception is outlined.

PMID- 10349775
TI  - [Sexual practices in the school milieu].
AB  - OBJECTIVE: To appreciate the real sexual practice among students. POPULATION AND
      METHODS: From 29th April to 10th May 1997, 1,867 students from lower and upper
      schools have accepted to take part in the investigation being carried on their
      practice of sexuality. RESULTS: 1,333 students, that is 72% of the group, have
      already had sexual intercourse. The average age of the very first sexual
      intercourse was 17 years and the extreme ages range from 8 to 24 years. 72.7% of
      the students have already had sexual intercourse less once a month, mostly it is
      by love in 68.6% or by desire in 21.1%. Among more than half of the girl
      students, that is 59.5%, their partners was students. 31.3% were at least once
      pregnant. CONCLUSION: The outcome of this study revealed that sexual activity
      among students is rare and sporadic. It is motivated by love.

PMID- 10349776
TI  - [Galenic, concerted choice and compliance in hormonal replacement therapy].
AB  - A survey was conducted in May-June 1998 among 394 French menopausal women in
      order to better understand opinions, attitudes and habits of HRT users. Matters
      such as information, importance of a concerted choice between doctor and patient
      and treatment improvement were also mentioned for a better compliance.

PMID- 10349777
TI  - [Assisted reproduction. Rules and laws. International comparisons].

PMID- 10349778
TI  - [A micro-epidemic of tuberculosis in the South Moravia Region].
AB  - In the South Moravian region which is the area with the lowest prevalence of
      bacillary tuberculosis in the Czech Republic (6.6 per 100,000 population in 1996)
      in 1993-1996 a total of six local and family microepidemics of tuberculosis were
      detected. For their identification the RFLP fingerprinting method was used based
      on evidence of repeated sequence of IS6110 in the chromosomal DNA of the examined
      strains of Mycobacterium tuberculosis predigested with restrictive enzyme PvuII.
      The profiles of fingerprints of each microepidemic were included by means of a
      computer programme into the hierarchy of the fingerprint dendrogram of 184
      strains of M. tuberculosis which made it possible to identify possible identical
      profiles of strains from patients from remote places in the Czech Republic. In
      three family microepidemics involving always two members no identical fingerprint
      profiles of other Czech strains of M. tuberculosis were revealed. To the fourth
      cluster formed by six members of one family an identical RFLP profile of a female
      patient living in a nearby locality was added. In another microepidemic recorded
      in three brothers identical fingerprints were found another four patients from
      the South Moravian region and in one from the Central Bohemian region. The last
      cluster of two brothers was surprisingly enlarged by six identical RFLP profiles
      of patients from the West Bohemian region and one from Prague. These findings
      suggest that in areas with a low prevalence tuberculosis persists more frequently
      than in areas with a high prevalence as familial or local microepidemics.

PMID- 10349780
TI  - [An unusual isolation of Neisseria meningitidis].
AB  - The authors describe a unique case of isolation of Neisseria meningitidis
      C:2a:P1.2,P1.5 in August 1997 from a 7-year-old female patient from a vaginal
      smear during purulent inflammation of the external genital following injury. This
      is the first described case of isolation of N. meningitidis from this site
      described in our country. The authors draw attention to the necessity to consider
      uncommon occurrences of N. meningitidis, and to examine atypical materials also
      under the microscope and to identify by biochemical methods all isolated
      Neisseriae incl. gonococci.

PMID- 10349779
TI  - [Evaluation of time trends in the weekly count of diseases].
AB  - In routine systems investigating the morbidity according to diagnosis it is very
      useful to analyse the development in time (for example the development of weekly
      reports). This paper is concerned with the methodology of such analyses. In
      practice it appears that the number of cases depends on season. It stands to
      reason, that it is necessary to consider also long-term trends. In this paper two
      different approaches are discussed--the Box-Jenkins analysis, which describes the
      random error and the Method of Trend Decomposition which spread the number of
      cases into the systematic component (long term trend and seasonal effect) and
      random variability. The authors describe the method of smoothing the estimate of
      the time series by kernel estimate. In both approaches they use weekly reports
      from the whole Czech Republic of diagnoses viral hepatitis A, rubella and
      salmonellosis.

PMID- 10349781
TI  - [Determination of chlorine levels in Presept, a modern disinfectant].
AB  - Presept (containing sodium dichloroisocyanurate as active component) was shown to
      be an excellent analytical reagent superior to classical Chloramine T and
      Chloramine B. Potentiometric titration of potassium ferrocyanide was found to be
      most suitable for estimation of chlorine content in Presept solutions. The
      presence of serum albumin can block or reverse the oxidation of ferrocyanide
      completely, whereas that of a detergent is of little importance. The content of
      available chlorine in various Presept tablets was found to be as a rule slightly
      higher than that guaranteed by the dilution rules of Johnson & Johnson. Presept
      solutions are remarkably stable, paradoxically the concentration of available
      chlorine in open vessels remains higher than in perfectly closed vessels.

PMID- 10349782
TI  - [Sensitivity to blood bactericidal activity and hydrophobicity of Acinetobacter
      baumannii after treatment with imipenem].
AB  - Sensitivity to the serum bactericidal activity and surface hydrophobicity of
      Acinetobacter baumannii strains isolated from the urinary (UT) or respiratory
      tract (RT) of patients after exposure to imipenem at subinhibitory concentrations
      (sub-MICs) (1/4, 1/8 or 1/16 of their MICs) were tested. The antibiotic at the
      mentioned concentrations decreased significantly the sensitivity of strain UT to
      the bactericidal activity of human serum. Sensitivity to the bactericidal
      activity of serum of strain RT was affected only very ineffectively. Imipenem at
      1/4 of their MICs reduced the cell surface hydrophobicity to 76.1% (strain UT)
      and to 81.9% (strain RT) compared with control values (without imipenem). Lower
      concentrations of antibiotic influenced cell surface hydrophobicity only to a
      smaller extent. Possible decrease in sensitivity of bacteria to the bactericidal
      activity of serum after treatment with imipenem in "in vivo" experiments would
      manifest an increase in virulence of these strains.

PMID- 10349783
TI  - [Determination of tobacco mosaic viruses and tar carcinogens using
      electromagnetic resonance in smokers].
AB  - Distance monitoring of viral diseases in the zone of MHz frequencies makes rapid
      non-contact investigation of the presence of tobacco mosaic viruses (VTM) in
      cigarettes and secretions of smokers possible by using electromagnetic resonance.
      The incidence of VTM in common cigarettes was assessed as well as in several
      smokers, in dermatitis, arthralgias and in tumours (of the large intestiner, in
      mastopathy). Also in neuritis of the optic nerve, in suspected sclerosis
      multiplex of smokers. After sanation of VTM by resonance therapy with Sanator
      (Bradna AO 272,361) VTM disappeared as well as symptoms of this viral mosaic
      disease. Electromagnetic resonance with tar made it possible to make this
      investigation in cigarettes filters after smoking as well as in the secretions of
      smokers. The authors proved the hastening effect of cigarette smoke with tar on
      the growth of VTM on cultivation as well as an increase of the bioelectric
      activity of tumours. It proved possible to abolish the electromagnetic distance
      action of tar by interaction with pyridsoxine similarly as in foods containing
      tar (smoked meat, fish, frankfurters, black coffee, cocoa). Filters with
      pyridoxine proved useful. VTM monitoring was quick, in tumours it was possible to
      follow the accompanying viral agent as well as the action of cancerogens on their
      bioelectromagnetic activity. It also made it possible to follow up disintegrating
      action of MHz resonance frequencies of the Sanator.

PMID- 10349784
TI  - [The treatment of anal fissure with botulinum toxin].
AB  - BACKGROUND: The use of botulinic toxin has led to new perspectives in the
      treatment of anal fissures. However, the most effective dose, length of treatment
      and long term results require further studies to determine the most appropriate
      place for this therapy. PATIENTS AND METHODS: A prospective study was carried out
      in 40 consecutive patients diagnosed with anal fissure of more than 3 months in
      duration. Fifteen U of botulinic toxin were injected in the external anal
      sphincter and the evolution was studied over 6 months. The patients completed a
      pain scale designed for the study after 1 week, and 1, 3 and 6 months after the
      injection. The degree of pain, healing and need for surgery were evaluated during
      the follow up. RESULTS: Healing occurred in 17 patients after 3 months (42.5%)
      and after 6 months in 3 more patients (50%). Eight patients required surgery
      during follow up (20%). In the remaining patients, the pain significantly
      decreased allowing conservative management. Only 2 patients demonstrated
      incontinence for slight, transitory gases (5%). CONCLUSIONS: Injection of
      botulinic toxin is well tolerated and is relatively effective as an alternative
      in the treatment of anal fissure. Most patients respond in the first days after
      treatment and the effect persists for at least 6 months. The use of doses higher
      than those used in this study merits further studies.

PMID- 10349786
TI  - [A relative bioavailability study of 2 oral formulations of omeprazole after
      their administration in repeated doses to healthy volunteers].
AB  - To determine the relative bioavailability of Ulceral (study formula) with respect
      to Losec (reference standard formula) and establish their bioequivalence daily
      doses of 20 mg of omeprazole were given during 5 consecutive days to 24 healthy
      volunteers. No significant differences were observed in the area under the curve
      (AUC0-t), a parameter directly related to the inhibition of acid secretion
      induced by omeprazole. The confidence interval of 90% for the difference between
      the two formulations for AUC0-t was within the interval of acceptance (0.80
      1.25). The confidence interval for the difference between the two formulations
      for Cmax were also within the range of acceptance (0.70-1.43). In relation to the
      time for achieving (Cmax (tmax), the difference between the two formulations and
      the confidence interval of 95% for the tmax was 0.75 (-0.5-1.75) h indicating
      that no significant differences were observed between the two treatments. This
      study confirms the bioequivalence of Ulceral with the standard reference
      formulation as well as the tolerability of the two formulae.

PMID- 10349785
TI  - [The endoscopic placement of self-expanding metal prostheses as palliative
      treatment in colorectal stenosis of tumor origin].
AB  - BACKGROUND: The aim of this study was to retrospectively analyze the endoscopic
      placement of autoexpandible metallic prostheses of the colon carried out in our
      department as palliative treatment in patients with colorectal stenosis of
      tumoral origin. PATIENTS AND METHODS: From may, 1995 to august, 1998,
      autoexpandible metallic prostheses were placed in 14 patients (11 males and 3
      females, mean age 64.5 years, range 41-92). All the patients presented tumoral
      stenosis by adenocarcinoma, 5 of which had been previously treated by surgery.
      RESULTS: All the stenoses were found in the rectum/sigma at less than 35 cm from
      the anal margin. In 7 patients endoscopic dilatation was performed prior to
      placement of the autoexpandible metallic prostheses. The prostheses used had a
      diameter of 18 mm and were of variable length. The placement of the prostheses
      was successfully achieved in all the patients except 2 (one due to technical
      difficulties and in the other because of early migration of the same, in both the
      autoexpandible metallic prostheses was placed without complications within 24 h).
      In two cases early complications were observed (14%): one case due to perforation
      and one to early migration. In two patients stenosis of the prostheses was
      observed during follow up and in a third patient late migration occurred.
      CONCLUSIONS: Endoscopic placement of autoexpandible metallic prostheses in
      patients with colorectal stenosis of tumoral origin is a simple technique with
      few complications and may be used as a definitive palliative treatment in these
      patients.

PMID- 10349787
TI  - [Non-immunoallergic hepatotoxicity due to mesalazine].
AB  - Mesalazine is an aminosalicillic derivative considered as a safe alternative to
      the relative frequency (5-55%) of adverse effects observed with sulfasalazine.
      The well known hepatoxicity associated with sulfasalazine and attributed to its
      sulfamidic fraction is limited to few cases described in the treatment with
      mesalazine. We herein present a new case of hepatoxicity by mesalazine in a
      patient with lymphocytic colitis. The possible pathogenic mechanism is also
      commented upon.

PMID- 10349788
TI  - [Acute hepatitis E in Spain].
AB  - Hepatitis E virus (HEV) is the worldwide leading cause of non-A non-B enterically
      transmitted hepatitis, and affects most commonly the population in developing
      countries. Cases outside this area, are nearly always imported, although apparent
      local acquisition has been occasionally reported. We assisted three patients with
      acute HEV hepatitis, confirmed by the presence of serum anti-HEV IgM. One of them
      did not report travelling outside of Spain in the previous years. HEV has to be
      included in the differential diagnosis of acute non-A non-B non-C hepatitis, even
      in cases in which an exposure in endemic areas cannot be recalled.

PMID- 10349789
TI  - [Sinusoidal portal hypertension secondary to nodular regenerative hyperplasia of
      the liver].
AB  - Regenerative hepatic nodular hyperplasia is infrequent and generally appears in
      association with many other diseases, the most frequent being the Felty syndrome.
      It may cause portal hypertension and variceal bleeding. A histologic study is
      necessary for diagnosis since certain biologic data and the nodular appearance of
      the hepatic surface may be confused with hepatic cirrhosis from which it may
      basically be, apart from the histologic features, distinguished by its good
      prognosis due to the absence of liver failure. We present the case of a
      seropositive patient with regenerative hepatic nodular hyperplasia and rheumatoid
      arthritis with marked portal hypertension shown in the hemodynamic study
      performed by our department for presentation of a persistent elevation in
      transaminases and ultrasonography alterations suggesting hepatic cirrhosis.

PMID- 10349790
TI  - [Acute azathioprine-induced pancreatitis in a female patient with Crohn's
      disease].
AB  - A case of acute pancreatitis induced by azathioprine presented in a 22-year-old
      patient with Crohn's disease is reported. The patient erroneously took the drug
      once again repeating the appearance of acute pancreatitis, earlier and with
      greater severity.

PMID- 10349792
TI  - [Definitions and diagnostic criteria of digestive hemorrhage and its causes in
      cirrhosis].

PMID- 10349791
TI  - [Trefoil peptides, cellular repair and progression].

PMID- 10349793
TI  - [The indications for laparoscopic surgery in the palliative treatment of
      digestive cancer].

PMID- 10349794
TI  - [Immunosuppressors and inflammatory bowel disease].

PMID- 10349795
TI  - [An actinomycotic inflammatory pseudotumor of the transverse colon].

PMID- 10349796
TI  - [A vertiginous syndrome due to sulfasalazine].

PMID- 10349797
TI  - [Spontaneous bacterial peritonitis and sepsis due to Aeromonas hydrophila].

PMID- 10349798
TI  - [Ischemic necrosis of the spleen and gastric fundus. A rare complication of acute
      pancreatitis].

PMID- 10349799
TI  - [Iron-deficiency anemia in celiac disease].

PMID- 10349800
TI  - Leptin regulation of aromatase activity in adipose stromal cells from regularly
      cycling women.
AB  - OBJECTIVES AND DESIGN: Leptin, a product of adipocytes, is a cytokine with
      multiple effects on the reproductive axis. Leptin causes the activation of STAT
      proteins within target cells. The aromatase gene promoter in adipose stromal
      cells contains a functional STAT binding region, leading to the hypothesis that
      leptin may regulate aromatase activity in fat tissue. To test this hypothesis,
      adipose stromal cells were isolated from subcutaneous abdominal fat or breast fat
      then placed into tissue culture. MATERIALS AND METHODS: The cells were treated
      for three days with increasing concentrations of recombinant human leptin.
      Aromatase activity in the stromal cells was measured by the release of 3H2O from
      radiolabeled androstenedione precursor. RESULTS: Basal aromatase activity varied
      markedly between, but there were no differences between abdominal fat and breast
      fat. Leptin concentrations in the physiological range of normal weight or thin
      women (10 ng/ml) had no effect on aromatase activity. In 2 of 8 abdominal fat
      cultures and 1 of 2 breast fat cultures, a high obese concentration of leptin
      (100 ng/ml) stimulated a significant increase in aromatase activity. In the
      remaining subjects there was no effect of leptin, even at high concentrations.
      CONCLUSIONS: These data demonstrate that in approximately 30 percent of our
      subject population leptin was able to stimulate aromatase activity in adipose
      stromal cells at high concentrations. The elevated levels of aromatase activity
      may contribute to increase circulating estrogen levels in certain obese women and
      suggest that elevated leptin concentrations in obese women may cause locally
      elevated estrogen concentrations in the breast and thereby promote tumor
      formation.

PMID- 10349801
TI  - [The comparison of efficiency of supplement of the second phase in the program
      IVF-ET by dydrogesterone and progesterone].
AB  - The retrospective study was carried out to compare effectiveness of progesteron
      and dydrogesteron luetal phase support following in vitro fertilisation and
      embryo transfer. Two hundred and fifty eight patients undergoing IVF ET received
      progesteron in itramuscular injections. Two hundred sixty patients received
      dydrogesteron three times daily p.o. There were no differences in stimulation
      protocols, indications for IVF and IVF procedures. Pregnancy rate, implantation
      rate and spontaneous abortion rate were similar in both groups. The effectiveness
      of luteal phase support in patients undergoing IVF ET program by dydrogesteron
      and progesteron is similar with significantly lower costs for the last one.

PMID- 10349802
TI  - [Monozygotic pregnancy after the treatment for infertility by transfer of frozen
      thawed embryos].
AB  - OBJECTIVES: It has been suggested that monozygotic pregnancies occur more
      frequently after in vitro fertilisation. This phenomenon is attributed to a
      number of factors including in vitro culture conditions, malformation of the zona
      pellucida due to manipulation on the oocytes and artificial opening of the zona
      pellucida. DESIGN: Retrospective analysis of monozygotic pregnancies in an IVF-ET
      procedures and obstetrical these pregnancies outcome. MATERIALS AND METHODS: A
      total of 2254 IVF-ET procedures were analysed. Three protocols were used for
      ovarian stimulation: short or long protocols with gonadotropins releasing hormone
      analogue or clomiphene citrate with hMG. In 811 cases male factor was diagnosed
      and intracitoplasmatic sperm injections were performed. RESULTS: 549 clinical
      pregnancies were achieved in analysed group. In six cases ultrasound examination
      5 weeks after embryo transfer showed a greater number of foetus than the number
      of embryo transferred. In three of those cases the embryos were obtained after
      ICSI. Age and average thickness of zona pellucida were similar in group of
      patients with monozygotic pregnancies when compared with all pregnant patients
      after IVF treatment. CONCLUSIONS: The incidence of monozygotic pregnancy is
      increased in group pregnancies resulting from IVF ET. No single risk factor can
      explain this phenomena. This type of pregnancy needs special obstetrical
      attention.

PMID- 10349803
TI  - [Changes in morphological picture of the semen in the group of men from infertile
      couples in the Lower Silesia in 1977-1993].
AB  - OBJECTIVES: To reveal the trends of the particular semen parameters changes
      during the 17 years period. DESIGN: Semen analysis results were retrospectively
      evaluated. MATERIALS AND METHODS: We have analysed semiograms from 618 men from
      infertile couples in 1977-1993. Regression analysis of the results from years of
      observation was performed. RESULTS AND CONCLUSIONS: We showed the statistically
      important increase in the percentage of pathological sperms (R2 = 0.89, p <
      0.0001), the slight increase in the semen volume (R2 = 0.30, p < 0.02). The total
      sperm count in the semen samples revealed a slight increase (R2 = 0.33, p <
      0.02). The sperm concentrations and the percentage of the motile sperms remained
      relatively stable and relatively constant.

PMID- 10349804
TI  - [Sperm morphology and xenogenic human sperm-hamster oocyte penetration assay in
      vitro].
AB  - The aim of this study was to evaluate sperm morphology (teratozoospermia) and its
      effect on xenogenic human sperm-hamster oocyte penetration assay (HOPA). Sperm
      morphology assessment was performed in 140 infertile patients and 25 healthy
      individuals. According to Kruger's strict criteria teratozoospermia was diagnosed
      in 38 individuals out of 140 infertile males. HOPA assay was performed for 20
      teratozoospermic patients and 10 healthy volunteers. No significant decrease in
      HOPA values was observed in cases of isolated teratozoospermia. The sperm anomaly
      severely influencing HOPA values was asthenozoospermia. We believe that
      evaluation of sperm morphology according to the strict criteria of Kruger should
      be applied for routine andrological practice which reflects rapidly changing
      'normal' values of human semen.

PMID- 10349805
TI  - [Prolonged ovarian pregnancy: a case report].
AB  - OBJECTIVES: Case of advanced ovarian pregnancy are exceptional because ovarian
      pregnancy itself is very rare. STUDY DESIGN: The authors describe a case of
      prolonged ovarian pregnancy with retention of the dead fetus for more than a
      year. Usually ovarian pregnancy finishes in rupture which occurs before the end
      of the first trimester. It is then difficult to make out the integrity of the
      organs and in particular of the tube and indeed to recognize them. On the other
      hand when the mass persists intact with the development of pregnancy in a retort
      shape, it is easy to see how confusion is possible and arises between it and an
      intra-uterine pregnancy. In this case, however, the different anatomical forms
      are clear and an almost definite diagnosis can be made at the time of operation
      (the three first criteria of Spiegelberg). The diagnosis of ovarian pregnancy is
      never made before operation. At the very best one can say, when things happen
      early, that an extra-uterine pregnancy has ruptured, or in certain particular
      circumstances like in the case we are reporting lithopedian. The presence of
      ovarian tissue in the wall of the sac, which is the fourth criterion of
      Siegelberg, is easier to recognize in early accidents than in advanced cases of
      ovarian pregnancy in which the parenchyma of the ovary is compressed, distended
      and laminated by the increasing development of the fetus and the adnexae. The
      absence of the placenta being adherent to other organs than the ovary can then be
      kept as a worthwhile criterion of ovarian pregnancy.

PMID- 10349806
TI  - [Neurofibroma plexiforme of the small pelvis: a case report].
AB  - There are reports of rare cases of nerve tissue tumors of the small bowel, ovary,
      urinary bladder or retroperitoneal space. We report a case of neurofibroma
      plexiforme of pelvis minoris in 42-year-old woman. The first diagnosis was
      adnexal tumor. Laparotomy was performed and a big, solid tumor of left
      parametrium was found. The histology of the tumor was described as neurofibroma
      plexiforme. There was also an inflammatory tumor of appendix involving right
      Fallopian tube. The described by other authors cases suggest, that diagnosis of
      nerve tissue tumors in pelvis minoris is very difficult. Surgery is an adequate
      way of final diagnosis and management.

PMID- 10349807
TI  - [Individualization of surgical treatment for female pelvic floor disorders].
AB  - The side effects of female pelvic floor disorders surgical treatment (as the
      disease per se) may worsen the quality of life. The aim of this paper is to
      indicate how these side effects may be reduced. The author concludes that this
      goal may be achieved by: 1. thorough anamnesis and physical examination, 2.
      precise diagnosis of affected compartments, 3. individualized surgery (original
      list of surgical methods and their possible side effects on reproduction, sexual
      and physical activity is presented), 4. adequate patient's information including
      possible side effects and limitation of the treatment.

PMID- 10349808
TI  - [The evaluation of lipid peroxidation products and antioxidative enzymes activity
      in cord blood and placental homogenates of pregnant diabetic women].
AB  - The aim of our study was to estimate the concentration of lipid peroxidation
      products and antioxidant system activity in cord blood and placental homogenates
      of 13 pregnant women with type I diabetes, 15 patients with gestational diabetes
      and 16 healthy pregnant women. Malondialdehyde (MDA) concentration, glutathione
      (GSH) content and the activity of CuZn superoxide dismutase (SOD) (Bioxytech,
      Oxis International S. A.) were measured. MDA and GSH levels increased
      significantly, whereas SOD activity was markedly diminished in diabetics,
      especially in these with type I, in comparison with the control group. Our
      results support the hypothesis that diabetic pregnant women and their
      fetuses/neonates are exposed to an increased oxidative stress. Moreover, we
      suggest that the measurement of oxidative stress level may be useful in clinical
      practice to assess fetus/neonate state and the risk of possible complications.

PMID- 10349809
TI  - [Epidemiological analysis of congenital infections in newborns].
AB  - The aim of this study was to review 2567 deliveries in the District Hospital in
      Bialystok in 1997. In 2388 term labours and 179 preterm ones we noticed the
      congenital infections; in 90 (3.8%) and in 58 (32.4%) newborns respectively. The
      main etiologic factors of infections were Escherichia coli and Staphylococcus
      epidermidis in term newborns and Staphylococcus epidermidis and Escherichia coli
      in preterm babies. Clinical signs of the urinary tract infection were most
      frequent in mature infants, whereas the sepsis was quite common in premature
      newborns.

PMID- 10349810
TI  - [Clinical analysis of patients operated with squamous cell carcinoma of the
      uterine cervix].
AB  - OBJECTIVES: The aim of our study was clinical analysis of patients operated with
      squamous cell carcinoma of the uterine cervix. MATERIALS AND METHODS: Between
      1972 and 1991 at the 2nd Department of Obstetrics and Gynecology Medical
      University of Gdansk 687 total hysterectomies in Wertheim-Meigs method were
      performed in the patients with, various clinical stages cervical carcinoma. The
      clinical analysis has been done in 499 patients with diagnosed invasive cervical
      cancer stages Ia2, Ib and IIa. The clinical progression of cancer was established
      on the basis of FIGO classification from the year 1985. In the 18 patients
      invasive cervical cancer occurred together with a pregnancy (cervical cancer was
      diagnosed in the I, II and III trimester). In this group squamous carcinoma was
      diagnosed in 16 cases (88.8%). Endocervical type was diagnosed in 8 cases (1.6%),
      among which 4 cases were of a squamous type (0.8%). Two 10-year-periods of time
      have been separated: since 01.01.1972 to 31.12.1981 and since 01.01.1982 to
      31.12.1991. RESULTS AND CONCLUSIONS: In the studied 20-year period (1972-1991) in
      all 499 performed operations squamous carcinoma was the most often occurring
      histological type of cervical cancer--439 cases (88.0). Comparing the incidence
      of squamous carcinoma in both 10-year periods of time there were no significant
      differences (only almost a 3-fold decrease of the incidence of microcellular
      cancer in the second decade was observed). It was stated that a percentage share
      of squamous carcinoma in the clinical stages Ib and IIa did not change. The
      number of pregnancies and labours in the patients with squamous carcinoma was
      close to the patients with other histological types of cervical cancer. The mean
      age of patients with squamous carcinoma was 45.6 (22-74) and was lower than the
      age of patients with adenocarcinoma--49.1 years (22-73). The clinical symptoms of
      a cancer occurred in 81.4% of the studied group. Asymptomatic course was seen in
      18.6% of patients. The incidence of positive lymph nodes in the patients with
      squamous carcinoma stages Ib-IIa was close to the patients with carcinoma
      adenosquamous (25.0% and 23.7% respectively) and lower than in the case of
      adenocarcinoma (34%) or anaplastic carcinoma (33.3%, because of a small number of
      patients in this group the figures are not reliable). In the patients with
      squamous carcinoma the highest 5-year survival (almost 80.4%) was stated.

PMID- 10349811
TI  - [Clinical analysis of patients operated for adenocarcinoma and adenosquamous
      carcinoma of uterine cervix].
AB  - OBJECTIVES: The aim of our study was clinical analysis of patients with operated
      adenocarcinoma and adenosquamous carcinoma of uterine cervix. STUDY DESIGN: The
      mean age, number of pregnancies and labours, the incidence of adenocarcinoma and
      carcinoma adenosquamous in the stage Ib and IIa, and also in 2 following decades
      (1972-81 and 1982-91), the influence of positive lymph nodes on the survival have
      been estimated. MATERIALS AND METHODS: Between 1972 and 1991 at the 2nd
      Department of Obstetrics and Gynecology, Medical University of Gdansk, 499
      radical hysterectomies were performed in the patients with cervical cancer stage
      Ia, Ib and IIa. In this group there were 41 (8.2%) patients selected with
      adenocarcinoma and 16 (3.2%) with carcinoma adenosquamous. In the group of 18
      pregnant women (3.6% of the whole group) there was diagnosed 1 case of
      adenocarcinoma and 1 case of carcinoma adenosquamous. The incidence of both
      adenocarcinoma and carcinoma adenosquamous amounted to 11.4%. RESULTS: The number
      of pregnancies and labours was similar to other histological types. Nulliparas
      made up respectively 10.5% adenocarcinoma and 6.25% carcinoma adenosquamous. The
      incidence of adenocarcinoma stage Ib has been found to be more than twice higher
      than the incidence of adenocarcinoma stage IIa (9.0% and 3.8% respectively). The
      percentage of carcinoma adenosquamous in those two clinical stages was similar.
      The three times decrease in the incidence of adenocarcinoma, and the four times
      increase in the incidence of carcinoma adenosquamous has been found in the years
      1982-91 in comparison to 1972-81. It was also stated that an adenouse type,
      comparing to other histological types, most often occurs without any clinical
      symptoms--in 23.1% a course of the disease was asymptomatic. As for an
      adenosqamous type the figures were lower--12.5%. In the patients with
      adenocarcinoma the incidence of positive pelvic nodes in the stage Ib-IIa was
      34%. The incidence of positive lymph nodes in the patients with carcinoma
      adenosqamous and adenocarcinoma was lower and similar--25% and 23.7%
      respectively. The analysis of the 5-year survival showed 69.8% in patients with
      adenocarcinoma stage Ib-IIa and 66.3% in patients with carcinoma adenosquamous
      the (same stages). The difference is not statistically significant (p = 0.8).

PMID- 10349812
TI  - [Initial estimation effect of body mass on survival of patients with endometrial
      carcinoma].
AB  - OBJECTIVES: It has long been known that the risk of some cancers, including
      endometrial, are associated with obesity. A question that remains is whether over
      weight is associated with significant difference in survival rate between
      patients with different body mass index (BMI). STUDY DESIGN: During the period
      1984-1996 121 patients with endometrial carcinoma have been evaluated
      retrospectively in the Department of Gynecology & Obstetrics in Hospital of
      Slupsk. RESULTS: The middle age of women with endometrial carcinoma was 60.2
      years, the youngest has been 38 years old and the oldest--86 years. In the city
      lived 74.4% women and in the village 25.6%. The percentage of nulliparas was
      11.6%, in women group with 1-2 parity 42.1% and when they had more than 2 parity
      46.3%. The middle age of nulliparas was lower than multiparas (59.4 vs 63.6
      years). In our material endomeriosis was found in association with endometrial
      carcinoma in 12 (9.9%) of 121 cases. In two cases of endometriosis carcinoma
      developed. Of 121 patients with endometrial carcinoma 22.3% had over-weight; 9.9%
      hypertension; 0.8% diabetes mellitus, 28.1% over-weight and hypertension, 2.5%
      over-weight and diabetes mellitus, 0.8% hypertension and diabetes mellitus, 7.4%
      over-weight with hypertension and diabetes mellitus. 28.1% patients hadn't these
      diseases. There was statistically significant difference in survival rate between
      patients with BMI (p = 0.02). On the whole, five-year-survival was observed in
      73.0% of women. Five-year-survival patients with BMI (25-29) was 86.8%; with BMI
      (30-34) was 74.1%; with BMI (> 34) was 67.4%. The patients with BMI (20-24) five
      year-survival was lowest 67.4% and the same as in patients with highest obesity
      [BMI (> 34)]. CONCLUSIONS: Endometrial carcinoma patients with BMI (25-29), were
      found to have better survival rate than patients with other BMI. There wasn't
      effect of hypertension and diabetes mellitus on of survival rate of patients with
      endometrial carcinoma (p = 0.25 and p = 0.26). The study was limited by the
      confinent and bias of a retrospective analysis, but this finding was
      statistically significant (p = 0.02).

PMID- 10349813
TI  - [Clinical usefulness of color doppler flow examination during treatment of
      gestational trophoblastic disease].
AB  - Neovascularisation is the integral part of tumor development. Presence and type
      of pathological vascularisation can be used in therapy monitoring and follow up.
      The value of beta HCG and pulsatility index (PI) and resistance index (RI) in 14
      women treated for nonmetastatic persistent trophoblastic disease (NMTD) were been
      compared. There was statistical, significant correlation between dropped BHCG
      level and increased value of RI. No correlation between BHCG blood concentration
      and values of PI was observed. In summary it should be stated that color Doppler
      ultrasonography is useful method in monitoring patients with NMTD.

PMID- 10349815
TI  - [Early primary abdominal pregnancy treated by laparoscopy].
AB  - Our study describes abdominal pregnancy in 28-years old woman. Patient was
      admitted to Gynecological Surgery Department of Polish Mother's Memorial Hospital
      in Lodz with lasting for a few hours strong abdominal pain. We carried out
      detailed diagnostics, that showed the main importance of beta-human chronic
      gonadotropin level monitoring and helpful role of the ultrasonography study in
      abdominal pregnancy diagnosis. This woman was treated by laparoscopy that surely
      confirmed the diagnosis and allowed for total cure.

PMID- 10349814
TI  - [Factor V leiden and venous thromboembolism in a woman taking second generation
      oral contraceptives: a case report].
AB  - The most common cause of thrombophilia is a point mutation in factor V gene
      (G1691A), leading to factor V Leiden synthesis, which is resistant to the
      inhibition by activated protein C. Administration of oral contraceptives is
      associated with an increased risk of venous thromboembolism in carriers of factor
      V Leiden mutation. We describe here a case of 44-year-old woman who developed
      right popliteal and superficial deep vein thrombosis after a 2-month use of a
      contraceptive which consists of 0.15 mg levonorgestrel and 0.03 mg
      ethynylestradiol. The mutation G1691A of factor V gene was detected with the
      polymerase chain reaction. No other inherited or acquired risk factors for
      thrombosis was found in this patient. Treatment with low molecular weight heparin
      and subsequently, oral anticoagulation was effective. Women with factor V Leiden
      should be discouraged from taking oral contraceptives. Screening for factor V
      Leiden in these women appears to be useful and contribute to the prevention of
      thrombosis in risk situations.

PMID- 10349816
TI  - [Coexistence of ovarian epithelial tumor of borderline malignancy with pregnancy:
      a case report].
AB  - OBJECTIVES: Ovarian tumors during pregnancy are a rare event. In most cases the
      tumors are detected accidentally during routine examination, ultrasound or a
      caesarean section at term. Histologic subtypes and prognosis do not differ from
      tumors not associated with pregnancy, it seems however, that there are more
      lesions of borderline malignancy and of low grade. STUDY DESIGN: The patient age
      26 during 16 week of pregnancy was operated in Department of Gynecology &
      Obstetrics in Hospital of Slupsk. RESULTS: During laparotomy ovarian epithelial
      tumor of borderline malignancy stage I A has been diagnosed and unilateral
      cystectomy after meticulous surgical exploration was done. A successful
      spontaneous delivery occurred subsequently when the patient was in 38 week of
      pregnancy. The patient is followed for disease status every three month and her
      health is good. CONCLUSIONS: Serous low malignant potential ovarian tumors during
      pregnancy have microscopic and clinical features suggesting aggressive behavior,
      however, these features appear to regress at the termination of pregnancy.
      Limited resection, after meticulous surgical exploration is adequate therapy for
      women of reproductive age.

PMID- 10349817
TI  - [Fibrinolytic substances formation by cancer. Pathogenetic sequelae].
AB  - A survey of literature has been presented relating to fibrinolytic substances
      secreted by malignant tumors, and the role of those substances in the progression
      of cancer. Particular attention has been given to the effects of plasmin
      proteolysis which is generated in the extracellular matrix by urokinase
      plasminogen activator (uPA) complexed with its receptor (uPAR). The paper also
      discusses the usefulness of the markings of the substances under discussion for
      diagnostic-prognostic purposes, and a perspective of using the new research in
      therapy, for example, by using antibodies anti-uPA and anti-uPAR.

PMID- 10349818
TI  - Teaching students about nursing and the environment: Part 1--Nursing role and
      basic curricula.
AB  - Since the time of Nightingale, the phenomena of health, person, nursing, and
      environment have been considered central to nursing. However, of all the
      concepts, environment appears to have been the least explored, practiced, and
      researched. Nursing education does not adequately prepare nurses to understand
      the impact of the environment on health or to implement environmental
      interventions. This 2-part series is designed to assist faculty in teaching this
      content. Part 1 provides historical background, the role of nursing, a basic
      curriculum, and student learning activities.

PMID- 10349819
TI  - Teaching students about nursing and the environment: Part 2--Legislation and
      resources.
AB  - This 2-part series is designed to assist faculty in teaching students about the
      impact of the environment on health. Part 1 (Gerber & McGuire, 1999/this issue)
      provides historical background, the role of nursing, a basic curriculum, and
      student learning activities. Part 2 presents national environmental health
      objectives, pertinent legislation, organization of environmental health services,
      global environmental health, and student learning activities. We designed the
      material to be practical, so that this critical area becomes a routine part of
      assessment data for nurses as they care for clients.

PMID- 10349820
TI  - A study of the relationship of caregiving appraisal to depressive symptomatology
      and home care utilization.
AB  - This study assessed the relationship of caregiving appraisal to depressive
      symptomatology and utilization of home health care. One-hundred family caregivers
      to functionally impaired older adults were interviewed in their homes about
      depressive symptoms, dimensions of caregiving appraisal, and use of home care.
      Satisfaction, impact, and mastery significantly predicted depressive
      symptomatology. These dimensions of caregiving appraisal were not significantly
      different between those caregivers with and without home health care. Nursing
      needs to plan interventions to maximize the appraisal of caregiving.

PMID- 10349821
TI  - Health concerns and risk behaviors of rural adolescents.
AB  - Although much has been written about the health status of adolescents, little is
      known about adolescents' perception of their own health. The purpose of this
      article is to describe the health concerns of rural adolescents. Two national
      studies, the Youth Risk Behavior Survey and the National Longitudinal Study of
      Adolescent Health (Add Health Project), are used as comparisons. Data from the
      rural survey represent 624 community adolescents attending 4 rural Pennsylvania
      schools. The students were in the 9th, 10th, and 11th grades. The Adolescent
      Health Inventory was used to report concerns related to general health,
      psychosocial issues, and risk behaviors. Overall, rural adolescents in the study
      reported an average of 6.5 (SD = 3.2) health concerns with frequencies of
      occurrence being always or often and reported an average involvement in 1 (SD =
      1.3) risk behavior. Psychosocial issues were reported by 28%, and 23% worried
      about their general health. Frequently reported risk behaviors included alcohol
      use, drug use, and a lack of exercise. There was minimal concern expressed
      regarding venereal disease or AIDS, whereas 12% expressed concern about the
      possibility of pregnancy. These results suggest the likelihood that adolescents
      perceive health from a holistic perspective and that health promotion programs
      should consider involving adolescents in planning, both (a) to ensure congruence
      of the plan of care with adolescents' concerns and (b) to clarify the
      interpretation and meaning of their concerns. We present implications for the
      community health nurse.

PMID- 10349822
TI  - Creating alternative immunization clinics to maintain and improve community
      immunization rates.
AB  - Immunization campaigns are among the most effective means for improving community
      health, yet underimmunized groups leave communities at risk for vaccine
      preventable diseases. In 1993, the Childhood Immunization Initiative (CII) was
      implemented to address this risk. The goal of the CII, to achieve immunization
      coverage 90% or greater among 2-year-old children, was reached nationwide by
      1996. However, individual states ranged from 81% to 99% for specific vaccines
      (Centers for Disease Control and Prevention, 1997b). The work of the CII is
      ongoing and was expanded in 1996 to address the immunization needs of
      adolescents. The purpose of this article is to present a model for providing
      immunization services in alternative sites, in which the community health nurse
      takes the service to the people. Building linkages with local communities,
      preparing the clinic site and supplies, arranging for staffing of an alternative
      clinic, and evaluation after service provision are key elements to a successful
      outreach clinic.

PMID- 10349824
TI  - Is there evidence to show that fetal alcohol syndrome can be prevented?
AB  - Fetal Alcohol Syndrome (FAS) is currently the major cause of mental retardation
      in the Western world. Since FAS is not a natural phenomenon and is created by
      mixing alcohol and pregnancy, the solution to decreasing the incidence of all
      alcohol-related birth defects is therefore entirely preventable. To date, little
      is known about the effectiveness of prevention programs in reducing the incidence
      of FAS. Therefore, it is the intention of this article to review the
      effectiveness of prevention programs in lowering the incidence of FAS. The
      present review revealed that prevention programs, to date, have been successful
      in raising awareness of FAS levels across the groups examined. However, this
      awareness has not been translated into behavioral changes in "high risk" drinkers
      as consumption levels in this group have decreased only marginally, indicating
      prevention programs have had minimal or no impact in lowering the incidence of
      FAS. Urgent steps must now be taken to fully test prevention programs, and find
      new strategies involving both sexes, to reduce and ultimately eliminate the
      incidence of FAS.

PMID- 10349825
TI  - Psychosocial moderators of substance use among middle school-aged adolescents.
AB  - Recent statistics show a decrease in the overall use of drugs and alcohol in the
      general population [1]. In sharp contrast to this trend is the indication that
      adolescents' use of drugs and alcohol is increasing [2]. Because the use of drugs
      and alcohol can have serious implications for adolescents' physical, emotional,
      and social development, it is important that human service practitioners working
      with them understand those factors that influence their substance use, in order
      to develop effective interventions to deal with this growing problem. This
      article reports the findings of a study of drug and alcohol use among a sample of
      779 adolescents who attended middle schools in a large urban city in the
      southwest United States. The study examines the relationships between substance
      use, social support, and a variety of other psychosocial factors. The
      implications of those relationships for human service practice and research are
      discussed.

PMID- 10349826
TI  - Attitudes of Israeli Jewish and Arab high school students toward alcohol control
      measures.
AB  - This article describes a study carried out in the winter of 1997 in order to
      determine the attitudes of 2,186 adolescents of four religions in the north of
      Israel toward eight alcohol control measures: Taxation on alcohol, age limit for
      buying alcohol, restrictions on types of outlets which are allowed to sell
      alcohol to minors, restrictions on opening hours of pubs, restrictions on
      advertising of alcohol, limit of blood level of alcohol when driving, the
      authority of policemen concerning the testing of drunk drivers, and restrictions
      on roadside alcohol outlets. Findings indicate that the majority of the
      respondents tend to enhance alcohol control measures pertaining to alcohol and
      driving issues, but only about a third of the participants tend to enhance
      alcohol control measures in the other domains. In addition, Arabs tend to favor
      restrictive attitudes toward alcohol control measures in comparison with Jews,
      and Arab females tend to favor such attitudes more than Arab males. Implications
      for prevention and effective alcohol policy are discussed.

PMID- 10349827
TI  - Focusing on the family in the treatment of substance abusing criminal offenders.
AB  - Aftercare services are acknowledged in the criminal justice system as critical to
      enabling drug offenders to avoid relapse and reincarceration, but the content too
      often is unsupported through research. One program funded under the Department of
      Justice in Maryland interviewed 150 inmates after three months in the community
      to determine what environmental influences were having the greatest impact on
      drug reuse. Findings suggest that more emphasis is needed on family relationships
      before and after release since satisfaction with family life is strongly
      correlated with drug abuse.

PMID- 10349828
TI  - Children of alcoholics: a school-based comparative study.
AB  - This study investigates children of alcoholics (COAs) and their cohorts who are
      not affected by parental alcoholism (non-COAs). Participants include fourth
      through sixth grade students who are identified as COAs and non-COAs. The study
      examines differences between COAs and non-COAs on measures of internalized shame,
      self-esteem, perceived support, and teacher behavior ratings. Results indicate
      that COAs and non-COAs demonstrate no significant differences on measures of
      social support and shame. In contrast, self-esteem and teacher ratings for COAs
      are significantly lower in comparison to ratings for non-COAs. In addition,
      teacher ratings of male COAs are significantly negatively affected by their COA
      status, whereas female COA and non-COA teacher ratings do not differ
      significantly.

PMID- 10349829
TI  - Trends from 1987 to 1991 in alcohol, tobacco, and other drug (ATOD) use among
      adolescents exposed to a school district-wide prevention intervention.
AB  - This study involved a school-based prevention program initiated to reduce
      alcohol, tobacco, and other drug (ATOD) use among adolescents in the Troy School
      District in the Detroit area. One purpose was to describe the current ATOD
      situation by investigating changes in reported ATOD use from 1987 to 1991.
      Another purpose was to explore and identify the most salient risk and protective
      factors present. In 1987, 1,490 students (comprising grades 8 and 11) and in
      1991, 3,171 students (comprising grades 8 to 12) completed questionnaires.
      Significant decreases were found for use of most drugs with the exception of
      alcohol. Involvement in problem behaviors was identified as the most salient risk
      factor, while having a member of a non-using peer group was the most salient
      protective factor. Implications for the design of subsequent intervention
      programs are discussed.

PMID- 10349830
TI  - Antisilencing: myelin proteolipid protein gene expression in oligodendrocytes is
      regulated via derepression.
AB  - Antisilencer or antirepressor elements have been described, thus far, for only a
      few eukaryotic genes and were identified by their ability not to augment gene
      expression per se but to override repression mediated via negative transcription
      regulatory elements. Here we report the first case of antisilencing for a neural
      specific gene, the myelin proteolipid protein (PLP) gene (Plp). PLP is the most
      abundant protein found in CNS myelin. The protein is synthesized in
      oligodendrocytes, and its expression is regulated developmentally. Previously we
      have shown that a PLP-lacZ transgene (which includes the entire sequence for Plp
      intron 1) is regulated in mice, in a manner consistent with the spatial and
      temporal expression of the endogenous Plp gene. In the present report, we
      demonstrate by transfection analyses, using various PLP-lacZ deletion constructs,
      that Plp intron 1 DNA contains multiple elements that collectively regulate Plp
      gene expression in oligodendrocytes. One of these regulatory elements functions
      as an antisilencer element, which acts to override repression mediated by at
      least two negative regulatory elements located elsewhere within Plp intron 1 DNA.
      The mechanism for antisilencing appears to be complex as the intragenic region
      that mediates this function binds multiple nuclear factors specifically.

PMID- 10349831
TI  - TATA-driven transcriptional initiation and regulation of the rat serotonin 5-HT1A
      receptor gene.
AB  - The transcriptional initiation and regulation of the rat serotonin 5-HT1A
      receptor gene were characterized. By three types of analyses, a single brain
      specific site of transcriptional initiation was localized to -967 bp upstream of
      the translation initiation codon that is utilized both in hippocampus and in the
      rat raphe RN46A cell line. This major site of transcriptional initiation was
      located 58 bp downstream from a consensus TATA element, suggesting TATA-driven
      transcription of the rat 5-HT1A receptor. To identify the promoter activity of
      the receptor gene, progressive 5' deletions of the -2,719/-117-bp fragment of the
      5-HT1A promoter linked to luciferase gene were transfected into 5-HT1A-negative
      (pituitary GH4C1, L6 myoblast, and C6 glioma) and 5-HT1A-positive (septal SN-48
      and raphe RN46A) cell lines. Enhancer regions were identified within a fragment
      between nucleotides -426 and -117 that selectively enhanced transcription in 5
      HT1A-positive cells. A nonselective enhancer/promoter that mediated expression in
      all cell lines was located upstream between -1,519 and -426 bp in a DNA segment
      containing consensus TATA, CCAAT, SP-1, and AP-1 elements as well as a poly-GT26
      dinucleotide repeat. Strong repression of transcription in all cell lines was
      conferred by the region upstream of -1,519 bp that contains a 152-bp DNA segment
      with >80% identity to RANTES, tumor necrosis factor-beta, and other immune system
      genes. Our results indicate that TATA-driven expression of the 5-HT1A receptor is
      regulated by a novel proximal tissue-specific enhancer region, a nonselective
      promoter, and an upstream repressor region that is distinct from previously
      identified neuron-specific repressors.

PMID- 10349832
TI  - Contrasting calcium dependencies of SAPK and ERK activations by glutamate in
      cultured striatal neurons.
AB  - Stress-activated protein kinase (SAPK) and extracellular signal-regulated kinase
      (ERK), both members of the mitogen-activated protein kinase (MAPK) family, may in
      some circumstances serve opposing functions with respect to cell survival.
      However, SAPK and ERK can also be coordinately activated in neurons in response
      to glutamate stimulation of NMDA receptors. To explore the mechanisms of these
      MAPK activations, we compared the ionic mechanisms mediating SAPK and ERK
      activations by glutamate. In primary cultures of striatal neurons, glutamatergic
      activation of ERK and one of its transcription factor targets, CREB, showed a
      calcium dependence typical of NMDA receptor-mediated responses. In contrast,
      extracellular calcium was not required for glutamatergic, NMDA receptor-mediated
      activation of SAPK and phosphorylation of its substrate, c-Jun. Increasing
      extracellular calcium enhanced ERK activation but reversed SAPK activation,
      further distinguishing the calcium dependencies of these two NMDA receptor
      mediated effects. Finally, reducing extracellular sodium prevented the
      glutamatergic activation of SAPK but only partially blocked that of ERK. These
      contrasting ionic dependencies suggest a mechanism by which NMDA receptor
      activation may, under distinct conditions, differentially regulate neuronal MAPKs
      and their divergent functions.

PMID- 10349833
TI  - Radicicol potentiates neurotrophin-mediated neurite outgrowth and survival of
      cultured sensory neurons from chick embryo.
AB  - Radicicol, an antifungal antibiotic with markedly low toxicity, is a potent
      inhibitor of the Src family of protein tyrosine kinases and causes morphological
      reversion of v-src-transformed fibroblasts. Recently, this antibiotic was also
      found to inhibit Raf kinase. In the present study, we found that nanomolar
      concentrations of radicicol (10 ng/ml) enhanced the survival and neurite
      outgrowth of neurons from embryonic chick dorsal root ganglia (DRGs) and
      sympathetic ganglia. It potentiated the trophic effects of nerve growth factor,
      brain-derived neurotrophic factor, and neurotrophin-3 on the cultured DRG
      neurons. This concentration of radicicol did not alter the tyrosine
      phosphorylation of Trk receptors or the activity of mitogen-activated protein
      (MAP) kinases. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3
      kinase), did not inhibit radicicol, excluding the involvement of PI3-kinase in
      the radicicol-dependent trophic actions. These results suggest that radicicol
      mediates neuronal growth presumably via a mechanism not involving the activation
      of Trk receptors, MAP kinase, or PI3-kinase.

PMID- 10349834
TI  - Bone morphogenetic protein-2 promotes survival and differentiation of striatal
      GABAergic neurons in the absence of glial cell proliferation.
AB  - We examined the potential neurotrophic effects of bone morphogenetic protein
      (BMP)-2 on the survival and differentiation of neurons cultured from the rat
      developing striatum at embryonic day 16, a period during which the mRNAs for BMP
      2 and its receptor subunits (types IA, IB, and II) were detected. BMP-2 exerted
      potent activity to promote the survival of striatal neurons and increased the
      number of surviving microtubule-associated protein-2-positive cells by 2.4-fold
      as compared with the control cultures after 4 days in vitro. Although basic
      fibroblast growth factor (bFGF) also showed relatively high activity to promote
      the survival of striatal neurons, transforming growth factor-beta1, -beta2, and 
      beta3, glial cell line-derived neurotrophic factor, or brain-derived neurotrophic
      factor promoted their survival weakly. Striatal neurons cultured in the presence
      of BMP-2 or bFGF possessed extensive neurite outgrowths, the majority of which
      were GABA-immunoreactive. Inhibition of glial cell proliferation by 5
      fluorodeoxyuridine did not affect the capacity of BMP-2 to promote the survival
      of striatal GABAergic neurons. In contrast, the ability of bFGF to promote the
      survival of striatal neurons was inhibited significantly by the treatment of
      cells with 5-fluorodeoxyuridine. All these results suggest that BMP-2 exerts
      potent neurotrophic effects on the striatal GABAergic neurons in a glial cell
      independent manner.

PMID- 10349835
TI  - Cyclic AMP-responsive element binding protein in brain mitochondria.
AB  - Cyclic AMP-responsive element binding protein (CREB) is critically involved in
      many important brain functions, including the formation of long-term memory. CREB
      is the best characterized member of a family of transcription factors (CREB/ATF
      family) recognized to be important nuclear targets for intracellular signal
      transduction systems. Here we show, by using different approaches, that CREB is
      unexpectedly localized to mitochondria of the rat brain. Controlled subcellular
      fractionation of hippocampus and cerebral cortex showed that both synaptic and
      nonsynaptic mitochondria exhibited immunoreactivity to the phosphorylated form of
      CREB (pCREB). Moreover, CREB extracted from synaptic mitochondria is able to be
      phosphorylated by the catalytic subunit of protein kinase A and dephosphorylated
      by protein phosphatase 1 or 2B. DNA mobility shift assays showed the presence of
      binding activity to the calcium-cyclic AMP-responsive element in mitochondrial
      extracts from hippocampus; this binding complex was specifically supershifted by
      an anti-CREB antibody. Immunoelectron microscopic analysis of hippocampal
      subcellular fractions revealed that pCREB immunoreactivity is localized in close
      association with the inner mitochondrial membrane. These results, together with
      recent findings describing the presence and phosphorylation of CREB in developing
      dendrites, suggest that CREB may participate in different mechanisms involved in
      the communication between extracellular signals and the expression of genes.

PMID- 10349836
TI  - Inhibition of cholesterol production but not of nonsterol isoprenoid products
      induces neuronal cell death.
AB  - Deficiency of nonsterol isoprenoids, intermediate metabolites of the cholesterol
      biosynthetic pathway, has been known to cause an inhibition of DNA synthesis and
      cell growth, and to induce apoptosis in nonneuronal cells. To investigate whether
      this is also the case in neurons, we examined the effect of a 3-hydroxy-3
      methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor on the viability of
      neuronal cultures prepared from fetal rat brains. Treatment with compactin, a
      competitive inhibitor of HMG-CoA reductase, induced neuronal death in a dose
      dependent manner. Concurrent treatment with cholesterol, beta-migrating very low
      density lipoprotein, mevalonate, or squalene substantially inhibited the
      induction of neuronal death by compactin. Cell death was also induced by
      treatment with squalestatin, which specifically inhibits cholesterol biosynthesis
      at a site downstream from the generation of nonsterol metabolites. Furthermore,
      squalestatin-induced neuronal death was inhibited by concurrent incubation with
      squalene but not mevalonate. In contrast, cell growth of proliferating cells such
      as NIH 3T3 and PC12 cells was exclusively dependent on the level of nonsterol
      isoprenoid products and not that of cholesterol. The results of this study
      clearly indicate that the viability of neurons, different from that of
      nonneuronal cells, depends on the intracellular cholesterol content and not on
      the intermediate nonsterol isoprenoid products.

PMID- 10349837
TI  - Transforming growth factor beta1-regulated cell proliferation and expression of
      neural cell adhesion molecule in B104 neuroblastoma cells: differential effects
      of ethanol.
AB  - The expression and activity of factors influencing early neuronal development are
      altered by ethanol. Such factors include growth factors, for example, platelet
      derived growth factor and basic fibroblast growth factor (for cell
      proliferation), and cell adhesion molecules (for neuronal migration). One agent,
      transforming growth factor beta1 (TGFbeta1), may affect both events. We tested
      the hypothesis that ethanol alters myriad TGFbeta1-mediated activities [i.e.,
      cell proliferation and neural cell adhesion molecule (N-CAM) expression] using
      B104 neuroblastoma cells. TGFbeta1 inhibited the proliferation of B104 cells as
      evidenced by decreases in cell number and [3H]thymidine ([3H]dT) incorporation.
      TGFbeta1 induced sustained activation of extracellular signal-regulated kinases
      (ERKs), which are part of the family of mitogen-activated protein kinases
      (MAPKs). Treatment with PD98059 (a MAPK kinase blocker) abolished TGFbeta1
      regulated inhibition of [3H]dT incorporation. TGFbeta1-mediated growth inhibition
      was potentiated by ethanol exposure. Ethanol also produced prolonged activation
      of ERK, an effect that was partially eliminated by treatment with PD98059. On the
      other hand, TGFbeta1 up-regulated N-CAM expression, and this up-regulation was
      not affected by treatment with PD98059. Ethanol inhibited the TGFbeta1-induced up
      regulation of N-CAM expression in a concentration-dependent manner. Thus,
      TGFbeta1 affects ERK-dependent cell proliferation and ERK-independent N-CAM
      expression in B104 cells. Both activities are sensitive to ethanol and may
      underlie the ethanol-induced alterations in the proliferation and migration of
      CNS neurons.

PMID- 10349838
TI  - Nerve growth factor determines survival and death of PC12 cells by regulation of
      the bcl-x, bax, and caspase-3 genes.
AB  - We investigated the effects of nerve growth factor (NGF) and NGF withdrawal on
      expression of members of the bcl-2 family of genes and caspase-3 in PC12 cells.
      NGF regulated several members of the bcl-2 family and caspase-3 in a manner
      consistent with its effect on apoptosis in PC12 cells. Levels of bcl-xl, bcl-xs,
      and caspase-3 mRNAs were increased by NGF treatment. The increases in caspase-3
      and bcl-xs levels should have disposed the cells toward apoptosis but were
      opposed by the simultaneous increase in bcl-xl level. NGF withdrawal resulted in
      abrupt down-regulation of bcl-xl and up-regulation of bax, favoring apoptosis.
      Forced expression of bcl-xl after NGF withdrawal was sufficient to prevent cell
      death. Cell death was rapid when NGF was withdrawn after 5 days of treatment but
      relatively slow when NGF was withdrawn after only 1 or 2 days of treatment. This
      was consistent with the reduced accumulation of caspase-3 mRNA with shorter NGF
      treatments. These results indicate that Bcl-xl, Bcl-xs, Bax, and caspase-3 are
      important regulators of apoptosis in PC12 cells. Furthermore, regulation of their
      mRNA levels is implicated in the signal transduction of NGF.

PMID- 10349839
TI  - Truncation releases olfactory receptors from the endoplasmic reticulum of
      heterologous cells.
AB  - Olfactory receptors are difficult to express functionally in heterologous cells.
      We found that olfactory receptors traffic poorly to the plasma membrane even in
      cells with neuronal phenotypes, including cell lines derived from the olfactory
      epithelium. Other than mature olfactory receptor neurons, few cells appear able
      to traffic olfactory receptors to the plasma membrane. In human embryonic kidney
      293 cells and Xenopus fibroblasts, olfactory receptor immunoreactivity overlapped
      with a marker for the endoplasmic reticulum (ER) but not with markers for the
      Golgi apparatus or endosomes. Except for the ER, olfactory receptors were
      therefore absent from organelles normally involved in the plasma membrane
      trafficking of receptors. Olfactory receptors truncated prior to transmembrane
      domain VI were expressed in the plasma membrane, however. Co-expression of the
      missing C-terminal fragment with these truncated receptors prevented their
      expression in the plasma membrane. Intramolecular interactions between N- and C
      terminal domains joined by the third cytoplasmic loop appear to be responsible
      for retention of olfactory receptors in the ER of heterologous cells. Our results
      are consistent with misfolding of the receptors but could also be explained by
      altered trafficking of the receptors.

PMID- 10349840
TI  - Prostate apoptosis response-4 production in synaptic compartments following
      apoptotic and excitotoxic insults: evidence for a pivotal role in mitochondrial
      dysfunction and neuronal degeneration.
AB  - Synapses are often located at great distances from the cell body and so must be
      capable of transducing signals into both local and distant responses. Although
      progress has been made in understanding biochemical cascades involved in neuronal
      death during development of the nervous system and in various neurodegenerative
      disorders, it is not known whether such cascades function locally in synaptic
      compartments. Prostate apoptosis response-4 (Par-4) is a leucine zipper and death
      domain-containing protein that plays a role in neuronal apoptosis. We now report
      that Par-4 levels are rapidly increased in cortical synaptosomes and in dendrites
      of hippocampal neurons in culture and in vivo, following exposure to apoptotic or
      excitotoxic insults. Par-4 expression is regulated at the translational level
      within synaptic compartments. Par-4 antisense treatment suppressed mitochondrial
      dysfunction and caspase activation in synaptosomes and prevented death of
      cultured hippocampal neurons following exposure to excitotoxic and apoptotic
      insults. Local translational regulation of death-related proteins in synaptic
      compartments may play a role in programmed cell death, adaptive remodeling of
      synapses, and neurodegenerative disorders.

PMID- 10349841
TI  - The lipid peroxidation product 4-hydroxynonenal inhibits neurite outgrowth,
      disrupts neuronal microtubules, and modifies cellular tubulin.
AB  - Oxidative stress is believed to be an important factor in the development of age
      related neurodegenerative diseases such as Alzheimer's disease (AD). The CNS is
      enriched in polyunsaturated fatty acids and is therefore particularly vulnerable
      to lipid peroxidation. Indeed, accumulation of lipid peroxidation products has
      been demonstrated in affected regions in brains of AD patients. Another feature
      of AD is a change in neuronal microtubule organization. A possible causal
      relationship between lipid peroxidation products and changes in neuronal cell
      motility and cytoskeleton has not been investigated. We show here that 4-hydroxy
      2(E)-nonenal (HNE), a major product of lipid peroxidation, inhibits neurite
      outgrowth and disrupts microtubules in Neuro 2A cells. The effect of HNE on
      microtubules was rapid, being observed after incubation times as short as 15 min.
      HNE can react with target proteins by forming either Michael adducts or pyrrole
      adducts. 4-Oxononanal, an HNE analogue that can form only pyrrole adducts but not
      Michael adducts, had no effect on the microtubules. This suggests that the HNE
      induced disruption of microtubules occurs via Michael addition. We also show that
      cellular tubulin is one of the major proteins modified by HNE and that the HNE
      adduction to tubulin occurs via Michael addition. Inhibition of neurite
      outgrowth, disruption of microtubules, and tubulin modification were observed at
      pathologically relevant HNE concentrations and were not accompanied by
      cytotoxicity. Our results show that these are proximal effects of HNE that may
      contribute to cytoskeletal alterations that occur in AD.

PMID- 10349842
TI  - Glial cells protect neurons against oxidative stress via transcriptional up
      regulation of the glutathione synthesis.
AB  - We examined the effects of oxidative stress on rat cultured mesencephalic neurons
      and glial cells. Glial cells were more resistant to 6-hydroxydopamine (6-OHDA)
      and H2O2 toxicity than neurons. In glial cells, incubation with 6-OHDA and H2O2
      induced a significant increase in the expression of gamma-glutamylcysteine
      synthetase (the rate-limiting enzyme in glutathione synthesis) mRNA, which
      correlated well with increased TPA-response element (TRE)-binding activity.
      Furthermore, a subsequent elevation in cellular total glutathione content was
      also observed. In neurons, both agents decreased TRE-binding activity, and these
      cells failed to up-regulate the glutathione synthesis. We also examined the
      mechanisms of the neuroprotective effects of glial cells using a glia conditioned
      medium. Neurons maintained in glia conditioned medium up-regulated the level of
      TRE-binding activity, gamma-glutamylcysteine synthetase mRNA expression, and
      total glutathione content in response to 6-OHDA or H2O2, and became more
      resistant to both agents than cells maintained in a normal medium. Neurons
      maintained in normal medium failed to up-regulate the glutathione synthesis. Our
      results suggest that transcriptional up-regulation of glutathione synthesis in
      glial cell appears to mediate brain glial cell resistance against oxidative
      stress, and that glial cells protect neurons via transcriptional up-regulation of
      the antioxidant system.

PMID- 10349843
TI  - Adenosine stimulates cone photoreceptor myoid elongation via an adenosine A2-like
      receptor.
AB  - In several parts of the nervous system, adenosine has been shown to function as
      an extracellular neuromodulator binding to surface receptors on target cells.
      This study examines the possible role of adenosine in mediating light and
      circadian regulation of retinomotor movements in teleost cone photoreceptors.
      Teleost cones elongate in the dark and contract in the light. In continuous
      darkness, the cones continue to elongate and contract at subjective dusk and dawn
      in response to circadian signals. We report here that exogenous adenosine
      triggers elongation (the dark/night movement) in isolated cone inner segment-cone
      outer segment preparations (CIS-COS) in vitro. Agonist/antagonist potency
      profiles indicate that adenosine's effect on cone movement is mediated by an A2
      like adenosine receptor, which like other A2 receptors enhances adenylate cyclase
      activity. Although closest to that expected for A2 receptors, the antagonist
      potency profile for CIS-COS does not correspond exactly to any known A2 receptor
      subtype, suggesting that the cone receptor may be a novel A2 subtype. Our
      findings are consistent with previous reports that retinal adenosine levels are
      higher in the dark, and further suggest that adenosine could act as a
      neuromodulatory "dark signal" influencing photoreceptor metabolism and function
      in the fish retina.

PMID- 10349844
TI  - Suppression of heme oxygenase-1 mRNA expression by interferon-gamma in human
      glioblastoma cells.
AB  - Heme oxygenase is a rate-limiting enzyme in heme catabolism that cleaves heme to
      form biliverdin, carbon monoxide, and iron. Heme oxygenase-1 is an inducible
      isozyme and is expressed in many types of cells and tissues. Large amounts of
      these heme degradation products may be noxious to the host, especially in the
      brain. We therefore searched for the factors that suppress the expression of heme
      oxygenase-1. Northern blot analysis showed that treatment with interferon-gamma
      and with interleukin-1beta for 24 h decreased the expression levels of heme
      oxygenase-1 mRNA to approximately 20 and approximately 50% of the control levels,
      respectively, in a human glioblastoma cell line, T98G. Treatment with a
      combination of these two cytokines additively decreased the expression levels of
      heme oxygenase-1 mRNA. Western blot analysis showed that the expression level of
      heme oxygenase-1 protein was also decreased by treatment with interferon-gamma,
      but not with interleukin-1beta. Moreover, pretreatment with interferon-gamma
      partially suppressed the induction of heme oxygenase-1 mRNA expression caused by
      either sodium nitroprusside, cadmium, or hemin. These findings raise the
      possibility that the expression of heme oxygenase-1 is down-regulated by
      interferon-gamma in the nervous system.

PMID- 10349845
TI  - Differential generation of high-density lipoprotein by endogenous and exogenous
      apolipoproteins in cultured fetal rat astrocytes.
AB  - Most peripheral cells generate cholesterol-rich high-density lipoprotein (HDL)
      with exogenous apolipoprotein as one of the mechanisms for the maintenance of
      cellular cholesterol homeostasis. Astrocytes isolated from fetal rat brain showed
      a unique behavior in this reaction. Consistent with previous findings, the
      astrocytes synthesized apolipoprotein (apo) E and generated cholesterol-rich pre
      beta-HDL-like lipoprotein with this apoE, and cellular cholesterol and
      phospholipids. When exogenous apoA-I and E were added to the medium, they caused
      generation of additional HDL with cellular phospholipid. It is interesting that
      this additional part was very poor in cholesterol except for the generation of
      relatively cholesterol-rich HDL only in the initial few hours of the incubation.
      The mobilization of intracellular cholesterol for this reaction was also very
      limited, reflecting the poor cholesterol incorporation into the HDL. Thus, the
      results demonstrated a unique profile of HDL generation and cholesterol efflux by
      apolipoproteins in rat astrocytes, with endogenous apoE producing cholesterol
      rich HDL and exogenous apolipoproteins producing cholesterol-poor HDL. These
      lipoproteins may play differential roles in cholesterol transport in the CNS.

PMID- 10349846
TI  - The endogenous lipid oleamide activates serotonin 5-HT7 neurons in mouse thalamus
      and hypothalamus.
AB  - Oleamide is an endogenous lipid that accumulates during sleep deprivation and has
      hypothermic effects when administered to rodents. The mechanisms for its activity
      remain unknown. Intraperitoneal injections of oleamide elicited dramatic
      increases in content of c-fos mRNA and Fos protein in distinct brain regions,
      including cingulate and somatosensory cortical areas and numerous nuclei of the
      thalamus and hypothalamus, indicating that there are explicit targets for its
      action. In the thalamus and hypothalamus a majority of neurons induced for c-fos
      expression also expressed the serotonin 5-HT7 receptor, an allosteric target for
      oleamide in in vitro studies. These data suggest that oleamide may act at 5-HT7
      receptors to elicit alterations in transcription that result in some of its
      physiological effects.

PMID- 10349847
TI  - Relationships between ligand affinities for the cerebellar cannabinoid receptor
      CB1 and the induction of GDP/GTP exchange.
AB  - The hypothesis of these studies is that ligand efficacy at the neuronal CB1
      receptor is dependent on the ratio of ligand affinities for the active and
      inactive states of the receptor. Agonist efficacy was determined in rat
      cerebellar membranes using agonist-induced guanosine 5'-O-(3
      [35S]thiotriphosphate) binding; efficacy was variable among the CB1 agonists
      examined. Ligand affinities for the active and inactive state of the CB1 receptor
      were determined by competition with [3H]CP55940 and [3H]SR141716A in the presence
      of 5'-guanylylimidodiphosphate, respectively. All of the agonists investigated
      had a higher affinity for the active state than the inactive state. The fraction
      of CB1 receptors in the active state at a maximally effective concentration was
      calculated for each agonist and was found to correlate significantly with agonist
      efficacy. These studies demonstrate that the CB1 receptor of the cerebellum can
      assume an active conformation in the absence of agonist and that the variability
      in efficacy among CB1 receptor agonists can be explained by the relative
      affinities of these ligands for the CB1 receptor in the active and inactive
      states.

PMID- 10349848
TI  - Differential activation of mitogen-activated protein kinase pathways in PC12
      cells by closely related alpha1-adrenergic receptor subtypes.
AB  - Coupling of the three known alpha1-adrenergic receptor (alpha1-AR) subtypes to
      mitogen-activated protein kinase (MAPK) pathways were studied in stably
      transfected PC12 cells. Subclones stably expressing alpha1A-, alpha1B-, and
      alpha1D-ARs under control of an inducible promoter, or at high and low receptor
      density, were isolated and characterized. Radioligand binding showed similar
      ranges of expression of each subtype. Norepinephrine (NE) increased inositol
      phosphate formation and intracellular Ca2+ level in these cells in a manner
      dependent on receptor density. However, alpha1A-ARs activated these second
      messenger responses more effectively than alpha1B-ARs, whereas alpha1D-ARs were
      least effective. NE stimulated activation of extracellular signal-regulated
      kinases (ERKs) in cells expressing all three alpha1-AR subtypes, although alpha1A
      and alpha1B-ARs caused larger ERK activation than did alpha1D-ARs. Nerve growth
      factor (NGF) caused similar levels of ERK activation in all subclones. NE also
      activated p38 MAPK in alpha1A- and alpha1B- but not alpha1D-transfected cells and
      activated c-Jun NH2-terminal kinase (JNK) only in alpha1A-transfected cells. NE,
      but not NGF, strongly stimulated tyrosine phosphorylation of a 70-kDa protein
      only in alpha1A-transfected PC12 cells. NE caused neurite outgrowth only in
      alpha1A-expressing PC12 cells, but not in alpha1B- or alpha1D-transfected cells,
      whereas NGF caused neurite outgrowth in all cells. These studies show that
      alpha1A-ARs activate all three MAPK pathways, alpha1B-ARs activate ERKs and p38
      but not JNKs, and alpha1D-ARs only activate ERKs. Only the alpha1A-AR-expressing
      cells differentiated in response to NE. The relationship of these responses to
      second messenger pathways activated by these subtypes is discussed.

PMID- 10349849
TI  - Repeated cocaine alters glutamate receptor subunit levels in the nucleus
      accumbens and ventral tegmental area of rats that develop behavioral
      sensitization.
AB  - Increased glutamate transmission in the nucleus accumbens and ventral tegmental
      area has been proposed as a mechanism underlying sensitized behavioral responses
      to repeated cocaine administration. GluR1, GluR2/3, and NMDAR1 subunits of
      glutamate receptors were quantified from immunoblots in these brain nuclei in
      rats at 24 h and 3 weeks after discontinuing 1 week of daily cocaine injections.
      Motor behavior was monitored after the first and last injections of daily
      cocaine, and those rats that showed >20% increase in motor activity after the
      last compared with the first injection were considered to have developed
      behavioral sensitization. The subjects that developed behavioral sensitization
      showed a significant increase in GluR1 levels in the nucleus accumbens at 3 weeks
      but not at 24 h of withdrawal. Conversely, sensitized animals showed a
      significant increase in NMDAR1 and GluR1 levels in the ventral tegmental area at
      1 day but not at 3 weeks of withdrawal. None of these increases occurred in the
      rats exposed to daily cocaine that did not develop behavioral sensitization (<20%
      increase in motor activity), and no changes were measured in the level of GluR2/3
      in any treatment group. The functional importance of the increases in glutamate
      receptor subunit levels is suggested by the fact that the changes were present
      only in rats that developed behavioral sensitization to repeated cocaine
      administration.

PMID- 10349850
TI  - Conserved extracellular cysteine pair in the M3 muscarinic acetylcholine receptor
      is essential for proper receptor cell surface localization but not for G protein
      coupling.
AB  - Most G protein-coupled receptors contain a conserved pair of extracellular
      cysteine residues that are predicted to form a disulfide bond linking the first
      and second extracellular loops. Previous studies have shown that this disulfide
      bond may be critical for ligand binding, receptor activation, and/or proper
      receptor folding. However, the potential importance of the two conserved cysteine
      residues for proper receptor cell surface localization has not been investigated
      systematically. To address this issue, we used the rat M3 muscarinic receptor as
      a model system. Most studies were carried out with a modified version of this
      receptor subtype (lacking potential N-glycosylation sites and the central portion
      of the third intracellular loop) that could be readily detected via western blot
      analysis. Cys-->Ala mutant receptors were generated, transiently expressed in COS
      7 cells, and then examined for their subcellular distribution and functional
      properties. ELISA and immunofluorescence studies showed that the presence of both
      conserved cysteine residues (corresponding to C140 and C220 in the rat M3
      muscarinic receptor sequence) is required for efficient expression of the M3
      muscarinic receptor on the cell surface. On the other hand, these residues were
      found not to be essential for protein stability (determined via immunoblotting)
      and receptor-mediated G protein activation (studied in second messenger assays).
      These results shed new light on the functional role of the two extracellular
      cysteine residues present in most G protein-coupled receptors.

PMID- 10349851
TI  - Inducible nitric oxide synthase up-regulation in a transgenic mouse model of
      familial amyotrophic lateral sclerosis.
AB  - Mutations in copper/zinc superoxide dismutase (SOD1) are associated with a
      familial form of amyotrophic lateral sclerosis (ALS), and their expression in
      transgenic mice produces an ALS-like syndrome. Here we show that, during the
      course of the disease, the spinal cord of transgenic mice expressing mutant SOD1
      (mSOD1) is the site not only of a progressive loss of motor neurons, but also of
      a dramatic gliosis characterized by reactive astrocytes and activated microglial
      cells. These changes are absent from the spinal cord of age-matched transgenic
      mice expressing normal SOD1 and of wild-type mice. We also demonstrate that,
      during the course of the disease, the expression of inducible nitric oxide
      synthase (iNOS) increases. In both early symptomatic and end-stage transgenic
      mSOD1 mice, numerous cells with the appearance of glial cells are strongly iNOS
      immunoreactive. In addition, iNOS mRNA level and catalytic activity are increased
      significantly in the spinal cord of these transgenic mSOD1 mice. None of these
      alterations are seen in the cerebellum of these animals, a region unaffected by
      mSOD1. Similarly, no up-regulation of iNOS is detected in the spinal cord of age
      matched transgenic mice expressing normal SOD1 or of wild-type mice. The time
      course of the spinal cord gliosis and iNOS up-regulation parallels that of motor
      neuronal loss in transgenic mSOD1 mice. Neuronal nitric oxide synthase expression
      is only seen in neurons in the spinal cord of transgenic mSOD1 mice, regardless
      of the stage of the disease, and of age-matched transgenic mice expressing normal
      SOD1 and wild-type mice. Collectively, these data suggest that the observed
      alterations do not initiate the death of motor neurons, but may contribute to the
      propagation of the neurodegenerative process. Furthermore, the up-regulation of
      iNOS, which in turn may stimulate the production of nitric oxide, provides
      further support to the presumed deleterious role of nitric oxide in the
      pathogenesis of ALS. This observation also suggests that iNOS may represent a
      valuable target for the development of new therapeutic avenues for ALS.

PMID- 10349852
TI  - Expression of cytokines by human astrocytomas following stimulation by C3a and
      C5a anaphylatoxins: specific increase in interleukin-6 mRNA expression.
AB  - C3a and C5a anaphylatoxins are two proinflammatory peptides generated during
      complement activation that act through distinct Gi protein-coupled receptors
      named C3aR and C5aR, respectively. We have demonstrated previously that human
      astrocytes expressed C3aR and C5aR constitutively and were able to produce a
      functional complement. In this study, we examined the effect of an anaphylatoxin
      stimulation on cytokine expression by human astrocyte cell lines. Interleukin
      (IL)-1beta, IL-6, tumor necrosis factor-alpha, and transforming growth factor
      beta mRNA expression was studied by quantitative RT-PCR. Whereas IL-1beta, tumor
      necrosis factor-alpha, and transforming growth factor-beta mRNA levels remained
      unchanged, stimulation of astrocytoma cells (T98G, CB193, U118MG) by C3a, C5a,
      and peptidic C3aR and C5aR agonists induced an increase in the IL-6 mRNA level.
      The amount of IL-6 was markedly increased at 3 and 6 h and returned to the basal
      level at 9 h of stimulation. This response was specific, because pretreatment of
      cells with pertussis toxin or with polyclonal anti-C3aR or anti-C5aR antibodies
      completely blocked the IL-6 mRNA increase. The IL-6 response was also
      investigated at the protein level, but IL-6 protein was detected neither in cell
      lysates nor in supernatants of stimulated cells. The anaphylatoxin-mediated
      transcriptional activation of IL-6 gene suggests that C3a and C5a could play a
      role in priming glial cells during the inflammatory process in the brain.

PMID- 10349853
TI  - Modulation of dopamine transporter activity by nicotinic acetylcholine receptors
      and membrane depolarization in rat pheochromocytoma PC12 cells.
AB  - To elucidate the regulation of the rat dopamine transporter (rDAT), we
      established several PC12 variants overexpressing the rDAT. Treating these cells
      with a nicotinic agonist (1,1-dimethyl-4-phenylpiperazinium iodide, 30 microM)
      depolarized the plasma membrane potential from -31 +/- 2 to 43 +/- 5 mV and
      inhibited rDAT activity significantly in a calcium- and protein kinase C
      independent manner. Membrane depolarization by a high external K+ concentration
      or two K+ channel blockers (tetraethylammonium hydroxide and BaCl2) also resulted
      in a marked inhibition of rDAT activity. Such inhibition of dopamine uptake is
      due to a reduction in Vmax, with no marked effect on the Km for dopamine. The
      potency of cocaine in inhibiting dopamine uptake was not significantly altered,
      whereas that of amphetamine was slightly enhanced by membrane depolarization.
      Removing extracellular Ca2+ or blocking the voltage-sensitive L-type calcium
      channels using nifedipine did not exert any significant effect on the inhibition
      of rDAT activity by depolarization. These data confirm that calcium influx on
      depolarization is not required for inhibition of the rDAT. Collectively, our data
      suggest that rDAT activity can be altered by a neurotransmitter that modulates
      the membrane potential, thus suggesting an exquisite mechanism for the fine
      tuning of dopamine levels in the synapse.

PMID- 10349854
TI  - [1-(13)C]glucose metabolism in the tumoral and nontumoral cerebral tissue of a
      glioma-bearing rat.
AB  - C6 cells were used to establish a glioma-bearing rat model by stereotaxic
      injection in the left caudate nucleus. The tumor status was evaluated by magnetic
      resonance imaging and conventional histology. The glioma-bearing rats were
      infused for 1 h with a [1-(13)C]glucose solution. Perchloric acid extracts of the
      tumor and the ipsilateral and contralateral hemispheres were analyzed by 13C-NMR
      spectroscopy. The 13C-labeling patterns in compounds, mainly amino acids,
      indicated no drastic modification of carbon metabolism in both ipsilateral and
      contralateral hemispheres, as compared with control rats, whereas profound
      metabolic differences between brain tissue and tumor were observed. Glutamine C4
      enrichment was lower in the glioma than in the brain [mean +/- SD values, 5.4 +/-
      2.3 (n = 5) and 15.0 +/- 0.8% (n = 10), respectively] and also lower than the
      glutamate C4 enrichment in the glioma (mean +/- SD value, 22.6 +/- 4.2%; n = 5),
      indicating that tumor glutamine was neither synthesized inside the glioma nor
      taken up from the surrounding brain. The glutamine C4 enrichment in the serum
      (6.7 +/- 0.5%; n = 10) suggested that the glioma imported glutamine from the
      blood, a process probably connected with angiogenesis.

PMID- 10349855
TI  - Sequential cleavage of poly(ADP-ribose)polymerase and appearance of a small Bax
      immunoreactive protein are blocked by Bcl-X(L) and caspase inhibitors during
      staurosporine-induced dopaminergic neuronal apoptosis.
AB  - To assess the role of Bcl-X(L) and its splice derivative, Bcl-X(S), in
      staurosporine-induced cell death, we used a dopaminergic cell line, MN9D,
      transfected with bcl-xL (MN9D/Bcl-X(L)), bcl-xS (MN9D/Bcl-X(S)), or control
      vector (MN9D/Neo). Only 8.6% of MN9D/Neo cells survived after 24 h of 1 microM
      staurosporine treatment. Caspase activity was implicated because a caspase
      inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-fmk),
      attenuated staurosporine-induced cell death. Bcl-X(L) rescued MN9D cells from
      death (89.4% viable cells), whereas Bcl-X(S) had little or no effect. Bcl-X(L)
      prevented morphologically apoptotic changes as well as cleavage of poly(ADP
      ribose)polymerase (PARP) induced by staurosporine. It is interesting that a small
      Bax-immunoreactive protein appeared 4-8 h after PARP cleavage in MN9D/Neo cells.
      The appearance of the small Bax-immunoreactive protein, however, may be cell type
      specific as it was not observed in PC12 cells after staurosporine treatment. The
      sequential cleavage of PARP and the appearance of the small Bax-immunoreactive
      protein in MN9D cells were blocked either by Z-VAD-fmk or by Bcl-X(L). Thus, our
      present study suggests that Bcl-X(L) but not Bcl-X(S) prevents staurosporine
      induced apoptosis by inhibiting the caspase activation that may be directly or
      indirectly responsible for the appearance of the small Bax-immunoreactive protein
      in some types of neurons.

PMID- 10349856
TI  - Activity of alpha-secretase as the common final effector of protein kinase C
      dependent and -independent modulation of amyloid precursor protein metabolism.
AB  - The metabolic fate of the amyloid precursor protein (APP) is one of the key
      factors in the pathogenesis of Alzheimer's disease (AD). A complex cellular
      mechanism regulates the rate at which the precursor is cleaved by alpha-secretase
      and released as soluble protein in the extracellular space. We show here that
      alpha-secretase constitutes the common final effector of several independent
      means of stimulation of soluble APP (sAPP) release. The release of sAPP by alpha
      secretase resembles that of several other membrane-bound proteins with soluble
      counterparts, a process that is sensitive to matrix metalloprotease inhibitors.
      The hydroxamic acid-based compound KD-IX-73-4 inhibits phorbol ester-mediated
      sAPP release from COS cells with an IC50 of 8 microM, consistent with previous
      data for the same compound against leukocyte L-selectin shedding. Beyond direct
      protein kinase C (PKC) activation we show that KD-IX-73-4 inhibits also receptor
      mediated sAPP release induced by carbachol in SH-SY5Y cells and by bradykinin in
      human skin fibroblasts, with the latter being a PKC-independent mechanism.
      Altogether these data suggest that all pharmacological means of stimulating sAPP
      release converge to a hydroxamic acid-based inhibitor-sensitive proteolytic
      enzyme. Moreover, because KD-IX-73-4 was effective in the inhibition of
      stimulated but not constitutive sAPP release, these data suggest the existence of
      different enzymes regulating the two metabolic pathways leading to sAPP
      secretion.

PMID- 10349857
TI  - Magnetic resonance spectroscopy studies on changes in cerebral calcium and zinc
      and the energy state caused by excitotoxic amino acids.
AB  - Under control conditions, superfused hippocampal slices exhibited a significantly
      higher phosphocreatine (PCr)/ATP ratio than cortical slices; the evidence
      suggests that this is due to lower concentrations of ATP, rather than higher
      concentrations of PCr. Glutamate caused relatively rapid decreases in PCr and ATP
      levels to approximately 45%, accompanied or immediately followed by an increased
      free intracellular calcium concentration ([Ca2+]i) and the release of Zn2+ in the
      cortex. In the hippocampus PCr and ATP decreased further to approximately 20% of
      control values, but the changes in [Ca2+]i and Zn2+ content were slower. This is
      in contrast to the effects of depolarisation, which produced the same rapid
      changes in the energy state and [Ca2+]i, with no detectable Zn2+, in both
      tissues. NMDA causes effects similar to those of glutamate in the cortex
      (decreases in the energy state, increased [Ca2+]i, and release of Zn2+).
      Pretreatment of the cortex for 1 h with the NMDA blocker MK-801 prevented all of
      the observed effects of NMDA. In contrast, pretreatment with MK-801 had no
      detectable effect on the increase in [Ca2+]i or the decreases in PCr and ATP
      caused by glutamate, although it prevented the release of zinc. The results are
      discussed in relation to the function of the NMDA subtype of glutamate receptor
      in excitotoxicity.

PMID- 10349858
TI  - Intracellular accumulation of detergent-soluble amyloidogenic A beta fragment of
      Alzheimer's disease precursor protein in the hippocampus of aged transgenic mice.
AB  - To study amyloid beta-protein (A beta) production and aggregation in vivo, we
      created two transgenic (Tg) mouse lines expressing the C-terminal 100 amino acids
      of human amyloid precursor protein (APP): Tg C100.V717F and Tg C100.WT. Western
      blot analysis showed that human APP-C100 and A beta were produced in brain and
      some peripheral tissues and A beta was produced in serum. Using antibodies
      specific for the A beta C terminus we found that Tg C100.V717F produced a 1.6
      fold increase in A beta42/A beta40 compared with Tg C100.WT. Approximately 30% of
      total brain A beta (approximately 122 ng/g of wet tissue) was water-soluble. The
      remaining 70% of A beta partitioned into the particulate fraction and was
      completely sodium dodecyl sulfate-soluble. In contrast, human Alzheimer's disease
      brain has predominantly sodium dodecyl sulfate-insoluble A beta.
      Immunohistochemistry with an A beta(5-8) antibody showed that A beta or A beta
      containing fragments accumulated intracellularly in the hippocampus of aged Tg
      C100.V717F mice. The soluble A beta levels in Tg brain are similar to those in
      normal human brain, and this may explain the lack of microscopic amyloid deposits
      in the Tg mice. However, this mouse model provides a system to study the
      intracellular processing and accumulation of A beta or A beta-containing
      fragments and to screen for compounds directed at the gamma-secretase activity.

PMID- 10349859
TI  - Differences in the activation of the mitochondrial permeability transition among
      brain regions in the rat correlate with selective vulnerability.
AB  - Mitochondria from different regions of the brain were prepared, and the
      activation of the mitochondrial permeability transition (MPT) by calcium was
      investigated by monitoring the associated mitochondrial swelling. In general, the
      properties of the MPT in brain mitochondria were found to be qualitatively
      similar to those observed in liver and heart mitochondria. Thus, swelling was
      inhibited by adenine nucleotides (AdNs) and low pH (<7.0), whereas thiol reagents
      and alkalosis facilitated swelling. Cyclosporin A and its nonimmunosuppressive
      analogue N-methyl-Val-4-cyclosporin A (PKF 220-384) both inhibited swelling and
      prevented the translocation of cyclophilin D from the matrix to the membranes of
      cortical mitochondria. However, the calcium sensitivity of the MPT differed in
      mitochondria from three brain regions (hippocampus > cortex > cerebellum) and is
      correlated with the susceptibility of these regions to ischemic damage. Depleting
      mitochondria of AdNs by treatment with pyrophosphate ions sensitized the MPT to
      [Ca2+] and abolished regional differences, implying regional differences in
      mitochondrial AdN content. This was confirmed by measurements showing significant
      differences in AdN content among regions (cerebellum > cortex > hippocampus). Our
      data add to recent evidence that the MPT may be involved in neuronal death.

PMID- 10349860
TI  - A novel presenilin-2 splice variant in human Alzheimer's disease brain tissue.
AB  - Mutations in the presenilin-1 (PS-1) and presenilin-2 (PS-2) genes account for
      the majority of cases of early-onset familial Alzheimer's disease (AD).
      Alternative splicing forms of the PS-1 and PS-2 gene products have previously
      been reported in fibroblast and brain tissue from both familial and sporadic AD
      patients, as well as from normal tissues and cell lines. We demonstrate here
      unusual alternative splicing of the PS-2 gene that leads to the generation of
      mRNA lacking exon 5 in human brain tissue. This product was more frequently
      detected in brain tissue from sporadic AD patients (70.0%; 21 of 30) than from
      normal age-matched controls (17.6%; three of 17). In cultured neuroblastoma
      cells, this splice variant was generated in hypoxia but not under other forms of
      cellular stress. Hypoxia-mediated induction of this splice variant was blocked by
      pretreatment of neuroblastoma cells with the protein synthesis inhibitor
      cycloheximide or antioxidants such as N-acetylcysteine and diphenyl iodonium,
      suggesting that hypoxia-mediated oxidant stress might, at least in part, underlie
      the alternative splicing of PS-2 mRNA through de novo protein synthesis.
      Furthermore, the stable transfectants of this splice variant produced the N
      terminal part of PS-2 protein (15 kDa) and were more susceptible to cellular
      stresses than control transfectants. These results suggest the possibility that
      altered presenilin gene products in stress conditions may also participate in the
      pathogenesis of AD.

PMID- 10349861
TI  - Requirement for nitric oxide in retinal neuronal cell death induced by activated
      Muller glial cells.
AB  - Retinal Muller glial cells express the inducible isoform (-2) of nitric oxide
      (NO) synthase (NOS) in vitro after stimulation by lipopolysaccharide (LPS) and
      interferon-gamma (IFN-gamma) or in vivo in some retinal pathologies. Because NO
      may have beneficial or detrimental effects in the retina, we have used cocultures
      of retinal neurons with retinal Muller glial (RMG) cells from mice disrupted for
      the gene of NOS-2 [NOS-2 (-/-)] to clarify the role of NO in retinal
      neurotoxicity. We first demonstrated that NO produced by activated RMG cells was
      not toxic for RMG cells themselves. Second, the NO released from LPS/IFN-gamma
      stimulated RMG cells induced neuronal cell death, because no neuronal cell death
      has been observed in cocultures with RMG cells from NOS-2 (-/-) mice and because
      inhibition of NOS-2 induction by transforming growth factor-beta or blockade of
      NO release by different NOS inhibitors prevented neuronal cell death. Addition of
      urate, a peroxynitrite scavenger, or superoxide dismutase partially prevented
      neuronal cell death induced by NO, whereas the presence of a poly(ADP-ribose)
      synthetase inhibitor, caspase inhibitors, or a guanylate cyclase inhibitor had no
      significant effect on cell death. These results demonstrated that a large release
      of NO from RMG cells is responsible for retinal neuronal cell death in vitro,
      suggesting a neurotoxic role for NO and peroxynitrite during retinal inflammatory
      or degenerative diseases, where RMG cells were activated.

PMID- 10349862
TI  - Mazindol attenuates the 3,4-methylenedioxymethamphetamine-induced formation of
      hydroxyl radicals and long-term depletion of serotonin in the striatum.
AB  - The formation of hydroxyl radicals following the systemic administration of 3,4
      methylenedioxymethamphetamine (MDMA) was studied in the striatum of the rat by
      quantifying the stable adducts of salicylic acid and D-phenylalanine, namely, 2,3
      dihydroxybenzoic acid (2,3-DHBA) and p-tyrosine, respectively. The repeated
      administration of MDMA produced a sustained increase in the extracellular
      concentration of 2,3-DHBA and p-tyrosine, as well as dopamine. The MDMA-induced
      increase in the extracellular concentration of both dopamine and 2,3-DHBA was
      suppressed in rats treated with mazindol, a dopamine uptake inhibitor. Mazindol
      also attenuated the long-term depletion of serotonin (5-HT) in the striatum
      produced by MDMA without altering the acute hyperthermic response to MDMA. These
      results are supportive of the view that MDMA produces a dopamine-dependent
      increase in the formation of hydroxyl radicals in the striatum that may
      contribute to the mechanism whereby MDMA produces a long-term depletion of brain
      5-HT content.

PMID- 10349863
TI  - The glutathione system of peroxide detoxification is less efficient in neurons
      than in astroglial cells.
AB  - The ability of neurons to detoxify exogenously applied peroxides was analyzed
      using neuron-rich primary cultures derived from embryonic rat brain. Incubation
      of neurons with H2O2 at an initial concentration of 100 microM (300 nmol/3 ml)
      led to a decrease in the concentration of the peroxide, which depended strongly
      on the seeding density of the neurons. When 3 x 10(6) viable cells were seeded
      per dish, the half-time for the clearance by neurons of H2O2 from the incubation
      buffer was 15.1 min. Immediately after application of 100 microM H2O2 to neurons,
      glutathione was quickly oxidized. After incubation for 2.5 min, GSSG accounted
      for 48% of the total glutathione. Subsequent removal of H2O2 caused an almost
      complete regeneration of the original ratio of GSH to GSSG within 2.5 min.
      Compared with confluent astroglial cultures, neuron-rich cultures cleared H2O2
      more slowly from the incubation buffer. However, if the differences in protein
      content were taken into consideration, the ability of the cells to dispose of
      H2O2 was identical in the two culture types. The clearance rate by neurons for
      H2O2 was strongly reduced in the presence of the catalase inhibitor 3
      aminotriazol, a situation contrasting with that in astroglial cultures. This
      indicates that for the rapid clearance of H2O2 by neurons, both glutathione
      peroxidase and catalase are essential and that the glutathione system cannot
      functionally compensate for the loss of the catalase reaction. In addition, the
      protein-normalized ability of neuronal cultures to detoxify exogenous cumene
      hydroperoxide, an alkyl hydroperoxide that is reduced exclusively via the
      glutathione system, was lower than that of astroglial cells by a factor of 3.
      These results demonstrate that the glutathione system of peroxide detoxification
      in neurons is less efficient than that of astroglial cells.

PMID- 10349864
TI  - Estrogen hormones reduce lipid peroxidation in cells and tissues of the central
      nervous system.
AB  - Effects of estrogen hormones on lipid peroxidation (LPO) were examined in rat
      brain homogenates (RBHs), hippocampal HT 22 cells, rat primary neocortical
      cultures, and human brain homogenates (HBHs). Dose-response curves indicated half
      maximal effective concentrations (EC50) of 5.5 and 5.6 mM for iron-induced LPO in
      RBHs and HT 22 homogenates. Incubation of living rat primary neocortical cultures
      with iron resulted in an EC50 of 0.5 mM, whereas culture homogenates showed an
      EC50 of 1.2 mM. Estrogen hormones reduced LPO in all systems: In RBHs, estrone
      inhibited iron-induced LPO to 74.1 +/- 5.8% of control levels (17beta-estradiol:
      71.3 +/- 0.1%) at a concentration of 10 microM. In hippocampal HT 22 cell
      homogenates, levels of LPO were reduced to 74.8 +/- 5.5% by estrone and to 47.8
      +/- 6.2% by 17beta-estradiol. In living neocortical cultures, 17beta-estradiol
      decreased iron-induced LPO to 79.2 +/- 4.8% and increased the survival of
      cultured neuronal cells. Of the other steroid compounds tested (corticosterone,
      progesterone, testosterone), only progesterone decreased LPO in HT 22 cell
      homogenates. In HBHs, LPO was dose-dependently increased by iron concentrations
      from 2.7 to 6.0 mM. Incubation with estrogens resulted in a dose-dependent
      inhibition of LPO to 53.8 +/- 8.6% with 10 microM 17beta-estradiol, whereas
      estrone failed to affect iron-induced LPO to a significant extent. Nonestrogenic
      steroids, including hydrocortisol, did not show significant effects on LPO in
      HBHs.

PMID- 10349865
TI  - Characterization of the dimerization of metabotropic glutamate receptors using an
      N-terminal truncation of mGluR1alpha.
AB  - The metabotropic glutamate receptor mGluR1alpha in membranes isolated both from
      rat brain and from cell lines transfected with cDNA coding for the receptor
      migrates as a disulphide-bonded dimer on sodium dodecyl sulphate-polyacrylamide
      gels. Dimerization of mGluR1alpha takes place in the endoplasmic reticulum
      because it is not prevented by exposing transfected human embryonic kidney (HEK)
      293 cells to the drug brefeldin A, a drug that prevents egress of proteins from
      the endoplasmic reticulum. Dimerization was also not dependent on protein
      glycosylation as it was not prevented by treatment of the cells with tunicamycin.
      Using a mammalian expression vector containing the N-terminal domain of
      mGluR1alpha, truncated just before the first transmembrane domain (NT
      mGluR1alpha), we show that the N-terminal domain is secreted as a soluble
      disulphide-bonded dimeric protein. In addition, the truncated N-terminal domain
      can form heterodimers with mGluR1alpha when both proteins are cotransfected into
      HEK 293 cells. However, mGluR1alpha and its splice variant mGluR1beta did not
      form heterodimers in doubly transfected HEK 293 cells. These results show that
      although the N-terminal domain of mGluR1alpha is sufficient for dimer formation,
      other domains in the molecule must regulate the process.

PMID- 10349866
TI  - Uptake of 13C-tracer arachidonate and gamma-linolenate by the brain and liver of
      the suckling rat observed using 13C-NMR.
AB  - Arachidonic acid (AA; 20:4n-6) is one of the principal components of the
      phosphoglycerides in neural cell membranes. During the critical period of
      postnatal development in mammals, AA is supplied preformed, directly from the
      milk or derived from precursor fatty acids such as gamma-linolenic acid (GLA;
      18:3n-6). In this study, 13C-NMR spectroscopy was applied to investigate the
      incorporation of [1-(13)C]AA and [3-(13)C]GLA into liver and brain lipids of 7-15
      day-old rats. The main objective was to establish the importance of dietary GLA
      for tissue AA accretion relative to the contribution from preformed dietary AA.
      [1-(13)C]AA and [3-(13)C]GLA were injected into the stomach of 7-day-old rats as
      a mixture. 13C-NMR spectroscopy of lipid extracts revealed incorporation of [1
      (13)C]AA and [5-(13)C]AA (the latter derived from metabolism of the injected [3
      (13)C]GLA) into phosphoglycerides and triacylglycerols. Preformed AA was 10
      (liver)-17 (brain) times more efficient in contributing to tissue AA than AA
      derived from precursor GLA. In separate experiments, NMR spectroscopy was used to
      assess uptake of [1-(13)C]AA directly in living rats and intact organs. Results
      showed that intact liver and brain contain an appreciable amount of NMR
      detectable lipids. The in vivo/in vitro information obtained from organs provided
      details on the mobility and turnover of tissue lipids.

PMID- 10349867
TI  - Translocation and down-regulation of protein kinase C-alpha, -beta, and -gamma
      isoforms during ischemia-reperfusion in rat brain.
AB  - We investigated the distribution of protein kinase C (PKC) isoforms in the
      subcellular fractions (P1, 1,000-g pellet; P2, 10,000-g pellet; P3, 100,000-g
      pellet; S, 100,000-g supernatant) of rat forebrain after ischemia or reperfusion
      by immunoblotting. PKC-delta and -epsilon isoforms were predominant in the P2
      (synaptosome-rich) fraction, whereas PKC-alpha, -beta, -gamma, -epsilon, and 
      zeta isoforms were rich in the S (cytosolic) fraction. With time of ischemia (5
      30 min), PKC-alpha, -beta, and -gamma translocated to the P2 and P3 fractions,
      whereas reperfusion for 60 min after 30 min of ischemia reduced PKC-beta activity
      greatly and PKC-alpha and -gamma activities to a lesser extent. There was no
      redistribution of PKC-delta, -epsilon, and -zeta after ischemia or reperfusion. A
      calpain inhibitor, acetylleucylleucylnorleucinal, inhibited the down-regulation
      of PKC-beta, through intravenous injection. The PKC translocation to the P2
      fraction was accompanied by their dephosphorylation, transition of PKC-alpha from
      dimer to trimer, and the decrease in activity. These data show that PKC-alpha, 
      beta, and -gamma isoforms translocate chiefly to the synaptosome in ischemic
      brain in association with the dephosphorylation, multimeric change, and
      inactivation, followed by the proteolysis of PKC-beta by calpain after
      postischemic reperfusion.

PMID- 10349868
TI  - Effects of erythropoietin on neuronal activity.
AB  - Recently, erythropoietin (EPO) receptors and synthesis of EPO have been
      identified in the brain. To clarify the effects of EPO on neuronal cells, we
      investigated the effects of EPO on Ca2+ uptake, intracellular Ca2+ concentration,
      membrane potential, cell survival, release and biosynthesis of dopamine, and
      nitric oxide (NO) production in differentiated PC12 cells, which possess EPO
      receptors. EPO (10(-12)-10(-10) M) increased 45Ca2+ uptake and intracellular Ca2+
      concentration in PC12 cells in a dose-related manner; these increases were
      inhibited by nicardipine (1 microM) or anti-EPO antibody (1:100 dilution). EPO
      induced membrane depolarization in PC12 cells. After a 5-day culture without
      serum and nerve growth factor (NGF), viable cell number decreased to 50% of that
      of the control cells cultured with serum and NGF. EPO (10(-13)-10(-10) M)
      increased the number of viable cells cultured without serum and NGF; this
      increase was blunted by nicardipine or anti-EPO antibody. Incubation with EPO
      (10(-13)-10(-10) M) stimulated mitogen-activated protein kinase activity in PC12
      cells. EPO (10(-13)-10(-10) M) increased dopamine release from PC12 cells and
      tyrosine hydroxylase activity; these increases were sensitive to nicardipine or
      anti-EPO antibody. Following a 4-h incubation with EPO (10(-14)-10(-10) M), NO
      production was increased, which was blunted by nicardipine and anti-EPO antibody.
      In contrast, maximal NO synthase activity was not changed by EPO. These results
      suggest that EPO stimulates neuronal function and viability via activation of
      Ca2+ channels.

PMID- 10349869
TI  - A lysosomal proteinase, the late infantile neuronal ceroid lipofuscinosis gene
      (CLN2) product, is essential for degradation of a hydrophobic protein, the
      subunit c of ATP synthase.
AB  - The specific accumulation of the hydrophobic protein, subunit c of ATP synthase,
      in lysosomes from the cells of patients with the late infantile form of neuronal
      ceroid lipofuscinosis (LINCL) is caused by lysosomal proteolytic dysfunction. The
      defective gene in LINCL (CLN2 gene) has been identified recently. To elucidate
      the mechanism of lysosomal storage of subunit c, antibodies against the human
      CLN2 gene product (Cln2p) were prepared. Immunoblot analysis indicated that Cln2p
      is a 46-kDa protein in normal control skin fibroblasts and carrier heterozygote
      cells, whereas it was absent in cells from four patients with LINCL. RT-PCR
      analysis indicated the presence of mRNA for CLN2 in cells from the four different
      patients tested, suggesting a low efficiency of translation of mRNA or the
      production of the unstable translation products in these patient cells. Pulse
      chase analysis showed that Cln2p was synthesized as a 67-kDa precursor and
      processed to a 46-kDa mature protein (t(1/2) = 1 h). Subcellular fractionation
      analysis indicated that Cln2p is localized with cathepsin B in the high-density
      lysosomal fractions. Confocal immunomicroscopic analysis also revealed that Cln2p
      is colocalized with a lysosomal soluble marker, cathepsin D. The immunodepletion
      of Cln2p from normal fibroblast extracts caused a loss in the degradative
      capacity of subunit c, but not the beta subunit of ATP synthase, suggesting that
      the absence of Cln2p provokes the lysosomal accumulation of subunit c.

PMID- 10349870
TI  - A novel subtype of prostacyclin receptor in the central nervous system.
AB  - Recently, in the course of our search for the prostacyclin receptor in the brain,
      we found a novel subtype, designated as IP2, which was finely discriminated by
      use of the specific ligand (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin
      (15R-TIC) and specifically localized in the rostral part of the brain. In the
      present study, the tritiated compound 15R-[15-(3)H]TIC was synthesized and
      utilized for more specific research on IP2. The specificity of binding to rat
      brain regions was confirmed by use of several prostacyclin derivatives including
      15S-TIC. Mapping of 15R- and 15S-[3H]TIC binding in adjacent pairs of frozen
      sections of rat brain demonstrated a quite similar pattern of distribution in
      almost all rostral brain regions, indicating that the regions may contain only
      the IP2 subtype. On the other hand, 15R-[3H]TIC binding was very faint as
      compared with 15S-[3H]TIC binding in the caudal medullary region. High densities
      of 15R-[3H]TIC binding sites were shown in the dorsal part of the lateral septal
      nucleus, thalamic nuclei, limbic structures, and some of the cortical regions.
      Scatchard plot analysis showed two components of high-affinity 15R-[3H]TIC
      binding in the rostral regions, one with a K(D) value at approximately 1 nM and
      the other with approximately 30 nM. These results strengthen our previous finding
      that a different subtype of prostacyclin receptor is expressed in the CNS, and
      the map with 15R-[3H]TIC obtained here could guide further studies on the
      molecular and functional properties of the IP2.

PMID- 10349871
TI  - Biochemical and autoradiographic measurements of brain serotonin synthesis rate
      in the freely moving rat: a reexamination of the alpha-methyl-L-tryptophan
      method.
AB  - Biochemical approaches were used in freely moving rats to determine, under steady
      state conditions, the brain/arterial plasma partition coefficients of L
      tryptophan and alpha-[3H]methyl-L-tryptophan, from which the lumped constant for
      the alpha-methyl-L-tryptophan method of estimating the rate of brain serotonin
      synthesis is calculated. The lumped constants were significantly different in the
      various structures examined: 0.149 +/- 0.003 in the raphe dorsalis, 0.103 +/-
      0.002 in the raphe centralis, 0.087 +/- 0.003 in the reticular formation, and
      0.62 +/- 0.08 in the pineal gland. From these data we proposed a two-compartment
      model to calculate the rate of serotonin synthesis by quantitative
      autoradiography using a three-time point experiment. Rates of synthesis for the
      raphe dorsalis and the reticular formation (620 +/- 57 and 80 +/- 35 pmol/g of
      tissue/min, respectively) were similar to those measured simultaneously by
      biochemical means, but rates were 50% higher for the raphe centralis (568 +/- 90
      vs. 381 +/- 31 pmol/g of tissue/min). The lack of dynamic equilibrium of the
      tracer between plasma and tissue pools may explain the discrepancy between the
      two methods. Our findings did not confirm previous data, indicating that the
      application of the autoradiographic method to measure the rate of brain serotonin
      synthesis using alpha-methyl-L-tryptophan as tracer has limitations.

PMID- 10349872
TI  - Oxidized low-density lipoprotein induces neuronal death: implications for
      calcium, reactive oxygen species, and caspases.
AB  - Low-density lipoprotein (LDL) exists within the brain and is highly vulnerable to
      oxidative modifications. Once formed, oxidized LDL (oxLDL) is capable of
      eliciting cytotoxicity, differentiation, and inflammation in nonneuronal cells.
      Although oxLDL has been studied primarily for its role in the development of
      atherosclerosis, recent studies have identified a possible role for it in
      neurological disorders associated with oxidative stress. In the present study
      application of oxLDL, but not LDL, resulted in a dose- and time-dependent death
      of cultured rat embryonic neurons. Studies using pharmacological inhibitors
      implicate the involvement of calcium, reactive oxygen species, and caspases in
      oxLDL-induced neuronal death. Coapplication of oxLDL with either amyloid beta
      peptide or glutamate, agents that enhance oxidative stress, resulted in increased
      neuronal death. Taken together, these data demonstrate that oxLDL induces
      neuronal death and implicate a possible role for oxLDL in conditions associated
      with increased levels of reactive oxygen species, including Alzheimer's disease.

PMID- 10349874
TI  - Sepsis increases intracellular free calcium in brain.
AB  - Using magnetic resonance methods and a clinically relevant rodent model of
      sepsis, we have made in vivo measurements of increased intracellular calcium in a
      pathologic state in the CNS. The intracellular calcium concentration was
      increased nearly twofold in septic rat brain compared with controls (p < 0.0001).
      This result, in a fully intact functioning mammalian system, ties together a
      previous spectrum of indirect evidence from numerous laboratories suggesting an
      important role for elevated intracellular calcium in sepsis. In addition, levels
      of the proinflammatory cytokine tumor necrosis factor-a were elevated threefold
      in septic rat brain (p < 0.02), and electron microscopic examination revealed
      scattered injury in approximately 0.25% of glial cells. These findings are
      discussed in light of the current understanding of the pathophysiology of sepsis.

PMID- 10349873
TI  - Effect of ATP depletion on the palmitoylation of myelin proteolipid protein in
      young and adult rats.
AB  - The present study was designed to determine whether the palmitoylation of the
      hydrophobic myelin proteolipid protein (PLP) is dependent on cellular energy. To
      this end, brain slices from 20- and 60-day-old rats were incubated with
      [3H]palmitate for 1 h in the presence or absence of various metabolic poisons. In
      adult rats, the inhibition of mitochondrial ATP production with KCN (5 mM),
      oligomycin (10 microM), or rotenone (10 microM) reduced the incorporation of
      [3H]palmitate into fatty acyl-CoA and glycerolipids by 50-60%, whereas the
      labeling of PLP was unaltered. Incubation in the presence of rotenone (10 microM)
      plus NaF (5 mM) abolished the synthesis of acyl-CoA and lipid palmitoylation, but
      the incorporation of [3H]palmitate into PLP was still not different from that in
      controls. In rapidly myelinating animals, the inhibition of both mitochondrial
      electron transport and glycolysis obliterated the palmitoylation of lipids but
      reduced that of PLP by only 40%. PLP acylation was reduced to a similar extent
      when slices were incubated for up to 3 h, indicating that exogenously added
      palmitate is incorporated into PLP by ATP-dependent and ATP-independent
      mechanisms. Determination of the number of PLP molecules modified by each of
      these reactions during development suggests that the ATP-dependent process is
      important during the formation and/or compaction of the myelin sheath, whereas
      the ATP-independent mechanism is likely to play a role in myelin maintenance,
      perhaps by participating in the periodic repair of thioester linkages between the
      fatty acids and the protein.

PMID- 10349875
TI  - Role of conserved serine residues in the interaction of agonists with D3 dopamine
      receptors.
AB  - To understand the role of conserved serine residues in the fifth transmembrane
      domain (Ser192, Ser193, and Ser196) of the D3 dopamine receptor, these have been
      mutated individually to alanine, and the ligand binding properties of the mutant
      receptors have been evaluated. The mutations had little or no effect on the
      binding of the antagonist spiperone and the agonist quinpirole, indicating that
      the overall conformation of the receptor was unaffected. The binding of dopamine
      and 7-hydroxydipropylaminotetralin, agonists containing hydroxyl groups, was,
      however, of lower affinity for the Ser192 mutation but unaffected by the other
      mutations (Ser193 and Ser196). Therefore, for the agonists tested, the hydroxyl
      groups interact exclusively with Ser192.

PMID- 10349876
TI  - Calcium neurotoxicity.

PMID- 10349877
TI  - New findings in the genetics of alcoholism.

PMID- 10349878
TI  - Schizophrenia researchers striving for early detection and intervention.

PMID- 10349879
TI  - Eradication efforts need needle-free delivery.

PMID- 10349882
TI  - From the Centers for Disease Control and Prevention. Assessment of public health
      computer readiness for 2000--United States, 1999.

PMID- 10349880
TI  - From the Centers for Disease Control and Prevention. Knowledge and use of folic
      acid by women of childbearing age--United States, 1995 and 1998.

PMID- 10349883
TI  - From the Centers for Disease Control and Prevention. Back pain among persons
      working on small or family farms--eight Colorado counties, 1993-1996.

PMID- 10349884
TI  - Low-dose hydrocortisone for chronic fatigue syndrome.

PMID- 10349885
TI  - Low-dose hydrocortisone for chronic fatigue syndrome.

PMID- 10349887
TI  - Care of prison inmates by impaired disciplined physicians.

PMID- 10349886
TI  - Low-dose hydrocortisone for chronic fatigue syndrome.

PMID- 10349888
TI  - Care of prison inmates by impaired disciplined physicians.

PMID- 10349889
TI  - Care of prison inmates by impaired disciplined physicians.

PMID- 10349890
TI  - Dose of tricyclic antidepressants in elderly patients.

PMID- 10349891
TI  - Are enteric infections associated with unpasteurized orange juice?

PMID- 10349892
TI  - Fall-induced injuries and deaths among older adults.
AB  - CONTEXT: Although various fall-induced injuries and deaths among older adults are
      increasing, little is known about the epidemiology of these events. OBJECTIVE: To
      determine the trends in the number and incidence of fall-induced injuries and
      deaths of older adults in a well-defined white population. DESIGN AND SETTING:
      Secular trend analysis of the population of Finland, using the Finnish National
      Hospital Discharge Register and the Official Cause-of-Death Statistics of
      Finland. PARTICIPANTS: All persons aged 50 years or older who were admitted to
      hospitals in Finland for primary treatment of a first fall-induced injury from
      the years of 1970 to 1995, and for comparison, all fall-induced deaths in the
      same age group from the years 1971 to 1995. MAIN OUTCOME MEASURE: The number and
      the age-specific and age-adjusted incidence rate (per 100000 persons) of fall
      induced injuries and deaths in each year of the study. RESULTS: For the study
      period, both the total and population-adjusted number (per 100000 persons) of
      Finns aged 50 years or older with fall-induced injury increased substantially.
      Total fall-induced injuries increased from 5622 in 1970 to 21 574 in 1995, a 284%
      increase, and the rate increased from 494 to 1398 per 100000 persons, a 183%
      increase. The age-adjusted incidence also increased in both women (from 648 in
      1970 to 1469 in 1995, a 127% increase) and men (from 434 in 1970 to 972 in 1995,
      a 124% increase). Moreover, the number of deaths due to falls in the overall
      population increased from 441 in 1971 to 793 in 1995, an 80% increase, and the
      rate increased from 38 in 1971 to 51 in 1995, a 34% increase. However, after age
      adjustment the incidence of fall-induced death did not show a clear upward trend.
      CONCLUSIONS: In a well-defined white population, the number of older persons with
      fall-induced injuries is increasing at a rate that cannot be explained simply by
      demographic changes. Preventive measures should be adopted to control the
      increasing burden of these injuries. Fortunately, the age-adjusted incidence of
      the fall-induced deaths shows no increasing trend over time.

PMID- 10349893
TI  - Are guidelines following guidelines? The methodological quality of clinical
      practice guidelines in the peer-reviewed medical literature.
AB  - CONTEXT: Practice guidelines play an important role in medicine. Methodological
      principles have been formulated to guide their development. OBJECTIVE: To
      determine whether practice guidelines in peer-reviewed medical literature adhered
      to established methodological standards for practice guidelines. DESIGN:
      Structured review of guidelines published from 1985 through June 1997 identified
      by a MEDLINE search. MAIN OUTCOME MEASURES: Mean number of standards met based on
      a 25-item instrument and frequency of adherence. RESULTS: We evaluated 279
      guidelines, published from 1985 through June 1997, produced by 69 different
      developers. Mean overall adherence to standards by each guideline was 43.1%
      (10.77/25). Mean (SD) adherence to methodological standards on guideline
      development and format was 51.1% (25.3%); on identification and summary of
      evidence, 33.6% (29.9%); and on the formulation of recommendations, 46% (45%).
      Mean adherence to standards by each guideline improved from 36.9% (9.2/25) in
      1985 to 50.4% (12.6/25) in 1997 (P<.001). However, there was little improvement
      over time in adherence to standards on identification and summary of evidence
      from 34.6% prior to 1990 to 36.1 % after 1995 (P = .11). There was no difference
      in the mean number of standards satisfied by guidelines produced by subspecialty
      medical societies, general medical societies, or government agencies (P = .55).
      Guideline length was positively correlated with adherence to methodological
      standards (P = .001). CONCLUSION: Guidelines published in the peer-reviewed
      medical literature during the past decade do not adhere well to established
      methodological standards. While all areas of guideline development need
      improvement, greatest improvement is needed in the identification, evaluation,
      and synthesis of the scientific evidence.

PMID- 10349894
TI  - Risk of meningococcal infection in college students.
AB  - CONTEXT: The number of meningococcal outbreaks on college campuses have been
      increasing in the past few years. However, no published studies have documented
      the incidence of invasive meningococcal infection in college students or whether
      the incidence is higher than in the general population of the same age.
      OBJECTIVE: To compare the incidence of invasive meningococcal infection in
      Maryland college students with that of the general population of the same age.
      DESIGN: Retrospective cohort study. SETTING AND PATIENTS: Maryland residents with
      meningococcal infection from 1992-1997 identified from active, laboratory-based,
      statewide surveillance for invasive meningococcal disease. MAIN OUTCOME MEASURES:
      Incidence of invasive meningococcal infection. RESULTS: Of 228 patients with
      invasive meningococcal infection, 67 were aged 16 to 30 years; 11 and 3 of these
      attended Maryland 4- and 2-year colleges, respectively. Of these, 12 (86%) had
      infection caused by Neisseria meningitidis serogroups included in the current
      meningococcal vaccine. The average annual incidence was 1.74 per 100000 among
      students in 4-year schools vs 1.44 per 100000 for the general population of the
      same age (P=.60). Among students in 4-year schools, the incidence was 3.24 per
      100000 in on-campus residents vs 0.96 per 100000 in off-campus residents
      (relative risk, 3.4; 95% confidence interval, 1.0-11.6; P=.05). CONCLUSIONS: The
      incidence of meningococcal infection in college students is similar to the
      incidence in the general population of the same age, but college students
      residing on campus appear to be at higher risk than those residing off campus.

PMID- 10349895
TI  - Tourism and hotel revenues before and after passage of smoke-free restaurant
      ordinances.
AB  - CONTEXT: Claims that ordinances requiring smoke-free restaurants will adversely
      affect tourism have been used to argue against passing such ordinances. Data
      exist regarding the validity of these claims. OBJECTIVE: To determine the changes
      in hotel revenues and international tourism after passage of smoke-free
      restaurant ordinances in locales where the effect has been debated. DESIGN:
      Comparison of hotel revenues and tourism rates before and after passage of 100%
      smoke-free restaurant ordinances and comparison with US hotel revenue overall.
      SETTING: Three states (California, Utah, and Vermont) and 6 cities (Boulder,
      Colo; Flagstaff, Ariz; Los Angeles, Calif; Mesa, Ariz; New York, NY; and San
      Francisco, Calif) in which the effect on tourism of smoke-free restaurant
      ordinances had been debated. MAIN OUTCOME MEASURES: Hotel room revenues and hotel
      revenues as a fraction of total retail sales compared with preordinance revenues
      and overall US revenues. RESULTS: In constant 1997 dollars, passage of the smoke
      free restaurant ordinance was associated with a statistically significant
      increase in the rate of change of hotel revenues in 4 localities, no significant
      change in 4 localities, and a significant slowing in the rate of increase (but
      not a decrease) in 1 locality. There was no significant change in the rate of
      change of hotel revenues as a fraction of total retail sales (P=.16) or total US
      hotel revenues associated with the ordinances when pooled across all localities
      (P = .93). International tourism was either unaffected or increased following
      implementation of the smoke-free ordinances. CONCLUSION: Smoke-free ordinances do
      not appear to adversely affect, and may increase, tourist business.

PMID- 10349896
TI  - Clinical epidemiological quality in molecular genetic research: the need for
      methodological standards.
AB  - CONTEXT: A genetic basis has been identified for many medical conditions and some
      molecular tests have been commercialized. However, little attention has been
      given to the quality of clinical epidemiology in molecular studies. OBJECTIVE: To
      examine the clinical epidemiological quality of recent publications on molecular
      genetic analysis. DESIGN: Cross-sectional study of original research articles
      published in 1995, identified by manually searching 4 general clinical journals.
      Of 83 articles identified, 40 were selected for analysis; these 40 discussed
      molecular genetic techniques, studied 10 or more patients, and had inferential
      conclusions. MAIN OUTCOME MEASURE: Compliance of the selected articles with 7
      methodological standards for clinical epidemiological science (reproducibility,
      objectivity, delineation of case group, adequacy of spectrum in case group,
      delineation of comparison group, adequacy of comparison group, and quantitative
      summary of results). RESULTS: Among the 40 inferential articles that studied 10
      or more patients, only 5 (12.5%) complied with all 7 applicable standards, and 10
      (25.0%) complied with all but 1 standard, whereas 25 articles (62.5%) failed to
      comply with 2 or more standards and 9 (22.5%) failed 4 or 5 standards. Most
      articles did not comply with standards for reproducibility (n = 25, 62.5%) or
      objectivity (n = 27, 67.5%); however, the majority of articles did comply with
      standards for adequacy of case group (n = 35, 87.5 %), adequacy of comparison
      group (n = 35, 87.5%), and quantitative summary of results (n = 36, 90%).
      CONCLUSIONS: Despite major laboratory advances in molecular genetic analysis, our
      data suggest that reported applications in clinical journals often have troubling
      omissions, deficiencies, and lack of attention to the different, but necessary,
      principles of clinical epidemiological science. Without suitable attention to
      fundamental methodological standards, the expected benefits of molecular genetic
      testing may not be achieved.

PMID- 10349897
TI  - Meta-analysis of trials comparing beta-blockers, calcium antagonists, and
      nitrates for stable angina.
AB  - CONTEXT: Which drug is most effective as a first-line treatment for stable angina
      is not known. OBJECTIVE: To compare the relative efficacy and tolerability of
      treatment with beta-blockers, calcium antagonists, and long-acting nitrates for
      patients who have stable angina. DATA SOURCES: We identified English-language
      studies published between 1966 and 1997 by searching the MEDLINE and EMBASE
      databases and reviewing the bibliographies of identified articles to locate
      additional relevant studies. STUDY SELECTION: Randomized or crossover studies
      comparing antianginal drugs from 2 or 3 different classes (beta-blockers, calcium
      antagonists, and long-acting nitrates) lasting at least 1 week were reviewed.
      Studies were selected if they reported at least 1 of the following outcomes:
      cardiac death, myocardial infarction, study withdrawal due to adverse events,
      angina frequency, nitroglycerin use, or exercise duration. Ninety (63%) of 143
      identified studies met the inclusion criteria. DATA EXTRACTION: Two independent
      reviewers extracted data from selected articles, settling any differences by
      consensus. Outcome data were extracted a third time by 1 of the investigators. We
      combined results using odds ratios (ORs) for discrete data and mean differences
      for continuous data. Studies of calcium antagonists were grouped by duration and
      type of drug (nifedipine vs nonnifedipine). DATA SYNTHESIS: Rates of cardiac
      death and myocardial infarction were not significantly different for treatment
      with beta-blockers vs calcium antagonists (OR, 0.97; 95% confidence interval
      [CI], 0.67-1.38; P = .79). There were 0.31 (95% CI, 0.00-0.62; P = .05) fewer
      episodes of angina per week with beta-blockers than with calcium antagonists.
      beta-Blockers were discontinued because of adverse events less often than were
      calcium antagonists (OR, 0.72; 95% CI, 0.60-0.86; P<.001). The differences
      between beta-blockers and calcium antagonists were most striking for nifedipine
      (OR for adverse events with beta-blockers vs nifedipine, 0.60; 95% CI, 0.47
      0.77). Too few trials compared nitrates with calcium antagonists or beta-blockers
      to draw firm conclusions about relative efficacy. CONCLUSIONS: beta-Blockers
      provide similar clinical outcomes and are associated with fewer adverse events
      than calcium antagonists in randomized trials of patients who have stable angina.

PMID- 10349898
TI  - A 44-year-old woman with severe pain at the end of life.

PMID- 10349899
TI  - A 55-year-old man with attention-deficit/hyperactivity disorder, 1 year later.

PMID- 10349900
TI  - Prophylactic cesarean delivery for the prevention of perinatal human
      immunodeficiency virus transmission: the case for restraint.

PMID- 10349902
TI  - JAMA Patient Page: fall-induced injuries.

PMID- 10349901
TI  - The trials and tribulations of clinical practice guidelines.

PMID- 10349903
TI  - Expanding mobilized progenitors for hematotherapy.

PMID- 10349904
TI  - Ex vivo expansion of hematopoietic stem and progenitor cells: are we there yet?
AB  - Ex vivo expansion of hematopoietic stem and progenitor cells is a very ambitious
      idea that would have major implications in the areas of stem cell transplantation
      and somatic gene therapy. However, successful ex vivo expansion has evaded and
      frustrated scientists for a number of years. The goal of ex vivo expansion is to
      induce cell division and proliferation of stem cells while maintaining their
      primary functional characteristic, namely, their ability to engraft and sustain
      long-term hematopoiesis. Only when a balance between these two requirements is
      reached can ex vivo expansion of stem cells be considered successful.
      Establishing such a balance has not been easy. However, many lessons have been
      learned along the way, and today we have a more profound understanding of the
      potential obstacles facing ex vivo expansion than we did only a few years ago. In
      this review, we discuss these obstacles and evaluate the current status of ex
      vivo expansion of stem and progenitor cells both from the perspective of basic
      stem cell biology and from the viewpoint of clinical utility of these cells in
      transplantation.

PMID- 10349905
TI  - Peripheral blood stem cell mobilization for high-dose chemotherapy.
AB  - Several studies have clearly documented a more rapid hematopoietic recovery with
      growth factor-mobilized PBSC than with bone marrow. Time to engraftment for
      neutrophils and platelets average 8-12 days in contrast to 2-4 weeks after bone
      marrow. This rapid hematopoietic recovery with PBSC has decreased the duration of
      hospitalization, transfusion requirements, and costs. Although growth factors
      alone may mobilize enough PBSC for high-dose chemotherapy, administration of
      growth factor after submyeloablative chemotherapy increases the yield of CD34+
      cells. Based on the current data, CD34+ cell content of PBSC appears to be the
      single most powerful predictor of hematopoietic recovery. Infusion of > or =5 x
      10(6) CD34+ cells/kg is associated with a rapid engraftment of neutrophils and
      platelets, although successful engraftment has also been reported with infusion
      of 2.5-5 x 10(6) CD34+ cells/kg. Age, prior radiotherapy, marrow involvement, and
      prior chemotherapy regimens are important factors influencing the yield of stem
      cells. Therefore, using these pa-rameters, we may identify the patients who will
      fail to mobilize sufficient numbers of PBSC before collection and use new
      strategies for stem cell mobilization. Because of the ease of collection and
      rapid engraftment after myeloablative therapy, PBSC have replaced bone marrow for
      autologous transplantation and may supplant bone marrow for allogeneic
      transplantation in the near future.

PMID- 10349906
TI  - Clinical scale expansion of cryopreserved small volume whole bone marrow
      aspirates produces sufficient cells for clinical use.
AB  - Ex vivo expansion of bone marrow (BM) mononuclear cells (MNC) in a perfused
      culture system produces stem-progenitor cell type(s) in sufficient number(s) for
      hematopoietic reconstitution. The limitations in using fresh BM MNC for ex vivo
      expansion include additional cell processing and inflexibility in patient
      treatment. Cryopreservation of whole bone marrow (WBM) eliminates processing
      costs of MNC or CD34+ cell selection and allows for flexibility in patient
      treatment. We developed a convenient system to cryopreserve and thaw small volume
      WBM aspirations (n = 13) and then compared the expandability of unprocessed
      normal cryopreserved/thawed (C/T) WBM to that of fresh BM MNC cultured in the
      presence of erythropoietin, PIXY 321, and Flt3-ligand. Ex vivo expansion
      potential was retained in WBM aspirates after C/T. When initiated with 225
      million viable nucleated cells, clinical scale expansion cultures (n = 6) yielded
      9.7+/-2.8 x 10(8) total cells, which contained 10.4+/-5.8 x 10(6) colony-forming
      units-granulocyte-macrophage (CFU-GM), 1.3+/-1.4 x 10(4) LTCIC, and 2.2 x 10(6)
      CD34+Lin- cells, sufficient cell numbers for clinical use. These studies
      demonstrate that ex vivo perfusion culture expansion of unfractionated C/T WBM (<
      or =30 ml) provides doses of stem-progenitor cells similar in composition to
      expanded fresh BM MNC, previously demonstrated to achieve hematopoietic
      reconstitution.

PMID- 10349907
TI  - Large ex vivo expansion of human umbilical cord blood CD4+ and CD8+ T cells.
AB  - The use of human umbilical cord (UC) blood as a source of transplantable
      hematopoietic stem cells and progenitor cells may present some advantages over
      the use of BM. For example, it has been suggested that the degree of HLA matching
      may be less stringent, and the risk of GvHD may be lower. We have been studying
      the ex vivo expansion of UC blood T lymphocytes with a view to their use in the
      adoptive immunotherapy of cancer, autoimmunity, and infectious disease. We have
      developed a new method involving the use of a conditioned medium (XLCM) that
      consistently results in levels of UC blood T cell expansion not hitherto
      possible. Primary cultures of unfractionated low-density MNC (LDMNC) derived from
      UC blood treated with 5% XLCM routinely show expansions greater than 10,000-fold
      within 4 weeks. By contrast, similar FBS-free cultures treated with IL-2 expand
      less than 10-fold and not after 1 week, and cultures treated with IL-2 and
      concanavalin A (ConA) expand to a maximum of only 300-500-fold over 2 weeks and
      fail to continue to proliferate thereafter. The MAb, OKT3, which, when combined
      with IL-2 and FBS, is known to stimulate proliferation of adult peripheral blood
      lymphocytes, permitted only a 17-fold expansion of UC blood lymphocytes under the
      same conditions. Thus, XLCM, which can also stimulate adult peripheral blood
      lymphocyte expansion to levels exceeding 100,000-fold in 3-4 weeks, is uniquely
      able to stimulate proliferation of UC blood lymphocytes to high levels. From
      initiation of the UC blood or adult peripheral blood LDMNC/XLCM cultures up to
      approximately 2 weeks, the cultures are dominated by CD4+ T lymphocytes. By 4
      weeks, >80% of the cultured cells bear the CD8+ phenotype, whereas UC blood T
      lymphocytes cultured in the presence of IL-2 are predominantly CD8+. Thus, XLCM
      not only allows high levels of expansion of UC blood T lymphocytes not heretofore
      possible but also permits the selective expansion of different T lymphocyte
      subsets from a single source.

PMID- 10349908
TI  - Fetal cord blood as an alternative source of hematopoietic progenitor cells:
      immunophenotype, maternal cell contamination, and ex vivo expansion.
AB  - The present study was performed to investigate the character of hematopoietic
      progenitor cells in fetal cord blood (CB). Thirty blood samples from fetuses at a
      median of 24 weeks of gestation (range 19-29) and 30 neonatal CB samples were
      analyzed for their immunophenotype by three-color flow cytometry and examined for
      the presence of female cells by fluorescence in situ hybridization (FISH). We
      tested the effects of different cytokine combinations (rhIL-1beta, rhIL-3, rhIL
      6, rh erythropoietin [rhEPO], rhGM-CSF plus rhSCF, and rhSCF plus rhflt3-ligand)
      on the differentiation of 100 CD34+-enriched neonatal CB cells for up to 21 days.
      Ex vivo expansion of 32 unselected fetal blood samples cells was performed in the
      presence of rhSCF and rhflt3-ligand. The percentage of CD34+ cells in fetal blood
      was significantly higher compared with neonatal CB (1.24%+/-0.82% versus 0.33%+/
      0.18%, p = 0.0001) and inversely correlated with the age of gestation. The
      contamination of fetal and neonatal CB with maternal cells was low (1.72%+/
      0.89%, range 1.0%-4.0%). By using rhflt3-ligand we were able to expand committed
      progenitor cells while maintaining cells with stem cell function. The use of
      expanded fetal immature progenitors might have implications for in utero
      transplantation and autologous gene therapy.

PMID- 10349909
TI  - G-CSF-mobilized leukapheresis products: cellular characteristics and clinical
      performance in allografting.
AB  - Twenty-five G-CSF-mobilized leukapheresis products (mLP) were screened for
      cellular composition, including CD34+DR-, CD34+DR+ and leukocyte profile, to
      compare with 5 native (unstimulated) LP (nLP) and 16 BM inoculi. G-CSF
      stimulation led to an increase in CD34+ cells and CD15+ cells but did not
      influence the lymphocyte content of mLP. Two groups of 14 and 16 patients were
      allografted with phenotypically defined mLP (1-4 mLP were used for each patient)
      and BM, respectively. mLP used for allografting had significantly more CD34+
      cells, including CD34+DR- cells, monocytes, T cells, and B cells as compared with
      BM inoculi. Patients were followed for median observation time of 289 days and
      409 days for the mLP (PBPC) and BM groups, respectively. The two groups were well
      matched in regard to age, sex, and stage of disease, with a slight prevalence of
      major blood group incompatibility (7 of 14 versus 3 of 16) and a lower
      donor/recipient weight ratio (0.8+/-0.2 vs 1.5+/-0.6, p = 0.002) in the PBPC
      group. Granulocyte and platelet recovery was faster in the PBPC group than in the
      BM group. The time of reaching 20,000/microl platelets but not 500/microl
      granulocytes correlated with the number of CD34+ cells in each inoculum. The
      survival curves of the PBPC and BM groups were similar, as was the incidence of
      acute GvHD (aGvHD). This was also valid for aplastic anemia cases (7 and 5
      patients in the PBPC and BM group, respectively), who benefited from a high
      number of CD34+ grafted cells but did not experience aGvHD. Thus, mLP do not
      appear to elicit aGvHD with higher frequency than BM and may be preferable for
      hematotherapy.

PMID- 10349910
TI  - Factors influencing mobilization and engraftment in patients with metastatic
      breast cancer undergoing PBSC transplantation.
AB  - Factors influencing mobilization and engraftment of PBSC were analyzed in 38
      patients with metastatic breast cancer who were undergoing PBSC transplantation.
      None of these patients had had previous chemotherapy for metastatic disease. PBSC
      were mobilized with cyclophosphamide (CY) and G-CSF (n = 21) or CY and etoposide
      (CY-etoposide) and G-CSF (n = 17). All received cyclophosphamide 6000 mg/m2,
      thiotepa 500 mg/m2, and carboplatin 800 mg/m2 (CTCb) as preparative regimen. PBSC
      infusion was followed by G-CSF at 5 microg/kg in 30 patients or 10 microg/kg in 8
      patients. A median number of 27 x 10(6) CD34+ cells/kg was obtained with a median
      of four aphereses. Previous chemotherapy, radiation therapy, marrow disease, time
      from previous chemotherapy to mobilization, and type of mobilization regimen did
      not have a statistically significant effect on collection efficiency (CE). CE was
      defined as the total number of CD34+ collected/number of collections. Engraftment
      was rapid, with patients reaching a neutrophil count of 0.5 x 10(9)/L a median of
      9 days (range 7-23) and a platelet count of 20 x 10(9)/L a median of 12 days
      (range 8-28) after transplantation. Shorter times to platelet recovery were
      associated with a higher number of CD34+ cells infused (p = 0.012), CY
      mobilization (p = 0.033), and a lower number of prior chemotherapy cycles (p =
      0.022). When the number of CD34+ cells was included in the proportional hazard
      model, no other variables were found to be significant predictors of platelet
      engraftment. Time to neutrophil recovery was negatively associated with the dose
      of G-CSF used after transplantation (p = 0.036) CD34 cell dose is an important
      predictor of engraftment kinetics. A posttransplant dose of G-CSF improves
      neutrophil recovery. For patients with metastatic breast cancer and no previous
      chemotherapy for metastatic disease, we have no evidence for a difference between
      CY and CY-Etoposide as the mobilization regimen.

PMID- 10349911
TI  - Successful PBSC mobilization with high-dose G-CSF for patients failing a first
      round of mobilization.
AB  - PBSC are the preferred source of stem cells for autologous transplantation.
      However, regardless of the mobilization procedure used, 10%-20% of patients fail
      to collect an adequate number to ensure prompt engraftment. There is as yet no
      standard mobilization procedure for patients who fail a first mobilization
      attempt. Here, we describe a highly efficient strategy to obtain an adequate
      number of stem cells for patients who failed a first mobilization attempt.
      Seventy-four patients with various hematologic malignancies underwent initial
      mobilization with various regimens including hematopoietic growth factors with or
      without chemotherapy. In 72% of patients, > or =2 x 10(6) CD34+ stem cells/kg
      were collected in the initial mobilization attempt, and patients engrafted in a
      median of 10 days for neutrophils and 12 days for platelets. Eighteen patients
      failed to mobilize adequate numbers of stem cells, defined as the inability to
      collect 0.2 x 10(6) CD34+ stem cells/kg/day in the first 2-3 days. These patients
      had their apheresis halted. Patients were immediately given G-CSF (32
      microg/kg/day) for 4 days as a second attempt at mobilization. Eighty-eight
      percent of these patients achieved the target of > or =2 x 10(6) CD34+ cells/kg,
      with a median duration of apheresis of 5 days (including the first and second
      mobilizations). The mean CD34+ cells/kg/day increased after administration of
      high-dose G-CSF from 0.16 after the first mobilization attempt to 0.61 (p =
      0.0002) after the second mobilization. All patients engrafted in a median of 11
      and 13 days for neutrophils and platelets, respectively. We conclude that
      patients whose apheresis yield is <0.4 x 10(6) CD34+ cells/kg after the first two
      apheresis collections can be successfully mobilized if high-dose G-CSF is
      administered immediately and continued until achieving > or =2 x 10(6) CD34+ stem
      cells/kg.

PMID- 10349912
TI  - The relation between the number of PBSC and number of leukaphereses in children.
AB  - Although PBSC transplantation has an advantage over BM transplantation in that
      fewer burdens are placed on the patient at the time of stem cell collection, the
      number of collected cells decreases when leukapheresis is done repeatedly. We
      examined the relation between the number of times leukapheresis is performed and
      the number of mononuclear cells (MNC), CD34+ cells, and colony-forming unit
      granulocyte-macrophages (CFU-GM) collected. The percentage of CD34+ cells was
      measured by flow cytometry and the number of CFU-GM was measured by a progenitor
      assay. The number of cells collected was significantly decreased by the third
      collection. Therefore, to secure enough cells for transplantation, leukapheresis
      ideally should be performed no more than twice if PBSC collection is to be
      efficient.

PMID- 10349913
TI  - Use of merocyanine 540 for the isolation of quiescent, primitive human bone
      marrow hematopoietic progenitor cells.
AB  - Merocyanine 540 (MC540) is a membrane probe that inserts preferentially into
      loosely packed domains in the phospholipid bilayer of intact cells. Previous
      experiments have demonstrated that MC540 will bind to human bone marrow (BM)
      hematopoietic progenitor cells (HPC). Fractions of mononuclear BM cells
      expressing high MC540 fluorescence have been shown to be enriched for myeloid
      progenitors and cells residing in the S/G2 + M phases of the cell cycle. We
      rationalized that MC540 uptake could be used to distinguish between quiescent and
      metabolically active cells and, therefore, to fractionate normal and leukemic BM
      cells and normal mobilized peripheral blood (MPB) cells into functionally
      distinct groups of progenitors. BM and MPB cells were separated into fractions
      ranging in fluorescence from MC540Bright to MC540Dim. Cell cycle analysis of
      these fractions revealed that the MC540Dim fraction of normal and CML BM CD34+
      cells constituted the most quiescent fraction, and the MC540Bright fractions from
      these cell types contained the most actively cycling cells. However, no
      differences in the percentage of cells in G/G1 were observed between MC540Bright
      and MC540Dim fractions of MPB CD34+ cells. To investigate if these cell cycle
      status differences translated into distinct functional properties, the
      hematopoietic potential of BM CD34+MC540Bright and CD34+MC540Dim cell fractions
      was analyzed in vitro in long-term BM cultures and limiting dilution analysis
      (LDA) assays. CD34+MC540Dim cells produced more total and committed progenitor
      cells in long-term cultures than did the CD34+MC540Bright fraction. The
      CD34+MC540Dim fraction also contained a 2-fold higher number of long-term
      hematopoietic culture-initiating cells (LTHCIC) than the CD34+MC540Bright
      fraction, as defined by LDA assays. These data demonstrate that MC540 can be a
      useful probe for the isolation of primitive HPC from some hematopoietic tissues
      and may assist in monitoring structural changes in the phospholipid bilayer
      during proliferation and differentiation of HPC.

PMID- 10349914
TI  - Megakaryocyte ex vivo expansion potential of three hematopoietic sources in serum
      and serum-free medium.
AB  - Megakaryocytes (MK) were expanded from purified human CD34+ cells obtained from
      three sources, bone marrow (BM), mobilized peripheral blood progenitor cells
      (PB), and umbilical cord (UC) blood. CD34+-selected cells were cultured for 12
      days with 10 ng/ml thrombopoietin (TPO), 10 ng/ml IL-3, 10 ng/ml TPO + 10 ng/ml
      IL-3, or 200 ng/ml promegapoietin (PMP), a chimeric dual agonist of the c-Mpl and
      human IL-3 receptors. MK production was compared in serum-free versus human serum
      supplemented liquid media. PMP and the combination of TPO and IL-3 (TPO + IL-3)
      increased MK production similarly. Culturing CD34+ cells with PMP in serum-free
      medium resulted in a twofold increase in MK yield compared with serum
      supplemented medium. CD34+ cells from UC proliferated more than those from either
      BM or PB in liquid culture, resulting in much greater MK production under all
      conditions. Phenotypic analysis of the uncultured CD34+ cells showed that BM had
      a higher frequency of CD34+/CD41+ cells than PB or UC. TPO + IL-3 or PMP produced
      larger and greater numbers of BFU-MK and CFU-MK per seeded CD34+/CD41+ cell from
      UC than from either BM or PB. Thus, although uncultured CD34+-selected BM cells
      contained a higher frequency of committed mature MK progenitors, UC CD34+ cells
      had a greater proliferative capacity and, therefore, were more productive. PMP
      induced megakaryocytopoietic activity comparable to that achieved with TPO + IL-3
      and may be useful for ex vivo expansion of MK for clinical trials.

PMID- 10349916
TI  - Hematotherapy Literature Watch.

PMID- 10349915
TI  - Isolation of highly purified autologous and allogeneic peripheral CD34+ cells
      using the CliniMACS device.
AB  - The CliniMACS CD34+ selection device was used for positive selection of apheresis
      products for autologous transplantation from 10 patients with malignant diseases
      and for allogeneic transplantation from 26 healthy donors. A total of 71
      separations were performed. In 1 allogeneic donor, CD34+ progenitors were also
      isolated from bone marrow. Between 0.27 and 8.9 x 10(10) nucleated cells (median
      4.9 x 10(10)) containing 0.09%-10.8% (median 0.67%) CD34+ progenitor cells were
      separated. After separation, a median number of 227 x 10(6) mononuclear cells
      (MNC) (51-524) were recovered, with a median viability of 99% (22%-100%) and a
      median purity of 97.0% (68.3%-99.7%) CD34+ cells. Depletion of T cells was
      extensive, with a median of 0.04% residual CD3+ cells (range <0.01%-0.92%).
      Residual CD19+ cells were between <0.01% and 17%, including CD34+CD19+ cells.
      Recovery of CD34+ cells was calculated according to the ISHAGE guidelines and
      ranged from 24% to 105% (median 71%). We conclude that with the CliniMACS device
      CD34+ cells with high purity and recovery can be isolated with concomitant
      effective T cell depletion in the allogeneic setting and with a high purging
      efficacy in the autologous setting.

PMID- 10349917
TI  - Withdrawal of treatment in the intensive care unit.

PMID- 10349918
TI  - Thoracic epidurals: is analgesia all we want?

PMID- 10349919
TI  - A comparison of thoracic and lumbar epidural techniques for post-thoracoabdominal
      esophagectomy analgesia.
AB  - PURPOSE: To compare thoracic epidural analgesia (TEA) using a
      bupivacaine/fentanyl mixture and lumbar epidural analgesia (LEA) with morphine,
      in respect to the time to extubation and the quality of post-operative analgesia,
      in patients having thoracoabdominal esophagectomy. METHODS: Twenty two patients
      scheduled for elective thoracoabdominal esophagectomy were randomized to TEA or
      LEA. Postoperatively, the TEA group received Patient Controlled Epidural
      Analgesia (PCEA) with bupivacaine 0.125% and 5 microg x ml(BI) fentanyl, and the
      LEA group received PCEA with 0.2 microg x ml(BI) morphine. A blinded observer
      assessed criteria for tracheal extubation and the time of tracheal extubation was
      recorded. Early extubation was defined as tracheal extubation within four hours
      postoperatively. Visual analogue pain scores at rest (Static Visual Analogue Pain
      Scores, SVAPS) and with movement (Dynamic Visual Analogue Pain Scores, DVAPS)
      were recorded at 1, 6, 12, 18 and 24 hr post-extubation. Failure of the epidural
      protocol (FEP) was defined as a request for additional analgesia. RESULTS:
      Tracheal extubation was achieved in 70% of the LEA and 100% of the TEA at four
      hours postoperatively (P=NS). However, the TEA group achieved earlier extubation
      times when assessed with log rank testing (P = 0.01). By six hours post
      extubation FEP had occurred in 50% of the LEA group but in none of the TEA group
      (P = 0.01). Mean SVAPS and DVAPS were lower in the TEA than in the LEA group at
      all measured times (P < 0.01). CONCLUSION: This study has demonstrated superior
      pain control in patients undergoing thoraco-abdominal esophagectomy treated with
      TEA than with LEA, particularly for pain with movement. Tracheal extubation
      occurred earlier in the TEA group, but this difference was not significant at
      four hours postoperatively.

PMID- 10349920
TI  - Hemodynamic effects of medical antishock trousers during mechanical ventilation.
AB  - PURPOSE: To compare the hemodynamic effects of medical antishock trousers (MAST)
      inflation in mechanically ventilated patients with normal and poor left
      ventricular function. METHODS: Twelve patients requiring respiratory support were
      divided into two groups according to baseline transesophageal echocardiography
      (TEE) measurements: normal left ventricular dimensions and fractional area of
      contraction (FAC=61 +/- 5%) (n=7) and dilated cardiomyopathy with reduced FAC (21
      +/- 1%) (n=5). All patients were studied when two successive levels of load (mild
      load by inflation of the leg compartment of MAST at 50 cmH2O and high load by
      adding the abdominal compartment of MAST inflated at 30 cmH2O) were applied.
      Global left ventricular systolic function was assessed on the TEE transgastric
      short-axis view. End-systolic wall stress (ESWS) was used as an indicator of left
      ventricular afterload. RESULTS: Total respiratory, lung and chest wall
      compliances were reduced by 48%, 51% and 27% respectively at the high load level
      (P < 0.05). Whereas no hemodynamic changes occurred at mild load, the high load
      level produced an increase in left ventricular afterload as evidenced by
      concomitant increases in diastolic arterial blood pressure (66 +/- 6 to 79 +/- 6
      mmHg, P < 0.05) and ESWS (69 +/- 12 to 74 +/- 12 Kdyn x cm(-2) x m(-2), P <
      0.05). In patients with dilated cardiomyopathy, this increase in afterload
      impaired the left ventricular systolic function and end-systolic area increased
      (19.0 +/- 2.5 to 21.4 +/- 2.9 cm2 x m(-2), P < 0.05) while FAC decreased (22 +/-
      2 to 16 +/- 2%, P < 0.05). Left ventricular end-diastolic area remained unchanged
      during the study in both groups. CONCLUSION: MAST inflation impairs respiratory
      mechanics and global left ventricular systolic function in cardiac patients
      without changes in left ventricular preload.

PMID- 10349921
TI  - Sevoflurane exposure time and the neuromuscular blocking effect of vecuronium.
AB  - PURPOSE: To determine the effect of sevoflurane exposure time on the duration of
      vecuronium neuromuscular blockade. METHODS: In 40 adult patients anesthesia was
      induced with 1.5-2 mg x kg(-1) propofol and 3-5 microg x kg(-1) fentanyl and the
      trachea was intubated without the aid of muscle relaxant. Patients were
      randomized into four groups of 10. In group 1, 0.05 mg x kg(-1) vecuronium was
      administered with N2O and anesthesia was maintained by propofol infusion and
      fentanyl. Vecuronium was administered with sevoflurane 2% in 30 patients,
      commencing at the same time (group 2) and at 30, and 60 min after sevoflurane
      (groups 3, 4). Adductor pollicis force of contraction to train-of-four ulnar
      nerve stimulation was recorded. Times from vecuronium injection to 95%, maximal
      block, and recovery times to 25% recovery were recorded. RESULTS: There were no
      differences in times to 95% and maximal block in the four groups. Recovery times
      were longer in groups 3 and 4 than in groups 2 and 1 (P < 0.01). Times to 5%
      recovery were 15.0 +/- 3.7, 17.8 +/- 4.8, 28.2 +/- 9.9, and 29.5 +/- 9.5, and to
      25% recovery were 22.3 +/- 5.2, 27.2 +/- 6.4, 42.3 +/- 16.3, and 50.5 +/- 16.4 in
      groups 1, 2, 3, and 4 respectively. No differences were found between group 1 and
      group 2 nor between group 3 and group 4. CONCLUSION: Sevoflurane produced time
      dependent potentiation of vecuronium. After 30 min exposure, 25% recovery was
      prolonged by 89% and after 60 min by more than 100% compared with the control
      group.

PMID- 10349922
TI  - Reduced efficacy of simulated epidural test doses in sevoflurane-anesthetized
      adults.
AB  - PURPOSE: To determine the hemodynamic responses to, and the efficacy of
      epinephrine-containing epidural test doses, during sevoflurane anesthesia, based
      on the conventional heart rate (HR) increase > or = 20 beats x min(-1), the
      modified HR increase if > or = 10 beats x min(-1), and the systolic blood
      pressure (SBP) increase 15 mmHg criteria. METHODS: One hundred and twenty
      patients were randomised to receive sevoflurane 0.5, 1 or 2% end-tidal (n = 40
      each) and nitrous oxide 67% in oxygen after tracheal intubation. Each group of
      patients was further divided into groups receiving 3 ml lidocaine 1.5% plus 15
      microg epinephrine (1:200,000) i.v., or 3 ml normal saline (n = 20 each). The HR
      and SBP were monitored for four minutes after injection of the study drug.
      RESULTS: Intravenous injection of the test dose produced HR increases > or = 20
      beats x min(-1) in 18 (90%), 16 (80%) and 14 (70%) patients at sevoflurane
      concentrations at 0.5, 1 and 2%, respectively, while those receiving saline
      developed no HR changes. Based on the modified HR criterion, sensitivity,
      specificity, and positive and negative predictive values were all 100% under
      sevoflurane concentrations of 0.5 and 1%, but not 2%. On the other hand, all
      patients in the test dose groups and none in the saline groups developed SBP > or
      = 15 mmHg, ensuring 100% efficacy based on the conventional SBP criterion under
      all sevoflurane concentrations studied. In all patients receiving the intravenous
      test dose, peak HR occurred 30-45 sec earlier than that of SBP. CONCLUSION:
      During stable sevoflurane anesthesia, peak HR increase > or = 10 beats x min(-1)
      should be regarded as a positive response with end-tidal sevoflurane
      concentration < or = 1%, and peak SBP increase > or = 15 mmHg is applicable at
      sevoflurane concentrations between 0.5 and 2%.

PMID- 10349923
TI  - Tracheal resection and reconstruction.
AB  - PURPOSE: To review the literature on tracheal and carinal resection and
      reconstruction, and to report the general approach to these patients, as well as
      the general guidelines for the safe administration of anesthesia. The airway
      management is extensively reviewed. SOURCE: Articles obtained from a Medline
      search (1960 to October 1997; keywords: tracheal surgery, carinal surgery, airway
      management). Textbook literature including the bibliographies were also
      consulted. PRINCIPAL FINDINGS: Benign or malignant tracheal and carinal pathology
      causing obstruction can be managed in several ways but resection and
      reconstruction are the treatment of choice for most patients with tracheal
      stenosis or tumour. Surgery of the trachea is a special endeavour where the
      airway is shared by the surgeon and the anesthesiologist. The principal
      anesthetic consideration is ventilation and oxygenation in the face of an open
      airway. Ventilation can be managed in different ways, including manual oxygen jet
      ventilation, high frequency jet ventilation, distal tracheal intubation,
      spontaneous ventilation, and cardiopulmonary bypass. CONCLUSION: The management
      of anesthesia for tracheal surgery presents many challenges to the
      anesthesiologist. Knowledge of the various techniques for airway management is
      crucial. Meticulous planning and communication between the anesthesia and
      surgical teams are mandatory for the safe and successful outcome of surgery for
      patients undergoing this procedure.

PMID- 10349924
TI  - Amniotic fluid embolism and isolated disseminated intravascular coagulation.
AB  - PURPOSE: Disseminated intravascular coagulation (DIC) is a well-known
      complication of an amniotic fluid embolus. However, clinical experience has shown
      that, in some patients, clinical hemorrhage may be the initial presentation.
      Mortality in this subset of patients is high. This report describes a patient
      with a suspected amniotic fluid embolus who survived and in whom the initial
      presentation was post partum hemorrhage. CLINICAL FEATURES: During the post
      delivery repair of a fourth degree perineal tear a 29 yr old prima gravida was
      noted to have excessive vaginal bleeding despite a well contracted uterus.
      Laboratory investigations revealed a decrease in hemoglobin from 126 g x l(-1) to
      86 g x l(-1) and a severe disseminated intravascular coagulopathy (PT 27.5 sec,
      APPT 149 sec, direct fibrinogen < 0.6 g x l(-1), FDP > 640 g x l(-1)). Treatment
      included massive blood component therapy and, eventually, total abdominal
      hysterectomy. The patient subsequently recovered without sequelae. In the absence
      of any other explanation, the coagulopathy was considered to be secondary to
      amniotic fluid embolus. CONCLUSION: Amniotic fluid embolus remains an important
      cause of maternal mortality. Clinical reports, reviews of the literature, and the
      development of the national registry have all contributed to our understanding of
      this syndrome. Contrary to earlier beliefs, not all patients present with sudden
      cardiorespiratory collapse. As the present case illustrates, a less common
      presentation is the development of an isolated DIC in the peripartum period
      without antecedent hemodynamic or respiratory instability. Therefore,
      anesthesiologists must maintain a high index of suspicion for the disorder in
      order to facilitate early recognition and treatment.

PMID- 10349925
TI  - Thyroplasty under general anesthesia using a laryngeal mask airway and fibreoptic
      bronchoscope.
AB  - PURPOSE: To report the management of a patient, with unilateral vocal cord
      paralysis, undergoing thyroplasty, under general anesthesia. CLINICAL FEATURES: A
      25-yr-old man developed hoarseness and occasional episodes of pulmonary
      aspiration, caused by unilateral vocal cord paralysis. He was scheduled for
      thyroplasty, in an attempt to ease phonation and to decrease or prevent further
      episodes of pulmonary aspiration. He refused local anesthesia with sedation and
      it was therefore decided to attempt the procedure under general anesthesia. The
      paralysed vocal cord was displaced inwards by a wedge inserted through a window
      in the thyroid cartilage. We assessed the ideal position of the wedge by using a
      fibreoptic bronchoscope and laryngeal mask airway during general anesthesia,
      instead of phonation. CONCLUSION: We describe the successful use of a general
      anesthetic for a thyroplasty, a procedure normally done under local anesthesia
      with or without sedation, in a patient who was keen to have surgery, but who
      refused local anesthesia with sedation.

PMID- 10349926
TI  - Back pain and collapse associated with receding subarachnoid blockade.
AB  - PURPOSE: Back pain and sudden loss of consciousness during recovery from spinal
      anesthesia are rare. Severe pain may raise fears of serious neurological damage
      and result in inappropriate management. Bladder distention may present in this
      way and clinicians should be alert to this possibility and communicate this to
      nursing staff. CLINICAL FEATURES: A lumbar spinal anesthetic was performed during
      a volunteer study, using 15 mg hyperbaric bupivacaine in a healthy 31 yr old man.
      During recovery, five hours later, as the block regressed to the L1-2 level, he
      complained of acute, severe back pain and briefly lost consciousness secondary to
      profound bradycardia. Bladder cathetherization yielded 900 mL urine with
      immediate and complete relief of symptoms. CONCLUSION: Severe pain secondary to
      bladder overdistention in the presence of neuroaxial blockade may be referred to
      the thoracolumbar area, mediated by intact sympathetic afferents. As the saccral
      parasympathetic supply remains paralyzed, there is no subjective sensation of
      bladder stretching. If untreated, bladder distention can lead to excessive
      supraspinal parasympathetic outflow resulting in vasovagal syncope.

PMID- 10349927
TI  - Ropivacaine vs bupivacaine in major surgery in infants.
AB  - PURPOSE: To assess and compare the onset time and duration of neuroblockade
      obtained after ropivacaine or bupivacaine in infants undergoing major abdominal
      surgery. We also evaluated the efficacy and safety of employing ropivacaine
      instead of bupivacaine to provide operative anesthesia and postoperative
      analgesia. METHODS: In a prospective double blind study 28 infants, aged 1-12
      months, undergoing elective major abdominal surgery, were randomly allocated to
      receive, after induction of general anesthesia, either 0.7 ml x kg(-1)
      bupivacaine 0.25% (group B) or ropivacaine 0.2% (group R) via lumbar epidural
      block. The onset time, total surgical time and duration of analgesia were
      recorded. RESULTS: No differences were noted in demographic data, hemodynamic
      variables or duration of surgery. The onset time for sensory blockade was 13.1
      min +/- 2.1 (group B) and 11.7 +/- 2.4 min (group R). The duration of analgesia
      was 491 +/- 291 (group R) and 456 min +/- 247 (group B). Eight patients in group
      B and six in group R needed codeine and acetaminophen rescue on at least one
      occasion during the 24 hr study period. No major side effects were noted in
      either groups. CONCLUSIONS: In infants undergoing major abdominal surgery under
      combined epidural/light general anesthesia, ropivacaine 0.2% produces sensory and
      motor blockade similar in onset, duration of action and efficacy to that obtained
      from an equal volume, 0.7 ml x kg(-1), of bupivacaine 0.25%.

PMID- 10349928
TI  - Hydroxyl radical formation during inhalation anesthesia in the reperfused working
      rat heart.
AB  - PURPOSE: To determine whether isoflurane, sevoflurane and halothane influenced
      hydroxyl radical production in the ischemic rat heart. METHODS: Twenty-four male
      Wistar rats were divided into four groups; control (C), isoflurane 1.4% (I),
      sevoflurane 2.5% (S) and halothane 1% (H). The hearts were perfused with modified
      Krebs-Henseleit bicarbonate buffer by a working heart model for 10 min. Then,
      whole heart ischemia was induced by severely restricting coronary perfusion for
      15 min. Reperfusion of the hearts after this ischemic period lasted for 20 min.
      The coronary effluent was collected before and during ischemia and at 1, 5, 10,
      20 min after reperfusion. At the end of reperfusion, hearts were removed and
      prepared for measurement. Hydroxyl radicals were identified by their reaction
      with salicylic acid to yield dihydroxybenzoic acids (DHBAs). RESULTS: Before and
      after ischemia, there were no differences in coronary flow and heart rate among
      the four groups, but cardiac output and LV dP/dt maximum in the anesthetic groups
      were lower than in the control group. Hydroxyl radical products in the heart were
      significantly lower in the I group than the other groups (e.g. C vs I, 278.1 +/-
      24.3 vs 219.3 +/- 14.4 microM x g(-1), P < 0.05). The concentrations of DHBAs in
      the coronary effluent at some points in the I and H groups were less than in the
      C and S groups. CONCLUSION: These results indicate that isoflurane and halothane
      (to a lesser extent), reduce hydroxyl radical production in the ischemic heart,
      but sevoflurane does not.

PMID- 10349929
TI  - Prilocaine induces apoptosis in osteoblastic cells.
AB  - PURPOSE: To determine whether prilocaine, a local anesthetic, induces apoptosis
      in osteoblastic cells. METHODS: After reaching subconfluence, human osteoblastic
      Saos-2 and MG63 cells and mouse osteoblastic MC3T3-E1 cells were exposed for 48
      hr to varying concentrations of prilocaine up to 10 mM and the cytotoxicity of
      the cells was analyzed by phase-contrast microscopy and WST-1 assay. Saos-2 cells
      treated for 48 hr with 5 mM prilocaine were stained with Hoechst 33342 and
      nuclear fragmentation was examined under a fluorescence microscope. DNA was
      extracted from the cells treated with 5 mM prilocaine and DNA ladder formation (a
      hallmark of apoptosis) was analyzed by agarose gel electrophoresis. RESULT:
      Prilocaine induced cell death in Saos-2 cells in a dose- and time-dependent
      manner up to the concentration of 10 mM. Marked nuclear condensation and
      fragmentation of chromatin were observed in the prilocaine-treated cells. DNA
      ladder formation also was induced by prilocaine treatment. Prilocaine-induced DNA
      ladder formation was dose-dependent with maximal effect at a concentration of 5
      mM and was time-dependent from 12 to 48 hr. DNA ladder formation was also induced
      by prilocaine treatment in human osteoblastic MG63 cells and mouse osteoblastic
      MC3T3-E1 cells. Cycloheximide prevented prilocaine-induced apoptosis in Saos-2
      cells in a dose-dependent fashion up to 20 microM as determined by WST-1 assay
      and DNA ladder formation in agarose gel electrophoresis. CONCLUSION: Osteoblastic
      cells treated with prilocaine exhibit both morphological and biochemical features
      indicative of apoptosis. The apoptotic mechanisms involve transcriptional
      regulation of specific proteins or protein synthesis.

PMID- 10349930
TI  - Evaluation of a mathematical model to predict intrapulmonary shunt non
      invasively.
AB  - PURPOSE: We have previously published a mathematical model of oxygen transport.
      Using several physiological assumptions, the model provides a non-invasive
      estimate of intrapulmonary shunt. During a larger study of lung injury in a pig
      model, we had the opportunity to check the validity of our assumptions and the
      accuracy of the model's predictions. METHODS: We used six female pigs, average
      weight 12.8 kg. Following general anesthesia, tracheostomy and insertion of
      pulmonary venous and arterial lines, lung injury was induced by repeated saline
      lung lavage. Using hemodynamic measurements made at different levels of inspired
      oxygen, intrapulmonary shunt was calculated both by the traditional shunt
      equation and also by our mathematical model based on non-invasive measurements of
      FIO2 and SaO2. RESULTS: There was good agreement between the two methods of shunt
      calculation. Using linear regression the correlation coefficient was 0.95. Bland
      and Altman analysis showed a bias of -0.8 and precision of 12%. CONCLUSION: In a
      controlled setting, intrapulmonary shunt can be estimated from non-invasive
      measurements to a reasonable degree of accuracy. However, the calculation
      requires too many assumptions to be of general clinical value. The equations used
      provide a validated physiological model that acts as a useful tool for teaching
      cardiorespiratory physiology.

PMID- 10349931
TI  - Accuracy of radial artery blood pressure determination with the Vasotrac.
AB  - PURPOSE: To evaluate the accuracy of a new non-invasive method (Vasotrac) to
      measure blood pressure (BP) with accompanying arterial wave-form and pulse-rate
      display when compared with BP and waveform measured invasively. METHODS: Healthy
      volunteers (n=53) served as subjects for the study. Blood pressures and waveforms
      obtained via a radial artery catheter (IABP) were compared with non-invasive
      measurements obtained every 12-15 beats by the new system (Vasotrac BP) from the
      opposite radial artery. In a sub-group of volunteers (n=11), BP was acutely
      increased and decreased with isoproterenol, phenylephrine and sodium
      nitroprusside. Data were analyzed by determining correlation and agreement
      between the two systems of measurement. Waveforms obtained by the two systems
      were qualitatively examined. RESULTS: Non-invasive BP measured every 12-15 beats
      by the Vasotrac correlated with IABP (systolic r2 = 0.89; diastolic r2 = 0.88;
      mean r2 = 0.94). The actual values obtained by the two methods agreed closely
      with > 90% of readings being within 2SDs when plotted by the Bland Altman method.
      This was also true during vasoactive drug infusion when BP changed acutely and
      swiftly. During this dynamic period, Vasotrac BP accurately tracked the changes
      in IABP with correlations (systolic r2 = 0.82; diastolic r2 = 0.89; mean r2 =
      0.95) and close agreement (> 90% of readings were within 2 SDs in the Bland
      Altman plot). Waveforms displayed by the two systems were qualitatively very
      similar. Pulse rates measured by the two systems were identical. CONCLUSIONS: The
      Vasotrac system displayed an arterial waveform which was similar to that obtained
      directly and measured BP and pulse rate accurately. It should be a convenient
      device to measure BP continually in a non-invasive fashion.

PMID- 10349932
TI  - Ethical and practical considerations of withdrawal of treatment in the intensive
      care unit.
AB  - PURPOSE: To discuss the medical, ethical and legal basis of decisions to
      discontinue life-support therapy in the adult intensive care unit (ICU), and to
      provide practical guidelines for the discontinuation of life support therapy.
      SOURCE: Relevant articles were retrieved through Medline (1991-present; terms:
      ethics, life support discontinuation, double effect, beneficence, non
      maleficence). Other sources include legal references, and personal files.
      PRINCIPAL FINDINGS: Understanding the legal and ethical principles of autonomy,
      beneficence, non-maleficence and double effect are crucial when withdrawing life
      support therapy. The law respects a competent patient's right to direct his/her
      healthcare but does not uphold his/her right to demand futile care. Surrogate
      decision makers can be used when the patient is incompetent, provided they are
      acting in the patient's best interest. Euthanasia is illegal and the distinction
      between discontinuation of therapy and euthanasia is legally clear. Skillful
      administration of palliative therapy cannot be construed as euthanasia when the
      aforementioned ethical principals are respected. The various practical methods of
      discontinuing therapy are discussed. Every ICU should develop its own guidelines
      and a checklist to help caregivers during this difficult time. Caregivers must
      anticipate the mechanism of death and direct interventions at the symptoms that
      are likely to cause discomfort. Drugs and dosages must be individualized, and
      depend on the underlying disease, anticipated mechanism of death, and the
      patient's pharmacological history. When prescribing a drug, the intention should
      be clear. CONCLUSIONS: Appropriate discontinuation of therapy in the ICU allows
      patients a dignified and comfortable death.

PMID- 10349933
TI  - The unanticipated difficult airway.

PMID- 10349934
TI  - LMA/FOI and CAFG.

PMID- 10349935
TI  - The Charlottetown Click.

PMID- 10349936
TI  - Does smoking really increase the requirements for rocuronium?

PMID- 10349937
TI  - Anesthesia in Poland syndrome.

PMID- 10349938
TI  - Missed cuff herniation despite fibreoptic bronchoscopy.

PMID- 10349939
TI  - Non-dependent axillary artery compression during needlescopic thoracic
      sympathectomy.

PMID- 10349940
TI  - Being wired for a year.

PMID- 10349941
TI  - Biopsy forceps as a source of bacterial contamination leading to overgrowth of
      Helicobacter pylori culture medium with Pseudomonas aeruginosa.

PMID- 10349943
TI  - A convenient way to avoid venipuncture and finger contamination.

PMID- 10349942
TI  - The Costa Rican experience on the serological response to the hepatitis B vaccine
      in health professionals.

PMID- 10349944
TI  - Development of nursing home infection control.

PMID- 10349945
TI  - An outbreak of acute gastroenteritis in a geriatric long-term-care facility:
      combined application of epidemiological and molecular diagnostic methods.
AB  - OBJECTIVE: To assess possible transmission modes of, and risk factors for,
      gastroenteritis associated with Norwalk-like viruses (NLVs) in a geriatric long
      term-care facility. METHODS: During a prolonged outbreak of acute
      gastroenteritis, epidemiological data on illness among residents and employees
      were collected in conjunction with stool, vomitus, and environmental specimens
      for viral testing. NLVs were identified by electron microscopy in stool and
      vomitus specimens, and further characterized by reverse-transcriptase polymerase
      chain reaction and nucleotide sequencing. Potential risk factors were examined
      through medical-record review, personal interview, and a self-administered
      questionnaire sent to all employees. RESULTS: During the outbreak period, 52
      (57%) of 91 residents and 34 (35%) of 90 employees developed acute
      gastroenteritis. Four case-residents were hospitalized; three residents died at
      the facility shortly after onset of illness. A point source was not identified;
      no association between food or water consumption and gastroenteritis was
      identified. A single NLV strain genetically related to Toronto virus was the only
      pathogen identified. Residents were at significantly higher risk of
      gastroenteritis if they were physically debilitated (relative risk [RR], 3.5; 95%
      confidence interval [CI95], 1.0-12.9), as were employees exposed to residents
      with acute gastroenteritis (RR, 2.6; CI95, 1.1-6.5) or ill household members (RR,
      2.3; CI95, 1.4-3.6). Adherence to infection control measures among the nursing
      staff may have reduced the risk of gastroenteritis, but the reduction did not
      reach statistical significance. CONCLUSIONS: In the absence of evidence for food
      borne or waterborne transmission, NLVs likely spread among residents and
      employees of a long-term-care facility through person-to-person or airborne
      droplet transmission. Rapid notification of local health officials, collection of
      clinical specimens, and institution of infection control measures are necessary
      if viral gastroenteritis transmission is to be limited in institutional settings.

PMID- 10349946
TI  - Control of transmission of vancomycin-resistant Enterococcus faecium in a long
      term-care facility.
AB  - OBJECTIVES: To describe the investigation and control of transmission of
      vancomycin-resistant enterococci (VRE) in a residential long-term-care (LTC)
      setting. OUTBREAK INVESTIGATION: A strain of vancomycin-resistant Enterococcus
      faecium not previously isolated in Ontario colonized five residents of a 254-bed
      LTC facility in Toronto. The index case was identified when VRE was isolated from
      a urine culture taken after admission to a local hospital. Screening of rectal
      swabs from all 235 residents identified four others who were colonized with the
      same strain of E faecium. CONTROL MEASURES: Colonized residents were cohorted.
      VRE precautions were established as follows: gown and gloves for resident
      contact, restriction of contact between colonized and noncolonized residents, no
      sharing of personal equipment, and daily double-cleaning of residents' rooms and
      wheelchairs. OUTCOME: Two colonized residents died of causes unrelated to VRE.
      Although bacitracin therapy (75,000 units four times a day x 14 days) failed to
      eradicate carriage in two of three surviving residents, both cleared their
      carriage within 7 weeks. Repeat rectal swabs from 224 residents (91%) 2 months
      after isolation precautions were discontinued and from 125 residents (51%) 9
      months later identified no new cases. Total cost of investigation and control was
      $12,061 (Canadian). CONCLUSION: VRE may be transmitted in LTC facilities, and
      colonized LTC residents could become important VRE reservoirs. Control of VRE
      transmission in LTC facilities can be achieved even with limited resources.

PMID- 10349947
TI  - Enterococcal bacteremia: risk factors for vancomycin resistance and predictors of
      mortality.
AB  - OBJECTIVE: To identify risk factors for vancomycin resistance and mortality in
      enterococcal bacteremia. DESIGN: Historical cohort study. SETTING: A large
      academic medical center with a high prevalence of vancomycin-resistant
      enterococci (VRE). PATIENTS: Two hundred sixty patients with enterococcal
      bacteremia, of whom 72 (28%) had VRE. RESULTS: Independent risk factors for
      infection with VRE were the mean number of antibiotic days (P<.001), renal
      insufficiency (P<.001), mean days of vancomycin use (P = .005), and neutropenia
      (P = .013). A trend toward a significant association between metronidazole use
      and VRE also was noted (P = .068). Mortality was attributable to the bacteremia
      in 96 patients (37%). Severity of illness (P<.001) and age (P = .020) were
      independent risk factors for mortality. Vancomycin resistance was not, however,
      an independent predictor of mortality. CONCLUSION: These results suggest that
      restrictions on antibiotic use, particularly in patients with renal insufficiency
      and neutropenia, may help to combat the rising incidence of VRE. Although
      patients with VRE bacteremia demonstrated higher mortality rates than patients
      with infection due to susceptible isolates, vancomycin resistance was not an
      independent predictor of mortality in these patients and likely serves more as a
      marker of underlying severity of illness.

PMID- 10349948
TI  - The mycobactericidal efficacy of ortho-phthalaldehyde and the comparative
      resistances of Mycobacterium bovis, Mycobacterium terrae, and Mycobacterium
      chelonae.
AB  - OBJECTIVES: To assess the mycobactericidal efficacy of an agent relatively new to
      disinfection, ortho-phthalaldehyde (OPA) and to compare the resistances of three
      Mycobacterium species. Mycobacterium bovis (strain BCG) was compared with
      Mycobacterium chelonae and Mycobacterium terrae to investigate the feasibility of
      using either of the latter two species in tuberculocidal testing. M. chelonae (a
      rapid grower) and M. terrae (an intermediate grower) both grow faster and are
      less virulent than M. bovis (a slow grower). DESIGN: The quantitative suspension
      protocol specified by the Environmental Protection Agency (EPA), the
      Tuberculocidal Activity Test Method (EPA test), was used throughout this study.
      Standard suspensions of all three species were prepared in a similar manner. Two
      suspensions of M. bovis, created in different laboratories, were used. These were
      tested against two concentrations of alkaline glutaraldehyde to provide reference
      data. Two concentrations of OPA were evaluated against all mycobacterial test
      suspensions. Four replicates of each organism-disinfectant combination were
      performed. RESULTS: Results were assessed by analysis of variance. M. terrae was
      significantly more resistant to 0.05% OPA than either M. bovis or M. chelonae. At
      0.21% OPA, M. terrae was slightly more susceptible than one test suspension of M.
      bovis, but not significantly different from the other. M. chelonae was
      significantly less resistant than the other species at both OPA concentrations.
      At their respective minimum effective concentration, OPA achieved a 6-log10
      reduction of M. bovis in nearly one sixth the time required by glutaraldehyde
      (5.5 minutes vs. 32 minutes). CONCLUSIONS: These data, along with other recent
      studies, lend support to the idea that M. terrae may be a suitable test organism
      for use in the tuberculocidal efficacy testing of disinfectants. They also
      confirm the relatively rapid tuberculocidal activity of OPA.

PMID- 10349949
TI  - Occupational injuries and exposures among Canadian dentists: the results of a
      national survey.
AB  - OBJECTIVES: To measure the frequency of occupational exposures reported by
      dentists in Canada and to identify factors associated with occupational exposure.
      DESIGN: A national mailed survey of a stratified random sample of 6,444 dentists
      with three follow-up attempts. Weighted data were analyzed using t tests,
      analysis of variance, and multiple logistic regression. RESULTS: The response
      rate was approximately 66%. Occupational exposures, percutaneous injuries, and
      mucous membrane exposures in the last year were reported by 67%, 62%, and 29% of
      respondents, respectively. Fewer than 1% reported exposure to human
      immunodeficiency virus or hepatitis B virus (HBV). Respondents reported means of
      1.5 mucous membrane and 3.0 percutaneous exposures per year. HBV immunization was
      reported by 91% of dentists, but of these 28% reported no post-immunization
      serology. Other reports of suboptimal compliance included use of a postexposure
      protocol by only 41% and HBV vaccination of all assistants or of hygienists by
      74% and 77% of respondents, respectively. Factors associated with percutaneous
      exposure included non-use of postexposure protocol or puncture-proof containers
      for sharps disposal, treating > or =20 patients per day, and male gender. Risk
      factors for mucous membrane exposure included non-use of eye protection or masks.
      CONCLUSION: This study provides evidence of the protective effect of puncture
      proof containers, eye protection, and masks and raises concerns related to HBV
      post-immunization serology and postexposure protocols. To reduce risk of
      infection, educational interventions are required to improve compliance with
      Universal Precautions, with emphasis on comprehensive HBV immunization and post
      immunization serology, the use of barriers, puncture-proof containers for sharps
      disposal, and postexposure protocols.

PMID- 10349951
TI  - Lack of transmission of vancomycin-resistant enterococci in three long-term-care
      facilities.
AB  - Three patients colonized with vancomycin-resistant Enterococcus were admitted to
      one or more of three long-term-care facilities. Six point-prevalence surveys
      revealed no transmission of vancomycin-resistant Enterococcus after a total of
      234 days of exposure during which moderately strict infection control measures
      were implemented. Four of 116 environmental cultures were positive.

PMID- 10349950
TI  - Trends in compliance with the guidelines for preventing the transmission of
      Mycobacterium tuberculosis among New Jersey hospitals, 1989 to 1996.
AB  - OBJECTIVE: To determine trends in compliance with the guidelines for preventing
      the transmission of Mycobacterium tuberculosis in healthcare facilities among New
      Jersey hospitals from 1989 through 1996. DESIGN: A voluntary questionnaire was
      sent to all 96 New Jersey hospitals in 1992. The 53 that responded were
      resurveyed in 1996. RESULTS: Of the 96 hospitals surveyed in 1992, 53 (55%)
      returned a completed questionnaire; 33 (64%) were community, nonteaching
      hospitals. In 1991, patients with tuberculosis (TB) were admitted at 38 (72%) of
      53 hospitals, and from 1989 through 1991, patients with multidrug-resistant (MDR)
      TB were admitted at 15 (29%) of 52 hospitals. Twenty-nine (57%) of 51 reported
      having rooms meeting the Centers for Disease Control and Prevention (CDC)
      criteria for acid-fast bacilli (AFB) isolation. A nonfitted surgical mask was
      used as a respiratory protective device by healthcare workers (HCWs) at 28 (55%)
      of 51 hospitals. Attending physicians were included in tuberculin skin-testing
      (TST) programs at 5 (11%) of 45 hospitals. In the 1996 resurvey, 48 (94%) of 53
      surveyed hospitals returned a completed questionnaire; 34 (81%) of 42 had TB
      patient admissions, and 4 (9%) of 43 had MDR TB patient admissions in 1996. Forty
      five (96%) of 47 reported having rooms that met CDC criteria for AFB isolation.
      N95 respiratory devices were used by HCWs at 45 (94%) of 48 hospitals. Attending
      physicians were included in the TST programs at 22 (54%) of 41 hospitals.
      CONCLUSION: New Jersey hospitals have made improvements in availability of AFB
      isolation rooms, use of proper respiratory protective devices, and expansion of
      TST programs for HCWs from 1989 through 1996.

PMID- 10349952
TI  - Hospital water supply as a source of disseminated Mycobacterium fortuitum
      infection in a leukemia patient.
AB  - Nosocomial acquisition of Mycobacterium fortuitum led to a disseminated infection
      in a leukemia patient. A linkage to showerhead water was supported by molecular
      typing of clinical and environmental isolates. Contamination of the hospital
      water system with microbes that are relatively resistant to common sanitation
      processes poses an increased risk of infection to neutropenic patients.

PMID- 10349953
TI  - Agrobacterium radiobacter as a cause of pseudobacteremia.
AB  - Agrobacterium radiobacter was isolated from 15 blood cultures collected from 15
      newborns. Contamination of blood cultures was suspected because, in most cases,
      the babies' illnesses seemed incompatible with infection. A radiobacter was
      isolated from citrated tubes used for clotting-factor studies. Review of
      venipuncture technique revealed that occasionally the coagulation study tubes
      were being inoculated before the blood-culture bottles. This investigation
      demonstrated how an environmental source coupled with faulty technique caused a
      cluster of false-positive blood cultures.

PMID- 10349954
TI  - Changing heat and moisture exchangers every 48 hours does not increase the
      incidence of nosocomial pneumonia.
AB  - This prospective study was conducted to evaluate the risk of nosocomial pneumonia
      when changing heat and moisture exchangers every 48 hours in 1996 instead of
      every 24 hours in 1995 for patients needing continuous mechanical ventilation.
      Medical and surgical patients in the two periods did not differ in terms of
      demographic characteristics and markers of acute or underlying illnesses. The
      incidence density of nosocomial pneumonia was not different in the two groups.
      Extended heat and moisture exchanger use reduces circuit manipulation and cost.

PMID- 10349955
TI  - Bacteremia due to persistent strains of coagulase-negative staphylococci in a
      neonatal intensive-care unit.
AB  - This retrospective case-control study was performed to determine risk factors for
      bacteremia due to persistent coagulase-negative staphylococci in our neonatal
      intensive-care unit. Enteral nutrition and the presence of a nasogastric tube
      were identified as possible risk factors for coagulase-negative staphylococcal
      bacteremia involving one of the persistent strains.

PMID- 10349956
TI  - Bacitracin versus mupirocin for Staphylococcus aureus nasal colonization.
AB  - We performed a randomized prospective study of 5-day treatment with topical
      mupirocin or bacitracin for the elimination of Staphylococcus aureus nasal
      colonization in healthcare workers (HCWs). Nasal cultures were obtained from 141
      HCWs, 37 (26%) of whom showed S. aureus. After 72 to 96 hours of treatment, the
      organism was eradicated in 15 (94%) of 16 by mupirocin and in 8 (44%) of 18 by
      bacitracin (P = .0031). Similar efficacy was demonstrated at 30 days. Mupirocin
      may be more effective than bacitracin for eradication of S. aureus in healthy
      HCWs.

PMID- 10349957
TI  - Outbreak of methicillin-resistant Staphylococcus aureus in a German tertiary-care
      hospital.
AB  - A biphasic outbreak of methicillin-resistant Staphylococcus aureus in intensive
      care units of a German tertiary-care hospital afflicted 89 patients within 4
      years. The spread of the outbreak most likely was facilitated by the
      contamination of mobile radiograph equipment. The outbreak was controlled by
      measures of hospital hygiene.

PMID- 10349958
TI  - Varicella serological status of healthcare workers as a guide to whom to test or
      immunize.
AB  - Only 1.6% of 1,331 hospital workers were seronegative for varicella-zoster virus
      (VZV), including 8.7% of those with a negative history and 0.5% of those with a
      positive history. Seronegativity was inversely related to age but unrelated to
      job category, exposure at work to VZV, country of origin, race, or gender.

PMID- 10349959
TI  - Infected pressure ulcers in the long-term-care facility.
AB  - Pressure ulcers occur with some frequency in the elderly, debilitated population
      in long-term-care facilities. Pressure ulcers cause morbidity and mortality and,
      by virtue of breaking the integumentary barrier, predispose to skin and soft
      tissue infections. The latter often are deep and require lengthy medical and
      surgical therapy. Prevention depends on avoidance of pressure, as well as
      providing adequate nutrition and meticulous skin care.

PMID- 10349960
TI  - Issues in the management of resistant bacteria in long-term-care facilities.
AB  - The prevalence of antibiotic-resistant bacteria in the long-term-care setting and
      the risk to nursing home residents is still unknown. Few studies have been done
      in community-based nursing homes, and most have focused on colonization rather
      than infection rates. Concerns about methicillin-resistant Staphylococcus aureus
      and vancomycin-resistant enterococci have been expressed most often, while
      relatively scant attention has been paid to the problem of antibiotic resistance
      in gram-negative bacilli. Antibiotic resistance precautions need to be developed
      for nursing homes that are simple, effective, inexpensive, and recognize the
      unique rehabilitative and long-term custodial missions of chronic-care
      facilities.

PMID- 10349961
TI  - Localization of nitric oxide synthase in the tree shrew retina.
AB  - Nitric oxide (NO) is a novel neuronal messenger that likely influences retinal
      function by activating retinal guanylyl cyclase to increase levels of cGMP. In
      the present study, the localization of neuronal nitric oxide synthase (nNOS, Type
      I NOS) in the cone-dominant tree shrew retina was studied using NADPH-d
      histochemistry and nNOS immunocytochemistry. Both NADPH-d and nNOS
      immunoreactivity (IR) labeled the inner segments of rods and the myoids of a
      regular subpopulation of cones, with their corresponding nuclei outlined. The
      labeled cone myoids were co-localized with a marker for short-wave-sensitive
      (SWS) cones (S-antigen) and also displayed the regular triangular packing and
      density (7%) characteristic of SWS cones in tree shrew and other mammalian
      retinas. These measures confirmed the identity of the labeled cones as SWS cones.
      Photoreceptor ellipsoids of all cones were strongly labeled by NADPH-d
      reactivity, but lacked nNOS-IR. Another novel finding in tree shrew retina was
      that both NADPH-d and nNOS-IR labeled Muller cells, which have not been labeled
      by nNOS-IR in other mammalian retinas. Consistent with findings in rod-dominant
      retinas, two types of amacrine cells at the vitreal edge of the inner nuclear
      layer and a subpopulation of displaced amacrine cells at the scleral edge of the
      ganglion cell layer were labeled by both NADPH-d and nNOS-IR. Processes of these
      labeled cells were seen to extend into the inner plexiform layer, where dense
      punctate label was seen, especially in the central sublamina. These results show
      that localization of NOS in the cone-dominant tree shrew retina shares some
      common properties with rod-dominant mammalian retinas, but also shows some
      species-specific characteristics. The new finding of nNOS localization in tree
      shrew SWS cones and rods, but not in other cones, raises interesting questions
      about the roles of NO in the earliest level of visual processing.

PMID- 10349962
TI  - Evidence for a ganglion cell contribution to the primate electroretinogram (ERG):
      effects of TTX on the multifocal ERG in macaque.
AB  - To assess the contribution of spiking inner retinal neurons to the multifocal
      electroretinogram (ERG), recordings were made from four monkeys (Macaca mulatta)
      before and after intravitreal injections of tetrodotoxin (TTX). TTX blocks all
      sodium-based action potentials and thus terminates spiking activity of amacrine
      and ganglion cells. TTX eliminated a large component from the control responses,
      and this TTX-sensitive component was present as early as 10 ms after the
      stimulus. Before injection with TTX, the 103 focal ERG responses varied in
      waveform across the retina. After TTX, the response waveforms were largely
      independent of retinal position, indicating that it was primarily the TTX
      sensitive component of the control response that was dependent upon retinal
      location. Given that retinal ganglion cells compose a sizable proportion of the
      retinal elements that produce action potentials, it is likely that part of the
      TTX-sensitive component is due to the spiking activity of these cells. Further,
      the systematic change in waveform of the TTX-sensitive component with distance
      from the optic nerve head suggests that part of the TTX-sensitive component may
      originate from the activity of the ganglion cell axons. Based on these findings,
      there is reason to be optimistic that the multifocal technique can be employed to
      study the effects of glaucoma and other diseases that affect the inner retina.

PMID- 10349963
TI  - Neurogenesis in the visual system of embryonic and adult zebrafish (Danio rerio).
      off.
AB  - The zebrafish has recently assumed a central position in the study of vertebrate
      development. Numerous studies of other fish have shown that their central nervous
      systems, and especially their visual systems, continue to add new neurons
      throughout life, which is probably related to their abilities to regenerate axons
      and whole nervous tissue. Retinal neurogenesis had not been examined in adult
      zebrafish, and two reports concluded that the optic tectum ceased neurogenesis
      early in life, so the question arose whether the zebrafish was anomalous in this
      regard. We labeled embryonic (24- and 48-h postfertilization) and adult zebrafish
      with the thymidine analog, bromo-deoxyuridine, and, after short and long
      survivals, examined the retina and brain for labeled cells. They were abundant in
      both the optic tectum and the retina. Although the rate of retinal growth slows
      considerably between embryonic and adult stages, the patterns of neurogenesis in
      both the embryo and the adult are similar to those described in other fish, so
      these "fish-specific" features of general interest can justifiably be studied in
      zebrafish.

PMID- 10349964
TI  - Horizontal cell glutamate receptor modulation by NO: mechanisms and functional
      implications for the first visual synapse.
AB  - Neurons of the horizontal cell retinal neural network are subject to modulation
      by the neurotransmitter nitric oxide (NO). We have examined the effects of NO on
      glutamate receptor function in isolated horizontal cells from the perch (Perca
      fluviatilis) using the concentration ramp technique to simultaneously record
      receptor current and agonist concentration. Dose-response curves for glutamate (0
      1 mM) and kainate (0-200 microM) were measured in the presence and absence of 1-2
      mM sodium nitroprusside (SNP), 1 mM 8-Br-cGMP, 100 microM cyclothiazide or 200
      microM dopamine as modulators. SNP increased the EC50 (i.e. decreased affinity)
      for glutamate and increased Imax (i.e. increased efficacy), whereas 8-Br-cGMP
      increased EC50, but not Imax. In the presence of the alpha-amino-3-hydroxy-5
      methyl-4-isoxazole-propionic acid (AMPA) receptor desensitization blocker
      cyclothiazide, the SNP-induced increase in EC50 persisted, but the increase in
      Imax was blocked. The increase in EC50, but not the increase in Imax was also
      observed when the non-desensitizing agonist kainate (100-200 microM) was applied
      in the presence of SNP. When 2 mM SNP and 200 microM dopamine were applied
      together, they increased Imax (740 vs. 2455 pA) and EC50 (422 vs. 682 microM).
      Our findings indicate that NO modulates horizontal cell glutamate responses by
      reducing the affinity of receptors for glutamate while simultaneously increasing
      the maximal current. The shift in affinity is cGMP-mediated and independent of
      desensitization. The action of NO on horizontal cell glutamate receptors is
      distinct from, but synergistic with. that of dopamine. Glutamate receptor
      modulation by NO qualitatively predicts the action of NO on horizontal cell light
      responses in situ and may alter transmission at visual synapses according to
      adaptational conditions.

PMID- 10349965
TI  - Projections of single retinal ganglion cells to the visual centers: an
      intracellular staining study in a plethodontid salamander.
AB  - The projection specificity of retinal ganglion cells and the morphology of their
      terminals were studied in the plethodontid salamander Plethodon jordani. In an in
      vitro approach, ganglion cells were stained with biocytin and reconstructed by
      means of light microscopy. Single retinal ganglion cells often have multiple
      terminal structures in the thalamus, pretectum, and tectum. The projection
      pattern in the diencephalic neuropils is related to the depth of the terminal
      arbor within the tectal fiber layer. Terminal arbors in the tectum differ in
      location, size, and branching pattern. The following types could be
      distinguished: The most superficial of the optic terminals in layer 1 are
      relatively small with a diameter of about 100 microm. With the exception of a few
      varicosities (beads) in the pretectal neuropils, their stem axons have no further
      collaterals or terminal arbors in the diencephalic neuropils. Intermediate
      terminals in layer 2 fan out to form a dense plexus with a medio-lateral extent
      of 180 microm on average. Some terminals in this layer show obvious antenna-like
      fibers reaching toward the surface of the tectum. The axons of layer 2 projecting
      neurons have additional collaterals and terminal arbors in the thalamus and
      pretectum. The deep layer 3 terminals spread out over a diameter of 400 microm on
      average and their degree of branching is moderate. The axons of layer 3
      projecting ganglion cells have dense additional terminal arbors in the thalamus
      and pretectum. The deepest retinal terminals in the tectum are found within the
      predominantly efferent fiber layers. This type consists of an unbranched, but
      beaded axon which runs rostro-caudally with several bends and loops. The stem
      axon has an additional very dense terminal arborization in the neuropil of the
      nucleus Bellonci pars medialis and additional sparse collaterals in the pretectal
      area.

PMID- 10349966
TI  - Sustained and transient oscillatory responses in the gamma and beta bands in a
      visual short-term memory task in humans.
AB  - In a visual delayed matching-to-sample task, compared to a control condition, we
      had previously identified different components of the human EEG that could
      reflect the rehearsal of an object representation in short-term memory (Tallon
      Baudry et al., 1998). These components were induced oscillatory activities in the
      gamma (24-60 Hz) and beta (15-20 Hz) bands, peaking during the delay at occipital
      and frontal electrodes, and two negativities in the evoked potentials. Sustained
      activities (lasting until the end of the delay) are more likely to reflect the
      continuous rehearsing process in memory than transient (ending before the end of
      the delay) activities. Nevertheless, since the delay duration we used in our
      previous experiment was fixed and rather short, it was difficult to discriminate
      between sustained and transient components. Here we used the same delayed
      matching-to-sample task, but with variable delay durations. The same oscillatory
      components in the gamma and beta bands were observed again during the delay. The
      only components that showed a sustained time course compatible with a memory
      rehearsing process were the occipital gamma and frontal beta induced activities.
      These two activities slowly decreased with increasing delay duration, while the
      performance of the subjects decreased in parallel. No sustained response could be
      found in the evoked potentials. These results support the hypothesis that objects
      representations in visual short-term memory consist of oscillating synchronized
      cell assemblies.

PMID- 10349967
TI  - Extracellular compartments of the blowfly eye: ionic content and topology.
AB  - To analyze the elemental composition and topology of the extracellular
      compartments of the compound eye, the eyes of blowflies Calliphora vicina were
      rapidly frozen and ultrathin cryosections were freeze dried. Three zones of an
      ommatidium, peripheral cytosol of visual cells, rhabdomeres, and ommatidial
      cavities were analyzed by X-ray microprobe analysis. The ommatidial cavity was
      found to contain sodium and potassium in proportion similar to that in the
      blowfly hemolymph. Potassium-to-sodium ratio in a cytosol was typical for a
      cytosol. The rhabdomeres displayed an electrolyte content intermediate between
      the above compartments. Three topologically connected extracellular compartments
      were characterized by the experiments with tracers, monastral blue and lanthanum:
      (1) common intercellular space of ommatidia including peripheral clefts between
      the visual cells, both tracers entered this compartment; (2) the ommatidial
      cavity, which is not accessible for monastral blue, however, as revealed by our X
      ray microanalysis, it was reachable for lanthanum; (3) rhabdomeric loops, which
      were accessible for lanthanum entering either via the cavity or from the common
      intercellular clefts. The above characteristics of the ionic content and topology
      of ommatidial compartments might suggest higher sodium and lower potassium
      content in the microvilli as compared with the cytosol. The rhabdomeric and
      "cavital" plasma membranes are assumed to be permeable for these ions so that a
      voltage of only 25-30 mV, negative inside, is probably formed across them, much
      lower than the known resting potential -60 mV across the peripheral plasma
      membrane of a visual cell.

PMID- 10349968
TI  - Substance P-immunoreactive neurons in hamster retinas.
AB  - Light-microscopic immunocytochemistry was utilized to localize the different
      populations of substance P-immunoreactive (SP-IR) neurons in the hamster retina.
      Based on observation of 2505 SP-IR neurons in transverse sections, 34% were
      amacrine cells whose pear-shaped or round cell bodies (7-8 microm) were situated
      in the inner half of the inner nuclear layer (INL) or in the inner plexiform
      layer (IPL), while 66% of SP-IR somata (6-20 microm) were located in the ganglion
      cell layer (GCL) which were interpreted to be displaced amacrine cells and
      retinal ganglion cells (RGCs). At least three types of SP-IR amacrine cells were
      identified. The SP-IR processes were distributed in strata 1, 3, and 5 with the
      densest plexus in stratum 5 of the inner plexiform layer. In the wholemounted
      retina, the SP-IR cells were found to be distributed throughout the entire retina
      and their mean number was estimated to be 4224 +/- 76. Two experiments were
      performed to clarify whether any of the SP-IR neurons in the GCL were RGCs. The
      first experiment demonstrated the presence of SP-IR RGCs by retrogradely labeling
      the RGCs and subsequently staining the SP-IR cells in the retina using
      immunocytochemistry. The second experiment identified SP-IR central projections
      of RGCs to the contralateral dorsal lateral geniculate nucleus. This projection
      disappeared following removal of the contralateral eye. The number of SP-IR RGCs
      was estimated following optic nerve section. At 2 months after sectioning the
      optic nerve, the total number of SP-IR neurons in the GCL reduced from 4224 +/-
      76 to a mean of 1192 +/- 139. Assuming that all SP-IR neurons in the GCL which
      disappeared after nerve section were RGCs, the number of SP-IR RGCs was estimated
      to be 3032, representing 3-4% of the total RGCs. In summary, findings of the
      present study provide evidence for the existence of SP-IR RGCs in the hamster
      retina.

PMID- 10349969
TI  - Immunocytochemical localization of excitatory and inhibitory neurotransmitters in
      the zebrafish retina.
AB  - The patterns of glutamate, gamma-aminobutyric acid (GABA), and glycine
      distribution in the zebrafish retina were determined using immunocytochemical
      localization of antisera at the light-microscope level. The observed GABA
      immunoreactivity (GABA-IR) patterns were further characterized using antibodies
      to both isoforms of glutamic acid decarboxylase (GAD65 and GAD67), the synthetic
      enzyme for GABA. Glutamate-IR was observed in all retinal layers with
      photoreceptors, bipolar cells, and ganglion cells prominently labeled. Bipolar
      cells displayed the most intense glutamate-IR and bipolar cell axon terminals
      were clearly identified as puncta arranged in layers throughout the inner
      plexiform layer (IPL). These findings suggest the presence of multiple subtypes
      of presumed OFF- and ON-bipolar cells, including some ON-bipolar cells
      characterized by a single, large (9 microm X 6 microm) axon terminal. GABA-, GAD
      , and glycine-IR were most intense in the inner retina. In general, the observed
      labeling patterns for GABA, GAD65, and GAD67 were similar. GABA- and GAD-IR were
      observed in a population of amacrine cells, a few cells in the ganglion cell
      layer, throughout the IPL, and in horizontal cells. In the IPL, both GABA- and
      GAD-IR structures were organized into two broad bands. Glycine-IR was observed in
      amacrine cells, interplexiform cells, and in both plexiform layers. Glycine
      positive terminals were identified throughout the IPL, with a prominent band in
      sublamina 3 corresponding to an immunonegative region observed in sections
      stained for GAD and GABA. Our results show the distribution of neurons in the
      zebrafish retina that use glutamate, GABA, or glycine as their neurotransmitter.
      The observed distribution of neurotransmitters in the inner retina is consistent
      with previous studies of other vertebrates and suggests that the advantages of
      zebrafish for developmental studies may be exploited for retinal studies.

PMID- 10349970
TI  - The role of spontaneous retinal activity before eye opening in the maturation of
      form and function in the retinogeniculate pathway of the ferret.
AB  - During early mammalian development, inputs from the two retinas intermix within
      the lateral geniculate nucleus (LGN), then segregate during the first postnatal
      week into layers that receive input from a single retina. Functionally, the LGN
      also changes markedly during the first postnatal month; early geniculate
      responses to retinal input are mainly excitatory, then inhibitory circuits mature
      within the LGN. These remarkable changes in form and function of the
      retinogeniculate pathway occur at a time when patterned visual activity is not
      present, but retinal ganglion cells already manifest spontaneous action potential
      activity. To examine the role of early retinal activity in these critical
      developmental processes, we placed the slow release polymer Elvax embedded with
      tetrodotoxin (TTX) into the vitreous chamber of one or both eyes of neonatal
      ferrets. Animals receiving monocular injection of TTX had the other eye treated
      with Elvax containing control citrate buffer. Intraocular injection of
      horseradish peroxidase was made at the end of the period of TTX treatment to
      reveal the retinal terminals in the LGN. Chronic monocular or binocular blockade
      of retinal activity during the first postnatal week did not prevent eye-specific
      segregation, although it made the boundaries between layers less distinct.
      Retinal terminals ended preferentially in the appropriate layer, but a large
      number of terminals were also present in the inappropriate layer. Further
      segregation was achieved during the second postnatal week of activity blockade,
      when most retinal terminals ended preferentially in the appropriate geniculate
      layer and sharper layer boundaries were present. However, a small but significant
      number of terminals still extended into the inappropriate layer. Together, these
      findings indicate that monocular as well as binocular blockade of retinal
      activity resulted in some anomalous retinogeniculate projections and delayed eye
      specific patterning, but segregation was largely intact at the end of the second
      postnatal week. We also report here that intraocular tetrodotoxin had a marked
      effect on the maturation of intrinsic geniculate circuits prior to eye opening.
      Whole-cell patch-clamp recordings in the LGN slice preparation revealed that
      activity blockade prevented the maturation of the slow, but not the fast,
      hyperpolarizing potential of LGN neurons during the first postnatal month and up
      to P38, the oldest age studied. In conclusion, these results indicate that
      spontaneous retinal activity modulates the time course of binocular segregation
      but does not alone account for the segregation of retinogeniculate terminals.
      However, early retinal activity plays an important role in developing the
      intrinsic circuitry of the LGN.

PMID- 10349971
TI  - Contribution of rod, on-bipolar, and horizontal cell light responses to the ERG
      of dogfish retina.
AB  - Simultaneous extracellular ERG and intracellular recordings from horizontal and
      ON-bipolar cells were obtained from the dark-adapted retina of the dogfish. The
      light intensity-peak response relation (IR) and time course of on-bipolar cell
      responses closely resembled that of the ERG b-wave, but only at low light
      intensities [<10 rhodopsin molecules bleached per rod (Rh*)]. Block of on-bipolar
      cell responses with 50 microM 2-amino-4-phosphonobutyrate (APB) abolished the b
      wave and unmasked a vitreal-negative wave. Subtraction from the control ERG
      resulted in the isolation of a vitreal-positive ERG with an IR which matched that
      of on-bipolar cells over the full range of light intensities. The D.C. component
      of the ERG arises as a result of sustained depolarization of on-bipolar cells in
      response to long (>0.5 s) dim light stimuli, or following bright light flashes.
      The IR of horizontal cells and the vitreal-negative wave unmasked by APB could be
      matched by scaling at low light intensities (<5 Rh*). However, horizontal cell
      responses saturated at about 30 Rh*, while the vitreal-negative wave continued to
      increase in amplitude. The time course of horizontal cell membrane current with
      dim flashes could be matched to the rising phase of the vitreal-negative wave,
      assuming that the delay in generating the voltage response in horizontal cells is
      due to their long (100 ms) membrane time constant. Blocking post-photoreceptor
      activity resulted in a much smaller vitreal-negative wave than that unmasked by
      APB alone. We conclude that the b-wave arises from on-bipolar cell
      depolarization, while the leading edge of the a-wave is a composite of the change
      in extracellular voltage drop across the rod layer and a component (proximal
      PIII) reflecting a decrease in extracellular K+ as horizontal cell synaptic
      channels close with light.

PMID- 10349972
TI  - Cell types and response timings in the medial interlaminar nucleus and C-layers
      of the cat lateral geniculate nucleus.
AB  - Previous evidence concerning the physiological cell classes in the medial
      interlaminar nucleus (MIN) has been conflicting. We reexamined the MIN using
      standard functional tests to distinguish X-, Y- and W-cells. Discharge patterns
      to flashing spots also were used to identify some cells as lagged or nonlagged,
      as previously done for the geniculate A-layers. Also, each cell's response timing
      (latency and absolute phase) was measured from discharges to a spot undergoing
      sinusoidal luminance modulation. Of 71 MIN cells, 48% were Y, 27% were W, 8% were
      X, and 17% were unclassifiable. Lagged and nonlagged discharge profiles were
      observed in each cell group, with 28% of all cells being lagged. Lagged cells
      displayed a response suppression and long latency to discharge following spot
      onset, and a slow decay in firing at spot offset that was often preceded by a
      transient discharge. These profiles were indistinguishable from those of lagged
      cells in the A-layers. MIN cells also were heterogeneous in response timing,
      displaying a range of latency and absolute phase values similar to that in the A
      layers. We extended these analyses to 27 cells in the geniculate C-layers. In
      layer C, 35% of cells were Y, 10% were X, 25% were W, and 30% were
      unclassifiable. About 11% had lagged profiles, and were X-cells or unclassifiable
      cells. Layers C1 and C2 contained only W-cells and no lagged profiles. The range
      of timings in the C-layers was somewhat narrower than in the MIN. Overall, these
      results show that the MIN contains a greater variety of functional cell classes
      than heretofore appreciated. Further, it appears that mechanisms which create
      different timing delays in the A-layers also exist in the MIN and layer C. These
      timings may contribute to direction selectivity in extrastriate cortex.

PMID- 10349973
TI  - Cortical processing of second-order motion.
AB  - Neurons in the mammalian visual cortex have been found to respond to second-order
      features which are not defined by changes in luminance over the retina (Albright,
      1992; Zhou & Baker, 1993, 1994, 1996; Mareschal & Baker, 1998a,b). The detection
      of these stimuli is most often accounted for by a separate nonlinear processing
      stream, acting in parallel to the linear stream in the visual system. Here we
      examine the two-dimensional spatial properties of these nonlinear neurons in area
      18 using envelope stimuli, which consist of a high spatial-frequency carrier
      whose contrast is modulated by a low spatial-frequency envelope. These stimuli
      would fail to elicit a response in a conventional linear neuron because they are
      designed to contain no spatial-frequency components overlapping the neuron's
      luminance defined passband. We measured neurons' responses to these stimuli as a
      function of both the relative spatial frequencies and relative orientations of
      the carrier and envelope. Neurons' responses to envelope stimuli were narrowband
      to the carrier spatial frequency, with optimal values ranging from 8- to 30-fold
      higher than the envelope spatial frequencies. Neurons' responses to the envelope
      stimuli were strongly dependent on the orientation of the envelope and less so on
      the orientation of the carrier. Although the selectivity to the carrier
      orientation was broader, neurons' responses were clearly tuned, suggesting that
      the source of nonlinear input is cortical. There was no fixed relationship
      between the optimal carrier and envelope spatial frequencies or orientations,
      such that nonlinear neurons responding to these stimuli could perhaps respond to
      a variety of stimuli defined by changes in scale or orientation.

PMID- 10349974
TI  - Effects of norepinephrine on the activity of visual neurons in the superior
      colliculus of the hamster.
AB  - Single-unit recording and micropressure ejection techniques were used to test the
      effects of norepinephrine (NE) on the responses of neurons in the superficial
      layers (the stratum griseum superficiale and stratum opticum) of the hamster's
      superior colliculus (SC). Application of NE suppressed visually evoked responses
      by -30% in 75% of 40 neurons tested and produced > or = 30% augmentation of
      responses in only 5%. The decrement in response strength was mimicked by
      application of the alpha2 adrenoceptor agonist, p-aminoclonidine, the nonspecific
      beta agonist, isoproterenol, and the beta1 agonist, dobutamine. These agents had
      similar effects on responses evoked by electrical stimulation of the optic chiasm
      and visual cortex. The alpha1 agonist, methoxamine, augmented the light-evoked
      responses of 53% of 49 SC cells by > or = 30%, but had little effect on responses
      evoked by electrical stimulation of optic chiasm or visual cortex. The effects of
      adrenergic agonists upon the glutamate-evoked responses of SC cells that were
      synaptically "isolated" by concurrent application of Mg2+ were similar to those
      obtained during visual stimulation. Analysis of effects of NE on visually evoked
      and background activity indicated that application of this amine did not
      significantly enhance signal-to-noise ratios for most superficial layer SC
      neurons, and signal-to-noise ratios were in some cases reduced. These results
      indicate that NE acts primarily through alpha2 and beta1 receptors to suppress
      the visual responses of SC neurons. Activation of either of these receptors
      reduces the responses of SC neurons to either of their two major visual inputs as
      well as to direct stimulation by glutamate, and it would thus appear that these
      effects are primarily postsynaptic.

PMID- 10349975
TI  - Effects of norepinephrine upon superficial layer neurons in the superior
      colliculus of the hamster: in vitro studies.
AB  - Intracellular recording techniques were used to evaluate the effects of
      norepinephrine (NE) on the membrane properties of superficial layer (stratum
      griseum superficiale and stratum opticum) superior colliculus (SC) cells. Of the
      207 cells tested, 44.4% (N = 92) were hyperpolarized by > or = 3 mV and 8.7% (N =
      18) were depolarized by > or = 3 mV by application of NE. Hyperpolarization
      induced by NE was dose dependent (EC50 = 8.1 microM) and was associated with
      decreased input resistance and outward current which had a reversal potential of 
      94.0 mV. Depolarization was associated with a very slight rise in input
      resistance and had a reversal potential of -93.1 mV for the single cell tested.
      Pharmacologic experiments demonstrated that isoproterenol, dobutamine, and p
      aminoclonidine all hyperpolarized SC cells. These results are consistent with the
      conclusion that NE-induced hyperpolarization of SC cells is mediated by both
      alpha2 and beta1 adrenoceptors. The alpha1 adrenoceptor agonists, methoxamine and
      phenylephrine, depolarized 35% (6 of 17) of the SC cells tested by > or = 3 mV.
      Most of the SC cells tested exhibited responses indicative of expression of more
      than one adrenoceptor. Application of p-aminoclonidine or dobutamine inhibited
      transsynaptic responses in SC cells evoked by electrical stimulation of optic
      tract axons. Inhibition of evoked responses by these agents was usually, but not
      invariably, associated with a hyperpolarization of the cell membrane and a
      reduction in depolarizing potentials evoked by application of glutamate. The
      present in vitro results are consistent with those of the companion in vivo study
      which suggested that NE-induced response suppression in superficial layer SC
      neurons was primarily postsynaptic and chiefly mediated by both beta2 and beta1
      adrenoceptors.

PMID- 10349976
TI  - Cloning and characterization of six zebrafish photoreceptor opsin cDNAs and
      immunolocalization of their corresponding proteins.
AB  - Zebrafish (Danio rerio) represents an excellent genetic model for vertebrate
      visual system studies. Because the opsin proteins are ideal markers of specific
      photoreceptor cell types, we cloned six different zebrafish opsin cDNAs. Based on
      pairwise alignments and phylogenetic comparisons between the predicted zebrafish
      opsin amino acid sequences and other vertebrate opsins, the cDNAs encode
      rhodopsin, two different green opsins (zfgr1 and zfgr2), a red, a blue, and an
      ultraviolet opsin. Phylogenetic analysis indicates the zfgr1 protein occupies a
      well-resolved dendrogram branch separate from the other green opsins examined,
      while zebrafish ultraviolet opsin is closely related to the human blue- and
      chicken violet-sensitive proteins. Polyclonal antisera were generated against
      individual bacterial fusion proteins containing either the red, blue, or
      ultraviolet amino termini or the rod or green opsin carboxyl termini.
      Immunolocalization on adult zebrafish frozen sections demonstrates the green and
      red opsins are each expressed in different members of the double cone cell pair,
      the blue opsin is detected in long single cones, and the ultraviolet opsin
      protein is expressed in the short single cones. In 120-h postfertilization
      wholemounts, green, red, blue, and ultraviolet opsin-positive cells are detected
      in an orderly arrangement throughout the entire retina. The antibodies'
      photoreceptor-type specificity indicates they will be useful for characterizing
      both wild-type and mutant zebrafish retinas.

PMID- 10349977
TI  - Neuronal responses to orientation and motion contrast in cat striate cortex.
AB  - Responses of striate neurons to line textures were investigated in anesthetized
      and paralyzed adult cats. Light bars centered over the excitatory receptive field
      (RF) were presented with different texture surrounds composed of many similar
      bars. In two test series, responses of 169 neurons to textures with orientation
      contrast (surrounding bars orthogonal to the center bar) or motion contrast
      (surrounding bars moving opposite to the center bar) were compared to the
      responses to the corresponding uniform texture conditions (all lines parallel,
      coherent motion) and to the center bar alone. In the majority of neurons center
      bar responses were suppressed by the texture surrounds. Two main effects were
      found. Some neurons were generally suppressed by either texture surround. Other
      neurons were less suppressed by texture displaying orientation or motion (i.e.
      feature) contrast than by the respective uniform texture, so that their responses
      to orientation or motion contrast appeared to be relatively enhanced (preference
      for feature contrast). General suppression was obtained in 33% of neurons tested
      for orientation and in 19% of neurons tested for motion. Preference for
      orientation or motion contrast was obtained in 22% and 34% of the neurons,
      respectively, and was also seen in the mean response of the population. One
      hundred nineteen neurons were studied in both orientation and motion tests.
      General suppression was correlated across the orientation and motion dimension,
      but not preference for feature contrast. We also distinguished modulatory effects
      from end-zones and flanks using butterfly-configured texture patterns. Both
      regions contributed to the generally suppressive effects. Preference for
      orientation or motion contrast was not generated from either end-zones or flanks
      exclusively. Neurons with preference for feature contrast may form the
      physiological basis of the perceptual saliency of pop-out elements in line
      textures. If so, pop-out of motion and pop-out of orientation would be encoded in
      different pools of neurons at the level of striate cortex.

PMID- 10349978
TI  - Erratum: Temporal and spatial patterns of opsin gene expression in the zebrafish
      (Danio rerio): corrections with additions.
AB  - We report here a reexamination of the developmental expression of cone opsins in
      the zebrafish retina. The red- and blue-sensitive opsins appear at 51 h
      postfertilization (hpf) whereas ultraviolet (UV) opsin is not seen until after 55
      hpf. More cells show red cone opsin expression than blue at 51 and 55 hpf,
      indicating the sequence of cone opsin expression in zebrafish is first red, then
      blue, and finally UV. Curiously, morphological development of the cones is in
      reverse order; UV cones appear quite mature by day 6-7 postfertilization (pf),
      but morphologically, red cones do not appear adult-like until 15-20 days pf.

PMID- 10349979
TI  - Basal cell-specific anti-keratin antibody 34betaE12: optimizing its use in
      distinguishing benign prostate and cancer.

PMID- 10349980
TI  - The specific distribution of dendritic interstitial cells at the tumor border of
      major salivary gland pleomorphic adenomas.
AB  - To investigate the role of stromal cells at the tumor border of major salivary
      gland pleomorphic adenomas, we performed immunohistochemical analysis for
      detecting CD34-positive stromal cells (dendritic interstitial cells) and alpha
      smooth muscle actin (ASMA) -positive stromal cells (myofibroblasts) at the
      periphery of the tumor. We examined 21 pleomorphic adenomas of major salivary
      glands. All of the 21 pleomorphic adenomas examined had both dendritic
      interstitial cells and myofibroblasts at the tumor border. The ratio between the
      two cell types varied, and they exhibited a bilayered capsular structure;
      myofibroblasts were located in the inner layer of the tumor capsule, whereas
      dendritic interstitial cells derived from nearby vascular structures and nerves
      were located in the outer layer of the capsule. On the basis of the specific
      distribution of the dendritic interstitial cells in the present study, there is a
      possibility that dendritic interstitial cells are associated with the tumor
      growth regulation of major salivary gland pleomorphic adenomas.

PMID- 10349982
TI  - Myxoid synovial sarcoma: an underappreciated morphologic subset.
AB  - Focal myxoid change is a well-recognized feature of synovial sarcoma, but the
      presence of a predominantly myxoid stroma is rare. We describe seven cases of
      myxoid synovial sarcoma in which marked myxoid change initially obscured the
      diagnosis, leading to confusion (principally with malignant peripheral nerve
      sheath tumor). The median age (20 yr) and tumor location (four lower extremity,
      two upper extremity, and one head and neck region) were similar to those found in
      typical synovial sarcoma. Histologically, five cases were monophasic spindle cell
      lesions with a lacy appearance in areas with a prominent Alcian blue-positive
      myxoid stroma. Each case had foci with more typical features of synovial sarcoma,
      including a fascicular growth pattern with a variably collagenized stroma,
      stromal mast cells, a hemangiopericytoma-like vascular pattern, and
      calcification. Two cases showed small foci of glandular (biphasic)
      differentiation. Immunohistochemically, all of the seven cases were positive for
      epithelial membrane antigen, four of six were positive for pan-keratin, three of
      six were positive for S-100, two of four were positive for CD99, and six of six
      were negative for desmin. Clinical follow-up in six cases ranged from 8 to 48
      months (median, 21 mo). Local recurrence developed in three patients at 9, 20,
      and 24 months, respectively. In one of these three patients, lung metastases
      developed at 13 months, and the patient died of disseminated disease at 23
      months. In another of the three patients, lung metastases developed at 27 months.
      Three patients had no evidence of disease at 8, 15, and 15 months. Our data are
      too limited to indicate any clinical differences between myxoid synovial sarcoma
      and conventional synovial sarcoma Recognition of this rare histologic variant of
      synovial sarcoma is important because it can easily be mistaken for other myxoid
      spindle cell neoplasms, potentially resulting in suboptimal therapy.

PMID- 10349981
TI  - Immunohistochemical staining for Ber-EP4, p53, proliferating cell nuclear
      antigen, Ki-67, bcl-2, CD34, and factor XIIIa in nevus sebaceus.
AB  - Increased expression of p53 has been found in the majority of basal cell
      carcinomas (BCCs). The pattern and intensity of this staining, as well as
      staining for proliferation antigens, seems to correlate with behavior of
      histologic subtypes of BCC. Nevus sebaceus (NS) is considered a hamartoma.
      Multiple epithelial neoplasms do arise in NS, and, rarely, they show an
      aggressive biologic behavior. Significant numbers of these neoplasms, however,
      have areas of basaloid hyperplasia that are often reported as BCC. Although
      morphologically similar to BCC, the mechanism underlying the development of these
      areas has not been investigated, so we sought to evaluate the expression of Ber
      EP4, p53, proliferating cell nuclear antigen, Ki-67, bcl-2, Factor XIIIa, and
      CD34 in areas showing basaloid hyperplasia, arising in NS. We performed
      immunohistochemical stains for Ber-EP4, p53, proliferating cell nuclear antigen,
      Ki-67, bcl-2, Factor XIIIa, and CD34 on seven cases of NS with areas of basaloid
      hyperplasia. All of the eight cases of NS showed diffuse positive membrane
      staining for Ber-EP4 and negative nuclear staining for p53. Proliferating cell
      nuclear antigen and Ki-67 staining was only slightly increased in the areas of
      basaloid hyperplasia, compared with the surrounding epidermis and with areas of
      the epidermis peripheral to the hamartomatous proliferation, and bcl-2 was only
      focally positive. Factor XIIIa-positive cells and CD34-positive vascular
      endothelial cells were increased within the subjacent dermis, a pattern
      suggestive of follicular differentiation. Our findings suggest that even though
      areas of basaloid hyperplasia in NS are morphologically similar to BCC, they are
      induced by different stimulatory and molecular mechanisms. These different
      mechanisms result in expression of immunohistochemical markers more
      characteristic of benign follicular tumors than of BCC.

PMID- 10349983
TI  - Myxoid solitary fibrous tumor: a study of seven cases with emphasis on
      differential diagnosis.
AB  - Focal myxoid change is a well-recognized feature of solitary fibrous tumor (SFT),
      but to date, predominantly myxoid examples of SFT have not been reported. We
      describe seven cases of SFT in which stromal myxoid change affected 50% or more
      of the tumor examined, thus obscuring typical diagnostic features. Patients
      ranged in age from 35 to 68 years old (median, 45 yr), with an equal sex
      distribution. Tumor locations included pleura, orbit, and periparotid
      subcutaneous tissue, as well as four cases in deep soft tissue (two in the
      abdominal wall and one each in the chest wall and thigh). Myxoid areas were
      identified grossly in four cases. Histologically, the lesions were composed of
      bland spindle cells disposed haphazardly or with a lacy or reticulated appearance
      in a myxoid, richly vascularized stroma These myxoid areas were punctuated by
      small cellular aggregates in four cases, and areas showing diagnostic features of
      SFT were present in five of seven primary excision specimens. Atypical features
      suggestive of malignancy were not present in any of the cases.
      Immunohistochemically, all of the seven cases stained positively for CD34 and
      CD99 (013), and all were negative for smooth muscle actin, desmin, S-100 protein,
      epithelial membrane antigen, and pan-keratin. There were no recurrences or
      metastases reported in four patients with limited follow-up (median duration, 19
      mo). Recognition of this uncommon morphologic subset of SFT is important because
      of possible confusion, particularly in small biopsy specimens, with a variety of
      myxoid spindle cell neoplasms with different biologic potential. These include
      low-grade fibromyxoid sarcoma, myxoid synovial sarcoma, malignant peripheral
      nerve sheath tumor, low-grade myxofibrosarcoma, myxoid liposarcoma, myxoid
      spindle cell lipoma, myxoid neurofibroma, and so-called "hemangiopericytoma."

PMID- 10349984
TI  - Effect of formalin fixation and epitope retrieval techniques on antibody
      34betaE12 immunostaining of prostatic tissues.
AB  - Basal cell-specific, anti-high molecular weight cytokeratin (HMCK) antibody is
      often used to confirm the diagnosis of prostatic adenocarcinoma, particularly if
      limited amounts of tissue are available. HMCK is formalin sensitive and requires
      pretreatment by enzymes or heat if formalin-based fixatives are used. To date,
      the effect of prolonged formalin fixation on HMCK immunoreactivity has not been
      systematically studied; this is critical, because the diagnosis of malignancy is
      based on a negative immunoreaction. In this study, 5 tissue blocks obtained from
      each of 10 radical prostatectomy specimens were fixed in formalin from 6 hours to
      1 month. HMCK immunostaining was performed with monoclonal antibody clone
      34betaE12 after pretreatment of the sections by either enzymatic predigestion
      with pepsin, heat-induced epitope retrieval (HIER) with a microwave, or HIER with
      a hot plate. For scoring, the staining intensity at 6 hours of formalin fixation
      was considered as the baseline for that particular antigen retrieval technique.
      After pepsin predigestion or microwaving, there was progressive loss of HMCK
      immunoreactivity from 1 week or longer of formalin fixation. HIER with a hot
      plate yielded consistent results with no decrease in HMCK immunoreactivity with
      as long as 1 month of formalin fixation. The staining intensity was consistently
      stronger at all periods of formalin fixation when the hot plate method was used,
      compared with pepsin predigestion or microwaving. Generally weak HMCK positivity
      was observed in rare neoplastic cells of 3 of 10 specimens after hot plate HIER
      but not with pepsin predigestion or microwave antigen retrieval. This sporadic
      immunostaining of malignant cells was quantitatively and qualitatively distinct
      from the pattern seen in benign epithelium. We conclude that formalin fixation
      affects HMCK immunoreactivity over time and might impact its diagnostic
      usefulness. Efficacies of different antigen unmasking/epitope retrieval
      techniques vary and must be standardized for individual laboratories.

PMID- 10349985
TI  - Estimation of tumor stage and lymph node status in patients with colorectal
      adenocarcinoma using probabilistic neural networks and logistic regression.
AB  - Staging colorectal adenocarcinoma on the basis of biopsy specimens could identify
      patients who might benefit from neoadjuvant therapy without undergoing resection
      first. In this study, we evaluated the ability of artificial neural networks with
      genetic algorithms and multivariate logistic regression to predict the stage of
      99 patients with primary colorectal adenocarcinoma by analyzing age, tumor grade,
      and immunoreactivity to p53 and bcl-2 with use of endoscopically obtained biopsy
      specimens. We correlated results with regional lymph node status and tumor stage,
      identified in subsequent colectomy specimens. bcl-2 and p53 protein expression
      were demonstrated by immunohistochemical methods, using formalin-fixed, paraffin
      embedded biopsy tissues. Tumor grade was evaluated in hematoxylinand eosin
      stained sections. Patients were divided into training (n = 75) and testing cases
      (n = 24). Several probabilistic neural networks with genetic algorithm models
      were trained, using the four prognostic features as input neurons and regional
      lymph node status or stage as output neurons. Data were analyzed with univariate
      statistics and multivariate logistic regression. The cases were divided into
      training (n = 40) and testing (n = 59). The best two models classified correctly
      the lymph node status of 20 of 24 test patients (specificity, 80%; sensitivity,
      85%; positive predictive value, 86%) and the tumor stage of 21 of 24 test
      patients (specificity, 82%; sensitivity, 92%; positive predictive value, 85%),
      respectively. Tumor grade and p53 protein were statistically significant (P <
      .05) by analysis of variance for lymph node status and tumor stage. Logistic
      regression models with these two independent variables correctly estimated the
      probability of lymph node metastases in 44 of 59 test cases and the tumor stage
      of 43 of 59 test cases, respectively. Results indicated the usefulness of
      probabilistic neural networks in the population studied, but the findings should
      be validated with large groups of patients.

PMID- 10349986
TI  - Evaluation of rapid microsatellite analysis of paraffin-embedded specimens in
      screening for hereditary nonpolyposis colorectal cancer.
AB  - Length alterations in short repetitive DNA sequences, termed microsatellite
      instability (MSI), are used as a diagnostic criterion of replication errors
      caused by various mutations in at least five mismatch repair genes. Therefore,
      MSI analysis is useful in clinical practice to identify patients with hereditary
      nonpolyposis colorectal cancer (HNPCC). MSI can be detected by amplification of
      microsatellite loci in DNA extracted from paraffin-embedded tumor and
      corresponding peritumoral specimens after numerous time consuming steps limiting
      the clinical utilities. Rapid microsatellite analysis, a efficient and rapid DNA
      extraction technique based on Triton X-100 preincubation, was compared with the
      conventional DNA extraction for HNPCC screening in colorectal tumor specimens
      from 12 patients. Five complex and two noncomplex (CA)n microsatellite loci were
      tested, with use of multicolor fluorescent analysis. MSI and loss of
      heterozygosity in colorectal tumor samples could equally be assessed with the two
      DNA preparation methods, whereas the number of initially unsuccessful DNA
      extractions from paraffin-embedded tissue specimens and overall duration for MSI
      analysis were significantly reduced when rapid microsatellite analysis was used.
      A replication error-positive phenotype was detected in 2 of 10 patients with a
      positive family history for colorectal cancer, and diagnosis of HNPCC was finally
      confirmed by detection of a specific germline mutation. The described rapid
      microsatellite analysis is less time consuming and more efficient, and, in
      general, it reduces the risk of contamination by limiting the number of steps
      required. Therefore, it might replace current DNA extraction procedures.
      Furthermore, techniques using fluorescent polymerase chain reaction and
      semiautomated DNA sequencer allow for precise, observer-independent, and rapid
      scoring in MSI and loss of heterozygosity assessment. A combination of our rapid
      DNA extraction method and the use of a highly specific microsatellite marker
      might improve replication error analysis in HNPCC screening.

PMID- 10349987
TI  - Optimizing microvessel counts according to tumor zone in invasive ductal
      carcinoma of the breast.
AB  - We calculated microvessel counts (MVCs) by analyzing CD31-stained sections in
      three tumor zones (central, intermediate, and peripheral) in 147 cases of
      invasive ductal carcinoma (IDC). The purpose of the study was to discover whether
      there is a difference in MVC in the different zones of tumor, which zone contains
      the highest MVC within the tumor, from which zone the MVCs best correlate with
      tumor recurrence or tumor death, and which histologic factors correlate with the
      MVC of the tumor. Sections were scanned to assess the highest number of
      microvessels in any single 200 x field (0.384 mm2). In all of our cases, the
      average MVCs of the central, intermediate, and peripheral zones of the IDCs were
      34.4, 39.4, and 51.5 per 200x field, respectively. The MVC significantly
      increased from the central to the peripheral zones (P < .001). In the univariate
      analysis, in at least one tumor zone, the MVC was correlated with T
      classification, tumor necrosis, fibrotic focus (a scar-like area within IDCs),
      and c-erbB-2 protein expression. The only factor significantly correlated with a
      higher MVC in all of the three zones was fibrotic focus. Moreover, in the
      multivariate analysis, tumors having high MVCs in the peripheral zone were
      significantly associated with higher hazard ratios for tumor recurrence (P <
      .05). This study showed that the MVC of an IDC significantly increases from the
      central to the peripheral zones, and it showed that angiogenesis in the
      peripheral zone is associated with prognosis. Therefore, estimation of
      angiogenesis should be performed in the peripheral zone for reliable prediction
      of outcome in breast cancer patients. As a surrogate for angiogenesis, fibrotic
      focus seems to be a useful marker for malignant potential in breast cancer.

PMID- 10349988
TI  - Infiltrating micropapillary carcinoma of the breast.
AB  - Infiltrating micropapillary carcinoma of the breast is a recently described and
      poorly recognized aggressive variant of infiltrating ductal carcinoma for which
      the clinical significance and role of prognostic markers are not fully described.
      In 14 cases of infiltrating micropapillary carcinoma, we studied histologic
      characteristics; immunohistochemical expression of c-erbB-2, p53, and MIB-1;
      hormonal expression of these tumors; and genetic alterations on the p53 locus. We
      correlated these results with clinical outcome. Patient ages ranged from 37 to 58
      years (mean, 50 yr). Nine patients presented with a palpable tumor, one with an
      axillary mass. Three patients had abnormal mammograms. Five patients (36%)
      presented with Stage II disease, eight (57%) with Stage III, and one (7%) with
      Stage IV. The tumors were a modified Bloom-Richardson Grade II in nine cases
      (64%) and Grade III in 5 (36%). Mitoses ranged from 1 to 12 per 10 high power
      fields. Necrosis was uniformly absent. Psammoma bodies were present in 9 cases
      (64%) and lymphatic invasion in 10 (71%). In all of the cases, c-erbB-2 was
      identified immunohistochemically, and MIB-I was positive, staining 30 to 60% of
      the tumor cells. The cells were immunoreactive for p53 in six (75%) of eight
      cases, and, when present, stained 20 to 50% of the tumor cells. Loss of
      heterozygosity on locus 17p13.1 (p53) was identified in 4 of 5 informative
      samples. Molecular and immunohistochemical analyses had an 80% concordance.
      Follow-up was available in 11 patients, of whom 9 had recurrence in the skin and
      chest wall (average time of recurrence, 24 mo). Recognition of this distinctive
      and aggressive variant of infiltrating carcinoma is important because of its
      unfavorable prognosis and specific pattern of local recurrence. Its aggressive
      nature is supported by its advanced stage at presentation and expression of
      unfavorable prognostic markers.

PMID- 10349989
TI  - Reasoning with uncertainty in pathology: artificial neural networks and logistic
      regression as tools for prediction of lymph node status in breast cancer
      patients.
AB  - Axillary lymph node status is an important prognostic feature for patients with
      breast cancer, but the therapeutic value of axillary lymphadenectomy is
      controversial. It would be useful to be able to predict the status of axillary
      lymph nodes before lymphadenectomy from prognostic features evaluated in a
      previous breast biopsy. This prediction would be useful to optimize the treatment
      of patients with breast cancer who are unlikely to have nodal metastases. We
      studied 279 patients with invasive breast carcinoma treated with modified radical
      mastectomy or with lumpectomy combined with axillary lymph node dissection.
      Prognostic factors evaluated were age, histologic type of invasive tumor,
      presence of associated ductal and/or lobular carcinoma in situ, lesion size,
      histologic and nuclear grades, DNA index, presence of multiploidy by flow
      cytometric analysis, and immunocytochemical expression of estrogen and
      progesterone receptors, proliferating nuclear cell antigen, and HER-2/neu
      oncogene. Several probabilistic neural networks (NNs) with genetic algorithms
      were developed using prognostic features as input neurons and lymph node status
      (positive or negative) as output neurons. The data were also studied with
      multiple regression and logistic regression analysis. The best NN model trained
      with 224 cases using 19 input neurons. It classified correctly 49 (89.0%) of 55
      unknown cases (specificity, 97.2%; sensitivity, 80.0%; positive predictive value,
      93.8%; negative predictive value, 87.5%). Several statistically significant
      models could be fitted with both multiple regression and logistic regression. The
      logistic regression model fitted with 240 cases using 6 independent variables
      estimated correctly 26 (66%) of 39 holdout cases. NNs and logistic regression
      models offer potentially useful tools to estimate the status of axillary lymph
      nodes of breast cancer patients before axillary lymphadenectomy. Future
      prospective studies with larger groups of patients and perhaps better prognostic
      markers are needed before these predictive multivariate models become ready for
      clinical use.

PMID- 10349990
TI  - Chondromyxoid fibroma: a tumor showing myofibroblastic, myochondroblastic, and
      chondrocytic differentiation.
AB  - Chondromyxoid fibroma (CMF) is a rare primary benign tumor of bone that
      demonstrates variable histologic features and is often confused with
      chondrosarcoma. Although the chondroid elements in CMF have been reported to be S
      100 protein positive and to have chondrocytic features ultrastructurally, the
      immunohistochemical and ultrastructural profile of CMF, especially with respect
      to the peripheral nonchondroid elements, has not been extensively studied.
      Formalin-fixed, paraffin-embedded tissue from 10 CMFs were stained
      immunohistochemically with antibodies to vimentin, desmin, muscle actin, smooth
      muscle actin, S-100 protein, and CD34. Six tumors were also examined
      ultrastructurally. The chondroid areas showed variable staining for S-100 protein
      but did not stain for muscle actin or smooth muscle actin. The peripheral areas
      surrounding the chondroid areas stained diffusely for smooth muscle actin and
      muscle actin but did not stain for S-100 protein. CD34 highlighted the extensive
      vascularity that was especially prominent in the peripheral areas; no tumor cells
      stained for CD34. There was no staining for desmin. Ultrastructural examination
      showed three different cell types. Some cells showed the classic features of
      chondrocytes, other cells had the features of myofibroblasts, and the third cell
      type had the features of both chondrocytes and myofibroblasts
      ("myochondroblasts"). These findings support the conclusion that CMF is a tumor
      showing myofibroblastic, myochondroblastic, and chondrocytic differentiation.

PMID- 10349991
TI  - A clinicopathologic and immunohistochemical study of 22 intraductal papillary
      mucinous neoplasms of the pancreas, with a review of the literature.
AB  - Intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas are rare
      lesions. We undertook this study to analyze these tumors by focusing on the
      diagnostic criteria and correlating the histologic features with clinical
      prognosis. Twenty-two cases of IPMN were retrieved from the Endocrine Tumor
      Registry of the Armed Forces Institute of Pathology. Blocks or unstained slides
      were available for histochemical and immunohistochemical studies (including
      proliferative markers and cell cycle regulators) and K-ras oncogene mutations in
      15 cases. Patient follow-up was obtained in all of the cases. IPMN occurs in both
      genders with a slight male predominance, with a mean age at presentation of 64.4
      years (range, 48-85 yr). The patients presented with abdominal pain. The
      neoplasms were radiologically and grossly cystic, usually (18 cases of 22)
      located in the head of the pancreas. Histologically, the tumors consisted of
      intraductal papillary proliferations protruding into and expanding the pancreatic
      ducts. Invasion into the surrounding pancreatic parenchyma was detected in 15
      cases. Chronic pancreatitis was present in all of the cases. p27 immunoreactivity
      always exceeded the immunoreactivity of cyclin E. K-ras oncogene mutations were
      detected in two cases. Patients were treated with a complete surgical resection
      (n = 7) or a Whipple procedure (n = 13). Only 2 of 22 patients died of disease (3
      died immediately postoperatively and 3 died of unrelated causes), whereas the
      remaining 14 patients were alive at last follow-up, without evidence of disease,
      an average of 58.2 months after initial presentation. IPMNs are rare, distinctive
      neoplasms, with complex intraductal papillae, that can be easily separated from
      in situ ductal adenocarcinoma and mucinous cystic neoplasms. The high ratio of
      p27 protein to cyclin E supports the excellent prognosis of these neoplasms,
      despite the presence of invasion and K-ras oncogene mutation.

PMID- 10349992
TI  - Monoclonal antibody-based immunohistochemical diagnosis of rickettsialpox: the
      macrophage is the principal target.
AB  - Cutaneous biopsies of five eschars and two rash lesions from five patients from
      New York City with documented rickettsialpox were examined by immunohistochemical
      methods with a monoclonal antibody directed against spotted fever group
      rickettsial lipopolysaccharide for the presence and cellular location of
      Rickettsia akari Rickettsiae were identified in all of the five patients, with
      good concordance of results for the same biopsy tissues with previously reported
      results by the direct immunofluorescence method. In contrast with
      immunofluorescence, which did not reveal the location of the organisms,
      immunohistochemical examination demonstrated R. akari to be in perivascular
      cells, morphologically resembling macrophages. Evaluation with double staining
      for rickettsiae and either CD68 or Factor VIII-related antigen revealed that the
      predominant infected cell type was CD68-positive macrophages, and only a rare
      rickettsia was detected in vascular endothelium, the major target cell for other
      rickettsioses. These results provide a diagnostic method for rickettsialpox and
      other spotted fever group rickettsioses and indicate that the elucidation of the
      pathogenesis of rickettsialpox must take into account that its target cell
      differs from that of Rocky Mountain spotted fever, boutonneuse fever, louse-borne
      typhus fever, and murine typhus.

PMID- 10349993
TI  - Helicobacter heilmannii gastritis: association with acid peptic diseases and
      comparison with Helicobacter pylori gastritis.
AB  - We analyzed 2 antral and 1 corpus full-thickness random endoscopic gastric
      mucosal samples obtained from 946 patients with duodenal ulcers (6077 biopsies)
      and from 281 patients with nonsteroidal anti-inflammatory drug-associated gastric
      ulcers (1794 biopsies). We stained tissue sections with hematoxylin and eosin and
      Warthin-Starry silver stain and immunostained them with polyclonal antibodies
      against Helicobacter pylori. Hematoxylin- and eosin-stained sections from 6
      patients with Helicobacter heilmannii (18 biopsies) and 23 randomly selected
      patients with H. pylori (68 biopsies) were evaluated and semiquantitated for the
      presence of acute inflammation, chronic inflammation, glandular atrophy,
      intestinal metaplasia, H. pylori, H. heilmannii, lymphoid follicles, or
      vasodilatation. Additional specimens were obtained for H. pylori culture, a CLO
      test, and serologic examination. H. heilmannii was detected in 6 (0.49%) of 1227
      patients (14 [0.18%] of 7871 biopsies). Of these, 4 (0.42%) of 946 were patients
      with duodenal ulcers (9 [0.15%] of 6077 biopsies), and 2 (0.71%) of 281 were
      patients with nonsteroidal anti-inflammatory drug-associated gastric ulcers (5
      [0.28%] of 1794 biopsies). We found H. heilmannii with hematoxylin and eosin
      stain, Warthin-Starry stain, and immunoperoxidase stain for H. pylori. Culture
      for H. pylori was negative in the four patients with duodenal ulcers. The CLO and
      serologic tests were positive in three of five and five of five patients,
      respectively. Our results indicate that H. heilmannii, like H. pylori, is
      associated with peptic ulcer disease (both active and inactive gastritis) and
      that it preferentially colonizes the gastric antrum. The severity of the H.
      heilmannii-associated gastritis is less intense and lymphoid aggregates are less
      common than in H. pylori-associated gastritis. Morphologic detection seems to be
      the method of choice for detecting H. heilmanni. Immunoperoxidase stain specific
      for H. pylori also stains H. heilmannii, indicating cross-reacting antigenic
      epitopes between H. heilmannii and H. pylori.

PMID- 10349994
TI  - The expression of hamartin, the product of the TSC1 gene, in normal human tissues
      and in TSC1- and TSC2-linked angiomyolipomas.
AB  - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized
      by seizures, mental retardation, and hamartomatous tumors in multiple organs,
      including subependymal giant cell astrocytomas, cardiac rhabdomyomas, and renal
      angiomyolipomas. Mutations in two genes are associated with TSC: TSC1, which was
      cloned in 1997, and TSC2, which was cloned in 1993. We report here the expression
      of hamartin, the product of the TSC1 gene, in normal human tissues and in renal
      angiomyolipomas from TSC1- and TSC2-linked patients. By Western blot analysis,
      hamartin is strongly expressed in brain, kidney, and heart, all of which are
      frequently affected in TSC. By immunohistochemical analysis, the expression
      pattern of hamartin in normal human tissues was almost identical to that of
      tuberin, the product of the TSC2 gene. This is consistent with the recent finding
      that tuberin and hamartin interact and with the clinical similarity between TSC1-
      and TSC2-linked disease. Strong hamartin expression was seen in cortical neurons,
      renal tubular epithelial cells, pancreatic islet cells, bronchial epithelial
      cells, and pulmonary macrophages. Hamartin was also expressed in endocrine
      tissues, including islet cells of the pancreas, follicular cells of the thyroid,
      and the zona reticularis of the adrenal cortex. In eight angiomyolipomas from a
      TSC1-linked patient, no hamartin expression was detected, whereas tuberin, the
      product of the TSC2 gene, was expressed. In 19 angiomyolipomas from a TSC2-linked
      patient, in whose angiomyolipomas loss of tuberin expression had previously been
      shown, hamartin expression was present. These data suggest that tuberin and
      hamartin immunoreactivity can distinguish tumors with underlying TSC1 mutations
      from those with TSC2 mutations. This differentiation might have diagnostic
      implications.

PMID- 10349995
TI  - Prognostic significance of CD44v6 in diffuse large B-cell lymphoma.
AB  - Diffuse large B-cell lymphoma in the Revised European-American Lymphoma
      Classification encompasses various morphologic subtypes of diffuse large-cell
      lymphomas of B-cell origin. The category is biologically and clinically
      heterogeneous, even though it constitutes approximately 30% of all non-Hodgkin's
      lymphomas. Clinically, the International Prognostic Index that identifies high
      risk group in aggressive non-Hodgkin's lymphomas is widely accepted. Lacking,
      however, are biologic or molecular prognostic markers that might aid in
      understanding the pathogenesis and designing specific therapies. CD44 isoforms
      are involved in tumor dissemination and might be associated with aggressive
      behavior of non-Hodgkin's lymphomas. We studied immunohistochemical expression of
      CD44s and CD44v6 in the tumors and examined their clinical significance in a
      cohort of patients with primary nodal diffuse large B-cell lymphoma who were
      uniformly evaluated and treated with doxorubicin-containing chemotherapy (n =
      42). In contrast to CD44s signals, CD44v6 signals were weak in routinely
      processed non-Hodgkin's lymphoma sections. Therefore, we used a highly sensitive
      catalyzed reporter deposition system and successfully detected CD44v6 signals in
      diffuse large B-cell lymphomas. Overexpression of the isoform was verified by
      Southern blot of reverse transcription polymerase chain reaction products. CD44s
      and CD44v6 were positive in 17 (40%) of 42 and 13 (31%) of 42, respectively.
      CD44v6 was detected predominantly in lymphoma cells, whereas CD44s was often
      positive for nonneoplastic small lymphocytes as well. In univariate regression
      analysis, the B symptoms, being in the International Prognostic Index high-risk
      group, and CD44v6 expression emerged as significant parameters for poorer overall
      survival, but CD44s expression did not achieve statistical significance. When
      multivariate regression analysis was performed using the former three parameters,
      only CD44v6 expression remained significant (P = .017; relative risk = 3.48),
      indicating that CD44v6 is a molecule particularly important for predicting worse
      prognosis. CD44v6, which can be detected in the archival materials, might be a
      biologically and clinically useful marker in identifying the high-risk group in
      the diffuse large B-cell lymphoma category of the Revised European-American
      Lymphoma Classification.

PMID- 10349997
TI  - Interview with a distinguished pharmaceutical scientist. Bernard Testa.

PMID- 10349996
TI  - Usefulness of Telfa pads in the histologic assessment of stereotactic-guided
      breast biopsy specimens.
AB  - Stereotactic core-needle biopsies (SCNBs) are being increasingly used for the
      diagnosis of breast lesions. Focal mammographic calcifications are often
      considered significant and sampled by SCNB. We compared diagnostic outcomes in
      breast tissue cut from 59 core biopsy blocks using Telfa pad embedding with those
      of 48 routinely embedded blocks. Specifically, we addressed the total length of
      core tissue in the first histologic section, the continuity and average core
      length in the first section, the frequency with which mammographic calcifications
      were confirmed histologically, and the number of sections per case needed to
      assure histologic-mammographic correlation. The first level of Telfa pad-embedded
      material showed significantly greater aggregate tissue length, more core
      continuity, and greater average core length. With routine embedding, we missed 3
      of 17 radiologic calcific foci. With Telfa pad embedding, we detected all of the
      24 calcific foci and consumed 50% fewer slides in doing so. We conclude that
      Telfa pad embedding of SCNBs of the breast provides an improved, cost-effective
      approach to diagnosis and histologic-radiologic correlation.

PMID- 10349998
TI  - Soluble self-assembled block copolymers for drug delivery.

PMID- 10349999
TI  - Monolayers of human alveolar epithelial cells in primary culture for pulmonary
      absorption and transport studies.
AB  - PURPOSE: To develop a cell culture model of human alveolar epithelial cells in
      primary culture for the in vitro study of pulmonary absorption and transport.
      METHODS: Type II pneumocytes isolated from normal human distal lung tissue by
      enzyme treatment and subsequent purification were plated on fibronectin/collagen
      coated polyester filter inserts, and cultured using a low-serum growth medium.
      Characterization of the cell culture was achieved by bioelectric measurements,
      cell-specific lectin binding, immunohistochemical detection of cell junctions,
      and by assessment of transepithelial transport of dextrans of varying molecular
      weights. RESULTS: In culture, the isolated cells spread into confluent
      monolayers, exhibiting peak transepithelial resistance of 2,180 +/- 62 ohms x cm2
      and potential difference of 13.5 +/- 1.0 mV (n = 30-48), and developing tight
      junctions as well as desmosomes. As assessed by lectin-binding, the cell
      monolayers consisted of mainly type I cells with some interspersed type II cells,
      thus well mimicking the situation in vivo. The permeability of hydrophilic
      macromolecular FITC-dextrans across the cell monolayer was found to be inversely
      related to their molecular size, with Papp values ranging from 1.7 to 0.2 x 10(
      8) cm/sec. CONCLUSIONS: A primary cell culture model of human alveolar epithelial
      cells has been established, which appears to be a valuable in vitro model for
      pulmonary drug delivery and transport studies.

PMID- 10350000
TI  - Competitive inhibition of glycylsarcosine transport by enalapril in rabbit renal
      brush border membrane vesicles: interaction of ACE inhibitors with high-affinity
      H+/peptide symporter.
AB  - PURPOSE: To examine the inhibitory potential of enalapril [and other angiotensin
      converting enzyme (ACE) inhibitors] on glycylsarcosine (GlySar) transport by the
      high-affinity renal peptide transporter. METHODS: Studies were performed in
      rabbit renal brush border membrane vesicles in which the uptake of radiolabeled
      GlySar was examined in the absence and presence of captopril, enalapril,
      enalaprilat, fosinopril, lisinopril, quinapril, quinaprilat, ramipril and
      zofenopril. RESULTS: Kinetic analyses demonstrated that enalapril inhibited the
      uptake of GlySar in a competitive manner (Ki approximately 6 mM). Fosinopril and
      zofenopril had the greatest inhibitory potency (IC50 values of 55 and 81 microM,
      respectively) while the other ACE inhibitors exhibited low-affinity interactions
      with the renal peptide transporter. With respect to structure-function, ACE
      inhibitor affinity was strongly correlated with drug lipophilicity (r = 0.944, p
      < 0.001 for all ACE inhibitors; r = 0.983, p < 0.001 without enalaprilat,
      quinaprilat and quinapril). CONCLUSIONS: The data suggest that enalapril and
      GlySar compete for the same substrate-binding site on the high-affinity peptide
      transporter in kidney, and that ACE inhibitors can interact with the renal
      carrier and inhibit dipeptide transport.

PMID- 10350001
TI  - The pH-partition profile of the anti-ischemic drug trimetazidine may explain its
      reduction of intracellular acidosis.
AB  - PURPOSE: The anti-ischemic drug trimetazidine (TMZ) acts by a combination of
      molecular mechanisms which begin to be understood. Thus, it acts in the
      micromolar range to significantly reduce intracellular acidification during
      ischemia. To search for a possible physicochemical explanation of this
      phenomenon, we investigated the transfer mechanisms of the various electrical
      forms of this dibasic drug. METHODS: The transfer characteristics of TMZ were
      studied by electrochemistry at the water/1,2-dichloroethane interface. Cyclic
      voltammetry was used to measure the formal transfer potentials of singly and
      doubly protonated forms of TMZ (noted TH+ and TH(2)2+, respectively) as a
      function of aqueous pH, and the partition coefficient of neutral TMZ (log P(T))
      was measured by two-phase titration. RESULTS: log P(T) was measured to be 1.04 +/
      0.06, and the acid-base dissociation constants in water were deduced to be
      pK(w)a1 = 4.54 +/- .02 and pK(w)a2 = 9.14 +/- 0.02. The partition coefficients of
      TH+ and TH(2)2+ were found to be respectively log P0'TH+ = -3.78 +/- 0.16 and log
      P0'TH(2)2+ = -9.84 +/- 0.30, which agrees well with the charge being delocalized
      on two nitrogen atoms in TH+. The pH-partition profile of TMZ was then
      established in the form of its ionic partition diagram, which showed that the
      affinity of the ions for the organic phase is pH-dependent and strongly increased
      by the interfacial potential. CONCLUSIONS: This behavior suggests a
      physicochemical mechanism whereby efflux of protonated TMZ out of an acidified
      cell is facilitated, in effect exporting protons to extracellular space.

PMID- 10350002
TI  - Interplay between CYP3A-mediated metabolism and polarized efflux of terfenadine
      and its metabolites in intestinal epithelial Caco-2 (TC7) cell monolayers.
AB  - PURPOSE: To further characterize cytochrome P450 (CYP) and P-glycoprotein (Pgp)
      expression in monolayers of the Caco-2 cell clone TC7, a cell culture model of
      the human intestinal epithelium. To study the interplay between CYP3A and Pgp as
      barriers to intestinal drug absorption in TC7 cells using terfenadine and its
      metabolites as substrates. METHODS: mRNA expression of eight CYPs and Pgp was
      investigated in TC7 and parental Caco-2 (Caco-2p) cell monolayers using RT-PCR.
      The CYP3A kinetics was determined in microsomes from both cell lines. The
      transport, metabolism and efflux of terfenadine and its metabolites were
      investigated in TC7 monolayers. RESULTS: Both TC7 and Caco-2p cells expressed
      mRNA for Pgp and several important CYPs. However, mRNA for CYP3A4 was detectable
      anly from TC7 cells. The relative affinity of CYP3A for terfenadine metabolism in
      the two cell lines was comparable, but the maximum reaction rate in the TC7 cells
      was 8-fold higher. The rate of transport of terfenadine and its metabolites
      hydroxy-terfenadine (HO-T) and azacyclonol across TC7 monolayers was 7.1-, 3.5-
      and 2.1-fold higher, respectively, in the basolateral to apical direction than it
      was in the apical to basolateral (AP-BL) direction. Inhibition studies indicated
      that the efflux was mediated by Pgp. Ketoconazole increased the AP-BL transport
      terfenadine dramatically by inhibiting both terfenadine metabolism and Pgp
      efflux. CONCLUSIONS: Cell culture models such as TC7 provide qualitative
      information on drug interactions involving intestinal CYP3A and Pgp.

PMID- 10350003
TI  - The nitric oxide donor SIN-1 is free of tolerance and maintains its cyclic GMP
      stimulatory potency in nitrate-tolerant LLC-PK1 cells.
AB  - PURPOSE: Using an established cell culture model, the present study investigates
      whether linsidomine (SIN-1), a spontaneous donor of nitric oxide and active
      metabolite of the antianginal drug molsidomine, induces tolerance to its own
      cyclic GMP stimulatory action or shows a diminished response after tolerance
      induction with glyceryl trinitrate. METHODS: Incubations with nitric oxide donors
      were carried out in LLC-PK1 kidney epithelial cells. Intracellular levels of
      cyclic GMP, the vasodilatory second messenger of nitric oxide, were determined by
      radioimmunoassay. RESULTS: A 5-h preincubation with glyceryl trinitrate (0.01-100
      microM) led to complete inhibition of a subsequent cyclic GMP stimulation by
      glyceryl trinitrate but left the cyclic GMP response to SIN-1 unaltered.
      Similarly, cyclic GMP elevations by the spontaneous nitric oxide donors sodium
      nitroprusside and spermine NONOate were not affected after pretreatment with
      glyceryl trinitrate. Moreover, pretreatment with SIN-1 (1-1000 microM) had no
      significant effect on SIN-1-dependent cyclic GMP stimulation. CONCLUSIONS: Our
      results show that in LLC-PK1 cells, SIN-1 is free of tolerance induction and not
      cross-tolerant to glyceryl trinitrate. This may be due to the spontaneous nitric
      oxide release from SIN-1, which in contrast to nitric acid esters does not
      require enzymatic bioactivation and may therefore be unaffected by nitrate
      tolerance.

PMID- 10350004
TI  - Brain penetration and in vivo recovery of NMDA receptor antagonists amantadine
      and memantine: a quantitative microdialysis study.
AB  - PURPOSE: To determine free brain concentrations of the clinically used
      uncompetitive NMDA antagonists memantine and amantadine using microdialysis
      corrected for in vivo recovery in relations to serum, CSF and brain tissue levels
      and their in vitro potency at NMDA receptors. METHODS: Microdialysis corrected
      for in vivo recovery was used to determine brain ECF concentrations after steady
      state administration of either memantine or amantadine. Additionally CSF, serum,
      and brain tissue were analyzed. RESULTS: Following 7 days of infusion of
      memantine or amantadine (20 and 100 mg/kg/day respectively) whole brain
      concentrations were 44-and 16-fold higher than free concentrations in serum
      respectively. The free brain ECF concentration of memantine (0.83 +/- 0.05
      microM) was comparable to free serum and CSF concentrations. In case of
      amantadine, it was lower. A higher in vivo than in vitro recovery was found for
      memantine. CONCLUSIONS: At clinically relevant doses memantine reaches a brain
      ECF concentration in range of its affinity for the NMDA receptor and close to its
      free serum concentration. This is not the case for amantadine and different
      mechanisms of action may be operational.

PMID- 10350005
TI  - Immobilized artificial membrane (IAM)-HPLC for partition studies of neutral and
      ionized acids and bases in comparison with the liposomal partition system.
AB  - PURPOSE: To study the partitioning of model acids ((RS)-warfarin and salicylic
      acid), and bases (lidocaine, (RS)-propranolol and diazepam), with immobilized
      artificial membrane (IAM)-HPLC, as compared to partitioning in the standardized
      phosphatidylcholine liposome/buffer system. METHODS: The pH-dependent apparent
      partition coefficients D were calculated from capacity factors (k'IAM) obtained
      by IAM-HPLC, using a 11-carboxylundecylphosphocholine column. For lipophilic
      compounds k'IAM, values were determined with organic modifiers and extrapolation
      to 100% water phase (k'IAMw) was optimized. Temperature dependence was explored
      (23 to 45 degrees C), and Gibbs free energy (deltaG), partial molar enthalpy
      (deltaH) and change in entropy (deltaS) were calculated. Equilibrium dialysis was
      used for the partitioning studies with the liposome/buffer system. RESULTS: For
      extrapolation of k'IAMw, linear plots were obtained both with the respective
      dielectric constants and the mole fractions of the organic modifier. All tested
      compounds showed a similar pH-D diagram in both systems; however, significant
      differences were reproducibly found in the pH range of 5 to 8. In all cases,
      deltaG and deltaH were negative, whereas deltaS values were negative for acids
      and positive for bases. CONCLUSIONS: In both partitioning systems, D values
      decreased significantly with the change from the neutral to the charged
      ionization state of the solute. The differences found under physiological
      conditions, i.e. around pH 7.4, were attributed to nonspecific interactions of
      the drug with the silica surface of the IAM column.

PMID- 10350006
TI  - NMR studies of retinoid-protein interactions: the conformation of [13C]-beta
      ionones bound to beta-lactoglobulin B.
AB  - PURPOSE: Vitamin A (retinol) and its metabolites comprise the natural retinoids.
      While the biological action of these molecules are thought to be primarily
      mediated by ca. 55 kDa nuclear retinoic acid receptors, a number of structurally
      similar 15-20 kDa proteins are involved in the transport, and possibly
      metabolism, of these compounds. The milk protein beta-lactoglobulin B (beta-LG)
      is an 18 kDa protein which binds retinol and may be involved in oral delivery of
      retinol to neonates. beta-LG also binds drugs and other natural products and is
      of potential interest as a protective delivery vehicle. METHODS: To examine the
      conformation of the model retinoid beta-ionone both in solution and when bound to
      beta-LG, NMR and computational methods have been employed. RESULTS: Taken
      together, NMR studies of beta-ionone in solution measuring scalar and dipolar
      coupling, as well as CHARMm calculations, suggest beta-ionone prefers a slightly
      twisted 6-s-cis conformation. Isotope-edited NMR studies of 13C-labeled beta
      ionones bound to beta-LG, primarily employing the HMQC-NOE experiment, suggest
      beta-ionone also binds to beta-LG in its 6-s-cis conformation. CONCLUSIONS: The
      methods employed here allow estimates of protein-bound ligand conformation.
      However, additional sites of ligand labeling will be necessary to aid in binding
      site localization.

PMID- 10350007
TI  - Development of a mathematical model for the water distribution in freeze-dried
      solids.
AB  - PURPOSE: Development of a mathematical model to provide information about the
      amount of water associated with a protein and an excipient in a lyophilized
      product. METHODS: The moisture content of the product and the mass fraction of
      each component were used to derive a model for the calculation of the mass of
      water associating with each component. The model was applied to lyophilized
      formulations of rhDNase containing various amounts of mannitol or lactose. The
      total water content was investigated by thermogravimetry, crystalline properties
      by X-ray powder diffraction and water uptake behaviour using a moisture
      microbalance system. RESULTS: Calculations based on the model suggest that in a
      lyophilized rhDNase-mannitol formulation where the sugar is crystalline, most of
      the water is taken up by the protein. However, in the lyophilized rhDNase-lactose
      formulation where the sugar is amorphous, water is taken up by both the sugar and
      protein to a comparative extent. At high relative humidities when the amorphous
      sugar undergoes crystallization, the model can accommodate such a change by
      allowing for the formation of an additional crystalline phase. CONCLUSIONS: The
      rhDNase-sugar formulations show excellent conformity to the model which provides
      quantitative information about the distribution of water in the lyophilized
      binary protein-excipient products.

PMID- 10350008
TI  - Magnetic resonance imaging (MRI) as a method to investigate movement of water
      during the extrusion of pastes.
AB  - PURPOSE: To assess the potential of Magnetic Resonance Imaging (MRI) as a method
      of detecting water movement during the extrusion of pastes. METHODS: Plug samples
      were made from mixtures of model materials and microcrystalline cellulose with
      two water contents at two different ram speeds to simulate ram extrusion. The
      extrusion process was stopped at different stages and analyzed for water
      distribution using MRI to assess the influence of water content and the speed of
      ram on water movement as the extrusion process progresses. RESULTS: Two types of
      water movement were detected: vertical and radial. When extruding at the faster
      ram speed, water moved predominantly in the vertical direction, whereas when
      extruding at a slower ram speed it moved predominantly in the radial direction.
      At the beginning of the extrusion process a greater water movement in the wetter
      formulations was observed. CONCLUSIONS: MRI appears to be a useful approach to
      non-invasive water mapping, and is expected to contribute towards a greater
      understanding of the role of water in the extrusion of pastes.

PMID- 10350009
TI  - Determination of the viscosity of an amorphous drug using thermomechanical
      analysis (TMA).
AB  - PURPOSE: To evaluate thermomechanical analysis (TMA) as a technique for
      determining the viscosity of amorphous pharmaceutical materials. This property of
      amorphous drugs and excipients is related to their average rate of molecular
      mobility and thus to their physical and chemical stability. METHODS: Indomethacin
      was selected as a model amorphous drug whose viscosity has previously been
      reported in the literature. A Seiko TMA 120C thermomechanical analyzer was
      utilized in isothermal penetration mode to determine the viscosity of the
      amorphous drug over the maximum possible range of temperatures. RESULTS: Using a
      cylindrical penetration geometry it was possible to accurately determine the
      viscosity of amorphous indomethacin samples by TMA over the temperature range
      from 35 to 75 degrees C. The results were consistent with those reported in the
      literature using a controlled strain rheometer over the range 44-75 degrees C.
      The limiting lower experimental temperature for the TMA technique was extended to
      significantly below the calorimetric glass transition temperature (Tg
      approximately 42 degrees C), thus allowing a direct experimental determination of
      the viscosity at Tg to be made. CONCLUSIONS: Thermomechanical analysis can be
      used to accurately determine the viscosity of amorphous pharmaceutical materials
      at temperatures near and above their calorimetric glass transition temperatures.

PMID- 10350010
TI  - Preparation of biodegradable microparticles using solution-enhanced dispersion by
      supercritical fluids (SEDS).
AB  - PURPOSE: We have evaluated a new process, involving solution-enhanced dispersion
      by supercritical fluids (SEDS), for the production of polymeric microparticles.
      METHODS: The biodegradable polymers, Poly (DL-lactide-co-glycolide): copolymer
      composition 50:50 (DL-PLG), Poly (L-lactide) (L-PLA), Poly (DL-lactide) (DL-PLA)
      and Polycaprolactone (PCL), were used for preparation of microparticles using
      SEDS. Solutions of the polymers in organic solvents were dispersed and sprayed
      with supercritical CO2. Extraction of the organic solvents resulted in the
      formation of solid microparticles. The amounts of highly toxic solvents such as
      dichloromethane (MC) were reduced in the process. RESULTS: Microparticles were
      obtained from all polymers. The mean particle size and shape varied with the
      polymer used. The morphology of the particles was strongly affected by the choice
      of polymer solvent. Discrete spherical microparticles of DL-PLG were produced
      with a mean volumetric diameter of 130 microm. The microparticles of the L-PLA
      were almost spherical, and their size increased from 0.5 to 5 microm as the
      density of supercritical CO2 decreased. PCL formed microparticles with diameters
      of 30-210 microm and showed a strong tendency to form films at high pressure.
      CONCLUSIONS: The SEDS process appears a promising method for production of
      microparticles from biodegradable polymers without the use of toxic solvents.

PMID- 10350011
TI  - A novel system based on a poloxamer/PLGA blend as a tetanus toxoid delivery
      vehicle.
AB  - PURPOSE: Previous work on the encapsulation of proteins and antigens in
      poly(lactic-co-glycolic acid) (PLGA) microspheres has led to the conclusion that
      microencapsulated antigens are frequently inactivated due to their interaction
      with the polymer. To improve the compatibility of the antigen with the polymer,
      we have devised a novel microencapsulated system consisting of a blend of PLGA
      50:50 and poloxamer 188 (Pluronic F68) and applied it to the delivery of tetanus
      antigen. METHODS: Tetanus toxoid was encapsulated in microspheres containing
      different amounts of poloxamer using an anhydrous procedure based on an oil-in
      oil solvent extraction process. The compatibility of the polymers was studied by
      Fourier transform infrared (FT-IR) spectroscopy. Microspheres were assayed in
      vitro and in vivo for their ability to deliver active antigen for extended
      periods of time. RESULTS: Analysis by FT-IR spectroscopy evidenced the
      miscibility of both polymers by a hydrogen bonding mechanism. In vitro release
      studies revealed that microspheres containing poloxamer released antigenically
      active TT, in a pulsatile manner, for up to 50 days. In addition, it was observed
      that the intensity and duration of the pulses were dependent on both poloxamer
      content and TT loading in the microspheres. The in vivo evaluation of this new
      system showed that the neutralizing antibodies elicited by the TT encapsulated in
      poloxamer-PLGA microspheres were considerably higher and more prolonged than
      those obtained after administration of the aluminum phosphate-adsorbed toxoid.
      CONCLUSIONS: These results indicate the importance of devising new
      microencapsulation approaches specially adapted for preserving the activity of
      protein antigens incorporated within PLGA microspheres.

PMID- 10350012
TI  - Interaction of naproxen with alpha-cyclodextrin and its noncyclic analog
      maltohexaose.
AB  - PURPOSE: To study the effect of mechanical grinding on crystallinity changes of
      naproxen (NAP) in mixtures with alpha-cyclodextrin (alphaCd), amorphous alphaCd,
      and maltohexaose (M6); and the possible formation of a pseudo-inclusion complex
      between NAP and M6 in aqueous solution. METHODS: NAP-additive physical mixtures
      at 0.30, 0.18, and 0.10 mass fraction of drug were tested, after increasing
      grinding times, by differential scanning calorimetry (DSC) and X-ray powder
      diffractometry (XRD). Interaction in aqueous solution was examined by phase
      solubility and fluorescence analyses supported by molecular modelling. RESULTS:
      In the mixtures with each additive the fusion enthalpy per unit mass of NAP
      decreased and the half width at half maximum of selected X-ray diffraction peaks
      of NAP increased with the progress of grinding time following the loss of
      crystallinity of the samples. The mechanical treatment apparently did not affect
      the chemical integrity of the drug. Particularly active in the equimolar mixture
      was the best amorphizing agent, M6. Solution studies and molecular modelling
      confirmed M6 may have the feature of a supermolecule for NAP, which forms a 1:1
      pseudo-inclusion complex that was as stable as the true inclusion complex with
      alphaCd. CONCLUSIONS: The intrinsically amorphous linear analog of aCd might be a
      potential amorphism-inducing agent and solubilizer for scarcely water soluble
      drugs.

PMID- 10350013
TI  - Characterization of recombinant cytokine fragments using isotachophoresis
      capillary zone electrophoresis, reversed-phase high performance liquid
      chromatography, and mass spectrometry.
AB  - PURPOSE: Capillary zone electrophoresis with isotachophoretic sample
      preconcentration (ITP-CZE) and reversed-phase high performance liquid
      chromatography (RP-HPLC) with UV detection and on-line coupling to electrospray
      ionization mass spectrometry were investigated for their potential to separate
      and identify fragments of recombinant human interleukin-6 formed during acidic
      stress of the parent protein. RESULTS: Based on the orthogonal separation
      principles governing ITP-CZE and RP-HPLC, different peak patterns were observed
      using both methods. The selectivity of ESI-MS allowed identification of several
      co-migrating compounds. Data obtained by on-line ESI-MS were compared to results
      from off-line investigations by MALDI-TOF-MS performed with single fractions
      collected from the RP-HPLC system. Cleavage of the protein backbone occurred
      preferably at acid-labile Asp-sites. The total amount of rhIL-6 needed for ITP
      CZE-ESI-MS identification of all fragments was only in the upper femtomole range,
      while RP-HPLC required amounts of protein three orders of magnitude higher. On
      the other hand, the low CE sample volume opposes the collection of fractions to
      perform off-line analysis. CONCLUSIONS: Growing acceptance of CE with on-line MS
      detection for pharrmaceutical quality control of proteins is expected.

PMID- 10350015
TI  - The effect of collinearity on parameter estimates in nonlinear mixed effect
      models.
AB  - PURPOSE: To demonstrate how correlations among predictor variables in a
      population pharmacokinetic model affect the ability to discern which covariates
      should enter into the structural pharmacokinetic model. METHODS: Monte Carlo
      simulation was used to generate multiple-dose concentration-time data similar to
      that seen in a Phase III clinical trial. The drugs' pharmacokinetics were
      dependent on two covariates. Five data sets were simulated with increasing
      correlation between the two covariates. All data sets were analyzed using NONMEM
      both with and without inclusion of the covariates in the structural
      pharmacokinetic model. Summary measures for ill-conditioning and sensitivity
      analysis were used to examine how increasing correlation among covariates affects
      the accuracy and precision of the parameter estimates. RESULTS: When covariates
      were included in the structural pharmacokinetic model and the correlation between
      covariates increased, the standard error of the parameter estimates increased and
      the value of parameter estimates themselves became increasingly biased. When the
      correlation between predictor variables was 0.75, the standard errors of the
      parameter estimates were too large to declare statistical significance.
      CONCLUSIONS: Correlations among predictor variables greater than 0.5 when entered
      into the model simultaneously should be a warning to researchers because the (1)
      the accuracy of the parameter estimates themselves may be biased and (2) the
      precision of the estimates may be inflated due to ill-conditioning.

PMID- 10350014
TI  - A central composite design to investigate the thermal stabilization of lysozyme.
AB  - PURPOSE: The formulation and processing of protein drugs requires the
      stabilization of the native, biologically active structure. Our aim was to
      investigate the thermal stability of a model protein, lysozyme, in the presence
      of two model excipients, sucrose and hydroxypropyl-beta-cyclodextrin (HP-beta
      CD). METHODS: We used high sensitivity differential scanning calorimetry (HSDSC)
      in combination with a central composite design (CCD). As indicators of protein
      thermal stability, the measured responses were the unfolding transition
      temperature (Tm), the onset temperature of the denaturation (To), and the
      extrapolated onset temperature (To,e). RESULTS: A highly significant (F
      probability <0.001) statistical model resulted from analysis of the data The
      largest effect was due to pH (over the range 3.2-7.2), and the pH value that
      maximized Tm was 4.8. Several minor but significant effects were detected that
      were useful for mechanistic understanding. In particular, the effects of protein
      concentration and cyclodextrin concentration on Tm and To,e were found to be pH
      dependent This was indicative of the partially hydrophilic nature of protein
      protein interactions and protein-cyclodextrin interactions, respectively.
      CONCLUSIONS: Response surface methodology (RSM) proved efficient for the modeling
      and optimization of lysozyme thermal stability as well as for the physical
      understanding of the protein-sugar-cyclodextrin system in aqueous solution.

PMID- 10350016
TI  - Meal composition effects on the oral bioavailability of indinavir in HIV-infected
      patients.
AB  - PURPOSE: To study the influence of large-volume high-calorie protein, fat, and
      carbohydrate meals and a non-caloric hydroxypropylmethyl cellulose (HPMC) viscous
      meal on the oral bioavailability of indinavir in HIV-infected subjects. METHODS:
      Seven male HIV-infected subjects received caloric meal treatments and control
      meals in a randomized crossover fashion and the viscosity meal as a final
      treatment. The total volume of each meal treatment was 500 mL and the caloric
      meals each contained 680 kcal. Gastric pH was also monitored by radiotelemetry
      from one hour before to four hours after drug and caloric meal administration. A
      single Crixivan (indinavir sulfate) dose equivalent to 600 mg indinavir was
      administrated orally with 100 mL of water immediately following meal
      administration. Indinavir plasma concentrations were obtained using reverse-phase
      HPLC. RESULTS: All meal treatments significantly decreased the extent of
      indinavir absorption as compared to fasted control. AUC0-infinity decreased by
      68%, 45%, 34%, and 30% for protein, carbohydrate, fat, and viscosity meal
      treatments versus fasted control, respectively (p < 0.05). The mean Cmax was
      significantly decreased 74%, 59%, 46% and 36% (p < 0.05) and the mean tmax was
      significantly delayed from I hr in fasted controls to 3.8, 3.6, 2.1 and 2.0 hrs
      (p < 0.05) for protein, carbohydrate, fat, and viscosity meal treatments,
      respectively. The elimination half-life of indinavir determined in the fasted
      state was decreased in HIV-infected subjects as compared to the reported half
      life in normal healthy subjects. CONCLUSIONS: Reductions in indinavir plasma
      concentrations compared to drug administration in the fasted state are most
      severe with the high-calorie protein meal. This is consistent with an influence
      of elevated gastric pH on drug precipitation. Significant drug plasma
      concentration reductions observed with administration of the other meals in the
      absence of appreciably elevated gastric pH profile indicate that other factors
      are playing a role in the meal effects. The similarity in indinavir plasma
      profiles with protein and carbohydrate versus fat and viscosity suggests that the
      latter meals may reduce the impact of drug precipitation compared to the former
      meals.

PMID- 10350017
TI  - Production and characterization of 22 monoclonal antibodies directed against S
      20499, a new potent 5-HT1A chiral agonist: influence of the hapten structure on
      specificity and stereorecognition.
AB  - PURPOSE: An immunoconjugate model was proposed to produce stereoselective
      monoclonal antibodies (MAbs) for the quantitation of a 5-HT1A agonist, S 20499.
      MAbs produced were characterized in terms of stereoselectivity and specificity
      towards the opposite enantiomer and structural analogs. METHODS: The immunogen
      was formed following the effective addition of a butanoic acid spacer arm between
      the parent S 20499 structure and bovine serum albumin (BSA). After fusion
      (modified Kohler and Milstein's procedure), specificity of MAbs was obtained
      using the Abraham's criteria. Experimental and calculated partition coefficients
      were determined. RESULTS: Twenty-two hybridoma cell lines were established
      secreting MAbs (apparent association constants ranging from 1.1 x 10(8) to 2.8 X
      10(9) M(-1)). Several MAbs showed cross-reactivity levels of less than 5% with S
      20500 (optical antipode), which could allow a stereospecific assay to be set up.
      Both chroman and azaspiro moieties were part of the epitopic site. Dealkylation
      and hydroxylation(s) led to various crossreactivity levels. Four antibody
      families were described in terms of specificity. CONCLUSIONS: This study
      highlighted the influence of the immunoconjugate construction (coupling site and
      type of spacer arm) in the immuno-stereospecificity of Abs. The results obtained
      for two monohydroxylated metabolites suggest that the lipophilicity behavior
      could be a valuable tool for predicting Ab-crossreactivity.

PMID- 10350018
TI  - Microdialysis evaluation of the ocular pharmacokinetics of propranolol in the
      conscious rabbit.
AB  - PURPOSE: This study was conducted to assess the effects of anesthesia and aqueous
      humor protein concentrations on ocular disposition of propranolol. METHODS:
      Rabbits were anesthetized and a microdialysis probe was inserted into the
      anterior chamber of one eye; the contralateral eye served as a control. At timed
      intervals after probe placement, a 100-microl sample of aqueous humor was
      aspirated from each eye to determine protein concentration. In vitro protein
      binding parameters were used to simulate the impact of protein concentration on
      propranolol disposition. To assess the influence of anesthesia, probes were
      implanted in the anterior chamber of each eye. After >5-day stabilization,
      conscious and anesthetized rabbits (n = 3/group) received a 200-microg topical
      dose of [3H]DL-propranolol in each eye; propranolol was assayed in probe
      effluent. RESULTS: Changes in aqueous humor protein concentrations were observed
      following probe insertion. Simulations demonstrated that the unbound propranolol
      AUC (approximately 2.4-fold) in aqueous humor should be reduced due to protein
      influx. Intraocular propranolol exposure in anesthetized rabbits was
      approximately 8-fold higher than in conscious rabbits, and approximately 1.9-fold
      higher than in rabbits without a post-surgical recovery period. CONCLUSIONS:
      Anesthesia and time-dependent aqueous humor protein concentrations may alter
      ocular pharmacokinetics, and must be taken into account in the design of
      microdialysis experiments.

PMID- 10350019
TI  - Noninvasive assessment of tumor hypoxia with 99mTc labeled metronidazole.
AB  - PURPOSE: The assessment of tumor hypoxia by imaging modality prior to radiation
      therapy would provide a rational means of selecting patients for treatment with
      radiosensitizers or bioreductive drugs. This study aimed to develop a 99mTc
      labeled metronidazole (MN) using ethylene-dicysteine (EC) as a chelator and
      evaluate its potential use to image tumor hypoxia. METHODS: EC was conjugated to
      amino analogue of MN using Sulfo-N-hydroxysuccinimide and 1-ethyl-3-(3
      dimethylaminopropyl) carbodiimide-HCl as coupling agents, the yield was 55%.
      Tissue distribution of 99mTc-EC-MN was determined in breast tumor-bearing rats at
      0.5, 2, and 4 hrs. Planar imaging and whole-body autoradiograms were performed.
      The data was compared to that using 99mTc-EC (control), [18F]fluoromisonidazole
      (FMISO) and [(131)I] iodomisonidazole (IMISO). RESULTS: In vivo biodistribution
      of 9mTc-EC-MN in breast tumor-bearing rats showed increased tumor-to-blood and
      tumor-to-muscle ratios as a function of time. Conversely, tumor-to-blood values
      showed time-dependent decrease with 9mTc-EC in the same time period. Planar
      images and autoradiograms confirmed that the tumors could be visualized clearly
      with 99mTc-EC-MN from 0.5 to 4 hrs. There was no significant difference of tumor
      to-blood count ratios between 99mTc-EC-MN and [(131)I]IMISO at 2 and 4 hrs
      postinjection. From 0.5 to 4 hrs, both 9mTc-EC-MN and [(131)I]MISO have higher
      tumor-to-muscle ratios compared to [18]FMISO. CONCLUSIONS: It is feasible to use
      9mTc-EC-MN to image tumor hypoxia.

PMID- 10350020
TI  - Body distribution of camptothecin solid lipid nanoparticles after oral
      administration.
AB  - PURPOSE: The aim of this study was to investigate the specific changes in body
      distribution of camptothecin (CA) through incorporation into solid lipid
      nanoparticles (SLN) by peroral route. METHODS: Camptothecin loaded solid lipid
      nanoparticles (CA-SLN) coated with poloxamer 188 were produced by high pressure
      homogenization. The CA-SLN were characterized by transmission electron microscopy
      and electrophoretic mobility measurement. In vitro release characteristics of
      camptothecin from CA-SLN were studied at different pH media. The concentration of
      camptothecin in organs was determined using reversed-phase high-performance
      liquid chromatography with a fluorescence detector after oral administration of
      CA-SLN and a camptothecin control solution (CA-SOL). RESULTS: Our results showed
      that CA-SLN had an average diameter 196.8 nm with Zeta potential of -69.3 mV. The
      encapsulation efficiency of camptothecin was 99.6%, and in vitro drug release was
      achieved up to a week. There were two peaks in the camptothecin concentration
      time curves in plasma and tested organs after oral administration of CA-SLN. The
      first peak was the result of free drug and the second peak was indicative of gut
      uptake of CA-SLN after 3 hours. In tested organs, the area under curve (AUC) and
      mean residence time (MRT) of CA-SLN increased significantly as compared with CA
      SOL, and the increase of brain AUC was the highest among all tested organs.
      CONCLUSIONS: The results indicate SLN could be a promising sustained release and
      targeting system for camptothecin or other lipophilic antitumor drugs after oral
      administration.

PMID- 10350021
TI  - Electrorepulsion versus electroosmosis: effect of pH on the iontophoretic flux of
      5-fluorouracil.
AB  - PURPOSE: To delineate the contributions of electrorepulsion and electroosmosis to
      the iontophoretic flux of 5-FU across porcine skin in vitro. Also, the
      isoelectric point (pI) of the skin model was determined. METHODS: The
      electrotransport of 5-FU, anode-to-cathode ("anodal") and cathode-to-anode
      ("cathodal") was determined as a function of the pH of the electrolyte bathing
      the skin. RESULTS: At pH 8.5, the drug (pKa approximately 8) is negatively
      charged and "cathodal", viz. electrorepulsive, transport is much greater than
      that in the opposite direction. At pH 7.4, where approximately 25% of 5-FU is
      charged, electrorepulsive and electroosmotic ("anodal") fluxes are balanced.
      Decreasing the pH to 6, and then 5, reduces the percentage of ionized 5-FU such
      that "anodal" electroosmosis dominates across the negatively-charged membrane.
      But, at pH 4, "anodal" and "cathodal" fluxes are again equal suggesting
      neutralization of the skin (i.e., pI approximately 4). This is confirmed at pH 3,
      where "cathodal" electroosmosis dominates across the now net-positively charged
      barrier. CONCLUSIONS: Electrotransport is sensitive, mechanistically, to the
      properties of the permeant and of the skin; interactions of, for example, the
      drug or constituents of a formulation, that alter the barrier's net charge, can
      affect iontophoretic delivery. The pI of porcine ear skin is approximately 4.

PMID- 10350022
TI  - Preparation and characterization of carmustine loaded polyanhydride wafers for
      treating brain tumors.

PMID- 10350023
TI  - The human keratinocyte cell line HaCaT: an in vitro cell culture model for
      keratinocyte testosterone metabolism.

PMID- 10350025
TI  - More on potassium, the heart, and antipsychotic agents.

PMID- 10350024
TI  - Analyzing rich data using different methods provided by NONMEM: pharmacokinetics
      of telmisartan following intravenous infusion to healthy volunteers.

PMID- 10350026
TI  - Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk
      factors, and association with tardive dyskinesia.
AB  - Prevalence and risk factors for extrapyramidal syndromes (EPS) were investigated
      in a sample of 1,559 patients. The overall prevalence of EPS was 29.4% (N = 458).
      Among the EPS-diagnosed patients, parkinsonism as assessed by the presence of
      core parkinsonian symptoms (rigidity, tremor, bradykinesia) was present in 65.9%
      of patients (N = 302), akathisia in 31.8% (N = 145), and acute dystonia in 2.1%
      (N = 10). Old age and long-term neuroleptic drug (NL) treatment were
      significantly associated with EPS in both the univariate and the multivariate
      analyses, whereas no relationship was observed with average NL daily doses and
      current NL treatment. EPS was diagnosed in 50.2% of 285 patients with persistent
      tardive dyskinesia (TD). Distribution of EPS in patients with TD showed that
      tremor and akathisia were more frequent in peripheral TD cases than in orofacial
      TD cases. Furthermore, there was a stronger association of NL-induced
      parkinsonism with peripheral TD than with orofacial TD. This study suggests that
      the association between EPS and TD may be limited to specific subtypes of TD.
      Peripheral TD showed a higher association with parkinsonism and with akathisia,
      suggesting that these symptoms may share a common pathophysiology.

PMID- 10350027
TI  - Psychomotor, Cognitive, extrapyramidal, and affective functions of healthy
      volunteers during treatment with an atypical (amisulpride) and a classic
      (haloperidol) antipsychotic.
AB  - The primary objective of this study was to compare the objective and subjective
      effects of amisulpride with those of a classic antipsychotic, haloperidol, when
      both were given to healthy volunteers in representative therapeutic doses over 5
      days. The secondary objective was to compare the effects of relatively low and
      high doses of amisulpride to confirm the suspected duality of its pharmacologic
      activity. Twenty-one subjects participated in the four-way, randomized, double
      blind, crossover study with repeated daily doses of amisulpride 50 mg,
      amisulpride 400 mg, haloperidol 4 mg, and placebo. Subjects were
      institutionalized during treatment periods and were under 24-hour medical
      supervision. They underwent a series of psychomotor and cognitive tests 1 hour
      before and 3 and 6 hours after dosing on days 1 and 5. Their extrapyramidal
      disturbances and drug-related feelings were assessed at the end of each
      replication. Psychiatric interviews and ratings of depression, subjective well
      being, and negative symptoms occurred on day 4. Amisulpride 50 mg had no
      significant effect on any parameter. Amisulpride 400 mg had several adverse
      effects on psychomotor and, although less severe, on cognitive performance on the
      fifth day only. Amisulpride 400 mg produced no significant extrapyramidal
      disturbances in the group as a whole, although it may have in some individual
      subjects. Also, it produced no signs of mental disturbances on clinical rating
      scales or during a structured psychiatric interview. Haloperidol ubiquitously
      impaired psychomotor and cognitive performance in a similar fashion after the
      first and the final doses. It produced extrapyramidal disturbances in nearly
      every subject, the most common being akathisia and the most severe, in the case
      of one individual, being acute dystonia. Unlike amisulpride, haloperidol produced
      a number of mental disturbances, the most noteworthy being negative symptoms.
      Amisulpride seems to be a well-tolerated drug. Its side effects should be much
      less troublesome to patients using the drug on a long-term basis than those of
      classic antipsychotics, like haloperidol.

PMID- 10350028
TI  - Critical review of GABA-ergic drugs in the treatment of schizophrenia.
AB  - GABA-ergic medications may have a potential role in the treatment of
      schizophrenia. Laboratory evidence has generally supported the ability of gamma
      aminobutyric acid (GABA) to reduce dopaminergic activity and has suggested that
      GABA may be effective in combating hypofrontality by acting on
      mesoprefrontocortical tracts in patients resistant to treatment with
      antipsychotic drugs. Although the results of clinical trials of several GABA
      ergic compounds have been inconclusive because of methodologic limitations and
      drug toxicity, benzodiazepines and valproate seem to be associated with favorable
      treatment outcomes, especially when combined with typical antipsychotic agents.
      This study concludes that further investigation of the use of GABA in
      schizophrenia is likely to improve the understanding of the psychopathology of
      this illness and to expand our treatment alternatives. Also provided are
      suggestions to enhance the design of future studies, improve the potential for
      favorable treatment outcomes, and assist in predicting patients' responses to
      GABA-ergic medications.

PMID- 10350029
TI  - Influence of endogenous progesterone on alprazolam pharmacodynamics.
AB  - The results of a recently completed study demonstrated that postmenopausal women
      were more sensitive to triazolam-induced psychomotor performance impairment when
      progesterone was administered concomitantly. That clinical evidence agrees with
      the emerging in vitro information regarding the rapid membrane effects of a
      progesterone metabolite that positively modulates the gamma-aminobutyric acid-A
      benzodiazepine receptor complex. The objective of this study in premenopausal
      women was to determine whether the response to a benzodiazepine is altered when
      endogenous progesterone concentrations are high (luteal phases of a menstrual
      cycle) compared with when progesterone concentrations are low (follicular phases
      of a menstrual cycle). The pharmacokinetics and pharmacodynamics of oral
      alprazolam were evaluated in twelve healthy, normally menstruating women who were
      not receiving oral contraceptive agents. On two separate occasions, once during
      each phase of the menstrual cycle, the women randomly received an oral alprazolam
      2-mg dose. Blood samples were collected, and psychomotor performance tests were
      conducted at selected times before and after dosing. These data show that
      fluctuations of endogenous progesterone across the menstrual cycle do not
      influence alprazolam pharmacodynamics. Despite endogenous progesterone
      concentrations being significantly higher during the midluteal than during the
      midfollicular drug administrations, no differences were observed in either the
      digit-symbol substitution test, card sorting by suit, or sedation scores on these
      two occasions. No pharmacokinetic differences were observed between the two
      menstrual cycle-phase drug administrations. In conclusion, the lack of changes
      during the menstrual cycle in demonstrable cognitive impairment and
      pharmacokinetics after alprazolam administration is reassuring. This implies that
      a dose adjustment made on the basis of menstrual timing is not required.

PMID- 10350030
TI  - Ongoing lithium treatment prevents relapse after total sleep deprivation.
AB  - Forty bipolar depressed inpatients underwent three consecutive cycles of total
      sleep deprivation (TSD). At the beginning of the study, 20 patients were free of
      psychotropic drugs and 20 had been receiving lithium medication for at least 6
      months. Mood was rated on the Hamilton Rating Scale for Depression before and
      after TSD; perceived mood changes during treatment were evaluated with self
      administered visual analog scales. Patients undergoing long-term lithium
      treatment showed a significantly better response to TSD as rated on both scales:
      13 of 20 patients (vs. 2 of 20 patients without lithium) showed a sustained
      response during a follow-up period of 3 months. This preliminary evidence of a
      positive interaction of TSD and long-term lithium treatment could be explained by
      a synergistic effect of both treatments on brain serotonergic function, possibly
      via a desensitization of 5-hydroxytryptamine-1A inhibitory autoreceptors.

PMID- 10350031
TI  - Plans, designs, and analyses for clinical trials of anti-cocaine medications:
      where we are today. NIDA/VA/SU Working Group on Design and Analysis.
AB  - Increased interest in addiction psychopharmacology has raised unique methodologic
      issues in the design, conduct, and analysis of outcomes in clinical trials of
      therapeutic agents for drug dependence. This article summarizes issues raised at
      a meeting in Palo Alto, California, on November 4, 1996, that was sponsored by
      the Medication Development Division of the National Institute on Drug Abuse and
      the Department of Veterans Affairs Cooperative Studies Program to discuss the
      methodologic issues in clinical trials of cocaine pharmacotherapy.

PMID- 10350032
TI  - Controlled trial of high doses of pemoline for adults with attention
      deficit/hyperactivity disorder.
AB  - Despite the increasing awareness of attention-deficit/hyperactivity disorder
      (ADHD) in adults, there are a limited number of controlled pharmacologic studies
      of this disorder. Because the stimulant medication magnesium pemoline (Cylert,
      Abbott Laboratories, Abbott Park, IL) has been found effective in treating ADHD
      in pediatric groups, we tested its efficacy in adults with ADHD using higher
      daily doses than those previously studied. We conducted a 10-week, double-blind,
      placebo-controlled, crossover design study of pemoline at a target daily dose of
      3 mg/kg per day in 35 adult patients with DSM-III-R and -IV ADHD. We used
      standardized structured psychiatric instruments for diagnosis. To measure
      improvement, we used separate assessments of ADHD, depressive, and anxiety
      symptoms at baseline and at each biweekly visit. ADHD outcome was determined
      using the ADHD symptom checklist and Clinical Global Impression scales of
      Severity and Improvement. Of the 35 adults with ADHD who were randomized in the
      trial, 27 (77%) completed the protocol. Treatment with pemoline in the final week
      of the 4-week active phase was best tolerated at doses substantially lower than
      the target dose of 3 mg/kg per day (mean dose, 2.2 mg/kg per day; mean+/-SD,
      148+/-95 mg). Pemoline was significantly better at reducing ADHD symptoms
      compared with placebo (z = 2.4,p < 0.02). Using a predefined 30% reduction in
      symptoms as an indication of improvement, 50% of pemoline-treated subjects and
      17% of subjects in the placebo group were considered positive responders (chi2 =
      7.1, p = 0.008). These results indicate that pemoline is moderately effective in
      the treatment of ADHD in adults. Although robust doses were targeted, most adults
      preferred more moderate dosing (120-160 mg/day). Given the limited efficacy,
      tolerability, and concerns of hepatic dysfunction, pemoline should be considered
      as second-line medication for treating ADHD in adults.

PMID- 10350033
TI  - Opioid withdrawal during risperidone treatment.
AB  - A small but significant percentage of opioid-dependent patients will require
      neuroleptic treatment. Several classes of drugs have been shown to affect opioid
      metabolism. Two patients who were hospitalized with a diagnosis of opioid
      dependence received concomitant treatment with opioids and risperidone. After
      receiving risperidone for several days, both patients exhibited symptoms of
      opioid withdrawal despite having no change in their opioid doses. These
      withdrawal symptoms resolved soon after risperidone was discontinued. This
      finding suggests the possibility that risperidone may precipitate opioid
      withdrawal in opioid-dependent patients.

PMID- 10350034
TI  - Effect of buspirone on sexual dysfunction in depressed patients treated with
      selective serotonin reuptake inhibitors.
AB  - To evaluate the possible influence of buspirone on sexual dysfunction in
      depressed patients treated with a selective serotonin reuptake inhibitor (SSRI),
      we analyzed data from a placebo-controlled trial designed to explore the efficacy
      of buspirone as add-on treatment for patients not responding to an SSRI alone. At
      baseline, all patients met the criteria for a major depressive episode according
      to DSM-IV and had received citalopram or paroxetine during a minimum of 4 weeks
      without responding to the treatment. Buspirone (flexible dosage, 20-60 mg/day) or
      placebo was added to the SSRI for 4 weeks; the mean daily dose of buspirone at
      endpoint was 48.5 mg (SD = 1.0). Sexual dysfunction was evaluated using a
      structured interview. Before starting medication with buspirone or placebo, 40%
      (47 of 117) reported at least one kind of sexual dysfunction (decreased libido,
      ejaculatory dysfunction, orgasmic dysfunction). During the 4 weeks of treatment,
      approximately 58% of subjects treated with buspirone reported an improvement with
      respect to sexual function; in the placebo group, the response rate was 30%. The
      difference between placebo and active drug treatment was more pronounced in women
      than in men. The response was obvious during the first week, with no further
      improvement during the course of the study. It is suggested that the effect of
      buspirone on sexual dysfunction is a result of a reversal of SSRI-induced sexual
      side effects rather than of an antidepressant effect of the drug.

PMID- 10350035
TI  - Interaction between olanzapine and haloperidol.

PMID- 10350036
TI  - Olanzapine: weight gain and therapeutic efficacy.

PMID- 10350037
TI  - Schizophrenia and schizoaffective disorder treated with high doses of olanzapine.

PMID- 10350038
TI  - Risperidone-induced tardive dyskinesia in first-episode psychotic patients.

PMID- 10350039
TI  - Effectiveness of anticholinergics and neuroleptic dose reduction on neuroleptic
      induced pleurothotonus (the Pisa syndrome)

PMID- 10350040
TI  - Trazodone in the treatment of delirium.

PMID- 10350041
TI  - Prolonged sedation and slowly decreasing clozapine serum concentrations after an
      overdose.

PMID- 10350042
TI  - Venlafaxine in the treatment of resistant postpsychotic depressive symptoms of
      schizophrenia.

PMID- 10350043
TI  - Serotonin syndrome as a result of clomipramine monotherapy.

PMID- 10350044
TI  - Oxybutynin enhances the metabolism of clomipramine and dextrorphan possibly by
      induction of a cytochrome P450 isoenzyme.

PMID- 10350045
TI  - Suspected ciprofloxacin inhibition of olanzapine resulting in increased plasma
      concentration.

PMID- 10350046
TI  - MEK is a negative regulator of Stat5b in PDGF-stimulated cells.
AB  - In this study we show that platelet-derived growth factor (PDGF)-induced DNA
      binding as well as transcriptional activation of Stat5b are markedly increased by
      inhibition of the MAP (mitogen-activated protein) kinase kinase MEK. In addition
      to the previously demonstrated tyrosine phosphorylation, we show that serine and
      threonine phosphorylation of Stat5b is increased in response to PDGF stimulation.
      However, inhibition of MEK had no effect on the phosphorylation level of Stat5b
      or on the nuclear translocation of Stat5b. These observations indicate that MEK
      is a negative modulator of PDGF-induced Stat5b activation through a mechanism not
      involving direct phosphorylation of Stat5b.

PMID- 10350047
TI  - Regulation of UCP3 by nucleotides is different from regulation of UCP1.
AB  - UCP3 is an isoform of UCP1, expressed primarily in skeletal muscle. Functional
      properties of UCP3 are still largely unknown. Here, we report about the
      expression of UCP3 and of UCP1 in inclusion bodies of Escherichia coli. On
      solubilization and reconstitution into proteoliposomes, both UCP3 and UCP1
      transport Cl- at rates equal to the reconstituted native UCP1. Cl- transport is
      inhibited by low concentrations of ATP, ADP, GTP and GDP. However, no H+
      transport activity is found possibly due to the lack of a cofactor presents in
      UCP from mitochondria. The specificity of inhibition by nucleoside tri- and
      diphosphate is different between UCP1 and UCP3. UCP1 is more sensitive to tri-
      than diphosphate whereas in UCP3, the gradient is reverse. These results show a
      new paradigm for the regulation of thermogenesis at various tissues by the
      ATP/ADP ratio. In brown adipose tissue, the thermogenesis is correlated with a
      low ATP/ADP whereas in skeletal muscle, non-shivering thermogenesis is active at
      a high ATP/ADP ratio, i.e. in the resting state.

PMID- 10350048
TI  - Phosphorylation of rat brain calpastatins by protein kinase C.
AB  - Calpastatin, the natural inhibitor of calpain, is present in rat brain in
      multiple forms, having different molecular masses, due to the presence of one
      (low Mr form) or four (high Mr form) repetitive inhibitory domains. Recombinant
      and native calpastatin forms are substrates of protein kinase C, which
      phosphorylates a single serine residue at their N-terminus. Furthermore, both low
      and high Mr calpastatins are phosphorylated by protein kinase C at the same site.
      These calpastatin forms are phosphorylated also by protein kinase A, although
      with a lower efficiency. The incorporation of a phosphate group determines an
      increase in the concentration of Ca2+ required to induce the formation of the
      calpain-calpastatin complex. This effect results in a large decrease of the
      inhibitory efficiency of calpastatins. We suggest that phosphorylation of
      calpastatin represents a mechanism capable to balance the actual amount of active
      calpastatin to the level of calpain to be activated.

PMID- 10350049
TI  - Regulation of Ca-sensitive inactivation of a 1-type Ca2+ channel by specific
      domains of beta subunits.
AB  - Ca2+ channel auxiliary beta subunits have been shown to modulate voltage
      dependent inactivation of various types of Ca2+ channels. The beta1 and beta2
      subunits, that are differentially expressed with the L-type alpha1 Ca2+ channel
      subunit in heart, muscle and brain, can specifically modulate the Ca2+-dependent
      inactivation kinetics. Their expression in Xenopus oocytes with the alpha1C
      subunit leads, in both cases, to biphasic Ca2+ current decays, the second phase
      being markedly slowed by expression of the beta2 subunit. Using a series of beta
      subunit deletion mutants and chimeric constructs of beta1 and beta2 subunits, we
      show that the inhibitory site located on the amino-terminal region of the beta2a
      subunit is the major element of this regulation. These results thus suggest that
      different splice variants of the beta2 subunit can modulate, in a specific way,
      the Ca2+ entry through L-type Ca2+ channels in different brain or heart regions.

PMID- 10350050
TI  - Dual specificity antibodies using a double-stranded oligonucleotide bridge.
AB  - The covalent conjugation of oligonucleotides to antibody Fab' fragments was
      optimized by using oligonucleotides modified with a hexaethylene linker arm
      bearing three amino groups. One oligonucleotide was coupled to antibody of one
      specificity and a complementary oligonucleotide to antibody of a second
      specificity. The antibodies were then allowed to hybridize by base pairing of the
      complementary nucleotide sequences and the generation of bispecific antibody was
      analyzed on SDS-PAGE and confirmed using BIAcore analysis. The strategy of
      complementary oligonucleotide-linked bispecific molecules is not limited to
      antibodies but is applicable to linking any two molecules of different
      characteristics.

PMID- 10350051
TI  - Rpn4p acts as a transcription factor by binding to PACE, a nonamer box found
      upstream of 26S proteasomal and other genes in yeast.
AB  - We identified a new, unique upstream activating sequence (5'-GGTGGCAAA-3') in the
      promoters of 26 out of the 32 proteasomal yeast genes characterized to date,
      which we propose to call proteasome-associated control element. By using the one
      hybrid method, we show that the factor binding to the proteasome-associated
      control element is Rpn4p, a protein containing a C2H2-type finger motif and two
      acidic domains. Electrophoretic mobility shift assays using proteasome-associated
      control element sequences from two regulatory proteasomal genes confirmed
      specific binding of purified Rpn4p to these sequences. The role of Rpn4p to
      function as a transregulator in yeast is corroborated by its ability of
      stimulating proteasome-associated control element-driven lacZ expression and by
      experiments using the RPT4 and RPT6 gene promoters coupled to the bacterial cat
      gene as a reporter. Additionally, we found the proteasome-associated control
      element to occur in a number of promoters to genes which are related to the
      ubiquitin-proteasome pathway in yeast.

PMID- 10350052
TI  - Effect of mutations in the beta1-thyroid hormone receptor on the inhibition of T3
      binding by desethylamiodarone.
AB  - Desethylamiodarone (DEA) acts as a competitive inhibitor of triiodothyronine (T3)
      binding to the alpha1-thyroid hormone receptor (TR alpha1) but as a non
      competitive inhibitor with respect to TR beta1. To gain insight into the position
      of the binding site of desethylamiodarone on TR beta1 we investigated the
      naturally occurring mutants Y321C, R429Q, P453A, P453T and the artificial mutants
      L421R and E457A in the ligand binding domain of human TR beta1. The IC50 values
      (in microM) of DEA for P453A (50 +/- 11) and P453T (55 +/- 16) mutant TR beta1
      are not different from that for the wild type TR beta1 (56 +/- 15), but the IC50
      values of R429Q (32 +/- 7; P<0.001) and E457A (17 +/- 3; P<0.001) are
      significantly lower than of the wild type. Scatchard plots and Langmuir analyses
      indicate a non-competitive nature of the inhibition by DEA of T3 binding to all
      four mutant TR beta1s tested. Mutants P453A and P453T do not influence overall
      electrostatic potential, and also do not influence the affinity for DEA compared
      to wild type. Mutant E457A causes a change from a negatively charged amino acid
      to a hydrophobic amino acid, enhancing the affinity for DEA. Mutant R429Q,
      located in helix 11, causes an electrostatic potential change from positive to
      uncharged, also resulting in greater affinity for DEA. We therefore postulate
      that amino acids R429 and E457 are at or close to the binding site for DEA, and
      that DEA does not bind in the T3 binding pocket itself, in line with the non
      competitive nature of the inhibition of T3 binding to TR beta1 by DEA.

PMID- 10350053
TI  - Evidence that cytosolic phospholipase A2 is down-regulated by protein kinase C in
      intact human platelets stimulated with fluoroaluminate.
AB  - We reported that protein kinase C (PKC) inhibitors increase the release of
      arachidonic acid induced by fluoroaluminate (AlF4-), an unspecific G-protein
      activator, in intact human platelets. Now we demonstrate that this effect is
      independent of the extracellular Ca2+ concentration and that AlF4(-)-induced
      release of AA is abolished by BAPTA, an intracellular Ca2+ chelator, even in the
      presence of GF 109203X, a specific and potent PKC inhibitor. This compound also
      blocks the liberation of the secretory phospholipase A2 in the extracellular
      medium, indicating that this enzyme is not involved in the potentiation of
      arachidonic acid by PKC inhibitors. On the other hand, the latter effect is
      completely abolished by treatment of platelets with AACOCF3, a specific inhibitor
      of cytosolic phospholipase A2 (cPLA2). These observations indicate that cPLA2 is
      responsible for the AlF4(-)-induced release of arachidonic acid by a mechanism
      that is down-regulated by PKC.

PMID- 10350054
TI  - Quantitative structure activity relationships for the electron transfer reactions
      of Anabaena PCC 7119 ferredoxin-NADP+ oxidoreductase with nitrobenzene and
      nitrobenzimidazolone derivatives: mechanistic implications.
AB  - The steady state single electron reduction of polynitroaromatics by ferredoxin
      NADP+ oxidoreductase (EC 1.18.1.2) from cyanobacterium Anabaena PCC 7119 has been
      studied and quantitative structure activity relationships are described. The
      solubility of the polynitroaromatics as well as their reactivity towards
      ferredoxin-NADP+ oxidoreductase are markedly higher than those for previously
      studied mononitroaromatics and this enabled the independent measurement of the
      kinetic parameters-k(cat) and Km. Interestingly, the natural logarithm of the
      bimolecular rate constant, k(cat)/Km, and also the natural logarithm of k(cat)
      correlate with the calculated energy of the lowest unoccupied molecular orbital
      of the polynitroaromatic substrates. The minimal kinetic model in line with these
      quantitative structure activity relationships is a ping-pong mechanism which
      includes substrate binding equilibria in the second half reaction.

PMID- 10350055
TI  - Water-soluble 2,3,7,8-tetrachlorodibenzo-p-dioxin complex with human alpha
      fetoprotein: properties, toxicity in vivo and antitumor activity in vitro.
AB  - The conditions for the formation of a non-covalent complex between 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD) and the human transport fetal protein, alpha
      fetoprotein (AFP), have been studied. TCDD has been shown to form a stable
      complex with AFP in a 2:1 (TCDD:AFP) ratio. The apparent solubility of TCDD in
      water increases 10(5)-fold after complex formation. The toxicity of the TCDD:AFP
      complex injected into mice by the intravenous route is comparable with that of
      free TCDD administered in oil solution per os. The complex manifests very much
      higher toxicity (200-1400 times) against human tumor cells (CEM, MCF-7, HepG2) in
      vitro and surpasses TCDD in selectivity. AFP may facilitate TCDD transport in
      embryonic tissues and enhance its embryotoxic and teratogenic effects.

PMID- 10350056
TI  - The acceptor substrate specificity of human beta4-galactosyltransferase V
      indicates its potential function in O-glycosylation.
AB  - In order to assess the function of the different human UDP-Gal:GlcNAc beta4
      galactosyltransferases, the cDNAs of two of them, beta4-GalT I and beta4-GalT V,
      were expressed in the baculovirus/insect cell expression system. The soluble
      recombinant enzymes produced were purified from the medium and used to determine
      their in vitro substrate specificities. The specific activity of the recombinant
      beta4-GalT V was more than 15 times lower than that of beta4-GalT I, using GlcNAc
      beta-S-pNP as an acceptor. Whereas beta4-GalT I efficiently acts on all
      substrates having a terminal beta-linked GlcNAc, beta4-GalT V appeared to be far
      more restricted in acceptor usage. Beta4-GalT V acts with high preference on
      acceptors that contain the GlcNAc beta1-->6GalNAc structural element, as found in
      O-linked core 2-, 4- and 6-based glycans, but not on substrates related to V
      linked or blood group I-active oligosaccharides. These results suggest that beta4
      GalT V may function in the synthesis of lacNAc units on O-linked chains,
      particularly in tissues which do not express beta4-GalT I, such as brain.

PMID- 10350057
TI  - Synechococcus mutants resistant to an enamine mechanism inhibitor of glutamate-1
      semialdehyde aminotransferase.
AB  - An enamine mechanism-based inactivator of mammalian delta-aminobutyric acid
      aminotransferase, 4-amino 5-fluoropentanoic acid is a potent inhibitor of cell
      growth and pigment formation in the cyanobacterium Synechococcus PCC 6301. It was
      demonstrated that 4-amino 5-fluoropentanoic acid inhibits the aminolaevulinate
      synthesis at glutamate 1-semialdehyde aminotransferase and that in the mutant
      obtained by exposing cells to 40 microM 4-amino 5-fluoropentanoic acid, this
      enzyme was insensitive to the inhibitor. The specific activity of glutamate 1
      semialdehyde aminotransferase in cell extracts was lower in the mutant, although
      the cell growth rate was unaffected. The decrease in sensitivity to 4-amino 5
      fluoropentanoic acid in the mutant is due to a structural gene mutation, a single
      base change in the hemL gene resulting in a S162T substitution in the gene
      product.

PMID- 10350058
TI  - Subcellular localization and partial purification of prelamin A endoprotease: an
      enzyme which catalyzes the conversion of farnesylated prelamin A to mature lamin
      A.
AB  - The nuclear lamina protein, lamin A is produced by proteolytic cleavage of a 74
      kDa precursor protein, prelamin A. The conversion of this precursor to mature
      lamin A is mediated by a specific endoprotease, prelamin A endoprotease.
      Subnuclear fractionation indicates that the prelamin A endoprotease is localized
      at the nuclear membrane. The enzyme appears to be an integral membrane protein,
      as it can only be removed from the nuclear envelope with detergent. It is
      effectively solubilized by the detergent n-octyl-beta-D-glucopyranoside and can
      be partially-purified (approximately 1200-fold) by size exclusion and cation
      exchange (Mono S) chromatography. Prelamin A endoprotease from HeLa cells was
      eluted from Mono S with 0.3 M sodium chloride as a single peak of activity. SDS
      PAGE analysis of this prelamin A endoprotease preparation shows that it contains
      one major polypeptide at 65 kDa and smaller amounts of a second 68 kDa
      polypeptide. Inhibition of the enzyme activity in this preparation by specific
      serine protease inhibitors is consistent with the enzyme being a serine protease.

PMID- 10350059
TI  - Hepatitis B virus genotype assignment using restriction fragment length
      polymorphism patterns.
AB  - Hepatitis B virus (HBV) is classified into genotypes A-F, which is important for
      clinical and etiological investigations. To establish a simple genotyping method,
      68 full-genomic sequences and 106 S gene sequences were analyzed by the molecular
      evolutionary method. HBV genotyping with the S gene sequence is consistent with
      genetic analysis using the full-genomic sequence. After alignment of the S
      sequences, genotype specific regions are identified and digested by the
      restriction enzymes, HphI, NciI, AlwI, EarI, and NlaIV. This HBV genotyping
      system using restriction fragment length polymorphism (RFLP) was confirmed to be
      correct when the PCR products of the S gene in 23 isolates collected from various
      countries were digested with this method. A restriction site for EarI in genotype
      B was absent in spite of its presence in all the other genotypes and genotype C
      has no restriction site for AlwI. Only genotype E is digested with NciI, while
      only genotype F has a restriction site for HphI. Genotype A can be distinguished
      by a single restriction enzyme site for NlaIV, while genotype D digestion with
      this enzyme results in two products that migrates at 265 and 186 bp. This simple
      and accurate HBV genotyping system using RFLP is considered to be useful for
      research on HBV.

PMID- 10350060
TI  - A low rate of nucleotide changes in Escherichia coli K-12 estimated from a
      comparison of the genome sequences between two different substrains.
AB  - Two genome sequences of Escherichia coli K-12 substrains, one partial W3110 and
      one complete MG1655, have been determined by Japanese and American genome
      projects, respectively. In order to estimate the rate of nucleotide changes, we
      directly compared 2 Mb of the nucleotide sequences from these closely-related E.
      coli substrains. Given that the two substrains separated about 40 years ago, the
      rate of nucleotide changes was estimated to be less than 10(-7) per site per
      year. This rate was supported by a further comparison between partial genome
      sequences of E. coli and Shigella flexneri.

PMID- 10350061
TI  - Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP
      and phospholipase C-gamma1 with PECAM-1/CD31.
AB  - Recent studies have shown that, in addition to its role as an adhesion receptor,
      platelet endothelial cell adhesion molecule 1/CD31 becomes phosphorylated on
      tyrosine residues Y663 and Y686 and associates with protein tyrosine phosphatases
      SHP-1 and SHP-2. In this study, we screened for additional proteins which
      associate with phosphorylated platelet endothelial cell adhesion molecule 1,
      using surface plasmon resonance. We found that, besides SHP-1 and SHP-2, platelet
      endothelial cell adhesion molecule 1 binds the cytoplasmic signalling proteins
      SHIP and PLC-gamma1 via their Src homology 2 domains. Using two phosphopeptides,
      NSDVQpY663TEVQV and DTETVpY686SEVRK, we demonstrate differential binding of SHP
      1, SHP-2, SHIP and PLC-gamma1. All four cytoplasmic signalling proteins directly
      associate with cellular platelet endothelial cell adhesion molecule 1,
      immunoprecipitated from pervanadate-stimulated THP-1 cells. These results suggest
      that overlapping immunoreceptor tyrosine-based inhibition motif/immunoreceptor
      tyrosine-based activation motif-like motifs within platelet endothelial cell
      adhesion molecule 1 mediate differential interactions between the Src homology 2
      containing signalling proteins SHP-1, SHP-2, SHIP and PLC-gamma1.

PMID- 10350062
TI  - Involvement of cis-acting repressive element(s) in the 3'-untranslated region of
      human connective tissue growth factor gene.
AB  - To analyze the regulatory mechanism of connective tissue growth factor
      expression, the 3'-untranslated region (3'-UTR) of CTGF cDNA was amplified from
      HeLa cell RNA. Direct nucleotide sequencing revealed a single major population in
      the amplicon, which was nearly identical to other sequences. Subsequently, the
      effect of the 3'-UTR on gene expression was evaluated. When it was fused
      downstream of a firefly luciferase gene, the 3'-UTR strongly repressed luciferase
      gene expression. Interestingly, the repressive effect of the antisense 3'-UTR
      appeared to be more prominent than that of the sense one. Together with the fact
      that several consensus sequences for regulatory elements are found in it, these
      results suggest the involvement of multiple sets of regulatory elements in the
      CTGF 3'-UTR.

PMID- 10350063
TI  - Spontaneous rearrangements in RNA sequences.
AB  - The ability of RNAs to spontaneously rearrange their sequences under
      physiological conditions is demonstrated using the molecular colony technique,
      which allows single RNA molecules to be detected provided that they are
      amplifiable by the replicase of bacteriophage Qbeta. The rearrangements are Mg2+
      dependent, sequence-non-specific, and occur both in trans and in cis at a rate of
      10(-9) h(-1) per site. The results suggest that the mechanism of spontaneous RNA
      rearrangements differs from the transesterification reactions earlier observed in
      the presence of Qbeta replicase, and have a number of biologically important
      implications.

PMID- 10350064
TI  - Identification of the catalytic subunit of cAMP-dependent protein kinase from the
      photosynthetic flagellate, Euglena gracilis Z.
AB  - A gene named epk2 that encodes the amino acid sequence of a protein kinase was
      identified from the photosynthetic flagellate, Euglena gracilis Z. Homology
      search and phylogenetic analysis revealed that the deduced amino acid sequence of
      epk2 is most similar to that of the catalytic subunit of cAMP-dependent protein
      kinase (PKA). Northern blot analysis showed that Euglena cells express a 1.4-kb
      transcript of this gene. When the EPK2 protein was coexpressed with the rat
      regulatory subunit of PKA in cultured mammalian cells, these two proteins were
      coimmunoprecipitated. The association of EPK2 and the rat regulatory subunit of
      PKA was not detected in the cell lysate incubated with cAMP. EPK2
      immunoprecipitated from the transfected cells phosphorylated Kemptide, a
      synthetic peptide substrate for PKA, and the phosphorylation was inhibited by
      PKI, a PKA-selective protein kinase inhibitor. These results indicate that EPK2
      is a PKA homologue in the photosynthetic flagellate, and this is the first
      evidence for the occurrence of the PKA catalytic subunit in photosynthetic
      organisms.

PMID- 10350065
TI  - VacA from Helicobacter pylori: a hexameric chloride channel.
AB  - VacA is a unique protein toxin secreted by the human pathogen Helicobacter
      pylori. At a neutral pH, the cytotoxin self-associates into predominantly
      dodecameric complexes. In this report, we show that at an acidic pH, VacA forms
      anion selective channels in planar phospholipid bilayers. Similar to several
      other chloride channels, the VacA channel exhibits a moderate selectivity for
      anions over cations (P(Cl):P(Na) = 4.2:1), inhibition by the blocker 4,4'
      diisothiocyanatostilbene-2,2'-disulfonic acid and a permeability sequence, SCN-
      >> I- > Br- > Cl- > F, consistent with a 'weak field strength' binding site for
      the permeant anion. Single channel recordings reveal rapid transitions (486 s(
      1)) between the closed state and a single open state of 24 pS (+60 mV, 1.5 M
      NaCl). Evaluation of the rate of increase in macroscopic current as well as
      atomic force microscopy suggest that this VacA channel is a hexamer, formed by
      the assembly of membrane-bound monomers. Not only are these VacA channels likely
      to play an important role in the pathological activity of this toxin, but they
      may also serve as a model system to further investigate the mechanism of anion
      selectivity in general.

PMID- 10350067
TI  - H (0) blood group determinant is present on soluble human L-selectin expressed in
      BHK-cells.
AB  - In the present study we show that the H (0) blood group determinant Fuc alpha1
      2Gal beta1-4GlcNAc beta1-R is present on N-linked glycans of soluble human L
      selectin recombinantly expressed in baby hamster kidney (BHK) cells. The glycans
      were isolated using complementary HPLC techniques and characterized by a
      combination of exoglycosidase digestion and mass spectrometry. The linkage of the
      fucose residues was determined by incubation of the glycans with specific
      fucosidases. The H blood determinant Fuc alpha1-2Gal beta1-4GlcNAc beta1 was
      detected for bi-, 2,4 branched tri- and tetraantennary structures. To our
      knowledge, the proposed oligosaccharide structures represent a new glycosylation
      motif for recombinant glycoproteins expressed on BHK cells.

PMID- 10350066
TI  - Comparison of Escherichia coli and rabbit reticulocyte ribosome display systems.
AB  - Ribosome display is a technology for library selection and simultaneous molecular
      evolution in vitro. We present here a comparison between an optimized Escherichia
      coli system and different rabbit reticulocyte ribosome display systems, optimized
      in a number of parameters, as a coupled eukaryotic system had been suggested to
      result in high enrichment factors [He and Taussig (1997) Nucleic Acids Res. 25,
      5132-5134]. With all systems, antibody scFv fragments, complexed to the ribosomes
      and the corresponding mRNA, were enriched by binding to their cognate antigen and
      enrichment was always dependent on the absence of a stop codon and the presence
      of cognate antigen. However, the efficiency of the E. coli ribosome display
      system was 100-fold higher than an optimized uncoupled rabbit reticulocyte
      ribosome display system, with separate in vitro transcription and translation,
      which was in turn several-fold more efficient than the reported coupled system.
      Neither the E. coli nor the rabbit reticulocyte ribosome display system was
      dependent on the orientation of the domains of an antibody scFv fragment or on
      the spacer sequence. In summary, we could not detect any intrinsic advantage of
      using a eukaryotic translation system for ribosome display.

PMID- 10350069
TI  - Discrimination between ubiquitin-dependent and ubiquitin-independent proteolytic
      pathways by the 26S proteasome subunit 5a.
AB  - The 26S proteasome subunit 5a binds polyubiquitin chains and has previously been
      shown to inhibit the degradation of mitotic cyclins. Presumably inhibition
      results from S5a binding and preventing recognition of Ub-cyclin conjugates by
      the 26S proteasome. Here we show that S5a does not inhibit the degradation of
      full-length ornithine decarboxylase (ODC) consistent with previous reports that
      the enzyme is degraded in an antizyme-dependent, but ubiquitin-independent
      reaction. S5a does, however, inhibit degradation of short ODC translation
      products generated by internal initiation events. Because in vitro translation
      often produces some shortened products, the existence of ubiquitin conjugated to
      a 35S-labeled protein is not necessarily evidence that the full-length protein is
      a substrate of the Ub-dependent proteolytic pathway.

PMID- 10350068
TI  - A fusion protein of interleukin-11 and soluble interleukin-11 receptor acts as a
      superagonist on cells expressing gp130.
AB  - Interleukin-11 is a hematopoietic cytokine that signals via the signal transducer
      gp130. Although gp130 is ubiquitously expressed, interleukine-11 responsiveness
      is restricted to cells that express the interleukine-11 receptor alpha-subunit.
      The interleukine-11 receptor alpha-subunit can be functionally replaced by its
      soluble form indicating that the transmembrane and cytoplasmic parts are not
      required for signal transduction. Here, we show that a recombinant fusion protein
      of a fragment of the human interleukine-11 receptor alpha-subunit ectodomain
      linked to human interleukine-11 acts as a superagonist on cells expressing gp130
      but lacking the membrane-bound interleukine-11 receptor alpha-subunit. It induces
      acute phase protein synthesis in hepatoma cells and efficiently promotes
      proliferation of Ba/F3 cells stably, transfected with gp130. In these bioassays,
      the fusion protein of a fragment of the human interleukine-11 receptor alpha
      subunit ectodomain linked to human interleukine-11 is 50 times more potent than
      the combination of interleukine-11 and the soluble interleukine-11 receptor alpha
      subunit. Thus, our findings support the concept that covalent fusion of two
      soluble proteins required for receptor activation dramatically increases their
      bioactivity.

PMID- 10350070
TI  - A novel 45 kDa secretory protein from rat olfactory epithelium: primary structure
      and localisation.
AB  - cDNA clones encoding the 45 kDa protein were isolated from a rat olfactory
      epithelium cDNA library and their inserts were sequenced. The reconstructed
      protein sequence comprises 400 amino acids with a calculated molecular mass of
      46,026 Da. A homology was revealed between the amino acid sequence of the 45 kDa
      protein and the proteins involved in the transfer of hydrophobic ligands. Using
      in situ hybridisation, the 45 kDa protein mRNA expression was detected in the
      layer of supportive cells of olfactory epithelium, apical region of trachea,
      surface layer of the ciliated bronchial epithelium in lung and in skin epidermis.

PMID- 10350071
TI  - Interaction of the p70 subunit of RPA with a DNA template directs p32 to the 3'
      end of nascent DNA.
AB  - Human replication protein A is a heterotrimeric protein involved in various
      processes of DNA metabolism. To understand the contribution of replication
      protein A individual subunits to DNA binding, we have expressed them separately
      as soluble maltose binding protein fusion proteins. Using a DNA construct that
      had a photoreactive group incorporated at the 3'-end of the primer strand, we
      show that the p70 subunit on its own is efficiently cross-linked to the primer at
      physiological concentrations. In contrast, crosslinking of the p32 subunit
      required two orders of magnitude higher protein concentrations. In no case was
      the p14 subunit labelled above background. p70 seems to be the predominant
      subunit to bind single-stranded DNA and this interaction positions the p32
      subunit to the 3'-end of the primer.

PMID- 10350072
TI  - Inorganic Fe2+ formation upon Fe-S protein thermodestruction in the membranes of
      thermophilic cyanobacteria: Mossbauer spectroscopy study.
AB  - A model description of the Mossbauer spectrum (80 K) of native membranes of the
      thermophilic cyanobacterium Synechococcus elongatus is suggested on the basis of
      the known values of quadrupole splitting (deltaE(Q)) and isomer shift (deltaFe)
      for the iron-containing components of the photosynthetic apparatus. Using this
      approach, we found that heating the membranes at 70-80 K results in a decrease of
      doublet amplitudes belonging to F(X), F(A), F(B) and ferredoxin and simultaneous
      formation of a new doublet with deltaE(Q) = 3.10 mm/s and delta-Fe = 1.28 mm/s,
      typical of inorganic hydrated forms of Fe2+. The inhibition of electron transfer
      via photosystem I to oxygen, catalyzed by ferredoxin, occurs within the same
      range of temperatures. The data demonstrate that the processes of thermoinduced
      Fe2+ formation and distortions in the photosystem I electron transport in the
      membranes are interrelated and caused mainly by the degradation of ferredoxin.
      The possible role of Fe2+ formation in the damage of the photosynthetic apparatus
      resulting from heating and the action of other extreme factors is discussed.

PMID- 10350073
TI  - Mutation of Lys-75 affects calmodulin conformation.
AB  - Some properties of synthetic calmodulin and its five mutants with replacement of
      Lys-75 were analyzed by means of electrophoresis, limited proteolysis and MALDI
      mass-spectrometry. A double mutant of calmodulin containing insert KGK between
      residues 80 and 81 and replacement of Lys-75 by Pro has a highly flexible central
      helix which is susceptible to trypsinolysis in the presence of Ca2+. Two mutants,
      K75P and K75E, having a distorted central helix demonstrate high resistance to
      trypsinolysis in the absence of Ca2+. Arg-90 and Arg-106 being the primary site
      of trypsinolysis of synthetic calmodulin are partially-protected in K75P and K75E
      mutants. The central helix of K75A and K75V mutants is stabilized by hydrophobic
      interactions between residues located in positions 71, 72 and 75. In the presence
      of Ca2+, the central helix of K75V is resistant to trypsinolysis. Mutations K75A
      and K75V decrease the rate of trypsinolysis of the central helix with a
      simultaneous increase of the rate of trypsinolysis in the C-terminal domain of
      calmodulin. It is concluded that the point mutation in the central helix has a
      long distance effect on the structure of calmodulin.

PMID- 10350074
TI  - Modelling charge interactions in the prion protein: predictions for pathogenesis.
AB  - Calculations are presented for the pH-dependence of stability and membrane charge
      complementarity of prion protein fragments. The theoretical results are compared
      with reported characterisations of prion protein folding in vitro. Discussion of
      models for conformational change and pathogenesis in vivo leads to the prediction
      of amino acids that could mediate sensitivity to the endosomal pH and to a design
      strategy for recombinant prion proteins with an increased susceptibility to prion
      proteinSc-like properties in vitro. In this model, the protective effect of
      certain basic polymorphisms can be interpreted in terms of oligomerisation on a
      negatively-charged surface.

PMID- 10350075
TI  - Antigen recognition by conformational selection.
AB  - Conformational adaptation between antigen and antibody can modulate the antibody
      specificity. The phenomenon has often been proposed to result from an 'induced
      fit', which implies that the binding reaction induces a conformational change in
      the antigen and the antibody. Thus, an 'induced fit' requires initial complex
      formation followed by a conformational change in the complex. However, an
      antibody may select those antigen molecules that happen to be in a fitting
      conformational state. This leads to the same end result as an induced fit. Here,
      we demonstrate conformational selection by a single chain antibody fragment,
      raised against a random coil variant of the leucine zipper domain of
      transcription factor GCN4, when it cross-reacts with the wild-type dimeric
      leucine zipper. Kinetic and equilibrium data show that the single chain antibody
      fragment fragment selects monomeric peptides from the population in equilibrium
      with the leucine zipper dimer.

PMID- 10350076
TI  - Bleaching of bacteriorhodopsin by continuous light.
AB  - A new two step photobleaching process is observed under continuous illumination
      of bacteriorhodopsin. This photobleaching is considerable even at physiological
      temperatures and becomes large at 50-60 degrees C. The photobleaching also
      increases with increasing pH from 7 to 10. We suggest that the bleaching at its
      final stage could be due to the dissociation of the retinal and a local thermal
      denaturation-like process. These facts may question the generally held belief
      that BR is a stable protein in vivo for a long period of time. Our results may
      have relevance also to practical applications of bacteriorhodopsin where the
      stability of bacteriorhodopsin is a key issue. In certain instances, the use of
      bacteriorhodopsin may require cooled conditions. Here, we defined the conditions
      under which bacteriorhodopsin is stable. The permanent photobleaching offers a
      new way of picture imaging and information input for bacteriorhodopsin-based
      optical devices.

PMID- 10350077
TI  - Glycodelin and beta-lactoglobulin, lipocalins with a high structural similarity,
      differ in ligand binding properties.
AB  - Human glycodelin, a lipocalin with a high amino acid similarity to beta
      lactoglobulins, appears as various glycoforms with different biological
      activities in endometrium (glycodelin-A) and seminal plasma (glycodelin-S). We
      found that the structures of these glycodelins and beta-lactoglobulin are
      similar. Despite this structural similarity, unlike beta-lactoglobulin,
      glycodelin-A binds neither retinoic acid nor retinol. It was impossible to detect
      any endogenous retinoids or steroids in any of the two purified glycodelins. Both
      their glycoforms share similar thermodynamic parameters of reversible
      denaturation suggesting that native folding of glycodelin-A and glycodelin-S is
      not influenced by the differences in glycosylation or by ligand binding.

PMID- 10350078
TI  - Reaction centers of photosystem II with a chemically-modified pigment
      composition: exchange of pheophytins with 13(1)-deoxo-13(1)-hydroxy-pheophytin a.
AB  - Isolated reaction centers of photosystem II with an altered pigment content were
      obtained by chemical exchange of the native pheophytin a molecules with
      externally added 13(1)-deoxo-13(1)-hydroxy-pheophytin a. Judged from a comparison
      of the absorption spectra and photochemical activities of exchanged and control
      reaction centers, 70-80% of the pheophytin molecules active in charge separation
      are replaced by 13(1)-deoxo-13(1)-hydroxy-pheophytin a after double application
      of the exchange procedure. The new molecule at the active branch was not active
      photochemically. This appears to be the first stable preparation in which a redox
      active chromophore of the reaction center of photosystem II was modified by
      chemical substitution. The data are compatible with the presence of an active and
      inactive branch of cofactors, as in bacterial reaction centers. Possible
      applications of the 13(1)-deoxo-13(1)-hydroxy-pheophytin a-exchanged preparation
      to the spectral and functional analysis of native reaction centers of photosystem
      II are discussed.

PMID- 10350079
TI  - News in chloroplast protein import.

PMID- 10350080
TI  - GRAB proteins, novel members of the NAC domain family, isolated by their
      interaction with a geminivirus protein.
AB  - Geminiviruses encode a few proteins and depend on cellular factors to complete
      their replicative cycle. As a way to understand geminivirus-host interactions, we
      have searched for cellular proteins which interact with viral proteins. By using
      the yeast two-hybrid technology and the wheat dwarf geminivirus (WDV) RepA
      protein as a bait, we have isolated a family of proteins which we termed GRAB
      (for Geminivirus Rep A-binding). We report here the molecular characterization of
      two members, GRAB1 and GRAB2. We have found that the 37 C-terminal amino acids of
      RepA are required for interaction with GRAB proteins. This region contains
      residues conserved in an equivalent region of the RepA proteins encoded by other
      viruses of the WDV subgroup. The N-terminal domain of GRAB proteins is necessary
      and sufficient to interact with WDV RepA. GRAB proteins contain an unique acidic
      C-terminal domain while their N-terminal domain, of ca. 170 amino acids, are
      highly conserved in all of them. Interestingly, this conserved N-terminal domain
      of GRAB proteins exhibits a significant amino acid homology to the NAC domain
      present in proteins involved in plant development and senescence. GRAB1 and GRAB2
      mRNAs are present in cultured cells and roots but are barely detectable in
      leaves. GRAB expression inhibits WDV DNA replication in cultured wheat cells. Our
      studies highlight the importance that the pathway(s) mediated by GRAB proteins,
      as well as by other NAC domain-containing proteins, might have on geminivirus DNA
      replication in connection to plant growth, development and senescence pathways.

PMID- 10350081
TI  - Developmentally regulated patterns of expression directed by poplar PAL promoters
      in transgenic tobacco and poplar.
AB  - Phenylalanine ammonia-lyase (PAL) catalyzes the first step in phenylpropanoid
      metabolism and plays a central role in the biosynthesis of phenylpropanoid
      compounds. We have previously cloned two PAL genes, PALI and PAL2, from a Populus
      trichocarpa x P. deltoides F1 hybrid. Here, we describe the properties of PALI
      and PAL2 promoters and their expression patterns in transgenic tobacco and
      poplar. The promoters were 75% identical in the regions sequenced, and each
      contained two copies of AC-rich putative cis-acting elements that matched a
      consensus plant myb transcription factor binding site sequence. In transgenic
      tobacco, PALI-GUS and PAL2-GUS fusions directed similar patterns of expression in
      developing primary xylem of leaves, stems, and other organs, and in secondary
      xylem of stems. Contrary to previously documented patterns of PAL1/2 expression
      in poplar, no expression of either fusion was detected in epidermal or
      subepidermal cell layers of young tobacco leaves or stems. In poplar, the PAL2
      GUS fusion directed the highest levels of expression in roots and young leaves
      and stems. In young leaves and stems, high GUS activity was detected in epidermal
      or subepidermal cells as well as in primary xylem and phloem fibers. GUS activity
      was low in woody stems, and was weak or absent in developing secondary xylem. The
      patterns of PAL2-GUS expression in poplar are very similar to those of PAL1/2
      mRNA accumulation in poplar. However, the distinct patterns of expression
      directed by the PAL2 promoter in poplar and tobacco show that PAL2-GUS expression
      in tobacco does not accurately reflect all aspects of PAL2 expression in poplar.

PMID- 10350082
TI  - Characterization of the Arabidopsis lecRK-a genes: members of a superfamily
      encoding putative receptors with an extracellular domain homologous to legume
      lectins.
AB  - An Arabidopsis cDNA clone that defines a new class of plant serine/threonine
      receptor kinases was found to be a member of a family of four clustered genes
      (lecRK-a1-a4) which have been cloned, sequenced and mapped on chromosome 3. This
      family belongs to a large superfamily encoding putative receptors with an
      extracellular domain homologous to legume lectins and appears to be conserved at
      least among dicots. In the Columbia ecotype only the lecRK-a1 and perhaps the
      lecRK-a3 gene is functional, since lecRK-a2 is disrupted by a Ty-copia
      retroelement and lecRK-a4 contains a frameshift mutation. Structural analysis of
      the lecRK-al and lecRK-a3 deduced amino-acid sequences suggests that the lectin
      domain is unlikely to be involved in binding monosaccharides but could interact
      with complex glycans and/or with hydrophobic ligands. Immunodetection of lecRK
      gene products in plasma membranes purified by free-flow electrophoresis showed
      that the lecRK-a proteins are probably highly glycosylated integral plasma
      membrane components.

PMID- 10350083
TI  - Genetic engineering of shikonin biosynthesis hairy root cultures of Lithospermum
      erythrorhizon transformed with the bacterial ubiC gene.
AB  - The biosynthetic pathway to 4-hydroxybenzoate (4HB), a precursor of the
      naphthoquinone pigment shikonin, was modified in Lithospermum erythrorhizon hairy
      root cultures by introduction of the bacterial gene ubiC. This gene of
      Escherichia coli encodes chorismate pyruvate-lyase (CPL), an enzyme that converts
      chorismate into 4HB and is not normally present in plants. The ubiC gene was
      fused to the sequence for a chloroplast transit peptide and placed under control
      of a constitutive plant promoter. This construct was introduced into L.
      erythrorhizon by Agrobacterium rhizogenes-mediated transformation. The resulting
      hairy root cultures showed high CPL activity. 4HB produced by the CPL reaction
      was utilized for shikonin biosynthesis, as shown by in vivo inhibition of the
      native pathway to 4HB with 2-aminoindan-2-phosphonic acid (AIP), an inhibitor of
      phenylalanine ammonia-lyase. A feeding experiment with [1,7-13C2]shikimate showed
      that in the absence of AIP the artificially introduced CPL reaction contributed
      ca. 20% of the overall 4HB biosynthesis in the transgenic cultures. ubiC
      transformation did not lead to a statistically significant increase of shikonin
      formation, but to a 5-fold increase of the accumulation of menisdaurin, a nitrile
      glucoside which is presumably related to aromatic amino acid metabolism.

PMID- 10350084
TI  - The Arabidopsis thaliana dhdps gene encoding dihydrodipicolinate synthase, key
      enzyme of lysine biosynthesis, is expressed in a cell-specific manner.
AB  - Lysine synthesis in prokaryotes, some phycomycetes and higher plants starts with
      the condensation of L-aspartate-beta-semialdehyde (L-ASA) and pyruvate into
      dihydrodipicolinic acid. The enzyme that catalyses this step, dihydrodipicolinate
      synthase (DHDPS), is inhibited by the end-product lysine and is therefore thought
      to have a regulatory control on lysine synthesis. We have cloned and sequenced an
      Arabidopsis thaliana DNA fragment containing 900 bases upstream of the dhdps
      coding sequence. A transcriptional fusion of this fragment with the beta
      glucuronidase reporter gene (uidA. Gus) was used to study the transcription
      properties of this promoter fragment (DS). No lysine-induced repression on
      transcription could be detected. Expression of DS-Gus activity in transformed
      Arabidopsis thaliana and Nicotiana tabacum was found to be cell type-specific. In
      the vegetative parts of the plant, GUS activity was located in meristems and
      young vasculature of roots, in vasculature of stem and leaves and in the
      meristems of young shoots. In flowers, high expression was found in the carpels,
      style, stigma, developing embryos, tapetum of young anthers and pollen. We
      demonstrated that the Arabidopsis DS promoter can direct its cell type-specific
      expression in a heterologous plant, Nicotiana tuabacum. The importance of
      transcriptional regulation of the dhdps gene, and in more general genes involved
      in amino acid biosynthesis, is discussed.

PMID- 10350085
TI  - Cloning, characterization and expression of a bifunctional fructose-6-phosphate,
      2-kinase/fructose-2,6-bisphosphatase from potato.
AB  - We have isolated cDNA clones encoding the regulatory enzyme fructose-6
      phosphate,2-kinase/fructose-2,6-bisphosphatase from a potato (Solanum tuberosum)
      leaf cDNA library. All clones represented transcripts of the same gene (F2KP1).
      Functionality of the encoded protein was verified by expression of the active
      enzyme in Escherichia coli. The expressed enzyme had both kinase activity which
      forms fructose-2,6-bisphosphate from fructose-6-phosphate and ATP, and
      phosphatase activity which degrade fructose-2,6-bisphosphate. The recombinant
      potato enzyme was radiolabelled by [2-32P]fructose-2,6-bisphosphate verifying
      conservation of the phosphatase catalytic mechanism which involves a phospho
      protein intermediate. The deduced amino acid sequence corresponding to the
      catalytic core for F2KPI is homologous to the fructose-6-phosphate, 2
      kinase/fructose-2,6-bisphosphatase isolated from animals and yeast, with
      conservation of amino acids involved in substrate binding and catalytic
      mechanisms. The sequence for F2KP1 also includes a 102 amino acids long NH2
      terminal with no homology to any previously identified enzymes. This NH2 terminal
      may be even longer since an upstream stop codon has not yet been identified.
      Northern blot analysis of potato showed that the F2KP1 transcript is present in
      several tissues including source leaves, sink leaves and flowers, whereas the
      transcripts were not detectable in developing tubers. Southern blot analysis of
      Solanum phureja suggest there to be only one copy of the gene.

PMID- 10350086
TI  - An example of intron junctional sliding in the gene families encoding squalene
      monooxygenase homologues in Arabidopsis thaliana and Brassica napus.
AB  - Sequences of three Arabidopsis thaliana and two Brassica napus cDNAs encoding
      squalene monooxygenase homologues (Sqp1 and Sqp2) are reported. Southern analysis
      confirmed that these cDNAs are derived from small gene families in both species.
      Expression analysis indicates that Sqp1 genes in B. napus are strongly expressed
      in leaves but not roots or developing seeds. Comparison of cDNA and genomic
      sequences indicate that the 3' splice site of an intron in these genes has
      undergone junctional sliding. The evolutionary significance of this phenomenon is
      discussed.

PMID- 10350087
TI  - A novel calcium-binding protein is expressed in Brassica pistils and anthers late
      in flower development.
AB  - We describe the cloning and characterization of PCP, a novel calcium-binding
      protein that is expressed predominantly in the pistils and anthers of Brassica
      flowers late in flower development. A PCP cDNA - isolated from a subtracted cDNA
      library enriched in transcripts present in the pistil late in flower development 
      potentially encodes a 175 amino acid protein with a calculated molecular weight
      of 19.1 kDa. Other than limited homology to a repetitive C-terminal polyacidic
      region of PCP, none of the sequences in the GenBank database shares identity to
      PCP. This unique protein was purified from an Escherichia coli expression system
      and shown to bind calcium in a specific manner, both in a protein blot assay and
      by equilibrium dialysis. PCP binds 29 mol of calcium per mol of PCP protein with
      an apparent affinity constant of 3.2 x 10(2)/M, values consistent with the
      presence of a high capacity/low-affinity calcium-binding domain. PCP-specific
      mRNAs are detected predominantly in the stigma and style of pistils excised from
      open flowers; much lower levels of expression are seen in anthers of open flowers
      and in root and leaf tissue. Expression in the pistil steadily increases during
      flower development and peaks at flower opening. A PCP-specific antibody first
      detects the protein in pistils at one day prior to flowering, with higher levels
      of the protein seen in the pistils of open flowers. A low level of the protein is
      present in anthers of open flowers; however, PCP is not detected in either root
      or leaf extracts. The pattern of PCP expression is consistent with a possible
      role for PCP in pollen-pistil interactions or in pistil development. The results
      are also discussed in light of the central role calcium maintains in pollen tube
      growth and fertilization.

PMID- 10350088
TI  - Expression of a dehydrin gene during embryo development and drought stress in ABA
      deficient mutants of sunflower (Helianthus annuus L.).
AB  - The synthesis of a particular class of proteins, the dehydrins, is a common
      response to drought in plants. Dehydrins are known to be synthesized by the cell
      in response to abscisic acid, which represents a link between environment and
      nuclear activity, though dehydrin genes may be expressed even constitutively. We
      have investigated the relationship between abscisic acid (ABA) and accumulation
      of a dehydrin mRNA in sunflower, in which a dehydrin cDNA (HaDhnla) was isolated.
      In particular, we studied changes in the steady-state level of dehydrin
      transcripts in two mutants for ABA synthesis and accumulation: nd-1 (an albino,
      non-dormant and lethal mutant with a very low ABA content and no ABA accumulation
      in response to stress) and w-1 (a wilty mutant, with reduced ABA accumulation)
      during embryo and plantlet development and drought stress. Differences between
      genotypes were observed through embryogenesis: w-1 shows a lower content of
      dehydrin transcripts in the early stages compared to control plants, indicating
      that ABA affects dehydrin mRNA accumulation; however, dehydrin transcripts level
      appears independent of ABA content in late embryogenesis. Also during drought
      stress in w-1 adult leaves, ABA is not quantitatively related to the steady-state
      level of the HaDhn1a transcripts. Finally, data on nd-1 mutant show a high level
      of dehydrin transcripts after drought stress in plantlet cotyledons and leaflets.
      These results indicate the existence of two regulation pathways of HaDhn1a
      transcripts accumulation, an ABA-dependent and an ABA-independent one, which may
      have cumulative effects.

PMID- 10350089
TI  - Characterization of the subtilase gene family in tomato (Lycopersicon esculentum
      Mill.).
AB  - The gene family of subtilisin-like serine proteases (subtilases, SBTs) in tomato
      (Lycopersicon esculentum Mill.) comprises at least 15 members, 12 of which have
      been characterized in this study. Sequence comparison revealed that tomato
      subtilases fall into 5 distinct subfamilies. Single genes were shown to exist for
      LeSBT1, LeSBT2 and tmp), while 5 and 6 genes were found in the LeSBT3/4 and P69
      subfamilies, respectively. With the exception of tmp, tomato subtilase genes were
      found to lack introns. Expression of subtilase genes was confirmed at the mRNA
      level by northern blot analysis and/or by primer extension experiments. For each
      of the 5 subtilase subfamilies, a distinctive pattern of expression was observed
      in tomato organs. At least one of the subtilases was found to be expressed in
      each organ analysed. Structural features evident from deduced amino acid
      sequences are discussed with reference to the related mammalian proprotein
      convertases.

PMID- 10350091
TI  - Isolation of lipoxygenase cDNA clones from pea nodule mRNA.
AB  - The pattern of lipoxygenase (LOX) gene expression was investigated in pea nodule
      tissues using the technique of in situ hybridization. Five lipoxygenase cDNAs
      were cloned from nodule mRNA by the RT-PCR and 3' RACE procedures. These clones
      (loxN1 to loxN5) show a high degree of sequence homology, except in the 3'
      untranslated region. Gene-specific riboprobes were therefore generated from
      subclones carrying the 3'-untranslated regions in order to investigate tissue
      specific gene expression. Northern blotting analysis revealed that loxN1
      corresponded to a transcript that was expressed exclusively in roots and nodules
      but not in the aerial parts of the plant. However, none of the LOX genes appeared
      to be up-regulated in nodule tissue relative to uninfected roots. Starting with
      the incomplete cDNA clone for loxN1, the full coding sequence termed lox1:P.s:1
      was obtained by further rounds of RT-PCR and 5' RACE procedures. In situ
      hybridization with nodule tissues revealed several different patterns of
      expression for the various LOX probes. However, none of the corresponding
      transcripts was expressed exclusively in the invasion zone, as might have been
      expected if one LOX gene product had been uniquely associated with the invasion
      process. In conclusion, this study provides no evidence for a direct role for any
      LOX gene product in plant-microbe interaction or host defence, but the fact that
      all the transcripts were expressed at the nodule apex suggests that LOX could be
      involved in the development of this organ.

PMID- 10350092
TI  - Enhanced expression and differential inducibility of soybean chalcone synthase
      genes by supplemental UV-B in dark-grown seedlings.
AB  - By developing gene-specific RT-PCR and using filters to allow transmission down
      to 290 nm (UV-B+) or blocking all radiation below 320 nm (UV-B(-)), the effect of
      UV-B+ and UV-B- light on expression of each of the presently known seven members
      of soybean chalcone synthase (CHS) gene family in dark-grown seedlings was
      analyzed. Dark expression was detectable already in 18 h dark-germinating
      embryos, with progressive increases on successive days, suggesting that chs
      belongs to a class of genes expressed very early during germination, and that the
      expression at this stage is either constitutive or induced by non-light-dependent
      factors present in the seed or made available following imbibition. Exposure of
      18 h dark-germinating embryos to UV-B- or to UV-B+ light did not lead to an
      increase in chs signal. However, the 24 h dark-germinating embryos showed a
      distinct effect of UV-B+, interestingly coinciding with the stage when the head
      of seedlings was in the process of being pushed up above ground by stem
      elongation, suggesting the possibility of a developmental switch modulating the
      appearance of UV-B response. The response to UV-B- was most prominent in chs1 and
      almost silent in chs2, while the up-regulation by UV-B+ was most prominent in
      chs5 and chs6 and much less so in chs2. Interestingly, chs2 was noted to be the
      only member of the Gmchs gene family devoid of H-box, raising the possibility
      that the H-box may be a good indicator of the photo-inducibility of a chs gene.

PMID- 10350090
TI  - A novel family of plant splicing factors with a Zn knuckle motif: examination of
      RNA binding and splicing activities.
AB  - An important group of splicing factors involved in constitutive and alternative
      splicing contain an arginine/serine (RS)-rich domain. We have previously
      demonstrated the existence of such factors in plants and report now on a new
      family of splicing factors (termed the RSZ family) from Arabidopsis thaliana
      which additionally harbor a Zn knuckle motif similar to the human splicing factor
      9G8. Although only around 20 kDa in size, members of this family possess a multi
      domain structure. In addition to the N-terminal RNA recognition motif (RRM), a Zn
      finger motif of the CCHC-type is inserted in an RGG-rich region; all three motifs
      are known to contribute to RNA binding. The C-terminal domain has a
      characteristic repeated structure which is very arginine-rich and centered around
      an SP dipeptide. One member of this family, atRSZp22, has been shown to be a
      phosphoprotein with properties similar to SR proteins. Furthermore, atRSZp22 was
      able to complement efficiently splicing deficient mammalian S100 as well as h9G8
      depleted extracts. RNA binding assays to selected RNA sequences indicate an RNA
      binding specificity similar to the human splicing factors 9G8 and SRp20. Taken
      together, these result show that atRSZp22 is a true plant splicing factor which
      combines structural and functional features of both h9G8 and hSRp20.

PMID- 10350093
TI  - The Tpv2 family of retrotransposons of Phaseolus vulgaris: structure, integration
      characteristics, and use for genotype classification.
AB  - The Tpv2 family of transposable elements of common bean, Phaseolus vulgaris,
      belongs to the Ty1/copia group of long terminal repeat (LTR) containing
      retrotransposons. By reverse transcriptase (RT)-PCR and by analysis of genomic
      clones, we characterized four of the approximately 40 copies present in the
      Phaseolus genome, and the genomic environment of their integration sites. Tpv2
      integrated preferentially into actively transcribed regions. While none of the
      isolated elements had all the functional domains necessary for transposition,
      analysis of bean cultivars suggested that some members of the Tpv2 family
      transposed in recent breeding history. Probes derived from Tpv2, as well as
      flanking genomic sequences, may be useful for classifying Phaseolus cultivars.

PMID- 10350094
TI  - Characterization of a desiccation-responsive small GTP-binding protein (Rab2)
      from the desiccation-tolerant grass Sporobolus stapfianus.
AB  - We have used differential display to detect altering mRNA levels in response to
      desiccation and rehydration in leaves of the desiccation tolerant grass
      Sporobolus stapfianus. One of the RT-PCR products identified was used to isolate
      a cDNA of 999 bp which encodes a protein of 210 amino acids (predicted size 23
      kDa). This protein displays considerable sequence similarity to mammalian and
      plant Rab2, a small GTP-binding protein, possessing several conserved motifs
      common to these regulatory proteins. Sporobolus Rab2 was expressed in Escherichia
      coli yielding a protein with an apparent molecular mass of ca. 30 kDa which was
      shown to have the ability to bind GTP. Rab2 transcript accumulated early in
      response to a decrease in relative water content (RWC) and remained high even in
      dried leaves. Rehydration of desiccated leaves resulted in a decrease in levels
      within 3 h of rewetting, with a brief increase at ca. 12 h. Accumulation of Rab2
      transcript was also evident during drying and rehydration of the roots of S.
      stapfianus, as well as in leaves of the desiccation-sensitive grass Sporobolus
      pyramidalis. Earlier work on S. stapfianus concluded that the plant hormone ABA
      has little effect on inducing desiccation tolerance, however Rab2 transcript does
      exhibit a small increase in accumulation in response to exogenous ABA. A possible
      role for Rab2 with respect to desiccation tolerance and damage repair is
      discussed.

PMID- 10350095
TI  - Degradation of oat mRNAs during seed development.
AB  - The genes AV1, AV10, and Z1 encode proteins that accumulate during oat seed
      development. In developing endosperm of Avena sativa (cultivated oat), AV1, AV10
      and Z1 mRNAs reach maximal levels midway through seed development but fall to
      very low levels in mature seeds. Similarly, mRNAs for these proteins peak during
      endosperm development of Avena fatua (wild oat) and are later degraded. However,
      during late maturation of A. fatua seeds, populations of mRNA fragments shorter
      than the intact transcripts accumulate as the full-length transcripts decline in
      abundance. The smaller RNA molecules, which are apparently long-lived decay
      intermediates, are derived randomly from the entire transcripts and are most
      likely not generated by cleavage at precisely defined sites. Other A. fatua
      endosperm mRNAs that are degraded during late seed development, such as those for
      ADP glucose pyrophosphorylase and starch synthase, do not produce detectable
      decay intermediates. Decay intermediates of AV1 and Z1 mRNAs persist at high
      levels during late seed development of two other undomesticated oat species,
      Avena strigosa and Avena barbata. The persistence of decay intermediates for
      these endosperm mRNAs in wild grass species may represent a model system for
      studying RNA decay process in plant tissues.

PMID- 10350096
TI  - The 68 kDa DNA compacting nucleoid protein from soybean chloroplasts inhibits DNA
      synthesis in vitro.
AB  - Nucleoids were purified from chloroplasts of dividing soybean cells and their
      polypeptide composition analyzed by SDS-polyacrylamide gel electrophoresis. Of
      the 15-20 nucleoid-associated polypeptides, several demonstrated DNA binding
      activity. Upon disruption of the nucleoids with high concentrations of NaCl, a
      subset of these proteins and the majority of chloroplast DNA were recovered in
      the supernatant after centrifugation. Removal of the salt by dialysis resulted in
      formation of nucleoprotein complexes resembling genuine nucleoids. Purification
      of these structures revealed three major proteins of 68, 35 and 18 kDa. After
      purification of the 68 kDa protein to homogeneity, this protein was able to
      compact purified chloroplast DNA into a nucleoid-like structure in a protein
      concentration-dependent fashion. Addition of the 68 kDa protein to an in vitro
      chloroplast DNA replication system resulted in complete inhibition of nucleotide
      incorporation at concentrations above 300 ng of 68 kDa protein per microg of
      template DNA. These results led to in situ immunofluorescence studies of
      chloroplasts replicating DNA which suggested that newly synthesized DNA is not co
      localized with nucleoids. Presumably, either the plastid replication machinery
      has means of removing nucleoid proteins prior to replication or the concentration
      of nucleoid proteins is tightly regulated and the proteins turned over in order
      to allow replication to proceed.

PMID- 10350097
TI  - Cloning sulfur assimilation genes of Brassica juncea L.: cadmium differentially
      affects the expression of a putative low-affinity sulfate transporter and
      isoforms of ATP sulfurylase and APS reductase.
AB  - The heavy-metal accumulator Brassica juncea L. is a high-biomass crop able to
      extract heavy-metal ions from the soil, a substantial part being translocated
      from root to shoot. Previous work has shown that Cd accumulation is accompanied
      by massive formation of phytochelatins (PCs). Rapid de novo synthesis of PCs in
      roots and leaves requires an increased synthesis of the tripeptide glutathione
      (GSH), which in turn depends on increased sulfur assimilation. Therefore. we have
      cloned cDNAs for three enzymes involved in sulfur assimilation, i.e. a putative
      low-affinity sulfate transporter (LAST) and two isoforms each for ATP sulfurylase
      (ATPS) and APS reductase (APSR). As degradation of glucosinolates might provide
      an additional sulfur source under stress, we also cloned a myrosinase (MYR). RNA
      blot analysis of transcript amounts indicated that upon Cd exposure (25 microM)
      the expression of ATPS and APSR in roots and leaves of 6-week-old Brassica juncea
      plants was strongly increased, whereas the expression of MYR was unaffected. LAST
      transcripts were significantly reduced in the root but remained unchanged in the
      leaves. Concomitant with Cd induction of ATPS and APSR mRNAs, cysteine
      concentrations in roots and leaves increased by 81% and 25%, respectively,
      whereas GSH concentrations decreased in roots and leaves by 39% and 48%,
      respectively. In agreement with our previous report on Cd induction of gamma
      glutamylcysteine synthetase in B. juncea, the results indicate coordinate changes
      of expression for several sulfur assimilation enzymes in response to an increased
      demand for cysteine during PC synthesis.

PMID- 10350099
TI  - Expanding the use of total mitral valve preservation in combination with
      implantation of the CarboMedics heart valve prosthesis.
AB  - BACKGROUND: Preservation of the mitral valve and subvalvular apparatus was
      introduced into the clinic in the early sixties, but for two decades the standard
      technique for mitral valve replacement included excision of both leaflets and
      their attached chordae tendineae. Lately, increased emphasis has again been
      placed on retention of the mitral subvalvular apparatus during valve replacement
      because of its role on left ventricular function. METHODS: We have preserved the
      valvular and subvalvular mitral apparatus, when possible, in connection with
      mitral valve replacement during the last seven years and the present
      investigation (partly prospective and partly retrospective) was done with the aim
      of making up the results of our mitral preservation technique. In the period
      between January 1990 and December 1995, 30% of the patients who underwent mitral
      valve replacement had complete retention of all mitral tissue. In 1996, the
      percentage had increased to 50, and during the first seven months of 1997, 70% of
      the patients had complete retention of all mitral tissue. Since January 1997, we
      have exclusively used the CarboMedics mitral heart valve prosthesis. A total of
      56 patients were identified to have had a CarboMedics heart valve prosthesis
      implanted. There were 33 men and 23 women with a mean age of 63 years, range 23
      77 years. Coronary bypass was a concomitant procedure in 22 patients. In seven
      patients, both the mitral and aortic valves were replaced. A severely altered
      valve with thickened and or calcified leaflets, stenotic leaflets, or shortened,
      retracted and thickened chordae tendineae were not a contraindication for the
      procedure. Calcified plaques were removed. Adhesion between anterior and
      posterior leaflets was treated with sharp dissection. Valve and subvalvular
      tissue were preserved. The leaflets were reefed within the valve-sutures and
      compressed between the sewing ring and the native annulus when implanting the
      valve prosthesis. Chordal tension on the ventricle was thereby maintained and the
      chordae pulled away from the valve effluent. Echocardiography with measurement of
      ejection-fraction was performed preoperatively during the postoperative course in
      case of cardiac problems and on a routine basis 1 month after surgery and at
      various intervals when the patient was seen in the outpatient clinic. Left
      ventricular outflow tract gradients were measured during the postoperative course
      in case of cardiac problems and routinely 1 month postsurgically. RESULTS: Five
      patients died in the postoperative period and one patient had transient
      neurological symptoms. In none of the patients was death or transient
      neurological symptoms a consequence of the retention of mitral leaflets with
      subvalvular apparatus. The remaining 51 patients were all alive at follow-up.
      Postoperative echocardiography demonstrated a preserved left ventricular function
      and a left ventricular outflow tract without obstruction. CONCLUSIONS: We find
      that the described technique in combination with implantation of a CarboMedics
      heart valve prosthesis is very useful even in patients with a severely altered
      valve, when preserving the mitral leaflets with subvalvular apparatus during
      valve replacement. The technique is without procedure related complications and
      preserves left ventricular function without obstructing the left ventricular
      outflow tract.

PMID- 10350098
TI  - Cloning and characterization of six embryogenesis-associated cDNAs from somatic
      embryos of Picea glauca and their comparative expression during zygotic
      embryogenesis.
AB  - Six somatic embryogenesis-associated cDNAs (PgEMB2, 6, 7, 8, 24 and 34) from
      white spruce (Picea glauca (Moench) Voss) somatic embryos have been
      characterized. Transcript accumulation during somatic embryo development and
      subsequent germination related to these genes, indicated that they were
      developmentally regulated. The transcripts related to clones PgEMB2, 6, 24 and 34
      were also detected during zygotic embryo development, but transcripts of clones
      PgEMB7 and 8 were not. PgEMB24 had a similar gene expression pattern to spruce Em
      like late embryo abundant (lea) gene, but other clones had no similarities in
      gene expression to either spruce lea-like or storage protein genes. Abscisic
      acid, a stimulator for spruce somatic embryo maturation, did not obviously affect
      gene expression corresponding to these cDNAs. The predicted proteins are
      distinguishable from known LEA proteins based on analyses of hydropathy plots,
      amino acid compositions and deduced protein structures. The similarities of the
      spruce cDNAs, and protein sequences predicted from these cDNAs, to other sequence
      data are described.

PMID- 10350100
TI  - Ventricular performance following valve replacement for chronic mitral
      regurgitation: importance of chordal preservation.
AB  - OBJECTIVE: To assess immediate and late changes in left ventricular performance
      after mitral valve replacement (MVR) for mitral regurgitation with or without
      preservation of chordae tendineae. EXPERIMENTAL DESIGN: a prospective, one year
      follow-up, study. SETTING: university cardiosurgical hospital. PATIENTS: Fourteen
      patients with symptomatic chronic mitral regurgitation were divided into Group A
      (n = 7), which underwent MVR with chordal preservation, and Group B (n = 7) which
      underwent MVR with chordal transection. METHODS: Transesophageal
      echocardiography, obtained simultaneously with radial artery and pulmonary
      capillary wedge pressures over a range of loading conditions, was used to
      estimate left ventricular elastance (Eps), calculated as the slope of peak
      systolic pressure/end-systolic volume relation, and preload recruitable stroke
      work (PRSW). Measurements were taken intraoperatively before and after
      cardiopulmonary bypass, 6 hours later and 10 days later. Transthoracic
      echocardiography follow-up data were obtained after 3 months and one year.
      RESULTS: Eps significantly decreased immediately after MVR (p = 0.018), with no
      difference among 2 groups. Eps gradually increased to preoperative levels 10 days
      after surgery. PRSW also significantly decreased after MVR (p = 0.01). The
      decrease was significantly larger in Group B (p = 0.038). During follow-up, Group
      A showed a significantly better ejection fraction (p = 0.008), and a smaller end
      systolic volume index (p = 0.01) and left ventricular mass index (p = 0.04), than
      Group B. CONCLUSIONS: These data support the hypothesis that chordal preservation
      during MVR has beneficial effects on left ventricular performance.

PMID- 10350101
TI  - Impaired lung oxygenation in acute aortic dissection.
AB  - BACKGROUND: In the early phase after the onset of acute aortic dissection,
      oxygenation impairment often occurs. However, the etiology and clinical course of
      this phenomenon have not been established. We examined the serial changes of
      oxygenation, inflammatory reaction and laboratory data in patients with acute
      aortic dissection. METHODS: Nine patients (DeBakey type I; 4, type II; 3 and type
      IIIb; 2), aged 46 to 82 years were included in this study. All patients were
      managed in the intensive care unit, and systolic arterial pressure was maintained
      at around 110 to 120 mm Hg. Oxygenation was impaired in all patients, three (33%)
      of whom required mechanical ventilatory support. RESULTS: Pleural effusion was
      observed in eight (89%) of nine patients. Respiratory index was 0.98+/-0.19 (mean
      +/-SEM) at the time of admission, and elevated to 1.59+/-0.35, 1.58+/-0.21,
      1.60+/-0.28 respectively, at day 1, 2 and 3. Oxygenation index was 318+/-34 at
      the time of admission, and decreased to 271+/-34, 255+/-19, 263+/-26,
      respectively, at day 1, 2 and 3. These values recovered to normal after day 4.
      The increase of white blood cells and high fever (>38 degrees C) continued until
      day 3. Platelet counts recovered after day 4. The serum bilirubin level was
      highest (2.0+/-0.5 mg/dl) at day 3, and decreased gradually after day 4. In two
      recent patients whose serum interleukin-8 (IL-8) was measured, IL-8 levels
      increased according to the impaired oxygenation or aneurysmal enlargement.
      Impaired oxygenation, inflammatory changes, platelet consumption and bilirubin
      elevation continued until day 3 and resumed normal levels after day 4.
      CONCLUSIONS: These changes may be due to hemolysis, consumption coagulopathy or
      inflammation associated with acute aortic dissection. IL-8 elevation may be
      associated with aneurysmal enlargement and these phenomena.

PMID- 10350102
TI  - Coronary sinus retroperfusion during acute experimental coronary artery
      occlusion.
AB  - BACKGROUND: This study was planned to show the effect of retroperfusion and
      cardiopulmonary bypass on myocardial hemodynamic recovery. METHODS: Eighteen dogs
      entered this study. After, left anterior descending artery (LAD) was dissected
      and occluded, the animals were divided into three equal groups; Group I:
      retrograde coronary sinus perfusion, group II: cardiopulmonary bypass and
      retrograde coronary sinus perfusion, Group III: control group, left anterior
      descending artery occlusion only. RESULTS: In Group III, deterioration of the
      hemodynamic values progressed parallel with the degree of ischemic damage but in
      Group I, hemodynamic parameters were better because of the retrograde coronary
      sinus perfusion and minimally affected by the reperfusion. In Group II, at the
      end of the cardiopulmonary bypass minimal myocardial damage was observed.
      CONCLUSIONS: There is no statistical difference between Group I and II if we
      examine the data that was taken after reperfusion although myocardial performance
      was better in Group II.

PMID- 10350104
TI  - The diagnostic and prognostic value of cardiac Troponin T in bypass surgery.
AB  - BACKGROUND: The purpose of this study was to verify the utility of serum Troponin
      T (TnT) in the diagnosis of myocardial damage after coronary surgery performed
      using different methods of myocardial protection. The prognostic value of TnT
      peak for a poor postoperative course was also investigated. METHODS: Forty-three
      patients were enrolled and randomised in 2 group: Group A (n. 22) receiving warm
      blood cardioplegia and Group B (n. 21) receiving cold blood cardioplegia.
      According to TnT peak levels 3 subgroups were identified: Subgroup 1 (TnT peak <
      than 1 ng/ml); Subgroup 2 (TnT peak between 1 and 3 ng/ml), Subgroup 3 (TnT peak
      >3 ng/ml). A comparison with the standard criteria for diagnosis of myocardial
      ischemia was performed for each subgroup of patients. A 12 months follow-up for
      the patients of subgroups 1 and 2 was also completed in order to evaluate the
      prognostic value of a higher TnT peak. RESULTS: The overall patients subdivision
      in subgroup 1, 2 and 3 was 20 (46.5%), 14 (32.5%) and 9 (20.9%) respectively with
      no statistical difference for Group A or B. Only 7 of the patients of subgroup 3
      (87%) matched the WHO diagnostic criteria for myocardial infarction. At the
      overall follow-up, 2 (14.28%) patients of subgroup 2, and 4 (20.0%) of subgroup
      3, revealed a residual ischemia at the ECG-stress test even if none of these
      needed reoperation. CONCLUSIONS: Our data confirmed the high sensitivity and
      specificity of TnT measurement in the diagnosis of myocardial infarction and
      minor myocardial damage. This study, however, failed to show any statistically
      significant difference of the TnT peak when using different strategies of
      myocardial protection. The late prognostic value of the TnT increase in the early
      post-operative course has to be confirmed from a further study.

PMID- 10350103
TI  - Stunned myocardium and cellular damage in patients undergoing valvular cardiac
      surgery and pretreated with captopril.
AB  - BACKGROUND: Following extracorporeal cardiac surgery, transient myocardial
      dysfunction (stunning) and cellular damage may develop in relation, among other
      mechanisms, to the production of free radicals (FR) during reperfusion. The
      purpose of this study is to evaluate whether captopril (CTP), an angiotensin
      converting enzyme inhibitor with a thiolic group, which has been shown to be
      useful as an antioxidant agent both in in vitro and in vivo studies, can prevent
      emergence of those problems when used as pretreatment within 24 hours in patients
      undergoing valvular cardiac surgery. METHODS:  EXPERIMENTAL DESIGN: prospective
      and randomized study. Comparison of data pre-ischemic (pre-aortic clamping) and
      post-reperfusion (post-cardiac rewarming) was performed. Ejection fraction was
      compared pre-surgery, after surgery and after 3 months. SETTING: cardiology and
      cardiovascular surgery services in a general hospital. PATIENTS OR PARTICIPANTS:
      thirty patients who had to undergo valvular replacement surgery were randomly
      allocated to two similar groups, one group pretreated with captopril (CTP group,
      n = 15) and the other group without it (CON group, n = 15). Exclusion criteria
      (left ventricular ejection fraction <40%, evidence of angiographic coronary
      disease or prior myocardial infarction and peroperative myocardial infarction).
      INTERVENTION: in CTP group, the dose of captopril administered was 12.5 mg every
      8 hours orally, from 24 hours before. MEASURES: using electron microscopy of
      myocardial biopsies taken prior to aortic clamping and post-reperfusion, a semi
      quantitative analysis was performed on the degree of myocytic damage (MD),
      mitochondrial swelling (MS), sarcoplasmic reticulum swelling (SRS) and content in
      glycogen granules (GLY). Left ventricular ejection fraction was evaluated
      isotopically at three timepoints, preoperatively (EF1), at 2-3 days (EF2) and at
      3 months (EF3). Also, analytical data were collected from the coronary sinus to
      determine creatine phosphokinase (CPK) and activity of the angiotensin converting
      enzyme (ACE). RESULTS: We noted that, in general, cellular damage resulting from
      valvular surgery is low, the degree of MS and SRS being lower in the CTP group.
      In the CTP group, however, there is a stunning phenomenon (EF1: 54.9+/-6.9%; EF2:
      50.8+/-8.5%; EF3: 57.7+/-7.7%) which does not occur in the CON group (EF1: 58.0+/
      8.3%; EF2: 60.8+/-10.9%; EF3: 63.0+/-9.3%). CONCLUSIONS: We conclude that the
      cellular damage caused during valvular replacement surgery is small, and
      emphasize that pretreatment with CTP further minimizes both MS and SRS; however,
      for reasons as yet unknown, CTP pretreatment may induce myocardial stunning, an
      indication that at these low rates of cellular damage, CTP has no beneficial
      effect, either because it is ineffective as an antioxidant agent or because FR
      formation has little repercussion in human beings, pointing out to the likely
      existence of other mechanisms that may induce an appearance of postsurgical
      myocardial stunning.

PMID- 10350105
TI  - Unpreconditioned free revascularized dynamic cardiomyoplasty. Is it feasible?
AB  - BACKGROUND: Cardiomyoplasty is a new ventricular bioassist device for myocardial
      failure. But there are some limitations in standard cardiomyoplasty, such as the
      orientation of the muscle and fiber and the efficiency of the contractile segment
      of the flap. Free revascularized latissimus dorsi flap may be a good idea for
      solving these problems. METHODS: We designed a canine free latissimus dorsi flap
      by revascularizing the flap with the left internal thoracic vessels by micro
      surgical technique. Group I (n = 3) as control was performed by standard
      cardiomyoplasty, and the Group II (n = 10) was performed by the revascularized
      method. The heart was then wrapped by the revacularized flap. Group II was
      divided into IIa (n = 6, no pre-treatment before revascularization) and IIb (n =
      4, normal saline pre-treatment before revascularization) by the different
      preservation methods. Hemodynamic data were recorded. RESULTS: Group I all
      survived the 8-week training period. But Group II, Group IIa and IIb, all died in
      3 days, but survived more than 12 hours. The hemodynamic analysis in Group I did
      not show any significant change except left ventricular end diastolic pressure.
      It showed elevated left ventricular pressure when the cardiostimulator was ON.
      CONCLUSIONS: According to the result of this experiment, it seemed impossible to
      get a satisfactory result of more than 3 days for free revascularized
      cardiomyoplasty at present. There were a lot of problems waiting to be solved,
      such as preservation method during ischemia, bulky mass of the flap, and the
      potential problem of neuromuscular atrophy.

PMID- 10350106
TI  - Pulmonary Rhizopus rhizopodiformis cavitary abscess in a cardiac allograft
      recipient.
AB  - Pulmonary mucormycosis is rare in solid organ transplant recipients. Only one
      case has been reported previously in a cardiac allograft recipient. However, the
      Rhizopus species in that study was not identified. We report a case of successful
      surgical treatment of pulmonary cavitary mucormycosis due to Rhizopus
      rhizopodiformis in a cardiac allograft transplant recipient. A review of the
      literature on pulmonary mucormycosis occurring in solid organ transplant
      recipients is also presented.

PMID- 10350107
TI  - Perioperative management of a patient with Werlhof disease undergoing myocardial
      revascularization.
AB  - We herein report the case of a patient with idiopathic thrombocytopenic purpura
      (Werlhof disease) and coronary artery disease undergoing myocardial
      revascularization. The use of monomeric immunoglobulins, corticosteroids,
      platelets transfusion, use of a cell saver, normothermic cardiopulmonary bypass,
      aprotinine and homologous blood transfusion were combined in order to minimize
      the risk of bleeding complications in the postoperative period.

PMID- 10350108
TI  - Simultaneous surgery for infective endocarditis and endophthalmitis.
AB  - A 54-year-old woman was diagnosed as having septicemia secondary to infective
      endocarditis with aortic regurgitation which was complicated by endophthalmitis.
      Her septicemia was controlled by intravenous antibiotic therapy. Then the
      localized eye infection and the aortic regurgitation with a massive vegetation
      were surgically treated simultaneously. She had no relapse of infection after
      intensive postoperative antibiotic therapy.

PMID- 10350109
TI  - Recurrent myxoma of the left ventricle. Case report and review of the literature.
AB  - A 29-year-old female was found to have a left ventricular mass while in the 14th
      week of gestation. Seven years earlier she had undergone removal of a left
      ventricular myxoma. At re-operation, after elective interruption of pregnancy, a
      recurrent left ventricular myxoma was successfully excised. According to a review
      of the literature recurrence of an isolated, localized left ventricular myxoma
      has not been previously reported.

PMID- 10350110
TI  - Heparin-induced vascular occlusion in vasculosurgical patients. An evaluation of
      the disease in 13 cases.
AB  - OBJECTIVE: To describe the diagnosis and treatment of adverse reaction to heparin
      (heparin-induced thrombocytopenia [HIT]) administered prophylactically for
      thrombosis and embolism. EXPERIMENTAL DESIGN: case series. SETTING: vascular
      surgical division in a University hospital. PATIENTS: thirteen patients treated
      for HIT type II between October 1994 and June 1997. Measures/Interventions:
      diagnosis of heparin-induced complications is based on exact medical history and
      regular measurement of platelet counts. Confirmation can be obtained with the
      aggregation test, serotonin-release test, heparininduced platelet release (HIPA)
      test, and platelet factor 4/heparin ELISA. Vasculosurgical reconstruction is
      usually required to eliminate vessel occlusion. RESULTS: In our series, HIT was
      confirmed by HIPA test (11 patients) and aggregation test (2 patients). All
      patients had positive cross reaction with low-molecular-weight heparin, and six
      had cross reaction with heparinoid danaproid sodium (Orgaran). Occlusions
      occurred between day 2 and 22 after the start or resumption of heparin
      administration (mean, 11 days). Anticoagulation treatment with hirudin or
      danaproid sodium was given to 5 patients, in conjunction with vasculosurgical
      reconstruction. Three of those patients died and the other two required
      amputation. CONCLUSIONS: Heparin-induced vascular occlusion is a rare but severe
      adverse effect of heparin treatment. When HIT is suspected, heparin
      administration must be stopped, with substitution of dextran and acetylsalicylic
      acid. Laboratory tests must be used for confirmation or exclusion. However, the
      diagnosis can be obscured by a normal platelet count due to pre-existing
      polycythemia and by false-negative test results. Surgery is usually warranted,
      depending on the degree and localization of ischemia.

PMID- 10350111
TI  - Exclusion of internal iliac arterial aneurysm concomitant with abdominal aortic
      aneurysm repair.
AB  - BACKGROUND: To study the long-term outcomes after exclusion of internal iliac
      arterial aneurysm performed concomitantly with abdominal aortic aneurysm repair
      in patients with ruptured aortic aneurysm or other high-risk conditions. METHODS:
      The 31 patients who participated in this study underwent emergency (N = 9) or
      elective surgery (N = 22). The abdominal aortic aneurysm and the common iliac
      artery were excluded together with the internal iliac aneurysm in 7 patients.
      Forty-three (12 bilateral and 19 unilateral) internal iliac aneurysms were
      excluded: 35 by proximal ligation only, 5 by proximal and distal ligation, and 3
      by partial resection of the proximal part of the aneurysm. The platelet count and
      fibrinogen level were evaluated pre- and postoperatively. Pelvic organ ischemia,
      classed as ischemic colitis, buttock claudication and sexual dysfunction, was
      examined. RESULTS: The inferior mesenteric artery was reimplanted in 21 patients.
      The platelet count dropped significantly postoperatively, but the fibrinogen
      level increased and no bleeding tendency was noted. Ischemic colitis occurred in
      7 patients, resulting in colonic infarction in 2 patients. The operative
      mortality was 16%, and the postoperative observation periods ranged from 4 days
      to 217 months (mean, 60 months). The incidence of buttock claudication and sexual
      dysfunction was 12% and 39%, respectively. The excluded aneurysms were all
      thrombosed at discharge, and no late rupture was noted. The 5- and 10-year
      survival rate after surgery was 56% and 51%, respectively. CONCLUSIONS: Exclusion
      of the internal iliac aneurysm concomitant with abdominal aortic aneurysm repair
      shows acceptable outcome when performed in patients with high-risk conditions.

PMID- 10350112
TI  - Clamping ischemia, threshold ischemia and delayed insertion of the shunt during
      carotid endarterectomy with patch.
AB  - BACKGROUND: Shunt insertion during carotid endarterectomy (CEA) is mandatory to
      avoid neurological damage due to clamping ischemia; however shunt insertion
      before plaque removal has many inconveniences (atheroembolism, intimal
      dissection, difficulty of endarterectomy). The aim of this study is to verify
      whether and how long shunt insertion may be safely delayed to permit plaque
      removal and ensure cerebral perfusion during the further time consuming
      manoeuvres of CEA (peeling, patch angioplasty). METHODS: From July 1990 to
      February 1996 383 patients underwent 411 CEAs under general anesthesia with EEG
      continuous monitoring and PTFE patch angioplasty. A Pruitt-Inahara shunt was
      routinely inserted only after atherosclerotic plaque removal. In 316 CEAs (76.9%)
      without EEG signs of cerebral ischemia (Group A) the mean clamping time was 10
      min +/-4.8 (range 2-37 min). In 95 CEAs (23.1%) with EEG signs of cerebral
      ischemia (Group B) it was 7.3 min +/-3.5 (range 3-20 min). All patients had
      normal EEG signals after delayed shunt insertion and reperfusion (mean 21 min,
      range 5-45 min). RESULTS: In the short term results (within 30 days) there was a
      relevant neurological complication rate of 0.96% (2 major stroke and 2 lethal
      stroke); at awakening we observed 5 RINDs (1.21% of total) 1 in a patient of
      Group A (0.31%) and the other 4 in patients of Group B (4.21%). CONCLUSIONS:
      These data confirm the rationale of a delayed insertion of the shunt: actually
      the cerebral parenchyma may tolerate under general anesthesia a sufferance due to
      carotid clamping, EEG detectable, without neurological deficits for at least 7.3
      min. This time is sufficient to perform the most difficult steps of CEA (plaque
      removal, distal intima checking) allowing shunt insertion in a clean operatory
      field, without inconveniences. Finally the shunt allows complementary time
      consuming steps, as patch angioplasty, with improvement of both short- and long
      term results.

PMID- 10350113
TI  - Matrix metalloproteinases. Their role in degenerative chronic diseases of
      abdominal aorta.
AB  - BACKGROUND: The main chronic degenerative diseases of the abdominal aorta, namely
      aneurysmatic and steno-obstructive pathologies, have a common denominator:
      atherosclerosis. Both pathologies are characterised by the destruction of the
      structural integrity of the extracellular protein matrix (ME). A number of
      studies have shown the presence and involvement of a group of enzymes with
      proteolytic activity towards one or more ME components, the matrix
      metalloproteinases (MMPs), in the pathogenesis of aneurysms of the abdominal
      aorta. Other authors have underlined the role of MMPs in the proliferation and
      migration process of smooth muscle cells into the intima in the pathogenesis of
      atheromasic plaque. The aim of this study was to evaluate the possible role of
      these enzymes in the pathogenesis of chronic degenerative diseases of the aorta.
      METHODS: Fragments of aortic wall were removed from patients undergoing elective
      aortic surgery for aneurysms (14 patients) or aortic steno-obstruction (4
      patients). The samples obtained were treated appropriately and then subject to
      immunohistochemical analysis. The preparations were incubated with specific anti
      MMP antibodies and were also incubated with substrate and chromogen, forming a
      pigmented precipitate on the site of the antigen, before being observed using an
      optic microscopic at an enlargement of 250x. Nuclear positivity linked to the
      presence of the antigen testified the validity of staining. Lastly, the MMP
      INDEX, or in other words the number of positive cells out of 100, was stained in
      the adventitia and in the tunica media in each preparation. RESULTS: MMPs were
      divided into three main groups: interstitial collagenase (MMP1) which degrade
      type I and III native collagen; gelatinases (MMP9, MMP2) which act on elastin and
      type IV collagen; stromelysins (MMP3) with specific proteolytic action towards
      proteoglycans, fibronectin and laminine. In our experience, those preparations
      obtained from aorta affected by steno-obstructive pathologies (4 patients)
      revealed the presence of MMPs with a preferential localisation on the intimal
      side of the tunica media. In particular, the increased activity of gelatinases
      MMP9 in atherosclerotic aorta might be responsible for destroying the internal
      elastic lamina and fostering the proliferation and migration of smooth muscle
      cells and the formation of atheromasic plaque. On the other hand, preparations
      obtained from aneurysmatic aorta (14 patients) showed an opposite situation with
      a preferential localisation within the adventitia and on the adventitial side of
      the media. Above all, the loss of elastin represents an essential stage in the
      formation of aortic aneurysms. CONCLUSIONS: This study concords with numerous
      authors who have demonstrated the involvement of proteinase MMPs in the
      development of aortic aneurysms and their possible role in the pathogenesis of
      atheromasic plaque. The different origin of these enzymes (inflammatory cells and
      macrophages or endothelial cells) may be the result of different pathogenetic
      mechanisms. Although they present different pathogenetic features, aortic
      aneurysms and steno-obstructions have a common denominator in atherosclerosis.
      The mechanisms responsible for their evolution towards one or other form are not
      known. The different expression of MMPs in the context of the aortic wall
      represents a field for future research.

PMID- 10350114
TI  - Primary antiphospholipid syndrome: a cause of catastrophic shunt thrombosis in
      the newborn.
AB  - This is a unique report of systemic-to-pulmonary artery shunt thromboses
      secondary to primary antiphospholipid syndrome and antithrombin III deficiency in
      a neonate with cyanotic congenital heart disease. This infant with tricuspid
      atresia experienced thromboses of two modified Blalock-Taussig shunts en route to
      a bidirectional cavo-pulmonary shunt and potential future Fontan operation.
      Chronic warfarin anticoagulation has prevented additional thrombo-embolic events.

PMID- 10350115
TI  - Subclavian steal syndrome and flow-related aneurysm. Another reason to treat.
AB  - A 48-year-old woman presented with a symptomatic right subclavian steal syndrome
      due to proximal subclavian artery stenosis. Anatomically the innominate artery
      was absent. Collateral circulation followed the vertebro-vertebral pathway with
      reversal of blood flow in the ipsilateral vertebral artery. There was also
      multiple dilated intervertebral collaterals and an associated saccular aneurysm
      on one of them. Surgical carotid-subclavian transposition permitted relief of
      clinical symptoms, disappearance of collateral circulation and subtotal
      regression of the aneurysm. This spontaneous evolution confirmed the role of high
      flow in the pathogenesis of some aneurysms and the habitually good prognosis of
      flow-related aneurysms with correction of the cause. Arteriography still appears
      essential in diagnosis, pretherapeutic assessment and sometimes post-treatment
      evaluation in subclavian steal syndrome.

PMID- 10350116
TI  - Arterial homografts in the management of infected axillofemoral prosthetic
      grafts.
AB  - Two lower limb amputees with infected contralateral axillofemoral prosthetic
      grafts received preserved human arteries after removal of the infected materials.
      Both grafts grew organisms (Enterococcus species, plus Staphylococcus species in
      one). Long length arterial conduits were fashioned from freshly harvested (in one
      patient) and cryopreserved (in another one) cadaveric iliac and femoral arteries.
      One arterial homograft had ABO-compatibility with the recipient. No
      immunosuppressive drugs were administered after repeat arterial reconstructions.
      After 12 and 15 months both grafts are still patent, without parietal changes at
      ultrasonography; the patients have a viable remaining lower extremity and are
      free of symptoms or re-infection.

PMID- 10350117
TI  - Acute ischemia of the lower limb. An unusual complication of Paget's disease of
      bone.
AB  - Paget's disease of bone (osteitis deformans) is one of the most common skeletal
      diseases, characterised by bone distortion and the loss of interior structure.
      Asymptomatic evolution is usual, so diagnosis is likely to be made only when
      complications of the disease appear. This paper describes such a diagnosis made
      in a patient with acute lower limb ischemia caused by the compression of the
      superficial femoral artery between the adductor muscles and an exostosis of the
      femur.

PMID- 10350118
TI  - Repair of abdominal aortic aneurysm in severe Factor VII deficiency.
AB  - Congenital Factor VII deficiency is a rare disorder associated with reduced
      levels of Factor VII activity. Replacement therapy is necessary to control
      hemorrhaging or if surgery is needed. We report operative treatment of one case
      of chronic abdominal aortic aneurysm in a patient affected by a severe form of
      congenital Factor VII deficiency (endogenous FVII level <1%). The operation was
      carried out after the administration of Factor VII concentrate raised the Factor
      VII concentration to hemostatic levels. The patient continued to receive the
      concentrate every 6 hrs during the first three postoperative days. Dosage was
      assessed to obtain Factor VII levels not lower than 25%. No postoperative
      bleeding or thrombotic events were observed. The patient was discharged in
      excellent condition.

PMID- 10350119
TI  - Thoracic aortic aneurysm: a new etiology of pulmonary cavity.
AB  - The most frequent chest X-ray finding of descending thoracic aortic aneurysm is
      an enlargement of medial mediastinum. Haemoptysis caused by thoracic aortic
      aneurysm is rare and, normally, when it occurs, it is due to an aorto
      bronchopulmonary fistula. We report the case of an 88 year-old male, heavy smoker
      with arterial hypertension, who had been operated on for abdominal aneurysm five
      years before, whose unique symptom was scant haemoptysis and radiologically
      presented a cavity mass in the upper left lobe. Autopsy revealed that the
      pulmonary cavity mass was due to a descending thoracic aortic aneurysm.

PMID- 10350120
TI  - Hepatic arterial anatomy: two new variants.
AB  - Many modifications of hepatic arterial anatomy have been reported. The new,
      previously non-described variants are presented in two patients with hepatic
      malignancies. The significance of unusual hepatic vascular anatomy for liver
      surgery and vascular intervention are discussed.

PMID- 10350121
TI  - Pectus excavatum: special surgical technique, perioperative management and long
      term results.
AB  - BACKGROUND: It is generally accepted that pectus excavatum should be repaired in
      childhood if possible. The procedure could be performed conveniently even without
      implantation of any foreign material. In contrast there are several adult
      patients with aesthenic or marfanoid habitus and poor thorax cosmetics, who seek
      medical help especially surgical correction due to late awareness or
      cardiopulmonary dysfunction. METHODS: Between 1989 and 1997, 22 adult patients
      (mean age 26 years, 18 males and 4 females) underwent repair of the pectus
      excavatum in our institution. Patients data were analysed retrospectively.
      Indication was mainly for aesthetics or cardiopulmonary symptoms, in 3 patients
      for recurrence after primary repair elsewhere. The total surgical repair
      technique consisted of V-shape osteotomy of the ribs at the outer and inner limit
      of the funnel and transverse osteotomy of the sternum without displacement of the
      posterior cortical The sternal and chest wall stabilization in corrected position
      was performed with at least two metal struts installed transsternal and
      transversely. In most of our cases other diagonal struts on both sides were
      needed to achieve further stabilization of the lowest costal cartilages. The
      metal struts are removed 1 year after the procedure. RESULTS: All repairs were
      completed with a low complication rate. Chest radiographs and pulmonary function
      studies were performed routinely before and after corrective surgery. Good to
      satisfactory chest contour was achieved in 20 patients (91%), with a follow-up
      from 5 months to 8 years. CONCLUSIONS: Our current technique with perioperative
      management is successfully performed in adults and will be presented.

PMID- 10350122
TI  - Tumor markers kinetic in malignant lung neoplasms.
AB  - BACKGROUND: No studies about correlation between post-operative half-life of
      tumor markers and prognosis in lung cancer exist in literature. The aim of our
      study was to determine the half-life of CEA, TPA, NSE and CYFRA 21-1 in
      postoperative period after surgery of bronchogenic carcinoma, and to correlate it
      with the prognosis and survival of the patients. METHODS: From March 1997 to
      March 1998, 35 patients with bronchogenic carcinoma were studied (29 males and 6
      females, mean age 64.9 years, range 51-77 and 61.0 years, range 52-77
      respectively). The mean follow-up for males was 125.70 days (from 30 to 198)
      after surgery and for females 125.79 days (from 30 to 180). CEA and NSE were
      tested by immunoenzymatic automated method, whereas TPA and CYFRA 21-1 were
      assayed by immunoradiometric techniques. For each patient both the dismission
      curve and the half-life of considered markers were calculated during follow-up.
      RESULTS: A statistically significant difference was found for preoperative values
      of TPA (p = 0.027) and CYFRA 21-1 (p = 0.025) between SqCLC and adenocarcinoma.
      The preoperative levels of markers were higher in patients who would develop a
      relapse, even if statistical significance was not reached. CEA half-life was of
      1.4 days, while in patients with a history of relapse or metastatic spreading was
      4.5 days. No differences were revealed concerning CYFRA 21-1 between the two
      groups. CONCLUSIONS: Seriate determination of some markers (CEA and TPA in
      particular) during postoperative follow-up after surgery for bronchogenic
      carcinomas can be a useful prognostic tool. Longer follow-up would provide
      additional informations in order to determine individual predictive threshold
      between poor and good prognosis.

PMID- 10350123
TI  - Combined use of steroid, antibiotics and early bougienage against stricture
      formation following caustic esophageal burns.
AB  - BACKGROUND: If an esophageal burn is diagnosed, the aim is to prevent stricture
      formation. The combined use of steroid, antibiotics and early bougienage (SAEB)
      is one of the currently used treatment protocols. The effect of SAEB treatment
      against stricture formation following caustic esophageal burn has been evaluated
      retrospectively. METHODS: Forty-nine children of 282 admitted with a history of
      caustic substance ingestion were found to have esophageal burns. Forty-nine
      children underwent treatment against stricture formation. SAEB was begun within
      48 hours of ingestion. RESULTS: Eight children of 12 who ingested sodium
      hydroxide and five children of 20 who ingested acids developed strictures in
      spite of the therapy. Additionally two esophageal perforations were encountered
      in patients who ingested sodium hydroxide. CONCLUSIONS: This protocol has been
      found to carry a risk of perforation without preventing stricture formation after
      strong alkali ingestion. Therefore other treatment modalities for preventing
      strictures should be evaluated especially in children who have ingested products
      containing strong alkalis.

PMID- 10350124
TI  - Video-assisted thoracoscopic pericardiectomy for severe pericardial effusions.
AB  - Video-assisted thoracic surgery (VATS) has proven to be extremely useful in the
      diagnosis and treatment of multiple thoracic problems. We used the VATS technique
      to successfully treat refractory pericardial effusions associated with
      pericarditis by performing pericardiectomy.

PMID- 10350125
TI  - Arterial switch with internal pulmonary artery banding. A new palliation for TGA
      and VSD in complex cases.
AB  - In most cases, one stage repair by arterial switch operation (ASO) is the optimal
      treatment for neonates with transposition of the great arteries (TGA).
      Nevertheless, a ventricular septal defect (VSD) associated with TGA remains a
      major risk factor for early death and reoperation after complete repair in
      neonates with complex anatomy. A new palliative approach for such specific cases
      is proposed. An internal pulmonary artery banding (IPAB), as that already used to
      palliate other cardiac malformations, is performed in association with ASO
      instead of VSD closure. At the end of ASO, a circular polytetrafluorethylene
      (PTFE) patch with a 4-mm central hole is oversewn into the neo-pulmonary trunk.
      We adopted this method in a 17-day-old boy with TGA, VSD, hypoplastic tricuspid
      valve and diminutive right ventricle. After the operation the child thrived and
      was doing well without medication. Satisfactory growth of the right ventricle and
      tricuspid valve was observed by echocardiography during the following months. The
      patient successfully underwent VSD closure and IPAB removal 2 years after the
      first procedure. ASO with IPAB could be appropriate in all forms of TGA and VSD
      in which VSD closure appears too challenging in the neonatal period and in
      patients with uncertain suitability for biventricular repair. We preferred to use
      IPAB instead of classic PAB in order to reduce the risk of pulmonary valve
      damage, pulmonary artery distortion, and above all pulmonary artery dilatation
      and related coronary compression. In the presented case the strategy as well as
      IPAB worked according to our expectations.

PMID- 10350126
TI  - Magnetic resonance angiography in axillofemoral grafting.

PMID- 10350127
TI  - A mediastinal schwannoma causing left atrial compression.

PMID- 10350128
TI  - Transcriptional and translational regulation of gene expression in haploid
      spermatids.
AB  - During spermiogenesis, round spermatids undergo complex morphological,
      biochemical, and physiological modifications resulting in the formation of mature
      spermatozoa. While in round spermatids histones and non-histone proteins are
      replaced by transition proteins, in elongating spermatids, transition proteins
      are removed from the condensing chromatin and are replaced by protamines, which
      are the principal basic nuclear proteins of mature spermatozoa. The tightly
      packed DNA-protamine complexes cease transcription several days before the
      completion of spermiogenesis. Thus, major modifications in both nuclear and
      cytoplasmic structures continue throughout spermiogenesis, stringent temporal and
      stage-specific gene expression is a prerequisite for the correct differentiation
      of round spermatids into mature spermatozoa. The genes for transition proteins
      and protamines are transcribed in round and elongating spermatids. Transcription
      is regulated via methylation and trans-acting factors that bind to the TATA-box,
      the CRE-box, or other specific DNA sequences in the promoter region. The
      transcripts are stored as ribonucleoprotein particles in a translationally
      repressed state for several days and are translated in elongating and elongated
      spermatids. It has been demonstrated that, in haploid spermatids, essentially
      every mRNA exhibits evidence of translational repression. Translational
      regulation involves protein repressors that bind to the poly-A tail or specific
      RNA sequences located in the 3'-UTR.

PMID- 10350129
TI  - Cytoarchitecture of Caudiverbera caudiverbera stage VI oocytes: a light and
      electron microscope study.
AB  - The general characteristics and salient features of the full-grown stage VI
      Caudiverbera caudiverbera oocyte at the light and electron microscopy level are
      described. The oocyte is a huge cell with radial symmetry and distinct polarity.
      A black animal hemisphere, rich in pigment granules and containing the nucleus,
      is clearly distinguished from the unpigmented white-yellowish vegetal hemisphere.
      The cell is surrounded by a highly invaginated plasma membrane, with numerous
      microvilli. The cortex underlying the plasma membrane contains cortical and
      pigment granules, mitochondria, rough endoplasmic reticulum and coated vesicles.
      Cytoskeletal components, such as actin filaments and microtubules, are also found
      in this region. The predominant structures, distributed throughout the cell, are
      the yolk platelets, which show a gradient in size with small platelets in the
      animal half and very large ones in the vegetal zone. Mitochondria are also very
      abundant in both hemispheres and clouds of these organelles are found in the
      perinuclear region, frequently associated with microtubules. Developed Golgi
      complexes are present in the cytoplasm and occasionally, annulate lamellae appear
      towards the inner zones. The nucleus is a large structure containing numerous
      nucleoli. The nuclear envelope is highly invaginated, especially at the side
      facing the vegetal pole. It is regularly perforated by large nuclear pores. Our
      results show that the structural organization of Caudiverbera oocytes, although
      similar to that of other amphibian oocytes, differs from them especially
      concerning the spatial distribution of several structural components.

PMID- 10350130
TI  - Trefoil factor family (TFF)-domain peptides in the mouse: embryonic
      gastrointestinal expression and wounding response.
AB  - Trefoil factor family (TFF)-domain peptides are mucin-associated molecules that
      play a role in maintaining gastrointestinal (GI) epithelial integrity. They are
      expressed in specific patterns in adult mammals, but their embryonic expression
      has not been clarified. Developmental TFF mRNA in mice was studied by non
      isotopic whole mount in situ hybridization. All TFF's (1-3) were seen in the
      stomach from E13 to E16. TFF1 was gastric at E13, then spread to the small
      intestine (E15) and caecum on E16. Froin E19 TFF1 expression was gastric. TFF2
      was gastric at E13, and absent in lower intestines till E17 when duodenal, small
      intestinal and caecal expression was seen. Afterwards, TFF2 was confined to the
      gastric region. TFF3 was in the stomach at E13. On E15 and 16 TFF3 was
      ubiquitous, except for E15 caecum. From E17, TFF3 was confined to small intestine
      and the distal gut. WOUNDS: E17 and 18 GI tissues were subjected to incisional
      wounds in vitro. TFF1 induction was seen only in stomach, after as short as 30
      min incubation. TFF2 was only induced at E18 in the stomach. TFF3 was induced
      within 5 min in the rectum. No change in overall expression patterns were seen
      after wounding. CONCLUSIONS: TFF expression is developmentally controlled in the
      GI tract, and appears before mucous cell differentiation in several tissues. Gene
      regulation is predicted to be under different control(s) in utero compared with
      post-natal life. The response to incisional wounding of fetal GI tissue shows
      differences to the adult.

PMID- 10350131
TI  - A comparison of blood-brain barrier and blood-nerve barrier endothelial cell
      markers.
AB  - A number of major properties of endothelial cells (EC) at the blood-brain barrier
      (BBB) have been shown to be astrocyte-dependent. Whether analogous properties at
      the blood-nerve barrier (BNB) are induced and maintained by Schwann cells has not
      been investigated. As a preliminary investigation we have undertaken a
      comparative study of six EC membrane markers at the BBB and BNB and perineurium.
      Employing immunoblotting and immunocytochemistry the relative distribution
      between rat brain cortex and sciatic nerve was determined for the glucose
      transporter (GLUT-1), the transferin receptor (OX-26), the endothelial barrier
      antigen (EBA) and the OX-47 antigen. Using enzyme cytochemistry the same
      comparison was made for gamma-glutamyl transpeptidase (GGTP) and alkaline
      phosphatase. By immunocytochemistry GLUT-1 was uniformly strongly represented in
      brain EC, nerve EC and perineurium. OX-26 was strongly positive in brain EC but
      present only in trace quantities in nerve EC and perineurium. EBA similarly
      showed strong positivity in brain EC and trace amounts in nerve EC but was absent
      from perineurium. OX-47 was present moderately in brain EC and perineurium but
      absent from nerve EC. Quantitative immunoblotting of brain and sciatic nerve
      homogenates showed statistically significant differences in the level of
      expression of EBA and OX-26 between the two tissues. Enzyme cytochemistry showed
      that GGTP was strongly positive in brain EC but absent from nerve EC and
      perineurium. Alkaline phosphatase stained strongly in brain and nerve EC and was
      absent from perineurium. In summary the six membrane markers were heterogeneously
      represented in nerve compared with brain. This pattern of distribution in the
      nerve cannot simply be accounted for by the absence of astrocytes and their
      inductive influences. Any inductive influences of Schwann cells require
      investigation.

PMID- 10350132
TI  - Fine structure of bovine morulae and blastocysts in vivo and in vitro.
AB  - The ultrastructure of bovine morulae and blastocysts developed from in vitro
      matured and -fertilized oocytes in a serum-supplemented medium was compared with
      that of morulae and blastocysts collected non-surgically from superovulated cows.
      In the in vivo-derived morulae, two characteristic cells types could be
      identified by the electron-density of their cytoplasm and by their
      ultrastructural features. One type appeared light in color with low electron
      dense cytoplasm. These cells were located in the peripheral layer of the cluster
      of blastomeres, possessed numerous cellular organelles such as mitochondria and
      Golgi apparatus and had microvilli projecting into the perivitelline space. The
      other cell type was distinguished by cytoplasm that stained more densely than
      that of the lighter-appearing cells. The darker-appearing cells generally
      possessed fewer organelles than the lighter cells, but many lysosome-like
      structures were present in the cytoplasm. The in vitro-developed morulae also
      contained two types of cells similar to those observed in the in vivo morulae.
      However, most of the in vitro-developed cells possessed numerous lipid droplets
      and contained fewer lysosome-like structures than the cells of the in vivo
      derived morulae. The blastocysts, both in vivo and in vitro, showed a clear
      differentiation of trophoblast cells and inner cell mass (ICM)-cells. In the in
      vivo-derived blastocyst, the apical membrane of trophoblast cells was covered
      with large, numerous microvilli and well-developed junctional complexes were
      observed. Lipid droplets were present in the cytoplasm of trophoblast and ICM
      cells but were not abundant. In vitro-developed blastocysts showed less well
      developed junctional complexes between trophoblast cells, less well-developed
      apical microvilli on the trophoblast cells, and contained large numbers of lipid
      droplets. This accumulation of lipid droplets was higher in the trophoblast cells
      than in the ICM-cells. The zonae pellucidae of in vitro-developed embryos were
      thinner than that of the in vivo-derived embryos. This study demonstrates
      conspicuous differences in the ultrastructural features between the in vivo
      derived and in vitro-developed embryos, suggesting that the ultrastructure may
      reflect the various physiological anomalies observed in previous studies.

PMID- 10350133
TI  - Development of full-length Trk B-immunoreactive structures in the hippocampal
      formation of the macaque monkey.
AB  - Distribution and morphological changes of cells containing the signal transducing
      neurotrophin receptor, full-length Trk B (fl-Trk B), were investigated in the
      hippocampal formation of the macaque monkey between embryonic day 140 and the
      adult stage. Western blot analysis showed that one main protein band, which
      migrated at 141 kDa, was detected in both the embryonic and adult hippocampal
      formation. In the pyramidal cells in CA1 and CA3 subfields, the subiculum, and
      the entorhinal cortex, fl-Trk B-immunoreactive dendrites were observable in the
      embryonic stage. In contrast, in the granule cells of the dentate gyrus, few
      dendrites were immunoreactive during embryonic and early developmental stages.
      This difference may be due to the later growth of the granule cells of the
      dentate gyrus. The existence of fl-Trk B immunoreactivity in the cell body and
      dendrites in the embryonic hippocampal neurons, suggests that BDNF and/or NT4/5
      act on the hippocampal cells by autocrine/paracrine mechanisms. In the entorhinal
      cortex, fl-Trk B immunoreactivity became localized in the stellate cells in layer
      II and the pyramidal cells in layers III, V and VI in adulthood. This indicates
      that BDNF and/or NT4/5 are important for the maintenance of the projection
      neurons in the entorhinal cortex at the adult stage. The strongest fl-Trk B
      immunoreactivity in the hippocampal neurons occurred at postnatal month 4,
      corresponding to the period of greatest synapse production in the monkey
      hippocampus, suggesting that BDNF and/or NT4/5 with fl-Trk B may play a role in
      synapse formation in the monkey hippocampus.

PMID- 10350134
TI  - Early development of descending supraspinal pathways: a tracing study in fixed
      and isolated rat embryos.
AB  - Early brainstem-spinal cord projections were studied in the rat using the
      carbocyanine dye DiI in fixed embryos and biotinylated dextran amine (BDA) in an
      isolated embryonic brain-spinal cord preparation. A system of staging embryos was
      used that allows direct comparison with data in other mammals. With both
      techniques it was shown that in embryos of at least 12 days of age (E12), i.e.,
      at the time of closure of the posterior neuropore, already a variety of brainstem
      centers innervate the spinal cord. In the interstitial nucleus of the fasciculus
      longitudinalis medialis and various parts of the reticular formation -
      mesencephalic, pontine as well as medullary - DiI or BDA labelled neurons were
      observed. Mainly large immature, bipolar neurons were labeled. In later stages
      (E13, E14) the number of labeled neurons increased and more mature, multipolar
      cells were found. Labeled neurons were also observed in the vestibular nuclear
      complex and in the medullary raphe. Just below the cerebellum a conspicuous small
      group of neurons was found labeled in a position reminiscent of the locus
      coeruleus. Comparison with available data on the time of neuron origin of
      brainstem neurons suggests that interstitiospinal and reticulospinal neurons
      start projecting spinalwards shortly after they are generated. The earliest
      brainstem projections to the spinal cord all pass via the fasciculus
      longitudinalis medialis.

PMID- 10350135
TI  - Extracellular matrix and development of lamination in the dorsal lateral
      geniculate nucleus in the tree shrew (Tupaia belangeri).
AB  - In the tree shrew (Tupaia belangeri), the cytoarchitectonic lamination of the
      lateral geniculate nucleus cannot be detected at birth; it only appears during
      the early postnatal period. However, a laminated pattern was revealed with rapid
      Golgi staining and retinal afferents were segregated into the appropriate laminae
      well before cytoarchitectonic lamination could be seen. Both observations
      indicate that the extracellular matrix may play a role in the separation of
      lateral geniculate nucleus cells into laminae. In the present study, the
      organization of the extracellular matrix was investigated during development
      using immunohistochemical and in situ hybridization techniques. For
      immunohistochemistry, peanut agglutinin (PNA) lectin and antibodies against
      tenascin (TN) were chosen, while for in situ hybridization, mTN riboprobes were
      used, simultaneously, with antibodies against Vimentin (Vim) and microtubule
      associated protein (MAP-2). The results showed that the pattern of PNA-binding
      glycoproteins and that of tenascin were relatively similar, although tenascin
      appeared later and disappeared earlier. The first interlaminar spaces to be
      detected were those between layers innervated by opposite eyes. The TN specific
      mRNA was detected in the lateral geniculate nucleus at P0, but was no longer
      visible at P7. By comparing TN mRNA and Vim or MAP-2 stainings a correspondence
      could be observed. The extracellular matrix lamination therefore seems to precede
      cytoarchitectonic lamination, suggesting that the extracellular matrix may play a
      role in the development of laminated structures. The TN-producing cells seem to
      be developing astrocytes and neurons.

PMID- 10350136
TI  - Morphological and electrophysiological features of F76 and D1 neurones of the sub
      oesophageal ganglia of Helix aspersa in vitro and in culture.
AB  - Identified neurones F76 and D1 of the suboesophageal ganglia of Helix aspersa
      were studied in the isolated ganglia in vitro and in culture. The neurones were
      examined electrophysiologically with current clamp and morphologically either
      with intracellular injections of Lucifer Yellow or biocytin. These nerve cells
      had very similar resting membrane potentials and responses to injected current.
      The projections of D1 and F76 have been characterised, with both neurones having
      two main axons. The F76 neurones project to the left pallial, right pallial,
      anal, and visceral nerves as well as to the left and right pleural ganglia. The
      D1 neurones have similar projections except that they do not project to the anal
      and visceral nerves. The bilateral symmetry to the pallial nerves and pleural
      ganglia is discussed. These cells were also studied electrophysiologically after
      mechanical isolation and culture. F76 and D1 neurones were separated by
      dissection (no enzymes) and cultured in three ways. In normal snail Ringer they
      remained viable for up to two weeks with no development. In Ringer preincubated
      with a ganglia or containing endothelial growth factor, neurite outgrowths were
      seen. Membrane potentials were significantly lower in cultured neurones than in
      vitro and the after hyperpolarization never went below resting in cultured cells
      but it did in vitro.

PMID- 10350137
TI  - The effect of adenosine and its analogues on histamine release from mast cells.

PMID- 10350138
TI  - Selective effects of antileukotrienes on leukotriene and histamine release in
      human dispersed lung cells.

PMID- 10350139
TI  - Modulation of the immunological activation of human basophils by carbon monoxide.

PMID- 10350140
TI  - Effects of free radical scavengers on histamine release from human basophils
      stimulated by immunological and non-immunological secretagogues.

PMID- 10350141
TI  - Pyrethroids and the synergist piperonyl-butoxide (PBO) affect T-cells and
      basophils.

PMID- 10350142
TI  - Inhibition of human basophil degranulation by successive histamine dilutions:
      results of a European multi-centre trial.

PMID- 10350143
TI  - Histamine content of human eosinophil granulocytes.

PMID- 10350144
TI  - The effect of some anti-inflammatory drugs on histamine and serotonin release
      from rat peritoneal mast cells.

PMID- 10350146
TI  - On the use of ionophores as probes for calcium signalling. Observations with rat
      mast cells.

PMID- 10350145
TI  - Isolation and properties of mast cells from rat prostate.

PMID- 10350147
TI  - Nitric oxide does not affect histamine release from rat peritoneal mast cells.

PMID- 10350148
TI  - Prostanoid DP receptor activation inhibits anti-IgE induced histamine release
      from rat peritoneal mast cells.

PMID- 10350149
TI  - Histamine content and mast cell number in tissues of mutant mice of (mi/mi)
      genotype.

PMID- 10350150
TI  - Mercuric chloride releases preformed mediators from mast cells of the mouse and
      rat.

PMID- 10350151
TI  - Mercuric chloride synergistically increases ionophore-induced secretion of IL-4
      from murine mast cells.

PMID- 10350152
TI  - Is endogenous histamine involved in the contraction of the isolated trachea,
      evoked by muscarinic agonist?

PMID- 10350153
TI  - Mast cell number, histamine concentration and placental vascular response to
      histamine in preeclampsia.

PMID- 10350154
TI  - Mast cells and histamine in intrauterine growth retardation--relation to the
      development of placental microvessels.

PMID- 10350155
TI  - Pilot study on histamine release from basophils of atopic individuals with low
      specific IgE serum levels against casein.

PMID- 10350156
TI  - The basophil histamine release test in the diagnosis of atopic bronchial asthma
      in children.

PMID- 10350157
TI  - Randomised study comparing a non-ionic with an ionic contrast medium in patients
      with malignancies: first answer with a new diagnostic approach.

PMID- 10350158
TI  - Prediction of postoperative outcome from perioperative changes of mediators in
      cholecystectomy--an application of Bayes' Theorem.

PMID- 10350159
TI  - Influence of histamine H1+H2 receptor antagonists on abdominal infections
      following minimally invasive versus conventional surgery: studies in large
      samples of rats following the new concept of clinic modelling randomised trials
      (CMRT).

PMID- 10350160
TI  - Blood histamine levels in patients with chronic lymphocytic leukemia.

PMID- 10350161
TI  - An attempt to disclose brain histamine localisation in portocaval shunted rats.

PMID- 10350162
TI  - Histaminergic H2 receptor ligands modulate acetylcholine release in the ventral
      striatum.

PMID- 10350163
TI  - Histamine H3 receptor binding sites in rat cortex following L-histidine loading.

PMID- 10350164
TI  - Analysis of the effects of histaminergic compounds on experimental nociception
      and body temperature in mice.

PMID- 10350165
TI  - Acetylcholine release from hippocampus of freely moving rats is modulated by
      thioperamide and cimetidine.

PMID- 10350166
TI  - The manipulation of brain histamine concentrations failed to modify voluntary
      alcohol intake by rats.

PMID- 10350167
TI  - Histamine H2-receptor modulation in two mouse models of seizure susceptibility.

PMID- 10350168
TI  - Morphobiochemical investigations of the thyroid gland of the guinea pig after the
      application of some receptor antagonists and histamine.

PMID- 10350169
TI  - H1 antihistamines, cytochrome P450 and multidrug resistance: is there a link?

PMID- 10350170
TI  - Changes in H2 receptor expression and coupling during Ca2+-induced
      differentiation in mouse epidermal keratinocytes.

PMID- 10350171
TI  - The involvement of the histamine degradation pathway by diamine oxidase in
      manifest gastrointestinal allergies.

PMID- 10350172
TI  - Histaminase (diamine oxidase) activity in human cataract.

PMID- 10350173
TI  - Molecular cloning of mammalian diamine oxidase genes and cDNAs.

PMID- 10350174
TI  - Diamine oxidase and catalase are expressed in the same cells but are present in
      different subcellular compartments in porcine kidney.

PMID- 10350175
TI  - Analysis of the glycosylation of porcine diamine oxidase.

PMID- 10350176
TI  - Increase of histidine decarboxylase in human monocytes during macrophage colony
      stimulating factor induced in vitro phagocytic differentiation.

PMID- 10350177
TI  - Detection of histidine decarboxylase in peripheral blood leukocytes by flow
      cytometry.

PMID- 10350178
TI  - Is histamine involved in milk ejection in goats?

PMID- 10350179
TI  - No sex difference in the urinary excretion of the histamine metabolite
      methylimidazoleacetic acid (MeImAA) when corrected for creatinine excretion.

PMID- 10350180
TI  - Determination of histamine in tissues using reversed phase-HPLC with post column
      fluorimetric detection.

PMID- 10350181
TI  - Influence of selective 5-HT agonists and myocardial preconditioning on
      ischaemia/reperfusion induced changes in isolated heart of the rat.

PMID- 10350182
TI  - The influence of intestinal ischaemia on energy balance in the myocardium during
      ischaemia-reperfusion induced cardiac injury in the rat.

PMID- 10350183
TI  - Role of the endothelium in the vasorelaxing influence of histamine on isolated
      human subcutaneous resistance arteries.

PMID- 10350184
TI  - Role of nitric oxide and histamine in the reflux-related gastric mucosal injury
      in the rat.

PMID- 10350185
TI  - Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes.
AB  - Nicotine C-oxidation by recombinant human cytochrome P450 (P450 or CYP) enzymes
      and by human liver microsomes was investigated using a convenient high
      performance liquid chromatographic method. Experiments with recombinant human
      P450 enzymes in baculovirus systems, which co-express human nicotinamide adenine
      dinucleotide phosphate (reduced form) (NADPH)-P450 reductase, revealed that
      CYP2A6 had the highest nicotine C-oxidation activities followed by CYP2B6 and
      CYP2D6; the Km values by these three P450 enzymes were determined to be 11.0,
      105, and 132 microM, respectively, and the Vmax values to be 11.0, 8.2, and 8.6
      nmol/min per nmol P450, respectively. CYP2E1, 2C19, 1A2, 2C8, 3A4, 2C9, and 1A1
      catalysed nicotine C-oxidation only at high (500 microM) substrate concentration.
      CYP1B1, 2C18, 3A5, and 4A11 had no measurable activities even at 500 microM
      nicotine. In liver microsomes of 16 human samples, nicotine C-oxidation
      activities were correlated with CYP2A6 contents at 10 microM substrate
      concentration, whereas such correlation coefficients were decreased when the
      substrate concentration was increased to 500 microM. Contribution of CYP2B6 (as
      well as CYP2A6) was demonstrated by experiments with the effects of orphenadrine
      (and also coumarin and anti-CYP2A6) on the nicotine C-oxidation activities by
      human liver microsomes at 500 microM nicotine. CYP2D6 was found to have minor
      roles since quinidine did not inhibit microsomal nicotine C-oxidation at both 10
      and 500 microM substrate concentrations. These results support the view that
      CYP2A6 has major roles for nicotine C-oxidation at lower substrate concentration
      and both CYP2A6 and 2B6 play roles at higher substrate concentrations in human
      liver microsomes.

PMID- 10350186
TI  - Enzyme-mediated dichloromethane toxicity and mutagenicity of bacterial and
      mammalian dichloromethane-active glutathione S-transferases.
AB  - The kinetic properties of bacterial and rat liver glutathione S-transferases
      (GST) active with dichloromethane (DCM) were compared. The theta class
      glutathione S-transferase (rGSTTI-1) from rat liver had an affinity for
      dihalomethanes lower by three orders of magnitude (K(app) > 50 mM) than the
      bacterial DCM dehalogenase/GST from Methylophilus sp. DM11. Unlike the bacterial
      DCM dehalogenase, the rat enzyme was unable to support growth of the dehalogenase
      minus Methylobacterium sp. DM4-2cr mutant with DCM. Moreover, the presence of DCM
      inhibited growth with methanol of the DM4-2cr transconjugant expressing the rat
      liver GSTT1-1. In Salmonella typhimurium TA1535, expression of rat and bacterial
      DCM-active GST from a plasmid in the presence of DCM yielded up to 5.3 times more
      reversions to histidine prototrophy in the transconjugant expressing the rat
      enzyme. Under the same conditions, however, GST-mediated conversion of DCM to
      formaldehyde was lower in cell-free extracts of the transconjugant expressing the
      rat GSTT1 than in the corresponding strain expressing the bacterial DCM
      dehalogenase. This provided new evidence that formaldehyde was not the main
      toxicant associated with GST-mediated DCM conversion, and indicated that an
      intermediate in the transformation of DCM by GST, presumably S
      chloromethylglutathione, was responsible for the observed effects. The marked
      differences in substrate affinity of rat and bacterial DCM-active GST, as well as
      in the toxicity and genotoxicity associated with expression of these enzymes in
      bacteria, suggest that bacterial DCM dehalogenases/GST have evolved to minimise
      the toxic effects associated with glutathione-mediated catalysis of DCM
      conversion.

PMID- 10350187
TI  - Glutathione S-transferase (GST) M1 and GST T1 genotypes and hematopoietic effects
      of benzene exposure.
AB  - This study investigated whether or not the genotypes glutathione S-transferase
      theta (GST T1) and mu (GST M1) correlated with low white blood cell (WBC) count
      found in benzene exposed workers. We found that individuals with genotypes
      positive for both GST T1 and GST M1 showed the highest prevalence of low WBC
      [odds ratio (OR) = 4.67, P = 0.046, 95% confidence interval (CI) = 1.02-24.15]
      when the benzene exposure was high. Multiple logistic regression showed that
      benzene exposure (OR = 2.81, P = 0.062, 95% CI = 0.96-8.30) was associated with
      increased OR on low WBC and interactions between the benzene exposure and the
      genotype of GST T1 were also observed. These observations suggest that GST T1 and
      GST M1 may play important roles in the biotransformation of benzene, the effect
      which leads to its hematotoxicity.

PMID- 10350188
TI  - Effect of d-amphetamine repeated administration on rat antioxidant defences.
AB  - The purpose of this study was to evaluate rat tissue antioxidant status after
      repeated administration of d-amphetamine. Three groups of four rats each were
      used: control, d-amphetamine sulphate dosed (s.c., 20 mg/kg per day), and pair
      fed. After 14 days of d-amphetamine daily administration, superoxide dismutase
      (CuZnSOD and MnSOD), catalase, glutathione peroxidase (GPx), glutathione
      reductase (GRed), glutathione-S-transferase (GST), glutathione (GSH), cysteine
      and thiobarbituric acid reactive substances (TBARS) were measured in liver,
      kidney, and heart. Various serum and urine parameters were also analysed. d
      Amphetamine treatment induced an increase of liver GSH, as well as a decrease of
      cysteine and MnSOD levels in this organ. A small increase in serum transaminases
      was also observed in comparison to the pair-fed group. Hepatic levels of TBARS,
      GPx, GRed and CuZnSOD were found to be similar among the three groups of rats. d
      Amphetamine treatment induced an increase of kidney GST, GRed and catalase
      levels, and an elevation of N-acetyl-beta-D-glucosaminidase efflux to the urine,
      accompanied by a decrease in urinary creatinine, compared to the pair-fed group.
      In d-amphetamine treated animals, heart cysteine levels were significantly
      depleted when compared to the pair-fed group, but all three groups of rats were
      found to have similar heart antioxidant enzyme levels. These results indicate
      that repeated administration of d-amphetamine caused a certain degree of stress
      in liver and kidney, which was followed by adaptations of antioxidant defences.
      The mechanisms involved in d-amphetamine-induced toxicity may explain the
      different adaptations observed for the studied organs.

PMID- 10350189
TI  - Altered activity of heme biosynthesis pathway enzymes in individuals chronically
      exposed to arsenic in Mexico.
AB  - Our objective was to evaluate the activities of some enzymes of the heme
      biosynthesis pathway and their relationship with the profile of urinary porphyrin
      excretion in individuals exposed chronically to arsenic (As) via drinking water
      in Region Lagunera, Mexico. We selected 17 individuals from each village studied:
      Benito Juarez, which has current exposure to 0.3 mg As/l; Santa Ana, where
      individuals have been exposed for more than 35 years to 0.4 mg As/l, but due to
      changes in the water supply (in 1992) exposure was reduced to its current level
      (0.1 mg As/l), and Nazareno, with 0.014 mg As/l. Average arsenic concentrations
      in urine were 2058, 398, and 88 microg As/g creatinine, respectively. The more
      evident alterations in heme metabolism observed in the highly exposed individuals
      were: (1) small but significant increases in porphobilinogen deaminase (PBG-D)
      and uroporphyrinogen decarboxylase (URO-D) activities in peripheral blood
      erythrocytes; (2) increases in the urinary excretion of total porphyrins, mainly
      due to coproporphyrin III (COPROIII) and uroporphyrin III (UROIII); and (3)
      increases in the COPRO/URO and COPROIII/COPROI ratios. No significant changes
      were observed in uroporphyrinogen III synthetase (UROIII-S) activity. The direct
      relationships between enzyme activities and urinary porphyrins, suggest that the
      increased porphyrin excretion was related to PBG-D, whereas the increased URO-D
      activity would enhance coproporphyrin synthesis and excretion at the expense of
      uroporphyrin. None of the human studies available have reported the marked
      porphyric response and enzyme inhibition observed in rodents. In conclusion,
      chronic As exposure alters human heme metabolism; however the severity of the
      effects appears to depend on characteristics of exposure not yet fully
      characterized.

PMID- 10350190
TI  - Age-related changes in rat testicular oxidative stress parameters by
      hexachlorocyclohexane.
AB  - Effect of repeated oral administration of hexachlorocyclohexane (HCH; 10 and 20
      mg/kg body weight per day for 7, 15 and 30 days) on antioxidant defence system
      and lipid peroxidation (LPX) in the testis was compared between immature (15-day
      old) and mature (90-day-old) rats. In both age-groups of rats, the pesticide
      elicited a significant decrease in the activities of cytosolic superoxide
      dismutase (SOD; total and CN(-)-resistant) and catalase, and ascorbic acid
      content together with an increase in the levels of LPX (both in crude homogenate
      and subcellular fractions) and H2O2. Testicular glutathione peroxidase (GPx;
      total and non-selenium-dependent) activity was enhanced in both the age-groups of
      rats while the testicular glutathione content as well as glutathione reductase
      activity remained unaltered. HCH treatment resulted in a decrease of total
      epididymal sperm number with a higher incidence of dead and damaged spermatozoa,
      and sperms having anomalous head. Statistical analyses suggest that the
      alterations in the testicular antioxidant defence profile in the rat are not only
      dependent on the duration of pesticide treatment, but also influenced by age.

PMID- 10350191
TI  - Selective toxicity of ochratoxin A in primary cultures from different brain
      regions.
AB  - Ochratoxin A (OTA) is a mycotoxin produced by moulds from the Aspergillus and
      Penicillium genera. It is a natural contaminant of a wide variety of both human
      and animal foodstuffs. Via dietary intake, OTA passes into the blood of both
      humans and animals and accumulates in several organs, such as the kidney and the
      brain with selective toxicity in the ventral mesencephalon and in the cerebellum.
      In order to confirm the regional selectivity to OTA cytotoxicity in rat brain,
      investigations were designed to study the mechanism of the cytotoxicity of OTA in
      primary cultures of the above-mentioned structures (ventral mesencephalon and
      cerebellum), and to compare their sensitivity to the toxin. Protein and DNA
      synthases, lactate dehydrogenase (LDH) release and production of malondialdehyde
      (MDA) were assayed in astrocytes and neurones of the selected structures in the
      presence of OTA. After 48 h incubation, OTA (10-150 microM) induced an inhibition
      of protein and DNA syntheses in a concentration-dependent manner with a selective
      higher toxicity in the cells of the ventral mesencephalon [50% inhibitory
      concentrations (IC50) of protein and DNA syntheses were 14 +/- 2 microM for
      neurones and 40 +/- 5 microM for astrocytes] compared to the cerebellum values
      (24 +/- 7 microM for neurones and 69 +/- 9 microM for astrocytes). In parallel, a
      significant increase in levels of MDA and LDH release were noted. Altogether
      these results indicate that OTA is also a neurotoxic substance in addition to its
      well-documented nephrotoxicity and that the effects are likely to be restricted
      within particular structures of the brain.

PMID- 10350193
TI  - The interaction of sarin and soman with plasma proteins: the identification of a
      novel phosphonylation site.
AB  - Incubation of both sarin and soman with human plasma has shown that binding
      occurs to a tyrosine residue. Similar binding occurs when sarin and soman are
      incubated with human serum albumin. This binding may provide an important
      biological marker, which retains full structural information concerning the
      identity of the agent, in cases of allegations of chemical warfare use.

PMID- 10350192
TI  - Acute soman poisoning in primates neither pretreated nor receiving immediate
      therapy: value of gacyclidine (GK-11) in delayed medical support.
AB  - Organophosphorus (OP) nerve agents are still used as warfare and terrorism
      compounds. Classical delayed treatment of victims of organophosphate poisoning
      includes combined i.v. administration of a cholinesterase reactivator (an oxime),
      a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine
      anticonvulsant (diazepam). The objective of this study was to evaluate, in a
      realistic setting, the therapeutic benefit of administration of GK-11
      (gacyclidine), an antiglutamatergic compound, as a complement to the above
      therapy against organophosphate poisoning. Gacyclidine was injected (i.v.) in
      combination with atropine/diazepam/pralidoxime at man-equivalent doses after a 45
      or 30-min latency period to intoxicated primates (2 LD50). The effects of
      gacyclidine on the animals' survival, electroencephalographic (EEG) activity,
      signs of toxicity, recovery after challenge and central nervous system histology
      were examined. The present data demonstrated that atropine/diazepam/pralidoxime
      alone or combined with gacyclidine did not prevent signs of soman toxicity when
      treatment was delayed 45 min after poisoning. Atropine/diazepam/pralidoxime also
      did not control seizures or prevent neuropathology in primates exhibiting severe
      signs of poisoning when treatment was commenced 30 min after intoxication.
      However, in this latter case, EEG recordings revealed that additional treatment
      with gacyclidine was able to stop soman-induced seizures and restore normal EEG
      activity. This drug also totally prevented the neuropathology observed 5 weeks
      after soman exposure in animals treated with atropine/diazepam/pralidoxime alone.
      Overall, in the case of severe OP-poisoning, gacyclidine represents a promising
      adjuvant therapy to the currently available polymedication to ensure optimal
      management of organophosphate poisoning in man. This drug is presently being
      evaluated in a human clinical trial for a different neuroprotective indication.
      However, it should always be kept in mind that, in the case of severe OP
      poisoning, medical intervention must be conducted as early as possible.

PMID- 10350194
TI  - The significance of routine chest X-ray in acute stroke.
AB  - We retrospectively evaluated the significance of making a chest X-ray in the
      acute stage of a stroke. Forty percent of the chest X-rays were of suboptimal
      quality. Abnormal chest X-rays were, in part, the reason for consultation of
      chest specialists in 5%. A chest X-ray in patients with acute stroke should only
      be performed if there is clinical suspicion of pulmonary or cardiac pathology,
      not as a routine.

PMID- 10350195
TI  - Imaging the pyramidal tract in patients with brain tumors.
AB  - The clinical usefulness of diffusion-weighted magnetic resonance imaging (DWI) of
      the pyramidal tract was evaluated in patients with brain tumors. Five normal
      volunteers and seven patients with glioma (n = 4) or meningioma (n = 3) near the
      pyramidal tract underwent coronal echo planar DWI. Greyscale DWIs in each of the
      three orthogonal diffusion gradients were transformed into graduations, color
      coded as red, green or blue, respectively, and then composited to form a combined
      color image. The entire pyramidal tract was visualized on a single fiber mapping
      image by combining the upper half of the image slice including the primary motor
      cortex, the corona radiata and the internal capsule with the lower half of the
      image slice including the internal capsule, the cerebral peduncle and the ventral
      brain stem. Fiber mapping images demonstrated the pyramidal tract as a distinct
      band indicating nerve fiber integrity in all volunteers. The entire pyramidal
      tract from the primary motor subcortex to the ventral brain stem could be traced.
      Fiber mapping images showed the ipsilateral pyramidal tract as either
      discontinuous due to impaired anisotropy or compressed due to mass effect in
      patients with brain tumors. These findings corresponded well with the pre- and
      postoperative motor functions. Fiber mapping images are useful for evaluating the
      white matter neuronal tracts and can provide indications for determining surgical
      strategy.

PMID- 10350196
TI  - Early clinical signs and symptoms in occult spinal dysraphism: a retrospective
      case study of 47 patients.
AB  - Since occult spinal dysraphism can lead to irreversible neurological
      complications, early diagnosis and treatment are necessary. We retrospectively
      studied the presenting clinical signs and symptoms in all 47 cases of occult
      spinal dysraphism identified in two university hospitals in The Netherlands since
      1965. Dermal sinus had been diagnosed in 12, lipomyelomeningocele in nine, and
      diastematomyelia in eight patients. Thirty-three patients had symptoms due to
      tethering of the spinal cord, leading to a clinical suspicion of occult spinal
      dysraphism in only eight cases. Twenty-eight patients had cutaneous back lesions
      that led to further investigation in eight cases. Nineteen patients had a small
      backmass leading to further examination in 13 cases. Three patients with dermal
      sinus presented with meningitis caused by an unusual aetiological agent. This
      study stresses the importance of identification of neurological dysfunction due
      to tethered cord syndrome, cutaneous back lesions, a small backmass and
      meningitis caused by an unusual aetiological agent for the early diagnosis of
      occult spinal dysraphism.

PMID- 10350197
TI  - Cobalt-55 positron emission tomography in recurrent ischaemic stroke.
AB  - The present study investigates if Cobalt-55 (55Co) positron emission tomography
      (PET) allows us to distinguish and detect recent, recurrent strokes in patients
      who had already suffered a previous infarct in the same vascular territory.
      Fourteen patients with recurrent strokes underwent a 55Co PET scan of the brain.
      Recently infarcted areas, less than 2 months old, had a high 55Co uptake ratio,
      whereas infarcts of 6 months to 1 year had an uptake ratio comparable to normal
      brain tissue. In infarcts older than 2 years the 55Co uptake ratio was decreased
      compared to the control values. The evolution in 55Co uptake ratios with time can
      be explained by the dynamics of the inflammatory response within the infarct
      core. 55Co PET allows to demonstrate stroke recurrence and suggests that single
      photon emission tomography, using 57Co as the tracer, could be a more easy
      alternative to be used in routine neurological practice.

PMID- 10350198
TI  - Meningioma presenting as Tolosa-Hunt syndrome.
AB  - A 23-year-old woman was admitted with headache, nausea, vomiting and blurred
      vision on the left side. Neurological examination showed ptosis with a complete
      internal and external ophthalmoplegia and a red fullness around the left orbita.
      Computed tomographic scanning of the brain revealed no abnormalities. As she
      improved on high doses of steroids a diagnosis of Tolosa-Hunt syndrome (THS)
      seemed to be indicated. However, magnetic resonance imaging (MRI) showed a lesion
      with intermediate signal intensity in the left cavernous sinus. Craniotomy was
      performed when symptoms of THS recurred. Histopathological examination revealed a
      meningioma with a papillary aspect and some mitoses. This case illustrates that:
      (1) THS is still a diagnosis by exclusion; (2) MRI and histopathological
      examination are important if there is any doubt about the diagnosis; and (3) also
      when there is no doubt, improvement after steroid therapy may be a diagnostic
      pitfall. Therefore, not only MRI but also orbital phlebography and angiography
      should seriously be considered.

PMID- 10350199
TI  - Midbrain infarction: a rare presentation of cryptococcal meningitis.
AB  - A 20-year-old farmer who had headache and fever for 1 month, suddenly developed
      left hemiplegia, tremor in left arm and titubation followed by deep coma. Cranial
      CT scan revealed an infarction in right crus of midbrain. His CSF revealed 66
      mg/dl protein, 10 lymphocytes/mm3, and 70 mg/dl glucose. CSF was positive for
      cryptococcal antigen. He improved following i.v. amphotericin 0.5 mg/kg and
      fluconazole 200 mg daily, continued for 6 and 12 weeks respectively. Infarctions
      though rare in cryptococcal meningitis should be considered in patients with
      chronic meningitis with vasculitis.

PMID- 10350200
TI  - Solitary olfactory groove schwannoma: case report with review of the literature.
AB  - A 45-year-old man presented with headaches of 6 months' duration and generalized
      seizures in a cluster 2 days prior to admission. Examination revealed bilateral
      papilloedema and no focal deficits. CT scan showed an isodense enhancing mass
      lesion in the right frontobasal region with perilesional edema. Bifrontal
      craniotomy (with total excision of the tumor) revealed a tumor in the region of
      the right olfactory groove attached to the cribriform plate. Histopathological
      examination disclosed it to be a hyalinised schwannoma. Solitary schwannomas
      arising from the olfactory groove are extremely rare. Only six other cases have
      been reported so far. The presentation. CT scan findings and histogenesis of the
      tumor are discussed along with a review of the literature.

PMID- 10350201
TI  - Supplementary motor area aphasia: a case report.
AB  - A 72-year-old right-handed woman developed aphasia after a left supplementary
      motor area (SMA) infarct. She had a right hemiparesis, more paretic on the leg, a
      tendency to look to her left, and loss of spontaneity. Neuropsychological
      deficits were mainly in the initiation of language production. She did not speak
      spontaneously, but responded and articulated well to questions. She named objects
      correctly when presented, and could repeat words, phrases, and sentences well.
      She had a difficulty in reading aloud, writing spontaneously and writing to
      dictation, but preserved the ability to copy written material. This is another
      rare case of SMA aphasia.

PMID- 10350202
TI  - Intravascular lymphomatosis of the brain: a diagnostic problem.
AB  - Intravascular lymphomatosis (of B- or T-cell origin) is a rare
      lymphoproliferative disorder characterised by neoplastic proliferation of
      lymphoid cells within the lumen of capillaries, small veins and arteries with no
      or minimal involvement of the parenchyma. Its predilection sites are the skin and
      the brain. We studied a 44-year-old man who presented with a 2 year history of
      unexplained LDH elevation followed by a neurological syndrome without systemic
      involvement. Brain biopsy showed an intravascular lymphoma of the B-cell lineage.
      This report illustrates the diagnostic challenge of this rare disorder with a
      grim prognosis.

PMID- 10350204
TI  - Neurogenic ST depression in stroke.
AB  - BACKGROUND: Stroke is occasionally associated with ECG repolarization changes
      including ST depression. Recent evidence suggests a neurogenic contribution to
      these abnormalities in stroke patients. Animal studies implicate the insular
      cortex in cardiovascular control. We describe a patient with a left insular
      infarct and without cardiac or coronary artery disease, who developed ST
      depression indicating a neurogenic etiology. CASE DESCRIPTION: A 48 year-old
      female, with no risk factors for stroke, developed sudden expressive aphasia. MRI
      brain showed an infarct in the left insular cortex. Twenty-four hour Holter
      monitoring on the third day revealed transient ST depression more than 1.5 mm,
      which was not reproducible on subsequent monitoring. Transesophageal echo
      cardiography (TEE) was normal. She had no cardiac symptoms and serial ECGs,
      cardiac enzymes (CKMB) and adenosine thallium scan were normal. To-date, there
      had been no cardiac events like congestive heart failure or myocardial ischemia.
      CONCLUSION: These findings suggest neurogenic ST depression is related to the
      left insular infarct in view of the normal adenosine thallium scan, non
      reproducibility and evanescence of the ST segment changes and lack of associated
      cardiac symptoms. When neurogenic ST depression is combined with underlying
      coronary artery disease, it may adversely influence cardiac outcome after stroke.

PMID- 10350203
TI  - Dural arteriovenous malformation in the anterior cranial fossa.
AB  - Two cases of dural arteriovenous malformation (AVM) at the base of the anterior
      cranial fossa are described. In both cases an intracerebral hematoma following
      the rupture of the AVM was the first indication of the disease. In one case, the
      malformation was supplied both by the anterior ethmoidal artery and frontopolar
      artery draining into the superior sagittal sinus. In the second case, the right
      anterior ethmoidal artery with draining veins into the superior sagittal sinus
      and sphenoparietal sinus was the feeding vessel. Surgical evacuation of the
      hematoma and excision of the malformation was performed on both patients. The
      typical clinical signs and radiological findings are described. A review of the
      pertinent literature is given.

PMID- 10350205
TI  - Bilateral ptosis and changes in state of alertness in thalamic infarction.
AB  - Uni- or bilateral supranuclear ptosis is known to be caused by cerebral lesion.
      The exact anatomical cortical and subcortical basis is still undefined. We report
      a case of a patient developing bilateral ptosis with a left thalamic lesion. The
      bilateral ptosis was associated with transient changes in the state of alertness.
      We postulate that the thalamus, especially the anterior region, may have an
      influential role on the pathway from the cortex via the posterior branch of the
      internal capsule to the levator palpebrae superioris nuclei.

PMID- 10350206
TI  - Prothrombin gene variant (G20210A) in a patient with cerebral venous sinus
      thrombosis.
AB  - We describe a 33-year-old woman, who presented with lowered consciousness level
      and seizures, due to cerebral venous sinus thrombosis with venous haemorrhagic
      infarcts. The patient. who was taking oral contraceptives, appeared to be
      heterozygous for a prothrombin gene variant, which is due to a G-->A transition
      at position 20210. This 20210A prothrombin has recently been established as an
      important risk factor for cerebral venous sinus thrombosis, which interacts with
      oral contraceptive use.

PMID- 10350207
TI  - Cerebellar ataxia following whooping cough.
AB  - Bordetella pertussis (BP), the agent of whooping cough, has not been recognized
      so far as a cause of permanent cerebellar ataxia in human. We describe three
      patients who developed a disabling and permanent cerebellar syndrome soon after
      whooping cough. In two patients, diagnosis of BP infection was confirmed by
      culture of nasopharyngeal secretions. The infection occurred between the age of
      13 and 15 years, with neurological symptoms beginning after a delay varying from
      3 weeks to 3 months. In our three patients, the cerebellar syndrome was
      characterized by dysmetria of ocular saccades, scanning speech and ataxic gait.
      Brain MRI demonstrated a pancerebellar atrophy. The pathogenesis of this
      cerebellar degeneration is not established. Experimental studies have
      demonstrated that the cerebellum is particularly vulnerable to lymphocytosis
      promoting factor (LPF), one of the exotoxins from BP. The mechanism of this
      toxicity might be a marked increase in the cellular levels of 3',5'cyclic
      guanosine monophosphate (cGMP). Since whooping cough is a bacterial exotoxin
      mediated disease, this is the first report of a cerebellar syndrome triggered by
      a bacterial exotoxin.

PMID- 10350208
TI  - Vertebrobasilar artery territory infarction as an initial manifestation of
      systemic lupus erythematosus.
AB  - Cerebral infarction is a well-documented complication of systemic lupus
      erythematosus (SLE), that usually occurs several years after the diagnosis of
      SLE. To our knowledge, however, strokes associated with vertebrobasilar artery
      involvement were not reported to present as an initial manifestation of SLE. We
      report two patients, who presented with vertebrobasilar territory infarction as
      an initial manifestation of SLE. Patient 1 was a 16-year-old girl, who developed
      dysarthria and ataxia. MRI showed multiple infarcts in the pons, cerebellum and
      thalamus. Four-vessel cerebral angiography showed multifocal stenoses in the
      vertebral and basilar arteries with beaded appearance. Patient 2 was a 26-year
      old woman, who developed headache associated with dysarthria, dizziness and
      ataxia. MRI showed multiple infarcts in the cerebellum, medulla, pons, midbrain
      and thalamus. Cerebral angiography revealed occlusion of both vertebral arteries
      at the first cervical vertebral level with non-visualization of the basilar
      artery. Both patients were diagnosed as having SLE supported by laboratory
      results. Although rare, posterior circulation stroke can present as an initial
      manifestation of SLE, which may be attributed to vasculitis or dissection in the
      vertebral/basilar artery.

PMID- 10350209
TI  - Regulation of store-operated calcium entry: lessons from a polarized cell.

PMID- 10350210
TI  - Phosphorylation of p97(VCP) and p47 in vitro by p34cdc2 kinase.
AB  - The hexameric ATPase p97/yeast Cdc48p has been implicated in a number of cellular
      events that are regulated during mitosis, including homotypic membrane fusion,
      spindle pole body function, and ubiquitin-dependent protein degradation.
      p97/Cdc48p contains two conserved consensus p34cdc2 kinase phosphorylation sites
      within its second ATP binding domain. This domain is likely to play a role in
      stabilising the hexameric form of the protein. We therefore investigated whether
      p97 could be phosphorylated by p34cdc2 kinase in vitro, and whether
      phosphorylation might influence the oligomeric status of p97. Monomeric, but not
      hexameric, p97 was phosphorylated by p34cdc2 kinase, as was the p97-associated
      protein p47. However, phosphorylation by p34cdc2 kinase did not impair subsequent
      re-hexamerisation of p97, implying that the phosphorylated residue(s) are not
      critical for interaction between p97 monomers. Moreover, p97 within both
      interphase and mitotic cytosols was almost exclusively hexameric, suggesting that
      the activity of p97 is not regulated during mitosis by influencing the extent of
      oligomerisation.

PMID- 10350211
TI  - Characterization of the activity of a plastid-targeted green fluorescent protein
      in Arabidopsis.
AB  - In Arabidopsis thaliana the PALE CRESS (PAC) gene product is required for both
      chloroplast and cell differentiation. Transgenic Arabidopsis plants expressing a
      translational fusion of the N-terminal part of the PAC protein harboring the
      complete plastid-targeting sequence and the green fluorescent protein (GFP)
      exhibit high GFP fluorescence. Detailed analyses based on confocal imaging of
      various tissues and cell types revealed that the PAC-GFP fusion protein
      accumulates in chloroplasts of mature stomatal guard cells. The GFP fluorescence
      within the guard cell chloroplasts is not evenly distributed and appears to be
      concentrated in suborganellar regions. GFP localization studies demonstrate that
      thin tubular projections emanating from chloroplasts and etioplasts often connect
      the organelles with each other. Furthermore, imaging of non-green and etiolated
      tissue further revealed that GFP fluorescence is present in proplastids,
      etioplasts, chromoplasts, and amyloplasts. Even photobleaching of carotenoid-free
      plastids does not affect PAC-GFP accumulation in the organelles of the guard
      cells indicating that the protein translocation machinery is functional in all
      types of plastids. The specific accumulation of GFP in guard cell chloroplasts,
      their tubular connections, the translocation of the precursor polypeptide into
      the different types of organelles, as well as the use of a plastid-targeted GFP
      protein as a versatile marker is discussed in the context of previously described
      observations.

PMID- 10350212
TI  - Decrease in mitochondrial DNA and concurrent increase in plastid DNA in
      generative cells of Pharbitis nil during pollen development.
AB  - The amount of organellar DNA in a generative cell of Pharbitis nil was observed
      when squashed pollen grains collected on the day of flowering were stained with
      the DNA-specific fluorochrome 4',6-diamidino-2-phenylindole (DAPI). Using both
      DAPI-fluorescence microscopy and electron microscopy, observation of the same
      thin section of Technovit 7100 resin-embedded material revealed that all of the
      organellar DNA in mature generative cells is plastid DNA, and there is no
      mitochondrial DNA. During pollen development, we observed organellar DNA in
      fluorescence microscopic images using double-staining with DAPI and 3,3'
      dihexyloxacarbocyanine iodide (DiOC6) and quantified the DNA using a video
      intensified microscope photon counting system (VIMPCS). In the vegetative cells,
      the amounts of both mitochondrial and plastid DNA progressively decreased and had
      disappeared by 2 days before flowering. In the generative cells, mitochondrial
      DNA disappeared sooner than in the vegetative cells, indicating a more active
      mechanism for the decrease in mitochondrial DNA in the generative cells. In
      contrast, plastid DNA in the generative cells increased markedly. The DNA content
      per plastid was at a minimum value (corresponding to one copy of the plastid
      genome) 7 days before flowering, but it increased to a maximum value
      (corresponding to over 10 copies of the plastid genome) 2 days before flowering.
      Similar results were also obtained with immunogold electron microscopy using an
      anti-DNA antibody. These results suggest that the DNA content of mitochondria and
      plastids in P. nil is controlled independently during pollen development.

PMID- 10350213
TI  - Rac-GTPase, osteoclast cytoskeleton and bone resorption.
AB  - The members of the Rho-GTPase subfamily, Rac1 and Rac2, are intimately involved
      in the organization of the cytoskeleton, and the p21-activated kinases or PAKs
      are targets of these proteins. Rac1 and Rac2 are also essential components of
      NADPH oxidase, the enzyme responsible for generating free radicals. The
      cytoskeleton modulates the adhesion of osteoclasts to bone and its subsequent
      resorption. These cells contain NADPH diaphorase activity, and free radicals
      influence bone resorption. The influence of Rac1, Rac2 and PAK1 on the
      cytoskeleton, resorbing activity and NADPH diaphorase activity of disaggregated
      rat osteoclasts was investigated by permeabilisation with saponin and introducing
      specific anti-Rac1, anti-Rac2 or anti-PAK1 antibodies. Rhodamine-phalloidin stain
      was used to identify actin in osteoclasts cultured on plastic slides, and the
      bone-slice method was used to measure resorption. Saponin permeabilisation did
      not affect the cytoskeletal organization or bone resorption. Anti-Rac antibodies
      caused dose- and time-dependent cytoskeletal changes. The osteoclasts rounded up
      and developed retraction fibers; actin rings were disrupted and large actin dots
      were seen at the periphery of the cells. Osteoclast resorptive activity was
      depressed after incubation with the antibodies. The total area resorbed by
      treated cells and the mean pit area were smaller than those of controls. Anti
      PAK1 antibody caused similar changes. None of the antibodies altered the NADPH
      diaphorase activity. Thus, Rac-GTPases are present in rat osteoclasts and are
      involved in the organization of the actin cytoskeleton and in resorptive
      activity. These effects may be mediated by PAK1 kinase, but do not influence
      osteoclast NADPH diaphorase activity.

PMID- 10350214
TI  - Serum albumin as a potential carrier for the apocrine secretion of proteins in
      the rat coagulating gland.
AB  - A protein of 66k was purified to homogeneity from the total secretion of rat
      coagulating gland. Its close structural relationship to serum albumin was
      demonstrated by N-terminal amino acid sequence analysis, proteolytic
      fingerprinting and Western blotting studies using polyclonal antibodies raised
      against the 66k protein and rat serum albumin. Immunofluorescence staining showed
      that the 66k protein was localised in the cytoplasm of coagulating gland
      epithelial cells from which it is released via apocrine blebs. Performing
      immunoelectron microscopy, the 66k protein was by no means detectable in the
      endoplasmic reticulum and the Golgi apparatus. Reverse transcription-PCR,
      Northern blotting studies and in situ hybridisation experiments demonstrated that
      mRNA of albumin is not expressed by coagulating gland epithelial cells.
      Therefore, intravascular albumin should be transferred into the epithelial cells
      of the rat coagulating gland followed by secretion via aposomes. Furthermore,
      overlay blots proved that the 66k protein binds to the apocrine proteins carbonic
      anhydrase II and secretory transglutaminase and vice versa. In contrast, no
      binding was evident to the merocrine 115k protein and to cytoplasmic resident
      proteins e.g. lactate dehydrogenase. These findings point to the assumption that
      serum albumin taken up from extracellular sources could function as a selective
      carrier for cytoplasmic proteins destined for apocrine secretion.

PMID- 10350216
TI  - Interactions between coiled-coil proteins: Drosophila lamin Dm0 binds to the
      bicaudal-D protein.
AB  - In a yeast two-hybrid screen we identified an interaction between Drosophila
      lamin Dm0, a structural nuclear protein, and BICD, a protein involved in oocyte
      development. The interaction can be reconstituted in vitro and takes place
      between segments of both proteins predicted to form coiled coils. The affinity
      for lamin Dm0 of the minimal binding site on BICD is modulated in a complex
      fashion by other BICD segments. A point mutation, F684I, that causes the
      dominant, bicaudal, Bic-D phenotype inhibits lamin binding in the context of the
      minimal lamin-binding site, but not in a larger BICD fragment. The minimal lamin
      binding site of BICD binds to a few other coiled-coil proteins, but binding to
      these proteins is not influenced by the F684I point mutation, suggesting that the
      interaction with lamin may play a role in Bic-D function. Our structural studies
      demonstrated that BICD is 60-70% alpha-helical, is a dimer, and consists of two
      parts: a thin rod-shaped part of about 32 nm, and a thicker rod-shaped part of
      about 26 nm. Likely, the thinner rod-shaped part of full-length BICD consists of
      the N-terminal half of the protein, and the lamin-binding site is located within
      the thicker rod-shaped part.

PMID- 10350215
TI  - Cytoplasmic dynein and dynactin as likely candidates for microtubule-dependent
      apical targeting of pancreatic zymogen granules.
AB  - The critical role of microtubules in vectorial delivery of post-Golgi carrier
      vesicles to the apical cell surface has been established for various polarized
      epithelial cell types. In the present study we used secretory granules of the rat
      and chicken pancreas, termed zymogen granules, as model system for apically bound
      post-Golgi carrier vesicles that underlie the regulated exocytotic pathway. We
      found that targeting of zymogen granules to the apical cell surface requires an
      intact microtubule system which contains its colchicine-resistant organizing
      center and, thus, the microtubular minus ends close to the apical membrane
      domain. Purified zymogen granules and their membranes were found to be associated
      with cytoplasmic dynein intermediate and heavy chain and to contain the major
      components of the dynein activator complex, dynactin, i.e. p150Glued, p62, p50,
      Arp1, and beta-actin. Kinesin heavy chain and the kinesin receptor, 160 kD
      kinectin, were not detected as components of zymogen granules. Immunofluorescence
      staining showed a zymogen granule-like distribution for dynein and dynactin
      (p150Glued, p62, p50, Arpl) in the apical cytoplasm, whereas kinesin and kinectin
      were largely concentrated in the basal half of the cells in a pattern similar to
      the distribution of calreticulin, a component of the endoplasmic reticulum.
      Secretory granules of non-polarized chromaffin cells of the bovine adrenal
      medulla, that are assumed to underlie microtubular plus end targeting from the
      Golgi apparatus to the cell periphery, were not found to be associated with
      dynein or dynactin. To our knowledge, this is the first demonstration of major
      components of the dynein-dynactin complex associated with the membrane of a
      biochemically and functionally well-defined organelle which is considered to
      underlie a vectorial minus end-driven microtubular transport critically involved
      in precise delivery of digestive enzymes to the apically located acinar lumen.

PMID- 10350217
TI  - Immunogold EM reveals a close association of plectin and the desmin cytoskeleton
      in human skeletal muscle.
AB  - Plectin is a multifunctional cytoskeletal linker protein with an intermediate
      filament-binding site and sequence elements with high homology to actin-binding
      domains. Mutations of the human plectin gene as well as the targeted inactivation
      of its murine analog cause a generalized blistering skin disorder and muscular
      dystrophy, thus implying its essential role in cells that are exposed to
      mechanical stress. In the present study we report the characterization of two new
      domain-specific plectin antibodies as well as ultrastructural localization of
      plectin in normal human skeletal muscle. Using immunogold electron microscopy, we
      localized plectin at three prominent sites: 1) Plectin is found at regularly
      spaced intervals along the cytoplasmic face of the plasma membrane. 2) It is
      distinctly localized at filamentous bridges between Z-lines of peripheral
      myofibrils and the sarcolemma and 3) at structures forming the intermyofibrillar
      scaffold. At the latter two locations, plectin and desmin were found to
      colocalize. Our ultrastructural analysis suggests that plectin may have a central
      role in the structural and functional organization of the intermediate filament
      cytoskeleton in mature human skeletal muscle.

PMID- 10350219
TI  - Recruitment of participants in the childhood Asthma Management Program (CAMP). I.
      Description of methods: Childhood Asthma Management Program Research Group.
AB  - The Childhood Asthma Management Program (CAMP), a multicenter clinical trial
      sponsored by the Division of Lung Diseases of the National Heart, Lung, and Blood
      Institute (NHLBI), is the largest outcome study of mild to moderate asthma in
      children to be undertaken, with eight clinical centers in the United States and
      Canada participating. The initial recruitment goal was 960 children within an 18
      month recruitment period. Recruitment was extended to 23 months, with 1041
      children randomized from late December, 1993, to early September, 1995. In this
      time interval each of the eight centers met the recruitment goal of 120 using a
      variety of self-selected recruitment strategies. The goal for minority recruiting
      was 33%, or 320 of the planned 960 children to be recruited. CAMP achieved the
      overall goal for the number of minorities, with 330 patients. Three centers
      recruited at or above the expected rate from the beginning. The other five
      centers had significant delays in recruitment. Examination of the recruitment
      experiences of the centers with and without delays did not indicate any single
      recruitment strategy that was certain to be successful. The most commonly cited
      factors for success were a cohesive staff, endorsement of participation by the
      child's primary care provider, and ability of the staff to be flexible and honest
      in assessing progress and the value of recruiting methods being used.

PMID- 10350220
TI  - Asthma hospitalization rates and socioeconomic status in New York State (1987
      1993).
AB  - This study examined the geographic distribution of asthma hospitalizations in New
      York State (NYS) and its association with socioeconomic status. Statewide asthma
      hospitalization data (1987-1993) were merged with 1990 census data by residential
      zip code. The asthma hospitalization rate increased in NYS from 1987 (2.54 per
      1000) through 1993 (2.87 per 1000) and the increase is largely attributable to
      increases for children 4 years old and younger. The risk factors for asthma
      admission varied in different areas. However, rates of hospitalization because of
      asthma were generally higher in the zip codes areas with higher proportions of
      poverty, unemployment, poorly educated residents, African-Americans, and
      Hispanics.

PMID- 10350218
TI  - How important is patient recruitment in performing clinical trials?

PMID- 10350221
TI  - Tourette's syndrome mimicking asthma.
AB  - Tourette's syndrome is a neurological disorder consisting of chronic motor tics
      and involuntary vocalizations. Some of these vocalizations include coughing,
      grunting, and wheezing. We report two adolescents with a history of chronic
      coughing who presented for further evaluation of previously diagnosed asthma. A
      careful history suggested that Tourette's syndrome might be responsible for the
      patients' symptoms. Neurology evaluation confirmed the correct diagnosis of
      Tourette's syndrome for both patients. Treatment specific for this disease led to
      ablation of all symptoms. A history of repetitive coughing in adolescents may be
      the presenting symptom of Tourette's syndrome, thereby mimicking cough-equivalent
      asthma.

PMID- 10350222
TI  - Cigarette smoking and asthma symptom severity among adult asthmatics.
AB  - Contrary to what would be expected, smoking habits of asthmatics do not differ
      from those of the general population: approximately 30% of asthmatic patients
      smoke cigarettes. Although the relationship between smoking and the incidence of
      asthma has been well explored, little attention has been paid to documenting the
      relationship between smoking and asthma symptoms among adults with asthma. The
      objective of this study was to assess the association of cigarette smoking with
      asthma symptom severity. The present report is of a cross-sectional study of 225
      asthmatics, aged 20-54 years, from six general practice clinics in East Anglia,
      U.K. The outcome measures are overall asthma symptom score (range 6.3-28) and
      three asthma symptom domains: respiratory (range 1.3-8), daily activity
      interference (range 2-8), and physical activity interference (range 3-12),
      generated from the sum of ordinal responses to questions on asthma symptom
      severity. Of the sample, 27.0% were current and 22.1% were former smokers.
      Current smokers more frequently had bothersome asthma symptoms than nonsmokers in
      both unadjusted analyses and analyses controlling for age, gender, recent visits
      to the general practitioner for asthma, and asthma medication use (p = 0.06).
      Respiratory symptoms (p = 0.03) and symptoms that affect daily activities (p =
      0.03) were more strongly associated with smoking than symptoms that affect
      physical activities (p = 0.62). Our data suggest that smoking hastens asthma
      progression or affects disease control. Increased frequency of symptoms may be an
      indicator for potential morbidity among asthmatics, especially those who smoke
      cigarettes. The hazards associated with smoking among asthmatics need to be more
      clearly emphasized by physicians and public health officials in order to convince
      people with asthma who smoke to stop.

PMID- 10350223
TI  - Effect of zafirlukast on cough reflex sensitivity in asthmatics.
AB  - In patients with asthma, increased sensitivity of airway sensory nerves may be
      involved in producing bronchospasm and cough. To evaluate the effect of a
      leukotriene-modifying agent on cough reflex sensitivity, we measured the cough
      response to inhaled capsaicin before and after a 1 4-day course of therapy with
      zafirlukast, a cysteinyl leukotriene receptor antagonist, in a group of stable
      asthmatics. The concentration of capsaicin inducing two or more (C2) and five or
      more (C5) coughs was not altered by zafirlukast, even in those subjects
      demonstrating a significant change (increment or decrement) in forced expiratory
      volume in 1 sec (FEV1). These findings support previous evidence that cough and
      bronchoconstriction are modulated by distinct neural pathways.

PMID- 10350224
TI  - An investigation of the medical care utilization of children with severe asthma
      according to their type of insurance.
AB  - A comparison of the medical care utilization of children with severe asthma
      according to insurance type was performed. Subjects were grouped by which type of
      insurance they had: capitated, fee for service, or Medicaid insurance. Medical
      records were coded into utilization categories, by presenting complaint, sick- or
      well-child visit, and if a generalist or specialist provided care during the
      visit. The Medicaid group had less specialist, sick-child care than the groups
      with capitated or fee for service insurance. The Medicaid group also had more
      emergency room visits than the other two groups. The three groups had a similar
      amount of total physician/clinic visits. Even though similar care was shown to be
      available for those with Medicaid insurance, this low resource group often uses
      expensive emergency room care.

PMID- 10350225
TI  - The prevalence of allergic diseases and atopy in Ankara, Turkey: a two-step
      population-based epidemiological study.
AB  - To assess the prevalence of allergic diseases and atopy in adults, a two-step
      population-based epidemiological study was undertaken in Ankara, the capital city
      of Turkey. In step 1, a screening questionnaire adapted from the European
      Community Respiratory Health Survey (ECRHS) was applied in a cross-sectional
      manner. In step 2, a nested case-controlled design study was conducted and
      subjects were evaluated in the clinical setting for history, physical
      examination, skin prick tests (SPTs), and serum total IgE and phadiotop
      measurements. According to the results, self-reported current asthma prevalence
      in step 1 was lower compared with that in step 2 (3% vs. 7%, p < 0.05). The
      prevalences of food and drug allergy were 6.2% and 3.9%, respectively, in step 1,
      but were not demonstrated in any of the subjects in step 2. The overall
      prevalence of atopy was 25% after step 2 evaluation. In conclusion, allergic
      disorders are not uncommon in our adult population; however, sole application of
      a screening questionnaire appeared to be ineffective in revealing the accurate
      figures of asthma, and food or drug allergy.

PMID- 10350226
TI  - Peak expiratory flow associated with change in positioning of the instrument:
      comparison of five peak flow meters.
AB  - To determine if peak expiratory flow (PEF) is altered by incorrect positioning of
      five peak flow meters (PFMs), 16 adults with clinically stable persistent asthma
      were evaluated. After inhaling two puffs of albuterol via AeroChamber, patients
      were instructed over the next 15 min in correct PFM technique and two incorrect
      techniques (PFM angled 20 degrees left in mouth and PFM pointed 20 degrees
      downward as patient leaned forward with maximal exhalation). Order of use of five
      peak flow meters and correct vs. incorrect techniques were random. Although mean
      values generally indicated no clinically meaningful effect of positioning of the
      PFM, inaccurate PEFs were recorded for several subjects with both incorrect
      methods and all PFMs.

PMID- 10350227
TI  - A successful effort to improve asthma care outcome in an inner-city emergency
      department.
AB  - The purpose of this study was to improve asthma care and outcome in an inner-city
      emergency department. Consecutive adult patients (19,802) presenting with the
      diagnosis of acute asthma exacerbation to an inner-city municipal hospital
      emergency department, between July 1991 and December 1993, were prospectively
      evaluated. These patients were compared to a historical control group of 7923
      consecutive asthma emergency department patients presenting in the year prior to
      our intervention. An asthma treatment guideline was implemented through a
      continuous quality improvement process. Asthma relapse rate and admission rate
      were obtained before and after the guidelines were instituted. Data after
      interventions were also prospectively compared to asthma outcomes at all other
      New York City municipal hospital emergency departments. After intervention, mean
      monthly asthma relapse rates showed a significant reduction from 12.18% to 7.83%
      (p < 0.001). A similar decrease was also noted in the monthly asthma admission
      rate, from 4.85 to 3.90 per 100 emergency department visits (p < 0.05). Asthma
      treatment guidelines along with continuous quality improvement techniques can
      significantly improve the outcome of inner-city emergency department asthma
      patients.

PMID- 10350228
TI  - High-intensity exercise and muscle glycogen availability in humans.
AB  - This study investigated the effects of muscle glycogen availability on
      performance and selected physiological and metabolic responses during high
      intensity intermittent exercise. Seven male subjects completed a regimen of
      exercise and dietary intake (48 h) to either lower and keep low (LOW-CHO) or
      lower and then increase (HIGH-CHO) muscle glycogen stores, on two separate
      occasions at least a week apart. On each occasion the subjects completed a short
      term (<10 min) and prolonged (>30 min) intermittent exercise (IEX) protocol, 24 h
      apart, which consisted of 6-s bouts of high-intensity exercise performed at 30-s
      intervals on a cycle ergometer. Glycogen concentration (mean +/- SEM) in m.
      vastus lateralis before both IEx(short) and IEx(long) was significantly lower
      following LOW-CHO [180 (14), 181 (17) mmol kg (dw)(-1)] compared with HIGH-CHO
      [397 (35), 540 (25) mmol kg (dw)(-1)]. In both IEx(short) and IEx(long),
      significantly less work was performed following LOW-CHO compared with HIGH-CHO.
      In IEx(long), the number of exercise bouts that could be completed at a pre
      determined target exercise intensity increased by 265% from 111 (14) following
      LOW-CHO to 294 (29) following HIGH-CHO (P < 0.05). At the point of fatigue in
      IEx(long), glycogen concentration was significantly lower with the LOW-CHO
      compared with HIGH-CHO [58 (25) vs. 181 (46) mmol kg (dw)(-1), respectively]. The
      plasma concentrations of adrenaline and nor-adrenaline (in IEx(short) and
      IEx(long)), and FFAand glycerol (in IEx(long)), increased several-fold above
      resting values with both experimental conditions. Oxygen uptake during the
      exercise periods in IEx(long), approached 70% of Vo2max. These results suggest
      that muscle glycogen availability can affect performance during both short-term
      and more prolonged high-intensity intermittent exercise and that with repeated
      exercise periods as short as 6 s, there can be a relatively high aerobic
      contribution.

PMID- 10350229
TI  - Swelling of sarcoplasmic reticulum in the periphery of muscle fibres after
      isometric contractions in rat semimembranosus lateralis muscle.
AB  - The decline in isometric force, swelling of sarcoplasmic reticulum and loss of
      desmin was measured in semimembranosus lateralis muscle of male Wistar rats
      immediately after a short series of brief (500 ms) maximal isometric
      contractions. For the active muscle, the series ended below (protocol A) and just
      over muscle optimum length (protocol AA). In one protocol, the muscle remained
      passive and was extended to lengths just over muscle optimum length (protocol P).
      After all experimental protocols, no loss of desmin was observed and sarcomere
      appearance was normal. Protocol A produced swelling (87%) of the sarcoplasmic
      reticulum but no decline in isometric force. Protocol AA produced larger swelling
      (147%) of the sarcoplasmic reticulum and an isometric force decline (<49%) at
      short muscle lengths. Swelling of sarcoplasmic reticulum was observed mainly in
      the periphery of muscle fibres. Protocol P did not result in swelling of the
      sarcoplasmic reticulum and isometric force decline. It is concluded that swelling
      of the sarcoplasmic reticulum in the periphery of muscle fibres after brief
      maximal isometric contractions is associated with muscle force and not muscle
      length.

PMID- 10350230
TI  - Loss of potassium from muscle during moderate exercise in humans: a result of
      insufficient activation of the Na+-K+-pump?
AB  - In this study, we have investigated whether the muscle net potassium (K+) loss,
      observed during two-legged intermittent static knee-extensions at 30% MVC (n =
      9), is caused by an insufficient activation of the Na+-K+-pumps. Furthermore, we
      have investigated whether the changes in the K+ homeostasis can be causally
      related to fatigue. K+ loss was calculated from the arterio-venous concentration
      difference and plasma flow. In three subjects, femoral venous K+ concentration
      was measured continuously with a K+ selective electrode. Na+-K+-pump activity was
      estimated from the rate of removal of K+ from the blood during 30-s pauses
      inserted into the exercise protocol. A large net K+ loss took place during the
      first minutes of exercise, but diminished quickly and disappeared after 20 min.
      An increasing net K+ loss reappeared after 30 min. Only 10% of the lost K+ had
      been regained after the 20-min recovery. A lag in the activation of the Na+-K+
      pumps may explain the K+ loss at the beginning of exercise, but gradual pump
      activation prevented a net K+ loss after 20 min of exercise. The reappearance of
      the net K+ loss in the later stage of exercise and the subsequent slow recovery
      of intracellular K+ seemed to be caused by an insufficient further activation of
      the pumps, rather than by the capacity of the pumps being surpassed. Fatigue was
      not related to the accumulation of K+ in the interstitium. However, during
      exercise, the decrease in intracellular K+ content was linearly related to the
      fall of maximal force. We conclude that during repeated isometric contractions,
      insufficient activation of the Na+-K+-pumps causes a continuous muscle K+ loss
      which was associated with fatigue.

PMID- 10350231
TI  - Reflection coefficient for albumin and capillary fluid permeability in cat calf
      muscle after traumatic injury.
AB  - Surgery and traumatic injury are often followed by tissue oedema and a low plasma
      albumin concentration, indicating leakage of fluid and proteins from the
      intravascular to the interstitial space. Transcapillary leakage can be referred
      to as an increase in capillary hydraulic conductance and/or a decrease in the
      reflection coefficient for plasma macromolecules. This study evaluates if time
      dependent variations in the reflection coefficient for albumin and capillary
      hydraulic conductance can be confirmed experimentally following a surgical trauma
      using a blood perfused cat skeletal muscle in vivo preparation. The hydraulic
      conductance was estimated by the capillary filtration coefficient, and was used
      to evaluate variation in capillary fluid permeability. According to the Starling
      fluid equilibrium, the ratio between the reflection coefficients for albumin on
      two occasions can be calculated from the maximum osmotic absorption rates induced
      by a fixed intravenous bolus infusion of albumin (0.5 g kg(-1)) and from the
      capillary filtration coefficients. We found a decrease in the reflection
      coefficient of about 30% up to 10 h after the preparation. The capillary
      filtration coefficient showed no significant change over time, but decreased by 5
      10% following the albumin infusion. We conclude that: (1) the reflection
      coefficient for albumin is reduced after a trauma, whereas the effects on the
      capillary fluid permeability are small, (2) albumin in plasma contributes to
      preserve normal capillary fluid permeability and, (3) the model seems to be
      useful for evaluation of relative variations in the reflection coefficient for
      albumin.

PMID- 10350232
TI  - The influence of transmural pressure and longitudinal stretch on K+- and Ca2+
      induced coronary artery constriction.
AB  - The aim of the study was to investigate transmural pressure and longitudinal
      stretch modulation of K+- and Ca2+-induced constriction of porcine conductance
      coronary arteries. In a pressure myograph set-up, left anterior descendent
      coronary arteries from 70 to 90 kg pigs were investigated at pressures from 20 to
      120 mmHg. Longitudinal extension ratio (lambda = L/L0(-1), where L0 is the in
      situ length and L the examination length) varied between 0.9 and 1.1. Two
      protocols were carried out: (1) Outer diameter response to maximal depolarization
      by K+ 125 mM at 20-120 mmHg and lambda at 0.90-1.10. (2) Concentration-response
      curves with K+ (4.7-125 mM) and Ca2+ (0.05-4.0 mM) at four combinations of P and
      lambda (P = 100 mmHg, lambda = 0.9; P = 100 mmHg, lambda = 1.1; P = 40 mmHg,
      lambda = 0.9; p = 40 mmHg, lambda = 1.1). RESULTS: Endothelial function was
      preserved. A slight (<5% diameter reduction) basal tone and no myogenic response
      was found. Protocol 1: the constriction to K+ 125 mM was maximal in a wide
      pressure range from 40 to 120 mmHg. Despite the fact that K+-induced diameter
      changes were statistically insignificant between 40 and 120 mmHg, there was a
      linear trend towards smaller diameter changes in this pressure range (r = -0.54,
      P < 0.01). Stretch influenced constriction at 20 mmHg because lambda = 0.90 and
      0.95 resulted in smaller diameter-reductions than lambda = 1.00-1.10 (P < 0.05
      for all). Contrastingly, at 120 mmHg the constriction at lambda = 1.10 was
      smaller than the responses at lambda = 0.90-1.05 (P < 0.05 for all). Protocol 2:
      EC50 and EC10 values for K+- and Ca2+ were generally higher (more sensitive) at
      40 compared with 100 mmHg. Stretch was of no significant importance for EC50 and
      EC10 at 40 and 100 mmHg. It is concluded that porcine coronary artery
      constriction to non-metabolized agonists is maximal at 40 mmHg with a trend
      towards smaller diameter changes with higher pressures. Longitudinal stretch
      affects responsiveness at pressure extremes.

PMID- 10350233
TI  - Cardiodepressant mediators are released after myocardial ischaemia: modulation by
      catecholamines and adenosine.
AB  - The interaction of recently characterized cardiodepressant mediators with
      catecholamines and adenosine after myocardial ischaemia was investigated using a
      model of sequential perfusion of two isolated guinea-pig hearts. Sequential
      perfusion was initiated after 10, 20, and 30 min (group I, II, and III) of global
      ischaemia in the first heart. At the onset of sequential perfusion LVdP/dtmax and
      min of Heart II decreased by 46 and 44% in group I, by 28 and 34% in group II,
      and increased by 60 and 24% in group III. Infusion of the beta1-receptor
      antagonist metoprolol (2.8 micromol L(-1)) into Heart II did not modulate
      contractile changes after 10 min of ischaemia in Heart I, prevented the
      attenuation of the cardiodepressant effect after 20 min of ischaemia, and
      completely reversed the positive inotropic effect after 30 min of ischaemia. The
      A1- and A2-receptor antagonists DPCPX (2 micromol L(-1)) and DMPX (20 micromol L(
      1)) enhanced the positive inotropic and lusitropic effects in Heart II
      (LVdP/dtmax +154%, LVdP/dtmin +71%) during sequential perfusion after 30 min of
      ischaemia in Heart I. It is concluded that the effects of cardiodepressant
      mediators released after myocardial ischaemia are counteracted by a time
      dependent release of catecholamines. Endogenous cardiac adenosine, in turn,
      attenuates the modulatory effects of catecholamines.

PMID- 10350234
TI  - The Kety-Schmidt technique for repeated measurements of global cerebral blood
      flow and metabolism in the conscious rat.
AB  - Cerebral activation will increase cerebral blood flow (CBF) and cerebral glucose
      uptake (CMRglc) more than it increases cerebral uptake of oxygen (CMR(O2)). To
      study this phenomenon, we present an application of the Kety-Schmidt technique
      that enables repetitive simultaneous determination of CBF, CMR(O2), CMRglc and
      CMRlac on awake, non-stressed animals. After constant intravenous infusion with
      133Xenon, tracer infusion is terminated, and systemic arterial blood and cerebral
      venous blood are continuously withdrawn for 9 min. In this paper, we evaluate if
      the assumptions applied with the Kety-Schmidt technique are fulfilled with our
      application of the method. When measured twice in the same animal, the intra
      individual variation for CBF, CMR(O2), and CMRglc were 10% (SD: 25%), 8% (SD:
      25%), and 9% (SD: 28%), respectively. In the awake rat the values obtained for
      CBF, CMR(O2) and CMRglc were 106 mL [100 g](-1) min(-1), 374 micromole [100 g](
      1) min(-1) and 66 micromole [100 g](-1) min(-1), respectively. The glucose taken
      up by the brain during wakefulness was fully accounted for by oxidation and
      cerebral lactate efflux. Anaesthesia with pentobarbital induced a uniform
      reduction of cerebral blood flow and metabolism by approximately 40%. During
      halothane anaesthesia CBF and CMRglc increased by approximately 50%, while
      CMR(O2) was unchanged.

PMID- 10350235
TI  - The protein tyrosine kinase pathway is not involved in the regulation of K+
      transport across the rat colon.
AB  - The protein tyrosine kinase inhibitor, genistein, is known to activate the cystic
      fibrosis transmembrane regulator (CFTR) Cl- channel and to inhibit K+ currents
      across the rat colonic epithelium. The aim of the present study is to answer the
      question whether these effects are involved in the regulation of transepithelial
      K+ transport. Therefore, the action of genistein on K+ transport in rat proximal
      and distal colon was studied by measuring unidirectional fluxes, uptake and
      efflux of Rb+ in mucosa-submucosa preparations. All effects of genistein (5 x 10(
      5) mol L(-1)) were tested in the presence of a low concentration of forskolin (2
      x 10(-7) mol L(-1)), because prestimulation of the cAMP pathway has been shown to
      be a prerequisite for a secretory action of genistein. Forskolin caused an
      increase in the serosa-to-mucosa flux of Rb+ (J(Rb)sm) thereby stimulating net K+
      secretion in the proximal and distal colon. None of these effects was further
      enhanced after administration of genistein. Neither mucosal uptake of Rb+,
      representing mainly the activity of the H+-K+-ATPase in the distal colon, nor
      serosal Rb+ uptake, representing, e.g. the activity of the Na+-K+-2Cl-
      cotransporter, were affected by genistein. Also the efflux of Rb+ across the
      apical or the basolateral membrane, an indicator for the apical and basolateral
      K+ conductance, was unchanged in the presence of genistein. These results
      demonstrate that the K+ channels inhibited by genistein are not involved in
      transepithelial K+ transport.

PMID- 10350236
TI  - Time course of the inflammatory response to histamine and allergen skin prick
      test in guinea-pigs.
AB  - Plasma exudation and vasodilatation are key microvascular features of acute
      inflammation. Exudation and vasodilatation responses in the weal area after skin
      prick testing with histamine are essentially completed within 30 min. There is
      evidence to suggest that vasodilatation lasts considerably longer after
      provocation with allergen, but there is no information on the duration of plasma
      exudation. The purpose of this study was to measure the time course of the
      microvascular inflammatory response in the skin after histamine and allergen
      provocation. Skin prick tests were performed with histamine, allergen (ovalbumin)
      or saline (control) on guinea-pigs which were shaved on their backs. Radioactive
      113mIn was used to label transferrin as a plasma tracer. Radioactivity was
      recorded from the superficial part of the skin by external detection of
      conversion electrons from the decay of 113mIn. The increase in count rate,
      corresponding to tracer accumulation by vasodilatation and/or plasma exudation,
      was used as a measure of the microvascular inflammatory response to skin prick
      test. The microvascular response was studied immediately and up to 30 min after
      provocation. The largest response to histamine and allergen occurred immediately
      after provocation. The exudative response then gradually declined to be absent
      after 25-30 min. Skin prick test with saline resulted in a small response of
      shorter duration. We conclude that the microvascular reaction to histamine as
      well as allergen provocation in guinea-pig skin has a rapid onset and a duration
      of approximately 30 min.

PMID- 10350237
TI  - Effects of hydrogen peroxide on the guinea-pig tracheobronchial mucosa in vivo.
AB  - Lumenal entry of plasma (mucosal exudation) is a key feature of airway
      inflammation. In airways challenged with histamine-type mediators and allergen
      the mucosal exudation response occurs without causing epithelial derangement and
      without increased airway absorption. In contrast, reactive oxygen metabolites may
      cause mucosal damage. In this study, involving guinea-pig airways, we have
      examined effects of H2O2 on airway exudation and absorption in vivo. Vehicle or
      H2O2 (0.1 and 0.5 M) was superfused onto the tracheobronchial mucosal surface
      through an oro-tracheal catheter. 125I-albumin, given intravenously, was
      determined in tracheobronchial tissue and in lavage fluids 10 min after challenge
      as an index of mucosal exudation of plasma. The tracheobronchial mucosa was also
      examined by scanning electron microscopy. In separate animals, 99mTc-DTPA was
      superfused 20 min after vehicle or H2O2 (0.1 and 0.5 M) had been given. A gamma
      camera determined the disappearance rate of 99mTc-DTPA from the airways as an
      index of airway absorption. The high dose of H2O2 (0.5 M) produced epithelial
      damage, increased the absorption of 99mTc-DTPA (P < 0.001), and increased the
      exudation of plasma (P < 0.001). Notably, it appeared that all extravasated
      plasma had entered the airway lumen within 10 min. These data demonstrate that
      H2O2 differs from exudative autacoids such as histamine by causing both
      epithelial damage and plasma exudation responses. These data also agree with the
      view that the epithelial lining determines the rate of absorption and is
      responsible for the valve-like function that allows lumenal entry of extravasated
      bulk plasma without any increased inward perviousness.

PMID- 10350238
TI  - Physiological significance of absolute heart rate variability in postural change.

PMID- 10350242
TI  - Workforce demand for neurosurgeons in the United States of America: a 13-year
      retrospective study.
AB  - OBJECT: The workforce demand for neurosurgeons was quantified by a review and an
      analysis of journal recruitment advertisements published over the past 13 years.
      METHODS: A retrospective analysis of recruitment advertisements from July 1985
      through June 1998 was performed by examining issues of the Journal of
      Neurosurgery and Neurosurgery. Advertisement information that appeared in each
      journal during the last 3 years was collected from alternating months (July to
      May); information that appeared prior to that time was collected from alternating
      recruitment years back to 1985. The authors examined the following workforce
      parameters: practice venue, subspecialization, and practice size. They found no
      significant decrease in neurosurgical recruitment advertisements. There was an
      average of 102.7+/-22.4 (standard deviation) advertised positions per year during
      the most recent 3 years compared with 92.6+/-17.9 advertised positions per year
      during the preceding decade. Similarly, there has been no decline in advertised
      positions either in academic (33+/-6.1/year for the most recent 3 years compared
      with 32.8+/-5.9/year for 1985-1995) or private practice (69.7+/-21.6/year for the
      most recent 3 years compared with 59.8+/-13.4/year for 1985-1995). A shift in
      demand toward subspecialty neurosurgery was observed. During the past 3 years,
      31.2+/-5.9% of advertised positions called for subspecialty expertise, compared
      with 18.5+/-2.8% for the preceding decade (p < 0.05). The largest number of
      subspecialty advertisements designated positions for spine and pediatric
      neurosurgeons. Private practice advertisements increasingly sought to add
      neurosurgeons to group practices. CONCLUSIONS: Contrary to previous reports and a
      prevailing myth, our data show no decrease in workforce demand for neurosurgeons
      in the United States over the past 3 years compared with the prior decade. A
      shift toward subspecialist recruitment, particularly for spine neurosurgeons, has
      been demonstrated in both academic and private practice venues.

PMID- 10350243
TI  - Neural network analysis of preoperative variables and outcome in epilepsy
      surgery.
AB  - OBJECT: Because appropriate patient selection is essential for achieving
      successful outcomes after epilepsy surgery, the need for more robust methods of
      predicting postoperative seizure control has been created. Standard multivariate
      techniques have been only 75 to 80% accurate in this regard. Recent use of
      artificial intelligence techniques, including neural networks, for analyzing
      multivariate clinical data has been successful in predicting medical outcome.
      METHODS: The authors applied neural network techniques to 80 consecutive patients
      undergoing epilepsy surgery in whom data on demographic, seizure, operative, and
      clinical variables to predict postoperative seizures were collected. Neural
      networks could be used to predict postoperative seizures in up to 98% of cases.
      Student's t-tests or chi-square analysis performed on individual variables
      revealed that only the preoperative medication index was significantly different
      (p = 0.02) between the two outcome groups. Six different combinations of input
      variables were used to train the networks. Neural network accuracies differed in
      their ability to predict seizures: using all data (96%); all data minus
      electroencephalography concordance and operative side (93%); all data except
      intra- or postoperative variables such as tissue pathological category (98%); all
      data excluding pathological category, intelligence quotient (IQ) data, and Wada
      results (84%); only demographics and tissue pathological category (65%); and only
      IQ data (63%). CONCLUSIONS: Analysis of the results reveals that several networks
      that are trained with the usual accepted variables characterizing the typical
      evaluation of epilepsy patients can predict postoperative seizures with greater
      than 95% accuracy.

PMID- 10350244
TI  - Prefrontal dysfunction following unilateral posteroventral pallidotomy in
      Parkinson's disease.
AB  - OBJECT: Pre- and postoperative cognitive function was evaluated in 25 patients
      with Parkinson's disease (PD) who underwent unilateral posteroventral pallidotomy
      (PVP) to clarify the effects of this operation on cognitive function. METHODS:
      Cognitive function was assessed before surgery and 1 month and 3 months afterward
      by using a battery of neuropsychological tests consisting of orientation, digit
      span (forward and backward), digit learning, 5-minute memory of five words,
      similarities, serial sevens, animal name listing, and the kana pick-out test, as
      well as the Japanese version of the Mini-Mental State. Preoperative evaluation
      revealed that patients experienced difficulties in performing the
      neuropsychological tasks of reasoning and abstraction, working memory of
      numerals, word fluency, and concept formation compared with 36 healthy volunteers
      (p < 0.05). A simple regression analysis showed strong relationships in a
      negative fashion between preoperative (r = 0.81, p = 0.002) and 1-month (r =
      0.79, p = 0.0059) and 3-month (r = 0.85, p = 0.0016) postoperative gross-total
      scores and Hoehn and Yahr staging. Preoperative and postoperative scores at 1
      month and 3 months were analyzed by analysis of variance, but only the Fisher's
      post hoc test revealed the source of difference. All tasks except orientation (p
      = 0.0292) were unchanged in the 10 patients who underwent surgery on the right
      side. The scores for this task at 1 month postsurgery were significantly lower (p
      = 0.0203) but improved to preoperative values by 3 months. In the 15 patients who
      underwent surgery on the left side significant differences among tasks were
      revealed for serial sevens (p = 0.0471) and animal naming (p = 0.0425). The
      scores for these tasks were significantly lower at 1 month postoperatively (p =
      0.0431 for serial sevens and p = 0.0408 for animal naming), but improved by 3
      months after the operation. CONCLUSIONS: The present data revealed that cognitive
      dysfunction in patients with PD relates to advancement of Hoehn and Yahr stage,
      but PVP is not associated with significant long-lasting cognitive deficits.

PMID- 10350245
TI  - Double-blind, randomized, vehicle-controlled study of high-dose tirilazad
      mesylate in women with aneurysmal subarachnoid hemorrhage. Part I. A cooperative
      study in Europe, Australia, New Zealand, and South Africa.
AB  - OBJECT: Findings from previous multicenter clinical trials have suggested that
      tirilazad mesylate, a synthetic nonhormonal 21-aminosteroid, might be effective
      in preventing delayed cerebral ischemia following subarachnoid hemorrhage (SAH).
      This beneficial effect, however, was greater in males than females, possibly
      because of gender-related pharmacokinetic differences. The authors sought to
      assess the effects of administering a larger dose of tirilazad in women with SAH.
      METHODS: To test the efficacy of a higher tirilazad mesylate dose in female
      patients, a prospective randomized, double-blind, vehicle-controlled trial was
      conducted at 56 neurosurgical centers in Europe, Australia, New Zealand, and
      South Africa. Eight hundred nineteen patients were randomly assigned to receive
      either 15 mg/kg/day of tirilazad mesylate or a placebo containing the citrate
      vehicle. The two groups were similar in prognostic factors for delayed cerebral
      ischemia and overall outcome. High-dose tirilazad appeared to be well tolerated
      because no differences in the incidence of untoward medical events were noted
      between the two groups. Medical and surgical interventions were no different in
      the two treatment groups except for hyperdynamic therapy (intentional
      hypervolemia, induced hypertension, and/or hemodilution), which was more often
      used in the placebo-treated group to counteract symptomatic vasospasm (24% of
      patients given placebo compared with 18% of patients given tirilazad, p = 0.02).
      Mortality rates and overall outcome, assessed using the Glasgow Outcome Scale at
      3 months post-SAH, were not different between the two groups, despite a
      significantly lower incidence of delayed cerebral ischemia in patients given
      tirilazad. Post hoc subgroup analysis by neurological grade also did not reveal
      significant differences in outcome, although a trend toward a lower mortality
      rate favoring the study drug was present in patients with neurological Grade IV
      and V at admission (32% compared with 37%). Symptomatic vasospasm occurred in
      33.7% of the placebo-treated patients as opposed to 24.8% of the patients who
      were given tirilazad (p = 0.005). The severity of symptomatic vasospasm was also
      attenuated by administration of the study drug (severe symptomatic vasospasm was
      reported in 11% of the placebo-treated patients compared with 6% of patients in
      the tirilazad-treated group (p = 0.008). Clinical cerebral infarction from
      vasospasm was also reduced from 13% in the vehicle-treated group to 8% in the
      tirilazad-treated group (p < 0.04). CONCLUSIONS: The authors conclude that high
      dose tirilazad mesylate is well tolerated in women with aneurysmal SAH. Although
      a significant reduction in the incidence of symptomatic vasospasm was observed in
      the treatment group, the primary end point (mortality rate at 3 months post-SAH)
      was not affected by the study drug. The use of other potentially effective rescue
      therapies (that is, hypervolemia, hemodilution, and induced hypertension) to
      counteract vasospasm may have been responsible for these contrasting observations
      between the two groups.

PMID- 10350246
TI  - Double-blind, randomized, vehicle-controlled study of high-dose tirilazad
      mesylate in women with aneurysmal subarachnoid hemorrhage. Part II. A cooperative
      study in North America.
AB  - OBJECT: To test the safety and efficacy of high-dose (15 mg/kg/day) tirilazad
      mesylate in women suffering from aneurysmal subarachnoid hemorrhage (SAH), a
      prospective randomized, double-blind, vehicle-controlled trial (parallel to the
      one conducted in Europe, Australia, New Zealand, and South Africa) was performed
      at 65 North American neurosurgical centers. METHODS: Of the 832 patients who were
      randomized, 823 received at least one dose of tirilazad (410 patients) or placebo
      vehicle containing citrate (413 patients). The two groups were similar with
      respect to their prognostic factors for overall outcome and delayed cerebral
      ischemia. There were no differences in medical and surgical interventions
      including hyperdynamic therapy (intentional hypervolemia, induced hypertension,
      and/or hemodilution) between the two treatment groups. In contrast to the
      accompanying study, the protocol for the North American study was formally
      amended, in that a sequential analysis of the primary efficacy end point,
      mortality rate at 91 days postdosing, was performed. This analysis revealed a
      statistically significant difference in mortality rates, favoring the study drug,
      among patients who were neurological Grade IV or V at admission (24.6% compared
      with 43.4% in the placebo-treated group, p = 0.016). No significant differences,
      however. were found when the entire patient population was considered (15.6% in
      the placebo-treated group and 13% in the tirilazad-treated group). Other major
      and secondary end points, which included rate of favorable outcome (74% in the
      placebo-treated group and 71% in the tirilazad-treated group); symptomatic
      vasospasm (38% in the placebo-treated group and 35% in the tirilazad-treated
      group); and vasospasm severity (severe symptomatic vasospasm in 14% of patients
      in both groups), were also not significantly different between the two groups. In
      patients with neurological Grades I through III, rates of favorable outcome
      advantageous to the vehicle-treated group were observed (83.3% compared with
      76.7%, p = 0.04). CONCLUSIONS: High-dose tirilazad mesylate is well tolerated in
      women with aneurysmal SAH. Sequential analysis revealed a significant reduction
      in mortality rates among patients with neurological Grades IV and V, favoring the
      study drug and confirming the same effect observed in male patients in previous
      large studies. No beneficial effect was observed in patients who were in a good
      neurological grade at admission.

PMID- 10350247
TI  - Endovascular coil placement compared with surgical clipping for the treatment of
      unruptured middle cerebral artery aneurysms: a consecutive series.
AB  - OBJECT: The goal of this study was to delineate the angioanatomical features that
      determine whether a patient with an unruptured middle cerebral artery (MCA)
      aneurysm is treated using endovascular coil placement or surgical clipping.
      METHODS: Thirty consecutive patients harboring 34 unruptured MCA aneurysms were
      evaluated. Patients with unruptured aneurysms are managed prospectively according
      to the following protocol: the primary treatment recommendation is endovascular
      packing with Guglielmi detachable coils (GDCs). Surgical clipping is recommended
      after failed attempts at coil placement or in the presence of angioanatomical
      features that contraindicate that type of endovascular therapy. Of 34 unruptured
      MCA aneurysms, two (6%) were successfully embolized and 32 (94%) were clipped. Of
      these 32 surgically treated aneurysms, in 11 (34%) an attempt at GDC embolization
      had failed, whereas in 21 (66%) primary clipping was performed because of
      unfavorable angioanatomy. Of the 13 aneurysms treated endovascularly, two (15%)
      were successfully excluded, whereas GDC treatment failed in 11 (85%). An
      unfavorable dome/neck ratio (< 2) and an arterial branch originating at the
      aneurysm base were the reasons for embolization failure. CONCLUSIONS: Careful
      evaluation of the angioanatomy of unruptured aneurysms allows selection of the
      most appropriate treatment. However, for unruptured MCA aneurysms, surgical
      clipping appears to be the most efficient treatment option. Series of unruptured
      aneurysms are ideal for comparing treatment results.

PMID- 10350248
TI  - Carotid artery angioplasty and use of stents in high-risk patients with
      contralateral occlusions.
AB  - OBJECT: The risks associated with carotid endarterectomy (CEA) are increased in
      the presence of contralateral carotid artery (CA) occlusion. The 30-day stroke
      and death rate for patients in the North American Symptomatic Carotid
      Endarterectomy Trial (NASCET) who had contralateral CA occlusion was 14.3%. The
      authors analyze their experience with angioplasty and/or stent placement in
      patients with contralateral CA occlusion to determine the safety and efficacy of
      endoluminal revascularization in this subgroup. METHODS: Twenty-six procedures
      were evaluated in 23 patients with high-grade CA stenosis and contralateral CA
      occlusion. The first 15 procedures were evaluated retrospectively, and the next
      11 prospectively. All patients had severe medical comorbidities and were
      considered too high risk for CEA, even without considering the contralateral
      occlusion. Clinical follow-up review was performed an average of 18 months later
      (median 15 months). CONCLUSIONS: The average ipsilateral CA stenosis according to
      NASCET criteria was 78% preprocedure and 5% postprocedure. There were no changes
      in neurological or functional outcome immediately postoperatively in any patient.
      The 30-day postoperative stroke and death rates were zero. However, there was one
      symptomatic femoral hematoma that resolved without surgery. At follow up, there
      were three patients who had suffered stroke or death. One patient died secondary
      to respiratory arrest at 2 months; one died secondary to prostate carcinoma at 12
      months; and one patient experienced a minor stroke contralateral to the treated
      artery at 41 months. Despite the substantial preoperative risk factors in
      patients in this series, the 30-day stroke and death rate for angioplasty and/or
      stent placement appears to be lower than that of CEA in patients with
      contralateral occlusions.

PMID- 10350249
TI  - An ultrarapid prognostic index in microprolactinoma surgery.
AB  - OBJECT: Prolactinomas account for approximately 40% of pituitary tumors. If the
      tumor does not exceed 10 mm at its largest diameter (microprolactinoma), the
      chances of definitive cure as a result of surgery alone vary from 62 to 89%
      depending on the series. Until now, however, there was no mechanism to predict
      whether total excision of a tumor had been accomplished. To improve the chances
      of total excision, we compared the peri- and postoperative kinetics of
      circulating prolactin (PRL) in patients judged to be cured and those not cured.
      METHODS: The pre-, peri-, and postoperative variations in blood PRL
      concentrations were determined using assays conducted at 10-minute intervals. Of
      the 36 patients included in the study, 27 were considered cured (resumption of a
      normal menstrual cycle within 6 months, PRL concentration at 9 days [mean +/-
      standard deviation 2.5+/-2.1 ng/ml] and 12 months [4.5+/-2.2 ng/ml] after the
      operation < 10 ng/ml and normally stimulated by metoclopramide and thyrotropin
      releasing hormone [TRH]). Nine patients were not cured (PRL 20+/-15.7 ng/ml at 9
      days after surgery, with no response to metoclopramide and TRH). The kinetics of
      PRL decrease in definitively cured patients were characterized by the following:
      1) the initial slope of the curve decreased by at least 11% within the first 10
      minutes after resection, and 2) immediate postoperative PRL concentrations were
      20 ng/ml or less. CONCLUSIONS: The measurement of the kinetics of PRL decrease
      during surgery allows the chance of gross-total resection to be successfully
      predicted less than 25 minutes after excision of the adenoma. Provided an
      ultrarapid assay is available (the test used in the present study took < 15
      minutes), this prognostic index would be useful to make a decision to continue
      the surgical procedure when the initial PRL slope is judged to be insufficient.
      Its use may also be extended to other pituitary tumors such as somatotropic
      adenoma and basophilic adenoma (Cushing's disease).

PMID- 10350250
TI  - Propofol in the treatment of moderate and severe head injury: a randomized,
      prospective double-blinded pilot trial.
AB  - OBJECT: Sedation regimens for head-injured patients are quite variable. The short
      acting sedative-anesthetic agent propofol is being increasingly used in such
      patients, yet little is known regarding its safety and efficacy. In this
      multicenter double-blind trial, a titratable infusion of 2% propofol accompanied
      by low-dose morphine for analgesia was compared with a regimen of morphine
      sulfate in intubated head-injured patients. In both groups, other standard
      measures of controlling intracranial pressure (ICP) were also used. METHODS:
      Forty-two patients from 11 centers were evaluated to assess both the safety and
      efficacy of propofol: 23 patients in the propofol group (mean time of propofol
      usage 95+/-87 hours) and 19 patients in the morphine group (mean time of morphine
      usage 70+/-54 hours). There was a higher incidence of poor prognostic indicators
      in the propofol group than in the morphine group: patient age older than 55 years
      (30.4% compared with 10.5%, p < 0.05), initial Glasgow Coma Scale scores of 3 to
      5 (39.1% compared with 15.8%, p < 0.05), compressed or absent cisterns on initial
      computerized tomography scanning (78.3% compared with 57.9%, p < 0.05), early
      hypotension and/or hypoxia (26.1% compared with 10.5%, p = 0.07). During
      treatment there was a trend toward greater use of vasopressors in the propofol
      group. However, the mean daily ICP and cerebral perfusion pressure were generally
      similar between groups and, on therapy Day 3, ICP was lower in the propofol group
      compared with the morphine group (p < 0.05). Additionally, there was less use of
      neuromuscular blocking agents, benzodiazepines, pentobarbital, and cerebrospinal
      fluid drainage in the propofol group (p < 0.05). At 6 months postinjury, a
      favorable outcome (good recovery or moderate disability) was observed in 52.1% of
      patients receiving propofol and in 47.4% receiving morphine; the mortality rates
      were 17.4% and 21.1%, respectively. Patients who received the highest doses of
      propofol for the longest duration tended to have the best outcomes. There were no
      significant differences between groups in terms of adverse events. CONCLUSIONS:
      Despite a higher incidence of poor prognostic indicators in the propofol group,
      ICP therapy was less intensive, ICP was lower on therapy Day 3, and long-term
      outcome was similar to that of the morphine group. These results suggest that a
      propofol-based sedation and an ICP control regimen is a safe, acceptable, and,
      possibly, desirable alternative to an opiate-based sedation regimen in intubated
      head-injured patients.

PMID- 10350251
TI  - Anterior interosseous nerve compression after supracondylar fracture of the
      humerus: a metaanalysis.
AB  - OBJECT: The authors conducted a metaanalysis of reports of anterior interosseous
      nerve syndrome, a rare nerve compression neuropathy that affects only the motor
      branch of the median nerve. This syndrome is characterized by paralysis of the
      flexor pollicis longus, the flexor digitorum profundus to the index finger, and
      the pronator quadratus, with weakness on flexion of the interphalangeal joint of
      the thumb and the distal interphalangeal joint of the index finger without
      sensory loss. METHODS: The authors reviewed reports of 34 cases of anterior
      interosseous nerve syndrome combined with supracondylar fractures of the humerus
      in children. They have added a new case identified in a 7-year-old boy in whom a
      diagnosis was made from the clinical findings and whose treatment and outcome are
      analyzed. The ages of patients reported in the literature ranged from 4 to 10
      years. Ten patients (29%) were treated with closed reduction and application of a
      cast, whereas 25 patients (71%) were treated with open reduction and fixation of
      the fracture. CONCLUSIONS: All patients regained full flexion and strength after
      4 to 17 weeks. The fractures that were surgically treated showed no entrapment of
      the anterior interosseous nerve.

PMID- 10350252
TI  - Anatomical and functional connectivity of the transected ulnar nerve after
      intercostal neurotization in cats.
AB  - OBJECT: Acute transfer of three intercostal nerves to the ulnar nerve was
      performed in cats for histological and clinical evaluation of a distal muscle
      reinnervation. METHODS: Infraclavicular intercostal-ulnar communications were
      created after dividing the motor branches of the upper intercostal nerves in 14
      adult cats. Reinnervation of distal forelimb muscles in the ulnar territory was
      assessed by electromyographic (EMG) studies and motor function rating each month
      until 18 months postsurgery. In five of these treated animals, and in tour
      controls, horseradish peroxidase (HRP) was applied to the ulnar or intercostal
      nerves to study the amount and distribution of retrograde motor neuron labeling
      in the spinal cord. Also, samples of reinnervated muscles and neurotized ulnar
      nerves were processed to assess regeneration. Simple ulnar transection without
      reconstruction led to permanent atrophy of ulnar muscles, lack of recovery
      according to EMG or clinical studies, and disappearance of the ulnar motor neuron
      pool. In contrast, ulnar neurotization with the intercostal nerves led to a high
      rate of functional recovery, which began 5 months postsurgery, and progressed
      from muscle activity synchronized with ventilatory movements to spontaneous
      movements that were independent of respiration. This recovery was accompanied by
      substantial retrograde labeling of intercostal motor neurons after HRP
      application in the ulnar nerve. Cell counts showed that practically the whole
      motor neuron pool of the involved intercostal nerves contributed to reinnervation
      of the transected ulnar nerve. CONCLUSIONS: These findings demonstrate that the
      use of intercostal nerves to neurotize long brachial plexus nerves can achieve
      long-lasting and successful reinnervation of distal forelimb muscles.

PMID- 10350254
TI  - Hormonal effects on glioblastoma multiforme in the nude rat model.
AB  - OBJECT: The authors studied the effect of gender and hormonal status on survival
      in nude rats implanted with human glioblastoma multiforme (GBM) cell lines.
      METHODS: Nude rats received intracerebral implants of either wild-type U87MG
      cells or U87MG cells transfected with the gene for endothelin-1 (U87/ET-1). In
      the initial study, survival was compared in males and females for each of the two
      cell lines. The six second-phase study groups were composed of: 1) males; 2)
      females; 3) ovariectomized females; 4) sham ovariectomized females; 5)
      ovariectomized rats given 10 microg/day estradiol benzoate for 21 days; and 6)
      ovariectomized rats given 20 mg/kg/day progesterone for 21 days. All rats in the
      second phase were implanted with U87/ET-1 cells. Animals were killed when they
      exhibited initial signs of neurological deterioration. Female nude rats survived
      longer than male rats implanted with either U87 or U87/ET-1 cells. In the second
      phase, ovariectomized, male, and progesterone-treated rats died at approximately
      19 days, whereas the female, sham-treated, and estrogen-treated animals died 23
      to 25 days after tumor cell implantation. CONCLUSIONS: The authors demonstrate
      that female nude rats implanted with human GBM cells have a survival advantage
      over male rats and that estrogen provides the advantage.

PMID- 10350253
TI  - Effects of continuous localized infusion of granulocyte-macrophage colony
      stimulating factor and inoculations of irradiated glioma cells on tumor
      regression.
AB  - OBJECT: Glioblastoma multiforme (GBM) is a malignant tumor of the central nervous
      system that directly suppresses immunological defenses in vitro and in vivo. The
      authors used the peripheral delivery of continuously infused granulocyte
      macrophage colony-stimulating factor (GM-CSF) in the presence of irradiated tumor
      antigens as a tumor-specific stimulant to dendritic cells to initiate an immune
      response to GBM in rats. METHODS: The 9L gliosarcoma tumors were established in
      the flanks of syngeneic Fischer 344 rats. Osmotic minipumps implanted in the
      animals' contralateral flanks continuously delivered recombinant GM-CSF (0, 0.1,
      1, or 10 ng/day) for 28 days. Irradiated gliosarcoma cells were intermittently
      injected at the site of the GM-CSF infusion. Animals in the saline control group
      (0 ng/day GM-CSF) died on Day 59 with average tumor volumes greater than 30,000
      mm3. This control group was significantly different from the GM-CSF-treated
      animals, which all survived with average tumor volumes that peaked on Day 23 and
      later regressed completely. Tumor growth as well as peak tumor volumes (5833+/
      2284 mm3, 3294+/-1632 mm3, and 1979+/-1142 mm3 for 0.1, 1, and 10 ng/day GM-CSF,
      respectively) in the different treatment groups reflected a significant dose
      response relationship with the GM-CSF concentrations. All animals treated with GM
      CSF and irradiated cells were resistant to additional challenges of peripheral
      and intracerebral gliosarcoma, even when they were inoculated 8 months after
      initial immunotherapy. The colocalization of GM-CSF and inactivated tumor
      antigens was required to stimulate immunoprotection. To test the efficacy of a
      peripherally administered immunological therapy on intracerebral brain tumors the
      authors transplanted 10(6) gliosarcoma cells into the striatum of treated and
      control animals. Subcutaneous pumps that released GM-CSF (10 ng/day) and
      irradiated gliosarcoma cells were placed in the treated animals. The control
      animals all died within 31 days after intracerebral tumor implantation. In
      contrast, 40% of the animals receiving GM-CSF-irradiated cell vaccinations
      survived beyond 300 days. These long-term survivors showed no evidence of
      gliosarcoma at the injection site on evaluation by magnetic resonance imaging.
      CONCLUSIONS: These results suggest that the continuous localized delivery of
      subcutaneous GM-CSF in conjunction with inactivated tumor antigens can initiate a
      systemic response that leads to the regression of distant peripheral and
      intracerebral tumors. The success of this treatment illustrates the feasibility
      of tumor-specific peripheral immunological stimulation after tumor resection to
      prevent the recurrence of malignant brain tumors.

PMID- 10350255
TI  - Contribution of polyamine oxidase to brain injury after trauma.
AB  - OBJECT: The possible role of the polyamine interconversion pathway on edema
      formation, traumatic injury volume, and tissue polyamine levels after traumatic
      brain injury (TBI) was studied using an inhibitor of the interconversion pathway
      enzyme, polyamine oxidase. METHODS: Experimental TBI was induced in Sprague
      Dawley rats by using a controlled cortical impact device at a velocity of 3
      m/second, resulting in a 2-mm deformation. Immediately after TBI was induced, 100
      mg/kg of N1,N4-bis(2,3-butadienyl)-1,4-butanediamine 2HCl (MDL 72527) or saline
      was injected intraperitoneally. Brain water content and tissue polyamine levels
      were measured at 24 hours after TBI. Traumatic injury volume was evaluated using
      2% cresyl violet solution 7 days after TBI occurred. The MDL 72527 treatment
      significantly reduced brain edema (80.4+/-0.8% compared with 81.2+/-1.2%, p <
      0.05) and injury volume (30.1+/-6.6 mm3 compared with 42.7+/-13.3 mm3, p < 0.05)
      compared with the saline treatment. The TBI caused a significant increase in
      tissue putrescine levels at the traumatized site (65.5+/-26.5 nmol/g [corrected]
      in the cortex and 70.9+/-22.4 nmol/g [corrected] in the hippocampus) compared
      with the nontraumatized site (7+/-2.4 nmol/g [corrected] in the cortex and 11.4+/
      6.4 nmol/g [corrected] in the hippocampus). The increase in putrescine levels in
      both the traumatized and nontraumatized cortex and hippocampus was reduced by a
      mean of 60% with MDL 72527 treatment. CONCLUSIONS: These results demonstrate, for
      the first time, that the polyamine interconversion pathway has an important role
      in the increase of putrescine levels after TBI and that the polyamine oxidase
      inhibitors, blockers of the interconversion pathway, can be neuroprotective
      against edema formation and necrotic cavitation after TBI.

PMID- 10350256
TI  - Immediate early gene expression in vascular smooth-muscle cells synergistically
      induced by hemolysate components.
AB  - OBJECT: Vasospasm after subarachnoid hemorrhage is associated with changes in
      modulators of vascular tone in the arterial wall and is related to the presence
      of erythrocyte hemolysate in the subarachnoid space. The purpose of this study
      was to determine the compounds in erythrocyte hemolysate that are responsible for
      changing smooth-muscle cell gene expression. METHODS: Rat aorta smooth-muscle
      cells were exposed to erythrocyte hemolysate in vitro and the effects on
      immediate early gene messenger (m)RNA levels were determined by competitive
      reverse transcriptase-polymerase chain reaction. Message levels for c-fos, jun B,
      and c-jun were increased in the presence of hemolysate, reaching maximum
      expression between 30 and 60 minutes, whereas the level of jun D mRNA was
      unaffected. Increasing doses of hemolysate caused greater expression of c-fos and
      jun B, but not c-jun. Adenosine triphosphate and hemoglobin, possible spasmogens
      present in hemolysate, caused much smaller and more rapid increases in c-fos
      expression than whole hemolysate. Size fractionation showed that all of the c-fos
      mRNA-inducing activity of hemolysate was recovered with molecules greater than 6
      kD. Following separation of hemolysate proteins by hydrophobic interaction
      chromatography, only one of the three fractions had partial activity. Recombining
      the three fractions, however, yielded greater c-fos activation than any
      combination of two. CONCLUSIONS: Multiple high-molecular-weight components
      present in erythrocytes have synergistic effects on gene expression in smooth
      muscle cells. The differences in patterns of gene induction suggest that multiple
      signaling pathways are activated.

PMID- 10350257
TI  - Mitogen-activated protein kinase mediation of hemolysate-induced contraction in
      rabbit basilar artery.
AB  - OBJECT: Mitogen-activated protein kinase (MAPK) is an important signaling factor
      in vascular proliferation and contraction, which are the two features of cerebral
      vasospasm that follow subarachnoid hemorrhage. The authors studied the possible
      involvement of MAPK in hemolysate-induced signal transduction and contraction in
      rabbit basilar artery (BA). METHODS: Isometric tension was used to record the
      contractile response of rabbit BA to hemolysate, and Western blots were obtained
      using antibodies for MAPK. The following results are reported. 1) Hemolysate
      produced a concentration-dependent contraction of rabbit BA; however,
      preincubation of arteries with the MAPK kinase (MEK) inhibitor PD-98059 markedly
      reduced this contraction. The administration of PD-98059 also relaxed, in a
      concentration-dependent fashion, the sustained contraction induced by 10%
      hemolysate. 2) The Janus tyrosine kinase 2 inhibitor AG-490, preincubated with
      arterial rings, reduced the contractile response to hemolysate but failed to
      relax the sustained contraction induced by this agent. The Src-tyrosine kinase
      inhibitor damnacanthal and the phosphatidylinositol 3-kinase inhibitor wortmannin
      failed to reduce hemolysate-induced contraction. 3) Hemolysate produced a time
      dependent elevation of MAPK immunoreactivity as seen on Western blots of rabbit
      BA. The MAPK was enhanced 1 minute after hemolysate exposure and the effect
      reached maximum levels at 5 minutes. The immunoreactivity of MAPK decayed slowly
      over time, but the level of this kinase was still higher than the basal level,
      even at 2 hours after exposure to hemolysate. Preincubation of arteries with the
      MEK inhibitor PD-98059 abolished the effect of hemolysate on MAPK
      immunoreactivity. CONCLUSIONS: Hemolysate produced contraction of rabbit BA,
      possibly by activation of MAPK, and therefore MAPK inhibitors may be useful in
      the treatment of cerebral vasospasm.

PMID- 10350258
TI  - Inducible nitric oxide synthase: a possible key factor in the pathogenesis of
      chronic vasospasm after experimental subarachnoid hemorrhage.
AB  - OBJECT: The role of nitric oxide (NO) in the pathogenesis of cerebral vasospasm
      after subarachnoid hemorrhage (SAH) is not well understood. Nitric oxide is a
      well-established vasodilatory substance; however, in SAH, NO may become a major
      source for the production of injurious free-radical species, leading to chronic
      cerebral vasospasm. Reactive overproduction of NO to counteract vascular
      narrowing might potentiate the detrimental effects of NO. The focus of the
      present study is to determine the extent of reactive induction of inducible
      nitric oxide synthase (iNOS) after experimental SAH. METHODS: Chronic vasospasm
      was induced in male Wistar rats by an injection of autologous blood (100 microl)
      into the cisterna magna followed by a second injection 24 hours later. A control
      group of 10 animals was treated with injections of 0.9% sodium chloride solution.
      Vasospasm was verified by pressure-controlled angiography after retrograde
      cannulation of the external carotid artery 7 days later. In 11 of 15 animals
      radiographic evidence of cerebral vasospasm was seen. The animals were perfusion
      fixed and their brains were removed for immunohistochemical assessment. With the
      aid of a microscope, staining for iNOS was quantified in 40-microm floating
      coronal sections. Immunohistochemical staining for iNOS was markedly more intense
      in animals with significant angiographic evidence of vasospasm. Virtually no
      staining was observed in control animals. Seven days after the second
      experimental SAH, labeling of iNOS was found in endothelial cells, in vascular
      smooth-muscle cells, and, above all, in adventitial cells. Some
      immunohistochemical staining of iNOS was observed in rod cells (activated
      microglia), in glial networks, and in neurons. CONCLUSIONS: The present study
      demonstrates induction of iNOS after experimental SAH.

PMID- 10350259
TI  - Antisense preproendothelin-oligoDNA therapy for vasospasm in a canine model of
      subarachnoid hemorrhage.
AB  - OBJECT: The purpose of this study is twofold: 1) to test antisense genetic
      techniques used in the prevention of cerebral vasospasm in a canine model of
      subarachnoid hemorrhage (SAH), targeting the endothelin-1 (ET-1) gene; and 2) to
      determine if fibrinolysis of subarachnoid clot with recombinant tissue
      plasminogen activator (rtPA) could enhance the effect of antisense treatment.
      METHODS: A total of 39 dogs were studied in this experiment. Placebo (six
      animals), rtPA (six animals), antisense preproET-1 oligodeoxynucleotide (ASOD;
      five animals), or rtPA plus ASOD (combined treatment; six animals) was injected
      into the cisterna magna 30 minutes after a second SAH was induced on the 2nd day
      of the experiment. The animals were observed until Day 7, when they underwent
      follow-up angiography and then were killed; their basilar arteries were removed
      for analysis. Control animals included in this study (two animals in each group)
      received placebo, rtPA, ASOD, or rtPA plus ASOD without induction of SAH, or rtPA
      with mismatched (nonsense) preproET-1 oligodeoxynucleotide following SAH. Six
      additional dogs were analyzed earlier following SAH. Dogs that received placebo
      developed severe vasospasm (51+/-8% of baseline caliber). Administration of ASOD
      alone resulted in a mild reduction in vasospasm (64+/-13% of baseline caliber)
      and rtPA alone resulted in a moderate reduction in vasospasm (81+/-5% of baseline
      caliber); however, the combined therapy of rtPA plus ASOD almost completely
      prevented vasospasm (95+/-6%, of baseline caliber), which was significantly
      different from all other groups (p < 0.05). Morphological analysis of the basilar
      arteries yielded results similar to angiography with respect to vasospasm
      severity. The ASOD treatment combined with rtPA resulted in reduced ET-1
      expression, as demonstrated by immunohistochemical staining of the arteries, and
      reduced preproET-1 levels on Day 4, as measured by reverse transcription
      polymerase chain reaction. Nonsense DNA sequences had no effect on the vessels.
      CONCLUSIONS: Antisense preproET-1 oligodeoxynucleotide treatment, when combined
      with clot lysis caused by rtPA, reduced vasospasm in the canine model of SAH, and
      this effect appeared to be related to reduced ET-1 synthesis. The results of this
      experiment support a causative role for ET-1 early in the course of vasospasm
      development in dogs. The apparent additive therapeutic effects of antisense and
      fibrinolytic treatments could be due to clot lysis, which allows better delivery
      of oligodeoxynucleotides to arteries within the subarachnoid space.

PMID- 10350261
TI  - Endoscopic ventriculocystocisternostomy of a quadrigeminal cistern arachnoid
      cyst. Case report.
AB  - The authors present the case of an elderly patient with a quadrigeminal arachnoid
      cyst who was successfully treated with endoscopic fenestration through the
      posterior wall of the third ventricle via the anterior horn of the lateral
      ventricle. This 71-year-old man suffered from progressive gait instability and
      disorientation. Radiological examination revealed hydrocephalus caused by a
      quadrigeminal arachnoid cyst. The patient underwent endoscopic fenestration of
      the quadrigeminal cistern arachnoid cyst and third ventriculostomy via one burr
      hole placed at the coronal suture. This method is less invasive and is effective
      for quadrigeminal cistern arachnoid cyst and accompanying hydrocephalus.

PMID- 10350260
TI  - Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed
      with tumor antigens.
AB  - OBJECT: An approach toward the treatment of intracranial gliomas was developed in
      a rat experimental model. The authors investigated the ability of "professional"
      antigen-presenting cells (dendritic cells) to enhance host antitumor immune
      responses when injected as a vaccine into tumor-bearing animals. METHODS:
      Dendritic cells, the most potent antigen-presenting cells in the body, were
      isolated from rat bone marrow precursors stimulated in vitro with granulocyte
      macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell
      populations were confirmed to be functional antigen-presenting cells on the basis
      of expressed major histocompatibility molecules, as analyzed by fluorescence
      activated cell sorter cytofluorography. These dendritic cells were then pulsed
      (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty
      eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors
      were treated with three weekly subcutaneous injections of either control media
      (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with
      peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen
      pulsed dendritic cells (12 animals). The animals were followed for survival. At
      necropsy, the rat brains were removed and examined histologically, and spleens
      were harvested for cell-mediated cytotoxicity assays. The results indicate that
      tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats
      with established intracranial 9L tumors implanted 7 days prior to the initiation
      of vaccine therapy in vivo. Immunohistochemical analyses were used to document a
      significantly increased perilesional and intratumoral infiltration of CD8+ and
      CD4+ T cells in the groups treated with tumor antigen-pulsed dendritic cells
      compared with the control groups. In addition, the results of in vitro
      cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic
      cells can induce specific cytotoxic T lymphocytes against 9L tumor cells.
      CONCLUSIONS: Based on these results, dendritic antigen-presenting cells pulsed
      with acid-eluted peptides derived from autologous tumors represent a promising
      approach to the immunotherapy of established intracranial gliomas. which may
      serve as a basis for designing clinical trials in patients with brain tumors.

PMID- 10350262
TI  - Sporadic unifocal infantile myofibromatosis involving the skull. Case report.
AB  - Infantile myofibromatosis involving the skull is a benign disease if there is a
      solitary lesion. However, the multifocal form with skull involvement may portend
      a lethal course in the 1st year of life if there is involvement of the heart,
      lungs, or gastrointestinal tract. The authors report the case of a 3-year-old boy
      with an enlarging left parietal skull lesion that had been present since infancy.
      Increasing pain and the need to obtain tissue for diagnosis led to resection of
      the lesion by means of a small craniectomy. Further evaluation revealed no other
      lesions. A distinctly rare disease is presented, and the need for staging in
      children younger than 2 years of age is suggested to rule out cardiac, pulmonary,
      or gastrointestinal involvement.

PMID- 10350263
TI  - Selective motor hyperreinnervation by using contralateral C-7 motor rootlets in
      the reconstruction of an avulsion injury of the brachial plexus. Case report.
AB  - Brachial plexus avulsion injuries are a clinical challenge. In recent
      experimental studies the authors have demonstrated the high degree of muscle
      reinnervation attained when a C-4 motor rootlet was directly connected to the
      musculocutaneous nerve. This degree of reinnervation was attributed to the good
      chance that a muscle fiber can be reinnervated by a motor fiber when the number
      of regenerating motor neurons is increased and when competitive sensory fibers
      are excluded from the process. The authors present the first clinical case in
      which this phenomenon has been observed. This 26-year-old man, who was involved
      in an automobile accident, presented with an upper brachial plexus avulsion, for
      which he underwent operation 4 months later. The axillary and suprascapular
      nerves were directly surgically connected to the motor rootlets of the C-7
      contralateral root by using two cables of sural nerve graft. Two years
      postsurgery, the patient was able to perform shoulder abduction of 120 degrees
      and hold an 800-g weight at 90 degrees. These results are encouraging, and in
      selected patients motor rootlet transfer might prove to be a useful surgical
      strategy.

PMID- 10350264
TI  - Surgical treatment of multiple neurofibromas of the ulnar nerve in segmental
      neurofibromatosis. Case report.
AB  - The case of an 18-year-old man with numerous neurofibromas along his left ulnar
      nerve is described. The patient had a painful mass in the medial third of the
      internal aspect of his left forearm, and two additional symptomatic painful
      masses were identified during clinical examination: one in the distal portion of
      the retroepitroclear groove and another near the Guyon tunnel in the wrist. The
      main symptom was neurogenic pain; however, sensory and motor disturbances were
      also present. No other stigma of neurofibromatosis (NF) was found, and no cases
      of NF were known in the patient's family. During surgery many neurofibromas were
      found; the three painful neurofibromas and some of the other larger lesions were
      microsurgically excised. The patient's symptoms fit the criteria for segmental NF
      or NF5. This is a very rare form of NF characterized by lesions located in a
      particular area of the body.

PMID- 10350265
TI  - Diabetes insipidus arising from hypothalamic diffuse axonal injury. Case
      illustration.

PMID- 10350266
TI  - Pituitary abscess secondary to neurobrucellosis. Case illustration.

PMID- 10350267
TI  - Treatment of postoperative subgaleal cerebrospinal fluid fistulas by using fibrin
      sealant. Technical note.
AB  - The authors describe a simple technique by which a postoperative subgaleal
      cerebrospinal fluid fistula is treated by local tapping and injection of fibrin
      sealant through the same needle.

PMID- 10350268
TI  - Resection of malignant gliomas of childhood.

PMID- 10350269
TI  - Coagulation of the petrosal vein for MVD.

PMID- 10350270
TI  - Fatal transplant cyst.

PMID- 10350271
TI  - Trochlear nerve.

PMID- 10350273
TI  - How to avoid "unblinding" the peer review process.

PMID- 10350272
TI  - Accentuate the negative.

PMID- 10350274
TI  - Complications of no biopsy.
AB  - OBJECTIVE: We present three cases in which complications occurred after CT-guided
      procedures were not carried out, supporting the contention that some
      complications occurring after CT-guided procedures may not be true procedural
      complications. CONCLUSION: Although most complications after CT-guided procedures
      are indeed caused by the antecedent procedure, some complications may be
      unrelated to the procedure and may in fact occur without any procedure being
      performed at all.

PMID- 10350275
TI  - Radiation therapy of suspected brain tumor without definitive diagnosis.

PMID- 10350276
TI  - MR characteristics of oxidized cellulose (Surgicel).
AB  - OBJECTIVE: Oxidized regenerated cellulose (Surgicel) is one of the most commonly
      used bioabsorbable topical hemostatic agents. Surgicel may mimic an abscess on
      both CT and sonography when a patient undergoes imaging early in the
      postoperative period. The objective of our study was to describe the appearance
      of Surgicel on postoperative MR imaging. CONCLUSION: Surgicel has a short
      relaxation time on T2-weighted images, resulting in low signal intensity in the
      early postoperative period. MR imaging may be helpful in differentiating Surgicel
      from an abscess and therefore in preventing unnecessary attempts at aspiration.

PMID- 10350277
TI  - Ureteral calculi: diagnostic efficacy of helical CT and implications for
      treatment of patients.
AB  - OBJECTIVE: The purpose of this study was to evaluate whether unenhanced helical
      CT of the abdomen and pelvis, supplemented as necessary with delayed enhanced CT
      of the pelvis, is sufficient for urologists to treat patients with acute renal
      colic. MATERIALS AND METHODS: CT scans from 99 patients were analyzed
      retrospectively for the presence, size, and location of ureteral calculi and the
      presence and severity of secondary signs of obstruction. Clinical follow-up was
      analyzed by reviewing charts, directly communicating with patients, and reviewing
      surgical reports. Clinical information was correlated with CT findings. RESULTS:
      The findings of 51 CT scans were positive for calculi, and the findings of 48
      were negative for calculi. The findings from two CT scans were false-positive,
      and none of the findings were false-negative. The sensitivity, specificity, and
      accuracy of helical CT were 100%, 96%, and 98%, respectively. A significant
      difference in stone size was found between patients who were treated
      conservatively (3.3 +/- 1.3 mm) and patients who underwent a urologic procedure
      (7 +/- 6.2 mm) (p < .01) and between patients in whom successful ureteral stent
      placement was the sole intervention (3.9 +/- 2.8 mm) and patients in whom initial
      stent placement failed and who then underwent a second urologic procedure (7.4 +/
      3 mm) (p < .05). We found no statistically significant difference between the
      conservatively and interventionally treated groups with respect to stone
      location. The presence and severity of secondary signs of obstruction were not
      significantly different between the two groups. CONCLUSION: Stone size alone was
      found to correlate with patient treatment. Stone location and the presence and
      severity of secondary signs of obstruction did not affect patient treatment.
      Because the degree of obstruction and relative renal function are not relevant to
      the initial treatment of patients with ureteral stone obstruction, CT is adequate
      for both diagnosis and treatment.

PMID- 10350278
TI  - Radiologic investigation of renal colic: unenhanced helical CT compared with
      excretory urography.
AB  - OBJECTIVE: Our aim was to compare unenhanced helical CT and excretory urography
      in the assessment of patients with renal colic. SUBJECTS AND METHODS: Fifty-three
      of 70 consecutive patients with acute signs of renal colic were prospectively
      examined with unenhanced helical CT, which was followed immediately by excretory
      urography. Two radiologists who were unaware of the findings independently
      interpreted these examinations to determine the presence or absence of ureteral
      obstruction. On all CT scans that had positive findings for ureteral stones or
      obstruction, we looked for secondary signs of obstruction (perinephric or
      periureteral fat stranding, ureteral wall edema, ureteral dilatation, and
      blurring of renal sinus fat). RESULTS: A stone was recovered in 45 of the 53
      patients, nine before and 36 after imaging. The latter 36 patients had their
      stones identified on CT, whereas only 24 patients had their stones identified on
      excretory urography. Eight patients without stone disease had normal ureters on
      both CT and excretory urography. Of the 45 patients who had stone disease, 26 had
      ureteral dilatation on both CT and excretory urography, and 36 patients who
      recovered a stone after CT had secondary signs of obstruction. Of the nine
      patients who recovered a stone before CT, three had secondary signs of
      obstruction. Two patients had periureteral fat stranding, ureteral wall edema,
      and renal sinus fat blurring. One patient had only ureteral wall edema.
      CONCLUSION: Compared with excretory urography, unenhanced helical CT is better
      for identifying ureteral stones in patients with acute ureterolithiasis.
      Secondary CT signs of obstruction, including renal sinus fat blurring, were
      frequently present even when the stone was eliminated before imaging.

PMID- 10350279
TI  - Complex renal cysts: findings on MR imaging.
AB  - OBJECTIVE: We retrospectively evaluated our experience with complex cystic renal
      masses on MR imaging, using T1-weighted, T2-weighted, and gadolinium-enhanced
      images, to determine whether imaging features could permit distinction between
      benign and malignant lesions. MATERIALS AND METHODS: Thirty-seven patients with
      complex cystic renal lesions were included in this retrospective study. The
      patients selected had undergone T1-weighted, T2-weighted, and gadolinium-enhanced
      MR imaging examinations using 1.5-T scanners, with at least one of the following
      findings: cyst fluid of heterogeneous signal intensity, mural irregularity,
      septa, mural masses or nodules, increased mural thickness, or intense mural
      enhancement. The diagnosis was established by histology in 19 patients and by
      follow-up studies in the remaining 18 patients. RESULTS: Fifty-five complex renal
      cystic lesions were present in the 37 patients. Among the 55 lesions, of 37 that
      contained fluid of a heterogeneous signal intensity, eight were malignant (22%);
      of 16 with irregular walls, 10 were malignant (63%); of four with septa, two were
      malignant (50%); of four with mural masses or nodules, three were malignant
      (75%); of 14 with a thick wall (>2 mm), 10 were malignant (71%); and of 32 with
      intense mural enhancement, 14 were malignant (44%). As independent variables,
      mural irregularity, mural masses or nodules, increased mural thickness, and
      intense mural enhancement each were highly associated with malignancy (p = .0003
      .0022). The combination of mural irregularity and intense mural enhancement had
      the highest correlation with malignancy (p = .0002). CONCLUSION: The combination
      of mural irregularity and intense mural enhancement is a strong predictor of
      malignancy in renal cystic lesions. However, the appearance of benign and
      malignant lesions may overlap, suggesting that distinct separation of these
      entities is not currently possible in all cases with MR imaging.

PMID- 10350280
TI  - Renal MR angiography at 1.0 T: three-dimensional (3D) phase-contrast techniques
      versus gadolinium-enhanced 3D fast low-angle shot breath-hold imaging.
AB  - OBJECTIVE: The purpose of this study was to evaluate the diagnostic usefulness of
      three different MR angiographic techniques at 1.0 T. SUBJECTS AND METHODS: In 22
      patients with renal artery stenosis confirmed at intraarterial catheter
      angiography, we also performed unenhanced and gadolinium-enhanced three
      dimensional phase-contrast MR angiography and gadolinium-enhanced single breath
      hold three-dimensional fast low-angle shot MR angiography. We determined
      circulation time to optimize signal acquisition in gadolinium-enhanced breath
      hold MR angiography after bolus injection of contrast material. RESULTS:
      Sensitivity, defined as the detection of a hemodynamically significant stenosis
      (>50% luminal narrowing), was 85% for enhanced phase-contrast MR angiography, 91%
      for gadolinium-enhanced MR angiography, and 95% for unenhanced phase-contrast MR
      angiography. The combination of unenhanced phase-contrast MR angiography and
      gadolinium-enhanced MR angiography yielded 100% sensitivity for hilar artery
      stenoses. There were 13 false-positive findings with unenhanced phase-contrast MR
      angiography, 10 with enhanced phase-contrast MR angiography, and four with
      gadolinium-enhanced MR angiography (specificity: 38%, 52%, and 79%,
      respectively). Accessory renal arteries were not seen on unenhanced or enhanced
      phase-contrast MR angiography (0/8 patients) but were detected with gadolinium
      enhanced MR angiography in five of the eight patients. Interobserver agreement
      (kappa = .62) was best with gadolinium-enhanced MR angiography. The quality of
      the images was unsatisfactory for adequate evaluation of segmental renal arteries
      with all three MR angiographic techniques. CONCLUSION: A combination of
      unenhanced phase-contrast MR angiography and gadolinium-enhanced MR angiography
      at 1.0 T proved useful as a screening protocol for renal artery stenosis.

PMID- 10350281
TI  - Contrast-enhanced MR angiography in the assessment of arteriovenous fistula after
      renal transplant biopsy.

PMID- 10350282
TI  - Transvaginal saline hysterosonography: characteristics distinguishing malignant
      and various benign conditions.
AB  - OBJECTIVE: The objective of this study is to establish criteria for
      distinguishing endometrial polyps, submucosal leiomyomas, endometrial
      hyperplasia, and endometrial carcinoma on saline hysterosonography. MATERIALS AND
      METHODS: Sixty-three saline hysterosonograms with histologic confirmation were
      retrospectively analyzed. We found 26 endometrial polyps, 16 submucosal
      leiomyomas, three endometrial hyperplasias, one abnormal endometrium associated
      with a sloughed polyp, one pseudopolyp, and three endometrial carcinomas; 15
      sonograms revealed no abnormality. In two patients, sonography revealed both
      polyps and submucosal leiomyomas. The sonographic appearance of these
      abnormalities was analyzed to define criteria for their diagnosis. RESULTS:
      Twenty-five of 26 polyps were uniformly echogenic with smooth borders and either
      had a stalk or formed acute angles with underlying endometrium. Sixteen of 16
      submucosal leiomyomas showed heterogeneous echogenicity; however, 13 were sessile
      and three were pedunculated. Endometrial hyperplasia was manifested by wall
      thickening in two patients and tiny polypoid excrescences in one patient. In all
      patients with endometrial carcinoma, the endometrial cavities were poorly
      distensible despite successful cervical os cannulation. All patients with
      abnormalities other than endometrial carcinoma had fully distensible uterine
      cavities. CONCLUSION: Malignant and various benign endometrial conditions may be
      accurately distinguished on saline hysterosonography. Uniformity of echogenicity
      distinguished all polyps from submucosal leiomyomas, but the angulation formed
      with the endometrial wall by the intracavitary mass did not distinguish all
      polyps from submucosal leiomyomas. Lack of distensibility of the endometrial
      canal is a potential sign of endometrial carcinoma.

PMID- 10350283
TI  - Comparison of laparoscopic sonography with surgical pathology in the evaluation
      of pelvic lymph nodes in women with cervical cancer.
AB  - OBJECTIVE: This study compared laparoscopic sonography with surgical pathology in
      the evaluation of pelvic lymph nodes in women with cervical cancer. SUBJECTS AND
      METHODS: Intraoperative laparoscopic sonography of pelvic lymph nodes was
      performed in 31 women with biopsy-proven cervical cancer. A lymph node that was
      rounded (longitudinal-transverse axis ratio of <2) or showed absence of central
      hilum was defined as positive for metastasis. For comparison, lymph nodes from
      each hemipelvis were grouped anatomically into paraaortic, common, internal, and
      external iliac chains during evaluation on laparoscopic sonography and on
      surgical pathologic examination. RESULTS: Pelvic dissection in 31 women yielded
      630 lymph nodes. There were 54 metastatic nodes in 12 women. Laparoscopic
      sonography revealed 32 (59%) of all pathologically metastatic lymph nodes.
      Sensitivity on laparoscopic sonography when comparing groups by hemipelves was
      93.3% and by anatomic lymph node chains was 76.2%. Metastatic nodes were most
      commonly located in the common iliac region and were characteristically rounded,
      hypoechoic, showed absence of central hilum, and occasionally showed central
      necrosis. Nine (28%) of 32 metastatic lymph nodes revealed by laparoscopic
      sonography measured 1 cm or less. Six benign nodes in four patients were also
      visualized with laparoscopic sonography. CONCLUSION: Laparoscopic sonography
      achieved a sensitivity exceeding 90% in the detection of metastatic lymph nodes
      in the hemipelves of women with cervical cancer. Laparoscopic sonography is a
      feasible and promising technique for the evaluation of pelvic lymph nodes in
      women with cervical cancer and merits further evaluation.

PMID- 10350284
TI  - Primary sclerosing cholangitis: MR imaging features.
AB  - OBJECTIVE: The purpose of this study was to evaluate the spectrum of MR imaging
      features of primary sclerosing cholangitis. MATERIALS AND METHODS: A
      retrospective review was performed of MR imaging findings including MR
      cholangiography and multiphasic contrast-enhanced dynamic sequences in 22
      patients with primary sclerosing cholangitis. MR imaging analysis included
      abnormalities of intra- and extrahepatic bile ducts, abnormalities of liver
      parenchyma, changes in liver morphology, and lymphadenopathy. RESULTS: Abnormal
      findings of bile ducts were seen in all 22 patients; the most common finding was
      intrahepatic bile duct dilatation (77%), followed by intrahepatic bile duct
      stenosis (64%), extrahepatic bile duct wall enhancement (67%), extrahepatic bile
      duct wall thickening (50%), extrahepatic bile duct stenosis (50%), and
      intrahepatic bile duct beading (36%). Increased enhancement of the liver
      parenchyma on dynamic arterial-phase images, predominantly in the peripheral
      areas of the liver, was identified in 56% of patients. Other findings included
      periportal lymphadenopathy (77%), periportal high signal intensity on T2-weighted
      images (68%), hypertrophy of the caudate lobe (68%), and abnormal hyperintensity
      of the liver parenchyma on T1-weighted images (23%). CONCLUSION: On MR imaging,
      primary sclerosing cholangitis showed several characteristic features, including
      bile duct abnormalities and increased enhancement of the liver parenchyma. MR
      cholangiography and contrast-enhanced dynamic MR techniques are useful for
      revealing intra- and extrahepatic signs of primary sclerosing cholangitis.

PMID- 10350285
TI  - MR diagnosis of adenomyomatosis of the gallbladder and differentiation from
      gallbladder carcinoma: importance of showing Rokitansky-Aschoff sinuses.
AB  - OBJECTIVE: We evaluated the MR imaging features of adenomyomatosis of the
      gallbladder with particular emphasis on Rokitansky-Aschoff sinuses. MATERIALS AND
      METHODS: MR images of 17 patients with histologically proven adenomyomatosis were
      retrospectively reviewed. The presence of Rokitansky-Aschoff sinuses was
      evaluated and analyzed; four T2-weighted (fast spin-echo with a surface coil,
      with or without breath-holding, fast spin-echo with a phased-array coil with
      breath-holding, and half-Fourier rapid acquisition with relaxation enhancement
      with breath-holding) and two contrast-enhanced dynamic pulse sequences were
      studied. These six pulse sequences were separately rated on a 5-point scale by
      two radiologists for comparison. Interobserver differences were evaluated. Other
      MR findings were also analyzed. RESULTS: Among the six pulse sequences studied,
      three T2-weighted with breath-holding sequences were found to be superior to the
      other three sequences in showing Rokitansky-Aschoff sinuses. In particular, the
      half-Fourier rapid acquisition with relaxation enhancement was scored the highest
      by the two observers and received the highest kappa coefficient in our
      statistical analysis of the scoring. Diffuse-type adenomyomatosis typically
      showed early mucosal and subsequent serosal enhancement. Localized
      adenomyomatosis exhibited homogeneous enhancement, showing smooth continuity with
      the surrounding gallbladder epithelium. CONCLUSION: MR imaging may be able to
      provide important information in the diagnosis of adenomyomatosis.

PMID- 10350286
TI  - MR cholangiography of late biliary complications after liver transplantation.
AB  - OBJECTIVE: The aim of our study was to assess the role of MR cholangiography in
      the diagnosis of late biliary complications after liver transplantation. SUBJECTS
      AND METHODS: Twenty-three liver transplantation patients (18 men and five women;
      mean age, 46 years) underwent MR cholangiography using a nonbreath-hold, fat
      suppressed three-dimensional turbo spin-echo sequence (TR/TE, 3000/700; echo
      train length, 128) optimized on a 0.5-T magnet. Inclusion criteria were liver
      function tests with abnormal results and hyperbilirubinemia with a clinical
      pattern not specific for biliary obstruction. All patients were referred by
      clinicians for contrast-enhanced cholangiography. Diagnostic confirmation was
      obtained with percutaneous transhepatic cholangiography (n = 4), endoscopic
      retrograde cholangiography (n = 8), T-tube cholangiography (n = 1), or clinical
      follow-up (n = 10). RESULTS: In 11 patients, no abnormalities of the biliary
      tract were revealed by MR cholangiography. In 11 patients, twelve strictures were
      diagnosed (nine anastomotic, two nonanastomotic-intrahepatic, and one
      nonanastomotic-extrahepatic, with association between anastomotic and
      nonanastomotic strictures in two cases). In one other patient, kinking of the
      common bile duct at the level of the anastomosis was observed. In all cases, MR
      cholangiography correctly showed the site of the stricture and the dilatation of
      bile ducts above, with excellent correlation with contrast-enhanced
      cholangiographic findings. Strictures were correctly graded in eight of 10
      patients and were overestimated in two. Other findings included a 1-cm stone
      detected proximal to the obstructed common bile duct in one patient and multiple
      intrahepatic stones in another patient. CONCLUSION: MR cholangiography can show
      biliary obstruction and provide important information for planning therapeutic
      procedures.

PMID- 10350287
TI  - Detection of hepatocellular carcinoma arising in cirrhotic livers: comparison of
      gadolinium- and ferumoxides-enhanced MR imaging.
AB  - OBJECTIVE: We prospectively compared the detectability of hepatocellular
      carcinoma (HCC) arising in cirrhotic livers using dynamic gadolinium-enhanced
      fast low-angle shot (FLASH), ferumoxides-enhanced T2-weighted turbo spin-echo,
      and ferumoxides-enhanced T2*-weighted FLASH MR imaging. SUBJECTS AND METHODS:
      Fifty-three patients with HCC (32 men and 21 women) who were 33-86 years old
      (mean, 63 years old) were enrolled in a prospective MR study to assess hepatic
      lesions using both gadopentetate dimeglumine and ferumoxides. Dynamic gadolinium
      enhanced imaging was obtained before and 30, 60, and 180 sec after rapid bolus
      injection of gadopentetate dimeglumine (0.1 mmol/kg). Ferumoxides-enhanced T2
      weighted turbo spin-echo imaging and ferumoxides-enhanced T2*-weighted FLASH
      imaging were performed between 30 min and 2 hr after i.v. infusion of ferumoxides
      (10 micromol/kg). Images were analyzed qualitatively and quantitatively. A
      receiver operating characteristic curve study was performed to compare the
      diagnostic value of gadolinium-enhanced imaging with that of ferumoxides-enhanced
      imaging for the detection of HCC. RESULTS: Quantitative analysis revealed a
      significantly higher percentage of signal-intensity loss and higher liver-lesion
      contrast-to-noise ratio on ferumoxides-enhanced T2*-weighted FLASH imaging than
      on ferumoxides-enhanced T2-weighted turbo spin-echo imaging. The percentage of
      signal-intensity loss and liver-lesion contrast-to-noise ratio on ferumoxides
      enhanced images was significantly higher in patients with mild liver cirrhosis
      (Child's class A) than in patients with severe liver cirrhosis (Child's class C).
      Qualitative analysis showed that dynamic gadolinium-enhanced images revealed
      significantly higher lesion conspicuity than did ferumoxides-enhanced T2-weighted
      turbo spin-echo images. According to receiver operating characteristic analysis,
      dynamic gadolinium-enhanced FLASH imaging achieved the highest sensitivity, and
      ferumoxides-enhanced T2*-weighted FLASH imaging was the second most sensitive. We
      found that ferumoxides-enhanced turbo spin-echo imaging was the least valuable
      technique for revealing HCC lesions. Gadolinium-enhanced imaging revealed more
      HCC lesions than did ferumoxides-enhanced imaging, particularly for lesions
      smaller than 2 cm in diameter. CONCLUSION: Ferumoxides-enhanced imaging revealed
      fewer findings, such as lesion conspicuity of HCCs arising in cirrhotic livers,
      than did gadolinium-enhanced FLASH imaging.

PMID- 10350288
TI  - Metastases to the pancreas from renal cell carcinoma: findings on three-phase
      contrast-enhanced helical CT.
AB  - OBJECTIVE: Our goal was to define the lesion enhancement characteristics of renal
      cell carcinoma metastases to the pancreas using three-phase helical CT. MATERIALS
      AND METHODS: Thin-section three-phase contrast-enhanced CT scans of nine patients
      with renal cell carcinoma metastases to the pancreas were evaluated. The helical
      CT protocol included 3-mm collimation and a 2:1 pitch. Scans through the pancreas
      were obtained in three series beginning 25, 60, and 120 sec after the start of
      administration of i.v. contrast material delivered at 3 ml/sec. The Hounsfield
      densities of the pancreatic lesions and normal pancreatic parenchyma during each
      of the enhancement phases were recorded and compared. RESULTS: The enhancement
      patterns of the metastatic deposits and the normal pancreas differed. Thirty-four
      lesions ranging in size from 6 to 110 mm were identified. All metastases showed
      rapid enhancement during the early (arterial and portal) phases, resulting in
      differential attenuations (compared with normal pancreatic parenchyma) of
      approximately 50-100 H. The differential attenuations were approximately 5-45 H
      on delayed-phase scans, resulting in poorer conspicuity of the lesions.
      Multifocal metastases were clearly identified on the early-phase scans in seven
      patients. CONCLUSION: Renal cell carcinoma metastases to the pancreas enhance
      most conspicuously during the early phases of helical CT. Such metastases may
      fail to be appreciated in the delayed phase. In patients with suspected renal
      cell carcinoma metastases to the pancreas, early-phase scanning after i.v.
      contrast administration should be performed.

PMID- 10350289
TI  - Are oblique views needed for trauma radiography of the distal extremities?
AB  - OBJECTIVE: To our knowledge, few studies exist on the importance of the oblique
      view when radiography of the distal extremities is performed after acute trauma.
      Our prospective study aimed to determine whether the oblique view uniquely
      revealed abnormalities or clarified findings when it was obtained along with
      routine frontal and lateral radiographs. SUBJECTS AND METHODS: We prospectively
      interpreted 1461 consecutive radiographic examinations of the distal extremities
      in patients presenting with acute trauma to four family medicine clinics. The
      anatomic sites radiographed included the ankle, foot, toe, wrist, hand, finger,
      and thumb. Each study was interpreted and given a diagnostic certainty score
      using the lateral and posteroanterior or anteroposterior views only and then
      scored again with the oblique view added. RESULTS: The examinations included 421
      with abnormal findings, 34 with equivocal findings, and 1006 with normal
      findings. The addition of the oblique view changed the interpretation in 70
      (4.8%) of the 1461 examinations. Of these changed interpretations, 39 were
      changed from equivocal to either positive or negative, three from positive to
      negative, and 28 from negative to positive. Addition of the oblique view
      increased diagnostic confidence: The percentage of examinations scored as having
      probably normal, equivocal, and probably abnormal findings decreased from 13.9%
      with two views to 8.4% with three views (p < .0001). The oblique view was equally
      valuable in the ankle, foot, toe, wrist, hand, finger, and thumb. CONCLUSION: In
      the distal extremities, the oblique view uniquely reveals abnormalities and
      increases the confidence of the final radiographic diagnosis when the oblique
      view is interpreted along with frontal and lateral radiographs.

PMID- 10350290
TI  - MR imaging of the subcoracoid bursa.
AB  - OBJECTIVE: The subcoracoid bursa, a bursa anterior to the shoulder joint, can be
      identified on MR images. Awareness of the MR appearance and location of this
      bursa, which can connect with the subacromial-subdeltoid bursa, enables
      appropriate diagnosis in patients with shoulder pain. MATERIALS AND METHODS:
      Dictated reports involving all MR imaging of the shoulder (n = 1545) performed at
      our institution from June 1993 to February 1998 were reviewed from computer
      archives. Films were reviewed in 16 cases describing a subcoracoid bursa; in nine
      MR imaging correctly revealed this bursa, whereas in seven MR imaging revealed
      the subscapular recess, an outpouching of the glenohumeral joint often confused
      with the subcoracoid bursa. RESULTS: Of the 1545 shoulders examined, MR imaging
      revealed the subcoracoid bursa in nine (0.6%) patients. Two cases from a teaching
      file were also included, for a total of 11 cases. In five (45%) of the 11 cases,
      the subcoracoid bursa contained a small amount of fluid (<1 cm in largest
      diameter on sagittal images). In the remaining six cases (55%), the subcoracoid
      bursa contained a moderate (1-2 cm in largest diameter) or a large amount (>2 cm
      in largest diameter) of fluid. Of the 11 cases, six (55%) also showed connection
      with the subacromial-subdeltoid bursa. CONCLUSION: It is important to correctly
      identify the subcoracoid bursa on MR imaging because it is believed to cause
      isolated shoulder pain. Fluid in the subcoracoid bursa can also communicate with
      the subacromial-subdeltoid bursa.

PMID- 10350291
TI  - MR imaging-guided MR arthrography of the shoulder: clinical experience on a
      conventional closed high-field system.

PMID- 10350292
TI  - Pericruciate meniscal cysts arising from tears of the posterior horn of the
      medial meniscus: MR imaging features that simulate posterior cruciate ganglion
      cysts.
AB  - OBJECTIVE: The purpose of this study is to describe MR imaging features of an
      unusual type of meniscal cyst arising from tears of the posterior horn of the
      medial meniscus in 10 patients. MATERIALS AND METHODS: Retrospective review of MR
      examinations of the knee was performed of 10 patients (nine men, one woman; mean
      age, 39 years) in whom evidence of a meniscal tear and a cyst-like structure
      around the posterior cruciate ligament (PCL) was seen. RESULTS: An oval mass with
      low signal intensity on T1-weighted MR images and increased signal intensity on
      T2-weighted MR images posterior to the PCL, simulating a PCL ganglion cyst, was
      seen in all 10 patients. A tear of the posterior horn of the medial meniscus was
      also seen in all patients. The sites of communication between the cyst and
      meniscal tear were observed in sagittal MR images in eight patients. Septation
      within the cyst and associated joint effusion were seen in eight and four
      patients, respectively. Arthroscopy in eight patients and transmeniscal needle
      drainage in the other two patients confirmed both the meniscal tear and the
      pericruciate meniscal cyst. CONCLUSION: Pericruciate meniscal cysts cause fluid
      collections posterior to the PCL, simulating a PCL ganglion cyst. Careful
      analysis of the posterior horn of the medial meniscus should be performed when a
      cyst-like structure is seen adjacent to the PCL.

PMID- 10350293
TI  - Quantitative MR imaging of carpal tunnel syndrome.
AB  - OBJECTIVE: Previous MR imaging studies have produced evidence of changes to
      structures within the wrist believed to be associated with carpal tunnel
      syndrome. In an attempt to resolve the conflicting and inconclusive results of
      these studies, we report here the results of an MR imaging study at a field
      strength of 3.0 T, which is higher than that previously reported. SUBJECTS AND
      METHODS: Patients with carpal tunnel syndrome and control groups of asymptomatic
      subjects were studied using MR imaging. We evaluated electrophysiologically the
      median nerve function of the affected wrists of all patients. A gradient-recalled
      echo pulse sequence was used to study 13 3-mm-thick slices within the wrist of
      each patient or asymptomatic subject. Spatial resolution was approximately 0.3 x
      0.3 mm2. The median nerve and other structures associated with the carpal tunnel,
      which were clearly shown on the MR images, were analyzed to yield structural
      data. RESULTS: Analysis revealed that the cross-sectional area of the nerve
      within and proximal to the carpal tunnel was approximately 50% larger in patients
      with carpal tunnel syndrome than in asymptomatic subjects. We found no
      significant difference in the area of the nerve within the carpal tunnel
      compartment compared with the area of the nerve proximal to the carpal tunnel
      either in patients or in asymptomatic subjects. Also, flattening of the nerve on
      entering the carpal tunnel was not significantly different in patients than in
      asymptomatic subjects. In patients an increase in the palmar bowing of the flexor
      retinaculum was found only at the level of the hamate compared with that found in
      asymptomatic subjects. The cross-sectional area of the carpal tunnel was of a
      similar size in patients and in asymptomatic subjects. Comparison of
      electrodiagnostic results indicated no correlations between the MR parameters and
      electrophysiologic dysfunction of the median nerve for patients. CONCLUSION: The
      only statistically significant differences found between patients with carpal
      tunnel syndrome and asymptomatic subjects were that the median nerve was
      approximately 50% larger within and proximal to the carpal tunnel in patients
      with carpal tunnel syndrome and palmar bowing of the flexor retinaculum occurred
      in patients only at the level of the hamate.

PMID- 10350294
TI  - Tophaceous pseudogout of the sternoclavicular joint.

PMID- 10350295
TI  - Treatment of venous outflow stenoses in thigh grafts with Wallstents.
AB  - OBJECTIVE: We studied the effectiveness of Wallstent deployment to treat elastic
      femoral and iliac vein stenoses in patients with lower extremity hemodialysis
      grafts. MATERIALS AND METHODS: Between August 31, 1992, and October 13, 1997, 44
      metallic stents were deployed in 20 patients to treat stenoses exhibiting
      immediate, significant elastic recoil after angioplasty. Twenty-four stents were
      placed in the femoral and saphenous veins, and the remaining 20 stents were
      placed in the iliac veins. Follow-up was provided by the nephrology and surgical
      service at our institution and by electronic review of patients' charts. The
      follow-up period was from August 31, 1992, until October 1, 1998. RESULTS: Stents
      were successfully inserted and stenotic lesions dilated in 100% of procedures.
      Each patient successfully completed at least one session of dialysis after the
      procedure. The primary patency rate of stents was 87% 60 days after the
      procedure, 51% 180 days after, 39% 1 year after, and 20% 2 years after. The
      secondary patency rate was 95% 60 days after the procedure, 92% 180 days after,
      81% 1 year after, and 62% 2 years after. Complications were limited to two graft
      infections that developed 5 and 7 days after stent placement. CONCLUSION:
      Treatment of elastic venous stenoses is effective in patients with lower
      extremity dialysis grafts using metallic stents. The patency rates of these
      devices placed in the iliac and femoral veins are comparable with those of
      metallic stents placed in upper extremity and central veins.

PMID- 10350296
TI  - Hepatic falciform artery: is prophylactic embolization needed before short-term
      hepatic arterial chemoinfusion?
AB  - OBJECTIVE: The purpose of this study was to assess the need for prophylactic
      embolization of the hepatic falciform artery (HFA) to prevent supraumbilical skin
      rash before short-term hepatic arterial chemoinfusion with or without subsequent
      embolization. MATERIALS AND METHODS: Transcatheter arterial chemoinfusions or
      chemoembolizations were performed on 127 consecutive patients with hepatocellular
      carcinoma between August 1997 and September 1997. Hepatic angiography findings
      regarding the anatomic variations of the hepatic artery and the presence and
      origin of the HFA were analyzed. The patients were followed up for 35-143 days
      (mean, 78 days). The incidence of supraumbilical skin rash was assessed for two
      groups of patients, those with an HFA and those without. We also evaluated other
      factors that seemed closely related to the presence of an HFA. RESULTS: An HFA
      was identified in 16 (13%) of 127 patients. Each HFA originated either in the
      left hepatic artery (n = 14) or the middle hepatic artery (n = 2). In the 16
      patients with an HFA, serum bilirubin levels were significantly higher than in
      patients without one (p < .05), whereas serum albumin levels and prothrombin
      times were significantly lower (p < .05) and more prolonged (p = .02) than in
      patients without one. Portal venous collateral vessels were more frequently seen
      in patients with an HFA (50%) than in those without one (31%), but the frequency
      was not significant (p = .157). However, supraumbilical skin rash was not seen in
      any patient. CONCLUSION: We found no need for prophylactic embolization of the
      HFA to prevent supraumbilical skin rash before short-term hepatic arterial
      chemoinfusion with or without subsequent embolization.

PMID- 10350298
TI  - Doppler spectral waveform analysis of arteries of the hand in patients with
      Raynaud's phenomenon as compared with healthy subjects.
AB  - OBJECTIVE: We sought to characterize and compare the blood flow patterns of
      peripheral arteries of the hand in patients with Raynaud's phenomenon and in
      healthy subjects. SUBJECTS AND METHODS: We used Doppler sonography to assess the
      blood flow pattern of the proper palmar digital artery and the deep radial arch
      in the hands of 79 healthy subjects and 24 patients with primary and secondary
      Raynaud's phenomenon. We determined the resistive index, pulsatility index, peak
      systolic velocity, and end-diastolic velocity of these peripheral arteries at
      rest and after cold immersion. RESULTS: The proper palmar digital artery of
      healthy subjects showed higher end-diastolic velocities and lower resistive
      indexes than did the deep radial arch. Compared with healthy subjects, patients
      with Raynaud's phenomenon had higher resistive and pulsatility indexes but lower
      peak systolic and end-diastolic velocities in these arteries. Accordingly, the
      differences in end-diastolic velocity and resistive index seen in the two
      peripheral arteries of healthy subjects were not seen in patients with Raynaud's
      phenomenon. Analysis of receiver operating characteristic curves showed high
      diagnostic accuracy in detecting the disease. Cold-immersion studies revealed
      that for the proper palmar digital arteries throughout the time after immersion,
      all these Doppler parameters were significantly lower for the velocities and
      higher for the indexes in patients with Raynaud's phenomenon than in healthy
      subjects. CONCLUSION: Taken together, these results suggest a legitimate role for
      Doppler sonography in the assessment of Raynaud's phenomenon.

PMID- 10350297
TI  - Clinical outcomes of untreated symptomatic patients with negative findings on
      sonography of the thigh for deep vein thrombosis: our experience and a review of
      the literature.
AB  - OBJECTIVE: Our objective was to determine whether immediate venography or other
      additional imaging is necessary in symptomatic patients who have negative
      findings on sonography of the thigh for deep vein thrombosis (DVT). MATERIALS AND
      METHODS: We retrospectively evaluated the clinical outcomes of 146 patients with
      physical signs or symptoms consistent with DVT in whom sonography of the thigh
      was negative for DVT. We combined our results with those of three prospective
      studies that evaluated symptomatic patients with suspected DVT in whom sonography
      of the thigh had negative findings. Propagated DVT (from calf to thigh) and
      pulmonary emboli were considered adverse outcomes. RESULTS: Only one pulmonary
      embolus (0.7%) occurred in our patient population. However, one (7.7%) of 13
      patients who underwent second examinations because of persistent symptoms
      developed thigh DVT. Review of the literature found four (0.2%) of 1797 patients
      subsequently developed pulmonary emboli after undergoing sonography of the thigh
      that was initially interpreted as having negative findings. Fifteen (12.5%) of
      120 patients who underwent second sonographic examinations developed DVT of the
      thigh. No deaths from pulmonary emboli occurred in patients in our study or
      patients in the studies published in the medical literature. CONCLUSION:
      Immediate venography or other additional imaging is not necessary in symptomatic
      patients in whom sonography of the thigh is negative for DVT, given the
      exceedingly low risk of a pulmonary embolus. Follow-up sonography is indicated in
      persistently symptomatic patients to detect propagation of calf DVT into the
      thigh.

PMID- 10350299
TI  - Absence of the infrarenal inferior vena cava with preservation of the suprarenal
      segment as revealed by CT and MR venography.

PMID- 10350300
TI  - Selective angiography of the common carotid artery with gadopentetate dimeglumine
      in a patient with renal insufficiency.

PMID- 10350301
TI  - Use and cost of breast imaging for postmenopausal women undergoing hormone
      replacement therapy.
AB  - OBJECTIVE: The purpose of this study was to evaluate the use and associated costs
      of breast imaging studies for postmenopausal women undergoing hormone replacement
      therapy (HRT). MATERIALS AND METHODS: Clinical findings, mammographic findings,
      and imaging studies performed on 1133 postmenopausal women during a 5-month
      period in 1996 were retrospectively reviewed. Cost was estimated using Medicare
      reimbursement rates. RESULTS: Of the 1133 women, 699 (62%) underwent HRT. The
      number of women with breast complaints was similar for those undergoing (n = 62,
      9%) and not undergoing (n = 26, 6%) HRT. Benign findings were more common for
      women undergoing HRT (n = 186, 27%) than for women not undergoing HRT (n = 92,
      21%) (p = .04). Masses were noted in 133 of the women undergoing HRT (19%),
      compared with 42 women not undergoing HRT (10%) (p < .000). Specifically, cysts
      were seen in 46 women undergoing HRT (7%), compared with five women not
      undergoing HRT (1%) (p < .0001). Diagnostic mammograms and sonograms were more
      commonly obtained in women undergoing HRT (33 and 13 per 100 women, respectively)
      than in women not undergoing HRT (24 and seven per 100, respectively) (p = .014
      and .0007, respectively). The overall cost of breast imaging was $89 for each
      woman undergoing HRT and $87 for each woman not undergoing HRT. CONCLUSION:
      Benign mammographic findings, primarily cysts, in women undergoing HRT result in
      an increased use of diagnostic mammography and sonography. The minimal increase
      in cost should not be a significant factor in the decision to use HRT.

PMID- 10350302
TI  - Sonography of solid breast lesions: observer variability of lesion description
      and assessment.
AB  - OBJECTIVE: The purpose of this study was to measure the level of inter- and
      intraobserver agreement and to evaluate the causes of variability in
      radiologists' descriptions and assessments of sonograms of solid breast masses.
      MATERIALS AND METHODS: Sixty sonograms of solid masses were evaluated
      independently by five radiologists. Observers used the lexicon of a recently
      published benchmark report on sonographic appearances of breast masses to
      determine mass shape, margin, echogenicity, echo texture, presence of echogenic
      pseudocapsule, and acoustic transmission. Final diagnostic assessments were
      determined by applying the rule-based model of the same benchmark report to the
      radiologists' descriptions. In addition, one observer interpreted each case twice
      to evaluate intraobserver variability. Inter- and intraobserver variability were
      measured using Cohen's kappa statistic. We also investigated causes of
      variability in radiologists' descriptions. RESULTS: Interobserver agreement
      ranged from lowest for determining the presence of an echogenic pseudocapsule
      (kappa = .09) to highest for determining mass shape (kappa = .8). Intraobserver
      agreement was lowest for mass echo texture (kappa = .24) and greatest for mass
      shape (kappa = .79). Variability in descriptions of lesions contributed to
      interobserver (kappa = .51) and some intraobserver (kappa = .66) inconsistency in
      assessing the likelihood of malignancy. CONCLUSION: Lack of uniformity among
      observers' use of descriptive terms for solid breast masses resulted in
      inconsistent diagnoses. The need for improved definitions and additional
      illustrative examples could be addressed by developing a standardized lexicon
      similar to that of the Breast Imaging Reporting and Data System.

PMID- 10350303
TI  - Clinical validity of helical CT being interpreted as negative for pulmonary
      embolism: implications for patient treatment.
AB  - OBJECTIVE: The purpose of our study was to assess the clinical usefulness of
      helical CT findings that are interpreted as negative for pulmonary embolism.
      MATERIALS AND METHODS: One hundred twenty-six patients underwent 132 helical CT
      examinations and 352 patients underwent ventilation-perfusion scanning for
      suspected acute pulmonary embolism over a 17-month period at a single
      institution. Findings from clinical follow-up at a minimum of 6 months were
      assessed, with a special focus on the presence of recurrent thromboembolism and
      mortality in 78 consecutive patients in whom helical CT findings were interpreted
      as negative for pulmonary embolism and anticoagulant therapy was not administered
      (group I). During the same 17-month period, 46 patients underwent ventilation
      perfusion scanning that was interpreted as normal (group II), and 132 patients
      underwent ventilation-perfusion scanning that was interpreted as showing a very
      low to low probability for pulmonary embolism (group III). Patients in groups II
      and III did not undergo helical CT or pulmonary angiography and did not receive
      anticoagulant therapy. However, clinical follow-up was solicited. Patients from
      groups II and III were used as control subjects. RESULTS: Nine patients in group
      I died, one of whom was found to have a microscopic pulmonary embolism at
      autopsy. In group II, four patients died, none of whom were shown to have a
      missed or recurrent pulmonary embolism. Of the 18 patients in group III who died,
      three had a recurrent or missed pulmonary embolism (mean interval, 9 days), and
      two were found to have deep vein thrombosis on sonography of the leg (mean
      interval, 12 weeks). Negative predictive values for helical CT, normal lung
      scanning, and low-probability ventilation-perfusion scanning were 99%, 100%, and
      96%, respectively (p = .299). CT provided either additional findings or an
      alternate diagnosis in 42 (53.8%) of the 78 patients in whom helical CT findings
      had been interpreted as negative for pulmonary embolism. CONCLUSION: A helical CT
      scan can be effectively used to rule out clinically significant pulmonary emboli
      and may prevent further investigation or unnecessary treatment of most patients.

PMID- 10350305
TI  - Standardized high-resolution CT of the lung using a spirometer-triggered electron
      beam CT scanner.

PMID- 10350304
TI  - Gas in the sternoclavicular joints of patients with blunt chest trauma:
      significance and frequency of CT findings.
AB  - OBJECTIVE: In trauma patients, gas (vacuum phenomenon) in the sternoclavicular
      joints could represent sequelae of significant distraction forces and thus serve
      as a potential marker for severe intrathoracic injury. We evaluated the
      significance and frequency of the finding of gas in the sternoclavicular joints
      on chest CT of patients with blunt trauma. SUBJECTS AND METHODS: We prospectively
      studied all chest CT examinations performed at our institution over a 14-week
      period for the finding of gas in the sternoclavicular joints. Chest CT
      examinations (n = 267) were performed in 234 patients. We excluded data from
      follow-up CT examinations (n = 33), limiting our evaluation to the initial CT
      examination for each patient. Of the study population, 103 patients (83 men and
      20 women) who ranged in age from 14 to 79 years (mean, 40 years) had sustained
      blunt chest trauma. For all trauma patients, we recorded the mechanism of injury
      and the associated thoracic injuries. RESULTS: CT revealed gas in the
      sternoclavicular joints in 47 patients (21%). Gas was unilateral in 27 patients
      and bilateral in 20 patients. Sternoclavicular joint gas was seen in 39 (38%) of
      the 103 trauma patients but was found in only eight (6%) of the 131 nontrauma
      patients (p < .0001). In the 39 trauma patients with sternoclavicular joint gas,
      associated thoracic injuries were seen in 17 patients (44%); either a sternal
      fracture or a retrosternal hematoma was seen in three patients. Radiographically
      evident thoracic injury was revealed in 20 (31%) of the 64 trauma patients who
      had no gas in the sternoclavicular joint; however, 10 of these 20 patients had
      either a sternal fracture or a mediastinal hematoma. CONCLUSION: Although gas in
      the sternoclavicular joints is more frequently seen in patients with blunt chest
      trauma than in patients undergoing chest CT for other indications, this finding
      does not indicate a greater risk of significant mediastinal or thoracic injury.

PMID- 10350306
TI  - Idiopathic pulmonary vein thrombosis: detection by CT and MR imaging.

PMID- 10350307
TI  - Pulmonary interstitial emphysema: CT findings.

PMID- 10350308
TI  - Pulmonary hamartoma.

PMID- 10350309
TI  - Single breath-hold left ventricular volume measurement by 0.3-sec turbo fast low
      angle shot MR imaging.
AB  - OBJECTIVE: In this study, we measured global cardiac parameters during a single
      breath-hold using T1-weighted single-shot turbo fast low-angle shot (turboFLASH)
      MR imaging. SUBJECTS AND METHODS: Ten cardiac patients who had undergone cardiac
      catheterization were examined with MR imaging to evaluate cardiac function. On
      average, 10 slices, which covered enough of the heart to measure the left
      ventricular volume, were acquired in a single breath-hold. During the acquisition
      of each slice, T1-weighted turboFLASH MR imaging with inversion recovery of both
      end diastole and end systole was sequentially accomplished twice in the same R-R
      interval. The end-diastolic volume, end-systolic volume, and ejection fraction
      calculated from MR images were compared with data obtained from left
      ventriculography. RESULTS: In these 10 cardiac patients, the ejection fraction
      calculated from turboFLASH MR images showed a good correlation with the
      measurements from radiographic left ventriculography (r = .87). The inter- and
      intraobserver variabilities in calculating the ejection fraction were 7.8% and
      4.7%, respectively. CONCLUSION: Single-shot turboFLASH MR imaging with inversion
      recovery can provide data for the quantification of the ejection fraction during
      a single breath-hold.

PMID- 10350310
TI  - Localized radiolucent chest lesions in neonates: causes and differentiation.

PMID- 10350311
TI  - Azygos continuation of the inferior vena cava: sonographic demonstration of the
      renal artery ventral to the azygos vein as a clue to diagnosis.
AB  - OBJECTIVE: The purpose of this report is to describe the relationship between the
      renal artery and the azygos vein in patients with congenital infrahepatic
      interruption of the inferior vena cava with azygos continuation. CONCLUSION:
      Using abdominal sonography, we showed that in patients with interruption of the
      inferior vena cava with azygos continuation, the renal artery is ventral to the
      azygos vein. Because this malformation is frequently associated with cardiac and
      situs anomalies, awareness of the anatomic relationship between the renal artery
      and the azygos vein can aid in diagnosis and may substitute for more expensive
      and invasive diagnostic procedures.

PMID- 10350312
TI  - MR imaging of Tornwaldt's cysts.
AB  - OBJECTIVE: The purpose of this study was to assess the characteristics of
      Tornwaldt's cysts as revealed by routine MR studies. MATERIALS AND METHODS: We
      retrospectively reviewed MR images of the brain in 1208 consecutive subjects who
      ranged in age from 3 weeks to 93 years (mean, 57.1 years). The signal intensity,
      shape, and size of Tornwaldt's cysts were assessed. Patients with Tornwaldt's
      cysts were then questioned about the presence of persistent nasal discharge,
      occipital headaches, and halitosis and an unpleasant taste in the mouth and about
      a history of adenoidectomy. RESULTS: Tornwaldt's cysts were found in 23 patients
      (1.9%) who ranged in age from 39 to 78 years (mean, 57.3 years). Of the 23
      Tornwaldt's cysts, all were isointense to CSF on T2-weighted images and
      hyperintense to gray matter on the fluid-attenuated inversion-recovery images.
      The cysts showed high signal intensity compared with muscle on T1-weighted
      images. Nineteen cysts were round and four were oval. The mean size of the
      lesions was 6.0 mm in the major axis and 5.5 mm in the minor axis. Two patients
      with Tornwaldt's cysts had persistent nasal discharge and occipital headaches,
      and another patient had occipital headaches alone. None of the patients had
      undergone an adenoidectomy. CONCLUSION: Lesions consistent with Tornwaldt's cysts
      were found in 1.9% of the routine MR studies of the brain. The cysts had high
      signal intensity on T1-weighted, T2-weighted, and fluid-attenuated inversion
      recovery images.

PMID- 10350313
TI  - Imaging of head and neck paragangliomas with three-dimensional time-of-flight MR
      angiography.

PMID- 10350314
TI  - Temporal bone: comparison of isotropic helical CT and conventional direct axial
      and coronal CT.
AB  - OBJECTIVE: The objective of the study was to compare helical CT (with reformation
      of coronal images from the axial data set) with conventional direct axial and
      coronal CT of the temporal bones. SUBJECTS AND METHODS: Nineteen patients
      underwent both conventional 1-mm direct axial and coronal CT and helical 0.5-mm
      axial CT. The helical data set was reconstructed at 0.2-mm increments, and axial
      and coronal images were reconstructed in a plane similar to that of the
      conventional study, with a slice width of 0.5 mm and 0.5-mm increments. Forty
      small structures were evaluated independently by three observers, who were
      unaware of the method of imaging. Observers graded the 40 structures using a
      modified Likert scale. The graded differences between the two techniques were
      evaluated using a paired t test. Correlation between observers' gradings was
      evaluated using analysis of variance. RESULTS: The helical CT technique scored
      significantly higher than the conventional technique for many individual
      structures and groups of structures (scutum [p = .041], stapes footplate [p =
      .006], stapes crura [p = .004], oval window [p = .026], crista falciformis [p =
      .006], whole temporal bone [P = .012], middle ear [p = .033], inner ear [p =
      .021], ossicles [p = .044], and stapes [p = .010]). The correlation coefficient
      among observers was .91 for the whole temporal bone. CONCLUSION: Helical CT using
      0.5-mm technique and reconstruction produces diagnostic images comparable with or
      superior to conventional 1-mm technique because helical CT can obtain thinner
      slices.

PMID- 10350315
TI  - CT and MR imaging of focal calvarial lesions.

PMID- 10350316
TI  - Midgut volvulus with "whirlpool" signs.

PMID- 10350317
TI  - Helical CT after aortic stent-graft implantation.

PMID- 10350318
TI  - Gas lock obstruction of the colon, or bursting the bubble.

PMID- 10350319
TI  - Lower extremity sonography and the nondiagnostic lung scan.

PMID- 10350320
TI  - Elastofibroma dorsi anatomy.

PMID- 10350321
TI  - False-negative findings of core biopsy of the breast and malpractice issues in
      radiology.

PMID- 10350322
TI  - Improving tolerance of MR imaging with medical hypnosis.

PMID- 10350323
TI  - Multiple giant cell tumors complicating Paget's disease.

PMID- 10350324
TI  - MR imaging appearance of cutaneous sporotrichosis.

PMID- 10350325
TI  - Chronic lower extremity deep vein thrombosis associated with femoral vein
      compression by a lipoma.

PMID- 10350326
TI  - Venous infarction from a venous angioma occurring after thrombosis of a drainage
      vein.

PMID- 10350327
TI  - Scimitar syndrome: diagnosis with MR angiography.

PMID- 10350328
TI  - The potential for monocyte-mediated immunotherapy during infection and
      malignancy. Part I: apoptosis induction and cytotoxic mechanisms.
AB  - The mononuclear phagocyte system consists of peripheral blood monocytes and
      tissue macrophages that collectively play a major role in host immunity. Far from
      existing solely as phagocytic scavengers of cell debris and foreign matter,
      monocytes are highly active and responsive to inflammatory and immunological
      signals that activate their microbicidal and tumoricidal functions. Cytokines
      that are secreted as an integral component of the innate immune response such as
      granulocyte-macrophage colony-stimulating factor (GM-CSF) and -IFN may directly
      activate the functions of the monocyte system. A key mediator of the effector
      functions of monocytes is tumour necrosis factor (TNF) which transduces its
      signals upon binding to specific transmembrane receptors. TNF is highly cytotoxic
      to micro-organisms and susceptible malignant cells and in most cases delivers its
      cytotoxic signal to tumour cells by highly regulated mechanisms of programmed
      cell death or apoptosis. We believe that the numerous functions of the monocyte
      system may be harnessed for therapeutic gain both in the context of
      microbiological infection and malignant disease. In this review, the mechanisms
      by which secreted and monocyte cell-membrane-associated TNF induce apoptosis will
      be discussed. In addition, the cell-associated and secretory immunological
      mechanisms employed by monocytes in host defence will be discussed in the context
      of the their ability to combat infection and neoplasia.

PMID- 10350329
TI  - Chromosomal rearrangement of the PAX-5 locus in lymphoplasmacytic lymphoma with
      t(9;14)(p13;q32).
AB  - B-cell non-Hodgkin's lymphoma (NHL) consists of heterogeneous subtypes based on
      histologic, immunophenotypic, and clinical findings. Recent advances in molecular
      biology have provided us new insights into the pathogenesis of this neoplasm at
      the genetic level, such as the deregulation of the protooncogenes adjoining the
      immunoglobulin gene (Ig) loci, which is a specific event in mature B-cell tumors.
      Moreover, involvement of certain protooncogenes corresponds to certain subtypes
      of NHL. Recently, we found that t(9;14)(p13;q32) chromosomal translocation
      associated with lymphoplasmacytic lymphoma (LPL) juxtaposes PAX-5 gene encoding
      for an essential transcription factor (BSAP: B-cell specific activator protein)
      for B-cell proliferation and differentiation to the Ig heavy chain gene (IgH)
      locus. This results in deregulated expression of the PAX-5 mRNA. We also
      developed a diagnostic FISH (fluorescence in situ hybridization) procedure which
      is able to detect 80% of the widely scattering 9p13 breakpoints involved in this
      translocation. Thus, an understanding of the PAX-5 gene's physiological role in B
      cell development and the pathological role in tumorigenesis may lead to the
      optimal clinical treatment strategy for LPL and LPL-derived diffuse large cell
      lymphoma (DLCL).

PMID- 10350331
TI  - BCL2 overexpression in diffuse large B-cell lymphoma.
AB  - Translocation (14;18)(q32;q21), which is detected in 20-30% of diffuse large B
      cell lymphomas (DLBCL), is regarded as a major mechanism for BCL2 protein
      overexpression. Nevertheless, BCL2 overexpression is not always caused by
      t(14;18), because it is often detected in lymphomas without BCL2 rearrangement.
      Recent studies have shown that increased expression of BCL2 may also result from
      BCL2 gene amplification in DLBCL. Similarly, it has been speculated that the
      mutations of the open reading frame might cause increased expression of BCL2 by
      affecting the interactions of BCL2 with other proteins. The results obtained from
      studies on the association of BCL2 protein overexpression with survival of DLBCL
      are controversial, although a correlation with decreased overall survival seems
      to exist. However, BCL2 rearrangement does not seem to have any major association
      with poor prognosis, but it is difficult to assess its true impact on prognosis
      due to differences in treatment and follow-up, and methodologies applied to study
      the BCL2 rearrangement. This review summarizes the BCL2 expression studies in
      DLBCL and discusses the prognostic relevance of BCL2 overexpression and its
      mechanisms.

PMID- 10350330
TI  - Syndecan-1 (CD 138) in myeloma and lymphoid malignancies: a multifunctional
      regulator of cell behavior within the tumor microenvironment.
AB  - Syndecan-1 is a transmembrane proteoglycan expressed on the surface of tumor
      cells of various origins including myeloma, Hodgkin's disease, and certain human
      immunodeficiency virus (HIV) associated lymphomas. Functional studies in myeloma
      reveal that syndecan-1 may act as a multifunctional regulator of cell behavior in
      the tumor microenvironment; it mediates cell-cell adhesion, binding of myeloma
      cells to type I collagen, and inhibits tumor cell invasion into collagen gels. In
      addition, syndecan-1 is released from the surface of myeloma cells and this shed
      form of the molecule inhibits growth and induces apoptosis of myeloma cells and
      may modulate myeloma bone disease by inhibiting osteoclast formation and
      promoting osteoblast formation. In view of its effects on tumor cell growth,
      survival, adhesion and invasion and on bone cell differentiation, syndecan-1 may
      be an important potentially beneficial regulator of myeloma pathobiology. Further
      studies are needed to define the clinical significance of syndecan-1 in myeloma
      and to examine its functional significance in other lymphoid malignancies.

PMID- 10350332
TI  - Dissemination of T cell lymphoma to target organs: a post-homing event
      implicating ICAM-1 and matrix metalloproteinases.
AB  - There is increasing evidence that metastasis of a tumor cell (its ability to
      induce the "development of a tumor" at distant sites following intravasation) is
      manifested only after homing to distant site(s). All tumor cells, however, do not
      necessarily undergo uncontrolled cellular division to form secondary tumors once
      they have "homed" to a target site. One of the major rate-limiting steps in
      metastasis is in fact related to the ability of the extravasated tumor cells to
      find an appropriate "nest", where favorable growth conditions will allow them to
      form a secondary tumor upon massive cell division (1). But to establish such a
      favorable nest (referred herein as the "nidification" process), tumor cells must
      penetrate deep into the stroma of the target tissue. This process is facilitated
      when tumor cells produce of specific proteases, which degrade structural proteins
      of the extracellular matrix (2,3). The production of proteases by stromal cells
      can also occur; these enzymes will degrade stroma surrounding the tumor cells,
      resulting in a massive remodeling of the local parenchyma that may interfere with
      the vital functions of a target organ as well as help nidification (4). In this
      review, we focus our attention on post-extravasation events involving adhesion
      molecules and MMP in the metastatic process of lymphoma cells. We propose that
      during dissemination of LFA-1-positive lymphoma cells to peripheral organs, the
      interaction between lymphoma cells and vascular endothelial cells upregulates the
      local expression of MMP and TIMPs. Since control of lymphoma metastasis appears
      to occur at the post-extravasation level, we hypothesize that in addition to
      extravasation, adhesion molecules are implicated in the control of post
      extravasation events.

PMID- 10350333
TI  - Interleukin-10 and Gp130 cytokines in human multiple myeloma.
AB  - Interleukin (IL)-10 is a critical cytokine involved in the terminal
      differentiation of B cells into plasma cells. IL-10 is also involved in multiple
      myeloma, a malignant plasma cell disorder. IL-6 and, more generally the cytokines
      activating the gp130 IL-6 transducer, are major survival and proliferation
      factors of myeloma cells. IL-10 is also a growth factor of malignant plasma
      cells, produced by myeloma cells from about half the patients and is detected in
      the plasma of patients with plasma cell leukemia or solitary plasmacytoma. The
      myeloma cell growth activity of IL-10 is mediated through a gp130 cytokine,
      oncostatin M (OSM), that is frequently produced by myeloma cells. Myeloma cells
      fail to express OSM receptors but IL-10, by inducing it, confers on them the
      sensitivity to OSM.

PMID- 10350334
TI  - Risks, costs, and alternatives to platelet transfusions.
AB  - The use of platelet transfusions has increased greatly in the past decade and is
      likely to continue to escalate because of the risks of thrombocytopenia in
      patients receiving dose-intensive cancer chemotherapy, the increased use of
      hematopoietic progenitor cell transplantation, and the prevalence of human
      immunodeficiency virus infection. Despite marked advances in procedures for
      ensuring the safety of platelets, including intensive donor screening, infectious
      disease marker testing, and increased use of leukodepletion techniques, platelet
      transfusions carry a significant risk for immunologic disorders and transmission
      of bacterial, viral, and perhaps other diseases and can entail a very high cost.
      In addition, thrombocytopenia has the potential to interfere with delivery of
      chemotherapy on schedule and at the planned doses, thus potentially compromising
      treatment outcome. The limitations of platelet transfusions have prompted the
      development of agents with the potential to stimulate platelet production and
      thus reduce or eliminate the need for transfusions. Two such agents, interleukin
      11 (IL-11) and thrombopoietin (TPO), have demonstrated promise in clinical
      trials. In November, 1997, IL-11 received FDA approval for the prevention of
      severe thrombocytopenia in high risk patients receiving myelosuppressive
      chemotherapy. Thrombopoietic growth factors have the potential to greatly
      simplify and increase the safety of transfusion medicine.

PMID- 10350335
TI  - Expression of the C-kit receptor (CD117) is a feature of almost all subtypes of
      de novo acute myeloblastic leukemia (AML), including cytogenetically good-risk
      AML, and lacks prognostic significance.
AB  - Because of conflicting reports on the prognosis of patients with c-kit receptor
      positive AML and lacking correlations with cytogenetic analyses, we prospectively
      evaluated the c-kit receptor expression in 917 AML patients (750 adult patients;
      167 children) using flow cytometry and compared the results to the
      immunophenotype, morphological and cytogenetic findings as well as clinical
      outcome. Expression of the c-kit receptor was present in 63% of all AML
      investigated. Among these an immature immunophenotype was more frequent and 30%
      had a CD34+/CD15- and 37% a CD34+/CD14- phenotype, whereas only 9% and 10% showed
      these phenotypes in the c-kit receptor negative group, respectively. C-kit
      receptor expression ranged average in M0 and M1 subtypes (69% versus 70%) but was
      less pronounced among M5 subtypes (21%). Results of karyotyping were available in
      280 patients. C-kit receptor expression occurred in 37 of 42 (88%) patients with
      favorable cytogenetic abnormalities such as t(8;21), t(15;17) or inv(16) which
      exceeded the expression rate in patients with intermediate risk, poor risk or
      other abnormalities. Information about the clinical outcome was available in 228
      patients treated according to the protocols of two German multicenter trials (AML
      BFM, AMLCG). We found no difference of CR-rate or event-free survival (EFS) in
      adults with or without c-kit receptor expression. Children with c-kit receptor
      negative AML had a lower CR-rate and EFS, but also a lower median age and a
      higher frequency of M5 subtype as compared to children with c-kit receptor
      expression. In conclusion, analysis of c-kit receptor expression may help to
      identify phenotypically immature AML but fails to identify myeloid
      differentiation of leukemic blasts in approximately one third of patients. We
      found no evidence of an adverse prognosis in AML patients with c-kit receptor
      expression. Analysis for c-kit receptor expression does not appear to add
      information to established prognostic parameters in AML.

PMID- 10350336
TI  - Expression of CD44 isoforms on isolated bone marrow plasma cells and peripheral
      CD19+ B cells of patients with multiple myeloma and healthy individuals.
AB  - The expression of certain isoforms of CD44 was shown to correlate with
      aggressiveness and metastatic potential of various tumour types. We analysed the
      expression of the adhesion molecule CD44 and its variant domains (v6, v7, v7/8,
      v10) on isolated bone marrow (BM) plasma cells and peripheral blood (PBL) CD19+ B
      cells of 21 patients with MM and 15 healthy donors. B cells and plasma cells were
      isolated by immunomagnetic sorting and analysed by two-colour flow cytometry. The
      expression of CD44 isoforms was significantly higher on PBL B cells of patients
      with MM than in healthy controls. The elevated expression of CD44 isoforms (v6,
      v7/8, v10) on PBL B cells correlated with reduced overall survival in MM. CD44
      isoforms were more strongly expressed on "larger", activated B cells.
      Furthermore, CD44 isoforms were found to be simultaneously expressed with CD38hi
      and CD56 on both, B lymphocytes and plasma cells of patients with MM. The
      determination of CD44 isoforms on circulating B cells may be helpful in defining
      prognostically unfavourable subgroups in MM.

PMID- 10350338
TI  - Primary bilateral adrenal lymphoma.
AB  - Primary adrenal lymphoma is a rare primary neoplastic disease of the adrenal
      glands, with up to 65 cases reported in the literature over the past 40 years.
      The increasing use and sophistication of medical diagnostic imaging has allowed
      this disease to be diagnosed more frequently premortem, presenting more
      opportunity for treatment. The true incidence of these neoplasms is not known,
      nor is it clear why historical autopsy series have not reported this neoplasm
      more frequently, and why its existence has been documented more recently with
      advanced diagnostic imaging. This review has presented our new case, and reviewed
      5 more in the literature, bringing the total number of cases to over 70.
      Accumulation of more cases and the experience treating these cases is needed to
      develop a better picture of diagnostic procedures and treatment regimens that
      have maximum efficacy.

PMID- 10350337
TI  - The administration of 10 microg/kg granulocyte colony-stimulating factor (G-CSF)
      alone results in a successful peripheral blood stem cell collection when previous
      mobilization with chemotherapy and hematopoietic growth factor failed.
AB  - Some heavily pretreated cancer patients fail to mobilize enough peripheral blood
      stem cells (PBSC) after stimulation with chemotherapy and hematopoietic growth
      factors. For these patients the best way to obtain an adequate PBSC collection is
      unknown. Here we report 6 heavily pretreated cancer patients who failed to
      mobilize sufficient PBSC after stimulation with chemotherapy and G-CSF 5
      microg/kg/day. In these cases, we used G-CSF 10 microg/kg/day alone for six days
      at least 3 weeks after the last chemotherapy. After three consecutive
      leukaphereses starting on day 5, five patients had adequate PBSC collections.
      With 6 days of G-CSF 10 microg/kg/day alone, 2.8 x 10(6) (+/- 1) CD34+ cells/kg
      were collected. This was significantly higher than the number of CD34+ cells/kg
      collected after chemotherapy and G-CSF 5 microg/kg 0.3 x 10(6) (+/- 0.1) [P =
      0.05]. Four patients received high-dose chemotherapy with PBSC support.
      Hematologic recovery observed in these patients was as expected. In conclusion, G
      CSF 10 microg/kg alone can mobilize progenitor cells into peripheral blood when
      previous mobilization with chemotherapy and G-CSF 5 microg/kg fails.

PMID- 10350339
TI  - Feasibility of ESHAP + G-CSF as peripheral blood hematopoietic progenitor cell
      mobilisation regimen in resistant and relapsed lymphoma: a single-center study of
      22 patients.
AB  - The purpose was study the feasibility of ESHAP + G-CSF for peripheral blood
      hematopoietic progenitor cell (PBPC) mobilisation in resistant/relapsed Hodgkin's
      disease (HD) and non-Hodgkin's lymphoma (NHL). Twenty-two consecutive patients
      with HD (8) and N-HL (14) received ESHAP chemotherapy and G-CSF (5 microg/Kg/d).
      When a minimum number of 10,000 peripheral blood CD34+ cells/mL was observed
      patients underwent leukapheresis until a CD34+ cell dose > or = 2.5x10(6)/Kg was
      collected or the PBPC peak was lost. Blood cells kinetics and toxicity were
      analysed. Data concerning the day of first apheresis, number of procedures per
      patient, and cellular yield of the aphereses were recorded. Correlation between
      the CD34+ cell content in the apheresis product and the two diagnosis groups was
      attempted. Twelve patients (54%) developed short-lived severe neutropenia
      (<0.5x10(9)/L). Thrombocytopenia (<25x10(9)/L) had a median duration of 1 day.
      Fever appeared in 4 patients and CN Staph bacteriemia in 2 cases. Bleeding events
      did not supervene and no deaths occurred. Aphereses started at day +15 (median)
      and the median number of apheresis/patient was 2. Seventeen patients underwent 1
      or 2 leukaphereses. Thirteen patients (59%) achieved the CD34+ cell target in the
      first apheresis. NHL patients obtained statistically significant better CD34+
      cell collections than HD. Only 2 HD patients failed to mobilise, 1 previously
      treated with high-dose therapy and autologous bone marrow transplantation. ESHAP
      + G-CSF has been shown to be feasible for PBPC mobilisation in resistant/relapsed
      lymphoma. Toxicity was low and CD34+ cell yield high, especially in N-HL. This
      mobilisation regimen should be further explored in a larger patient population.

PMID- 10350340
TI  - Allogeneic versus autologous bone marrow transplantation for refractory and
      recurrent low-grade non-Hodgkin's lymphoma: updated results of the Utrecht
      experience.
AB  - This study was conducted to compare the results of myeloablative therapy followed
      either by autologous stem cell transplantation (SCT) or allogeneic SCT for poor
      risk low-grade non-Hodgkin's lymphoma. Eighteen patients received autologous SCT
      and 15 patients received allogeneic SCT. All autologous patients had
      chemosensitive disease while this was the case in only 8 allogeneic patients.
      Besides, 14 of 15 allogeneic patients still had overt lymphoma infiltration of
      the marrow, when SCT took place. Despite these unfavorable characteristics, all
      allogeneic patients achieved complete remission (CR) with this procedure and,
      until now, none has relapsed. In contrast, 14 of 18 autologous patients achieved
      CR with SCT but 11 (79%) relapsed. Four allogeneic patients (27%) had a treatment
      related death, whereas this did not occur with autologous SCT. The 3-year
      probabilities of relapse, overall survival, and event-free survival were 0%, 70%
      (95% CI, 38-87%), and 70% (95% CI, 38-87%) respectively for allogeneic SCT and
      78% (95% CI, 57-93%), 33% (95% CI, 13-54%), and 22% (95% CI, 7-43%) respectively
      for autologous SCT. The differences in relapse and event-free survival were
      highly significant, p = 0.0002 and p= 0.015, respectively. These data show that
      allogeneic SCT leads to prolonged disease-free survival in patients with advanced
      poor-risk low-grade lymphoma which rarely occurs after autologous SCT. There is
      substantial evidence for a graft-versus-low-grade lymphoma effect.

PMID- 10350341
TI  - Treatment of stage I and II Hodgkin's disease with NOVP (mitoxantrone,
      vincristine, vinblastine, prednisone) and radiotherapy.
AB  - We investigated the effectiveness of a new treatment regimen termed NOVP in early
      Hodgkin's disease, which reportedly has lower toxicity. Thirty-four patients were
      treated with three cycles of NOVP (mitoxantrone, vinblastine, vincristine,
      prednisone) and radiotherapy, 40% of them had unfavourable prognostic factors.
      All patients obtained complete remission. With a median follow up of 5 years, the
      overall survival (OS) and time to treatment failure (TTF) was 95% (95% confidence
      interval [CI], 87 to 103) and 89% (95% CI, 78 to 100), respectively. The presence
      of either B symptoms or pulmonary hilar involvement was associated with a
      significant decrease in TTF (91% VS 50% p=0.003 and 92% VS 30% p=0.02,
      respectively) but do not correlate with OS. The tolerance to NOVP was excellent
      with minimal toxicity. In conclusion, this regimen is associated with a
      favourable outcome and low toxicity in stage I and II Hodgkin's disease, although
      patients with B symptoms and pulmonary hilar involvement have a higher risk of
      relapse.

PMID- 10350342
TI  - Clinicopathological evaluation of the Revised European-American Classification of
      Lymphoid Neoplasms (REAL) in Japan.
AB  - After the publication of a Revised European-American Classification of Lymphoid
      Neoplasms (REAL classification) in 1994, there have been reports from Europe and
      America regarding its practical utility and clinical significance. However, no
      studies have been published from Eastern countries including Japan. It has been
      well recognized that the distribution of malignant lymphoma in Japan is quite
      different from that seen in Western countries. In addition, some new entities
      have also been described in the REAL classification. Therefore, it seems
      important to examine its practical utility and clinical significance in Japan. Of
      the 579 cases reviewed, approximately 68% were B-cell non-Hodgkin's lymphoma
      (NHL) followed by 27% T-cell lymphomas. Hodgkin's disease (HD) comprised only 5%
      of all cases, making the ratio of NHL to HD 20.6. The most common type was
      diffuse large B-cell lymphoma which represented about 37% of all cases.
      Peripheral T-cell lymphomas, unspecified (PTCL), occurred in 15% whereas marginal
      zone B-cell lymphoma followed (14.9%). However, follicle center lymphoma (FCL)
      was less common (4.4%) as has been previously reported. We evaluated the clinical
      significance of the new REAL classification in 244 cases. International
      Prognostic Index (IPI) was a powerful predictor of survival (p<0.0001), and the
      immunophenotype was significant (p<0.05). Furthermore, here, we also attempt to
      establish a prognostic scheme based on the histologic type. In conclusion, the
      REAL classification appears to be useful and clinically significant in Japan.

PMID- 10350343
TI  - 2-Chlorodeoxyadenosine (cladribine) in the treatment of elderly patients with B
      cell chronic lymphocytic leukemia.
AB  - The aim of our study was to determine the efficacy and toxicity of 2
      chlorodeoxyadenosine (2-CdA) in 2-hour infusions in the treatment of elderly
      patients with B-cell chronic lymphocytic leukemia (B-CLL). Forty three patients
      aged 70 years and older received 1 to 6 courses of 2-CdA (median 3) in a dose of
      0.12 mg/kg daily for 5 consecutive days. Thirty three of them were untreated and
      10 had relapsed or refractory to disease after prior therapy with chlorambucil,
      COP and CHOP. Complete response (CR) was achieved in 13 (30.2%) and partial
      response (PR) in 17 (39.6%) patients, giving an overall response rate of 69.8%.
      The difference in overall response rate between both groups were not
      statistically significant (69.8% and 50%, respectively). The most frequent side
      effects of 2-CdA treatment were thrombocytopenia observed in 18 (41.9%) and
      infections in 7 (16.3%) patients. Drug related neutropenia was observed in 6
      (13.9%) and allergic dermatitis in 2 patients. Six (13.9%) patients died, one
      because of drug related thrombocytopenia resulting in a central nervous system
      hemorrhage, two because of pneumonia and two of cardiovascular complications. In
      conclusion, our results suggest that 2-CdA is also effective treatment for
      elderly patients with CLL. The drug toxicity is acceptable and seems to be
      similar for that observed in younger patients.

PMID- 10350345
TI  - High dose methyl prednisolone in refractory chronic lymphocytic leukaemia.
AB  - We treated 14 patients with advanced, resistant chronic lymphocytic leukaemia
      (CLL) including three with >10% prolymphocytes (CLL/PL) with high dose methyl
      prednisolone (HDMP). All patients had stage C CLL or bulky stage B disease. There
      were 11 males and 3 females with a median age of 58.5 years (range: 49-69). Six
      out of eleven CLL patients had a partial response as defined by the NCI
      guidelines, no patient had a complete remission. The mean duration of PR was 19.6
      months with a median of 8 months (range 6-78). Seven patients have died including
      the 5 non-responders. None of the 3 patients with CLL/PL had a measurable
      response. Previous treatments included chlorambucil, fludarabine,
      deoxycoformycin, anthracycline containing regimens such as CHOP and Campath-1H.
      HDMP was given at a dose of 1 g/m2 for five days, at monthly intervals for one to
      seven courses depending on the response. H2 antagonists and antimicrobial
      prophylaxis were given concurrently. Acyclovir prophylaxis was given if there was
      a recent history of herpes infection. HDMP was generally well tolerated. Side
      effects included fluid retention, hyperglycaemia, bradycardia (1 patient), herpes
      simplex (1), and pneumonia (1) in a patient with a previous history of recurrent
      chest infection and pneumonia. These results suggest that HDMP may be beneficial
      in the treatment of refractory CLL but is of no value in CLL/PL.

PMID- 10350344
TI  - In vitro evaluation of B-CLL cells apoptotic responses to irradiation.
AB  - Defective apoptosis is a mechanism which could possibly explain B chronic
      lymphocytic leukemia (B-CLL) cell accumulation. Differences in evolution and
      prognosis of B-CLL patients may be due to heterogeneity in apoptotic cell death.
      We studied the apoptotic response to in vitro gamma radiation of blood
      mononuclear cells from 18 untreated B-CLL patients. In cells irradiated with 2, 4
      or 8 Gy and then cultured for 20 hours, the percentage of trypan blue excluding
      (viable) cells was not modified (>92%). An apoptotic response to irradiation was
      detected in the majority of the patients, but the individual percentage of
      apoptotic cells varied widely (8 to 81% after 8 Gy irradiation) in individual
      cases. The flow cytometric analysis of nick-end DNA labeling demonstrated a dose
      effect of irradiation, particularly in patients with an apoptotic response of
      over 20%. In the future, a valuable clue to the selection of irradiation regimens
      for B-CLL patients may be the investigation of correlations between in vitro
      radiation-induced apoptosis and the in vivo response to radiation therapy.

PMID- 10350346
TI  - Multi-drug resistance in chronic lymphocytic leukemia.
AB  - We evaluated 45 chronic lymphocyte leukemia (CLL) patients for the presence of
      multi-drug resistance (MDR) by the ex vivo techniques: 1) a functional assay
      utilizing doxorubicin (dox) retention with modulation; 2) a cytotoxicity assay
      (MTT) with modulation; 3) and four monoclonal antibodies. Ex vivo tests were
      correlated with disease stage and prior treatment, and were repeated as patients
      became resistant to alkylating agents, fludarabine and VAD chemotherapy (infusion
      of vincristine, dox, and oral dexamethasone). The majority of patients (64.4%)
      were in early stage and were untreated (62.2%). P-glycoprotein (p-gp 170) was
      detected most frequently by the monoclonal antibody MRK-16 (48%) and by
      functional modulation of dox retention by PSC-833 (40.6%) and by functional
      modulation of the MTT assay with vincristine (0.29) and dox (0.39) with PSC-833
      at 1.0 microg/mL. Functional modulation of dox retention with PSC-833 was
      significantly associated with stage, but not with either the MTT assay or any of
      the monoclonal antibodies. None of the tests correlated with prior chlorambucil
      treatment. Correlation of dox retention with the monoclonal antibodies was mild
      to moderate and became stronger following chlorambucil treatment. Three patients
      who became resistant to VAD were found to express p-gp 170. We conclude that MDR
      can frequently be detected in patients with CLL. Furthermore, the expression of p
      gp 170 increases with advancing stage, but not prior alkylating agent therapy.
      The functional expression of p-gp 170 increases with advancing stage and prior
      treatment and correlates well with monoclonal antibody detection (especially MRK
      16). Patients who become resistant to VAD more frequently express p-gp 170 by a
      variety of techniques. PSC-833 is a more potent modulator of MDR than cyclosporin
      A (CsA) ex vivo, and correlates better with stage of disease.

PMID- 10350347
TI  - Bone lesions with soft-tissue mass: magnetic resonance imaging diagnosis of
      lymphomatous involvement of the bone marrow versus multiple myeloma and bone
      metastases.
AB  - Bone metastases from solid primary tumors, as well as multiple myeloma and
      secondary lymphoma may all present with bone lesions and associated soft-tissue
      masses on magnetic resonance images of the spine. In bone metastases and myeloma,
      the cortex of the affected bone is usually destroyed and a bulging contour is
      observed at the site of extraosseous spread. In cases of lymphomatous involvement
      of the bone marrow, however, we have observed that spread to the extraosseous
      soft-tissues occurs without alteration of the shape or contour of the affected
      bone. In order to assess whether this pattern of spread is indeed suggestive or
      even diagnostic of lymphoma of the bone marrow, we reviewed spinal bone marrow MR
      images of 66 patients, with bone metastases from solid primary tumors (33
      patients), multiple myeloma (20 patients) and stage IV lymphoma with bone marrow
      involvement (13 patients), who had bone lesions and contiguous soft-tissue
      masses. If tumor was present on either side of the bony cortex but the contour of
      the affected bone was preserved, a "wrap-around" sign was diagnosed. A "wrap
      around" sign was found in 12 of the 13 patients with lymphoma but in none of the
      patients with metastases or myeloma. On MR images of the bone marrow, the
      demonstration of tumor spread beyond the bony cortex without disruption of the
      outline of the diseased bone may favor the diagnosis of lymphoma more than that
      of metastases or multiple myeloma.

PMID- 10350348
TI  - Graft-versus-lymphoma effect after allogeneic peripheral blood stem cell
      transplantation for primary central nervous system lymphoma.
AB  - Allogeneic peripheral blood stem cell transplantation (allo PBSCT) is a
      recognized treatment modality for hematological malignancies resistant to
      conventional chemoradiotherapy. The post-transplant immune-mediated graft-versus
      leukemia effect has major curative potential. In this case presentation, the
      allogeneic approach to resistant recurrent primary central nervous system (CNS)
      lymphoma using peripheral blood stem cells from an HLA identical sibling after
      immuno-suppressive non-myeloablative conditioning, was examined clinically. The
      patient in question had relapsing refractory primary CNS lymphoma and is the
      first to be treated with this modality. She developed early skin and liver
      localized grade II graft-versus-host disease after allo PBSCT, which then
      responded to short-term treatment. Chimeric studies at the time showed 100% donor
      cells and repeated magnetic resonance imaging of the brain revealed gradual
      shrinkage of the tumor. Three months after transplant the cerebral mass was no
      longer evident and currently, 30 months after transplantation, the patient
      continues to be disease free. The absence of any signs of malignancy suggests the
      development of a durable graft-versus-lymphoma effect in this brain tumor and
      indicates that this effect may be achieved even after non-myeloablative
      conditioning.

PMID- 10350349
TI  - Persisting bone marrow aplasia following interferon-alpha combined with ara-C for
      chronic myelogenous leukemia.
AB  - A 37-year-old man with a newly diagnosed chronic myelogenous leukemia received
      induction therapy with hydroxyurea and interferon-alpha, and maintenance therapy
      with low-dose ara-C and interferon-alpha. Subsequent to a rapid hematological
      remission, a continuously aggravating pancytopenia with bone marrow aplasia
      developed which persisted after withdrawal of maintenance therapy. Bone marrow
      examination exhibited aplastic areas and residual hematopoiesis with impaired
      maturation; cytogenetically, there was a 100% persistence of Philadelphia
      chromosome-positive metaphases. By allogeneic bone marrow transplantation, a
      complete reconstitution of hematopoiesis was achieved.

PMID- 10350350
TI  - Primary multifocal lymphoma of bone presenting as hypercalcemic crisis: report of
      a rare manifestation of extranodal lymphoma.
AB  - Primary non-Hodgkin's lymphoma of bone is uncommon and usually manifests
      clinically as localized bone pain. Here we report a woman who presented with
      hypercalcemic crisis and extensive investigation revealed a primary multifocal
      lymphoma of bone. The course of the disease was very aggressive and despite
      intensive supportive care and urgent chemotherapy the patient died within 1
      month. Since her blood PTH and calcitriol levels were suppressed and her
      parathyroid-hormone-related peptide (PTHrp) was mildly elevated, we believe that
      release of cytokines combined with PTHrp, as well as extensive osteolytic
      lesions, were the causes of the hypercalcemia. This is an unusual presenting
      symptom of lymphomas and to the best of our knowledge severe symptomatic
      hypercalcemia and crisis has never been reported in primary lymphoma of bone
      before.

PMID- 10350352
TI  - The classification of plasma cell dyscrasias: alternatives to the Durie & Salmon
      diagnostic system.

PMID- 10350351
TI  - Teaching cases from the Royal Marsden and St Mary's Hospitals case 19:
      pancytopenia following Hodgkin's disease.

PMID- 10350353
TI  - Lithium administration affects gene expression of thyroid hormone receptors in
      rat brain.
AB  - Even though lithium has received wide attention in the treatment of manic
      depressive illness, the mechanisms underlying its mood stabilizing effects are
      not understood. Lithium is known to interact with the thyroid axis and causes
      hypothyroidism in a subgroup of patients, which compromises its mood stabilizing
      effects. Since lithium was recently reported to alter thyroid hormone metabolism
      in the rat brain, the present study investigated whether these effects were
      mediated through regulation of thyroid hormone receptor (THR) gene expression.
      Adult male euthyroid rats were either given a diet containing 0.25% lithium or
      one without lithium for 14 days. Rats were sacrificed in the evening and RNA was
      isolated from different brain regions to quantitate the isoform specific mRNAs of
      THRs. Following 14 days of lithium treatment, THR alpha1 mRNA levels were
      increased in the cortex and decreased in hypothalamus; THR alpha2 mRNA levels
      were increased in the cortex and THR beta mRNA levels were decreased in the
      hypothalamus. No significant difference in the expression of these THR isoforms
      was observed in the hippocampus or cerebellum. Thus, chronic lithium treatment
      appeared to regulate THR gene expression in a subtype and region specific manner
      in the rat brain. It remains to be determined whether the observed effects of
      lithium on THR gene expression are related to its therapeutic efficacy in the
      treatment of bipolar disorder.

PMID- 10350355
TI  - High salt intake differentially regulates kidney angiotensin IV AT4 receptors in
      Wistar-Kyoto and spontaneously hypertensive rats.
AB  - Functional angiotensin IV (Ang IV) receptors (denoted AT4) are localized to the
      outer stripe of the medulla in the rat kidney, and may play a critical role in
      salt homeostasis. The purpose of this study was to determine if AT4 receptor
      binding in the kidney is differently regulated in the salt-sensitive
      spontaneously hypertensive (SH) rat compared to Wistar Kyoto (WKY) controls. AT4
      receptor binding was determined using in vitro receptor autoradiography. AT4
      receptor binding in the outer stripe of the medulla was similar in WKY and SH
      rats maintained on a 1% salt diet. A high salt diet (8%) resulted in a
      statistically significant increase (28%) in AT4 receptor binding in kidneys from
      WKY rats. However, there was no change in AT4 receptor binding in the kidneys of
      SH rats fed the same diet. The present data indicate that AT4 binding sites are
      regulated by salt intake. In addition, regulation of this receptor may be
      impaired in the kidneys of SH rats, explaining in part the salt-sensitivity of
      this strain.

PMID- 10350354
TI  - A specific loss of C-series gangliosides in pancreas of streptozotocin-induced
      diabetic rats.
AB  - Gangliosides in pancreas, kidney, and liver tissues from streptozotocin-induced
      diabetic rats were analyzed by methods including thin-layer chromatographic (TLC)
      immunostaining with a specific monoclonal antibody to c-series gangliosides. In
      rats suffering diabetes for one month, the composition of major gangliosides in
      pancreatic tissue was almost identical to control, except for a slight increase
      in the content of GM3. Though c-series gangliosides such as GT3, GT2, GQ1c, and
      CP1c were expressed in normal pancreatic tissue, they were practically lost in
      pancreas of diabetic animals. A specific loss of c-series gangliosides was also
      observed in pancreatic tissue from rats suffering diabetes only for three days.
      While the composition of major gangliosides in the kidney did not change,
      streptozotocin-induced diabetic conditions brought about significant increases in
      contents of practically all major ganglioside species in liver tissue. No change
      was observed in the amount and composition of c-series gangliosides in both
      tissues. These results strongly suggest that c-series gangliosides are
      specifically localized in pancreatic B cells.

PMID- 10350356
TI  - Hormonal modulation of branchial Na+-K+-ATPase subunit mRNA in a marine teleost
      Sparus sarba.
AB  - The effect of hormone treatment on the abundance of Na+-K+-ATPase alpha- and beta
      subunit mRNA in Sparus sarba branchial tissue was investigated. Groups of
      seawater (33/1000) and hypo-osmotic (6/1000) acclimated fish were injected daily,
      with either saline, cortisol, recombinant bream growth hormone (rbGH) or ovine
      prolactin (oPRL). Total RNA from branchial tissue was analyzed by Northern
      blotting using PCR amplified Na+-K+-ATPase alpha- and beta-subunit cDNA clones.
      Na+-K+-ATPase alpha- and beta- subunit transcripts of 3.3kb and 2.4kb
      respectively, were detected and their abundance, after hormone treatment was
      assessed using RNA dot blots. The abundance of subunit mRNAs increased 1.4-1.9
      fold, relative to controls, after cortisol treatment. The alpha:beta mRNA ratio
      also increased in cortisol treated seawater acclimated fish. Growth hormone
      treatment did not cause any significant changes in Na+-K+-ATPase subunit mRNA,
      whereas prolactin significantly reduced alpha-subunit mRNA levels by
      approximately 0.5 fold in both seawater and hypo-osmotic conditions. The data
      from this study add further support to the generally accepted roles that cortisol
      and prolactin have in the modulation of Na+-K+-ATPase activity. It can be
      concluded from this study that S. sarba branchial Na+-K+-ATPase subunit
      expression is multihormonally regulated.

PMID- 10350357
TI  - Genes involved in the pathophysiology of perinatal asphyxia.
AB  - Mechanisms in the pathogenesis of perinatal asphyxia (PA) at the gene level are
      only beginning to be elucidated, although gene hunting using differential display
      has revealed differences in gene expression between hypoxic and normoxic cells in
      vitro. As no information on gene expression was available from in vivo studies,
      we decided to use a non-invasive and clinically relevant animal model of PA for
      mRNA hunting applying the subtractive hybridization method. mRNAs from normoxic
      rat brain and brain of rat pups with 20 min of asphyxia were isolated and
      compared by this technique. The resulting subtracted mRNAs were converted to
      cDNA, sequenced and identified by gene bank data. A series of transcripts
      representing transcription factors, transporters, metabolic factors, were found
      to be up- or downregulated providing insight into mechanisms of PA, and on the
      other hand, genes with unknown functions could be given a preliminary role i.e.
      in PA. Results obtained with this powerful tool are now challenging quantitative
      determination of these genes and gene products at the protein and activity level
      to confirm their role in PA.

PMID- 10350358
TI  - 5-Hydroxytryptamine inhibits the tachycardia induced by selective preganglionic
      sympathetic stimulation in pithed rats.
AB  - It has been shown in several species that serotonin (5-hydroxytryptamine; 5-HT)
      is able to inhibit the responses produced by sympathetic stimulation in a wide
      variety of blood vessels and other organs, including the heart. However, in
      pithed rats, the analysis of potential sympatho-inhibitory actions of 5-HT is
      hampered by the fact that 5-HT (given as i.v. bolus injections) produces
      tachycardia per se. Moreover, most studies have investigated 5-HT-induced
      sympatho-inhibition at only one frequency of stimulation. Thus, the present study
      set out to find the experimental conditions to overcome these problems. In this
      regard, we analyzed the potential ability of 5-HT, administered as i.v.
      continuous infusions, to inhibit the tachycardia caused by stimulation of the
      preganglionic (C7-T1) sympathetic outflow in pithed rats. Sympathetic
      cardiostimulation (0.01-3 Hz) resulted in frequency-dependent increases in heart
      rate; these responses were potentiated after desipramine (50 microg/kg, i.v.).
      During continuous infusions of 5-HT (3.1-10 microg/kg.min, i.v.), but not saline,
      the sympathetically-induced tachycardia was dose-dependently inhibited in both
      control and desipramine-pretreated rats. This inhibitory effect of 5-HT was
      significantly more pronounced at lower frequencies of stimulation. In contrast,
      the above infusions of 5-HT did not inhibit the tachycardia induced by i.v. bolus
      injections of noradrenaline in both control and desipramine-pretreated rats.
      Taken together, the above findings confirm that 5-HT induces inhibition of the
      sympathetic chronotropic outflow in the rat by acting at receptors located
      prejunctionally, without evoking tachycardia, over a wide range of stimulation
      frequencies.

PMID- 10350359
TI  - Age-associated decline in responses of naive T cells to in vitro immunization
      reflects shift in glucocorticoid sensitivity.
AB  - Naive T lymphocytes from young mice can be immunized to protein antigens in vitro
      if the initial exposure to antigen is followed by a brief period of clonal
      expansion in the presence of both the glucocorticoid dexamethasone (at 10(-8) M)
      and antibodies to Interleukin-10 (IL-10). These cultures produce cell lines that
      respond to antigen rechallenge by proliferation and cytokine secretion. T cells
      from older mice, however, do not respond under these conditions unless the
      dexamethasone concentration is raised to levels (10(-7) M) that are inhibitory
      for T cells of young mice. Suitably timed exposure to dexamethasone can also
      increase proliferative responses to polyclonal activation via the CD3 component
      of the T cell receptor, and again optimal responses are obtained from old mice
      only at steroid concentrations that are super-optimal for young T cells.
      Diminished sensitivity to glucocorticoid effects may contribute to the poor
      responses of aged mice to novel immunogens.

PMID- 10350360
TI  - Pulmonary toxicity caused by acute exposure to mercury vapor is enhanced in
      metallothionein-null mice.
AB  - This study examined the protective role of metallothionein (MT) against pulmonary
      damage caused by acute exposure to metallic mercury (Hg0) vapor using MT-null and
      wild-type mice. Both strains of mice were exposed to Hg0 at 6.6 to 7.5 mg/m3 for
      4 hr each day for 3 consecutive days. This dosing protocol was lethal to over 60%
      of MT-null mice but did not kill any wild-type mice. More severe pulmonary damage
      was found by histopathological observation in MT-null mice than in wild-type
      mice. MT levels in the lung were elevated in wild-type mice after Hg0 vapor
      exposure, and gel filtration of the lung cytosol revealed that most of the
      mercury was associated with MT. In MT-null mice, MT levels were below the limit
      of detection (0.2 microg/g tissue) for the MT assay even after exposure. After
      exposure to Hg0 vapor for 3 consecutive days, the pulmonary mercury levels in
      wild-type mice were significantly higher than in MT-null mice. These findings
      suggest that MT plays a protective role against the acute pulmonary toxicity of
      Hg0 vapor.

PMID- 10350362
TI  - Involvement of endogenous digitalis-like factors in voluntary selection of
      alcohol by rats.
AB  - This study tested the hypothesis that endogenous digitalis-like factor (DLF) is
      involved in the development of alcohol dependence in rats. In 33 male Wistar rats
      in conditioned place preference (CPP) experiment, ethanol evoked increase in time
      spent in the ethanol-associated compartment (702+/-82 in ethanol-treated vs.
      426+/-86 sec in the controls). Digoxin pretreatment (125 microg/kg, i/p) did not
      affect the time spent in the water-associated compartment (476+/-80 sec), but
      prevented the acquisition of ethanol CPP (385+/-112 sec in ethanol-paired side,
      P<0.05). In a two bottle choice test, where rats (n=6 per group) chose between
      drinking water and 9% ethanol, immunization against two putative DLFs,
      marinobufagenin and ouabain (MBG and OLC) resulted in a 60% increase of ethanol
      consumption. Acute intragastric administration of 9% ethanol to the rats was
      associated with increased OLC in cerebrospinal fluid, and stimulated urinary
      excretion of MBG and OLC. Thus, in rats, digoxin, which mimics the effects of
      DLFs, suppresses the free choice of alcohol, while immunization against DLFs is
      associated with alcohol seeking behavior.

PMID- 10350361
TI  - Effects of alprazolam on the free-choice ethanol consumption induced by isolation
      stress in aged rats.
AB  - Late-onset drinking is a common problem in elderly people related to stress
      induced by social isolation. Experiments were performed in order to evaluate the
      effects of alprazolam, a benzodiazepine agonist anxiolytic, on the free-choice
      ethanol consumption in aged rats subjected to isolation stress. The animals we
      offered a two-bottle choice consumption (one of 0.2% saccharin and the other with
      10% ethanol/0.2% saccharin) and then exposed to 4 days of isolation stress on an
      irregular, unpredictable schedule. Stress resulted in significant increase in
      ethanol consumption. Treatment with alprazolam (1 mg/Kg) partially reversed this
      adverse effect of stress.

PMID- 10350363
TI  - The androgenic effect of norethisterone and 5alpha-norethisterone on the
      contractile response of the rat vas deferens to methoxamine and serotonin.
AB  - Norethisterone (NET) and its metabolite 5alpha-norethisterone (5alpha-NET) are
      competitors for the androgen receptor. The sensitivity of the rat vas deferens to
      the contractile action of methoxamine and serotonin is regulated by hormonal and
      anatomical factors. The aim of this study was to evaluate the ability of NET and
      5alpha-NET to induce the androgen-regulated contractile response to methoxamine
      and serotonin in the epididymal and prostatic portions of rat vas deferens. Adult
      male rats either intact, castrated or steroid-treated castrated were used. The
      contractility was recorded isometrically, and non-cumulative concentration
      response curves to either methoxamine or serotonin were obtained. NET and 5alpha
      NET partially restored the sensitivity to methoxamine and serotonin in the
      epididymal portion of castrated rats. The maximal responses to both agonists were
      significantly higher than those observed in castrated rats, and significantly
      lower than the responses observed in either intact or androgen-treated castrated
      rats. The prostatic portion was less responsive to both agonists than the
      epididymal portion, in all groups but castrated rats, as castration induced
      sensitivity to both agonists. NET and 5alpha-NET displayed a partial though
      similar androgenic activity in the rat vas deferens. These results contrast with
      previous reports where a decrease of androgenic effect due to the 5alpha
      reduction of NET has been found.

PMID- 10350364
TI  - In vitro and in vivo wound healing activity of asiaticoside isolated from
      Centella asiatica.
AB  - The activity of asiaticoside, isolated from Centella asiatica, has been studied
      in normal as well as delayed-type wound healing. In guinea pig punch wounds
      topical applications of 0.2% solution of asiaticoside produced 56% increase in
      hydroxyproline, 57% increase in tensile strength, increased collagen content and
      better epithelisation. In streptozotocin diabetic rats, where healing is delayed,
      topical application of 0.4% solution of asiaticoside over punch wounds increased
      hydroxyproline content, tensile strength, collagen content and epithelisation
      thereby facilitating the healing. Asiaticoside was active by the oral route also
      at 1 mg/kg dose in the guinea pig punch wound model. It promoted angiogenesis in
      the chick chorioallantoic membrane model at 40 microg/disk concentration. These
      results indicate that asiaticoside exhibits significant wound healing activity in
      normal as well as delayed healing models and is the main active constituent of
      Centella asiatica.

PMID- 10350365
TI  - Evaluation of the gastric antiulcer activity of fixed oil of Ocimum sanctum (Holy
      Basil).
AB  - The fixed oil of Ocimum sanctum L. (Labiatae) was found to possess significant
      antiulcer activity against aspirin-, indomethacin-, alcohol-, histamine-,
      reserpine-, serotonin- and stress-induced ulceration in experimental animal
      models. Significant inhibition was also observed in gastric secretion and aspirin
      induced gastric ulceration in pylorus ligated rats. The lipoxygenase inhibitory,
      histamine antagonistic and antisecretory effects of the oil could probably have
      contributed towards antiulcer activity. O. sanctum fixed oil may be considered to
      be a drug of natural origin which possesses both anti-inflammatory and antiulcer
      activity.

PMID- 10350366
TI  - Studies on the anti-inflammatory and analgesic activity of Cedrus deodara (Roxb.)
      Loud. wood oil.
AB  - The volatile oil extracted by steam distillation of the wood of Cedrus deodara
      was examined for its oral anti-inflammatory and analgesic activity at the doses
      of 50 and 100 mg/kg body weight. It produced significant inhibition of
      carrageenan-induced rat paw edema and of both exudative-proliferative and chronic
      phases of inflammation in adjuvant arthritic rats at doses of 50 and 100 mg/kg
      body weight. The oil at both tested doses was found to possess analgesic activity
      against acetic acid-induced writhing and hot plate reaction in mice.

PMID- 10350368
TI  - Protective effects of the flavonoid mixture, silymarin, on fetal rat brain and
      liver.
AB  - We investigated the possibility that the flavonoid mixture, silymarin (SY),
      administered as the compound Silymarin Phytosome (PHYTO), could protect the fetus
      from maternally ingested EtOH. Seventy-six female rats were randomly assigned to
      one of seven groups: pair-fed control; chow fed control; EtOH; and four groups
      receiving EtOH and PHYTO in varying dosages. All groups except the chow-fed
      control were maintained on a liquid diet. On day 1 of pregnancy the dams began
      the treatment protocol. On day 21 of pregnancy the rats were sacrificed and the
      fetuses removed. Gamma glutamyl transpeptidase (GGTP) activity was determined for
      liver and brain tissue from both the fetuses and the dams. GGTP activity in the
      EtOH/silymarin treatment groups did not differ significantly from that observed
      for the pair-fed control group. The observed GGTP activity levels for the EtOH
      only group were significantly higher than those attained by the pair-fed control
      group. Although GGTP activity did not vary significantly with the quantity of
      PHYTO administered, as PHYTO dose was increased, GGTP activity decreased.

PMID- 10350367
TI  - Ayahoasca: an experimental psychosis that mirrors the transmethylation hypothesis
      of schizophrenia.
AB  - The experimental psychosis observed after drinking Ayahoasca, a South American
      hallucinogenic beverage from the Amazon Indians, reproduces the pathologic
      transmethylation theory of schizophrenia. This theory postulates a decrease in
      the monoamine oxidase (MAO) activity, which results in the accumulation of
      methylated indolealkylamines, such as bufotenin (5-hydroxy-N,N
      dimethyltryptamine), N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N
      dimethyltryptamine. These substances are strong hallucinogens as has been
      previously confirmed experimentally. On the other hand, it is known that
      Ayahoasca is a beverage usually prepared by boiling two plants, one of them rich
      in beta-carbolines, which are naturally occurring strong inhibitors of MAO, and
      the other with high quantities of DMT. This particular combination reproduces
      what is supposed to occur under pathologic conditions of different psychoses. The
      effects of Ayahoasca were studied in subjects, assessing urine levels of DMT by
      gas chromatography-mass spectrometry (GC-MS) before and after the intake of the
      beverage. The results of this study confirm that the hallucinogenic compounds
      detected in the healthy subjects' (post-Hoasca, but not before) urine samples are
      the same as those found in samples from acute psychotic unmedicated patients. The
      chemical composition of the Ayahoasca beverage, and of the plant material used
      for its preparation are also reported as well as psychometric and neuroendocrine
      subject parameters.

PMID- 10350369
TI  - Euphorbia hirta leaf extracts increase urine output and electrolytes in rats.
AB  - Euphorbia hirta is locally used in Africa and Australia to treat numerous
      diseases, including hypertension and edema. The diuretic effect of the E. hirta
      leaf extracts were assessed in rats using acetazolamide and furosemide as
      standard diuretic drugs. The water and ethanol extracts (50 and 100 mg/kg) of the
      plant produced time-dependent increase in urine output. Electrolyte excretion was
      also significantly affected by the plant extracts. The water extract increased
      the urine excretion of Na+, K+ and HCO3-. In contrast, the ethanol extract
      increased the excretion of HCO3- decreased the loss of K+ and had little effect
      on renal removal of Na+. Acetazolamide, like the water extract, increased urine
      output and enhanced the excretion of Na+, K+ and HCO3-. The high-ceiling
      diuretic, furosemide, increased the renal excretion of Na+ and Cl-; but had no
      effect on K+ and HCO3- loss. This study suggests that the active component(s) in
      the water extract of E. hirta leaf had similar diuretic spectrum to that of
      acetazolamide. These results validate the traditional use of E. hirta as a
      diuretic agent by the Swahilis and Sukumas.

PMID- 10350370
TI  - Screening of seven selected Rwandan medicinal plants for antimicrobial and
      antiviral activities.
AB  - Aqueous EtOH (80%) extracts of seven plants used by Rwandan traditional healers
      to treat infections, were screened for antibacterial, antifungal, and antiviral
      activities. Only two of the selected plants showed a true antiviral activity
      against herpes simplex virus type 1, while all of them exhibited virucidal
      properties against several enveloped viruses including herpes simplex, measles,
      Semliki forest, and vesicular stomatitis viruses. Four plants were diversely
      active against gram-positive bacteria, two of these showing bactericidal effect
      against the acid-fast Mycobacterium fortuitum. None of the selected plants was
      active against gram-negative bacteria or the yeast Candida albicans. From a
      bioassay-guided fractionation procedure using herpes simplex virus type I as the
      target model, a virucidal mixture, the maesasaponin mixture A, was isolated from
      the MeOH extract of Maesa lanceolata. The maesasaponin mixture A exhibited a
      virucidal activity against herpes simplex types 1 and 2, and vesicular stomatitis
      viruses.

PMID- 10350371
TI  - Role of antimicrobial central venous catheters for the prevention of associated
      infections.

PMID- 10350372
TI  - Inhibitor-resistant TEM beta-lactamases: phenotypic, genetic and biochemical
      characteristics.
AB  - Beta-lactamases represent the main mechanism of bacterial resistance to beta
      lactam antibiotics. The recent emergence of bacterial strains producing inhibitor
      resistant TEM (IRT) enzymes could be related to the frequent use of beta
      lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam in
      hospitals and in general practice. The IRT beta-lactamases differ from the
      parental enzymes TEM-1 or TEM-2 by one, two or three amino acid substitutions at
      different locations. This paper reviews the phenotypic, genetic and biochemical
      characteristics of IRT beta-lactamases in an attempt to shed light on the
      pressures that have contributed to their emergence.

PMID- 10350373
TI  - A review of the role of antibiotic policies in the control of antibiotic
      resistance.
AB  - The optimal antibiotic control measures remain to be described and probably vary
      between institutions. Nevertheless, various control measures have been shown to
      be useful in reducing costs of therapy and total amounts of prescribing, while
      maintaining quality of care. More recently, interest has turned to whether
      antibiotic policies can reduce the spread of resistance and even reverse current
      high levels. Early studies indicated this was feasible, but mathematical models
      and the recent discovery of the role of transposons and integrons in multi-drug
      resistance have both cast doubt on likely future success in this area.
      Nevertheless, there have been some major successes in recent studies, both in the
      community and hospital. While cross-infection is a major impediment to control of
      resistance, there is little doubt that careful antibiotic prescribing can curtail
      the emergence and reduce the prevalence of resistance.

PMID- 10350374
TI  - Evaluation of a new 3-h hybridization method for detecting the mecA gene in
      Staphylococcus aureus and comparison with existing genotypic and phenotypic
      susceptibility testing methods.
AB  - A new 3-h hybridization assay for detection of the staphylococcal mecA gene and
      the Staphylococcus aureus nuclease gene was evaluated by comparing the assay with
      existing genotypic and phenotypic methods. A total of 275 S. aureus strains were
      tested, including 257 epidemiologically unrelated strains (135 mecA-positive and
      122 mecA-negative; collection I), and 18 strains with known borderline resistance
      to methicillin (collection II). Complete agreement was obtained for both
      collections when comparing the new assay with genotypic methods. We further
      evaluated a range of phenotypic susceptibility methods recommended in Europe
      and/or USA using the presence of the mecA gene as the defining standard. For
      collection I a high degree of agreement was found for both Etests (256 strains)
      and the oxacillin screen plate test (255 strains); the degree of agreement was
      lower for agar dilution methicillin (250 strains) and oxacillin 1 microg discs
      (239 strains). For the borderline strains a high degree of agreement was only
      obtained by the oxacillin screen plate test (17 of 18 strains). The other tests
      were less accurate, in the following order: agar dilution methicillin, Etest
      methicillin, Etest oxacillin and oxacillin discs with disagreement for four,
      five, nine and 13 strains, respectively. In conclusion, the new hybridization
      assay is a rapid and exact method for detecting the mecA gene and the S. aureus
      nuclease gene. This study confirms that phenotypic tests for methicillin
      resistance in S. aureus strains creates both false-susceptible and false
      resistant results, especially for borderline resistant strains.

PMID- 10350375
TI  - A comparative evaluation of Etest and broth microdilution methods for fluconazole
      and itraconazole susceptibility testing of Candida spp.
AB  - The Etest strip is a promising tool of broad application in clinical
      microbiology. The method provides MIC readings and is easier to perform than
      broth microdilution. We carried out a study to compare the MICs of fluconazole
      and itraconazole obtained by the Etest with those obtained by broth
      microdilution, performed according to the guidelines of the NCCLS document M27-A,
      with 402 clinical isolates (360 Candida albicans, 17 Candida tropicalis, nine
      Candida krusei, nine Candida glabrata and seven Candida parapsilosis) and seven
      control isolates. The agreement between MICs by the two methods (at +/- 2
      dilutions) was 74.5% for fluconazole and 61.4% for itraconazole. These results
      suggest that further development is necessary to standardize the medium and
      incubation conditions before introduction of the Etest as a routine method in the
      clinical microbiology laboratory for fluconazole and itraconazole susceptibility
      testing.

PMID- 10350377
TI  - Collaboration of human phagocytes with LY 303366 for antifungal activity against
      Aspergillus fumigatus.
AB  - LY 303366, an inhibitor of 1, 3-beta-D-glucan synthase, was tested alone, or in
      co-culture with neutrophils or monocytes, for antifungal activity against
      Aspergillus fumigatus using the XTT metabolism assay. LY 303366 at 0.1 mg/L for
      48 h significantly inhibited growth by conidia in a microtest plate XTT assay
      system. Inhibition was similar if the drug was removed after only 24 h.
      Microscopically this correlated with less growth and stunted malformed hyphae. LY
      303366 (0.1 mg/L) also inhibited the further growth of germlings (43%) in a 24 h
      assay. Antifungal activity of neutrophils against 24 h control hyphal growth was
      limited at an effector: target ratio of 400:1. In co-cultures of neutrophils plus
      drug with hyphal growth from 24 h LY 303366 cultures the antifungal activity was
      additive. Neutrophils had a similar additive effect even if the drug were not
      present (i.e. when germinating conidia were pretreated with drug). Under
      conditions where monocytes did not have significant antifungal activity against
      hyphae, they collaborated with LY 303366 for significantly increased inhibition
      from 38% by LY 303366 alone to 67% by co-culture. Thus, LY 303366 has activity
      against germinating or germinated conidia of Aspergillus, human effector cells
      act co-operatively with LY 303366, and LY 303366 can sensitize germinating
      conidia for damage by host cells.

PMID- 10350376
TI  - Prediction of the antimicrobial effects of trovafloxacin and ciprofloxacin on
      staphylococci using an in-vitro dynamic model.
AB  - To compare the pharmacodynamics of trovafloxacin and ciprofloxacin, three
      clinical isolates of Staphylococcus aureus with different MICs (0.03, 0.15, 0.6
      and 0.1, 0.25, 1.25 mg/L, respectively) were exposed to decreasing concentrations
      of the quinolones according to their half-lives of 9.25 and 4 h, respectively.
      With each organism, single doses of trovafloxacin and twice-daily doses of
      ciprofloxacin were designed to provide 8-fold ranges of the ratio of area under
      the concentration-time curve (AUC) to the MIC, 58-466 and 116-932 (mg x
      h/L)/(mg/L), respectively. The antimicrobial effect was expressed by its
      intensity: the area between the control growth in the absence of antibiotics and
      the antibiotic-induced time-kill/regrowth curves (I(E)). Linear relationships
      established between I(E) and log AUC/MIC were bacterial strain-independent but
      specific for the quinolones (r2 = 0.99 in both cases). At a given AUC/MIC ratio,
      the I(E)s of trovafloxacin were greater than those of ciprofloxacin, suggesting
      that the antimicrobial effect of trovafloxacin compared with ciprofloxacin
      against staphylococci may be even greater than might be expected from the
      difference in their MICs. These data were combined with previous results obtained
      with three Gram-negative bacteria. Again, I(E) correlated well with the log
      AUC/MIC of trovafloxacin and ciprofloxacin in a strain- and species-independent
      fashion (r2 = 0.94 and 0.96, respectively). On this basis, a value of the AUC/MIC
      of trovafloxacin which might be equivalent to Schentag's AUC/MIC = 125 (mg x
      h/L)/(mg/L) reported as the breakpoint value for ciprofloxacin was estimated at
      71 (mg x h/L)/(mg/L) with the respective MIC breakpoint of 0.27 mg/L. Based on
      the I(E)-log AUC/MIC relationships, the I(E)s were plotted against the logarithm
      of trovafloxacin and ciprofloxacin dose (D) for hypothetical representatives of
      S. aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa
      with MICs corresponding to the MIC50s. These I(E)-log D relationships allow
      prediction of the effect of a given quinolone on a representative strain of the
      bacterial species.

PMID- 10350378
TI  - Efficacy of beta-lactam and inhibitor combinations in a diffusion chamber model
      in rabbits.
AB  - Using a diffusion chamber in rabbits, we evaluated therapy with the combination
      of ceftriaxone plus the beta-lactamase inhibitor tazobactam in comparison with
      ceftriaxone alone. One sensitive and one resistant strain of Escherichia coli,
      Enterobacter cloacae and Klebsiella pneumoniae were inoculated into one of the
      six diffusion chambers, implanted in the same animal. In order to simulate
      pharmacokinetics in humans, both substances were administered in decreasing
      doses. Ceftriaxone was given 0, 2, 4 and 6 h after infection in dosages of 45,
      35, 25 and 15 mg/kg of body weight, while tazobactam was administered either in
      one dose at 0 h, or divided into two doses at 0 and 1 h or 0 and 4 h, or divided
      into three doses at 0, 1 and 4 h after infection. The ratio of
      ceftriaxone:tazobactam was fixed at 8:1. Ceftriaxone, in combination with
      tazobactam, given in one dose immediately after infection showed a significant
      reduction in bacterial count. All other combinations of ceftriaxone and
      tazobactam did not differ from ceftriaxone in monotherapy. Co-administration of
      the beta-lactamase inhibitor tazobactam significantly enhanced the activity of
      ceftriaxone against all three tested species.

PMID- 10350379
TI  - Antimicrobial susceptibility of Enterobacteriaceae isolated from vegetables.
AB  - There is potential for the normal faecal flora of humans to be augmented by
      resistant strains of bacteria, acquired from food. The frequency of resistance in
      the aerobic Gram-negative faecal flora is often very high. The purpose of this
      study was to find out whether food strains contribute to this resistance. One
      hundred and thirty-seven vegetable samples were studied, 48 of Finnish origin,
      and 89 imported. From these samples, 535 different strains of bacteria belonging
      to the family Enterobacteriaceae were isolated. Enterobacter spp. were most
      frequent, Escherichia coli was rare. Sensitivity testing was undertaken only for
      isolates with different biotypes and antibiograms. No resistance was found to
      cefotaxime, aztreonam, imipenem, gentamicin, nalidixic acid or ciprofloxacin. The
      frequency of trimethoprim resistance was 0.2%, sulphamethoxazole resistance 1.3%,
      and tetracycline resistance 5.5%. These frequencies were much lower than those
      found in faecal flora. Chloramphenicol and cefuroxime resistance was found in 12%
      and 14% of isolates, respectively. The only statistically significant differences
      between the Finnish and imported strains were for these two; the Finnish isolates
      were more resistant to cefuroxime, whereas the imported ones were more resistant
      to chloramphenicol. Consequently, bacteria from vegetables are not responsible
      for the high prevalence of resistant Enterobacteriaceae in faecal flora in
      Finland; they are in fact unusually susceptible to the antibiotics studied.
      Multiresistance profiles, typical of strains associated with human activities,
      were not identified in these isolates.

PMID- 10350380
TI  - Prevalence of Helicobacter pylori resistance to metronidazole, clarithromycin,
      amoxycillin, tetracycline and trovafloxacin in The Netherlands.
AB  - Successful treatment of Helicobacter pylori infection is becoming compromised by
      emerging resistance. We report the prevalence rates of H. pylori resistance to
      metronidazole, clarithromycin, amoxycillin, tetracycline and trovafloxacin in The
      Netherlands. A total of 231 H. pylori clinical isolates were collected throughout
      the country over a period of 6 months during 1997-1998. The MICs of the above
      mentioned antibiotics were determined in a single laboratory. The overall
      percentage of resistance for clarithromycin and metronidazole was 1.7% and 21.2%,
      respectively. None of the strains was resistant to amoxycillin or tetracycline.
      The primary resistance rate of trovafloxacin was as high as 4.7%. Since
      trovafloxacin has not yet been introduced on to the Dutch market, the resistance
      is probably induced by the use of other quinolones. Our data indicate that
      treatment outcome would benefit from susceptibility testing before starting
      therapy, especially when prescribing metronidazole.

PMID- 10350381
TI  - Quality of antimicrobial susceptibility testing in the UK: a Pseudomonas
      aeruginosa survey revisited.
AB  - As part of a programme to assess the usefulness of routine antimicrobial
      susceptibility data as a surveillance tool, we reviewed the results of a national
      survey of resistance in Pseudomonas aeruginosa, undertaken in 1993. Twenty-four
      UK laboratories contributed isolates for centralized MIC testing, indicating also
      their own susceptibility test data. As reported previously (Chen et al. (1995)
      Journal of Antimicrobial Chemotherapy 35, 521-34), the rate of false resistance
      (isolates reported susceptible, but found resistant on MIC testing/all isolates
      reported susceptible) was 0.6-8%, according to the antimicrobial and breakpoint.
      Review showed that this favourable position reflected the fact that >88% of
      isolates were susceptible to any given antimicrobial and--in most cases--were
      correctly reported as such. Reporting was more erratic for resistant isolates:
      for beta-lactams and amikacin, isolates resistant at the highest MIC breakpoints
      were equally likely to be reported as 'susceptible' or 'resistant'; such
      misreporting was less common with ciprofloxacin and gentamicin but still occurred
      in 9-20% of cases. Conversely, up to 73% of the isolates reported as resistant
      proved to be susceptible at high breakpoints, and up to 44% were susceptible at
      low breakpoints. Miscategorizations did not reflect failure to detect particular
      mechanisms but, rather, the fact that MIC and zone breakpoints for P. aeruginosa
      serve to cut 'tails' of resistant organisms from continuous distributions, not to
      distinguish discrete populations. In this situation, some disagreement between
      routine tests and MICs is inevitable, but the frequency at which highly resistant
      isolates were reported as sensitive is disturbing. For surveillance, we conclude
      that resistance rates based on routine tests are unreliable for P. aeruginosa.
      This situation may improve with greater standardization of routine testing, but
      the continuous susceptibility distributions without discrete resistant and
      susceptible populations militate against perfect agreement. Despite these
      deficiencies, routine data should allow trend analysis.

PMID- 10350382
TI  - Continuous infusion versus intermittent administration of meropenem in critically
      ill patients.
AB  - This prospective crossover study compared the pharmacokinetics of meropenem by
      continuous infusion and by intermittent administration in critically ill
      patients. Fifteen patients were randomized to receive meropenem either as a 2 g
      iv loading dose, followed by a 3 g continuous infusion (CI) over 24 h, or by
      intermittent administration (IA) of 2 g iv every 8 h (q8h). Each regimen was
      followed for a period of 2 days, succeeded by crossover to the alternative
      regimen for the same period. Pharmacokinetic parameters (mean +/- SD) of CI
      included the following: concentration at steady state (Css) was 11.9+/-5.0 mg/L;
      area under the curve (AUC) was 117.5+/-12.9 mg/L x h. The maximum and minimum
      serum concentrations of meropenem (Cmax, Cmin) and total meropenem clearance
      (CItot) for IA were 110.1+/-6.9 mg/L, 8.5+/-1.0 mg/L and 9.4+/-1.2 L/h,
      respectively. The AUC during the IA regimen was larger than the AUC during CI (P
      < 0.001). In both treatment groups, meropenem serum concentrations remained above
      the MICs for the most common bacterial pathogens. We conclude that CI of
      meropenem is equivalent to the IA regimen and is therefore suitable for treating
      critically ill patients. Further studies are necessary to compare the clinical
      effects of CI and IA in this patient group.

PMID- 10350383
TI  - Levofloxacin versus cefuroxime axetil in the treatment of acute exacerbation of
      chronic bronchitis: results of a randomized, double-blind study.
AB  - A randomized, double-blind, double-dummy, three-arm parallel design, multicentre
      study was conducted among adult patients with acute exacerbation of chronic
      bronchitis (AECB) in order to compare the efficacy and safety of two different
      doses of levofloxacin with cefuroxime axetil. A total of 832 patients were
      randomized to receive oral levofloxacin (250 mg od or 500 mg od) or oral
      cefuroxime axetil (250 mg bd) for 7-10 days. The primary efficacy analysis was
      based on the clinical response in patients with bacteriologically confirmed AECB,
      determined 5-14 days after the end of therapy (per-protocol population). Of 839
      patients enrolled (at 71 centres in 14 countries), seven were not treated, giving
      an intention-to-treat (ITT) population of 832. In total, 281 patients received
      levofloxacin 250 mg, 280 received levofloxacin 500 mg and 271 received cefuroxime
      axetil. The cure rates in the ITT population were: levofloxacin 250 mg, 70%
      (196/281); levofloxacin 500 mg, 70% (195/280); cefuroxime axetil, 61% (166/271);
      those in the per-protocol population were: 78% (121/156), 79% (108/137) and 66%
      (88/134), respectively. Both doses of levofloxacin were at least as effective as
      cefuroxime axetil and were active against the main pathogens of clinical
      relevance (Haemophilus influenzae, Streptococcus pneumoniae and Moraxella
      catarrhalis). All three treatment regimens were equally well tolerated. In
      conclusion, the results show that levofloxacin (250 mg and 500 mg) od is
      effective and well tolerated in the treatment of AECB in adult patients.

PMID- 10350384
TI  - Five-day dirithromycin therapy is as effective as seven-day erythromycin therapy
      for acute exacerbations of chronic bronchitis.
AB  - In a meta-analysis of two identically designed, well-controlled, randomized,
      double-blind clinical trials, we compared 5 days of dirithromycin with 7 days of
      erythromycin for acute exacerbations of chronic bronchitis. Five hundred and
      thirty-one patients were randomized to receive dirithromycin (500 mg od) for 5
      days and 526 patients were randomized to receive erythromycin (250 mg qid) for 7
      days. Clinical and bacteriological responses were assessed 3-5 days after therapy
      and at termination from the study. Adverse events were collected from both groups
      and compared with each other, before and after treatment. Of the 690 patients
      clinically appraisable at the post-therapy visit, 298 (84.2%) dirithromycin
      treated patients and 270 (80.4%) erythromycin-treated patients showed a
      favourable response. At termination, 273 (77.1%) dirithromycin-treated patients
      and 243 (72.3%) erythromycin-treated patients showed a favourable response. The
      microbiological cure was equivalent in the two groups (75% of dirithromycin
      treated patients and 74.1% of erythromycin-treated patients showed a favourable
      response at termination). After therapy, dirithromycin was as effective as
      erythromycin in eradicating Streptococcus pneumoniae (77.8% vs 90.9%),
      Haemophilus influenzae (71.7% vs 72.2%), Moraxella catarrhalis (93.3% vs 88.9%)
      and Staphylococcus aureus (81.8% vs 82.1%). Although not statistically
      significant, fewer dirithromycin-treated patients reported adverse events than
      did erythromycin-treated patients. Nausea (6.8% vs 7.8%), headache (7.3% vs 8.2%)
      and diarrhoea (6.6% vs 9.5%) were the most frequently reported adverse events in
      both groups. In the treatment of acute exacerbations of chronic bronchitis, 5
      days of dirithromycin is as effective as 7 days of erythromycin.

PMID- 10350385
TI  - Treatment of community-acquired pneumonia in the elderly: the role of cefepime, a
      fourth-generation cephalosporin.
AB  - In a prospective, multicentre double-blind trial, 151 patients over the age of 65
      years were randomly assigned to receive either cefepime 2 g every 12 h for a
      minimum of 3 days and up to 14 days or ceftriaxone 1 g every 12 h for a minimum
      of 3 days and up to 14 days. Antibiotics were maintained until 48 h after fever
      had resolved; no other antibiotics were permitted. The average age in each group
      exceeded 77 years and significant co-morbidity was found in the majority of
      patients. The mean total duration of therapy was 5.8+/-2.4 days for the cefepime
      group and 6.7+/-2.7 days for the ceftriaxone group (P = 0.06). The clinical
      success rate at the end of therapy was 79.1% with cefepime and 75.4% with
      ceftriaxone (P = 0.62). At the end of follow-up, 91.7% of the cefepime-treated
      patients and 86.5% of the ceftriaxone patients had a satisfactory clinical
      response (P = 0.38). In 35 bacteriological evaluable patients, potential
      pathogens were eradicated in all but one patient receiving cefepime. Seven
      patients in each group died during the study period but in each case the death
      was unrelated to study drug. The commonest side-effect was diarrhoea (cefepime,
      five patients; ceftriaxone, two patients). The clinical and microbiological
      efficacy of cefepime is similar to that of ceftriaxone in elderly patients with
      community-acquired pneumonia requiring hospitalization. Cefepime is an
      appropriate choice for the treatment of community-acquired respiratory tract
      infections in the elderly.

PMID- 10350386
TI  - Correlation between genotype and beta-lactamases of clinical and environmental
      strains of Stenotrophomonas maltophilia.
AB  - Heterogeneity of beta-lactamase production by 17 clinical and nine environmental
      isolates of Stenotrophomonas maltophilia was investigated using MICs of six
      different beta-lactam antibiotics, isoelectric focusing (IEF) and pulsed field
      gel electrophoresis. There was no clear correlation between the results of IEF,
      genotype and MIC determination. Environmental isolates were more susceptible than
      clinical isolates; eight clinical and none of the environmental isolates
      expressed high-level resistance to meropenem. Only two isolates expressed high
      level resistance to ceftazidime. These results indicate that further studies are
      required to elucidate the extent of genetic heterogeneity within the L1 and L2
      beta-lactamase genes.

PMID- 10350387
TI  - Inducible or constitutive expression of resistance in clinical isolates of
      streptococci and enterococci cross-resistant to erythromycin and lincomycin.
AB  - Thirty-five of 40 clinical isolates of enterococci and streptococci cross
      resistant to erythromycin and lincomycin and harbouring erm genes were inducibly
      resistant to these drugs, suggesting that ribosomal methylation is predominantly
      inducibly expressed in these bacterial genera. Regulatory regions located
      upstream of the erm genes of four inducible and three constitutive strains were
      amplified and sequenced. Expression of constitutive resistance in two strains of
      Streptococcus pneumoniae and Enterococcus faecalis could be accounted for by a
      large deletion or a DNA duplication within the regulatory regions, respectively.

PMID- 10350388
TI  - In-vitro activities of 16 non-beta-lactam antibiotics against penicillin
      susceptible and penicillin-resistant Streptococcus pneumoniae.
AB  - MICs of 16 non-beta-lactams were determined by agar dilution for 283 penicillin
      susceptible, 122 intermediate and 23 fully penicillin-resistant isolates of
      pneumococci. Penicillin-resistant pneumococci were more likely to be resistant to
      tetracyclines, macrolides and related compounds. In the latter group,
      quinupristin/dalfopristin was the only compound whose activity was not influenced
      by penicillin resistance. Among the fluoroquinolones, clinafloxacin and
      trovafloxacin showed excellent activity. Strains resistant to macrolides,
      tetracycline and penicillin were concentrated in serogroups 6, 9, 14, 19 and 23.

PMID- 10350389
TI  - Comparative in-vitro activities of moxifloxacin, trovafloxacin,
      quinupristin/dalfopristin and linezolid against staphylococci.
AB  - The antistaphylococcal activities of four newly developed antibiotics,
      moxifloxacin (an 8-methoxyfluoroquinolone), trovafloxacin (a naphthyridone),
      quinupristin/dalfopristin (a semisynthetic streptogramin) and linezolid (an
      oxazolidinone), were examined and compared with those of ciprofloxacin,
      vancomycin and teicoplanin, using an agar dilution method. A total of 245
      clinical isolates of staphylococci, including a large number of clonally
      different methicillin-resistant strains, were tested. The new agents tested
      exhibited wide-spectrum antistaphylococcal activity against both methicillin
      susceptible and methicillin-resistant strains. In contrast to the quinolones, the
      in-vitro activities of quinupristin/dalfopristin, linezolid and the glycopeptides
      remained almost unchanged, irrespective of the resistance phenotype for
      methicillin. A number of isolates with elevated quinolone MICs were observed.

PMID- 10350390
TI  - Evaluation of the Etest for susceptibility testing of Mycoplasma hominis and
      Ureaplasma urealyticum.
AB  - The Etest was used for antibiotic susceptibility testing of Mycoplasma hominis
      and Ureaplasma urealyticum isolates and the results were compared with those
      obtained with the broth microdilution method. For 50 clinical isolates of M.
      hominis the MICs of doxycycline, ofloxacin and ciprofloxacin agreed within +/-
      one dilution and +/- two dilutions in 82-98% and 98-100% of cases, respectively.
      The MICs of erythromycin, azithromycin, doxycycline, ofloxacin and ciprofloxacin
      were evaluated for 50 clinical isolates of U. urealyticum. The corresponding
      levels of agreement were 70-98% and 94-100%, respectively. Reference isolates M.
      hominis PG-21 and U. urealyticum T-960 were also used. The Etest seems to be an
      alternative method for determination of MICs of antibiotics with M. hominis and
      U. urealyticum.

PMID- 10350391
TI  - The antifungal activity of mupirocin.
AB  - The antibacterial agent mupirocin (pseudomonic acid A) is used as a topical agent
      in the treatment of superficial infections by Gram-positive bacteria,
      particularly Staphylococcus aureus. However, we demonstrate here that the
      compound also inhibits the growth of a number of pathogenic fungi in vitro,
      including a range of dermatophytes and Pityrosporum spp. It inhibited the
      incorporation of amino acids and precursors of RNA, but not that of acetate, by
      Trichophyton mentagrophytes. It also inhibited the isoleucyl-tRNA synthetase from
      Candida albicans, indicating a mechanism of action similar to that in bacteria.
      When administered topically, mupirocin was efficacious in a T. mentagrophytes
      ringworm model in guinea pigs. These results suggest that mupirocin could have
      clinical utility for superficial infections caused by dermatophytes.

PMID- 10350392
TI  - Effect of antifungal agents on the binding of Candida albicans to immobilized
      amino acids and bovine serum albumin.
AB  - In this study the effects of different antifungal agents on the binding of
      Candida albicans yeast cells to different supports were examined. Pre-treatment
      with amphotericin B or dithiothreitol (DTT) severely reduced the ability of C.
      albicans yeasts to bind to plastic, while the effects of pre-treatment with
      fluconazole, ketoconazole or flucytosine were less marked. Both DTT and
      amphotericin B reduced the binding of yeasts to bovine serum albumin (BSA) and
      amino acids at low concentrations, while the other antifungal agents were
      effective at concentrations several-fold higher than their MICs. These data
      suggest that DTT and amphotericin B affect the yeast cell wall components, and
      alter both hydrophobic interactions with plastic, and the more specific
      interactions with BSA and amino acids. By contrast, the effect of the azoles and
      flucytosine appears to be largely restricted to hydrophobic interactions.

PMID- 10350393
TI  - Effect of teicoplanin on isolation of Staphylococcus aureus from blood culture
      media.
AB  - Intraoperative bacteraemia has been used as an indicator of the efficacy of
      prophylactic antibiotics. Two clinical isolates of Staphylococcus aureus in
      nutrient broth, with or without human serum, were exposed to teicoplanin (50
      mg/L) and, either immediately or after 30 min, inoculated into blood culture
      bottles. Bottles with and without resin were used and the experiment was repeated
      five times with one strain. In the absence of teicoplanin, an inoculum of 10
      cfu/mL produced growth in both resin and non-resin bottles. In the presence of
      teicoplanin, an inoculum of at least 10(5) cfu/mL was required in non-resin
      bottles to obtain growth, but this was reduced to 10(2)-10(3) cfu/mL for resin
      bottles. Intraoperative blood cultures overestimate the efficacy of bacterial
      killing by prophylactic antibiotics during surgery.

PMID- 10350394
TI  - Concentration and bactericidal activity of fusidic acid and cloxacillin in serum
      and synovial fluid.
AB  - Fusidic acid and cloxacillin were studied in patients who underwent joint
      aspiration for noninfectious disorders. Nine patients were given oral 500 mg
      fusidic acid tid for 72 h, the last dose being given 4, 8 or 12 h before the
      joint aspiration. Cloxacillin was administered in a single 2 g iv dose to 9
      patients, 0.5, 4 or 8 h before the aspiration. Bactericidal activity was
      determined against five isolates each of methicillin-susceptible and methicillin
      resistant Staphylococcus aureus. Satisfactory activity (> or = 1:3) was detected
      in the serum in patients who received fusidic acid, while in the synovial fluids
      titres reflected borderline effectiveness (c. 1:2). Despite drug concentrations
      and excellent MICs, fusidic acid demonstrated markedly lower inhibitory and
      bactericidal activity against S. aureus than did cloxacillin.

PMID- 10350395
TI  - Fungal infection and liposomal amphotericin B (AmBisome) therapy in liver
      transplantation: a 2 year review.
AB  - We reviewed the use of liposomal amphotericin B in 30 patients receiving therapy
      following liver transplantation over a 2 year period. Five of these patients were
      treated for presumed invasive aspergillosis: four of them died despite therapy,
      each having combined renal and respiratory failure at the time of diagnosis of
      presumed aspergillosis. Post-mortem examination of three of these patients
      confirmed the diagnosis of aspergillosis. Twenty-five patients were treated
      empirically; 11 died and supportive evidence for invasive fungal infection
      following commencement of therapy was found in only one case. Following liver
      transplantation, the use of liposomal amphotericin B following confirmation of
      aspergillus infection or for empirical therapy is of uncertain value, and
      strategies based on selective prophylaxis for high-risk cases may be preferable.

PMID- 10350396
TI  - Early switch from intravenous to oral antibiotics: guidelines and implementation
      in a large teaching hospital.
AB  - In recent years 'switch therapy' has been advocated: short intravenous antibiotic
      therapy, for 2-3 days, followed by oral treatment for the remainder of the
      course. Little is known about the number of patients that could benefit from
      early switch therapy and the consequences of introducing this strategy in
      everyday practice. We prospectively registered all antibiotic courses on wards
      for Internal Medicine, Surgery, and Pulmonology during a 2 month period, before
      (n = 362, inventorial phase) and after (n = 281, implementation phase) the
      introduction of guidelines for switching therapy. Approximately 40% of all
      patients who started on iv antibiotics were candidates for an early iv-oral
      switch. During the inventorial phase, 54% (52/97) of eligible patients were
      switched to oral treatment, after a median of 6 days (range 2-28 days). After
      implementation of the guidelines, this percentage rose to 83% (66/80) (difference
      29%, 95% CI 16-42%; P < 0.001). Therapy was also switched earlier, after a median
      of 4 days (range 2 to 16 days). In the 6 weeks after completion of the oral
      course, recurrence of infections, or readmissions due to reinfections did not
      occur. Compared with the inventorial phase, 43% of iv administrations could be
      avoided, that is >6000 per year. This means a potential annual reduction of
      dfl.60,000 (c. US$30,000) of administration costs. The potential savings in
      purchase costs of the antibiotics were dfl.54,000 (US$27,000) annually. In
      conclusion, a substantial number of patients starting on iv antibiotics were
      candidates for an early iv-oral switch. The guidelines were well accepted by the
      physicians and substantial savings in costs and nursing time were achieved.

PMID- 10350397
TI  - Identification of oprG, a gene encoding a major outer membrane protein of
      Pseudomonas aeruginosa.

PMID- 10350398
TI  - Outer membrane permeability of the antibiotic-supersusceptible lipid A mutants of
      Escherichia coli to hydrophobic steroid probes.

PMID- 10350399
TI  - Evaluation of the Etest for determining the in-vitro susceptibilities of
      Prevotella intermedia isolates to metronidazole.

PMID- 10350400
TI  - Comparative in-vitro activities of topical antibiotics against conjunctival
      isolates.

PMID- 10350401
TI  - Dehydro-epiandrosterone and ageing.

PMID- 10350402
TI  - Stroke units: more trials needed.

PMID- 10350403
TI  - Accuracy of diagnosis in patients with presumed Parkinson's disease.
AB  - OBJECTIVES: to study the diagnostic accuracy for parkinsonism and Parkinson's
      disease in a community-based sample of subjects on anti-parkinsonian medication.
      METHODS: computerized prescribing records in general practice were used to create
      a community-based disease register for Parkinson's disease. Subjects were
      examined to establish the likely diagnosis using recommended clinical diagnostic
      criteria. RESULTS: of 402 cases, parkinsonism was confirmed in 74% and clinically
      probable Parkinson's disease in 53%. The commonest causes of misdiagnosis were
      essential tremor, Alzheimer's disease and vascular pseudo-parkinsonism. Over one
      quarter of subjects did not benefit from anti-parkinsonian medication.
      CONCLUSIONS: there is difficulty in diagnosing parkinsonism and Parkinson's
      disease in elderly subjects and we suggest early referral of those suspected of
      having parkinsonism for specialist assessment.

PMID- 10350404
TI  - Age: a critical factor in cancer management. A prospective comparative study of
      400 patients.
AB  - BACKGROUND: older people are often excluded from cancer treatments solely on the
      grounds of age. AIMS: to compare cancer treatment in older and younger patients.
      PATIENTS AND METHODS: between June 1992 and September 1994, 400 cancer patients
      were included in this prospective comparative study. The factors compared between
      younger and older subjects were performance status, associated chronic diseases,
      delay in diagnosis, stage of disease and initial treatment. RESULTS: 54 patients
      (25.5%) under 70 years of age were asymptomatic at the time of diagnosis, in
      comparison with 25 (12.5%) of the 200 older patients (P < 0.001). Associated
      chronic pathologies were more frequent in the older patients (55% vs 18.5%, P <
      0.001). There were no statistical differences between both groups in diagnostic
      delay. Localized disease was found in 127 (63%) of the younger patients and in
      109 (54%) of the older patients, the difference not being significant. The
      percentage of patients who underwent oncological treatment was higher in the
      younger than the older group (87.5% vs 56%, P < 0.001). The main cause of
      therapeutic exclusion in both groups was poor performance status; however, in the
      older group other variables--such as the presence of chronic disease and
      patients' or relatives' wishes and doctors' opinions--influenced the decision not
      to give specific treatment. CONCLUSIONS: this study confirms that the clinical
      characteristics and treatment of aged people with cancer are different from those
      of younger patients. Nevertheless, there is considerable doubt about whether an
      arbitrary age limit should continue to be accepted as a discriminatory factor in
      some diagnostic and therapeutic procedures in cancer patients.

PMID- 10350405
TI  - Factors associated with prolonged symptoms and severe disease due to Clostridium
      difficile.
AB  - OBJECTIVE: toxigenic Clostridium difficile is responsible for a spectrum of
      disease severity ranging from mild diarrhoea to fulminant colitis. This study
      attempts to determine the proportion of patients in each category of severity and
      evaluate the risk factors for a more prolonged and complicated course. DESIGN:
      prospective cohort study. SETTING: university teaching hospital. SUBJECTS: all
      patients with symptomatic C. difficile infection during 4 months of an outbreak
      (January-April 1995); n=73; median age 74 years (range 17-91). MEASUREMENTS:
      incidence of C. difficile-associated disease (CDAD); severity of disease;
      percentage of patients in each category of severity; risk factors for severe
      disease/prolonged symptoms (univariate and multivariable analyses). RESULTS: the
      incidence of CDAD was 0.93%. Of the cases identified, 18 (24.7%) had mild, self
      limiting disease; 26 (35.6%) had moderately severe disease; 23 (31.5%) had
      prolonged symptoms and six (8.2%) had a complicated course. Although CDAD was
      more common in older patients (P < 0.001), increasing age was not a risk factor
      for severity. Significant risk factors for severe CDAD included low Barthel and
      abbreviated mental test scores (P < 0.01, P < 0.001 respectively) and recent
      endoscopy (P=0.03). Logistic regression analysis revealed the following
      independent predictors of severe CDAD: endoscopy [odds ratios (OR) 4.0, P=0.03]
      and cognitive impairment (OR 11.0, P < 0.01). A trend towards significance was
      noted for nasogastric tube insertion (OR 3.1, P=0.08). Complications of infection
      included dehydration, malnutrition and faecal incontinence (which was
      statistically significantly associated with more severe disease; P < 0.01).
      CONCLUSION: risk factors for severity of CDAD include functional disability,
      cognitive impairment, and recent endoscopy. Anticipation of severe CDAD may limit
      morbidity and mortality.

PMID- 10350406
TI  - Clinical significance of delirium subtypes in older people.
AB  - OBJECTIVE: to examine the relative frequency and outcome of clinical subtypes of
      delirium in older hospital patients. DESIGN: prospective observational study.
      SETTING: acute geriatric unit in a teaching hospital. SUBJECTS: 94 patients with
      delirium from a prospective study of 225 admissions. MEASUREMENTS: clinical
      subtypes of delirium were determined according to predefined criteria.
      Characteristics examined in these subgroups included illness severity on
      admission, prior cognitive impairment, mortality, duration of hospital stay and
      hospital-acquired complications. RESULTS: of the 94 patients, 20 (21%) had a
      hyperactive delirium, 27 (29%) had a hypoactive delirium, 40 (43%) had a mixed
      hypoactive-hyperactive psychomotor pattern and seven (7%) had no psychomotor
      disturbance. There were significant differences between the four groups in
      illness severity (P < 0.05), length of hospital stay (P < 0.005) and frequency of
      falls (P < 0.05). Patients with hypoactive delirium were sicker on admission, had
      the longest hospital stay and were most likely to develop pressure sores.
      Patients with hyperactive delirium were most likely to fall in hospital. There
      were no differences in aetiological factors between the groups. CONCLUSION:
      outcomes of hospitalization differ in different clinical subtypes of delirium.

PMID- 10350407
TI  - The prognosis of falls in elderly people living at home.
AB  - BACKGROUND: there are few longitudinal studies of the prognosis of falling at
      home. OBJECTIVE: to determine outcomes in older people who fall once and more
      than once. DESIGN: longitudinal prospective cohort study. SETTING: primary care
      in the UK. SUBJECTS: 1815 subjects over 75 who had a standardized and validated
      health check. METHOD: annual interviews over 4 years. Practice records were used
      to establish death and admission to institutions. RESULTS: risk of death was
      increased at 1 year [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.7]
      and 3 years (OR 1.9, 95% CI 1.2-3.0) for recurrent fallers but not single fallers
      (OR 0.9, 95% CI 0.5-1.6 at 1 year; OR 0.97, 95% CI 0.7-1.4 at 3 years). Risk of
      admission to long-term care over 1 year was markedly increased both for single
      fallers (OR 3.8, 95% CI 1.8-8.3) and recurrent fallers (OR 4.5, 95% CI 1.7-12).
      Functional decline was not related to faller status, the latter being very
      variable from one year to the next. CONCLUSIONS: the stronger relationship
      between falling and admission to long-term care rather than mortality supports
      the hypothesis that the perceived risks for those who fall only once are
      exaggerated.

PMID- 10350408
TI  - Carotid sinus hypersensitivity--a modifiable risk factor for fractured neck of
      femur.
AB  - BACKGROUND: the potential impact on morbidity, mortality and health care
      economics makes it important to identify patients at risk of fracture, in
      particular fractured neck of femur (FNOF). Older patients with carotid sinus
      hypersensitivity (CSH) are more likely to have unexplained falls and to
      experience fractures, particularly FNOF. Our objective was to determine the
      prevalence of CSH in patients with FNOF. DESIGN: case-controlled prospective
      series. METHODS: consecutive cases were admissions over 65 years with FNOF.
      Controls were consecutive patients admitted for elective hip surgery, frail
      elderly people admitted to hospital medical wards and day-hospital patients. All
      patients had a clinical assessment of cognitive function, physical abilities and
      history of previous syncope, falls and dizziness, in addition to repeated carotid
      sinus massage with continuous heart rate and phasic blood pressure measurement.
      RESULTS: heart rate slowing and fall in systolic blood pressure was greater for
      patients with FNOF than those admitted for elective hip surgery (P < 0.05 and P <
      0.001). CSH was present in 36% of the FNOF group, none of the elective surgery
      group, 13% of the acutely ill controls and 17% of the outpatients. It was more
      likely to be present in FNOF patients with a previous history of unexplained
      falls or an unexplained fall causing the index fracture. The heart rate and
      systolic blood pressure responses to carotid sinus stimulation were reproducible.
      CONCLUSION: older patients with an acute neck of femur fracture who do not give a
      clear history of an accidental fall or who have had previously unexplained falls
      are likely to have CSH. CSH may be a modifiable risk factor for older patients at
      risk of hip fracture.

PMID- 10350409
TI  - Residential status and risk of hip fracture.
AB  - OBJECTIVE: to examine the association between residential status and risk of hip
      fracture in older people. DESIGN: population-based case-control study. SETTING:
      Auckland, New Zealand. SUBJECTS: a random sample of all individuals > or = 60
      years, hospitalized with a fracture of the proximal femur between July 1991 and
      February 1994. Controls were age and gender frequency-matched to the cases,
      randomly selected from a random sample of general practitioners. MAIN OUTCOME
      MEASURES: radiographically-confirmed fracture of the proximal femur. Fractures
      sustained as a result of major trauma, such as in a motor vehicle crash, and
      those associated with pre-existing pathological conditions were excluded.
      RESULTS: individuals living in institutions were almost four times more likely to
      sustain a hip fracture [age- and gender-adjusted odds ratio (OR)=3.8; 95%
      confidence interval (CI): 3.0-4.8] than those living in private homes. After
      adjustment for potential confounding factors, the risk of hip fracture associated
      with living in an institution remained significantly increased (P< 0.0001),
      although the magnitude of the risk was somewhat diminished (OR=2.2; 95% (CI: 1.5
      3.5). CONCLUSIONS: living in an institution is associated with an increased risk
      of hip fracture in older people. Specific factors that place these individuals at
      increased risk need to be identified, in order to develop intervention
      strategies.

PMID- 10350411
TI  - Activity patterns in very old people: a survey of cognitively intact subjects
      aged 90 years or older.
AB  - AIM: to measure activity patterns in very old people, the factors related to this
      and the association of different types of activity with well-being. METHODS: a
      study of 105 people, aged 90 years or older, who were not cognitively impaired,
      living in Stockholm. The activities carried out during the previous day were
      recorded and each activity was rated. RESULTS AND CONCLUSIONS: the degrees of
      intellectual, social and physical activity are independent of each other. Very
      elderly people tended to have variable but relatively low activity levels over a
      day. Good health and not moving home were associated with greater intellectual
      activity. Extraversion and negative life events (such as death of close friend or
      family member) were associated with greater social activity, while relatively
      younger age and better health were associated with greater physical activity.
      There was positive association between physical activity and well-being.

PMID- 10350410
TI  - Serological response to influenza vaccination and nutritional and functional
      status of patients in geriatric medical long-term care.
AB  - INTRODUCTION: in the UK the Department of Health recommends influenza vaccination
      for elderly people resident in institutional care. However, the efficacy of
      vaccination may be reduced in very frail elderly people with functional
      impairment, undernutrition and multiple pathologies. Nutritional and functional
      status is claimed to affect vaccine responses in healthy elderly subjects. We
      wished to determine if a relationship could be seen between nutritional and
      functional status and seroconversion in patients receiving long- term care.
      METHODS: all patients in geriatric medical long-term care were offered vaccine.
      Consenting patients had pre- and post-vaccine serology measured using single
      radial haemolysis. Anthropometry was measured to enable body mass index (BMI) to
      be calculated. Functional independence was assessed using the 20-point Barthel
      index. RESULTS: of 260 patients who received influenza vaccine, 137 (36 male, 101
      female) consented to venesection for serology and thus form the study population.
      Mean age was 82 years (SD 7.9). The median Barthel score was 3/20 and the mean
      BMI was 21.6 (SD 4.6, range 13-36.2). Antibodies to influenza A were undetectable
      both pre- and post-vaccination in 63/137 patients. In 49 patients the antibody
      titre rose after vaccination and 25 had detectable antibody titres pre
      vaccination which failed to rise post-vaccine. There were no significant
      associations between post-vaccination influenza antibody responses and BMI,
      Barthel score or age. CONCLUSION: frail elderly patients in geriatric medical
      long-term care had a poor antibody response to influenza vaccination. Within this
      group, serological responses could not be predicted by nutritional or functional
      status.

PMID- 10350412
TI  - Predictors of functional status in older people living at home.
AB  - OBJECTIVE: to describe changes in functional status of community-dwelling Spanish
      elderly people, followed for 2 years, and to identify socio-demographic and
      health characteristics that predict functional change. METHOD: we have analysed
      data from the first two waves of the longitudinal study, Ageing in Leganes, from
      a representative sample of community-dwelling people aged 65 and over (n=1273).
      Functional status was categorized according to a hierarchical scale as:
      completely functional, with functional limitations, with instrumental activities
      of daily living (IADL) disability, with activities of daily living (ADL)
      disability or deceased. Multinomial logistic regression was used to estimate the
      predictive value of selected 1993 socio-demographic and health status variables
      on 1995 functional status. RESULTS: prevalence of disability based on dependency
      in any of seven ADL items was 15.5%. Half of the respondents were disabled in at
      least one of 10 IADLs. Some improved functionally, others deteriorated. Men were
      more likely to recover function while women were more likely to enter and to
      remain in the IADL state. Socioeconomic factors were associated to baseline
      functional status and to functional status change on bivariate analysis. Number
      of chronic diseases, presence of cognitive problems and depressive symptoms
      predicted transitions, even after controlling for baseline functional status.
      CONCLUSION: although estimates of prevalence of disability among people over 65
      are higher in Spain than in other European and North American countries, the
      pattern of functional changes, both in the direction of improvement and decline,
      seems to be similar.

PMID- 10350413
TI  - Development of an activities of daily living scale to screen for dementia in an
      illiterate rural older population in India.
AB  - OBJECTIVE: to develop a measure of activities of daily living appropriate for use
      in assessing the presence of dementia in illiterate rural elderly people in
      India. DESIGN: identification of relevant items, pre-testing of items and
      refinement of administrative procedures and scoring in four successive groups of
      30 subjects each, pilot testing in a group of 100 subjects comparable to those
      for whom the measure is intended, administration to a representative sample of
      387 people aged 55 and older, and assessment of the reliability of the final
      measure. SETTING AND SUBJECTS: age-stratified random sample of older men and
      women in rural areas of Ballabgarh, Northern India. RESULTS: the original pool of
      35 items covering mobility, instrumental and personal care activities was reduced
      to an 11-item unidimensional scale (to which an additional item on mobility was
      added) with internal consistency (Cronbach's alpha)=0.82, perfect inter- and
      intra-rater reliability, test-retest reliability (intraclass correlation)=0.82
      (any disability) and 0.92 (unable to perform for 'mental' reasons). Women, older
      subjects, the totally illiterate and subjects with poorer cognitive function
      performed significantly more poorly (P < or = 0.02 for all). PRODUCT: a brief,
      reliable and valid activities of daily living measure, with norms, which is
      appropriate for use in assessing dementia in illiterate rural elderly people in
      India.

PMID- 10350414
TI  - Validity and reliability of the Medical Outcomes Study Short Form-20
      questionnaire as a measure of quality of life in elderly people living at home.
AB  - BACKGROUND: the Medical Outcomes Study Short Form-20 (SF-20) questionnaire is
      recommended for health-related quality of life research, but there is little
      information on its utility in older people. We assessed the validity, reliability
      and feasibility of using the SF-20 in an elderly community-dwelling population.
      METHODS: the SF-20 was administered to a stratified, random sample of 333 elderly
      subjects. FINDINGS: assessment of content validity revealed that important
      domains were lacking, while others appeared to be inappropriately combined. Using
      Spearman correlation coefficients, the SF-20 had acceptable convergent and
      discriminant validity. A principal components analysis provided evidence for
      internal consistency for some of the subscales. Evidence for test-retest
      reliability was good. INTERPRETATION: while the reliability and feasibility of
      the SF-20 appear satisfactory, concerns about validity and responsiveness should
      temper enthusiasm for its use with elderly people living at home.

PMID- 10350415
TI  - Lactose malabsorption and rate of bone loss in older women.
AB  - OBJECTIVES: to study the prevalence of lactose malabsorption with increasing age
      and to determine whether lactose malabsorbers consume less dietary calcium, have
      lower bone mineral density or display faster bone loss than lactose absorbers.
      DESIGN: 80 healthy Caucasian women aged 40-79 years (20 per decade) were studied
      for 1 year. METHODS: breath hydrogen exhalation was measured for 3 after a 50 g
      oral lactose challenge. Bone density was assessed in the radius, femoral neck,
      lumbar spine and total body by dual energy x-ray absorptiometry and dietary
      calcium intake was estimated by 4-day diet records and food-frequency
      questionnaires. RESULTS: lactose malabsorption rose with age (15% in those aged
      40-59 years versus 50% in those aged 60-79; P < 0.01). Malabsorbers aged 70-79
      years consumed significantly less calcium than lactose absorbers of this age (P <
      0.05). Baseline total body calcium values were lower in lactose malabsorbers
      (n=26) than in lactose absorbers (n=54) but age-adjustment eliminated this
      difference. Bone change (% per year) was correlated with dietary calcium intake
      at the femoral neck and trochanter (P < 0.05) but was not statistically greater
      in malabsorbers than in absorbers. CONCLUSIONS: the ability to absorb lactose
      declines in the 7th decade. This may contribute to decreased dietary intakes of
      milk products and calcium in elderly women. However, lactose malabsorption
      without reduction in calcium intake has little effect on bone mineral density or
      the rate of bone loss.

PMID- 10350416
TI  - Small bowel bacterial overgrowth in subjects living in residential care homes.
AB  - OBJECTIVES: in elderly people, bacterial overgrowth of the small bowel may be
      occult. The significance of positive breath tests are uncertain: many fit elderly
      subjects with positive tests show no evidence of malabsorption. We assessed the
      prevalence and significance of bacterial overgrowth in the small bowel in a
      relatively unselected elderly population. METHODS: residents of seven elderly
      people's homes had a glucose hydrogen breath test. A medical history and
      anthropomorphic measurements were recorded. Volunteers with positive breath tests
      were given doxycycline. After 4 months all volunteers were reassessed. RESULTS:
      of 140 residents, 62 were tested. Nine (14.5%) had a positive breath test. There
      was no difference in anthropomorphic and bowel habit data between those with
      positive and those with negative breath tests. After 4 months of antibiotic
      treatment, volunteers with a positive breath test had increased weight and body
      mass index, while those with a negative test had decreased weight and body mass
      index. CONCLUSIONS: the percentage of volunteers with a positive breath test was
      much lower than in previous studies. This may be due to the relatively unselected
      nature of the volunteers. Treatment of bacterial overgrowth resulted in a small
      but significant improvement in anthropometric indices. The lack of association of
      positive breath tests with baseline anthropomorphic measurements or bowel habit
      highlights the occult nature of the bacterial overgrowth and questions its
      clinical importance.

PMID- 10350417
TI  - Costing for long-term care: the development of Scottish health service resource
      utilization groups as a casemix instrument.
AB  - OBJECTIVE: to create a casemix measure with a limited number of categories which
      discriminate in terms of resource use and will assist in the development of a
      currency for contracting for the provision of health care. DESIGN: nursing staff
      completed a questionnaire providing clinical data and also gave estimates of
      relative patient resource use; ward-based costs were collected from appropriate
      unit managers. SETTING: National Health Service continuing-care wards in 50
      Scottish hospitals. SUBJECTS: 2783 long-stay patients aged 65 years and over.
      RESULTS: inter-rater reliability was assessed using 1402 patients; percentage
      agreement between raters for individual variables varied from 68% for feeding to
      97% for clinically complex treatments. Nursing costs gave 62% agreement given
      categories of high, medium and low. The Scottish health service resource
      utilization groups (SHRUG) measure was developed using 606 cases, and 67%
      consistency was achieved for the five categories. The relative weights for the
      SHRUG categories ranged from 0.56 to 1.41. The five categories explain 35% of
      variance in costs. CONCLUSIONS: the five SHRUG casemix categories show good
      discrimination in terms of costs. The SHRUG measure compares favourably with
      diagnosis-related groups in the acute sector and with other casemix instruments
      for long-term care previously piloted in the UK. SHRUG is a useful measurement
      instrument in assessing the resource needs of elderly people in long-term care.

PMID- 10350418
TI  - Validity of reported age and centenarian prevalence in New England.
AB  - INTRODUCTION: the age reported by or on behalf of centenarians may be suspect
      unless proven correct. We report the validity of age reports in a population
      based sample of centenarians living in New England and the prevalence of
      centenarians in an area within the North Eastern USA. METHODS: cohort study. All
      centenarians in a population-based sample detected by local censuses. Ages were
      confirmed by birth certificate. Type of residence and whether the subject was
      living independently were also recorded. RESULTS: from a population of about
      450,000 people, 289 potential centenarians were reported by the censuses of the
      eight towns participating in the study. Of these, 186 (64%) had died at the time
      centenarian prevalence was determined. Of the 80 still alive, 13 (16%) had
      incorrect birth years recorded by the censuses. The specificity of the censuses
      for stating the number of centenarians alive and living in the sample was 28-31%.
      Using additional sources, only four more centenarians were located, indicating
      that the sensitivity of the censuses approached 100%. We had an 83% success rate
      in obtaining proof of age in those families we interviewed. In all instances, age
      and birth order of children were an important source of corroborative evidence
      and in no case did we detect inconsistencies with the families' reported ages of
      the centenarian subjects. Therefore, there were at least 46 centenarians or
      approximately 1 centenarian per 10,000 people. CONCLUSIONS: age validation can be
      performed for most centenarians in the North Eastern USA. Self or family reports
      of those between the ages of 100 and 107 years were dependable.

PMID- 10350419
TI  - Mortality trends of elderly people in Taiwan from 1974 to 1994.
AB  - BACKGROUND: the hypothesis that disability and death will eventually be
      compressed to a period late in life needs empirical confirmation. OBJECTIVES: we
      have examined the secular trends of life expectancy and common causes of death in
      the aged population of Taiwan. METHOD: we compared the life expectancy, causes of
      death and probability of death for people at birth, at age 65 and at age 85 for
      both sexes from 1974 to 1994 using data from Taiwan government statistics.
      RESULTS: there has been a substantial gain in life expectancy, especially for men
      age 85 and over, in the past 20 years. . Mortality due to stroke, ischaemic heart
      disease, hypertension and chronic pulmonary disease has declined. There has been
      a steep increase in cancer deaths and deaths associated with diabetes mellitus.
      Tuberculosis and injury-related deaths have declined but pneumonia deaths have
      increased. For elderly people, the probability of dying from cancer and ischaemic
      heart disease increased with time. However, the probability of dying from stroke
      decreased. Although there was a decrease in probability of deaths associated with
      falls, there was an increase of deaths due to 'frailty' (as judged by falls,
      pneumonia and septicaemia). CONCLUSIONS: cancer is a major cause of death in the
      elderly population of Taiwan. This rapidly expanding elderly population seemed to
      suffer from poorer health in the later period of their life.

PMID- 10350420
TI  - A preliminary study of dietary aluminium intake and risk of Alzheimer's disease.
AB  - BACKGROUND: epidemiological studies of Alzheimer's disease and aluminium intake
      have focused on aluminium in drinking water. There have been no studies
      investigating the relation between the disease and the consumption of foods
      containing large amounts of aluminium additives. OBJECTIVES: to conduct a pilot
      study to determine whether dietary intake of aluminium additives differs in
      individuals with and without Alzheimer's disease. DESIGN: matched case-control
      study. Controls were matched to cases on age, gender and date of admission to the
      centre. SETTING: Syracuse, New York, USA. SUBJECTS: 46 participants comprising 23
      matched sets. METHODS: residents of the Loretto Geriatric Center with and without
      newly-diagnosed Alzheimer's disease were selected. Next-of-kin were asked to
      complete information on the resident's medical history, lifestyle behaviour and
      dietary intake before admission to the centre. An expanded form of the Health
      Habits and History Questionnaire was used to determine dietary intake.
      Consumption of foods containing elevated levels of aluminium additives was
      compared between cases and controls. RESULTS: the crude odds ratio for daily
      intake of foods containing high levels of aluminium was 2.0 and, when adjusted
      for covariates, was 8.6 (P=0.19). Intake of pancakes, waffles, biscuits, muffins,
      cornbread and/or corn tortillas differed significantly (P=0.025) between cases
      and controls. Adjusted odds ratios were also elevated for grain product desserts,
      American cheese, chocolate pudding or beverages, salt and chewing gum. However,
      the odds ratio was not elevated for tea consumption. CONCLUSION: past consumption
      of foods containing large amounts of aluminium additives differed between people
      with Alzheimer's disease and controls, suggesting that dietary intake of
      aluminium may affect the risk of developing this disease. Larger studies are
      warranted to corroborate or refute these preliminary findings.

PMID- 10350421
TI  - Correlation of serum L-carnitine and dehydro-epiandrosterone sulphate levels with
      age and sex in healthy adults.
AB  - OBJECTIVES: L-carnitine and dehydro-epiandrosterone (DHEA) independently promote
      mitochondrial energy metabolism. We therefore wondered if an age-related
      deficiency of L-carnitine or DHEA may account for the declining energy metabolism
      associated with age. METHODS: we evaluated serum levels of L-carnitine and the
      sulphated derivative of DHEA (DHEAS) in cross-sectional study of 216 healthy
      adults, aged 20-95. RESULTS: serum DHEAS levels declined, while total carnitine
      levels increased with age (P < 0.0001). Total and free carnitine and DHEAS levels
      were lower in women than men (P < 0.0001). Esterified/free (E/F) carnitine
      (inversely related to carnitine availability) increased with age in both sexes
      (P=0.012). CONCLUSION: reduced carnitine availability correlates with the age
      related decline of DHEAS levels. These results are consistent with the hypothesis
      that decreased energy metabolism with age relates to DHEAS levels and carnitine
      availability.

PMID- 10350422
TI  - Relationships between age, dehydro-epiandrosterone sulphate and plasma glucose in
      healthy men.
AB  - BACKGROUND: dehydro-epiandrosterone sulphate (DHEAS) has been reported to
      ameliorate diabetes mellitus in rats. AIM: we investigated the relationships
      between plasma glucose, age, serum DHEAS and weight in healthy men. METHODS: we
      measured the serum DHEAS, fasting plasma glucose, plasma cortisol and body mass
      index in 169 subjects (mean age 46.5 years). RESULTS: there was a significant
      decline in serum DHEAS with age (P < 0.0001). Multiple linear regression showed
      significant relationships with plasma glucose for all measured variables. Age was
      not a significant determinant of plasma glucose after adjusting for log serum
      DHEAS, body mass index and log serum cortisol. CONCLUSIONS: a lowered serum DHEAS
      is paralleled by an elevated plasma glucose within the normal reference interval,
      and this may contribute to the rise in fasting plasma glucose which occurs with
      ageing.

PMID- 10350423
TI  - Functional integrity of the CD28 co-stimulatory pathway in T lymphocytes from
      elderly subjects.
AB  - INTRODUCTION: the antigen CD28, expressed in most T cells, has co-stimulatory
      properties and plays a pivotal role in clonal T cell anergy mechanisms. METHODS:
      we have compared proliferative T cell responses after anti-CD3 or in phorbol
      myristate acetate activation with concomitant CD28 signal in peripheral blood
      mononuclear cells from healthy donors aged over 65 [elderly donors; ED] and young
      healthy donors (YD); mean age 30+/-2.7 years). RESULTS: no proliferative
      responses were observed in ED and YD with anti-CD28 monoclonal antibody alone.
      These responses both were defective in ED, particularly after anti-CD3 monoclonal
      antibody stimulus (7604 compared with 12,438 c.p.m. in YD, P=0.001) and were
      corrected when anti-CD28 monoclonal antibody was added to the culture (17,216 vs
      18,536, not significant). Functional integrity of the CD28 co-stimulatory pathway
      was demonstrated by analysis of CD25 expression, interleukin-2 secretion and
      interleukin-2 gene expression on T cells from ED and YD. Age-associated
      phenotypic T cell changes were not crucial for an adequate CD28 response.
      CONCLUSION: these experiments demonstrate the integrity of the CD28 pathway in
      elderly people, and suggest that ageing does not affect different T cell
      activation pathways equally.

PMID- 10350425
TI  - A case of coprophagia presenting with sialadenitis.
AB  - PRESENTATION: a 94-year-old woman with dementia was admitted to an acute
      geriatric ward with increasing confusion and falls. On two occasions she
      developed submandibular masses. Faeces were aspirated from her mouth and a
      diagnosis made of recurrent submandibular sialadenitis secondary to coprophagia.
      OUTCOME: the submandibular mass settled with antibiotics and oral care.
      Coprophagia was not observed on the ward, but faecal smearing was noted. With
      regular toileting, this behaviour ceased and sialadenitis did not recur.

PMID- 10350424
TI  - Nasal colonization by Staphylococcus aureus in active, independent, community
      seniors.
AB  - OBJECTIVE: to evaluate the prevalence of nasal colonization with Staphylococcus
      aureus (SA) in active, independent community seniors and old people in a nursing
      home. DESIGN: cross-sectional brief questionnaire and screening culture of
      anterior nares specimens from 165 elders at a community centre and cross
      sectional data from a recent survey in a nursing home. RESULTS: the prevalence of
      SA colonization in community seniors (27%) was similar to that in the nursing
      home (29%). The proportion of SA isolates that were methicillin-resistant was
      much lower in the community seniors (2.3%) than in the nursing-home residents
      (31%). There was less antibiotic resistance in those living at home. CONCLUSION:
      in community seniors the prevalence of SA colonization was similar to that in
      nursing-home residents, but the prevalence of methicillin-resistant SA was lower.
      Susceptibility patterns of antibiotics tested against the SA showed less
      resistance than isolates from nursing-home patients.

PMID- 10350426
TI  - Collagenous colitis: a modifiable cause of diarrhoea in older people.

PMID- 10350427
TI  - Declaration of Yuste. European Working Party.

PMID- 10350429
TI  - Agitation and aggressiveness in elderly people at home.

PMID- 10350428
TI  - Air-terminal stress and the older traveller.

PMID- 10350430
TI  - Anxiety as the reason why previous psychiatric illness is a risk factor for
      dementia.

PMID- 10350432
TI  - Community hospitals...and district general hospitals.

PMID- 10350431
TI  - Inappropriate acute admissions from nursing homes.

PMID- 10350433
TI  - Community hospitals...and district general hospitals.

PMID- 10350434
TI  - Vitamin D and breast cancer risk: the NHANES I Epidemiologic follow-up study,
      1971-1975 to 1992. National Health and Nutrition Examination Survey.
AB  - We analyzed data from the first National Health and Nutrition Examination Survey
      Epidemiologic Follow-up Study to test the hypothesis that vitamin D from sunlight
      exposure, diet, and supplements reduces the risk of breast cancer. We identified
      190 women with incident breast cancer from a cohort of 5009 white women who
      completed the dermatological examination and 24-h dietary recall conducted from
      1971-1974 and who were followed up to 1992. Using Cox proportional hazards
      regression, we estimated relative risks (RRs) for breast cancer and 95%
      confidence intervals, adjusting for age, education, age at menarche, age at
      menopause, body mass index, alcohol consumption, and physical activity. Several
      measures of sunlight exposure and dietary vitamin D intake were associated with
      reduced risk of breast cancer, with RRs ranging from 0.67-0.85. The associations
      with vitamin D exposures, however, varied by region of residence. The risk
      reductions were highest for women who lived in United States regions of high
      solar radiation, with RRs ranging from 0.35-0.75. No reductions in risk were
      found for women who lived in regions of low solar radiation. Although limited by
      the relatively small size of the case population, the protective effects of
      vitamin D observed in this prospective study are consistent for several
      independent measures of vitamin D. These data support the hypothesis that
      sunlight and dietary vitamin D reduce the risk of breast cancer.

PMID- 10350435
TI  - Environmental exposure to hexachlorobenzene (HCB) and risk of female breast
      cancer in Connecticut.
AB  - Earlier studies have provided inconclusive results relating hexachlorobenzene
      (HCB), an organochlorine fungicide, to female breast cancer risk. The current
      study, with a total of 304 breast cancer cases and 186 controls recruited in
      Connecticut between 1994 and 1997, examined the association by directly comparing
      breast adipose tissue levels of HCB between incident breast cancer cases and
      noncancer controls. The cases and controls were patients who had breast biopsies
      or surgery at the Yale-New Haven Hospital (New Haven, CT) and histologically
      diagnosed either as breast cancer or benign breast disease. Information on major
      known or suspected risk factors for breast cancer was obtained through in-person
      interview by trained interviewers. No significant difference in mean breast
      adipose tissue levels of HCB was observed between breast cancer patients (21.0
      ppb) and controls (19.1 ppb) in this large case-control study. The risk also did
      not vary significantly by menopausal status, estrogen or progesterone receptor
      status of the breast cancer cases, breast cancer histology, stage of diagnosis,
      or type of benign breast disease. Among parous women who reported ever breast
      feeding, an odds ratio (OR) of 0.5 [95% confidence interval (CI), 0.2-1.4] was
      observed when the highest quartile was compared with the lowest quartile.
      However, no association was observed among parous women who reported never breast
      feeding (OR = 0.7; 95% CI, 0.3-1.7 for the fourth quartile). For nulliparous
      women, the adjusted OR was 2.1 (95% CI, 0.5-8.8) for the third tertile when
      compared with the lowest based on few subjects. Therefore, our study does not
      support a positive association between environmental exposure to HCB and risk of
      breast cancer.

PMID- 10350436
TI  - Oral contraceptive use and other risk factors in relation to HER-2/neu
      overexpression in breast cancer among young women.
AB  - This study was undertaken to explore whether the incidence of breast tumors that
      overexpress HER-2/neu protein product (HER-2/neu+) is more strongly associated
      with oral contraceptives (OCs) and other factors than is the incidence of tumors
      that do not (HER-2/neu-). In a population-based sample of women <45 years, 42.9%
      (159 of 371) of in situ and invasive breast cancer cases were HER-2/neu+ as
      assessed by immunohistochemistry in archived tissue. Polytomous logistic
      regression was used to calculate the odds ratios (ORs) and 95% confidence
      intervals (CIs) for HER-2/neu+ and HER-2/neu-breast cancer, as compared with 462
      population-based controls, in relation to OCs and other factors. The ratio of the
      ORs (HER-2/neu+ versus HER-2/neu-tumors) was used as an indicator of
      heterogeneity in risk. There was little heterogeneity in risk for OC use of 6
      months or more by HER-2/neu status (age-adjusted ratio of ORs, 1.29; 95% CI, 0.83
      2.00). Among early pill users (< or =18 years of age) heterogeneity was apparent
      (2.39; 95% CI, 1.08-5.30), which was attenuated in a multivariate model (1.99;
      95% CI, 0.87-4.54); among cases with estrogen receptor-negative tumors,
      heterogeneity increased to 5-fold. For other risk factors, there was no marked
      heterogeneity between + and - tumors for HER-2/neu. In summary, the incidence of
      breast cancer among younger women in relation to OC use at an early age varied
      with HER-2/neu status, with the odds ratio for +tumors twice that for -tumors.

PMID- 10350437
TI  - Family history, ethnicity, and relative risk of breast cancer in a prospective
      cohort study of older women.
AB  - In a cohort of 27,578 postmenopausal Iowa women, we examined whether the risk
      with a family history of breast cancer differs by self-reported ethnicity. A
      total of 1042 breast cancer cases occurred over 10 years of follow-up. Using a
      phylogenetic tree, ethnicities were combined into five groups: Scandinavian;
      English, Scottish, Welsh, and Dutch (ESWD); Irish; German; and Other European.
      The incidence of breast cancer did not differ significantly by ethnicity,
      although the highest rates were observed among Scandinavian women (488 per
      100,000 per year) and the lowest among Irish women (353 per 100,000 per year).
      The prevalence of a family history of breast cancer was not significantly
      associated with ethnicity when only first-degree relatives were considered (P =
      0.17), but inclusion of data on second-degree relatives increased the statistical
      significance of the association (P = 0.003). Differences in mean levels of breast
      cancer risk factors between ethnicities were generally small but statistically
      significant. Proportional hazards regression was performed to evaluate potential
      interactions of family history with ethnicity on breast cancer incidence. A
      family history of breast cancer was associated with increased relative risks
      among ESWD, Germans, and Other Europeans but not among Irish and Scandinavians.
      Relative risk estimates were not attenuated upon addition of known breast cancer
      risk factors to the model, implying that the distribution of these risk factors
      by ethnicity is unlikely to explain some of the observed ethnic-specific
      differences between family history and risk of breast cancer. Results of this
      study could have implications for studies of common genetic polymorphisms and
      cancer risk.

PMID- 10350439
TI  - p53 Mutations in lung cancer associated with residential radon exposure.
AB  - Unusual mutation patterns in lung tumors among underground miners have been
      indicated, suggesting radon-specific alterations in the genome, but the data are
      not consistent. To investigate the association between residential radon exposure
      and p53 mutations in lung tumors, we performed a study on cases from a nation
      wide population-based investigation in Sweden. Our study included 83 nonsmoking
      lung cancer cases and 250 smoking lung cancer cases, diagnosed 1980-1984, with a
      time-weighted average radon exposure over 140 Bq/m3 or up to 50 Bq/m3. Radon was
      measured in dwellings occupied by the study subjects at some time since 1947.
      Information on smoking habits and other risk factors was obtained from
      questionnaires. After exclusions because of the initiation of treatment or
      insufficient material, the p53-status of 243 tumors was determined using PCR
      single-stranded conformation polymorphism analysis and sequencing determination
      of exons 5-8. The overall mutation prevalence was 23.9%. An increased mutation
      prevalence was suggested among those with high exposure to residential radon
      [odds ratio (OR), 1.4; 95% CI, 0.7-2.6], especially among nonsmokers (OR, 3.2;
      95% CI, 0.7-15.5), but no specific mutational pattern was indicated. Furthermore,
      the mutation prevalence seemed to be higher among smoking lung cancer cases than
      among nonsmoking cases (OR, 2.1; 95% CI, 0.9-5.0), and particularly among those
      smoking less than 10 cigarettes per day. It may be concluded that residential
      exposure to radon seems to contribute to a higher mutation prevalence of the p53
      gene in lung tumors.

PMID- 10350438
TI  - Molecular and genetic damage from environmental tobacco smoke in young children.
AB  - To assess the risks of early life exposure to environmental tobacco smoke (ETS),
      we tested whether four biomarkers in peripheral blood were associated with home
      ETS exposure in Hispanic and African-American children. The biomarkers included
      cotinine (a metabolite of nicotine) and three indicators of molecular and genetic
      damage from mutagens/carcinogens, protein adducts formed by the carcinogens 4
      aminobiphenyl (4-ABP) and polycyclic aromatic hydrocarbons (PAHs), and sister
      chromatid exchanges (SCEs). We also explored possible ethnic differences in
      biomarkers. The study cohort comprised 109 Hispanic and African-American
      preschool children (1-6 years of age). Plasma cotinine was analyzed by gas
      chromatography, 4-ABP-hemoglobin adducts by gas chromatography-mass spectroscopy,
      PAH-albumin adducts by ELISA, and SCEs by cytogenetic techniques. Data on the
      amount of smoking by mothers (average 10.5 cigarettes per day) and other
      household members and regular visitors (average 6.5 cigarettes per day) were
      obtained by interview-administered questionnaires. Cotinine, 4-ABP-hemoglobin
      adducts, and PAH-albumin were significantly higher (P < 0.05) in the ETS-exposed
      children compared with the unexposed. SCEs were marginally higher (P = 0.076).
      African-American children had higher levels of cotinine (P = 0.059) and PAH
      albumin (P = 0.02) than Hispanic children, after controlling for exposure to ETS.
      These results indicate molecular and genetic damage in minority children with

PMID- 10350440
TI  - Urinary excretion of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in
      White, African-American, and Asian-American men in Los Angeles County.
AB  - Meats, such as beef, pork, poultry, and fish, cooked at high temperatures produce
      heterocyclic aromatic amines, which have been implicated indirectly as
      etiological agents involved in colorectal and other cancers in humans. This study
      examined the urinary excretion of a mutagenic/carcinogenic heterocyclic aromatic
      amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), among 45 African
      American, 42 Asian-American (Chinese or Japanese), and 42 non-Hispanic white male
      residents of Los Angeles who consumed an unrestricted diet. Total PhIP (free and
      conjugated) was isolated from overnight urine collections, purified by
      immunoaffinity chromatography, and then quantified by high-pressure liquid
      chromatography combined with electrospray ionization mass spectrometry. Geometric
      mean levels of PhIP in Asian-Americans and African-Americans were approximately
      2.8-fold higher than in whites. The urinary excretion levels of PhIP were not
      associated with intake frequencies of any cooked meat based on a self
      administered dietary questionnaire, in contrast to our earlier finding (Ji et
      al., Cancer Epidemiol. Biomark. Prev., 3: 407-411, 1994) of a positive and
      statistically significant association between bacon intake and the urinary level
      of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) among this same group of
      study subjects. Although there is a statistically significant association between
      urinary levels of PhIP and MeIQx (2-sided P = 0.001), 10 subjects (8%) displayed
      extreme discordance between urinary PhIP and MeIQx levels. Several factors,
      including variable contents of heterocyclic aromatic amines in food, enzymic and
      interindividual metabolic differences, and analytical methodology determine the
      degree of concordance between the urinary excretion levels of PhIP and MeIQx.
      Accordingly, urinary excretion levels of a single heterocyclic aromatic amine can
      only serve as an approximate measure of another in estimating exposure to these
      compounds in humans consuming unrestricted diets.

PMID- 10350441
TI  - Conversion of glucosinolates to isothiocyanates in humans after ingestion of
      cooked watercress.
AB  - Isothiocyanates (ITCs), major constituents of cruciferous vegetables, can inhibit
      tumorigenesis in rodents by modulating the metabolism of carcinogens. ITCs that
      occur as glucosinolates are released by myrosinase-mediated hydrolysis when raw
      vegetables are chopped or chewed. However, because cruciferous vegetables are
      commonly consumed by humans after being cooked, it is important to examine
      whether dietary glucosinolates are converted to ITCs after cooked cruciferous
      vegetables in which myrosinase is deactivated have been consumed. This
      information is useful for evaluating the potential role of ITCs in cruciferous
      vegetables in the protection against human cancers. A urinary marker, based on a
      cyclocondensation product formed by the reaction of ITCs and their conjugates
      with 1,2-benzenedithiol, was used to quantify the uptake of dietary ITCs in
      humans. At breakfast and lunch, nine volunteers consumed a total of 350 g of
      cooked watercress in which the myrosinase activity was completely deactivated. On
      the basis of the analysis of ITCs in the cooked watercress upon adding exogenous
      myrosinase, the amount of glucosinolates ingested by each subject was estimated
      to be 475 micromol. The 24-h urine samples showed that the total urinary
      excretion of ITC conjugates in the subjects ranged from 5.6 to 34.8 micromol,
      corresponding to 1.2-7.3% of the total amount ingested. On the basis of our
      previous results that approximately 50% of dietary ITCs were excreted in the
      urine as conjugates, these values represent the minimal in vivo conversion of
      glucosinolates to ITCs. For purposes of comparison, we carried out a second
      experiment in which 150 g of uncooked watercress were consumed. The percentage of
      urinary ITC conjugates excreted in this study ranged from 17.2 to 77.7% of the
      total ingested ITCs. These results indicate that glucosinolates are converted to
      ITCs in humans after ingestion of cooked watercress, in which the myrosinase has
      been completely inactivated. The extent of conversion, however, is considerably
      less than that after ingesting uncooked vegetables. Furthermore, upon incubation
      of the cooked watercress juice with fresh human feces under anaerobic conditions,
      approximately 18% of glucosinolates was hydrolyzed to ITCs in 2 h. These results
      suggest that the microflora in the intestinal tract are a likely source for the
      hydrolysis of glucosinolates to ITCs in humans.

PMID- 10350442
TI  - Community-based interventions to improve breast and cervical cancer screening:
      results of the Forsyth County Cancer Screening (FoCaS) Project.
AB  - The FoCaS (Forsyth County Cancer Screening) Project was one of six projects
      funded by the National Cancer Institute "Public Health Approaches to Breast and
      Cervical Cancer" initiative. The goal of this project was to improve the use of
      breast and cervical cancer screening among low-income, predominately African
      American, women age 40 and older. Strategies implemented in the intervention city
      included public health clinic in-reach strategies (chart reminders, exam room
      prompts, in-service meetings, and patient-directed literature) and community
      outreach strategies (educational sessions, literature distribution, community
      events, media, and church programs). Baseline and follow-up data from independent
      cross-sectional samples in both the intervention and comparison cities were used
      to evaluate the effects of the intervention program. A total of 248 women were
      surveyed at baseline, and 302 women were surveyed 3 years later at follow-up. The
      proportion of women reporting regular use of mammography increased (31 to 56%; P
      < 0.001) in the intervention city. In the comparison city, a nonsignificant (ns)
      increase in mammography utilization was observed (33 to 40%; P = ns). Pap smear
      screening rates also improved in the intervention city (73 to 87%; P = 0.003) but
      declined in the comparison city (67 to 60%; P = ns). These relationships hold in
      multivariate models. The results suggest that a multifaceted intervention can
      improve screening rates in low-income populations. These results have important
      implications for community-based research and efforts in underserved populations.

PMID- 10350443
TI  - Alpha1-antitrypsin deficiency allele carriers among lung cancer patients.
AB  - Lung cancer (LC) and chronic obstructive pulmonary lung diseases (COPDs;
      including emphysema and chronic bronchitis) share a common etiology. Despite the
      known associations of alpha1-antitrypsin deficiency (alpha1AD) with COPD and COPD
      with LC, few studies examined the association of alpha1AD alleles and LC. We
      hypothesize that heterozygous individuals who carry a deficient allele of the
      alpha1AD gene Pi (protease inhibitor locus) are at an increased risk of
      developing LC. The Pi locus is highly polymorphic with >70 variants reported.
      There are at least 10 alleles associated with deficiency in alpha1-antitrypsin.
      Using an exact binomial test, we compared the alpha1AD carrier rate in 260 newly
      diagnosed Mayo Clinic LC patients to the reported carrier rate in Caucasians in
      the United States (7%). alpha1AD carrier status, determined by isoelectric
      focusing assay, was examined with respect to the history of cigarette smoking,
      COPD, and histological types. Thirty-two of the 260 patients (12.3%; 95%
      confidence interval, 8.6-16.9%) carried an alpha1AD allele, which was
      significantly higher than expected (P = 0.002). Twenty-four of the 32 carriers
      had allele S, 6 had allele Z, and 2 had allele I. Patients who never smoked
      cigarettes were three times more likely to carry a deficient allele (20.6%; P =
      0.008), although smokers had a higher carrier rate (11.1%; P = 0.025) when
      compared with the 7% rate. Patients with squamous cell or bronchoalveolar
      carcinoma had a significantly higher carrier rate than expected (15.9% and 23.8%,
      P < or = 0.01, respectively). Our preliminary findings suggest that individuals
      who carry an alpha1AD allele may have an increased risk for developing LC,
      specifically squamous cell or bronchoalveolar carcinoma.

PMID- 10350444
TI  - Lipoxygenase inhibitors as potential cancer chemopreventives.
AB  - Mounting evidence suggests that lipoxygenase (LO)-catalyzed products have a
      profound influence on the development and progression of human cancers. Compared
      with normal tissues, significantly elevated levels of LO metabolites have been
      found in lung, prostate, breast, colon, and skin cancer cells, as well as in
      cells from patients with both acute and chronic leukemias. LO-mediated products
      elicit diverse biological activities needed for neoplastic cell growth,
      influencing growth factor and transcription factor activation, oncogene
      induction, stimulation of tumor cell adhesion, and regulation of apoptotic cell
      death. Agents that block LO-catalyzed activity may be effective in preventing
      cancer by interfering with signaling events needed for tumor growth. In fact, in
      a few studies, LO inhibitors have prevented carcinogen-induced lung adenomas and
      rat mammary gland cancers. During the past 10 years, pharmacological agents that
      specifically inhibit the LO-mediated signaling pathways are now commercially
      available to treat inflammatory diseases such as asthma, arthritis, and
      psoriasis. These well-characterized agents, representing two general drug effect
      mechanisms, are considered good candidates for clinical chemoprevention studies.
      One mechanism is inhibition of LO activity (5-LO and associated enzymes, or 12
      LO); the second is leukotriene receptor antagonism. Although the receptor
      antagonists have high potential in treating asthma and other diseases where drug
      effects are clearly mediated by the leukotriene receptors, enzyme activity
      inhibitors may be better candidates for chemopreventive intervention, because
      inhibition of these enzymes directly reduces fatty acid metabolite production,
      with concomitant damping of the associated inflammatory, proliferative, and
      metastatic activities that contribute to carcinogenesis. However, because
      receptor antagonists have aerosol formulations and possible antiproliferative
      activity, they may also have potential, particularly in the lung, where topical
      application of such formulations is feasible.

PMID- 10350446
TI  - Informed decision making: an annotated bibliography and systematic review.

PMID- 10350448
TI  - A randomised controlled trial of different approaches to universal antenatal HIV
      testing: uptake and acceptability and Annex: Antenatal HIV testing - assessment
      of a routine voluntary approach.

PMID- 10350450
TI  - Assessing the costs of healthcare technologies in clinical trials.

PMID- 10350453
TI  - Remarkable stabilization of zwitterionic intermediates may account for a billion
      fold rate acceleration by thiamin diphosphate-dependent decarboxylases.
AB  - When the E91D variant of apo-yeast pyruvate decarboxylase (EC 4.1.1. 1) is
      exposed to C2alpha-hydroxybenzylthiamin diphosphate, this putative intermediate
      is partitioned on the enzyme between release of the benzaldehyde product (as
      evidenced by regeneration of active enzyme) and dissociation of the proton at
      C2alpha to form the enamine-C2alpha-carbanion intermediate. While the pKa (the
      negative log of the acid dissociation constant) for this dissociation is
      approximately 15.4 in water, formation of the enamine at pH 6.0 on the enzyme
      indicates a >9 unit pKa suppression by the enzyme environment. The dramatic
      stabilization of this zwitterionic enamine intermediate at the active center is
      sufficient to account for as much as a 10(9)-fold rate acceleration on the
      enzyme. This "solvent" effect could be useful for achieving the bulk of the rate
      acceleration provided by the protein over and above that afforded by the coenzyme
      on all thiamin diphosphate-dependent 2-oxo acid decarboxylases.

PMID- 10350454
TI  - The C-terminal domain of the adenine-DNA glycosylase MutY confers specificity for
      8-oxoguanine.adenine mispairs and may have evolved from MutT, an 8-oxo-dGTPase.
AB  - MutY is an adenine-DNA glycosylase with specificity for mismatches involving 8
      oxoguanine (oG.A) or guanine (G.A). In addition to a 25 kDa catalytic domain
      common to all members of its DNA glycosylase superfamily, MutY has a 14 kDa C
      terminal domain. Sequence analyses suggest that this C-terminal domain is
      distantly related to MutT, a pyrophosphohydrolase specific for 2'-deoxy-8
      oxoguanosine triphosphate (doGTP). Here we present biochemical evidence that the
      MutT-like domain of MutY is the principal determinant of oG specificity. First,
      MutY dissociates approximately 1500-fold more slowly from oG-containing product
      DNA than from G-containing product, but a truncated protein lacking the C
      terminal domain dissociates as rapidly from oG-DNA as the full-length protein
      dissociates from G-DNA. Second, MutY removes adenine from oG.A mismatches almost
      30-fold faster than from G.A mismatches in a pre-steady-state assay, but deletion
      of the C-terminal domain reduces this specificity for oG.A to less than 4-fold.
      The kinetic data are consistent with a model in which binding of oG to the C
      terminal domain of MutY accelerates the pre-steady-state glycosylase reaction by
      facilitating adenine base flipping. The observation that oG specificity derives
      almost exclusively from the C-terminal domain of MutY adds credence to the
      sequence analyses and suggests that specificity for oG.A mismatches was acquired
      by fusion of a MutT-like protein onto the core catalytic domain of an adenine-DNA
      glycosylase.

PMID- 10350455
TI  - Structure of the nucleotide-diphospho-sugar transferase, SpsA from Bacillus
      subtilis, in native and nucleotide-complexed forms.
AB  - The enzymatic formation of glycosidic bonds may be catalyzed by the transfer of
      the glycosyl moiety from an activated nucleotide-diphospho-sugar donor to a
      specific acceptor. SpsA is a glycosyltransferase implicated in the synthesis of
      the spore coat of Bacillus subtilis, whose homologues include cellulose synthase
      and many lipopolysaccharide and bacterial O-antigen synthases. The three
      dimensional crystal structure of SpsA has been determined by conventional MIR
      techniques at a resolution of 1.5 A. It is a two-domain protein with a nucleotide
      binding domain together with an acceptor binding domain which features a
      disordered loop spanning the active site. The structures of SpsA in complex with
      both Mg-UDP and Mn-UDP have also been determined at 2.0 and 1.7 A, respectively.
      These complexes, together with the sequence conservation, begin to shed light on
      the mechanism of this ubiquitous family of inverting glycosyltransferases.

PMID- 10350456
TI  - Total alanine-scanning mutagenesis of insulin-like growth factor I (IGF-I)
      identifies differential binding epitopes for IGFBP-1 and IGFBP-3.
AB  - The bioavailability of insulin-like growth factor I (IGF-I) in the serum and
      tissues is controlled by members of the IGF binding protein family (IGFBP). These
      proteins form high-affinity complexes with IGF-I and thereby either inhibit or
      potentiate its mitogenic and metabolic effects. Thus, understanding the IGF-IGFBP
      interaction at the molecular level is crucial for attempts to modulate IGF-I
      activity in vivo. We have systematically investigated the binding contribution of
      each IGF-I amino acid side chain toward IGFBP-1 and IGFBP-3, combining alanine
      scanning mutagenesis and monovalent phage display. Surprisingly, most IGF-I
      residues could be substituted by alanines, resulting in less than 5-fold affinity
      losses for IGFBP-3. In contrast, binding of IGFBP-1 was more sensitive to alanine
      substitutions in IGF-I. The glutamate and phenylalanine at positions 3 and 49
      were identified as major specificity determinants for IGFBP-1: the corresponding
      alanine mutations, E3A and F49A, selectively decreased IGFBP-1 binding by 34- and
      100-fold, whereas IGFBP-3 affinity was not affected or reduced maximally 4-fold.
      No side chain specificity determinant was found for IGFBP-3. Instead, our results
      suggest that the N-terminal backbone region of IGF-I is important for binding to
      IGFBP-3. The fact that the functional binding epitopes on IGF-I are overlapping
      but distinct for both binding proteins may be exploited to design binding protein
      specific IGF variants.

PMID- 10350457
TI  - Molecular characterization of the receptor-ligand complex for parathyroid
      hormone.
AB  - Molecular models for the interaction of parathyroid hormone (PTH) with its G
      protein-coupled receptors (PTH1 and PTH2) have been developed. The proposed
      ligand-receptor complex is based on experimental data from spectroscopic
      investigations of the hormone and receptor fragments as well as theoretical
      structure predictions based on homology analysis with proteins of known
      structure. From the insight afforded by the models, biochemical and
      pharmacological observations can be correlated with specific molecular or atomic
      interactions. The ligand selectivity of PTH2, specifically the lack of binding of
      His5-containing analogues, can be ascribed to unfavorable steric interactions
      (the binding pocket is markedly smaller in PTH2 than PTH1) as well as repulsive
      Coulombic forces between amino acids of like-charge (a positively charged H384 is
      located in the binding pocket in PTH2). The model of PTH1 suggests that the
      constitutive activity observed from the incorporation of a positively charged
      amino acid at position 223, found at the cytoplasmic end of TM2, is caused by a
      Coulombic attraction to E465, at the cytoplasmic end of TM7, leading to an
      association of TM2 and TM7 and thereby ligand-free activation. Additionally, a
      number of important interactions in the ligand-receptor complex are described
      along with predictions of the pharmacological profile which will result from
      specific modifications at these sites. In this regard, the models described here
      allow for atomic insight into the biochemical data currently available and allow
      targeting of future mutations to probe specific ligand/receptor interactions and
      thereby further our understanding of the functioning of this important hormone
      system.

PMID- 10350458
TI  - UV resonance Raman spectra reveal a structural basis for diminished proton and
      CO2 binding to alpha,alpha-cross-linked hemoglobin.
AB  - UV resonance Raman difference spectra between ligated and deoxyhemoglobin contain
      tryptophan and tyrosine signals which arise from quaternary H-bonds in the T
      state, which are broken in the R state. These H-bonds are unaffected by bis(3,5
      dibromosalicyl) fumarate cross-linking at the Lys alpha 99 residues, which
      prevents dissociation of Hb tetramers to dimers. However, when the pH is lowered
      from 9.0, or when NaCl is added, intensity is diminished for the tyrosine Y8 and
      tryptophan W3 bands of cross-linked deoxyHb, but not of native deoxyHb. This
      effect is attributed to weakening of tertiary H-bonds involving Tyr alpha 140 and
      Trp alpha 14, when the T state salt bridge between Val alpha 1 and Arg alpha 141
      is formed via protonation of the terminal amino group and anion binding. The Tyr
      alpha 140-Val alpha 93 H-bond connects the Arg alpha 141-bearing H helix with the
      Lys alpha 99-bearing G helix. Weakening of the H-bond reflects a tension between
      the fumarate linker and the salt-bridge. This tension inhibits protonation of the
      Val alpha 1 amino terminus, thus accounting for the diminution of both proton
      [Bohr effect] and CO2 binding in the T state as a result of cross-linking.

PMID- 10350459
TI  - Structural characterization of lactate dehydrogenase dissociation under high
      pressure studied by synchrotron high-pressure small-angle X-ray scattering.
AB  - The effect of high pressure on lactate dehydrogenase (LDH) was studied using
      small-angle X-ray scattering (SAXS). The SAXS results are interpreted in terms of
      the dissociation and association of LDH within a compression and decompression
      cycle and its temperature dependence. LDH consists of four identical subunits. At
      120 MPa and 25 degrees C, 50% of the LDH dissociates into subunits, while at 10
      degrees C, this occurs at 78 MPa. The hysteresis in the dissociation and
      association under pressure was confirmed in terms of the radius of gyration and
      was seen to be more conspicuous at low temperature. Forward scattering, I(0)/C,
      which is proportional to molecular weight, showed that LDH dissociated into dimer
      (not monomer) subunits under pressure. The application of high pressure to
      dissociated dimers induced irreversible aggregation. This result is in sharp
      contrast with the result of fluorescence spectroscopy suggesting a dissociated
      monomer [King, L., and Weber, G. (1986) Biochemistry 25, 3637-3640]. As for
      structural change after reassociation, there was little structural difference
      between native and drifted LDH. The difference was smaller than the structure
      change by ligand binding. At 200 MPa, the presence of five scattering peaks in
      the medium-angle region indicates that the dissociated dimer does not have a
      molten globule-like structure but a core structure. We propose a model of the
      dissociated dimer, based on the SAXS profile, in which the volume is reduced
      without disrupting the core structure.

PMID- 10350460
TI  - Mechanistic studies of the folding of human lysozyme and the origin of
      amyloidogenic behavior in its disease-related variants.
AB  - The unfolding and refolding properties of human lysozyme and two amyloidogenic
      variants (Ile56Thr and Asp67His) have been studied by stopped-flow fluorescence
      and hydrogen exchange pulse labeling coupled with mass spectrometry. The
      unfolding of each protein in 5.4 M guanidine hydrochloride (GuHCl) is well
      described as a two-state process, but the rates of unfolding of the Ile56Thr
      variant and the Asp67His variant in 5.4 M GuHCl are ca. 30 and 160 times greater,
      respectively, than that of the wild type. The refolding of all three proteins in
      0.54 M GuHCl at pH 5.0 proceeds through persistent intermediates, revealed by
      multistep kinetics in fluorescence experiments and by the detection of well
      defined populations in quenched-flow hydrogen exchange experiments. These
      findings are consistent with a predominant mechanism for refolding of human
      lysozyme in which one of the structural domains (the alpha-domain) is formed in
      two distinct steps and is followed by the folding of the other domain (the beta
      domain) prior to the assembly of the two domains to form the native structure.
      The refolding kinetics of the Asp67His variant are closely similar to those of
      the wild-type protein, consistent with the location of this mutation in an outer
      loop of the beta-domain which gains native structure only toward the end of the
      refolding process. By contrast, the Ile56Thr mutation is located at the base of
      the beta-domain and is involved in the domain interface. The refolding of the
      alpha-domain is unaffected by this substitution, but the latter has the effect of
      dramatically slowing the folding of the beta-domain and the final assembly of the
      native structure. These studies suggest that the amyloidogenic nature of the
      lysozyme variants arises from a decrease in the stability of the native fold
      relative to partially folded intermediates. The origin of this instability is
      different in the two variants, being caused in one case primarily by a reduction
      in the folding rate and in the other by an increase in the unfolding rate. In
      both cases this results in a low population of soluble partially folded species
      that can aggregate in a slow and controlled manner to form amyloid fibrils.

PMID- 10350461
TI  - Trinitrophenylated reactive lysine residue in myosin detects lever arm movement
      during the consecutive steps of ATP hydrolysis.
AB  - Trinitrophenylation of the reactive lysine (Lys84) in skeletal myosin subfragment
      1 (S1) introduces a chiral probe (TNP) into an interface of the catalytic and
      lever arm domains of S1 [Muhlrad (1977) Biochim. Biophys. Acta 493, 154-166].
      Characteristics of the TNP absorption and circular dichroism (CD) spectra in TNP
      modified S1 (TNP-Lys84-S1), and the Lys84 trinitrophenylation rate in native S1,
      indicate a one-to-one correspondence between ATPase transients and trapped
      phosphate analogues. Phosphate analogue-induced structures of TNP-Lys84-S1 were
      modeled using the crystallographic coordinates of S1 [Rayment et al. (1993)
      Science 261, 50-58] with swivels at Gly699 and Gly710 to approximate
      conformational changes during ATPase. The CD and absorption spectral
      characteristics of the model structures were compared to those observed for
      analogue-induced structures. The model calculations, first tested on a
      trinitrophenylated hexapeptide with known structure, were applied to TNP-Lys84
      S1. They showed that ATP binding initiates swiveling at Gly699 and that swiveling
      at both Gly710 and Gly699 accompanied ATP splitting just prior to product
      release. The computed lever arm trajectory during ATPase suggests (i) a plausible
      mechanism for the nucleotide-induced inhibition of Lys84 trinitrophenylation, and
      (ii) trinitrophenylation-induced changes in S1 Mg2+- and K+-EDTA ATPase are from
      collision of the lever arm with TNP at Lys84. TNP is a site-specific structural
      perturbant of S1 and a chiral reporter group for the effect of Lys84 modification
      on dynamic S1 structure. As such, TNP-Lys84-S1 is equivalent to a genetically
      engineered mutant with intrinsic sensitivity to structure local to the modified
      residue.

PMID- 10350462
TI  - Regulation of nitric oxide-responsive recombinant soluble guanylyl cyclase by
      calcium.
AB  - Calcium (Ca2+) and cyclic GMP (cGMP) subserve antagonistic functions that are
      reflected in their coordinated reciprocal regulation in physiological systems.
      However, molecular mechanisms by which Ca2+ regulates cGMP-dependent signaling
      remain incompletely defined. In this study, the inhibition of recombinant nitric
      oxide (NO)-stimulated soluble guanylyl cyclase (SGC) by Ca2+ was demonstrated.
      The alpha- and beta-subunits of recombinant rat SGC were heterologously
      coexpressed in HEK 293 cells which do not express NO synthase, whose Ca2+
      stimulated activity can confound the effects of that cation on SGC. Ca2+
      inhibited basal and NO-stimulated SGC in a concentration- and guanine nucleotide
      dependent fashion. This cation inhibited SGC in crude cell extracts and
      immunopurified preparations. Ca2+ lowered both the Vmax and Km of SGC via an
      uncompetitive mechanism through direct interaction with the enzyme. In intact HEK
      293 cells, increases in the intracellular Ca2+ concentration induced by
      ionomycin, a Ca2+ ionophore, and thapsigargin, which releases intracellular
      stores of that cation, inhibited NO-stimulated intracellular cGMP accumulation.
      Similarly, carbachol-induced elevation of the intracellular Ca2+ concentration
      inhibited NO-stimulated intracellular cGMP accumulation in HEK 293 cells. These
      data demonstrate that SGC behaves as a sensitive Ca2+ detector that may play a
      central role in coordinating the reciprocal regulation of Ca2+- and cGMP
      dependent signaling mechanisms.

PMID- 10350463
TI  - NMR experiments reveal distinct antibody-bound conformations of a synthetic
      disaccharide representing a general structural element of bacterial
      lipopolysaccharide epitopes.
AB  - The recognition reactions between a synthetic disaccharide alpha-Kdo-(2-->4)
      alpha-Kdo-(2-->O)-allyl and two monoclonal antibodies (mAbs) were studied by NMR,
      yielding two distinct bound conformations of the carbohydrate ligand. One mAb,
      S23-24, recognizes the disaccharides alpha-Kdo-(2-->4)-alpha-Kdo-(2-->O)-allyl
      and alpha-Kdo-(2-->8)-alpha-Kdo-(2-->O)-allyl with similar affinities, whereas
      mAb S25-2 binds to the disaccharide alpha-Kdo-(2-->8)-alpha-Kdo-(2-->O)-allyl
      with an approximately 10-fold higher affinity than to the disaccharide alpha-Kdo
      (2-->4)-alpha-Kdo-(2-->O)-allyl. Compared to S25-2, S23-24 binds to alpha-Kdo-(2-
      >4)-alpha-Kdo-(2-->O)-allyl with an approximately 50-fold increased affinity. We
      used NMR experiments that are based on the transferred NOE effect, specifically,
      trNOESY, trROESY, QUIET-trNOESY, and MINSY experiments, to show that the (2-->8)
      specific mAb, S25-2, stabilizes a conformation of the alpha-(2-->4)-linked
      disaccharide that is not highly populated in solution. S23-24 recognizes two
      conformations of alpha-Kdo-(2-->4)-alpha-Kdo-(2-->O)-allyl, one that is highly
      populated in aqueous solution and another conformation that is similar to the one
      bound by S25-2. This is the first example where it is experimentally shown that a
      carbohydrate ligand may adopt different bioactive conformations upon interaction
      with mAbs with different fine specificities. Our NMR studies indicate that a
      careful examination of spin diffusion is critical for the analysis of bioactive
      conformations of carbohydrate ligands.

PMID- 10350465
TI  - Crystal structure of the cyclin-specific ubiquitin-conjugating enzyme from clam,
      E2-C, at 2.0 A resolution.
AB  - The destruction of the cyclin B protein is necessary for the cell to exit from
      mitosis. The destruction of cyclin B occurs via the ubiquitin/proteasome system
      and involves a specific ubiquitin-conjugating enzyme (Ubc) that donates ubiquitin
      to cyclin B. Here we present the crystal structure of the cyclin-specific Ubc
      from clam, E2-C, determined at 2.0 A resolution. The E2-C enzyme contains an N
      terminal extension in addition to the Ubc core domain. The N-terminal extension
      is disordered, perhaps reflecting a need for flexibility as it interacts with
      various partners in the ubiquitination system. The overall structure of the E2-C
      core domain is quite similar to those in previously determined Ubc proteins. The
      interaction between particular pairs of E2-C proteins in the crystal has some of
      the hallmarks of a functional dimer, though solution studies suggest that the E2
      C protein exists as a monomer. Comparison of the E2-C structure with that of the
      other available Ubc structures indicates conserved surface residues that may
      interact with common components of the ubiquitination system. Such comparison
      also reveals a remarkable spine of conserved hydrophobic residues in the center
      of the protein that may drive the protein to fold and stabilize the protein once
      folded. Comparison of residues conserved only among E2-C and its homologues
      indicates surface areas that may be involved in mitotic-specific ubiquitination.

PMID- 10350464
TI  - Crystal structure of thiamin phosphate synthase from Bacillus subtilis at 1.25 A
      resolution.
AB  - The crystal structure of Bacillus subtilis thiamin phosphate synthase complexed
      with the reaction products thiamin phosphate and pyrophosphate has been
      determined by multiwavelength anomalous diffraction phasing techniques and
      refined to 1.25 A resolution. Thiamin phosphate synthase is an alpha/beta protein
      with a triosephosphate isomerase fold. The active site is in a pocket formed
      primarily by the loop regions, residues 59-67 (A loop, joining alpha3 and beta2),
      residues 109-114 (B loop, joining alpha5 and beta4), and residues 151-168 (C
      loop, joining alpha7 and beta6). The high-resolution structure of thiamin
      phosphate synthase complexed with its reaction products described here provides a
      detailed picture of the catalytically important interactions between the enzyme
      and the substrates. The structure and other mechanistic studies are consistent
      with a reaction mechanism involving the ionization of 4-amino-2-methyl-5
      hydroxymethylpyrimidine pyrophosphate at the active site to give the pyrimidine
      carbocation. Trapping of the carbocation by the thiazole followed by product
      dissociation completes the reaction. The ionization step is catalyzed by
      orienting the C-O bond perpendicular to the plane of the pyrimidine, by hydrogen
      bonding between the C4' amino group and one of the terminal oxygen atoms of the
      pyrophosphate, and by extensive hydrogen bonding and electrostatic interactions
      between the pyrophosphate and the enzyme.

PMID- 10350466
TI  - Structural analysis of the heparin-binding site of the NC1 domain of collagen XIV
      by CD and NMR.
AB  - Type XIV collagen, a fibril-associated collagen with interrupted triple helices
      (FACIT), interacts with the surrounding extracellular matrix and/or with cells
      via its binding to glycosaminoglycans (GAGs). To further characterize such
      interactions in the NC1 domain of chicken collagen XIV, we identified amino acids
      essential for heparin binding by affinity chromatography analysis after
      proteolytic digestion of the synthetic peptide NC1(84-116). The 3D structure of
      this peptide was then obtained using circular dichroism and NMR. The NC1(84-116)
      peptide appeared poorly structured in water, but the stabilization of its
      conformation by the interaction with hydrophobic surfaces or by using cosolvents
      (TFE, SDS) revealed a high propensity to adopt an alpha-helical folding. A 3D
      structure model of NC1(84-116), calculated from NMR data recorded in a TFE/water
      mixture, showed that the NC1-heparin binding site forms a amphipathic alpha-helix
      exhibiting a twisted basic groove. It is structurally similar to the consensus
      spatial alpha-helix model of heparin-binding [Margalit et al. (1993) J. Biol.
      Chem. 268, 19228-19231], except that the GAG binding domain of NC1 may be
      extended over 18 residues, that is, the NC1(94-111) segment. In addition, the
      formation of a hydrophobic groove upon helix formation suggests the contribution
      of additional sequences to ensure the stability of the GAG-binding domain.
      Overall the NC1(84-116) model exhibits a nativelike conformation which presents
      suitably oriented residues for the interaction with a specific GAG.

PMID- 10350467
TI  - Backbone dynamics of detergent-solubilized alamethicin from amide hydrogen
      exchange measurements.
AB  - Alamethicin is a 20 amino acid antibiotic peptide produced by the soil fungus
      Trichoderma viride. The peptide inserts into bacterial membranes and self
      associates to form ion channels, but the details of this process are unknown.
      Residue-specific acid- and base-catalyzed exchange data were obtained for 16 of
      18 backbone amides of alamethicin dissolved in sodium dodecyl sulfate micelles
      using high-resolution 2-dimensional heteronuclear nuclear magnetic resonance
      spectroscopy. To facilitate interpretation of the exchange data, we synthesized N
      acetyl-alpha-aminoisobutyric acid-N'-methyl and N-acetyl-alanine-N'-methyl and
      measured the pD dependence of their hydrogen-deuterium exchange rates to
      determine the sequence-dependent inductive and steric effects of the alpha
      aminoisobutyric acid residue. Intramolecular H-bonding in alamethicin was
      monitored through the exchange parameters kmin (minimum exchange rate) which
      indicate that the backbone is significantly more stable than the backbones of
      alanine-based helical peptides. Rapid exchange at Gly-11 suggests a highly local
      conformational flexibility in the middle of the peptide. Interactions with the
      detergent micelle were revealed by the exchange parameters pDmin (pD of minimum
      exchange) which suggest that the N-terminus of alamethicin interacts more
      strongly with the detergent micelle than does the C-terminus. A periodicity in
      pDmin difference data reveals that one surface of the helix interacts more
      strongly with the micelle. The surface consists of residues 1, 5, 9, 13, 16, and
      20. The opposite face of the helix contains several polar residues (two
      glutamines and a glycine), suggesting that, on average, this face of the helix is
      directed toward the solvent. These results serve as a model for the interaction
      of the peptide with membranes containing anionic lipid. In combination with
      published molecular dynamics simulations [Gibbs et al. (1997) Biophys. J. 72,
      2490-2495], the present results also offer insight into the mechanisms of
      hydrogen-deuterium exchange in helical peptides.

PMID- 10350468
TI  - Structural changes in the transition state of protein folding: alternative
      interpretations of curved chevron plots.
AB  - The interpretation of folding rates is often rationalized within the context of
      transition state theory. This means that the reaction rate is linked to an
      activation barrier, the height of which is determined by the free energy
      difference between a ground state (the starting point) and an apparent transition
      state. Changes in the folding kinetics are thus caused by effects on either the
      ground state, the transition state, or both. However, structural changes of the
      transition state are rarely discussed in connection with experimental data, and
      kinetic anomalies are commonly ascribed to ground state effects alone, e.g.,
      depletion or accumulation of structural intermediates upon addition of
      denaturant. In this study, we present kinetic data which are best described by
      transition state changes. We also show that ground state effects and transition
      state effects are in general difficult to distinguish kinetically. The analysis
      is based on the structurally homologous proteins U1A and S6. Both proteins
      display two-state behavior, but there is a marked difference in their kinetics.
      S6 exhibits a classical V-shaped chevron plot (log observed rate constant vs
      denaturant concentration), whereas U1A's chevron plot is symmetrically curved,
      like an inverted bell curve. However, S6 is readily mutated to display U1A-like
      kinetics. The seemingly drastic effects of these mutations are readily ascribed
      to transition state movements where large kinetic differences result from
      relatively small alterations of a common free energy profile and broad activation
      barriers.

PMID- 10350469
TI  - Differences between the pressure- and temperature-induced denaturation and
      aggregation of beta-lactoglobulin A, B, and AB monitored by FT-IR spectroscopy
      and small-angle X-ray scattering.
AB  - We examined the temperature- and pressure-induced unfolding and aggregation of
      beta-lactoglobulin (beta-Lg) and its genetic variants A and B up to temperatures
      of 90 degrees C in the pressure range from 1 bar to 10 kbar. To achieve
      information simultaneously on the secondary, tertiary, and quaternary structures,
      we have applied Synchrotron small-angle X-ray diffraction and Fourier transform
      infrared spectroscopy. Upon heating a beta-Lg solution at pH 7.0, the radius of
      gyration Rg first decreases, indicating a partial dissociation of the dimer into
      the monomers, the secondary structures remaining essentially unchanged. Above 50
      degrees C, the infrared spectroscopy data reveal a decrease in intramolecular
      beta-sheet and alpha-helical structures, whereas the contribution of disordered
      structures increases. Within the temperature range from 50 to 60 degrees C, the
      appearance of the pair distance distribution function is not altered
      significantly, whereas the amount of defined secondary structures declines
      approximately by 10%. Above 60 degrees C the aggregation process of 1% beta-Lg
      solutions is clearly detectable by the increase in Rg and intermolecular beta
      sheet content. The irreversible aggregation is due to intermolecular S-H/S-S
      interchange reactions and hydrophobic interactions. Upon pressurization at room
      temperature, the equilibrium between monomers and dimers is also shifted and
      dissociation of dimers is induced. At pressures of approximately 1300 bar, the
      amount of beta-sheet and alpha-helical structures decreases and the content of
      disordered structures increases, indicating the beginning unfolding of the
      protein which enables aggregation. Contrary to the thermal denaturation process,
      intermolecular beta-sheet formation is of less importance in pressure-induced
      protein aggregation and gelation. The spatial extent of the resulting protein
      clusters is time- and concentration-dependent. The aggregation of a 1% (w/w)
      solution of A, B, and the mixture AB results in the formation of at least
      octameric units as can be deduced from the radius of gyration of about 36 A. No
      differences in the pressure stability of the different genetic variants of beta
      Lg are detectable in our FT-IR and SAXS experiments. Even application of higher
      pressures (up to 10 kbar) does not result in complete unfolding of all beta-Lg
      variants.

PMID- 10350470
TI  - Thermodynamic analysis of unfolding and dissociation in lactose repressor
      protein.
AB  - Lactose repressor protein, regulator of lac enzyme expression in Escherichia
      coli, maintains its structure and function at extremely low protein
      concentrations (<10(-)12 M). To examine the unfolding and dissociation of this
      tetrameric protein, structural transitions in the presence of varying
      concentrations of urea were monitored by fluorescence and circular dichroism
      spectroscopy, analytical ultracentrifugation, and functional activities. The
      spectroscopic data demonstrated a single cooperative transition with no evidence
      of folded dimeric or monomeric species of this protein. These spectroscopic
      transitions were reversible provided a long incubation step was employed in the
      refolding reaction at approximately 3 M urea. The refolded repressor protein
      possessed the same functional and structural properties as wild-type repressor
      protein. The absence of concentration dependence expected for tetramer
      dissociation to unfolded monomer (M4 <--> 4U) in the spectral transitions
      indicates that the disruption of the monomer-monomer interface and monomer
      unfolding are a concerted reaction (M4 <--> U4) that may occur prior to the
      dissociation of the dimer-dimer interface. Thus, we propose that the unfolded
      monomers remain associated at the C-terminus by the 4-helical coiled-coil
      structure that forms the dimer-dimer interface and that this intermediate is the
      end point detected in the spectral transitions. Efforts to confirm the existence
      of this species by ultracentrifugation were inhibited by the aggregation of this
      intermediate. Based upon these observations, the wild-type fluorescence and CD
      data were fit to a model, M4 <--> U4, which resulted in an overall DeltaG degrees
      for unfolding of 40 kcal/mol. Using a mutant protein, K84L, in which the monomer
      monomer interface is stabilized, sedimentation equilibrium results demonstrated
      that the dimer-dimer interface of lac repressor could persist at higher levels of
      urea than the monomer-monomer interface. The tetramer-dimer transition monitored
      using this mutant repressor yields a DeltaG degrees of 20.4 kcal/mol. Using this
      free energy value for the dissociation process of U4 <--> 4U, an overall free
      energy change of approximately 60 kcal/mol was calculated for dissociation of all
      interfaces and unfolding of the tetrameric lac repressor, reflecting the
      exceptional stability of this protein.

PMID- 10350471
TI  - Proteolysis of blood coagulation factor VIII by the factor VIIa-tissue factor
      complex: generation of an inactive factor VIII cofactor.
AB  - Activation of factor VIII by thrombin occurs via limited proteolysis at R372,
      R740, and R1689. The resultant active factor VIIIa molecule consists of three
      noncovalently associated subunits: A1-a1, A2-a2, and A3-C1-C2 (50, 45, and 73 kDa
      respectively). Further proteolysis of factor VIIIa at R336 and R562 by activated
      protein C subsequently inactivates this cofactor. We now find that the factor
      VIIa-tissue factor complex (VIIa-TF/PL), the trigger of blood coagulation with
      restricted substrate specificity, can also catalyze limited proteolysis of factor
      VIII. Proteolysis of factor VIII was observed at 10 sites, producing 2 major
      fragments (47 and 45 kDa) recognized by an anti-factor VIII A2 domain antibody.
      Time courses indicated the slow conversion of the large fragment to 45 kDa,
      followed by further degradation into at least two smaller fragments. N-Terminal
      sequencing along with time courses of proteolysis indicated that VIIa-TF/PL
      cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and
      R372. Although cleavage of the light chain at R1689 was observed, the majority
      remained uncleaved after 17 h. Consistent with this, only a transient 2-fold
      increase in factor VIII clotting activity was observed. Thus, heavy chain
      cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor
      no longer capable of activation by thrombin. In addition, VIIa-TF/PL was found to
      inactivate thrombin-activated factor VIII. We hypothesize that these proteolyses
      may constitute an alternative pathway to regulate coagulation under certain
      conditions. In addition, the ability of VIIa-TF/PL to cleave factor VIII at 10
      sites greatly expands the known protein substrate sequences recognized by this
      enzyme-cofactor complex.

PMID- 10350472
TI  - Penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus:
      kinetic characterization of its interactions with beta-lactams using electrospray
      mass spectrometry.
AB  - Penicillin-binding protein 2a (PBP2a) is the primary beta-lactam resistance
      determinant of methicillin-resistant Staphylococcus aureus (MRSA). MecA, the gene
      coding for PBP2a, was cloned with the membrane-anchoring region at the N-terminus
      deleted. The truncated protein (PBP2a) was overexpressed in Escherichia coli
      mostly in the soluble form accounting for approximately 25% of soluble cell
      protein and was purified to homogeneity. The purified protein was shown to
      covalently bind beta-lactams in an 1:1 ratio as determined by electrospray mass
      spectrometry. A novel method based on HPLC-elctrospray mass spectrometry has been
      developed to quantitatively determine the formation of the covalent adducts or
      acyl-PBP2a complexes. By using this method, combined with kinetic techniques
      including quench flow, we have extensively characterized the interactions between
      PBP2a and three beta-lactams and determined related kinetic parameters for the
      first time. The apparent first-order rate constants (ka) of PBP2a acylation by
      benzylpenicillin showed a hyperbolic dependence on the concentration of
      benzylpenicillin. This is consistent with the mechanism that the binding of the
      penicillin to PBP2a consists of reversible formation of a Michaelis complex
      followed by formation of the penicilloyl-PBP2a adduct, and allowed the
      determination of the individual kinetic parameters for these two steps, the
      dissociation constant Kd of 13.3 mM and the first-order rate constant k2 of 0.22
      s-1. From these values, the second-order rate constant k2/Kd, the value
      reflecting the overall binding efficiency of a beta-lactam, of 16.5 M-1 s-1 was
      obtained. The fairly high Kd value indicates that benzylpenicillin fits rather
      poorly into the protein active site. Similar studies on the interaction between
      PBP2a and methicillin revealed k2 of 0.0083 s-1 and Kd of 16.9 mM, resulting in
      an even smaller k2/Kd value of 0.49 M-1 s-1. The rate constants k3 for
      deacylation of the acyl-PBP2a complexes, the third step in the interactions, were
      measured to be <1.5 x 10(-)5 s-1. These results indicate that the resistance of
      PBP2a to penicillin inactivation is mainly due to the extremely low penicillin
      acylating rate in addition to the low association affinity, but not to a fast
      rate of deacylation. Acylation of PBP2a by a high-affinity cephalosporin,
      Compound 1, also followed a saturation curve of ka versus the compound
      concentration, from which k2 = 0.39 s-1, Kd = 0.22 mM, and k2/Kd = 1750 M-1 s-1
      were obtained. The 100-fold increase in the k2/Kd value as compared with that of
      benzylpenicillin is mostly attributable to the decreased (60-fold) Kd, indicating
      that the cephalosporin fits much better to the binding pocket of the protein.

PMID- 10350473
TI  - Characterization of the gene encoding human TAFI (thrombin-activable fibrinolysis
      inhibitor; plasma procarboxypeptidase B).
AB  - Thrombin-activable fibrinolysis inhibitor (TAFI) is a recently described human
      plasma zymogen that is related to pancreatic carboxypeptidase B. The active form
      of TAFI (TAFIa), which is formed by thrombin cleavage of the zymogen, likely
      inhibits fibrinolysis by removal from partially degraded fibrin of the carboxyl
      terminal lysine residues which act to stimulate plasminogen activation. We have
      isolated and characterized genomic clones which encompass the entire human TAFI
      gene from lambda phage and bacterial artificial chromosome genomic libraries. The
      complete TAFI gene contains 11 exons and spans approximately 48 kb of genomic
      DNA. The positions of intron/exon boundaries are conserved between the TAFI gene
      and the rat pancreatic carboxypeptidase A1, A2, and B and the human mast cell
      carboxypeptidase A genes, indicating that these carboxypeptidases arose from a
      common ancestral gene. However, the intron lengths diverge significantly among
      all of these genes. The TAFI promoter lacks a consensus TATA sequence, and
      transcription is initiated from multiple sites. Transient transfection of
      reporter plasmids containing portions of the TAFI 5'-flanking region into
      mammalian cells allowed localization of the promoter and identified a
      approximately 70 bp region crucial for liver-specific transcription. Sequence
      analysis of cDNA clones obtained from human liver RNA indicated that the TAFI
      transcript is polyadenylated at three different sites. Our findings will
      facilitate the assessment of the regulation of TAFI expression by transcriptional
      and/or posttranscriptional mechanisms. Furthermore, knowledge of the genomic
      structure of the TAFI gene will aid in the identification of mutations that may
      be associated with the tendency to either bleed or thrombose.

PMID- 10350474
TI  - The ferric uptake regulation (Fur) repressor is a zinc metalloprotein.
AB  - The Fur protein regulates the expression of a wide variety of iron-responsive
      genes; however, the interaction of this repressor with its cognate metal ion
      remains controversial. The iron-bound form of Fur has proved difficult to obtain,
      and conflicting results have been published using Mn(II) as a probe for in vitro
      DNA-binding studies. We report here that the purified protein contains tightly
      bound zinc and propose that Zn(II) is bound to the protein in vivo. Upon
      purification, Fur retains ca. 2.1 mol of Zn(II)/mol of Fur monomer (Zn2Fur). One
      zinc is easily removed by treatment of Zn2Fur with zinc chelating agents,
      resulting in Zn1Fur with ca. 0.9 mol of Zn(II)/mol of protein. The remaining zinc
      in Zn1Fur can only be removed under denaturing conditions to yield apo-Fur with
      ca. 0.1 mol of Zn(II)/mol of protein. Our results suggest that many literature
      descriptions of purified Fur protein do not correspond to the apo-protein, but to
      Zn1Fur or Zn2Fur. Dissociation constants (Kd) of protein-DNA complexes are ca. 20
      nM for both Zn2Fur and Zn1Fur as determined by electrophoretic mobility shift
      assays and DNase I footprinting assays. The two metalated forms, however, show
      qualitative differences in the footprinting assays while apo-Fur does not bind
      specifically to the operator. The existence of these Zn(II) binding sites in Fur
      may resolve some discrepancies in the literature and have implications concerning
      Zur, a Fur homologue in E. coli that regulates zinc-responsive genes.

PMID- 10350475
TI  - Inhibition of restriction endonuclease cleavage by triple helix formation with
      RNA and 2'-O-methyl RNA oligonucleotides containing 8-oxo-adenosine in place of
      cytidine.
AB  - The ability of homopyrimidine oligoribonucleotides (RNA) and oligo-2'-O-methyl
      ribonucleotides (2'-O-methyl RNA) containing 8-oxo-adenosine (AOH) and 8-oxo-2'-O
      methyl (AmOH) adenosine to form stable, triple-helical structures with sequences
      containing the recognition site for the class II-S restriction enzyme, Ksp632-I,
      was studied as a function of pH. The AOH- and AmOH-substituted RNA and 2'-O
      methyl RNA oligonucleotides were shown to bind within the physiological pH range
      in a pH-independent fashion, without a compromise in specificity. The
      substitutions of three cytidine residues with AOH showed higher endonuclease
      inhibition than the substitution of either one or two cytidine residues with AOH.
      In particular, the 2'-O-methyl RNA oligonucleotide with only one cytidine
      substituted with AmOH showed higher endonuclease inhibition than the
      homopyrimidine RNA and 2'-O-methyl RNA oligonucleotides and the RNA
      oligonucleotides containing either one or two AOH moieties. Furthermore, the AmOH
      substituted 2'-O-methyl RNA oligonucleotides were stable (53%) after an
      incubation in 10% fetal bovine serum for 8 h, whereas the RNA oligonucleotides
      were completely degraded. Increased resistance to nucleases is observed with the
      introduction of 2'-O-methylnucleosides. This stabilization should help us to
      design much more efficient third strand homopyrimidine oligomer and antisense
      nucleic acid-based antiviral therapies, which could be used as tools in cellular
      biology.

PMID- 10350476
TI  - Catalytic roles of divalent metal ions in phosphoryl transfer by EcoRV
      endonuclease.
AB  - The rate constant for the phosphoryl transfer step in site-specific DNA cleavage
      by EcoRV endonuclease has been determined as a function of pH and identity of the
      required divalent metal ion cofactor, for both wild-type and T93A mutant enzymes.
      These measurements show bell-shaped pH-rate curves for each enzyme in the
      presence of Mg2+ as a cofactor, indicating general base catalysis for the
      nucleophilic attack of hydroxide ion on the scissile phosphate, and general acid
      catalysis for protonation of the leaving 3'-O anion. The kinetic data support a
      model for phosphoryl transfer based on wild-type and T93A cocrystal structures,
      in which the ionizations of two distinct metal-ligated waters respectively
      generate the attacking hydroxide ion and the proton for donation to the leaving
      group. The model concurs with recent observations of two metal ions bound in the
      active sites of the type II restriction endonucleases BamHI and BglI, suggesting
      the possibility of a similar catalytic mechanism functioning in many or all
      members of this enzyme family.

PMID- 10350477
TI  - Decreasing the chlorophyll a/b ratio in reconstituted LHCII: structural and
      functional consequences.
AB  - Trimeric (bT) and monomeric (bM) light-harvesting complex II (LHCII) with a
      chlorophyll a/b ratio of 0.03 were reconstituted from the apoprotein
      overexpressed in Escherichia coli. Chlorophyll/xanthophyll and
      chlorophyll/protein ratios of bT complexes and 'native' LHCII are rather similar,
      namely, 0.28 vs 0. 27 and 10.5 +/- 1.5 vs 12, respectively, indicating the
      replacement of most chlorophyll a molecules with chlorophyll b, leaving one
      chlorophyll a per trimeric complex. The LD spectrum of the bT complexes strongly
      suggests that the chlorophyll b molecules adopt orientations similar to those of
      the chlorophylls a that they replace. The circular dichroism (CD) spectra of bM
      and bT complexes indicate structural arrangements resembling those of 'native'
      LHCII. Thermolysin digestion patterns demonstrate that bT complexes are folded
      and organized like 'native' trimeric LHCII. Surprisingly, in the bT complexes at
      77 K, half of the excitations that are created on either chlorophyll b or
      xanthophyll are transferred to chlorophyll a. No or very limited triplet transfer
      from chlorophyll b to xanthophyll appears to take place. However, the efficiency
      of triplet transfer from chlorophyll a to xanthophyll is close to 100%, even
      higher than in 'native' LHCII at 77 K. It is concluded from the triplet-minus
      singlet and CD results that the single chlorophyll a molecule that on the average
      is present in each bT complex binds preferably next to a xanthophyll molecule at
      the interface between the monomers.

PMID- 10350478
TI  - Tertiary interactions between the fifth and sixth transmembrane segments of
      rhodopsin.
AB  - We have used cysteine scanning mutagenesis and disulfide cross-linking in a split
      rhodopsin construct to investigate the secondary structure and tertiary contacts
      of the fifth (TM5) and sixth (TM6) transmembrane segments of rhodopsin. Using a
      simple increase in pH to promote disulfide bond formation, three cross-links
      between residues on the extracellular side of TM5 (at positions 198, 200, and
      204) and TM6 (at position 276) have been identified and characterized. The
      helical pattern of cross-linking observed indicates that the fifth transmembrane
      helix extends through residue 200 but does not include residue 198. Rhodopsin
      mutants containing these disulfides demonstrate nativelike absorption spectra and
      light-dependent activation of transducin, suggesting that large movements on the
      extracellular side of TM5 with respect to TM6 are not required for receptor
      activation.

PMID- 10350479
TI  - Competitive binding of acetate and chloride in photosystem II.
AB  - The binding of chloride and acetate to photosystem II (PSII) was examined to
      elucidate the mechanism of acetate inhibition. The mode of inhibition was
      studied, and individual binding sites were assigned by steady-state O2 evolution
      measurements in correlation with electron paramagnetic resonance (EPR) results.
      Two binding sites were found for acetate, one chloride-sensitive on the electron
      donor side and one chloride-insensitive on the electron acceptor side. The
      respective binding constants were as follows: KCl = 0.5 +/- 0.2 mM (chloride
      binding to the donor side), KI = 16 +/- 5 mM (acetate binding to the donor side),
      and KI' = 130 +/- 40 mM (acetate binding to the acceptor side). When acetate was
      bound to the acceptor side of PSII, 200 K illumination induced a narrowed form of
      the QA-FeII EPR signal, the yield of which was independent of the chloride
      concentration. When acetate was bound to the donor side, room-temperature
      illumination produced the S2YZ* state. EPR measurements showed that both the
      yield and formation rate of this state increased with acetate concentration.
      Increasing chloride concentrations slowed the rate of formation of the S2YZ*
      state, but did not affect the steady-state yield of the S2YZ* state. These
      findings indicate that the light-induced reactions in acetate-inhibited PSII are
      modulated by both donor side and acceptor side binding of acetate, while the
      steady-state yield of the S2YZ* state at the high PSII concentrations used for
      EPR measurements depends primarily on acceptor side turnover. Our data further
      support a close proximity of chloride to YZ*, indicating a possible role for
      chloride in the electron-transfer mechanism at the O2-evolving complex.

PMID- 10350480
TI  - Role of proximal His93 in nitric oxide binding to metmyoglobin. Application of
      continuum solvation in Monte Carlo protein simulations.
AB  - Monte Carlo protein simulations with continuum solvation were used to explore the
      conformational mobility of NO within the active site of metmyoglobin. To the best
      of our knowledge this is the first application of a continuum solvation model for
      exploring protein binding sites. The usefulness of the Monte Carlo conformational
      analysis was demonstrated in comparative molecular dynamics simulations. Analysis
      of conformer populations revealed that Monte Carlo conformational analysis is
      more effective in mapping the relevant region of the potential surface.
      Distribution of low-energy conformers obtained for the metmyoglobin-NO complex
      was found to depend on the orientation of proximal His93. Different charge
      distributions corresponding to the two experimentally verified possible torsions
      of this proximal residue result in strong binding of NO or its release to a
      nearby hydrophobic trap. Conformer populations obtained by Monte Carlo
      conformational analysis were grouped into three main families: one, with the NO
      directly bound to the iron, appears when the CA-CB-CG-CD2 torsion of His93 is at
      its ligand binding value (-113 degrees); and two conformers exist where NO is
      trapped in a nearby hydrophobic pocket, the same cavity that was determined to be
      the geminate trap of CO in ferrous Mb as a result of the torsional flip of His93
      to its ligand releasing state (-125 degrees). Based on this analysis, we suggest
      that the electrostatic rearrangement coupled to the conformational fluctuation of
      the proximal His leads to the geminate trapping of the ligand. Conformational
      rearrangement of the proximal side would provide the possibility of rebinding of
      the ligand to Fe.

PMID- 10350481
TI  - Contribution of hydrogen bonds to the conformational stability of human lysozyme:
      calorimetry and X-ray analysis of six Ser --> Ala mutants.
AB  - To further examine the contribution of hydrogen bonds to the conformational
      stability of the human lysozyme, six Ser to Ala mutants were constructed. The
      thermodynamic parameters for denaturation of these six Ser mutant proteins were
      investigated by differential scanning calorimetry (DSC), and the crystal
      structures were determined by X-ray analysis. The denaturation Gibbs energy
      (DeltaG) of the Ser mutant proteins was changed from 2.0 to -5.7 kJ/mol, compared
      to that of the wild-type protein. With an analysis in which some factors that
      affected the stability due to mutation were considered, the contribution of
      hydrogen bonds to the stability (Delta DeltaGHB) was extracted on the basis of
      the structures of the mutant proteins. The results showed that hydrogen bonds
      between protein atoms and between a protein atom and a water bound with the
      protein molecule favorably contribute to the protein stability. The net
      contribution of one intramolecular hydrogen bond to protein stability (DeltaGHB)
      was 8.9 +/- 2.6 kJ/mol on average. However, the contribution to the protein
      stability of hydrogen bonds between a protein atom and a bound water molecule was
      smaller than that for a bond between protein atoms.

PMID- 10350482
TI  - A single amino acid residue contributes to distinct mechanisms of inhibition of
      the human multidrug transporter by stereoisomers of the dopamine receptor
      antagonist flupentixol.
AB  - Both cis and trans isomers of the dopamine receptor antagonist flupentixol
      inhibit drug transport and reverse drug resistance mediated by the human
      multidrug transporter P-glycoprotein (Pgp) with a stereoselective potency. The
      rate of ATP hydrolysis by Pgp and photoaffinity labeling of Pgp with the
      substrate analogue [125I]iodoarylazidoprazosin ([125I]IAAP) are modulated by each
      isomer in an opposite manner, suggesting different mechanisms for the inhibitory
      effect on drug transport. In this study we demonstrate that substitution of a
      single phenylalanine residue at position 983 (F983) with alanine (F983A) in
      putative transmembrane (TM) region 12 selectively affects inhibition of Pgp
      mediated drug transport by both isomers of flupentixol. In F983A the stimulatory
      effect of cis(Z)-flupentixol and the inhibitory effect of trans(E)-flupentixol on
      ATP hydrolysis and [125I]IAAP labeling were significantly altered. This indicates
      that F983 contributes to inhibition of drug transport by both isomers of
      flupentixol and plays an important role in stimulation and inhibition of ATP
      hydrolysis and [125I]IAAP labeling by cis(Z)- and trans(E)-flupentixol,
      respectively. The near-wild-type level of drug transport by the F983A Pgp mutant
      dissociates susceptibility to inhibition by flupentixol from drug translocation,
      indicating the allosteric nature of the flupentixol interaction. The inhibitory
      effects of cyclosporin A on drug transport, drug-stimulated ATP hydrolysis, and
      [125I]IAAP labeling as well as the stimulatory effect of verapamil on ATP
      hydrolysis by Pgp were minimally affected by substitution of F983, suggesting no
      global alteration in the structural and functional integrity of the mutant. Taken
      together, our data suggest that distinct mechanisms of inhibition of Pgp-mediated
      drug transport by the cis and trans isomers of flupentixol are mediated through a
      common site of interaction.

PMID- 10350483
TI  - Stop-flow analysis of cooperative interactions between GLUT1 sugar import and
      export sites.
AB  - The human erythrocyte sugar transporter is thought to function either as a simple
      carrier (sugar import and sugar export sites are presented sequentially) or as a
      fixed-site carrier (sugar import and sugar export sites are presented
      simultaneously). The present study examines each hypothesis by analysis of the
      rapid kinetics of reversible cytochalasin B binding to the sugar export site in
      the presence and absence of sugars that bind to the sugar import site.
      Cytochalasin B binding to the purified, human erythrocyte glucose transport
      protein (GLUT1) induces quenching of GLUT1 intrinsic tryptophan fluorescence. The
      time-course of GLUT1 fluorescence quenching reflects a second-order process
      characterized by simple exponential kinetics. The pseudo-first-order rate
      constant describing fluorescence decay (kobs) increases linearly with
      [cytochalasin B] while the extent of fluorescence quenching increases in a
      saturable manner with [cytochalasin B]. Rate constants for cytochalasin B binding
      to GLUT1 (k1) and dissociation from the GLUT1.cytochalasin B complex (k-1) are
      obtained from the relationship: kobs = k-1 + k1[cytochalasin B]. Low
      concentrations of maltose, D-glucose, 3-O-methylglucose, and other GLUT1 import
      site reactive sugars increase k-1(app) and reduce k1(app) for cytochalasin B
      interaction with GLUT1. Higher sugar concentrations decrease k1(app) further. The
      simple carrier mechanism predicts that k1(app) alone is modulated by import- and
      export-site reactive sugars and is thus incompatible with these findings. These
      results are consistent with a fixed-site carrier mechanism in which GLUT1
      simultaneously presents cooperative sugar import and export sites.

PMID- 10350484
TI  - Mechanism of CheA protein kinase activation in receptor signaling complexes.
AB  - The chemotaxis receptor for aspartate, Tar, generates responses by regulating the
      activity of an associated histidine kinase, CheA. Tar is composed of an
      extracellular sensory domain connected by a transmembrane sequence to a
      cytoplasmic signaling domain. The cytoplasmic domain fused to a leucine zipper
      dimerization domain forms soluble active ternary complexes with CheA and an
      adapter protein, CheW. The kinetics of kinase activity within these complexes
      compared to CheA alone indicate approximately a 50% decrease in the KM for ATP
      and a 100-fold increase in the Vmax. A truncated CheA construct that lacks the
      phosphoaccepting H-domain and the CheY/CheB-binding domain forms an activated
      ternary complex that is similar to the one formed by the full-length CheA
      protein. The Vmax of H-domain phosphorylation by this complex is enhanced
      approximately 60-fold, the KM for ATP decreased to 50%, and the KM for H-domain
      decreased to 20% of the values obtained with the same CheA construct in the
      absence of receptor and CheW. The kinetic data support a mechanism of CheA
      regulation that involves perturbation of an equilibrium between an inactive form
      where the H-domain is loosely bound and an active form where the H-domain is
      tightly associated with the CheA active site and properly positioned for
      phosphotransfer. The data are consistent with an asymmetric mechanism of CheA
      activation [Levit, M., Liu, I., Surette, M. G., and Stock, J. B. (1996) J. Biol.
      Chem. 271, 32057-32063] wherein only one phosphoaccepting domain of CheA at a
      time can interact with an active center within a CheA dimer.

PMID- 10350485
TI  - Electric fields in active sites: substrate switching from null to strong fields
      in thiol- and selenol-subtilisins.
AB  - Although known to be important factors in promoting catalysis, electric field
      effects in enzyme active sites are difficult to characterize from an experimental
      standpoint. Among optical probes of electric fields, Raman spectroscopy has the
      advantage of being able to distinguish electronic ground-state and excited-state
      effects. Earlier Raman studies on acyl derivatives of cysteine proteases [Doran,
      J. D., and Carey, P. R. (1996) Biochemistry 35, 12495-502], where the acyl group
      has extensive pi-electron conjugation, showed that electric field effects in the
      active site manifest themselves by polarizing the pi-electrons of the acyl group.
      Polarization gives rise to large shifts in certain Raman bands, e.g. , the C=C
      stretching band of the alpha,beta-unsaturated acyl group, and a large red shift
      in the absorption maximum. It was postulated that a major source of polarization
      is the alpha-helix dipole that originates from the alpha-helix terminating at the
      active-site cysteine of the cysteine protease family. In contrast, using the acyl
      group 5-methylthiophene acryloyl (5-MTA) as an active-site Raman probe, acyl
      enzymes of thiol- or selenol-subtilisin exhibit no polarization even though the
      acylating amino acid is at the terminus of an alpha-helix. Quantum mechanical
      calculations on 5-MTA ethyl thiol and selenol ethyl esters allowed us to identify
      the conformational states of these molecules along with their corresponding
      vibrational signatures. The Raman spectra of 5-MTA thiol and selenol subtilisins
      both showed that the acyl group binds in a single conformation in the active site
      that is s-trans about the =C-C=O single bond. Moreover, the positions of the C=C
      stretching bands show that the acyl group is not experiencing polarization.
      However, the release of steric constraints in the active site by mutagenesis, by
      creating the N155G form of selenol-subtilisin and the P225A form of thiol
      subtilisin, results in the appearance of a second conformer in the active sites
      that is s-cis about the =C-C=O bond. The Raman signature of this second conformer
      indicates that it is strongly polarized with a permanent dipole being set up
      through the acyl group's pi-electron chain. Molecular modeling for 5-MTA in the
      active sites of selenol-subtilisin and N155G selenol-subtilisin confirms the
      findings from Raman spectroscopic studies and identifies the active-site features
      that give rise to polarization. The determinants of polarization appear to be
      strong electron pull at the acyl carbonyl group by a combination of hydrogen
      bonds and the field at the N-terminus of the alpha-helix and electron push from a
      negatively charged group placed at the opposite end of the chromophore.

PMID- 10350486
TI  - The kinetic behavior of chicken liver sulfite oxidase.
AB  - A comprehensive kinetic study of sulfite oxidase has been undertaken over the pH
      range 6.0-10.0, including conventional steady-state work as well as rapid kinetic
      studies of both the reaction of oxidized enzyme with sulfite and reduced enzyme
      with cytochrome c (III). A comparison of the pH dependence of kcat, kred, and kox
      indicates that kred is principally rate limiting above pH 7, but that below this
      pH the pH dependence of kcat is influenced by that of kox. The pH independence of
      kred is consistent with our previous proposal concerning the reaction mechanism,
      in which attack of the substrate lone pair of electrons on a Mo(VI)O2 unit
      initiates the catalytic sequence. The pH dependence of kred/Kdsulfite indicates
      that a group on the enzyme having a pKa of approximately 9.3 must be deprotonated
      for effective reaction of oxidized enzyme with sulfite, possibly Tyr 322, which
      from the crystal structure of the enzyme constitutes part of the substrate
      binding site. There is no evidence for the HSO3-/SO32- pKa of approximately 7 in
      the pH profile for kred/Kdsulfite, suggesting that enzyme is able to oxidize the
      two equally well. By contrast, kcat/Kmsulfite and kred/Kdsulfite exhibit distinct
      pH dependence (the former is bell-shaped, the latter sigmoidal), again consistent
      with the oxidative half-reaction contributing to the kinetic barrier to catalysis
      at low pH. The pH dependence of kcat/Km(cyt c) (reflecting the second-order rate
      of reaction of free enzyme with free cytochrome) is bell-shaped and closely
      resembles that of kox/Kd(cyt c), reflecting the importance of the oxidative half
      reaction in the low substrate concentration regime. The pH profile for kox/Kd(cyt
      c) indicates that two groups with a pKa of approximately 8 are involved in the
      reaction of free reduced enzyme with cytochrome c, one of which must be
      deprotonated and the other protonated. These results are consistent with the
      known electrostatic nature of the interaction of cytochrome c with its
      physiological partners.

PMID- 10350487
TI  - Residues 48 and 82 at the N-terminal hydrophobic pocket of rabbit skeletal muscle
      troponin-C photo-cross-link to Met121 of troponin-I.
AB  - It has been proposed [Herzberg et al. (1986) J. Biol. Chem. 261, 2638-2644], and
      confirmed by structural studies [Gagne et al. (1995) Nat. Struct. Biol. 2, 784
      789], that the binding of Ca2+ to the triggering sites in troponin-C (TnC) causes
      the opening of the N-terminal hydrophobic pocket bound by the B, C, and D
      helices. This conformational change is believed to provide an additional binding
      site for troponin-I (TnI) and to lead to further events in the Ca2+ regulation
      process. To answer the question of which part of TnI interacts with this
      hydrophobic patch of TnC, we constructed two TnC mutants, each with a single
      cysteine, one at residue 48 between helices B and C and the other at residue 82
      on the D helix. Each mutant was labeled with the photoactivatable cross-linker
      benzophenone-4-iodoacetamide, followed by reconstitution and UV irradiation.
      Studies were made in the binary complex composed of TnC and TnI, the ternary
      complex composed of TnC, TnI, and troponin-T (TnT), and the synthetic thin
      filament composed of troponin, tropomyosin, and F-actin. TnC-TnI photo-cross
      linking was observed for both mutants and for all three types of complexes.
      Although no Ca2+ dependence in the photo-cross-linking was observed on the binary
      and ternary complexes, the extent of cross-linking was reduced in the absence vs
      the presence of Ca2+ in the thin filament. TnI Met121, five residues from the C
      terminus of the inhibitory region, was identified as the cross-linking site for
      both TnC mutants using microsequencing and mass spectrometry following
      proteolysis. These results, obtained with intact TnC.TnI complexes, indicate that
      the TnI segment containing Met121 is in close contact with the N-terminal
      hydrophobic patch of TnC, and that in the thin filament the segment containing
      this residue moves away slightly from the hydrophobic patch in the absence of
      Ca2+, possibly triggering the translocation of the actin-binding region(s) of TnI
      toward actin.

PMID- 10350488
TI  - Structure of the agonist-binding sites of the Torpedo nicotinic acetylcholine
      receptor: affinity-labeling and mutational analyses identify gamma Tyr-111/delta
      Arg-113 as antagonist affinity determinants.
AB  - Photoaffinity labeling of the Torpedo nicotinic acetylcholine receptor (nAChR)
      with [3H]d-tubocurarine (dTC) has identified a residue within the gamma-subunit
      which, along with the analogous residue in delta-subunit, confers selectivity in
      binding affinities between the two agonist sites for dTC and alpha-conotoxin
      (alpha Ctx) MI. nAChR gamma-subunit, isolated from nAChR-rich membranes
      photolabeled with [3H]dTC, was digested with Staphylococcus aureus V8 protease,
      and a 3H-labeled fragment was purified by reversed-phase high-performance liquid
      chromatography. Amino-terminal sequence analysis of this fragment identified 3H
      incorporation in gamma Tyr-111 and gamma Tyr-117 at about 5% and 1% of the
      efficiency of [3H]dTC photoincorporation at gamma Trp-55, the primary site of
      [3H]dTC photoincorporation within gamma-subunit [Chiara, D. C., and Cohen, J. B.
      (1997) J. Biol. Chem 272, 32940-32950]. The Torpedo nAChR delta-subunit residue
      corresponding to gamma Tyr-111 (delta Arg-113) contains a positive charge which
      could confer the lower binding affinity seen for some competitive antagonists at
      the alpha-delta agonist site. To test this hypothesis, we examined by voltage
      clamp analysis and/or by [125I]alpha-bungarotoxin competition binding assays the
      interactions of acetylcholine (ACh), dTC, and alpha Ctx MI with nAChRs containing
      gamma Y111R or delta R113Y mutant subunits expressed in Xenopus oocytes. While
      these mutations affected neither ACh equilibrium binding affinity nor the
      concentration dependence of channel activation, the gamma Y111R mutation
      decreased by 10-fold dTC affinity and inhibition potency. Additionally, each
      mutation conferred a 1000-fold change in the equilibrium binding of alpha Ctx MI,
      with delta R113Y enhancing and gamma Y111R weakening affinity. Comparison of
      these results with previous results for mouse nAChR reveals that, while the same
      regions of gamma- (or delta-) subunit primary structure contribute to the agonist
      binding sites, the particular amino acids that serve as antagonist affinity
      determinants are species-dependent.

PMID- 10350489
TI  - Regulation of PTP1B via glutathionylation of the active site cysteine 215.
AB  - The reversible regulation of protein tyrosine phosphatase is an important
      mechanism in processing signal transduction and regulating cell cycle. Recent
      reports have shown that the active site cysteine residue, Cys215, can be
      reversibly oxidized to a cysteine sulfenic derivative (Denu and Tanner, 1998; Lee
      et al., 1998). We propose an additional modification that has implications for
      the in vivo regulation of protein tyrosine phosphatase 1B (PTP1B, EC 3.1.3.48):
      the glutathionylation of Cys215 to a mixed protein disulfide. Treatment of PTP1B
      with diamide and reduced glutathione or with only glutathione disulfide (GSSG)
      results in a modification detected by mass spectrometry in which the cysteine
      residues are oxidized to mixed disulfides with glutathione. The activity is
      recovered by the addition of dithiothreitol, presumably by reducing the cysteine
      disulfides. In addition, inactivated PTP1B is reactivated enzymatically by the
      glutathione-specific dethiolase enzyme thioltransferase (glutaredoxin),
      indicating that the inactivated form of the phosphatase is a glutathionyl mixed
      disulfide. The cysteine sulfenic derivative can easily oxidize to its
      irreversible sulfinic and sulfonic forms and hinder the regulatory efficiency if
      it is not converted to a more stable and reversible end product such as a
      glutathionyl derivative. Glutathionylation of the cysteine sulfenic derivative
      will prevent the enzyme from further oxidation to its irreversible forms, and
      constitutes an efficient regulatory mechanism.

PMID- 10350491
TI  - Reaction of alanine racemase with 1-aminoethylphosphonic acid forms a stable
      external aldimine 

PMID- 10350490
TI  - Forming the phosphate layer in reconstituted horse spleen ferritin and the role
      of phosphate in promoting core surface redox reactions.
AB  - Apo horse spleen ferritin (apo HoSF) was reconstituted to various core sizes (100
      3500 Fe3+/HoSF) by depositing Fe(OH)3 within the hollow HoSF interior by air
      oxidation of Fe2+. Fe2+ and phosphate (Pi) were then added anaerobically at a 1:4
      ratio, and both Fe2+ and Pi were incorporated into the HoSF cores. The resulting
      Pi layer consisted of Fe2+ and Pi at about a 1:3 ratio which is strongly attached
      to the reconstituted ferritin mineral core surface and is stable even after air
      oxidation of the bound Fe2+. The total amount of Fe2+ and Pi bound to the iron
      core surface increases as the core volume increases up to a maximum near 2500
      iron atoms, above which the size of the Pi layer decreases with increasing core
      size. Mossbauer spectroscopic measurements of the Pi-reconstituted HoSF cores
      using 57Fe2+ show that 57Fe3+ is the major species present under anaerobic
      conditions. This result suggests that the incoming 57Fe2+ undergoes an internal
      redox reaction to form 57Fe3+ during the formation of the Pi layer. Addition of
      bipyridine removes the 57Fe3+ bound in the Pi layer as [57Fe(bipy)3]2+, showing
      that the bound 57Fe2+ has not undergone irreversible oxidation. This result is
      related to previous studies showing that 57Fe2+ bound to native core is
      reversibly oxidized under anaerobic conditions in native holo bacterial and HoSF
      ferritins. Attempts to bury the Pi layer of native or reconstituted HoSF by
      adding 1000 additional iron atoms were not successful, suggesting that after its
      formation, the Pi layer "floats" on the developing iron mineral core.

PMID- 10350492
TI  - Disposition of radioactivity after injection of liver-targeted proteins labeled
      with 111In or 125I. Effect of labeling on distribution and excretion of
      radioactivity in rats.
AB  - The effect of radiolabeling liver-specific proteins on the in vivo disposition of
      radioactivity was investigated. The suitability of 111In and 125I as radiolabels
      for protein disposition studies in vivo was examined. Galactosylated and
      cationized bovine serum albumin were labeled with either 125I by the chloramine-T
      method or 111In, using 1-(4-isothiocyanatobenzyl)ethylenediaminetetraacetic acid
      (SCN-BZ-EDTA) or diethylenetriaminepentaacetic acid (DTPA) as bifunctional
      chelating agents (BCAs) and administered intravenously to rats. 125I
      radioactivity disappeared rapidly from the liver with subsequent excretion in the
      urine and bile, mainly in the TCA soluble fraction. 111In-associated
      radioactivity, on the other hand, remained in the hepatic tissue in considerably
      higher amounts during the experiment and was excreted in the bile and urine to a
      lower extent when compared with 125I. When the effect of BCA on excretion of
      111In radioactivity was compared, no significant differences were observed in the
      urinary clearances. However, biliary excretion was significantly higher for 111In
      SCN-BZ-EDTA-bound radioactivity. In conclusion, when compared with 125I, 111In
      labeling seems to more accurately characterize the in vivo distribution of liver
      targeted proteins after their iv administration in rats and allows a more
      accurate pharmacokinetic evaluation to be performed.

PMID- 10350493
TI  - Oleate salt formation and mesomorphic behavior in the propranolol/oleic acid
      binary system.
AB  - Thermal analysis of propranolol/oleic acid mixtures prepared by solvent
      evaporation enabled construction of the binary system phase diagram. This allowed
      both physical and chemical interactions to be identified, including complex
      formation at the equimolar composition. An incongruent melting complex with a
      characteristic reaction point was identified in excess oleic acid compositions, a
      common property of fatty acid/fatty acid salt binary systems. The equimolar
      complex was confirmed to be propranolol oleate using infrared spectroscopy. Wide
      angle X-ray powder diffractometry demonstrated that propranolol oleate possessed
      long-range positional order ( approximately 25 A d spacing) accompanied by a
      degree of disorder over shorter d spacings. Such a pattern suggested mesophase
      formation, explaining the unctuous nature of propranolol oleate at room
      temperature. Accurate measurement of the long-range d spacing was achieved using
      small-angle X-ray scattering, permitting differentiation of the three different
      phases identified (phase I: 25.4 A, phase II: 24.6 A, phase III: 25.4-25.5 A).
      The implications of drug fatty acid salt formation and also mesomorphism in
      pharmaceutical systems are discussed.

PMID- 10350494
TI  - Physicochemical characterization and preliminary in vivo efficacy of bioadhesive,
      semisolid formulations containing flurbiprofen for the treatment of gingivitis.
AB  - In this study, the physicochemical properties and preliminary in vivo clinical
      performance of formulations containing hydroxyethylcellulose (HEC; 3, 5, 10%
      w/w), poly(vinylpyrrolidone) (PVP; 3, 5% w/w), polycarbophil (PC; 1, 3, 5% w/w),
      and flurbiprofen (5% w/w) were examined. Flurbiprofen release into PBS pH 7.4 was
      performed at 37 degrees C. The mechanical properties (hardness, compressibility,
      adhesiveness, initial stress) and syringeability of formulations were determined
      using a texture analyzer in texture profile analysis (TPA) and compression modes,
      respectively. In general, the time required for release of 10 and 30% of the
      original mass of flurbiprofen (t10%, t30%) increased as the concentration of each
      polymeric component increased. However, in the presence of either 5 or 10% HEC
      and 5% PC, increased PVP concentration decreased both t10%, t30% due to excessive
      swelling (and disintegration) of these formulations. Increased concentrations of
      HEC, PVP, and PC significantly increased formulation hardness, compressibility,
      work of syringe expression, and initial stress due to the effects of these
      polymers on formulation viscoelasticity. Similarly, increased concentrations of
      PC (primarily), HEC, and PVP increased formulation adhesiveness due to the known
      bioadhesive properties of these polymers. Clinical efficacies of formulations
      containing 3% HEC, 3% PVP, 3% PC, and either 0% (control) or 5% (test)
      flurbiprofen, selected to offer optimal drug release and mechanical properties,
      were evaluated and clinically compared in an experimental gingivitis model. The
      test (flurbiprofen-containing) formulation significantly reduced gingival
      inflammation, as evaluated using the gingival index, and the gingival crevicular
      fluid volume, whereas, these clinical parameters were generally increased in
      volunteers who had received the control formulation. There were no observed
      differences in the plaque indices of the two subject groups, confirming that the
      observed differences in gingival inflammation could not be accredited to
      differences in plaque accumulation. This study has shown both the applicability
      of the in vitro methods used, particularly TPA, for the rational selection of
      formulations for clinical evaluation and, additionally, the clinical benefits of
      the topical application of a bioadhesive semisolid flurbiprofen-containing
      formulation for the treatment of experimental gingivitis.

PMID- 10350495
TI  - Experimental and theoretical analysis of the interaction of (+/-)-cis
      ketoconazole with beta-cyclodextrin in the presence of (+)-L-tartaric acid.
AB  - 1H NMR spectroscopy was used for determining the optical purity of cis
      ketoconazole enantiomers obtained by fractional crystallization. The chiral
      analysis was carried out using beta-cyclodextrin in the presence of (+)-L
      tartaric acid. The mechanism of the chiral discrimination process, the stability
      of the complexes formed, and their structure in aqueous solution were also
      investigated by 1H and 13C chemical shift analysis, two-dimensional NOE
      experiments, relaxation time measurements, and mass spectrometry experiments.
      Theoretical models of the three-component interaction were built up on the basis
      of the available NMR data, by performing a conformational analysis on the
      relevant fragments on ketoconazole and docking studies on the components of the
      complex. The model derived from a folded conformation of ketoconazole turned out
      to be fully consistent with the molecular assembly found in aqueous solution, as
      inferred from NOE experiments. An explanation of the different association
      constants for the complexes of the two enantiomers is also provided on the basis
      of the interaction energies.

PMID- 10350496
TI  - Novel sorbitan monostearate organogels.
AB  - Sorbitan monostearate, a hydrophobic nonionic surfactant, gels a number of
      organic solvents such as hexadecane, isopropyl myristate, and a range of
      vegetable oils. Gelation is achieved by dissolving/dispersing the organogelator
      in hot solvent to produce an organic solution/dispersion, which, on cooling sets
      to the gel state. Cooling the solution/dispersion causes a decrease in the
      solvent-gelator affinities, such that at the gelation temperature, the surfactant
      molecules self-assemble into toroidal inverse vesicles. Further cooling results
      in the conversion of the toroids into rod-shaped tubules. Once formed, the
      tubules associate with others, and a three-dimensional network is formed which
      immobilizes the solvent. An organogel is thus formed. Sorbitan monostearate gels
      are opaque, thermoreversible semisolids, and they are stable at room temperature
      for weeks. The gels are affected by the presence of additives such as the
      hydrophilic surfactant, polysorbate 20, which improves gel stability and alters
      the gel microstructure from a network of individual tubules to star-shaped
      "clusters" of tubules in the liquid continuous phase. Another solid monoester in
      the sorbitan ester family, sorbitan monopalmitate, also gels organic solvents to
      give opaque, thermoreversible semisolids. Like sorbitan monostearate gels, the
      microstructure of the palmitate gels comprise an interconnected network of
      rodlike tubules. Unlike the stearate gels, however, the addition of small amounts
      of a polysorbate monoester causes a large increase in tubular length instead of
      the "clustering effect" seen in stearate gels. The sorbitan stearate and
      palmitate organogels may have potential applications as delivery vehicles for
      drugs and antigens.

PMID- 10350497
TI  - Water-in-sorbitan monostearate organogels (water-in-oil gels).
AB  - Novel multicomponent organogels containing an aqueous phase are described, and
      some properties which influence their potential as delivery devices for
      hydrophilic drugs and vaccines are discussed. The gel is produced by preparing a
      hot water-in-oil (w/o) emulsion using sorbitan monostearate, a nonionic
      surfactant which is also the organogelator, as the principal emulsifying agent.
      On cooling at room temperature, the w/o emulsion sets to an opaque, semisolid,
      thermoreversible organic gel. Cooling the emulsion results in a reduced
      solubility of the sorbitan monostearate in the oil, with a corresponding decrease
      in solvent-surfactant affinities, causing surfactant self-assembly into
      aggregates. The microstructure of the w/o gel is seen by light microscopy to
      consist of a network of tubules and fibrils (containing the aqueous phase)
      dispersed in the organic medium. X-ray diffraction and freeze-fracture studies
      suggest that the tubular aggregates in the w/o gel are made up of surfactant
      molecules arranged in inverted bilayers and that the aqueous phase is
      accommodated within these inverted bilayers, bound by the polar headgroups of the
      surfactant molecules. The presence of water in the tubular skeleton of the
      organic gels results in the establishment of percolating electroconductive
      aqueous channels in the organogel. Increasing the water content of a w/o gel
      causes the surfactant tubules to swell with a corresponding increase in
      conductivity until the tubules are saturated. Further increase in the water
      content results in the excess water accumulating in droplets within the organic
      medium and a decrease in conductivity as the gel integrity is compromised. The
      w/o gels (containing a model antigen, radiolabeled bovine serum albumin, in the
      aqueous phase) have demonstrated depot properties after intramuscular
      administration to mice, entrapped antigen being released over a period of days.

PMID- 10350499
TI  - Thermodynamic analysis of the binding of a hepatoprotectant drug, thioctic acid,
      by beta-cyclodextrin.
AB  - Spectroscopic and thermodynamic studies of the binding of a hepatoprotectant
      drug, thioctic acid, by beta-cyclodextrin (beta-CD) have been carried out using
      UV-vis and pH potentiometric measurements. The UV-vis spectra and the pH of the
      aqueous solutions of the drug were measured (i) as a function of total drug
      concentration in the absence of cyclodextrin, and (ii) as a function of
      cyclodextrin concentration at constant drug concentration. The spectroscopic
      study was done at pH = 7 and 25 degrees C, while the potentiometric study was
      performed at several temperatures ranging from 15 to 40 degrees C. From the
      spectroscopic data, the molar absorption coefficient, epsilon, for the pure drug
      in aqueous media and the stoichiometry of the inclusion complex with beta-CD were
      determined. The dissociation constant, Ka, of the pure drug (which is a weak
      acid), and the association constants of the complexes formed by beta-cyclodextrin
      and both the nonionized (HTIO) and ionized (TIO-) forms of the drug, have been
      simultaneously determined at several temperatures from the pH data, without the
      necessity of working with buffered solutions. The nonionic forms are complexed by
      the beta-CD with higher affinity than their ionic counterparts. From the
      dependency of the association constants on temperature (van't Hoff analysis), the
      inclusion complexes formed by HTIO or TIO- and the beta-CD were found to be
      enthalpy driven, with a favorable enthalpic term dominant over an unfavorable
      entropic term. Both contributions were found to show a possible dependence with
      temperature (DeltaCpo not equal 0). This pattern may reveal the contribution of
      van der Waals interactions, hydrophobic effect, and solvent reorganization as the
      main driving forces promoting the complexation.

PMID- 10350498
TI  - In vitro models of the blood-brain barrier to polar permeants: comparison of
      transmonolayer flux measurements and cell uptake kinetics using cultured cerebral
      capillary endothelial cells.
AB  - Given that the cerebral microvasculature within the brain constitutes the rate
      limiting barrier to drug entry, primary cultures of cerebral capillary
      endothelial cells would appear to offer a potentially useful model system for
      predicting drug delivery to the central nervous system. In the present study, the
      predictive capabilities of two potential models of the in vivo blood-brain
      barrier (BBB) to the passive diffusion of polar permeants were assessed. A
      comparison of the logarithms of the in vitro transmonolayer permeability
      coefficients (Pmonolayer) for several polar permeants varying in lipophilicity
      (from this study and literature data) with the well-established relationship
      between the logarithms of the in vivo BBB permeability coefficients (log PBBB)
      and permeant lipophilicity as measured by the logarithm of the octanol/water
      partition coefficient (log PCoctanol/water) demonstrated that in vitro permeation
      across these monolayers is largely insensitive to polar permeant lipophilicity as
      a result of the predominance of the paracellular component in the transmonolayer
      flux. Conversely, kinetic studies of uptake of the same compounds into monolayers
      yielded transfer rate constants (kp) reflecting membrane permeability
      coefficients ranging over several orders of magnitude, similar to the variation
      in permeant lipophilicity. Furthermore, a linear relationship could be
      demonstrated between the logarithms of kp and in vivo BBB log P (slope = 1.42 +/-
      0.35; r = 0. 92). In conclusion, this preliminary investigation suggests that
      monitoring the kinetics of cell uptake into cerebral capillary endothelial cell
      monolayers may be superior to transmonolayer flux measurements for predicting the
      passive diffusion of polar permeants across the BBB in vivo.

PMID- 10350500
TI  - Effects of taraxacum mongolicum on the bioavailability and disposition of
      ciprofloxacin in rats.
AB  - Taraxacum mongolicum (TM), also known as dandelion, is a herb widely used in the
      East for its antibacterial activity. The high mineral content of TM presents a
      potential problem for the absorption of quinolone antibiotics. This study was
      undertaken to discern the significance of a drug-drug interaction between TM and
      ciprofloxacin. Two groups of Sprague Dawley rats (220-250 g) were employed; one
      received a single oral dose of ciprofloxacin (20 mg/kg) with concomitant oral
      administration of an aqueous TM extract (2 g crude drug/kg) while the control
      group received oral ciprofloxacin (20 mg/kg) only. Ciprofloxacin in plasma and
      urine, collected over 6 and 24 h, respectively, was determined by HPLC.
      Noncompartment analysis was employed for pharmacokinetic parameter estimation.
      Results indicated that, as compared to control, maximum plasma concentration
      (Cmax) of ciprofloxacin was significantly lowered by 73% in rats receiving
      concurrent TM dosing. Oral TM also caused a 3-fold increase in both apparent drug
      distribution volume (Vd,lambdaz/F: 92. 0 vs 30.8 L/kg) and terminal elimination
      half-life (t1/2,lambdaz; 5. 71 vs 1.96 h). Partly due to the changes in drug
      distribution and elimination, relative bioavailability of ciprofloxacin, as
      assessed by AUC0-->infinity, remained similar for both dosing groups. These
      findings suggest the possibility of a multifactorial drug-drug interaction
      between TM and ciprofloxacin. Thus, the implications of concomitant dosing of the
      two agents should not be overlooked.

PMID- 10350501
TI  - Characterization of the effects of drug addition on the structure of glyceryl
      monoolein/water gel systems using low frequency dielectric spectroscopy.
AB  - The influence of propantheline bromide incorporation on the phase structure of
      glyceryl monoolein/water systems has been investigated using low-frequency
      dielectric spectroscopy over a frequency range of 10(-2) to 10(6) Hz at 20
      degrees C. The responses of glyceryl monoolein systems composed of 10% and 30%
      w/w were measured and the spectra modeled using an equivalent circuit based on
      the Maxwell-Wagner theory.1,2 Marked changes in the dielectric responses of the
      systems were noted on addition of the propantheline bromide at concentrations up
      to 10% w/w. For the lamellar (10% w/w water) glyceryl monoolein systems, an
      increase in the imaginary permitivity was seen, corresponding to an increase in
      conductivity due to the presence of additional ionic species within the system.
      Evidence was also obtained for the incorporation of the drug directly into the
      lipid bilayers, particularly at higher concentrations (10% drug) at which
      dielectric behavior corresponding to bilayer disruption was seen. Incorporation
      of 3% and 5% w/w drug into the cubic phase systems (30% w/w water) resulted in a
      change to the lamellar phase. However, circuit modeling indicated that the system
      formed structures which showed features of both the lamellar and cubic phases at
      3% w/w drug loadings. The study has therefore demonstrated that dielectric
      analysis may provide a novel means of studying the effects of drug incorporation
      on the phase behavior of complex gel systems.

PMID- 10350502
TI  - Encapsulation of lysozyme in a biodegradable polymer by precipitation with a
      vapor-over-liquid antisolvent.
AB  - Lysozyme was encapsulated in biodegradable polymer microspheres which were
      precipitated from an organic solution by spraying the solution into carbon
      dioxide. The polymer, either poly(l-lactide) (l-PLA) or poly(DL-lactide-co
      glycolide) (PGLA), in dichloromethane solution with suspended lysozyme was
      sprayed into a CO2 vapor phase through a capillary nozzle to form droplets which
      solidified after falling into a CO2 liquid phase. By delaying precipitation in
      the vapor phase, the primary particles became sufficiently large, from 5 to 70
      microm, such that they could encapsulate the lysozyme. At an optimal temperature
      of -20 degrees C, the polymer solution mixed rapidly with CO2, and the
      precipitated primary particles were sufficiently hard such that agglomeration was
      markedly reduced compared with higher temperatures. More uniform particles were
      formed by flowing CO2 at high velocity in a coaxial nozzle to mix the droplets at
      the CO2 vapor-liquid interface. This process offers a means to produce
      encapsulated proteins in poly(DL-lactide-co-glycolide) microspheres without
      earlier limitations of massive polymer agglomeration and limited protein
      solubility in organic solvents.

PMID- 10350503
TI  - Occupational cancer in europe 
AB  - This monograph summarizes the current research on the epidemiology and prevention
      of occupational cancer in Europe. Eleven peer-reviewed articles offer a composite
      view of the current status and future perspectives of this discipline at a time
      of major economic and political changes in Europe. The monograph includes a brief
      history of occupational cancer research in Europe and the current burden of
      cancer from occupational exposure. A large portion of the monograph is devoted to
      reviews of occupational cancer in various European countries or groups of
      countries. The first two reviews describe those regions with the strongest
      tradition of research in the field: the Nordic countries and the United Kingdom.
      These countries are characterized by high-quality cancer registries and routinely
      collected information on occupation, e.g., on the occasion of censuses, allowing
      record linkage studies. Four articles address the situation in the remaining
      large Western European countries--France, Germany, Italy, and Spain. Although
      these countries have a strong tradition in occupational health research, with the
      possible exception of Spain, their epidemiologic research dates back only to the
      1970s and 1980s; in recent years, however, research on occupational cancer has
      expanded considerably. The last two articles of the geographic overview describe
      the occupational cancer research in the Central European countries and the
      European territories of the Commonwealth of Independent States. The authors of
      these two articles critically review the available data on occupational cancer
      from former Socialist countries and provide reliable information on the extent
      and amount of occupational exposure to carcinogens. The two final articles of the
      monograph address specific thematic issues: the importance of asbestos as an
      occupational carcinogen in Europe and the use of routinely collected data to
      investigate occupational cancer in women, based on the experience in England and
      Wales. Despite the heterogeneity of these articles, which reflects to a large
      extent the differences in quality and completeness of the available data on
      occupational cancer, they represent an original attempt to provide a systematic
      overview of occupational cancer research in Europe. This publication is
      originally a partial result of two projects on occupational cancer in Europe
      funded by the European Commission, Directorate General XII (grants BMH1-CT92-1110
      and BMH1-CT95-1100) and has been expanded to include non-European Union
      countries.

PMID- 10350504
TI  - Introduction: Epidemiologic research and prevention of occupational cancer in
      Europe.
AB  - Research on occupational cancer epidemiology has been an important area of
      occupational health in Europe since the early studies were conducted in the
      United Kingdom in the 1950s and 1960s. During the last decade, occupational
      cancer research in Europe has gained an international dimension and become
      increasingly interdisciplinary in nature. At present, occupational exposures
      might be responsible for 13 to 18% of lung cancers, 2 to 10% of bladder cancers,
      and 2 to 8% of laryngeal cancers in European men; among women these figures are 1
      to 5%, 0 to 5%, and 0 to 1%, respectively. A notable aspect of current
      occupational cancer research in Europe is the decreasing importance of
      traditional circumstances of high exposure to recognized occupational carcinogens
      and the increasing importance of new industries, mainly in the service sector
      where possible cancer hazards are poorly known. In addition, the political
      changes in Central and Eastern Europe open new possibilities for the
      investigation of high-exposure circumstances and occupational cancer in women.

PMID- 10350506
TI  - Occupational cancer in the United Kingdom.
AB  - Most of the known occupational hazards of cancer have occurred in the United
      Kingdom. Over recent decades a contraction of manufacturing industry and legal
      controls on carcinogens have led to reductions in exposure, but cases continue to
      occur, often as a consequence of exposures 20 or more years ago. By far the most
      important occupational cause of cancer in the United Kingdom is asbestos, which
      currently accounts for some 600 cases of mesothelioma and perhaps 100 cases of
      bronchial carcinoma per year. Recent trends suggest that the number of
      mesothelioma cases attributable to asbestos will increase over the next few
      decades. Exposure to sunlight in outdoor work may cause several hundred cases of
      nonmelanomatous skin cancer per year, and occupational exposure to polycyclic
      aromatic hydrocarbons could be responsible for a similar number of skin and lung
      tumors. Other known occupational hazards of cancer are unlikely to account for
      more than 100 cases per year in total.

PMID- 10350505
TI  - Occupational cancer research in the Nordic countries.
AB  - Occupational cancer research in the Nordic countries benefits from certain
      structural advantages, including the existence of computerized population
      registries, national cancer registries with high-quality data on cancer
      incidence, and a personal identification number for each inhabitant. This article
      outlines the utilization of this research infrastructure in Denmark, Finland,
      Iceland, Norway, and Sweden, together with research examples from the different
      countries. Future research on occupational cancer in this region requires that
      national legislation on electronic handling of sensitive personal information
      should not be stricter than the European Union Directive on individual protection
      with regard to personal data. A personal identification number is essential both
      for keeping up the high quality of data of the registers and for the high quality
      of the process of linking the different data sources together. Although previous
      occupational research has focused on male workers, a broader approach is needed
      in the future, including a study of how cancer risk in women may be affected by
      occupational activity and the question of possible cancer risk in offspring of
      men and women exposed to workplace carcinogens.

PMID- 10350507
TI  - Occupational cancer in France: epidemiology, toxicology, prevention, and
      compensation.
AB  - This article is a description of the current situation in France with regard to
      occupational cancer: research, prevention, and occupation. Toxicologic
      experiments are carried out using (italic)in vitro(/italic) and (italic)in
      vivo(/italic) tests, particularly using transgenic mice. Several epidemiologic
      studies have been conducted over the last decades: population-based case-control
      studies; mortality studies and cancer incidence studies carried out in historical
      cohorts of workers employed in the industry; and case-control studies nested in
      occupational cohorts. French ethical aspects of toxicologic and epidemiologic
      studies are described. The results thus obtained are used to establish
      regulations for the prevention and the compensation of cancers attributable to
      occupational exposure. This French regulation for prevention of occupational
      cancer involves several partners: (italic)a(/italic)) the states authorities,
      including labor inspectors, responsible for preparing and implementing the labor
      legislation and for supervising its application, particularly in the fields of
      occupational health and safety and working conditions; (italic)b(/italic)) the
      Social Security Organisation for the analysis of present or potential
      occupational risks based on tests, visits in plants, complaints or requests from
      various sources, and statistics. These activities are performed within the
      framework of the general French policy for the prevention of occupational cancer.
      This organization includes the National Institute for Research and Safety,
      particularly involved in research in the various fields of occupational risks-
      animal toxicology, biologic monitoring, exposure measurements epidemiology,
      psychology, ergonomy, electronic systems and machineries, exposure to chemicals,
      noise, heat, vibration, and lighting; and (italic)c(/italic)) companies where the
      regulation defines the role of the plant manager, the occupational physician, and
      the Health, Safety and Working Conditions Committee (comprising the manager,
      employees' representatives, the occupational physician, and the safety
      department) in dealing with any problem regarding safety, occupational hygiene,
      and working conditions. These organizations along with medical practitioners are
      involved with the compensation of occupational cancers. The regulation for
      compensation includes the tables of occupational cancer, the possibility of
      recognition of a cancer case when the requirements of the tables are not met, and
      the postprofessional follow-up of workers exposed to a carcinogenic agent.

PMID- 10350508
TI  - Occupational cancer in Germany.
AB  - As in probably mostly all other European countries, the incidence of occupational
      cancer in Germany increased steadily after World War II. In 1994 about 1,600
      cases of occupational cancer were compensated--more than ever before. More than
      half of these cases were lung cancer, most caused either by asbestos (n=545) or
      by ionizing radiation ((italic)n(/italic)=306). Other frequent target organs of
      asbestos were the pleura and the peritoneum with 495 cases of mesotheliomas.
      Asbestos was the single most important risk factor for occupational cancer,
      causing more than 1000 deaths per year. All other malignant diseases, such as
      bladder cancer, leukemia, angiosarcoma of the liver, adenocarcinoma of the nose
      or nasal sinuses, and skin cancer, were comparatively rare. Although primary
      exposure to ionizing radiation in uranium ore mining occurred in the 1950s and
      attributable lung cancers seem to be on the decline, this is not true for
      asbestos, where the peak incidence in lung cancer and mesothelioma has not been
      reached yet.

PMID- 10350510
TI  - Occupational cancer in Spain.
AB  - The knowledge of specific problems of occupational cancer in Spain is scarce. The
      environment of the workplace has improved over the last few years after a long
      period distinguished by bad working conditions, incomplete legislation, and
      insufficient safety measures and control. It has been estimated that 3,083,479
      workers (25.4% of employees) were exposed to carcinogens. The most common
      occupational exposures to carcinogenic agents were solar radiation, environmental
      tobacco smoke, silica, and wood dust. The highest number of employees were
      exposed to silica crystalline (404,729), diesel engine exhaust (274,321), rubber
      products (99,804), benzene (89,932), ethylene dibromide (81,336), agents used in
      furniture and cabinet making (72,068), and formaldehyde (71,189). The percentage
      of total cancer deaths attributed to occupational exposure was 4% (6% in men,
      0.9% in women). Compared with other European countries, the incidence of lung
      cancer and leukemia in Spain are one of the lowest, but it is rapidly increasing.
      The incidence of urinary bladder and larynx cancer, on the contrary, are one of
      the highest. Few studies on occupational cancer have been conducted in Spain. The
      main problems are the availability of death certificates and the quality of the
      information on occupation in mortality of statistics. It is necessary to improve
      methods of assessment of exposures using expert hygienists and biologic markers
      of exposure and diseases. Reduction of cancer by limiting or avoiding exposure to
      known occupational carcinogens is still necessary.

PMID- 10350511
TI  - Occupational cancer in central European countries.
AB  - The countries of central Europe, including Poland, the Czech Republic, Slovakia,
      Hungary, Romania, and Bulgaria, suffer from environmental and occupational health
      problems created during the political system in place until the late 1980s. This
      situation is reflected by data on workplace exposure to hazardous agents. Such
      data have been systematically collected in Skovakia and the Czech Republic since
      1977. The data presented describe mainly the situation in the early 1990s. The
      number of workers exposed to risk factors at the workplace represent about 10% of
      the working population in Slovakia and 30% in Poland. In Slovakia in 1992 the
      percentage of persons exposed to chemical substances was 16.4%, to ionizing
      radiation 4.3%, and to carcinogens 3.3% of all workers exposed to risk factors.
      The total number of persons exposed to substances proven to be carcinogens in
      Poland was 1.3% of the employees; 2.2% were exposed to the suspected carcinogens.
      The incidence of all certified occupational diseases in the Slovak Republic was
      53 per 100,000 insured employees in 1992. Cancers certified as occupational
      cancers are skin cancer caused by occupational exposure to carcinogens, lung
      cancer caused by ionizing radiation, and asbestosis together with lung cancer.
      Specific information on occupational cancers from Romania and Bulgaria was not
      available for this paper. It is difficult to predict a trend for future
      incidences of occupational cancer. Improved control technology, governmental
      regulatory activity to reduce exposure, surveillance of diseases and risk
      factors, and vigilant use of preventive measures should, however, ultimately
      reduce occupational cancer.

PMID- 10350509
TI  - Occupational cancer in Italy.
AB  - This article is a discussion of occupational cancer in Italy. The introduction
      provides the necessary context of Italian industrialization and occupational
      health regulation. This is followed by a review of Italian epidemiologic studies
      of occupational cancer risks considered in terms of relative measures of risk and
      attributable risk of carcinogenic agents or exposure circumstances. We attempt to
      establish the number of workers exposed to carcinogens in Italy and the intensity
      of their exposures. Finally, the Italian system of compensation for occupational
      cancer is discussed. Several cohort and case-control studies have addressed the
      issue of occupational risks, mostly among male workers. The results of these
      studies suggest that the growing incidence of and mortality by mesothelioma is
      explained by the widespread and intense exposure to asbestos in some Italian
      industrial settings. A high attributable risk of lung tumors among male
      populations in industrial areas of northern Italy is explained by occupational
      exposures. However, insufficient data are available for clear definition of the
      extent and intensity of occupational exposure to carcinogenic substances. In
      Italy, we must prioritize and maximize resources in occupational cancer
      epidemiology and revitalize the role of national institutions. Recent legislation
      has established new regulations on the handling of carcinogenic substances in
      industrial settings, a new list of occupational diseases, and a national registry
      of mesothelioma linked to asbestos exposure. These legislative changes are
      expected to have positive effects.

PMID- 10350512
TI  - Occupational cancer in the European part of the Commonwealth of Independent
      States.
AB  - Precise information on the number of workers currently exposed to carcinogens in
      the Commonwealth of Independent States (CIS) is lacking. However, the large
      number of workers employed in high-risk industries such as the chemical and metal
      industries suggests that the number of workers potentially exposed to carcinogens
      may be large. In the CIS, women account for almost 50% of the industrial work
      force. Although no precise data are available on the number of cancers caused by
      occupational exposures, indirect evidence suggests that the magnitude of the
      problem is comparable to that observed in Western Europe, representing some
      20,000 cases per year. The large number of women employed in the past and at
      present in industries that create potential exposure to carcinogens is a special
      characteristic of the CIS. In recent years an increasing amount of high-quality
      research has been conducted on occupational cancer in the CIS; there is, however,
      room for further improvement. International training programs should be
      established, and funds from international research and development programs
      should be devoted to this area. In recent years, following privatization of many
      large-scale industries, access to employment and exposure data is becoming
      increasingly difficult.

PMID- 10350513
TI  - Asbestos and cancer: An overview of current trends in Europe.
AB  - This review assesses the contribution of occupational asbestos exposure to the
      occurrence of mesothelioma and lung cancer in Europe. Available information on
      national asbestos consumption, proportions of the population exposed, and
      exposure levels is summarized. Population-based studies from various European
      regions on occupational asbestos exposure, mesothelioma, and lung cancer are
      reviewed. Asbestos consumption in 1994 ranged, per capita, between 0. 004 kg in
      northern Europe and 2.4 kg in the former Soviet Union. Population surveys from
      northern Europe indicate that 15 to 30% of the male (and a few percent of the
      female) population has ever had occupational exposure to asbestos, mainly in
      construction (75% in Finland) or in shipyards. Studies on mesothelioma combining
      occupational history with biologic exposure indices indicate occupational
      asbestos exposure in 62 to 85% of the cases. Population attributable risks for
      lung cancer among males range between 2 and 50% for definite asbestos exposure.
      After exclusion of the most extreme values because of methodologic aspects, most
      of the remaining estimates are within the range of 10 to 20%. Estimates of women
      are lower. Extrapolation of the results to national figures would decrease the
      estimates. Norwegian estimates indicate that one-third of expected asbestos
      related lung cancers might be avoided if former asbestos workers quit smoking.
      The combination of a current high asbestos consumption per capita, high exposure
      levels, and high underlying lung cancer rates in Central Europe and the former
      Soviet Union suggests that the lung cancers will arise from the smoking-asbestos
      interaction should be a major concern.

PMID- 10350514
TI  - Cancer and occupation in women: identifying associations using routinely
      collected national data.
AB  - Some potentially important findings from an analysis of 119,227 cancers
      registered in women in England over the 7-year period 1981 to 1987 are discussed.
      Data are presented for four cancer sites with established occupational etiologies
      (bladder, pleura, lung, larynx), three occupational groups in which women
      predominate (teachers, nurses, barstaff), and the main female cancers of the
      reproductive system (breast, uterus, cervix, ovary). Excesses of bladder cancer
      in female rubber workers (proportional registration ratio [PRR] 350, 95%
      confidence interval [CI] 141-723), pleural cancer in female carpenters (PRR 1596,
      95% CI 329-4665) and lung cancer in female construction workers (PRR 269, 95% CI
      154-437) and barstaff (PRR 138, 95%CI 124-156) are noted. It is concluded that
      analyses of routinely collected data on cancer and occupation in women have the
      potential to provide valuable pointers for further research.

PMID- 10350515
TI  - Environmental tobacco smoke: exposure assessment in the workplace 
AB  - The Johns Hopkins University School of Hygiene and Public convened a
      multidisciplinary workshop 12-13 September 1997 to assess current understanding
      of environmental tobacco smoke (ETS) exposure in the workplace. Invited
      participants represented areas of expertise in building systems, measurement of
      ETS, biomarkers of ETS exposure, time-activity patterns, and exposure models.
      Workshop participants were asked to conduct reviews in their specific areas of
      expertise relevant to the following general charge: to address key issues related
      to ETS exposure in the workplace to prepare the groundwork for risk assessment of
      the hazard that ETS poses to workers. Discussions focused on the extent of the
      data available on exposures of workers to ETS and approaches used to estimate
      exposures to ETS in the workplace. The monograph based on this workshop includes
      individual contributions that provide in-depth coverage of the specific areas and
      a summary of the discussion that describes an approach to estimating exposures of
      the nation's workers to ETS as well as research recommendations.

PMID- 10350516
TI  - Workshop summary: assessing exposure to environmental tobacco smoke in the
      workplace.
AB  - Environmental tobacco smoke (ETS) is a term now widely used to refer to the
      mixture of sidestream smoke and exhaled mainstream smoke that pollutes air in
      locations where tobacco smoking is taking place. A multidisciplinary workshop was
      convened to address key issues related to ETS exposure in the workplace in order
      to prepare the groundwork for a risk assessment of the hazard ETS poses to
      workers. Workshop participants concluded that substantial evidence was now
      available on worker exposure to ETS using both direct and indirect approaches to
      exposure assessment and that these data could be used to project distribution of
      exposures to ETS in the nation's workplaces. This summary of the discussions at
      the workshop is an overview of the suggested approach to exposure assessment.

PMID- 10350517
TI  - Tracers for assessing exposure to environmental tobacco smoke: what are they
      tracing?
AB  - The effectiveness of various tracers for measurements of exposure to
      environmental tobacco smoke (ETS) as a complex chemical mixture is based on the
      physicochemical properties of four major organic components and their dynamic
      behavior in indoor environments. For the particulate matter (PM) component and
      the very volatile organic compounds, emission and ventilation rates are generally
      the most important processes controlling indoor concentrations and exposures of
      nonsmokers. For the volatile organic compounds (VOCs) and semivolatile organic
      compounds (SVOCs), sorption on and desorption from indoor surfaces are additional
      processes that influence exposures. Laboratory and modeling studies of the
      dynamic behavior of nicotine, an SVOC, and PM indicate that nicotine can be used
      to estimate PM exposures from ETS in indoor environments when certain criteria
      are met: (italic>a(/italic>) smoking occurs regularly in the environment,
      (italic>b(/italic>) the system is near quasi-steady state, and
      (italic>c(/italic>) sampling time is longer than the characteristic times for
      removal processes. Measurements in residential and workplace buildings also
      support the use of nicotine as a tracer for PM in ETS. Recent laboratory and
      field data indicate that the VOCs from ETS can be traced using compounds with
      similar physicochemical properties, such as 3-ethenylpyridine, pyrrole, or
      pyridine. The effectiveness of nicotine for estimating exposures to the VOCs and
      SVOCs has not been determined, although these constitute major mass fractions of
      ETS.

PMID- 10350518
TI  - Exposure of U.S. workers to environmental tobacco smoke.
AB  - The concentrations of environmental tobacco smoke (ETS) to which workers are
      exposed have been measured, using nicotine or other tracers, in diverse
      workplaces. Policies restricting workplace smoking to a few designated areas have
      been shown to reduce concentrations of ETS, although the effectiveness of such
      policies varies among work sites. Policies that ban smoking in the workplace are
      the most effective and generally lower all nicotine concentrations to less than 1
      microg/m3; by contrast, mean concentrations measured in workplaces that allow
      smoking generally range from 2 to 6 microg/m3 in offices, from 3 to 8 microg/m3
      in restaurants, and from 1 to 6 microg/m3 in the workplaces of blue-collar
      workers. Mean nicotine concentrations from 1 to 3 microg/m3 have been measured in
      the homes of smokers. Furthermore, workplace concentrations are highly variable,
      and some concentrations are more than 10 times higher than the average home
      levels, which have been established to cause lung cancer, heart disease, and
      other adverse health effects. For the approximately 30% of workers exposed to ETS
      in the workplace but not in the home, workplace exposure is the principal source
      of ETS. Among those with home exposures, exposures at work may exceed those
      resulting from home. We conclude that a significant number of U.S. workers are
      exposed to hazardous levels of ETS.

PMID- 10350519
TI  - Occupational exposure to environmental tobacco smoke: results of two personal
      exposure studies.
AB  - Personal monitoring is a more accurate measure of individual exposure to airborne
      constituents because it incorporates human activity patterns and collects actual
      breathing zone samples to which subjects are exposed. Two recent studies
      conducted by our laboratory offer perspective on occupational exposure to
      environmental tobacco smoke (ETS) from a personal exposure standpoint. In a study
      of nearly 1600 workers, levels of ETS were lower than or comparable to those in
      earlier studies. Limits on smoking in designated areas also acted to reduce
      overall exposure of workers. In facilities where smoking is permitted, ETS
      exposures are 10 to 20 times greater than in facilities in which smoking is
      banned. Service workers were exposed to higher levels of ETS than workers in
      white-collar occupations. For the narrower occupational category of waiters,
      waitresses, and bartenders, a second study in one urban location indicated that
      ETS levels to which wait staff are exposed are not considerably different from
      those exposure levels of subjects in the larger study who work in environments in
      which smoking is unrestricted. Bartenders were exposed to higher ETS levels, but
      there is a distinction between bartenders working in smaller facilities and those
      working in multiroom restaurant bars, with the former exposed to higher levels of
      ETS than the latter. In addition, ETS levels encountered by these more highly
      exposed workers are lower that those estimated by the Occupational Safety and
      Health Administration. Concomitant area monitoring in the smaller study suggests
      that area samples can only be used to estimate individual personal exposure to
      within an order of magnitude or greater.

PMID- 10350521
TI  - Validity of the uniform mixing assumption: determining human exposure to
      environmental tobacco smoke.
AB  - When using the mass balance equation to model indoor air quality, the primary
      assumption is that of uniform mixing. Different points in a single compartment
      are assumed to have the same instantaneous pollutant concentrations as all other
      points. Although such an assumption may be unrealistic, under certain conditions
      predictions (or measurements) of exposures at single points in a room are still
      within acceptable limits of error (e.g., 10%). In this article, three studies of
      the mixing of environmental tobacco smoke (ETS) pollutants are reviewed, and data
      from several other ETS field studies are presented. Under typical conditions for
      both short sources (e.g., 10 min) and the continuous sources of ETS in smoking
      lounges, I find that average exposure concentrations for a single point in a room
      represent the average exposure across all points in the room within 10% for
      averaging times ranging from 12 to 80 min. I present a method for determining
      theoretical estimates of acceptable averaging times for a continuous point
      source.

PMID- 10350520
TI  - Biomarkers of environmental tobacco smoke exposure.
AB  - Biomarkers are desirable for quantitating human exposure to environmental tobacco
      smoke (ETS) and for predicting potential health risks for exposed individuals. A
      number of biomarkers of ETS have been proposed. At present cotinine, measured in
      blood, saliva, or urine, appears to be the most specific and the most sensitive
      biomarker. In nonsmokers with significant exposure to ETS, cotinine levels in the
      body are derived primarily from tobacco smoke, can be measured with extremely
      high sensitivity, and reflect exposure to a variety of types of cigarettes
      independent of machine-determined yield. Under conditions of sustained exposure
      to ETS (i.e., over hours or days), cotinine levels reflect exposure to other
      components of ETS. Supporting the validity of cotinine as a biomarker, cotinine
      levels have been positively correlated to the risks of some ETS-related health
      complications in children who are not cigarette smokers.

PMID- 10350522
TI  - An introduction to the indirect exposure assessment approach: modeling human
      exposure using microenvironmental measurements and the recent National Human
      Activity Pattern Survey.
AB  - Indirect exposure approaches offer a feasible and accurate method for estimating
      population exposures to indoor pollutants, including environmental tobacco smoke
      (ETS). In an effort to make the indirect exposure assessment approach more
      accessible to people in the health and risk assessment fields, this paper
      provides examples using real data from (italic>a(/italic>) a week-long personal
      carbon monoxide monitoring survey conducted by the author; and
      (italic>b(/italic>) the 1992 to 1994 National Human Activity Pattern Survey
      (NHAPS) for the United States. The indirect approach uses measurements of
      exposures in specific microenvironments (e.g., homes, bars, offices), validated
      microenvironmental models (based on the mass balance equation), and human
      activity pattern data obtained from questionnaires to predict frequency
      distributions of exposure for entire populations. This approach requires fewer
      resources than the direct approach to exposure assessment, for which the
      distribution of monitors to a representative sample of a given population is
      necessary. In the indirect exposure assessment approach, average
      microenvironmental concentrations are multiplied by the total time spent in each
      microenvironment to give total integrated exposure. By assuming that the
      concentrations encountered in each of 10 location categories are the same for
      different members of the U.S. population (i.e., the NHAPS respondents), the
      hypothetical contribution that ETS makes to the average 24-hr respirable
      suspended particle exposure for Americans working their main job is calculated in
      this paper to be 18 microg/m3. This article is an illustrative review and does
      not contain an actual exposure assessment or model validation.

PMID- 10350523
TI  - Mathematical models for predicting indoor air quality from smoking activity.
AB  - Much progress has been made over four decades in developing, testing, and
      evaluating the performance of mathematical models for predicting pollutant
      concentrations from smoking in indoor settings. Although largely overlooked by
      the regulatory community, these models provide regulators and risk assessors with
      practical tools for quantitatively estimating the exposure level that people
      receive indoors for a given level of smoking activity. This article reviews the
      development of the mass balance model and its application to predicting indoor
      pollutant concentrations from cigarette smoke and derives the time-averaged
      version of the model from the basic laws of conservation of mass. A simple table
      is provided of computed respirable particulate concentrations for any indoor
      location for which the active smoking count, volume, and concentration decay rate
      (deposition rate combined with air exchange rate) are known. Using the indoor
      ventilatory air exchange rate causes slightly higher indoor concentrations and
      therefore errs on the side of protecting health, since it excludes particle
      deposition effects, whereas using the observed particle decay rate gives a more
      accurate prediction of indoor concentrations. This table permits easy comparisons
      of indoor concentrations with air quality guidelines and indoor standards for
      different combinations of active smoking counts and air exchange rates. The
      published literature on mathematical models of environmental tobacco smoke also
      is reviewed and indicates that these models generally give good agreement between
      predicted concentrations and actual indoor measurements.

PMID- 10350524
TI  - Diazepam-induced neuroprotection: dissociating the effects of hypothermia
      following global ischemia.
AB  - Global cerebral ischemia produces hippocampal CA1 neuronal loss which in turn
      leads to deficits in memory related tasks. Previous studies have shown that the
      benzodiazepine diazepam is effective at attenuating this cell death and the
      related behavioural impairments. However these studies have been confounded by
      diazepam-induced hypothermia. In this study we sought to determine the
      neuroprotective efficacy of diazepam in the absence of hypothermia. Diazepam (10
      mg/kg) was administered to two groups of gerbils at 30 and 90 min following a 5
      min ischemic insult. In one group the brain temperature was monitored for 24 h
      post-ischemically but not regulated. In the second group, post-ischemic brain
      temperature was maintained at 36.5 degrees C to counteract the hypothermia
      produced by diazepam. Both behaviour (open field performance) and CA1 cell counts
      from these groups were compared to those from sham/normal, no drug ischemic and
      vehicle ischemic groups at 10 days survival. In animals treated with diazepam
      without temperature regulation, there was significant histological and
      behavioural protection at 10 days compared to untreated ischemic animals.
      Preventing hypothermia in diazepam-treated animals resulted in a decrease in the
      number of cells surviving (from 41.2 to 31.6% of sham) and abolished behavioural
      protection. Diazepam appears to have limited ability to attenuate neuronal loss
      and its neuroprotective efficacy is augmented by the concurrent hypothermic
      actions of the drug itself.

PMID- 10350525
TI  - Redistribution of MAP2 immunoreactivity in the neurohypophysial astrocytes of
      adult rats during dehydration.
AB  - The low-molecular-weight microtubule-associated protein-2 (LMW MAP2) is expressed
      in immature and developing brains, and decreases its content dramatically along
      with maturation of the central nervous system. In our previous studies, we
      demonstrated through western blots and dual-labeling immunohistochemistry that
      LMW MAP2 is expressed in the pituicytes, modified astrocytes of the
      neurohypophysis in adult rats. The present study aimed to examine changes in the
      MAP2 immunoreactivity within pituicyte in adult rats under various hydration
      states using quantitative morphometrical analysis to demonstrate in vivo shape
      conversion of the pituicyte morphology. In well-hydrated control rats, light
      microscopic observation revealed that MAP2-stained pituicytes ramified long and
      well-branched processes. At electron microscopic level, MAP2 immunoreactivity was
      found in the fine process and cell body of all pituicyte cytoplasm, but not in
      the axonal terminals containing neurosecretory vesicles. The quantitative
      analysis demonstrated that the cell size and perimeter of MAP2-stained pituicytes
      were significantly greater as compared with those of cells stained with glial
      fibrillary acidic protein (GFAP). When the rats were dehydrated with water
      deprivation or drinking of 2% saline solution, the process of MAP2-stained
      pituicytes was less branched due to retracting their cellular processes as
      compared with those of well-hydrated control and rehydrated rats. The
      quantitative analysis further demonstrated that water deprivation significantly
      reduced the cell size, perimeter and length of cellular processes of MAP2-stained
      pituicytes as compared with those of control. The present finding indicates that
      MAP2 staining is better method for investigating in vivo shape conversion of the
      pituicyte morphology than GFAP one. Moreover, the finding that hydration states
      significantly and reversibly alter in vivo pituicyte shape supports the
      hypothesis that the plastic shape conversion of pituicyte morphology is
      responsible for morphological plasticity in the neurohypophysis.

PMID- 10350526
TI  - Diverse stimuli induce calpain overexpression and apoptosis in C6 glioma cells.
AB  - Calpain, a Ca2+-activated cysteine protease, has been implicated in apoptosis of
      immune cells. Since central nervous system (CNS) is abundant in calpain, the
      possible involvement of calpain in apoptosis of CNS cells needs to be
      investigated. We studied calpain expression in rat C6 glioma cells exposed to
      reactive hydroxyl radical (.OH) [formed via the Fenton reaction (Fe2++H2O2+H+-
      >Fe3++H2O+.OH)], interferon-gamma (IFN-gamma), and calcium ionophore (A23187).
      Cell death, cell cycle, calpain expression, and calpain activity were examined.
      Diverse stimuli induced apoptosis in C6 cells morphologically (chromatin
      condensation as detected by light microscopy) and biochemically [DNA
      fragmentation as detected by TdT-mediated dUTP Nick-End Labeling (TUNEL) assay].
      Oxidative stress arrested a population of C6 cells at the G2/M phase of cell
      cycle. The levels of mRNA expression of six genes were analyzed by the reverse
      transcriptase-polymerase chain reaction (RT-PCR). Diverse stimuli did not alter
      beta-actin (internal control) expression, but increased calpain expression, and
      the upregulated bax (pro-apoptotic)/bcl-2 (anti-apoptotic) ratio. There was no
      significant increase in expression of calpastatin (endogenous calpain inhibitor).
      Western blot analysis showed an increase in calpain content and degradation of
      myelin-associated glycoprotein (MAG), a calpain substrate. Pretreatment of C6
      cells with calpeptin (a cell-permeable calpain inhibitor) blocked calpain
      overexpression, MAG degradation, and DNA fragmentation. We conclude that calpain
      overexpression due to.OH stress, IFN-gamma stimulation, or Ca2+ influx is
      involved in C6 cell death, which is attenuated by a calpain-specific inhibitor.

PMID- 10350527
TI  - The role of brain cytokines in mediating the behavioral and neuroendocrine
      effects of intracerebral mycoplasma fermentans.
AB  - Intracerebral administration of Mycoplasma fermentans (MF), a small microorganism
      that has been found in the brain of some AIDS patients, induces behavioral and
      neuroendocrine alterations in rats. To examine the role of tumor necrosis factor
      alpha (TNFalpha) and interleukin-1 (IL-1) in mediating these effects we measured
      MF-induced expression of TNFalpha and IL-1beta mRNA in various brain regions, and
      the effects of TNFalpha synthesis blockers and IL-1 receptor antagonist (IL-1ra)
      on MF-induced sickness behavior and adrenocortical activation.
      Intracerebroventricular (i.c.v.) administration of heat-inactivated MF induced
      the expression of both TNFalpha and IL-1beta mRNA in the cortex, dorsal
      hippocampus, amygdala, and hypothalamus. Pre-treatment of rats with either
      TNFalpha synthesis blockers, pentoxifylline or rolipram, or with IL-1ra did not
      attenuate MF-induced anorexia, body weight loss, and suppression of social
      behavior. However, simultaneous administration of both pentoxifylline and IL-1ra
      markedly attenuated MF-induced anorexia and body weight loss, but had no effect
      on the suppression of social behavior. Pre-treatment with pentoxifylline, but not
      with IL-1ra, significantly attenuated MF-induced corticosterone (CS) secretion.
      Together, these findings indicate that both TNFalpha and IL-1 participate, in a
      complementary manner, in mediating some of the behavioral effects of MF, whereas
      only TNFalpha, but not IL-1, is involved in mediating MF-induced adrenocortical
      activation. We suggest that cytokines within the brain are involved in mediating
      at least some of the neurobehavioral and neuroendocrine abnormalities that may be
      produced by MF in AIDS patients.

PMID- 10350528
TI  - Comparison of the effects of aging on 5-HT7 and 5-HT1A receptors in discrete
      regions of the circadian timing system in hamsters.
AB  - The circadian timekeeping system exhibits many functional changes with aging,
      including a loss of sensitivity to time cues such as systemic injections of the
      serotonergic agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In
      order to elucidate the neurochemical mechanisms responsible for this age-related
      loss of sensitivity of the circadian pacemaker to serotonin agonists, the present
      study used quantitative autoradiography to determine whether aging decreases
      serotonin receptor populations in male Syrian hamsters. Four neuroanatomical
      regions that regulate circadian timekeeping were studied (the suprachiasmatic
      nuclei [SCN], the lateral geniculate nuclei [LGN], and the median raphe nucleus
      [MRN] and dorsal raphe nucleus [DRN]). The specific binding of [3H]8-OH-DPAT to
      serotonin7 (5-HT7) and serotonin1A (5-HT1A) receptors was investigated by
      competitive inhibition with ritanserin and pindolol, respectively. The results
      showed that the SCN, IGL, MRN, and DRN of the male Syrian hamster exhibited
      specific binding of [3H]8-OH-DPAT to both the 5-HT7 and 5-HT1A receptors, and
      that the latter receptor subtype is more abundant in all of these regions. At 17
      19 months of age, a 50% decrease in 5-HT7 receptors was found in the DRN but not
      in any other regions. No significant age-related changes in 5-HT1A receptors were
      observed in any regions examined. The finding that a marked decrease in 5-HT7
      receptors occurs in the DRN at the age previously characterized by loss of
      sensitivity to 8-OH-DPAT suggests that this region and this receptor subtype play
      important roles in 8-OH-DPAT induction of circadian phase shifts in vivo and that
      they constitute an important locus of aging in the circadian timing system.

PMID- 10350529
TI  - Post-treatment with an inhibitor of poly(ADP-ribose) polymerase attenuates
      cerebral damage in focal ischemia.
AB  - Poly(ADP-ribose) polymerase (PARP) is thought to play a physio-logical role in
      maintaining genomic integrity and in the repair of DNA strand breaks. However,
      the activation of PARP by free radical-damaged DNA plays a pivotal role in
      mediating ischemia-reperfusion injury. The excessive activation of PARP causes a
      rapid depletion of intracellular energy leading to cell death. The present study
      examined the effect of post-ischemic pharmacological inhibition of PARP in a rat
      focal cerebral ischemia model. In Long-Evans rats, focal cerebral ischemia was
      produced by cauterization of the right distal middle cerebral artery (MCA) with
      bilateral temporary common carotid artery (CCA) occlusion for 90 min. A PARP
      inhibitor, 3, 4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ;
      IC50=1 microM/l) was injected i.p. 30 min after the onset of MCA occlusion
      (control: 10, 20, 40 and 80 mg/kg; n=7 each). Twenty-four hours later, the total
      infarct volume was measured. Regional blood flow in the right parietal cortex
      decreased to approximately 20% of the baseline following MCA occlusion in all
      groups. PARP inhibition lead to a significant decrease in damaged volume in all
      treated groups with the largest reduction in the 40 mg/kg group (111.5+/-24. 8
      mm3, mean+/-SD, p<0.01), compared to the control group (193.5+/-28. 6 mm3). We
      also found there was a significant increase of poly(ADP-ribose) immunoreactivity
      in the ischemic region, as compared to the contralateral side, with DPQ treatment
      diminishing poly(ADP-ribose) production. These findings indicate that DPQ exerts
      its neuroprotective effects in vivo by PARP inhibition and that PARP inhibitors
      may be effective for treating ischemic stroke, even when the treatment is
      initiated after the onset of ischemia.

PMID- 10350530
TI  - Effects of a D1 antagonist and of sexual experience on copulation-induced Fos
      like immunoreactivity in the medial preoptic nucleus.
AB  - The medial preoptic nucleus (MPN) of the medial preoptic area (MPOA) and the
      medial amygdala are two brain regions in which male rat sexual behavior increased
      Fos-like immunoreactivity (Fos-Li). Dopamine is released in the MPOA during male
      rat sexual behavior and facilitates copulation. Psychostimulants, which increase
      dopamine levels, induce Fos-Li in the striatum through D1 receptors. We examined
      whether copulation-induced Fos-Li in the MPN was also mediated through D1
      receptors. In Experiment 1, sexually inexperienced male rats that received the D1
      antagonist Schering 39166 prior to their first sexual experience had fewer Fos-Li
      cells in the MPN than did those that received vehicle. In Experiment 2, no
      significant effect of the D1 antagonist was observed on copulation-induced Fos-Li
      in male rats that had received repeated sexual experiences prior to the drug test
      day. Sexual experience increases copulatory efficiency; the mechanisms by which
      this improvement occurs are unclear. In Experiment 3, copulation by highly
      experienced male rats led to greater Fos-Li in the MPN than did copulation by
      sexually naive males. Although there were no differences between groups in
      amygdala Fos-Li in these studies, in several groups Fos-Li in the medial amygdala
      was positively correlated with the post-ejaculatory interval. These experiments
      indicate that (1) stimulation of D1 receptors may contribute to the transient
      copulation-induced increase in Fos-Li in the MPN, and (2) repeated sexual
      experiences enhanced copulation-induced Fos-Li in the MPN, which may represent a
      marker of altered responsiveness of neurons in the MPN to sexual or conditioned
      stimuli.

PMID- 10350531
TI  - Differential effects of excitatory amino acid receptor antagonism in the ventral
      respiratory group.
AB  - This study tested the hypothesis that selective antagonism of excitatory amino
      acid (EAA) receptors within the ventral respiratory group (VRG) would induce
      changes in both respiratory rhythm and pattern. In the paralyzed, decerebrate,
      vagotomized and ventilated cat, baseline values for respiratory (Ttot),
      inspiratory (Ti), and expiratory (Te) durations and peak integrated phrenic nerve
      (integralPN) amplitude were established. Microinjection of the non-NMDA (N-methyl
      d-aspartate) receptor antagonist NBQX (2, 3-dihydroxy-6-nitro-7-sulfamoyl
      benzo(F)quinoxaline) into rostral/inspiratory-modulated (iVRG) or
      caudal/expiratory-modulated VRG elicited an immediate apnea. When PN activity
      resumed, Ttot was significantly decreased, and integralPN amplitude was
      attenuated. NMDA receptor antagonism with microinjections of AP5 (2-amino-5
      phosphonopentanoic acid) into iVRG decreased Te for more than 30 min. NMDA
      receptor antagonism in inspiratory/expiratory-modulated VRG (level of obex,
      transitional VRG) yielded either apnea or a significant reduction in Ttot, Ti and
      integralPN amplitude. Our data suggest that endogenous EAA receptor-mediated
      neurotransmission throughout the VRG is active in the determination of both
      respiratory timing and pattern. Our data further suggest that tVRG serves a
      unique function within the respiratory network.

PMID- 10350532
TI  - Isoflurane induces dose-dependent changes of thalamic somatosensory information
      transfer.
AB  - In spite of several reports about suppressive effects of volatile anesthetics on
      somatosensation, their neuronal mechanisms are largely unknown. The present study
      investigates somatosensory impulse transmission at the thalamic level in rats
      under varied concentrations of isoflurane by recordings of neuronal responses to
      mechanical stimulation of the body surface. Single-unit recordings of thalamo
      cortical relay neurons (TCNs, third order neurons; n=28) and presumed trigemino
      thalamic fibers (TTFs, second order neurons; n=7) were performed in the ventral
      posteromedial nucleus. Functional response characteristics were quantified
      following defined tactile stimulation (trapezoidal or vibratory deflection of
      sinus hairs or fur) applied to the neuronal receptive fields. End-tidal
      isoflurane concentration was increased in steps of 0.2% between 0.6% (baseline)
      and 2.0%. The response activity in all TCNs studied was suppressed in a dose
      dependent manner (2.0% isoflurane decreased responses to 3. 5+/-1.1% of baseline;
      mean+/-S.E.M.); the response activity in TTFs was much less affected (decrease to
      55.0+/-8.2%). Suppression of ongoing activity, however, was similar for both,
      TCNs and TTFs. Furthermore, in TCNs, the response characteristics changed with
      increasing isoflurane between 1.0% and 1.8%: tonic and sustained responses were
      converted to phasic on-responses. In contrast, the tonic and sustained response
      characteristics of TTFs were preserved even at higher isoflurane concentrations.
      The results indicate that isoflurane attenuates the output of somatosensory
      signals in the specific nucleus of the rat's thalamus, while its input is only
      marginally affected. The observed changes of thalamic neuronal response
      characteristics, at least in part, may cause the loss in sensory discrimination
      observed during general anesthesia.

PMID- 10350533
TI  - Age-associated changes in rhesus CNS composition identified by MRI.
AB  - Multispectral automated segmentation of MR images of the brains of 10 young (5-8
      years), 10 middle-aged (12-17 years), and 11 old (21-27 years) female rhesus
      monkeys revealed age-associated changes in brain volume and composition. Total
      brain parenchymal volume (expressed as fraction of intracranial volume-%ICV)
      decreased at a linear rate of 0.3+/-0.04% ICV/year. Up to age approximately 15
      years, this loss was almost entirely due to gray matter loss, with a compensatory
      increase in cerebrospinal fluid (CSF), and possibly some white matter. Brain
      tissue composition, expressed as the gray matter/white matter volume ratio
      confirmed that gray matter loss exceeded white matter loss, but the rate of
      decline in the gray/white ratio began to slow after approximately 15 years.
      Comparison of these age-associated changes in rhesus brain with those in humans
      suggest that the brain aging in rhesus is a good model of human brain aging, but
      occurs approximately 3-fold faster.

PMID- 10350534
TI  - Relative amounts and molecular forms of NESP55 in various bovine tissues.
AB  - NESP55 (neuroendocrine secretory protein with Mr 55,000) comprises a novel
      chromogranin-like protein, which is paternally imprinted at the genomic level. We
      used antisera raised against GAIPIRRH, a peptide present at the C-terminus of
      this protein, and against TC-14, a peptide located in the N-terminal half of
      NESP55. Radioimmunoassay, gel-filtration chromatography and immunoblotting were
      used to determine the levels and the molecular forms of NESP55 in different
      bovine organs. The tissues with the highest levels of GAIPIRRH immunoreactivity
      were, in decreasing order: the adrenal medulla, the anterior pituitary, the
      posterior pituitary, various brain regions, and the intestine. The degree of
      proteolytic processing revealed differences among the tissues analyzed. The
      lowest processing was detected in the anterior pituitary and in the brain where
      only a peak corresponding to the intact precursor was present. This was also true
      for cerebrospinal fluid (CSF). In the posterior pituitary and in the intestine,
      the free peptide GAIPIRRH was the predominant molecular form. GAIPIRRH-IR, as in
      the CSF, is present in serum mainly as an intact precursor. A relatively high
      concentration of GAIPIRRH-IR was found in the kidney medulla, probably due to an
      endocytotic re-uptake of this molecule from the tubuli after filtration in the
      glomeruli. The present study is consistent with the concept that NESP55, like the
      other chromogranins, becomes proteolytically processed. The function of this new
      chromogranin-like protein, therefore, might be to represent a precursor of
      biologically active peptides.

PMID- 10350535
TI  - Abnormal expression of tyrosine hydroxylase immunoreactivity in cerebellar cortex
      of ataxic mutant mice.
AB  - Expression of tyrosine hydroxylase (TH) was examined immunohistochemically in the
      cerebellum of two ataxic mutants, Rolling mouse Nagoya (RMN) and dilute-lethal
      mice (DL). In littermate controls of both mutants, a few TH-positive Purkinje
      cells were distributed sparsely and their number was smaller than in the mutants
      at any ages examined. In RMN, TH-positive Purkinje cells were distributed in
      lobule IX and X, and were arranged into parasagittal bands at 2 weeks of age. TH
      positive Purkinje cells increased in number and were widely distributed
      throughout the vermis at 3 weeks of age. In adult RMN, TH-positive Purkinje cells
      were found in all lobules of the cerebellum. Their parasagittal bands also became
      evident in the hemisphere. In DL, TH-positive Purkinje cells were mainly
      distributed in vermal lobules IX and X, and the flocculus at 3 weeks of age. They
      were also found as bands in lobules IX and X. The results suggest that abnormal
      expression of TH in Purkinje cells may not be specific to the allelic group.
      Since TH promoter is activated by Ca2+, TH expression in the mutant Purkinje
      cells may predict neuronal dysfunction caused by alterations in cellular Ca2+
      currents.

PMID- 10350536
TI  - Morphine-induced activity attenuates phase shifts to light in C57BL/6J mice.
AB  - Circadian rhythms can be phase shifted and entrained by daily schedules of light
      and by non-photic stimuli such as locomotor activity. Relatively little is known
      of how photic and non-photic stimuli interact to regulate circadian phase.
      Morphine injections were used to examine the effects of locomotor activity on
      phase shifts to light pulses in mice free-running in constant dark. Morphine
      injections scheduled early or late in the active period (subjective night)
      induced hyperactivity, but did not induce phase shifts. Light pulses late in the
      subjective night induced phase advance shifts that were significantly attenuated
      (63% smaller, p<0. 01) by pretreatment with morphine. This inhibitory effect of
      morphine on light-induced phase advances was blocked by preventing mice from
      running for 6 h after the injections. Light pulses early in the subjective night
      induced phase delay shifts that were only weakly attenuated (15% smaller, p=0.06)
      by morphine. These results demonstrate behavioral inhibition of light-induced
      phase resetting of circadian rhythms in mice, and suggest that the strength of
      this effect may be phase dependent, although other interpretations are possible.

PMID- 10350537
TI  - Antisense inhibition of angiotensinogen attenuates vasopressin release in the
      paraventricular hypothalamic nucleus of spontaneously hypertensive rats.
AB  - It has been reported that intracerebroventricularly injected antisense
      oligonucleotide to angiotensinogen reduces arterial pressure in spontaneously
      hypertensive rats (SHR), but the mechanism and the sites of action remain
      unclear. In the present study, we examined whether injection of antisense
      oligonucleotide to angiotensinogen into the paraventricular hypothalamic nucleus
      (PVN) would influence arterial pressure and vasopressin release. For this
      purpose, 12-week-old male SHR were cannulated into the bilateral PVN. One week
      later, we injected antisense or sense oligonucleotide to angiotensinogen into the
      bilateral PVN (0.2 nmol/200 nl each side). After 24 h, we directly monitored
      arterial pressure, and then took blood samples to measure plasma vasopressin,
      catecholamines and renin activity. Mean arterial pressure did not change in
      either group (from 144+/-3 to 154+/-4 mmHg for the antisense oligonucleotide
      group, n=11; from 147+/-4 to 156+/-3 mmHg for the sense oligonucleotide group,
      n=11). Antisense oligonucleotide attenuated vasopressin release compared with
      sense oligonucleotide (1.30+/-0.28 vs. 3.29+/-0.60 pg/ml, respectively, P<0.01).
      Plasma catecholamines also decreased in the antisense oligonucleotide group
      compared with the sense oligonucleotide group. However, the plasma renin activity
      did not differ between the groups. In the additional experiment, we examined the
      neurohormonal and cardiovascular effects of intracerebroventricularly injected
      antisense oligonucleotide to angiotensinogen in SHR. Mean arterial pressure,
      plasma vasopressin and plasma norepinephrine were significantly lower in the
      antisense oligonucleotide group than in the sense oligonucleotide group. These
      results suggest that angiotensinogen in PVN plays important roles in vasopressin
      release and sympathetic nerve activity, but may not contribute to the maintenance
      of arterial pressure in SHR.

PMID- 10350538
TI  - Comparison of cerebral blood flow and injury following intracerebral and subdural
      hematoma in the rat.
AB  - Subdural hematomas (SDH) can induce ischemia and neuronal damage in the
      underlying cortex. However, the extent to which intracerebral hematomas (ICH)
      produce reductions in cerebral blood flow (CBF) sufficient to cause ischemic
      damage is uncertain. Intracranial hemorrhage was induced by the injection of 100
      or 200 microl of blood into the subdural space (SDH) or into the caudate nucleus
      (ICH) of the rat. CBF was measured using [14C]-iodoantipyrine autoradiography at
      4 h. Brain damage was measured using 2,3, 5-triphenyl tetrazolium chloride (TTC)
      staining at 24 h and brain edema was measured using the wet/dry weight method.
      Brain ion contents were measured at 24 h using a flame photometer and
      chloridometer. In the CBF studies, the volume of tissue perfused below the
      ischemic threshold (<20 ml/100 g/min) for SDH was 122+/-35 mm3 (sham: 3.3+/-1.7
      mm3). Following ICH, there was a small volume of tissue perfused below the
      ischemic threshold 50+/-11 mm3 (sham: 3. 3+/-2.5 mm3) but this volume
      corresponded closely to the volume of clot (71+/-5 mm3). The extent of brain
      damage, measured by TTC staining, in the cerebral cortex correlated with the
      increasing volume of the subdural blood clot (sham: 9+/-3 mm3; 200 microl: 81+/
      19 mm3; P<0.01). Conversely, minimal brain damage was detected following ICH. The
      injection of blood into the subdural space or into the brain parenchyma induced
      blood volume-dependent increases in brain water content at 24 h. Increases in
      brain water content after SDH, were confined to the cerebral cortex (sham: 0.1+/
      0.1 g/g dry weight; 200 microl: 0.8+/-0.3 g/g dry weight; P<0.001). In contrast,
      increases in brain water content after ICH were predominantly in the subcortical
      region (sham: 0.1+/-0.1 g/g dry weight; 200 microl: 0.4+/-0.2 g/g dry weight;
      P<0.01). The present investigations demonstrate differences in CBF, brain injury
      and edema formation following SDH and ICH indicating that these conditions may
      require different therapeutic interventions.

PMID- 10350539
TI  - Inhibition of cardiovascular activity following microinjection of novel opioid
      like neuropeptide nociceptin (orphanin FQ) into the rat rostral ventrolateral
      medulla.
AB  - Nociceptin (orphanin FQ), the newly discovered endogenous ligand for the novel
      opioid receptor-like 1 receptor, has been initially found to participate in pain
      modulation. In this study, centrally mediated cardiovascular actions of this
      peptide were investigated in the alpha-chloralose/urethane-anesthetized rats. We
      found that bilateral injection of nociceptin (10 nmol) into the rostral
      ventrolateral medulla (RVLM), wherein injection of excitatory amino acid dl
      homocysteic acid (3 nmol) induced typical pressor responses, significantly
      reduced arterial blood pressure and heart rate by -32% and -15%, respectively.
      Reduction of blood pressure and heart rate in response to intra-RVLM injection of
      nociceptin was dose-dependent with a threshold dose being 3 nmol. Pretreatment
      with the selective nociceptin receptor antagonist, [Phe1psi(CH2-NH)Gly2]NC(1
      13)NH2 (10 nmol), into the RVLM abolished the nociceptin-induced cardiovascular
      inhibition. In contrast, non-selective opioid receptor antagonist, naloxone (10
      nmol), did not modify the hypotension and bradycardia induced by nociceptin, even
      though naloxone at the same dose prevented reduction of blood pressure and heart
      rate induced by intra-RVLM injection of methionine-enkephalin (3 nmol). Both
      [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 and naloxone injection alone had no significant
      effect on baseline blood pressure and heart rate. These data suggest that the
      newly discovered opioid-like neuropeptide nociceptin in the CNS exert powerful
      influence on hemodynamic activity by affecting the RVLM neurons. This influence
      is inhibitory in nature, which may not be active in normal physiological
      conditions. Moreover, the cardiovascular effects of nociceptin were mediated by
      activation of specific nociceptin receptors rather than typical naloxone
      sensitive opioid receptors.

PMID- 10350540
TI  - L-DOPA transport properties in an immortalised cell line of rat capillary
      cerebral endothelial cells, RBE 4.
AB  - The present study aimed to determine the kinetics of L-3, 4
      dihydroxyphenylalanine (L-DOPA) uptake in an immortalised cell line of rat
      capillary cerebral endothelial cells (clones RBE 4 and RBE 4B), to define the
      type of inhibition produced by L-5-hydroxytryptophan (L-5-HTP), 2
      aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BHC) and N-(methylamino)
      isobutyric acid (MeAlB) and its sodium dependence. Non-linear analysis of the
      saturation curves for L-DOPA and L-5-HTP revealed in RBE 4 cells Km values (in
      microM) of 72 and 102 and in RBE 4B cells Km values (in microM) of 60 and 118,
      respectively. IC50 values for L-5-HTP (RBE 4, 1026 microM; RBE 4B, 831 microM)
      obtained in the presence of a nearly saturating (250 microM) concentration of L
      DOPA were almost 5-fold those obtained when non-saturating (25 microM)
      concentrations of L-DOPA were used. IC50 values for BHC obtained in the presence
      of a nearly saturating (250 microM) concentration of L-DOPA were also 6- to 5
      fold those obtained when non-saturating (25 microM) concentrations of L-DOPA were
      used. MeAlB (up to 2.5 mM) was found not to interfere with the uptake of L-DOPA.
      In RBE 4 cells, Vmax values for L-DOPA uptake were identical in the absence and
      the presence of 150 microM L-5-HTP or 150 microM BHC, but Km values (microM) were
      significantly greater (P<0.05) when L-DOPA uptake was studied in the presence of
      L-5-HTP or BHC. Similar findings were observed when RBE 4B cells were used.
      Uptake of (250 microM) L-DOPA in the absence of sodium in the incubation medium
      was similar to that observed in the presence of increasing concentrations of
      sodium (20 to 140 mM). It is concluded that RBE 4 and RBE 4B cells are endowed
      with the L-type amino acid transporter through which L-DOPA and L-5-HTP can be
      taken up, and suggested that this immortalised cell line of rat capillary
      cerebral endothelium might constitute an interesting in vitro model for the study
      of BBB mechanisms, namely those concerning solute and nutrient transfer across
      the brain capillary endothelium.

PMID- 10350541
TI  - Actions of NMDA and cholinergic receptor antagonists in the rostral ventromedial
      medulla upon beta-endorphin analgesia elicited from the ventrolateral
      periaqueductal gray.
AB  - Analgesia elicited by morphine in the ventrolateral periaqueductal gray is
      mediated in part by NMDA and cholinergic receptors in the rostral ventromedial
      medulla because selective receptor antagonists applied to the latter structure
      reduced morphine analgesia elicited from the former structure. Previous studies
      have demonstrated that morphine and beta-endorphin employ different anatomical
      and neurochemical pathways in exerting their supraspinal analgesic effects. The
      present study evaluated whether pretreatment with either competitive (AP7, 3-10
      microg) or non-competitive (MK-801, 3-10 microg) NMDA antagonists, or muscarinic
      (scopolamine, 5 microg) or nicotinic (mecamylamine, 1 microg) cholinergic
      antagonists administered into the rostral ventromedial medulla altered beta
      endorphin (15 microg) analgesia elicited from the ventrolateral periaqueductal
      gray as measured by the tail-flick and jump tests in rats. Whereas AP7 produced
      minimal (11%) and transient (30 min) reductions in beta-endorphin analgesia on
      the jump test, MK-801 produced minimal (9%) and transient (30 min) reductions in
      beta-endorphin analgesia on the tail-flick test. Whereas mecamylamine failed to
      reduce beta-endorphin analgesia on either measure, scopolamine produced small
      (23%) and transient (30 min) reductions in beta-endorphin analgesia on the tail
      flick test. Each of these antagonists administered into the rostral ventromedial
      medulla at comparable or lower doses virtually eliminated morphine analgesia
      elicited from the ventrolateral periaqueductal gray. The opioid mediation of beta
      endorphin analgesia in the ventrolateral periaqueductal gray was confirmed by its
      sensitivity to naltrexone (1-20 microg) pretreatment into the same structure.
      These data provide further evidence for dissociations between the descending
      neuroanatomical and neurochemical circuitry mediating the supraspinal analgesic
      responses induced by morphine and beta-endorphin, and indicate that the latter
      response is mediated by either non-cholinergic and non-NMDA synapses within the
      rostral ventromedial medulla, and/or by brainstem sites outside of the rostral
      ventromedial medulla.

PMID- 10350542
TI  - A single oral dose of S 22153, a melatonin antagonist, blocks the phase advancing
      effects of melatonin in C3H mice.
AB  - Disorders of the circadian system have been associated with adverse mental and
      physical conditions, raising the possibility that pharmacological agents acting
      on the circadian system could have therapeutic benefit. Compounds acting as
      agonists or antagonists of melatonin, an endogenous hormone able to feed back on
      the circadian clock, are currently under development for possible use in
      modulating circadian rhythmicity. In the present study, we examined the ability
      of an oral dose of S 22153, a synthetic melatonin antagonist, to block the phase
      advancing effect of a melatonin injection at circadian time 10 in free running
      C3H mice. Our results show that S 22153 had no effect per se on the phase or the
      period of the locomotor activity rhythm but was able to block the phase advancing
      effect of melatonin, suggesting potent antagonist effects at melatonin receptors.
      Availability of a melatonin antagonist may yield new insight into the role of
      melatonin in physiological processes and such compounds may find widespread
      clinical applications.

PMID- 10350543
TI  - The use of fMRI for determining the topographic organization of cortical fields
      in human and nonhuman primates.
AB  - In this study, we demonstrate activation of somatosensory cortex in the
      anesthetized macaque monkey and awake human using fMRI, and confirm the
      topographic organization of somatosensory cortex previously described in both
      species. The macaque model provides an efficient means of addressing questions
      regarding the capabilities and neurophysiological relevance of fMRI, and serves
      as an interface between established invasive electrophysiological methods in
      nonhuman primates, and noninvasive imaging assays of functional activation in
      humans.

PMID- 10350544
TI  - Opioid receptor gene: cytokine response element and the effect of cytokines.
AB  - Previous studies demonstrated that cytokines regulate opioid and opioid receptor
      gene expression in neuronal and immune cells. The gene sequence analysis of
      opioid receptors revealed that mu-, delta- and kappa-opioid receptor promoter
      regions contain potential cytokine response elements (NF-IL6 binding sites). It
      was postulated that the response elements present in opioid receptor promoter
      regions may have a role in the cytokine effects on opioid receptor gene
      expression through cis-trans interaction. The present study investigated whether
      cytokines have an effect on opioid receptor gene expression by cytokine-induced
      transcription factor, NF-IL6, using a number of immune cell lines which respond
      to cytokines. Further investigation was made to determine whether the potential
      cytokine response element DNA sequences on opioid receptor promoter region have
      functional significance which may be affected by the DNA context of the opioid
      receptor promoter in immune cell lines. Tandem repeats of conserved cytokine
      response elements of IL-6 gene fused to a heteropromoter SV40 were utilized as a
      positive control and expressed 2-fold increased promoter activity after cytokine
      stimulation. Transient transfection studies in time courses (24-72 h) and
      different dose treatments (100-500 U/ml for IL-6 and 50-200 U/ml for IL-1
      alpha+beta) were also carried out to investigate the possibility that the
      upregulated gene expression may be transient or cytokine-dose-dependent. Our data
      demonstrated that there was no significant cytokine-stimulated opioid receptor
      gene expression in immune cells tested. In addition, the cytokine response
      elements (NF-IL6 binding sites) in opioid receptor genes are not functional.
      These results contradict the previous reports in which cytokines modulated the
      expression of opioid and opioid receptors in neuronal and immune cells. The
      possible reasons regarding the different results were discussed.

PMID- 10350545
TI  - Effects of striatal injections of 8-bromo-cyclic-AMP on pilocarpine-induced
      tremulous jaw movements in rats.
AB  - Previous work has suggested that muscarinic agonist-induced jaw movements in rats
      were related to stimulation of M4 receptors, and that these movements could be
      suppressed by a full D1 agonist. In view of the involvement of cyclic-adenosine
      monophosphate (c-AMP) mechanisms in the response to stimulation of these two
      receptors, the present study investigated the effects of 8-bromo-c-AMP, which is
      a cell permeable analogue of c-AMP. In the first experiment, it was shown that
      local infusion of 8-bromo-c-AMP directly into ventrolateral striatum (VLS) was
      able to suppress the jaw movements induced by pilocarpine. The suppressive
      effects of 8-bromo-c-AMP occurred within a dose range of 5.0-10.0 microg.
      Injections of the highest dose of 8-bromo-c-AMP (10.0 microg) directly into the
      neocortex overlying the VLS had no significant effects on pilocarpine-induced jaw
      movements. These data demonstrate that mimicking the effects of c-AMP by
      administration of 8-bromo-c-AMP can suppress cholinomimetic-induced jaw
      movements. In addition, the present results suggest that one manifestation of the
      acetylcholine/dopamine interaction in striatum is that M4 and D1 receptors may
      interact to regulate c-AMP production.

PMID- 10350546
TI  - Sex differences in late behavioral response to subcutaneous formalin injection in
      mice.
AB  - We investigated sex- or gender-dependent differences in nociception using the
      formalin test in mice. In addition to typical biphasic responses, a new, late
      phase (Phase 3) was observed. A local anesthetic QX-314 injected at the end of
      Phase 2 blocked Phase 3. Phase 3 in female mice was significantly greater than
      that in male mice regardless the stage of the estrus cycle.

PMID- 10350547
TI  - Trophic effects of selegiline on cultured dopaminergic neurons.
AB  - Trophic effects of the neuroprotective agent selegiline on cultured dopaminergic
      neurons were investigated and compared with the effects produced by brain derived
      neurotrophic factor (BDNF). Both treatments increased the total length of TH
      positive neurites, but selegiline increased the average length of neuritic
      branches, whereas BDNF increased the formation of new branches. This trophic
      effect of selegiline may contribute to its action in neurodegenerative disease
      treatment.

PMID- 10350548
TI  - Occlusive responses to adenosine A1 receptor and muscarinic M2 receptor
      activation on hippocampal presynaptic terminals.
AB  - There is substantial evidence for an interaction between adenosine A1 and
      muscarinic M1/M3 receptors in some tissues, either at the level of the receptors
      themselves or at the associated transduction system. We have now addressed the
      question of whether there is a similar interaction between A1 and presynaptic M2
      receptors in the hippocampus. The effects of cyclopentyladenosine (CPA) were
      studied alone or in combination with the M2 receptor agonist oxotremorine-M. The
      ability of both to depress synaptic transmission presynaptically at the
      concentrations used was confirmed using paired-pulse inhibition. When combined at
      a range of concentrations, the effects of the two agents were less than additive,
      suggesting that they are acting by a common transduction system. The results
      indicate that the modulatory, antagonistic effects of A1 adenosine receptors are
      exerted not only on postjunctional M1/M3 receptors but also at M2 presynaptic
      receptors.

PMID- 10350549
TI  - Anteroventral third ventricle (AV3V) lesions alter c-fos expression induced by
      salt loading.
AB  - Lesion of the anteroventral third-ventricle region (AV3VX) reduced saline
      consumption. Salt loading in AV3VX rats resulted in reduced but not completely
      abolished c-fos expression in the supraoptic and paraventricular nuclei.
      Intrinsic osmosensitivity of the magnocellular neurons, or input from other brain
      areas, such as the subfornical and median preoptic nuclei, may account for this
      residual c-fos expression. These regions showed c-fos expression following salt
      loading.

PMID- 10350550
TI  - Malondialdehyde binding of rat cerebral proteins is reduced in experimental
      hypothyroidism.
AB  - To determine the effect of thyroid hormones (TH) on cerebral tissue
      malondialdehyde (MDA) content and accumulation of MDA-bound proteins,
      hyperthyroid rats and hypothyroid rats were compared to euthyroid controls.
      Hyperthyroidism was induced by daily injection of l-3,5, 3'-triiodothyronine (15
      ug (100 g)-1) intraperitoneally daily for 10 days. Hypothyroidism was induced
      with 0.025% methimazole in the drinking water for 4 weeks. Immunoblot analysis of
      cerebral and plasma proteins was carried out using a specific anti-MDA-protein
      antiserum. MDA was measured as thiobarbituric acid reactive substance.
      Hypothyroidism was associated with significant reduction in MDA-proteins of
      plasma (59.3+/-9.5% vs. 99.8+/-23.0% of control p<0.05) and cerebral tissue
      (17.6+/-19.9% vs. 100.2+/-29.0% of control p<0.001). Hyperthyroidism did not
      significantly alter MDA-protein distribution. These changes did not correlate
      with cerebral tissue or plasma MDA concentration. It is concluded that
      hypothyroidism in rats is associated with significant decrease in MDA-bound
      proteins. This may have some clinical and biological implications.

PMID- 10350551
TI  - Convergence of trigeminal input with visceral and phrenic inputs on primate C1-C2
      spinothalamic tract neurons.
AB  - Trigeminal, spinal and vagal afferent fibers overlap in C1-C2 segments. We
      hypothesized that trigeminal input from the superior sagittal sinus (SSS) can
      excite C1-C2 spinothalamic tract (STT) neurons receiving thoracic visceral or
      phrenic inputs. Effects of SSS stimulation were evenly divided among cells
      responding to each nerve stimulus; magnitude of responses to ipsilateral vagal
      input was greater in neurons excited by SSS input. Somatic fields of 80% of
      neurons responding to SSS stimulation included face areas innervated by the
      trigeminal nerve, whereas somatic fields of 89% of neurons unaffected by SSS
      stimulation were located only on areas innervated by cervical spinal nerves.
      Results are consistent with the idea that pain referred to trigeminal areas could
      originate in thoracic organs.

PMID- 10350552
TI  - Acute peripheral inflammation induces moderate glial activation and spinal IL
      1beta expression that correlates with pain behavior in the rat.
AB  - Our laboratory has previously shown that glial activation and increased
      proinflammatory cytokine expression are observed in the rat spinal cord following
      peripheral nerve injuries that result in neuropathic pain behaviors. In the
      present study, we sought to determine whether acute peripheral inflammation
      induces changes in central glial and cytokine (Interleukin-1beta) expression
      similar to those seen following peripheral spinal nerve transection. Two models
      of peripheral inflammation were used in this study: formalin (5% solution) or
      zymosan (25 mg/ml) injected subcutaneously into the plantar portion of the left
      hind paw of male Holtzman-strain Sprague-Dawley rats. The rats were euthanized at
      1 h, 6 h, and 1, 3, 7 days post-injection (n=4 or 5/group/time point). As
      expected, the animals treated with formalin showed a spontaneous pain response
      and mechanical allodynia that persisted for approximately 60 min following
      injection. The animals treated with zymosan exhibited mild spontaneous pain
      responses during the first hour and mechanical allodynia at 6 h and 1 day
      following injection. Immunohistochemistry for glial activation and cytokine
      expression was performed on L4-L5 spinal levels in all rats. Spinal sections from
      both formalin and zymosan treated animals exhibited microglial and astrocytic
      activation and increased Interleukin-1beta immunoreactivity at 1 and 6 h,
      respectively. Spinal glial activation and upregulation of Interleukin-1beta
      appear to parallel the development and maintenance of zymosan and formalin
      induced mechanical allodynia. These findings support a unifying theory that glial
      activation and cytokine expression have a similar, if not related, role in
      producing hyperalgesia following either peripheral inflammation or peripheral
      nerve injury.

PMID- 10350553
TI  - Spinal cord noradrenergic dynamics in diabetic and hypercortisolaemic states.
AB  - Disorders of pain sensation including spontaneous pain, allodynia and
      hyperalgesia are commonly seen in neuropathic diabetic patients. A wealth of
      evidence indicates that spinal monoamine systems are implicated in pain
      modulation but whether abnormalities in these systems underlay such disorders is
      unclear. The present study was therefore initiated to investigate spinal
      noradrenergic dynamics during diabetes. Spinal release of norepinephrine (NE)
      represented by 3-methoxy-4-hydroxyphenylglycol (MHPG)/NE ratio was markedly
      suppressed in 30-day streptozotocin (STZ)-treated diabetic male and female rats.
      The density of [3H] p-aminoclonidine binding sites and the level of expression of
      mRNA encoding for alpha2A-adrenoceptor subtype were also reduced as a function of
      diabetes. In contrast, an increase in the density of [3H] prazosin binding to
      spinal synaptosomal membranes was evident in these animals. Clonidine-induced
      elevation in nociceptive threshold was attenuated in diabetics. Control animals
      subjected to chronic treatment with a supraphysiological dose of glucocorticoid
      (GC) exhibited a neurochemical pattern which is similar in many respects to that
      produced by the diabetic state. Both insulin and the GC receptor blocker, RU 486,
      restored most of the neurochemical and behavioural abnormalities of diabetes.
      Overall, the present study supports the concept that a diabetes-related deficit
      in spinal noradrenergic dynamics may be a reflection of an overactivity of the
      hypothalamic-pituitary-adrenal axis.

PMID- 10350554
TI  - Oxidized lipoproteins increase reactive oxygen species formation in microglia and
      astrocyte cell lines.
AB  - Lipoproteins exist in the central nervous system and surrounding vasculature
      possibly mediating effects upon cells in the brain during times of oxidative
      stress or compromised blood-brain barrier. The focus of the present study was to
      determine the effect of unmodified and oxidatively modified lipoproteins on
      astrocytes and microglia. Application of oxidized low-density lipoprotein
      resulted in an increase in DCF fluorescence, which was inhibited by pretreatment
      with antioxidants, consistent with the formation of reactive oxygen species
      (ROS). Low-density at concentrations below 20 microg/ml likewise increased ROS
      formation. Because ROS are associated with numerous astrocyte and microglia
      activities including proliferation, activation, and cytokine production it is
      possible that lipoproteins may mediate such effects on glial cells in the central
      nervous system.

PMID- 10350555
TI  - Morphine treatment during juvenile isolation increases social activity and opioid
      peptides release in the adult rat.
AB  - The consequences of juvenile isolation and morphine treatment on general
      activity, social activity and endogenous opioid release during a social
      interaction test were investigated in the adult rat. Rats were either isolated or
      socially housed during weeks 4 and 5 of age and treated daily during this
      isolation period subcutaneously with either saline or morphine. Directly after a
      social interaction test at 10 weeks of age, rats were injected with [3H]
      diprenorphine and subsequently prepared for in vivo autoradiography. The
      autoradiographic technique was used to visualise neuroanatomical changes in
      opioid receptor occupancy, probably reflecting changes in opioid peptide release,
      as a result of social activity. Juvenile isolation increased general activity
      during the social interaction test, an effect which was accompanied by a
      reduction of opioid receptor occupancy in many brain areas, suggesting an
      increased opioid peptide release as a consequence of socially-induced general
      activity. Morphine treatment in isolated rats caused an increase in adult social
      activity and enhanced opioid peptide release in some cortical regions and the
      ventral tegmental area as compared to saline treated rats. Both social activity
      and opioid receptor occupancy were unaffected by morphine treatment in non
      isolated rats. The present study underscores the role of opioid systems in adult
      social behaviors as a consequence of juvenile isolation. The results suggest a
      relationship between social activity and opioid peptide release during social
      contact. Increased social activity seems to be accompanied by elevated opioid
      peptide release in distinct brain areas after morphine treatment during juvenile
      isolation.

PMID- 10350556
TI  - Electrical stimulation of the anterior ethmoidal nerve produces the diving
      response.
AB  - Stimulation of the upper respiratory tract usually produces apnea, but it can
      also produce a vagally mediated bradycardia and a sympathetically mediated
      increase in peripheral vascular resistance. This cardiorespiratory response,
      often called the diving response, is usually initiated by nasal stimulation. The
      purpose of this research was to investigate the anterior ethmoidal nerve (AEN)
      that innervates the nasal mucosa of muskrats (Ondatra zibethicus). Electrical
      stimulation of the AEN (typically 50 Hz, 100 micros and 500 microA) produced
      immediate and sustained bradycardia and cessation of respiration similar to that
      of the diving response. Heart rate (HR) significantly decreased from 264+/-18 to
      121+/-8 bpm, with a concurrent 4.2+/-0.9 s apnea, during the 5 s stimulation
      period. BP decreased from 97.9+/-4.8 to 91.2+/-6.4 mmHg. Using estimations from
      (1) cross-sectional areas of AEN trigeminal ganglion cells labeled with WGA-HRP,
      and (2) electron microscopic analysis of the AEN, we found that approximately 65%
      of the AEN is composed of unmyelinated C-fibers. In addition, 72.4% of myelinated
      fibers from the nerves that innervate the nasal passages were of small diameter
      (<6 microm, presumably Adelta fibers). Thus, the AEN of the muskrat contains a
      high concentration of small diameter fibers (89.8%). We conclude that electrical
      stimulation of small diameter fibers within the AEN of muskrats can produce the
      cardiovascular and respiratory responses similar to that of the diving response.

PMID- 10350557
TI  - Dissociation between the effects of interleukin-1 on excitotoxic brain damage and
      body temperature in the rat.
AB  - The cytokine interleukin-1beta (IL-1beta) mediates and exacerbates excitotoxic
      brain damage in the rat striatum. Co-injection of the selective glutamate
      receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA)
      with human recombinant IL-1beta (hrIL-1beta) in the striatum of rats results in
      both local (striatal) damage and extensive, distant neuronal death in the cortex.
      The objective of the present study was to investigate the mechanisms underlying
      IL-1beta actions on excitotoxic damage, and to determine whether this effect of
      IL-1beta, a potent pyrogen, is due to modification of body temperature. Striatal
      infusion of S-AMPA (7.5 nmol) in anaesthetised rats produced localised striatal
      damage. Intrastriatal co-infusion of hrIL-1beta (10 ng) with S-AMPA caused
      similar striatal damage, but also produced extensive cortical damage, together
      with a modest increase in body temperature (0.9 degrees C) compared to rats
      infused with S-AMPA alone. Infusion of S-AMPA into the striatum, together with
      intracerebroventricular (i.c.v.) injection of hrIL-1beta, produced a similar rise
      in temperature to striatal co-infusion of S-AMPA and hrIL-1beta, but resulted in
      only local (striatal) neuronal damage, that was similar to that caused by
      striatal infusion of S-AMPA alone. These data suggest that the effects of IL
      1beta on AMPA-receptor mediated neuronal damage in the striatum can be
      dissociated from its pyrogenic effects on body temperature.

PMID- 10350558
TI  - Food and water intake suppression by intracerebroventricular administration of
      substance P in food- and water-deprived rats.
AB  - The purpose of this present experiment was to determine the effect of substance P
      (SP) on the feeding and drinking behavior. This was investigated in male rats
      totally food and water deprived for a period of 24 h. The intracerebroventricular
      (i.c.v.) administration of SP (20 microg 10 microl-1 rat-1) suppressed food and
      water intakes during the 8 h following administration. At 24 h after i.c.v.
      injection of SP, the rats were not recovered 10.5% of their feeding and 24.9% of
      their drinking behavior. However, contrary to what happened with SP, i.c.v.
      injection of the vehicle of SP did not suppress feeding and drinking behavior, as
      was observed also in the rats (second control) cannulated i.c.v. but which did
      not receive any injection. At 48 h after SP injection, no alteration of food and
      water intakes was observed. These results indicated that SP may function as an
      endogenous anorexigenic peptide.

PMID- 10350559
TI  - Single vs. paired visual stimulation: superposition of early neuromagnetic
      responses and retinotopy in extrastriate cortex in humans.
AB  - Neuromagnetic techniques were used in conjunction with magnetic resonance imaging
      (MRI) techniques to: (1) localize and characterize cortical sources evoked by
      visual stimuli presented at different locations in the lower right visual field;
      (2) examine the superposition of cortical responses by comparing the summation of
      responses to the presentation of single stimuli with responses to paired stimuli;
      and (3) examine the spatial resolution of magnetoencephalographic (MEG)
      techniques by comparing the identified source locations evoked by the
      presentation of single vs. paired stimuli. Using multi-dipole, non-linear
      minimization analyses, three sources were localized for each stimulus condition
      during the initial 80-170 ms poststimulus interval for all subjects. In addition
      to an occipital source, two extrastriate sources were identified: occipital
      parietal and occipital-temporal. Each source evidenced a systematic shift in
      location associated with changes in stimulus placement parallel to the vertical
      meridian. To our knowledge, this is the first demonstration of retinotopic
      organization of extrastriate areas, using non-invasive neuromagnetic techniques.
      The paired presentation of stimuli reflected superposition of the responses
      evoked by single stimuli but only for early activity up to 150 ms poststimulus.
      Undersummation was evident after 150 ms. All sources identified for single
      stimuli were also identified in the paired-stimulus responses; but at the expense
      of larger errors for some of the estimated parameters.

PMID- 10350560
TI  - Food deprivation modulates chronic stress effects on object recognition in male
      rats: role of monoamines and amino acids.
AB  - An object recognition task was used to determine if chronic restraint stress (6
      h/day for 21 days) impairs non-spatial memory, since chronic restraint is known
      to impair spatial memory. In addition, food deprivation was tested as a possible
      modulating factor of any stress effect in this non-reward-dependent task.
      Following 3 weeks of daily restraint, subjects were tested for open field
      activity and object recognition (over different delay intervals) during one week
      in two separate experiments. Experiment 1 involved testing under low demand
      conditions (small arena) while experiment 2 involved testing under higher-demand
      conditions (large arena). Basal monoamine and amino acid levels (home cage) were
      assessed in experiment one and monoamine arousal levels (following a sample
      trial) were assessed in experiment two. We observed that chronic stress impaired
      object recognition when the delay was extended beyond 1 h, and that food
      deprivation could attenuate the degree of impairment. In addition, chronic stress
      was associated with increased norepinephrine levels in both the amygdala and
      hippocampus, and dopamine (HVA/DA, DOPAC/DA) in prefrontal cortex. These changes
      were not observed in stress subjects that were subsequently food deprived. Food
      deprived subjects had higher basal serotonin activity in prefrontal cortex and
      hippocampus as well as higher serum CORT levels. Results suggest that food
      deprivation may act as a novel stress, thereby increasing subjects' arousal and
      attention toward the objects, which aids stressed subjects, especially in low
      demand conditions. Both restraint and food deprivation affected select limbic
      areas associated with memory functioning.

PMID- 10350561
TI  - Sulfated and unsulfated steroids modulate gamma-aminobutyric acidA receptor
      function through distinct sites.
AB  - Sulfated and unsulfated neurosteroids such as pregnenolone sulfate,
      dehydroepiandrosterone sulfate (DHEAS), pregnanolone, and allopregnanolone,
      modulate ionotropic amino acid neurotransmitter receptors, and may function as
      endogenous neuromodulators. The gamma-aminobutyric acid type A (GABAA) receptor
      exhibits both negative and positive modulation by neurosteroids, but the
      interaction between negative and positive modulators is not well-understood. For
      a number of neuroactive steroids, sulfation at C-3 reverses the direction of
      modulation from positive to negative, suggesting that sulfation could be an
      important control point for the activity of endogenous neurosteroids. Modulation
      by endogenous and synthetic steroids of the response to exogenous or synaptically
      released GABA was examined in primary chick spinal cord and rat hippocampal
      neurons, and in Xenopus laevis oocytes expressing alpha1beta2gamma2S GABAA
      receptors. Inhibitory activity is retained when hemisuccinate is substituted for
      sulfate at C-3, suggesting that it is the negative charge, rather than the
      sulfate group, that confers inhibitory efficacy. The interaction between steroid
      negative and positive modulators is not competitive, indicating that steroid
      negative and positive modulators act through distinct sites. Some steroids, such
      as 11-ketopregnenolone sulfate, appear to act at both negative and positive
      modulatory sites, as indicated by an 'off-response' upon washout. A similar off
      response is also observed after co-application of the negative modulator DHEAS
      and the positive modulator allopregnanolone. The observation that simultaneous
      application of sulfated and unsulfated steroids, such as DHEAS and
      allopregnanolone, act at distinct sites implies that steroid negative and
      positive modulators can act independently or coordinately to regulate GABA
      mediated inhibition in the central nervous system.

PMID- 10350562
TI  - Fibroblast growth factor-8 protects cultured rat hippocampal neurons from
      oxidative insult.
AB  - Basic fibroblast growth factor (bFGF) has been reported to have neuroprotective
      properties following excitotoxic, metabolic, and oxidative insults. We report
      here that another FGF family member, FGF-8 is able to protect rat hippocampal
      cultures from oxidative stress. The b isoform of FGF-8 protected hippocampal
      cultures from hydrogen peroxide with an EC50 of approximately 25 ng/ml. In a time
      course study, using pre-, co-, post-treatment paradigms, we report that bFGF and
      FGF-8b were neuroprotective when added as a pre-treatment, co-treatment, and even
      at 2 h post-insult. Using neuronal enriched cultures, we demonstrate that bFGF
      and FGF-8b neuroprotection partially results from a direct action of the growth
      factors on neurons. The direct action on neurons may work in concert with normal
      and FGF-stimulated glial secretion products to give the full FGF protective
      effect. FGF-8b showed maximal protection at 50 ng/ml, whereas bFGF showed maximal
      protection at 10 ng/ml. Despite requiring higher concentrations to elicit
      protection, FGF-8b is able to attain levels of protection equivalent to that of
      bFGF (attenuation of 75-80% of hydrogen peroxide induced death). We also report
      that bFGF and FGF-8b are able to protect the human neuroblastoma cell line, SK-N
      MC, from peroxide-induced LDH release by 50%. From these studies, we conclude
      that FGF-8b is another member of the FGF family which may show in vivo efficacy
      for the treatment of oxidative insults, such as stroke.

PMID- 10350563
TI  - Sepsis facilitates brain serotonin activity and impairs learning ability in rats.
AB  - Sepsis often provokes various neurological disorders. Because many neurologic
      symptoms are caused by changes in neurotransmissions, we investigated the
      relationship between behavioral alterations and changes in activities of the
      monoaminergic systems in rats. Sepsis was induced by cecal ligation and puncture.
      A step-through passive avoidance test was used for the behavioral evaluation.
      Passive avoidance retention in animals subjected to learning immediately before
      the septic or sham operation was examined after 24 or 48 h. Retention performance
      in animals subjected to learning 24 h after the operation was also examined after
      a further 24 h. Plasma concentrations of amino acids were determined 24 h after
      the operation. The activities of the brain monoaminergic systems were evaluated
      by ratios of metabolites to monoamines. Marked damage was found in the septic
      rats in the blood analysis 24 h after the operation. The plasma concentrations of
      tyrosine and arginine in the septic rats were decreased to 69% and 70% of those
      in the sham-operated animals, respectively. Retention performance was impaired in
      the septic rats when they were subjected to learning 24 h after the operation,
      but it was not impaired when animals were subjected to learning before the septic
      operation. The brain concentration of serotonin was increased in the cerebral
      cortex, striatum, and hippocampus 48 h after the septic operation, but not after
      24 h. The concentration of 5-hydroxyindoleacetic acid, a metabolite of serotonin,
      was increased in the above three regions both 24 and 48 h after the operation,
      but not in the hypothalamus. Facilitation of the serotonergic activity in the
      telencephalon and hippocampus is suggested to be involved in the impairment of
      learning ability in sepsis.

PMID- 10350564
TI  - Brain parenchyma vessels and the angiotensin system.
AB  - It is now recognized that the brain contains an autonomous angiotensin (AG)
      system, including the aminopeptidases A and N required for angiotensin
      metabolism. Using immunohistochemical techniques, we show that capillary
      pericytes and periendothelial cells of other vessels express aminopeptidase A
      (APA) and aminopeptidase N (APN) at their plasma membrane in adult mouse brain
      parenchyma. We therefore investigated the localization of angiotensin II(III),
      known as putative substrates for these enzymes, as well as that of their
      precursor angiotensin I. We report here the presence of immunoreactivity to
      angiotensin I and II(III) around most brain vessels. Angiotensins are present at
      the plasma membrane of brain parenchymal cells, presumably perivascular
      astrocytes which are also immunoreactive to AT1-receptor antibodies. The very
      close relationship between AGII(III) and their metabolizing enzymes APA and APN
      suggests a specific functional role for brain perivascular angiotensins.

PMID- 10350565
TI  - Expression of inducible nitric oxide synthase (iNOS/NOS II) in the cochlea of
      guinea pigs after intratympanical endotoxin-treatment.
AB  - Since NO is believed to be involved in cochlear physiology, presence of the
      constitutive isoforms of nitric oxide synthase (NOS), and the target enzyme of
      NO, soluble guanylyl cyclase (sGC) in structures of the mammalian cochlea have
      been demonstrated. To date, no reports have been published regarding the
      detection of the inducible isoform (NOS II) in the cochlea. In order to show the
      capability of iNOS expression in cochlear tissue, a mixture of proinflammatory
      bacterial lipopolysaccharides (LPS) and tumor necrosis factor alpha (TNF-alpha)
      was injected into the tympanic cavity of guinea pigs, vs. saline-solution as
      control. Paraffin sections of LPS/TNF-alpha treated and saline-treated cochleae
      (6 h) were examined immunohistochemically with specific antibodies to neuronal,
      endothelial and inducible NOS and to sGC. Initiated expression of iNOS in the
      cochlea was observed in the wall of blood vessels of the spiral ligament (SL) and
      the modiolus, in supporting cells of the organ of Corti, in the limbus, in nerve
      fibers and in a part of the perikarya of the spiral ganglion after LPS/TNFalpha
      treatment. iNOS was not detected in saline-treated control tissue. Expression of
      both constitutive NOS-isoforms (endothelial and neuronal NOS) and of sGC showed
      no significant differences in both experimental groups. Endothelial eNOS and
      neuronal bNOS were detected co-localized in ganglion cells, in nerve fibers, in
      cells of the SL and in supporting cells of the organ of Corti, but not in sensory
      cells. Strong labeling for bNOS became evident in the endosteum of the cochlea,
      while in the endothelium of blood vessels and in the epithelium of the limbus
      only eNOS could be labeled. sGC could be detected in SL, in supporting and
      sensory cells of the organ of Corti, in nerve fibers, ganglion cells, in the wall
      of blood vessels and in the limbus-epithelium. While small amounts of NO,
      generated by bNOS and eNOS, seem to support the cochlear blood flow and auditory
      function as well as neurotransmission, high amounts of iNOS-generated NO could
      have dysregulative and neurotoxic effects on the inner ear during bacterial and
      viral infections of the middle and inner ear.

PMID- 10350566
TI  - NMDA receptor-mediated changes of spontaneous activity patterns in
      thalamocortical slice cultures.
AB  - Spontaneous activity is a hallmark of the thalamocortical system in vivo. Up
      until now, in vitro preparations of this system have been shown to be
      spontaneously active only when inhibition was reduced or N-methyl-D-aspartate
      (NMDA) receptor-mediated currents were facilitated via low extracellular
      magnesium levels. This study investigated the dependence of spontaneous
      thalamocortical activity patterns on NMDA receptor function via variation of
      extracellular magnesium levels (0-1 mM) and by the application of the specific
      NMDA receptor-antagonist D-2-amino-5-phosphonovalerate (AP5) in the absence of
      magnesium. We used cocultures of rat neocortical and thalamic slices which have
      been shown to develop reciprocal synaptic connections similar to those in vivo.
      Multi-site extracellular recordings revealed that the cultures were spontaneously
      active at all concentrations of magnesium and AP5, albeit with a high variability
      among cultures. Activity consisted of burst-like events which were largely
      synchronized within as well as among the neural tissues, and thalamic background
      activity during periods of neocortical quiescence. Each tissue was capable of
      triggering activity in the other, indicating that both thalamocortical and
      corticothalamic synaptic connections were functional. With increasing magnesium
      concentration, activity rates declined in both tissues and the site of origin of
      the synchronous, burst-like events shifted from neocortex to thalamus. AP5 in
      magnesium-free perfusion solution had qualitatively similar effects. We conclude
      that thalamic activity is not as dependent on the facilitation of NMDA receptor
      mediated currents as neocortical activity and consequently, that the thalamus is
      the pacemaker of thalamocortical synchronized activity in physiological in vitro
      conditions.

PMID- 10350567
TI  - Adrenergic modulation of astroglial phospholipase D activity and cell
      proliferation.
AB  - As phospholipase D (PLD) activation has been associated with mitogenic signalling
      in several cell types, we tested an association between adrenergic activation of
      PLD and cellular proliferation in primary cultures of rat cortical astrocytes. In
      2-week old cultures, PLD activation by noradrenaline (EC50: 0.49 microM) was
      inhibited by prazosin, a specific antagonist at alpha1-adrenergic receptors
      (IC50: 0.23 microM). Adrenergic PLD activation was not affected by genistein, an
      inhibitor of tyrosine kinases, or by Ro 31-8220, an inhibitor of protein kinase C
      (PKC), but was dose-dependently depressed in the presence of brefeldin A (1-100
      microg/ml), an inhibitor of ARF activation. In experiments measuring cell
      proliferation, noradrenaline potently (EC50: 20 nM) reduced [3H]thymidine
      incorporation to 20-30% of basal values. This action was mimicked by the beta
      specific agonist isoprenaline and was inhibited by the beta-antagonist
      propranolol in a concentration-dependent manner. The alpha1-adrenergic agonists,
      phenylephrine and methoxamine, also reduced DNA synthesis. The adrenergic
      inhibition of astroglial DNA synthesis was not reduced, but further potentiated
      in the presence of brefeldin A, ethanol, and 1- and 2-butanol; 1-butanol, a
      substrate of PLD, was equally effective as 2-butanol, a non-substrate. We
      conclude that adrenergic PLD activation in astrocytes is not involved in
      mitogenic signalling. The involvement of ARF in the activation of PLD via alpha1
      adrenoceptors indicates a role in protein trafficking.

PMID- 10350568
TI  - Both oxidative stress-dependent and independent effects of amyloid beta protein
      are detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide
      (MTT) reduction assay.
AB  - 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction
      assay has been widely used for evaluating amyloid beta protein (Abeta) toxicity.
      However, the potency of Abeta in inhibiting cellular MTT reduction and the
      underlying mechanism have been reported with some discrepancies among
      researchers. To understand what makes such discrepancies, the effect of Abeta
      detected by MTT reduction assay was re-examined in detail by using cultured rat
      hippocampal neurons. Micromolar concentrations (>10 microM) of Abeta caused a
      decrease in cell viability, which resulted in a decrease in MTT reduction per
      well regardless of assay time. The micromolar Abeta-induced decrease of cellular
      MTT reduction was significantly attenuated by antioxidants (catalase, propyl
      gallate or Trolox). On the other hand, nanomolar Abeta did not affect cellular
      MTT reduction activity at an initial stage of assay (<1 h), and decreased the
      total production of MTT formazan by accelerating the exocytosis of MTT formazan
      when MTT assay was performed for a longer time (>2 h). The assay time-dependent,
      nanomolar Abeta-induced decrease of cellular MTT reduction was not at all
      affected by antioxidants. Furthermore, subtoxic concentration of H2O2 failed to
      mimic the effect of nanomolar Abeta on MTT reduction. These results indicate that
      micromolar Abeta-induced, oxidative cell death is detected by MTT assay
      regardless of assay time, whereas nanomolar Abeta-induced acceleration of MTT
      formazan exocytosis is not mediated by oxidative stress and detected only when
      MTT assay is performed for a longer time. The time of MTT assay should be
      properly chosen depending on the purpose of the study.

PMID- 10350569
TI  - Expression of nitric oxide synthase (NOS)-2 following permanent focal ischemia
      and the role of nitric oxide in infarct generation in male, female and NOS-2 gene
      deficient mice.
AB  - Considerable evidence implicates nitric oxide (NO) in the pathological events
      following cerebral ischemia and, depending on the enzyme/cell source, NO is
      considered to be either damaging or protective. As a role for the enzyme nitric
      oxide synthase (NOS)-2 in permanent focal ischemia is not clear, we examined its
      expression following permanent middle cerebral artery occlusion in mice. At 24 h
      after occlusion, NOS-2 was expressed in cells infiltrating the infarct, while at
      later times, there was also expression in astrocytes around the infarct. To
      reveal a role for NO derived from this source, we compared infarct size in male
      and female mice with littermates in which the NOS-2 gene was disrupted. No
      differences were found between gender and genotype at 24 h. At 72 h, the infarct
      was increased in male mice, but not in females or in either gender with the gene
      disruption. These results suggest that NOS-2 plays a role in the later
      development of the infarct in male mice. Female mice are protected either against
      the damaging effects of NO, or because NOS-2 expression/activity is modulated by
      steroids.

PMID- 10350570
TI  - Circadian rhythms of melatonin-synthesizing enzyme activities and melatonin
      levels in planarians.
AB  - In most vertebrates and several insects, melatonin (N-acetyl-5-methoxytryptamine)
      is synthesized enzymatically from serotonin (5-hydroxytryptamine) by the
      sequential action of arylalkylamine N-acetyltransferase (NAT) and hydroxyindole-O
      methyltransferase (HIOMT). In the freshwater planarian Dugesia japonica, which
      belongs to the most primitive metazoan phylum, activities of NAT and HIOMT, as
      well as melatonin, were found. The apparent Michaelis constants for substrates of
      NAT and HIOMT in the planarian were similar to those reported for the mammalian
      pineal gland and retina. When the planarians were maintained under a 12 h
      light:12 h dark cycle, the activities of NAT and HIOMT and melatonin levels
      exhibited a significant diurnal variation, peaking at the mid-dark time. In
      constant darkness, NAT activity and melatonin levels fluctuated with a circadian
      (about 24 h) rhythm. These data demonstrate that the planarian synthesizes
      melatonin through the same pathways as those in most vertebrates and several
      insects, and that its melatonin synthesis fluctuates in a circadian manner. Thus,
      it is strongly suggested that the planarian contains a circadian clock
      controlling melatonin synthesis.

PMID- 10350571
TI  - Expression of the 71 kDa dystrophin isoform (Dp71) evaluated by gene targeting.
AB  - To investigate the function of the major non-muscle dystrophin isoform, Dp71, we
      substituted a beta-galactosidase (betagal) reporter gene for Dp71 by homologous
      recombination in embryonic stem cells. Staining for betagal activity in chimeric
      mice revealed Dp71 promoter activity in glial cells in the CNS, in neurons of the
      inner nuclear and inner plexiform layers of the retina, and in the kidney tubules
      and collecting ducts. Our observations demonstrate that Dp71 is widely expressed
      in the adult CNS (retina, cerebellum, cerebral cortex, ependyma, and choroid) as
      well as the adult kidney epithelium and suggest a broad function for Dp71 in
      differentiated tissues.

PMID- 10350572
TI  - Influence of serum-free culture conditions on steroid 5alpha-reductase mRNA
      expression in rat C6 glioma cells.
AB  - Immunocytochemical studies previously showed that serum deprivation resulted in
      the appearance of steroid 5alpha-reductase (5alpha-R) in the cytoplasm of rat C6
      glioma cells. To determine whether this increase in cytoplasmic 5alpha-R was due
      to changes in 5alpha-R gene expression, the effect of serum deprivation on 5alpha
      R mRNA expression was examined. No significant change in the mRNA levels was
      observed in cells grown in serum-free culture medium. Therefore, the appearance
      of 5alpha-R immunoreactivity in the cell cytoplasm observed under serum-free
      conditions is probably not due to changes in 5alpha-R gene expression.

PMID- 10350573
TI  - Interrelations of opioids with monoamines in descending inhibition of nociceptive
      transmission at the spinal level: an immunocytochemical study.
AB  - This study was designed to reexamine a previous proposal of whether the opioid
      like substances (OLS) being acting mainly as an intrinsic spinal mediator in the
      descending inhibition of nociception of the bulbospinally projecting NE-ergic,
      and/or 5-HT-ergic terminals in the dorsal horn by using an immunocytochemical
      method. The effects of intrathecal (i.t.) phentolamine (Ph), cyproheptadine
      (Cyp), and naloxone (Nal), administered separately or coadministered by two of
      them, on the expression of Fos-like-immunoreactive (FLI) neurons were observed on
      both sides of the lumbar dorsal horn of rats, in which equal volumes of formalin
      were injected into two hindpaws and the ipsilateral dorsolateral funiculus (DLF)
      was transected at the thoracic level antecedently. The results showed: (1) when
      rats were pretreated with i.t. saline, the number of nociceptive FLI neurons was
      significantly lowered 44% (p<0.01) on the side of the lumbar dorsal horn with
      intact DLF compared to the opposite side with sectioned DLF; (2) when rats were
      separately pretreated with i.t. Ph, Cyp and Nal, the reduction of FLI neurons on
      the DLF-intact side were decreased by 27% (p<0.01), 21% (p<0.01), and 25%
      (p<0.01), respectively; (3) when rats were pretreated with combined i.t. Ph+Cyp,
      the reduction on the intact side was eliminated almost completely (4%); (4) when
      rats were pretreated with combined i.t. Ph+Nal, the reduction on the intact side
      was 21% (p<0.01); and (5) when rats were pretreated with i.t. Cyp+Nal, the
      reduction on the intact side was 9.1%. These results suggest that: (1) nearly all
      the suppressive action exerted by the DLF-descending fibers are produced by the
      release of either NE or 5-HT as neurotransmitters at the spinal level; (2) most
      of the opioid-like substances act as an intrinsic spinal mediator mainly for the
      descending NE-ergic, but in a lesser extent for the 5-HT-ergic terminals in the
      dorsal horn circuitry; and (3) some OLS-ergic interneurons may only be activated
      by local nociceptive input.

PMID- 10350574
TI  - Role of the anterior region of the third ventricle in the cardiovascular
      responses produced by systemic injection of a nitric oxide synthase inhibitor.
AB  - This study examined whether a prior electrolytic lesion of the tissue surrounding
      the anteroventral third ventricle (AV3V) would affect the increase in mean
      arterial blood pressure (MAP) and the fall in heart rate (HR) produced by
      systemic injection of the nitric oxide synthesis (NOS) inhibitor, NG-nitro-L
      arginine methyl ester (L-NAME; 25 micromol/kg, i.v.) in conscious rats. L-NAME
      produced a smaller increase in MAP in AV3V-lesion than in sham-lesion rats (+19+/
      3 vs. +40+/-3 mmHg, respectively; P<0.05). In contrast, L-NAME produced similar
      falls in HR in the AV3V-lesion and sham-lesion rats (-103+/-15 vs. -97+/-8 bpm,
      respectively; P<0.05). These findings demonstrate that the L-NAME-induced pressor
      response is dependent upon the integrity of the AV3V region, whereas the L-NAME
      induced bradycardia is not.

PMID- 10350575
TI  - PACAP-induced formation of cyclic AMP in the chicken brain: regional variations
      and the effect of melatonin.
AB  - We have studied the effects of pituitary adenylate cyclase-activating polypeptide
      (PACAP27 and PACAP38) on cyclic AMP formation in chick brain, and the action of
      melatonin upon the PACAP-evoked effects. PACAP stimulated cyclic AMP production
      in the hypothalamus>cerebral cortex>pineal gland>optic lobes. In the hypothalamus
      and cerebral cortex, the rank-order of both PACAP forms and VIP in evoking the
      cyclic AMP response was: PACAP38 approximately PACAP27>>VIP, suggesting the
      presence in the tested tissues of PAC1 receptors. Melatonin suppressed (IC50=19.8
      nM) the PACAP27 (0.1 microM)-induced cyclic AMP response in the hypothalamus, but
      not in the cerebral cortex. Melatonin also suppressed the hypothalamal cyclic AMP
      synthesis stimulated by forskolin, but not that evoked by histamine or
      isoprenaline. Our observations show that PACAP is capable of potently stimulating
      cyclic AMP formation in some regions of the chick brain, and suggest that the
      hypothalamus may be a site for a functional interaction between PACAP and the
      pineal hormone melatonin.

PMID- 10350576
TI  - Bleomycin hydrolase immunoreactivity in senile plaque in the brains of patients
      with Alzheimer's disease.
AB  - Bleomycin hydrolase (BH), a cysteine protease belonging to the papain
      superfamily, is one of the candidate beta secretases. We performed
      immunohistochemical studies of Alzheimer's disease (AD) brains using an antibody
      to BH. Polyclonal antibody to BH immunostained neocortical neurons. The
      immunoreactivity was also found in senile plaques in AD. These results may
      suggest a role of BH in amyloid formation.

PMID- 10350577
TI  - Thalamocortical afferents of Lorente de No: medial geniculate axons that project
      to primary auditory cortex have collateral branches to layer I.
AB  - The injection of anterograde tracers into the ventral division of the medial
      geniculate body (MGV) of both rats and rabbits labels terminal axons in layer I
      of auditory cortex as well as the more conventional terminal arbors in layers
      III/IV. Whether these layer I projections represent a separate lemniscal pathway
      to the molecular layer or arise as collaterals of axons terminating in III/IV has
      not been addressed. Focal injections of the anterograde tracers biocytin or
      biotinylated dextran amine were made into the MGV of young rabbits. Serial
      section reconstruction of single MGV axons in auditory cortex revealed that layer
      I axons were collaterals of thalamocortical afferents that formed multiple
      divergent patches within III/IV. MGV collaterals to layer I often coursed
      tangentially for several millimeters before terminating. In some cases, the layer
      I collaterals descended to arborize within a thalamocortical patch in layers
      III/IV. These results suggest considerable radial and tangential divergence in
      the auditory thalamocortical pathway and argue for an expanded role for layer I
      in the processing of specific sensory stimuli.

PMID- 10350578
TI  - Ecosystem health and human well being: the mission of the international programme
      on plant bioassays.
AB  - In a broad sense, since humans are ultimately a part of the ecosystem, we may
      conclude that ecosystem health encompasses human health. A preventative measure
      that detects the environmental hazards that infringe on human health should be
      established on a global scale. Plant bioassays, which are most sensitive in
      detecting genotoxicity of environmental agents, can serve as the first alert for
      the presence of environmental hazards in water, air, and soil-the essential
      elements of life. Three plant bioassays including the Allium/Vicia root test, the
      Tradescantia-Stamen-Hair-Mutation and Tradescantia-Micronucleus tests, which have
      been validated by the International Programme on Chemical Safety (IPCS), were
      selected to serve this purpose. The major activity of the International Programme
      on Plant Bioassays (IPPB) which was formerly sponsored by the IPCS has been
      devoted to the monitoring and testing of the genotoxicity of environmental
      pollutants using these three bioassays since 1996 after the hands-on workshop
      conducted in Qingdao, China. The general aim of this programme was not only to
      identify the substance and situations that may entail a significant risk to
      humans as proposed by ICPEMC and IAEMS but also by using these single, quick, and
      inexpensive plant bioassays to demonstrate the effects of pollution and to carry
      on environmental education to the general public at an early age. The monitoring
      network in China could be used as the model for a global scale study to aid in
      restoring ecosystem health. The Chinese policy is to identify the hazards and to
      eliminate the sources of pollution.

PMID- 10350579
TI  - The international program on plant bioassays and the report of the follow-up
      study after the hands-on workshop in China.
AB  - Among the seven plant bioassays reviewed by the US Environmental Protection
      Agency (EPA) Gene-Tox program in 1980, the Allium/Vicia root tip chromosome
      aberration assay and the Tradescantia stamen hair mutation and micronucleus
      assays were adopted by the International Program on Plant Bioassays (IPPB) for
      monitoring or testing environmental pollutants. These assays are highly sensitive
      and capable of detecting mutagens, clastogens and carcinogens from the
      environment. They are effective in situ monitors. These bioassays were validated
      and their protocols were standardized through a program under the International
      Program on Chemical Safety (IPPB), the precursor of the IPPB program which
      currently is in operation under the auspices of the United Nations Environment
      Program (UNEP). Six different categories of environmental studies, ranging from
      wastewater, surface or ground water, soil samples, ambient air, pesticides, and
      radiation, were carried out and are reported in this special issue. The mission
      of the IPPB/UNEP is to use these bioassays to monitor or test environmental
      mutagens and clastogens in the air, water, and soil to safeguard the quality of
      these essential elements in life and to use these simple and clear indicators of
      pollution damage as the tool for environmental education for the general public.
      The published reports of the monitoring and testing results will establish the
      database for environmental conditions in a number of locations around the world.
      An international monitoring network for the detection of genotoxicity of
      environmental pollutants is being established under the auspices of UNEP to
      protect the global environment.

PMID- 10350580
TI  - Higher plant assays for the detection of chromosomal aberrations and gene
      mutations-a brief historical background on their use for screening and monitoring
      environmental chemicals.
AB  - Higher plants are recognized as excellent indicators of cytogenetic and mutagenic
      effects of environmental chemicals and are applicable for the detection of
      environmental mutagens both indoor and outdoor. They are highly reliable
      bioassays with a high sensitivity for monitoring and testing for genotoxins. A
      brief review of major steps in the development of higher plant genotoxic assays
      is given.

PMID- 10350581
TI  - Tradescantia-micronucleus assay for the assessment of the clastogenicity of
      Austrian water.
AB  - Seven water samples collected from Vienna and Salzburg areas in Austria were
      tested for their clastogenicity with the Tradescantia-micronucleus (Trad-MCN)
      assay. There was no indication of clastogenic activity in two drinking water
      samples; likewise, samples from two major rivers (Danube and Salzburg) and of a
      river that received effluents from a paper mill also gave negative results. Urban
      river water as well as ground water samples which were collected near an
      industrial waste dump site caused a statistically significant and dose dependent
      increase of the MCN frequencies.

PMID- 10350582
TI  - In situ monitoring of the ambient air around the chloroprene rubber industrial
      plant using the Tradescantia-stamen-hair mutation assay.
AB  - The city of Yerevan, the capital of Armenia, has been one of the heavily polluted
      cities since the earlier USSR era. A Chloroprene Rubber Industrial Plant has been
      the major contributor of air pollution in this city. The first attempt has been
      undertaken to detect the mutagenic effect of the ambient air around this
      industrial complex using the Tradescantia-stamen-hair-mutation (Trad-SHM) assay.
      Tradescantia clone 02 was used for this study. Pots of Tradescantia plants were
      exposed to ambient air in 10 different locations around the industrial
      establishment during the months of May and June, 1991 and 1992. Three series of
      in situ monitoring experiments were carried out. In the first series, sites
      numbers 1 through 4 were located in the industrial complex, and the second
      series, sites numbers 5 through 7 were located 1.0-1.3 km away from the Rubber
      Plant and the third series, sites numbers 8 though 10 were situated 1.5 km from
      the chemical plant and the monitoring plants were elevated at 5, 13, and 32 m
      above ground. A control group of plants were grown in a greenhouse about 13 km
      away from the polluted air from the chemical plant. Results of these two
      consecutive year's study show significantly elevated high levels of pink mutation
      events (PME) over the control at sites 1, 2, and 4 in the first series of the
      study. Positive responses were observed at all sites in the second series of the
      study. Only site 8 (June 1991) in the third series of the study was significantly
      higher in PME over the control.

PMID- 10350583
TI  - Genotoxicity of water samples from Dianchi lake detected by the Vicia faba
      micronucleus test.
AB  - Dianchi Lake covers about a 300 km2 area. Kunming city on the edge of the lake is
      surrounded by industrial establishments. Farm land surrounds the remaining areas
      of the lake. The lake water is polluted by the Kunming city municipal sewage from
      3 million inhabitants, the industrial effluent and farm runoff. Water samples
      were collected from 12 sites along the shore of the lake during the dry (May) and
      rainy (August) seasons for genotoxicity testing with the Vicia micronucleus assay
      during the year 1995. Genotoxicity in terms of micronuclei (MCN) frequencies in
      the root tip cells of Vicia showed a consistent elevated frequency of MCN over
      the control sample at the 0.05-0.01 levels of significance in both seasons. The
      MCN frequencies of sites A (Daguanhe), B (Gaoqiao) and C (Xiyuan) were 3.5-4
      times as high as the control values (5.25/1000 cells) in the dry season. In the
      rainy season, the MCN frequencies of water samples from most of the 12 sites were
      relatively lower than those of the dry season except sites J (Haikou), and K
      (Kunyang). The average MCN frequency of the dry season samples was 14.97 per 1000
      cells and that of the rainy season samples was 12.24 per 1000 cells while the
      average control value was around 5.00/1000 cells.

PMID- 10350584
TI  - Tradescantia bioassays for the determination of genotoxicity of water in the
      Panlong River, Kunming, People's Republic of China.
AB  - The Panlong river passes through Kunming City and receives a large quantity of
      municipal sewage and wastewater from industrial effluent. Along the river, 20
      sites were selected to collect water samples to assess the genotoxicity using two
      Tradescantia assays, the micronucleus (Trad-MCN) and the stamen-hair-mutation
      (Trad-SHM) assays. The lowest frequencies in the Trad-MCN assay and the Trad-SHM
      assay are 3.19 MCN/100 tetrads and 1.32 M/1000 stamen hairs, respectively. In the
      water samples obtained from the Songhua Reservoir, the MCN frequencies and
      mutation rates are not statistically significantly different from the data found
      for the negative control (2.49 MCN/100 tetrads and 0.71 M/1000 stamen hairs).
      Among the other water samples, 19 in Trad-MCN assay and 17 in Trad-SHM assay show
      significantly higher genotoxicity than the control. The highest genotoxicity was
      in samples No. 19 for the MCN assay (8.73 MCN/100 cells), over three times higher
      than the negative control, and in sample No. 11 for the SHM assay (4.30 M/1000),
      six times higher than the negative control, and were about the same as for the
      positive control (10.0 mg/l NaN3, 9.28 MCN/100 tetrads and 7.44 SHM/1000 stamen
      hairs), respectively. The peak frequencies for the Trad-MCN assays were observed
      in the water samples obtained from the sites that were near industrial and
      municipal wastewater that ran into the river as effluent. In general, the
      frequency of MCN and SHM mutations increased where the river passed through
      Kunming. The Trad-MCN assay seemed more sensitive than that of the Trad-SHM assay
      in detecting genotoxicity of the river water pollution.

PMID- 10350585
TI  - Vicia root-micronuclei assays on the clastogenicity of water samples from the Kui
      River near Xuzhou city, People's Republic of China.
AB  - The Vicia root-micronucleus (VR-MCN) bioassay was used to determine the
      genotoxicity of water samples collected from the Kui River near Xuzhou city,
      China. Results show that all water samples induced elevated MCN frequencies over
      background. This indicates that the river water was polluted with genotoxic
      material. The source of pollutants in this river is discussed.

PMID- 10350586
TI  - Genetoxicity of water samples from the scenic Lijang river in the Guilin area,
      China, evaluated by Tradescantia bioassays.
AB  - The Lijang river which passes through the Guilin mountains, and Guilin city is a
      world renowned scenic spot on the southwest border of China. The river and its
      tributaries receive water from the mountain tops and springs underground. The
      river water was clean two decades ago before the development of industrial
      establishments and extra heavy tourism. Deforestation over the mountain tops on
      the upper stream and its tributaries in the last decades has created serious
      erosion and increased sedimentation in the river. In the present study, the
      Tradescantia micronucleus (Trad-MCN) and Tradescantia stamen hair mutation (Trad
      SHM) assays were used to evaluate the genetoxicity of water samples collected
      from 60 different sites along the river. Results indicate that most of the water
      samples from the tributaries were highly mutagenic, and that pollutants had
      accumulated in the main river in the Guilin city area from the industrial
      effluent and city sewage. Both the Trad-MCN and Trad-SHM assays were highly
      effective for the detection of mutagens in the water samples.

PMID- 10350587
TI  - Vicia root micronucleus assay on the clastogenicity of water samples from the
      Xiaoqing River in Shandong Province of the People's Republic of China.
AB  - Vicia root micronucleus assay was used to determine the clastogenicity of water
      samples from Xiaoqing River that passes through Jinan City. Positive results were
      obtained from eight water collecting sites. This indicates that the water in most
      areas of this river was polluted with industrial waste and municipal sewage.
      Results of this study proves that biomonitoring with Vicia root micronucleus test
      is an efficient way to assess the water quality of this river.

PMID- 10350588
TI  - Clastogenicity of chromium contaminated soil samples evaluated by Vicia root
      micronucleus assay.
AB  - Chromium compounds have been known to be highly toxic in biological systems and
      to some individuals act as strong allergens. A chromium processing plant in
      Tianjin city has been abandoned for many years and the chromium residue has been
      dispersed into the nearby soil. This study was designed to detect the
      genotoxicity of contaminated soil samples collected at various distances of 100
      to 1000 m from the source using the Vicia faba root micronucleus test. Water
      solutions extracted from the soil samples were used to treat the roots of the
      Vicia beans. Micronuclei frequencies observed from the root meristems were used
      to determine the degree of genotoxicity. Micronuclei frequencies of the
      contaminated soil samples show linear dose responses to chromium contents in the
      soil, which were inversely proportional to the distance from the source.

PMID- 10350589
TI  - The Tradescantia-micronucleus test on the genotoxicity of UV-B radiation.
AB  - Lanzhou city is located in north central China near inner Mongolia. The solar UV
      B background radiation in this area is occasionally extremely high (8
      microW/cm2). Such high background solar UV-B radiation could be attributed to the
      sporadic depletion of the ozone layer in the stratosphere. The excessive UV-B
      radiation is a potential hazard in the environment. This prompted the present
      study on the effect of UV-B radiation on the cytogenetic damage to pollen mother
      cells of the plant Tradescantia. The Tradescantia-micronucleus (Trad-MCN) test
      was used to determine the genotoxicity of UV-B radiation. In addition to the
      usual 10 h of solar emission of UV light a series of increasing dosages (2, 4, 6,
      8 h) of artificial UV-B radiation was applied to Tradescantia (clone 3) plant
      cuttings. Inflorescences of the treated and control plants were fixed and used
      for preparation of microslides. Micronuclei frequencies were observed in the
      early tetrads to show the degree of genotoxicity. Results of two repeated
      experiments show a dose-related increase of MCN frequencies under normal sunshine
      days. In the third experiment conducted under a cloudy and rainy day and an
      extraordinary high solar UV-B background, the MCN frequencies were markedly
      higher than that of the negative control but did not show the clear dose response
      to the treatment as in the first two experiments. The Trad-MCN test has
      successfully detected the effect of artificial UV-B radiation over the solar UV-B
      background radiation.

PMID- 10350590
TI  - Tradescantia-micronucleus assay on the water quality of lake Hongzhe in Jiangsu
      Province, China.
AB  - Lake Hongzhe, located in the northwest part of the Province of Jiangsu, is one of
      the five largest freshwater lakes in China. It has great economic importance for
      the fishery industry and for scenic beauty. Effluents from the industrial
      development and runoff from farm chemicals have contributed increasingly to the
      water pollutants in recent years. For many years, water quality has been
      monitored only by chemical analysis. No information is provided from the chemical
      analysis on the toxicity level of the aquatic forms in the lake and the
      ecosystems that directly or indirectly depend upon this water. In the present
      study, some chemical components were determined from water samples collected from
      the lake and in addition, the genotoxicity of the same water samples was
      determined using the Tradescantia-micronucleus bioassay. Results confirmed that
      the quantity of pollutants in the water bears some relationship with the
      genotoxicity in terms of chromosome damage. High nitrates and nitrogen content
      were the main contributing factors observed. The use of bioassays such as the
      Tradescantia-micronucleus test together with chemical analyses to monitor the
      water quality is highly recommended for the general practice for the
      environmental monitoring stations through the country.

PMID- 10350591
TI  - Pollution monitoring of three rivers passing through Fuzhou City, People's
      Republic of China.
AB  - The Tradescantia-micronucleus (Trad-MCN) bioassay was used to determine the
      pollution levels of three rivers passing through Fuzhou city. Results indicate
      that all three rivers are polluted but at different levels. They are ranked as
      follows: Antai River > Baima River > Jinan River. Positive results were obtained
      when full strengths of the water samples were used to treat the plant cuttings
      when compared with the negative control (tap water) group. Negative responses
      were obtained when the Baima and Jinan river water was diluted to 50% but not for
      the sample from the Antai river. Micronuclei frequencies of the Antai river group
      were higher than the positive control using the Ping-Yang antibiotic drug (Huapei
      Drug Manufacturer) at 0.2 microg/ml concentration.

PMID- 10350592
TI  - Monitoring the genotoxicity of soil extracts from two heavily polluted sites in
      Prague using the Tradescantia stamen hair and micronucleus (MNC) assays.
AB  - We have taken soil samples from two sites in Prague, the capital of the Czech
      Republic, that are heavily polluted by motor vehicles. As a negative control,
      soil samples from a recreational site in Prague with no motor vehicle traffic
      were used. Soil samples from these sites were extracted with water or 5%
      dimethylsulphoxide (DMSO) for 24 h and cuttings of Tradescantia clone 4430 were
      immersed for 12 h at 25 degrees C in the extraction solutions. As a positive
      control Tradescantia plants have been treated with the promutagenic arylamine o
      phenylenediamine at the same treatment conditions. None of the tested soil
      extractions significantly increased the frequency of somatic mutations in the
      stamen hair assay. By contrast, a 5% DMSO soil extract from one of the tested
      sites (entrance of the Letna tunnel) significantly increased the frequency of
      micronuclei (MNC) in the pollen mother tetrad cells. A repetition of the
      treatment 14 days later also resulted in an increase in the frequency of MNC,
      however the increase was not statistically significant. This study was conducted
      for the International Programme on Plant Bioassays.

PMID- 10350593
TI  - Assessment of the genotoxicity of contaminated soil with the Allium/Vicia
      micronucleus and the Tradescantia-micronucleus assays.
AB  - The present study concerns the genotoxicity of contaminated soil near Metz,
      France. Three plant bioassays, the Vicia faba (broad bean), the Allium cepa
      (white onion) and the Tradescantia (spiderwort) micronuclei tests were used to
      evaluate for genotoxicity. Two soil samples were tested: soil sample A (from an
      industrial waste site) and soil sample B (from a cokeworks waste site). Maleic
      hydrazide was used as the positive control. Aqueous extracts of the soil samples
      were used to treat the roots of Vicia and Allium, and plant cuttings of
      Tradescantia according to the standard protocol for these plant assays
      established by the International Program on Chemical Safety and the World Health
      Organization. The results of these tests showed differential sensitivity in the
      three different bioassays. Soil sample A was more toxic than soil sample B.

PMID- 10350594
TI  - Assessment of the genotoxicity of mine-dump material using the Tradescantia
      stamen hair (Trad-SHM) and the Tradescantia-micronucleus (Trad-MCN) bioassays.
AB  - The Tradescantia-stamen hair (Trad-SHM) and -micronucleus (Trad-MCN) bioassays
      were used to determine the genotoxicity of two eluates derived from mine
      tailings. The goal was to test the suitability of the Tradescantia bioassays as
      screening tools for this kind of waste material. Leachates obtained using the
      current standard German leaching test methods (S4 eluate) as well as leachates
      obtained using a new eluation method (pHstat4) were tested and compared.
      Concentration of heavy metals in the pHstat4 eluate were much higher than in the
      S4 eluate. The chemical analysis corresponded well with the results of the
      bioassays. Exposure to solutions containing more than 1% pHstat4 eluate caused a
      significantly higher number of micronuclei. The Trad-SHM bioassay also showed an
      increased pink mutation rate when plants were exposed to 8 or 16% eluate
      solutions. In contrast, the S4 eluate only caused increased mutation rates when
      solutions containing more than 32% eluate were used. The low pH of the pHstat4
      eluate was not responsible for the genotoxicity observed using both bioassays, as
      indicated by the lack of significant mutation rates in the nitric acid controls.
      This demonstrates that the Tradescantia bioassays can be used as tools to assess
      the genotoxic potential of environmental samples with a wide range of pH values,
      without the need for sample modification.

PMID- 10350595
TI  - Genotoxicity of wastewater samples from sewage and industrial effluent detected
      by the Allium root anaphase aberration and micronucleus assays.
AB  - The genotoxicity of wastewater samples from sewage, and industrial effluent from
      the Amritsar, India, area were investigated using the Allium micronucleus and
      anaphase aberration assays. Raw sewage samples and acetone extracts of the
      dehydrated sewage were use for treatment of the Allium roots. Industrial
      effluents were collected and stored in the form of sludge (semi-dried matter).
      The acetone extracts of the sludge samples were also used for treatment of the
      Allium roots. From the Allium root micronuclei tests on the sewage extracts, no
      significant increase in the number of micronuclei was found in comparison with
      negative controls. All the other extracts from industrial effluent showed
      positive responses both in the micronucleus and anaphase aberration assays.

PMID- 10350596
TI  - Monitoring of mutagens in urban air samples.
AB  - This research was designed to examine the presence of mutagenic/carcinogenic
      compounds in urban airborne particulates sampled with the inhalable PM-10 high
      volume sampler in two different streets of Brescia, a heavily industrialized town
      in northern Italy, using the Tradescantia/micronucleus test and a bacterial
      mutagenicity test (Kado test, a more sensitive version of the Ames test). In
      addition, the Tradescantia/micronucleus test was used for in situ monitoring of
      gaseous pollutants in other urban areas of Brescia and in two car tunnels, one
      with heavy car traffic in Perugia, a town in central Italy, and one in Brescia
      with moderate traffic. The Tradescantia-micronucleus test carried out on extracts
      of airborne particulates gave positive results only for the sample collected in
      the traffic-congested street where also higher bacterial mutagenicity was found.
      The in situ monitoring of the urban areas with the Tradescantia/micronucleus test
      always gave negative results. Monitoring carried out in the two car tunnels
      showed a significant increase in micronuclei frequency only in flowers exposed in
      the smaller and more polluted tunnel.

PMID- 10350597
TI  - Tradescantia-micronucleus and -stamen hair mutation assays on genotoxicity of the
      gaseous and liquid forms of pesticides.
AB  - The clastogenic and mutagenic effects of the insecticide Dimethoate (Cygon-2E),
      herbicides Atrazine, Simazine (Princep), Dicamba (Banvel D) and Picloram (Tordon)
      were studied using the Tradescantia-micronucleus (Trad-MCN) and Tradescantia
      stamen hair mutation (Trad-SHM) assays. In clone 4430, dimethoate fumes both
      significantly increased the pink mutation events and reduced the number of stamen
      hairs per filament with increasing dosages. The pink mutation events were
      elevated by the liquid treatment with Picloram at 100 ppm concentration. The
      result of Trad-MCN test on Dimethoate fumes was not significantly different
      between the control and treated groups. The herbicide Atrazine showed positive
      effects at 10-50 ppm dose (liquid) and signs of overdose at 100 and 500 ppm
      concentrations. Simazine was mildly positive in elevating the MCN frequencies in
      the dose range of 5 to 200 ppm (liquid doses). Both Dicamba and Picloram induced
      a dosage-related increase in MCN frequencies in the Trad-MCN tests using
      Tradescantia clone 03. However, in higher dosages (200 ppm or higher), there were
      signs of overdose, reduction of MCN frequencies and physical damage of the leaves
      and buds of plant cuttings.

PMID- 10350599
TI  - Genotoxicity of leachates from a landfill using three bioassays.
AB  - In the city of Queretaro, around 500 tons of solid wastes are produced everyday
      and are deposited in a landfill. This is the result of social and economic
      activities of human beings or from their normal physiological functions. As a
      result of rain, leachates are produced, which, if not handled and treated
      correctly, may pollute the underground water. Among the bioassays developed for
      the detection of mutagenicity in environmental pollutants, plant systems have
      been proven to be sensitive, cheap, and effective. The purpose of this study was
      to determine the presence of genotoxic agents in the leachates of the landfill of
      the city using three bioassays: Tradescantia-micronucleus (Trad-MCN),
      Tradescantia stamen hair mutations (Trad-SHM) and Allium root anaphase
      aberrations (AL-RAA) and make a comparison of the results in the three assays.
      Leachates were sampled during both the dry and rainy seasons. Plant cuttings of
      Tradescantia or the roots of Allium were treated by submerging them in the
      leachates. Three replicates of each sample were analyzed in each of the three
      bioassays. As expected the samples of leachates collected during the dry season
      showed a higher genotoxicity than those collected during the rainy season. In
      conclusion, there are substances present in the leachates capable of inducing
      genotoxicity in the plant assays. On the other hand, the plant assays showed
      different degrees of sensitivity: the more sensitive was the Trad-MCN bioassay
      and the less sensitive the Trad-SHM assay. Therefore, when analyzing
      environmental pollutants it is recommended to use a battery of bioassays.

PMID- 10350598
TI  - Genotoxicity of the extracts from the compost of the organic and the total
      municipal garbage using three plant bioassays.
AB  - The production of compost is one of the alternatives for the disposal of non
      hazardous solid wastes. Compost is used in agriculture and gardening as
      fertilizer. In the State of Queretaro, Mexico, there is a project to produce
      compost from the municipal garbage which could be used as a fertilizer. The
      presence of mutagenic compounds in the compost could be a major disadvantage for
      the selection of this alternative. For the above reason, this study was initiated
      as a pilot project to determine the potential mutagenic activity in the compost
      using three plant bioassays: Tradescantia-micronucleus (Trad-MCN), Tradescantia
      stamen hair mutations (Trad-SHM) and Allium root anaphase aberrations (AL-RAA).
      Compost was produced using both aerobic and anaerobic processes from either
      organic waste (from the residential area) or from the total components of the
      municipal garbage. Extractions from the compost were done using distilled water
      and organic solvents and shaking the sample for about 12 h under relatively low
      temperatures (15-20 degrees C). Plant cuttings of Tradescantia or the roots of
      Allium were treated by submerging them in the extracts. Three replicates of each
      sample were analyzed in each one of the three bioassays. As expected the samples
      of compost from the total garbage showed a higher genetoxicity than those from
      organic waste. In conclusion, there are some substances present in the compost
      capable of inducing genotoxicity in the plant assays and therefore there must be
      some restrictions for its use as a fertilizer.

PMID- 10350600
TI  - Genotoxicity of soil from farmland irrigated with wastewater using three plant
      bioassays.
AB  - Three well known plant bioassays, the Allium root chromosome aberration (AL-RAA)
      assay, the Tradescantia micronucleus (Trad-MCN) assay, and the Tradescantia
      stamen hair (Trad-SHM) mutation assay were validated in 1991 by the International
      Programme on Chemical Safety (IPCS) under the auspices of the World Health
      Organization, and the United Nations Environment Programme (UNEP). These plant
      bioassays have proven to be efficient tests for chemical screening and especially
      for in situ monitoring for genotoxicity of environmental pollutants. As a result
      of this validation study, standard protocols of these three plant bioassays were
      used by some of the 11 participating countries in the IPCS to carry on
      genotoxicity tests on air, water and soil as a follow up activity. In the city of
      Queretaro, Mexico, wastewater coming from both industrial and domestic sources
      and without any treatment is used to irrigate the farm crops, polluting the soil.
      Potentially the pollutants could reach the food chain. For the above reason, soil
      irrigated with wastewater was sampled and monitored for the presence of genotoxic
      agents using the above three bioassays. Extracts from soil samples were made
      using distilled water and organic solvents by shaking the sample for about 12 h
      under a relatively low temperature (15-20 degrees C). Plant cuttings of
      Tradescantia or the roots of Allium were treated by submerging them in the
      extracts. Three replicates of each sample were analyzed in each of the three
      bioassays. Extracts using DMSO, ethanol and distilled water tested positive in
      the three bioassays and there were no differences for the genotoxicity of the
      extracts with the different solvents.

PMID- 10350601
TI  - Genetic effects observed in tetrads of Tradescantia induced by radon.
AB  - Inflorescences of Tradescantia clone 4430 were exposed to different
      concentrations of radon (Rn) gas (0.85, 12.10, 36.50 and 98.16 kBq/m3) from
      plants placed in an acrylic chamber that received radon from a container with
      pitchblende (containing uranium mineral). The exposure time was 24 h, afterwards
      the plants were left for 6 h in water and constantly aerated. Positive control
      plants were irradiated with gamma rays (0.8 Gy) and negative control plants
      received ambient air only (the background measurement had a mean of 0.38 kBq/m3).
      Micronuclei (MCN) in the tetrads induced by alpha particles emitted from Rn were
      tabulated and a linear concentration response was obtained. The potency of radon
      to induce MCN from the slope of the regression line was 0.13 MCN/kBq/m3 of alpha
      radiation. Radon could reach the anthers by diffusion through the aerial spaces
      within the buds.

PMID- 10350602
TI  - Genotoxicity of contaminated soil and shallow well water detected by plant
      bioassays.
AB  - Three major plant bioassays, i.e., the Allium root anaphase aberration (Allium
      AA), the Tradescantia-micronucleus (Trad-MCN) and the Tradescantia stamen hair
      mutation (Trad-SHM) tests, were utilized in soil solutions or shallow well water
      samples to determine the degree of their genotoxicity. Shallow well water samples
      were collected from five different farms, and soil solutions were extracted with
      distilled water or dimethyl sulfoxide (DMSO) from pesticide-contaminated
      (metolachlor, atrazine, extrazine, and 2, 4-D) and pesticide-free soil samples.
      Genotoxicity was expressed in terms of anaphase aberration (AA) frequencies in
      the Allium-AA test, in terms of micronuclei frequencies in the Trad-MCN test, and
      in terms of pink mutation events in the Trad-SHM test. On average, results of
      Allium-AA tests showed a 2.78-3.01 fold increase in anaphase aberration
      frequencies in contaminated soil solution samples and well water samples as
      compared with the negative control. Results of Trad-MCN tests showed a 1.66-4.75
      fold increase of MCN frequencies in contaminated soil solution samples and
      shallow well water samples as compared with the frequencies of the controls.
      Results of Trad-SHM tests showed a 2.7-2.86 fold increase of pink mutation events
      in the contaminated soil solution samples over that of the controls. Control
      groups of the Allium-AA tests had an average of 0.75/1000 anaphase figures, and
      control groups of the Trad-MCN tests had an average of 3.2 MCN/100 tetrads, while
      control groups of the Trad-SHM tests had an average of 1.4 mutation events/1000
      hairs. In general, soil solutions of DMSO extracts showed higher genotoxicity
      than that of distilled water extracts. Among these three plant bioassays, the
      Trad-MCN test has the highest efficiency. The highest toxicity, based upon the
      Trad-MCN test results, was found in the pesticide contaminated soil samples from
      Monroe's farm. Water samples from the Fountain Green/Bushnell area ranked second
      in genotoxicity.

PMID- 10350603
TI  - Exploring the clastogenic effects of air pollutants in Sao Paulo (Brazil) using
      the Tradescantia micronuclei assay.
AB  - This study was designed to determine the clastogenicity of particulate matter
      (aerodynamic diameter smaller than 10 microm) in the urban polluted air in the
      city of Sao Paulo. The Tradescantia-micronucleus (Trad-MCN) assay was used
      throughout this study to evaluate the clastogenicity of the extracts of the
      particulate matter. Tradescantia pallida (Rose) Hunt. cv. purpurea, an indigenous
      cultivar, was used in the Trad-MCN assay. The efficacy of this plant material for
      the Trad-MCN assay was validated with dose-response studies using formaldehyde
      and beta radiation. Dose-response curves were established with these known
      mutagens. The extracts of the PM10 particles at concentrations between 5 and 50
      ppm induced a dose-related increase in MCN frequencies. The results indicate that
      T. pallida is equally sensitive to mutagens as the standard Tradescantia clone
      4430 or 03 and the particulate matter in the urban air are clastogenic to the
      chromosomes of this plant. Inhalation of these particles by urban dwellers may
      affect their health by inducing similar genetic damage.

PMID- 10350604
TI  - Thermodynamics of nucleotide binding to the chaperonin GroEL studied by
      isothermal titration calorimetry: evidence for noncooperative nucleotide binding.
AB  - We characterized the thermodynamics of binding reactions of nucleotides ADP and
      ATPgammaS (a nonhydrolyzable analog of ATP) to GroEL in a temperature range of 5
      degrees C to 35 degrees C by isothermal titration calorimetry. Analysis with a
      noncooperative binding model has shown that the bindings of nucleotides are
      driven enthalpically with binding constants of 7x103 M-1 and 4x104 M-1 for ADP
      and ATPgammaS, respectively, at 26 degrees C and that the heat capacity change
      DeltaCp is about 100 cal/mol.K for both the nucleotides. The stoichiometries of
      binding were about 8 and 9 molecules for ADP and ATPgammaS, respectively, per
      GroEL tetradecamer at 5 degrees C, and both increased with temperature to reach
      about 14 (ADP) and 12 (ATPgammaS) for both nucleotides at 35 degrees C. The
      absence of initial increase of binding heat as well as Hill coefficient less than
      1.2, which were obtained from the fitting to the model curve by assuming positive
      cooperativity, showed that there was virtually no positive cooperativity in the
      nucleotide bindings. Incorporating a difference in affinity for the nucleotide
      (ADP and ATPgammaS) between the two rings of GroEL into the noncooperative
      binding model improved the goodness of fitting and the difference in the affinity
      increased with decreasing temperature.

PMID- 10350605
TI  - Binding of polylysine to GroEL. Inhibition of the refolding of mMDH.
AB  - Luminescence techniques have been used to investigate the interaction of GroEL
      with polylysine tagged with a fluorescent probe. The fluorescence emitted by
      anthraniloyl-polylysine, upon excitation at 320 nm, is enhanced by the addition
      of stoichiometric amounts of GroEL. The equilibrium dissociation constant of the
      complex (Kd=50 nM) was determined by fluorometric titrations. The rate and extent
      of recovery of the catalytic activity of denatured mitochondrial malate
      dehydrogenase, assisted by GroEL, is influenced by either polylysine or
      anthraniloyl-polylysine. It is suggested that interaction of the positively
      charged poly-amino acid with the apical domain of GroEL prevents binding of the
      unfolded protein substrate.

PMID- 10350606
TI  - Binding modes of a new epoxysuccinyl-peptide inhibitor of cysteine proteases.
      Where and how do cysteine proteases express their selectivity?
AB  - Papain from Carica papaya, an easily available cysteine protease, is the best
      studied representative of this family of enzymes. The three dimensional structure
      of papain is very similar to that of other cysteine proteases of either plant
      (actinidin, caricain, papaya protease IV) or animal (cathepsins B, K, L, H)
      origin. As abnormalities in the activities of mammalian cysteine proteases
      accompany a variety of diseases, there has been a long-lasting interest in the
      development of potent and selective inhibitors for these enzymes. A covalent
      inhibitor of cysteine proteases, designed as a combination of epoxysuccinyl and
      peptide moieties, has been modeled in the catalytic pocket of papain. A number of
      its configurations have been generated and relaxed by constrained simulated
      annealing-molecular dynamics in water. A clear conformational variability of this
      inhibitor is discussed in the context of a conspicuous conformational diversity
      observed earlier in several solid-state structures of other complexes between
      cysteine proteases and covalent inhibitors. The catalytic pockets S2 and even
      more so S3, as defined by the pioneering studies on the papain-ZPACK, papain-E64c
      and papain-leupeptin complexes, appear elusive in view of the evident flexibility
      of the present inhibitor and in confrontation with the obvious conformational
      scatter seen in other examples. This predicts limited chances for the development
      of selective structure-based inhibitors of thiol proteases, designed to exploit
      the minute differences in the catalytic pockets of various members of this
      family. A simultaneous comparison of the three published proenzyme structures
      suggests the enzyme's prosegment binding loop-prosegment interface as a new
      potential target for selective inhibitors of papain-related thiol proteases.

PMID- 10350607
TI  - Functionally important residues tyrosine-171 and serine-158 in sepiapterin
      reductase.
AB  - The active site of sepiapterin reductase (SPR), which is a member of the NADP(H)
      preferring short-chain dehydrogenase/reductase (SDR) family and acts as the
      terminal enzyme in the biosynthetic pathway of tetrahydrobiopterin cofactor
      (BH4), was investigated by truncation and site-directed mutagenesis. The
      truncation mutants showed that N-terminal and C-terminal residues contribute to
      bind coenzyme and substrate, respectively. The mutant rSPRA29V showed decreased
      activity; however, the A-X-L-L-S sequence, which has been reported as a putative
      pterin binding site, was estimated to preferably work as a component in the
      region for binding coenzyme rather than substrate. Site-directed mutants of
      rSPRS158D, rSPRY171V, and rSPRK175I showed low, but significant, activity having
      similar Km values and kcat/Km values less than 25%, for both sepiapterin and
      NADPH. Both amino acids Tyr-171 and Ser-158 are located within a similar distance
      to the carbonyl group of the substrate in the crystal structure of mouse SPR, and
      the double point mutant rSPRY171V+S158D was indicated to be inactive. These
      results showed that Ser-158, Tyr-171, and Lys-175 contributed to the catalytic
      activity of SPR, and both Tyr-171 and Ser-158 are simultaneously necessary on
      proton transfer to the carbonyl functional groups of substrate.

PMID- 10350609
TI  - S' subsite mapping of serine proteases based on fluorescence resonance energy
      transfer.
AB  - A microassay based on fluorescence resonance energy transfer has been developed
      to determine the S' specificity of serine proteases. The protease-catalyzed acyl
      transfer from a fluorescing acyl donor ester to a P'1/P'2 variable hexapeptide
      library of nucleophiles labeled with a fluorescence quencher leads to an
      internally quenched peptide product and a fluorescent hydrolysis product. The
      amount of fluorescence quenching allows one to draw conclusions about the
      interaction of the nucleophile at the S' sites of the protease. o-Aminobenzoic
      acid and 3-nitrotyrosine were used as an efficient donor-acceptor pair for the
      resonance energy transfer. The P'1/P'2 variable hexapeptide library with the
      general structure H-Xaa-Ala-Ala-Ala-Tyr(NO2)-Gly-OH and H-Ala-Xaa-Ala-Ala
      Tyr(NO2)-Gly-OH, where Xaa represents Arg, Lys, Met, Phe, Ala, Gly, Ser, Gln and
      Glu, was prepared by solid-phase synthesis. Investigations of the S' specificity
      of trypsin, chymotrypsin and trypsin variants show that this assay is a fast and
      sensitive screening method for S' subsite mapping of serine proteases and is
      suitable for a high throughput screening. The assay might be useful for the
      development of restriction proteases and the estimation of yields in enzymatic
      peptide synthesis.

PMID- 10350608
TI  - Membrane topography of the renal phosphate carrier NaPi-2: limited proteolysis
      studies.
AB  - The rat sodium/phosphate cotransporter NaPi-2 is a 70 kDa polypeptide (p70) for
      which eight transmembrane segments have been predicted. We have shown that p70
      exists predominantly as p45 and p40 fragments which are linked by disulfide
      bonds. In this work, the p40 fragment, corresponding to the C-terminus of NaPi-2,
      was purified from renal brush-border membranes using non-reducing and then
      reducing column electrophoresis followed by enzymatic deglycosylation and SDS
      PAGE. The N-terminal sequence obtained for this fragment, VEAIG, indicates that
      the formation of p45 and p40 arises from the cleavage of p70 between arginine-319
      and valine-320. In order to determine the membrane topography of NaPi-2, brush
      border membrane vesicles were digested with various proteases and the transporter
      derived proteolytic peptides were subsequently identified by Western blotting
      using N- and C-terminal-directed antibodies. Our results lead us to propose an
      alternative topographical model in which p45 and p40 possess three transmembrane
      domains each and indicate that the processing site of p70 for the generation of
      p45 and p40 is localized in a large protein core facing the extracellular milieu.
      This localization of the cleavage site indicated that NaPi-2 could either be
      processed intracellularly by vesicular proteases or extracellularly by secretory
      proteases or by brush-border membrane ectoenzymes.

PMID- 10350610
TI  - Effect of acrylamide on aldolase structure. I. Induction of intermediate states.
AB  - Acrylamide is a fluorescence quencher frequently applied for analysis of protein
      fluorophores exposure with the silent assumption that it does not affect the
      native structure of protein. In this report, it is shown that quenching of
      tryptophan residues in aldolase is a time-dependent process. The Stern-Volmer
      constant increases from 1.32 to 2.01 M-1 during the first 100 s of incubation of
      aldolase with acrylamide. Two tryptophan residues/subunit are accessible to
      quenching after 100 s of aldolase interaction with acrylamide. Up to about 1.2 M
      acrylamide concentration enzyme inactivation is reversible. Independent analyses
      of the changes of enzyme activity, 1ANS fluorescence during its displacement from
      aldolase active-site, UV-difference spectra and near-UV CD spectra were carried
      out to monitor the transition of aldolase structure. From these measurements a
      stepwise transformation of aldolase molecules from native state (N) through
      intermediates: I1, T, I2, to denatured (D) state is concluded. The maxima of I1,
      T, I2 and D states populations occur at 0.2, 1.0, 2.0 and above 3.0 M of
      acrylamide concentration, respectively. Above 3.5 M, acrylamide aldolase
      molecules become irreversibly inactivated.

PMID- 10350611
TI  - Effect of acrylamide on aldolase structure. II. Characterization of aldolase
      unfolding intermediates.
AB  - Molecules of muscle aldolase A exposed to acrylamide change their conformation
      via I1, T, I2, D intermediates [1] and undergo a slow irreversible chemical
      modification of thiol groups. There is no direct correlation between activity
      loss and thiol groups modification. In the native enzyme two classes of Trp
      residues of 1. 8 ns and 4.9 ns fluorescence lifetime have been found. Acrylamide
      (0. 2-0.5 M) increases lifetime of longer-lived component, yet the transfer of
      aldolase molecules even from higher (1.0 M) perturbant concentration to a buffer,
      allows regain original Trp fluorescence lifetime. I1, detected at about 0.2 M
      acrylamide, represents low populated tetramers of preserved enzyme activity. T,
      of maximum population at about 0.7-1.0 M acrylamide, consists of meta-stable
      tetramers of partial enzymatic activity. These molecules are able to exchange
      their subunits with aldolase C in opposition to the native molecules. At
      transition point for I2 appearance (1.8 M acrylamide), aldolase becomes highly
      unstable: part of molecules dissociate into subunits which in the absence of
      perturbant are able to reassociate into active tetramers, the remaining part
      undergoes irreversible denaturation and aggregation. Some expansion of aldolase
      tetramers takes place prior to dissociation. D, observed above 3.0 M acrylamide,
      consists of irreversibly denatured enzyme molecules.

PMID- 10350612
TI  - Pyruvate phosphate dikinase from a thermophilic actinomyces Microbispora rosea
      subsp. aerata: purification, characterization and molecular cloning of the gene.
AB  - Various thermophilic bacteria were analyzed by Southern hybridization analysis
      using oligonucleotide probes coding for the pyruvate phosphate dikinase (PPDK)
      gene from Clostridium symbiosum, and positive hybridization signals were observed
      in the chromosomal DNAs from Microbispora rosea subsp. aerata (IFO 14047). PPDK
      activity was detected in lactose induced cells and the enzyme was purified to
      homogeneity. The molecular mass of PPDK was estimated to be 230000 by gel
      filtration chromatography and 91000 by SDS-PAGE, suggesting that PPDK is a
      dimeric enzyme. This enzyme was specific for adenine nucleotide and the apparent
      Km values for AMP, PPi, and phosphoenolpyruvate were 5, 38, and 280 microM,
      respectively. It was stable in the pH range 6 to 11, and retained 80% activity
      after 60 min heat treatment at 60 degrees C. We cloned the PPDK gene from M.
      rosea. It consists of 878 amino acids with a molecular mass of 95514. Sequence
      comparison indicates around 50% similarity with other PPDKs and it has all the
      highly conserved regions of the related enzymes. We expressed the PPDK gene in
      Escherichia coli and obtained enzymatically active protein.

PMID- 10350613
TI  - Interaction of FliI, a component of the flagellar export apparatus, with
      flagellin and hook protein.
AB  - FliI is a key component of the flagellar export apparatus in Salmonella
      typhimurium. It catalyzes the hydrolysis of ATP which is necessary for flagellar
      assembly. Affinity blotting experiments showed that purified flagellin and hook
      protein, two flagellar axial proteins, interact specifically with FliI. The
      interaction of either of the two proteins with FliI, increases the intrinsic
      ATPase activity. The presence of either flagellin or hook protein stimulates
      ATPase activity in a specific and reversible manner. A Vmax of 0.12 nmol Pi min-1
      microgram-1 and a Km for MgATP of 0.35 mM was determined for the unstimulated
      FliI; the presence of flagellin increased the Vmax to 0.35 nmol Pi min-1
      microgram-1 and the Km for MgATP to 1.1 mM. The stimulation induced by the axial
      proteins was fully reversible suggesting a direct link between the catalytic
      activity of FliI and the export process.

PMID- 10350614
TI  - Solution structure of alpha-conotoxin ImI determined by two-dimensional NMR
      spectroscopy.
AB  - The three-dimensional structure of alpha-conotoxin ImI, a potent antagonist
      targeting the neuronal alpha7 subtype of nicotinic acetylcholine receptor
      (nAChR), has been investigated by NMR spectroscopy. On the basis of 181
      experimental constraints, a total of 25 converged structures were obtained. The
      average pairwise atomic root mean square difference is 0.40+/-0.11 A for the
      backbone atoms. The resulting structure indicates the presence of two successive
      type I beta-turns and a 310 helix for residues Cys2-Cys8 and Ala9-Arg11,
      respectively, and shows a significant structural similarity to that of alpha
      conotoxin PnIA, which is also selective for the neuronal nAChR.

PMID- 10350615
TI  - Effect of self-association of alphas1-casein and its cleavage fractions alphas1
      casein(136-196) and alphas1-casein(1-197),1 on aromatic circular dichroic
      spectra: comparison with predicted models.
AB  - The self-association of native alphas1-casein is driven by a sum of interactions
      which are both electrostatic and hydrophobic in nature. The dichroism of aromatic
      side chains was used to derive regio-specific evidence in relation to potential
      sites of alphas1-casein polymerization. Near-ultraviolet circular dichroism (CD)
      revealed that both tyrosine and tryptophan side chains play a role in alphas1
      casein associations. Spectral evidence shows these side chains to be in an
      increasingly nonaqueous environment as both ionic strength and protein
      concentration lead to increases in the degree of self-association of the protein
      from dimer to higher oligomers. Near-UV CD investigation of the carboxypeptidase
      A treated peptide, alphas1-casein(1-197), indicated that the C-terminal residue
      (Trp199) may be superficial to these interactions, and that the region
      surrounding Trp164 is more directly involved in an aggregation site. Similar
      results for the cyanogen bromide cleavage peptide alphas1-casein(136-196)
      indicated the presence of strongly hydrophobic interactions. Association
      constants for the peptides of interest were determined by analytical
      ultracentrifugation, and also were approximated from changes in the near-UV CD
      curves with protein concentration. Sedimentation equilibrium experiments suggest
      the peptide to be dimeric at low ionic strength; like the parent protein, the
      peptide further polymerizes at elevated (0.224 M) ionic strength. The initial
      site of dimerization is suggested to be the tyrosine-rich area near Pro147, while
      the hydrophobic region around Pro168, containing Trp164, may be more significant
      in the formation of higher-order aggregates.

PMID- 10350616
TI  - Conformational analysis of the hydrophobic peptide alphas1-casein(136-196).
AB  - Hydrophobic interactions are important in the self-association of milk proteins,
      including alphas1-casein. The extent to which casein interaction sites are
      influenced by local secondary structure is not widely known. Both primary amino
      acid sequence and local secondary structure are shown to affect the self
      association of the hydrophobic peptide alphas1-casein(136-196). The peptide is
      aggregated at low concentrations (7 microM and above), as determined by 1H
      nuclear magnetic resonance (NMR) measurements at pH 6.0 in phosphate buffer.
      Increase in temperature is shown to induce side chain mobility (melting) as
      indicated by both 1H NMR and near-UV circular dichroism (CD) measurements. As
      determined by far-UV CD, there is also a loss in the global amount of extended
      structure with increasing temperature, while beta-turn structures and some
      aromatic dichroism are conserved at temperatures as high as 70 degrees C. Similar
      retention of structure occurs at pH 2 and in 6 M guanidine HCl. The observed
      stability of beta-turns and some side chains in alphas1-casein(136-196) supports
      previous assumptions that hydrophobic, proline-based turns are important
      interaction sites in the self-association of alphas1-casein, and possibly in the
      formation of the calcium transport complexes, the casein micelles. It may be
      speculated that these areas of the peptide represent a 'molten globule-like',
      heat stable, core structure for alphas1-casein.

PMID- 10350617
TI  - The insulin receptor tyrosine kinase domain in a chimaeric epidermal growth
      factor-insulin receptor generates Ca2+ signals through the PLC-gamma1 pathway.
AB  - The receptors for insulin (IR) and epidermal growth factor (EGFR) are members of
      the tyrosine kinase receptor (TKR) family. Despite homology of their cytosolic TK
      domains, both receptors induce different cellular responses. Tyrosine
      phosphorylation of insulin receptor substrate (IRS) molecules is a specific IR
      post-receptor response. The EGFR specifically activates phospholipase C-gamma1
      (PLC-gamma1). Recruitment of substrate molecules with Src homology 2 (SH2)
      domains or phosphotyrosine binding (PTB) domains to phosphotyrosines in the
      receptor is one of the factors creating substrate specificity. In addition, it
      has been shown that the TK domains of the IR and EGFR show preferences to
      phosphorylate distinct peptides in vitro, suggesting additional mechanisms of
      substrate recognition. We have examined to what extent the substrate preference
      of the TK domain contributes to the specificity of the receptor in vivo. For this
      purpose we determined whether the IR TK domain, in situ, is able to tyrosine
      phosphorylate substrates normally used by the EGFR. A chimaeric receptor,
      consisting of an EGFR in which the juxtamembrane and tyrosine kinase domains were
      exchanged by their IR counterparts, was expressed in CHO-09 cells lacking
      endogenous EGFR. This receptor was found to activate PLC-gamma1, indicating that
      the IR TK domain, in situ, is able to tyrosine phosphorylate substrates normally
      used by the EGFR. These findings suggest that the IR TK domain, in situ, has a
      low specificity for selection and phosphorylation of non-cognate substrates.

PMID- 10350618
TI  - EXAFS study of zinc coordination in bacitracin A.
AB  - Bacitracin is a dodecapeptide antibiotic produced by Bacillus sp. The
      antibacterial activity depends upon the peptide binding a divalent metal.
      Hitherto, the exact coordination of the cation has not been established. In
      particular the role played by the sulphur and nitrogen atoms of the thiazoline
      ring of bacitracin A has not been clear. Here the coordination of Zn2+ by
      bacitracin A has been studied using extended X-ray absorption fine structure. The
      experimental data are consistent with a model in which zinc is coordinated by one
      oxygen and three nitrogen atoms with the sulphur atom of the thiazoline ring not
      being directly involved in the zinc coordination.

PMID- 10350620
TI  - Structural properties of human glycodelin A in water and in water-alcohol
      mixtures: a comparison with bovine beta-lactoglobulin A.
AB  - Human glycodelin A (GdA) is a glycoprotein that is highly homologous to bovine
      beta-lactoglobulin A (beta-LgA) because the amino acid sequences are 50-60%
      identical. The structural characteristics of human GdA and beta-LgA were compared
      in water and 2-propanol/water solutions. Circular dichroism spectra reveal that
      in water the two proteins have a very similar beta-sheet secondary structure. In
      the presence of 2-propanol/water mixtures (up to 50% v/v) the alpha-helix
      structure of both proteins increases. A further increase in the alcohol
      percentage of the solvent (up to 80% v/v 2-propanol) causes the formation of a
      new folded tertiary structure containing mainly beta-sheet features. Synchrotron
      radiation small angle X-ray scattering indicates that, in a neutral pH aqueous
      solution, GdA is a dimer. Its radius of gyration value (Rg), 25.1+/-0.4 A, is
      greater than that of beta-LgA (21.1+/-0.3 A), probably because of the
      contribution of polysaccharides bound to Asn-28 and Asn-63 residues of GdA.
      Conversely, small angle X-ray scattering and gel permeation chromatography data
      on GdA in 2-propanol have revealed a massive aggregation of the protein.

PMID- 10350619
TI  - Characterisation of several Hsp70 interacting proteins from mammalian organelles.
AB  - Since both the spectrum and characteristics of in vivo substrates with affinity
      for Hsp70 members are largely unknown, we have investigated the range and type of
      mammalian organellar proteins which selectively interact with immobilised
      Escherichia coli Hsp70 (DnaK). Amongst a subset of organellar proteins
      selectively retained on DnaK, the major constituents represent unstable proteins
      and subunits of oligomeric proteins. The interactions with DnaK were diminished
      in the presence of mt-Hsp70 and BiP, while the complexes formed with DnaK were
      dissociated in the presence of K+ and GrpE-like co-chaperones, suggesting that
      these organellar proteins constitute general Hsp70 substrates. Protein sequence
      analysis identified the major DnaK interacting constituents as the mitochondrial
      transcription factor A, the alpha- (but not the beta-) subunit of succinyl CoA
      synthetase, mitochondrial 2,4-dienoyl CoA reductase, endoplasmic reticulum
      cyclophilin-B, peroxisomal multifunctional enzyme and a previously undescribed
      peroxisomal protein suspected to represent an isoform of 2,4-dienoyl CoA
      reductase. The selective retention of these fully synthesised proteins on Hsp70
      most likely reflects the function of this molecular chaperone in protein
      biogenesis, but additionally, could extend the known functions of Hsp70 to
      include modulating the activities of certain proteins or enzymes which are
      important in cellular homeostasis.

PMID- 10350621
TI  - NifL of Klebsiella pneumoniae: redox characterization in relation to the nitrogen
      source.
AB  - In Klebsiella pneumoniae, NifL modulates the activity of the transcriptional
      activator NifA in response to combined nitrogen or external molecular oxygen. We
      recently showed that K. pneumoniae NifL is a flavoprotein which apparently senses
      oxygen through a redox-sensitive, conformational change. In order to study
      whether the nitrogen signal might be transmitted to NifA through a stable
      modification of NifL we characterized the redox properties of NifL synthesized in
      Escherichia coli in the presence of different nitrogen sources. FAD analyses
      showed that purified NifL carried FAD as cofactor independent of nitrogen and
      oxygen availability. The redox potential of NifL synthesized in the presence of
      ammonium was -277+/-5 mV at pH 8.0 and 25 degrees C, as determined by reduction
      with dithionite or with enzymatic reduction by xanthine oxidase in the presence
      of methyl viologen as redox mediator. When synthesized under nitrogen-limiting
      conditions, NifL showed a redox potential of -274+/-6 mV at pH 8.0 and 25 degrees
      C. Fully reduced NifL fractions, synthesized under either condition listed above,
      reoxidized rapidly in the presence of molecular oxygen. These results indicate
      that for NifL synthesized in E. coli, the redox potential of the NifL-bound FAD
      is not influenced by the nitrogen source. The two NifL fractions differed,
      however, in that a non-flavin specific absorbance at 420 nm was found only in
      NifL synthesized in the presence of ammonium.

PMID- 10350622
TI  - Optimising the signal peptide for glycosyl phosphatidylinositol modification of
      human acetylcholinesterase using mutational analysis and peptide-quantitative
      structure-activity relationships.
AB  - Glycosyl phosphatidylinositol (GPI)-modified proteins have a C-terminal signal
      peptide (GPIsp) that mediates the addition of a GPI-anchor to an amino acid
      residue at the cleavage and modification site (omega-site). Within the GPIsp, a
      stretch of hydrophilic amino acid residues are found which constitutes the spacer
      region that separates the omega-site residue from a hydrophobic C-terminus.
      Deletions and insertions into the spacer region of human acetylcholinesterase
      (AChE) show that the length of this spacer region is very important for efficient
      GPI-modification. Surprisingly, the natural length of the spacer region in human
      AChE was not optimal for the highest degree of GPI modification. The importance
      of the two adjacent residues downstream of the omega-site, the omega+1 and
      omega+2 residues, was investigated by peptide-quantitative structure-activity
      relationships (Peptide-QSAR). A model was made that predicts the efficiency of
      the GPI modification when these residues are substituted with others, and
      suggests important features for these residues. The most preferred omega+1 and
      omega+2 residues, predicted by the model, in combination with an ideal spacer
      length resulted in an optimised GPIsp. This mutant protein is more efficiently
      GPI-modified than any mutant AChE tested thus far.

PMID- 10350624
TI  - Kinetic analysis on nitric oxide binding of recombinant Prolixin-S, a nitric
      oxide transport protein from the bloodsucking bug, Rhodnius prolixus.
AB  - Kinetics of the NO binding and removal reaction of recombinant Prolixin-S
      (rProlixin-S) were analyzed using stopped-flow spectrophotometry. The reaction
      was observed as a biphasic process. The rate constant of the fast phase increased
      linearly as NO concentration increased. The rate constant at the slow phase
      increased as NO concentrations increased at low NO concentration, then reached a
      plateau at high NO concentration. These NO dependencies of the reaction are
      characteristic of a bimolecular two-step consecutive reaction. The reaction
      consisted of the fast NO binding reaction of rProlixin-S and the following slow
      structural change of NO-protein complex. Kinetic studies revealed that the NO
      binding rate constant was independent of pH, but the rate constant of the NO
      removal reaction increased as pH increased. The apparent NO dissociation constant
      (Kd) of rProlixin-S was also calculated from the values of the kinetic parameters
      obtained in this work. The Kd value increased as pH and temperature increased.
      The Kd value of rProlixin-S and NO was 10-300 nM in regular physiological
      condition, which is 103 higher and 103 lower than those of the other ferric and
      ferrous hemoproteins and NO, respectively. These results indicate that Prolixin-S
      is one of NO transport proteins regulating blood pressure.

PMID- 10350623
TI  - Bradykinin modulates the ouabain-insensitive Na+-ATPase activity from basolateral
      membrane of the proximal tubule.
AB  - This paper studies the modulation by bradykinin of the ouabain-insensitive Na+
      ATPase activity in both renal cortex homogenate and basolateral membrane from
      proximal tubule. The increase in bradykinin concentration from 10-14 to 10-10 M
      stimulated the ouabain-insensitive Na+-ATPase activity in cortex homogenates
      about 2.2-fold, but inhibited the enzyme activity of basolateral membrane
      preparations by 60%. In both preparations, the maximal effect was obtained with
      10-10 M bradykinin. Further increase in the concentration of bradykinin
      completely abolished these effects. The antagonist of the B2 receptor, Hyp3,
      completely abolished the effect of 10-10 M bradykinin on the Na+-ATPase activity
      in the basolateral membrane preparation in a dose-dependent manner, but had no
      effect on the bradykinin stimulated enzyme activity of the cortex homogenate.
      Furthermore, in the presence of 10-7 M Hyp3, 10-10 M bradykinin stimulated the
      Na+-ATPase activity by 45% in the basolateral membrane preparations. The increase
      in des-Arg9-bradykinin concentration from 10-12 to 10-7 M, an agonist of the B1
      receptor, stimulated the Na+-ATPase activity of the cortex homogenates and of the
      basolateral membrane preparations by 105 and 148%, respectively. In the presence
      of 25 microM mergetpa, an inhibitor of kininase I, the increase in bradykinin
      concentration from 10-12 to 10-10 M promoted similar inhibition of the Na+-ATPase
      activity of both cortex homogenates and basolateral membrane preparations. These
      results suggest that bradykinin stimulated the Na+-ATPase activity of proximal
      tubule through the interaction with B1 receptors and inhibited the enzyme through
      the interaction with B2 receptors. Furthermore, the cortex homogenate expresses a
      kininase I activity that cleaves bradykinin to des-Arg9-bradykinin.

PMID- 10350625
TI  - Structure-reactivity probes for active site shapes of cholesterol esterase by
      carbamate inhibitors.
AB  - 4,4'-Biphenyl-di-N-butylcarbamate (1), (S)-1,1'-bi-2-naphthyl-2, 2'-di-N
      butylcarbamate (S-2), (S)-1, 1'-bi-2-naphthyl-2-N-butylcarbamate-2'-butyrate (S
      3), 2, 2'-biphenyl-di-N-butylcarbamate (4), 2, 2'-biphenyl-2-N-octadecylcarbamate
      2'-N-octylcarbamate (5), 2, 2'-biphenyl-2-N-octadecylcarbamate-2'-N
      phenylcarbamate (6), 2, 2'-biphenyl-2-N-butylcarbamate-2'-butyrate (7), 2, 2'
      biphenyl-2-N-butylcarbamate-2'-ol (8), 2, 2'-biphenyl-2-N-octylcarbamate-2'-ol
      (9), (R)-1, 1'-bi-2-N-naphthyl-2-butylcarbamate-2'-ol (R-10), and glyceryl-1,2, 3
      tri-N-butylcarbamate (11) are prepared and evaluated for their inhibition effects
      on porcine pancreatic cholesterol esterase. All inhibitors are irreversible
      inhibitors of the enzyme. Carbamates 1-3 and 7-10 are the first alkyl chain and
      esteratic binding site-directed irreversible inhibitors due to the fact that the
      reactivity of the enzyme is protected by the irreversible inhibitor,
      trifluoroacetophenone in the presence of these carbamates. Carbamate 1 is the
      least potent inhibitor for the enzyme probably due to the fact that the inhibitor
      molecule adopts a linear conformation and one of the carbamyl groups of the
      inhibitor molecule covalently interacts with the first alkyl chain binding site
      of the enzyme while the other carbamyl group of the inhibitor molecule exposes
      outside the active site. With near orthogonal conformations at the pivot bond of
      biaryl groups, one carbamyl group of carbamates S-2, S-3, and R-10 covalently
      binds to the first alkyl chain binding site of the enzyme while the other
      carbamyl, butyryl, or hydroxy group can not bind covalently to the second alkyl
      chain binding site probably due to the orthogonal conformations. Carbamates 4-9
      and 11 are very potent inhibitors for the enzyme probably due to the fact that
      all these molecules freely rotate at the pivot bond of the biphenyl or glyceryl
      group and therefore can fit well into the bent-shaped first and second alkyl
      chains binding sites of the enzyme. Although, carbamates 4-6 and 11 are
      irreversible inhibitors of cholesterol esterase, the enzyme is not protected but
      further inhibited by trifluoroacetophenone in the presence of these carbamates.
      Therefore, carbamates 4-6 and 11 covalently bind to the first alkyl chain binding
      site of the enzyme by one of the carbamyl groups and may also bind to the second
      alkyl chain binding site of the enzyme by the second carbamyl group. Besides the
      bent-shaped conformation, the inhibition by carbamate 6 is probably assisted by a
      favorable pi-pi interaction between Phe 324 at the second alkyl chain binding
      site of the enzyme and the phenyl group of the inhibitor molecule. For
      cholesterol esterase, carbamates 8-10 are more potent than carbamates S-2, 4, and
      5 probably due to the fact that the inhibitor molecules interact with the second
      alkyl chain binding site of the enzyme through a hydrogen bond between the phenol
      hydroxy group of the inhibitor molecules and the His 435 residue in that site.

PMID- 10350626
TI  - O-Crystallin, arginine kinase and ferritin from the octopus lens.
AB  - Three proteins have been identified in the eye lens of the octopus, Octopus
      dofleini. A 22 kDa protein comprising 3-5% of the soluble protein of the lens is
      35-43% identical to a family of phosphatidylethanolamine-binding proteins of
      vertebrates. Other members of this family include the immunodominant antigen of
      the filarial parasite, Onchocerca volvulus, putative odorant-binding proteins of
      Drosophila and a protein with unknown function of Caenorhabditis elegans. We have
      called this protein O-crystallin on the basis of its abundance in the transparent
      lens. O-Crystallin mRNA was detected only in the lens. Two tryptic peptides of
      another octopus lens protein, less abundant than O-crystallin, showed 80%
      identity to arginine kinase of invertebrates, a relative of creatine kinase of
      vertebrates. Finally, ferritin cDNA was isolated as an abundant cDNA from the
      octopus lens library. Northern blots showed that ferritin mRNA is not lens
      specific.

PMID- 10350627
TI  - cDNA sequence, mRNA expression, and chromosomal localization of human carbonic
      anhydrase-related protein, CA-RP XI.
AB  - A full-length cDNA clone of a human carbonic anhydrase-related protein, CA-RP XI
      encoded by CA11, was obtained and sequenced. The cDNA sequence was 1475 bp long
      and predicted to encode a 328-amino acid polypeptide with a molecular mass of
      36200 Da. The deduced amino acid sequence of CA-RP XI showed an overall
      similarity of 42-53% to the active site residues of other active CA isozymes;
      however, it lacked three zinc-binding histidine residues, raising questions
      regarding its CA catalytic activity. Northern blot analysis demonstrated strong
      expression of an approx. 1.5 kb transcript in the human brain, particularly in
      the cerebellum, cerebral cortex, and putamen. A single copy of the CA11 gene was
      localized to the human chromosome 19q13.2-3. These results suggest that CA-RP XI
      plays a general role in the human central nervous system.

PMID- 10350628
TI  - Cloning and preliminary characterization of a 121 kDa protein with multiple
      predicted C2 domains.
AB  - In the course of characterizing proteins present in a preparation of vesicles
      from rat adipocytes containing glucose transporters, we examined a protein that
      migrated at 115 kDa upon SDS gel electrophoresis (designated vp115). Sequences of
      tryptic peptides were obtained, and from this information the cDNA for rat vp115
      was cloned. The cDNA encodes an open reading frame for a protein of 121 kDa.
      Computer-aided sequence analysis predicted that vp115 has a potential membrane
      inserted or membrane-spanning domain toward its amino terminus, followed by five
      C2 domains. Immunoblotting revealed that vp115 was not actually a component of
      the glucose transporter-containing vesicles, was most abundant in the plasma
      membranes and high density microsome fractions of rat adipocytes, and was
      expressed in all the major rat tissues.

PMID- 10350629
TI  - Cloning and characterization of a 5.9 kb promoter region of the human pyruvate
      dehydrogenase alpha subunit gene.
AB  - A human genomic clone containing a 5.9 kb promoter region of the human pyruvate
      dehydrogenase (E1) alpha subunit gene (PDHA1) was isolated from a human X
      chromosome library. The nucleotide sequence showed two Alu repeats at the -2880
      and -2200 bp regions. Comparison between the -1400 bp E1alpha promoter and the 
      1241 bp E1beta promoter revealed a 57% homology, with a high degree of homology
      at the putative protein binding regions in these two promoters. Computer-aided
      transcription factor binding consensus sequence analysis revealed the presence of
      PPAR, HOXD, MyoD and other tissue-specific transcription factor binding sites.
      Promoter function analysis using the chloramphenicol acetyltransferase reporter
      gene indicated that the -2.2 kb/-1.7 kb and -5.9 kb/-5.2 kb regions of the
      E1alpha promoter may possess negative regulatory elements which are likely to
      function in a tissue-specific manner.

PMID- 10350630
TI  - Isolation and characterization of the gene encoding the starch debranching enzyme
      limit dextrinase from germinating barley.
AB  - The gene encoding the starch debranching enzyme limit dextrinase, LD, from barley
      (Hordeum vulgare), was isolated from a genomic phage library using a barley cDNA
      clone as probe. The gene encodes a protein of 904 amino acid residues with a
      calculated molecular mass of 98.6 kDa. This is in agreement with a value of 105
      kDa estimated by SDS-PAGE. The coding sequence is interrupted by 26 introns
      varying in length from 93 bp to 825 bp. The 27 exons vary in length from 53 bp to
      197 bp. Southern blot analysis shows that the limit dextrinase gene is present as
      a single copy in the barley genome. Gene expression is high during germination
      and the steady state transcription level reaches a maximum at day 5 of
      germination. The deduced amino acid sequence corresponds to the protein sequence
      of limit dextrinase purified from germinating malt, as determined by automated N
      terminal sequencing of tryptic fragments coupled with matrix assisted laser
      desorption mass spectrometry. The sequenced peptide fragments cover 70% of the
      entire protein sequence, which shows 62% and 77% identity to that of starch
      debranching enzymes from spinach and rice and 37% identity to Klebsiella
      pullulanase. Sequence alignment supports the multidomain architecture and
      identifies both secondary structure elements of the catalytic (beta/alpha)8
      barrel substrate, catalytic residues, and specificity associated motifs
      characteristic of members of the glycoside hydrolase family 13 which cleave alpha
      1,6-glucosidic bonds. A remarkable distribution of the secondary structure
      elements to individual exons is observed.

PMID- 10350631
TI  - Cloning, sequence analysis, and expression of the Pseudomonas putida 33/1 1H-3
      hydroxy-4-oxoquinoline 2,4-dioxygenase gene, encoding a carbon monoxide forming
      dioxygenase.
AB  - 1H-3-hydroxy-4-oxoquinoline 2,4-dioxygenase (Qdo) from the 1H-4-oxoquinoline
      utilizing Pseudomonas putida strain 33/1, which catalyzes the cleavage of 1H-3
      hydroxy-4-oxoquinoline to carbon monoxide and N-formylanthranilate, is devoid of
      any transition metal ion or other cofactor and thus represents a novel type of
      ring-cleavage dioxygenase. Gene qdo was cloned and sequenced. Its overexpression
      in Escherichia coli yielded recombinant His-tagged Qdo which was catalytically
      active. Qdo exhibited 36% and 16% amino acid identity to 1H-3-hydroxy-4
      oxoquinaldine 2,4-dioxygenase (Hod) and atropinesterase (a serine hydrolase),
      respectively. Qdo as well as Hod possesses a SXSHG motif, resembling the motif
      GXSXG of the serine hydrolases which comprises the active-site nucleophile
      (X=arbitrary residue).

PMID- 10350632
TI  - Differential regulation of mu-opioid receptor mRNA in the nucleus accumbens shell
      and core accompanying amphetamine behavioral sensitization.
AB  - Repeated amphetamine (AMPH) administration results in behavioral sensitization.
      To investigate the participation of the opioid system in this phenomenon, we
      examined the effects of acute and repeated AMPH administration on mu-opioid
      receptor (MOR) mRNA levels in the nucleus accumbens (NAc) and striatum (STR) of
      rats, by quantitative non-radioactive in situ hybridization. Five injections of d
      AMPH (1.5 mg kg-1, i.p., once every other day), resulted in a sensitization
      response profile and a significant down-regulation of MOR mRNA levels in the NAc
      shell, whereas no change was observed in MOR mRNA levels in the NAc core compared
      to the saline controls. Conversely, MOR mRNA levels were up-regulated in the
      rostral STR of AMPH-sensitized rats compared to saline controls. No changes in
      MOR mRNA levels were observed after acute AMPH treatment in any of the brain
      regions studied. These results suggest that the opioid system participates in the
      neurobiological underpinnings of behavioral sensitization and that opioid
      receptor (OR) expression in the STR and NAc shell and core is differentially
      modulated by repeated AMPH exposure.

PMID- 10350633
TI  - Localization of rabbit huntingtin using a new panel of monoclonal antibodies.
AB  - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder
      caused by the expansion of a CAG repeat which is expressed as a polyglutamine
      tract near the N-terminus of the gene product, huntingtin. N-terminal huntingtin
      fragments form intranuclear aggregates in HD patients and these may be involved
      in the pathogenesis. Monoclonal antibodies (mAbs) against three different regions
      of huntingtin (amino acids 997-1276, 1844-2131 and 2703-2911) have been produced
      and two of the epitopes have been identified using phage displayed peptide
      libraries. All mAbs reacted with 350 kDa huntingtin on Western blots and one mAb
      from each region was selected for further study by strong immunoreactivity with
      neurons in different regions of rabbit brain and by ability to immunoprecipitate
      native huntingtin. Subcellular fractionation and sucrose density centrifugation
      of rabbit brain extract showed that most of the huntingtin exists as a high
      molecular weight complex in the cytoplasm. Two outstanding problems have been
      addressed; the location of huntingtin in tissues outside the central nervous
      system and whether huntingtin is present in the nucleus of normal cells. We
      conclude that huntingtin is present at low levels in most non-neuronal cells
      though we have identified an interstitial cell type in skin with very high
      immunoreactivity. Using both immunolocalization and nuclear purification methods,
      we were unable to exclude the possibility that a small proportion of full-length
      huntingtin is present in the nucleus.

PMID- 10350634
TI  - Expression of p75(NTR), trkB and trkC in nonmanipulated and axotomized
      motoneurons of aged rats.
AB  - Several lines of evidence indicate that adult neurons remain dependent on
      neurotrophins and that changes in tissue expression of neurotrophins and/or their
      receptors may play a role in senile neurodegeneration. We have studied the
      expression of p75NTR, trkB and trkC, respectively, in lumbar motoneurons of young
      adult (2-3 months) and aged (30 months) rats subjected to sciatic transection
      using in situ hybridization and immunohistochemistry. Nonmanipulated age-matched
      animals were processed in parallel. In nonmanipulated aged rats, high levels of
      p75NTR could be seen in a number of motoneurons (10-15%), while in young adult
      animals no p75NTR could be detected. Seven days following sciatic axotomy, a
      conspicuous ipsilateral upregulation p75NTR was observed in young adult rats.
      Also in aged rats there was a marked ipsilateral increase in number of p75NTR
      expressing neurons ( approximately 100%). In comparison to young adult rats, aged
      rats showed a decreased expression of both trkB (5/6 animals) and trkC (6/6
      animals). Furthermore, in response to sciatic transection, 3 out of 5 aged rats
      did not show an increased expression of trkB. In aged rats, axotomy did not
      induce any significant change in trkC expression. In the young adult rats, we
      recorded a side-to-side effect with lower values ipsilaterally, however, it
      cannot be excluded that this difference was caused by an upregulation in the
      contralateral motoneurons. Oligonucleotide probes against BDNF and NT3 mRNA
      showed only very few faintly positive neurons in both age groups. Our results
      indicate that the pattern of regulatory changes of NT receptors in response to
      axotomy is different in aged and young adult rats. The lack of covariation
      between p75NTR and trkB and trkC regulation in aged rats indicates a changed role
      for p75NTR in senescent motoneurons.

PMID- 10350635
TI  - Promoter activity of mouse kappa opioid receptor gene in transgenic mouse.
AB  - The biological activity of mouse kappa opioid receptor (KOR) gene promoter was
      examined in transgenic mice using a beta-galactosidase (lacZ) reporter strategy
      for the first time. A lacZ cDNA was inserted at the 5th amino acid in the coding
      region of a mouse KOR genomic segment containing 3 kb of the 5' regulatory
      region, to generate a Kor-lacZ fusion gene which was then used to generate
      transgenic mice. The expression of transgene was demonstrated at the RNA level by
      reverse transcription-polymerase chain reaction (RT-PCR), and at the protein
      level by in situ lacZ enzyme assay. From studying three independent transgenic
      mouse lines that express this transgene, it is concluded that Kor-lacZ expression
      begins at embryonic day 9.5 (E9.5) and increases in several brain areas and
      neural tube as embryos develop. At E12.5 and E13.5, Kor-lacZ expression is found
      primarily in the mantle layer of midbrain, hindbrain and medulla oblongata,
      cranial ganglion and vagus nerve. At E15.5 and E17.5, the transgene is expressed
      in eye, ear, neopallial cortex, caudate putamen, lateral ventricle, thalamus,
      hypothalamus and pons. Therefore, the 3 kb 5' regulatory sequence of the mouse
      KOR gene is functional in transgenic animals and directs a specific expression
      pattern recapitulating that of the endogenous KOR gene expression during
      developmental stages. However, in adult animals, this transgene is only expressed
      in the brain, indicating that the regulatory information for peripheral
      expression in the adult is not encoded within this 3 kb upstream sequence.

PMID- 10350636
TI  - Transient expression of GABAA receptor subunit mRNAs in the cellular processes of
      cultured cortical neurons and glia.
AB  - In this study, we have studied by in situ hybridisation histochemistry the
      expression and intracellular distribution of the GABAA receptor subunit mRNAs in
      cultured neurons obtained from postnatal day 1-3 rats in order to determine how
      neurotransmitter receptor expression may be regulated during development of the
      nervous system. In postnatal cortical cells, we found that GABAA receptor subunit
      mRNAs coding for alpha2, alpha5, beta2, beta3 and gamma2 subunits were
      transiently expressed in the cellular processes and growth cones after 1-3 days
      in culture. These observations indicate that GABAA receptor subunit mRNAs are
      transported (or trafficked) into the cellular processes of early postnatal
      cortical cells. These selective localisations were rarely observed after 5 days
      in culture and only in cells which had not made cell-to-cell contact. The
      localisation of subunit mRNAs in the processes was more effectively maintained up
      to 5 days or even longer if cell-to-cell contact was avoided by culturing the
      cells at low density or by inhibiting neurite sprouting pharmacologically with
      the GABA receptor channel antagonist TBPS. Finally, immunocytochemistry revealed
      the expression of GABAA receptors in the growth cones of pyramidal neurons in
      culture. Thus, the expression of mRNA correlates to the expression of protein.
      These results suggest that the selective trafficking of GABAA receptor subunit
      mRNAs during synaptogenesis may be regulated by synapse formation and/or glial
      neural communication.

PMID- 10350637
TI  - Temporo-spatial expression of bFGF and TGFbeta2 in embryonic dopaminergic grafts
      in a rat model of Parkinson's disease.
AB  - In the present study we analyzed the temporo-spatial expression pattern of basic
      fibroblast growth factor (bFGF) and transforming growth factor beta 2 (TGFbeta2)
      in embryonic dopaminergic transplants in the 6-hydroxydopamine rat model of
      Parkinson's disease. The grafts differentiated for 1, 2, 4 and 8 weeks,
      respectively and were then analyzed using antibodies directed against tyrosine
      hydroxylase, bFGF and TGFbeta2. At all time points investigated, grafts contained
      tyrosine hydroxylase immunoreactive neurons. One week after transplantation the
      grafts displayed no immunoreactivity for bFGF and TGFbeta2. In more mature grafts
      (starting at 2 weeks post transplantation) bFGF and TGFbeta2 immunoreactivity
      became detectable within the graft and at the graft-host interface but was
      restricted only to astrocytes. In the striatum surrounding the graft, a transient
      increase of TGFbeta2 immunoreactive astrocytic processes was observed between 1
      and 2 weeks after transplantation. This temporo-spatial expression pattern of
      TGFbeta2 immunoreactive astrocytes suggests that the upregulation of TGFbeta2 is
      more likely due to the trauma imposed by the transplantation procedure than to an
      intrinsic differentiation program. Lack of both bFGF and TGFbeta2 expression in
      grafted dopaminergic neurons compared to their normal expression in the adult rat
      substantia nigra indicates that these transplanted neurons do not develop their
      complete physiological phenotype. Together with the observed deficiency in
      astrocytic bFGF early after grafting this may be responsible for the poor
      survival of grafted embryonic dopaminergic cells.

PMID- 10350638
TI  - Genomic organization and regulatory elements of the rat latexin gene, which is
      expressed in a cell type-specific manner in both central and peripheral nervous
      systems.
AB  - Latexin, a carboxypeptidase A inhibitor, is expressed in a cell type-specific
      manner in both central and peripheral nervous systems in the rat. In the
      neocortex, a specific subpopulation of neurons in layers V and VI expresses
      latexin. In the primary sensory ganglia, the expression is restricted to smaller
      diameter neurons. As a first step to clarify regulatory mechanisms underlying
      cell type-specific expression of latexin, we have determined the organization of
      the rat latexin gene and analyzed its regulatory elements. The latexin gene spans
      approximately 5.8 kb, and consists of six exons and five introns. Three
      transcription initiation sites were mapped. The upstream region lacks typical
      TATA or CAAT boxes but has several GC-rich sites. To assess promoter activity,
      the luciferase reporter gene fused to the 5'-flanking region (6.4 kb) of the
      latexin gene was transiently transfected into several cell lines. Luciferase
      activity was 2-8 times higher in latexin-expressing cells (PC12) than non
      expressing cells (NS20 and L6). Deletion analysis with PC12 cells revealed that a
      core promoter is located between nucleotide positions -261 and -201 relative to
      the A of the initiation codon. Nerve growth factor (NGF)-responsive element(s) is
      located between positions -518 and -262, in which AP-1, AP-2 and NF-kappaB
      binding sites are found. Furthermore, we demonstrate that a 1.3 kb genomic
      fragment containing the first intron has transcriptional enhancing activity in
      PC12 cells. These results suggest that up and downstream regulatory elements are
      involved in the control of cell type-specific expression of latexin.

PMID- 10350639
TI  - Molecular cloning and characterization of two putative G protein-coupled
      receptors which are highly expressed in the central nervous system.
AB  - We have cloned from a rat hypothalamic cDNA library two closely related G protein
      coupled receptors (GPCRs) which we have designated GPCR/CNS1 and GPCR/CNS2. The
      peptide sequences of these two G protein-coupled receptors shared 42% identity
      with each other and were next most closely related to the endothelin receptors
      and the bombesin-like peptide receptors (approximately 25% identity). Northern
      blot analysis showed that both GPCR/CNS1 and GPCR/CNS2 were very highly expressed
      in rat brain. In situ hybridization of rat brain demonstrated broad distribution
      of both receptors throughout the central nervous system. GPCR/CNS1 appeared to be
      expressed primarily in glial cells of the fiber tracts, while GPCR/CNS2 was
      expressed primarily in cells of the gray matter. The different distribution
      patterns of these two receptors in rat brain suggests distinct functional roles
      for each receptor in the central nervous system. Expression of these two
      receptors in Xenopus oocytes showed no response to any known endothelin and
      bombesin-like peptides. Therefore, the endogenous ligands and physiological
      significance of GPCR/CNS1 and GPCR/CNS2 remain to be elucidated, but may be
      related to the endothelins or bombesins. The very abundant expression in brain by
      these two receptors, however, suggests that they play important roles in the
      central nervous system.

PMID- 10350640
TI  - The toxicity of 6-hydroxydopamine on PC12 and P19 cells.
AB  - Considerable evidence implicates the involvement of mitochondrial dysfunction in
      neurodegenerative diseases. 6OHDA is a mitochondrial complex I inhibitor which is
      frequently used to model Parkinson's disease-like cell loss. We investigated the
      cell death pathways triggered by 6OHDA in PC12 and P19 cells with a view to
      shedding light on the molecular basis of Parkinson's disease. We found that 6OHDA
      triggered mostly necrosis and less than 5% apoptosis in PC12 cells, whereas 6OHDA
      induced death in P19 cells was apoptotic. While desipramine, a dopamine uptake
      blocker, attenuated 6OHDA-induced apoptosis in PC12 cells, this compound had no
      effect on the large scale necrotic death. Furthermore, desipramine failed to
      reduce apoptosis in 6OHDA-treated P19 cells, suggesting that the mechanism of
      6OHDA toxicity does not require uptake via the dopamine transporter. As cell
      death triggered by 6OHDA was not blocked by free radical scavengers or NMDA
      receptor antagonists, a non-specific extracellular mechanism may be involved.

PMID- 10350641
TI  - Identification of a novel gene, OASIS, which encodes for a putative CREB/ATF
      family transcription factor in the long-term cultured astrocytes and gliotic
      tissue.
AB  - Gliosis is a characteristic response of astrocytes to inflammation and trauma of
      the central nervous system (CNS). To study the mechanisms underlying gliosis, we
      performed differential display screening for genes specifically induced in long
      term cultured astrocytes used as an in vitro gliosis model. We identified and
      characterized a gene (named OASIS, for old astrocyte specifically-induced
      substance) expressed in long-term cultured mouse astrocytes, or 'old astrocytes
      (OA)'. The OASIS gene encoded a putative transcription factor belonging to the
      cyclic AMP responsive element binding protein/activating transcription factor
      (CREB/ATF) gene family, with homology to box B-binding factor-2 (BBF-2), a
      Drosophila transcription factor. Its expression was developmentally regulated;
      OASIS mRNA was primarily expressed in the salivary gland and cartilage in the
      mouse embryo and it was transiently upregulated in the brain during postnatal two
      weeks. The expression became weaker in the adult brain. We also demonstrated that
      an expression of the OASIS mRNA was induced in response to the cryo-injury of the
      mouse cerebral cortex. The distribution pattern of the OASIS-positive cells in
      the injured cortex was very similar to that of the glial fibrillary acidic
      protein (GFAP)-positive cells. These results suggest that OASIS protein may play
      a role in gliotic events.

PMID- 10350642
TI  - No requirement of alpha-internexin for nervous system development and for radial
      growth of axons.
AB  - Alpha-Internexin is a type IV intermediate filament protein that is expressed
      abundantly in neurons during development of the peripheral and central nervous
      systems as well as in few neurons of the adult central nervous system. It has
      been suggested that alpha-internexin may act as a scaffold for the formation of
      neuronal intermediate filaments during early development. In addition, recent
      reports suggest that alpha-internexin could play a major role in two degenerative
      neurological disorders. We report here an analysis of mice with a targeted
      disruption of alpha-internexin gene. Unexpectedly, alpha-internexin -/- mice
      developed normally and did not exhibit overt phenotypes. Moreover, the absence of
      alpha-internexin did not interfere with neurite extension of cultured DRG
      neurons. The number and caliber of L4 ventral root axons remained unchanged in
      alpha-internexin -/- mice. In the retina, alpha-internexin begins to be expressed
      in retinal ganglion cells when their first axons reach the optic chiasma. Using
      HRP tracer, we show that the projection pattern of the RGC axons is not modified
      by the absence of alpha-internexin. Electron microscopy did not reveal
      significant differences in axonal calibers, in myelination of axons and in
      neurofilament structures between alpha-internexin -/- and control mice during
      development and at adult stage. These data indicate that alpha-internexin is not
      required for the polymerization of neurofilament in vivo. Mice deficient for both
      alpha-internexin and neurofilament light chain (NF-L) exhibited no over
      phenotypes as well. No intermediate filament structures were detectable in optic
      nerve of alpha-internexin -/-; NF-L -/- mice. Ours results do not support the
      hypothesis of a role for type IV intermediate filaments in axonal outgrowth
      during development of nervous system.

PMID- 10350643
TI  - Expression of preprogalanin mRNA following acute and chronic restraint stress in
      brains of normotensive and hypertensive rats.
AB  - Exposure to stress is known to induce widespread changes in the central nervous
      system (CNS) involving multiple neuropeptides. The neuropeptide galanin has been
      implicated in the central response to different stressors; however, the role of
      galanin in the response to restraint stress has not been reported. Therefore,
      this study utilised in situ hybridisation histochemistry to observe the effects
      of acute and chronic restraint stress on preprogalanin (preproGAL) mRNA
      expression in the CNS of normotensive (Wistar Kyoto; WKY) and Spontaneously
      Hypertensive (SHR) rats. Rats were exposed to 1 h of restraint for 0 (control),
      1, 3, 5, or 10 consecutive days, and central preproGAL mRNA expression following
      these restraint periods was compared between strains. Significant differences in
      the basal expression of preproGAL mRNA were detected, with expression decreased
      by approximately 50% in the supraoptic nucleus (SON; P<0. 01) and increased by
      approximately 100% in the rostral ventrolateral medulla (RVLM; P<0.05) of SHR
      when compared to WKY. Following acute restraint (1 session), preproGAL mRNA
      expression was significantly increased by approximately 135% in the central
      nucleus of the amygdala (CeA; P<0.05) in WKY. In SHR, significant increases of up
      to 300% were observed in the CeA (P<0.01) and SON (P<0.05) following chronic
      restraint (up to 10 days). In addition, expression of preproGAL mRNA was
      significantly decreased in the locus coeruleus (LC) of SHR following acute
      restraint (1 session) (P<0.05). These results provide the first evidence that
      both acute (LC) and chronic (CeA, SON) restraint stress is associated with
      alterations in preproGAL mRNA expression. As such, the present study provides
      further evidence linking neurons containing galanin with the central response to
      restraint stress.

PMID- 10350644
TI  - Regulation of transcription factor C/ATF by the cAMP signal activation in
      hippocampal neurons, and molecular interaction of C/ATF with signal integrator
      CBP/p300.
AB  - The CCAAT/enhancer binding proteins related activating transcription factor,
      C/ATF, is a mouse leucine-zipper transcription factor which is structurally
      homologous to ApCREB2, a suppressor integral to long-term synaptic plasticity in
      Aplysia. To gain a clue to whether C/ATF is involved in long-term plasticities of
      brain, we examined if the expression levels of C/ATF are modulated by cAMP, an
      inducer crucial for memory formation in Aplysia, Drosophila and mice. Our in situ
      hybridization analysis revealed the expression of C/ATF mRNA in hippocampal
      neurons. C/ATF protein levels increased after the cAMP signal stimulation in
      hippocampal neurons, while C/ATF mRNA levels remained constant. The human
      activating transcription factor 4 (hATF4), another homolog of ApCREB2, interacts
      with multiple domains of the coactivator CREB-binding protein (CBP), resulting in
      the potentiation of its ability to activate transcription. As expected, C/ATF was
      found to interact with three domains of CBP including CREB binding domain or
      kinase-inducible interaction (KIX) domain, the third cysteine-histidine-rich
      region (CH3 domain) and the nuclear receptor coactivator p160/SRC-1-interacting
      domain. Interestingly, C/ATF was further found to interact strongly with CREB
      binding protein/p300 (CBP/p300) CH1 domain. Mammalian two hybrid assays indicated
      that the interaction between C/ATF and CBP/p300 can occur in mammalian cells, and
      that the p300 CH1 domain is critical for the interaction. Thus, C/ATF may be
      implicated in transcription-dependent phase of hippocampal long-term plasticities
      through the modulation of its protein level under cAMP signal and the interaction
      with signal integrator, CBP/p300.

PMID- 10350645
TI  - Tumor necrosis factor alpha expression produces increased blood-brain barrier
      permeability following temporary focal cerebral ischemia in mice.
AB  - Alteration of blood-brain barrier (BBB) function occurs in both permanent and
      temporary cerebral ischemia. Studies in vivo and in vitro have shown that tumor
      necrosis factor-alpha (TNFalpha) is involved in changes of BBB permeability.
      However, the relationship between TNFalpha expression and BBB disruption during
      reperfusion is unclear. The aim of this study is to find the cell source of
      TNFalpha and to determine the relationship between TNFalpha expression and BBB
      disruption following temporary focal cerebral ischemia in mice. Adult CD-1 mice
      received 1 h middle cerebral artery occlusion (MCAO) followed by 2 h, 6 h, 12 h,
      24 h, and 48 h of reperfusion. MCAO was achieved using an intraluminal suture
      technique and reperfusion was performed by the suture withdrawal. Neutralizing
      monoclonal anti-mouse TNFalpha antibody was administrated intraventricularly
      immediately after reperfusion. TNFalpha expression was determined by double
      labeling immunohistochemistry. BBB permeability was determined by albumin
      immunostaining. TNFalpha immunoreactivity (IR) was observed in the ipsilateral
      hemisphere from 1 h MCAO with 2 h reperfusion. TNFalpha positive cells included
      neurons, astrocytes, and ependymal cells. BBB disruption was detected beginning
      at 6 h reperfusion but was not present at 2 h of reperfusion. The areas of BBB
      disruption were significantly enlarged at 12 h reperfusion and plateaued at 24 h
      to 48 h reperfusion. BBB disruptions were significantly attenuated in the anti
      TNFalpha antibody treated mice (p<0.05). Our results demonstrate that TNFalpha IR
      existed in neurons, astrocytes, and ependymal cells during reperfusion. TNFalpha
      IR following temporary focal cerebral ischemia precedes increased BBB
      permeability. Treatment with TNFalpha antibody reduces BBB disruption, suggesting
      TNFalpha may be an important mediator in altering BBB permeability during
      reperfusion.

PMID- 10350646
TI  - Long-term increase of Sp-1 transcription factors in the hippocampus after kainic
      acid treatment.
AB  - Systemic administration of kainic acid (KA), a glutamate receptor agonist, causes
      robust seizures and has been used as an excellent rodent model for human temporal
      lobe epilepsy. Recently, we have demonstrated that a single injection of KA
      increases the steady-state levels of proenkephalin (PENK) mRNA in the rat
      hippocampus for at least one year. However, the molecular mechanisms underlying
      this long-term increase in PENK mRNA levels have not been clearly defined. To
      determine the possible involvement of the Sp-1 transcription factors in this
      regulation, electrophoresis mobility-shift assays were used to study the
      expression of Sp-1 factors in the hippocampus after KA treatment. The results
      showed that there are long-lasting increases in Sp-1 DNA-binding activity. The Sp
      1 DNA-binding complexes were only competed by the non-radioactive Sp-1 element
      and not by ENKCRE2, AP-1 or CRE elements, indicating the specificity of Sp-1 DNA
      binding activity. Since the expression of Sp-1 parallels the time course of long
      lasting increase in the expression of PENK mRNA and mossy fiber sprouting after
      KA treatment, we hypothesize that the increase in Sp-1 activity may be associated
      with the long-term changes in the plasticity of hippocampal function after KA
      induced seizures.

PMID- 10350647
TI  - Dopaminergic modulation of pallidal preproenkephalin mRNA.
AB  - The present study examines dopaminergic regulation of neuropeptide gene
      expression within a relatively poorly characterized population of cells, the
      preproenkephalin (PPE) mRNA containing neurons of the globus pallidus (GP). Rats
      that received 6-hydroxydopamine (6-OHDA) lesions or repeated D1 or D2 antagonist
      administration were compared to control animals. One month after 6-OHDA lesions,
      PPE mRNA was elevated in the GP ipsilateral to the lesion, with a smaller
      elevation also being observed in the contralateral GP. Repeated administration of
      eticlopride, but not SCH 23390, also resulted in elevated PPE mRNA expression in
      the GP. These data reveal a novel effect of decreased dopamine transmission on
      the GP, and draw attention to this subpopulation of pallidal neurons.

PMID- 10350648
TI  - A rat brain fraction and different purified peroxidases catalyzing the formation
      of dopaminochrome from dopamine.
AB  - Dopaminochrome formation is catalyzed by commercially available purified
      peroxidases (EC 1.11.1.7) such as horseradish, lacto- and myelo-peroxidase using
      dopamine, hydrogen peroxide or promethazine sulfoxide as substrates. A rat brain
      fraction (RBF) catalyzes a similar reaction and its catalytic power increases
      after preincubation with hydrogen peroxide/ascorbic acid. The activity of both
      the purified enzymes and the RBF preparation is inhibited by carnosine and
      characterized by excess substrate inhibition. The enzymes recognize different
      substrates but show the highest affinity for dopamine. The RBF fraction is
      strongly buffered against oxidation by compounds such as glutathione and by
      bioreductive enzymes such as DT-diaphorase (EC 1.6.99.2) which can use as a
      substrate menadione or dopaminochrome. The rat brain dopamine peroxidizing
      activity appeared to be mostly bound to the synaptosomal fraction. The reaction
      catalyzed by the purified peroxidases was followed by electron spin resonance
      spectroscopy and, unlike that catalyzed by RBF, was shown to produce the signal
      of a transient dopamine-o-semiquinone radical.

PMID- 10350649
TI  - Dietary soybean protein moderates the deleterious disturbance of lipid metabolism
      caused by exogenous oxidized cholesterol in rats.
AB  - Effects of dietary protein on oxidized cholesterol-induced disturbance of lipid
      metabolism were examined in 4 week old male Sprague-Dawley rats, using casein and
      soybean protein as dietary protein source. The rats were given one of the two
      proteins in 0. 078% cholesterol (control), 0.25% cholesterol or 0.25% oxidized
      cholesterol mixture (containing 0.078% cholesterol) diets. Dietary oxidized
      cholesterol, compared to cholesterol, tended to inhibit hepatic sterol
      biosynthesis in casein-fed rats, whereas this inhibitory action was slightly
      moderated by intake of soybean protein. As a result, the hepatic 3-hydroxy-3
      methylglutaryl-CoA reductase activity was rather higher in the rats fed oxidized
      cholesterol than in those fed cholesterol in the soybean protein-fed group. The
      hepatic cholesterol 7alpha-hydroxylase activity tended to be higher in the rats
      fed oxidized cholesterol than in those fed control diet in the soybean protein
      fed group, despite the fact that oxidized cholesterol lowered the hydroxylase
      activity in the casein-fed group. On the other hand, dietary oxidized cholesterol
      tended to slightly enhance the hepatic Delta6 desaturase activity in the casein
      fed group; however, this observation was not shown in the soybean protein-fed
      group. Moreover, dietary soybean protein facilitated fecal oxidized cholesterol
      excretion and simultaneously inhibited the accumulation of oxidized cholesterol
      in serum and liver. In conclusion, dietary soybean protein alleviated the
      deleterious actions of exogenous oxidized cholesterol on hepatic cholesterol and
      linoleic acid metabolism, although these efficacies were not necessarily
      significant. A great part of these moderations may be exerted by the specific
      hypocholesterolemic function of soybean protein, such as the stimulation of fecal
      oxidized cholesterol excretion, the change of hormonal release and modulation of
      lipoprotein catabolism.

PMID- 10350650
TI  - Folate and homocysteine metabolism in copper-deficient rats.
AB  - To investigate the effect of copper deficiency on folate and homocysteine
      metabolism, we measured plasma, red-cell and hepatic folate, plasma homocysteine
      and vitamin B-12 concentrations, and hepatic methionine synthase activities in
      rats. Two groups of male Sprague-Dawley rats were fed semi-purified diets
      containing either 0. 1 mg (copper-deficient group) or 9.2 mg (control group) of
      copper per kg. After 6 weeks of dietary treatment, copper deficiency was
      established as evidenced by markedly decreased plasma and hepatic copper
      concentrations in rats fed the low-copper diet. Plasma, red-cell, hepatic folate,
      and plasma vitamin B-12 concentrations were similar in both groups, whereas
      plasma homocysteine concentrations in the copper-deficient group were
      significantly higher than in the control group (P<0.05). Copper deficiency
      resulted in a 21% reduction in hepatic methionine synthase activity as compared
      to the control group (P<0.01). This change most likely caused the increased
      hepatic 5-methyltetrahydrofolate and plasma homocysteine concentrations in the
      copper-deficient group. Our results indicate that hepatic methionine synthase may
      be a cuproenzyme, and plasma homocysteine concentrations are influenced by copper
      nutriture in rats. These data support the concept that copper deficiency can be a
      risk factor for cardiovascular disease.

PMID- 10350651
TI  - Hydroxopentaamminechromium(III) promoted phosphorylation of bovine serum albumin:
      its potential implications in understanding biotoxicity of chromium.
AB  - Evidence for chromium(III) induced phosphorylation of a biomarker protein bovine
      serum albumin (BSA) is presented. Radiolabelled adenosine 5'-triphosphate (ATP)
      was reacted with BSA in the presence of various Cr(III) salts. While
      [Cr(NH3)5(H2O)]3+ brought about phosphorylation of BSA, several Cr(III)
      complexes, viz. [Cr(bpy)3]3+, [Cr(phen)3]3+, [Cr(en)3]3+, [Cr(salen)(H2O)2]+ and
      [Cr(salprn)(H2O)2]+, did not phosphorylate BSA. The Cr(III) mediated the transfer
      of gamma- and alpha-phosphates but not the adenine and the sugar moieties of the
      ATP molecule to BSA. The observed stoichiometry was 0.75 mol Pi to mol BSA for
      the gamma-phosphate and 0.5 mol Pi to mol BSA for the alpha-phosphate of ATP. The
      presence of serine phosphate and threonine phosphate was detected in the
      hydrolysate of phosphorylated BSA by means of comparison of Rf values with
      authentic samples of phosphoserine and phosphothreonine after chromatographic
      separation and autoradiography. [Cr(NH3)5(H2O)]3+ at pH 7.4 is known to exist as
      the conjugate base [Cr(NH3)5(OH)]2+ and is capable of ligand substitution
      involving metal-oxygen bond retention. Such anation reaction of [Cr(NH3)5(OH)]2+
      with ATP subsequently leads to the esterification of alcoholic hydroxyl groups of
      serine and threonine of BSA. Possible consequences of chromium(III) induced in
      vivo phosphorylation of proteins are discussed.

PMID- 10350653
TI  - Physicochemical characterization of Cajanus cajan lectin: effect of pH and metal
      ions on lectin carbohydrate interaction.
AB  - The association constant of Cajanus cajan lectin for methyl alpha-D
      mannopyranoside was studied by equilibrium dialysis method. An attempt was also
      made to understand the metal ion requirements and to establish that ionizable
      groups are responsible for lectin-carbohydrate interaction. The N-terminal
      sequence up to 27 amino acid residues was found to be more than 80% homologous
      with other mannose-specific legume lectins of the tribe Viceae. Like concanavalin
      A and pea lectin it also exhibits high affinity for the sugar alpha-methyl
      mannose and at 37 degrees C the association constant was found to be 1.4x104 M-1.
      The lectin required one Ca2+ and one Mg2+ per mole and during the lectin sugar
      interaction two ionizable groups with pK of 3.75 and 8.3 are ionized. Whether the
      secondary structure is similarly affected with pH changes and presence or absence
      of metal ion was investigated by circular dichroism studies. Results suggested
      that changes in carbohydrate binding properties of the Cajanus cajan lectin due
      to change in pH and addition of metal ions are not accompanied by any significant
      change in secondary structure.

PMID- 10350652
TI  - Cellular balance of glutathione levels through the expression of gamma
      glutamylcysteine synthetase and glutathione thiol transferase genes in human
      hepatic cells resistant to a glutathione poison.
AB  - Buthionine sulfoximine (BSO) is a synthetic amino acid that irreversibly inhibits
      glutathione biosynthesis and deranges reduced glutathione (GSH) metabolism in
      liver cells. We isolated two BSO-resistant lines, HLE/BSO2-1 and HLE/BSO2-2, from
      human hepatic HLE/WT cells. Cellular levels of the Pi class glutathione thiol
      transferase (GSTP1) were 3-fold lower in BSO-resistant lines than in HLE/WT
      cells. By contrast, gamma-glutamylcysteine synthetase (GCS) heavy subunit (GCSh)
      mRNA levels were markedly decreased in HLE/BSO2-1 and HLE/BSO2-2 as compared with
      HLE/WT. The expression of a dominant-negative mutant of c-Jun inhibited the GCSh
      promoter activity in HLE/WT, but not in HLE/BSO2-1. Cellular levels of AP-1,
      however, were not decreased in either BSO-resistant cell line. Transfection of
      GCSh promoter of various lengths driven reporter constructs showed no sequence
      specific increase in the promoter activities in HLE/BSO2-1. However, transfection
      of GSTP1 cDNA into HLE/BSO2-1 and HLE/BSO2-2 restored the levels of GCSh mRNA and
      the GCSh promoter activity to those of HLE/WT. Sequences between -315 and -241 bp
      of the 5' region contained an AP-1 site responsible for the enhanced GCSh
      promoter activity in GSTP1 transfectants of HLE/BSO2-1. In vivo footprint
      analysis showed a specific protection of the AP-1 site on GCSh promoter in GSTP1
      transfected HLE/BSO2-1. GSH homeostasis thus appears to be maintained by an
      interaction between GSTP1 and GCS in human hepatic cells resistant to the GSH
      poison.

PMID- 10350654
TI  - Effect of interferon-gamma on purine catabolic and salvage enzyme activities in
      rats.
AB  - To determine whether interferon-gamma affects rat purine catabolic and salvage
      enzyme activities, rats were injected with interferon-gamma (600000 U/kg, i.p.)
      and, similarly to a vehicle-injected control group, killed before or after
      injection at 6, 12, and 24 h. Organ homogenates were prepared and enzymatic
      reactions with substrates were carried out, after which the products were
      measured either chromatographically or spectrophotometrically. Western and
      Northern blotting also were performed. In contrast to the vehicle-injected rats,
      interferon-gamma-injected rats showed a significant rise in xanthine
      oxidoreductase activity in the liver, while enzyme activity was unchanged in the
      spleen, kidney, and lung. Western analysis of hepatic xanthine oxidoreductase
      showed an increased concentration of this protein 12 and 24 h after interferon
      gamma injection. Northern analysis disclosed an enhanced mRNA expression coding
      for this enzyme, peaking 12 h after injection. Contrastingly, the activities of
      adenosine deaminase, purine nucleoside phosphorylase, hypoxanthine guanine
      phosphoribosyltransferase, and adenine phosphoribosyltransferase were not
      affected by interferon-gamma in any organ tested. While interferon-gamma causes
      an increased hepatic biosynthesis of xanthine oxidoreductase, the physiologic
      role of this enzyme induction remains undetermined.

PMID- 10350655
TI  - Secretion of prosaposin, a multifunctional protein, by breast cancer cells.
AB  - Western blotting and immunodetection with three antibodies were used to probe
      conditioned media of breast cancer cells (MDA231, MDA435, MCF-7) for prosaposin,
      a lysosomal protein that occurs in milk. It was readily detected in media from
      these cells, and from that of an sv40-transformed mammary epithelial cell,
      HBL100, but not from medium of human neural tumor cells (SK-N-MC). In cultures of
      MCF-7 cells, the prosaposin pattern of secretion over time closely resembled that
      of procathepsin D, another lysosomal protein occurring in milk. Supplementing
      medium with 17beta-estradiol (0. 1-100 nM) dose dependently increased secretion
      of both proteins after 48 h without changes in cell viability. The influence of
      17beta-estradiol on secretion could play a role in the trophic activity of
      prosaposin in cellular differentiation and cell death protection. In concert with
      other lysosomal proteins in the tumor environment, such as procathepsin D,
      prosaposin may be a factor in eliminating barriers to tumor metastasis by
      facilitating hydrolysis of membrane glycolipids. The number of milk proteins
      known to be secreted by breast cancer cells is growing. There is evidence that at
      least some of these may be secreted in an endocrine manner in the normal, non
      lactating breast.

PMID- 10350657
TI  - Partial nuclear localization of a bovine phosphoprotein, BCNT, that includes a
      region derived from a LINE repetitive sequence in Ruminantia.
AB  - BCNT, named after Bucentaur, is a protein that contains a 324-amino-acid region
      derived from part of a long interspersed DNA sequence element (LINE) in
      Ruminantia. However, the unique portion is completely missing in human and mouse
      BCNTs. Since no significant information on their function has been obtained by
      homology search, we at first examined cellular localization and biochemical
      characteristics of bovine BCNT to get a hint on its function. Subcellular
      fractionation and immunohistochemical analyses using a normal bovine epithelial
      cell line and bovine brain revealed that a significant amount of bovine BCNT is
      localized in the nuclei, while the major portion is present in the cytosol.
      Furthermore, it was shown that bovine BCNT is a phosphoprotein and that both
      bovine and human BCNTs are phosphorylated by casein kinase II in vitro. These
      results show that BCNTs consist of a unique family, probably a substrate of
      casein kinase II, which may contribute further to the understanding of gene
      evolution.

PMID- 10350656
TI  - Metabolic capacity for L-citrulline synthesis from ammonia in rat isolated
      colonocytes.
AB  - Ammonia is present at high concentration in the colon lumen and is considered a
      colon cancer suspect. Furthermore, ammonia usually eliminated by the liver in the
      ornithine cycle is considered highly toxic to cerebral function when present in
      excess in the blood plasma. Therefore, the metabolic pathways involved in ammonia
      metabolism in colonocytes were studied in the present study. Rat colonocytes were
      found equipped with low carbamoylphosphate synthase I activity, high ornithine
      carbamoyltransferase and arginase activities and low argininosuccinate synthase
      activity. High (10 and 50 mmol/l) NH4Cl concentrations but not low concentrations
      (1 and 5 mmol/l) were found able to increase respectively 3- and 10-fold the
      conversion of radioactive L-arginine to L-citrulline. In contrast, very low
      capacity for L-citrulline conversion to L-arginine is found in colonocytes. It is
      concluded that an incomplete ornithine cycle is operative in colonocytes which
      results in ammonia stimulated L-citrulline production. The contribution of this
      metabolic pathway in relation to ammonia detoxication by colonocytes is
      discussed.

PMID- 10350659
TI  - Federal health budget 1999: part 2--health research, health information and
      prevention.

PMID- 10350660
TI  - Why research?

PMID- 10350661
TI  - The security blanket.

PMID- 10350662
TI  - The change of cost: reference-based pricing and the statins.

PMID- 10350663
TI  - Development and testing of a new hostility scale.
AB  - Evidence suggests that assessment of global type A behaviour as a coronary risk
      factor may not be the most fruitful strategy because some components,
      particularly hostility, may be more harmful than others. Measurement of hostility
      has been primarily through two types of instrumentation: the Type A Structured
      Interview (SI) and the Cook-Medley (Ho) scale. Deficiencies in the measurement of
      hostility have resulted from a lack of conceptual clarity because definitions of
      hostility have been blurred by overlap with the concepts of anger and aggression.
      The main objective of this study was to develop and test an instrument that
      focuses hostility on attitude rather than emotion or behaviour. Psychometric
      properties of the Hostile Attitude Scale (HAS) were Cronbach's alpha, 0.80, and
      correlation of 0.56 with the Ho scale and 0.43 with the SI. In a clinical
      investigation that used the HAS, SI and Ho scale, all measures were significantly
      correlated with angiogram outcome, although the strongest relationship was with
      the HAS. Hostile attitude alone (HAS) accounted for 6% of explained variance in
      angiogram outcome based on regression analysis. The HAS is offered as a short,
      easily administered measure of hostility, with particular emphasis on cognitive
      aspects of the construct.

PMID- 10350664
TI  - Efficacy and safety of cerivastatin in primary hypercholesterolemia: a long term
      comparative titration study with simvastatin.
AB  - OBJECTIVE: To compare cerivastatin with simvastatin in their long term safety and
      efficacy in reducing low density lipoprotein cholesterol (LDL-C). DESIGN:
      Multicentre, randomized, double-blind, parallel group study. SETTING: Thirteen
      Canadian centres. PATIENTS AND METHODS: A total of 387 patients with primary
      hypercholesterolemia received treatment with either cerivastatin (0. 05 to 0.3
      mg/day) or simvastatin (5 to 40 mg/day) to achieve plasma LDL-C levels below 3.36
      mmol/L (130 mg/dL) for an initial 32-week dose-titration phase and a subsequent
      72-week extension phase. MAIN RESULTS: Cerivastatin and simvastatin produced
      clinically significant reductions in LDL-C of 28.4% and 35.4%, respectively, at
      the end point for the 32-week study, and reductions of 32.8% and 35. 0%,
      respectively, at the end of the extension phase of the study. Response rates (a
      greater than 15% drop in LDL-C) were comparable for the two treatments (88.9%
      cerivastatin versus 93.2% simvastatin) at the 32-week end point. Response rates
      were 100% for both treatments at the end of the 72-week extension phase. Both
      treatments also reduced total cholesterol, apolipoprotein B and very low density
      lipoprotein cholesterol levels. Cerivastatin and simvastatin increased HDL-C
      levels significantly by 8.8% and 11.0%, respectively, at the end point for the 32
      week study, and by 8.6% and 12.1%, respectively, at the end of the extension
      phase of the study. Treatments were well tolerated, and the incidence of adverse
      effects was similar in both groups. CONCLUSIONS: This forced titration study
      demonstrates that cerivastatin, given once daily at doses up to 0.3 mg/day, is
      effective and well tolerated. The results of this study support further
      investigation of higher doses of cerivastatin given the excellent safety profile
      at doses up to 0.3 mg.

PMID- 10350665
TI  - Similar, the same or just not different: a guide for deciding whether treatments
      are clinically equivalent. [Dept. of Medicine, Division of Cardiology, Univ. of
      Western Ontario, London, Ontario].
AB  - Most clinical trials are designed to demonstrate superiority of one intervention
      over another. A less common goal is to show that any differences are sufficiently
      small to consider them interchangeable or clinically equivalent. Although similar
      to effectiveness trials, equivalence trials pose distinct methodological and
      interpretive challenges. Emphasis is placed on the distinction between a study
      designed to show 'equivalence' and a study designed to show 'superiority' that
      fails in its quest but in the end claims equivalence. Strategies used to minimize
      bias in superiority trials may actually increase the probability of showing no
      difference. Although there is no consensus as to the best statistical approach in
      describing the results of equivalence trials, an approach based on confidence
      intervals may be easier for clinicians to comprehend. A guide was developed to
      assist readers in determining whether claims of clinical equivalence are valid.

PMID- 10350666
TI  - Impaired endothelial function in hypertensive elderly patients evaluated by high
      resolution ultrasonography.
AB  - BACKGROUND: Multiple investigations both in experimental models and in middle
      aged patients with essential hypertension have demonstrated impaired endothelium
      dependent vasodilation. OBJECTIVE: To determine whether hypertension exerts an
      additional negative effect on endothelial function of large arteries in
      hypertensive elderly patients who may already be affected by endothelial
      dysfunction due to aging. PATIENTS AND METHODS: Thirteen elderly patients with
      hypertension (69 9 years of age [mean SD]) were compared with 13 matched healthy
      elderly subjects (72 6 years of age). High resolution vascular ultrasound was
      used to measure brachial artery responses to reactive hyperemia (with increased
      flow causing endothelium-dependent dilation) and to sublingual nitroglycerine
      (causing endothelium-independent dilation). RESULTS: Flow-mediated diameter (FMD)
      was significantly impaired in the hypertensive elderly group (6.7 3.3% versus
      13.3 3.8% in the control group, P<0.05). No significant difference could be found
      in nitroglycerine-induced dilation between the elderly control group (12.1 4.9%)
      and the hypertensive elderly (10.2 6.8%). On simple linear analysis, FMD was
      inversely correlated with age (r=-0.60, P=0. 03) in the healthy elderly group.
      FMD in the hypertensive elderly was inversely related to age (r=-0.41, P=0.04)
      and mean blood pressure (r=-0.67, P=0.01). CONCLUSIONS: This study showed
      decreased FMD with aging even in the healthy elderly, with a further decline in
      hypertensive elderly compared with healthy elderly subjects. This impairment of
      FMD in the hypertensive elderly group was related to age and mean blood pressure,
      indicating that aging and hypertension may impair endothelial function in the
      brachial artery of elderly patients with hypertension.

PMID- 10350667
TI  - Tear propagation in isolated, pressurized porcine thoracic aortas.
AB  - OBJECTIVE: To determine the pressure required for the initial medial tear, and
      for propagtion of dissections, within the media of isolated pressurized porcine
      thoracic aorta, and to determine whether these vary with tear depth. DESIGN:
      India ink-stained saline was injected into the media of 48 fresh porcine
      descending thoracic aorta that were distended with 130 mmHg pressure. The fluid
      was infused into the media through a 25 gauge needle connected to a constant
      infusion pump, and the pressure at the entrance to the needle was monitored with
      a Cobe pressure transducer. The two lumens were not connected. Blebs were made at
      different depths and measured at the end of the experiment with a Starrett gauge.
      Seven casts were made in pressurized aortas and nine in nonpressurized ones to
      determine the shape of the blebs by injecting different volumes of mercox casting
      material into the media by hand. RESULTS: Mean tearing pressure, expressed as the
      transmural pressure between the bleb and the true lumen (which was at 130 mmHg)
      was 547 mmHg (range 208 to 995). Mean propagation pressure was 54 mmHg (range 25
      to 93). The ratio of the two pressures was 10.1 (range 5.2 to 21.7). None of
      these pressures was correlated with tear depth. Casts showed that the leading
      edge was sharp in all directions. Small blebs were roughly spherical, and large
      ones were cylindrical with roughly hemispherical ends between the cylinder and
      the sharp leading edge. CONCLUSIONS: Dissections can propagate at pressures that
      could be reached under physiological and certainly pathological conditions. The
      initial tear requires pressures that are too high to create biologically except
      with trauma. The leading edge of the dissection appears to be very sharp and
      likely explains why the dissection propagates at relatively low pressures. Tear
      depth does not affect the results.

PMID- 10350668
TI  - A cost effective approach to the investigation of syncope: relative merit of
      different diagnostic strategies.
AB  - OBJECTIVE: To compare the cost effectiveness of a conventional diagnostic work-up
      with that of several different diagnostic cascades for the investigation of
      undifferentiated syncope. DESIGN: A MEDLINE search established a weighted
      estimate of diagnostic yield for several diagnostic investigations. 'High-end'
      and 'low-end' cost estimates were calculated for these investigations based on
      figures from four representative Canadian tertiary care centres in four different
      provinces. Several diagnostic models were applied to a hypothetical cohort of 100
      patients with undifferentiated syncope. RESULTS: The conventional diagnostic
      cascade resulted in a diagnosis in 85% of patients, at a cost per diagnosis of
      $467 to $959. The optimal model increased the diagnostic yield to 98.9%, at a
      cost of $460 to $1043 per diagnosed patient. CONCLUSION: A combination of new
      technology and selective use of investigations has the potential to raise
      diagnostic yield without appreciably increasing cost per diagnosis.

PMID- 10350669
TI  - Canadian contributions to heart valve transplantation for cardiac valve
      replacement.

PMID- 10350670
TI  - Evidence for the role of oxidative stress in acute ischemic heart disease: a
      brief review.
AB  - BACKGROUND: Although contractile performance of the acutely damaged ischemic
      heart is invariably depressed on reperfusion (myocardial stunning), the
      mechanisms of cardiac dysfunction in stunned myocardium are poorly understood.
      OBJECTIVES: To review briefly the current state of knowledge and to provide
      further experimental evidence of whether oxidative stress plays a crucial role in
      cardiac dysfunction and membrane abnormalities due to ischemia-reperfusion.
      MATERIALS AND METHODS: Isolated rat hearts perfused in the absence or presence of
      superoxide dismutase (SOD) plus catalase, a well known oxyradical scavenger
      system, were subjected to 30 mins of global ischemia and 60 mins of reperfusion.
      Cardiac performance, hydrogen peroxide and calcium contents, lipid peroxidation
      and membrane activities associated with calcium transport were measured in the
      control, ischemic and ischemic- reperfused hearts. RESULTS: Cardiac dysfunction,
      as reflected by depressed left ventricular developed pressure, +dP/dt and -dP/dt
      as well as elevated left ventricular end-diastolic pressure, in the ischemic
      reperfused heart was associated with increased hydrogen peroxide, calcium and
      malondialdehyde contents as well as increased formation of conjugated dienes.
      These changes due to ischemia-reperfusion were attenuated in hearts treated with
      SOD plus catalase. Both ischemia and ischemic-reperfused hearts showed
      depressions in sarcolemmal Na+/K+-ATPase and sodium-calcium exchange, as well as
      sarcoplasmic reticular calcium uptake and calcium release activities; these
      membrane abnormalities were also partially prevented by the presence of SOD plus
      catalase. CONCLUSIONS: Oxidative stress due to the formation of hydrogen peroxide
      leading to lipid peroxidation and sulfhydryl group oxidation during ischemia
      reperfusion seems to be one of the mechanisms that may produce membrane defects
      and result in intracellular calcium overload and cardiac contractile dysfunction
      in the stunned myocardium.

PMID- 10350671
TI  - Mediastinal irradiation: A risk factor for atherosclerosis of the internal
      thoracic arteries.
AB  - Previous radiotherapy to the thorax is a risk factor for coronary artery disease.
      Patients with radiation-induced atherosclerosis tend to be young and frequently
      have lesions involving the coronary ostia and left anterior descending artery.
      Bypass is often the most suitable method of revascularization, and given the
      young age of the patient, arterial conduits would be considered superior to vein
      grafts. However, the internal thoracic arteries can lie within the radiation
      field and may not be free of atherosclerosis. A 40-year-old man who required
      coronary artery bypass grafting for multivessel coronary artery disease 11 years
      following radiotherapy for Hodgkin's lymphoma is reported. Preoperative
      angiography showed that the right internal thoracic artery had significant
      atherosclerosis and was unsuitable as a conduit.

PMID- 10350672
TI  - Coronary vasospasm as a cause of angina following interventional recanalization.
AB  - Angina following a coronary intervention may be due to vasospasm rather than
      restenosis. Two cases of angina following a previously successful recanalization
      are described. In both cases vasospasm was documented as the cause of angina,
      determined in one case by using an ergonovine provocative test and in the other
      by using lesion response to nitroglycerine. Rather than another intervention,
      vasodilator treatment was instituted, with effective symptom amelioration.

PMID- 10350673
TI  - Physician resources.

PMID- 10350674
TI  - What is apoptosis and what is its relevance to vascular biology?
AB  - To maintain vascular mass and structure, an intricate balance must be maintained
      between apoptosis (programmed cell death) and cell proliferation. Apoptosis is
      thought to be regulated by a complex cascade of specific protease activations.
      Increased rates of apoptosis, which occur during limited time windows, have been
      implicated in animal models of hypertension and cardiac hypertrophy. In these
      models, apoptosis was effectively upregulated by three of the four
      antihypertensive agents studied. Work to identify the gene that controls
      apoptosis is ongoing.

PMID- 10350675
TI  - What is the relevance of apoptosis to the myocardium?
AB  - Direct and indirect evidence from a number of studies demonstrates that apoptosis
      is an important process in heart failure in humans. It is thought that a
      proapoptotic shift in conditions occurs during heart failure, involving the
      entire population of cardiac myocytes. A complex mechanism of programmed cell
      death has been postulated, involving such factors as Fas, Bax and Bcl-2; tumour
      necrosis may also play a role. Given the myriad apoptotic pathways, a number of
      opportunities for treatment have been identified.

PMID- 10350676
TI  - Germline polymorphisms in cardiovascular medicine. Is that the whole story?
AB  - A wealth of recent data points to the importance of germline mutations and
      polymorphisms in the pathophysiology of heart and blood vessel disease. In
      addition, new data suggest that somatic mutations and perturbation in epigenetic
      pathways may be involved in diseases of the cardiovascular system. This focused
      discussion uses examples in hypertension and atherosclerosis to highlight these
      emerging concepts.

PMID- 10350677
TI  - Infectious agents that play a role in atherosclerosis and vasculopathies. What
      are they? What do we do about them?
AB  - Much of the published data suggest a link between herpes infection and
      atherosclerosis, as well as herpes infection and restenosis. Mechanistically,
      herpesvirus has been shown to promote inflammation, thrombin generation and
      platelet binding, and infected cells have been shown to be resistant to
      apoptosis. There is also good evidence of a link between Chlamydia pneumoniae
      infection and atherosclerosis. In preliminary studies, antichlamydial antibiotic
      intervention has been shown to reduce significantly the incidence of cardiac
      events in patients with coronary artery disease and in myocardial infarction
      survivors.

PMID- 10350678
TI  - Controversies in primary prevention among hyperlipidemic patients.
AB  - Data from a number of population-based primary prevention trials clearly indicate
      that reducing total serum cholesterol levels leads to a reduced risk of coronary
      artery disease and death. Similarly, for patients with coronary artery disease,
      reducing total serum cholesterol levels proved to be an effective secondary
      prevention strategy, leading to a reduced risk of coronary events and death.
      Targeting high risk patients is a particularly important component of primary
      prevention. The overall benefit of treatment is significantly reduced when
      cholesterol-lowering strategies are initiated later in life. To assist in both
      primary and secondary prevention strategies, an outline of guidelines developed
      by a Health Canada working group for the management of hyperlipidemia have
      recently been published.

PMID- 10350679
TI  - Insulin resistance.
AB  - It is thought that a number of interrelated variables, all involved in insulin
      resistance, may play a role in the pathophysiology of coronary artery disease.
      These include dyslipidemia, dysglycemia and hyperinsulinemia. Insulin resistance,
      the insulin resistance syndrome and atherogenesis are all thought to involve
      endothelial dysfunction, though in different vascular beds.

PMID- 10350680
TI  - Antioxidants are useful in preventing cardiovascular disease: a debate. Pro
      antioxidants.
AB  - Antioxidants are a heterogeneous group of agents; their mechanisms of action are
      diverse and are not well understood. Nonetheless, it is clear that some
      antioxidants, such as vitamin E, are beneficial agents in the prevention of
      cardiovascular disease.

PMID- 10350681
TI  - Antioxidants are useful in preventing cardiovascular disease: a debate. Con
      antioxidants.
AB  - There is no doubt that antioxidants and other micronutrients, taken in their
      proper form in vegetables and fruits, confer a number of overall health benefits.
      However, routine antioxidant supplementation is neither warranted nor
      recommended. This view is in keeping with those of both the American Heart
      Association and the American College of Cardiology. While much of the
      experimental animal data suggest that antioxidants would be of value in human
      subjects, a very large body of human clinical data do not bear this out. On the
      contrary, while some clinical benefits have been observed, routine antioxidant
      supplementation has been associated with a small increase in major adverse
      outcomes. Unlike the trials conducted with cholesterol-lowering agents, beta
      blockers and acetylsalicylic acid, the results of trials conducted with
      antioxidants are inconsistent at best.

PMID- 10350682
TI  - BANFF: an update.
AB  - Data from the Brachial Artery Normalization of Forearm Function (BANFF) trial
      indicate that angiotensin-converting enzyme (ACE) inhibitors and other vasoactive
      substances appear to differ in their ability to improve endothelial dysfunction.
      Only quinapril, which is a lipophilic ACE inhibitor with high affinity for tissue
      ACE, produced a significant improvement in flow-mediated brachial artery dilation
      in coronary artery disease patients; enalapril, losartan and amlodipine did not.
      Quinapril showed highly significant improvement in subjects with one copy of the
      insertion allele, either the ACE-ID or the ACE-II genotype. It is anticipated
      that the effects of QUinapril On Vascular ACE and Determinants of ISchemia (QUO
      VADIS) trial will further differentiate ACE inhibitors (quinapril versus
      captopril) according to their effects on vascular tissue taken from pretreated
      patients undergoing coronary artery bypass graft surgery.

PMID- 10350683
TI  - Homocyst(e)ine, vitamins and genetic interactions in vascular disease.
AB  - Blood homocyst(e)ine levels are an important, independent and frequent risk
      factor for clinical atherosclerosis and venous thrombosis. Folic acid, vitamins
      B6 and B12, renal and thyroid functions, certain medications and certain
      genotypes are known to modulate plasma homocyst(e)ine levels. Intake of B
      vitamins through diet, supplementation and fortified foods effectively reduces
      homocyst(e)ine concentration and thus may reduce the risk of cardiovascular
      disease. This is true even in individuals who are genetically predisposed to
      hyperhomocyst(e)inemia. Randomized clinical trials are needed to investigate
      these effects further.

PMID- 10350685
TI  - Symposium on Protection of End-Organ Damage: Benefits of 24 h Blood Pressure
      Control.

PMID- 10350684
TI  - Hyperhomocyst(e)inemia--determining factors and treatment.
AB  - Elevated homocyst(e)ine levels are associated with an increased risk of vascular
      disease, particularly aorto-iliac, coronary and cerebrovascular disease. In
      patients with confirmed disease, plasma homocyst(e)ine is a strong predictor of
      death. In addition to B vitamins, folic acid and certain genotypes, renal
      function is an independent determinant of plasma homocyst(e)ine level. There also
      may be a polygenic component contributing to elevated homocyst(e)ine levels in
      confirmed vascular disease. Possible mechanisms of homocyst(e)ine-induced
      vascular change include proliferation of vascular smooth muscle cells,
      endothelial cell dysfunction and a procoagulant state. The definition of
      hyperhomocyst(e)inemia is based on arbitrary cut-points (eg, the 90th
      percentile). In most populations, this is approximately 15 microM/L. Patients
      with hyperhomocyst(e)inemia should be treated with at least 400 micrograms of
      folic acid per day. Alternative treatments are vitamin B6 and B12
      supplementation, although optimal doses have yet to be identified.

PMID- 10350686
TI  - Ambulatory blood pressure monitoring: A proposal for new Canadian guidelines.
AB  - OBJECTIVE: To provide background information on the scientific basis for new
      Canadian guidelines on ambulatory blood pressure monitoring and the process for
      developing recommendations for clinical practice. DATA SOURCES: A comprehensive
      review of the literature on ambulatory blood pressure monitoring was conducted
      using a computerized literature search and a bibliography of key scientific
      articles. STUDY SELECTION AND DATA EXTRACTION: Studies of the highest scientific
      quality were used to support recommendations based on established rules for
      grading evidence. DATA SYNTHESIS: A series of recommendations for the use of
      ambulatory blood pressure monitoring in routine clinical practice directed
      towards both untreated patients with a diagnosis of possible hypertension and
      treated patients with a suspected 'white coat' component to their office readings
      have been proposed for consideration by the Canadian Hypertension Society.
      CONCLUSIONS: There are now sufficient data available to support the use of
      ambulatory blood pressure monitoring in accordance with specific clinical
      practice guidelines.

PMID- 10350687
TI  - Intermittent blood pressure control: Potential consequences for outcome.
AB  - Although both blood pressure (BP) and left ventricular (LV) mass at initial
      evaluation predict future cardiovascular risk, the actual BP and LV mass achieved
      over years of treatment more clearly relate to cardiovascular event rates.
      Intermittent compliance or noncompliance is the major reason for uncontrolled
      hypertension and presumably persistent LV hypertrophy. In general, drugs with
      rapid onset and short duration of action are not desirable because this profile
      may lead to large variations in BP lowering effect during actual drug intake and
      rapid disappearance of the antihypertensive effect with missed doses. In
      addition, intermittent compliance per se introduces the potential for adverse
      events. For drugs requiring several dose-titrations (eg, alpha1-blockers),
      restarting at full doses may lead to excessive drug action and symptomatic
      hypotension. For other drugs (eg, short acting beta-blockers or clonidine-like
      drugs), sudden discontinuation with intermittent compliance may lead to rebound
      enhanced sympathetic responsiveness after one to two days, resulting not only in
      side effects, but also in adverse events, particularly in patients with (silent)
      coronary artery disease. The rapid onset, short acting dihydropyridines cause
      intermittent BP control at each dosing, particularly at higher doses. This
      intermittent control of BP is even more apparent at dosing intervals that are
      long relative to the duration of action. Thus, sympathetic activation and
      potential for adverse events can be anticipated at each dosing unless these drugs
      are being taken frequently at relatively low doses. For diuretics, angiotensin
      converting enzyme inhibitors and angiotensin I receptor blockers, no adverse
      effects have been identified with intermittent compliance. Intermittent BP
      control is, in general, not an appropriate approach to the management of
      hypertension and introduces additional risks depending on the type of
      antihypertensive drug. In contrast, drugs with slow onset and long duration of
      action provide a more consistent effect during actual drug intake and a more
      persistent effect during short periods of noncompliance.

PMID- 10350688
TI  - Angiotensin-converting enzyme inhibitors and end-organ damage in heart failure.
AB  - Angiotensin-converting enzyme (ACE) inhibitors play an important role in
      protecting various organs in patients with congestive heart failure. The
      mechanisms of action of ACE inhibitors in congestive heart failure are multiple
      and may involve important effects on endothelial function in addition to the well
      known hemodynamic and neurohormonal effects. Skeletal muscle fatigue can play an
      important role in the pathophysiology of congestive heart failure, and only
      aggressive treatment with ACE inhibitors and exercise training can improve
      exercise tolerance and reduce the risk of further deterioration of cardiac
      function. ACE inhibitors should be introduced with caution in patients with
      severe heart failure and hypotension to prevent renal dysfunction. Unlike some
      other ACE inhibitors, perindopril seems to cause no first dose hypotension. It
      also appears to have a neutral effect on renal function in patients with severe
      congestive heart failure.

PMID- 10350689
TI  - [Erectile dysfunction: epidemiology and etiopathogeny]

PMID- 10350690
TI  - [Detection and diagnosis of erectile dysfunction in psychiatry]

PMID- 10350691
TI  - [Psychogenic factors in erectile dysfunction]

PMID- 10350692
TI  - [Psychodrugs in erectile dysfunction. Therapeutic alternatives]

PMID- 10350693
TI  - [Discovery and clinical development of Sildenafil]

PMID- 10350694
TI  - [Are all sedation scales equally useful for nursing assessment?].
AB  - The usefulness of three clinical scales for monitoring sedation in intensive care
      units was compared. The Ramsay scale, Cook modification of the Glasgow scale, and
      combined Ramsay-Cook scale were evaluated. Thirty-five patients with continuous
      intravenous sedation were monitored using all three clinical scales. The scores
      were collected simultaneosly with a two-observer method carried out by the nurse
      in charge of the patient and a second observer (nurse or physician). The three
      scales were considered valid and reproductible, with "good" agreement for the
      Ramsay scale and "very good" agreement for the Cook modified coma scale and the
      combined Ramsay-Cook scale. In conclusion, since the Cook modified Glasgow scale
      was the most reproducible, it is preferred for use in research and daily
      practice. The Ramsay scale is more subjective, but may be useful for daily
      nursing activities.

PMID- 10350695
TI  - [Care levels in an intensive care unit. Analysis of therapeutic requirements and
      severity scales].
AB  - The APACHE II and TISS scales usually are used in intensive medicine services to
      assess patient's severity and therapeutic requirements, respectively. Both scales
      serve to classify ICU patient's into three care levels, each of which has its own
      well-defined surveillance and care requirements. Nursing personnel have used the
      TISS scale to determine work loads and plan nurse-patient ratios. However, this
      scale is complex and its application is time-consuming, thus impeding its routine
      use. In recent years, the NEMS (Nine Equivalents of Nursing Manpower) scale has
      been validated for this purpose. This scale uses just nine variables to
      objectively quantify nursing requirements. In order to determine if the NEMS
      scale could be used to evaluate the severity and nursing requirements of
      patient's admitted to our ICU and to establish care levels, we designed a
      descriptive study of a sample of 78 patients. The results showed that the APACHE
      II, TISS and NEMS scales has a good correlation and that the NEMS scale could be
      used to determine patient care requirements in our service. Based on the TISS and
      NEMS correlation, we determined discriminative numerical NEMS values for
      assigning patient's to different care levels.

PMID- 10350696
TI  - [Cardiac rehabilitation].
AB  - Cardiac rehabilitation (CR) has been carried out in a progressively larger number
      of intensive care and coronary units since it was defined in 1964 by the WHO, but
      emphasis on CR has varied at different times. At present, CR is considered a
      priority task in the secondary prevention of ischemic heart disease in these
      units. One of its clearest objectives is to improve the quality of life, but we
      have more specific goals, such as preventing the harmful effects of prolonged bed
      rest, controlling risk factors, improving the patient's knowledge on his or her
      disease, involving the family in CR, particulary its last phases, preventing
      and/or correcting psychological problems such as anxiety and depression,
      increasing the patient's self-confidence and will to live, improving his or her
      capacity for physical effort with a program of aerobic physical exercise,
      facilitating familial, occupational and social reinsertion, and finally, if we
      achieve these goals, reducing the hospital stay and, perhaps, morbidity and
      mortality as well. A detailed explanation is given of the need for CR programs,
      which are divided into several categories (cardiovascular, musculoskeletal,
      hydroelectrolytic, hematic, respiratory and psychological). Increased knowledge
      of the benefits of CR will make nurses better prepared and motivated to include
      this program in coronary intensive care units (ICU, wards and specialized post
      hospitalization centers).

PMID- 10350697
TI  - The Theoretical Concept of At-Risk Adolescents.
AB  - The opening article of this issue defines and reviews the concept of risk-taking
      during adolescence and presents a theoretical model for understanding the
      mechanisms for the onset and maintenance of risk behaviors. The individual
      behaviors (sexual behavior, substance use, and vehicle use) are often
      interrelated and the mechanisms for onset may be similar.

PMID- 10350698
TI  - Adolescent Health: Current Trends and Critical Issues.
AB  - The demography and predominant mortalities and morbidities of adolescents are
      reviewed, including motor vehicle accidents, suicide, homicide and violent crime,
      pregnancy, sexually transmitted diseases, alcohol and drug use, tobacco use, and
      runaway and homeless youth. Then various approaches to intervention and health
      promotion are covered.

PMID- 10350699
TI  - Clinical Assessment and Management of Health Risk Behaviors in Adolescents.
AB  - Risk-taking behavior in adolescents has a clear development basis and is
      augmented by a combination of social and cultural factors. This paper presents an
      approach to clinical assessment and management of risk-taking behavior and
      emphasizes the critical responsibility of the health professional in taking
      appropriate steps to protect adolescents against adverse consequences.

PMID- 10350700
TI  - Family Violence and Adolescents.
AB  - This article examines adolescent involvement in violent family relations, both as
      victims and perpetrators. The author points out that adolescents have been the
      missing persons in the family violence literature and explains their role in
      various circumstances of violence and abuse, concluding with steps for treatment
      and prevention of this problem.

PMID- 10350701
TI  - The Gang Phenomenon and the American Teenager.
AB  - The authors review basic concepts of current teenage gangs in America: (1) normal
      adolescent behavior as a basis for understanding gang behavior, (2) definition
      and location of gangs, (3) comparison of gangs with other adolescent peer groups,
      (4) history of the gang movement with a description of modern gang structure, (5)
      research of gang formation with demographic comparisons, and (6) female gangs.
      Current theories on potential solutions to the problem are presented, with
      emphasis on dealing with society's role in the formation of modern teenage gangs.

PMID- 10350702
TI  - Are Today's Adolescents Growing Up Too Fast?
AB  - The author explains three approaches to the question addressed in the title of
      this article: (1) the biological/evolutionary perspective, (2) the
      sociological/historical perspective, and (3) the psychological perspective. His
      aim is to review the answers that each of these approaches provides and to arrive
      at a more general answer that takes all three approaches into account.

PMID- 10350704
TI  - Injuries: The Leading Cause of Morbidity and Mortality in Adolescents.
AB  - Injuries are the major health problem of adolescents, and current work in this
      area incorporates the application of epidemiologic research principles to the
      problem of adolescent injuries, including behavioral approaches in intervention.
      The author reviews the epidemiology of the problem, discusses the environments
      where injuries occur, and suggests areas for future improvement in research
      methodologies.

PMID- 10350703
TI  - Adolescent Depression and Suicide.
AB  - The clinical syndrome of depression and the problem of suicidal behavior do not
      usually coincide in adolescents, and consequently the author reviews each
      individually. Both are the subject of much current research, and new findings
      suggest that management of both problems will incorporate more and more
      biological information in the coming years.

PMID- 10350705
TI  - Preventing Adolescent Pregnancy.
AB  - The problem of high rates of unintended adolescent pregnancy in the United States
      continues unchecked. The author discusses efforts to prevent adolescent pregnancy
      and to ameliorate its effects, including sex education, community outreach and
      clinical services, and the development of innovative local programs. Other
      approaches include counseling, use of social learning theory, use of
      developmental theory, skills building, and self-concept development.

PMID- 10350706
TI  - Prevention of Substance Abuse in Children and Adolescents.
AB  - Although a recent national survey has shown an encouraging decrease in the use of
      drugs by adolescents, the problem remains large and continues. In this article
      substance abuse is defined and then theories of prevention and causation are
      discussed. Prevention programs that have been in use in the past are reviewed and
      current trends in preventive efforts described.

PMID- 10350707
TI  - Solutions: The Role of the Private Practitioner.
AB  - I. Continuity and Communication II. Financial Considerations III. Adolescent
      Gynecology IV. Contraceptive Counseling: A Dissenting View This article discusses
      four subjects that are essential considerations for physicians and other health
      care providers to deal successfully with adolescent patients. The first focuses
      on the integration of adolescents into a general pediatric practice. The second
      section examines financial considerations in the provision of adolescent health
      care. The third discusses confidentiality, common problems, and adolescent
      sexuality as part of adolescent gynecology. The fourth section discusses
      contraceptive counseling and suggests that more consideration be given to those
      factors innate to the adolescent psyche in counseling contraceptive methods.

PMID- 10350709
TI  - Cutaneous Manifestations of Common Systemic Diseases in Adolescents.

PMID- 10350708
TI  - Television and Adolescents: Sex, Drugs, Rock 'n' Roll.
AB  - Television and other media represent an important and widely unrecognized
      influence on adolescent behavior in American society. This article is a review of
      the major media to which teenagers are heavily exposed-television, movies, radio,
      print media, and pornography. The potential concerns of practitioners and parents
      and society as a whole are emphasized and some solutions suggested.

PMID- 10350710
TI  - Dermatologic Manifestations of Sexually Transmitted Diseases.
AB  - Cutaneous signs and symptoms are important because they may represent the most
      prominent, earliest, or only evidence of sexually transmitted disease. AIDS and
      HIV infection are increasingly serious problems of adolescence, and the
      recognition of non-AIDS STDs in adolescents now has the added importance of
      identifying a population at high risk for HIV infection.

PMID- 10350711
TI  - Diagnosis and Management of Disorders of the Scalp and Hair in Adolescents.
AB  - A practical approach is offered to the diagnosis and management of the more
      common hair and scalp problems in adolescents, including seborrheic dermatitis,
      psoriasis, tinea capitis, and others.

PMID- 10350712
TI  - Psoriasis in Adolescents.
AB  - Psoriasis is a chronic condition that is difficult to treat. Clinical
      presentation, diagnosis, and therapeutic approach to the adolescent patient are
      addressed. Therapy requires extensive patient education, emotional support, and
      flexibility, bearing in mind that the young psoriatic patient may require
      treatment over a lifetime.

PMID- 10350713
TI  - Endocrine Aspects of Adolescent Acne.
AB  - Hormonal influences on the pathogenesis of acne, endocrine control of sebaceous
      glands, endocrine abnormalities, and endocrine therapy for acne are discussed.

PMID- 10350714
TI  - Acne Vulgaris: Its Pathogenesis and Management.
AB  - The prognosis for the thousands of young people who seek treatment for acne is
      growing considerably brighter. Elimination of old misconceptions, together with
      many promising and proven new medications, has done much to improve the
      management of acne. The author emphasizes that therapy must be individualized,
      with appropriate variations and modifications as the severity of the disorder
      fluctuates.

PMID- 10350715
TI  - Isotretinoin (Accutane) Therapy for Acne in Adolescents.
AB  - The introduction of 13-cis-retinoic acid (isotretinoin, Accutane) represents a
      major advance in the treatment of severe, disfiguring, cystic acne. This article
      addresses the course of treatment, teratogenicity, laboratory evaluation, side
      effects, and management of complications.

PMID- 10350716
TI  - Bacterial Skin Infections in Adolescents.
AB  - This article reviews the salient features of diagnosis and treatment of the more
      common bacterial infections in adolescents, including impetigo contagiosa,
      bullous impetigo, cellulitis and erysipelas, folliculitis, furunculosis and
      carbunculosis, blistering distal dactylitis, toxic shock syndrome, and dog and
      cat bites.

PMID- 10350718
TI  - Warts and Their Management in Adolescents.
AB  - Warts are a common dermatologic problem in adolescents. The etiology,
      pathogenesis, clinical presentations, and various approaches to treatment of
      warts are presented.

PMID- 10350717
TI  - Tinea Infections in Adolescents.
AB  - Superficial fungal and yeast infections of the skin are common during
      adolescence. This article describes the causes, clinical manifestations,
      differential diagnosis, and treatment of four infections that increase in
      frequency during adolescence: tinea versicolor, tinea pedis, fungal nail
      infections, and tinea cruris.

PMID- 10350719
TI  - Dermatoses of the Foot in Adolescents.
AB  - The author describes diagnosis and management of the seven skin conditions that
      are the most common on the feet of adolescents: tinea pedis, plantar warts,
      juvenile plantar dermatosis, allergic contact dermatitis, psoriasis, granuloma
      annulare, and scabies.

PMID- 10350720
TI  - Scabies and Lice.
AB  - Identification and destruction of both types of infestations require accurate
      diagnosis, adequate therapy, and instructions for follow-up if an infestation
      recurs.

PMID- 10350721
TI  - Sunburn and Sun Reactions.
AB  - Most teenagers believe that it is both healthy and fashionable to have a glowing
      suntan. However, the long-term hazardous effects of sun exposure have been well
      documented, and are the focus of this chapter. Discussion also encompasses sun
      reactions, the tanning response, recommended sunscreen protection factors, and
      abnormal responses to sun.

PMID- 10350722
TI  - Management of Vascular Lesions in Adolescents.
AB  - Congenital and acquired cutaneous vascular lesions often present a difficult
      management problem in children and adolescents. This discussion outlines a
      practical approach to the evaluation and treatment of cutaneous vascular lesions
      such as hemangiomas, telangiectasias, angiokeratomas, and progressive pigmented
      purpura. Excisional surgery, laser surgery, and corrective cosmetics used in
      combination may produce the best cosmetic results.

PMID- 10350723
TI  - The Use of Topical Corticosteroids in Dermatology.
AB  - Topical corticosteroids are invaluable in the treatment of a wide variety of
      dermatologic problems. General guidelines are offered to govern their use,
      including the amount needed for daily application, side effects, and selection of
      low to high potency concentrations.

PMID- 10350724
TI  - The Epidemiology and Control of Sexually Transmitted Diseases in Adolescents.
AB  - Teenagers are at higher risk for sexually transmitted infection than other age
      groups for a variety of behavioral, biological, and psychosocial reasons. This
      article discusses the importance and trends of sexually transmitted diseases
      (STDs) in teenagers, factors affecting the trends in adolescent STDs,
      implications of STDs for the future health of adolescents, and implications for
      activities directed at control of STDs in this high-risk group.

PMID- 10350725
TI  - Acquired Immunodeficiency Syndrome (AIDS) in Adolescents.
AB  - This chapter reviews the epidemiology of acquired immunodeficiency syndrome
      (AIDS) and human immunodeficiency virus (HIV) infection among adolescents,
      presents a theoretical model for defining risk, and reviews factors that put
      adolescents at risk for HIV infection. Issues pertaining to risk assessment, HIV
      counseling and testing, and approaches to care for HIV-infected teens are
      discussed. Finally, practical strategies for HIV prevention and risk reduction
      are provided.

PMID- 10350726
TI  - Genital Human Papillomavirus Infections.
AB  - The author describes the clinical manifestations, diagnosis, and treatment of
      human papillomavirus (HPV) infections. The association of HPV with anogenital
      cancer is also discussed.

PMID- 10350727
TI  - Genital Herpes in Adolescents and Young Adults.
AB  - The acquisition of genital herpes simplex virus (HSV) is still a significant risk
      to sexually active individuals. This chapter addresses the epidemiology and
      natural history of genital herpes, and new therapies that have changed the
      natural course of events following infection. The possibility of an HSV vaccine
      is also discussed.

PMID- 10350728
TI  - Gonococcal Infections in Adolescents.
AB  - Gonorrhea is the most frequently reported communicable disease in the United
      States. This chapter elucidates the clinical features of gonococcal infections
      and discusses current treatment guideline. Several complications of gonorrhea,
      including pelvic inflammatory disease and disseminated gonococcal infection, are
      also described.

PMID- 10350729
TI  - Office Approach to Urethritis, Vaginitis, and Cervicitis in Adolescents.
AB  - Urethritis, cystitis, vulvovaginitis, and cervicitis in females, and urethritis
      in males, are among the most common genitourinary tract syndromes. A number of
      organisms may cause each of these entities, and most of these organisms may cause
      more than one clinical syndrome. Similarly, several syndromes are associated with
      common presenting symptoms. This article discusses evaluation, diagnosis, and
      management of each of these syndromes by the practitioner in an office setting.

PMID- 10350730
TI  - Pelvic Inflammatory Disease in Adolescent Females.
AB  - The most important medical and economic complication of sexually transmitted
      disease presently for young women is the development of pelvic inflammatory
      disease (PID) and its associated sequelae of ectopic pregnancy and infertility.
      This chapter discusses the epidemiology, pathogenesis, diagnosis, treatment, and
      sequelae of PID, with emphasis on the adolescent female.

PMID- 10350731
TI  - Sexually Transmitted Diseases in Homosexual Youth.
AB  - The prevalence of sexually transmitted diseases (STDs) in homosexual populations
      is due to a complex interrelationship of host and pathogen factors. This chapter
      explores the risk factors, epidemiology, microbiology, clinical aspects, and
      prevention of STDs in homosexual youth. This discussion focuses on male
      adolescents, because STDs are uncommon among exclusively homosexual women.

PMID- 10350732
TI  - Office and Laboratory Testing for STDs: Present and Future.
AB  - This chapter is aimed at the clinician in private practice or in a small clinic
      setting dealing with sexually transmitted diseases (STDs) but lacking immediate
      access to larger laboratories. Tests that should be routinely available for
      patients with STDs are described. Some of these tests may be performed on site,
      whereas others must be sent out to appropriate laboratories. Among the tests
      described are Gram stain testing, culture of Neisseria gonorrhoeae, darkfield
      examination, as well as testing for Chlamydia trachomatis, herpes simplex virus,
      chancroid, and syphilis.

PMID- 10350733
TI  - Psychosocial, Behavioral, and Educational Factors in Preventing Sexually
      Transmitted Diseases.
AB  - The risk of exposure to sexually transmitted diseases (STDs) among adolescents is
      determined by sociodemographic, environmental, psychosocial, behavioral, and
      biologic factors. These factors are complex, interrelated, and often poorly
      understood by health professionals caring for adolescents. This chapter aims to
      (1) describe specific risk factors associated with acquisition and transmission
      of STDs (with particular focus on behavioral risk factors); (2) discuss briefly
      various determinants and correlates of STD risk factors; and (3) propose
      strategies for education and prevention of STDs among teenagers.

PMID- 10350734
TI  - Chlamydia trachomatis Infections in Adolescents.
AB  - C. trachomatis is the most common bacterial cause of sexually transmitted
      diseases in the U.S. and represents a major health threat to sexually active
      adolescents. This chapter addresses special features involving the occurrence,
      consequences, diagnosis, treatment, and prevention of chlamydial genital
      infections.

PMID- 10350736
TI  - The Sports Physical.
AB  - This chapter discusses the preparticipation examination and outlines its
      components. Sports participation history and physical forms recently published by
      the Sports Medicine Committee of the American Academy of Pediatrics are provided.
      The author stresses the importance of performing a musculoskeletal assessment as
      part of the sports physical, and describes the "two-minute orthopedic
      examination."

PMID- 10350735
TI  - Sexually Transmitted Diseases Through the Ages.
AB  - The earliest recognized and traditionally described STDs, as well as HIV
      infection in the modern era, are discussed to show not only the evolution of
      their diagnosis and treatment, but also the complex nature of associated
      misconceptions, myths, and attitudes, some of which persist today.

PMID- 10350737
TI  - Medical Exclusion from Sport.
AB  - This chapter presents the American Academy of Pediatrics guidelines for
      participation in competitive sports, and discusses several conditions that may
      require exclusion. These conditions include absence of paired organs, hernia,
      Down syndrome, hypertension, cardiac and respiratory diseases, diabetes mellitus,
      dermatologic infections, and neurologic disorders.

PMID- 10350738
TI  - The Athlete and Menstruation.
AB  - In the past 20 years, a large number of female children and adolescents have
      begun participating in sports and physical activities previously not open to
      them. Female athletes may present with disorders of menstruation, such as delayed
      menarche, amenorrhea, oligomenorrhea, dysmenorrhea, and anovulation with
      irregular cycles. This chapter addresses these clinical situations and methods of
      treatment.

PMID- 10350739
TI  - Stress and the Adolescent Athlete.
AB  - Some degree of stress is inherent in all competitive situations. But some
      athletes experience excessive chronic stress that can contribute to a variety of
      psychological as well as physical maladies. This chapter emphasizes that an
      understanding of the antecedents, dynamics, and consequences of athletic stress
      can pave the way for preventive, diagnostic, and remedial measures. The role of
      physicians in helping coaches, parents, and adolescent athletes to keep
      competition with a healthy perspective is addressed, and a relaxation training
      program is described.

PMID- 10350740
TI  - The Status of Adolescent Fitness.
AB  - Over the past decade numerous reports have cited the health benefits associated
      with physical activity and regular exercise. This chapter reviews the current
      status of adolescent physical fitness, describes the benefits of physical
      fitness, and suggests methods the physician can use to improve the physical
      activity and fitness of adolescents.

PMID- 10350741
TI  - Steroids.
AB  - Anabolic steroids have been used by athletes for more than three decades in an
      attempt to improve athletic performance in sports requiring great strength and
      size. Within the last decade, use of these drugs has spread, involving not only
      elite athletes, but recreational athletes as well. In the last several years it
      has become apparent that adolescents are using anabolic steroids. The author
      describes the physiological effects and side effects of steroids, and reasons for
      their use by adolescents. The role of the physician in screening for and
      preventing steroid use is also addressed.

PMID- 10350742
TI  - Death on the Playing Field.
AB  - Sudden death during activity in children and adolescents is a rare event,
      considering the larger number of hours spent by this population in recreational
      and organized physical activities. The shock following such an occurrence
      frequently results in the family and physician's questioning whether the death
      could have been avoided. Common misconceptions are (1) that the physical fitness
      of a child correlates with the condition of the heart, and (2) that cardiac
      disorders responsible for sudden death give ample symptoms or clues to forecast
      these tragedies. This article discusses the more common disorders that cause
      sudden death during exercise, and addresses what, if any, practical measures can
      be taken to prevent it.

PMID- 10350743
TI  - Epidemiology of Sports Injuries in Adolescents.
AB  - This chapter discusses the epidemiology of injuries in organized sports in
      adolescents from junior high school through college age. Epidemiology includes
      the study of the distribution, causes, and prevention of disease. Epidemiologic
      data on sports injuries can help pediatricians to counsel families about the
      risks of specific sports, to know what injuries to expect in a given activity, to
      help athletic programs plan for medical care, and to advise athletes and coaches
      on injury prevention.

PMID- 10350744
TI  - Management of Soft Tissue Injuries.
AB  - This chapter is intended to help primary care physicians and other providers of
      health care to adolescents to become more knowledgeable about the management of
      soft tissue injuries. Discussion includes the pathophysiology of injury, the
      assessment of the degree of injury, and the rationale for the RICE (rest, ice,
      compression, and elevation) method of acute treatment. Principles of
      rehabilitation are also discussed along with objective criteria that can be used
      to make return-to-play decisions following a soft tissue injury.

PMID- 10350745
TI  - Minor Head Injuries in Sports.
AB  - This chapter describes the incidence, diagnosis, and management of cerebral
      concussions. A scheme for grading the severity of a concussion is presented and
      guidelines are given for when to allow the athlete to return to competition.
      Other types of head injuries described include epidural and subdural hematoma,
      subarachnoid hemorrhage, and malignant brain edema syndrome.

PMID- 10350746
TI  - Catastrophic Head and Neck Injuries.
AB  - Although all athletic injuries require careful attention, the evaluation and
      management of injuries to the head and neck should proceed with particular
      consideration. The actual or potential involvement of the nervous system creates
      a high-risk situation in which the margin for error is low. This chapter presents
      guidelines for classification, evaluation, and emergency management of
      catastrophic injuries that occur to the head and neck as a result of
      participation in competitive and recreational activities.

PMID- 10350747
TI  - Overuse Syndromes of the Shoulder and Arm.
AB  - The purpose of this chapter is to provide the physician with guidelines for the
      diagnosis and treatment of overuse syndromes. The author describes the normal
      anatomy of the shoulder and elbow, the physical examination of the patient with
      overuse syndrome, and various possible etiologies. The value of a conditioning
      program for the prevention of overuse syndromes is also discussed.

PMID- 10350748
TI  - Overuse Syndromes of the Back and Legs in Adolescents.
AB  - Common overuse syndromes of the back and lower extremities are discussed in terms
      of relevant history, physical examination, and treatment options. These syndromes
      are most often associated with a significant change or increase in normal
      training habits or with repetitive stresses to structures that are abnormally
      loaded. Strategies for treatment and prevention of recurrence are emphasized,
      along with the philosophy of "let the kids play the game at their own pace."

PMID- 10350749
TI  - Parents and Society: How Much the Problem; How Much the Solution?
AB  - Adolescence is a psychosocial maturational process-the developmental continuum
      between childhood and adulthood during which profound and dramatic physical,
      psychosocial, cognitive, and moral-ethical changes occur. Many problems that
      become manifest during adolescence are strongly influenced by parental,
      environmental, and societal factors. This article uses several case studies to
      examine the types of problems that can occur.

PMID- 10350750
TI  - Physicians, Parents, and Adolescents.
AB  - In treating adolescents, physicians have tended to be illness-oriented and less
      concerned with the psychosocial considerations of adolescence or the associated
      effects of health disorders. This article describes changing trends in family
      structure and society and examines ways in which the physician can better
      understand adolescents and bring about more comprehensive and effective health
      care.

PMID- 10350751
TI  - Principles of Office Counseling: The Healthy Adolescent.
AB  - The focus of this chapter is the parents of healthy adolescents and the problems
      that practitioners encounter when trying to meet the sometimes competing needs of
      parents and adolescents. Potential pitfalls in counseling parents of healthy
      adolescents are explored and practical approaches to common problems are
      described. Issues such as discipline, dating and social activities, and advice
      giving are addressed.

PMID- 10350753
TI  - Office Evaluation and Management of Family Dysfunction.
AB  - When adolescents present for medical care, they present as members of a family.
      This chapter discusses the interrelationship between family functioning and
      adolescent health, with guidelines for the practitioner on how to identify and
      work with dysfunctional families. Two case examples are provided to put this
      discussion in a clinical perspective.

PMID- 10350752
TI  - Principles of Office Counseling: The High-risk or Troubled Adolescent.
AB  - Skillfully interviewing, assessing, and counseling a troubled adolescent must be
      based on a method of understanding the origins of problem behaviors. The authors
      describe the HEADS model of assessment and intervention used in the High-risk
      Youth Programs at Childrens Hospital of Los Angeles and present recommendations
      for effective counseling for these patients.

PMID- 10350754
TI  - Single Parenting of the Adolescent.
AB  - This article discusses issues that are of interest and concern to all parents of
      adolescents, but that may be particularly difficult for single parents to manage.
      It also provides a framework for examining the areas of similarity as well as
      difference between the adolescent and the single parent. Attention is paid to the
      potential advantages of single-parent status.

PMID- 10350756
TI  - Parenting the Substance-Abusing Teenager: The Case Against ToughLove.
AB  - This chapter discusses the claims that ToughLove has made regarding successful
      outcomes and discusses concerns that need to be addressed by health care
      professionals who wish to endorse or refer patients to this organization.

PMID- 10350755
TI  - Parenting the Substance-Abusing Adolescent: ToughLove: A Parent Self-Help Group.
AB  - ToughLove is a self-help support group for parents of troubled teenagers and
      young adults who have had a pattern of serious and uncontrollable antisocial
      behaviors. In this chapter the authors describe the benefits of this program.

PMID- 10350757
TI  - Helping Parents of Suicidal or Depressed Adolescents.
AB  - Depression and suicide are common in the United States, especially in
      adolescents. This chapter discusses the ways that the physician may help parents
      of these adolescents and presents various options for parental involvement in the
      treatment process.

PMID- 10350758
TI  - Parenting the Chronically Ill Adolescent.
AB  - This chapter describes the role of the primary care physician in helping parents
      of chronically ill adolescents. The primary care practitioner can help parents
      (1) to become advocates for adolescents by helping them to understand the
      workings of the tertiary care system; (2) to be cognizant of important issues
      concerning the effect of the adolescent's illness on family functioning; and (3)
      to coordinate multidisciplinary treatment so that the care of the adolescent does
      not become fragmented.

PMID- 10350759
TI  - The Physician as Educator and Counselor of the Chronically Ill Adolescent.
AB  - The goal in counseling parents of adolescents with a chronic condition is to
      facilitate their understanding of adolescence and the disease process. This must
      be accomplished concurrently in a manner that promotes the teenager's healthy
      growth and development. This article focuses on the needs of parents in relation
      to this goal of promoting healthy development, with specific guidelines
      identified for health care providers.

PMID- 10350760
TI  - The Parents of the Pregnant Adolescent.
AB  - This chapter suggest ways in which practitioners can serve as advocates for
      parents of pregnant adolescents and can provide knowledgeable, nonjudgmental
      support of the entire family.

PMID- 10350761
TI  - Management of Adolescents with Eating Disorders: Role of the Primary Physician
      and Family.
AB  - It has been demonstrated that family dynamics and relationships are important in
      the development, promulgation, and potential resolution of eating disorders in
      adolescents. This chapter emphasizes the role of the health care provider in
      working with the adolescent patient with eating disorders and his or her family.

PMID- 10350762
TI  - Parenting the Sexually Abused Adolescent.
AB  - This article address the special problems and concerns for parents of adolescent
      girls who have been sexually assaulted. Parental responses to the sexual abuse of
      their child, the effects of sexual abuse on a child's behavior, and strategies
      that may help the parent and the adolescent to copy with the emotional crisis
      created by the assault are discussed.

PMID- 10350764
TI  - Obstacles to Adolescent Care in General Practice.
AB  - The physician who provides care for the adolescent must integrate a number of
      issues outside the usual framework of medical practice. The adolescent alternates
      between the child and young adult, and so creates a series of challenges for his
      or her physician relative to the young person's autonomy and the continued legal
      role of the family. This article outlines several problems inherent in work with
      adolescents. ADOLESC MED 2:389-396, 1991

PMID- 10350763
TI  - The Office Setting for Adolescent Care: Concerns of Physicians, Patients and
      Parents.
AB  - Rickey L. Williams The author describes several issues of concern to physicians
      caring for adolescents. Methods of recruiting adolescent patients and the problem
      of confidentiality are described. The care of adolescents with special needs is
      also discussed.

PMID- 10350765
TI  - Incorporating Adolescent Gynecology into a General Practice.
AB  - Including adolescent gynecologic services in a physician's practice provides
      patients with complete medical care, and the advantage to adolescent patients is
      tremendous: A sensitive area in their life can be addressed in a safe, familiar
      setting that will minimize the trauma of confronting this new and scary
      experience. This article describes the sequence of activities involved in an
      adolescent gynecologic examination and discusses the issue of confidentiality.
      Common gynecologic complaints of adolescents are also described.

PMID- 10350766
TI  - Overcoming Obstacles to Care: Ethical Issues.
AB  - The focus of this article is the conflict between the principle of autonomy and
      the principle of beneficence as they relate to the medical care of teenagers, and
      more specifically the thoughts involved in deciding which one applies more
      appropriately in a given circumstance.

PMID- 10350767
TI  - Obstacles to Adolescent Care: Economic Issues.
AB  - This article discusses economic issues that are relevant to a medical practice
      that deals with teenagers. The economic obstacles are divided into four major
      categories: (1) attitude toward physician; (2) sources of referrals and
      recruitment of patients; (3) overhead; and (4) billing procedures and accounts
      receivable.

PMID- 10350768
TI  - Overcoming Obstacles to Adolescent Care: Legal Issues.
AB  - Although the complex patchwork of laws governing adolescent health care remains
      imperfect and continues to present obstacles for some adolescents seeking care,
      the recent trend in the law represents a move toward a beneficial accommodation
      of the interest of adolescents, their parents, and the state.

PMID- 10350770
TI  - Infectious Mononucleosis.
AB  - This chapter reviews basic virology and immunopathogenesis of Epstein-Barr virus
      (EBV), clinical and laboratory features of infectious mononucleosis, and recent
      work on prevention and treatment of EBV-induced disease.

PMID- 10350769
TI  - Principles of Care for the Ill Adolescent.
AB  - This chapter outlines principles to assist the primary health care provider in
      the care of the ill adolescent. The focus is on how illness affects the ability
      of the adolescent to function rather than on specific illnesses and their
      manifestations.

PMID- 10350771
TI  - Chronic Fatigue Syndrome and Fibromyalgia in Adolescence.
AB  - A complaint of persistent, debilitating fatigue in an adolescent, accompanied by
      symptoms that meet the recently adopted criteria for chronic fatigue syndrome
      (CFS), presents a difficult challenge for the clinician. This article describes
      the diagnostic criteria for CFS and fibromyalgia, and discusses the epidemiology,
      etiology, and management of these conditions.

PMID- 10350772
TI  - Gastrointestinal Disorders in Adolescents.
AB  - Gastrointestinal disorders are common in adolescents. Chronic abdominal pain,
      lactose intolerance, constipation, and irritable bowel syndrome represent the
      most common gastrointestinal complaints, while inflammatory bowel disease is the
      major chronic disorder of concern to clinicians. Gallstones and pancreatitis may
      also be seen in this age group. The authors describe the diagnosis and treatment
      of these gastrointestinal disorders.

PMID- 10350773
TI  - Hepatitis in Adolescents.
AB  - Hepatitis virus infection poses an important health problem to adolescents
      because of the morbidity of acute disease, the risk of chronic hepatitis, and the
      risk of vertical transmission during pregnancy. This paper reviews the
      epidemiology, clinical course, and prevention of hepatitis viral infections in
      adolescents.

PMID- 10350774
TI  - Thyroid Disorders in Adolescents and Young Adults.
AB  - Common thyroid disorders affecting adolescents and young adults are reviewed.
      Normal physiology of the thyroid gland and diagnostic tests are discussed and
      specific disorders and their treatment are described.

PMID- 10350775
TI  - Diabetes Mellitus in Adolescents.
AB  - This chapter focuses on new scientific developments in the physiology,
      management, and psychological impact of diabetes in adolescents.

PMID- 10350776
TI  - Arthritis in Adolescence.
AB  - Arthritis may be one of many symptoms of a systemic illness or a sole
      manifestation of an inflammatory or infectious condition localized to the
      joint(s). The differential diagnosis of arthritis and the more common conditions
      encountered in adolescents that may begin with arthritis are discussed.

PMID- 10350777
TI  - Essential Hypertension.
AB  - From blood pressure studies in younger individuals it has become clear that
      essential hypertension may have its origin in childhood and adolescence. This
      chapter addresses the diagnosis and management of blood pressure abnormalities in
      adolescents.

PMID- 10350778
TI  - Lipid Disorders in Adolescents.
AB  - Hyperlipidemias affect one person in ten, increasing the risk of illness and
      premature death. Although they are asymptomatic early in life, their
      identification and successful treatment in adolescence can establish management
      regimens and habits that protect and extend life. This chapter describes the
      diagnosis and management of hyperlipidemias and discusses the value of universal
      screening of adolescents.

PMID- 10350780
TI  - Asthma in Adolescence.
AB  - Asthma is the most common chronic illness in adolescents and is one of the most
      important causes of school absenteeism, emergency room visits, and
      hospitalizations. The authors provide the clinician with an updated review of
      recent developments in the diagnosis and treatment of asthma.

PMID- 10350779
TI  - Acute Respiratory Disorders in Adolescents.
AB  - Acute respiratory infections are the most common reason that people seek medical
      care. This chapter emphasizes evaluation and management of uncomplicated acute
      respiratory infections that are commonly encountered in the clinical practice of
      adolescent medicine. Serious complications and conditions encountered in
      chronically ill adolescents are briefly discussed.

PMID- 10350781
TI  - Seizures in Adolescents.
AB  - Adolescents with seizure disorders are seen frequently in pediatric practice, and
      caring for such patients requires a thoughtful approach to their biological and
      psychosocial needs. The diagnosis and management of seizure types and seizure
      syndromes commonly seen in adolescence are discussed.

PMID- 10350782
TI  - Hematuria and Proteinuria.
AB  - Evaluation of an adolescent with proteinuria or hematuria must address several
      general issues. Are the urinary abnormalities clinically significant? What is the
      etiology of the proteinuria or hematuria? What treatment, if any, is needed?
      These issues are addressed, and the evaluation and workup of these patients are
      described.

PMID- 10350784
TI  - The Adolescent with Chronic Pains: Basic Principles of Psychosomatic Medicine.
AB  - This chapter examines the diagnosis and management of psychosomatic illness in
      adolescents. Included are case studies and discussions of chronic pain, including
      chronic abdominal pain, chronic chest pain, and chronic headaches.

PMID- 10350783
TI  - Urinary Tract Infection.
AB  - Urinary tract infections are among the most common bacterial diseases encountered
      by clinicians in practice. They are estimated to result in more than five million
      office visits annually, at a cost of more than one billion dollars. The etiology,
      presentation, diagnosis, and treatment of urinary tract infections in female and
      male adolescents are reviewed.

PMID- 10350785
TI  - Europe: managed care principles gaining ground. Interview by Lisa Paul.

PMID- 10350786
TI  - Managing managed care.
AB  - Managed care trends--such as acquisitions of local physician practices, mergers
      among payor and provider organizations and changes to the current role of
      managing care--means a difference in the way information systems must operate.

PMID- 10350787
TI  - Seize the disease! If you don't take charge of your high-risk, high-cost
      patients, your competitors will.

PMID- 10350788
TI  - Behavior's problem. Overwhelmingly regulated by managed care, behavioral health
      providers still struggle for--and against--computerization.

PMID- 10350789
TI  - Desktop management. Bringing improved services to the users.

PMID- 10350790
TI  - Spotlight. Managed care information systems.

PMID- 10350791
TI  - Using activity-based costing and theory of constraints to guide continuous
      improvement in managed care.
AB  - Activity-based costing and the theory of constraints have been applied
      successfully in many manufacturing organizations. Recently, those concepts have
      been applied in service organizations. This article describes the application of
      activity-based costing and the theory of constraints in a managed care mental
      health and substance abuse organization. One of the unique aspects of this
      particular application was the integration of activity-based costing and the
      theory of constraints to guide process improvement efforts. This article
      describes the activity-based costing model and the application of the theory of
      constraint's focusing steps with an emphasis on unused capacities of activities
      in the organization.

PMID- 10350792
TI  - Harnessing technology: the creation of an electronic care management record in a
      social health maintenance organization.
AB  - Information technology has been used successfully to improve quality and
      efficiency in serving customers. This article describes how a Social HMO
      developed a proprietary software program that enables personal care planners to
      gather and exchange patient information from laptop computers in members' homes.
      What is unique about this program is that it enables the health plan to monitor
      and assess the medical and social needs of frail seniors in real time.

PMID- 10350793
TI  - Building global billing and payment systems.
AB  - Global fees for episodes of care is perhaps one of the most progressive risk
      based contracting techniques to emerge in managed care. Although global fees are
      theoretically a far more advanced and efficient payment technique than either fee
      for-service or capitation, the chief obstacle preventing their implementation is
      the archaic billing and claims transaction systems operating in most "modern"
      health plans, hospitals, and physician offices. This article discusses various
      billing techniques available to interested parties who desire to enter into
      episode of care contracting venues.

PMID- 10350794
TI  - Integrated delivery systems: non fait accompli.
AB  - This article explores the themes that advocates of integrated delivery systems
      (IDSs) hoped would allow them to favorably leverage the final stages of managed
      care evolution: revenue generation, cost control, and quality improvement. In
      reality, however, IDSs have been highly unsuccessful in growing market share,
      competing against other managed care forms, and integrating delivery systems-
      their raison d'etre. Two key concepts in global theory, risk and episodic
      management, are introduced, and utilized to show how IDSs addressed these
      fundamental properties inappropriately. As a result, financial results and system
      performance have been dismal. A prognosis is given as well as suggestions for
      improvement through risk bifurcation, global fees, and integrated episodes of
      care.

PMID- 10350795
TI  - Enhancing managed care's role in long-term care: building on the aging network.
AB  - As Medicare managed care organizations grow, they will likely enroll more
      functionally impaired older people, as well as individuals with special
      linguistic and cultural needs. Traditional aging network service providers have
      special expertise to serve these populations. To date, however, the aging network
      has only been integrated into the operations of managed care on a very limited
      basis, primarily by demonstration projects. This article highlights program
      examples of collaboration between the aging network providers and managed care
      organizations for case management, screening, assisted living, and adult day
      care. The steps managed care organizations should take to build on the expertise
      of the aging network are described.

PMID- 10350796
TI  - Coming to grips with risk-sharing: capitation in the long-term care industry.
AB  - "Risk" means the transference of the financial payment for specified services
      from one entity to another. Risk transfers can occur from payers to providers or
      between providers. Risk can be transferred through a number of different payment
      structures. The concept of sharing risk originated several decades ago as
      employers began to tighten their health care budgets. Meticulous attention to
      details is a necessity if risk contracting is to be a profitable venture for long
      term care providers. Long-term care providers are in different stages of
      development with risk-sharing contracting. With some attention to detail, the
      formation of the right team, and an understanding of costs, ancillary provider
      risk sharing can be profitable for all partners involved. This article details
      issues that should be considered before entering into a risk-sharing arrangement.

PMID- 10350797
TI  - Postacute care organizations: a solution for Medicare risk HMOs.
AB  - A postacute care organization is a company that contracts with HMOs and other
      types of insurers and risk-bearing groups to ensure the health plan's appropriate
      and cost-effective use of medical services available outside of the hospital
      setting. Through proactive and intensive case management of patients and
      postacute care providers, these organizations minimize inappropriate or
      unnecessary hospitalizations and deliver the following results to clients:
      reduced overall medical costs; higher quality postacute care services; increased
      plan retention of members through increased patient, family, and provider
      satisfaction. Postacute care organizations represent a solution for Medicare Risk
      HMOs and other health plans who are experiencing great difficulty in managing the
      financial risk and operational challenges related to their benefit plans for
      higher risk groups. Coordinated Care Solutions, Inc. (CCS) is an example of a
      company meeting the rapidly growing demand for postacute care management
      services. This article describes why there is a need for these services and
      studies CCS's model of delivering postacute care management services and value to
      its clients.

PMID- 10350798
TI  - German health care system: an option uber alles?

PMID- 10350799
TI  - Consolidation: the changing face of the behavioral health care industry.

PMID- 10350800
TI  - How to implement a case-mix system in less than a year.

PMID- 10350801
TI  - How to talk to children about death.

PMID- 10350802
TI  - Giving new life through the Eden Alternative.

PMID- 10350803
TI  - Easing cancer pain through treatment options.
AB  - The diagnosis of life-threatening illness delivers patients and families into new
      and often unfamiliar territory--a place one author has named "the country of
      illness." There are no easy road maps in that new world, and the way is made
      harder by the burdens thrust upon its inhabitants. For cancer patients, one of
      the greatest burdens is the pain that comes with the disease.

PMID- 10350804
TI  - The power of empowerment.
AB  - Several years ago, when "Community General Hospital" became part of "Big State
      Health System," its board of trustees became a "subsidiary operating board." Big
      State's Board now holds final authority over budget, strategic plans, CEO
      selection and board appointments.

PMID- 10350805
TI  - Donation--a difficult but most important discussion.
AB  - Organ and tissue donation is an important topic that needs to be discussed with
      each family before, during or after the loss of a loved one. Currently in
      Michigan there are more than 2,400 people waiting for an organ or cornea
      transplant and many more in need of heart valves, bone, vein or skin grafts.
      Donation gives a grieving family a choice that could be the one positive outcome
      to a tragic or untimely death--saving or greatly improving the quality of
      someone's life.

PMID- 10350806
TI  - New guidelines in place.
AB  - On Dec. 1, 1998, the Office of the Inspector General (OIG) of the Department of
      Health and Human Services published its Compliance Program Guidance for Third
      Party Medical Billing Companies to assist companies in the development of
      compliance programs to promote adherence to applicable laws.

PMID- 10350807
TI  - Don't be a dope about drug testing.

PMID- 10350808
TI  - The second Tuesday. We talk about feeling sorry for yourself.
AB  - The following is an excerpt from Tuesdays with Morrie, a best-selling book by
      Mitch Albom about his relationship with a former professor and mentor. Albom
      rediscovered Morrie Schwartz in the last months of the older man's life. Knowing
      he was dying, Morrie visited with Mitch in his study every Tuesday. Their
      rekindled relationship turned into one final class: lessons in how to live.

PMID- 10350810
TI  - It's time for a revolution.

PMID- 10350809
TI  - Service with S.O.U.L. (smile, open, undivided attention, learn).

PMID- 10350812
TI  - MHA supports passage of pain management legislation.

PMID- 10350811
TI  - Taking charge of uncompensated care, Part II.

PMID- 10350813
TI  - What road will you take? Part II. Charting an organizational course for community
      accountability.
AB  - Across the country, numerous perception studies have been conducted to gauge the
      public's opinion of America's health care system and the role local providers
      play in serving community health needs. The results consistently show that, in
      general, people are unaware of the myriad of benefits above and beyond the
      provision of general acute care services provided by not-for-profit community
      health care organizations.

PMID- 10350814
TI  - Gaining wholeness.

PMID- 10350815
TI  - Stewardship requires financial health.

PMID- 10350817
TI  - Building support for an intranet.

PMID- 10350816
TI  - Improving end-of-life care: what providers need to know.
AB  - There is no question that advanced medicine and improved public health have made
      living into old age a reality for many people. Currently the average life
      expectancy for women is 79 years; for men the age is 73. Many of us can
      reasonably assume that we will live longer lives than did our parents and
      grandparents. Unfortunately, many also assume that modern medical care has
      improved care for people in the last phase of life. However, this may not be the
      case.

PMID- 10350818
TI  - Is there a doctor in the house?. Interview by Bill Siwicki.

PMID- 10350819
TI  - Taking a 'necessary step'. A specialty clinic uses a records system to improve
      care by automating protocols, tracking medications and more.

PMID- 10350820
TI  - Putting an end to the paper chase.

PMID- 10350821
TI  - Choosing a network backbone.

PMID- 10350822
TI  - The new generation of pharmacy systems.

PMID- 10350823
TI  - Why build an interactive site?

PMID- 10350824
TI  - Bring cutting-edge 'MedTeams' concepts to your ED: novel program eliminates
      errors, cuts liability risks.

PMID- 10350825
TI  - Proven, error-reducing approaches--try them in your ED.

PMID- 10350826
TI  - Communicate with bone conduction.

PMID- 10350827
TI  - Update on EMTALA and managed care: HCFA issues special advisory bulletin.

PMID- 10350828
TI  - 'Tracking codes' may increase compliance with HEDIS.

PMID- 10350829
TI  - Capitation's technical component: a potential deal-breaker.

PMID- 10350830
TI  - Zero-based budgeting eases the transition to specialty capitation.
AB  - Zero-based budgeting--a simple payment methodology for specialists still
      transitioning to capitation--is being touted as preferable to the popular contact
      cap model. Here's how it works.

PMID- 10350831
TI  - Health plan strives to create true partnership with capitated physicians.

PMID- 10350832
TI  - Do your capitation expenses match these benchmarks?
AB  - Data Insight: By understanding the percentage of premium dollars allocated to
      each category of expense, you can determine how much to expect in percent-of
      premium contracts and how much to allocate for subcapitation.

PMID- 10350833
TI  - Disease-specific report card pushes for improved care.
AB  - A California plan has unveiled a report card rating physician groups on their
      treatment of asthma patients. Is this the long-awaited signal that capitated
      physicians will be evaluated more by their management of care than their impact
      on the bottom line?

PMID- 10350834
TI  - Mission-driven marketing: a rural example.
AB  - Marketing receives little attention in the academic healthcare management
      literature, possibly because it is associated with pursuit of profit rather than
      community benefit. However, a marketing perspective can be applied to the pursuit
      of the traditional missions of healthcare delivery organizations. Mission
      oriented market selection criteria could include characteristics such as
      relevance to mission, underserved or vulnerable population status, resistance to
      care, limited resources, and low accessibility. A survey conducted in a rural
      county is used to demonstrate ways that underserved market segments can be
      identified and targeted. In the market surveyed, men used less medical care than
      women; depressed people and those with low levels of education used less medical
      care than people without these characteristics. Consumers were more likely to
      defer care because of cost if they lacked health insurance coverage, were female,
      were under age 55, had fair health status, were depressed, and were chronically
      ill. Marketing strategies worthy of consideration relate to price (e.g., free
      care, coupons and sales for eligible individuals), distribution (e.g., visiting
      nurses, malls and fairs, occupational medicine programs), product (e.g.,
      satisfaction, waiting time, attractiveness, assertive follow-up), and promotion
      (education about insurance benefits, facilitating development of regular sources
      of care, health education).

PMID- 10350835
TI  - In their own words: how hospitals present corporate restructuring in their annual
      reports.
AB  - Hospitals operate in an environment with strong institutional pressures, in which
      legitimacy is critical to an organization's access to resources. In such an
      environment, organizations can increase their legitimacy by engaging in
      activities or discussing them in a manner that signals that the organization
      adheres to values held by its costituents. One important symbol of organizational
      actions or intentions is the formal organizational structure. When hospitals
      began to adopt a corporate structure in the early eighties, the way in which they
      presented this decision to the public was as important as the technical merits of
      the decision itself. This study investigates, through an analysis of annual
      reports, what hospitals signaled about their adoption of a corporate structure.
      The findings suggest that through restructuring, hospitals signaled that they
      were in line with practices advocated in the industry and literature (e.g.,
      adhering to business values, protection of assets, or increasing patient
      services). By presenting multiple reasons for restructuring, hospitals could
      signal their attention to the needs of various constituents, and by touching only
      briefly on each reason, they could ignore the potential conflict between demands
      such as lower hospital cost and increased services. The findings also suggest
      that the first hospitals to adopt a corporate structure sought to educate
      constituents about restructuring by devoting a greater share of their annual
      report to the topic than later adopters and by enumerating a larger number of
      anticipated benefits from the structure, which would have enhanced the
      innovation's legitimacy in the early years.

PMID- 10350837
TI  - Interview with U. S. Air Force Surgeon General, Charles H. Roadman, II, M.D..
      Interview by James A. Johnson.

PMID- 10350838
TI  - Leadership: some things to think about.

PMID- 10350836
TI  - Evaluation of the VA mobile clinics demonstration project.
AB  - In 1988 the Veterans' Benefits and Services Act attempted to solve the problem of
      the lack of adequate VA healthcare facilities in rural areas by establishing a
      demonstration program using mobile clinics. Six clinics operated in areas that
      were at least 100 miles from a VA healthcare facility during the time period
      between October 1, 1992 and May 28, 1994. This article evaluated the effect of
      the mobile clinics' structural limitations on clinical care, the increased number
      of sites on VA usage, and cost. Limited space for storage of medical records and
      the unavailability of laboratory, electrocardiographic, or radiographic
      facilities significantly affected clinical practice. However, even with these
      space limitations, veterans' use of healthcare in the areas served by the mobile
      clinics increased significantly in comparison to reference areas. The direct
      costs per visit averaged more than three times what the VA would have reimbursed
      the private sector.

PMID- 10350839
TI  - Structuring managed care: lessons from traditional insurance.

PMID- 10350840
TI  - Animated simulation: a valuable decision support tool for practice improvement.
AB  - Animated computer simulation is a powerful tool for healthcare operation
      improvement. As a decision support tool, it offers a systematic method to compare
      alternative approaches to healthcare operations. Because staff interaction is
      encouraged by this tool, simulation projects facilitate staff team building and
      process change ownership. Information that is not used as applied knowledge for
      the purpose of improvement is worthless. Simulation offers management detailed
      knowledge of processes, enabling management to make better-informed decisions by
      providing performance data, such as resource usage rates, patient wait times,
      capacity rates, and process performance information. Alternatives under
      consideration can be compared and modified without high financial, personal, and
      customer costs to the healthcare operation. The knowledge gained from each
      alternative's simulation response variables can be evaluated against set
      criteria, the status quo, and each other to determine the best option. Current
      automation systems and software products allow decision makers to use this tool
      without investing resources in errant options. A simulation project strategy with
      examples and a case study of change and renovation of a family practice clinic
      are provided.

PMID- 10350841
TI  - Little League Coaches Training Program.

PMID- 10350842
TI  - Riley Riders Bike Safety Smart Program.

PMID- 10350843
TI  - Baseline assessments of patient satisfaction: what one academic practice did with
      the findings.

PMID- 10350844
TI  - Ambulatory care centers: the pre-planning process.

PMID- 10350845
TI  - Using information to avoid financial disaster in physician practice purchase and
      employment.

PMID- 10350846
TI  - Mobilizing the power of ambulatory care to meet your system's strategic
      objectives.

PMID- 10350847
TI  - The promise and plight of IT to IDNs.

PMID- 10350848
TI  - Eight trends in ambulatory facility design.

PMID- 10350849
TI  - SACP and INTELLIMED International Corp.: offering the ambulatory care
      professional an arsenal of comparative data tools!!

PMID- 10350850
TI  - The paradox of new construction to save dollars.

PMID- 10350851
TI  - The Evanston and Glenbrook Hospitals breast health and mammography center at
      Nordstrom.

PMID- 10350852
TI  - Where does ambulatory care fit in your hospital's integrated delivery system?

PMID- 10350853
TI  - Mobile medical clinics offer alternative to renovation and construction.
AB  - Mobile Health Care Programs have many attributes. Every organization genuinely
      concerned with client access to their services should consider having one. When
      the need to service outlying areas arises, a mobile clinic offers more
      flexibility and is the most economically feasible alternative. Granted, there is
      no shortage of vacant structures for rent or purchase in rural America. That, of
      course, is just the start; you also have the expense of renovating the interior
      to accommodate the patients and staff. And do not forget the four P's: Planners,
      Permits, Politics and Payola (taxes and fees).

PMID- 10350854
TI  - 1997 Quality Awards. Society for Ambulatory Care Professionals, American Hospital
      Association.

PMID- 10350855
TI  - Trinity Regional Health System's new outpatient campus: patient-centered design
      to create a healing, therapeutic environment.

PMID- 10350856
TI  - Organization renewal for ambulatory care.

PMID- 10350857
TI  - The psychology of major gifts.

PMID- 10350858
TI  - Taking a tip from an old tune: "It ain't necessarily so!".
AB  - Unchallenged assumptions can cause development departments to spend money
      unproductively, markedly increasing fund-raising costs. They can cause us to
      unwittingly alienate donors, reducing development revenues in ways that are
      difficult to detect. In short, conventional wisdoms are dangerous.

PMID- 10350859
TI  - The art and science of donor walls.
AB  - Thanking donors, in an appropriate manner, can be a challenge. When a significant
      contribution is received, one that makes an impact on your organization, how do
      you show your sincere appreciation to the donor, and at the same time herald the
      gift to the community? The solution for many organizations is the donor wall.

PMID- 10350860
TI  - How do you teach baby boomers philanthropy?

PMID- 10350861
TI  - New I.R.S. valuation rate gives charitably inclined significant tax savings.

PMID- 10350863
TI  - Maintaining hospital security after two bus crashes in 72 hours.

PMID- 10350862
TI  - Hospital center granted arrest powers for its security officers.

PMID- 10350864
TI  - An interview with: R. Steve Truluck on hospital security in a college campus
      setting.

PMID- 10350865
TI  - Gaunt: don't underestimate Y2K challenge to disaster-management plans.

PMID- 10350866
TI  - Customer-friendly approaches: can they reduce ER and ICU waiting area security
      problems?
AB  - Physical confrontations and verbal abuse plus incessant complaints and arguments
      involving families of ER and ICU patients vs. staff members and families vs.
      families. In many hospitals, that can be the daily fare. The answer for most has
      been more security to prevent matters from getting out of hand. Two hospitals
      Johnson City Medical Center, Johnson City, TN, and Sinai Hospital, Baltimore, MD-
      have taken "customer-friendly" approaches that sound like public relations
      pitches but in actual practice have led to a sharp drop in security-related
      problems and an equally dramatic improvement in customer relations, officials
      say. In this report, we'll give details on what they are doing and how it is
      working out.

PMID- 10350868
TI  - Best healthcare project. Galter Medical Pavilion Swedish Covenant Hospital,
      Chicago.

PMID- 10350867
TI  - How hospital dealt with press during DiMaggio's stay.

PMID- 10350869
TI  - Clinical decision making--what every non-clinician manager should know but was
      never taught.
AB  - The management of a health care system requires making decisions and establishing
      policies that can affect the process of patient care. Clinicians often complain
      that these decisions and policies are made by people without clinical training.
      Clinical knowledge is not a prerequisite for a career in health policy or
      management. Even graduates of accredited health administration programs are not
      required to understand the process of clinical decision making or the nature of
      medical practice. Much of the health services literature advocates a shared
      decision-making model for clinicians and managers. However, most of the
      literature focuses on how to involve physicians in management decision making;
      almost none discusses management involvement in clinical decisions. This paper
      briefly examines how non-clinician managers can support the clinical decision
      making process and then specifies the knowledge and skills required for them to
      play this role.

PMID- 10350870
TI  - Graduate education in health decision support systems (HDSSs): reconfiguring the
      health information system (HIS) basket or putting HDSS Humpty Dumpty together
      again?
AB  - Building on previous discussions in graduate health information system (HIS)
      education, this article focuses on the design of a course in health decision
      support systems (HDSSs). The goal here is not simply to add to existing
      prospectives of HIS theories and methodologies, but to prepare these students for
      changing trends in HIS technologies and applications and for new challenges in
      HIS administration and impacts arising from these emerging, more advanced, and
      complex technologies. Specifically, advancing HDSS technology: (1) promises to
      close the gap between theory and practice, (2) creates a new perspective for the
      application of information technologies in health care organizations, and (3)
      enhances innovations in the management and implementation of health information
      technologies. This paper highlights the need for graduate education in HDSS
      domain knowledge and how such knowledge can be taught in preparing students for
      managing change in the future health care environment.

PMID- 10350871
TI  - The Socratic Method: analyzing ethical issues in health administration.
AB  - The Socratic Method has long been recognized by the legal profession as an
      effective tool for promoting critical thinking and analysis in the law. This
      article describes ways the technique can be used in health administration
      education to help future administrators develop the "ethical rudder" they will
      need for effective leadership. An illustrative dialogue is provided.

PMID- 10350872
TI  - Use of the Internet for real-time class instruction in a graduate health services
      administration program.
AB  - The Internet has been used as a medium for distance learning for several years.
      Many universities are using Internet technologies such as electronic mail,
      LISTSERVs, newsgroups, and web pages to supplement or replace traditional
      classroom meetings. However, these modes of communication when used in place of
      traditional classroom instruction lack the interactivity among students and
      between the students and the instructor that would be achieved in the ideal
      classroom setting. Internet teleconferencing, however, appears to offer the
      opportunity for real-time, interactive class meetings on the Internet. This paper
      details the use of the Internet for real-time teleconferencing as a substitute
      for classroom meetings at the graduate university level, and offers some insight
      into the quality and usability of Internet teleconferencing given currently
      available hardware, software, and communications links.

PMID- 10350873
TI  - Executive team building as a management strategy in international health care
      settings: case study of the planning, implementation, and evaluation of a
      collaborative educational intervention.

PMID- 10350874
TI  - The use of computer-based simulation in a Master of Health Administration
      curriculum.
AB  - In this paper, the use of a simulation tool to support the appreciation of data
      and information by health administration students with varied backgrounds and
      educational training is discussed. Specifically, the authors developed
      educational and training material that can be used in a variety of courses to
      improve information management and decision making. Improved information
      management is being recognized as a critical component of the movement to achieve
      consistent quality in patient care, institutional performance, and policy
      planning. This is now especially important as new information systems are making
      data and good quality evidence increasingly more available. Ultimately, it is
      hoped that this process will lead to findings that will assist evidence-based
      decision making within all health providers.

PMID- 10350875
TI  - Codman Award winners share success stories.

PMID- 10350876
TI  - JCR sends international accreditation standards to field review.

PMID- 10350877
TI  - Reducing errors in health care.

PMID- 10350879
TI  - Resolving adverse accreditation decisions.

PMID- 10350878
TI  - ORYX requirements modified for behavioral health and home care organizations.

PMID- 10350880
TI  - Public information policy revised.

PMID- 10350881
TI  - Success with electronic PPS.

PMID- 10350882
TI  - Designing an effective admissions process.

PMID- 10350883
TI  - Bringing the medical team on board.

PMID- 10350884
TI  - Reviewing admissions policies under PPS.

PMID- 10350885
TI  - Reengineering nursing services.

PMID- 10350886
TI  - Hammering out new "arrangements".

PMID- 10350887
TI  - States tackle long-term care issues.

PMID- 10350888
TI  - From assessment to outcomes: dynamic care planning.

PMID- 10350889
TI  - Software supplier survey.

PMID- 10350890
TI  - When hiring, look for outcomes.

PMID- 10350891
TI  - Adapting staff to a new environment.

PMID- 10350892
TI  - Feds set antifraud sights on assisted living.

PMID- 10350893
TI  - Turning a new leaf: fall prevention.

PMID- 10350894
TI  - Laboratory's/laboratorians' duty to provide information not just data.

PMID- 10350895
TI  - The use of interactive technology in the classroom.
AB  - This article discusses the benefits that clinical laboratory science students and
      instructors experienced through the use of and integration of computer
      technology, microscopes, and digitizing cameras. Patient specimens were obtained
      from the participating clinical affiliates, slides stained or wet mounts
      prepared, images viewed under the microscope, digitized, and after labeling,
      stored into an appropriate folder. The individual folders were labeled as
      Hematology, Microbiology, Chemistry, or Urinalysis. Students, after obtaining the
      necessary specimens and pertinent data, created case study presentations for
      class discussions. After two semesters of utilizing videomicroscopy/computer
      technology in the classroom, students and instructors realized the potential
      associated with the technology, namely, the vast increase in the amount of
      organized visual and scientific information accessible and the availability of
      collaborative and interactive learning to complement individualized instruction.
      The instructors, on the other hand, were able to provide a wider variety of
      visual information on individual bases. In conclusion, the appropriate use of
      technology can enhance students' learning and participation. Increased student
      involvement through the use of videomicroscopy and computer technology heightened
      their sense of pride and ownership in providing suitable information in case
      study presentations. Also, visualization provides students and educators with
      alternative methods of teaching/learning and increased retention of information.

PMID- 10350896
TI  - Scholarly activities among clinical laboratory science faculty.
AB  - OBJECTIVES: To describe the research and scholarly productivity of faculty in
      four-year college and university clinical laboratory science (CLS) programs. To
      identify meaningful scholarship, to assign values to that scholarship, and to
      list the top 15 CLS programs according to faculty research productivity. DESIGN:
      In 1996, a national study involving 127 college and university CLS programs was
      conducted to determine whether faculty were participating in research. A
      questionnaire was distributed to 505 faculty members. Data from 286 respondents
      (57% response) representing 114 of 127 (90%) CLS programs were analyzed. SETTING:
      The study took place at The Ohio State University with collaboration from the
      University of Tennessee-Memphis and the University of Minnesota. PARTICIPANTS:
      All CLS faculty within a four-year university or college sponsoring a CLS program
      were invited to participate. MAIN OUTCOME MEASURES: To determine whether CLS
      faculty scholarly activities have been strengthened in the last decade, to
      quantitate scholarship productivity by point assessment, and to list the top 15
      CLS programs according to faculty research productivity. RESULTS: Research
      productivity included time spent in research, numbers of publications and
      presentations, and grantsmanship. Data indicate that faculty who possess earned
      doctorates and are employed by research universities have higher levels of
      research productivity. While 46% of the CLS faculty hold doctorates and 50% are
      tenured, 42% of all CLS faculty members have not published a research paper or
      abstract since 1990. Conversely, faculty in some non-research institutions may
      not be expected to participate in such scholarly activities. On the other hand,
      23% of the faculty responding had published six or more articles or abstracts
      since 1990, 46% were successful in obtaining external funding, and 15% of faculty
      members had been awarded grants larger than $100,000. CONCLUSIONS: The top 10% of
      clinical laboratory science faculty researchers are performing approximately one
      half of all scholarly activities. The top fifteen research programs in CLS are
      identified, and not surprisingly, are located in research universities. In the
      past decade, and generally speaking, CLS faculty have made progress in
      scholarship including highest degree obtained, publications, presentations, and
      grantsmanship.

PMID- 10350897
TI  - Clinical laboratory technician to clinical laboratory scientist articulation and
      distance learning.
AB  - Laboratory workers and educators alike are challenged to support access to
      education that is current and provides opportunities for career advancement in
      the work place. The clinical laboratory science (CLS) program at the Medical
      College of Georgia in Augusta developed a clinical laboratory technician (CLT) to
      CLS articulation option, expanded it through distance learning, and integrated
      computer based learning technology into the educational process over a four year
      period to address technician needs for access to education. Both positive and
      negative outcomes were realized through these efforts. Twenty-seven students
      entered the pilot articulation program, graduated, and took a CLS certification
      examination. Measured in terms of CLS certification, promotions, pay raises, and
      career advancement, the program described was a success. However, major problems
      were encountered related to the use of unfamiliar communication technology;
      administration of the program at distance sites; communication between
      educational institutions, students, and employers; and competition with CLT
      programs for internship sites. These problems must be addressed in future efforts
      to provide a successful distance learning program. Effective methods for meeting
      educational needs and career ladder expectations of CLTs and their employers are
      important to the overall quality and appeal of the profession. Educational
      technology that includes computer-aided instruction, multimedia, and
      telecommunications can provide powerful tools for education in general and CLT
      articulation in particular. Careful preparation and vigilant attention to
      reliable delivery methods as well as students' progress and outcomes is critical
      for an efficient, economically feasible, and educationally sound program.

PMID- 10350898
TI  - Strategies for program survival: the College of St. Scholastica.

PMID- 10350899
TI  - Punishing the pain. Treating chronic pain with prolotherapy.

PMID- 10350900
TI  - The future looks bright.

PMID- 10350901
TI  - A remedy for reticent reimbursement.

PMID- 10350902
TI  - Decoding the mystery. Evaluating complementary and alternative medicine.

PMID- 10350903
TI  - Motivating the back injury patient.

PMID- 10350905
TI  - Gene patents push labs to their limits.

PMID- 10350904
TI  - Technology through television. Pediatric telemedicine furthers rehab's continuum
      of care.

PMID- 10350907
TI  - A modern merger.

PMID- 10350906
TI  - More than one way to look for HER2.

PMID- 10350908
TI  - Anatomic pathology computer systems.

PMID- 10350909
TI  - Diagnosing antiphospholipid antibody syndrome.

PMID- 10350910
TI  - From toy to tool: the development of immersive virtual reality environments for
      psychotherapy of specific phobias.
AB  - Virtual Reality (VR) entered the mental health field some years ago. While the
      technology itself has been available for more than ten years now, there is still
      a certain amount of uncertainty among researchers and users as to whether VR will
      one day fulfill all it's promises. In this chapter we are giving an overview of
      the implementation of the technology in our mental health research facility in
      Basel, Switzerland. The development of two applications for use with
      claustrophobic and acrophobic patients perspectively serves just as an example
      within this context. Some may say, the chapter is too much based on technical
      considerations. Strictly speaking, VR is pure technology, even knowing that this
      special form of technology has sensory, psychological and even philosophical
      implications not known from other human computer interfaces so far. As far as we
      are concerned, the development of the technology for use within the mental health
      sector has merely just begun. As today's mostly used immersive output devices
      (Head-mounted Displays, shutter glasses) do not have a satisfactory resolution,
      do restrict movements and prevent multi-user-capabilities, there will be a soar
      of mental health applications the day some or at least the most important of
      these obstacles have been overcome.

PMID- 10350911
TI  - Virtual reality therapy: an effective treatment for phobias.
AB  - Behavioral therapy techniques for treating phobias often includes graded exposure
      of the patient to anxiety-producing stimuli (Systematic Desensitization).
      However, in utilizing systematic desensitization, research reviews demonstrate
      that many patients appear to have difficulty in applying imaginative techniques.
      This chapter describes the Virtual Reality Therapy (VRT), a new therapeutical
      approach that can be used to overcome some of the difficulties inherent in the
      traditional treatment of phobias. VRT, like current imaginal and in vivo
      modalities, can generate stimuli that could be utilized in desensitization
      therapy. Like systematic desensitization therapy, VRT can provide stimuli for
      patients who have difficulty in imagining scenes and/or are too phobic to
      experience real situations. As far as we know, the idea of using virtual reality
      technology to combat psychological disorders was first conceived within the Human
      Computer Interaction Group at Clark Atlanta University in November 1992. Since
      then, we have successfully conducted the first known pilot experiments in the use
      of virtual reality technologies in the treatment of specific phobias: fear of
      flying, fear of heights, fear of being in certain situations (such as a dark
      barn, an enclosed bridge over a river, and in the presence of an animal [a black
      cat] in a dark room), and fear of public speaking. The results of these
      experiments are described.

PMID- 10350912
TI  - Experiential cognitive therapy: a VR based approach for the assessment and
      treatment of eating disorders.
AB  - Even if there has been significant progress in research on eating disorders,
      little empirical work has been done yet to specify the content of clinical
      guidelines and to validate their efficacy in treatment. In particular there are
      at least three themes that are somehow neglected by current guidelines: body
      experience disturbances, motivation for change and the integration between the
      different approaches used. This chapter details the characteristics of the
      Experiential Cognitive Therapy (ECT), an integrated approach ranging from
      cognitive-behavioral therapy to virtual reality (VR) sessions. In particular,
      using VR, ECT is able to address both body experience disturbances and motivation
      for change. In the chapter a description of all the phases of this approach are
      offered by using an actual clinical case: a 22-year old female anorectic patient.

PMID- 10350913
TI  - A VR based therapy for the treatment of impotence and premature ejaculation.
AB  - The use of psycho-dynamic psychotherapy integrating virtual reality (VR) dealt
      with in this study on the treatment of erection dysfunctions and premature
      ejaculation started several years ago, after having seen the scarce results we
      obtained using exclusively a psycho-dynamic approach (accompanied by pre-recorded
      sound and music). Considering the particular way that full-immersion VR involves
      the subject who experiences it, we hypothesized that better results could be
      obtained during therapy for these sexual disorders and in particular regarding
      the nature of erection dysfunction, commonly referred to as impotence "a
      persistent or recurrent inability to attain, or to maintain until completion of
      the sexual activity, an adequate erection." The plan for therapy consisted of 12
      hour-long sessions over a 25-week period, and the methods involved the use of a
      VR helmet, joystick and miniature television screens that projected specially
      designed CD-ROM programs on psychological development.

PMID- 10350914
TI  - Virtual reality for palliative medicine.
AB  - The technology of virtual reality (VR) offers several advantages in the field of
      medicine because it enables us to practice medical procedures repeatedly, and can
      provide a variety of experiences by using virtual organs in different patients.
      It also aids in learning about a clinical procedure and facilitates objective
      evaluation by a supervisor. In the field of clinical oncology, a virtual
      environment can be useful for simulating surgery, diagnosing cancer invasion,
      obtaining informed consent or enhancing patient education, and for clinical
      communication using network-based VR. This technology can also be used to improve
      a patient's living conditions and to treat the psychological problems and/or
      stress of cancer patients. In the present chapter advanced VR research for
      palliative medicine at the National Cancer Center Hospital Japan is described and
      discussed.

PMID- 10350915
TI  - Personal stories within virtual environments: creating three experiences in
      cancer information software.
AB  - Virtual environments can create a relaxed mood, increasing a patient's
      receptivity to learning. Personal stories and an individual approach to the
      content, rather than abstract facts, make the CD-generated experience vivid and
      informative. With the user in control, selecting content and interacting
      constantly with the program, the virtual experience is more meaningful than the
      one created by simply retrieving information. This chapter explains how three CD
      ROMs containing cancer information--Breast Cancer Lighthouse, Easing Cancer Pain
      and Cancer Prevention Park--embody personal stories and medical information in
      virtual environments.

PMID- 10350916
TI  - Current uses of virtual reality for children with disabilities.
AB  - Technological advances, including the use of virtual reality, have contributed
      enormously to improving the treatment, training, and quality of life of children
      with disabilities. This paper describes the advantages of VR for children with
      disabilities, how VR can minimize the effects of a disability, the role of VR in
      training and skills enhancement, and how social participation and the child's
      quality of life may be improved through the use of VR. Examples from published
      literature and Internet sites are given of current and completed projects which
      focus on improving the lives of children with disabilities. The research
      describing the efficacy of knowledge and skills transfer from a virtual
      environment to the real world are examined in relation to children with
      disabilities. Finally, the current limitations and future directions of VR for
      children with disabilities are considered.

PMID- 10350917
TI  - Virtual reality in psychotherapy: the MYTHSEEKER software.
AB  - This chapter outlines the use in psychotherapy and medical diagnosis of an
      intelligent software system that helps clients to explore Personal Myth within
      virtual reality environments. Patented MYTHSEEKER software will allow clients to
      work with mythic analogues of lifeshapes and aspirations. This can help to focus
      therapy directions, find ways to participate with the person's world, and allow a
      kind of personal expression not previously possible. The software phases of
      assessment, facilitation, and enaction are described by which the client is
      assisted to explore systems of mythology or spirituality (called Depth Systems)
      that are traditional, ancient or newly-arising. The client builds a Personal
      Depth System representing Personal Myth, based on experiencing other Depth
      Systems, which can itself be experienced in the virtual environment. This paper
      outlines our methodology and technology to realize these operations. Space
      limitations prevent further description in the present chapter of MYTHSEEKER
      software technology or psychotherapy scenarios of involvement.

PMID- 10350918
TI  - The potential relevance of attachment theory in assessing relatedness with
      virtual humans.
AB  - Primary efforts to create virtual humans have been in the production of computer
      generated ergonomically correct objects that look like humans. Although there has
      been concern with essential human factors, absent are the metrics of human
      relatedness, or the ability to assess the degree to which a virtual human elicits
      human emotions. We discuss the potential application of attachment theory as a
      context for the development of such an assessment paradigm, and specifically the
      application of the Ainsworth Strange Situation in the evaluation of a "Virtual
      Mom". Virtual relatedness fidelity is discussed as a macrometric to define
      relatedness that would occur with virtual humans. Potential lessons learned are
      discussed as they apply to the selection of those to develop the model, and its
      impact on the introduction of virtual humans into clinical psychiatry and
      psychology.

PMID- 10350919
TI  - Virtual reality in neuroscience: a survey.
AB  - Some research projects have begun to test the possibility of using Virtual
      Environments (VEs) for research in neuroscience, neurosurgery and for the study
      and rehabilitation of human cognitive and functional activities. In fact, VEs let
      users navigate and interact with computer-generated 3-D environments in real
      time, allowing for the control of complex stimulus presentations. VEs enable the
      neuroscientist to present a wide variety of controlled stimuli and to measure and
      monitor a wide variety of responses made by the user. This paper highlights
      recent and ongoing research related to the applications of VEs in the
      neuroscience arena. In particular it focuses on the European and US applications
      in this field.

PMID- 10350920
TI  - Gait and Parkinson's disease: a conceptual model for an augmented-reality based
      therapeutic device.
AB  - This chapter presents an augmented-reality based therapeutic device designed to
      overcome gait problems associated with Parkinson's Disease (PD). A normal model
      of gait is proposed followed by a model of Parkinsonian gait with the goal of
      construction of a gait enabling therapeutic device. The fundamental underlying
      tenet of the model is that vision pathology is responsible for the majority of
      Parkinsonian gait pathology. The basis for such a claim is the well documented
      phenomenon known as Kinesia Paradoxa, whereby in the presence of certain so
      called visual cues a PD subject can be transformed from a totally immobile,
      helpless victim of this disease into a near normal walking individual. Several
      gait-enabling devices are also described.

PMID- 10350921
TI  - Virtual reality in paraplegia: a VR-enhanced orthopaedic appliance for walking
      and rehabilitation.
AB  - Spinal cord injuries (SCIs) have a profound physical, social and emotional cost
      to patients and their families. Obviously SCIs severely disrupt normal patterns
      of interaction with the environment. Firstly, the opportunities for active
      interaction are inevitably diminished due to motor or sensory impairment.
      Moreover, such problems may increase as the time since injury lengthens and the
      patient becomes more withdrawn and isolated in all spheres of activity. However,
      advances in Information Technology are providing new opportunities for
      rehabilitation technology. These advances are helping people to overcome the
      physical limitations affecting their mobility or their ability to hear, see or
      speak. In this chapter an overview is given of the design issues of a VR-enhanced
      orthopaedic appliance to be used in SCI rehabilitation. The basis for this
      approach is that physical therapy and motivation are crucial for maintaining
      flexibility and muscle strength and for reorganizing the nervous system after
      SCIs. First some design considerations are described and an outline of aims which
      the tool should pursue given. Finally, the design issues are described focusing
      both on the development of a test-bed rehabilitation device and on the
      description of a preliminary study detailing the use of the device with a long
      term SCI patient.

PMID- 10350922
TI  - Basic issues in the use of virtual environments for mental health applications.
AB  - In order for Virtual Environments (VE) to be efficiently developed in the areas
      of clinical psychology and neuropsychology, a number of basic theoretical and
      pragmatic issues need to be considered. The current status of VE's in these
      fields, while provocative, is limited by the small number of controlled studies
      that have been reported which apply this technology to clinical populations. This
      is to be expected considering it's relatively recent development, expense, and
      the lack of familiarity with the technology by mainstream researchers in these
      fields. In spite of this, some work has emerged which can begin to provide a
      basic foundation of knowledge which could be useful for guiding future research
      efforts. Although much of the work does not involve the use of fully immersive
      head mounted displays (HMD's), studies reporting PC-based flatscreen approaches
      are providing valuable information on issues necessary for the reasonable and
      measured development of VE/mental health applications. In light of this, the
      following review will focus on basic issues that we see as important for the
      development of both HMD and non-HMD VE applications for clinical psychology,
      neuropsychological assessment, and cognitive rehabilitation. These basic issues
      are discussed in terms of decision-making for choosing to develop and apply a VE
      for a mental health application. The chapter covers the issues involved with
      choosing a VE approach over already existing methods, deciding on the "fit"
      between a VE approach and the clinical population, level of presence, navigation
      factors, side effects, generalization, and general methodological and data
      analysis concerns.

PMID- 10350923
TI  - Uses of virtual reality in clinical training: developing the spatial skills of
      children with mobility impairments.
AB  - In this chapter we review some of the ways in which the skills learned in virtual
      environments (VEs) transfer to real situations, and in particular how information
      about the spatial layouts of virtual buildings acquired from the exploration of
      three-dimensional computer-simulations transfers to their real equivalents. Four
      experiments are briefly described which examined VR use by disabled children. We
      conclude that spatial information of the kind required for navigation transfers
      effectively from virtual to real situations. Spatial skills in disabled children
      showed progressive improvement with repeated exploration of virtual environments.
      The results are discussed in relation to the potential future benefits of VR in
      special needs education and training.

PMID- 10350924
TI  - Virtual environments in brain damage rehabilitation: a rationale from basic
      neuroscience.
AB  - The potential of virtual environments in assessment and training of cognitive
      function is a more than adequate reason for their application to
      neurorehabilitation. However, there is a more fundamental justification, and one
      which is firmly rooted in the neuroscience literature. Over the last half century
      there has been a wealth of published evidence that enriching the environments of
      laboratory rats stimulates neuroplastic change in the cerebral cortex, enhances
      learning and problem solving in normal rats and reduces cognitive impairment in
      brain damaged rats. Central to all three effects of enrichment are the increased
      levels of interaction with the physical environment engendered by enrichment.
      Placing humans who have damaged brains in virtual environments is one way of
      enhancing their levels of environmental interaction which, because of cognitive
      impairments and sensory and motor disabilities, is otherwise difficult to
      achieve. In this chapter we explore the potential of virtual environments as
      enriched environments within the rehabilitation regime. The underlying
      assumption, that interaction with a virtual environment is functionally
      equivalent to interaction with a real environment, is examined. Three lines of
      relevant evidence are reviewed, neuroimaging studies and psychophysiological
      studies of people in virtual environments and studies of transfer of training
      from virtual to real tasks. An agenda for future research in this are is
      proposed.

PMID- 10350925
TI  - VR experience with neurological patients: basic cost/benefit issues.
AB  - The future of VR applications for mental health is currently regarded as
      depending on the rational development of ideas and systems. Criteria to guide
      this development have been suggested that are both clear and agreeable. Their
      application, however, may not be easy at this stage. While we may already be able
      to predict costs of specific VR applications, a period of more extensive clinical
      research is needed in order to assess adequately any benefit. In our still
      limited experience, the development of VR applications to increase the diagnostic
      sensitivity of traditional tests to strategy application disorders is worthwhile,
      but the uniqueness of VR assets may make the adherence to some of the proposed
      criteria somewhat problematic.

PMID- 10350926
TI  - Virtual reality: past, present and future.
AB  - This report provides a short survey of the field of virtual reality, highlighting
      application domains, technological requirements, and currently available
      solutions. The report is organized as follows: section 1 presents the background
      and motivation of virtual environment research and identifies typical application
      domain, section 2 discusses the characteristics a virtual reality system must
      have in order to exploit the perceptual and spatial skills of users, section 3
      surveys current input/output devices for virtual reality, section 4 surveys
      current software approaches to support the creation of virtual reality systems,
      and section 5 summarizes the report.

PMID- 10350927
TI  - An investigation into factors influencing immersion in interactive virtual
      reality environments.
AB  - Two interactive virtual reality environments were used to identify factors that
      may affect, or be affected by, the degree of immersion in a virtual world. In
      particular, the level of stress in a "swimming with dolphins" simulation is
      measured, as is the degree of simulator sickness resulting form a virtual roller
      coaster. Analysis of the results indicates that a relationship between the degree
      of immersion and the following factors: excitement, comfort, quality and age. The
      following factors are found to depend on the degree of immersion: simulator
      sickness, control, excitement and desire to repeat the experience.

PMID- 10350929
TI  - Current limitations into the application of virtual reality to mental health
      research.
AB  - Virtual Reality (VR) environments have significant potential as a tool in mental
      health research, but are limited by technical factors and by mental health
      research factors. Technical difficulties include cost and complexity of virtual
      environment creation. Mental health research difficulties include current
      inadequacy of standards to specify needed details for virtual environment design.
      Technical difficulties are disappearing with technological advances, but the
      mental health research difficulties will take a concerted effort to overcome.
      Some of this effort will need to be directed at the formation of collaborative
      projects and standards for how such collaborations should proceed.

PMID- 10350928
TI  - The effects of immersiveness on physiology.
AB  - The effects of varying levels of immersion in virtual reality environments on
      participant's heart rate, respiration rate, peripheral skin temperature, and skin
      resistance levels were examined. Subjective reports of presence were also noted.
      Participants were presented with a virtual environment of an airplane flight both
      as seen from a two-dimensional computer screen and as seen from within a head
      mounted display. Subjects were randomly assigned to different order of conditions
      presented, but all subjects received both conditions. Differences between the non
      phobics' physiological responses and the phobic's response when placed in a
      virtual environment related to the phobia were noted. Also noted were changes in
      physiology based on degree of immersion.

PMID- 10350930
TI  - Virtual reality and imaginative techniques in clinical psychology.
AB  - The great potential offered by Virtual Reality (VR) derives prevalently from the
      central role, in psychotherapy, occupied by the imagination and by memory. These
      two elements, which are fundamental in the life of every one of us, present
      absolute and relative limits to individual potential. Thanks to virtual
      experiences, it is possible to transcend these limits. The re-created world may
      at times be more vivid and real than the one that most subjects are able to
      describe through their own imagination and through their own memory. This chapter
      focuses on imaginative techniques to find new ways of applications in therapy. In
      particular the chapter analyses in which way VR can be used to improve the
      efficacy of current techniques. VR produces a change with respect to the
      traditional relationship between client and therapist. The new configuration of
      this relationship is based on the awareness of being more skilled in the
      difficult operations of recovery of past experiences, through the memory, and of
      foreseeing of future experiences, through the imagination. At the same time, the
      subject undergoing treatment perceives the advantage of being able to re-create
      and use a real experiential world within the walls of the clinical office of his
      own therapist.

PMID- 10350931
TI  - Virtual reality: a new clinical setting lab.
AB  - Virtual Reality (VR) is a new technology halfway between television and computer.
      It constitutes another step in the evolution of our use of a tool that allows us
      to see, to hear and to feel in a world created graphically in three dimensions,
      and to interact with it. VR is, mainly, a mental experience which makes the user
      believe that "he is there", that he is present in the virtual world. With this
      new tool, the user is no longer a mere observer of that which is happening on a
      screen, but he "feels" that he is immersed in that world and participates in it,
      in spite of the fact that they are spaces and objects that only exist in the
      memory of the computer and in the user's mind. This chapter seeks to carry out
      different reflections at different levels. First, we will analyze the
      relationships between VR and Psychology, one of the disciplines that has made
      more efforts in order to understand how we obtain knowledge from the world and
      from ourselves. We will also analyze the impact VR can have in one of the applied
      disciplines of Psychology, which is Clinical Psychology. With regard to this
      application environment, VR becomes a tool which can generate useful models for
      Psychology (both normal and abnormal), and it is offered as a research context
      for Clinical Psychology; as a "realistic" laboratory where we can study
      behaviours, emotions, thoughts, etc.; and a new means to develop psychological
      treatments.

PMID- 10350932
TI  - Possibility of virtual reality for mental care.
AB  - The possibility of applying Virtual Reality (VR) techniques to the mental care of
      patients is discussed in this chapter. VR technology holds much promise for
      providing supportive activities and promoting cooperation among caregivers.
      Interactivity with media may give the feeling of control to patients and thus
      provide a greater joy than passively watching television. Immersion in VR is
      expected to reduce pain and relieve anxieties for a while. Some kinds of VR
      content would make patients relaxed or encourage them in their fight against
      disease. Moreover, networked VR could offer a virtual space where patients meet,
      communicate, organize activities, and share experiences with other people--other
      patients, friends, family members, medical doctors, social workers, and so on. A
      basic study and trials to evaluate our developed VR system, called the 'Bedside
      Wellness System,' provide evidence for the effectiveness of this approach. Future
      research tasks are also discussed.

PMID- 10350934
TI  - OIG opinion is cause for concern.

PMID- 10350933
TI  - Virtual environments special needs and evaluative methods.
AB  - This paper presents an overview of the development of the Learning in Virtual
      Environments programme (LIVE), carried out in special education over the last
      four years. It is more precisely a project chronology, so that the reader can
      sense the historical development of the programme rather than giving emphasis to
      any one particular feature or breakthrough, which are covered in other papers and
      available through the authors. The project conception in a special school in
      Nottingham is followed by a description of the development of experiential and
      communicational virtual learning environments. These are followed, in turn, by
      the results of our testing programmes which show that experience gained in a
      virtual environment can transfer to the real world and that their use can
      encourage self-directed activity in students with severe learning difficulties.
      Also included is a discussion of the role of virtual learning environments (VLEs)
      in special education and of its attributes in the context of contemporary
      educational theory.

PMID- 10350935
TI  - Maximizing tele-oncology efficiency with a patient self-response symptom
      checklist.

PMID- 10350936
TI  - Smile for the camera: telemedicine comes to your local dentist's office.
AB  - Dentistry has faced the same access issues that have spurred telemedicine
      development in other fields. However, until recently dentistry has lagged behind
      in adopting telemedicine. The findings of the Association of Telemedicine Service
      Provider's (ATSP; www.atsp.org) 1998 Report on US Telemedicine Activity, done
      collaboratively with Telemedicine Today Magazine, are instructive. Of over 40,000
      teleconsults among 139 U.S. programs performed in 1997, only 200 were dental
      teleconsults--all done by one program. Although that figure represents a
      significant increase over the 4 dental teleconsults reported in 1996,
      teledentistry has a long way to go. The first steps are now being taken. At the
      schools of dentistry at the University of California at Los Angeles and the
      University of Bristol in Bristol, England, two different approaches to
      teledentistry are being actively explored. Telemedicine Today spoke with lead
      researchers at each school to discuss these programs.

PMID- 10350937
TI  - Seven years of 'HausTeleDienst' in Frankfurt/Main Germany. A CATV-based
      interactive video service for elderly people.

PMID- 10350938
TI  - Networked telemedicine: from islands of technology to integration.

PMID- 10350939
TI  - Integrating telemedicine into the HIN: adventures in convergence--let's get our
      wires uncrossed!

PMID- 10350940
TI  - Integrating telemedicine into the HIN: Vitel Net's telemedicine 'software
      toolbox' is growing up.

PMID- 10350941
TI  - A 'what if' scenario for telemedicine reimbursement based on ATSP/TT survey
      findings.

PMID- 10350942
TI  - The webification of information systems and the emergence of the Internet as the
      WAN of choice.

PMID- 10350943
TI  - Telepathology's slow start.

PMID- 10350945
TI  - Cookie sheets and frozen sections: the high-tech world of telepathology.

PMID- 10350944
TI  - Telepathology in Japan.

PMID- 10350946
TI  - How to evaluate and implement clinical policies.

PMID- 10350947
TI  - Practicing without paper.

PMID- 10350948
TI  - Tips for making inpatient care more efficient.

PMID- 10350949
TI  - Teenage parent programs. A synthesis of the long-term effects of the New Chance
      Demonstration, Ohio's Learning, Earning, and Parenting Program, and the Teenage
      Parent Demonstration.
AB  - This article synthesizes the long-term findings from three major evaluations of
      programs that began in the late 1980s and were designed to improve the self
      sufficiency of teenage mothers on welfare. Although each of the programs
      emphasized a different approach, an important story emerges. Economic outcomes
      for the mothers improved over time, and the interventions had some positive
      effects, particularly for the women who began these programs while they were
      enrolled is school. However, the interventions did not affect fertility, and the
      data on outcomes for the mothers' children raise concern.

PMID- 10350950
TI  - Using group mean centering for computing adjusted means by site in a randomized
      experimental design. The case of California's Work Pays Demonstration Project.
AB  - When analyzing data from a randomized experiment that is replicated across
      multiple sites and includes covariates, the covariates can adjust for differences
      from either the grand mean or the group (site) mean. The analysis strategy
      determines the reference point. Pooling the sites and using a standard analysis
      of covariance (ANCOVA) adjusts for differences around the grand mean, whereas
      analyzing each site separately adjusts for differences around each group (site)
      mean. This article demonstrates that group mean centering permits pooling data
      from multiple sites into a single analysis while still using the group mean as a
      reference point for evaluating the covariate.

PMID- 10350951
TI  - Evaluating the vocational rehabilitation program using longitudinal data.
      Evidence for a quasiexperimental research design.
AB  - The study presents benefit-cost ratios for 14 disability cohorts served by the
      Vocational Rehabilitation (VR) Program. The earnings impacts are estimated in a
      quasiexperimental framework using an internal comparison group. The earnings data
      are from a unique national panel constructed by linking client data of the
      Rehabilitative Services Administration with earnings histories from the Social
      Security Administration. These earnings data accommodate a series of statistical
      tests that allow us to identify and control for the presence of selection bias
      when estimating treatment impacts. The results indicate that the VR program is
      cost-effective in general, although not universally so across specific
      disabilities.

PMID- 10350952
TI  - The impact profile approach to policy merit. The case of research grants and the
      university.
AB  - In writings on the theory of valuing, many take the position that impacts on the
      relevant outcome dimensions should be aggregated to arrive at one summary
      assessment of program merit. A contrary position is taken here, specifying that
      the impacts should be kept separate and unweighted and expressed only in their
      own original measurement scales. All impacts, however, should be portrayed,
      including those for which no rigorous data analysis has been carried out. It is
      argued that aggregating, even by the individual stakeholder, is both futile and
      misleading. An extensive evaluation of the effects of research grants on the
      university is included as a full-scale illustration of the method. Financial
      impacts are considered, as well as impacts on faculty and student quality, on
      university prestige, and on the quality of instruction.

PMID- 10350953
TI  - Using outcomes to make inferences about nursing home quality.
AB  - Recent concerns about containing the growth of public expenditures on nursing
      home care and the development of prospective and casemix reimbursement systems
      with incentives for cost containment have increased the importance of monitoring
      quality in nursing homes. The current view is that quality assurance systems
      should include more outcome measures to improve quality. This article discusses
      why it is difficult to develop facility-level outcome measures that can be used
      to evaluate and compare the quality of care of nursing homes. The article places
      the current interest in outcomes measures in its historical policy context and
      reviews important conceptual and methodological issues associated with outcome
      based quality assessment. The authors discuss the difficulty in isolating the
      facility effect when studying nursing home outcomes and implications of using
      different estimation approaches. In conclusion, they discuss the need to
      integrate research with outcome-based quality assurance systems to allow ongoing
      evaluation and quality improvement.

PMID- 10350954
TI  - What patients should ask of consumers' guides to health care quality.
AB  - Consumers' guides that profile the quality of care of individual health care
      providers may be influential in shaping health care markets. We propose four
      simple questions that can be used to evaluate such guides: (a) Does the guide
      measure distinct and important domains of health care quality? (b) Are the
      individual measures of quality described simply and precisely? (c) Do the
      measures take into account relevant differences between patients? (d) Are the
      ratings of quality presented fairly? Using these four questions, we examine the
      validity of one prominent guide that annually identifies America's best hospitals
      and present a set of recommendations for the design of future guides. Although
      the evaluation of health care quality is undoubtedly complex, the four questions
      that we pose provide a basis for developing a more rational approach to informing
      the public about health care quality.

PMID- 10350955
TI  - Diagnostic clusters in infants as child health outcomes. Variation among
      socioeconomic areas in one community.
AB  - Objectives were to examine geographic variation in rates of infant
      hospitalization for diagnostic clusters in Monroe County (Rochester), New York
      and to assess these clusters as indexes of child health. ICD-9 codes were used to
      cluster all 7,883 hospitalizations of infants (< 24 months) between 1985 and 1991
      on the basis of their avoidability. Environmentally sensitive clusters accounted
      for 63% of admissions. These clusters included environmental,
      environmental/constitutional, and other infectious disease. Disparities in
      morbidity between inner city and suburbs were greatest for the environmental
      cluster, followed by the environmental/constitutional, and other infectious
      disease clusters. For the constitutional and quality indicator clusters,
      differences between inner-city and suburban risk were minimal. Environmental
      interventions may be more important than improved health services to reducing
      racial and economic disparities in child health. Analysis of morbidity clusters,
      ascertained from available administrative data bases and aggregated for small
      geographic areas, may guide child health policy well.

PMID- 10350956
TI  - A randomized trial of providing house staff with patient social history
      information. Effect on patient outcomes.
AB  - The purpose of this project was to assess if providing physicians (house staff)
      with routine comprehensive social history information on their patients will
      improve patient outcomes. Comprehensive social history information was gathered
      over a 5-month period on 134 consecutive patients. Patients were randomized to
      have social history information provided or not provided to the resident
      physician caring for them. Outcomes of interest were: patient satisfaction,
      length of stay, and early unplanned readmission. Analysis was with analysis of
      covariance, controlling for patient severity of illness and amount of social
      history information documented by the house officer. Outcomes were the same for
      patients for whom house staff were provided social history information versus
      those for whom the information was not provided. The authors conclude that
      providing house staff with routine comprehensive social history information did
      not influence patient outcomes.

PMID- 10350957
TI  - The Prevention Minimum Evaluation Data Set (PMEDS). A tool for evaluating teen
      pregnancy and STD/HIV/AIDS prevention programs.
AB  - This article presents the Prevention Minimum Evaluation Data Set (PMEDS), a ready
      to-use questionnaire or tool for evaluating teen pregnancy prevention and teen
      STD/HIV/AIDS prevention programs. Recognizing the diversity of approaches taken
      by these programs, PMEDS has two parts. Part 1 contains a primary questionnaire
      applicable to all programs. Part 2 consists of 15 additional supplementary
      modules for optional use by programs with a more specific target population or
      intervention approach that matches the module's content. It is hoped that PMEDS
      will facilitate the conducting of high-quality evaluations, first by highlighting
      important aspects of a program model that should be included in an evaluation,
      such as the demographic profile of the target population, the specific aspects of
      the intervention or treatment received by each participant, and the short-term
      outcomes and long-term goals that the program is trying to affect; second, by
      presenting measures for these evaluation constructs that have been extensively
      pretested and used in large-scale national studies and for which national
      comparison norms and data exist.

PMID- 10350958
TI  - Postal surveys versus electronic mail surveys. The tortoise and the hare
      revisited.
AB  - The advent of computer-based technology has led to a consideration of change in
      research methods that exploit the advantages of computer-mediated communications.
      In survey research, electronic mail (e-mail) has anecdotally shown particular
      promise as a data collection tool. This article compares traditional postal and
      nontraditional e-mail surveys within the context of a larger listserv evaluation
      project in terms of overall return rate, distribution of survey returns over
      time, response to initial and follow-up mailings, representativeness of
      respondent groups, thoroughness of survey completion, and the likelihood of
      respondents to include additional written comments. In summary, whereas postal
      surveys were shown to be superior to e-mail surveys with regard to response rate,
      all things being equal, the decision of which to use may be situation-specific,
      dependent on issues such as survey cost, desire for convenience and timeliness in
      data collection, and need for higher response rates, among others.

PMID- 10350960
TI  - Development of an Attitudes Toward Health Care Teams Scale.
AB  - The authors describe the development and psychometric testing across three study
      phases of an Attitudes Toward Health Care Teams Scale. The measure contains two
      subscales: Quality of Care/Process (14 items) and Physician Centrality (6 items).
      The Quality of Care/Process subscale measures team members' perceptions of the
      quality of care delivered by health care teams and the quality of teamwork to
      accomplish this. The Physician Centrality subscale measures team members'
      attitudes toward physicians' authority in teams and their control over
      information about patients. Tests of reliability and validity demonstrate that
      each subscale is a strong measure of its respective underlying concept. The
      measure has potential for use as a research tool and as a pre- and posttest tool
      for educational interventions with teams and for evaluating clinically based team
      training programs for medical and health professions students and residents.

PMID- 10350959
TI  - Prevalence and predictors of the use of self-care resources.
AB  - Health care reform goals are to reduce costs and increase access while
      maintaining quality of care. A potentially effective avenue for achieving these
      difficult goals is to activate the untapped potential of consumers in managing
      their own health care. This study focuses on three Northwest communities and
      examines the prevalence of the use of self-care resources and the correlates of
      use. A random sample of households was surveyed using a mail-out questionnaire.
      The findings indicated that the use of self-care resources was high in the three
      community populations. Consulting a self-care book was the most commonly used
      resource, followed by telephone advice nurses. Communities do vary in their level
      of self-care resource use. Understanding this variability may help communities to
      expand the use of such resources and lessen the demand for formal health care
      services. Suggestions for future studies are discussed.

PMID- 10350961
TI  - Outcomes research and the quality of health care: the beacon of an ethics of
      evidence.
AB  - Beyond the dazzling achievements of high-technology medicine, the spiraling cost
      of health care and lack of access for many have long been the subject of national
      debate. Driven by the interaction of powerful economic forces, managed care is
      now taking over the health care system, while there is growing popular interest
      in alternative medicine. But amid the changing structures and financial
      incentives, much uncertainty still remains concerning the safety and
      effectiveness of medical interventions. The author, a mathematical scientist
      engaged in medical research and education for more than 30 years, has proposed
      the "ethics of evidence" as an approach to medical uncertainty, to be adopted as
      a vital component of biomedical ethics. The ethics of evidence comprises two
      imperatives. The first imperative calls for the creation, dissemination, and use
      of the best possible scientific evidence as a basis for every phase of medical
      decision making. Complementing it, the second imperative focuses on the need to
      increase awareness of, and come to terms with, the extent and ultimately
      irreducible nature of uncertainty. After a brief sketch of the genesis of this
      concept, the ethics of evidence is further explored here in the context of
      current outcomes research, the focus on quality of health care, and related
      problems of contemporary medicine.

PMID- 10350962
TI  - The ethical use of evidence in biomedicine.
AB  - Valerie Mike's proposal of an "ethics of evidence" is an interesting, important
      venture into a little explored field. Mike's two rules (use the best possible
      knowledge and acknowledge uncertainty) have been implicit but need to become
      explicit in a world where information and knowledge have enormous power-
      especially in medical practice and research, where evidence is essential to
      clinical decisions, policy formulation, and dissemination of results. A fully
      developed ethics of evidence would depend on a still underdeveloped theory of
      evidence, that is, on some conception of the nature of evidence, the logic of its
      use, and the epistemology of discovery and explanation. Until such a groundwork
      is developed, practical guidelines are deducible in the ethics of data collection
      and dissemination. This article examines those ethics, suggesting criteria for
      the morally responsible treatment of evidence collection, dissemination, and use.

PMID- 10350963
TI  - What can you teach about cardiopulmonary resuscitation (CPR) in 30 seconds?
      Evaluation of a television campaign.
AB  - This study evaluated an 8-month media campaign, implemented in western
      Washington, to educate people on the basic steps of cardiopulmonary resuscitation
      (CPR) for cardiac arrest. A telephone survey was conducted with a total of 384
      adults randomly selected from two towns, one that had been exposed to the
      campaign (intervention town) and one that had not been exposed to the campaign
      (comparison town). Results showed that respondents in the intervention town were
      more likely than respondents in the comparison town to report (a) having heard
      messages on CPR in the past month, (b) having seen the CPR media campaign, and
      (c) knowing the three basic steps of CPR. Respondents who had seen the campaign
      evaluated it very favorably. There were no differences between respondent groups
      in self-reported CPR training or intentions to perform CPR, suggesting that the
      campaign had a greater impact on knowledge and awareness than on intentions and
      behavior.

PMID- 10350964
TI  - Modified therapeutic community for mentally ill chemical abusers: outcomes and
      costs.
AB  - Several studies have established that the personal and social consequences of
      substance abuse are extensive and costly. These consequences are frequently
      compounded by mental illness. Although interventions that target mentally ill
      chemical abusers (MICAs) present several challenges, the potential benefits of
      successful interventions are significant. This article presents outcomes and
      costs of a modified therapeutic community (TC) intervention for homeless MICAs.
      Outcomes at follow-up are compared with those for a control group of homeless
      MICAs receiving standard services in a "treatment-as-usual" (TAU) condition.
      Annual economic costs for the modified TC and the average weekly cost of treating
      a single client are estimated. Treatment and other health service costs at 12
      months postbaseline are compared for modified TC and TAU clients. The results of
      this study indicate that, suitably modified, the TC approach is an effective
      treatment alternative for homeless MICAs, with the potential to be highly cost
      effective relative to standard services.

PMID- 10350965
TI  - Faculty ratings as part of a competency-based evaluation clinic grading system.
AB  - The traditional system for determining grades in dental school clinic courses has
      been counts of productivity and daily marks for degree of technical excellence.
      One dental school with a competency-based educational model has redesigned its
      evaluation system to include assessment of understanding as well as performance
      of procedures, diagnosis and judgment, and patient management. Competency tests
      were instituted in all disciplines to replace the required volume of work. A
      quarterly rating system was developed to replace daily grading. Results from one
      of the first administrations of the ratings are presented. They show excellent
      face validity and rater consistency in some cases. Gradients of generalizability
      are reported, demonstrating that the ratings satisfy the school's standard for
      grade defensibility.

PMID- 10350966
TI  - Practice brief. A HIPAA checklist. American Health Information Management
      Association.

PMID- 10350967
TI  - A "geek speak" primer.

PMID- 10350968
TI  - Managed care in the age of accountability.
AB  - We know that managed care offers opportunities to HIM professionals, but what
      role does information itself play? This article surveys the kinds of health
      information that managed care organizations need to make decisions. The author
      looks at processes related to care delivery and gives examples of the type of
      information each area requires.

PMID- 10350969
TI  - Measuring, managing, making a difference.
AB  - What is disease management, and how does it work? The author offers an overview
      of this process and describes how HIM professionals can play an important role in
      this initiative.

PMID- 10350970
TI  - The elements of provider credentialing.
AB  - HIM professionals manage patient information. But in the provider credentialing
      process, another kind of information management is necessary--handling the varied
      and important information compiled on doctors throughout the country. Here's how
      the credentialing process works.

PMID- 10350971
TI  - The converging roads of HIM and managed care.
AB  - The authors explore the definition of managed care and how the health information
      manager's skills apply to a managed care setting. In addition, HIM professionals
      who have made the transition to the managed care setting share their experiences.

PMID- 10350972
TI  - Managed care poses challenges to home care.

PMID- 10350973
TI  - AHIMA (American Health Information Management Association) census results: focus
      on compliance.

PMID- 10350975
TI  - What is diversity?

PMID- 10350974
TI  - Teamwork and compliance go hand in hand.

PMID- 10350976
TI  - Alternative medicine: growing trend for the new millennium.

PMID- 10350977
TI  - Writing the fine print.

PMID- 10350978
TI  - Learning is fundamental: the impact of education on successful clinical pathway
      implementation.
AB  - Successful implementation of a clinical pathway program is a complex,
      multifaceted task. Medical and hospital staff education is often overlooked or
      minimized during the implementation process. Even with a clinically sound pathway
      and a state-of-the-art variance-tracking system, implementation can fail
      miserably if the medical and hospital staff do not completely understand and
      support the pathway initiative. A well-developed plan for education provides
      staff members with the foundation they need to be successful within the pathway
      program.

PMID- 10350979
TI  - David Nash on performance assessment, outcomes, and performance guarantees.
      Interview by Luc R. Pelletier.

PMID- 10350980
TI  - A collaborative effort to establish a long-term care benchmark process.
AB  - Several long-term care facilities in the Rochester, NY, area developed a
      benchmark process that was customer driven, analytical in its approach to problem
      solving, measurable, and flexible enough to be applicable to any area of care
      within the facilities. The facilities benefited by gaining a process that
      improves their operations and has a positive impact on residents' quality of
      life.

PMID- 10350981
TI  - On leadership.

PMID- 10350982
TI  - Building the road map for a performance-driven organization.
AB  - The strategic importance of performance improvement (PI) in healthcare is being
      recognized across the country. Organizations that recognize PI's importance and
      support PI will be better prepared for a healthcare future that mandates
      measurable value. Building the foundation for success is neither a simple task
      nor a cheap one. It requires a total systems perspective on improving processes
      and systems, a commitment to continual learning, and recognition of what other
      industries have already learned--to succeed, you must constantly innovate and
      improve. This article discusses one organization's approach to building the
      foundation for a performance-driven 21st-century healthcare system.

PMID- 10350983
TI  - A data-driven approach to improving clinical outcomes in cardiac care.
AB  - The performance improvement department at The Queen's Medical Center (QMC) in
      Honolulu, has been monitoring the outcomes of cardiovascular interventional
      procedures and cardiothoracic surgical procedures. By using an institution-wide
      database as well as participating in national cardiac databases, a set of
      clinical indicators is tracked, and quarterly reports are provided to the
      cardiovascular medicine (CV) and thoracic and cardiovascular surgery (TCV)
      services. After reviewing the data, a combined CV/TCV/anesthesia morbidity and
      mortality committee meets monthly to further evaluate the data, review cases, and
      formulate action plans based upon the findings. Using these tools and methods, we
      have seen a marked improvement in clinical outcomes among cardiac patients.

PMID- 10350984
TI  - Using a process action team to improve patient education.
AB  - To develop an effective, coordinated, and integrated process for patient
      education in primary care, the Department of Veterans Affairs, Western New York
      Healthcare System, launched a process action team. The interdisciplinary team
      utilized a variety of methods, including flowcharts, cause-and-effect diagrams,
      and variance matrices. The team developed, implemented, and analyzed a data
      collection plan involving chart reviews, staff interviews, and patient-staff
      surveys. An improvement plan was initiated in collaboration with staff. The
      results highlight the importance of using a data collection plan to understand
      the causes of problems as well as the need for staff involvement.

PMID- 10350985
TI  - College priorities during the 106th Congress.

PMID- 10350986
TI  - The surgical knife.

PMID- 10350987
TI  - In their own words. Joint Commission on Accreditation of Healthcare
      Organizations.

PMID- 10350989
TI  - The 1999 Medicare fee schedule.

PMID- 10350988
TI  - Clinical trials methods: a course for surgeons.

PMID- 10350990
TI  - The key to excellence: successful executives keep the flame alive at work and
      home!

PMID- 10350991
TI  - Vascular sealing devices: are the advantages sustainable?

PMID- 10350992
TI  - Into the third millennium: the changing face of cardiology practice.

PMID- 10350993
TI  - Measuring cost effectiveness of cardiac care.

PMID- 10350994
TI  - Forming the single specialty IPA.

PMID- 10350995
TI  - Strategic and cost effective role for preventive cardiology.

PMID- 10350996
TI  - Marketing cardiovascular programs: positioning for success.

PMID- 10350997
TI  - A cost analysis of complications associated with arterial closure following
      diagnostic and therapeutic cardiac catheterization.

PMID- 10350998
TI  - Is managed care going into a stall?

PMID- 10350999
TI  - Aged care beyond 2001--a dream or a reality?

PMID- 10351000
TI  - Record keeping in an oncology outpatient department.

PMID- 10351001
TI  - HIMs in practice: data management in a breast cancer screening service.

PMID- 10351002
TI  - Medical informatics. A bluffer's guide to HL7.

PMID- 10351003
TI  - Coffee break quality improvement.

PMID- 10351004
TI  - Health Information Association of New Zealand.

PMID- 10351005
TI  - Single-specialty carve-outs: a threat to integrated care?
AB  - Single-specialty carve-out contracts under capitation are booming nationwide,
      fueled by economic and practice management incentives. What isn't clear yet is
      how these arrangements between health plans and physicians will affect integrated
      health systems, multispecialty group practice-based medical management, and the
      roles and referral patterns of primary care physicians. For many primary care
      physicians and multispecialty group leaders, carve-outs represent an economically
      driven challenge to good medical management. But health plans, and many
      specialists, argue that carve-outs help patients/plan members, physicians, and
      the care management process. One's viewpoint on the issue seems to depend largely
      on the health system interests one has at stake.

PMID- 10351006
TI  - Time for clinicians to take the reins in healthcare?

PMID- 10351007
TI  - Health plan capitation strategy: do you have what it takes? What we're looking
      for as a health plan.

PMID- 10351008
TI  - Ambulance rule raises new questions about SNF responsibilities.

PMID- 10351009
TI  - Sen. Grassley introduces bill to allow for exemptions to therapy cap.

PMID- 10351010
TI  - MedPAC suggests modifications to SNF PPS system, new RUG III group may be an
      option.

PMID- 10351011
TI  - Quarterly financial results of post acute/subacute companies.

PMID- 10351012
TI  - Prices paid for nursing facilities up despite PPS concerns.

PMID- 10351013
TI  - The incredible shrinking diet office.

PMID- 10351014
TI  - Tips from the trayline doctor. Part 1: How to diagnose and treat common problems.

PMID- 10351015
TI  - The breakfast buffet cart. A viable alternative for oncology patients.

PMID- 10351016
TI  - Culinary demonstrations. Applications in food service and nutrition.

PMID- 10351017
TI  - Implications of health promotion for integrated health systems.
AB  - Summarizes key conclusions and recommendations found in the Centre for Health
      Promotion's position paper on the role of health promotion within integrated
      health systems. The original position paper was based on advice received from a
      working group of organizations and practitioners interested in health promotion.
      This group was established to formulate recommendations for the government of the
      Province of Ontario, which was in the process of reforming its system of health
      care delivery.

PMID- 10351018
TI  - A framework for developing evaluation capacity in health care settings.
AB  - The purpose of this paper is to provide a framework for developing an effective
      evaluation practice within health care settings. Three features are reviewed;
      capacity building, the application of evaluation to program activities and the
      utilization of evaluation recommendations. First, the organizational elements
      required to establish effective evaluation practice are reviewed emphasizing that
      an organization's capacity for evaluation develops over time and in stages.
      Second, a comprehensive evaluation framework is presented which demonstrates how
      evaluation practice can be applied to all aspects of a program's life cycle, thus
      promoting the scope of evidence-based decision making within an organization.
      Finally, factors which influence the adoption of evaluation recommendations by
      decision makers are reviewed accompanied by strategies to promote the utilization
      of evaluation recommendations in organization decision making.

PMID- 10351019
TI  - Survival during and after hospitalization: a medical record linkage.
AB  - BACKGROUND: In Sweden, hospital stays, deaths, and censuses have long been stored
      on electronic media. AIMS: To apply post-hospital survival measures to hospitals
      having different degrees of specialization by linking existing data in census and
      in-patient registers. METHOD: In-patient records totaling 3.6 million were
      collected. They were linked to the 1985 and 1990 censuses regarding patients'
      background data, and the cause of death registers. Observed three-month
      mortalities in 27 diagnoses were contrasted against the expected. RESULTS: The
      three-month survival was lower than expected in some large, and, more often, in
      small hospitals [corrected].

PMID- 10351020
TI  - An analytical approach to determining the competitive advantage of TQM in health
      care.
AB  - The utilization of total quality management (TQM) is advocated by some experts,
      as a partial remedy to the ills of the healthcare industry. However, some
      healthcare administrators are not yet sold on TQM. Some healthcare administrators
      still question the impact of TQM on the operational, financial and strategic
      health of their institutions. They consider the investment in TQM as
      unjustifiable because the return on such investment in their mind is
      questionable. This study illustrates how the constant market share model can be
      utilized to show the competitive benefits of TQM. Based on the results of this
      study, it is concluded that the fears of some healthcare administrators are
      unfounded. Not only that TQM does not compromise organizational effectiveness,
      but it actually improves it, as it contributes to increasing market share.

PMID- 10351021
TI  - Medicare risk contracting: analyzing managed care for the aging population in the
      USA.
AB  - This paper focuses on Medicare risk contracting in the USA. The issue of the
      current method of reimbursement versus Medicare risk contracting is explored.
      Risk sharing and payment mechanisms are described and analyzed. The strengths and
      weaknesses (score-card) of Medicare beneficiaries entering HMOs are reviewed.
      Finally, the issue of selection bias in Medicare HMOs is discussed regarding
      future implementation strategy.

PMID- 10351022
TI  - Clinical governance.

PMID- 10351023
TI  - Managing by numbers: using outcome measures in the NHS.
AB  - The paper explores the literature concerning outcome measures used in health
      services. The need to measure outcomes subsequent to encounters with health
      services has been identified and occurs as a result of the current "value for
      money" approaches being used within the NHS. Provider units are required to
      establish the effects which interventions have had on the health of each
      individual using their services, despite the fact that definitions of health
      outcomes used by both professionals and managers are problematic. It is suggested
      here, however, that outcome measures which answer all requirements will remain
      elusive, and their effectiveness will vary according to the circumstances of
      their generation and use. Moreover, the very use of outcome measures as
      management tools can lead to a subversion of the meaning which led to their
      selection in the first place. Managing by (outcome measure) numbers is not a
      realistic way forward.

PMID- 10351024
TI  - Incorporating clinical outcomes and economic consequences into drug formulary
      decisions: a practical approach.
AB  - BACKGROUND: In 1994, Regence BlueShield (Regence), a large non-staff model health
      plan, adopted guidelines governing the review of new and existing drug products.
      However, certain limitations were apparent: adequate data were not available in a
      timely fashion; unpublished studies and information on unapproved indications
      were difficult to obtain; data addressing humanistic and economic outcomes were
      not routinely supplied by manufacturers; and the time required by Regence staff
      clinical pharmacists to assemble and summarize published clinical studies for the
      pharmacy and therapeutics (P&T) committee was excessive. OBJECTIVE: To describe
      the process used by Regence to collect and review clinical, economic, and other
      health outcomes data as part of the plan's drug formulary adoption process.
      PROCESS DESCRIPTION: To address these limitations, Regence revised its process to
      require pharmaceutical manufacturers to submit a detailed dossier with clinical
      and economic data from published and unpublished studies, along with a disease
      based economic model projecting the potential impact that introducing the product
      would have on health outcomes and economic consequences occurring across the
      entire Regence system. After performing independent literature reviews to ensure
      the accuracy and comprehensiveness of the information obtained, clinical
      pharmacists at Regence complete a detailed summary of each drug for the P&T
      committee. CONCLUSION: The new process has addressed the limitations of the
      previous system and, by improving the timeliness and relevance of available
      information, it supports Regence's goal of maintaining an evidence-based
      formulary.

PMID- 10351026
TI  - Dissecting cost-effectiveness analysis for preventive interventions: a guide for
      decision makers.
AB  - BACKGROUND: Decision makers usually limit their use of economic evaluations of
      preventive interventions to the cost-effectiveness ratio. OBJECTIVE: To show
      decision makers how economic evaluations can be used to understand the cost
      effectiveness of different options for altering health intervention strategies.
      OBSERVATIONS: Cost-effectiveness analysis provides insights into many factors
      that contribute to the overall benefits, hazards, and costs of interventions.
      This article reviews how epidemiologic and intervention characteristics, costs,
      natural history, targeting, and current interventions influence the value of
      prevention strategies. CONCLUSION: Understanding the factors that contribute to
      the overall costs and effectiveness of interventions should allow decision makers
      to better adapt interventions to their needs.

PMID- 10351025
TI  - Economic impact of delaying or preventing AIDS in persons with HIV.
AB  - OBJECTIVES: To investigate how preventing or delaying the development of acquired
      immune deficiency syndrome (AIDS) [or other severe conditions related to the
      human immunodeficiency virus (HIV)] through antiretroviral therapy affects the
      lifetime cost of HIV/AIDS care, and to compare the cost of therapy with the
      potential savings in HIV/AIDS-related end-of-life care. METHODS: The analysis
      utilized a previously developed economic model of HIV/AIDS-related medical care
      costs under various disease progression scenarios to compare the costs and
      benefits of antiretroviral therapy. RESULTS: The analysis suggests that: (1)
      recent projections of long-term medical care cost savings due to highly effective
      protease inhibitor combination therapies are probably illusory; (2) it makes
      relatively little difference to the overall long-term cost of HIV/AIDS care
      whether combination antiretroviral therapy completely prevents or just
      substantially delays progression to AIDS; and (3) although combination therapy is
      not likely to save economic resources in the long run, it nevertheless can be
      highly cost effective. CONCLUSIONS: The health-related benefits of antiretroviral
      therapy are not free, but appear to be worth the cost.

PMID- 10351027
TI  - Opportunities for improving managed care for individuals with dementia: Part 1-
      The issues.
AB  - In this first part of a two-part article, we review the prevalence of, costs
      associated with, and treatments for Alzheimer's disease and related dementias, a
      leading cause of disability in the elderly. New, innovative, and costly drugs to
      combat dementia are being introduced, causing pharmacy costs to rise. These new
      drugs, however, may reduce overall medical costs and improve the quality of life
      of patients with dementia and their caregivers. Issues of cost, excessive service
      utilization, and quality of life will have significant impact on managed care
      organizations in the near future as the rapidly aging population experiences
      significant disability and illness related to dementia. In the second part of
      this article, we describe the framework for a disease management program for
      patients with dementia, similar to programs in existence for diabetes and other
      chronic diseases, that could enable managed care organizations to effectively
      care for these patients.

PMID- 10351028
TI  - Opportunities for improving managed care for individuals with dementia: Part 2--A
      framework for care.
AB  - In this second part of a review of dementia, we argue that managed care
      organizations must develop strategies to identify and manage patients with
      dementia, whose numbers will increase dramatically in the near future. Improved
      coding and use of validated self-report instruments that include caregivers as
      information sources could assist in identifying patients with dementia who could
      benefit from disease management programs. These programs should include
      population-based screening efforts; the development of practice guidelines; the
      use of case managers; education of caregivers, case managers, and physicians in
      issues such as availability of community services, patient/caregiver self
      management techniques, and the latest developments in efficacious treatment; and
      monitoring of care through quality assurance activities. Dementia is a highly
      prevalent, devastating, and costly chronic illness of the elderly, but it is also
      eminently manageable. Managed care has the potential to improve the quality of
      life and care for these patients, while managing the costs.

PMID- 10351029
TI  - Erectile dysfunction: the primary care practitioner's view.

PMID- 10351030
TI  - Drug-nutrient interactions.

PMID- 10351031
TI  - Evidence-based decision making: using submission guidelines to inform formulary
      approvals.

PMID- 10351032
TI  - Increasing market share in an information-intensive world: lessons for
      healthcare. Part 1: Product differentiation and information leverage.

PMID- 10351033
TI  - The future of physician leadership education: customer value and technology in
      PEMBA (Physician Executive MBA).

PMID- 10351034
TI  - Quality-based compensation crawling toward acceptance.

PMID- 10351035
TI  - Maturing Colorado collective tackles measurement, financial challenges.

PMID- 10351036
TI  - Policies and procedures reduce hospitals' liability in releasing patient
      information.

PMID- 10351037
TI  - Establishing external renew panels: a proactive or defensive measure?

PMID- 10351038
TI  - Market share: product, patient-provider experience to drive marketing for IDSs.
      Interview by Therese Droste.

PMID- 10351039
TI  - A site where hospitals can click to shop.

PMID- 10351040
TI  - Best-practice guidelines for utilizing facilitators.
AB  - It appears that the majority of hospitals and other health care organizations use
      facilitators in team development. While some organizations use facilitators more
      extensively than others, facilitators appear to serve pivotal roles for teamwork
      in most health care organizations. A review of the literature, however, suggests
      that there is no clear consensus regarding the best way to use facilitators. This
      lack of consensus is, in part, due to the lack of clear best-practice guidelines
      for utilizing facilitators in health care. The purpose of this article is to
      provide such guidelines.

PMID- 10351041
TI  - The challenge of competency assessment.
AB  - Regulatory agencies now require more than credentialing, quality assurance, and
      educational programs to prove that health care workers are competent. There is
      confusion over exactly what competency is and how we can assess it in an
      environment of strict cost restriction. This article presents an overview of the
      current situation and some techniques for assessing competencies. Emphasis is on
      clinical laboratory approaches.

PMID- 10351042
TI  - Collaborations to improve hospital-based student practicums.
AB  - Hospital educators who place students from area nursing schools noted that the
      information provided to students in orientation to the hospital was being
      repeated at the beginning of every clinical rotation. This was costly for the
      hospitals, and monotonous and time consuming for students. The hospital educators
      collaborated to develop a generic orientation to be given annually rather than
      every 10 weeks. Realizing they could better accomplish their goals with the
      involvement of the nursing schools, they formed a second collaboration with
      administrators and faculties of area nursing schools. After identifying problems,
      specific requirements were developed to ease the process of clinical
      affiliations. Both hospital educators and nursing school administrators saw only
      benefits arising from the new processes.

PMID- 10351043
TI  - Restructuring clinical time to professionalize the RN-BSN student.
AB  - The needs of the RN-BSN student are unique. If the RN-BSN student is to be
      successful in a degree completion program, it is important that the program be
      designed with the needs of the student in mind. It is important that the program
      be tailored to the needs of the student who may already possess expertise in
      nursing. This will enhance the likelihood that the student will stay in the
      program and that learning will occur.

PMID- 10351044
TI  - The name of the game is commitment.
AB  - The success of health care institutions depends largely on how committed its
      employees are. Profiles of personal commitments can vary markedly. Major
      components of all these profiles are: dedication to employers, bonding with
      fellow professionals, and loyalty to one's work group or team. We discuss how
      employers and leaders can create a culture that features more commitment. The
      rewards and risks of personal commitment and the characteristics of committed
      employees are presented.

PMID- 10351045
TI  - The perioperative process: a system of providing quality, convenient, cost
      effective surgical services.
AB  - In the current health care environment, many customary procedures, developed in
      an era when cost containment and market competition were not major concerns are
      no longer compatible with the operation of a successful surgery service. This
      article outlines a perioperative system that accomplishes the goals of cost
      containment and patient and surgeon satisfaction without sacrificing quality of
      care. This system entails streamlining the entire perioperative process, from the
      initial interface with the surgeon's office to discharge from the facility. In
      addition, the system eliminates unnecessary waste that remains rampant in most
      surgery departments, and addresses scheduling problems that limit efficiency.

PMID- 10351046
TI  - Managing diversity in the health care workplace.
AB  - Cultural diversity is increasing in the United States as increasing numbers of
      minorities enter the United States from abroad, and cultural diversity is
      especially prevalent in the health care workplace. In fact, the health care
      professions are particularly interested in the presence of minorities among
      caregivers because this often enhances the cultural competence of care delivery.
      Nevertheless, subtle discrimination can still be found, and managers must be
      alert that such behavior is not tolerated. Use of the Giger-Davidhizar Cultural
      Assessment Model can provide managers with information needed to respond to
      diversity among staff appropriately.

PMID- 10351047
TI  - Alternative dispute resolution programs in health care: a study of organizational
      utilization.
AB  - The hyperturbulence in today's health care environment acts as a primer that
      escalates the frequency and severity of business conflicts. Several alternative
      dispute resolution (ADR) programs are described, with ADR suggested as a viable
      approach in assisting organizations in resolving conflicts. The data indicate
      that all of the health care organizations surveyed utilize some form of ADR to
      resolve conflict. The most common conflict resolution objective found is win/win,
      and respondents felt that ADR effectively met intended objectives. While the data
      gathered for this study are from a limited geographic region in Central Florida,
      the results can likely be generalized to many socially and ethnically diverse
      regions of the country.

PMID- 10351048
TI  - From idea to print: writing for a professional journal.
AB  - Those who have occasionally thought about writing for a professional journal
      should be encouraged by the fact that most journal writers are just like journal
      readers--practitioners and educators with something of value to share with
      others. There are career-enhancing advantages to journal writing, and there can
      be a significant amount of personal satisfaction as well. Succeeding at writing
      and placing a journal article requires: selecting an appropriate topic; knowing
      the publication and its audience and framing the article in the style they
      require; working with the journal editor to create an acceptable manuscript,
      which includes responding positively to the editor's criticisms and suggestions;
      and observing all submission requirements and deadlines. One who follows this
      entire process to its positive conclusion will find that journal writing can be
      an exacting, demanding, frustrating--and immensely satisfying--professional
      activity.

PMID- 10351049
TI  - Whom do we serve?

PMID- 10351050
TI  - Profitability is no measure of viability.

PMID- 10351051
TI  - Privacy, confidentiality, and security: protecting "personally identifiable
      information".

PMID- 10351052
TI  - Information systems for IDSs: meeting the challenges.
AB  - Integrated delivery systems (IDSs) face many challenges in implementing
      information systems. An IDS's senior management staff can meet these challenges
      by choosing the right information systems design team and ensuring that
      information systems staff have sufficient training and expertise to successfully
      assemble the needed information systems capabilities. To effectively fulfill its
      role, the information systems design team needs to understand the IDS's managed
      care strategy, know the level of information systems functionality required,
      obtain components from a limited number of vendors while using technology that
      integrates disparate components, build or enhance communication networks,
      consolidate where possible, and be willing to adopt new tools.

PMID- 10351053
TI  - Choosing an advantageous risk-sharing arrangement.
AB  - Providers entering into risk-sharing arrangements with managed care organizations
      have several options regarding the amount of risk they can assume. The four most
      common forms of arrangements are based on service guarantees, case rates, episode
      rates, and global capitation. Providers must determine carefully which of these
      arrangements is most beneficial for them.

PMID- 10351054
TI  - Designing compliance programs that foster ethical behavior.
AB  - The federal government continues to expand its initiatives to uncover healthcare
      fraud, waste, and abuse. It is therefore more important than ever that healthcare
      organizations have an effective compliance program in place. The organization
      should have a compliance officer with adequate authority and staff to carry out
      the compliance program's functions. The program should include an ethics code, an
      internal hotline that employees can use to report compliance concerns, and
      education and training for all employees. In addition, the program should be
      audited periodically to ensure its viability. To be successful, a compliance
      program also needs the support of the healthcare organization's senior
      management.

PMID- 10351055
TI  - Third-party biller compliance guidance emphasizes risk awareness.
AB  - The voluntary compliance guidance for third-party billing companies released by
      the HHS Office of Inspector General (OIG) in December 1998, like the OIG's
      previously released guidance directed at hospitals, home health agencies, and
      clinical laboratories, identifies seven minimum elements for an effective
      corporate compliance program: written compliance policies, designation of a
      compliance officer, ongoing training, open lines of communication, guidelines to
      ensure the enforcement of compliance standards, internal monitoring and auditing
      of compliance activity, and procedures to respond to and correct errors. Three
      areas of concern for third-party billing companies are emphasized in the new
      guidance document: compliance risk, claims documentation, and disclosure of
      suspected misconduct or fraud.

PMID- 10351057
TI  - PRRB mediation pilot program expedites payment dispute resolution.

PMID- 10351056
TI  - Financial implications of implementing a hospitalist program.
AB  - The use of hospitalists, who are physicians specializing in providing hospital
      inpatient care, has become increasingly popular. Preliminary data suggest that
      hospitalists can shorten inpatient lengths of stay and lower costs without
      compromising clinical outcomes or patient satisfaction. The role of hospitalists,
      their position in the organizational framework, and their contractual and
      financial relationships are influenced by the structure of the healthcare
      organization in which they work. Although hospitalist programs can benefit
      hospitals and medical groups financially, they rarely become self-supporting
      through professional fees alone. The long-term viability of hospitalist programs
      frequently will depend on the support the programs receive from whichever entity
      benefits from hospitalist-generated efficiencies.

PMID- 10351058
TI  - Data trends. Who provides the best quality of care?

PMID- 10351059
TI  - Late for Y2K? You can begin today, say experts, and you should begin now.

PMID- 10351060
TI  - Medicare's ready ... but a glitch-free Jan. 1 depends on you.

PMID- 10351061
TI  - Common Y2K issues.

PMID- 10351063
TI  - Clinical paths, wound clinics expand home care.

PMID- 10351062
TI  - HCFA's new 'transfer DRGs' can cost your hospital money.

PMID- 10351065
TI  - Medical staff competency: how much is enough?

PMID- 10351064
TI  - Iv insulin: culprit in med errors.

PMID- 10351066
TI  - National health policy influence on Medicare home health.
AB  - National health policy regulates the delivery of Medicare home health services.
      These services have grown exponentially over the past several years. Current
      challenges to service delivery revolve around attempts to contain costs while
      ensuring quality of and access to care. To meet these challenges, providers must
      be aware of the societal and ideological influences on national health policies
      that impact service delivery. This article uses Wong's model of the progression
      of health care reform to address past health policy influences on Medicare home
      health delivery, investigate recent sociological trends for relevance to health
      policy, and propose changes based on current ideology.

PMID- 10351067
TI  - Retention of clients in service under two models of home health care for
      HIV/AIDS.
AB  - OBJECTIVE: To determine if a Transprofessional, care-management approach
      (experimental group) produces different patterns of retention in home treatment
      as compared to a Traditional treatment approach (control group). The care
      management approach utilizes an interdisciplinary mix of allied health
      professionals who adhere to a service delivery protocol based on active medical,
      surgical treatment (curative services) as well as on pain, symptoms, and
      emotional care (palliative services). Initially, the Transprofessional Model
      should lead to a greater retention rate in the program as patients bond to
      blended care managers, but in later stages clients needing hospice should be
      moved off-services resulting in lower retention rates in the medical-surgical
      home care venue. DATA SOURCES AND STUDY SETTING: Data were collected from 549
      AIDS patients admitted for medical/surgical home-care services to the Visiting
      Nurse Association of Los Angeles (VNA-LA). Demographic and disease-specific data
      were collected from admitting records; service-utilization data were collected
      from the VNA-LA's computerized data system. STUDY DESIGN: Upon admission for home
      care services, patients were randomly assigned to an experimental
      (Transprofessional) or control (Traditional) treatment group. Service levels were
      comparable. PRIMARY FINDING: In the earliest stages, Transprofessional patients
      tend to be more likely to stay in treatment, probably due to the greater bonding
      to the program. After about one year, the Transprofessional patients are more
      likely to leave the program as they are transitioned into hospice care.
      CONCLUSIONS: An integrated model of service delivery, which is based on
      interdisciplinary care-management and blended modalities of service, provides a
      quality of life enhancing and a cost-effective method in the provision of home
      care services for terminally ill AIDS patients.

PMID- 10351068
TI  - Patients' and caregivers' transition from hospital to home: needs and
      recommendations.
AB  - Given the greatly decreased length of hospital stays, concern about the
      transition from hospital to home has increased. This descriptive study focused on
      a sample of hospitalized patients discharged to home with home care services.
      Patient and caregiver interviews revealed that satisfaction with home care
      services was positively related to receipt of information from the home care
      staff about medications, equipment/supplies, and self-care. Caregiver burden was
      inversely related to receiving this information. Recommendations for improving
      the transition from hospital to home included providing more information, more
      reassurance and emotional support, and more household assistance. Several
      possible methods of implementing these recommendations are proposed.

PMID- 10351069
TI  - The role of home care in integrated delivery systems.
AB  - The health care field is moving rapidly toward integrated delivery systems (IDS).
      The role of home care in such system is unclear. This study seeks to describe the
      current status of home care in IDS and to examine health care administrators'
      perceptions about the importance of IDS components. A random sample of 1600
      administrators was surveyed, 400 each from home care agencies, hospitals, nursing
      homes, and medical groups. Results reveal that hospitals lead integration,
      nursing homes are least involved, and home care agencies and medical groups fall
      in between. Administrator's opinions vary considerably about the importance of
      select services and integrating mechanisms.

PMID- 10351070
TI  - The conceptual and empirical link between health behaviors, self reported health,
      and the use of home health care in later life.
AB  - The primary qualification for Medicare's home health care benefit is being
      homebound, typically by a chronic disability. Disability and functional ability
      in late-life are heavily influenced by the long-term practice of health
      behaviors. One of the goals of Healthy People 2000 is to increase the years of
      healthy life which are measured, in part, by self reported health status. This
      compression of morbidity would, in effect, reduce the need for long term care.
      This paper examines three conceptual models linking health behaviors to self
      reported health in a unique sample of older adults who have chosen to participate
      in a corporate sponsored wellness program. It is hoped that these findings will
      encourage further research on formulating empirical pathways from health
      behaviors to reduced need for home health care.

PMID- 10351071
TI  - Third Circuit rules physician protected by Title III of ADA. Menkowitz v.
      Pottstown Memorial Medical Center.

PMID- 10351072
TI  - Courts reject ERISA and Medicare preemption defenses.

PMID- 10351073
TI  - Get the most from staff an ancillaries.

PMID- 10351074
TI  - Collect premium fees for premium care?

PMID- 10351075
TI  - Skillful hands, a generous heart.

PMID- 10351077
TI  - How do expert witnesses get away with lying?

PMID- 10351076
TI  - Bad news--they've discovered a cure for cancer.

PMID- 10351078
TI  - How to respond when a patient complains.

PMID- 10351079
TI  - How to ban job burnout.

PMID- 10351080
TI  - A court muddies the water for HMO liability.

PMID- 10351081
TI  - Your practice: time to make big changes?

PMID- 10351082
TI  - Washington: will Congress stop playing politics with health care?

PMID- 10351083
TI  - What could you earn in a group practice now?

PMID- 10351084
TI  - We solved our phone problem without spending a dime.

PMID- 10351085
TI  - Let us bring tidings of comfort to the dying.

PMID- 10351086
TI  - How big a staff do you need?

PMID- 10351087
TI  - Death in the OR: trial by tabloid.

PMID- 10351088
TI  - Internists: in search of their identity.

PMID- 10351090
TI  - Throw a party for your patients.

PMID- 10351089
TI  - See yourself through your staff's eyes.

PMID- 10351091
TI  - Staff salaries. Are you underpaying your office manager?

PMID- 10351092
TI  - Would a healthier population buy time for Medicare?

PMID- 10351093
TI  - I was sued for Medicare fraud--over an innocent error.

PMID- 10351094
TI  - How to be your own best expert witness.

PMID- 10351095
TI  - IRS rulings OK doc gain-sharing.

PMID- 10351096
TI  - Jury deciding verdict in Kan. fraud case.

PMID- 10351098
TI  - Colo. hospitals find success with HMOs.

PMID- 10351097
TI  - HMO hits W.Va. hospital's bottom line.

PMID- 10351099
TI  - Hospital sees rich future in poor area.

PMID- 10351100
TI  - Failed merger worries Inc. community.

PMID- 10351101
TI  - Transplant trauma. Renowned Boston surgeon cites merger conflicts among reasons
      for plans to switch hospitals.

PMID- 10351102
TI  - Fallout from nowhere. Effects mushroom from S.C. lease that wasn't consummated.

PMID- 10351103
TI  - Tenn. market splits into two systems.

PMID- 10351104
TI  - Feeling the pain, seeking to regain. Provider groups fighting uphill battle to
      repeal parts of the Balanced Budget Act of 1997.

PMID- 10351105
TI  - Still alone after all these years. Despite integration fever, many independent
      hospitals remain, and some are even profitable.
AB  - While the healthcare seas roil with mergers, partnerships and care continuums,
      many hospitals still prefer to go it alone, and some of them are doing quite
      well, thanks to fortuitous locations, financial prudence, community support and
      strong physician relationships.

PMID- 10351106
TI  - Spending slowdown hits systems vendors.

PMID- 10351107
TI  - Stock buybacks take a toll on ratings. Analysts question whether hospital
      companies' repurchasing strategy may be avoiding issues.

PMID- 10351108
TI  - Demise of Medicare fund seen as delayed.

PMID- 10351109
TI  - Feds use billing to enforce quality.

PMID- 10351110
TI  - Navigating through a legal storm.

PMID- 10351111
TI  - Preventing abuse in ICFs/MR.

PMID- 10351112
TI  - Targeting ancillary costs under PPS.

PMID- 10351113
TI  - New diets for people with dysphagia.

PMID- 10351114
TI  - Ultrasound contrast. Oral and i.v. agents amplify the image.

PMID- 10351115
TI  - Power Doppler bolsters breast tumor evaluations.

PMID- 10351116
TI  - Scintigraphic imaging of lower-extremity acute venous thrombosis.
AB  - The need for a radiopharmaceutical that will yield a definitive diagnosis of
      acute venous thrombosis in the lower extremities is evident from (1) the current
      difficulty in making a diagnosis on the basis of clinical signs and symptoms
      alone; (2) the sometimes inadequate or less sensitive diagnosis made on the basis
      of contrast venography or ultrasound; and (3) the need to prevent pulmonary
      embolism, death, and other long-term sequelae that may result from undetected
      acute venous thrombosis. A new radiopharmaceutical was recently approved for use
      in the scintigraphic imaging of acute venous thrombosis in the lower extremities
      of patients who have signs and symptoms of acute venous thrombosis. This
      radiopharmaceutical (ACUTECT) is a complex of the small synthetic peptide
      apcitide and the radionuclide technetium (Tc) 99m (99mTc-apcitide). Apcitide
      binds to glycoprotein IIb/IIIa receptors, which are expressed on the surface of
      activated platelets, making the radiopharmaceutical specific for acute, not
      chronic, thrombi. 99mTc-Apcitide allows accurate imaging of the entire lower
      extremities, including the calf. It has an excellent safety profile, is easy to
      administer by injection into an antecubital vein, and allows early imaging of
      acute deep-vein thrombosis (10 to 60 minutes postinjection). 99mTc-Apcitide may
      be used as an alternative to contrast venography and a complement to
      ultrasonography in the detection of acute venous thrombosis in the lower
      extremities.

PMID- 10351117
TI  - Use of a polyvalent bacterial lysate in patients with recurrent respiratory tract
      infections: results of a prospective, placebo-controlled, randomized, double
      blind study.
AB  - Respiratory tract infections (RTIs) are the most common infections in humans, and
      it is difficult to effectively treat patients with increased susceptibility to
      these ailments. LW 50020 (Luivac; Paspat oral), an oral immunomodulator
      consisting of the antigens of seven bacteria commonly involved in RTIs, has been
      developed for the induction of specific and nonspecific immune responses of the
      mucosa-associated lymphoid tissue. In this placebo-controlled study, the efficacy
      and safety of the tablet formulation of LW 50020 were evaluated in children and
      adults with recurrent RTIs. Tablets were taken once daily during two periods of 4
      weeks each, interrupted by a treatment-free interval of 4 weeks. The main
      endpoint of the study, a clinical severity score that evaluated treatment
      benefits, was significantly lower in the second study period in patients treated
      with the bacterial lysate compared to patients given placebo. A comparison of the
      infection rates in the first and second study periods of patients treated with LW
      50020 revealed a placebo-corrected reduction of 39% in children and a placebo
      corrected reduction of 44% in adolescents and adults. The placebo-corrected
      duration of infections was shortened by 47% in children and by 55% in older
      patients. No serious drug-related side effects occurred. This study demonstrated
      that the oral bacterial immunomodulator LW 50020 is efficacious in treating
      patients with recurrent RTIs.

PMID- 10351119
TI  - Comparison of solid and liquid forms of homeopathic remedies for tonsillitis.
AB  - The efficacy of three plants used in homeopathy to treat acute tonsillitis was
      evaluated. A fixed combination of three plant substances (Phytolacca americana,
      Guajacum officinale, Capsicum annuum) was used in either solid (tablet) or liquid
      (drop) formulation: 107 patients were treated and no antibiotics were used. The
      objective and subjective symptoms of acute tonsillitis were noted. A significant
      decrease in symptoms was observed as early as 2.5 days after treatment startup;
      no serious adverse effects were reported. It was concluded that acute tonsillitis
      can be treated with a homeopathic remedy characterized by its immunomodulatory,
      analgesic, and anti-inflammatory properties.

PMID- 10351118
TI  - Safety and efficacy evaluation of a fitness club weight-loss program.
AB  - It is well documented that excess weight is a major risk factor for many chronic
      diseases, and, despite considerable expenditure of time, money, and effort,
      little or no progress has been made in reversing the trend toward increased
      weight. Although fitness and athletic clubs offer one potential for tackling this
      problem, few provide information about the efficacy of their weight-loss
      programs. There is general agreement that an efficacious weight-loss program
      should reduce body fat, maintain or increase fat-free mass (FFM), and lower total
      and low-density lipoprotein (LDL) cholesterol. This study was designed to compare
      changes in body composition and serum cholesterol associated with participation
      in a fitness club program (EXP) versus changes that occurred when participants
      pursued a program of their own choosing (CTL). The EXP group participated in the
      Bally's Total Fitness program that included exercise, behavior modification, and
      dietary supplements. Although only small differences in body weight were noted
      between groups, participation in the EXP program led to significant (sixfold)
      reductions in fat mass, increases in FFM, and improvements in body composition.
      These data highlight the importance of using measures of body composition rather
      than scale weight in evaluating the efficacy of weight-loss programs.
      Additionally, the EXP group achieved significant reductions in total and LDL
      cholesterol, particularly among individuals with baseline total cholesterol
      levels above 200 micrograms/dL. It is also worth noting that respective
      cholesterol levels were maintained for participants with total cholesterol levels
      between 150 and 199 micrograms/dL and were increased for those with levels at or
      below 150 micrograms/dL.

PMID- 10351120
TI  - Connecting blood glucose results to the LIS: the next level in POCT data
      integrity.

PMID- 10351121
TI  - Diagnosis of bladder cancer: a challenge for urine cytology by tumor markers?

PMID- 10351123
TI  - A urine test system for HIV-1 antibodies.

PMID- 10351122
TI  - Concepts and principles of evidence-based laboratory medicine.

PMID- 10351124
TI  - Validation of an automated assay for vitamins A and E in serum by SPE-HPLC.

PMID- 10351125
TI  - Current status and trends of aerosol inhalation diagnosis and therapy in Japan.

PMID- 10351126
TI  - Characterization of heparin aerosols generated in jet and ultrasonic nebulizers.
AB  - Inhaled heparin has been used for asthma treatment, but results have been
      inconsistent, probably due to highly varying lung doses. We determined the output
      per unit time and the particle size distributions of sodium heparin, calcium
      heparin, and low molecular weight (LMW) heparin formulations in five
      concentrations from Sidestream jet nebulizers (Medic-Aid, Bognor Regis, England)
      and an Ultraneb 2000 ultrasonic nebulizer (DeVilbiss, Langen, Germany). We also
      determined the inhaled mass and the estimated respirable mass for some
      combinations. For the jet nebulizer, output per minute increased with increasing
      concentration and flow rate, and particle size decreased from 3.64 to 2.01
      microns (mass median diameter [MMD]). The percentage of particles less than 3
      microns ranged from 41% to 74%. For the ultrasonic nebulizer, maximum output per
      minute was achieved at a concentration of 7000 i.u./mL; this maximum depended
      upon the viscosity and temperature of the solution. MMD was independent of
      formulation, temperature, or concentration and ranged from 5.61 to 7.03 microns.
      Sodium heparin/calcium heparin in a concentration of 20,000 i.u./mL in the jet
      nebulizer driven at 10 L/min produced the highest dose of heparin capable of
      reaching the lower respiratory tract. Mass balance was determined for these
      combinations with the jet nebulizer run until visible aerosol generation ceased.
      Of a loading dose of 80,000 i.u. of heparin, 45,000 i.u. remained in the dead
      space of the nebulizer, 20,000 i.u. was deposited on the exhalation filter, and
      15,000 i.u. was captured on the inhalation filter (inhaled mass). This
      corresponds to a respirable mass of 10,000 i.u. of heparin with a high
      probability of reaching the lower respiratory tract in normal healthy adults.

PMID- 10351127
TI  - Inhalation of estradiol for sustained systemic delivery.
AB  - Large porous estradiol particles were formulated by spray drying estradiol in
      combination with various U.S. Food and Drug Administration (FDA)-approved or
      endogenous excipients. The powders were characterized in terms of their
      geometrical size, mass density, and aerosolization properties. Small nonporous
      particles were also prepared using the same excipients and were physically
      characterized to insure that they possessed a similar mean aerodynamic size as
      the large porous particles. The two powders were aerosolized into the lungs of
      rats via an endotracheal tube or subcutaneously injected as a control to assess
      relative bioavailability. Two different large porous particle formulations were
      found to produce elevated systemic estradiol concentrations upon inhalation for
      approximately 5 days, with relative bioavailabilities of 59.7% and 86.0%.
      Systemic estradiol concentrations following inhalation of two different small
      nonporous particle powders remained elevated for only approximately 1 day, with
      relative bioavailabilities of 18.3% and 38.7%. Bronchoalveolar lavage was
      performed up to 96 hours after inhalation of porous and nonporous estradiol
      powders. Small changes in neutrophil and macrophage populations were observed
      following inhalation of both the porous and nonporous powders.

PMID- 10351128
TI  - Health effects of sulfur-related environmental air pollution: the pulmonary
      surfactant system is not disturbed by exposure to acidic sulfate and neutral
      sulfite aerosols.
AB  - The goal of this study was to assess the impact of long-term exposure to
      environmental sulfur-related aerosols on the biochemical and biophysical
      properties of lung surfactant. Eight Beagle dogs were housed under clean air
      conditions for 450 days, followed by an exposure period of 400 days to 0.36 mg/m3
      of sulfite (16.5 h/d) and to 5.66 mg/m3 of sulfate (6 h/d) equivalent to a
      pulmonary hydrogen burden of 15 mumol/m3. Other dogs kept in clean air for the
      whole study period were additional controls. Serial bronchoalveolar lavages
      (BALs) were analyzed for total phospholipid concentration, content and ratio of a
      surfactant-rich large aggregate (LA) fraction and a small aggregate (SA)
      fraction, in vitro surface area cycling of LAs into SAs as a measure of alveolar
      extracellular pulmonary surfactant aggregate metabolism, and surface activity of
      native and lipid-extracted LA. No significant changes over time and no
      differences between the clean air period and the exposure period were observed.
      Thus, long-term environmental exposure of dogs to the sulfur-related air
      pollution tested does not lead to alterations in the amount, extracellular
      metabolism, or surface-active properties of pulmonary surfactant.

PMID- 10351130
TI  - Symposium on Hemapheresis, international forum. Dordrecht, The Netherlands.
      Abstracts.

PMID- 10351129
TI  - Estimation of pulmonary deposition of aerosol using gamma scintigraphy.
AB  - Following delivery of technetium 99m-labeled aerosols through a ventilator
      circuit, the amount of radioactivity in the lungs of 58 ventilated rabbits was
      estimated first by gamma scintigraphy via gamma camera and later by direct
      counting of the excised lungs (n = 116 specimens) with a gamma counter. The in
      situ radioactivity measured via scintigraphy was closely correlated with the
      gamma counter ex vivo tissue counts of the radioactivity (R2 = 0.997, P < 0.001).
      Overall, gamma scintigraphy gave slightly lower values of activity than the
      tissue counts from the gamma counter, but the limits of agreement between the two
      measurements were narrow enough for us to consider that the tissue and
      scintigraphy methods were in agreement. We conclude that gamma scintigraphy
      provides a convenient and noninvasive means for the accurate estimation of
      aerosol deposition in the lungs of small animals and possibly in small infants.

PMID- 10351131
TI  - International forum: Japan report on informed consent in blood transfusions.

PMID- 10351133
TI  - Evaluation of CAPTURE CMV solid phase testing over the allowable shelf-life of
      red blood cells (adenine-saline added).
AB  - BACKGROUND: CAPTURE CMV (IMMUCOR Inc., Norcross, GA) is a solid-phase screening
      test used to detect IgM and IgG antibodies to cytomegalovirus (CMV). CAPTURE CMV
      is licensed for testing whole blood (WB) in citrate phosphate dextrose (CPD)
      preserved segments of units of red blood cells (RBC) only up to 7 days of
      storage. We determined if CAPTURE CMV could produce consistent results in CPD
      preserved WB segments from RBC adenine-saline added (ASA) for their 42 day shelf
      life. METHODS: Ten CMV-seropositive and 10 CMV-seronegative RBC (ASA) tested by
      CAPTURE CMV during the first week of storage were studied. Segments were tested
      weekly for 6 weeks. RESULTS: All 10 units that initially tested as CMV
      seropositive remained strongly seropositive. All 10 units initially CMV
      seronegative, remained seronegative. CONCLUSION: CAPTURE CMV testing provides
      consistent results over the entire shelf-life of RBC (ASA).

PMID- 10351132
TI  - Platelet cold agglutinins: a flow cytometric analysis.
AB  - Spontaneous EDTA-independent cold platelet agglutination is a rare phenomenon
      that produces pseudothrombocytopenia when blood samples are analyzed in automated
      cell counters. We report a case of platelet cold agglutinins and an analysis by
      flow cytometry. A 49 year old woman presented with abnormal vaginal bleed
      secondary to uterine fibroids. Platelet clumping was observed in blood samples
      taken in EDTA-, heparin- and citrate-containing tubes. In flow cytometric tests,
      patient serum agglutinated 16% of normal platelets at 22 degrees C, and 7% of
      platelets after incubation at 37 degrees C; in contrast, 3% and < 1% of platelets
      were agglutinated at 22 and 37 degrees C, respectively, after incubation with
      normal serum. Minimal agglutination (< 10%) was observed with patient serum at a
      titre of 1:5 or at temperatures > 30 degrees C. After incubation at 4 degrees C,
      IgM antibody and C3 were increased on the patient's platelets; no significant
      amount of IgM or C3 was detected on normal platelets. The specificity of the
      platelet cold agglutinin was determined by competitive inhibition by monoclonal
      anti-CD41(GPIIbIIIa). Before the addition of monoclonal antibody, patient's serum
      agglutinated 16% of normal platelets at 22 degrees C; after addition of anti-CD41
      only 2% of the platelets were agglutinated. This blocking effect was not observed
      with anti-CD42. The patient's platelets functioned normally as determined by CD62
      and CD63 expression in response to thrombin, normal platelet aggregation in
      response to collagen, ADP, and ristocetin, and a normal template bleeding time.
      In summary, platelet agglutination by a platelet cold agglutinin was quantitated
      by flow cytometry, the responsible antibody was characterized as a low titre IgM
      with minimal activity > 30 degrees C, and competitive binding studies supported
      the GPIIbIIIa complex as the binding site for the antibody. Since the antibody
      did not affect platelet function, we believe that these patients will not suffer
      complications from their platelet cold agglutinin, but it could pose a problem
      under circumstances such as cardiac surgery with hypothermia.

PMID- 10351134
TI  - The history of idiopathic thrombocytopenic purpura (ITP).
AB  - Purpura, initially recognized in ancient times, was defined into clinical
      syndromes in the 16th, 17th and 18th centuries. With advances in microscope
      science in the nineteenth century, the platelet was identified, leading to the
      recognition of the thrombocytopenic component of idiopathic thrombocytopenic
      purpura (ITP). The 20th century brought recognition of the pathophysiology of the
      disorder and the clinical states were refined and treatments for ITP developed.
      The latter half of the 20th century has focused on the autoimmune components of
      ITP, attempting to develop diagnostic tests, apply new therapies, and elucidate
      the immune dysregulation associated with, and underlying, the disorder.

PMID- 10351135
TI  - Platelet autoantibodies in immune thrombocytopenic purpura.
AB  - In summary, the search for a useful clinical laboratory diagnostic assay for the
      antiplatelet antibodies has been long and difficult. Measurement of platelet
      associated IgG (PAIgG) has been disappointing as a way to detect autoantibodies.
      This is primarily due to the fact that platelets normally contain IgG in their
      alpha granules in an amount that varies with plasma IgG levels and age of the
      platelets. Furthermore, the amounts of platelet associated IgG is affected by the
      presence of circulating immune complexes, platelet activation, and drug dependent
      antibodies. The newer, platelet antigen capture techniques are promising, but
      further testing will be needed to confirm their value to the clinician. Methods
      that allow incubation of patient serum or plasma with intact platelets (MAIPA and
      immunobead) have greater sensitivity than techniques in which the patient
      antibody is tested against previously isolated platelet glycoproteins. These
      assays are currently available in a only a limited number of platelet immunology
      laboratories. Platelet autoantibodies are directed against a number of
      glycoprotein antigens on the platelet surface. Most studies have shown that anti
      GPIIb/IIIa antibodies are the most common, although antibodies against GPIb/IX
      and other targets are frequently detected. Many patients have multiple
      antiplatelet antibodies circulating simultaneously. The clinical significance of
      antibodies with different specificity is under investigation. The precise
      epitopes on GPIIIa that bind antiplatelet autoantibodies have been studied to a
      limited extent. Some investigators report that the vast majority of platelet
      antigens are conformation dependent, being destroyed by treatment with EDTA
      (separation of GPIIb and GPIIIa) or denaturation with detergents. Others report
      sequence specific peptide antigens. Further investigation promises to better
      define the targets for platelet autoantibodies; improved clinical management of
      patients with ITP is the long term goal of these studies.

PMID- 10351136
TI  - The cellular immunology associated with autoimmune thrombocytopenic purpura: an
      update.
AB  - Chronic autoimmune thrombocytopenic purpura (AITP) is an organ specific
      autoimmune bleeding disease in which autoantibodies are directed against the
      individual's own platelets, resulting in increased Fc-mediated platelet
      destruction by macrophages in the reticuloendothelial system. Although AITP is
      primarily mediated by IgG auto-antibodies, their production is regulated by the
      influence of T lymphocytes and antigen presenting cells (APC). This review argues
      that enhanced T helper cell/antigen presenting cell interactions in patients with
      AITP may be responsible for IgG anti-platelet auto-antibody production.
      Understanding these cellular immune responses in AITP may lead to the development
      of more immune specific therapies for the management of this disease.

PMID- 10351137
TI  - Virus-associated idiopathic thrombocytopenic purpura.
AB  - Two-thirds of children with acute idiopathic thrombocytopenic purpura (ITP) have
      a history of an infectious illness a few days to a few weeks before the onset of
      thrombocytopenia. In a subset of affected children, identification of a specific
      virus can be made, such as varicella zoster virus, rubella, Epstein-Barr virus,
      influenza, or human immunodeficiency type 1 virus, indicating an etiological role
      for preceding viral infection in these children with ITP. While inhibition of
      thrombopoiesis has been established to play a role in thrombocytopenia associated
      with infection with some viruses, it does not appear to play a major role in the
      etiology of most typical ITP cases. Rather, enhanced clearance of platelets by
      the reticuloendothelial system is considered to be, at least in part, responsible
      for the thrombocytopenia which occurs during the viremic phase of acute virus
      infection or which develops days to weeks following the virus illness. Molecular
      mimicry between viral antigens and host proteins has been implicated in a number
      of autoimmune phenomena, and may be involved in the enhanced platelet clearance
      in virus-associated ITP.

PMID- 10351138
TI  - Management of children with acute and chronic immune thrombocytopenic purpura.
AB  - Immune thrombocytopenic purpura (ITP) is divided in an acute and chronic form
      based on the duration of the disease. Persistence of thrombocytopenia for more
      than 6 months defines chronic ITP. The disease occurs in both children and adults
      with acute ITP as the predominant form of childhood and chronic ITP occurring in
      approximately 20% of children and almost all adult patients. The diagnostic
      procedures and the therapeutic consequences are discussed with respect to the
      many open and unresolved questions recently identified by a panel of pediatric
      and adult hematologists on behalf of The American Society of Hematology. Research
      activities with identification of priorities are important to better understand
      the disease resulting in an optimal evidence-based management of children and
      adults with ITP.

PMID- 10351139
TI  - Management of chronic autoimmune thrombocytopenic purpura (ITP) in adults.
AB  - The management of thrombocytopenia in adults is a therapeutic challenge requiring
      not only the science but the art of medicine. The disease is usually chronic and
      a third of those affected will have significant thrombocytopenia despite attempts
      at presently accepted forms of management. Adults tolerate moderate degrees of
      thrombocytopenia and treatment of asymptomatic patients with platelet counts
      greater than 30 x 10(9)/L is usually not required. Steroids, splenectomy, and the
      use of steroid-sparing immunosuppressive drugs remain the mainstay of treatment,
      although short-term responses to intravenous immunoglobulin (IVIg) and anti-D may
      be beneficial. The multitude of therapies with anecdotal reports of responses
      attests to the frustration felt by hematologists in the management of this
      disease when conventional treatments fail.

PMID- 10351140
TI  - Intravenous immunoglobulin G and anti-D as therapeutic interventions in immune
      thrombocytopenic purpura.
AB  - Immune thrombocytopenic purpura (ITP) is a disorder caused by accelerated
      destruction of antibody-coated platelets in the reticuloendothelial system (RES),
      especially the spleen. Inhibition of RES function following intravenous
      administration of high-dose immunoglobulin G (IVIG) or intravenous anti-D leads
      to rapid, albeit usually temporary, reversal of thrombocytopenia in the majority
      of children and adults with ITP. In emergency situations high-dose IVIG is
      preferred over anti-D because of the more rapid rate of platelet response; for
      maintenance therapy in Rh positive ITP patients (e.g. children with chronic ITP
      pre-splenectomy) anti-D is preferred because of its comparable efficacy to IVIG
      plus ease of administration and lower cost. In children with typical acute ITP
      and platelet counts < 20 x 10(9)/L IVIG is preferred over anti-D; however other
      approaches in this patient cohort should be considered before high-dose IVIG,
      specifically careful observation alone with therapy given only to children with
      clinically significant haemorrhage or short course oral prednisone at a starting
      dose of approximately 4 mg/kg/day. Studies are required to define the short and
      longer term effects of both IVIG and anti-D on the immune system in order to plan
      more rational use of these immunomodulatory therapies in this model autoimmune
      disorder.

PMID- 10351141
TI  - Intravenous immunoglobulin and anti-D in idiopathic thrombocytopenic purpura
      (ITP): mechanisms of action.
AB  - Infusion of large amounts of intravenous immunoglobulin (IVIG) or anti-D can
      reverse the low platelet count in patients with ITP within hours of the
      initiation of treatment. In some cases, the effects of IVIG appear to far outlast
      several half-lives of the product. Several mechanisms have been proposed to
      explain these rapid and long term effects and these will be discussed in this
      review.

PMID- 10351142
TI  - The Canadian experience using plasma exchange for immune thrombocytopenic
      purpura. Canadian Apheresis Group.
AB  - The effect of plasma exchange (PE) for the treatment of acute immune
      thrombocytopenic purpura (ITP) was assessed both through an analysis of the use
      of PE for ITP in Canada from 1980 to 1997, and in a study of 23 patients with
      acute ITP. Thirteen of these 23 patients were treated by PE (10 were exchanged
      with albumin and three with FFP) plus prednisone and 10 were treated with
      prednisone alone. At the 6 month follow-up, 11 of 19 patients were considered
      complete responders and six were considered partial responders. The difference in
      response rates between the PE and prednisone groups was not statistically
      significant. All patients had platelet specific antibodies at the time of entry
      into the study. Antibody concentration was reduced following PE in 10 of the 12
      patients tested, and a response to PE was seen in all 10 patients who had a
      reduction in the level of platelet antibody. In contrast, antibody levels did not
      change in the patients who received steroid treatment only. This observation
      suggests that antibody removal may be of direct benefit in patients with ITP.
      Analysis of our results indicated that PE increased the length of time before
      splenectomy but did not alter the need for splenectomy. Short term benefits of PE
      were accomplished with no increase in morbidity or mortality which confirms that
      PE is a safe procedure in patients with ITP.

PMID- 10351143
TI  - Variation in weights of fresh frozen plasma.

PMID- 10351144
TI  - Effect of intravenous immunoglobulin therapy on plasma complement.
AB  - The effect of the intravenous immunoglobulin preparation (Sandoglobulin) on the
      complement system and the formation of circulating immune complexes (CIC) was
      investigated in 10 patients with primary humoral immunodeficiency and in 12
      normal volunteers. Infusion of 9 g of the pH4 treated preparation did not show
      relevant changes in total hemolytic complement activity, plasma levels of C4, C3,
      and factor B. C3dg fragments, however, increased markedly in some individuals in
      both groups immediately after infusion. CIC measured by 125 I-C1q binding were
      not detectable. Furthermore, the initially low C1q concentrations in immune
      deficient patients correlated with the pre-infusion IgG levels (p < 0.05) and
      rose significantly 24 h after therapy (p < 0.001). In contrast, in vitro
      incubation of the immunoglobulin preparation with normal human serum did not
      reveal spontaneous anticomplementary activity nor did it lead to formation of
      immune aggregates. The results indicate that immunoglobulin infusions may
      moderately activate complement in vivo, as evidenced by increased C3dg fragments;
      in addition, partial C1q deficiency in hypogammoglobulinemia seems to be related
      to IgG concentration and can be corrected by immunoglobulin substitution.

PMID- 10351146
TI  - NBA/NBS perspective on nvCJD.

PMID- 10351145
TI  - Update on leucocyte depletion of blood components by filtration.
AB  - It has long been recognized that allogenic leucocytes from donor blood are
      responsible for serious untoward effects in some transfused patients such as
      alloimmunization, febrile reactions, platelet refractoriness, transfusion
      associated acute lung injury, immunosuppression as well as transmission or
      reactivation of viruses such as CMV, HTLV or EBV. Leucocytes are also known to
      accelerate the rate of storage lesion. The optimal method to remove leucocytes
      from blood components has been shown to be filtration. However, many variables
      exist in the properties of leuco-depletion filters (material, composition,
      surface charge, mechanisms of leucocyte entrapment), the blood components to be
      filtered (composition, age), and the filtration method (pre- or post-storage,
      priming and rinsing, temperature, flow rate). In this paper principles of
      filtration and subsequent logistic consequences will be discussed. It is
      recommended to carefully select a filter for a specific blood component and to
      perform leuco-depletion procedures under controlled conditions according to
      validated methods meeting Good Manufacturing Practice (GMP) and Good Laboratory
      Practice (GLP).

PMID- 10351147
TI  - The risk of transmission of nvCJD by blood transfusion and the potential benefits
      of leucodepletion.

PMID- 10351148
TI  - French evaluation of conditions for the systematic implementation of leucocyte
      removal in labile blood products (LBP).

PMID- 10351149
TI  - Potential clinical benefits and cost savings of universal leucocyte-depletion of
      blood components.

PMID- 10351150
TI  - International views on universal leucodepletion: the perspective in NBS, England.

PMID- 10351151
TI  - International views on universal leucodepletion: the perspective in NBS, Ireland.

PMID- 10351152
TI  - International views on universal leucodepletion: the perspective in Portugal.

PMID- 10351153
TI  - International views on universal leucodepletion: the perspective in The
      Netherlands.

PMID- 10351154
TI  - Perspective on Nordic views on selective/universal leukodepletion.

PMID- 10351156
TI  - Universal leucodepletion--practical and regulatory consequences.

PMID- 10351155
TI  - International views on universal leucodepletion: the perspective in Germany.

PMID- 10351157
TI  - Validation approaches selective/universal leucodepletion: the need for
      standardised validation strategies.

PMID- 10351158
TI  - Operational and research approaches to universal leucodepletion in Scotland.

PMID- 10351159
TI  - NBS approaches to the approval of suppliers of leucodepletion systems.

PMID- 10351160
TI  - Logistical problems of supplying leucodepleted blood components within the
      national blood service.

PMID- 10351161
TI  - Developing effective working partnership with manufacturers.

PMID- 10351162
TI  - Challenges in QA of leucodepleted blood component and current standard(s).
      Challenges in quality assurance of leukoreduced components.

PMID- 10351163
TI  - Leukodepleted blood components: definition of a standard.

PMID- 10351164
TI  - Leukocyte-poor platelet concentrates in routine production: preparation and cost.

PMID- 10351165
TI  - The timing of leuko-depletion of apheresis platelets with a Sepacell PLS-5A
      filter does not affect glycoprotein IIb/IIIa-dependent platelet function in
      vitro.

PMID- 10351166
TI  - Evaluation of sampling procedures for quality monitoring of red cell
      concentrates: the need for improving sampling and sample handling techniques of
      red cell concentrate.

PMID- 10351167
TI  - Flow cytometric determination of residual leucocytes in filter-depleted blood
      products: an evaluation of Becton-Dickinson's LeucoCOUNT system.

PMID- 10351168
TI  - III-7 evaluation of IMAGN 2000: a new system for absolute leucocyte count.

PMID- 10351169
TI  - Out of the darkness and into the light: women's experiences with depression after
      childbirth.
AB  - While becoming a mother can be a fulfilling and joyful experience, 10-28% of
      women are affected by an intense emotional response commonly called postpartum
      depression. This phenomenon is distinguishable from the "transitory baby blues"
      and is often characterized by crying, confusion, fatigue, depression, insomnia,
      difficulty caring for the baby and self, and suicidal thoughts. Research on
      postpartum depression has largely concentrated on investigating its possible
      causes and predictors utilizing quantitative methodology. Women are the experts
      of their own lives, yet their voices are missing in the existing body of
      knowledge about depression after childbirth. In this exploratory qualitative
      study, I used a feminist perspective to explore the experiences of eight women
      who had recovered from postpartum depression. A three-stage model emerged that
      demonstrated how women made sense of that time in their lives. The findings of
      this study provide a contextual picture of women's experiences with depression
      after childbirth. The knowledge created has important implications for informing
      the practice of professionals and the implementation of policy and programs that
      meet the needs of new mothers and their families.

PMID- 10351170
TI  - Injection drug use and HIV infection among the seriously mentally ill: a report
      from Vancouver.
AB  - A recently reported outbreak of HIV among injection drug users in Vancouver
      determined that, in early 1997, 23% of this population was HIV-positive, and that
      HIV-negative injection drug users were becoming positive at the rate of 18.6% per
      year, the highest rate reported in North America. One significant factor behind
      the outbreak is the high prevalence of injection cocaine use among drug addicts
      in Vancouver. Cocaine, because it has a short "high," creates a need for more
      frequent injections and therefore increases the likelihood of needle sharing and
      HIV transmission. The mentally ill in Vancouver are particularly at risk for HIV
      infection because of their vulnerability to substance misuse and because large
      numbers of them reside in the main drug-using neighborhood. The provincial and
      federal governments have made $4,700,000 available to respond to this public
      health emergency, to be spent on the expansion of community services, including a
      number of needle-exchange sites. Accessing these and other health care services
      continues to be a challenge for injection drug users who also suffer from serious
      mental illnesses; for these persons an assertive case management model may be the
      most effective way of maintaining continuity of care.

PMID- 10351171
TI  - Rethinking the role of residential treatment for individuals with substance abuse
      problems.
AB  - The Substance Abuse Bureau of the Ontario Ministry of Health recently launched
      the Ontario Addictions Treatment Services Rationalization Project to increase the
      capacity of existing services and restructure the service delivery system. One of
      the recommended strategies was to shorten the length of stay of residential
      treatment from four to three weeks. Concerns have been expressed by some service
      providers that this policy change is not consistent with available empirical
      evidence. This paper reviews relevant research evidence and suggests a new role
      for residential treatment of substance abusers.

PMID- 10351172
TI  - Mental health issues of abused women: the perceptions of shelter workers.
AB  - While some studies have documented the mental health symptoms of battered women,
      we know little of the extent to which shelter residents present with mental
      health and substance abuse symptoms, or the effect of these issues on other
      residents, staff, and children. Further, it is not clear whether shelter staff
      feel sufficiently trained to safely and adequately address such concerns. The
      current survey was an effort to document what proportion of shelter residents
      present with severe symptomatology and its effect on the shelter environment. The
      survey was completed by 158 staff from 23 of Alberta's 30 shelters. Since
      shelters are one aspect of a community network of services, it was of interest to
      identify how well mental health and substance abuse services complement each
      other and whether shelters have developed strategies to better connect with other
      agencies.

PMID- 10351173
TI  - Life insurance: opportunities for reducing claims loss?

PMID- 10351174
TI  - The impact of excess mortality on life expectancy--tables based on levels of EDR
      (Excess Death Rate) and rates in the U.S. decennial life tables for 1989-91
      (white population).

PMID- 10351175
TI  - Influence of age on survival of patients treated surgically for lower limb
      ischemia.
AB  - BACKGROUND: Investigators in Norway reported long-term survival experience in
      patients treated surgically for lower leg occlusive atherosclerotic disease over
      the period 1974 to 1993. RESULTS: Ten-year survival data were provided for seven
      age groups. Average annual mortality ratios decreased with age at time of surgery
      from a high of 460% in the 50-54 year-old age group to a low of 212% in patients
      > 80 years of age. CONCLUSIONS: Excess mortality was related to age. This same
      mortality pattern is observed with most impairments, i.e., mortality ratios are
      usually highest at younger ages, intermediate in the middle-aged people, and
      lower in the very elderly.

PMID- 10351176
TI  - Comparative mortality of patients diagnosed with localized and in situ melanomas.
AB  - BACKGROUND: The rates for incidence and mortality from melanoma are continuing to
      rise, although long term survival experience for patients with in situ and
      localized melanomas is favorable. RESULTS: Excess mortality varied with age at
      diagnosis, sex, duration since diagnosis and tumor thickness. CONCLUSIONS:
      Compared to the general white population in the United States, patients with
      localized melanoma experience a mild increase in Excess Death Rates (EDRs) the
      first year following diagnosis. For 1-5 years following diagnosis the EDRs are
      markedly increased across all age groups and decline thereafter. At 15-20 years
      following diagnosis the EDRS are not elevated except among patients < 40 years of
      age at diagnosis. Patients with tumors > 1.5 mm thick have mild to moderate
      increases in EDR for the first year following diagnosis, and extremely high EDRs
      up to 5 years. There is no elevation in mortality ratios or EDR for patients
      diagnosed with in situ melanomas.

PMID- 10351177
TI  - Underwriting implications of premalignant disease.
AB  - The study of premalignant disease may hold the promise of cancer prevention and,
      in some cases, this potential is already being realized. In other instances,
      however, increased risk of mortality and morbidity has been identified without
      clear data to guide treatment. This series reviews the current state of
      information about premalignant disease from the perspective of diagnosis,
      treatment and underwriting risk. The first article will focus on prostatic
      intraepithelial neoplasia.

PMID- 10351178
TI  - An update on EBCT (Ultrafast CT) scans for coronary artery disease.
AB  - OBJECTIVES: To determine the predictive value of electron beam computerized
      tomographic scans for calcium in the detection of coronary artery disease.
      DESIGN: Literature review and meta-analysis of published studies of electron beam
      computerized tomographic scans for coronary calcification. METHODS: Six studies
      comparing EBCT scan and coronary angiography findings comprising 2,717 patients
      were reviewed. Bayesian analyses were performed for the entire cohort and
      subgroups. Bayesian analyses plots are presented. RESULTS: EBCT scans for the
      detection of coronary artery disease have a sensitivity that ranges from 68% to
      100% and a specificity that ranges from 31% to 74% for the presence of
      significant coronary disease. (Overall, sensitivity = 94%; specifity = 42%)
      Sensitivities and specificities of EBCT scans for any coronary disease range from
      80% to 97% and 52% to 65%, respectively. (Overall, sensitivity = 91%; specificity
      = 55%). CONCLUSIONS: EBCT scans are being performed with increasing frequency as
      an adjunctive means to diagnose coronary disease. Although EBCT scans are
      unlikely to ever become a substitute for direct angiographic visualization of the
      coronary arteries, in certain instances they can be helpful in excluding or
      increasing the likelihood of significant coronary disease. The results of EBCT
      scans should be interpreted in the light of other available evidence, including
      such information as age, sex, the presence of risk factors for coronary disease,
      and the results of other tests such as ECG stress tests and imaging procedures.
      In general, although the presence of coronary artery calcification tends to be of
      more value in indicating that significant coronary disease is not present. The
      use of Bayesian analyses plots may prove of value in helping determine the
      significance of EBCT scan findings.

PMID- 10351180
TI  - The role of the life insurance medical director: a view from Asia.

PMID- 10351179
TI  - Prognostic aspects of the metabolic syndrome.
AB  - Is the "good life" syndrome taken seriously enough in medicine underwriting? We
      all know the insurance applicant with the typical signs of having lived the "good
      life" of Western industrialized countries: overweight with slightly elevated
      blood lipid levels, hypertension and, not uncommonly, slightly elevated liver
      functioning tests and hyperuricaemia. Though it bears witness to an overindulgent
      lifestyle, this constellation of findings is quite often accepted as normal. This
      article describes the "good life" syndrome as a clinical entity, discusses the
      significance of the syndrome for medical underwriting and identifies prognostic
      factors. It deals mainly with those stages of the condition in which neither
      diabetes mellitus nor coronary heart disease (CHD) has yet developed.

PMID- 10351181
TI  - Chronic eosinophilic pneumonia.
AB  - Chronic eosinophilic pneumonia (CEP) belongs to a group of syndromes manifested
      by pulmonary infiltrates with peripheral eosinophilia (PIE syndromes). The role
      of the eosinophil as a destructive agent in CEP is discussed. The degree of
      manifested eosinophilia at the time of diagnosis, the frequency of relapses of
      pneumonia, the response to steroid therapy, the status of current physical and x
      ray findings, and especially the trend in pulmonary function data, all appear to
      be critical factors in determining the potential mortality risk of CEP cases.

PMID- 10351182
TI  - Compression-of-morbidity vs. increasing misery in our aging population.

PMID- 10351183
TI  - Increased cancer mortality following a history of nonmelanoma skin cancer.

PMID- 10351184
TI  - Biochemical outcome after radical prostatectomy, external beam radiation therapy,
      or interstitial radiation therapy for clinically localized prostate cancer.

PMID- 10351185
TI  - The risk of a diagnosis of cancer after primary deep venous thrombosis or
      pulmonary embolism.

PMID- 10351186
TI  - Valuing health-related quality of life. Issues and controversies.
AB  - An important consideration when establishing priorities in healthcare is the
      likely effect that alternative allocations will have on the health-related
      quality of life (HR-QOL) of the relevant population. This paper considers some of
      the important issues and controversies surrounding the valuation of HR-QOL. It
      considers the theoretical and empirical evidence regarding 3 crucial questions:
      (i) what is to be valued?; (ii) how is it to be valued?; and (iii) who is to
      value it? Many important yet unresolved issues emerge and directions for future
      research are suggested. It is argued that this research agenda should have the
      gathering and analysis of qualitative data at its forefront.

PMID- 10351187
TI  - The effect of managed care on prescription drug costs and benefits.
AB  - This review discusses the approaches to prescription drug payment practices taken
      by managed care to influence drug use and costs, and presents the research
      evidence supporting these interventions. In the US, drugs were infrequently
      covered as an ambulatory benefit under fee-for-service indemnity insurance;
      however, health maintenance organisations almost always provide outpatient drugs
      and consequently have developed approaches to influence drug use and manage its
      costs. Managed care as a set of tools and as an organisational form is moving
      toward more restrictions on direct access to pharmaceuticals as a covered
      benefit. Options for influencing drug use and cost may address access, ingredient
      costs, dispensing fees and cost sharing. The formulary process is the foundation
      for a managed pharmacy benefit and integrates these options. The limited
      empirical evidence for an effect of managed care on drug costs and use is
      reviewed. A proposed research agenda includes evaluation of the effects of
      restrictive formularies, capitation, disease management and other programmes to
      influence the cost and use of pharmaceuticals.

PMID- 10351188
TI  - Determining clinically important differences in health status measures: a general
      approach with illustration to the Health Utilities Index Mark II.
AB  - The objective of this article was to describe and illustrate a comprehensive
      approach for estimating clinically important differences (CIDs) in health-related
      quality-of-life (HR-QOL). A literature review and pilot study were conducted to
      determine whether effect size-based benchmarks are consistent with CIDs obtained
      from other approaches. CIDs may be estimated based primarily upon effect sizes,
      supplemented by more traditional anchor-based methods of benchmarking (i.e.
      direct, cross-sectional or longitudinal approaches). A literature review of
      articles discussing CIDs provided comparative data on effect sizes for various
      chronic conditions. A pilot study was then conducted to estimate the minimum CID
      of the Health Utilities Index (HUI) Mark II, and to compare the observed between
      group differences observed in a recent randomised trial of an acute stroke
      intervention with this benchmark. The use of standardised effect size benchmarks
      has a number of advantages-for example, effect sizes are efficient, widely
      accepted outside HR-QOL, and have well accepted benchmarks based upon external
      anchors. In addition, our literature review and pilot study suggest that effect
      size-based CID benchmarks are similar to those which would be obtained using more
      traditional methods. For most HR-QOL instruments, we do not know the changes in
      score which constitute CIDs of various magnitudes. This makes interpretation of
      HR-QOL results from clinical trials difficult, and having a benchmarking process
      which is relatively straightforward would be highly desirable.

PMID- 10351189
TI  - Health-related quality-of-life measurement in patients with Parkinson's disease.
AB  - Outcome measures are increasingly used to assess the impact of diseases such as
      Parkinson's disease (PD) from the patient's perspective. These measures, in the
      form of questionnaires to assess health-related quality of life (HR-QOL), are of
      2 main kinds: generic and disease-specific. The former is intended to be relevant
      to the widest range of health problems; the latter is developed specifically to
      assess HR-QOL for a specific condition. Possible consequences of PD have been
      assessed by generic instruments such as the Sickness Impact Profile (SIP), the
      Nottingham Health Profile (NHP), the Medical Outcomes Study 36-Item Short Form
      (SF-36) Health Survey and also by disease-specific instruments; in particular,
      the Parkinson's Disease Quality-of-Life Questionnaire (PDQL) and 39-Item
      Parkinson's Disease Questionnaire (PDQ-39). This article summarises the criteria
      whereby such instruments should be evaluated by potential users and describes in
      more detail the methods of developing and testing such disease-specific
      instruments for use in PD. There is a range of valid and feasible methods
      available for taking into account patients' views of PD outcomes. These will
      become important outcome measures in future clinical trials of treatment regimes.

PMID- 10351190
TI  - Pharmacoeconomic considerations in treating patients with acute leukaemia.
AB  - Whereas individual cost-effectiveness analyses of new agents for acute leukaemia
      should be performed in target populations, any meaningful pharmacoeconomic
      evaluation of treatment options for this condition should include the many types
      of costs and outcomes in unselected, representative groups of patients. Both
      direct costs (e.g. costs for medication and hospitalisation) and indirect costs
      (e.g. lost productivity costs and reduced quality of life) are important
      parameters to assess, as are the costs of chronic adverse effects, research and
      development costs for new agents, and costs of procedure-related deaths. Complete
      remission, cure and survival are the 'success' response criteria for acute
      leukaemia treatments, in addition to prolonged life with acceptable quality of
      life for patients with incurable acute leukaemia. Death is 'failure', caused
      either by resistant disease (relapse and progressive disease) inspite of optimal
      chemotherapy or, sometimes, by insufficient treatment. All of these parameters
      should be taken into account when a pharmacoeconomic evaluation is performed
      (either for administrative or scientific purposes) in order to ensure a
      comprehensive and reliable background for the evaluation in question. Treatment
      of acute leukaemia is expensive with a total cost of about $US3000 per patient
      per day during the induction. Although 80% of children with acute leukaemia are
      cured, only less than 50% of adults are cured. Thus, a great cost is associated
      with death during treatment and only optimal medical treatment with full-scale
      combination chemotherapy and full supportive treatment can keep the number of
      deaths to a minimum.

PMID- 10351191
TI  - Cost effectiveness of recombinant human insulin-like growth factor I therapy in
      patients with ALS.
AB  - OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative
      neuromuscular disease characterised by a progressive loss of voluntary motor
      activity. Recombinant human insulin-like growth factor I (rhIGF-I) has been shown
      to be useful in treating ALS. The purpose of this study was to examine the cost
      effectiveness of rhIGF-I therapy in patients who have ALS. DESIGN: We performed a
      cost-effectiveness analysis from the societal perspective on 177 patients who
      received treatment with rhIGF-I or placebo in a North American randomised
      clinical trial. We estimated the incremental cost-effectiveness ratio of rhIGF-I
      using resource utilisation and functional status measurements from the clinical
      trial. Costs were estimated from 1996 US Medicare reimbursement schedules.
      Utility weights were elicited from ALS healthcare providers using the standard
      gamble technique. MAIN OUTCOME MEASURES AND RESULTS: The overall cost per quality
      adjusted life-year (QALY) gained for rhIGF-I therapy compared with placebo was
      $US67,440. For the subgroups of patients who were progressing rapidly or were in
      earlier stages of disease at enrolment, rhIGF-I cost $US52,823 and $US43,197 per
      QALY gained, respectively. CONCLUSIONS: Treatment with rhIGF-I is most cost
      effective in ALS patients who are either in earlier stages of the disease or
      progressing rapidly. The cost effectiveness of rhIGF-I therapy compares
      favourably with treatments for other chronic progressive diseases.

PMID- 10351193
TI  - Thesaurus of health informatics.

PMID- 10351192
TI  - Approaches to missing data inference results from CaPSURE: an observational study
      of patients with prostate cancer.
AB  - OBJECTIVE: There are multiple reasons for missing data in observational studies;
      excluding patients with missing data can lead to significant bias. In this study,
      we evaluated several methods for assigning missing values to health service
      utilisation. DESIGN AND SETTING: Cancer of the Prostate Strategic Urologic
      Research Endeavor (CaPSURE) is a US national database of men with prostate
      cancer. Physician visits and diagnostic tests for 342 patients newly diagnosed
      with prostate cancer were evaluated. PATIENTS AND PARTICIPANTS: Patients were
      followed for a full year (observed data, n = 228) and patients with incomplete
      data (predicted data, n = 114) were included. INTERVENTIONS: We used the
      following approaches for imputing missing data: assigning the group mean, a time
      specific mean, a patient-specific mean, a stratified mean (by age, localised
      disease and insurance status) and carrying the last observation forward and/or
      backward. MAIN OUTCOME MEASURES AND RESULTS: All prediction strategies resulted
      in higher estimates (19.3 to 23.1) for annual physician visits than was observed
      (17.1 +/- 15.5), and differences were statistically significant for both the last
      observation carried forward (23.1 +/- 15.5) and the patient's individual mean
      (22.7 +/- 36.1) when predicting physician visits. The same strategies had higher
      predicted values for x-rays (1.8 +/- 5.1 and 1.8 +/- 4.4 vs 1.1 +/- 1.9 for the
      observed group), although the last observation carried forward was not
      statistically different from the observed value. CONCLUSIONS: We were unable to
      identify a single optimal strategy. However, imputation from individual means and
      the last observation carried forward methods did not perform as well as the other
      strategies. While the differences observed in this study were small, we
      anticipate that with increased length of follow-up and more dropouts, there would
      be greater differences among strategies.

PMID- 10351194
TI  - Proceedings of the 2nd Biannual Meeting of the International Research Society of
      Spinal Deformities. Burlington, Vermont, USA. June 1998.

PMID- 10351195
TI  - Successful time management.
AB  - The payoff to successful time management is getting more out of your life and
      your career. This is accomplished by spending less time with your time robbers
      and more time on things that really have value to you. To gather data on how time
      management principles apply to clinical laboratory managers, in-depth surveys
      were conducted. These interviews produced some interesting findings about typical
      time robbers of clinical laboratory managers, as well as some innovative
      solutions. This article focuses on three principles of time management: Principle
      #1: Do Some Analysis of Your Use of Time. Principle #2: List Goals and Set
      Priorities. Principle #3: Plan Your Time Regularly.

PMID- 10351196
TI  - Managing change isn't good enough.
AB  - One lesson learned from past reengineering is that to be successful in the next
      decade, organizations will need to create and lead transformation, not just
      manage the process. Two critical aspects of transformation are that it is a
      process and that it requires leadership. The "five Cs" of transformation are
      imperative: create the vision, create the plan, communicate the vision and the
      plan, cultivate motivated and empowered stakeholders, and cement change in the
      organization's culture. Business skills, the ability to lead others, and the
      ability to forge and maintain relationships are needed for effective leadership.
      For successful transformation, businesses must avoid the mistakes made in the
      past decade, including too much complacency, too little and/or inappropriate
      communication, and underestimating the importance of vision and leadership to the
      transformation effort.

PMID- 10351197
TI  - Hospital-physician relationships in the integrated delivery system: an ethical
      analysis.
AB  - The need to compete for managed care contracts is causing hospitals and
      physicians to dramatically change how they do business with each other. Most
      significant is the formation of integrated delivery health-care systems. The
      emergence of these systems creates an enhanced need for physicians and
      administrators to better understand what the other actually does. This article
      examines the new health-care marketplace from both perspectives and how
      integrated delivery systems affect individual and community patient care, and it
      offers guidelines for effective hospital-physician relationships within
      integrated delivery systems.

PMID- 10351198
TI  - The hidden traps in decision making.
AB  - Bad decisions can often be traced back to the way the decisions were made--the
      alternatives were not clearly defined, the right information was not collected,
      the costs and benefits were not accurately weighed. But sometimes the fault lies
      not in the decision-making process but rather in the mind of the decision maker.
      The way the human brain works can sabotage the choices we make. Eight
      psychological traps that are particularly likely to affect the way we make
      business decisions are examined. The anchoring trap leads us to give
      disproportionate weight to the first information we receive. The status-quo trap
      biases us toward maintaining the current situation--even when better alternatives
      exist. The sunk-cost trap inclines us to perpetuate the mistakes of the past. The
      confirming-evidence trap leads us to seek out information supporting an existing
      predilection and to discount opposing information. The framing trap occurs when
      we misstate a problem, undermining the entire decision-making process. The
      overconfidence trap makes us over-estimate the accuracy of our forecasts. The
      prudence trap leads us to be overcautious when we make estimates about uncertain
      events. And the recallability trap leads us to give undue weight to recent,
      dramatic events. The best way to avoid all the traps is awareness--forewarned is
      forearmed. The authors show how to take action to ensure that important business
      decisions are sound and reliable.

PMID- 10351199
TI  - Dollar$ & $en$e. Part I: The value chain.

PMID- 10351200
TI  - Observations from the CLMA 1998 annual conference: Part 2--"And then there were
      six".

PMID- 10351201
TI  - As we see it. Y2K compliance: and it's a leap year, too!

PMID- 10351202
TI  - Critical factors for improved end-of-life care. Changing the culture of a
      hospital.

PMID- 10351203
TI  - Life-or-death decisions and informed consent. Communication key to hospital
      informed consent policies.

PMID- 10351204
TI  - Genetic information resources: a new field for medical librarians.
AB  - The Human Genome Project is generating unprecedented quantities of new genetic
      information. The new discipline of bioinformatics has created many new molecular
      biology databanks to store the results of the Human Genome Project. This data is
      expected to be the information source for biomedical science in the 21st century.
      As molecular biology research moves out of the laboratory and becomes molecular
      medicine, a growing number of people need access to genetic information. Medical
      students, healthcare practitioners and patients need help in finding appropriate
      information. Medical librarians should know how to search key genetic information
      resources and should have a basic understanding of the type of information
      contained in each.

PMID- 10351206
TI  - Influencing new ways of networking information: MIRON and Database Access Project
      (DAPs).

PMID- 10351205
TI  - Meeting the information needs of clinicians for the practice of evidence-based
      healthcare.
AB  - This article reports on clinicians' use of library resources and the competencies
      they require to access information necessary for the practice of evidence-based
      healthcare. It is based on the results of a study commissioned by North Thames
      Region to identify the training needs of clinicians for the adoption and practice
      of evidence-based healthcare. Participants in this qualitative research study
      included librarians, clinicians (doctors, nurses and PAMs) and managers from four
      Acute and Community Trusts in and around London. The research indicates that the
      majority of clinicians recognize the need to keep up-to-date with changes in
      their specialty and many visit their libraries on a frequent basis, however, few
      appear to be searching for information with which to inform their immediate
      clinical decisions. Our sample acknowledged their low usage of journals such as
      Bandolier, the Health Effectiveness Bulletin and Journal of Evidence-Based
      Medicine. Similarly, low use of electronic databases, such as Cochrane and
      Cinahl, were reported. Examination of skill and self-efficacy levels in accessing
      and using information databases revealed wide variations across professions,
      specialities and Trusts. Qualitative research methods were employed to elicit the
      key competencies required to access clinically relevant research evidence, and a
      framework for integrating these competencies is presented.

PMID- 10351207
TI  - Collecting, maintaining and using evidence of clinical effectiveness: experience
      at a district health authority.

PMID- 10351208
TI  - The information needs and information seeking behaviour of medical research
      staff.

PMID- 10351209
TI  - Are research priorities a priority for research?

PMID- 10351210
TI  - HEDIS audits: meeting the challenge.
AB  - The Health Plan Employer Data and Information Set (HEDIS) is a tool to measure
      and report managed care performance. HEDIS has become the industry standard for
      assessing and comparing the quality of managed care organizations (MCOs), so it
      is imperative that MCOs collect and communicate HEDIS data correctly and
      efficiently. Several primary issues face MCOs in compiling HEDIS data. In
      particular, this article examines the HEDIS audit process and outlines the
      preparation required to undergo an audit, common errors uncovered in the audit
      process, and steps that can be taken to ensure compliance with HEDIS technical
      specifications.

PMID- 10351211
TI  - Best practices in the development of clinical practice guidelines.
AB  - Clinical practice guidelines (CPGs) have been used to reduce unnecessary and
      undesirable variations in clinical practice. Many facilities succeed in
      developing and using these tools, while others conclude that they are not worth
      the effort. This article describes the results of a systemwide analysis of the
      processes a healthcare system used to plan, develop, implement, and measure CPGs
      after several years of experience. Extensive interviews were conducted at
      facilities in which the CPG program was active to determine what factors had
      contributed to its success or failure. The result is a series of recommendations
      that will facilitate CPG implementation in virtually any clinical setting.

PMID- 10351212
TI  - Reorganization and quality management of psychiatric and substance abuse
      patients.
AB  - We conducted a study in the mental health and behavioral sciences program at
      Hines Veterans Administration Hospital to determine if a recent reorganization of
      the mental health services had resulted in the efficient use of treatment
      resources according to patients' needs. The Brief Symptom Inventory was used to
      assess symptomatology when patients were admitted to the inpatient psychiatry,
      dual diagnosis, or substance abuse lodger units. The results indicated that the
      groups differ significantly from one another on eight of nine symptom dimensions
      and on all three global indices of psychopathology. The results also reinforced
      the supposition that patients are receiving appropriate treatment and that
      resources are being used efficiently.

PMID- 10351213
TI  - Development of an oncology services performance improvement team.
AB  - Baystate Medical Center is a 750-bed tertiary-care referral center in western
      Massachusetts. In 1995 Baystate reorganized the structure of its quality
      assurance (QA) program from an individual departmentally based QA committee
      structure to a series of multidisciplinary service-line performance improvement
      teams. The new approach sought to implement total quality management techniques
      that had been proven effective in major industrial settings but were not widely
      applied in the healthcare sector. The oncology services performance improvement
      team is cochaired by an attending surgical oncologist and the nursing supervisor
      of a dedicated inpatient oncology unit. Its membership comprises a broad spectrum
      of oncology subspecialists and allied support staff. The team supports multiple
      performance improvement initiatives, including analyses of various cancer-related
      outcomes (e.g., patient satisfaction, morbidity and mortality data) and peer
      review analysis. Systems issues not falling under the aegis of the oncology
      services team are referred to other service-line teams. The performance
      improvement activities are carefully designed to meet the needs of the facility's
      patient population and the accreditation requirements of the Joint Commission on
      Accreditation of Healthcare Organizations and the American College of Surgeons
      Commission on Cancer.

PMID- 10351214
TI  - Increasing patient feedback in ambulatory settings.
AB  - Patient satisfaction survey data provide valuable information about how well
      healthcare organizations and their individual departments are meeting the needs
      and expectations of their patients. Lack of sufficient data can severely inhibit
      an organization's ability to understand its strengths and to target areas in
      which performance can be improved. This article describes a performance
      improvement project that a hospital used to increase response rates to its
      patient satisfaction surveys in its ambulatory care settings. The results were
      significant: five times more surveys were returned 6 months after implementation
      of the project than had been returned at baseline. Managers and staff now have
      the information they need to understand how well they are meeting their patients'
      needs and to make sound decisions related to performance improvement efforts.

PMID- 10351215
TI  - Improving clinical effectiveness in an integrated care delivery system.
AB  - HealthEast, an integrated care delivery system based in St. Paul, MN, established
      a care management program in 1993. At HealthEast, care management is defined as
      "an interdisciplinary process of coordinating client-centered services across the
      continuum of care to achieve quality and cost-effective outcomes." The program
      included establishing a collaborative practice model that was used to drive the
      organization's improvement efforts. The use of this model has been instrumental
      in achieving significant improvements in financial and clinical performance. As a
      result, HealthEast received a leadership award for "Improving Clinical
      Effectiveness within a Healthcare System" from VHA, Inc., a nationwide membership
      alliance of approximately 1,700 community healthcare organizations.

PMID- 10351217
TI  - Thinking global: embracing a world view.

PMID- 10351216
TI  - How one British National Health Service Trust follows the path to continuous
      quality improvement.
AB  - Most hospitals in the United Kingdom are not convinced that total quality
      management (TQM) is a feasible or appropriate method for dealing with National
      Health Service (NHS) problems. However, continuous quality improvement (CQI),
      with its emphasis on quality outcomes, is being adopted with great enthusiasm at
      most NHS sites. This article describes how Brighton Health Care NHS Trust in the
      south of England follows the CQI path and discusses some of its achievements and
      the problems encountered along the way.

PMID- 10351218
TI  - Kuwait steps into performance improvement.
AB  - Faculty of Kuwait University have been active promotors of quality assurance in
      their host country, yet despite many attempts the concept has failed. Managing
      the change process seems to be the primary issue and may hold the key to success.

PMID- 10351219
TI  - Patient satisfaction with quality of care in a hospital system in Qatar.
AB  - This article presents the results of a patient satisfaction survey carried out in
      an acute care hospital complex in Doha, Qatar, in the Middle East. The objectives
      were to determine the level of patient satisfaction as follows: in general, in 18
      different patient areas and services, for Qatar citizens and noncitizens, among
      patients with different sociodemographic characteristics, and in technical and
      interpersonal areas of care. The quantitative, descriptive survey design involved
      two 73-item questionnaires, one in English and one in Arabic. It was given to
      medical, surgical, and obstetric and gynecologic patients. Satisfaction was rated
      on a 5-point scale, and univariate statistics and chi-square analysis were used
      to determine frequencies and statistical differences. The response rate was 77%;
      84% rated the overall quality of care excellent or very good. Respondents gave
      nursing services the highest ratings and slightly favored technical over
      interpersonal care. The results show that patients are willing to participate in
      the survey process and that the questionnaire is a valuable tool for measuring
      satisfaction and for obtaining feedback and continuous evaluation of services.

PMID- 10351220
TI  - Healthcare system performance indicators: a new beginning for a reformed Canadian
      healthcare system.
AB  - Canada's healthcare system is the envy of many other countries and their citizens
      around the world. And like other members of the Organization for Economic
      Cooperation and Development, Canada is under pressure to reduce healthcare
      expenditures. One strategy being explored by Canadian provincial governments is
      to regionalize or decentralize the delivery of healthcare services. To ensure
      achievement of its goals for each region, the Ministry of Health requires each
      regional health authority to submit a business plan and annual report, including
      performance information and underlying performance indicators. Performance
      indicators are used to measure process and outcome as well; they are useful for
      generating questions about the behavior or the performance of a provider or
      organization. A system for defining systemic performance measures for a publicly
      funded healthcare system does not exist. However, the performance indicators
      described in this article provide a sampling of provider-based healthcare
      performance.

PMID- 10351221
TI  - Introducing quality in healthcare: an international perspective.
AB  - Several models for implementing quality improvement have been developed, but they
      have been applied primarily in the United States. One model developed by the U.S.
      Agency for International Development Quality Assurance Project has been applied
      in several other countries. This article discusses the steps to introduce the
      continuous quality improvement process, issues related to successful
      implementation of the process, and the methods by which Jordan and Saudi Arabia
      have introduced quality improvement into their healthcare systems.

PMID- 10351223
TI  - Out of the box. Software online cuts costs.

PMID- 10351222
TI  - Exploring the relationship between cultural values, beliefs, and practices and
      patient falls: a Middle Eastern study.
AB  - Patient falls have been a concern in North American healthcare for many years.
      Studies have examined environmental, clinical, and patient variables for purposes
      of risk identification and fall reduction, primarily in the context of Western
      societies. An investigation at King Faisal Specialist Hospital and Research
      Centre in Riyadh, Saudi Arabia, began in 1993 to determine whether commonly
      reported risk factors apply to the Saudi patient population and whether cultural
      values, beliefs, and practices such as the performance of ablution before prayer,
      fasting during the holy month of Ramadan, and the need for socialization
      influence the rate of patient falls. The study included all inpatients (N = 379)
      who fell during a 3-year period.

PMID- 10351224
TI  - Tune up your information system and watch it go vroom! vroom!

PMID- 10351225
TI  - Next stop: Utopia. Partners blaze trail to total supply chain integration.

PMID- 10351226
TI  - To choose the best sterilization technology ... ask away!

PMID- 10351227
TI  - Clearly clean. Show off those buffed-up pumps!

PMID- 10351228
TI  - Tick ... tick ... tick. Time is running out for AbTox users.

PMID- 10351229
TI  - 10 ways to make sure your case cart system won't work.

PMID- 10351230
TI  - Declaration of interdependence. How a simple stockout sparked a revolution.
      Interview by Jaime Shimkus.

PMID- 10351231
TI  - Cover your assets.

PMID- 10351232
TI  - Be a smart shopper. Choose the instrument management system that's best for you.

PMID- 10351233
TI  - Money: it isn't everything.

PMID- 10351234
TI  - Heart smarts. Choosing a pacemaker--it's all about partnership.

PMID- 10351235
TI  - Battling bugs.

PMID- 10351236
TI  - Fast track to UPN (Universal Product Number). Here's how to reach the finish
      line.

PMID- 10351237
TI  - Snap! Side-by-side snapshots reveal shifts in supply prices.

PMID- 10351238
TI  - What's cooking? Soup and sandwich or the meatloaf platter?

PMID- 10351239
TI  - Soft touch. How to clean and disinfect special devices.

PMID- 10351240
TI  - Hail to the chief. Historian shares presidential leadership lessons. Interview by
      Shari Mycek.

PMID- 10351241
TI  - Emergency care: in search of balance.

PMID- 10351242
TI  - A fast drive to good health: supermarket staffers reap the rewards of a wellness
      program that rolls up to the door of their store, complete with counselors and
      coaches.

PMID- 10351243
TI  - The new direction in disability management. When the system breaks down.

PMID- 10351244
TI  - What's happened to employers' push for quality?

PMID- 10351245
TI  - OTCs: the wild card in cost effectiveness.

PMID- 10351247
TI  - Prime time for domestic partner benefits.

PMID- 10351246
TI  - Countdown to patient protection.

PMID- 10351249
TI  - Datawatch. The balanced budget boomerang.

PMID- 10351248
TI  - Health care help for small biz, near-poor.

PMID- 10351250
TI  - Are unions the future of medicine?

PMID- 10351251
TI  - Clinical management as boundary management. A comparative analysis of Canadian
      and UK health-care institutions.
AB  - Focuses on the critical role played by professionals in the management of
      healthcare institutions in the UK and Canada. Using empirical data, examines the
      structural models of clinical management, the roles of clinical managers and
      their relationships with colleague professionals. Compares the approaches taken
      in the UK and Canada, and explores issues of context, history and relative power.
      Questions the extent to which professionals are losing autonomy to other
      professions and management. In particular examines whether the sharing of power
      inter-professionally may lead to greater, overall collective professional
      autonomy. Develops themes of the contextual influences on the process of change,
      and whether professionals are more effectively managed by internal or external
      processes of control.

PMID- 10351252
TI  - Competition as a means of procuring public services. Lessons for the UK from the
      US experience.
AB  - Competition is now widely used as the means of choosing the providers of
      essential public services in the USA and the UK. Many different approaches are
      found in the USA and there are useful lessons for the UK. With particular
      reference to mental health and substance abuse services, describes the effects of
      using competitive tendering on users, providers, purchasers and citizens and
      examines the problems of specification, transaction costs, the use of
      consultants, supply, the level playing field, trust, innovation, local
      accessibility and accountability. Ends with discussion of co-operation and
      collaboration and the emergence of monopolies and integrated delivery systems in
      the USA and concludes by finding politics and political decision making of
      overriding importance.

PMID- 10351253
TI  - Tracks of change in hospitals: a study of quasi-market transformation.
AB  - Examines the process of change in hospitals that has emerged following the
      introduction of the health quasi-market in 1991. Blends empirical evidence with
      Greenwood and Hinings' archetype and tracks of change concepts to analyse the
      process which is labelled quasi-market transformation (QMT). Argues that, before
      1991, hospitals tended to operate within structures and systems underpinned by an
      interpretive scheme. Represents these similarities of configuration as the
      directly-managed (DM) hospital archetype. When change initiatives challenged this
      configuration, the outcomes were negotiated and resulted in "adjustmental"
      change. In contrast, shows the introduction of the quasi-market to have involved
      the first transformation of the DM archetype's interpretive scheme, systems and
      structures. Analyses four years of transition to reveal that QMT has been
      interpreted differently within hospitals. However, presents data to suggest that
      many hospitals now display significant similarities in terms of configuration.
      Represents these similarities within the emerging Trust hospital archetype.

PMID- 10351254
TI  - Control and accountability in the NHS market: a practical proposition or logical
      impossibility?
AB  - Before the imposition of the NHS internal market, systems of accountability and
      control were far from adequate and could be criticized on a number of grounds.
      The market was offered as a panacea to address these inadequacies. However, in
      practice there have only been partial improvements which could have been achieved
      without the imposition of the market. The market also creates new problems and a
      number of crises and scandals seem to be addressed at the political level by
      pleas to utilize resources more effectively. These pleas mean that more and more
      the focus is turning back to central planning in the provision of care and
      further away from so-called market mechanisms. The NHS "managed" market has been
      imperfect and will continue to be so. Argues that there is no alternative but to
      return to the planned provision of health care in order to improve on
      accountability and control in the NHS. Hopefully the adverse impact of the market
      on clinicians and others will force a more rational reappraisal of the
      fundamental raison d'etre of the NHS and the need for those involved in the
      delivery of services, at all levels, to be more openly accountable.

PMID- 10351255
TI  - Health-care reforms in the People's Republic of China--strategies and social
      implications.
AB  - Analyses the features, strategies and characteristics of health-care reforms in
      the People's Republic of China. Since the 14th Central Committee of the Chinese
      Communist Party held in 1992, an emphasis has been placed on reform strategies
      such as cost recovery, profit making, diversification of services, and
      development of alternative financing strategies in respect of health-care
      services provided in the public sector. Argues that the reform strategies
      employed have created new problems before solving the old ones. Inflation of
      medical cost has been elevated very rapidly. The de-linkage of state finance
      bureau and health service providers has also contributed to the transfer of
      tension from the state to the enterprises. There is no sign that quasi-public
      health-care insurance is able to resolve these problems. Finally, cooperative
      medicine in the rural areas has been largely dismantled, though this direction is
      going against the will of the state. Argues that a new balance of responsibility
      has to be developed as a top social priority between the state, enterprises and
      service users in China in order to meet the health-care needs of the people.

PMID- 10351256
TI  - The changing role of the regional tier of the NHS.
AB  - Reviews the past role of regional health authorities in the the British NHS and
      gives details of the recent changes to regions associated with the functions and
      responsibilities paper. Goes on to give details of the research project in which
      we are currently involved and reports on our interim findings (as of April 1996).
      In a final discussion section, reflects on those findings in terms of the
      evolving problems of influence and control in a national service operating in a
      devolved quasi-market.

PMID- 10351257
TI  - Managerialism, information technology and health reform in New Zealand.
AB  - Recent health reform in New Zealand has transformed public hospitals and related
      health services into Crown Health Enterprises (CHEs), which have a statutory
      objective to operate as successful and efficient businesses. Examines
      managerialist interpretations of a proposed executive information system (EIS) at
      one CHE. Arguably, the use of computerized information systems signals managerial
      competence and rationality, and there was an implicit assumption among senior CHE
      managers that "business-like" and "efficient" management required the use of
      information technology. In the end, in the context of continuing organizational
      restructuring, the EIS was never implemented.

PMID- 10351258
TI  - Kindly technicians: hospital administrators immediately before the NHS.
AB  - Presents the results of a qualitative analysis of copies of The Hospital, a
      journal for UK hospital administrators, from 1946-1948: immediately prior to the
      establishment of the NHS. Characterises administrators in that period as kindly
      technicians. Analyses administrators' ways of thinking; spheres of influence and
      level of education. Also notes their concern for the running of support services;
      their implicit and unexamined deference to medical staff and an explicit belief
      in the need to carry out their role with kindliness. Concludes by highlighting
      the changes in managerial thinking between the 1940s and today and speculates
      that these changes may be best understood, following Foucault, as phenomena of
      rupture and discontinuity rather than as linear progression.

PMID- 10351259
TI  - Managerialism and the British GP: the GP as manager and as managed.
AB  - The focus of the paper is on the relationship between General Practitioners (GPs)
      and central government. This relationship dates from the introduction of national
      health insurance in the UK. From the outset it had an impact on GPs' medical
      role, their professional status and income. The structure created in 1911 meant
      that GPs operated as franchisees and, notwithstanding Labour's policy objective
      of creating a salaried service, this role continued, effectively unchanged, after
      the creation of the National Health Service (NHS) in 1948. General practice was
      also the poor relation in contrast to hospital medicine, a feature intensified by
      the priorities of the NHS. These forces meant that GPs had a dual role: that of
      clinician and gatekeeper to specialist hospital services, a role in which they
      exercised substantial clinical freedom: and running a small business, a feature
      which was exaggerated by the absence of grant aid to improve premises prior to
      the Family Doctor Charter of 1965. This structural relationship has been
      progressively transformed by changes in the 1980s and 1990s. On the one hand the
      emphasis on cost control has seen central government attempting to combine a
      financial with a clinical gate-keeping keeping role. The crucial change in this
      respect is the creation of GP fundholding which, in turn, could be seen to have
      implications for the subordinate status of GPs within the medical profession.
      However, this has been combined with trends to greater measures of control over
      GPs. Of central importance in this respect were the changes introduced by the
      1990 GP contract. The contract involved an attempt to substantially reduce
      clinical autonomy by building in much more detailed contractual duties with
      respect, for example, to health promotion activities. This was combined with the
      use of financial incentives to reach, for example, immunization targets. Control
      over clinical autonomy has also involved constraints over prescribing and the
      shift from Family Practitioner Committees to Family Health Service Authorities.
      The rationale for this shift is the move from an administrative to a managerial
      body, acting as the agent of central government in enforcing the contract and
      imposing financial norms. GPs are thus to be made managerially accountable. The
      paper analyses the place of general practitioners in central government's
      approach to health strategy and examines the tensions generated by the
      combination of conferring new powers on GPs and increasing controls over them.
      These tensions are related to current disputes over out-of-hours working and
      attempts by GPs to redefine a "core of service" approach to their job. The
      ambiguities of reliance on professionals combined with the desire to exert
      greater controls is traced in the recent policy statement by the Secretary of
      State, Primary Care: The Future (1996). The paper thus aims to contribute to the
      critical discussion of the impact of central government managerialist initiative
      on key professional groups in the welfare state.

PMID- 10351260
TI  - Willingness of families caring for victims of dementia to pay for nursing home
      care: results of a pilot study in Taiwan.
AB  - In order to examine the value family caregivers attach to the benefits associated
      with nursing home services, this contingent survey was designed to investigate
      the willingness of family caregivers of dementia victims to pay for nursing home
      care. A total of 136 members of families of dementia patients from the department
      of neurology and psychiatry of four medical centers in Taiwan were interviewed by
      phone. These family members provided in-home care for dementia victims and had
      expressed the need for nursing home placement. These family caregivers were asked
      to explicitly state the maximum amount of family income per month they are able
      to give up to receive nursing home services. The willingness to pay (WTP) for
      nursing home care ranged from US$185 to $2,407 per month, and 37.5 percent of the
      family caregivers interviewed indicated a willingness to pay at least 50 percent
      of the monthly family income for nursing home placement. The amount of monthly
      family income was strongly associated with the WTP for nursing home care in
      dollars. Age and education of the caregiver, and accessibility of nursing home
      care were significantly associated with WTP in both cost range and percentage of
      monthly family income. Interviewees who were older than 65 years (odds ratio is
      3.52), and educated equal to or above senior high school (odds ratio is 5.57)
      were inclined to pay at least 50 percent of monthly family income for nursing
      home placement. As other variables were adjusted, respondents older than 65 years
      were willing to pay US$208.4 per month more than those younger than 65 years for
      nursing home placement; and the educated equal to or above senior high school
      were inclined to pay US$171.9 per month more than those with less than a senior
      high school education. The easier it was to find nursing home agencies near the
      residence, the more willing the family was to pay at least 50 percent of their
      monthly family income for nursing home services; with an odds ratio of 16.51. The
      families with the higher accessibility to nursing home agencies were willing to
      pay US$174.3 per month more than caregivers with lower accessibility. Family
      caregivers, who were older than 65 years, educated above the senior high school
      level, with a higher family income, and easier accessibility to nursing home
      services, were likely to attach higher economic values to nursing home placement.

PMID- 10351261
TI  - New Zealand Polynesian women's access to information about cervical screening.
AB  - Immigration by Pacific Island people into New Zealand has raised issues of equal
      access to a range of government and social services, including health
      information. This study reports on an investigation of access to information by
      women in Pacific Island cultures resident in Palmerston North. The New Zealand
      health environment is quickly changing and features market-style reforms, greater
      accent on privately-funded health schemes and an ideological shift in the
      direction of individual responsibility for one's health. We describe what we
      found to be the major impediments to quality of health information accessible by
      Pacific Island women and conclude with proposals for changes and developments in
      public health communications.

PMID- 10351262
TI  - From contracts to service agreements: what can be learned from total purchasing?
AB  - Total purchasing is an experimental extension of GP fundholding through which GP
      practices can purchase community, secondary and tertiary services not included in
      standard fundholding budgets, for their registered patient populations. The paper
      presents selected findings from a study of contracting by TPPs during the first
      year of purchasing, concentrating on the perceived relationship between aspects
      of the contracting process and the achievement of TPP's strategic objectives.
      These findings are of relevance to the development of commissioning by primary
      care groups in light of the Government's proposal that contracts be replaced by
      long-term service agreements as competition within the NHS internal market is
      replaced by more collaborative arrangements between commissioners and providers.
      The paper identifies features of the contracting process which have been
      instrumental to the achievement of TPPs' service development objectives and may
      need to be preserved to ensure effective commissioning within the context of the
      new service agreements.

PMID- 10351263
TI  - Comparative perspectives on doctors in management in the UK and The Netherlands.
AB  - The role of doctors in hospitals continues to change due to both external
      (policy) and internal (organisational change) pressures. Comparisons between The
      Netherlands and the UK highlight that several models of medical management are
      formulated and exist alongside each other, leading to more flexibility in the
      roles of both doctors and managers. In particular, the agendas concerning the
      quality of clinical care and cost-effectiveness are converging, emphasising the
      increasingly important role of medical managers.

PMID- 10351264
TI  - Medical managers can make research-based management decisions.
AB  - The paper has three messages. First, doctors in management can use evaluation
      methods and research to make better management decisions and to manage projects.
      Second, health policy makers and managers can no longer afford not to make a
      greater use of evaluation in making and implementing decisions. Third, the model
      of evidence-based medicine is not appropriate for management decisions, but there
      are other approaches which can be used to develop evaluation-informed health
      management.

PMID- 10351266
TI  - Hormones and the mind. Estrogen therapy could help women's memory.

PMID- 10351265
TI  - Seamless health care for chronic diseases in a dual health care system: managed
      care and the role of family physicians.
AB  - Neither private nor state run health care systems are perfect. Although there is
      increasing evidence that Health Maintenance Organizations (HMOs) provide
      comparable care at lower cost, HMOs tend to select healthy patients. The dual
      health care system in Hong Kong spends about 3.9 per cent of GDP, with health
      indices among the best in the world. Hong Kong still faces the problem of
      escalating health care expenditure. One should take advantage of the dual health
      care system to evolve a new paradigm for a primary-led seamless health care
      service. The Diabetes Centre of a university teaching hospital together with the
      University of Community and Family Medicine has started a structured shared care
      programme in diabetes mellitus, involving general practitioners in both the
      private and public sectors integrating the primary and secondary care, and the
      private and public sectors. This programme starts to develop an infrastructure
      for providing quality care at an affordable cost for a large pool of patients
      with chronic disease. Unlike other "managed care schemes", this one is not run by
      profit-oriented companies, but by health professionals with an interest in
      providing best possible care at an affordable cost. The "disease management"
      approach needs a care delivery system without traditional boundaries; and a
      continuous improvement process which develops and refines the knowledge base,
      guidelines and delivery system.

PMID- 10351267
TI  - A place they can call home: many African-American seniors are facing a novel
      question: how, and with whom, to live after a life of work?

PMID- 10351268
TI  - HIPAA's impact on healthcare.
AB  - The Health Insurance Portability and Accountability Act of 1996 is having a
      profound impact on fraud and abuse detection and prevention, electronic
      communication standards, and health information security. Moving forward into the
      new millennium, we can expect acceleration of its ongoing programs, and expansion
      of its scope to electronic medical record standards.

PMID- 10351269
TI  - HIPAA--why bother? One health system's experience.

PMID- 10351270
TI  - Innovative touchscreen-driven solution for diabetics.

PMID- 10351271
TI  - Nifty high tech tools make the physician's life easier.

PMID- 10351272
TI  - The managed care technology toolkit.

PMID- 10351273
TI  - Taming the security tiger.

PMID- 10351274
TI  - IT staffing: retention is cheaper than recruiting.

PMID- 10351275
TI  - Integrated delivery systems: how they improve quality of care.

PMID- 10351276
TI  - What works. Streamline sales process increases memberships and improves
      efficiencies.

PMID- 10351277
TI  - What works. Swedish Medical Center website attracts $50,000 a month in referrals.

PMID- 10351278
TI  - What works. Clinical data/information system provides information within seconds.

PMID- 10351279
TI  - HotList: pharmacy systems.

PMID- 10351280
TI  - Mobile computing in healthcare.

PMID- 10351281
TI  - Hospital credentialing for laparoscopic cholecystectomy: is stricter better?
AB  - OBJECTIVE: Hospital credentialing standards for laparoscopic cholecystectomy were
      established to improve surgical outcomes, but standards vary by hospital. We
      hypothesized that more stringent credentialing would result in better outcomes.
      DESIGN: Univariate and multivariate logistic analyses were performed using a 1996
      survey on hospital credentialing practices. Surgical-outcome data were obtained
      from statewide hospital discharge abstracts and hospital chart reviews.
      Multivariate logistic analysis was used to calculate the effects of hospital
      credentialing stringency and nine credentialing practices on operative and
      postoperative outcomes (including death), controlling for patient and hospital
      characteristics. SETTING: Short-stay community hospitals performing laparoscopic
      cholecystectomy. PATIENTS: Statewide hospital discharge data included 1995
      inpatient discharges for laparoscopic cholecystectomy. Medical-records review
      included 843 laparoscopic cholecystectomy patients selected from 14 North
      Carolina hospitals with widely different credentialing practices. RESULTS:
      Surgical complications from laparoscopic cholecystectomies appeared unrelated to
      stringency of the hospital credentialing environment. Important factors
      predicting complications included hospital volume and other hospital
      characteristics such as the number of registered nurses per patient day.
      CONCLUSIONS: Given current levels of training, performance, and credentialing
      standards, tightening of credentialing practices may not improve patient outcomes
      for laparoscopic cholecystectomy.

PMID- 10351282
TI  - Preventable trauma deaths: evaluation by peer review and a guide for quality
      improvement. Emergency Medical Study Group for Quality.
AB  - BACKGROUND: The trauma-injury severity-score (TRISS) methodology was developed in
      the United States to calculate the probability of survival for trauma patients
      presenting for emergency care. OBJECTIVE: We assessed the utility of using the
      TRISS methodology to identify preventable trauma deaths and compared the results
      to peer review using explicit standards. METHODS: Explicit peer review standards
      were developed by a focus group. The validity of these standards was evaluated by
      comparing the results of peer review performed by two independent expert panels.
      All trauma cases admitted to 10 centers in Japan between April 1, 1994, and March
      31, 1996, were evaluated using the TRISS methodology. Cases with an expected
      probability of survival of more than 0.5 were considered preventable. These cases
      were subjected to peer review. Patients who were dead on arrival were excluded
      from analysis. RESULTS: Of 3,125 patients who were not dead on arrival, the TRISS
      methodology identified 2,525 as having a probability of survival greater than
      0.5. In this group, 189 patients died; thus, 25.3% of all deaths were considered
      preventable by the TRISS method. Peer review found that only 11.2% of the deaths
      were preventable; thus, only 46.6% of preventable deaths identified by TRISS were
      confirmed by peer review. Agreement between the two expert peer review panels was
      very good (kappa = 0.62). CONCLUSION: TRISS can be used as a screening tool to
      identify potentially preventable trauma deaths. Peer review is appropriate to
      confirm preventability and to identify potential medical errors.

PMID- 10351283
TI  - A quality management approach to optimizing delivery and administration of
      preoperative antibiotics.
AB  - OBJECTIVE: To optimize the process for delivering and administering preoperative
      antibiotics in order to prevent potential adverse patient outcomes. DESIGN: Using
      a multidisciplinary quality-improvement team, an evaluation of the preoperative
      medication order and delivery process was conducted. Charts were reviewed by
      selected time periods, with winter 1994 discharges for orthopedic surgeries (n =
      97) and spring 1995 discharges for open heart procedures (n = 50) being used to
      arrive at baseline data (n = 147). A plan was devised to mainstream the
      medication-use process so that it would be standardized hospitalwide. A goal of
      administering preoperative antibiotics within 30 to 60 minutes prior to cut time
      was established. Following redesign and education, a repeat chart review of
      orthopedic surgeries (n = 33) and open heart procedures (n = 168) was conducted
      during April 1997 for discharges from the same diagnosis-related groups to total
      (n = 201). SETTING: A nearly 1,000-bed tertiary referral center and teaching
      hospital with three separate campuses. RESULTS: We identified multiple ordering
      mechanisms, multiple medication sources and delivery sites, multiple
      administration sites and administering personnel, and other logistical conflicts.
      Thirty-one percent of cases received antibiotics less than 30 minutes prior to
      start time, 39% between 30 to 60 minutes, and 30% greater than 60 minutes before
      start time. Following the multidisciplinary redesign and education, an increase
      from 39% to 61% receiving preoperative antibiotics between 30 to 60 minutes prior
      to surgery start time and a decrease from 31% to 18% receiving them in less than
      30 minutes was documented. The percentage of patients receiving preoperative
      antibiotics in 60 minutes or less increased from 70% to 80%. CONCLUSION: A
      continuous quality-improvement approach that engages all departments involved in
      patient care is necessary to achieve meaningful change in complicated hospital
      processes.

PMID- 10351284
TI  - Utilizing national nosocomial infection surveillance system data to improve
      urinary tract infection rates in three intensive-care units.
AB  - OBJECTIVE: To reduce catheter-related urinary tract infection rates in three
      intensive-care units to at or below the National Nosocomial Infection
      Surveillance System pooled mean for similar units. DESIGN: A nursing team,
      physician team, and laboratory team reviewed and revised protocols and procedures
      for better catheter management. SETTING: A 500-bed community teaching hospital.
      INTERVENTIONS: The teams developed medical indications for urinary catheter
      placement and criteria that allowed the registered nurse to remove a catheter
      without a physician's order when no longer medically necessary. They created a
      computer prompt to assure a urinalysis accompanied all urine cultures. RESULTS:
      After introducing the new protocols, the incidence density of catheter-related
      urinary tract infections fell 17% in the surgical intensive-care unit, 29% in the
      medical intensive-care acute unit, and 45% in the coronary intensive-care acute
      unit. The registered nurses' compliance in removing the catheter per protocol was
      88%. Physician ordering of a concomitant urinalysis with each urine culture
      achieved 93%. CONCLUSIONS: A multidisciplinary approach assisted in reducing
      catheter-associated urinary tract infections in three intensive-care units,
      although not to the extent desired. The teams are investigating preconnected and
      antimicrobial-coated catheters further.

PMID- 10351285
TI  - Surveillance of handwashing episodes in adult intensive-care units by measuring
      an index of soap and paper towel consumption.
AB  - OBJECTIVE: To determine whether handwashing surveillance could be conducted by
      measurements of soap and towel consumption. DESIGN AND PARTICIPANTS: In the
      medical intensive-care unit (MICU) of the Omaha Veterans' Affairs Medical Center,
      10 4-hour day-time observation periods encompassing 409 handwashing episodes were
      scheduled in a 51-day period. In the surgical intensive-care unit (SICU), 7 4
      hour periods encompassing 350 episodes were scheduled in a 49-day period. An
      observer measured paper towel height, towel weight, and soap weight at each sink.
      The observer also counted handwashing episodes and bed occupancy. Using
      handwashing episodes as a dependent variable, stepwise linear regression was
      performed with changes in towel height, towel weight, and soap weight as
      independent variables. RESULTS: Mean handwashing episodes per hour per occupied
      bed were 2.39 +/- 0.80 (standard deviation) in the MICU and 2.83 +/- 0.72 in the
      SICU. Correlation r with handwashing episodes for MICU changes was 0.891 for
      towel height, 0.950 for towel weight, and 0.882 for soap weight. Corresponding
      correlations for the SICU were 0.881, 0.918, and 0.904. For both units, stepwise
      regression retained changes in the weight of towels and soap as independent
      variables (P < .0001), with R2 0.965 (MICU) and 0.981 (SICU). CONCLUSION: Because
      soap and towel consumption measurements are closely related to handwashing
      frequency and because these measurements are easy to obtain, they offer a means
      of handwashing surveillance that can be sustained indefinitely. This can
      facilitate feedback-based interventions to improve handwashing frequency.

PMID- 10351286
TI  - Hospitalk: an exploratory study to assess what is said and what is heard between
      physicians and nurses.
AB  - OBJECTIVE: Collaboration and effective communication between healthcare
      professionals has been demonstrated to improve patient outcomes and job
      satisfaction. The purpose of this study was to examine physician and nurse
      communication in a hospital setting during a time of very rapid change. DATA
      SOURCES AND STUDY SETTING: Full-time attending internal medicine physicians (n =
      5), registered nurses (n = 18), and medical residents (n = 12) working on two
      adult medical units in a 325-bed tertiary-care hospital in the mid-Atlantic
      region from fall 1996 to summer 1997. STUDY DESIGN: Descriptive survey and
      interview. DATA COLLECTION METHODS: Each subject completed a written
      questionnaire, Physician-Nurse Communication Scale, and a structured interview
      with a trained social linguistics team. PRINCIPAL FINDINGS: Physicians and nurses
      shared similar perceptions regarding their roles in communication processes, such
      as giving orders, asking for information, and asking for and giving opinions.
      They differed significantly in the perceptions of the physician and nurse roles
      in giving information, orienting, and providing education. Generally, physicians
      perceived that nurses initiated certain types of communication significantly less
      often than did nurses. Both groups expressed an interest in more interaction;
      nurses particularly expressed the need to be "listened to" or respected more.
      Nurses were significantly more likely to express the need to change interactions
      with house staff than with attending physicians (P = .02). CONCLUSIONS:
      Interactions between physicians and nurses are perceived differently by the two
      groups, leading to misunderstanding of motive and meaning. Recommendations are
      made to improve communication between these two professional groups.

PMID- 10351287
TI  - Distance education and technology.
AB  - This first in a series of columns regarding distance education identifies
      existing offerings and introduces conceptual issues. Continuing professional
      education can be achieved through a variety of means, but university-based
      distance education degree programs offer particularly valuable attributes.
      Although a growing number of universities are offering such programs, few pertain
      specifically to infection control, hospital epidemiology, and health-service
      quality improvement. This first installment concludes by asking whether the
      Society for Healthcare Epidemiology of America should be partnering or otherwise
      collaborating with universities to maintain its leadership position in bringing
      high-quality educational opportunities to infection control practitioners and
      healthcare epidemiologists.

PMID- 10351288
TI  - Quality improvement in an integrated urban healthcare system: a necessary
      journey.
AB  - Public hospitals and clinics in the United States provide health care for the
      needs of large numbers of people who are medically indigent, homeless,
      chronically mentally ill, and suffer medical and social disorders associated with
      poverty. These "safety-net" healthcare providers traditionally struggle with
      barriers to providing high-quality, patient-sensitive care, including decaying
      physical facilities, burdensome bureaucracies, underfunded capital equipment and
      construction programs, and complex, politically driven budgets and governance.
      However, these same institutions now must compete for their own Medicaid and
      Medicare clientele because the private sector is marketing to those patients.
      They also must continue to provide increasing services to growing numbers of
      uninsured patients. To accomplish this, these institutions must reinvent
      themselves as patient-focused, high-quality, cost-effective healthcare providers.
      The Denver Health system is the public safety-net provider for the city and
      county of Denver. This large public institution has instituted a multifaceted
      performance-improvement program. The program includes training employees for
      patient-focused service, implementing continuous quality-improvement practices,
      instituting clinical pathways, revising the preexisting ambulatory quality
      management program, reengineering key aspects of ambulatory clinic services, and
      redesigning the hospital-based patient-care services. Major successes have been
      achieved in some initiatives, but not in all. Many key "lessons learned" may
      guide others.

PMID- 10351289
TI  - A Hawthorne strategy: implications for performance measurement and improvement.
AB  - The Hawthorne experiments are a backdrop for diverse studies assessing the impact
      of treatment and experimentation on human and organizational performance. The
      Hawthorne effect is used to describe the positive impact on behavior that
      sometimes occurs in a study or experiment as a result of the interest shown by
      the experimenter in humans who are being treated, studied, or observed. We
      propose that the Hawthorne effect can be viewed as an active construct to develop
      a coherent strategy for performance improvement. We propose a "Hawthorne
      strategy" that transcends the Hawthorne effect in that it offers an approach to
      improving performance indefinitely. This strategy uses external observations of
      performance to increase internal commitment to performance improvement. The focus
      of individual responsibility increases as does the perceived connection between
      individual efforts and external performance improvement. The sense of
      accountability is maintained by institutional recognition and periodic
      reinforcement of individual behaviors that contribute to performance improvement.
      A successful Hawthorne strategy encourages providers of care to be evaluators of
      their performance as individuals, as members of groups, and as members of
      institutions.

PMID- 10351290
TI  - Overseas ... clinic preparation.

PMID- 10351291
TI  - Medical records storage--an electronic solution.

PMID- 10351292
TI  - What is clinical governance?

PMID- 10351293
TI  - Treatment's last frontier? The criminal-justice system is trying to build a
      culture of compassion. Will it promote recovery?

PMID- 10351294
TI  - Rethinking child welfare. Experimenters discover the behavioral model doesn't
      always fit.

PMID- 10351296
TI  - Using the latest tools will promote recovery.

PMID- 10351295
TI  - Death by restraint. Horror stories continue, but best practices are also being
      identified.

PMID- 10351297
TI  - Managed care's atypical response. New antipsychotics show promise, but are they
      getting into enough hands?

PMID- 10351298
TI  - 'Low-grade' depression. Primary care physicians need a crash course in detection
      and treatment.

PMID- 10351299
TI  - Making an investment in psychotropic drugs.

PMID- 10351300
TI  - Computerizing the Texas Medication Algorithm Project.

PMID- 10351301
TI  - Developing business opportunities in a provider-sponsored organization.

PMID- 10351302
TI  - Behavioral disease management: preview to a paradigm shift.

PMID- 10351303
TI  - Congress gets serious about records privacy.

PMID- 10351304
TI  - Right place, right time.

PMID- 10351305
TI  - Why transactions aren't flowing.

PMID- 10351306
TI  - A physician as the CIO. Interview by Tyler L. Chin.

PMID- 10351307
TI  - Building a consumer brand.

PMID- 10351308
TI  - Wringing out the costs. Preferred provider organizations are using technology to
      get the job done.
AB  - The thin margins in the PPO business mean that these managed care plans must make
      sure they are deploying information technology in ways that improve efficiency.
      Information technology professionals at PPOs also are being called upon to
      develop initiatives that will give their organizations a competitive edge.

PMID- 10351309
TI  - Group practices explore EDI options.
AB  - Although physician groups have been relatively slow to take advantage of
      electronic commerce, more are discovering the benefits. Once group practice
      administrators get beyond their initial trepidation and realize that EDI is
      efficient, many are pleased with the results. And some are automating other
      transactions, including verifying patient eligibility for insurance coverage,
      gaining insurance authorization for referrals to specialists and checking the
      status of claims.

PMID- 10351310
TI  - Call centers: phone lines, protocols, and patient care management in the 21st
      century.

PMID- 10351311
TI  - High-tech meets high-touch in call centers.

PMID- 10351312
TI  - "Virtual medicine": the future of American health care.

PMID- 10351313
TI  - Are you ready for Y2K? Here's what you need to know.

PMID- 10351314
TI  - Three-level plan for Y2K helps break problem down into 'critical subsystems'.

PMID- 10351315
TI  - Use protocols to improve communication with patients.

PMID- 10351316
TI  - A unified organizational structure: ED nurses, physicians working under the same
      roof.

PMID- 10351317
TI  - Strengthening provider relations.

PMID- 10351318
TI  - Technology and the care of the elderly.

PMID- 10351319
TI  - Enhancing customer service over the phone.

PMID- 10351320
TI  - A partnership to serve high-risk women.

PMID- 10351321
TI  - Caring for ESRD patients.

PMID- 10351322
TI  - Seeking perspectives from members.

PMID- 10351323
TI  - External review. Consumer advocates, health plans, and policy makers weigh the
      merits of external review.

PMID- 10351324
TI  - An analysis of regulatory models.

PMID- 10351325
TI  - R-e-s-p-e-c-t. Managed care makes a name for itself in the years following the
      1973 federal HMO Act.

PMID- 10351327
TI  - The measurement of pediatric chronic care.

PMID- 10351326
TI  - Thinking narrow.

PMID- 10351328
TI  - A matter of the heart.

PMID- 10351329
TI  - By the numbers. Physicians and health plans.

PMID- 10351330
TI  - Health care quarrels.

PMID- 10351331
TI  - True grit: stamping out breast cancer.

PMID- 10351332
TI  - The Medicaid market.

PMID- 10351333
TI  - Coordinating organ transplants.

PMID- 10351334
TI  - A new front in the war on AIDS.

PMID- 10351335
TI  - A pilgrim on a difficult road. A woman with AIDS offers her perspectives on
      doubt, health, and care.

PMID- 10351336
TI  - Amnesia. When it comes to health care, Americans seem to have forgotten the
      lessons of the recent past.

PMID- 10351337
TI  - Getting feedback from physicians.

PMID- 10351338
TI  - Americans abroad. Why United HealthCare went to Germany--and what it learned
      there.

PMID- 10351339
TI  - Fostering member loyalty.

PMID- 10351340
TI  - By the numbers. Health plans ensure health of diverse members.

PMID- 10351341
TI  - Better data, better care. Interview by Carl Peterson.

PMID- 10351342
TI  - Eating you up inside. Health plans struggle to understand and treat the plague of
      eating disorders.

PMID- 10351343
TI  - Health plans help frail elderly.

PMID- 10351345
TI  - Provider profiling.

PMID- 10351346
TI  - Protecting confidentiality & improving health.

PMID- 10351347
TI  - The first years last forever. Community and national organizations work together
      to educate parents of young children.

PMID- 10351344
TI  - Round one: managed care and the 105th Congress.

PMID- 10351348
TI  - Stand by me. To thrive as the new American health care system managed care will
      have to go beyond consumer satisfaction and once again earn the public's trust.

PMID- 10351349
TI  - Healing the rift.

PMID- 10351350
TI  - Back on the job. Managed care strategies are changing the face of workers'
      compensation.

PMID- 10351352
TI  - Bad medicine for health care.

PMID- 10351353
TI  - Prospects for radical improvement. The National Guidelines Clearinghouse project
      debuts on the Internet.

PMID- 10351351
TI  - By the numbers. Health plans and coverage of prescription drugs.

PMID- 10351355
TI  - Straight talk from managed care members.

PMID- 10351354
TI  - Getting moms to quit.

PMID- 10351356
TI  - A crossroads in Medicare. Unless policy makers address the problems with
      Medicare, private-sector participation could wane.

PMID- 10351357
TI  - Round two: the 106th Congress. What does the new Congress have in store for
      managed care?

PMID- 10351358
TI  - A new way to calculate capital requirements.

PMID- 10351359
TI  - By the numbers. Health plans address risk in pregnancy.

PMID- 10351360
TI  - When guilt boils over: how to diffuse the anger when a family member attacks.

PMID- 10351361
TI  - A cautious thumbs-up to off-hours surveys.

PMID- 10351362
TI  - A prescription for managing drug costs under PPS.

PMID- 10351363
TI  - Serving seniors better in the coming century.

PMID- 10351364
TI  - To partner or not to partner? More than ever, hospitals are open to working with
      SNFs.

PMID- 10351365
TI  - Testing the water. Tubs and showers are getting better, but there's still room
      for improvement.

PMID- 10351366
TI  - Waste not, want not. A tradition of fiscal discipline has positioned HCR Manor
      Care for continued success under PPS.

PMID- 10351367
TI  - Drafting loan commitments that will hold up in court.

PMID- 10351368
TI  - After the fall. Will the nursing home chains rise again?

PMID- 10351369
TI  - Sunshine and turnip greens. Medication is not always the best cure for
      depression.

PMID- 10351370
TI  - MD practice purchases by hospitals seem to be slowing down, experts say.
AB  - Many hospital-owned medical group practices lost millions in 1998. Although the
      boom days of these purchases are over, some experts say hospitals will continue
      to buy physician practices at a more cautious pace.

PMID- 10351371
TI  - Some MSOs are making money; here's how.

PMID- 10351372
TI  - Gatekeeper products losing favor in many markets.

PMID- 10351373
TI  - Finding reinsurer can be tricky business.

PMID- 10351374
TI  - Hospitals, execs could be in hot water with IRS rule.

PMID- 10351375
TI  - Internet gets fast results for outcomes project.

PMID- 10351376
TI  - Physician report cards more prevalent among MCOs, but do they work?
AB  - At least one payer is releasing public report cards on physicians, and others are
      expected to follow. Experts say it is unlikely payers will go through the expense
      of creating these report cards for hospitals. However, they do believe payers
      will increasingly ask hospitals to release their own clinical and patient
      satisfaction data as part of the managed care contracts. They say this is a two
      part trend: First, payers are being forced by competition to find new ways to
      market their plans to employers and the public. Second, there is a national push
      to hold physicians and other providers more accountable to the public.

PMID- 10351377
TI  - Listen to what payers say about MD ratings.

PMID- 10351378
TI  - Do you know how much risk your PHO should take?

PMID- 10351379
TI  - PHOs, IPAs members must comply with Stark regs.

PMID- 10351380
TI  - 1,001 Americans describe their health care wish list--a Lou Harris Poll.

PMID- 10351381
TI  - Evolution of a decision: one lab's move to a single testing platform.

PMID- 10351382
TI  - Nurses' attitudes towards cost-effectiveness and quality of care.
AB  - OBJECTIVE: To describe nurses' attitudes toward cost-effectiveness in nursing
      practice and its perceived effects on quality of care, and to examine the
      influence of role, education, and experience on these attitudes. DESIGN: A
      comparative, descriptive design was used. SETTING: Two community hospitals in the
      midwest. SUBJECTS: Registered nurses and licensed practical nurses. MEASUREMENTS
      AND MAIN RESULTS: Blaney Hobson Nursing Attitude Scale was used to measure
      nurses' attitudes toward cost-effectiveness. Demographic information was obtained
      by asking open-ended questions. Scores ranged from 30 to 96, with a mean score of
      65.57 (SD = 13.58). CONCLUSIONS: Nurses with greater than 10 years experience had
      more positive attitudes than nurses with 10 years or less experience. Nurses in
      administration/management positions had more positive attitudes than did staff
      nurses. No significant correlation was found between education level and
      attitudes toward cost-effectiveness. The major concern of participants was that
      quality of care would suffer due to cost containment efforts. The majority of
      participants agreed that education in cost containment and budgetary issues
      should begin in basic nursing school and should be included in employer
      orientation programs.

PMID- 10351383
TI  - Coordination of benefits.

PMID- 10351384
TI  - Patient communication in the era of managed care. Improving compliance and
      outcomes while reducing risk.

PMID- 10351385
TI  - The current state of critical care medicine.

PMID- 10351386
TI  - The art and science of the handoff. How hospitalists share data.

PMID- 10351387
TI  - What's wrong with treating medicine like a business.

PMID- 10351388
TI  - Hiring a consultant is easy. Now what? Working with a consultant to get
      implemented results.

PMID- 10351389
TI  - Eight alternatives to adding more patients. Practice growth strategies.

PMID- 10351390
TI  - From the UCLA Medical Center: a clinical pathway for gastrointestinal bleeding.

PMID- 10351391
TI  - A diagnostic checklist for managed care. Improving the bottom line without
      sacrificing quality.

PMID- 10351392
TI  - Physicians are still looking for the right business leadership.

PMID- 10351393
TI  - Where it was, where it is, and where it should go. Historical perspectives of
      healthcare policy and the evolution of a new model for healthcare delivery.

PMID- 10351394
TI  - The value marketing chain in health care.
AB  - In health care, Michael Porter's value chain can be reconceptualized as a "Value
      Marketing Chain," in which value is reinforced during each step of the customer
      recruitment and retention process. "Value" is a concept that must jointly be
      defined by buyer and seller as they interact every step of the way during the
      process. This requires the establishment of end-to-end mechanisms for soliciting
      feedback from customers.

PMID- 10351396
TI  - How physician networks are selling themselves.
AB  - A growing number of physicians are creating discount networks due to the anger
      they feel about their loss of professional autonomy and financial compensation to
      managed care. They are seeking a niche among patients who lack adequate health
      insurance coverage or are dissatisfied with their plans. To win patients, the
      physician networks are marketing services that are deeply discounted.

PMID- 10351395
TI  - Managing stakeholder loyalty.
AB  - The authors question the utility of relying on the conventional wisdom in
      healthcare that satisfaction is the proper measure of strategic health. They
      offer four reasons why "stakeholder value" is the more appropriate measure. They
      present a case of a large midwestern HMO that has evolved to a stakeholder value
      approach. They demonstrate the linkages among the different components of the
      Stakeholder Value Information System, how stakeholder assessments of value drive
      loyalty and other key measures, and how that system can be used to inform
      strategic and operational decision making.

PMID- 10351397
TI  - Developing a hospital Web site as a marketing tool: a case study.

PMID- 10351398
TI  - The role of service recovery in HMO satisfaction.
AB  - Complaint handling and service recovery by HMOs may be more efficient to
      implement and more determinant of customer satisfaction and retention than other
      approaches such as improving access to care. The current findings are consistent
      with research on recovery efforts in other industries. Complaint handling systems
      must achieve rapid and comprehensive identification and resolution of HMO member
      problems. Both cultural change and appropriate incentives to re-educate employees
      within HMO organizations are additional requisites to effective service recovery.
      The benefits to the HMO of expenditures on service recovery should be more
      immediate and sustainable than the benefits derived from other methods of
      increasing member satisfaction.

PMID- 10351399
TI  - When the new millennium rolls in, will your facility still be standing?
AB  - The health care industry as a whole lags far behind other industries in preparing
      for the year 2000. Experts say about half of health care providers won't be
      ready. Important first steps are taking an inventory of medical devices and
      systems that may have year 2000-related glitches and then making a prioritized
      list of what to fix first. Experts advise making contingency plans such as having
      extra staff available Dec. 31, 1999, and stocking up on battery-powered radios
      and lights.

PMID- 10351400
TI  - Hospital saves $1 million by outsourcing laundry.
AB  - Thirty-five percent of hospitals nationwide are outsourcing laundry services,
      according to the Textile Rental Services Association. Pennsylvania Hospital cut
      its cost per pound of laundry from 61.5 cents to 46 cents, saving $1 million in
      its first year of outsourcing. Outsourcing also brought the hospital better
      inventory control, more efficient delivery, and fewer complaints about missing
      items.

PMID- 10351401
TI  - JCAHO recognizes quality improvement leaders.
AB  - The Joint Commission's Codman Award recognizes health care organizations that use
      outcomes measurement to improve their quality of care. Atascadero (CA) State
      Hospital's analysis of violent incidents led to a 40% drop in mealtime aggressive
      incidents and a savings of 70 nursing staff hours a day. Susquehanna Lutheran
      Village of Millersburg, PA, did an outcomes study that led to the elimination of
      restraint usage on residents. More residents are discharged to home, and staff
      turnover has decreased.

PMID- 10351402
TI  - Nurses, patients benefit from evaluation process.
AB  - The privileging process at St. Marys Hospital Medical Center in Madison, WI,
      provides a framework for professional growth of nurses. Key areas for
      professional development outlined in the process include intellectual, technical,
      interpersonal, and ethical. Specific functions and responsibilities are
      delineated in charts the nurses use to track their progress.

PMID- 10351403
TI  - GHA, AHA join forces on health care compliance.

PMID- 10351404
TI  - Welfare reform eases one burden, creates another.

PMID- 10351405
TI  - New developments define hospital obligations under EMTALA.

PMID- 10351406
TI  - Quality counts to large employers.

PMID- 10351407
TI  - HMOs adopt external review programs.

PMID- 10351408
TI  - Stats & facts. The appeals process: what have we learned?

PMID- 10351409
TI  - Will physician practice management companies learn from their mistakes?

PMID- 10351410
TI  - Patient retention issues in Medicare risk-contracting HMOs.
AB  - Positive patient-physician interaction is essential to a successful practice.
      Positive patient-practice experiences may also result in decreased medical
      liability costs. However, most medical practices are not organized according to
      this mind-set. As managed care physicians in either closely linked medical groups
      or loose affiliations consider signing Medicare risk contracts, the importance of
      a "patient-focused" orientation is critical for success. Measured patient
      retention is the positive outcome of such efforts.

PMID- 10351411
TI  - The role of the Internet in patient empowerment.

PMID- 10351412
TI  - Assessing the critical behavioral competencies of outstanding managed care
      primary care physicians.
AB  - This study used job competence assessment to identify the behavioral
      characteristics that distinguish outstanding job performances of primary care
      physicians (PCPs) within a network-model HMO. Primary care physicians were chosen
      for the study based on six standard performance measures: (1) member
      satisfaction, (2) utilization, (3) patient complaints, (4) emergency room
      referrals, (5) out-of-network referrals, and (6) medical record completeness.
      Outstanding PCPs (N = 16) were identified as those performing within one standard
      deviation above the mean on all six of the performance measures. A control group
      of typical PCPs (N = 10) was selected from those performing outside the peer
      group mean on at least two performance measures. Subjects were administered the
      Behavioral Event Interview and the Picture Story Exercise. Higher overall
      competency levels of achievement orientation, concern for personal influence,
      empathic caregiving, and empowerment drive distinguished outstanding from typical
      PCPs. Outstanding PCPs also had higher overall frequency of competency in
      building team effectiveness and interpersonal understanding when compared with
      typical PCPs. This study suggests that PCP performance is the product of
      measurable competencies that are potentially amenable to improvement. Competency
      assessment and development of PCPs may benefit both organizational efficiency and
      physician and patient satisfaction.

PMID- 10351413
TI  - How well can Medicare recipients evaluate Medicare+Choice options?

PMID- 10351414
TI  - Developing a managed care-pharmaceutical research partnership.
AB  - Increasingly, MCOs ask pharmaceutical companies for evidence of a new product's
      cost effectiveness before adding it to the formulary. This article examines a
      research partnership between a pharmaceutical company and 14 MCOs to assess the
      cost effectiveness of a new medication for osteoarthritis. The research
      partnership, a study protocol, and research activities are discussed.

PMID- 10351416
TI  - Want to sew up $1 million in savings? Surgeons hold key.

PMID- 10351415
TI  - Seeking a comprehensive vision plan.
AB  - The demand for vision care services continues to rise rapidly. A comprehensive
      vision benefit can be of tremendous value to the employer and employee alike.
      Although nationwide standards do not exist for the provision of vision care
      services, the authors outline the features of a vision benefit that are crucial
      to offering a quality plan.

PMID- 10351417
TI  - Small changes, vendor partnerships drive down hospital's imaging costs.
AB  - Imaging departments offer great potential for cost reductions. That's what
      Baptist Hospital of Miami found out when they put their operation under the
      microscope and solicited assistance from some of their vendors. By paying
      attention to the details, the hospital reduced costs by more than $500,000 a
      year. Find out how.

PMID- 10351418
TI  - Select timely data and local benchmarks to profile MDs.
AB  - DATA BENCHMARKS: Seeking an effective way to let their physicians know their
      costs were too high and LOS too long, managers at two New York health care
      organizations began profiling the physicians by using data the physicians
      themselves deemed most appropriate. Find out what data they selected. And review
      samples of the reports they prepare for their physicians. It's all part of a new
      book from the publisher of CRR.

PMID- 10351419
TI  - New marketing strategy has CA hospital saying 'in with the old and out with the
      new'.
AB  - Redesigning the marketing department can offer a sweet surprise of savings. Long
      Beach (CA) Memorial Hospital revamped its marketing operations as an afterthought
      to a hospitalwide reengineering effort. Little did they know they could slash
      close to $1 million out of their advertising and marketing budget and redesign
      job functions to meet the changes taking shape within the entire facility. Learn
      their cost-saving secrets.

PMID- 10351420
TI  - Provider-sponsored plans reveal keys to survival.

PMID- 10351421
TI  - Provider plan in Medicare risk shares experience, offers advice.
AB  - Sound advice from a survivor. Yellowstone Community Health Plan in Billings, MT,
      is one of the few rural Medicare Choices demonstration programs still operating.
      Leaders of this provider-sponsored HMO reveal what all providers need to know
      about the universal problems in Medicare risk and transitioning into
      Medicare+Choice.

PMID- 10351422
TI  - Pediatric system uses contracts with providers, plans to shape its role in
      managed Medicaid.
AB  - CASE STUDY: A pediatric provider system seeks control in managed Medicaid. By
      creating its own provider network, and making some unusual contracting
      arrangements, Cook Children's Health Care System in Fort Worth, TX, has lowered
      utilization and even paid bonuses to physicians under its first full-risk
      contracts with three Medicaid plans. See how this system's providers set
      themselves up to succeed.

PMID- 10351423
TI  - Medicare county rates climb; plans still expect less in 2000.
AB  - Data File: In this two-part column, take a look at 1999 and 2000 base capitation
      rates for several counties in Florida, a growing market for Medicare HMOs, and
      review Medicare HMO patient satisfaction survey results.

PMID- 10351424
TI  - Medicare members like plans, providers, but could be happier.

PMID- 10351425
TI  - Be conservative when sizing up chronically ill senior population.
AB  - Tip of the Month: Watch how you select claims data. A consultant points out that
      providers using past Medicare claims data to determine which members have chronic
      conditions and how much they are likely to cost can make inaccurate estimates by
      using unfocused selection criteria.

PMID- 10351427
TI  - Diabetics need special attention in the hospital setting.
AB  - As many as half of all MCOs have a diabetes DM program, but what happens when
      those patients must be admitted to the hospital? New guidelines on inpatient
      management of diabetes patients go hand in hand with outpatient disease
      management efforts.

PMID- 10351426
TI  - Federal medical record privacy law likely by September.

PMID- 10351428
TI  - Pediatric asthma program reaches the youngest patients.
AB  - Asthma attacks can set pre-schoolers and their parents into a panic. A new
      program designed just for kids ages 4-8 shows that even the youngest patients can
      be taught to control their asthma with the right education and tools.

PMID- 10351429
TI  - Inexpensive program led by trained patients widens the reach of disease
      management.
AB  - Patients with chronic diseases have a lot in common, and one researcher is
      bringing them together in peer led self-care programs that are proving effective
      in reducing utilization and costs.

PMID- 10351430
TI  - Cardiac program plugs into high-risk patients, zooms in on savings.
AB  - A coronary artery disease program that identifies high-risk patients and "keeps
      tabs" on them for 24 hours is creating dramatic results--decreased ER visits,
      admissions, and LOS along with better clinical outcomes.

PMID- 10351431
TI  - Can providers survive when accepting pharmacy risk?

PMID- 10351432
TI  - Does your capitation contract include these 'top 12' clauses?
AB  - Providers that accept global capitation sometimes fail to protect themselves from
      excessive risk because they omit a few relatively simple clauses from their
      contracts, like this consultant's "Top 12".

PMID- 10351433
TI  - One PHO succeeds at risk after painstaking preparation.
AB  - As part of its calculated approach to risk-based contracting, a PHO in Washington
      state designed a compensation formula that emphasizes simplicity over equality by
      creating a "single-pod" risk pool.

PMID- 10351434
TI  - Use MGMA data to benchmark revenues, costs under capitation.

PMID- 10351435
TI  - Use this sample contract to evaluate stop-loss arrangements.

PMID- 10351436
TI  - Perspectives. SCHIP's (State Children's Health Insurance Program) success
      inspires incrementalists to pursue ideas for expanding coverage; tax-based
      proposals draw fresh interest.

PMID- 10351437
TI  - Award-winning disease management program yields big results.

PMID- 10351438
TI  - The healing power of food comes to the hospital.

PMID- 10351439
TI  - Ergonomics programs should be tailored to HCWs.

PMID- 10351441
TI  - CHF valve repair may supplant replacement.

PMID- 10351440
TI  - Increasing regulations could guarantee your job.

PMID- 10351442
TI  - Tools that support PCP-managed asthma care.

PMID- 10351443
TI  - In-home medication management for the elderly.

PMID- 10351444
TI  - The evolution of orthopedic outcomes measurement.

PMID- 10351445
TI  - Revocation of hospital privileges due to exclusive contracts. Garibaldi vs.
      Applebaum.

PMID- 10351446
TI  - Health care compliance plans.

PMID- 10351448
TI  - Management services coupled with control equals exemption: Priv. Ltr. Rul. 98-47
      033.

PMID- 10351447
TI  - Hospital-physician compensation methods under the Stark Act.

PMID- 10351449
TI  - Pediatric home care as a viable new service.
AB  - From a business perspective, pediatric home care looks like a successful line of
      service. It is a growing specialty that generates consistent profits. Agencies
      thinking of moving in this direction, however, need to know what they might be
      getting into.

PMID- 10351450
TI  - Communicating in end-of-life care.
AB  - In pediatric cases communication is a key element of care--more so than for any
      other type of care because parents and other family members are as involved as
      the child is. Thus, learning effective communication skills is essential for
      successful care. End-of-life settings make the need for quality communication
      even more important. Providers can learn skills from this article to apply to any
      pediatric care situation.

PMID- 10351451
TI  - Effective ways to communicate with the dying.

PMID- 10351452
TI  - Is home care feasible in a developing country?
AB  - One organization in Buenos Aires leads the country in providing pediatric home
      care. It is also responsible for educating much of the country about the rewards
      of such care.

PMID- 10351453
TI  - Children's health insurance program: opportunity to expand care.
AB  - Late in the summer of 1997, President Clinton signed the Children's Health
      Insurance Program into law. The program follows the example of many states that
      have expanded health coverage for uninsured children through Medicaid or other
      state programs. Through combining funds, federal and state governments seek to
      provide for all of the children in America who currently have insufficient health
      coverage.

PMID- 10351454
TI  - The changing face of children's health: a positive state perspective.
AB  - In the midst of health care cutbacks, imposed or increasing copays, and managed
      care crises, the face of children's health care is undergoing significant
      changes. These, quite fortunately for the children of Texas, are positive
      changes, including the establishment of the Texas Healthy Kids Corporation and
      utilization of the newly implemented Children's Health Insurance Plan.

PMID- 10351455
TI  - The small guy can survive.

PMID- 10351456
TI  - Pay for travel: protecting the employer.
AB  - Home care companies need to protect themselves from potential lawsuits regarding
      pay for travel time for those employees who travel between clients' homes. The
      costs of not doing so can be enormous, particularly as pre-empting such cases
      takes relatively simple policies.

PMID- 10351457
TI  - Support for families and children with special needs.
AB  - One home care agency's staff identified community needs and developed three
      pediatric programs to address those needs. The programs include case management,
      a respite program, and parent education to prevent child abuse or neglect. All
      programs strengthen the families and thus the community this agency serves and
      are thus good examples of an agency's use of all resources at hand.

PMID- 10351458
TI  - Calling all volunteers.

PMID- 10351459
TI  - National organization works for volunteers ... National Volunteer Fire Council.

PMID- 10351460
TI  - Trauma care in EMS: where are we? A look at the nature, origins, controversies
      and future of prehospital trauma services.

PMID- 10351461
TI  - Mass casualty and disaster communications.

PMID- 10351462
TI  - EMS incident management: personnel roles and responsibilities.

PMID- 10351463
TI  - Bay Area blackout. EMS response to city-wide power outage.

PMID- 10351464
TI  - Child health promotion in developing countries: the case for integration of
      environmental and social interventions?
AB  - In spite of improving epidemiological knowledge in relation to child health, the
      challenge of promoting the survival and quality of life of infants and children
      in most parts of the developing world remains an abiding public health problem,
      for both the countries and the international agencies involved. Current infant
      and child health programmes largely reflect western style medical care, with
      emphasis placed on reducing mortality, and the preventive aspects confined mainly
      to immunisation, improved nutrition, provision of micronutrients, promotion of
      breast-feeding and birth spacing. In contrast, environmental and social factors
      which underpin the proliferation of disease agents are receiving minimal
      attention. This paper presents a critical review of current strategies for
      promoting child health in developing countries, and examines the environmental,
      social, and political factors that influence child health. Presenting a specific
      example of infant and childhood diarrhoea, the authors argue that in order for a
      real reduction in mortality, and improvements in quality of life to be sustained,
      attention needs to be focused equally on the environmental and social factors
      that underlie much of the childhood diseases in the developing world. This will
      involve the adoption of a broader strategy aimed at reducing childhood diarrhoea,
      using the hazard analysis critical control point (HACCP) system in combination
      with other methods.

PMID- 10351465
TI  - Injuries in Pakistan: directions for future health policy.
AB  - Injuries result in major financial and productivity losses to nations while
      inflicting tremendous personal burden on the injured and their families. Two
      thirds of the global deaths from injuries occur in the developing world,
      consuming substantial health sector resources. Pakistan is a developing country
      with a population of 136 million and no reported estimate of the national impact
      of injuries. This study presents a profile of injuries in Pakistan, estimates the
      impact on the country and recommends strategies to further delineate this
      important public health problem. A methodical review of published, unpublished
      and government literature was undertaken and data collected for all types of
      injuries principally over the 1982-1994 period. Motor vehicle injuries,
      homicides, assaults, work-related injuries, poisonings and risk factors have been
      included. Selected epidemiological estimates have been generated and the WHO
      motorization index has been used to assess road-side accident risk. The lack of
      reliable data and under-reporting of work-related injuries is revealing. The
      rising time trend in all injuries, the significant loss of life from injuries and
      the age of those injured have a critical impact on the national economy and
      health system. Data on injuries in Pakistan are primarily recorded by police
      authorities and used for legal purposes. Pakistan must institute an information
      system to evaluate the true impact of injuries and develop national safety
      standards. Implementation of such standards is especially important for road
      traffic safety and occupational health in industrial units within the country.

PMID- 10351466
TI  - The effect of delivery mechanisms on the uptake of bed net re-impregnation in
      Kilifi District, Kenya.
AB  - The results of recently completed trials in Africa of insecticide-treated bed
      nets (ITBN) offer new possibilities for malaria control. These experimental
      trials aimed for high ITBN coverage combined with high re-treatment rates. Whilst
      necessary to understand protective efficacy, the approaches used to deliver the
      intervention provide few indications of what coverage of net re-treatment would
      be under operational conditions. Varied delivery and financing strategies have
      been proposed for the sustainable delivery of ITBNs and re-treatment programmes.
      Following the completion of a randomized, controlled trial on the Kenyan coast, a
      series of suitable delivery strategies were used to continue net re-treatment in
      the area. The trial adopted a bi-annual, house-to-house re-treatment schedule
      free of charge using research project staff and resulted in over 95% coverage of
      nets issued to children. During the year following the trial, sentinel dipping
      stations were situated throughout the community and household members informed of
      their position and opening times. This free re-treatment service achieved between
      61-67% coverage of nets used by children for three years. In 1997 a social
      marketing approach, that introduced cost-retrieval, was used to deliver the net
      re-treatment services. The immediate result of this transition was that
      significantly fewer of the mothers who had used the previous re-treatment
      services adopted this revised approach and coverage declined to 7%. The future of
      new delivery services and their financing are discussed in the context of their
      likely impact upon previously defined protective efficacy and cost-effectiveness
      estimates.

PMID- 10351467
TI  - Characteristics of private medical practice in India: a provider perspective.
AB  - Supply factors, depicted by input market conditions and government regulations,
      and demand factors, depicted by financing mechanisms and utilization patterns,
      are likely to determine the shape and character of private medical practice. The
      interaction of this complex set of factors will have considerable implications
      for the cost access and quality of services offered by this sector. Understanding
      these characteristics from a provider perspective is imperative to influence the
      behaviour of providers in this sector. This paper describes some of the important
      characteristics of private medical practice using a case study of an urban
      district in India, Ahmedabad, and analyzes their implications. Using survey data
      of 130 private doctors in the allopathic system, the paper describes broad
      characteristics of private medical practice using parameters such as growth of
      private practice, patient load and referrals within the sector, payment methods
      and determinants, patient concerns, and risks associated with private practice.
      The paper presents views on the prevalence of various undesirable practices in
      the private medical sector. It also discusses the awareness of providers about
      selected important regulations. The findings suggest that growing capital
      intensity due to cost of location, medical equipment and technology, and
      financial sources of capital investments are some unfavourable environmental
      factors experienced by private providers. The findings also indicate a high
      prevalence of various undesirable practices and low awareness of the objectives
      of important legislation among practicing doctors. Lack of awareness of important
      and relevant legislation raises serious questions about the implementation of
      these laws. The paper identifies the strong need for instituting and implementing
      an effective continuing medical education programme for practicing doctors, and
      linking it with their registration and continuation of their license to practice.
      The paper also suggests that cost of health care, access and quality problems
      will worsen with the growth of the private sector. The public policy response to
      check some of the undesirable consequences of this growth is critical and should
      focus on strengthening the existing institutional mechanisms to protect patients,
      developing and implementing an appropriate regulatory framework and strengthening
      the public health care delivery system. The study also discusses various other
      policy implications arising.

PMID- 10351468
TI  - Does antenatal care make a difference to safe delivery? A study in urban Uttar
      Pradesh, India.
AB  - Evidence to support that antenatal screenings and interventions are effective in
      reducing maternal mortality has been scanty and studies have presented
      contradictory findings. In addition, antenatal care utilization is poorly
      characterized in studies. As an exposure under investigation, antenatal care
      should be well defined. However, measures typically only account for the
      frequency and timing of visits and not for care content. We introduce a new
      measure for antenatal care utilization, comprised of 20 input components covering
      care content and visit frequency. Weights for each component reflect its relative
      importance to better maternal and child health, and were derived from a survey of
      international researchers. This composite measure for antenatal care utilization
      was studied in a probability sample of 300 low to middle income women who had
      given birth within the last three years in Varanasi, Uttar Pradesh, India.
      Results showed that demarcating women's antenatal care status based on a simple
      indicator--two or more visits versus less--masked a large amount of variation in
      care received. Logistic regression analyses were conducted to examine the effect
      of antenatal care utilization on the likelihood of using safe delivery care, a
      factor known to decrease maternal mortality. After controlling for relevant socio
      demographic and maternity history factors, women with a relatively high level of
      care (at the 75th percentile of the score) had an estimated odds of using trained
      assistance at delivery that was almost four times higher than women with a low
      level of care (at the 25th percentile of the score) (OR = 3.97, 95% CI = 1.96,
      8.10). Similar results were obtained for women delivering in a health facility
      versus at home. This strong positive association between level of care obtained
      during pregnancy and the use of safe delivery care may help explain why antenatal
      care could also be associated with reduced maternal mortality.

PMID- 10351469
TI  - The immunization programme in Bangladesh: impressive gains in coverage, but gaps
      remain.
AB  - The paper reviews the achievements in tetanus immunization coverage and child
      immunization in Bangladesh. It uses data from the 1993-94 Bangladesh Demographic
      and Health Survey to identify and examine the programmatic and non-programmatic
      factors that influence the coverage of tetanus (TT) immunization during
      pregnancy, and full immunization among children 12-23 months old in rural
      Bangladesh. The purpose of this analysis is to identify the areas that need
      further programme attention. The logistic regression results show that the
      coverage of TT immunization was significantly associated with proximity to
      outreach clinics and the presence of a health worker in the community. Home
      visits by health/family planning fieldworkers and the proximity to outreach
      clinics had larger influences on TT coverage of poorer households compared to
      those better-off. The effect of distance to static clinics varied by regions.
      Among children, full immunization coverage (coverage of all of BCG, DPT1, DPT2,
      DPT3, Polio1 Polio2, Polio3) was significantly associated with distance to
      outreach clinics, the greater the distance to the clinics, the less the
      likelihood of immunization.

PMID- 10351470
TI  - Reforming health service delivery at district level in Ghana: the perspective of
      a district medical officer.
AB  - Many countries in sub-Saharan Africa face the problem of organizing health
      service delivery in a manner that provides adequate quality and coverage of
      health care to their populations against a background of economic recession and
      limited resources. In response to these challenges, different governments,
      including that of Ghana, have been considering or are in the process of
      implementing varying degrees of reform in the health sector. This paper examines
      aspects of health services delivery, and trends in utilization and coverage,
      using routine data over time in the Dangme West district of the Greater Accra
      region of Ghana, from the perspective of a district health manager. Specific
      interventions through which health services delivery and utilization at district
      level could be improved are suggested. Suggestions include raising awareness
      among care providers and health managers that increased resource availability is
      only a success in so far as it leads to improvements in coverage, utilization and
      quality; and developing indicators of performance which assess and reward use of
      resources at the local level to improve coverage, utilization and quality. Also
      needed are more flexibility in Central Government regulations for resource
      allocation and use; integration of service delivery at district level with more
      decentralized planning to make services better responsive to local needs; changes
      in basic and inservice training strategies; and exploration of how the public and
      private sectors can effectively collaborate to achieve maximum coverage and
      quality of care within available resources.

PMID- 10351471
TI  - Cost-effectiveness analysis of humanitarian relief interventions: visceral
      leishmaniasis treatment in the Sudan.
AB  - Spending by aid agencies on emergencies has quadrupled over the last decade, to
      over US$6 billion. To date, cost-effectiveness has seldom been considered in the
      prioritization and evaluation of emergency interventions. The sheer volume of
      resources spent on humanitarian aid and the chronicity of many humanitarian
      interventions call for more attention to be paid to the issue of 'value for
      money'. In this paper we present data from a major humanitarian crisis, an
      epidemic of visceral leishmaniasis (VL) in war-torn Sudan. The special
      circumstances provided us, in retrospect, with unusually accurate data on excess
      mortality, costs of the intervention and its effects, thus allowing us to express
      cost-effectiveness as the cost per Disability Adjusted Life Year (DALY) averted.
      The cost-effectiveness ratio, of US$18.40 per DALY (uncertainty range between
      US$13.53 and US$27.63), places the treatment of VL in Sudan among health
      interventions considered 'very good value for money' (interventions of less than
      US$25 per DALY). We discuss the usefulness of this analysis to the internal
      management of the VL programme, the procurement of funds for the programme, and
      more generally, to priority setting in humanitarian relief interventions. We feel
      that in evaluations of emergency interventions attempts could be made more often
      to perform cost-effectiveness analyses, including the use of DALYs, provided that
      the outcomes of these analyses are seen in the broad context of the emergency
      situation and its consequences on the affected population. This paper provides a
      first contribution to what is hoped to become an international database of cost
      effectiveness studies of health interventions during relief operations, which use
      a comparable measure of health outcome such as the DALY.

PMID- 10351472
TI  - Determinants of attendance and patient satisfaction at eye clinics in south
      western Uganda.
AB  - PURPOSE: To identify the reasons for subjects deciding to attend or not attend
      local and referral ophthalmology clinics in south-west Uganda, and to establish
      the levels of satisfaction of clinic attenders with the services they received.
      METHODS: A population survey identified subjects with ocular conditions who were
      referred to the local clinic or the district hospital. All non-attenders and a
      group of attenders were interviewed at home. RESULTS: 31% of those referred did
      not attend the local clinic. The most common reasons were 'too busy' (29%) or
      'unwilling to buy spectacles' (17%). Less than half of attenders were satisfied,
      mainly because of no perceived clinical improvement or having to buy spectacles.
      Only 13% of those referred to the district hospital clinic attended. The main
      reasons for non-attendance were high transport cost and fear of the clinic.
      CONCLUSION: Attendance and satisfaction with the community ophthalmology service
      could be improved by more intensive motivation and explanation for patients, and
      assistance with spectacle and transport costs. The use of aphakic motivators
      should be tested in this context.

PMID- 10351473
TI  - Comment on 'How to do (or not to do) ... a logical framework', Health Policy and
      Planning 13(2):189-193.

PMID- 10351474
TI  - Defusing gang activity: different hospitals take different approaches.

PMID- 10351475
TI  - How hospital reduced worker's comp claims by $2.2 million in one year.

PMID- 10351476
TI  - Hospital liability for negligent hiring and supervision.

PMID- 10351477
TI  - Reducing needlesticks and blood exposure: tracking, training, technology.
AB  - Healthcare workers--especially nurses and phlebotomists who routinely use needles
      to draw blood and start intravenous catheters--are susceptible to injuries from
      cuts from sharp objects like needlesticks, of which about one million injuries
      are reported annually. Through such injuries, workers risk infection (the average
      infection risk from injuries is 1 in 300) with deadly diseases such as Hepatitis
      B or C, or HIV, the virus that causes AIDS. In addition, hospital security
      officers continue to face risks from exposure to blood and body fluids, usually
      when called on to deal with violent or potentially violent ER patients. In this
      report, we will focus on new ways that have been developed to track these
      healthcare risks, proactive and reactive programs being instituted by several
      hospitals to deal with needlesticks, and the latest devices developed by
      manufacturers to prevent or reduce their occurrences.

PMID- 10351478
TI  - Royal visits. Why roll out the red carpet....

PMID- 10351479
TI  - US healthcare. Boom or bust?

PMID- 10351480
TI  - Archie's enemies.

PMID- 10351481
TI  - Data briefing. Air pollution.

PMID- 10351482
TI  - On the evidence. Dental restoration.

PMID- 10351483
TI  - Storm of the century: contingency planning can help you weather Y2K's worst.

PMID- 10351484
TI  - Tooling around. CEIT (Clinical Engineering Improvement Tools)--tools you can use
      to keep your clinical engineering department clicking along.

PMID- 10351485
TI  - Getting a lock on risk. JCAHO standards for security management programs.

PMID- 10351486
TI  - Zero tolerance. Even a little mercury is too much.

PMID- 10351487
TI  - Price survey. Stent prices down, but not enough.

PMID- 10351488
TI  - Novation rebounding after CEO's departure.

PMID- 10351489
TI  - Back to the future with linen rental service.

PMID- 10351490
TI  - MedEcon acquisition turns nasty after six months.

PMID- 10351491
TI  - Catholic identity: a unifying force.

PMID- 10351493
TI  - How do you help patients feel comfortable?

PMID- 10351492
TI  - Daily news links you to the information you need.

PMID- 10351494
TI  - Baltimore Hospital is "staying in the struggle". An interview with Sr. Helen
      Amos, RSM. Interview by Gordon Burnside.

PMID- 10351496
TI  - Assisted living for changing needs. Strategies and working examples clarify
      challenges in mission-driven senior housing.

PMID- 10351495
TI  - Mission at the millennium. Catholic healthcare systems are beginning to develop
      professional mission leaders.

PMID- 10351497
TI  - Health ministry vitalizes parishes. Health system helps parishes add meaning to
      the parish community.

PMID- 10351498
TI  - Evolution of a community health ministry. Parish-based efforts to promote health
      and wellness benefit the entire community.

PMID- 10351499
TI  - Four keys to success in parish nursing. A California hospital and local churches
      cooperate to bring healthcare to the neighborhood.

PMID- 10351500
TI  - Collaborating to provide parish-based health services.

PMID- 10351501
TI  - Parish-based programs that serve aging and chronically ill persons.

PMID- 10351502
TI  - Bridges from welfare to work. Mercy Medical Center's program helps people in
      transition.

PMID- 10351503
TI  - Opposing moral error in society. Assisted suicide bill illustrates need to
      respect various viewpoints.

PMID- 10351504
TI  - Better care for the dying. Hawaii healthcare system develops a manual for end-of
      life care.
AB  - In early 1996, as it became clear that Americans were becoming increasingly
      concerned about end-of-life care, the leaders of St. Francis Healthcare System
      (SFHS), Honolulu, convened a meeting at which local people--community and parish
      representatives as well as healthcare professionals--discussed the matter. The
      meeting's participants identified 10 issues as essential in end-of-life care:
      decision making, pain management and comfort care, pastoral and spiritual care,
      psychosocial care, hospice and home care, cardiopulmonary resuscitation,
      futility, withholding and withdrawing treatment, artificial nutrition and
      hydration, physician-assisted suicide and euthanasia. The participants then
      divided themselves into 10 teams, each of which spent six months studying one of
      the identified essential issues. In each case, the team reviewed the relevant
      SFHS policies and procedures and compared them with national standards. The team
      also interviewed staff members about the policies and procedures, comparing the
      written versions with actual practices. Each team then wrote a chapter on its
      assigned issue, after which a core committee wove the chapters into an end-of
      life care manual for SFHS. The manual was published in June 1997. The system's
      leaders currently use the manual to educate staff members in good end-of-life
      care.

PMID- 10351506
TI  - Low-cost marketing can reap big results.

PMID- 10351505
TI  - Executive compensation.

PMID- 10351507
TI  - Integrating cultures: a tool for mission leaders and others in collaborating
      organizations.
AB  - This resource, Integrating Cultures, is a direct response to numerous requests
      received last fall from mission leaders in CHA-member organizations struggling
      with the cultural realities of strategic alliances. This tool presents the
      learnings of five authors who shared their significant experience of
      collaborative activities in ministry organizations, ranging from joint operating
      agreements to full mergers of assets and expenses. This resource specifically
      addresses the challenges facing organizations in the first 18 to 24 months follow
      the finalization of a collaboration. Strategies are presented here for bringing
      together previously distinct communities of people into positive, healthy new
      cultures that reflect the visions and purposes of the collaborative activities.
      Future articles will recommend culture integration strategies appropriate at
      other points along the collaboration timeline: the period of initial
      investigation, the stage of due diligence, and the ongoing life of collaborating
      entities two years and more after signing the final papers. Integrating Cultures
      and a resource from CHA collaboration with other-than-Catholic organizations (set
      for publication later this spring) were developed in response to members'
      requests for the accurate information they need as they proceed with integration
      strategies in today's healthcare environment. These resources are examples of the
      powerful knowledge e transfer and wisdom sharing that is possible when ministry
      leaders work with and for one another to make Christ's healing presence more
      evident in our world.

PMID- 10351508
TI  - Community networks. Alzheimer's Respite Care Program, Youngstown, OH.

PMID- 10351509
TI  - A pastoral voice in the healthcare wilderness.

PMID- 10351510
TI  - Medicare tightens rules for ambulance reimbursement.

PMID- 10351511
TI  - Update: sexual harassment & EMS.

PMID- 10351512
TI  - Managers seek creative solutions to assisting.

PMID- 10351513
TI  - Turnover time: is all the study worth the effort?

PMID- 10351514
TI  - BSN, master's enrollment fall.

PMID- 10351515
TI  - Spinal cages: managing the costs.

PMID- 10351516
TI  - How to keep a GI lab humming.

PMID- 10351517
TI  - Good policies are guide to add-on surgical cases.

PMID- 10351518
TI  - Trial of Denver nurses points up system flaws.

PMID- 10351519
TI  - Benchmarks. Knee arthroscopy supply costs.

PMID- 10351520
TI  - Home health claims must report 15-minute service increments.

PMID- 10351521
TI  - Keeping afloat with Year 2000 contingency planning.

PMID- 10351522
TI  - No time for the poor. Physicians dependent on managed care provide less
      assistance to the uninsured.

PMID- 10351523
TI  - Pregnancy and pills. New research finds prescriptions may be safer than you
      think.

PMID- 10351525
TI  - Medicare: healthier for now. But a windfall masks the coming problem.

PMID- 10351526
TI  - Almost a fountain of youth. The politicians ignore medical marvels that will cut
      the costs of Medicare.

PMID- 10351524
TI  - Checking your kid's cholesterol. A researcher calls the current standard flawed.

PMID- 10351527
TI  - Mothers with another's eggs. As demand for donors accelerates, questions on the
      price of a child.

PMID- 10351528
TI  - It may be all the rage, but does it work? Some doubt anger-management class
      helps.

PMID- 10351529
TI  - The silent killer. By the time diabetes is diagnosed, it may be too late.

PMID- 10351530
TI  - Celebrating what we HAVE. Hospital Awards for Volunteer Excellence.

PMID- 10351531
TI  - Eleven tips for free publicity.

PMID- 10351532
TI  - Growing pains: Irving's changing voice.

PMID- 10351533
TI  - Davidson keynote: calling on volunteers to help shape the AHA's future.

PMID- 10351534
TI  - Seven strategies for creating a legacy of leadership.

PMID- 10351535
TI  - Anticipating change: demographics of the emerging workforce.

PMID- 10351536
TI  - How the new volunteers will change volunteer management.

PMID- 10351537
TI  - Is it time ... for a national health promotion research agenda?

PMID- 10351538
TI  - Assessment of stages of change for exercise within a worksite lifestyle screening
      program.

PMID- 10351539
TI  - Patterns of colon cancer screening among companies in the U.S.: a descriptive
      survey.

PMID- 10351540
TI  - Differences in nutritional risk and nutrition-related behaviors in exercising and
      nonexercising rural elders.

PMID- 10351541
TI  - Perceptions of secondary school staff toward the implementation of school-based
      activities to prevent weight-related disorders: a needs assessment.

PMID- 10351542
TI  - The correlation between spiritual well-being and health behaviors.

PMID- 10351543
TI  - An analysis of breast cancer coverage in selected women's magazines, 1987-1995.
AB  - PURPOSE: Women's magazines are a significant source of health information for
      many women, but there is some concern that the media may misrepresent a woman's
      risk of breast cancer. This review analyzes breast cancer articles in selected
      women's magazines to determine if the information presented is accurate and
      balanced. SEARCH METHODS: For the years 1987 to 1995, the quantity and content of
      breast cancer articles were examined in four popular women's magazines and three
      magazines with a large African-American audience. Fifty-nine lead factual breast
      cancer articles were analyzed for the information presented on prevention
      measures, risk factors, incidence/mortality statistics, and lifetime risk. The
      age at diagnosis for women featured in these articles was also determined.
      SUMMARY OF IMPORTANT FINDINGS: Breast cancer was the topic of 34.9% of the 585
      cancer articles published in these seven magazines. Mammography screening
      guidelines were recommended in 68% of articles that discussed prevention; 66%
      presented the American Cancer Society guidelines. Risk factors for breast cancer
      were reported as age greater than 50 in 41% and family history in 78% of the
      articles that discussed risk factors. Twenty articles used the lifetime risk
      statistic of developing breast cancer; six explained what this statistic means.
      The average age of diagnosis for women featured in the articles was 40.5. MAJOR
      CONCLUSIONS: The proportion of breast cancer articles to all cancer articles in
      these magazines (34.9%) was similar to breast cancer incidence (32.2%) but was
      higher than its contribution to either female cancer mortality (17.2%) or overall
      female mortality (4.0%). Magazines that targeted the African-American audience
      had fewer breast cancer articles than the other four magazines. Risk factors for
      breast cancer were not discussed in proportion to their impact on risk. The
      popular lifetime risk statistic was not explained in the majority of cases where
      it was presented. The average age of diagnosis for the women featured in these
      articles was far below the median age of diagnosis of 65. Thus, magazine reports
      may be contributing to women's misunderstanding of their true breast cancer risk.

PMID- 10351544
TI  - Comparison of the scope of allopathic and osteopathic medical school health
      promotion programs for students.
AB  - PURPOSE: To compare the number and scope of health promotion programs for
      students in allopathic and osteopathic medical schools in the U.S. and Canada.
      DESIGN: A one-time cross-sectional survey design was applied in this study.
      SETTING: This study was conducted in 141 accredited allopathic and 17 accredited
      osteopathic medical schools. SUBJECTS: A total of 158 representatives from the
      allopathic and osteopathic medical schools participated in this study. The
      response rate for the survey was 100%. MEASURES: A structured telephone interview
      was conducted to survey representatives from the medical schools. The survey
      contained 85 multiple-choice questions organized into four sections:
      administrative characteristics, types of institutional and health promotion
      program policies, participation incentives and facilities, and type/scope of
      health promotion program activities. Chi-square analysis was used to analyze
      survey variables by type of medical education and level of intervention. RESULTS:
      Of the 158 medical schools, only 20% (n = 32) provided a health promotion program
      for students. Although osteopathic institutions (29.4%) had a greater percentage
      of programs than allopathic schools (19.2%), there was no significant difference
      in scope of program offerings by type of medical education. Allopathic programs
      offered exercise and nutrition/weight management significantly more often and at
      a higher level of intervention. Lastly, allopathic programs had significantly
      more monetary resources available for programming. Following prudent research
      protocol, investigators should be mindful of the limitations of this study. In
      this study, some school representatives chose not to answer personnel- and
      finance-related questions. Additionally, because of the self-report nature of the
      survey, the responses given to the questions may not have been accurate.
      CONCLUSION: Allopathic and osteopathic medical school health promotion programs
      for students were very similar in scope.

PMID- 10351545
TI  - The reliability and validity of a wellness inventory.

PMID- 10351546
TI  - Practice improvement project measures radiology quality.

PMID- 10351547
TI  - Feds accept no excuses in push to eliminate Medicare fraud.

PMID- 10351548
TI  - The electronic medical record.

PMID- 10351549
TI  - New security rules aim to tighten up access to data.

PMID- 10351550
TI  - Internet approach promises cost-benefits to PACS users.

PMID- 10351551
TI  - Building a cohesive employee team in a post-merger practice: a plan to manage
      change.
AB  - Merging medical practices may be a wise business decision, but the reality of
      implementing changes and the emotional fallout with the individuals affected by
      the changes can be harrowing. This paper offers advice on easing the transitions.

PMID- 10351552
TI  - The evolution of evaluation and management coding.
AB  - The government's efforts to devise a uniform coding system for evaluation and
      management of Medicare has been fraught with problems and received mixed
      reactions from physicians. This paper explores the history of the coding system
      and the importance of compliance by physicians and administrators.

PMID- 10351553
TI  - Welcome to professional courtesy discounts: the medical community's pandora's
      box.
AB  - Recent government regulations on fraud and abuse have transformed the tradition
      of professional courtesy discounts into a legal minefield threatening to explode
      on the uninformed medical provider. This paper offers an understanding of the
      issues involved and provider options.

PMID- 10351554
TI  - Process modeling for health care organizations.
AB  - Process models can be useful tools for managers seeking to correct problems
      within their organization. This paper explores how two such process models can be
      utilized in a medical practice.

PMID- 10351555
TI  - Quality improvement in health care. A brief history of the Medicare Peer Review
      Organization (PRO) initiative.
AB  - The Medicare Peer Review Organization (PRO) program began in the mid 1980s in
      response to concerns with medical necessity and quality of care of services
      delivered to the elderly and disabled, and paid for by the federal Medicare
      program. As part of their legislated oversight, PROs reviewed a random sample of
      hospital medical records. Using locally developed and maintained clinical
      criteria, PRO nurse and physician reviewers made determinations about the medical
      necessity of the inpatient stay and services, and identified issues with the
      quality of care delivered. Within 10 years of its initiation, however, criticisms
      of the PRO program, based in the reliability and validity of review findings,
      combined with national interest in quality improvement, led HCFA to refocus the
      program. PROs currently emphasize clinical and process quality improvement,
      through collaborative working relationships with providers and consumers.

PMID- 10351556
TI  - The empowering potential of quality improvement data.
AB  - Data are being used to redefine, transform, and empower the roles of providers,
      payers, and patients. The empowering potential of data on these three groups, and
      their changing roles are reviewed. The use of data to transform care and increase
      equality is not new, yet the comprehensive application of principles of
      continuous quality improvement to the delivery processes is just beginning. The
      approach to the quality improvement processes employed by peer review
      organizations includes idea capture, development of intuitively appealing quality
      indicators, formulating the intervention, formalizing the research architecture,
      and quantifying the impact of the interventions. The multifaceted interventions
      for improvement are discussed. The future of medicine includes a greater use of
      data and the quantitative sciences to inspire improvement across the health care
      delivery continuum.

PMID- 10351557
TI  - Improving appropriate selection of radical prostatectomy for prostate cancer.
AB  - Men 70 and older should usually not have radical prostatectomies to treat
      prostate cancer. Using Medicare claims data, 10 hospitals were identified that
      performed 29% of the radical prostatectomies in men 70 and older in Kentucky and
      Indiana. A quality improvement project was conducted with the purpose of
      decreasing the performance of radical prostatectomy in men 70 and older. On the
      advice of an expert committee, the peer review organization and the 10 hospitals
      collaborated in developing and implementing improvement plans that included
      institutional review of practices and informed consent policies. The project was
      associated with significant improvement in the use of radical prostatectomy. In
      addition, substantial savings in Medicare payments were observed, and improvement
      in the quality of life for Medicare men was anticipated.

PMID- 10351558
TI  - Cooperative Cardiovascular Project (CCP) quality improvement in Maine, New
      Hampshire, and Vermont.
AB  - The Cooperative Cardiovascular Project (CCP) is a nationwide quality improvement
      project (quality indicator measurement, feedback, remeasurement) in Medicare
      acute myocardial infarction (AMI) patients sponsored by the Health Care Financing
      Administration (HCFA). In Maine, New Hampshire, and Vermont, 3,472 baseline
      records were abstracted from 76 hospitals from January 1994 to February 1995.
      After feedback, 2,270 remeasurements were collected from October 1996 to May
      1997. At remeasurement, performance improved significantly for "ideal" candidates
      (defined by the CCP) on five quality indicators--aspirin during hospitalization
      88% to 93% (p < .001), thrombolytic timing 60% to 69% (p < .01), discharge
      aspirin 83% to 90% (p < .001), discharge beta-blockers 69% to 82% (p < .01), and
      calcium channel blocker avoidance 83% to 93% (p < .05). Reperfusion, angiotensin
      converting enzyme inhibitors, and smoking cessation advice did not improve
      significantly. This study demonstrates that evidence-based indicators, nationally
      designed data collection, and locally based interventions can significantly
      improve AMI care.

PMID- 10351559
TI  - Quality improvement in the diagnosis and treatment of heart failure by
      participating Indiana and Kentucky hospitals.
AB  - Acute-care hospitals in Kentucky and Indiana collaborated with Health Care Excel,
      the Medicare peer review organization, to improve the care of patients admitted
      with heart failure. Current guidelines for the treatment of heart failure support
      a focus on quality indicators including confirmation of diagnosis, choice of
      therapeutic agents, education of patients and their caregivers, and discharge
      planning. Significant improvement occurred in use of diagnostic tests to confirm
      diagnosis and in patient education and discharge planing. Improvement in use of
      therapeutic agents was minimal or lacking in most hospitals. This project
      demonstrated an opportunity and need for continued improvement efforts in the
      care of heart failure patients.

PMID- 10351560
TI  - A congestive heart failure project with measured improvements in care.
AB  - This project was designed to improve the in-hospital management of Medicare
      beneficiaries with congestive heart failure (CHF). Eleven hospitals were studied
      using two indicators: (a) assessment of left ventricular (LV) function, and (b)
      use of angiotensin converting enzyme (ACE) inhibitors in patients with systolic
      dysfunction. Baseline performance rates were obtained for 990 cases with the
      Diagnosis Related Group (DRG) 127 for CHF discharged January 1994 to December
      1994. Baseline data feedback presentations in 1995 spurred quality improvement
      plans with interventions such as physician education, critical care maps, and
      standing orders. Follow-up abstractions were performed on 612 discharges October
      1995 through April 1997. The study demonstrated 12% improvement (53% to 65%, p <
      .01) in assessing LV function and 20% improvement (54% to 74%, p < .01) in
      appropriate ACE inhibitor use. Projects emphasizing Health Care Quality
      Improvement Program (HCQIP) principles can successfully affect health care
      management for the Medicare population.

PMID- 10351561
TI  - Improving the appropriateness of red blood cell transfusions in patients
      undergoing orthopedic surgery.
AB  - Orthopedic surgery is a common procedure among the elderly, and patients are at
      risk of receiving unnecessary blood transfusions. The goals of this project were
      to analyze current transfusion practices, identify opportunities for improvement,
      implement hospital-based quality improvement programs, and measure their impact
      on transfusion practices. Our aims were to decrease unnecessary transfusions and
      overall exposure to blood products. Data were abstracted from medical records, at
      baseline and postintervention. The results demonstrated significant improvements:
      a 55% decrease in avoidable transfusion events (from 42% to 19%, p < .001) and a
      decrease in the pre-transfusion hematocrit from a baseline of 29% to 26.9% in the
      postintervention period (p < .01). The percentage of single unit transfusion
      events increased from 71.9% to 77.2% (p = .05). These results suggest that the
      interventions had a significant impact on the use of blood. In the long term,
      these results should translate into cost savings and improved patient outcomes.

PMID- 10351562
TI  - The impact of a physician intervention program on older women's mammography use.
AB  - The Mammography Optimum Referral Effort (MORE) is a physician office-based
      intervention program initiated by the Connecticut Peer Review Organization (CPRO)
      to increase mammography use among older women in Connecticut. Three locales in
      the state were targeted for the MORE intervention based on identified low
      mammography rates in women aged 65 years and older. Thirty-seven physicians
      participated from March 1, 1996, to August 31, 1996. Annual mammography rates
      were derived by merging Medicare Part B mammography claims with a database from
      the Connecticut Tumor Registry. This strategy allowed us to exclude women with a
      prior history of breast cancer from the analysis, in order to estimate screening
      rates. The MORE intervention was associated with an absolute increase of 5.9%,
      which represents a relative increase of 15.4%, in annual mammography use. Our
      findings suggest that a multifaceted physician intervention is capable of
      increasing mammography use among older women.

PMID- 10351563
TI  - Quality of care improvements for patients with pneumonia. Florida Medical Quality
      Assurance, Inc.
AB  - Pneumonia is a leading cause of morbidity and mortality among the elderly.
      Previous studies have shown that timely antibiotic administration on
      hospitalization can improve patient outcomes and shorten hospital stays.
      Antibiotic administration within 4 hours of admission has been recommended in
      national guidelines. We initiated a project with eight Florida hospitals to
      improve the timely delivery of antibiotics to pneumonia patients. Secondary goals
      were the collection of sputum and blood samples prior to antibiotic therapy.
      After gathering baseline data from review of pneumonia patient charts,
      participating hospitals initiated various interventions aimed at improving their
      processes of care. Reevaluation after implementation of the interventions found
      that a significantly larger fraction of patients received antibiotics within 4
      hours of admission (a 62% improvement), and the median time of antibiotic
      administration was also significantly decreased. No significant changes were
      observed in the rates of sputum or blood collection.

PMID- 10351564
TI  - Quality improvement at the national level. Lessons from the Cooperative
      Cardiovascular Project.
AB  - Most quality improvement projects address care delivered in one service of a
      hospital, such as the operating suite or the obstetrics service. Some projects
      are collaborative efforts involving groups of hospitals with similar interests.
      Few projects attempt to change care on a population basis (i.e., involving all
      providers in entire states or the nation as a whole.) The Cooperative
      Cardiovascular Project (CCP), sponsored by the Health Care Financing
      Administration, is attempting to improve care for all Medicare patients suffering
      from acute myocardial infarctions nation-wide. The CCP has been active since 1993
      and, in a pilot project, has demonstrated that care can be improved on a
      population basis (i.e., in four entire states). This article explores the lessons
      learned from the CCP pilot and from the evolving CCP national experience.

PMID- 10351565
TI  - Risk management strategies for an integrated health care delivery system.

PMID- 10351566
TI  - Do satisfied patients depend on satisfied employees? Or, do satisfied employees
      depend on satisfied patients?

PMID- 10351567
TI  - The ABCs of hepatitis C.
AB  - HCV is a both a major public health concern and a specific concern for HCWs. All
      occupational exposures must be reported to supervisors, and medical attention
      must be sought and follow-up testing performed, both to comply with the
      bloodborne pathogens standard and to ensure greater safety for HCWs Postexposure
      follow-up consists of base-line blood testing for the source (if consent to
      testing is obtained in accordance with state and other laws) and for the person
      exposed. Follow-up testing should occur at four to six months. HCV RNA testing
      can provide earlier detection and may be performed at four to six weeks.

PMID- 10351568
TI  - Medicaid in Alabama: the search for a long-term funding solution.

PMID- 10351569
TI  - Coastal Insurance Group: meeting the needs of the health care field.

PMID- 10351571
TI  - Labor unions come a'courtin'.

PMID- 10351570
TI  - Stepping into the next millennium of care.

PMID- 10351572
TI  - Zero tolerance--even a little mercury is too much.

PMID- 10351573
TI  - OR and materials: the yin and yang.

PMID- 10351574
TI  - Capital ideas.

PMID- 10351575
TI  - Strategy: outsourcing. Task: ID the right candidate.

PMID- 10351576
TI  - Stress busters. How to relieve workplace burnout.

PMID- 10351577
TI  - The drape escape. Lose the layers and save some scratch.

PMID- 10351578
TI  - Gunning for glutaraldehyde. How one medical center gained control.

PMID- 10351579
TI  - Stats. Benchmarking DRGs: managed care pays off.

PMID- 10351580
TI  - Adding managed care to the physician education equation.

PMID- 10351581
TI  - Starting a community-based resident training program.
AB  - A guide by collaborators in Oregon recommends putting all would-be partners'
      goals on the table and lining up solid financial support before undertaking an
      alliance of managed care, medical school and health system.

PMID- 10351582
TI  - Maturing Colorado collective tackles measurement, financial challenges.

PMID- 10351584
TI  - Computer-aided drug selection can sharply cut adverse events.
AB  - Intermountain Health Care and Brigham and Women's Hospital both have invested
      millions of dollars and countless hours in powerful computer systems that aid
      physicians' drug choices. One expert says he doesn't see how other hospitals can
      afford not to do the same.

PMID- 10351583
TI  - Partnering with academic institutions to improve population health.
AB  - Eager to make the most of local knowledge, hospitals, medical schools and managed
      care organizations are forming alliances to shape healthcare delivery in their
      regions. Such collaborations often involve training residents to work within
      managed care, but others are pursuing disease management and population health
      improvement.

PMID- 10351585
TI  - 10 targets for reducing adverse drug events. Institute for Healthcare
      Improvement.

PMID- 10351586
TI  - Changing hospital culture and systems reduces drug errors and adverse events.
AB  - To reduce adverse drug events, a hospital must make its environment one that
      encourages staff to report and investigate errors. It must also make drug
      ordering as standardized as possible and set a commitment to eliminate the root
      cause of drug errors.

PMID- 10351587
TI  - Medication and problem list.
AB  - A Wisconsin physician has set up detailed information sheets for nearly 1,500
      patients, sending them home with a summary of their medications, allergies,
      treatment history and more. The informal summary has proven popular not only as a
      patient education tool, but as an aid to emergency personnel in case of accident
      or sudden illness, he says.

PMID- 10351588
TI  - Preadmission screening of patients scheduled for hip and knee replacement: impact
      on length of stay.
AB  - OBJECTIVE: An evaluation of the impact of a social work preadmission program on
      length of stay (LOS) of orthopedic patients undergoing elective total hip or
      total knee replacement surgeries (under diagnosis-related groups [DRGs]) at the
      Hadassah Ein-Kerem Hospital in Jerusalem is Israel. INTERVENTION: The social work
      interventions included preadmission psychosocial evaluation and preliminary
      discharge planning, coordination of nursing and physiotherapy evaluations,
      ensuring completion of all medical tests prior to admission, and additional
      psychosocial follow-up during hospitalization to carry out the original discharge
      plan or prepare alternatives. PATIENTS: The intervention patients were divided
      into two groups in order to see changes over time: May through December 1994 (n =
      48), and January through December 1995 (n = 81). The comparison groups included
      patients operated on at the same hospital during 1993 (n = 51) and during January
      through April 1994 (n = 21) and at the Hadassah Mount Scopus Hospital during the
      same time periods. Patients in the comparison groups received usual social work
      intervention, as necessary, only after hospitalization. RESULTS: Mean LOS was
      reduced significantly in the intervention patient groups, as compared to the
      preintervention patient groups in the same hospital, from 14.2 days (standard
      deviation [SD], 4.7) in 1993 and 14.7 (SD, 5.1) in January through April 1994 to
      10.9 (SD, 3.0) in May through December 1994 and to 9.1 (SD, 2.8) in 1995 (P <
      .01). Length of stay also was reduced in the comparison hospital, but by 1995 was
      longer than in the intervention patients. No differences in LOS by gender, age,
      or marital status were found. Length of stay was significantly longer for those
      undergoing total hip replacement as compared to those undergoing total knee
      replacement in all the groups. CONCLUSIONS: Preadmission screening and case
      management by a social worker can contribute to the efforts to decrease LOS of
      orthopedic patients by early multidisciplinary evaluations, discharge planning,
      and coordination of services.

PMID- 10351589
TI  - Inappropriateness of cataract extraction: an analysis in two Israeli hospital
      settings.
AB  - OBJECTIVE: To assess and compare the appropriateness of cataract extraction in
      two Israeli regional hospitals. SETTINGS: Two Israeli hospitals located in
      different geographic areas. DESIGN: A randomized sample of 150 patients was drawn
      from a list of all patients who underwent cataract surgery at the two study
      hospitals during 1995. Detailed extraction of hospital medical records was
      performed. The appropriateness of cataract surgery was assessed using the Medical
      Review System, an interactive expert system that assesses the appropriateness of
      selected medical and surgical procedures. RESULTS: The rates of cataract surgery
      in the two hospitals were 0.54 and 0.59 operations per 1,000 population,
      respectively, and the age-adjusted rates per 1,000 population were 5.7 and 6.2,
      respectively. The percentage of patients with only light perception or hand
      motion perception in the operated eye before the operation was 62.2%, with no
      difference in the two hospitals. There was not a significant difference in the
      distribution of visual acuity before the operation; however, there was a
      significant difference in the distribution of visual acuity after the surgery.
      Rates of inappropriate surgeries in the two hospitals were found to be similar to
      the inappropriate rate in the United States (1.3%). The preoperative visual
      acuity of patients undergoing cataract surgery in Israel was inferior to the
      visual acuity of patients undergoing cataract surgery in the United States.
      CONCLUSION: To increase quality and cost-effectiveness in the Israeli medical
      system, future studies of this type are warranted in connection with surgical
      procedures.

PMID- 10351590
TI  - The challenges of automating a real-time clinical practice guideline.
AB  - OBJECTIVE: To elucidate the types of problems encountered during implementation
      of a World Wide Web-based clinical practice guideline to manage
      hyperbilirubinemia in newborn infants. DESIGN: Formative assessment of an
      automated clinical-practice guideline in a large-scale implementation. SETTING:
      Primary-care clinics and offices, inpatient clinics, and emergency department
      affiliated with an academic children's hospital. PARTICIPANTS: General
      pediatricians, neonatologists, pediatric nurses, and computer scientists.
      RESULTS: Existing guidelines for hyperbilirubinemia management could not be
      translated directly into web pages. Modifications of the original guidelines were
      required to represent the clinical intent of the guidelines accurately. In
      addition, the automated guideline was augmented to incorporate a mechanism for
      generating clinical encounter forms in order for the system to be accepted into
      the clinical work flow. Other clinical considerations that influenced the final
      form of the automated guideline included limitations of computer resources and
      time constraints during patient encounters. CONCLUSIONS: Many existing guidelines
      are not amenable to straightforward implementation in automated systems.
      Strategies to increase the efficacy of the automated guidelines included
      guideline modifications, as well as careful consideration of the flow of clinical
      work. Repeated cycles of development and pilot testing are needed to design
      methods to accommodate the constraints imposed by clinical use.

PMID- 10351591
TI  - An anecdote of distance learning.
AB  - The Information Technology column in last quarter's issue provided an overview of
      continuing professional education options. The experience of a Society for
      Healthcare Epidemiology of America member as a student in one of the previously
      described distance-education degree programs is related in this column. The
      Medical College of Wisconsin, Milwaukee, distance learning Masters of Public
      Health program provided a means for advancing this member's education that
      otherwise would not have been practical.

PMID- 10351592
TI  - Public disclosure of process and outcome measures.
AB  - There is a long history of resistance to public disclosure of data comparing the
      quality of doctors or hospitals. Examples of data ultimately disclosed are risk
      adjusted cardiac bypass surgery mortality data, cesarean section rates, doctor
      immunization practices, and state medical board rates of serious disciplinary
      actions. Recent studies on postoperative infection rates in Veterans' Affairs
      hospitals show large differences even after risk adjustment. It is inevitable
      that more comparative quality data involving both the process and outcome of
      medical care will be made public after proper adjustment for risks.

PMID- 10351593
TI  - Counterpoint: public disclosure of process and outcome measures.
AB  - Bad data is a toxic substance. In the release of process and outcome measures in
      the field of health care, numerous examples exist of published bad data. In 1986,
      the Healthcare Financing Administration released 14 volumes of data concerning
      Medicare mortality rates which, on analysis, were misleading and unrelated to
      quality of care. Good data on outcome measures need to follow accepted, rational,
      and scientific procedures. Such procedures include appropriate definitions of the
      process or outcome to be measured and careful description of the population being
      observed, risk adjusted for severity of illness. When this is done, the data can
      be published with some confidence that it will have value.

PMID- 10351594
TI  - Costs of providing primary care: comparison of an academic general medicine
      practice with an MGMA benchmark.
AB  - Market-based healthcare reform has placed great financial pressures on academic
      departments of internal medicine. The current emphasis and increased recruiting
      for primary care have not been accompanied by a financially supportive
      institutional culture or favorable third-party reimbursement system for the
      generalist practitioners. In one department's analysis, there was a large
      difference in revenue (-$130,000) compared to a Medical Group Management
      Association (MGMA) standard, yet a reduced level of compensation for primary-care
      physicians, $61,000 less per full-time equivalent (FTE). Total overhead per FTE
      in our department was $80,000 greater than comparable practices of the MGMA
      standard. We have estimated the institutional strategic costs of having primary
      care clinics in three separate locations in the city of Richmond ($74,000/FTE).
      No viable cost-cutting options placed the primary-care program in positive
      balance, but the analysis contributed to a creative institutional approach for a
      solution.

PMID- 10351596
TI  - Medicare fraud initiative makes strange bedfellows.

PMID- 10351595
TI  - Red blood cell transfusions for elective hip and knee arthroplasty: opportunity
      to improve quality of care and documentation.
AB  - OBJECTIVES: To assess current practice for red blood cell transfusion relative to
      the American College of Physicians guideline for red blood cell transfusion; to
      determine comparative rates and relative appropriateness of autologous versus
      allogeneic blood use; and, to assess cost implications of current transfusion
      practices. DESIGN: Computerized quality-of-care algorithm applied retrospectively
      to medical-record and blood-bank data. SETTING: Twenty-six hospitals in Colorado,
      Connecticut, Georgia, Oklahoma, and Virginia. PATIENTS: Medicare beneficiaries
      (2,137) who were hospitalized in 1993 for two elective surgical procedures: total
      hip arthroplasty and total knee arthroplasty. Of the 1,195 patients who received
      a preoperative or postoperative transfusion, 728 were excluded from the analysis
      because the hospital medical record did not contain the clinical documentation
      necessary to apply the American College of Physicians guideline to each unit
      transfused. The remaining 467 patients comprised the sample. RESULTS: For 467
      patients who underwent these two procedures and received a total of 651 units of
      preoperative or postoperative blood, there were 256 excess units transfused. Two
      hundred four of these units were autologous, and 52 were allogeneic. These excess
      units accounted for $48,200 of the total $121,000 direct cost of transfused
      units. CONCLUSIONS: These findings demonstrate that current medical records lack
      the documentation necessary to evaluate transfusion practice for the majority of
      Medicare beneficiaries undergoing elective hip and knee arthroplasty. The direct
      costs of preoperative and postoperative blood transfusion for these two
      procedures could be reduced by nearly 40% through adherence to the American
      College of Physicians guideline. The majority of this cost saving would be
      realized through reduction in unnecessary collection and use of autologous blood.

PMID- 10351597
TI  - Others await promise of Mississippi's experiment with pharmaceutical care.

PMID- 10351598
TI  - Compensation monitor. Primary care physicians worked harder and were rewarded, if
      not commensurately.

PMID- 10351599
TI  - HMO liability: how will it affect physicians? Come on in! The water fine!

PMID- 10351600
TI  - Special considerations apply when taking Medicare risk.

PMID- 10351601
TI  - Making a case for a single-payer system. Interview by Patrick Mullen.

PMID- 10351602
TI  - Physician, HEDIS (Health Employer Data and Information Set) thyself.

PMID- 10351604
TI  - Trust should be thrust of managed care system.

PMID- 10351603
TI  - Persuade the HMO that a contract change you propose is also in the plan's
      interest.

PMID- 10351605
TI  - Managed care outlook. Employer retention big motivator for HMOs' workers' comp
      activities.

PMID- 10351606
TI  - Development and implementation of guidelines for management of sedation and
      agitation in critically ill patients.
AB  - The article describes the development, implementation, and success of guidelines
      for pharmacological management of sedation and agitation in critically ill
      patients in a community hospital. Guidelines were developed with careful review
      of published literature and in cooperation with thought leaders in the
      institution. The primary focus of the guidelines was choice of medication and
      monitoring parameters and an educational campaign to ensure use of the
      guidelines. A prospective pharmacist intervention program was initiated for
      further enforcement of the guidelines. Implementation of these guidelines has
      resulted in a significant reduction in the cost of sedation and agitation (annual
      cost savings, > $40,000 per year).

PMID- 10351607
TI  - Cost-effectiveness analysis of oral ondansetron and prochlorperazine for
      preventing nausea and vomiting after moderately emetogenic chemotherapy.
AB  - The article reports a study comparing the cost-effectiveness of ondansetron
      tablets and prochlorperazine capsules in preventing nausea and vomiting after
      moderately emetogenic chemotherapy in an outpatient setting. A decision analysis
      model was constructed to compare the cost-effectiveness of the two antiemetics
      from the perspective of third party health care payers. Probability estimates of
      the model were derived from a reanalysis of data obtained from a clinical trial
      directly comparing the two antiemetics. Effectiveness was defined as the number
      of patients with no emetic episodes and no drug-related adverse events during the
      3-day period after receiving chemotherapy. Cost-estimates were based on Average
      Wholesale Price for medications and national average for hospital services
      adjusted to 1996 U.S. dollars. Cost-effectiveness ratios for ondansetron and
      prochlorperazine were $261 and $268 per effectively treated patient,
      respectively. A series of sensitivity analyses were performed to identify the
      limits of generalizability of study results. Despite the initial price
      differential between the two antiemetics, ondansetron was more cost effective
      than prochlorperazine when the duration of therapy was shorter than 3 days, the
      total cost of rescue therapy per patient was more than $71, the treatment cost of
      adverse events was less than $24, the complete relief rate for ondansetron was
      greater than 58.9 percent, and the complete relief rate for prochlorperazine was
      less than 26.5 percent.

PMID- 10351608
TI  - Pharmacists' practice opportunities in women's health.
AB  - The article discusses the rising interest in women's health issues, including
      demographics, economic issues, and the unique health concerns of the
      postmenopausal woman. Practice opportunities abound regarding hormone therapy;
      heart disease; diabetes; osteoporosis; and psychosocial, health and diet, and
      lifestyle issues for this age group. Barriers to effective communication between
      the pharmacist and the postmenopausal woman are examined, and suggestions are
      made to improve communication skills. Patient assessment and the development and
      implementation of care plans and continued patient monitoring are reviewed.
      Resources for women's health care are suggested for both the practitioner and the
      patient.

PMID- 10351609
TI  - Patient record documentation and confidentiality.

PMID- 10351610
TI  - Joint Commission survey questions and answers.

PMID- 10351611
TI  - How good can health care get? Health care service quality.

PMID- 10351612
TI  - Improving customer satisfaction: ten lessons from service masters.

PMID- 10351614
TI  - HCFA to allow imposition of CMPs (civil monetary penalties) up to $10,000 for
      single violations.

PMID- 10351613
TI  - Industry groups fault GAO reports for failing to address real problems with
      enforcement system.

PMID- 10351615
TI  - Subacute SNFs struggle to meet demands of Medicare PPS: uncertainty of ground
      rules, payment cuts pose biggest challenges. Part I: Managing uncertainty,
      reduced payments and patient admissions.

PMID- 10351616
TI  - Keeping it real. Even people with dementia need purposeful activities.

PMID- 10351617
TI  - Rehabilitating your rehab. A three-pronged approach to success under PPS.

PMID- 10351618
TI  - Don't be a slave to wages. To control labor costs, focus on direct-care staffing.

PMID- 10351619
TI  - Going postal. How to defuse employee violence.

PMID- 10351620
TI  - Chain survey. The CLTC 50-plus. Nursing chains hunkered down while assisted
      living forged ahead.

PMID- 10351621
TI  - Putting patient care first. An information systems strategy for PPS compliance.

PMID- 10351622
TI  - Medical directors revisited. New responsibilities under PPS require a new
      contract.

PMID- 10351623
TI  - Rebuilding strong bones. Treatment may help prevent millions of fractures.

PMID- 10351624
TI  - Better care for the dying. Interview by Yvonne Parsons.

PMID- 10351625
TI  - Medicare Commission fails to reach agreement.

PMID- 10351626
TI  - Hospital Medicare margins shrink under BBA.

PMID- 10351627
TI  - MedPAC's report to Congress raises concern. PPS system for rehabilitation
      hospitals and units.

PMID- 10351628
TI  - Premium support program isn't answer to Medicare's woes.

PMID- 10351629
TI  - Changing hospital culture, systems reduces drug errors.

PMID- 10351630
TI  - PPMC difficulties providing hospitals with new opportunities.

PMID- 10351631
TI  - PACS saves money, staff time, but alienates radiologists in N.Y. system.

PMID- 10351632
TI  - Reengineering implementation forces analysis of training, IT and staff issues.

PMID- 10351633
TI  - Consumer and purchaser use of the Internet sends profound message to providers,
      payers.

PMID- 10351634
TI  - An introduction to automatic smoke blinds.

PMID- 10351635
TI  - Understanding commissioning and handing over.

PMID- 10351636
TI  - Disability Discrimination Act: hospital managers--don't wait until 2004.

PMID- 10351638
TI  - NHS waiting list activity figures.

PMID- 10351637
TI  - Hospitals: computerising healthcare units.

PMID- 10351639
TI  - North American approach to smoke management.
AB  - The term smoke is used to mean the airborne products of combustion and air that
      is mixed with those products. A smoke control system is used to mean a system
      intended to manage smoke by pressurisation, and smoke management system is a
      broader term that includes systems that use any combination of compartmentation,
      dilution, air flow, pressurization or buoyancy. Smoke control systems include
      zoned smoke control, pressurized stairwells, and elevator smoke control. Over the
      past few decades there have been a number of full scale fire tests that
      demonstrate that pressure differences can prevent smoke migration from the low
      pressure side to the high pressure side of a barrier. While there are equations
      that can be used for smoke control design, network computer models can account
      for the effects of complex building leakage paths. For simplicity the term atrium
      was used in this paper in a generic sense to mean almost any large space (such as
      arcades, sports arenas, and exhibition halls). In North America most atria rely
      on sprinkler protection for spaces connected to the atrium and fan powered
      exhaust at or near the top of the atrium. Because the ability of sprinklers to
      suppress fires in spaces with ceilings higher than about 11m is limited, smoke
      exhaust is especially important for fires that start in the atrium. Equations and
      computer zone models can be used for the design of atrium exhaust systems. When
      these approaches are inappropriate, CFD modelling or physical modelling can be
      used.

PMID- 10351640
TI  - Drugs: budget busters or cost cutters in future health care?

PMID- 10351641
TI  - Best outcomes may be salvation for shriveling managed care cost savings.
AB  - The "easy" managed care cost savings that come from provider discounts are coming
      to an end, but an answer for managed care may be to find ways to cut costs and
      improve quality through best outcomes, writes Ed Egger.

PMID- 10351642
TI  - Redefining processes to create a more humane patient environment.
AB  - With all that is happening in health care, too many hospital administrators
      forget that the organization is not guaranteed long-term success just because
      illness will never become extinct. David Gordon, Ph.D., writes that hospitals
      must satisfy patients by improving processes that ensure the hospital's long-term
      viability.

PMID- 10351643
TI  - 'Trust' magic ingredient in physician pacts.

PMID- 10351644
TI  - Hospital-physician relationships: what's working, what's not working.
AB  - A new survey by McManis Associates shows that hospitals and health systems are
      moving toward shard hospital-doctor partnerships and away from physician
      employment arrangements and MSOs. McManis'Kate Berry writes about what's working
      and what's not.

PMID- 10351645
TI  - Small market hospitals urged to start HMOs.

PMID- 10351646
TI  - Education gaining integral role in managed care's disease management efforts.

PMID- 10351647
TI  - Succeeding beyond the Year 2000: how to rise to the challenges of the new
      millennium. Interview by Jill L. Sherer.
AB  - Are you ready to take your organization into the 21st century? Do you fully grasp
      the implications of current and emerging trends in the field? Healthcare
      Executive talked with six healthcare experts and asked them what they saw as the
      greatest challenge for both executives and their organizations in the new
      millennium. Although the experts' opinions vary, their responses emphasize the
      importance of repairing old relationships and building new partnerships between
      those working in healthcare organizations, as well as bringing a consumer focus
      back to healthcare delivery.

PMID- 10351648
TI  - Preparing for Y2K.

PMID- 10351649
TI  - Why join an affiliated group?

PMID- 10351650
TI  - Work vs. family.

PMID- 10351651
TI  - Finding a compatible corporate culture.

PMID- 10351652
TI  - The new Medicare outpatient PPS.

PMID- 10351653
TI  - Satisfying your dissatisfied customers.

PMID- 10351654
TI  - Buy-in for new technologies.

PMID- 10351655
TI  - Privacy and the Internet.

PMID- 10351656
TI  - Millennium management: new rules for 21st century healthcare organizations.

PMID- 10351657
TI  - Raising management standards in American healthcare.

PMID- 10351658
TI  - The myths of employee satisfaction.

PMID- 10351660
TI  - Adding value via the Internet.

PMID- 10351659
TI  - Advice from the experts. Experts address the professional concerns of healthcare
      executives.

PMID- 10351661
TI  - Building cohesive physician networks.

PMID- 10351662
TI  - Healthcare advocacy. Get to know your legislators.

PMID- 10351663
TI  - Abuse of power. Misuse of authority compromises your patients and employees.

PMID- 10351664
TI  - Ethics self-assessment. American College of Healthcare Executives.

PMID- 10351665
TI  - Interview with ACHE's new Chairman. Interview by Deborah A. Labb.

PMID- 10351666
TI  - Towards an integrated needs and outcome framework.
AB  - The British National Health Service alongside many other western countries is
      faced with competing pressures for limited health care resources which reflect,
      along with an increased accountability of both purchasers and providers of health
      care, the need for a clear function of explicit prioritisation from those who
      purchase health care. To enable limited health resources to be thus allocated,
      purchasers of health care must, therefore, be able to quantify not only the needs
      of their populations, but to predict and measure the outcomes from a health care
      intervention. This paper is concerned with the value framework underlying the
      twin dimension of needs and outcome assessment and seeks to address this
      framework from the sociological, philosophical and economic perspective and to
      determine the implications for the underlying distributive ethic.

PMID- 10351667
TI  - Profit, payment and pharmaceutical practices: perspectives from hospitals in
      Bangkok.
AB  - Means by which to improve the quality of care offered in the private sector have
      received increasing interest. This paper considers the influences upon hospital
      physician prescribing practices. It presents data on drug management practices
      and prescribing patterns in a sample of private for-profit, private non-profit
      and public hospitals in Bangkok. Clear differences emerge in prescription
      patterns between the different groups of hospitals: public hospitals exhibit
      greater use of essential drugs and generic prescribing than either group of
      private hospital, and prescriptions at private for-profit hospitals tended to
      have more essential drugs and drugs prescribed by generic name than non-profit
      hospitals. Prescribing patterns in public hospitals are probably largely
      explained by national government policy on pharmaceutical procurement. In
      contrast, prescribing patterns in private for-profit hospitals appear heavily
      influenced by pressure upon management to contain costs, in circumstances where
      high drug costs cannot be passed on to purchasers. Hence hospital management have
      developed policies encouraging the use of generic drugs and essential drugs.
      These same financial pressures also explain some less desirable forms of
      behaviour in private for-profit hospitals such as prescribing courses of
      antibiotic treatment of extremely short duration. Possible measures which
      government may take to encourage appropriate prescribing within private hospitals
      are discussed.

PMID- 10351668
TI  - Indonesian heath care and the economic crisis: is managed care the needed reform?
AB  - The ramifications of the current economic crisis are being felt throughout Asia,
      but problems are particularly acute in Indonesia; in the midst of high inflation
      and unemployment the government is considering expanding managed care reform. In
      this paper, we discuss the impact of the recent economic crisis on the health
      sector in Indonesia, and analyze the potential for implementing effective reform
      following the managed care model. The health sector is discussed, highlighting
      pre-existing problems in the health care supply environment. The determinants of
      the economic crisis are summarized, and the broad impacts of the crisis to date
      on the health sector are assessed. Next the prospects for success of current
      managed-care reform proposals are examined in some detail: viability of expanded
      managed care reform measures are assessed in light of the continuing crisis and
      its likely impacts on the consumers and suppliers of health care. Analysis of the
      potential impact of the continuing crisis focuses on key participants in health
      care reform: households, the government, and private health care providers. In
      conclusion the potential viability of managed care appears poor, given the
      current economic, political, and institutional conditions and likely future
      impacts, and suggest some alternative reform measures.

PMID- 10351669
TI  - Raising the quality of cost-utility analyses: lessons learnt and still to learn.
AB  - Heightened awareness by health care funders of the need to find more efficient
      ways of using scarce health care resources has led to greater demand for evidence
      of cost-effectiveness. Implicit in this demand is that evidence is generated
      using clear reporting and accepted methods. The research reported here updates an
      earlier review of published cost-utility analyses (CUAs) to address whether
      previously identified gaps in reporting have diminished over time. Raising CUA
      standards requires systematic and regular reviews of published material to allow
      adequate monitoring and evaluation. There is also a need to 'appraise the
      appraisers' in the sense of reviewing peer-review processes. This is particularly
      so in those journals which are growing in importance as outlets for economic
      evaluation information. The findings from this study indicate continuing
      variation in the quality of reporting. At the lower end of this spectrum
      improvements could be made in the reporting of comparators, in the clarity of
      effectiveness evidence, in the assignment of utility weights to health states and
      in reporting of sensitivity analysis. CUAs published in peer-reviewed specialist
      medical journals were more likely to be lower in quality suggesting guidance on
      the appraisal of economic submissions needs to be extended to the editors of
      these particular journals. These findings could be used to help to target
      attempts to raise the quality of evidence-based CUA information.

PMID- 10351670
TI  - The willingness of families caring for victims of stroke to pay for in-home
      respite care--results of a pilot study in Taiwan.
AB  - This contingent survey was designed to investigate the willingness of family
      caregivers of stroke victims to pay for in-home respite care. Between September
      1996 and December 1996, a designated family member from each family of 174
      vascular accident patients hospitalized in the Taipei Metropolitan Area,
      including two medical centers, received the first interview during preparation
      and planning for discharge of the patient from the hospital, and follow up
      interview in their own homes at the end of the second month after the patient was
      discharged from the hospital. A willingness to pay for in-home respite care was
      measured as the percentage of monthly family income which would be sacrificed to
      receive the respite care. Logistic regressions were used to perform multivariate
      analysis. The willingness to pay for respite care ranged from US$ 363 to 2182,
      and 42.5% of the family caregivers interviewed indicated a willingness to pay at
      least 50% of monthly family income for respite care. Family income was strongly
      associated with the amount of money that family caregivers were willing to pay
      for respite care. After results were adjusted for the effect of variance in
      income level, the degree of dependence of patients on the caregiver was
      significantly associated with the percentage of monthly family income for respite
      care. The more severe the physical dysfunction of patient, the higher the
      willingness to pay for in-home respite care utilization. Initially, respite care
      could be provided to families caring for patients with severe dysfunction, and
      then the scope enlarged to include caregivers taking care of patients with mild
      dysfunction.

PMID- 10351671
TI  - Does the UK National Health Service need a fourth hurdle for pharmaceutical
      reimbursement to encourage the more efficient prescribing of pharmaceuticals?
AB  - Reform of the existing mechanisms that influence pricing for pharmaceuticals in
      the UK NHS is overdue. Currently, the prescribing pricing policy favours the
      needs of industry over those of the NHS and of individual patients. In a recent
      consultation document, the UK Government indicated an emerging policy that will
      provide for the assessment of the effectiveness and cost effectiveness of
      important pharmaceuticals in the NHS. In developing and implementing this policy,
      much can be learnt from the situation in Australia, where pricing of drugs is
      related directly to an assessment of their value for money in specific patient
      groups. In fact, the differing circumstances between the UK and Australia suggest
      that the progress achieved by the Australians may be supplemented by further
      reform to encourage a more rational relationship between the NHS and the
      pharmaceutical industry. Australia has led the world in demonstrating that a
      modest form of assessment of 'value for money' may be incorporated practically in
      the process of licensing and reimbursing new drugs. It is important that this
      finding is built upon in the UK NHS for the benefit of patients and for society
      as a whole. It is not clear that the current proposals for reform from the UK
      Department of Health go far enough to achieve the required changes in drug
      licensing and regulation.

PMID- 10351672
TI  - Celebrating teamwork in health facility design and construction. 1998 ASHE
      Project Team Vista Awards.

PMID- 10351673
TI  - Star search. [Pointers on picking the best talent to headline your construction
      project].

PMID- 10351674
TI  - Razing the roof. Knowing when to rip it off or patch it up.

PMID- 10351675
TI  - All shook up. Seismic upgrades prevent hospitals from falling through the cracks.

PMID- 10351676
TI  - Wild bunch. Microbes. They're here to stay. But the CDC has tips on how to tame
      them.

PMID- 10351677
TI  - Health services reform and human resource management in Hong Kong public
      hospitals.
AB  - This article discusses the empirical study of reform in the human resource
      management function in the Hong Kong Hospital Authority. It describes the prior
      management of the hospitals based on the civil service administration model
      before looking at management reform in general. From this research, the creative
      tensions between the centrifugal and centripetal forces in the pursuit of
      'effectiveness', 'efficiency' and 'economy' are explored in terms of
      decentralization. A survey of line managers, in eleven Hospital Authority
      hospitals, revealed the progress of decentralization: a majority of respondents
      felt that, over the previous five years, managers at their level had been given
      greater responsibility for human resource management issues. In spite of the
      widespread perception of increased decentralization, however, it was recognized
      that there are limits to decentralization. It was the routine administration
      rather than the policy formulation and interpretation which had been
      decentralized, and hospitals continued to rely on the Hospital Authority Head of
      Office for guidance on policy interpretation. Several barriers to the effective
      decentralization of responsibility for human resource management were identified,
      including a lack of management skill, knowledge and time, the attitudes of some
      managers and the tight control of budget.

PMID- 10351678
TI  - Health care financing in Hong Kong: a case for tax-based financing.
AB  - With the new government of the Hong Kong Special Administrative Region currently
      conducting a review of Hong Kong's health care financing system, this article
      argues that the existing tax based system not only works well at present, but is
      also sustainable in the future. The performance of the system is analysed in
      terms of cost, health outcomes and access. The arguments for change are
      discussed, and the case for maintaining the status quo is presented. The author
      concludes that the way forward would be to fine tune the existing system rather
      than to replace it with other systems which are known to have higher transaction
      costs and more serious supply-side moral hazards.

PMID- 10351679
TI  - A description of outpatient drug use in rural China: evidence of differences due
      to insurance coverage.
AB  - This paper describes the effects of health financing systems (insurance) on
      outpatient drug use in rural China. 1320 outpatients were interviewed (exit
      interview) in the randomly selected county, township and village health care
      facilities in five counties in three provinces of central China. The interview
      was face to face. Questions were asked by a trained interviewer and were answered
      by patient him/herself. The main finding was that health insurance appeared to
      influence drug use in outpatient services. The average number of drugs per visit
      was 2.56 and drug expenditures per visit was 16.9 yuan. Between insured and
      uninsured (out-of-pocket) groups, there were significant differences in the
      number of drugs and drug expenditures per visit. The insured had a lower number
      of drugs and a higher drug expenditure per visit than the uninsured, implying the
      use of more expensive drugs per visit than the uninsured. There were also
      significant differences in the number of drugs and drug expenditures per visit
      between the types of insurance. One third of the drugs were anti-infectives, most
      of which were penicillin, gentamycin, and sulfonamides. The results imply that
      uninsured patients do not receive the same care as the insured do even if they
      have the same needs. The fee-for-service financing for hospitals and health
      insurance have changed health providers' and consumers' behaviour and resulted in
      the increase of medical expenditure.

PMID- 10351680
TI  - Economic analysis of outreach assessment clinics in breast screening programmes.
AB  - A model is developed for the economic evaluation of outreach assessment clinics
      following screening and used to identify the cost-minimizing strategy for
      assessing women from three island communities in the Scottish Breast Screening
      Programme (SBSP). There are four options of interest depending on: whether the
      women are assessed on the mainland or at outreach assessment clinics; and whether
      all women have two view screening rather than only those being screened for the
      first time. The benefits of outreach assessment are assumed to be solely in terms
      of convenience to women and reductions in the time and travel costs of women
      recalled for assessment. The costs are modelled in order to compare outreach and
      no outreach options. The results show that for the numbers of women currently
      screened outreach assessment is the cost-minimizing strategy. The model provides
      useful guidance with respect to screening policy and is readily applied to the
      case of outreach assessment in mainland communities outwith major population
      centres and to breast and other screening programmes in other countries.

PMID- 10351681
TI  - Children's health insurance programs: beware of hidden risks.

PMID- 10351682
TI  - Provider resource planning. A study of methods in multispecialty groups and
      systems.
AB  - This article profiles the state of the art in provider resource planning based on
      a sample of large multispeciality group practices. Senior administrative
      representatives from a geographically dispersed sample of 12 practices, each
      employing over 100 physicians, participated in telephone interviews to discuss
      their respective organization's provider resource planning practices. There was
      significant variation with regard to the structural and process components and
      evaluation criteria used to plan provider resources. Variability was most
      pronounced by the lack of consensus and experience within and across
      organizations regarding the number and type of criteria deemed useful in
      evaluating new position requests. This research suggests that there is an
      opportunity to develop more objective provider resource planning methods that
      recognize differences across organizations and their respective markets. The
      authors recommend a series of research steps to develop methods that would
      identify needs prospectively, minimize the complexities of provider resource
      planning and maximize the alignment of strategic plans and operations.

PMID- 10351683
TI  - Capital and medical groups. Key issues facing physicians and practice
      administrators.
AB  - More and more physician groups are considering taking a capital partner, whether
      a physician practice management company, a hospital or other organization. But
      physicians have questions about how partnership will affect their salary in the
      short and long run, whether it will affect practice overhead, quality of care and
      physician control. They also want to know what to do if the relationship doesn't
      work out. This article answers those questions and recommends that groups do a
      careful self-evaluation and scrutinize any potential partners before making a
      move.

PMID- 10351684
TI  - Selecting an MSO. How to assess options and compatibility.
AB  - Despite significant changes within the physician practice management and
      management services industry, physicians across the country are continuing to
      choose to affiliate with management services organizations (MSO). Now, more than
      ever, it is crucial that physicians first assess their own unique situation,
      conduct thorough due diligence of the potential partner and educate themselves on
      the important terms of any potential deal. As a part of the assessment,
      physicians must evaluate whether a potential partner's goals are aligned with
      their own, needed services will be provided at a fair price and the personnel
      have appropriate expertise and experience. This assessment will enable physicians
      to effectively determine their options and ensure an informed and strategic
      decision.

PMID- 10351685
TI  - Leaders balance vision and practical solutions.

PMID- 10351686
TI  - Resume database. Essential professional tool.
AB  - Job applicants tend to send mass mailings of the same resume to potential
      employers. It is more effective to send customized resumes drawn from a resume
      database, a detailed, descriptive list of past successes in professional and
      personal life. This article offers a step-by-step guide to creating a resume
      based on results that gets results.

PMID- 10351687
TI  - Networking, trust, friendships and adding value make MGMA. An interview with new
      MGMA chair Bob Wright. Interview by Pamela L. Moore and Dennis L. Barnhardt.

PMID- 10351688
TI  - Is it worth it?

PMID- 10351689
TI  - Why Medicare's risk-adjusted payments won't be widely acclaimed.

PMID- 10351690
TI  - Assessing primary care's contribution to academic health centers.
AB  - Operating losses are being suffered by academic and private health centers
      operating primary care practices. The MGMA Cost Survey: 1998 Report Based on 1997
      Data reports hospital-owned primary care practices receive an average of $80,819
      in financial support for operating costs per full-time equivalent physician.
      However, little research has been conducted on the factors contributing to the
      primary care deficit. Moreover, few studies exist regarding the quantification of
      the benefit of primary care. This presentation seeks to demonstrate (a) the
      factors contributing to the deficit of a primary care practice and (b) the
      quantification of primary care referrals to an academic health center.

PMID- 10351691
TI  - Lessons for outsourcing and interim management relationships.
AB  - Few decisions can affect an organization more than the selection of an
      outsourcing or interim management partner. More and more health care
      organizations face such decisions in today's competitive market in order to face
      new business needs. Making these relationships successful can be important for
      health care organizations seeking competitive advantages or seeking immediately
      accessible management support. These relationships, however, require careful
      partner selection and development. Success in outsourcing and interim management
      relationships is contingent upon a thorough selection process, a strong contract
      that has clearly and explicitly detailed responsibilities and a culture-sensitive
      business rapport between the client and selected partner.

PMID- 10351692
TI  - Using the "legacy factor" for organizational success.

PMID- 10351693
TI  - It takes more than money. Keys to success in leading and managing physician
      groups.
AB  - Hospitals, health systems and physician practice management companies (PPMCs)
      that have acquired physician practices are losing millions of dollars a year on
      those practices. They wonder. "We're paying those physicians a lot of money. They
      should be highly motivated employees. Why aren't they?" Managing physicians with
      compensation is not enough. To manage physician groups well, all the interests
      and values of physicians must be addressed. Managing a physician group requires a
      management style that actively involves individual physicians. This article
      presents our insights into structuring the leadership and management of physician
      groups.

PMID- 10351694
TI  - Zeroing in on expense management: effective tools to manage costs.
AB  - In the face of declining reimbursement, practices are under increasing pressure
      to control costs. This article reviews various methodologies to analyze expenses
      and identifies strategies to improve financial performance.

PMID- 10351695
TI  - Surgery center joint ventures.
AB  - Surgery centers have been accepted as a cost effective, patient friendly vehicle
      for delivery of quality ambulatory care. Hospitals and physician groups also have
      made them the vehicles for coming together. Surgery centers allow hospitals and
      physicians to align incentives and share benefits. It is one of the few types of
      health care businesses physicians can own without anti-fraud and abuse violation.
      As a result, many surgery center ventures are now jointly owned by hospitals and
      physician groups. This article outlines common structures that have been used
      successfully to allow both to own and govern surgery centers.

PMID- 10351696
TI  - Defining core knowledge, helping teams ACMPE goals. An interview with new ACMPE
      president Sherry Gentry. Interview by Pamela L. Moore and Dennis L. Barnhardt.
AB  - Sherry Gentry, M.B.A., FACMPE, the new president of the American College of
      Medical Practice Executives (ACMPE), took time to share her vision of ACMPE and
      the state of group practice with MGM Journal editor Pamela L. Moore, Ph.D., and
      MGMA Communications Director Dennis L. Barnhardt, APR. Physician-administrator
      teams need to be at the heart of health care, she said.

PMID- 10351697
TI  - Why employees resist change in medical group practice acquisitions.
AB  - Understanding employees' values and considerations is important in undergoing
      major organizational change. This research provides an insight of the business
      and financial aspects vs. the human relations aspects of acquiring a medical
      group practice. The five employees interviewed in this analysis provide insight
      as to the factors that employees consider in resisting change. Considering how
      employees feel through communicating will have a significant impact on
      efficiency, effectiveness and turnover.

PMID- 10351699
TI  - How to develop a cost management systems.

PMID- 10351698
TI  - The new medical organization.

PMID- 10351700
TI  - Medical relief team heads for Balkans.

PMID- 10351701
TI  - How far they have fallen. Once sought after, rehabilitation therapists hit by
      changes in Medicare reimbursement.

PMID- 10351702
TI  - Kan. referral arrangement verdict: guilty. Decision may prompt hospital execs to
      review contractual relationships, set up legal safeguards.
AB  - The conviction in Kansas City, Kan., last week of two hospital executives and two
      physicians for engaging in a kickbacks-for-referrals scheme has rocked the
      healthcare industry. The shock waves will almost certainly affect future
      arrangements between doctors and hospitals.

PMID- 10351703
TI  - Hospitals settle 'dumping' charges.

PMID- 10351704
TI  - Providers say they're due Medicare rebate.

PMID- 10351705
TI  - Home health, Medicare patients hurting.

PMID- 10351706
TI  - The third way. Palliative care gives providers a chance to treat chronic
      conditions better while lowering costs.

PMID- 10351707
TI  - Study: capitated risk not always understood.

PMID- 10351708
TI  - Downgrades don't hinder bond deals.

PMID- 10351709
TI  - IRS releases regs for tax form access.

PMID- 10351711
TI  - Complementary and alternative medicine. Integrative medicine: business risks and
      opportunities.
AB  - Much of the buzz over integrative medicine is well deserved. The opportunities
      seem to outweigh the risks, but superior management skills are needed to guide
      these programs through adolescence into clinical and business maturity. By
      carefully considering the staffing, team building, compensation methods,
      marketing, and program evaluation and development issues explored in this
      article, health care and physician executives should be able to steer between the
      rocks on their way to integrative medicine decisions that are right for their
      organizations. Many claim that integrative medicine has the potential to reshape
      health care delivery in a more patient-centered direction. While this may be
      true, such programs must prove themselves from financial and clinical operational
      perspectives in order to achieve this potential. Luminary clinical skills are not
      enough to guarantee the survival of such programs--a strong clinical base of
      expertise in alternative therapies is a key success factor. As with any health
      care venture, there are no substitutes for clinical excellence or sound
      management.

PMID- 10351710
TI  - Complementary and alternative medicine. The daunting challenge.
AB  - There is no question that the past few years have seen a tremendous surge in
      interest in what has come to be known as complementary and alternative medicine
      (CAM). Health plans contemplating adding CAM benefits face a daunting challenge.
      How should a plan define CAM benefits? How should a plan define appropriate CAM
      providers? How can these benefits be managed? Will the addition of CAM benefits
      undermine coverage policies for conventional biomedicine? The answer to these
      questions lies largely in uncharted waters, as even CAM advocates will agree that
      many alternative therapies (even those like Oriental medicine which has been in
      practice for some 5,000 years) have not yet undergone the type of rigorous,
      evidence-based analysis that is required to validate conventional biomedicine.
      This article explores options for CAM benefit design by considering two basic
      approaches-creating an uninsured benefit or insured benefit.

PMID- 10351712
TI  - Managing organ transplant issues. A guide for approaching controversial, high
      tech procedures.
AB  - With the increase in the requests for high intensity medical procedures such as
      organ transplantation, the physician executive often is placed in the middle
      between competing interests. Whether he or she represents the provider or payer
      side, there is frequently great pressure to make decisions involving complex
      medical situations in short time-frames. It is necessary to have in place a fair,
      consistent approach to handling such issues in order to withstand both medical
      and ethical scrutiny. A process is detailed that will lead the organization to
      developing such an approach. Although presented in the context of transplant
      issues, this process can be applied to any similar high technology procedure.

PMID- 10351713
TI  - Resource allocation. The cost of care: two troublesome cases in health care
      ethics.
AB  - With the cost of health care rising rapidly, both physicians and administrators
      regularly face resource allocation decisions. Under these conditions of relative
      scarcity, the equitable and appropriate distribution of limited resources becomes
      an ethical as well as a financial issue. Through ethical analysis, physician
      executives can assist their physician colleagues and fellow administrators to
      find rationally defensible answers to questions regarding the distribution of
      limited resources. Six criteria are frequently "weighted in the balance" by
      ethicists when analyzing whether justice is served in the distribution of a
      limited resource: need, equality, contribution, ability to pay, effort, and
      merit. The authors argue that, from an ethical standpoint, the best single
      criterion upon which one can base an allocation decision is that of merit,
      defined as the potential to benefit from the investment of additional resources.

PMID- 10351714
TI  - Making the health care delivery system accountable.
AB  - Accountability has become the fact of life for the health care provider and the
      delivery system. Until recently, accountability has been viewed primarily through
      the judicial process as issues of fraud and liability, or by managed care
      entities through evaluation of the financial bottom line. It is this second
      consideration and its ramifications that will be explored in this article.
      Appropriate measurement tools are needed to evaluate services, delivery,
      performance, customer satisfaction, and outcomes assessment. Measurement tools
      will be considered in light of the industry's unique considerations and
      realities. All participants, including insurers, employers, management, and
      health care providers and recipients, bear responsibilities which necessitate
      assessment and analysis. However, until the basic question, "Who is the
      customer?" is resolved, accountability issues remain complex and obscured.
      Accountability costs and impacts must be evaluated over time. They go way beyond
      bottom line cost containment and reduction. Accountability will be accomplished
      when the health care industry implements quality and measurement concepts that
      yield the highest levels of validity and appropriateness for health care
      delivery.

PMID- 10351715
TI  - Attracting qualified physicians to underserved areas. Part 1: Why has the U.S.
      experienced such difficulty?
AB  - With health networks searching for additional market share and with a projected
      30.2 million to be enrolled in Medicaid HMOs by 2000, more health executives will
      be weighing various strategies of how to attract qualified physicians to practice
      in poor inner-city and rural areas. Most frequently cited as solutions are:
      supplying more physicians, encouraging more medical school graduates to pursue
      primary care residencies, and modifying the number of international medical
      graduates entering U.S. residency programs. Part 1 of this article reviews the
      efficacy of these approaches, while the second part, which will appear in the
      January/February 1999 issue, explores a more pragmatic option: to simply improve
      the working conditions and just pay substantially more to physicians who practice
      in "less desirable" locations.

PMID- 10351716
TI  - Veteran's health care: time for a change?
AB  - The Department of Veterans Affairs' mission is "to care for him who are shall
      have borne the battle for his widow and orphan." The Veterans Health
      Administration comprises 172 hospitals that are the hub of the health care
      delivery system. It is the largest provider of graduate medical education, and
      one of the major research organizations in the United States. The medical care
      budget exceeds $17 billion annually. Most of the persons cared for are not
      legally entitled to this health care based on service connected disability. The
      utilization of acute care hospital beds appears excessive when compared to that
      obtainable with managed care for Medicare or commercial insurance beneficiaries-
      the cost per member per month is three times higher. There may also be
      exploitation of the Veterans Administration hospitals by university medical
      schools. The Veterans Health Administration is a very expensive way to deliver
      care to entitled service connected veterans. Therefore, it is suggested that
      privatization be considered as an alternative vehicle for delivering health care.

PMID- 10351718
TI  - How to cope with behavioral interviewing questions.
AB  - What should a potential employee do when asked behavioral or highly intrusive
      questions during the interview? Here are some suggestions to help you be prepared
      should the interviewer ask you personal or objectionable questions: (1) Take some
      time for introspection; (2) be prepared to draw the line; (3) complain; and (4)
      write it off. And remember: A show of determination and setting boundaries in an
      interview may advance your progress. Coolness under fire is an attractive
      personality trait.

PMID- 10351717
TI  - The 13 errors.
AB  - The reality is that most change efforts fail. McKinsey & Company carried out a
      fascinating research project on change to "crack the code" on creating and
      managing change in large organizations. One of the questions they asked--and
      answered--is why most organizations fail in their efforts to manage change. They
      found that 80 percent of these failures could be traced to 13 common errors. They
      are: (1) No winning strategy; (2) failure to make a compelling and urgent case
      for change; (3) failure to distinguish between decision-driven and behavior
      dependent change; (4) over-reliance on structure and systems to change behavior;
      (5) lack of skills and resources; (6) failure to experiment; (7) leaders'
      inability or unwillingness to confront how they and their roles must change; (8)
      failure to mobilize and engage pivotal groups; (9) failure to understand and
      shape the informal organization; (10) inability to integrate and align all the
      initiatives; (11) no performance focus; (12) excessively open-ended process; and
      (13) failure to make the whole process transparent and meaningful to individuals.

PMID- 10351719
TI  - Performance evaluations of physician executives. Interview by Barbara J. Linney.
AB  - Six senior physician executives were interviewed to see how they were doing or
      not doing performance reviews in their organizations. There seems to be a trend
      toward doing them, but it is in the beginning stages. Of the physician executives
      surveyed, the experience ranges from formal lengthy evaluations with rating
      scales to reviewing a short list of goals. Several are in the process of
      developing new systems or revising old ones. Probably the most useful part of a
      performance evaluation is the conversation between the physician executive and
      the person he or she reports to. If you can stop approaching performance
      evaluations as passing negative judgments on people, but as having a conversation
      to hear their concerns, learn what their goals are, and offer ways to help them
      achieve their potential, they can be useful, enjoyable experiences for both
      people.

PMID- 10351720
TI  - Complementary and alternative medicine. Considering the alternatives.
AB  - Therapies variously described as alternative, complementary, or unconventional
      because they lie outside the realm of scientific medicine practiced by graduates
      of orthodox U.S. medical schools are gaining mainstream respectability despite
      many questions about their efficacy and safety. Depending on definitions, surveys
      indicate that fewer than 10 percent to nearly 40 percent of Americans supplement
      or substitute for conventional health care with alternative systems of medical
      practice. Spending for complementary and alternative medicine (CAM) nationwide
      has been estimated at up to $14 billion a year. Establishment of an Office of
      Alternative Medicine in the National Institutes of Health in 1992 has heartened
      advocates of CAM, increased interest and government funding for research into
      unorthodox therapies, and lent credibility to CAM modalities. Embracing marginal
      therapies may represent an opportunity for physicians and health systems to
      reduce inappropriate consumption, offer a wider range of choices to patients, and
      profit from a lucrative market.

PMID- 10351721
TI  - Becoming who you are.
AB  - It's difficult to predict success based only on educational background and career
      experience, important as they are. More is needed. And one of the aspects that
      needs to be evaluated is the degree of self-actualization. Self-actualized
      individuals have worked out their personal issues well enough that their personal
      life no longer has to intrude into their professional lives and actions. In a
      word, they are free people. In career terms, self-actualized people are "company
      people," but not "yes-people." They are executives who have freed themselves to
      be able to internalize the growth, development, and strategic planning of their
      organization--because they are able to rise above personal considerations, to
      shed emotionalism, and see more clearly. Some methods you can use to figure out
      where you stack up are: Conduct a self-evaluation; identify role models; do what
      is called "a 360 evaluation."

PMID- 10351722
TI  - Nursing home care: ensuring quality.
AB  - There are more than 17,000 nursing homes in the United States providing care for
      1.7 million disabled and elderly individuals. Medicare and Medicaid paid $28
      billion in 1997 for nursing home services, more than one half of all nursing home
      expenditures. Improvements in the quality of care in these facilities and
      ensuring value for public expenditures has been a long sought after goal. Recent
      actions by the federal government are designed to strengthen state and federal
      authority and processes to accomplish this goal. Physician leadership in this
      area is essential to its success.

PMID- 10351723
TI  - The physician executive in a changing world.
AB  - Physicians are losing their historic franchise as sole and primary providers of
      medical care. In addition to eroding moral and scientific authority, physicians
      are also losing income and status. It is no wonder that physicians are
      retrenching--confused and angry about the increasing marginalization of their
      profession and about society's changing expectations. Physicians are caught in a
      transition zone between the world that was and the one that will soon be. This is
      destabilizing and causes great anxiety. Rather than being buffeted by changing
      social and cultural definitions of health care, physicians must become
      proactively involved in the future of their profession. Physicians can only do
      this by offering a better mental model of health, medicine, and the community.
      This cannot be a defensive retreat from engagement. Rather, it must be an
      imaginative vision, vigorously set forth--a vision that will enlist the support
      of all constituencies involved in the effort to improve the health and well-being
      of all members of our society. The physician executive needs to work with
      physicians to orchestrate this effort to create a new vision of health in the
      21st century.

PMID- 10351724
TI  - A dance in anger: physician responses to changes in practice.
AB  - Although "managed care" means different things to different people, it has become
      an icon for health care change and is commonly cited as the principle cause for
      the physician's lament. Successful leaders are finding ways to address the signs,
      symptoms, and causes of the physician grief reaction to the tumultuous
      marketplace changes affecting how they view themselves as professionals and how
      they practice medicine. Health care CEOs continue to place the search for
      solutions, physician-hospital integration, and the alignment of system and
      physician incentives as their number one strategic priority. This article reviews
      common sources of anger and identifies potential solutions. Strategies for
      dealing with the anger include: (1) recognizing the issues, causes, signs, and
      symptoms; (2) restoring balance and power; (3) developing new economic
      partnerships; (4) managing the organizational culture; and (5) educating one
      another and developing leadership.

PMID- 10351725
TI  - Executive coaching an Rx for MDs.

PMID- 10351727
TI  - Physician career management: organizational strategies for the 21st century.
AB  - Burnout is a state of physical, emotional, and mental exhaustion caused by long
      term involvement in situations that are emotionally demanding. It is not stress,
      per se, that causes burnout, as many thrive in stressful, demanding careers.
      Rather, burnout results when stress continuously outweighs the sense of
      effectiveness, accomplishment, and reward. And, this fate is sealed when one
      feels helpless to effect significant change in the conditions that fuel the
      stress. Establishing an organizational environment that reduces the risk of
      physician burnout requires a new commitment of resources, one that can be
      challenging to justify to decision-makers with a strictly short-term, bottom line
      orientation. The key issues to consider in shaping a physician career management
      program include: (1) entry of new physician employees into the organization; (2)
      productivity measures; (3) responsiveness to safety concerns; (4) administrative
      and policy issues; and (5) variety and growth opportunities.

PMID- 10351726
TI  - Physician anger: Leggo dem managed care blues--leadership beyond the era of
      managed cost.
AB  - While managed care has caused great disruption, it has also provided physician
      executives with a natural leadership raison d'etre. Managed care, with all its
      pros and cons, is largely a response to certain unrelenting trends. The core
      functions of leaders comprise the stewardship of organizations and colleagues in
      response to these trends. Four trends are explored: (1) The demise of open-ended
      funding of American health care; (2) continued competition for health care
      resources; (3) thriving pluralism; and (4) patients continually adjusting to
      assure themselves of appropriate health care access, quality, and service. In the
      21st century, the industry will need a new brand of leader, one capable of
      balancing the needs of the professionals with the business and accountability
      requirements of a permanently competitive and resource-constrained service
      industry. The keys to successful leadership in the future include: (1) Clear
      service differentiation and a compelling vision to match it; (2) recruiting and
      retaining top clinical talent, including the required return to physician self
      direction and governance; (3) successful partnerships with others outside your
      organization; and (4) a steady focus on performance in all its dimensions.

PMID- 10351728
TI  - The value circle. A profile of J. Richard Gaintner, MD.
AB  - This article describes how the arrival of CEO J. Richard Gaintner, MD, at Shands
      HealthCare signaled a time for refocusing the organization's direction and
      helping physicians to cope with the changes buffeting the industry. He saw angst
      and disenfranchisement, sentiments that characterized not only Shands and the
      University of Florida Health Science Center, but also the entire establishment of
      American scientific medicine. Gaintner believes--and continually preaches--that
      practicing medicine in a cost-effective manner will improve, not harm, the
      quality of care. His willingness to face reality objectively is perhaps his
      greatest asset in helping physicians deal with managed care. He conveys heartfelt
      empathy with the day-to-day conflicts they face. But he does not allow himself
      the temporary luxury of cynicism, and he refuses to accept negativity and
      pessimism in others. Rather, he asks that physicians and managers understand the
      system and develop the capacity to work within it and take responsibility for
      improving it. Beyond exhorting physicians to be accountable for the success of
      the enterprise, Gaintner creates mechanisms for meaningful physician
      participation in enterprise management.

PMID- 10351729
TI  - We can be heroes.
AB  - Physician executives are engaged in a search for ways to maintain balance,
      enthusiasm, and gratification in today's health care delivery environment. The
      primary resource for effecting positive change is themselves. This article
      addresses both pragmatic and philosophical initiatives that could assist them in
      their search. It postulates the premise that physician executives help
      themselves, their patients, and the state of health care service when they help
      each other.

PMID- 10351730
TI  - Physician anger--Part 1. Changing perception: an interview with Charles E. Dwyer,
      PhD. Interview by Richard L. Reece.
AB  - On January 21, Richard Reece, MD, interviewed Charles E. Dwyer, PhD, to talk
      about solutions for changing the perceptions of today's beleaguered physicians.
      He discusses the state of affairs of physician executives in this turbulent
      industry and how they need to move beyond their thinking about organizations and
      their current responses to change. The key, Dwyer emphasizes, is influencing
      people to do what you want them to do. "If you want somebody to do something
      other than what they are doing now, then you must bring them to perceive that
      what you want them to do is better than what they are doing now in terms of what
      is important to them." He also explores how physicians can change their responses
      to the health care environment: "You can actually decide how you are going to
      respond conceptually, emotionally, and behaviorally to anything that happens in
      your life." Part 2 of this interview will appear in the upcoming May/June issue
      and will provide hands-on strategies for dealing with physician anger, fear, and
      resentment.

PMID- 10351731
TI  - The disruptive physician. A quality of professional life factor.
AB  - Medical leaders need to understand that attending to quality of professional life
      issues includes dealing with the insidious costs and stress associated with
      disruptive physician behavior. The disruptive physician or professional
      undermines practice morale, heightens turnover in the organization, steals from
      productive activities, increases the risks for ineffective or substandard
      practice, and causes distress among colleagues. Physician executives need to help
      reduce or prevent this behavior and develop accepted systems in which to manage,
      confront, and rehabilitate the person labeled "disruptive." Suggested strategies
      to consider in developing a system include: (1) Defining reasonable and competent
      interpersonal behavior; (2) educating in interpersonal skills; (3) evaluating
      interpersonal skills; (4) developing disruptive policy; and (5) assessing,
      confronting, and rehabilitating.

PMID- 10351732
TI  - Just row.
AB  - To learn anything outside of our usual experience is to try on a new way of
      being. Doing something new--dealing with change--calls for a commitment to be
      where you are, to be present in the experiment, even while you are uncertain
      about the outcome. Being present and committed to the moment is as essential in
      management or self-management as it is in rowing a boat. How, for instance, can
      you tell the difference between intuition and fear? In the midst of a crisis, a
      change, a white water passage, a "learning opportunity," what if you get this gut
      feeling that something is wrong? If the feeling goes away when you drop into the
      present, into your body, and "just row," it's not an intuition, it's fear. The
      opportunity is to know the difference between opinion and intuition, between
      judgments and experience. Because judgments and opinions carry extraordinarily
      high price tags.

PMID- 10351733
TI  - The art and science of starting a new job.
AB  - To be successful in a new job out-of-town, physician executives need to develop a
      plan for a smooth transition into the organization. A checklist to prepare
      yourself for the new position should include: Updating your research; (2) staying
      in close contact with your new boss; (3) visiting the office; (4) hiring your own
      support person; (5) planning the first week; (6) telling the troops how to manage
      you; (7) making early decisions; and (8) meeting your peers. The focus should be
      on the job and connecting with your new boss, medical staff, and coworkers--and
      not exclusively on the environment of your home-to-be.

PMID- 10351734
TI  - How to be viewed as a sage in your elder years.
AB  - Journal Writing, meditation, and telling our stories by reviewing our lives and
      harvesting the wisdom we've gained are productive activities for the present. The
      practice of journal writing is an integral part of accepting the aging process
      and making the elder years enjoyable and fulfilling. Meditation provides a way to
      center yourself and is particularly helpful during stressful times. It increases
      your chances of not worrying and improves your ability to concentrate. Another
      task of successful age-ing that is fueled by journal writing and meditation is
      life review and passing on your knowledge to others. These disciplines are
      explored as tools for inner growth and instruction is provided to help get you
      started.

PMID- 10351735
TI  - Be positive--it's a necessary strategy.
AB  - The hallmarks of successful health care organizations include: A positive
      physician culture; meaningful physician involvement in governance and top
      management; and stability and strong community roots. Success is most likely
      where physicians in the facilities are having professional fun, where freedom
      from negativity allows them to perform at their highest level of quality. When a
      positive physician culture takes hold, remarkable things can occur. In the best
      scenarios, physicians are deeply involved in strategic direction, as well as in
      practice. They are part of making the decisions, instead of merely grumbling
      about decisions made by others. The column provides suggestions for creating a
      positive physician culture.

PMID- 10351736
TI  - Medically necessary?
AB  - Coverage decisions can ultimately be traced back to three words in the original
      health policy contract: medically necessary and investigational. Investigational
      as a coverage exclusion applies to the minority of cases, in which there is
      inadequate data to validate the effectiveness of the intervention. In contrast,
      the majority of coverage decisions are based on medical necessity. Over the years
      the concept of medical necessity has evolved to encompass a multitude of medical
      management strategies. This discussion highlights the variable uses of the
      concept of medical necessity in terms of: (1) Determining the most appropriate
      intensity of service and place of service; (2) determining whether the proposed
      therapy is medically appropriate for the patient's condition; (3) distinguishing
      between medically necessary services and those that are performance enhancing or
      discretionary in nature; (4) making a distinction between medically necessary,
      cosmetic, and reconstructive services; and (5) defining medical necessity in
      accordance with generally accepted principles of good medical practice.

PMID- 10351737
TI  - Managed care liability.
AB  - Debate is heating up concerning proposals that patients have the right to sue
      their managed care plans for damages from wrongful denial of benefits or delays
      in care. Some states have recently passed legislation to address this issue and
      it is expected to be an area of intense legislative debate during this year. As
      managed care entities increasingly enter the realm of medical decision-making,
      the additional burden of this responsibility is taking shape. Whether managed
      care plans should be treated like providers of care and be held accountable for
      decisions that impact patient outcomes, or be viewed only as insurers is a policy
      question of immense proportion.

PMID- 10351738
TI  - Distributed imaging links physicians with imaging services.

PMID- 10351739
TI  - Installing PACS--lessons learned.
AB  - In 1997, Carson-Tahoe Hospital in Carson City, Nev., looked into the possibility
      of installing its own PACS system. Increased productivity was the main business
      goal the hospital hoped a PACS system would meet. Only two of three chosen
      vendors seriously considered the request to bid because of the small number of
      films produced by the hospital. After installation, the hospital identified the
      referring physicians who used the most film and then directed its marketing
      efforts to them. Lessons learned include the tremendous need for training of
      staff, referring physicians and radiologists. Expect everyone to be slow the
      first week the new system is running. Map out all processes to prepare for
      contingencies. Make plans for archiving and be flexible in assigning tasks--next
      week things may change. Consider bringing in an outside consultant to measure
      people's expectations and fears. After nearly a year, neither the technologists
      nor physicians express any regrets about the installation of PACS at Carson
      Tahoe.

PMID- 10351740
TI  - Children's hospitals and PACS: six profiles of planning and implementation.
AB  - Six pediatric hospitals were interviewed at length about the status of PACS in
      their facilities. Children's Hospital Medical Center in Cincinnati, Ohio entered
      electronic imaging communications in 1993. Several nearby clinics were connected
      through teleradiology and by 1998, the radiology department had developed a
      business plan for the implementation of PACS. Two hospitals in Atlanta, Egleston
      Hospital and Scottish Rite Children's. Medical Center, merged in 1998 to become
      one entity with two medical campuses. They now treat 60 percent of Atlanta's
      pediatric patients. Merging incompatible systems has been the administrator's
      most immediate problem. One director of imaging services is responsible for the
      recently merged Mary Bridge Children's Hospital and Tacoma General Hospital, plus
      a network of clinics and medical facilities scatted throughout Tacoma and the
      South Puget Sound area in Washington state. A state-of-the-art mini-PACS and
      teleradiology system were implemented at Primary Children's Medical Center, Salt
      Lake City, in 1991. Over the years, it has added modalities into an electronic
      system that now results in significantly improved use of physicians' time and
      patient relations. St. Louis Children's Hospital, with both a director of
      radiology and a PACS administrator, has implemented teleradiology and an
      ultrasound mini-PACS, and has plans for an enterprise-wide PACS. Children's
      Hospital in Birmingham, Ala., a major trauma center, provides specialized
      pediatric care to nearly all 67 counties in Alabama. With a 20-year history of
      online computerization, it is now reengineering its emergency department and will
      implement CR there first.

PMID- 10351741
TI  - Process reengineering for the filmless environment.
AB  - Facilities that are converting to filmless operations can learn from the
      University of Kentucky Chandler Medical Center's (UKMC) experience: that dramatic
      reengineering processes must take place before radiologists' productivity can
      increase. To convert a radiology department to soft copy interpretation, a piece
      by-piece implementation of new systems or upgrades is customary. The first step
      may be to link each modality that is already digital into modality-specific mini
      PACS, then to link the mini-PACS. Bringing other modalities on-line as new
      equipment is purchased and expanding the image information system (IIS) to the
      remainder of the healthcare facility rounds out the transition and may take
      several years. The downside of this kind of evolutionary approach is that the
      radiology department temporarily operates in two environments, the traditional
      film and the new filmless environments. To make the move from film to filmless,
      an administrator and the radiology staff must reengineer nearly every
      departmental process. Total quality management (TQM) techniques offer tools that
      are ideal for the task. Other recommendations include using a multidisciplinary
      team of staff members who are familiar with film-handling to create flow charts
      of all departmental processes. Each step should be validated to show its value to
      the overall process, the department or the institution. Next, flow charts of the
      expanded or new processes should be developed with input from the IIS manager,
      referring physicians and key IS personnel. Follow with estimates of staffing
      requirements that meet the needs of the completed flow charts and, finally, train
      staff members for the implementation of the new processes.

PMID- 10351742
TI  - A new approach to RIS/DR interconnection.
AB  - The article focuses on a new, standards-based approach for linking modalities to
      a radiology information system (RIS) in the radiology department. Computers have
      been used in radiology for quite some time-for the complex processing of
      algorithms used by CT and MR, for example. The advent of computed radiography
      (CR) and direct radiography (DR) has helped bring x-ray film into the world of
      computers. DR uses a technology similar to that in digital cameras to convert the
      intensity and location of the diagnostic image into digital form. Many radiology
      departments now store images on disks and read from computer monitors in a
      reading room. With its high-volume radiology department, the Cleveland Clinic
      Foundation (CCF) has been a long-time user of one particular RIS system. As the
      department moved to DR implementation, it required a means to automatically
      include patient demographic information with the image at the time of study
      acquisition, so this information would be associated with the image throughout
      its history. Using an approach developed by several companies in connection with
      CCF, technologists now use only two interfaces on one computer screen. Further, a
      technologist can close the study from the DR unit, allowing more time for patient
      care. The collaborative effort between CCF and the companies involved has
      resulted in an exciting standards-based approach to linking its RIS and DR
      systems.

PMID- 10351744
TI  - Managing an imaging department with a business perspective. A view from the other
      side.
AB  - I came to the position of director of radiology at Winchester Hospital with two
      advanced degrees, in business administration and in health-care administration,
      to replace a director of 35 years, who had come from a technical background. That
      this community hospital outside Boston nourishes the entrepreneurial spirit is
      one of the premises underlying its success. I was supported from the beginning
      both by the radiologists, who supported the concept of a business-person running
      the department, and by the manager, whose acceptance of my role helped set the
      tone for the department. My goal was to create a vision for the department, which
      I could do only by establishing a relationship with the supervisory staff.
      Communication became my greatest challenge: to listen and learn from my staff and
      to articulate how we could move to a new level of performance. My management
      philosophy included giving budget responsibility to the supervisors, to teach how
      revenue and expense directly impact the department's business. We learned
      together the importance of customer service and how it, too, could impact our
      business. Finally, I helped supervisors offer their own ideas to solve department
      problems. Joining the AHRA, reading its publications and attending its
      conferences have helped me gain a broader perspective of the industry. Now, I see
      my role as a facilitator who sets a vision for the department and provides the
      proper support, tools and guidance for the staff to achieve results. Together, we
      have created a successful balance between the business and the patient care
      components.

PMID- 10351743
TI  - Radiology integration in a multi-hospital system.
AB  - In 1989, Salt Lake City's Intermountain Health Care (IHC) began a process to
      reduce costs and streamline processes. Divided into four geographic regions, IHC
      consists of 24 hospitals and 100 clinics, a 400-member practitioner-physician
      group, and a staff of 23,000. IHC determined that three Salt Lake Valley
      hospitals, part of its Urban Central Region, must become one entity with shared
      management and a reduced staff to cover operations at all three hospitals.
      Management of the three radiology departments were charged with creating an
      integration process for the three hospitals. Two directors were selected to
      manage radiology and meet the outlined goals. Difficulty arose when one director
      needed to make changes in a facility managed by the other. The directors found
      that structuring by modality allowed them to plan for all three facilities,
      standardize equipment purchases and create integrated rather than departmental
      programs. As consolidation was taking place in top management, employees worried
      what the resulting changes meant for their jobs. Many were unfamiliar with the
      concepts of team structure and continuous quality improvement. Various courses
      and meetings were held to educate staff members and bring them up to new
      standards. Most successful were the meetings that allowed staff from different
      facilities to come together and share ideas. Although travel was an issue, these
      meetings quickly helped move the integration processes forward as peer
      relationships were developed. Employees were recruited for cross-training and new
      staff worked wherever needed. As they began to share data, the three hospitals
      identified best-practice and internal benchmarks. IHC is now ready to hire a
      single director to manage the radiology departments at the three Salt Lake Valley
      hospitals.

PMID- 10351745
TI  - Consortium's early results show collaborative guidelines work.

PMID- 10351746
TI  - To win quality award, BJC emphasizes experimentation.

PMID- 10351747
TI  - Reducing variation in care.
AB  - What care a patient receives reflects not only best practices and available
      technology but also geography, provider experience and patient preference.
      Spurred on by payers and a growing body of evidence-based methodology, providers
      are seeking to make patient care more consistently reflect best practices.

PMID- 10351748
TI  - Making changes at a regional level.

PMID- 10351749
TI  - Beyond the clinic: redefining hospital ambulatory care.
AB  - Responding to changes in health care financing, government policy, technology,
      and clinical judgment, and the rise of managed care, hospitals are shifting
      services from inpatient to outpatient settings and moving them into the
      community. Institutions are evolving into integrated delivery systems, developing
      the capacity to provide a continuum of coordinated services in an array of
      settings and to share financial risk with physicians and managed care
      organizations. Over the past several years, hospitals in New York City have
      shifted considerable resources into ambulatory care. In their drive to expand and
      enhance services, however, they face serious challenges, including a well
      established focus on hospitals as inpatient centers of tertiary care and medical
      education, a heavy reliance upon residents as providers of medical care, limited
      access to capital, and often inadequate physical plants. In 1995, the United
      Hospital Fund awarded $600,000 through its Ambulatory Care Services Initiative to
      support hospitals' efforts to meet the challenges of reorganizing services,
      compete in a managed care environment, and provide high-quality ambulatory care
      in more efficient ways. Through the initiative, 12 New York City hospitals
      started projects to reorganize service delivery and build an infrastructure of
      systems, technology, and personnel. Among the projects undertaken by the
      hospitals were:--broad-based reorganization efforts employing primary care models
      to improve and expand existing ambulatory care services, integrate services, and
      better coordinate care;--projects to improve information management, planning and
      testing new systems for scheduling appointments, registering patients, and
      tracking ambulatory care and its outcomes;--training programs to increase the
      supply of primary care providers (both nurse practitioners and primary care
      physicians), train clinical and support staff in the skills needed to deliver
      more efficient and better ambulatory care, prepare staff for practicing in a
      managed care environment, and help staff communicate with a culturally diverse
      patient population and promote the importance of primary care within the
      community. Significant innovations and improvements were realized through the
      projects. Several hospitals expanded the availability of primary care services,
      trained new primary care providers, and helped patients gain access to primary
      care clinicians for the first time. Better methods for documenting ambulatory
      care were introduced. To increase efficiency and improve service to patients,
      some of the hospitals instituted automated appointment systems and improved
      medical record services. To reduce fragmentation and contain personnel costs,
      support staff positions were redesigned, and staff were retrained to carry out
      new multi-tasked responsibilities. Many of the components vital to high-quality
      ambulatory care can take years to develop, and significant investments of
      capital. Increased primary care capacity, new specialty group practices, state-of
      the-art equipment for diagnosis and treatment, advanced information technology to
      manage and coordinate care and link services at multiple locations, and highly
      trained clinical and support staff all require strong commitment and support from
      a team of senior management executives and medical staff leaders, sufficient
      staffing resources, and outside expertise. Once the infrastructure is in place,
      hospitals must continue to reach out to their communities, helping people to
      understand the health care system and use it effectively.

PMID- 10351750
TI  - Chemo in question. Higher doses may not help breast cancer--yet.

PMID- 10351751
TI  - Pen, paper, power! Confessional writing can be good for you.

PMID- 10351752
TI  - Patient power: getting the drug you need.

PMID- 10351753
TI  - Are house calls the answer to chronic care system redesign?

PMID- 10351754
TI  - Time for institutions to rethink physician motivation.

PMID- 10351755
TI  - New-era organizations will need a "consumer-innovative" culture and five core
      competencies.

PMID- 10351756
TI  - Capitation and its effects on physician satisfaction.
AB  - OBJECTIVE: Capitation is an increasingly common method of paying physicians, but
      few data exist on its impact on physician satisfaction. This study examines the
      perceived effects of capitation on physician satisfaction at a large, academic
      medical center. STUDY DESIGN: Survey of physicians at a single, tertiary care
      hospital. METHODS: Physicians in a physician hospital organization were surveyed
      at an urban teaching hospital which received capitation for 5% of patients at the
      time of the survey but was preparing for a sharp increase in capitation. We used
      a 5-point Likert scale to assess physicians' satisfaction with their practice,
      and to compare satisfaction under fee-for-service and expected satisfaction under
      capitation. RESULTS: Of the 734 physicians surveyed, 147 were excluded because
      they had no direct patient care responsibilities. Of the remaining 587
      physicians, 363 replied, giving a response rate of 62%. Overall, 57% of
      physicians were satisfied with their practice. Compared to their satisfaction
      under fee-for-service reimbursement, they were much less satisfied with their
      ability to care for capitated patients (17 of 19 questions, p < 0.05). The
      greatest differences were for freedom to order necessary tests and freedom to
      obtain referrals (0.9 and 0.8 on the 5-point scale, respectively, both p <
      0.0001). Multiple logistic regression analyses revealed four independent
      predictors of overall satisfaction: patient load (OR = 2.7, 95% CI = 1.9-3.9),
      efficiency in resource utilization (OR = 1.5, 95% CI = 1.1-2.1), perceived
      employment stability (OR = 1.7, 95% CI = 1.3-2.2), and control over clinical time
      schedule (OR = 1.6, 95% CI = 1.2-2.0). CONCLUSIONS: Physicians initially
      encountering capitation payment have strong negative perceptions about it, even
      for areas in which some policy experts expect capitation to benefit patient care.
      Physician education and focusing on management relations may help smooth the
      transition to capitated reimbursement.

PMID- 10351757
TI  - An old approach to solving the senior readmission problem.

PMID- 10351758
TI  - Medical economics and professional unions. A nickel paid is a chance taken.

PMID- 10351759
TI  - A new twist on exclusive contracting. Do the medical staff bylaws of a hospital
      constitute an enforceable employment contract?

PMID- 10351760
TI  - A hospitalist's diary.

PMID- 10351761
TI  - What the role of the modern ED should be.
AB  - Managed care organizations (MCOs) have recently focused on the high cost per
      patient visit in the Emergency Department (ED). MCOs emphasize preventing low
      acuity patients access to the ED, believing that billions of healthcare dollars
      will be saved. However, a review of emergency department studies suggests a
      different outcome. Combined with new ED service lines, perhaps another, rather
      paradoxical approach to managing healthcare costs in the ED is more patient
      focused and more cost-effective long-term. This approach is more comprehensive
      and offers more services, not less. The ED is an important community resource and
      entry port to healthcare. It is the only place open 24-hours per day, 7 days per
      week with no appointment necessary, and all lab and radiology services available.
      The very claim that it is "overutilized" is an indication of its success. In
      large volume EDs, certain patient populations may be more specifically served
      with pediatric emergency, industrial medicine, and fast track physicians. Special
      facilities for chest pain patients or observation can treat patients more
      quickly, keep them out of hospital beds, thus lowering costs. In smaller
      hospitals, the well rounded ED physician can treat patients of all acuities. In
      the most rural communities the ED can become the local 24-hour clinic with short
      term stay beds. EDs are fixed costs to hospitals. Extracting low acuity patients
      from the ED will raise costs for emergency patients and leave the facility
      underutilized. By appropriately raising prices for emergencies and decreasing low
      acuity patient charges to reflect marginal expense, the ED becomes a cost
      friendly environment for the low acuity patient.

PMID- 10351762
TI  - Physician and hospital executive compensation under attack.

PMID- 10351763
TI  - The principles of economic analysis.

PMID- 10351764
TI  - Don't skip crucial benchmarking step: develop critical success indicators.
AB  - If you don't know where you're headed, you'll never get there. Critical success
      indicators can help you define what you need to succeed as a business. You need
      eight to 10 critical success indicators that are based on your strategic plan,
      are easily measurable, and are on the macro level. Everyone on your staff, from
      the CEO to maintenance, needs to know what the critical success indicators are
      and how individual jobs relate.

PMID- 10351765
TI  - Will HCFA be able to pay up on Jan. 1, 2000? Agency says it will be ready; GAO
      says no way.
AB  - A report from the General Accounting Office (GAO) states the Health Care
      Financing Administration (HCFA) will likely experience system failures as a
      result of the year 2000 (Y2K) computer problem. Translation: You might not get
      paid. HCFA Administrator Nancy-Ann DeParle insists that claims will be paid on
      Jan. 1 and that GAO is overstating the risks. One Y2K expert advises cautious
      optimism coupled with extensive individual preparations.

PMID- 10351766
TI  - Provider-patient e-mail could transform medicine.
AB  - Experts say 5% to 10% of physicians are communicating with their patients by e
      mail. E-mail can help physicians use their time more effectively, give them the
      ability to follow-up with patients more easily, improve relationships with
      existing patients, and help attract new ones. E-mail is an easy way to handle
      administrative tasks such as setting appointments and refilling prescriptions. It
      also provides written documentation of conversations that can be placed in the
      patient's paper chart.

PMID- 10351767
TI  - SC starts on-line physician comparison data system.
AB  - South Carolina will soon give physicians the ability to access physician-specific
      comparison data on hospitalizations, length of stay, complications, and outcomes
      through the Internet. The project director says this will allow physicians to
      manage care and dramatically improve outcomes. The state's two medical schools
      plan to use the data to drive their decisions on which continuing medical
      education programs to offer.

PMID- 10351768
TI  - Hospital cuts time on ventilators, ICU LOS.
AB  - A grass-roots effort led by nurses allowed a North Carolina hospital to cut the
      length of stay for patients on ventilators by 34% and the overall ICU length of
      stay by 25% in nine months. A ventilator protocol approved by physicians lets
      nurses and respiratory therapists begin weaning patients without calling the
      physician at every turn. Ventilator patients averaged savings of $35,000 in
      hospital charges during the nine-month study period.

PMID- 10351769
TI  - Preemption of a state "legislatively created" right to sue HMOs for negligence.
      Corporate Health Ins. Inc. v. Texas Dept. of Insurance.

PMID- 10351770
TI  - Billing company compliance program guidelines published by OIG.

PMID- 10351771
TI  - Third party billing service liability for False Claims Act violations. United
      States vs. Emergency Physicians Billings Services, Inc.

PMID- 10351772
TI  - Woman arrested in PR infant kidnapping; FL abduction still unsolved.

PMID- 10351774
TI  - New integrated access control system improves security, efficiency.

PMID- 10351773
TI  - Security and safety at Detroit's new downtown VA Medical Center.

PMID- 10351775
TI  - Behind the drop in most crime statistics at UC Davis and its med center.

PMID- 10351776
TI  - Hurricane Georges and New Orleans hospitals: preparing for a killer storm--Part
      I.
AB  - Last year, the city of New Orleans, LA, was spared what could have been one of
      the greatest tragedies to ever befall a major American city. In September,
      Hurricane Georges, which had caused hundreds of deaths and massive destruction in
      the Caribbean, was heading straight toward New Orleans. The vicious storm had the
      strength to potentially submerge the low-lying city, protected only by levees.
      Although New Orleans escaped serious damage when Georges veered off at the last
      moment, the threat posed by the hurricane resulted in a massive evacuation. More
      than 1.5 million people were ordered or urged to vacate the city and coastal
      Louisiana, though not all complied. About 10,000 people took shelter in the
      Superdome, home of the New Orleans Saints, while thousands more filled other
      designated shelters in the city. At local hospitals, people took refuge in
      offices, waiting rooms, conference rooms, hallways, and any other space
      available. In this report, we'll give details on how six hospitals and health
      facilities prepared to meet the hurricane, how they fared during the emergency,
      and how their disaster plans worked. Three of them are covered in this month's
      issue.

PMID- 10351777
TI  - Health system opts for in-house over contract after in-depth evaluation.

PMID- 10351778
TI  - Clinical governance. Carry that weight.

PMID- 10351779
TI  - US healthcare. Running on empty.

PMID- 10351780
TI  - Professions allied to medicine. Toeing the line.

PMID- 10351781
TI  - Consultant appointments. Appoint well made.
AB  - The appointment of consultants is of crucial importance to a trust's success. The
      introduction of mandatory training for all consultants involved in making
      appointments has proved successful, despite initial scepticism. The use of a
      competency framework in assessing candidates has eased the selection process.

PMID- 10351782
TI  - Public health. Historical novel.
AB  - Public health thinking has failed to keep pace with changes in society. A basic
      shift is needed to address the needs of a deindustrialised society. Attention
      should be given to promoting self-esteem as a way of encouraging healthy living.

PMID- 10351783
TI  - Evidence-based practice. Data day.
AB  - A project assessing the feasibility of using research data in routine clinical
      practice showed that most clinicians found it too time-consuming. Obtaining
      relevant research articles took an average of three days with an on-site library,
      and a week without one. The most serious barrier was the poor state of the
      information itself. Investment should focus on developing the information,
      followed by effective and easy-to-use search methods.

PMID- 10351784
TI  - Minority share scheme.

PMID- 10351785
TI  - Sometimes, death means you don't go by the book.

PMID- 10351786
TI  - Helping ex-gang members erase the past.

PMID- 10351787
TI  - Office morale rises--and falls--with you.

PMID- 10351788
TI  - Name that practice!

PMID- 10351789
TI  - Managed care 1999. Hang on--the ride's going to get rougher.

PMID- 10351790
TI  - Managed care 1999. Drug costs could come out of your pocket.

PMID- 10351791
TI  - Managed care 1999. How capitation can raise your overhead.

PMID- 10351792
TI  - Managed care 1999. Could your ipa go under? Steer it to safety.

PMID- 10351793
TI  - Managed care 1999. Your report card is about to go public.

PMID- 10351794
TI  - Managed care 1999. Clinical guidelines: a malpractice safety net?

PMID- 10351796
TI  - Need a chuckle? Check out these codes.

PMID- 10351795
TI  - Sexual harassment: prevention is the best defense.

PMID- 10351797
TI  - We need to get better at "customer service".

PMID- 10351798
TI  - I was the plaintiffs' lone target--and my insurance was gone.

PMID- 10351799
TI  - Ever feel like Dilbert in a white coat?

PMID- 10351800
TI  - Columbia execs to get their day in court.

PMID- 10351801
TI  - CEOs calling it quits. ACHE survey shows turnover is near record level.

PMID- 10351802
TI  - Changes cause tax horrors for Amityville.

PMID- 10351803
TI  - CHW eyes Calif. for-profit hospital.

PMID- 10351804
TI  - Boston hospital settles charges.

PMID- 10351805
TI  - GOP budget blueprint doesn't erase cuts.

PMID- 10351806
TI  - Mich. hospital rescues troubled HMO.

PMID- 10351807
TI  - When feds smell fraud, they settle in.

PMID- 10351808
TI  - Aetna, Johns Hopkins catch site of success.

PMID- 10351809
TI  - Dems adopt a GOP insurance solution.

PMID- 10351810
TI  - Big deals are a big deal. Supplier mergers may limit product choice and harm the
      industry companies claim to help.

PMID- 10351811
TI  - Will Quorum deliver? Company says it's turning problems around, but Wall Street
      says, 'Show me'.
AB  - These are challenging times for Quorum Health Group executives. They continue to
      grapple with vexing operational problems as well as the legal fallout involving a
      whistleblower lawsuit. The executives say they're turning things around, but Wall
      Street is saying, 'Show me.'

PMID- 10351812
TI  - Sticker shock. Complexities of healthcare delivery can lead to some wild price
      swings, locally and nationally.

PMID- 10351813
TI  - The Cardinal rules: growth, agility. Interview by Scott Hensley.

PMID- 10351815
TI  - Doctors try to escape noncompete restraints.

PMID- 10351814
TI  - Healthcare leaders strategize quality.

PMID- 10351816
TI  - Rural hospital parent files for Chapter 11.

PMID- 10351818
TI  - Mass. Blues goes public with R.I. bid.

PMID- 10351817
TI  - Medicare HMO misinformation abounds.

PMID- 10351819
TI  - State medical boards have busy year.

PMID- 10351820
TI  - Rolling in the black. For-profits Columbia, Quorum, HMA enjoy solid quarter.

PMID- 10351821
TI  - Va. allows tax refunds to go to uninsured.

PMID- 10351822
TI  - 'Insiders' on hospital boards worrisome.

PMID- 10351823
TI  - Bad deals with docs. Miscalculated contracts help put La. hospital on the block.

PMID- 10351824
TI  - Missouri ruling could dull CEOs' ax.

PMID- 10351825
TI  - VHA to market Web resource nationwide.

PMID- 10351826
TI  - Plan could cut providers out of Medicare.

PMID- 10351827
TI  - Physicians fighting rules they sought.

PMID- 10351828
TI  - Remembering the specialists. After spending billions on primary-care networks,
      hospitals are cozying up to top revenue generators.
AB  - After hospitals and practice management companies spent the better part of this
      decade snapping up primary-care doctors, they suddenly remembered the
      specialists. You know, those guys in white coats who generate much of the
      revenues.

PMID- 10351829
TI  - HCFA reviews OASIS (Outcome and Assessment Information Set) reporting rule.

PMID- 10351830
TI  - Millennium stockpiling. Hospitals fear that overzealous materials managers could
      strain the supply chain.

PMID- 10351831
TI  - Credits on the fringe benefit bond insurer.

PMID- 10351832
TI  - CHA joins groups as access champion.

PMID- 10351833
TI  - Creating and sustaining healthy communities.

PMID- 10351834
TI  - Family focus. When hospitals put the emphasis on patients and families, everyone
      benefits.
AB  - Adopting a family-centered approach to care requires a profound cultural change-
      from an emphasis on technology and science to one of sharing and collaboration
      among staff, patients, and family. Organizations that make the shift find that,
      despite the hard work, everyone ends up happier and healthier.

PMID- 10351835
TI  - I used to be from somewhere--a portrait of street kids in crisis.
AB  - They are called street kids, and they bring paralyzing elements to communities
      and hospitals--long-term repercussions from untreated disease, poverty, drug
      abuse, prostitution, teen pregnancy, and mental illness. The president of
      Covenant House has some practical suggestions for how hospitals can help now and
      save money--and lives--in the long run.

PMID- 10351836
TI  - Partners. The culture of a healthy community.

PMID- 10351837
TI  - How can leaders ensure organizational integrity?

PMID- 10351838
TI  - An internal operation. How Granada Hills reinvented its management.
AB  - When the board of a California community hospital found that it had drastically
      miscalculated its earnings for 1998 and was actually in the red, trustees knew
      they had to act fast. Resisting the "cut and slash" advice of a turnaround
      specialist, the board chose to "reinvent" its management structure. That's how it
      could maintain its community health mission and still end up in the black.

PMID- 10351839
TI  - Board committees: who's at the helm?

PMID- 10351840
TI  - Teetering on the edge of chaos. Giving up control and embracing uncertainty can
      lead to surprising creativity.

PMID- 10351841
TI  - Search and you shall find. How trustees can recruit the best executive.

PMID- 10351842
TI  - Doctors behaving badly--and the people who let them.

PMID- 10351843
TI  - Patients. To serve and protect.

PMID- 10351844
TI  - Patch Adams the movie: laughter makes for bad medicine.

PMID- 10351845
TI  - What every board should know.
AB  - Even the most experienced trustees can learn something new. Ther's no way you can
      do your job well without updating your knowledge of the field. Experts discuss
      what you need to know--and how you can go about learning it.

PMID- 10351846
TI  - Eugenia Eng: recipient of the 1999 Robert F. Allen symbol of H.O.P.E. Award.

PMID- 10351848
TI  - Are practical methods of evaluating body fat in African-American women accurate?
AB  - Sixteen African American females were evaluated for body fat to assess the
      accuracy of several practical methods of estimation: near-infrared interactance,
      bioelectrical impedance, and Sloan and Jackson skinfold equations. Most methods
      produced different results from hydrostatic weighing and produced different body
      fat values from each other suggesting that practical methods do not provide
      accurate measurements.

PMID- 10351847
TI  - Inactive Australian college students' preferred activities, sources of
      assistance, and motivators.
AB  - a cross-sectional survey was sent to students at four college campuses to assess
      self-reported physical activity, sources of assistance to exercise, and
      motivators for regular activity . The study focused on 864 (40%) of 2148 students
      surveyed who were classified as inactive. Attributes of inactive male and female
      college students differed by gender. such differences may be used in tailoring
      health promotion interventions to increase physical activity.

PMID- 10351849
TI  - The relationship of economic factors and stress among employed, married women
      with children.
AB  - A convenience sample of 62 married women with children at home were measured on
      five economic variables and three stress-related variables: mother/marital role
      satisfaction, mother work role fulfillment and physical indicators of stress. The
      analysis reveals several significant relationships for the fulfillment and stress
      variables. Regression analysis also was used to model the relationship among
      economic and stress-related variables. The study suggests that financial health
      modules be integrated into stress management and other health enhancement
      programs for married, employed women.

PMID- 10351850
TI  - Psychosocial and demographic correlates of television viewing.
AB  - PURPOSE: The present study was grounded in the notion that previously identified
      physical activity determinants were associated in reverse with television
      viewing. Identifying demographic and psychosocial correlates and other potential
      determinants of television viewing may allow for the development and
      conceptualization of models and interventions to reduce sedentary behavior.
      DESIGN: Cross-sectional data from self-report measures were analyzed using
      multiple hierarchical regression. SETTING: Data were collected from 1995 to 1996
      on seniors attending a large public university in southern California. SAMPLE:
      Subjects were 321 female and 255 male university seniors attending a public
      university in southern California. The sample's ethnic distribution was 53.8%
      European-American, 16.3% Latino, 16.6% Asian/Pacific Islander, 16.1% African
      American, and 4.3% other. MEASURES: Typical television viewing practices on
      weekdays and weekends were assessed using self-report items. Physical activity
      determinants were assessed using self-report measures derived from social
      cognitive theory and the transtheoretical model of behavior change. RESULTS: The
      variables explaining a significant amount of variance after controlling for
      ethnicity and employment status in females were barriers to physical activity (p
      < .05), body image dissatisfaction (p < .01), and processes of change (p < .02).
      The entire model for females captured 16% of the variance, with the psychosocial
      variables accounting for 8% of the variance. The significant variables in the
      male model were quality of life (p < .01) and grade point average (p < .03). The
      full model accounted for 15% of the variance, with nondemographic variables
      accounting for 5% of the variance in television viewing. CONCLUSIONS:
      Relationships between television viewing and potential determinants were found.
      However, additional variables that may influence the amount of television viewing
      need to be conceptualized and investigated.

PMID- 10351851
TI  - Incentives and barriers to physical activity for working women.
AB  - A questionnaire was completed by 393 working women to examine incentives and
      barriers to physical activity based on the stages of change from the
      transtheoretical model. Using Chi Square tests, differences were found across the
      five stages suggesting that work site programs be designed and tailored for women
      at different stages of readiness.

PMID- 10351852
TI  - Applying the health promotion model to development of a worksite intervention.
AB  - INTRODUCTION: Consistent use of hearing protection devices (HPDs) decreases noise
      induced hearing loss, however, many workers do not use them consistently. Past
      research has supported the need to use a conceptual framework to understand
      behaviors and guide intervention programs; however, few reports have specified a
      process to translate a conceptual model into an intervention. PURPOSE: The
      strongest predictors from the Health Promotion Model were used to design a
      training program to increase HPD use among construction workers.
      SUBJECTS/SETTING: Carpenters (n = 118), operating engineers (n = 109), and
      plumber/pipefitters (n = 129) in the Midwest were recruited to participate in the
      study. DESIGN: Written questionnaires including scales measuring the components
      of the Health Promotion Model were completed in classroom settings at worker
      trade group meetings. MEASURES: All items from scales predicting HPD use were
      reviewed to determine the basis for the content of a program to promote the use
      of HPDs. Three selection criteria were developed: (1) correlation with use of
      hearing protection (at least .20), (2) amenability to change, and (3) room for
      improvement (mean score not at ceiling). RESULTS: Linear regression and Pearson's
      correlation were used to assess the components of the model as predictors of HPD
      use. Five predictors had statistically significant regression coefficients:
      perceived noise exposure, self-efficacy, value of use, barriers to use, and
      modeling of use of hearing protection. Using items meeting the selection
      criteria, a 20-minute videotape with written handouts was developed as the core
      of an intervention. A clearly defined practice session was also incorporated in
      the training intervention. CONCLUSION: Determining salient factors for worker
      populations and specific protective equipment prior to designing an intervention
      is essential. These predictors provided the basis for a training program that
      addressed the specific needs of construction workers. Results of tests of the
      effectiveness of the program will be available in the near future.

PMID- 10351853
TI  - Improving exercise behavior: an application of the stages of change model in a
      worksite setting.
AB  - Randomized trial of 527 corporate employees was conducted to evaluate an exercise
      intervention based on the transtheoretical model and tailored to individual
      stages of change. No significant difference in physical activity by stage was
      evident at baseline among three treatment groups. At follow-up, the group
      receiving a staged-based message increased activity by 13% and a significant
      difference was evident in the magnitude and direction of movement across stages,
      suggesting that tailored messages to stages of change may be an effective
      strategy for physical activity interventions.

PMID- 10351854
TI  - Diet and physical activity patterns of urban American Indian women.
AB  - A cross sectional survey was conducted of American Indian women ages 18 years and
      older and residing in Minneapolis to assess dietary and physical activity
      practices. Results indicate a high amount of fat foods and low amount of fruits
      or vegetables consumed, and little regular physical activity. For adequate
      dietary intake, barriers included expense, and for physical activity barriers
      included lack of child care, health problems and safety concerns.

PMID- 10351856
TI  - User Acceptance of Health Telematics Applications: Looking for Convincing Cases.
      Proceedings of a conference. Thessaloniki, Greece, 12-13 December 1997.

PMID- 10351855
TI  - Six-month outcomes of an alcohol prevention program for inner-city youth.
AB  - Six-hundred and fifty 6th grade students were randomly assigned with the
      intervention group receiving the STARS for Families Program, an alcohol reduction
      program consisting of standardized health consultations provided by nurses and
      mailed follow-up information. The control group received minimum information.
      Students in the study attended either a neighborhood or a bused inner-city middle
      school. Students receiving the intervention had significantly less intentions to
      use alcohol in the future and less alcohol quantity. The study suggests that
      brief, provider-involved interventions may be a viable school based approach to
      prevention.

PMID- 10351857
TI  - A convincing case for the provision of telemedicine services to ocean going
      vessels: the MERMAID paradigm.
AB  - MERMAID is an EU financed telemedicine project with global reach and 24-hour,
      multilingual capability. It aspires to provide a model for the provision of
      health care services based on the electronic transmission of medical information,
      via ISDN based videoconferencing. This model will not be limited to medical
      diagnostics but it will encompass all cases where the actual delivery of health
      care services involves a patient who is not located where the provider is. Its
      implementation requires the commissioning of an expensive telecommunications
      infrastructure and the exploration of a number of solutions. In fact, all
      categories of telemedical applications (audio and video conferencing, multimedia
      communications, flat file and image transfer with low, medium and high bandwidth
      data requirements) are considered while the full range of network choices
      (Digital land lines, Cellular/Wireless, Satellite and Broadband) are being tested
      in terms of cost/performance tradeoffs that are inherent to them and the
      developmental state each of these options occupies in their in its life cycle.
      Finally, out that MERMAID utilises advanced land based line transmission
      technologies to aid the remote patient by making available the specialist care
      that is best suited in the particular case.

PMID- 10351858
TI  - Telematics in the northern United Kingdom.
AB  - The application, integration and development of methods and technology
      facilitating the seamless interchange of clinical, demographic and administrative
      information presented the medical and clinical community with unforeseen
      problems. Surprisingly, the wealth of existing solutions did not find the
      expected application and acceptance in hospital/General Practice environments.
      Even more surprising was the fact of the failure of many computer-based solutions
      to deliver the expected benefits. This paper outlines the Telematics project
      established in the Northern United Kingdom and its success in maintaining a
      working balance between technological needs and the clinical requirements. The
      result is a robust service linking five major Trusts and 12 General Practices in
      terms of clinical and administrative data, e-mail and other facilities.

PMID- 10351859
TI  - The strategic plans of OTE concerning the development of telemedicine
      applications based on the Euro-ISDN technology.
AB  - OTE SA, the Hellenic Telecommunications Organization, is the major public network
      operator of Greece and aims to actually promote all services made available
      through this technology and more peculiarly that of telemedicine. Through its
      modernization plan in progress, OTE aims at providing wide/range, high/quality
      competitive services on the basis of customer oriented policies. Its activities
      cover, besides basic telephony (5.9 million lines), data communications, leased
      lines, maritime communications and value-added services. The public health
      service has a lot to profit from efficient use of telecommunications. The
      greatest challenge the health service is faced with, is the growing gap between
      the expectations of the population, and the resources that society can set-aside
      for health purposes. Increasing the level of efficiency and co-operation is
      therefore the best probable response to the challenge. Telecommunications may
      contribute to a more effective utilization of resources, typing together those
      that could be in benefit of the health sectors in the process of implementing a
      large number of telemedical services.

PMID- 10351860
TI  - Information system for clinical resource management in a regional setting.
AB  - The Hospital District of Varsinais-Suomi consists of five hospitals for non
      psychiatric diseases to deliver specialised health care for the population of
      440,000 inhabitants in South-western Finland. We have applied an open regional
      information system to aid clinical resource management in such a complex expert
      organisation. The main areas of application have been assessment of inpatient
      care usage in different communities and in different diagnosis-related-groups
      (DRG), measurement of length of hospital stay in different DRGs and comparison of
      DRG unit weight costs of different hospitals. The open structure of the data base
      and its distribution to all parties of health care professionals has resulted in
      mutual decisions on structural changes and increased cost containment activities.

PMID- 10351861
TI  - Medical informatics education.
AB  - Medical Informatics is a multidisciplinary field, dealing mainly with informatics
      and technology applications in health care. Medical Informatics is composed from
      a number of sub-areas such as computer based patient record (CPR), processing of
      multimedia information (signals, images), coding and transmission through high
      speed networks of medical information (telematics), medical decision support
      systems, data security and integrity, integration of technologies in hospital and
      regional environments, and development of educational tools. The people who
      receive such an education are capable of development, integration and maintenance
      of complex hospital and health information systems both at departmental and
      regional levels. A very important issue however is the acceptance of information
      technology (IT) solutions engineered by medical informaticians from the medical
      personnel. In this paper we shall deal with the set-up of a medical informatics
      and medical technology educational environment, as well as the areas from medical
      informatics that the average user needs to be familiar with in order for the
      successful deployment of IT solutions in health care.

PMID- 10351862
TI  - The handbook of medical informatics and its web site.
AB  - Since the new Handbook of Medical Informatics was published in 1997, a beta
      version of a web site ("MI WEB") has been opened that supports the teaching of
      the Handbook. MI Web refers to the text of the full Handbook, using an extensive
      Glossary that is shared by both the paper Handbook and the web site. New material
      for teaching will continuously be added to the MI Web, realizing that the field
      of health informatics is progressing exponentially, that the teaching of medical
      informatics is of great importance for students in medicine and health care, and
      that these students will be the health professionals of the future. Training in
      medical informatics is also of value for practicing clinicians who are
      overwhelmed by the avalanche of systems that are available on the market.

PMID- 10351863
TI  - Health and nursing informatics education.
AB  - In Europe, coordinated activities in healthcare informatics education started in
      the late 1980's with the establishment of European Courses in Health Telematics.
      At the same time the European Commission foresaw the need for spreading the
      knowledge of IT in the Healthcare Sector. Therefore the EC, since then, have
      supported the initiatives that aim to create awareness, stimulate diffusion,
      educate and train the users (healthcare professionals) in the application of
      Information Technology to the Healthcare Sector. Such initiatives are the
      NIGHTINGALE project, which is an essential project in the planning and
      implementation of strategy in training the Nursing profession in using and
      applying healthcare information systems, the IT EDUCTRA project, which is a very
      practical project in the field of the education and training of the Healthcare
      Professionals in Information Technologies, and the ERASMUS Master's Course, which
      is aiming at giving those working, or intending to work in the health service and
      related activities a broad, advanced postgraduate education in Health
      Informatics.

PMID- 10351864
TI  - Integrated computerized patient records: the DIOGENE 2 distributed architecture
      paradigm with special emphasis on its middleware design.
AB  - DIOGENE 2 is a full-scale distributed/open hospital information system that by
      June 1995 had already achieved its migration from a former mainframe system.
      Thanks to that architecture there is an obvious need for a common "glue" devoted
      to tightening up scattered applications into a middleware-based network of
      interoperability. After this the design of open/distributed Electronic Patient
      Records (EPRs) became feasible. A brief historical sketch of DIOGENE is presented
      from its initial to its present phase. A working prototype of these distributed
      EPRs is discussed showing current achievements during its first stage of
      production in the clinics of the University Hospitals of Geneva. On-going
      expansion to other public hospitals, as well as to general practioners (GPs) in
      the Geneva area, are partly described.

PMID- 10351865
TI  - Common sense as a key requirement for promoting the electronic healthcare record:
      two years of experience in the Belgian National PROREC Centre.
AB  - PROREC-BE vzw is the first national PROREC centre that has been created to
      promote the use of high quality electronic healthcare records in line with
      European standards and insights. The mission of the centre is to satisfy the
      needs of all actors playing in the electronic healthcare record theatre. This is
      realised by setting up discussion fora and technical groups, and by adhering to
      common sense principles such as acceptance of each other's competence, looking at
      responsibilities instead of rights, and preferring win-win over zero-sum games.
      After two year of working, the Belgian PROREC centre has satisfactorily shown
      that working along these principles pays off, and is beneficial for all.

PMID- 10351866
TI  - Euromedies: from requirement analysis to pilot trial.

PMID- 10351867
TI  - World Wide Web based access to clinical and radiological patient data.
AB  - The authors believe that the WWW-based access to clinical and radiological data
      is the only suitable approach that is in the same way technically possible,
      clinically acceptable and financially affordable with the today existing
      restrictions in the healthcare sector.

PMID- 10351868
TI  - Towards user acceptance of telemedicine services.

PMID- 10351869
TI  - Communication technologies and applications in a medical environment.
AB  - As we move into the next millennium, we anticipate a rapid introduction of
      Information and Communication Technologies (ICTs) into the medical environment.
      In applying these technologies in Health Care Environments, the basic goals are
      to improve: (a) the collaboration between the different partners in the health
      sector, (b) the access to care and (c) the medical education, and to enhance
      overall quality (by increasing the availability of some applications, improve the
      quality of others and facilitate some completely new ones), and all these at
      affordable cost. This requires close interaction between health care
      practitioners and information technologists to ensure that the proposed
      technologies satisfy current user's needs, and anticipate future. The public
      awareness and the acceptance of the new medical environments by the users are key
      factors for successful implementations.

PMID- 10351870
TI  - Promoting the convincing cases--towards acceptable and beneficial health
      telematics applications and services in Europe.

PMID- 10351871
TI  - IMASIS. A multicenter hospital information system--experience in Barcelona.
AB  - The present study aimed to analyse physicians' attitudes towards IMASIS, and
      their potential influence on IMASIS medical record project. IMAS (Institut
      Municipal d'Assistencia Sanitaria) is the health care organisation of the City
      Council of Barcelona. IMAS hospital information system (IMASIS), which first
      applications were designed and implemented in 1984, is currently facing a new
      phase, focused on clinical information management. Our approach included a
      personal interview with representatives of every hospital unit, and a self
      administered questionnaire distributed to every clinician. Both provided a worthy
      insight into the cultural patterns to be considered in the HIS implementation
      process. Moreover, the results helped to define the subsequent steps of IMASIS
      evolution. Our experience is proposed as a tool to assess clinical informations
      systems from a user point of view.

PMID- 10351872
TI  - A regional university hospital in the framework of a regional information
      network: the experience of Lille.
AB  - Information is essential for the taking care of the patients and is also a
      guarantee for the quality of cares. In this objective, the University Hospital of
      Lille has developed for 10 years a politic based on information and communication
      divided in 3 phases: 1. The University Hospital has developed a HIS based on the
      communication between hospitals and medical centers for a better sharing of data
      concerning the patient. 2. The second phase consisted in the integration of
      external platforms to the HIS with a middleware. 3. The actual phase consists in
      the opening of the HIS to the external environment of the hospital and especially
      to the GPs through a Regional Medical Information System.

PMID- 10351873
TI  - Telematics Applications Programme--achievements and prospects in user acceptance
      of telematics applications.

PMID- 10351874
TI  - Databases for angiography and percutaneous transluminal angioplasty.

PMID- 10351875
TI  - Health informatics in Copenhagen, Denmark.

PMID- 10351876
TI  - Implementation of a hospital information system in a Greek university hospital.
AB  - Application of an integrated Hospital Information System in Areteion University
      Hospital was launched 3 years ago. As it was the very first time that a fully
      fledged Hospital Information System was applied in complex university hospital
      environment, numerous problems and issues were brought up during this first
      period. The most critical issues are described in this paper, giving simply the
      essence of the problem and the general strategic line which was followed. Issues
      of hospital's strategic goals, behavioural aspects of the users, technical
      problems of the software application, as well as issues of maturity of key
      players and tools per se and in their interaction, were faced by the management
      team of Hospital Information System.

PMID- 10351877
TI  - The AEDMI project, an example of prototype development for a clinical decision
      helping system.
AB  - The AEDMI project, carried out in the Bellvitge University Hospital, near
      Barcelona, is proposed as an example of clinical decision system prototype
      development. Several difficulties have been encountered to develop this project.
      One of them was to find the adequate understanding for the project and proper
      funding for personnel resources. The support by FIS grants and from the hospital
      structures was essential to the survival of the project; however the resources
      always have been below the real needs for development. The difficulties with
      clinical coding systems, the excessive expectancies upon prototypes, and the lack
      of culture in information methods were other relevant hinders. The complexity of
      clinical realm, the uncertainty of medical decisions, and the current trends to
      substitute the clinical information by data obtained from electronic devices, or
      analytical monitoring of patients, are additional problems for clinical
      information managing.

PMID- 10351878
TI  - Electronic health care record systems--new possibilities of processing health
      care activities and medical information.
AB  - The simultaneous events of Health Care reorganisation, Information Technology
      progress and increased demands on Health Care outcome evaluation have created a
      new concept of a more sophisticated way how to use an electronic health care
      patient record. The importance of health care process analysis and case
      processing is illustrated and an operating patient record system in Umea, Sweden,
      is demonstrated.

PMID- 10351879
TI  - Convincing cases: important component of user acceptance.
AB  - This paper is presenting the rational that lead to the organisation of the
      European workshop on Acceptance of Telematics Applications by Healthcare
      Professionals "Looking for the convincing cases," that took place in Thesaloniki
      12-13 December, 1997. A brief overview is presented of the health telematics
      sector, the current situation of the usage of some applications, and major
      challenges towards wide implementation of health telematics applications. It
      focuses on user acceptance as one of the critical challenges towards wider
      implementation. It concludes that the support and promotion "Convincing cases"
      are important components contributing to user acceptance.

PMID- 10351880
TI  - The convincing case for electronic healthcare record systems in primary care.

PMID- 10351881
TI  - Working in regional health network.
AB  - This paper describes the conditions for, and actually use of telematics in a
      regional Health Network in a Danish county. This paper gives an introductory view
      over the organisation of the Danish health care system, and the general
      practitioners place in it. The advantages experienced and the actual use of
      telematics in general practice today is described. Finally, the expectations for
      the near future is mentioned.

PMID- 10351882
TI  - Telematics in prehospital emergency care: the Hector Pilot of Crete.
AB  - Emergency Medicine is considered the neglected specialty of contemporary
      medicine, although it is widely acknowledged that improvement in the outcome of
      the acutely and critically ill depends on its timely and effective management
      during the critical first hour [1], the so called "golden hour". The crucial
      question therefore is whether Telematics can affect this outcome and in
      particular how they can assist the existing models of Prehospital Emergency
      Medical Services (EMS) to meet this goal. The Hector Pilot of Crete tries to give
      a convincing answer to this question, taking into account the concept and some of
      the requirements of Emergency Medicine.

PMID- 10351888
TI  - Decreasing mortality and morbidity in adult AIDS patients from 1995 to 1997 in
      Sao Paulo, Brazil.

PMID- 10351889
TI  - Global challenges of the AIDS epidemic: perspectives. Introductory remarks.

PMID- 10351890
TI  - Confronting AIDS: a global economic perspective.

PMID- 10351891
TI  - Economic perspectives on the global AIDS epidemic.

PMID- 10351892
TI  - UNAIDS priorities in the battle against AIDS.

PMID- 10351893
TI  - A personal look at the AIDS crisis in South Africa.

PMID- 10351894
TI  - Public policy update. Review of the 105th Congress.

PMID- 10351895
TI  - Protease inhibitors and subtypes.

PMID- 10351896
TI  - Activists dialog about pricing.

PMID- 10351897
TI  - AZT helps with birth weight.

PMID- 10351899
TI  - Vaccine based on dendritic cells.

PMID- 10351898
TI  - Drug targets cellular enzyme.

PMID- 10351900
TI  - Alabama highest for gonorrhea.

PMID- 10351901
TI  - Canada introduces hepatitis C test.

PMID- 10351902
TI  - STD rates increasing.

PMID- 10351903
TI  - Culturally relevant behavioral intervention dramatically reduces STDs.

PMID- 10351904
TI  - Medical students remain at risk for disease through accidental needlesticks.

PMID- 10351905
TI  - Neutrophil rheology and transit through capillaries and sinusoids.

PMID- 10351906
TI  - Increased rigidity and priming of polymorphonuclear leukocytes in sepsis.
AB  - It has been proposed that abnormal mechanical properties may contribute to
      capillary retention of polymorphonuclear leukocytes (PMN) in sepsis, leading to
      the development of organ dysfunction. The present study was designed to determine
      whether PMN rigidity is increased in severe sepsis, and whether changes in the
      rheologic behavior of PMN correlate with the clinical course in sepsis. Eighteen
      adults with severe sepsis were studied over a period of 14 d; 11 survived and
      seven died. PMN deformation behavior was investigated via micropore filtration,
      using the cell transit analyzer. On Day 0, PMN rigidity was 2.5-fold greater for
      sepsis patients than for five normal controls (p < 0.001). PMN rigidity
      progressively improved over the 14 d study period for patients who recovered, but
      not for those who died; clinical indicators correlated with PMN rigidity. Patient
      PMN also exhibited a 5-fold greater increase in rigidity in response to formyl
      methionylleucylphenylalanine (fMLP) than did control PMN. Both the increased
      rigidity and enhanced response to fMLP could be simulated in vitro by incubation
      of normal PMN with tumor necrosis factor-alpha (TNF-alpha). We conclude that
      circulating PMN are more rigid in severe sepsis, and are "primed" for an
      augmented response to chemotactic stimuli. These findings support the hypothesis
      that cytokine-mediated increases of PMN rigidity may lead to sequestration of
      these cells in capillaries and to the consequent impairment of microvascular
      perfusion in sepsis.

PMID- 10351907
TI  - Modeling hypersomnolence in sleep-disordered breathing. A novel approach using
      survival analysis.
AB  - The etiology of excessive daytime sleepiness in patients with sleep-disordered
      breathing (SDB) is not well defined. In this study, we examined the relationships
      between several clinical and polysomnographic parameters and the degree of
      hypersomnolence in 741 patients with SDB (apnea-hypopnea index [AHI] >/= 10
      events/h). The study sample was obese (body mass index [BMI]: 35.3 +/- 8.5 kg/m2)
      and had evidence of moderate SDB (AHI: 47.6 +/- 29.3 events/h). Hypersomnolence
      was quantified with the multiple sleep latency test (MSLT) and survival analysis
      was used to assess the risk factors for hypersomnolence. In a multivariate
      proportional hazards model, AHI and nocturnal hypoxemia were independent
      predictors of hypersomnolence (MSLT < 10 min). The adjusted relative risks (RR)
      of hypersomnolence were 1.00, 1.30, and 1.65 for patients with an AHI of 10 to
      29.9, 30 to 59.9, and >/= 60 events/h, respectively. A positive association
      between hypersomnolence and oxyhemoglobin desaturation (DeltaSaO2) was observed
      with RR of 1.00, 1.18, 1.43, and 1.94 for a DeltaSaO2 of </= 5%, 5.1 to 10%, 10.1
      to 15%, and > 15%, respectively. Sleep fragmentation, as assessed by the
      distribution of sleep stages, was also an independent predictor of
      hypersomnolence. Using stage 1 sleep as a reference, an increase in stage 2 and
      slow wave sleep (SWS) were protective from hypersomnolence. For a 10% increase in
      stage 2 or SWS the adjusted RR for hypersomnolence were 0.93 and 0.79,
      respectively. REM sleep showed no significant association with the degree of
      hypersomnolence. These results suggest that AHI, nocturnal hypoxemia, and sleep
      fragmentation are independent determinants of hypersomnolence in SDB.

PMID- 10351908
TI  - Abnormal tissue oxygenation and cardiovascular changes in endotoxemia.
AB  - Experimental sepsis induces disturbances in microcirculatory flow and nutrient
      exchange that may result in impaired tissue oxygenation. Volume resuscitation is
      a principal clinical intervention in patients with sepsis. Nitric oxide (NO) has
      been implicated in the pathophysiology of endotoxemia, but few data exist
      concerning the effects of either NO synthase inhibition (NOSi) or volume
      resuscitation on microvascular regulation and tissue oxygenation. Amperometric
      measurements were made of skeletal muscle (tissue) oxygen tension (PtO2) and its
      response to changes in fraction of inspired oxygen (FIO2) in rats rendered
      endotoxemic. Simultaneous measurements were made of systemic hemodynamic indices
      and arterial blood gas tensions. At normal PaO2, PtO2 in endotoxemic animals was
      significantly lower than in control animals, with marked attenuation of the
      response to increasing FIO2. These changes were associated with significant
      metabolic acidemia. In volume-resuscitated endotoxemic rats, PtO2 and blood pH
      were unchanged. A significant reduction in the PtO2 response to hyperoxia was
      observed in animals treated with the NOS inhibitor NG-nitro-L-arginine methyl
      ester (L-NAME), an effect not reversed by fluid resuscitation. These data suggest
      that significant tissue hypoxia and abnormal microvascular control occur in
      endotoxemia. Volume resuscitation can reverse the changes in PtO2, whereas nitric
      oxide synthase (NOS) inhibition has deleterious effects on muscle PtO2 in both
      control and endotoxemic animals.

PMID- 10351909
TI  - Response of ventilator-dependent patients to different levels of pressure support
      and proportional assist.
AB  - The ventilator's response to the patient's effort is quite different in
      proportional assist ventilation (PAV) and pressure support ventilation (PSV). We
      wished to determine whether this results in different ventilatory and breathing
      pattern responses to alterations in level of support and, if so, whether there
      are any gas exchange consequences. Fourteen patients were studied. Average
      elastance (E) was 22.8 (range, 14 -36) cm H2O/L and average resistance (R) was
      15. 7 (range, 9-21) cm H2O/L/s. The highest PSV support (PSVmax) was that
      associated with a tidal volume (VT) of 10 ml/kg (20.4 +/- 3.2 cm H2O), and the
      highest level of PAV assist (PAVmax) was 78 +/- 7% of E and 76 +/- 7% of R. Level
      of assist was decreased in steps to the lowest tolerable level (PSVmin, PAVmin).
      Minute ventilation, VT, ventilator rate (RRvent), and arterial gas tensions were
      measured at each level. We also determined the patient's respiratory rate (RRpat)
      by adding the number of ineffective efforts (DeltaRR) to RRvent. There was no
      difference between PSVmin and PAVmin in any of the variables. At PSVmax, VT was
      significantly higher (0.90 +/- 0.30 versus 0.51 +/- 0.16 L) and RRvent was
      significantly lower (13.2 +/- 3.9 versus 27.6 +/- 10.5 min-1) than at PAVmax. The
      difference in RRvent was largely related to a progressive increase in ineffective
      efforts on PSV as level increased (DeltaRR 12.1 +/- 10.1 vs 1.4 +/- 2.1 with
      PAVmax); there was no significant difference in RRpat. The differences in
      breathing pattern had no consequence on arterial blood gas tensions. We conclude
      that substantial differences in breathing pattern may occur between PSV and PAV
      and that these are largely artifactual and related to different patient
      ventilator interactions.

PMID- 10351910
TI  - Effects of endurance training on skeletal muscle bioenergetics in chronic
      obstructive pulmonary disease.
AB  - Physiologic adaptations after an 8-wk endurance training program were examined in
      13 patients with chronic obstructive pulmonary disease (COPD) (age, 64 +/- 4 [SD]
      yr; FEV1, 43 +/- 9% pred; PaO2, 72 +/- 8 mm Hg; and PaCO2, 36 +/- 2 mm Hg) and in
      eight healthy sedentary control subjects (61 +/- 4 yr). Both pre- and post
      training studies included: (1) whole-body oxygen consumption (V O2) and one-leg
      O2 uptake (V O2leg) during exercise; and (2) intracellular pH (pHi) and inorganic
      phosphate to phosphocreatine ratio ([Pi]/[PCr]) during exercise; and half-time of
      [PCr] recovery. After training, the two groups increased peak V O2 (p < 0.05
      each) and showed a similar fall in submaximal femoral venous lactate levels (p <
      0.05 each). However, control subjects increased peak V E (p < 0.01) and raised
      peak O2 delivery (p = 0.05), not shown in patients with COPD. Both groups
      increased post-training O2 extraction ratio (p < 0.05). The most consistent
      finding, however, was in patients with COPD, who had a substantial improvement in
      cellular bioenergetics: (1) half-time of [PCr] recovery fell from 50 +/- 8 to 34
      +/- 7 s (p = 0.02); and (2) at a given submaximal work rate, [Pi]/[PCr] ratio
      decreased and pHi increased (p < 0.05 each). We conclude that beneficial effects
      of training in patients with COPD essentially occurred at muscle level during
      submaximal exercise.

PMID- 10351911
TI  - Asthma guidelines: an assessment of physician understanding and practice.
AB  - In 1997 the NHLBI updated guidelines for the diagnosis and management of asthma.
      We hypothesized that not all components of the updated guidelines are well
      understood by the physicians who care for asthmatics. To develop appropriate
      educational interventions that address areas of physician misunderstanding, it is
      important to identify these components. Based upon NHLBI guidelines, we developed
      a multiple-choice test of asthma knowledge that was distributed to physicians at
      the University of Iowa; 108 physicians completed the test, including 20 asthma
      specialists, 11 asthma specialty fellows, 11 General Medicine faculty, five
      Family Medicine faculty, 51 Internal Medicine residents, and five Family Medicine
      residents. The mean correct total score for all physicians was 60 +/- 2% (mean +/
      SEM). Asthma specialists scored higher in total score and in pharmacology and
      prevention. However, no group performed well on estimating disease severity. We
      further identified deficits in the use of spirometry and anti-inflammatory agents
      in caring for asthmatic patients. Thus, deficits exist in physician understanding
      and implementation of the NHLBI guidelines for the diagnosis and management of
      asthma. By identifying specific areas of misunderstanding, we can design better
      educational interventions. Clearly, educational programs should emphasize new
      models for estimating chronic disease severity.

PMID- 10351912
TI  - Risk factors for developing pneumonia within 48 hours of intubation.
AB  - Two hundred fifty intubated patients were followed during the first 48 h after
      intubation in order to identify potential risk factors for developing pneumonia
      within this period. Thirty-two developed pneumonia during this time. Univariate
      analysis established that large volume aspiration, presence of sedation,
      intubation caused by respiratory/cardiac arrest or decrease in the level of
      consciousness, emergency procedure, cardiopulmonary resuscitation (CPR), and
      Glasgow coma score < 9 were significantly associated with pneumonia. In contrast,
      prior infection and prior antimicrobial use were associated with a protective
      effect. Presence of subglottic secretion drainage and 15 other variables had no
      significant effect. Multivariate analysis selected CPR (odds ratio [OR] = 5.13,
      95% confidence intervals [CI] = 2.14, 12.26) and continuous sedation (OR = 4.40,
      95% CI = 1.83, 10.59) as significant risk factors for pneumonia, while antibiotic
      use (OR = 0.29, 95% CI = 0.12, 0.69) showed a protective effect. Our findings
      emphasize that risk factors for pneumonia change during the intubation period,
      and preventing pneumonia requires a combined approach.

PMID- 10351913
TI  - Growth of lungs after transplantation in infants and in children younger than 3
      years of age.
AB  - We report serial measurements of lung volume and airflow in small children after
      lung transplantation. We expected that immature lungs could grow and develop
      normal volumes after transplantation, despite denervation and immunosuppression.
      At predetermined intervals, functional residual capacity (FRC) and forced
      expiratory flow were measured 86 times in 23 recipients younger than 3 yr of age
      (age at transplant, 13.2 +/- 8.4 mo; range, 2 to 30 mo). FRC was measured using
      open-circuit N2 washout. Maximal flow at FRC by rapid thoracoabdominal
      compression was used to distinguish between infants with and those without
      airflow obstruction. The slope of FRC (in milliliters) versus body length (in
      centimeters) for all 23 recipients studied was 8.63. For those children without
      obstruction (flow at FRC >/= 0.9 FRC/s, n = 16), the slope of FRC versus length
      was 6.61. The coefficient of variation for FRC measurements for all infants was
      3.90 +/- 2.80% (range, 0.3 to 16.9%). We conclude that in the absence of
      significant airflow obstruction the volume of transplanted immature lungs
      increases at a rate similar to that reported in normal infants.

PMID- 10351914
TI  - Hyperinflation-induced lung injury during alveolar flooding in rats: effect of
      perfluorocarbon instillation.
AB  - Mechanical nonuniformity of diseased lungs may predispose them to ventilator
      induced lung injury (VILI) by overinflation of the more compliant, aerated zones.
      Perfluorocarbon (PFC) may reduce this nonuniformity by suppressing air-liquid
      interfaces. Saline (6.8 ml/kg) was instilled into the trachea to mimic alveolar
      edema and reduce aerated lung volume before mechanical ventilation (6, 16, 24, or
      32 ml/kg tidal volume [VT]) for 10 min in rats. Flooding significantly aggravated
      VILI when VT was 24 or 32 ml/kg, with an increase in the distribution space of
      albumin in lungs (p < 0.001). Tracheal instillation of a low dose (3.3 ml/kg) of
      PFC (Liquivent) either before or after the instillation of saline considerably
      reduced VILI (p < 0.001). Saline instillation raised the lower inflection point
      of the respiratory system pressure-volume curve to values as high as 25 cm H2O,
      and produced a significant increase in end-inspiratory pressure (from 38 +/- 2.0
      cm H2O to 61 +/- 2.4 cm H2O, for a VT of 32 ml/kg; p < 0.001). PFC significantly
      reduced the pressure at the lower inflection point and normalized end-inspiratory
      pressure. These decreases were correlated with a smaller albumin distribution
      space (p < 0.001). Animals in which PFC instillation failed to reduce the albumin
      space had pressures similar to those of animals given saline alone. In
      conclusion, the effectiveness of PFC instillation in reducing VILI may be
      predicted by the shape of the pressure-volume curve. These findings may help in
      designing safer clinical studies of mechanical ventilation and in reducing the
      cost of partial liquid ventilation by reducing doses of PFC.

PMID- 10351915
TI  - Norepinephrine and nomega-monomethyl-L-arginine in porcine septic shock: effects
      on hepatic O2 exchange and energy balance.
AB  - We compared the effects of norepinephrine (NOR; n = 11) and the nonselective
      nitric oxide synthase inhibitor Nomega-monomethyl-L-arginine (L-NMMA; n = 11) on
      hepatic blood flow (Q liv), O2 exchange, and energy metabolism over 24 h of
      hyperdynamic, normotensive porcine endotoxic shock. Endotoxin (ETX; n = 8) caused
      a continuous fall in mean arterial pressure (MAP) despite a sustained 50%
      increase in cardiac output (Q) achieved by adequate fluid resuscitation. NOR
      maintained MAP at preshock levels owing to a further rise in Q, while the
      comparable hemodynamic stabilization during L-NMMA infusion resulted from
      systemic vasoconstriction, increasing the systemic vascular resistance (SVR)
      about 30% from shock level after 6 h of treatment concomitant with a reduction in
      Q to preshock values. Whereas NOR also increased Q liv and, hence, hepatic O2
      delivery (hDO2), but did not affect hepatic O2 uptake (hVO2), L-NMMA influenced
      neither Q liv nor hDO2 and hVO2. Mean capillary hemoglobin O2 saturation (HbScO2)
      on the liver surface as well as HbScO2 frequency distributions, which mirror
      microcirculatory O2 availability, remained unchanged as well. Neither treatment
      influenced the ETX-induced derangements of cellular energy metabolism reflected
      by the progressive decrease in hepatic lactate uptake rate and increased hepatic
      venous lactate/pyruvate ratios. ETX nearly doubled the endogenous glucose
      production (EGP) rate, which was further increased with NOR, whereas L-NMMA
      nearly restored EGP to preshock levels. Nevertheless, despite the different
      mechanisms in maintaining blood pressure neither treatment influenced ETX-induced
      liver dysfunction.

PMID- 10351916
TI  - Manifestation of pulmonary hypertension during REM sleep in obstructive sleep
      apnea syndrome.
AB  - The effect of sleep stage change on pulmonary circulation has not been well
      documented in patients with obstructive sleep apnea syndrome (OSAS). We
      investigated whether or not stage-specific change can affect pulmonary artery
      pressure (Ppa) in patients with OSAS. Thirty-one patients with OSAS underwent
      right cardiac catheterization in the daytime and the following night, including
      19 patients in whom Ppa could be measured throughout non-rapid eye movement
      (NREM) and rapid eye movement (REM) sleep. Ten of the 19 patients had daytime
      pulmonary hypertension (PH) defined by a mean Ppa (Ppa) >/= 20 mm Hg. Then we
      analyzed Ppa response to hypoxia spontaneously occurring during the period of
      sleep apnea. The slopes of the regression lines between arterial oxygen
      saturation measured by pulse oximeter (SpO2) and Ppa curves were almost the same
      in both NREM and REM patient groups with or without daytime PH, whereas the
      response curve was significantly shifted upward in REM compared with NREM
      patients with daytime PH. Furthermore, Ppa was elevated more markedly in
      association with REM burst, phasic REM, compared with tonic REM. We conclude that
      vascular tone of pulmonary artery could be elevated in association with REM sleep
      which is independent of the degree of hypoxia, and that this state-specific
      change is manifested in patients with daytime PH.

PMID- 10351917
TI  - Cigarette smoking and ozone-associated emergency department use for asthma by
      adults in New York City.
AB  - The association between ambient ozone (O3) and hospital use for asthma in
      children and adults is well documented. The question remains of whether there are
      susceptible subpopulations of asthmatic individuals who are particularly
      vulnerable to high O3 levels. Because tobacco use was prevalent in our cohort of
      inner-city adult asthmatic individuals (n = 1,216) in New York City (NYC), we
      investigated whether cigarette smoking was an effect modifier for asthma
      morbidity. We examined the relationship between personal tobacco use and O3
      associated emergency department (ED) use for asthma in public hospitals in NYC.
      Three subpopulations were defined: never smokers (0 pack-yr), heavy smokers (>/=
      13 pack-yr) and light smokers (< 13 pack-yr). Time-series regression analysis of
      ED use for asthma and daily O3 levels was done while controlling for temperature,
      seasonal/long-term trends, and day-of-week effects. Heavy smokers displayed an
      increased relative risk (RR) of ED visits for asthma in response to increases in
      2-d lagged O3 levels (RR per 50 ppb O3 = 1.72; 95% confidence interval: 1.13 to
      2.62). Logistic regression analysis confirmed that heavy cigarette use was a
      predictor of ED use for asthma following days with high O3 levels. Although
      adverse health effects of ambient O3 have also been documented in asthma
      populations not using cigarettes (e.g., children), our results suggest that in
      adult asthmatic individuals, heavy personal tobacco use may be an effect modifier
      for O3-associated morbidity.

PMID- 10351918
TI  - Docosahexaenoic acid and smoking-related chronic obstructive pulmonary disease.
      The Atherosclerosis Risk in Communities Study Investigators.
AB  - If the inflammatory response to inhalation of cigarette smoke causes chronic
      obstructive pulmonary disease (COPD), suppression of that natural response might
      be beneficial. We hypothesized that a smoker's risk of developing COPD is
      inversely related to physiologic levels of two fatty acids that have
      antiinflammatory properties: eicosapentaenoic acid (EPA, C20:5) and
      docosahexaenoic acid (DHA, C22:6). The proportion of each fatty acid in plasma
      lipids was measured in 2,349 current or former smokers. COPD was identified and
      defined by clinical symptoms and/or spirometry. After adjustment for smoking
      exposure and other possible confounders, the prevalence odds of COPD were
      inversely related to the DHA (but not to the EPA) content of plasma lipid
      components in most of the models. For example, as compared with the first
      quartile of the DHA distribution, the prevalence odds ratios (ORs) for chronic
      bronchitis were 0.98, 0.88, and 0.69 for the second, third, and fourth quartiles,
      respectively (p for linear trend = 0.09). The corresponding ORs for COPD as
      defined spirometrically, were 0.65, 0.51, and 0.48 (p < 0. 001). Among 543
      current heavy smokers, adjusted mean values of FEV1 (lowest to highest DHA
      quartile) were 2,706, 2,785, 2,801, and 2,854 ml. DHA may have a role in
      preventing or treating COPD and other chronic inflammatory conditions of the
      lung. Pilot testing of that hypothesis in experimental models seems warranted.

PMID- 10351919
TI  - Differential effect of formoterol on adenosine monophosphate and histamine
      reactivity in asthma.
AB  - Short-acting beta2-agonists provide greater protection against
      bronchoconstriction induced by adenosine 5'-monophosphate (AMP) than by direct
      acting bronchoconstrictors such as histamine and methacholine. AMP is thought to
      cause bronchoconstriction via release of mediators from mast cells, which
      suggests that these drugs stabilize mast cells in vivo. This in vivo property has
      not yet been demonstrated for long-acting beta2-agonists. We undertook a double
      blind, randomized, placebo-controlled, cross-over study to investigate the
      effects of a single dose of formoterol inhaled via Turbuhaler (12 micrograms) and
      of albuterol inhaled via Turbuhaler (200 micrograms) on airway responsiveness to
      AMP and histamine in 16 subjects with mild atopic asthma. Albuterol reduced
      airway responsiveness to AMP and histamine by 4.1 +/- 0.5 and 3.5 +/- 0.4
      doubling doses, respectively. In contrast, formoterol caused a greater protective
      effect against AMP than against histamine challenge, decreasing airway
      responsiveness by 6.0 +/- 0.8 and 4.2 +/- 0.4 doubling doses, respectively (p <
      0.05). Thus, the long-acting beta2-agonist formoterol appears to have a mast cell
      stabilizing effect in vivo in mild asthma.

PMID- 10351920
TI  - The DD genotype of the angiotensin converting enzyme gene is negatively
      associated with right ventricular hypertrophy in male patients with chronic
      obstructive pulmonary disease.
AB  - The renin angiotensin system plays an important role in the development of
      pulmonary artery remodeling and right ventricular hypertrophy in hypoxia-induced
      pulmonary hypertension as may occur in patients with COPD. Several polymorphisms
      of genes encoding for components of the renin angiotensin system such as the
      M235T polymorphism in the angiotensinogen gene, the 287-base-pair insertion
      (I)/deletion (D) polymorphism at intron 16 of the ACE gene, and the A1166C
      polymorphism in the angiotensin II type 1 receptor gene have been associated with
      an increased risk of cardiovascular diseases. With respect to the pulmonary
      circulation, only limited data exist on possible associations between
      polymorphisms of these genes and pulmonary hypertension and/or right ventricular
      hypertrophy. The objective of the present study was to investigate a possible
      relationship between polymorphisms of the renin angiotensin system and
      electrocardiographic evidence of right ventricular hypertrophy in patients with
      COPD. We therefore determined the angiotensinogen (M235T), angiotensin converting
      enzyme (I/D), and angiotensin II type 1 receptor (A1166C) genotypes in 87
      patients with severe COPD and correlated these data with electrocardiographic
      parameters of right ventricular hypertrophy. Thirty-one patients (36%) of 87
      patients with COPD showed electrocardiographic evidence of right ventricular
      hypertrophy. In the male, but not in the female, subgroup, the angiotensin
      converting enzyme DD genotype was negatively associated with electrocardiographic
      evidence of right ventricular hypertrophy (male: chi2 = 3.8, p = 0.05; female:
      chi2 = 0.05, p = 0.82). We found no associations between the investigated
      polymorphisms in the angiotensinogen and angiotensin II type 1 receptor genes and
      electrocardiographic evidence of right ventricular hypertrophy.

PMID- 10351921
TI  - Suggestive evidence for genetic linkage between IgE phenotypes and chromosome 14q
      markers.
AB  - Chromosome 14q was screened for loci modulating immunoglobulin E (IgE) phenotypes
      in 15 extended and 45 nuclear asthmatic families using a panel of 14
      microsatellite markers. We examined the reported linkage between the TCR A/D
      locus on 14q11.2 and specific (cognate) allergic responses and observed
      supportive evidence for linkage between a general skin prick test reactivity
      trait (but not with total serum IgE) and TCRA microsatellite (in the total sample
      of informative sib-pairs p = 0.039, in selected sample of one or zero affected
      parent p = 0.017). We also show suggestive evidence for a novel linkage between
      markers D14S75 and D14S63 on 14q13-23 and log total serum IgE (p = 0.034 and p =
      0.0029). The evidence for linkage with marker D14S63 on 14q23 is strengthened by
      the finding of association of allele 165 to log IgE (p = 0.0029). We conclude
      that chromosome 14q may contain a locus close to TCR A/D at 14q11.2 linked to
      skin prick reactivity and a locus at 14q13- 23 linked to total serum IgE.

PMID- 10351922
TI  - Dysfunction of pulmonary surfactant in asthmatics after segmental allergen
      challenge.
AB  - Increased airway resistance in asthma may be partly due to poor function of
      pulmonary surfactant. This study investigated the inflammatory changes of
      bronchoalveolar lavage fluid (BALF) and the performance of BALF surfactant in
      healthy control subjects (n = 9) and patients with mild allergic asthma (n = 15)
      before and after segmental challenge. BALF was obtained for baseline values, and
      24 h after challenge with saline solution in one lung segment and with allergen
      in another. Cell counts, phospholipid and protein concentrations, and ratios of
      small to large surfactant aggregates (SA/LA) were analyzed. Surface tension was
      determined with a pulsating bubble surfactometer, and the ability of the BALF
      surfactant to maintain airway patency was assessed with a capillary
      surfactometer. Baseline values of control subjects and asthmatics were not
      different. Challenge with saline and antigen raised total inflammatory cells in
      both control subjects and asthmatics. Allergen challenge of asthmatics, but not
      of healthy volunteers, significantly increased eosinophils, proteins, SA/ LA, and
      surface tension at minimum bubble size, and diminished the time the capillary
      tube is open. In conclusion, allergen challenge in asthmatics induced surfactant
      dysfunction, probably mainly because of inhibiting proteins. During an asthma
      attack, narrow conducting airways may become blocked, which might contribute to
      an increased airway resistance.

PMID- 10351923
TI  - Exhaled nitric oxide as a noninvasive assessment of chronic cough.
AB  - Exhaled nitric oxide (ENO) has been suggested as a marker of airway inflammation.
      This study aimed to evaluate the role of ENO in the investigation of chronic
      cough. We measured ENO in 38 adult patients reporting chronic cough, in 23
      healthy control subjects, and in 44 asthmatics. In addition to the regular
      investigation, ENO was measured by a chemiluminescent analyzer using the
      restricted breath technique. In the chronic cough group, 30 were considered as
      nonasthmatic, whereas asthma was diagnosed in eight by a positive methacholine
      challenge. ENO values were significantly higher in patients with chronic cough
      attributable to asthma as compared with those with chronic cough not attributable
      to asthma and to healthy volunteers (75.0 ppb; 16.7 ppb; and 28.3 ppb,
      respectively). The sensitivity and specificity of ENO for detecting asthma, using
      30 ppb as the ENO cutoff point, were 75 and 87%, respectively. The positive and
      negative predictive values were 60 and 93%, and the positive and negative
      likelihood ratios were 5.8 and 0.3, respectively. We conclude that ENO may have a
      role in the evaluation of chronic cough. In this group of patients, low ENO
      suggested little likelihood of asthma. The patients with chronic cough not
      attributable to asthma showed a low ENO value as compared with healthy volunteers
      and asthmatics.

PMID- 10351924
TI  - Randomized placebo-controlled study comparing a leukotriene receptor antagonist
      and a nasal glucocorticoid in seasonal allergic rhinitis.
AB  - Allergic rhinitis is an inflammatory disorder associated with local leukotriene
      release during periods of symptoms. Therefore, it has been suggested that
      antileukotrienes may be beneficial in the treatment of this disease. Leukotriene
      receptor antagonists have recently become available for asthma treatment, but
      little is known of their effects on allergic rhinitis. We have evaluated the
      effects of the leukotriene receptor antagonist zafirlukast versus placebo in
      patients with allergic rhinitis during the grass pollen season, using the nasal
      glucocorticoid beclomethasone dipropionate (BDP) as a positive treatment control.
      Thirty-three patients with seasonal allergic rhinitis were in a double-blind,
      double-dummy fashion randomized to treatments with oral zafirlukast (20 mg twice
      a day), intranasal beclomethasone dipropionate (200 microg twice a day), or
      placebo. The treatment was initiated 3 wk prior to the expected beginning of the
      grass pollen season. Patients completed a daily symptom-score list for sneezing,
      rhinorrhea, nasal itch, and nasal blockage during the 50-d treatment period.
      Nasal biopsies for quantification of local tissue eosinophilia
      (immunohistochemistry; EG2) were taken 1 mo before initiation of treatment and
      immediately after the peak of grass pollen season. Patients receiving treatment
      with zafirlukast had degrees of nasal symptoms similar to those in the placebo
      group, whereas the BDP group had significantly less symptoms compared with both
      treatments (p = 0.01 and p = 0.005, respectively). The numbers of activated
      eosinophils in the nasal tissue increased significantly during the pollen season
      in both the zafirlukast and the placebo groups, but not in the BDP group. These
      results obtained with a limited number of patients do not support any clinical
      efficacy of regular treatment with an oral antileukotriene in seasonal allergic
      rhinitis but rather favor the use of a nasal glucocorticoid.

PMID- 10351925
TI  - Exercise-induced bronchospasm in children: effects of asthma severity.
AB  - The prevalence of exercise-induced bronchospasm (EIB) in asthmatic individuals
      has been reported to vary from 40% to 90%. There are, however, few studies
      addressing the effects of asthma severity on airway responsiveness to exercise.
      The purpose of the present study was to investigate the effects of asthma
      severity on EIB in children. We studied 164 children classified as having
      intermittent (n = 63), mild persistent (n = 30), moderate persistent (n = 40),
      and severe persistent asthma (n = 31) according to the Global Initiative for
      Asthma classification. Subjects exercised for 6 min on a cycle ergometer at 80%
      of their maximum heart rate, and spirometry was performed before and 5, 10, and
      20 min after exercise challenge. The prevalence of EIB in children with moderate
      or severe persistent asthma was significantly greater than in children with
      intermittent asthma (p < 0.001). EIB-positive children with intermittent asthma
      exhibited smaller changes in FEV1 than children in the other three groups (p <
      0.001). There was no significant relationship between baseline FEV1 and the
      decline in FEV1 after exercise. We conclude that the prevalence of EIB is greater
      in children with more severe asthma, and that the intensity of response to
      exercise is not consistently related to the clinical severity of asthma.

PMID- 10351926
TI  - Increased glutathione and glutathione peroxidase in lungs of individuals with
      chronic beryllium disease.
AB  - Reactive oxygen species (ROS) are mediators of chronic tissue damage and
      fibrosis. Endogenous antioxidants may increase in response to oxidants and reduce
      tissue injury. We investigated the antioxidant response of the lungs to the
      chronic release of ROS, as occurs in the immune-specific granulomatous
      inflammation of chronic beryllium disease (CBD), and compared it with that in
      healthy controls and individuals exposed to cigarette smoke. The antioxidants
      superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and
      glutathione (GSH) were quantitated in lung epithelial lining fluid (ELF) and
      serum from control subjects (n = 10), cigarette smokers (n = 8), and individuals
      with CBD (n = 9). GPx activity and extracellular GPx (eGPx) protein were
      increased in the ELF of subjects with CBD in comparison with that of control
      subjects and smokers (eGPx in ELF: controls, 1.3 +/- 0.2 microgram/ml, smokers,
      1.9 +/- 0.3 microgram/ml, CBD, 3.8 +/- 0.8 microgram/ml; p = 0.002; GPx U/ml ELF,
      controls 1.4 +/- 0.3, smokers 1.8 +/- 0.4, CBD, 4.5 +/- 1, p = 0.02). Smokers'
      ELF had higher levels of GSH than that of controls, but CBD patients' ELF
      contained much more GSH than that of either controls or smokers (p < 0.001).
      Increases in GSH were correlated with eGPx, indicating similar inducing
      mechanisms for these antioxidants. Thus, coordinate augmentation of the
      glutathione antioxidant system occurs in granulomatous lung inflammation.

PMID- 10351927
TI  - Expression of costimulatory molecules on alveolar macrophages in hypersensitivity
      pneumonitis.
AB  - To verify whether alveolar macrophages (AM) of patients with hypersensitivity
      pneumonitis (HP) increase their antigen-presenting capacity by upregulating the
      expression of B7 costimulatory molecules (CD80, CD86), and whether a viral
      infection enhances this expression whereas cigarette smoking abrogates it, we
      performed bronchoalveolar lavage (BAL) on 18 patients with HP; 10 asymptomatic,
      virus-exposed subjects (AS); 18 nonsmokers; and 12 smokers. Influenza virus
      infection of AM from nonsmokers and smokers was induced in vitro. Expression of
      CD80 and CD86 on AM, and of CD28 and CTLA4 on T cells, was evaluated. The
      percentage of CD80(+) AM was greater in HP patients (34.6 +/- 7.7) and in AS
      (23.9 +/- 7.6) than in nonsmokers (6.7 +/- 1.6) or smokers (2.5 +/- 0.3). An
      increase in CD86(+) cells (62.3 +/- 5.9) was found in HP patients as compared
      with nonsmokers (24.2 +/- 3.8) and smokers (4.5 +/- 1.0). CD28 and CTLA4
      molecules were highly expressed on all T cells. In vitro virus infection
      upregulated CD80 and CD86 expression in AM of normal nonsmoking subjects but not
      on those of smokers. These results suggest that: (1) an upregulation of B7
      molecule expression is involved in the lymphocytic alveolitis of HP; (2) a viral
      infection could enhance HP by increasing B7 expression; and (3) the protective
      effect of cigarette smoking in HP may be due to the low level of expression of
      costimulatory molecules on AM from smokers, and to their resistance to further
      upregulation.

PMID- 10351928
TI  - Pneumonia acquired in the community through drug-resistant Streptococcus
      pneumoniae.
AB  - The aim of the study was to determine the incidence of and risk factors for drug
      resistance of Streptococcus pneumoniae, and its impact on the outcome among
      hospitalized patients of pneumococcal pneumonia acquired in the community.
      Consecutive patients with culture-proven pneumococcal pneumonia were
      prospectively studied with regard to the incidence of pneumococcal drug
      resistance, potential risk factors, and in-hospital outcome variables. A total of
      101 patients were studied. Drug resistance to penicillin, cephalosporin, or a
      macrolide drug was found in pneumococci from 52 of the 101 (52%) patients; 49% of
      these isolates were resistant to penicillin (16% intermediate resistance, 33%
      high resistance), 31% to cephalosporin (22% intermediate and 9% high resistance),
      and 27% to a macrolide drug. In immunocompetent patients, age > 65 yr was
      significantly associated with resistance to cephalosporin (odds ratio [OR]: 5.0;
      95% confidence interval [CI]: 1.3 to 18.8, p = 0. 01), and with the presence of >
      2 comorbidities with resistance to penicillin (OR: 4.7; 95% CI: 1.2 to 19.1; p <
      0.05). In immunosuppressed patients, bacteremia was inversely associated with
      resistance to penicillin and cephalosporin (OR: 0.04; 95% CI: 0.003 to 0.45; p <
      0.005; and OR: 0.46; 95% CI: 0.23 to 0.93; p < 0.05, respectively). Length of
      hospital stay, severity of pneumonia, and complications were not significantly
      affected by drug resistance. Mortality was 15% in patients with any drug
      resistance, as compared with 6% in those without resistance. However, any drug
      resistance was not significantly associated with death (relative risk [RR]: 2. 5;
      95% CI: 0.7 to 8.9; p = 0.14). Moreover, attributable mortality in the presence
      of discordant antimicrobial treatment was 12%, as compared with 10% (RR: 1.2; 95%
      CI: 0.3 to 5.3; p = 0.67) in the absence of such treatment. We conclude that the
      incidence of drug-resistant pneumococci was high. Risk factors for drug
      resistance included advanced age, comorbidity, and (inversely) bacteremia.
      Outcome was not significantly affected by drug resistance.

PMID- 10351929
TI  - Inhalation of dry powder mannitol improves clearance of mucus in patients with
      bronchiectasis.
AB  - Bronchiectasis is a disease characterized by hypersecretion and retention of
      mucus requiring physical and pharmacologic treatment. Recently we reported that
      inhalation of dry powder mannitol markedly increases mucociliary clearance (MCC)
      in asthmatic and in healthy subjects (Daviskas, E., S. D. Anderson, J. D.
      Brannan, H. K. Chan, S. Eberl, and G. Bautovich. 1997. Inhalation of dry-powder
      mannitol increases mucociliary clearance. Eur. Respir. J. 10:2449-2454). In this
      study we investigated the effect of mannitol on MCC in patients with
      bronchiectasis. Eleven patients 40 to 62 yr of age inhaled mannitol
      (approximately 300 mg) from a Dinkihaler. MCC was measured over 90 min, in the
      supine position, on three occasions involving: mannitol or control or baseline,
      using a radioaerosol technique. On the control day patients reproduced the
      breathing maneuvers and the number of coughs induced by the mannitol. Mannitol
      significantly increased MCC over the 75 min from the start of the intervention
      compared with control and baseline in the whole right lung, central, and
      intermediate region. Mean (+/- SEM) clearance with mannitol was 34.0 +/- 5.0%
      versus 17.4 +/- 3.8% with control and 11.7 +/- 4.4% with baseline in the whole
      right lung (p < 0.0001). The mean number of coughs induced by mannitol was 49 +/-
      11. In conclusion, inhalation of dry powder mannitol increased clearance of mucus
      and thus has the potential to benefit patients with bronchiectasis.

PMID- 10351930
TI  - Incidence and mortality after acute respiratory failure and acute respiratory
      distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group.
AB  - To determine the incidence and 90-d mortality of acute respiratory failure (ARF),
      acute lung injury (ALI), and the acute respiratory distress syndrome (ARDS), we
      carried out an 8-wk prospective cohort study in Sweden, Denmark, and Iceland. All
      intensive care unit (ICU) admissions (n = 13,346) >/= 15 yr of age were assessed
      between October 6th and November 30th, 1997 in 132 of 150 ICUs with resources to
      treat patients with intubation and mechanical ventilation (I + MV) >/= 24 h. ARF
      was defined as I + MV >/= 24 h. ALI and ARDS were defined using criteria
      recommended by the American-European Consensus Conference on ARDS. Calculation to
      correct the incidence for unidentified subjects from nonparticipating ICUs was
      made. No correction for in- or out-migration from the study area was possible.
      The population in the three countries >/= 15 yr of age was 11.74 million. One
      thousand two hundred thirty-one ARF patients were included, 287 ALI and 221 ARDS
      patients were identified. The incidences were for ARF 77.6, for ALI 17.9, and for
      ARDS 13.5 patients per 100,000/yr. Ninety-day mortality was 41.0% for ARF,
      including ALI and ARDS patients, 42.2% for ALI not fulfilling ARDS criteria, and
      41.2% for ARDS.

PMID- 10351931
TI  - Combined treatment with surfactant and specific immunoglobulin reduces bacterial
      proliferation in experimental neonatal group B streptococcal pneumonia.
AB  - Neonates suffering from group B streptococcal (GBS) pneumonia often lack type
      specific opsonizing antibodies. We studied the influence of combined
      intratracheal treatment with surfactant and a specific antibacterial polyclonal
      antibody (IgG fraction) on bacterial proliferation and lung function in an animal
      model of GBS pneumonia. Near-term newborn rabbits received an intratracheal
      injection of either the specific IgG antibody, nonspecific IgG, surfactant, a
      mixture of surfactant and the antibody, or 0.9% saline. At 30 min the rabbits
      were infected with a standard dose (10(8)) of the encapsulated GBS strain 090 Ia.
      After 5 h of mechanical ventilation the mean estimated increase in bacterial
      number in lung homogenate (log10 colonies/g) was 0.76 in the antibody group, 0.92
      in the nonspecific IgG group, 0.55 in the surfactant group, and 1.29 in the
      saline group. A mean decrease in bacterial number (-0.05) was observed in the
      group that received combined treatment with surfactant and antibody (p < 0.05
      versus all other groups). Lung-thorax compliance was significantly higher in both
      groups of surfactant-treated animals compared with saline or IgG treatment. We
      conclude that in experimental neonatal GBS pneumonia combined treatment with
      surfactant and a specific immunoglobulin against GBS reduced bacterial
      proliferation more effectively than either treatment alone.

PMID- 10351932
TI  - Value of the polymerase chain reaction assay in noninvasive respiratory samples
      for diagnosis of community-acquired pneumonia.
AB  - We studied the causes of community-acquired pneumonia (CAP) in 184 patients.
      Microbiologic evaluation included sputum examination, blood culture, assessment
      of acute and convalescent antibody titers for Legionella pneumophila, Mycoplasma
      pneumoniae, Chlamydia pneumoniae, Coxiella psitacci, Coxiella burnetii and
      respiratory viruses, polymerase chain reaction (PCR) assays for M. pneumoniae and
      C. pneumoniae in throat swab, and PCR assay based on the amplification of
      pneumolysin gene fragment in sera. The causative pathogen was identified in 78
      patients (Streptococcus pneumoniae, 44; M. pneumoniae, 26; C. pneumoniae, 1;
      others, 7). S. pneumoniae was detected in serum by the PCR assay in 41 patients,
      five of whom also had a positive blood culture. PCR assay was negative in two
      patients with positive blood culture for S. pneumoniae. C. pneumoniae was
      detected by PCR in nine patients, but only one showed seroconversion. M.
      pneumoniae was detected by PCR in only three patients (two without
      seroconversion). The diagnosis of pneumonia caused by S. pneumoniae was five
      times greater using PCR in serum than with blood culture. Detection of C.
      pneumoniae by PCR without fulfilling criteria for acute infection may be
      considered a prior infection. The PCR assay for the diagnosis of M. pneumoniae
      has a lower sensitivity than serologic methods.

PMID- 10351933
TI  - A novel, short, and simple questionnaire to measure health-related quality of
      life in patients with chronic obstructive pulmonary disease.
AB  - A novel, short, and simple questionnaire, the Airways Questionnaire 20 (AQ20),
      has been developed to measure and quantify disturbances in the health-related
      quality of life (HRQoL) of patients with asthma or chronic obstructive pulmonary
      disease (COPD). The AQ20 has 20 items with yes/no responses, and should take 2
      min to complete and score. The purpose of this study was to assess the
      discriminative properties and responsiveness of the AQ20 in patients with COPD.
      First, in a cross- sectional study, 165 patients with mild-to-severe COPD (mean
      age, 69 +/- 7 yr; FEV1, 40 +/- 16% of predicted) completed the AQ20, the St.
      George's Respiratory Questionnaire (SGRQ), the Chronic Respiratory Disease
      Questionnaire (CRQ), pulmonary function tests, a progressive cycle ergometer
      exercise test, and an assessment of their dyspnea and anxiety. The score
      distribution of the AQ20 was skewed toward the mild end of the scale, whereas the
      SGRQ and CRQ showed a normal distribution. The AQ20 showed a moderately strong
      correlation with the maximal oxygen uptake and the assessment of dyspnea
      (Spearman's correlation coefficients [rs] = -0.49, -0.60, respectively), but a
      weak correlation with the FEV1 (rs = -0.18). Moderate to strong correlations were
      also recognized between the AQ20 and SGRQ and CRQ (rs = -0.80, -0.72,
      respectively). Multiple regression analysis revealed that dyspnea and anxiety
      accounted for 43% of the variance in the AQ20, almost the same as in the SGRQ and
      CRQ. Second, longitudinal changes over time in the FEV1, AQ20, SGRQ, and CRQ were
      examined in 86 patients with newly detected COPD (mean age, 69 +/- 8 yr; FEV1, 45
      +/- 19% of predicted). All three measures showed significant improvements in
      their scores over a 3-mo period after initiating medical intervention. The change
      in the AQ20 showed a moderate to strong correlation with each dimension of the
      SGRQ and CRQ (rs = 0.56, -0.52, respectively), but no significant correlation was
      noted with the FEV1. In conclusion, the AQ20 may have discriminative properties
      and responsiveness that are similar to more complex questionnaires such as the
      SGRQ and CRQ. Because it is short and can be quickly answered and scored, the
      AQ20 may be useful in studies with limited time for HRQoL assessments.

PMID- 10351934
TI  - Occupational asthma caused by isocyanates: patterns of asthmatic reactions to
      increasing day-to-day doses.
AB  - Inhalation challenges to isocyanates are conducted in specialized centers to
      confirm occupational asthma. The pattern of asthmatic reactions due to
      consecutively increasing daily doses of isocyanates is unknown. We conducted a
      study involving 24 subjects who had undergone specific inhalation challenges to
      isocyanates (toluene diisocyanate [TDI], n = 8; hexamethylene diisocyanate [HDI],
      n = 10; and methylene diisocyanate [MDI], n = 6) on three or more consecutive
      days. Challenge tests were given through a closed-circuit apparatus (n = 12) or
      in small cubicles (n = 12), allowing assessment of the total inhaled dose
      (concentration x duration). The pattern of asthmatic reactions was described. In
      addition, dose-response curves were analyzed and tested for their linear and
      quadratic trends. Four patterns of response were observed: (1) linear (n = 10);
      (2) minimal effect followed by a brisk change (n = 7); (3) significant change
      followed by tachyphylaxis or a plateau (n = 4); (4) biphasic (i.e., significant
      change followed by a reduction in the effect and significant change on the last
      day of exposure [n = 3]). Subjects with a linear dose-response pattern had been
      exposed to isocyanates at work for a significantly shorter interval (7.2 +/- 6.7
      yr) than subjects with a nonlinear pattern (20.0 +/- 13.1 yr). An analysis of
      variance covering a 3-d period for all subjects showed a significant linear model
      for the response (p < 0.0001); there was no quadratic trend. However, when the
      analysis was done on subjects with four or more days of challenge (n = 10), we
      found both linear and quadratic significant components. This analysis shows that
      the most common pattern of asthmatic reactions to inhaled isocyanates generated
      on consecutive days is linear; however, other patterns are also observed. In some
      individuals, particularly those in whom more days of challenge are required, we
      observed in addition to a strong linear component a quadratic component
      manifested by a brisk change on the last day of exposure.

PMID- 10351935
TI  - Health status in obstructive sleep apnea: relationship with sleep fragmentation
      and daytine sleepiness, and effects of continuous positive airway pressure
      treatment.
AB  - Patients with obstructive sleep apnea (OSA) have impaired health status that
      improves with nasal continuous positive airway pressure (nCPAP). The study
      reported here explored the relationships between health status, its improvement
      with nCPAP, sleep fragmentation, and daytime sleepiness. In the study, 51
      patients (46 male, five female) ranging from nonsnorers to individuals with
      severe OSA (median apnea/hypopnea index [AHI] 25, 90% central range: 1 to 98) had
      polysomnography with microarousal scoring, respiratory arousal scoring, and
      measurement of pulse transit time. The Short Form-36 Health Survey (SF-36)
      questionnaire was administered before and after 4 wk of nCPAP treatment; daytime
      sleepiness was also measured before starting nCPAP. Relationships between
      pretreatment health status and sleep fragmentation were weak, but significant
      associations were found between all sleep fragmentation indices and health status
      improvement with nCPAP (e.g., arousals according to the criteria of the American
      Sleep Disorders Association versus change in the physical component summary, r =
      0.44, p < 0.001). Compared with general population data, the dimensions of energy
      and vitality and physical role limitation were abnormal before nCPAP (p < 0.05)
      and normalized with treatment. Sleepiness and pretreatment SF-36 values
      correlated significantly (Epworth Sleepiness Scale versus energy and vitality, r
      = -0.47, p < 0.001; modified Maintenance of Wakefulness Test versus energy and
      vitality, r = 0.32, p < 0.05). We conclude that the health status of patients
      with OSA improves with nCPAP and this improvement correlates with sleep
      fragmentation severity. However, the correlation is not very close, which may
      reflect the improvement with nCPAP of other symptoms not directly related to
      disease severity.

PMID- 10351936
TI  - Association of radiologically ascertained pneumonia before age 3 yr with
      asthmalike symptoms and pulmonary function during childhood: a prospective study.
AB  - Epidemiologic evidence suggests an association between reports of pneumonia in
      early life and the subsequent development of diminished lung function. However,
      no studies are available in which the diagnosis of pneumonia was based on
      radiologic evidence. Lower respiratory illnesses with or without a radiologically
      confirmed diagnosis of pneumonia were assessed in a study of 888 children
      enrolled at birth. Pulmonary function tests, markers of atopy, asthma diagnosis,
      and prevalence of respiratory symptoms were assessed at different ages between
      birth and 11 yr. Incidence of pneumonia during the first 3 yr of life was 7.4%.
      Respiratory syncytial virus was the most frequent agent identified both in
      children with pneumonia and in those with lower respiratory tract illness (LRI)
      without pneumonia (36.4% versus 35.6%, respectively). Children with a diagnosis
      of pneumonia were more likely to have physician-diagnosed asthma and current
      wheezing at ages 6 and 11 yr than were those who had no LRIs. When compared with
      children without LRIs, those with a diagnosis of pneumonia had lower levels of
      maximal flows at FRC at mean age of 2 mo (albeit not significantly) and at age 6
      yr, and lower levels of FEV1 and FEF25-75 at age 11 yr. These deficits were
      independent of known confounders, including wheezing at the time of study, and
      were partly and significantly reversed after administration of a bronchodilator.
      We conclude that children with radiologically confirmed pneumonia have diminished
      airway function that is probably present shortly after birth. These deficits are
      at least in part due to alterations in the regulation of airway muscle tone.

PMID- 10351937
TI  - Coordination of swallowing and phases of respiration during added respiratory
      loads in awake subjects.
AB  - In order to test the hypothesis that different types of respiratory mechanical
      loads may differently modify the coordination of respiration and swallowing, we
      investigated the coordination of respiration and swallowing during resistive and
      elastic loads in 14 healthy subjects. Ventilation was monitored with a
      pneumotachograph and reflex swallowing was elicited by continuous infusion of
      distilled water into the pharynx (3 ml/min) and recorded on a submental
      electromyogram while the subject breathed through a device with a flow-resistive
      load (180 cm H2O/L/s), an elastic load (70 cm H2O/L), or without any external
      load. We found that addition of a flow-resistive load did not influence the
      frequency of swallowing, whereas addition of an elastic load caused a significant
      increase in swallowing frequency during continuous infusion of water. Analysis of
      the timing of swallowing in relation to respiratory cycle phase revealed that
      with flow-resistive loading, swallows occurred preferentially during the
      inspiratory-expiratory (I-E) transition, whereas with elastic loading, swallows
      occurred preferentially during the expiratory-inspiratory (E-I) transition. Signs
      of laryngeal irritation were observed most often during the elastic loading
      following E-I swallows. These results indicate that different types of
      respiratory mechanical loads can differently modify this coordination of
      respiration and swallowing, and suggest that the coordination may be compromised
      more with elastic loading than with flow-resistive loading.

PMID- 10351938
TI  - Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone
      propionate in exogenously activated human eosinophils.
AB  - We examined the effect of the highly lipophilic corticosteroid, fluticasone
      propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic
      phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in
      isolated human eosinophils in vitro. Eosinophils were isolated from peripheral
      blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of
      10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met
      leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from
      eosinophils was unchanged; however, when corrected for cell viability, LTC4
      secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6)
      cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB
      stimulated translocation of cPLA2 to the nuclear envelope assessed by specific
      immunohistochemical staining also was blocked by FP. By contrast, membrane
      expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h
      for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was
      reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in
      stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2
      (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP
      as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited
      stimulated secretion corresponds to inhibited translocation of cPLA2 to the
      nuclear envelope during cellular activation.

PMID- 10351939
TI  - Upregulation of T-helper 1 cytokines and chemokine expression in post-transplant
      airway obliteration.
AB  - The major obstacle to long-term survival after lung transplantation is chronic
      graft dysfunction manifest as bronchiolitis obliterans. Since the early stages
      are characterized by proliferation of itinerant cells (lymphocytes and
      macrophages), we hypothesized that cytokines and chemokines may play a role in
      the development of the fibroproliferative process. In a heterotopic rat tracheal
      transplant model, we studied isografts and allografts 3, 7, and 21 d after
      transplantation as representative time points for the triphasic time course in
      the evolution of allograft airway obliteration. Using a semiquantitative RT-PCR
      technique, intragraft gene expression of T-helper 1 (Th1)- and Th2-type cytokines
      and of C-C and C-X-C chemokines was examined. The results of our study show a
      distinct pattern of cytokine and chemokine gene expression in the development of
      post-transplant airway obliteration. Allografts, in contrast to isografts, showed
      a strong and persistent Th1-type response (expression of interleukin-2 and
      interferon-gamma genes), even after fibrous airway obliteration was complete,
      suggesting an ongoing allo-immune process until late in the fibroproliferative
      stage. RANTES and MCP-1 were also upregulated late after transplantation, whereas
      MIP-2 upregulation occurred early post-transplant and was not restricted to
      allografts alone, which might reflect alloantigen-independent processes after
      transplantation that are present in both allografts and isografts.

PMID- 10351940
TI  - Respiratory syncytical virus-induced chemokine expression in the lower airways:
      eosinophil recruitment and degranulation.
AB  - Characterization of chemokine expression patterns in virus-infected epithelial
      cells provides important clues to the pathophysiology of such infections. The aim
      of this study was to determine the chemokine response pattern of respiratory
      epithelium when infected with respiratory syncytial virus (RSV). Macrophage
      inflammatory protein-1-alpha (MIP-1-alpha), interleukin-8 (IL-8), and RANTES
      concentrations were measured from RSV-infected HEp-2, MRC-5, and WI-38 cell
      culture supernatants daily following infection. Additionally, MIP-1-alpha, IL-8,
      and RANTES concentrations were measured from lower respiratory secretions
      obtained from 10 intubated infants (0-24 mo) with RSV bronchiolitis, and from 10
      control subjects. Our results indicate that respiratory epithelial cells respond
      to RSV infection by producing MIP-1-alpha, IL-8, and RANTES. Production of MIP-1
      alpha required ongoing viral replication, whereas RANTES and IL-8 could be
      elicited by inactivated forms of the virus. MIP-1-alpha, RANTES, and IL-8 were
      also present in lower airway secretions obtained from patients with RSV
      bronchiolitis. Eosinophil cationic protein (ECP) and eosinophil-derived
      neurotoxin (EDN), the eosinophil secretory ribonucleases, were detected in lower
      airway secretions from RSV-infected patients; ECP concentrations correlated with
      MIP-1-alpha concentrations (r = 0.93). We conclude that MIP-1-alpha is present in
      the lower airways during severe RSV disease. The correlation between MIP-1-alpha
      and ECP concentrations suggests a role for eosinophil degranulation products in
      the pathogenesis of RSV bronchiolitis.

PMID- 10351941
TI  - Prostacyclin synthase expression is decreased in lungs from patients with severe
      pulmonary hypertension.
AB  - Prostacyclin is a powerful vasodilator and inhibits platelet adhesion and cell
      growth. We hypothesized that a decrease in expression of the critical enzyme PGI2
      synthase (PGI2-S) in the lung may represent an important manifestation of
      pulmonary endothelial dysfunction in severe pulmonary hypertension (PH).
      Immunohistochemistry and Western blot analysis were used to assess lung PGI2-S
      protein expression, and in situ hybridization was used to assess PGI2-S mRNA
      expression. In the normal pulmonary circulation (n = 7), PGI2-S was expressed in
      48% of small, 67% of medium, and 76% of large pulmonary arteries as assessed by
      immunohistochemistry. PPH (n = 12), cirrhosis-associated (n = 4) and HIV
      associated PH (n = 2) lungs exhibited a marked reduction in PGI2-S expression,
      involving all size ranges of pulmonary arteries. Vessels with concentric lesions
      showed complete lack of PGI2-S expression. Congenital heart (n = 4) and CREST (n
      = 2) cases exhibited a more variable immunohistological pattern of PGI2-S
      expression. These results were complemented by in situ hybridization and Western
      blots of representative lung samples. We conclude that the different sizes of the
      pulmonary arteries express PGI2-S differently and that the loss of expression of
      PGI2-S represents one of the phenotypic alterations present in the pulmonary
      endothelial cells in severe PH.

PMID- 10351942
TI  - Constitutive and cytokine-stimulated expression of eotaxin by human airway smooth
      muscle cells.
AB  - Airway eosinophilia is a prominent feature of asthma that is believed to be
      mediated in part through the expression of specific chemokines such as eotaxin, a
      potent eosinophil chemoattractant that is highly expressed by epithelial cells
      and inflammatory cells in asthmatic airways. Airway smooth muscle (ASM) has been
      identified as a potential source of cytokines and chemokines. The aim of the
      present study was to examine the capacity of human ASM to express eotaxin. We
      demonstrate that airway myocytes constitutively express eotaxin mRNA as detected
      by RT-PCR. Treatment of ASM for 24 h with different concentrations of TNF-alpha
      and IL-1beta alone or in combination enhanced the accumulation of eotaxin
      transcripts. Maximal mRNA expression of eotaxin was shown at 12 and 24 h
      following IL-1beta and TNF-alpha stimulation, respectively. The presence of
      immunoreactive eotaxin was demonstrated by immunocytochemistry, and constitutive
      and cytokine-stimulated release of eotaxin was confirmed in ASM culture
      supernatants by ELISA. Strong signals for eotaxin mRNA and immunoreactivity were
      observed in vivo in smooth muscle in asthmatic airways. In addition, chemotaxis
      assays demonstrated the presence of chemoattractant activity for eosinophils and
      PBMCs in ASM supernatants. The chemotactic responses of eosinophils were partly
      inhibited with antibodies directed against eotaxin or RANTES, and a combined
      blockade of both chemokines causes > 70% inhibition of eosinophil chemotaxis. The
      results of this study suggest that ASM may contribute to airway inflammation in
      asthma through the production and release of eotaxin.

PMID- 10351943
TI  - Identification and substance P content of vagal afferent neurons innervating the
      epithelium of the guinea pig trachea.
AB  - Both the nodose and jugular vagal ganglia provide sensory innervation to the
      airways. The purpose of this study was to localize and characterize the substance
      P (SP) content of vagal afferent neurons that project specifically to the
      tracheal epithelium. A retrograde neuronal tracer, fast blue dye or rhodamine
      labeled latex microspheres, was instilled into the guinea pig trachea. After 7 d,
      the nodose and jugular ganglia were removed, sectioned, and prepared for
      immunocytochemistry. Sections of tracheal mucosa demonstrated that fast blue dye
      diffused throughout the airway wall, whereas the rhodamine-labeled microspheres,
      as expected, did not penetrate the basement membrane and were thus localized to
      the epithelium. When the diffusible fast blue dye was used, approximately 60% of
      the labeled neurons were found in the nodose ganglia and 40% in the jugular
      ganglia. By contrast, when the beads were used to label only epithelial nerve
      fibers, 97 +/- 1% of the tracheal neurons taking up the dye were derived from
      jugular neurons, 60 +/- 6% of which contained SP immunoreactivity. These studies
      demonstrate that, in contrast to the submucosa, nerve fibers innervating the
      epithelium of the trachea are derived nearly exclusively from neurons with cell
      bodies in the jugular ganglia.

PMID- 10351944
TI  - Quantitative assessment of regional right ventricular function with color
      kinesis.
AB  - We used color kinesis, a recent echocardiographic technique that provides
      regional information on the magnitude and timing of endocardial wall motion, to
      quantitatively assess regional right ventricular (RV) systolic and diastolic
      properties in 76 subjects who were divided into five groups, as follows: normal
      (n = 20), heart failure (n = 15), pressure/volume overload (n = 14), pressure
      overload (n = 12), and RV hypertrophy (n = 15). Quantitative segmental analysis
      of color kinesis images was used to obtain regional fractional area change
      (RFAC), which was displayed in the form of stacked histograms to determine
      patterns of endocardial wall motion. Time curves of integrated RFAC were used to
      objectively identify asynchrony of diastolic endocardial motion. When compared
      with normal subjects, patients with pressure overload or heart failure exhibited
      significantly decreased endocardial motion along the RV free wall. In the
      presence of mixed pressure/volume overload, the markedly increased ventricular
      septal motion compensated for decreased RV free wall motion. Diastolic
      endocardial wall motion was delayed in 17 of 72 segments (24%) in patients with
      RV pressure overload, and in 31 of 90 segments (34%) in patients with RV
      hypertrophy. Asynchrony of diastolic endocardial wall motion was greater in the
      latter group than in normal subjects (16% versus 10%: p < 0.01). Segmental
      analysis of color kinesis images allows quantitative assessment of regional RV
      systolic and diastolic properties.

PMID- 10351945
TI  - Patients with obstructive sleep apnea exhibit genioglossus dysfunction that is
      normalized after treatment with continuous positive airway pressure.
AB  - Obstructive sleep apnea syndrome (OSAS) is characterized by repetitive episodes
      of pharyngeal closure during sleep. The pathogenesis of OSAS is unclear. We
      hypothesized that the genioglossus (GG), the most important pharyngeal dilator
      muscle, would be abnormal in patients with OSAS. Further, because treatment with
      continuous positive airway pressure (CPAP) is very effective clinically in these
      patients, we investigated the effects of CPAP upon the structure and function of
      the GG. We studied 16 patients with OSAS (nine of them at diagnosis and seven
      after having been under treatment with CPAP for at least 1 yr) and 11 control
      subjects in whom OSAS was excluded clinically. A biopsy of the GG was obtained in
      each subject, mounted in a tissue bath, and stimulated through platinum
      electrodes. The following measurements were obtained: maximal twitch tension,
      contraction time, half-relaxation time, the force-frequency relationship, and the
      response to a fatiguing protocol. The percentage of type I ("slow twitch") and
      type II ("fast twitch") fibers was also quantified. Patients with OSAS showed a
      greater GG fatigability than did control subjects (ANOVA, p < 0.001).
      Interestingly, this abnormality was entirely corrected by CPAP. Likewise, the
      percentage of type II fibers was significantly higher in patients with OSAS (59
      +/- 4%) than in control subjects (39 +/- 4%, p < 0.001) and, again, these
      structural changes were corrected by CPAP (40 +/- 3%, p < 0.001). These results
      show that the function and structure of the GG is abnormal in patients with OSAS.
      Because these abnormalities are corrected by CPAP, we suggest that they are
      likely a consequence, not a cause, of the disease.

PMID- 10351946
TI  - Pulmonary immunity to Listeria is enhanced by elimination of alveolar
      macrophages.
AB  - To determine how resident alveolar macrophages (AM) regulate the antigen
      presenting-cell (APC) activities of pulmonary dendritic cells (DC) in the
      response to particulate antigen, we pretreated Lewis rats intratracheally with
      liposomes containing clodronate (LIP-CLOD), which eliminated AM in vivo. Controls
      received saline encapsulated in liposomes (LIP-SAL) or saline alone
      intratracheally. At Day 3, rats were injected intratracheally with 1 x 10(7) heat
      killed Listeria (HKL) and DC purified from lung were examined for their ability
      to stimulate HKL-immune T cells without added HKL. Only DC from LIP-CLOD-treated
      rats displayed enhanced APC activities for HKL. A second intratracheal HKL
      challenge at Day 14 yielded lymphocytic cuffing of the microvasculature in LIP
      CLOD-treated lungs only. Intratracheal adoptive transfer of normal syngeneic AM
      into LIP-CLOD-treated rats suppressed APC activities of DC in vitro and the
      lymphocytic response in vivo. Bronchoalveolar macrophages from rats treated with
      LIP-CLOD and HKL showed decreased production of nitric oxide (NO), a potent
      suppressor of DC and T-helper 1 lymphocyte activities as compared with those of
      controls. We conclude that eliminating AM in vivo reduces local production of NO
      and promotes pulmonary cell-mediated immunity to HKL.

PMID- 10351947
TI  - Lipopolysaccharide-induced diaphragmatic contractile dysfunction in mice lacking
      the inducible nitric oxide synthase.
AB  - The goal of this study was to evaluate the importance of the inducible nitric
      oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced diaphragmatic
      contractile dysfunction. Many investigators have proposed that iNOS induction in
      the ventilatory and limb muscles of animals injected with Escherichia coli LPS
      leads to impaired muscle contractility and increased fatigability. We tested this
      proposal by examining wild-type mice and iNOS-deficient (iNOS knockout) mice.
      Both types of mice were injected with either saline (control) or E. coli LPS and
      killed after 12 h. Diaphragm nitric oxide synthase (NOS) activity, NOS
      expression, and muscle contractility were assessed with L-citrulline assay,
      immunoblotting, and in vitro bath preparation, respectively. LPS injection in
      wild-type mice induced iNOS protein expression and augmented total diaphragmatic
      NOS activity, which coincided with impaired muscle force generated at frequencies
      higher than 30 Hz. In iNOS knockout mice, injection of LPS augmented constitutive
      muscle NOS activity, upregulated the expression of the neuronal NOS (nNOS), but
      elicited a significantly greater decline in force generated in response to high
      frequency of stimulation compared with wild-type animals. We conclude that iNOS
      may play a protective role in attenuating the inhibitory influence of LPS on
      muscle contractility.

PMID- 10351948
TI  - Analysis of the Kveim-Siltzbach test reagent for bacterial DNA.
AB  - The sarcoid spleen-derived reagent for the Kveim-Siltzbach test (KST) elicits a
      sarcoid-specific, granulomatous, cutaneous response used to establish the
      diagnosis of sarcoidosis. In the context of the ongoing discussion of a bacterial
      cause of sarcoidosis we asked the question whether bacterial DNA could be found
      in the KST reagent. For this purpose two different KST reagents, an identical
      preparation from a normal spleen, and a native sarcoid spleen were analyzed by
      polymerase chain reaction (PCR) employing universal primers detecting conserved
      DNA sequences coding for bacterial ribosomal 16S RNA. Neither KST reagents, the
      control preparation, nor the spleen yielded a positive signal, indicating that
      the preparations are free of bacterial contamination. Because the KST reagent
      elicits granuloma, these results do not support the hypothesis of a bacterial
      cause of sarcoid granuloma.

PMID- 10351949
TI  - Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with
      subclinical emphysema.
AB  - Evidence for the contribution of neutrophils to the pathogenesis of pulmonary
      emphysema is not convincing. We evaluated neutrophil involvement in subclinical
      pulmonary emphysema by measuring human neutrophil lipocalin (HNL) and two matrix
      metalloproteinases, gelatinase B (MMP-9) and neutrophil collagenase (MMP-8), in
      bronchoalveolar lavage fluid (BALF) from 65 community-based older volunteers. HNL
      is a recently isolated 24-kD protein secreted from secondary granules of
      activated neutrophils. Despite no appreciable increase in the number of
      neutrophils, the level of HNL was significantly increased in BALF from subjects
      with emphysema evidenced by computed tomography regardless of current smoking, as
      compared with smokers without emphysema. The levels of MMP-9 and MMP-8 were also
      significantly higher in current smokers with emphysema than in those without
      emphysema. The appearance of a 130-kD HNL/MMP-9 complex on gelatin zymography and
      HNL immunoblot indicated neutrophils to be a significant source of MMP-9 in the
      subjects' BALF. In a 24-h culture medium of alveolar macrophages, only a latent
      form of MMP-9 was detected, and there was no difference in the level of MMP-9
      between the groups. These data provide further evidence for neutrophil
      involvement in subclinical pulmonary emphysema.

PMID- 10351950
TI  - Diaphragm dimensions after single-lung transplantation for emphysema.
AB  - We used three-dimensional reconstructions obtained with spiral computed
      tomography to measure total diaphragm surface area (Adi), and the surface area of
      the dome (Ado) and of the zone of apposition (Aap) of the diaphragm in nine
      patients with single-lung transplantation (SLT) for emphysema and nine normal
      subjects matched for age, sex, height, and weight. Measurements were obtained at
      supine FRC, midinspiratory capacity, and TLC. In the normal subjects, Ado and Adi
      were greater on the right than on the left side, and the right dome was
      positioned more cranially than the left one, presumably because of the presence
      of the liver. Compared with either the ipsilateral side in the controls or the
      native side in the patients, Ado was smaller on the transplanted side because the
      mediastinum was shifted toward the graft. Adi showed a similar trend. On the
      other hand, the radius of curvature of the dome in the coronal and sagittal
      planes was similar on the side of the graft and on the ipsilateral side in the
      controls. In conclusion, we found that after SLT for emphysema, diaphragm
      configuration comes back to normal but Ado, and with it Adi, remain smaller than
      in normal subjects because the mediastinum is displaced toward the graft.

PMID- 10351951
TI  - Variable levels of normal RNA in different fetal organs carrying a cystic
      fibrosis transmembrane conductance regulator splicing mutation.
AB  - Disease severity varies among cystic fibrosis (CF) patients carrying the same
      cystic fibrosis transmembrane conductance regulator (CFTR) genotype and among
      organs of the same individual. It has been shown that the class V splicing
      mutation 3849 + 10 kb C--> T produces both normal and aberrantly spliced CFTR
      transcripts. We analyzed the levels of normal CFTR messenger RNA (mRNA) in
      different organs of an aborted fetus carrying the 3849 + 10 kb C--> T mutation,
      and found that they correlated with the histopathologic changes observed in these
      organs. We performed semiquantitative nondifferential reverse transcription
      polymerase chain reaction on several organs from a 22-wk aborted CF fetus
      carrying the 3849 + 10 kb C--> T mutation. A very low level (1%) of normal CFTR
      mRNA was detected in the severely affected ileum of this fetus. Higher levels
      were found in the histopathologically unaffected trachea (17%), colon (19%), and
      lung (26%). Thus, as early as in utero, the regulation of alternative splice-site
      selection is an important mechanism underlying variable CF severity.
      Understanding of the mechanisms regulating alternative splicing in different
      tissues will contribute to potential therapy for patients carrying splicing
      mutations in CF and other human disease genes.

PMID- 10351952
TI  - Nylon flock-associated interstitial lung disease.
AB  - A work-related interstitial lung disease has been diagnosed in workers at five
      nylon flock facilities in three different states and a Canadian province. The
      National Institute for Occupational Safety and Health hosted a workshop at which
      consulting pulmonary pathologists reviewed lung tissue samples from all the cases
      for which lung biopsy material was available (15 of 20 cases known in January
      1998). After independent review and scoring of these lung tissue specimens, the
      pathologists reached consensus that the histopathological findings revealed a
      characteristic lesion-a lymphocytic bronchiolitis and peribronchiolitis with
      lymphoid hyperplasia represented by lymphoid aggregates. The pathologists noted
      that the pathological findings were distinctive when compared with known lung
      conditions. The clinical presentation for the cases generally included cough,
      dyspnea, restrictive ventilatory defect with reduction in diffusing capacity, and
      interstitial markings on chest radiographs or high-resolution computed tomography
      (HRCT) scans. Six of the cases improved after removal from workplace exposure
      without medical treatment. Six others, who had recovered with medical treatment
      and removal from the workplace, had relapses in both symptoms and objective
      findings after attempting to return to nylon flock work. With this and other
      evidence supporting the existence of chronic interstitial pneumonitis associated
      with nylon flock processing, workshop participants recommended surveillance for
      early identification of affected workers and their removal from further workplace
      exposure.

PMID- 10351953
TI  - Sarcoid-like pulmonary disorder in human immunodeficiency virus-infected patients
      receiving antiretroviral therapy.
AB  - We report two cases of HIV-infected patients who presented with diffuse
      interstitial micronodular lesions on chest X-ray after institution of protease
      inhibitor-containing highly active antiretroviral therapy (HAART). Granulomatous
      pulmonary disorder mimicking sarcoidosis was diagnosed on histopathological
      studies revealing noncaseating granuloma and bronchoalveolar lavage analysis
      showing an intense CD4(+) lymphocyte alveolitis. Causative agents such as
      infectious organisms and environmental compounds were excluded. The relationship
      between sarcoid-like reaction and immune reconstitution under HAART is discussed.

PMID- 10351955
TI  - Prevention of human diaphragm atrophy with short periods of electrical
      stimulation.
AB  - We determined whether prolonged complete inactivation of the human diaphragm
      results in atrophy and whether this could be prevented by brief periods of
      electrical phrenic nerve stimulation. We studied a subject with high spinal cord
      injury who required removal of his left phrenic nerve pacemaker (PNP) and the
      reinstitution of positive-pressure ventilation for 8 mo. During this time, the
      right phrenic nerve was stimulated 30 min per day. Thickness of each diaphragm
      (tdi) was determined by ultrasonography. Maximal tidal volume (VT) was measured
      during stimulation of each diaphragm separately. After left PNP reimplantation,
      VT and tdi were measured just before the resumption of electrical stimulation and
      serially for 33 wk. On the previously nonfunctioning side, there were substantial
      changes in VT (from 220 to 600 ml) and tdi (from 0.18 to 0.34 cm). On the side
      that had been stimulated, neither VT nor tdi changed appreciably (VT from 770 to
      900 ml; tdi from 0.25 to 0.28 cm). We conclude that prolonged inactivation of the
      diaphragm causes atrophy which may be prevented by brief periods of daily phrenic
      nerve stimulation.

PMID- 10351954
TI  - Transcontinental spread of multidrug-resistant Mycobacterium bovis.
AB  - Globally, the proportion of all cases of tuberculosis (TB) caused by drug
      resistant strains is increasing. We report the case of a Canadian citizen who
      acquired a highly drug-resistant strain of Mycobacterium bovis while visiting a
      relative with AIDS-related tuberculosis in Spain. The origin of the strain was
      traced using spoligotyping, a polymerase chain reaction (PCR)-based fingerprint
      technology, and the European DNA database. The level of primary drug resistance
      all five first-line drugs and 19 of 21 second-line drugs-in this case was
      unprecedented in Canada. Isolation of this strain from a Canadian citizen
      represents the first report of its appearance in this hemisphere. The infection
      was contained and combined medical-surgical treatment delivered.

PMID- 10351956
TI  - The role of the C-C chemokine receptor 2 gene polymorphism V64I (CCR2-64I) in
      sarcoidosis in a Japanese population.
AB  - A number of chemokines are produced by alveolar cells in the course of
      inflammatory reactions of sarcoidosis. C-C chemokine receptor 2 (CCR2) is a
      prominent receptor for the monocyte chemoattractant protein (MCP) group of C-C
      chemokines. A transition causing a valine to isoleucine substitution in
      transmembrane domain I of the CCR2 gene (CCR2-64I) that has a protective effect
      against the progression of human immunodeficiency virus-1 (HIV-1) disease has
      been described. To elucidate the role of this CCR2 polymorphism in sarcoidosis,
      we investigated the distribution of the CCR2-64I in 100 subjects with sarcoidosis
      (40.2 +/- 18.6 yr [mean +/- SD], 37:63 [male:female]) and 122 healthy control
      subjects (44.4 +/- 14.1 yr, 75:47). The distribution of the CCR2-64I allele was
      significantly different between subjects with sarcoidosis and healthy control
      subjects (p < 0.001). The presence of the CCR2-64I allele conferred a lower risk
      for the development of sarcoidosis (adjusted odds ratio = 0.369, 95% CI = 0.203
      to 0.673). Our study suggests that this polymorphism may play a role in the
      pathogenesis of sarcoidosis, and further studies are needed to define the role of
      CCR2-64I.

PMID- 10351957
TI  - Evolution of sleep apnea syndrome in sleepy snorers: a population-based
      prospective study.
AB  - This study followed a small number of men previously studied polysomnographically
      10 yr earlier to investigate the relationship between the development of sleep
      disordered breathing and age, weight gain, and smoking. In 1984, 3,201 men
      answered a questionnaire including questions about snoring and excessive daytime
      sleepiness (EDS). Of those reporting symptoms related to obstructive sleep apnea
      syndrome (OSAS), a random sample of 61 men was investigated using whole-night
      polysomnography in 1985. Ten years later, 38 men participated in the present
      follow-up, which included a structured interview and polysomnography. During the
      10-yr period, nine men had been treated for OSAS. Of the 29 untreated subjects,
      the number of men with OSAS, defined as an apnea-hypopnea index (AHI) of >/= 5/h,
      increased from four in 1985 to 13 in 1995 (p < 0.01). In this small sample, no
      significant associations were found between DeltaAHI (i.e., AHI 1995 - AHI 1985)
      and age, weight gain, or smoking. We conclude that, among this small group of
      individuals who were selected for original polysomnographic study and follow-up
      because they were thought to have symptoms of sleep apnea, sleep-disordered
      breathing became significantly worse over time.

PMID- 10351961
TI  - Circulation online only : june 1, 1999 

PMID- 10351958
TI  - A new method to analyze lung compliance when pressure-volume relationship is
      nonlinear.

PMID- 10351962
TI  - Combined thrombolytic and platelet glycoprotein IIb/IIIa inhibitor therapy for
      acute myocardial infarction: will pharmacological therapy ever equal primary
      angioplasty?

PMID- 10351963
TI  - Stromelysin promoter 5A/6A polymorphism is associated with acute myocardial
      infarction.
AB  - BACKGROUND: Rupture of the fibrous cap of an atherosclerotic plaque is a key
      event that predisposes to acute myocardial infarction (AMI). Matrix
      metalloproteinases (MMPs) may contribute to weakening of the cap, which favors
      rupture. Stromelysin, a member of MMP family, is identified extensively in human
      coronary atherosclerotic lesions. It can degrade most of the constituents of
      extracellular matrix as well as activating other MMPs, which suggests that it may
      play an important role in plaque rupture. Recently, a common variant (5A/6A) in
      the promoter of the stromelysin gene has been identified. The 5A/6A polymorphism
      could regulate the transcription of the stromelysin gene in an allele-specific
      manner. METHODS AND RESULTS: To investigate the relation between the 5A/6A
      polymorphism in the promoter of the stromelysin gene and AMI, we conducted a case
      control study of 330 AMI patients and 330 control subjects. The prevalence of the
      5A/6A+5A/5A genotype was significantly more frequent in the patients with AMI
      than in control subjects (48.8% vs 32.7%, P<0.0001). In logistic regression
      models, the odds ratio of the 5A/6A+5A/5A was 2.25 (95% CI, 1.51 to 3.35). The
      association of 5A/6A polymorphism with AMI was statistically significant and
      independent of other risk factors. CONCLUSIONS: The 5A/6A polymorphism in the
      promoter of the stromelysin gene is a novel pathogenetic risk factor for AMI.

PMID- 10351964
TI  - Abciximab facilitates the rate and extent of thrombolysis: results of the
      thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 Investigators.
AB  - BACKGROUND: The TIMI 14 trial tested the hypothesis that abciximab, the Fab
      fragment of a monoclonal antibody directed to the platelet glycoprotein (GP)
      IIb/IIIa receptor, is a potent and safe addition to reduced-dose thrombolytic
      regimens for ST-segment elevation MI. METHODS AND RESULTS: Patients (n=888) with
      ST-elevation MI presenting <12 hours from onset of symptoms were treated with
      aspirin and randomized initially to either 100 mg of accelerated-dose alteplase
      (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 microg. kg
      1. min-1) alone or in combination with reduced doses of alteplase (20 to 65 mg)
      or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight
      adjusted heparin (70-U/kg bolus; infusion of 15 U. kg-1. h-1), whereas those
      treated with a regimen including abciximab received low-dose heparin (60-U/kg
      bolus; infusion of 7 U. kg-1. h-1). The rate of TIMI 3 flow at 90 minutes for
      patients treated with accelerated alteplase alone was 57% compared with 32% for
      abciximab alone and 34% to 46% for doses of streptokinase between 500 000 U and
      1.25 MU with abciximab. Higher rates of TIMI 3 flow at both 60 and 90 minutes
      were observed with increasing duration of administration of alteplase,
      progressing from a bolus alone to a bolus followed by either a 30- or 60-minute
      infusion (P<0.02). The most promising regimen was 50 mg of alteplase (15-mg
      bolus; infusion of 35 mg over 60 minutes), which produced a 76% rate of TIMI 3
      flow at 90 minutes and was tested subsequently in conjunction with either low
      dose or very-low-dose (30-U/kg bolus; infusion of 4 U. kg-1. h-1) heparin. TIMI 3
      flow rates were significantly higher in the 50-mg alteplase plus abciximab group
      versus the alteplase-only group at both 60 minutes (72% versus 43%; P=0.0009) and
      90 minutes (77% versus 62%; P=0.02). The rates of major hemorrhage were 6% in
      patients receiving alteplase alone (n=235), 3% with abciximab alone (n=32), 10%
      with streptokinase plus abciximab (n=143), 7% with 50 mg of alteplase plus
      abciximab and low-dose heparin (n=103), and 1% with 50 mg of alteplase plus
      abciximab with very-low-dose heparin (n=70). CONCLUSIONS: Abciximab facilitates
      the rate and extent of thrombolysis, producing early, marked increases in TIMI 3
      flow when combined with half the usual dose of alteplase. This improvement in
      reperfusion with alteplase occurred without an increase in the risk of major
      bleeding. Substantial reductions in heparin dosing may reduce the risk of
      bleeding even further. Modest improvements in TIMI 3 flow were seen when
      abciximab was combined with streptokinase, but there was an increased risk of
      bleeding.

PMID- 10351965
TI  - Relation between direct detection of Chlamydia pneumoniae DNA in human coronary
      arteries at postmortem examination and histological severity (Stary grading) of
      associated atherosclerotic plaque.
AB  - BACKGROUND: Numerous studies have suggested a link between Chlamydia pneumoniae
      infection, atherosclerosis, and coronary artery disease. However, it is still
      unclear whether C pneumoniae plays a causal role in the pathogenesis of these
      conditions. Accordingly, we have performed a systematic dissection of the 3
      coronary arteries on 33 postmortem subjects and studied the relationship in
      individual artery segments between the presence of C pneumoniae DNA and the
      severity of associated atherosclerosis. METHODS AND RESULTS: The prevalence of C
      pneumoniae DNA in arterial segments was determined by polymerase chain reaction
      (PCR) after controlling for the presence of PCR inhibitors. Atherosclerosis in
      each arterial segment was graded histologically with the Stary classification. C
      pneumoniae was detected by PCR in 78.8% of subjects, but there was no association
      between the presence of this DNA and cause of death or grade of atherosclerosis.
      When paired mild and severe atherosclerotic lesions within subjects were
      compared, mild lesions were as likely to be positive for C pneumoniae as severe
      lesions. CONCLUSIONS: This study demonstrates that C pneumoniae can frequently be
      detected in atheromatous plaques in coronary arteries. However, its distribution
      did not correlate with severity or extent of disease.

PMID- 10351966
TI  - Triggering of myocardial infarction by cocaine.
AB  - BACKGROUND: Cocaine has been implicated as a trigger of acute myocardial
      infarction in patients with and those without underlying coronary
      atherosclerosis. However, the magnitude of the increase in risk of acute
      myocardial infarction immediately after cocaine use remains unknown. METHODS AND
      RESULTS: In the Determinants of Myocardial Infarction Onset Study, we interviewed
      3946 patients (1282 women) with acute myocardial infarction an average of 4 days
      after infarction onset. Data were collected on the use of cocaine and other
      potential triggers of myocardial infarction. We compared the reported use of
      cocaine in the hour preceding the onset of myocardial infarction symptoms with
      its expected frequency by using self-matched control data based on the case
      crossover study design. Of the 3946 patients interviewed, 38 (1%) reported
      cocaine use in the prior year and 9 reported use within the 60 minutes preceding
      the onset of infarction symptoms. Compared with nonusers, cocaine users were more
      likely to be male (87% vs 67%, P=0.01), current cigarette smokers (84% vs 32%,
      P<0.001), younger (44+/-8 vs 61+/-13 years, P<0.001), and minority group members
      (63% vs 11%, P<0.001). The risk of myocardial infarction onset was elevated 23.7
      times over baseline (95% CI 8.5 to 66.3) in the 60 minutes after cocaine use. The
      elevated risk rapidly decreased thereafter. CONCLUSIONS: Cocaine use is
      associated with a large abrupt and transient increase in the risk of acute
      myocardial infarction in patients who are otherwise at relatively low risk. This
      finding suggests that studying the pathophysiological changes produced by cocaine
      may provide insights into the mechanisms by which myocardial infarction is
      triggered by other stressors.

PMID- 10351967
TI  - Multicenter clinical trial to evaluate the efficacy of correction for photon
      attenuation and scatter in SPECT myocardial perfusion imaging.
AB  - BACKGROUND: Soft tissue attenuation is a prominent cause of single-photon
      emission computed tomography (SPECT) imaging artifacts, which may result in
      reduced diagnostic accuracy of myocardial perfusion imaging. A method
      incorporating simultaneously acquired transmission data permits nonuniform
      attenuation correction and when incorporating scatter correction and resolution
      compensation may substantially reduce interpretive errors. METHODS AND RESULTS: A
      prospective multicenter trial was performed recruiting patients with
      angiographically documented coronary disease (n=96) and group of subjects with a
      low likelihood of disease (n=88). The uncorrected and attenuation/scatter
      corrected images were read independently, without knowledge of the patient's
      clinical data. The detection of >/=50% stenosis was similar using uncorrected
      perfusion data or with attenuation/scatter correction and resolution compensation
      (visual or visual plus quantitative analysis), 76% versus 75% versus 78%,
      respectively (P=NS). The normalcy rate, however, was significantly improved with
      this new methodology, using either the corrected images (86% vs 96%; P=0.011) or
      with the corrected data and quantitative analysis (86% vs 97%; P=0.007). The
      receiver operator characteristic curves were also found to be marginally but not
      significantly higher with attenuation/scatter correction than with tradition
      SPECT imaging. However, the ability to detect multivessel disease was reduced
      with attenuation/scatter correction. Regional differences were also noted, with
      reduced sensitivity but improved specificity for right coronary lesions using
      attenuation/scatter correction methodology. CONCLUSIONS: This multicenter trial
      demonstrates the initial clinical results of a new SPECT perfusion imaging
      modality incorporating attenuation and scatter correction in conjunction with
      99mTc sestamibi perfusion imaging. Significant improvements in the normalcy rate
      were noted without a decline in overall sensitivity but with a reduction in
      detection of extensive coronary disease.

PMID- 10351969
TI  - Significance of myocytes with positive DNA in situ nick end-labeling (TUNEL) in
      hearts with dilated cardiomyopathy: not apoptosis but DNA repair.
AB  - BACKGROUND: The presence of apoptotic myocytes has been reported in human hearts
      with dilated cardiomyopathy (DCM) on the basis of a positive finding of DNA in
      situ nick end-labeling (TUNEL). However, ultrastructural evidence of myocyte
      apoptosis has not been obtained. METHODS AND RESULTS: A total of 80
      endomyocardial biopsies were obtained from right and left ventricles of 20
      patients with DCM and 20 normal control subjects. TUNEL-positive myocytes were
      found by light microscope in 15% of DCM specimens (controls, 0%, P<0.05), and the
      percentage of TUNEL-positive myocytes per section in DCM was 1. 0+/-2.7% (mean+/
      SD). According to TUNEL at the electron microscopic level (EM-TUNEL), immunogold
      particles, which label DNA breaks with 3'-OH terminals, were markedly accumulated
      in the bizarre-shaped nuclei, with widespread clumping of chromatin (so-called
      "hypertrophied nuclei") of the myocytes obtained from DCM. Their ultrastructure
      was neither apoptotic nor necrotic but rather that of living cells. Taq
      polymerase-based DNA in situ ligation assay, which detects double-stranded DNA
      fragments more specifically than TUNEL, did not detect a positive reaction in any
      case. In mirror sections, all of the TUNEL-positive myocytes in DCM
      simultaneously expressed proliferating cell nuclear antigen, which is required
      for both DNA replication and repair, but Ki-67, a replication-associated antigen,
      was completely negative in all cases, which appeared to rule out cell
      proliferation activity. CONCLUSIONS: Most of the TUNEL-positive myocytes in
      hearts with DCM are not apoptotic but rather living cells with increasing
      activity of DNA repair.

PMID- 10351968
TI  - Dilated cardiomyopathy is associated with significant changes in collagen type
      I/III ratio.
AB  - BACKGROUND: It is controversial whether myocardial fibrosis in end-stage dilated
      cardiomyopathy (DCM) is associated with altered collagen type I/type III (Col
      I/Col III) ratio. METHODS AND RESULTS: Patients with DCM (ejection fraction [EF]
      <50%, n=12) and with mild global left ventricular dysfunction (EF >50%, n=18)
      were examined. Col I, Col III, and transforming growth factors-beta1 (TGF-beta1)
      and -beta2 (TGF-beta2) gene expression in endomyocardial biopsies was evaluated
      by quantitative competitive reverse transcriptase-polymerase chain reaction (qRT
      PCR). Collagen content was quantified after picrosirius red and
      immunohistological staining and by hydroxyproline assay. In patients with EF
      <50%, there was a pronounced 2- to 6-fold increase of myocardial Col I mRNA
      abundance (P<0.01), with a corresponding 1.6-fold increase at the protein level
      versus that found in patients with EF >50%. The Col III mRNA abundance showed a
      2.0-fold increase (P<0.04). There was a relevant shift in the Col I/Col III mRNA
      ratio for DCM patients (Col I/Col III, 8.2) compared with patients with an EF
      >50% (Col I/Col III, 6. 4). In addition, total collagen content was increased in
      patients with EF <50% (n=3) (4.3+/-0.1%) compared with patients with EF >50%
      (n=8) (2.7+/-0.9%) (P<0.004). The biochemically determined ratio of
      hydroxyproline/total protein (n=12) was correlated to the Col I mRNA abundance
      (P<0.05, r=0.77). TGF-beta1 and TGF-beta2 showed elevated myocardial mRNA
      abundances (1- to 7-fold and 4- to 5-fold, respectively) in DCM patients.
      CONCLUSIONS: Differential increase of Col I and Col III leads to an increased Col
      I/Col III ratio in DCM myocardium. Because Col I provides substantial tensile
      strength and stiffness, this may contribute to systolic and in particular
      diastolic dysfunction in DCM.

PMID- 10351970
TI  - Double-blind placebo-controlled trial of digoxin in symptomatic paroxysmal atrial
      fibrillation.
AB  - BACKGROUND: Digoxin is commonly prescribed in symptomatic paroxysmal atrial
      fibrillation (AF) but has never been evaluated in this condition. METHODS AND
      RESULTS: From a multicenter registry, 43 representative patients with frequent
      symptomatic AF episodes were recruited into a randomized, double-blind crossover
      comparison of digoxin (serum concentration, 1.29+/-0.35 nmol/L) and placebo. The
      study end point was the occurrence of 2 AF episodes (documented by patient
      activated monitors), censored at 61 days. The median time to 2 episodes was 13.5
      days on placebo and 18.7 days on digoxin (P<0. 05). The relative risk (95% CI) of
      2 episodes (placebo:digoxin) was 2.19 (1.07 to 4.50). A similar effect was seen
      on the median time to 1 episode: increased from 3.5 to 5.4 days (P<0.05),
      relative risk 1. 69 (0.88 to 3.24). The mean+/-SD ventricular rates during AF
      recordings during placebo and digoxin treatment were 138+/-32 and 125+/-35 bpm,
      respectively (P<0.01). Twenty-four-hour ambulatory ECG recordings did not show
      significant differences in the frequency or duration of AF or in ventricular
      rate. CONCLUSIONS: Digoxin reduces the frequency of symptomatic AF episodes.
      However, the estimated effect is small and may be due to a reduction in the
      ventricular rate or irregularity rather than an antiarrhythmic action.

PMID- 10351971
TI  - Rate-dependent conduction block of the crista terminalis in patients with typical
      atrial flutter: influence on evaluation of cavotricuspid isthmus conduction
      block.
AB  - BACKGROUND: The crista terminalis (CT) has been identified as the posterior
      boundary of typical atrial flutter (AFL) in the lateral wall (LW) of the right
      atrium (RA). To study conduction properties across the CT, rapid pacing was
      performed at both sides of the CT after bidirectional conduction block was
      achieved in the cavotricuspid isthmus by radiofrequency catheter ablation.
      METHODS AND RESULTS: In 22 patients (aged 61+/-7 years) with AFL (cycle length,
      234+/-23 ms), CT was identified during AFL by double electrograms recorded
      between the LW and posterior wall (PW). After the ablation procedure, decremental
      pacing trains were delivered from 600 ms to 2-to-1 local capture at the LW and PW
      or coronary sinus ostium (CSO). At least 5 bipolar electrograms were recorded
      along the CT from the high to the low atrium next to the inferior vena cava. No
      double electrograms were recorded during sinus rhythm in that area. Complete
      transversal conduction block all along the CT (detected by the appearance of
      double electrograms at all recording sites and craniocaudal activation sequence
      on the side opposite to the pacing site) was observed in all patients during
      pacing from the PW or CSO (cycle length, 334+/-136 ms), but it was fixed in only
      4 patients. During pacing from the LW, complete block appeared at a shorter
      pacing cycle length (281+/-125 ms; P<0.01) and was fixed in 2 patients. In 3
      patients, complete block was not achieved. CONCLUSIONS: These data suggest the
      presence of rate-dependent transversal conduction block at the crista terminalis
      in patients with typical AFL. Block is usually observed at longer pacing cycle
      lengths with PW pacing than with LW pacing. This difference may be a critical
      determinant of the counterclockwise rotation of typical AFL.

PMID- 10351972
TI  - Free-floating thrombi in the right heart: diagnosis, management, and prognostic
      indexes in 38 consecutive patients.
AB  - BACKGROUND: Floating right heart thrombi (FRHTS) are a rare phenomenon,
      encountered almost exclusively in patients with suspected or proven pulmonary
      embolism and diagnosed by transthoracic echocardiography. Their management
      remains controversial. METHODS AND RESULTS: We report on a series of 38
      consecutive patients encountered over the past 12 years. Thirty-two patients were
      in NYHA class IV, 20 in cardiogenic shock. Echocardiography usually demonstrated
      signs of cor pulmonale: right ventricular overload (91.7% of the population),
      paradoxical interventricular septal motion (75%), and pulmonary hypertension (86.
      1%). The thrombus was typically wormlike (36 of 38 patients). It extended from
      the left atrium through a patent foramen ovale in 4 patients. Pulmonary embolism
      was confirmed in all but 1. Mortality was high (17 of 38 patients) irrespective
      of the therapeutic option chosen: surgery (8 of 17), thrombolytics (2 of 9),
      heparin (5 of 8), or interventional percutaneous techniques (2 of 4). The in
      hospital mortality rate was significantly linked with the occurrence of cardiac
      arrest. Conversely, the outcome after discharge was usually good, because 18 of
      21 patients were still alive 47.2 months later (range, 1 to 70 months).
      CONCLUSIONS: Severe pulmonary embolism was the rule in our series of FRHTS
      (mortality rate, 44.7%). The choice of therapy had no effect on mortality.
      Emergency surgery is usually advocated. However, thrombolysis is a faster,
      readily available treatment and seems promising either as the only treatment or
      as a bridge to surgery. In patients with contraindications to surgery or lytic
      therapy, interventional techniques may be proposed.

PMID- 10351973
TI  - HLA class II associations with rheumatic heart disease are more evident and
      consistent among clinically homogeneous patients.
AB  - BACKGROUND: Discrepancies in reported HLA class II associations with rheumatic
      heart disease (RHD) may have been due to inaccuracies of serological typing
      reagents and/or lack of defined clinical classification of patients analyzed. The
      molecular association between HLA and RHD was investigated in patients with
      defined clinical outcome. METHODS AND RESULTS: Class II allele/haplotype
      distribution was determined in 2 groups of RHD patients (n=88) and a control
      group (n=59). Patients were divided into the mitral valve disease (MVD) category
      (ie, those with mitral regurgitation with or without mitral stenosis) and the
      multivalvular lesions (MVL) category, with impairment of aortic and/or tricuspid
      valves in addition to mitral valve damage. The MVD category (n=65) accounted for
      74% of patients and included significantly fewer recurrent RF episodes compared
      with MVL patients (P=0.002). CONCLUSIONS: Significant increases in DRB1*0701 and
      DQA1*0201 alleles and DRB1*0701-DQA1*0201 haplotypes were found in patients.
      Removal of the MVL patients from analysis increased the strength of HLA
      associations among the MVD sample. The frequency of DQA1*0103 allele was
      decreased and the DQB1*0603 allele was absent from the patient group, suggesting
      that these alleles may confer protective effects against RHD. DQ alleles in
      linkage disequilibrium with DR alleles appear to influence risk/protection
      effect: whereas the DRB1*13-DQA1*0501-3-DQB1*0301 haplotype showed a trend toward
      risk, the DRB1*13-DQA1*0103-DQB1*0603 haplotype was absent in the RHD sample. Our
      data indicate that certain class II alleles/haplotypes are associated with risk
      or protection from RHD and that these associations appear to be stronger and more
      consistent when analyzed in patients with relatively more homogeneous clinical
      manifestations.

PMID- 10351974
TI  - Acetylsalicylic acid reduces vegetation bacterial density, hematogenous bacterial
      dissemination, and frequency of embolic events in experimental Staphylococcus
      aureus endocarditis through antiplatelet and antibacterial effects.
AB  - BACKGROUND: Platelets are integral to cardiac vegetations that evolve in
      infectious endocarditis. It has been postulated that the antiplatelet aggregation
      effect of aspirin (ASA) might diminish vegetation evolution and embolic rates.
      METHODS AND RESULTS: Rabbits with Staphylococcus aureus endocarditis were given
      either no ASA (controls) or ASA at 4, 8, or 12 mg. kg-1. d-1 IV for 3 days
      beginning 1 day after infection. Vegetation weights and serial echocardiographic
      vegetation size, vegetation and kidney bacterial densities, and extent of renal
      embolization were evaluated. In addition, the effect of ASA on early S aureus
      adherence to sterile vegetations was assessed. In vitro, bacterial adherence to
      platelets, fibrin matrices, or fibrin-platelet matrices was quantified with
      either platelets exposed to ASA or S aureus preexposed to salicylic acid (SAL).
      ASA at 8 mg. kg-1. d-1 (but not at 4 or 12 mg. kg-1. d-1) was associated with
      substantial decreases in vegetation weight (P<0.05), echocardiographic vegetation
      growth (P<0.001), vegetation (P<0.05) and renal bacterial densities and renal
      embolic lesions (P<0.05) versus controls. Diminished aggregation resulted when
      platelets were preexposed to ASA or when S aureus was preexposed to SAL (P<0.05).
      S aureus adherence to sterile vegetations (P<0.05) or to platelets in suspension
      (P<0.05), fibrin matrices (P<0.05), or fibrin-platelet matrices (P<0.05) was
      significantly reduced when bacteria were preexposed to SAL. CONCLUSIONS: ASA
      reduces several principal indicators of severity and metastatic events in
      experimental S aureus endocarditis. These benefits involve ASA effects on both
      the platelet and the microbe.

PMID- 10351975
TI  - Differential 18F-2-deoxyglucose uptake in viable dysfunctional myocardium with
      normal resting perfusion: evidence for chronic stunning in pigs.
AB  - BACKGROUND: Viable, chronically dysfunctional myocardium can have normal or
      reduced resting flow. We previously produced hibernating myocardium with reduced
      resting flow in pigs with a chronic stenosis and hypothesized that hibernation is
      preceded by chronic stunning with normal resting perfusion. METHODS AND RESULTS:
      Pigs instrumented with a proximal left anterior descending coronary artery (LAD)
      stenosis were studied 1 or 2 months later in the closed-chest anesthetized state.
      Stenosis severity increased from 74+/-5% at 1 month to 83+/-6% at 2 months and
      was accompanied by anteroapical hypokinesis (wall motion score, 2.1+/-0.1 at 1
      month and 1.5+/-0.3 at 2 months; normal=3). Resting perfusion was similar in
      normal and dysfunctional regions, but the deposition of 18F-2-deoxyglucose (FDG)
      varied. At 1 month, subendocardial FDG deposition by excised tissue counting was
      similar in each region (0. 034+/-0.006 mL. g-1. min-1 LAD region versus 0.032+/
      0.004 mL. g-1. min-1 in normal regions, P=NS). At 2 months, subendocardial FDG
      deposition was increased (0.084+/-0.025 mL. g-1. min-1 LAD region versus 0.042+/
      0.017 mL. g-1. min-1 in normal regions, P<0.05). Increases in FDG uptake were
      inversely related to LAD subendocardial flow reserve during adenosine (3.5+/-0.6
      at 1 month versus 1.4+/-0.2 at 2 months, P<0.01). CONCLUSIONS: These data
      indicate a progression of physiological adaptations in pigs with viable,
      chronically dysfunctional myocardium. As coronary flow reserve decreases, fasting
      FDG uptake increases. Flow at rest remains normal, consistent with "chronic
      stunning," and contrasts with reduced flow and increased FDG characteristic of
      hibernating myocardium in similarly instrumented pigs after 3 months. This
      temporal progression of adaptations supports the hypothesis of a transition from
      a physiological phenotype of stunning to hibernation.

PMID- 10351976
TI  - Autonomic modification of the atrioventricular node during atrial fibrillation:
      role in the slowing of ventricular rate.
AB  - BACKGROUND: Postganglionic vagal stimulation (PGVS) by short bursts of
      subthreshold current evokes release of acetylcholine from myocardial nerve
      terminals. PGVS applied to the atrioventricular node (AVN) slows nodal
      conduction. However, little is known about the ability of PGVS to control
      ventricular rate (VR) during atrial fibrillation (AF). METHODS AND RESULTS: To
      quantify the effects and establish the mechanism of PGVS on the AVN, AF was
      simulated by random high right atrial pacing in 11 atrial-AVN rabbit heart
      preparations. Microelectrode recordings of cellular action potentials (APs) were
      obtained from different AVN regions. Five intensities and 5 modes of PGVS
      delivery were evaluated. PGVS resulted in cellular hyperpolarization, along with
      depressed and highly heterogeneous intranodal conduction. Compact nodal AP
      exhibited decremental amplitude and dV/dt and multiple-hump components, and at
      high PGVS intensities, a high degree of concealed conduction resulted in a
      dramatic slowing of the VR. Progressive increase of PGVS intensity and/or rate of
      delivery showed a significant logarithmic correlation with a decrease in VR
      (P<0.001). Strong PGVS reduced the mean VR from 234 to 92 bpm (P<0.001). The PGVS
      effects on the cellular responses and VR during AF were fully reproduced in a
      model of direct acetylcholine injection into the compact AVN via micropipette.
      CONCLUSIONS: These studies confirmed that PGVS applied during AF could produce
      substantial VR slowing because of acetylcholine-induced depression of conduction
      in the AVN.

PMID- 10351977
TI  - Copulsation balloon for right ventricular assistance: preliminary trials.
AB  - BACKGROUND: Options for management of acute right ventricular (RV) failure are
      limited. This report describes preliminary testing of a temporary RV assist
      device that acts by direct compression of the RV. The system comprises a pancake
      shaped silicone balloon (5 cm diameter) connected to a drive console that
      delivers a 65-mL pneumatic pulse during cardiac systole. METHODS AND RESULTS:
      Initial in vivo tests were performed on 6 pigs (weight, 41+/-4 kg). RV wall
      motion and stroke volume were monitored via transesophageal echocardiography.
      Acute RV failure was created by graded right coronary ligation, which yielded a
      63% reduction in RV stroke volume (39.9+/-8.2 to 14.7+/-1.9 mL; P<0.002). We
      secured the balloon over the RV free wall by attaching it to the edges of the
      opened pericardium. The sternum was then reapproximated, and data were collected
      with the device off and on (every beat). Device placement had no deleterious
      effect on RV function. Balloon activation returned RV stroke volumes to normal
      (37.8+/-9.2 mL) and increased mean pulmonary artery pressures from 13+/-2 to 16+/
      3 mm Hg (P<0.01). RV compression did not induce or exacerbate tricuspid
      regurgitation. Mean aortic pressure improved from postinfarction levels but did
      not return to normal. CONCLUSIONS: We conclude that the pulmonary circulation can
      be supported in the short term via cardiac compression and that balloon
      copulsation techniques for short-term RV failure should be tested in long-term
      models.

PMID- 10351978
TI  - Chaos and the transition to ventricular fibrillation: a new approach to
      antiarrhythmic drug evaluation.
AB  - Sudden cardiac death resulting from ventricular fibrillation can be separated
      into 2 components: initiation of tachycardia and degeneration of tachycardia to
      fibrillation. Clinical drug studies such as CAST and SWORD demonstrated that
      focusing exclusively on the first component is inadequate as a therapeutic
      modality. The hope for developing effective pharmacological therapy rests on a
      comprehensive understanding of the second component, the transition from
      tachycardia to fibrillation. We summarize evidence that the transition from
      tachycardia to fibrillation is a transition to spatiotemporal chaos, with
      similarities to the quasiperiodic transition to chaos seen in fluid turbulence.
      In this scenario, chaos results from the interaction of multiple causally
      independent oscillatory motions. Simulations in 2-dimensional cardiac tissue
      suggest that the destabilizing oscillatory motions during spiral-wave reentry
      arise from restitution properties of action potential duration and conduction
      velocity. The process of spiral-wave breakup in simulated cardiac tissue predicts
      remarkably well the sequence by which tachycardia degenerates to fibrillation in
      real cardiac tissue. Modifying action potential duration and conduction velocity
      restitution characteristics can prevent spiral-wave breakup in simulated cardiac
      tissue, suggesting that drugs with similar effects in real cardiac tissue may
      have antifibrillatory efficacy (the Restitution Hypothesis). If valid for the
      real heart, the Restitution Hypothesis will support a new paradigm for
      antiarrhythmic drug classification, incorporating an antifibrillatory profile
      based on effects on cardiac restitution and the traditional antitachycardia
      profile (classes 1 through 4).

PMID- 10351979
TI  - Arteriovenous fistulas of the circumflex and right coronary arteries with
      drainage into an aneurysmal coronary sinus.

PMID- 10351980
TI  - ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable
      angina: executive summary and recommendations. A Report of the American College
      of Cardiology/American Heart Association Task Force on Practice Guidelines
      (Committee on Management of Patients with Chronic Stable Angina).

PMID- 10351981
TI  - New ultrasensitive assays facilitate studies on the role of human glandular
      kallikrein (hK2) as a marker for prostatic disease.

PMID- 10351982
TI  - Prostate-specific antigen: advances and challenges.

PMID- 10351983
TI  - A two-year study of microscopic urinalysis competency using the urinalysis-review
      computer program.
AB  - BACKGROUND: The microscopic examination of urine sediment is one of the most
      commonly performed microscope-based laboratory tests, but despite its widespread
      use, there has been no detailed study of the competency of medical technologists
      in performing this test. One reason for this is the lack of an effective
      competency assessment tool that can be applied uniformly across an institution.
      METHODS: This study describes the development and implementation of a computer
      program, Urinalysis-ReviewTM, which periodically tests competency in microscopic
      urinalysis and then summarizes individual and group test results. In this study,
      eight Urinalysis-Review exams were administered over 2 years to medical
      technologists (mean, 58 technologists per exam; range, 44-77) at our academic
      medical center. The eight exams contained 80 test questions, consisting of 72
      structure identification questions and 8 quantification questions. The 72
      structure questions required the identification of 134 urine sediment structures
      consisting of 63 examples of cells, 25 of casts, 18 of normal crystals, 8 of
      abnormal crystals, and 20 of organisms or artifacts. RESULTS: Overall, the
      medical technologists correctly identified 84% of cells, 72% of casts, 79% of
      normal crystals, 65% of abnormal crystals, and 81% of organisms and artifacts,
      and correctly answered 89% of the quantification questions. The results are
      probably a slight underestimate of competency because the images were analyzed
      without the knowledge of urine chemistry results. CONCLUSIONS: The study shows
      the feasibility of using a computer program for competency assessment in the
      clinical laboratory. In addition, the study establishes baseline measurements of
      competency that other laboratories can use for comparison, and which we will use
      in future studies that measure the effect of continuing education efforts in
      microscopic urinalysis.

PMID- 10351984
TI  - Optimization of apolipoprotein(a) genotyping with pulsed field gel
      electrophoresis.
AB  - BACKGROUND: Increased lipoprotein(a) is a risk factor for atherosclerosis, and
      its concentration in serum is inversely correlated with the size of the
      apoliprotein(a) [apo(a)] component. The size of the apo(a) gene is determined
      mainly by the Kringle IV size polymorphism. We have optimized and characterized
      pulsed field gel electrophoresis (PFGE) for apo(a) genotyping. METHODS:
      Established PFGE protocols were adjusted. The changes included the following: (a)
      increased DNA yields by the use of all leukocytes for isolation from either 3 mL
      of fresh EDTA whole blood or 250 microL of frozen buffy coats; (b) increased
      efficiency of Kpn1 digestion by the inclusion of a digestion buffer wash; (c)
      reduction of assay time by the use of capillary blotting; (d) increased
      sensitivity by the use of four digoxigenin-labeled apo(a) probes; and (e)
      identification using a single film by the inclusion of a digoxigenin-labeled
      lambda marker probe in addition to apo(a) probes in the hybridization mix.
      RESULTS: In older Caucasians, 93% (buffy coats, n=468) were heterozygous for
      apo(a) gene size. An inverse correlation between serum lipoprotein(a) and the sum
      of Kringle IV alleles was found (y = -23x + 1553; r = -0.442; n = 468). Gel-to
      gel variation was minimal (3%). Imprecision (SD) was one Kringle IV repeat
      (control sample containing eight fragments of 72-233 kb; n=34 electrophoretic
      runs). CONCLUSIONS: The practicality and sensitivity of the apo(a) genotyping
      technique by PFGE were improved, and accuracy and reproducibility were preserved.
      The optimized procedure is promising for apo(a) genotyping on frozen buffy coats
      from large epidemiological studies.

PMID- 10351985
TI  - Strand displacement amplification and homogeneous real-time detection
      incorporated in a second-generation DNA probe system, BDProbeTecET.
AB  - BACKGROUND: Amplified DNA probes provide powerful tools for the detection of
      infectious diseases, cancer, and genetic diseases. Commercially available
      amplification systems suffer from low throughput and require decontamination
      schemes, significant hands-on time, and specially trained laboratory staff. Our
      objective was to develop a DNA probe system to overcome these limitations.
      METHODS: We developed a DNA probe system, the BDProbeTecTMET, based on
      simultaneous strand displacement amplification and real-time fluorescence
      detection. The system uses sealed microwells to minimize the release of amplicons
      to the environment. To avoid the need for specially trained labor, the system
      uses a simple workflow with predispensed reagent devices; a programmable,
      expandable-spacing pipettor; and the 96-microwell format. Amplification and
      detection time was 1 h, with potential throughput up to 564 patient results per
      shift. We tested 122 total patient specimens obtained from a family practice
      clinic with the BD ProbeTecET and the Abbott LCx(R) amplified system for the
      detection of Chlamydia trachomatis and Neisseria gonorrhoeae. RESULTS: Based on
      reportable results, the BDProbeTecET results for both organisms were 100%
      sensitive and 100% specific relative to the LCx. CONCLUSIONS: The BDProbeTecET is
      an easy-to-use, high-throughput, closed amplification system for the detection of
      nucleic acid from C. trachomatis and N. gonorrhoeae and other organisms.

PMID- 10351987
TI  - Development of an ultrasensitive immunoassay for human glandular kallikrein with
      no cross-reactivity from prostate-specific antigen.
AB  - BACKGROUND: Studies demonstrating that human glandular kallikrein (hK2) is
      increased in prostate cancer patients have prompted speculation that this marker
      may of use in addition to prostate-specific antigen (PSA). METHODS: An
      ultrasensitive hK2 sandwich immunoassay was developed, and its detection limit,
      cross-reactivity, analytical recovery, precision, and linearity of dilution were
      evaluated. hK2 was measured in seminal plasma and sera from healthy males,
      females, and prostatectomized patients. RESULTS: Our assay has an excellent
      detection limit (6 ng/L) and precision (>90%). Recovery studies indicated that
      hK2 binds to serum protease inhibitors. All sera from healthy males had
      measurable hK2 concentrations (median, 402 ng/L). Almost all female sera had
      undetectable hK2. Serum hK2 and PSA in males correlated positively (r = 0.44),
      but hK2 was present at concentrations approximately 2. 5-fold lower than PSA. The
      PSA/hK2 ratio in male sera was 0.1-34, with a median of 2.6. In seminal plasma,
      this ratio was 100-500. More than 94% of immunoreactive hK2 in serum was in the
      free form ( approximately 30 kDa); traces of hK2 complexed to alpha1
      antichymotrypsin were present. CONCLUSIONS: The limit of detection of the method
      for hK2 measurement described here ( approximately 20-fold lower than any other
      reported assay for hK2) allows the generation of new clinical information. When
      combined with a previously described method for PSA measurement that has no cross
      reactivity from hK2, this methods allows the relative proportions of hK2 and PSA
      in biological fluids to be measured.

PMID- 10351986
TI  - Quantitative reverse transcription-PCR measurement of thyroglobulin mRNA in
      peripheral blood of healthy subjects.
AB  - BACKGROUND: Thyroglobulin mRNA can be detected qualitatively in the peripheral
      blood of patients with metastatic thyroid cancer, thyroid cancer patients with
      residual thyroid bed uptake, and individuals with no known thyroid disease with
      intact thyroid glands by use of a lengthy, highly sensitive extraction technique.
      To improve and broaden the clinical usefulness of this assay, we developed a
      quantitative reverse transcription (RT)-PCR assay for thyroglobulin mRNA, using
      RNA recovered from whole blood with a simplified extraction technique. METHODS:
      Whole blood was drawn from 32 healthy subjects in standard EDTA blood collection
      tubes. Total RNA was extracted from whole blood, using the PUREscript RNA
      Isolation Kit. RT-PCR using intron-spanning primers was used to quantitatively
      amplify thyroglobulin mRNA, using the ABI PRISM 7700 Sequence Detection System
      with a fluorescent-labeled, thyroglobulin-specific oligonucleotide probe. Thyroid
      RNA calibration curves were created using total RNA recovered from a single
      nondiseased thyroid gland. RESULTS: Qualitative RT-PCR demonstrated the presence
      of thyroglobulin mRNA in the whole blood sample of each healthy subject. The mean
      concentration of thyroglobulin mRNA detected in these subjects was 433 +/- 69 ng
      of total thyroid RNA per liter of whole blood (range, 26-1502 ng/L). Overall
      assay imprecision (CV) was 24% for five samples analyzed 10 times each in
      separate analytical runs on different days. CONCLUSIONS: Thyroglobulin mRNA can
      be accurately detected and quantified in peripheral blood from healthy subjects.
      This new quantitative technique may improve the clinical utility of circulating
      thyroglobulin mRNA detection in patients with thyroid disease.

PMID- 10351988
TI  - Highly sensitive automated chemiluminometric assay for measuring free human
      glandular kallikrein-2.
AB  - BACKGROUND: Human glandular kallikrein (hK2) is a serine protease that has 79%
      amino acid identity with prostate-specific antigen (PSA). Both free hK2 and hK2
      complexed to alpha1-antichymotrypsin (ACT) are present in the blood in low
      concentrations. We wished to measure hK2 in serum with limited contribution from
      hK2-ACT for the results. METHODS: We developed an automated assay for hK2 with
      use of a select pair of monoclonal antibodies. The prototype assay was
      implemented on a Beckman Coulter ACCESS(R) analyzer. RESULTS: The detection limit
      of the assay was 1.5 ng/L, the "functional sensitivity" (day-to-day CV <15%) was
      <4 ng/L, cross-reactivity with PSA and PSA-ACT was negligible, and cross
      reactivity with hK2-ACT was 2%. After surgical removal of prostate glands, serum
      hK2 was <7 ng/L and was <15 ng/L in most healthy women. The median serum
      concentration of hK2 in healthy men without prostate cancer was 26 ng/L. The
      median concentration of hK2 was 72 ng/L for men having prostate cancer with lower
      Gleason scores compared with 116 ng/L for men with more advanced cancer. The
      concentration of hK2 correlated weakly with PSA, with the mean hK2 concentrations
      generally 30- to 80-fold lower than PSA concentrations. CONCLUSION: The
      availability of a robust, high sensitivity automated assay for hK2 should
      facilitate further investigations of the role of hK2 measurements in the
      management of patients with prostate disease.

PMID- 10351989
TI  - Assay of procarboxypeptidase U, a novel determinant of the fibrinolytic cascade,
      in human plasma.
AB  - BACKGROUND: Procarboxypeptidase U (proCPU) is a novel proenzyme found in human
      plasma. The active form, carboxypeptidase U (CPU; EC 3.4.17.20), retards the rate
      of fibrinolysis through its ability to cleave C-terminal lysine residues on
      fibrin partially degraded by plasmin. This reduces the number of high-affinity
      plasminogen-binding sites on fibrin. METHODS: We developed an assay to determine
      the proCPU concentration in human plasma. The assay involved quantitative
      conversion of proCPU to active CPU by thrombin-thrombomodulin, a very efficient
      activator of proCPU, followed by determination of the enzymatic activity of CPU
      with the substrate hippuryl-L-arginine, using an HPLC-assisted determination of
      the released hippuric acid. Using this method, we established a reference
      interval based on 490 healthy individuals. RESULTS: The mean proCPU
      concentration, determined after activation of the zymogen in diluted plasma and
      expressed as CPU activity, was 964 U/L, with a SD of 155 U/L. The population
      showed a gaussian distribution. However, we noticed important differences related
      to age and the use of hormone preparations. CONCLUSIONS: The sensitivity and
      precision of the method make it suitable for routine clinical determinations and
      as a reference procedure.

PMID- 10351990
TI  - Measurement of the complex between prostate-specific antigen and alpha1-protease
      inhibitor in serum.
AB  - BACKGROUND: Prostate-specific antigen (PSA) occurs in serum both free and in
      complex with protease inhibitors. The complex with alpha1-antichymotrypsin (ACT)
      is the major form in serum, and the proportion of PSA-ACT is higher in prostate
      cancer (PCa) than in benign prostatic hyperplasia (BPH). PSA also forms a complex
      with alpha1-protease inhibitor (API) in vitro, and the PSA-ACT complex has been
      detected in serum from patients with prostate cancer. The aim of the present
      study was to develop a quantitative method for the determination of PSA-API and
      to determine the serum concentrations in patients with PCa and BPH. METHODS: The
      assay for PSA-API utilizes a monoclonal antibody to PSA as capture and a
      polyclonal antibody to API labeled with a Eu-chelate as a tracer. For
      calibrators, PSA-API formed in vitro was used. Serum samples were obtained before
      treatment from 82 patients with PCa, from 66 patients with BPH, and from 22
      healthy females. RESULTS: The concentrations of PSA-API are proportional to the
      concentrations of total PSA. PSA-API comprises 1.0-7.9% (median, 2.4%) of total
      immunoreactive PSA in PCa and 1.3-12.2% (median, 3.6%) in BPH patients with serum
      PSA concentrations >4 microgram/L. In patients with 4-20 microgram/L total PSA,
      the proportion of PSA-API serum is significantly higher in BPH (median, 4.1%)
      than in PCa (median, 3. 2%; P = 0.02). CONCLUSIONS: The proportion of PSA-API in
      serum is lower in patients with PCa than in those with BPH. These results suggest
      that PSA-API is a potential adjunct to total and free PSA in the diagnosis of
      prostate cancer.

PMID- 10351992
TI  - Falsely increased immunoassay measurements of total and unbound phenytoin in
      critically ill uremic patients receiving fosphenytoin.
AB  - BACKGROUND: Fosphenytoin, a phosphate ester prodrug of phenytoin, is metabolized
      to phenytoin in vivo. Phenytoin metabolites accumulate in renal insufficiency and
      cross-react in some phenytoin immunoassays. Our aim was to determine the accuracy
      of phenytoin immunoassays in renal patients treated with fosphenytoin. METHODS:
      We measured phenytoin with HPLC and with the aca, ACS:180, TDx phenytoin II,
      Vitros, and AxSYM methods. Specimens were collected 2-120 h after fosphenytoin
      administration from 17 patients with renal insufficiency. RESULTS: The AxSYM, TDx
      phenytoin II, ACS:180, and Vitros assays displayed falsely increased phenytoin
      results up to 20 times higher than the HPLC results. The aca Star results for
      these specimens were comparable to the HPLC results. Although fosphenytoin can
      cross-react with phenytoin immunoassays, no fosphenytoin was detected by a
      sensitive HPLC method in any sample that was tested for its presence. CONCLUSION:
      These results are consistent with the formation of one or more novel metabolites
      or adducts of fosphenytoin that accumulate in some critically ill patients with
      renal insufficiency and that display significant cross-reactivity with some, but
      not all, phenytoin immunoassay methods.

PMID- 10351993
TI  - Hyperinsulinemia and related atherosclerotic risk factors in the population at
      cardiovascular risk: a community-based study.
AB  - BACKGROUND: A population-based study was conducted in Taiwan to investigate the
      prevalence of insulin resistance and high serum insulin concentrations and their
      relationships with potential atherosclerotic risk factors. METHODS: We studied
      2165 subjects, ages >35, from a community cohort. RESULTS: The distributions of
      fasting insulin were skewed to the right, with higher concentrations in women
      than in men. As age increased, insulin increased in women, but decreased in men.
      As fasting insulin concentrations increased, postloading insulin, glucose, blood
      pressure, body mass index, waist-to-hip ratio, total cholesterol, triglycerides,
      LDL-cholesterol, apoprotein B, plasminogen activator inhibitor 1, tissue
      plasminogen activator, and fibrinogen increased, but lipoprotein(a), HDL
      cholesterol, and apoprotein A1 decreased. Multiple logistic regression showed
      that obesity, high LDL-cholesterol, and low HDL-cholesterol were significant
      predictors of hyperinsulinemic status. CONCLUSION: The study subjects with
      insulin resistance syndrome and related risk factors may be at risk for
      atherosclerosis, thrombosis, and other coronary heart diseases.

PMID- 10351991
TI  - Impact of antibody specificity and calibration material on the measure of
      agreement between methods for cardiac troponin I.
AB  - BACKGROUND: Available assays for cardiac troponin I (cTnI) yield numerically
      different results. The aim of this study was to compare patient values obtained
      from four cTnI immunoassays. METHODS: We studied the Stratus(R) II assay, the
      Opus(R) II assay, the Access(R) assay, and a research-only cTnI heterogeneous
      immunoassay that uses the Dade Behring aca(R) plus immunoassay system equipped
      with two new noncommercial monoclonal antibodies. Because the aca plus cTnI assay
      is for research only, we first evaluated and analytically validated it for serum
      and citrated plasma. Initially, each method was calibrated using the method
      specific calibrator supplied by each manufacturer; however, the aca plus cTnI
      assay was calibrated using patient serum pools containing cTnI and selected on
      the basis of increased creatine kinase MB isoenzyme and with values assigned by
      use of the Stratus cTnI assay. For method comparisons, individual patient sample
      cTnI values were determined and compared with the Stratus II assay. RESULTS:
      Passing and Bablock regression analysis yielded slopes of 1.44 (r = 0.96; n = 72)
      for the Opus II vs Stratus II assays; 0.07 (r = 0.91; n = 72) for the Access vs
      Stratus II assays; and 0.90 (r = 0.91, n = 72) for the aca plus vs Stratus II
      assays. The recalibration of each method with a Stratus II-assigned serum pool
      improved, but did not entirely eliminate, the slope differences between the
      different assays (range, 1.00-1.16). The observed scatter in the correlation
      curves remained. CONCLUSION: There is a need to further explore the specificities
      of these assays with respect to the different circulating forms of cTnI.

PMID- 10351994
TI  - Improved immunoradiometric assay for plasma renin.
AB  - BACKGROUND: Our renin IRMA overestimated renin in plasmas with high prorenin-to
      renin ratios. We suspected that the overestimation of renin was caused less by
      cross-reactivity of the renin-specific antibody with prorenin than by a
      conformational change of prorenin into an enzymatically active form during the
      assay. METHODS: Because the inactive form of prorenin converts slowly into an
      active form at low temperature, we raised the assay temperature from 22 degrees C
      to 37 degrees C, simultaneously shortening the incubation time from 24 to 6 h.
      The former IRMA was performed in <1 working day with these modifications.
      RESULTS: The comeasurement of prorenin as renin was eliminated. Reagents were
      stable at 37 degrees C, and the new and old IRMAs were comparable in terms of
      precision and accuracy. The functional lower limit of the assay (4 mU/L) was
      below the lower reference limit (9 mU/L). The modified IRMA agreed closely with
      the activities measured with an enzyme-kinetic assay. Results were not influenced
      by the plasma concentration of angiotensinogen. At normal angiotensinogen
      concentrations, the IRMA closely correlated with the classical enzyme-kinetic
      assay of plasma renin activity. CONCLUSION: The modified IRMA, performed at 37
      degrees C, avoids interference by prorenin while retaining the desirable
      analytical characteristics of the older IRMA and requiring less time.

PMID- 10351995
TI  - Terbium and rhodamine as labels in a homogeneous time-resolved fluorometric
      energy transfer assay of the beta subunit of human chorionic gonadotropin in
      serum.
AB  - BACKGROUND: Fluorescence resonance energy transfer (FRET) is a powerful tool in
      analytical chemistry. The aim of the present work was to use FRET to design a
      homogeneous immunoassay. METHODS: We used a highly fluorescent terbium (Tb3+)
      chelate (donor) and the organic fluorochrome rhodamine (acceptor) combined with
      time-resolved detection of the acceptor emission in homogeneous assay format for
      the measurement of the beta subunit of human chorionic gonadotropin (betahCG) in
      serum. We used two antibodies labeled with Tb3+ and rhodamine, respectively,
      recognizing different epitopes on betahCG. The close proximity between the labels
      in the immunocomplex permitted energy transfer between the pulse-excited Tb3+
      donor (decay time >1 ms) and the acceptor rhodamine (decay time of 3.0 ns). The
      prolonged emission of donor-excited acceptor (energy transfer) was measured after
      the short-lived background and acceptor emissions had decayed. The emission of
      donor-excited rhodamine was measured at a wavelength of where the emission of
      unbound donor is minimal. RESULTS: The energy transfer signal was directly
      proportional to the betahCG concentration in the sample. The limit of detection
      was 0.43 microgram/L, and the assay was linear up to 200 microgram/L. Total assay
      imprecision in the range 10-185 microgram/L was between 7.5% and 2.8%.
      CONCLUSIONS: Although less sensitive than heterogeneous, dissociation-enhanced
      europium-based separation assays, the presented assay format has advantages such
      as speed and simplicity, which make the assay format ideal for assays requiring a
      high throughput.

PMID- 10351996
TI  - Quantification of riboflavin, flavin mononucleotide, and flavin adenine
      dinucleotide in human plasma by capillary electrophoresis and laser-induced
      fluorescence detection.
AB  - BACKGROUND: Riboflavin is the precursor of flavin mononucleotide (FMN) and FAD,
      which serve as cofactors for several redox enzymes. We have developed a capillary
      electrophoresis method for the determination of riboflavin and its two coenzyme
      forms in human plasma. METHODS: Trichloroacetic acid-treated plasma was subjected
      to solid-phase extraction on reversed-phase columns. The analytes were separated
      by micellar electrokinetic capillary chromatography in uncoated fused- silica
      capillaries filled with borate buffer containing 50 mmol/L sodium dodecyl
      sulfate, methanol, and N-methylformamide. Native fluorescence was monitored at
      530 nm, using an argon laser operating at 488 nm as excitation source. RESULTS:
      The assay was linear over a concentration range of two orders of magnitude, and
      the limit of detection was far below physiological concentrations for all
      vitamers. The within-day and between-day coefficients of variation were 4-9% and
      6-12%, respectively. The reference values (median, 5-95 percentiles) obtained by
      analyzing plasma from 63 healthy subjects were 8.6 nmol/L (2.7-42.5 nmol/L) for
      riboflavin, 7.0 nmol/L (3.5-13.3 nmol/L) for FMN, and 57.9 nmol/L (44.5-78.1
      nmol/L) for FAD. CONCLUSIONS: Capillary electrophoresis with laser-induced
      fluorescence detection allows determination of all riboflavin vitamers far below
      physiological concentrations. The method may become a useful tool for the
      assessment of riboflavin status in humans.

PMID- 10351997
TI  - A new approach for clinical biological assay comparison and standardization:
      application of principal component analysis to a multicenter study of twenty-one
      carcinoembryonic antigen immunoassay kits.
AB  - BACKGROUND: Principal component analysis (PCA) is a powerful mathematical method
      able to analyze data sets containing a large number of variables. To our
      knowledge, this method is applied here for the first time in the field of medical
      laboratory analysis. METHODS: PCA was used to evaluate the results of a blind
      comparative study of 21 carcinoembryonic antigen (CEA) reagent kits used to
      determine CEA concentration in a panel of sera from 80 patients. RESULTS: The
      mathematical technique first eliminated the variations attributable to the use of
      different calibrators. The PCA representation then gave a global view of the
      dispersion of the kits and allowed the identification of a main homogeneous group
      and of some discrepant kits. CONCLUSIONS: PCA applied to the in vitro diagnostic
      reagent field could contribute to the standardization process and improve the
      quality of medical laboratory analyses. A standardization method using a panel of
      patient sera is proposed.

PMID- 10351998
TI  - Necessary sample size for method comparison studies based on regression analysis.
AB  - BACKGROUND: In method comparison studies, it is of importance to assure that the
      presence of a difference of medical importance is detected. For a given
      difference, the necessary number of samples depends on the range of values and
      the analytical standard deviations of the methods involved. For typical examples,
      the present study evaluates the statistical power of least-squares and Deming
      regression analyses applied to the method comparison data. METHODS: Theoretical
      calculations and simulations were used to consider the statistical power for
      detection of slope deviations from unity and intercept deviations from zero. For
      situations with proportional analytical standard deviations, weighted forms of
      regression analysis were evaluated. RESULTS: In general, sample sizes of 40-100
      samples conventionally used in method comparison studies often must be
      reconsidered. A main factor is the range of values, which should be as wide as
      possible for the given analyte. For a range ratio (maximum value divided by
      minimum value) of 2, 544 samples are required to detect one standardized slope
      deviation; the number of required samples decreases to 64 at a range ratio of 10
      (proportional analytical error). For electrolytes having very narrow ranges of
      values, very large sample sizes usually are necessary. In case of proportional
      analytical error, application of a weighted approach is important to assure an
      efficient analysis; e.g., for a range ratio of 10, the weighted approach reduces
      the requirement of samples by >50%. CONCLUSIONS: Estimation of the necessary
      sample size for a method comparison study assures a valid result; either no
      difference is found or the existence of a relevant difference is confirmed.

PMID- 10352000
TI  - Contribution of the TATA-box genotype (Gilbert syndrome) to serum bilirubin
      concentrations in the Italian population.

PMID- 10351999
TI  - Antioxidant defense in erythrocytes and plasma of patients with active and
      quiescent Crohn disease and ulcerative colitis: a chemiluminescent study.

PMID- 10352001
TI  - Comparison of methods used to measure serum iron in the presence of iron
      gluconate or iron dextran.

PMID- 10352002
TI  - Simultaneous measurement of allantoin and urate in plasma: analytical evaluation
      and potential clinical application in oxidant:antioxidant balance studies.

PMID- 10352004
TI  - Glycohemoglobin results in samples with hemoglobin C or S trait: a comparison of
      four test systems.

PMID- 10352003
TI  - Collagen type I alpha1 gene Sp1 polymorphism in premenopausal women with primary
      osteoporosis: improved detection of Sp1 binding site polymorphism in the collagen
      type 1 gene.

PMID- 10352005
TI  - Simple precipitation-based method for the screening of type III
      hyperlipoproteinemia.

PMID- 10352007
TI  - Compiled by david E. Bruns, editor (dbruns@aacc.org) 

PMID- 10352006
TI  - Issues in genetic testing.

PMID- 10352008
TI  - Practice of coronary angioplasty in California in 1995 : comparison to 1989 and
      impact of coronary stenting.
AB  - BACKGROUND: This study seeks to analyze changes in the practice of PTCA in
      California between 1989 and 1995 by use of the Office of Statewide Health
      Planning and Development (OSHPD) data set. METHODS AND RESULTS: All hospital
      discharges in 1995 with a procedure code for PTCA or stent were identified. The
      1995 PTCA data were compared with previously published data from 1989 obtained
      from the same database. The number of PTCAs performed increased by 49% between
      1989 and 1995, from 24 883 to 37 118. The percentage of female patients increased
      from 29.8% to 32.7% (P=0.0001). The percentage of diabetics increased from 14.4%
      to 21.6% (P=0.0001) between 1989 and 1995. Procedures on patients with a
      principal diagnosis of acute myocardial infarction increased from 19.3% of all
      PTCAs in 1989 to 27.5% of PTCAs in 1995 (P=0.0001). In-hospital mortality
      increased from 1.4% in 1989 to 1.9% in 1995 (P=0.0001). There were 3087
      admissions with stent placement in 1995. In-hospital mortality after stent
      placement was 0.9% (P=0.0001 versus PTCA). Patients undergoing PTCA in hospitals
      performing >400 PTCAs in 1995 had a 4% incidence of death or emergency bypass
      surgery compared with a 6% incidence when PTCAs were performed in hospitals
      performing </=400 PTCA in 1995 (P<0.0001). Patients undergoing stent implantation
      in hospitals performing >75 stent procedures in 1995 had a 1.3% incidence of
      death or emergency bypass compared with an incidence of 4% when the procedure was
      performed in a hospital performing </=75 stent placements in 1995 (P<0.0001).
      CONCLUSIONS: The 1995 OSHPD data continue to suggest an inverse relationship
      between hospital PTCA and stent volume and adverse patient outcomes.

PMID- 10352009
TI  - Diastolic mitral regurgitation.

PMID- 10352010
TI  - Molecular bases for the recognition of tyrosine-based sorting signals.

PMID- 10352011
TI  - Heptahelical receptor signaling: beyond the G protein paradigm.

PMID- 10352012
TI  - The unstable F-box protein p58-Ctf13 forms the structural core of the CBF3
      kinetochore complex.
AB  - Kinetochores are smaller and more accessible experimentally in budding yeast than
      in any other eukaryote. Believing that simple and complex kinetochores have
      important structural and functional properties in common, we characterized the
      structure of CBF3, the essential centromere-binding complex that initiates
      kinetochore formation in Saccharomyces cerevisiae. We find that the four subunits
      of CBF3 are multimeric in solution: p23(Skp1) and p58(Ctf13) form a heterodimer,
      and p64(Cep3) and p110(Ndc10) form homodimers. Subcomplexes involving p58 and
      each of the other CBF3 subunits can assemble in the absence of centromeric DNA.
      In these subcomplexes, p58 appears to function as a structural core mediating
      stable interactions among other CBF3 proteins. p58 has a short half-life in
      yeast, being subject to ubiquitin-dependent proteolysis, but we find that it is
      much more stable following association with p64. We propose that p23(Skp1)-p58
      p64 complexes constitute the primary pool of active p58 in yeast cells. These
      complexes can either dissociate, reexposing p58 to the degradation pathway, or
      can bind to p110 and centromeric DNA, forming a functional CBF3 complex in which
      p58 is fully protected from degradation. This pathway may constitute an editing
      mechanism preventing the formation of ectopic kinetochores and ensuring the
      fidelity of chromosome segregation.

PMID- 10352013
TI  - NH2-Terminal targeting motifs direct dual specificity A-kinase-anchoring protein
      1 (D-AKAP1) to either mitochondria or endoplasmic reticulum.
AB  - Subcellular localization directed by specific targeting motifs is an emerging
      theme for regulating signal transduction pathways. For cAMP-dependent protein
      kinase (PKA), this is achieved primarily by its association with A-kinase
      anchoring proteins (AKAPs). Dual specificity AKAP1, (D-AKAP1) binds to both type
      I and type II regulatory subunits and has two NH2-terminal (N0 and N1) and two
      COOH-terminal (C1 and C2) splice variants (. J. Biol. Chem. 272:8057). Here we
      report that the splice variants of D-AKAP1 are expressed in a tissue-specific
      manner with the NH2-terminal motifs serving as switches to localize D-AKAP1 at
      different sites. Northern blots showed that the N1 splice is expressed primarily
      in liver, while the C1 splice is predominant in testis. The C2 splice shows a
      general expression pattern. Microinjecting expression constructs of D-AKAP1(N0)
      epitope-tagged at either the NH2 or the COOH terminus showed their localization
      to the mitochondria based on immunocytochemistry. Deletion of N0(1-30) abolished
      mitochondrial targeting while N0(1-30)-GFP localized to mitochondria. Residues 1
      30 of N0 are therefore necessary and sufficient for mitochondria targeting.
      Addition of the 33 residues of N1 targets D-AKAP1 to the ER and residues 1-63
      fused to GFP are necessary and sufficient for ER targeting. Residues 14-33 of N1
      are especially important for targeting to ER; however, residues 1-33 alone fused
      to GFP gave a diffuse distribution. N1(14-33) thus serves two functions: (a) it
      suppresses the mitochondrial-targeting motif located within residues 1-30 of N0
      and (b) it exposes an ER-targeting motif that is at least partially contained
      within the N0(1-30) motif. This represents the first example of a differentially
      targeted AKAP and adds an additional level of complexity to the PKA signaling
      network.

PMID- 10352015
TI  - Direct membrane insertion of voltage-dependent anion-selective channel protein
      catalyzed by mitochondrial Tom20.
AB  - Insertion of newly synthesized proteins into or across the mitochondrial outer
      membrane is initiated by import receptors at the surface of the organelle.
      Typically, this interaction directs the precursor protein into a preprotein
      translocation pore, comprised of Tom40. Here, we show that a prominent beta
      barrel channel protein spanning the outer membrane, human voltage- dependent
      anion-selective channel (VDAC), bypasses the requirement for the Tom40
      translocation pore during biogenesis. Insertion of VDAC into the outer membrane
      is unaffected by plugging the translocation pore with a partially translocated
      matrix preprotein, and mitochondria containing a temperature-sensitive mutant of
      Tom40 insert VDAC at the nonpermissive temperature. Synthetic liposomes harboring
      the cytosolic domain of the human import receptor Tom20 efficiently insert newly
      synthesized VDAC, resulting in transbilayer transport of ATP. Therefore, Tom20
      transforms newly synthesized cytosolic VDAC into a transmembrane channel that is
      fully integrated into the lipid bilayer.

PMID- 10352014
TI  - The J-related segment of tim44 is essential for cell viability: a mutant Tim44
      remains in the mitochondrial import site, but inefficiently recruits mtHsp70 and
      impairs protein translocation.
AB  - Tim44 is a protein of the mitochondrial inner membrane and serves as an adaptor
      protein for mtHsp70 that drives the import of preproteins in an ATP-dependent
      manner. In this study we have modified the interaction of Tim44 with mtHsp70 and
      characterized the consequences for protein translocation. By deletion of an 18
      residue segment of Tim44 with limited similarity to J-proteins, the binding of
      Tim44 to mtHsp70 was weakened. We found that in the yeast Saccharomyces
      cerevisiae the deletion of this segment is lethal. To investigate the role of the
      18-residue segment, we expressed Tim44Delta18 in addition to the endogenous wild
      type Tim44. Tim44Delta18 is correctly targeted to mitochondria and assembles in
      the inner membrane import site. The coexpression of Tim44Delta18 together with
      wild-type Tim44, however, does not stimulate protein import, but reduces its
      efficiency. In particular, the promotion of unfolding of preproteins during
      translocation is inhibited. mtHsp70 is still able to bind to Tim44Delta18 in an
      ATP-regulated manner, but the efficiency of interaction is reduced. These results
      suggest that the J-related segment of Tim44 is needed for productive interaction
      with mtHsp70. The efficient cooperation of mtHsp70 with Tim44 facilitates the
      translocation of loosely folded preproteins and plays a crucial role in the
      import of preproteins which contain a tightly folded domain.

PMID- 10352016
TI  - Budding yeast Bub2 is localized at spindle pole bodies and activates the mitotic
      checkpoint via a different pathway from Mad2.
AB  - The mitotic checkpoint blocks cell cycle progression before anaphase in case of
      mistakes in the alignment of chromosomes on the mitotic spindle. In budding
      yeast, the Mad1, 2, 3, and Bub1, 2, 3 proteins mediate this arrest. Vertebrate
      homologues of Mad1, 2, 3, and Bub1, 3 bind to unattached kinetochores and prevent
      progression through mitosis by inhibiting Cdc20/APC-mediated proteolysis of
      anaphase inhibitors, like Pds1 and B-type cyclins. We investigated the role of
      Bub2 in budding yeast mitotic checkpoint. The following observations indicate
      that Bub2 and Mad1, 2 probably activate the checkpoint via different pathways:
      (a) unlike the other Mad and Bub proteins, Bub2 localizes at the spindle pole
      body (SPB) throughout the cell cycle; (b) the effect of concomitant lack of Mad1
      or Mad2 and Bub2 is additive, since nocodazole-treated mad1 bub2 and mad2 bub2
      double mutants rereplicate DNA more rapidly and efficiently than either single
      mutant; (c) cell cycle progression of bub2 cells in the presence of nocodazole
      requires the Cdc26 APC subunit, which, conversely, is not required for mad2 cells
      in the same conditions. Altogether, our data suggest that activation of the
      mitotic checkpoint blocks progression through mitosis by independent and
      partially redundant mechanisms.

PMID- 10352017
TI  - Yeast Bim1p promotes the G1-specific dynamics of microtubules.
AB  - Microtubule dynamics vary during the cell cycle, and microtubules appear to be
      more dynamic in vivo than in vitro. Proteins that promote dynamic instability are
      therefore central to microtubule behavior in living cells. Here, we report that a
      yeast protein of the highly conserved EB1 family, Bim1p, promotes cytoplasmic
      microtubule dynamics specifically during G1. During G1, microtubules in cells
      lacking BIM1 showed reduced dynamicity due to a slower shrinkage rate, fewer
      rescues and catastrophes, and more time spent in an attenuated/paused state.
      Human EB1 was identified as an interacting partner for the adenomatous polyposis
      coli (APC) tumor suppressor protein. Like human EB1, Bim1p localizes to dots at
      the distal ends of cytoplasmic microtubules. This localization, together with
      data from electron microscopy and a synthetic interaction with the gene encoding
      the kinesin Kar3p, suggests that Bim1p acts at the microtubule plus end. Our in
      vivo data provide evidence of a cell cycle-specific microtubule-binding protein
      that promotes microtubule dynamicity.

PMID- 10352018
TI  - Arp2/3 complex and actin depolymerizing factor/cofilin in dendritic organization
      and treadmilling of actin filament array in lamellipodia.
AB  - The leading edge (approximately 1 microgram) of lamellipodia in Xenopus laevis
      keratocytes and fibroblasts was shown to have an extensively branched
      organization of actin filaments, which we term the dendritic brush. Pointed ends
      of individual filaments were located at Y-junctions, where the Arp2/3 complex was
      also localized, suggesting a role of the Arp2/3 complex in branch formation.
      Differential depolymerization experiments suggested that the Arp2/3 complex also
      provided protection of pointed ends from depolymerization. Actin depolymerizing
      factor (ADF)/cofilin was excluded from the distal 0.4 micrometer++ of the
      lamellipodial network of keratocytes and in fibroblasts it was located within the
      depolymerization-resistant zone. These results suggest that ADF/cofilin, per se,
      is not sufficient for actin brush depolymerization and a regulatory step is
      required. Our evidence supports a dendritic nucleation model (Mullins, R.D., J.A.
      Heuser, and T.D. Pollard. 1998. Proc. Natl. Acad. Sci. USA. 95:6181-6186) for
      lamellipodial protrusion, which involves treadmilling of a branched actin array
      instead of treadmilling of individual filaments. In this model, Arp2/3 complex
      and ADF/cofilin have antagonistic activities. Arp2/3 complex is responsible for
      integration of nascent actin filaments into the actin network at the cell front
      and stabilizing pointed ends from depolymerization, while ADF/cofilin promotes
      filament disassembly at the rear of the brush, presumably by pointed end
      depolymerization after dissociation of the Arp2/3 complex.

PMID- 10352019
TI  - Cyclic expression of endothelin-converting enzyme-1 mediates the functional
      regulation of seminiferous tubule contraction.
AB  - The potent smooth muscle agonist endothelin-1 (ET-1) is involved in the local
      control of seminiferous tubule contractility, which results in the forward
      propulsion of tubular fluid and spermatozoa, through its action on peritubular
      myoid cells. ET-1, known to be produced in the seminiferous epithelium by Sertoli
      cells, is derived from the inactive intermediate big endothelin-1 (big ET-1)
      through a specific cleavage operated by the endothelin-converting enzyme (ECE), a
      membrane-bound metalloprotease with ectoenzymatic activity. The data presented
      suggest that the timing of seminiferous tubule contractility is controlled
      locally by the cyclic interplay between different cell types. We have studied the
      expression of ECE by Sertoli cells and used myoid cell cultures and seminiferous
      tubule explants to monitor the biological activity of the enzymatic reaction
      product. Northern blot analysis showed that ECE-1 (and not ECE-2) is specifically
      expressed in Sertoli cells; competitive enzyme immunoassay of ET production
      showed that Sertoli cell monolayers are capable of cleaving big ET-1, an activity
      inhibited by the ECE inhibitor phosphoramidon. Microfluorimetric analysis of
      intracellular calcium mobilization in single cells showed that myoid cells do not
      respond to big endothelin, nor to Sertoli cell plain medium, but to the medium
      conditioned by Sertoli cells in the presence of big ET-1, resulting in cell
      contraction and desensitization to further ET-1 stimulation; in situ
      hybridization analysis shows regional differences in ECE expression, suggesting
      that pulsatile production of endothelin by Sertoli cells (at specific "stages" of
      the seminiferous epithelium) may regulate the cyclicity of tubular contraction;
      when viewed in a scanning electron microscope, segments of seminiferous tubules
      containing the specific stages characterized by high expression of ECE were
      observed to contract in response to big ET-1, whereas stages with low ECE
      expression remained virtually unaffected. These data indicate that endothelin
      mediated spatiotemporal control of rhythmic tubular contractility might be
      operated by Sertoli cells through the cyclic expression of ECE-1, which is, in
      turn, dependent upon the timing of spermatogenesis.

PMID- 10352020
TI  - Impairment of inhibitory synaptic transmission in mice lacking synapsin I.
AB  - Deletion of the synapsin I genes, encoding one of the major groups of proteins on
      synaptic vesicles, in mice causes late onset epileptic seizures and enhanced
      experimental temporal lobe epilepsy. However, mice lacking synapsin I maintain
      normal excitatory synaptic transmission and modulation but for an enhancement of
      paired-pulse facilitation. To elucidate the cellular basis for epilepsy in
      mutants, we examined whether the inhibitory synapses in the hippocampus from
      mutant mice are intact by electrophysiological and morphological means. In the
      cultured hippocampal synapses from mutant mice, repeated application of a
      hypertonic solution significantly suppressed the subsequent transmitter release,
      associated with an accelerated vesicle replenishing time at the inhibitory
      synapses, compared with the excitatory synapses. In the mutants, morphologically
      identifiable synaptic vesicles failed to accumulate after application of a
      hypertonic solution at the inhibitory preterminals but not at the excitatory
      preterminals. In the CA3 pyramidal cells in hippocampal slices from mutant mice,
      inhibitory postsynaptic currents evoked by direct electrical stimulation of the
      interneuron in the striatum oriens were characterized by reduced quantal content
      compared with those in wild type. We conclude that synapsin I contributes to the
      anchoring of synaptic vesicles, thereby minimizing transmitter depletion at the
      inhibitory synapses. This may explain, at least in part, the epileptic seizures
      occurring in the synapsin I mutant mice.

PMID- 10352021
TI  - Functions of c-Jun in liver and heart development.
AB  - Mice lacking the AP-1 transcription factor c-Jun die around embryonic day E13.0
      but little is known about the cell types affected as well as the cause of
      embryonic lethality. Here we show that a fraction of mutant E13.0 fetal livers
      exhibits extensive apoptosis of both hematopoietic cells and hepatoblasts,
      whereas the expression of 15 mRNAs, including those of albumin, keratin 18,
      hepatocyte nuclear factor 1, beta-globin, and erythropoietin, some of which are
      putative AP-1 target genes, is not affected. Apoptosis of hematopoietic cells in
      mutant livers is most likely not due to a cell-autonomous defect, since c-jun-/-
      fetal liver cells are able to reconstitute all hematopoietic compartments of
      lethally irradiated recipient mice. A developmental analysis of chimeras showed
      contribution of c-jun-/- ES cell derivatives to fetal, but not to adult livers,
      suggesting a role of c-Jun in hepatocyte turnover. This is in agreement with the
      reduced mitotic and increased apoptotic rates found in primary liver cell
      cultures derived from c-jun-/- fetuses. Furthermore, a novel function for c-Jun
      was found in heart development. The heart outflow tract of c-jun-/- fetuses show
      malformations that resemble the human disease of a truncus arteriosus persistens.
      Therefore, the lethality of c-jun mutant fetuses is most likely due to
      pleiotropic defects reflecting the diversity of functions of c-Jun in
      development, such as a role in neural crest cell function, in the maintenance of
      hepatic hematopoiesis and in the regulation of apoptosis.

PMID- 10352022
TI  - The heterotrimeric protein Go is required for the formation of heart epithelium
      in Drosophila.
AB  - The gene encoding the alpha subunit of the Drosophila Go protein is expressed
      early in embryogenesis in the precursor cells of the heart tube, of the visceral
      muscles, and of the nervous system. This early expression coincides with the
      onset of the mesenchymal-epithelial transition to which are subjected the cardial
      cells and the precursor cells of the visceral musculature. This gene constitutes
      an appropriate marker to follow this transition. In addition, a detailed analysis
      of its expression suggests that the cardioblasts originate from two
      subpopulations of cells in each parasegment of the dorsal mesoderm that might
      depend on the wingless and hedgehog signaling pathways for both their
      determination and specification. In the nervous system, the expression of Goalpha
      shortly precedes the beginning of axonogenesis. Mutants produced in the Goalpha
      gene harbor abnormalities in the three tissues in which the gene is expressed. In
      particular, the heart does not form properly and interruptions in the heart
      epithelium are repeatedly observed, henceforth the brokenheart (bkh) name.
      Furthermore, in the bkh mutant embryos, the epithelial polarity of cardial cells
      was not acquired (or maintained) in various places of the cardiac tube. We
      predict that bkh might be involved in vesicular traffic of membrane proteins that
      is responsible for the acquisition of polarity.

PMID- 10352024
TI  - Evidence for apical endocytosis in polarized hepatic cells: phosphoinositide 3
      kinase inhibitors lead to the lysosomal accumulation of resident apical plasma
      membrane proteins.
AB  - The architectural complexity of the hepatocyte canalicular surface has prevented
      examination of apical membrane dynamics with methods used for other epithelial
      cells. By adopting a pharmacological approach, we have documented for the first
      time the internalization of membrane proteins from the hepatic apical surface.
      Treatment of hepatocytes or WIF-B cells with phosphoinositide 3-kinase
      inhibitors, wortmannin or LY294002, led to accumulation of the apical plasma
      membrane proteins, 5'-nucleotidase and aminopeptidase N in lysosomal vacuoles. By
      monitoring the trafficking of antibody-labeled molecules, we determined that the
      apical proteins in vacuoles came from the apical plasma membrane. Neither newly
      synthesized nor transcytosing apical proteins accumulated in vacuoles. In
      wortmannin-treated cells, transcytosing apical proteins traversed the subapical
      compartment (SAC), suggesting that this intermediate in the basolateral-to-apical
      transcytotic pathway remained functional. Ultrastructural analysis confirmed
      these results. However, apically internalized proteins did not travel through SAC
      en route to lysosomal vacuoles, indicating that SAC is not an intermediate in the
      apical endocytic pathway. Basolateral membrane protein distributions did not
      change in treated cells, uncovering another difference in endocytosis from the
      two domains. Similar effects were observed in polarized MDCK cells, suggesting
      conserved patterns of phosphoinositide 3-kinase regulation among epithelial
      cells. These results confirm a long-held but unproven assumption that lysosomes
      are the final destination of apical membrane proteins in hepatocytes.
      Significantly, they also confirm our hypothesis that SAC is not an apical
      endosome.

PMID- 10352026
TI  - Perspectives on ion permeation 

PMID- 10352023
TI  - R-Ras signals through specific integrin alpha cytoplasmic domains to promote
      migration and invasion of breast epithelial cells.
AB  - Specificity and modulation of integrin function have important consequences for
      cellular responses to the extracellular matrix, including differentiation and
      transformation. The Ras-related GTPase, R-Ras, modulates integrin affinity, but
      little is known of the signaling pathways and biological functions downstream of
      R-Ras. Here we show that stable expression of activated R-Ras or the closely
      related TC21 (R-Ras 2) induced integrin-mediated migration and invasion of breast
      epithelial cells through collagen and disrupted differentiation into tubule
      structures, whereas dominant negative R-Ras had opposite effects. These results
      imply novel roles for R-Ras and TC21 in promoting a transformed phenotype and in
      the basal migration and polarization of these cells. Importantly, R-Ras induced
      an increase in cellular adhesion and migration on collagen but not fibronectin,
      suggesting that R-Ras signals to specific integrins. This was further supported
      by experiments in which R-Ras enhanced the migration of cells expressing integrin
      chimeras containing the alpha2, but not the alpha5, cytoplasmic domain. In
      addition, a transdominant inhibition previously noted only between integrin beta
      cytoplasmic domains was observed for the alpha2 cytoplasmic domain; alpha2beta1
      mediated migration was inhibited by the expression of excess alpha2 but not
      alpha5 cytoplasmic domain-containing chimeras, suggesting the existence of
      limiting factors that bind the integrin alpha subunit. Using pharmacological
      inhibitors, we found that R-Ras induced migration on collagen through a
      combination of phosphatidylinositol 3-kinase and protein kinase C, but not MAPK,
      which is distinct from the other Ras family members, Rac, Cdc42, and N- and K
      Ras. Thus, R-Ras communicates with specific integrin alpha cytoplasmic domains
      through a unique combination of signaling pathways to promote cell migration and
      invasion.

PMID- 10352027
TI  - Calcium channel permeation: A field in flux.

PMID- 10352025
TI  - Expression of the heparan sulfate proteoglycan, perlecan, during mouse
      embryogenesis and perlecan chondrogenic activity in vitro.
AB  - Expression of the basement membrane heparan sulfate proteoglycan (HSPG), perlecan
      (Pln), mRNA, and protein has been examined during murine development. Both Pln
      mRNA and protein are highly expressed in cartilaginous regions of developing
      mouse embryos, but not in areas of membranous bone formation. Initially detected
      at low levels in precartilaginous areas of d 12.5 embryos, Pln protein
      accumulates in these regions through d 15.5 at which time high levels are
      detected in the cartilage primordia. Laminin and collagen type IV, other basal
      lamina proteins commonly found colocalized with Pln, are absent from the
      cartilage primordia. Accumulation of Pln mRNA, detected by in situ hybridization,
      was increased in d 14.5 embryos. Cartilage primordia expression decreased to
      levels similar to that of the surrounding tissue at d 15.5. Pln accumulation in
      developing cartilage is preceded by that of collagen type II. To gain insight
      into Pln function in chondrogenesis, an assay was developed to assess the
      potential inductive activity of Pln using multipotential 10T1/2 murine embryonic
      fibroblast cells. Culture on Pln, but not on a variety of other matrices,
      stimulated extensive formation of dense nodules reminiscent of embryonic
      cartilaginous condensations. These nodules stained intensely with Alcian blue and
      collagen type II antibodies. mRNA encoding chondrocyte markers including collagen
      type II, aggrecan, and Pln was elevated in 10T1/2 cells cultured on Pln. Human
      chondrocytes that otherwise rapidly dedifferentiate during in vitro culture also
      formed nodules and expressed high levels of chondrocytic marker proteins when
      cultured on Pln. Collectively, these studies demonstrate that Pln is not only a
      marker of chondrogenesis, but also strongly potentiates chondrogenic
      differentiation in vitro.

PMID- 10352029
TI  - Ionic hopping defended.

PMID- 10352028
TI  - Progress and prospects in permeation.

PMID- 10352030
TI  - Modeling of ion channels.

PMID- 10352031
TI  - Tuning Ca2+ permeation in cyclic nucleotide-gated channels.

PMID- 10352032
TI  - Divalent cation selectivity is a function of gating in native and recombinant
      cyclic nucleotide-gated ion channels from retinal photoreceptors.
AB  - The selectivity of Ca2+ over Na+ is approximately 3.3-fold larger in cGMP-gated
      channels of cone photoreceptors than in those of rods when measured under
      saturating cGMP concentrations, where the probability of channel opening is 85
      90%. Under physiological conditions, however, the probability of opening of the
      cGMP-gated channels ranges from its largest value in darkness of 1-5% to
      essentially zero under continuous, bright illumination. We investigated the ion
      selectivity of cGMP-gated channels as a function of cyclic nucleotide
      concentration in membrane patches detached from the outer segments of rod and
      cone photoreceptors and have found that ion selectivity is linked to gating. We
      determined ion selectivity relative to Na+ (PX/PNa) from the value of reversal
      potentials measured under ion concentration gradients. The selectivity for Ca2+
      over Na+ increases continuously as the probability of channel opening rises. The
      dependence of PCa/PNa on cGMP concentration, in both rods and cones, is well
      described by the same Hill function that describes the cGMP dependence of current
      amplitude. At the cytoplasmic cGMP concentrations expected in dark-adapted intact
      photoreceptors, PCa/PNa in cone channels is approximately 7.4-fold greater than
      that in rods. The linkage between selectivity and gating is specific for divalent
      cations. The selectivity of Ca2+ and Sr2+ changes with cGMP concentration, but
      the selectivity of inorganic monovalent cations, Cs+ and NH4+, and organic
      cations, methylammonium+ and dimethylammonium+, is invariant with cGMP. Cyclic
      nucleotide-gated channels in rod photoreceptors are heteromeric assemblies of
      alpha and beta subunits. The maximal PCa/PNa of channels formed from alpha
      subunits of bovine rod channels is less than that of heteromeric channels formed
      from alpha and beta subunits. In addition, Ca2+ is a more effective blocker of
      channels formed by alpha subunits than of channels formed by alpha and beta
      subunits. The cGMP-dependent shift in divalent cation selectivity is a property
      of alphabeta channels and not of channels formed from alpha subunits alone.

PMID- 10352033
TI  - Potassium-dependent changes in the conformation of the Kv2.1 potassium channel
      pore.
AB  - The voltage-gated K+ channel, Kv2.1, conducts Na+ in the absence of K+. External
      tetraethylammonium (TEAo) blocks K+ currents through Kv2.1 with an IC50 of 5 mM,
      but is completely without effect in the absence of K+. TEAo block can be titrated
      back upon addition of low [K+]. This suggested that the Kv2.1 pore undergoes a
      cation-dependent conformational rearrangement in the external vestibule.
      Individual mutation of lysine (Lys) 356 and 382 in the outer vestibule, to a
      glycine and a valine, respectively, increased TEAo potency for block of K+
      currents by a half log unit. Mutation of Lys 356, which is located at the outer
      edge of the external vestibule, significantly restored TEAo block in the absence
      of K+ (IC50 = 21 mM). In contrast, mutation of Lys 382, which is located in the
      outer vestibule near the TEA binding site, resulted in very weak (extrapolated
      IC50 = approximately 265 mM) TEAo block in the absence of K+. These data suggest
      that the cation-dependent alteration in pore conformation that resulted in loss
      of TEA potency extended to the outer edge of the external vestibule, and
      primarily involved a repositioning of Lys 356 or a nearby amino acid in the
      conduction pathway. Block by internal TEA also completely disappeared in the
      absence of K+, and could be titrated back with low [K+]. Both internal and
      external TEA potencies were increased by the same low [K+] (30-100 microM) that
      blocked Na+ currents through the channel. In addition, experiments that combined
      block by internal and external TEA indicated that the site of K+ action was
      between the internal and external TEA binding sites. These data indicate that a
      K+-dependent conformational change also occurs internal to the selectivity
      filter, and that both internal and external conformational rearrangements
      resulted from differences in K+ occupancy of the selectivity filter. Kv2.1
      inactivation rate was K+ dependent and correlated with TEAo potency; as [K+] was
      raised, TEAo became more potent and inactivation became faster. Both TEAo potency
      and inactivation rate saturated at the same [K+]. These results suggest that the
      rate of slow inactivation in Kv2.1 was influenced by the conformational
      rearrangements, either internal to the selectivity filter or near the outer edge
      of the external vestibule, that were associated with differences in TEA potency.

PMID- 10352034
TI  - Regulation of type 1 inositol 1,4,5-trisphosphate-gated calcium channels by InsP3
      and calcium: Simulation of single channel kinetics based on ligand binding and
      electrophysiological analysis.
AB  - Cytosolic calcium acts as both a coagonist and an inhibitor of the type 1
      inositol 1,4,5-trisphosphate (InsP3)-gated Ca channel, resulting in a bell-shaped
      Ca dependence of channel activity (Bezprozvanny, I., J. Watras, and B.E. Ehrlich.
      1991. Nature. 351:751-754; Finch, E.A., T.J. Turner, and S.M. Goldin. 1991.
      Science. 252: 443-446; Iino, M. 1990. J. Gen. Physiol. 95:1103-1122). The ability
      of Ca to inhibit channel activity, however, varies dramatically depending on
      InsP3 concentration (Combettes, L., Z. Hannaert-Merah, J.F. Coquil, C. Rousseau,
      M. Claret, S. Swillens, and P. Champeil. 1994. J. Biol. Chem. 269:17561-17571;
      Kaftan, E.J., B.E. Ehrlich, and J. Watras. 1997. J. Gen. Physiol. 110:529-538).
      In the present report, we have extended the characterization of the effect of
      cytosolic Ca on both InsP3 binding and InsP3-gated channel kinetics, and
      incorporated these data into a mathematical model capable of simulating channel
      kinetics. We found that cytosolic Ca increased the Kd of InsP3 binding
      approximately 3.5-fold, but did not influence the maximal number of binding
      sites. The ability of Ca to decrease InsP3 binding is consistent with the
      rightward shift in the bell-shaped Ca dependence of InsP3-gated Ca channel
      activity. High InsP3 concentrations are able to overcome the Ca-dependent
      inhibition of channel activity, apparently due to a low affinity InsP3 binding
      site (Kaftan, E.J., B.E. Ehrlich, and J. Watras. 1997. J. Gen. Physiol. 110:529
      538). Constants from binding analyses and channel activity determinations were
      used to develop a mathematical model that fits the complex Ca-dependent
      regulation of the type 1 InsP3-gated Ca channel. This model accurately simulated
      both steady state data (channel open probability and InsP3 binding) and kinetic
      data (channel activity and open time distributions), and yielded testable
      predictions with regard to the regulation of this intracellular Ca channel.
      Information gained from these analyses, and our current molecular model of this
      Ca channel, will be important for understanding the basis and regulation of
      intracellular Ca waves and oscillations in intact cells.

PMID- 10352035
TI  - Agonist-dependent phosphorylation of the inositol 1,4,5-trisphosphate receptor: A
      possible mechanism for agonist-specific calcium oscillations in pancreatic acinar
      cells.
AB  - The properties of inositol 1,4,5-trisphosphate (IP3)-dependent intracellular
      calcium oscillations in pancreatic acinar cells depend crucially on the agonist
      used to stimulate them. Acetylcholine or carbachol (CCh) cause high-frequency (10
      12-s period) calcium oscillations that are superimposed on a raised baseline,
      while cholecystokinin (CCK) causes long-period (>100-s period) baseline spiking.
      We show that physiological concentrations of CCK induce rapid phosphorylation of
      the IP3 receptor, which is not true of physiological concentrations of CCh. Based
      on this and other experimental data, we construct a mathematical model of agonist
      specific intracellular calcium oscillations in pancreatic acinar cells. Model
      simulations agree with previous experimental work on the rates of activation and
      inactivation of the IP3 receptor by calcium (DuFour, J.-F., I.M. Arias, and T.J.
      Turner. 1997. J. Biol. Chem. 272:2675-2681), and reproduce both short-period,
      raised baseline oscillations, and long-period baseline spiking. The steady state
      open probability curve of the model IP3 receptor is an increasing function of
      calcium concentration, as found for type-III IP3 receptors by Hagar et al.
      (Hagar, R.E., A.D. Burgstahler, M.H. Nathanson, and B.E. Ehrlich. 1998. Nature.
      396:81-84). We use the model to predict the effect of the removal of external
      calcium, and this prediction is confirmed experimentally. We also predict that,
      for type-III IP3 receptors, the steady state open probability curve will shift to
      lower calcium concentrations as the background IP3 concentration increases. We
      conclude that the differences between CCh- and CCK-induced calcium oscillations
      in pancreatic acinar cells can be explained by two principal mechanisms: (a) CCK
      causes more phosphorylation of the IP3 receptor than does CCh, and the
      phosphorylated receptor cannot pass calcium current; and (b) the rate of calcium
      ATPase pumping and the rate of calcium influx from the outside the cell are
      greater in the presence of CCh than in the presence of CCK.

PMID- 10352037
TI  - Kvbeta1.2 subunit coexpression in HEK293 cells confers O2 sensitivity to kv4.2
      but not to Shaker channels.
AB  - Voltage-gated K+ (KV) channels are protein complexes composed of ion-conducting
      integral membrane alpha subunits and cytoplasmic modulatory beta subunits. The
      differential expression and association of alpha and beta subunits seems to
      contribute significantly to the complexity and heterogeneity of KV channels in
      excitable cells, and their functional expression in heterologous systems provides
      a tool to study their regulation at a molecular level. Here, we have studied the
      effects of Kvbeta1.2 coexpression on the properties of Shaker and Kv4.2 KV
      channel alpha subunits, which encode rapidly inactivating A-type K+ currents, in
      transfected HEK293 cells. We found that Kvbeta1.2 functionally associates with
      these two alpha subunits, as well as with the endogenous KV channels of HEK293
      cells, to modulate different properties of the heteromultimers. Kvbeta1.2
      accelerates the rate of inactivation of the Shaker currents, as previously
      described, increases significantly the amplitude of the endogenous currents, and
      confers sensitivity to redox modulation and hypoxia to Kv4.2 channels. Upon
      association with Kvbeta1.2, Kv4.2 can be modified by DTT (1,4 dithiothreitol) and
      DTDP (2,2'-dithiodipyridine), which also modulate the low pO2 response of the
      Kv4.2+beta channels. However, the physiological reducing agent GSH (reduced
      glutathione) did not mimic the effects of DTT. Finally, hypoxic inhibition of
      Kv4.2+beta currents can be reverted by 70% in the presence of carbon monoxide and
      remains in cell-free patches, suggesting the presence of a hemoproteic O2 sensor
      in HEK293 cells and a membrane-delimited mechanism at the origin of hypoxic
      responses. We conclude that beta subunits can modulate different properties upon
      association with different KV channel subfamilies; of potential relevance to
      understanding the molecular basis of low pO2 sensitivity in native tissues is the
      here described acquisition of the ability of Kv4. 2+beta channels to respond to
      hypoxia.

PMID- 10352036
TI  - Opening mechanism of a cyclic nucleotide-gated channel based on analysis of
      single channels locked in each liganded state.
AB  - Cyclic nucleotide-gated channels contain four subunits, each with a binding site
      for cGMP or cAMP in the cytoplasmic COOH-terminal domain. Previous studies of the
      kinetic mechanism of activation have been hampered by the complication that
      ligands are continuously binding and unbinding at each of these sites. Thus, even
      at the single channel level, it has been difficult to distinguish changes in
      behavior that arise from a channel with a fixed number of ligands bound from
      those that occur upon the binding and unbinding of ligands. For example, it is
      often assumed that complex behaviors like multiple conductance levels and
      bursting occur only as a consequence of changes in the number of bound ligands.
      We have overcome these ambiguities by covalently tethering one ligand at a time
      to single rod cyclic nucleotide-gated channels (Ruiz, ML., and J.W. Karpen. 1997.
      Nature. 389:389-392). We find that with a fixed number of ligands locked in place
      the channel freely moves between three conductance states and undergoes bursting
      behavior. Furthermore, a thorough kinetic analysis of channels locked in doubly,
      triply, and fully liganded states reveals more than one kinetically
      distinguishable state at each conductance level. Thus, even when the channel
      contains a fixed number of bound ligands, it can assume at least nine distinct
      states. Such complex behavior is inconsistent with simple concerted or sequential
      allosteric models. The data at each level of liganding can be successfully
      described by the same connected state model (with different rate constants),
      suggesting that the channel undergoes the same set of conformational changes
      regardless of the number of bound ligands. A general allosteric model, which
      postulates one conformational change per subunit in both the absence and presence
      of ligand, comes close to providing enough kinetically distinct states. We
      propose an extension of this model, in which more than one conformational change
      per subunit can occur during the process of channel activation.

PMID- 10352039
TI  - Staphylococcal infections in children: Part 1.

PMID- 10352038
TI  - Potassium uptake supporting plant growth in the absence of AKT1 channel activity:
      Inhibition by ammonium and stimulation by sodium.
AB  - A transferred-DNA insertion mutant of Arabidopsis that lacks AKT1 inward
      rectifying K+ channel activity in root cells was obtained previously by a reverse
      genetic strategy, enabling a dissection of the K+-uptake apparatus of the root
      into AKT1 and non-AKT1 components. Membrane potential measurements in root cells
      demonstrated that the AKT1 component of the wild-type K+ permeability was between
      55 and 63% when external [K+] was between 10 and 1,000 microM, and NH4+ was
      absent. NH4+ specifically inhibited the non-AKT1 component, apparently by
      competing for K+ binding sites on the transporter(s). This inhibition by NH4+ had
      significant consequences for akt1 plants: K+ permeability, 86Rb+ fluxes into
      roots, seed germination, and seedling growth rate of the mutant were each
      similarly inhibited by NH4+. Wild-type plants were much more resistant to NH4+.
      Thus, AKT1 channels conduct the K+ influx necessary for the growth of Arabidopsis
      embryos and seedlings in conditions that block the non-AKT1 mechanism. In
      contrast to the effects of NH4+, Na+ and H+ significantly stimulated the non-AKT1
      portion of the K+ permeability. Stimulation of akt1 growth rate by Na+, a
      predicted consequence of the previous result, was observed when external [K+] was
      10 microM. Collectively, these results indicate that the AKT1 channel is an
      important component of the K+ uptake apparatus supporting growth, even in the
      "high-affinity" range of K+ concentrations. In the absence of AKT1 channel
      activity, an NH4+-sensitive, Na+/H+-stimulated mechanism can suffice.

PMID- 10352040
TI  - Viral encephalitis.

PMID- 10352041
TI  - Index of suspicion. Case 1. Toxic shock syndrome.

PMID- 10352042
TI  - Earning CME credit--completing the PIR quiz 

PMID- 10352043
TI  - Hemolytic anemia: Part 2.

PMID- 10352045
TI  - Water heater temperatures 

PMID- 10352044
TI  - Consultation with the specialist. Brain abscess.

PMID- 10352046
TI  - [Sexual dysfunction associated to the use of psychodrugs. Present importance and
      therapeutic possibilities]

PMID- 10352047
TI  - Murray Enkin: celebration and tribute.

PMID- 10352048
TI  - Effects of female relative support in labor: a randomized controlled trial.
AB  - BACKGROUND: This study was a randomized controlled trial of primigravidas in
      Botswana to determine the effectiveness of the presence of a female relative as a
      labor companion on labor outcomes. METHODS: One hundred and nine primigravidas in
      uncomplicated spontaneous labor were randomly distributed into a control group
      who labored without family members present, and an experimental group who had a
      female relative with them during labor. RESULTS: Significantly more mothers in
      the experimental group had a spontaneous vaginal delivery (91% vs 71%), less
      intrapartum analgesia (53% vs 73%), less oxytocin (13% vs 30%), fewer amniotomies
      to augment labor (30% vs 54%), fewer vacuum extractions (4% vs 16%), and fewer
      cesarean sections (6% vs 13%) than in the control group. These differences were
      all significant at p < 0.05. Epidural analgesia was not used in the hospital at
      the time of the study. The only analgesics used were intramuscular pethidine or
      hyoscine N-butylbromide (Buscopan). CONCLUSIONS: The presence in labor of a
      female relative was shown to be associated with fewer interventions and a higher
      frequency of normal delivery compared with the outcomes of those without family
      member support. The presence of a female relative as a labor companion is a low
      cost, preventative intervention that is consistent with the traditional cultural
      practices in Botswana. In the light of this and previous studies, all women
      giving birth in a hospital should be offered the choice of a female relative as a
      companion to give support during labor.

PMID- 10352049
TI  - Commentary: practical and humanistic lessons from the third world for perinatal
      caregivers everywhere.

PMID- 10352050
TI  - Distribution of genital tract trauma in childbirth and related postnatal pain.
AB  - BACKGROUND: The full extent of genital tract trauma in spontaneous births is not
      well documented. The purpose of this study was to describe the range and extent
      of childbirth trauma and related postnatal pain using data from a large
      randomized clinical trial of perineal management techniques (n = 5471). METHODS:
      Descriptive analysis was conducted on trial participants who delivered
      spontaneously at term and were examined by their midwife after birth (n = 5404).
      Data are reported for sites of trauma, and the relation to episiotomy, suturing,
      and maternal reports of pain at 2 days, 10 days, and 3 months after birth.
      RESULTS: Eighty-five percent of all women experienced some form of trauma, with
      first- or second-degree perineal lacerations occurring in two-thirds of women and
      outer vaginal tears occurring in one-half. Tears to the rectum and vaginal vault
      were more common with episiotomy. Nearly all unsutured trauma was restricted to
      perineal first- or second-degree, outer vaginal, and labial sites. Pain declined
      over time, and a gradient in pain was observed according to the site and
      complexity of trauma. CONCLUSIONS: Genital tract trauma is extremely common with
      spontaneous vaginal birth. Effective measures to prevent or reduce its occurrence
      would benefit many new mothers.

PMID- 10352051
TI  - Women's experiences of giving birth after 35.
AB  - BACKGROUND: This research forms part of a longitudinal study comparing
      experiences of pregnancy, birth, and the first year of motherhood among women
      aged 35 years and over with women aged 20 to 29 years, in the light of the
      current trend toward later childbearing. METHODS: Data from 107 women were
      collected from medical records of labor and delivery, and women themselves
      evaluated control and pain management in labor, satisfaction with support from
      professionals, labor problems, and postnatal depression. Associations between
      maternal age and parity and 1) obstetric outcomes, 2) women's perceptions of
      labor and delivery, and 3) postnatal depression were calculated. RESULTS:
      Professionals were more likely to place women over 35 years than those aged 20 to
      29 years in a "high-risk" category, but medical records of labor and delivery
      revealed few maternal age effects. Older mothers were more likely than younger
      mothers to acknowledge that their baby's life might have been at risk during
      labor, and that they felt happy about the way staff managed labor problems. They
      were less likely than younger mothers to blame others for making labor pain
      worse. CONCLUSIONS: Older and younger women's experiences of labor differed in
      ways that were not mirrored by obstetric differences. Women over 35 years, even
      if healthy, may believe that their age makes their infants particularly
      vulnerable during labor. Their higher levels of concern do not necessarily have
      negative consequences for their experience of childbirth or for their postnatal
      emotional well-being.

PMID- 10352052
TI  - What is recommended for healthy women during pregnancy? A comparison of seven
      prenatal clinical practice guideline documents.
AB  - BACKGROUND: Several countries have developed clinical practice guidelines for the
      content of prenatal care. This study examines the consistency of recommendations
      in clinical practice guidelines describing routine prenatal care. METHODS: The
      recommendations for low-risk women in seven guideline documents were examined:
      two from Australia, two from the United States, two from Canada, and one from
      Germany. The recommendations were listed into the four areas of "general health
      screening and health promotion during pregnancy," "organization of care,"
      "clinical tests and screening," and "education specific for pregnancy." RESULTS:
      A total of 69 recommendations were identified within the seven documents, most of
      which fell within the "clinical tests and screening" domain. Notable differences
      were identified in the number of recommendations made within the same country. Of
      the 69 recommendations, only four were included in all seven documents.
      CONCLUSION: Little consistency was demonstrated within or among countries in
      terms of the content of their prenatal care guidelines, suggesting a need to
      reexamine their content and the evidence on which such recommendations are based.

PMID- 10352053
TI  - Intravenous therapy for women in labor: implementation of a practice change.
AB  - BACKGROUND: Intravenous therapy for women in labor has been routinely
      administered in many North American hospitals since the 1950s. The purpose of
      this study was to evaluate a change in intravenous therapy practice. METHODS: The
      evaluation study, using a posttest, quasi-experimental design, examined the
      responses of women in labor and nurses to a questionnaire. Proxy prestudy cohort
      data were used for comparison of some patient outcomes. The convenience sample
      comprised 219 women admitted to the labor and delivery unit of a community
      hospital in Toronto, Ontario, between August and October 1997. RESULTS: Under the
      new intravenous therapy protocol, 26 percent of the women in labor did not
      receive intravenous therapy compared with 100 percent under the old protocol. The
      primary reasons for therapy were to enable administration of prescribed
      medication and bolus intravenous administration associated with epidural
      anesthesia. At the first after-delivery void, 61 percent of study women-65
      percent of those who received intravenous therapy and 50 percent of those who
      received no intravenous therapy-tested negative for ketonuria. All 119 comments
      from nurses indicated comfort with their judgments related to the initiation of
      intravenous therapy. CONCLUSIONS: The change in the intravenous therapy protocol
      was supported by the study findings. Nurses should increase patient education
      about drinking and eating adequately throughout labor if appropriate, and
      resuming adequate fluid and food intake as quickly as possible after childbirth.

PMID- 10352054
TI  - Breastfeeding twins: guidelines for success.
AB  - BACKGROUND: Although the frequency of twin births has increased in Japan, little
      information is available about breastfeeding twins. An intervention of
      breastfeeding support was implemented to promote breastfeeding for mothers of
      twins and to compare the factors related to breastfed and formula-fed twins.
      METHODS: Eleven Japanese twins-mother pairs received breastfeeding support
      according to a breastfeeding protocol for twins, and a control group of seven
      pairs received routine care. Perinatal data were obtained from clinical records
      for analysis. RESULTS: No significant differences were evident between the two
      groups in terms of maternal age, gestational age, birthweight, the age at which
      breastfeeding was initiated, amount of supplementary feeding in hospital,
      infants' age at discharge, or duration of mothers' hospital stay. At age 3
      months, 13 infants in the intervention group were being exclusively breastfed and
      9 were almost exclusively breastfed. In the control group 4 infants were almost
      exclusively and 10 were exclusively formula-fed. The mothers in the intervention
      group breastfed and expressed milk significantly more frequently than the mothers
      in the control group during their hospital stay. CONCLUSIONS: Mothers of twins
      face many obstacles in breastfeeding, and health care professionals should offer
      individualized care and support.

PMID- 10352056
TI  - Commentary: what is this thing called "control"?

PMID- 10352055
TI  - Decision making in analyses of women's birth stories.
AB  - BACKGROUND: Complex interactions occur among women and caregivers throughout
      labor. Analyzing women's birth stories provides a rich data source on these
      interactions. The purpose of this qualitative study was to clarify how decisions
      were made in labor by analyzing women's birth stories. METHODS: A convenience
      sample of 15 primiparous and multiparous Midwestern women contributed a total of
      33 birth stories. Qualitative methods were used, including analyses of the
      content and themes of stories. RESULTS: The primary types of decision making that
      were identified ranged on a continuum from unilateral to joint (shared), and were
      associated with various emotions expressed by the women. CONCLUSIONS: A model of
      decision making was derived from the data that may help caregivers change
      practices in ways that will benefit women. Caregivers can also benefit by
      understanding women's critiques of the birth care they received, and can use this
      knowledge to improve women's experiences of birth and therefore their
      satisfaction with the process.

PMID- 10352057
TI  - In the literature: midwifery care: the "gold standard" for normal childbirth?

PMID- 10352059
TI  - Cancer practice: the front page

PMID- 10352058
TI  - Sheila Kitzinger's letter from Europe: obstetric metaphors and marketing.

PMID- 10352060
TI  - Cigars: danger ahead.

PMID- 10352061
TI  - A breast cancer patient involved in a child custody suit.

PMID- 10352062
TI  - Perception of chemotherapy side effects cancer versus noncancer patients.
AB  - PURPOSE: This study was conducted to identify and compare perceptions regarding
      the disruption in quality of life caused by chemotherapy side effects in patients
      with cancer receiving chemotherapy and in noncancer, chemotherapy-naive patients.
      DESCRIPTION OF STUDY: One hundred forty-six patients with cancer and 224 patients
      without cancer completed two instruments to assess the perceived magnitude of 41
      physical and psychosocial chemotherapy side effects. Instrument 1 used a 5-point
      Likert scale (1 = not at all; 2 = a little bit; 3 = somewhat; 4 = quite a bit;
      and 5 = very much) to summarize patient responses to the question, "How much did
      or would each of the following side effects of chemotherapy bother you?"
      Instrument 2 was a serial ranking questionnaire that asked patients to select the
      10 most bothersome side effects to numerically rank the top five. An index of the
      relative magnitude of chemotherapy side effects was calculated for each
      instrument. RESULTS: For patients with cancer, loss of hair 50%), changes in
      taste (46%), constantly being tired (42%), affects work duties (39%), changes in
      smell perception (35%) were most frequently perceived as bothering them "quite a
      bit" or "very much." Nausea and vomiting were ranked 11th and 22nd, respectively.
      With instrument 2, the five side effects perceived as most troublesome were, in
      decreasing order: nausea, loss of hair, constantly tired, vomiting, and changes
      in the way things taste. For noncancer patients, those factors potentially
      bothersome "quite a bit" or "very much" were: financial hardship (82%), hardship
      on family (78%), vomiting (73%), shortness of breath (70%), and ability to
      perform work duties (69%). Via instrument 2, the top five side effects, in
      decreasing order were: vomiting, hardship on family, loss of hair, financial
      hardship, nausea, having to move close to a treatment center. CLINICAL
      IMPLICATIONS: Noncancer, chemotherapy-naive patients perceived most chemotherapy
      associated side effects as having greater impact on the quality of life than did
      cancer patients who had received chemotherapy. These findings can be used to
      direct patient education, education of the public, specific materials concerning
      cancer chemotherapy. The expertise of various members of the healthcare team can
      maximize the patient's comprehension of the adverse effects of the treatment
      options. The physician's knowledge of the overall treatment plan can assist in
      patient understanding; oncology pharmacists nurses are in a unique position to
      educate patients their families regarding potential chemotherapy side effects.

PMID- 10352063
TI  - Risk factors for pain after mastectomy/lumpectomy.
AB  - PURPOSE: Careful study of risk factors that predispose an individual to
      developing postmastectomy pain (PMP) after breast cancer surgery has not been
      reported. This study examined potential risk factors for PMP including
      demographic, disease, and treatment variables, as well as surgical factors, such
      as surgical technique and number of lymph nodes removed. DESCRIPTION OF THE
      STUDY: Data were collected via telephone interviews and review of medical
      records. Pain was assessed using the Brief Pain Inventory. The sample included
      134 breast cancer survivors who were a mean age of 55 years (SD = 9) and a mean
      of 35 months postsurgery (SD = 19). RESULTS: Women with PMP (n = 36) were not
      significantly different from women without PMP (n = 98) on demographic, disease,
      treatment, or surgical variables. PMP intensity was not significantly associated
      with age at diagnosis, time postsurgery, or time post-treatment. Contrary to
      expectation, PMP was found in women postlumpectomy without axillary dissection,
      women whose intercostobrachial nerve was spared, and women without documented
      postoperative complications. CLINICAL IMPLICATIONS: Findings suggest that cases
      of PMP cannot uniformly be identified based on the presence or absence of certain
      factors. Findings also underscore the need to screen all women for PMP after
      breast cancer surgery, particularly given the availability of effective pain
      management therapies.

PMID- 10352064
TI  - Family reports of cancer pain, pain relief, and prescription access.
AB  - PURPOSE: The authors 1) describe family caregiver reports of degree of pain, pain
      relief, and prescription access in persons with advanced cancer during the last 4
      weeks of life and 2) test for differences according to geographic location and
      care setting. DESCRIPTION OF STUDY: A randomized, stratified sample of 375
      caregivers was produced from a list of all state residents who died of cancer in
      1994. Written informed consent was received from 170 family caregivers (46%) who
      were then interviewed by telephone. Caregiver responses regarding pain intensity,
      pain relief, prescription access, and care setting were analyzed. RESULTS: Eighty
      six percent (n = 147) of caregivers reported that pain was a problem, and 61% (n
      = 103) recalled a great deal to quite a bit of pain compared with 25% (n = 44)
      who recalled some or little pain. The mean degree of pain was 2.23 (SD +/- 1.32)
      on a scale of 1 (a great deal) to 5 (no pain). Of 140 caregivers reporting pain
      relief data, 46% (n = 64) reported that interventions either stopped the pain or
      that pain became much better, whereas 54% (n = 76) reported that interventions
      made the pain a little better, had no effect, or made it worse. The overall mean
      of pain relief was 2.62 (SD +/-.87) on a scale of 1 (usually stopped the pain) to
      5 (made it worse). Greater degrees of pain were associated with reports of less
      pain relief (r = -19; P =.02). No differences in pain or pain relief were found
      across county type or patient care setting. Caregivers in the institution-only
      group (n = 18) recalled lower degrees of pain and the home-only group (n = 61)
      reported the most pain relief. Many in this latter group were served by hospice
      and home health nurses, and only 4% of the entire sample were served by
      physicians alone. Notably, 12% (n = 21) of the sample reported problems filling
      prescriptions. Of these, half had difficulty obtaining medicine because it was
      "not available." A total of 48 problems with prescription access were found that
      were distributed evenly across county types and patient care settings. CLINICAL
      IMPLICATIONS: Findings suggest that caregiver reports about the degree of pain or
      the effectiveness of pain interventions do not vary by residence or care setting
      at the end of life. Pain relief is moderate at best. Health professionals in all
      patient care settings should routinely address the issue of obtaining and paying
      for prescriptions, and local cancer pain task forces should be formed to advocate
      for better pain relief. An additional solution is to equip families with problem
      solving skills specific to cancer pain.

PMID- 10352065
TI  - Increasing mammography practice by African American women.
AB  - PURPOSE: This study examines the effectiveness of the Witness Project, a
      culturally competent cancer education program that trains cancer survivors to
      promote early detection and increased breast self-examination and mammography in
      a population of rural, underserved, African American women. DESCRIPTION OF STUDY:
      The primary setting for the Witness Project-an intensive, community-based,
      culturally sensitive educational program that incorporates spirituality and faith
      was the African American church. Baseline and 6-month follow-up surveys were
      obtained from 206 African American women in two intervention counties and from
      204 African American women in two control counties in the rural Mississippi River
      Delta region of Arkansas. RESULTS: Witness Project participants significantly
      increased (P <.0001) their practice of breast self-examination and mammography (P
      <.005) compared with the women in the control counties. CLINICAL IMPLICATIONS:
      These results demonstrate that intensive, community-based, culturally sensitive
      educational programming incorporating the spiritual environment of the faith
      community, such as the Witness Project, can positively influence breast cancer
      screening behaviors among rural, underserved African American women. Through the
      use of community churches and cancer survivors, breast cancer screening
      activities can be improved in this population.

PMID- 10352067
TI  - Cancer genetic counseling: need for confidentiality versus responsibility to
      notify.

PMID- 10352066
TI  - Gender and cancer support group participation.
AB  - PURPOSE: Although support groups are offered to many patients who have received a
      diagnosis of cancer, a majority of patients choose not to participate. This
      article reports the results of a study comparing the behavior of men diagnosed
      with prostate cancer and women diagnosed with breast cancer in their responses to
      invitations to participate in support groups. DESCRIPTION OF STUDY: One hundred
      thirty women with breast cancer and 87 men with prostate cancer completed a
      structured telephone interview. The interview included questions about the
      patients' choices about support group participation. RESULTS: Interview findings
      showed that men are less likely to join a support group, but those men who do
      join attend meetings for about 1 year, as do the women who join. Men and women
      cite essentially the same reasons for participation: to learn more about their
      diagnosis, to share their, concerns to compare their physical and emotional
      progress with other individuals. CLINICAL IMPLICATIONS: These results indicate
      the need for further exploration of effective interventions for men and women who
      have been diagnosed with prostate and breast cancer, respectively, in an effort
      to offer support for the difficult psychological and emotional issues associated
      with their diagnoses. Although more women than men join support groups, the
      majority of both populations (67% for women, 87% for men) do not attend any
      support group meetings. Innovative approaches are needed to encourage
      participation in existing support groups or to design alternative interventions.

PMID- 10352068
TI  - Resources for helping children whose parent (or other loved one) has cancer.

PMID- 10352070
TI  - Cancer practice: the front page

PMID- 10352069
TI  - Drug update: emerging therapies for breast cancer.

PMID- 10352071
TI  - The multidisciplinary team partners in patient safety.

PMID- 10352072
TI  - Colorectal cancer in a 43-year-old man.

PMID- 10352073
TI  - Premature menopause after cancer treatment.
AB  - PURPOSE: The purpose of this report is to examine the impact that cancer
      therapies have on ovarian function. OVERVIEW: Symptoms of and conditions due to
      estrogen deficiency after cancer therapy are described, and interventions are
      proposed. The consequences of short-term as well as prolonged estrogen deficiency
      including vasomotor instability, infertility, genitourinary atrophy, coronary
      artery disease, and osteoporosis-are discussed. CLINICAL IMPLICATIONS: Symptoms
      and conditions associated with premature menopause may cause additional stress
      for women who undergo cancer therapy. Knowledge about what happens to these women
      can enable healthcare providers to help them make decisions about cancer
      treatment, engage in self-care activities, and explore options for preserving
      fertility.

PMID- 10352074
TI  - Man to Man prostate cancer support groups.
AB  - PURPOSE: In this report, the authors describe Man to Man prostate cancer support
      group characteristics and functioning to identify ways to strengthen the program
      as it expands nationally and internationally. DESCRIPTION OF STUDY: A mail survey
      of 38 groups in Florida collected data on group meeting practices, facilitator
      background, training, and perceived needs, and on participant characteristics and
      satisfaction with the group. Descriptive statistics and bivariate analyses of
      survey data were performed. RESULTS: Typical groups included both survivors and
      significant others, met on a monthly basis, and followed a format that combined
      educational content with sharing of personal experiences. Facilitators and
      participants alike were typically retired white men in their 60s and 70s from
      well-educated professional backgrounds, who joined the groups after undergoing
      treatment for prostate cancer. High levels of satisfaction with the program's
      organization and functioning were reported. Perceived needs were in the areas of
      increasing access to support services, achieving a more diverse membership, and
      better outreach to newly diagnosed patients. CLINICAL IMPLICATIONS: Healthcare
      professionals can play a key role in informing newly diagnosed prostate cancer
      patients about the availability of support groups in their communities. Earlier
      referral to support groups would enhance patients' access to shared experiences
      and resources for guidance in treatment decisions. Greater attention to
      psychosocial issues in Man to Man support groups might better meet the emotional
      needs of patients and families.

PMID- 10352075
TI  - Presurgery experiences of prostate cancer patients and their spouses.
AB  - PURPOSE: In this article, the authors describe the experiences of men with
      prostate cancer and their spouses between diagnosis and surgery. DESCRIPTION: As
      part of a longitudinal qualitative study, semistructured interviews were held
      with 34 prostate cancer patients who were waiting for surgery. Separate
      interviews were held with their spouses. RESULTS: Six main components of
      experience were evident from the analysis of transcripts related to the
      presurgery period: 1) the news of a diagnosis of prostate cancer came initially
      as a shock for both partners, the impact of which lessened over time; 2) the new
      reality of illness necessitated readdressing the marital relationship, most often
      resulting in a sense of renewed connection and commitment; 3) the illness crisis
      precipitated a search for information to guide decisions about treatment; 4)
      there was a need for couples to decide who to inform about the cancer diagnosis
      and how much to say about it; 5) couples attempted to seek a semblance of
      normality in their lives, especially after treatment decisions had been made; and
      6) despite attempts to minimize the potential impact of upcoming surgery, anxiety
      was typically experienced at least intermittently by one or both partners.
      CLINICAL IMPLICATIONS: Physicians, nurses, social workers, and other health
      professionals need to facilitate attempts by the patient to gather and synthesize
      information. Cancer specialists can play a positive role in reducing distress in
      couples, and, thus, the attention of the specialists to communication issues is
      critical. The strain of waiting for surgery must be considered when treatment
      recommendations are made; watchful waiting protocols require further study from a
      psychological perspective. Clinicians need to be alert to the balance between
      being positive and carrying on as normal, and acknowledging and dealing with the
      distress that arises.

PMID- 10352076
TI  - Complementary therapy use among older cancer patients.
AB  - PURPOSE: The purpose of this study was to assess the use of complementary
      therapies among older cancer patients, to report patterns of use, and to
      understand who is more likely to use complementary therapies. DESCRIPTION OF
      STUDY: A survey was conducted of 699 older cancer patients at 4 weeks and 6 weeks
      into cancer treatment. All participants were 64 years of age or older, had
      received a diagnosis of breast, colorectal, prostate, or lung cancer, and were
      recruited from community cancer treatment centers throughout Michigan. Measures
      of interest included self-reported physical symptoms, depressive symptomatology,
      optimism, spirituality, and use of conventional and complementary health
      services. RESULTS: Approximately 33% of older cancer patients reported using
      complementary therapies. These individuals were more likely to be women, to be
      breast cancer patients, and to have a higher level of education. The three most
      frequently used therapies were exercise, herbal therapy, and spiritual healing.
      Complementary therapy users were significantly more optimistic than nonusers.
      Also, there were significant differences between users and nonusers on types of
      physical symptoms experienced, but no differences on reported depressive
      symptomatology or spirituality. CLINICAL IMPLICATIONS: Oncology providers need to
      be aware that one third of their older patients are likely to supplement
      conventional care with complementary therapies. Therefore, providers should be
      knowledgeable about the safety and efficacy, in particular, of various exercise
      programs, herbal and vitamin therapies, and spiritual healing. It would be
      beneficial to develop a system within cancer centers by which patients could
      easily report on their use of complementary therapies, allowing providers to work
      in partnership with their patients.

PMID- 10352077
TI  - Limited literacy revisited implications for patient education.
AB  - PURPOSE: It is important to determine whether teaching materials are understood
      and deemed accurate by the cancer patients being served. The authors used a
      series of patient participatory interviews to evaluate two brochures:
      Chemotherapy: What It Is and How It Helps by the American Cancer Society; and
      Helping Yourself During Chemotherapy: 4 Steps for Patients by the National Cancer
      Institute. The authors sought to determine whether 1) the brochures were clear;
      2) differences in presentation were perceived by patients; and 3) differences
      influenced respondents' understanding and opinions of the brochures. DESCRIPTION
      OF STUDY: A qualitative, focus-group methodology was used. Twelve cancer
      patients, eight of whom were women and six of whom were African American, were
      recruited from three outpatient clinics. Participants ranged in age from 31 to 62
      years of age, and in education from completion of ninth grade to graduate school.
      Patients participated in a series of five groups, with a series of semistructured
      questions about content and format being asked of each group. All sessions were
      audiotaped. The investigators reviewed data both independently and together to
      identify content and format evaluations. RESULTS: Findings showed that most
      participants were drawn first by the National Cancer Institute format; the
      American Cancer Society brochure was seen as having more information; the two
      brochures were seen as complementary; some confusion arose from the content of
      both brochures; and the discussions of emotional and sexual aspects were
      important. CLINICAL IMPLICATIONS: These findings support the need for simple,
      clearly written brochures rather than brochures of varying literacy levels. The
      confusion caused by differences in advice given by the two organizations
      indicates the need to address specific areas in which dissimilarities exist.
      Finally, the project demonstrates the utility of patient focus groups for
      evaluation of patient education material.

PMID- 10352078
TI  - Alternative nutritional regimens targeted to persons with cancer.

PMID- 10352079
TI  - Patients resources: cancer survivorship information resources from the US
      government.

PMID- 10352081
TI  - CagA and cytotoxicity of Helicobacter pylori are not markers of peptic ulcer in
      Japanese patients.
AB  - BACKGROUND: The infection with cagA-positive Helicobacter pylori strains is
      reported to be associated with peptic ulcer disease in developed countries, but
      it is controversial in Asia. To investigate the relationship between the
      virulence factors of H. pylori and peptic ulcer disease in Japan, we compared
      these between ulcer and nonulcer patients. MATERIALS AND METHODS: Seventy-four
      strains of clinically isolated H. pylori obtained from 22 gastric ulcer (GU), 23
      duodenal ulcer (DU), and 29 chronic gastritis (CG) patients were studied. The
      presence of vacA and cagA gene was examined by polymerase chain reaction method
      using two different primer sets. We evaluated the proliferation-inhibiting and
      lethal cytotoxicity of culture supernatants using the alamarBlue assay. RESULTS:
      The vacA gene was identified in all strains by the original primers. S1 strains
      were found in 90.9% (20/22) from GU, 95.7% (22/23) from DU, and 96.6% (28/29)
      from CG patients. The prevalence of cagA gene determined by the first, and second
      primers was 90.9% (20/22), 90.9% (20/22) in strains from GU, 87.0% (20/23), 91.3%
      (21/23) from DU, and 86.2% (25/29), 89.7% (26/29) from CG patients, respectively.
      The supernatant showed cytolethal effect in 95.5% (21/22) of strains from GU, in
      100% (23/23) from DU, and in 93.1% (27/29) from CG patients. There was no
      significant difference in the prevalence of the virulence factors between H.
      pylori strains isolated from patients with peptic ulcers and those with chronic
      gastritis. CONCLUSIONS: These results indicate that cagA gene status and the
      proliferation-inhibiting and lethal cytotoxicity of supernatant are not reliable
      markers of ulcerogenicity of H. pylori in Japanese patients.

PMID- 10352080
TI  - Update on antifungal therapy.

PMID- 10352082
TI  - In vitro aging of Helicobacter pylori: changes in morphology, intracellular
      composition and surface properties.
AB  - BACKGROUND: During the conversion from the bacillary into the coccoid form,
      Helicobacter pylori organisms are known to change extensively. The aim of this
      study was to determine some of the changes that occur regarding morphology,
      intracellular composition and surface properties during the aging of bacteria in
      vitro. MATERIALS AND METHODS: H. pylori from agar plate cultures of different
      ages was used in this study. The intracellular composition of the two
      morphological forms of the bacteria was tested by density centrifugation, DNA
      extraction and quantitative OD, mRNA and ATP measurements. Immunoblotting was
      used to observe changes in secreted/superficial protein patterns, and
      hydrophobicity measurements were used to observe changes in surface properties.
      RESULTS: All bacillary H. pylori organisms changed morphology gradually over 10
      days of culture. Rods had a higher density than cocci; bacteria stored in PBS had
      the highest density and bacteria stored in water had the lowest. The quantitative
      DNA, RNA and ATP content were reduced in the aging bacteria. Fewer immunogenic
      proteins were expressed, and an increased surface hydrophobicity was observed in
      the older cultures. CONCLUSION: This study highlights several aspects of H.
      pylori aging in vitro and shows some of the differences that exist between
      bacillary and coccoid forms. This information is important for understanding the
      transmission and survival of H. pylori outside the human host, as the degradative
      changes in the intracellular composition and the surface properties shown here
      point to dead bacteria, and not to a viable but nonculturable form.

PMID- 10352083
TI  - Characterization of Helicobacter felis by pulsed-field gel electrophoresis,
      plasmid profiling and ribotyping.
AB  - BACKGROUND: Helicobacter felis, an organism naturally infecting both canine and
      feline gastric mucosa, has been largely used as in animal models to study the
      ecology and treatment of human Helicobacter pylori infections. H. felis has not
      yet been studied at the genetic level. METHODS: The aims of this study were to
      modify an in situ DNA isolation method suitable for H. felis and, by the use of
      pulsed-field gel electrophoresis (PFGE), plasmid profiling, and ribotyping, to
      determine the degree of genetic variation among H. felis strains isolated from
      cats and dogs from various geographic locations, and to determine the genome size
      of H. felis. Furthermore, the ability of these new H. felis strains to colonize
      mice was tested. RESULTS: Most H. felis strains were distinguishable from each
      other, and 20 distinct PFGE types were detected. Four pairs of strains within a
      country and animal species produced identical patterns. All strains tested were
      found to carry several plasmids and plasmid profiling was equally discriminatory
      to PFGE. Ribotyping was not able to discriminate all the strains. CONCLUSIONS:
      The genome size of H. felis was found to be approximately 1.6 Mb.

PMID- 10352084
TI  - Predominance of a single strain of Helicobacter pylori in gastric antrum.
AB  - BACKGROUND: Diversity of DNA among H. pylori strains isolated from different
      patients can serve as a useful marker for differentiating strains. DNA profiles
      of H. pylori obtained from sequential gastric biopsies were identical in most
      patients indicating that a given strain can persist from months to years.
      Patients colonized with more than two strains isolated mainly from different
      anatomical sites have been reported. This work examined whether the gastric
      antrum of patients with dyspepsia is colonized by single or multiple strains of
      H. pylori as well as the in vitro competition of different strains of H. pylori.
      MATERIALS AND METHODS: Two antral biopsy specimens from each of the 124 patients
      were cultured for H. pylori. DNA fingerprinting of H. pylori isolates was
      performed using random amplified polymorphic DNA (RAPD) analysis. To elucidate
      the possible interaction among H. pylori isolates, bacterial populations of two
      H. pylori strains cogrown in broth medium over 21 days were enumerated and DNA
      fingerprinting was compared. RESULTS: A total of 58 patients showed the presence
      of H. pylori in both antral specimens, while five patients had H. pylori in only
      one of the two samples. These 58 patients were shown to harbor a single strain of
      H. pylori as analyzed by RAPD fingerprinting. In vitro studies of bacterial
      interaction of two different strains of H. pylori showed growth competition
      resulting in the predominance of a single strain. CONCLUSIONS: The results
      support the concept that a single strain predominates in the gastric antrum site
      of patients studied.

PMID- 10352085
TI  - Oral immunization with Helicobacter pylori-loaded poly(D, L-lactide-co-glycolide)
      nanoparticles.
AB  - BACKGROUND: Helicobacter pylori is a major cause of chronic antral gastritis and
      peptic ulcer diseases. Many researchers have examined the possibility of
      immunologically-mediated prevention of H. pylori infection using an oral vaccine.
      The purpose of this study is to investigate whether mucosal and systemic immune
      responses are induced by oral immunization with H. pylori lysate-loaded poly(D, L
      lactide-coglycolide)[PLG] nanoparticles, and if so, how the distribution of serum
      IgG subclasses are produced. METHODS: PLG nanoparticles (H. pylori-PLG) with
      encapsulated H. pylori lysates were prepared by the solvent evaporation method,
      and the physical properties of the nanoparticles were investigated. Following the
      oral immunization of the H. pylori-PLG nanoparticles into mice, antibody
      induction was assayed in serum and gut washings, and the pattern of serum IgG
      subclasses was determined by ELISA. RESULTS: The prepared H. pylori-PLG
      nanoparticles were spherical, nonporous particles with a mean diameter of less
      than 1 microm. The multiple oral immunization with H. pylori-PLG nanoparticles
      induced significantly H. pylori-specific mucosal IgA response as well as serum
      IgG responses. The serum antibody subclasses elicited were predominantly IgG1 and
      IgG2b. CONCLUSION: Our results suggested that oral immunization of H. pylori-PLG
      nanoparticles induced the H. pylori-specific mucosal and systemic responses in
      mice and enhanced Th2-type responses.

PMID- 10352086
TI  - The role of endoscopic findings for the diagnosis of Helicobacter pylori
      infection: evaluation in a country with high prevalence of atrophic gastritis.
AB  - BACKGROUND: This study examines endoscopic findings in the diagnosis of
      Helicobacter pylori (H. pylori) in the Japanese population. MATERIALS AND
      METHODS: The endoscopic findings (including gastric fold findings and degree of
      atrophy by the Kimura-Takemoto classification system), histologic severity of
      inflammation, and glandular atrophy were assessed according to the Sydney system
      in 642 patients (419 men; 223 women; mean age 43.5 years, range 13-86). H. pylori
      infection was evaluated by Giemsa staining and serum IgG antibodies. RESULTS: 391
      of 642 patients (60.9%) were diagnosed as having endoscopic gastritis. Of the 391
      patients with endoscopic gastritis, 318 (82.6%) had histologic gastritis and 310
      (79.3%) had H. pylori infection. Of the 251 patients with endoscopically normal
      stomachs, 43 (17.1%) had histologic gastritis and 32 (12.7%) had H. pylori
      infection. Atrophic gastritis was the most prevalent finding (56.3%) among those
      with endoscopic gastritis. The prevalence of H. pylori infection in patients with
      atrophic gastritis (92.7%) and rugal hyperplastic gastritis (92.3%) was
      significantly higher than in those with other types of gastritis or with a normal
      stomach (12. 7%). A markedly high prevalence of H. pylori infection was found in
      subjects with tortuosity, hyperrugosity, and/or hyporugosity of the gastric
      folds. CONCLUSIONS: The accurate endoscopic assessment of gastritis according to
      the Sydney system along with gastric fold findings and the endoscopically
      identified extent of gastric atrophy are valuable indicators for determining H.
      pylori infection and histologic gastritis in the Japanese population.

PMID- 10352087
TI  - Accuracy of four commercially available serologic tests, including two office
      based tests and a commercially available 13C urea breath test, for diagnosis of
      Helicobacter pylori.
AB  - BACKGROUND: Diagnosis of H. pylori infection may be made by endoscopic (invasive)
      tests, or by nonendoscopic (noninvasive) tests. Our aim was to evaluate recently
      available nonendoscopic tests, including two office-based serologic tests and a
      commercially available 13C urea breath test. METHODS: Gastric biopsy specimens
      (for culture and stain) from 178 patients (mean age 46 +/- 13.3 years, 79 men and
      99 women), none of whom had received anti-H. pylori therapy, were tested for H.
      pylori infection. These tests were compared against two commercial serum IgG
      antibody immunoassays (Biowhittaker's Pyloristat, and Quidel), 2 office-based
      serum qualitative IgG antibody tests (FlexSure HP, and QuickVue One-Step), the
      Meretek 13C urea breath test, and the CLOtest (a biopsy urease test). RESULTS:
      The breath test (n = 147) had the best accuracy (96%) of the noninvasive tests
      studied. The serologic tests had similar accuracy to one another (84%-90%). The
      major drawback of the serologic tests was suboptimal specificity (75%-87%).
      Diagnosis of H. pylori based on the two office-based tests were not significantly
      different compared to the quantitative IgG antibody tests. The CLOtest had an
      accuracy of 97%. CONCLUSIONS: The Meretek 13C urea breath test is an excellent
      test, but is considerably more expensive than serologic tests. The FlexSure HP
      and the QuickVue One-Step office-based qualitative IgG serologic antibody tests
      gave similar results to laboratory based quantitative antibody tests, and are
      acceptable for initial diagnosis of H. pylori infection. The advantages of the
      office-based tests are low cost, simplicity, and immediacy of results.

PMID- 10352088
TI  - High dose omeprazole plus amoxicillin and azithromycin in eradication of
      Helicobacter pylori in duodenal ulcers.
AB  - BACKGROUND: The aim of our study was to establish whether one-week triple therapy
      regimen (omeprazole, amoxicillin, azithromycin) with low dose (2 x 20 mg/day) or
      high dose omeprazole (2 x 40 mg/day) is more effective in curing H. pylori
      infection in patients with active duodenal ulcer disease. METHODS: One hundred
      and twenty patients with duodenal ulcer and H. pylori infection were treated with
      amoxicillin 2 x 1000 mg/day for the first 7 days plus azithromycin 500 mg/day for
      the first 6 days. Patients were randomly assigned to receive either omeprazole 2
      x 20 mg/day for the first 7 days (group A; n = 60) or omeprazole 2 x 40 mg/day
      for the first 7 days (group B; n = 60). After 7 days all patients in both groups
      continued treatment with omeprazole (40 mg/day (days 8-14) and 20 mg/day (days 15
      28)). H. pylori status was determined by urease test and histology before the
      treatment and 4 weeks after cessation of any medication. RESULTS: One hundred and
      thirteen patients completed the study. H. pylori infection was eradicated in
      73.2% [41/56] of patients in group A (intention-to-treat [ITT] analysis: 68.3%;
      95% CI: 58.6-80.4%) vs. 82.5% [47/57] of patients in group B (ITT analysis:
      78.3%; 95% CI: 67.8-87.9%; NS). All ulcers had healed after 4 weeks of omeprazole
      treatment. Side effects, usually minor, were recorded in 12.5% (group A) and in
      14% (group B) of patients (NS), but therapy was discontinued for only one patient
      in group B (NS). CONCLUSION: There was no statistically significant difference
      between one-week triple therapy regimen (omeprazole, amoxicillin, azithromycin)
      with high dose omeprazole (2 x 40 mg/day) and regimen with low dose omeprazole (2
      x 20 mg/day) in curing H. pylori infection in patients with active duodenal ulcer
      disease.

PMID- 10352089
TI  - Ranitidine bismuth citrate therapy regimens for treatment of Helicobacter pylori
      infection: a review.

PMID- 10352090
TI  - Low prevalence of Helicobacter pylori infection in Swiss adolescents.

PMID- 10352091
TI  - Role of osteopontin in bone remodeling caused by mechanical stress.
AB  - Changes in the number and proportion of osteopontin mRNA (Opn) expressing
      osteocytes and osteoclasts caused by the mechanical stress applied during
      experimental tooth movement were examined in the present study. Opn expression
      was detected in the osteocytes on the pressure side at the early stage, and
      gradually spread to those on the tension side and also to the osteoblasts and
      bone-lining cells in the alveolar bone. Only 3.3% of the osteocytes located on
      the pressure side expressed Opn in the interradicular septum of control rats; in
      contrast, the value was increased to 87.5% at 48 h after the initiation of tooth
      movement. These results indicate that these cells responded to mechanical stress
      loaded on the bone with expression of the osteopontin gene. Following the
      increased expression of Opn in these cells, a 17-fold greater number of
      osteoclasts compared with the control and numerous resorption pits were observed
      on the pressure side of the alveolar bone. Injection of arginine-glycine-aspartic
      acid-serine peptide but not that of arginine-glycine-glutamic acid-serine peptide
      strongly inhibited the increase in the number of osteoclasts. Furthermore, an in
      vitro migration assay demonstrated the chemotactic activity of osteopontin (OPN)
      on the precursor of osteoclasts. Our study strongly suggests that OPN is an
      important factor triggering bone remodeling caused by mechanical stress.

PMID- 10352092
TI  - Osteopontin in skeletal tissue homeostasis: An emerging picture of the
      autocrine/paracrine functions of the extracellular matrix.

PMID- 10352093
TI  - Physiological importance of the 1,25(OH)2D3 membrane receptor and evidence for a
      membrane receptor specific for 24,25(OH)2D3.
AB  - We have recently identified a membrane vitamin D receptor (mVDR) specific for
      1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and shown that it mediates the rapid
      activation of protein kinase C (PKC) in growth zone chondrocytes (GCs). In this
      study, we examine the role of the 1, 25(OH)2D3-mVDR in chondrocyte physiology and
      provide evidence for the existence of a specific membrane receptor for 24, 25
      dihydroxyvitamin D3 (24,25(OH)2D3-mVDR). Fourth-passage cultures of growth plate
      chondrocytes at two distinct stages of endochondral development, resting zone
      (RC) and growth zone (GC) cells, were used to assess the role of the mVDR in cell
      proliferation, PKC activation, and proteoglycan sulfation. To preclude the
      involvement of the nuclear vitamin D receptor (nVDR), we used hybrid analogs of
      1, 25(OH)2D3 with <0.1% affinity for the nVDR (2a, 1alpha-CH2OH-3beta-25D3; 3a,
      1alpha-CH2OH-3beta-20-epi-22-oxa-25D3; and 3b, 1beta-CH2OH-3alpha-20-epi-22-oxa
      25D3). To determine the involvement of the mVDR, we used an antibody generated
      against the highly purified 1,25(OH)2D3 binding protein from chick intestinal
      basolateral membranes (Ab99). Analog binding to the mVDR was demonstrated by
      competition with [3H]1,25(OH)2D3 using matrix vesicles (MVs) isolated from
      cultures of RC and GC cells. Specific recognition sites for 24,25(OH)2D3 in RC
      MVs were demonstrated by saturation binding analysis. Specific binding of
      24,25(OH)2D3 was also investigated in plasma membranes (PMs) from RC and GC cells
      and GC MVs. In addition, we examined the ability of Ab99 to block the stimulation
      of PKC by analog 2a in isolated RC PMs as well as the inhibition of PKC by analog
      2a in GC MVs. Like 1,25(OH)2D3, analogs 2a, 3a, and 3b inhibit RC and GC cell
      proliferation. The effect was dose dependent and could be blocked by Ab99. In GC
      cells, PKC activity was stimulated maximally by analogs 2a and 3a and very
      modestly by 3b. The effect of 2a and 3a was similar to that of 1, 25(OH)2D3 and
      was blocked by Ab99, whereas the effect of 3b was unaffected by antibody. In
      contrast, 2a was the only analog that increased PKC activity in RC cells, and
      this effect was unaffected by Ab99. Analog 2a had no effect on proteoglycan
      sulfation in RC cells, whereas analogs 3a and 3b stimulated it and this was not
      blocked by Ab99. Binding of [3H]1,25(OH)2D3 to GC MVs was displaced completely
      with 1,25(OH)2D3 and analogs 2a, 3a, and 3b, but 24, 25(OH)2D3 only displaced 51%
      of the bound ligand. 24,25(OH)2D3 displaced 50% of [3H]1,25(OH)2D3 bound to RC
      MVs, but 2a, 3a, and 3b displaced <50%. Scatchard analysis indicated specific
      binding of 24, 25(OH)2D3 to recognition sites in RC MVs with a Kd of 69.2 fmol/ml
      and a Bmax of 52.6 fmol/mg of protein. Specific binding for 24, 25(OH)2D3 was
      also found in RC and GC PMs and GC MVs. GC membranes exhibited lower specific
      binding than RC membranes; MVs had greater specific binding than PMs in both cell
      types. 2a caused a dose-dependent increase in PKC activity of RC PMs that was
      unaffected by Ab99; it inhibited PKC activity in GC MVs, and this effect was
      blocked by Ab99. The results indicate that the 1, 25(OH)2D3 mVDR mediates the
      antiproliferative effect of 1,25(OH)2D3 on chondrocytes. It also mediates the
      1,25(OH)2D3-dependent stimulation of PKC in GC cells, but not the 2a-dependent
      increase in RC PKC activity, indicating that 24,25(OH)2D3 mediates its effects
      through a separate receptor. This is supported by the failure of Ab99 to block 2a
      dependent stimulation of PKC in isolated PMs. The data demonstrate for the first
      time the presence of a specific 24, 25(OH)2D3 mVDR in endochondral chondrocytes
      and show that, although both cell types express mVDRs for 1,25(OH)2D3 and
      24,25(OH)2D3, their relative distribution is cell maturation-dependent.

PMID- 10352094
TI  - Developmental regulation of nitric oxide synthase expression in rat skeletal
      bone.
AB  - Nitric oxide (NO) has been implicated in bone growth and remodeling by studies
      showing that inhibition of NO-synthase (NOS) activity retards normal gain in bone
      mineral density both during skeletal development and after sexual maturity. In
      the present study, we aimed to assess the level of expression and cellular
      localization of the three NOS isoforms during skeletal bone development from
      neonatal to sexual maturity in female Wistar rats. Reverse transcription
      polymerase chain reaction (RT-PCR) was used to analyze the presence of NOS1
      (neuronal), NOS2 (inducible), and NOS3 (endothelial) transcripts in femoral bone
      from neonatal, 4-, 8-, and 12-week-old rats. RT-PCR amplified NOS1, NOS2, and
      NOS3 transcripts of 472-, 807-, and 289-bp, respectively. There were no
      detectable differences in the levels of NOS1 mRNA between the groups; however,
      NOS2 mRNA was more abundant in the neonatal group compared with 4-, 8-, and 12
      week groups. Expression of NOS1 protein could not be detected in bones by either
      Western blotting or immunocytochemistry in any of the age groups investigated.
      Western blots for NOS2 revealed expression in the neonatal group only and it was
      not detected in any of the older age groups. Immunostaining for NOS2 was also
      most evident in the neonatal group and was localized specifically to trabecular
      osteoblasts and osteoclasts. In all age groups studied, NOS3 mRNA and protein
      were found in bone-resorbing osteoclasts, cuboidal active osteoblasts, and
      osteocytes. Semiquantitative RT-PCR provided evidence of down-regulation of NOS3
      transcripts during the skeletal development. This was confirmed using in situ
      hybridization, which showed higher expression in neonatal and 4-week groups than
      in other groups. Western blots and counting the ratio of trabecular osteoblasts
      that were NOS3 immunoreactive showed parallel down-regulation of NOS3 protein
      during skeletal development. Taken together, these data show that there is
      regulation of NOS2 and in particular NOS3 expression during skeletal development
      and this may be significant to trabecular bone growth and remodeling.

PMID- 10352095
TI  - No evidence for mutations in the calcium-sensing receptor gene in sporadic
      parathyroid adenomas.
AB  - Inactivating mutations of the calcium-sensing receptor gene (CaR) might explain
      abnormalities in the regulation of both parathyroid cell proliferation and
      parathyroid hormone secretion. In a previous study, using RNAse A protection
      assay, no mutations were identified in a series of parathyroid specimens from
      patients with primary and secondary hyperparathyroidism, but the analysis was
      incomplete, since part of exon 6 could not be analyzed. In the present study, we
      examined the presence of mutations in the CaR gene in 20 parathyroid adenomas
      using direct sequencing. The entire coding region of the CaR gene was
      successfully amplified by polymerase chain reaction and directly sequenced. This
      analysis did not identify CaR gene mutations in any tumors studied. A
      polymorphism that encoded a single amino acid change (Ala826Thr) was identified
      in 4 parathyroid adenomas and in 8 of 50 normal unrelated subjects. Loss of
      heterozygosity studies were also performed on adenomas using markers for the
      locus of the CaR gene on chromosome 3q. No allelic loss was demonstrated. In
      conclusion, our results extend previous observation and suggest that clonal
      somatic mutations of the CaR gene and allelic loss at the CaR locus on chromosome
      3q do not play a major role in the pathogenesis of sporadic parathyroid tumors.

PMID- 10352096
TI  - Matrix vesicle plasma cell membrane glycoprotein-1 regulates mineralization by
      murine osteoblastic MC3T3 cells.
AB  - A naturally occurring nonsense truncation mutation of the inorganic pyrophosphate
      (PPi)-generating nucleoside triphosphate pyrophosphohydrolase (NTPPPH) PC-1 is
      associated with spinal and periarticular ligament hyperostosis and cartilage
      calcification in "tiptoe walking" (ttw) mice. Thus, we tested the hypothesis that
      PC-1 acts directly in the extracellular matrix to restrain mineralization.
      Cultured osteoblastic MC3T3 cells expressed PC-1 mRNA and produced hydroxyapatite
      deposits at 12-14 days. NTPPPH activity increased steadily over 14 days.
      Transforming growth factor-beta and 1,25-dihydroxyvitamin D3 increased PC-1 and
      NTPPPH in matrix vesicles (MVs). Because PC-1/NTPPPH was regulated in
      mineralizing MC3T3 cells, we stably transfected or infected cells with
      recombinant adenovirus, in order to express 2- to 6-fold more PC-1. PC-1/NTPPPH
      and PPi content increased severalfold in MVs derived from cells transfected with
      PC-1. Furthermore, MC3T3 cells transfected with PC-1 deposited approximately 80
      90% less hydroxyapatite (by weight) than cells transfected with empty plasmid or
      enzymatically inactive PC-1. ATP-dependent 45Ca precipitation by MVs from cells
      overexpressing active PC-1 was comparably diminished. Thus, regulation of PC-1
      controls the PPi content and function of osteoblast-derived MVs and matrix
      hydroxyapatite deposition. PC-1 may provide a novel therapeutic target in certain
      disorders of bone mineralization.

PMID- 10352097
TI  - Isolation and characterization of MC3T3-E1 preosteoblast subclones with distinct
      in vitro and in vivo differentiation/mineralization potential.
AB  - A series of subclonal cell lines with high or low differentiation/mineralization
      potential after growth in the presence of ascorbic acid (AA) were derived from
      murine MC3T3-E1 cells. Subclones were characterized in terms of their ability to
      mineralize a collagenous extracellular matrix both in vitro and in vivo and
      express osteoblast-related genes. When compared with nonmineralizing cells,
      mineralizing subclones selectively expressed mRNAs for the osteoblast markers,
      bone sialoprotein (BSP), osteocalcin (OCN), and the parathyroid hormone
      (PTH)/parathyroid hormone-related protein (PTHrP) receptor. In contrast, alkaline
      phosphatase mRNA was present in certain nonmineralizing as well as mineralizing
      subclones, suggesting that its expression may be subject to different controls
      from other osteoblast markers. Only highly differentiating subclones exhibited
      strong AA-dependent induction of a transiently transfected OCN promoter
      luciferase reporter gene, indicating that there was a good correlation between
      mRNA levels and transcriptional activity. Consistent with its postulated role in
      biomineralization, BSP as measured by Western blotting was only present in
      mineralizing subclones. After implantation into immunodeficient mice, highly
      differentiating subclones formed bone-like ossicles resembling woven bone, while
      poorly differentiating cells only produced fibrous tissue. Interestingly,
      subclones with both high and low differentiation potential produced similar
      amounts of collagen in culture and expressed comparable basal levels of mRNA
      encoding Osf2/Cbfa1, an osteoblast-related transcription factor. Although some
      strongly differentiating cells exhibited a modest AA-dependent up-regulation of
      Osf2/Cbfa1 mRNA, there was no clear relationship between levels of this message
      and induction of mRNAs for other differentiation markers. Thus, the mere presence
      of Osf2/Cbfa1 in a subclone was not sufficient for osteoblast differentiation.
      These subclones will be very useful for studying critical events in osteoblast
      differentiation and mineralization.

PMID- 10352098
TI  - Two human osteoblast-like osteosarcoma cell lines show distinct expression and
      differential regulation of parathyroid hormone-related protein.
AB  - Parathyroid hormone (PTH)-related protein (PTHrP) acts as a local regulator of
      osteoblast function via mechanisms that involve PTH/PTHrP receptors linked to
      protein kinase A (PKA) and C (PKC). However, the regulation of PTHrP production
      and mRNA expression in human osteoblasts is poorly understood. Here we have
      characterized alternative PTHrP mRNA 3' splicing variants, encoding PTHrP
      isoforms of 139, 141, and 173 amino acids, and studied the regulation of PTHrP
      and its mRNAs by activated PKA and PKC in two human osteoblast-like cell lines
      (KPDXM and TPXM). Using exon-specific Northern analysis and reverse transcriptase
      coupled polymerase chain reaction, we identified mRNAs encoding PTHrP(1-139) and
      PTHrP(1-141) in both cell lines. PTHrP(1-139) mRNAs predominated in TPXM cells
      and PTHrP(1-173) mRNAs were only detected in TPXM cells. Activation of PKA or PKC
      resulted in different effects on PTHrP and its mRNAs in the two cell lines. In
      TPXM cells, peptide-specific immunoassays detected high basal levels of PTHrP,
      increasing by 2-fold in cell extracts and 4-fold in culture media at 7 h and 24 h
      after exposure to forskolin, respectively, paralleling changes in PTHrP mRNA
      expression. Phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA), a PKC
      activator, had no effect. In KPDXM cells, PTHrP was not detected in culture media
      under basal experimental conditions, and barely detectable amounts were present
      in cell extracts of TPA-treated cells, although the mRNA levels increased
      substantially in response to TPA. In the responsive cell lines, the effects on
      mRNA levels were dose dependent, and increased by 6.9- to 10.5-fold and 2.0- to
      4.1-fold at 4 h in TPXM and KPDXM cells after exposure to 10 microM forskolin and
      150 nM TPA, respectively. PTHrP mRNA levels then declined but were sustained
      above controls also at 12 h in both cell lines, albeit at considerably higher
      levels in TPXM cells. The different responsiveness to agents activating PKA- and
      PKC-dependent pathways may depend on the cellular state of differentiation, or
      alternatively, cancer cell line-specific defects. Our data demonstrating distinct
      differences in mRNA species and the amounts of PTHrP produced by the two cell
      lines as compared with roughly equivalent overall mRNA levels may suggest that
      post-transcriptional mechanisms play an important role in limiting the production
      of intracellular and secreted PTHrPs in human osteoblastic cells.

PMID- 10352099
TI  - Stimulation of osteoblast proliferation by C-terminal fragments of parathyroid
      hormone-related protein.
AB  - Parathyroid hormone (PTH)-related protein (107-139) (PTHrP(107-139)) and
      PTHrP(107-111) have been reported to be potent inhibitors of isolated osteoclast
      activity, and inhibition of bone resorption by PTHrP(107-139) occurs in vivo.
      However, the actions of C-terminal PTHrP on osteoblast activity has not been
      studied much. The present study addresses this issue by examining the effect of
      PTHrP(107-139), PTHrP(107-119), PTHrP(120-139), and PTHrP(107-111) on the
      proliferation of fetal rat osteoblasts. Treatment with PTHrP(107-139) for 24 h
      caused a dose-dependent increase in cell number, [3H]thymidine and
      [3H]phenylalanine incorporation in cultured osteoblasts. The effect was apparent
      at concentrations of 10-10 M and greater and was sustained over time. PTHrP(107
      119) and PTHrP(107-111) had effects on cell number, DNA, and protein synthesis
      which were comparable to those of PTHrP(107-139), whereas PTHrP(120-139) was
      without effect. Retroverted PTHrP(107-111) also stimulated all three activities
      but was only one tenth as potent as PTHrP(107-139). PTHrP(107-139) had no effect
      on osteoblast apoptosis. It is concluded that PTHrP(107-139) is not only an
      inhibitor of osteoclastic bone resorption but that it also stimulates osteoblast
      growth. This activity resides within the pentapeptide fragment PTHrP(107-111).
      These findings support a possible role for C-terminal fragments of PTHrP in the
      normal regulation of bone cell function and, possibly, bone mass.

PMID- 10352100
TI  - Expression and localization of estrogen receptor-beta in murine and human bone.
AB  - Estrogens have profound effects on bone metabolism. Cellular responses to
      estrogens are mediated by estrogen receptors (ERs) which belong to the nuclear
      receptor superfamily. Two estrogen receptors, ERalpha and ERbeta, have been
      cloned. Previously expression of ERalpha has been shown in osteoblasts. Here we
      demonstrate that the transcript for ERbeta can be detected in the human
      osteosarcoma cell lines (MG-63 and SaOS-2) and in cultured human osteoblast-like
      cells. We also show that ERbeta protein is present in nuclear extracts from these
      cells. Furthermore, ERbeta immunoreactivity is found in sections of murine and
      human bone. Murine and human osteoblast and osteocyte nuclei are immunoreactive
      for ERbeta. Osteoclasts are also ERbeta immunoreactive but the staining is mainly
      cytoplasmic. The present study demonstrates that ERbeta is present in all the
      cellular compartments involved in bone formation and bone resorption, both in
      human and in murine bone tissue.

PMID- 10352101
TI  - Steady and transient fluid shear stress stimulate NO release in osteoblasts
      through distinct biochemical pathways.
AB  - Fluid flow has been shown to be a potent stimulus in osteoblasts and osteocytes
      and may therefore play an important role in load-induced bone remodeling. The
      objective of this study was to investigate the characteristics of flow-activated
      pathways. Previously we reported that fluid flow stimulates rapid and continuous
      release of nitric oxide (NO) in primary rat calvarial osteoblasts. Here we
      demonstrate that flow-induced NO release is mediated by shear stress and that
      this response is distinctly biphasic. Transients in shear stress associated with
      the onset of flow stimulated a burst in NO production (8.2 nmol/mg of protein/h),
      while steady flow stimulated sustained NO production (2.2 nmol/mg of protein/h).
      Both G-protein inhibition and calcium chelation abolished the burst phase but had
      no effect on sustained production. Activation of G-proteins stimulated dose
      dependent NO release in static cultures of both calvarial osteoblasts and UMR-106
      osteoblast-like cells. Pertussis toxin had no effect on NO release. Calcium
      ionophore stimulated low levels of NO production within 15 minutes but had no
      effect on sustained production. Taken together, these data suggest that fluid
      shear stress stimulates NO release by two distinct pathways: a G-protein and
      calcium-dependent phase sensitive to flow transients, and a G-protein and calcium
      independent pathway stimulated by sustained flow.

PMID- 10352102
TI  - Macrophage colony stimulating factor increases bone resorption in dispersed
      osteoclast cultures by increasing osteoclast size.
AB  - Several reports indicate that macrophage colony stimulating factor (MCSF) is one
      of the major factors required for osteoclast proliferation and differentiation.
      Paradoxically, it has also been reported that MCSF inhibits osteoclastic
      activity. We therefore decided to investigate in detail the effects of MCSF on
      resorption and osteoclast formation to try and clarify this issue. Osteoclast
      containing cultures were obtained from rabbit long bones and cultured on plastic
      culture dishes or devitalized bovine bone slices. MCSF (4-400 ng/ml) stimulated
      osteoclastic bone resorption in a time-dependent manner and at all doses
      examined. After 48 h of culture in the presence of MCSF, we observed a 2-fold
      increase in the total area of bone resorbed, as well as a significant increase in
      the area of bone resorbed per osteoclast and the number of resorption pits per
      osteoclast. This effect was paralleled by an increase in the number of larger
      osteoclasts (as determined by the number of nuclei per cell) and an increase in
      the size and depth of the resorption pits. Since the total number of osteoclasts
      remained the same, the MCSF-induced increase in resorptive activity appeared to
      be related to an increase in the average size of the osteoclasts. When resorption
      was expressed as the amount of bone resorbed per osteoclast nucleus, larger
      osteoclasts resorbed more per nucleus, suggesting that large osteoclasts, as a
      population, are more effective resorbers than small osteoclasts. Interestingly,
      when osteoclasts were plated at one-fifth the standard density, the amount of
      bone resorbed per osteoclast decreased considerably, indicating that resorptive
      activity is also affected by cell density of osteoclasts and/or of other cells
      present. However, at this lower density MCSF still increased osteoclast size and
      resorption by the same fold increase over control, suggesting that the effect of
      MCSF was independent of factors related to cell density.

PMID- 10352103
TI  - The role of the plasminogen system in bone resorption in vitro.
AB  - The plasminogen/plasmin proteolytic cascade plays an important role in
      extracellular matrix remodeling. The presence of the two plasminogen activators
      (PAs), tissue-type plasminogen activator (tPA), and urokinase-type plasminogen
      activator (uPA), and their inhibitor type 1 (PAI-1) in bone cells, suggests a
      role in one or more aspects of bone resorption such as osteoclast formation,
      mineral dissolution, and degradation of the organic matrix. These different
      processes were assayed in vitro using cells derived from mice with either tPA
      (tPA-/-), uPA (uPA-/-), PAI-1 (PAI-1-/-) inactivation or with a combined
      inactivation (tPA-/-:uPA-/-) and compared with wild-type mice (WT). First,
      osteoclast formation, assessed by investigating the number and characteristics of
      tartrate-resistant acid phosphatase-positive multinucleated cells formed in
      cocultures of primary osteoblasts and bone marrow cells treated with 1alpha,25
      dihydroxyvitamin D3, was not different between the different cell types. Second,
      dentine resorption, an assay for osteoclast activity, was not affected by the
      combined deficiency of both tPA and uPA. Finally, the ability to degrade
      nonmineralized bone-like matrix was however, significantly reduced in tPA-/-:uPA
      /- cells compared with WT cells (28.1 +/- 0.6%, n = 6 vs. 56.4 +/- 3.1%, n = 6,
      respectively, p < 0.0001). Surprisingly, collagen proteolysis by bone cells was
      not dependent on the presence of plasmin as suggested by degradation assays
      performed on type I 3H-collagen films. Taken together, these data suggest that
      the plasminogen activator/plasmin system is not required for osteoclast
      formation, nor for the resorption of the mineral phase, but is involved in the
      removal of noncollagenous proteins present in the nonmineralized bone matrix.

PMID- 10352105
TI  - Intermittent parathyroid hormone (1-34) treatment increases callus formation and
      mechanical strength of healing rat fractures.
AB  - The influence of intermittent parathyroid hormone (PTH(1-34)) administration on
      callus formation and mechanical strength of tibial fractures in rats was
      investigated after 20 and 40 days of healing. A dose of 60 microg of PTH(1
      34)/kg/day and 200 microg of PTH(1-34)/kg/day, respectively, was administered
      during the entire periods of healing, and control animals with fractures were
      given vehicle. The dose of 200 microg of PTH(1-34)/kg/day increased the ultimate
      load and the external callus volume of the fractures by 75% and 99%,
      respectively, after 20 days of healing and by 175% and 72%, respectively, after
      40 days of healing. The dose of 60 microg of PTH(1-34)/kg/day did not influence
      either ultimate load or external callus volume of the fractures after 20 days of
      healing, but the ultimate load was increased by 132% and the external callus
      volume was increased by 42% after 40 days of healing. During the healing period,
      the callus bone mineral content (BMC) increased in all groups. After 40 days of
      healing, the callus BMC was increased by 108% in the 200 microg of PTH(1
      34)/kg/day group and by 76% in the 60 microg of PTH(1-34)/kg/day group. Both
      doses of PTH(1-34) steadily augmented the contralateral intact tibia BMC (20 days
      and 40 days: 60 microg of PTH (1-34)/kg/day 9% and 19%, respectively; 200 microg
      of PTH (1-34)/kg/day 12% and 27%, respectively) and bone mineral density (20 days
      and 40 days: 60 microg of PTH(1-34)/kg/day 11% and 12%, respectively; 200 microg
      of PTH(1-34)/kg/day 11% and 15%, respectively).

PMID- 10352104
TI  - Systemic administration of acidic fibroblast growth factor (FGF-1) prevents bone
      loss and increases new bone formation in ovariectomized rats.
AB  - There are no universally accepted agents that will substantially increase bone
      mass in osteoporotic patients. A number of peptides important in normal bone
      formation, such as members of the transforming growth factor-beta superfamily,
      are not satisfactory for this purpose either because their beneficial effects are
      predominantly local or there is systemic toxicity associated with their
      administration. We have examined the effects of exogenous fibroblast growth
      factor-1 and -2 (FGF-1 and FGF-2) on bone in vivo, since FGFs have been shown
      recently to be essential for normal skeletal development. FGF-1 was injected
      daily (0.2 mg/kg intravenously) for 28 days into the tail vein of adult female
      rats immediately following and 6 months after sham operation or ovariectomy
      (OVX). In rats treated immediately post-OVX, OVX produced more than a 30%
      decrease in tibial bone density, which was prevented by FGF-1 and estrogen.
      However, FGF-1 also had an anabolic effect. In sham-operated rats, FGF-1
      increased bone density to 2-fold, whereas estrogen had no effect. In rats 6
      months post-OVX, severe bone loss and disruption of trabecular microarchitecture
      occurred similar to that seen in patients with severe osteoporosis. In these
      rats, administration of FGF-1 induced extensive new woven bone formation with new
      trabecular-like structures filling much of the marrow spaces, and bone density in
      the tibial metaphysis increased 3-fold. FGF-1 and FGF-2 were also administered
      subcutaneously over the calvaria of mice in doses of 2-2000 microg/day for 3 days
      and shown to produce substantial increases in bone formation when examined
      morphologically. Thus, we conclude that both local and systemic FGF-1 increases
      new bone formation and bone density, and systemic FGF-1 also appears to restore
      bone microarchitecture and prevent bone loss associated with estrogen-withdrawal.

PMID- 10352106
TI  - Effect of bisphosphonate (incadronate) on fracture healing of long bones in rats.
AB  - This study was designed to test whether bisphosphonates disturb the process of
      fracture healing. Female Sprague-Dawley rats were injected with either two doses
      of bisphosphonate (incadronate) (10 microg/kg and 100 microg/kg) or vehicle three
      times a week for 2 weeks. Right femora were then fractured and fixed with
      intramedullary wires. Incadronate treatment was stopped in pretreatment groups (P
      10 and P-100 groups), while the treatment was continued in continuous treatment
      groups (C-10 and C-100 groups). Animals were sacrificed at 6 and 16 weeks after
      surgery. Soft X-ray of all fractured femora was taken. After mechanical testing,
      fractured femora were stained in Villanueva bone stain and embedded in methyl
      methacrylate. Cross-sections near fracture line were analyzed by microradiography
      and histomorphometry. Radiographic study showed that bony callus was present in
      all the fractures and incadronate treatment led to a larger callus, especially in
      C-100 group at both 6 and 16 weeks. Histologic study showed that the process of
      fracture healing in pretreatment groups was delayed at 6 weeks, but reached
      control level thereafter and showed same characteristics as in control at 16
      weeks. Woven bony callus could still be seen in continuous treatment groups at 16
      weeks. Mechanical study indicated that the ultimate load of C-100 group was
      slightly higher than the other treatment groups and control. The results suggest
      that pretreatment with incadronate did not affect fracture healing at 16 weeks
      after fracture. However, continuous incadronate treatment could lead to larger
      callus, but it delayed remodeling process during fracture healing, especially
      with high-dose treatment.

PMID- 10352107
TI  - Bone's early responses to mechanical loading differ in distinct genetic strains
      of chick: selection for enhanced growth reduces skeletal adaptability.
AB  - Bone's functional competence is established and maintained, at least partly, by
      mechanisms involving appropriate adaptation to mechanical loading. These appear
      to fail in chickens selectively bred either for maximum egg (Egg-type) or meat
      (Meat-type) production, which show high rates of fracture and skeletal
      abnormality, respectively. By measuring several early strain-induced responses in
      cultured embryonic tibiotarsi from commercially bred (Egg-type and Meat-type) and
      wild-type (Wild-type) chicks, we have investigated the possibility that these
      skeletal failures are the product of a compromised ability to respond
      appropriately to loading-induced mechanical strain. Axial loads engendering peak
      dynamic (1 Hz) longitudinal strains of between -1300 microepsilon and -1500
      microepsilon (for 10 minutes) in vitro in tibiotarsi from the three types of 18
      day-old chicks increased periosteal osteoblast glucose 6-phosphate dehydrogenase
      (G6PD) activity in both Wild-type (26%, p < 0.01) and Egg-type (49%, p < 0.001)
      chicks in situ, while Meat-type chicks did not show any significant changes
      (11%). Load-induced increases in medium nitrite accumulation (stable nitric oxide
      [NO] metabolite) were produced in Egg-type and Wild-type tibiotarsi (82 +/- 12%,
      p < 0.01; 39 +/- 8%, p < 0.01), respectively. In contrast, loading produced no
      change in NO release from Meat-type chick tibiotarsi. These changes in NO release
      correlated with load-related increases in G6PD activity (R2 = 0.98, p < 0.05) in
      the different chick types. Wild-type and Meat-type tibiotarsal periosteal
      osteoblasts responded in a biphasic manner to exogenous prostacyclin (PGI2), with
      maximal stimulation of G6PD activity at 10(-7) M and 10(-6) M PGI2. However, Egg
      type chick osteoblasts showed smaller, progressive increases up to 10(-5) M PGI2.
      These results indicate that early phases of the adaptive response to loading
      differ in different genetic strains of embryonic chick; that skeletal
      abnormalities which develop in genetically selected, high growth rate chicks may
      reflect a compromised ability to respond to load; and that load-induced increases
      in osteoblastic G6PD activity appear to be closely associated with increased
      rates of NO release. It is probable that similar genetically related differences
      in bones' responsiveness to mechanical loading occur in other species.

PMID- 10352108
TI  - A tibial shaft fracture sustained in childhood or adolescence does not seem to
      interfere with attainment of peak bone density.
AB  - High peak bone mass or density in early adulthood is an important protective
      factor against osteoporotic fractures in later life, but it is not known whether
      injuries on growing bones affect the attainment of peak bone mass and density.
      The purpose of this study was therefore to examine with dual-energy X-ray
      absorptiometry the areal bone mineral density (BMD) of the injured and uninjured
      extremity (the femoral neck, trochanter area of the femur, distal femur, patella,
      proximal tibia, and distal tibia), lumbar spine, and distal radius of young
      adults with a history of early life tibial shaft fracture and to find out whether
      the fracture had affected the attainment of peak bone density of these patients.
      The second objective was to clarify whether any background or clinical follow-up
      variable would predict the BMD difference between the affected and unaffected
      extremity. Thus, the BMD and clinical status of 45 patients (34 men and 11
      women), who had sustained a tibial shaft fracture in childhood or in adolescence
      (between 7 and 15 years of age) an average 11 years before the study, were
      examined. The results showed that the fracture had created a small but
      statistically significant injured-to-uninjured side BMD difference (proximal
      tibia -1.7%; p = 0.011, and distal tibia 2.6%; p = 0.014), while the other sites
      showed no significant side-to-side differences. There were neither significant
      differences in the spinal or radial BMDs between the patients and their age-,
      height-, and weight-matched healthy controls. A further analysis of the data
      showed that the better the muscle strength in the injured lower limb, the lower
      the side-to-side BMD deficit in the proximal tibia of the same limb (r = 0.51; p
      < 0.001). Smoking had a significant association with the relative BMD in the
      injured distal tibia (mean injured-to-uninjured side BMD difference: smokers 6.1%
      vs. nonsmokers -0.6%, p = 0.016). Also patient's age at the time of the injury
      showed an association: the younger the patient at the time of the injury, the
      lower the side-to-side BMD deficit in the injured distal tibia (r = -0.35; p =
      0.048). In conclusion, this study indicates that early life tibial fracture leads
      to a small long-term BMD deficit in the fractured bone while the other sites of
      the skeleton seem not to be affected. Thus, a tibial shaft fracture sustained in
      childhood or adolescence seems to only marginally interfere the attainment of
      peak bone density, the important predictor of the osteoporotic fractures in later
      life.

PMID- 10352109
TI  - Longitudinal bone mineral density changes in female child artistic gymnasts.
AB  - Changes in bone mineral density (BMD), and related factors, in female child
      artistic gymnasts (n = 9) and their age- (+/-0.3 years), height- (+/-2.8 cm), and
      weight- (+/-1.7 kg) matched controls (n = 9) were prospectively examined. It was
      hypothesized that gymnasts would possess higher BMD at baseline, 6, and 12 months
      later and have greater gains in BMD over 1 year compared with controls. BMD
      (g/cm2) of the total proximal femur (TPF), Ward's triangle (WT), trochanter
      (Troch), femoral neck (FN), lumbar spine (LS, L1-L4), and total body (TB) were
      measured by dual-energy X-ray absorptiometry. Physical activity was measured by a
      7-day recall; daily dietary intakes of energy and nutrients were estimated from 3
      day records. Serum osteocalcin and urinary pyridinium cross-links were measured
      by radioimmunoassay and high performance liquid chromatography, respectively.
      Gymnasts versus controls possessed significantly higher BMD at all sites
      measured. Although not significantly different (p > 0.05), gymnasts compared with
      controls had moderately larger percentage changes in Troch (% Delta = 8.6 +/- 3.0
      vs. 3.8 +/- 5.1%, d = 0.41), FN (% Delta = 6.1 +/- 1.2 vs. 3.9 +/- 1.6%, d =
      0.55), LS (% Delta = 7.8 +/- 1.1 vs. 6.8 +/- 1.6%, d = 0.26), and TB BMD (% Delta
      = 5.6 +/- 0.8 vs. 3.4 +/- 0.7%, d = 0.98) as evidenced by the magnitude of the
      effect sizes (d). Gymnasts versus controls possessed a lower percentage body fat
      (p < 0.01) and engaged in more hours of very hard activity (p < 0.0001). Calcium,
      as a percentage of adequate intake, decreased over 12 months (p < 0.01), and
      urinary cross-links significantly decreased over 6 months in both groups. Female
      child gymnasts possess higher BMD at the TPF and related sites, LS, and TB
      compared with nongymnast controls, and 1 year of gymnastics training moderately
      increases Troch, FN, LS, and TB BMD for gymnasts compared with controls. These
      findings lend support to the idea that gymnastics training in childhood helps
      maximize peak BMD.

PMID- 10352111
TI  - Mechanical loading and skeletal integrity: much needed debate.

PMID- 10352110
TI  - The effect of warfarin therapy on the charge properties of urinary prothrombin
      fragment 1 and crystallization of calcium oxalate in undiluted human urine.
AB  - Urinary prothrombin fragment 1 (UPTF1) is the principal protein in calcium
      oxalate (CaOx) crystals precipitated from human urine and is a potent inhibitor
      of CaOx crystallization, a property that should depend, at least in part, upon
      the extent of gamma-carboxylation of the 10 glutamic residues in its N-terminal
      region. Warfarin therapy limits full gamma-carboxylation of vitamin K-dependent
      proteins, including UPTF1. The aims of this study were to determine the effect of
      warfarin therapy on UPTF1, its occlusion into CaOx urinary crystals, and its
      influence on the crystallization of CaOx in undiluted human urine. In the first
      part of the study, urines were collected from six men prior to cardiac surgery
      and after stabilization on long-term warfarin treatment. Proteins in the urines
      and in the matrix of CaOx crystals precipitated from them were analyzed by two
      dimensional SDS-PAGE and Western blotting. In urine, at least two charge variants
      of UPTF1 with low isoelectric point (pI) values were detected before and during
      warfarin therapy, but additional higher pI forms of the protein were also seen
      during anticoagulation. Nonetheless, the majority of UPTF1 was present in the
      more fully gamma-carboxylated state. CaOx crystals precipitated from the same
      urine samples contained only low pI forms of UPTF1. The effect of warfarin
      treatment on CaOx crystallization in urine was tested by collecting two
      consecutive 24-h urine samples from 16 men prior to cardiac surgery and during
      subsequent warfarin treatment. CaOx crystallization was induced in each sample by
      the addition of sodium oxalate. The size and volume of the particles deposited
      were determined using a Coulter counter, and the crystals were examined by
      scanning electron microscopy (SEM). There were no significant differences between
      the urinary metastable limits before or during warfarin treatment or in the total
      volume of crystals precipitated. A slight increase in the mean diameter of the
      crystalline particles precipitated from the urines during anticoagulant therapy
      was not significant. SEM showed little evidence of changes in overall particle
      size, although individual crystals of CaOx tended to be larger during warfarin
      treatment. It was concluded from these studies that the binding of UPTF1 to CaOx
      crystal surfaces is related to the degree of gamma-carboxylation of its Gla
      domain, which would also influence the protein's inhibitory effects on CaOx
      crystallization. However, during warfarin therapy the majority of UPTF1 exists in
      a highly charged state, indicating that it is completely, or almost completely,
      gamma-carboxylated, which would explain the lack of any difference between CaOx
      crystallization parameters in the urine of subjects before and during warfarin
      administration. We conclude that physiologically significant reductions in the
      inhibitory potency of UPTF1 would be likely to occur only as a result of
      proscription of gamma-carboxylation more extensive than that induced by warfarin.

PMID- 10352112
TI  - Reply: much NeededellipsisFurther study 

PMID- 10352113
TI  - Pseudohypohyperparathyroidism-pseudohypoparathyroidism type Ib.

PMID- 10352114
TI  - Osteology: further debate.

PMID- 10352115
TI  - Osteology: further debate: osteologist and osteoatrist.

PMID- 10352116
TI  - Abstracts from the bone and tooth society annual meeting 

PMID- 10352117
TI  - Apoptosis versus necrosis: which should be the aim of cancer therapy?

PMID- 10352118
TI  - Vitamin D and prostate cancer.
AB  - Classically, the actions of vitamin D have been associated with bone and mineral
      metabolism. More recent studies have shown that vitamin D metabolites induce
      differentiation and/or inhibit cell proliferation of a number of malignant and
      nonmalignant cell types including prostate cancer cells. Epidemiological studies
      show correlations between the risk factors for prostate cancer and conditions
      that can result in decreased vitamin D levels. The active metabolite of vitamin
      D, 1,25-dihydroxyvitamin D3 (calcitriol), inhibits growth of both primary
      cultures of human prostate cancer cells and cancer cell lines, but the mechanism
      by which the cells are growth-inhibited has not been clearly defined. Initial
      studies suggest that calcitriol alters cell cycle progression and may also
      initiate apoptosis. One of the disadvantages of using vitamin D in vivo is side
      effects such as hypercalcemia at doses above physiological levels. Analogs of
      calcitriol have been developed that have comparable or more potent
      antiproliferative effects but are less calcemic. Further research into the
      mechanisms of vitamin D action in prostate and identification of suitable analogs
      for use in vivo may lead to its use in the treatment or prevention of prostate
      cancer.

PMID- 10352119
TI  - Caloric restriction abolishes enhanced metabolic efficiency induced by ectopic
      agouti protein in yellow mice.
AB  - Caloric restriction (CR), from approximately 3 months of age, at 70% of the ad
      libitum (AL) caloric intake prevented development of overt obesity in female
      "viable yellow" Avy/A (BALB/cStCrlfC3Hf/Nctr x VY/WffC3Hf/Nctr-Avy) F1 hybrid
      mice. In adult yellow Avy/A mice, caloric restriction eliminated the increased
      metabolic efficiency associated with the presence of agouti protein in ectopic
      sites. At 4 weeks of age, the yellow Avy/A mice were approximately 14% heavier
      and by 12 weeks of age, when caloric restriction began, they were approximately
      24% heavier than the congenic agouti A/a mice. Between 4 and 12 weeks, the yellow
      mice gained approximately 63% in body weight, whereas the agouti mice gained only
      approximately 44%. While the comparable AL Avy/A mice gained approximately 128%
      and the AL A/a mice gained approximately 41% between 12 and 51 weeks of age, the
      CR Avy/A and A/a mice gained only 16% and 15%, respectively. Mean brain weights
      of CR mice of both genotypes were lower than those of the comparable ad libitum
      fed (AL) groups; however, CR Avy/A mice had slightly, but significantly (P <
      0.0001), higher brain weights than CR A/a mice. The larger mean brain weight and
      retention, during caloric restriction, of the somewhat greater prerestriction
      Avy/A mean body weight compared with prerestriction A/a mice were consonant with
      the hypothesis that ectopic agouti protein affects somatic growth directly or
      indirectly. This may be related to altered developmental/metabolic programming in
      yellow mice, indicated by greater metabolic efficiency and by an early transient
      increase in circulating IGF-1 levels. The specific cellular processes modulated
      by the agouti protein in ectopic sites remain to be identified.

PMID- 10352120
TI  - Induction of EGFR tyrosine kinase in the gastric mucosa of diabetic rats.
AB  - Diabetes mellitus is associated with spontaneous gastric mucosal injury and
      enhanced susceptibility of the mucosa to damaging agents. Little information is
      available about the biochemical changes that occur in the gastric mucosa of
      diabetes mellitus. Evidence is accumulating that tyrosine kinases, particularly
      the EGF-receptor (EGFR), are involved in regulating a variety of structural and
      functional properties of the gastric mucosa. The primary objectives of this
      investigation were to determine whether diabetes induces morphological changes in
      the gastric mucosa, and if so, whether these changes are associated with
      alterations in EGFR tyrosine kinase. Diabetes-induced changes in gastric mucosal
      morphology were also examined. Diabetes was induced in 3- to 4-month-old male
      Fischer-344 rats by streptozotocin (STZ; 45 mg/kg; i.v.). Four weeks after
      induction of diabetes mellitus, the gastric mucosa of overnight-fasted rats was
      found to be slightly atrophic. A reduction in gastric mucosal thickness with
      deposition of fibrous tissue above the muscularis layer was observed in the
      stomach of overnight-fasted diabetic rats. These changes were associated with a
      marked stimulation in tyrosine kinase activity and protein expression of EGFR.
      The relative concentrations of several precursor forms of TGF-alpha in both
      membrane and cytosolic fractions from the gastric mucosa of overnight-fasted
      diabetic rats were also found to be significantly above the corresponding
      controls. This suggests that endogenous TGF-alpha may play a critical role in
      regulating mucosal EGFR tyrosine kinase through a juxtacrine/paracrine mechanism.

PMID- 10352121
TI  - Glucocorticoid metabolism in proximal tubules modulates angiotensin II-induced
      electrolyte transport.
AB  - The hormonal interactions that regulate electrolyte transport in the proximal
      tubule are complex and incompletely understood. Since endogenous glucocorticoids
      and angiotensin II each can affect electrolyte transport in this renal segment,
      we hypothesized that local metabolism of glucocorticoids by the enzyme 11beta
      hydroxysteroid dehydrogenase (11beta-HSD) might alter the response to angiotensin
      II. Studies were conducted in cultured origin defective SV-40 transformed
      immortalized renal proximal tubule cells (IRPTC) derived from weanling Wistar rat
      kidney. The 11beta-HSD contained in these cells uses NADP+, has an apparent Km
      for corticosterone of 1.6 microM, but functions only as a dehydrogenase
      (corticosterone --> 11-dehydro-corticosterone). When mounted in modified Ussing
      chambers, IRPTC generate a transmembrane current, and angiotensin II (10 pM to 10
      microM) increases this sodium-dependent current. Cells incubated with
      corticosterone (100 nM) and the 11beta-HSD inhibitor carbenoxolone (CBX) (1
      microM) for 24 hr and then acutely stimulated with angiotensin (10 nM) show a
      greater rise in current than do cells exposed to corticosterone alone and
      stimulated with angiotensin (corticosterone + CBX: 64.2% +/- 20.5% vs.
      corticosterone: 18.8% +/- 5.9%; P < 0.02 at 180 min)[mean +/- SE percentage above
      baseline, n = 8/group]. Cells exposed to corticosterone (100 nM) or CBX (1
      microM) alone for 24 hr and then stimulated with angiotensin II (10 nM) had
      responses similar to controls. Thus glucocorticoids can enhance angiotensin II
      induced electrolyte transport in proximal tubule epithelial cells when local
      11beta-HSD is inhibited.

PMID- 10352122
TI  - Effect of estradiol and soy phytoestrogens on choline acetyltransferase and nerve
      growth factor mRNAs in the frontal cortex and hippocampus of female rats.
AB  - We report here the effects of oral micronized estradiol and soy phytoestrogens on
      uterine weight, choline acetyltransferase (ChAT) and nerve growth factor (NGF)
      mRNAs in the frontal cortex and hippocampus of ovariectomized young and retired
      breeder rats. Within each age category, 15 bilaterally ovariectomized rats were
      randomized equally into three groups: control (OVX), estradiol (E2), and soy
      phytoestrogens (SBE). The OVX rats were fed a casein/lactalbumin-based control
      diet; the E2 rats were fed with the control diet with added estradiol; and the
      SBE rats were fed with the control diet with added soy phytoestrogens. After 8
      weeks of treatment, blood, uteri, frontal cortex, and hippocampus were collected
      at necropsy. Results showed that the uterine weights and serum estradiol
      concentrations were significantly higher in the E2 group compared with those in
      the OVX and SBE groups. In the hippocampus of young rats, E2 treatment resulted
      in significantly higher NGF mRNA levels than no treatment (OVX), and NGF mRNA
      levels in the SBE group were intermediate between the E2 and OVX groups. ChAT
      mRNA levels were significantly higher in the frontal cortex of E2 and SBE-treated
      retired breeder rats compared to OVX retired breeder rats. There were no
      differences among treatment groups for ChAT mRNA levels in the frontal cortex of
      young rats and in the hippocampus of both young and retired breeder rats. Our
      data suggest that soy phytoestrogens may function as estrogen agonists in
      regulating ChAT and NGF mRNAs in the brain of female rats.

PMID- 10352123
TI  - Brain aromatase in control versus castrated Norway Brown, Sprague-Dawley and
      Wistar adult rats.
AB  - Brain aromatase cytochrome P450 converts androgens to estrogens that play a
      critical role in the development of sexually dimorphic neural structures, the
      modulation of neuroendocrine function(s), and the regulation of sexual behavior.
      We characterized the influence of surgical castration on brain aromatase in
      Norway Brown and Wistar adult rats and compared their responses to Sprague-Dawley
      rats that were surgically or biochemically castrated (with flutamide, a known
      androgen receptor blocker). Aromata enzyme activity was measured by the tritiated
      water release assay in the medial basal hypothalmus/preoptic area (MBH/POA) and
      amygdala brain regions. The present results demonstrate that independent of the
      rat strain examined, MBH/POA aromatase is regulated by androgens (in Sprague
      Dawley, Norway Brown and Wistar males). However, intact Wistar animals displayed
      significantly higher MBH/POA aromatase levels compared to Sprague-Dawley control
      values. Conversely, in the amygdala region, there was an apparent lack of
      androgen hormone action upon aromatase enzyme activity in some of the rat strains
      tested. The importance of brain aromatase regulating estrogen biosynthesis and
      influencing brain development and function is covered.

PMID- 10352124
TI  - Brain aromatase and 5alpha-reductase, regulatory behaviors and testosterone
      levels in adult rats on phytoestrogen diets.
AB  - The purpose of this study was to examine the short-term effects of phytoestrogens
      in the diet on regulatory behaviors (food/water intake and locomotor activity),
      prostate weight, testosterone levels, and brain androgen metabolizing enzyme
      activity levels in adult male rats. Sprague-Dawley rats were fed phytoestrogen
      containing versus phytoestrogen-free diets for 29 days. Standard methods were
      used to measure open field behavior, reproductive, hormonal parameters, and
      enzymatic activity levels. The phytoestrogen diet contained approximately 200
      microg/g of isoflavones whereas in the phytoestrogen-free diet, no phytoestrogens
      were detected by HPLC analysis. There were no significant differences in any of
      the regulatory behaviors (food/water intake or locomotor activity), prostate
      weight, or testosterone levels between the treatment groups. Furthermore, there
      was no significant influence of phytoestrogens on brain aromatase activity
      levels, in either the medial basal hypothalamic-preoptic area (MBH-POA) or
      amygdala brain tissue sites examined. However, significant alterations in MBH-POA
      and amygdala 5alpha-reductase activities were detected in animals receiving the
      phytoestrogen-containing versus the phytoestrogen-free diets.

PMID- 10352125
TI  - Inhibition of water permeability in the rat collecting duct: effect of
      imidazoline and alpha-2 compounds.
AB  - Arginine vasopressin (AVP) increases water permeability in the collecting duct of
      the nephron via activation of adenylyl cyclase. Alpha-2 (alpha2) agonists inhibit
      AVP-stimulated water permeability via binding to alpha2 adrenoceptors that have
      been divided into 3 subtypes- alpha2A, alpha2B, and alpha2C. Some biological
      effects mediated by alpha2 agonists result from nonadrenergic imidazoline
      receptors that exist in the rat kidney. Thus, alpha2-inhibition of AVP-stimulated
      water permeability in the rat collecting duct could be caused by imidazoline
      receptors. The purpose of this study was to test agonists and antagonists
      selective for alpha2 and imidazoline receptors on AVP-stimulated water
      permeability in the rat inner medullary collecting duct (IMCD). Some experiments
      were conducted where water permeability was stimulated by a nonhydrolyzable
      analog of adenosine 3', 5'-cyclic monophosphate (cAMP). Agonists included
      dexmedetomidine, clonidine, oxymetazoline, agmatine and rilmenidine. The latter
      two are selective imidazoline agonists. Antagonists included yohimbine, RX821002,
      atipamezole, prazosin, WB4101, idazoxan, and BU239. Prazosin and WB4101
      demonstrate selectivity for the alpha2B and alpha2C subtypes, respectively, and
      oxymetazoline and RX821002 are selective for the alpha2A subtype. BU239 is
      selective for imidazoline receptors. Wistar rat terminal IMCDs were isolated and
      perfused to determine the osmotic water permeability coefficient (Pf). All
      agonists except agmatine inhibited AVP-stimulated Pf. Inhibition by rilmenidine
      indicated a different mechanism of action from other agonists. Dose-response data
      show dexmedetomidine to be the most potent inhibitor. Oxymetazoline and clonidine
      inhibited cAMP-stimulated Pf indicating that the mechanism involves postcAMP
      cellular events. It was reported previously that dexmedetomidine inhibits cAMP
      stimulated Pf (1). All antagonists except prazosin and WB4101 reversed alpha2
      inhibition of AVP-stimulated Pf. BU239 was effective at 1 microM but not at 100
      nM. Results suggest that alpha2A adrenoceptors modulate water permeability in the
      IMCD. The involvement of imidazoline receptors is inconclusive.

PMID- 10352127
TI  - Message from the editor-in-chief 

PMID- 10352126
TI  - Copper deprivation potentiates oxidative stress in HL-60 cell mitochondria.
AB  - Cytochrome-c oxidase is the copper-dependent terminal respiratory complex
      (complex IV) of the mitochondrial electron transport chain whose activity in a
      variety of tissues is lowered by copper deficiency. Because inhibition of
      respiratory complexes increases the production of reactive oxygen species by
      mitochondria, it is possible that copper deficiency increases oxidative stress in
      mitochondria as a consequence of suppressed cytochrome-c oxidase activity. In
      this study, the activities of respiratory complex I + III, assayed as
      NADH:cytochrome-c reductase, complex II + III, assayed as succinate:cytochrome-c
      reductase, complex IV, assayed as cytochrome-c oxidase, and fumarase were
      measured in mitochondria from HL-60 cells that were grown for seven passages in
      serum-free medium that was either unsupplemented or supplemented with 50 n M
      CuSO4. Fumarase activity was not affected by copper supplementation, but the
      complex I + III:fumarase and complex IV:fumarase ratios were reduced 30% and 50%,
      respectively, in mitochondria from cells grown in the absence of supplemental
      copper. This indicates that copper deprivation suppressed the electron transfer
      activity of copper-independent complex I + III as well as copper-dependent
      complex IV. Manganese superoxide dismutase (MnSOD) content was also increased 49%
      overall in the cells grown in the absence of supplemental copper. Furthermore,
      protein carbonyl groups, indicative of oxidative modification, were present in
      100-kDa and 90-kDa proteins of mitochondria from copper-deprived cells. These
      findings indicate that in cells grown under conditions of copper deprivation that
      suppress cytochrome-c oxidase activity, oxidative stress in mitochondria is
      increased sufficiently to induce MnSOD, potentiate protein oxidation, and
      possibly cause the oxidative inactivation of complex I.

PMID- 10352128
TI  - Osteology: further debate.

PMID- 10352129
TI  - Public health aspects of breast cancer gene testing in Canada.

PMID- 10352130
TI  - Public health aspects of breast cancer gene testing in Canada. Part 1: risks and
      interventions.
AB  - The risks (penetrance) of breast and ovarian cancer in carriers of the BRCA1 or
      BRCA2 genes are high, but it is likely that estimates based on selected large
      multicase families are inflated by selection bias. Estimates based on a
      population survey of Ashkenazi Jews are lower, but other population-based
      estimates are still not available. The proportion of breast or ovarian cancers
      related to the genes is similarly lower in population-based samples than in
      referred selected families, and, even for subjects with cancer onset at young
      ages or with a family history, it is quite small. Other genes with lower
      prevalence are also important, and there is evidence of some gene environmental
      interactions. The management of female BRCA gene carriers includes intensive
      surveillance, prophylactic surgery and the use of tamoxifen. Apart from screening
      justified by randomized trials in the general community, such as mammography,
      recommendations for surveillance and prophylactic surgery are based only on
      expert opinion, and there has been little consideration of risk-benefit or cost
      benefit comparisons. Tamoxifen reduced breast cancer incidence in one trial of
      high-risk women, but not in two other smaller trials, and the effect on mortality
      has not been determined. The limitations of genetic testing, and particularly of
      intervention strategies, deserve close scrutiny.

PMID- 10352132
TI  - Public health aspects of breast cancer gene testing in Canada. Part 3: A model of
      potential need and demand.
AB  - Centres offering expert counselling and genetic testing are already experiencing
      high levels of demand, and yet the potential demand is much greater. There have
      been few attempts to estimate the potential demand created by particular
      guidelines for referral or testing. A model of need and demand for genetic
      services is presented, and research questions are identified that should assist
      in better prediction of future requirements for genetic counselling and testing.
      The value of integrated routine data on referral criteria, demand and clinical
      service load is considerable. Attention needs to be paid to referral at primary
      care and general specialist levels as well as to expert centres.

PMID- 10352131
TI  - Public health aspects of breast cancer gene testing in Canada. Part 2: selection
      for and effects of testing.
AB  - Criteria set by clinical services for referral for counselling and genetic
      testing are variable and often arbitrary. Empirical data and computer models are
      available to estimate the probability of being a mutation carrier, based on
      family and personal history. Surveys show that high proportions of women at risk
      of cancer and of women in the general population are interested in being tested,
      but this may be based on inflated perceptions of personal risk and limitations in
      understanding of the tests used and their implications. A high proportion of
      women with a positive family history have a greatly overestimated perception of
      their own risk, and even expert counselling has little impact on this. This risk
      perception may produce psychological distress and may reduce participation in
      screening programs. Counselling, while improving understanding, may also have
      little impact on prior interest in being tested. Interest in being tested relates
      to a wish to assess the risk for children, and hazards include potential health
      insurance discrimination. Testing may result in a reduction of psychological
      disturbance in those shown to be non-carriers, with little change in those shown
      to be carriers, but unwillingness to be tested may be related to psychological
      distress. The impact of publicity concerning genetic testing on perceptions of
      risk and on psychological disturbance, and the subsequent impact of counselling
      and intervention, require further assessment.

PMID- 10352133
TI  - Deaths due to dementia: An analysis of multiple-cause-of-death data.
AB  - This study analyzes multiple-cause-of-death information from over 113,000 death
      certificates of Canadians aged 65+ and identifies causes that are significantly
      likely and significantly unlikely to combine with dementia to cause death. For
      dementia as a mentioned cause and as the underlying cause of death, frequencies
      and rates of death were calculated. Dementia was mentioned on death certificates
      2.4 times as often as it occurred as the underlying cause of death. Among the
      causes least associated with dementia were some cancers, chronic respiratory
      diseases and rheumatoid arthritis. Causes of death that rarely occur with
      dementia should be further investigated in terms of their potential role in
      preventing or delaying the onset of dementia. In particular, further study of the
      role of anti-inflammatory drugs and nicotine in reducing the risk of dementia is
      indicated. Causes positively associated with dementia largely reflect the
      physical deterioration it confers.

PMID- 10352134
TI  - Health consequences of smoking among Canadian smokers: An update.
AB  - The expected number of deaths in four hypothetical Canadian cohorts (male current
      smokers, male never-smokers, female current smokers and female never-smokers) was
      examined by constructing abridged life tables. The expected number of premature
      deaths (before age 70) among lifelong smokers was found to be about twice that
      expected among lifelong never-smokers for both males (2.3) and females (1.9). The
      higher number of premature deaths in the smoking cohorts resulted mainly from
      cancer and coronary heart disease. The results of this paper highlight the
      dramatic impact that smoking has on premature mortality.

PMID- 10352135
TI  - Lentiviral vectors and gene therapy.
AB  - Gene therapy is a novel method under investigation for the treatment of genetic,
      metabolic and neurologic diseases, cancer and AIDS. The primary goal of gene
      therapy is to deliver a specific gene to a pre-determined target cell, and to
      direct expression of such a gene in a manner which will result in a therapeutic
      effect. Retroviral vectors have the ability to integrate in the host cell DNA
      irreversibly and therefore, are suitable vectors for permanent genetic
      modification of cells. Retrovirus-mediated gene transfer has been limited,
      however, by the inability of onco-retroviruses to productively infect non
      dividing cells. Lentiviruses are unique among retroviruses because of their
      ability to infect target cells independently of their proliferation status. This
      chapter presents an up-to-date description of available lentiviral vectors,
      including vector design, applications to disease treatment and safety
      considerations. In addition, general aspects of the biology of lentiviruses with
      relevance to vector development will be discussed.

PMID- 10352136
TI  - Ribozymes in gene therapy of HIV-1.
AB  - Human immunodeficiency virus type 1 (HIV-1) is the primary etiologic agent for
      Aquired Immune Deficiency Syndrome (AIDS). HIV-1 is a lentivirus, a separate
      genus of the Retroviridae, which are complex RNA viruses that integrate into the
      genome of host cells and replicate intracellularly. Ribozymes are catalytic RNA
      molecules with enzyme-like cleavage properties, that can be designed to target
      specific RNA sequences within the HIV-1 genome. In addition to the genomic RNA,
      several RNA intermediates, including splice variants, can be targeted by a single
      ribozyme. We and others have demonstrated the ability of ribozymes to suppress
      HIV-1 replication in a variety of cultured cells. Ribozyme gene therapy for HIV-1
      infection is a therapeutic approach that offers several potential advantages over
      conventional therapies in that it can potentially impact on both viral load and
      restoration of the immune system. Ribozyme gene therapy may be used as an adjunct
      to chemotherapeutic drugs, effecting viral suppression, and facilitating immune
      restoration without problems of patient compliance. Currently, an anti-HIV-1
      ribozyme is being tested in two separate Phase I Clinical Trials.

PMID- 10352137
TI  - Aldehyde-protein adducts in the liver as a result of ethanol-induced oxidative
      stress.
AB  - A number of systems that generate oxygen free radicals and reactive aldehydic
      species are activated by excessive ethanol consumption. Recent studies from human
      alcoholics and from experimental animals have indicated that acetaldehyde and
      aldehydic products of lipid peroxidation, which are generated in such processes,
      can bind to proteins forming stable adducts. Adduct formation may lead to several
      adverse consequences, such as interference with protein function, stimulation of
      fibrogenesis, and induction of immune responses. The presence of protein adducts
      in the centrilobular region of the liver in alcohol abusers with an early phase
      of histological liver damage indicates that adduct formation is one of the key
      events in the pathogenesis of alcoholic liver disease. Dietary supplementation
      with fat and/or iron strikingly increases the amount of aldehyde-derived epitopes
      in the liver together with promotion of fibrogenesis.

PMID- 10352139
TI  - Workshop purpose and structure 

PMID- 10352138
TI  - Oxidant anti-oxidant imbalance and effects of ethanol.
AB  - This article discusses some of the mechanisms through which alcohol, delivered
      pre- or postnatally, alters the activity of the rodent hypothalamic-pituitary
      adrenal (HPA) axis. We show that blockade of prostaglandin synthesis, but not
      opiate receptors, modestly interfered with the HPA axis to acute alcohol
      injection. Pretreatment with a low dose of alcohol (0.3 g/kg) did not
      significantly modify the ability of cytokines to stimulate ACTH release in intact
      rats, but higher doses (>2.0 g/kg) did unless corticosteroid feedback was
      abolished by adrenalectomy. Animals exposed to an alcohol diet for 7 days showed
      a significant blunting of their ACTH response to vasopressin and immune signals.
      This influence was reversed by blockade of nitric oxide with arginine
      derivatives, suggesting that this gas participates in the inhibitory action of
      prolonged alcohol on the HPA axis. Finally, adult rats exposed to the drug
      prenatally showed the expected enhancement of stress-induced ACTH secretion.

PMID- 10352140
TI  - How cells (might) sense microgravity.
AB  - This article is a summary of a lecture presented at an ESA/NASA Workshop on Cell
      and Molecular Biology Research in Space that convened in Leuven, Belgium, in June
      1998. Recent studies are reviewed which suggest that cells may sense mechanical
      stresses, including those due to gravity, through changes in the balance of
      forces that are transmitted across transmembrane adhesion receptors that link the
      cytoskeleton to the extracellular matrix and to other cells (e.g., integrins,
      cadherins, selectins). The mechanism by which these mechanical signals are
      transduced and converted into a biochemical response appears to be based, in
      part, on the finding that living cells use a tension-dependent form of
      architecture, known as tensegrity, to organize and stabilize their cytoskeleton.
      Because of tensegrity, the cellular response to stress differs depending on the
      level of pre-stress (pre-existing tension) in the cytoskeleton and it involves
      all three cytoskeletal filament systems as well as nuclear scaffolds. Recent
      studies confirm that alterations in the cellular force balance can influence
      intracellular biochemistry within focal adhesion complexes that form at the site
      of integrin binding as well as gene expression in the nucleus. These results
      suggest that gravity sensation may not result from direct activation of any
      single gravioreceptor molecule. Instead, gravitational forces may be experienced
      by individual cells in the living organism as a result of stress-dependent
      changes in cell, tissue, or organ structure that, in turn, alter extracellular
      matrix mechanics, cell shape, cytoskeletal organization, or internal pre-stress
      in the cell-tissue matrix.--Ingber, D. How cells (might) sense microgravity.

PMID- 10352141
TI  - Regulation of growth in the adult cardiomyocytes.
AB  - Cardiomyocytes of adult myocardium increase their cellular mass in response to
      growth stimuli. They undergo hypertrophic growth but they do not proliferate in
      contrast to immature cardiomyocytes. Growth stimuli of the adult cardiomyocytes
      include classical growth hormones, various neuroendocrine factors, and the
      increase in mechanical load. The signal transduction of alpha1-adrenoceptor
      stimulation has been investigated in greatest detail and may therefore be taken
      as a reference for other humoral stimuli. It involves the activation of protein
      kinase C (PKC) and, downstream of PKC activation, of two separate signaling
      pathways, one including the mitogen-activated protein kinase and another
      including PI3-kinase and p70(s6k) as key steps. Activation of the first pathway
      leads to re-expression of fetal genes, activation of the second pathway to a
      general activation of protein synthesis, and cellular growth. In neonatal
      cardiomyocytes, mechanical stretch causes growth by an activation of an autocrine
      mechanism including angiotensin II and endothelin. This mechanism does not
      operate, however, in adult cardiomyocytes. A mechanism of mechanotransduction has
      not yet been identified on adult cardiomyocytes but integrins may play a part. In
      microgravity, the scenario of myocardial growth stimulation is altered. On the
      systemic level, there are changes in hemodynamic and neuroendocrine regulation
      that exert indirect effects on the myocardium. Microgravity may also exert a
      direct cellular effect by the absence of a constant gravitational load component.

PMID- 10352142
TI  - The kinetics of translocation and cellular quantity of protein kinase C in human
      leukocytes are modified during spaceflight.
AB  - Protein kinase C (PKC) is a family of serine/threonine kinases that play an
      important role in mediating intracellular signal transduction in eukaryotes. U937
      cells were exposed to microgravity during a space shuttle flight and stimulated
      with a radiolabeled phorbol ester ([3H]PDBu) to both specifically label and
      activate translocation of PKC from the cytosol to the particulate fraction of the
      cell. Although significant translocation of PKC occurred at all g levels, the
      kinetics of translocation in flight were significantly different from those on
      the ground. In addition, the total quantity of [3H]PDBu binding PKC was increased
      in flight compared to cells at 1 g on the ground, whereas the quantity in
      hypergravity (1.4 g) was decreased with respect to 1 g. Similarly, in purified
      human peripheral blood T cells the quantity of PKCdelta varied in inverse
      proportion to the g level for some experimental treatments. In addition to these
      novel findings, the results confirm earlier studies which showed that PKC is
      sensitive to changes in gravitational acceleration. The mechanisms of cellular
      gravisensitivity are poorly understood but the demonstrated sensitivity of PKC to
      this stimulus provides us with a useful means of measuring the effect of altered
      gravity levels on early cell activation events.

PMID- 10352143
TI  - Growth factor-induced signal transduction in adherent mammalian cells is
      sensitive to gravity.
AB  - Epidermal growth factor (EGF) activates a well-characterized signal transduction
      cascade in a wide variety of cells. This activation leads to increased cell
      proliferation in most cell types. Among the early effects evoked by EGF are
      receptor clustering, cell rounding, and early gene expression. The influence of
      gravity on EGF-induced EGF receptor clustering and gene expression as well as on
      actin polymerization and cell rounding have been investigated in adherent A431
      epithelial cells with the use of sounding rockets to create microgravity
      conditions. EGF-induced c-fos and c-jun expression decreased in microgravity.
      This was caused by alteration of the EGF receptor and protein kinase C-mediated
      signal transduction pathways. In contrast, neither the binding of EGF to the
      receptor nor the receptor clustering were changed under microgravity conditions.
      Because cell morphology was also modulated under microgravity conditions, and the
      growth factor-induced signal transduction cascades have been demonstrated to be
      linked to the actin microfilament system, it is tempting to suggest that the
      actin microfilament system constitutes the gravity-sensitive cell component.

PMID- 10352144
TI  - Microgravity alters protein phosphorylation changes during initiation of sea
      urchin sperm motility.
AB  - European Space Agency (ESA) studies demonstrated that bull sperm swim with higher
      velocity in microgravity (microG) than at 1 G. Coupling between protein
      phosphorylation and sperm motility during activation in microG and at 1 G was
      examined in the ESA Biorack on two space shuttle missions. Immotile sperm were
      activated to swim (86-90% motility) at launch +20 h by dilution into artificial
      seawater (ASW). Parallel ground controls were performed 2 h after the flight
      experiment. Activation after 0, 30, and 60 s was terminated with electrophoresis
      sample buffer and samples analyzed for phosphoamino acids by Western blotting.
      Phosphorylation of a 130-kDa phosphothreonine-containing protein (FP130) occurred
      three to four times faster in microG than at 1 G. A 32-kDa phosphoserine
      containing protein was significantly stimulated at 30 s but returned to 1 G
      control levels at 60 s. The rate of FP130 phosphorylation in microG was
      attenuated by D2O, suggesting that changes in water properties participate in
      altering signal transduction. Changes in FP130 phosphorylation triggered by the
      egg peptide speract were delayed in microG. These results demonstrate that
      previously observed effects of microG on sperm motility are coupled to changes in
      phosphorylation of specific flagellar proteins and that early events of sperm
      activation and fertilization are altered in microG.

PMID- 10352145
TI  - Mechanosensitive channels in bacteria as membrane tension reporters.
AB  - The purpose of this short review is to discuss recent data on the molecular
      structure and mechanism of gating of MscL, a mechanosensitive channel of large
      conductance from Escherichia coli. MscL is the first isolated molecule shown to
      convert mechanical stress of the membrane into a simple response, the opening of
      a large aqueous pore. The functional complex appears to be a stable homo-pentamer
      of 15-kDa subunits, the gating transitions in which are driven by stretch forces
      conveyed through the lipid bilayer. We have measured the open probability of MscL
      and the kinetics of transitions as a function of membrane tension. The parameters
      extracted from the single-channel current recordings and dose-response curves
      such as the energy difference between the closed, open, and intermediate
      conducting states, and the transition-related changes in protein dimensions
      suggest a large conformational rearrangement of the channel complex. The
      estimations show that in native conditions MscL openings could be driven
      primarily by forces of osmotic nature. The thermodynamic and spatial parameters
      reasonably correlate with the available data on the structure of a single MscL
      subunit and multimeric organization of the complex. Combined with the functional
      analysis of mutations, these data give grounds to hypotheses on the nature of the
      channel mechanosensitivity.

PMID- 10352146
TI  - Intra- and intercellular Ca2+ signaling in retinal pigment epithelial cells
      during mechanical stimulation.
AB  - The intercellular communication (IC) was investigated between cultured rat
      retinal pigment epithelial (RPE) cells isolated from Long-Evans (LE) or
      dystrophic Royal College of Surgeons (RCS) rats and grown in solutions containing
      normal and high glucose concentrations, or after modulation of protein kinase C
      (PKC). This was performed by studying the conduction of the free Ca2+
      concentration ([Ca2+]i) wave elicited by mechanical stimulation and by analyzing
      the fluorescence recovery after photobleaching (FRAP). Mechanical stimulation of
      LE-RPE cells triggers Ca2+ influx, mediated by stretch-sensitive cation channels
      followed by intracellular Ca2+ release. A regenerative [Ca2+]i wave was found
      with a lower propagation rate in RCS-RPE cells. This rate could be increased by
      PKC down-regulation. Mechanical stimulation caused a [Ca2+]i increase in the
      mechanically stimulated (MS) cell followed after a delay by a [Ca2+]i rise in the
      adjacent cell layers. The intercellular [Ca2+]i wave propagation could be blocked
      by gap junction blockers such as halothane or PKC activation. An inhibition of
      the [Ca2+]i-wave propagation similar to that induced by halothane could be
      observed in cells grown in solutions containing 14 mM or higher concentrations of
      glucose. PKC down-regulated cells grown in glucose-rich medium did not develop
      this inhibitory effect on gap junction communication (GJC). FRAP experiments
      confirmed that the observed changes were consistent with a PKC-mediated
      inhibitory effect of high glucose concentrations on GJC.

PMID- 10352147
TI  - Graviresponses of certain ciliates and flagellates.
AB  - Protozoa are eukaryotic cells and represent suitable model systems to study the
      mechanisms of gravity perception and signal transduction due to their clear
      gravity-induced responses (gravitaxis and gravikinesis). Among protists, parallel
      evolution for graviperception mechanisms have been identified: either sensing by
      distinct stato-organelles (e.g., the Muller vesicles of the ciliate Loxodes) or
      by sensing the density difference between the whole cytoplasm and the
      extracellular medium (as proposed for Paramecium and Euglena). These two models
      are supported by experiments in density-adjusted media, as the gravitaxis of
      Loxodes was not affected, whereas the orientation of Paramecium and Euglena was
      completely disturbed. Both models include the involvement of ion channels in the
      cell membrane. Diverse experiments gave new information on the mechanism of
      graviperception in unicellular systems, such as threshold values in the range of
      10% of gravity, relaxation of the responses after removal of the stimulus, and no
      visible adaptation phenomena during exposure to hypergravity or microgravity
      conditions for up to 12 days.

PMID- 10352148
TI  - Discoidin domain receptors: structural relations and functional implications.
AB  - Multicellular life relies on the presence of extracellular matrix to provide
      scaffolding for cells and tissue compartments. To provide communication between
      cells and tissues, a multitude of cell surface receptors are triggered by soluble
      ligands and components of the extracellular matrix. A large family of these
      receptors transmit signals through the use of an intrinsic tyrosine kinase
      function. The subgroup of discoidin domain receptors (DDRs) is distinguished from
      other members of the receptor tyrosine kinase family by a discoidin homology
      repeat in their extracellular domains that is also found in a variety of other
      transmembrane and secreted proteins. Sequence comparisons show that non-mammalian
      orthologs of DDRs exist: three closely related genes in Caenorhabditis and one in
      the sponge Geodia cydonium. Recently, various types of collagen have been
      identified as the ligands for the two mammalian discoidin domain receptor
      tyrosine kinases, DDR1 and DDR2. The binding of collagen to DDRs results in a
      delayed but sustained tyrosine kinase activation. Both receptors display several
      potential tyrosine phosphorylation sites that are able to relay the signal by
      interacting with cytoplasmic effector proteins. The potential cross-talk to other
      receptors for collagen and the clinical aspects of DDR function are discussed.

PMID- 10352149
TI  - In vitro reestablishment of cell-cell contacts in adult rat cardiomyocytes.
      Functional role of transmembrane components in the formation of new intercalated
      disk-like cell contacts.
AB  - Primary adult rat cardiomyocytes (ARC)in culture are shown to be a model system
      for cardiac cell hypertrophy in vitro. ARC undergo a process of morphological
      transformation and grow only by increase in cell size, however, without loss of
      the cardiac phenotype. The isolated cells spread and establish new cell-cell
      contacts, eventually forming a two-dimensional heart tissue-like synchronously
      beating cell sheet. The reformation of specific cell contacts (intercalated
      disks) is shown also between ventricular and atrial cardiomyocytes by using
      antibodies against the gap junction protein connexin-43 and after microinjection
      into ARC of N-cadherin cDNA fused to reporter green fluorescent protein (GFP)
      cDNA. The expressed fusion protein allowed the study of live cell cultures and of
      the dynamics of the adherens junction protein N-cadherin during the formation of
      new cell-cell contacts. The possible use of the formed ARC cell-sheet cells under
      microgravity conditions as a test system for the reformation of the cytoskeleton
      of heart muscle cells is proposed.

PMID- 10352150
TI  - The syndecans, tuners of transmembrane signaling.
AB  - Syndecans, a family of transmembrane proteoglycans, are putative integrators of
      extracellular signals. The interaction of syndecans with extracellular ligands
      via particular motifs in their heparan sulfate chains, their clustering,
      association with particular cytoskeletal structures, binding to cytoplasmic
      effectors, and intracellular phosphorylation represent as many means to bring
      this role to a successful conclusion. In this review, we will briefly address the
      characteristics of syndecans as heparan sulfate proteoglycans (HSPGs) and focus
      mainly on the properties, binding interactions, and potential signaling functions
      of the cytoplasmic domains of these molecules.

PMID- 10352151
TI  - Mechanotransduction in bone--role of the lacuno-canalicular network.
AB  - The capacity of bone tissue to alter its mass and structure in response to
      mechanical demands has long been recognized but the cellular mechanisms involved
      remained poorly understood. Over the last several years significant progress has
      been made in this field, which we will try to summarize. These studies emphasize
      the role of osteocytes as the professional mechanosensory cells of bone, and the
      lacuno-canalicular porosity as the structure that mediates mechanosensing. Strain
      derived flow of interstitial fluid through this porosity seems to mechanically
      activate the osteocytes, as well as ensuring transport of cell signaling
      molecules and nutrients and waste products. This concept allows an explanation of
      local bone gain and loss, as well as remodeling in response to fatigue damage, as
      processes supervised by mechanosensitive osteocytes.

PMID- 10352152
TI  - Electron microscopic analysis of gravisensing Chara rhizoids developed under
      microgravity conditions.
AB  - Tip-growing, unicellular Chara rhizoids that react gravitropically on Earth
      developed in microgravity. In microgravity, they grew out from the nodes of the
      green thallus in random orientation. Development and morphogenesis followed an
      endogenous program that is not affected by the gravitational field. The cell
      shape, the polar cytoplasmic organization, and the polar distribution of cell
      organelles, except for the statoliths, were not different from controls that had
      grown on earth (ground controls). The ultrastructure of the organelles and the
      microtubules were well preserved. Microtubules were excluded from the apical zone
      in both ground controls as well as microgravity-grown rhizoids. The statoliths
      (vesicles containing BaSO4 crystals in a matrix) in microgravity-grown rhizoids
      were spread over a larger area (up to 50 microm basal to the tip) than the
      statoliths of ground controls (10-30 microm). Some statoliths were even located
      in the subapical zone close to microtubules, which was not observed in ground
      controls. The crystals in statoliths from microgravity-grown rhizoids appeared
      more loosely arranged in the vesicle matrix compared with ground controls. The
      chemical composition of the crystals was identified as BaSO4 by X-ray
      microanalysis. There is evidence that the amount of BaSO4 in statoliths of
      rhizoids developed in microgravity is lower than in ground controls, indicating
      that the gravisensitivity of microgravity-developed rhizoids might be reduced
      compared with ground controls. Lack of gravity, however, does not affect the
      process of tip growth and does not inhibit the development of the structures
      needed for the gravity-sensing machinery.

PMID- 10352153
TI  - Osteoblast fibronectin mRNA, protein synthesis, and matrix are unchanged after
      exposure to microgravity.
AB  - The well-defined osteoblast line, MC3T3-E1 was used to examine fibronectin (FN)
      mRNA levels, protein synthesis, and extracellular FN matrix accumulation after
      growth activation in spaceflight. These osteoblasts produce FN extracellular
      matrix (ECM) known to regulate adhesion, differentiation, and function in
      adherent cells. Changes in bone ECM and osteoblast cell shape occur in
      spaceflight. To determine whether altered FN matrix is a factor in causing these
      changes in spaceflight, quiescent osteoblasts were launched into microgravity and
      were then sera activated with and without a 1-gravity field. Synthesis of FN
      mRNA, protein, and matrix were measured after activation in microgravity. FN mRNA
      synthesis is significantly reduced in microgravity (0-G) when compared to ground
      (GR) osteoblasts flown in a centrifuge simulating earth's gravity (1-G) field 2.5
      h after activation. However, 27.5 h after activation there were no significant
      differences in mRNA synthesis. A small but significant reduction of FN protein
      was found in the 0-G samples 2.5 h after activation. Total FN protein 27.5 h
      after activation showed no significant difference between any of the gravity
      conditions, however, there was a fourfold increase in absolute amount of protein
      synthesized during the incubation. Using immunofluorescence, we found no
      significant differences in the amount or in the orientation of the FN matrix
      after 27.5 h in microgravity. These results demonstrate that FN is made by sera
      activated osteoblasts even during exposure to microgravity. These data also
      suggest that after a total period of 43 h of spaceflight FN transcription,
      translation, or altered matrix assembly is not responsible for the altered cell
      shape or altered matrix formation of osteoblasts.

PMID- 10352154
TI  - The effect of microgravity on morphology and gene expression of osteoblasts in
      vitro.
AB  - The mass and architecture of the skeletal system adapt, to some extent, to their
      mechanical environment. A site-specific bone loss of 1-2% is observed in
      astronauts and in-flight animals after 1 month of spaceflight. Biochemical data
      of astronauts and histomorphometric analysis of rat bones show that the change in
      bone mass is a result of decreased bone formation in association with normal (or
      increased) bone resorption. The changes in bone formation appear to be due in
      part to decreased osteoblast differentiation, matrix maturation, and
      mineralization. Recent data show that spaceflight alters the mRNA level for
      several bone-specific proteins in rat bone, suggesting that the characteristics
      of osteoblasts are altered during spaceflight. A possible underlying mechanism is
      that osteoblasts themselves are sensitive to altered gravity levels as suggested
      by several studies investigating the effect of microgravity on osteoblasts in
      vitro. Changes in cell and nuclear morphology were observed as well as
      alterations in the expression of growth factors (interleukin-6 and insulin-like
      growth factor binding proteins) and matrix proteins (collagen type I and
      osteocalcin). Taken together, this altered cellular function in combination with
      differences in local or systemic factors may mediate the effects of spaceflight
      on bone physiology.

PMID- 10352155
TI  - Plant graviperception and gravitropism: a newcomer's view.
AB  - Gravitropism is an adaptable mechanism corresponding to the directed growth by
      which plants orient in response to the gravity vector. The overall process is
      generally divided into three distinct stages: graviperception, gravitransduction,
      and asymmetric growth response. The phenomenology of these different steps has
      been described by using refined cell biology approaches combined with formal and
      molecular genetics. To date, it clearly appears that the cellular organization
      plays crucial roles in gravisensing and that gravitropism is genetically
      different between organs. Moreover, while interfering with other physical or
      chemical stimuli and sharing probably some common intermediary steps in the
      transduction pathway, gravity has its own perception and transduction systems.
      The intimate mechanisms involved in these processes have to be unveiled at the
      molecular level and their biological relevance addressed at the cellular and
      whole plant levels under normal and microgravitational conditions. gravitropism:
      a newcomer's view.

PMID- 10352156
TI  - Statoliths motions in gravity-perceiving plant cells: does actomyosin counteract
      gravity?
AB  - Statocytes from plant root caps are characterized by a polar arrangement of cell
      organelles and sedimented statoliths. Cortical microtubules and actin
      microfilaments contribute to development and maintenance of this polarity,
      whereas the lack of endoplasmic microtubules and prominent bundles of actin
      microfilaments probably facilitates sedimentation of statoliths. High-resolution
      video microscopy shows permanent motion of statoliths even when sedimented. After
      immunofluorescence microscopy using antibodies against actin and myosin II the
      most prominent labeling was observed at and around sedimented statoliths.
      Experiments under microgravity have demonstrated that the positioning of
      statoliths depends on the external gravitational force and on internal forces,
      probably exerted by the actomyosin complex, and that transformation of the
      gravistimulus evidently occurs in close vicinity to the statoliths. These results
      suggest that graviperception occurs dynamically within the cytoplasm via small
      distance sedimentation rather than statically at the lowermost site of
      sedimentation. It is hypothesized that root cap cells are comparing randomized
      motions with oriented motions of statoliths and thereby perceiving gravity.

PMID- 10352157
TI  - Chromosome mechanics of fungi under spaceflight conditions--tetrad analysis of
      two-factor crosses between spore color mutants of Sordaria macrospora.
AB  - Spore color mutants of the fungus Sordaria macrospora Auersw. were crossed under
      spaceflight conditions on the space shuttle to MIR mission S/MM 05 (STS-81). The
      arrangement of spores of different colors in the asci allowed conclusions on the
      influence of spaceflight conditions on sexual recombination in fungi. Experiments
      on a 1-g centrifuge in space and in parallel on the ground were used for
      controls. The samples were analyzed microscopically on their return to earth.
      Each fruiting body was assessed separately. Statistical analysis of the data
      showed a significant increase in gene recombination frequencies caused by the
      heavy ion particle stream in space radiation. The lack of gravity did not
      influence crossing-over frequencies. Hyphae of the flown samples were assessed
      for DNA strand breaks. No increase in damage was found compared with the ground
      samples. It was shown that S. macrospora is able to repair radiation-induced DNA
      strand breaks within hours.

PMID- 10352158
TI  - Implications for interrelationships between nuclear architecture and control of
      gene expression under microgravity conditions.
AB  - Components of nuclear architecture are functionally interrelated with control of
      gene expression. There is growing appreciation that multiple levels of nuclear
      organization integrate the regulatory cues that support activation and
      suppression of genes as well as the processing of gene transcripts. The linear
      representation of genes and promoter elements provide the potential for
      responsiveness to physiological regulatory signals. Parameters of chromatin
      structure and nucleosome organization support synergism between activities at
      independent regulatory sequences and render promoter elements accessible or
      refractory to transcription factors. Association of genes, transcription factors,
      and the machinery for transcript processing with the nuclear matrix facilitates
      fidelity of gene expression within the three-dimensional context of nuclear
      architecture. Mechanisms must be defined that couple nuclear morphology with
      enzymatic parameters of gene expression. The recent characterization of factors
      that mediate chromatin remodeling and identification of intranuclear targeting
      signals that direct transcription factors to subnuclear domains where gene
      expression occurs link genetic and structural components of transcriptional
      control. Nuclear reorganization and aberrant intranuclear trafficking of
      transcription factors for developmental and tissue-specific control occurs in
      tumor cells and in neurological disorders. Compromises in nuclear structure
      function interrelationships can occur as a consequence of microgravity-mediated
      perturbations in cellular architecture.

PMID- 10352159
TI  - Age-dependent atrophy and microgravity travel: what do they have in common?
AB  - Space travel and extending human lifespan are two of the many advances of the
      twentieth century. However, both of these scientific wonders exact a price for
      their gains; i.e. deleterious effects on normal physiological processes. For
      example, both old age and prolonged microgravity travel are associated with
      atrophy in heart, muscle, and bone. The underlying signal transduction pathways,
      the control mechanisms for the processes of proliferation, differentiation, and
      apoptosis, may prove to be similarly altered in both old age and microgravity
      travel. We suggest that the mechanical events involved in space travel provide a
      telescopic compression of lifespan changes in these tissues; if so, space travel
      provides an excellent opportunity to investigate how long-term degeneration
      occurs on Earth. With the aid of biochip technology for multi-factorial analysis,
      a platform can be generated to create therapeutic modalities to contain, retard,
      reduce, or prevent this tissue atrophy, either in space or on Earth.

PMID- 10352160
TI  - Workshop conclusions & recommendations.

PMID- 10352161
TI  - Treatment of severe ocular-surface disorders with corneal epithelial stem-cell
      transplantation.
AB  - BACKGROUND: Conditions that destroy the limbal area of the peripheral cornea,
      such as the Stevens-Johnson syndrome, ocular pemphigoid, and chemical and thermal
      injuries, can deplete stem cells of the corneal epithelium. The result is
      scarring and opacification of the normally clear cornea. Standard corneal
      transplantation cannot treat this form of functional blindness. METHODS: We
      performed and evaluated 70 transplantations of corneal epithelial stem cells from
      cadaveric eyes into 43 eyes of 39 patients with severe ocular-surface disorders
      and limbal dysfunction. Medical treatment had failed in all patients. The
      patients had a mean preoperative visual acuity of 0.004 (only being able to count
      the number of fingers presented by the examiner) in the affected eyes, which
      satisfies the criteria for legal blindness in most countries. In 28 eyes, we also
      performed standard corneal transplantation. Stem-cell transplantations were
      performed as many as four times on 1 eye if the initial results were not
      satisfactory; 19 eyes had multiple transplantations. Patients were followed for
      at least one year after transplantation. RESULTS: A mean of 1163 days after stem
      cell transplantation, 22 of the 43 eyes (51 percent) had corneal
      epithelialization; of the 22 eyes, 7 eyes had corneal stromal edema and 15 eyes
      had clear corneas. Mean visual acuity improved from 0.004 to 0.02 (vision
      sufficient to distinguish the largest symbol on the visual-acuity chart from a
      distance of 1 m) (P<0.001). The 15 eyes in which the cornea remained clear had a
      final mean visual acuity of 0.11 (the ability to distinguish the largest symbol
      from a distance of 5 m). Complications of the first transplantation included
      persistent defects in the corneal epithelium in 26 eyes, ocular hypertension in
      16 eyes, and rejection of the corneal graft in 13 of 28 eyes. The epithelial
      defects eventually healed in all but two of the eyes. CONCLUSIONS:
      Transplantation of corneal epithelial stem cells can restore useful vision in
      some patients with severe ocular-surface disorders.

PMID- 10352162
TI  - Transplantation of anergic histoincompatible bone marrow allografts.
AB  - BACKGROUND: Successful allogeneic bone marrow transplantation relies on global
      immunosuppression or elimination of T cells. In contrast, the induction of anergy
      can inactivate specific sets of alloreactive T cells in the donor marrow.
      Previous work has shown that anergy can be induced by blocking the interaction of
      the B7 molecule on the surface of antigen-presenting cells with the CD28 molecule
      on the surface of T cells, thus preventing key signaling events essential for the
      activation of T cells. To investigate the feasibility of this approach with
      respect to transplantation of histoincompatible bone marrow, we undertook a
      clinical trial of ex vivo induction of anergy in T cells present in donor marrow
      to recipient alloantigens. METHODS: Outcomes in 12 transplant recipients were
      evaluated. The recipients' peripheral-blood lymphocytes were collected before
      myeloablation and served as alloantigen-presenting cells. To induce alloantigen
      specific anergy, bone marrow from a donor mismatched with the recipient for one
      HLA haplotype was cocultured with irradiated cells from the recipient for 36
      hours in the presence of CTLA-4-Ig, an agent that inhibits B7:CD28-mediated
      costimulation. After conventional myeloablation and immunoprophylaxis, the
      treated donor cells were transfused into the recipient. RESULTS: After the
      induction of anergy, the frequency of T cells capable of recognizing alloantigens
      of the recipient in donor marrow was sharply reduced (P<0.001), whereas the
      responsiveness to alloantigens from persons unrelated to the recipient or the
      donor was unaffected (P=0.51). In the 11 patients who could be evaluated, the
      haploidentical bone marrow cells engrafted. Of these 11 patients, 3 had acute
      graft-versus-host disease (GVHD) confined to the gastrointestinal tract. No
      deaths were attributable to GVHD. Five of the 12 patients were alive and in
      remission 4.5 to 29 months after transplantation. CONCLUSIONS: Donor bone marrow
      treated ex vivo to induce anergy to alloantigens from the recipient can
      reconstitute hematopoiesis in vivo with a relatively low risk of GVHD.

PMID- 10352164
TI  - A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant
      women.
AB  - BACKGROUND: Acute fatty liver of pregnancy and the HELLP syndrome (hemolysis,
      elevated liver-enzyme levels, and a low platelet count) are serious hepatic
      disorders that may occur during pregnancy in women whose fetuses are later found
      to have a deficiency of long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase.
      This enzyme resides in the mitochondrial trifunctional protein, which also
      contains the active site of long-chain 2,3-enoyl-CoA hydratase and long-chain 3
      ketoacyl-CoA thiolase. We undertook this study to determine the relation between
      mutations in the trifunctional protein in infants with defects in fatty-acid
      oxidation and acute liver disease during pregnancy in their mothers. METHODS: In
      24 children with 3-hydroxyacyl-CoA dehydrogenase deficiency, we used DNA
      amplification and nucleotide-sequence analyses to identify mutations in the alpha
      subunit of the trifunctional protein. We then correlated the results with the
      presence of liver disease during pregnancy in the mothers. RESULTS: Nineteen
      children had a deficiency only of long-chain 3-hydroxyacyl-CoA dehydrogenase and
      presented with hypoketotic hypoglycemia and fatty liver. In eight children, we
      identified a homozygous mutation in which glutamic acid at residue 474 was
      changed to glutamine. Eleven other children were compound heterozygotes, with
      this mutation in one allele of the alpha-subunit gene and a different mutation in
      the other allele. While carrying fetuses with the Glu474Gln mutation, 79 percent
      of the heterozygous mothers had fatty liver of pregnancy or the HELLP syndrome.
      Five other children, who presented with neonatal dilated cardiomyopathy or
      progressive neuromyopathy, had complete deficiency of the trifunctional protein
      (loss of activity of all three enzymes). None had the Glu474Gln mutation, and
      none of their mothers had liver disease during pregnancy. CONCLUSIONS: Women with
      acute liver disease during pregnancy may have a Glu474Gln mutation in long-chain
      hydroxyacyl-CoA dehydrogenase. Their infants are at risk for hypoketotic
      hypoglycemia and fatty liver.

PMID- 10352163
TI  - Immunologic and virologic status after 14 to 18 years of infection with an
      attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort.
AB  - BACKGROUND AND METHODS: The Sydney Blood Bank Cohort consists of a blood donor
      and eight transfusion recipients who were infected before 1985 with a strain of
      human immunodeficiency virus type 1 (HIV-1) with a deletion in the region in
      which the nef gene and the long terminal repeat overlap. Two recipients have died
      since 1994, at 77 and 83 years of age, of causes unrelated to HIV infection; one
      other recipient, who had systemic lupus erythematosus, died in 1987 at 22 years
      of age of causes possibly related to HIV. We present longitudinal immunologic and
      virologic data on the six surviving members and one deceased member of this
      cohort through September 30, 1998. RESULTS: The five surviving recipients remain
      asymptomatic 14 to 18 years after HIV-1 infection without any antiretroviral
      therapy; however, the donor commenced therapy in February 1999. In three
      recipients plasma concentrations of HIV-1 RNA are undetectable (<200 copies per
      milliliter), and in two of these three the CD4 lymphocyte counts have declined by
      9 and 30 cells per cubic millimeter per year (P=0.3 and P=0.5, respectively). The
      donor and two other recipients have median plasma concentrations of HIV-1 RNA of
      645 to 2850 copies per milliliter; the concentration has increased in the donor
      (P<0.001). The CD4 lymphocyte counts in these three cohort members have declined
      by 16 to 73 cells per cubic millimeter per year (P<0.001). In the recipient who
      died after 12 years of infection, the median plasma concentration of HIV-1 RNA
      was 1400 copies per milliliter, with a decline in CD4 lymphocyte counts of 17
      cells per cubic millimeter per year (P=0.2). CONCLUSIONS: After prolonged
      infection with this attenuated strain of HIV-1, there is evidence of immunologic
      damage in three of the four subjects with detectable plasma HIV-1 RNA. The CD4
      lymphocyte counts appear to be stable in the three subjects in whom plasma HIV-1
      RNA remains undetectable.

PMID- 10352165
TI  - Images in clinical medicine. Immunologic crosstalk.

PMID- 10352166
TI  - Use of alternative medicine by women with early-stage breast cancer.
AB  - BACKGROUND: We analyzed the use of alternative medicine by women who had received
      standard therapy for early-stage breast cancer diagnosed between September 1993
      and September 1995. METHODS: A cohort of 480 patients with newly diagnosed early
      stage breast cancer was recruited from a Massachusetts statewide cohort of women
      participating in a study of how women choose treatment for cancer. Alternative
      medical treatments, conventional therapies, and health-related quality of life
      were examined. RESULTS: New use of alternative medicine after surgery for breast
      cancer was common (reported by 28.1 percent of the women); such use was not
      associated with choices about standard medical therapies after we controlled for
      clinical and sociodemographic variables. A total of 10.6 percent of the women had
      used alternative medicine before they were given a diagnosis of breast cancer.
      Women who initiated the use of alternative medicine after surgery reported a
      worse quality of life than women who never used alternative medicine. Mental
      health scores were similar at base line among women who decided to use
      alternative medicine and those who did not, but three months after surgery the
      use of alternative medicine was independently associated with depression, fear of
      recurrence of cancer, lower scores for mental health and sexual satisfaction, and
      more physical symptoms as well as symptoms of greater intensity. All groups of
      women reported improving quality of life one year after surgery. CONCLUSIONS:
      Among women with newly diagnosed early-stage breast cancer who had been treated
      with standard therapies, new use of alternative medicine was a marker of greater
      psychosocial distress and worse quality of life.

PMID- 10352167
TI  - Treatments for wasting in patients with the acquired immunodeficiency syndrome.

PMID- 10352168
TI  - Epithelial stem-cell transplantation for severe ocular-surface disease.

PMID- 10352169
TI  - The new immunology--the end of immunosuppressive drug therapy?

PMID- 10352170
TI  - Naturally attenuated HIV--lessons for AIDS vaccines and treatment.

PMID- 10352171
TI  - Use of alternative medicine--a marker for distress?

PMID- 10352172
TI  - Purification and characterization of human DNA topoisomerase IIIalpha.
AB  - Human topoisomerase IIIalpha (hTopo IIIalpha), the recently identified first
      member of the topoisomerase IA subfamily in humans, has a central domain which is
      highly homologous to the yeast topoisomerase III, but an overall organization
      closer to that of Escherichia coli DNA topoisomerase I. In order to determine the
      properties of hTopo IIIalpha, compared to those of other topoisomerase IA
      subfamily members, we purified this enzyme to near homogeneity, together with an
      active site-mutant Y337F. We show that hTopo IIIalpha is able to relax negatively
      supercoiled DNA in a distributive manner, leading to the total disappearance of
      the initial substrate and the appearance of intermediate topoisomers. This DNA
      relaxation activity is magnesium-dependent, although a low concentration of
      MgCl2is sufficient to obtain efficient catalysis. 32P-transfer experiments
      demonstrated that hTopo IIIalpha is able to cleave a single-stranded
      oligonucleotide and to bind covalently to the 5'-end of the cleaved DNA. Addition
      of 0.5 M NaCl reverses the reaction, leading to the religation of the oligo
      nucleotide. Experiments utilizing several different single-stranded
      oligonucleotides permitted us to map several cleavage sites and to deduce a
      consensus sequence for DNA cleavage (CANNN downward arrow), which is different
      from that for other members of the Topo IA subfamily.

PMID- 10352174
TI  - NMR observation of T-tetrads in a parallel stranded DNA quadruplex formed by
      Saccharomyces cerevisiae telomere repeats.
AB  - We report here the NMR structure of the DNA sequence d-TGGTGGC containing two
      repeats of Saccharomyces cerevisiae telomere DNA which is unique in that it has a
      single thymine in the repeat sequence and the number of Gs can vary from one to
      three. The structure is a novel quadruplex incor-porating T-tetrads formed by
      symmetrical pairing of four Ts via O4-H3 H-bonds in a plane. This is in contrast
      to the previous results on other telomeric sequences which contained more than
      one T in the repeat sequences and they were seen mostly in the flexible regions
      of the structures. We observed that the T4-tetrad was nicely accommodated in the
      center of the G-quadruplex, but it caused a small underwinding of the right
      handed helix. The T tetrad stacked well on the adjacent G3-tetrad, but poorly on
      the G5 tetrad. Likewise, T1 also formed a stable T-tetrad at the 5' end of the
      quadruplex. To our knowledge, this is the first report of T-tetrad formation in
      DNA structures. These observations are of significance from the points of view of
      both structural diversity and specific recognitions.

PMID- 10352173
TI  - Identification of the telomere in Trypanosoma cruzi reveals highly heterogeneous
      telomere lengths in different parasite strains.
AB  - Here we describe the cloning and characterisation of the Trypanosoma cruzi
      telomere. In the Y strain, it is formed by typical GGGTTA repeats with a mean
      size of approximately 500 bp. Adjacent to the telomere repeats we found a DNA
      sequence with significant homology to the T.cruzi 85 kDa surface antigen (gp85).
      Examination of the telomere in nine T.cruzi strains reveals differences in the
      organisation of chromosome ends. In one group of strains the size of the telomere
      repeat is relatively homogeneous and short (0.5-1.5 kb) as in the Y strain, while
      in the other, the length of the repeat is very heterogeneous and significantly
      longer, ranging in size from 1 to >10 kb. These different strains can be grouped
      similarly to previously existing classifications based on isoenzyme loci, rRNA
      genes, mini-exon gene sequences, randomly amplified polymorphic DNA and rRNA
      promoter sequences, suggesting that differential control of telomere length and
      organisation appeared as an early event in T. cruzi evolution. Two-dimensional
      pulsed field gel electrophoresis analysis shows that some chromosomes carry
      telomeres which are significantly larger than the mean telomere length.
      Importantly, the T.cruzi telomeres are organised in nucleosomal and non
      nucleosomal chromatin.

PMID- 10352175
TI  - hPop4: a new protein subunit of the human RNase MRP and RNase P ribonucleoprotein
      complexes.
AB  - RNase MRP is a ribonucleoprotein particle involved in the processing of pre-rRNA.
      The RNase MRP particle is structurally highly related to the RNase P particle,
      which is involved in pre-tRNA processing. Their RNA components fold into a
      similar secondary structure and they share several protein subunits. We have
      identified and characterised human and mouse cDNAs that encode proteins
      homologous to yPop4p, a protein subunit of both the yeast RNase MRP and RNase P
      complexes. The human Pop4 cDNA encodes a highly basic protein of 220 amino acids.
      Transfection experiments with epitope-tagged hPop4 protein indicated that hPop4
      is localised in the nucleus and accumulates in the nucleolus. Immunoprecipitation
      assays using extracts from transfected cells expressing epitope-tagged hPop4
      revealed that this protein is associated with both the human RNase MRP and RNase
      P particles. Polyclonal rabbit antibodies raised against recombinant hPop4
      recognised a 30 kDa protein in total HeLa cell extracts and specifically co
      immunoprecipitated the RNA components of the RNase MRP and RNase P complexes.
      Finally we showed that anti-hPop4 immunoprecipitates possess RNase P enzymatic
      activity. Taken together, these data show that we have identified a protein that
      represents the human counterpart of the yeast Pop4p protein.

PMID- 10352176
TI  - High conservation of the fine-scale organisation of chromosome 5 between two
      pathogenic Leishmania species.
AB  - In a previous work we showed a remarkable conservation of the general structure
      of the genome (chromo-some number and synteny) among different pathogenic species
      of Old World Leishmania, indicating the absence of major interchromosomal
      rearrangements during evolution. In the present study, we have compared the fine
      structure of chromo-some 5 among two of these divergent species (Leishmania major
      and Leishmania infantum) by means of physical mapping. Remarkably, the 42 markers
      jointly mapped on these two chromosomes were found in an identical order along
      the chromosome. This perfect colinearity of the markers is in striking contrast
      to the large genetic distance that separates these species and suggests that
      conservation of the fine-scale organisation of chromosomes may be critical in
      Leishmania. If this colinearity is confirmed on the whole of the chromosome set,
      the current systematic sequencing programme of the genome of L.major should
      greatly help in the development of comparative genetics between different species
      of Leishmania.

PMID- 10352177
TI  - Characterisation of holoenzyme lacking sigmaN regions I and II.
AB  - The sigma-N (sigmaN) protein associates with bacterial core RNA polymerase to
      form a holoenzyme that is silent for transcription in the absence of enhancer
      binding activator proteins. Here we show that the acidic Region II of sigmaN from
      Klebsiella pneumoniae is dispensable for polymerase isomerisation and trans
      cription under conditions where the inhibited state of the holoenzyme is relieved
      by removal of sigmaN Region I sequences. Holoenzymes lacking Region I or Regions
      I+II were equally susceptible to the order of addition-dependent inhibition or
      stabilisation of DNA binding afforded by in trans Region I sequences. Region I+II
      deleted [sigma] formed a holoenzyme with a DNA-binding activity more susceptible
      to inhibition by non-specific DNA than that lacking Region I. Region II sequences
      appear more closely associated with formation of a holoenzyme and [sigma]
      proficient in DNA binding than with changes in holoenzyme conformation needed for
      unmasking a single-strand DNA-binding activity used for open complex for-mation.
      Region II may therefore function to optimise DNA interactions for an efficient
      sigma cycle.

PMID- 10352178
TI  - A 2,2"-bipyridine ligand for incorporation into oligodeoxynucleotides: synthesis,
      stability and fluorescence properties of ruthenium-DNA complexes.
AB  - A non-nucleoside linker based upon the ligand 2,2'-bipyridine and ethylene glycol
      is prepared and placed into the backbone of a number of oligonucleo-tides. The
      bipyridine ligand is reacted with cis -dichloro bis(2,2'-bipyridyl) Ru(II) to
      generate the relatively substitutionally inert complex based upon the well
      characterized tris -2,2'-bipyridyl Ru(II). The ruthenium-containing DNA complexes
      exhibited UV and fluorescence characteristics that are consistent with those
      previously observed for simple tris -2,2'-bipyridyl Ru(II) complexes.
      Oligonucleotides containing the ruthenium complex will form both DNA duplexes and
      triplexes with stabilities that are slightly better than those formed from simple
      tethered oligonucleotide probes in which the two hybridizing sequences are
      tethered by simple tri(ethylene glycol) or hexa(ethylene glycol) linkers.

PMID- 10352179
TI  - Analysis of the cooperative thermal unfolding of the td intron of bacteriophage
      T4.
AB  - The thermal stability of folded transcripts of the td intron of bacteriophage T4
      that carried up to three base substitutions was investigated by temperature
      gradient gel electrophoresis (TGGE) and UV melting. The unfolding of this
      autocatalytic group I intron is endothermic and entropically driven. Although the
      effects of mutations in base pairs follow in most cases the expected order G-C>A
      U>G.U>A.C, the extent of global destabilization varies strongly according to the
      helix in which substitutions are located. Effects are more pronounced in the P7
      helix which forms, together with the P3 helix, the central pseudoknot of group I
      introns. The stability of the tertiary fold was also monitored as a function of
      ionic concentration and of the nature of the ion. At low ionic strength, the
      stabilizing effect of divalent ions is independent of the nature of the ion.
      However, with increasing ionic concentration, stabilization is most pronounced
      for Mg2+and less for Mn2+with Ca2+having intermediate effects. Ammonium ions
      stabilize folding with a similar slope, but at concentrations about 400 times
      higher than divalent ions. The apparent enthalpic change associated with the
      tertiary structure thermal unfolding increases strongly with increasing
      concentrations of divalent ions. A similar increase is observed with the
      monovalent ammonium ions. However, in the presence of NH4+ions, the apparent
      enthalpy peaks at 2.0 M and decreases beyond.

PMID- 10352180
TI  - DNA repair of pyrimidine dimers and 6-4 photoproducts in the ribosomal DNA.
AB  - The nucleolus is a unique structural component of interphase nuclei where the
      ribosomal genes, trans-cribed by RNA polymerase I (RNA pol I), are organized. In
      the present study, the repair of UV-induced photolesions was investigated in the
      ribosomal DNA (rDNA) in relation to RNA pol I transcription. We used hamster
      cells because their repair phenotype permits the separate analysis of the major
      photo-products induced by UV light. Immunofluorescent labeling of UV-induced DNA
      repair and transcription sites showed that the nucleolar regions were defic-ient
      in DNA repair despite the presence of abundant RNA pol I transcription foci.
      Immunological staining indicated that various NER proteins, including TFIIH
      (subunits p62 and p89), p53, Gadd 45 and prolifer-ating cell nuclear antigen are
      all enriched in the nuclei but distinctly absent in nucleoli. This lack of
      enrichment of NER factors in the nucleolus may be responsible for the inefficient
      repair of photo-products in the rDNA. UV irradiation generates two major
      photoproducts, the cyclobutane pyrimidine dimers (CPDs) and the 6-4 photoproducts
      (6-4 PPs). The repair kinetics of these two lesions were assessed simultaneously
      by the immunological isolation of bromodeoxyuridine (BudR) containing excision
      repair patches using an antibody to BudR. We found that the repair of the
      photolesions was less efficient in the rDNA compared to that of the endo-genous
      housekeeping gene, dihydrofolate reductase (DHFR). Gene specific repair of each
      of these two photoproducts was then measured separately in the rDNA and in the
      DHFR gene, which is transcribed by RNA pol II. The removal of CPDs was deficient
      in the rDNA as compared to the DHFR gene. On the contrary, 6-4 PPs were removed
      efficiently from the rDNA although somewhat slower than from the DHFR gene. The
      relatively efficient repair of 6-4 PPs in the rDNA is consistent with the notion
      that the 6-4 PPs are repaired efficiently in different genomic regions by the
      global genome repair pathway.

PMID- 10352181
TI  - Palindromy is eliminated through a structure-specific recombination process in
      rodent cells.
AB  - Higher eukaryotes are proficient at remodeling palindromic DNA. As shown here, a
      fully palindromic 15.4 kb circular DNA can be introduced into rodent cells with
      the novel result that the molecule is reproducibly and site-specifically
      converted to a monomeric circle. The dimer-to-monomer conversion has not been
      described previously, and in particular is undetectable in Escherichia coli.
      Comparative DNA sequence analyses of the new junctions found within the monomer
      circles suggest that the resolution process involves formation of hairpin DNA
      structures followed by the introduction of single-strand nicks near their
      termini. By extension, hairpin nicking combined with non-homologous end-joining
      may be important as a general mechanism for the main-tenance of genomic stability
      in mammalian cells. It is suggested that the absence of a comparable strategy for
      coping with palindrome-induced structure in E.coli and other unicellular
      organisms underlies a fundamental difference in DNA sequence organiz-ation in the
      genomes of prokaryotes versus higher eukaryotes.

PMID- 10352182
TI  - An element in the 5' common exon of the NCAM alternative splicing unit interacts
      with SR proteins and modulates 5' splice site selection.
AB  - The neural cell adhesion molecule (NCAM) gene contains an 801 nt exon that is
      included preferentially in neuronal cells. We have set up an in vitro splicing
      system that mimics the neuro-specific alternative splicing profile of NCAM exon
      18. Splicing regulation is observed using model pre-mRNAs that contain competing
      5' or 3' splice sites, suggesting that distinct pathways regulate NCAM 5' and 3'
      splice site selection. While inclusion of exon 18 is the predom-inant choice in
      neuronal cells, an element in the 5' common exon 17 improves exon 17/exon 19
      splicing in a neuronal cell line. A similar behavior is observed in vitro as the
      element can stimulate the 5' splice site of exon 17 or a heterologous 5' splice
      site. The minimal 32 nt sequence of the exon 17 enhancer consists of purine
      stretches and A/C motifs. Mutations in the purine stretches compromise the
      binding of SR proteins and decreases splicing stimulation in vitro. Mutations in
      the A/C motifs do not affect SR protein binding but reduce enhancing activity.
      Our results suggest that the assembly of an enhancer complex containing SR
      proteins in a 5' common exon ensures that NCAM mRNAs lacking exon 18 are made in
      neuronal cells.

PMID- 10352183
TI  - Interaction between human topoisomerase I and a novel RING finger/arginine-serine
      protein.
AB  - The N-terminus of human topoisomerase I participates in the binding of this
      enzyme to helicases and other proteins. Using the N-terminal 250 amino acids of
      human topoisomerase I and a yeast two-hybrid/ in vitro binding screen, a novel
      arginine-serine-rich peptide was identified as a human topoisomerase I-binding
      protein. The corresponding full-length protein, named topors, contains a
      consensus RING zinc finger domain and nuclear localization signals in addition to
      the arginine-serine-rich region. The RING finger domain of topors is homologous
      to a similar domain in a family of viral proteins that are involved in the
      regulation of viral transcription. When expressed in HeLa cells as a green
      fluorescent protein fusion, topors localizes in the nucleus in a punctate pattern
      and co-immunoprecipitates with topoisomerase I. These data suggest that topors is
      involved in trans-cription, possibly recruiting topoisomerase I to RNA polymerase
      II transcriptional complexes.

PMID- 10352184
TI  - Determinants of nucleotide sugar recognition in an archaeon DNA polymerase.
AB  - Vent DNA polymerase normally discriminates strongly against incorporation of
      ribonucleotides, 3'-deoxyribonucleotides (such as cordycepin) and 2',3'
      dideoxyribonucleotides. To explore the basis for this discrimination we have
      generated a family of variants with point mutations of residues in conserved
      Regions II and III and assayed incorporation of nucleo-tides with modified sugars
      by these variants, all of which were created in an exonuclease-deficient form of
      the enzyme. A Y412V variant incorporates ribonucleotides at least 200-fold more
      efficiently than the wild-type enzyme, consistent with Y412 acting as a 'steric
      gate' to specifically exclude ribonucleotides. The most striking variants tested
      involved changes to A488, a residue predicted to be facing away from the
      nucleotide binding site. The pattern of relaxed specificity at this position
      roughly correlates with the size of the substituted amino acid sidechain and
      affects a variety of modified nucleotide sugars.

PMID- 10352185
TI  - An extra tRNAGly(U*CU) found in ascidian mitochondria responsible for decoding
      non-universal codons AGA/AGG as glycine.
AB  - Amino acid assignments of metazoan mitochondrial codons AGA/AGG are known to vary
      among animal species; arginine in Cnidaria, serine in invertebrates and stop in
      vertebrates. We recently found that in the mitochondria of the ascidian
      Halocynthia roretzi these codons are exceptionally used for glycine, and
      postulated that they are probably decoded by a tRNA(UCU). In order to verify this
      notion unambig-uously, we determined the complete RNA sequence of the
      mitochondrial tRNA(UCU) presumed to decode codons AGA/AGG in the ascidian
      mitochondria, and found it to have an unidentified U derivative at the anticodon
      first position. We then identified the amino acids attached to the tRNA(U*CU), as
      well as to the conventional tRNAGly(UCC) with an unmodified U34, in vivo. The
      results clearly demonstrated that glycine was attached to both tRNAs. Since no
      other tRNA capable of decoding codons AGA/AGG has been found in the mitochondrial
      genome, it is most probable that this tRNA(U*CU) does actually translate codons
      AGA/AGG as glycine in vivo. Sequencing of tRNASer(GCU), which is thought to
      recognize only codons AGU/AGC, revealed that it has an unmodified guanosine at
      position 34, as is the case with vertebrate mitochondrial tRNASer(GCU) for codons
      AGA/AGG. It was thus concluded that in the ascidian, codons AGU/AGC are read as
      serine by tRNASer(GCU), whereas AGA/AGG are read as glycine by an extra
      tRNAGly(U*CU). The possible origin of this unorthodox genetic code is discussed.

PMID- 10352186
TI  - Sequence-specific and conformation-dependent binding of yeast telomerase RNA to
      single-stranded telomeric DNA.
AB  - Telomerase is a ribonucleoprotein reverse trans-criptase responsible for the
      maintenance of one strand of telomere terminal repeats. The mechanisms whereby
      telomerase recognizes chromosomal ends are not fully characterized. Earlier
      studies showed that the yeast telomerase RNP could bind the dG-rich strand of
      yeast telomeres with high affinity and sequence specificity. Further analysis of
      telomerase-telomere complex formation in vitro as described in this report led to
      the following conclusions. First, telomerase binding to short DNAs is magnesium
      dependent, while binding to long DNAs is magnesium-independent, consistent with
      the existence of more than one interaction site. Second, binding is likely to be
      mediated largely through the RNA subunit of telomerase (TLC1), because de
      proteinated TLC1 RNA also binds telomeres with high affinity and sequence
      specificity, and exhibits the same length and divalent cation dependence as
      telomerase RNP. The crucial role of RNA in binding is further supported by the
      ability of TLC1 transcripts synthesized in vitro to form stable complexes with
      telomeric DNA. Finally, results from deletion analysis and RNase H-mediated
      cleavage suggest that a specific conformation(s) of the RNA is required for
      stable binding, and that non-template regions of the TLC1 RNA may contribute
      directly or indirectly to the stability of the RNA-DNA complex.

PMID- 10352187
TI  - Urothelial lesions in Chinese-herb nephropathy.
AB  - Rapidly progressive renal fibrosis after a slimming regimen including Chinese
      herbs containing aristolochic acid (AA) has been identified as Chinese-herb
      nephropathy (CHN). We reported urothelial atypia in three patients with CHN, with
      the subsequent development in one patient of overt transitional cell carcinoma
      (TCC). Therefore, it was decided to remove the native kidneys, as well as the
      ureters, in all patients with CHN. Nineteen kidneys and ureters removed during
      and/or after renal transplantation from 10 patients were studied to assess
      critically urothelial lesions and to characterize the cellular expression of p53,
      a tumor-suppressor gene overexpressed in several types of malignancies.
      Multifocal high-grade flat TCC in situ (carcinoma in situ; CiS) was observed,
      mainly in the upper urinary tract, in four patients, a prevalence of 40%. In one
      of those patients, a superficially invasive flat TCC of the right upper ureter,
      as well as two additional foci of noninvasive papillary TCC, were found in the
      right pelvis and left lower ureter, respectively. This patient also presented
      recurrent noninvasive papillary TCC of the bladder. Furthermore, in all cases,
      multifocal, overall moderate atypia was found in the medullary collecting ducts,
      pelvis, and ureter. All CiS and papillary TCC, as well as urothelial atypia,
      overexpressed p53. These results show that the intake of Chinese herbs containing
      AA has a dramatic carcinogenic effect. Carcinogenesis is associated with the
      overexpression of p53, which suggests a role for a p53 gene mutation. The
      relationship of this mutation with the reported presence of AA DNA adducts in the
      kidney remains to be explored.

PMID- 10352188
TI  - Induction of microalbuminuria by l-arginine infusion in healthy individuals: an
      insight into the mechanisms of proteinuria.
AB  - Despite evidence from individuals with diabetes mellitus or reduced renal mass,
      the actual relationship between protein- or amino acid-induced changes in renal
      function and urinary albumin excretion (UAE) is largely unknown in subjects
      without renal disease. In humans, infusions of l-arginine have been used recently
      in vascular and renal pathophysiological studies. The present study was
      undertaken to analyze the mechanisms involved in a particular effect; namely, the
      behavior of UAE during amino acid loading. A prospective interventional protocol
      was performed on 10 healthy adults by means of an intravenous infusion of l
      arginine. The main results show that l-arginine induced a significant increase in
      UAE from 13.1 +/- 3.8 before to 53.3 +/- 11.1 microgram/min after the infusion (P
      < 0.005). This increment was simultaneous to an increase in glomerular filtration
      rate (GFR) and renal plasma flow (RPF). Furthermore, l-arginine markedly
      increased the urinary excretion of beta2-microglobulin. UAE correlated
      significantly with GFR (r = 0. 738; P = 0.014) and RPF (r = 0.942; P < 0.0001),
      but not with urinary beta2-microglobulin (r = 0.05; P = not significant).
      Furthermore, marked differences (P = 0.001) were found between the percentage of
      increase in UAE (306.8% +/- 163.2%) with respect to either albumin filtered load
      (FLAlb; 57.9% +/- 16.3%) and beta2-microglobulin excretion (1,088.5% +/- 424.6%).
      No changes were found in vehicle-infused individuals. In conclusion, the present
      study shows, in controlled conditions, that l-arginine infusion induces a
      relevant increase in UAE in healthy individuals that significantly exceeds that
      expected from the increase in GFR alone. The intense and simultaneous increment
      in beta2-microglobulin excretion strongly suggests that the effect of l-arginine
      on UAE is, in a relevant part, mediated through a blockade in the tubular protein
      reabsorption pathways. However, the profound differences observed in the changes
      induced by l-arginine on UAE and beta2-microglobulin excretion and the
      differences in the correlation of UAE and beta2-microglobulin with respect to GFR
      suggest that substantial diversity exists in the mechanisms by which l-arginine
      affects the renal management of albumin and beta2-microglobulin. These findings
      are relevant for understanding the renal response to l-arginine and protein/amino
      acid loads.

PMID- 10352189
TI  - Prognosis after a complete remission in adult patients with idiopathic membranous
      nephropathy.
AB  - This review of the long-term outcome after a complete remission of proteinuria
      includes 82 adult patients with biopsy-proven idiopathic membranous
      glomerulonephritis (IMGN), who represented 25% of the total cases (82 of 323
      cases) of IMGN in our registry. Complete remission was defined as at least two
      consecutive follow-up evaluations showing proteinuria of 0.3 g/d or less of
      protein. Before remission, 70% of the patients had nephrotic-range proteinuria
      (61% at presentation, 9% during follow-up), and 30% were always subnephrotic
      (protein level < 3.5 g/d). Mean total observation time was 101 +/- 56 months,
      with a postremission period of 69 +/- 60 months. Seventy-one percent of the
      patients remained in remission and 29% relapsed. In the relapse group, 46%
      relapsed to nephrotic-range proteinuria and 54% relapsed to subnephrotic levels.
      The plasma creatinine level remained stable in 86% of the patients (71 of 82
      patients) but became or remained elevated despite a period of complete remission
      in the remaining 14% (8 of 82 patients). No patient went on to end-stage renal
      disease. Seventy-seven percent of the patients had no specific treatment within 6
      months of remission, whereas 23% had steroid therapy alone or in combination with
      an immunosuppressive agent. In a multivariate analysis, the factors that favored
      both remission and its durability were persistent lower levels of proteinuria and
      female sex. Complete remission indicates an excellent long-term prognosis in
      patients with IMGN, but relapses are common and, in a small percentage, chronic
      renal insufficiency occurs. Thus, our data suggest that even this group of
      patients should be monitored on a regular basis.

PMID- 10352190
TI  - Evolution of experimentally induced papillary necrosis to focal segmental
      glomerulosclerosis and nephrotic proteinuria.
AB  - Bromoethylamine (BEA)-induced papillary necrosis is a reproducible model for
      analgesic nephropathy. We induced this lesion in groups of male Sprague-Dawley
      rats and followed the functional and histological changes for 1 year. We found
      that by 1 month, necrosis of the papilla was complete, glomerular filtration rate
      was depressed, and urine albumin excretion was increased. There was an extensive
      interstitial fibrosis characterized by a mononuclear cell infiltrate and patchy
      tubular atrophy. By 6 months, there was re-epithelialization of the papillary
      stump accompanied by a marked increase in albuminuria and an improvement in
      concentrating ability. Changes seen at 9 months were more advanced. There was
      extensive cortical fibrosis manifested by pitting of the surface of the kidney.
      At 1 year, renal function remained impaired (creatinine clearance reduced by 65%
      to 0.26 mL/min/100 g), and the animals were now markedly nephrotic, with
      albuminuria of 254 mg of albumin/24 h. In the BEA rats, there was selective
      destruction of the deep nephrons leading to an increase in the volume-ratio of
      superficial to deep nephrons. Glomerular changes, affecting approximately 60% of
      the glomeruli, were characteristic of focal segmental glomerular sclerosis. This
      model of papillary necrosis/interstitial fibrosis is associated with chronic
      renal insufficiency and leads to the development of focal glomerular sclerosis
      and nephrotic proteinuria by 6 to 12 months after its induction.

PMID- 10352191
TI  - Exacerbation of glomerulonephritis in subjects with chronic hepatitis C virus
      infection after interferon therapy.
AB  - We previously reported the glomerular deposition of hepatitis C virus (HCV) core
      antigen (Ag) in HCV-related nephropathy. In this study, we analyzed 23 HCV
      positive subjects with exacerbation of proteinuria and/or hematuria during
      interferon (IFN) therapy and measured urinary protein selectivity. We also
      examined the involvement of HCV-related Ag using anti-HCV core (capside) Ag
      murine monoclonal antibody (Ab) and anti-core2 rabbit polyclonal Abs in nine
      subjects. Of 17 subjects, 13 (78%) showed low selective proteinuria. We found
      mesangial proliferative glomerulonephritis in 9 subjects, membranoproliferative
      glomerulonephritis in 1 subject, and nephrosclerosis in 1 subject.
      Immunofluorescence study showed the glomerular deposition of immunoglobulin G
      (IgG) or IgA and complements in all 9 subjects examined. Trace amounts only of
      HCV core Ag were detected along the glomerular capillary wall in 3 of 9 subjects
      (33%). Electron microscopy showed subendothelial or mesangial electron-dense
      deposits and also foot process effacement (20% to 72.5% of glomerular capillary
      walls) in all subjects and endothelial swelling in 4 subjects. In conclusion, IFN
      therapy for HCV may exacerbate the underlying glomerulopathies, unrelated to HCV
      Ags, through direct or indirect effects on glomerular endothelial and epithelial
      cells. Physicians should carefully distinguish HCV-related nephropathy from other
      glomerular diseases when they administer IFN therapy to HCV-positive subjects.

PMID- 10352192
TI  - Exaggerated systemic antibody response to mucosal Helicobacter pylori infection
      in IgA nephropathy.
AB  - Numerous studies in the literature report aberrant immune responsiveness in
      immunoglobulin A (IgA) nephropathy. However, all these studies investigate immune
      responses invoked by an artificially engineered antigen challenge. For the first
      time in IgA nephropathy, we report the systemic humoral responses generated as
      part of an active mucosal immune response against a common environmental
      pathogen, Helicobacter pylori (Hp). We studied 22 patients with IgA nephropathy
      and 9 controls without renal disease who were shown to be infected with Hp, using
      a 13C-urea breath test. Hp antigen-specific enzyme-linked immunosorbent assays
      were established to measure the anti-Hp IgA, IgG, and IgA and IgG subclass
      antibody levels. In addition, anti-Hp responses in the monomeric and polymeric
      (pIgA) fractions of serum IgA were measured after separation by gel filtration
      high-performance liquid chromatography. IgA nephropathy was associated with both
      a greater rate of IgA anti-Hp seropositivity (P < 0.05) and a more pronounced IgA
      anti-Hp antibody response (P < 0.01). In almost all cases, IgA anti-Hp was IgA1,
      and more than 90% was polymeric. There was no difference in the frequency of IgG
      anti-Hp seropositivity, but patients produced a much greater IgG anti-Hp response
      (P < 0.01). In addition, the IgG subclass responses were markedly different, with
      IgG1 predominant in controls and IgG2 and IgG3 the major subclasses produced in
      IgA nephropathy. We have shown an exaggerated systemic antibody response to
      mucosal infection caused by Hp in patients with IgA nephropathy, predominantly
      consisting of pIgA1, IgG2, and IgG3. This suggests that in IgA nephropathy, not
      only is pIgA1 production poorly controlled, but regulation of IgG isotype
      switching in response to mucosal pathogens is also deranged.

PMID- 10352193
TI  - Long-term furosemide treatment in the normal rat: dissociation of glomerular
      hypertrophy and glomerulosclerosis.
AB  - Furosemide treatment produces glomerular hypertrophy and augments glomerular
      capillary hydraulic pressure in the normal rat. Similar processes have been
      implicated in the progression of glomerulosclerosis (GS). Whereas prior
      experiments with furosemide treatment of 6 to 8 weeks duration have produced no
      detrimental effects on renal function or structure, the effects of more prolonged
      treatment are unknown. Male Munich-Wistar rats were pair fed with or without
      furosemide, 40 mg/d, from the time of weaning through 10 months of age. At
      selected time points, 24-hour urine collections were obtained for total protein
      and volume determination. At the end of the study, light and electron microscopic
      morphometric studies were performed. Renal cortical hypertrophy and glomerular
      hypertrophy were sustained throughout the 9 months of treatment in the group
      receiving furosemide. The cortical interstitial area was increased in the
      furosemide group, but this did not appear to be the result of fibrosis. Proximal
      and distal tubule diameter were unaffected by treatment. No differences in GS or
      glomerular ultrastructure were shown. This study provides no evidence of
      detrimental glomerular effects of furosemide in normal animals. Further studies
      of furosemide treatment under conditions of preexisting renal pathological
      conditions are warranted to confirm the safety of this treatment in situations
      analogous to those seen in the clinical setting. Interstitial expansion also
      warrants further study in this setting.

PMID- 10352194
TI  - Lack of association of angiotensin-converting enzyme (DD/II) and angiotensinogen
      M235T gene polymorphism with renal function among Chinese patients with type II
      diabetes.
AB  - The prevalence of diabetic nephropathy is greater in nonwhite patients with type
      II diabetes, including the Chinese, and genetic variation appears to have a role.
      We examined angiotensin-converting enzyme (ACE) DD/II and angiotensinogen (Atg)
      M235T polymorphism in a cohort of Chinese patients with type II diabetes with an
      average duration of diabetes of 14 years. Group A (n = 88) did not have
      significant diabetic nephropathy (creatinine levels </= 130 micromol/L [</=1.48
      mg/L], without macroalbuminuria), and group B (n = 80) had significant diabetic
      nephropathy (macroalbuminuria or creatinine level >130 micromol/L [>1.48 mg/d],
      and those undergoing dialysis). The two groups were matched in different aspects,
      including age, duration of diabetes, blood pressure, and glycemic control. The
      results showed: (1) no difference of genotype distribution between groups A and B
      (DD:DI:II, 14%:45%:41% v 8%:38%:54%; P = 0.20; TT:TM/MM, 70%:30% v 76%:24%; P =
      0.43), (2) no evidence of synergistic effect of ACE (DD/II) and Atg M235T gene
      polymorphisms, (3) no difference of allele frequencies between groups A and B
      (D:I, 36%:64% v 27%:73%; P = 0.20 and T:M, 86%:16% v 86%:14%; P = 0.73), and (4)
      ACE activity was greatest in patients with DD genotype and least in those with II
      genotype (DD:DI:II = 66. 9 +/- 13.3 U/L:61.5 +/- 19.9 U/L:45.0 +/- 17.0 U/L; P <
      0.005). The data do not support a role of ACE (DD/II) or Atg M235T polymorphism
      in the development of diabetic nephropathy in Chinese patients with type II
      diabetes, and no synergistic effect was found between them. Greater ACE activity
      was associated with DD genotype, and its role in diabetic nephropathy remains to
      be elucidated.

PMID- 10352195
TI  - Angiotensin I-converting enzyme genotype significantly affects progression of IgA
      glomerulonephritis in an italian population.
AB  - To evaluate the role of angiotensin-converting enzyme (ACE) gene
      insertion/deletion (I/D) polymorphism in the progression of immunoglobulin A
      glomerulonephritis (IgA-GN), genotype distribution in 81 biopsy-proven cases of
      IgA-GN was studied. A logistic regression model showed that the risk for
      homozygous DD was not significantly elevated in patients with IgA-GN compared
      with healthy subjects (odds ratio = 1.16; confidence interval [CI], 0.4 to 3.3).
      However, the 5-year (78% v 90%) and 10-year (52% v 82%) renal survival rates for
      47 patients with serum creatine (Cr) levels of 1.5 mg/dL or less at biopsy was
      significantly less in DD patients (n = 18; chi2 = 5.41; P = 0.02). The hazard
      ratio (HR) for DD (multivariate analysis from Cox proportional model after
      adjustment for known factors of progression, such as hypertension [HPT] and
      proteinuria [PTO]) was 3.07 (CI, 1.1 to 9.4). The HR for heavy PTO was 6.1 (CI,
      1.9 to 19). The association of DD genotype with progression was even more
      striking when patients with other risk factors (heavy proteinuria) were excluded,
      as shown by DD-related risk in the absence (HR = 3.6; CI, 1.1 to 12) and presence
      (HR = 2; CI, 0.4 to 10) of PTO. The risk ratio was further increased by the
      coexistence of DD + PTO (HR = 9.16; CI, 1.8 to 15.7). Furthermore, in a cross
      sectional study among patients with IgA-GN, a logistic regression model showed
      that the risk for homozygous DD was greater, although not at a statistically
      significant level in the end-stage renal failure subgroup compared with the
      normal renal function subgroup (odds ratio = 3.16; CI, 0.7 to 13.7) after
      adjustment by sex, age at biopsy, HPT, PTO, and therapy. Last, DD was
      significantly more frequent in those patients who started hemodialysis at an
      earlier age (chi2 for trend = 6.81; P = 0.009). Our study further supports that
      ACE genotype is a risk factor not for the development, but for the worsening of
      IgA-GN clinical course. However, on the basis of current knowledge, we cannot
      exclude that I/D polymorphism may simply serve as a prognostic marker, eventually
      linked with other discrete loci involved in the progression of renal damage.

PMID- 10352196
TI  - Dobutamine stress echocardiography for the detection of significant coronary
      artery disease in renal transplant candidates.
AB  - Prophylactic coronary revascularization may reduce the risk for cardiac events in
      diabetic renal transplant candidates. No published data exist on the accuracy of
      dobutamine stress echocardiography (DSE) for the diagnosis of angiographically
      defined coronary artery disease (CAD) in renal transplant candidates. The purpose
      of this study is to examine the accuracy of DSE for the detection of CAD in high
      risk renal transplant candidates compared with coronary angiography. Fifty renal
      transplant candidates with diabetic nephropathy (39 patients) or end-stage renal
      disease (ESRD) from other causes (11 patients) underwent prospectively performed
      DSE, followed by quantitative coronary angiography (QCA) and qualitative visual
      assessment of CAD severity. Twenty of 50 DSE tests were positive for inducible
      ischemia. Twenty-seven patients (54%) had a stenosis of 50% or greater by QCA, 12
      patients (24%) had a stenosis of greater than 70% by QCA, and 16 patients (32%)
      had a stenosis greater than 75% by visual estimation. The sensitivity and
      specificity of DSE for CAD diagnosis were respectively 52% and 74% compared with
      QCA stenosis of 50% or greater, 75% and 71% compared with QCA stenosis greater
      than 70%, and 75% and 76% for stenosis greater than 75% by visual estimate. On
      long-term follow-up (22.5 +/- 10.1 months), 6 of 30 patients (20%) with negative
      DSE results and 11 of 20 patients (55%) with positive DSE results had a cardiac
      death, myocardial infarction (MI), or coronary revascularization. Six of 27
      patients (22%) with a QCA stenosis of 50% or greater had a cardiac death or MI
      compared with none of the 23 patients (0%) with QCA stenosis less than 50% (P =
      0.025). We conclude that DSE is a useful but imperfect screening test for
      angiographically defined CAD in renal transplant candidates.

PMID- 10352197
TI  - Prognosis of parathyroid function after successful percutaneous ethanol injection
      therapy guided by color Doppler flow mapping in chronic dialysis patients.
AB  - Selective percutaneous ethanol injection therapy (PEIT) of the parathyroid glands
      has been shown to be effective in chronic dialysis patients with severe secondary
      hyperparathyroidism. In this study, we examined whether it was possible to
      maintain parathyroid function within target range (intact parathyroid hormone
      [iPTH], 160 to 360 pg/mL) in the long term after successful destruction of
      hyperplastic tissue. PEIT was performed in 46 patients resistant to calcitriol
      pulse therapy, and all glands larger than 5 mm in diameter were destroyed by
      ethanol, guided by power Doppler flow mapping. Serum iPTH levels decreased from
      633.3 +/- 359.9 to 226.3 +/- 204.7 pg/mL at 3 weeks and were maintained at 289.9
      +/- 222.4 pg/mL at 1 year after PEIT. Total alkaline phosphatase activity
      decreased from 384.9 +/- 160.1 to 234.0 +/- 110.5 IU/L at 1 year after PEIT. In
      19 patients, iPTH levels decreased into relative hypoparathyroidism (iPTH < 160
      pg/mL) at 3 weeks after PEIT; however, they recovered at 1 year after PEIT (191.1
      +/- 29.6 pg/mL). Parathyroid function was maintained within target range in 80.4%
      of the patients at 1 year after PEIT with appropriate medical therapy. Surgical
      parathyroidectomy was not required in any patient. Conversely, in eight other
      patients with recurrent hyperparathyroidism after subtotal parathyroidectomy,
      iPTH levels recovered in only 50% of the patients at 1 year after PEIT. Thus,
      destruction of hyperplastic tissue should be optimized in such patients.
      Recurrent nerve palsy was observed in only one patient, but was reversible. In
      conclusion, selective PEIT guided by color Doppler flow mapping is an effective
      and safe adjunct to medical therapy with a low risk for hypoparathyroidism.

PMID- 10352198
TI  - Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with
      renal failure.
AB  - Patients with renal failure have an increased incidence of atherosclerotic
      disease. Numerous studies have shown that these patients show increased serum
      lipoprotein(a) [Lp(a)] concentrations compared with the control population.
      However, variable alleles at the apolipoprotein(a) [apo(a)] gene locus determine
      to a large extent the Lp(a) concentration in the general population. We therefore
      undertook the present study to evaluate apo(a) phenotypes and Lp(a) serum
      concentrations in a large number of patients with renal disease. Seventy-nine
      patients treated by hemodialysis (HD), 47 patients treated by continuous
      ambulatory peritoneal dialysis (CAPD), 68 patients with mild/moderate chronic
      renal failure (CRF) and serum creatinine levels of 1.8 to 8 mg/dL, and 73 healthy
      controls were studied. All patients showed significantly elevated median serum
      Lp(a) concentrations in comparison with controls: HD patients, 15.7 mg/dL (P <
      0.01); CAPD patients, 20 mg/dL (P < 0. 005); CRF patients, 15.1 mg/dL (P < 0.01)
      versus controls, 7 mg/dL. The greater Lp(a) values in all groups were not
      explained by differences in isoform frequencies, whereas their increase was
      apo(a)-type specific. Thus, patients in all groups with high-molecular-weight
      (HMW) apo(a) isoforms showed a significant elevation of Lp(a) levels, whereas
      serum Lp(a) concentrations in patients with low-molecular-weight (LMW) isoforms
      were not significantly different from controls, except for CAPD patients, who
      presented increased serum Lp(a) concentrations. We conclude that in patients with
      renal failure, even of mild/moderate degree, as well as in patients with end
      stage renal disease undergoing HD or CAPD, elevated Lp(a) concentrations are
      mainly observed in those with HMW apo(a) phenotypes.

PMID- 10352199
TI  - A protocol-based treatment for intradialytic hypotension in hospitalized
      hemodialysis patients.
AB  - Human serum albumin is used in hemodialysis (HD) units as treatment for
      hypotension despite its high cost and undetermined efficacy. During a 4-month
      period in 1995, albumin was used in 22% of 1,296 consecutive HD treatments in the
      HD unit or intensive care units (ICUs) at our tertiary-care hospital. We
      evaluated the safety and efficacy of a protocol designed to minimize albumin use
      for treating HD-associated hypotension (HDAH). The protocol consisted of the
      stepwise use of saline, mannitol, and albumin for the purpose of achieving
      physician-determined ultrafiltration goals. Patients were exempted from receiving
      the protocol for age younger than 18 years, freshly declotted angioaccess, or
      cardiovascular instability. The protocol was evaluated prospectively in 2,559
      consecutive dialysis sessions (15% in ICUs) in 442 patients. Hypotension occurred
      during 608 sessions (24%), and attending nephrologists elected to initiate the
      protocol in 71% of these cases. Of the 433 instances in which the protocol was
      begun, reversal of hypotension was achieved without the need for albumin in 91%
      and with the addition of albumin in an additional 2%. Protocol treatment was not
      completed because of nursing error in 1% or clotting of filter or angioaccess in
      4%. Use of the protocol failed to reverse hypotension in only 2% of the cases in
      which it was completed. Albumin was administered in only 6% of the 2,559 HD
      treatments. In summary, our protocol-based approach to HDAH was effective, easy
      for nurses to use, albumin sparing, and cost reducing.

PMID- 10352200
TI  - Effect of dialysate temperature on energy balance during hemodialysis:
      quantification of extracorporeal energy transfer.
AB  - An impaired vascular response is implicated in the pathogenesis of dialysis
      induced hypotension, which is at least partly related to changes in
      extracorporeal blood temperature (Temp). However, little is known about changes
      in core Temp and differences in energy balance between standard and cool
      dialysis. In this study, core Temp and energy transfer between extracorporeal
      circuit and patient, as well as the blood pressure response, were assessed during
      dialysis with standard (37.5 degrees C) and cool (35.5 degrees C) Temp of the
      dialysate. Nine patients (4 men, 5 women; mean age, 69 +/-10 [SD] years) were
      studied during low- and standard-Temp dialysis, each serving as his or her own
      control. Bicarbonate dialysis and hemophane membranes were used. Energy transfer
      was assessed by continuous measurement of Temp in the arterial (Tart) and venous
      side (Tven) of the extracorporeal system according to the formula: c.
      rho.Qb*(Tven - Tart)*t, where c = specific thermal capacity (3.64 kJ/kg* degrees
      C), Qb = extracorporeal blood flow, rho = density of blood (1,052 kg/m3), and t =
      dialysis time (hours). Core Temp was also measured by Blood Temperature
      Monitoring (BTM; Fresenius, Bad Homburg, Germany). Core Temp increased during
      standard-Temp dialysis (36.7 degrees C +/- 0.3 degrees C to 37.2 degrees C +/-
      0.2 degrees C; P < 0.05) despite a small negative energy balance (-85 +/- 43 kJ)
      from the patient to the extracorporeal circuit. During cool dialysis, energy loss
      was much more pronounced (-286 +/- 73 kJ; P < 0.05). However, mean core Temp
      remained stable (36.4 degrees C +/- 0.6 degrees C to 36.4 degrees C +/- 0.3
      degrees C; P = not significant), and even increased in some patients with a low
      predialytic core Temp. Both during standard and cool dialysis, the increase in
      core Temp during dialysis was significantly related to predialytic core Temp (r =
      0.88 and r = 0.77; P < 0.05). Systolic blood pressure (RR) decreased to a greater
      degree during standard-Temp dialysis compared with cool dialysis (43 +/- 21 v 22
      +/- 26 mm Hg; P < 0.05), whereas diastolic RR tended to decrease more (15 +/- 10
      v 0 +/- 19 mm Hg; P = 0.07). Core Temp increased in all patients during standard
      Temp dialysis despite a small net energy transfer from the patient to the
      extracorporeal system. Concluding, Core Temp remained generally stable during
      cool dialysis despite significant energy loss from the patient to the
      extracorporeal circuit, and even increased in some patients with a low
      predialytic core Temp. The change in core Temp during standard and cool dialysis
      was significantly related to the predialytic blood Temp of the patient, both
      during cool- and standard-Temp dialysis. The results suggest that the
      hemodialysis procedure itself affects core Temp regulation, which may have
      important consequences for the vascular response during hypovolemia. The removal
      of heat by the extracorporeal circuit and/or the activation of autoregulatory
      mechanisms attempting to preserve core Temp might be responsible for the
      beneficial hemodynamic effects of cool dialysis.

PMID- 10352201
TI  - Normalizing hematocrit in dialysis patients improves brain function.
AB  - Recombinant human erythropoietin (rHuEPO) treatment has been shown to improve
      brain and cognitive function in anemic dialysis patients. Significant debate
      continues, however, regarding the appropriate target hematocrit (Hct) that will
      lead to the greatest benefits while considering possible side effects and costs
      of rHuEPO. Current practice results in an Hct averaging only 31% to 32% in
      dialysis patients, a level less than that achieved in the initial clinical trials
      and well less than normal. This study was designed to evaluate dialysis patients
      at the current practice Hct levels versus normal Hct levels (40% to 45%) to see
      if improvement in brain function resulted. Twenty patients with end-stage renal
      disease (ESRD) currently being treated with rHuEPO (mean Hct, 31.6%) were
      administered additional rHuEPO to reach normal Hct levels (mean, 42. 8%).
      Electroencephalogram (EEG) frequency analysis showed a significant decrease in
      EEG slowing at greater Hct values, and the auditory oddball and Continuous
      Performance Task tasks yielded significant electrode and time-by-electrode
      effects for P300 amplitude. Changes in P300 latency significantly correlated with
      increased Hct in the auditory oddball task. These findings suggest that further
      correction of anemia to normal Hct levels may result in continued improvement in
      neurocognitive function by improving the ability to sustain attention in easier
      tasks and by enhancing the ability to recognize, discriminate, and hold stimuli
      in memory for more difficult tasks.

PMID- 10352202
TI  - Effect of intradialytic parenteral nutrition on delivered Kt/V.
AB  - The purpose of the study is to determine the effect of intradialytic parenteral
      nutrition (IDPN) and its components on delivered Kt/V (Kt/Vd). Nineteen patients
      undergoing routine outpatient hemodialysis and receiving IDPN were enrolled onto
      this prospective, crossover study. To reduce the confounding of time, assigned
      treatment in the first week was random, with patient crossover in the fourth
      week. Patients served as their own controls. In the successive 6 weeks, patients
      received IDPN solutions differing in whether amino acids (AAs), dextrose, or
      lipids were included or excluded. The primary end point was Kt/Vd, measured with
      a single-pool, variable-volume urea kinetic model. Other factors with the
      potential to impact on Kt/Vd were controlled and/or monitored. The administration
      of IDPN with all three components resulted in a significantly reduced mean Kt/Vd.
      When patients received AA-containing solutions, mean Kt/Vd was significantly less
      than when IDPN was withheld. Administration of solutions without AA resulted in a
      mean Kt/Vd not significantly different from mean Kt/Vd when IDPN was withheld.
      The mean prescribed Kt/V did not differ from mean Kt/Vd when IDPN was withheld.
      Simulation analyses of increased urea generation (Gu) showed an increase in
      patient urea volume and decreased Kt/V similar to the study findings. AA
      containing IDPN solutions resulted in a significant reduction in Kt/Vd, possibly
      mediated by increased Gu. Administration of IDPN solutions may have important
      clinical and economic consequences that warrant further investigation.

PMID- 10352203
TI  - Tolerance of large exchange volumes by peritoneal dialysis patients.
AB  - Improving clearances on peritoneal dialysis involves either more exchanges,
      greater fill volume, or both. An increase in the number of exchanges is
      inconvenient, resulting in noncompliance. Therefore, the best option is to
      increase the exchange volumes; however, patients are often reluctant for fear of
      discomfort. We tested the tolerance of 20 patients blinded to randomly sequenced
      volumes of 2, 2.5, and 3 L, performed incenter by the dialysis nurse. Each
      patient underwent one to three exchanges with each volume. At the end of a 4-hour
      dwell, the patient scored discomfort and estimated the infused volume. Only one
      study exchange was performed each day; the rest of the time, the patient
      continued his or her usual prescription. Fifteen of the patients (75%) were not
      able to identify the exchange volumes. Four of the five patients who determined
      the correct exchange volume for 67% to 78% of the exchanges (P < 0.04 compared
      with 33% expected by chance) had a body surface area greater than 1.75 m2. Of 123
      exchanges, 84% were associated with no discomfort, 10% with mild discomfort, and
      6% with moderate discomfort. Patients were not more likely to have discomfort
      with 3-L compared with lower fill volumes. Peritoneal clearances of creatinine
      (6.1 v 6.6 v 7.7 mL/min/1.73 m2) and urea nitrogen (7.3 v 8.6 v 9.5 mL/min) were
      progressively greater with increasing exchange volumes (P < 0.001). We conclude
      that the majority of small as well as large patients will tolerate 2.5- and 3-L
      exchange volumes. If encouraged to do so, many patients could tolerate greater
      exchange volumes than they are presently using. Exchange volumes should be
      readily increased as residual renal function declines.

PMID- 10352204
TI  - Role of interferon-alpha in the treatment of primary glomerulonephritis.
AB  - Interferon-alpha (IFN-alpha) is a naturally occurring cytokine. It was the first
      cytokine used with clinical benefit in the treatment of viral hepatitis and
      malignancies. Patients with viral hepatitis B or C may have complications with
      glomerulonephritis (GN). Improvement in proteinuria with or without clearing of
      viral markers after IFN-alpha therapy has been reported. This encouraged us to
      offer IFN-alpha therapy to four patients with GN. These patients refused
      treatment with steroids and/or cyclophosphamide because of concerns about side
      effects. One patient with membranous GN and two patients with mesangial GN
      (MesGN) had a remission of nephrotic syndrome. In one patient with type II
      diabetes and MesGN, renal insufficiency and proteinuria did not subside; however,
      renal function remained stable. The mechanism of action of IFN-alpha is
      discussed, with its possible role in the treatment of primary GN.

PMID- 10352205
TI  - Distal renal tubular acidosis and high urine carbon dioxide tension in a patient
      with southeast Asian ovalocytosis.
AB  - Southeast Asian ovalocytosis (SAO) is the best-documented disease in which
      mutation in the anion exchanger-1 (AE1) causes decreased anion (chloride [Cl
      ]/bicarbonate [HCO3-]) transport. Because AE1 is also found in the basolateral
      membrane of type A intercalated cells of the kidney, distal renal tubular
      acidosis (dRTA) might develop if the function of AE1 is critical for the net
      excretion of acid. Studies were performed in a 33-year-old woman with SAO who
      presented with proximal muscle weakness, hypokalemia (potassium, 2.7 mmol/L), a
      normal anion gap type of metabolic acidosis (venous plasma pH, 7. 32;
      bicarbonate, 17 mmol/L; anion gap, 11 mEq/L), and a low rate of ammonium (NH4+)
      excretion in the face of metabolic acidosis (26 micromol/min). However, the
      capacity to produce NH4+ did not appear to be low because during a furosemide
      induced diuresis, NH4+ excretion increased almost threefold to a near-normal
      value (75 micromol/L/min). Nevertheless, her minimum urine pH (6.3) did not
      decrease appreciably with this diuresis. The basis of the renal acidification
      defect was most likely a low distal H+ secretion rate, the result of an
      alkalinized type A intercalated cell in the distal nephron. Unexpectedly, when
      her urine pH increased to 7.7 after sodium bicarbonate administration, her urine
      minus blood carbon dioxide tension difference (U-B Pco2) was 27 mm Hg. We
      speculate that the increase in U-B Pco2 might arise from a misdirection of AE1 to
      the apical membrane of type A intercalated cells.

PMID- 10352206
TI  - Glomerulonephritis in a patient with complement factor I deficiency.
AB  - Complement factor I deficiency is known to be associated with recurrent pyogenic
      infections. The patient described here had recurrent attacks of otitis,
      sinusitis, and bronchopneumonia since childhood. At the age of 24 years, he had
      an acute episode of systemic vasculitis with purpura, but no nephritis. A factor
      I deficiency was diagnosed when he was 36 years old. Because of the uncontrolled
      activation of the alternative pathway of complement, several other components
      were depleted, in particular C3, which explained the predisposition for pyogenic
      infections. A progressive loss of renal function accompanied by proteinuria and
      hematuria started after the age of 40 years. Renal biopsy showed a focal
      segmental glomerulonephritis (GN) with glomerular deposits of immunoglobulins and
      complement C3 and C4 fragments. The glomerular podocytes showed an almost
      complete loss of complement receptor 1 (CR1; CD35). The expression of CR1 was
      very low on erythrocytes, as well. Thus, CR1, the most efficient cell-bound
      cofactor for the inactivation of C4b/C3b by factor I, appears to be consumed when
      factor I is missing. Although this is the first report of factor I deficiency
      associated with GN, it is unlikely that the development of the nephritis was
      fortuitous because GN has been found in many other diseases characterized by
      uncontrolled activation of the alternative pathway.

PMID- 10352208
TI  - Extraskeletal Ewing's sarcoma in a kidney transplant patient.
AB  - Organ transplant recipients are prone to develop a variety of malignancies, most
      of which are encountered uncommonly in the general population. Approximately 5%
      to 7% of these malignancies are sarcomas, of which most are Kaposi's sarcomas.
      Ewing's sarcoma is an extremely uncommon tumor in organ transplant recipients,
      and only one case of skeletal Ewing's sarcoma has been reported in the transplant
      literature. We present a case of extraskeletal Ewing's sarcoma (EES) in a renal
      transplant patient.

PMID- 10352207
TI  - Effect of pituitary microsurgery on acromegaly complicated nephrotic syndrome
      with focal segmental glomerulosclerosis: report of a rare clinical case.
AB  - A case of nephrotic syndrome complicated by acromegaly is presented. The first
      renal biopsy specimen showed minor glomerular abnormalities with glomerular
      hypertrophy, corresponding with minimal change nephrotic syndrome. Corticosteroid
      therapy led to a partial remission, followed by frequent relapses after reduction
      of the drug. A diagnosis of atypical focal segmental glomerulosclerosis (FSGS)
      was made based on the second renal biopsy results 6 months after the first. We
      combined steroid therapy with the administration of an anticoagulant, cytotoxic
      agents, angiotensin-converting enzyme inhibitor, and low-density lipoprotein
      adsorption. Except for the angiotensin-converting enzyme inhibitor, these
      medications were not effective in terms of allowing a reduction in the high
      dosage of steroid, which in turn threatened progressive osteoporosis and lumbar
      vertebrae fracture. Administering the steroid at a moderate dosage, treatment was
      focused on the complicating acromegaly from pituitary microadenoma. Subcutaneous
      injections of octreotide acetate, a somatostatin analogue, reduced proteinuria
      and increased urine volume. Subsequent transsphenoidal microsurgery of the
      adenoma resulted in the normalization of the elevated creatinine clearance and
      the further reduction in steroid dosage while maintaining a remission state. This
      is the first reported clinical case with acromegaly followed by FSGS, and it is
      suggested that hypersecretion of growth hormone participates in the development
      and progression of glomerular disease.

PMID- 10352209
TI  - Severe access recirculation secondary to free flow between the lumens of a dual
      lumen dialysis catheter.
AB  - Over the last decade, it has been increasingly recognized that recirculation is
      present to some extent in all dual-lumen dialysis catheters. In addition, despite
      the recognition that dual-lumen dialysis catheters are not ideal as long-term
      hemodialysis access, their use for this purpose has increased secondary to both
      poor vascular access in an older and sicker dialysis population as well as their
      convenience. Although infection and thrombosis remain the most common
      complications of dialysis catheters, we report a case of severe access
      recirculation secondary to free flow between the two lumens of a tunneled, cuffed
      silicone dual-lumen dialysis catheter. We take this opportunity to discuss
      recirculation in dialysis catheters and to review potential causes of catheter
      breakdown.

PMID- 10352210
TI  - On a nephrotoxic and carcinogenic slimming regimen.

PMID- 10352211
TI  - Interferon therapy: a double-edged sword?

PMID- 10352212
TI  - What crit?

PMID- 10352213
TI  - Environmental distal renal tubular acidosis in Thailand: an enigma.
AB  - Distal renal tubular acidosis is a common health problem in northeastern
      Thailand, with the population background of the low potassium intake, low urine
      citrate, and decreased red blood cell Na-K adenosine triphosphatase (ATPase)
      activity and the environment of the high soil vanadium. The disease is usually
      seen in the people with low socioeconomic status in summer. The patients have
      decreased gastric acidity and low urine potassium. There are varying degrees of
      renal function from normal to impairment. Gastric hypoacidity is an important
      clue. Defects in H-K ATPase and anion exchange (AE2) mechanism are considered.
      The urine vanadium is higher in the patients than that of normal rural
      northeastern villagers. Inhibition of H-K ATPase by vanadium seems possible and
      requires more supporting evidence. AE1 gene mutation is noted in few patients.
      The cause of dRTA is not apparent. The AE2 gene and H-K ATPase gene remain to be
      studied. Both environmental and genetic factors could contribute to the
      pathogenesis of the disease.

PMID- 10352215
TI  - Autosomal dominant distal renal tubular acidosis and the AE1 gene.

PMID- 10352214
TI  - Erythropoietin and iron use in peritoneal dialysis patients. Report from the 1997
      HCFA end-stage renal disease core indicators project.
AB  - The HCFA ESRD Core Indicators Project is designed to assess several key
      indicators of care in peritoneal dialysis patients, including anemia management.
      Information on hematocrit levels, epoetin alfa dosing, estimates of iron stores,
      and iron therapy as obtained in a national sample of 1,219 peritoneal dialysis
      patients are described. The average hematocrit was 32.8% +/- 3.8%, and severe
      anemia (hematocrit < 25%) occurred in 1.4% of PD patients. The mean weekly
      epoetin alfa dose was 134.6 U/kg. In general, there was an inverse relationship
      between hematocrit and epoetin alfa doses. Most (83%) of PD patients received
      iron therapy, with only 8% of patients receiving intravenous iron. The mean serum
      ferritin was 303 ng/mL, with 64% of patients having a ferritin greater than 100
      ng/mL. The mean transferrin saturation was 28%, with 60% of patients having a
      value of less than 20%. There was an inverse relationship between serum ferritin
      levels and hematocrit but no relationship between hematocrit and transferrin. It
      is concluded that there could be improvement in the epoetin alfa and iron
      management in many patients.

PMID- 10352216
TI  - TTP-Like syndrome in a 44-year-old woman with SLE and nephritis.

PMID- 10352217
TI  - Intradialytic parenteral nutrition treatment.

PMID- 10352218
TI  - Hemodynamic stability during dialysis and cardiovascular disease in end-stage
      renal disease patients.

PMID- 10352219
TI  - 1997 Peritoneal Dialysis-Core Indicators Study: Dialysis Adequacy and Nutritional
      Indicators Report.
AB  - The 1997 Peritoneal Dialysis-Core Indicators Study: Dialysis Adequacy and
      Nutritional Indicators Report documents the current status of peritoneal dialysis
      within the United States. A national random sample of adult peritoneal dialysis
      (PD) patients participating in the United States End Stage Renal Disease (ESRD)
      program was surveyed. PD subjects were large, with a mean body weight of 76 +/-
      18.9 kg (mean +/- 1 SD) and a body mass index (BMI) of 27 +/- 6.4. The dialysis
      prescriptions documented achieved a mean weekly Kt/Vurea (wKt/V) and weekly
      creatinine clearance (wCrCl) of 2. 45 +/- 2.29 and 65.5 +/- 35.2 L/wk/1.73m2,
      respectively. The serum albumin of these patients was 3.5 +/- 0.48 g/dL, their
      normalized protein equivalent of nitrogen appearance (nPNA) 1.0 +/- 0.63 g/kg/d,
      and their normalized creatinine appearance rate (nCAR) 14 +/- 6.0 mg/kg/d. Serum
      albumin correlated meagerly but in a positive fashion with BMI, nPNA, and nCAR,
      and negatively with wCrCl. Among adult US PD patients, serum albumin values
      appear to correlate poorly with alternative measures of nutritional status and
      are inversely related to the intensity of renal replacement therapy. The
      presumptive dietary protein intake (nPNA) and creatinine appearance rate (nCAR)
      derived for PD patients do correlate in a positive fashion with dialysis
      delivery, at least up to a wCrCl of 60 to 80 L/wk/1.73 m2 and wKt/V = 2.1, but
      their values suggest that 30% to 50% of PD patients have marginal nutritional
      status.

PMID- 10352220
TI  - Strongyloidiasis as a possible cause of nephrotic syndrome.
AB  - Chronic strongyloidiasis is a mild disease and has never been reported to be
      associated with nephrotic syndrome. Disseminated strongyloidiasis is known to
      have high mortality, but it frequently is not diagnosed until autopsy. We report
      a patient with nephrotic syndrome developing disseminated strongyloidiasis after
      steroid therapy. The findings in renal biopsy, the time course of the
      development, and resolution of nephrotic syndrome after thiabendazole treatment
      suggested a possible causal relationship between chronic strongyloidiasis and
      nephrotic syndrome. The case also demonstrated the importance of early diagnosis
      in disseminated strongyloidiasis and the good clinical outcome of early treatment
      before the development of organ failure.

PMID- 10352221
TI  - Hemolytic uremic syndrome due to Capnocytophaga canimorsus bacteremia after a dog
      bite.
AB  - The hemolytic uremic syndrome (HUS) is known to have several causes, including
      infectious diseases, drugs, pregnancy, and malignant disease. We report a patient
      who developed acute renal failure attributable to HUS in the course of
      Capnocytophaga canimorsus bacteremia. Acute tubular necrosis as well as HUS
      should be considered as a cause of acute renal failure in the setting of
      Capnocytophaga canimorsus bacteremia.

PMID- 10352222
TI  - Idiopathic thrombocytopenia after cytomegalovirus infection in a renal transplant
      recipient.
AB  - Infection with cytomegalovirus (CMV) is a frequent complication of organ
      transplantation and presents a spectrum of disease ranging from asymptomatic
      viremia to life-threatening tissue-invasive disease. CMV is also lymphotrophic,
      with the potential to induce autoimmune disease, although immunosuppressive
      therapy may prevent or attenuate the clinical course in transplant patients. We
      report a case of idiopathic thrombocytopenic purpura occurring in a renal
      transplant recipient after primary CMV infection and discuss the possible
      mechanisms involved.

PMID- 10352223
TI  - Renal transplantation in a patient with common variable immunodeficiency.
AB  - A 15-year-old girl developed end-stage renal disease requiring renal
      transplantation. Posttransplantation immunosuppression therapy consisted of
      antithymocyte globulin, glucocorticosteroids, cyclosporine A, and azathioprine.
      The patient's clinical course after transplantation was complicated by several
      episodes of graft rejection, chronic anemia, oral candidiasis, and numerous
      infections of the sinopulmonary tract that were recalcitrant to antibiotics and
      surgical intervention. An immunologic evaluation showed marked immune
      abnormalities beyond that expected by the transplant immunosuppression.
      Examination of serum samples taken before the transplant confirmed a diagnosis of
      common variable immunodeficiency. The difficulties of managing
      posttransplantation immunosuppression in a patient with a primary
      immunodeficiency are discussed. Patients with end-stage renal disease and a
      history of recurrent sinopulmonary infections may require immunologic screening
      before renal transplantation.

PMID- 10352224
TI  - Renal hemorrhage in polyarteritis nodosa: diagnosis and management.
AB  - We report a patient with biopsy-proven polyarteritis nodosa with massive
      hemorrhage from presumed interlobar artery rupture. The use of interventional
      radiology techniques such as embolization are discussed in the acute management
      of such patients. Embolization by interventional radiology should be considered a
      useful alternative to surgery in these patients. The utility of angiography as a
      diagnostic and therapeutic tool is demonstrated in this case.

PMID- 10352225
TI  - Cis-regulation of inter-allelic exchanges in mutation at human minisatellite
      MS205 in yeast.
AB  - Tandemly repeated DNA is a major component of the human genome, and includes loci
      contributing to human disease. Minisatellites include the most variable human
      loci described to date, and the mechanisms by which this variation is generated
      in humans have been studied in detail. Integration of human minisatellites into
      yeast not only provides a model for further dissecting the molecular basis of
      length change mutation at these loci, but also more generally allows the study of
      complex recombinational events in yeast. We have used human minisatellite MS205
      integrated into yeast to study the structural details of length change mutations.
      Apart from showing that mutation at this locus in yeast has features similar to
      those observed at some minisatellites in humans, including meiosis-specificity,
      and polarity, in which exchange events are localised to one extremity of the
      array, we here, for the first time, directly demonstrate that a flanking element
      in yeast regulates the mutation process. The results therefore support the
      hypothesis that flanking initiators are involved in minisatellite mutation in
      humans. Furthermore, mutant alleles showed more complex rearrangements in one
      orientation than the other. The data also suggest that the mutational pathway for
      deletions might be different from the pathway generating inter-allelic exchanges
      and duplications.

PMID- 10352226
TI  - Characterization of the glyceraldehyde-3-phosphate dehydrogenase gene [correction
      of glyceraldehyde-3-phosphate gene] and the use of its promoter for heterologous
      expression in Cryptococcus neoformans, a human pathogen.
AB  - The GPD gene encoding glyceraldehyde-3-phosphate dehydrogenase was isolated from
      Cryptococcus neoformans, a heterobasidiomycetous yeast that is pathogenic to
      humans. The gene contains 11 introns, differing from the conserved intron
      positions found in the GPD genes of Basidiomycetes. The predicted amino-acid
      sequence of this gene is extremely similar to that reported from GPD proteins of
      other basidiomycetes. The promoter region of the C. neoformans GPD gene was
      similar to those of other basidiomycetes. Plasmid constructs containing up to
      1600 base pairs upstream of the native GPD open reading frame were used to
      express either the native URA5 gene in a ura5 mutant or the heterologous hphI
      gene (a bacterial gene that confers resistance to the aminoglycoside hygromycin)
      in a wild-type strain of C. neoformans. Transformation frequencies resulting from
      the plasmid-borne Gpdp::URA5 gene were at levels similar to those of the native
      URA5, which suggested that all the sequences necessary for proper expression were
      present. Transformation frequencies using the Gpdp::hphI gene constructs were
      poor. However, addition of DNA sequences flanking the 3'-end of an native C.
      neoformans gene significantly improved the transformation frequencies resulting
      from the expression of the heterologous hphI gene.

PMID- 10352227
TI  - Structure of human ornithine decarboxylase antizyme 2 gene.
AB  - Ornithine decarboxylase antizyme 1, a negative regulator of polyamine levels,
      acts by destabilizing the first enzyme in the polyamine biosynthetic pathway
      (ODC) and by inhibiting uptake of polyamines. Recently, a second mammalian
      antizyme was discovered. Here, we report the genomic organization and chromosomal
      position of the new human gene, HuAZ2, and make a comparison with its antizyme 1
      homologue. Fluorescence in-situ hybridization (FISH) localized the sequences from
      a bacterial artificial chromosomal (BAC) clone containing HuAZ2 at band 22 of the
      long arm of chromosome 15. This gene spans at least 15kb and contains five exons.
      No CAAT or TATA sequences could be identified within 800bp upstream of the
      translation initiation codon, but the 5'-flanking region contains several
      putative binding sites for other transcription factors. Transcription initiation
      of this gene appears to be heterogeneous.

PMID- 10352228
TI  - Identification and characterization of a protein containing formin homology
      (FH1/FH2) domains.
AB  - A novel member of the Formin/Diaphanous family of proteins was cloned and
      characterized. A 4kB mRNA is ubiquitously expressed but is found in abundance in
      the spleen. FHOS (Formin Homologue Overexpressed in Spleen) contains a 3414bp
      open reading frame and encodes for an approximately 128kDa protein. FHOS has
      sequence homology to Diaphanous and Formin proteins within the Formin Homology
      (FH)1 and FH2 domains. FHOS also contains a coiled-coil, a collagen-like domain,
      two nuclear localization signals, and several potential PKC and PKA
      phosphorylation sites. FHOS-specific antiserum was generated and used to
      determine that FHOS is a predominantly cytoplasmic protein and is expressed in a
      variety of human cell lines. FHOS was mapped to chromosome 16q22 between
      framework markers WI-5594 and WI-9392.

PMID- 10352229
TI  - Polymorphism in structure of the retrotransposable element 412 in Drosophila
      simulans and D. melanogaster populations.
AB  - The structure of the 412 retrotransposable element was investigated in various
      natural populations of D. melanogaster and D. simulans by a restriction enzyme
      analysis. We show that although the canonical structure of the 412 element was
      the same in both species, a high structural polymorphism existed with various
      rearranged elements. A 412 family was thus composed of heterogeneous copies of
      different sizes, with a large proportion of full-size copies. D. simulans had
      more rearranged copies than D. melanogaster, with some specific copies, such as a
      5.6-kb BsrBI fragment, present in all populations of D. simulans. Full-size and
      rearranged copies were detected in both the euchromatin and the heterochromatin,
      with many rearranged copies in D. simulans, suggesting a recent mobilization of
      the 412 element in this species.

PMID- 10352231
TI  - Genomic structure, tissue expression and chromosomal location of the LIM-only
      gene, SLIM1.
AB  - Human SLIM1 is a recently described gene of the LIM-only class encoding four and
      a half tandemly repeated LIM domains. LIM domains are double zinc finger
      structures which provide an interface for protein/protein interactions and are
      conserved in a variety of nuclear and cytoplasmic factors important in cell fate
      determination and cellular regulation. Here we report the structural
      organization, expression pattern and chromosomal localization of the human SLIM1
      gene. SLIM1 was found to contain at least five exons with all four introns
      disrupting the coding region at a similar position relative to the respective
      complete LIM domains. Northern blot analysis confirmed strikingly high expression
      of SLIM1 in skeletal muscle and heart, with much lower expression observed in
      several other tissues including colon, small intestine and prostate. The SLIM1
      gene was assigned to human chromosome Xq26 using fluorescence in situ
      hybridization.

PMID- 10352230
TI  - Drosophila has several genes for gap junction proteins.
AB  - The Innexin gene family forms gap junctions in invertebrates. Many genes in this
      family have been identified in Caenorhabditis elegans, but only two in
      Drosophila. We have used PCR techniques to identify three new members of this
      family from Drosophila. These are designated pas-related proteins (prp) 6, 7, and
      33. The putative proteins coded by these new genes show 25-35% identity and 39
      66% similarity to other Drosophila innexins and share a similar hydrophobicity
      profile. The genes form two small clusters on the X-chromosome, with three of the
      genes sitting within 10kb of each other. The closeness in sequence and location
      suggests an evolutionary origin of these genes via local duplication. In situ
      hybridization shows expression in the CNS, gut and epidermis. Each gene has a
      distinct pattern of expression in different tissues at different developmental
      times. However, parts of the expression patterns overlap, especially for prp33
      and ogre which may be expressed from the same transcriptional enhancers. This
      suggest that the Prp33 and Ogre proteins may join in forming heteromeric gap
      junction channels.

PMID- 10352232
TI  - Cloning, central nervous system expression and chromosomal mapping of the mouse
      PAK-1 and PAK-3 genes.
AB  - Two cDNAs encoding PAK kinases were isolated from a mouse embryo library by
      screening with a PCR-generated probe derived from the kinase domain of a rat PAK
      kinase. These cDNAs, designated PAK-1 and PAK-3, encode mouse PAK kinases of 545
      and 544 amino acids, respectively. Both proteins possess an N-terminal Cdc42/Rac
      interacting binding domain (CRIB) and a C-terminal serine/threonine kinase
      domain. Comparison of the two mouse PAK kinases revealed that the proteins show
      87% amino acid identity. Northern analysis of a multiple mouse tissue blot with a
      PAK-1 probe detected a 3.0kb transcript that was almost exclusively expressed in
      the brain and spinal cord compared to other tissues such as lung, liver and
      kidney. A similar pattern of central nervous system tissue expression of PAK-3
      transcripts of 3.6 and 8kb was also observed. Analysis of two multilocus genetic
      crosses localized Pak1 and Pak3 to a position on chromosome 7 and X,
      respectively. The high level of PAK-1 and PAK-3 kinase expression in the mouse
      brain and spinal cord suggests a potentially important role for these kinases in
      the control of the cellular architecture and/or signaling in the central nervous
      system.

PMID- 10352233
TI  - Transcriptional organization of the Azotobacter vinelandii algGXLVIFA genes:
      characterization of algF mutants.
AB  - Azotobacter vinelandii forms desiccation-resistant cysts which contain a high
      proportion of the exopolysaccharide alginate in their envelope. We have
      previously shown that the A. vinelandii alginate biosynthetic genes algA and algL
      are transcribed from a promoter located somewhere upstream of algL. In this study
      we sequenced the A. vinelandii algX, algL, algV, algI and algF genes located
      between algG and algA. We carried out primer extension analysis of the algG, algX
      and algL genes and detected transcription start sites upstream algG but not
      upstream algX or algL, implying that algG and algX form part of the previously
      identified algL-A operon. A promoter upstream algA was also detected; however,
      transcription of algA exclusively from this promoter is not sufficient for the
      AlgA levels required for alginate production. An algF mutant (AJ34) was
      constructed by insertion of the Omega-tetracycline cassette in the non-polar
      orientation. As expected, AJ34 produced unacetylated alginate. Viability of 35day
      old cysts formed by strain AJ34, but not of those formed by the wild type, was
      reduced, indicating that acetylation of alginate plays a role in cyst resistance
      to desiccation.

PMID- 10352235
TI  - Selection, the impersonal engineer.

PMID- 10352234
TI  - Embodied artificial life.

PMID- 10352236
TI  - Coevolving predator and prey robots: do "arms races" arise in artificial
      evolution?
AB  - Coevolution (i.e., the evolution of two or more competing populations with
      coupled fitness) has several features that may potentially enhance the power of
      adaptation of artificial evolution. In particular, as discussed by Dawkins and
      Krebs [3], competing populations may reciprocally drive one another to increasing
      levels of complexity by producing an evolutionary "arms race." In this article we
      will investigate the role of coevolution in the context of evolutionary robotics.
      In particular, we will try to understand in what conditions coevolution can lead
      to "arms races." Moreover, we will show that in some cases artificial coevolution
      has a higher adaptive power than simple evolution. Finally, by analyzing the
      dynamics of coevolved populations, we will show that in some circumstances well
      adapted individuals would be better advised to adopt simple but easily modifiable
      strategies suited for the current competitor strategies rather than incorporate
      complex and general strategies that may be effective against a wide range of
      opposing counter-strategies.

PMID- 10352237
TI  - Evolutionary body building: adaptive physical designs for robots.
AB  - Creating artificial life forms through evolutionary robotics faces a "chicken and
      egg" problem: Learning to control a complex body is dominated by problems
      specific to its sensors and effectors, while building a body that is controllable
      assumes the pre-existence of a brain. The idea of coevolution of bodies and
      brains is becoming popular, but little work has been done in evolution of
      physical structure because of the lack of a general framework for doing it.
      Evolution of creatures in simulation has usually resulted in virtual entities
      that are not buildable, while embodied evolution in actual robotics is
      constrained by the slow pace of real time. The work we present takes a step in
      addressing the problem of body evolution by applying evolutionary techniques to
      the design of structures assembled out of elementary components that stick
      together. Evolution takes place in a simulator that computes forces and stresses
      and predicts stability of three-dimensional brick structures. The final printout
      of our program is a schematic assembly, which is then built physically. We
      demonstrate the functionality of this approach to robot body building with many
      evolved artifacts.

PMID- 10352238
TI  - Online evolution for a self-adapting robotic navigation system using evolvable
      hardware.
AB  - Great interest has been shown in the application of the principles of artificial
      life to physically embedded systems such as mobile robots, computer networks,
      home devices able continuously and autonomously to adapt their behavior to
      changes of the environments. At the same time researchers have been working on
      the development of evolvable hardware, and new integrated circuits that are able
      to adapt their hardware autonomously and in real time in a changing environment.
      This article describes the navigation task for a real mobile robot and its
      implementation on evolvable hardware. The robot must track a colored ball, while
      avoiding obstacles in an environment that is unknown and dynamic. Although a
      model-free evolution method is not feasible for real-world applications due to
      the sheer number of possible interactions with the environment, we show that a
      model-based evolution can reduce these interactions by two orders of magnitude,
      even when some of the robot's sensors are blinded, thus allowing us to apply
      evolutionary processes online to obtain a self-adaptive tracking system in the
      real world, when the implementation is accelerated by the utilization of
      evolvable hardware.

PMID- 10352239
TI  - Cutting edge: clonally restricted production of the neurotrophins brain-derived
      neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2
      polarized expression of their receptors.
AB  - Neurotrophins, such as neurotrophin-3 (NT-3) and brain-derived neurotrophic
      factor (BDNF), are potent regulators of neuronal functions. Here we show that
      human immune cells also produce NT-3 mRNA, secrete BDNF, and express their
      specific receptors trkB and trkC. The truncated trkB receptor, usually expressed
      in sensory neurons of the central nervous system, was also constitutively
      expressed in unstimulated Th cells. Full-length trkB was detectable in stimulated
      PBMC, B cell lines, and Th1, but not in Th2 and Th0 cell clones. Clonally
      restricted expression was also observed for trkC, until now not detected on blood
      cells. The Th1 cytokine IL-2 stimulated production of trkB mRNA but not of trkC,
      whereas the Th2 cytokine IL-4 enhanced NT-3 but not BDNF mRNA expression.
      Microbial Ags, which influence the Th1/Th2 balance, could therefore modulate the
      neurotrophic system and thereby affect neuronal synaptic activity of the central
      nervous system.

PMID- 10352240
TI  - Cutting edge: contrasting roles of TNF receptor-associated factor 2 (TRAF2) and
      TRAF3 in CD40-activated B lymphocyte differentiation.
AB  - In B lymphocytes, CD40 signals contribute to the activation of Ab secretion,
      isotype switching, T cell costimulation, and immunological memory. TRAF proteins
      appear to be important components of the CD40 signal transduction complex, but
      their roles in the activation of B cell effector functions are poorly understood.
      We examined the contributions of TNF receptor-associated factor 2 (TRAF2) and
      TRAF3 to CD40-activated differentiation in mouse B cells transfected with
      inducible TRAF and dominant-negative TRAF cDNAs. We find that binding of TRAF2
      and TRAF3 to CD40 is not required for the induction of Ab secretion, but that
      both TRAF molecules can regulate the activation process. We demonstrate a
      negative regulatory role for TRAF3 and that this activity is dependent on the
      availability of an intact TRAF3-binding site in the cytoplasmic domain of CD40.
      In contrast, TRAF2 appears to play a positive role in B cell differentiation, and
      this activity is apparent even when its binding site on CD40 is disrupted.

PMID- 10352241
TI  - Cutting edge: apoptosis of superantigen-activated T cells occurs preferentially
      after a discrete number of cell divisions in vivo.
AB  - Staphylococcal enterotoxins are bacterial products that display superantigen
      activity in vitro as well as in vivo. For instance, staphylococcal enterotoxin B
      (SEB) polyclonally activates T cells that bear the Vbeta8 gene segment of the
      TCR. SEB-activated T cells undergo a burst of proliferation that is followed by
      apoptosis. Using an in vivo adaptation of a fluorescent cell division monitoring
      technique, we show here that SEB-activated T cells divide asynchronously, and
      that apoptosis of superantigen-activated T cells is preferentially restricted to
      cells which have undergone a discrete number of cell divisions. Collectively, our
      data suggest that superantigen-activated T cells are programmed to undergo a
      fixed number of cell divisions before undergoing apoptosis. A delayed death
      program may provide a mechanistic compromise between effector functions and
      homeostasis of activated T cells.

PMID- 10352242
TI  - Inhibition of B cell receptor-mediated apoptosis by IFN.
AB  - IFNs are a family of cytokines that are involved in the regulation of immune and
      inflammatory responses. Clinical use of IFN-alpha/beta encompasses treatment for
      a variety of diseases; however, prolonged exposure to IFN-alpha/beta results in
      elevated levels of autoreactive Abs. In this study, we investigated the potential
      of IFNs to modulate apoptotic signals in B cells. We demonstrate that IFN-alpha
      or IFN-beta inhibit Ag receptor-mediated apoptosis in a dose-dependent manner.
      Inhibition of phosphatidylinositol 3' (PI3)-kinase did not abolish the effect of
      IFN, indicating that the antiapoptotic mechanism is PI3-kinase- and protein
      kinase B/Akt-independent. Instead, IFN-alpha and IFN-beta, but not IFN-gamma,
      significantly increase the levels of the survival protein Bcl-2, and to a lesser
      extent, Bcl-xL expression. Thus, IFN-alpha/beta-mediated inhibition of B cell Ag
      receptor-triggered apoptosis may offer a model for the process that leads to the
      escape of self-reactive B cells from negative selection and consequently results
      in autoantibody production.

PMID- 10352243
TI  - The role of environmental antigens in the spontaneous development of autoimmunity
      in MRL-lpr mice.
AB  - It has been proposed that the "normal" stimulation of the immune system that
      occurs from interactions with environmental stimuli, whether infectious or
      dietary, is necessary for the initiation and/or continuation of autoimmunity. We
      tested this hypothesis by deriving a group of MRL-lpr mice into a germfree (GF)
      environment. At 5 mo of age, no differences between GF and conventional MRL-lpr
      mice were noted in lymphoproliferation, flow cytometric analysis of lymph node
      cells (LN), or histologic analysis of the kidneys. Autoantibody levels were
      comparably elevated in both groups. A second experiment tested the role of
      residual environmental stimuli by contrasting GF mice fed either a low m.w.,
      ultrafiltered Ag-free (GF-AF) diet or an autoclaved natural ingredient diet (GF
      NI). At 4 mo of age, both groups showed extensive lymphoproliferation and
      aberrant T cell formation, although the GF-AF mice had approximately 50% smaller
      LNs compared with sex-matched GF-NI controls. Autoantibody formation was present
      in both groups. Histologic analysis of the kidneys revealed that GF-AF mice had
      much lower levels of nephritis, while immunofluorescence analysis demonstrated no
      difference in Ig deposits but did reveal a paucity of C3 deposition in the
      kidneys of GF-AF mice. These data do not support a role for infectious agents in
      the induction of lymphoproliferation and B cell autoimmunity in MRL-lpr mice.
      Furthermore, they suggest that autoantibodies do not originate from B cells that
      were initially committed to exogenous Ags. They do suggest a possible
      contributory role for dietary exposure in the extent of lymphoproliferation and
      development of nephritis in this strain.

PMID- 10352244
TI  - Cross-linking of membrane CD43 mediates dendritic cell maturation.
AB  - CD43/leukosialin is a major sialoglycoprotein of the dendritic cell (DC) surface,
      which can regulate cell adhesion and has the potential to mediate cell activation
      signals. Monocyte-derived DC transiently incubated with the anti-CD43 mAb, MEM
      59, or with F(ab')2 fragments, but not with monovalent Fab fragments or control
      IgG, 24 h later showed increased levels of membrane HLA-DR, CD54, CD40, CD80,
      CD86, and CD83. In parallel, CD43 cross-linking induced synthesis and release of
      IL-1beta, IL-6, TNF-alpha, IL-12, and IL-10. CD43 ligation inhibited the
      endocytic activity of DC, and enhanced the capacity of DC to stimulate T cell
      proliferation in the primary allogeneic and autologous MLR assay. In addition,
      anti-CD43-treated DC were less efficient at presenting native HIV-1 reverse
      transcriptase to a specific CD4+ T cell clone, whereas presentation of the
      reverse transcriptase 55-72 peptide to the same clone was increased. Finally, MEM
      59 or its F(ab')2 fragments elicited a rise in intracellular free calcium and
      tyrosine phosphorylation of a 25-kDa protein in DC. The results thus indicate
      that CD43 cross-linking with specific ligands induces activation and functional
      maturation of DC.

PMID- 10352245
TI  - Phosphatidylinositol 3-kinase-dependent and -independent cytolytic effector
      functions.
AB  - Two distinct forms of short-term cytolysis have been described for CD8+ CTLs, the
      perforin/granzyme- and Fas ligand/Fas (CD95 ligand (CD95L)/CD95)-mediated
      pathways. However, the difference in signal transduction events leading to these
      cytolytic mechanisms remains unclear. We used wortmannin, an irreversible
      antagonist of phosphatidylinositol 3-kinase (PI3-K) activity, to investigate the
      role of PI3-K in influenza-specific CD8+ CTL cytolytic effector function. We
      found that the addition of wortmannin at concentrations as low as 1 nM
      significantly inhibited both the Ag/MHC-induced cytolysis of CD95- target cells
      and serine esterase release. In strong contrast, W did not inhibit the Ag/MHC
      induced CD95L expression or the CD95L/CD95-mediated cytolysis of CD95+ targets. A
      combination of wortmannin and blocking mAb against CD95L inhibited the cytolysis
      of CD95+ targets, indicating that the wortmannin-independent cytolysis was due to
      CD95L/CD95 mediated cytolysis. These findings suggest a differential role for PI3
      K in mediating cytolysis and, thus far, the earliest difference between
      perforin/granzyme- and CD95L/CD95-dependent cytolysis. Our data reinforce the
      idea of a TCR with modular signal transduction pathways that can be triggered or
      inhibited selectively, resulting in differential effector function.

PMID- 10352246
TI  - Antigen secreted from noncytosolic Listeria monocytogenes is processed by the
      classical MHC class I processing pathway.
AB  - Intracellular bacteria can reside in a vacuolar compartment, or they can escape
      the vacuole and become free living in the cytoplasm. The presentation of Ag by
      class I MHC molecules has been defined primarily for Ag present in the cytoplasm.
      It was therefore thought that Ags from bacteria that remain in a vacuole would
      not be presented by MHC class I molecules. Although some studies have provided
      data to support this idea, it is not necessarily true for all intracellular
      bacteria. For example, we have previously demonstrated that an epitope from the
      p60 protein secreted by LLO- Listeria monocytogenes, which does not reside in the
      cytoplasm, can be presented by MHC class I molecules to a T cell clone specific
      for the epitope, p60217-225. We have further examined the route by which Ag
      secreted by LLO- L. monocytogenes is presented by MHC class I molecules. Using
      pharmacological inhibitors, we demonstrate that MHC class I presentation of the
      p60 epitope derived from by LLO- L. monocytogenes requires phagolysosome fusion
      and processing by the proteasome. Lysosomal cathepsins, however, are not required
      for processing of the p60 epitope. Similarly, processing of the AttM epitope,
      secreted by LLO- L. monocytogenes and presented by H2-M3, also requires
      phagolysosome fusion and cleavage by the proteasome. Thus, p60 and AttM secreted
      by LLO- L. monocytogenes are processed via the classical class I pathway for
      presentation by MHC class I molecules.

PMID- 10352247
TI  - Selection and long-term persistence of reactive CTL clones during an EBV chronic
      response are determined by avidity, CD8 variable contribution compensating for
      differences in TCR affinities.
AB  - Recent studies have suggested that the diversity of TCR repertoire after primary
      immunization is conserved in memory T cells and that a progressive narrowing of
      this repertoire may take place during recall infections. It now remains to be
      investigated which parameters determine the repertoire of the memory response and
      possibly restrict its diversity after subsequent antigenic challenges. To address
      this question, we took advantage of a panel of CD8+ T cell clones from the joint
      of a rheumatoid arthritis patient and selected for their reactivity against a
      single MHC/peptide complex. Characterization of both TCR chains documented a
      great diversity among those clones and the persistence of clonotypes over a 2-yr
      period. Strikingly, despite the observed repertoire heterogeneity, all clones
      displayed a narrow range of MHC/peptide density requirements in cytotoxicity
      assays (ED50 between 9 and 36 nM). TCR affinities were then indirectly estimated
      by blocking CD8 interaction with an anti-CD8 mAb. We found a wide range of TCR
      affinities among the different clonotypes that segregated with Vbeta usage. We
      thus propose that during an in vivo chronic response, a narrow range of avidity
      of the TCR-CD8 complex conditions long-term clonotype persistence, and that the
      level of CD8 contribution is adjusted to keep clonotypes with variable TCR
      affinities within this avidity window.

PMID- 10352248
TI  - The Src-homology domain 2-bearing protein tyrosine phosphatase-1 inhibits antigen
      receptor-induced apoptosis of activated peripheral T cells.
AB  - Restimulation of Ag receptors on peripheral T lymphocytes induces tyrosine
      phosphorylation-based signaling cascades that evoke Fas ligand expression and
      induction of Fas-mediated programmed cell death. In view of the role for the Src
      homology domain 2-bearing protein tyrosine phosphatase-1 (SHP-1) in modulating
      TCR signaling, we investigated the influence of SHP-1 on TCR-mediated apoptosis
      by assaying the sensitivity of peripheral T cells from SHP-1-deficient viable
      motheaten (mev) mice to cell death following TCR restimulation. The results of
      these studies revealed mev peripheral T cells to be markedly more sensitive than
      wild-type cells to induction of cell death following TCR stimulation. By
      contrast, PMA/ionophore and anti-Fas Ab-induced apoptotic responses were no
      different in mev compared with wild-type activated cells. Enhanced apoptosis of
      TCR-restimulated mev lymphocytes was associated with marked increases in Fas
      ligand expression as compared with wild-type cells, but was almost abrogated in
      both mev and wild-type cells by Fas-Fc treatment. Thus, the increased sensitivity
      of mev T cells to apoptosis following TCR restimulation appears to reflect a TCR
      driven phenomenon mediated through up-regulation of Fas-Fas ligand interaction
      and induction of the Fas signaling cascade. These findings, together with the
      hyperproliferative responses of mev peripheral T cells to initial TCR
      stimulation, indicate that SHP-1 modulation of TCR signaling translates to the
      inhibition of both T cell proliferation and activation and, as such, is likely to
      play a pivotal role in regulating the expansion of Ag-stimulated T cells during
      an immune response.

PMID- 10352249
TI  - Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo
      alloresponses in murine recipients of MHC disparate T cells.
AB  - Blockade with B7 antagonists interferes with CD28:B7 and CTLA-4:B7 interactions,
      which may have opposing effects. We have examined the roles of CD28:B7 and CTLA
      4:B7 on in vivo alloresponses. A critical role of B7:CD28 was demonstrated by
      markedly compromised expansion of CD28-deficient T cells and diminished graft
      versus-host disease lethality of limited numbers of purified CD4+ or CD8+ T
      cells. When high numbers of T cells were infused, the requirement for CD28:B7
      interaction was lessened. In lethally irradiated recipients, anti-CTLA-4 mAb
      enhanced in vivo donor T cell expansion, but did not affect, on a per cell basis,
      anti-host proliferative or CTL responses of donor T cells. Graft-versus-host
      lethality was accelerated by anti-CTLA-4 mAb infusion given early post-bone
      marrow transplantation (BMT), mostly in a CD28-dependent fashion. Donor T cells
      obtained from anti-CTLA-4 mAb-treated recipients were skewed toward a Th2
      phenotype. Enhanced T cell expansion in mAb-treated recipients was strikingly
      advantageous in the graft-versus-leukemia effects of delayed donor lymphocyte
      infusion. In two different systems, anti-CTLA-4 mAb enhanced the rejection of
      allogeneic T cell-depleted marrow infused into sublethally irradiated recipients.
      We conclude that blockade of the selective CD28-B7 interactions early post-BMT,
      which preserve CTLA-4:B7 interactions, would be preferable to blocking both
      pathways. For later post-BMT, the selective blockade of CTLA-4:B7 interactions
      provides a potent and previously unidentified means for augmenting the GVL effect
      of delayed donor lymphocyte infusion.

PMID- 10352250
TI  - Maturation of dendritic cells accompanies high-efficiency gene transfer by a CD40
      targeted adenoviral vector.
AB  - Important therapeutic applications of genetically modified dendritic cells (DC)
      have been proposed; however, current vector systems have demonstrated only
      limited gene delivery efficacy to this cell type. By means of bispecific Abs, we
      have dramatically enhanced gene transfer to monocyte derived DC (MDDC) by
      retargeting adenoviral (Ad) vectors to a marker expressed on DC, CD40. Adenovirus
      targeted to CD40 demonstrated dramatic improvements in gene transfer relative to
      untargeted Ad vectors. Fundamental to the novelty of this system is the capacity
      of the vector itself to modulate the immunological status of the MDDC. This
      vector induces DC maturation as demonstrated phenotypically by increased
      expression of CD83, MHC, and costimulatory molecules, as well as functionally by
      production of IL-12 and an enhanced allostimulatory capacity in a MLR. In
      comparing this vector to other Ad-based gene transfer systems, we have
      illustrated that the features of DC maturation are not a function of the Ad
      particle, but rather a consequence of targeting to the CD40 marker. This vector
      approach may thus mediate not only high-efficiency gene delivery but also serve a
      proactive role in DC activation that could ultimately strengthen the utility of
      this vector for immunotherapy strategies.

PMID- 10352251
TI  - Cellular basis of B cell clonal populations in old mice.
AB  - Previous studies from this laboratory have shown that >85% of old mice have
      stable B cell clonal populations detectable by Ig heavy chain complementary
      determining region 3 mRNA size analysis and confirmed by sequence analysis. B
      cells from the same clone are frequently detected in several lymphoid
      compartments of the same mouse. We now report the phenotype of all ten stable B
      cell clonal populations detected in five 20-month-old C57BL/6 mice. These clonal
      B cells appear to develop in the periphery and nine of the ten B cell clonal
      populations expressed the CD5 cell surface marker. Stable B cell expansions may
      be dominated by cells at two stages of differentiation. Some B cell populations
      were detected with DNA as well as RNA and represent large clonal populations of B
      cells, detectable in several lymphoid compartments. These populations are found
      predominantly in B cell populations expressing CD45R/B220 and the mRNA coding for
      the membrane-bound form of the mu Ig heavy chain, which suggests a predominance
      of B lymphocytes in these populations. In other cases, smaller clonal populations
      were detected only in splenic RNA samples. These clonal populations were found
      predominantly among CD45R/B220- B cells and did not express the membrane-bound
      form of the micro Ig heavy chain. We offer the hypothesis that the B cell clonal
      populations present in old mice may be precursors of the two types of B cell
      neoplasms which are dominated by CD5+ B cells (B cell chronic lymphocytic
      leukemia) or plasma cells (multiple myeloma).

PMID- 10352252
TI  - Evidence for Fas-dependent and Fas-independent mechanisms in the pathogenesis of
      experimental autoimmune encephalomyelitis.
AB  - To determine whether Fas or Fas ligand (FasL) plays a role in susceptibility to
      experimental autoimmune encephalomyelitis (EAE), we bred a TCR transgenic mouse
      specific for the Ac1-11 peptide of myelin basic protein to mice with inactivating
      mutations in Fas (lpr) or FasL (gld). Disease induction by peptide immunization
      in such mice produced similar disease scores, demonstrating that Fas/FasL
      interactions were not necessary to generate EAE. However, adoptive transfer
      experiments showed evidence that these interactions can play a role in the
      pathogenesis of EAE, shown most dramatically by the absence of disease following
      transfer of cells from a normal myelin basic protein TCR transgenic mouse into a
      Fas-deficient lpr recipient. Furthermore, transfer of cells lacking FasL (gld)
      into normal or gld recipients gave a diminished disease score. Thus, Fas/FasL
      interactions can play a role in the pathogenesis of EAE, but they are not
      required for disease to occur.

PMID- 10352254
TI  - Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T cells.
AB  - NKT cells, defined as T cells expressing the NK cell marker NK1.1, are involved
      in tumor rejection and regulation of autoimmunity via the production of
      cytokines. We show in this study that two types of NKT cells can be defined on
      the basis of their reactivity to the monomorphic MHC class I-like molecule CD1d.
      One type of NKT cell is positively selected by CD1d and expresses a biased TCR
      repertoire together with a phenotype found on activated T cells. A second type of
      NKT cell, in contrast, develops in the absence of CD1d, and expresses a diverse
      TCR repertoire and a phenotype found on naive T cells and NK cells. Importantly,
      the two types of NKT cells segregate in distinct tissues. Whereas thymus and
      liver contain primarily CD1d-dependent NKT cells, spleen and bone marrow are
      enriched in CD1d-independent NKT cells. Collectively, our data suggest that
      recognition of tissue-specific ligands by the TCR controls localization and
      activation of NKT cells.

PMID- 10352253
TI  - Induction of T cell anergy by low numbers of agonist ligands.
AB  - Engagement of TCR by its ligand, the MHC/peptide complex, causes T cell
      activation. T cells respond positively to stimulation with agonists, and are
      inhibited by antagonist MHC/peptide ligands. Failure to induce proper
      conformational changes in the TCR or fast TCR/MHC dissociation are the leading
      models proposed to explain anergy induction by antagonist ligands. In this study,
      we demonstrate that presentation of between 1 and 10 complexes of agonist/MHC II
      by unfixed APC induces T cell anergy that persists up to 7 days and has
      characteristics similar to anergy induced by antagonist ligand or TCR occupancy
      without costimulation. Furthermore, anergy-inducing doses of hemagglutinin 306
      318 peptide led to the engagement of less than 1000 TCR/CD3 complexes. Thus,
      engagement of a subthreshold number of TCR by either a low density of agonist/MHC
      or a 2-3 orders of magnitude higher density of antagonist/MHC causes anergy.
      Moreover, we show that anergy induced by low agonist concentrations is inhibited
      in the presence of IL-2 or cyclosporin A, suggesting involvement of the
      calcineurin signaling pathway.

PMID- 10352255
TI  - Expression of multiple unique rejection antigens on murine leukemia BALB/c RLmale
      symbol1 and the role of dominant Akt antigen for tumor escape.
AB  - Using the pRL1a Ag-loss RLmale symbol1 tumor variant cell line RM2-1, we
      demonstrated the presence of tumor Ags other than pRL1a that were recognized by
      CTLs on RLmale symbol1 cells. Semiallogeneic CB6F1 or syngeneic BALB/c CTLs
      generated against RM2-1 lysed RM2-1 and RLmale symbol1 cells to a similar extent,
      but no killing was observed with any other tumor or normal cells examined. Clonal
      analysis and sensitization with reversed phase-HPLC fractions revealed that there
      were Dd- and Ld-binding peptides recognized by RM2-1 CTLs. Lysis by bulk CTLs
      stimulated against RLmale symbol1 and limiting dilution analysis suggested that
      the pRL1a peptide was dominantly recognized to the RM2-1 peptides by CTLs on
      RLmale symbol1 cells. The rejection response against the parental RLmale symbol1
      tumor was much less than that against RM2-1 cells in either CB6F1 or BALB/c mice,
      suggesting that the presence of altered Akt molecules from which the dominant
      pRL1a peptide was derived inhibited the rejection response against RLmale
      symbol1. Depletion of CD4 T cells caused the regression of RLmale symbol1 at the
      doses in which the tumor grew in untreated mice. The generation of pRL1a CTLs was
      inhibited in RLmale symbol1-bearing mice. Thus, immunoregulatory CD4 T cells were
      most likely activated by the altered Akt molecules and inhibited the efficient
      generation of CTLs against the dominant pRL1a Ag in RLmale symbol1.

PMID- 10352256
TI  - Calreticulin displays in vivo peptide-binding activity and can elicit CTL
      responses against bound peptides.
AB  - Calreticulin is an endoplasmic reticulum (ER) chaperone that displays lectin
      activity and contributes to the folding pathways for nascent glycoproteins.
      Calreticulin also participates in the reactions yielding assembly of peptides
      onto nascent MHC class I molecules. By chemical and immunological criteria, we
      identify calreticulin as a peptide-binding protein and provide data indicating
      that calreticulin can elicit CTL responses to components of its bound peptide
      pool. In an adoptive immunotherapy protocol, dendritic cells pulsed with
      calreticulin isolated from B16/F10.9 murine melanoma, E.G7-OVA, or EL4 thymoma
      tumors elicited a CTL response to as yet unknown tumor-derived Ags or the known
      OVA Ag. To evaluate the relative efficacy of calreticulin in eliciting CTL
      responses, the ER chaperones GRP94/gp96, BiP, ERp72, and protein disulfide
      isomerase were purified in parallel from B16/F10.9, EL4, and E.G7-OVA tumors, and
      the capacity of the proteins to elicit CTL responses was compared. In both the
      B16/F10.9 and E.G7-OVA models, calreticulin was as effective as or more effective
      than GRP94/gp96 in eliciting CTL responses. Little to no activity was observed
      for BiP, ERp72, and protein disulfide isomerase. The observed antigenic activity
      of calreticulin was recapitulated in in vitro experiments, in which it was
      observed that pulsing of bone marrow dendritic cells with E.G7-OVA-derived
      calreticulin elicited sensitivity to lysis by OVA-specific CD8+ T cells. These
      data identify calreticulin as a peptide-binding protein and indicate that
      calreticulin-bound peptides can be re-presented on dendritic cell class I
      molecules for recognition by CD8+ T cells.

PMID- 10352257
TI  - Effective stimulation for IL-12 p35 mRNA accumulation and bioactive IL-12
      production of antigen-presenting cells interacted with Th cells.
AB  - Bioactive IL-12 is composed of two subunits, p35 and p40. In the APC-Th cell
      interaction, p40 mRNA accumulation in APC was shown to be up-regulated by
      stimulation with CD40 ligand (CD40L) on Th cells. However, the CD40-CD40L
      interaction scarcely induced p35 mRNA accumulation in APC. In the present
      experiments, p35 mRNA accumulation was induced in splenic macrophages/dendritic
      cells by the interaction with paraformaldehyde-fixed Th1 cells in the presence of
      Ag, and the p35 mRNA accumulation was abrogated by the inclusion of anti-I-A in
      cultures to block TCR/MHC class II interaction. The accumulation was also induced
      by the stimulation with agonistic anti-I-A. These results indicate that the
      interaction of the MHC class II molecule with TCR evokes an activation signal for
      p35 mRNA accumulation in APC. Furthermore, the production of bioactive IL-12 in
      macrophages/dendritic cells stimulated with CD40L was enhanced by the inclusion
      of agonistic anti-I-A. The p35 mRNA accumulation and IL-12 production of
      macrophages/dendritic cells induced by stimulation with OVA-specific fixed Th1
      clone expressing CD40L were also enhanced by adding OVA in cultures. These
      results indicate that the p35 mRNA accumulation induced by MHC class II
      stimulation plays a role in bioactive IL-12 production.

PMID- 10352258
TI  - In vivo inhibition of NF-kappa B in T-lineage cells leads to a dramatic decrease
      in cell proliferation and cytokine production and to increased cell apoptosis in
      response to mitogenic stimuli, but not to abnormal thymopoiesis.
AB  - To understand the role of NF-kappa B complexes in T cell development and
      activation, we have generated transgenic mice in which RelA and c-Rel complexes
      were selectively inhibited in the T-lineage cells by specific expression of a
      trans-dominant form of I kappa B alpha. Transgene expression did not affect the
      thymic development, but led to lowered numbers of splenic T cells and to a
      dramatic decrease in the ex vivo proliferative response of splenic T lymphocytes.
      Analysis of IL-2 and IL-2R alpha expression demonstrated that the perturbation of
      the proliferation response was not attributable to an abnormal expression of
      these genes. In contrast, expression of IL-4, IL-10, and IFN-gamma was strongly
      inhibited in the transgenic T cells. The proliferative deficiency of the
      transgenic T cells was associated with an increased apoptosis. These results
      point out the involvement of NF-kappa B/Rel family proteins in growth signaling
      pathways by either regulating proteins involved in the IL-2 signaling or by
      functionally interfering with the cell cycle progression.

PMID- 10352259
TI  - Highly cross-reactive T cell responses to myelin basic protein epitopes reveal a
      nonpredictable form of TCR degeneracy.
AB  - We identified two nonoverlapping epitopes in myelin basic protein presented by I
      Au that are responsible for mediating tolerance induction to this self-Ag. A
      large number of T cells expressing diverse TCRs are strongly cross-reactive to
      both epitopes. Surprisingly, the TCR contact residues in each peptide are highly
      dissimilar. Furthermore, functional TCR contacts cannot be interchanged between
      the two epitopes, indicating that the TCR contacts in each peptide can only be
      recognized within the context of the other amino acids present in that peptide's
      sequence. This observation indicates that both buried and exposed residues of
      each peptide contribute to the sculpting of completely distinct antigenic
      surfaces. We propose that the cross-reactive TCRs adopt mutually exclusive
      conformations to recognize these dissimilar epitopes, adding a new dimension to
      TCR degeneracy. This unpredictable TCR plasticity indicates that using just the
      TCR contacts on a single epitope to define other cross-reactive peptides will
      identify only a subset of the complete repertoire of cross-reactive epitopes.

PMID- 10352260
TI  - The SH2-containing 5'-inositol phosphatase (SHIP) is tyrosine phosphorylated
      after Fc gamma receptor clustering in monocytes.
AB  - Current models of Fc gamma R signal transduction in monocytes describe a
      molecular cascade that begins upon clustering of Fc gamma R with the
      phosphorylation of critical tyrosine residues in the cytoplasmic domains of Fc
      gamma RIIa or the gamma-chain subunit of Fc gamma RI and Fc gamma RIIIa. The
      cascade engages several other tyrosine-phosphorylated molecules, either enzymes
      or adapters, to manifest ultimately an array of biological responses, including
      phagocytosis, cell killing, secretion of a variety of inflammatory mediators, and
      activation. Continuing to assess systematically the molecules participating in
      the cascade, we have found that the SH2-containing 5'-inositol phosphatase (SHIP)
      is phosphorylated on tyrosine early and transiently after Fc gamma R clustering.
      This molecule in other systems, such as B cells and mast cells, mediates an
      inhibitory signal. We find that clustering of either Fc gamma RIIa or Fc gamma RI
      is effective in inducing SHIP phosphorylation, that SHIP binds in vitro to a
      phosphorylated immunoreceptor tyrosine-based activation motif, peptide from the
      cytoplasmic domain of Fc gamma RIIa in activation-independent fashion, although
      SHIP binding increases upon cell activation, and that Fc gamma RIIb and Fc gamma
      RIIc are not responsible for the observed SHIP phosphorylation. These findings
      prompt us to propose that SHIP inhibits Fc gamma R-mediated signal transduction
      by engaging immunoreceptor tyrosine-based activation motif-containing cytoplasmic
      domains of Fc gamma RIIa and Fc gamma RI-associated gamma-chain.

PMID- 10352261
TI  - Generation of IL-2-dependent cytolytic T lymphocytes (CTLs) with altered TCR
      responses derived from antigen-dependent CTL clones.
AB  - Ag-specific CD8+ CTL clones require TCR stimulation to respond to IL-2 for
      growth. Because IL-2 may be produced in the vicinity of CD8+ CTLs when Ag is
      limiting at the end of an immune response, we have examined the effect of
      culturing viral-specific CTL clones in IL-2 in the absence of antigenic
      stimulation. Limiting dilution analysis revealed a high precursor frequency for
      CTL clones derived from IL-2 propagation (termed CTL-factor dependent (FD)) that
      are dependent upon exogenous IL-2 for growth and survival and no longer require
      TCR stimulation to proliferate. Culturing CTL-FDs with infected splenocytes
      presenting Ag and IL-2 did not revert the clones but did lead to a TCR-induced
      inhibition of proliferation. The derived CTL-FDs have lost the ability to kill
      via the perforin/granule exocytosis mechanism of killing, although they express
      similar levels of TCR, CD3epsilon, CD8alphabeta, CD45, and LFA-1 compared with
      the parental clones. The CTL-FDs retain Fas ligand/Fas-mediated cytotoxicity, and
      IFN-gamma production and regulate the expression of CD69 and IL-2Ralpha when
      triggered through the TCR. A parental CTL protected BALB/c mice from a lethal
      challenge of influenza virus, whereas a CTL-FD did not. These findings represent
      a novel regulatory function of IL-2 in vitro that, if functional in vivo, may
      serve to down-regulate cellular immune responses.

PMID- 10352262
TI  - Glucocorticoids affect human dendritic cell differentiation and maturation.
AB  - Because dendritic cells (DC) play a major role in the initiation of T cell
      mediated immunity, we studied the effects of glucocorticoids, well-known
      inhibitors of the immune and inflammatory response, on the differentiation and
      maturation of human DC. DC were differentiated from human monocytes by culture
      with GM-CSF and IL-4 for 7 days with and without dexamethasone (Dex). Cells
      treated with Dex (10-8 M) (Dex-DC) developed a characteristic dendritic
      morphology; however, membrane phenotype analysis demonstrated that they were not
      fully differentiated. Dex-DC expressed low levels of CD1a and, unlike untreated
      cells, high levels of CD14 and CD16. Molecules involved in Ag presentation (CD40,
      CD86, CD54) were also impaired. In contrast, molecules involved in Ag uptake
      (mannose receptor, CD32) and cell adhesion (CD11/CD18, CD54) were up-regulated.
      After exposure to TNF-alpha or CD40 ligand, Dex-DC expressed lower levels of CD83
      and CD86 than untreated cells. Dex-DC showed a higher endocytic activity, a lower
      APC function, and a lower capacity to secrete cytokines than untreated cells.
      Overall, these results indicate that DC differentiated in the presence of Dex are
      at a more immature stage. Moreover, Dex also partially blocked terminal
      maturation of already differentiated DC. In conclusion, our data suggest that
      glucocorticoids may act at the very first step of the immune response by
      modulating DC differentiation, maturation, and function.

PMID- 10352263
TI  - Altered expression level of a systemic nuclear autoantigen determines the fate of
      immune response to self.
AB  - One of the hallmarks of systemic autoimmune diseases is immune responses to
      systemic nuclear autoantigens. We have examined the fate of the immune response
      against a nuclear autoantigen using human U1 small nuclear ribonucleoprotein-A
      protein (HuA) transgenic (Tg) mice by adoptive transfer of autoreactive
      lymphocytes. We obtained two Tg lines that have different expression levels of
      the transgene. After spleen cells from HuA-immunized wild-type mice were
      transferred to Tg mice and their non-Tg littermates, these recipients were
      injected with HuA/IFA to induce a recall memory response. HAB69, which expressed
      a lower amount of HuA, exhibited a vigorous increase in the autoantibody level
      and glomerulonephritis. Moreover, the autoreactivity spread to 70K autoantigen.
      Alternatively, in HAB64, which expressed a higher amount of HuA, the production
      of autoantibody was markedly suppressed. The immune response to HuA autoantigen
      was impaired as demonstrated in a both delayed-type hypersensitivity response and
      proliferation assay. This inhibition was Ag-specific and was mediated by T cells.
      These data suggest that the expression level of systemic autoantigens influences
      the outcome of the immune response to self.

PMID- 10352264
TI  - Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T
      cell activation, differentiation, and cell death.
AB  - Polyclonal, generalized T cell defects, as well as Ag-specific Th clones, are
      likely to contribute to pathology in murine lupus, but the genetic bases for
      these mechanisms remain unknown. Mapping studies indicate that loci on
      chromosomes 1 (Sle1), 4 (Sle2), 7 (Sle3), and 17 (Sle4) confer disease
      susceptibility in the NZM2410 lupus strain. B6.NZMc7 mice are C57BL/6 (B6) mice
      congenic for the NZM2410-derived chromosome 7 susceptibility interval, bearing
      Sle3. Compared with B6 controls, B6.NZMc7 mice exhibit elevated CD4:CD8 ratios
      (2.0 vs 1.34 in 1- to 3-mo-old spleens); an age-dependent accumulation of
      activated CD4+ T cells (33.4% vs 21.9% in 9- to 12-mo-old spleens); a more
      diffuse splenic architecture; and a stronger immune response to T-dependent, but
      not T-independent, Ags. In vitro, Sle3-bearing T cells show stronger
      proliferation, increased expansion of CD4+ T cells, and reduced apoptosis (with
      or without anti-Fas) following stimulation with anti-CD3. With age, the B cells
      in this strain acquire an activated phenotype. Thus, the NZM2410 allele of Sle3
      appears to impact generalized T cell activation, and this may be causally related
      to the low grade, polyclonal serum autoantibodies seen in this strain. Epistatic
      interactions with other loci may be required to transform this relatively benign
      phenotype into overt autoimmunity, as seen in the NZM2410 strain.

PMID- 10352265
TI  - A critical role for antigen-specific Th1 cells in acute liver injury in mice.
AB  - A novel liver injury model was established in mice by targeting of OVA-containing
      liposomes into the liver, followed by adoptive transfer of OVA-specific Th1
      cells. Combined treatment of mice with OVA-containing liposomes and Th1 cell
      transfer caused an increase in serum transaminase activity that was paralleled
      with an elevation of serum IFN-gamma levels. In sharp contrast, OVA-specific Th2
      cell transfer resulted in an increase of serum IL-4 levels, but did not induce
      liver injury. Neither NK, NK T, nor CD8+ T cells were required for the Th1
      induced liver injury. The liver injury was blocked by anti-IFN-gamma mAb and anti
      TNF-alpha mAb, but not by anti-Fas ligand mAb. The Fas/Fas ligand independency
      was also demonstrated using Fas-deficient lpr mice. These findings indicate that
      Th1 cells are the major effector cells in acute liver injury.

PMID- 10352266
TI  - rC5a directs the in vitro migration of human memory and naive tonsillar B
      lymphocytes: implications for B cell trafficking in secondary lymphoid tissues.
AB  - Human C5a is a potent chemoattractant for granulocytes, monocytes, and dendritic
      cells. In mice C5a has been shown to be chemotactic for germinal center (GC) B
      cells. To date, no information is available on the effects of C5a on human B cell
      locomotion. Here we demonstrate that rC5a increases polarization and migration of
      human tonsillar B cells. The locomotory response was due to both chemokinetic and
      chemotactic activities of rC5a. Moreover, memory and, at a lesser extent, naive B
      cell fractions from purified tonsillar populations displayed rC5a-enhanced
      migratory properties, whereas GC cells did not. Flow cytometry revealed C5aR
      (CD88) on approximately 40% memory and 10% naive cells, respectively, whereas GC
      cells were negative. Immunohistochemistry showed that a few CD88+ cells were of
      the B cell lineage and localized in tonsillar subepithelial areas, where the
      majority of memory B cells settle. Pretreatment of memory B cells with the CD88
      mAb abolished their migratory responsiveness to rC5a. Finally, the C5 gene was
      found to be expressed in naive, GC, and memory B lymphocytes at both the mRNA and
      the protein level. This study delineates a novel role for C5a as a regulator of
      the trafficking of human memory and naive B lymphocytes and supports the
      hypothesis that the B cells themselves may serve as source of C5 in secondary
      lymphoid tissues.

PMID- 10352267
TI  - Ig alpha and Ig beta are required for efficient trafficking to late endosomes and
      to enhance antigen presentation.
AB  - The B cell Ag receptor (BCR) is a multimeric complex, containing Ig alpha and Ig
      beta, capable of internalizing and delivering specific Ags to specialized late
      endosomes, where they are processed into peptides for loading onto MHC class II
      molecules. By this mechanism, the presentation of receptor-selected epitopes to T
      cells is enhanced by several orders of magnitude. Previously, it has been
      reported that, under some circumstances, either Ig alpha or Ig beta can
      facilitate the presentation of Ags. However, we now demonstrate that if these Ags
      are at low concentrations and temporally restricted, both Ig alpha and Ig beta
      are required. When compared with the BCR, chimeric complexes containing either
      chain alone were internalized but failed to access the MHC class II-enriched
      compartment (MIIC) or induce the aggregation and fusion of its constituent
      vesicles. Furthermore, Ig alpha/Ig beta complexes in which the immunoreceptor
      tyrosine-based activation motif tyrosines of Ig alpha were mutated were also
      incapable of accessing the MIIC or of facilitating the presentation of Ag. These
      data indicate that both Ig alpha and Ig beta contribute signaling, and possibly
      other functions, to the BCR that are necessary and sufficient to reconstitute the
      trafficking and Ag-processing enhancing capacities of the intact receptor
      complex.

PMID- 10352268
TI  - Early arrest in B cell development in transgenic mice that express the E41K
      Bruton's tyrosine kinase mutant under the control of the CD19 promoter region.
AB  - Bruton's tyrosine kinase (Btk) is a nonreceptor protein kinase that is defective
      in X-linked agammaglobulinemia in humans and in X-linked immunodeficiency in
      mice. To study the effect of Btk activation in early B cell development in vivo,
      we have created transgenic mouse strains expressing Btk under the control of the
      human CD19 promoter region. The transgenic expression of wild-type human Btk
      corrected all X-linked immunodeficiency features in mice carrying a targeted
      disruption of the Btk gene. In contrast, expression of an activated form of Btk,
      the E41K mutant, resulted in an almost complete arrest of B cell development in
      the immature IgM+IgD- B cell stage in the bone marrow, irrespective of the
      presence of the endogenous intact Btk gene. Immature B cells were arrested at the
      progression from IgMlow into IgMhigh cells, which reflects the first immune
      tolerance checkpoint at which autoreactive B cells become susceptible to
      apoptosis. As the constitutive activation of Btk is likely to mimic B cell
      receptor occupancy by autoantigens in the bone marrow, our findings are
      consistent with a role for Btk as a mediator of B cell receptor-induced apoptotic
      signals in the immature B cell stage. Whereas the peripheral mature B cell pool
      was reduced to <1% of the normal size, significant numbers of IgM-secreting
      plasma cells were present in the spleen. Serum IgM levels were substantial and
      increased with age, but specific Ab responses in vivo were lacking. We conclude
      that the residual peripheral B cells were efficiently driven into IgM+ plasma
      cell differentiation, apparently without functional selection.

PMID- 10352269
TI  - Plasma membrane potential in thymocyte apoptosis.
AB  - Apoptosis is accompanied by major changes in ion compartmentalization and
      transmembrane potentials. Thymocyte apoptosis is characterized by an early
      dissipation of the mitochondrial transmembrane potential, with transient
      mitochondrial swelling and a subsequent loss of plasma membrane potential (DeltaP
      sip) related to the loss of cytosolic K+, cellular shrinkage, and DNA
      fragmentation. Thus, a gross perturbation of DeltaPsip occurs at the
      postmitochondrial stage of apoptosis. Unexpectedly, we found that blockade of
      plasma membrane K+ channels by tetrapentylammonium (TPA), which leads to a DeltaP
      sip collapse, can prevent the thymocyte apoptosis induced by exposure to the
      glucocorticoid receptor agonist dexamethasone, the topoisomerase inhibitor
      etoposide, gamma-irradiation, or ceramide. The TPA-mediated protective effect
      extends to all features of apoptosis, including dissipation of the mitochondrial
      transmembrane potential, loss of cytosolic K+, phosphatidylserine exposure on the
      cell surface, chromatin condensation, as well as caspase and endonuclease
      activation. In strict contrast, TPA is an ineffective inhibitor when cell death
      is induced by the potassium ionophore valinomycin, the specific mitochondrial
      benzodiazepine ligand PK11195, or by primary caspase activation by Fas/CD95 cross
      linking. These results underline the importance of K+ channels for the regulation
      of some but not all pathways leading to thymocyte apoptosis.

PMID- 10352271
TI  - Analysis of adjuvant function by direct visualization of antigen presentation in
      vivo: endotoxin promotes accumulation of antigen-bearing dendritic cells in the T
      cell areas of lymphoid tissue.
AB  - T cell activation requires exposure to processed Ag and signaling by cytokines
      and costimulatory ligands. Adjuvants are thought to enhance immunity primarily
      through up-regulation of the latter signals. Here, we explore the effect of the
      bacterial adjuvant, endotoxin, on Ag presentation by B cells and dendritic cells
      (DC). Using an mAb (C4H3) specific for the hen egg lysozyme (HEL) 46-61
      determinant bound to I-Ak, we analyze processed Ag expression and the tissue
      distribution of presenting cells following systemic administration of soluble HEL
      to mice. In both LPS-responsive and -hyporesponsive mice given endotoxin
      containing HEL, B cells rapidly display surface 46-61/I-Ak complexes. In marked
      contrast, in LPS-hyporesponsive mice, splenic DC show little gain in C4H3
      staining. In LPS-responsive animals, interdigitating DC in T cell areas show no
      staining above background at early times after HEL administration, but C4H3+ DC
      rapidly accumulate in the outer periarteriolar lymphoid sheaths (PALS) and in
      follicular areas. Within a few hours, C4H3+ DC appear in the T cell areas,
      concomitant with a decline in C4H3+ cells in the outer PALS, suggesting migration
      between these two sites. Endotoxin enhancement of C4H3 staining is seen for both
      CD8alpha- and CD8alpha+ DC subsets. These data suggest that a major effect of
      adjuvants is to promote mobilization of Ag-bearing DC to the T areas of lymphoid
      tissue, and possibly also to enhance Ag processing by these DC. Thus, microbial
      products promote T cell immunity not only through DC activation for cosignaling,
      but through improvement in signal 1 delivery.

PMID- 10352270
TI  - Potential role of CD4+ T cell-mediated apoptosis of activated astrocytes in
      Theiler's virus-induced demyelination.
AB  - Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into
      susceptible mouse strains results in a chronic, immune-mediated demyelinating
      disease similar to human multiple sclerosis. Here, we examined the role of
      astrocytes as an APC population in TMEV-induced demyelination and assessed the
      potential consequences of T cell activation following Ag presentation. IFN-gamma
      pretreated astrocytes were able to process and present all the predominant T cell
      epitopes of TMEV to virus-specific T cell hybridomas, clones, as well as bulk T
      cells. Despite low levels of proliferation of T cells due to prostaglandins
      produced by astrocytes, such Ag presentation by activated astrocytes induced the
      production of IFN-gamma, a representative proinflammatory cytokine, in TMEV
      specific Th cell clones derived from the CNS of virus-infected mice. Furthermore,
      these Th cell clones mediate lysis of the astrocytes in vitro in a Fas-dependent
      mechanism. TUNEL staining of CNS tissue demonstrates the presence of apoptotic
      GFAP+ cells in the white matter of TMEV-infected mice. These results strongly
      suggest that astrocytes could play an important role in the pathogenesis of TMEV
      induced demyelination by activating T cells, subsequently leading to T cell
      mediated apoptosis of astrocytes and thereby compromising the blood-brain
      barrier.

PMID- 10352272
TI  - Molecular cloning and characterization of a novel CD1 gene from the pig.
AB  - Much effort is underway to define the immunological functions of the CD1
      multigene family, which encodes a separate lineage of Ag presentation molecules
      capable of presenting lipid and glycolipid Ags. To identify porcine CD1
      homologues, a cosmid library was constructed and screened with a degenerate CD1
      alpha3 domain probe. One porcine CD1 gene (pCD1.1) was isolated and fully
      characterized. The pCD1.1 gene is organized similarly to MHC class I and other
      CD1 genes and contains an open reading frame of 1020 bp encoding 339 amino acids.
      Expression of pCD1.1 mRNA was observed in CD3- thymocytes, B lymphocytes, and
      tissue macrophages and dendritic cells. The pCD1.1 cDNA was transfected into
      Chinese hamster ovary cells, and subsequent FACS analysis demonstrated that mAb
      76-7-4, previously suggested to be a pig CD1 mAb, recognizes cell surface pCD1.1.
      Structurally, the pCD1.1 alpha1 and alpha2 domains are relatively dissimilar to
      those of other CD1 molecules, whereas the alpha3 domain is conserved. Overall,
      pCD1.1 bears the highest similarity with human CD1a, and the ectodomain sequences
      characteristically encode a hydrophobic Ag-binding pocket. Distinct from other
      CD1 molecules, pCD1.1 contains a putative serine phosphorylation motif similar to
      that found in human, pig, and mouse MHC class Ia molecules and to that found in
      rodent, but not human, MHC class-I related (MR1) cytoplasmic tail sequences.
      Thus, pCD1.1 encodes a molecule with a conventional CD1 ectodomain and an MHC
      class I-like cytoplasmic tail. The unique features of pCD1.1 provoke intriguing
      questions about the immunologic functions of CD1 and the evolution of Ag
      presentation gene families.

PMID- 10352273
TI  - Modulation of CD28 expression: distinct regulatory pathways during activation and
      replicative senescence.
AB  - The costimulatory molecule CD28 has a restricted tissue distribution and is
      expressed on T cells and some plasmacytoma cells. Although CD28 is constitutively
      expressed, its expression is transiently down-regulated following T cell
      activation and declines progressively with in vitro senescence. In vivo, CD8+ T
      cells and, less frequently, CD4+ T cells may completely lose CD28 surface
      expression during chronic infections and with aging. This correlates with changes
      of nuclear protein-binding activities to two motifs, site alpha and beta, within
      the CD28 minimal promoter. Both alpha- and beta-bound complexes are found only in
      lymphoid tissues, in CD28+ T cells, and in some transformed B cells. These
      complexes are coordinately expressed except during replicative senescence, which
      is characterized by the down-modulation of site beta- but not site alpha-binding
      activities. In contrast, T cell activation induces a parallel decline in both
      site alpha- and beta-binding activities. CD4+ and CD8+ T cells differ in their
      beta-binding profiles, which may explain the more pronounced down-regulation of
      CD28 in senescent CD8+ T cells. In vivo expanded CD4+CD28null and CD8+CD28null T
      cells uniformly lack alpha- and beta-bound complexes, resembling the pattern seen
      in chronically activated cells and not of senescent cells.

PMID- 10352274
TI  - Active sites in complement components C5 and C3 identified by proximity to indels
      in the C3/4/5 protein family.
AB  - We recently suggested that sites of length polymorphisms in protein families
      (indels) might serve as useful guides for locating protein:protein interaction
      sites. This report describes additional site-specific mutagenesis and synthetic
      peptide inhibition studies aimed at testing this idea for the paralogous
      complement C3, C4, and C5 proteins. A series of C5 mutants was constructed by
      altering the C5 sequence at each of the 27 indels in this protein family. Mutants
      were expressed in COS cells and were assayed for hemolytic activity and protease
      sensitivity. Mutants at five indels showed relatively normal expression but
      substantially reduced sp. act., indicating that the mutations damaged sites
      important for C5 function. Twenty-three synthetic peptides with C5 sequences and
      10 with C3 sequences were also tested for the ability to inhibit C hemolytic
      activity. Three of the C5 peptides and one of the C3 peptides showed 50%
      inhibition of both C hemolytic and bactericidal activities at a concentration of
      100 microM. In several cases both the mutational and peptide methods implicated
      the same indel site. Overall, the results suggest that regions important for
      function of both C3 and C5 lie proximal to residues 150-200 and 1600-1620 in the
      precursor sequences. Additional sites potentially important for C5 function are
      near residue 500 in the beta-chain and at two or three sites between the N
      terminus of the alpha'-chain and the C5d fragment. One of the latter sites, near
      residue 865, appears to be important for proteolytic activation of C5.

PMID- 10352276
TI  - Characteristics of sequences around individual nucleotide substitutions in IgVH
      genes suggest different GC and AT mutators.
AB  - Somatic hypermutation affects Ig genes during T-dependent B cell responses and is
      characterized by a high frequency of single base substitutions. Hypermutation is
      not a completely random process; a study of mutations in different systems has
      revealed the presence of sequence motifs that target mutation. In a recent
      analysis of the sequences surrounding individual mutated bases in out-of-frame
      human IgVH genes, we found that the target motifs around mutated G's and C's are
      reverse complements of each other. This finding suggests that hypermutation acts
      on both strands of DNA, which contradicts evidence of a strand-dependent
      mechanism as suggested by an observed bias in A and T mutations and the
      involvement of transcriptional machinery. We have now extended our database of
      out-of-frame genes and determined the sequence motifs flanking mutated A and T
      nucleotides. In addition, we have analyzed the flanking sequences for different
      types of nucleotide substitutions separately. Our results confirm the
      relationship between the motifs for G and C mutations and show that the motifs
      surrounding mutated A's and T's are weaker and do not have the same relationship.
      Taken together with our observation of A/T strand bias in out-of-frame genes,
      this observation suggests that there is a semitargeted G/C mutator that is strand
      independent and a separate A/T mutator that is strand-dependent and is less
      reliant on the local target sequence.

PMID- 10352275
TI  - Characterization of scFv-Ig constructs generated from the anti-CD20 mAb 1F5 using
      linker peptides of varying lengths.
AB  - The heavy (VH) and light (VL) chain variable regions of the murine anti-human
      CD20 mAb 1F5 were cloned, and four single-chain Ab (scFv) molecules were
      constructed using linker peptides of variable lengths to join the VH and VL
      domains. Three constructs were engineered using linker peptides of 15, 10, and 5
      aa residues consisting of (GGGGS)3, (GGGGS)2, and (GGGGS)1 sequences,
      respectively, whereas the fourth was prepared by joining the VH and VL domains
      directly. Each construct was fused to a derivative of human IgG1 (hinge plus CH2
      plus CH3) to facilitate purification using staphylococcal protein A. The
      aggregation and CD20 binding properties of these four 1F5 scFv-Ig derivatives
      produced were investigated. Both size-exclusion HPLC column analysis and Western
      blots of proteins subjected to nonreducing SDS-PAGE suggested that all four 1F5
      scFv-Ig were monomeric with m.w. of approximately 55 kDa. The CD20 binding
      properties of the four 1F5 scFv-Ig were studied by ELISA and flow cytometry. The
      1F5 scFv-Ig with the 5-aa linker (GS1) demonstrated significantly superior
      binding to CD20-expressing target cells, compared with the other scFv-Ig
      constructs. Scatchard analysis of the radiolabeled monovalent GS1 scFv-Ig
      revealed a binding avidity of 1.35 x 108 M-1 compared with an avidity of 7.56 x
      108 M-1 for the native bivalent 1F5 Ab. These findings suggest that the GS1 scFv
      Ig with a short linker peptide of approximately 5 aa is the best of the
      engineered constructs for future studies.

PMID- 10352277
TI  - Antigen-induced somatic diversification of rabbit IgH genes: gene conversion and
      point mutation.
AB  - During T cell-dependent immune responses in mouse and human, Ig genes diversify
      by somatic hypermutation within germinal centers. Rabbits, in addition to using
      somatic hypermutation to diversify their IgH genes, use a somatic gene conversion
      like mechanism, which involves homologous recombination between upstream VH gene
      segments and the rearranged VDJ genes. Somatic gene conversion and somatic
      hypermutation occur in young rabbit gut-associated lymphoid tissue and are
      thought to diversify a primary Ab repertoire that is otherwise limited by
      preferential VH gene segment utilization. Because somatic gene conversion is
      rarely found within Ig genes during immune responses in mouse and human, we
      investigated whether gene conversion in rabbit also occurs during specific immune
      responses, in a location other than gut-associated lymphoid tissue. We analyzed
      clonally related VDJ genes from popliteal lymph node B cells responding to
      primary, secondary, and tertiary immunization with the hapten FITC coupled to a
      protein carrier. Clonally related VDJ gene sequences were derived from FITC
      specific hybridomas, as well as from Ag-induced germinal centers of the popliteal
      lymph node. By analyzing the nature of mutations within these clonally related
      VDJ gene sequences, we found evidence not only of ongoing somatic hypermutation,
      but also of ongoing somatic gene conversion. Thus in rabbit, both somatic gene
      conversion and somatic hypermutation occur during the course of an immune
      response.

PMID- 10352278
TI  - ICAM-2 and a peptide from its binding domain are efficient activators of
      leukocyte adhesion and integrin affinity.
AB  - Cell adhesion mediated by the CD11/CD18 integrins and their ligands, the ICAMs,
      is required for many leukocyte functions. In resting cells the integrins are
      nonadhesive, but when activated they become adhesive for their ligands. Previous
      findings have shown that a peptide derived from the first Ig domain of ICAM-2
      (P1) binds to LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) and activates leukocyte
      aggregation. Because its mechanism of action has remained poorly understood, we
      have now studied the peptide-induced ligand binding in detail. Here we show that
      P1 was able to induce CD11/CD18-dependent adhesion of human T lymphocytes to
      immobilized, purified ICAM-1, -2, and -3. The optimal peptide concentration was
      150 micrograms/ml, whereas concentrations higher than 400 micrograms/ml did not
      have any stimulatory effect. The increase in adhesion was detectable within 10
      min of treatment with the peptide; it was dependent on energy, divalent cations,
      temperature, and an intact cytoskeleton but was unaffected by protein kinase C
      and protein tyrosine kinase inhibitors. Peptide treatment resulted in strong
      stimulation of the binding of soluble, recombinant ICAMs to T lymphocytes,
      showing that the integrin affinity toward its ligands was increased. Importantly,
      soluble ICAM-2Fc was also able to induce T lymphocyte adhesion to purified ICAM
      1, -2, and -3, and it was a more potent stimulatory molecule than ICAM-1Fc or
      ICAM-3Fc.

PMID- 10352279
TI  - CD28 costimulation augments IL-2 secretion of activated lamina propria T cells by
      increasing mRNA stability without enhancing IL-2 gene transactivation.
AB  - The pathways leading to activation in lamina propria (LP) T cells are different
      from peripheral T cells. LP T cells exhibit enhanced IL-2 secretion when
      activated through the CD2 pathway. Coligation of CD28 leads to synergistic
      enhancement of IL-2 secretion. Previous studies have characterized the CD28
      augmentation of TCR-mediated signaling in peripheral blood T cells through
      transcriptional activation of an IL-2 promoter CD28 response element (CD28RE),
      along with enhanced mRNA stability. This study characterized molecular events
      involved in CD28 costimulation of IL-2 production in LP mononuclear cells (LPMC).
      LPMC exhibited increased IL-2 production in response to CD28 costimulation,
      compared with cells activated through CD2 alone. IL-2 secretion was paralleled by
      increased expression of IL-2 mRNA, resulting from enhanced IL-2 mRNA stability.
      In contrast to transcriptional activation in PBMC, EMSA revealed that CD28
      coligation of CD2-activated LPMC does not result in increased binding of trans
      factors to the CD28RE, nor did Western blots detect changes in I-kappaBalpha or I
      kappaBbeta levels following CD28 coligation. Furthermore, CD28 coligation fails
      to enhance IL-2 promoter-reporter or RE/AP construct expression in CD2-activated
      LPMC. The results reported herein indicate that the molecular mechanisms involved
      in CD28 cosignaling and regulation of IL-2 secretion in LP T cells are unique to
      that compartment and differ from those seen in peripheral blood T cells. These
      observations suggest a biological significance for different mechanisms of IL-2
      activation in initiation and maintenance of the cytokine repertoire found in the
      mucosa.

PMID- 10352280
TI  - A peptide binding motif for I-Eg7, the MHC class II molecule that protects E
      alpha-transgenic nonobese diabetic mice from autoimmune diabetes.
AB  - The nonobese diabetic (NOD) mouse, a model of spontaneous insulin-dependent
      diabetes mellitus (IDDM), fails to express surface MHC class II I-Eg7 molecules
      due to a deletion in the E alpha gene promoter. E alpha-transgenic NOD mice
      express the E alpha E beta g7 dimer and fail to develop either insulitis or IDDM.
      A number of hypotheses have been proposed to explain the mechanisms of
      protection, most of which require peptide binding to I-Eg7. To define the
      requirements for peptide binding to I-Eg7, we first identified an I-Eg7
      restricted T cell epitope corresponding to the sequence 4-13 of Mycobacterium
      tuberculosis 65-kDa heat shock protein (hsp). Single amino acid substitutions at
      individual positions revealed a motif for peptide binding to I-Eg7 characterized
      by two primary anchors at relative position (p) 1 and 4, and two secondary
      anchors at p6 and p9. This motif is present in eight of nine hsp peptides that
      bind to I-Eg7 with high affinity. The I-Eg7 binding motif displays a unique p4
      anchor compared with the other known I-E motifs, and major differences are found
      between I-Eg7 and I-Ag7 binding motifs. Analysis of peptide binding to I-Eg7 and
      I-Ag7 molecules as well as proliferative responses of draining lymph node cells
      from hsp-primed NOD and E alpha-transgenic NOD mice to overlapping hsp peptides
      revealed that the two MHC molecules bind different peptides. Of 80 hsp peptides
      tested, none bind with high affinity to both MHC molecules, arguing against some
      of the mechanisms hypothesized to explain protection from IDDM in E alpha
      transgenic NOD mice.

PMID- 10352281
TI  - Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)
      deficient mice.
AB  - The mucosal lymphocyte integrin alpha E(CD103)beta 7 is thought to be important
      for intraepithelial lymphocyte (IEL) localization or function. We cloned the
      murine integrin gene encoding alpha E, localized it to chromosome 11, and
      generated integrin alpha E-deficient mice. In alpha E-/- mice, intestinal and
      vaginal IEL numbers were reduced, consistent with the known binding of alpha E
      beta 7 to E-cadherin expressed on epithelial cells. However, it was surprising
      that lamina propria T lymphocyte numbers were diminished, as E-cadherin is not
      expressed in the lamina propria. In contrast, peribronchial, intrapulmonary,
      Peyer's patch, and splenic T lymphocyte numbers were not reduced in alpha E
      deficient mice. Thus, alpha E beta 7 was important for generating or maintaining
      the gut and vaginal T lymphocytes located diffusely within the epithelium or
      lamina propria but not for generating the gut-associated organized lymphoid
      tissues. Finally, the impact of alpha E deficiency upon intestinal IEL numbers
      was greater at 3-4 wk of life than in younger animals, and affected the TCR alpha
      beta+ CD8+ T cells more than the gamma delta T cells or the TCR alpha beta+
      CD4+CD8- population. These findings suggest that alpha E beta 7 is involved in
      the expansion/recruitment of TCR alpha beta+ CD8+ IEL following microbial
      colonization. Integrin alpha E-deficient mice will provide an important tool for
      studying the role of alpha E beta 7 and of alpha E beta 7-expressing mucosal T
      lymphocytes in vivo.

PMID- 10352282
TI  - The tumorigenicity of IL-2 gene-transfected murine M-3D melanoma cells is
      determined by the magnitude and quality of the host defense reaction: NK cells
      play a major role.
AB  - Transfection of a variety of tumor lines with the IL-2 gene strongly reduces
      their tumorigenic potential when applied to either euthymic or athymic animals.
      To elucidate the mechanisms underlying this phenomenon, we inoculated IL-2
      transfected M-3D melanoma (M-3D-IL-2) cells into DBA/2 mice immunosuppressed by
      gamma-irradiation. Animals thus treated developed pigmented tumors, suggesting
      that IL-2 transfection of melanoma cells, instead of altering their neoplastic
      growth properties, renders them capable of evoking a tumoricidal host response.
      To define the critical effector cell, we injected M-3D-IL-2 and, for control
      purposes, nontransfected M-3D cells into DBA/2 recipients and analyzed the
      injection site. We found that 1) IL-2-expressing M-3D cells induce a much
      stronger inflammatory reaction than wild-type cells, 2) in both instances the
      infiltrate consists mainly of macrophages (40-60%) and granulocytes (30-40%), and
      3) only the infiltrate of M-3D-IL-2 cell deposits contains a minor fraction of NK
      cells (approximately 1-2%). When we reconstituted sublethally irradiated animals
      with various leukocyte subsets, we found that unfractionated as well as
      macrophage-depleted peritoneal lavage cells but not NK cell-depleted peritoneal
      lavage cells were able to suppress the growth of IL-2-expressing M-3D cells. In
      vivo leukocyte depletion experiments showed that the NK cell-depleting asialo-GM1
      antiserum, but not anti-macrophage and/or anti-granulocyte reagents, restored the
      tumorigenicity of M-3D-IL-2 cells. Our results indicate that the inflammatory
      tissue response evoked by IL-2-transfected cancer cells includes the attraction
      and/or activation of NK cells and that, in the experimental system used, these
      cells are critically needed for successfully controlling cancer growth in vivo.

PMID- 10352283
TI  - Perforin is a major contributor to NK cell control of tumor metastasis.
AB  - We provide the first demonstration, using experimental and spontaneous models of
      metastasis in C57BL/6 (B6) (RM-1 prostate carcinoma) and BALB/c (DA3 mammary
      carcinoma) mice, that tumor metastasis is primarily controlled by perforin
      dependent cytotoxicity mediated by NK1.1+ cells. MHC class Ilow RM-1 and DA3
      tumor cells were sensitive in vitro to Fas-mediated lysis or spleen NK cells in a
      perforin-dependent fashion. Perforin-deficient NK cells did not lyse these
      tumors, and perforin-deficient mice were 10-100-fold less proficient than wild
      type mice in rejecting the metastasis of tumor cells to the lung. Fas ligand
      mutant gld mice displayed uncompromised protection against tumor metastasis.
      Depletion of NK subsets resulted in greater numbers of metastases than observed
      in perforin-deficient mice, suggesting that perforin-independent effector
      functions of NK cells may also contribute to protection from tumor metastasis.

PMID- 10352284
TI  - Combination gene therapy with CD86 and the MHC class II transactivator in the
      control of lung tumor growth.
AB  - Early reports suggest that the costimulatory molecule CD86 (B7-2) has sporadic
      efficacy in tumor immunity, whereas changes in cancer immunity mediated by the
      MHC class II transactivator (CIITA) have not been extensively investigated. CIITA
      activates MHC class II expression in most cells; however, in the Line 1 lung
      carcinoma model system, CIITA activates MHC class I and well as class II. Here we
      show that CD86 is very effective in inducing a primary immune response against
      Line 1. Tumor cells expressing CD86 grew in only 50% of the mice injected with
      live cells, and those mice that developed tumors did so with significantly
      delayed kinetics. Furthermore, irradiated CD86-expressing Line 1 cells served as
      an effective tumor vaccine, demonstrating that CD86 is effective in inducing
      tumor immunity in the Line 1 system. These data suggest that if CIITA and CD86
      cooperate, enhanced tumor immunity could be achieved. CIITA alone was mildly
      beneficial in slowing primary tumor growth but only when expressed at low levels.
      Clones expressing high levels of class II MHC grew as fast as or faster than
      parental tumor, and CIITA expression in a tumor vaccine assay lacked efficacy.
      When CIITA and CD86 were coexpressed, there was no cooperative immune protection
      from tumor growth. Cells that coexpress both genes also failed as a cancer
      vaccine, suggesting a negative role for CIITA in this lung carcinoma. These data
      suggest that human cancer vaccine trials utilizing CIITA gene therapy alone or in
      combination with CD86 should be approached with caution.

PMID- 10352285
TI  - Therapeutic effects of tumor-reactive type 1 and type 2 CD8+ T cell
      subpopulations in established pulmonary metastases.
AB  - Cytolytic CD8+ T cells fall into two subpopulations based on cytokine-secretion.
      Type 1 CD8+ cells (Tc1) characteristically secrete IFN-gamma, whereas type 2 CD8+
      cells (Tc2) secrete IL-4 and IL-5. We assessed the relative therapeutic effects
      of adoptively transferred OVA-specific Tc1 and Tc2 CD8+ cells in mice bearing
      established OVA-transfected B16 melanoma lung metastases. Both Tc1 and Tc2
      subpopulations mediated a reduction in lung tumor growth that subsequently
      prolonged survival times in mice with both early (day 7) and more advanced (day
      14) levels of tumor development. CD8+ T cell populations recovered from spleens
      of tumor-bearing mice receiving Tc1 or Tc2 cells showed markedly enhanced tumor
      Ag-specific cytolytic and cytokine-releasing activities that correlated with
      delays in tumor cell growth and progression. Initially, both tumor-reactive Tc1
      and Tc2 effector cells accumulated at the tumor site with nearly equal frequency.
      Tc1 cells persisted, whereas Tc2 cell numbers progressively diminished over time.
      Titration of Tc1 and Tc2 effector cells showed that protection was dose dependent
      with the former being 5-fold more effective. Tc2 cells achieved a comparable
      reduction in lung tumor cell growth at higher concentrations of cell transfer.
      Tc1 effectors from IFN-gamma-deficient mice were less therapeutically effective
      than wild-type mice, but there was no significant reduction in activity between
      corresponding Tc2 populations. We speculate that the effectiveness of Tc1 and Tc2
      cells may depend on different mechanisms. These studies suggest a potential role
      for Tc1 and Tc2 CD8+ subpopulations in tumor regression and immunotherapy.

PMID- 10352286
TI  - Presence of effector CD8+ T cells in hepatitis C virus-exposed healthy
      seronegative donors.
AB  - CTL responses against multiple hepatitis C virus (HCV) epitopes were detected in
      7 of 29 (24.1%) healthy family members (HFM) persistently exposed to chronically
      HCV-infected patients (HCV-HFM). These precursor CTL were at very low or
      undetectable frequencies, as determined by limiting dilution analysis. However,
      when HCV-specific effector CD8+ T cells, freshly isolated from PBMC of HCV-HFM,
      were assessed by a sensitive enzyme-linked immunospot assay, their frequencies
      were severalfold higher than those of precursor CTL. These results indicate that
      the two assays detect two functionally distinct T cell populations and that the
      effector cells are not assayed by the 51Cr-release assay. Furthermore, the
      combination of cell depletion and enzyme-linked immunospot analyses showed that
      the effector cells were confined into a CD8+ CD45RO+ CD28- population. The
      persistence of effector CD8+ T cells specific for both the structural and
      nonstructural viral proteins in uninfected HCV-HFM, suggest that: 1) an
      immunological memory is established upon a subclinical infection without any
      evidence of hepatitis, in a large cohort of HCV-exposed individuals; 2) because
      these cells required neither restimulation nor the addition of particular
      cytokines in vitro for differentiating in effectors, they should be capable of
      prompt HCV-specific effector function in vivo, possibly providing antiviral
      protection; and 3) the maintenance of effector T cell responses may be sustained
      by persisting low-level stimulation induced by inapparent infections.

PMID- 10352287
TI  - CD40-CD40 ligand interaction is central to cell-mediated immunity against
      Toxoplasma gondii: patients with hyper IgM syndrome have a defective type 1
      immune response that can be restored by soluble CD40 ligand trimer.
AB  - Cell-mediated immunity that results in IL-12/IFN-gamma production is essential to
      control infections by intracellular organisms. Studies in animal models revealed
      contrasting results in regard to the importance of CD40-CD40 ligand (CD40L)
      signaling for induction of a type 1 cytokine response against these pathogens. We
      demonstrate that CD40-CD40L interaction in humans is critical for generation of
      the IL-12/IFN-gamma immune response against Toxoplasma gondii. Infection of
      monocytes with T. gondii resulted in up-regulation of CD40. CD40-CD40L signaling
      was required for optimal T cell production of IFN-gamma in response to T. gondii.
      Moreover, patients with hyper IgM (HIGM) syndrome exhibited a defect in IFN-gamma
      secretion in response to the parasite and evidence compatible with impaired in
      vivo T cell priming after T. gondii infection. Not only was IL-12 production in
      response to T. gondii dependent on CD40-CD40L signaling, but also, patients with
      HIGM syndrome exhibited deficient in vitro secretion of this cytokine in response
      to the parasite. Finally, in vitro incubation with agonistic soluble CD40L trimer
      enhanced T. gondii-triggered production of IFN-gamma and, through induction of IL
      12 secretion, corrected the defect in IFN-gamma production observed in HIGM
      patients. Our results are likely to explain the susceptibility of patients with
      HIGM syndrome to infections by opportunistic pathogens.

PMID- 10352288
TI  - Murine cytomegalovirus infection down-regulates MHC class II expression on
      macrophages by induction of IL-10.
AB  - Herpesviruses utilize many strategies for weakening the host immune response. For
      CMV, this includes avoidance of NK clearance and inhibition of MHC class I and
      class II presentation pathways. In this study, we report that mouse CMV (MCMV)
      specifically causes a premature and transient activation of host IL-10 very early
      in the course of infection, resulting in a dramatic and selective reduction in
      MHC class II surface expression. The expression of IL-10 is normally late in the
      immune response to a pathogen, serving to dampen the response by suppression of
      the production of inflammatory cytokines. In infection of macrophages, we show
      that MCMV induces the production of IL-10, leading to an early and selective
      reduction in the expression of MHC class II on the surface of the cells.
      Inhibition of MHC class II expression was not observed in the presence of
      neutralizing Abs to IL-10 or in macrophages from IL-10-deficient mice. Moreover,
      MCMV-infected IL-10-deficient mice developed an early and significantly more
      robust macrophage MHC class II induction than normal mice. Altogether, our
      results demonstrate that viral induction of an IL-10 autocrine pathway plays an
      essential early role in selectively reducing MHC class II expression on the
      surface of APC prior to stimulation by IFN-gamma.

PMID- 10352289
TI  - Expression and contribution of B7-1 (CD80) and B7-2 (CD86) in the early immune
      response to Leishmania major infection.
AB  - CD28 interactions promote T cell responses, and whether B7-1 or B7-2 is utilized
      may influence Th cell subset development. CD28 blockade by CTLA-4Ig treatment or
      by targeted gene disruption has yielded different conclusions regarding the role
      of CD28 in the development of Th1 and Th2 cells following Leishmania major
      infection. In this study, we demonstrate that B7-mediated costimulation is
      required for the development of the early immune response following infection of
      resistant or susceptible mice. In contrast, CD28-/- BALB/c mice infected with L.
      major produce cytokines comparable to those of infected wild-type mice. Treatment
      of CD28-/- mice with CTLA-4Ig did not diminish this response, suggesting that a
      B7-independent pathway(s) contributes to the early immune response in these mice.
      In conventional BALB/c or C3H mice, B7-2 functions as the dominant costimulatory
      molecule in the initiation of early T cell activation following L. major
      infection, leading to IL-4 or IFN-gamma production, respectively. The
      preferential interaction of B7-2 with its ligand(s) in the induction of these
      responses correlates with its constitutive expression relative to that of B7-1.
      However, B7-1 can equally mediate costimulation for the production of either IL-4
      or IFN-gamma when expressed at high levels. Thus, in leishmaniasis, costimulation
      involving B7-1 or B7-2 can result in the production of either Th1 or Th2
      cytokines, rather than a preferential induction of one type of response.

PMID- 10352290
TI  - Induction of genital immunity by DNA priming and intranasal booster immunization
      with a replication-defective adenoviral recombinant.
AB  - Mice immunized through different routes such as i.m., intradermally, or
      intratracheally with a DNA vaccine to rabies virus developed high titers of serum
      Ab but only borderline levels of mucosal Abs determined from vaginal secretions.
      DNA vaccines given by either route enhanced vaginal IgA and IgG2a secretion upon
      a subsequent intranasal booster immunization with an E1-deleted adenoviral
      recombinant expressing the same Ag of rabies virus. DNA vaccine priming reduced
      the Ab response to the adenoviral Ags and counterbalanced the impaired B cell
      response to the rabies virus Ag expressed by the adenoviral recombinant in mice
      preimmune to adenovirus. The vaginal B cell response could further be enhanced by
      using the Th2-type cytokines IL-4 or IL-5 as genetic adjuvants concomitantly with
      the DNA vaccine before intranasal booster immunization with the recombinant
      vaccine.

PMID- 10352291
TI  - IL-12 delivery from recombinant vaccinia virus attenuates the vector and enhances
      the cellular immune response against HIV-1 Env in a dose-dependent manner.
AB  - To develop vaccination strategies against HIV-1 infection aimed to specifically
      enhance the cell-mediated immunity (CMI), we have engineered vaccinia virus (VV)
      recombinants expressing HIV-1 Env (rVVenv) and murine IL-12 (rVVlucIL-12) genes
      or coexpressing both genes (rVVenvIL-12). In mice inoculated with rVVlucIL-12
      there is a rapid clearance of the virus, and this correlates with the induction
      of high levels of IL-12 and IFN-gamma in serum and spleen early after infection.
      Enzyme-linked immunospot analysis of mice inoculated with rVVlucIL-12, revealed a
      nearly 2-fold increase in the number of specific anti-VV CD8+ T cells compared
      with that in mice given control rVV, and the serum Ab response was biased in
      favor of a Th1 response. An enhancement of about 2-fold in the number of anti
      gp160 IFN-gamma-secreting CD8+ T cells was observed in mice inoculated with
      rVVenvIL-12, when a dose of 1 x 107 PFU/mouse was used, but this enhancement was
      not observed when mice were given 5 x 107 PFU. This variation with virus dosage
      was confirmed in mice immunized simultaneously with different multiplicities of
      rVV expressing singly the env or IL-12 genes. The highest specific CMI was
      obtained in mice coadministered a low dose (2 x 104 PFU) of rVVlucIL-12 and 1 x
      107 PFU of rVVenv. Our findings provide evidence for specific enhancement of the
      CMI to HIV-1 Env by the differential expression of IL-12 and env genes delivered
      from VV recombinants. This approach can be of wide vaccination interest as a
      means to improve immune responses to other Ags.

PMID- 10352292
TI  - Improved clearance of Mycobacterium avium upon disruption of the inducible nitric
      oxide synthase gene.
AB  - Mice genetically deficient in the inducible NO synthase gene (iNOS-/-) were used
      to study the role played by NO during infection by Mycobacterium avium. iNOS-/-
      macrophages were equally able to restrict M. avium growth in vitro following
      stimulation by IFN-gamma and TNF-alpha as macrophages from wild-type mice. In
      vivo, the infection progressed at similar rates in wild-type and NO-deficient
      mice during the first 2 mo of infection, but the latter mice were subsequently
      more efficient in clearing the mycobacteria than the former. The increased
      resistance of iNOS-/- mice was associated with higher IFN-gamma levels in the
      serum and following in vitro restimulation of spleen cells with specific Ag,
      increased formation of granulomas and increased survival of CD4+ T cells. We show
      that NO is not involved in the antimycobacterial mechanisms of M. avium-infected
      macrophages and, furthermore, that it exacerbates the infection by causing the
      suppression of the immune response to the pathogen.

PMID- 10352293
TI  - Mycobacterium tuberculosis CDC1551 induces a more vigorous host response in vivo
      and in vitro, but is not more virulent than other clinical isolates.
AB  - Mycobacterium tuberculosis CDC1551, a clinical isolate reported to be
      hypervirulent and to grow faster than other isolates, was compared with two other
      clinical isolates (HN60 and HN878) and two laboratory strains (H37Rv and Erdman).
      The initial (1-14 days) growth of CDC1551, HN60, HN878, and H37Rv was similar in
      the lungs of aerosol-infected mice, but growth of Erdman was slower. Thereafter,
      the growth rate of CDC1551 decreased relative to the other strains which
      continued to grow at comparable rates up to day 21. In the lungs of CDC1551
      infected mice, small well-organized granulomas with high levels of TNF-alpha, IL
      6, IL-10, IL-12, and IFN-gamma mRNA were apparent sooner than in lungs of mice
      infected with the other strains. CDC1551-infected mice survived significantly
      longer. These findings were confirmed in vitro. The growth rates of H37Rv and
      CDC1551 in human monocytes were the same, but higher levels of TNF-alpha, IL-10,
      IL-6, and IL-12 were induced in monocytes after infection with CDC1551 or by
      exposure of monocytes to lipid fractions from CDC1551. CD14 expression on the
      surface of the monocytes was up-regulated to a greater extent by exposure to the
      lipids of CDC1551. Thus, CDC1551 is not more virulent than other M. tuberculosis
      isolates in terms of growth in vivo and in vitro, but it induces a more rapid and
      robust host response.

PMID- 10352294
TI  - Mice lacking NK cells develop an efficient Th1 response and control cutaneous
      Leishmania major infection.
AB  - NK cells are believed to play a critical role in the development of immunity
      against Leishmania major. We recently found that transplantation of wild-type
      bone marrow cells into neonatal tgepsilon 26 mice, which are deficient in T and
      NK cells, resulted in normal T cell development, but no or poor NK cell
      development. Using this novel model we analyzed the role of NK cells in the
      development of Th1 response and control of cutaneous L. major infection. Mice
      selectively lacking NK cells (NK-T+) developed an efficient Th1-like response,
      produced significant amounts of IL-12 and IFN-gamma, and controlled cutaneous L.
      major infection. Administration of neutralizing IL-12 Abs to NK-T+ mice during L.
      major infection resulted in exacerbation of the disease. These results
      demonstrate that NK cells are not critical for development of protective immunity
      against L. major. Furthermore, they indicate that IL-12 can induce development of
      Th1 response independent of NK cells in NK-T+ mice following L.major infection.

PMID- 10352295
TI  - Mice lacking two or all three selectins demonstrate overlapping and distinct
      functions for each selectin.
AB  - Selectins support the capture and rolling of leukocytes in venules at sites of
      inflammation and in lymphocyte homing. Gene-targeted mice with null mutations at
      the L-, E-, or P-selectin locus develop normally and show mild (E-/-) to moderate
      (P-/-, L-/-) defects in inflammatory cell recruitment. Mice lacking both P- and E
      selectin (E/P-/-) have severe neutrophilia and spontaneous skin infections that
      limit their life span. Other combinations of selectin deficiency have not been
      investigated. We have generated novel mice lacking L- and P-selectin (L/P-/-), L-
      and E-selectin (L/E-/-), or all three selectins (E/L/P-/-) by bone marrow
      transplantation. L/P-/- mice (only E-selectin present) show an absence of
      leukocyte rolling after trauma and severely reduced rolling (by approximately
      90%) in inflammation induced by TNF-alpha. Residual rolling in L/P-/- mice was
      very slow (3.6 +/- 0.2 micrometers/s after TNF-alpha). L/E-/- mice (only P
      selectin present) showed rolling similar to that of L-/- at increased velocities
      (15.1 +/- 0.3 micrometer/s). The number of adherent leukocytes after 2 or 6 h of
      TNF-alpha treatment was not significantly reduced in L/E-/- or L/P-/- mice. E/L/P
      /- mice showed very little rolling after TNF-alpha, all of which was blocked by
      mAb to alpha4 integrin. Adherent and emigrated neutrophils were significantly
      reduced at 6 h after TNF-alpha. We conclude that any one of the selectins can
      support some neutrophil recruitment but eliminating all three selectins
      significantly impairs neutrophil recruitment.

PMID- 10352296
TI  - C5a suppresses the production of IL-12 by IFN-gamma-primed and lipopolysaccharide
      challenged human monocytes.
AB  - IL-12 is a key mediator of the immune response, skewing T lymphocytes toward a
      type 1 cytokine pattern. Priming with IFN-gamma or GM-CSF is required for
      expression of IL-12p70 by cells in which IL-12 is inducible by bacterial products
      such as LPS. We here show for the first time that the production of bioactive IL
      12 by human monocytes can be significantly suppressed by C5a if applied to IFN
      gamma-primed monocytes before LPS stimulation. There was a dose-dependent
      suppression by IL-12 (p70) on the levels of intracellular cytokine production and
      cytokine secretion. mRNA studies consistently showed a reduction of IL-12p40 and
      IL-12p35 expression by stimulation in the presence of C5a. The results of several
      different experimental approaches suggest that IL-12 down-regulation was not due
      to endogenous IL-10, IL-4, or PGE2 production induced by C5a. Moreover,
      stimulation of IFN-gamma-primed monocytes with C5a did not lead to a down
      regulation of the CD14 Ag, which is an LPS receptor. These findings show that the
      anaphylatoxin C5a has the capacity to directly interact with the complex
      regulation of IL-12.

PMID- 10352297
TI  - Differential regulation of the IL-12 p40 promoter and of p40 secretion by CpG DNA
      and lipopolysaccharide.
AB  - Challenge of macrophages with DNA containing an internal CpG motif results in IL
      12 p40 secretion. In the presence of IFN-gamma, CpG DNA induces more p40
      secretion than does LPS. In the RAW 264 macrophage cell line, both CpG DNA and
      LPS activate a p40 promoter-reporter construct, and the promoter response to
      either agent is augmented 2- to 5-fold by IFN-gamma. While either LPS or CpG DNA
      induces p40 promoter activity, only CpG DNA induces an increase in p40 mRNA or
      protein secretion. Even though IFN-gamma augmented LPS-driven p40 promoter
      activity in RAW 264 cells, the combination of IFN-gamma and LPS induced less p40
      mRNA or protein secretion than the combination of IFN-gamma and CpG DNA. The
      ability of IFN-gamma to augment LPS or CpG DNA-induced p40 promoter activation
      was observed with truncation mutants of the IL-12 promoter containing as few as
      250 bp 5' of the TATA box. Although LPS alone is a poor inducer of p40
      transcription, both LPS and CpG DNA induce similar nuclear translocation of NF
      kappaB. This binding is not augmented by costimulation with IFN-gamma. Thus, CpG
      DNA induces p40 transcription by a mechanism that includes NF-kappaB
      translocation; however, CpG DNA appears to induce other factor(s) necessary for
      p40 transcription. These results illustrate fundamental differences between CpG
      DNA and LPS with respect to activation of IL-12 p40 secretion.

PMID- 10352298
TI  - Negative regulation by protein tyrosine phosphatase of IFN-gamma-dependent
      expression of inducible nitric oxide synthase.
AB  - Treatment of cultured peritoneal macrophages with IFN-gamma resulted in tyrosine
      phosphorylation of IkappaBalpha and IkappaBbeta, NF-kappaB activation, and
      expression of inducible NO synthase (iNOS). Since tyrosine phosphorylation of
      IkappaBalpha is sufficient to activate NF-kappaB in Jurkat cells, macrophages
      were treated with the protein tyrosine phosphatase inhibitor peroxovanadate
      (POV), which elicited an intense tyrosine phosphorylation of both IkappaB.
      However, this phosphorylation failed to activate NF-kappaB. Treatment with POV of
      macrophages stimulated with IFN-gamma or LPS potentiated the degradation of
      IkappaBalpha and IkappaBbeta, the activation of NF-kappaB, and the expression of
      iNOS. Analysis of the iNOS gene promoter activity corresponding to the 5'
      flanking region indicated that POV potentiates the cooperation between IFN-gamma
      activated transcription factors and NF-kappaB. These results indicate that
      tyrosine phosphorylation of IkappaB is not sufficient to activate NF-kappaB in
      macrophages and propose a negative role for protein tyrosine phosphatase in the
      expression of iNOS in response to IFN-gamma.

PMID- 10352299
TI  - Lysosomal accumulation and recycling of lipopolysaccharide to the cell surface of
      murine macrophages, an in vitro and in vivo study.
AB  - In this study, we detailed in a time-dependent manner the trafficking, the
      recycling, and the structural fate of Brucella abortus LPS in murine peritoneal
      macrophages by immunofluorescence, ELISA, and biochemical analyses. The
      intracellular pathway of B. abortus LPS, a nonclassical endotoxin, was
      investigated both in vivo after LPS injection in the peritoneal cavity of mice
      and in vitro after LPS incubation with macrophages. We also followed LPS
      trafficking after infection of macrophages with B. abortus strain 19. After
      binding to the cell surface and internalization, Brucella LPS is routed from
      early endosomes to lysosomes with unusual slow kinetics. It accumulates there for
      at least 24 h. Later, LPS leaves lysosomes and reaches the macrophage cell
      surface. This recycling pathway is also observed for LPS released by Brucella S19
      following in vitro infection. Indeed, by 72 h postinfection, bacteria are
      degraded by macrophages and LPS is located inside lysosomes dispersed at the cell
      periphery. From 72 h onward, LPS is gradually detected at the plasma membrane. In
      each case, the LPS present at the cell surface is found in large clusters with
      the O-chain facing the extracellular medium. Both the antigenicity and
      heterogenicity of the O-chain moiety are preserved during the intracellular
      trafficking. We demonstrate that LPS is not cleared by macrophages either in
      vitro or in vivo after 3 mo, exposing its immunogenic moiety toward the
      extracellular medium.

PMID- 10352300
TI  - Promotion of neutrophil chemotaxis through differential regulation of beta 1 and
      beta 2 integrins.
AB  - Migration of neutrophils requires sequential adhesive and deadhesive interactions
      between beta 1 and beta 2 integrins and components of the extracellular matrix.
      Prompted by reports that describe interaction of soluble beta-glucan with the
      beta 2 integrin Mac-1, a role for beta-glucan in regulation of integrin-mediated
      migration was investigated. Neutrophil migration in response to fMLP was assessed
      using an agarose overlay method with slides precoated with fibronectin (Fn) +/-
      beta-glucan. On Fn, random migration in excess of directed migration was
      observed. In contrast, migration on Fn + beta-glucan was directional, with marked
      diminution of random migration. This conversion of random to directed migration
      was seen neither when Fn was supplemented with alternative polysaccharides nor
      when beta-glucan was applied to other components of the extracellular matrix.
      This effect of beta-glucan was shown to be cation dependent and to be effected by
      Arg-Gly-Asp-containing peptides consistent with an integrin-mediated event. mAb
      inhibition studies demonstrate that beta-glucan effects this shift toward
      directed migration through suppression of migration mediated by Mac-1 and very
      late Ag 5 and enhancement of very late Ag 3-mediated migration. Adhesion assays
      suggest that the prochemotactic influence of beta-glucan is due, in part but not
      entirely, to modulation of PMN adhesion to Fn. In summary, these data support a
      novel role for beta-glucan in regulation of beta 1- and beta 2-mediated
      neutrophil migration on Fn.

PMID- 10352301
TI  - Macrophage recognition of ICAM-3 on apoptotic leukocytes.
AB  - Cells undergoing apoptosis are cleared rapidly by phagocytes, thus preventing
      tissue damage caused by loss of plasma membrane integrity. In this study, we show
      that the surface of leukocytes is altered during apoptosis such that the first Ig
      like domain of ICAM-3 (CD50) can participate in the recognition and phagocytosis
      of the apoptotic cells by macrophages. Macrophage recognition of apoptotic cell
      associated ICAM-3 was demonstrated both on leukocytes and, following transfection
      of exogenous ICAM-3, on nonleukocytes. The change in ICAM-3 was a consistent
      consequence of apoptosis triggered by various stimuli, suggesting that it occurs
      as part of a final common pathway of apoptosis. Alteration of ICAM-3 on apoptotic
      cells permitting recognition by macrophages resulted in a switch in ICAM-3
      binding preference from the prototypic ICAM-3 counterreceptor, LFA-1, to an
      alternative macrophage receptor. Using mAbs to block macrophage/apoptotic cell
      interactions, we were unable to obtain evidence that either the alternative ICAM
      3 counterreceptor alpha d beta 2 or the apoptotic cell receptor alpha v beta 3
      was involved in the recognition of ICAM-3. By contrast, mAb blockade of
      macrophage CD14 inhibited ICAM-3-dependent recognition of apoptotic cells. These
      results show that ICAM-3 can function as a phagocytic marker of apoptotic
      leukocytes on which it acquires altered macrophage receptor-binding activity.

PMID- 10352302
TI  - Paclitaxel enhances macrophage IL-12 production in tumor-bearing hosts through
      nitric oxide.
AB  - Tumor-induced macrophages (Mphis) mediate immunosuppression, in part, through
      increased production of factors that suppress T cell responsiveness and
      underproduction of positive regulatory cytokines. Pretreatment of tumor-bearing
      host (TBH) Mphis with the anticancer agent paclitaxel (Taxol) partially reverses
      tumor-induced Mphi suppressor activity, suggesting that paclitaxel may restore
      TBH Mphi production of proimmune factors. Because paclitaxel demonstrates LPS
      mimetic capabilities and increased production of the LPS-induced
      immunostimulatory cytokine IL-12 could account for enhanced T cell
      responsiveness, we investigated whether paclitaxel induces Mphi IL-12 production.
      Tumor growth significantly down-regulated Mphi IL-12 p70 production through
      selective dysregulation of IL-12 p40 expression. LPS stimulation failed to
      overcome tumor-induced dysregulation of p40 expression. In contrast, paclitaxel
      significantly enhanced both normal host and TBH Mphi IL-12 p70 production in
      vitro, although TBH Mphi IL-12 production was lower than that of similarly
      treated normal host Mphis. Paclitaxel enhanced p40 expression in a dose-dependent
      manner. Through reconstituted Mphi IL-12 expression, paclitaxel pretreatment
      relieved tumor-induced Mphi suppression of T cell alloreactivity. Blocking Mphi
      NO suppressed paclitaxel's ability to induce IL-12 production. This suggests that
      paclitaxel-induced activities may involve a NO-mediated autocrine induction
      pathway. Collectively, these data demonstrate that paclitaxel restores IL-12
      production in the TBH and ascribe a novel immunotherapeutic component to the
      pleiotropic activities of NO. Through its capacity to induce IL-12 production,
      paclitaxel may contribute to the correction of tumor-induced immune dysfunction.

PMID- 10352303
TI  - Mechanisms of IL-10 production in human microglia-T cell interaction.
AB  - IL-10, a cytokine with important anti-inflammatory properties, is generated
      within the CNS during neuroinflammation. The mechanism for its production is
      poorly understood. Since infiltrating lymphocytes come into close proximity with
      the macrophage-like cells of the CNS, the microglia, we have used an in vitro
      human microglia-T cell coculture system to address the mechanisms of IL-10
      production. We demonstrate that microglia or activated T cells alone secrete
      negligible amounts of IL-10, but that their coculture results in significant IL
      10 production, which was effected by both cell types. IL-10 generation was cell
      contact dependent, and treatment with anti-CD40, CTLA-4-Fc, or anti-CD23
      decreased the IL-10 content in microglia-T cell cocultures. The combination of
      anti-CD40 and CTLA-4-Fc reduced IL-10 levels to the negligible amounts seen with
      T cells or microglia in isolation. By also measuring TNF-alpha levels,
      specificity of cytokine regulation was observed; while anti-CD40 and CTLA-4-Fc
      reduced IL-10 and TNF-alpha levels, anti-CD23 did not affect TNF-alpha while
      attenuating IL-10 generation. Anti-very late Ag-4, which decreased TNF-alpha
      levels, did not affect IL-10. These results implicate the CD40, B7, and CD23
      pathways in IL-10 production following microglia-T cell encounter and have
      relevance to the regulation of an anti-inflammatory response within the CNS.

PMID- 10352304
TI  - IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease:
      expression and localization in intestinal mucosal cells.
AB  - IL-18, a novel immunoregulatory cytokine with potent IFN-gamma-inducing
      activities, may play an important role in Th1-mediated chronic inflammatory
      disorders. The aim of the present study was to characterize the expression and
      localization of IL-18 in colonic specimens and isolated mucosal cell populations
      from patients with Crohn's disease (CD), a prototypic Th1-mediated disorder.
      Using a semiquantitative RT-PCR protocol, IL-18 mRNA transcripts were found to be
      increased in freshly isolated intestinal epithelial cells (IEC) and lamina
      propria mononuclear cells (LPMC) from CD compared with ulcerative colitis (UC)
      and noninflamed control (cont) patients, and were more abundant in IEC compared
      with LPMC. Immunohistochemical analysis of surgically resected colonic tissues
      localized IL-18 to both LPMC (specifically, macrophages and dendritic cells) as
      well as IEC. Staining was more intense in CD compared with UC and cont, and in
      involved (inv) vs noninvolved (n inv) areas. Western blot analysis revealed that
      an 18. 3-kDa band, consistent with both recombinant and mature human IL-18
      protein, was found predominantly in CD vs UC intestinal mucosal biopsies; a
      second band of 24 kDa, consistent with the inactive IL-18 precursor, was detected
      in n inv areas from both CD and UC biopsies and was the sole form found in
      noninflamed cont. To our knowledge, this report is the first describing increased
      expression of IL-18 in a human Th1-mediated chronic inflammatory disease. In
      addition, our studies further support the concept that IEC and dendritic cells
      may possess important immunoregulatory functions in both normal, as well as
      pathological, mucosal immunity.

PMID- 10352305
TI  - De novo autoimmunity to cardiac myosin after heart transplantation and its
      contribution to the rejection process.
AB  - Allograft rejection is initiated by an immune response to donor MHC proteins. We
      recently reported that this response can result in breakdown of immune tolerance
      to a recipient self Ag. However, the contribution of this autoimmune response to
      graft rejection has yet to be determined. Here, we found that after mouse
      allogeneic heart transplantation, de novo CD4+ T cell and B cell autoimmune
      response to cardiac myosin (CM), a major contractile protein of cardiac muscle,
      is elicited in recipients. Importantly, CM is the autoantigen that causes
      autoimmune myocarditis, a heart autoimmune disease whose histopathological
      features resemble those observed in rejected cardiac transplants. Furthermore, T
      cell responses directed to CM peptide myhcalpha 334-352, a known myocarditogenic
      determinant, were detected in heart-transplanted mice. No responses to CM were
      observed in mice that had received an allogeneic skin graft or a syngeneic heart
      transplant, demonstrating that this response is tissue specific and that
      allogeneic response is necessary to break tolerance to CM. Next, we showed that
      sensitization of recipient mice with CM markedly accelerates the rejection of
      allogeneic heart. Therefore, posttransplant autoimmune response to CM is relevant
      to the rejection process. We conclude that transplantation-induced autoimmune
      response to CM represents a new mechanism that may play a significant role in
      cardiac transplant rejection.

PMID- 10352307
TI  - Cytolytic T lymphocytes recognize an antigen encoded by MAGE-A10 on a human
      melanoma.
AB  - From melanoma patient LB1751, cytolytic T lymphocytes (CTL) were generated that
      lysed specifically autologous tumor cells. To establish whether these CTL
      recognized one of the Ags that had previously been defined, a CTL clone was
      stimulated with cells expressing various MAGE genes. It produced TNF upon
      stimulation with target cells expressing MAGE-A10. The Ag was found to be
      nonapeptide GLYDGMEHL (codons 254-262), which is presented by HLA-A2.1. This is
      the first report on the generation of anti-MAGE CTL by autologous mixed
      lymphocyte-tumor cell culture (MLTC) from a melanoma patient other than patient
      MZ2, from whom the first MAGE gene was identified. MAGE genes are expressed in
      many tumors but not by normal tissues except male germline cells and placenta,
      which do not express HLA molecules. Therefore, the identification of an antigenic
      peptide derived from MAGE-A10 adds to the repertoire of tumor-specific shared Ags
      available for anti-tumoral vaccination trials.

PMID- 10352306
TI  - Helminth- and Bacillus Calmette-Guerin-induced immunity in children sensitized in
      utero to filariasis and schistosomiasis.
AB  - Infants and children are routinely vaccinated with bacillus Calmette-Guerin (BCG)
      in areas of the world where worm infections are common. Because maternal helminth
      infection during pregnancy can sensitize the developing fetus, we studied whether
      this prenatal immunity persists in childhood and modifies the immune response to
      BCG. Children and newborns living in rural Kenya, where BCG is administered at
      birth and filariasis and schistosomiasis are endemic, were examined. T cells from
      2- to 10-year-old children of mothers without filariasis or schistosomiasis
      produced 10-fold more IFN-gamma in response to mycobacterial purified protein
      derivative than children of helminth-infected mothers (p < 0.01). This
      relationship was restricted to purified protein derivative because maternal
      infection status did not correlate with filarial Ag-driven IL-2, IFN-gamma, IL-4,
      or IL-5 responses by children. Prospective studies initiated at birth showed that
      helminth-specific T cell immunity acquired in utero is maintained until at least
      10-14 mo of age in the absence of infection with either Wuchereria bancrofti or
      Schistosoma haematobium. Purified protein derivative-driven T cell IFN-gamma
      production evaluated 10-14 mo after BCG vaccination was 26-fold higher for
      infants who were not sensitized to filariae or schistosomes in utero relative to
      subjects who experienced prenatal sensitization (p < 0.01). These data indicate
      that helminth-specific immune responses acquired during gestation persist into
      childhood and that this prenatal sensitization biases T cell immunity induced by
      BCG vaccination away from type 1 IFN-gamma responses associated with protection
      against mycobacterial infection.

PMID- 10352308
TI  - Induction of HLA class I-restricted CD8+ CTLs specific for the major outer
      membrane protein of Chlamydia trachomatis in human genital tract infections.
AB  - HLA class I-restricted CD8+ CTLs specific for the major outer membrane protein
      (MOMP) of Chlamydia trachomatis are present in the peripheral blood of humans who
      acquired genital tract infections with the organism. Three HLA-A2-restricted
      epitopes and two HLA-B51-restricted epitopes were identified in serovar E-MOMP.
      One of the five epitopes spans a variable segment of MOMP and is likely a serovar
      E-specific epitope. The other four epitopes are localized in constant segments
      and are C. trachomatis species specific. CTL populations specific for one or more
      of the four constant segment epitopes were isolated from all 10 infected subjects
      tested, regardless of infecting serovars, but from only one of seven uninfected
      subjects tested. The CTLs failed to recognize corresponding peptides derived from
      Chlamydia pneumoniae MOMP, further suggesting that they indeed resulted from
      genital tract infections with C. trachomatis. Significantly, ME180 human cervical
      epithelial cells productively infected with C. trachomatis were killed by the
      MOMP peptide-specific CTLs. Further investigations of the ability of such CTLs to
      lyse normal infected epithelial cells and their presence at inflamed sites in the
      genital tract will help understand the protective or pathological role of CTLs in
      chlamydial infections. The MOMP CTL epitopes may be explored as potential
      components of a subunit vaccine against sexually transmitted diseases caused by
      C. trachomatis. Moreover, the knowledge provided here will facilitate studies of
      HLA class I pathways of chlamydial Ag processing and presentation in
      physiologically relevant human APCs.

PMID- 10352309
TI  - Regulation of pulmonary T cell responses to inhaled antigen: role in Th1- and Th2
      mediated inflammation.
AB  - DO11.10 transgenic mice, expressing an OVA-specific TCR, were used to study
      pulmonary T cell responses to inhaled Ags. Before OVA inhalation, the activation
      of lung parenchymal T cells elicited both strong proliferative responses and IL-2
      production. However, following Ag inhalation the proliferative responses of the
      lung T cells, when restimulated in vitro with OVA323-339 peptide or immobilized
      anti-CD3, were severely attenuated and associated with a decrease in the level of
      production of IL-2 but not IFN-gamma. Such immune regulation was tissue-specific,
      because T cell responses in the lymph nodes and spleens were normal. This
      dramatic aerosol-induced attenuation of parenchymal T cell proliferation was also
      observed in BALB/c mice immunized with OVA and in BALB/c mice following adoptive
      transfer of DO11.10 T cells bearing either a Th1 or Th2 phenotype. In mice that
      had received Th2 cells, the reduced proliferative responses were associated with
      a decrease in IL-2 expression but augmented IL-4 and IL-5 production. Invariably,
      the inhibition of proliferation was a consequence of the action of F4/80+
      interstitial macrophages and did not involve alveolar macrophages or their
      products. These observations demonstrate that clonal expansion of T cells in the
      lung compartment is prevented following the onset of either Th1- or Th2-mediated
      inflammation. This form of immune regulation, which appears as a selective defect
      in IL-2-driven proliferation, may serve to prevent the development of chronic
      pulmonary lymphoproliferative responses.

PMID- 10352310
TI  - Human breast carcinoma patients develop clonable oncofetal antigen-specific
      effector and regulatory T lymphocytes.
AB  - Oncofetal Ag (OFA) is a 44-kDa glycoprotein expressed during early to mid
      gestation fetal development and re-expressed as a surface Ag by tumor cells soon
      after transformation. The Ag is detectable on all types of human and rodent
      tumors tested, but is undetectable on normal cells. In experimental animals it is
      autoimmunogenic and induces potentially protective T cell responses both after
      experimental immunization and during tumor development subsequent to carcinogenic
      insult. To determine whether this tumor-associated Ag is also immunogenic for
      human T lymphocytes, breast carcinoma patients' peripheral blood mononuclear
      leucocytes were stimulated in vitro with autologous tumor cells in the presence
      of IL-2, gamma-IFN, and IL-6 for 2 wk. The tumor-reactive cells were then
      restimulated and cloned by limiting dilution, and the clones were analyzed. We
      established 24, 19, 11, and 16 tumor-reactive clones from the four respective
      patients. Of those, 4, 6, 4, and 7, respectively, proliferated specifically to
      purified OFA. Both CD4 and CD8 OFA-specific clones were established, which
      responded equally well to purified OFA or 32- to 44-kDa immature laminin receptor
      protein. All were CD3+, TCR-alpha beta+. All CD4 clones secreted gamma-IFN, but
      neither secreted IL-4 nor IL-10. Both IFN-gamma-secreting cytotoxic CD8 clones
      and IL-10-secreting inhibitory CD8 clones were established. Thus, during human
      cancer development, the same types of OFA-specific effector and regulatory T
      cells are induced as during murine T lymphomagenesis.

PMID- 10352311
TI  - Intracellular expression and release of Fc epsilon RI alpha by human eosinophils.
AB  - Although Fc epsilon R have been detected on human eosinophils, levels varied from
      moderate to extremely low or undetectable depending on the donor and methods
      used. We have attempted to resolve the conflicting data by measuring levels of
      IgE, Fc epsilon RI, and Fc epsilon RII in or on human eosinophils from a variety
      of donors (n = 26) and late-phase bronchoalveolar lavage fluids (n = 5). Our
      results demonstrated little or no cell surface IgE or IgE receptors as analyzed
      by immunofluorescence and flow cytometry. Culture of eosinophils for up to 11
      days in the presence or absence of IgE and/or IL-4 (conditions that enhance Fc
      epsilon R on other cells) failed to induce any detectable surface Fc epsilon R.
      However, immunoprecipitation and Western blot analysis of eosinophil lysates
      using mAb specific for Fc epsilon RI alpha showed a distinct band of
      approximately 50 kDa, similar to that found in basophils. Western blotting also
      showed the presence of FcR gamma-chain, but no Fc epsilon RI beta. Surface
      biotinylation followed by immunoprecipitation again failed to detect surface Fc
      epsilon RI alpha, although surface FcR gamma was easily detected. Since we were
      able to detect intracellular Fc epsilon RI alpha, we examined its release from
      eosinophils. Immunoprecipitation and Western blotting demonstrated the release of
      Fc epsilon RI alpha into the supernatant of cultured eosinophils, peaking at
      approximately 48 h. We conclude that eosinophils possess a sizable intracellular
      pool of Fc epsilon RI alpha that is available for release, with undetectable
      surface levels in a variety of subjects, including those with eosinophilia and
      elevated serum IgE. The biological relevance of this soluble form of Fc epsilon
      RI alpha remains to be determined.

PMID- 10352312
TI  - Does IgE bind to and activate eosinophils from patients with allergy?
AB  - Human eosinophils have been reported to express both the mRNA and protein for the
      high affinity IgE receptor (FcepsilonRI); it is speculated that this receptor
      plays a role in eosinophil mediator release in allergic diseases. However,
      questions still remain. How much of the FcepsilonRI protein is actually expressed
      on the cell surface of the eosinophil? If they are present, are these IgE
      receptors associated with effector functions of eosinophils? To address these
      issues, we studied blood eosinophils from patients with ragweed hay fever. A high
      level of low affinity IgG receptor (FcgammaRII, CD32), but no expression of
      FcepsilonRI, was detectable on the eosinophil surface by standard FACS analysis.
      However, after in vitro sensitization with biotinylated chimeric IgE (cIgE), cell
      bound cIgE was detected by PE-conjugated streptavidin. This cIgE binding was
      partially inhibited by anti-FcepsilonRI mAb, suggesting that eosinophils do
      express minimal amounts of FcepsilonRI detectable only by a sensitive method.
      Indeed, FACS analysis of whole blood showed that eosinophils express
      approximately 0.5% of the FcepsilonRI that basophils express. When stimulated
      with human IgE or anti-human IgE, these eosinophils did not exert effector
      functions; there was neither production of leukotriene C4 or superoxide anion nor
      any detectable degranulation response. In contrast, eosinophils possessed
      membrane-bound human IgG and showed functional responses when stimulated with
      human IgG or anti-human IgG. Thus, IgG and/or cytokines, such as IL-5, appear to
      be more important for eosinophil activation in allergic diseases than IgE.

PMID- 10352313
TI  - HLA-class II-associated control of antigen recognition by T cells in leprosy: a
      prominent role for the 30/31-kDa antigens.
AB  - The recognition of 16 mycobacterial Ags by a panel of T cell lines from leprosy
      patients and healthy exposed individuals from an endemic population was examined
      within the context of expressed HLA-DR molecules. Although overall no significant
      differences were found between the frequencies of Ag recognition in the different
      subject groups, when Ag-specific T cell responses were examined within the
      context of HLA-DR, a highly significant difference was found in the recognition
      of the 30/31-kDa Ag. HLA-DR3 appeared to be associated with high T cell
      responsiveness to the 30/31-kDa Ag in healthy contacts (p = 0.01), but,
      conversely, with low T cell responsiveness to this Ag in tuberculoid patients (p
      = 0.005). Within the group of HLA-DR3-positive individuals, differences in 30/31
      kDa directed T cell responsiveness were highly significant not only between
      healthy individuals and tuberculoid patients (p < 0. 0001), but also between
      healthy individuals and lepromatous patients (p = 0.009), and consequently
      between healthy individuals compared with leprosy patients as a group (p <
      0.0001). A dominant HLA-DR3-restricted epitope was recognized by healthy contacts
      in this population. It has been proposed that secreted Ags may dominate acquired
      immunity early in infection. The low T cell response to the secreted,
      immunodominant 30/31-kDa Ag in HLA-DR3-positive leprosy patients in this
      population may result in retarded macrophage activation and delayed bacillary
      clearance, which in turn may lead to enhanced Ag load followed by T cell-mediated
      immunopathology.

PMID- 10352314
TI  - Cellular immunity to beta 2-glycoprotein-1 in patients with the antiphospholipid
      syndrome.
AB  - Patients with antiphospholipid syndrome (APS) suffer recurrent thromboses,
      thrombocytopenia, and/or fetal loss in association with Abs that can be detected
      in phospholipid-dependent assays. Despite the name, the Igs associated with APS
      are predominantly directed against epitopes on phospholipid-binding plasma
      proteins, such as beta 2-glycoprotein-1 (beta 2GP1) and prothrombin. The aim of
      this study was to examine the cellular immune response to beta 2GP1 in patients
      with APS. Using a serum-free stimulation assay, PBMCs from 8 of 18 patients with
      APS proliferated to purified beta 2GP1 or to the beta 2GP1 present in serum,
      whereas no stimulation was observed by PBMCs from healthy individuals, patients
      with other autoimmune diseases, or anticardiolipin Ab-positive patients without
      histories of thromboses or fetal loss. The immune response was Ag-specific,
      requiring class II molecules, CD4+ T cells, and APCs, and was associated with a
      selective expansion of CD4+ but not CD8+ T cells. The proliferating T cells
      produced IFN-gamma but not IL-4, indicating a bias toward a type 1 immune
      response. Chronic low grade stimulation of autoreactive beta 2GP1-specific, IFN
      gamma-producing Th1 CD4+ T cells may contribute to the high risk of thromboses
      and pregnancy failure in patients with APS.

PMID- 10352315
TI  - Cyclosporin A-induced autologous graft-versus-host disease: a prototypical model
      of autoimmunity and active (dominant) tolerance coordinately induced by recent
      thymic emigrants.
AB  - Cyclosporin A (CSA)-induced autologous graft-vs-host disease (autoGVHD) is an
      autoimmune syndrome initiated by autoeffector T cells presumed to be exported
      from the thymus during CSA treatment. The appearance of noncytotoxic
      immunoregulatory T cell activity after cessation of CSA treatment is also thymus
      dependent. In the present study, we have tested the hypothesis that both
      autoeffector and immunoregulatory T cells in CSA-treated rats are recent thymic
      emigrants (RTEs). Local syngeneic graft-vs-host reaction (synGVHR) and timed
      thymectomy (Tx) assays revealed that autoeffector T cells appear initially in the
      thymus and are promptly exported to lymph nodes (LN) during the first week of CSA
      treatment. In contrast, immunoregulatory thymocytes are first detectable by local
      synGVHR inhibition assays during the second week of CSA treatment but are not
      exported to LN until approximately 4 days post-CSA. Both the autoeffector and
      immunoregulatory T cells in LN express Thy-1, a selective marker for RTEs in the
      rat. However, the autoeffector RTEs have a CD4+8+ phenotype, whereas the
      immunoregulatory RTEs have a CD4+8- phenotype. Thus, the coordinate formation in
      and release from the thymus cortex and medulla of autoeffector and
      immunoregulatory T cells in CSA-treated rats directly demonstrates that centrally
      induced, nondeletional tolerance can serve as a fail-safe mechanism by which
      clones of autoeffector T cells that have escaped intrathymic negative selection
      for self-MHC class II Ag can be suppressed postthymically.

PMID- 10352316
TI  - Treatment of breast cancer with fibroblasts transfected with DNA from breast
      cancer cells.
AB  - This investigation was based on the hypothesis that weakly immunogenic, breast
      cancer-associated Ags, the products of mutant or dysregulated genes in the
      malignant cells, will be expressed in a highly immunogenic form by semiallogeneic
      IL-2-secreting fibroblasts transfected with DNA from breast cancer cells.
      (Classic studies indicate that transfection of genomic DNA can stably alter both
      the genotype and the phenotype of the cells that take up the exogenous DNA.) To
      investigate this question, we transfected LM mouse fibroblasts (H-2k) modified to
      secrete IL-2 with genomic DNA from a breast adenocarcinoma that arose
      spontaneously in a C3H/He mouse (H-2k). To increase their nonspecific immunogenic
      properties, the fibroblasts were also modified before transfection to express
      allogeneic MHC determinants (H-2Kb). Afterward, the IL-2-secreting semiallogeneic
      cells were cotransfected with DNA from the spontaneous breast neoplasm, along
      with a plasmid (pHyg) conferring resistance to hygromycin. Pooled colonies of
      hygromycin-resistant cells were then tested in C3H/He mice for their
      immunotherapeutic properties against the growth of the breast neoplasm. The
      results indicated that tumor-bearing mice immunized with the transfected cells
      survived significantly longer than mice in various control groups. Similar
      beneficial effects were seen in C57BL/6 mice injected with a syngeneic breast
      carcinoma cell line (EO771) and semiallogeneic, IL-2-secreting fibroblasts
      transfected with DNA from EO771 cells. The immunity was mediated by CD8+ T cells
      since immunized mice depleted of CD8+ cells failed to resist tumor growth.

PMID- 10352317
TI  - New class I and II HLA alleles strongly associated with opposite patterns of
      progression to AIDS.
AB  - The genetics of resistance to infection by HIV-1 cohort consists of 200 slow and
      75 rapid progressors to AIDS corresponding to the extremes of HIV disease outcome
      of 20,000 Caucasians of European descent. A comprehensive analysis of HLA class I
      and class II genes in this highly informative cohort has identified HLA alleles
      associated with fast or slow progression, including several not described
      previously. A quantitative analysis shows an overall HLA influence independent of
      and equal in magnitude (for the protective effect) to the effect of the CCR5
      Delta32 mutation. Among HLA class I genes, A29 (p = 0.001) and B22 (p < 0.0001)
      are significantly associated with rapid progression, whereas B14 (p = 0.001) and
      C8 (p = 0.004) are significantly associated with nonprogression. The class I
      alleles B27, B57, C14 (protective), and C16, as well as B35 (susceptible), are
      also influential, but their effects are less robust. Influence of class II
      alleles was only observed for DR11. These results confirm the influence of the
      immune system on disease progression and may have implications on peptide-based
      vaccine development.

PMID- 10352318
TI  - [Scintigraphy with 99MTc-HMPAO labeled leukocytes and computed tomography in the
      diagnosis of vascular graft infection. A comparative study].
AB  - The purpose of this work was to compare the results obtained with a scitigraphy
      using 99mTc-HMPAO labeled leukocyte and a computed tomography (CT) in the
      diagnosis of vascular graft infection (VGI). We carried out 22 studies with both
      scintigraphy and CT in 20 patients with vascular grafts with VGI suspicion. One
      patient had two grafts, thus a total of 23 grafts were analyzed. In addition, 6
      control studies were performed. The persistent increase in leukocyte uptake in
      the graft area was considered as evidence of VGI and the scintigraphy with HMPAO
      99mTc labeled leukocytes. For the CT, the presence of perigraft fluid and/or gas
      collection in the graft bed was also considered to be evidence of VGI. The total
      number of VGI was 12. The VGI diagnosis was confirmed by culture in all cases.
      The sensitivity and specificity of the scintigraphy in the diagnosis of VGI was
      100%, while the CT has a sensitivity of 58% and specificity of 91%. Five grafts
      presented pseudoaneurysm in distal aorto-bifemoral graft anastomosis. All theses
      cases were detected with CT and only one patient with pseudoaneurysms showed
      scintigraphic evidence of VGI. In addition, both techniques detected two soft
      tissue infections associated with cutaneous fistulae, one case of abdominal
      abscess and another of acute diverticulitis. The scintigraphy was also pathologic
      in one infection of the surgical wound while that the CT was negative. In
      conclusion, although both techniques are useful to evaluate patients with
      suspicion of VGI, the scintigraphy with 99m-Tc-HMPAO labeled leukocytes has been
      shown to be more sensitive than the CT in the assessment of patients with VGI
      suspicion.

PMID- 10352319
TI  - [Clinical-biological differences between invasive ductal carcinomas and breast
      lobular carcinomas. Preliminary results].
AB  - In order to know the biological differences between both histological types, we
      have analyzed some clinical and biological parameters in tissues of women having
      infiltrating carcinomas (247 ductal (IDCs) 17 and lobular (ILCs) of the breast.
      Our preliminary results led us to suggest the following. 1) In negative axillary
      lymph node involvement (N-) patients, ILCs were more frequently associated with
      diploidy and the existence of multiple foci; likewise, they had higher pS2
      cytosolic levels than IDC; 2) in N+ patients, ILC were associated with
      multicentricity and had higher concentrations of progesterone receptors and 3)
      these findings could help to explain us the clinical and biological
      peculiarities, as well as, the clinical outcome of both histological types.

PMID- 10352320
TI  - [Absence of correlation between the concentrations of carcinoembryonic antigen
      (CEA) and the tumor growth factor beta 2 (TGFB2) in the two main types of breast
      macrocysts].
AB  - In order to study the possible correlation between carcinoembryonic antigen (CEA)
      and cellular proliferation, we assayed the concentrations of this substance in
      the fluid of 77 bening macrocysts of the breast classified according to their
      Na+/K+ ratio and compared them with those of transforming growth factor beta 2.
      CEA levels correlated positively and significantly with the cationic ratio, the
      concentrations of albumin, glucose, Cl- and pH and were higher (range: 2.5-81.5,
      median 12.8 vs range: 0.4-41.5, median 3.2 ng/ml (p: 0.00000) in type 2 (Na+/K+ >
      3) than in type 1 (Na+/K+ < 3) cysts. There was no correlation between CEA and
      TGFb2, nor between the former and dehydroepiandrosterone sulphate levels. These
      results led us to suggest that the high CEA concentrations in type 2 cysts seem
      to be the consequence of loos of cellular differentiation and disruption of the
      cyst wall lining as well as the acquisition of embryonary properties by the
      latter as a consequence of a reduced hormonal microenvironment.

PMID- 10352321
TI  - [An alternative method to determine the radiochemical purity of the 99mTC
      tetrofosmine preparations].
AB  - This paper describes a new quality control method to determine the radiochemical
      purity (RCP) value of Technetium-99m-Tetrofosmin preparations. The results of
      this procedure were compared with the results obtained with the method suggested
      by the manufacturer of the kit (classic method), consisting in thin-layer
      chromatography involving the use of a single strip of ITLC/SG as the stationary
      phase, and a acetone:dichlorometane 35:65 (Ac:DCM) solvent mixture as the mobile
      phase. The method that is proposed in this paper (alternative method) uses the
      same stationary phase but it is developed in a single solvent, methylethylketone
      (MEK). This method has the following advantages: a better capacity to separate
      the 99mTc-Tetrofosmin complex from 99mTcO4- and 99mTcO2 impurities, a faster
      chromatographic developing time and the use of a single solvent in the quality
      control.

PMID- 10352322
TI  - [Gammagraphy of somatostatin receptors in an ACTH secreting thymic carcinoid].
AB  - Ectopic ACTH secretion represent 10 to 15% in the causes of Cushing's syndrome.
      Carcinoid tumor of the thymus is a rare neoplasm and is currently believed to
      arise from population of thymic cells of neural crest origin. We present the case
      of a 43-year-old man with a corticotropin hormone (ACTH) secreting thymus
      carcinoid. 111In-octreotide scintigraphy demonstrated an intense uptaken on the
      lesion. The surgical specimen measured 17 x 18 x 18 cm and weighed 1. 25 kg.
      Postoperatively the patient was treated by chemotherapy and radiotherapy. A
      follow-up 111In-octreotide scintigraphy was normal. Very few scintigraphic images
      of these lesions have been published in the literature. Somatostatin receptor
      scintigraphy can be successful in the detection and follow-up of ACTH-secreting
      neuroendocrine tumors.

PMID- 10352324
TI  - [Soft tissue visualization with 99m Tc-HDP in a case of dermatomyositis].

PMID- 10352323
TI  - [Utility of the hepatic grammagraphy with red blood cells marked with 99mTC in
      the differential diagnosis between cavernous hemangioma and hepatocarcinoma:
      based on one clinical case].
AB  - The tomographic red blood cell imaging is useful in the investigation the
      cavernous hemangioma of the liver (specificity: 100%). In all positive studies,
      with negative cytology for malignancy, and absence of complications (bleeding,
      growth, etc.) It'll could adopt conservation aptness.

PMID- 10352325
TI  - [Brain SPECT with 99m Tc-HMPAO in a patient diagnosed of megacisterna magna].

PMID- 10352326
TI  - [Contribution of nuclear medicine to lymphatic mapping and sentinel node
      identification in oncology].
AB  - An overview of the current applications of nuclear medicine for lymphatic mapping
      and sentinel node identification is given. The validation of the sentinel node
      concept in oncology has led to the rediscovery of lymphoscintigraphy. By
      combining preoperative lymphatic mapping with intraoperative gamma probe
      detection this nuclear medicine procedure is increasingly used to identify and
      detect the sentinel node in melanoma, breast cancer, and in other malignancies
      such as penile cancer and vulvar cancer. In melanoma, the adequate combination of
      dynamic and static gamma camera images enables lymph node visualization with
      identification of the sentinel node in more than 97% of the cases. The
      variability in drainage in areas such as trunk, head and neck makes
      lymphoscintigraphy indispensable in protocols of sentinel node biopsy. The
      reproducibility of lymphoscintigraphy for sentinel node detection varies from 85%
      to 88% and the method appears to have a high interobserver agreement. In contrast
      to the procedure of lymphoscintigraphy for melanoma, for which the only dilemma
      remaining is probably the choice of the tracer, in breast cancer there has not
      yet been reached a consensus for many topics such as tracer characteristics,
      injection volume, and principally the site of administration. Lymphoscintigraphy
      by subdermal tracer administration is able to detect axillary lymph nodes in 98%
      of the cases but the method is accompanied by a low visualization incidence (2%)
      of drainage outside the lower axilla such as the internal mammary chain. This
      latter aspect appears to occur in 16% to 35% in the series using peri- or
      intratumoural administration with an axillary rate of visualization of 75% to
      98%. Although peritumoural administration is predominantly associated with late
      lymph node detection, the early appearance observed after subdermal and
      intratumoural tracer injection justifies the obtention of early gamma camera
      images. The strategies of identification of the sentinel node depend strongly on
      the results of lymphoscintigraphy. In melanoma, the rapid lymphatic drainage and
      the visualization of afferent lymphatic vessels enables sentinel node
      identification by lymphoscintigraphy in almost the totality of the cases and
      intraoperative probe detection may subsequently be performed. In breast cancer,
      the slower drainage pattern may hamper image interpretation and diagnostic
      conclusion. Considering the first appearing node and the visualization of an
      afferent lymphatic vessel as the major criteria to identify the sentinel node,
      scintigraphy may be considered conclusive in approximately 75% of the cases, and
      not conclusive in about a fourth part of the cases in which 2 or more lymph nodes
      appear simultaneously without lymph vessel delineation. When lymphoscintigraphy
      is not conclusive, additional lymphatic mapping with blue dye is recommended to
      definitively identify the sentinel node. The use of nuclear medicine techniques
      for the sentinel node procedure will become an important part of clinical work in
      the nuclear medicine and surgical oncology practice of the next years.
      Principally mammary lymphoscintigraphy demands from the nuclear medicine
      community and allied disciplines a prompt standardization of the technique to
      solving some controversial aspects such as tracer requirements, administration
      route and interpretation criteria.

PMID- 10352327
TI  - [Informed consent in the treatment of differentiated neoplasms of the thyroids].

PMID- 10352328
TI  - Establishment and characterization of a CD95 (Fas/Apo-1)-negative myeloma cell
      line.
AB  - Although expression of CD95 (Fas/Apo-1) on myeloma cells has been reported, its
      significance is not clearly understood. We established a myeloma cell line, KHM
      11ad (11ad), from a parental cell line, KHM-11, by collecting cells adhered to a
      plastic dish. KHM-11 cells have been reported to be positive for CD45 and CD95
      (Fas/Apo1), and negative for a myelomonocytic antigen, CD13. Interestingly, CD95
      was not detected in 11ad. Expression of CD45 was also significantly decreased in
      11ad cells while expression of CD13 was detected in these cells. The growth rate
      of 11ad cells was 1.7 times lower than that of KHM-11 cells. Analysis of adhesion
      molecules showed that expression of VLA4 and CD44 was significantly suppressed in
      11ad. The IC50 of melphalan (L-PAM) for 11ad cells was 50 times higher than that
      for KHM-11, indicating that 11ad is significantly refractory to L-PAM than KHM-11
      cells. Induction of apoptosis by doxorubicin and cycloheximide was suppressed in
      11ad cells compared with those in KHM-11 cells. Western blot analysis for Bcl-2
      family of proteins showed that Bax was expressed at a 2.2 times lower level in
      11ad cells than in KHM-11 cells while there was no difference in expression of
      Bcl-2, Bcl-Xs nor Bcl-XL. These results suggest that CD95-negative myeloma cells
      may have characteristics as follows: (1) slow proliferation; (2) low sensitivity
      to apoptosis; (3) low expression of VLA4, CD44 and Bax. Although these
      intraclonal variations were based on the findings of cell lines, these may
      reflect similar variations in vivo. The 11ad line may be a suitable model for
      analyzing intraclonal variation of myeloma cells.

PMID- 10352329
TI  - Transcripts of immunoglobulin germline mu: an amplified myeloid and B-lymphoid
      common gene program in various leukemias.
AB  - To investigate the clinical implications of germline C mu transcription, the
      splice region between the 3' end of the enhancer and the first exon of
      immunoglobulin germline mu; was analyzed by RT-PCR in 63 samples from 59 patients
      with leukemia. Immunophenotypes of 33 samples from patients with acute leukemia
      were analyzed using a panel of these monoclonal antibodies: anti-immature/stem
      cell (HLA-DR, CD34); anti-mature myeloid (CD33, CD15); anti-T lymphoid (CD2, CD3,
      CD5, CD7, CD8), and anti-B lymphoid (CD10, CD19, CD20). Of the 63 samples, 33
      (52%) contained germline C mu transcripts: 2/2 patients with chronic lymphocytic
      leukemia; 17/26 (65.4%) patients with acute myeloblastic leukemia; all 4 patients
      with chronic myelogenous leukemia in blast crisis and 1 in accelerated phase;
      9/12 patients with acute lymphocytic leukemia. A clear correlation between
      germline transcripts and HLA-DR expression was observed among germline-positive
      cases (p < 0. 01). C mu expression and response to therapy clearly indicated that
      germline-mu-positive leukemia patients responded poorly to chemotherapy and had a
      worse clinical prognosis compared with C mu-negative patients (p < 0.01). After
      two courses of chemotherapy, 7/9 C mu-negative patients achieved complete
      remission compared to only 7/29 C mu-positive patients (p < 0.01). We conclude
      that the gene-regulating immunoglobulin germline C mu may be amplified in myeloid
      and B-lymphoid cells during leukemogenesis. Such genetic changes may be
      correlated with cellular terminal differentiation injury, resistance to
      chemotherapy and uncontrolled malignant cell proliferation.

PMID- 10352330
TI  - Effect of granulocyte/colony-stimulating factor on the onset of the adult
      respiratory distress syndrome.
AB  - To evaluate the effect of granulocyte/colony-stimulating factor (G-CSF) on the
      onset of the adult respiratory distress syndrome (ARDS), we investigated whether
      the incidence of ARDS due to pulmonary infection differed between the G-CSF group
      which received chemotherapy with G-CSF and historical controls without G-CSF. We
      evaluated 132 patients with hematological malignancy in complete remission
      without any main organ dysfunction who had been treated between April 1983 and
      December 1997. We compared the incidence of ARDS due to pulmonary infection
      between those who received G-CSF and those who did not. There was no remarkable
      difference in the number of patients, gender, age, or distribution of primary
      diseases between the two groups. The intensity of chemotherapy was not considered
      to significantly differ between the two groups, though the chemotherapy regimens
      administered differed slightly. In the G-CSF group, the duration of neutropenia
      was significantly shorter and the frequency of documented infection was
      significantly decreased. We could not find any relationship between ARDS due to
      pulmonary infection and any anticancer agent or antibiotics. There was no
      relationship between the kind of G-CSF and the incidence of ARDS due to pulmonary
      infection (per chemotherapy session; p > 0.10, per case; p > 0.30, chi2 test).
      The incidence of ARDS due to pulmonary infection per chemotherapy session was
      4.21%, and showed a higher tendency in the G-CSF group (p < 0.100, chi2 test).
      The incidence of ARDS due to pulmonary infection per case was 25.4% and was
      significantly higher in the G-CSF group (p < 0.025, chi2 test). The incidence of
      ARDS due to pulmonary infection was higher in the G-CSF group than in the
      controls, suggesting that G-CSF promotes the development of ARDS due to pulmonary
      infection.

PMID- 10352331
TI  - Automated enumeration of cellular composition in bone marrow aspirate with the
      CELL-DYN 4000 automated hematology analyzer.
AB  - The present study was designed to evaluate the automated analysis of bone marrow
      aspirates with the CELL-DYN 4000 (CD4000) hematology analyzer. Bone marrow
      aspirates were diluted twice with phosphate-buffered saline and assayed with the
      CD4000. The percentages of subpopulations including lymphocytes, neutrophils, and
      erythroblasts were obtained with the CD4000, and as a reference, differential
      counts by microscopic observation of May-Grunwald-Giemsa-stained films of bone
      marrow aspirate were performed (n = 48). Significant correlations (p < 0.0001)
      between the results with the two methods were obtained for total nucleated cell
      count, lymphocytes, neutrophils, erythroid cells, and the myeloid/erythroid
      ratio. The present method can provide quantitative data of bone marrow aspirate
      and will be useful in bone marrow screening.

PMID- 10352332
TI  - Isolation of large and pure samples of human erythroid precursors at different
      stages of maturation using immunomagnetic separation of cells from liquid
      cultures.
AB  - The two-phase liquid culture, which supports the development of human erythroid
      progenitors into hemoglobin-containing orthochromatic normoblasts, provides high
      yield of erythroblasts with synchronized development. However, other cell types
      are also present in the culture. In the present report, we used immunomagnetic
      separation for the purification of the developing erythroid precursors. At
      different stages of the culture, aliquots of the cells were incubated with anti
      glycophorin A, B monoclonal antibodies, followed by anti-mouse IgG-coated
      magnetic beads, and separated by a magnet. In mature cultures, all isolated
      glycophorin-positive cells contained hemoglobin, as indicated by their staining
      with benzidine. All glycophorin-negative cells were benzidine negative. In
      earlier cultures, morphological examination and measurements of hemoglobin
      content showed that the erythroid precursors could be isolated at different
      stages of maturation. Thus, the combination of the liquid culture procedure with
      the immunomagnetic separation technique permitted to obtain large samples of pure
      erythroid cells, which were synchronized at subsequent stages of maturation. The
      method enables comprehensive studies of developing erythroid cells from normal
      donors as well as from patients with various disorders of erythropoiesis.

PMID- 10352333
TI  - Influence of aspirin on platelet count and volume in humans.
AB  - Platelet volume and total platelet mass are parameters of platelet activity and
      have become a prognostic factor in coronary heart disease. We have studied the
      influence of aspirin on platelet count, volume and total platelet mass in vitro
      and in a randomized double-blind, placebo-controlled study in 20 healthy young
      male volunteers in vivo. Aspirin had no influence in vitro on either platelet
      count, volume or mass. Repeated blood sampling during a 7-day treatment with 250
      mg aspirin daily showed an increased platelet count (7.3% on day 1, 3.0% on day
      2, 6.8% on day 4 and 9.3% on day 7; p < 0.01) and total platelet mass (7.2, 5.0,
      8.6 and 11.5% on days 1, 2, 4 and 7, respectively, p < 0.01). Aspirin treatment
      without repeated blood withdrawal had no effect. These data indicate that aspirin
      may affect the circulating platelet mass under certain conditions.

PMID- 10352334
TI  - Effect of desferrioxamine in acute haemolytic anaemia of glucose-6-phosphate
      dehydrogenase deficiency.
AB  - The effectiveness of desferrioxamine (DFO) in ameliorating the severity of the
      acute haemolysis of glucose-6-phosphate dehydrogenase (G6PD) deficiency was
      studied in 167 children with G6PD deficiency during an acute haemolytic crisis.
      All patients received packed cell transfusion on admission if their Hb levels
      were <8 g/dl, which was repeated as needed. Eighty patients also received a
      single dose of DFO 30-40 mg/kg by slow intravenous infusion (DFO group). The
      remaining 87 children did not receive DFO (control group). The need for more than
      one transfusion was less frequent in the DFO group as compared to the control
      group (p = 0. 01). The need for late transfusion (transfusion after 36 h of
      admission) was also less in the DFO group (7%) compared to 21% in the control
      group (p = 0.02). On average, children in the DFO group needed less packed red
      blood cells (16.5 ml/kg body weight) than the control group (22.8 ml/kg body
      weight) and the difference was highly significant (p = 0.0001). We conclude from
      this study that DFO in a small dose is effective in the treatment of acute
      haemolytic crises of G6PD deficiency. It shortens the duration of the crisis and
      decreases the amount of blood transfusion needed.

PMID- 10352335
TI  - Portal vein thrombosis in paroxysmal nocturnal haemoglobinuria.
AB  - A 28-year-old man was hospitalized with nausea, vomiting, abdominal pain and low
      grade fever. He had a 6-month history of paroxysmal nocturnal haemoglobinuria
      (PNH), and laboratory data showed anaemia and liver dysfunction. An abdominal
      ultrasonography showed ascites and portal vein thrombosis. After receiving
      antithrombotic treatment, the portal vein thrombosis did not extend. Portal vein
      thrombosis is very rare but should be considered when we encounter liver
      dysfunction associated with PNH as well as hepatic vein thrombosis.
      Ultrasonography is very useful in detecting portal vein thrombosis and
      facilitating early diagnosis. Warfarin is very effective in preventing
      exacerbation of portal vein thrombosis in PNH.

PMID- 10352337
TI  - Th1/Th2 milieu in adult hemophagocytic syndrome.

PMID- 10352336
TI  - Response to granulocyte colony-stimulating factor in an autoimmune neutropenic
      adult.
AB  - Clinical value of granulocyte colony-stimulating factor (G-CSF) for autoimmune
      neutropenia (AIN) has not been well established. We experienced an adult case of
      AIN which showed an excellent response to G-CSF. A 75-year-old female was
      admitted with high-grade fever. Her neutrophil count was remarkably low
      (neutrophil 0.09 x 10(9)/l). Antigranulocyte autoantibody was demonstrated in her
      serum by an immunofluorescence method and she was diagnosed as AIN.
      Administration of G-CSF (filgrastim 5 microgram/kg) gave a rapid increase of
      neutrophils (from 0.11 x 10(9)/l to 2.10 x 10(9)/l on the second day), which has
      enabled us to preserve the use of G-CSF for emergency, that is, for overt serious
      infection.

PMID- 10352338
TI  - Anticardiolipin antibodies in myelodysplastic syndromes.

PMID- 10352339
TI  - Simple indicators for determining the timing of efficient collection of
      autologous peripheral blood stem cells in children with malignancies.

PMID- 10352340
TI  - Minor role of Cl- secretion in non-cystic fibrosis and cystic fibrosis human
      nasal epithelium.
AB  - Na+ and Cl- currents were studied in primary cultures of human nasal epithelium
      derived from non-cystic fibrosis (non-CF) and cystic fibrosis (CF) patients. We
      found that Na+ absorption dominates transepithelial transport and the Na+ current
      contains an amiloride-sensitive and amiloride-insensitive component. In non-CF
      tissue both components contribute about equally to the entire short-circuit
      current (ISC), whereas in CF tissues the major part of the current is amiloride
      sensitive. Na+ removal reduced ISC to values close to zero. Several Cl- channel
      blockers were used to identify the remaining tiny Na+-independent current. Under
      unstimulated, physiological conditions in the presence of Cl- on both sides and
      amiloride on the apical side of the epithelium diphenylamine-2-carboxic acid
      (DPC), 4,4'-diisothiocyanatostilbene-2, 2'- disulfonic acid (DIDS) and 5-nitro-2
      (3-phenylpropylamino)-benzoic acid (NPPB) failed to induce clearcut inhibition of
      ISC. cAMP as well as ATP did not affect ISC either in CF or in non-CF epithelia.
      Reduction of apical Cl- increased ISC and depolarized transepithelial potential;
      however, the observed increase was insensitive to DIDS, DPC and NPPB. From these
      data we conclude that Cl- conductances in primary cultures of human nasal
      epithelium derived from CF patients as well as from non-CF patients are present
      only in low numbers or do not contribute significantly to transepithelial ion
      transport.

PMID- 10352341
TI  - Effect of Cd2+ on Kv4.2 and Kv1.4 expressed in Xenopus oocytes and on the
      transient outward currents in rat and rabbit ventricular myocytes.
AB  - The aim of the present study was to compare the biophysical properties and Cd2+
      sensitivity of Kv4.2 and Kv1.4 in Xenopus oocytes with those of native transient
      outward potassium currents in rat and rabbit ventricular myocytes. In Xenopus
      oocytes, Kv4.2 inactivated at hyperpolarized voltages (V(1/2)inact = -58.4 +/-
      0.96 mV, n = 12) and recovered from inactivation rapidly (time constant = 224 +/-
      23 ms, n = 3). Cd2+ induced large (approx. 30 mV with 500 microM Cd2+),
      concentration-dependent rightward shifts in Kv4.2 steady-state activation and
      inactivation. Kv1.4 inactivated over more depolarized voltages than Kv4.2
      (V(1/2)inact = -49.3 +/- 1.4 mV, n = 12). Recovery from inactivation of Kv1.4 was
      dominated by a large slow component (time constant = 9,038 +/- 1,178 ms, n = 4).
      Cd2+ exerted only modest effects on Kv1.4 gating, with 500 microM Cd2+ shifting
      the voltage dependence of steady-state activation and inactivation by
      approximately 12 mV. We show that the biophysical properties and Cd2+ sensitivity
      of rat ventricular Ito resemble those of heterologously expressed Kv4.2. These
      findings support previous suggestions that Kv4.2 is an important molecular
      component of Ito in adult rat heart. In addition, our findings show that Ito in
      rabbit ventricular myocytes and Kv1.4-based currents in Xenopus oocytes share
      similar biophysical properties and sensitivity to Cd2+, suggesting that Kv1.4 may
      underlie Ito in rabbit ventricle. However, a number of discrepancies exist
      between the properties of native currents and their putative molecular
      counterparts, suggesting that additional proteins and/or modulatory factors may
      also play a role in determining the biophysical and pharmacological properties of
      these native currents.

PMID- 10352342
TI  - p53 enhances BAK and CD95 expression in human malignant glioma cells but does not
      enhance CD95L-induced apoptosis.
AB  - The temperature-sensitive murine p53val135 mutant was introduced into 3 human
      malignant glioma cell lines to examine the effects of the p53 status on BCL-2
      family protein expression, CD95 expression, and sensitivity to CD95 ligand
      (CD95L)-induced apoptosis. p53val135 behaves as a dominant negative mutant at
      38.5 degrees C but assumes p53 wild-type properties. In order to dissect (i)
      specific effects of wild-type versus mutant p53, and (ii) transdominant-negative
      versus gain-of-function effects of mutant p53, we included glioma cell lines with
      functional wild-type (LN-229), mutant (LN-18) or deleted (LN-308) p53 genes. Wild
      type, but not mutant, p53val135 promoted G2/M arrest and accumulation of BAK
      protein in all cell lines. The levels of other BCL-2 family members including
      BAX, BCL-2, BCL-X or MCL-1 were not consistently modulated by mutant or wild-type
      p53val135. Wild-type, but not mutant, p53val135 enhanced CD95 expression in all
      cell lines. CD95L-evoked caspase 3 activity was unaffected by wild-type p53 in
      all cell lines. Unexpectedly, mutant p53val135 differentially modulated caspase 3
      activity in a gain-of-function fashion in that caspase 3 activity induced by
      CD95L was enhanced in LN-229 and LN-308 cells but reduced in LN-18 cells. Yet,
      mutant p53val135 enhanced the sensitivity to CD95L in LN-18 cells, had no effect
      in LN-229 cells, and decreased the sensitivity of LN-308 cells. Corresponding to
      the unaltered CD95L-evoked caspase 3 activity, wild-type p53val135 had no major
      effect on CD95L-induced apoptosis, except for a moderate sensitization of LN-229
      cells but only when protein synthesis was inhibited. Thus, wild-type p53 induces
      BAK and CD95 expression in human glioma cells without enhancing their
      susceptibility to CD95-mediated apoptosis, and mutant p53 modulates CD95L-evoked
      apoptotic signalling in a gain-of-function fashion up-stream and down-stream of
      caspase 3 activation.

PMID- 10352343
TI  - Antioxidant-sensitive triiodothyronine effects on characteristics of rat liver
      mitochondrial population.
AB  - Whole mitochondrial population and three mitochondrial fractions were resolved by
      differential centrifugation from liver homogenates from euthyroid, hyperthyroid
      (ten daily i.p. injections of triiodothyronine (T3), 10 microg/100 g body weight)
      and hyperthyroid vitamin E-treated (ten daily i.m. vitamin E injections, 20
      mg/100 g body weight) rats. Homogenates and mitochondrial preparations were
      examined for their protein content, oxidative capacity, lipid peroxidation,
      antioxidant status, and susceptibility to oxidative stress. In all groups,
      antioxidant level was smaller and oxidative capacity, lipid peroxidation, and
      susceptibility to oxidants were greater in the heavy mitochondrial fraction. T3
      treatment was associated with increased oxidative capacity, lipid peroxidation,
      and susceptibility to oxidative stress, and decreased antioxidant levels in all
      preparations. It was also associated with increased mitochondrial protein content
      of homogenate and altered quantitative presence of the mitochondrial fractions.
      The vitamin E effects on the T3-induced changes were different for the different
      parameters. Vitamin E did not modify the mitochondrial protein content in liver
      and oxidative capacity of the various preparations, reduced the changes in both
      susceptibility to oxidants and contribution of each fraction to the whole
      mitochondrial population, and reinstated euthyroid values for antioxidant
      capacity and lipid peroxidation. The incomplete recovery of euthyroid resistance
      to oxidants in vitamin E-treated rats is due to the vitamin inability to
      reinstate the levels of both antioxidants and hemoproteins, on which such a
      resistance depends. The vitamin E effect on the composition of the mitochondrial
      population is more difficult to explain, because of the complexity of the
      mechanisms underlying the mitochondrial population modulation by thyroid hormone.
      However, available data suggest that such a modulation occurs through changes in
      the turnover of the mitochondrial fractions to which an induction of
      mitochondrial protein synthesis and accelerated antioxidant-sensitive degradation
      contribute in different measure.

PMID- 10352344
TI  - Epithelial-mesenchymal interactions in development of the mouse fetal genital
      tubercle.
AB  - Epithelial-mesenchymal interactions play a central role in the development of
      urogenital organs. We hypothesized that normal development of the external
      genitalia depends upon proper mesenchymal-epithelial signaling. The mesenchyme of
      the adult mouse penis consists of a corpus cavernosum and proximal and distal
      bones. The differentiation of penile mesenchyme into bone and cartilage begins
      after birth and can be accelerated by androgens. After determining the sex,
      genital tubercles of fetal mice at gestational day 15 were removed. The genital
      tubercles were trypsinized and microdissected to remove the epidermis and urethra
      from the mesenchyme. Recombinant specimens were created by combining genital
      tubercle mesenchyme with genital tubercle epithelium, bladder epithelium or tail
      epidermis. Tissues were grafted under the renal capsule of male athymic mice.
      After 3 weeks of growth, grafts were removed from the kidney, weighed and stained
      with hematoxylin and eosin, Alcian blue and peanut agglutinin. Male and female
      grafts showed no difference in growth or differentiation. Intact grafts and
      recombinant grafts, irrespective of the epithelial source, grew significantly
      more than grafts of the mesenchyme only. Recombinant grafts demonstrated a
      significantly higher prevalence of cartilage formation and mesenchymal
      differentiation compared to grafts of the mesenchyme without epithelium. Since
      heterologous epithelium is able to induce equivalent growth and differentiation
      of phallic mesenchyme, epithelium carries a permissive, but critical, role in
      genital mesenchyme development.

PMID- 10352346
TI  - Fetomaternal attachment and anchorage in the early diffuse epitheliochorial
      placenta of the camel (Camelus dromedarius). Light, transmission, and scanning
      electron microscopic study.
AB  - Placentae of 22 one-humped camel concepti with crown-rump lengths (CRL) ranging
      from 2.5 to 26 cm were studied. The placentae were processed for light,
      transmission and scanning electron microscopy of exposed surfaces and
      microvascular corrosion casts. In very early stages of pregnancy (2.5-4.5 cm CRL)
      three froms of fetomaternal interrelationship are described. (1) Precontact,
      where the mononuclear trophoblast cells are still separated from the uterine
      epithelium by a gap containing interareolar histotroph. Both fetal and maternal
      epithelia develop apical ectoplasmic pads in this location. (2) Apposition, where
      microvilli of the apical cell membrane of the trophoblast contact the uterine
      epithelium focally. Multinuclear trophoblast giant cells develop beside the
      population of already present mononuclear trophoblast cells. Uterine ectoplasmic
      pads can be observed. (3) Adhesion occurs when apical cell membranes of fetal and
      maternal epithelia adhere to each other closely, thus forming a 'normal'
      intercellular space of 20 nm width, without any intervening uterine luminal
      space. Microvillous interdigitation in this location varies from a non
      microvillous 'smooth adhesion', to a distinctly villiform 'rough adhesion', and a
      'semismooth adhesion' is achieved when trophoblastic microvilli make intimate
      contact with the non-microvillous uterine apical cell membranes of ectoplasmic
      pads. This fetomaternal attachment process is sufficient until the conceptus
      reaches approximately 9 cm CRL. Then, from 10 to 13 cm CRL, additional anchorage
      of the placenta to the endometrium is accomplished by the growth of temporary
      grooves and ridges of the allantochorion and the endometrium, which indent each
      other in a complementary fashion. The height of these groove-ridge structures
      increases gradually in 14 to 18 cm CRL fetuses, and they also widen at about 25
      cm CRL, thus forming globular fetal troughs and irregular, thick maternal ridges.
      These together create units responsible for improved fetomaternal anchorage and
      metabolic exchange for the increasing needs of the growing fetus.

PMID- 10352345
TI  - A single low dose of RGTA, a new healing agent, hastens wound maturation and
      enhances bone deposition in rat craniotomy defects.
AB  - RGTA, a new family of dextran-derived healing agents, promotes the repair of
      various tissues, including bone. In this study, we examined whether a dose of
      RGTA lower than in our previous studies could still modify the healing pattern in
      craniotomy defects. In 24 rats, two defects (3 mm diameter) were drilled on
      either side of the calvaria sagittal suture. The right defect was filled with a
      piece of collagen soaked with RGTA in phosphate-buffered saline (PBS; 4
      microg/ml), and the left one with collagen soaked in PBS only. After 7, 14 and 21
      days, the calvaria were removed and processed for histometry. On day 7, in
      contrast with the control defects, the treated sites were inflammation-free and
      centripetal bone plates had started to grow. By day 14, the bone filling was
      significantly enhanced in the treated defects (+290%, p<0.05), and isolated bone
      nodules had formed within the fibrous connective tissue (= fibrous hammock)
      joining the defect edges. The hammock had already differentiated by day 7 in all
      the RGTA-treated defects, and it was significantly thicker on days 14 (+190%,
      p<0.05) and 21 (+139%, p<0.05). The colonization of the hammock by mast cells was
      increased in the treated sites (+320%, p<0.05 on day 21). On day 7, most of the
      bony edges of the treated defects had been resorbed by osteoclasts, while the
      process only started in the controls. These data indicate that a low dose of RGTA
      modified the cascade of events occurring at the initial stages of repair, so that
      the tissular maturation of the treated defects was more rapid. In fact the use of
      RGTA in the wounds provoked a shift from a fibrous repair as seen in the
      controls, to a bone reconstruction favoring defect closure.

PMID- 10352347
TI  - The pituitary intermediate lobe of the hydrated and dehydrated gerbil. An
      immunohistochemical and electron-microscopic study.
AB  - The pituitary intermediate lobe was studied by immunocytochemistry on semithin
      sections and by electron microscopy in gerbils (Gerbillus pyramidum) caught in
      summer and winter in the natural biotope or experimentally submitted to chronic
      hydration or dehydration. In the gerbil, the intermediate lobe was formed by a
      predominating population of tightly packed melanotrophic cells the
      immunocytochemical and morphological features of which were comparable to those
      described in other mammals. A few typical corticotrophic cells were scattered in
      the contact zone with the neural lobe. Folliculostellate cells labelled with
      antibodies against glial fibrillary acid protein and vimentin were interspersed
      between the glandular cells; they formed small follicles in the vicinity of which
      the apical cytoplasm contained conspicuous dense granules. Both glandular cell
      types were innervated by axons most probably colocalizing dopamine and gamma
      aminobutyric acid. In the pituitaries from the gerbils caught in winter, as from
      those having free access to hydrated food, the melanotrophic cells exhibited
      morphological characteristics of high functional activity. In the gerbils caught
      in summer or receiving exclusively dry food, the secretory activity of the cells
      was obviously depressed. The corticotrophic cells were unaffected. These
      observations raise the question of the role of the intermediate lobe in the
      adaptation to desert life.

PMID- 10352348
TI  - Effects of maternal alcohol consumption on the allometric growth of muscles in
      fetal and neonatal rats.
AB  - The effect of maternal alcohol consumption during pregnancy as well as the
      neonatal period on allometric growth of skeletal muscles of fore and himdlimbs
      was studied in 252 rats (126 males and 126 females). At the inception of the
      study the dams of alcohol-exposed groups received 10% ethanol (v/v) in water for
      2 weeks and 20% ethanol (v/v) for another 3 weeks. They were then bred overnight
      by introducing 1 male per 4 females into the cage. Following diagnosis of
      pregnancy, the two alcohol-exposed groups received 30% ethanol (v/v) till
      delivery. Neonatally the pre- and postnatal alcohol-exposed group continued to
      receive alcohol till weaning at 21 days of age. The offspring randomly selected
      (7 males and 7 females) from each group were killed at 3, 5, 7, 9, 11 and 14
      weeks of age. The body weights, muscle weights and percentage of body weights
      contributed by each muscle were significantly smaller in the offspring of the
      alcohol-exposed groups as compared to the controls. These parameters were
      significantly higher in the group exposed to alcohol only prenatally as compared
      to those exposed both pre- and postnatally up to the 7th week of age, and
      thereafter were similar in the subsequent weeks. Although the alcohol-exposed
      groups grew faster than the controls from 9 to 14 weeks of age, they were,
      however, not able to catch up. This demonstrated that allometric growth of
      muscles of fetal and neonatal rats was adversely affected by maternal consumption
      of alcohol during pregnancy and neonatally.

PMID- 10352349
TI  - A rare anomaly of the abductor digiti minimi muscle of the foot.
AB  - One case with anomalous fascicles in the abductor digiti minimi muscle (ADM),
      noted in the course of dissecting the left lower extremity of a 62-year-old male
      cadaver, is described. The ADM had proximally three bellies and distally one. One
      of the proximal bellies presented the normal belly and others were the
      supernumerary fascicles. Both fascicles arose from the calcaneus, one was
      inserted into the base of the fifth metatarsal (FMB) and the other into the
      tuberosity of the fifth metatarsal (FMT). One belly coursing distally arose from
      the FMB and was inserted into the proximal phalanx of the fifth digit. The normal
      belly ended in the FMB and also both in the distal belly and in the flexor digiti
      minimi muscle. One of the supernumerary fascicles (medial fascicle) crossed the
      lateral plantar artery. To our knowledge, this is an anatomic variation which has
      never been described before. The morphology of this anomaly is discussed in
      relation to previously described anomalies of the plantar muscles.

PMID- 10352350
TI  - Liver ischemia modifies the concentration of plasmatic catecholamines after
      reperfusion in the rat.
AB  - Pulmonary hypertension is one of the most frequent and severe consequences of
      liver ischemia. The aim of this study is to evaluate the presence of humoral
      vasoactive mediators, generated during liver ischemia, which could be able to
      determine the onset of pulmonary hypertension. Thus, we evaluated the plasmatic
      concentration of catecholamines (adrenaline, noradrenaline, dopamine) during the
      immediate reperfusion period. Wistar rats were used. Animals (n = 89) were
      divided into four groups. Group 1 served as control (sham-operated). In group 2
      animals underwent 60 min of left hepatic exclusion. In group 3 animals underwent
      to bilateral adrenectomy. In group 4 animals had both bilateral adrenectomy and
      liver ischemia. Ischemia in group 2 and 4 was induced by interrupting the
      vascular supply to the left and median lobes, so avoiding the use of a portal
      shunt. Blood samples were collected from the suprahepatic inferior caval vein
      immediately after reperfusion. Strips of the main pulmonary artery were put into
      an isolated organ bath and tested for the response to noradrenaline, adrenaline
      and plasma samples. Plasma samples collected after ischemia caused a
      significantly greater (p < 0.01) contraction of the pulmonary artery compared to
      controls. Plasma samples collected after adrenectomy caused a weak contraction
      which was not different from that obtained in the adrenectomy + ischemia group.
      Plasma concentrations of catecholamines after liver ischemia were significantly
      increased in the control group (p < 0. 01). In adrenectomized rats only the
      adrenaline level was greatly reduced. However ischemia did not increase plasma
      catecholamines as it occurred in sham-operated rats.

PMID- 10352352
TI  - Successful autotransplantation of microvessel fragments into the rat heart.
AB  - We examined whether microvessel fragments (Mvf), autologously transplanted with
      myofibroblasts (Mf) into the heart, could survive and form connections to the
      host's coronary microcirculation. Neither achievement has been reported before in
      the heart. Mvf and Mf were prepared from Sprague-Dawley rat epididymal fat pads.
      A mixture of Mvf (labeled with the fluorescent probe DiI-acetylated low-density
      lipoprotein, DiI-Ac-LDL) and Mf was injected into the superficial myocardium
      under general anesthesia. Rats (n = 5 in each group) were killed on postoperative
      days 7, 14, 21, 42 and 49, and India ink was perfused through the coronary
      arteries. Frozen sections of the injected area were examined under fluorescence
      and light microscopes. Some DiI-Ac-LDL-labeled Mvf survived in each group, and
      India ink was present in the lumina of microvessels coincident with DiI-Ac-LDL
      labeled autotransplanted Mvf. Hematoxylin and eosin staining revealed mild
      inflammatory reactions followed by some fibrosis at the injection sites. These
      findings indicate that autotransplanted Mvf can survive for at least 49 days, and
      that patent microvascular anastomoses can form between them and the host's
      coronary microvessels. Possibly, autotransplantation of Mvf could lead to the
      development of a new collateral microcirculation, a phenomenon especially
      important in the ischemic heart.

PMID- 10352351
TI  - Xenogeneic, extracorporeal liver perfusion in primates improves the ratio of
      branched-chain amino acids to aromatic amino acids (Fischer's ratio).
AB  - In fulminant hepatic failure (FHF), the development of hepatic encephalopathy is
      associated with grossly abnormal concentrations of plasma amino acids (PAA).
      Normalization of the ratio of branched-chain amino acids to aromatic amino acids
      (Fischer's ratio) correlates with clinical improvement. This study evaluated
      changes in PAA metabolism during 4 h of isolated, normothermic extracorporeal
      liver perfusion using a newly designed system containing human blood and a rhesus
      monkey liver. Bile and urea production were within the physiological range.
      Release of the transaminases AST, ALT and LDH were minimal. The ratio of branched
      (valine, leucine, isoleucine) to aromatic (tyrosine, phenylalanine) amino acids
      increased significantly. These results indicate that a xenogeneic extracorporeal
      liver perfusion system is capable of significantly increasing Fischer's ratio and
      may play a role in treating and bridging patients in FHF in the future.

PMID- 10352353
TI  - In vivo studies on insulin permeability of an immunoisolation device intended for
      islet transplantation using the microdialysis technique.
AB  - In this study, insulin was injected into Theracyte immunoisolation devices to
      analyze changes in the permeability of the device over time after implantation.
      The recovery of insulin was studied after subcutaneous implantation of the
      devices in rats, using the microdialysis technique. The area under the insulin
      concentration vs. time curves (AUC) after insulin injection in devices implanted
      1 day previously did not differ significantly from the AUC after subcutaneous
      injection. At 1, 2 and 4 weeks after implantation, the recovery of insulin was
      significantly reduced, but at 3 months, the AUC was not significantly different
      from that in the control group. Histological examination showed that the number
      of vascular profiles within 15 microm of the device were significantly higher at
      2, 4 weeks and 3 months after transplantation when compared to numbers at 1 week.
      The design of the device allows transplantation of cells at a chosen time point
      after its implantation. Delayed filling of the device would allow
      neovascularization of the device surface before graft implantation and we suggest
      that such a schedule might improve function of the encapsulated graft.

PMID- 10352354
TI  - Immunomodulating effects of second-generation calcium channel blockers on
      experimental heart transplantation.
AB  - The administration of second-generation calcium channel blockers (CCBs) to
      counteract the adverse effects of conventional immunosuppression gains more and
      more acceptance. Since these newly developed molecules differ in their chemical
      structure and possess specific pharmacokinetic profiles, we hypothesized that
      exposure to clinically relevant concentrations may have a significant
      immunomodulatory potential. The effects of various second-generation CCBs,
      felodipine, amlodipine, mibefradil and clentiazem, on cardiac allograft survival
      were therefore evaluated. Inbred male Lewis rats were used as recipients and
      Brown-Norway rats as donors. After abdominal implantation of the donor heart,
      allograft recipients were exposed to felodipine (31 microg/kg/day), amlodipine
      (25 microg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). Other
      allograft recipients were treated with low-dose cyclosporine (CsA) alone (2
      mg/kg/day) or with low-dose CsA combined with amlodipine (25 microg/kg/day),
      mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). All drugs were given
      daily by gavage. Median survival time of untreated cardiac allografts was 6.5
      days. When given alone, not all the second-generation CCBs elicited a positive
      effect: the dihydropyridines felodipine and amlodipine were ineffective (median
      survival time was 6.5 and 7.0 days, respectively), the T- and L-type CCB
      mibefradil had a significant but minor impact (median survival time = 9.0 days, p
      <0.0015) while the benzothiazepine clentiazem produced the most significant
      result (median survival time = 16.0 days, p <0.0033). Neither amlodipine nor
      mibefradil modified the extent of survival provided by low-dose CsA (median
      survival time = 9.0 days), while clentiazem had a significant positive effect.
      These data indicate that second-generation CCBs differ in their immunomodulatory
      potential. These observations of pharmacodynamic specificity appear to be related
      to differences in their chemical structure as well as their interaction with
      other sites than the calcium channel.

PMID- 10352355
TI  - Isolated lung perfusion with melphalan prolongs survival in a rat model of
      metastatic pulmonary adenocarcinoma.
AB  - INTRODUCTION: Survival after isolated lung perfusion (ILuP) with melphalan was
      tested in a model of unilateral pulmonary adenocarcinoma. METHODS: On day 0, rats
      were randomized into four groups: Group 1 (n = 9) received tumor cells
      intravenously for induction of bilateral lung metastases, whereas groups 2-4 (n =
      21) underwent a 10-min occlusion of the right pulmonary artery during tumor cell
      injection for induction of unilateral left lung metastases. On day 7, groups 1
      and 2 received no treatment. Group 3 underwent left ILuP with melphalan (2.0
      mg/kg) while group 4 received melphalan intravenously (0.5 mg/kg). The end point
      of the study was death from metastatic disease. RESULTS: Median survival of ILuP
      treated animals (81 +/- 12 days) was significantly longer compared to group 1 (18
      +/- 1 days; p = 0.0001), group 2 (28 +/- 3 days; p = 0.0002) and group 4 (37 +/-
      6; p = 0.0004). CONCLUSIONS: ILuP with melphalan prolongs survival in the
      treatment of experimental metastatic pulmonary carcinoma.

PMID- 10352356
TI  - Azoxymethane-induced aberrant crypt foci and colorectal tumors in F344 rats:
      sequential analysis of growth.
AB  - Previous studies are consistent with the hypothesis that aberrant crypt foci
      (ACF) could be intermediate biomarkers in colorectal carcinogenesis. The present
      controlled experimental trial was performed to sequentially analyze ACF
      progression in rat colonic mucosa. F344 rats were administered 2-weekly doses of
      azoxymethane (15 mg/kg body weight, s.c.) and sacrificed 6, 12, 20, 30 and 36
      weeks after the first carcinogen injection. Control groups of untreated rats were
      sacrificed at the same time points. The number of ACF per area, their
      multiplicity (number of crypts per focus), ACF frequency and multiplicity
      according to each colonic site, histology of ACF and macroscopic lesions were
      recorded. No ACF were found in control animals. In treated animals, the number of
      ACF per area and the multiplicity progressively and significantly increased
      throughout the study. ACF were prevalent in the mid colon. Lower frequencies were
      registered in the distal colon and rectum. ACF were rare in the proximal colon
      and cecum. By histology, ACF presented superficial and extensive hyperplasia.
      Tumors were found in the 30th and 36th week. Adenomas and well-differentiated
      adenocarcinomas were in the distal colon. All proximal neoplasms were signet ring
      cell carcinomas. In our study, ACF growing features and distribution are not
      correlated to adenoma and adenocarcinoma distribution. It is conceivable that
      signet ring cell carcinomas arising in the proximal colon, where ACF are rare,
      could present a different pathway of growth. The preneoplastic role of ACF and
      their function as intermediate biomarkers in colorectal carcinogenesis remain to
      be clarified.

PMID- 10352357
TI  - Secretion of IL-6, monocyte chemoattractant protein-1, macrophage inflammatory
      protein-1alpha, and TNFalpha by cultured intact human peritoneum.
AB  - The peritoneum is an important site of host defence. The mesothelial cells,
      lining the peritoneum, and the fibroblasts found in the layers below are potent
      sources of a variety of mediators. Furthermore, granulocytes, mast cells, and
      macrophages, either resident or attracted by inflammatory processes, are
      interspersed within the tissue. We investigated the production of mediators by
      samples of fresh human peritoneum. The method described here has the advantage
      that the cellular composition of the human peritoneum remains intact. Samples of
      peritoneum were excised at the beginning of elective abdominal operations in
      infection-free patients. The tissue was placed across the wells of a microtitre
      plate, fixed in place by the plate cover and incubated with culture medium with
      or without lipopolysaccharide (LPS) for up to 5 h. The accumulation of IL-6,
      monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein
      1alpha (MIP-1alpha) and TNFalpha in culture supernatants was measured by ELISA.
      Production of MCP-1 and IL-6 occurred spontaneously during incubation and was
      enhanced by as much as 4-fold in the presence of different concentrations of LPS
      (0. 5-500 ng/ml) in a dose-dependent manner. MIP-1alpha and TNFalpha were
      detected in culture supernatants of LPS-stimulated samples with concentrations
      about 8 times as high as those of samples cultured with no such stimulus. The
      addition of IL-1beta resulted in an increase in the release of IL-6 and MCP-1,
      similar to that observed with LPS stimulation, but failed to increase the
      production of TNFalpha. MIP-1alpha production was only marginally enhanced by IL
      1beta. In conclusion, our experimental system is suitable for the investigation
      of chemokine and cytokine production by the human peritoneum, with the aim of
      assessing aspects of local immunocompetence.

PMID- 10352358
TI  - Endothelin-induced contraction of the portal vein in cirrhosis.
AB  - Endothelin (ET) is one of the most potent vasoconstrictors known so far. It has
      been proposed that the ET-induced contraction of hepatic stellate cells (Ito,
      endothelial cells) is an important mechanism for the development of portal
      hypertension. The purpose of this study was to investigate in an in vitro model
      whether ET causes a contraction of the portal vein which can contribute to portal
      hypertension in cirrhosis. Portal veins from normal and cirrhotic rats were used
      for experiments. Measurements were performed in vitro for cumulative
      concentrations of ET-1 and ET-3 (1, 5, 10, 50 and 100 nM). Both ETs caused a dose
      dependent increase in portal venous tension; the maximal tension (Tmax) was
      measured at 50 nM. The measured Tmax was higher for cirrhotic (ET-1: Tmax = 189%;
      ET-3: Tmax = 175%) than for normal rats (ET-1: Tmax = 130%; ET-3: Tmax = 151%).
      ET-3 produced a higher tension of portal veins in normal rats than ET-1. In
      conclusion, this study shows that portal veins from cirrhotic rats react more
      sensitively to ET than those from normal rats. Besides the ET-induced contraction
      of hepatic stellate cells, contraction of the portal vein and its intrahepatic
      branches, especially in cirrhotic individuals, has to be considered as a further
      mechanism of ET contributing to portal hypertension.

PMID- 10352360
TI  - Cell cycle regulatory proteins in glomerular disease.
AB  - The growth response of resident glomerular cells is determined by the underlying
      disease. Thus glomerular cells can proliferate, fail to proliferate, hypertrophy
      or apoptose. Cell growth is controlled by cell cycle regulatory proteins, and
      cell proliferation requires that cyclin-dependent kinases (CDK) be activated by
      partner cyclins. Inhibiting CDK2 reduces mesangial cell proliferation. Mesangial
      cell proliferation also requires that levels of specific cyclin kinase inhibitors
      (CKI) decrease. In contrast, the visceral glomerular epithelial cells' inability
      to proliferate may be due to increased levels of CKI. Moreover it is becoming
      increasingly clear that mesangial cell hypertrophy in diabetes requires increased
      CKI expression. Finally, apoptosis, which is often linked to proliferation, may
      also be due to the increased activity of CDK2. Thus, identifying specific cell
      cycle regulatory proteins following injury may provide future targets for therapy
      in glomerular disease.

PMID- 10352359
TI  - Regulation of the ROMK potassium channel in the kidney.
AB  - ROMK is a gene encoding inwardly rectifying adenosine triphosphate regulated K+
      channels. Alternative splicing of ROMK exons yields several different
      transcripts, ROMK 1-3, that are differentially expressed along the nephron.
      Cloned ROMK channels expressed in Xenopus oocytes exhibit properties similar to
      those of the native low-conductance K+ secretory channels in cortical collecting
      duct and medullary thick ascending limb, as manifested by use of the patch-clamp
      technique. These similarities between the cloned and native channels suggest that
      ROMK represents the low-conductance secretory K+ channels in the kidney. We
      studied the role of dietary K+ and aldosterone in the regulation of ROMK mRNA
      expression in the rat kidney. K+ deficiency downregulated ROMK mRNA in cortex and
      medulla. Adrenalectomy markedly downregulated cortical ROMK, while it increased
      it in the medulla. In adrenalectomized rats K+ deficiency decreased ROMK mRNA in
      cortex and medulla similarly to intact rats. Na-K-ATPase subunits alpha1 and
      beta1 were regulated in parallel to the regulation of ROMK. In the medulla ROMK
      mRNA correlated highly with serum K+ and with the alpha1 and beta1 subunits of Na
      K-ATPase. These results show that cortical ROMK expression is regulated by
      aldosterone and K+, while the medullary ROMK mRNA is regulated by serum K+,
      irrespective of aldosterone.

PMID- 10352361
TI  - Parathyroid hormone-related protein: roles in the glomerulus.
AB  - Parathyroid hormone (PTH) and PTH-related protein (PTHrP) produce similar
      biological effects through the PTH/PTHrP receptor. Less is known about the
      physiological role of PTHrP which was first identified as the agent of the
      humoral hypercalcemia of malignancy. Despite the widespread production of PTHrP
      in healthy individuals, the concentration of the protein is below the detectable
      limit of current assays, suggesting that PTHrP normally functions locally in an
      autocrine or paracrine manner. Thus, some differences in their biological
      activities have been described, and they may be related to the presence of
      different receptors. In this regard, a second receptor which binds selectively to
      PTH has also been found. Recent studies have demonstrated the expression of both
      PTH/PTHrP receptor and protein in the renal glomeruli. Moreover, there are
      convincing data that support a direct role of PTH and PTHrP in modulating renal
      blood flow and glomerular filtration rate. This multifunctional protein, PTHrP,
      also has a proliferative effect on mesangial cells, supporting the notion that it
      may play a role in the normal glomerulus and in injured kidney.

PMID- 10352362
TI  - Effect of human natural xenoantibody depletion and complement inactivation on
      early pig kidney function.
AB  - Preformed xenoreactive natural antibodies (XNA) and complement mediate hyperacute
      xenograft rejection (HXR) in pig-to-human discordant xenotransplantation. In a
      pig kidney-human blood xenoperfusion model, we investigated whether XNA depletion
      and/or human complement inactivation preserved early pig kidney function. Pig
      kidneys were perfused for 180 min with pig blood (AUTO group, n = 8), human blood
      (HETER group, n = 6), complement-inactivated human blood (COMi group, n = 5), XNA
      depleted human blood (ABd group, n = 5) or complement-inactivated and XNA
      depleted human blood (ABd&COMi group, n = 5). HETER kidneys were rejected after
      15-30 min and showed vascular microthrombi and interstitial hemorrhages. XNA
      depletion and/or complement inactivation prevented HXR. The glomerular filtration
      rate in ABd, COMi and ABd&COMi groups was significantly lower than in the AUTO
      group. Also, beyond 60 min, the COMi group showed a significantly lower
      glomerular filtration rate than that observed in ABd and ABd&COMi groups. Kidneys
      from ABd, COMi and ABd&COMi groups displayed endothelial cell edema, as well as
      higher soluble P-selectin levels and a higher renal myeloperoxidase content than
      the AUTO group kidneys. COMi and ABd&COMi groups had a significantly lower renal
      myeloperoxidase level than the HETER group. Also, in contrast to HETER and ABd
      groups, these complement-inactivated groups failed to show a positive correlation
      between P-selectin and renal myeloperoxidase. We also investigated platelet
      activating factor (PAF) as possible mediator for these functional and pathologic
      changes. We found that blood PAF levels were similar in HETER, ABd, COMi and
      ABd&COMi groups and significantly higher than in the AUTO group. Also, when PAF
      was added to porcine endothelial cell monolayers, morphological changes due to
      cytoskeleton contraction were observed, and these changes were prevented by
      preincubation with a PAF receptor antagonist. In conclusion, although depletion
      of XNA and/or complement inactivation prevent HXR, the pig kidney function is not
      preserved at the level of the autologous combination. The PAF overproduction
      observed in the xenogenic combination, which is independent of the presence of
      XNA and complement, may be, at least in part, responsible for early endothelial
      cell morphological changes still present when HXR is prevented.

PMID- 10352363
TI  - Ramipril inhibits in vitro human mesangial cell proliferation and platelet
      derived growth factor expression.
AB  - Angiotensin-converting enzyme (ACE) inhibitors are antihypertensive drugs that
      have been shown to reduce proteinuria and to slow down the progression of renal
      function deterioration in different models of chronic glomerular disease. Major
      pathogenetic features of progressive glomerular injury leading to
      glomerulosclerosis are mesangial cell proliferation and platelet-derived growth
      factor (PDGF) expression. The aim of the present study was to evaluate the effect
      of ramipril, an ACE inhibitor, on these two potential therapeutic targets. Thus,
      the effect of ramipril on DNA synthesis, cell proliferation and PDGF A and B
      chain gene expression in fetal calf serum (FCS)-activated cultured human
      glomerular mesangial cells was investigated. DNA synthesis was evaluated by
      tritiated thymidine incorporation, cell proliferation by direct cell counting and
      cell viability by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
      (MTT). PDGF A and B chain gene expressions were studied by Northern blot and RT
      PCR, respectively. In a dose-dependent manner ramipril inhibited the FCS-induced
      DNA synthesis and cell proliferation. This effect was not dependent upon a toxic
      effect as demonstrated by MTT. The antiproliferative effect of ramipril was most
      likely independent of its ability to inhibit ACE present in the FCS and/or
      expressed by the cells, since a synthetic peptide that specifically inhibits ACE,
      at the same molar concentrations, did not inhibit FCS-stimulated DNA synthesis.
      Moreover, ramipril significantly reduced FCS-induced PDGF A and B chain gene
      expression. Finally, ramipril completely abolished the PDGF A and B chain gene
      expression induced by phorbol 12-myristate 13-acetate, a specific protein kinase
      C activator, suggesting a site of action downstream of this enzyme in the
      mitogenic signal transduction pathway. Our study would suggest that the
      modulatory action of ramipril on activated mesangial cell proliferation and PDGF
      expression is independent of its ability to inhibit ACE and could represent an
      additional mechanism in the renal protective effects of this drug.

PMID- 10352364
TI  - Inhibition of erythrocyte aminolevulinate dehydratase by a 56.2-kD peptide from
      uremic plasma.
AB  - Among the abnormalities in erythrocyte porphyrin metabolism already described in
      patients with chronic renal failure on hemodialysis, a decrease in blood
      aminolevulinate dehydratase activity has been reported, suggesting the presence
      in uremic plasma of an inhibitor of the enzyme. The aim of this work has been to
      isolate and characterize such an inhibitor. Blood samples from 105 patients with
      chronic uremia were collected; plasma was applied to Sephadex G-100 columns and
      the fraction with the highest inhibiting capacity was identified and purified by
      subsequent SDS-polyacrylamide gel electrophoresis, followed by electroelution and
      electroblotting. It was demonstrated that the factor present in plasma of uremic
      patients inhibited blood aminolevulinate dehydratase in a concentration-dependent
      manner; its inhibitory properties were abolished after heat, trypsin and TCA
      treatment indicating its peptidic nature. The purified inhibitor has an apparent
      molecular mass of 56.2 kD, it inhibits blood aminolevulinate dehydratase in a
      competitive way and the Ki value is 12x10(-6) M. The amino acid composition of
      the inhibitor has been determined and it has been found that its N-terminal amino
      acid is blocked. The isolated peptide may play a role in heme biosynthesis
      disturbances and in the pathogenesis of uremic anemia.

PMID- 10352365
TI  - The calcium channel blocker nitrendipine attenuates renal and glomerular
      hypertrophy in diabetic rats.
AB  - The efficacy of the calcium channel blocker nitrendipine in preventing early
      renal and glomerular hypertrophy and increased urinary albumin excretion (UAE)
      was studied in experimental diabetes in rats, starting treatment at the onset of
      diabetes. Female Wistar rats were randomised into four groups: diabetic and non
      diabetic rats were given either placebo or nitrendipine (250 mg/kg) in the diet
      for 8 weeks. After 8 weeks the kidneys in the diabetic animals had increased
      significantly compared to the non-diabetic controls. In the diabetic nitrendipine
      treated animals renal and glomerular hypertrophy was significantly smaller than
      in the diabetic placebo-treated group (p < 0.05). After an initial increment
      within the first week, the UAE remained constant throughout the study period in
      the diabetic nitrendipine-treated animals, while a steady increase was seen in
      the diabetic placebo-treated group (p < 0.05). No differences were seen in
      systemic blood pressure between calcium- channel-blocker-treated groups and
      placebo-treated groups. In conclusion, administration of nitrendipine to diabetic
      rats for 8 weeks had a significant inhibitory effect on renal and glomerular
      hypertrophy, and showed a tendency towards a reduction in UAE (p = 0. 06) without
      affecting metabolic control or systemic blood pressure.

PMID- 10352366
TI  - Cadmium nephrotoxicity assessed in isolated rat glomeruli and cultured mesangial
      cells: evidence for contraction of glomerular cells.
AB  - Cadmium (Cd), an important pollutant, causes severe damage at the renal tubular
      level. Numerous previous studies have focused upon Cd tubular nephrotoxicity. The
      present study of Cd-induced glomerular damage examined the vasoactive effect of
      Cd in freshly isolated glomeruli and mesangial cells. Glomeruli were isolated by
      passing rat renal cortex pulp through calibrated sieves followed by culture for
      outgrowth of cells. Quantitative evaluation of glomerular and cellular
      contractions was performed by morphometric measurement of the area with an
      automatized image analyzer following different incubation times with Hanks'
      balanced salt solution or Cd2+. Each glomerulus or mesangial cell served as its
      own control. Cd lethality was measured with microassay methods (neutral red, MTT
      uptake, and lactate dehydrogenase release), allowing the determination of an
      IC50. This ranged from 35 to 60 microM. CdCl2 induced a time-dependent
      contractile effect on isolated glomeruli; planar surface area decreases were 6.9%
      (1 microM), 7.5% (0.1 microM), and 7% (0.01 microM). The decrease started as soon
      as Cd was in contact with glomeruli and ended 40 min later: T5 (2%), T10 (3.5%),
      T20 (4. 2%), T30 (6.3%), T40 (7%). Cell size reduction was 19% (1 microM), 14%
      (0.1 microM), and 18% (0.01 microM) and was also time-dependent. To confirm that
      contractile events occurred during the cell shape changes, examination of the
      mesangial alpha-actin network was performed concurrently. These results indicate
      that Cd contracts glomerular structures. This may, in part, explain the reduction
      in glomerular filtration seen in Cd nephrotoxicity.

PMID- 10352367
TI  - Transfer of genetically engineered cells to the glomerulus.
AB  - In the rat, cultured cells injected into the renal circulation are entrapped in
      the glomerulus. This peculiar property allows to create chimeric glomeruli in
      which genetically engineered cells are populated. Using glomerular cells
      engineered in vitro, it is feasible to generate glomeruli that produce
      recombinant gene products. This approach would be useful for identification of
      local function of a certain gene product in the glomerulus and for therapeutic
      intervention in glomerular disease. Transfer of activated leukocytes to the
      glomerulus is useful to elucidate pathologic actions of infiltrating cells on the
      glomerular structure and function. Use of leukocytes in which certain gene
      function is selectively reinforced or deleted should enable to disclose exact
      roles of leukocyte-associated genes in glomerular pathophysiology. Transfer of
      engineered leukocytes also allows to investigate how resident cells modulate the
      activity of infiltrating cells in normal and pathologic circumstances. This
      article summarizes current experience with adoptive transfer of engineered cells
      to the glomerulus and addresses its potential application to kidney research.

PMID- 10352368
TI  - Application of genetically engineered tubular epithelial cells in kidney disease.
AB  - We constructed an ex vivo gene transfer system to deliver cytokines into the
      kidney and circulation using genetically modified renal tubular epithelial cells
      (TEC). TEC were infected with recombinant retroviruses expressing macrophage
      (Mphi) growth factors using a retroviral Moloney murine leukemia virus-based MFG
      vector. These infected TEC have the capacity to secrete stable and sustained
      amounts of cytokines for prolonged periods (>4 months) in vitro and in vivo (>28
      days). Implanting genetically modified TEC secreting Mphi growth factors under
      the kidney capsule initiates severe local renal injury in mice with a deficiency
      in Fas (Faslpr gene). This system offers a novel and powerful approach to probe
      for the impact of sustained cytokine expression in the progression of kidney
      destruction.

PMID- 10352369
TI  - [Effect of a standardized acupuncture treatment on complains, blood pressure and
      serum lipids of hypertensive, postmenopausal women. A randomized, controlled
      clinical study].
AB  - BACKGROUND: Acupuncture according to the Chinese syndrome is often used in
      patients with postmenopausal complaints. Often these patients have an increased
      blood pressure. As experienced therapists report that acupuncture is efficient
      also in hypertension, our aim was to investigate whether the acupuncture used for
      the treatment of postmenopausal syndrome also has an effect on blood pressure.
      PATIENTS AND METHODS: The efficacy of a standardized acupuncture according to the
      Chinese syndrome was evaluated in a randomized, single-blind, placebo-controlled
      cross-over study with 10 postmenopausal patients with mild hypertension. Blood
      pressure was measured by 24-hour ambulatory blood pressure measurement.
      Complaints and well-being were evaluated by validated questionnaires. In
      addition, serum lipids and excretion of catecholamines in the 24-hour urine were
      measured. RESULTS: Blood pressure was altered neither by verum nor placebo
      acupuncture, however, complaints were significantly reduced and well-being was
      improved after verum treatment. The improvement lasted less than two months.
      Serum lipids did not change, but the excretion of normetanephrine was reduced by
      verum acupuncture. CONCLUSIONS: Acupuncture with a standardized combination of
      acupuncture points according to the Chinese syndrome can transitorily reduce
      postmenopausal complaints, but does not alter blood pressure or serum lipids at
      the same time.

PMID- 10352370
TI  - [Medicinal baths for treatment of generalized fibromyalgia].
AB  - OBJECTIVE: We studied whether whirl baths with plain water or with water
      containing pine oil or valerian have a different influence on pain, disturbed
      sleep or tender point count. METHODS: A randomized, comparative and investigator
      blinded study was performed. Out-patients with generalized fibromyalgia were
      randomized into three treatment groups. INTERVENTIONS: Therapy consisted of
      either whirl bath with plain water or with the addition of pine oil or valerian.
      The baths were carried out 10 times, three times a week. MAIN OUTCOME MEASURES:
      General pain, change of pain intensity during the day, general well-being and
      occurrence of disturbed sleep were recorded before and after the therapy. The
      number of tender points was assessed by digital palpation, the pain threshold on
      the shinbone and the middle part of the deltoid muscle was measured by the
      dolorimeter of A. Fischer. The same instrument was used for recording pain
      threshold and pain tolerance of both trapezius muscles. The tissue compliance of
      these muscles was measured as well. RESULTS: 30 out of 39 patients included in
      the study were evaluated statistically. After treatment with valerian bath (n =
      12) well-being and sleep were significantly improved and also the tender point
      count decreased significantly. Pine oil added to the bath water (n = 7) resulted
      in a significant improvement of well-being, but unfortunately also in a
      significant decrease of pain threshold of the shinbone and the right deltoid
      muscle. Whirl bath in plain water (n = 11) reduced general and maximum pain
      intensity significantly. CONCLUSIONS: Our cautious conclusion of this study is -
      with respect to the small number of treated patients - that different effects of
      whirl baths with or without medicinal bath oils can be detected in fibromyalgia
      patients. Plain water baths modify the pain intensity, medicinal baths improve
      well-being and sleep.

PMID- 10352371
TI  - [Hyperthermia-induced priming effect in neutrophil granulocytes].
AB  - BACKGROUND AND OBJECTIVE: Whole-body infrared-A irradiation (WBIAI) according to
      Ardenne is a newly developed version of hyperthermia. In clinical use benefits
      for patients with chronic infections have been reported. In order to find out
      more about the immunological background of the method we studied the question
      whether hyperthermia leads to priming effects in human polymorphonuclear
      leukocytes (PMN). MATERIAL AND METHODS: We therefore investigated the production
      of reactive oxygen radical species (ROS) measured by lucigenin-dependent
      chemiluminescence after stimulation with N-formylpeptide (FMLP, 10(-6) and 10(-7)
      M), C5a complement (10(-7) and 10(-8) M) or phorbolester (PMA, 10(-7) and 10(-8)
      M) in isolated PMN of 8 volunteers undergoding a 60-min hyperthermia treatment
      with the WBIAI. Blood was drawn 0/60/240/510 min after the start of hyperthermia
      treatment. In addition, we measured blood pressure, pulse, and temperature.
      RESULTS: In 5 cases a significant increase in ROS (p < 0.05) could be measured
      beginning 240 min after start of hyperthermia and further increasing until the
      510-min time point. These results suggest a priming effect in PMN lasting far
      beyond the actual treatment period. The increase of ROS production following
      stimulation with FMLP, C5a or PMA was 60.4 +/- 21.6, 86.0 +/- 23.3, and 63.3 +/-
      15.9% (SEM), respectively. Moreover, in all probands the maximal ROS production
      in PMN was observed 510 min after the beginning of WBIAI treatment. In 3 cases no
      difference in ROS could be observed. There was no difference in temperature,
      blood pressure, and pulse between responders and nonresponders. CONCLUSIONS: Our
      results show a hyperthermia-dependent priming effect of ROS production in PMN,
      suggesting an increase in immune reaction within the observation period of 510
      min. Further investigations are necessary in order to specify responders and
      nonresponders and to characterize the results in specific diseases and the
      constitutions of the patients.

PMID- 10352372
TI  - [Problems of study designs with randomization, blinding and placebos].
AB  - As randomised double-blind trials are not rarely demanded as a prerequisite for
      the scientific acceptance of complementary medicine, the author has analysed the
      soundness of this demand on the basis of the international literature. As a
      result there appeared a number of methodological, practical and ethical problems
      which question the theoretically deduced primal value of this study design
      relative to the needs of medical practice and of health insurance issues. The
      experimental instruments of randomisation, blinding and placebo deliberately
      exclude essential therapeutic factors which are integral elements of
      complementary medical concepts; therefore, it is suggested to supplement
      quantitatively and collectively oriented experimental research by non
      experimental procedures, which adequately reflect the context- and practice
      related individual reality.

PMID- 10352373
TI  - [Alternative medicine therapy in dermatology: dimensions, chances and approaches
      to an integrative understanding].
AB  - Skin diseases may bring considerable psychosocial stress for the affected
      patients. The therapist must strive to relieve the symptoms and also to provide
      long-lasting prevention of recurrences, especially in chronic skin diseases.
      Clinical experience has shown complementary procedures, especially the classical
      naturopathy, to be promising supplements to conventinal therapy. Proof of
      efficacy in dermatological applications has been found in controlled studies for
      some of these procedures. By far the majority of these applications in
      dermatology still require controlled investigation. The required efficacy studies
      should orient to internationally accepted criteria for clinical studies and
      record not only clinical efficacy but also quality of life factors and cost of
      treatment in a therapy comparison. Psychosomatic relationships play a particular
      role in dermatological treatment. In addition to their importance as occasional
      originators or potentiaters of skin disease, emotional factors are crucial in the
      secondary stress associated with the disease due to the numerous visible effects
      on the skin. An integrative dermatological therapy makes the attempt both to
      determine and to treat the co-eliciting emotional factors and to support the
      patient's mode of coping with the disease. The doctor-patient relationship is
      especially important here. In summary, conventional, complementary and
      psychosomatic procedures can be mutually beneficial in dermatological therapy.

PMID- 10352374
TI  - [Phytotherapy in chronic dermatoses and wounds: what is the evidence?].
AB  - Phytotherapeutic preparations and synthetic derivatives of plant origin have been
      used in conventional dermatology for a long time. A further spectrum of
      phytotherapeutic agents for the treatment of dermatological diseases and wounds
      is known from alternative medical treatment. To the efficacy of these
      phytotherapeutic agents only few data from studies are available. Own studies and
      studies published in the specialist literature, especially on chamomile, arnica,
      calendula, hamamelis, Aloe vera, cardiospermum, Mahonia aquifolium, oak bark,
      bittersweet stalk, and capsaicin indicate that these plants may be of value in
      selected dermatological indications. Other controlled clinical efficacy studies
      and pharmacological studies are needed to prove the assumed effects, to record
      the spectrum of side effects, and to clarify the mechanisms of action.

PMID- 10352375
TI  - [Regulative therapy: treatment with nonspecific stimulants in dermatology in
      traditional and modern perspectives].
AB  - Stimulation or regulation therapies are old therapeutic procedures based on
      models reaching back to traditional medical faculties in ancient times and in the
      Middle Ages. Among this heterogeneous group are acupuncture, purgative procedures
      (especially the Aschner methods), autohemotherapy, fasting therapy, homeopathy,
      microbiological and physical therapies. The basic principle underlying all of
      these procedures is that stimulants applied in proper doses to the organism
      elicit counterregulation. The counterregulation stimulates 'self-healing
      processes' within the organism. The efficacy of stimulation therapies was
      originally deduced mostly from traditional explanatory models which have lost
      their relevance for modern medicine. However, it has been found in applications
      in dermatology that many of these stimulation therapies can lead to clinical
      improvement in selected indications and that modern explanatory models can be
      found for these effects. This presentation reports on exemplary applications of
      stimulation therapies in dermatology. Traditional and modern concepts of action
      are compared.

PMID- 10352376
TI  - [From neuropeptides and cytokines to psychotherapy. Skin diseases between
      psychoneuroimmunology research and psychosomatic treatment].
AB  - Most therapists recognize that emotional factors influence the course of
      neurodermitis (ND). Most studies concerning the influence of experimental, acute
      stressors brought only inconsistent results in ND. Most likely, the experimental
      stressors chosen thus far were only able to poorly simulate the reactions to real
      stressors in neurodermitis patients. More recent articles, however, were able to
      demonstrate changes in psychoimmunological parameters under experimental stress
      conditions in ND in comparison with a control group of persons with healthy skin.
      Retrospective studies, serial analyses over time and psychotherapeutic evaluation
      studies were able to demonstrate even more clearly that emotional factors
      influence the course of ND.

PMID- 10352377
TI  - Effects of Mahonia aquifolium ointment on the expression of adhesion,
      proliferation, and activation markers in the skin of patients with psoriasis.
AB  - OBJECTIVE: To examine the effects of topical therapy with Mahonia aquifolium on
      the expression of pathogenetically relevant molecules in psoriatic skin by
      immunohistochemistry. STUDY DESIGN: Prospective-randomized, half-side comparison
      study with subsequent immunohistochemical assessment of biopsies. METHODS: The
      study areas were treated with Mahonia aquifolium ointment 3( daily and with
      dithranol in rising concentrations 1( daily, respectively. Biopsies of lesional
      skin from the test areas were carried out in 49 patients a) prior to therapy and
      b) 4 weeks after the start of therapy. Immunohistochemical stainings were
      performed with the following monoclonal antibodies: anti-ICAM-1, -CD3, -HLA-DR, 
      keratin 6, -keratin 16, -Ki-67. Evaluation of staining was made by two
      independent examiners using established semiquantitative scores. RESULTS: Marked
      staining with all of the cited monoclonal antibodies was observed in the lesional
      skin prior to therapy. After 4 weeks of therapy there was a marked reduction in
      the expressions of ICAM-1, CD 3, HLA-DR and keratin 6 and 16. There were
      significantly greater reductions of ICAM-1, CD3, and HLA-DR at sites treated with
      dithranol. The expression of Ki-67 was not reduced by either therapy.
      CONCLUSIONS: These results indicate efficacy of Mahonia aquifolium and dithranol
      in psoriatic skin both on cellular cutaneous immune mechanisms and on the
      hyperproliferation of keratinocytes. The effect of dithranol appears to be more
      potent than that of Mahonia aquifolium.

PMID- 10352379
TI  - Attitudes and prior experience with respect to alternative medicine among
      dermatological patients: the Freiburg questionnaire on attitudes to naturopathy
      (FAN).
AB  - OBJECTIVES: 1) Development and validation of a questionnaire on the attitudes and
      prior therapies with respect to naturopathy. 2) Clinical application in patients
      with atopic dermatitis in conventional and unconventional inhospital therapy.
      METHODS: A questionnaire for patients with skin diseases was developed, which
      includes the following areas: 1. prior therapies (conventional, unconventional,
      and psychotherapeutic procedures), 2. attitudes to the procedures, 3. previous
      therapists, 4. sources of information about the disease. The questionnaire was
      validated on 1,288 inpatients and outpatients in three clinics. A comparison
      study using the questionnaire was performed with 73 inpatients with atopic
      dermatitis under conventional therapy and 59 inpatients under alternative-medical
      therapy. RESULTS: The patients undergoing alternative-medical therapy reported
      significantly more prior experience in both conventional and unconventional
      procedures. The unconventional procedures were rated significantly higher by
      these patients, while the patients under conventional treatment rated several
      conventional procedures significantly higher. With respect to previous
      therapists, patients under unconventional treatment had been treated
      significantly more frequently by physicians oriented toward naturopathy and
      nonmedical practitioners. Prior information concerning the disease had been
      obtained significantly more frequently by the patients under alternative-medical
      treatment. DISCUSSION: Patients with atopic dermatitis under conventional or
      alternative medical treatment differ widely from one another with respect to
      previous therapies and prior experience and attitudes to conventional and
      unconventional procedures. These selection effects must be taken into
      consideration when comparing various therapeutic approaches, e. g. in multicenter
      studies.

PMID- 10352378
TI  - Psychosocial characterization of patients with atopic dermatitis in conventional
      versus alternative-medical therapy.
AB  - OBJECTIVE: Recording of psychosocial differences between patients with atopic
      dermatitis (AD) undergoing conventional versus alternative-medical treatment as
      indication of a center-related selection effect. STUDY DESIGN: In this
      prospective comparative study, inpatients of an alternative-medical clinic and of
      the University Dermatology Clinic Freiburg were given standardized questionnaires
      on psychosocial characteristics in the areas of disease-specific stress, social
      support, and coping with the disease. PATIENTS: Fifty-nine consecutive AD
      patients were recruited at the alternative-medical clinic and 79 AD patients at
      the University Dermatology Clinic. Fifty-five (93.2%) and 73 (92.4%) patients
      respectively returned completed questionnaires. RESULTS: The two treatment groups
      differed markedly from one another with respect to psychosocial parameters.
      Patients of the alternative-medical clinic showed greater disease-specific
      stress, lower social integration, and higher values in the coping scales
      'depressive coping' and 'religious conviction and search for meaning'. Compared
      to patients with acne vulgaris, both patient groups were under significantly
      greater disease-specific stress. The factor 'social integration' was determined
      by logistical regression analysis to be the most important differentiation
      characteristic between the groups. CONCLUSIONS: Patients under alternative
      medical treatment may show significant psychosocial differences in comparison
      with conventionally treated patients. In comparative studies between conventional
      and alternative-medical therapy centers, selection effects must be assumed and
      taken into account when evaluating the study.

PMID- 10352380
TI  - Intravenous iron therapy in pregnancy anemia: hematological response in relation
      to gestational age.
AB  - This study was undertaken to evaluate the response to parenteral administration
      of iron in 62 pregnant patients with asiderotic anemia and mean initial
      hemoglobin (Hb) concentrations (Hb1) of 9.91+/-(SD) 1.13 g/dl. Iron (742+/-366
      mg) was administered intravenously, and the response to treatment was classified
      according to the rise in Hb (VarHb; 0.97+/-0.77 g/dl) and evaluated after 19.5+/
      14.6 (range 4-57) days. It was found that the VarHb was inversely correlated with
      the Hb1 value (r = -0.46; p<0.001) and only weakly correlated with the number of
      vials administered. In addition, two-cluster analysis of patients on the basis of
      VarHb and gestational age resulted in two significantly different groups
      (p<0.001): >28 weeks of pregnancy (n = 39, group 1: 1.27+/-0.66, range 0.1-3.3
      g/dl) and < or =28 weeks of pregnancy (n = 23, group 2: 0.45+/- 0.69, range 0.4
      2.3 g/dl). No difference was found between groups 1 and 2 in relation to Hb1,
      iron dose, and therapy duration. The number of patients with VarHb >0.8 g/dl was
      found to be higher in group 2 than in group 1: 31/39 versus 8/23 (p<0.001). These
      results indicate that the response to intravenous iron therapy in pregnancy
      anemia is related to Hb1 level and gestational age at the onset of treatment and
      probably depends on the erythropoietin response to anemia.

PMID- 10352381
TI  - Simplified biophysical profile: an antepartum fetal screening test.
AB  - A total of 330 high-risk pregnant women with gestational ages of 32-42 weeks were
      followed until delivery using the biophysical profile (BPP) and a screening test
      consisting of the amniotic fluid index together with fetal acoustic stimulation
      under ultrasound M-mode scanning. The test was compared with the BPP and
      nonstress test (NST) for predicting abnormal outcome. The sensitivities of the
      BPP, NST and the proposed test were 100, 98.4 and 100%, respectively, the
      negative predictive values were 100, 99.4 and 100%, while the false-positive
      rates were 21.3, 39.3 and 67%. Our simplified biophysical testing method is
      suggested to be a good negative preliminary screening test, while positive
      results require further fetal testing methods. This test reduced the need for BPP
      in many high-risk patients and had the advantages of simplicity, low cost and
      less time consumption.

PMID- 10352382
TI  - Immunologic and biochemical factors in hyperemesis gravidarum with or without
      hyperthyroxinemia.
AB  - OBJECTIVE: This study was set up to investigate the relationship between immune
      process and high levels of human chorionic gonadotropin-beta (betahCG) in
      hyperemesis patients with or without hyperthyroxinemia. METHODS: betahCG, immune
      parameters and thyroid related hormones were assayed in hyperemesis patients and
      in controls. RESULTS: Mean serum betahCG, fT4 and TSH levels were significantly
      higher in hyperemesis patients than in controls (p<0. 01, p<0.01, p<0.05,
      respectively). Further, immune parameters regarding IgG, IgM, C3, C4 and
      lymphocyte count were significantly higher in patients than in controls (p<0.05,
      p<0.01, p<0.01, p<0.05, p<0.01, respectively). In hyperemesis patients with
      hyperthyroxinemia, mean serum betahCG, IgG and IgM were significantly higher than
      in hyperemesis women without hyperthyroxinemia (p<0.001, p<0.05, p<0.05,
      respectively). BetahCG was positively correlated with fT4 (r = 0.45, p<0.05),
      with lymphocyte count (r = 0.47, p<0.01), with IgM (r = 0.38, p<0.05) and with C3
      (r = 0.40, p<0.05) in hyperemesis patients. A negative correlation between
      betahCG and TSH (r = -0.43, p<0.05) was noted in the hyperemesis group. Free T4
      showed a positive association to IgM (r = 0.49, p<0.01), to IgG (r = 0.40,
      p<0.05), to lymphocyte count (r = 0.45, p<0.05). CONCLUSION: Immunologic activity
      in pregnancy may have an effect or role on the stimulatory mechanism of betahCG
      in hyperemesis patients with or without hyperthyroxinemia.

PMID- 10352383
TI  - Fetal compromise assessed by Doppler ultrasound of venous flow in pregnancy
      induced hypertension.
AB  - The purpose of this study was to determine the change of venous flow patterns in
      the inferior vena cava of fetuses in pregnancy-induced hypertension (PIH). We
      studied 80 normal pregnant women and 46 pregnant women with PIH and their
      fetuses. We determined the pulsatility index (PI) for arterial vessels, the ratio
      of peak flow velocities in early diastole and late diastole (E/A) in
      atrioventricular valves, and the preload index for the inferior vena cava. Twelve
      of the 46 PIH women showed an umbilical artery PI higher than the 95th percentile
      in normal pregnant women. Five of them demonstrated a decreased middle cerebral
      artery PI. Three of the 5 had an increased mitral E/A. Two of them had a
      decreased tricuspid E/A, an increased preload index, and a poor prognosis. An
      increased preload index suggests severe compromise in fetuses with a
      redistribution of arterial and intracardiac blood flow.

PMID- 10352384
TI  - Umbilical artery waveforms in triplet and quadruplet pregnancies.
AB  - The incidence of abnormal umbilical waveforms in triplet and quadruplet
      pregnancies and its correlation with adverse pregnancy outcome was studied by a
      retrospective review of all our triplet and quadruplet pregnancies (1986-1993)
      with documented Doppler flow assessment. Obstetrical outcomes were analyzed in
      relation to abnormal umbilical artery waveforms. Nineteen triplet and 4
      quadruplet pregnancies were studied. Of 73 fetuses, 6 had abnormal umbilical
      artery waveforms (8.2%). All abnormal waveforms were characterized by persistent
      absence of the end-diastolic velocities (AEDV). In comparing the abnormal and
      normal groups, significant differences were found in birth weights (910+/-433 vs.
      1,724+/-434 g; p = 0.0004), small for gestational age rate [5/6 (83%) vs. 5/67
      (7.5%); p = 0.0003], and perinatal mortality rate [3/6 (50%) vs. 2/67(3%); p =
      0.001]. There were no differences in congenital anomalies, gestational age at
      birth, and neonatal intensive care admission. In conclusion, it seems that
      Doppler umbilical artery waveforms in multiple pregnancies were either normal or
      extremely abnormal (e.g. AEDV). AEDV was associated with adverse perinatal
      outcomes such as low birth weight, growth restriction and perinatal mortality.

PMID- 10352385
TI  - Case series of labor induction in twin gestations with an Intrauterine Balloon
      catheter.
AB  - The efficacy and safety of labor induction using an intrauterine balloon catheter
      in twin pregnancies has been evaluated. During the study period (1992-1997),
      labor was induced at 36-42 weeks in 17 twin gestations. Labor induction was
      indicated for preeclampsia (n = 10), birth weight discordance (n = 3), suspected
      fetal distress (n = 2) and postdates (n = 2). Twin A was in vertex presentation
      in all cases. An intrauterine balloon catheter was inserted transcervically
      followed by augmentation whenever required. Vaginal delivery was achieved in 15
      (88.2%) patients. The mean interval from balloon insertion to delivery was 17.05
      h, with 80% deliveries occurring within 24 h of catheter insertion and 80%
      occurring within 12 h of catheter expulsion. Birth weight was 2,514+/-244 and
      2,421+/-367 g for twin A and B, respectively. Oxytocin was required in 4
      patients. Postpartum hemorrhage was noted in 1 patient. One patient with no
      progress of labor and 1 with suspected intrapartum fetal distress required
      cesarean section. All neonates had a 5-min Apgar score of 10. The data suggest
      that an intrauterine balloon catheter appears to be safe and effective to induce
      labor in twin gestations.

PMID- 10352386
TI  - Distribution of glutathione S-transferases in the human ovary: an
      immunohistochemical study.
AB  - The glutathione S-transferases (GSTs) are a family of isoenzymes with several
      functions. These include the metabolism of endogenous and exogenous toxic
      compounds, an isomerase activity in steroidogenesis and intracellular transport.
      This study has used immunohistochemistry to demonstrate the distribution of the
      three classes of GST (alpha, mu and pi) in the human ovary at different stages of
      the menstrual cycle. Alpha-GST was found in cells related to steroid hormone
      production and probably acts as a delta4-5 isomerase. Mu-GST was predominantly
      found in the non-luteinized stromal cells and its function is obscure. Pi-GST was
      found in surface 'epithelial' inclusions and the media of arteries where it is
      thought to play a detoxifying role.

PMID- 10352388
TI  - Treatment of recurrent bleeding disorders during hormone replacement therapy by
      transcervical endometrial ablation.
AB  - If bleeding disorders, which could not be treated by modification of steroid
      dosages, occurred during sequential hormone replacement therapy (HRT), most of
      the patients stopped HRT. In these cases a diagnostic outpatient hysteroscopy
      with biopsy was carried out. In most of the cases no intrauterine cause for the
      bleeding disorder was found. In 35 patients we performed an endometrial ablation
      without intra- or postoperative complications. After this procedure all patients
      received a combined continuous HRT. In a follow-up of 12 months 34 patients were
      amenorrheic and satisfied with the treatment. One patient stopped HRT because of
      suffering from other side effects. Endometrial ablation represents a method of
      treating patients with bleeding disorders without intrauterine causes with a
      minimal invasive procedure. A continuous combined HRT is possible after the
      endometrial ablation in perimenopausal and postmenopausal patients without
      bleeding disorders. In selected cases endometrial ablation can contribute to the
      increase of the compliance with HRT.

PMID- 10352387
TI  - Endometrial development was improved by transdermal estradiol in patients treated
      with clomiphene citrate.
AB  - The objective of this study was to examine the effect of transdermal estrogen
      therapy on the endometrial thickness and serum hormone levels in anovulatory
      patients treated with clomiphene citrate (CC). There was a significant difference
      in endometrial thickness between the CC + transdermal estrogen group and the CC
      only group from day -2 to day +2. Serum estradiol (E2) levels in the CC +
      transdermal estrogen group were significantly higher than those in the CC only
      group on day -2 and day 0. Our results support that addition of transdermal E2 to
      the treatment protocol of the women treated with CC elicited a favorable response
      of the endometrium.

PMID- 10352389
TI  - Short-term treatment of uterine fibromyomas with danazol.
AB  - The aim of this study was to evaluate the effects of danazol in reducing the
      volume of fibromyomas and in the treatment of associated symptoms. Twenty women
      (34-42 years) with uterine fibromyomas were treated with 400 mg/day of danazol
      for 4-month periods. The women underwent ultrasound examination to determine
      their uterine volume at enrollment in the follicular phase and after 2 and 4
      months. The examination was repeated by the same sonographer 3 and 6 months after
      the end of therapy. Blood samples were taken on the same days for LH, FSH,
      estradiol and progesterone assays. After therapy, fibromyoma volume decreased
      significantly (p<0.01) by an average of 23.6+/-5%. All patients experienced
      partial or complete relief of symptoms while using danazol. Three and six months
      after the end of treatment the fibromyoma volume had only increased slightly with
      respect to the volume at the end of therapy, but was still lower than the
      starting volume. The present study shows the efficacy of danazol at a dose of 400
      mg/day for 4 months in reducing the volume of fibromyomas and associated
      symptoms. The mechanism by which danazol reduces the volume of fibromyomas may be
      due to reduced estrogen concentrations and to its antiprogesterone effects on
      uterine myomas.

PMID- 10352390
TI  - Experience with isotonic 2.2% glycine as distension medium for hysteroscopic
      endomyometrial resection.
AB  - The feasibility of performing hysteroscopic endomyometrial resection using
      isotonic 2.2% glycine as distension medium was studied in 181 consecutive
      operations. A standard continuous flow loop-resectoscope was used. Distension was
      achieved by means of a gravity-fed system and glycine flowed out under its own
      pressure. The mean (+/-SEM) glycine deficit was 160+/-20 ml and in only 7
      patients was it >1 liter (maximum 1,800 ml). Only in patients with >1 liter
      glycine absorption was there a significant decrease in serum sodium level (mean 9
      mmol/l), while serum osmolality remained normal. Apart from 1 case of transient
      nausea, these patients had no sequelae. We experienced isotonic 2.2% glycine as a
      useful and safe distending medium for operative hysteroscopy.

PMID- 10352391
TI  - Onapristone suppresses prolactin production in explant cultures of leiomyoma.
AB  - OBJECTIVE: To assess the action of onapristone, a type I antiprogestin, on
      prolactin (PRL) production by explant cultures of leiomyoma and myometrium.
      DESIGN: Explant cultures of myometrium and leiomyomas from 3 premenopausal women
      undergoing hysterectomy in the proliferative phase of the menstrual cycle. MAIN
      OUTCOME MEASURES: PRL secretion measured by radioimmunoassay. RESULTS: PRL
      secretion was decreased in leiomyomas by onapristone. There was no effect in the
      myometrium. There was no additional effect with the addition of the type II
      antiprogestin mifepristone (RU 486). CONCLUSION: PRL production is suppressed in
      leiomyomas but not in myometrium after treatment with onapristone in vitro. This
      suppression may serve as a marker for the clinical effectiveness of agents used
      in the treatment of leiomyomas.

PMID- 10352392
TI  - Cervical adenoid cystic carcinoma coexisting with multiple human papillomavirus
      associated genital lesions. A common etiology?
AB  - Adenoid cystic carcinoma of the uterine cervix is a rare tumor with unknown
      etiology. We report a case of adenoid cystic carcinoma occurring in a young
      woman, associated with multiple human papillomavirus (HPV)-related lesions
      including condyloma acuminata, vulvar intraepithelial neoplasm, cervical
      intraepithelial neoplasm and invasive basaloid squamous cell carcinoma. While
      adenoid cystic carcinoma has previously been found to coexist with squamous cell
      carcinoma or cervical intraepithelial neoplasia, its association with such a
      variety of HPV-related lesions in our case has not been previously reported, and
      raises the speculation that HPV may also be the causative factor for adenoid
      cystic carcinoma. However, in situ DNA hybridization and polymerase chain
      reaction in our current study failed to demonstrate the existence of HPV DNA in
      adenoid cystic carcinoma.

PMID- 10352393
TI  - Pseudohypoparathyroidism type 1b in pregnancy.
AB  - Calcium-regulating hormones were serially measured during the second pregnancy in
      a woman with pseudohypoparathyroidism type 1b. Calcium levels corrected for serum
      albumin were maintained almost normal during her second pregnancy with 1alpha
      hydroxycalciferol (2.0 microg daily) though they were slightly decreased in late
      pregnancy. 1,25-Dihydroxyvitamin D levels were higher in early and mid-pregnancy,
      but not in late pregnancy compared to those after delivery. Parathyroid hormone
      levels were higher in late pregnancy than after delivery.

PMID- 10352394
TI  - Insulin-like growth factor binding proteins: new proteins, new functions.
AB  - The insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and IGFBP
      proteases regulate somatic growth and cellular proliferation both in vivo and in
      vitro. IGFs are potent mitogens whose actions are determined by the availability
      of free IGFs to interact with IGF receptors. IGFBPs comprise a family of six
      proteins that bind IGFs with high affinity and specificity and thereby regulate
      IGF-dependent actions. IGFBPs have recently emerged as IGF-independent regulators
      of cell growth. Cleavage of IGFBPs by specific proteases modulate levels of free
      IGFs and IGFBPs and thereby their actions. IGFBP-related proteins (IGFBP-rPs)
      bind IGFs with low affinity and also play important roles in cell growth and
      differentiation. The GH-IGF-IGFBP axis is complex and powerful. Future research
      on its physiology promises exciting insights into cell biology as well as
      therapies for diseases such as cancer and diabetes mellitus.

PMID- 10352395
TI  - Validity of height velocity as a diagnostic criterion for idiopathic growth
      hormone deficiency and Turner syndrome.
AB  - A deflecting growth curve over several years is sometimes the only indication for
      the possible presence of a growth disorder. In this study we looked at the
      potential diagnostic role of long-term downward deflection of the growth curve.
      It reports on the diagnostic validity of height velocity over 1, 2 or 3 years for
      isolated idiopathic growth hormone deficiency and for Turner syndrome in
      prepubertal children with a height that is still above -2.5 standard deviation
      scores (SDS). 1-year height velocity was found to have no diagnostic value
      because of an almost complete overlap of height velocity distributions with
      normal prepubertal children. However, height velocity over 3 years was found to
      have an acceptable validity in children 5-12 years old. In this age range a
      change in height SDS of -0.75 can be used as a valid criterion for further
      examination of karyotype and GH secretion capacity even if there are no other
      clear signs of a particular growth disorder.

PMID- 10352396
TI  - Long-term systemic administration of human recombinant interleukin-1beta induces
      a dose-dependent fall in circulating parathyroid hormone in rats.
AB  - The synergism/antagonism between interleukin (IL)-1beta and parathyroid hormone
      (PTH) has been the subject of in vitro and in vivo work, but a possible direct
      action of the cytokine on PTH release has not been reported. We have investigated
      the effect of a continuous infusion of human recombinant IL-1beta (rIL-1beta) on
      circulating PTH during a 14-day period in 7-week-old female rats. This time
      interval was chosen in order to exclude initial hypercalcemia and to enable data
      collection under steady-state conditions. Five groups of 20 animals each had
      miniosmotic pumps (Alzet 2002, 200 microl) implanted subcutaneously and primed to
      release either distilled water (controls) or 100, 500, 1,000 and 2, 000 ng/24 h
      of rIL-1beta. Blood was drawn on days 1 and 14 for PTH, corticosterone and Ca2+
      determinations. Adequate biological activity of the infused rIL-1beta was
      supported by elevated rectal temperature records and significant elevations of
      plasma corticosterone on day 14. The 100-ng dose had no effect but 500-2, 000 ng
      rIL-1beta/24 h significantly reduced plasma PTH in a dose-dependent manner down
      to 54% of basal value (20.4 +/- 1.1 vs. 15.3 +/- 1.4 pg/ml for 500 ng, p < 0.005;
      20.5 +/- 1.3 vs 12.3 +/- 1.1 for 1,000 ng, p < 0.001, and 19.5 +/- 2.0 vs. 10.6
      +/- 1.1 pg/ml for 2,000 ng, p < 0.0008). Despite these findings, no differences
      in blood Ca2+ could be detected between treated animals and controls. The
      following conclusions can be inferred from the foregoing: Systemic administration
      of rIL-1beta to rats induced a dose-dependent fall in circulating PTH without
      altering calcemia, calling into question the biological relevance of the former
      finding. Although the recorded PTH depression may indeed not have been severe
      enough to cause hypocalcemia, it can be hypothesized that osteoclast activation
      by rIL-1beta would enhance bone mineral release into the pool compensating for
      depressed PTH activity.

PMID- 10352399
TI  - Male pseudohermaphroditism related to complications at conception, in early
      pregnancy or in prenatal growth.
AB  - We examined whether male pseudohermaphroditism, when unexplained, is associated
      with reduced prenatal growth. Birth weight SD scores of 29 children with male
      pseudohermaphroditism were compared. The scores of children with an unexplained
      condition (median -2.1 SD) were found to be lower (p = 0.0001) than those of
      children with an explained condition (median -0.4 SD). In the majority of cases
      of unexplained male pseudohermaphroditism, there was a complicated history before
      conception or in early pregnancy. In conclusion, hitherto unexplained male
      pseudohermaphroditism was found to be associated with reduced prenatal growth and
      complications at conception or in early pregnancy.

PMID- 10352397
TI  - Low-dose growth hormone treatment with diet restriction accelerates body fat
      loss, exerts anabolic effect and improves growth hormone secretory dysfunction in
      obese adults.
AB  - Growth hormone (GH) can induce an accelerated lipolysis. Impaired secretion of GH
      in obesity results in the consequent loss of the lipolytic effect of GH. Dietary
      restriction as a basic treatment for obesity is complicated by poor compliance,
      protein catabolism, and slow rates or weight loss. GH has an anabolic effect by
      increasing insulin-like growth factor (IGF)-I. We investigated the effects of GH
      treatment and dietary restriction on lipolytic and anabolic actions, as well as
      the consequent changes in insulin and GH secretion in obesity. 24 obese subjects
      (22 women and 2 men; 22-46 years old) were fed a diet of 25 kcal/kg ideal body
      weight (IBW) with 1.2 g protein/kg IBW daily and were treated with recombinant
      human GH (n = 12, 0.18 U/kg IBW/week) or placebo (n = 12, vehicle injection) in a
      12-week randomized, double-blind and placebo-controlled trial. GH treatment
      caused a 1.6-fold increase in the fraction of body weight lost as fat and a
      greater loss of visceral fat area than placebo treatment (35.3 vs. 28.5%, p <
      0.05). In the placebo group, there was a loss in lean body mass (-2.62 +/- 1.51
      kg) and a negative nitrogen balance (-4.52 +/- 3.51 g/day). By contrast, the GH
      group increased in lean body mass (1.13 +/- 1.04 kg) and had a positive nitrogen
      balance (1.81 +/- 2.06 g/day). GH injections caused a 1.6-fold increase in IGF-I,
      despite caloric restriction. GH response to L-dopa stimulation was blunted in all
      subjects and it was increased after treatment in both groups. GH treatment did
      not induce a further increase in insulin levels during an oral glucose tolerance
      test (OGTT) but significantly decreased free fatty acid (FFA) levels during OGTT.
      The decrease in FFA area under the curve during OGTT was positively correlated
      with visceral fat loss. This study demonstrates that in obese subjects given a
      hypocaloric diet, GH accelerates body fat loss, exerts anabolic effects and
      improves GH secretion. These findings suggest a possible therapeutic role of low
      dose GH with caloric restriction for obesity.

PMID- 10352398
TI  - Effects of dexamethasone and dexamethasone plus naltrexone on pituitary response
      to GnRH and TRH in normal women.
AB  - The hypothesis that glucocorticoids have a direct central inhibitory effect on
      the reproductive axis is sutained by the identification of glucocorticoid
      receptors on GnRH-secreting neurons and gonadotropic pituitary cells. It has been
      proposed that glucocorticoids and opioids interact centrally in the regulation of
      the GnRH-LH axis. The inhibitory effect of glucocorticoids may manifest not only
      directly through the hormone-receptor link, but also indirectly through an
      increase in opioid tone. The aim of this study was to evaluate the role of
      glucocorticoids and glucocorticoids combined with an opioid antagonist, in the
      regulation of basal and GnRH- and TRH-stimulated secretion of LH, FSH and Prl in
      7 women with normal menstrual cycles. Blood samples were obtained every 10 min
      for an hour. GnRH (50 microgram) and TRH (200 microgram) were administered and
      blood sampling was continued every 15 min for 2 h (day 1). At 5 a.m. the next
      day, naltrexone (50 mg) was given and at 8 a.m. the GnRH-TRH test was repeated
      (day 2). At 5 a.m. on day 3, the patients took 2 mg oral dexamethasone and the
      test was repeated. At 5 a.m. on day 4, the patients took naltrexone and
      dexamethasone and at 8 a.m. the GnRH-TRH test was repeated. Administration of
      naltrexone did not cause significant changes in basal concentrations of LH and
      FSH and their response to GnRH. The area under the curve of the LH response to
      GnRH on day 3 was significantly less than on days 1, 2 and 4. Administration of
      naltrexone (day 2) did not cause any significant increase in basal and TRH
      stimulated levels of Prl with respect to day 1. On day 3, dexamethasone caused a
      reduced response of Prl to TRH. Pretreatment with naltrexone (day 4) prevented
      this reduction. These results suggest that suppression of the response of LH to
      GnRH induced by dexamethasone may be partly mediated by endogenous opioids.
      Dexamethasone led to a reduction in the response of Prl to TRH, and naltrexone
      blocked this suppression. Hence the suppression of Prl and LH by dexamethasone
      must be partly mediated by endogenous opioids, which must therefore inhibit
      pituitary secretion of Prl.

PMID- 10352400
TI  - Ten-year follow-up in a boy with Leydig cell tumor after selective surgery.
AB  - In a 4(8)/12-year-old boy with precocious puberty and an enlarged right testis, a
      Leydig cell tumor was diagnosed. Surgical exploration revealed an encapsulated
      tumor which was selectively removed without orchiectomy. Within 1 year the signs
      of precocious puberty disappeared. Ten years later, the patient remained free of
      disease and had developed normal spontaneous puberty. Despite of highly advanced
      bone age at the time of diagnosis (13 years according to Greulich and Pyle), his
      height at age 15 was in the upper normal range and within the familial target
      height. Most of these prepubertal patients affected by this tumor underwent
      orchiectomy, although no malignant course of Leydig cell tumors before puberty
      has been reported. This work provides the first example of long-term follow-up of
      a prepubertal boy after testis-sparing surgery for a Leydic cell tumor. We
      conclude that selective removal of the tumor may be the procedure of choice in
      this entity.

PMID- 10352401
TI  - Three cases of congenital growth hormone deficiency with micropenis and
      hypospadias: what does growth hormone have to do with it?
AB  - This paper reports 3 cases of congenital GH deficiency with male
      pseudohermaphroditism. All 3 showed a normal male karyotype, hypospadias of
      different degrees, and, for 2 of them, micropenis. No mullerian structure was
      individualized since pelvic ultrasound and genitography were normal. Patient 1
      was born with multiple anomalies and patient 3 showed partial agenesia of the
      corpus callosum. Only 1 patient showed complete anterior pituitary deficiency.
      Gonadotropin defects were not investigated. We postulate that GH might play a
      role in early testosterone stimulation, and thus in male sexual differentiation.

PMID- 10352402
TI  - Role of mesangial cell damage in progressive renal disease.
AB  - Mesangial cell proliferation and matrix accumulation are considered to contribute
      to the development of glomerulosclerosis. To investigate the pathological role
      played by mesangial cell damage in progressive renal disease appropriate
      progressive models initiated by a mesangial cell injury should be developed.
      Monoclonal antibody (mAb) 1-22-3 (IgG3) recognizes a critical epitope of the Thy
      1.1 molecule on the mesangial cell surface, binding of which induces more severe
      mesangial cell injury than in the case of OX-7, a commercially obtainable anti
      Thy-1.1 mAb. The mAb 1-22-3 has enabled us to develop irreversible models of
      renal damage induced by two consecutive injections, by a single injection into
      unilaterally nephrectomized rats, or by a single simultaneous injection with
      another mAb, in addition to the corresponding reversible model. Detailed
      examinations using the combination of both types of models, all of which are
      initiated by an immune mechanism directed against the identical epitope on the
      Thy-1.1 molecule, are expected to provide new insights into mechanisms of
      irreversible renal injury initiated by mesangial cell damage and also to develop
      novel and rational therapeutic approaches to progressive, primarily mesangial
      diseases.

PMID- 10352403
TI  - Role of glomerular endothelial damage in progressive renal disease.
AB  - Although glomerular lesions are caused by multiple mechanisms, when the lesion is
      severe, it frequently results in segmental or global sclerosis regardless of
      etiology, and contributes to progression of renal disease. Initially, glomerular
      mesangial cell injury was considered to be central to glomerular sclerosis.
      Recently, glomerular epithelial cell injury has attracted attention as the
      primary event of the sclerosis. Less attention has been paid to glomerular
      endothelial cell injury. However, the latter is acquiring increasing interest as
      to whether endothelial cell injury is also a crucial factor in the cause and
      progression of glomerular sclerosis. It has been clearly demonstrated that
      regeneration of impaired glomerular capillary networks plays an important role in
      the repair process of glomerular lesions. Glomerular endothelial cell injury
      exerts significant influences on the progression and repair process of glomerular
      disease. When the glomerular lesion is severe, angiogenesis is prevented due to
      endothelial cell injury, with subsequent sclerosis taking place in the impaired
      region. These glomerular endothelial cell injuries inevitably affect mesangial
      and epithelial cells and presumably modify the progression of renal disease by
      reciprocally interacting with them.

PMID- 10352404
TI  - Macrophage activation and programming and its role for macrophage function in
      glomerular inflammation.
AB  - Macrophages have a central role in the control of inflammation because, depending
      on the local microenvironment, they can develop into cells that cause further
      injury or facilitate tissue repair. Understanding what signals determine whether
      macrophages develop into cells that promote injury or facilitate repair is one of
      the most important issues in inflammatory cell biology, not least because of the
      opportunities for developing novel therapies. This is highly relevant to
      glomerulonephritis because of the prominence of the macrophage infiltrate in all
      types of severe or progressive nephritis, and the present unsatisfactory nature
      of treatments for these diseases. This review will focuses on how macrophages are
      activated in vitro and in normal and inflamed glomeruli. The new concept of
      'macrophage programming' is introduced and novel strategies to alter macrophage
      function within nephritic glomeruli that could be used for the treatment of
      glomerular inflammation are highlighted.

PMID- 10352405
TI  - How does podocyte damage result in tubular damage?
AB  - Severe podocyte damage including detachment from the GBM leads to adhesion of the
      glomerular tuft to Bowman's capsule, thus to a local loss of the separation of
      the tuft from the interstitium. Perfused capillaries contained in the tuft
      adhesion deliver their filtrate no longer into Bowman's space but into the
      interstitium. In response, interstitial fibroblasts create a cellular cover
      around the focus of misdirected filtration, interpreted teleologically, aiming at
      preventing the entry of this fluid into the interstitium. This results in the
      formation of a crescent-shaped, fluid-filled paraglomerular space overarching the
      segmental glomerular lesion. Extension of this space over the entire glomerulus
      leads to global sclerosis; extension of this space via the urinary pole onto the
      outer aspect of the corresponding tubule leads to the degeneration of the tubule.
      Since, as we postulate, such misdirected filtration and filtrate spreading is the
      crucial mechanism of damage progression in 'classic' focal segmental
      glomerulosclerosis (FSGS), the most characteristic structural injury of FSGS is
      the merger of the tuft with the interstitium, represented by a tuft adhesion,
      later a synechia. Therefore, histopathologically, 'classic' FSGS is best defined
      by an adhesion/synechia of the tuft to Bowman's capsule.

PMID- 10352406
TI  - Proteinuria as a mediator of tubulointerstitial injury.
AB  - Proteinuria is one of the most potent risk factors for renal disease progression
      in patients with glomerular diseases. Studies in disease models have helped to
      delineate mechanisms leading to renal structural damage due to persistent
      dysfunction of the glomerular barrier to proteins, even when the primary immune
      or nonimmune insult to the kidney has ceased. The main focus of this review is
      the role of the tubular epithelial cell in the induction of interstitial
      inflammatory and fibrogenic reactions to ultrafiltered proteins. Antiproteinuric
      drugs (angiotensin-converting enzyme inhibitors, ACEi) while preserving the
      integrity of the glomerular permselective barrier limit both proteinuria and
      protein-dependent processes which contribute to tubulointerstitial injury, and in
      so doing ACEi halt the progression of proteinuric nephropathies toward terminal
      renal failure.

PMID- 10352407
TI  - Chronic interstitial damage in proteinuria. Does complement mediate
      tubulointerstitial injury?
AB  - Tubulointerstitial injury is seen in some patients with glomerular proteinuria
      and when present is a poor prognostic indicator. However, the mechanism by which
      proteinuria results in tubular and interstitial damage is unknown. Activation of
      the complement system has been implicated in many forms of tissue injury,
      including immune-mediated renal disease. Immunohistochemical studies suggest that
      complement is deposited on the tubular epithelium in proteinuric states raising
      the possibility that complement activation may contribute to tubular injury. In
      this review, we discuss how complement proteins reach the tubular epithelium and
      why the complement system is activated at this site. We also discuss the effects
      this may have on tubular cells and how this could result in progressive
      interstitial disease. The possibility that complement inhibition may reduce
      progression of tubulointerstitial injury is also considered.

PMID- 10352408
TI  - Role of tubular cells in progressive renal disease.
AB  - It is generally accepted that the progressive loss of kidney function results
      from a pathogenic process that is independent of the original etiology,
      functioning as a final common pathway. Part of this response is characterized by
      triggering of interstitial infiltration and induction of tubular damage. As a
      consequence, tubular epithelial cells (TEC) can become activated and begin to
      express several inflammatory mediators. In the present review, we will summarize
      the potential role of TEC in progressive renal disease. Much emphasis will be put
      on studies using in vitro cultured TEC. These studies have provided more insight
      into the different signals involved in the regulation of the production of
      inflammatory mediators like complement, cytokines and chemokines, as well as
      progression factors like growth factors and matrix component by TEC.

PMID- 10352409
TI  - Vasoactive factors and tubulointerstitial injury.
AB  - Morphological changes of the tubulointerstitial architecture are a major
      determinant in the progression of chronic renal disease. The evolution of the
      tubulointerstitial lesion includes early tubular hypertrophy, recruitment of
      inflammatory cells into the tubulointerstitial space, and proliferation of
      interstitial fibroblasts resulting in the irreversible changes of tubular atrophy
      and tubulointerstitial fibrosis. Many of these diverse effects are mediated by
      autocrine or paracrine release of growth factors, cytokines, and chemokines.
      Proteinuria, reduction in functional renal mass per se, alterations in tubular
      fluid reabsorption, and well as hemodynamic changes in the injured kidney may all
      stimulate local release of such growth factors. A more recent conception is that
      vasoactive substances, traditionally viewed to be only involved in the regulation
      of vascular tone, could actually mediate many of these functions of the more
      'classical' growth factors and cytokines. In this regard, one of the most
      intensively studied vasoactive substances is angiotensin II which has been linked
      to the progression of renal disease by a host of mechanisms, including the
      induction of tubular hypertrophy and proliferation of interstitial fibroblasts.
      There is also increasing evidence that other vasoconstrictive factors such as
      endothelins and eicosanoids are involved in pathophysiological changes leading
      eventually to tubulointerstitial fibrosis. On the other hand, natriuretic
      peptides may exert antifibrogenic properties. Although interference with the
      renin angiotensin system is currently the only treatment being effective in
      attenuating the loss of function in patients with chronic renal insufficiency, it
      is likely that future studies will also investigate the role of other vasoactive
      substances in the progression of human chronic renal disease.

PMID- 10352410
TI  - Interstitial pathomechanisms underlying progressive tubulointerstitial damage.
AB  - Progressive renal disease poses an increasing problem for the medical community.
      Though the causes of end-stage renal failure are multiple, the histologic
      pictures of chronic renal disease are remarkably similar being characterized by
      interstitial infiltration, fibrosis, tubular atrophy and dilatation. This
      similarity points to a final common pathway. In addition, renal disease often
      progresses despite elimination or amelioration of the inciting stimulus. This
      review deals with the pathomechanisms of progressive renal failure proposing a
      three-step model of fibrogenesis with an induction phase, a phase of
      inflammatory, and, lastly, a phase of postinflammatory matrix synthesis. The
      central role of the tubular epithelial cell as a mediator of interstitial
      inflammation and its participation in matrix synthesis will be discussed
      particularly. Finally, a brief overview is listed on new therapeutic approaches
      to limit the progressive nature of fibrogenesis.

PMID- 10352411
TI  - Progression of diabetic nephropathy. Insights from cell culture studies and
      animal models.
AB  - Nephropathy in patients with type I and II diabetes mellitus is a rapidly
      increasing problem worldwide. Studies using both glomerular and tubular cells
      have delineated some of the consequences induced by acute hyperglycemia. In vitro
      studies have clearly demonstrated that exposure of cultured renal cells, such as
      glomerular mesangial cells and proximal tubular epithelial cells, to elevated
      glucose concentrations, may alter cell proliferation and/or extracellular matrix
      turnover. The latter is effected both directly and indirectly by the alteration
      of cytokine generation. Furthermore, these in vitro studies have allowed detailed
      examination of the mechanisms by which exposure of these cells to high ambient
      glucose concentrations may alter cell function. Extension of these studies to the
      experimental in vivo situation has confirmed most of the in vitro findings.
      Important insights gained from models of type I diabetes (i.e. streptocotocin
      induced diabetes) as well as type II diabetes (i.e. Goto-Kakizaki (GK) rats and
      obese Zucker rats) include: (1) The demonstration that increased glomerular cell
      proliferation and renal matrix accumulation, driven by TGF-beta and/or PDGF,
      occur in streptocotocin-induced diabetes, yet that nephropathy in these rats does
      not progress to renal failure. (2) The demonstration that prolonged mild type II
      diabetes does induce morphological changes characteristic of pre-clinical
      diabetic nephropathy in GK-rats but does not result in albuminuria or progressive
      renal disease. (3) The demonstration that the association of type II diabetes
      with hyperlipidemia in obese Zucker rats results in early podocyte damage and
      subsequent progression to glomerulosclerosis, tubulointerstitial damage, and
      renal insufficiency. Identification of the mediators involved in the above
      processes and in particular of the conditions that will determine progression of
      subclinical morphological changes to overt nephropathy and renal failure will
      likely result in future novel therapeutic approaches to diabetic nephropathy.

PMID- 10352412
TI  - Toward a simpler surgical management of Chiari I malformation in a pediatric
      population.
AB  - A wide variety of surgical adjuvants to the standard bony decompression have been
      advocated in the treatment of the Chiari I malformation, especially when the
      tonsillar herniation is associated with hydrosyringomyelia. These include various
      shunting procedures, duroplasty, obex plugging, and resection of the cerebellar
      tonsils. Our practice has been to avoid these adjuvants and to perform a simple
      limited occipital craniectomy, C1 laminectomy, and dural opening. The dura mater
      is left open and overlain with oxidized cellulose. To evaluate the efficacy of
      this more limited procedure, a retrospective review was performed of the medical
      records of 31 consecutive patients treated over a 6-year period. Twenty-six (84%)
      of these patients had an associated spinal cord syrinx; all underwent the same
      procedure. The follow-up period ranged from 15 to 93 months, with all patients
      having at least one postoperative magnetic resonance imaging at 6 months. Twenty
      three of the 26 patients (88%) who presented with a syrinx had significant
      resolution of the syrinx on follow-up scans with concomitant improvement of
      presenting signs and symptoms. Of the remaining 3 patients, 1 had progressive
      hydrocephalus and received a ventriculoperitoneal shunt, with symptom resolution.
      In the other 2 patients the syrinx did not diminish; both received syringopleural
      shunts. Postoperative morbidity includes a 26% incidence of headaches, of which
      half resolved within 5 days, and only 1 persisted beyond 2 weeks. Nausea and
      vomiting occurred in 16%. Neither of these figures significantly exceeds those of
      other large surgical series in which the dura mater was closed with a patch
      graft. Three patients (10%) did have a postoperative cerebrospinal fluid leak;
      all responded to bedside suturing without further sequelae. This study indicates
      that a simple bone removal and open dural decompression of the cervicomedullary
      junction is a safe, effective operative treatment for Chiari I malformation in
      children. Shunts, duroplasty, obex plugging, and tonsillar resection offer no
      benefit regarding the outcome when our series is compared to others in which such
      adjuvants were used.

PMID- 10352413
TI  - Unique clinical presentation of pediatric shunt malfunction.
AB  - INTRODUCTION: A cerebrospinal fluid (CSF) shunt is the primary treatment for most
      etiologies of hydrocephalus in the pediatric population. Malfunction of the shunt
      may present with unique symptoms and signs. This retrospective review
      investigates the presenting signs and symptoms of pediatric patients with shunt
      malfunction. Clinical MATERIAL AND METHOD: One-hundred-and-thirty CSF diversion
      procedures were performed at two affiliated pediatric hospitals over a 2-year
      period. Seventy consecutive cases of CSF shunt revision were reviewed. These 70
      operations were performed on 65 patients. Their medical records and radiographic
      studies were reviewed, and supplemented with a telephone interview to obtain a
      minimum of 3 months follow-up. RESULTS: The 65 patients' age ranged from 3 months
      to 16 years. The original etiology of the hydrocephalus was Chiari II
      malformation in 17, idiopathic in 15 and intraventricular hemorrhage in 10,
      neoplasm in 8 patients and meningitis in 5 patients. The most frequent presenting
      symptoms were headache (39 admissions), nausea/vomiting (28) and drowsiness (21).
      Seven Chiari patients (41%) presented with neck pain, 2 (12%) presented with
      lower cranial nerve palsy, and 2 (12%) presented with symptomatic syrinx,
      complaints not reported by non-Chiari patients (p < 0.01, chi2 analysis). Four
      myelodysplastic patients presented with a new-onset or recurrent seizure episode,
      which was significantly more frequent than in nonmyelodysplastic patients (p <
      0.05, chi2 analysis). On examination, increased head circumference was noted in
      17 patients. Parinaud's syndrome was noted more prominently in patients with a
      history of intracranial neoplasm (4 of 8 cases) than in patients with
      nonneoplastic diseases (2 of 62 cases; p < 0.05, chi2 analysis). Other
      interesting presenting signs were pseudocyst (2), syringomyelia (2), hemiparesis
      (2) and Parkinson-like rigidity (2). CONCLUSION: Pediatric shunt malfunction
      generally presents with headache, nausea/vomiting, altered mental status,
      increased head circumference and bulging fontanelle. Other less frequent but
      unique presenting signs and symptoms, such as neck pain, syringomyelia and lower
      cranial nerve palsy in the myelodysplastic population, and Parinaud's syndrome in
      patients with a history of intracranial neoplasm are frequently associated with
      shunt malfunction and should prompt a radiographic workup.

PMID- 10352414
TI  - Predictors of posttraumatic convulsions in head-injured children.
AB  - The purpose of this study was to determine predictors of posttraumatic
      convulsions in children. Study subjects included children under 12 years of age,
      who were admitted to the Safdarjang Hospital, New Delhi, during the year 1997
      (January to December) after suffering head trauma. The occurrence of first
      convulsion after head injury was taken as the outcome variable in the study.
      Medical records were reviewed for data about clinical, radiological and
      epidemiological features of such children. The study revealed that children
      younger than 2 years of age (odds ratio, OR 2.96; 95% confidence interval, CI
      1.42-6.21), those suffering severe head injuries, i.e. with low Glasgow Coma
      Score (OR 3.07; 95% CI 1.40-6.77), and those with longer period of
      unconsciousness after head trauma, especially longer than 12 h (OR 1.71; 95% CI
      0.69-4.19) have higher likelihood of suffering convulsions after head injury.
      However, none of the radiological findings were found to be significantly
      associated with posttraumatic convulsions.

PMID- 10352415
TI  - Malignant glial tumor arising from the site of a previous
      hamartoma/ganglioglioma: coincidence or malignant transformation?
AB  - Gangliogliomas are generally considered benign tumors. Although more commonly
      found in the brain, spinal cord ganglioglioma is a well established, albeit
      infrequent, entity. We describe a 2-decade clinical course of a patient initially
      diagnosed with a thoracolumbar 'glial-neuronal hamartoma' at age 4. Seventeen
      years after his first operation, local recurrence was noted. Despite subsequent
      multiple gross total resections and adjuvant therapy, histologic features became
      increasingly ominous and ultimately proved fatal. This is an unusual report and
      histologic presentation of a resected spinal cord ganglioglioma recurring as an
      anaplastic ependymoma/astrocytoma and subsequently a glioblastoma. It is quite
      likely that the originally resected ganglioglioma was actually part of a
      primitive neuroectodermal tumor which had undergone extensive maturation.

PMID- 10352416
TI  - Intracavernous teratoma in a school-aged child.
AB  - An eight-year-old boy presented with left eye pain, photophobia, proptosis, third
      nerve paresis and decreased visual acuity. Magnetic resonance imaging revealed a
      nonenhancing mass filling the cavernous sinus. Using an extradural fronto
      orbitozygomatic approach, the cavernous sinus was approached laterally, and a
      teratoma was removed from within the cavernous sinus. This is the first case of a
      truly intracavernous teratoma in a child and the fourth case of a teratoma
      reported in the cavernous sinus region overall. This report outlines the
      diagnosis and treatment of this unusual cavernous sinus tumor.

PMID- 10352417
TI  - Intramedullary spinal teratoma and diastematomyelia. Case report and review of
      the literature.
AB  - The authors present a patient with diastematomyelia and a spinal intramedullary
      teratoma, remote from the split cord malformation. A split cord malformation at
      the L2-L3 level was initially discovered during investigations for thoracic
      congenital scoliosis, and this was treated surgically. The teratoma, which was at
      the level of the scoliosis, went undiagnosed until neurological deterioration
      occurred many years later. Surgical removal of the teratoma resulted in return to
      normal function. The potential for coexisting congenital anomalies at separate
      levels of the spinal cord must be considered in radiological investigations of a
      developmental spinal lesion.

PMID- 10352419
TI  - Interventional magnetic resonance imaging guided aspiration and biopsy of a
      cystic midbrain tumor.
AB  - Interventional magnetic resonance imaging defines the intraoperative application
      of magnetic resonance imaging technology, permitting the surgeon to work in an
      open magnetic field. The application of this technology to pediatric neurosurgery
      allows precise intraoperative localization of pathology, real-time assessment of
      the anatomical consequences of surgical and anesthetic interventions,
      accountability of brain shifts, confirmation of the exact site of biopsy or
      completeness of lesion removal, and immediate identification of some
      intraoperative and early postoperative complications. We present the case of a
      young boy with a cystic left midbrain tumor who underwent interventional magnetic
      resonance imaging guided aspiration and biopsy to illustrate the surgical
      advantages of this technology.

PMID- 10352418
TI  - Low-pressure shunt 'malfunction' following lumbar puncture in children with
      shunted obstructive hydrocephalus.
AB  - Most shunt malfunctions present with signs and symptoms of high intracranial
      pressure, and computed tomography scans demonstrate ventricular enlargement.
      However, several authors have described a rare 'low-pressure' hydrocephalic state
      in which ventricular enlargement can occur in the face of low, or even negative,
      intracranial pressures. We report 2 children with obstructive hydrocephalus in
      whom this 'low-pressure state' followed a lumbar puncture; in both children, the
      shunts were functioning properly despite increased ventricular size on computed
      tomography scans, and all symptoms resolved (and the ventricles returned to
      baseline) following a period of enforced recumbency without shunt revision. We
      hypothesize that subarachnoid cerebrospinal fluid leakage through the puncture
      site in the lumbar theca decreases the intracranial pressures globally to a point
      below the opening pressures of the shunt valves. The ventricular cerebrospinal
      fluid, unable to be drained through either the subarachnoid space or the shunt,
      accumulates within the ventricular system under low pressure. One consistent
      feature in our 2 patients has been the postural nature of the headaches. We
      recommend enforced recumbency and, if necessary, a blood patch to seal the lumbar
      leakage. Shunt revision or prolonged external ventricular drainage appears to be
      unnecessary in these patients. Finally, neurosurgeons should be aware of this
      potential complication.

PMID- 10352420
TI  - A 2-month-old female infant with progressive macrocephaly and irritability 
      clinical conference-.

PMID- 10352421
TI  - Histamine H2 receptor antagonism by T-593: studies on cAMP generation in Hepa
      cells expressing histamine H2 receptor.
AB  - Histamine H2 receptor antagonism by T-593 was investigated in Hepa cells
      expressing canine histamine H2 receptors. T-593 inhibited generation of cAMP in
      Hepa cells stimulated by 10(-5) mol/l histamine with an IC50 value of 2.3 x 10(
      6) mol/l, (S)-(-)-T-593, one of the enantiomers comprising racemic T-593,
      inhibited cAMP generation with an IC50 value of 6.1 x 10(-7) mol/l. On the other
      hand, the other enantiomer (R)-(+)-T-593 exhibited only a negligible effect.
      Incubation of the cell with (S)-(-)-T-593 for 60 min depressed the maximal
      response of the concentration-response curve of histamine with a nonparallel
      rightward shift. The slope of a Schild plot was 1.27. In contrast, (S)-(-)-T-593
      caused a parallel rightward shift of the curve, with a Schild plot slope that did
      not significantly differ from unity, by treating the cells for 15 min. The H2
      receptor-blocking action of (S)-(-)-T-593 remained almost unaffected after
      washing out the drug, whereas the effect of ranitidine was reversible after
      washing. These results suggest that T-593 possesses a time-dependent
      insurmountable antagonistic action against histamine H2 receptor. T-593 may
      interact with the histamine H2 receptor molecule in a slowly associable and
      dissociable manner.

PMID- 10352422
TI  - Influence of L-365,260, a CCK-B/gastrin receptor antagonist, on tetragastrin
      stimulated mucin metabolism in rat gastric mucosa.
AB  - The effect of L-365,260, a CCK-B/gastrin receptor antagonist, on gastric mucus
      metabolism induced by tetragastrin was investigated in rats. In vivo application
      of L-365,260 at a dose of 3 mg/kg p.o. significantly reduced the tetragastrin (12
      microg/kg s.c. )-stimulated gastric acid secretion, but 0.3 mg/kg of L-365,260
      did not affect the gastric acid secretion induced by the tetragastrin
      administration. A single administration of 12 microg/kg of tetragastrin caused an
      increase in gastric mucin content in the soluble mucus (175% of control), the
      mucus gel (155% of control) and the surface mucosa (125% of control). L-365,260
      at the doses of 0.3 and 3 mg/kg considerably inhibited the tetragastrin-induced
      mucus secretion in the soluble mucus (70-80% of tetragastrin) and the mucus gel
      (45-70% of tetragastrin) and resumed the mucus accumulated in the surface mucosa
      to the control situation (80% of tetragastrin). In the in vitro incubation system
      of rat gastric mucosa, L-365,260 (0.1-10 micromol/l) caused no significant change
      in gastric mucin synthesis. An in vivo study also showed that the increase in
      total gastric mucin content and the distributional changes in mucin content
      induced by 12 microg/kg of tetragastrin reverted with 3 mg/kg of L-365,260
      pretreatment to the control situation. It is evident from these results that the
      CCK-B/gastrin receptor is involved in the mechanism of the stimulation of mucus
      secretion and/or mucus accumulation in rat gastric mucosa and not directly
      concerned with the action of gastrin-induced gastric acid secretion.

PMID- 10352423
TI  - Enhancement by arginine vasopressin of the L-type Ca2+ current in guinea pig
      ventricular myocytes.
AB  - Effects of arginine-vasopressin (AVP) on the cardiac L-type Ca2+ current (ICa,L)
      were investigated in single ventricular cells of guinea pig hearts by the
      conventional and nystatin-perforated patch clamp methods. Using the conventional
      whole-cell clamp method, AVP (0.01-1 micromol/l) appeared to have little effect
      on ICa,L, but the same concentrations of AVP consistently increased ICa,L using
      the nystatin-perforated patch clamp mode. The stimulatory effect was blocked by
      either OPC-21268 (8 micromol/l), a selective V1 receptor antagonist, or
      staurosporine (10 nmol/l), an inhibitor of protein kinases. AVP further increased
      the amplitude of ICa,L previously augmented maximally by isoprenaline (1
      micromol/l). When myocytes were pretreated with ryanodine (2 micromol/l) or
      cyclopiazonic acid (3 micromol/l), the increase in ICa,L by AVP was partially
      reduced. The present results indicate that protein kinase C might be involved in
      the AVP-induced increase of ICa,L. The AVP-induced increase in ICa,L may require
      intracellular constituents, which might be washed out during the use of the
      conventional whole-cell patch clamp method.

PMID- 10352424
TI  - Effects of green tea catechins on membrane fluidity.
AB  - Catechins originating from green tea have been used in plaque inhibition for
      caries prevention and treatment for liver damage because of their antibacterial
      activity against cariogenic bacteria and protective activity on hepatic cells.
      The effects of catechins on membrane fluidity were studied by a fluorescence
      polarization method using liposomes prepared with dipalmitoylphosphatidylcholine
      and dioleoylphosphatidylcholine to assess their pharmacological mechanism at
      micromol/l levels found in human body fluids after clinical application. All
      eight catechins tested, ranging from 1 to 1,000 micromol/l, significantly reduced
      membrane fluidity in both hydrophilic and hydrophobic regions of lipid bilayers.
      Catechin gallate esters were superior in fluidity reduction to the corresponding
      nonesters. The fluidity-reducing degree was different between the cis and trans
      forms, suggesting the stereospecific activity of catechins. A reference
      antiplaque agent, chlorhexidine, similarly reduced membrane fluidity at the
      antibacterial concentration. (+)-Catechin (250 micromol/l) and (-)
      epigallocatechin gallate (2.5 micromol/l) significantly prevented the membrane
      fluidization induced by hepatotoxic chloroform. These results indicate that the
      reduction in membrane fluidity is responsible for the antiplaque and
      hepatoprotective effects of green tea catechins.

PMID- 10352425
TI  - Distribution of neutral endopeptidase activity along the rat and rabbit nephron.
AB  - Neutral endopeptidase (NEP) activity was measured in various nephron segments
      dissected from rat and rabbit kidney. In the rat, only the proximal straight
      tubule and glomerulus had measurable NEP activity of 86 +/- 11.3 pmol/min/mm
      tubule length and 5.8 +/- 1.5 pmol/min/glomerulus, respectively. In the rabbit,
      significant activity was observed in both the proximal convoluted tubule (70.8 +/
      7.2 pmol/min/mm) and proximal straight tubule (29.6 +/- 2.3 pmol/min/mm) as well
      as in the glomerulus (12.8 +/- 2.2 pmol/min/glomerulus). In the rat proximal
      tubule, phosphoramidon and thiorphan inhibited NEP activity, with IC50 values of
      26.6 +/- 6.0 and 6.9 +/- 1.6 nmol/l, respectively. Incubation of rat proximal
      tubules with phorbol 12-myristate 13-acetate resulted in a 50% reduction in
      membrane-associated NEP activity. The results demonstrate that in both the rat
      and rabbit NEP is restricted to the glomerulus and proximal tubule. This
      localized distribution of NEP and its potential regulation by the protein kinase
      C pathway may play a key role in determining local concentrations of important
      regulatory peptides in the kidney.

PMID- 10352426
TI  - Heme oxygenase inhibitors transiently increase serum ferritin concentrations
      without altering other acute-phase reactants in man.
AB  - Sn protoporphyrin (SnPP) and Sn mesoporphyrin (SnMP), potent inhibitors of heme
      oxygenase (HO), significantly suppress bilirubin production, lower serum and
      biliary bilirubin levels and increase biliary heme output in animals and man. In
      this study, 20 healthy volunteers, 7 patients with primary biliary cirrhosis and
      4 patients with idiopathic hemochromatosis were treated with SnPP and 4 healthy
      volunteers with SnMP. In all cases, serum ferritin levels increased substantially
      but transiently after administration of these HO inhibitors. Values returned to
      baseline within a few days. Infusion of hematin in 4 healthy volunteers did not
      significantly affect ferritin levels. No increases occurred in 7 other acute
      phase reactants. The observation that these HO inhibitors transiently increase
      serum ferritin levels implies a link between ferritin, iron metabolism and HO
      activity which may be usefully explored in disorders of iron metabolism.

PMID- 10352427
TI  - Does it take a village to write a case report?

PMID- 10352428
TI  - Microtia repair: creation of a functional postauricular sulcus.
AB  - OBJECTIVE: Auricular reconstruction for repair of severe congenital microtia can
      provide the patient with a realistic-looking pinna. However, an unseen functional
      cephaloauricular sulcus is necessary, especially for patients with eyeglasses.
      TECHNIQUE: (1) A skin graft is harvested. (2) The ear framework is separated
      substantially from the side of the head. (3) A crescent of hair-bearing scalp
      skin is excised. (4) The donor skin graft is divided. One part of the graft
      surfaces the superolateral and medial portions of the auricular framework into
      the sulcus depth; the remainder covers the side of the head. RESULTS: This simple
      technique was effective. Minor transient sequelae have included granulation
      tissue (2 patients), localized infection (2 patients), and adhesion (1 patient).
      Patients requiring glasses have worn frames soon after surgery, and no sulcus
      problems have resulted. CONCLUSION: Creation of this postauricular sulcus during
      microtia reconstruction is easily performed and offers the patient a durable and
      functional space, especially for eyeglass wear.

PMID- 10352429
TI  - Preventing myringotomy closure with topical mitomycin C in rats.
AB  - The purpose of this study was to determine whether mitomycin C could be used to
      prolong the patency of the myringotomy site in the absence of ventilation tubes
      in rats. We examined the effect of increased exposure time and repeat application
      of mitomycin C to the myringotomy site. Sixty animals were separated into 4
      groups: group A had a single application of mitomycin C for 10 minutes; group B
      had a single application for 20 minutes; group C received 2 10-minute
      applications separated by 1 week; and group D received 2 applications (20 and 10
      minutes) separated by 1 week. Mitomycin C and bacteriostatic saline solution were
      applied to the right and left myringotomy sites in each rat, respectively.
      Experimental ears in groups A, B, C, and D remained open for a median time of
      6.5, 5.5, 6.5, and 8.5 weeks, respectively. The control ears healed within 1. 5
      weeks. This difference was statistically significant with P < 0.001 for each
      group. We conclude that mitomycin C is effective in prolonging the patency of
      myringotomies in rat tympanic membranes. Increased exposure time or repeat
      application of mitomycin C did not statistically alter the patency rate.

PMID- 10352430
TI  - Hearing screening in the newborn intensive care nursery: comparison of methods.
AB  - Patients in the neonatal intensive care unit were tested by hearing screening
      tests including auditory brain stem response (ABR), transient and distortion
      product otoacoustic emissions (TEOAEs and DPOAEs), and acoustic stapedius reflex
      (ASR), and by middle ear function tests including multifrequency tympanometry and
      pneumatic otoscopy. Pass rates on hearing tests were 75% to 89%. TEOAEs produced
      the lowest pass rate, and DPOAEs the highest. TEOAE, DPOAE, or ASR testing
      followed by ABR testing of initial failures produced pass rates of about 90%. The
      most efficient combination was DPOAEs followed by ABR. Pass rates tended to
      decrease with age. Of patients who failed 226-Hz and 678-Hz tympanometry, 30% to
      67% passed hearing tests, suggesting a high false-positive rate for these
      immittance tests. The 3 ears that failed the 1000-Hz tympanogram failed all
      hearing tests. Many ears were abnormal by pneumatic otoscopy but passed hearing
      tests, suggesting that the usual ear examination criteria may not apply to
      infants.

PMID- 10352431
TI  - Asymmetric sensorineural hearing loss in a community-based population.
AB  - Asymmetric sensorineural hearing loss (ASNHL) is fairly common, but it can be an
      indication of retrocochlear pathology. The incidence of acoustic neuroma (AN) has
      been estimated at 1/100,000; however, the incidence of AN in patients with ASNHL
      is unknown. The limitation of health care resources challenges otolaryngologists
      to develop reasonable cost-containment guidelines for the evaluation of patients
      with ASNHL for the presence of retrocochlear pathology. A 5-year (1990 to 1994)
      retrospective study of all patients with ASNHL who were evaluated in a community
      based general otolaryngology practice was performed. Demographic, historic, and
      audiologic data and results from ABRs and radiologic studies were summarized.
      ASNHL was present in 325 patients. Auditory brain stem response tests were
      performed in 179 patients (55%), and 92% (164 of 179) were normal. Patients with
      abnormal or inconclusive auditory brain stem responses and patients with severe
      SNHL were evaluated with radiologic studies (46 patients). Among the 193 patients
      who had diagnostic studies, 4 were found to have ANs, for a prevalence of 2.1%.
      The charge of diagnosis per AN was more than $41,000. In summary, a small
      percentage of patients with ASNHL have retrocochlear pathology, and the charge of
      diagnosis per AN can be excessive. A cost-containment approach for the evaluation
      and management of patients with ASNHL is proposed.

PMID- 10352432
TI  - Incidental discovery of acoustic neuromas.
AB  - Our objective is to report 4 cases of incidentally discovered acoustic neuromas
      (ANs) and to determine the incidence of asymptomatic ANs. A prospective study of
      161 consecutive patients undergoing gadolinium-enhanced MRI (Gd-MRI) at a
      tertiary-care university-affiliated medical center was carried out from September
      1994 to April 1995. The Gd-MRI scans were performed for tentative diagnoses other
      than AN or sensorineural hearing loss. In 161 consecutive patients examined, no
      ANs were found incidentally on Gd-MRI scans. Previous studies have suggested that
      the incidence of occult ANs is as high as 1%. On the basis of our results, we
      suggest that the actual incidence may be lower. However, our study is limited by
      its small size and the low incidence of ANs in the general population. Also
      reported are the clinical and MRI characteristics of 4 patients with incidentally
      diagnosed ANs.

PMID- 10352433
TI  - Impact of laryngeal paralysis and its treatment on the glottic aperture and upper
      airway flow characteristics during exercise.
AB  - Patients with unilateral vocal fold paralysis occasionally report shortness of
      breath during exercise. This symptom may persist in some patients after
      medialization thyroplasty. A review of the literature revealed no study that
      objectively evaluated laryngeal dynamics or airway flow characteristics during
      exercise after medialization thyroplasty for unilateral laryngeal paralysis. This
      study evaluates glottic aperture size and configuration as well as upper airway
      flow characteristics during exercise in 16 subjects. Six patients who underwent
      medialization thyroplasty for unilateral vocal fold paralysis were compared with
      10 healthy control subjects. During a standardized exercise protocol on an
      incremental ergometer (bicycle type), real-time videolaryngoscopy was obtained
      and correlated in a synchronized fashion with maximum-effort respiratory efforts
      at the beginning, midpoint, and end of the exercise period. Direct calculations
      of glottic size during various phases of the exercise period were performed from
      digitized images. These data were correlated with inspiratory flow data for each
      patient. Patients with laryngeal paralysis demonstrated smaller mean glottic
      areas and lower peak inspiratory flow rates than controls both at rest and during
      all phases of the exercise period. This study suggests that after treatment of
      unilateral laryngeal paralysis with medialization thyroplasty, inspiratory flow
      rate and glottic area are significantly less than in normal controls.

PMID- 10352434
TI  - Transnasal transsphenoidal hypophysectomy: choice of approach for the
      otolaryngologist.
AB  - Increasingly, the otolaryngologist is called on to provide exposure for the
      neurosurgeon performing transsphenoidal hypophysectomy. The 3 most common
      approaches for this exposure are the transnasal transseptal, sublabial
      transseptal, and external rhinoplasty approaches. We reviewed our series of 135
      patients undergoing transnasal hypophysectomy for postoperative complications. In
      our series, we found that 18% of patients had a postoperative septal perforation,
      2% of which were symptomatic; 6% of patients reported nasal cosmetic deformity;
      13% reported transient lip numbness; and 3% reported postoperative nasal
      dysfunction. When comparing our complication rate with those published for the
      sublabial and external rhinoplasty approaches, we found the transnasal approach
      provides excellent exposure with less dissection and fewer postoperative
      complications. On the basis of these results, we believe that the transnasal
      transseptal approach provides excellent exposure for transsphenoidal
      hypophysectomy in all patients who require pituitary surgery.

PMID- 10352435
TI  - Oral and oropharyngeal squamous cell carcinoma in young adults: a report on 13
      cases and review of the literature.
AB  - OBJECTIVE: Squamous cell carcinoma (SCC) of the head and neck is rare in patients
      younger than 45 years. Patients aged 18 to 45 years with SCC of the oral cavity
      (OC) and oropharynx (OP) were retrospectively compared with older control
      subjects. METHODS: Twenty of 127 patients with OC/OP SCC were young adults.
      Thirteen patients (10 men) comprise the present series; 9 had OC lesions. Seven
      case controls were identified. RESULTS: Overall, 15.75% of patients with OC/OP
      SCC were 18 to 45 years old. Seven OC lesions were early stage, and 2 were late
      stage; OP lesions were evenly divided. Eleven of 13 patients were disease free at
      the time of their last visit; 2 died of disease. Thirty-one percent of young
      patients were heavy drinkers; 77% of them smoked. CONCLUSIONS: Young adults'
      survival rate resembles that reported for all patients with head and neck cancer
      stage for stage. Tobacco and alcohol abuse prevention among young people is
      imperative. Health care providers who encounter a young patient with a suspicious
      head or neck lesion must include malignancy in their differential diagnosis.

PMID- 10352437
TI  - Two faces of orbital hematoma in intranasal (endoscopic) sinus surgery.
AB  - Orbital hematoma and blindness can occur during or after sinus surgery. All
      orbital hematomas in 3500 endoscopic sinus ethmoidectomies were identified and
      evaluated for type, treatment, and sequelae. Fifteen orbital hematomas were
      identified, with 1 case of temporary blindness and no cases of permanent
      blindness. Two types of orbital hematoma were identified-slow (venous) and fast
      (arterial)-which differ in management. The venous type results from penetration
      of the lamina papyracea and disruption of veins. The arterial hematoma is caused
      by anterior or posterior ethmoid artery injury. The treatment approach to each is
      different, with blindness more likely occurring from a fast (arterial) hematoma.
      Of the 2 types of orbital hematoma that can occur during sinus surgery, surgical
      decompression and hemorrhage control are more likely with the fast arterial
      hematoma, which has not been the subject of any prior presentation. Cause and
      management of each will be discussed.

PMID- 10352436
TI  - Incidence rates of salivary gland tumors: results from a population-based study.
AB  - Salivary gland tumors are uncommon, and their epidemiology has not been well
      described. We conducted a descriptive epidemiologic study of parotid,
      submaxillary, and sublingual gland tumors newly diagnosed in Jefferson County,
      Alabama, hospitals from 1968 to 1989. Incidence rates were estimated with a
      population-based subset of cases diagnosed during the years 1979 to 1980, 1983 to
      1984, or 1987 to 1988. Among 248 incident cases, 84.3% were benign and 15.7% were
      malignant. Eighty-six percent of cases arose in the parotid gland, and 14% arose
      in the submaxillary gland. No sublingual gland tumor was identified. The benign
      mixed tumor was the most frequent tumor (65.6%), followed by Warthin's tumor
      (29.2%). Mucoepidermoid carcinoma was the most frequent malignant tumor (51.3%).
      The average annual age-adjusted incidence rate per 100,000 was 4.7 for benign
      tumors and 0.9 for malignant tumors. Incidence rates for both benign and
      malignant tumors increased with age until ages 65 to 74 years and then declined.
      Benign mixed tumors occurred more frequently in female patients, whereas
      Warthin's tumors and malignant tumors occurred more frequently in male patients
      (P < 0.05). Warthin's tumor was rare in black patients (P < 0.001). We conclude
      that salivary gland tumors are an uncommon but epidemiologically diverse group of
      tumors. Their causes are also likely to differ.

PMID- 10352438
TI  - Use of postoperative chest x-ray after elective adult tracheotomy.
AB  - Surgeons have been creating tracheotomies since at least 124 AD, when first
      reported by Asclepiades (Price HC, Postma DS. Ear Nose Throat J 1983;62:44-59).
      Intraoperative and postoperative complications specifically associated with this
      procedure have been well established. The incidence of pneumothorax ranges from
      0% to 17%, depending on the age group studied. To evaluate this complication, it
      is generally accepted that a postoperative chest film should routinely be
      obtained after a tracheotomy in adult patients. In adult nonemergent
      tracheotomies, the routine use of a postoperative chest film has a low yield for
      detecting a pneumothorax in patients without clinical findings of pneumothorax.
      To evaluate the use of postoperative chest x-ray in adult tracheotomy patients, a
      retrospective review of tracheotomies performed at the Boston Medical Center from
      January 1994 to June 1996 was undertaken. Data examined consisted of age, sex,
      surgical indication, urgency, operating service, intraoperative and postoperative
      complications, difficulty of procedure, anesthetic technique, findings on
      postoperative chest film, signs and symptoms of pneumothorax, and specific
      treatment of pneumothorax if present. In total, 250 patients were identified. The
      main indication for tracheostomy in this study was ventilator dependence,
      accounting for 77% of the procedures. A complication rate of 11.6% was
      encountered, with no deaths. Postoperative hemorrhage was the most common
      complication (3.6%). Pneumothorax was documented by chest x-ray in 3 (1.2%)
      patients, 1 of whom had bilateral pneumothoraces. The most common symptom of a
      pneumothorax was tachycardia, with 8.8% of the patients exhibiting at least 1
      episode. Of the 3 cases of pneumothorax in this study, only 1 was clinically
      relevant and required treatment. Furthermore, the clinical signs and symptoms in
      this patient clearly supported the diagnosis of pneumothorax before a
      postoperative chest film was obtained. Thus postoperative chest radiographs did
      not change the treatment or outcome of any of the patients undergoing a
      tracheotomy. This suggests that postoperative chest x-ray after adult tracheotomy
      is not required in routine cases. Chest radiographs should be obtained after
      emergent procedures, after difficult procedures, or in patients exhibiting signs
      or symptoms of pneumothorax.

PMID- 10352439
TI  - Health impact of head and neck cancer.
AB  - A multidimensional Head and Neck Quality of Life (HNQOL) instrument and a general
      health status measure were administered to 397 patients with head and neck
      cancer. Scores for the 4 domains of the HNQOL (communication, eating, pain, and
      emotional well-being) were calculated. Patient demographics, comorbidities,
      clinical characteristics, treatment data, disability status, and a global
      "overall bother" score were assessed. When compared with the US population aged
      55 to 64 years, the group had significantly worse scores in the 8 health domains
      of the SF-36. Patients' overall bother scores from the head and neck cancer
      treatment correlated best with the HNQOL emotion domain (r = 0.71) and the HNQOL
      pain domain (r = 0.63), and least with the patients' perception of their response
      to treatment (r = 0.39). Pain, eating, emotion, physical component summary score,
      age, and an interaction term between eating and emotion were significant
      predictors for overall bother. Of the 217 patients who were working before the
      diagnosis of cancer, 74 (34. 1%) reported that they had become disabled. Patients
      who had more than 1 type of treatment were 5.9 times more likely to report
      themselves as disabled (odds ratio [OR] = 5.94, P < 0.01), even after adjusting
      for age, emotion score, and physical component summary score, which were other
      factors that predicted disability.

PMID- 10352440
TI  - Reflux in infants with laryngomalacia: results of 24-hour double-probe pH
      monitoring.
AB  - Laryngomalacia is the most common cause of stridor in children. Previous studies
      using barium esophagrams or single-probe esophageal pH testing have indicated
      that 68% to 80% of infants with laryngomalacia have reflux. A recent study in a
      large series of pediatric patients has shown that these 2 testing modalities are
      relatively insensitive in detecting reflux when compared with 24-hour double
      probe pH testing. This study was undertaken to determine the incidence and
      frequency of reflux in children with laryngomalacia by use of 24-hour double
      probe pH monitoring. Twenty-four children with endoscopically diagnosed
      laryngomalacia underwent 24-hour double-probe pH testing. The distal probe was
      placed in the lower esophagus, and the proximal probe was placed just above the
      cricopharyngeus immediately posterior to the larynx. All 24 (100%) children had
      pharyngeal acid exposure as judged by the proximal pH probe. These children had a
      mean of 15.21 episodes of reflux to the level of the pharynx during the 24-hour
      study period. In contrast, only 16 (66%) children had abnormal acid exposure as
      measured by the distal esophageal probe. These results indicate that essentially
      all children with laryngomalacia have reflux of gastric acid to the pharyngeal
      level. Multiple authors have documented the detrimental effects of acid and the
      accompanying pepsin in the larynx and tracheobronchial tree. Persistent laryngeal
      edema is an almost universal finding in patients with reflux to the pharyngeal
      level and is a common finding in children with laryngomalacia. In some patients
      with laryngomalacia, reflux may be the primary cause of their airway compromise,
      whereas in others it may be a significant cofactor exacerbating a preexisting
      neurologic or anatomic abnormality.

PMID- 10352441
TI  - Needs assessment for an undergraduate otolaryngology curriculum.
AB  - A needs assessment was conducted to determine what family doctors need to know
      about otolaryngology. A survey was mailed to a group of community
      otolaryngologists and family doctors. They were asked to rate the importance of
      46 otolaryngologic topics. A true needs assessment was carried out with a small
      group of family practice residents to examine which needs were perceived to be
      significantly different in importance between these 2 survey groups. A list of
      important topics was generated from the survey. There were many statistically
      significant differences between the survey groups, but only 2, vertigo and
      epistaxis, appeared to be potentially important. The family practice residents (n
      = 8) were asked to complete a short-answer test about epistaxis management and
      then to demonstrate placement of an anterior nasal pack. Despite having already
      faced this problem in 50% of cases, the residents had average scores of less than
      30%, indicating a lack of knowledge in this area.

PMID- 10352442
TI  - Localized sinus inflammation in a rabbit sinusitis model induced by Bacteroides
      fragilis is accompanied by rigorous immune responses.
AB  - We evaluated inflammatory and immune responses against Bacteroides fragilis in a
      rabbit sinusitis model. Bacteroides was inoculated into the left maxillary sinus,
      and inflammatory (histology, cell number/cytology, lactose dehydrogenase, and
      apoptosis) and immune responses in the sinus, airway, and peripheral blood (PB)
      were determined for up to 4 weeks. In the inflamed sinus, the lactose
      dehydrogenase level was markedly elevated, with neutrophilic infiltration, severe
      tissue inflammation, and increased apoptosis. Low-grade tissue inflammation was
      present in the contralateral and sham-operated sinuses, but other parameters
      remained unchanged, and so did those in the airway and PB in the inoculated
      rabbits. Serum IgG antibody levels increased rapidly, were highest at 3 weeks,
      and began to decline at 4 weeks. Cellular immune responses (proliferation and
      interferon-gamma mRNA expression) against Bacteroides were detected in the PB of
      all inoculated rabbits. Vigorous immune responses against Bacteroides may have
      localized but failed to terminate inflammation in the sinus, indicating
      importance of microenvironmental factors.

PMID- 10352443
TI  - Muscle fiber-type changes induced by botulinum toxin injection in the rat larynx.
AB  - This study examined muscle fiber-type alterations after single or multiple
      botulinum toxin (BT) injections to better understand possible morphologic changes
      induced by therapeutic BT injections in patients with spasmodic dysphonia. Muscle
      fiber staining was accomplished in rat intrinsic laryngeal muscles with
      antibodies to specific myosin heavy chains. Results indicated that the typical
      baseline distributions of type II muscle fibers (ie, types IIa, IIb, IIx, and
      IIL) were altered by BT injection, while no change was observed in type I fibers.
      Embryonic fibers were observed only along the needle insertion site at 7 days
      post BT injection. Although inferences from these animal data to human
      neuromuscular function must be made with caution, our findings provide insight
      into the possible cellular and molecular changes characterizing BT-injected
      muscles.

PMID- 10352444
TI  - Mucin production in the middle ear in response to lipopolysaccharides.
AB  - OBJECTIVE: This study examined the response of middle ear tissue to establish the
      lowest dose of lipopolysaccharide to induce mucin production in a rat otitis
      media model. METHODS: Twenty-six male Sprague-Dawley rats' eustachian tubes were
      obstructed before transtympanic inoculation of the bulla tympanica with 35 microL
      of Krebs Ringer or 1, 10, 100, or 1000 microgram/mL lipopolysaccharide. After 7
      days the effusion and a lavage were collected for mucin ELISA measurement, and
      tissue was collected for histologic evaluation. RESULTS: Mucin secretion was
      significantly increased in the 100 microgram/mL 51.20 +/- 13.6 microgram/mL (SE)
      and 1000 microgram/mL 69.42 +/- 8.57 microgram/mL groups when compared with the
      Krebs Ringer control group 1.84 +/- 0.28 microgram/mL (P < 0.05). Histologic
      evaluation shows goblet cell metaplasia and hyperplasia in the middle ear
      epithelium in the 1000 and 100 microgram/mL groups. CONCLUSIONS: The histology
      and ELISA results suggest that a middle ear effusion is generated with a dose of
      lipopolysaccharide as low as 100 microgram/mL.

PMID- 10352445
TI  - Food pollution.
AB  - Food can influence the human body in many ways, both positively and negatively.
      Several key elements of contemporary food cultivation and production are
      presented, along with their potential consequences to our health. The history of
      food cultivation and consumption is contrasted between early hunter-gatherer
      societies and modern day societies. Natural nutrient-rich foods produced from the
      soil in early societies have been replaced with artificial supplements and
      treated with pesticides and herbicides to control plant disease. The evolution of
      pesticides is chronicled from the synthesis of DDT in 1870 to present day.
      Several commonly used chemicals are described along with their documented side
      effects. A number of methods of pest control from ancient to modern day are
      offered as alternatives to polluting chemicals. Integrated pest management is
      proposed as a promising, economically feasible method of pest management,
      reducing pollution and risk to wildlife and human health.

PMID- 10352446
TI  - A new technique for securing cochlear implants.

PMID- 10352447
TI  - Signal transduction pathway in human middle ear cholesteatoma.
AB  - Phospholipase C-gamma1 plays a central role in signal transduction, and it is
      important in cellular growth, differentiation, and proliferation. Human
      cholesteatoma in the middle ear is characterized by the presence of a
      keratinizing epithelium that is believed to have hyperproliferative properties.
      The purpose of this study is to elucidate the distribution of phospholipase C
      gamma1 in cholesteatoma matrix and deep meatal skin with Western blot analysis
      and immunohistochemistry. In conclusion, overexpression of phospholipase C-gamma1
      in cholesteatoma matrix suggests a possible derangement of enhanced growth signal
      transduction in keratinocytes.

PMID- 10352448
TI  - Pharyngeal branch of the vagus nerve carries intraepithelial afferent fibers in
      the cat pharynx: an elucidation of the origin and central and peripheral
      distribution of these components.
AB  - The presence of a sensory component in the pharyngeal branch of the vagus nerve
      (PhB), including its peripheral distribution and central projection, was studied
      by denervation and tracer experiments in the cat. The distribution of nerve
      fibers immunoreactive to protein gene product 9.5, a sensitive neuronal marker;
      calcitonin gene-related peptide; and substance P in the pharyngeal epithelium was
      analyzed in both intact animals and animals subjected to partial denervation by
      means of sectioning two of the three nerve trunks, the glossopharyngeal nerve,
      the superior laryngeal nerve, and the PhB, while leaving one intact. The results
      of this study show that the glossopharyngeal nerve and superior laryngeal nerve
      carry nerve fibers to the pharyngeal epithelium rostral and caudal to the middle
      level of the epiglottis, respectively, whereas the PhB carries nerve fibers to
      the mesopharyngeal epithelium. Tracer experiments, by applying wheat germ
      agglutinin-horseradish peroxidase to the PhB, demonstrated retrogradely labeled
      primary sensory neurons in the jugular ganglion and transganglionic labeling of
      terminals in the interstitial subnucleus of the nucleus of the tractus
      solitarius. These results indicate that the PhB contains a sensory component that
      originates from the jugular ganglion, innervates the mesopharyngeal epithelium,
      and projects to the nucleus of the tractus solitarius.

PMID- 10352450
TI  - Wegener's granulomatosis.

PMID- 10352449
TI  - Long-term sequelae after surgery for orbital floor fractures.
AB  - A surgical technique involving exact repositioning and rigid fixation is required
      for the reduction of fractures of the orbital floor. Even then, sequelae may be
      present long after the trauma. The aim of this study was to establish the
      frequency and type of sequelae after surgery for orbital floor fractures and to
      investigate the extent to which the method of surgery had any impact on the
      severity of the sequelae. A questionnaire was sent to all 107 patients (response
      rate 77%) 1 to 5 years after the injury. Further clinical data were obtained from
      the patients' charts. Eighty-three percent of the patients were affected by some
      kind of permanent sequelae in terms of sensibility, vision, and/or physical
      appearance. A high frequency of diplopia (36%) was related to the reconstruction
      of the orbital floor with a temporary "supporting" antral packing in the
      maxillary sinus, a technique which has now been abandoned at our department in
      favor of orbital restoration with sheets of porous polyethylene. Our conclusion
      is that, because long-term sequelae are common, the surgical technique must be
      subjected to continuous quality control to minimize future problems for this
      group of patients.

PMID- 10352451
TI  - Otoendoscopic view of a persistent stapedial artery.

PMID- 10352452
TI  - Bilateral acute coalescent mastoiditis in an immunocompromised infant with a rare
      leukocyte adhesion deficiency.

PMID- 10352453
TI  - Temporal augmentation with a layered expanded polytetrafluoroethylene implant.

PMID- 10352454
TI  - Pleomorphic adenoma of the pediatric tongue.

PMID- 10352455
TI  - Extensive extramedullary amyloid-rich plasmacytoma of the mandible.

PMID- 10352456
TI  - Use of a superficial temporal fascia flap for coverage of an exposed cochlear
      implant.

PMID- 10352457
TI  - Nasopharyngeal Warthin's tumor.

PMID- 10352458
TI  - Survey: management of paralytic lagophthalmos and paralytic ectropion.

PMID- 10352459
TI  - Hemangioma of the intratemporal vestibular nerve.

PMID- 10352460
TI  - Surgical options in columellar reconstruction.

PMID- 10352461
TI  - Chondrosarcoma of the temporomandibular joint.

PMID- 10352463
TI  - Introduction to Advances in Clinical Pathology.

PMID- 10352462
TI  - Sudden hearing loss as a presenting manifestation of leukemia.

PMID- 10352464
TI  - Prognostic factors and management of primary breast cancer.

PMID- 10352465
TI  - The Spectrum of AIDS-Related Lymphoproliferative Disorders.

PMID- 10352466
TI  - Pathology of prostate cancer. Old problems and new facts.
AB  - Based on autopsy and epidemiologic data the lifetime risk of developing prostate
      cancer for a 50-year-old man is 42%, but only 9.5% will develop a clinically
      manifest disease and only 2.9% will die from this disease. The actual rate of
      carcinoma detection using PSA, digital rectal examination and transrectal
      ultrasound is 1%-3%. The majority of prostate carcinoma never progress to
      clinically significant disease, a minor portion remains confined to the prostate
      for many years and other carcinomas progress rapidly to a life threatening
      disease. The dilemma for clinicians and pathologists dealing with this tumor is
      how to distinguish these three biologically different types. Pathologists play an
      important role in preoperative diagnosis and in the postoperative prognosis
      oriented evaluation of the prostatectomy material. Volunteer PSA screening trials
      have led to an enormous increase in core-needle biopsies of the prostate. Since
      biopsies are often performed in men without palpable or ultrasound-visible
      nodules, are now faced with an increasing number of equivocal morphological
      features which can not be clearly defined, even with standardized criteria.
      Further investigations are also required to elucidate the clinical importance of
      PIN detection in biopsies. The heterogeneous histomorphology of prostate
      carcinoma can not be used as a prognostic factor. Therefore the histological
      grading is a very important factor for the assessment of prognosis. Carcinoma
      grading in biopsies is also of limited value in predicting tumor stage.
      Currently, several different grading systems are in use. Gleason's grading is the
      most favored, although its reproducibility is very low. The stage of the prostate
      carcinoma is still the best prognostic factor. In order to accurately assess the
      pTNM stage, TUR or prostatectomy material must be subject to extensive and
      standardized processing. Additionally, the volume of the tumor, the vascular
      invasion, the amount of extension of the tumor through the prostate capsule and
      perhaps the neoangiogenesis might be valid prognostic factors for disease
      progress and for survival. The value of novel methods (p53, bcl-2, apoptosis,
      microvessel density, interphase cytogenetics, androgen receptor mutation,
      neuroendocrine cells, E-Cadherin) remains to be proved. DNA ploidy is a good
      prognostic factor after prostatectomy and can be used to plan adjuvant hormone
      therapy.

PMID- 10352467
TI  - Preneoplastic lesions of the prostate.
AB  - For urologists and pathologists one of the two main issues in prostate pathology
      is the identification of those prognostic factors that could predict the exact
      outcome of individual patients with prostate cancer (PC). Therefore, the goal is
      to tailor the therapeutic approach to the clinical, morphological and biological
      features of each patient. The other issue involves the early detection of PC,
      preferably in the preinvasive phase, in order to treat the patient efficaciously.
      For this reason, understanding the biology of preinvasive or precursors lesions
      has become increasingly important. Prostatic intraepithelial neoplasia is only
      one of these lesions, and the best known to date. The role of others, such as
      atypical adenomatous hyperplasia, is considered as worth exploring. Prostatic
      intraepithelial neoplasia (PIN) represents the putative precancerous end of the
      morphologic continuum of cellular proliferations within prostatic ducts and
      acini. Two grades of PIN are identified (low grade and high grade), and high
      grade PIN is considered the direct precursor of invasive carcinoma. The continuum
      which culminates in high grade PIN and early invasive cancer is characterised by
      basal cell layer disruption, basement membrane disruption, progressive loss of
      markers of secretory differentiation, increasing nuclear and nucleolar
      abnormalities, increasing proliferative potential, and increasing variation in
      DNA content (aneuploidy). Clinical studies suggest that PIN predates carcinoma by
      ten years or more, with low grade PIN first emerging in men in the third decade
      of life. The clinical importance of recognising PIN is based on its strong
      association with carcinoma; its identification in biopsy specimens of the
      prostate warrants further search for concurrent invasive carcinoma. The issue of
      precursors of prostate cancer has several facets which reflect the multiplicity
      of patterns and variants of PC. A big step forward in understanding some basic
      aspects has already been made, especially in relation to PIN. More will be
      available soon. A large contribution to the management of isolated PiN lesions
      found in prostate biopsies is expected from molecular pathology and quantitation
      analysis.

PMID- 10352468
TI  - Quantitative evaluation of the Myotatic Reflex in Hemiplegic and Paraplegic
      patients.
AB  - The aim of this study was the quantitative evaluation of the myotatic reflex in a
      group of 11 subjects affected by spastic paresis of the lower limbs (8 hemiplegic
      and 3 paraplegic patients) and, for comparison, in a group of 7 healthy subjects.
      The parameters taken into account were the gain of the reflex and the time delay
      between the input and the mechanical output. The gain was calculated as the ratio
      between: i) the peak value of the input force (FPH) measured by means of an
      instrumented hammer with which the patellar tendon was hit; and ii) the peak
      value of the corresponding reflex force of the quadriceps femoris (FPQ) measured
      by means of a load cell connected to the subject's ankle. The gain of the reflex
      (FPQ/FPH) was found to be 1.9 to 2.4 times larger in patients as compared to
      control subjects and, among the patients to be twice at low, as compared to high,
      levels of stimulation. Among the hemiplegic patients, significant differences
      were found in the time delay of the response between the affected and unaffected
      limbs. Since both the intensity of the reflex and its gain were found to depend
      on the mechanical energy input, both parameters must be taken in to account if a
      diagnosis of spasticity has to be made.

PMID- 10352469
TI  - DNA Content in End-Stage Heart Failure.
AB  - AIM OF THE STUDY: Heart failure is the final clinical presentation of a variety
      of cardiovascular diseases, such as coronary artery disease, hypertensive, toxic,
      and inflammatory heart disease. However, the cellular mechanisms responsible for
      the progressive deterioration of myocardial function observed in heart failure
      remain unclear and may result from cell death (programmed or not) and from an
      increase in number of nuclei and in the degree of their ploidy. METHODS: We
      examined thirty-eight explanted hearts obtained during transplantation for DNA
      content in the myocytic population. All thirty-eight patients had severe chronic
      heart failure: 23 had idiopathic dilated cardiomyopathy, and 15 had ischemic
      cardiomyopathy. Ten hearts of people whose death was not due to primary heart
      disease or as a consequence of major risk factors of coronary artery disease,
      including hypertension, diabetes, obesity, or severe atherosclerosis, were used
      as controls. DNA content in the myocytic population was evaluated using Image
      Cytometry. RESULTS: The DNA content per nucleus and per myocyte in
      cardiomyopathic hearts are characterized by: a) a decrease of the diploid DNA
      content of myocytic nuclei; b) an increase of DNA ploidies higher than 4c; c) a
      decrease in mononucleated myocytes; d) an increase in binucleated and
      multinucleated myocytes. The changes are more prominent in dilated
      cardiomyopathy. e) The total ploidy index, used to calculate the total DNA
      content, is related to heart weight and ventricular weight. CONCLUSIONS: Ischemic
      and dilated cardiomyopathies result in reduction of ventricular mass-to-chamber
      volume ratio and in discrete foci of myocyte cell death, leading to an elevation
      in systolic and diastolic stress on the remaining viable cells. Therefore
      mechanical stimuli generated by global and local loading abnormalities associated
      with end-stage failure may contribute to activate genes implicated in cell
      proliferation. Observations in this investigation are consistent with recent
      results documenting that in the presence of overload conditions the myocytes may
      retain their capacity to proliferate throughout life and this growth reserve
      mechanism may become operative in response to severe myocardial dysfuntion and
      overt failure. Polyploidization and multinucleation are prominent phenomena in
      the end-stage of ischemic and dilated cardiomyopathy in humans.

PMID- 10352471
TI  - "The R.E.A.L. classification" of non-Hodgkin's Lymphomas: is it a real ultimate
      classification?

PMID- 10352470
TI  - Estradiol, progesterone and steroid receptors. Benign cycling versus malignant
      non cycling cells.
AB  - Levels of estradiol and progesterone from blood together with oestrogen (ER) and
      progesterone receptors (PgR) from breast tissue were studied from a total of 2500
      data bank cases of breast neoplastic disease. We report here, 340 premenopausal
      women with recorded menstrual cycle data which enabled the study of the effect of
      peripheral hormone variation on ER and PgR with respect to cycle phase. The
      findings were also correlated with 30 immunohistochemical specimens. In the
      specimens with benign neoplasm (141 cases, age 28 +/- 18 years) the ER levels
      were low (9.2+/-9.4 fmol/mg protein) as in normal breast tissue, whereas PgR
      levels were high ( 76+/-102.4 fmol/mg protein). Both ER and PgR levels decreased
      in association with the peak of blood progesterone of the early secretory phase.
      In the 15 cases of benign neoplasm from the luteinic phase studied by
      immunohistochemistry there were few ER positive cells (29+/-15%) which were small
      (265+/-27 pixels) and faintly stained (MOD: 34+/-3UA), while the PgR positive
      cells were more numerous (79+/-15%), bigger (377+/-70 pixels), strongly stained
      (MOD: 48+/-5UA), and centrally located in the breast ducts. The differences in
      size and optical density were statistically significant indicating that both
      receptors are expressed by different cells. The cell cycle dependence of these
      differences is discussed. In the series of malignant neoplasms (199 cases, age
      41+/-6 years), ER and PgR cytosol levels were both generally high (ER: 38+/-75.9,
      PgR: 86.6+/-137), and did not show variations due to the menstrual cycle, while
      blood progesterone, PgR, and the percentage of ER positive cases increased during
      the menstrual cycle. The 15 malignant cases in the luteinic phase showed, through
      immunohistochemistry, that size and staining intensities of receptor positive
      cells were similar to the other 199 cases and were not found to be directly
      influenced by hormonal activity related to the menstrual cycle. Comparisons
      between benign and malignant specimens showed significant biochemical and
      immunohistochemical differences in the degree of ER positivity while, on the
      contrary, PgR levels were similar.

PMID- 10352472
TI  - Telepathology and the Internet.

PMID- 10352473
TI  - Serous borderline tumors of the ovary.
AB  - The distinction of borderline tumors from invasive carcinomas is one of the
      commonest problems in ovarian tumor pathology. The borderline tumors are
      characterized by absence of destructive stromal invasion although they can
      implant on peritoneal surfaces. The implants may in turn invade the underlying
      tissue. Serous borderline tumors (SBTs) account for one-quarter to one-third of
      malignant serous tumors. Mostly, they are confined to the ovary (Stage 1),
      whereas in some cases they spread within the pelvis (Stage 2) or upper abdomen
      (Stage 3). As recently shown, typical SBTs may contain foci of microinvasion, a
      finding that does not appear to influence the prognosis. SBTs are associated with
      peritoneal implants in about 30% of cases. Peritoneal implants most often appear
      similar to the primary ovarian tumor, although they could show more or less
      atypia than the primary tumor. The peritoneal implants of SBTs have been
      classified into non-invasive and invasive categories. Recently, some studies
      showed that in SBTs associated with peritoneal implants, separation of the
      implants into invasive and non-invasive categories has important prognostic
      implications. Furthermore, severe nuclear atypia and mitotic activity in the
      implants are independently related with a poor prognosis. In addition, these
      studies suggest that chemotherapy is appropriate only for patients with invasive
      implants without taking into account lymph node status. Finally, it has recently
      been established that tumors with a morphology identical to that of SBTs may
      arise as primary tumors of the peritoneum with absent or minimal involvement of
      ovarian surfaces.

PMID- 10352474
TI  - B-cell lymphomagenesis and human autoimmune models.
AB  - The concept that B-cell lymphomagenesis represents a multistep process is widely
      accepted. Pathogenetic events should be better defined both in early and late
      stages of lymphoproliferation. In the past few years, novel study approaches have
      been focused on understanding the mechanisms of lymphomagenesis. In particular,
      immune stimulation by infectious agents or autoantigens, T-cell help, altered
      immunocompetence, and local cytokine networks seem to be crucial in favouring B
      cell expansions. In turn, actively proliferating B cells are at higher risk of
      undergoing genetic alterations that make the clone capable of fully autonomous
      growth, i.e., fully neoplastic. Peculiar human autoimmune diseases predisposing
      to B-cell lymphoma represent relevant models to characterize and dissect the
      temporal sequence of the different lyphomagenetic events. The present review,
      particularly, focuses on Sjoegren's syndrome, and on recent findings regarding
      the putative role of hepatitis C virus in B-cell lymphoproliferation. The
      biologic and clinical implications may be of major relevance for other B-cell
      disorders characterized by higher prevalence and morbidity.

PMID- 10352475
TI  - Molecular Techniques in Oncologic Pathology.
AB  - Molecular techniques have already earned a place in the management of oncologic
      disorders. The requests of Clinical Oncologists to Pathologists include, besides
      the diagnosis, any additional information useful for prognosis and therapeutic
      choices, as well as expertise and technologies to follow-up patients. To fulfill
      these commitments, pathologists have been resorting to classical morphology,
      cytochemistry, immunocytochemistry, and have only recently come to include
      molecular genetic techniques. Most of the molecular methods of practical utility
      are based on the analysis of DNA. The DNA methodologies of routine applicability
      mainly include Southern blotting and polymerase chain reaction (PCR). Southern
      blotting recognizes major DNA rearrangements, whereas PCR-based methods allow to
      recognize both gross chromosomal modifications and fine gene alterations,
      including point mutations. PCR techniques may also be used for many purposes
      using the partially degraded DNA from formalin-fixed paraffin-embedded tissues.
      Here we will draw a brief overview of the role of molecular genetic techniques in
      the pathology practice for the diagnosis, prognosis and follow-up of neoplastic
      diseases, using examples from our experience in hematology and gastroenterology.

PMID- 10352476
TI  - The Mammalian cell cycle and its aberrations in cancer cells.
AB  - In eukariotic cells each phase of the cell cycle is controlled by the sequential
      activation of various cyclin-dependent kinases (Cdks). These kinases, which are
      dimers of a catalytic (cdc) and a regulatory (cyclin) subunit, are known to
      phosphorylate various substrates whose activity is crucial for cell cycle
      progression. As key regulators of the cell cycle cdks must be under control by
      both extracellular and intracellular signals. There are several distinct
      mechanisms for controlling the activity of the different cdks: regulated
      synthesis and destruction of the regulatory subunit (cyclin), regulated
      activation and destruction of inhibitory subunits (cki) and postranslational
      modifications of the catalytic subunit by specific kinases and phosphatases. In
      this review I will discuss the elements controlling the mammalian cell cycle and
      their relationship with the genesis of cancer.

PMID- 10352477
TI  - The Failing Heart.
AB  - Heart failure is a highly lethal condition which carries a shorter life
      expectancy than most common malignancies. Despite the large number of efforts
      dedicated to understand why the heart fails, only limited possibilities are
      available to improve survival. This because the problem is very complex and is
      dependent upon multiple changes in the anatomical and functional properties of
      the heart as well as of other organs, together with modifications in systemic and
      local hormonal and neuronal interactions. This review has been focused on some
      results obtained in pathologic hearts explanted from subjects with intractable
      heart failure or in hearts from animals with spontaneous or induced myocardial
      damage with different degrees of cardiac dysfunction and failure performed in the
      last few years in our laboratories. Hearts in failure have different alterations
      at the anatomical, histological and cellular level that may justify, at least in
      part, the functional impairment and the progressive evolution of the disease.
      Recent findings of apoptotic myocyte cell death and myocytic hyperplasia are
      exciting prospectives to be followed with the expectation that new strategies may
      be discovered to alter the unfavourable outcome of heart failure. However, the
      complexity of the problem seems to require a large number of efforts before the
      results obtained can be applied to human beings. Thus, basic researches must be
      stimulated to explore the mechanisms which allow the development of heart failure
      despite the persistence in the damaged myocardium of a large number of
      contractile cells.

PMID- 10352478
TI  - Meningioma: the impact of new techniques for the diagnosis and prognosis.
AB  - Our knowledge of meningioma has expanded considerably in the last few years.
      Immunohistochemistry, cytogenetics and molecular biology have given an important
      contribution to this improvement. Meningiomas can have almost endless variations
      in cellular morphology, architectural patterns and metaplastic changes. The
      majority of them have no prognostic implications. But a few variants should be
      recognised because of peculiar clinico-pathologic correlations or biological
      behavior. Histological features useful in distinguishing benign from potentially
      aggressive meningiomas have been identified. According to the WHO classification
      meningiomas are classified as benign (Grade 1), atypical (Grade 2) and anaplastic
      (Grade 3). Since histological appearance fails to predict accurately the clinical
      behaviour in a significant percentage of meningiomas, the attention has turned
      from tumor histology to tumor biology. Proliferative indices can be used,
      together with other histologic features, in assessing the prognosis as well as
      the postoperative management of the patients. Karyotyping may be of use to
      identify a subgroup of patients at higher risk for recurrence who may need
      special follow-up and treatment. The most consistent chromosome aberration in
      meningiomas seems to be a monosomy 22. As the karyotype becomes progressively
      abnormal, the tumor becomes more aggressive. Molecular genetic analysis has shown
      that TP53 gene mutation may be considered as a marker for malignant
      transformation in meningioma. P53 immunoreactivity is not always associated with
      the gene mutation but is not detectable in benign meningiomas.

PMID- 10352480
TI  - Proceedings of the First Italian Meeting on Telepathology. Udine, Italy, April
      19th, 1997.

PMID- 10352481
TI  - Intestinal type mucinous borderline tumors of the ovary.

PMID- 10352479
TI  - EGFr and c-erB2mRNA expression in urinary bladder superficial carcinomas.
AB  - AIM: The biological behaviour of superficial type transitional carcinomas of the
      urinary bladder can not be predicted. To try to differentiate those tumors that
      will present aggressive behaviour with infiltrative recurrences from those that
      will not, we studied, at the mRNA level, the expression of two membrane proteins,
      EGFr and c-erbB2, and of k-ras oncogene. METHODS: The mRNAs relative quantitation
      as performed, after RT-PCR, from histological sections cut from formalin-fixed
      and paraffin-embedded tissues. Twenty-three patients with urinary bladder
      transitional carcinoma have been studied for EGF-receptor, c-erbB2 and k-ras
      oncogene. The expression has been correlated with the outcomes of the follow-up
      period (infiltrative or superficial recurrences). RESULTS: The mRNA or EGFr was
      in average more expressed in tumors that continue to be superficial in the
      relapses, but for c-erbB2 the level of mRNA was similar in both, the more and
      less aggressive groups. The expression of k-ras was higher in cases associated
      with more infiltrative tumor relapses. CONCLUSIONS: In this preliminary study we
      did not identify any specific marker that can clearly predict the prognosis of
      superficial type transitional carcinoma of the urinary bladder; only k-ras
      expression is connected in some cases with the aggressiveness of the tumors. The
      expression of EGFr gave us intriguing results, it is in fact higher in the
      superficial carcinomas that do not tend to become infiltrative of the urinary
      bladder wall.

PMID- 10352482
TI  - Cut and die: proteolytic cascades regulating apoptosis.
AB  - Cell death by apoptosis is an amazing mechanism which plays a primary function in
      governing both development and tissue homeostasis in multicellular organisms.
      Different cells, from nematodes to humans, utilize the same evolutionary
      conserved genetic program controlling apoptosis. The key event in the execution
      of the suicide program is the activation of specific proteases belonging to the
      caspase family (cysteine protease specific for aspartic residues). Following
      their activation, caspases process key substrates which probably orchestrate the
      complex cellular changes that mark apoptosis. This review will focus on the
      recent advances in our understanding of the proteolytic events regulating
      apoptosis.

PMID- 10352483
TI  - In vitro cultures of pathological thyroid cells: a powerful diagnostic technique.
AB  - In order to get a correct predictivity from molecular and functional markers in
      neoplastic disease, cell cultures, correspondent to in vivo existing populations,
      should be available. The difficulty, as yet, to correlate in vivo conditions with
      in vitro molecular and functional markers, represents a hurdle for a better
      prognosis in several neoplastic diseases. We tackled the problem establishing
      cultures from surgical samples of human thyroid glands bearing various
      pathologies (pathological diagnosis were obtained for all samples). Cells were
      frozen after 2 passages, and molecular markers (thyroglobulin, TPO, TTF-1 and PAX
      8) and functional parameters (TSH-dependent cAMP production and thymidine
      incorporation) were investigated after thawing. The "in vitro profile"
      (functional parameters and molecular markers) was found to correlate with the
      pathological diagnosis and the degree of differentiation of the starting
      specimens. The data presented suggest that our culture technique allows in vitro
      growth of cell populations that may be used to perform functional assays and may
      make the molecular characterization of pathological samples easier. These
      findings could be especially useful to better define prognosis and also help to
      develop innovative therapies.

PMID- 10352484
TI  - Treatment intensification of malignant lymphomas with autologous bone marrow
      transplantation and granulocyte colony stimulating factor.
AB  - Treatment intensification with autologous bone marrow transplantation (ABMT) was
      administered to 37 cases of Hodgkin's and non-Hodgkin's lymphoma (HL and NHL) who
      were in complete or partial remission (CR or PR) after chemotherapy (MOPP/ABVD or
      F-MACHOP respectively) and to 12 cases of HL and NHL who were in relapse. ABMT
      treatment was BAVC for NHL and BEAM for HL. Marrow cells were harvested from the
      marrow and cryopreserved. The number of mononuclear marrow cells that was
      reinfused ranged between 0.19 and 0.80 x 108/Kg b.w. (median 0.39). All the
      patients were treated with granulocyte colony stimulating factor (G-CSF,
      Filgrastim) at a dose of 5 mg/Kg b.w. from day +4 until the absolute neutrophil
      count exceeded 1 x109/L for 3 consecutive days. Engraftment was observed in all
      cases, and no transplant-related deaths occurred. The patients with NHL and HL
      received a median of 12 (range 2-19) and 14.5 (range 9-27) doses of G-CSF
      respectively. Median time to 20 x 109/L platelet count was 14 to 17 days. Median
      time to an absolute neutrophil count 0.5x109/L was 13 days. A febrile episode
      during the period of post-transplant aplasia was documented in 35 patients (71%).
      Fever was associated with Gram+ bacteraemia in 31% of the cases and with Gram-
      bacteraemia in 11% of cases. Herpes Simplex infection was documented in two
      cases. No fungal infections were recorded. Median hospitalisation time from
      reinfusion ranged between 19.5 days (NHL) and 23 days (HL). Thirty-four of 37
      cases (92%) who were transplanted in CR or in PR are currently alive and in
      continuous CR with a median follow-up time of 37 months after ABMT. Three of 12
      cases (25%) who were transplanted in relapse are alive and in CR. Our data point
      out that ABMT followed by G-CSF is a safe and a very effective procedure for high
      risk malignant lymphomas, when ABMT is planned and is performed not as a rescue
      procedure but when it is integrated in the treatment strategy from the very
      beginning.

PMID- 10352485
TI  - Adriatic Society of Pathology. 12th International Meeting. Proceedings of a
      symposium. Ostuny (BA), Italy, June 27-29, 1997.

PMID- 10352486
TI  - TRANSCRIPTION FACTORS AND CANCER. THE EXAMPLE OF PAX GENES.
AB  - Pax genes encode for transcription factors important in cell differentiation and
      embryonic development. These genes are very much conserved in vertebrates and
      homologous genes are also present in lower eukaryotics. Pax genes are defined by
      the presence of the paired box, a sequence encoding for a protein domain able of
      sequence-specific DNA recognition. Full-length Pax protein control a large
      variety of developmental decisions. Mutations of Pax genes give rise to abnormal
      phenotypes both in human and mouse. Recently, various studies have revealed the
      role that Pax genes may have in human tumours. Both "in vitro" and "in vivo"
      assays demonstrate that these genes possess an oncogenic potential. Moreover,
      misexpression or structural alterations of these genes have been detected in
      several human tumours. Together with studies that have revealed the critical
      biochemical and biological properties of Pax proteins, in this review we focus on
      their relevance in human cancer and, in particular, on target genes that may
      mediate their biological effects. A systematic identification of genes which are
      targets of Pax proteins may have a great impact in understanding molecular basis
      of neoplastic disease.

PMID- 10352487
TI  - Diagnosis of Alzheimer's disease.
AB  - For the postmortem diagnosis of Alzheimer's disease, both b-protein
      immunoreactivity and hyperphosphorylated t-protein immunoreactivity have to be
      found in the neocortex. The former is age-related, and the latter occurs in
      several neurodegenerative diseases. The cooccurrence of these lesions in the
      neocortex of Alzheimer patients is likely the result of the abnormal
      vulnerability of selected nerve cell populations to b-protein.

PMID- 10352488
TI  - The clinical management of early and advanced colorectal cancer.
AB  - Despite the impressive developments in the fields of preclinical research and
      chemoprevention of colorectal cancer, this disease remains the second most common
      cause of cancer death after lung cancer in the western hemisphere. Things are
      moving along, however, and it is common opinion that the medical treatment of
      colorectal cancer is the field of Medical Oncology where the most signifcant
      advances have been achieved in the last 10 years. The value of adjuvant
      chemotherapy for colorectal cancer has been confirmed in several randomized
      trials and it has been firmly established that systemic chemotherapy doubles the
      survival of patients with advanced colorectal cancer compared to untreated
      controls. In addition, for the first time in 40 years since 5-fluorouracil
      development, there seem to be valuable alternatives/ adjuncts to the
      fluoropyrimidines. The management of individual patiens, however, remains a very
      challenging matter both in the adjuvant and the advanced setting. In this
      connection, no rigid guidelines can be given, as too many factors play crucial
      roles in the clinical decision-making. The purpose of this article is reviewing
      the evidence to suggest the most appropriate treatment for each condition.

PMID- 10352489
TI  - PROGNOSTICATION OF BREAST CANCER BY MULTIVARIATE METHODS.
AB  - Three multivariate prognostic models based on Cox's regression were tested in
      terms of how they predicted prognosis in a material of 134 patients with breast
      cancer. The multivariate models all incorporated tumor size, mitotic activity
      index (MAI), and axillary lymph node status in their formulas, and were
      originally produced through studies on different patient materials. The
      predictive behavior of MAI was also tested separately in the same material. The
      multivariate models gave roughly parallel predicted percentages of survival at
      two years (CV=5.2%), but showed clearly greater variation later (12.3% and 24.4%
      at 5 and 9 years, respectively). The results were more uniform between the
      multivariate models, than between the prediction by MAI and the multivariate
      models. The variation between repeated estimates was smaller within multivariate
      models than within the estimation of one of their components (MAI). We found the
      use of the multivariate models easy. However, traditional hospital practice does
      not necessarily favor the use of multivariate models, although they seem to group
      patients more reliably than single prognostic features.

PMID- 10352490
TI  - Parathyroid adenomas and malignant neoplasms: coincidence or etiological
      association?
AB  - OBJECTIVE: To evaluate the possible association between primary
      hyperparathyroidism and malignant neoplasms. DESIGN: An historical cohort study.
      SETTING: The only Regional General Hospital of the Province of Udine, Italy
      (population = 500.000). PARTICIPANTS: All the 101 patients with surgically
      treated parathyroid adenomas. MAIN OUTCOME MEASURE: The incidence rate of
      malignant tumor was calculated for this cohort based on the number of incidence
      cases and the person-years at risk. Standardized morbidity rate ratios (SMR) were
      calculated to infer the cancer relative risk of the study cohort as compared with
      the general population. RESULTS: A total of 13 cases of malignant neoplasms were
      ascertained among cohort members. The overall number of observed cases of
      malignancy did not exceed the number of expected cases (SMR = 1.0). However,
      strong and statistically significant direct associations were found with bladder
      cancer (SMR = 5.1) and polycythemia vera (SMR = 62.5). CONCLUSIONS: Due to the
      magnitude of the associations between parathyroid and bladder cancer and
      polycythemia vera, it is unlikely that they might be explained completely by bias
      or chance. Rather, biologically plausible explanations were identified.
      Particularly, non-paraneoplastic hypercalcemia due to primary hyperparathyroidism
      may increase the risk of these malignancies.

PMID- 10352491
TI  - Carcinosarcoma of penis. Case report and review of the literature.
AB  - AIMS OF THE STUDY: Carcinosarcomas (sarcomatoid carcinomas) are controversial,
      biphasic tumors composed of both carcinomatous and sarcomatous elements. They are
      uncommon and occur in numerous locations. At the time of this report only 3 cases
      of carcinosarcoma of penis have been reported in the literature. The aim of this
      article is to provide a discussion of these lesions, using informations gleaned
      from the pertinent literature as well as the personal experience of the authors.
      METHODS: The formalin-fixed paraffin-embedded tissue was stained with hematoxylin
      and eosin, reticulum, alcian blue and Mallory's trichrome stains. Section from
      selected paraffin-embedded blocks, were stained with antibodies to citokeratins,
      EMA, vimentin, desmin, and a actin. RESULTS: In our case the carcinomatous
      elements were admixed with areas of "divergent differentiation": spindle-cell and
      giant-cell sarcomatoid component with bone and cartilage differentiation were
      noted. In situ carcinoma was also detected. Immunohistochemistry showed
      reactivity for keratin and epithelial membrane antigen (EMA). In most of
      pleomorphic spindle elements. Immunoreactivity for vimentin, desmin and actin
      were focally found. CONCLUSIONS: The carcinosarcomas may demonstrate "divergent"
      differentiation into bone, cartilage or myogenous tissue, so it is possible that
      the cell of origin could be heterogeneous. In our case myogenous differentiation
      was focally found. Although the clinical data, available from the only three
      cases of the literature, demonstrate that the behaviour of this tumors was not
      different from those of squamous cell carcinoma, the authors recommended a
      constant careful follow-up of the patients.

PMID- 10352492
TI  - Spiradenocarcinoma: morphological and immunohistochemical features.
AB  - Malignant transformation of spiradenoma is a very rare event and its biologic
      features have not been fully described. Clinically, these tumours are
      characterized by the rapid enlargement of a long-standing cutaneous nodule.
      Microscopic examination discloses the presence of the two components, benign and
      malignant, whose morphological distinction is not always easy. We report the
      occurrence of a spiradenocarcinoma within a pre-existing spiradenoma of the cheek
      in a 48 year old man and review the previously reported cases especially on the
      basis of their morphological and immunohistochemical characteristics.

PMID- 10352493
TI  - Protective effect of monounsaturated fat against breast cancer.

PMID- 10352494
TI  - Benefits of induced sputum for the evaluation of therapeutic efficacy in patients
      with bronchial asthma.
AB  - Airway inflammation is a major factor in the pathogenesis of asthma. Inducing
      sputum by hypertonic saline is a noninvasive method of assessment of the airway
      inflammation in asthmatic patients. To investigate sputum induction as a method
      for assessing airway inflammation and to evaluate the effect of inhaled
      beclomethasone dipropionate (BDP) in asthmatic patients, we examined the
      bronchial hyperresponsibility (BHR), pulmonary function and differential cell
      counts in induced sputum of the patients before and after BDP therapy. In
      asthmatic patients, the percentage of eosinophils in induced sputum was
      significantly higher than that in non-asthmatic subjects. Ten patients with
      atopic asthma (four men and six women; mean [+/- SD] age, 30.5 +/- 12.4 years)
      participated. Their mean percentage of eosinophils (% eosinophils) in induced
      sputum fell from 22.9 +/- 7.2% to 13.9 +/- 8.3% (p < 0.05) by 3 months of BDP
      treatment. The percentage of eosinophils in induced sputum before BDP treatment
      was significantly correlated with the ratio of the forced expiratory volume in
      one second to the forced vital capacity (FEV1%) at baseline (r = -0.75, p <
      0.05), but not with log Dmin at baseline (p = 0.18). The change in FEV1% between
      at baseline and post-treatment correlated significantly with the change in the
      sputum eosinophil percentage (r = -0.79, p < 0.01). In addition, there was a
      significant correlation between the change of log Dmin and the change of the
      sputum eosinophil percentage (r = -0.64, p < 0.05). In conclusion, analysis of
      induced sputum is a safe, noninvasive, repeatable and useful method to assess the
      clinical condition of bronchial inflammation in patients with bronchial asthma.

PMID- 10352495
TI  - Two-step approach for the operation of male breast cancer: report of a case at
      high risk for surgery.
AB  - We report herein the rare case of a 61-year-old man with a history of dissecting
      aortic aneurysm as well as right breast cancer. He complained of abdominal pain
      due to a progress of aortic dissection in preparation for the radical operation
      for breast cancer. Blood pressure was initially controlled and he was
      administered a simple mastectomy under local anesthesia. One month after the
      first operation, a radical operation for breast cancer was successfully
      performed. The tumor was in stage II, and two years after the operation, the
      patient remained free of recurrent disease. This two-step approach for the
      operation of male breast cancer may be used as a treatment of breast cancer if a
      patient is too frail for normal surgery.

PMID- 10352496
TI  - Inhibition by lysophosphatidylcholine of nitric oxide production in interleukin 1
      beta-stimulated vascular smooth muscle cells.
AB  - In vascular smooth muscle cells (VSMC), inflammatory cytokines such as
      interleukin 1 beta(IL-1 beta) stimulated nitric oxide (NO) production via the
      expression of an inducible type of NO synthase (iNOS). Lysophosphatidylcholine
      (LPC) is a major phospholipid component of atherogenic oxidized low density
      lipoprotein (Ox-LDL). In this study, we examined the effect of LPC on IL-1 beta
      stimulated NO production in cultured. VSMC. LPC by itself did not stimulate the
      production of nitrite, a stable metabolite of NO, but dose-dependently inhibited
      IL-1 beta-stimulated nitrite production. LPC inhibited IL-1 beta-stimulated iNOS
      protein expression, whereas LPC did not inhibit IL-1 beta-stimulated iNOS mRNA
      expression. Analysis of iNOS protein degradation rate revealed that LPC had no
      effect on degradation rate of iNOS protein, suggesting that LPC inhibited iNOS
      translation. Moreover, Ox-LDL inhibited IL-1 beta-stimulated NO production by
      inhibiting iNOS protein expression without affecting iNOS mRNA expression. These
      results indicate that Ox-LDL negatively modulates IL-1 beta-induced NO production
      through the action of LPC, probably by blocking translation of iNOS mRNA.

PMID- 10352497
TI  - Altered epidemiological characteristics of ulcer disease.
AB  - Dynamics and distribution of ulcer disease in population in the period 1987-1996
      were analyzed on the basis of morbidity and mortality rate registered at clinics
      and institutes in Novi Sad. During the analyzed period 4.111 cases of ulcer
      disease were hospitalized and 47 with lethal outcome. Duodenal ulcer (2,739) is
      twice as frequent as gastric ulcer (1,372). Both localisations of ulcer disease
      are more frequent in males, and specific morbidity shows constant rise towards
      the older age groups. Duodenal ulcer shows sudden increase in the age group of
      over 20, and gastric ulcer in the age group of over 60. Gastric ulcer mortality
      (1.6%) is higher in comparison to duodenal ulcer mortality (0.9%) and it
      increases constantly towards the older age groups. Unfavourable result is
      statistically significantly higher in persons over 60. During the monitored
      period the increasing trend in duodenal ulcer is sharp, while figures in gastric
      ulcer are without significant changes. Both localisations have become a frequent
      health problem in population over 40 years of age.

PMID- 10352498
TI  - [Evaluation of left ventricular diastolic function using Doppler
      echocardiography].
AB  - INTRODUCTION: Clinical studies have shown that approximately 40% of patients with
      congestive heart failure have predominantly diastolic left ventricular
      dysfunction. Doppler echocardiography is a simple, noninvasive and safe technique
      that can be used for measurement of diastolic filling and, therefore for
      assessment of diastolic function. PHYSIOLOGY OF DIASTOLE: Diastole is divided
      into four phases: isovolumetric relaxation, rapid filling, slow filling
      (diastasis) and atrial contraction. Diastolic filling can be defined as the
      period from the onset of mitral valve opening to mitral valve closure.
      DETERMINANTS OF DIASTOLIC FILLING: The two major determinants of diastolic
      filling are ventricular relaxation (characterized by the rate and duration of the
      decrease of left ventricular pressure after systole) and compliance (defined by
      volume changes over the change in pressure during diastolic filling). NORMAL
      TRANSMITRAL FLOW PATTERN: When pulsed Doppler sample volume is placed at the tips
      of mitral leaflets, recorded transmitral velocity pattern is composed of two
      principal deflections: the E wave, occurring during the rapid filling phase, and
      the lower A wave, arising from atrial contraction. These two waves are usually
      separated with relatively low velocity signal during diastasis. Numerous indices
      derived from this pattern have been proposed as markers of diastolic function
      (peak and integrated velocities of the E and A waves, their ratio, and
      acceleration and deceleration times of the E wave). However, it should be noted
      that these indices, in fact, measure diastolic filling, rather than function.
      Even in healthy individuals, numerous factors may have impact on transmitral flow
      pattern, including age, heart rate, loading conditions and filling pressures.
      NORMAL PULMONARY VENOUS FLOW PATTERN: Analysis of pulmonary venous flow pattern
      (obtained by pulsed Doppler sample volume placed in pulmonary vein) gives
      additional information and may help in the assessment of left ventricular
      filling. Usually, three distinct velocity waves can be observed: S wave,
      occurring during ventricular systole; 1) wave, diastolic wave that begins after
      mitral wave opening: and finally, AR wave, reversal velocity during atrial
      contraction. When diastolic filling is altered, typically there is an inverse
      relationship between transmitral E and pulmonary venous S wave, as well as
      transmitral A and pulmonary venous D wave. PATHOLOGIC FILLING PATTERNS: There are
      three different pathologic filling patterns: 1) delayed (prolonged, impaired)
      relaxation pattern, characterized by prolonged isovolumetric relaxation time and
      deceleration time, low E and high A wave velocities with an E/A wave ratio
      typically 1; 2) restrictive pattern, associated with shortened isovolumetric
      relaxation time, increased peak E wave velocity with very short deceleration
      time, and small (or even absent) A wave, leading to an E/A wave ratio 2; and 3)
      pseudonormal pattern, usually an intermediate stage between delayed relaxation
      and restrictive filling, as a consequence of disease progression; it may be
      unmasked by Valsalva maneuver and is characteristically associated with atrial
      dilatation and prominent pulmonary venous AR reversal. CLINICAL APPLICATIONS:
      Impaired diastolic function is frequently the first detectable abnormality in
      many of cardiac diseases. With serial recordings, changing of filling patterns,
      from delayed relaxation, through pseudonormalization, and, finally, to
      restrictive filling pattern can be observed. These changes have been demonstrated
      to correspond well with progression of cardiac diseases. According to the
      severity of symptoms and transmitral filling pattern, four-grade model of
      diastolic dysfunction has been proposed. It has been shown that the E/A ratio 2
      and deceleration time 150 ms indicate poor prognosis in patients with dilated
      cardiomyopathy, cardiac amyloidosis and old myocardial infarction, independently
      of the severity of systolic dysfunction. (ABS

PMID- 10352499
TI  - [New findings on the physiopathology of acute hemolytic transfusion reactions].
AB  - INTRODUCTION: Acute hemolytic transfusion reactions (HTRs) are among the most
      feared transfusion-associated complications, principally because severe toxicity
      and rapid death may result. Recently there has been expansion in knowledge
      concerning the pathophysiology of shock, inflammation and disseminated
      intravascular coagulation, factors affecting the outcome of HTRs. A new class of
      biologic mediators/modulators of inflammatory and immune response, interleukins
      (IL) has been discovered to be of the central importance in the modulation of
      such responses. RESULTS: In models of acute IgM-mediated RBC incompatibility in
      experimental HTRs, plasma TNF-alpha rise sharply in a dose- and time-dependent
      manner, peaking at 2 hours. It is responsible for fever, hypotension and
      capillary leak leading to acute shock. After 4-6 hours levels of interleukin-8
      and MCP-1, monocyte chemoattractants and activators of neutrophils rise, and
      remain in plasma significantly elevated 48 hours. In IgG-mediated HTRs, within 6
      hours the concentrations of IL-1, IL-6, and IL-8 increase significantly and
      remain elevated next 24 hours, resulting in fever, hypotension, leucocytosis,
      shock, the proliferation of T-cells and stimulation of immunoglobulin production.
      Cytokines also play an important role in the development of disseminated
      intravascular coagulation (DIC). It is associated with the activation of tissue
      factor pathway and promoting of hypercoagulable state by their effects on
      endothelial cells. IL-1 and tumor necrosis factor (TNF) induce changes in the
      hemostatic properties of endothelial cells surface which leads to increased
      tissue factor and decrease thrombomodulin expression and suppression of protein C
      activity. Thrombin, bradykinin, epinephrine and IL-1 activation induce acute
      renal failure, which leads to renal hypoperfusion and widespread fibrin
      deposition. In etiology of acute lung injury participate: TNF, releasing large
      quantities of enzyme neutrophil elastase via neutrophil degranulation and
      pulmonary capillary endothelial injury. IL-8 and MCP-1 released from endothelial
      cells also promote localised inflammation and thrombosis. CONCLUSION: IL-1, TNF
      alpha and IL-6 and IL-8 are all critical mediators of immune and inflammatory
      response and are known to synergize with each other in a number of in vitro
      systems. They are responsible for major signs of acute hemolytic transfusion
      reaction. A future therapeutic strategy of HTRs has to be aimed at modulation of
      underlying pathophysiologic alterations triggered by HTRs.

PMID- 10352501
TI  - [Characteristics of laser light].
AB  - Laser is one of the greatest technical discoveries of the 20th century. It is
      important in basic sciences, but particularly in diagnosis and therapy of various
      pathologic conditions of human organism. It is electromagnetic radiation, not X
      irradiation and, as such, it is not expected to produce new generation of
      iatrogenic malignancies. Laser falls between infrared and ultraviolet on the
      spectrum mainly in the visible light spectrum. Properties of laser light are:
      monochromacity (the same color), coherence (all of the light waves are in phase
      both spatially and temporally), collimation (all rays are parallel to each other
      and do not diverge significantly even over long distances). Lasers were first
      conceived by Einstein in 1917 when he wrote his "Zur Quantum Theorie der
      Strahlung" (the quantum theory of radiation) which enumerated concepts of
      stimulated and spontaneous emission and absorption. Drs. Arthur Schawlow and
      Charles Townes, in 1956, extended lasers into the optical frequency range and
      Maiman, in 1960, operated the first laser using ruby as the active medium (ruby
      laser). Laser is an acronym for Light Amplification by Stimulated Emission of
      Radiation. To understand the acronym, it is necessary to understand the basic
      physics of the atom. However, if the atom that is in the excited state is struck
      by another photon of energy before it returns to the ground state, two photons of
      equal frequency and energy, travelling in the same direction and in perfect
      spatial and temporal harmony, are produced. This phenomenon is termed stimulated
      emission of radiation. An external power source hyperexcites the atoms in the
      laser medium so that the number of atoms possessing upper energy levels exceeds
      the number of atoms in a power energy level, a condition termed a population
      inversion. This "pumping system" which imparts additional energy to the atoms may
      be optical, mechanical, or chemical. These atoms in a hyperexcited state
      spontaneously emit photons of light. The laser chamber or optical cavity contains
      an active lasing medium which usually determines the name of each laser. There
      are four types of lasing material commonly employed. Solid state lasers use a
      solid matrix material such as a ruby crystal. Gas lasers use a gas or mixture of
      gases such as helium, argon, and CO2. Dye lasers employ a complex organic dye in
      liquid solution or suspension such as rhodamine. Semiconductor lasers use two
      layers of semiconductor substances such as gallium arsenide.

PMID- 10352500
TI  - [Genetic factors in the onset of schizophrenia].
AB  - The importance of inheritance in the development of schizophrenia was recorded in
      classic papers by Kraepelin and Bleuler. These observations have been confirmed
      by the contemporary research. In this paper, we summarize the results of genetic
      epidemiological studies that include family, twin and adoption studies, as well
      as the results of segregation analysis and molecular-genetic research. Family
      studies indicate increased morbidity risk in the relatives of patients with
      schizophrenia, that augments with the degree of relation. Twin studies also
      suggest the importance of genetic factors demonstrating higher rates of
      concordance for the disorder in monozygotic (MZ) than in dizygotic (DZ) twins and
      consistent MZ/DZ ratios across the studies. Adoption studies provide further
      evidence for genetic vulnerability, showing an association between biological
      relatives separated at birth. The concept of "schizophrenia spectrum" is based on
      the observation of the familial aggregation of several hierarchically defined
      disorders in relatives of schizophrenic probands. Schizophrenia, schizoaffective
      disorder, schizotypal and paranoid personality disorder, other nonaffective
      psychoses and psychotic affective disease, according to this concept, represent
      manifestations of varying severity, of the same underlying vulnerability, which
      is transmitted within families. The results of segregation analyses support
      rather polygenic than monogenic inheritance, if schizophrenia is genetically
      homogeneous. However, the possibility of genetic heterogeneity augments the
      interest for searching for vulnerability genes with linkage. The results of
      linkage studies, indicating association between schizophrenia and markers on
      chromosomes 5, 6, 8 and 22, have not yet been replicated on independent samples
      of probands. Recent findings indicate that schizophrenia may be caused by
      unstable DNA (the expansion of trinucleotide repeated sequences at the disease
      locus). This could explain the departure from Mendelian inheritance, highly
      variable phenotype and wide ranging age of onset in schizophrenia. Further
      research in this field could not only clarify the mode of the transmission of the
      liability for schizophrenia and the relationship of genetic and environmental
      factors in the development of the disorder, but also determine which
      characteristics, behavior and physiological variables schizophrenia genes code
      for. This would, in addition, contribute to our understanding of the biological
      basis of schizophrenia.

PMID- 10352503
TI  - [Prolactin and the menstrual cycle].
AB  - In order to estimate serum prolactin levels during particular menstrual cycle
      phases, the authors analyzed values of follicle-stimulating hormone, luteinizing
      hormone and prolactin in 50 women of reproductive age with normal menstrual
      cycles and established ovulation. Blood samples were taken 3-5 times during
      follicullar, ovulatory and lutheal phase of menstrual cycle. There were 582
      radioimmunoassays performed (194 per each hormone), and the upper referent value
      for prolactin was 20.9 ug l. The 2nd group comprised women (250) with menstrual
      cycle disorders (olygomenorrhea and amenorrhea) in whom involvement of
      hyperprolactinemia in these conditions have been done. The obtained results
      showed that the mean prolactin value changed in each phase of the menstrual
      cycle. The highest one was recorded in the periovulatory period, whereas the
      difference was statistically significant in relation to the follicular and
      lutheal phase (p < 0.05). The difference between the follicular and lutheal phase
      was not statistically significant, 54 (21.6%) women from the group of menstrual
      cycle disorders presented with increased values of prolactin.

PMID- 10352502
TI  - [Diagnostic importance of fibronectin in chronic liver diseases].
AB  - Plasma fibronectin was determined in 29 patients with decompensated cirrhosis (7
      patients had bacterial infection) and 23 patients with malignant liver disease.
      The obtained values were compared with the fibronectin values in 20 healthy
      subjects belonging to the control group in order to determine the possible
      diagnostic value of this dimer glycoprotein of high molecular weight whose role
      in the organism has not been completely explained. Fibronectin was determined on
      nephelometer with the use of specific antiserum by Behringwerke. The results
      expressed as mean values and SD were compared with monofactorial variance
      analysis (method One-way ANOVA). Fibronectin values in patients with liver
      cirrhosis were statistically significantly lower than in the control group (p <
      0.01), which is also the case with correlation with malignant liver disease (p <
      0.01). The fibronectin values in patients with malignant diseases were almost the
      same as the control group values (p < 0.01). In 7 patients with liver cirrhosis
      and bacterial infection the fibronectin values were statistically significantly
      higher in relation to those in the remaining 22 patients with cirrhosis but
      without bacterial infection (p < 0.001). The investigation in this study
      indicated that the decrease of mean fibronectin values is related to hepatic
      failure which is of diagnostic value, while normal values in malignant diseases
      do not favor the opinion on fibronectin as a tumor marker. Higher fibronectin
      values in infection in patients with liver cirrhosis are not clear, which
      indicated the total complexity of the relation between fibronectin as a dimer
      glycoprotein and chronic liver diseases including malignant.

PMID- 10352504
TI  - [Acute sensorineural hearing loss at the Otorhinolaryngology Department of the
      General Hospital in Subotica 1991-1996].
AB  - INTRODUCTION: Sudden sensorineural hearing loss is an acute hearing loss of a
      perceptive type, of unknown etiology, in most cases one-sided, or, a every sudden
      sensorineural deafness that occurs in the period of three days or less. Modern
      scientific literature points to three possible etiological factors: viral
      cochleitis, vascular lesion of the labyrinth and unrecognized rupture of the
      membranous labyrinth. The therapy for this disease is extremely various. There
      are dozens of reported different (or similar) healing protocols, including
      vasodilators, Hydroxyethyl starch, low molecular dextran, diuretics,
      defibrinogenation, fibrmolytic therapy, steroids, prostacyclin, oxygen therapy,
      hyperbaric oxygen therapy, vitamins, etc. The aim of the study was to
      recapitulate in brief modern views of etiology and therapy of the sudden
      sensorineural hearing loss, to analyze cases of this illness within the period of
      1991-1996 in our Otorhinolaryngology Department and to compare these data with
      the same or similar data of other authors. MATERIAL AND METHODS: In this study,
      medical records of patients admitted in the period of 1991-1996 in the
      Otorhinolaryngology Department of the Health Center in Subotica with a diagnosis
      of sudden sensorineural hearing loss were used. There were 53 patients with this
      diagnosis. All patients were treated in the hospital with infusions of rheoactive
      drugs. During the diagnostic procedure, all patients underwent a complete
      clinical otorhinolaryngologic examination, detailed anamnesis was taken, acoustic
      impedance tests (tympanometry) and tonal liminal audiometry were performed.
      Routine blood test was made (including complete blood picture, sedimentation
      rate, blood sugar) and a complete urine examination. Sometimes we demanded x-ray
      of the temporal bones (Schnller and Stenwers). A short increment sensitivity
      index (SISI) test and Carhart test were also made, if necessary. Function of the
      vestibular system was tested in cases when the vestibular symptoms were more
      strongly expressed. This test was made after passing an acute attack of
      vertiginous symptoms. Control audiometry was made on the seventh and on the
      fourteenth day after admission. This therapy consisted of an infusion of
      physiologic solution (NaCl) 250 or 500 ml twice daily to which 300 mg xanthinol
      nicotinate ampulla, paracetam 1 g ampulla, dipyridamole 10 mg ampulla and C
      vitamin 10% 500 mg ampulla were applied. The number of paracetam and xanthinol
      nicotinate ampullas was raised on the 14/day, and then it fell to the starting
      value. The therapy lasted 17 days. Patients were given multivitamine peroral
      therapy, tranquilizers and diet without coffee, smoking and allergenic food.
      RESULTS AND DISCUSSION: The study included 53 patients, 27 (50.94%) female and 26
      (49.06%) males (Graph 1). Their age (Graph 2) ranged between 16-71 years. The
      biggest group of patients was between 40-49 (39.62%) years of age. Distribution
      per year (Graph 3) shows that the incidence of the acute sensorineural hearing
      loss differs from the findings of other authors, especially in the period of 1991
      1994, due to very few cases. Connection of this illness with seasons is shown in
      Graph 4. We had most cases during summer time (August, 16.98%). There is a mild
      rise in winter (December, 13.21%). The degree of the hearing loss in decibels is
      shown in the Graph 5. Most of the patients (75.47%) had mild or severely damaged
      hearing (40-85 dB). Period of the deafness before patients were admitted to the
      hospital, is shown in Graph 7. Most of them came in the first seven days after
      they experienced acute deafness (52.83%). Symptomatology of the persons with
      acute hearing loss is shown in Table 1. All of them had the feeling of deafness,
      and 50.94% also had tinnitus. Table 2 shows that only two patients had a
      pathologic finding (hypo function) on the vestibular caloric test. 57.14% of
      patients tested by this method showed a normal function of the vestibular
      apparatus. The recovery of he

PMID- 10352505
TI  - [Deliveries in the outpatient birthing facility in Ruma during 1989 and between
      1992 and 1995].
AB  - INTRODUCTION: The outpatient maternity home in Ruma offers health care to women
      during normal delivery. On the occasion of patient's admittance into the
      maternity home, indications for hospitalization during the delivery are strictly
      observed. Ruma community is a bordering area of SR Yugoslavia and, in the period
      of the war in ex Yugoslavia, it gave shelter to a great number of refugees and
      exiles. Health care was offered to pregnant women and to the ones who were giving
      birth and to the refugees in the Health Centre Ruma. The period from 1992-1996 is
      characterized by war, migration of people, UN sanctions imposed on Yugoslavia and
      low standard of living. PURPOSE: The purpose of this paper was to find out if
      there was a difference in indices regarding pregnancy and course of delivery in
      1989 and in the period 1992-1996 in the Ruma and Irig communities population and
      in refugees and exiles. MATERIAL AND METHODS: The data were collected from the
      obstetrical records in outpatient maternity home Ruma in 1989 and 1992-1996. By
      data processing the following parameters were obtained: number of deliveries,
      percentage of spontaneous miscarriages and premature births, percentage of
      pregnancy-induced hypertension (PIH) and anemia in pregnancy, the rate of early
      neonatal morbidity and mortality; weight, length, circumferences of head and
      chest with the newborn infants. RESULTS: There were 321 deliveries in 1989; 12
      women gave birth with PIH (3.73%). 37 women had a spontaneous miscarriage
      (11.52%). Anemia was corrected with 12 women after delivery (3.73%). There was
      one premature birth in 1989 (0.3%). 4 newborn infants were hospitalized after
      delivery (12.46 promiles). There was no mortality of the newborn infants and
      mothers. The following has been established for women giving birth in the period
      1992-1996 from the territory of Ruma and Irig communities: number of deliveries
      (in 1992--563, in 1993--503, in 1994--481, in 1995--418) constantly falls. The
      percentage of PIH in pregnancy was 19.54% in 1992 (110 women) and 0.18% eclampsia
      (1 case), 11.3% (56 women) in 1993, 5.61% (27 women) in 1994, 5.82% (31 women) in
      1995. In 1992 80 women giving birth had spontaneous miscarriages in their
      previous pregnancies (14.2%), in 1993--44 women (8.74%), in 1994--38 women (7.9%)
      in 1995--45 women (8.45%). An anemia correction after delivery was with 31 women
      (5.5%) in 1992, in 1993 with 24 women (4.26%), in 1994 with 18 women (3.74%) and
      in 1995 with 30 women (6.24%). There were 22 premature births in 1992 (3.9%), in
      1993--7 (1.39%), in 1994--10 (2.07%) and in 1995--9 (1.69%). 14 children were
      hospitalized after delivery in 1992 (24.86 promiles), in 1993--20 children (39.76
      promiles), in 1994--18 children (37.42 promiles), in 1995--35 children (65.7
      promiles). In 1992 one child died after delivery because of left heart hypoplasia
      and pneumonia; in 1993 one woman delivered fetus mortus: one child died, in 1994,
      with diaphragmatic hernia and lung hypoplasia; in 1995 there were no deaths after
      delivery. Mothers' mortality was 0. In the period from 1992-1996, 62 women from
      Republic of Serb Krajina (hereinafter referred as RSK) were delivered and 67
      women from Serb Repubic (hereinafter referred as SR). 5 women from RSK had a
      spontaneous misciarriage (8.06%), and 4 women from SR (5.97%). 8 women (12%) from
      RSK had PIH, and 5 women (7.46%) from SR. There were premature births with 3
      women (4.82%) from RSK and with 2 women (2.98%) from SR. 2 newborn infants (32.25
      promiles) from RSK were hospitalized after delivery and 3 (29.8 promiles) from
      RS. In 1995 one women delivered fetus mortus in utero (diabetica fetopathy) (14.9
      promiles) from RSK. DISCUSSION: By analyzing the deliveries in the course of 1989
      and in the period 1. 01. 1992 to 31. 12. 1995 the following has been established:
      the number of deliveries is greater in the period 1992-1996 in relation 1989, but
      there is a constant fall from 1992-1996. (ABSTRACT TRUNCATED)

PMID- 10352506
TI  - Denture cleaning techniques in the elderly affecting the occurrence of denture
      induced stomatitis.
AB  - The aim of this paper was to establish if and to what extent being informed on
      oral hygiene procedures affects occurrence of denture-induced stomatitis in the
      elderly population. The investigation included 150 elderly denture wearers. The
      following was examined: denture cleaning techniques, incidence of denture-induced
      stomatitis, source of information in regard to oral health and level of
      education. The level of denture plaque was registered on the denture surface and
      expressed in percents. Only 30% of dentures were clean. It has been established
      that there is a statistically significant difference in occurrence of denture
      induced stomatitis in patients who clean their dentures correctly and those who
      do it incorrectly. In patients with dentures demonstrating a greater level of
      plaque, the incidence of denture-induced stomatitis was higher. Only 18% denture
      wearers were given instructions on denture cleaning by their dentists. The level
      of education is not directly connected with oral health care. Apart from others,
      dentists should pay more attention to oral health care of the elderly.

PMID- 10352507
TI  - [Clinico-epidemiologic characteristics of superficial multiple basal cell
      carcinoma at the Dermatovenereology Clinic in Novi Sad 1986-1996].
AB  - INTRODUCTION: Multiple superficial basal cell carcinomas of the skin (MSBCC)
      appear as a rare clinical form of basal cell carcinoma (BCC) on the trunk. The
      aim of this paper was to display the clinical characteristics and frequency of
      superficial basal cell carcinomas on the trunk. MATERIAL AND METHODS: The
      examination was done on a 10-years material of the Department of Dermatological
      Oncology of the Dermatovenererology Clinic in Novi Sad (in the period 1986-1996).
      The examination included only MSBCC. RESULTS: In the 10-year period the total
      number of nonmelanotic malignant epithelial tumors of the skin (NMETS) was 2218
      with 22 of MSBCC with total incidence of 0.99%. The average annual number of
      NMETS was 221.8. The average annual number of MSBCC was 2.2. In regard to the
      incidence of BCC of the skin in the same period, the total number of BCC of the
      skin was 1220, with the incidence of MSBCC 1.80%. The total number of changes of
      the superficial types BCC in the examined group was 110, and the average number
      of changes 5. The localization of MSBCC in the examined group shows the greatest
      number of tumors on the skin of the back (42--38.18%), hence thorax (29--26.36%),
      abdomen (25--22.73%) and the least on the presternum (14--12.73%). The average
      period from discovery of MSBCC in the examined group until the moment of
      inspection was about 2.5 years. In one case nevocellular syndrome was
      established, MSBCC was established in 35 patients, while in 80 cases these were
      different types of BCC of the face, capillitium, neck, trunk and extremitites. In
      the examined group 22.73% patients with positive familial anamnesis in regard to
      malignancy. Most were pensioners (11 cases--50.00%) mainly living in towns, while
      agriculturers are on the second place (7 cases--31.82%) mostly living in the
      village. In regard to the age, it appears that increasing number of patients are
      in the seventh decade of life. DISCUSSION: The recent literature data point to
      the genetic dispositions for MSBCC on the skin of the trunk, probably due to
      poorphotoexposition of the skin. CONCLUSION: Authors principally point to the
      genetic pre-disposition as the main etiological factor for MSBCC of the skin of
      the trunk. Professional or accidental photoexposition to ultraviolet radiation,
      also have a secondary role. The disease mostly affects the elderly and mostly
      males.

PMID- 10352509
TI  - [Dermatofibrosarcoma protuberans: case report].
AB  - OBJECTIVE: Dermatofibrosarcoma protuberans (DFSP) is a relatively rare, slow
      growing, fibrohistiocytic sarcoma of intermediate malignancy. The tumor appears
      most frequently on the trunk and extremities as a slow-growing indurated plaque
      or nodule. It appears mostly between the second and fifth decades of life.
      METHODS: This is a case presentation of a 59-year-old woman with a 10 x 12 cm
      dermal erythematous plaque on the anterior chest wall. RESULTS: The patient has a
      two year history of painless tumor on the chest. The lesion started as a small
      erythematous plaque and gradually increased in size. At that time the histologic
      examination revealed a benign fibrous histiocytoma. Less than two years later the
      lesion was firm, painless to palpation and movable over deeper structures. The
      second histologic examination revealed a myxoid liposarcoma. The third incisional
      biopsy was diagnostic for DFSP showing a dermal tumor consiting of a storiform
      pattern with cartwheel-like cells arranged around collagenous hubs. The patient
      underwent a standard surgical treatment. CONCLUSION: We report an interesting
      case of dermatofibrosarcoma protuberans where limitations of standard vertical
      histology section resulted in postponed conformation of the diagnosis.

PMID- 10352508
TI  - [Rapid adaptation response after extensive resection of the small intestine: case
      report].
AB  - INTRODUCTION: Short-gut syndrome is defined as any of the malabsorptive
      conditions resulting from massive resection of small bowel. Clinically the
      syndrome is manifested by malnutrition, weight loss; steatorrhea, and diarrhea
      that occur because of decreased absorptive capacity. Intestinal failure is the
      end result of several complex interacting mechanisms relating in: reduced
      enterocyte mass, short small bowel length (8-15% of normal) with consequent
      reduced mucosal contact time for absorption, massive proximal loop dilatation
      with poor propulsion. Intraluminal stasis and bacterial overgrowth cause
      bacterial translocation to the liver and "liver injury" presents as intrahepatic
      cholestasis, with rapid onset and relentless in its progression to end stage
      hepatic failure. Patients with short bowel must be totally or partly supported
      with intravenous nutrition until enteral absorption can sustain survival and
      growth. Autologous bowel reconstruction attempts to reconfigure the residual
      bowel to eliminate negative factors of bowel dilatation and stasis, and to
      redistribute the absorptive mucosa to enhance the adaptation response. CASE
      REPORT: A case of a newborn with extensive small bowel resection (about 80%)
      because of malrotation with volvulus and bowel gangrene is presented. The newborn
      had been six days on total parenteral nutrition and then enteral nutrition had
      been started. The adaptation response on twentieth day had been satisfactory so
      that parenteral nutrition was completely suspended. Full adaptation was achieved
      after two months when the child had one yellow colored bowel movement per day.
      Presently, the baby grows normally and gains weight. CONCLUSION: What makes this
      case interesting is a really unusually rapid adaptation response towards complete
      enteral independence.

PMID- 10352510
TI  - [The family physician within the health care system].
AB  - Having in mind the importance, place and role of a family physician within the
      health care system and its contribution to health improvement both of individuals
      and groups, the authors present the most important statements from the World
      Health Organisation's Charter for General Practice Family Medicine, and its
      characteristics--accessibility, integrity, continuity, team work, orientation
      towards the person, family and community, confidentiality, coordination. The
      paper also gives conditions for development of family medicine, such as
      structural, organisational and professional, as well as specific quality
      concerning the activity of a family physician.

PMID- 10352511
TI  - The effect of preemptive analgesia on subacute postoperative pain.

PMID- 10352512
TI  - Future trends in research of cardiopulmonary resuscitation.

PMID- 10352513
TI  - [Recommendations for the treatment of serious adult head injury. I. Initial
      evaluation, prehospital observation and treatment, hospitalization criteria,
      systemic and cerebral monitoring. Societza Italiana di Anestesia, Analgesia,
      Rianimazione e Terpia Intensiva].

PMID- 10352514
TI  - [Recommendations for the treatment of serious adult head injury. II. Medical
      treatment criteria. Societza Italiana di Anestesia, Analgesia, Rianimazione e
      Terpia Intensiva].

PMID- 10352515
TI  - Propofol in the anaesthetic management of percutaneous rhizolysis for trigeminal
      neuralgia.
AB  - BACKGROUND: To evaluate the efficacy of propofol as the sole anaesthetic agent
      for the anaesthetic management of the trigeminal rhizolysis. METHODS: 
      EXPERIMENTAL DESIGN: retrospective study. SETTING: operating room of the
      Neurosurgery Department at University. PATIENTS: 200 patients were studied, 115
      males and 85 females, with mean age of 62.8 +/- 3.6 years, ASA status I, II or
      III and with various underlying medical problems. INTERVENTIONS: patients were
      premedicated with atropine 0.01 mg/kg i.v. 10 min before the induction of
      anaesthesia. The induction dose of P was titrated to the desired level in
      according to age and clinical conditions. After induction of anaesthesia the
      surgeon started the needle placement through the foramen ovale in the trigeminal
      cistern. MEASUREMENTS: during both procedures the mean dose of P, induction and
      recovery times, side effects and complications and quality of anaesthesia were
      assessed. Statistical analysis of the data was carried out using ANOVA for
      repeated measures and Bonferroni "t"-test and a value of p < 0.05 was considered
      to be significant. RESULTS: Anaesthesia was successfully induced after a mean
      dose of 1.9 mg/kg of P during PG and of 2.1 mg/kg during PR. A few side effects
      and short recovery time were recorded in all cases. P also provided an adequate
      cardiovascular stability during PG and PR. CONCLUSIONS: In conclusion, P can be
      considered suitable for this particular neurosurgical procedure requiring short
      period of anaesthesia and rapid recovery time in order to communicate with the
      neurosurgeon during the sensory testing.

PMID- 10352516
TI  - [Postoperative pain? No, thanks!].

PMID- 10352517
TI  - [The Catalan model in the management of transplantation. The Catalan organization
      for transplantation (OCATT)].

PMID- 10352518
TI  - [Organ donation in Italy and Europe].

PMID- 10352519
TI  - [Laryngotracheal resection and reconstruction by Grillo's technic for
      postintubation stenosis].
AB  - BACKGROUND: Tracheal resection and reconstruction is the standard treatment for
      postintubation stenosis. However, when the stenosis extends proximally to the
      subglottic larynx surgical treatment is particularly difficult. Specific surgical
      techniques have to be used in order to preserve the recurrent laryngeal nerves.
      The aim of this study is to evaluate the results obtained at our Department with
      laryngotracheal resection and reconstruction with the Grillo technique for
      postintubation stenosis. METHODS: From January 1984 to December 1997, 83 patients
      with tracheal and laryngotracheal lesions underwent surgical treatment. Eighteen
      patients had postintubation stenosis of the upper trachea and subglottic larynx
      and underwent single-stage laryngotracheal resection and reconstruction. Mean
      stenosis length was 3.5 cm (range 3-5 cm). Twelve patients underwent
      anterolateral laryngotracheal reconstruction, and 6 patients had a
      circumferential laryngotracheal reconstruction. A Montgomery suprahyoid laryngeal
      release was required in 4 cases. RESULTS: There was no surgical mortality.
      Surgical results were excellent or good in 17 cases and satisfactory in one case.
      No recurrence of stenosis has been observed. CONCLUSIONS: Cricoid cartilage
      involvement in postintubation stenosis should not be considered a
      contraindication to surgical treatment. However, laryngotracheal resection and
      reconstruction is technically difficult and should be performed only in selected
      cases.

PMID- 10352520
TI  - Benign biliary stricture. Personal experience and technical notes.
AB  - BACKGROUND: Benign biliary strictures are a binding situation for clinicians when
      choosing the best treatment. This is a benign disease and needs safe, effective
      and lasting therapy. Up to day non surgical treatment have been suggested as the
      first therapeutical option but surgery seems to support the best late results.
      METHODS: The authors report their experience in 206 patients, 64 males and 142
      females, aged from 27 to 77 years, affected by postoperative (160 patients) or
      inflammatory (46 patients) biliary strictures. All the patients but three had
      been treated by surgical procedures. RESULTS: Postoperative morbidity and
      mortality were 18.4% and 3.4% respectively. Follow-up ranged from 2 to 16 years.
      Late stricture of bilio-enteric anastomosis has been observed in 8.2% of patients
      and peptic ulcer or cholangitis in 4.9% of cases. Restenosis appeared after a
      mean time of 2.5 years (range 20 months-6 years), supporting the need for a long
      term follow-up. Effective late results have been reported in 91.5% of patients.
      No late complications of ineffective results have been observed after
      transduodenal sphincterotomy. CONCLUSIONS: The authors propose some guidelines
      for choice charce of treatment, analysing the limits of non surgical therapy and
      underlying the best surgical tactics. Bilio-enteric anastomosis is a safe,
      effective and lasting therapy for biliary strictures; Hepp-Couinaud hepatico
      jejunostomy is the best choice for high-medium stricture; transduodenal
      sphincterotomy preserves its important role in low biliary stenosis.

PMID- 10352521
TI  - [Tension-free hernioplasty. Our experience].
AB  - BACKGROUND: In recent years the "tension-free" techniques have been progressively
      replacing conventional hernioplasty by Bassini and Shouldice. Personal experience
      in the application of various techniques using a prosthesis to make the back wall
      of the inguinal canal stronger is described. METHODS: From January 1995 to
      February 1996, 119 non-selected patients were examined; they were operated by
      Trabucco's (100 cases), Lichtenstein's (16 cases), Gilbert's (13 cases) and
      Rives's (1 case) techniques, using polypropylene prostheses. Patients were
      followed for ten months (range 4-18) after surgery with Day-hospital checks at 1
      month, 4 months, 1 year and 18 months. RESULTS: Mortality was not observed.
      Morbility presented in 12 cases: 2 suppurating wounds, 3 seromas, 2 hematomas, 2
      temporary neuralgias of the genito-femoral nerve and 2 scrotal edemas. There was
      a recurrence (0.8%). CONCLUSIONS: The cases presented confirm the validity of the
      "tension-free" techniques, both for reduced incidence of complications and
      recurrences, and for a better compliance of the patient, compared with
      conventional techniques.

PMID- 10352522
TI  - [The single-stage surgery of perforated colon carcinoma. Our experience of 46
      cases].
AB  - BACKGROUND: 46 cases of perforated colonic neoplasm (4.6% of the entire series):
      11 (24%) of the right colon, 35 (76%) of the left colon; 19 males (41%) and 27
      females (59%); mean age 67 years old, range 32-92 years. pTNM: stage II, 1 case
      (2%); stage III: 27 cases (59%); stage IV, 18 cases (39%). The aim of this study
      was to resolve the perforation and to treat the neoplasm in a single operation.
      METHODS: The various types of perforation included: 35/46 = 76% perforations in
      situ; 6/47 = 13% recent perforations upstream; and 5/46 = 11% at a distance from
      the neoplasia. The following types of peritonitis were observed: purulent
      localised 10/46 = 22%, purulent generalised 12/46 = 26%, fecaloid 18/46 = 39%,
      fecal 6/46 = 13%. In 24 cases/46 = 52% the perforation had occurred in an
      occluded colon. The preoperative finding of pneumoperitoneum in 12/46 = 26%
      indicated generalised fecaloid-fecal peritonitis. Surgery commenced by suturing
      the perforation followed wherever possible by standard colectomy: on the right in
      all 11 cases = 100%, on the left in 15/35 = 43%; only in the event of prohibitive
      local or in particular general conditions was Hartmann's segmentary colectomy
      used in 10 cases/35 = 29%, or a definitive preternatural anus in 10/35 = 29%. The
      following aspects are essential in this single-stage surgery: the emergency
      nature of the operation; massive dose antibiotic treatment limited to the pre-
      and perioperative stages and above all peritoneal cleansing using accurate,
      methodical, repeated and abundant lavage with 8-10-20 or more litres of
      polysaline isotonic solution at 37 degrees C, but only used 500 ml at a time.
      This lavage is essential to reduce bacterial load contributes to the rapid
      hydroelectrolytic re-equilibrium in severe conditions of peritonitis. When
      necessary, colonic preparation was carried out using direct colostomic
      perioperative lavage. The peritonisation of the retroperitoneum with the omentum
      is important, as is the protection of the anastomosis using omental wrapping and
      active lavage and aspiration of the colorectal anastomosis, even using the 3-way
      tube, in a transanal trans- or subanastomotic position. Total parenteral feeding
      is useful and almost indispensable for 6-8 days. RESULTS: Postoperative morbidity
      was negligible and mortality occurred in 14/46 cases = 30%, of whom 13/32 = 41%
      were over 60 and 1/14 = 7% under 60; if the cases are divided into two periods,
      pre-Gullino tube (1974-84) mortality was 8/22 = 36% and with Gullino's tube (1985
      95) it was 6/24 = 25%; postoperative stay was 18 days in the first period and
      only 11 days in the second. The 11 cases at stage IV who survived the operation
      all died following the spread of neoplasms within 2-30 months, mean 10 months;
      the over-5-year survival rate for the only case at stage II and the 19 at stage
      III was 38% (Kaplan-Meier). CONCLUSIONS: By using this courageous single-stage
      surgery and operating patients at such a severe stage, both the immediate and
      long-term results appear to be more than satisfactory. It is important to
      underline, however, that not all neoplastic perforations appeared to be caused by
      endoluminal hypertension-ischemia; in those cases with non-occluded colon, about
      half might have been the consequence of biological problems of immune
      hyperreactivity of a rejection reaction type (Arthus, Snarelli-Shwartzman
      phenomenon and similar).

PMID- 10352523
TI  - [Conservative surgical treatment in differentiated thyroid carcinoma].
AB  - BACKGROUND: Purpose of the present study was to compare survival of patients
      affected by differentiated thyroid carcinoma after total and partial
      thyroidectomy. METHODS: The study has been carried in a retrospective way; mean
      follow-up has been 160 months. Surgical setting has been the Institute of
      Emergency Surgery at the University of Catania, where about 80 thyroid surgical
      procedures are performed every year. Patients have been divided into two groups:
      the first included 65 patients who underwent total thyroidectomy, while the
      second group included 67 patients who underwent partial thyroidectomy. Ten
      patients affected by a T3-T4, N0-N1 tumor were ruled out of the study to allow
      better uniformity of data. Besides early postoperative complications (recurrent
      nerve lesion, hypoparathyroidism), patients have been followed by periodic
      clinical and instrumental examinations. RESULTS: Follow-up has shown similar
      survival between patients treated by total thyroidectomy and those who underwent
      partial thyroidectomy (respectively 92.3% and 92.5%). Postoperative complications
      were instead significantly less in group 2. CONCLUSIONS: For patients affected by
      differentiated thyroid carcinoma at early stages it is suggested to perform a
      partial thyroidectomy since, compared to total thyroidectomy, a similar survival
      rate and a lower incidence of postoperative complications are obtained. According
      to personal opinion, total thyroidectomy should be performed in cases of thyroid
      carcinoma with vascular involvement and metastases.

PMID- 10352524
TI  - [Breast reconstruction: a possible balance between oncological therapy,
      reconstructive methods and the patients].
AB  - BACKGROUND: Based on their experience of oncological surgery and wishing to
      respond to the patients' reconstructive requirements, the authors analyse the
      damage caused by medical therapy (chemo-hormone therapy and radiotherapy) in
      terms of reconstructive techniques; they aim to establish whether the tissues
      used in reconstruction interfere with the diagnosis and treatment of
      recidivations and to identify the best reconstructive strategy in relation to
      "timing"; lastly, they examine the possibility of realising a cosmetically
      improved breast. METHODS: A 2-year retrospective study was made during which 3
      patients underwent immediate reconstruction using expanders (including 2 with
      bilateral reconstruction) and 1 patient underwent postradiotherapy differed
      reconstruction; all patients were followed up for a maximum of 4 years. The
      following surgical methods were used to improve cosmetic results: 1) conservation
      of the pectoralis minor which was turned sideways to create the muscular pocket;
      2) costal and sternal disinsertion of the pectoralis major; 3) the implant was
      covered with the muscular pocket in the upper quadrants and with subcutaneous
      tissue in the lower quadrants; 4) realisation of a mammary groove; 5) immediate
      mastopexy of the surviving breast. All patients underwent intraoperative and
      postoperative polychemotherapy. RESULTS: At present (January 1997) none of the
      patients treated shows signs of locoregional recidivation or general metastases.
      Complications were observed in the form of subacute infection of the prosthetic
      flap exposing the expander and infection of the suture material used to reshape
      the breast in contralateral mastopexy in the patient undergoing reconstruction
      after radiotherapy. When evaluating the cosmetic results, scar diastasis varied
      in all patients. Smoothing of the scars, slight implant distortion observed
      echographically, grade 2 contraction of the periprosthetic capsule were assessed
      using Baker's scale and all patients were found to be grade I or II. In the light
      of these results and their personal experience, the authors then analyse, with
      reference to the literature, the effect of radiotherapy on reconstruction using
      tissular expansion, the effect of chemotherapy on reconstruction using expansion
      or autologous implants; the combined effect of radio and chemotherapy on
      reconstruction using autologous implants or tissues. Timing and the difficulty of
      diagnosis locoregional recidivation are also discussed. CONCLUSIONS: The authors
      fully agree with the need to carry out immediate reconstruction, when indicated
      (above all in bilateral reconstruction) using implants since it is simpler.
      Chemotherapy does not interfere with the expansion process whereas, if it is
      deemed necessary to use radiotherapy, it is certainly better to undertake
      reconstruction using autologous tissues. For special reconstruction methods
      (replacement of the expander, differed reconstruction with expander), greater use
      should be made of the day hospital, or better still office surgery.

PMID- 10352527
TI  - [Acute pseudoabdomen and mitral stenosis. A clinical report of a very unique
      case].
AB  - Acute alithiasic cholecystitis is uncommon and often secondary to other
      pathologies. The authors report the case of a patient with mitral valvulopathy
      which had not been diagnosed until the onset of clinical symptoms of acute
      cholecystitis, confirmed by abdominal ultrasonography. Emergency cholecystectomy
      was chosen as the most suitable form of surgery, although the authors were
      "unaware" of the real circumstances: in hindsight it may be said that emergency
      surgery eliminated the risk of infective complications which might have led to a
      general deterioration of the patient's conditions already jeopardized by cardiac
      disorders. Hepatic biopsy performed during the course of the operation enabled
      the hepatic situation to be clarified with stenosis caused by impeded venous
      return to the heart.

PMID- 10352526
TI  - [Vascular complications during laparoscopy. An analysis of a personal case].
AB  - Vascular complications of laparoscopy most often occur during Veress needle or
      primary trocar placement. Veress needle punctures are insignificant and require
      no further treatment, whereas trocar induced vascular injuries can be
      catastrophic. The frequency of vascular or viscus injuries is difficult to
      calculate since several complications are not published. A vascular complication
      occurred in a young girl with neurologic problems and a kyphoscoliosis operated
      on in laparoscopy for a gastroesophageal reflux is discussed. After the
      establishment of pneumoperitoneum, an important hemoperitoneum was rapidly
      evident at insertion of the laparoscope. An open laparotomy was performed showing
      right common iliac vessel injuries and several intestinal perforations. After a
      complex vascular reconstruction and a multiple intestinal suture, the Nissen
      fundoplication with pyloroplasty was performed traditionally and the patient
      leave the hospital free of symptoms after 20 days. In laparoscopy, as in all
      areas of surgery, experience knowledge and meticulous attention to details are
      the most important factors in order to avoid complications. The authors believe
      that the open approach with Hasson cannula is the most important factor in
      avoiding complications.

PMID- 10352528
TI  - Superficial femoral artery as a substitute for common carotid artery affected by
      malignant cervical tumors.
AB  - Tumoral disease of the arteries is uncommon. It is possible that, in tumoral
      reoperations affecting cervical structures, periarterial fibrosis due to
      radiotherapy and previous surgery and metastatic adherences to the arterial wall
      makes radical surgery difficult. We present a case where the surgical treatment
      of a regional relapse from laryngeal neoplasm needed the removal of the common
      carotid artery and its reconstruction with autologous patent superficial femoral
      artery. Surgical technique included a PTFE graft interposition in the leg.

PMID- 10352525
TI  - [The surgical therapy of renal carcinomas. The prognostic factors and long-term
      results].
AB  - BACKGROUND: Image diagnosis of kidney neoplasms allows good preoperative staging
      using the TNM system, but surgical management cannot be based on these data
      because a tumour apparently confined to the kidney may have produced metastasis
      in extraregional lymph nodes. METHODS: Thirty-three patients with renal carcinoma
      were observed over a seven-year period. Preoperative staging using the TNM system
      was performed and then compared with postoperative staging. Radical nephrectomy
      and regional lymphadenectomy were performed in all patients. Extensive
      lymphadenectomy was undertaken in 10 cases presenting neoplasms larger than 10
      cm. At the preoperative assessment, 20 patients were stage T2, 13 stage T3, for
      factor N six were N1, two M1; postoperative staging confirmed T2 in 15 cases,
      whereas five T2 became T3. After postoperative staging, the N1 patients increased
      from 6 to 13. Fifteen patients were at Robson's stage II, four at stage IIA,
      twelve IIIB and two stage IV. RESULTS: The 5-year survival rate was 63.2%.
      CONCLUSIONS: The authors conclude that from an analysis of the correlation
      between tumour size and lymph node metastasis it can be seen that low T values do
      not represent grounds for conservative treatment.

PMID- 10352529
TI  - [Carcinoid tumor of the appendix. A not especially rare entity].
AB  - Carcinoid tumors arise from neuroendocrine system and one of their preferred
      sites is the appendix. Most of appendiceal carcinoids almost always are
      clinically silent and are incidentally found at histological examination. For
      this reason, histological examination of the appendix is recommended in every
      case of the appendicectomy. Prognostic factors are: tumor stage, histologic
      pattern and differentiation. The authors present 6 cases of appendiceal carcinoid
      tumor, clinically silent and found at histologic examination (3 cases of
      appendicectomy for acute appendicitis, 3 cases of appendicectomy associated with
      abdominal surgical interventions for other pathology) and compare their
      experience with the most recent literature on this subject. The conclusion is
      drawn that the size of this tumor is the main factor that surgeons must consider
      for the choice of surgical treatment. Incidental, clinical silent, small (less
      than 2 cm in size) appendiceal carcinoid tumors can be treated by appendicectomy,
      and they do not need follow-up. Greater (more than 2 cm in size) appendiceal
      carcinoid tumors, in young patients must be treated with a right hemicolectomy
      and they need follow-up (periodically radiological, ultrasonographic and
      endoscopic examinations, tumor markers) because there is the possibility of
      recurrence or metastases.

PMID- 10352530
TI  - [Merkel-cell carcinoma. A report of 3 clinical cases].
AB  - The finding of Merkel cell carcinoma is a rare but important event owing to the
      highly aggressive nature of this neoplasm. The authors report three cases of
      Merkel cell carcinoma with different onsets which were representative of the
      possible range of clinical symptoms and the prognosis of this pathology. In two
      cases diagnosis was made by chance, but in the third case a preoperative biopsy
      was initially performed with subsequent radicalization. The authors examine the
      diagnostic and therapeutic protocols proposed by other authors and compare them
      to their personal experience to ensure early diagnosis and radical therapy.
      Surgery is the obligatory initial choice, followed by radiotherapy and an
      accurate follow-up. The authors evaluate the use of Octeotride therapy for
      tumours of neuroendocrine origin and hence its application to Merkel cell
      carcinoma.

PMID- 10352531
TI  - [The hemorrhagic complication of peptic ulcer].
AB  - The hemorrhagic complication of peptic ulcer is a pathology which is still
      responsible for a high mortality. After reviewing the etiopathogenesis and
      physiopathology of hemorrhagic complications in the light of the recent
      discoveries regarding H. pylori, the authors report their experience and confirm
      the important role of surgery in the treatment of this pathology. Resolution is
      improved by the use of surgical staplers which are regarded as particularly
      valuable in emergency surgery where the need to cut operating times has undoubted
      advantages in terms of patient survival.

PMID- 10352532
TI  - [The endorectal repair of rectovaginal fistulae].
AB  - BACKGROUND: Twenty-one patients who had simple rectovaginal fistulas were treated
      at the Surgical Department of "Tor Vergata" University from 1992 to 1996 all of
      whom were at the first approach. METHODS: The fistulas were treated with complete
      excision of the external tract and primary closure of the internal opening with
      advancement of a rectal mucosal flap, distal to the origin fistulas opening. The
      vaginal side is left open for drainage. RESULTS: Eighteen of the twenty-one
      patients had good results; three patients required reoperation for recurrences;
      all of them had satisfactory results. CONCLUSIONS: The advancement flap technique
      was very useful for simple rectovaginal fistulas with any sphincter damage, and
      it is very well tolerated by patients.

PMID- 10352533
TI  - [Our experience with the use of Absolok polydioxanone resorbable clips in
      laparoscopic surgery].
AB  - BACKGROUND: The study aims to evaluate the efficacy of resorbable clips in
      polydioxanone in laparoscopic surgery. METHODS: The authors report their personal
      experience regarding the use of Absolok (ABL) resorbable clips in laparoscopic
      surgery. Out of a total of 745 laparoscopic operations performed from September
      1992 to February 1997, 438 included the use of resorbable clips in place of metal
      clips, both for cystic duct section during cholecystectomy and vascular
      structures, or to lock continuous sutures. ABL clips were also used for major
      vessels (e.g. mesenteric artery) during laparoscopic colic resections. RESULTS:
      In all cases when they were used, ABL never gave rise to complications, such as
      biliary outflow or hemorrhage caused by the dislocation of the clips themselves.
      CONCLUSIONS: The authors conclude by affirming the value and safety of this type
      of clip.

PMID- 10352534
TI  - [Hormone substitution therapy. Side-effects and compliance of various therapeutic
      regimens].
AB  - BACKGROUND: The aim of this study is to evaluate the tolerability and long-term
      compliance of four Estrogen Progestin treatments (HRT) for menopause. METHODS:
      One hundred and ten symptomatic menopausal women were divided into four groups
      according to therapeutic regimens: A) Estradiol (E2) transdermal treatment 50
      micrograms (TTS 50) continuously administered (cont.) plus Medroxyprogesterone
      Acetate (MPA) 10 mg/die for twelve days a month: 35 women. B) Conjugated Equine
      Estrogens (CEE) 0.625 mg/die cont. plus MPA for twelve days a month: 25 women. C)
      Estradiol transdermal 50 micrograms (cont.) plus MPA 2.5 mg/die cont.: 26 women.
      D) CEE 0.625 mg/die cont. plus MPA 2.5 mg/die cont.: 24 women. RESULTS:
      Menopausal symptoms were significantly reduced with all treatments. During the
      first year group C and D patients showed irregular bleeding (group C: 46%, group
      D: 61%). After 24 months the bleeding frequency was reduced (group C: 11%, group
      D: 13%). Mastodynia was the more frequent side-effect in particular among women
      who were utilizing cont.comb. regimens. The total percentage of drop out (D.O.)
      after 2 years was more than 30% (Group A: 31%, Group B: 33%, Group C: 39%, Group
      D: 35%). The most frequent reasons for abandoning HRT (79% of all DO) were not
      linked to therapy side-effects. 19% of DO switched to other hormonal regimens.

PMID- 10352535
TI  - [Sexuality in menopause. Importance of adequate replacement therapy].
AB  - BACKGROUND AND AIMS: The harmful repercussions of estrogen deficiency in
      menopause on the female organism are also responsible for reduced libido and
      uncomfortable trophic disorders of the genitourinary tract leading to reduced
      vaginal lubrication and severe alterations affecting sexual function, as well as
      for the more commonplace vasomotor phenomena and psychoemotive changes. METHODS:
      The authors treated 102 menopausal patients who presented reduced libido and
      orgasmic difficulties, as well as other menopausal problems, with 17-beta
      estradiol+noretisterone acetate using a transdermal route. The main advantage
      offered by the transdermal route is that conjugated estrogens "bypass" the liver
      and reach the target organs in an unmodified manner. This treatment is well
      tolerated by almost all patients, even those suffering from slight gastroenteric
      and hepatic problems. RESULTS AND CONCLUSIONS: This study showed the good
      tolerability and almost complete innocuousness of the drug used. None of the
      patients receiving replacement therapy reported any collateral effects worthy of
      note or the onset of malignant lesions of the breast or pelvic organs. The
      results obtained show that the use of 17-beta estradiol+noretisterone acetate can
      effectively modify menopausal symptoms, improving both quality of life and sexual
      function.

PMID- 10352536
TI  - [Vaginal delivery following previous cesarean section].
AB  - BACKGROUND AND AIM: The increased use of cesarean section (CS) over the past 30
      years has raised a problem which has been much debated in obstetric practice: is
      it always necessary to repeat CS in women who have previously undergone cesarean
      section? The aim of this study was to establish whether women previously
      undergoing CS can start trial labour? METHODS: The authors examined 195 pregnant
      women who had previously undergone 1 or 2 CS. Medical history, clinical
      examination and maternal and fetal monitoring techniques were used to select the
      women who could start trial labour.

PMID- 10352537
TI  - [Research on physician-patient relations in a Center for Artificial
      Insemination].
AB  - AIMS: To investigate, within the domain of the doctor-patient relationship in an
      Artificial Insemination Centre, whether not only a precise aetiological diagnosis
      about the physical impairment, but also an accurate analysis of the request of
      help by the infertile couple is actually performed. If the hidden meanings
      underlying many patients' requests for help are not investigated, there could be
      the risk of psychopathological developments. METHODS: Eight gynaecologists of the
      Artificial Insemination Centre staff and twenty-nine infertile couples who went
      to the Centre for a consultation about infertility were interviewed by means of
      two semistructured interviews, constructed after preliminary observations of the
      doctor-patient relationship. A qualitative content analysis was performed on the
      data so obtained. RESULTS: The results are that, although doctors felt that the
      problems were more complicated than they seemed to be, they had been trained to
      deal only with physical impairment, and not with so many underlying problems,
      like family and social ties, and even self-confidence as individuals and as a
      consistent couple. CONCLUSIONS: The Centre generally provides two kinds of
      services: a precise aetiological diagnosis about the physical impairment, and, if
      it is possible, its correction. We assume it would, be better if a third service
      were available for the couples: a Psychological Consultation Service, especially
      in case of risk of psycho-pathological developments.

PMID- 10352538
TI  - [Breast screening in women considering pregnancy].
AB  - Breast cancer is the most frequent malignant tumor in pregnancy, with a prognosis
      that is made worse due to the delay at diagnosis; moreover, because of the
      current tendencies to delay the age of a pregnancy, its incidence is destined to
      increase. Our purpose was to optimize breast screening for women attempting to
      become pregnant in order to avoid the delay of breast cancer diagnosis with a
      preconceptional individual screening program. The greatest problems of pregnancy
      associated breast cancer, the various categories of risk, and the methods of
      screening for breast cancer have been analysed. A breast screening program for
      women attempting to become pregnant has been worked out; this program determines
      a clinical examination and mammography on the basis of predetermined category of
      risk, aside from age. The diagnostic difficulties that pregnancy associated
      breast cancer presents, must motivate the obstetrician to include breast
      screening among preconceptional exams and to conclude the diagnostic and if
      necessary therapeutic iter before the beginning of pregnancy; it is useful to
      this end, to consider the decision of the screening on the basis of the age of
      the patient and of the categories of risk.

PMID- 10352539
TI  - [Climacteric and quality of life].
AB  - BACKGROUND: Menopause is for women a critical period of their life, in which
      organic troubles and psychological problems cherish themselves. With particular
      reference to hot flushes and impaired sleep (the frequently found troubles), the
      benefits of physical exercise in women of this age have been evaluated. METHODS:
      A study based on a questionnaire has been carried out on 79 women of age between
      51 and 58 (who practised regular physical activity, selected at sporting
      centers), and 481 women of age between 52 and 58, selected between patients who
      came to the University Hospital for reasons not ascribed to menopause. All the
      women selected in the study underwent to natural menopause, and didn't use
      hormonal therapy. The questionnaire evaluated symptomatology and its level of
      severity. RESULTS: In the first group 57% of the women didn't report symptoms,
      30% light symptoms, 12% medium, 1% severe. In the second group 52% didn't report
      symptoms, 15% light symptoms, 22% medium, 11% severe. CONCLUSIONS: Besides
      verifying a bigger well-being among women who practice physical activity, the
      interesting result is that 52% of the second group didn't refer symptomatology.
      The advantages of a balanced diet, with particular attention to food with
      phytoestrogens, is discussed and the psychosocial problems of woman in menopause,
      covering a fundamental role to explain a great part of the symptomatology, are
      underlined. Finally, the guide lines for a right preparation to menopause are
      presented.

PMID- 10352540
TI  - [Hormone replacement therapy and the wellbeing of menopausal women].
AB  - BACKGROUND AND AIMS: The authors performed a retrospective analysis of 682
      patients attending the Menopause Centre from 1994 to today. These patients were
      referred for a wide variety of symptoms occurring in premenopause and menopause.
      METHODS: All patients initially underwent general screening which was followed by
      appropriate therapy on the basis of objective examination, blood chemical and
      instrumental tests, and the subjective clinical situation. RESULTS AND
      CONCLUSIONS: It was found that the most frequently used treatment was sequential
      or combined oestroprogestin replacement treatment (63%), with tibolone in 9% of
      cases and veralipride in 5%. The best results from the point of view of the
      improved wellbeing of the woman were obtained using HRT and tibolone.

PMID- 10352541
TI  - [Apropos of a case of Dandy-Walker syndrome associated with chromosome
      abnormalities].
AB  - A case of Dandy-Walker syndrome associated with chromosome abnormalities (46,XX,
      21, +der(13)t(13;21)(q22;q11), diagnosed during pregnancy is reported. This is a
      pathology characterized by malformations of the central nervous system, mainly of
      the cerebellum. Due to several aspects and different prognosis between classic
      Dandy-Walker and its variants, many clinical and therapeutic problems may raise.

PMID- 10352542
TI  - [Mucinous adenocarcinoma of the ovary in pregnancy].
AB  - A clinical case of ovarian adenocarcinoma during pregnancy is reported. The
      diagnostic and therapeutic problems which may be encountered, are illustrated.
      The data found in the literature concerning ovarian carcinoma in pregnancy are
      not so many. Most authors agree for the prosecution of pregnancy, with a careful
      observation of the patient. Also in this case, with a careful observation, an
      outcome without risk for the mother and the fetus has been obtained. After one
      month from birth, the surgical therapy has been completed. The tumoral markers CA
      125 and CA 72-4 after birth were normal. After one year from intervention, the
      patient is good health.

PMID- 10352544
TI  - [Innate nonspecific antiviral immunity].
AB  - Participation of macrophages, NK cells, gamma delta T and alpha beta T
      lymphocytes to creation of innate antiviral defence is described in the review.
      Antiviral activity of interferons, members of tumour necrosis factor family,
      interleukins, chemokines and their possible role in formation of nonspecific
      immunity is reviewed. The hypothesis on the nature and function of receptors
      important for innate immunity and its interdependence with acquired immunity is
      discussed.

PMID- 10352543
TI  - [Hydatidiform mole. A case of hydrothorax, expression of a non-neoplastic
      complication].
AB  - Marked stimulation of the chorionic gonadotropins underlies the frequent finding
      in the mole of larger ovaries with multiple luteal cysts, identifiable using
      ultrasound imaging, resembling ovarian hyperstimulation syndrome. The authors
      report a case of hyadatid pregnancy which presented serious non-neoplastic
      complications. Laboratory tests showed high values of beta-hCG and GOT/GPT,
      electrolytic alterations, hypoproteinemia, hypoalbuminemia, associated with
      conditions of severe dyspnea and tachycardia following hydrothorax diagnosed by X
      ray. USG showed hypertrophic placenta containing anechoid lacunar areas and
      swollen ovaries with multiple luteal cysts. Positive results were achieved by
      using intensive therapy leading to the restitutio ad integrum of damaged
      functions. Endocrine hyperactivity of the molar trophoblast, with high levels of
      beta-hCG was responsible for ovarian hyperstimulation. Important findings for the
      early diagnosis of hyadatid pregnancy are: beta-hCG assay and ultrasound scan;
      moreover, an adequate follow-up lasting about 6 months is necessary to evaluate
      the serial trend of beta-hCG and the disappearance of ovarian luteal cysts.

PMID- 10352545
TI  - [Interferon gamma as a regulator of immune cell function].
AB  - The article reviews the literature with regard to identification of lymphocyte
      subsets that respond to specific inducers and produce IFN-gamma, the structure of
      IFN-gamma gene, the IFN signal transduction pathway that initiates biochemical
      changes at cellular level and influences the function of immunocompetent cells:
      mononuclear phagocytes, T and B lymphocytes. The interaction of IFN-gamma with
      other cytokines in regulation of immune response is also discussed.

PMID- 10352546
TI  - [Oxidation mechanisms and anti-oxidation in HIV infected patients--effect on
      disease progression].
AB  - Recently it has been proposed that reactive oxygen species (ROS) are involved in
      pathogenesis of many human diseases. An elevated level of these molecules causes
      oxidative stress and is toxic for living cells. Oxidative stress is the reason of
      many damages of cellular structures, as result of free radical reactions with
      proteins, lipids, nucleic acids etc. In most of human diseases overproduction of
      ROS is characteristic for early stage of disease. Some of infectious factors,
      e.g. viruses can cause oxidative stress by disturbance of cellular antioxidants
      system or induction of oxidative reactions. There is some evidence of presence of
      oxidative stress in early stage of HIV infection (glutathione and other
      antioxidants loss in serum and decreased activity of antioxidant enzymes). All
      these metabolic disturbances may be involved in AIDS pathogenesis, for example
      through incorrect induction of lymphocyte apoptosis, tumours related to AIDS and
      high rate of HIV mutation. This suggests a possible, important role of oxidative
      stress in AIDS pathogenesis and that administration of antioxidant drugs, by HIV
      infected patients, may offer protection against mechanisms responsible for
      lymphocyte apoptosis and AIDS related carcinogenesis.

PMID- 10352547
TI  - [Adhesive glycoproteins of the extracellular matrix].
AB  - Glycoproteins of the extracellular matrix and basement membrane play crucial role
      in cell recognition, adhesion, migration and proliferation. Morphogenesis and
      tissue and organ development in embryo, as well as healing processes in adults
      are dependent on the interactions of extracellular proteins with cell surface
      receptors. In this paper the structure and function of major adhesive proteins:
      fibronectin, tenascin, laminin and nidogen are reviewed. Recent data on the role
      of small leucine-rich and modular proteoglycans, such as decorin, biglycan,
      fibromodulin, versican, perlecan, neurocan, agrecan, agrin and other are given.
      Modifications of the expression and localization of extracellular glycoproteins
      in pathology are also presented.

PMID- 10352548
TI  - [Local application of G-CSF, GM-CSF and EGF in treatment of wounds].
AB  - G-CSF, GM-CSF and EGF play an important role in wound healing as components of
      the cytokine network which regulates cooperation of cells in the repair
      processes. The first two cytokines have been registered as hematopoietic drugs
      under the names Neupogen (Roche) and Leucomax (Sandoz). Both G-CSF and GM-CSF
      stimulate phagocytosis in maturated leucocytes and enhance proliferation of
      endothelial cells. G-CSF, GM-CSF and EGF which is known as mitogenic agent were
      applied as topical drugs for wound care; the application resulted in acceleration
      of wound healing. Preliminary suggestions as to the topical dosage of the
      cytokines in the treatment of wounds are put forward.

PMID- 10352549
TI  - [Human gastric alcohol dehydrogenase].
AB  - A new form of alcohol dehydrogenase (class IV), designated mu-ADH or sigma-ADH,
      was identified in human stomach mucosa. We report here the enzymatic properties
      and molecular characterization of this human class IV and her contribution in
      ethanol and other biological substances metabolism.

PMID- 10352550
TI  - [Adrenomedullin].
AB  - Adrenomedullin (ADM) is a recently discovered peptide with potent vasorelaxing
      and natriuretic properties originally isolated from human pheochromocytoma.
      Adrenomedullin has been reported to be present in normal adrenal medulla, heart,
      lung and kidney as well as in plasma and urine. ADM shares some structural
      homology with calcitonin gene related peptide (CGRP). ADM acts on target cells
      through its unique receptors and CGRP1 receptors. In both cases cyclic AMP seems
      to be the main second messenger. ADM may function as a circulating hormone and as
      an autocrine/paracrine mediator involved in the regulation of cardiovascular
      system and renal function. Plasma concentration of ADM is elevated in patients
      with congestive heart failure, arterial hypertension, pulmonary hypertension,
      renal failure and sepsis suggesting its role in pathophysiology of these
      disorders. Recently another product od adrenomedullin gene, proadrenomedullin N
      terminal 20-peptide (PAMP) has been described. This peptide has also vasodilating
      activity resulting from its inhibitory action on norepinephrine release from
      sympathetic endings and adrenal medulla.

PMID- 10352551
TI  - Olfactory P3 in young and older adults.
AB  - Olfactory event-related potentials (OERPs) were recorded monopolarly at the Fz,
      Cz, and Pz electrode sites in 16 young adults and 16 older adults to assess aging
      effects on the olfactory P3. Amyl acetate was used to elicit the OERPs, with an
      intertrial interval of 45 s. Young adults produced significantly larger P3
      amplitudes and shorter P3 peak latencies than older adults. The olfactory P3
      response appears to be sensitive to age-related changes in the olfactory system
      and may reflect cognitive slowing in the central nervous system.

PMID- 10352552
TI  - The usefulness of partial information: effects of go probability in the
      choice/Nogo task.
AB  - In the present study, we examined whether the use of partial information for
      response preparation depends on the utility of that partial information for
      meeting task demands. Using a choice/Nogo task, the utility of the partial
      information was varied by manipulating the proportion of Go relative to Nogo
      signals, and preliminary response preparation was indexed by the degree of
      lateralized readiness potential (LRP) activity on Nogo trials. The Nogo LRP was
      clearly present when Go probability was high (67% Go) and, to a lesser extent,
      when Go and Nogo signals were equiprobable. However, the Nogo LRP disappeared
      when the probability of a Go signal was low (25% Go). This pattern of results
      supports the hypothesis that response preparation will be based on partial
      stimulus information only when the information has significant utility in the
      context of the overall task requirements.

PMID- 10352553
TI  - Cardiac activity during sleep onset.
AB  - Alterations in a number of measures of cardiac activity were examined during
      sleep onset in 6 participants over 3 experimental nights. Each sleep onset was
      divided into four consecutive phases: wakefulness, mixed alpha and theta
      activity, stage 2 NREM sleep with arousals, and stable stage 2 sleep. The
      variables measured were heart rate (HR), respiratory sinus arrhythmia (RSA), pre
      ejection period (PEP) and T-wave amplitude (TWA). Respiration rate (RR) was also
      measured. HR and RR were lower in stable Stage 2 sleep compared with wakefulness,
      whereas PEP, TWA and RSA did not change significantly. During the second and
      third phases of sleep onset, HR decreased at each transition into sleep and
      increased following each spontaneous arousal. This increase resolved rapidly,
      with a return to sleep levels by 12 beats after the arousal. HR changes are
      discussed with reference to RSA, PEP, TWA and the concept of a waking reflex.

PMID- 10352554
TI  - Processing of incongruous mental calculation problems: evidence for an arithmetic
      N400 effect.
AB  - We investigated if incongruent solutions of simple multiplication problems would
      elicit similar event-related brain potentials as inappropriate words in
      sentences. In Experiment I, 12 subjects verified the appropriateness of solutions
      of multiplication problems or of final words in short sentences. Both incongruent
      solutions and incongruent words evoked a phasic negative shift between 300 and
      500 ms having a similar topography. In Experiment II, we tested with another
      sample of 13 subjects if the amplitude of this arithmetic N400 effect was
      affected differently by different stimulus onset asynchronies (SOA = 200 and 500
      ms) and by errors that were either table-related or table-unrelated to the
      preceding operands. Again, incorrect solutions elicited an arithmetic N400 effect
      whose amplitude depended on both the relatedness of the solution and the SOA. The
      ascending part of the N400 effect was always larger for unrelated than for
      related errors independently of the SOA, whereas the maximum of the N400 effect
      was larger for unrelated errors in case of a long SOA only. This pattern of
      effects was similar to that observed with semantic material varying lexical
      associations. These results suggest that arithmetic incongruencies are handled by
      the system in a manner functionally similar to that of semantic incongruencies.

PMID- 10352555
TI  - Facial flushing during provocation in women.
AB  - Facial flushing was studied in 38 young women who scored high or low on trait
      anger. To induce anger in the subjects, their task was to solve a difficult
      puzzle, with or without harassment from a female research assistant. Facial blood
      flow increased in response to provocation, together with increases in
      cardiovascular and electrodermal activity. Flushing was associated with large
      increases in electrodermal activity and small increases in diastolic blood
      pressure. Subjects high in trait anger reported most anger and embarrassment, but
      physiological activity did not differ from subjects with low trait anger. The
      findings suggest that sympathetically mediated vasodilatation in facial blood
      vessels competes with cutaneous vasoconstriction during anger. Unpleasant
      sensations of facial warmth might heighten aversive emotional experiences, but
      dilatation of facial blood vessels could also act as a type of "safety valve" by
      opposing increases in blood pressure. An angry predisposition may influence the
      subjective experience of anger in women, but does not seem to have a major
      influence on physiological reactivity to mild provocation.

PMID- 10352556
TI  - Impedance pneumography: noise as signal in impedance cardiography.
AB  - Thoracic impedance is modulated by events within the respiratory cycle, which
      represents a source of "noise" in impedance cardiography. Respiration itself,
      however, is a physiological rhythm of interest to psychophysiologists. We report
      here methods and validation for deriving impedance pneumographic measures of
      respiration from impedance cardiography signals, based on standard tetrapolar
      band electrodes. We recorded the change in impedance (delta Z), the first
      derivative of the change in impedance (dZ/dt), output from a strain-gauge
      respirometer, and criterion spirometry from eight healthy adults during rest,
      paced breathing, abdominal breathing, thoracic breathing, and a mental arithmetic
      task. Transfer function analyses revealed that a delta Zd signal (derived by
      integration of the dZ/dt signal) provided the best estimate of the criterion
      spirometric measure for all parameters (coherence, phase, and gain), accounting
      for almost 90% of the variance in respiratory waveform morphology. The results
      document the potential utility of impedance pneumography, as derived from
      standard impedance cardiography signals.

PMID- 10352557
TI  - Dissociating beliefs about heart rates and actual heart rates in patients with
      cardiac pacemakers.
AB  - Performance on heartbeat counting tasks is usually interpreted in terms of
      cardiac sensitivity. We tested the hypothesis that heartbeat counting is
      influenced by beliefs about heart rates by dissociating beliefs about heart rates
      and actual heart rates. In a within-subjects design, heart rates of 50 patients
      with cardiac pacemakers were set to a low (50 bpm), medium (75 bpm), or high (110
      bpm) pacing rate unknown to the patients via remote control while they performed
      a heartbeat tracking task. Results showed that patients' heartbeat counting did
      not follow the shifts in their actual heart rates adequately, although their
      overall performance was comparable to that of young and healthy control
      participants. As a result, tracking scores decreased significantly in the high
      pacing rate condition where beliefs about heart rates and actual heart rates were
      most extremely dissociated. The findings suggest that tracking scores reflect
      beliefs about heart rates rather than cardiac sensitivity.

PMID- 10352558
TI  - P300 sequence effects differ between children and adults for auditory stimuli.
AB  - Variation of the P300 component was studied in normal children and adults during
      an auditory oddball paradigm. In children, the target stimuli that were preceded
      by a large number of standard stimuli elicited about twice as large P300 with a
      significantly shorter latency, a more widespread distribution, and an earlier
      positivity in the frontal area than those that were preceded by a small number of
      standard stimuli. The P300 variation was not as marked in adults as in children.
      Based on the context updating theory of the P300, the finding suggests that a
      long intertarget interval (ITI) results in a profound decay of the neural
      representation of the target stimulus in children; consequently, more resources
      are needed to update the neural representation, and the target may even be
      processed as a novel input. The P300 variation may provide information about the
      brain functions related to memory, attention, and orienting in children. This
      variation should be considered when assessing cognitive brain functions with
      event-related potentials in children.

PMID- 10352559
TI  - The effect of response execution on P3 latency, reaction time, and movement time.
AB  - This study examined the effect of response selection and execution on P3 latency
      during the performance of simple reaction time (RT) and stimulus-response
      compatibility tasks. Response time on these tasks was defined in terms of RT and
      movement time (MT). Event-related brain potentials were recorded from 67 female
      participants concurrently with the performance measures. On the simple RT task,
      the distance of the response button from the home button was varied (7, 15, and
      23 cm). When stimulus evaluation demands were minimal, response execution
      affected P3 latency, with increased response button distance resulting in
      increased P3 latency. However, these movement effects were modest, and in most
      protocols, would not be a confounding factor. The stimulus-response compatibility
      task examined the interaction of stimulus evaluation demands and response
      requirements. RT, MT, and P3 latency were affected by stimulus congruency,
      whereas RT and P3 amplitude were affected by response compatibility.

PMID- 10352560
TI  - The lateralized readiness potential: relationship between human data and response
      activation in a connectionist model.
AB  - Psychophysiological measures such as the lateralized readiness potential (LRP)
      have been used to study information processing in the Eriksen flankers task. The
      data provided by these measures are consistent with a continuous flow theory,
      which proposes that the output of stimulus evaluation is continuously available
      to the response channels. Cohen et al. (1992) realized this theory in a
      connectionist model and showed that its behavior corresponded to that of human
      subjects in the flankers task. We report here a modification of the model and an
      analysis of the degree to which simulated LRPs (based on the activation functions
      of the response units of the model) resemble the actual LRPs of human subjects in
      the same task. Across a variety of different experimental conditions and
      outcomes, there was a marked correspondence between the simulated and actual
      LRPs. These observations strengthen the propriety of the connectionist model and
      of the continuous flow theory on which it is based.

PMID- 10352561
TI  - Laser pain fails to inhibit innocuous-related activity in the central
      somatosensory pathways.
AB  - Our recent work suggests that innocuous somatosensory activity elicited by a
      brief electrical stimulus is inhibited by pain evoked by the same electrical
      stimulus but not by pain evoked by continuous heat. These results led to the
      hypothesis, tested in the present experiment, namely that pain only inhibits
      innocuous somatosensation when the painful and innocuous stimuli have short
      durations and close temporal and spatial overlap. A painful 200-ms laser pulse
      did not produce a decrease in the perceived magnitude of the innocuous electrical
      stimulus or in the amplitude of a scalp potential that earlier work suggested is
      generated by neurons involved in innocuous somatosensation. Hence, the pain
      related inhibition of innocuous somatosensation observed in these electrical
      studies cannot be attributed solely to the duration or to the temporal and
      spatial overlap of the innocuous and painful stimuli. Laser pain did produce a
      small increase in the subjective magnitude of the innocuous electrical stimulus,
      which the electrophysiological evidence suggests might be due to a change in the
      late- but not the midlatency responses in the central innocuous somatosensory
      pathways.

PMID- 10352562
TI  - Emotion-processing deficit in alexithymia.
AB  - College undergraduates were identified as alexithymic or control, based on their
      scores on the Toronto Alexithymia Scale (TAS; Taylor, Ryan, & Bagby, 1985). All
      subjects were presented standardized emotion-eliciting color slides for 6 s while
      facial muscle, heart rate, and skin conductance activity were recorded. Stimuli
      were presented a second time while subjects were asked to provide emotion self
      reports using a paper-and-pencil version of the Self-Assessment Manikin (SAM;
      Lang, 1980) and to generate a list of words describing their emotional reaction
      to each slide. Consistent with the definition of alexithymia as a syndrome
      characterized, in part, by a deficit in the identification of emotion states,
      high TAS subjects supplied fewer emotion-related words than did controls to
      describe their response to the slides. Alexithymics also indicated less variation
      along the arousal dimension of the SAM, produced fewer specific skin conductance
      responses and showed less heart rate deceleration to the slides, regardless of
      category. No valence-related differences between alexithymic and control subjects
      were noted.

PMID- 10352564
TI  - On separating processes of event categorization, task preparation, and mental
      rotation proper in a handedness recognition task.
AB  - We investigated the nature of event-related potential (ERP) effects in a
      handedness recognition task requiring mental rotation. Thirty subjects were
      tested with rotated and sometimes reflected alphanumeric characters while ERPs
      were recorded from 18 electrodes. On each trial, a cue provided valid information
      about the angular displacement of the following probe. This design allowed a
      distinction between three processing episodes: evaluation of the difficulty of
      the forthcoming task, preparation for the task, and the mental rotation task
      itself. The three episodes were accompanied by distinct ERP effects having
      distinct polarities, a different rank order of amplitudes for different probe
      orientations, and a different topography. These data confirm previous findings
      showing that mental rotation is accompanied by a parietal negativity. However,
      they also suggest that the rotation-related negativity found after tilted stimuli
      in standard mental rotation tasks is most likely overlapping with another,
      simultaneously triggered ERP effect functionally related to an evaluation of task
      difficulty.

PMID- 10352565
TI  - A componential analysis of the ERP elicited by novel events using a dense
      electrode array.
AB  - In this study, we examined the relationship between the novelty P3 and the P300
      components of the brain event-related potential (ERP). Fifteen subjects responded
      manually to the rare stimuli embedded either in a classical auditory oddball
      series or in a series in which "novel" stimuli were inserted. The
      electroencephalogram (EEG) was recorded with a dense array of 129 electrodes. The
      data were analyzed by using spatial Principal Components Analysis (PCA) to
      identify a set of orthogonal scalp distributions, "virtual electrodes" that
      account for the spatial variance. The data were then expressed as ERPs measured
      at each of the virtual electrodes. These ERPs were analyzed using temporal PCA,
      yielding a set of "virtual epochs." Most of the temporal variance of the rare
      events was associated with a virtual electrode with a posterior topography, that
      is, with a classical P300, which was active during the virtual epoch associated
      with the P300. The novel stimuli were found to elicit both a classical P300 and a
      component focused on a virtual electrode with a frontal topography. We propose
      that the term Novelty P3 should be restricted to this frontal component.

PMID- 10352566
TI  - Cottage industry.

PMID- 10352563
TI  - Identification of neural circuits underlying P300 abnormalities in schizophrenia.
AB  - Event-related potentials (ERPs) provide a noninvasive method to evaluate neural
      activation and cognitive processes in schizophrenia. The pathophysiological
      significance of these findings would be greatly enhanced if scalp-recorded ERP
      abnormalities could be related to specific neural circuits and/or regions of the
      brain. Using quantitative approaches in which scalp-recorded ERP components are
      correlated with underlying neuroanatomy in schizophrenia, we focused on
      biophysical and statistical procedures (partial least squares) to relate the
      auditory P300 component to anatomic measures obtained from quantitative magnetic
      resonance imaging. These findings are consistent with other evidence that
      temporal lobe structures contribute to the generation of the scalp-recorded P300
      component and that P300 amplitude asymmetry over temporal recording sites on the
      scalp may reflect anatomic asymmetries in the volume of the superior temporal
      gyrus in schizophrenia.

PMID- 10352567
TI  - Car wash soap?!

PMID- 10352568
TI  - Hepatitis C: the physician's responsibility?

PMID- 10352570
TI  - Personality traits of incoming WVU medical students: phase I gender findings.
AB  - The purposes of this longitudinal research are to (1) identify personality traits
      and trait patterns of incoming WVU medical students; (2) reassess students
      shortly before their graduation; and (3) identify any trait or trait patterns
      which demonstrate significant correlations with choice of residency. Students (n
      = 181; 102 male, 79 female) were administered the Sixteen Personality Factor
      (16PF) Questionnaire during consecutive new student orientations (Fall 1995 and
      1996). Findings of the first phase of this research demonstrate significant
      differences in traits between our medical students and the general population.
      The most compelling findings, however, involve personality trait differences
      between female medical students and their male peers. Beyond offering training
      implications, these early findings suggest the utility of the 16PF in defining
      trait patterns with medical students.

PMID- 10352569
TI  - An estimate of prostate cancer prevalence for a demographically similar workforce
      population.
AB  - To obtain an estimate of prostate cancer prevalence when screening is applied to
      a workforce, we conducted a search of the English world literature from West
      Virginia University. Thirty-one papers which met selection criteria for screening
      were followed by histopathologic diagnosis. Publications using Prostate Specific
      Antigen (PSA) as a screening test were reviewed. The data from these papers were
      combined. Population characteristics were then selected to represent the
      demographics of a working population. Prostate cancer prevalence estimates for
      the demographics of a working population were calculated using a weighted mean
      after relevant studies lacked homogeneity and therefore failed meta-analysis. The
      expected prevalence of prostate cancer in a workplace surveillance population is
      2.03% (95% C.I. from 1.69% to 2.37%). This information is useful to entities
      considering workplace surveillance. Selection bias, geographic location, and
      uncertainty in prediction of a representative workforce population may strongly
      influence estimates.

PMID- 10352571
TI  - Merkel cell carcinoma: an aggressive neoplasm.
AB  - This article presents a rare case of Merkel cell carcinoma (MCC) of the skin.
      This tumor is also known as trabecular carcinoma or cutaneous small cell
      undifferentiated carcinoma (CSCUC). This patient had a palpable non-tender mass
      in her right upper thigh and a large palpable lymph node in the right inguinal
      area. Microscopic examination revealed Merkel cell carcinoma (MCC) in the skin of
      the upper thigh as well as in the inguinal lymph node. Immunoperoxidase stains
      confirmed the diagnosis. Due to its aggressiveness and very unfavorable
      prognosis, prompt diagnosis and adequate treatment are essential. Wide local
      excision with adequate margins followed by radiation therapy is the treatment of
      choice.

PMID- 10352572
TI  - Osteoporosis a critical problem in West Virginia.

PMID- 10352573
TI  - WHO Expert Committee on Specifications for Pharmaceutical Preparations.
AB  - The production, distribution and sale of counterfeit or substandard
      pharmaceutical products on the world market are of increasing concern to drug
      authorities and the international agencies that recommend standards for ensuring
      the quality, efficacy and safety of drugs. This report of an international group
      of experts convened by the World Health Organization presents recommendations
      concerning the quality assurance of pharmaceuticals and specifications for drug
      substances and dosage forms. It looks at activities related to the further
      development of The international pharmacopoeia and also covers good manufacturing
      practices, inspection and monitoring, and drug regulatory legislation. The aim of
      the report, of particular relevance to drug regulatory authorities, is to provide
      guidance to promote harmonization at an international level and encourage
      countries to establish and strengthen their own regulatory systems through
      national legislation and training programmes. A number of annexes attached to the
      report further develop areas where countries might themselves take action, and
      include detailed examples of provisional legislation and guidelines on specific
      aspects of good manufacturing practice, the inspection of drug distribution
      channels, and the development of training programmes for the inspection and
      examination of counterfeit pharmaceuticals.

PMID- 10352574
TI  - Programming for adolescent health and development. Report of a WHO/UNFPA/UNICEF
      Study Group on Programming for Adolescent Health.
AB  - One in every five persons is an adolescent (10-19 years of age). What happens, or
      does not happen, during the second decade of life has implications that last
      throughout a lifetime and affect both individual and public health. What sets
      adolescents apart from children is the increasing autonomy they demonstrate.
      Their own decisions, behaviours and relationships increasingly determine their
      health and development. Moreover, adolescence brings with it expanded capacities-
      for abstract thought and contemplating the future, for empathy and idealism, for
      critical thought including the questioning of self and others, and for
      reproduction. Yet the use of these new capacities is dependent on the environment
      in which adolescents live. So while adolescents display more self-reliance than
      children, they lack the status and resources of adults. Indeed, they are often
      dependent on adults to meet many of their basic needs. The consolidation of
      knowledge and experience acquired through the WHO/UNFPA/UNICEF Study Group on
      Programming for Adolescent Health is presented in this report. Verified by
      research, the report describes the guiding concepts and major interventions that
      are necessary components for country programming for adolescent health and
      development. The report asserts the value of addressing the health and
      development of adolescents simultaneously. It indicates the emerging evidence
      that actions to meet adolescents' needs for development also discourage them from
      adopting high-risk behaviours and protect them from the situations that lead to
      the major health problems. The report is illustrated by examples of programming
      efforts from around the world.

PMID- 10352575
TI  - Treatment of ethylether in air stream by a biotrickling filter packed with slags.
AB  - This paper reports results of studies using a biotrickling filter with blast
      furnace slag packings (sizes = 2-4 cm and specific surface area = 120 m2/m3) for
      treatment of ethylether in air stream. Effects of volumetric loading, superficial
      gas velocity, empty bed gas retention time, recirculation liquid flow rate, and
      biofilm renewal on the ethylether removal efficiency and elimination capacity
      were tested. Results indicate that ethylether removal efficieincies of more than
      95% were obtained with an empty bed retention time (EBRT) of 113 sec and loadings
      of lower than 70 g/m3/hr. At an EBRT of 57 sec, removal efficiencies of more than
      90% could only be obtained with loadings of lower than 35 g/m3/hr. The maximum
      elimination capacities were 71 and 45 g/m3/hr for EBRT = 113 and 57 sec,
      respectively. The maximum ethylether elimination capacities were 71 and 96
      g/m3/hr, respectively, before and after the renewal at EBRT = 113 sec. With an
      EBRT of 113 sec and a loading of lower than 38 g/m3/hr, the removal efficiency
      was nearly independent of the superficial liquid recirculation velocity in the
      range of 3.6 to 9.6 m3/m2/hr. From data regression, simplified masstransfer
      limited, and reaction- and mass-transfer limited models correlating the
      contaminant concentration and the packing height were proposed and verified. The
      former model is applicable for cases of low influent contaminant concentrations
      or loadings, and the latter is applicable for cases of higher ones. Finally, CO2
      conversion efficiencies of approximately 90% for the influent ethylether were
      obtained. The value is comparable to data reported from other related studies.

PMID- 10352576
TI  - VOC elimination in a compost biofilter using a previously acclimated bacterial
      inoculum.
AB  - A comparison of biodegradation efficiencies was done for volatile benzene,
      toluene, ethylbenzene, m-xylene, p-xylene, and o-xylene elimination in a compost
      biofilter. The column was first exposed to a synthetic mixture and then a free
      phase product mixture containing these compounds at increasing pollutant loads.
      The optimal moisture content of the system was determined, and this was used in
      the biodegradation experiments. An acclimated culture was used as an inoculum for
      the biofilter, the matrix of which consisted of composted forestry products,
      composted sewage sludge, lime, and perlite. Inlet and outlet concentrations were
      measured, and pollutant loads, elimination capacities, and removal efficiencies
      were determined for each of the compounds. Optimal moisture content for this
      system was found to be 40%, and the short lag times (one to five days) in
      acclimating to the compounds was ascribed to the presence of the well-acclimated
      inoculum. The compounds in the synthetic mixture had higher removal efficiencies
      (80-99%) even at the higher pollutant loads experienced, with the exception of o
      xylene. Dynamic removal efficiencies and acclimation periods were seen in the
      free phase product mixture, with a removal efficiency range from 70 to 95%. This
      was attributed to the presence of chlorinated aliphatics in the free phase
      product.

PMID- 10352577
TI  - Human breath emissions of VOCs.
AB  - The medical community has long recognized that humans exhale volatile organic
      compounds (VOCs). Several studies have quantified emissions of VOCs from human
      breath, with values ranging widely due to variation between and within
      individuals. The authors have measured human breath concentrations of isoprene
      and pentane. The major VOCs in the breath of healthy individuals are isoprene (12
      580 ppb), acetone (1.2-1,880 ppb), ethanol (13-1,000 ppb), methanol (160-2,000
      ppb) and other alcohols. In this study, we give a brief summary of VOC
      measurements in human breath and discuss their implications for indoor
      concentrations of these compounds, their contributions to regional and global
      emissions budgets, and potential ambient air sampling artifacts. Though human
      breath emissions are a negligible source of VOCs on regional and global scales
      (less than 4% and 0.3%, respectively), simple box model calculations indicate
      that they may become an important (and sometimes major) indoor source of VOCs
      under crowded conditions. Human breath emissions are generally not taken into
      account in indoor air studies, and results from this study suggest that they
      should be.

PMID- 10352578
TI  - Medical education and the RSNA.

PMID- 10352579
TI  - Decision making in radiology.

PMID- 10352580
TI  - Statistical methods for comparative qualitative analysis.

PMID- 10352581
TI  - Obstetric MR imaging.
AB  - The surge in the development of fast magnetic resonance (MR) techniques has
      revolutionized our ability to image the pregnant patient and the fetus. Fast MR
      imaging techniques provide excellent resolution for imaging the maternal and
      fetal anatomies without the need for sedation. This article addresses the use of
      fast MR imaging techniques in the evaluation of the pregnant patient for adnexal
      masses, pelvimetry, hydroureteronephrosis of pregnancy, and placenta accreta. In
      addition, fetal anomalies for which MR imaging has proved useful, such as
      ventriculomegaly, arachnoid cysts, and abdominal masses, are described.

PMID- 10352582
TI  - Ureterolithiasis: value of the tail sign in differentiating phleboliths from
      ureteral calculi at nonenhanced helical CT.
AB  - PURPOSE: To determine the value of the tail sign in differentiating phleboliths
      from ureteral calculi at nonenhanced helical computed tomography (CT). MATERIALS
      AND METHODS: The nonenhanced helical CT scans in 82 patients with a confirmed
      diagnosis of pelvic ureterolithiasis were retrospectively reviewed. Each
      calcification along the ureter was classified as a phlebolith or a ureteral
      calculus on the basis of clinical and imaging findings and was analyzed for the
      presence of a tail sign. RESULTS: Eighty-two patients each had a single ureteral
      calculus. None of these calculi were associated with a positive tail sign. Sixty
      nine phleboliths were present in 35 patients. Forty-five phleboliths (65%) were
      associated with a positive tail sign. Of the remaining 24 phleboliths, 17 (25%)
      were associated with a negative tail sign and seven (10%) were indeterminate. The
      tail sign has a sensitivity of 65% (45 of 69; 95% CI: 53%, 75%) and a specificity
      of 100% (82 of 82; 95% CI: 96%, 100%) in differentiating phleboliths from
      ureteral calculi. CONCLUSION: The tail sign is an important indicator that a
      suspicious calcification represents a phlebolith. Absence of the tail sign
      indicates that the calcification remains indeterminate.

PMID- 10352583
TI  - Renal volume measurements: accuracy and repeatability of US compared with that of
      MR imaging.
AB  - PURPOSE: To determine the accuracy and repeatability of ultrasonography (US) with
      the ellipsoid formula in calculating the renal volume. MATERIALS AND METHODS: The
      renal volumes in 20 volunteers aged 19-51 years were determined by using US with
      the ellipsoid formula and magnetic resonance (MR) imaging with the voxel-count
      method by two independent observers for each modality. The observers performed
      all measurements twice, with an interval between the first and second
      examinations. The voxel-count method was the reference standard. Repeatability
      was evaluated by calculating the SD of the difference (method of Bland and
      Altman). RESULTS: Renal volume was underestimated with US by 45 mL (25%) on
      average. A comparable underestimation was found when the ellipsoid formula was
      applied to MR images. This indicates that the inaccuracy of US renal volume
      measurements (a) occurred because the kidney does not resemble an ellipsoid and
      (b) was not primarily related to the imaging modality. Intra- and interobserver
      variations in US volume measurements were poor; the SD of the difference was 21
      32 mL. For comparison, the SD of the difference in reference-standard
      measurements was 5-10 mL. CONCLUSION: Use of US with the ellipsoid formula is not
      appropriate for accurate and reproducible calculation of renal volume.

PMID- 10352584
TI  - Liver tumors: utility of characterization at dual-frequency US.
AB  - PURPOSE: To evaluate the potential utility of a technique for analysis of
      ultrasonographic (US) images obtained at two center frequencies in a phantom
      model and in a clinical study of liver tumors. MATERIALS AND METHODS: A US
      phantom was built that contained target regions with polystyrene scatterers both
      smaller and larger than scatterers in the background material. High- and low
      frequency US images of target regions were obtained, and changes in the contrast
      to-noise ratio (CNR) of the targets relative to the background were determined.
      In a clinical evaluation, 12 hemangiomas, 13 liver metastases, one adenoma, and
      two hepatomas were evaluated in a similar manner, and the results were correlated
      with the histologic findings in resected lesions. RESULTS: For targets containing
      scatterers smaller than those in the background, there was an increase in CNR of
      higher frequency images. The converse was true for target regions having
      scatterers larger than those in the background. Liver metastases generally showed
      an increase in CNR of higher frequency images, whereas hemangiomas generally
      showed somewhat decreased CNR of higher frequency images, differing significantly
      from metastases (P < .01-.001). CONCLUSION: Changes in CNRs of relatively high-
      and low-frequency US images may give useful information on the frequency
      dependence of backscattering, which is descriptive of the histologic findings in
      lesions and which is not evident with conventional US images.

PMID- 10352585
TI  - Deep venous thrombosis: complete lower extremity venous US evaluation in patients
      without known risk factors--outcome study.
AB  - PURPOSE: To determine the diagnostic value of venous ultrasonography (US) that
      includes examination of calf veins in symptomatic patients suspected of having
      deep venous thrombosis (DVT) of the lower extremities. MATERIALS AND METHODS: A
      retrospective cohort study of the prevalence of DVT included 977 consecutive
      patients with possible DVT but without known risk factors for DVT. Color flow and
      compression US were performed. The outcome was the frequency of overlooked,
      clinically important DVT after negative initial results from bilateral venous US
      of above- and below-the-knee veins. Patient records (904 patients), mailed
      questionnaires (61 patients), and telephone contacts (12 patients) were used to
      establish a diagnosis of clinically relevant DVT. RESULTS: The prevalence of DVT
      was 15% (142 of 977), with DVT in 15% (21 of 142) restricted to the below-the
      knee veins. Follow-up (median, 34 months) in 835 patients with negative US
      findings showed one occurrence of venous thrombosis (superficial
      thrombophlebitis) during the first 3 months of follow-up. Three other cases of
      venous thrombosis occurred at 17, 18, and 48 months of follow-up but were
      believed not to be linked to the initial complaint. The incidence of overlooked
      DVT was 0% (95% CI, 0.0%, 0.4%). CONCLUSION: In patients without risk factors for
      DVT, a negative venous US study can help exclude the presence of clinically
      important DVT if the examination includes careful evaluation of the calf veins.

PMID- 10352586
TI  - Radio-frequency ablation of hepatic metastases: postprocedural assessment with a
      US microbubble contrast agent--early experience.
AB  - PURPOSE: To evaluate contrast agent-enhanced ultrasonography (US) in the
      detection of untreated tumor after radio-frequency (RF) ablation of hepatic
      metastases. MATERIALS AND METHODS: Twenty patients with solitary colorectal liver
      metastases underwent percutaneous RF tumor ablation. Pre- and postablation
      imaging was performed with nonenhanced and enhanced color and power Doppler US
      and contrast-enhanced helical computed tomography (CT). Initial follow-up CT and
      US were performed 24 hours after ablation. The findings at US and CT were
      compared. RESULTS: Nonenhanced US demonstrated intratumoral signal in 15 of 20
      metastases before ablation. This signal increased after contrast agent
      administration. Contrast-enhanced US performed 24 hours after ablation
      demonstrated residual foci of enhancement in three tumors, whereas no US signals
      were seen in any tumor on nonenhanced scans. CT demonstrated small (< 3-mm)
      persistent foci of residual enhancement in these three tumors and in three
      additional lesions that were not seen at US (US sensitivity, 50%; specificity,
      100%; diagnostic agreement with CT, 85%). All six patients with evidence of
      residual tumor underwent repeat RF ablation. CONCLUSION: Contrast-enhanced US may
      depict residual tumor after RF application and thereby enable additional directed
      therapy. The potential reduction in treatment sessions and/or ancillary imaging
      procedures might increase the ease and practicality of percutaneous ablation of
      focal hepatic metastases.

PMID- 10352587
TI  - Percutaneous gastrostomy and gastrojejunostomy with gastropexy: experience in 701
      procedures.
AB  - PURPOSE: To evaluate the safety and efficacy of fluoroscopically directed
      percutaneous gastrostomy and gastrojejunostomy catheter placement with
      gastropexy. MATERIALS AND METHODS: The authors retrospectively reviewed the
      charts from 643 patients referred for fluoroscopically directed percutaneous
      gastrostomy or gastrojejunostomy during a 9 1/2-year period. In 615 patients,
      placement was attempted with use of three T-fastener gastropexy devices followed
      by percutaneous gastric puncture. Placement of a 14-F gastrostomy or
      gastrojejunostomy catheter was then accomplished with the Seldinger technique.
      RESULTS: A catheter could not be placed in 28 patients (4.4%) owing to overlying
      viscera or prior gastric surgery. In the remaining patients, 701 procedures,
      including revisions, were performed, including 643 gastrojejunostomies (92%) and
      58 gastrostomies (8.3%). The success rate for catheter placement was 100%.
      Revision was necessary in 83 instances in 64 patients (13.5%). Forty-six (55%) of
      these were attributed to tube dislodgment, but only two repeat gastric punctures
      were necessary secondary to tract disruption. There were three major
      complications (0.5%) and 29 minor complications (5.3%). No complications were
      attributed directly to gastropexy. Thirty-day follow-up data were available for
      393 patients (64%), and 14-day follow-up data were available for 550 (89%). The
      30-day mortality rate was 5.8% (23 of 393 patients); none of the deaths were
      related to the procedure. CONCLUSION: Fluoroscopically directed percutaneous
      placement of gastrostomy and gastrojejunostomy catheters with routine gastropexy
      is a safe procedure. Catheter revision was necessary in 13% of patients and was
      usually secondary to tube dislodgment, with tract disruption an unusual
      complication.

PMID- 10352588
TI  - Malignant pleural mesothelioma: US-guided histologic core-needle biopsy.
AB  - PURPOSE: To assess the clinical use of ultrasonographically (US) guided core
      needle biopsy, performed with a one-hand automatic sampling technique, in the
      diagnosis of malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: The
      authors reviewed the findings in 70 patients with a tentative diagnosis of MPM
      who underwent US-guided core-needle biopsy at our institution during the past 10
      years. RESULTS: Fifty-two of the 70 patients who underwent automatic high-speed
      core-needle biopsy at our institution had MPM; 18 had other disorders. The
      correct diagnosis was made in 56 patients. Twelve of 14 inadequate biopsy
      specimens were false-negative for MPM. There were no false-positive biopsy
      results. In the detection of MPM, US-guided core-needle biopsy had a sensitivity
      of 77%, specificity of 88%, accuracy of 80%, positive predictive value of 100%,
      and negative predictive value of 57%. There were no serious complications.
      CONCLUSION: US-guided core-needle biopsy is highly effective in the diagnosis of
      MPM. Owing to its simplicity, low cost, and few side effects, it could be the
      biopsy method of choice for detection of this condition.

PMID- 10352589
TI  - Craniofacial arteriovenous malformation: preoperative embolization with direct
      puncture and injection of n-butyl cyanoacrylate.
AB  - PURPOSE: To evaluate the use of n-butyl cyanoacrylate (NBCA) for preoperative
      embolization of craniofacial arteriovenous malformation. MATERIALS AND METHODS:
      Fourteen patients with craniofacial arteriovenous malformation (forehead [n = 9],
      deep facial [n = 3], occipital [n = 1], or lip [n = 1] lesion) were treated with
      injection of NBCA. Forehead lesions were supplied by ophthalmic (n = 6) and/or
      superficial temporal arteries (n = 7); and facial and scalp lesions, by bilateral
      internal maxillary (n = 4), facial (n = 2), and/or occipital arteries (n = 1).
      Lesions were percutaneously punctured with a 20-gauge needle in the area of
      arteriovenous connection. Direct angiography was performed before and after
      compression of venous drainage, and NBCA diluted 30%-50% with iodized oil was
      injected during venous compression. RESULTS: Postembolization arteriograms showed
      that six lesions were completely devascularized after single or multiple (one to
      nine) injections, and five were effectively devascularized (> or = 90%). Although
      three lesions were 60%-70% devascularized after injection, two of these were
      successfully extirpated with no notable blood loss. In nine patients, the
      ophthalmic arterial supply had disappeared after embolization. There were no
      procedure-related complications. CONCLUSION: Direct-puncture embolization with
      NBCA is an effective and safe technique for preoperative devascularization of
      craniofacial arteriovenous malformation. For safe and effective
      devascularization, compression of draining venous channels is thought to be
      important.

PMID- 10352590
TI  - Renal arteries: optimization of three-dimensional gadolinium-enhanced MR
      angiography with bolus-timing-independent fast multiphase acquisition in a single
      breath hold.
AB  - PURPOSE: To compare two different three-dimensional (3D) gadolinium-enhanced
      magnetic resonance (MR) angiographic techniques. MATERIALS AND METHODS: In 26
      patients suspected of having renal artery stenosis, results with fast multiphase
      3D MR angiography were compared to those with standard 3D MR angiography in 37
      patients. With both techniques, 31-second breath-hold acquisitions were
      performed. Multiphase angiography comprised five discrete 6.4-second acquisitions
      without bolus timing, and standard angiography comprised a single acquisition
      based on test-bolus timing. Two readers evaluated images obtained with both
      techniques in terms of image quality, artifacts, and vessel conspicuity. Accuracy
      of findings on the multiphase 3D MR angiograms for assessment of renal artery
      stenosis was determined by comparing them to digital subtraction angiograms and
      surgical findings. RESULTS: In the early arterial phase, multiphase 3D MR
      angiograms showed no image degradation by venous overlay, whereas standard 3D MR
      angiograms depicted at least minor overlay in 53 of 83 renal arteries (P < .001).
      Less parenchymal enhancement in the early arterial phase resulted in a higher
      vessel conspicuity for the divisions and segmental arteries (P < .001). Both
      readers detected and correctly graded 18 of 20 stenoses on the multiphase
      angiograms with almost perfect interobserver agreement (kappa > 0.89).
      CONCLUSION: Renal multiphase 3D MR angiography is an accurate technique requiring
      no bolus timing. The performance of early arterial phase imaging leads to
      improved depiction, particularly of the distal renovascular tree, compared to
      that with standard single-phase 3D MR angiography.

PMID- 10352591
TI  - Pharmacokinetic imaging of 11C ethanol with PET in eight patients with
      hepatocellular carcinomas who were scheduled for treatment with percutaneous
      ethanol injection.
AB  - PURPOSE: To evaluate the carbon 11 ethanol kinetics with positron emission
      tomography after intratumoral injection of the tracer and assess its
      redistribution and dilution in patients who have hepatocellular carcinomas and
      who were scheduled for treatment with percutaneous ethanol injection. MATERIALS
      AND METHODS: The study included eight patients with hepatocellular carcinomas.
      11C ethanol was administered via a puncture needle positioned with
      ultrasonographic guidance. Parametric images based on the Fourier transformation
      were created for further analysis of the local distribution patterns of the
      tracer. The ratio of the 45-minute postinjection standardized uptake value to the
      5-minute postinjection standardized uptake value was used for the evaluation of
      ethanol dilution. RESULTS: Five of eight tumors demonstrated almost constant
      uptake values after the initial distribution phase. In contrast, a rapid
      elimination of the 11C ethanol from the tumor was documented in three of eight
      tumors. The 45 minute-to-5 minute ratio was 0.18-0.67 (median value, 0.56) in the
      tumors. The time-activity curves of the normal liver parenchyma increased slowly
      but steadily with time owing to a low ethanol elimination from the tumor. Fourier
      transformation demonstrated inhomogeneous parts on the amplitude images in seven
      of eight tumors and random redistribution on the phase images in six of eight
      tumors. CONCLUSION: Inhomogeneous drug distribution and drug dilution in the
      target area are likely to be the major limiting parameters for therapy response.

PMID- 10352592
TI  - CT-monitored percutaneous cryoablation in a pig liver model: pilot study.
AB  - PURPOSE: To determine the safety and feasibility of percutaneous cryoablation
      with computed tomographic (CT) guidance in a pig liver model. MATERIALS AND
      METHODS: Nine angiographic balloons (mean diameter, 9 mm) were placed in the
      livers of seven domestic pigs (mean weight, 30.0 kg +/- 14.0 [SD]) as tumor
      mimicking lesions. By using ultrasonographic and CT guidance, two 2.4- or 3.0-mm
      cryoprobes were placed flanking the balloon, and a 15-20-minute freezing process
      was performed. Hemostasis was achieved by placing absorbable cellulose fabric
      down the probe tract. After 24-96 hours, animals were sacrificed, and their
      livers were removed and were sectioned axially at 5-mm intervals for comparison
      with CT images. RESULTS: All animals survived the procedure without complication.
      No serious hemorrhage was found in any case. Ice balls were readily visualized at
      CT because they appeared as areas of decreased attenuation (1.0 HU +/- 20.7) when
      compared with areas of normal liver (48.2 HU +/- 6.3, P < .05). The mean ablative
      margin was 1.7 cm, and only one of nine cases, the one with probe failure, had a
      positive margin. Beam-hardening artifact from the metal probes was present but
      did not interfere with the procedure. Ice-ball size and shape corresponded
      closely to the area of necrosis determined at histopathologic analysis.
      CONCLUSION: CT-monitored percutaneous cryoablation is feasible and safe in this
      pig liver model.

PMID- 10352593
TI  - Plain and covered stent-grafts: in vitro evaluation of characteristics at three
      dimensional MR angiography.
AB  - PURPOSE: To evaluate the characteristics of various plain and covered stents as
      regards demonstration of the contained lumen with simulated contrast material
      enhanced fast three-dimensional (3D) magnetic resonance (MR) angiography.
      MATERIALS AND METHODS: Six stents (Easy Wallstent, Cragg, Palmaz, Cragg EndoPro
      System 1, Corvita, Passager) were implanted in plastic tubes and integrated into
      a closed-tubing circuit driven by a pulsatile roller flow pump. The circulating
      water was spiked with gadopentetate dimeglumine. Three-dimensional MR angiograms
      were obtained with an echo time of 1.4 or 2.1 msec and with partial (0.5 signal
      acquired) or full (one signal acquired) k-space sampling. The size of the stent
      associated artifact was determined relative to the tube diameter. RESULTS: The
      Easy Wallstent and Palmaz stent caused complete obliteration of the stent lumen
      with all sequences. The Cragg, Cragg EndoPro System 1, and Passager stents
      allowed good visualization of the stent lumen. The Corvita stent demonstrated
      major artifacts. The magnitude of the stent-associated artifact was related to
      the echo time (P < .01) but not to the type of k-space sampling (P = .35).
      CONCLUSION: The luminal patency of selected plain and covered stents can be
      assessed with contrast-enhanced 3D MR angiography.

PMID- 10352595
TI  - Diagnosis please. Case 11: perforated duodenal diverticulitis.

PMID- 10352594
TI  - Measurement of the distribution volume of gadopentetate dimeglumine at echo
      planar MR imaging to quantify myocardial infarction: comparison with 99mTc-DTPA
      autoradiography in rats.
AB  - PURPOSE: To measure the fractional distribution volume of gadopentetate
      dimeglumine in normal and reperfused infarcted myocardium at magnetic resonance
      (MR) imaging by using the fractional distribution volume of technetium 99m
      diethylenetriaminepentaacetic acid (DTPA) as an independent reference. MATERIALS
      AND METHODS: Rats were subjected to 1 hour of coronary artery occlusion and 1
      hour of reperfusion before inversion-recovery echo-planar imaging or
      autoradiography. Regional change in relaxation rate (delta R1) ratios for
      myocardium over blood were compared with radioactivity ratios for myocardium over
      blood after the injection of 99mTc-DTPA. RESULTS: Both delta R1 and radioactivity
      ratios demonstrated equilibrium distribution and hence represent partition
      coefficients (lambda). The fractional distribution volumes were greater in
      infarcted myocardium (0.90 +/- 0.05 for gadopentetate dimeglumine and 0.89 +/-
      0.04 for 99mTc-DTPA) than in normal myocardium (0.23 +/- 0.02 for gadopentetate
      dimeglumine and 0.16 +/- 0.01 for 99mTc-DTPA). Area at risk at autoradiography
      was not significantly different from that at histomorphometry. The infarction
      size defined by using triphenyltetrazolium chloride was 13% +/- 4 smaller than
      that defined by using autoradiography. CONCLUSION: The fractional distribution
      volumes of gadopentetate dimeglumine and 99mTc-DTPA are similar and indicate
      extracellular distribution in normal myocardium and intracellular as well as
      extracellular distribution in reperfused infarction. Because the failure of cells
      to exclude these agents is indicative of necrosis, contrast medium-enhanced MR
      imaging may be useful to quantify myocardial infarction.

PMID- 10352596
TI  - Orthotopic liver transplantation: evaluation with MR cholangiography.
AB  - PURPOSE: To determine the accuracy of magnetic resonance (MR) cholangiography for
      demonstration of the biliary tract and detection of biliary complications in
      patients who have undergone orthotopic liver transplantation. MATERIALS AND
      METHODS: Breath-hold half-Fourier rapid acquisition with relaxation enhancement
      MR cholangiography was performed in 25 patients who had undergone orthotopic
      liver transplantation. MR cholangiograms were prospectively and independently
      interpreted by two radiologists for depiction of the biliary tract and ductal
      anastomosis and for complications (eg, biliary dilatation, stricture, stones). MR
      cholangiographic findings were correlated with findings from direct
      cholangiography (n = 24) and surgery (n = 1). RESULTS: MR cholangiography
      completely demonstrated first-order intrahepatic bile ducts in 23 (92%) patients,
      the donor extrahepatic bile duct in 25 (100%), the recipient extrahepatic bile
      duct in 17 of 18 (94%), and the anastomosis in 24 (96%). The sensitivity,
      specificity, accuracy, positive predictive value, and negative predictive value
      of MR cholangiography for detection of biliary dilatation and stricture were each
      100%. Complete interobserver agreement occurred in the detection of biliary
      dilatation and stricture. The sensitivity, specificity, accuracy, positive
      predictive value, and negative predictive value of MR cholangiography for
      detection of stones were 100% for one radiologist and 86%, 100%, 96%, 100%, and
      95%, respectively, for the other. Both radiologists agreed on the diagnosis of
      bile duct stones in six of seven cases (kappa = 0.90). CONCLUSION: MR
      cholangiography enables accurate depiction of the biliary tract and detection of
      biliary complications in patients with an orthotopic liver transplant.

PMID- 10352597
TI  - Expanded gallbladder fossa: simple MR imaging sign of cirrhosis.
AB  - PURPOSE: To determine the frequency on magnetic resonance (MR) images of a
      widened pericholecystic space, which the authors call the expanded gallbladder
      fossa sign, and to assess the sensitivity and specificity of this sign for
      cirrhosis. MATERIALS AND METHODS: Three-hundred thirteen patients who underwent
      MR imaging were included in this study, including 190 with pathologically proved
      cirrhosis (cirrhosis patients) and 123 without history of chronic liver diseases
      (control subjects). MR images were qualitatively evaluated by three independent
      observers for the presence of the expanded gallbladder fossa sign. This sign was
      considered present if there was enlargement of the pericholecystic space (i.e.,
      gallbladder fossa) and the space was bounded laterally by the edge of the right
      hepatic lobe and medially by the edge of the left lateral segment, in conjunction
      with nonvisualization of the left medial segment. RESULTS: The expanded
      gallbladder fossa sign was seen in 129 cirrhosis patients and in three control
      subjects (P < .001). The sensitivity, specificity, accuracy, and positive
      predictive value of this sign for the MR diagnosis of cirrhosis were 68%, 98%,
      80%, and 98%, respectively. CONCLUSION: The expanded gallbladder fossa sign on MR
      images is a frequently present, specific indicator of cirrhosis. This sign can be
      used as a simple and highly specific sign of cirrhosis, if present, despite the
      overall sensitivity of 68%.

PMID- 10352598
TI  - Acute pancreatitis: interobserver agreement and correlation of CT and MR
      cholangiopancreatography with outcome.
AB  - PURPOSE: To assess the correlation between and the interobserver agreement of
      contrast medium-enhanced computed tomography (CT) and nonenhanced and contrast
      enhanced magnetic resonance (MR) imaging findings in patients with acute
      pancreatitis and to correlate these findings with outcome. MATERIALS AND METHODS:
      Two blinded reviewers separately assessed contrast-enhanced CT and nonenhanced
      and contrast-enhanced MR images in 30 patients with acute pancreatitis and
      established a severity index based on the presence of peripancreatic fluid
      collections and pancreatic necrosis. The Spearman rank correlation coefficient
      and weighted kappa statistic were used to assess the correlation between each
      imaging technique and the interobserver agreement, respectively. Correlation
      between hospitalization days, morbidity, and severity indexes were assessed by
      using linear correlation. RESULTS: A strong correlation existed for both
      reviewers when comparing contrast-enhanced CT with nonenhanced (r = 0.82, 0.79)
      or contrast-enhanced (r = 0.82, 0.79) MR cholangiopancreatography or when
      comparing nonenhanced and contrast-enhanced MR cholangiopancreatography (r =
      0.99, 1.00). The interobserver agreement in staging was stronger with nonenhanced
      (kappa = 0.76) and contrast-enhanced (kappa = 0.78) MR cholangiopancreatography
      than with contrast-enhanced CT (kappa = 0.70). There was no linear correlation
      between the severity index for contrast-enhanced CT and outcome, while there was
      a linear correlation between nonenhanced or contrast-enhanced MR
      cholangiopancreatographic staging and the patient morbidity rate. CONCLUSION: MR
      cholangiopancreatography could be an alternative to contrast-enhanced CT for the
      initial staging of acute pancreatitis.

PMID- 10352599
TI  - Mesenteric, omental, and retroperitoneal edema in cirrhosis: frequency and
      spectrum of CT findings.
AB  - PURPOSE: To determine the frequency and CT imaging spectrum of mesenteric,
      omental, and retroperitoneal edema in patients with cirrhosis. MATERIALS AND
      METHODS: Eighty patients were identified with liver cirrhosis and no other cause
      of edema. Five radiologists jointly reviewed the abdominal CT scans of these
      patients to assess, by majority decision, the presence, severity, distribution,
      and configuration of mesenteric edema and the presence of omental and
      retroperitoneal edema. Subcutaneous edema, ascites, pleural effusion,
      splenomegaly, varices, portal venous thrombosis, and serum albumin levels were
      also documented. RESULTS: Mesenteric edema was present in 69 (86%) patients.
      Mesenteric edema occurred alone in 26 (38%) and with omental or retroperitoneal
      edema in 40 (58%) of the 69 patients with edema. No patient had omental or
      retroperitoneal edema alone. Mesenteric edema was mild in 51 (74%) and moderate
      to severe in 18 (26%), patchy in 47 (68%) and diffuse in 22 (32%), purely
      infiltrative in 60 (87%) and infiltrative with superimposed masslike nodules in
      nine (13%) patients. These parameters had significant associations among
      themselves and with ascites, pleural effusions, subcutaneous edema, and low mean
      serum albumin levels but not with splenomegaly or varices. CONCLUSION:
      Mesenteric, omental, and retroperitoneal edema occur commonly in patients with
      cirrhosis. The appearance of mesenteric edema varies from a mild infiltrative
      haze to a severe masslike sheath that engulfs the mesenteric vessels.

PMID- 10352600
TI  - The accordion sign at CT: a nonspecific finding in patients with colonic edema.
AB  - PURPOSE: To determine whether the "accordion sign" is a specific computed
      tomographic (CT) sign of Clostridium difficile colitis. MATERIALS AND METHODS:
      Fifty-seven patients with CT evidence of severe colitis, as judged by colonic
      wall thickening, an abnormal haustral pattern, the target sign, and stranding of
      the pericolic fat, were identified from a computerized CT database for 25 months.
      CT images were retrospectively evaluated for the presence of oral contrast
      material in the colon and for the accordion sign. The medical and laboratory
      records of all patients were reviewed and correlated with CT findings to
      establish the cause of colitis. RESULTS: Oral contrast material had reached the
      colon in 35 of 57 patients at the time of the CT examination. The images in 15 of
      these patients demonstrated the accordion sign, and those in 20 patients did not.
      C difficile colitis was documented in four of the 15 cases displaying the
      accordion sign. In the remaining 11 patients, a different cause was documented.
      Oral contrast material had not reached the colon in the remaining 22 patients.
      Within this group with findings similar to the accordion sign, five patients had
      documented C difficile colitis, and four had colitis from other causes.
      CONCLUSION: The accordion sign is indicative of severe colonic edema or
      inflammation, but it is not specific for C difficile colitis.

PMID- 10352601
TI  - Bone contusions of the posterior lip of the medial tibial plateau (contrecoup
      injury) and associated internal derangements of the knee at MR imaging.
AB  - PURPOSE: To determine if there are any predictable patterns of internal
      derangement associated with a bone contusion of the posterior lip of the medial
      tibial plateau at magnetic resonance (MR) imaging and to offer a biomechanical
      explanation for the findings. MATERIALS AND METHODS: A retrospective review of
      215 consecutive MR examinations for knee trauma was conducted to identify
      contusions of the posterior lip of the medial tibial plateau. Any additional
      contusions and internal derangements were documented in the cases with these
      contusions. Medical charts and arthroscopic results, when available, were
      reviewed for mechanisms of injury. RESULTS: The specific medial tibial contusion
      was demonstrated in 25 of 215 (12%) knee MR examinations. Associated anterior
      cruciate ligament (ACL) tears were found in 25 of the 25 (100%) examinations.
      Injury to the meniscocapsular junction (14 of 25) or a peripheral tear of the
      posterior horn of the medial meniscus (10 of 25) occurred in a combined 96% of
      the cases. Lateral compartment contusions were noted in 24 (96%) cases. Pivot,
      twisting, or valgus forces were reported mechanisms of injury. CONCLUSION:
      Contusions involving the posterior lip of the medial tibial plateau may result
      from a contrecoup impaction injury directly following an ACL tear, as the knee
      reduces. These contusions are almost always associated with a far peripheral
      meniscal tear or with a meniscocapsular junction injury affecting the posterior
      horn of the medial meniscus.

PMID- 10352602
TI  - Posteromedial tibial plateau injury including avulsion fracture of the
      semimembranous tendon insertion site: ancillary sign of anterior cruciate
      ligament tear at MR imaging.
AB  - PURPOSE: To evaluate posteromedial tibial plateau injuries of or about the
      semimembranous tendon insertion site and their association with anterior cruciate
      ligament (ACL) tears on magnetic resonance (MR) images. MATERIALS AND METHODS: A
      retrospective study of MR images and conventional radiographs was performed in 10
      patients with posteromedial tibial plateau injuries, including avulsion fractures
      of the semimembranous tendon insertion site. Associated abnormalities were
      analyzed, including ACL tears, medial meniscal tears, and other lateral
      femorotibial compartment injuries. Findings from the clinical history and
      physical examination were correlated with radiographic and MR imaging findings.
      Nine patients had arthroscopically or surgically documented ACL tears. RESULTS:
      All 10 patients had ACL tears at MR imaging. Five patients had posteromedial
      tibial plateau fractures: Four had avulsion fractures of the tendon insertion
      site, and one had a fracture lateral to the site. Five patients had posteromedial
      tibial plateau bruises: Two had bruises at the tendon insertion site. Five
      patients had tears of the posterior horn of the medial meniscus. Two patients had
      posterior meniscocapsular separations. Three patients showed evidence of the
      O'Donoghue triad. Six patients had bruises of the lateral tibial plateau and of
      the lateral femoral condyle. CONCLUSION: There appears to be an association
      between posteromedial tibial plateau injuries and ACL tears. Posteromedial tibial
      plateau injuries may be predictive of ACL status.

PMID- 10352603
TI  - Cervical spine imaging in patients with trauma: determination of fracture risk to
      optimize use.
AB  - PURPOSE: To develop a method to use clinically apparent factors to determine
      cervical spine fracture risk to guide selection of optimal imaging strategies.
      MATERIALS AND METHODS: Records from 472 patients with trauma (168 with fractures,
      304 control patients) who visited the emergency department in 1994 and 1995 were
      reviewed for 20 potential predictors of cervical spine fracture in this
      retrospective case-control study. Simple logistic regression was used to
      determine predictors of cervical spine fracture. Prediction rules were formulated
      by using multiple logistic regression and recursive partitioning with bootstrap
      validation. Posttest fracture probabilities were calculated from base prevalence
      and likelihood ratios derived for predictors by using Bayes theorem. RESULTS:
      Predictors of cervical spine fracture included severe head injury (adjusted odds
      ratio [OR] = 8.5, 95% CI: 4.0, 17.0), high-energy cause (OR = 11.6, 95% CI: 5.4,
      25.0), and focal neurologic deficit (OR = 58, 95% CI: 12, 283). The prediction
      rule was used to stratify patients into groups with fracture probabilities of
      0.04%-19.70%. After adjusting for overfitting, the area under the receiver
      operating characteristic curve was 0.87. CONCLUSION: Clinically apparent factors,
      including cause of injury, associated injuries, and age, can be used to determine
      the probability of cervical spine fracture. Development of evidence-based imaging
      guidelines should incorporate knowledge of fracture probability.

PMID- 10352604
TI  - Occult lumbosacral dysraphism in children and young adults: diagnostic
      performance of fast screening and conventional MR imaging.
AB  - PURPOSE: To compare fast screening and conventional magnetic resonance (MR)
      imaging for the detection of occult dysraphic myelodysplasias in children and
      young adults. MATERIALS AND METHODS: A retrospective case-control study included
      101 patients (mean age, 4.9 years; range, 1 day to 26 years) suspected of having
      occult lumbosacral dysraphism. Sixty case patients had myelodysplastic lesions
      (19 filar lipoma, 14 syringomyelia, 10 intradural lipoma, eight dermal sinus,
      five diastematomyelia, five lipomyelomeningocele, two caudal regression
      syndrome); 41 control patients had no dysraphic lesions; 17 patients had
      associated renal anomalies. Two neuroradiologists reviewed MR images from
      conventional and fast screening protocols. Diagnostic performance parameters
      included sensitivity, specificity, and area under the receiver operating
      characteristic curve (Az value). RESULTS: The sensitivity of conventional and
      fast screening MR studies was 97.1% and 98.5%, respectively, the specificity was
      90.9% and 84.8%, respectively. The Az value was 0.973 for the fast screening and
      0.976 for the conventional MR studies (P = .83). Interobserver agreement was very
      good for fast screening images (kappa = 0.68) and excellent for conventional
      images (kappa = 0.75). For renal anomalies, the Az value was 0.786 and 0.853 for
      fast screening and conventional MR imaging, respectively (P = .28). CONCLUSION:
      Conventional three-plane lumbosacral MR imaging in children and young adults
      suspected of having occult dysraphism provides better diagnostic information than
      does fast screening two-plane MR imaging because of its higher specificity and
      interobserver agreement.

PMID- 10352605
TI  - The dense metaphyseal band sign.

PMID- 10352606
TI  - Carotid arterial stenosis: evaluation at CT angiography with the volume-rendering
      technique.
AB  - PURPOSE: To determine whether computed tomographic (CT) angiography with the
      volume-rendering technique (VRT) can be used to accurately quantify carotid
      arterial stenosis and to identify occlusions. MATERIALS AND METHODS: Spiral CT
      was performed in 23 patients who were referred for carotid stenosis evaluation.
      VRT images and shaded-surface display (SSD) images of 46 carotid arterial
      bifurcations were compared with findings from digital subtraction angiography
      (DSA). RESULTS: Agreement on stenosis category between VRT CT angiography and DSA
      was found in 39 (85%) of the 46 carotid arteries studied. VRT CT angiography was
      92% (49 of 53) sensitive and 96% (82 of 85) specific for the detection of grade 2
      3 stenoses (> or = 70% stenosis). Agreement on stenosis category between SSD CT
      angiography and DSA was found in 38 (83%) of the 46 carotid arteries studied. SSD
      CT angiography was 91% (48 of 53) sensitive and 93% (79 of 85) specific for the
      detection of grade 2-3 stenoses. Calcified stenoses were correctly graded at VRT
      CT angiography in 10 of the 10 cases with heavy mural calcified plaques, while
      eight of the 10 stenoses were accurately quantified at SSD CT angiography.
      CONCLUSION: These results indicate that VRT CT angiography is as accurate as SSD
      CT angiography in the evaluation of carotid arterial bifurcations.

PMID- 10352607
TI  - Measurement of brain structures with artificial neural networks: two- and three
      dimensional applications.
AB  - PURPOSE: To evaluate the ability of an artificial neural network (ANN) to
      identify brain structures. This ANN was applied to postprocessed magnetic
      resonance (MR) images to segment various brain structures in both two- and three
      dimensional applications. MATERIALS AND METHODS: An ANN was designed that learned
      from experience to define the corpus callosum, whole brain, caudate, and putamen.
      Manual segmentation was used as a training set for the ANN. The ANN was trained
      on two-thirds of the manually segmented images and was tested on the remaining
      one-third. The reliability of the ANN was compared against manual segmentations
      by two technicians. RESULTS: The ANN was able to identify the brain structures as
      readily and as well as did the two technicians. Reliability of the ANN compared
      with the technicians was 0.96 for the corpus callosum, 0.95 for the whole brain,
      0.86 (right) and 0.93 (left) for the caudate, and 0.71 (right) and 0.88 (left)
      for the putamen. CONCLUSION: The ANN was able to identify the structures used in
      this study as well as did the two technicians. The ANN could do this much more
      rapidly and without rater drift. Several other cortical and subcortical
      structures could also be readily identified with this method.

PMID- 10352608
TI  - Glial neoplasms: dynamic contrast-enhanced T2*-weighted MR imaging.
AB  - PURPOSE: To evaluate the role of T2*-weighted echo-planar perfusion imaging by
      using a first-pass gadopentetate dimeglumine technique to determine the
      association of magnetic resonance (MR) imaging-derived cerebral blood volume
      (CBV) maps with histopathologic grading of astrocytomas and to improve the
      accuracy of targeting of stereotactic biopsy. MATERIALS AND METHODS: MR imaging
      was performed in 29 patients by using a first-pass gadopentetate dimeglumine T2*
      weighted echo-planar perfusion sequence followed by conventional imaging. The
      perfusion data were processed to obtain a color map of relative regional CBV.
      This information formed the basis for targeting the stereotactic biopsy. Relative
      CBV values were computed with a nondiffusible tracer model. The relative CBV of
      lesions was expressed as a percentage of the relative CBV of normal white matter.
      The maximum relative CBV of each lesion was correlated with the histopathologic
      grading of astrocytomas obtained from samples from stereotactic biopsy or
      volumetric resection. RESULTS: The maximum relative CBV in high-grade
      astrocytomas (n = 26) varied from 1.73 to 13.7, with a mean of 5.07 +/- 2.79 (+/-
      SD), and in the low-grade cohort (n = 3) varied from 0.92 to 2.19, with a mean of
      1.44 +/- 0.68. This difference in relative CBV was statistically significant (P <
      .001; Student t test). CONCLUSION: Echo-planar perfusion imaging is useful in the
      preoperative assessment of tumor grade and in providing diagnostic information
      not available with conventional MR imaging. The areas of perfusion abnormality
      are invaluable in the precise targeting of the stereotactic biopsy.

PMID- 10352609
TI  - Diffusion-weighted imaging with navigated interleaved echo-planar imaging and a
      conventional gradient system.
AB  - PURPOSE: To demonstrate the technical feasibility and precision of a navigated
      diffusion-weighted (DW) MR imaging method with interleaved echo-planar imaging
      and test its diagnostic sensitivity for detection of ischemic stroke. MATERIALS
      AND METHODS: Apparent diffusion coefficient (ADC) measurements were performed in
      phantoms, and six healthy adult volunteers were examined to determine
      intrasubject (precision) and intersubject (reference range) variations in
      absolute ADC and relative ADC (rADC) measurements. DW imaging maps and lesion
      rADC values were also obtained in 34 consecutive stroke patients to evaluate the
      sensitivity and reliability of DW-interleaved echo-planar imaging for detection
      of ischemic brain damage. RESULTS: Phantom and volunteer ADC values were in
      excellent agreement with published data. The intrasubject variation of rADC was
      6.2%. The ADC precision ranged from 6.5% in the subcortical white matter in the
      frontal lobe to 12.9% in the head of the caudate nucleus. Interleaved echo-planar
      imaging enabled rapid acquisition of high-quality images of the entire brain
      without substantial artifacts. Within the 1st week, the sensitivity of DW
      interleaved echo-planar imaging for detection of acute infarction was 90% (18 of
      20 true-positive studies) and independent of lesion location. CONCLUSION: DW
      interleaved echo-planar imaging with phase navigation and cardiac triggering is
      robust, reliable, and fast. With high sensitivity for detection of early ischemic
      infarction, it is useful for examining stroke patients by using MR systems with
      conventional gradient hardware.

PMID- 10352610
TI  - MR imaging response of brain metastases after gamma knife stereotactic
      radiosurgery.
AB  - PURPOSE: To characterize the magnetic resonance (MR) imaging response of brain
      metastases after gamma knife stereotactic radiosurgery and determine whether
      imaging features and tumor response rates correlate with local tumor control and
      survival. MATERIALS AND METHODS: Serial MR examinations were performed in 48
      patients (25 men, 23 women; mean age, 58 years) with 78 lesions. Pretreatment and
      follow-up enhancing lesion volumes and imaging features were assessed. Rates of
      response to stereotactic radiosurgery were calculated. Prognostic imaging
      features affecting local control and survival were analyzed. RESULTS: Local tumor
      control was achieved in 66 (90%) of 73 metastases at 20 weeks after stereotactic
      radiosurgery; 61% maintained local control at 2 years. A homogeneous baseline
      enhancement pattern and initial good response rate (> 50% lesion volume
      reduction) predicted local control. Five metastases demonstrated a transient
      volume increase after treatment. The median survival time after stereotactic
      radiosurgery was 53 weeks and correlated with systemic disease burden and primary
      tumor type. CONCLUSION: Baseline homogeneous tumor enhancement and initial good
      response correlate with local control. Initial lesion growth does not preclude
      local control and may represent radiation-related change. Recognition of these
      serial MR imaging findings may guide image interpretation and influence treatment
      in patients with stereotactic radiosurgery-treated metastases.

PMID- 10352611
TI  - Cross-sectional nodal atlas: a tool for the definition of clinical target volumes
      in three-dimensional radiation therapy planning.
AB  - Virtual three-dimensional clinical target volume definition requires the
      identification of areas suspected of containing microscopic disease (frequently
      related to nodal stations) on a set of computed tomographic (CT) images, rather
      than the traditional approach based on anatomic landmarks. This atlas displays
      the clinically relevant nodal stations and their correlation with normal
      lymphatic pathways on a set of CT images.

PMID- 10352612
TI  - Cancer in patients aged 90 years or older: radiation therapy.
AB  - PURPOSE: To investigate the clinical efficacy of radiation therapy for cancer in
      patients aged 90 years or older. MATERIALS AND METHODS: Cancer cases in 32
      patients (11 men, 21 women) aged 90 years or older who underwent radiation
      therapy in 1970-1997 were retrospectively analyzed. The mean patient age was 92.2
      years, with a range of 90-98 years. Head and neck cancer (n = 14 [44%]) and skin
      cancer (n = 6 [19%]) were the most common. RESULTS: Eleven (79%) of the 14
      patients with head and neck cancer were treated with curative intent. Radiation
      response without any severe complication was observed in nine (90%) of the 10
      patients with head and neck cancer treated with curative intent who finished
      treatment. The median survival time was 8 months (range, 3-55 months) in the 10
      patients with head and neck cancer who completed treatment with curative intent.
      Complete response was achieved in all of the patients with skin cancer without
      any major sequelae. Complete response was also observed in all three of the
      patients with non-Hodgkin lymphoma, but two patients treated with adjuvant
      chemotherapy died of drug-induced pneumonitis. Palliation was achieved in all
      nine of the patients treated with palliative intent. CONCLUSION: Age of 90 years
      or older is not a limiting factor for radiation therapy.

PMID- 10352613
TI  - Sentinel lymph node biopsy after percutaneous diagnosis of nonpalpable breast
      cancer.
AB  - PURPOSE: To determine the technical success rate of sentinel lymph node biopsy in
      women with nonpalpable infiltrating breast cancer diagnosed by using percutaneous
      core biopsy and to determine the frequency with which sentinel lymph node biopsy
      obviated axillary dissection. MATERIALS AND METHODS: Retrospective review
      revealed 33 women who underwent sentinel node biopsy after percutaneous core
      biopsy diagnosis of nonpalpable infiltrating breast cancer. Sentinel nodes were
      identified with radioisotope and blue dye; the procedure was technically
      successful if sentinel nodes were found at surgery. All sentinel nodes were
      excised. Axillary dissection was performed if tumor was present in sentinel
      nodes. RESULTS: Sentinel nodes were found at surgery in 30 women (91%). Sentinel
      nodes were identified with both radioisotope and blue dye in 22 (73%) of these
      women, with only radioisotope in six (20%), and with only blue dye in two (7%).
      Sentinel nodes were found in 12 (80%) of 15 women in the first half of the study
      versus all 18 (100%) women in the second half (P = .08). Sentinel nodes were free
      of tumor in 23 (77%) of 30 women. In six (86%) of seven women with tumor in
      sentinel nodes, the sentinel nodes were the only nodes with tumor. CONCLUSION:
      Sentinel node biopsy was successful in 30 women (91%) with nonpalpable
      infiltrating carcinoma diagnosed with percutaneous core biopsy and obviated
      axillary dissection in 23 women (70%). Using both radioisotope and blue dye may
      increase the success rate. A learning curve exists, and success improves with
      experience.

PMID- 10352614
TI  - BI-RADS categorization as a predictor of malignancy.
AB  - PURPOSE: To determine the positive predictive value (PPV) of the American College
      of Radiology Breast Imaging Reporting and Data System (BI-RADS) categories 0, 2,
      3, 4, and 5 by using BI-RADS terminology and by auditing data on needle
      localizations. MATERIALS AND METHODS: Between April 1991 and December 1996, 1,400
      mammographically guided needle localizations were performed in 1,109 patients.
      Information entered into the mammographic database included where the initial
      mammography was performed (inside vs outside the institution), BI-RADS category,
      mammographic finding, and histopathologic findings. A recorded recommendation was
      available for 1,312 localizations in 1,097 patients, who composed the study
      population. RESULTS: The 1,312 localizations yielded 449 (34%) cancers (139 [31%]
      were ductal carcinoma in situ [DCIS]; 310 [69%] were invasive cancers) and 863
      (66%) benign lesions. There were 15 (1%) category 0 lesions; the PPV was 13% (two
      of 15 lesions). There were 50 (4%) category 2 lesions; the PPV was 0% (0 of 40
      lesions). There were 141 (11%) category 3 lesions; the PPV was 2% (three of 141
      lesions). The three cancers in this group were all non-comedotype DCIS. There
      were 936 (71%) category 4 lesions; the PPV was 30% (279 of 936 lesions). There
      were 170 (13%) category 5 lesions; the PPV was 97% (165 of 170 lesions).
      CONCLUSION: Placing mammographic lesions into BI-RADS categories is useful for
      predicting the presence of malignancy. Perhaps, most important, a lesion placed
      into BI-RADS category 3 is highly predictive of benignity, and short-term
      interval follow-up as an alternative to biopsy would decrease the number of
      biopsies performed in benign lesions.

PMID- 10352615
TI  - Pulmonary emphysema: subjective visual grading versus objective quantification
      with macroscopic morphometry and thin-section CT densitometry.
AB  - PURPOSE: To compare subjective visual grading of pulmonary emphysema with
      macroscopic morphometry and computed tomographic (CT) densitometry. MATERIALS AND
      METHODS: In 62 consecutive patients who underwent thinsection CT before surgical
      lung resection, emphysema was objectively quantified with computer-assisted
      macroscopic morphometry and CT densitometry. The percentage of lung
      macroscopically occupied by emphysema was compared with the percentage occupied
      on CT scans by pixels with attenuation values lower than a predefined threshold
      (CT densitometry). Three readers with varying degrees of expertise subjectively
      graded emphysema with visual assessment at two reading sessions. Data from
      objective quantification and subjective grading were analyzed with correlation
      coefficients, and interobserver and intraobserver agreement were calculated.
      RESULTS: Subjective grading of emphysema showed less agreement with the
      macroscopic reference standard results (r = 0.439-0.505; P < .05) than with
      objective CT densitometric results (r = 0.555-0.623; P < .001). The 95% CIs for
      the intercepts of the linear regression lines were suggestive of systematic
      subjective overestimation of emphysema by all three readers. Interobserver
      agreement was moderate (kappa = 0.431-0.589). Intraobserver agreement was good to
      excellent (kappa = 0.738-0.936). The expertise of individual readers did not
      substantially influence results. CONCLUSION: Systematic overestimation and
      moderate interobserver agreement may compromise subjective visual grading of
      emphysema, which suggests that subjective visual grading should be supplemented
      with objective methods to achieve precise, reader-independent quantification of
      emphysema.

PMID- 10352616
TI  - Acute interstitial pneumonia: thin-section CT findings in 36 patients.
AB  - PURPOSE: To characterize the computed tomographic (CT) findings of acute
      interstitial pneumonia and to correlate the pattern and the extent of
      abnormalities with the time between symptom onset and CT. MATERIALS AND METHODS:
      The study included 36 patients (20 men, 16 women; age range, 22-83 years; mean
      age, 61 years) with histopathologically proved acute interstitial pneumonia who
      were identified retrospectively. The time between symptom onset and CT was 2-90
      days (mean, 22 days; median, 17 days). The presence, extent, and distribution of
      various CT findings were evaluated. Disease duration and extent of each finding
      were compared by using the Spearman rank correlation coefficient. RESULTS: Areas
      with ground-glass attenuation, traction bronchiectasis, and architectural
      distortion were present in all 36 patients. Airspace consolidation was present in
      33 patients (92%). The extent of areas of ground-glass attenuation (r = 0.45, P <
      .01) and the extent of traction bronchiectasis (r = 0.35, P < .05) correlated
      with disease duration. No other significant correlation was found between the CT
      findings and disease duration. CONCLUSION: A combination of ground-glass
      attenuation, airspace consolidation, traction bronchiectasis, and architectural
      distortion is seen in the majority of patients with acute interstitial pneumonia.
      The extent of ground-glass attenuation and traction bronchiectasis increases with
      disease duration.

PMID- 10352617
TI  - Pulmonary MR angiography with ultrasmall superparamagnetic iron oxide particles
      as a blood pool agent and a navigator echo for respiratory gating: pilot study.
AB  - In nine healthy adult volunteers, pulmonary magnetic resonance angiography was
      performed with the blood pool agent NC100150 injection combined with respiratory
      gating with a navigator echo. With increasing doses of the contrast agent, higher
      signal intensities and vessel branch order visualization were achieved. No motion
      artifacts were seen. The blood pool agent NC100150 injection in combination with
      respiratory navigator gating permitted acquisition of high-quality MR angiograms
      of the pulmonary vasculature during continuous breathing.

PMID- 10352618
TI  - Abdominal helical CT: milk as a low-attenuation oral contrast agent.
AB  - One hundred ten consecutive patients were given either whole (4%) milk, 2% milk,
      water, barium suspension, or no oral contrast agent before abdominal computed
      tomography (CT). Results with whole milk were superior to those with all other
      agents for gastrointestinal distention, mural visualization, and pancreas
      duodenum discrimination. In bowel loop discrimination, results with 4% milk were
      equal to those with barium but superior to those with all other agents. Whole
      (4%) milk is an effective low-attenuation oral contrast agent.

PMID- 10352619
TI  - Radiation field simulation of gynecologic malignancies: localization of the
      cervix and vagina with a flexible vaginal localizer contrast tampon.
AB  - The authors evaluated a flexible vaginal localizer contrast tampon for radiation
      therapy simulation. In 51 patients, the degree of cervical or vaginal cuff
      displacement secondary to the contrast tampon was evaluated by comparing
      simulation radiographs (with tampon) and initial portal radiographs (without
      tampon). The same comparisons were made on the radiographs obtained in 25 control
      subjects who underwent simulation without a tampon. Mean displacement in the
      group who underwent simulation with a tampon was minimal (< or = 5 mm in each
      direction) and similar to that in the control group. This technique provides
      reliable cervical and vaginal cuff localization.

PMID- 10352620
TI  - Cervical spine tomography with an angiographic C-arm.
AB  - Phantom studies were performed to develop a technique for linear tomography of
      the craniocervical junction with a digital fluoroscopic angiographic C-arm unit.
      Section thicknesses were similar to those used at conventional tomography, and
      the radiation dose was lower. C-arm tomography was possible with a 6-second
      exposure and a 40 degrees arc. C-arm tomography is a practical method for
      decreasing patient turnaround time.

PMID- 10352621
TI  - Platinum subdural grid: MR imaging compatibility testing.

PMID- 10352622
TI  - Thoracic aorta.

PMID- 10352623
TI  - ER docs happy as CPR training made compulsory in Ontario.

PMID- 10352624
TI  - Cost of seat-belt-related whiplash injuries rising.

PMID- 10352625
TI  - First worldwide public health treaty on the way.

PMID- 10352627
TI  - An incidental tourist.

PMID- 10352626
TI  - Blue in the face.

PMID- 10352628
TI  - Rethinking the numbers on adverse drug reactions.

PMID- 10352630
TI  - Norwood reconstruction.

PMID- 10352629
TI  - Coming in from the cold.

PMID- 10352631
TI  - Debating thrombolysis in stroke.

PMID- 10352632
TI  - Risk factors for resistance to "first-line" antimicrobials among urinary tract
      isolates of Escherichia coli in children.
AB  - BACKGROUND: There are increasing concerns regarding antimicrobial resistance in
      Canada. Data are limited on the prevalence, patterns of resistance and risk
      factors associated with resistant organisms, including coliforms, in children.
      This study was done to address these issues as they relate to urinary tract
      isolates of Escherichia coli in a tertiary care pediatric centre in Ottawa.
      METHODS: A surveillance study was conducted from December 1992 to December 1994.
      Susceptibility testing of urinary tract isolates of E. coli was performed using a
      panel of antimicrobial agents. A case-control study was also conducted for
      subjects with isolates resistant to trimethoprim-sulfamethoxazole (T-S), this
      drug being used a representative "first-line" agent. RESULTS: A total of 1636
      consecutive isolates were obtained from 967 subjects. Of the 1636 isolates, 736
      (45.0%) were resistant to ampicillin, 514 (31.4%) were resistant to T-S, 363
      (22.2%) were resistant to both ampicillin and T-S, and 27 (1.7%) were resistant
      to both ampicillin and gentamicin. In the case-control study 274 children with
      isolates resistant to T-S were matched with 274 children who had T-S-sensitive
      isolates obtained during the study period or the preceding or subsequent 6
      months. Multivariate analyses indicated that subjects who had received
      antimicrobials for more than 4 weeks in the previous 6 months were about 23 times
      more likely to have isolates resistant to T-S than were subjects without this
      risk factor (odds ratio [OR] 23.4, 95% confidence interval [CI] 12.0-47.6).
      Children with genitourinary tract abnormalities were 2.4 times more likely to
      have resistant isolates than those without such abnormalities (95% CI 1.2-4.5).
      Compared with children who had no hospital admissions in the previous year, those
      with 1 admission in that period were more likely to have resistant isolates (OR
      2.3, 95% CI 1.4-7.5), as were those with 2 or more admissions in that period (OR
      3.2, 95% CI 1.1-4.8). Compared with children aged 2-6 years, children under 2
      years of age were less likely to have resistant isolates (OR 0.3, 95% CI 0.2
      0.8). INTERPRETATION: Selective antimicrobial pressure and multiple admissions to
      hospital were among the risk factors associated with antimicrobial resistance.
      The finding of a low but definite level of resistance to both ampicillin and
      gentamicin is important for the selection of empiric therapy for sepsis in
      neonates. The role of inexpensive first-line agents in the outpatient treatment
      and prevention of urinary tract infections requires re-examination, particularly
      in children who have recently received antimicrobial therapy.

PMID- 10352633
TI  - Quality of care in unlicensed homes for the aged in the eastern townships of
      Quebec.
AB  - BACKGROUND: The recent proliferation of unlicensed homes for the aged in Quebec,
      coupled with the increased needs of the population they serve, has raised
      concerns about the quality of case these homes provide. The authors compared the
      quality of care in unlicensed homes with that in licensed long-term care
      facilities in a region of Quebec. METHODS: The study involved 301 impaired people
      aged 65 and over in 88 residential care facilities (52 unlicensed, 36 licensed)
      in the Eastern Townships of Quebec. Study participants were chosen according to a
      2-stage sampling scheme: stratified sampling of the primary units (facilities)
      and random sampling of the secondary units (residents). Quality of care was
      measured using the QUALCARE scale, a multidimensional instrument that uses a 5
      point scale to assess 6 dimensions of care: environmental, physical, medical
      management, psychosocial, human rights and financial. A mean score of more than 2
      was considered indicative of inadequate care. RESULTS: Overall, the quality of
      care was similar in the unlicensed and licensed facilities (mean global score
      1.61 [standard error of the mean (SEM) 0.06] and 1.47 [SEM 0.09] respectively).
      Examination of dimension-specific quality-of-care scores revealed that the
      unlicensed homes performed worse than the licensed facilities in 2 areas of care:
      physical care (mean score 1.80 [SEM 0.08] v. 1.51 [SEM 0.09] respectively, p =
      0.017) and medical management (1.37 [SEM 0.06] v. 1.14 [SEM 0.05], p = 0.004).
      The dimension-specific scores also revealed that both types of homes lacked
      appropriate attention to the psychosocial aspect of care. Overall, 25% of the
      facilities provided inadequate care to at least one resident. This situation was
      especially prevalent among homes with fewer than 40 residents, where up to 20% of
      the residents received inadequate care. INTERPRETATION: Most of the unlicensed
      homes for the aged that were studied delivered care of relatively good quality.
      However, some clearly provided inadequate care.

PMID- 10352634
TI  - Impact of treating hyperlipidemia or hypertension to reduce the risk of death
      from coronary artery disease.
AB  - OBJECTIVE: To compare the prevalence of modifiable risk factors for
      cardiovascular disease among hypertensive and nonhypertensive adults and to
      estimate the effect of treating hyperlipidemia or hypertension to reduce the risk
      of death from coronary artery disease. METHODS: The authors evaluated a sample of
      7814 subjects aged 35-74 years free of clinical cardiovascular disease from the
      Canadian Heart Health Surveys to estimate the prevalence of cardiovascular risk
      factors. They identified hyperlipidemic subjects (ratio of total cholesterol to
      high-density lipoprotein cholesterol [total-C/HDL-C] 6.0 [corrected] or more for
      men and 5.0 [corrected] or more for women) and hypertensive subjects (systolic or
      diastolic blood pressure 160/90 mm Hg or greater, or receiving pharmacologic or
      nonpharmacologic treatment). A life expectancy model was used to estimate the
      rate of death from coronary artery disease following specific treatments.
      RESULTS: An elevated total-C/HDL-C ratio was significantly more common among
      hypertensive than nonhypertensive men aged 35-64 (rate ratio [RR] 1.56 for age 35
      54, 1.28 for age 55-64) and among hypertensive than nonhypertensive women of all
      ages (RR 2.73 for age 35-54, 1.58 for age 55-64, 1.31 for age 65-74). Obesity and
      a sedentary lifestyle were also more common among hypertensive than among
      nonhypertensive subjects. According to the model, more deaths from coronary
      artery disease could be prevented among subjects with treated but uncontrolled
      hypertension by modifying lipids rather than by further reducing blood pressure
      for men aged 35-54 (reduction of 50 v. 29 deaths per 100,000) and 55-64
      (reduction of 171 v. 104 deaths per 100,000) and for women aged 35-54 (reduction
      of 44 v. 39 deaths per 100,000). Starting antihypertensive therapy in subjects
      aged 35-74 with untreated hypertension would achieve a greater net reduction in
      deaths from coronary artery disease than would lipid lowering. Nonetheless, the
      benefits of lipid therapy were substantial: lipid intervention among hypertensive
      subjects aged 35-74 represented 36% of the total benefits of treating
      hyperlipidemia in the total hyperlipidemic population. INTERPRETATION: The
      clustering of hyperlipidemia and the potential benefits of treatment among
      hypertensive adults demonstrate the need for screening and treating other
      cardiovascular risk factors beyond simply controlling blood pressure.

PMID- 10352636
TI  - "Mine own countree": quality of care in nursing homes.

PMID- 10352635
TI  - Utilization of health care resources by obese Canadians.
AB  - BACKGROUND: The prevalence of obesity in Canada has been increasing in recent
      years. Using data from the National Population Health Survey (NPHS), the authors
      determined the prevalence of obesity among Canadians, the associated
      comorbidities and the patterns of resource utilization by obese people. METHODS:
      The NPHS, a cross-sectional survey conducted in 1994, was administered to 17,626
      Canadians 12 years of age or older who were not long-term residents of hospitals
      or long-term care facilities and were not residing on First Nations reserves or
      Canadian Armed Forces bases, or in the Yukon and Northwest Territories. For the
      authors' analysis, the study population consisted of 12,318 Canadians aged 20-64
      years who were not pregnant and for whom the body mass index (BMI) had been
      calculated. The prevalence of comorbidities, health status index scores, self
      esteem, self-rated health, restriction of activity, health care resource
      utilization (physician visits, disability days, admissions to hospital and
      medication use) were determined for obese people (BMI of 27 or greater) and
      nonobese people. RESULTS: The NPHS data revealed that 35.2% of men and 25.8% of
      women in Canada were obese in 1994. Obese respondents were more likely than
      nonobese respondents to suffer from stress (adjusted odds ratio [OR] 1.20, 95%
      confidence interval [CI] 1.11-1.31), activity restrictions (adjusted OR 1.39, 95%
      CI 1.26-1.54) and a number of chronic comorbidities. Obese respondents were also
      more likely to consult with physicians (adjusted OR 1.32, 95% CI 1.22-1.43), be
      prescribed a number of medications and to require excess disability days
      (adjusted OR 1.22, 95% CI 1.08-1.36). INTERPRETATION: Obesity represents a
      substantial burden on the health of Canadians and on Canada's health care
      resources.

PMID- 10352637
TI  - The evolving paradigm of health technology assessment: reflections for the
      millennium.

PMID- 10352638
TI  - Substance abuse at the turn of the millennium.

PMID- 10352639
TI  - Waiting lists for health care: a necessary evil?

PMID- 10352641
TI  - Systolic and diastolic learning: an analogy to the cardiac cycle.
AB  - It has been observed that the active-passive classification of adult learning can
      be viewed in terms of a systolic-diastolic model. This model represents an
      analogy to the cardiac cycle and the work done by the heart during these two
      phases of the cycle. The determinants of systolic and diastolic learning can be
      compared to the determinants of cardiac function: preload, afterload and
      contractility. Similarly, dysfunction in these two phases of learning can be
      compared to cardiac dysfunction from a pathophysiologic perspective.

PMID- 10352640
TI  - Living a "shady life": sun-protective behaviour for Canadians.

PMID- 10352642
TI  - Tuberculosis: 5. Pediatric disease.

PMID- 10352643
TI  - RN = really neglected, angry nurses say.

PMID- 10352644
TI  - Chaos reigns at medical schools over hepatitis B testing.
AB  - Health Canada guidelines require that all physicians be immunized against
      hepatitis B--a policy that the CMA opposes. Where does that leave medical
      students?

PMID- 10352645
TI  - Manitoba hires spiritual care coordinator to promote nonmedical side of healing.

PMID- 10352646
TI  - Influence of age on characteristics of polymyositis and dermatomyositis in
      adults.
AB  - In a retrospective study of 79 consecutive patients, we evaluated characteristics
      of polymyositis (PM) and dermatomyositis (DM) and compared clinical presentation,
      biochemical findings, histologic changes, evolution, complications, and mortality
      rate of elderly patients (aged > or = 65 yr) and younger patients (aged < or = 64
      yr) at the onset of PM/DM. We found a high prevalence of PM/DM in elderly
      patients: 23 patients (29%) were aged 65 years or over. We also found that
      esophageal involvement (34.8% versus 16.1%, respectively) and bacterial pneumonia
      related to both ventilatory insufficiency and esophageal impairment (21.7% versus
      5.4%, respectively) were more common in elderly patients compared with younger
      patients, resulting in increased morbidity and mortality rates. Moreover,
      malignancy frequency was higher in elderly patients compared with younger
      patients (47.8% versus 9.1%, respectively, p = 0.0001), particularly patients
      with DM (10/11). Fifty percent of malignancies were colon malignancies in elderly
      patients. Erythrocyte sedimentation rate, C-reactive protein, fibrinogen, and
      ferritin levels were also higher in the elderly patient group compared with the
      younger group, and the presence of serum hypoprotidemia, hypoalbuminemia, and
      anemia was more frequent. Finally, PM/DM complete remission was less frequent
      (13.6% versus 41.1%) and the mortality rate (47.8% versus 7.3%) was higher in
      elderly patients than in younger patients. The main causes of death in elderly
      patients were bacterial pneumonia, due to ventilatory insufficiency and
      esophageal impairment, and malignancies. Our findings therefore indicate that
      PM/DM-related esophageal and lung involvement should be systematically searched
      for in elderly patients. Esophageal manometry and pulmonary function tests should
      become an integral part of initial evaluation in elderly patients for early
      detection of impairment. Moreover, as we observed a marked overrepresentation of
      colon cancer in elderly patients with DM, we suggest that the search for
      malignancies in elderly patients with DM should include lower gastrointestinal
      tract investigations.

PMID- 10352647
TI  - Renal involvement in systemic lupus erythematosus. A study of 180 patients from a
      single center.
AB  - Charts of 180 patients (147 women, 33 men) with systemic lupus erythematosus
      (SLE) complicated by renal involvement were retrospectively analyzed from a
      series of 436 patients. Mean age at renal disease onset was 27 years. Thirty-six
      percent of the patients had renal involvement after diagnosis of lupus, for 30.7%
      of that group it was more than 5 years later. Renal involvement occurred more
      frequently in young male patients of non-French non-white origin. Patients with
      renal involvement suffered more commonly from malar rash, psychosis, myocarditis,
      pericarditis, lymphadenopathy, and hypertension. Anemia, low serum complement,
      and raised anti-dsDNA antibodies were more frequent. According to the 1982 World
      Health Organization classification, histologic examination of initial renal
      biopsy specimen in 158 patients showed normal kidney in 1.5% of cases, mesangial
      in 22%, focal proliferative in 22%, diffuse proliferative in 27%, membranous in
      20%, chronic sclerosing glomerulonephritis in 1%, and other forms of nephritis in
      6.5%. Distribution of initial glomerulonephritis patterns was similar whether
      renal involvement occurred before or after the diagnosis of lupus. Transformation
      from 1 histologic pattern to another was observed in more than half of the
      analyzable patients (those who underwent at least 2 renal biopsies). Nephritis
      evolved toward end-stage renal disease in 14 patients despite the combined use of
      steroids and cyclophosphamide in 12. Initial elevated serum creatinine levels,
      initial hypertension, non-French non-white origin, and proliferative lesions on
      the initial renal biopsy were indicators of poor renal outcome. Twenty-four
      patients died after a mean follow-up of 109 months from SLE diagnosis. Among our
      436 patients, the 10-year survival rate was not significantly affected by the
      presence or absence of renal involvement at diagnosis (89% and 92%,
      respectively).

PMID- 10352648
TI  - Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A
      multicenter prospective study of 1,000 patients. European Working Party on
      Systemic Lupus Erythematosus.
AB  - In the present study we assessed the frequency and characteristics of the main
      causes of morbidity and mortality in SLE during a 5-year period and analyzed the
      prognostic significance for morbidity and mortality of the main immunologic
      parameters used in clinical practice. We started in 1990 a multicenter study of
      1,000 patients from 7 European countries. All had medical histories documented
      and underwent medical interview and routine general physical examination when
      entered in the study, and all were followed prospectively by the same physicians
      during the ensuing 5 years (1990-1995). Four hundred thirteen patients (41.3%)
      presented 1 or more episodes of arthritis, 264 (26.4%) had malar rash, 222
      (22.2%) active nephropathy, 139 (13.9%) fever, 136 (13.6%) neurologic
      involvement, 132 (13.2%) Raynaud phenomenon, 129 (12.9%) serositis (pleuritis
      and/or pericarditis), 95 (9.5%) thrombocytopenia, and 72 (7.2%) thrombosis. Two
      hundred seventy patients (27%) presented infections, 113 (11.3%) hypertension, 75
      (7.5%) osteoporosis, and 59 (5.9%) cytopenia due to immunosuppressive agents.
      Sixteen patients (1.6%) developed malignancies, with the most frequent primary
      localizations the uterus and the breast. Several immunologic parameters (anti
      dsDNA or antiphospholipid antibodies) were found to have a predictive value for
      the development of SLE manifestations during the period of the study. Forty-five
      patients (4.5%) died; the most frequent causes of death were divided similarly
      among active SLE (28.9%), infections (28.9%), and thromboses (26.7%). A survival
      probability of 95% at 5 years was found. A lower survival probability (92%) was
      detected in those patients who presented at the beginning of the study with
      nephropathy.

PMID- 10352649
TI  - Spinal cord schistosomiasis. A report of 2 cases and review emphasizing clinical
      aspects.
AB  - Schistosomal myeloradiculopathy (SMR) is a severe and little known form of
      presentation of schistosomiasis mansoni and hematobic schistosomiasis. The
      literature concerning the entity is scarce, and most publications are limited to
      isolated case reports. Thus, to consolidate and analyze the knowledge currently
      available about the disease, I reviewed 231 cases, with emphasis on clinical
      aspects. Although variations occur, in most cases the clinical picture of SMR is
      highly suggestive in individuals with epidemiologic antecedents of the infection.
      Thus, a patient with SMR is usually a young male with no other manifestations of
      schistosomal infection who presents with lumbar pain, often of a radicular
      nature, soon followed by weakness and sensory loss of rapid progression in the
      lower limbs associated with autonomic dysfunction, particularly bladder
      dysfunction. The most suggestive elements of the entity, and therefore of higher
      diagnostic value, are the low localization of the spinal cord lesion, the acute
      or subacute onset of the disease, and the association of manifestations due to
      medullary and radicular involvement. SMR is commonly classified into clinical or
      anatomoclinical forms. However, I observed no consensus in this classification
      even in terms of the terminology used. The analysis performed in this review
      permitted the introduction of a new concept not yet reported in the literature
      regarding the possibility that the disease consists of a continuous spectrum,
      with asymptomatic egg laying in the spinal cord at 1 end of the spectrum and
      devastating forms at the other end, with most cases occupying an intermediate
      position and with the various types of damage overlapping and associated to
      different degrees. This concept applies not only to different patients but also
      to the same patient at different stages of the disease. Chemical and
      cytomorphologic examination of cerebrospinal fluid (CSF) almost always revealed
      mildly or moderately increased total protein concentration and predominantly
      lymphocytic pleocytosis. Eosinophils, the least nonspecific finding, were
      detected in the CSF of less than half (40.8%) the patients. Myelography and
      computed tomography-myelography were altered in 63.3% of cases, but this
      proportion may be an overestimate. The most frequent changes were images of a
      filling defect due to expansion of the spinal cord and were almost always
      demonstrated by the 2 imaging modalities. Although still few in number, early
      reports suggest that magnetic resonance imaging is more sensitive; however, the
      changes are also nonspecific, such as those revealed by myelography and computed
      tomography-myelography. Parasite eggs were demonstrated frequently in a biologic
      specimen (88.3%), but difficulty in detection was not uncommon. Peripheral blood
      eosinophilia was detected in 64.5% of patients and represented a nonspecific
      finding. The detection of anti-Schistosoma antibodies in the serum or CSF was
      also frequent (94.9% and 84.8%, respectively). The presence of anti-Schistosoma
      antibodies in serum is of limited value for the diagnosis of schistosomiasis in
      general, especially among individuals living in endemic areas; however, their
      quantification in the CSF has proved to be promising for diagnosis in the few
      studies conducted for this purpose. The large number of variables concerning
      treatment (such as drugs used and duration of disease at the beginning of
      treatment), together with the relative lack of information about the natural
      history of the disease, limit the analysis of aspects related to treatment and
      prognosis. Nevertheless, it was possible to conclude that corticosteroids and
      antischistosomotic drugs have a favorable effect on disease outcome and should be
      administered as early as possible. In addition to early treatment, factors linked
      to the disease itself affect prognosis. The new cases of SMR reported here are
      typical and illustrate the data discussed in this literature survey.

PMID- 10352650
TI  - Group B streptococcal osteomyelitis in adults.

PMID- 10352651
TI  - Pseudochylothorax. Report of 2 cases and review of the literature.
AB  - We report 2 cases of pseudochylothorax and review 172 published cases.
      Tuberculosis is by far the most frequent cause of pseudochylothorax, accounting
      for 54% of all caes, with a remarkable association with previous collapse therapy
      and long-term effusions. The remaining etiologies, including rheumatoid
      arthritis, are infrequent. Tuberculous pseudochylothorax is usually sterile.
      Successful treatment of an acute tuberculous pleurisy does not preclude the
      development of long-term complications such as pseudochylothorax. We do not
      recommend pleural biopsy initially because of its low yield for etiologic
      diagnosis. Currently, adenosine deaminase (ADA) values in pleural fluid are not
      useful to sustain diagnosis or therapeutic decisions. We advise draining only
      symptomatic cases and treating patients with positive Ziehl-Neelsen stain or
      Lowenstein culture, and those with growing effusions of suspected tuberculous
      origin, with antituberculous chemotherapy. Pulmonary decortication should be the
      last therapeutic step for recurrent and symptomatic cases.

PMID- 10352652
TI  - Acute pain mechanisms.
AB  - The systems activated by tissue-injuring stimuli are complex. The nociceptive
      primary afferents have little spontaneous activity under normal conditions;
      however, after tissue injury, they display longlasting, ongoing activity. This
      results, in part, because the injury elicits the release of active factors that
      sensitize or excite the peripheral nerve terminal. A threshold that is lowered to
      the extent that body temperature and the pressure of edema are adequate stimuli
      results in spontaneous pain. This phenomenon is mediated by a variety of blood
      borne active factors released during plasma extravasation, by agents released
      from local inflammatory cells, and by neurotransmitters released from the
      peripheral terminals of the primary afferent fibers themselves. Well-defined
      projections into the dorsal horn convey the "pain message" to at least two well
      defined populations of neurons: those that are nociceptive specific and those
      that display an intensity-linked discharge over a range of stimuli from innocuous
      to noxious. Convergence from various fiber types, modalities, and end organs
      permits the encoding of afferent traffic with respect to intensity and location.
      The convergence of axons from somatic and visceral structures reflects the
      mechanism for the so-called "referred pain state." Most importantly, these dorsal
      horn systems have a dynamic component in addition to the hard-wiring; their
      output can be regulated both up and down. The up-regulation provides the basis
      for much of the facilitated processing that is believed to account for a
      significant percentage of the postinjury pain state. The facilitated state has a
      unique pharmacology, with the underlying mechanisms reflecting a cascade of
      actions that starts with the NMDA receptor and proceeds through the spinal
      release of intermediaries, such as prostaglandins and nitric oxide. Conversely,
      the ability to down-regulate the dorsal horn stimulus response function accounts
      for the powerful control exerted by a wide variety of diverse factors, including
      the spinal delivery of opioid and nonopioid analgesics and the "endogenous
      analgesia system." These linkages reflect the complexity of the encoding
      mechanisms that transduce the tissue injury into the behavioral sequela known as
      pain. This article also emphasizes that, although considerable progress has been
      made in the past decade, the current pace of research promises greater insights.

PMID- 10352653
TI  - Measurement of pain.
AB  - Pain is a personal, subjective experience influenced by cultural learning, the
      meaning of the situation, attention, and other psychologic variables. Approaches
      to the measurement of pain include verbal and numeric self-rating scales,
      behavioral observation scales, and physiologic responses. The complex nature of
      the experience of pain suggests that measurements from these domains may not
      always show high concordance. Because pain is subjective, patients' self-reports
      provide the most valid measure of the experience. The VAS and the MPQ are
      probably the most frequently used self-rating instruments for the measurement of
      pain in clinical and research settings. The MPQ is designed to assess the
      multidimensional nature of pain experience and has been demonstrated to be a
      reliable, valid, and consistent measurement tool. A short-form MPQ is available
      for use in specific research settings when the time to obtain information from
      patients is limited and when more information than simply the intensity of pain
      is desired. The DDS was developed using sophisticated psychophysical techniques
      and was designed to measure separately the sensory and unpleasantness dimensions
      of pain. It has been shown to be a valid and reliable measurement of pain with
      ratio-scaling properties and has recently been used in a clinical setting.
      Behavioral approaches to the measurement of pain also provide valuable data.
      Further development and refinement of pain measurement techniques will lead to
      increasingly accurate tools with greater predictive powers.

PMID- 10352654
TI  - Analgesic agents for the postoperative period. Opioids.
AB  - Opioids are the most commonly used medication for patients with acute pain.
      Morphine is the prototype with which all other opioids are compared. Synthetic
      and semisynthetic derivatives of morphine have unique properties, allowing for
      the use of a larger selection of medication. An understanding of the mechanisms
      of action, adverse effects, and routes of administration of the various potent
      opioids is important for good postoperative pain management.

PMID- 10352655
TI  - Analgesic agents for the postoperative period. Nonopioids.
AB  - For many reasons, nonopioid analgesics have proven to be of immense benefit in
      postoperative pain relief. Consideration of the limitations and side effects of
      opioids confirms the need for alternative, complementary analgesics. The current
      understanding of pain pathophysiology recognizes that many tissue and neuronal
      factors and changes are invoked by tissue damage, producing peripheral and
      central sensitization, and some of these may be modulated by the use of NSAIDs,
      NMDA antagonists, and local anesthetic agents. If successful preemptive analgesic
      techniques are developed, they will likely include the use of NSAIDs and perhaps
      NMDA antagonists. Nonopioids are of benefit in multimodal analgesia and allow
      acute rehabilitation of surgical patients. Acetaminophen, NSAIDs, alpha 2
      antagonists, and NMDA antagonists are in routine use as components of multimodal
      analgesia, in combination with opioids or local anesthetic techniques. Tramadol
      is interesting because it has nonopioid and opioid actions that can be attributed
      to the two isomers found in the racemic mixture. Spinal neostigmine and the use
      of adenosine represent completely different mechanisms of nonopioid analgesia
      being investigated. Nonopioids, including lidocaine, ketamine, the
      anticonvulsants, and the antidepressants, are necessary for the treatment of
      patients with the difficult clinical problem of neuropathic pain that can present
      in the postoperative period.

PMID- 10352656
TI  - Patient-controlled analgesia.
AB  - In appropriately selected patients, PCA safely provides analgesia superior to
      that obtained with traditional IM prn opioid administration; however, to date, no
      compelling evidence shows that PCA is associated with a reduction in morbidity or
      a more rapid recovery. PCA is deceptively easy to prescribe; however, to use it
      effectively and safely requires experience, frequent patient assessment, and a
      skilled and knowledgeable nursing staff.

PMID- 10352657
TI  - Epidural and spinal agents for postoperative analgesia.
AB  - The discovery of opioid receptors and the subsequent development of the technique
      of epidural and intrathecal opioid administration are undoubtedly two of the most
      significant advances in pain management in recent decades. The use of spinal
      opioids is widespread and increasing. The technique is used widely to treat
      intraoperative, postoperative, traumatic, obstetric, chronic, and cancer pain.
      Newer developments include the increasing use of combined local anesthetics and
      opioids or nonopioids and also PCEA, particularly in the obstetric population.
      Meta-analysis of controlled trials has demonstrated improved pulmonary outcome in
      patients receiving epidural postoperative analgesia. Although rare, respiratory
      depression continues to be a major problem of the technique. None of the
      currently available opioids is completely safe; however, extensive international
      experience has shown that patients receiving spinal opioids for postoperative
      analgesia can be safely nursed on regular wards, provided that trained personnel
      and appropriate guidelines are available. The importance of a good acute pain
      service to provide the safe and effective use of spinal opioids cannot be
      overemphasized.

PMID- 10352658
TI  - Local and regional block in postoperative pain control.
AB  - Local and regional block provides an effective means for the control of
      postoperative pain. In surgery involving the trunk, it serves as a useful
      alternative to epidural analgesia. With the increasing use of low molecular
      weight heparin, the use of peripheral nerve block is increasingly popular for
      patients undergoing lower limb surgery.

PMID- 10352659
TI  - Management of pain in intensive care settings.
AB  - An organized treatment plan for providing analgesia in ICU settings can make a
      significant difference in patient comfort and outcome. Advanced analgesic
      techniques are available for use at each level of the "pain pathway." These
      include agents and methods that act at the periphery, at the spinal cord level,
      and through a systemic approach. Consultation with specialists in pain management
      can help achieve optimum therapy for patients in the ICU setting.

PMID- 10352660
TI  - Pain management in cardiothoracic practice.
AB  - All analgesia regimens have benefits and side effects, and personal expertise can
      greatly influence the efficacy of regional techniques. A multimodal approach to
      analgesic management allows physicians to achieve maximum analgesic efficacy
      while limiting side effects. An appropriate analgesic plan takes into account the
      extent of pain associated with the type of incision and adjusts this according to
      each patient's individual needs. As we enter the new millennium, thoracic and
      cardiac surgery is becoming more innovative, and the life expectancy of people in
      the first world is constantly increasing. Older people with less physiologic
      reserve and more multisystem dysfunction are undergoing more major surgical
      procedures, and adequate pain control in the postoperative period is becoming
      increasingly important.

PMID- 10352661
TI  - Postoperative pain control in ambulatory surgery.
AB  - Optimizing postoperative pain control is the key to further advancement in the
      field of ambulatory anesthesia. The current situation in postoperative pain
      management indicates room for improvement, especially in the area of patient
      education and the development of individualized discharge analgesic packages.
      Multimodal analgesia provides superior analgesia with a lower side-effect
      profile. Preoperative administration of analgesia would decrease the
      intraoperative analgesic requirement, which may lead to a smooth and rapid
      recovery. Finally, new, portable analgesic delivery systems are under
      investigation and may prove to be the method of choice for future postoperative
      pain, management in ambulatory anesthesia.

PMID- 10352662
TI  - Acute pain control and accelerated postoperative surgical recovery.
AB  - Postoperative pain relief continues to demand our awareness, and surgeons should
      be fully aware of the potential physiologic benefits of effective dynamic pain
      relief regimens and the great potential to improve postoperative outcome if such
      analgesia is used for rehabilitation. To achieve advantageous effects,
      accelerated multimodal postoperative recovery programs should be developed as a
      multidisciplinary effort, with integration of postoperative pain management into
      a postoperative rehabilitation program. This requires revision of traditional
      care programs, which should be adjusted according to recent knowledge within
      surgical pathophysiology. Such efforts must be expected to lead to improved
      quality of care for patients, with less pain and reduced morbidity leading to
      cost efficiency.

PMID- 10352663
TI  - The big book of aldehyde dehydrogenase sequences. An overview of the extended
      family.

PMID- 10352664
TI  - Reaction-chemistry-directed sequence alignment of aldehyde dehydrogenases.

PMID- 10352665
TI  - Three-dimensional structure of mitochondrial aldehyde dehydrogenase. Mechanistic
      implications.

PMID- 10352666
TI  - A structural explanation for the retinal specificity of class 1 ALDH enzymes.

PMID- 10352667
TI  - Structure and function of betaine aldehyde dehydrogenase. An enzyme within the
      multienzyme aldehyde dehydrogenase system.

PMID- 10352668
TI  - Evaluation of the roles of the conserved residues of aldehyde dehydrogenase.

PMID- 10352669
TI  - Aldehyde dehydrogenase catalytic mechanism. A proposal.

PMID- 10352670
TI  - Inhibition of human mitochondrial aldehyde dehydrogenase by metabolites of
      disulfiram and structural characterization of the enzyme adduct by HPLC-tandem
      mass spectrometry.

PMID- 10352671
TI  - Mechanism of inhibition of rat liver class 2 ALDH by 4-hydroxynonenal.

PMID- 10352672
TI  - Aldehyde inhibitors of aldehyde dehydrogenases.

PMID- 10352673
TI  - Covalent modification of sheep liver cytosolic aldehyde dehydrogenase by the
      oxidative addition of coloured phenoxazine, phenothiazine and phenazine
      derivatives.

PMID- 10352674
TI  - A thioester analogue of an amino acetylenic aldehyde is a suicide inhibitor of
      aldehyde dehydrogenase and an inducer of apoptosis in mouse lymphoid cells
      overexpressing the bcl2 gene.

PMID- 10352675
TI  - Reaction between sheep liver mitochondrial aldehyde dehydrogenase and a
      chromogenic 'reporter group' reagent.

PMID- 10352677
TI  - Alpha, beta-unsaturated aldehydes mediate inducible expression of glutathione S
      transferase in hepatoma cells through activation of the antioxidant response
      element (ARE).

PMID- 10352676
TI  - Activity of the human aldehyde dehydrogenase 2 promoter is influenced by the
      balance between activation by hepatocyte nuclear factor 4 and repression by
      perosixome proliferator activated receptor delta, chicken ovalbumin upstream
      promoter-transcription factor, and apolipoprotein regulatory protein-1.

PMID- 10352678
TI  - Effect of arachidonic acid alone or with prooxidant on aldehyde dehydrogenases in
      hepatoma cells.

PMID- 10352679
TI  - Prepubertal regulation of the rat dioxin-inducible aldehyde dehydrogenase
      (ALDH3).

PMID- 10352680
TI  - Effects of tamoxifen and toremifene on ALDH1 and ALDH3 in human retinal pigment
      epithelial cells and rat liver.

PMID- 10352681
TI  - Negative regulation of rat hepatic aldehyde dehydrogenase 3 by glucocorticoids.
AB  - The expression of the aldehyde dehydrogenase 3 gene is known to be controlled by
      multiple regulatory processes. In liver, inducible expression appears to be
      mediated by two AhRE sequences which allow regulation of this gene by xenobiotic
      compounds which are ligands for the Ah receptor (Takimoto et al., 1994; this
      work). Constitutive expression of ALDH3 in tissues such as the cornea also
      involves the -3,500 region which contains an AhRE (Boesch et al., 1996; Boesch et
      al, 1998). However, the constellation of transcription factors which appear to
      interact with the AhRE in constitutively expressing corneal cells does not
      include either the Ah receptor nor the prototypical ARNT protein (Boesch et al.,
      1998). For both inducible and constitutive ALDH3 expression the more distal 5'
      flanking region sequences appear to interact with more proximal regulatory
      elements. Of particular interest is the region near -1 kb which includes the GC (
      930 to -910) and cAMP (-1057 to -991) responsive elements as well as the 2 NF1
      sites (-916 to -815), all of which appear to act as negative modulators of ALDH3
      expression. A second putative ALDH3 negative regulatory region lies even more
      distal than -3,500 bp. To date, this region has been little studied, but appears
      to be involved in regulating both inducible and constitutive ALDH3 expression.
      This region may also be responsible for some of the tissue-specificity of ALDH3
      expression. With respect to the work described here, in both isolated hepatocytes
      and HepG2 cells, no consistent negative regulation by glucocorticoids was
      observed in the basal expression of ALDH3. This indicates that the mechanism of
      GC-mediated negative regulation involves direct interference with ALDH3 gene
      activation mediated by the Ah receptor. Our results suggest a complex interplay
      between multiple transcription factors, including the GC and Ah receptors,
      regulates the hepatic expression of the ALDH3 gene. Active recruitment of
      transcription factors needed for gene transactivation, amelioration of the
      actions of negative regulatory trans-acting factors or cis-acting elements and/or
      chromatin remodeling may be required for achieve proper regulation of the
      aldehyde dehydrogenase 3 gene.

PMID- 10352682
TI  - Modulation of class 3 aldehyde dehydrogenase gene expression. An eye opening
      experience.

PMID- 10352683
TI  - Susceptibility of hepatoma cells to lipid peroxidation and adaptation of ALDH 3C
      activity to iron-induced oxidative stress.

PMID- 10352684
TI  - The lack of AHD4 induction by TCDD in corneal cells may involve tissue-specific
      regulatory proteins.

PMID- 10352685
TI  - Human corneal and lens aldehyde dehydrogenases. Localization and function(s) of
      ocular ALDH1 and ALDH3 isozymes.

PMID- 10352686
TI  - The role of retinoid metabolism by alcohol and aldehyde dehydrogenases in
      differentiation of cultured neuronal cells.

PMID- 10352687
TI  - Metabolism of retinaldehyde by human liver and kidney.

PMID- 10352688
TI  - The hunt for a retinal-specific aldehyde dehydrogenase in sheep liver.

PMID- 10352689
TI  - Cardiac metabolism of enals.

PMID- 10352690
TI  - Oxidation of ethanol to acetaldehyde in brain and the possible behavioral
      consequences.

PMID- 10352691
TI  - Cloning and expression of a cDNA encoding a constitutively expressed rat liver
      cytosolic aldehyde dehydrogenase.

PMID- 10352692
TI  - The roles of acetaldehyde dehydrogenases in Saccharomyces cerevisiae.

PMID- 10352693
TI  - Characterization of an aldehyde dehydrogenase gene fragment from mung bean (Vigna
      radiata) using the polymerase chain reaction.

PMID- 10352694
TI  - Aldehyde dehydrogenase gene superfamily. The 1998 update.

PMID- 10352695
TI  - Human alcohol dehydrogenase family. Functional classification, ethanol/retinol
      metabolism, and medical implications.

PMID- 10352696
TI  - Dynamics in alcohol dehydrogenase elucidated from crystallographic
      investigations.

PMID- 10352697
TI  - Studies on variants of alcohol dehydrogenases and its domains.

PMID- 10352698
TI  - Uncompetitive inhibitors of alcohol dehydrogenases.

PMID- 10352699
TI  - Tandem mass spectrometry of alcohol dehydrogenase and related biomolecules.

PMID- 10352700
TI  - Function of alcohol dehydrogenase and aldehyde dehydrogenase gene families in
      retinoid signaling.

PMID- 10352701
TI  - Primary role of alcohol dehydrogenase pathway in acute ethanol-induced impairment
      of protein kinase C-dependent signaling system.

PMID- 10352702
TI  - Class II alcohol dehydrogenase. A suggested function in aldehyde reduction.

PMID- 10352703
TI  - Zinc binding characteristics of the synthetic peptide corresponding to the
      structural zinc site of horse liver alcohol dehydrogenase.

PMID- 10352704
TI  - Amphibian alcohol dehydrogenase. Purification and characterization of classes I
      and III from Rana perezi.

PMID- 10352705
TI  - Extracellular acidification: a novel detection system for ligand/receptor
      interactions. Demonstration with bioactive peptides and CHO or pancreatic beta
      cells, but of possible interest for tracing putative receptors in ethanol
      metabolism.

PMID- 10352706
TI  - Multiplicity and complexity of SDR and MDR enzymes.

PMID- 10352708
TI  - Bioinformatics in studies of SDR and MDR enzymes.

PMID- 10352707
TI  - Regulatory factors and motifs in SDR enzymes.

PMID- 10352709
TI  - The protective role of 11 beta-hydroxysteroid dehydrogenase/carbonyl reductase
      against tobacco-smoke related lung cancer.

PMID- 10352710
TI  - Structure-function relationships of 3 beta-hydroxysteroid dehydrogenases involved
      in bile acid metabolism.

PMID- 10352711
TI  - Cloning and sequencing of a new Comamonas testosteroni gene encoding 3 alpha
      hydroxysteroid dehydrogenase/carbonyl reductase.

PMID- 10352712
TI  - Comparative properties of three pteridine reductases.

PMID- 10352713
TI  - Effect of androgen structures on the inhibition of metyraponeinreductase in rat,
      mouse, and human liver.

PMID- 10352714
TI  - Physiological relevance of aldehyde reductase and aldose reductase gene
      expression.

PMID- 10352715
TI  - The aldo-keto reductases and their role in cancer.

PMID- 10352716
TI  - Structure-function studies of FR-1. A growth factor-inducible aldo-keto
      reductase.

PMID- 10352717
TI  - 4-Hydroxynonenal metabolism by aldo/keto reductase in hepatoma cells.

PMID- 10352718
TI  - Interconversion pathways of aldose reductase induced by thiol compounds.

PMID- 10352719
TI  - Aldo-keto reductases in norepinephrine metabolism.

PMID- 10352720
TI  - Rotamers of tolrestat and their binding mode to aldose reductase.

PMID- 10352721
TI  - Stereoselective high-affinity reduction of ketonic nortriptyline metabolites and
      of ketotifen by aldo-keto reductases from human liver.

PMID- 10352722
TI  - Formation of lens aldose reductase mixed disulfides with GSH by UV irradiation
      and its proteolysis by lens calpain.

PMID- 10352723
TI  - Inhibition of aldose reductase by gossypol and gossypol-related compounds.

PMID- 10352724
TI  - Inhibition of human aldose and aldehyde reductases by non-steroidal anti
      inflammatory drugs.

PMID- 10352725
TI  - Regulation of aldose reductase by aldehydes and nitric oxide.

PMID- 10352726
TI  - The cytotoxicity of methylglyoxal and 3-deoxyglucosone is decreased in the
      aldehyde reductase gene-transfected cells.

PMID- 10352727
TI  - Enzymes metabolizing aldehydes in HL-60 human leukemic cells.

PMID- 10352728
TI  - Rat carbonyl reductase. How many genes?

PMID- 10352729
TI  - Cytostatic drug resistance. Role of phase-I daunorubicin metabolism in cancer
      cells.

PMID- 10352730
TI  - Expression of mRNAs for dihydrodiol dehydrogenase isoforms in human tissues.

PMID- 10352731
TI  - Alterations in the expression of daunorubicin phase-I metabolising enzymes in
      different carcinoma cell lines.

PMID- 10352732
TI  - Laparoscopic training: results of a Belgian survey in trainees. Belgian Group for
      Endoscopic Surgery (BGES).
AB  - The assurance of adequate training in laparoscopic surgery still is a significant
      problem. This report aims to provide data and to formulate suggestions, based on
      the results of a questionnaire completed by 53 trainees, on a literature review
      and on discussions within the committee on training of the Belgian Group for
      Endoscopic Surgery (BGES). About 2/3 trainees think that their theoretical
      competence in laparoscopy is satisfactory or excellent. In contrast, 2/3 consider
      that their practical training is inadequate; only 53% of the sixth year trainees
      felt confident about their practical competence. The vast majority (72%) of
      senior trainees (5th and 6th year) performed less than 50 laparoscopic
      cholecystectomies or appendicectomies as first surgeon. Very few of them had the
      opportunity to perform advanced procedures, e.g. fundoplication or colon
      resection. Laparoscopic appendicectomy is the most common operation done by young
      trainees (3-4th year): 56% performed more than 10 procedures. In the majority of
      surgical centres, the trainee has few opportunities to perform supervised
      laparoscopic surgery because of the limited experience of the surgical staff, the
      learning curve of tutors, and the limited number of laparoscopic operations in
      some centres. Several solutions are proposed: training courses with laparoscopic
      procedures on animals, set up of quota (also for tutors), pelvi-trainer,
      recommended participation in theoretical courses (trainee session), more free
      time for attendance at scientific meetings and for reading surgical books and
      journals. Up to now, no formal process for certification of surgical competence
      in laparoscopy has been promoted. Moreover, not only the organisation and
      monitoring, but also the cost of training must be managed, and responsabilities
      must be taken by all persons and instances involved: teachers, teaching centres,
      professional board, government.

PMID- 10352733
TI  - Changing patterns in advanced gastric carcinoma.
AB  - A retrospective study on patients with gastric cancer during the periods 1984-88
      (n = 63 patients) and 1989-93 (n = 59 patients) was made. The aim of the study
      was to assess any changing patterns in tumour distribution, surgical management
      and survival during the two periods. When the diagnosis was made, the majority of
      tumours were advanced: 58 were stage IV and 21 were stage IIIB, with 43 tumours
      at earlier stages. The incidence of proximally located gastric adenocarcinomas
      increased from 15.9 to 27.1%, while the incidence of carcinomas located in the
      body decreased from 34.9 to 23.7%. The majority of patients underwent
      conservative gastrectomy. The proportion of proximal gastrectomies increased from
      3.2 to 15.3 per cent (p = 0.02), whereas the proportion of combined resection of
      adjacent organs decreased from 38.1 to 22.0 per cent (p = 0.04). Perioperative
      mortality rate decreased from 17.5 to 1.7 per cent (p = 0.003). Prognosis
      remained unchanged in the two periods; overall 5-year survival is calculated as
      12 per cent.

PMID- 10352734
TI  - Cost-benefit analysis of endovascular versus open abdominal aortic aneurysm
      treatment.
AB  - OBJECTIVE: To compare the costs and benefits of open versus endovascular repair
      of abdominal aortic aneurysm (AAA). METHODS: A consecutive series of 29 elective
      patients (open treatment, N = 20 and endovascular treatment, N = 9) were compared
      retrospectively. RESULTS: Operating time was significantly shorter for
      endovascular treatment (mean 90 vs. 125 min, p = 0.026). No endovascular
      procedure was converted to open surgery; one early endoleak was seen which sealed
      spontaneously. Endovascular treatment resulted in a shorter ICU and hospital stay
      (0 days vs. 2 days, p. 0.001 and 5 days vs. 11 days, p = 0.01 respectively). Mean
      total cost did not differ 361,938 BEF (9,048 Euro) vs. 382,995 BEF (9,575 Euro),
      p = 0.46. Endovascular treatment generated significantly less hospitalization
      costs (73,162 BEF or 1,829 Euro vs. 18,2740 BEF or 4,568 Euro, p = 0.001) but
      required a more expensive implant (153,293 BEF or 3,832 Euro vs. 38,296 BEF or
      957 Euro, p = 0.001). Mean total cost for the patient was significantly higher in
      the endovascular treatment group (66,309 BEF or 1,658 Euro vs. 24,969 BEF or 624
      Euro, p = 0.003). CONCLUSION: Our experience confirms the feasibility and safety
      of endovascular AAA treatment. It is associated with a shorter ICU and hospital
      stay and less morbidity. Overall cost for society does not differ significantly
      as the benefit, of lower hospitalization costs is undone by the high cost of the
      endovascular graft.

PMID- 10352735
TI  - Results of distal revascularization in elderly patients for critical ischemia of
      the lower limbs.
AB  - Thirty eight patients over 75 years of age were operated upon of 40 distal
      arterial revascularizations for critical ischaemia of the lower limbs. Arterial
      reconstruction was proposed to ambulatory, self sufficient patients, with a
      patent artery of the leg or the foot in continuity with pedal arch, at
      arteriography. The revascularized artery was the peroneal in 14 cases, the
      anterior tibial in 11, the posterior tibial in 9, the dorsalis pedis in 5, and
      the external plantar artery in 1 case. Postoperative mortality was 2.6%. No
      postoperative arterial occlusion occurred and no postoperative amputation needed
      to be performed. The mean follow-up of 37 patients surviving operation was 21
      months (ext. 2-52 months). At 36 months interval, patients' survival was 43%,
      primary patency rate was 57%, and limb salvage rate was 76%, at life-table
      analysis. Distal revascularization enables a good number of elderly patients in
      critical ischaemia of the lower limb, to enjoy an active, independent life, with
      a viable limb.

PMID- 10352736
TI  - Effects of L-thyroxine and zinc therapy on wound healing in hypothyroid rats.
AB  - Unfavourable effects of hypothyroidism and zinc deficiency on wound healing are
      well known. This experimental study was conducted on rats to evaluate the effects
      of hormone replacement and zinc supplement on wound healing. A total of 50 rats
      were divided into 5 groups of 10 rats as follows: Control group (A), a
      hypothyroidism group (B), a L-thyroxine receiving hypothyroidism group (C), a
      zinc receiving hypothyroidism group (D), and a L-thyroxine plus zinc receiving
      hypothyroidism group (E). In order to develop hypothyroidism, 5-propyl 2
      thiouracil had been given intraperitoneally for a period of 21 days to all groups
      except the control group. A laparotomy with a 4 cm median incision was performed
      in all rats. The first half of the rats was sacrificed on the 7th day and the
      remaining on the 14th day. Breaking strength, hydroxyproline concentrations in
      the healing scar tissue and blood serum zinc levels were measured. Although both
      values--breaking strength and hydroxyproline levels--, compared to all others,
      were found to be higher in the L-thyroxine plus zinc receiving group (group E) on
      the 7th day, differences among the groups were not statistically significant.
      However, on the 14th day, these differences were found to be significant. We
      conclude that the hormone replacement therapy in hypothyroidism cases was
      beneficial with regard to wound healing and the results were more satisfactory if
      zinc was added to the therapy.

PMID- 10352737
TI  - Granulocytic sarcoma (chloroma) of the small intestine.
AB  - Granulocytic sarcoma or Chloroma may develop before, at the time or after
      presentation of acute myeloid leukemia. We report the case of a 66-year old man
      presenting with intermittent abdominal pain during one month before developing a
      peritonitis due to perforation of small bowel followed by irreversible shock and
      death. Nearly the entire length of small bowel and bone marrow were infiltrated
      by giant promyelocytic cells. Abnormal circulating cells were never discovered.
      The literature is briefly reviewed.

PMID- 10352738
TI  - Frantz's tumour of the pancreas presenting as a post-traumatic pancreatic
      pseudocyst.
AB  - A case of a solid, pseudopapillary and cystic tumour of the pancreas in a 13-year
      old girl was presented. Shortly after a blunt abdominal trauma, an abdominal mass
      became manifest. Clinical features and radiological findings suggested a
      traumatic pseudocyst of the pancreas. Laparotomy and pathology revealed a
      Frantz's tumour, which was totally resected. Twelve months after surgery the
      patient is asymptomatic and CT-scan shows no signs of recurrence or metastasis.
      To our knowledge, no such acute presentation has ever been described in the
      literature since the first clinical report of this tumour in 1959.

PMID- 10352739
TI  - Rupture of the spleen associated with Enterobacter cloacae.
AB  - A 58-year-old male, with abdominal pain but no signs of sepsis, was admitted as a
      medical emergency. During hospitalization, spontaneous splenic rupture was
      diagnosed and splenectomy successfully performed. A smear revealed presence of
      Enterobacter cloacae on the splenic surface; histopathology demonstrated
      granulocytous infiltration of the spleen.

PMID- 10352740
TI  - Cystic dystrophy in heterotopic pancreas of the duodenal wall: medical and
      surgical treatment.
AB  - A patient with cystic dystrophy in heterotopic pancreatic tissue, localized in
      the second duodenum, is described. Diagnosis was assessed by computed tomography,
      endosonography and magnetic nuclear resonance (MNR). Medical treatment with
      octreotid during three weeks was effective but duodenal stenosis persisted.
      Finally, pylorus preserving pancreaticoduodenectomy was performed. Microscopy
      examination confirmed the diagnosis and the efficiency of medical treatment. A
      review of the literature about cystic dystrophy is done.

PMID- 10352741
TI  - Combined surgical and medical approach to intravenous leiomyomatosis with cardiac
      extension.
AB  - Intravenous leiomyomatosis with cardiac extension is a rare entity. The case of a
      49-year-old patient is described: she was operated on for intracaval intra-atrial
      leiomyomatosis. After an incomplete procedure (the tumour appeared not totally
      resectable), the patient was treated for a period of three years with a GnRH
      analogue, whereafter the patient was doing clinically well and the tumour,
      although it regained some growth, was in a stable situation. This new strategy
      seems of certain importance to the surgeon, as it carries an alternative to a
      high-risk reoperation. To our knowledge, this is the first description of such a
      combined therapeutical approach.

PMID- 10352742
TI  - Surgical management of intramedullary hemangioblastoma of the spinal cord.
AB  - This is a study on 19 patients, who underwent complete excision of an
      intramedullary hemangioblastoma of the spinal cord during the period 1984-1997.
      The study was conducted to evaluate their functional outcome. Some peculiarities
      of their clinical presentation and surgical treatment are discussed as well.
      There were 12 males and 7 females whose age ranged from 16 to 69 years. Five of 6
      patients were affected by Lindau's disease had multiple intramedullary tumors.
      The length of their history averaged 22.6 months. While pain was the most common
      complaint at presentation, 12 out of 19 patients had progressive sensorimotor
      deficits. A total of 22 operation was performed. One patient underwent resection
      of a minute tumor residue a few months after the first operation. In 2 patients
      with multiple tumors a second tumor, which became clinically relevant, was
      resected 17 and 36 months after the first operation. There was no mortality. One
      patients developed a wound infection which required secondary closure. The
      functional status of the patients registered at discharge was worse in 22.7%,
      unchanged in 59.1%, and improved in 18.2% of the patients. At follow-up (6-142
      months), the status of 9.1% of the patients was still worse, in 50% was unchanged
      and in 40.9% better than the preoperative one. All but one patients had complete
      postoperative pain relief. The data support the concept that radical excision of
      intramedullary hemangioblastomas can be achieved at low levels of surgical
      mortality and morbidity. Symptomatic patients should undergo surgery before they
      develop extensive sensorimotor deficits. In patients with multiple lesions,
      tumors distant from the symptomatic one should not be tackled.

PMID- 10352743
TI  - Surgical outcome of intramedullary spinal cord ependymoma.
AB  - Surgical outcome of intramedullary spinal cord ependymoma was investigated in
      order to define the treatment strategy. We have operated on 18 cases of
      intramedullary spinal cord ependymoma based on the principle of radical
      resection. The follow-up periods ranged from 10 months to 249 months with an
      average of 86.2 months. Postoperative neurological status in the long follow-up
      periods was compared to the pre-operative status and was correlated with the
      histological grade of malignancy. Total removal of the tumour was achieved in 17
      cases, and subtotal removal followed by radiation therapy was conducted in 1
      case. There was neither surgical mortality nor radiological evidence of
      recurrence in the long-term follow-up periods. The final outcome of the
      neurological condition was improved in 1 case, unchanged in 15 cases (including a
      case of subtotal removal) and deteriorated in 2 cases. The deterioration was in
      the form of gait disturbance due to the worsening of proprioception in 2 cases
      and dysaethesia in 1 case. Histological examination showed no evidence of
      anaplasia in 6 cases, evidence of early anaplasia in 10 cases, and moderate
      evidence of anaplasia in 2 cases. No relationship between the histological
      malignancy and clinical course was found. Intramedullary spinal cord ependymoma
      should be removed radically as early as possible while taking great care to avoid
      posterior column injury. Histologically malignant ependymoma might be a clinical
      exception.

PMID- 10352744
TI  - Comparison of two types of surgery for thoraco-lumbar burst fractures: combined
      anterior and posterior stabilisation vs. posterior instrumentation only.
AB  - This retrospective study compares clinical outcome following two different types
      of surgery for thoracolumbar burst fractures. Forty-six patients with
      thoracolumbar burst fractures causing encroachment of the spinal canal greater
      than 50% were operated on within 30 days performing either: combined anterior
      decompression and stabilisation and posterior stabilisation (Group 1) or
      posterior distraction and stabilisation using pedicle instrumentation (AO
      internal fixator) (Group 2). We evaluated: neurological status (Frankel Grade),
      spinal deformities, residual pain, and complications. The average follow-up was 6
      years. There were no significant differences between the patients in both groups
      concerning age, sex, cause of injury and the presence of other severe injuries.
      Neurological dysfunction was present in 39% of all cases. Bony union occurred in
      all patients. Loss of reduction greater than 5 degrees and instrumentation
      failure occurred significantly more often in Group 2 compared to Group 1, but the
      kyphosis angle at late follow-up did not differ between groups, due to some
      degree of overcorrection initially after surgery in Group 2. The clinical outcome
      was similar in both groups, and all but one patient with neurological deficits
      improved by at least one Frankel grade. Indirect decompression of the spinal
      canal by posterior distraction and short-segment stabilisation with AO internal
      fixator is considered appropriate treatment for the majority of unstable
      thoracolumbar burst fractures. This is a less extensive surgical procedure than a
      combined anterior and posterior approach.

PMID- 10352745
TI  - Interdisciplinary management results in 100 patients with ruptured and unruptured
      posterior circulation aneurysms.
AB  - The authors report on a series of 100 posterior circulation aneurysms managed by
      surgical and endovascular procedures. The series consisted of 41 elective
      admissions more than 14 days after SAH or for unruptured aneurysms and 59 acute
      admissions after subarachnoid haemorrhage (SAH). In this first interdisciplinary
      series after the introduction of electrolytically detachable coils, surgical
      clipping was maintained as treatment of choice in good grade patients while
      endovascular therapy was primarily offered for patients in poor clinical grade or
      if the aneurysm was judged difficult to be accessed surgically. A total of 70
      patients underwent aneurysm elimination, 54 surgically and 16 by the endovascular
      route. In 30 patients the aneurysm was not treated, either because of persisting
      grade 5 WFNS after SAH or because the risk of treatment appeared excessive with
      some complex unruptured aneurysms. A complication leading to permanent morbidity
      or mortality occurred after 5 surgical and 1 endovascular procedure (8.6%).
      Regarding overall management results after acute SAH, 14 of the total of 59
      patients admitted with acute SAH died, corresponding to a management mortality of
      24%. Although the present series cannot provide statistically firm conclusions,
      the authors believe from the actual experience and the accumulating literature,
      that the principal complementary aspect of the two treatment modalities is
      aneurysm location. Size and shape do not appear to be a primary factor to favour
      one or the other modality. The hope that endovascular therapy improves the
      prognosis of poor grade patients with posterior circulation aneurysms probably
      has been overstated. The good results of endovascular treatment with small narrow
      necked aneurysms on proximal arteries of the posterior circulation, as seen in
      the present series and as reported in the accumulating literature, suggest that
      in future surgical and endovascular treatment should be considered as
      alternatives in these special cases while in large and broad-necked aneurysms
      surgery should be considered first.

PMID- 10352746
TI  - Effects of bypass on CO2 cerebrovascular reactivity in ischaemic cerebrovascular
      diseases--based on the intra-operative LCBF and CO2 cerebrovascular reactivity
      studies.
AB  - The authors evaluated the effects of superficial temporal to middle cerebral
      artery (STA-MCA) bypass on CO2 cerebrovascular reactivity (CVR) in ischaemic
      cerebrovascular diseases (CVDs). Local cerebral blood flow (LCBF) and CO2 CVR in
      19 patients with ischaemic CVD subjected to standard STA-MCA bypasses were
      examined during surgery. Single photon emission computed tomography (SPECT) with
      acetazolamide (ACZ) activation was also performed before and at 1 month after
      surgery. The results are as follows. 1) Before bypass, the average CO2 CVR value
      was -1.50 +/- 2.30%/mmHg (mean +/- SD). SPECT showed disturbed response to ACZ in
      all cases. Fifteen cases showed the steal phenomenon. After bypass, the mean CO2
      CVR value significantly (p < 0.05) increased, and four cases resolved their steal
      phenomenon. 2) Before bypass, the mean LCBF was significantly (p < 0.05) lower
      than the control level. After bypass, the mean LCBF significantly (p < 0.05)
      increased. 3) In the postoperative SPECT findings, 13 cases showed a disturbed
      response to ACZ. The CO2 CVR value in these 13 cases was -1.21 +/- 1.19%/mmHg,
      which was significantly (p < 0.05) low compared to the values for the 6 cases
      showing normal postoperative ACZ responses. In ischaemic CVDs before bypass, the
      CO2 CVR values were extremely low. After bypass, however, CO2 CVR and LCBF values
      significantly improved. SPECT findings, including ACZ challenge, correlated well
      to the LCBF and CO2 CVR values. STA-MCA by pass exerted a favourable effect on
      the CO2 CVR and LCBF values immediately after bypass in the cases showing a
      reduced pre-operative response to CO2.

PMID- 10352747
TI  - Efficacy of direct revascularization in adult Moyamoya disease: haemodynamic
      evaluation by positron emission tomography.
AB  - To evaluate the efficacy of direct cerebrovascular reconstruction to prevent
      intracranial bleeding from the point of view of haemodynamic status, we performed
      positron emission tomography (PET) studies in 5 adult patients with Moyamoya
      disease before and after superficial temporal artery to middle cerebral artery
      (STA-MCA) anastomosis. Regional cerebral blood flow (rCBF), regional cerebral
      metabolic rate of oxygen (rCMRO2) and regional oxygen extraction fraction (rOEF)
      in the MCA territories and regional cerebral blood volume (rCBV) in the striatum
      were measured before and after STA-MCA anastomosis. Correlation between the
      change of these PET parameters and post-operative decreased opacification of
      Moyamoya vessels were analyzed. Pre-operatively, significant elevation of rCBV
      were observed in the basal ganglia as well as significant reduction of rCBF and
      elevation of rOEF with reduction of rCMRO2 in the MCA territories, indicating
      "misery" perfusion in the cerebral hemisphere and blood pooling in the Moyamoya
      vessels under increased haemodynamic stress. Post-operative PET study showed
      improvement of misery perfusion and reduction of rCBV in the basal ganglia.
      Reduction of rCBV in the basal ganglia generally compatible with decreasing
      Moyamoya vessels on angiographic findings. Our results suggests that direct
      bypass surgery could have a potential both for decreasing haemodynamic stress on
      Moyamoya vessels and to improve misery perfusion in the hemisphere.

PMID- 10352748
TI  - The factors influencing haematoma volume due to arteriovenous malformations.
AB  - Haemorrhage due to cerebral arteriovenous malformations (AVMs) varies from
      massive, requiring urgent operations, to clinically silent. The present study was
      designated to identify factors influencing haematoma size, and the
      pathophysiological mechanisms of massive haemorrhage were studied. 55 patients
      with intracerebral haematomas due to supratentorial AVMs were included in this
      study. Angiographic and clinical findings were retrospectively evaluated in
      relation to haematoma size. Statistical analysis demonstrated that small size and
      the presence of only one draining vein were high risk factors for massive
      haemorrhage. The haematoma volume in small AVMs (30 +/- 4 cm3) was significantly
      larger than in other AVMs (7 +/- 3 cm3) (p = 0.0005). AVMs with only one draining
      vein were associated with massive haematoma volume as compared to AVMs with two
      or more draining veins (30 +/- 4 versus 11 +/- 3 cm3, p = 0.0023). Our previous
      study demonstrated that feeding artery pressure (FAP) was significantly higher in
      AVMs with haemorrhage than in those without, as was draining vein pressure (DVP),
      and FAP and DVP were inversely related to the number of draining veins and the
      size of the AVMs. Thus, in small AVMs and AVMs with only one draining vein, local
      increase in DVP may thus contribute to massive haemorrhage.

PMID- 10352749
TI  - Non-neoplastic cystic lesions of the sellar region presentation, diagnosis and
      management of eight cases and review of the literature.
AB  - The differential diagnosis of a sellar lesion includes pituitary adenoma, cranio
      pharyngioma, tumour cyst, benign cyst, and other less common lesions such as
      aneurysm, squamous cell carcinoma and metastases. Pure cystic lesions within the
      sella turcica are not uncommon and may appear clinically and radiologically as
      pituitary adenoma. Intrasellar cysts are broadly classified as neoplastic or non
      neoplastic; the latter may be primary lesions of the pituitary fossa or they may
      arise from the parasellar region and invade into the sella. The lesions occupy
      space and may cause disturbance of pituitary function; if they extend into the
      suprasellar region they can affect visual fields and acuity. Non-neoplastic
      cystic lesions usually appear well defined radiologically and have distinct
      pathological features. Modern imaging modalities, such as computed axial
      tomography and magnetic resonance imaging, are important complementary tools of
      investigation for reaching a differential diagnosis, and for surgical planning.
      Most non-neoplastic sellar cysts can be approached through the trans-sphenoidal
      route, but large lesions with suprasellar extension may require transcranial
      surgery. We report the presentation and management of eight cases (four males,
      four females, all adult) of non-neoplastic cyst involving the sella turcica and
      the parasellar region. Investigations included computed tomography scan of the
      head for all and magnetic resonance imaging for six (75%) patients. Work-up
      included endocrinological and opthalmological evaluations. All presented with
      headache; six (75%) had visual acuity change, two (25%) had evidence of visual
      field defects, four (50%) had optic atrophy on fundoscopy, three (37.5%) had
      endocrine symptoms and hormone reduction was found in four (50%).

PMID- 10352750
TI  - Does octreotide treatment improve the surgical results of macro-adenomas in
      acromegaly? A randomized study.
AB  - It is not clear whether the pre-operative treatment of GH-secreting pituitary
      adenomas with Octreotide improves the surgical remission rates of acromegaly. In
      a prospective controlled study the results of transsphenoidal surgery in newly
      diagnosed GH-secreting macro-adenomas were compared in patients with (n = 11,
      group A) and without (n = 13, group B) preoperative Octreotide treatment. During
      the treatment with a daily dosage of 470 +/- 160 micrograms Octreotide for 16.5
      +/- 10 weeks, the GH- and IGF-1-values of group A dropped significantly from 38.9
      +/- 34.1 to 6.8 +/- 4.9 micrograms/l and from 2.7 +/- 1 to 1.7 +/- 0.7 arbitrary
      units respectively. The adenoma-shrinkage from 5.9 +/- 5.8 to 4.7 +/- 4.9 cm3
      missed statistical significance by little. There was no statistically significant
      difference between the postoperative acromegaly remission rates of 55% in group A
      and 69% in group B. Of the adenomas that postoperatively were not in remission,
      80% in group A and 75% in group B disclosed an infiltrative growth pattern not
      influenced by the Octreotide pretreatment. All other patients not cured presented
      with initial GH-values of > 50 micrograms/l. There was no statistically
      significant difference between the postoperative anterior pituitary function in
      the two patient groups. In this study Octreotide was not beneficial in improving
      the results of GH-secreting pituitary macro-adenoma surgery. However, larger
      prospective controlled studies are needed to address this issue.

PMID- 10352751
TI  - The chronic cell death with DNA fragmentation after post-ischaemic hypothermia in
      the gerbil hippocampus.
AB  - The long-term effects of post-ischaemic hypothermia are controversial. The
      purpose of this study was to examine the long-term effects of post-ischaemic
      hypothermia on neuronal survival in gerbils in terms of morphology and function.
      Hypothermia was induced at 32 degrees C for 4 h immediately after ischaemia.
      Examination was performed at 1 week and at 1 month after ischaemia. Post
      ischaemic hypothermia prevented CA1 neuronal damage 1 week after ischaemia. At 1
      month after ischaemic insult, however, the degree of the protective effect of
      post-ischaemic hypothermia was reduced in the lateral and medial CA1 areas. DNA
      fragmentation was also observed at 1 month. The errors in the 8-arm radial maze
      trial were increased at 1 month. These data may indicate that cells in the CA1
      area are very vulnerable to ischaemia and die after post-ischaemic hypothermia,
      and that their death is associated with apoptosis.

PMID- 10352753
TI  - Transsphenoidal microsurgical selective removal of multiple (triple) adenomas of
      the pituitary gland.
AB  - This is the first case of multiple (triple) pituitary micro-adenomas documented
      by magnetic resonance imaging (MRI) in a living patient and treated by a
      transsphenoidal microsurgical approach. The patient, a 37-year-old woman,
      complained of a long history of bifrontal headache, weight gain and
      oligomenorrhea. Physical examination revealed moderate hirsutism and a slight fat
      pad overlying the vertebrae. Routine laboratory studies and endocrinological
      biochemical investigations were normal. A gadolinium-enhanced MRI of the
      pituitary region revealed three intrapituitary micro-adenomas. A transsphenoidal
      microsurgical approach to the pituitary gland was carried out and micro-adenomas
      were completely removed one at a time. One year follow-up showed complete
      resolution of clinical symptoms and signs and normal biochemical parameters of
      pituitary function.

PMID- 10352752
TI  - Related changes in sympathetic activity, cerebral blood flow and intracranial
      pressure, and effect of an alpha-blocker in experimental subarachnoid
      haemorrhage.
AB  - We investigated the changes in sympathetic nerve activity (SNA) and cerebral
      blood flow (CBF) with or without increase in intracranial pressure (ICP) in the
      acute stage of experimental subarachnoid haemorrhage (SAH). ICP was increased or
      controlled by rapid or slow injection of blood and saline, and the effect of an
      alpha-blocker, phentolamine, was also investigated in each condition. Following
      marked increase in ICP induced by rapid injection of blood or saline, increase in
      intracranial and general SNA and decrease in CBF were observed. Both changes were
      significantly decreased in magnitude by prior administration of phentolamine.
      When increase in ICP was not induced, by slow injection of blood, both SNA and
      CBF decreased, and these changes were alleviated by phentolamine. However, when
      increase in ICP was not induced by saline, neither SNA nor CBF significantly
      changed. These findings suggest that marked increase in ICP is the primary cause
      of the pathological changes occurring immediately after SAH, and that the
      decrease in CBF in mild SAH without increase in ICP is caused by blood itself.
      Administration of an alpha-blocker may be effective in improving the abnormal
      sympathetic nervous system induced by marked increase in ICP.

PMID- 10352754
TI  - Dumbbell-shaped trigeminal neurinoma in a child.
AB  - We experienced a case of solitary trigeminal neurinoma in a 10-year-old boy
      without stigmata of neurofibromatosis. This boy presented with progressive
      cerebellar ataxia, right abducens palsy and right hemiparesis. Magnetic resonance
      images (MRI) demonstrated a tumour extending into both the middle and posterior
      fossas forming a dumbbell-shaped mass lesion with a size of 35 x 30 x 45 mm. The
      tumour was successfully removed free of complications by a two-stage operation
      composed of right subtemporal and suboccipital retromastoid approaches. It is
      extremely rare for a solitary neurinoma to occur at this site in a child without
      neurofibromatosis. Surgical approaches in this type of tumour are discussed with
      a review of the literature.

PMID- 10352755
TI  - Immediate grafting of the damaged obturator nerve by gynaecological surgery.

PMID- 10352756
TI  - Trigeminal neuralgia caused by compression from petrosal vein transfixing the
      nerve.

PMID- 10352757
TI  - Herpesvirus-6 (HHV-6) encephalitis in a child presenting as a focal necrotic
      lesion.

PMID- 10352758
TI  - On the role of PGD2 metabolites as markers of mast cell activation in asthma.
AB  - Prostaglandin D2 (PGD2) is the major cyclooxygenase metabolite of arachidonic
      acid released after stimulation of mast cells. Quantification of metabolites of
      PGD2 can be used as an objective indices of PGD2 production and hence mast cell
      activation in vivo. The aim of this thesis was to investigate the feasibility of
      measuring the primary urinary metabolite of PGD2, 9 alpha,11 beta-PGF2 with
      enzyme immunoassay (EIA). Measurements of 9 alpha,11 beta-PGF2 in urine made by
      EIA were compared with values obtained by negative ion chemical ionisation gas
      chromatography-mass spectrometry (NCI GC-MS), the gold standard method. Levels of
      9 alpha,11 beta-PGF2, in urine samples measured by NCI GC-MS were consistently
      lower than those obtained by EIA. NCI GC-MS analysis revealed the presence of two
      additional dinor compounds, shorter metabolites of 9 alpha,11 beta-PGF2 in the
      urine. One of the compounds was identical to 9 alpha,11 beta-2,3-dinor-PGF2 which
      was generated by beta-oxidation of 9 alpha,11 beta-PGF2 and identified by
      electron impact (EI GC-MS). Thus, urinary 9 alpha,11 beta-PGF2 concentrations
      measured by EIA represent the sum of three PGD2 metabolites. For convenience
      sake, the metabolites are collectively referred to as 9 alpha,11 beta-PGF2 in the
      subsequent studies. A 3-fold increase in the urinary excretion of 9 alpha,11 beta
      PGF2 was documented after allergen-induced bronchoconstriction in nine atopic
      asthmatics. This challenge was considered a positive control since it is
      unambiguous that mast cell activation occurs during the early phase of allergen
      induced airway obstruction. Histamine-induced bronchoconstriction did not result
      in an increase in the levels of 9 alpha,11 beta-PGF2 demonstrating that PGD2 was
      not formed as a consequence of the bronchoconstriction per se. Moreover,
      bronchial challenge with lysine-aspirin in eight aspirin-intolerant asthmatics
      elicited bronchoconstriction and was accompanied by a significant increase in the
      urinary excretion of 9 alpha,11 beta-PGF2. Challenge with a higher dose of
      aspirin produced an even greater increase in 9 alpha,11 beta-PGF2 levels,
      indicating a dose-dependent release of PGD2 during aspirin-induced
      bronchoconstriction. The pattern of mediator release during the early (EAR) and
      late asthmatic response (LAR) to allergen was investigated by subjecting twelve
      mild atopic asthmatics to allergen challenge. Within one hour of the maximal
      bronchoconstrictor response, there was a significant increase in the urinary
      concentrations of the mast cell markers, 9 alpha,11 beta-PGF2 and N tau
      methylhistamine, urinary metabolite of histamine, and the end product of the
      cysteinyl-leukotrienes, leukotriene (LT)E4. Levels of all three mediators were
      also significantly elevated above baseline during the LAR. Urinary levels of
      eosinophil protein X (EPX), a marker of eosinophil activation, remained unaltered
      during both the EAR and LAR. Preliminary evidence suggests a diurnal variation in
      the urinary excretion of EPX. Increased airway fluid osmolarity in the lower
      airways as a result of exercise, has been suggested to trigger mast cell
      activation and subsequent bronchoconstriction in a subset of asthmatics. Twelve
      subjects with a history of exercise-induced bronchoconstriction (EIB), exercised
      on a stationary bicycle ergometer for 5 minutes. Seven of the subjects
      (responders) experienced bronchoconstriction, whereas, the pulmonary function of
      the remaining five subjects (non-responders) remained stable. The urinary
      excretion of 9 alpha,11 beta-PGF2 in the responder group increased significantly
      compared to the non-responders at 30 and 90 minutes after exercise. The urinary
      excretion of LTE4 and N tau-methylhistamine was not significantly different
      between the two groups at either time point after exercise, although there was a
      tendency for elevated levels of N tau-methylhistamine in the responder group.
      (ABSTRACT TRUNCATED)

PMID- 10352759
TI  - Supplements.

PMID- 10352760
TI  - The natural history of acute, isolated, nonoperatively treated posterior cruciate
      ligament injuries. A prospective study.
AB  - We sought to determine prospectively the natural history of acute, isolated,
      nonoperatively treated posterior cruciate ligament injuries in athletically
      active patients. The study population consisted of 133 patients (average age,
      25.2 years at time of injury). All patients completed a subjective questionnaire
      each year for an average of 5.4 years (range, 2.3 to 11.4). Sixty-eight of the
      133 patients returned to the clinic for long-term follow-up evaluation.
      Objectively, physical examination revealed no change in laxity from initial
      injury to follow-up. No correlation was found between radiographic joint space
      narrowing and grade of laxity. The mean modified Noyes knee score was 84.2
      points, the mean Lysholm score was 83.4, and the mean Tegner activity score was
      5.7. Patients with greater laxity did not have worse subjective scores. No
      correlation was found between subjective knee scores and time from injury.
      Regardless of the amount of laxity, half of the patients returned to the same
      sport at the same or higher level, one-third returned to the same sport at a
      lower level, and one-sixth did not return to the same sport. Results of this
      study suggest that athletically active patients with acute isolated posterior
      cruciate ligament tears treated nonoperatively achieved a level of objective and
      subjective knee function that was independent of the grade of laxity.

PMID- 10352761
TI  - Evaluation of the single-incision arthroscopic technique for anterior cruciate
      ligament replacement. A study of tibial tunnel placement, intraoperative graft
      tension, and stability.
AB  - The tension in an anterior cruciate ligament graft may not be normal when the
      femoral tunnel is placed using the single-incision arthroscopic technique because
      the femoral tunnel is drilled through the tibial tunnel. We hypothesized that the
      in vivo tensile behavior of the double-looped semitendinosus and gracilis tendon
      graft can be normal or abnormal compared with the native anterior cruciate
      ligament, that the placement and angle of the tibial tunnel can predict the
      tensile behavior of the graft, that the graft with abnormal tensile behavior is
      associated with a nonanatomically placed tibial tunnel, and that the tensile
      behavior of the graft determines the stability of the reconstructed knee at 1
      year. Total tension in the graft and knee flexion angle were measured in 14
      subjects as the knee was flexed from 0 degree to 90 degrees. A graft force
      greater than 40 N at 80 degrees of flexion was considered abnormal. One year
      after surgery, the angle and position of the tibial tunnel were determined from
      roentgenograms, and knee stability was measured with a KT-1000 arthrometer. The
      criteria for anatomic tibial tunnel placement in the sagittal and coronal planes
      were derived from magnetic resonance images of uninjured knees. The tensile graft
      behavior was either normal (4 of 14) or abnormal (10 of 14) with the single
      incision arthroscopic technique. The angle of the tibial tunnel in the coronal
      plane was predictive of abnormal tensile behavior. Abnormal tensile behavior
      occurred in anatomically placed tibial tunnels and was compatible with a stable
      and functional reconstructed knee at 1 year.

PMID- 10352762
TI  - The incidence of injury in Texas high school basketball. A prospective study
      among male and female athletes.
AB  - Recent publications have reported differences in the incidence, rate, risk, and
      type of sports injury among men and women. We undertook a prospective study to
      determine the incidence of injury among high school basketball players and to
      examine the differences in injury type, incidence, rate, and risk between male
      and female athletes. During a single basketball season, an injury survey of
      girls' varsity teams at 100 class 4A and 5A high schools in Texas was conducted.
      These data were previously reported. We surveyed the same 100 high schools during
      a subsequent season to gather injury data from the boys' varsity teams. The
      athletic trainer collected data on each reportable injury and reported the data
      weekly to the University Interscholastic League. A reportable injury was defined
      as one that occurred during a practice or a game, resulted in missed practice or
      game time, required physician consultation, or involved the head or the face. The
      boys' and girls' data were compared and statistically analyzed. The rate of
      injury was 0.56 among the boys and 0.49 among the girls. The risk of injury per
      hour of exposure was not significantly different between the two groups. In both
      groups, the most common injuries were sprains, and the most commonly injured area
      was the ankle, followed by the knee. Female athletes had a significantly higher
      rate of knee injuries including a 3.79 times greater risk of anterior cruciate
      ligament injuries. For both sexes, the risk of injury during a game was
      significantly higher than during practice.

PMID- 10352763
TI  - Biceps load test: a clinical test for superior labrum anterior and posterior
      lesions in shoulders with recurrent anterior dislocations.
AB  - We describe the biceps load test for evaluating the integrity of the superior
      glenoid labrum in shoulders with recurrent anterior dislocations. With the
      shoulder in an abducted, externally rotated position and the forearm supinated,
      active flexion of the elbow against resistance relieves the discomfort of a
      standard apprehension test for anterior shoulder instability. A group of 75
      patients with proven unilateral anterior shoulder dislocations were prospectively
      examined in a double-blind fashion with arthroscopic examination and the biceps
      load test. Sixty-three patients had a negative test and 62 of these had an intact
      biceps tendon-superior labrum complex; the remaining patient had a type II
      superior labral anterior and posterior lesion. Twelve patients had positive
      tests, and 10 had superior labral lesions; the other 2 patients had intact
      superior labra. Therefore, the biceps load test revealed a sensitivity of 90.9%,
      a specificity of 96.9%, a positive predictive value of 83%, a negative predictive
      value of 98%, and a kappa coefficient of 0.846.

PMID- 10352764
TI  - Primary repair of patellar tendon rupture without augmentation.
AB  - Repair of patellar tendon ruptures has often relied on cerclage augmentation and
      prolonged immobilization in extension. We are reporting our experience with
      avulsion injuries as well as midsubstance ruptures, both treated with primary
      repair without augmentation, allowing early mobilization in the athlete less than
      40 years of age. Repairs were performed to allow knee flexion to more than 60
      degrees. Rehabilitation was performed with heel slides, allowing flexion to 45
      degrees for the first 3 weeks, increasing to 90 degrees at 3 to 6 weeks, and
      thereafter without restriction. An accelerated weightbearing and muscle
      strengthening program was adopted. At a mean follow-up of 2.6 years (range, 20 to
      61 months), 12 patients had returned to their previous levels of activity. No
      loss of extension or extensor lag was noted; mean flexion loss was 5 degrees.
      Patellofemoral symptoms and signs were present in five patients, but activity was
      limited in only two. Mean peak torque at 60 deg/sec was 92% (range, 73% to 105%).
      Mean Lysholm score was 94 +/- 2.5 points. Primary repair with immediate,
      protected range of motion resulted in uniformly excellent results and obviated
      the need for manipulation or subsequent hardware removal.

PMID- 10352765
TI  - Treatment of simple elbow dislocation using an immediate motion protocol.
AB  - The results of treatment after closed reduction of elbow dislocation vary. Twenty
      consecutive patients with closed posterior elbow dislocations were treated
      prospectively on a rapid motion, nonimmobilized functional regimen. This
      treatment protocol emphasizes immediate active range of motion under close
      supervision. No slings or splints were employed. Final range of motion averaged 
      4 degrees to 139 degrees. All patients attained final extension within 5 degrees
      of the contralateral side. Each patient achieved his final range of motion within
      an average of 19 days after reduction of the dislocation. Arm circumference
      returned to normal at an average of 6.5 days. There was one redislocation. After
      treatment, all patients met qualification for graduation from the U.S. Naval
      Academy and were able to pursue unrestricted athletic and career options. Our
      findings suggest that an aggressive immediate motion rehabilitation allows nearly
      full final elbow motion and an excellent functional outcome.

PMID- 10352766
TI  - Knee joint laxity and neuromuscular characteristics of male and female soccer and
      basketball players.
AB  - Anterior cruciate ligament injuries are occurring at a higher rate in female
      athletes compared with their male counterparts. Research in the area of anterior
      cruciate ligament injury has increasingly focused on the role of joint
      proprioception and muscle activity in promoting knee joint stability. We measured
      knee joint laxity, joint kinesthesia, lower extremity balance, the amount of time
      required to generate peak torque of the knee flexor and extensor musculature, and
      electromyographically assessed muscle activity in 34 healthy, collegiate-level
      athletes (average age, 19.6 +/- 1.5 years) who played soccer or basketball or
      both. Independent t-tests were used to determine significant sex differences.
      Results revealed that women inherently possess significantly greater knee joint
      laxity values, demonstrate a significantly longer time to detect the knee joint
      motion moving into extension, possess significantly superior single-legged
      balance ability, and produce significantly greater electromyographic peak
      amplitude and area of the lateral hamstring muscle subsequent to landing a jump.
      The excessive joint laxity of women appears to contribute to diminished joint
      proprioception, rendering the knee less sensitive to potentially damaging forces
      and possibly at risk for injury. Unable to rely on ligamentous structures,
      healthy female athletes appear to have adopted compensatory mechanisms of
      increased hamstring activity to achieve functional joint stabilization.

PMID- 10352767
TI  - How three methods for fixing a medial meniscal autograft affect tibial contact
      mechanics.
AB  - We evaluated three methods for fixing a medial meniscal autograft to determine
      which method restored tibial contact mechanics closest to normal. The contact
      mechanics (maximum pressure, mean pressure, contact area, and location of the
      center of maximum pressure) of the medial tibial articular surface were
      determined using pressure-sensitive film while knee specimens were loaded in
      compression to 1000 N at 0 degree, 15 degrees, 30 degrees, and 45 degrees of
      flexion. Pressure was measured for the intact knee, the knee after meniscectomy,
      and the knee with the original meniscus removed and reimplanted as an autograft
      using three different fixation methods. The contact mechanics of the autograft
      reinserted with bone plug fixation were closest to normal; however, the maximum
      pressure was significantly greater than in the intact knee. Adding peripheral
      sutures neither improved nor worsened the contact mechanics. Fixation with
      sutures only did not restore normal contact mechanics. We concluded that medial
      meniscal transplantation requires anatomic fixation of bone plugs attached to the
      anterior and posterior horns to restore contact mechanics closest to normal.
      Fixation of the meniscal horns with sutures alone cannot be recommended.

PMID- 10352768
TI  - Intraarticular anterior cruciate ligament graft placement on the average most
      isometric line on the femur. Does it reproducibly restore knee kinematics?
AB  - In the past, there has been a plausible hypothesis that anterior cruciate
      ligament graft placement at isometric sites, such that the tibial and femoral
      attachment sites remain equidistant from each other throughout knee range of
      motion, would increase the likelihood of a satisfactory outcome. For a given
      tibial placement we wanted to determine whether placing the graft on the average
      of the most isometric femoral line, a fixed distance from the outlet of the
      intercondylar notch, would return normal laxity to all knees. The three
      dimensional kinematics of seven cadaveric knees were measured for angles from
      full extension to 90 degrees of flexion at 15 degrees increments. Physiologic
      levels of quadriceps muscle forces were applied to the intact knee, after
      transection of the anterior cruciate ligament, and after ligament reconstruction
      with a patellar tendon graft. On average, the reconstruction was found to return
      anterior-posterior translation, internal-external rotation, and varus-valgus
      rotation to levels not significantly different from those of the intact knee.
      However, the ranges of the translation and rotations were large. Placing the
      graft on the average most isometric femoral line did not restore knee laxity to
      normal in all knees. This supports the need to customize graft placement in each
      knee at the time of surgery.

PMID- 10352769
TI  - Radiographic abnormalities of the lumbar spine in college football players. A
      comparative analysis.
AB  - The purpose of this study was to make a direct comparison between lumbar spine
      radiographs of incoming college football players and of an age-matched control
      group to determine whether there is a higher prevalence of lumbar spine
      abnormalities in football players before competing at the Division I level. We
      reviewed 187 lumbar spine radiographs. Of these, 104 were taken as a standard
      part of the preparation physical examination for incoming college football
      players. The remaining 83 radiographs were taken during routine preemployment
      physicals at a local factory. Each radiograph was read independently by three
      separate orthopaedic radiologists in a blinded fashion. Data were collected and
      statistically evaluated for 13 variables. The rate of spondylolysis was only 4.8%
      in our group of athletes and 6.0% in the control group (not significantly
      different). Only in the category of degenerative changes was a significant
      difference found. The control group had a 16.9% incidence of disk space narrowing
      and spurring and the football players had a 6.7% incidence. The remainder of the
      variables were not significantly different between the two groups. Our findings
      differ from previously published reports and indicate that football players
      entering college at the Division I level may have a similar prevalence of
      radiographic lumbar spine abnormalities, including spondylolysis and
      spondylolisthesis, as age-matched controls.

PMID- 10352770
TI  - Biomechanics of the Bankart repair: the relationship between glenohumeral
      translation and labral fixation site.
AB  - The specific aim of this study was to quantify glenohumeral translations in
      cadaveric shoulders after repair of the superior and middle regions of a
      surgically created Bankart lesion and after repair of the superior, middle, and
      inferior regions of the same lesion. Anterior-posterior, superior-inferior, and
      medial-lateral translations in nine cadaveric specimens were tested with
      shoulders in 0 degree, 45 degrees, and 90 degrees of humeral abduction and
      varying degrees of humeral rotation. There was statistically significantly less
      anterior and inferior translation after three-site labral repair compared with
      after two-site labral repair, and this effect was greatest at 90 degrees of
      glenohumeral abduction. The decreased translations demonstrated with three-site
      repair emphasized the importance of careful repair of the labrum to the inferior
      glenoid rim during a Bankart reconstruction and suggested that failure to do so
      may be a contributing factor to recurrent instability after anterior shoulder
      reconstruction.

PMID- 10352771
TI  - Patellar tendinitis: the significance of magnetic resonance imaging findings.
AB  - We evaluated the significance of magnetic resonance imaging findings in patients
      with patellar tendinitis. Midline sagittal magnetic resonance images were taken
      of 12 knees from 10 patients and of 17 knees from 15 age- and activity-matched
      subjects who underwent imaging for reasons other than patellar tendinitis. Of the
      12 magnetic resonance imaging scans of knees with clinical patellar tendinitis, 3
      (25%) exhibited no defect and only 7 (58%) had unequivocal intratendinous
      lesions. Among the 17 scans of subjects without clinical patellar tendinitis, 5
      (34%) showed no defect and 4 (24%) had unequivocal intratendinous lesions.
      Proximal tendon width was significantly larger for the tendinitis patient group
      (5.0 +/- 1.7 mm versus 3.9 +/- 1.0 mm), although considerable overlap was
      present. All subjects with unequivocal intratendinous signal changes had a
      significantly longer nonarticular inferior patellar pole and were significantly
      older (38.1 years versus 26.8 years). Only Blazina stage III lesions were
      associated with abnormal findings on magnetic resonance imaging. As a whole, the
      sensitivity and specificity of magnetic resonance imaging was 75% and 29%,
      respectively. In younger patients with relatively mild symptoms, magnetic
      resonance imaging did not show significant changes; in older, active patients
      changes may be present in asymptomatic knees.

PMID- 10352772
TI  - Effect of a patellar realignment brace on patients with patellar subluxation and
      dislocation. Evaluation with kinematic magnetic resonance imaging.
AB  - The object of this study was to evaluate the effect of a patellar realignment
      brace on patients with patellar subluxation or dislocation. Twenty-one patients
      (24 patellofemoral joints) with clinical evidence of patellar subluxation (N =
      16) or dislocation (N = 5) were examined with the joint inside a positioning
      device to allow active-motion, kinematic magnetic resonance imaging. To analyze
      the patellar tracking pattern, the same imaging parameters (patellar tilt angle,
      bisect offset, and lateral patellar displacement) and section locations were used
      before and after application of a patellar realignment brace. No statistically
      significant differences were found in any of the three parameters for the
      patellofemoral relationships before or after wearing the patellar brace. The
      results indicated no stabilizing effect of the tested brace in patients with
      patellar subluxation or dislocation during active joint motion.

PMID- 10352773
TI  - The effects of dilute epinephrine saline irrigation on the need for tourniquet
      use in routine arthroscopic knee surgery.
AB  - A prospective, randomized, double-blinded study was performed to determine
      whether dilute epinephrine saline irrigation (1 mg/l) delivered by gravity flow
      would significantly reduce the need for tourniquet use during routine
      arthroscopic surgery. One hundred five patients requiring straightforward
      arthroscopic knee surgery were randomly assigned to either an epinephrine group
      that received dilute epinephrine irrigation by gravity flow or to a placebo group
      that received normal saline irrigation by gravity flow. The need for tourniquet
      use and the tourniquet time, total operative time, and volume of irrigation fluid
      used were documented and compared between the two groups. A tourniquet was
      required 50% less often in the epinephrine group than in the placebo group. This
      difference was found to be statistically significant using the Student's t-test
      (P < 0.008, alpha < or = 0.05). If a tourniquet was required, the presence of
      dilute epinephrine in the irrigation fluid did not affect the overall tourniquet
      time or the ratio of tourniquet time to total operative time. We believe this
      study proved that dilute epinephrine irrigation is effective in decreasing the
      need for tourniquet use during routine arthroscopic knee surgery.

PMID- 10352774
TI  - The effect of cryotherapy on intraarticular temperature and postoperative care
      after anterior cruciate ligament reconstruction.
AB  - The objective of this study was to elucidate how cryotherapy after anterior
      cruciate ligament reconstruction affects intraarticular temperature and clinical
      results. A prospective and randomized study was performed on 21 knees of 21
      patients. The ligament reconstruction was performed by single-incision
      arthroscopy using autogenous hamstring tendon. On completion of the surgery,
      thermosensors were implanted in the suprapatellar pouch and the intracondylar
      notch, and the intraarticular temperature was monitored while the joint was
      cooled. Cooling was performed in one group at 5 degrees C (N = 7) and in another
      at 10 degrees C (N = 7), for 48 hours. A control group (N = 7) did not undergo
      cryotherapy. The cooled groups showed three temperature phases: a low-temperature
      phase immediately after the ligament reconstruction, followed by a temperature
      rising phase and a thermostatic phase. The control group had no low-temperature
      phase and immediately entered a thermostatic phase. During the low-temperature
      phase in the treated groups, the temperature of the suprapatellar pouch and of
      the intercondylar notch were significantly lower than the body temperature. The
      pain score and the number of times an analgesic had to be administered were both
      significantly lower in the 10 degrees C group than in the control group. Blood
      loss was significantly less in the 5 degrees C group than in the control group.

PMID- 10352775
TI  - Insulin-like growth factor I accelerates functional recovery from Achilles tendon
      injury in a rat model.
AB  - We studied the effects of insulin-like growth factor I on Achilles tendon healing
      in a rat model. Rats were randomized into groups of six each: sham surgery,
      transection alone, and transection plus growth factor. Postoperatively, rats
      treated with growth factor had a significantly smaller maximum functional deficit
      and a decreased time to functional recovery than rats in the untreated groups.
      Biomechanical testing revealed no significant differences in the measured
      parameters between the treated and the untreated groups after transection. To
      study the mechanism of action, six additional animals received an Achilles tendon
      injection of the inflammatory agent carrageenan alone and six received
      carrageenan plus growth factor. Rats treated with growth factor did not show the
      inflammation-induced functional deficit experienced by the control rats.
      Spectrometric myeloperoxidase assays on the remaining eight rats after Achilles
      tendon transection demonstrated no significant difference between the untreated
      and the growth factor-treated groups, indicating a mechanism other than
      neutrophil recruitment by which the growth factor limits inflammation. Histologic
      studies were performed on carrageenan-injected rats at postinjection day 2 and on
      surgically treated rats at postoperative day 15. No gross histologic differences
      were seen between untreated and growth factor-treated groups. This study
      demonstrated that via a possible antiinflammatory mechanism, insulin-like growth
      factor I reduces maximum functional deficit and accelerates recovery after
      Achilles tendon injury.

PMID- 10352776
TI  - An aneurysm involving the axillary artery and its branch vessels in a major
      league baseball pitcher. A case report and review of the literature.
AB  - Baseball pitchers appear to be prone to aneurysms of the axillary artery and its
      branches. The cause is probably related to repetitive compression of or tension
      on the vessels at the level of the pectoralis minor muscle and the humeral head,
      which is exacerbated by the pitching motion. The incidence of aneurysms of the
      axillary artery and its branches among pitchers and other athletes is not known,
      nor is it clear whether pitchers who are at high risk of vascular injury can be
      identified before irreversible damage to the vessels has occurred. Perhaps
      patients who have documented compression or occlusion of the vessel with the arm
      in the abducted, externally rotated position are at higher risk. Screening
      pitchers to identify those with axillary artery compression, aneurysm, or
      thrombosis has also not been shown to be effective. Certainly, many pitchers will
      have some level of compression of the axillary artery with their arm in the
      pitching position but will never develop any clinical abnormality requiring
      treatment. Screening would therefore probably lead to a high false-positive rate.
      It is clear, however, that pitchers who complain of ischemia-type symptoms such
      as early fatigue or who have evidence of emboli require a complete evaluation to
      rule out any abnormality of the axillary artery or one of its branches.
      Orthopaedic surgeons who see pitchers and other athletes involved in repetitive
      overhead motions need to be aware of this disorder so that they order the
      appropriate tests and obtain a vascular consultation--and make a prompt
      diagnosis. Treatment will vary depending on the type of lesion and on which
      vessel or vessels are involved, and should be decided on by the team of surgeons
      treating the patient.

PMID- 10352777
TI  - Bilateral subluxating popliteus tendons. A case report.

PMID- 10352778
TI  - Skiing injuries.
AB  - Skiing is a winter sport enjoyed by approximately 200 million people worldwide.
      An overall injury rate of approximately 3 per 1000 skier-days means that skiing
      certainly is the riskiest sport undertaken by adults on a routine basis. However,
      the data suggest that one can anticipate years of enjoyable recreation free from
      injury. Many troubling injuries, particularly to the lower leg, have shown a
      steady decline over the past 20 to 30 years because of advances in boot design
      and binding capabilities. In addition, as information has been gathered regarding
      the importance of proper maintenance and adjustments, equipment now available can
      protect a skier more effectively than at any time in the past. Nevertheless,
      skiing continues to present inherent risks that can be minimized through the
      following strategies: 1. Enroll in a conditioning program before skiing that
      focuses on strength and endurance components particularly of the legs and back.
      2. Have equipment that is compatible with the skier both from the standpoint of
      size and expertise. 3. Have equipment adjusted professionally. 4. Do routine
      testing of binding releases each day before beginning to ski. 5. Ski under
      control at speeds that are consistent with ability. 6. Stop skiing before fatigue
      becomes the limiting factor.

PMID- 10352779
TI  - Five-year results of single-incision arthroscopic anterior cruciate ligament
      reconstruction with patellar tendon autograft.

PMID- 10352781
TI  - Upper extremity weight-training modifications for the injured athlete. A clinical
      perspective.

PMID- 10352780
TI  - Acute skier's thumb repaired with a proximal phalanx suture anchor.

PMID- 10352782
TI  - [Limits to the duty to treat in intensive care: not every possibility must be
      followed].

PMID- 10352783
TI  - [Limits to the duty to treat in intensive care. 1. Explanation of the guidelines
      in the DGAI].
AB  - Every form of active euthanasia is a punishable offence under sections 216 of the
      Penal Code; nor is there any ethical justification for it from a medical point of
      view. The many strands of the movement in favour of making "death on demand"
      exempt from punishment in Germany as it is in The Netherlands cannot change this.
      In the area of passive euthanasia the limits of the intensive care team's duty to
      treat depends on various factors: The patient's declared or assumed wishes. It is
      not permissible to carry out procedures refused by the patient, even when these
      alone would make an extension of life possible. The indications for medical
      treatment. In the twilight zone between life and death, procedures with no
      prospect of success can no longer help the patient. In these circumstances they
      are pointless and are not medically indicated. According to Supreme Court
      rulings, the medical decision on whether to implement procedures designed to
      extend life or whether to withhold such procedures is based almost exclusively on
      the wishes or the assumed wishes of the patient, even though interpretation of
      the "assumed wishes" can be difficult and is quite often liable to subjective
      influences. The question of using the presence or absence of medical indications
      for treatment as an objective criterion, in contrast, has so far been disregarded
      in rulings. If no life-extending procedures are implemented the physician's duty
      to provide suitable basic care for the patient, in the sense of palliative care,
      remains. To make decisions easier, the authors discriminate between the essential
      "ordinary" remedies that must be provided to all patients and the "extraordinary"
      remedies of intensive care that are available for patients who can still benefit
      from them. There is some controversy over the correct assignment of artificial
      nutrition; according to German legislation it belongs in the category of
      extraordinary remedies. The palliative procedures that make up basic care include
      adequate pain relief, which can be a form of indirect euthanasia. The Supreme
      Court has ruled that it is the physician's duty to prescribe adequate pain relief
      even when it might have the unavoidable side effect of unintentionally
      accelerating the patient's death.

PMID- 10352784
TI  - [Limits to the duty to treat in intensive care. 2. Guidelines of the German
      Society for Anesthesiology and Intensive Medicine].

PMID- 10352785
TI  - [Hemodynamic effects of a ventriculo-cisternal perfusion of bupivacaine].
AB  - OBJECTIVES: The cardiotoxic properties of bupivacain have been well documented
      under in-vitro, as well as under in-vivo conditions. A further mechanism of
      cardiovascular impairment by bupivacaine via the central nervous system gained
      investigational interest in animal studies. The aim of our study was to
      demonstrate the effect of a ventriculocisternal perfusion of bupivacain on
      systemic hemodynamic variables and their reversibility by wash-out with mock-CSF.
      METHODS: After obtaining animal investional committee consent, nine anaesthetized
      and relaxed pigs were prepared for a ventriculocisternal perfusion (VCP).
      Hemodynamic data were obtained by invasive blood pressure measurements in the
      high and low pressure system as well as cardiac output (thermodilution
      technique), intracranial pressure and electrocardiogram. Systemic vascular
      resistance and stroke volume were calculated using standard formulas. A second
      group of three animals were exposed to an intravenous infusion of the same dose
      of bupivacain over the same period of time to rule out direct cardiac effects.
      After instrumentation baseline data were obtained (K0 1) under VCP with mock-CSF
      for 30 minutes. The mock-CSF was replaced by 0.05% bupivacaine in mock-CSF and
      VCP was continued with 3 ml.h-1 for 20 minutes. After administration of 500
      micrograms bupivacaine data were collected (BU). The bupivacaine solution was
      replaced by mock-CSF and after twenty minutes hemodynamic measurement were
      repeated (K02). RESULTS: The intravenous administration of 500 micrograms
      bupivacaine had no effect on all measured variables. VCP of the same dose
      resulted in significant increase in heart rate, systolic, diastolic and mean
      arterial blood pressures. Left and right heart filling pressures as well as
      systemic vascular resistance were not affected while the stroke volume decreased.
      After continuation of VCP with mock-CSF hemodynamic changes were reversed.
      DISCUSSION: Our results demonstrate that bupivacaine initiates an indirect
      cardiovascular stimulating effect of a VCP with 500 micrograms of bupivacaine via
      the central nervous system. The intravenous administration of the same dose had
      no effect. The centrally mediated cardiovascular effect of bupivacaine was
      reversed by wash-out with mock-CSF. The cardiovascular stimulation observed in
      this animal experiment may be of clinical relevance as a potential sign of toxic
      effects of bupivacaine on the CNS.

PMID- 10352787
TI  - [Perioperative monitoring of hemoglobin fractions in homozygous sickle cell
      disease].
AB  - This case report presents the perioperative management of double-sided hip
      arthroplasty in a patient (female, 25 years old) homozygous for sickle cell
      anemia (SS). The fraction of sickle hemoglobin (Hb S) to total hemoglobin was
      monitored with an automated cation exchange microcolumn chromatography. The main
      purpose of ion exchange chromatography is to measure glycated hemoglobin A
      (HbA1c) in diabetic patients. Furthermore, as a by-product, this test enables the
      quantitative assessment of aberrant hemoglobin molecules such as sickle cell
      hemoglobin Hb S with sufficient precision and selectivity. The standard method,
      hemoglobin-electrophoresis is more complicated and not generally available. For
      the perioperative estimation of the risk for sickle cell related complications
      and as a guide for transfusion therapy, knowledge of preoperative Hb S level is
      essential. In this case report, the clinical use of a rapid laboratory test at
      low costs with common equipment in a patient with known homozygous sickle cell
      anemia is demonstrated.

PMID- 10352786
TI  - [Circulatory function and oxygenation during hemihepatectomy. Dopamine versus
      dopexamine].
AB  - OBJECTIVE: The aim of this study was to compare low dose dopamine and dopexamine
      with respect to of liver-venous oxygen saturation, oxygen delivery and--demand,
      liver function tests and cardiocirculatory effects in the reperfusion period
      during a hemihepatectomy operation with occlusion of the liver hilus. METHODS:
      Twenty patients were studied in a randomised, doubleblind setting. They either
      received 2 micrograms/kg per min dopamine or 0.5 microgram/kg per min dopexamine
      perioperatively. For monitoring purposes a pulmonary artery and a liver venous
      catheter were placed. At four different time points hemodynamic parameter were
      assessed and blood samples were drawn. RESULTS: Significant changes between
      groups were found 5 min after opening the liver hilus for the cardiac index and
      the systemic oxygen delivery, as well as at the end of the operation for
      pulmonary shunt volume, which had increased more in the dopexamine group. No
      significant difference between liver venous oxygen saturation and liver function
      tests was found. CONCLUSION: Until more detailed studies concerning the influence
      of dopamine on the hepatic-splanchnic region during liver surgery are performed,
      dopexamine can not be considered superior to dopamine during these operations.

PMID- 10352788
TI  - [Venous paradoxical air embolism].
AB  - Paradoxical air embolism may occur with any venous air embolism. Air may either
      enter the systemic circulation through a patent foramen ovale or through
      transpulmonary passage of air. While small venous air emboli are mostly well
      tolerated, even the smallest paradoxical air emboli can have fatal consequences
      in the systemic circulation. Therapy and prophylaxis of paradoxical air embolism
      equal those of venous air embolism. This is especially true, since paradoxical
      air embolism may not become obvious under general anesthesia. More specific
      therapeutic regiments, such as hyperbaric oxygenation and the infusion of
      perfluorocarbons, are still in an experimental stage.

PMID- 10352789
TI  - [Is spinal anesthesia for operations in the prone or jackknife position
      suitable?].
AB  - There is still controversy on the usefulness of spinal anesthesia for operations
      performed in the prone or jackknife position. There is about the risk of
      inadvertent increase of the sensomotory blockade with the patient in the prone
      position and the difficulty of managing consecutive cardiorespiratory
      complications or inducing general anesthesia in case of failures. This article
      reviews the current literature in terms of safety and effectiveness of spinal
      anesthesia for such operations. For lower-limb or perianal operations with
      limited extension and blood loss, performed in the prone position, spinal
      anesthesia seems to be a safe, effective and economic technique in patients
      without severe a cardiac history. Substantial knowledge about the onset time,
      fixation time, duration of sensomotory block and baricity of the applied local
      anesthetic is crucial in this setting. Obese patients are at risk for sudden
      extension of the block when turned into the prone position. Additional narcotics
      and sedatives should be avoided and continuous monitoring of hemodynamic and
      respiratory parameters, of the level of the blockade and vigilance of the patient
      is mandatory.

PMID- 10352790
TI  - [The history of the development of intensive care medicine in Germany.
      Contemporary reflections. 4. Structural development of operative intensive care
      medicine in the former German Democratic Republic].

PMID- 10352791
TI  - [Hydrocortisone in catecholamine regulated circulatory insufficiency].

PMID- 10352792
TI  - [Latex-free explantations?].

PMID- 10352793
TI  - [Accompanying medication. Necessity, side effects and interactions in the
      perioperative phase].

PMID- 10352794
TI  - [Clarification of a compliance cure with demonstrative proof. A reply to a paper
      in Der Anaesthesist 12/98, S. 1007-1010].

PMID- 10352795
TI  - [Guidelines--a misleading path for the physician?].

PMID- 10352796
TI  - [The trouble with guidelines].

PMID- 10352797
TI  - [Prophylaxis against obstetric acid aspiration syndrome in the German Federal
      Republic in 1997. A review based on results of a federal survey].
AB  - A survey of all German hospitals providing obstetric anesthesia was performed in
      1997 (n = 1061, recovery rate 82%; comprising about 700,000 deliveries and
      115,000 cesareans, resp.) concerning the routine prophylactic measures for acid
      aspiration syndrome (AAS) in pregnant patients and before obstetric procedures
      (i.e., prevention of aspiration by positioning, Sellick's manoeuvre, reduction of
      intragastric volume, or reduction of gastric content acidity). In pregnant
      patients, any prophylaxis of AAS is performed in 36%. Of the patients expecting
      delivery in the labour ward, only 7% receive pharmacological AAS treatment.
      Before scheduled (urgent, non-emergency) cesarean section in general anesthesia,
      93% (94%) of patients receive prophylactic treatment, either pharmacological or
      non-pharmacological. Before regional anesthesia, the corresponding numbers are
      52% for both scheduled or urgent CS.

PMID- 10352798
TI  - National publication output in medical research.
AB  - OBJECTIVE: Both the total number of publications and the number of publications
      in high-ranking journals determine a country's reputation in scientific research.
      A predominance of national authors in a country's international high-ranking
      journals has occasionally been presumed. We therefore analysed the publication
      output of various countries and the proportion of national authors in
      international high-ranking journals. METHODS: The database EMBASE (Excerpta
      Medica) by means of the online service Dialog was used to analyse the national
      publication output of various countries during the years 1986 to 1990 and 1991 to
      1995 and the proportion of national authors in The Lancet and The New England
      Journal of Medicine (NEJM.). RESULTS: American and British publications played
      the leading roles in the total number of medical publications from 1986 to 1990
      (35.6% and 8.8%, respectively) and also from 1991 to 1995 (34.3% and 9.1%,
      respectively). A more detailed analysis revealed an unexpectedly high national
      publication output (publications per million inhabitants) of smaller countries,
      which exceeded that of larger nations during both periods studied (national
      publication output 1986-90 vs. 1991-95: Israel: (3386 vs. 3447), Sweden: (3303
      vs. 3620), Switzerland: (2930 vs. 3722), Denmark: (2884 vs. 3167), UK: (2186 vs.
      2825), USA: (2042 vs. 2388)). Furthermore, the proportion of national authors
      during both periods (1986-90 vs. 1991-95) studied was 41.8% vs. 34.1% in the case
      of The Lancet and 77.9% vs. 69.5% in the case of The New England Journal of
      Medicine. CONCLUSIONS: The present study found an unexpectedly high national
      publication output of smaller countries as well as a clearly disproportionate
      number of published articles from national authors in The Lancet and the NEJM
      during the years 1986 to 1990 and 1991 to 1995.

PMID- 10352799
TI  - [Knowledge-based diagnosis and therapeutic recommendations with fuzzy-set theory
      methods in patients with acute lung failure (ARDS)].
AB  - OBJECTIVE: Since the treatment of patients with severe ARDS using the
      extracorporal lung assist (ECLA) methods remains a cost intensive and speculative
      procedure, a knowledge based computer system should be created and evaluated in
      order to support clinical decisions. METHODS: The model was based on the fuzzy
      set theory and therefore able to give decisions between yes and no, that means
      that a criterion could also be fulfilled to 35% or 80% for example. The
      development of this computer program consists of two steps: first, the entry
      criteria for the ECLA therapy were established within a framework of an
      international evaluation of clinical data from 3 centres (Berlin, Marburg,
      Vienna). Here, inherent vagueness, uncertainty of the occurrence and limited
      availability of medical data are to be considered to establish a useful tool.
      Secondly, this was done by grouping and weighting of parameters by the system and
      the status of each patient or patient group was assigned by the percentage of
      fulfillment of the criterion. RESULTS: By using a mixed sample of patients from
      these three centres, the fulfillment of entry criteria according either to
      definitions of Berlin or to definition of Marburg was different (68% versus 36%).
      Other differences (36% vs. 22% and 68% vs. 60%) were found between the fuzzy
      based score and the crisp score which represents the usually performed method.
      CONCLUSIONS: This now preevaluated minimal data set to describe severe ARDS
      patients based on the fuzzy set theory may be useful to evaluate patients for
      ECLA therapy or for another controlled ARDS-therapy.

PMID- 10352800
TI  - [Lactate: a marker for tissue hypoxia].

PMID- 10352801
TI  - Biosensors for clinical diagnostics.
AB  - Biosensors for diabetes monitoring and use in blood gas, blood electrolyte
      analyzers are now commercially available. Performance of these sensors differs
      from manufacturer to manufacturer, but clinical usefulness has been shown for
      several applications (see articles in this series).

PMID- 10352802
TI  - [Clinical evaluation and methodological aspects of serum lactate].

PMID- 10352803
TI  - [Lactate for assessing physical performance, load capacity and monitoring of
      training].

PMID- 10352804
TI  - Lactate in sepsis and trauma--hindrance or help?
AB  - Physiologic hyperlactatemia must be distinguished from lactate acidosis (lactate
      > 5 mM/L, pH < 7.32). Sustained lactic acidosis, or changes in lactate in
      response to inotropic support, are useful predictors of mortality in severe
      sepsis and trauma, and superior to hemodynamic markers such as DO2 and VO2. Base
      deficit is a readily available surrogate for plasma lactate, and the addition of
      gastric tonometry enhances its predictive ability.

PMID- 10352805
TI  - [Lactate as an indicator of ischemic-traumatic brain injury].

PMID- 10352806
TI  - [Plasma lactate concentration in post-ischemic reperfusion of human hearts under
      treatment with sodium nitroprusside].

PMID- 10352807
TI  - [The continuous monitoring of hepatic venous oxygen saturation in patient
      monitoring following hemihepatectomy].
AB  - Increasing numbers of liver tumours and liver metastases from other tumours are
      treated by liver resection. During resection the ligamentum hepatoduodenale is
      occluded and the liver is exposed to warm ischemia. Duration and intensity of
      resulting liver ischemia can not be evaluated without special monitoring devices.
      A fiberoptic catheter placed in a liver vein facilitates continuous recording of
      the hepatic-venous oxygen saturation (ShvO2). CASE REPORT: We present a case
      where such a catheter was placed perioperatively in a patient undergoing
      hemihepatectomy. The liver venous catheter was positioned by guidance of the
      saturation curve and X-ray. The preoperative oxygen saturation in this liver vein
      was 80%. During the whole operation, the ShvO2 was continuously monitored. Blood
      for blood gas analyses was drawn before, during and after the occlusion of the
      ligamentum hepatoduodenale. Hemodynamic parameters were documented at the same
      time. The ShvO2 already decreased in the preparation period before the actual
      occlusion of the ligamentum hepatoduodenale. During the occlusion the ShvO2
      dropped to an average of 30% with the lowest value being 13%. After reopening of
      the hepatic hilus the ShvO2 increased rapidly but did not reach preoperative
      values which were recorded not earlier than at the end of the operation.
      CONCLUSION: Duration and intensity of the decreased ShvO2 were recognized early
      by the liver venous catheter. It was demonstrated that desaturation of the
      hepatico-splanchnic region already occurred during the period of liver
      preparation before the ligamentum hepatoduodenale was occluded. Interventions to
      protect the liver from ischemia should therefore be applied some time before
      occlusion of the liver hilus. However, clearly defined indications for this
      invasive monitoring cannot be given at this time. In situations of extended liver
      resection or in cases of expected technical difficulties a continuous monitoring
      of the liver-venous oxygen saturation might be beneficial.

PMID- 10352808
TI  - [New on the Internet: www.thieme.de/ains. The theme server: www.anaesthesie.com].

PMID- 10352809
TI  - [The polytraumatized patient. I. W. Mauritz. AINS 1998: 33:441-456].

PMID- 10352810
TI  - [Commentary: alternatives to endotracheal intubation in polytrauma patients].

PMID- 10352811
TI  - [Inguinal hernia of the bladder. Report of 6 cases].
AB  - The authors report 6 cases of inguinal hernia of the bladder seen between 1976
      and 1996. All patients were males with a mean age of 67 years (range: 53 to 80
      years). The hernia was situated in the right groin in all patients. No patients
      presented any suggestive clinical features. In 5 patients, the diagnosis was
      established by IVU, indicated for another disease associated with the hernia and,
      in one patient, the hernia was discovered after an operative wound to the
      bladder. Treatment consisted of elimination of bladder neck obstruction in 3
      patients and reintegration of the bladder and abdominal wall repair in 4
      patients. The postoperative course was uneventful.

PMID- 10352812
TI  - [Traumatic rupture of the bladder. Report of 12 cases].
AB  - Over the previous 8 years, the authors have treated 12 patients (11 males and 1
      female with a mean age of 32 years (26 to 54 years)) with traumatic rupture of
      the bladder. Rupture was secondary to direct trauma to the full bladder in one
      case and pelvic trauma in 11 cases. Associated lesions were pelvic trauma (11
      cases), head injury (4 cases), chest trauma (2 cases), rupture of the spleen (1
      case) and small bowel perforation (1 case). The clinical features were dominated
      by suprapubic pain (11 cases), haematuria (10 cases), haemorrhagic shock (4
      cases) and peritoneal syndrome (3 cases). IVU confirmed the diagnosis in 6 out of
      8 cases. Retrograde cystourethrography was conclusive whenever it was performed.
      The retroperitoneal rupture was treated by indwelling catheter for 15 days.
      Intraperitoneal ruptures were treated surgically. The breach was situated in the
      dome in 10 cases and on the posterior surface in 1 case. The size of the wound
      ranged from 2 to 8 cm. Treatment consisted of suture of the rupture and
      indwelling catheter for an average of 12 days. Cure was always obtained without
      sequelae.

PMID- 10352813
TI  - [Vesico-uterine fistulas. Report of 30 cases].
AB  - The authors report a series of 30 vesico-uterine fistulas (VUF) observed over a
      25-year period. The mean age of the patients was 28 years (range: 18 to 40
      years). VUF were secondary to caesarean section (23 cases), abnormal delivery (5
      cases) and rupture of the bladder and uterus (2 cases). The presenting complaint
      was a permanent total and isolated urinary incontinence (22 cases), partial
      urinary incontinence associated with menstrual haematuria (4 cases), vesical
      menstrual bleeding associated with a oligomenorrhoea (3 cases) and menouria (1
      case). The diagnosis was established on clinical findings in 14 patients. IVU,
      performed in 30 patients, visualized the uterine cavity in only 12 patients.
      Retrograde cystography, performed in 4 cases, demonstrated opacification of the
      uterine cavity. Hysterosalpingography, performed in 6 cases, confirmed the
      diagnosis of VUF in all 6 patients. Treatment was surgical, via a
      transperitoneovesical incision (22 cases) or a transvesical incision (8 cases)
      and consisted of isolation of the bladder and uterus and uterine and vesical
      suture. Urine drainage was performed by urethral catheter (28 cases) or
      cystostomy (2 cases). Urinary continence was perfectly restored in 24 patients, 6
      patients presented residual fistulas another patient had a reduction of her
      bladder capacity. The objective of this study is to analyse the aetiological,
      diagnostic and therapeutic aspects of this disease.

PMID- 10352814
TI  - [Urological complications of endometriosis].

PMID- 10352815
TI  - [The Martius flap in the treatment of vesicovaginal fistulas. Report of 20
      cases].
AB  - The authors report a series of 20 cases of vesicovaginal fistula (VVF) treated
      according to the Martius procedure. The mean age of the patients was 30 years
      (range: 20 to 37 years). All fistulas were secondary to obstetric trauma. The
      mean diameter of the fistula orifice was 4 cm. Fourteen fistulas were cervico
      trigonal and 6 were urethro-cervico-trigonal. A rectovaginal fistula was
      associated with VVF in 2 patients. Five of the 20 patients had never been
      previously operated, while 15 patients had already been operated without success.
      Fifteen patients were cured immediately, while a second Martius procedure was
      necessary in 3 cases. Failure was considered to be definitive in 2 cases.

PMID- 10352816
TI  - [Posterior urethral polyps in children. A case report].
AB  - Posterior urethral polyps are rare. A case is reported in a 7-year-old boy
      presenting with pain and burning micturition. Ultrasound and cystography revealed
      the diagnosis by showing a round solid structure in the bladder neck. Cystoscopy
      confirmed the diagnosis by showing its implantation base at the summit of the
      verumontanum. The polyp was removed by endoscopic resection and histological
      examination of the resection specimen showed a fibrous polyp. A brief review of
      the clinical features, diagnostic methods, natural history and treatment of this
      benign tumour is presented.

PMID- 10352817
TI  - [Urethrorectal fistula. Report of 11 cases].
AB  - The authors report a series of 11 urethrorectal fistulas observed over a 25-year
      period. The mean age of the patients was 37 years (range: 15 to 70 years). The
      aetiologies were surgical trauma (5 cases), fracture of the pelvis (2 cases),
      inflammatory lesions (3 cases), and one fistula was congenital. The clinical
      features were dominated by urine discharge from the anus (11 cases), urinary
      tract infection (8 cases), spurious diarrhoea (6 cases), faecaluria (4 cases),
      pneumaturia (2 cases). Digital rectal examination was normal in 7 patients. IVU
      demonstrated opacification of the rectum in 5 out of 8 cases. Cystourethrography,
      performed in 9 patients, demonstrated the communication in each case.
      Urethrocystoscopy visualized the fistula in each case in which it was performed.
      Treatment consisted of bladder drainage by urethral catheter in all patients,
      allowing closure of the fistula in 2 patients. Colostomy was performed in 2
      patients, internal urethrotomy and urethral catheter was performed in 2 cases.
      Surgical closure of the fistula was performed in 7 patients, via an
      abdominoperineal (3 cases), perineal (2 cases), transperitoneal (1 case) or
      transanosphincteric incision (1 case).

PMID- 10352818
TI  - [Congenital urethrocele in children. A case report].
AB  - Congenital urethrocele is a fairly rare disease in children. The authors report
      the case of a 9-year-old child presenting with a penoscrotal mass. Pressure on
      the mass produced urine. The diagnosis of urethrocele was established by
      ultrasonography and cystourethrography. Urethroplasty was successfully performed.

PMID- 10352819
TI  - [Perineal recurrence of resected penile cancer. A case report].
AB  - The authors report an unusual case of perineal recurrence of squamous carcinoma
      of the penis in a 50-year-old, white man, circumcised during infancy and operated
      5 years previously for stage T3N0M0 squamous carcinoma of the penis by total
      amputation of the penis. Clinical examination revealed a very large, infected
      perineal tumour associated with bilateral inguinal lymphadenopathy. This stage
      T4N2M0 tumour was treated palliatively by cystostomy, emasculation with perineal
      tumour reduction and antibiotics. The patient became afebrile and the infection
      resolved and was referred to the radiotherapy department for further treatment.

PMID- 10352820
TI  - [Epididymal cysts in adolescents].
AB  - Epididymal tumours are uncommon in children and adolescents and are usually
      benign. Epididymal cyst is exceptionally reported in the literature, although it
      is certainly underdiagnosed. The authors report 3 cases of epididymal cyst in 3
      children, 12, 14 and 16 years of age. These children presented with an
      uncomfortable scrotal mass and were treated by excision of the cyst in every
      case. The aetiology of epididymal cysts is unclear. It is probably a congenital
      abnormality related to hormonal disorders during embryonic life. Physical
      examination is very important, but not sufficient for the diagnosis and must be
      completed by scrotal ultrasonography, which shows an echo-free cystic epididymal
      structure. Despite ultrasonography, the differential diagnosis of other scrotal
      cystic masses and even some solid epididymal tumours, which may present all of
      the sonographic characteristics of a cyst, must be considered. The treatment of
      symptomatic epididymal cyst in children must be surgical. For asymptomatic cysts
      diagnosed by sonography, clinical follow-up to document stability of the mass is
      justified.

PMID- 10352821
TI  - [Scrotal pseudoabscess revealing congenital diverticulum of the anterior urethra
      in children].
AB  - The authors report a case of infected congenital diverticulum of the anterior
      urethra in a 6-week-old infant. This diverticulum presented clinically in the
      form of a scrotal abscess. Retrograde cystourethrography established the
      diagnosis. Two-stage treatment was preferred because of the infection: aspiration
      of the diverticulum and antibiotics, subsequently followed by surgical repair
      with resection of the diverticulum and immediate urethral reconstruction. The
      immediate postoperative course was marked by demonstration of hypertrophic pylori
      stenosis, which had not been previously investigated despite the presence of
      symptoms predating the diverticulum (repeated vomiting at the age of one month).
      Treatment was surgical. A brief review of diverticula of the anterior urethra is
      presented, defining the aetiological factors as well as the diagnostic and
      therapeutic features.

PMID- 10352822
TI  - [Survival and prognostic factors of germ cell tumors of the testis in the
      departments of Bas-Rhin, Isere, and Somme].
AB  - The authors report a study of the prognosis of germ cell tumours of the testis in
      populations of the Bas-Rhin, Isere and Some departments. This study was performed
      on French Eurocare data (European testicular cancer register study). 247 patients
      diagnosed between 1987 and 1993 were studied. Estev's method and model were used
      to estimate the relative survival and for prognosis analysis with reference to
      the French age-matched male population. 84.6% of patients were between the ages
      of 20 and 49 years. The 5-years relative survival was 90.1%; 95 CI% [85.5-94.8].
      The 5-year relative survival was lower (63.9%) in advanced forms (stage III).
      Univariate analysis in 223 patients demonstrated the following significant
      prognostic factors: stage, metastatic sites, treatment, retroperitoneal lymph
      node dissection and testicular vascular invasion. Multivariate analysis
      identified: stage, age, CNS metastases, retroperitoneal lymph node dissection and
      treatment. This study confirms the generally good prognosis of this cancer. As
      reported in the literature, factors negatively influencing relative survival are
      those related to advanced disease. Age, a controversial factor in the literature,
      was correlated with relative survival in this study.

PMID- 10352823
TI  - [A dermatologic check-up at 40].

PMID- 10352824
TI  - [Dermatology in Lebanon].

PMID- 10352825
TI  - [Quality of life assessment: from public health to dermatology].

PMID- 10352826
TI  - [Cutaneous periarteritis nodosa: diagnostic and therapeutic aspects of 9 cases].
AB  - BACKGROUND: Cutaneous periarteritis nodosa (PAN) is distinguished from systemic
      PAN by the lack of visceral involvement. The aim of this study was to describe
      the clinical presentation, laboratory findings, clinical course, and treatment in
      cutaneous PAN. PATIENTS AND METHODS: We retrospectively reviewed the files of
      patients hospitalized for vasculitis in our Dermatology unit where approximately
      20 cases of vasculitis are seen each year. Inclusion criteria were skin signs
      suggestive of PAN and a histological image of leukocytoclastic vasculitis of an
      arteriole. RESULTS: Nine cases of cutaneous PAN were treated in our unit between
      1976 and 1997. Follow-up ranged from 32 months to 22 years. No cases of systemic
      PAN had been diagnosed during this period. These 9 cases of cutaneous PAN all had
      the same clinical presentation: nodules on the lower limbs in all cases
      associated with nodules on the upper limbs in half of the cases. Neuropathy was
      found in 3 of the 9 cases. No systemic involvement was observed. The most
      frequently used treatment protocol was general corticosteroid therapy (0.5
      mg/kg/d prednisone or prednisolone). Immunosuppressive drugs, colchicine,
      dapsone, non-steroidal anti-inflammatory drugs and intravenous immunoglobulins
      were also used with efficacy. DISCUSSION: Cutaneous PAN is a particular form of
      vasculitis associating skin signs with locoregional neuromuscular involvement.
      The differential diagnosis with other types of vasculitis is sometimes a
      difficult task. The clinical course is the fundamental diagnostic clue in
      cutaneous PAN. A benign course and the absence of visceral involvement allow
      initiating a symptomatic treatment such as colchicine. The development of
      neuromuscular signs may warrant the use of general corticosteroid therapy.

PMID- 10352827
TI  - [Leg ulcers. Allergologic studies of 359 cases].
AB  - INTRODUCTION: Leg ulcers are a common disease in dermatology. Their social and
      economic implications are important, especially when contact dermatitis
      complicates these wounds. PATIENTS AND METHODS: In this study a total of 359
      patients had contact dermatitis investigations over a period of 5 years. Patch
      tests were performed on 116 men and 243 women hospitalized with venous and/or
      arterial leg ulcers, with or without clinical appearance of periulcerous contact
      dermatitis. Standard patch-tests of the ICDRG (International Contact Dermatitis
      Research Group) were systematically performed as well as a specific series of 40
      tests. RESULTS AND DISCUSSION: Positive patch tests were observed in 82.5 p. 100
      of the patients, indicating a very high rate of contact allergy in patients with
      leg ulcers. Peru balsam, lanolin and neomycin were the most frequent culprits of
      positive patch-tests in this population. Five percent of patch-tests with eosin
      were positive in our study. This is not common in the literature. Moreover, we
      highlight the high rate of contact sensitization to corticosteroids in this
      population. According to these results and to the literature, a new series of
      patch-tests for leg ulcers is suggested. CONCLUSION: Polysensitization in
      patients with chronic wounds is very frequent. A series of patch-tests in leg
      ulcers may lead to some interesting conclusions but a good questioning of the
      patient is always necessary to complete this series.

PMID- 10352828
TI  - [ECLA grading: a system of acne classification for every day dermatological
      practice].
AB  - BACKGROUND: Different acne gradings have been proposed: global grading, semi
      global grading, quantitative grading and photographic grading. They are mainly
      used in clinical studies for the evaluation of acne treatment. However, it would
      be important for physicians to have an acne grade which would be useful for
      assessing acne lesions prior to treatment and following treatment efficacy.
      METHODS: Six French dermatologists developed an acne grading scaled called "ECLA"
      which only takes 2 minutes to fill out and specifically designed for use by
      dermatologist practitioners. In addition, the intra- and inter-observer
      reliability of the grading scale was assessed. RESULTS: This analysis
      demonstrated the excellent reliability of the ECLA grading scale both in terms of
      intra- and inter-observer variability except for the retentional factor. The
      cross physician reliability decreased with time specificity for the retention
      factor, indicating that previous training prior to a multicentric clinical study
      would be necessary. CONCLUSION: ECLA grading appears to be an interesting and
      useful tool in dermatology for the follow-up of acne patients.

PMID- 10352829
TI  - [Tolerance and feasibility of adjuvant treatment of stage II malignant melanoma
      with high-dose interferon-alpha].
AB  - BACKGROUND: The use of high-dose interferon alpha as adjuvant therapy has been
      shown for the first time to improve recurrence-free and overall survival in stage
      II malignant melanoma. The aim of our work was to evaluate the toxicity of this
      therapeutic scheme during a 1-year period in 13 patients with malignant melanoma.
      PATIENTS AND METHODS: Thirteen patients, mean age 56 years, with stage II
      melanoma were included. Interferon alpha was administered at the dose of 20 MU
      per m2 body surface area five days per week for four weeks during the induction
      phase and at the dose of 10 MU subcutaneously three times a week for 48 weeks in
      the maintenance phase. Patients underwent clinical assessment daily and had blood
      tests twice a week during the induction phase. Weekly blood tests and monthly
      examinations were then performed during the maintenance phase. Clinical and
      biological toxicity was evaluated in accordance with the WHO scores. Grade 3
      toxicity led to a 30 p. 100 dose reduction and treatment was interrupted in case
      of grade 4 toxicity. RESULTS: A flu-like syndrome (grade 1-2) and digestive
      disorders, nausea, anorexia related to dysgeusia or dry mouth were observed in
      most of the patients during the induction phase and persisted in 30% of the
      patients during the maintenance phase. Six patients developed a state of
      depression (grade 2-3) which persisted during the maintenance phase, inciting us
      to prescribe an antidepressor regimen for all our patients. One patient developed
      major reversible alopecia at dose reduction. Nine patients had grade 1 or grade 2
      neutropenia and four had grade 3 neutropenia. Seven patients developed grade 1-2
      thrombocytopenia, six had elevated transaminase levels (grade 1-2) and two
      moderately elevated CPK. CONCLUSION: At the end of the induction phase of
      interferon alpha therapy in 13 patients with malignant melanoma, 8/13 had
      received 100 p. 100 of the theoretical dose and 11/13 had received 80 p. 100. At
      the end of the treatment protocol, 5/10 patients had received 100 p. 100 of the
      theoretical dose and 8/10 more than 80 p. 100. The proposed protocol appears to
      be feasible without major risk. Rigorous clinical and biological surveillance is
      mandatory.

PMID- 10352830
TI  - [Symmetrical benign lipomatosis of the tongue and Launois-Bensaude lipomatosis].
AB  - BACKGROUND: There are many causes of macroglossia, including fatty infiltration.
      Unlike unique or multiple lipomas of the tongue, non-encapsulated adipocyte
      masses develop in the tongue in symmetrical benign lipomatosis. Only six cases
      have been reported in the literature. CASE REPORT: A 69-year-old man with a
      history of chronic alcoholism developed a soft tumefied formation on the lateral
      margins of the tongue. A yellow-colored content was perceived through the thin
      mucosa. The formation was bilateral and had developed for more than 10 years. The
      patient also presented Launois-Bensaude lipomatosis localized on the neck, the
      nuchal region and the shoulders. DISCUSSION: This is, to our knowledge, the first
      reported case of symmetrical benign lipomatosis associated with Launois-Bensaude
      lipomatosis. An analogy between these two conditions has been suggested, but the
      six earlier cases of lipomatosis of the tongue reported in the literature
      developed in patients without cutaneous lipomatosis.

PMID- 10352831
TI  - [Flutamide-induced late cutaneous pseudoporphyria].
AB  - BACKGROUND: Pseudoporphyria is a condition characterized by clinical and
      histological changes resembling porphyria cutanea tarda, in the absence of any
      demonstrable abnormality in porphyrin metabolism. Etiologies of pseudoporphyria
      are hemodialysis for chronic renal failure, chronic UV irradiation, and several
      drugs, particularly naproxen. We report a case of flutamide induced
      pseudoporphyria. CASE REPORT: A 75-year-old man had prostatic carcinoma and was
      treated with flutamide for 1-1/2 years. He presented with a several months
      history of blisters on the back of the hands and fingers, occurring after sun
      exposures. The bullae were associated with skin fragility and atrophic scarring.
      Histopathological examination and direct immunofluorescence showed
      ultrastructural features close to those described in porphyria cutanea tarda.
      Quantitative analysis of porphyrins in urine and laboratory blood tests were
      normal. Flutamide was stopped, leading to healing of the lesions, with no relapse
      after 11 months. DISCUSSION: Flutamide is an antiandrogen used for the treatment
      of prostatic carcinoma. Its principal side-effect is represented by liver
      toxicity. Cutaneous side-effects of flutamide are uncommon; three cases of photo
      allergic dermatitis have been described, and we report with our observation, the
      third case of cutaneous pseudoporphyria induced by flutamide.

PMID- 10352832
TI  - [D-penicillamine-induced pemphigus, polymyositis and myasthenia].
AB  - BACKGROUND: D-penicillamine can induce autoimmune disease, particularly in
      patients with associated immune disorders. CASE REPORT: A 67-year old woman who
      had been taking D-penicillamine for 15 months for rheumatoid arthritis was
      hospitalized due to the development of a bullous eruption and proximal muscle
      deficiency. Search for intercellular antisubstance antibodies in serum was
      negative. The skin biopsy histology revealed intra-epidermal cleavage in the
      mucosal body and direct immunofluorescence revealed epidermal frame-marking with
      anti-IgG and anti-C3 antibodies. Other tests revealed muscular cytolysis, and
      anti-acetylcholine receptor antibodies. The electromyogram showed neuromuscular
      block without muscle deficiency and muscle biopsy showed moderate myositis. D
      penicillamine was interrupted and was followed by cure of the pemphigus and
      aggravation of the myositis, requiring high-dose systemic corticosteroid therapy.
      DISCUSSION: This patient developed D-penicillamine induced pemphigus, a rather
      frequent observation. The desmoglein immunolabelling favored drug-induced
      pemphigus and the course was rapidly favorable after withdrawal. Pemphigus had
      developed simultaneously with signs of myasthenia and polymyositis. Polymyositis
      and myasthenia are also known complications of D-penicillamine therapy. The
      association of these three complications suggests that D-penicillamine can unmask
      certain antigens or have an immunomodulator effect.

PMID- 10352833
TI  - [Neonatal monoblastic leukemia revealed by transitory specific skin lesions].
AB  - BACKGROUND: Specific cutaneous involvement is frequently observed in congenital
      leukemia and may be the inaugural sign. Lesions may be non-specific and even
      regress spontaneously, misleading diagnosis and delaying care. CASE REPORT: A
      infant in good health had diffuse ecchymotic maculae at birth which totally
      regressed within 10 days. On day 20, a macular rash and three violet nodules
      developed. The physical examination found enlarged nodes, liver enlargement and
      poor general status. Blood cell counts and the myelogram led to the diagnosis of
      type 5 acute myeloblastic leukemia (AML 5). Search for extension revealed
      cutaneous leukemia and meningeal and renal involvement. DISCUSSION: The
      predominance of myelocyte forms is specific for neonatal leukemia (AML 5 and 4).
      Specific skin lesions are frequent (25 to 30 p. 100 of cases) and sometimes
      precede (7 p. 100) anomalies in peripheral and medullary smears. Skin biopsy with
      direct smear can provide rapid diagnosis. Classically subcutaneous nodules or
      bluish macropapulae give the blueberry muffin baby aspect. The polymorphous
      features and the remarkably fluctuating skin lesions in our case are unusual,
      especially since the infant did not have spontaneously reversible neonatal
      leukemia, a rare unpredictable phenomenon described in newborns with a normal
      phenotype which can mislead therapeutic management.

PMID- 10352834
TI  - [The profile of skin diseases in Lebanon].

PMID- 10352835
TI  - [Anaphylactic reaction after local injection of GM-CSF in venous leg ulcer].

PMID- 10352836
TI  - [Quality of life assessment in patients with chronic disease: fundamental
      principles].

PMID- 10352837
TI  - [Quality of life evaluation: public health aspects].

PMID- 10352838
TI  - [Quality of life evaluation tools in dermatology].

PMID- 10352839
TI  - [Quality of life in dermatology: limitations and uncertainties].

PMID- 10352840
TI  - [Developmental genes: definitions and contribution to skin biology].

PMID- 10352841
TI  - [Is vascular laser for facial erythro-blotches contraindicated in patients with
      systemic lupus erythematosus?].

PMID- 10352842
TI  - [Do late drug-induced erythematous reactions exist?].

PMID- 10352843
TI  - [Acute urticaria in infants and young children].

PMID- 10352844
TI  - [The cutaneous drug reaction database].

PMID- 10352845
TI  - Public health in the twentieth century: advances and challenges.
AB  - Substantial advances in public health methods, practice, and the health of the
      public have occurred in the twentieth century. Some of the contributions most
      notable for their impact on mortality and longevity are vaccine development and
      widespread use, smallpox eradication, large reductions in communicable disease
      epidemics, and the rise and decline of several serious chronic diseases. Many
      methodological advances have facilitated better understanding of disease
      processes and opportunities for control. Epidemiological methods have advanced,
      but studies often ignore the determinants of health at the community level and
      above, leading to simplistic formulations of multiple risk factors contributing
      to chronic and other diseases and injuries. Occupational and environmental health
      developed as disciplines in this century, making significant contributions to
      current and future population health. The health care system became more
      organized, technologically sophisticated, and costly. New tools to assess health
      and the burden of ill health, to improve the effectiveness of interventions, and
      to measure economic effects of alternative investments promise greater efficiency
      and effectiveness for public health. An increasingly fragmented public health
      infrastructure must confront unprecedented challenges including dramatic global
      population growth, increased aging of the population associated with enhanced
      longevity, and possible irreversible changes in key environmental health
      determinants.

PMID- 10352847
TI  - A future for epidemiology?
AB  - This paper considers ways of thinking about causes and prevention that could
      guide epidemiology beyond the present era. Discontent with modern epidemiology,
      in the face of its substantial achievements, is taken as a sign that the guiding
      principles of the discipline warrant reconsideration. To begin this task, current
      practices are placed within an historical perspective, in a review of the
      dominant ideas of successive eras in epidemiology. Then the premises and
      constraints of the present era of chronic disease epidemiology, with its risk
      factor paradigm, are specified. Finally, elements of a causal paradigm for an
      emerging era are proposed. This paradigm encourages thinking about causes at
      multiple levels of organization and within the historical context of both
      societies and individuals. The proposed approach aims to preserve and build on
      the contributions of past eras, as well as the present one.

PMID- 10352846
TI  - Personal reflections on occupational health in the twentieth century: spiraling
      to the future.
AB  - The history of occupational health in the United States during the twentieth
      century demonstrates pendular swings, with periods of rapid progress followed by
      periods of reversal. Happily, the last three decades have witnessed the most
      impressive gains, with establishment of a near-universal system for regulating
      conditions in the workplace, legitimization and growth of the occupational health
      professions, a marked increase in scientific research, most notably epidemiology,
      and the transfer of knowledge about occupational health to affected workers and
      the larger US population. Not surprisingly, rates of injury and illness have
      fallen. However, analysis of these cyclical historic changes suggests that
      extrinsic factors--broad social currents, changes in health care financing, and
      societal perceptions of health and disease--have dominated over enhanced
      scientific knowledge, technologic changes or professional achievements, usually
      the determinants of medical or public health advances. Practitioners of
      occupational health are not, and have never been, in a particularly advantageous
      position to fashion future events in their own field, and the current situation,
      however encouraging, is likely no exception.

PMID- 10352848
TI  - Lessons in environmental health in the twentieth century.
AB  - Environmental health has evolved rapidly in recent decades, drawing largely on
      new analytic technologies, advanced data acquisition and modeling, mechanistic
      studies in toxicology, and the conceptual framework of risk assessment. The
      latter combines toxicologic and epidemiologic data with improved techniques for
      quantifying exposure, producing estimates of risks from environmental hazards or
      conditions to selected target populations. The public and governments have become
      increasingly concerned with environmental health and quality. The major lessons
      have been (a) environmental-health scientists must participate in policy debates;
      (b) environmental health problems are exceedingly complex and require
      interdisciplinary research; and (c) environmental health is a global issue. The
      globalization of commerce, the untested impact of international trade agreements,
      increased migration, and especially increased population, have profound impact on
      the quality as well as availability of air, water, land, and food. Global
      atmospheric transport of pollutants and the effect on atmosphere and climate are
      two examples of globalization of environmental health.

PMID- 10352849
TI  - US health care: a look ahead to 2025.
AB  - The chapter begins with a reminder that forecasting changes in the health care
      sector a quarter to a third of a century in the future is likely to be a losing
      effort, based on past experience. It next considers changing organization and
      financing and questions that managed care and market competition will be the key
      forces introducing change. The author looks forward to the passage of universal
      health insurance coverage for essential care by early in the new century, with
      patients having to pay for more choice and more quality. The analysis next
      focuses on the physician supply and points to three challenges: how to moderate
      the numbers being trained; whether to reconsider the conventional wisdom of
      training more generalists; and how to support more resources for the National
      Health Service Corps to improve coverage in underserved areas. The author
      predicts the restructuring of acute care hospitals, with a marked reduction of in
      patient beds, and that leading-edge research-oriented academic health centers
      should be able to remain out in front. There are also potential gains in health
      status from prevention and molecular medicine in a nation where chronic disease
      will dominate.

PMID- 10352850
TI  - Health education's contributions to public health in the twentieth century: a
      glimpse through health promotion's rear-view mirror.
AB  - A lesson of the first half of the century was that growth and technological
      development brought new health problems and challenges in their wake, many of
      which were to prove more intractable to technological fixes than the ones that
      had been so dramatically fixed before. Massive expansions of resources in support
      of the extension of these medical fixes resulted in an escalation of costs that
      had to be reigned in by breaking from the resource-based planning cycle that had
      prevailed through two eras of expansion. The 1970s ushered in an era of cost
      containment as the central theme of new policies. They included provisions for
      health promotion that sought to find new handles on the intractable social and
      behavioral aspects of the demand for health care resources, especially through
      primary prevention and building of capacity for community, family, and individual
      self-management of health problems and programs. Lessons from this era for public
      health in the next century are considered.

PMID- 10352851
TI  - Understanding changing risk factor associations with increasing age in adults.
AB  - With an increasingly older population, there is considerable interest in
      understanding the potential for risk factor interventions in order to prevent,
      postpone, or slow down the common diseases seen in older persons. However, it is
      often reported that the strength of association between risk factors and common
      disease outcomes decreases with increasing age. Actually, many different age
      related patterns are observed. Understanding these patterns requires knowledge of
      issues related to the pathophysiology of aging, including age-related physiologic
      and metabolic alterations, detection and diagnosis of disease in the elderly,
      measurement of risk factors, sample selection, comorbidity, competing risks,
      selective survival, ceiling effects, and methods of analysis in aging
      populations.

PMID- 10352852
TI  - Advances in clinical trials in the twentieth century.
AB  - This article considers the rise of the randomized clinical trial during the
      twentieth century. Before such development could begin, probability and
      statistics needed to merge. Sir RA Fisher introduced randomization in the 1920s
      and, beginning in the 1930s and 1940s, randomized clinical trials in humans were
      being performed by using the statistical-hypothesis-testing paradigm.
      Randomization gave unbiased comparisons and a way to perform hypothesis testing
      without model assumptions. To preserve the benefits of randomization, a type of
      analysis called intent-to-treat analysis is appropriate. Needed development has
      occurred and is occurring in refining ethical standards, monitoring trials of
      serious irreversible endpoints while preserving type-I error, and instituting
      independent data- and safety-monitoring boards. Recent methodology has also been
      concerned with the appropriateness of using surrogate endpoints. A current area
      of debate is the appropriateness of using Bayesian statistical methods in this
      context.

PMID- 10352853
TI  - Methods for analyzing health care utilization and costs.
AB  - Important questions about health care are often addressed by studying health care
      utilization. Utilization data have several characteristics that make them a
      challenge to analyze. In this paper we discuss sources of information, the
      statistical properties of utilization data, common analytic methods including the
      two-part model, and some newly available statistical methods including the
      generalized linear model. We also address issues of study design and new methods
      for dealing with censored data. Examples are presented.

PMID- 10352854
TI  - Time-dependent covariates in the Cox proportional-hazards regression model.
AB  - The Cox proportional-hazards regression model has achieved widespread use in the
      analysis of time-to-event data with censoring and covariates. The covariates may
      change their values over time. This article discusses the use of such time
      dependent covariates, which offer additional opportunities but must be used with
      caution. The interrelationships between the outcome and variable over time can
      lead to bias unless the relationships are well understood. The form of a time
      dependent covariate is much more complex than in Cox models with fixed (non-time
      dependent) covariates. It involves constructing a function of time. Further, the
      model does not have some of the properties of the fixed-covariate model; it
      cannot usually be used to predict the survival (time-to-event) curve over time.
      The estimated probability of an event over time is not related to the hazard
      function in the usual fashion. An appendix summarizes the mathematics of time
      dependent covariates.

PMID- 10352855
TI  - Lessons from 12 years of comparative risk projects.
AB  - Can an analytical tool for comparing environmental risks and policy activities be
      used to evaluate their relative efficacy in ultimately changing the allocation of
      public funds? Some insight is possible through a review of comparative risk
      projects that have been carried out at the city, state, and national levels, as
      well as among Indian tribes, over the past 12 years. The lessons from this review
      should apply to the field of public health. For every comparison of environmental
      issues, such as clean-air standards with fish consumption advisories, there is a
      parallel discussion of public health priorities and strategies, such as
      antismoking and pregnancy prevention programs, immunization programs and disease
      surveillance efforts, or well-baby clinics and food safety programs. Lessons from
      comparative risk projects and processes may offer the public health community new
      ways of thinking about using stakeholder assessment processes in developing
      public health policy.

PMID- 10352856
TI  - Unexplained increases in cancer incidence in the United States from 1975 to 1994:
      possible sentinel health indicators?
AB  - To search for unexplained patterns in cancer incidence, we analyzed data from
      1975 to 1994 that represent approximately 10% of the population of the United
      States. Our analysis focused on long-term time trends in incidence and on
      deviations from those trends attributable to birth cohorts or to calendar
      periods. On average, cancer incidence rose 0.8% annually in white women and 1.8%
      in white men. After removing several cancers related to smoking and increased
      screening, average annual increases fell to 0.1% in white women but persisted at
      1.7% in white men. In particular, yearly increases in non-Hodgkin's lymphoma
      averaged 2.4% in white women and 4.7% in white men. Among men, incidence changes
      attributable to cohorts grew progressively larger from one cohort to the next.
      Cancer incidence patterns among black men and women were similar to those among
      whites despite smaller population sizes. Unexplained patterns of cancer incidence
      may signal changes in underlying risk factors and highlight the continuing need
      for research on cancer etiology and prevention.

PMID- 10352857
TI  - Eradication of vaccine-preventable diseases.
AB  - Eradication is the permanent reduction to zero of the worldwide incidence of
      infection caused by a specific agent as a result of deliberate efforts;
      intervention measures are no longer needed. To date, the only infectious disease
      that has been eradicated is smallpox. Poliomyelitis is targeted for eradication
      by the year 2000, and the eradication initiative is well under way, with the
      Western Hemisphere certified as being polio-free and more than one year having
      passed since polio cases occurred in the Western Pacific Region of the World
      Health Organization. A review of the technical feasibility of eradicating other
      diseases preventable by vaccines currently licensed for civilian use in the
      United States indicates that measles, hepatitis B, mumps, rubella, and possibly
      disease caused by Haemophilus influenzae type b are potential candidates. From a
      practical point of view, measles seems most likely to be the next target. Global
      capacity to undertake eradication is limited, and care must be taken to ensure
      that a potential measles eradication effort does not impede achievement of polio
      eradication. Even in the absence of eradication, major improvements in control
      are both feasible and necessary with existing vaccines. New and improved vaccines
      may give further possibilities of eradication in the future. Eradication
      represents the ultimate in sustainability and social justice.

PMID- 10352858
TI  - Immunization registries in the United States: implications for the practice of
      public health in a changing health care system.
AB  - Although immunization rates among children are rising across the country, rates
      in inner-city areas have remained at approximately 50%-60%, < or = 30% lower than
      corresponding suburban or state immunization levels. The failure to raise
      immunization levels in poor, underserved populations is caused in part by the
      lack of timely and accurate child-specific immunization information for providers
      and parents. Immunization registries are a new tool in health care that can be
      used to address these and other barriers to effective immunization delivery.
      Moreover, immunization registries have the potential to help health care
      officials track and improve delivery for a broad range of important child health
      services. An immunization registry is a computerized database of information on
      children (usually preschool-age children) in a defined population (e.g. those
      enrolled in a health maintenance organization or living in a specific geographic
      area), which is used to record and track all immunizations received by each
      child. The registry receives the information primarily from public and private
      providers that administer immunizations, as well as from parents, schools, and
      other agencies. A fully functioning immunization registry can be used to identify
      individual children in need of immunizations and to report on immunization rates
      by population characteristics such as child age, assigned provider, or geographic
      area (e.g. neighborhood, city). Today, > 250 local public health departments have
      immunization registries that are in various stages of planning or development.
      Only a small number of these registries meet the minimum functional criteria of
      maintaining records on 95% of all eligible 2-year-old children in the target
      population and providing an electronic immunization record that is accessible to
      providers. Nascent immunization registries represent innovative technologic
      solutions to the challenge of monitoring health problems and health care access
      on a population basis. This is a fundamental activity of public health agencies,
      but one that is increasingly shared by large health maintenance organizations.
      The study of the development of immunization registries across the United States
      provides an important case study for how public health agencies will use the
      rapidly developing health information infrastructure to perform health assessment
      and health assurance activities in a managed care environment.

PMID- 10352860
TI  - The social environment and health: a discussion of the epidemiologic literature.
AB  - The environment can be thought of in terms of physical and social dimensions. The
      social environment includes the groups to which we belong, the neighborhoods in
      which we live, the organization of our workplaces, and the policies we create to
      order our lives. There have been recent reports in the literature that the social
      environment is associated with disease and mortality risks, independent of
      individual risk factors. These findings suggest that the social environment
      influences disease pathways. Yet much remains to be learned about the social
      environment, including how to understand, define, and measure it. The research
      that needs to be done could benefit from a long tradition in sociology and
      sociological research that has examined the urban environment, social areas,
      social disorganization, and social control. We summarize this sociological
      literature and discuss its relevance to epidemiologic research.

PMID- 10352859
TI  - Teen pregnancy prevention: do any programs work?
AB  - This paper begins with a review of the problem of teen pregnancy in the United
      States. Domestic trends are compared with those of other developed countries.
      Antecedents of the problem are discussed. New developments in addressing the
      problem are then described, including the following: (a) a renewed emphasis on
      abstinence on the one hand; (b) a move toward a more positive view of teen
      sexuality on the other; (c) the development of new prevention initiatives such as
      STD/HIV/AIDS prevention programs, community-wide teen pregnancy prevention
      collaboratives, broad-based youth development programs, and state and local
      government initiatives; and (d) the lauching of the National Campaign to Prevent
      Teen Pregnancy. An analysis of the different ways in which the problem can be
      framed and the implications for solutions of the problem follow. Examples of
      promising teen pregnancy and STD/HIV/AIDS prevention programs are provided. The
      paper ends with a recommendation for an eclectic approach to framing the problem
      and possible solutions.

PMID- 10352861
TI  - Health status assessment methods for adults: past accomplishments and future
      challenges.
AB  - Over the past 30 years, health status assessment methods for adults have
      proliferated. Numerous generic, disease-specific, and preference-based measures
      now exist that tap diverse aspects of functioning, well-being, symptom states,
      and subjective perceptions of health. The evolution of the state of the art in
      adult health status assessment is reviewed. Applications of these tools in health
      services research, health policy, and clinical practice are discussed.
      Recommendations are offered for selecting among the armamentaria of tools.
      Conceptual and methodological challenges that confront instrument users and
      developers alike are identified and discussed.

PMID- 10352862
TI  - Patient Outcomes Research Teams: contribution to outcomes and effectiveness
      research.
AB  - This paper describes the key methodological and substantive findings of Patient
      Outcomes Research Teams, the first outcomes and effectiveness research centers
      funded by the Agency for Health Care Policy and Research. Patient Outcomes
      Research Teams contributed to our increased understanding of how to perform meta
      analysis on nontrial data, use administrative data to characterize patterns of
      care, develop general and disease-specific outcome measures, and disseminate
      important outcome information to patients and physicians to reduce practice
      variation. Patient Outcomes Research Teams also influenced the development of
      outcomes measurement in the private sector.

PMID- 10352863
TI  - Pharmacy benefit management companies: dimensions of performance.
AB  - Research on pharmacy benefit management companies focuses on descriptive accounts
      of the organizations and the scope of their services. This review provides a
      critical analysis of publicly available research on contemporary issues
      surrounding the operations and effects of pharmacy benefit management companies.
      There has been very little systematic, empirical research on these issues; major
      questions concerning the impact of pharmacy benefit management companies on
      quality, costs, and patient outcomes remain unanswered. We analyze what is known
      and what needs to be known, and we explore major research challenges that lie
      ahead in the assessment of the pharmacy benefit management company's role in the
      health care system and in improving the public's health.

PMID- 10352864
TI  - The key to the door: Medicaid's role in improving health care for women and
      children.
AB  - Medicaid is the nation's major public financing program for providing health
      insurance coverage and long-term care services to the poor. This article assesses
      Medicaid's contributions over the last three decades to improving the coverage,
      access to care, and health of low-income children and women. The article reviews
      Medicaid's impact on the low-income population covered by this program,
      demonstrating both the role insurance plays and its limitations as a strategy for
      improving the health of vulnerable populations. Medicaid has shown over the last
      three decades that it is an important lever to help open the door to better
      health care, and ultimately to improved health for America's poor women and
      children, by substantially expanding coverage of the low-income population and
      helping to reduce differentials in access to care between the poor and the
      privately insured. Gaps in coverage and limitations in access persist, but
      overall the program has resulted in better coverage, access, and health care for
      millions of poor children and their parents.

PMID- 10352865
TI  - Neurosciences in Germany.

PMID- 10352866
TI  - Apolipoprotein E and Alzheimer's disease: a genetic, molecular and neuroimaging
      review.
AB  - Alzheimer's disease (AD) is the most common cause of dementia in the elderly and
      an increasingly significant health concern in our aging population. In the past
      10 years, our understanding of this disease has increased dramatically. While the
      discovery of three rare genetic mutations that can cause AD has provided much
      information about the causes and progression of the disease, a great deal of
      attention has been focused on apolipoprotein (ApoE) because of its involvement in
      the more common, later onset form of AD. Due to the rapid pace of recent
      advances, it has not been easy for health care professionals, researchers and the
      general public to keep abreast of these developments. This paper reviews recent
      research in ApoE and late-onset AD, emphasizing molecular neuropathological,
      genetic and neuroimaging findings and highlighting current controversies that
      remain to be addressed.

PMID- 10352867
TI  - Management of Parkinson's disease a review of current and new therapies.
AB  - The management of Parkinson's disease has undergone recent changes with the
      advent of new therapies, both pharmacotherapy and surgery. Available
      interventions are discussed. Levodopa remains the mainstay of therapy. New drugs
      include the dopamine agonists and COMT inhibitors. New dopamine agonists which
      may have a levodopa "sparing effect;" it has been suggested that some of the
      drugs should be considered as first line treatments for newly diagnosed
      Parkinson's disease patients. We review roles of these drugs. The concept of
      neuroprotection in neurodegenerative disorders such as Parkinson's disease became
      popular in the mid 1980s and it is hoped that eventually therapy will be directed
      at slowing progression of the disease. A great deal more work needs to be done
      before a suitable agent is identified as being neuroprotective. Potential
      neuroprotective agents are reviewed. Surgical therapies for Parkinson's disease
      consisting of various forms of lesion surgery as well as stimulation procedures
      are reviewed. Complications of drug therapy include motor problems such as motor
      response fluctuations, as well as psychiatric complications including levodopa
      induced psychosis. Atypical neuroleptic agents and ECT for psychiatric syndromes
      associated with Parkinson's disease are discussed. Algorithms for the management
      of early disease as well as the management of psychosis in Parkinson's disease
      are included. Treatment options for advanced disease are tabulated.

PMID- 10352869
TI  - Seizures in the elderly: etiology and prognosis.
AB  - PURPOSE: To determine the etiology, early mortality, predictors of prognosis and
      diagnostic yields of EEG and CT scans of the head in new-onset seizures in
      elderly patients. METHODS: EEG records for the north-central region of
      Saskatchewan, between 01/94 and 12/95 were reviewed to identify all adults aged
      60 years or older with new-onset seizures. Information on demographics, seizure
      type, etiology, EEG and neuroimaging studies, anti-epileptic treatment and course
      of epilepsy was obtained by review of medical records and interview with the
      patient and/or family member. RESULTS: Of 88 eligible subjects, 61 (69%) were
      contacted for follow-up, 19 (22%) were deceased (12 of whom who had a serious
      underlying etiology to their seizures, which was obvious at the time of initial
      presentation and led shortly to their demise), 4 (5%) were lost to follow-up and
      4 (5%) refused participation. Excluding those refusing participation, 74/84 (88%)
      patients presented with partial or secondarily generalized seizures. Seizures
      were cryptogenic in 38/84 (45%), and due to stroke in 19/84 (23%). EEGs were
      abnormal in 61/84 (73%) cases, with epileptiform discharge in 33/84 (39%). CT
      scans were abnormal in 57/84 (68%) cases with acute pathology in 29/84 (35%). Of
      the 61 patients participating in the follow-up interview, 54 (89%) were treated
      with anti-epileptic medication and seizure control was usually successful.
      Predictors for ongoing seizures were more than 3 seizures at presentation,
      epileptiform activity on initial EEG and discontinuation of anti-epileptic
      medication for lack of efficacy. CONCLUSION: Prognosis of new-onset seizures in
      elderly patients is favorable if seizures are not symptomatic of a life
      threatening disorder.

PMID- 10352870
TI  - Access to multiple sclerosis diagnosis for Canadian neurologists.
AB  - BACKGROUND: Access to multiple sclerosis (MS) diagnosis in Canada has never been
      assessed. This study was designed to examine the pattern of MS diagnosis in
      Canada, including neurologists' diagnostic approach and waiting times for
      investigations. METHODS: A mail survey was forwarded to every registered
      neurologist in Canada (n = 479) in late 1996. Questions included their diagnostic
      approach to MS including perceived waiting times for various investigations
      including MRI. Actual MRI waiting periods were separately obtained from booking
      clerks or neuroradiologists from every MRI unit in Canada. RESULTS: 153 responses
      were received. Neurological assessment is obtained, on average, 1 month after
      referral. MRI is routinely ordered by 92% of neurologists for suspected MS
      followed by evoked potentials (EP) (36%) and lumbar puncture (LP) (17%). The
      perceived waiting period for EP and LP is less than one month but 3 months for
      MRI. This is very similar to the actual waiting periods obtained from the MRI
      units surveyed (mean of 101 days). There is a trend for longer waiting periods as
      one moved east to west (Eastern provinces--mean of 62 days, Ontario--95 days,
      Quebec--102 days and 122 days in the Western provinces). Private MRI units have
      appeared in the Western provinces and have the shortest waiting periods (2 weeks
      maximum). The current MRI/million population ratio in Canada is 1.8, far below
      the ratios of other developed nations. CONCLUSIONS: Canadian neurologists prefer
      MRI of the brain to confirm an MS diagnosis and desire greater access to it.
      Access to neurological assessment, EP and LP is probably adequate but the average
      wait for MRI of 3 months is relatively long. The perceived average waiting period
      for MRI is similar to the actual waiting times of 3 months, with the Western
      provinces of Canada having the longest waits. Canada continues to have one of the
      lowest MRI/population ratios in the developed world.

PMID- 10352868
TI  - Relationship between O6-methylguanine-DNA methyltransferase levels and clinical
      response induced by chloroethylnitrosourea therapy in glioma patients.
AB  - BACKGROUND: Adjuvant nitrosourea chemotherapy fails to prolong survival
      significantly as many tumors demonstrate resistance to these drugs. It has been
      documented in cell lines that O6-methylguanine DNA methyltransferase (MGMT) plays
      an important role in chloroethylnitrosourea (CENU) drug resistance. METHODS: We
      evaluated MGMT expression in 22 glioma specimens by using an immunofluorescence
      assay and compared the results with clinical responses of the patients to CENU
      based chemotherapy. RESULTS: Eight tumor samples had no detectable MGMT, whereas
      other samples had from 9,989 to 982,401 molecules/nucleus. In one group (12
      patients), the tumor decreased in size or was stable (effective group), whereas
      in the other group (10 patients), the tumor demonstrated continuous growth during
      chemotherapy (progressive group). The Mer- patients (MGMT < 60,000
      molecules/nucleus) appeared to have more chance of stable disease or response to
      CENU therapy than the Mer+ patients (MGMT > 60,000 molecules/nucleus) (X2 =
      4.791, p = 0.0286). In patients with glioblastomas multiforme (GBMs), the median
      time to progression (TTP) of Mer+ patient was shorter than that of Mer- patient
      (t = 2.04, p = 0.049). As a corollary, the MGMT levels were significantly higher
      in GBM tumors from the progressive group than those from the effective group (t =
      2.26, p = 0.029). However, there was no significant correlation between MGMT
      levels and either the survival time (r = 0.04, p = 0.8595) or TTP (r = 0.107, p =
      0.6444). CONCLUSION: This study suggests that being MGMT positive is indicative
      of a more aggressive disease that progresses more rapidly with CENU therapy.
      However, MGMT negative tumors are not always sensitive to CENU agents, suggesting
      that other factors are also important.

PMID- 10352871
TI  - The prevalence of motor neurone disease in the Province of Alberta.
AB  - Using data from the Alberta Health Care Insurance Plan, the prevalence of motor
      neurone disease (MND) was estimated for the Province of Alberta, Canada. Between
      January 1, 1994 and December 31, 1995, 208 cases of MND (125 males, 83 females)
      were identified from physician billing records giving a period prevalence of 7.38
      (8.9 for males, 5.9 for females) per 100,000 population. On prevalence day, July
      1, 1995, there were 171 cases (103 males, 68 females) of MND giving a point
      prevalence estimate of 6.07 (7.3 for males, 4.8 for females) per 100,000
      population. Males were more likely to be diagnosed (OR = 1.52, 95% CI 1.1, 2.1)
      with MND and there was an increased risk of receiving a diagnosis with increasing
      age (chi 2trend = 281, p < 0.001). The mean age of the cases was 59.2 years (58.5
      for males, 60.3 for females) and did not differ significantly between the sexes.
      Geographically, there was no statistically significant difference in the
      prevalence across regions of the Province. During the study period, 28% of the
      cases had died (30% of males, 25% of females). The prevalence of MND in Alberta,
      is among the highest reported in the literature and requires additional
      investigation to verify these estimates and identify possible causative factors.

PMID- 10352872
TI  - Botulism: heart rate variation, sympathetic skin responses, and plasma
      norepinephrine.
AB  - BACKGROUND: Botulism may involve the autonomic nervous system. METHODS: We
      assessed the autonomic function of 6 botulism patients with heart rate
      variations, sympathetic skin responses, and plasma norepinephrine. RESULTS: Two
      weeks after onset, all the patients had absent sympathetic skin response in the
      palm and sole. Compared with controls, the heart rate variation of botulism
      patients was significantly decreased at rest (3.1 +/- 1.2% vs. 20.9 +/- 2.0%, p =
      0.0018) and during deep breathing (4.3 +/- 2.3% vs. 29.7 +/- 2.6%, p = 0.0018).
      The botulism patients had significantly lower plasma norepinephrine levels
      (supine 29.2 +/- 10.1 pg/ml vs. 257.5 +/- 65.8 pg/ml, p = 0.0018; standing 40.3
      +/- 13.1 pg/ml vs. 498.5 +/- 85.6 pg/ml, p = 0.0018). The heart rate variation
      and sympathetic skin response was greatly improved 6 months after onset.
      CONCLUSIONS: Heart rate variation, absence of sympathetic skin response, and low
      plasma norepinephrine are all manifestations of autonomic dysfunction in botulism
      patients.

PMID- 10352873
TI  - Diffuse Lewy body disease presenting as multiple system atrophy.
AB  - OBJECTIVES: The majority of patients with diffuse Lewy body disease have
      cognitive or psychiatric manifestations as part of their initial presentation. A
      sizable minority present with parkinsonian features alone. Autonomic features may
      also occur, typically after the development of cognitive changes. We aim to
      demonstrate that diffuse Lewy body disease may rarely also present with
      parkinsonism accompanied by marked autonomic dysfunction in the absence of
      significant cognitive or psychiatric abnormalities. METHODS: Case report based on
      a retrospective chart review and neuropathological examination. RESULTS: We
      report on a patient in whom a clinical diagnosis of multiple system atrophy was
      made based on a presentation of parkinsonism with prominent and early autonomic
      involvement. The former included postural tremor, rigidity and bradykinesia,
      while the latter consisted of repeated falls due to orthostasis and the
      subsequent development of urinary incontinence midway through the course of her
      illness. She was poorly tolerant of dopaminergic therapy due to accentuated
      orthostasis. Benefit from levodopa was limited and only evident when attempted
      withdrawal resulted in increased rigidity. There was no history of spontaneous or
      drug-induced hallucinations, delusions or fluctuating cognition, and in contrast
      to the prominence and progression of her parkinsonian and autonomic features over
      the first several years, cognitive impairment did not occur until the final
      stages of her illness, seven years after the onset of initial symptoms.
      Neuropathological examination revealed numerous Lewy bodies in both neocortical
      as well as subcortical structures consistent with a diagnosis of diffuse Lewy
      body disease. There was marked neuronal loss in the substantia nigra as well as
      the autonomic nuclei of the brainstem and spinal cord. CONCLUSIONS: In addition
      to cognitive, psychiatric, and parkinsonian presentations, diffuse Lewy body
      disease may present with parkinsonism and prominent autonomic dysfunction,
      fulfilling proposed criteria for the striatonigral form of MSA.

PMID- 10352874
TI  - Neurosciences in the Third Reich: from Ivory Tower to death camps.
AB  - It is commonly thought that the horrific medical abuses occurring during the era
      of the Third Reich were limited to fringe physicians acting in extreme locales
      such as the concentration camps. However, it is becoming increasingly apparent
      that there was a widespread perversion of medical practice and science that
      extended to mainstream academic physicians. Scientific thought, specifically the
      theories of racial hygiene, and the political conditions of a totalitarian
      dictatorship, acted symbiotically to devalue the intrinsic worth to society of
      those individuals with mental and physical disabilities. This devaluation served
      to foster the medical abuses which occurred. Neurosciences in the Third Reich
      serves as a backdrop to highlight what was the slippery slope of medical practice
      during that era. Points on this slippery slope included the "dejudification" of
      medicine, unethical experimentation in university clinics, systematic attempts to
      sterilize and euthanasize targeted populations, the academic use of specimens
      obtained through such programs and the experimental atrocities within the camps.

PMID- 10352875
TI  - IGIV in neurology--evidence and recommendations.
AB  - OBJECTIVE: To summarize the evidence for neurologic uses of immunoglobulin,
      intravenous (IGIV) in light of present-day clinical usage. This summary guided
      the development of practice recommendations for the effective and efficient use
      of IGIV in Neurology. METHODS: MEDLINE was searched to identify pertinent English
      language review articles and original reports (n = 231) on the use of IGIV in
      neurology (excluding editorials, letters, and comments) published before March
      1998. Evidence on alternative therapies was only included as compared to IGIV.
      The relevant original reports and review articles and older classic studies (n =
      92) were synthesized into an information foundation. Extracted data included
      laboratory and clinical findings, objective measures, and clinical impressions.
      Clinical recommendations were based on evidence quality, graded by study design,
      clinical experiences of IGIV in Neurology Advisory Board members, and the
      conditions of IGIV use in therapy. RESULTS AND CONCLUSIONS: In neurology, many
      disorders are poorly understood, and the mechanisms behind beneficial regimens
      even less so. As a result, it is fairly common for best-practice decisions to
      rest on weaker evidence. The usefulness of IGIV in neurology can be described by
      a "combined score" based on evidence quality and strength of impact. Combined
      scores ranged from A+ (strongly recommended) to C (recommended as a last resort).
      The following clinical recommendations are made: IGIV is: strongly recommended
      for the treatment of Guillain-Barre syndrome (A+); favorably recommended for the
      treatment of chronic inflammatory demyelinating polyradiculoneuropathy,
      dermatomyositis, and multifocal motor neuropathy (A); recommended as a second
      resort for the treatment of multiple sclerosis and myasthenia gravis (B); and
      recommended as a last resort for the treatment of polymyositis, inclusion-body
      myositis, intractable epilepsies, and stiff-man syndrome (C).

PMID- 10352876
TI  - Minimal standards for digital/quantitative electroencephalography in Canada.

PMID- 10352877
TI  - Stereotactic radiosurgery for acoustic neuroma: a Canadian perspective.

PMID- 10352878
TI  - Rodent tumor models for anti-cancer drug testing: an overview.

PMID- 10352879
TI  - Preclinical assessment of anti-cancer therapeutic strategies using in vivo
      videomicroscopy.
AB  - Preclinical in vivo studies of agents targeted against metastasis have to date
      been based primarily on end-point assays. Such assays can determine whether a
      treatment affects the number or size of metastases in an organ at a given time,
      but are poorly suited to determining how and at what stage in the process the
      treatment affected the end point. High resolution in vivo videomicroscopy permits
      direct observation of the process of metastasis as it occurs in living animals
      over time. Studies based on this technique and a cell accounting procedure we
      have devised, have shown that early steps in the metastatic process (survival in
      the circulation, extravasation) contribute relatively little to cell loss and
      metastatic inefficiency. Steps that occur after extravasation appear to be
      primarily responsible for the significant losses that result in metastatic
      inefficiency, and these steps may represent good targets for the design of new
      antimetastatic therapies. Matrix metalloproteinases have been implicated
      functionally in metastasis, and are viewed as an appropriate target in the
      development of inhibitors of metastasis. Using both endogenous and synthetic
      exogenous metalloproteinase inhibitors, we have shown that the inhibition of
      metastasis which these agents produce is not due to inhibition of cell
      extravasation from the circulation into the tissue, but to reduction of
      angiogenesis within metastases. A similar conclusion was reached concerning the
      mechanism of action, on metastasis, of carboxyamidotriazole, an inhibitor of
      calcium-mediated signal transduction which is currently in Phase II single agent
      clinical trials. In vivo videomicroscopy of sequential steps in metastasis,
      coupled with methods that allow precise quantification of cell loss at specific
      steps in the metastatic process, as well as standard histological assessment at
      stages identified as crucial, allow characterization of the details of metastasis
      as an ongoing process. This provides a powerful complement to end-point assays,
      for it allows mechanistic information to be obtained from in vivo experiments, an
      approach which provides better understanding of how and when a drug may function
      in vivo to inhibit metastasis.

PMID- 10352880
TI  - Orthotopic transplant mouse models with green fluorescent protein-expressing
      cancer cells to visualize metastasis and angiogenesis.
AB  - There have been major efforts in metastasis research in recent years, especially
      on the role of angiogenesis in the metastatic process. Much of the information in
      this area has been obtained from model systems that are not representative of
      clinical cancer. The technique of surgical orthotopic implantation (SOI) has
      allowed the development of clinically relevant metastatic models of human cancer
      in immunodeficient rodents such as the nude and SCID mouse. In order to allow
      direct visualization of the metastatic process, we took advantage of the green
      fluorescent protein (GFP) of the jellyfish, Aequorea victoria. A series of cancer
      cell lines have been stably transfected with vectors containing humanized GFP
      cDNA. To utilize GFP expression for metastasis studies, fragments of
      subcutaneously growing tumor, which were comprised of GFP-expressing cells, were
      implanted by SOI in nude mice. Subsequent metastases were visualized in systemic
      organs by GFP fluorescence in the lung, liver, bones, brain and other organs down
      to the single-cell level. With this fluorescent tool, we detected and visualized
      for the first time tumor cells at the microscopic level in fresh viable tissue in
      their normal host organs even in the live animal. Angiogenesis is readily
      visualized in the transplanted GFP-expressing tumors in real time in situ in the
      live animal using simple laparotomy and fluorescent techniques. The results with
      the GFP-transfected tumor cells, combined with the use of SOI, demonstrate a
      fundamental advance to visualize and study cancer metastasis and the role of
      angiogenesis and other factors in the metastatic process.

PMID- 10352881
TI  - Orthotopic models are necessary to predict therapy of transplantable tumors in
      mice.
AB  - Rapid evaluation of new cytotoxic agents and biological response modifiers for
      therapy of cancer and elucidation of their mechanisms of action require the use
      of relevant animal models. It is well established that the faithful reproduction
      of the tumor microenvironment that allows the emergence of subpopulations of
      tumor cells with the biological and metastatic properties observed in clinical
      cancer occurs with orthotopic tumor models (transplantable and transgenic). This
      review summarizes the evidence that phenotypic properties of metastatic cells are
      governed by the expression of genes that are regulated by interaction with the
      relevant organ environment. While ectopic models of cancer allow rapid screening
      of new compounds and transgenic models afford opportunities to study early
      cellular and molecular events in tumor progression and metastasis, orthotopic
      transplantation of tumor cells remains an affordable, reproducible and reliable
      methodology for the study of organ-specific determinants of the biology and
      therapy of cancer.

PMID- 10352882
TI  - The bacterial lacZ gene: an important tool for metastasis research and evaluation
      of new cancer therapies.
AB  - The bacterial lacZ gene has been used to genetically tag tumor cells. This has
      been of value, specifically in metastasis research where it allowed to visualize
      micrometastases and single tumor cells in tissues. lacZ tagging has also provided
      the feasibility of re-isolating metastatic tumor cell populations for ex vivo
      molecular analyses. This review summarizes studies that have utilized lacZ tagged
      tumor cells to understand aspects of metastasis including dormancy, tumor-host
      interactions, gene modulation and anti-tumor immunity. lacZ tagging is also a
      valuable tool for evaluating cancer therapies.

PMID- 10352883
TI  - Why transgenic and knockout animal models should be used (for drug efficacy
      studies in cancer).

PMID- 10352884
TI  - What is the optimal rodent model for anti-tumor drug testing?
AB  - One of the most serious obstacles facing investigators involved in the
      development and assessment of new anti-cancer drugs is the failure of preclinical
      rodent tumor models to predict in a reliable way whether a given drug will have
      anti-tumor activity and acceptable toxicity in humans. Most previous
      investigations for assessing drug activity in vivo have utilized rapidly growing
      non-metastatic transplantable mouse or human tumors injected ectopically in
      syngeneic or nude mice, respectively. Some of the reasons for the inadequacy of
      such models are well known and, as a result, there has been a gradual movement
      toward the use of transgenic oncomouse models for anti-cancer drug testing. It is
      too early to conclude, one way or the other, whether these will be superior to
      transplantable tumor models. Moreover, such transgenic models have a number of
      limitations which are not widely appreciated. It is argued that transplantable
      tumor models, with various modifications, might be made significantly more
      predictive than current models, and would thus constitute a more economic
      alternative to the use of large numbers of transgenic oncomice. These
      modifications include the use of slower growing and genetically tagged (e.g. LacZ
      or GFP) tumors which are transplanted initially into orthotopic organ sites.
      These methods would facilitate the growth and detection of distant microscopic
      and macroscopic metastases, the response of which to anti-cancer drugs, using
      'clinically equivalent doses,' could be evaluated.

PMID- 10352885
TI  - Early development of the mullerian duct in avian embryos with reference to the
      human. An ultrastructural and immunohistochemical study.
AB  - In vertebrates, the female reproductive system arises from the Mullerian
      (paramesonephric) duct which develops in both sexes under the influence of the
      Wolffian (mesonephric) duct. For a better understanding of the interactions
      between the Mullerian duct and its adjacent tissues, we present a systematic
      scanning and transmission electron microscopic investigation of early stages of
      avian Mullerian duct development. This starts within the cranial part of the
      Mullerian ridge from a placode-like thickening and deepening of the coelomic
      epithelium containing nephrostomes as remnants of the last pronephric and first
      mesonephric tubules. Groups of cells detach from this placode and rapidly expand
      caudally as a solid cord. This becomes canalized, but the tip region remains
      mesenchymal and is found enclosed within the basal lamina of the Wolffian duct.
      Immunostaining reveals that the Mullerian duct migrates within a matrix rich in
      laminin and entactin. When the canalized duct has opened into the coelomic
      cavity, one or more secondary ducts are found immediately caudal of the main
      funnel, for a short period only, possibly to supply material to the expanding
      duct. BrdU-anti-BrdU reaction reveals a high proliferation of the duct
      epithelium. The thickened epithelium of the Mullerian ridge dissolves to form the
      mesenchymal layers of the duct. Immunostaining with vimentin argues against a
      cellular contribution of Wolffian duct cells to the Mullerian duct. Comparing the
      data from avian embryos with those of human indicates that the modalities of
      early Mullerian duct development are similar in both species.

PMID- 10352886
TI  - Modulation of alpha-actin and alpha-actinin proteins in cardiomyocytes by
      retinoic acid during development.
AB  - Early heart development is known to be sensitive to retinoid concentrations.
      Although the influence of retinoids on cardiac morphogenesis has been described
      previously, the effect of retinoids on cardiomyocyte differentiation during
      development has not been characterized. We quantified the effects of the retinoic
      acids all-trans RA and 13-cis RA on alpha-actin and alpha-actinin at the
      subcellular level in cultures of chick embryo cardiomyocytes obtained from
      Hamburger and Hamilton's (HH) stage 22, 32 and 40 embryos. The retinoids
      increased the concentration of alpha-actin and alpha-actinin in the cytoplasmic
      and cytoskeletal fractions of cells at all three stages of development. The
      effect was greatest in cardiomyocytes treated for 24 h with all-trans RA and in
      cells from HH22 embryos. The greatest increases in alpha-actin concentration
      occurred in the cytoskeletal fraction of HH22 cells cultured for 24 h with all
      trans or 13-cis RA, whereas the greatest increases in alpha-actinin were found in
      the cytoplasmic fraction of HH22 cells exposed to retinoids for 24 h. We conclude
      that retinoic acid plays a role in the reorganization of the pattern of
      sarcomeric protein expression during cardiomyocyte differentiation.

PMID- 10352887
TI  - Histological effects of vitamin A on the tail-amputated tadpoles of Polypedates
      maculatus with special reference to homeotic transformation.
AB  - Vitamin A is a very common teratogen causing severe embryonic malformations and
      changes in pattern formation in amphibians. The effects of vitamin A include the
      induction of duplication of skeletal structures in the anteroposterior,
      proximodistal and dorsoventral axes. The purpose of this investigation was to
      study the histological changes in the regenerating tail of the tadpoles of
      Polypedates maculatus by treatment with vitamin A. The histological changes
      brought about by vitamin A included the development of multilayered epidermis and
      thickened basement membrane, enlargement of the notochord and the nerve cord and
      the clumping of muscles. In addition, single, paired and supernumerary homeotic
      limbs were visible from day 20 onwards at ectopic sites. Initially, the limb
      consisted of only procartilage cells. Muscles and digits appeared from day 48
      onwards. In contrast, such observations were not found in the control tails. The
      significance of such changes is discussed.

PMID- 10352888
TI  - Microvascularisation of the lips in the fetus and neonate.
AB  - The differences observed in the microvascularisation of the lips in the perinatal
      period correspond to the differences in the histological structures of the
      cutaneous, glabra, intermediate cutaneous, villous, intermediate mucosal and
      mucosal parts. A basic pattern is found in each part: on the surface, a papillary
      or mucosal network, at a deeper level, reticular or submucosal networks and their
      pedicles. The vascular changes correspond to the transition of tissue
      (mucocutaneous junction) and are indicative of the functional aspect. The same
      histological and microcirculatory structures were found in all the preparations,
      irrespective of the subject's age. Knowledge of the microvascularisation makes it
      possible to interpret magnetic resonance imaging of the lip better and finds its
      application in the surgery of the lips.

PMID- 10352889
TI  - Anatomical variations in the origin of the human ophthalmic artery with special
      reference to the cavernous sinus and surrounding meninges.
AB  - The origin of the human ophthalmic artery (OA) and surrounding structures was
      investigated in 109 cadavers by three different methods: macroscopic,
      stereomicroscopic, and histological observations. The following results were
      obtained. (1) Macroscopic observation: In 39% of the specimens the origin of the
      OA was observable in the cranial cavity and defined as the intradural (i.d.)
      type. The other 61% were named the extradural (e.d.) type. (2) Stereomicroscopic
      observation: In 59% of the cases, the OA originated from the internal carotid
      artery over or on the cavernous roof and at least a part of the OA was exposed
      within the cranial cavity. In the other 41% the OA originated within the
      cavernous wall or cavity and entered directly the optic dural sheath, thus no
      part of the OA was visible in the cranial cavity. Therefore, approximately 20% of
      the origins of the OA might be of the i.d. type, although they could not be
      macroscopically identified in the cranial cavity since they might emanate from
      the internal carotid artery between the optic canal and the optic nerve, even
      above the cavernous roof. (3) Histological observation: The proximal portion of
      the OA runs alongside the optic nerve within the subarachnoid space in the cases
      of the i.d. type. In contrast, the corresponding portion of the e.d. type was
      embedded in the dense fibrous tissue which was continuous both with the dura
      mater of the cavernous wall and the periosteum of the sphenoid. These anatomical
      data may provide important information for understanding the variety of the
      pathology in this region and is also useful for designing operative strategies.

PMID- 10352890
TI  - Physical principles of magnetic resonance angiography.
AB  - This review provides a brief introduction to the basic concepts of MRA techniques
      with specific discussions on imaging of coronary arteries. These techniques,
      especially those for imaging of coronary arteries, are still rapidly evolving.
      The goals of future research include obtaining faster imaging, higher SNR, and
      higher resolution. These three aspects are closely interconnected and major
      breakthrough in one area could result in improvements in all three areas. Some of
      the areas of important developments in the future will include continued
      improvement of imaging hardware and software to allow use of even faster imaging
      techniques, further testing and development of intravascular contrast agents, and
      continued improvement of radiofrequency coils [37]. A key area of research for
      imaging of coronary arteries is further improvement of techniques for
      compensation for motion. MRA has played important clinical roles in many areas
      and will find more applications in the near future.

PMID- 10352891
TI  - Current developments in and future direction of coronary magnetic resonance
      angiography.

PMID- 10352892
TI  - Magnetic resonance imaging of the aorta and branch vessels.
AB  - Magnetic resonance imaging (MRI) can provide a comprehensive evaluation of the
      aorta and its major branches. T1-weighted spin-echo images and cine-MRI have long
      been known to be useful for the evaluation of congenital aortic anomalies, aortic
      aneurysms, and aortic dissections. Gadolinium (Gd)-enhanced three-dimensional
      magnetic resonance angiography (MRA) is a more recent development that affords
      better spatial resolution. This technique can be performed during an individual
      breath-hold and does not require electrocardiographic gating. The data from Gd
      enhanced three-dimensional MRA, furthermore, can be used both for projectional
      angiographic viewing and for multiplanar reformation. In this article, MRI of the
      aorta and its major branches will be reviewed, with emphasis on the newer
      technique of Gd-enhanced three-dimensional MRA.

PMID- 10352893
TI  - Magnetic resonance angiography of renal arterial stenosis.
AB  - Recent developments in renal magnetic resonance angiography (MRA) have led to a
      significant improvement in the technical success rate and diagnostic accuracy of
      the methods. Specifically, three-dimensional contrast-enhanced MRA methods have
      been shown to provide a more reliable depiction of renal artery morphology than
      do older MRA techniques. In addition, preliminary work using adjunctive MRA
      techniques suggests that it is possible to determine the hemodynamic significance
      of renal artery disease using MRA and magnetic resonance imaging. MRA methods
      will therefore likely play an important role in the evaluation of patients with
      renovascular disease.

PMID- 10352894
TI  - Magnetic resonance pulmonary angiography.
AB  - Just recently, use of magnetic resonance imaging for thoracic investigations has
      become increasingly appealing. This resurgence has been triggered by the enormous
      improvements in image quality with the development of scanners with faster data
      acquisition capabilities and the routine use of contrast agents. In particular,
      magnetic resonance pulmonary angiography, an examination that once had been
      hampered by blurring from respiratory and cardiac motion and magnetic
      susceptibility-related signal loss, has become a robust technique in this
      scenario. Initial efforts and current trends are reviewed, focusing on fast
      imaging protocols employing contrast agents that have provided exquisite images
      of the pulmonary vasculature. In addition, the recent introduction of magnetic
      resonance lung perfusion and ventilation scans has made available new potential
      methods for characterization of diseases that, combined with magnetic resonance
      pulmonary angiography, may provide for the first time the practical approach for
      the diagnosis of difficult conditions such as pulmonary embolism that has long
      been awaited.

PMID- 10352895
TI  - High dose dipyridamole myocardial imaging: simultaneous sestamibi scintigraphy
      and two-dimensional echocardiography in the detection and evaluation of coronary
      artery disease. Italian Group of Nuclear Cardiology.
AB  - BACKGROUND: Dipyridamole stress combined with echocardiography or perfusion
      scintigraphy can be used to detect coronary artery disease, but head-to-head
      comparative data are lacking. The aim of this study was to compare the relative
      accuracy of high-dose dipyridamole stress imaging (up to 0.84 mg/kg over 10 min)
      with two-dimensional echocardiography and sestamibi perfusion scintigraphy in
      detecting coronary artery disease. METHODS: One-hundred and one patients with a
      history of chest pain and no previous myocardial infarction, were studied
      simultaneously using planar perfusion scintigraphy and echocardiography during a
      high-dose dipyridamole stress, at seven different institutions. RESULTS: During
      coronary angiography, 21 patients had non-significant lesions, and 80 had
      significant lesions (> or = 50% diameter reduction): 37 had single-, 19 double-
      and 24 triple-vessel disease. Sensitivity for disease detection was 78% [95%
      confidence interval (CI) 67-86%] for echocardiography and 79% (CI 68-87%) for
      scintigraphy. The specificity was 76% (CI 67-84%) for echocardiography and 90%
      (CI 83-95%) for scintigraphy. The inter-center variation in accuracy ranged from
      50 to 100% for echocardiography (coefficient of variation 19.7%) and from 71 to
      100% for scintigraphy (coefficient of variation 15%). The angiographically
      assessed extent and severity of coronary artery disease, evaluated using the Duke
      score, was correlated to the extent and severity of perfusion defects with
      scintigraphy (r = 0.65, P < 0.0001) and regional wall motion abnormalities by
      echocardiography (r = 0.57, P < 0.0001). CONCLUSIONS: Perfusion scintigraphy and
      echocardiography have similar accuracies for the non-invasive identification of
      angiographically assessed coronary artery disease during high-dose dipyridamole
      stress. Inter-center variability in diagnostic accuracy is higher for
      echocardiography than scintigraphy. Both methods allow a reasonably accurate
      estimation of extent and severity of disease, via a semiquantitative assessment
      of extent and severity of perfusion of functional defects.

PMID- 10352896
TI  - Effects of nifedipine on myocardial blood flow and systolic function in humans
      with ischemic heart disease.
AB  - OBJECTIVE: To test the hypothesis that, in humans with ischemic heart disease,
      nifedipine is a primary dilator of the coronary circulation and in general exerts
      a net positive effect on the balance of myocardial oxygen supply and demand.
      METHODS: Positron-emission tomography with [13N]-ammonia was used to measure
      myocardial blood flow in patients at rest, and during infusion of adenosine and
      ingestion of nifedipine (10 mg capsule, a bite-and-chew technique). Myocardial
      segments were defined physiologically on the basis of blood flow to adenosine as
      being normal or having mild, moderate, or severe impairment of dilator reserve.
      Myocardial systolic function was assessed under comparable physiologic conditions
      using gated single-photon-emission computed tomography radionuclide
      ventriculography. RESULTS: Our study population consisted of 13 male patients and
      one female patient. Ingestion of nifedipine increased heart rate (from 63 +/- 11
      to 80 +/- 16 beats/min, P < 0.001) and, as intended, lowered systolic arterial
      pressure (from 148 +/- 20 to 123 +/- 14 mmHg, P < 0.001) but had no effect on
      heart rate-pressure product (which changed from 9283 +/- 1576 to 9942 +/- 2162
      mmHg/min). Myocardial blood flow in patients at rest in segments with mild,
      moderate, and severe reductions of dilator capacity (0.63 +/- 0.20, 0.67 +/-
      0.25, and 0.58 +/- 0.27 ml/min per g, respectively) was less (P < 0.01) than
      normal (0.91 +/- 0.29 ml/min per g). Nevertheless, flow of blood was increased
      versus that at rest (P < 0.01) by infusion of adenosine (to 1.78 +/- 0.13, 1.29
      +/- 0.16, and 0.75 +/- 0.22 ml/min per g) and ingestion of nifedipine (to 1.17 +/
      0.51, 1.06 +/- 0.36, 0.85 +/- 0.42 ml/min per g) in segments with mild,
      moderate, and severe reduction of dilator capacity as well as in normal segments
      (to 3.18 +/- 0.85 ml/min per g with adenosine and 1.68 +/- 0.65 ml/min per g with
      nifedipine). Global left ventricular systolic function remained unchanged versus
      baseline (ejection fraction 0.74 +/- 0.09) with nifedipine (0.76 +/- 0.10).
      Regional contraction expressed in normalized amplitude units also remained
      unchanged versus baseline in response to nifedipine. CONCLUSION: Nifedipine
      increases myocardial blood flow in humans with ischemic heart disease in normal
      segments as well as in segments with mild, moderate, and severe reductions of
      dilator capacity, albeit to a lesser extent with increasing impairment of dilator
      capacity. Both global and regional left ventricular contractile function also are
      not adversely affected by nifedipine. These improvements in myocardial blood flow
      in face of no change or a decrease in myocardial demand for oxygen reflect an
      overall favorable effect on the balance between the supply of and demand for
      myocardial oxygen.

PMID- 10352898
TI  - Bibliography. Current world literature.

PMID- 10352897
TI  - Electromechanical characterization of myocardial hibernation in a pig model.
AB  - BACKGROUND: This study attempted to assess in-vivo electromechanical changes
      following gradual coronary artery occlusion in a pig ameroid constrictor model
      using a novel three-dimensional left ventricular mapping system. METHODS AND
      RESULTS: We measured unipolar and bipolar voltage potentials and local
      endocardial shortening in the ischemic lateral and non-ischemic anterior zones in
      animals at rest (n = 9) 5 weeks after the implantation of ameroid constrictors
      around the left circumflex artery. Echocardiography was used to assess regional
      contractility (percentage myocardial thickening), and an echo-contrast perfusion
      study was performed using acoustic densitometry methods. The ischemic lateral
      zone showed reduced myocardial perfusion at rest (peak intensity; 3.4 +/- 1.7
      versus 20.7 +/- 14.8, P = 0.005), impaired mechanical function (percentage wall
      thickening 22 +/- 19% versus 40 +/- 11%, P = 0.03; local endocardial shortening
      2.9 +/- 5.5% versus 11.7 +/- 2.1%, P = 0.002), and preserved electrical activity
      (unipolar voltage 12.4 +/- 4.7 versus 14.4 +/- 1.9 mV, P = 0.25; bipolar voltage
      4.1 +/- 1.1 versus 3.8 +/- 1.5 mV, P = 0.62), compared with the anterior region.
      CONCLUSIONS: Gradual coronary artery occlusion resulting in regional reduced
      perfusion and function at rest (i.e. hibernating myocardium) is characterized by
      preserved electrical activity. An electromechanical left ventricular mapping
      procedure such as the one described here may be of diagnostic value for
      identifying the hibernating myocardium.

PMID- 10352899
TI  - Immune-derived cytokines in the nervous system: epigenetic instructive signals or
      neuropathogenic mediators?
AB  - The investigation of the effects of inflammatory cytokines (IC) on the growth and
      differentiation of neural cells has provided new insights on the role of such
      soluble mediators in nervous system development and/or plastic remodeling as well
      as in the pathogenesis of inflammatory neurodegenerative disorders, which are
      characterized by chronic IC dysregulation in the central nervous system (CNS).
      Thus, the study of the interaction between CNS and immune-derived soluble signals
      in physiological or pathological conditions is of increasing interest. This
      review first discusses experimental evidence supporting the
      instructive/permissive role of immune-derived cytokines on CNS development and
      plasticity. Next, we focus on human neurological disease states such as multiple
      sclerosis and the neurodegeneration associated to the acquired immune deficiency
      syndrome in which different inflammatory cytokines have been proposed as
      potential neuropathogenic mediators.

PMID- 10352900
TI  - Initiation of systemic autoimmunity and sequence specific anti-DNA
      autoantibodies.
AB  - Antibodies to double-stranded DNA (dsDNA) are a defining feature of Systemic
      Lupus Erythematosus (SLE). The molecular characterization of anti-dsDNA
      autoantibodies reveals that they are actively selected for binding to antigen.
      Evidence for antigen selection includes the use of suitable rearrangement
      products, the switching of IgM isotype to IgG, and the acquisition of somatic
      mutations that raise the affinity for dsDNA. Through a process of specificity
      maturation, anti-dsDNA antibodies can arise from anti-single stranded DNA (ssDNA)
      antibodies that also occur in nonautoimmune individuals. To clarify circumstances
      leading to the initiation of systemic autoimmunity, we compare features of immune
      responses to nucleic acids that operate before and after disease develops.
      Evidence indicating that anti-dsDNA antibodies bind with DNA sequence preference
      is highlighted to propose that sequence-specific anti-dsDNA antibodies may be
      induced by an infectious agent and in turn may extend the response to endogenous
      nuclear antigens. Thus, sequence-specific anti-dsDNA B cells may provide an
      important stimulus to break the tolerance to self.

PMID- 10352901
TI  - Transcriptional regulation in B cell differentiation.
AB  - B cell development is a multistage differentiation process that ultimately
      generates antibody-secreting plasma cells. This model developmental pathway is
      governed by a choreographed pattern of expression from genes encoding stage and
      lineage-specific proteins. This is achieved by the interaction of distinct
      transcription factors with regulatory elements, placing these proteins in a
      central position in B cell ontogeny. The importance of distinct transcription
      factors is also supported by the notion that B cell development is disrupted in
      mice bearing homozygous null alleles of certain factors involved in the control
      of B-cell-specific genes. In this review we compare and contrast the
      transcriptional regulation of well-studied B lymphoid restricted genes, on a gene
      by gene basis, focusing on the functional structure of transcription control
      regions and interacting transcription factors.

PMID- 10352902
TI  - Th1 and Th2 cytokines in organ transplantation: paradigm lost?
AB  - Identification of CD4+ T helper lymphocyte subsets that exhibit distinct cytokine
      elaboration patterns has provided a valuable framework for understanding the
      heterogeneity of the immune response. Much progress has been made in recent years
      in defining the cellular and molecular mechanisms by which cytokines induce T
      cell differentiation. In transplantation models, the Th1 cytokine profile often
      associates with allograft rejection, while the Th2 profile favors the acquisition
      of tolerance. However, this paradigm may not be sufficient to explain the
      recently demonstrated in vivo effects of cytokine manipulation on allograft
      survival. Th2 cytokines may not be necessary for tolerance induction, while Th1
      cytokines may even be beneficial in promoting allograft survival. However, such
      data should be interpreted in light of the diverse and often redundant effects
      displayed by cytokine networks in vivo. Understanding the complex interactions of
      cytokines in the alloimmune cascade therefore is critical for designing
      therapeutic strategies that abrogate allograft rejection and induce donor
      specific tolerance, an elusive goal in organ transplantation.

PMID- 10352904
TI  - Cytomorphology of metastatic mesothelioma in fine-needle aspiration specimens.
AB  - The morphologic features of mesothelioma occurring in serous fluids, as well as
      fine-needle aspiration (FNA) of primary tumors, have been extensively described.
      Descriptions of the FNA findings in metastatic lesions of mesothelioma, however,
      are limited to single cases. In this report, we illustrate the cytomorphologic
      features of four cases of metastatic mesothelioma which underwent FNA, and one
      additional cytologic preparation taken from a surgically-excised metastatic
      lesion. The cytomorphologic features of metastatic mesothelioma varied greatly
      among individual cases with respect to the degree of nuclear pleomorphism, amount
      of cytoplasm, and degree of cellular cohesion. However, one feature which was
      consistently seen was the presence of numerous distinct, uniformly small
      intracytoplasmic vacuoles, believed to represent intracellular fat and glycogen.
      These morphologic features are illustrated, and the differential diagnosis of
      intracytoplasmic vacuoles within epithelioid tumor cells in primary and
      metastatic lesions is discussed.

PMID- 10352903
TI  - Cytopathologic evaluation of lung carcinomas presenting as brain metastasis.
AB  - Brain metastasis is an uncommon initial presentation of lung carcinoma. One arm
      of this analysis is a retrospective review of 137 cases of surgically diagnosed
      solitary brain metastasis, which were eventually found to be of lung origin,
      encountered at Hines VA Hospital during the period 1958 to 1996. The second arm
      is composed of fine-needle aspiration biopsy specimens of primary lung tumor in
      23 patients with an initial clinical diagnosis of brain metastasis and without
      the benefit of surgery, seen from 1981 through 1996. Our results in both analyses
      indicate that pulmonary adenocarcinoma is the predominant primary tumor that
      initially manifests as a brain metastasis, approaching 76% (107 and 17 cases,
      respectively), followed by small-cell carcinoma at 20% (24 and five cases,
      respectively) and large-cell undifferentiated carcinoma and squamous-cell
      carcinoma at 2% each. The predominance of adenocarcinoma as a source of brain
      metastasis in lung cancer patients probably reflects its rising incidence overall
      of late. Collateral findings also suggest that surgical resection of a solitary
      and small brain metastasis as well as of a discrete lung primary, whenever
      feasible, as the most effective procedure to improve survival and quality of life
      of patients.

PMID- 10352905
TI  - Detection of immunoglobulin heavy chain gene rearrangements by polymerase chain
      reaction analysis on lymph node imprints and fine-needle aspirate smears: a
      comparison of five different imprint preparations.
AB  - Five different preparations of lymph node imprints from 39 patients were studied
      to determine which preparations are suitable for obtaining interpretable results
      with polymerase chain reaction (PCR)-based detection of immunoglobulin heavy
      chain gene rearrangements and whether there are significant discrepancies in the
      patterns obtained. The sensitivity and specificity of this test for the diagnosis
      of B-cell lymphoma were assessed. The five imprints were stained with May
      Grunwald-Giemsa (MGG) and coverslipped, stained with MGG but not coverslipped,
      fixed in acetone only, air-dried only, or immunostained, respectively. The
      efficiency of the PCR was 0% for immunocytochemically stained slides, 87% for air
      dried only and air-dried/MGG-stained/coverslipped slides, 95% for air-dried/MGG
      stained/not coverslipped slides, and 100% for imprints that were air
      dried/acetone-fixed. There was total agreement in results in 87% cases studied.
      Discrepancies never resulted in false-positive test results. The overall
      sensitivity was 50%, and specificity was 100%. Based on these results, we have
      devised guidelines for tissue treatment when only stained slides are available.
      In a prospective study with 19 fine-needle aspirate specimens, the efficiency of
      the PCR increased to 100%, and sensitivity improved to 81%.

PMID- 10352906
TI  - Fine-needle aspiration of renal masses in adults: analysis of results and
      diagnostic problems in 108 cases.
AB  - Fine-needle aspiration (FNA) biopsy of the kidney has a traditionally well
      defined role in the diagnosis and treatment of renal lesions. Recent improvements
      in renal imaging techniques have also brought renal FNA to the forefront, since
      small and asymptomatic renal masses are increasingly being detected. Before the
      physician institutes a treatment plan, such lesions usually require a definitive
      diagnosis that is best provided by FNA. To assess various aspects of renal FNA,
      including specimen adequacy, questionable cytologic patterns, and diagnostic
      pitfalls, we retrospectively evaluate our experience with 108 FNA biopsies
      performed for the evaluation of renal masses in adults. For each case, the smears
      were reviewed and correlated with tissue sections from cell blocks, surgical
      specimens, or autopsy material, when available. The cytologic diagnoses were
      confirmed by cell block (59 cases), nephrectomy or autopsy (35 cases), or
      clinical follow-up. Of the 108 FNA biopsy samples, 17 showed evidence of blood,
      soft tissue, necrotic material, glomeruli, or tubular cells and were classified
      as unsatisfactory. The following diagnostic categories were noted in the 91
      satisfactory aspirates: renal abscess (four cases), benign cyst (30 cases),
      suspicious lesions (11 cases), and malignant lesions (46 cases). In four cases of
      renal abscess, FNA found abundant clusters of neutrophils. For the 30 cases
      interpreted on cytologic evidence as benign cysts, the diagnosis was confirmed in
      28 cases; the two remaining cases were acquired cystic kidney and cystic renal
      cell carcinoma, respectively. Among the 11 suspicious lesions, the final
      diagnoses were one benign simple cyst, one angiomyolipoma, two multilocular
      cystic nephromas, two adult polycystic kidneys, one acquired cystic kidney, three
      cystic papillary renal-cell carcinomas, and one solid renal-cell carcinoma. Cases
      classified as suspicious shared characteristic cytologic patterns that
      distinguished them from simple benign cysts and from classic renal-cell
      carcinoma. Among the 46 malignant lesions, as evidenced on cytologic examination,
      27 were renal-cell carcinomas, five were transitional-cell carcinomas, four were
      lymphomas, one was a small-cell undifferentiated carcinoma, and nine were
      metastatic carcinomas. False-positive or false-negative cases were not
      encountered in this category. In conclusion, FNA is an excellent method to
      diagnose space-occupying lesions of the kidney. For cystic lesions, cytologic
      radiographic correlation is needed to avoid misinterpretation. Our study defines
      a spectrum of suspicious patterns characteristic of a group of renal lesions that
      are distinct from both benign simple cyst and straightforward renal malignancy.

PMID- 10352907
TI  - Diagnostic accuracy of effusion cytology.
AB  - The aim of this investigation was to report on the diagnostic accuracy of
      conventional effusion cytology. Cytological diagnoses of 300 pleural effusions
      and 300 ascites were compared with clinical and/or histological follow-ups of the
      respective patients. Sensitivity of our cytological diagnoses on pleural
      effusions was 50.0%, specificity 97.0%, positive predictive value 95.7%, and
      negative predictive value 86.4%. Sensitivity in ascitic effusions was 62.4%,
      specificity 98.0%, positive predictive value 100.0%, and negative predictive
      value 88.3%; 5.8% of diagnoses for pleural and 4.4% for peritoneal effusions were
      suspicious or doubtful. The overall false-positive rate was 0.5%, while the false
      negative rate was 31.5%. False-negative results were due to sampling errors in
      71% of pleural and 73% of peritoneal effusions and to screening errors in 29% and
      27%, respectively. Our data and those from the literature show that diagnostic
      accuracy of effusion cytology is still unsatisfactory and should be improved.
      Therefore, the use of different adjuvant methods is recommended.

PMID- 10352908
TI  - Cytologic diagnosis of adenoid cystic carcinoma of salivary glands.
AB  - The cytomorphologic features in fine-needle aspiration (FNA) biopsies from 31
      primary and 33 recurrent adenoid cystic carcinomas (ACC) were investigated. The
      correct FNA diagnosis was established in 24 of 31 primary ACC (77%). The
      diagnostic clue in aspirates from ACC are large globules of extracellular matrix,
      partially surrounded by basaloid tumor cells. In FNAs with predominance of
      basaloid tumor cells, but lacking characteristic globules, all other benign and
      malignant salivary gland tumors of epithelial-myoepithelial differentiation
      should be considered in the cytologic diagnosis. Pleomorphic adenoma is most
      frequently confused with ACC, and therefore, the cytologic findings in FNAs from
      50 pleomorphic adenomas were compared with those diagnosed as ACC. Furthermore,
      rare neoplasms of salivary glands with epithelial-myoepithelial cell
      differentiation, including basal-cell adenoma and carcinoma, epithelial
      myoepithelial carcinoma, and polymorphous low-grade adenocarcinoma, as well as
      some nonsalivary gland neoplasms presenting an adenoid cystic pattern, must be
      considered. The cytologic features of these entities are discussed in detail with
      respect to the cytologic diagnostic criteria of ACC.

PMID- 10352909
TI  - Fine-needle aspiration cytology of metastatic squamous-cell carcinoma arising in
      a pilonidal sinus, with literature review.
AB  - Fewer than 50 cases of carcinoma arising in a pilonidal sinus have been reported,
      with only 5 patients having documented inguinal lymph node metastases. This is
      the first report of the fine-needle aspiration (FNA) diagnosis of this uncommon
      clinical situation of squamous-cell carcinoma arising in a pilonidal sinus,
      metastatic to an inguinal lymph node. We report on a 59-yr-old male with squamous
      cell carcinoma arising in a pilonidal sinus who presented with inguinal
      adenopathy. FNA biopsy of a lymph node was performed, resulting in a diagnosis of
      metastatic squamous-cell carcinoma. FNA biopsy is useful in the evaluation of
      patients with inguinal adenopathy and a history of malignancy arising in a
      pilonidal sinus. The possibility of this rare complication should also be
      considered when metastatic squamous-cell carcinoma to an inguinal lymph node is
      diagnosed by FNA cytology in patients having an unknown primary except for a
      change in a long-standing pilonidal cyst.

PMID- 10352910
TI  - Lymphoepithelial cyst (LEC) of the pancreas: cytomorphology and differential
      diagnosis on fine-needle aspiration (FNA).
AB  - Lymphoepithelial cyst (LEC) of the pancreas is an extremely rare benign entity.
      We describe the cytopathologic findings of such a lesion in a 49-yr-old woman who
      was examined for epigastric pain. A trans-esophageal ultrasound-guided fine
      needle aspiration of a pancreatic mass disclosed an intimate mixture of squamous
      epithelial cells and small, mature lymphocytes in a background of keratinaceous
      debris, anucleate squames, and multinucleated histiocytes. On histopathologic
      examination, a subsequent resection showed a multiloculated cystic lesion with a
      stratified squamous epithelial lining surrounded by well-formed lymphoid tissue,
      suggestive of LEC. The differential diagnosis includes other pancreatic
      pseudocysts, dermoid cyst, mucinous cystic neoplasms, adenosquamous carcinoma,
      and metastatic squamous cell carcinoma.

PMID- 10352911
TI  - Cytomorphological features of salivary duct carcinoma ex pleomorphic adenoma:
      diagnosis by fine-needle aspiration biopsy with histologic correlation.
AB  - We report a case of salivary duct carcinoma arising from a pleomorphic adenoma
      (ex pleomorphic adenoma) in a parotid salivary gland of a 70-yr-old man. Fine
      needle aspiration biopsy showed two distinct subsets of cells. There was the
      typical biphasic pattern of pleomorphic adenoma consisting of bland epithelial
      cells admixed with uniform spindle-shaped cells and chondromyxoid stroma. In
      addition, there were features of salivary duct carcinoma best demonstrated by
      necrosis and the presence of large polygonal cells arranged either singly or in
      rosettes, clusters or sheets reminiscent of ductal carcinoma of the breast. This
      case illustrates that the presence of background large polygonal cells and
      necrosis in an otherwise typical pleomorphic adenoma may suggest the diagnosis of
      a high-grade carcinoma, namely salivary duct carcinoma, which portends poor
      prognosis and requires aggressive treatment. Differential diagnosis from other
      carcinomas known to arise in pleomorphic adenoma is discussed.

PMID- 10352912
TI  - Pseudo-Gaucher cells in peritoneal fluid: an uncommon manifestation of
      extramedullary hematopoiesis.
AB  - Pseudo-Gaucher cells have been observed in the bone marrow of patients suffering
      from a variety of hematologic disorders, including chronic myeloid leukemia,
      multiple myeloma, and immune thrombocytopenic purpura, as well as other
      conditions, such as rheumatoid arthritis. While the presence and potential
      clinical significance of pseudo-Gaucher cells have been documented in the
      hematology literature, references in standard cytology texts and journals are
      lacking. We report a case of ascites developing in the context of myelofibrosis,
      in which abdominal paracentesis yielded numerous pseudo-Gaucher cells as part of
      a mixed cellular population containing immature hematopoietic elements,
      consistent with extramedullary hematopoiesis.

PMID- 10352913
TI  - Peripheral T-cell lymphoma presenting as ascites: a case report and review of the
      literature.
AB  - Here we report an unusual case of T-cell lymphoma presenting as ascites. A 49-yr
      old woman was admitted to the hospital for abdominal discomfort associated with
      increasing abdominal girth over the course of 3 mo. She also complained of
      nausea, vomiting, and diarrhea. On physical examination, a tense and distended
      abdomen and edema of the lower extremities were noted. Neither hepatosplenomegaly
      nor lymphadenopathy was found. A CT scan of the abdomen and pelvis showed a large
      abdominal/pelvic mass surrounding the small bowel and omentum and small nodes in
      the para-aortic and mesenteric regions. The cytospin prepared from the peritoneal
      fluid was hypercellular and composed of a population of monotonous, noncohesive
      cells with a high nuclear/cytoplasmic ratio and a single prominent central
      nucleolus. The cells were positive for leukocyte common antigen and Leu-22 (CD43)
      but negative for keratin, L26, UCHL-1, kappa, lambda, CD3, Ki-1 (CD30), S-100,
      and carcinoembryonic antigen. Morphologic and immunologic findings were
      suggestive of T-cell immunoblastic lymphoma. Peripheral T-cell lymphomas rarely
      present as ascites; this case demonstrates the value of effusion cytology in
      making this diagnosis.

PMID- 10352915
TI  - Fine-needle aspiration cytological features of dermoid cyst of the parotid gland:
      a report of two cases.
AB  - We describe the cytological features of dermoid cyst of the parotid gland the
      value of preoperative diagnosis by fine-needle aspiration (FNA) cytological
      evaluation. Both patients had painless parotid masses. On physical examination, a
      freely movable parotid mass was found in each case. CT scan showed a cystic mass
      in the parotid gland in each patient. FNA in both cases showed anucleated and
      nucleated squamous epithelium and keratin debris. The clinical features and
      cytological findings in each case were interpreted as suggestive of a dermoid
      cyst. Histological examination of surgical specimens confirmed the presence of a
      dermoid cyst of the parotid gland in each case. FNA is a reliable method for
      preoperative diagnosis and permits selection of an appropriate form of surgical
      procedure for dermoid cyst of the parotid gland.

PMID- 10352914
TI  - Cryptococcosis of thoracic vertebra simulating tuberculosis: diagnosis by fine
      needle aspiration biopsy cytology--a case report.
AB  - A rare case of cryptococcosis of sixth thoracic vertebra (T6) along with
      pulmonary involvement in an old diabetic patient is presented. The infection
      resulted in lytic lesion of T6 vertebra and girdle pain. A computerized
      tomographic (CT) guided fine-needle aspiration biopsy (FNAB) cytology was
      performed, which showed encapsulated fungal spores of Cryptococcus neoformans
      with granulomatous reaction, later confirmed by fungal culture.

PMID- 10352916
TI  - Millipore filter cell block preparation: an alternative to cell block in
      nongynecologic specimens of limited cellularity.
AB  - The use of membrane filters to concentrate cytology specimens was first described
      by Seal (Cancer 1956; 9:866-868). We report on a technique in which a portion of
      Papanicolaou-stained Millipore filter (Millipore Corp, Bedford, MA) preparation
      can be converted into a paraffin block for hematoxylin-eosin (H&E) preparations
      and immunocytochemical analysis (ICC). Seven cases with moderate cellularity and
      no cell block preparation were retrieved from our cytopathology files. The
      specimens included: 4 pleural effusions with metastatic adenocarcinoma, and 3 FNA
      specimens (1 metastatic melanoma, 1 metastatic adenocarcinoma, and 1
      thyroid/papillary carcinoma). The filter was removed from the slide, cut in half,
      and subjected to paraffin embedding in the usual fashion (postfixed in 10%
      neutral-buffered formalin). Four-micron-thick sections were cut onto Probe-On
      (Fisher Scientific, Pittsburgh, Pa) slides. ICC was performed using the avidin
      biotin-peroxidase complex technique and capillary gap technology. Antibodies
      included CAM5.2, AE1/AE3, CEA, CD15, LCA, PanCK, S100, HMB45, and thyroglobulin.
      All cases showed excellent preservation of cellular morphology on H&E. ICC
      performed on Millipore filter cell block preparations showed specific antibody
      staining patterns with preservation of cellular details. All antibodies showed
      their specific staining patterns with clean background and lack of nonspecific
      staining. This technique has the following advantages: 1) offers an alternative
      to cell blocks in moderately cellular specimens; 2) clean background; 3)
      preservation of cytology specimens for future studies.

PMID- 10352917
TI  - Cytokeratin positivity in fine-needle aspirates of metastatic malignant melanoma:
      fact or fiction?

PMID- 10352918
TI  - The epidemiology of polycystic ovary syndrome. Prevalence and associated disease
      risks.
AB  - Polycystic ovary syndrome is a common problem affecting approximately 5% of women
      of reproductive age when defined by clinical features of anovulation and
      hyperandrogenism. Metabolic derangements associated with this condition may
      predispose to a range of diseases with attendant morbidity and mortality risks.
      In general, available data support significantly increased rates of type II
      diabetes mellitus, dyslipidemia, and endometrial cancer in PCOS that are not
      completely explained by obesity; data also suggest that rates of hypertension,
      gestational diabetes, and pregnancy-induced hypertension may likewise be
      increased, although the extent to which obesity mediates these risks is not
      clear. The increased prevalence of several cardiovascular risk factors in PCOS
      and limited cross-sectional data suggest that cardiovascular disease should be
      more likely in PCOS, but prospective data are lacking to confirm this
      supposition. Limited data have suggested an association between PCOS and ovarian
      cancer risk and require further study. The present data do not support an
      increased risk for breast cancer in this condition. Long-term prospective data
      are clearly needed to better delineate the nature and magnitude of disease risks
      associated with PCOS, with appropriate adjustment for associated obesity. Such
      information is a necessary background for understanding the role of established
      and emerging PCOS therapies, including oral contraceptives, intermittent
      progesterone, ovulation induction agents, and insulin sensitizers, in modifying
      such risks. In the meantime, close follow-up of women with PCOS and encouragement
      of lifestyle practices likely to reduce disease risks, such as regular exercise
      and weight control, should be standard practice.

PMID- 10352919
TI  - Ovarian and adrenal function in polycystic ovary syndrome.
AB  - Androgens are secreted by both the ovaries and adrenal glands in response to
      their respective trophic hormones LH and ACTH. Androgens in women are not
      specifically under negative feedback control by these pituitary hormones because
      they are by-products of estradiol and cortisol secretion. Rather, androgen
      secretion seems to be regulated mostly by intraglandular mechanisms. Functional
      ovarian hyperandrogenism is found in about 70% of patients with PCOS. It is
      characterized by excessive secretion of 17-hydroxyprogesterone in response to
      GnRH agonist or hCG stimulation. Failure of dexamethasone to suppress plasma free
      testosterone normally in the presence of normal adrenocortical suppression is
      also typical. Functional adrenal hyperandrogenism is found in about half of
      patients with PCOS. It is most often characterized by moderately increased
      secretion of the 17-ketosteroid DHEA in response to ACTH. The most likely cause
      of the excessive androgen secretion by both glands seems to be abnormal
      regulation (dysregulation) of the 17-hydroxylase and 17,20-lyase activities of P
      450c17, the rate-limiting step in androgen biosynthesis. There are also subtle
      generalized disturbances of steroid metabolism, including tendencies toward
      excessive estrogen and cortisol secretion. The cause of dysregulation of
      steroidogenesis is unknown. The hyperinsulinemia that is compensatory for
      resistance to the glucose-metabolic effect of insulin seems to have a role in
      many cases. In most cases, intrinsic intraovarian or intra-adrenal autocrine or
      paracrine regulatory mechanisms are most likely malfunctioning.

PMID- 10352920
TI  - Neuroendocrine aspects of polycystic ovary syndrome.
AB  - A series of investigations have emphasized the heterogeneous nature of the
      clinical condition known as PCOS and have delineated several factors that may
      contribute to the hyperandrogenemia and anovulation in this condition. Currently,
      it remains unclear whether intrinsic abnormalities of ovarian steroidogenesis,
      the effects of hyperinsulinemia in augmenting LH stimulation of ovarian androgen
      production, and the persistent rapid frequency of LH/GnRH secretion are primary
      factors in all patients. Indeed, these factors may have variable roles in
      different patients, all of whom present with the clinical syndrome of PCOS. A
      consensus has emerged that abnormalities in the neuroendocrine control of GnRH
      secretion exist in a significant subset of patients and lead to persistent
      hypersecretion of LH, which seems to be an important component of the syndrome,
      particularly in nonobese patients. The relative frequency of primary
      abnormalities in the regulation of GnRH secretion versus secondary changes
      reflecting altered circulating concentrations of ovarian steroid remains
      uncertain. No clear evidence exists for an underlying neuroendocrine abnormality
      of GnRH regulation in all patients. The recent data showing insensitivity of the
      hypothalamic GnRH pulse generator to E2 progesterone feedback have suggested
      potential mechanisms that may explain the abnormalities of GnRH secretion seen in
      adolescent girls in whom the clinical syndrome of PCOS is destined to develop.
      Further studies are required in adolescents to establish whether GnRH regulation
      is impaired during puberty or whether data in adults simply reflect the long-term
      effects of elevated androgens, estrogens, or other hormones on the hypothalamus.
      Studies in carefully delineated subgroups of patients with PCOS are needed to
      establish these points, with a long-term goal of providing patients with improved
      methods of inducing ovulation and reducing hyperandrogenemia.

PMID- 10352922
TI  - Insulin action in the polycystic ovary syndrome.
AB  - Research on insulin action in PCOS has been intensive after the identification of
      insulin resistance as a feature of the syndrome in 1980. It is now clear that
      PCOS is a metabolic as well as a reproductive disorder and an important cause of
      type 2 diabetes mellitus in women. The cellular and molecular mechanisms of
      insulin resistance in PCOS are distinct from those in other insulin resistance
      syndromes. Elucidating these mechanisms promises to provide considerable insight
      into insulin receptor signal specificity. Conversely, insulin resistance is now
      known to have an important role in the pathogenesis of the reproductive
      disturbances of PCOS. It is thought that one or several genetic defects may cause
      both the insulin resistance and reproductive abnormalities characteristic of
      PCOS.

PMID- 10352921
TI  - Growth factor action on ovarian function in polycystic ovary syndrome.
AB  - Insulin-like growth factors, their receptors, binding proteins, and binding
      protein proteases are important in normal and abnormal ovarian follicle
      development. IGFs stimulate ovarian cellular mitosis and steroidogenesis and
      inhibit apoptosis. Patterns of expression of IGF family members are
      characteristic of whether follicles are estrogen- or androgen-dominant. The PCOS
      follicle is androgen-dominant but does not appear to be atretic and has
      characteristic IGF family expression. Available data strongly support an
      intraovarian, as opposed to endocrine, role for this growth factor family in
      ovarian follicle growth, steroidogenesis, and atresia.

PMID- 10352923
TI  - Insulin action in the normal and polycystic ovary.
AB  - Insulin has a stimulatory effect on steroidogenesis by granulosa cells of normal
      and polycystic ovaries and interacts with gonadotropins in an additive or, as in
      the case of LH, a synergistic manner. These actions seem to be mediated
      specifically by the insulin receptor rather than by cross-reaction with the type
      I IGF receptor, even in tissue obtained from women with PCOS with biochemical
      evidence of insulin resistance. The authors suggest that hyperinsulinemia makes a
      significant contribution to premature arrest of follicle growth, which is
      characteristic of anovulation in women with PCOS, and that the interaction of
      insulin with LH is a key element in this process. Insulin may also have a role in
      amplifying LH-induced androgen production by theca cells, which may help explain
      the prominence of symptoms of hyperandrogenism in obese subjects with PCOS. The
      results of recent clinical studies of insulin-sensitizing agents such as
      metformin and the thiazoladinedione troglitazone in PCOS have provided
      encouragement that improvement of insulin sensitivity and consequent lowering of
      circulating insulin levels by these agents may be of therapeutic value in the
      management of both anovulation and hirsutism.

PMID- 10352924
TI  - Polycystic ovary syndrome. Phenotype to genotype.
AB  - Available studies suggest there is a strong familial component to PCOS regardless
      of the diagnostic criteria used to ascertain probands and to assign affected
      status in kindreds. Investigation of all kindred members using the same
      systematic screen for metabolic and reproductive abnormalities strengthens the
      validity of conclusions. There is no substitute for direct biometric or
      biochemical proof of the phenotype. Initial studies by the author and his
      colleagues suggest that hyperandrogenemia in sisters is a valid phenotype
      characteristic. Further study is necessary to establish other phenotypes in the
      families. Large family clusterings of PCOS offer the best opportunity for
      identifying unique strains of PCOS. These families may represent a homogeneous
      etiology of the syndrome despite significant phenotypic heterogeneity within a
      given pedigree. Linkage analysis should be performed between polymorphic markers
      spaced at regular genetic intervals, and these familial traits may identify
      critical regions for further investigation.

PMID- 10352925
TI  - Diagnosis of polycystic ovary syndrome.
AB  - The clinical features of polycystic ovary syndrome (PCOS) include hirsutism and
      irregular menses, which are the results of ovarian hyperandrogenism and chronic,
      unopposed estrogen secretion. The discovery that most women with PCOS are insulin
      resistant and have compensatory hyperinsulinemia, with increased risk for type 2
      diabetes mellitus, designates this condition as a reproductive-metabolic
      disorder. That the symptoms of PCOS may be mimicked by other endocrine disorders
      of the ovary and adrenal glands warrants careful evaluation to exclude these
      associated conditions.

PMID- 10352926
TI  - Antiandrogen treatment of polycystic ovary syndrome.
AB  - Although hirsutism and androgenetic alopecia are cosmetic problems, they can be
      psychologically devastating for women. Mechanical hair removal may control the
      cosmetic appearance of hirsutism, but the underlying problem usually continues to
      progress. Topical therapies for androgenetic alopecia provide for modest
      improvement at best, and no topical therapy has been shown to be effective for
      hirsutism. Antiandrogens, combined with ovarian suppression, offer the best hope
      for the improvement of hirsutism and androgenetic alopecia in women with PCOS.
      Improvement will occur in most women. Unless the underlying cause of the PCOS is
      corrected, medical therapy will need to be continued indefinitely.

PMID- 10352927
TI  - Insulin-lowering therapeutic modalities for polycystic ovary syndrome.
AB  - This article summarizes the relationship between insulin and androgen excess,
      with a focus on what is known regarding two related issues in polycystic ovary
      syndrome: (1) defects in insulin secretion in PCOS and their role in the
      development of glucose intolerance in this population; and (2) pharmacologic
      interventions designed to attenuate hyperinsulinemia and its sequelae in PCOS.

PMID- 10352928
TI  - Cardiovascular consequences of polycystic ovary syndrome.
AB  - Polycystic ovary syndrome (PCOS), a syndrome of hyperandrogenism and anovulation
      with numerous associated derangements, is typified by a substantially increased
      incidence of type 2 diabetes mellitus and coronary disease in mid-adult life. A
      marker of the disorder, and a potential determinant of the macroangiopathy, is
      insulin resistance. Thus, in addition to altered lipid metabolism, hypertension,
      hormonal derangements, obesity, and altered coagulation--all of which may
      contribute to the development of vascular disease--the insulin resistance and
      dysinsulinemia may underlie impaired fibrinolysis and related derangements within
      the vessel walls that may be modifiable by attenuation of insulin resistance and
      amelioration of hyperinsulinemia.

PMID- 10352929
TI  - Testing tumors for microsatellite instability.
AB  - The methods for determining microsatellite instability in tumors are highly
      heterogeneous. Recently a 5-marker panel of microsatellites was suggested for
      this purpose. In this review attention is drawn to the fact that microsatellite
      instability can be assessed by analyzing tumor DNA with a single marker, BAT-26,
      and that normal tissue DNA from the same individual needs to be analyzed only
      when an aberrant allele is seen in the tumor. Whilst this simple procedure does
      not distinguish between different types and degrees of instability, it should be
      sufficient for many purposes, such as screening colorectal cancers for mismatch
      repair deficiency.

PMID- 10352930
TI  - Novel six-nucleotide deletion in the hepatic fructose-1,6-bisphosphate aldolase
      gene in a patient with hereditary fructose intolerance and enzyme structure
      function implications.
AB  - Hereditary fructose intolerance (HFI) is an autosomal recessive human disease
      that results from the deficiency of the hepatic aldolase isoenzyme. Affected
      individuals will succumb to the disease unless it is readily diagnosed and
      fructose eliminated from the diet. Simple and non-invasive diagnosis is now
      possible by direct DNA analysis that scans for known and unknown mutations. Using
      a combination of several PCR-based methods (restriction enzyme digestion, allele
      specific oligonucleotide hybridisation, single strand conformation analysis and
      direct sequencing) we identified a novel six-nucleotide deletion in exon 6 of the
      aldolase B gene (delta 6ex6) that leads to the elimination of two amino acid
      residues (Leu182 and Val183) leaving the message inframe. The three-dimensional
      structural alterations induced in the enzyme by delta 6ex6 have been elucidated
      by molecular graphics analysis using the crystal structure of the rabbit muscle
      aldolase as reference model. These studies showed that the elimination of Leu182
      and Val183 perturbs the correct orientation of adjacent catalytic residues such
      as Lys146 and Glu187.

PMID- 10352931
TI  - A case of discordance between genotype and phenotype in a malignant hyperthermia
      family.
AB  - Malignant hyperthermia (MH) is an inherited autosomal dominant pharmacogenetic
      disorder and is the major cause of anaesthesia-induced death. Malignant
      hyperthermia susceptibility is usually diagnosed by the in vitro contracture test
      (IVCT) performed on fresh muscle biopsies exposed to caffeine and halothane,
      respectively. Around 50% of affected families are linked to the ryanodine
      receptor (RYR1) gene. The human RYR1 gene maps to chromosome 19q13.1 and encodes
      a protein that associates as a homotetramer and acts as a calcium-release channel
      from the sarcoplasmic reticulum. To date, 17 mutations have been identified in
      the coding region of the RYR1 gene and appear to be associated to the MH
      susceptible phenotype. Here we describe a rare case of discordance between
      genotype (characterised by the presence of the Arg614Cys mutation in the RYR1
      gene) and MH-normal typed phenotype. Although the IVCT remains a very reliable
      procedure for the assessment of MH status, genetic data can provide in some cases
      an additional aid to clinical diagnosis.

PMID- 10352932
TI  - Mosaic trisomy 17 in amniocytes: phenotypic outcome, tissue distribution, and
      uniparental disomy studies.
AB  - Mosaicism for trisomy 17 in amniocyte cultures is a rare finding, whilst
      postnatal cases are exceptional. In order to gain insight into the possible
      effects of the distribution of the trisomic line and of uniparental disomy (UPD)
      on embryofoetal development, we have performed follow-up clinical, cytogenetic
      and molecular investigations into three newly detected prenatal cases of trisomy
      17 mosaicism identified in cultured amniotic fluid. In the first case, the
      pregnancy ended normally with the birth of a healthy girl, and analysis of
      newborn lymphocytes and of multiple extra-embryonic tissues was indicative of
      confined placental mosaicism. The second case was also associated with a normal
      pregnancy outcome and postnatal development, and only euploid cells were found in
      peripheral blood after birth. However, maternal isodisomy 17 consequent to a
      meiosis II error and loss of a chromosome 17 homologue was detected in peripheral
      lymphocytes postnatally. In the third case, pathological examination after
      termination of pregnancy showed growth retardation and minor dysmorphisms, and
      the trisomic line was detected in foetal skin fibroblasts. In addition,
      biparental derivation of chromosome 17 was demonstrated in the euploid lineage.
      These results, together with previously reported data, indicate that true
      amniotic trisomy 17 mosaicism is more commonly of extra-embryonic origin and
      associated with normal foetal development. Phenotypic consequences may arise when
      the trisomic line is present in foetal tissues. Case 2 also represents the first
      observation of maternal UPD involving chromosome 17; the absence of phenotypic
      anomalies in the child suggests that chromosome 17 is not likely to be subject to
      imprinting in maternal gametes.

PMID- 10352933
TI  - Genetic refinement and physical mapping of a chromosome 18q candidate region for
      bipolar disorder.
AB  - Recent genetic studies have implicated chromosome 18 in bipolar disorder (BP)
      with putative loci in the pericentromeric region and on 18q. We reported linkage
      to chromosome 18q21.33-q23 in a large family. In this study we typed additional
      markers in the family and were able to reduce the candidate region significantly.
      All affected family members are sharing alleles for markers spanning a genetic
      distance of maximal 8.9 cM. Haplotype analysis provided a marker order in
      agreement with published genetic and physical maps. Using yeast artificial
      chromosomes, we constructed a contig map that will help to identify positional
      candidate genes for bipolar disorder.

PMID- 10352934
TI  - Human-specific insertion/deletion polymorphisms in Indian populations and their
      possible evolutionary implications.
AB  - DNA samples from 396 unrelated individuals belonging to 14 ethnic populations of
      India, inhabiting various geographical locations and occupying various positions
      in the socio-cultural hierarchy, were analysed in respect of 8 human-specific
      polymorphic insertion/deletion loci. All loci, except Alu CD4, were found to be
      highly polymorphic in all populations. The levels of average heterozygosities
      were found to be very high in all populations and, in most populations, also
      higher than those predicted by the island model of population structure. The
      coefficient of gene differentiation among Indian populations was found to be
      higher than populations in most other global regions, except Africa. These
      results are discussed in the light of two possible scenarios of evolution of
      Indian populations in the broader context of human evolution.

PMID- 10352935
TI  - Y chromosomal polymorphisms reveal founding lineages in the Finns and the Saami.
AB  - Y chromosomal polymorphisms were studied in 502 males from 16 Eurasian ethnic
      groups including the Finns, Saami (Inari Lake area and Skolt Saami), Karelians,
      Mari, Mokshas, Erzas, Hungarians (Budapest area and Csangos), Khanty, Mansi,
      Yakuts, Koryaks, Nivkhs, Mongolians, and Latvians. The samples were analysed for
      polymorphisms in the Y chromosome specific Alu insertion (YAP) and six
      microsatellites (DYS19, DYS389-I and II, DYS390, DYS392, DYS393). The populations
      were also screened for the recently described Tat polymorphism. The incidence of
      YAP+ type was highest in the Csangos and in other Hungarians (37.5% and 17.5%,
      respectively). In the Karelians and the Latvians it was present at approximately
      the same level as commonly found in other European populations, whilst absent in
      our further samples of Eurasian populations, including the Finns and the Saami.
      Aside from the Hungarians, the C allele of the Tat polymorphism was common in all
      the Finno-Ugric speaking populations (from 8.2% to 63.2%), with highest incidence
      in the Ob-Ugrian Khanty. The C allele was also found in the Latvians (29.4%). The
      haplotypes found associated with the Tat C allele showed consistently lower
      density than those associated with the T allele, indicating that the T allele is
      the original form. The computation of the age of the Tat C suggested that the
      mutation might be a relatively recent event giving a maximum likelihood estimate
      of 4440 years (95% confidence interval about 3140-6200 years). The distribution
      patterns of the 222 haplotypes found varied considerably among the populations.
      In the Finns a majority of the haplotypes could be assigned to two distinct
      groups, one of which harboured the C allele of the Tat polymorphism, indicating
      dichotomous primary source of genetic variation among Finnish males. The presence
      of a bottleneck or founding effect in the male lineages of some of the
      populations, namely in the Finns and the Saami, would appear to be one likely
      interpretation for these findings.

PMID- 10352936
TI  - Analysis of mtDNA HVRII in several human populations using an immobilised SSO
      probe hybridisation assay.
AB  - Several populations were typed for the hypervariable region II (HVRII) of the
      mitochondrial DNA (mtDNA) control region using immobilised sequence-specific
      oligonucleotide (SSO) probes. A total of 16 SSO probes was used to type 1081
      individuals from eight different ethnic groups (African Americans, Somali, US
      Europeans, US Hispanics, Bosnians, Finns, Saami and Japanese). Data was compared
      with already published sequence data by analysis of principal components, genetic
      distances and analysis of the molecular variance (AMOVA). The analyses performed
      group the samples in several clusters according to their geographical origins.
      Most of the variability detected is assigned to differences between individuals
      and only 7% is assigned to differences among groups of populations within and
      between geographical regions. Several features are patent in the samples studied:
      Somali, as a representative East African population, seem to have experienced a
      detectable amount of Caucasoid maternal influence; different degrees of admixture
      in the US samples studied are detected; Finns and Saami belong to the European
      genetic landscape, although Saami present an outlier position attributable to a
      strong maternal founder effect. The technique used is a rapid and simple method
      to detect human variation in the mtDNA HVRII in a large number of samples, which
      might be useful in forensic and population genetic studies.

PMID- 10352937
TI  - Reconstruction of a historical genealogy by means of STR analysis and Y
      haplotyping of ancient DNA.
AB  - Archaeological excavations in St Margaretha's church at Reichersdorf, Germany, in
      1993 led to the discovery of eight skeletons, so far assumed to be of the Earls
      of Konigsfeld, who used the church as a family sepulchre over a period of seven
      generations from 1546 to 1749. DNA-based sex testing and analysis of autosomal
      short tandem repeat systems (STR) was carried out to confirm the assumption of
      kinship. Since five of the individuals were determined as males, analysis of Y
      specific STRs seemed feasible. A comparison of Y-haplotypes revealed that one
      individual could not be linked to the Konigsfeld patrilineage, an observation
      supported by autosomal STR evidence. Two individuals typed as females posed an
      identification problem, since supposedly only male members of the family were
      buried in St Margaretha's. Nevertheless, these individuals could tentatively be
      identified as members of the House of Konigsfeld through genetic fingerprinting.

PMID- 10352938
TI  - A comparison of genomic structures and expression patterns of two closely related
      flanking genes in a critical lung cancer region at 3p21.3.
AB  - In the search for a tumour suppressor gene in the 3p21.3 region we isolated two
      genes, RBM5 and RBM6. Gene RBM5 maps to the region which is homozygously deleted
      in the small cell lung cancer cell line GLC20; RBM6 crosses the telomeric
      breakpoint of this deletion. Sequence comparison revealed that at the amino acid
      level both genes show 30% identity. They contain two zinc finger motifs, a
      bipartite nuclear signal and two RNA binding motifs, suggesting that the proteins
      for which RBM5 and RBM6 are coding have a DNA/RNA binding function and are
      located in the nucleus. Northern and Southern analysis did not reveal any
      abnormalities. By SSCP analysis of 16 lung cancer cell lines we found only in
      RBM5 a single presumably neutral mutation. By RT-PCR we demonstrated the
      existence of two alternative splice variants of RBM6, one including and one
      excluding exon 5, in both normal lung tissue and lung cancer cell lines.
      Exclusion of exon 5 results in a frameshift which would cause a truncated protein
      of 520 amino acids instead of 1123 amino acids. In normal lung tissue, the
      relative amount of the shorter transcript was much greater than that in the lung
      tumour cell lines, which raises the question whether some tumour suppressor
      function may be attributed to the derived shorter protein.

PMID- 10352939
TI  - Detailed transcript map of a 810-kb region at 11p14 involving identification of
      10 novel human 3' exons.
AB  - A limited number of genes, including the human brain-derived neutrotrophic factor
      (BDNF) gene, have been identified in the human chromosome 11p14 region. Since
      this area is involved in a genetic disorder (WAGR syndrome) and because of
      interest in studying the regulation of the human BDNF gene, we have established a
      detailed transcript map of a 810-kb region clone in a yeast artificial chromosome
      (YAC), corresponding to a portion of this genomic locus. A set of nested deletion
      mutants has been generated to map genes at a mean resolution of 75kb. Four genic
      markers from available mapping databases have been mapped on the YAC. Ten
      potential novel human exons have been isolated by a 3' terminal exon trapping
      procedure directly applied to purified YAC DNA. Most of these exons display
      polyadenylation signals and they all yield positive signals in RT-PCR
      experiments, confirming their status of transcribed sequences. The BDNF gene is
      now co-localised with three other genes on a 120 kb DNA fragment.

PMID- 10352940
TI  - Mucolipidosis type IV: the origin of the disease in the Ashkenazi Jewish
      population.
AB  - Mucolipidosis type IV (MLIV) is a neurodegenerative lysosomal storage disease in
      which most of the patients diagnosed hitherto are Ashkenazi Jews. The basic
      metabolic defect causing this disease is still unknown and the relevant gene has
      not yet been mapped or cloned. Seventeen Israel Ashkenazi families with MLIV
      patients had been interviewed to study their family origin. Although the families
      immigrated to Israel from various European countries they all could trace their
      roots three to four generations back to northern Poland or the immediate
      neighbouring country, Lithuania. Furthermore, there are only one or two
      ultraorthodox families among the 70-80 Ashkenazi families with MLIV patients
      worldwide, a marked under-representation of this group which constitutes at least
      10% of the Ashkenazi population. This data indicate that MLIV mutation occurred
      only around the 18th and 19th centuries, after the major expansion of this
      population, in a founder in this defined European region belonging to a more
      modern, secular family.

PMID- 10352941
TI  - Genetic heterogeneity and absence of founder effect in a series of 36 French
      cerebral cavernous angiomas families.
AB  - Cerebral cavernous angiomas malformations (CCM) can be inherited as an autosomal
      dominant condition. CCM1, a yet unidentified gene mapping on 7q21-q22, was shown
      to be involved in all CCM Hispano-American families, with a strong founder
      effect. Genetic heterogeneity in non Hispano-American families was established in
      two families. We conducted a genetic linkage analysis on 36 French CCM families
      using eight microsatellite markers mapping within the CCM1 interval. Admixture
      analysis showed that 65% of these families were linked to the CCM1 locus.
      Haplotypes analysis of CCM1-linked families did not show any evidence for a
      strong founder effect.

PMID- 10352942
TI  - Is the perinatal lethal form of Gaucher disease more common than classic type 2
      Gaucher disease?
AB  - In recent years there has been increased recognition of a severe perinatal lethal
      form of Gaucher disease, the inherited deficiency of lysosomal
      glucocerebrosidase. We previously reported a case of severe type 2 Gaucher
      disease which was seen in a medical center in Rotterdam and now present three new
      cases from two other families seen at the same center. Mutational analyses of
      these cases revealed two novel mutations, H311R and V398F, located in exons 8 and
      9, respectively. The identification of four cases of lethal type 2 Gaucher
      disease in a single center seems to be a function of increased awareness of this
      phenotype, rather than of geographic clustering. The actual incidence of lethal
      type 2 Gaucher disease may be underestimated, as many cases may have been
      misclassified as collodion babies or hydrops of unknown cause.

PMID- 10352943
TI  - A tale of tags: report on a HUGO/EU SAGE workshop, 29 January-1 February 1999,
      Hilversum, The Netherlands.

PMID- 10352944
TI  - Commentary: FISHing for the light at the ends of chromosomes.

PMID- 10352946
TI  - The carbohydrate crystalean and colonic microflora modulate expression of
      glutathione S-transferase subunits in colon of rats.
AB  - BACKGROUND: Glutathione S-transferases (GSTs)* are an important class of phase
      II, predominantly detoxifying, enzymes. The supergene family is composed of
      several isoenzymes, hetero- and homodimers, with tissue specific distribution and
      levels of expression. The hypothesis is that a higher expression of individual
      proteins within a specific tissue may be associated with a decreased burden of
      exposure to reactive carcinogens and ultimately with a decreased cancer risk in
      this tissue. AIMS OF THE STUDY: Since nutrition is expected to contribute to the
      gene expression, it was the aim of this study to investigate the impact of
      dietary factors, especially resistant starch, and of the gut microflora, which
      may be influenced by diet, on the GSTs in colon cells of rats. METHODS: For this,
      a technique using high pressure liquid chromatography was established with which
      for the first time GST isoenzymes were analysed in colon cells and compared to
      the levels of the corresponding proteins in the liver of the same rat. RESULTS:
      It was found that colon cells contain mainly GST pi and low amounts of mu but not
      GST alpha. In contrast, the predominant form of GSTs in the liver was alpha, then
      mu and hardly and pi Altogether, liver cells had approximately tenfold more total
      GSTs than colon cells. The feeding of "Crystalean", a retrograded, high amylose
      starch which alters the fermentation profile and the composition of the
      microflora, led to higher levels of GST pi in the colon. Furthermore, the
      comparison of GSTs in colon cells of germ-free rats revealed they were much lower
      than those observed in rats with conventional microflora. CONCLUSIONS: These
      findings clearly demonstrate that the gut bacteria, or their metabolic products,
      enhance GST expression. The studies support the hypothesis that nutrition--by
      affecting the gut flora--may induce this potentially protective and important
      class of phase II enzymes in important tumor target cells.

PMID- 10352945
TI  - The concept of iron bioavailability and its assessment.
AB  - In this review a broad overview of historical and current methods for the
      assessment of iron bioavailability was given. These methods can be divided into
      iron solubility studies, iron absorption studies, endpoint measures, and
      arithmetic models. The pros and cons of all methods were discussed. First,
      studies on in vitro and in vivo iron solubility have been described. The
      disadvantages of iron solubility include the impossibility of measuring
      absorption or incorporation of iron. Furthermore, only the solubility of nonheme
      iron, and not heme iron, can be studied. Second, we focused on iron absorption
      studies (either with the use of native iron, radioiron or stable iron isotopes),
      in which balance techniques, whole-body counting or postabsorption plasma iron
      measurements can be applied. In vitro determination of iron absorption using
      intestinal loops or cell lines, was also discussed in this part. As far as
      absorption studies using animals, duodenal loops, gut sacs or Caco-2 cells were
      concerned, the difficulty of extrapolating the results to the human situation
      seemed to be the major drawback. Chemical balance in man has been a good, but
      laborious and expensive, way to study iron absorption. Whole-body counting has
      the disadvantage of causing radiation exposure and it is based on a single meal.
      The measurement of plasma iron response did not seem to be of great value in
      determining nutritional iron bioavailability. The next part dealt with endpoint
      measures. According to the definition of iron bioavailability, these methods gave
      the best figure for it. In animals, the hemoglobin-repletion bioassay was most
      often used, whereas most studies in humans monitored the fate of radioisotopes or
      stable isotopes of iron in blood. Repletion bioassays using rats or other animals
      were of limited use because the accuracy of extrapolation to man is unknown. The
      use of the rat as a model for iron bioavailability seemed to be empirically
      based, and there were many reasons to consider the rat as an obsolete model in
      this respect. The double-isotope technique was probably the best predictor of
      iron bioavailability in humans. Disadvantages of this method are the single meal
      basis and the exposure to radiation (as far as radioisotopes were used). Finally,
      some arithmetic models were described. These models were based on data from iron
      bioavailability studies and could predict the bioavailability of iron from a
      meal.

PMID- 10352947
TI  - Plant sterols in vegetables and fruits commonly consumed in Sweden.
AB  - Plant sterols are known to have serum cholesterol lowering effects. A high
      dietary intake might therefore have a positive impact on health. All food items
      of vegetable origin contain some amount of plant sterols. The aim of this study
      was to analyse the plant sterol content of vegetables and fruits commonly
      consumed in Sweden, and to compare fresh and cooked samples of the same items.
      Altogether 20 different vegetables and 14 fruits were analysed. All vegetables
      and fruits were purchased in two shops in the city of Gothenburg, Sweden.
      Lyophilization was performed within one month of the items being purchased. The
      samples were frozen at -20 (C and analysed within six months, with a GLC method
      after acid hydrolysis, alkaline hydrolysis and silylation with tri
      methylsilylether. The acid hydrolysis was done in order to detect the fraction of
      glycosylated plant sterols, which are split during boiling with HCl. The median
      plant sterol content of vegetables was 14 (3.8-50) mg/100 g edible portion. The
      highest concentrations were found in broccoli. Brussels sprouts, cauliflower and
      olives. The median plant sterol content of fruits was 16 (3-44) mg/100 g edible
      portion. The highest concentrations were found in oranges and passion fruits. The
      plant sterol concentrations were thus low in vegetables and fruits commonly
      consumed in Sweden. A serum cholesterol lowering effect attributed to the plant
      sterols in vegetables and fruits would therefore be of limited significance.

PMID- 10352948
TI  - Plasma levels of antioxidant vitamins and cholesterol in a large population
      sample in central-northern Italy.
AB  - BACKGROUND: In a population-based multicenter case-control study of diet, life
      style, and gastric cancer a large series of adults, aged 30-75 years (mean 58.9
      years), were randomly sampled from the general population in 3 areas of Central
      Northern Italy. AIM OF THE STUDY: To evaluate the relationship between plasma
      levels of antioxidant vitamins and cholesterol, and sociodemographic
      characteristics, life-style factors, and dietary intake of selected nutrients in
      a sample of the Italian population. METHODS: A fasting blood sample was available
      for 945 subjects (553 men, 392 women). The plasma concentrations of ascorbic
      acid, carotene, retinol, alpha-tocopherol, and cholesterol were determined by a
      centralized laboratory. All participants answered to a detailed questionnaire
      collecting information on sociodemographic and anthropometric characteristics,
      smoking, alcohol drinking, and dietary habits. Covariance analysis models, with
      post hoc Dunnett tests, including terms for age, sex, study center, and period of
      blood drawing, were used for selected multiple-way comparisons of mean values of
      plasma nutrients. RESULTS: Mean plasma values of retinol were higher among men
      while women had higher levels of plasma carotene, ascorbic acid, alpha
      tocopherol, and cholesterol. Plasma carotene levels showed an inverse association
      with body mass index, alcohol consumption, and smoking and a positive association
      with social class. Carotene concentrations were higher in plasma samples obtained
      in spring/summer, while ascorbic acid levels were higher in autumn/winter.
      Partial correlation co-efficients between plasma vitamin levels showed a strong
      correlation between carotene and ascorbic acid (0.69 in men; 0.74 in women),
      between carotene and alpha-tocopherol (0.44; 0.37), and between alpha-tocopherol
      and ascorbic acid (0.45; 0.41). Plasma alpha-tocopherol and retinol correlated
      with plasma cholesterol. On the other hand, plasma carotene and ascorbic acid
      were correlated with their estimated dietary intakes, while the intakes of other
      nutrients, as expected, correlated rather poorly with the respective plasma
      concentrations. CONCLUSIONS: Socio-economic factors, life-style, and specific
      nutrient intake, in addition to gender, are related to nutrient plasma levels in
      Italian adults and may provide specific suggestions for the prevention of chronic
      diseases.

PMID- 10352949
TI  - Leptin enhances the synthesis of oleoyl-estrone from estrone in white adipose
      tissue.
AB  - BACKGROUND: Oleoyl-estrone elicits powerful slimming effects on lean and obese
      rats, sparing protein, lowering appetite and maintaining energy expenditure.
      Leptin synthesis is markedly reduced by oleoyl-estrone. However, this effect is
      not observed in the obese Zucker fa/fa rats; these rats do not fully respond to
      leptin but they lose fat under oleoyl-estrone treatment. AIM OF THE STUDY: To
      determine the role of leptin in the conversion of estrone to fatty-acyl estrone
      in white adipose tissue both in vivo in Zucker lean and obese rats, and in vitro.
      METHODS: Two series of experiments were performed: a) Growth and differentiation
      of 3T3L1 preadipocytes into adipocytes followed by incubation with tritium
      labeled estrone in the medium in the presence/absence of 1 nM leptin, and
      estimation of the incorporation of label into estrone and estrone ester fractions
      of cell extracts. b) Zucker lean (Fa/?) [ZL] and obese (fa/fa) [ZO] rats were
      injected i.v. with carrier-free oleoyl-estrone in chylomicra-sized liposomes,
      then euthanized after 10 min. Free and esterified estrone were measured in blood,
      liver, muscle, skin, white adipose tissue (WAT), and brown adipose tissue (BAT).
      RESULTS: In the first study, in a 72-h incubation, adipocytes took up 20-27% of
      the medium estrone. In the leptin(-) controls, 47% of the label in the cell
      fraction was in the form of estrone esters and 45% as free estrone; in the
      leptin(+) cells, 71% of the label was in the estrone ester fraction and 24% was
      free estrone. In the second study, a large part of the injected tritium-label
      remained in the ZO blood, with only a small part remaining in ZL. In ZL 39% of
      the label was found in the tissues in the form of free estrone, and in ZO only
      22%; in both cases about half of it was in WAT. Plasma free estrone levels were
      0.3 +/- 0.1 nM in ZL and 0.5 +/- 0.3 nM in ZO, and esterified estrone was 242 +/-
      99 nM for ZL and 201 +/- 29 nM for ZO. Plasma leptin levels were 1.73 +/- 0.16
      ng/ml in ZL and 61.0 +/- 1.4 ng/ml in ZO. CONCLUSION: The presence of an infact
      leptin pathway is critical for the uptake and synthesis of estrone esters as well
      as for the plasma acyl-estrone turnover. The presented results show a direct
      relationship between oleoyl-estrone and leptin in the WAT. A fully functional
      leptin pathway is needed for the synthesis of acyl-estrone and the removal of
      free estrone from the bloodstream, as well as for the disposal of excess
      circulating oleoyl-estrone. This has a direct bearing on human and animal
      obesity, since estrone induces increases in fat deposition.

PMID- 10352950
TI  - Optimization of cationic liposome-mediated gene transfer to human bronchial
      epithelial cells expressing wild-type or abnormal cystic fibrosis transmembrane
      conductance regulator (CFTR).
AB  - We determined optimum conditions for delivering DNA to transformed human
      bronchial epithelial cells expressing wild-type (BEAS) or abnormal (2CF) cystic
      fibrosis transmembrane conductance regulator (CFTR) using cationic liposomes
      (Lipofectin, [N-(N,N-dimethylaminoethane)carbamyl] cholesterol[DC
      Chol]/dioleoylphosphatidylethanolamine[DOPE], or LipofectAMINE) and reporter
      genes which measured overall transgene expression (luciferase) or the fraction of
      cells transfected (heat-stable alkaline phosphatase). All liposomes showed dose
      related toxicity. Optimal liposome and lipid: DNA ratios were different for BEAS
      than for 2CF cells. For all 3 liposome preparations, small particle size and net
      cationic charge related to transfection efficiency. Both LipofectAMINE and DC
      Chol/DOPE transfected a maximum of 3% of BEAS cells, but luciferase expression
      could be increased without increasing the fraction of cells transfected.
      LipofectAMINE transfected a maximum of 6% of 2CF cells, and luciferase expression
      could be increased with no further increase in fraction of transfected cells. DC
      Chol/DOPE transfected over 12% of 2CF cells with relatively small increases in
      luciferase expression. We conclude that an optimal cationic liposome and lipid:
      DNA ratio for transfecting bronchial epithelial cells depends on: (1) small
      particle size and net cationic charge, (2) whether the cells have the cystic
      fibrosis defect, and (3) whether the desired outcome is transfection of the
      maximum fraction of the cells or maximum total expression of the transgene.

PMID- 10352951
TI  - Selective inhibition of collagen gene expression in fibroblasts by an interferon
      gamma transgene.
AB  - Because interferon-gamma (IFN-gamma) selectively inhibits collagen gene
      expression, we hypothesized that expression of IFN-gamma cDNA in fibroblasts
      might be a useful strategy to inhibit the development of fibrosis. A replication
      deficient E1-, E3- adenovirus vector encoding murine IFN-gamma (AdCM VmIFN gamma)
      was constructed. Infection of murine fibroblasts with AdCM VmIFN gamma in vitro
      was well tolerated. The results showed that IN F-gamma mRNA was expressed in
      infected cells, and as much as 17.7 ng of mIFN-gamma/10(6) cells was secreted
      into culture supernatants. Steady-state levels of alpha 1 (I) procollagen mRNA
      were decreased by 90% in infected cells compared to uninfected cells. The
      inhibition of collagen mRNA expression was partially abrogated with a
      neutralizing anti-mIFN-gamma antibody. Secretion of total collagen by AdCM VmIFN
      gamma-infected fibroblasts was decreased by 60% compared to uninfected cells.
      Induction cells. Induction of cytokine responsive gene-2 expression in AdCM VmIFN
      gamma-infected cells demonstrated that suppression of collagen production was a
      selective response. The results suggest a novel strategy of cytokine gene
      transfer and expression for the treatment of fibrotic lung diseases.

PMID- 10352952
TI  - Respiratory epithelial cells release interleukin-8 in response to a thermophilic
      bacteria that causes hypersensitivity pneumonitis.
AB  - Hypersensitivity pneumonitis (HP) is a granulomatous inflammatory lung disease
      that is usually triggered by organic antigens. At early time points after
      inhalation of antigen, neutrophilic inflammation is prominent in the lungs.
      Interleukin (IL)-8 is a potent chemoattractant for neutrophils and it is known
      that alveolar macrophages can release IL-8 after exposure to organic antigens.
      However, the role of respiratory epithelial cells in the production of IL-8 in HP
      is unknown. We exposed A549 epithelial cells to the thermophilic bacteria
      Saccharopolyspora rectivirgula (SR), and measured IL-8 release via enzyme-linked
      immunosorbent assay (ELISA) and IL-8 messenger RNA (mRNA) induction via Northern
      analysis. We observed a dose- and time-dependent release of IL-8 in response to
      SR. The maximal release of IL-8 was measured at 24-48 hours after exposure. There
      was also an increase in release of IL-6 in a time-dependent fashion. SR induced a
      peak increase in IL-8 mRNA at 12-24 hours. SR also triggered expression of the
      DNA-binding activity of NF-kappa B, a transcription factor that mediates
      activation of the IL-8 gene. Both corticosteroids and IL-10 blocked the
      production of IL-8. The release of IL8 was not mediated through IL-1 beta. These
      data suggest that SR-induced IL-8 production in airway epithelium may play a role
      in the initial inflammatory response in HP.

PMID- 10352953
TI  - Sulfuric acid aerosol induces changes in alveolar surface tension in the guinea
      pig but not in the rat.
AB  - The purpose of this study was to investigate the effects of an acid aerosol, at
      high concentration, on the surface properties of the extracellular fluid lining
      the airways and alveolae. Guinea pigs and rats were exposed to 43 mg/m3 and 94
      mg/m3 of sulfuric acid aerosol mass median aerodynamic diameter (MMAD) 0.9 micron
      or water aerosol (control), respectively, for 4 hours in an exposure chamber.
      Surfactant material was extracted from bronchoalveolar lavage fluid (BAL) by
      centrifugation, and phospholipid, protein, and cell concentrations measured. The
      extract was reconstituted to 300 micrograms/mL of phospholipid, and its surface
      properties assessed with a captive bubble surfactometer. The minimum surface
      tension for the acid-exposed guinea pig BAL was 12.1 +/- 8.48 (mean +/- SD) mN/m,
      which was significantly higher than the control group, 2.0 +/- 0.43 (mean +/- SD)
      or the acid-exposed rats, 1.29 +/- 0.11 (mean +/- SD). The change in film area
      obtained by compressing the film from equilibrium surface tension (25 mN/m) to
      its minimum value (gamma min) was 62.9 +/- 13.83 (mean +/- SD)% for acid-exposed
      guinea pigs, compared to 16.3 +/- 5.77 (mean +/- SD)% for the control guinea
      pigs. The most sensitive index of surfactant inhibition was found to be the
      maximum film compressibility (Cmax) of the compression isotherm. This index was
      119 times greater for the acid-exposed guinea pigs compared to control animals.
      These abnormalities were associated with an elevation of total protein (0.95 +/-
      0.33 [mean +/- SD] mg/mL compared to 0.13 +/- 0.03 [mean +/- SD] mg/mL in
      controls) and polymorphonuclear leucocytes in the BAL. There was no change in
      total phospholipids. By contrast BAL retrieved from rats exposed to approximately
      twice the concentration of acid aerosol showed no cellular nor biochemical
      abnormalities and its surface tension properties were normal. We conclude that
      the abnormalities of surfactant activity in the acid-exposed guinea pigs result
      from the cellular and humoral responses of acute lung injury rather than a direct
      effect of acid.

PMID- 10352954
TI  - Induction of ICAM-1 expression on alveolar epithelial cells during lung
      development in rats and humans.
AB  - Intercellular adhesion molecule-1 (ICAM-1) is an adhesion protein involved in
      immune and inflammatory cell recruitment and activation. In normal, uninflamed
      adult rat lung, ICAM-1 is expressed at high levels on type I alveolar epithelial
      cells and is minimally expressed on type II cells. ICAM-1 expression by alveolar
      epithelial cells in vitro is a function of the state of cellular differentiation,
      and is regulated by factors influencing cell shape. Based upon this observation,
      we hypothesized that ICAM-1 expression by fetal lung epithelial cells is
      developmentally regulated. To investigate this hypothesis, rat and human lung
      tissues were obtained at time points that represent the canalicular, saccular,
      and alveolar stages of development. The relative expression of ICAM-1 protein and
      mRNA were determined in rat lungs from gestational days 18 and 21 (term = 22
      days), from day 8 neonatal rats, and from adult rats. ICAM-1 protein was
      detectable at low level on day 18 and increased progressively during development.
      Relative expression of ICAM-1 protein was maximal in adult lung. Expression of
      ICAM-1 mRNA paralleled that of ICAM-1 protein. By immunohistochemical methods in
      rat and human lung, ICAM-1 was expressed at low level on cuboidal and flattening
      epithelial cells in the developing alveolar space at the canalicular and saccular
      stages; however, ICAM-1 expression was increased as epithelial cells spread and
      flattened during alveolarization. ICAM-1 was predominantly expressed on type I
      cells rather than type II cells at the alveolar stage in both the rat and human
      lungs. Thus, relative ICAM-1 expression progressively increased during lung
      development. ICAM-1 expression is correlated with the increase in surface area as
      alveolar structures develop and type I cell differentiation takes place. These
      data indicate that alveolar epithelial cell ICAM-1 expression is developmentally
      regulated.

PMID- 10352955
TI  - Migration of 3T3 and lung fibroblasts in response to calcitonin gene-related
      peptide and bombesin.
AB  - Neuropeptides found in airways, such as bombesin and calcitonin gene-related
      peptide (CGRP), are known to elicit proliferation of several cell types,
      including fibroblasts and epithelial cells in culture and in vivo. However, the
      effects of these neuropeptides on fibroblast migration, which may also be a
      necessary part of airway repair, have not been well established. To determine if
      these peptides could stimulate fibroblast chemotaxis, we grew NIH 3T3 and IM R-90
      cells in culture and studied migration using 48-well blindwell chambers. 3T3
      cells were treated with 10(-14) to 10(-7) M bombesin or 10(-14) to 10(-7) M CGRP
      and permitted to migrate through a gelatin-coated filter for 2-24 hours. Both
      bombesin and CGRP elicited 3T3 migration which was both time and concentration
      dependent. After 6 hours, migration of 3T3 cells treated with 10(-7) M bombesin
      was 33.9 +/- 4.4 cells versus control migration of 4.0 +/- 1.2 cells per 10 high
      power fields (hpf) (P < .01, n = 4). Migration of 3T3 cells treated with 10(-9) M
      CGRP was 30.2 +/- 5.4 cells versus control migration of 10.7 +/- 1.4 cells per 10
      hpf (P < 0.02, n = 6). IMR-90 cells migrated in a similar manner in response to
      CGRP and bombesin. The response to each neuropeptide was both chemotactic and
      chemokinetic, and could be blocked completely with an appropriate receptor
      antagonist. We demonstrate that both bombesin and CGRP are chemotactic for 3T3
      and IMR-90 fibroblasts in culture. These peptides therefore may have multiple
      roles in repair and healing of airway injury.

PMID- 10352956
TI  - Application of biotinylated tyramine to amplify reactions with horseradish
      peroxidase labelling.

PMID- 10352957
TI  - Hybridocytochemical detection of mRNA for calcitonin, CGRP, somatostatin and NPY
      in cultured cells of medullary thyroid carcinoma using immunomax technique.

PMID- 10352959
TI  - Studies on cultured cells of thyroid medullary carcinoma with the use of
      immunocytochemical techniques.

PMID- 10352958
TI  - Control of calcitonin gene expression in thyroid parafollicular cells co-cultured
      with thyroid follicular cells.

PMID- 10352961
TI  - Proliferative activity of thyroid follicular cells in non-neoplastic goitre and
      the level of selected thyroid hormones in blood serum.

PMID- 10352962
TI  - Histoenzymatic investigations of the thyroid gland of guinea pig after the
      application of some receptor antagonists and histamine.

PMID- 10352960
TI  - Preliminary immunocytochemical study of C cells of the thyroid and parathyroid
      glands in five species of wild and laboratory rodents.

PMID- 10352964
TI  - Preliminary observations of the cytological structure of the hypothalamo
      neurohypophyseal magnocellular neuroendocrine system in field voles after acute
      thermal stress.

PMID- 10352963
TI  - Ultraimmunocytochemical analysis of pancreatic islet hormones.

PMID- 10352965
TI  - Prosomatostatin and somatostatin in pig pineal gland. An immunohistochemical
      study.

PMID- 10352966
TI  - The ultrastructure of the pineal gland in the goat.

PMID- 10352967
TI  - The anti-PCNA reaction in the seminiferous tubule cells of Lewis rat testis. Part
      I: The topography of reaction.

PMID- 10352968
TI  - The anti-PCNA reaction in the seminiferous tubule cells of Lewis rat testis. Part
      II: The unilateral inflammatory effect of Freund's complete adjuvant.

PMID- 10352969
TI  - Immunocytochemical localization of S-100 protein in the European bison testis and
      epididymis.

PMID- 10352970
TI  - Permeability of blood-testis and blood-epididymis barriers to Hoechst 33342 dye.

PMID- 10352971
TI  - Alterations in the mitochondria of rat spermatozoa after experimental
      hyperprolactinemia.

PMID- 10352972
TI  - Immunolocalization of aromatase and estrogen receptors in bank vole Leydig cells.

PMID- 10352973
TI  - Subpopulations of the granulosa layer differentiated by histo- and
      immunocytochemical methods in the preovulatory follicle of the rat.

PMID- 10352974
TI  - Localization of NADPH-diaphorase and NOS isoforms in the oviduct of the pig.

PMID- 10352975
TI  - NADPH-diaphorase in porcine uterus after infusions of Escherichia coli endotoxin.

PMID- 10352976
TI  - Salivary glandular lobuli architectonics in rabbit revealed by various staining
      methods.

PMID- 10352977
TI  - Changes of the ATPase, acid phosphatase and alkaline phosphatase reaction
      intensity in the parotid and submandibular glands of rabbits in experimental
      diabetes.

PMID- 10352978
TI  - Morphobiochemical studies on alpha-amylase secretion by parotid gland acini of
      guinea pigs after the application of exogenous histamine.

PMID- 10352979
TI  - Elastase activity and histological changes in lungs and in pancreas due to
      experimental pancreatitis.

PMID- 10352980
TI  - Ultrastructural study of hepatocytes in the experimental model of acute
      pancreatitis.

PMID- 10352981
TI  - Ultrastructural studies of the liver during experimental hypercholesterolaemia.

PMID- 10352982
TI  - The preliminary evaluation of liver damage in rats intoxicated with methanol.

PMID- 10352983
TI  - Parenchymal cell mitochondria in the liver of rats after methanol intoxication.

PMID- 10352984
TI  - Activity of neutrophilic granulocytes in rats following intoxication with
      vanadium and zinc.

PMID- 10352985
TI  - The effects of tetrachloroplatinum (II) ions on guinea pig peritoneal exudate
      neutrophil (heterophil) granulocytes.

PMID- 10352986
TI  - The effect of met-enkephalin on granulocyte functions in vitro.

PMID- 10352987
TI  - The effect of met-enkephalin and aprotinin on heterophil (neutrophil) granulocyte
      phagocytosis and chemotaxis.

PMID- 10352988
TI  - The effect on neurotensin on granulocyte functions in vitro.

PMID- 10352989
TI  - Induction of apoptosis in cells of GH3 line by bromocryptine.

PMID- 10352990
TI  - The effect of quercetin on induction of apoptosis.

PMID- 10352991
TI  - Apoptosis in mouse skeletal muscles after physical exercise.

PMID- 10352992
TI  - Effect of acute hypobaric hypoxia on the histological changes of diaphragm in
      mice.

PMID- 10352993
TI  - Effect of pentoxifylline on the development of apoptosis-like changes in
      experimental lung damage.

PMID- 10352994
TI  - Evaluation of apoptosis and necrosis induction in cultured cells of lung
      carcinomas under effect of cytostatic drugs in vitro.

PMID- 10352996
TI  - Ultrastructure of lung granulocytes in the development of the primary focus of
      Morris hepatoma 5123 subjected to the action of rhTNF-alpha and its mutein VI.

PMID- 10352995
TI  - Evaluation of individual sensitivity to cytostatic drugs of in vitro cultured
      lung tumor cells.

PMID- 10352997
TI  - Assessment of proliferative activity of type II pneumocytes adjacent to non-small
      cell lung cancer tumours by AgNOR analysis.

PMID- 10352998
TI  - Usefulness of morphometric evaluation of AgNOR granules in differential
      diagnostics of eosinophilic cell carcinomas of the thyroid--preliminary studies.

PMID- 10352999
TI  - A correlation between the expression of nucleolar organizer regions (AgNORs) and
      some clinico-pathological features of sigmorectal adenocarcinomas.

PMID- 10353000
TI  - The evaluation of cytokeratin 18 expression in cervical squamous cell carcinoma.

PMID- 10353001
TI  - Expression of MPM2, p53 and Bcl2 proteins in Hodgkin's disease.

PMID- 10353003
TI  - Coiled bodies in the nuclei of undifferentiated crypt base cells in the human
      small intestine.

PMID- 10353002
TI  - Expression of CD79a antigen in acute lymphoblastic leukaemias in children.

PMID- 10353004
TI  - Cathepsin A and chymotrypsin-like activity of the proteasome in human blood
      platelets.

PMID- 10353005
TI  - Estimation of early G1 phase keratinocyte frequencies in gingival epithelium as a
      tool for studies of gingival epithelium proliferation.

PMID- 10353006
TI  - Morphometric measurements of several parameters of rat epidermis after a 28-day
      period of vitamin A derivative (etretinate) administration and a 28-day pause.

PMID- 10353007
TI  - Pattern of cytokeratin 8 expression in the developing rat thymus.

PMID- 10353009
TI  - [Role of psychiatry in liver transplantation].

PMID- 10353008
TI  - Analysis of some biophysical and biochemical parameters of long bones of spiny
      mouse (Acomys cahirinus) in its life cycle.

PMID- 10353010
TI  - [Alcoholic cirrhosis and liver transplantation: which criteria for indication?
      Work Group for Indication Criteria for Transplantation for Alcoholic Cirrhosis].

PMID- 10353011
TI  - [Importance of liver puncture biopsy and endoscopic retrograde cholangiography in
      patients with chronic anicteric unexplained cholestasis. A retrospective study in
      79 patients].
AB  - AIM: To determine the diagnostic value of systematic liver needle biopsy and
      endoscopic retrograde cholangiography in patients with unexplained chronic
      anicteric cholestasis. METHODS: Seventy nine patients presented with anicteric
      cholestasis for over 6 months as defined by: a concomitant increase in at least 2
      of 3 cholestatic enzymes (GGT, alkaline phosphatase, 5'nucleotidase); a low
      cytolytic ratio (ALT/AP (xN/xN) < or = 5); and negative test results (normal
      ultrasound scan; no antimitochondrial antibodies, viral, drug-induced, or toxic
      hepatitis, or known ulcerative cholitis). Based on liver biopsy and endoscopic
      retrograde cholangiography, 5 groups were determined; group A: normal liver
      biopsy and endoscopic retrograde cholangiography; group B: primary sclerosing
      cholangitis with histological biliary lesions; group C: primary sclerosing
      cholangitis with normal histology; group D: histologic biliary lesions alone;
      group E: other (aspecific histologic lesions, isolated anomalies of intrahepatic
      bile ducts on endoscopic retrograde cholangiography). RESULTS: Diagnosis of
      cholestasis was fortuitous in 43% of cases. Group A: 5 patients had normal liver
      biopsy and endoscopic retrograde cholangiography; group B (10 patients): 5 with
      destructive cholangitis, 5 with degenerative cholangitis, associated with portal
      fibrosis in 90%; group C: none of the patients had primary sclerosing cholangitis
      with normal histology; group D: 39 patients {idiopathic ductopenia (1), Caroli's
      disease (1), benign recurrent cholestasis (1), regenerative nodular hyperplasia
      (4), destructive cholangitis without ductopenia (7), degenerative cholangitis
      (15), ductular proliferation (10)}; group E: 24 patients with aspecific
      histologic lesions, and one patient with isolated anomalies of the intrahepatic
      bile ducts on endoscopic retrograde cholangiography. CONCLUSIONS: In the present
      population: a) 13% presented with intense cholangitis and primary sclerosing
      cholangitis on endoscopic retrograde cholangiography; b) 49% presented with
      various histologic biliary lesions without primary sclerosing cholangitis. We
      conclude that in chronic anicteric cholestasis of unexplained origin, first
      choice work-up should include liver biopsy, and endoscopic retrograde
      cholangiography should only be performed when intense histologic cholangitis is
      observed.

PMID- 10353013
TI  - [Molecular genetics of familial cholestasis].

PMID- 10353012
TI  - [Endoscopic sphincteroclasy for choledocholithiasis of the principal bile duct.
      Short-term results and follow-up].
AB  - AIMS: The hydrostatic dilatation of the papilla of Vater, or sphincteroclasy, has
      been recently proposed as an alternative to endoscopic sphincterotomy. Our aim
      was to assess short term results and follow-up after sphincteroclasy for
      choledocholithiasis. METHODS: From August, 1994 to December, 1996, 52 patients
      were included for endoscopic therapy of choledocholithiasis (mean age 66 +/- 17
      years). Patients were prospectively followed on the short term-period (24 h, 48 h
      and 30 days) and longer term after treatment (every 6 months) by clinical and
      biological controls. MAIN RESULTS: Forty-eight sphincteroclasies were performed
      successfully (92.3%). Thirty seven patients had a choledocolithiasis. Eleven were
      stone-free. Eight had undergone former gastric surgery and 8 had impaired
      coagulation test. Complete stone clearance was achieved in 98% of patients. Mild
      pancreatitis were observed in three patients (6.25%). Thirty-day mortality was
      nil. Long term follow-up (mean 21.4 +/- 7 months) revealed: 2 patients with
      cholecystitis 6 and 13 months after treatment, one of which was followed 8 months
      later by a fatal septic shock, and 3 patients with cholangitis, 2 of which in the
      same patient, 9, 12 and 24 months after sphincteroclasy. The global long term
      biliary complication rate was 8.4%, 4.2% of which were potentially related to the
      endoscopic procedure. CONCLUSION: Sphincteroclasy is an efficient procedure for
      the treatment of choledocholithiasis. Its short term results are similar to those
      of endoscopic sphincterotomy. Complications after 2 years appear to be scarce,
      but longer follow-up is required before routinely performing sphincteroclasy.

PMID- 10353014
TI  - [Evaluation of esophageal motility disorders triggered by ingestion of solids in
      the case of non-obstructive dysphagia].
AB  - The aim of this study was to define the normal manometric pattern of esophageal
      motility in response to food ingestion and to evaluate the contribution of
      esophageal manometry in the management of patients complaining of functional
      dysphagia. PATIENTS AND METHODS: Twenty-one healthy volunteers and 25 consecutive
      patients complaining of functional dysphagia with normal conventional esophageal
      manometry were included in this prospective study. An event marker was used to
      study the relationship between dysphagia and motility events. RESULTS: Twenty-two
      out of 25 patients (88%) reported dysphagia during esophageal manometry with food
      ingestion, while none complained of dysphagia during conventional esophageal
      manometry. Significantly, food ingestion induced in healthy volunteers and in
      patients: an increase in the amplitude and duration of esophageal body
      peristaltic contractions, and a decrease in their propagation speed; an increase
      in the basal pressure and a decrease in the relaxation percentage of the lower
      esophageal sphincter during deglutition. The percentage of solid swallows with
      one or several of the 7 abnormal motility patterns studied prospectively was
      significantly higher among patients (53.7%) than among healthy volunteers (4.3%)
      (P < 0.0001); it was also significantly higher among patients during swallows
      with dysphagia (70.1%) than without dysphagia (33.6%) (P < 0.0001). CONCLUSION:
      Esophageal manometry with food ingestion is an effective means of defining
      abnormal motility patterns and their relationship with dysphagia during
      functional dysphagia.

PMID- 10353015
TI  - [Solid pseudopapillary tumors of the pancreas. Pathology report of 13 cases].
AB  - OBJECTIVES: Solid pseudopapillary tumors of the pancreas are exceptional. The
      aims of our study were to reevaluate the mode of presentation of these tumors and
      to analyze the role of pathological examination in diagnostic assessment and
      prognostic evaluation. PATIENTS: We report the clinical, radiological and
      pathological findings in a retrospective series of 13 patients in whom a
      diagnosis of solid pseudopapillary tumor of the pancreas was made between 1983
      and 1997. There were 12 females (median age: 22.5 years) and one male, aged 73.
      RESULTS: The tumor was discovered incidentally (3 cases) or because of
      nonspecific digestive symptoms (10 cases). Biological data were uninformative.
      The tumor was pancreatic in 12 cases and duodenal in 1. In all cases, imaging
      techniques showed an heterogeneous lesion with no or poor vascularization. A
      cystic component was identified in 4 cases. Surgical resection was performed in
      all cases. Pathological examination showed an encapsulated tumor in 8 cases, a
      non-encapsulated but well-limited lesion in 3 cases and an infiltrative tumor in
      2 cases. At the time of diagnosis, multiple liver metastases were present in 1
      case. Mean duration of follow-up was 24 months (range: 3-168). At last follow-up,
      all patients, including the patient with synchronous metastatic disease, were
      alive, without local recurrence. CONCLUSION: Our study confirms that most cases
      of solid pseudopapillary tumors of the pancreas present with a suggestive
      clinical picture, including their occurrence in young women and their good
      prognosis after surgical resection. However, our results also underline the
      occurrence of cases presenting with unusual features, including old age, male
      sex, extra-pancreatic localization and malignant evolution. Histopathological
      examination is essential for the establishment of the diagnosis but morphological
      data are of little prognostic value.

PMID- 10353016
TI  - [Incidence of treatment modalities for cancer of the small intestine in Burgundy
      (France)].
AB  - AIMS: To determine the epidemiological characteristics and management of cancers
      of the small bowel, on a population-based survey. METHODS: The registry of
      digestive tumors of Burgundy recorded all new cases of cancers of the small
      intestine in the departments of Cote d'Or and Saone et Loire (1,052,000
      inhabitants). RESULTS: Two hundred and ten new cases of malignant tumors of the
      small intestine were recorded between 1976 and 1995 including 4 main histological
      types: adenocarcinomas (39.5%), carcinoids (26.2%), lymphomas (18.6%) and
      sarcomas (10.5%). Age-standardized incidence rates for males and females were
      respectively 8.8 and 5.6 per 1,000,000 inhabitants. There was evidence of lymph
      node invasion in 29.5% and visceral metastasis in 31.4%. Treatment was primarily
      surgical (90.5%), with a post-operative death rate of 17.1%. The rate of curative
      surgery remained constant over time, averaging 58.6%, 20% of the patients
      underwent chemotherapy, with a high proportion of lymphomas, often in association
      with surgery. The relative survival rates at 1, 3 and 5 years were 51.2, 38.3 and
      32.7%, respectively. The multivariate analysis showed that survival was linked to
      age, and strongly to histological type and stage of diagnosis. CONCLUSION:
      Cancers of the small intestine are an heterogeneous group of rare tumors, often
      diagnosed at advanced stage. No significant improvement has been achieved in
      their management over the past 20 years.

PMID- 10353017
TI  - [Evaluation of recombinant retrovirus and adenovirus for gene transfer to normal
      and pathologic intestinal tissue].
AB  - Intestinal tract is an attractive target for gene therapy. A number of diseases
      could benefit from gene transfer into this organ and in particular inflammatory
      diseases such as Crohn's disease. In the present report, we have evaluated the
      efficiency of retroviral and adenoviral recombinant vectors for transferring a
      marker gene (beta galactosidase from E. Coli) in two parts of the intestinal
      tract: the small bowel and the left part of the colon. Retroviruses were
      inefficient for the transfer of the marker gene in these two sites either in
      normal conditions or after induction of inflammation by treatment with acetic
      acid or trinitrobenzene. Conversely, beta galactosidase positive cells were found
      in small bowel as well as colon following gene transfer with adenoviral vectors.
      Moreover the location of the positive cells in the intestinal wall was dependent
      upon the route of injection of the adenoviral vectors (transparietal, endoluminal
      or intramural).

PMID- 10353018
TI  - [Pharmacologic actions and therapeutic importance of botulinum toxin in digestive
      diseases].

PMID- 10353019
TI  - [Budd-Chiari syndrome due to membranous obstruction of the inferior vena cava of
      congenital origin. Ten-year follow-up after radiologic treatment].
AB  - We report a case of Budd-Chiari syndrome due to membranous obstruction of the
      inferior vena cava with a congenital malformation composed of a left inferior
      vena cava at the sub-renal level with an azygo-caval continuation without a
      retrohepatic segment of the inferior vena cava. To our knowledge, this is the
      first report of this association. The congenital venous malformation suggests a
      congenital etiology to the inferior vena cava membrane. The membranous
      obstruction was treated by percutaneous transluminal angioplasty. During the 10
      year follow-up, there was no recurrence of the membranous obstruction as seen
      with Doppler ultrasound and magnetic resonance imaging.

PMID- 10353020
TI  - [Labor complications of the HELLP syndrome without any predictive factors].
AB  - Liver disease is a rare complication of pregnancy which can be serious for both
      the mother and the infant. In particular, HELLP syndrome (hemolysis, elevated
      liver enzymes and a low platelet count) is a life threatening complication of
      severe preeclampsia. Pregnancies complicated by the HELLP syndrome are usually
      associated with increased maternal and perinatal morbidity and mortality
      including disseminated intravascular coagulopathy, pulmonary and cerebral oedema,
      acute renal failure, rupture of the liver hematoma and a variety of hemorrhagic
      complications. The HELLP syndrome occurs in 4 to 12% of patients with severe
      preeclampsia and prompt delivery is the only treatment. We report two cases of
      HELLP syndrome which developed in women during delivery and without any
      predictive factors during pregnancy.

PMID- 10353021
TI  - [Chronic acquired hepatocerebral degeneration: the role of manganese and
      treatment by endovascular occlusion of a porto-systemic shunt].
AB  - This case report describes a 74 year-old woman with cirrhosis who developed
      choreo-athetotic movements associated with elevated whole blood manganese and
      symmetric hyperintense pallidum on T1-weighted magnetic resonance imaging. The
      diagnosis was chronic acquired hepatocerebral degeneration. The endovascular
      occlusion of portal-systemic shunts was temporarily effective.

PMID- 10353022
TI  - [Para-esophageal hiatal hernia with acute gastric volvulus].
AB  - We report 3 observations of acute gastric volvulus on paraesophageal hiatus
      hernia requiring emergency laparotomy. The main characteristics of this
      complication of hiatus hernia are described and the importance of early
      diagnosis, because of unfavorable prognosis, is stressed.

PMID- 10353023
TI  - [Liver metastases of a choriocarcinoma: a rare cause of hemoperitoneum].

PMID- 10353024
TI  - [Digestive hemorrhage due to rupture of the caecal varices in a patient with
      cirrhosis].

PMID- 10353025
TI  - [Pancreatic metastasis from piriform sinus carcinoma].

PMID- 10353026
TI  - [Immediate treatment of esophageal perforation after endoscopic dilatation of
      tumoral stenoses using a self-expanding covered metal stent].

PMID- 10353027
TI  - [Primary epidermoid carcinoma of the colon].

PMID- 10353028
TI  - [Weber-Christian syndrome and intraductal papillary mucinous tumor of the
      pancreas].

PMID- 10353029
TI  - [Colorectal cancer: when and how to look for hereditary nonpolyposis colorectal
      neoplasm syndrome?].

PMID- 10353030
TI  - Sequential change of MR signal intensity of the brain after manganese
      administration in rabbits. Correlation with manganese concentration and
      histopathologic findings.
AB  - RATIONALE AND OBJECTIVES: High signal intensity in the basal ganglia on T1
      weighted MR imaging has been reported in chronic manganese (Mn) poisoning.
      However, the exact meaning of the high signal intensity remains unclear: does it
      result from Mn itself, secondary pathologic changes of the brain tissue, or both?
      The goal of this study was to evaluate the sequential change of MR signal
      intensity and to correlate the MR intensity of the globus pallidus and the
      hypothalamus with the Mn concentration in the blood and the brain tissue, and
      with the histopathologic findings. METHODS: Ten milligrams per kilogram of Mn was
      administered once a week for 4 weeks to 14 rabbits. The rabbits in the control
      group (n = 2) were killed without Mn administration; those in group I (n = 4)
      were killed 1 day after the completion of Mn administration, those in group II (n
      = 4) were killed at 4 weeks, and those in group III (n = 6) were killed at 8
      weeks. Sequential MR imaging, blood and tissue concentration measurement, and
      pathologic examination were performed. Sequential changes of the percent
      contrasts, contrast-to-noise ratios, and T1 relaxation times were analyzed with
      blood and tissue concentrations and histopathologic findings. RESULTS: The signal
      intensity of the basal ganglia on T1-weighted imaging was highest 1 day after
      cessation of Mn administration and sequentially washed out. The contrast,
      contrast-to-noise ratio, and T1 relaxation time showed significant correlations
      with blood concentration. Only the T1 relaxation time of the globus pallidus
      showed a significant correlation with tissue concentration. Histopathologic
      examination disclosed mild abnormalities in the globus pallidus, thalamus, and
      hypothalamus. CONCLUSIONS: The high signal intensity on T1-weighted MR imaging
      presumably indicates mainly the exposure marker of Mn, although mild pathologic
      findings were observed.

PMID- 10353031
TI  - The use of an interactive software program for quantitative characterization of
      microcalcifications on digitized film-screen mammograms.
AB  - RATIONALE AND OBJECTIVES: Mammography is relatively nonspecific for the early
      detection of breast cancer. This study evaluates the accuracy of mammographic
      interpretation using quantitative features characterizing microcalcifications,
      which are extracted by a computerized system. METHODS: A computer-aided diagnosis
      (CAD) system enabling digitization of film-screen mammograms and automatic
      feature extraction was developed. A classification scheme (discriminant analysis)
      based on these features was constructed and trained on 217 cases with known
      pathology. The diagnostic performance of the classification scheme was tested
      against the radiologist's conventional interpretation on 45 additional cases of
      microcalcifications, each analyzed independently by four radiologists. RESULTS:
      The sensitivity of the CAD system analysis (95.7%) was significantly better than
      that of conventional interpretation (84.8%). The positive predictive value of
      interpretation increased significantly, as did the area under the receiver
      operating characteristic curve. CONCLUSIONS: This classification scheme for
      microcalcifications, based on quantitative features characterizing the lesion,
      significantly improved the accuracy of mammographic interpretation.

PMID- 10353032
TI  - Evaluation of liposomal contrast agents for liver CT in healthy rabbits.
AB  - RATIONALE AND OBJECTIVES: To evaluate the efficiency of two new liposomal
      contrast agents aimed at the reticuloendothelial system for liver CT in
      comparison to an extracellular contrast agent. METHODS: Two liposomal contrast
      agents (BR2 and BR21, respectively), containing free as well as encapsulated
      iomeprol at different concentrations, and commercially available free
      extracellular iomeprol were studied. In 60 experiments, the three contrast agents
      were tested at five different doses in rabbits. Intravenous injection was
      followed by dynamic CT studies over a period of 0 to 120 minutes (0 to 6 hours in
      3 animals). A quantitative analysis of the enhancement in aorta and liver was
      performed. RESULTS: In healthy rabbits, the two liposomal contrast agents induced
      a significantly higher and more persistent increase in liver density at doses of
      > or = 1.5 mL/kg compared with the extracellular agent. The density enhancement
      induced by the two liposomal agents was dose-dependent and reached a maximum of
      +102 Hounsfield units (HU), compared with +87 HU for the extracellular contrast
      agent, at 2.0 mL/kg, without any appreciable increases at higher dosages. An
      adequate liver enhancement of at least +40 HU persisted for up to 90 minutes
      after injection of the liposomal contrast agents, compared with < 5 minutes after
      the extracellular agent. BR2 tended to provide a higher and more persistent
      enhancement than BR21. CONCLUSIONS: Liposomal contrast agents induce a more
      pronounced and much more persistent increase in liver density than conventional
      extracellular agents. Liposomes thus have the potential for optimizing CT
      examinations of the liver by providing a larger imaging window.

PMID- 10353033
TI  - NMRD assessment of Gd-DTPA-bis(methoxyethylamide), (Gd-DTPA-BMEA), a nonionic MRI
      agent.
AB  - RATIONALE AND OBJECTIVES: Gd-DTPA-BMEA, a nonionic bis(methoxyethylamide)
      derivative of Gd-DTPA, is the active ingredient of OptiMARK, now awaiting FDA
      approval. In this study, we compare the relaxivities of Gd-DTPA-BMEA (OptiMARK)
      with those of the commercially available DTPA-based agents Gd-DTPA2- (Magnevist)
      and Gd-DTPA-BMA (Omniscan) at different field strengths (1/T1 nuclear magnetic
      relaxation dispersion (NMRD) profiles). In addition, we study how changes in
      structural attributes of small paramagnetic chelate complexes of Gd3+ ions
      influence 1/T1 NMRD profiles. METHODS: 1/T1 NMRD profiles of Gd-DTPA-BMEA
      (OptiMARK) were measured at 5 degrees and 35 degrees C and a set of values for
      the parameters that describe relaxation by Gd(3+)-proton magnetic dipolar
      interactions was obtained. The rotational (tau R) and the diffusional (tau D)
      correlation times for Gd-DTPA-BMA were adjusted for the 15% greater molecular
      weight of Gd-DTPA-BMEA. tau M (the resident lifetime of Gd(3+)-bound water) was
      obtained from available 17O NMR relaxation data. For tau S0 and tau V (the low
      field relaxation time of the Gd3+ moment and its correlation time), Gd-DTPA-BMA
      values were taken as initial values and tau S0 refined as needed. RESULTS:
      Although, at 35 degrees C, tau M is comparable for the two neutral agents and an
      order of magnitude longer than that for Gd-DTPA2-, the 1/T1 NMRD profiles of Gd
      DTPA-BMEA are indistinguishable from those of Gd-DTPA2- and Gd-DTPA-BMA. A 40%
      increase in the value of tau S0 from Gd-DTPA2- is required for agreement of data
      and theory for Gd-DTPA-BMEA. CONCLUSIONS: Based on their 1/T1 NMRD profiles, the
      efficacy of the three agents should be identical in typical clinical MRI
      applications. The data can be fit reliably to theory, and differences in the fit
      parameters (and structure) have no effect on the three profiles at 35 degrees C.
      The relatively long values of tau M for the two neutral agents would only be of
      importance at low temperatures.

PMID- 10353034
TI  - Dose and image quality of electron-beam CT compared with spiral CT.
AB  - RATIONALE AND OBJECTIVES: To examine dose and image quality of electron-beam CT
      (EBCT) with continuous volume scan versus spiral CT. METHODS: An EBCT scanner was
      compared with a spiral CT (SCT) scanner. Three phantoms were used to measure low
      contrast resolution, high-contrast resolution, slice width, and dose. RESULTS:
      The EBCT scans showed 30% lower high-contrast resolution for most settings. The
      dose was comparable to that of spiral CT with 3 mm collimation and 76%/106%
      higher with EBCT for 1.5 mm/6 mm collimation. Low-contrast resolution was
      comparable to that of spiral CT using 3 mm collimation, slightly worse for 1.5
      mm, and bad for 6 mm EBCT collimation (four times higher dose to reach comparable
      contrast-to-noise ratio). CONCLUSIONS: Significant restrictions were found using
      EBCT with continuous volume scan. The authors found that 3 mm collimation can
      yield acceptable high-contrast resolution and good low-contrast resolution
      compared with spiral CT. The use of 6 mm or 1.5 mm collimation needs to be
      restricted to selected cases.

PMID- 10353035
TI  - Influence of helical CT parameters on spatial resolution in CT angiography
      performed with a subsecond scanner.
AB  - RATIONALE AND OBJECTIVES: In helical CT, the beam collimation, table feed (TF)
      per tube rotation, voltage, current, reconstruction increment, kernel, linear
      interpolation algorithm (LIA), and contrast are variable parameters. The purpose
      of this study was to determine which of these parameters are most important to
      minimize partial volume effects for improving spatial resolution in CT
      angiography. METHODS: Phantom vessel stenoses of different lengths (2, 8 mm) and
      diameters (0.5, 1, 2, 3, 4 mm) were scanned with helical CT using a constant tube
      rotation time of 0.75 sec and 42 selected combinations of the above-mentioned
      parameters. Orthogonal targeted maximum intensity projections of the stenoses
      were ordered according to the increase in blurring and noise in a consensus
      reading by two radiologists blinded to the parameters used. RESULTS: Three
      millimeters of collimation and TF in conjunction with a 180 degrees LIA and > 250
      Hounsfield unit contrast density was considered the optimal parameter combination
      and enabled a continuous visualization of the stenoses down to 0.5 mm in
      diameter. A collimation of 1 or 2 mm and 5 mm was considered inferior to a
      collimation of 3 mm because of, respectively, noise and blurring. With 3 mm
      collimation, significant blurring occurred when a pitch larger than 1.5 was used.
      A 3 mm collimation with a pitch of 2 (6 mm TF) was found to be superior to a
      collimation of 5 mm in conjunction with a pitch of 1 (5 mm TF). With 5 mm
      collimation, the short stenoses could be visualized only when using a 180 degrees
      LIA and a TF per tube rotation smaller than 7 mm. Eight and 10 mm collimations
      failed to depict the short stenoses. CONCLUSIONS: Collimation had the most
      influence on image quality in CT angiography, followed by LIA, pitch, and
      contrast density. Decreasing the reconstruction increment to less than one third
      of the TF or increasing the voltage or current beyond standard values did not
      improve the delineation of the stenoses. For screening examinations, the authors
      recommend the use of 3 mm collimation, 180 degrees LIA, and a pitch of 2.

PMID- 10353036
TI  - MRI enhancement and microvascular density in gliomas. Correlation with tumor cell
      proliferation.
AB  - RATIONALE AND OBJECTIVES: Angiogenesis and proliferation activity are important
      indicators of tumor behavior in human gliomas. The authors studied how tumor
      enhancement in MR imaging and intratumoral vascular density were correlated with
      cell proliferation in cerebral gliomas. METHODS: The authors studied
      retrospectively 62 cerebral gliomas. Patients were examined before surgery with
      contrast-enhanced MR imaging. Microvessel density and the cell proliferation rate
      of tumor specimens were measured immunohistochemically using factor VIII and MIB
      1 antibodies. Contrast enhancement of the tumors was evaluated by two
      radiologists. RESULTS: Contrast enhancement was observed in 45 tumors and was
      correlated with histologic cell proliferation (P = 0.0007) and microvessel
      density (P = 0.01). There was also a correlation between tumor vascular density
      and the cell proliferation rate (r = 0.51, P < 0.0001). Histologic tumor grade
      was associated with vascular density (P = 0.001). CONCLUSIONS: Lesion enhancement
      on preoperative contrast-enhanced MR imaging correlates with vascularity and
      proliferation activity of gliomas. The additional correlation between tumor
      vascularity and proliferation suggests that intratumoral microvessel density
      could be useful in estimating tumor proliferation.

PMID- 10353037
TI  - Indirect MR arthrography of the unexercised glenohumeral joint in patients with
      rotator cuff tears.
AB  - RATIONALE AND OBJECTIVES: To evaluate the diagnostic utility of indirect MR
      arthrography of the unexercised glenohumeral joint in patients with rotator cuff
      tears confirmed by arthroscopy or arthrotomy as the gold standard. METHODS:
      Twenty-six patients underwent conventional MR imaging and indirect MR
      arthrography of the stationary glenohumeral joint using a wrap-around surface
      coil. Unenhanced T1-weighted spin echo/T2-weighted fast spin echo sequences and
      T1-weighted gradient echo sequences, adding spectral fat suppression after
      intravenous administration of contrast medium, were performed in the oblique
      coronal and oblique sagittal planes. Images were analyzed by three experienced
      radiologists in consensus. Levels of diagnostic confidence were evaluated using a
      four-point scale of diagnostic certainty. RESULTS: Performing indirect MR
      arthrography of the unexercised shoulder leads to a diagnostically efficient
      enhancement of joint fluid (120% at 4 minutes and 145% at 8 minutes after
      intravenous injection of gadodiamide). In terms of soft tissue delineation,
      characterization of rotator cuff tears was significantly improved by using
      enhanced fat-suppressed T1-weighted gradient echo sequences compared with
      conventional MR imaging. CONCLUSIONS: Indirect MR arthrography without
      glenohumeral joint exercise in the diagnosis of rotator cuff tears is feasible
      and represents a more convenient and less time-consuming alternative to indirect
      MR arthrography after joint exercise.

PMID- 10353038
TI  - Multiple organ failure. How valid is the "two hit" model?
AB  - Inflammatory "one hit" and "two hit" models have recently been proposed to
      account for the development of multiple organ failure (MOF) in trauma and
      critically ill surgical patients when no source of infection can be found. In the
      "one hit" model, the initial insult is so massive that a systemic inflammatory
      response syndrome is triggered and leads rapidly to MOF. In the "two hit"
      scenario, initially less severely injured patients eventually develop MOF as a
      result of a reactivation of their inflammatory response caused by an adverse and
      often minor intercurrent event. At first sight, the theory is attractive because
      it seems to fit commonly observed clinical patterns. Indeed, injured patients
      often respond to initial resuscitation but, after an insult of some sort, develop
      organ dysfunction and die. The "two hit" model is furthermore mirrored at the
      cellular level. Inflammatory cells are indeed susceptible of being primed by an
      initial stimulus and reactivated subsequently by a relatively innocuous insult.
      However, in the absence of clinical and biological corroboration based on
      cytokine secretion patterns, these models should not be accepted uncritically.

PMID- 10353039
TI  - CS exposure--clinical effects and management.
AB  - The number of people exposed to CS spray presenting to accident and emergency
      departments is on the increase. Its effects, though usually minor and short
      lived, involve several systems and can occasionally be life threatening. It is
      therefore important that staff are able to manage these patients and know when
      and how to protect themselves and others from further contamination.

PMID- 10353040
TI  - AKA unknown male Foxtrot 23/4: alias assignment for unidentified emergency room
      patients.
AB  - OBJECTIVES: To introduce a unique system of alias assignment for patients whose
      identity is initially unknown at time of admission to the emergency unit; to
      prevent confusion and cases of mistaken identity. METHODS: At the triage area the
      "unknown" patient is given a "forename" using the phonetic alphabet according to
      the stage of the current name cycle. The sex of the patient is included as well
      as the unknown status and a "surname" is added as the numerical date. Thus an
      unknown male patient admitted on the 24th of April at the start of a new name
      cycle would be known as "unknown male Alpha 24/4". RESULTS: Ten thousand alias
      assignments have been issued to patients since the introduction of the system in
      1985. CONCLUSION: This system is a simple yet effective, tried and tested method
      for the unique identification of unknown patients, which allows easy
      communication and retrieval of data for inquiries.

PMID- 10353041
TI  - Who calls 999 and why? A survey of the emergency workload of the London Ambulance
      Service.
AB  - BACKGROUND: In 1996-97 there were 623,000 emergency (999) calls made to the
      London Ambulance Service (LAS) and this represents a 30% increase over the
      previous five years. The reasons for this increase, which is also observed
      nationally, remain unknown. It has been suggested that some callers may be using
      the 999 service "inappropriately" but no data are available from the ambulance
      service. OBJECTIVE: To describe the workload of the emergency ambulance service
      in London with specific reference to the nature and characteristics of 999 calls,
      to determine who dials 999 and why, and to establish the number and types of
      calls that could most appropriately be dealt with by other agencies. DESIGN: A
      one week census of all emergency calls responded to by the LAS. SETTING: Sixty
      eight LAS stations. METHODS: Collation of all routine LAS incident forms (LA4)
      including the classification of the crews' free text description of the incident.
      This was supplemented by a detailed workload questionnaire for 25% of calls.
      RESULTS: There were 10,921 calls responded to from 29 April to 5 May 1996. The
      census showed that the daily number of calls was highest on Saturday and lowest
      on Wednesday with about half being made during normal general practitioner (GP)
      working hours. Half of all calls were for women and one third were for people
      aged > or = 65. Accidents were the commonest type of incident (24%). The
      remainder comprised various medical conditions such as respiratory, cardiac, and
      obstetric problems. In 1.5% of calls there was no illness, injury, or assistance
      required and 5% were for "general assistance" and mostly concerned people aged >
      or = 65. The workload survey indicated that two thirds of incidents occurred at
      home and 70% of callers had not tried to contact a GP before dialing 999. In the
      professional opinion of the responding crew, 60% of calls required a 999
      response, with the remainder thought more appropriately dealt with by other
      services such as primary care, psychiatric services, and social services.
      CONCLUSIONS: This study suggests that while the majority of 999 calls were
      "appropriate", part of the 999 workload could be dealt with by other services.
      More research is required to clarify why people contact the 999 service for non
      emergency incidents and also to establish the views of GPs and other agencies as
      to the role and function of the IAS.

PMID- 10353042
TI  - Does the Manchester triage system detect the critically ill?
AB  - BACKGROUND: The Manchester triage system (MTS) is now widely used in UK accident
      and emergency (A&E) departments. No clinical outcome studies have yet been
      published to validate the system. Safety of triage systems is related to the
      ability to detect the critically ill, which has to be balanced with resource
      implications of overtriage. OBJECTIVES: To determine whether the MTS can reliably
      detect those subsequently needing admission to critical care areas. METHODS:
      Analysis of emergency admissions to critical care areas and comparison with
      original A&E triage code by a nurse using the MTS at time of presentation.
      Retrospective coding of all cases according to the MTS by experts and case
      analysis to determine whether any non-urgent coding was due to the system or to
      incorrect coding. RESULTS: Sixty one (67%) of the patients admitted to a critical
      care area were given triage category 1 or 2 (that is, to be seen within 10
      minutes of arrival). Eighteen cases given lower priority were due to incorrect
      coding by the triage nurse. Six cases were correctly coded by the MTS, of which
      five deteriorated after arrival in the A&E department. Only one case was
      critically ill on arrival and yet was coded as able to wait for up to one hour.
      CONCLUSIONS: The MTS is a sensitive tool for detecting those who subsequently
      need critical care and are ill on arrival in the A&E department. It did fail to
      detect some whom deteriorated after arrival in A&E. Most errors were due to
      training problems rather than the system of triage. Analysis of critically ill
      patients allows easy audit of sensitivity of the MTS but cannot be used to
      calculate specificity.

PMID- 10353044
TI  - Early prediction of neurological outcome after falls in children: metabolic and
      clinical markers.
AB  - Falls are the foremost reason for non-fatal injuries and are second only to motor
      vehicle accidents in causing accidental death. The purpose of this study was to
      identify the clinical and metabolic predictors of the outcome of head injury
      caused by falls from a height. Medical records of 61 children who had been
      admitted to the paediatric intensive care unit from 1990 to 1993 after falling
      from a height were reviewed retrospectively. Outcomes were categorised as good,
      moderate, severe, and poor. Glasgow coma scores, pupillary responses, brain
      oedema, and midline shift are significantly associated with poor outcome (p <
      0.05). Metabolic markers associated with poor outcome included hyperglycaemia and
      hypokalaemia. Children with a poor outcome had, at admission, significantly
      higher glucose concentrations compared with children with good outcomes (mean
      SD): 20.0 (7.1) v 9.31 (4.0) mmol/l, p < 0.01), and lower potassium
      concentrations compared with children with good, moderate, and severe outcomes
      (mean (SD): 2.8 (0.4) v 3.7 (0.4) mmol/l, p < 0.001, 3.5 (0.3) mmol/l, p < 0.01,
      and 3.41 (0.3) mmol/l, p < 0.05, respectively). These findings allow for an early
      allocation of effort and resources to children injured from such falls.

PMID- 10353043
TI  - Outcome after severe head injury treated by an integrated trauma system.
AB  - OBJECTIVES: To describe outcome after treatment of severe head injury within an
      integrated trauma system. METHODS: A retrospective analysis of all patients with
      severe head injury admitted to the Royal London Hospital by the Helicopter
      Emergency Medical Service (HEMS) between 1991 and 1994. Type of injury was
      defined on initial computed tomography of the head and outcomes assessed 12
      months after injury using the Glasgow outcome score. RESULTS: 6.5% of HEMS
      patients had long term severe disability (severe disability or persistent
      vegetative state on the outcome score); 34.5% made a good recovery. CONCLUSIONS:
      The concern that a large number of severely disabled long term survivors might
      result as a consequence of this system of trauma management is not confirmed. The
      case mix of severity of extracranial injuries in these patients makes comparison
      with other published series difficult, but these data fit the hypothesis that pre
      hospital correction of hypoxia and hypotension after head injury improves
      outcome.

PMID- 10353045
TI  - Injury surveillance in a children's hospital--overcoming obstacles to data
      collection.
AB  - OBJECTIVE: To understand the problems involved in collection of injury
      surveillance (Glasgow Children Hospital Injury Reporting and Prevention
      Programme, CHIRPP) forms. METHODS: Glasgow CHIRPP forms were issued by the
      clerical staff to all eligible child carers for details of the injury or
      ingestions by the child, and the retrieval rate of forms was monitored. Reasons
      for the poor collection of forms were identified and rectified. RESULTS: The
      collection rate of Glasgow CHIRPP forms was poor when the system was introduced
      in 1993. It improved when the forms were issued by nursing staff, and
      considerable improvement was noted when the triage nurse was made responsible.
      CONCLUSIONS: When a named individual was made responsible there was an
      improvement in the retrieval of Glasgow CHIRPP forms. A few other simpler
      problems relating to the retrieval of forms were identified and rectified.

PMID- 10353046
TI  - Analysis of illicit ecstasy tablets: implications for clinical management in the
      accident and emergency department.
AB  - OBJECTIVE: To examine the composition of illicitly manufactured "ecstasy" tablets
      sold on the UK drugs market. METHODS: Analysis by gas chromatography of 25
      illicit ecstasy tablets handed in under amnesty to Leeds Addiction Unit. RESULTS:
      Illicitly manufactured ecstasy tablets contain a range of ingredients, of widely
      differing concentrations, and even tablets with the same brand name have variable
      concentrations of active ingredients. Concentrations of 3,4
      methylenedioxymethamphetamine (MDMA) more popularly known as ecstasy, varied 70
      fold between tablets. Nine tablets contained neither MDMA nor related analogues.
      CONCLUSIONS: These results have implications for emergency workers attending to
      those who have become casualties of the drug ecstasy. Those claiming to have
      ingested ecstasy may actually have taken other agents that require different
      clinical management.

PMID- 10353047
TI  - Open water scuba diving accidents at Leicester: five years' experience.
AB  - OBJECTIVES: The aim of this study was to determine the incidence, type, outcome,
      and possible risk factors of diving accidents in each year of a five year period
      presenting from one dive centre to a large teaching hospital accident and
      emergency (A&E) department. METHODS: All patients included in this study
      presented to the A&E department at a local teaching hospital in close proximity
      to the largest inland diving centre in the UK. Our main outcome measures were:
      presenting symptoms, administration of recompression treatment, mortality, and
      postmortem examination report where applicable. RESULTS: Overall, 25 patients
      experienced a serious open water diving accident at the centre between 1992 and
      1996 inclusive. The percentage of survivors (n = 18) with symptoms of
      decompression sickness receiving recompression treatment was 52%. All surviving
      patients received medical treatment for at least 24 hours before discharge. The
      median depth of diving accidents was 24 metres (m) (range 7-36 m). During the
      study period, 1992-96, the number of accidents increased from one to 10 and the
      incidence of diving accidents increased from four per 100,000 to 15.4 per
      100,000. Over the same time period the number of deaths increased threefold.
      CONCLUSIONS: The aetiology of the increase in the incidence of accidents is
      multifactorial. Important risk factors were thought to be: rapid ascent (in 48%
      of patients), cold water, poor visibility, the number of dives per diver, and the
      experience of the diver. It is concluded that there needs to be an increased
      awareness of the management of diving injuries in an A&E department in close
      proximity to an inland diving centre.

PMID- 10353048
TI  - Clinical ECG interpretation--an introduction.

PMID- 10353049
TI  - The additional lead electrocardiogram in acute myocardial infarction.

PMID- 10353051
TI  - Towards evidence based emergency medicine: best BETs from the Manchester Royal
      Infirmary. Treatment of ruptured Achilles tendon.

PMID- 10353052
TI  - Towards evidence based emergency medicine: best BETs from the Manchester Royal
      Infirmary. Treating avulsion fractures of the base of the fifth metatarsal.

PMID- 10353050
TI  - Clearing the cervical spine of adult victims of trauma.

PMID- 10353053
TI  - Towards evidence based emergency medicine: best BETs from the Manchester Royal
      Infirmary. Magnetic resonance imaging in acute knee haemarthrosis.

PMID- 10353054
TI  - Towards evidence based emergency medicine: best BETs from the Manchester Royal
      Infirmary. Mobilisation of lateral ligament ankle sprains.

PMID- 10353055
TI  - Organising a medical conference.

PMID- 10353056
TI  - Abdominal pain as an atypical presentation of meningococcaemia.
AB  - An atypical presentation of meningococcaemia without purpura poses diagnostic
      problems. The importance of the identification of shock manifest as delayed
      capillary refill in two children with meningococcal septicaemia presenting with
      fever and abdominal pain is discussed. Abdominal pain is an unusual presentation
      of meningococcal disease.

PMID- 10353057
TI  - Hyponatraemic convulsion secondary to desmopressin treatment for primary
      enuresis.
AB  - The case of a 6 year old child who presented with convulsions and coma after
      unsupervised self administration of intranasal desmopressin (DDAVP) for nocturnal
      enuresis is presented. Children with enuresis can be embarassed by their
      condition and may believe that multiple doses of their nasal spray may bring
      about a rapid resolution. Water intoxication is an uncommon but serious adverse
      effect of treatment with intranasal DDAVP. These patients may present with
      seizure, mental state changes, or both. Basic management consists of stopping the
      drug, fluid restriction, and suppressive treatment for seizures. Recovery is
      usually rapid and complete. Administration of the nasal spray in children should
      be supervised by parents to prevent highly motivated children from accidental
      overdose. The risks of high fluid intake need to be carefully explained to both
      parents and children.

PMID- 10353058
TI  - Hyperkalaemic paralysis--a bizarre presentation of renal failure.
AB  - Paralysis due to hyperkalaemia is rare and the diagnosis may be overlooked in the
      first instance. However it is rapidly reversible and so long as electro
      cardiography and serum potassium measurement are urgently done in all patients
      presenting with paralysis, it will not be missed. A case of hyperkalaemic
      paralysis is described and a review of the emergency management discussed.

PMID- 10353059
TI  - An unusual case of urinary retention due to imperforate hymen.
AB  - A 15 year old girl presented to the accident and emergency (A&E) department with
      a 24 hour history of lower abdominal pain, and was found to have acute urinary
      retention. She was discovered to have an imperforate hymen with associated
      haematocolpos and haematometrium. This is rare and is hence a very unusual
      presentation to the A&E department. Patients presenting with retention of urine
      should be carefully assessed for the cause.

PMID- 10353060
TI  - Axillary vein thrombosis mimicking muscular strain.
AB  - Axillary vein thrombosis may occur on strenuous activity with a clinical picture
      similar to a simple strain. It carries significant morbidity but a good outcome
      is possible with early treatment. The aetiology, investigation, and treatment are
      discussed.

PMID- 10353061
TI  - Boerhaave's syndrome presenting as tension pneumothorax.
AB  - Boerhaave's syndrome can present initially as a case of tension pneumothorax.
      Mortality rate with delayed treatment is very high, therefore diagnosis should be
      made rapidly in the emergency department. Multidisciplinary cooperation,
      immediate radiological confirmation, prompt aggressive resuscitation, and
      surgical intervention offer the best chance of survival.

PMID- 10353062
TI  - Securing intercostal drains.

PMID- 10353064
TI  - Changing incidence and mortality of coronary heart disease.

PMID- 10353063
TI  - Ingested coins.

PMID- 10353065
TI  - International trends in coronary heart disease mortality and incidence rates.

PMID- 10353066
TI  - Decreasing mortality from acute myocardial infarction: effect of incidence and
      prognosis.
AB  - Coronary heart disease (CHD) mortality rates have declined for the past 25 years
      in most western countries. During the 1970s and early 1980s, a decline in
      incidence was the main factor in the decline in mortality, but more recently,
      improvements in treatment and prognosis have played a larger role. Most of the
      change is a result of improvements in the treatment of risk factors among
      patients with chronic CHD, while the treatment of acute myocardial infarction has
      contributed a smaller part. CHD mortality has consistently decreased more than
      incidence, which may have led to an increased prevalence of CHD. Simultaneously,
      the treatment practice patterns and possibly also clinical presentation of CHD
      has changed so that hospitalizations as a result of CHD diagnoses other than
      myocardial infarction have increased, while definite myocardial infarctions have
      decreased. Furthermore, the stabilizing rates of incident myocardial infarction
      combined with the aging population tend to increase the numbers of CHD patients.
      Therefore, the total burden of CHD to the community has decreased less than one
      would expect on the basis of age-standardized mortality rates. There is a need to
      re-emphasize primary prevention, since heavy reliance on expensive treatments for
      the post-war baby-boom generation presents a major concern for public health
      resources.

PMID- 10353067
TI  - Differences in the treatment of acute myocardial infarction between regions of
      countries and the impact on prognosis.
AB  - Differences in the incidence, prevalence of and mortality from coronary heart
      disease (CHD) are observed between and within countries. These differences are
      believed to be related to differing levels of CHD risk factors and medical care.
      Medical care for acute myocardial infarction has changed significantly in the
      past decades, with the development of new methods for diagnosis and treatment.
      Although widely known, these technologies are not consistently applied for
      reasons of availability and cost, as well as local medical cultures and
      traditions. The outcomes of medical care for acute myocardial infarction are best
      measured by case fatality of those hospitalized. Since the early 1960s, case
      fatality has fallen to less than half that observed previously. This has occurred
      in the context of widespread use of coronary care unit monitoring, innovative
      pharmacologic agents and invasive reperfusion treatments. A common debate
      compares aggressive invasive management with more conservative pharmacologic
      methods. In this context, studies have produced mixed results with no clear
      advantage to one approach when both methods are available and effectively applied
      to appropriately selected patients.

PMID- 10353068
TI  - Sex differences in survival rates after acute myocardial infarction.

PMID- 10353069
TI  - Lipoprotein (a) and apoprotein B in an apparently healthy population of fighter
      pilots and ground personnel: their significance as potential markers of
      atherosclerosis.
AB  - BACKGROUND: Individuals who carry cardiovascular risk factors (CVRF) have a
      higher incidence of cardiovascular pathology. Among the most commonly screened
      CVRF are apoprotein A and B and lipoprotein (a), which represent 'independent'
      risk factors for atherosclerosis. In the air force community, cardiovascular
      pathology has been reported as the primary reason for grounding pilots. DESIGN:
      The aim of this study was to evaluate the frequency of CVRF in an apparently
      healthy population of military fighter pilots (group B, n = 50), and military
      ground personnel (group A, n = 50) who were matched for age, sex and body mass
      index but not involved in flight activity, and to evaluate whether any particular
      pattern of CVRF might be related to flight. METHODS: Each subject fasted
      overnight, and underwent the following measurements: blood pressure and resting
      ECG recording; and determination of serum levels of total and high-density
      lipoprotein cholesterol, triglycerides, uric acid and plasma levels of glucose.
      In addition, serum levels of apolipoprotein A, B and lipoprotein (a) were
      detected. RESULTS: An overall risk index for coronary artery disease was
      calculated using the Framingham equation. This risk index was slightly but not
      significantly increased in group A compared with group B. By contrast, a
      significant increase in both apoprotein B (P < 0.005) and lipoprotein (a) (P <
      0.0005) was found in group B compared with group A. No significant differences
      between groups were detected for the other parameters evaluated. CONCLUSIONS: We
      suggest the presence in group B of an underlying trend towards the development of
      atherosclerosis, which may not be identified by a routine approach. Moreover, on
      a purely theoretical basis with no experimental evidence, the issue of the
      possible pathophysiological mechanism of these findings and their relationship to
      flight environment is also addressed.

PMID- 10353070
TI  - Hormone replacement therapy and ischaemic heart disease among postmenopausal
      women.
AB  - The beneficial effect of hormone replacement treatment (HRT) on osteoporosis and
      menopausal symptoms has been well documented in randomised trials, but the impact
      of oestrogen-mediated metabolic changes on the risk of ischaemic heart disease
      (IHD) is still debated. Randomised studies have shown that HRT increases levels
      of high-density lipoprotein cholesterol while causing a reduction in the levels
      of low-density lipoprotein cholesterol, serum fibrinogen, plasminogen activator
      inhibitor and homocysteine. In addition, HRT increases insulin sensitivity in
      both normoglycaemic and diabetic women. Unlike oral contraceptives, HRT has not
      been associated with an increase in arterial blood pressure, whereas a small
      increase in the risk of breast cancer and of venous thromboembolism appears to
      occur with both treatments. Interestingly, some data suggest that oestrogen
      preparations may have different effects on lipids. For instance, the beneficial
      effect on cholesterol metabolism observed with oral conjugated oestrogen does not
      occur with transdermal oestradiol, suggesting that the first-pass effect through
      the portal circulation may be necessary to achieve the full metabolic effect of
      oestrogen treatment. Nevertheless, although a wealth of observational studies
      show that HRT is associated with a significant reduction in morbidity and
      mortality from IHD, the only randomised data available to date do not support
      these findings in postmenopausal women with established coronary artery disease.

PMID- 10353072
TI  - Bibliography. Current world literature.

PMID- 10353071
TI  - Comparison of the efficacy of atorvastatin and micronized fenofibrate in the
      treatment of mixed hyperlipidemia.
AB  - OBJECTIVE: To evaluate and compare the influences of micronized fenofibrate and
      atorvastatin on serum lipid profile, including lipoprotein(a) levels, and on
      fibrinogen levels in a large group of patients with primary mixed hyperlipidemia
      (serum total and low-density lipoprotein cholesterol levels > 240 and 160 mg/dl,
      respectively, and serum triglyceride level > 200 mg/dl). METHODS: This was a 16
      week, open-label, parallel-design study conducted in our lipid clinic. After a 6
      week dietary baseline phase, we implemented a treatment phase, during which
      patients received 10 mg/day atorvastatin (n = 45) or 200 mg/day micronized
      fenofibrate (n = 46) for 16 weeks. Patients were assigned to one of the drugs in
      sequential orders. Serum lipid profiles, including levels of lipoprotein(a) and
      fibrinogen, as well as muscle and liver enzymes, were measured during screening,
      and during weeks -4, -2, 0, 8, and 16 of the treatment period. RESULTS:
      Atorvastatin was more effective than was micronized fenofibrate at lowering
      levels of total and low-density lipoprotein cholesterol, whereas fenofibrate was
      more effective at lowering levels of triglycerides, and raising levels of high
      density lipoprotein cholesterol and apolipoprotein A1. However, micronized
      fenofibrate could significantly decrease plasma fibrinogen levels, whereas
      atorvastatin evoked a small increase. CONCLUSION: Both atorvastatin in small
      doses and micronized fenofibrate are effective for improving serum lipid profiles
      of patients with mixed hyperlipidemia. However, there are considerable
      differences between the two drugs concerning their influences on plasma
      fibrinogen levels.

PMID- 10353073
TI  - Identification and impact of risk and protective factors for drug use among urban
      African American adolescents.
AB  - Identified 10 risk and 12 protective factors associated with drug use among
      African American 8th graders (N = 994) in an urban school system. Regression
      analyses identified 7 risk and 7 protective factors with minimal overlap. The
      total number of risk factors was significantly related to the prevalence of use
      for cigarettes, beer or wine, liquor, marijuana, and a composite measure of drug
      use. The Protective Factor Index (PFI) was a significant moderator of the
      relation between risk and use of beer or wine, liquor, marijuana, and the
      composite measure. Longitudinal analyses of data on 650 students across the
      transition from middle to high school indicated that the sum of risk factors
      predicted changes in all drug use categories except the composite. The PFI
      significantly predicted changes in beer or wine, liquor, and composite drug use
      over this 1-year period. It also moderated risk for cigarette use, but not for
      other drugs. Results replicated prior studies and highlighted the importance of
      protective factors such as adaptive functioning in school and family influences.

PMID- 10353074
TI  - Family protective factors among urban African American youth.
AB  - Examined the relations among family protective factors, stressful events, and
      behavioral adjustment of 64 African American 6th graders. The youths reported on
      family stressors, father-figure involvement, and kin support. Their primary
      caregivers reported on parenting, father-figure involvement, and family
      stressors. Teachers reported on child social skill deficits, acting out, and shy
      or anxious behavior. Based on regression analyses, stress exposure associated
      positively with child social skill deficits, acting out, and shy or anxious
      behavior. Parental warmth was associated negatively with shy or anxious behavior.
      Parental use of corporal punishment was associated positively with child acting
      out. For youth exposed to high numbers of family stressors, parental
      demandingness was associated negatively with child acting out and kin support was
      associated negatively with acting out and shy or anxious behavior, suggesting
      that these family factors partially shield children from the negative effects of
      stress.

PMID- 10353075
TI  - Availability of family support as a moderator of exposure to community violence.
AB  - Examined the role of availability of family support in moderating the negative
      effects of exposure to community violence on internalizing symptoms. Participants
      were 75 low-income African American children between the ages of 10 and 15. Two
      measures of availability of family support (mother's presence in the home and
      family size) were evaluated as moderators of the relations between exposure to
      community violence and depression and posttraumatic stress disorder (PTSD)
      symptoms. After controlling for age, sex, and concurrent life stress, mother's
      presence in the home moderated the relation between exposure to community
      violence and depressive symptoms but not the relation between exposure to
      community violence and PTSD symptoms. Children living in mother-absent families
      were at increased risk of depressive symptoms as exposure to community violence
      increased. In addition, family size approached significance as a moderator of
      depressive symptoms but not PTSD symptoms, revealing a trend toward children from
      smaller families being at increased risk of depressive symptoms as exposure to
      community violence increased. These findings suggest that although availability
      of family support is an important moderator for depressive symptoms, this is not
      the case for PTSD symptoms.

PMID- 10353076
TI  - Barriers to treatment participation and therapeutic change among children
      referred for conduct disorder.
AB  - Examined predictors of therapeutic change among children seen in outpatient
      therapy. Children (N = 200) referred for oppositional, aggressive, and antisocial
      behavior and their families participated. The major findings were that (a)
      socioeconomic disadvantage, parent psychopathology and stress, and child
      dysfunction predicted therapeutic change from pretreatment to posttreatment; (b)
      barriers to participation in treatment also were significantly associated with
      therapeutic change and this effect was not explained by the other family, parent,
      and child predictors; (c) as the level of perceived barriers to participation in
      treatment increased among families, the amount of therapeutic change decreased;
      and (d) among children at risk for relatively little therapeutic change, the
      perception of few barriers to treatment increased the degree of child
      improvement. The implications for further work on predictors of therapeutic
      change and the role of barriers in the treatment process are discussed.

PMID- 10353077
TI  - Influence of the teacher-student relationship on childhood conduct problems: a
      prospective study.
AB  - Examined the influence of the quality of the teacher-student relationship on
      children's subsequent levels of aggression in a sample of 61 second and third
      grade children nominated and rated by their teachers as aggressive. The stability
      of teachers' and children's reports of relationships quality across academic
      years was in the low to moderate range. Teachers and children showed little
      agreement in their reports of relationship quality. Teachers' and children's
      reports of relationship quality in year 1 (Y1) predicted teacher-rated aggression
      the following year, controlling for Y1 ratings of aggression. Teachers' reports
      of relationship quality across Y1 and Y2 predicted peer-rated aggression, but not
      teacher-rated aggression, in Y3, controlling for Y1 aggression. Consistent with a
      buffering role for teacher-student relationships, a positive teacher-student
      relationship was of greatest benefit to children whose mothers reported rejecting
      parenting histories. We discuss implications for school-based prevention
      programs.

PMID- 10353079
TI  - Links between mothers' and children's social competence and associations with
      maternal adjustment.
AB  - Extended previous research on family factors related to children's social
      competence by examining links between 3 domains of maternal social competence
      (social skills, social frames, network size) and 3 domains of children's social
      competence (social skills, peer-rated social preference, and network size) in a
      sample of 78 mothers and their kindergarten children (42 girls, 36 boys). The
      mediational role of maternal social competence in the association between
      mothers' depression and interpersonal sensitivity symptoms and children's social
      competence was also tested. Results supported associations between all 3 domains
      of mothers' and children's social competence, with maternal social skills the
      most frequent predictor of children's social competence. Gender differences
      suggested that maternal social competence was more strongly related to sons' peer
      acceptance and daughters' social skills. A mediational model received preliminary
      support for girls, with maternal psychological symptoms related to girls' social
      competence via maternal social skills. Implications include the need for
      continued study of maternal social competence as a family factor related to
      children's peer functioning and the development of family-based interventions for
      young children experiencing peer problems.

PMID- 10353078
TI  - Homesickness in preadolescent and adolescent girls: risk factors, behavioral
      correlates, and sequelae.
AB  - Examined homesickness in 117 girls ages 8 to 16 during a 2-week stay at summer
      camp. (Homesickness is the distress or impairment caused by an actual or
      anticipated separation from home. It is characterized by acute longing and
      preoccupying thoughts of home and attachment objects.) Elevated preseparation
      levels of homesickness, high expectations of homesickness, negative separation
      attitudes, low decision control, and little previous separation experience
      predicted in-camp levels of homesickness. During the separation, homesickness was
      associated with insecure interpersonal attitudes, negative initial impressions of
      the novel environment, high perceived distance from home, and low perceived
      control. Female surrogate caregivers rated homesick girls as having lower social
      status and more somatic complaints, social problems, and externalizing behavior
      than less homesick girls. Although the prevalence, intensity, and longitudinal
      course of homesickness in girls did not differ from analogous samples of boys,
      girls' profile of risk factors, correlates, and sequelae is unique in its mixed
      behavioral presentation and small correlations with age and experience.

PMID- 10353080
TI  - Preliminary examination of sex differences in depressive symptoms among
      adolescent psychiatric inpatients: the role of anxious symptoms and generalized
      negative affect.
AB  - Assessed the emerging view that generalized negative affect and anxious symptoms
      are important in understanding sex differences in depressive symptoms. Sixty
      three adolescent psychiatric inpatients (32 boys, 31 girls), ages 12 to 16 (M =
      13.87, SD = 1.36), completed measures of positive and negative affect and anxious
      and depressive symptoms. Results demonstrated, as predicted, that depressive and
      anxious symptoms were more highly associated in adolescent girls than boys.
      Furthermore, girls with depressive symptoms were more likely to have comorbid
      anxious symptoms than boys with depressive symptoms. Sex differences were not
      found for adolescents with specific depressive symptoms and specific anxious
      symptoms (i.e., the absence of comorbidity). Our findings supported the
      possibility that sex differences in pure forms of depression are overestimated
      and that comorbid internalizing conditions may be more prevalent in adolescent
      girls than boys.

PMID- 10353081
TI  - Anxious children and their parents: what do they expect?
AB  - Assigned 73 children, ages 7 to 14, to 1 of 3 groups (anxious, clinical control,
      and nonclinical control) according to their diagnostic status. Within the anxious
      group, children were assigned to 1 of 2 further groups on the basis of self
      reported parental anxiety--either the child anxiety only group or the child +
      parent anxiety group. All children completed an experimental task (giving a brief
      talk in front of a video camera), which was the focus for a series of structured
      family discussions between the child and his or her parents. The aims of the
      study were to measure and compare across groups (a) the evaluations of children
      and their parents regarding the child's predicted anxiety and skill level and (b)
      the effect of the family discussion on children's expectations. Results indicated
      that, prior to the family discussion, anxious children's expectations of their
      future performance did not differ from those of control children. Similarly,
      there were no differences in children's expectations between the child anxiety
      group and the child + parent anxiety group. Second, compared to mothers in the
      child anxiety group, mothers in the child + parent anxiety group expected that
      their children would be more anxious and more likely to choose an avoidant
      problem solution (but not less skilled). Finally, the family discussion was found
      to produce no changes in anxious children's expectations of their future
      performance. The implications of these findings are discussed.

PMID- 10353082
TI  - Posttraumatic stress symptoms in children following orthopedic or traumatic brain
      injury.
AB  - Examined posttraumatic stress (PTS) symptoms in children following pediatric
      traumatic brain injury (TBI). Children (ages 6-12) with TBI (n = 81) and
      orthopedic injury (OI; n = 59) were assessed 6 and 12 months postinjury. Parents
      of children with severe TBI reported higher levels of child PTS symptoms than did
      parents of children with moderate TBI or OI at the 6- and 12-month follow-ups.
      Group differences in child-reported PTS symptoms emerged at the 12-month follow
      up with higher symptom levels reported by children with severe TBI than by those
      with moderate TBI or OI. At both follow-ups, rates of clinically significant
      symptom levels were higher in the severe TBI group than in the moderate TBI or OI
      groups. The group differences in parent and child reports were significant even
      after taking ethnicity, social disadvantage, and age at injury into account.
      Parent and child reports of child PTS symptoms were related to family
      socioeconomic status. Implications for clinical intervention with children and
      families following pediatric TBI are discussed.

PMID- 10353083
TI  - Attachment-based classifications of children's family drawings: psychometric
      properties and relations with children's adjustment in kindergarten.
AB  - Investigated an attachment-based theoretical framework and classification system,
      introduced by Kaplan and Main (1986), for interpreting children's family
      drawings. This study concentrated on the psychometric properties of the system
      and the relation between drawings classified using this system and teacher
      ratings of classroom social-emotional and behavioral functioning, controlling for
      child age, ethnic status, intelligence, and fine motor skills. This nonclinical
      sample consisted of 200 kindergarten children of diverse racial and socioeconomic
      status (SES). Limited support for reliability of this classification system was
      obtained. Kappas for overall classifications of drawings (e.g., secure) exceeded
      .80 and mean kappa for discrete drawing features (e.g., figures with smiles) was
      .82. Coders' endorsement of the presence of certain discrete drawing features
      predicted their overall classification at 82.5% accuracy. Drawing classification
      was related to teacher ratings of classroom functioning independent of child age,
      sex, race, SES, intelligence, and fine motor skills (with p values for the
      multivariate effects ranging from .043-.001). Results are discussed in terms of
      the psychometric properties of this system for classifying children's
      representations of family and the limitations of family drawing techniques for
      young children.

PMID- 10353084
TI  - Preschoolers' characterizations of multiple family relationships during family
      doll play.
AB  - Investigated 4-year-olds' depictions of family relationships during a
      semistructured doll play task. Examined developmental and family correlates of
      these depictions, and their relative stability over a 1-month period. Forty-nine
      children related stories about happy, sad, mad, and worried families using dolls
      reflecting their own family configuration. For each story, coders recorded (a)
      proportion of total story time devoted to each family dyad and (b) number of
      conflictive, aggressive, and affectionate acts per dyad. Children divided their
      focus during stories evenly between father-child, mother-child, and father-mother
      relationships with child-sibling interactions occurring regularly among
      participants with siblings. Depictions of affection and aggression among family
      figures were relatively commonplace, related to mothers' reports of family
      climate, and stable across a 1-month period. Results substantiated preschoolers'
      awareness and discrimination of intrafamily relationship dynamics and provided
      some guidelines and cautions to practitioners who employ doll family assessments
      in their clinical work.

PMID- 10353085
TI  - Children's fantasy play and emotional understanding.
AB  - Examined the relation between affective and cognitive processes in fantasy play
      and emotional understanding. Sixty-six children in the 1st and 2nd grades played
      with puppets (Affect in Play Scale; Russ, 1993), answered questions about their
      understanding of emotions (Kusche Affective Interview-Revised; Kusche, Greenberg,
      & Beilke, 1988), and completed a measure of verbal intelligence (Wechsler
      Intelligence Scale for Children-III; Wechsler, 1991). The major finding of this
      study was that consistent, yet modest, relations were found between dimensions of
      fantasy play and emotional understanding. Cognitive dimensions of fantasy play,
      but not affect expression, were related to facets of emotional understanding.
      These relations were independent of verbal ability. A composite fantasy play
      score accounted for a significant amount of variance in a composite emotional
      understanding score when verbal ability was accounted for. Variations in the
      pattern of correlations for girls and boys suggest sex differences in the
      relation between fantasy play and emotional understanding. Implications for
      clinical research and interventions are discussed.

PMID- 10353086
TI  - The health care industry: in evolution or revolution?
AB  - The health care industry has experienced dramatic changes during the last 25
      years and will likely undergo even more dramatic changes in the next 25 years.
      Many firms in the health care industry will thrive just as many firms have
      thrived during the last 25 years. The ultimate key to success will be management
      and their attention to the basics of good business management. Management has
      always been the key ingredient and will continue to be the most critical success
      factor.

PMID- 10353087
TI  - Benchmarking physicians' practices: trends toward the millennium.
AB  - The health care industry has enjoyed--and suffered--no shortage of changes in the
      last year. Many are the effects of the ongoing trends internal and external to
      the industry and others are the seemingly spontaneous events the industry is
      beginning to take as "business as usual." The challenges facing health care come
      as much from the internal dynamics of an industry in rapid consolidation and
      transition as from the societal, economic, cultural, and political contexts in
      which it operates.

PMID- 10353088
TI  - Those conversion blues.
AB  - With the ever-increasing market penetration of capitated payment systems
      throughout health care markets, average payment rates for health services have
      dropped correspondingly. At the same time, the added competitive pressures from
      managed care organizations have served to increase the demand for new capital
      investment in information systems, lower cost facilities, and innovative modes
      for delivering all types of health care services. As a result, many nonprofit
      health care organizations have converted, or have attempted to convert, to for
      profit status in an effort to gain access to the public equity capital markets.
      As hospitals, Blue Cross and Blue Shield organizations, and other nonprofit
      health care organizations across the U.S. seek to convert to for-profit status,
      they are finding the path is not easy. Access to capital, operating efficiencies,
      and the need to accelerate movement into new markets are offset by public benefit
      obligations, potential private inurement, and significant political cost issues.
      The bottom line is whether the conversion will be structured to both protect the
      public interest and allow the health care organization the flexibility and access
      to capital it needs in order to continue as a viable, competitive organization
      into the next millennium.

PMID- 10353089
TI  - Ambulatory surgery center joint ventures involving tax-exempt entities.
AB  - This article provides an overview of the tax-exempt related issues for ambulatory
      surgery center joint ventures involving tax-exempt entities. The article analyzes
      the key points of analysis of the guidance released by the IRS, in particular
      General Counsel Memorandum 39862, Revenue Ruling 98-15, and Redlands Surgical
      Services v. Commissioner of the Internal Revenue Service. These key points
      include whether the venture results in private inurement to insiders and whether
      the venture furthers the charitable purposes of the tax-exempt entity. The
      article also provides practical guidance to analyze the documents and structure
      of the joint venture to ensure compliance with the IRS guidance. These practical
      considerations include, among other things, whether the charitable purposes of
      the tax-exempt entity are clearly expressed in the documents and whether the tax
      exempt entity has sufficient control over the joint venture to ensure the
      charitable purposes are being adhered to.

PMID- 10353091
TI  - Do managerial efficiency and social responsibility drive long-term financial
      performance of not-for-profit hospitals before acquisition?
AB  - Due to steep declines in charitable support and reduced demand for traditional
      hospital services, economic goals are increasingly important to not-for-profit
      hospitals. Effects of efficient management and effective pursuit of not-for
      profit status (for example, levels of Medicare, indigent patients, and
      unprofitable services) on financial viability are explored. While previous
      research compared hospitals of different ownership status, not-for-profit
      hospital operations before acquisition by for-profit hospital chains are
      investigated--"neutral ground" relative to ownership. Results suggest minor links
      between efficiency and long-term profitability despite effectiveness in pursuit
      of non taxable status.

PMID- 10353090
TI  - How much profit can a not-for-profit hospital make? A defense of the property tax
      exemption.
AB  - After St. Luke's Regional Medical Center in Boise, Idaho, reported a profit of
      $18 million, Ada County revoked its property tax exemption as a not-for-profit
      and billed St. Luke's for $3.4 million in property taxes. This article describes
      how St. Luke's successfully defended its tax exemption in an appeal to the Idaho
      Board of Tax Appeals and how proposed legislation would reduce uncertainty about
      taxation of not-for-profit hospitals in Idaho.

PMID- 10353092
TI  - Rethinking anti-smoking media campaigns: two generations of research and issues
      for the next.
AB  - This article provides a variety of alternative theoretical issues and new
      research directions for smoking media campaign research. The first two
      generations of smoking media campaign research are reviewed and new ideas about
      public resistance and resolving complex issues are explored. The authors critique
      the limits of current campaign theory and their premise that how the public
      resolves issues such as smoking cessation needs to be seen in a broader context.
      The consciousness raising, working through, and resolution stages each present a
      series of different research challenges and issues for investigators. These are:
      (1) an assessment of the perceived credibility by the target audience toward mass
      media, news media, health care providers, tobacco firms, area health care
      agencies, the health care delivery system, and different classes of providers,
      (2) how smokers and nonsmokers differ on the linkage among biomedical,
      epidemiological, and toxicological controversies, (3) how smoking issues are
      managed within arenas, (4) how arenas potentially undermine popular participation
      in public policy formation, and (5) how in the creation of dialogue there should
      be dual emphases on the viability of the concept and tactics.

PMID- 10353093
TI  - Analysis of induced sputum: a new approach to the study of airway inflammation in
      asthma.
AB  - Induced sputum is a simple method that enables the analysis of lower respiratory
      tract material obtained through non-invasive methods. Validation of the technique
      for the study of airway inflammation in asthma and other respiratory diseases,
      together with the most relevant findings reported in the literature, are reviewed
      herein. Accurate methods that can be applied to the analysis of induced sputum
      samples, such as immunocytochemistry, flow cytometry or polymerase chain reaction
      are also discussed.

PMID- 10353094
TI  - Does eosinophil cationic protein in sputum and blood reflect bronchial
      inflammation and obstruction in allergic asthmatics?
AB  - In the assessment of asthma severity and monitoring of asthma drug therapy,
      eosinophils and eosinophil cationic protein (ECP) have been identified in blood
      but rarely in sputum. The aim of our study was to determine if ECP concentrations
      in blood and sputum reflect bronchial inflammation and obstruction in allergic
      asthmatics and if inhaled steroids influence this relationship. We carried out a
      descriptive, cross-sectional study of 42 allergic asthmatic outpatients from a
      respiratory medicine department, of whom 22 were on beta 2-adrenergic agonists
      only and 20 were treated with low doses of inhaled steroids. Spirometry and
      methacholine challenge were performed and eosinophils and ECP values in induced
      sputum and blood were determined. The age and FEV1 were similar in both groups.
      It was found that in patients receiving inhaled steroids, the methacholine PD20
      was higher than in patients on beta 2-adrenergic agonists only. However, there
      were no significant differences in serum and sputum ECP between the groups
      (median 14.5 micrograms/l vs. 17.2 micrograms/l and 235 micrograms/l vs. 301
      micrograms/l, respectively). In patients not receiving steroids, sputum ECP
      correlated positively with eosinophils in sputum (r = 0.61, p < 0.01) and
      inversely with FEV1 (r = -0.43, p < 0.05). Serum ECP correlated with blood
      eosinophils and methacholine PD20. In patients treated with inhaled steroids most
      correlations were no longer significant. We concluded that ECP in sputum, rather
      than in blood, seems to reflect both eosinophilic inflammation and bronchial
      obstruction in asthmatics not receiving inhaled steroids. Asthmatics on low doses
      of inhaled steroids had increased ECP levels in sputum and serum, indicating
      persistent eosinophilic inflammation of the airways.

PMID- 10353095
TI  - Diurnal variation of airborne pollen at two different heights.
AB  - The diurnal variation in airborne pollen concentrations in the air of Cordoba at
      two different heights (1.5 m and 15 m) was studied during 2 consecutive years
      with the help of two Hirst volumetric samplers. According to pollen percentages
      obtained every hour, we determined whether every taxon studied presented a
      morning or an afternoon pattern, and whether this model was homogeneous (with a
      slight difference between the time of maximum and minimum reading) or
      heterogeneous (with a large difference between the two readings). We observed
      that the taxa that had many species in the area, such as Plantago, Poaceae, and
      Chenopodiaceae-Amaranthaceae showed a homogeneous model, while those taxa with
      few species present, such as Cupressaceae and Urticaceae showed a more
      heterogeneous model. Furthermore, the pattern of the plants with a large presence
      in the study area was more heterogeneous at 1.5 m because the pollen collected at
      this height is released from anthers. In the sampler placed at 15 m we detected
      airborne pollen, found that the curves were smoother and also observed a slight
      time delay for the taxa that were highly present in the area of study.

PMID- 10353096
TI  - Quantitative changes in peripheral blood lymphocytes in erosive rheumatoid
      arthritis patients treated with methotrexate. Correlation with disease activity.
AB  - In order to better understand the immunological mechanisms involved in the
      pathogenesis of rheumatoid arthritis (RA), the level of various lymphocyte
      subsets in the peripheral blood of 29 patients with erosive RA was determined.
      All the patients were treated with methotrexate for 2 years. The total number and
      the proportion of CD3 cells, CD3+CD4+ and CD3+CD8+ cells did not change during
      the study. The initially increased level of CD19+ B-cells and CD19+CD5+ cells
      decreased during the treatment. The percentage of CD3-CD16+ natural killer cells
      was not affected by the treatment. At the inception of the study, we observed a
      deficiency of CD4+ CD45RA+ cells and the level of CD3+CD29+ cells was slightly
      increased. During the treatment we noticed significant elevation of CD45RA cells.
      Consequently, the CD29/CD45RA ratio significantly decreased. We showed
      significant correlation between changes in disease activity and changes in the
      level of CD19+ cells and CD4+CD29+ cells. Our results suggest that low-dose
      methotrexate may affect immunocompetent cells. The lowering in the CD29+ subset
      population associated with depletion of CD19 B-cells after methotrexate therapy
      may limit abnormal CD4+ cell activation and reduce the migration of lymphocytes
      into inflamed synovium.

PMID- 10353097
TI  - Patient satisfaction and allergen immunotherapy.
AB  - Although health-related quality of life and patient satisfaction are shifting
      doctors' attention to the patient, the scant number of publications on quality of
      life questionnaires and allergen immunotherapy contrasts with the quickly growing
      number of those dealing with this topic and pharmacotherapy. We delivered an
      original, self-administered patient satisfaction questionnaire to 95 patients
      (age = 17.7 +/- 7.9 years) suffering from allergic rhinoconjunctivitis (45%)
      and/or asthma (55%), who had been receiving allergen immunotherapy for more than
      1 year (22.2 +/- 10.5 months). The anonymous, voluntary questionnaire was filled
      in at home; although only 32% were returned, we found no significant differences
      relating to age, sex, asthma, allergen sensitization or allergen immunotherapy
      regimen between the source sample and those who replied. Patient expectations,
      which were scored on a scale of 1 to 10 points, were rather poor, in sharp
      contrast with patient perception score after treatment (5.4 +/- 1.8 vs. 8.0 +/-
      2.0, p < 0.0001). Perception scores did not differ between patients receiving
      seasonal or perennial allergen immunotherapy, nor did they depend on the duration
      of treatment. In addition, patient age, sex, diagnosis or sensitization did not
      appear to influence perceptions. In conclusion, our data suggest that when a
      voluntary, anonymous questionnaire is used, patients express a poor opinion of
      allergen immunotherapy, in contrast with high satisfaction after treatment,
      provided that allergen immunotherapy lasts long enough.

PMID- 10353098
TI  - Serum levels of immunoglobulins in children with recurrent otitis media.
AB  - Seventy-seven children with recurrent otitis media took part in the study at the
      Department of Otorhinolaryngology and Pediatrics of the University of Sao Paulo
      from February 1992 to March 1995. They were administered serum immunoglobulins
      and the relationship between recurrent otitis media and immunodeficiency was
      evaluated. No total IgG and IgM values were detected below the normal level;
      however, seven children with low levels of subclasses of IgG were detected and a
      below normal IgA value was detected in a child.

PMID- 10353099
TI  - Long-term immunotherapy with an optimal maintenance dose of a standardized
      Dermatophagoides pteronyssinus extract in asthmatic patients.
AB  - In a previous dose-titration study of specific immunotherapy (SIT) with a
      Dermatophagoides pteronyssinus extract in asthmatic patients, we proposed a dose
      of 3.2 micrograms of Der p and 1/1.6 micrograms of Der p 2 as an optimal
      maintenance dose. Changes presented by a high-dose immunotherapy group, with a
      maximum tolerated dose between 4 and 16 micrograms Der p 1, were compared with
      those of a conventional immunotherapy group, with a maximum tolerated dose of 3.2
      micrograms Der p 1 or lower. After 2 years of SIT, both groups achieved the same
      level of clinical benefit. We now present the results of long-term monitoring of
      25 of these patients, covering the 5 years of SIT in which the maintenance dose
      was set at 3.2 micrograms Der p 1. The aims of the study were firstly to examine
      if this maintenance dose could sustain the changes induced by immunotherapy in
      the first 2 years; and secondly, to determine if this dose is clinically
      effective in patients known to tolerate higher maintenance doses. The clinical
      severity index (CSI), medication and symptom scores, cutaneous sensitivity and
      specific IgE and IgG4 to D. pteronyssinus, Der p 1 and Der p 2 were measured.
      Positive clinical and immunological changes presented in the first 2 years of SIT
      were sustained (CSI, medication score, specific IgE) or even increased (symptom
      score, cutaneous sensitivity) after 3 additional years of SIT. In conclusion, a
      maintenance dose of 3.2 micrograms of Der p 1/1.6 micrograms of Der p 2 induced
      intense clinical and immunological changes which were sustained during a 5-year
      course of treatment, even in patients able to tolerate higher doses.

PMID- 10353100
TI  - Patterns of immunoglobulin E sensitization to chironomids in exposed and
      unexposed subjects.
AB  - We present our study of four patients with occupational type I allergy to red
      midge larvae (group 1) who we compared with seven individuals also sensitized to
      red midge larvae but who had not apparently been exposed to them (group 2). All
      patients showed elevated specific IgE against Chironomus thummi, and positive
      skin prick tests (SPT) and provocation tests with red midge larvae. We carried
      out SPT with Dermatophagoides pteronyssinus, Acarus siro, shrimp, cockroach and
      common mosquito (Culex pipiens) and specific serum IgE was also determined. The
      red midge larvae wheal size was significantly larger in group 1 (x = 149.2 mm2)
      than in group 2 (x = 18 mm2). Significant differences between levels of IgE anti
      C. thummi were also found in group 1 (x = 52.12 kU/l) and in group 2 (x = 1.5
      kU/l). The patients in group 2 had high levels of specific IgE against other
      allergens (D. pteronyssinus, shrimp and/or common mosquito) and had positive SPTs
      with these allergens, while the patients in group 1 were only sensitized to
      chironomids. The IgE-immunoblotting profile was quite different in both groups.
      The patients in group 1 seemed to have IgE against Chi t 1, the main Chironomus
      allergen, while the patients in group 2 had IgE against several protein bands in
      Chironomus, mosquito, shrimp and D. pteronyssinus extracts, some of them with
      equivalent molecular weights. We believe that the patients in group 2 were
      sensitized to Chironomus as a result of cross-reactivity with other insect or
      crustacean species.

PMID- 10353101
TI  - Urticaria from Trichomonas vaginalis infection.
AB  - We report the case of a 32-year-old woman who had pruritic urticarial skin
      lesions associated with episodes of arthralgia. The first site affected by the
      eruption was the inside surface of the thighs; the patient also reported the
      presence of leukorrhea. The woman had previously been treated with H1 antagonist
      with moderate and transitory results; skin lesions reappeared just after the
      interruption of the treatment. Her biochemical data showed increased levels of
      erythrocyte sedimentation rate, blood eosinophilia and hypocomplementemia.
      Antinuclear antibodies, rheumatoid factor, cryoglobulins and serological
      diagnosis for hepatitis or mononucleosis viruses resulted negative. Considering
      the initial site of the cutaneous features and the presence of leukorrhea, we
      requested a vaginal smear and a culture of the cervical secretion, which revealed
      the presence of a Trichomonas infection. Furthermore, the SDS-PAGE revealed the
      presence of a molecular mass of 230,000 Da (230-kDa) in the serum, which
      indicated a Trichomonas surface protein. The following treatment with oral
      metronidazole caused the eradication of the Trichomonas infection after 3 weeks
      and subsequently the resolution of the urticarial clinical features. We wish to
      underline that in the presence of a case of urticaria vasculitis syndrome which
      seems to be without cause, it is important to investigate every diagnostic
      suspicion scrupulously.

PMID- 10353102
TI  - Anaphylactic reactions to suxamethonium (succinylcholine).
AB  - We present the case of a woman who had two severe anaphylactic episodes with
      hypotension and bradycardia in relation to the administration of general
      anesthesia. In the allergy evaluation, IgE antibodies to suxamethonium, a muscle
      relaxant which was used in both procedures, were detected by skin prick tests. No
      cross-reaction was found to other muscle relaxants derived from quaternary
      ammonium. The patient was able to be operated on, and did not present any adverse
      reactions to the use of local anesthesia or to general anesthesia using
      pancuronium as a muscle relaxant.

PMID- 10353103
TI  - When is a certification not a certification?

PMID- 10353104
TI  - Women's health issues and nuclear medicine, Part I: Women and heart disease.
AB  - This is the first article of a four-part series on women's health issues and
      nuclear medicine. This article will review women and heart disease. After reading
      this article the technologist will be able to: (a) compare and contrast the
      differences in diagnosing coronary artery disease between men and women; (b)
      explain the importance of radionuclide myocardial perfusion imaging in diagnosing
      and stratifying risk of coronary artery disease in women; and (c) list and
      explain the technical challenges of imaging women's hearts.

PMID- 10353105
TI  - Nuclear cardiology, Part IV: Viability.
AB  - After reading Part IV of this series of nuclear cardiology articles, the reader
      should be able to describe: (a) the differences between SPECT and PET techniques;
      (b) the various radiopharmaceuticals and imaging protocols used for detecting
      viability with SPECT; (c) the different radiopharmaceuticals and imaging
      protocols used for detecting viability with PET; and (d) the imaging patterns
      observed after reconstructing myocardial images.

PMID- 10353106
TI  - Technical aspects of sentinel node lymphoscintigraphy for breast cancer.
AB  - OBJECTIVE: A significant morbidity risk is associated with axillary nodal
      dissections for breast cancer. Many treatment decisions are based on axillary
      nodal status. Lymphatic mapping and sentinel node biopsy have been investigated
      to determine if the histology of the sentinel node reflects the remaining lymph
      node basin. We describe the technical aspects of sentinel node lymphoscintigraphy
      for breast cancer. METHODS: Ninety-three patients had lymphoscintigraphy for
      breast cancer. Patients with palpable lesions had 4 concentric injections around
      the site and lesions requiring localization had injections made through tubing
      connected to the localizing wire introducer needle. Immediate static images were
      acquired and the sentinel node was marked for surgery. Marks were reverified
      using a handheld gamma probe. RESULTS: Lymph nodes were visualized by
      lymphoscintigraphy in 87% of cases. Time to visualization of lymph nodes ranged
      from 1-120 min with a mean of 28 min. An average of 1.5 nodes were visualized.
      The overall success rate for identifying the sentinel node at time of surgery was
      85%. CONCLUSION: We conclude that lymphoscintigraphy for breast cancer is a
      detailed procedure that requires coordination with radiology and surgery teams to
      ensure proper identification of sentinel lymph nodes.

PMID- 10353107
TI  - External radioactive reference markers in SPECT imaging of the dopamine system.
AB  - OBJECTIVE: External radioactive reference markers have been used to localize the
      canthomeatal (CM) line and correct for head rotation in perfusion brain SPECT.
      This ensures that regardless of the subject's head position or rotation under the
      SPECT camera, reconstructed transaxial slices are reoriented parallel to the CM
      line. This study was undertaken to demonstrate the value of external radioactive
      reference markers in dopamine SPECT imaging. METHODS: We compared visual and
      marker methods of reorienting the transaxial slices between dopamine and
      perfusion brain SPECT studies, respectively. These consisted of imaging normal
      controls and patients with Alzheimer's or Parkinson's disease using a triple-head
      camera. Intra- and interoperator variability of the visual and marker methods of
      reorientation was determined for both perfusion and dopamine studies. RESULTS: In
      both intra- and interoperator studies, the variability of image reorientation was
      significantly reduced (P = 0.0066 and 0.014, respectively) by using the marker
      method on dopamine images. The variability of reorientation using the marker
      method for a single operator with dopamine images was 3.0% coefficient of
      variation (CV), and for the interoperator study (5 different operators) this was
      7.0% CV. CONCLUSION: This study demonstrated that SPECT imaging of the dopamine
      system with external radioactive reference markers significantly reduced the
      variability of determining the angle of reorientation. This resulted in a
      standardized and consistent method of reorienting transaxial slices, allowing
      comparison within and between subjects of pre- and postsynaptic dopamine SPECT
      studies.

PMID- 10353108
TI  - Quantitation of iodine-123-beta-CIT dopamine receptor uptake in a phantom model.
AB  - OBJECTIVE: The purpose of this study was to determine the effects of technical
      factors such as collimation and filtration on the measurement of 123I-beta-CIT
      uptake in the striatum. METHODS: All SPECT studies were performed using a brain
      phantom containing striata within a bone- and tissue-equivalent skull. The
      effects of collimator resolution and septal penetration were assessed from 99mTc
      and 123I studies containing variable activities in the striata and background
      regions. Optimum attenuation coefficients (mu) were determined from studies
      containing uniform activity in the brain. RESULTS: For 99mTc, mu was 0.095 cm-1
      and 0.07 cm-1 for parallel-hole and fanbeam collimators, respectively. For 123I,
      these values dropped to 0.09 cm-1 and 0.00 cm-1 (zero) for medium-energy and
      fanbeam collimators, respectively. Striatal uptake was significantly
      underestimated, particularly for medium-energy and general-purpose collimators.
      With 99mTc, fanbeam collimation gave a 50% increase in the measured striatal
      uptake, compared to medium-energy collimation. However, with 123I, this gain was
      eliminated by septal penetration and scatter. Increasing transaxial slice
      thickness, ROI size and decreasing filter cutoff frequency all degraded apparent
      striatal uptake. CONCLUSION: Partial volume effects, combined with the averaging
      effects of increasing slice thickness and ROI size, are the most significant
      factors affecting measurement of striatal uptake of 123I-beta-CIT. The increased
      resolution of low-energy high-resolution collimators, compared to a medium-energy
      collimator, is offset by the increased septal penetration and scatter.

PMID- 10353109
TI  - An assessment of the sensitivity of the Cedars-Sinai quantitative gated SPECT
      software to changes in the reconstruction of the short-axis slices.
AB  - OBJECTIVE: This study assessed whether variations in count density,
      reconstruction filtering parameters and the short-axis orientation selected for
      reconstructions of myocardial short-axis slices significantly influenced the left
      ventricular ejection fraction (LVEF) calculated from a gated myocardial perfusion
      SPECT study. METHODS: The Cedars-Sinai quantitative gated SPECT software package
      was used to estimate the LVEF from gated 99mTc-sestamibi and 201TI gated SPECT
      studies in 20 patients. Oblique slices were reconstructed 12 times for each
      study, independently varying the filter cutoff and the orientation of the short
      axis each time. RESULTS: There were no clinically significant changes in the LVEF
      over the range of cutoff frequencies or orientation for either the 201TI or 99mTc
      sestamibi studies. There was excellent agreement between the LVEF calculated from
      the 201TI and 99mTc-sestamibi studies on the same patients using the default
      filter (mean difference = 0.25% points). CONCLUSIONS: The Cedars-Sinai
      quantitative gated SPECT software package for parallel-hole collimators can be
      used with confidence to obtain an LVEF, and is not sensitive to variations in
      count density, filtering parameters or short-axis orientation.

PMID- 10353110
TI  - Improved renal cortical SPECT of neonates and young infants using narrow imaging
      pallets.
AB  - OBJECTIVE: The widths of most commercially-made imaging pallets limit the
      resolution of 99mTc DMSA SPECT imaging in neonates and young infants. We
      constructed a pediatric imaging pallet for 99mTc DMSA SPECT of neonates and young
      infants designed to allow close apposition of the camera to these patients during
      the entire orbit. METHODS: We designed the imaging pallet to replace the standard
      removable pallet on the imaging stand of a commercial gamma camera. The device
      consisted of two parts: a steel bracket attached to the imaging stand and a
      polyvinyl chloride imaging pallet. The imaging pallet consisted of
      interchangeable 15.24-cm (6-in) or 20.32-cm (8-in) diameter, 6.35-mm (1/4-in)
      thick polyvinyl chloride plumbing pipes cut in half lengthwise. RESULTS: The
      pallets were mechanically stable with loads 3 times that expected in clinical
      practice. Attenuation was acceptable and comparable to commercial pallets. The
      hemicylindrical shape provided side support and reduced patient motion, as well
      as allowing closer apposition of the camera head to the patient. The quality of
      these 99mTc DMSA SPECT images compared favorably with those obtainable in older
      children and adults. Specifically, the renal cortices were well delineated from
      the collecting systems and anatomic detail of normal cortex could be readily
      distinguished from abnormal cortex. CONCLUSION: Custom pediatric imaging pallets
      optimized for use in neonates and small children can be constructed
      inexpensively. These pallets are easy to use and are stable. Use of these pallets
      can optimize 99mTc DMSA SPECT images of neonates and young infants.

PMID- 10353111
TI  - The effects of selected antineoplastic agents on the labeling of erythrocytes
      with technetium-99m using the UltraTag RBC kit.
AB  - OBJECTIVE: Adverse affects of various drugs on the labeling efficiency of RBCs
      with 99mTc-pertechnetate have been known for several years. This study presents
      data on the ability of the UltraTag RBC kit to label RBCs with pertechnetate in
      the presence of various antineoplastic drugs. METHODS: Five different
      antineoplastic drugs, either alone or in combination, were incubated for 30 min
      at 37 degrees C with 2-mL samples of whole blood obtained from normal volunteers.
      Each sample was labeled with pertechnetate and the radiochemical purity
      determined according to the UltraTag RBC product package insert. Doxorubicin was
      specifically tested in molar ratios with stannous ion of greater than 1:1 to
      determine if there was any significant chelation effect that would affect the
      ability of the kit to label RBCs. In addition, patients were given a bolus
      injection of doxorubicin and a blood sample was drawn at 30 min to test whether
      the metabolites had any effect on labeling. RESULTS: The ability of the UltraTag
      RBC kit to label RBCs with pertechnetate was not adversely affected by the
      antineoplastic drugs when they were present alone or in combination. Likewise,
      doxorubicin metabolites did not interfere with the labeling efficiency of 99mTc
      RBCs using the UltraTag RBC kit. Molar ratios of doxorubicin-to-tin that exceeded
      1:1 also had no adverse effects on the labeling efficiency of the UltraTag RBC
      kit. CONCLUSION: When performing nuclear medicine exams involving the labeling of
      RBCs with pertechnetate on patients who have received doxorubicin, as well as
      certain other antineoplastic agents, a high RBC labeling efficiency can be
      obtained if the UltraTag RBC kit is used.

PMID- 10353112
TI  - [The relationship between the persistence of the BCR/ABL gene and relapse in
      adult patients with acute lymphoblastic leukemia].
AB  - BACKGROUND: The Philadelphia chromosome (Ph') is originated by the t(9;22) which
      determines the rearrangement BCR/ABL. This rearrangement has been associated with
      an unfavourable prognosis in patients diagnosed with adult acute lymphoblastic
      leukaemia (ALL). PATIENTS AND METHODS: The BCR/ABL gene (p210 and p190) was
      prospectively studied by nested RT-PCR in 17 adult patients diagnosed with ALL
      BCR/ABL-positive cases were monitored by RT-PCR and cytogenetic techniques over
      the treatment period (LAL-93 AR protocol). RESULTS: BCR/ABL mRNA was detected in
      8 out the 17 patients studied (47%). The Ph' chromosome was detected in 4 cases.
      Follow-up was completed in 6 out of the 8 BCR/ABL positive cases. PCR only became
      negative in one patient. The 5 patients with persistently positive BCR/ABL
      relapsed, whereas the case which became negative was still in complete remission
      after 24 months follow-up. In 3 out of the 4 Ph' positive patients, the karyotype
      was normal after induction therapy. CONCLUSIONS: This study clearly demonstrates
      the usefulness of molecular analysis in the diagnosis and follow-up of ALL
      compared with conventional cytogenetic techniques. The importance of molecular
      analysis to assess the efficacy of the treatment used has been emphasized and the
      poor evolution of BCR/ABL-positive patients has been confirmed.

PMID- 10353113
TI  - [Insulin secretion in women and insulin sensitivity in men constitute independent
      determinants of serum leptin concentration].
AB  - BACKGROUND: Although its effects in man are still unknown, leptin may play a role
      in the regulation of insulin sensitivity and insulin secretion. The aim of this
      study was to determine if these parameters are independent predictors of serum
      leptin levels. SUBJECTS AND METHODS: Twenty men and 22 women were evaluated
      through several anthropometric parameters, including percent fat mass (PFM),
      which was calculated using bioelectric impedance. A standard oral glucose
      tolerance test (OGTT) was performed in all subjects. Insulin sensitivity (SI) and
      insulin-secretion (AIRg) were determined through minimal model analysis. RESULTS:
      Area under the curve for glucose (AUCglu) and insulin (AUCins) levels after OGTT
      correlated with serum leptin level in men (r = 0.58, p = 0.005 and r = 0.72, p <
      0.0001, respectively). Only AUCins was associated with serum leptin levels in
      women (r = 0.50, p = 0.01), but this correlation disappeared after controlling
      for PFM. A linear correlation between serum leptin level and SI was observed (r =
      -0.67, p = 0.001, in men; r = -0.82, p < 0.0001, in women). In a multiple
      regression analysis, PFM (p = 0.0005), waist-to-hip ratio (p = 0.007) and SI (p =
      0.007) independently predicted serum leptin level in men (R2 = 0.82). In women
      with normal OGTT, only PFM (p = 0.0005) and insulin-secretion (p = 0.02)
      predicted serum leptin level (R2 = 0.85). CONCLUSIONS: Insulin-sensitivity in
      men, and insulin-secretion (calculated after intravenous glucose) in women
      independently predict serum leptin level. Furthermore, insulin response after
      oral glucose is independently associated with serum leptin level only in men.
      Leptin is a marker of insulin resistance in man, and, in this sense, might confer
      cardiovascular risk.

PMID- 10353114
TI  - [Hypertension-related mortality and arterial pressure in Spain].
AB  - BACKGROUND: Given the high figures of cardiovascular disease and hypertension in
      Spain, and the continuity of cardiovascular and total mortality risks at any
      level of blood pressure, mortality related to hypertension and blood pressure is
      estimated. SUBJECTS AND METHODS: Blood pressure distribution from a
      representative sample of the 35 to 64 years old Spanish population and the
      relative risks for death coming from valid and reasonably generalizable
      international studies (MRFIT, Framingham and Chicago Project) were used. The
      proportions and absolute numbers of cardiovascular and total deaths related to
      blood pressure and hypertension (categories of the US Joint National Committee VI
      [JNC VI]) have been calculated in middle-aged men and women. RESULTS: As many as
      42% of the coronary deaths, 46.4% of the stroke deaths and 25.5% of the total
      deaths are related to hypertension (> or = 140/90 mmHg), most of them in stages 1
      and 2. It follows high-normal plus normal blood pressure group (8.3, 10.2 and
      6.2% of these deaths, respectively). All together, 17,266 total deaths and 4,502
      cardiovascular deaths related to blood pressure took place annually, three
      quarters of them in males. Over the last ones, 65.5% are coronary and 34.5%
      cerebrovascular, prevailing the first ones in both sexes. Eight out of 10 deaths,
      cardiovascular or total, related to blood pressure are concentrated in the
      hypertension categories, and two out of 10 in the high-normal or normal blood
      pressure groups. CONCLUSIONS: One out of 3 total deaths and one out of 2
      cardiovascular deaths are related to blood pressure. One out of 4 total deaths
      and one out of 2.5 cardiovascular deaths are related to hypertension. A
      substantial part of these deaths come from stages 1 and 2 hypertension and from
      high-normal and normal blood pressure group.

PMID- 10353115
TI  - [Acute lymphoblastic leukemia: its clinical cure and molecular cure].

PMID- 10353116
TI  - [Health in Spain: the difficulty of everything for everyone and for free].

PMID- 10353117
TI  - [Changes in the long arm of chromosome 3 (3q) in malignant myeloid hemopathies. A
      study of 10 cases].
AB  - BACKGROUND: Abnormalities of the long arm of chromosome 3 (3q) involving bands
      3q21 and/or 3q26 occur in 2-6% of myeloid malignancies. Trilineage
      myelodysplasia, especially in the megakaryocytic line, is a characteristic
      feature. Additional abnormalities of chromosomes 5 and 7 are usually present. The
      response to treatment and prognosis are poor. PATIENTS AND METHODS: The main
      clinical, cytologic (bone marrow aspirate and biopsy) and cytogenetic
      characteristics as well as the response to the treatment in 10 patients with 3q
      abnormalities diagnosed in a single hospital in a period of 8 years are referred.
      RESULTS: Eight patients had acute non-lymphoblastic leukemia, being de novo in
      five of them. The median value of hemoglobin was 87 g/l (range: 51-148), white
      blood cells count 5.8 x 10(9)/l (1.2-47.1) and platelet count 34 x 10(9)/l (5
      182). The morphological findings in the study of the bone marrow were:
      dyserythropoietic features (7 patients), dysgranulopoietic abnormalities (5
      patients) and small-sized megakaryocytes with hypolobulated nuclei (8 patients).
      Fibrosis was observed in the 4 cases in which a bone marrow biopsy was performed.
      In addition to the 3q alteration, abnormalities of chromosomes 7 (4 patients), 5q
      (2 patients) and +8 (2 patients) were present. Four patients received intensive
      chemotherapy and in two of them a complete remission was achieved, but relapse
      occurred at 3 and 5 months, respectively. All patients have died, the median
      survival being 7 months. CONCLUSIONS: 3q abnormalities define a subtype of
      myeloid malignancies with characteristic clinical and morphological features. The
      response to therapy and survival are poor.

PMID- 10353118
TI  - [The principle of precaution and the drug treatment of obese subjects].

PMID- 10353119
TI  - [Physical activity and arteriosclerosis. The effects of physical activity on
      lipid oxidation, hemostasis and endothelial function].

PMID- 10353120
TI  - [The adverse effects of drugs: the hidden part of the iceberg].

PMID- 10353121
TI  - [Carnitine palmitoyltransferase deficiency as the cause of effort
      rhabdomyolysis].

PMID- 10353122
TI  - [The clinical utility of biochemical markers of bone remodeling].

PMID- 10353123
TI  - [Comments on the Image of the Week].

PMID- 10353124
TI  - [The quality of life and clinical benefit in oncology].

PMID- 10353126
TI  - The cephalic vein cutdown versus subclavian puncture for pacemaker/ICD lead
      implantation.

PMID- 10353127
TI  - Replacing abdominally implanted defibrillators: effect of procedure setting on
      cost.
AB  - Although most ICDs are currently placed using a pectoral approach, there exists a
      large population of patients with abdominally implanted ICDs who will require
      device replacement due to a depleted battery. The purpose of this study was to
      compare the cost, convalescence, and complication rate of replacing abdominally
      implanted ICDs in the OR versus the EP laboratory. Between August 1993 and
      September 1994, we prospectively enlisted nine consecutive patients who presented
      for their second ICD generator replacement and who had a prior generator
      replacement in the OR 3-4 years earlier. The mean age of the patients was 63 +/-
      17 years and their mean ejection fraction was 37% +/- 15%. ICD replacement was
      performed in the EP laboratory and consisted of explanting the old device,
      electronic interrogation of the lead system, and confirmation of defibrillation
      thresholds prior to implanting a new device. Local anesthesia was provided by
      lidocaine infiltration and sedation was achieved with intravenous (i.v.)
      midazolam and fentanyl. Following the procedure, the patients were returned to an
      outpatient monitored setting for 4 hours and were then discharged. Comparisons of
      the health care charges for the same procedure performed in the two different
      settings revealed a significant reduction in physician fees (from $3,621 +/- $556
      to $2,179 +/- $577, P < 0.05), in hospital charges (from $5,811 +/- $1,102 to
      $2,306 +/- 696, P < 0.05), and in total charges (from $9,431 +/- $1,375 to $4,541
      +/- $1,010, P < 0.05), exclusive of ICD cost, when the procedure was performed on
      an outpatient basis in the EP laboratory. Inpatient days averaged 3.0 +/- 0.3
      when the procedure was performed in the OR. On long-term follow-up there were no
      complications following abdominal ICD generator replacement in the OR (mean
      follow-up, 39 +/- 2 months) or in the EP laboratory (mean follow-up, 42 +/- 4
      months). Thus, ICD replacements in the EP laboratory cost less than in the OR due
      to significantly lower physician fees, hospital charges, and a shorter
      postprocedural convalescence.

PMID- 10353128
TI  - Paired ventricular pacing: an alternative therapy for postoperative junctional
      ectopic tachycardia in congenital heart disease.
AB  - Junctional ectopic tachycardia (JET) is one of the most life-threatening
      postoperative arrhythmias in children with congenital heart disease, and medical
      management is difficult. Paired ventricular pacing (PVP) may provide a safe
      alternative mode of management. We evaluated the safety and efficacy of PVP for
      the management of postoperative JET in patients with congenital heart disease. A
      retrospective collection of data was done from 1981-1995. PVP was successfully
      tried in five postoperative patients (age range: 37 days to 22 years, median: 10
      months). Onset of JET was 3-60 hours (mean +/- SD, 19 +/- 23 hours)
      postoperatively. The maximal JET rate was 261 +/- 39 beats/min. PVP was used as
      the first line of management in three patients and was successful in all
      patients. It resulted in an instantaneous increase in blood pressure from 66 +/-
      9 to 94 +/- 15 mmHg (42% increase) and was required for 12 +/- 14 hours (range 2
      36 hours). No complications were noted. Therefore, in our experience, this is a
      safe alternative modality for the control of postoperative JET.

PMID- 10353129
TI  - Complications related to permanent pacemaker therapy.
AB  - This study evaluates complications related to permanent endocardial pacing in the
      era of modern pacemaker therapy. There is only limited information available
      about the complications related to modern cardiac pacing. Most of the existing
      data are based on the 1970s and are no longer valid for current practice. The
      recent reports on pacemaker complications are focused on some specific
      complication or are restricted to early complications. Thus, there are no reports
      available providing a comprehensive view of complications related to modern
      cardiac pacing. Four hundred forty-six patients, who received permanent
      endocardial pacemakers between January 1990 and December 1995 at Kuopio
      University Hospital, were reviewed retrospectively using patient records.
      Attention was paid to the occurrence of any complication during the implantation
      or follow-up. An early complication was detected in 6.7%, and 4.9% of patients
      were treated invasively due to the early complication. Late complication
      developed in 7.2% and reoperation was required in 6.3% of the patients.
      Complications related to the implantation procedure occurred in 3.1%. Inadequate
      capture or sensing was observed in 7.4% of the patients. Pacemaker infection was
      detected in 1.8% and erosion in 0.9% of the patients. An AV block developed in
      3.6% (1.6%/year) patients who received an AAI(R)-pacemaker due to sick sinus
      syndrome. There was no mortality attributable to pacemaker therapy. A great
      majority (68%) of the complications occurred within the first 3 months after the
      implantation. Complications associated to modern permanent endocardial pacemaker
      therapy are not infrequent. Eleven percent of patients needed an invasive
      procedure due to an early or late complication.

PMID- 10353130
TI  - Epicardial, biatrial synchronous pacing for prevention of atrial fibrillation
      after cardiac surgery.
AB  - About 30% of patients develop AF after open heart surgery. Biatrial synchronous
      pacing (BSP) has been shown to promote sinus rhythm in patients with paroxysmal
      AF refractory to drug therapy. We conducted a prospective, randomized study to
      test the effect of BSP via epicardial electrodes on the incidence of AF after
      heart surgery, as compared to conventional therapy. To apply BSP, we attached two
      epicardial electrodes to the right and one to the left atrium. Immediately
      following surgery, BSP was initiated in the AAI-Mode at a rate of 10 beats/min
      above the underlying rhythm (maximum 110 beats/min) and continued for 3 days,
      during which the rhythm was continually monitored. After 21 (age 63 +/- 9 years)
      of the planned 200 patients, the study was prematurely aborted because of the
      proarrhythmic effect of BSP: 6 of the 12 patients treated with BSP developed
      sensing failure (P amplitude < 1 mV), which provoked AF in 5 of these 6 patients.
      BSP was discontinued due to diaphragmal stimulation in two patients and due to
      ventricular stimulation by a dislocated left atrial electrode in one patient. Two
      patients in the control group (n = 9) developed AF. Using the available standard
      technology, BSP via epicardial electrodes is not suitable to suppress AF after
      heart surgery, primarily due to postoperative deterioration of atrial sensing and
      its profibrillatory effect. In patients requiring atrial pacing after heart
      surgery, sensing thresholds must be closely monitored to prevent induction of AF.

PMID- 10353131
TI  - Atrial ectopy originating from the posteroinferior atrium during radiofrequency
      catheter ablation of atrioventricular nodal reentrant tachycardia.
AB  - Atrial ectopy sometimes appears during RF ablation of the slow pathway in
      patients with atrioventricular nodal reentrant tachycardia (AVNRT). However, its
      origin, characteristics, and significance are still unclear. To examine these
      issues, we analyzed 67 consecutive patients with AVNRT (60 with slow-fast AVNRT
      and 7 with fast-slow AVNRT), which was successfully eliminated by RF ablation to
      the sites with a slow potential in 63 patients and with the earliest activations
      of retrograde slow pathway conduction in 4 patients. During successful RF
      ablation, junctional ectopy with the activation sequence showing H-A-V at the His
      bundle region appeared in 52 patients (group A) and atrial ectopy with negative P
      waves in the inferior leads preceding the QRS and the activation sequence showing
      A-H-V at the His-bundle region appeared in 15 patients (group B). Atrial ectopy
      was associated with (10 patients) or without junctional ectopy (5 patients).
      Before RF ablation, retrograde slow pathway conduction induced during ventricular
      burst and/or extrastimulus pacing was more frequently demonstrated in group B
      than in group A (9/15 [60%] vs 1/52 [2%], P < 0.001). Successful ablation site in
      group A was distributed between the His-bundle region and coronary sinus ostium,
      while that in group B was confined mostly to the site anterior to the coronary
      sinus ostium. In group B, atrial ectopy also appeared in 21% of the unsuccessful
      RF ablations. In conclusion, atrial ectopy is relatively common during slow
      pathway ablation and observed in 8% of RF applications overall and 22% of RF
      applications that successfully eliminated inducible AVNRT. Atrial ectopy appears
      to be closely related to successful slow pathway ablation among patients with
      manifest retrograde slow pathway function.

PMID- 10353132
TI  - Effects of extracorporeal shock wave lithotripsy on tiered therapy implantable
      cardioverter defibrillators.
AB  - The effects of extracorporeal shock wave lithotripsy (ESWL) were tested on four
      advanced generation implantable cardioverter-defibrillators (ICDs) in vitro and
      in vivo in two patients. During in vitro testing, advancement of nonsustained
      episode counters occurred in one device, and a set screw and power source cell
      loosened in another, which was connected to an external power source. No
      arrhythmias occurred during in vivo procedures, but programmed parameters were
      reset and elective replacement indicated after one procedure. ESWL can be
      performed safely in selected patients with ICDs, but testing should be performed
      afterwards to confirm satisfactory function and component continuity.

PMID- 10353133
TI  - Analysis of heart rate variability five minutes before the onset of paroxysmal
      atrial fibrillation.
AB  - BACKGROUND: Various experimental and clinical observations suggest changes in
      sympathetic and vagal neural regulatory mechanisms play a critical role in
      altering cardiac electrical properties and favor the occurrence of arrhythmic
      events. There is limited information about the influences of the autonomic tone
      on the development of episodes of paroxysmal atrial fibrillation in patients with
      no evidence of organic heart disease. The aim of this study was to investigate
      changes in sympatho-vagal balance 5 minutes before the onset of atrial
      fibrillation. METHODS: We evaluated 28 patients with no history of heart disease
      who were not undergoing pharmacological treatment and who had at least one
      episode of paroxysmal atrial fibrillation recorded during an 24-hour ECG Holter
      monitoring. We analyzed values of frequency domain heart rate variability
      parameters 5 minutes before the onset of atrial fibrillation (prefa period)
      compared to an equivalent period at least 1 hour after from atrial fibrillation
      (random period). RESULTS: Thirty-six episodes of atrial fibrillation were
      recorded and our results showed we had two types of episodes. Eighteen were
      classified as Type A, in which we had an increase of low frequency (LF) (79.15 +/
      10.76 in comparison with 62.64 +/- 19.55) (P = 0.004) and a decrease of high
      frequency (HF) (20.82 +/- 10.74 in comparison with 37.64 +/- 20.20) (P = 0.004)
      consistent with an increase of sympathetic tone; and 18 were classified as Type B
      in which there was a decrease of LF (62.82 +/- 15.38 in comparison with 85.97 +/-
      8.48) (P < 0.001), and an increase of HF (36.79 +/- 14.72 compared with 14.01 +/-
      8.48) (P < 0.001), consistent with an increase of parasympathetic tone.
      CONCLUSION: We observed abrupt changes in sympathovagal balance in the last 5
      minutes preceding an episode of atrial fibrillation. This can be related to a
      double behavior in the neurogenic drive: in Type A episodes there is an increase
      of the LF spectrum, LF:HF ratio, and a decrease of the HF spectrum consistent
      with an increase of neurogenic sympathetic drive; in Type B episodes there is a
      reduction of the LF spectrum, LF/HF ratio, and an increase of HF spectrum
      consistent with an enhancement of the neurogenic parasympathetic drive. In some
      patients, we found that the two mechanisms operate during different hours of the
      day and that sometimes there is an increase of sympathetic tone, and in the same
      instances an increase of parasympathetic tone. Heart-rate variability measures
      fluctuation in autonomic inputs to the heart rather than the mean level of
      autonomic impulse; autonomic imbalance is probably more important than the vagal
      or sympathetic drive alone.

PMID- 10353134
TI  - Atrial flutter ablation using a technique for detection of conduction block
      within the posterior isthmus.
AB  - Catheter ablation orientated on the induction of a functional intraatrial block
      within the posterior isthmus of the tricuspid annulus has been shown to
      effectively abolish atrial flutter. In order to improve and simplify the current
      technique, a strategy based on an electrode catheter for combined right atrial
      and coronary sinus mapping and stimulation was explored prospectively. Twenty
      four consecutive patients referred for catheter ablation of recurrent type I
      atrial flutter were included. A steerable 7 Fr catheter (Medtronic/Cardiorhythm)
      composed of two segments with 20 electrodes was used for right atrial and
      coronary sinus activation mapping and stimulation. Multiple steering mechanisms
      allowing intubation and positioning of the distal part within the coronary sinus
      were incorporated into the device. Adequate positioning of the mapping catheter
      was achieved solely via a transfemoral approach in all patients after 7.7 +/- 4.6
      minutes, providing stable electrogram recordings during the entire ablation
      procedure. Radiofrequency current ablation (16.3 +/- 9.6 pulses) caused a
      significant bidirectional increase of the mean intraatrial conduction times via
      the posterior isthmus irrespective to the stimulation interval. Significant
      changes of intraatrial conduction properties were induced during ablation in 22
      of 24 patients (bidirectional block: n = 18, unidirectional block: n = 3,
      conduction delay: n = 1, unchanged conduction: n = 2). Following ablation atrial
      flutter was noninducible in all patients. Twenty-two of 24 patients (92%)
      remained free of atrial flutter episodes during a follow-up of 12.5 +/- 5.7
      months. Two of six patients without a bidirectional conduction block had a
      recurrence of atrial flutter. Atrial flutter ablation guided by the induction of
      an intraatrial conduction block can be effectively performed with this novel
      strategy for combined mapping of the posterior tricuspid isthmus, including
      coronary sinus and right atrial free wall. This transfemoral approach has a high
      accuracy with respect to the detection of radiofrequency current-induced changes
      of intraatrial conduction patterns.

PMID- 10353135
TI  - Does acute volume overloading in the setting of left ventricular dysfunction and
      pulmonary hypertension affect the defibrillation threshold?
AB  - The impact of acute volume overload hemodynamics on the DFT with concurrent
      moderate left ventricular systolic dysfunction is unknown. Ten mongrel dogs (17.2
      kg), using a crossover study design, each had baseline (study 1) hemodynamic,
      echocardiographic, and DFT measurements. These measurements were repeated after
      left ventricular dysfunction was induced using a norepinephrine (5 micrograms/kg
      per min) infusion (study 2). Hemodynamic and DFT parameters were obtained
      simulating acute heart failure by volume overload with an 0.9% normal saline
      infusion to an associated mean pulmonary capillary wedge pressure of > 19 mmHg
      (study 3). Numerous significant echocardiographic and hemodynamic parameters were
      noted when the animals from studies 1 and 2, 2 and 3, and 1 and 3 were compared.
      A significant difference in the DFT was observed only when study animals 1 and 3
      were compared (P < 0.02). None of the dogs were hypoxemic at the time of the
      acute heart failure DFT. The mechanism of this finding remains unknown. This data
      would suggest that acute volume overload with associated left ventricular
      dysfunction does adversely affect the DFT in a canine model.

PMID- 10353136
TI  - Clinical surveillance of a tined, bipolar, steroid-eluting, silicone-insulated
      ventricular pacing lead.
AB  - Since 1990, 1,068 Medtronic 5024 bipolar, silicone-insulated, tined, steroid
      eluting ventricular leads have been implanted at the Mayo Clinic (Rochester, MN)
      and Midelfort Clinic (Eau Claire, WI). Implantation data were favorable: median
      pacing thresholds of 0.5 V at 0.5 ms, median R wave of 13.4 mV, and median
      impedance of 593 omega. Of the 2.1% acute lead-related complications
      (dislodgment, microdislocation, diaphragmatic pacing, and undersensing), 1.2%
      necessitated reoperation. This rate is lower than that in most published series
      of other leads. During a median follow-up of 23 months (up to 76 months), 12
      (1.1%) chronic lead-related complications (high thresholds, loss of capture, and
      undersensing) and no instances of definite or suspected lead material failure
      occurred. This rate is much lower than that in studies of other leads. Thus, the
      5024 lead combines the reliability of silicone insulation with a low rate of
      chronic complications that is probably the result of its steroid elution. No
      evidence of failure of lead material has appeared up to 6 years after
      implantation.

PMID- 10353137
TI  - Oxygen uptake to work rate relation throughout peak exercise in normal subjects:
      relevance for rate adaptive pacemaker programming.
AB  - The oxygen uptake to work rate (VO2/WR) relationship observed throughout peak
      exercise testing is already being applied for rate adaptive pacemaker
      programming. However, the detailed curve design of VO2/WR with respect to the
      anaerobic threshold (AT) has not yet been investigated. It was the purpose of
      this study to determine the VO2/WR slope below and above the AT in a healthy
      control group. Seventy-eight healthy control subjects (45.9 +/- 17.4 years; 34
      women: 49.9 +/- 18.6 years 44 men: 43.6 +/- 16.6 years) were exercised on a
      treadmill with "breath-by-breath" gas exchange monitoring using the symptom
      limited "ramping incremental treadmill exercise" (RITE) protocol. The slope of
      the VO2/WR relationship from rest to peak exercise (r-p), rest to AT (slope A),
      and AT to peak exercise (slope B) in mL oxygen uptake per watt of external
      treadmill work was determined by linear regression analysis. [table: see text]
      The oxygen uptake to work rate relationship throughout peak exercise in the
      entire study group generated a significant slope change at the AT (31%, P <
      0.0001) with a decreasing slope during higher work load intensities. Female
      subjects demonstrated a greater percentage of slope change at AT (43%), as
      compared to men (22%, P < 0.01). When using the oxygen uptake to work rate
      relationship for the programming of the pacemaker's rate response to exercise,
      the significant slope change at the AT should be considered to more appropriately
      pace during higher work intensities supported by anaerobic metabolism. Female
      pacemaker patients should be programmed to generate a steeper VO2/WR slope below
      AT with a greater slope change at AT, as compared to men. Abnormally high oxygen
      uptake to work rate ratios above the AT may be possibly used as an indicator of
      overpacing.

PMID- 10353138
TI  - The chick embryo heart as an experimental setup for the assessment of myocardial
      remodeling induced by pacing.
AB  - The mechanisms regulating remodeling of the heart are not well understood and
      only rarely investigated for pacing. We therefore developed a model based on the
      well-established chick embryo heart preparation. Hamburger Hamilton 21 stage
      Leghorn chick embryos were used. Access to the heart was obtained after having
      dissected the shell membranes. The electrodes (platinum wires) were placed in
      ovo: the anode on the vitelline membrane and the cathode at different sites of
      the heart (sinus venosus, base/apex of the ventricle). Sensing and stimulation
      thresholds were measured. Survival of the paced chick was studied. Among 30 chick
      embryonic hearts, the stimulation thresholds were 1.4 mV +/- 0.5 SD for the
      atrium, 2.6 V +/- 1.4 SD at the base, and 3.2 V +/- 1.5 SD at the apex of the
      ventricle, while the sensing signals were 1.3 mV +/- 0.5 SD at the atrium, 19.6
      mV +/- 4.1 SD at the base, and 21.6 mV +/- 3.9 SD at the apex of the ventricle.
      Continuous pacing (pacing rate = intrinsic rate + 10%) could be maintained for
      1.5 hours +/- 0.5 SD at the atrium, 8.9 hours +/- 0.7 SD at the base of the
      ventricle, and 7.9 hours +/- 1 SD at the apex of the ventricle up to death of the
      embryos. By using intermittent electrical stimulation, the association of 5
      minutes on/5 minutes off pattern during 18 hours and 5 minutes on/15 minutes off,
      during 30 hours resulted in an effective pacing period of 19 hours in 60% of the
      experiments, reflecting 15 cell turnover cycles. This experimental setup will
      allow the study of morphological, metabolic, and molecular bases of ventricular
      remodeling induced by electrical stimulation.

PMID- 10353139
TI  - Radiofrequency catheter ablation of drug refractory symptomatic ventricular
      ectopy: short- and long-term results.
AB  - We performed radiofrequency catheter ablation (RFCA) in 12 consecutive patients
      (17-77 years) with daily, symptomatic, monomorphic ventricular ectopy (VE)
      (12,096 +/- 3,326 on 24-hour Holter) resistant to antiarrhythmic drugs. Nine
      patients had no apparent structural heart disease, 1 patient had a mild dilated
      cardiomyopathy, 1 patient had a treated mitral stenosis, and 1 patient had
      arrhythmogenic ventricular dysplasia. VE morphology was LBBB with inferior axis
      in 9 patients, RBBB with inferior axis in 2 patients, RBBB with superior axis in
      1 patient. None of the patients had spontaneous or inducible sustained
      ventricular tachycardia. The VE focus was targeted with RF energy at the earliest
      endocardial activation site and based on a matching 12-lead ECG pace map. The VE
      focus was localized in the right outflow tract in 9 patients and on the left
      ventricle in 3 patients. RFCA was delivered with a standard 4-mm tip electrode.
      The ablation was initially successful in 11 patients and unsuccessful in 1
      patient. All successfully ablated patients were asymptomatic and discharged
      without antiarrhythmic drugs. During follow-up (25 +/- 8; 17-38 months), two
      patients had a recurrence of symptoms, which were controlled by a previously
      ineffective drug. At the end of follow-up, 1,329 +/- 3198 VE were observed on
      Holter monitoring (P < 0.001 compared with initial values). No short- and long
      term complications were observed. RFCA is a safe and effective method for
      treating drug-resistant symptomatic monomorphic VE in carefully selected
      patients. A persistent benefit without complications was obtained over a 2-year
      follow-up.

PMID- 10353140
TI  - Optimized pulse durations minimize the effect of polarity reversal on
      defibrillation efficacy with biphasic shocks.
AB  - There are conflicting results on the effect of polarity change on the
      defibrillation efficacy of biphasic shocks possibly caused by different shock
      durations. The goal of the present study was to investigate the influence of
      polarity reversal on defibrillation efficacy for different biphasic shock
      durations in a porcine animal model. In eight anesthesized pigs using a
      transvenous/submuscular lead system DFTs for 4 phase 1 durations were determined:
      8.1 ms, 6 ms, 3.8 ms and 1.7 ms. The phase 1/phase 2 ratio was constant at
      60%/40%. For cathodal shocks, the defibrillation coil in the right ventricular
      apex was the cathode during phase 1 and for anodal shocks it was the anode. For
      both polarities, the strength-duration curve revealed a DFT minimum at 3.8 ms
      (cathodal shocks: 21.3 +/- 6.4 J, P < 0.001; anodal shocks: 21.9 +/- 8 J, P =
      0.05). For anodal shocks and phase 1 durations of 1.7, 3.8, and 6 ms there was no
      significant difference of the stored energy at the DFT compared to cathodal
      shocks. In contrast, significantly lower DFTs were observed for anodal shocks
      with a phase 1 duration of 8.1 ms (28.8 +/- 6.4 J compared to 33.1 +/- 5.9 J for
      cathodal shocks, P = 0.006). The effect of lower defibrillation energy
      requirements with polarity reversal depends on the total biphasic shock duration;
      for the pulse duration with the lowest DFT, polarity reversal does not increase
      defibrillation efficacy of biphasic shocks.

PMID- 10353141
TI  - Clinical disorders of the autonomic nervous system associated with orthostatic
      intolerance: an overview of classification, clinical evaluation, and management.
AB  - The disorders of autonomic control associated with orthostatic intolerance are a
      diverse group of infirmities that can result in syncope and near syncope (as well
      as a host of other complaints). A basic understanding of these disorders is
      essential to both diagnosis and proper treatment. These infirmities are not new,
      what has changed is our ability to recognize them. It has been said that "the
      world undergoes change in the human consciousness. As this consciousness changes,
      so does the world." On going studies will continue to help better define the
      broad spectrum of these disorders, and to elaborate better diagnostic and
      treatment modalities.

PMID- 10353142
TI  - Does one mechanism explain the tachycardias?

PMID- 10353143
TI  - Clinical practice patterns in implantable rhythm management device therapy: new
      players and new norms.

PMID- 10353144
TI  - Immediate and persistent complete heart block following a horse kick.
AB  - Nonpenetrating chest trauma has been reported to cause acute and transient
      disorders of impulse formation and propagation, including intraventricular
      conduction delay and heart block. We report a case of immediate and sustained
      complete heart block following blunt chest injury.

PMID- 10353145
TI  - Shear syndrome: the worst case scenario of crush syndrome.
AB  - Shear syndrome is described as a complication of crush syndrome. In addition to
      compression of and injury to the electrode, complete transection occurs. In this
      case, the free end migrated to the pulmonary artery with the potential for
      further complications.

PMID- 10353146
TI  - An interesting case of infant sudden death: severe hypertrophic cardiomyopathy in
      Pompe's disease.
AB  - Glycogen storage disease type II (Pompe's disease) is a rare inherited metabolic
      disorder, which often leads to infantile death from severe cardiomyopathy. This
      case of sudden death illustrates the features of the cardiac findings in the
      disorder, resulting from massive lysosomal accumulation of glycogen in the heart
      and other tissues. Pompe's disease should be considered in cases of unexplained
      infantile cardiomyopathy.

PMID- 10353147
TI  - Pulmonary embolization of a pacing electrode fragment complicating lead
      extraction.
AB  - We present a case that demonstrates an unusual complication of electrode
      extraction, namely asymptomatic embolization of a pacing electrode fragment into
      the pulmonary vascular bed.

PMID- 10353148
TI  - Inappropriate implantable cardioverter-defibrillator therapy due to the detection
      of premature ventricular complexes.
AB  - Inappropriate shocks delivered by implantable cardioverter-defibrillators may
      occur in 15%-40% of patients treated with these devices. This article describes a
      rare cause for inappropriate shocks. Two patients received inappropriate shocks
      due to the presence of premature ventricular complexes during attempted
      reconfirmation of ventricular fibrillation. Knowledge of device algorithms for
      detection and reconfirmation of ventricular fibrillation, designed to have a high
      degree of sensitivity and therefore lower specificity, allows for reprogramming
      to avoid further inappropriate shocks.

PMID- 10353149
TI  - TEE evidence of right atrial tachycardia with mechanical alternans, interatrial
      and atrioventricular 2:1 block.

PMID- 10353150
TI  - A case of dislodged atrial screw-in lead with migration to the ventricle 1 year
      postoperatively.
AB  - We report a rare case of a 53-year-old woman with a dislodged atrial screw-in
      lead that migrated to the ventricle 1 year after pacemaker implantation. While
      such an event is quite unusual, we should be aware of its possibility.

PMID- 10353151
TI  - Arteriovenous fistula after injury of the left internal mammary artery during
      extraction of pacemaker leads with a laser sheath.
AB  - The left internal mammary artery was severed and an arteriovenous fistula created
      during extraction of pacemaker leads with a laser sheath.

PMID- 10353152
TI  - Catheter reuse.

PMID- 10353154
TI  - Hypotriglyceridaemic activity of Ficus carica leaves in experimental
      hypertriglyceridaemic rats.
AB  - A model of hypertriglyceridaemia in rats is described, which was used to
      investigate the hypolipidaemic effect of an intraperitoneal (i./p.)
      administration of a Ficus carica leaf decoction. Hypertriglyceridaemia was
      induced in rats following the protocol: a fasting period of 22 h, 2 h of oral
      (p.o.) administration of 20% emulsion of longchain triglycerides (LCT emulsion),
      both repeated once. The plasma triglyceride and total cholesterol levels obtained
      2 h after the protocol were 5.7 +/- 2.5 mmol/L (p < 0.0001 vs basal levels) and
      1.7 +/- 0.3 mmol/L, respectively, n = 10. The new model was used to test the
      hypotriglyceridaemic effect of a single dose of Ficus carica (fig tree) leaf
      decoction administered i./p. (50 g dry wt/kg body wt). After the i.p. injection
      of serum saline (control group, n = 10) or Ficus carica extract (group A, n =
      10), plasma triglyceride levels in the control group and group A were 5.9 +/- 2.9
      mmol/L and 5.5 +/- 2.9 mmol/L just after the LCT emulsion protocol; 4.7 +/- 2.7
      mmol/L and 0.9 +/- 0.4 mmol/L, p < 0.005, 60 min after the LCT protocol; and 3.6
      +/- 2.9 mmol/L and 1.0 +/- 0.4 mmol/L, p < 0.05, 90 min after the LCT protocol.
      The plasma total cholesterol levels, which were not modified in our experimental
      model, showed no significant differences in relation to baseline levels in the
      presence or absence of Ficus carica treatment either. The clearly positive
      results suggest the presence in the fig leaf decoction of a compound or compounds
      that influence lipid catabolism.

PMID- 10353153
TI  - Anticancer potency of the milk extract of Semecarpus anacardium Linn. nuts
      against aflatoxin B1 mediated hepatocellular carcinoma bearing Wistar rats with
      reference to tumour marker enzymes.
AB  - Aflatoxin B1 is an important consideration in the aetiology of human and animal
      hepatocellular carcinoma. The influence of the drug, Semecarpus anacardium Linn.
      nut extract, on hepatocarcinogenicity of aflatoxin B1 was evaluated in adult
      albino male Wistar rats. Aflatoxin B1 was administered intraperitoneally to
      induce hepatocellular carcinoma. These cancer bearing animals were treated with
      Semecarpus anacardium Linn. nut extract (200 mg/kg body weight/day) in sunflower
      oil orally for 14 days. The plasma and the liver tumour tissue were investigated
      biochemically for lactate dehydrogenase, aspartate aminotransferase, alanine
      aminotransferase, alkaline phosphatase and gamma-glutamyl transpeptidase. The
      elevation of plasma concentration of these enzymes were indicative of the
      persistent deteriorating effect of aflatoxin B1 in cancer bearing animals.
      Lactate dehydrogenase and aminotransferases levels were decreased in liver,
      whereas alkaline phosphatase and gamma-glutamyl transpeptidase were increased in
      cancer conditions. These enzyme levels were reversed to near normal control
      values in drug treated animals. The analysis of marker enzyme activities clearly
      indicates the antitumour efficacy of Semecarpus anacardium Linn. nut extract on
      aflatoxin B1 induced hepatocellular carcinoma.

PMID- 10353155
TI  - Keishi-bukuryo-gan prevents the progression of atherosclerosis in cholesterol-fed
      rabbit.
AB  - In this study, we examined whether in vivo keishi-bukuryo-gan (a Kampo
      formulation) could prevent the progression of atherosclerosis in cholesterol-fed
      rabbits, an animal model for hypercholesterolaemia. Sixteen male Japanese white
      rabbits (2 kg body weight) were divided into two groups. Group A (n = 8) was fed
      standard rabbit chow containing 1% cholesterol for 8 weeks. Group B (n = 8) was
      fed standard rabbit chow containing 1% cholesterol and 1% keishi-bukuryo-gan for
      8 weeks. At the end of the experiment, average plasma concentrations of total
      cholesterol and IDL-cholesterol were 2055.9 +/- 201.8 mg/dL and 408.1 +/- 62.6
      mg/dL in group A and 1950.5 +/- 126.3 mg/dL and 407.6 +/- 56.6 mg/dL in group B,
      respectively. The percentage of the surface area of the total thoracic aorta with
      visible plaque was significantly reduced by keishi-bukuryo-gan administration;
      group A was 33.2% +/- 5.3% and group B was 14.3% +/- 2.9%. beta-very low density
      lipoprotein (VLDL) and low density lipoprotein (LDL) isolated from cholesterol
      fed rabbits treated with keishi-bukuryo-gan (group B) were shown to be highly
      resistant to oxidative modification by cupric ion. Sera isolated from rabbits
      administered keishi-bukuryo-gan had reduced lipid peroxide formation compared
      with those from rabbits without keishi-bukuryo-gan. Thus, keishi-bukuryo-gan
      prevents the progression of atherosclerosis in cholesterol-fed rabbits in vivo by
      limiting oxidative LDL modification.

PMID- 10353156
TI  - Effect of fenugreek seeds on blood lipid peroxidation and antioxidants in
      diabetic rats.
AB  - The effect of fenugreek seeds (Trigonella foenum graecum) on blood lipid
      peroxidation and antioxidant status in alloxan diabetic rats was studied.
      Increased lipid peroxidation and alterations in circulating antioxidants were
      observed in the diabetic state. The levels of glutathione, ascorbic acid and beta
      carotene in blood were significantly lowered and alpha-tocopherol content was
      increased. Supplementation of fenugreek seeds in the diet lowered lipid
      peroxidation. The contents of glutathione and beta-carotene were increased and
      the alpha-tocopherol content was lowered. The level of ascorbic acid was
      unaltered. The level of antioxidants were higher in normal rats which were fed
      with the fenugreek supplemented diet compared with control animals which were fed
      commercial rat chow. The study shows that disrupted free radical metabolism in
      diabetic animals may be normalized by fenugreek seed supplementation in the diet.

PMID- 10353157
TI  - Effect of xanthorrhizol, xanthorrhizol glycoside and trachylobanoic acid isolated
      from Cachani complex plants upon the contractile activity of uterine smooth
      muscle.
AB  - Xanthorrhizol, xanthorrhizol glycoside, and trachylobanoic acid, compounds
      isolated from medicinal plants that are grouped in the complex known as Cachani
      have been shown to inhibit the tonic contraction of rat uterus induced by: (a)
      depolarizing K+ solution (60 mM), (b) CaCl2 (1 mM), and (c) BAY K 8644 (0.3
      microM) in a concentration-dependent manner (1-30 micrograms/mL). The inhibitory
      potency was displayed as follows: xanthorrhizol > xanthorrhizol glycoside >
      trachylobanoic acid. These results suggest that the assayed compounds might block
      voltage operated calcium influx in myometrial cells as they displayed a calcium
      antagonistic activity. This effect is not due to peripheral receptor activation
      (beta 2-adrenergic, H2-histaminergic) as neither propranolol nor cimetidine
      modified the inhibitory effect of the compounds assayed. This is the first report
      showing that plants belonging to the Cachani complex may contain uterine smooth
      muscle bioactive substances.

PMID- 10353158
TI  - Argentine plant extracts active against polymerase and ribonuclease H activities
      of HIV-1 reverse transcriptase.
AB  - Lipophilic and hydrophilic extracts of four Argentine plants (Gamochaeta
      simplicaulis Cabr. 1, Achyrocline flaccida Wein. D. C. 2, Eupatorium buniifolium
      H. et A. 3, and Phyllanthus sellowianus Muell. Arg. 4) were examined in vitro for
      their ability to inhibit the polymerase and ribonuclease H (RNase H) activities
      of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) (wild
      and Y181C mutant types). The active extracts were also examined as inhibitors of
      viral replication in HLT4LacZ-1IIIB cell cultures, evaluating their cytotoxicity
      in parallel. Infusions 2I and 4I, among the crude extracts, showed the highest
      activity. These extracts were refractioned into four fractions; 2I4 and 4I4 were
      active as inhibitors of DNA-polymerase (wild and Y181C types) and RNase H
      activities. These fractions were potent as inhibitors of viral replication and
      were not cytotoxic. Refractionation of 2I4 yielded five new fractions, two of
      which, 2I4-4 and 2I4-5, showed notable activity. Refractionation of 4I4 yielded
      for new fractions; of these, 4I4-3 and 4I4-4 were active. The marked biological
      activity found in the infusion of A. flaccida and P. sellowianus makes them
      sufficiently attractive to be considered in the combined chemotherapy of the
      disease.

PMID- 10353159
TI  - Effect of molluscicidal components of Abrus precatorius, Argemone mexicana and
      Nerium indicum on certain biochemical parameters of Lymnaea acuminata.
AB  - Exposure to 40% and 80% of the 24 h LC50 of the molluscicidal component of Abrus
      precatorius (abrin and glycyrrhizin), Argemone mexicana (protopine and
      sanguinarine) and Nerium indicum (oleandrin) caused a significant decrease in the
      levels of protein, free amino acid, DNA and RNA in the nervous tissue of Lymnaea
      acuminata. Except for glycyrrhizin, all the above molluscicides caused a
      significant reduction in phospholipid levels and a simultaneous increase in the
      rate of lipid peroxidation in the nervous tissue of treated snails.

PMID- 10353160
TI  - Inhibition of keratinocyte growth by different Nepalese zanthoxylum species.
AB  - A total of 11 methanol extracts obtained from four different Nepalese Zanthoxylum
      species were screened for their antiproliferative activity against the growth of
      human keratinocytes (HaCaT cells). The extract obtained from Z. armatum barks was
      highly active with an IC50 value of 11 micrograms/mL. Also, the extracts obtained
      from Z. oxyphyllum barks and roots with IC50 values of 53 and 57 micrograms/mL,
      respectively, showed potent activity. Their antiproliferative activity was not
      due to cytotoxic effects on cell membranes, as documented by the activity of
      lactate dehydrogenase released from the cytoplasm of keratinocytes, which did not
      exceed that of the control value. Rather, they also protected against radical
      induced damage to model membranes stimulated with 2,2'-azo-bis(2-amidinopropane)
      dihydrochloride.

PMID- 10353161
TI  - The therapeutic effect of an herbal formula Badmaev 28 (padma 28) on experimental
      allergic encephalomyelitis (EAE) in SJL/J mice.
AB  - A herbal formula, Badmaev 28, was evaluated in the treatment of an induced attack
      in a chronic relapsing model of experimental allergic encephalomyelitis (EAE) in
      SJL/J mice. Chronic EAE was induced by immunization of 8 week old mice with an
      emulsion of syngeneic spinal cords with incomplete Freund's adjuvant supplemented
      with Mycobacterium tuberculosis. Therapy with Badmaev 28 was started on day 25
      after the immunization, and the formula was administered in the drinking water at
      doses of 7, 21, 83 and 166 mg/kg/day. The treatment resulted in significantly
      decreased mortality compared with the untreated control animals and the
      therapeutic effect occurred in one experiment in a dose-dependent fashion. Based
      on the experimental results it is difficult to name one particular mechanism
      responsible for the therapeutic effectiveness of the formula in the EAE model.
      Rather this protective effect could be explained by a broad protective mechanism
      of action discussed in the literature as nonspecific resistance (NSR) to the
      diversified biological and psychological stressors. The increase in NSR
      characterizes the action of pharmacological compounds termed adaptogens or
      bioprotectants.

PMID- 10353162
TI  - Effect of extracts of Orthosiphon stamineus Benth, Hieracium pilosella L.,
      Sambucus nigra L. and Arctostaphylos uva-ursi (L.) Spreng. in rats.
AB  - Aqueous extracts of Sambucus nigra and Arctostaphylos uva-ursi and hydroalcohol
      extracts of Orthosiphon stamineus and Hieracium pilosella were tested for their
      diuretic activities in rats; pharmacological evaluation revealed that they led to
      an increase in urine flow. Urinary sodium excretion in rats was increased with O.
      stamineus and S. nigra.

PMID- 10353164
TI  - Analgesic effect of extracts from Cotula cinerea (L).
AB  - Ethyl ether, ethyl acetate and n-butanol extracts of Cotula cinerea were
      administered to mice at a dose of 100 mg/kg in order to study their analgesic
      effects. Only the ethyl ether extract showed a significant effect.

PMID- 10353163
TI  - Studies on antifertility effect of pawpaw seeds (Carica papaya) on the gonads of
      male albino rats.
AB  - Preliminary studies on the antifertility effect of pawpaw seeds (Carica papaya)
      on the gonads of male albino (Wistar) rats was investigated. An oral dose of
      crude ripe pawpaw seeds at 100 mg/kg body weight and 50 mg/kg body weight were
      administered orally for 8 weeks. Histological observations at a high dose of 100
      mg/kg body weight showed degeneration of the germinal epithelium and germ cells,
      a reduction in the number of Leydig cells and the presence of vacuoles in the
      tubules. At a low dose of 50 mg/kg body weight little effect was observed.
      However, there was disorganization in some of the seminiferous tubules while
      others appeared normal. Leydig cells also appeared normal compared with the
      controls. At a high dose the epididymis showed many empty tubules containing
      degenerated spermatozoa and cell debris in the lumen. The epithelium appeared
      normal compared with the controls. At a low dose a milder effect was observed.
      The epithelial tissue appeared normal. A possible mechanism of action is
      discussed.

PMID- 10353165
TI  - Investigation of the effects of selected medicinal plants on experimental
      thrombosis.
AB  - Six medicinal plants indigenous to Africa were evaluated for their activity on
      experimental thrombosis in mice. Of the plants screened, the extract of
      Commiphora molmol exhibited the strongest antithrombotic activity, while the
      extract of Ageratum conyzoides showed no marked activity. This study established
      the antithrombotic effect of the extracts of Azadiractha indica, Bridelia
      ferruginea, Commiphora molmol, Garcinia kola and Curcuma longa.

PMID- 10353166
TI  - Effect of Choto-san, a kampo medicine, on impairment of passive avoidance
      performance in mice.
AB  - In mice with procephalic ischaemia loading, disrupted passive avoidance retention
      performance was dose-dependently improved by Choto-san, but this effect was
      antagonized by NAN-190, a serotonin1A receptor antagonist. In mice with decreased
      intracerebral serotonin concentration, Choto-san prevented disturbance in
      acquiring a passive avoidance response after scopolamine administration, but did
      not influence the decreased serotonin concentration. These results suggested that
      Choto-san showed the anti-amnestic effect based on the stimulation of serotonin1A
      receptors.

PMID- 10353167
TI  - Studies on in vitro metabolism of shikonin.
AB  - Shikonin is one of the active components isolated from the root of Arnebia
      euchrona (Royle) Johnst. It has been shown to possess significant antibacterial,
      antiinflammatory and antitumour activities and has been used clinically. In this
      paper, rat liver microsomes were incubated in vitro to study the metabolism of
      shikonin and a reverse-phase high performance liquid chromatography/photodiode
      array detector (DAD) method was used to separate and detect the metabolites. The
      effects of several factors on the metabolism were investigated and the metabolic
      system was optimized. The main metabolites were purified by RP-HPLC and their
      structures were determined by UV, 1H-NMR and MS. S-1 was dihydroxylated shikonin,
      S-2 was 2-OH shikonin and S-3 was 6-OH or 7-OH shikonin.

PMID- 10353168
TI  - Persistency of bioactive fractions of Indian plant, Polygonum hydropiper as an
      insect feeding deterrent.
AB  - An improved extraction procedure resulted into a six-fold yield of bioactive
      fraction than the usual extraction method with a high per cent of feeding
      deterrence against 3rd instar larvae of Spilarctia obliqua and Spodoptera litura.
      The effective concentration (EC50) of PH-2 was 4321 and 4155 ppm against the two
      insects. No loss in feeding deterrency was recorded when the bioactive ether
      fraction, PH-2 was exposed to sunlight for 6 h.

PMID- 10353169
TI  - Antimycotic activity against Saprolegnia ferax of extracts of Artemisia
      verlotorum and Santolina etrusca.
AB  - Methanol and aqueous extracts of Artemisia verlotorum and Santolina etrusca were
      screened in vitro against Saprolegnia ferax and for all extracts the MIC were
      determined. Screening was performed also on two fractions of the aqueous
      extracts.

PMID- 10353170
TI  - Antiviral properties of a crude extract from a green alga Caulerpa taxifolia
      (Vahl) C. Agardh.
AB  - A crude extract of Caulerpa taxifolia was tested for its antiviral activity. The
      chloroform-methanol residue showed an interesting inhibitor effect in vitro
      toward the feline immunodeficiency virus (FIV), a valid model for studying the
      acquired immunodeficiency syndrome. This extract reduced the virus-induced
      syncytia in the cultured cells, the viral reverse transcriptase activity and the
      viral capsid protein P24 expression.

PMID- 10353171
TI  - The effect of the aqueous extract of Cynomorium coccineum on the epididymal sperm
      pattern of the rat.
AB  - An aqueous extract of Cynomorium coccineum was administered by stomach tube to
      ten mature male Wistar rats, at a dose of 47 mg/100 kg body weight/day for 14
      consecutive days. Ten rats were kept as controls and received normal saline by
      oral route at the same dosing interval. Sperm was collected from the epididymes
      after decapitation. The results revealed that the water extract of the Cynomorium
      coccineum induced significant increase in the sperm count, improved the
      percentage of live sperm and their motility and decreased the number of abnormal
      sperm. Testicular histology showed increased spermatogenesis and seminiferous
      tubules full of sperm in the treated group compared with the controls.

PMID- 10353172
TI  - Inhibitory effects of Ougi-keishi-gomotsu-to, a traditional herbal medicine, on
      lipid peroxidation and protein oxidative modification of mouse brain homogenate
      induced by copper.
AB  - Ougi-Keishi-gomotsu-to a traditional herbal medicine, is used clinically for
      patients with abnormal sensations and pain in the legs in neuropathy. It was
      shown to have inhibitory effects on lipid peroxidation and protein oxidative
      modification of brain homogenate induced by copper. Its effect was stronger than
      those of mannitol and alpha-tocopherol as free radical scavenger and antioxidant.
      These results demonstrated that Ougi-kelshi-gomotsu-to has antioxidative effects
      on neuron injury derived from oxidative stress induced by metal.

PMID- 10353173
TI  - Mechanism of action of verbascoside on the isolated rat heart: increases in level
      of prostacyclin.
AB  - The mechanism of the positive cardioactive effects induced by verbascoside in the
      Lagendorff rat heart has been investigated. Isolated rat hearts treated with
      alpha- or beta-adrenergic agents did not show significant reduction of the
      positive chronotropism, inotropism and increased coronary perfusion rate mediated
      by verbascoside. A significant increase in prostacyclin levels (142%) observed
      following the administration of verbascoside suggests that prostacyclin
      stimulates formation of cAMP which induces the cardioactivity associated with
      verbascoside.

PMID- 10353174
TI  - Effects of Fructus schizandrae on cycloheximide-induced amnesia in rats.
AB  - The effects of Fructus Schisandrae (Schizandra Chinensis, (FS) on cycloheximide
      (CXM)-induced amnesia by using a passive avoidance task were studied in rats. FS
      at 0.25 and 0.75 g/kg administered for 1 week significantly prolonged the CXM
      shortened step-through latency (STL). Of the fractions (n-hexane, chloroform and
      water), only the water fraction at 25 mg/kg administered for 1 week prolonged the
      CXM-shortened STL. These results suggest that the water fraction is the main
      active fraction of FS.

PMID- 10353175
TI  - Modulation of lead toxicity by Spirulina fusiformis.
AB  - The modulatory effects of lead toxicity by Spirulina fusiformis
      (Oscillatoreaceae) were observed on the testes of Swiss albino mice at a dose of
      800 mg/kg body weight. The Spirulina fusiformis was non-toxic at the dose given.
      A significant enhancement in the survival time was observed in the pre- and post
      treated Spirulina group compared with the control (lead treated) group. Lead
      induced toxicity was also reduced in terms of testes weight, animal weight,
      tubular diameter in the pre Spirulina treated group. The modulatory effects of
      Spirulina may be attributed to the presence of the antioxidants, beta-carotene
      and SOD enzyme.

PMID- 10353176
TI  - Chemopreventive action by an extract from Brassica compestris (var Sarason) on
      7,12-dimethylbenz(a)anthracene induced skin papillomagenesis in mice.
AB  - We report the chemopreventive property of an ethanolic extract of the seeds of
      Brassica compestris var sarason (mustard seed) on DMBA (7,12
      dimethylbenz(a)anthracene induced skin papillomagenesis in male Swiss albino
      mice. A significant reduction in the values of tumour incidence, tumour burden
      and the cumulative number of papillomas was observed in mice treated orally with
      the seed extract of Brassica compestris var sarason, continuously at peri and
      post initiational stages of papillomagenesis compared with the control groups.
      The latency period in the experimental group significantly increased (11.3 +/-
      0.40 weeks) compared with the control group (7.8 +/- 0.17).

PMID- 10353177
TI  - Gastric antiulcerogenic effects of Stryphnodendron adstringens in rats.
AB  - The antiulcer activity of the total extract and the fractions of Stryphnodendron
      adstringens was studied in rats and compared with that of cimetidine. Ulcers were
      induced in rats by means of three experimental models: acute stress, acidified
      ethanol and indomethacin. The total extract and the fractions were found to have
      significant antiulcer activity in the case of the acute stress and acidified
      ethanol models. These findings support the use of S. adstringens extracts in the
      treatment of gastric lesions.

PMID- 10353179
TI  - Detection of viable myocardium: comparison of dobutamine echocardiography and
      echocardiography after hyperbaric oxygenation.
AB  - The study concerned the possibility of using echocardiography after hyperbaric
      oxygenation (HBO2) to detect viable myocardium. Results were compared with
      dobutamine stress echocardiography (DSE). Seventeen patients with left
      ventricular dysfunction were enrolled in this study. The regional wall motion of
      the left ventricle was assessed for every patient and a wall motion score index
      was calculated. A resting wall motion abnormality was found in 204 segments
      (75%), of which 119 segments (58%) improved during DSE, and 59 (29%) after HBO2.
      Of 119 segments with evidence of viability in DSE, HBO2 showed viability in 58
      segments. Of 85 segments non-viable in DSE, 84 segments were also non-viable
      after HBO2. The positive and negative predictive values of HBO2 compared to DSE
      were 98 and 58%, respectively. Comparing the wall motion score index at rest with
      the index after DSE 5 and 10 micrograms.kg-1.min-1 dobutamine and after HBO2,
      there was significant improvement (P < 0.005). Differences between DSE 5
      micrograms.kg-1.min-1 dobutamine and DSE 10 micrograms.kg-1.min-1 dobutamine and
      between HBO2 and DSE 10 micrograms.kg-1.min-1 dobutamine were also significant (P
      < 0.005). There was no significant difference between DSE 5 micrograms.kg-1.min-1
      and HBO2. Echocardiography after HBO2 is a new method for the detection of viable
      myocardium. It appears similar in accuracy to DSE 5 micrograms.kg-1.min-1, but is
      inferior to DSE 10 micrograms.kg-1.min-1.

PMID- 10353178
TI  - Endothelial damage by bubbles in the pulmonary artery of the pig.
AB  - A method for measuring endothelial damage caused by decompression was developed
      for vessels with a large radius. Segments of the pulmonary artery from pigs (8-12
      wk old) were tested for endothelium damage using a system for recording changes
      in the tension in the vessel wall. Substance P (SP) was used as an endothelial
      dependent dilation agonist. A significant decrease was found in the total
      response (Tmax) for SP as a result of endothelium damage, and the reduction in
      response was related to the number of bubbles. Furthermore, the sensitivity of
      the vessels to the agonist was significantly reduced after exposure to bubbles.
      Staining the endothelium with silver nitrate and light microscopy confirmed
      mechanical endothelium damage.

PMID- 10353180
TI  - Arterial baroreflex control during mild-to-moderate nitrous oxide narcosis.
AB  - We hypothesized that light-to-moderate inert gas narcosis might play a role in
      bradycardia in divers by altering sensitivity or response dynamics of arterial
      baroreflexes. Carotid-cardiac and carotid-mean arterial pressure (MAP) baroreflex
      response curves were generated by applying multiple levels of neck pressure and
      suction. Seven healthy volunteers were studied during air breathing (control) and
      during inhalation of 39% nitrous oxide (N2O). Baseline (pre-stimulus) heart rate
      (HR) and MAP were not altered by N2O. Range, threshold level, saturation level,
      and delay of responses did not differ between conditions. For hypertensive
      stimuli, sensitivity of responses did not differ between air control and N2O
      inhalation, but for hypotensive stimuli, maximal response gain for HR tended to
      be reduced with N2O inhalation (P = 0.054). Our results speak against inert gas
      narcosis as a primary mechanism for hyperbaric bradycardia, but it remains
      possible that an attenuation of tachycardic responses to hypotensive stimuli
      plays a role.

PMID- 10353181
TI  - Effect of hyperbaric oxygen therapy in experimental subcutaneous and pulmonary
      infections due to Pseudomonas aeruginosa.
AB  - About 80% of nosocomial infections are caused by aerobic bacteria. Pseudomonas
      aeruginosa is a Gram-negative bacterium belonging to the Pseudomonadaceae family;
      P. aeruginosa is responsible for 6-22% of all hospital infections. The aim of
      this study was to evaluate the efficacy of hyperbaric oxygen (HBO2) therapy (2
      atm abs x 55 min.day-1) alone for 8 days and combined with antibiotic
      chemotherapy (amikacin 15 mg.kg-1.day-1 for 8 days by intraperitoneal route) in
      rats infected subcutaneously and via the pulmonary route. In the rats infected by
      P. aeruginosa, HBO2 induced a reduction in mortality and morbidity with bacteria
      eradication in blood culture, bronchial aspirate, and skin biopsies when compared
      to control. These effects were increased by the use of amikacin, an antibiotic
      used for the treatment of sensitive Gram-negative bacteria.

PMID- 10353182
TI  - Immune function in hyperbaric environments, diving, and decompression.
AB  - The purpose of this review is to examine the influence of exposure to hyperbaric
      oxygen (HBO2) deep diving, and decompression on various facets of the immune
      response. Potential changes during exposure include a decrease in the CD4+:CD8+
      ratio, a decreased proliferation of lymphocytes, and an activation of neutrophils
      with migration to regions of high oxygen pressure. There may also be an
      activation of the complement cascade during decompression. Clinical indicators of
      overall immune suppression include a decreased response to antigens, a weakening
      of autoimmune responses, and a slower rejection of allografts. In professional
      divers, immune changes are at least partially offset by acclimatization, and seem
      to have little clinical significance. However, patients receiving HBO2 are a more
      vulnerable group; in their case, exposure may impair immune surveillance, and a
      careful monitoring of immune function may be important to the success of
      treatment.

PMID- 10353183
TI  - Hyperoxic myopia in a closed-circuit mixed-gas scuba diver.
AB  - A myopic shift occurred in a closed-circuit mixed-gas scuba diver using a 1.3 atm
      abs constant partial pressure of oxygen in a nitrogen-oxygen mix. This change was
      noticed after approximately 18 days of diving with a mean dive time of 4.04 h
      each day. The observed myopic shift was due to hyperoxic myopia, one sign of
      lenticular oxygen toxicity, and resolved over a 1 mo. period after diving was
      completed. On a subsequent drive trip, a myopic shift was found in both the index
      diver as well as two other divers breathing the same gasmix on similar profiles.
      Diving communities should be aware of the risk of both lenticular and pulmonary
      oxygen toxicity when conducting intensive diving at oxygen partial pressures in
      the 1.3-1.6 atm abs range.

PMID- 10353184
TI  - Incidence of carbon monoxide poisoning in the United States.

PMID- 10353185
TI  - Comments on risk of decompression sickness with patent foramen ovale.

PMID- 10353186
TI  - Liquid junction potential in potentiometric titrations. 5. Deduction of the
      potential functions for E.M.F. cells with complex formation and with liquid
      junctions of the type AY [symbol: see text] AY + BYz(B) + HY + AyL.
AB  - Equations were derived, in a general form, for the calculation of the total cell
      e.m.f. for cells containing liquid junctions of constant ionic medium type, where
      formation of strong complexes takes place. The total cell e.m.f. is: EJ = E0J +
      (g/zJ) log cJfJTS2 + ED + EDf Here, (A+, Y-) is the ionic medium, J is the
      potential-determining ion, Bz(B)+ is the central metal ion, ED is the ideal
      diffusion potential (Henderson term), EDf is the contribution of the activity
      coefficients to the diffusion potential, AyL is the ligand. fJTS2 denotes the
      activity coefficients in the terminal solution TS2. The concentration of a chosen
      ion of the ionic medium, C, should be in the range 0.5 < or = C < or = 3 mol dm
      3. The charge of the metal ion Bz(B)+ should be < or = 3. The total potential
      anomalies in the cells are delta EJ = (g/zJ) log fJTS2 + ED + EDf

PMID- 10353187
TI  - Synthesis of 1,3-dithianes and 1,3-dithiolanes. Baker's yeast reduction and
      lipase-catalyzed resolution for synthesis of enantiopure derivatives.
AB  - Three 1,3-dithiolanes and four 1,3-dithianes have been synthesised from 1-(1,3
      dithiolan-2-yl)-2-propanone and 1-(1,3-dithian-2-yl)-2-propanone, respectively.
      Asymmetric reductions of these ketones using baker's yeast gave the corresponding
      enantiopure (S)-alcohols. Baker's yeast also reduced the double bond in 3-(1,3
      dithian-2-yl)-3-buten-2-one enantioselectively to give (S)-3-(1,3-dithian-2-yl)-2
      butanone. 3-(1,3-Dithian-2-yl)-3-buten-2-one was also reduced chemo-selectively
      and the resulting 3-(1,3-dithian-2-yl)-3-buten-2-ol was resolved by
      transesterification in organic solvent using lipase B from Candida antarctica to
      yield the (S)-alcohol and the (R)-acetate with very high enantiomeric ratio, E.
      Racemic 1-(1,3-dithiolan-2-yl)-2-propanol and 1-(1,3-dithian-2-yl)-2-propanol
      were also resolved under similar conditions to give the (S)-alcohols and the
      corresponding (R)-acetates.

PMID- 10353188
TI  - Gene identification in bacterial and organellar genomes using GeneScan.
AB  - The performance of the GeneScan algorithm for gene identification has been
      improved by incorporation of a directed iterative scanning procedure. Application
      is made here to the cases of bacterial and organnellar genomes. The sensitivity
      of gene identification was 100% in Plasmodium falciparum plastid-like genome (35
      kb) and in 98% in the Mycoplasma genitalium genome (approximately 580 kb) and the
      Haemophilus influenzae Rd genome (approximately 1.8 Mb). Sensitivity was found to
      improve in both the Open Reading Frames (ORFs) which have been identified as
      genes (by homology or by other methods) and those that are classified as
      hypothetical. False positive assignments (at the nucleotide level) were 0.25% in
      H. influenzae genome and 0.3% in M. genitalium. There were no false positive
      assignments in the plastid-like genome. The agreement between the GeneScan
      predictions and GeneMark predictions of putative ORFs was 97% in M. genitalium
      genome and 86% in H. influenzae genome. In terms of an exact match between
      predicted genes/ORFs and the annotation in the databank, GeneScan performance was
      evaluated to be between 72% and 90% in different genomes. We predict five
      putative ORFs that were not annotated earlier in the GenBank files for both M.
      genitalium and H. influenzae genomes. Our preliminary analysis of the newly
      sequenced G + C rich genome of Mycobacterium tuberculosis H37Rv also shows
      comparable sensitivity (99%).

PMID- 10353189
TI  - Population dynamics of ticks on indigenous cattle in a pastoral dry to semi-arid
      rangeland zone of Uganda.
AB  - Studies on seasonality and population dynamics of ticks on indigenous cattle and
      their crosses (calves) were carried out in Buruli Ranching Scheme, Nabiswera,
      Luwero district of Uganda on three treatment groups of animals: group 1 (twice a
      week dipping), group 2 (once a month dipping) and group 3 (no tick control).
      During this study, four major species of ticks of economic importance were
      recorded in decreasing order of abundance: Rhipicephalus appendiculatus,
      Rhipicephalus evertsi evertsi, Amblyomma variegatum and Boophilus decoloratus. Of
      these ticks, a seasonal pattern of activity was only observed in R.
      appendiculatus ticks, with peak activities occurring during rainy seasons.
      Greater numbers of ticks were recorded on cows than calves in the three treatment
      groups, with the exception of A. variegatum where the reverse occurred. The mean
      numbers of ticks per animal were highly significantly different (p < 0.01) when
      group 1 animals were compared with group 2 and 3 animals. However, no significant
      differences (p > 0.05) were observed in mean tick numbers between group 2 and 3
      animals. Highly significant differences (p < 0.01) were observed in mean tick
      numbers on cows and calves (more than 12 months old) in different calving
      seasons. The state of lactation only affected tick counts on cows in group 1;
      significantly more ticks (p < 0.01) were observed in lactating than non-lactating
      cows. Furthermore, significantly greater (p < 0.05) numbers of ticks (with the
      exception of B. decoloratus) were recorded during the second year of study (March
      1992-May 1993) than the first year (January 1991-February 1992), despite lower
      rainfall during the former period.

PMID- 10353190
TI  - A phylogenetic analysis by multilocus enzyme electrophoresis and multiprimer
      random amplified polymorphic DNA fingerprinting of the Leishmania genome project
      Friedlin reference strain.
AB  - We have assessed the phylogenetic status of the Leishmania genome project
      Friedlin reference strain by MLEE and multiprimer RAPD including a set of 9
      stocks representative of the main Leishmania species and of the whole genetic
      diversity of the Leishmania genus. To our knowledge, the detailed genetic
      characterization of the Friedlin strain has never been published before. As
      previously recorded (Tibayrenc et al. 1993), MLEE and RAPD data gave congruent
      phylogenetic results. The Friedlin reference strain was definitely attributed to
      Leishmania (Leishmania) major Yakimoff et Schokhor, 1914. Five specific RAPD
      patterns made it possible to distinguish between the Friedlin strain and the 2
      other L. (L.) major stocks included in the study. Various specific MLEE and RAPD
      characters permitted to distinguish between the Leishmania species included in
      the study. All these characters are usable to detect accidental laboratory mix
      ups involving the Friedlin reference strain. In confirmation with previous
      studies involving a more limited set of genetic markers, the general genetic
      diversity of the Leishmania genus proved to be considerable. It must be made
      clear that only one strain cannot be considered as representative of the whole
      genetic variability of the genus Leishmania. In the future, it is therefore
      advisable to complement the results obtained in the framework of the Leishmania
      genome project with data from other strains that should be selected on a
      criterion of important genetic differences with the Friedlin strain.

PMID- 10353191
TI  - Changes in the personality profile of young women with latent toxoplasmosis.
AB  - Latent toxoplasmosis is the most widespread parasite infection in developed and
      developing countries. The prevalence of Toxoplasma gondii infection varies mostly
      between 20 to 80% in different territories. This form of toxoplasmosis is
      generally considered to be asymptomatic. Recently published results, however,
      suggest that the personality profiles of infected subjects differ from those of
      uninfected controls. These results, however, were obtained on non-standard
      populations (biologists or former acute toxoplasmosis patients). Here we studied
      the personality profiles of 191 young women tested for anti-Toxoplasma immunity
      during gravidity. The results showed that the differences between Toxoplasma
      negative and Toxoplasma-positive subjects exits also in this sample of healthy
      women. The subjects with latent toxoplasmosis had higher intelligence, lower
      guilt proneness, and possibly also higher ergic tension. The difference in
      several other factors (desurgency/surgency, alaxia/protension,
      naivete/shrewdness, and self-sentiment integration) concerned changes in the
      variances, rather than the mean values of the factors.

PMID- 10353192
TI  - Actin and major sperm protein in spermatozoa of a nematode, Graphidium strigosum
      (Strongylida: Trichostrongylidae).
AB  - In most amoeboid cells, the main protein involved in motility is actin. Nematode
      sperm are an exception, and their amoeboid motility is based on major sperm
      protein (MSP). We have studied the localization of actin and MSP in spermatids
      and spermatozoa of Graphidium strigosum (Dujardin, 1845), a species which has
      elongate male germ cells in which organelles are easily identified.
      Electrophoreses of G. strigosum sperm proteins indicate that the main protein
      band, about 15 kDa in molecular weight, is specifically recognized by an anti-MSP
      polyclonal antibody developed against MSP of Caenorhabditis elegans (Burke and
      Ward 1983). Actin is present in small quantities. Immunocytochemical observations
      reveal that actin and MSP have an identical localization in precise areas of the
      male germ cells. Spermatids are labelled as dots around a central unlabelled
      zone, and spermatozoa are labelled only at the level of the anterior cap.
      Observations in G. strigosum are similar to that previously obtained in
      Heligmosomoides polygyrus (Mansir and Justine 1996). Co-localization of actin and
      MSP in the anterior cap of the spermatozoon, the region associated with pseudopod
      production, does not demonstrate directly that actin is involved in amoeboid
      movements, but shows that the role of actin in the cytoskeleton of nematode sperm
      should be re-investigated.

PMID- 10353193
TI  - Heat shock proteins HSP70 and HSP60 in Echinococcus granulosus protoscolices.

PMID- 10353194
TI  - A high quality nuclear magnetic resonance solution structure of peptide
      deformylase from Escherichia coli: application of an automated assignment
      strategy using GARANT.
AB  - The NMR structure of the peptide deformylase (PDF) (1-150) from Escherichia coli,
      which is an essential enzyme that removes the formyl group from nascent
      polypeptides and represents a potential target for drug discovery, was determined
      using 15N/13C doubly labeled protein. Nearly completely automated assignment
      routines were employed to assign three-dimensional triple resonance, 15N-resolved
      and 13C-resolved NOESY spectra using the program GARANT. This assignment
      strategy, demonstrated on a 17 kDa protein, is a significant advance in the
      automation of NMR data assignment and structure determination that will
      accelerate future work. A total of 2302 conformational constraints were collected
      as input for the distance geometry program DYANA. After restrained energy
      minimization with the program X-PLOR the 20 best conformers characterize a high
      quality structure with an average of 0.43 A for the root-mean-square deviation
      calculated from the backbone atoms N, C alpha and C', and 0.81 A for all heavy
      atoms of the individual conformers relative to the mean coordinates for residues
      1 to 150. The globular fold of PDF contains two alpha-helices comprising residues
      25-40, 125-138, six beta-strands 57-60, 70-77, 85-88, 98-101, 105-111, 117-123
      and one 3(10) helix comprising residues 49-51. The C-terminal helix contains the
      HEXXH motif positioning a zinc ligand in a similar fashion to other
      metalloproteases, with the third ligand being cysteine and the fourth presumably
      a water. The three-dimensional structure of PDF affords insight into the
      substrate recognition and specificity for N-formylated over N-acetylated
      substrates and is compared to other PDF structures.

PMID- 10353195
TI  - Solid-state NMR triple-resonance backbone assignments in a protein.
AB  - Triple-resonance solid-state NMR spectroscopy is demonstrated to sequentially
      assign the 13C' and 15N amide backbone resonances of adjacent residues in an
      oriented protein sample. The observed 13C' chemical shift frequency provides an
      orientational constraint complementary to those measured from the 1H and 15N
      amide resonances in double-resonance experiments.

PMID- 10353197
TI  - A novel NMR experiment for the sequential assignment of proline residues and
      proline stretches in 13C/15N-labeled proteins.
AB  - A new pulse sequence is described for the sequential assignment of proline
      residues in 13C/15N-labeled proteins by correlating C delta and C alpha chemical
      shifts of proline residues with the H alpha chemical shift of the preceding
      residue. Notably, the experiment can provide the sequential connectivities in
      poly-proline stretches, which cannot be determined using standard triple
      resonance experiments. Excellent solvent suppression is achieved by coherence
      selection via a heteronuclear gradient echo. The new pulse sequence has been
      successfully applied to the 11 kDa HRDC domain.

PMID- 10353196
TI  - NMR structure of the chimeric hybrid duplex r(gcaguggc).r(gcca)d(CTGC) comprising
      the tRNA-DNA junction formed during initiation of HIV-1 reverse transcription.
AB  - A high-quality NMR solution structure of the chimeric hybrid duplex
      r(gcaguggc).r(gcca)d(CTGC) was determined using the program DYANA with its
      recently implemented new module FOUND, which performs exhaustive conformational
      grid searches for dinucleotides. To ensure conservative data interpretation, the
      use of 1H-1H lower distance limit constraints was avoided. The duplex comprises
      the tRNA-DNA junction formed during the initiation of HIV-1 reverse
      transcription. It forms an A-type double helix that exhibits distinct structural
      deviations from a standard A-conformation. In particular, the minor groove is
      remarkably narrow, and its width decreases from about 7.5 A in the RNA/RNA stem
      to about 4.5 A in the RNA/DNA segment. This is unexpected, since minor groove
      widths for A-RNA and RNA/DNA hybrid duplexes of approximately 11 A and
      approximately 8.5 A, respectively, were previously reported. The present, new
      structure supports that reverse transcriptase-associated RNaseH specificity is
      related primarily to conformational adaptability of the nucleic acid in 'induced
      fit'-type interactions, rather than the minor groove width of a predominantly
      static nucleic acid duplex.

PMID- 10353198
TI  - Improved low pH bicelle system for orienting macromolecules over a wide
      temperature range.
AB  - We have prepared and characterized a novel bicelle system composed of 1,2-di-O
      dodecyl-sn-glycero-3-phosphocholine (DIODPC) and 3
      (chloramidopropyl)dimethylammonio-2-hydroxyl-1-propane sulfonate (CHAPSO). At the
      optimal DIODPC/CHAPSO molar ratio of 4.3:1, this medium becomes magnetically
      oriented from pH 6.5 down to pH 1.0. Unlike previously reported bicelle
      preparations, these bicelles are chemically stable at low pH and are capable of
      inducing protein alignment, as illustrated by the large residual dipolar
      couplings measured for rusticyanin from Thiobacillus ferrooxidans at pH 2.1. The
      DIODPC/CHAPSO system is particularly useful for measuring residual dipolar
      couplings of macromolecules that require very acidic conditions.

PMID- 10353199
TI  - 1H, 15N, and 13C resonance assignments for the N-terminal 20 kDa domain of the
      DNA single-strand break repair protein XRCC1.

PMID- 10353200
TI  - Backbone and side-chain 1H, 15N, and 13C assignments for the topological
      specificity domain of the MinE cell division protein.

PMID- 10353201
TI  - 1H, 15N and 13C assignments of the DNA binding domain of transcription factor
      Mbp1 from S. cerevisiae in both its free and the DNA bound forms, and 1H
      assignments of the free DNA.

PMID- 10353202
TI  - Attachment change processes in the early years of marriage.
AB  - The authors examined 4 models of attachment change: a contextual model, a social
      cognitive model, an individual-difference model, and a diathesis-stress model.
      Models were examined in a sample of newlyweds over the first 2 years of marriage,
      using growth curve analyses. Reciprocal processes, whereby attachment
      representations and interpersonal life circumstances affect one another over
      time, also were studied. On average, newlyweds became more secure over time.
      However, there was significant within-subject variability on attachment change
      that was predicted by intra- and interpersonal factors. Attachment
      representations changed in response to contextual, social-cognitive, and
      individual-difference factors. Reciprocal processes between attachment
      representations and marital variables emerged, suggesting that these factors
      influence one another in an ongoing way.

PMID- 10353203
TI  - Introduction to the special section on the structure of emotion.
AB  - This section is devoted to articles about the structure of affect, the patterned
      interrelations of moods and emotions. Structural features of affect, such as a
      bipolar pleasantness-unpleasantness dimension, a circumplex ordering,
      prototypical discrete emotions, and separable positive and negative emotion
      clusters, are discussed. It is proposed that positive and negative affect systems
      create the conditions for the co-occurrence of discrete positive emotions with
      each other and of discrete negative emotions with each other. The experience of
      affect tends to be felt along a bipolar pleasantness-unpleasantness dimension
      because pleasant emotions and unpleasant emotions tend not to be experienced
      together at intense levels. To move beyond current knowledge, future research in
      the area must more often use non-self-report measures, more sophisticated
      statistical and measurement methods, dynamic as well as static data,
      systematically varied response formats, and experimental manipulations.

PMID- 10353204
TI  - Core affect, prototypical emotional episodes, and other things called emotion:
      dissecting the elephant.
AB  - What is the structure of emotion? Emotion is too broad a class of events to be a
      single scientific category, and no one structure suffices. As an illustration,
      core affect is distinguished from prototypical emotional episode. Core affect
      refers to consciously accessible elemental processes of pleasure and activation,
      has many causes, and is always present. Its structure involves two bipolar
      dimensions. Prototypical emotional episode refers to a complex process that
      unfolds over time, involves causally connected subevents (antecedent; appraisal;
      physiological, affective, and cognitive changes; behavioral response; self
      categorization), has one perceived cause, and is rare. Its structure involves
      categories (anger, fear, shame, jealousy, etc.) vertically organized as a fuzzy
      hierarchy and horizontally organized as part of a circumplex.

PMID- 10353205
TI  - Static, dynamic, and causative bipolarity of affect.
AB  - In what sense are pleasant and unpleasant moods "bipolar"? One must differentiate
      three types of affective bipolarity: static bipolarity (the zero-order
      correlation between measures of pleasant and unpleasant affect, net of
      distortions due to measurement error, tends to be strongly negative), dynamic
      bipolarity (pleasant and unpleasant feelings generally change in opposite
      directions and to approximately the same extent), and causative bipolarity (the
      influence of pleasant and unpleasant affect on other variables is approximately
      equal and opposite). It is argued that static bipolarity is often attenuated by
      measurement error, dynamic bipolarity can be masked by asymmetrical scaling
      artifacts, and causative bipolarity is often obscured by both. The experience and
      influence of pleasant and unpleasant affect may occur along bipolar lines even if
      the sources of these feelings are understood as physiologically separable systems
      with distinct neurological loci.

PMID- 10353206
TI  - Human defenses against Cryptococcus neoformans: an update.
AB  - Cryptococcus neoformans var. neoformans is an opportunistic fungal pathogen,
      especially in AIDS patients, and is found world-wide. On the other hand,
      Cryptococcus neoformans var. gatti (CN-g) is restricted to an association with
      two species of Eucalyptus trees. Alveolar macrophages (AM) constitute the first
      line of defense to Cryptococcus neoformans and offers some resistance. The
      inflammatory response to Cryptococcus neoformans with an influx of neutrophils
      and monocytes affords a second line of defense. Secretion of proinflammatory
      monokines by human AM is now being defined. The inflammatory phagocytes are
      efficient in killing Cryptococcus neoformans and offer strong resistance. T and B
      cell responses to infection, a third line of defense, results in production of
      lymphokines (IFNg, etc.) and specific antibodies. Enhancement of lymphocyte
      responses by IL-12 and IL-18 to Cryptococcus neoformans infection appears to be
      critical. Susceptibility of AIDS patients to Cryptococcus neoformans is
      associated with low CD4+ T cell counts and likely reduced efficacy of the second
      line of defense.

PMID- 10353207
TI  - Detection and expression of corticosteroid binding protein gene in human
      pathogenic fungi.
AB  - Participation of steroid hormones in the growth of several fungal species has
      been widely reported. The aim of the present study was to detect the presence and
      expression of the corticosteroid binding protein (CBP) gene in different
      pathogenic fungal isolates from human clinical specimens. Genomic DNA and total
      RNA were obtained from six different pathogenic fungal species and submitted to
      Southern blot and Reverse Transcription-Polymerase Chain Reaction respectively.
      The results indicated that all the fungi studied presented and expressed CBP
      gene. The sequence of a PCR product of CBP gene fragment corresponding to the
      carboxyl terminal region in Trichophyton mentagrophytes, which presented the
      highest CBP expression, showed an identity of 98% as compared to the previously
      reported gene sequence from Candida albicans. The overall results indicate that
      CBP is a highly conserved gene in fungi and suggest that steroid hormones should
      play an important physiological role in these eukaryotic organisms.

PMID- 10353208
TI  - Recovery of Cryptococcus neoformans from the nasopharynx of AIDS patients.
AB  - Nasopharyngeal swabbings, obtained from AIDS patients, were plated onto Niger
      seed agar containing antibiotics Cryptococcus neoformans was isolated from 35 out
      of 84 patients (41.7%) diagnosed as primary cryptococcal cases before antifungal
      administration, and 8 out of 86 (9.3%) cryptococcosis patients on antifungal
      therapy. The fungus could not be isolated from any of 447 samples from 194 AIDS
      patients not diagnosed with cryptococcosis. These findings are novel in that the
      presence of C. neoformans in AIDS patients at this site has never been looked at
      previously.

PMID- 10353209
TI  - Incidence of keratinophilic fungi in the soil of primary schools and public parks
      of Madras City, India.
AB  - The pattern of incidence of keratinophilic fungi inhabiting the soil of 30
      primary schools and 15 public parks in the city of Madras was studied using hair
      baiting technique. A total number of 31 species belonging to 15 genera were
      recovered, 16 of which were common to both the school and public park soil.
      Dermatophytes and closely related species were represented by 9 species, of which
      the following were the most commonly found species in soil: Chrysosporium
      tropicum (62.2%), C. keratinophilum (48.8%), M. gypseum (48.8%), C. pannorum
      (40%), T. mentagrophytes (37.7%), T. terrestre (31.1%) and C. anam. A. cuniculi
      (24.4%). The fungi encountered have also been discussed in relation to their
      global distribution.

PMID- 10353210
TI  - Exocellular proteases of Malbranchea gypsea and their role in keratin
      deterioration.
AB  - Malbranchea gypsea IMI 338,168 isolated from the soils of Keoladeo National Park,
      Bharatpur was studied for its ability to produce exocellular proteases on glucose
      gelatin medium at pH 7; 28 degrees C. The fungus was observed to be a potent
      producer of such enzymes. Protease production was optimal at 15 days of
      incubation. Asparagine was repressive to protease expression. No relationship
      existed between the amount of enzyme production and increase in biomass.
      Exogenous sugars suppressed enzyme production in descending order as follows:
      glucose > mannose > maltose > arabinose > fructose. The enzymes expressed showed
      the ability to degrade three keratinous substrates tested. Buffalo skin was the
      most actively degraded substrate when exogenous glucose was present, and was also
      the most resistant to degradation in the absence of glucose. The rate of keratin
      deterioration was independent of enzyme activity. Production of protease enzymes
      especially keratinases is ecologically important in a place like a National Park
      because such enzymes degrade keratinous detritus derived from mammals and birds.
      Accumulation of such materials can be a cause of pollution and can provide a
      breeding spot for various types of pathogens.

PMID- 10353211
TI  - A study of the enzymatic profile of soil isolates of Nocardia asteroides.
AB  - In this study, using the API-ZYM system, we have reported the enzyme profile of
      42 soil strains and 2 clinical strains of Nocardia asteroides isolated locally.
      Of the 19 enzymes tested, only 7 were demonstrable in over 90% of the soil
      isolates. These included alkaline phosphatase, esterase lipase, leucine
      arylamidase, acid phosphatase, phosphohydrolase, alpha-glucosidase and beta
      glucosidase. In addition, beta-galactosidase activity was demonstrated in all the
      strains by the O-nitrophenyl-beta-D-galactopyranoside (ONPG) test. The enzymes
      which were not demonstrable in > 95% of the strains included valine arylamidase,
      cystine arylamidase, trypsin, chymotrypsin, alpha-galactosidase, beta
      glucoronidase, N-acetyl-beta-glucosaminidase, alpha-mannosidase and alpha
      fucosidase. With the exception of valine arylamidase, which was lacking in all
      but one isolate, the enzyme profiles of the soil isolates were comparable with
      the clinical isolates of N. asteroides reported in previous studies. The reasons
      for this difference in the two sets of isolates is not clear. The study
      reinforces the view that specific differences in the enzymatic profiles of
      Nocardia species could be used for their rapid identification. However, more
      extensive studies are needed to establish the reproducibility of this method. To
      the best of our knowledge, this is the first study of the enzymatic profile of
      soil isolates of N. asteroides originating from a single geographic region.

PMID- 10353212
TI  - Impact of some ecological factors on the occurrence of poultry soil-inhabiting
      keratinophiles.
AB  - Investigations were conducted to assess the ecological factors governing
      distribution and survival of keratinophilic fungi in poultry farm soils. All the
      poultry farm soils were rich in humus and the keratinophilic fungi were generally
      found to be proportional to the soil organic matter. These soils were nearly
      neutral to weakly alkaline and organically rich with a high content of organic
      carbon, nitrogen, phosphorus, potassium, magnesium, calcium and iron.

PMID- 10353213
TI  - Viability studies on actinomycetes.
AB  - Eighty-nine Actinomycetes strains were tested for their viability, morphological
      and physiological characteristics after being kept under paraffin oil overlay and
      distilled water for a period between 10-30 years. Most of the studied strains
      belong to the "Lorenzo De Montemayor" collection. Almost all the recovered
      strains were 28-30 years old and had never been subcultured since the paraffin
      oil was overlaid. 71.4% of viable Streptomycetes strains had been kept on
      Sabouraud-dextrose agar and 28.6% were kept on Negroni and Bonfiglioli-medium.
      Streptomyces violaceusruber produced its characteristic pigment even after 28
      years under these conditions. All of the recovered strains were tested for their
      biological activity, but only Streptomyces lavendulae showed growth-inhibition
      against Staphylococcus aureus and Bacillus subtilis.

PMID- 10353214
TI  - Comparison between human and armadillo Paracoccidioides brasiliensis isolates by
      random amplified polymorphic DNA analysis.
AB  - Sixty-three Paracoccidioides brasiliensis isolates obtained from three nine
      banded armadillos (Dasypus novemcinctus), one Amazonian armadillo's and 19
      clinical isolates were compared by random amplified polymorphic DNA analysis with
      the primer OPG-19. The isolates were divided into three major clusters, I, II and
      III. Coincidences between human and armadillo isolates were observed in clusters
      I and II. Cluster III consisted only of armadillos' isolates. The results
      suggested that (I) humans may acquire P. brasiliensis infection by contact with
      armadillo's environment, (II) there may be P. brasiliensis genotypes peculiar to
      the animal, and (III) individual armadillos may be infected with P. brasiliensis
      cells with different genotypes.

PMID- 10353215
TI  - Chromoblastomycosis: a retrospective study of 325 cases on Amazonic Region
      (Brazil).
AB  - A retrospective study of 325 cases of chromoblastomycosis diagnosed in the last
      55 years in the Amazon region was carried out by the main Mycology services of
      the state of Para, Brazil (Department of Tropical Pathology--UFPA and Mycology
      Department of the Evandro Chagas Institute/FNS). The data obtained showed that:
      (a) the main age group affected by the diseases range from 41 to 70 years-old,
      (b) 86.1% of the patients were agricultural-workers, (c) 93.2% of them were males
      and (d) 80.7% showed lesions on the lower limbs (feet and legs). The diagnosis of
      62% of the cases was confirmed by laboratory studies considering the tissue form
      in histopathological analysis. In 24% of patients (78 cases), the etiological
      agent was isolated and identified through culture. Fonsecaea pedrosoi was present
      in 77 cases and Phialophora verucosa in only one case.

PMID- 10353216
TI  - Accumulation of a fusion protein containing 2S albumin induces novel vesicles in
      vegetative cells of Arabidopsis.
AB  - We have previously reported that precursor-accumulating (PAC) vesicles found
      exclusively in developing seeds are involved in a transport of seed storage
      proteins, such as 2S albumin, from the endoplasmic reticulum to protein-storage
      vacuoles. Here, we constructed chimeric genes that encode fusion proteins
      consisting of both various lengths of polypeptides derived from pumpkin 2S
      albumin and a selectable marker enzyme, phosphinothricin acetyltransferase. The
      chimeric genes were expressed in transgenic Arabidopsis in order to investigate
      the mechanism of the PAC vesicle formation. A fusion protein expressed by one of
      the chimeric genes is accumulated as a proprotein-precursor form, and localized
      in novel vesicles of vegetative cells. The vesicles show distinct features that
      well much to the PAC vesicles. Despite of the accumulation of the fusion protein,
      the transgenic Arabidopsis is still sensitive to phosphinothricin.
      Phosphinothricin acetyltransferase contained in the fusion protein is obviously
      compartmentalized in the PAC-like vesicles that do not permit the detoxification
      of this herbicide. These results indicate that the PAC-like vesicle can be
      induced in vegetative cells by the ectopic expression of the protein that is
      destined to be compartmentalized into the PAC vesicles.

PMID- 10353217
TI  - Expression of Atropa belladonna putrescine N-methyltransferase gene in root
      pericycle.
AB  - The cDNAs encoding putrescine N-methyltransferase (PMT), which catalyzes the S
      adenosylmethionine-dependent N-methylation of putrescine at the first committed
      step in the biosynthetic pathways of tropane alkaloids, were isolated from Atropa
      belladonna and Hyoscyamus niger. These PMTs, however, lacked the N-terminal
      tandem repeat arrays previously found in Nicotiana PMTs. AbPMT1 RNA was much more
      abundant in the root of A. belladonna than was AbPMT2 RNA. The 5'-flanking region
      of the AbPMT1 gene was fused to the beta-glucuronidase (GUS) reporter gene and
      transferred to A. belladonna. Histochemical analysis showed that GUS is expressed
      specifically in root pericycle cells and that the 0.3-kb 5'-upstream region was
      sufficient for pericycle-specific expression. Treatment of A. belladonna roots
      with methyl jasmonate did not up-regulate the expression of GUS or endogenous
      AbPMT genes. The regulation of tropane alkaloid biosynthesis is discussed and
      compared with that of nicotine biosynthesis.

PMID- 10353218
TI  - A wheat cold-regulated cDNA encoding an early light-inducible protein (ELIP): its
      structure, expression and chromosomal location.
AB  - Sequencing and computer analysis revealed that a wcr (wheat cold-regulated) cDNA,
      wcr12, contained a 525 bp open reading frame encoding a polypeptide of 174 amino
      acids. The deduced WCR12 protein had a high sequence similarity with Early light
      inducible proteins (ELIPs) which are known as nuclear-encoded chloroplast
      proteins induced by light stress. The accumulation of wcr12 transcripts was
      induced by low temperature below 8 degrees C and was also increased under a high
      light flux of 1,000 microEm-2 s-1, which are typical expression patterns of the
      genes for ELIPs in other plants. The dramatic increase in the level of wcr12
      transcripts was detected at 4 degrees C even under a low light condition (50
      microEm-2 s-1) and the level of transcripts became 20-fold higher than the
      control at 20 degrees C under a moderate light condition (250 microEm-2 s-1).
      Surprisingly, the accumulation of wcr12 mRNAs was also induced by cold treatment
      alone at 4 degrees C in the darkness. The level of wcr12 transcripts accumulated
      in the darkness at 4 degrees C reached the same level as that under a high light
      flux at 20 degrees C. These results indicate that light is not essential for the
      accumulation of wcr12 transcripts at a low temperature. To determine the
      chromosomal location of wcr12 gene, we performed Southern analysis using the
      nullitetrasomic lines. The data showed that the wcr12 gene or related homologues
      are located on the chromosomes of homoeologous group-5 in wheat.

PMID- 10353219
TI  - Isolation and characterization of two cDNA clones encoding for glutamate
      dehydrogenase in Nicotiana plumbaginifolia.
AB  - We have isolated two full length cDNA clones encoding Nicotiana plumbaginifolia
      NADH-glutamate dehydrogenase. Both clones share amino acid boxes of homology
      corresponding to conserved GDH catalytic domains and putative mitochondrial
      targeting sequence. One clone shows a putative EF-hand loop. The level of the two
      transcripts is affected differently by carbon source.

PMID- 10353220
TI  - A novel MYB-related gene from Arabidopsis thaliana expressed in developing
      anthers.
AB  - A novel MYB-like gene (AtMYB103) was isolated from a genomic library of
      Arabidopsis. Plants transgenic for chimeric AtMYB103 promoter/GUS genes expressed
      the enzyme in early anthers. In situ hybridization of flower sections showed a
      high level of AtMYB103 mRNA in the tapetum and middle layer of developing
      anthers.

PMID- 10353221
TI  - Localization of farnesyl diphosphate synthase in chloroplasts.
AB  - The subcellular localization of plant farnesyl diphosphate synthase (FPPS) was
      examined. Immunocytochemical staining using anti-FPPS1 antibody followed by
      electron microscopy showed that FPPS1 was localized to chloroplasts of rice
      mesophyll cells. Subcellular fractions from wheat leaves were examined by
      immunoblot analysis. FPPS was detected in the chloroplast fraction in wheat, and
      was protected from proteolysis following trypsin treatment of chloroplasts. FPPS
      was also detected in the chloroplast fraction of a dicot plant, tobacco.

PMID- 10353222
TI  - The use of preparative high performance liquid chromatography with tandem mass
      spectrometric directed fraction collection for the isolation and characterisation
      of drug metabolites in urine by nuclear magnetic resonance spectroscopy and
      liquid chromatography/sequential mass spectrometry.
AB  - Preparative high performance liquid chromatography (HPLC) coupled to tandem mass
      spectrometry has been used successfully for the isolation of several drug
      metabolites from urine. Nuclear magnetic resonance (NMR) spectroscopy has been
      employed to determine the exact chemical structure of these metabolites. The use
      of preparative HPLC has allowed the isolation of relatively large quantities of
      drug metabolites (> 0.5 mg) allowing insensitive, information-rich NMR
      experiments such as NOE, HMBC and HMQC to be performed. The coupling of the ion
      trap mass spectrometer, operating in automatic MS/MS mode, to preparative HPLC
      allows the simultaneous collection and mass spectrometric analysis of eluting
      analytes to be performed, thus allowing the position of fractions containing drug
      related material to be identified very rapidly.

PMID- 10353223
TI  - The application of fast gradient capillary liquid chromatography/mass
      spectrometry to the analysis of pharmaceuticals in biofluids.
AB  - Fast gradient capillary high performance liquid chromatography (HPLC) coupled to
      a mass spectrometer has been successfully used for the analysis of pharmaceutical
      compounds from biological matrices, in the femtogram on column range. In the work
      reported in this paper, the use of capillary HPLC, on the 180-micron internal
      diameter scale, has shown a 30-fold improvement in detection limits when compared
      to conventional 2-mm scale chromatography. The use of fast gradient elution
      resulted in a generic methodology which gave excellent chromatographic
      reproducibility and column longevity. This technique has been used in conjunction
      with simple protein precipitation, with no deleterious effect on either the
      column life or the chromatographic performance. The use of capillary HPLC in
      bioanalysis has the potential to give a significant increase in assay sensitivity
      with the equipment currently in use. In this paper the authors also present a
      modification to the current PE-Sciex ion-spray source which allows excellent
      spray adjustment in three dimensional accessibility, which is important when
      working with low flow rates, as well as reducing the inherent system dead volume.

PMID- 10353224
TI  - Tandem mass spectrometry linked fraction collection for the isolation of drug
      metabolites from biological matrices.
AB  - An automated mass spectrometric linked fraction collection system is described
      which enables on-line examination of isolated components based on molecular-ion
      and product-ion information. This system has been used successfully to
      specifically isolate drug-related material from complex biological fluids to aid
      structural identification. Metabolites have been isolated with sufficient purity
      to allow unequivocal characterisation by 1H nuclear magnetic resonance
      spectroscopy. This system has the advantage that isolation of the components of
      interest is not triggered by a simple contact closure. Therefore fraction
      collection is not biased by limitations in either the detector (e.g. insufficient
      sensitivity) or the analyst (e.g. programmed collection of predicted metabolites
      only). Furthermore, all isolated components are readily available post
      fractionation for additional screening.

PMID- 10353225
TI  - Development of an automated mass spectrometry system for the quantitative
      analysis of liver microsomal incubation samples: a tool for rapid screening of
      new compounds for metabolic stability.
AB  - There is a continuing need for increased throughput in the evaluation of new drug
      entities in terms of their pharmacokinetic parameters. One useful parameter that
      can be measured in vitro using liver microsomal preparations is metabolic
      stability. In this report, we describe an automated system that can be used for
      unattended quantitative analysis of liver microsomal samples for a series of
      compounds. This system is based on the Sciex API 150 (single quadrupole) liquid
      chromatography/mass spectrometry system and utilizes 96-well plate autosampler
      technology as well as a custom-designed AppleScript which executes the on-line
      data processing and report generation. It has the capability of analyzing at
      least 75 compounds per week or 300 compounds per month in an automated fashion.

PMID- 10353226
TI  - Liquid chromatography/electrospray ionization mass spectrometric characterization
      of flavonol glycosides in tomato extracts and human plasma.
AB  - Flavonoids continue to attract wide attention as possible very useful agents for
      combating free radical pathologies, i.e. the pathological states associated with
      free radical overproduction. Commonly used methods for the analysis of plant
      flavonoids include high performance liquid chromatography (HPLC) and capillary
      electrophoresis (CE). On the other hand, the soft-ionization approach based on
      electrospray ionization (ESI-MS) permits highly selective analysis of complex
      matrices. In this work, we examined firstly the ESI-MS behaviour of
      representative aglycones and glycosides of flavonols, flavones and isoflavones
      with the aim of suggesting a possible relationship between structure and mass
      spectra. Using HPLC coupled to a diode array detector (DAD) for on-line UV
      spectra acquisition, and in parallel to ESI-MS for mass spectra (LC/DAD-ESI-MS),
      we have developed methodology to observe flavonols directly in tomato puree
      extract. In this way, it has been possible to detect intact flavonol glycosides
      in tomato extracts and to characterize a flavonol trisaccharide. For the first
      time, using LC/ESI-MS, it has been possible to detect intact flavonol glycosides
      in plasma of healthy volunteers and to provide further evidence on the absorption
      of flavonoid glycosides after consumption of common vegetables like tomatoes.

PMID- 10353228
TI  - A suitable case for treatment.

PMID- 10353227
TI  - Accurate characterization of the tyrosine hydroxylase forensic allele 9.3 through
      development of electrospray ionization Fourier transform ion cyclotron resonance
      mass spectrometry.
AB  - Accurate and precise determination of the number of repeats from a short tandem
      repeat (STR) sequence for a human gene locus is demonstrated for the first time
      by electrospray ionization Fourier transform ion cyclotron resonance mass
      spectrometry (ESI-FTICR-MS). Specifically, the polymorphic human tyrosine
      hydroxylase (HUMTHO1) gene, a tetranucleotide STR forensic allele, was chosen as
      a model system to evaluate our approach for future characterization of both STRs
      and variable number of tandem repeats (VNTRs) by development of an ESI-FTICR-MS
      approach. The coding and noncoding strands from the HUMTHO1 9.3 allele are
      simultaneously resolved obtaining accurate (better than 70 ppm) average mass
      measurements of 25,783.23 and 24,754.55 Da for the coding and noncoding strands,
      respectively. The mass measurements are used to calculate the number of repeats
      for each strand, 'n', of 9.75169 and 9.75001 for the coding and noncoding
      strands, respectively. It will be shown how the value of 'n' can be used to
      directly determine the number of pure repeats and accurately determine the exact
      nature of the polymorphism within the repeat (if any). The single nucleotide
      deletion in the coding strand (adenine) and noncoding strand (thymine) were
      accurately identified using this approach. Interestingly, we observed the
      conversion of single-stranded to double-stranded DNA while the PCR product in the
      ESI buffer was being infused; the issues related to this observation will be
      presented. Previous results by other researchers investigating the HUMTHO1 9.3
      allele using matrix-assisted laser desorption/ionization time-of-flight (MALDI
      TOF) are directly compared with our results. Our results indicate that ESI-FTICR
      MS is a powerful approach to rapidly and accurately characterize tandem repeating
      sequences which will ultimately lead towards the understanding of a complex class
      of diseases and in human identity determination.

PMID- 10353229
TI  - French geneticists raise worries over use of new genome funds.

PMID- 10353230
TI  - UK debates public's role in science advice.

PMID- 10353231
TI  - Royal Society: GM food hazard claim is 'flawed'.

PMID- 10353232
TI  - NIH ethics office clamps down on Duke...as basic scientists feel the pinch in LA.

PMID- 10353233
TI  - US plan for consortium to seek AIDS vaccine.

PMID- 10353234
TI  - Cancer fellowships awarded on merit.

PMID- 10353235
TI  - Cancer fellowships awarded on merit.

PMID- 10353236
TI  - A shared but complex bridge.

PMID- 10353237
TI  - Cancer. Many vessels, faulty gene.

PMID- 10353238
TI  - Apoptosis. Dead end for neurodegeneration?

PMID- 10353239
TI  - Cell biology. Snail mail to the nucleus.

PMID- 10353240
TI  - Neurobiology. Rain Man's revelations.

PMID- 10353241
TI  - Transgenic pollen harms monarch larvae.

PMID- 10353242
TI  - The mystery of female beauty.

PMID- 10353243
TI  - The mystery of female beauty.

PMID- 10353244
TI  - Structure of importin-beta bound to the IBB domain of importin-alpha.
AB  - Cytosolic proteins bearing a classical nuclear localization signal enter the
      nucleus bound to a heterodimer of importin-alpha and importin-beta (also called
      karyopherin-alpha and -beta). The formation of this heterodimer involves the
      importin-beta-binding (IBB) domain of importin-alpha, a highly basic amino
      terminal region of roughly 40 amino-acid residues. Here we report the crystal
      structure of human importin-beta bound to the IBB domain of importin-alpha,
      determined at 2.5 A and 2.3 A resolution in two crystal forms. Importin-beta
      consists of 19 tandemly repeated HEAT motifs and wraps intimately around the IBB
      domain. The association involves two separate regions of importin-beta,
      recognizing structurally distinct parts of the IBB domain: an amino-terminal
      extended moiety and a carboxy-terminal helix. The structure indicates that
      significant conformational changes occur when importin-beta binds or releases the
      IBB domain domain and suggests how dissociation of the importin-alpha/beta
      heterodimer may be achieved upon nuclear entry.

PMID- 10353246
TI  - Desorption-ionization mass spectrometry on porous silicon.
AB  - Desorption mass spectrometry has undergone significant improvements since the
      original experiments were performed more than 90 years ago. The most dramatic
      change occurred in the early 1980s with the introduction of an organic matrix to
      transfer energy to the analyte. This reduces ion fragmentation but also
      introduces background ions from the matrix. Here we describe a matrix-free
      strategy for biomolecular mass spectrometry based on pulsed-laser desorption
      ionization from a porous silicon surface. Our method uses porous silicon to trap
      analytes deposited on the surface, and laser irradiation to vaporize and ionize
      them. We show that the method works at femtomole and attomole levels of analyte,
      and induces little or no fragmentation, in contrast to what is typically observed
      with other such approaches. The ability to perform these measurements without a
      matrix also makes it more amenable to small-molecule analysis. Chemical and
      structural modification of the porous silicon has enabled optimization of the
      ionization characteristics of the surface. Our technique offers good sensitivity
      as well as compatibility with silicon-based microfluidics and microchip
      technologies.

PMID- 10353245
TI  - Structure of the nuclear transport complex karyopherin-beta2-Ran x GppNHp.
AB  - Transport factors in the karyopherin-beta (also called importin-beta) family
      mediate the movement of macromolecules in nuclear-cytoplasmic transport pathways.
      Karyopherin-beta2 (transportin) binds a cognate import substrate and targets it
      to the nuclear pore complex. In the nucleus, Ran x GTP binds karyopherin-beta2
      and dissociates the substrate. Here we present the 3.0 A structure of the
      karyopherin-beta2-Ran x GppNHp complex where GppNHp is a non-hydrolysable GTP
      analogue. Karyopherin-beta2 contains eighteen HEAT repeats arranged into two
      continuous orthogonal arches. Ran is clamped in the amino-terminal arch and
      substrate-binding activity is mapped to the carboxy-terminal arch. A large loop
      in HEAT repeat 7 spans both arches. Interactions of the loop with Ran and the C
      terminal arch implicate it in GTPase-mediated dissociation of the import
      substrate. Ran x GppNHp in the complex shows extensive structural rearrangement,
      compared to Ran GDP, in regions contacting karyopherin-beta2. This provides a
      structural basis for the specificity of the karyopherin-beta family for the GTP
      bound state of Ran, as well as a rationale for interactions of the karyopherin
      Ran complex with the regulatory proteins ranGAP, ranGEF and ranBP1.

PMID- 10353247
TI  - A complete human pelvis from the Middle Pleistocene of Spain.
AB  - The Middle Pleistocene site of Sima de los Huesos in Sierra de Atapuerca, Spain,
      has yielded around 2,500 fossils from at least 33 different hominid individuals.
      These have been dated at more than 200,000 years ago and have been classified as
      ancestors of Neanderthals. An almost complete human male pelvis (labelled Pelvis
      1) has been found, which we associate with two fragmentary femora. Pelvis 1 is
      robust and very broad with a very long superior pubic ramus, marked iliac flare,
      and a long femoral neck. This pattern is probably the primitive condition from
      which modern humans departed. A modern human newborn would pass through the birth
      canal of Pelvis 1 and this would be even larger in a female individual. We
      estimate the body mass of this individual at 95 kg or more. Using the cranial
      capacities of three specimens from Sima de los Huesos, the encephalization
      quotients are substantially smaller than in Neanderthals and modern humans.

PMID- 10353248
TI  - Non-commutativity in the brain.
AB  - In non-commutative algebra, order makes a difference to multiplication, so that a
      x b not equal to b x a. This feature is necessary for computing rotary motion,
      because order makes a difference to the combined effect of two rotations. It has
      therefore been proposed that there are non-commutative operators in the brain
      circuits that deal with rotations, including motor circuits that steer the eyes,
      head and limbs, and sensory circuits that handle spatial information. This idea
      is controversial: studies of eye and head control have revealed behaviours that
      are consistent with non-commutativity in the brain, but none that clearly rules
      out all commutative models. Here we demonstrate non-commutative computation in
      the vestibulo-ocular reflex. We show that subjects rotated in darkness can hold
      their gaze points stable in space, correctly computing different final eye
      position commands when put through the same two rotations in different orders, in
      a way that is unattainable by any commutative system.

PMID- 10353249
TI  - Inhibition of caspase-1 slows disease progression in a mouse model of
      Huntington's disease.
AB  - Huntington's disease is an autosomal-dominant progressive neurodegenerative
      disorder resulting in specific neuronal loss and dysfunction in the striatum and
      cortex. The disease is universally fatal, with a mean survival following onset of
      15-20 years and, at present, there is no effective treatment. The mutation in
      patients with Huntington's disease is an expanded CAG/polyglutamine repeat in
      huntingtin, a protein of unknown function with a relative molecular mass of
      350,000 (M(r) 350K). The length of the CAG/polyglutamine repeat is inversely
      correlated with the age of disease onset. The molecular pathways mediating the
      neuropathology of Huntington's disease are poorly understood. Transgenic mice
      expressing exon 1 of the human huntingtin gene with an expanded CAG/polyglutamine
      repeat develop a progressive syndrome with many of the characteristics of human
      Huntington's disease. Here we demonstrate evidence of caspase-1 activation in the
      brains of mice and humans with the disease. In this transgenic mouse model of
      Huntington's disease, expression of a dominant-negative caspase-1 mutant extends
      survival and delays the appearance of neuronal inclusions, neurotransmitter
      receptor alterations and onset of symptoms, indicating that caspase-1 is
      important in the pathogenesis of the disease. In addition, we demonstrate that
      intracerebroventricular administration of a caspase inhibitor delays disease
      progression and mortality in the mouse model of Huntington's disease.

PMID- 10353250
TI  - In vivo cell sorting in complementary segmental domains mediated by Eph receptors
      and ephrins.
AB  - The restriction of intermingling between specific cell populations is crucial for
      the maintenance of organized patterns during development. A striking example is
      the restriction of cell mixing between segments in the insect epidermis and the
      vertebrate hindbrain that may enable each segment to maintain a distinct
      identity. In the hindbrain, this is a result of different adhesive properties of
      odd- and even-numbered segments (rhombomeres), but an adhesion molecule with
      alternating segmental expression has not been found. However, blocking
      experiments suggest that Eph-receptor tyrosine kinases may be required for the
      segmental restriction of cells. Eph receptors and their membrane-bound ligands,
      ephrins, are expressed in complementary rhombomeres and, by analogy with their
      roles in axon pathfinding, could mediate cell repulsion at boundaries.
      Remarkably, transmembrane ephrins can themselves transduce signals, raising the
      possibility that bi-directional signalling occurs between adjacent ephrin- and
      Eph-receptor-expressing cells. We report here that mosaic activation of Eph
      receptors leads to sorting of cells to boundaries in odd-numbered rhombomeres,
      whereas mosaic activation of ephrins results in sorting to boundaries in even
      numbered rhombomeres. These data implicate Eph receptors and ephrins in the
      segmental restriction of cell intermingling.

PMID- 10353251
TI  - The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen
      dependent proteolysis.
AB  - Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to
      hypoxia, including the regulation of genes involved in energy metabolism,
      angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the
      proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions
      or iron chelators mimic hypoxia, indicating that the stimuli may interact through
      effects on a ferroprotein oxygen sensor. Here we demonstrate a critical role for
      the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1
      regulation. In VHL-defective cells, HIF alpha-subunits are constitutively
      stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen
      dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL
      is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron
      chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings
      indicate that the interaction between HIF-1 and pVHL is iron dependent, and that
      it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus,
      constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL
      associated tumours. The pVHL/HIF-1 interaction provides a new focus for
      understanding cellular oxygen sensing.

PMID- 10353253
TI  - Histamine, polyamines, and cancer.
AB  - Mammalian ornithine decarboxylase and histidine decarboxylase present common
      structural and functional features, and their products also share pharmacological
      and physiological properties. Although accumulated evidence pointed for years to
      a direct involvement of polyamines and histamine in tumour growth, it has been
      only in the last few years that new molecular data have contributed to the
      clarification of this topic. The aim of this commentary is to review the
      molecular grounds of the role of histamine and polyamines in cancer and to point
      to possible directions for future research in emerging areas of interest.

PMID- 10353252
TI  - Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein.
AB  - Adenovirus E1A proteins prepare the host cell for viral replication, stimulating
      cell cycling and viral transcription through interactions with critical cellular
      regulatory proteins such as RB and CBP. Here we show that the E1A zinc-finger
      domain that is required to activate transcription of viral early genes binds to a
      host-cell multiprotein complex containing homologues of yeast Srb/Mediator
      proteins. This occurs through a stable interaction with the human homologue of
      Caenorhabditis elegans SUR-2, a protein required for many developmental processes
      in the nematode. This human Srb/Mediator complex stimulates transcription in
      vitro in response to both the E1A zinc-finger and the herpes simplex virus VP16
      activation domains. Interaction with human Sur-2 is also required for
      transcription to be activated by the activation domain of a transcription factor
      of the ETS-family in response to activated mitogen-activated protein (MAP)
      kinase.

PMID- 10353254
TI  - Therapy by taking away: the case of iron.
AB  - The recent finding of the beneficial effects of iron deprivation in the outcome
      of muscle necrosis in an animal model of genetic myopathy served as the basis of
      this commentary. Here, "taking away" iron by controlled dietary deprivation is
      proposed as a reasonable, feasible, cheap, and efficient clinical approach to
      many diverse diseases, all of which have a free radical component. Indeed, iron
      potentiates the generation of the highly reactive and toxic hydroxyl radical,
      and, thus, of oxidative damage. Iron deprivation may represent the first really
      efficient antioxidant, preventing oxidative stress in all subcellular
      compartments, tissues, and organs. Iron/iron deprivation also modulates
      programmed cell death (apoptosis), which should be the subject of further studies
      to better define the mechanisms mediating these complex effects. Finally, related
      to its antioxidant effects, iron deprivation may find applications in the anti
      aging field, whether programmed or premature aging, and whether in cosmetics or
      in gerontology.

PMID- 10353255
TI  - Sensitivity of L-(-)2,3-dideoxythiacytidine resistant hepatitis B virus to other
      antiviral nucleoside analogues.
AB  - L-(-)2',3'-Dideoxythiacytidine (L(-)SddC, Lamivudine) resistant hepatitis B virus
      (HBV) develops in patients after prolonged treatment. Point mutations detected in
      the viral genome from these patients have been shown to be responsible for L(
      )SddC resistance. Therefore, new drugs active against L(-)SddC resistant HBV are
      needed. Using a transient transfection system, we studied the sensitivity of L(
      )SddC resistant HBV to other anti-HBV nucleoside analogues. It was found that the
      L526M mutation alone caused greater resistance to penciclovir (PCV) than did the
      V553I mutation alone. Both mutations also caused the virus to be less sensitive
      to L(-)SddC and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU),
      although the degree of resistance was much less than that to PCV. The A546V
      mutation had no impact on the sensitivity to L(-)SddC, L-FMAU, and PCV. When
      these single mutations were coupled with the M550V/I mutation, all the double
      mutants were resistant to those drugs. Although 2',3'-dideoxy-2',3'-didehydro
      beta-L(-)-5-fluorocytidine (L(-)Fd4C) was also less active, the IC50 of L(-)Fd4C
      against the L(-)SddC resistant mutant was at least fifty times lower than that
      against cell growth in culture. DNA polymerase associated with L(-)SddC resistant
      virions was also found to be less sensitive than that with wild-type HBV to those
      L-nucleoside triphosphates. All the L(-)SddC resistant mutants were still
      sensitive to 9-(2-phosphonylmethoxyethyl)-adenine (PMEA). These results suggest
      that different mutations in the HBV genome have a different impact on its
      sensitivity to those compounds, and L(-)SddC resistant HBV may also be resistant
      to PCV, L-FMAU, and L(-)Fd4C. A nucleoside analogue less toxic than PMEA could be
      developed against L(-)SddC resistant HBV.

PMID- 10353256
TI  - Involvement of hydrogen peroxide and hydroxyl radical in chemically induced
      apoptosis of HL-60 cells.
AB  - Effects of three kinds of antagonists against reactive oxygen species were
      evaluated at the same time in chemically induced apoptosis of human leukemic HL
      60 cells. Apoptosis of HL-60 cells induced by actinomycin D, H7, 1-beta-D
      arabinofuranosylcytosine, and daunorubicin was inhibited significantly by radical
      scavengers (vitamin E, N-acetyl-L-cysteine, and mercaptoethanol), catalase, and a
      spin trap, N-t-butyl-alpha-phenylnitrone. These results suggest that hydrogen
      peroxide and hydroxyl radical are common mediators of apoptosis caused by these
      chemicals with apparently different functional mechanisms. The consumption of
      vitamin E to inhibit apoptosis induced by actinomycin D was undetectable,
      suggesting that the generation of reactive oxygen species during apoptosis was
      not very extensive. Radicals were suggested to be a mediator of apoptosis of HL
      60 cells induced by cisplatin based on the observations that the above
      inhibitors, except catalase, effectively inhibited apoptosis by the drug.

PMID- 10353257
TI  - Role of tyrosine kinase activity in 2,2',2''-tripyridine-induced nitricoxide
      generation in macrophages.
AB  - In this paper, we demonstrated that 2,2',2"-tripyridine (TP, 1-20 microM) is a
      potent inducer of nitric oxide (NO) synthase in the cultured murine macrophage
      RAW 264.7 cell line. TP increased not only nitrite but also inducible NO synthase
      (iNOS) protein and mRNA production. Co-treatment with either NOS inhibitors (N(G)
      monomethyl-L-arginine and aminoguanidine) or cycloheximide and actinomycin D all
      inhibited TP-induced nitrite production, indicating the requirement of protein
      and mRNA synthesis. The signaling pathway of TP-induced iNOS expression was
      explored, and the results obtained suggested that increased tyrosine kinase
      activity followed by inhibitor of nuclear factor for immunoglobulin kappa chain
      in B cells (IkappaB) degradation and then nuclear factor kappaB (NFkappaB)
      activation was involved in TP-induced iNOS expression. Tyrosine kinase inhibitors
      (e.g. genistein and tyrphostin AG126) inhibited both TP-induced nitrite and iNOS
      protein production. Whether the metalochelating property of TP was involved in
      these effects was explored by saturating TP with FeCl3. Although the ferrated TP
      became inactive, the specific iron chelator desferrioxamine, at a very high
      concentration of 400 microM, induced only a weak enhancement of nitrite
      production in this RAW cell line. It was thereby concluded that TP induces NO
      production through an increase in iNOS expression, which is initiated by a
      signaling pathway via tyrosine kinases leading to an activation of NFkappaB.
      Since TP is much more potent than desferrioxamine in increasing nitrite
      production, it is suspected that the primary event induced by TP was possibly
      mediated by TP's interacting with certain macromolecules in addition to its metal
      chelating property.

PMID- 10353258
TI  - Development of a recombinant cell-based system for the characterisation of
      phosphodiesterase 4 isoforms and evaluation of inhibitors.
AB  - We described the development of a recombinant cell-based system for the
      characterisation of phosphodiesterase (PDE) 4 isoforms and the evaluation of
      inhibitors. The Chinese hamster ovary (CHO) cell, which was found to have a low
      endogenous PDE4 background and no beta-adrenergic receptors (beta-AR), was
      transiently transfected with beta-AR and various PDE4 isoforms which were
      expressed as functionally coupled molecules. From correlations of elevation of
      adenosine 3',5'-cyclic monophosphate in situ and the inhibition of catalytic
      activity in vitro with the various PDE4 isoforms, it was apparent that PDE4A4,
      4B2, 4C2, 4D2, and 4D3 all adopted a high-affinity binding conformation (i.e.
      expressed the high-affinity rolipram binding site) in the CHO cell, whereas
      PDE4A330 was expressed in a low-affinity conformation in situ. This gives the
      opportunity of using this system to screen and optimise inhibitors against a low
      affinity conformation of PDE4 in situ and use a high-affinity conformation of
      PDE4 as a counterscreen, as inhibitor activity against this conformer has been
      linked with undesirable side effects. This system could also be utilised to
      screen inhibitors against various PDE4 isoforms in isolation against a low
      endogenous PDE background in situ for isoform-selective inhibitors.

PMID- 10353259
TI  - Interactions of prostaglandin A2 with the glutathione-mediated biotransformation
      system.
AB  - The cyclopentenone prostaglandin A2 (PGA2) is known to inhibit cell
      proliferation, and metabolism of this compound thus might be important in
      controlling its ultimate function. The glutathione-related metabolism of PGA2 was
      therefore investigated both with purified glutathione S-transferase P1-1 (GSTP1
      1) and with IGR-39 human melanoma cells. Firstly, the irreversible inhibition of
      human GSTP1-1 and its mutants C47S, C101S, and C47S/C101S was studied. PGA2
      appeared to inhibit GSTP1-1 mainly by binding to the cysteine 47 moiety of the
      enzyme. This binding was reversed by a molar excess of GSH, indicating that retro
      Michael cleavage occurs. Secondly, after exposing IGR-39 human melanoma cells to
      PGA2, both diastereoisomers of the PGA2-glutathione conjugate are excreted into
      the medium, although with a clear excess of the S-form, due to its preferential
      formation by the GSTP1-1 present in the cells. Thirdly, the effect of PGA2 on
      intracellular GST activity was determined by quantification of the excreted
      glutathione conjugate S-(2,4-dinitrophenyl)glutathione (DNPSG) after exposure to
      1-chloro-2,4-dinitrobenzene. DNPSG excretion was inhibited after incubation with
      10 or 20 microM PGA2 for 1 or 4 hr, as a result of glutathione depletion,
      reversible GST inhibition, and covalent modification of intracellular GST.
      Furthermore, PGA2 also inhibited transport of DNPSG by the multidrug resistance
      associated protein, an effect that was reversible and competitive. In conclusion,
      PGA2 modulates all three aspects of the glutathione-mediated biotransformation
      system, i.e. GSH levels, GSTP1-1 activity, and transport of GSH conjugates. A
      role for GSTP1-1 as a specific transport protein inside the cell is indicated.

PMID- 10353260
TI  - Synergistic effects of neurotensin and beta-adrenergic agonist on 3,5-cyclic
      adenosine monophosphate accumulation and DNA synthesis in prostate cancer PC3
      cells.
AB  - Since neurotensin is often co-stored with catecholamines and since it can excite
      the release of dopamine and norepinephrine, responses to this peptide might
      depend upon the activity of catecholaminergic systems. In this study, we used
      prostate cancer PC3 cells, which express neurotensin receptors and 12-adrenergic
      receptors, to demonstrate that neurotensin can potentiate the effects of
      isoproterenol on 3',5'-cyclic adenosine monophosphate (cAMP) formation and on
      inhibition of DNA synthesis. While neurotensin had only a slight effect on basal
      cAMP levels, it nearly doubled the response to isoproterenol even at maximal
      levels without altering potency. Neurotensin increased the rate of cAMP
      accumulation and the steady-state level achieved. Consistent with the known
      antimitogenic action of dibutyryl-cAMP in PC3 cells, isoproterenol was found to
      inhibit DNA synthesis concentration-dependently, measured using [3H]thymidine.
      Neurotensin enhanced DNA synthesis when given alone. However, it inhibited DNA
      synthesis when given with a threshold level of isoproterenol, which by itself had
      no significant effect. These results, demonstrating cross-talk in the neurotensin
      and beta-adrenergic signaling pathways, suggest that there may be other
      physiologic instances of similar interactions between neurotensin and
      catecholamines.

PMID- 10353261
TI  - Effects of the binding of a dextran derivative on fibroblast growth factor 2:
      secondary structure and receptor-binding studies.
AB  - CMDB (carboxymethyldextran-benzylamide) are dextrans statistically substituted
      with carboxymethyl and benzylamide groups which can mimick some of the biological
      properties of heparin. It has previously been shown that CMDB inhibit autocrine
      growth of breast tumor cells (Bagheri-Yarmand et al., Biochem. Biophys. Res.
      Commun. 239: 424-428, 1997) and selectively displace fibroblast growth factor 2
      (FGF-2) from its receptor. Here, we used circular dichroism and fluorescence
      anisotropy measurements to show that the conformation of FGF-2 was significantly
      altered upon its binding to CMDB and to short CMDB fragments prepared within this
      study. CMDB and fragments formed a stable 1:1 complex with FGF-2, with affinities
      being estimated as 20+/-10 nM from fluorescence anisotropy analysis. No such a
      complex was formed with insulin-like growth factor (IGF-1) or epidermal growth
      factor (EGF). CMDB competed with the FGF-2 receptor for binding to FGF-2 but did
      not disturb the binding of IGF-1 and EGF to their receptors. Thus, our results
      highlight the selectivity of CMDB and their fragments towards FGF-2. Heparin,
      however, competes with CMDB and their fragments for binding to FGF-2. The
      carboxymethyl and benzylamide groups of these molecules likely interact directly
      with a heparin-binding region of FGF-2. The resulting change in conformation
      disturbs the binding of FGF-2 to its receptor and consecutively its mitogenic
      activity.

PMID- 10353262
TI  - Expression of CYP2A genes in human liver and extrahepatic tissues.
AB  - Members of the human cytochrome P450 2A (CYP2A) subfamily are known to metabolize
      several promutagens, procarcinogens, and pharmaceuticals. In this study, the
      expression of the three genes found in the human CYP2A gene cluster was
      investigated in the liver and several extrahepatic tissues by gene-specific
      reverse transcriptase-polymerase chain reaction (RT-PCR). All three transcripts
      (CYP2A6, CYP2A7, and CYP2A13) were found to be present in liver. Quantitative RT
      PCR analysis showed that CYP2A6 and CYP2A7 mRNAs were present at roughly equal
      levels in the liver, while CYP2A13 was expressed at very low levels. Two putative
      splicing variants of CYP2A7 were found in the liver. Nasal mucosa contained a low
      level of CYP2A6 and a relatively high level of CYP2A13 transcripts. Kidney,
      duodenum, lung, alveolar macrophages, peripheral lymphocytes, placenta, and
      uterine endometrium were negative for all transcripts. This survey gives a
      comprehensive picture of the expression pattern of CYP2A genes in liver and
      extrahepatic tissues and constitutes a basis for a search for functional CYP2A
      forms and their roles in chemical toxicity in liver and nasal mucosa.

PMID- 10353263
TI  - Enhancement of excision repair of cisplatin-DNA adducts by cell-free extract from
      a cisplatin-resistant rat cell line.
AB  - To characterize the enhanced repair synthesis of defined DNA lesions,
      oligodeoxyribonucleotides were synthesized and inserted into plasmid DNA. The
      inserted plasmid DNA was treated with cis-diamminedichloroplatinum(II)
      (cisplatin) and subjected to in vitro DNA repair assay with soluble extract from
      the rat liver cell line Ac2F. All cisplatin adducts tested stimulated DNA repair
      synthesis. Moreover, two cisplatin-resistant cell lines, Ac2F-CR4 and Ac2F-CR10,
      were established by stepwise exposure of Ac2F cells to this drug. The DNA repair
      synthesis was enhanced 3- to 4-fold in the extract from cisplatin-resistant Ac2F
      cells relative to that from Ac2F cells. Such repair synthesis was suppressed by
      the specific DNA polymerase inhibitor aphidicolin. The results of the present
      study suggested that the enhanced repair activity induced by a cisplatin adduct
      can be detected by in vitro DNA repair assay with soluble cell extract.

PMID- 10353264
TI  - Up-regulation of interleukin-1beta-stimulated interleukin-8 in human
      keratinocytes by nitric oxide.
AB  - Nitric oxide (NO) is able to regulate the expression of a number of inflammatory
      mediators. In this study, the effect of NO on the expression of the chemokine
      interleukin-8 (IL-8) by primary human keratinocytes and the lines KB and HaCaT
      was examined. Incubation with the NO donor S-nitroso-N-acetylpenicillamine (SNAP)
      for 24 hr increased IL-8 protein only in HaCaT cells, partly due to the presence
      of constitutive interleukin-1 (IL-1). However, in combination with IL-1beta, SNAP
      enhanced both IL-8 mRNA and protein in all three cell types. Transfection of
      cells with an IL-8 promoter reporter gene construct showed that the effect of NO
      was at least partly due to transcriptional activation. Despite small variations
      in the response to NO by the three cell types, these results demonstrate that NO
      can up-regulate IL-1beta-stimulated IL-8 expression in human keratinocytes. This
      study provides a regulatory mechanism which may be important in the context of
      skin inflammation, and supports the role of NO as an inflammatory mediator in the
      skin.

PMID- 10353265
TI  - Inhibitory effect of tetrahydroswertianolin on tumor necrosis factor-alpha
      dependent hepatic apoptosis in mice.
AB  - We investigated the effect of tetrahydroswertianolin (THS), a hepatoprotective
      agent from Swertia japonica, on tumor necrosis factor-alpha (TNF-alpha)-dependent
      hepatic apoptosis induced by D-galactosamine (D-GalN) (700 mg/kg, i.p.) and
      lipopolysaccharide (LPS) (10 microg/kg, i.p.) in mice. Apoptotic symptoms were
      observed at the initial stage of liver damage. By 5 hr after intoxication,
      hepatic DNA fragmentation had risen to 2123%, with the value in untreated mice
      set at 100%, without a significant elevation of serum alanine transaminase (ALT)
      activity. There was a parallel increase in hepatocytes undergoing chromatin
      condensation and apoptotic body formation. By 8 hr after intoxication, serum ALT
      activity had risen to 3707 U/L. Pretreatment with THS (50 mg/kg, p.o.) at 18 and
      2 hr before intoxication significantly reduced DNA fragmentation to 821% of that
      in untreated mice and prevented the emergence of chromatin condensation and
      apoptotic body formation. A significant and dose-dependent reduction in serum ALT
      activity at 8 hr also was observed with THS pretreatment. These effects of THS
      were different from those observed from pretreatment with glycyrrhizin (GCR),
      which is a clinically used hepatoprotective agent with membrane-stabilizing
      activity. GCR pretreatment (100 mg/kg, p.o.) did not inhibit hepatic DNA
      fragmentation (1588% of untreated mice), although this compound significantly
      protected against serum ALT elevation (1463 U/L). These data suggest that an
      inhibitory effect on the progression of hepatic apoptosis prior to liver injury
      may be involved in the hepatoprotective mechanisms of THS, whereas it appears
      that GCR affects the processes after apoptosis. In a separate experiment, we
      found that the concentration of serum TNF-alpha rose to 2016 pg/mL at 1 hr after
      intoxication of mice with D-GalN and LPS, but this increase was suppressed by THS
      pretreatment (10, 50, or 200 mg/kg, p.o.) to 716, 454, or 406 pg/mL,
      respectively. Further study with a reverse transcriptase-polymerase chain
      reaction method showed that THS blocked TNF-alpha production at the
      transcriptional level. Because TNF-alpha is a critical mediator to elicit
      apoptosis in this model, the property of suppressing TNF-alpha production may be
      of prime importance for THS inhibition of hepatic apoptosis.

PMID- 10353267
TI  - ERAS: the cure for "RRAD".

PMID- 10353266
TI  - Inhibition of complement by covalent attachment of rosmarinic acid to activated
      C3b.
AB  - Rosmarinic acid has been reported to inhibit complement activation in vivo as
      well as in vitro. Previous studies suggested that the inhibitory effect was due
      to inhibition of C3/C5 convertases, but inhibition of C3b attachment would yield
      the same results. Recent work in our laboratory demonstrated that compounds with
      polyhydroxylated phenyl rings are highly reactive with the thioester bond in
      nascent C3b. These compounds block complement activation by preventing attachment
      of C3b to the activating surface. Because rosmarinic acid contains two 3,4
      dihydroxyphenyl groups, the current study was undertaken to re-examine the
      mechanism of inhibition by analyzing the effect of rosmarinic acid on C3b
      attachment. In assays using purified complement proteins, rosmarinic acid
      inhibited covalent attachment of C3b to cells with an 1C50 = 34 microM.
      Inhibition of C5 convertase activity required 1500 microM rosmarinic acid, and no
      significant inhibition of the C3 convertase enzyme, which produces C3b from C3,
      was observed at 10,000 microM. In hemolytic assays using human serum, rosmarinic
      acid was shown to inhibit activation of both the classical (IC50 = 180 microM)
      and the alternative (IC50 = 160 microM) pathways of complement. Rosmarinic acid
      concentrations up to 10,000 microM did not cause direct inactivation of C3.
      Radioiodination of rosmarinic acid was used to demonstrate covalent activation
      dependent incorporation of rosmarinic acid specifically into the thioester
      containing alpha'-chain of nascent C3b. These findings indicate that inhibition
      of complement activation by rosmarinic acid is due to the reaction of rosmarinic
      acid with the activated thioester of metastable C3b, resulting in covalent
      attachment of the inhibitor to the protein.

PMID- 10353268
TI  - Are medical education goals falling short?

PMID- 10353269
TI  - Setting better priorities for medical education.

PMID- 10353270
TI  - Medical students need more medicolegal education.

PMID- 10353271
TI  - Journal club devoted to educational issues.

PMID- 10353272
TI  - Occupational injuries and infection control.

PMID- 10353273
TI  - Improving communications with elderly patients.

PMID- 10353274
TI  - Revisiting physical diagnosis during the medical residency: it is time for a
      logbook--and more.

PMID- 10353275
TI  - Publish or perish--and bankrupt the medical library while we're at it.

PMID- 10353276
TI  - Carrying out the Medicine/Public Health Initiative: the roles of preventive
      medicine and community-responsive care.
AB  - Leaders in medicine and public health, recognizing the inherent interdependency
      of these fields, established the Medicine/Public Health Initiative in the mid
      1990s as "an evolving forum in which representatives of both sectors can explore
      their mutual interests in improving health and [can] define collaborative
      mechanisms to achieve that goal." The Initiative's participants developed six
      goals that they and others in medicine and public health across the nation should
      implement: engage the community; change the education process; create joint
      research efforts by clinical, public health, and preventive medicine
      investigators; develop a shared view of illness between medicine and public
      health; work together to provide health care; and work jointly to develop health
      care assessment measures. The authors describe the six goals in depth and explain
      the important combined roles of clinically-oriented preventive medicine and
      community-oriented preventive medicine--as practiced in a model of health care
      delivery called community-oriented primary care (COPC)--in implementing the
      Initiative's goals. They then report recent efforts, including two in Boston and
      Dallas, to merge medicine and public health, and state that academic health
      centers, which are in the process of reshaping themselves, can help themselves as
      well as the public by embracing their key role in the effort to integrate
      medicine and public health. In particular, they can expand and strengthen
      existing training programs in preventive medicine and COPC or add these programs
      to their curricula.

PMID- 10353277
TI  - Academic health centers can bridge the gulf between medicine and public health.
AB  - The authors review why the gulf between clinical medicine and public health has
      existed since the first schools of public health were established in 1916. They
      emphasize that academic health centers (AHCs) have the potential to bring
      together these two perspectives--as well as the health services perspective--to
      clarify what they offer and to find creative ways to build upon their combined
      strengths. The authors describe institutional approaches that can be taken to
      narrow the gulf, with examples from the initiatives of this type that are under
      way at The George Washington University Medical Center in Washington, D.C. For
      example, the authors state and discuss in detail that an AHC's medical, public
      health, and health services institutions should be physically and institutionally
      close; that collaboration between them requires well-structured interaction; that
      institutional structures are needed to ensure cooperation when internal
      competition is likely; and that collaboration is fostered by new opportunities
      and the potential for new resources. The authors conclude by stating that the
      future will require that the health education and prevention perspective of
      public health, the treatment perspective of medicine, and the financial and
      management perspective of health services be developed and integrated into the
      work of AHCs, and give examples of specific activities that would be possible
      with such integration.

PMID- 10353278
TI  - Academic medicine and managed care: seeking common ground.
AB  - The authors report the highlights of a one-day symposium, "Academic Medicine and
      Managed Care: Seeking Common Ground," sponsored in early 1997 by Tulane
      University Medical Center. The meeting was held to foster better understanding of
      the gap between managed care organizations (MCOs) and academic health centers
      (AHCs) and to define their common ground. There were 62 participants, mainly
      executives froin AHCs and MCOs, plus government officials and policy researchers
      interested in the interface of academic medicine and managed care. The
      participants agreed that there are indeed some common areas in which the two
      types of organizations can develop programs and interests that serve the missions
      of both. These include (1) a commitment to high-quality health care, objectively
      measured by outcomes; (2) issues of "customer service"; (3) certain areas of
      research (e.g., examining outcomes of medical interventions; measuring cost and
      cost-effectiveness; measuring quality of care); and (4) preventive medicine, an
      area in which both AHCs and MCOs are still relatively weak. On the other hand,
      large elements of AHCs' basic missions of education and research are not seen by
      MCOs as areas for developing a common agenda. Participants agreed that AHCs must
      do their best to improve and demonstrate the quality of their care, address the
      challenges of the market (i.e., take "customer service" seriously), address the
      issue of how many specialists and how many generalists should be trained, and
      define the cost of each of their missions. On the other hand, managed care must
      acknowledge that the missions of AHCs greatly benefit patients and society.
      Participants agreed that all approaches to AHC-MCO interfaces must be flexible
      and local, that common ground does exist, and that understanding can grow between
      these two kinds of organizations if acrimonious exchanges are avoided and serious
      efforts are made to work together for solutions.

PMID- 10353279
TI  - Electronic medical record systems at academic health centers: advantages and
      implementation issues.
AB  - The growth of managed care has fueled expectations for a more coordinated
      delivery of clinical services and a reduction of unnecessary utilization. Among
      the most important issues that constrain these expectations is the transfer of
      medical information. Electronic medical record (EMR) systems appear to offer
      substantive advantages over paper records for both containing costs and improving
      the quality of care. However, incorporation of EMR systems into practice settings
      has languished. Among the barriers to implementation are software problems of
      codification and entry of data, security issues, a dearth of integrated delivery
      systems, reluctant providers, and prohibitive costs. The training programs of
      academic health centers (AHCs) are optimal environments for testing and
      implementing EMR systems. AHCs have the expertise to resolve remaining software
      issues, the components necessary for integrated delivery, a culture for
      innovation in clinical practice, and a generation of future providers that can be
      acclimated to the requisites for computerized records. The authors critically
      review these and other issues of implementing EMR systems at AHCs and propose
      four necessary steps for financing their implementation.

PMID- 10353280
TI  - Preparing the ground: contributions of the preclinical years to medical education
      for care near the end of life. Working Group on the Pre-clinical Years of the
      National Consensus Conference on Medical Education for Care Near the End of Life.
AB  - The preclinical years of medical education have rich potential for preparing
      medical students to provide optimal end-of-life care. Most of the opportunities
      and settings for this education already exist in the curricula of most medical
      schools, although they are underutilized for this purpose. In this report The
      Working Group on the Pre-clinical Years of the National Consensus Conference on
      Medical Education for Care Near the End of Life identifies the most promising
      settings and suggests how they might be used for maximum benefit in end-of-life
      education. Basic end-of-life care competencies are in five domains: (1)
      psychological, sociologic, cultural, and spiritual issues; (2) interviewing and
      communication skills; (3) management of common symptoms; (4) ethical issues; and
      (5) self-knowledge and self-reflection. A centralized group should oversee
      educational activities related to end-of-life care at each medical school. This
      group would identify and facilitate teaching opportunities in the preclinical
      curriculum: basic science courses; problem-based learning seminars; courses in
      interviewing, the doctor-patient relationship, and introduction to clinical
      medicine; courses in ethics, humanities, and the social-behavioral sciences;
      clinical preceptorships; and longitudinal experiences with patients. The group
      would also assess the potential impact of the "hidden curriculum."

PMID- 10353281
TI  - Teaching and learning communication in medicine: a rhetorical approach.
AB  - The language people use both makes possible and constrains the thoughts they can
      have. More than just a vehicle for ideas, language shapes ideas--and the
      practices that follow from them. Thus, in medical education, teaching students
      how to talk about medical cases also teaches them how to think about patients and
      medical work, and how to define their relationships to both. Without a
      theoretical model, however, teaching efforts in this domain tend to be implicit
      and ad hoc, which can lead to serious problems. Rhetoric is one science that can
      deepen understanding of communication and improve teaching of this clinical
      skill. Rhetoric systematically studies the relationships between communication
      and its effects, between how things are named and how they are experienced,
      between discourse and socialization. Bringing language to the foreground of
      education, rhetoric directs attention to the relationship between what medical
      students learn to say and what they learn to value, believe, and practice.

PMID- 10353282
TI  - Preparing chief information officers for the clinical information systems
      environment.
AB  - Over the past decade, the chief information officer (CIO) in the health care
      enterprise has gained recognition as a member of the senior management team based
      on an understanding of business processes and business language. The clinical
      information system (CIS) in the health care environment poses a new frontier for
      CIOs, who are generally unfamiliar with both clinical languages and clinical
      processes. The authors discuss the role formal informatics training can have in
      preparing learners for future careers as CIOs in CIS environments. The health
      information management (HIM) specialization within the MBA program at the
      University of Illinois at Chicago is one example of an educational program
      designed to train future CIOs who can manage the business, technical, and
      clinical aspects of the health care environment.

PMID- 10353283
TI  - Toward creating physician-healers: fostering medical students' self-awareness,
      personal growth, and well-being.
AB  - To restore the "humanism" in medical care, medical education needs to espouse the
      goal of creating physician-healers. Critical, and often neglected, factors in
      healing are the personal development and well-being of the healer. Unexamined
      attitudes and biases and personal stress can interfere with patient care.
      Personal awareness and well-being can contribute to physicians' using their
      emotional reactions to patients for their patients' benefit. The authors suggest
      goals and objectives for medical education that can promote trainees' self
      awareness, personal growth, and well-being, and comment on how medical educators
      might achieve and evaluate these goals and objectives.

PMID- 10353284
TI  - The shift to specialism in medicine: the U.S. Army in World War II.
AB  - While many are aware that a rapid advance in medical specialism occurred as a
      result of the introduction in 1965 of Medicare, with its liberal funding for
      graduate medical education, not many realize that a perhaps more significant rise
      in the number of specialists began right after World War II. Specialists were in
      great demand as the army planned for the treatment of several hundred thousand
      battle casualties who were returned to the United States at the end of the war,
      and many recently discharged medical officers took advantage of the G.I. Bill to
      train in specialty and subspecialty medicine. The author describes his
      experiences as director of the Resources Analysis Division, which was charged
      with developing and implementing a plan for treating the battle casualties of
      World War II. In his role, the author was to ensure a military hospital system
      was in place to provide high-quality specialty care to returning soldiers. He
      discusses how he and others accomplished this goal and what happened in this
      specialty hospital system after the wounded returned and peace was declared.

PMID- 10353285
TI  - The predictable price of Proposition 209.

PMID- 10353286
TI  - Improving the health of the American public requires a broad research agenda.

PMID- 10353287
TI  - The impact of residency training on physicians' AIDS-related treatment practices:
      a longitudinal panel study.
AB  - PURPOSE: To determine the effects of aspects of residency training on AIDS
      related treatment practices. METHOD: The authors conducted a nationwide
      longitudinal panel study of 394 physicians who graduated in 1989 from six medical
      schools in New York State. Data were collected during the participants' fourth
      year of medical school, their third year of residency training, and six years
      after they had graduated from medical school. Questionnaires sought information
      about AIDS-related practice behaviors, including avoiding invasive procedures,
      minimizing contact, emphasizing AIDS prevention and education, and volume of
      people with AIDS treated. RESULTS: Aspects of residency training had a sustained
      impact on how the physicians cared for patients with AIDS but not on the numbers
      of patients they treated. Determinants of treatment practices included aspects of
      the residency environment (e.g., emphasis on problem solving, student
      orientation; p < .01), characteristics of the faculty (e.g., commitment to
      teaching, tolerance of varied viewpoints), cynicism about patient care (p <
      .001), social biases (homophobia and aversion to intravenous drug users; p <
      .001), and AIDS-related attitudes (p < .01). CONCLUSIONS: Fundamental changes to
      residency training, all of which are associated with learner-centered education,
      can improve physicians' treatment of their patients with HIV and AIDS.

PMID- 10353288
TI  - Patients don't present with five choices: an alternative to multiple-choice tests
      in assessing physicians' competence.
AB  - PURPOSE: To evaluate an open-ended, computer-scored testing format designed to
      overcome certain limitations of multiple-choice questions. METHOD: Test items
      covering content in family medicine were administered in two different formats to
      7,036 resident physicians in 380 training programs, and to 35 experienced, board
      certified physicians in conjunction with the In-training Examination of the
      American Board of Family Practice. Examinees completed a booklet of 40 open
      ended, uncued (UnQ) test items by selecting the answer to each item from a list
      of over 500 responses. Similar items were administered using the standard
      multiple-choice question (MCQ) format. One year later, another test of 40 UnQ
      test items dealing with core content in family medicine was administered to 7,138
      residents. RESULTS: Examinees completed over 560,000 UnQ responses with high
      compliance and few errors. Both reliability and validity for the UnQ format were
      higher than for the MCQ format, and the UnQ items discriminated more accurately
      among levels of physicians' experience. The UnQ format almost eliminated the
      possibility that the physicians could answer questions by sight recognition or
      random guessing, and it was particularly effective in measuring knowledge of core
      content. CONCLUSIONS: This study supports the feasibility of administering open
      ended test items to enhance tests of physicians' competence.

PMID- 10353289
TI  - Outcome measurement in postgraduate year one of graduates from a medical school
      with a pass/fail grading system.
AB  - PURPOSE: To measure the performances of first-year residents who had graduated
      from a medical school with a pass/fail grading system and to compare the
      preparedness of these graduates with that of their peers. METHOD: All 169
      graduates of Stanford University School of Medicine's classes of 1993 and 1994
      were included in this study. First-year program directors rated the performance
      of each Stanford graduate in 11 areas, compared the graduate's clinical
      preparedness with that of his or her peer group, and rated the accuracy of the
      dean's letter in presenting the graduate's capabilities. RESULTS: Responses were
      obtained for 144 of the 169 graduates (85%). The program directors rated the
      overall clinical competencies of most of the graduates as "superior" (76%) or
      "good" (22%); they rated very few as "unsatisfactory" (2%). When the Stanford
      graduates were compared with their peers, their clinical preparedness was judged
      "outstanding" (33%), "excellent" (44%), and "good" (20%); very few were judged
      "poor" (3%). Stratification of programs by either hospital or medical specialty
      did not reveal significant differences in overall clinical competence. Ninety-one
      percent of the responses reported that the dean's letters had accurately
      presented the capabilities of the graduates. CONCLUSION: Graduates from a medical
      school with a two-interval, pass/fail system successfully matched with strong,
      highly-sought-after postgraduate training programs, performed in a satisfactory
      to superior manner, and compared favorably with their peer group.

PMID- 10353290
TI  - What do family medicine patients think about medical students' participation in
      their health care?
AB  - PURPOSE: To find out what patients think about students' involvement in their
      health care. METHOD: After conducting semistructured interviews with 24 patients,
      the authors developed a questionnaire addressing patients' concerns about student
      involvement in health care. The questionnaire was administered to 735 patients in
      academic and community settings; 575 (78%) patients responded. RESULTS: Most
      responding patients (90%) were willing to have a student involved in their health
      care. Those who were unwilling commonly cited privacy concerns. A third of the
      patients reported that the student did at least part of the physical examination.
      Three fourths of the patients who saw a student, and half of those who did not,
      said they appreciated or would appreciate the attention they got from a medical
      student. Almost half the patients (39%) perceived that student involvement
      lengthened their visits. CONCLUSION: Most patients in family medicine are willing
      to allow students to be involved in their care, and most perceive it as
      beneficial.

PMID- 10353291
TI  - Academic versus non-academic women physicians: data from the Women Physicians'
      Health Study.
AB  - PURPOSE: To help encourage women physicians to enter academe, the authors
      gathered information about how academic and non-academic women physicians (AWPs
      and NAWPs) differed demographically, personally, and professionally. METHOD: The
      authors examined data from the Women Physicians' Health Study, a nationally
      representative questionnaire-based study conducted in 1993-1994. RESULTS: The 453
      AWPs were more likely to be U.S.-born, white, and self-defined as liberal than
      were the 3,986 NAWPs. The AWPs were more likely to be board-certified and to work
      in urban areas, reported fewer clinical and more non-clinical hours, earned less,
      and performed more continuing medical education. The AWPs reported less work
      control and were more likely to report working too much, but were also less
      likely, if they could relive their lives, to want to change specialty. AWPs and
      NAWPs had similar career satisfaction, work stress, and personal health habits.
      CONCLUSION: AWPs who come from a somewhat narrow demographic group, may not
      provide the variety of role models necessary for encouraging ethnic diversity in
      medical schools. Despite somewhat greater reported work hardships, AWPs are a
      very professionally satisfied and motivated group.

PMID- 10353292
TI  - Physicians in service to the underserved: an analysis of the practice locations
      of alumni of Western University of Health Sciences College of Osteopathic
      Medicine of the Pacific, 1982-1995.
AB  - PURPOSE: To determine how many osteopathic medical graduates (DOs) of the Western
      University of Health Sciences were practicing in underserved communities. METHOD:
      Practice address information was available for 765 of the 850 practicing DO
      alumni who had graduated from the University from 1982 through 1995. Alumni were
      categorized as practicing in underserved areas or not, following federally
      established guidelines; they were also categorized by gender, ethnicity, and
      medical specialty. RESULTS: Overall, 20.9% of these 765 alumni were practicing in
      underserved communities. The percentages of alumni practicing in underserved
      communities by gender, ethnicity, and specialty were: men, 20.9%; women, 21.0%;
      Caucasians, 20.5%; Asian Americans, 18.0%; African Americans, 25.0%; Hispanic
      Americans, 32.1%; Native Americans, 33.3%; primary care physicians, 20.9%; and
      non-primary care physicians, 20.9%. CONCLUSIONS: Approximately one in five
      practicing DO alumni of Western University was practicing in an underserved area.
      Examining these data by sex, ethnicity, and practice specialization suggested
      only weak associations between subgroup membership and practice in an underserved
      area.

PMID- 10353293
TI  - Selective estrogen receptor modulators: a look ahead.
AB  - Selective estrogen receptor modulators (SERMs) are structurally diverse compounds
      that bind to estrogen receptors (ER) and elicit agonist or antagonist responses
      depending on the target tissue and hormonal milieu. They are being evaluated
      primarily for conditions associated with aging, including hormone-responsive
      cancer, osteoporosis and cardiovascular disease. Several SERMs are marketed or
      are in clinical development, including triphenylethylenes (tamoxifen and its
      derivatives: toremifene, droloxifene and idoxifene), chromans (levormeloxifene),
      benzothiophenes (raloxifene, LY353381) and naphthalenes (CP336,156). Tamoxifen
      and toremifene, both used to treat advanced breast cancer, also have beneficial
      effects on bone mineral density and serum lipids in postmenopausal women.
      Tamoxifen was recently shown to decrease the risk of invasive breast cancer in
      women at high risk. Unfortunately, both drugs also have stimulatory effects on
      the endometrium. Raloxifene, used for prevention of postmenopausal osteoporosis
      and fragility fractures, also has favourable effects on bone mineral density,
      serum lipids and the incidence of invasive breast cancer in postmenopausal women
      but does not stimulate the endometrium. Like replacement estrogens, SERMs
      increase the risk of venous thromboembolism. SERMs offer post-menopausal women
      many of the advantages of estrogen replacement while mitigating some of the
      disadvantages, particularly the concern over breast cancer. Newer SERMs,
      exemplified by raloxifene, also eliminate the concerns over endometrial
      stimulation that were not addressed by first generation SERMs. The clinical
      success of SERMs has set the stage for a variety of drug therapies based on
      selective modulation of nuclear receptor activity.

PMID- 10353296
TI  - Heart rate as a risk factor for atherosclerosis and cardiovascular mortality: the
      effect of antihypertensive drugs.
AB  - The aim of this review is to highlight the importance of heart rate (HR) as a
      risk factor for cardiovascular disease, and to discuss the classes of drugs which
      can be potentially useful in clinical conditions in which an elevated HR may be
      present. Numerous studies have shown that high resting HR is prospectively
      related to the development of atherosclerosis and of cardiovascular events. This
      relationship was independent of other major risk factors for atherosclerosis and
      was observed in the general population, in elderly people, in hypertensive
      cohorts and in patients with myocardial infarction or heart failure. The
      clustering of several risk factors in individuals with fast heart rate may
      explain why cardiovascular morbidity is higher in individuals with tachycardia.
      Sympathetic overactivity seems to be responsible for both the increase in HR,
      blood pressure and the metabolic abnormalities. Experimental studies in monkeys
      have shown that HR can also exert a direct atherogenetic action on the arteries
      through increased wall stress. Moreover, tachycardia can favour the occurrence of
      ventricular arrhythmias and sudden death. Reduction of HR appears as an
      additional goal of antihypertensive therapy. If fast HR in hypertension is a
      marker of increased sympathetic tone, agents which decrease HR through a decline
      of sympathetic outflow should be particularly efficacious. Beta-blockers retard
      the development of coronary atherosclerosis in cholesterol-fed monkeys and have
      proven to be beneficial in patients with myocardial infarction or with heart
      failure, but their efficacy appear limited in hypertension, probably on account
      of their unfavourable metabolic profile. Phenylalkylamines are devoid of this
      untoward effect, and seem to act also through inhibition of sympathetic discharge
      from the CNS. Mibefradil, a more recent calcium antagonist that selectively
      blocks voltage-dependent T-type calcium channels decreases HR without affecting
      left ventricular contractility. New drugs with agonistic properties at the I1
      imidazoline receptors of the rostral ventrolateral medulla are effective in
      reducing blood pressure and HR by inhibiting the sympathetic outflow and improved
      metabolic parameters in obese or fructose-fed rats. The goal of antihypertensive
      therapy in the future will be to prevent or reverse those functional
      abnormalities which accompany the hypertensive condition. In patients with
      tachycardia the reduction of HR appears a desirable additional goal of therapy.

PMID- 10353297
TI  - Photodynamic therapy in the treatment of cancer: current state of the art.
AB  - Photodynamic therapy (PDT) is a treatment modality using a photosensitising drug
      and light to kill cells. The clinical use of PDT requires the presence of a
      photosensitising agent, oxygen and light of a specific wavelength which matches
      the absorption characteristics of the photosensitiser. When the photosensitiser
      is activated by the appropriate wavelength of light, it interacts with molecular
      oxygen to form a toxic, short-lived species known as singlet oxygen, which is
      thought to mediate cellular death. The appeal of PDT in oncology is that the
      photosensitiser tends to be retained in tumour tissues for a longer period of
      time as compared with normal tissues resulting in a large therapeutic index. This
      potential for minimal normal tissue toxicity has prompted an interest in studying
      PDT as a cancer treatment. Furthermore, the use of PDT is not precluded by prior
      radiotherapy, chemotherapy or surgery. The development of PDT has been hampered
      by the limitations of the older photosensitisers, namely limited depth of tissue
      penetration, and extended skin phototoxicity which limits the number of
      applications during a course of treatment. However, newer photosensitisers are
      being developed which allow greater depth of tissue penetration and have minimal
      skin phototoxicity allowing for multiple fractionated treatments. With such
      advancements, PDT has great potential to become an integral part of cancer
      treatment in the future.

PMID- 10353298
TI  - Cytomegalovirus reactivation in patients infected with HIV: the use of polymerase
      chain reaction in prediction and management.
AB  - Patients with HIV are living longer now than in the past, and with a better
      quality of life. During the advanced stages of HIV infection patients are at risk
      of cytomegalovirus (CMV) reactivation and subsequently CMV disease. It is
      important to review the evidence on whether CMV reactivation leads to CMV disease
      and what the best methods are for detecting such a reactivation. CMV polymerase
      chain reaction (PCR) can be used qualitatively to predict CMV disease and
      quantitatively to predict a general increase in mortality. CMV PCR can also be
      used to direct either prophylaxis or pre-emptive therapy to those most at risk of
      CMV disease. CMV PCR should be an integral part of the decision-making process
      when treating both new patients with CMV retinitis and those with disease
      reactivation.

PMID- 10353294
TI  - Renal protection and antihypertensive drugs: current status.
AB  - The renal protective effect of antihypertensive drugs is linked to 2 mechanisms.
      First, reduction in blood pressure (BP) is a fundamental prerequisite common to
      all antihypertensive drugs. The exact definition of the level to which BP should
      be reduced remains to be established, although there is some evidence that BP
      should be reduced below 130/85 mm Hg in patients with diabetic and nondiabetic
      nephropathies and below 125/75 mm Hg in patients with nondiabetic nephropathies
      and proteinuria >1 g/day. However, available data suggest that tight BP control
      (BP<140/80 mm Hg) can reduce the risk of cardiovascular complications in
      hypertensive patients with type 2 diabetes mellitus (non-insulin-dependent
      diabetes mellitus; NIDDM). Secondly, intrarenal actions on mechanisms such as
      glomerular hypertension and hypertrophy, proteinuria, mesangial cell
      proliferation, mesangial matrix production and probably endothelial dysfunction,
      which can cause and/or worsen renal failure, are relevant for the renal
      protective action of some drug classes. ACE inhibitors possess such properties
      and also seem to lower proteinuria more than other antihypertensive drugs,
      despite a similar BP lowering effect. Calcium antagonists likewise exert
      beneficial intrarenal effects, but with some differences among subclasses. It
      remains to be evaluated whether angiotensin II-receptor antagonists can exert
      intrarenal effects and antiproteinuric actions similar to those of ACE
      inhibitors. While primary prevention of diabetic nephropathy is still an unsolved
      problem. there is convincing evidence that in patients with type 1 (insulin
      dependent diabetes mellitus; IDDM) or 2 diabetes mellitus and incipient
      nephropathy ACE inhibitors reduce urinary albumin excretion and slow the
      progression to overt nephropathy. Similar effects have been reported with some
      long-acting dihydropyridine calcium antagonists, although less consistently than
      with ACE inhibitors. In patients with diabetic overt nephropathy, ACE inhibitors
      and nondihydropyridine calcium antagonists are particularly effective in reducing
      proteinuria and both drugs can slow the decline in glomerular filtration rate
      more successfully than other antihypertensive treatment. Available data in
      patients with nondiabetic nephropathies indicate that ACE inhibitors can be
      beneficial, principally in patients with significant proteinuria, in slowing the
      progression of renal failure. However, it is still unclear whether this
      beneficial effect of ACE inhibitors is particularly evident in patients with mild
      and/or more advanced renal failure and whether calcium antagonists possess a
      similar nephroprotective effect. Overall, data from clinical trials thus seem to
      indicate that ACE inhibitors and possibly calcium antagonists should be preferred
      in the treatment of patients with diabetic and nondiabetic nephropathies.
      However, further information is needed to understand renal protection.

PMID- 10353295
TI  - Epidemiology of risk factors for hypertension: implications for prevention and
      therapy.
AB  - We review the present knowledge of risk factors for arterial hypertension. Both
      genetic and environmental factors as well as their interaction and biological
      plausibility are reviewed. Recent data confirm that the interaction of genetics
      with multiple environmental risk factors explains the high prevalence of
      hypertension in the industrialised countries. The most important modifiable
      environmental risk factors are high salt intake, alcohol intake, obesity and low
      physical activity. The role of stress in the aetiology of high blood pressure is
      still under investigation, but recent clinical experimental and epidemiological
      data have shed light on how stress could be related to hypertension. The
      implications for prevention and treatment are discussed both at the population
      and individual levels. The population approach involves a public health policy
      aiming at modification of the major risk factors. The individual approach
      involves nonpharmacological measures to prevent the development of hypertension
      and to treat high normal blood pressure and mild hypertension with no additional
      cardiovascular risk factors. Pharmacological treatment of hypertension in most
      individuals should use agents that have been proven to be effective in randomised
      controlled trials with 'hard' endpoints such as cardiovascular and
      cerebrovascular morbidity and mortality.

PMID- 10353299
TI  - Practical recommendations for the drug treatment of bacterial infections of the
      male genital tract including urethritis, epididymitis and prostatitis.
AB  - Bacterial infections of the male genital tract in young men (<35 years old) are
      primarily caused by sexually transmissible bacteria like Chlamydia trachomatis,
      Neisseria gonorrhoeae but also Mycoplasma or Haemophilus spp. In men aged over 35
      years, Enterobacteriaceae are more frequently involved in urethritis,
      epididymitis and prostatitis. The traditional treatments suggested like
      tetracyclines or erythromycin are less effective since bacterial resistance is
      increasingly frequent, particularly in N. gonorrhoeae. Moreover, patient
      compliance with these drug treatments are frequently not well observed. New
      therapies including short term therapy with fluoroquinolones or azalides (e.g.
      azithromycin) are very effective and easy to use and thus eliminate any problem
      of compliance. However, we have to be vigilant for the emergence of resistant
      strains to these agents.

PMID- 10353300
TI  - Valsartan/hydrochlorothiazide.
AB  - Valsartan/hydrochlorothiazide (HCTZ) combines an angiotensin II AT1 receptor
      blocker with a thiazide diuretic to produce additive blood pressure reductions
      without major effects on heart rate. HCTZ did not significantly alter valsartan
      pharmacokinetics; during combination therapy, HCTZ pharmacokinetics differed from
      those seen with HCTZ monotherapy. In clinical trials in patients with essential
      hypertension, adding HCTZ 12.5 or 25 mg/day to valsartan 80 mg/day resulted in a
      greater blood pressure reduction than increasing the valsartan dosage from 80 to
      160 mg/day. The valsartan/HCTZ combination was generally more effective than
      either drug given alone. Efficacy of the combination was maintained during up to
      3 years of treatment. Valsartan/HCTZ was well tolerated in both short and long
      term trials. The most common adverse events were dizziness, headache and fatigue.
      The overall incidence of adverse events with the combination was similar to that
      with placebo. HCTZ-induced hypokalaemia was less common during combination
      therapy.

PMID- 10353301
TI  - Insulin aspart.
AB  - Insulin aspart is a recombinant analogue of human insulin. Following subcutaneous
      insulin injection (0.15 to 0.2 U/kg), significantly higher serum insulin
      concentrations are achieved in a shorter time with insulin aspart than with human
      insulin. The subsequent decline in serum insulin concentrations is also more
      rapid with insulin aspart. In healthy individuals undergoing euglycaemic glucose
      clamp testing, glucose infusion rates were higher and reached maximum
      concentrations significantly earlier after insulin aspart than after human
      insulin. Interindividual variability in pharmacodynamic and pharmacokinetic
      parameters with insulin aspart was generally less than that with human insulin,
      whereas the intraindividual variability in these parameters was similar after
      each insulin. In patients with type 1 diabetes postprandial glucose excursions
      were less pronounced with insulin aspart than human insulin. Daytime glucose
      control was better and minimum glucose levels during the night were not as low
      with insulin aspart as with human insulin. In diabetic patients treated with
      insulin aspart there was generally a lower frequency of hypoglycaemic events than
      in patients treated with human insulin.

PMID- 10353302
TI  - Inhaled fluticasone propionate: a review of its therapeutic efficacy at dosages <
      or = 500 microg/day in adults and adolescents with mild to moderate asthma.
AB  - Fluticasone propionate is a corticosteroid with comparatively high receptor
      affinity and topical activity. Inhaled fluticasone propionate < or =500
      microg/day provided effective corticosteroid maintenance treatment in patients
      with mild to moderate asthma in randomised, controlled clinical studies of 4 to
      24 weeks in duration. Dosages of 50 to 250 microg twice daily produced consistent
      improvement in spirometric measures of lung function, reduced the frequency of as
      needed beta2-agonist bronchodilator use, asthma symptom scores and night-time
      wakenings, and prevented asthma exacerbations compared with placebo. Fluticasone
      propionate < or =250 microg twice daily provided significantly greater
      improvements in lung function than nedocromil 4 mg 4 times daily, theophylline (5
      to 15 mg/L) or zafirlukast 20 mg twice daily. Health-related quality of life
      improved significantly with fluticasone propionate 88 microg twice daily, but not
      zafirlukast 20 mg twice daily or placebo. In comparative trials in which
      fluticasone propionate was given at half the dosage of beclomethasone
      dipropionate, budesonide or flunisolide, fluticasone propionate < or =250 microg
      twice daily produced equivalent or greater improvement in spirometric parameters
      and equivalent reductions in the use of as-needed beta2-agonists than
      beclomethasone dipropionate, budesonide or flunisolide. Fluticasone propionate
      250 microg twice daily was generally more effective than triamcinolone acetonide
      200 microg 4 times daily in two 24-week trials. The combination of inhaled
      fluticasone propionate < or =250 plus salmeterol < or =50 microg twice daily
      allowed for the use of lower dosages of the inhaled corticosteroid. The incidence
      of adverse events in patients receiving inhaled fluticasone propionate 50 to 250
      microg twice daily was similar to that in beclomethasone dipropionate 168 to 500
      microg twice daily and budesonide 100 to 600 microg twice daily recipients and
      greater than that in recipients of triamcinolone acetonide 200 microg 4 times
      daily in comparative trials. The incidence of oral candidiasis was < or =8% in
      patients treated with fluticasone propionate < or =250 microg twice daily or
      other agents. There was no evidence of clinically significant hypothalamo
      pituitary-adrenal (HPA) axis suppression with fluticasone propionate < or =250
      microg twice daily in comparative trials. CONCLUSIONS: Inhaled fluticasone
      propionate < or =500 microg/day is an effective antiinflammatory therapy for mild
      to moderate asthma in adolescents and adults. The drug is more effective than
      nedocromil, theophylline or zafirlukast and is at least as effective as other
      inhaled corticosteroids administered at twice the fluticasone propionate dosage.
      The addition of inhaled salmeterol allows the use of lower maintenance dosages of
      fluticasone propionate. The drug is well tolerated and there is no evidence of a
      clinically significant effect of this dosage on HPA axis function. Hence,
      fluticasone propionate < or =500 microg/day is a particularly suitable agent for
      patients with mild to moderate asthma.

PMID- 10353304
TI  - Symposium overview: Characterization of xenobiotic metabolizing enzyme function
      using heterologous expression systems.
AB  - Genetically modified cell lines can be very useful models for assessing the
      toxicologic effects of modulation of expression of individual gene products in
      comparison to their isogenic parental control cell lines. This symposium begins
      with an overview of general issues related to development and utilization of
      model systems created by transfection of cell lines to induce elevated expression
      of metabolic enzymes of toxicologic relevance. Selected studies that illustrate
      the heterologous expression rationale and various approaches to transgenic-cell
      model construction are represented. Results to date with cells engineered to
      express specific transfected genes are discussed, with emphasis on the effects of
      expression of selected phase I or phase II enzymes on cellular sensitivity to
      several toxic end-points. The individual sections highlight the utility of these
      model cell lines for examining the role of enzyme catalysis and function in
      metabolism of biologically active xenobiotic or endobiotic compounds of interest
      in toxicology. Both activating and detoxifying enzymes are discussed, with
      principal emphasis on the latter. This symposium includes talks on transfected
      cells that express aldehyde dehydrogenases, superoxide dismutase, UDP
      glycosyltransferases, glutathione transferases, and cytochrome P450 isozymes. In
      addition to the general toxicologic utility and advantages of these genetically
      engineered cell lines, this overview emphasizes their particular contributions to
      the insights obtained to date with the specific model cell lines.

PMID- 10353305
TI  - Concise review of the cytochrome P450s and their roles in toxicology.

PMID- 10353303
TI  - Piperacillin/tazobactam: an updated review of its use in the treatment of
      bacterial infections.
AB  - Piperacillin/tazobactam is a beta-lactam/beta-lactamase inhibitor combination
      with a broad spectrum of antibacterial activity encompassing most Gram-positive
      and Gram-negative aerobic bacteria and anaerobic bacteria, including many
      pathogens producing beta-lactamases. Evidence from clinical trials in adults has
      shown that piperacillin/tazobactam, administered in an 8:1 ratio, is an effective
      treatment for patients with lower respiratory tract, intra-abdominal, urinary
      tract, gynaecological and skin/soft tissue infections, and for fever in patients
      with neutropenia. Combination regimens of piperacillin/tazobactam plus an
      aminoglycoside are used to treat patients with severe nosocomial (hospital
      acquired) infections. In clinical trials, piperacillin/tazobactam was
      significantly more effective than ticarcillin/clavulanic acid in terms of
      clinical and microbiological outcome in patients with community-acquired
      pneumonia. In patients with intra-abdominal infections, clinical and
      bacteriological response rates were significantly higher with
      piperacillin/tazobactam than with imipenem/cilastatin (administered at a dosage
      lower than is recommended in countries outside Scandinavia).
      Piperacillin/tazobactam in combination with amikacin was at least as effective as
      ceftazidime plus amikacin in the treatment of ventilator-associated pneumonia and
      was significantly more effective than ceftazidime plus amikacin in the empirical
      treatment of febrile episodes in patients with neutropenia or granulocytopenia.
      In other trials, the efficacy of piperacillin/tazobactam was similar to that of
      standard aminoglycoside-containing and other treatment regimens in patients with
      intra-abdominal, skin/soft tissue or gynaecological infections.
      Piperacillin/tazobactam is generally well tolerated. The most frequent adverse
      events are gastrointestinal symptoms (most commonly diarrhoea) and skin
      reactions. The incidence of adverse events with piperacillin/tazobactam is higher
      when the combination is given in combination with an aminoglycoside than when
      given as monotherapy. CONCLUSION: Because of the broad spectrum of antibacterial
      activity provided by piperacillin/tazobactam, it is useful for the treatment of
      patients with polymicrobial infections caused by aerobic or anaerobic beta
      lactamase-producing bacteria. Piperacillin/tazobactam appears to have a
      particularly useful role in the treatment of patients with intra-abdominal
      infections and, in combination with amikacin, in the treatment of patients with
      febrile neutropenia, especially given the current prevalence of Gram-positive
      infections in this group.

PMID- 10353306
TI  - Toxicology of protein allergenicity: prediction and characterization.
AB  - The ability of exogenous proteins to cause respiratory and gastrointestinal
      allergy, and sometimes systemic anaphylactic reactions, is well known. What is
      not clear however, are the properties that confer on proteins the ability to
      induce allergic sensitization. With an expansion in the use of enzymes for
      industrial applications and consumer products, and a substantial and growing
      investment in the development of transgenic crop plants that express novel
      proteins introduced from other sources, the issue of protein allergenicity has
      assumed considerable toxicological significance. There is a need now for methods
      that will allow the accurate identification and characterization of potential
      protein allergens and for estimation of relative potency as a first step towards
      risk assessment. To address some of these issues, and to review progress that has
      been made in the toxicological investigation of respiratory and gastrointestinal
      allergy induced by proteins, a workshop, entitled the Toxicology of Protein
      Allergenicity: Prediction and Characterization, was convened at the 37th Annual
      Conference of the Society of Toxicology in Seattle, Washington (1998). The
      subject of protein allergenicity is considered here in the context of
      presentations made at that workshop.

PMID- 10353307
TI  - Symposium overview: alterations in cytokine receptors by xenobiotics.
AB  - A symposium entitled Alterations in Cytokine Receptors by Xenobiotics was held at
      the 37th Annual Meeting of the Society of Toxicology (SOT) in Seattle,
      Washington. The symposium was sponsored by the Immunotoxicology Specialty Section
      of SOT and was designed to present information on the effect of several different
      classes of xenobiotics on various aspects of receptor function (i.e., post
      receptor signal transduction of receptor expression), or the involvement of
      cytokine receptors in the action of the toxicant under consideration. This
      symposium brought together scientists in the area of receptor immunobiology whose
      expertise in receptor modulation encompassed those major signaling agents
      involved in the normal immune response, i.e., proinflammatory cytokines,
      chemokines, interleukins, and interferons. The following is a summary of each of
      the individual presentations.

PMID- 10353308
TI  - Estimation of the dermal absorption of m-xylene vapor in humans using breath
      sampling and physiologically based pharmacokinetic analysis.
AB  - A physiologically-based pharmacokinetic model, containing a skin compartment, was
      derived and used to simulate experimentally determined exposure to m-xylene,
      using human volunteers exposed under controlled conditions. Biological monitoring
      was conducted by sampling, in exhaled alveolar air and blood, m-xylene and
      urinary methyl hippuric acid concentrations. The dermal absorption of m-xylene
      vapor was successfully and conveniently studied using a breath sampling
      technique, and the contribution to m-xylene body burden from the dermal route of
      exposure was estimated to be 1.8%. The model was used to investigate the
      protection afforded by an air-fed, half-face mask. By iteratively changing the
      dermal exposure concentration, it was possible to predict the ambient
      concentration that was required to deliver the observed urinary excretion of
      methylhippuric acid, during and following inhalation exposure to 50 ppm m-xylene
      vapor. This latter extrapolation demonstrates how physiologically-based
      pharmacokinetic modeling can be applied in a practical and occupationally
      relevant way, and permitted a further step not possible with biological
      monitoring alone. The ability of the model to extrapolate an ambient exposure
      concentration was dependent upon human metabolism data, thereby demonstrating the
      mechanistic toxicological basis of model output. The methyl hydroxylation of m
      xylene is catalyzed by the hepatic mixed function oxidase enzyme, cytochrome P450
      2E1 and is active in the occupationally relevant, (<100 ppm) exposure range of m
      xylene. The use of a scaled-up in vitro maximum rate of metabolism (Vmaxc) in the
      model also demonstrates the increasingly valuable potential utility of biokinetic
      data determined using alternative, non-animal methods in human chemical-risk
      assessment.

PMID- 10353309
TI  - Predicting vehicle effects on the dermal absorption of halogenated methanes using
      physiologically based modeling.
AB  - Occupational and environmental settings present opportunities for humans to come
      into contact with a variety of chemicals via the dermal route. The chemicals
      contacting the skin are likely to be diluted with a vehicle or present as a
      component of a mixture. In order to support risk assessment activities, we
      evaluated the vehicle effects on dermal penetration of two halogenated
      hydrocarbons, dibromomethane (DBM) and bromochloromethane (BCM). In vivo
      exposures to 15 combinations of of these in water, mineral oil, and corn oil
      vehicles were conducted, and blood was sampled for dibromomethane and
      bromochloromethane during the exposure at 0.5, 1, 2, 4, 8, 12, and 24 h. A
      physiologically based pharmacokinetic (PBPK) model was used to estimate the total
      amounts of dibromomethane or bromochloromethane that were absorbed during the
      exposure, and the dermal permeability coefficients were determined. While the
      permeability coefficients for dibromomethane and bromochloromethane were
      approximately 73- and 40-fold higher, respectively, in the water vehicle than in
      the corn oil, the permeability coefficient, when normalized for the skin:vehicle
      matrix partition coefficient, varied by less than a factor of 2. The permeability
      in an aqueous vehicle was then successfully used to predict the permeability
      coefficient for dibromomethane in a nonpolar vehicle, peanut oil.

PMID- 10353310
TI  - Toxicokinetic interactions between orally ingested chlorzoxazone and inhaled
      acetone or toluene in male volunteers.
AB  - The aim of this study was to examine if the drug chlorzoxazone has any influence
      on the toxicokinetics of acetone and toluene. Chlorzoxazone is mainly metabolized
      by the same enzyme (Cytochrome P450 2E1) as ethanol and many other organic
      solvents. Ten male volunteers were exposed to solvent vapor (2 h, 50 watt) in an
      exposure chamber. Each subject was exposed to acetone only (250 ppm), acetone +
      chlorzoxazone, toluene (50 ppm) only, toluene + chlorzoxazone, and chlorzoxazone
      only. Chlorzoxazone (500 mg) was taken as two tablets 1 h prior to solvent
      exposure. Samples of blood, urine and exhaled air were collected before, during
      and until 20 h post exposure. The samples were analyzed by head-space gas
      chromatography (acetone and toluene) and high-performance liquid chromatography
      (chlorzoxazone, 6-hydroxychlorzoxazone and hippuric acid). The time-concentration
      curves of acetone and toluene in blood were fitted to one- and four-compartment
      toxicokinetic models, respectively. Intake of chlorzoxazone was associated with
      slight but significant increases in the area under the blood concentration-time
      curve (AUC) and steady state concentration of acetone in blood, along with non
      significant tendencies to an increased half time in blood and an increased AUC in
      urine. Except for a delayed excretion of hippuric acid in urine, no effects on
      the toluene toxicokinetics were seen after chlorzoxazone treatment. Small
      increases in chlorzoxazone plasma levels were seen after exposure compared to
      chlorzoxazone alone. These interactions, although statistically significant, seem
      to be small compared to the interindividual variability on metabolism and
      toxicokinetics.

PMID- 10353311
TI  - Compartmentalized uterotrophic effects of tamoxifen, toremifene, and estradiol in
      the ovariectomized Wistar (Han) rat.
AB  - The comparative uterotrophic responses of ovariectomized Wistar (Han) rats to
      tamoxifen, toremifene, and 17beta-estradiol have been determined over a period of
      72 h. Uterine wet weight; luminal epithelial cell hypertrophy; and BrdU labeling
      index in the different tissue compartments of the uterus, and the
      immunohistochemical expression of nuclear estrogen receptor alpha (nERalpha), and
      nuclear progesterone receptor (nPR) were examined. Luminal epithelial cell
      hypertrophy was produced by all three compounds to a similar degree. 17beta
      Estradiol produced an increase in uterine wet weight due to fluid imbibition over
      the 3-day period, and an increase in DNA synthesis in the endometrial stromal and
      myometrial compartments of the uterus, as measured by increased BrdU
      incorporation. Estradiol increased the expression of nERalpha and nPR in the
      myometrium with time and decreased nERalpha levels from the overexpressed levels
      in control ovariectomized rat luminal epithelial cells. Tamoxifen and toremifene
      caused a smaller increase in uterine weight and the BrdU labeling index in the
      endometrial stroma and myometrium than did estradiol, and they increased the
      expression of nERalpha and nPR in the myometrium. Tamoxifen and toremifene
      differed from estradiol in that they did not decrease the expression of nERalpha
      in the luminal epithelial cells of the uterus. The response of PR expression was
      the same for tamoxifen, toremifene, and estradiol, and was therefore considered
      to be the most reliable indication of an estrogen-agonist effect in this study.
      The ability to distinguish differential, compartmentalized effects for agonists
      of estrogen action in the uterus will allow a better risk assessment for new
      pharmaceuticals that are used as breast cancer chemotherapeutic agents,
      especially where their use may also be associated with an increased risk of
      uterine cancers, in particular.

PMID- 10353312
TI  - Development of a flow cytometry assay for the identification and differentiation
      of chemicals with the potential to elicit irritation, IgE-mediated, or T cell
      mediated hypersensitivity responses.
AB  - These studies were conducted to investigate the potential use of a flow
      cytometric analysis method for the identification and differentiation of
      chemicals with the capacity to induce irritation, IgE- or T cell-mediated
      hypersensitivity responses. An initial study investigated the ability of equally
      sensitizing concentrations (determined by local lymph node assay) of IgE-mediated
      (Toluene Diisocyanate-TDI) and T cell-mediated (Dinitrofluorobenzene-DNFB)
      allergens to differentially modulate the IgE+B220+ population in the lymph nodes
      draining the dermal exposure site. Sodium lauryl sulfate (SLS) was also tested as
      a nonsensitizing irritant control. Female B6C3F1 mice were dermally exposed once
      daily for 4 consecutive days, with the optimum time point for analysis determined
      by examining the IgE+B220+ population 8, 10, and 12 days post-initial chemical
      exposure. At the peak time point, day 10, the IgE+B220+ population was
      significantly elevated in TDI (41%), while moderately elevated in DNFB (18%)
      exposed animals when compared to the vehicle (0.8%), and remained unchanged in
      SLS (2.2%) exposed animals when compared to the ethanol control (2.5%).
      Experiments in our laboratory and others have demonstrated that the draining
      lymph node B220+ population becomes significantly elevated following exposure to
      allergens (IgE- and T cell-mediated), not irritants, allowing for their
      differentiation. An existing mouse ear swelling assay was used to identify
      chemical irritants. Therefore, using the endpoints of percent ear swelling,
      percent B220+ cells, and percent IgE+B220+ cells, a combined irritancy/phenotypic
      analysis assay was developed and tested with tetradecane (irritant), toluene
      diisocyanate, trimellitic anhydride (IgE-mediated allergens), benzalkonium
      chloride, dinitrofluorobenzene, oxazolone, and dinitrochlorobenzene (T cell
      mediated allergens) over a range of concentrations. Based upon the pattern of
      response observed, a paradigm was developed for continued evaluation: Irritant
      exposure will result in significant ear swelling without altering the B220+ or
      IgE+B220+ populations. Exposure to sensitizers (IgE-mediated or T cell-mediated)
      will increase the B220+ population and the percent ear swelling will remain
      unchanged or will significantly increase, depending on the irritancy capacity of
      the chemical. Both the IgE+B220+ and B220+ populations will become elevated at
      the same test concentration following exposure to IgE-mediated, hypersensitivity
      inducing allergens. At its peak, the percent of IgE+B220+ cells will be equal to
      the percent of B220+ cells. The B220+ population will increase at a lower test
      concentration than the IgE+B220+ population, following exposure to T cell
      mediated, hypersensitivity inducing allergens. At its peak, the percent of
      IgE+B220+ cells will reach less than half that of the percent of B220+ cells. The
      irritancy/phenotypic analysis method may represent a single murine assay able to
      identify and differentiate chemicals with the capacity to induce irritation, or
      IgE-mediated or T cell-mediated responses.

PMID- 10353313
TI  - Comparison of in vitro and in vivo human skin responses to consumer products and
      ingredients with a range of irritancy potential.
AB  - Human skin equivalent cultures were investigated as possible pre-clinical skin
      irritation screens to aid safety assessments for chemicals and product
      formulations, and to facilitate design of safe and efficient human studies. In
      vitro responses in human skin equivalent cultures were compared directly to in
      vivo human skin responses from historic or concurrent skin tests for
      representative chemicals and products, including surfactants, cosmetics,
      antiperspirants, and deodorants. The in vivo data consisted of visual scores
      (i.e., erythema and edema) from skin-patch tests and diary accounts of skin
      irritation from product-use studies. In the in vitro studies, cornified, air
      interfaced human skin cultures (EpiDerm) were evaluated using methods designed to
      parallel human clinical protocols with topical dosing of neat or diluted test
      substances to the stratum corneum surface of the skin cultures. The in vitro
      endpoints have previously been shown to be relevant to human skin irritation in
      vivo, including the MTT metabolism assay of cell viability, enzyme release
      (lactate dehydrogenase and aspartate aminotransferase), and inflammatory cytokine
      expression (Interleukin-1alpha). For surfactants, dose-response curves of MTT
      cell-viability data clearly distinguished strongly-irritating from milder
      surfactants and rank-ordered irritancy potential in a manner similar to repeat
      application (3x), patch-test results. For the antiperspirant and deodorant
      products, all the in vitro endpoints correlated well with consumer-reported
      irritation (r, 0.75-0.94), with Interleukin-1alpha (IL-1alpha) release, showing
      the greatest capacity to distinguish irritancy over a broad range. IL-1alpha
      release also showed the best prediction of human skin scores from 14-day
      cumulative irritancy tests of cosmetic products. These results confirm the
      potential value of cornified human skin cultures as in vitro pre-clinical screens
      for prediction of human skin irritation responses. A preliminary report of these
      results has been published.

PMID- 10353314
TI  - Pharmacokinetic considerations of dexamethasone-induced developmental toxicity in
      rats.
AB  - Dexamethasone (DEX) has been shown to elicit growth stunting and cleft palate in
      rat fetuses. This investigation characterized DEX dosimetry as various
      pharmacokinetic parameters and evaluated their impact on developmental toxicity
      endpoints. DEX pharmacokinetics was evaluated as a single dose on either
      gestation day (GD) 9 or 14, as well as on GD 14 after multiple daily dosing from
      GD 9 to GD 14. An additional set of pregnant rats was dosed with DEX on GD 9
      through GD 14, pharmacokinetic evaluation was conducted on GD 14 through GD 16,
      and teratological evaluation was conducted following sacrifice on GD 20. For all
      pharmacokinetic evaluations, a subcutaneous (sc) injection of 0.8 mg DEX/kg body
      weight together with 50 microCi 3H-DEX was administered to Sprague-Dawley rats.
      Blood, urine, and feces were collected for 24 or 48 h. At GD 20 sacrifice,
      maternal tissues as well as fetal brain and liver samples were collected as part
      of the laparotomy. All samples were assayed using scintillation spectrometry. DEX
      pharmacokinetic parameters remained similar whether dosing occurred early (GD 9)
      or late (GD 14) in organogenesis, or dosing occurred on multiple sequential days
      (GD 9-14). DEX produced maternal and fetal weight loss, fetal lethality, and
      cleft palate. DEX a-half-life was positively correlated with the percentage of
      implants affected [(number of non-live + number with cleft palate)/number of
      implants]/litter. Neither the area under the concentration-time curve (AUC), the
      maximum maternal plasma concentration (Cmax), nor the terminal phase beta-half
      life correlated with any fetal outcome parameters. The correlation between the
      percentage of the litter that was affected and half-life was improved if AUC was
      added in a stepwise multiple regression. These data suggest that the length of
      time that DEX is present in the maternal plasma at a sufficiently high
      concentration (i.e., slower tissue distribution of DEX) appears to be important
      in determining the risk of an adverse outcome in the offspring.

PMID- 10353315
TI  - Relative developmental toxicities of acrylates in rats following inhalation
      exposure.
AB  - The developmental toxicities of seven acrylates were studied in Sprague-Dawley
      rats after inhalation exposure for 6 h/day, during days 6 to 20 of gestation. The
      exposure concentrations were: for acrylic acid, 50, 100, 200, or 300 ppm; for
      methyl acrylate, 25, 50, or 100 ppm; for ethyl acrylate, 25, 50, 100, or 200 ppm;
      for butyl acrylate, 100, 200, or 300 ppm; for ethylhexyl acrylate, 50, 75, or 100
      ppm; for hydroxyethyl acrylate, 1, 5, or 10 ppm; and for hydroxypropyl acrylate,
      1, 5, or 10 ppm. No treatment-related increases in embryo/fetal mortality or
      fetal malformations were observed after exposure to any of these acrylates. Fetal
      toxicity, indicated by reduced fetal body weight, was observed after exposure to
      300 ppm acrylic acid, 100 ppm methyl acrylate, 200 ppm ethyl acrylate, and 200 or
      300 ppm butyl acrylate in the presence of overt signs of maternal toxicity. While
      there was evidence of maternal toxicity, no significant developmental toxic
      effects were observed after exposure to ethylhexyl acrylate, hydroxyethyl
      acrylate, or hydroxypropyl acrylate at any concentration. These results indicate
      that inhaled acrylic acid, methyl acrylate, ethyl acrylate, butyl acrylate,
      ethylhexyl acrylate, hydroxyethyl acrylate, and hydroxypropyl acrylate are not
      selectively toxic to the embryo or fetus.

PMID- 10353316
TI  - Uptake of 10 polar organic solvents during short-term respiration.
AB  - Respiratory uptake was investigated for 10 polar organic solvents with high
      blood/air partition coefficients (lambda(blood/air)): ethyl acetate
      (lambda(blood/air), 77), methyl iso-butyl ketone (90), methyl acetate (90),
      methyl propyl ketone (150), acetone (245), iso-pentyl alcohol (381), iso-propyl
      alcohol (848), methyl alcohol (2590), ethylene glycol monobutyl ether (EGBE,
      7970), and propylene glycol monomethyl ether (PGME, 12380). Test-air
      concentrations (Cinh) were 25 to 200 ppm. Four healthy male volunteers inhaled
      the test air for 10 min at rest and then room air for 5 min. The percentage of
      solvent in the end-exhaled air and in the mixed-exhaled air increased after the
      start of the test-air respiration, and reached a quasi-steady-state level within
      a few min. The speeds of these increases at the start of the test-air respiration
      became lower as lambda(blood/air) increased. The mean uptakes (U) for the last
      five min of the test air respiration were 67.3, 52.9, 60.4, 53.0, 52.6, 63.0,
      60.3, 60.8, 79.7, and 81.3%, respectively, for ethyl acetate, methyl iso-butyl
      ketone, methyl acetate, methyl propyl ketone, acetone, iso-pentyl alcohol, iso
      propyl alcohol, methyl alcohol, EGBE and PGME. Thus, U values of the alcohols
      were higher than those of the ketones and lower than the glycol ethers. The
      overall view, except for esters, showed that U increased with lambda(water/air)
      increases. This tendency can be explained by a hypothesis that solvent absorbed
      in the mucus layer of the respiratory tract is removed by the bronchial blood
      circulation. U values of ethyl acetate and methyl acetate were higher than those
      of methyl iso-butyl ketone and methyl propyl ketone, though the lambda(blood/air)
      values of these esters were nearly equal to those of the ketones. For the
      respiration of the esters, their metabolites, ethyl alcohol and methyl alcohol,
      were detected in the exhaled air. The exhalation percentage of the metabolites
      increased after the start of test-air respiration and reached a quasi-steady
      state level of 2 and 3%, respectively, by the 5th min. These data suggest that
      removal of the solvent via metabolism in the wall tissue of the respiratory tract
      plays an important role for the esters.

PMID- 10353317
TI  - Modulation of serum growth factor signal transduction in Hepa 1-6 cells by
      acetaminophen: an inhibition of c-myc expression, NF-kappaB activation, and Raf-1
      kinase activity.
AB  - Acetaminophen (APAP) is a widely used analgesic and antipyretic that can lead to
      severe liver damage when taken at excessive doses. APAP toxicity results when
      cytochrome P450-generated APAP metabolites trigger an oxidative stress and
      covalently modify target proteins. APAP has also been reported to inhibit cells
      from completing S-phase through a cytochrome P450-independent mechanism, raising
      the possibility that APAP may directly suppress liver regeneration and repair.
      Here we show that APAP also inhibits entrance of Hepa 1-6 cells into the cell
      cycle by blocking a number of events associated with the G0-G1 transition. We
      have found that APAP inhibits serum growth factor activation of c-myc expression,
      NF-kappaB DNA binding, and Raf kinase. Therefore, the ability of APAP to inhibit
      passage of cells through both G1 and S phases might interfere with organ
      regeneration and thus exacerbate acute liver damage caused by APAP.

PMID- 10353318
TI  - Modification of lipoprotein lipase catalytic activity by sialic acids.
AB  - The role of sialic acid linked with lipoprotein lipase (LPL) in its catalytic
      activity was studied. When LPL was treated with sialidase, the molecular weight
      decreased by 2000. The sialidase-treated LPL showed unchanged hydrolyzing
      activity for tributyrin, a water-soluble substrate of esterase, compared with the
      untreated LPL. The sialidase-treated LPL also showed similar hydrolyzing activity
      for triolein emulsified with Triton X-100, phosphatidylcholine and
      phosphatidylethanolamine, whereas it showed significantly increased hydrolyzing
      activity for triolein emulsified with phosphatidylserine and cardiolipin (152%
      and 183%, compared with untreated LPL, respectively). In addition, the sialidase
      treated LPL showed significantly increased hydrolyzing activity against triolein
      incorporated into very low-density lipoproteins and chylomicrons (151% and 186%,
      compared with the untreated LPL, respectively). These results suggest that the
      loss of sialic acids does not modify the function of the catalytic site of LPL,
      but facilitates the interaction of the enzyme with the interface of the surface
      of substrate lipoproteins.

PMID- 10353319
TI  - Evaluation of kits for measurement of the soluble transferrin receptor.
AB  - Three commercially available kits for determination of the soluble serum
      transferrin receptor (sTfR), R&D Systems, UK, Ramco Laboratories, USA and Orion,
      Finland were compared with respect to practicability, comparability and ability
      to discriminate between iron deficient and non-iron deficient subjects. Serum
      samples representing different concentrations of sTfR were tested. The three kits
      involved virtually the same laboratory procedures except for a predilution step
      for Ramco. Both the absolute amounts and the units (mg/L and nmol/L) differed
      among the kits, emphasizing the need for internationally accepted reference
      material and comparable units. The correlation coefficients were 0.974 (Ramco and
      R&D), 0.769 (R&D and Orion) and 0.759 (Ramco and Orion), indicating a lower
      comparability for Orion compared to the other two kits. The differences between
      the kits may be attributed to uncertainties in the reference intervals and to
      variations in kit format. This may have implications for studies of the
      usefulness of sTfR as a marker of iron deficiency.

PMID- 10353320
TI  - Short- and long-term uses of calcium acetate do not change hair and serum zinc
      concentrations in hemodialysis patients.
AB  - Calcium acetate (CaAc) acutely decreases absorption of concomitantly administered
      zinc gluconate (Hwang et al., AJKD 1992), but its long-term effect on zinc
      metabolism has not been studied. This study is intended to elucidate whether use
      of CaAc as phosphate binder on a daily basis affects zinc status in hemodialysis
      (HD) patients. Effects of CaAc on serum zinc were studied in 44 HD patients for 8
      weeks (short-term). In 10 of these patients, the changes of serum and hair zinc
      were followed for 8 months (long-term). The daily dose of CaAc contained 25.35
      mmol elemental calcium. Serum and hair zinc concentrations were measured by
      atomic absorptiometry. Our results were as follows: (i) in the short-term study,
      serum zinc concentrations did not show a significant difference compared to the
      baseline; (ii) in the long-term study, serum zinc concentrations showed no
      significant difference between different time points (11.0+/-0.5 in the
      beginning, 11.9+/-0.4 after 2 months, 11.4+/-0.4 after 4 months and 11.3+/-0.5
      micromol/L after 8 months, n=10). However, these values were all significantly
      lower than in the normal controls (15.7+/-0.5 micromol/L, n=16); (iii) hair zinc
      content was not significantly different from the baseline level (2.7+/-0.1 in the
      beginning, 2.4+/-0.1 after 2 months, 2.6+/-0.2 after 4 months, 3.1+/-0.1
      micromol/g hair, and from that of normal controls, 2.7+/-0.2 micromol/g hair). In
      conclusion, daily application of CaAc does not significantly interfere with zinc
      absorption and storage in HD patients. However, the comparable hair zinc content
      in the presence of decreased serum zinc concentrations indicates that the
      metabolic processing of zinc in HD patients is different from that of normal
      individuals.

PMID- 10353321
TI  - Age-related reference intervals for lymphocyte subsets in whole blood of healthy
      individuals.
AB  - Enumeration of various lymphocyte subsets is used widely in the diagnosis and
      monitoring of various disease states. With the development of flow cytometric
      technology and whole blood analysis, methodologies have become more sensitive. It
      is therefore important to establish reference intervals in normal, healthy
      individuals using these techniques to give a better indication of the border
      between health and disease. Since some lymphocyte subpopulations are known to
      change with age, we have enumerated common subsets in healthy individuals from
      all decades of adult life, including nonagenarian subjects. We report reference
      intervals for these subsets in each age group, which will be of use in diagnosis
      and disease monitoring, particularly in elderly subjects, the most rapidly
      expanding group within the population today.

PMID- 10353322
TI  - Comparison of urinary excretion of albumin and alpha-1-antitrypsin in patients
      with arterial hypertension.
AB  - The aim of the presented pilot study was to compare urinary excretion of two
      plasma proteins similar in molecular mass and isoelectric point: albumin and
      alpha-1-antitrypsin (AAT) in patients with different forms of arterial
      hypertension and in healthy subjects. The 24-h urinary excretion of albumin and
      AAT were assessed in 52 patients, 29 with essential hypertension and 23 with
      secondary hypertension, caused by renovascular hypertension, adrenal
      phaeochromocytoma and obturative sleep apnoea syndrome. The concentrations of
      albumin and AAT were determined by rocket immunodiffusion. An increase of mean
      albumin and AAT urinary excretion was demonstrated, as compared to the control
      group, both in the patients with essential hypertension and with secondary
      hypertension. In 93.2% of the healthy subjects no AAT presence in urine was
      detected. No correlation was found between the excretion of albumin and AAT with
      urine.

PMID- 10353323
TI  - Lipid peroxidation and antioxidant enzyme activities in patients with type 1
      diabetes mellitus.
AB  - To evaluate oxidative stress in type I diabetes mellitus, two antioxidant enzymes
      in erythrocytes, copper-zinc superoxide dismutase (SOD EC 1.15.1.1.) and seleno
      dependent glutathione peroxidase (GSH-Px; EC 1.11.19), and two indexes of
      peroxidation in plasma, thiobarbituric acid reactive substances (TBARS) and
      organic hydroperoxides (OHP), were measured in 118 patients with insulin
      dependent diabetes mellitus (IDDM), classified in accordance with the presence or
      absence of vascular complications and the degree of metabolic control established
      by the HbA1c level. Ninety healthy subjects made up the control group. According
      to our results, plasmatic TBARS and OHP concentrations are significantly higher
      in diabetics than in controls, and these differences are accentuated in diabetic
      people with vascular disorders. The GSH-Px activity was significantly reduced in
      diabetic patients with poor and medium metabolic control in relation to the
      control group, regardless of the existence or absence of vascular disorders. No
      differences in SOD activity between diabetic and control groups were found. A
      significant positive correlation between TBARS and HPO (r=0.683, p<0.001) was
      found in both the control and diabetic groups. Among the lipid parameters
      studied, there were only significantly positive correlations between TBARS and
      total cholesterol; TBARS and triglycerides; OHP and total cholesterol and OHP and
      triglycerides. Positive correlations between TBARS and HbA1c and between OHP and
      and HbA1c, and negative correlations between GSH-Px and HbA1c and between SOD and
      HbA1c were also found. The multiple regression analysis shows that TBARS and HPO
      correlate negatively with GSH-Px. There was no significant correlation with SOD.

PMID- 10353324
TI  - Aldosterone metabolism in cultures of rat renal cortical and medullary cells.
AB  - The metabolism of 4-(14)C-d-aldosterone (at 3 nM) was studied in the primary
      target organ of the hormone, in renal cortical and medullary cell cultures
      obtained from Wistar rats. Larger amounts of aldosterone were metabolized in
      medullary cells than in cortical cells, as measured by a decreased 4-(14)C-d
      aldosterone radioactivity concentration (26+/-9% and 12+/-7% of the initial
      aldosterone added, respectively (n=5, p<0.05)). The 14C radiometabolites of
      aldosterone in both cultures co-chromatographed with 5alpha dihydro- (DHA) and
      3alpha,3beta tetrahydroaldosterone (THA). Aldosterone metabolism was totally
      inhibited by a mineralocorticoid receptor antagonist canrenoat (Soldactone) (at
      10(-5) to 10(-3) M), while the glucocorticoid receptor antagonist RU 38486
      (Roussel UCLAF) (at 10(-5) to 10(-4) M) had no effect. Thus, the study confirmed
      that, in rat kidney, aldosterone can be converted to its reduced metabolites by a
      metabolism which is inhibited by a mineralocorticoid receptor antagonist. This
      indicated that the metabolism might play some role in modulation of the
      intracellular response to aldosterone in the kidney.

PMID- 10353325
TI  - Skin mini-erosion technique for monitoring metabolites in interstitial fluid: its
      feasibility demonstrated by OGTT results in diabetic and non-diabetic subjects.
AB  - The aim of this study was to evaluate a new interstitial fluid (IF) sampling
      technique and its application in diabetology. IF and venous whole blood were
      sampled serially during an oral glucose tolerance test (OGTT) on days 1 and 3
      after formation of a mini-erosion in eight non-diabetic controls and eight Type 2
      diabetic subjects. Glucose, lactate, glycerol, 3-hydroxybutyrate and insulin were
      assayed in IF and plasma. With solitary exceptions, the IF sample volumes were in
      excess of those required for measurement of all five substances. However, mean IF
      sampling rates differed significantly both between the non-diabetic and diabetic
      groups and between days 1 and 3 (p < 0.001 in all cases). In both groups, the
      OGTT curves of glucose, glycerol and 3-hydroxybutyrate were similar to the
      respective curves for plasma, whereas for lactate concentrations they were
      markedly greater in IF than in plasma (40% and 93% in the control group and 57%
      and 100% greater in the diabetic group on days 1 and 3, respectively). The
      reverse was true of insulin concentrations in the non-diabetic group, which were
      57% and 74% lower in IF than in plasma on days 1 and 3, respectively. In the non
      diabetic group, the baseline (pre-OGTT) insulin level in IF increased from 49 +/-
      22% (SD) of that in plasma on day 1 to 74 +/- 19% of that in plasma on day 3
      (p=0.005). Sampling site re-epithelialization was rapid. In conclusion, the
      feasibility of transdermal sampling of IF via a skin mini-erosion has been
      demonstrated in both diabetic and non-diabetic subjects.

PMID- 10353326
TI  - Aminoterminal propeptide of type I collagen and bone alkaline phosphatase in the
      study of bone metastases associated with prostatic carcinoma.
AB  - The aim of this work was to evaluate the usefulness of serum aminoterminal
      propeptide of type I collagen (PINP) in the early detection of bone metastases
      associated with prostatic carcinoma. The results were compared with those of bone
      isoenzyme of alkaline phosphatase (bAP). Levels of total alkaline phosphatase
      (TAP) and prostatic specific antigen (PSA), related to the existence of bone
      metastases, are also evaluated. Fifty-five male patients aged 70-80 years were
      studied. Nine presented a benign prostatic hyperplasia (BPH) and the rest
      clinically confirmed prostatic cancer. Cancer patients were classified in
      accordance with the staging grouping of the International Union Against
      Cancer/American Joint Committee on Cancer TNM 1992 Revision: stage 0 or BPH
      (n=9), I (n=6), II (n=12), III (n=18) and IV (n=10). According to this
      classification, patients of groups BPH, I, II and III have no evidence of
      metastases. Those of stage IV present any type of metastases. In the case of this
      work, all patients of group IV presented bone metastases. Some patients of group
      BPH, I and II were untreated. The rest of the patients were under treatment
      (radical prostatectomy, telecobaltotherapy or hormonal therapy) for a period of
      between 6 months and 15 years. Serum PSA (Quimioluminiscence, IMMULITE), PINP
      (RIA, Orion Diagnostica), bAP (IRMA, Tamdem R-Ostase, Hybritech), and TAP
      (autoanalyzer) were determined. We found the following sensitivities and
      specificities (relating the presence of bone metastases to values higher than the
      upper limit of normality and, in the case of PSA, to values higher than 100
      microg/L): (1) PINP: 100% (10/10) and 87% (39/45), (2) bAP: 90% (9/10) and 82%
      (37/45), (3) TAP: 60% (6/10) and 93% (42/45), (4) PSA: 40% (4/10) and 100%
      (45/45). These results suggest that PINP and bAP are adequate biochemical markers
      of bone formation to be used in the detection of bone metastases in prostatic
      carcinoma, improving the sensitivity and specificity of TAP and PSA. With respect
      to PINP, bAP presents the disadvantage of its cross-reactivity with liver
      isoenzyme.

PMID- 10353327
TI  - Infusion of plasma expanders may lead to unexpected results in urinary protein
      assays.
AB  - Overt proteinuria was detected in the urine of a potential kidney donor,
      ultimately leading to the refusal of the kidneys for transplantation purposes.
      Histological examination of the kidneys did not reveal any abnormalities.
      Searching for substances that could have interfered with the urinary total
      protein assay, the role of infused, modified gelatin plasma expanders was
      investigated. We therefore measured the concentration of protein before and after
      the addition of various artificial plasma expanders to urine. Only when Biuret
      reagent or Pyrogallol Red dye were used did we find elevated concentrations of
      protein. Other methods, including the turbidimetric assays, did not detect
      additional amounts of protein in the spiked urine. We conclude that the infusion
      of modified gelatin solutions may cause apparent proteinuria. This effect is not
      observed with starch-based plasma expanders. Clinical chemists and clinicians
      should be aware of this phenomenon and possibly repeat the analysis with a
      different technique.

PMID- 10353328
TI  - Plasma total homocysteine response to oral doses of folic acid and pyridoxine
      hydrochloride (vitamin B6) in healthy individuals. Oral doses of vitamin B6
      reduce concentrations of serum folate.
AB  - Plasma total homocysteine response was compared in four groups of healthy
      individuals given orally divided doses of vitamin supplementations for a duration
      of 5 weeks. The vitamin supplements; A, 0.3 mg folic acid; B, 120 mg vitamin B6;
      C, combination of 0.3 mg folic acid and 120 mg vitamin B6 or D, 0.6 mg folic acid
      reduced the concentrations of plasma total homocysteine 20, 17, 32 and 24%,
      respectively. However, the intergroup comparisons did not show a significant
      difference in the effects of vitamin supplements. Multivariate analysis with
      correction for differences in pre-supplement values indicated a significant
      effect of vitamin B6 supplementation on plasma total homocysteine and serum
      folate. Our data show that plasma total homocysteine concentrations are reduced
      with low to medium divided doses of folic acid alone or in combination with
      vitamin B6.

PMID- 10353329
TI  - Interaction of perindoprilat with human red blood cells.
AB  - The effects of perindoprilat on the morphology and dynamic properties of human
      erythrocytes were studied by light microscopy, electron spin resonance
      spectroscopy and spectrophotometric methods. Erythrocytes were exposed to
      perindoprilat at 37 degrees C for 30 and 120 min. It was shown that the drug at a
      concentration of 0.75 microg/ml did not cause significant changes in the
      structure of erythrocyte membranes. Higher doses of the drug (7.5 and 75
      microg/ml) induced changes in membrane fluidity in the hydrophobic core of the
      lipid bilayer, the conformation of membrane proteins, the number of SH groups and
      the activity of membrane-bound acetylcholinesterase (AChE). These modifications
      were accompanied by changes in the shape of erythrocytes and did not depend on
      time of incubation. Therefore, it is proposed that perindoprilat perturbs the
      lipid bilayer and disturbs the organization of the protein-lipid environment.

PMID- 10353330
TI  - Lack of correlation between sensitivity characteristics of the tests for
      hepatitis C virus antibodies estimated with serially diluted and natural low
      reactive control specimens.
AB  - Sensitivity characteristics of seven commercial ELISA test systems for the
      detection of antibodies to hepatitis C virus were assessed using control panels
      consisting of: (i) serial dilutions of pooled sera highly reactive for anti-HCV;
      (ii) serial dilutions of RIBA 3.0 HCV SIA positive control; and (iii) natural
      (non-diluted, non-spiked) sera low-reactive for anti-HCV. "Dilutional
      sensitivity" values estimated with these two kinds of highly reactive samples did
      not coincide and were not found to correlate with the proportion of natural low
      reactive specimens detected by each test. Thus, laboratories assessing
      sensitivity of anti-HCV ELISAs should take into consideration the nature and
      properties of the control material used. Natural low-reactive control specimens
      are preferable because they adequately reflect the real serological picture of
      early stage of HCV infection.

PMID- 10353331
TI  - Inhibition of neurite outgrowth from chick sympathetic neurons by cholinesterase
      inhibitors is not mediated by binding to cholinesterases.
AB  - Several studies have suggested a role for cholinesterases in regulating neurite
      outgrowth. Some acetylcholinesterase (AChE) inhibitors can inhibit neurite
      outgrowth, but it is unclear if this is due to inhibition of AChE. In this study,
      the effect of cholinesterase inhibitors on neurite outgrowth from chick
      sympathetic neurons was examined. Very high (micromolar) concentrations of
      tacrine and BW284c51 were needed to inhibit neurite outgrowth. In contrast,
      nanomolar concentrations were required to block cholinesterase activity. No
      correlation was found between the type of inhibitor or potency of cholinesterase
      inhibition and inhibition of neurite outgrowth. Both tacrine and BW284c51 were
      neurotoxic at concentrations that inhibited outgrowth. Therefore, the action of
      cholinesterase inhibitors on neurite outgrowth may be due to non-specific
      toxicity rather than to cholinesterase binding.

PMID- 10353332
TI  - Intracerebral administration of L-kynurenine decreases N-methyl-D-aspartate
      receptor-mediated production of cGMP in the cerebellum and hippocampus of
      unanaesthetized rats subjected to transcerebral microdialysis.
AB  - The effects of intracerebral administration of L-kynurenine (L-KYN) on the N
      methyl-D-aspartate (NMDA) receptor-mediated, nitric oxide (NO)-dependent cGMP
      responses have been studied in vivo in the cerebellum and hippocampus of freely
      moving rats subjected to transcerebral microdialysis. Administration of exogenous
      NMDA in the cerebellum through the dialysis probe evoked a 3-fold increase of
      basal extracellular levels of cGMP that was concentration-dependently reduced by
      co-infusion of L-KYN. In the hippocampus, local administration of cyclothiazide
      caused a significant enhancement of the cyclic nucleotide dialysate
      concentrations that was accompanied by behavioural manifestations characteristic
      of preconvulsive states. Co-infusion of L-KYN largely decreased the neurochemical
      effects of cyclothiazide and completely prevented the appearance of the
      behavioural episodes. It is concluded that administration of L-KYN by increasing
      endogenous kynurenic acid concentrations might exert neuroprotective and
      anticonvulsive effects through blockade of the NMDA receptor/NO/cGMP pathway.

PMID- 10353333
TI  - Laminin inhibits both Abeta40 and Abeta42 fibril formation but does not affect
      Abeta40 or Abeta42-induced cytotoxicity in PC12 cells.
AB  - Laminin has recently been reported to inhibit both Abeta40 and Abeta42 fibril
      formation in vitro. Laminin was thus suggested to be an effective therapeutic
      agent for Alzheimer's disease. However, some recent reports have shown that Abeta
      fibril formation may not necessarily be linked to the development of Abeta
      neurotoxicity. In the present study, we thus investigated whether or not laminin
      affects Abeta40 and Abeta42-induced neurotoxicity. The findings of the present
      study by using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
      (MTT) dye reduction test showed laminin not to have an inhibitory effect on
      Abeta40 or Abeta42-induced cytotoxicity in PC12 cells while Abeta fibril
      formation was inhibited under the conditions used in the present study. The
      findings of the present study therefore do not support the hypothesis that Abeta
      fibril formation is absolutely required for the development of Abeta
      cytotoxicity.

PMID- 10353334
TI  - Hyperammonemia: regulation of argininosuccinate synthetase and argininosuccinate
      lyase genes in aggregating cell cultures of fetal rat brain.
AB  - Hyperammonemia in the brain leads to poorly understood alterations of nitric
      oxide (NO) synthesis. Arginine, the substrate of nitric oxide synthases, might be
      recycled from the citrulline produced with NO by argininosuccinate synthetase
      (AS) and argininosuccinate lyase (AL). The regulation of AS and AL genes during
      hyperammonemia is unknown in the brain. We used brain cell aggregates cultured
      from dissociated telencephalic cortex of rat embryos to analyze the regulation of
      AS and AL genes in hyperammonemia. Using RNase protection assay and non
      radioactive in situ hybridization on aggregate cryosections, we show that both AS
      and AL genes are induced in astrocytes but not in neurons of aggregates exposed
      to 5 mM NH4Cl. Our work suggests that the hyperammonemic brain might increase its
      recycling of citrulline to arginine.

PMID- 10353335
TI  - Site and event specific increase of striatal adenosine release by adenosine
      kinase inhibition in rats.
AB  - The effects of the systemically administered adenosine kinase (AK) inhibitor, 5'
      deoxy-5-iodotubercidin (5'd-5IT) on the striatal adenosine (ADO) release evoked
      by the excitotoxin, kainic acid (KA) were examined using rat bilateral striatal
      microdialysis. Local KA perfusion of one rat striatum caused a significant
      ipsilateral elevation of striatal ADO levels compared to basal and contralateral
      (artificial CSF-perfused) striatal ADO levels. KA-evoked striatal ADO release was
      augmented in animals receiving systemic 5'd-5IT treatment (cumulative dose of 7.5
      micromol/kg, i.p.) compared with i.p. vehicle controls. In contrast, 5'd-5IT
      administration had no significant effect on basal or contralateral (artificial
      CSF-perfused) striatal ADO levels. Thus, consistent with the hypothesis of 'site
      and event specific' potentiation of ADO by AK inhibitors, 5'd-5IT unilaterally
      enhanced ADO levels in the striatum where KA-induced excitotoxic injury evoked
      endogenous ADO release, but not at the contralateral uninjured striatum.

PMID- 10353336
TI  - Nitric oxide synthase is increased following small intestinal transplantation in
      the rat.
AB  - Transplantation of the small intestine is a neural model that could include
      extrinsic denervation, loss of intrinsic enteric neurons, or loss of intrinsic
      neural pathways. Nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase
      activity was measured in normal rat ileum, ileum 3 months after resection of the
      jejunum, and ileum 3 months after isotransplantation of the ileum. The
      distribution of NADPH diaphorase activity and immunoreactive neuronal nitric
      oxide synthase were examined. Nicotinamide adenine dinucleotide phosphate
      diaphorase activity was increased in transplanted ileum (16.5+/-3.5 mU/mg
      protein) compared to normal controls (6.6+/-0.7) and resection controls (6.8+/
      0.6) (P < 0.05, ANOVA). Histologically, NADPH diaphorase activity and
      immunoreactive nitric oxide synthase appeared increased within nerve cell bodies
      following transplantation. These findings may represent an adaptive response of
      the enteric nervous system to extrinsic denervation. Loss of intrinsic neural
      pathways was not supported as a mechanism.

PMID- 10353337
TI  - The effects of long-term bed rest on H-reflex and motor evoked potential in the
      human soleus muscle during standing.
AB  - H-reflex and motor evoked potential (MEP) induced by transcranial magnetic
      stimulation (TMS) in soleus muscle of five normal subjects were investigated
      before and after 20 days 6 degree head-down bed rest (BR). Soleus H-reflex during
      standing following bed rest decreased in all five subjects. The size of the
      maximum H-reflex (Hmax), expressed as a percentage of the maximum M-response
      (Mmax), decreased from 63.3+/-23.3% before BR to 26.7+/-12.5% after BR. However,
      there were no significant differences between MEPs before and after bed rest.
      Moreover, MEP/Hmax after bed rest was larger than before bed rest in all
      subjects. These results indicate a strong inhibition of H-reflex and no
      adaptation of MEP in soleus muscle during standing following bed rest.

PMID- 10353338
TI  - Peripheral morphine analgesia resistant to tolerance in chronic morphine-treated
      mice.
AB  - Intraplantarly (i.pl.)-injected morphine showed a peripheral analgesia in
      experiments to assess the blockade of bradykinin (i.pl.)-induced nociceptive
      flexor response in mice. The peripheral morphine analgesia in mice which
      developed central analgesic tolerance to chronic morphine (10 mg/kg s.c., 5
      days), was equivalent to that in vehicle-treated mice in any doses between 0.1
      and 1 nmol (i.pl.). These findings suggest that morphine tolerance in the central
      analgesia may use unique mechanisms deficient in the peripheral nervous system.

PMID- 10353339
TI  - Independent processing of changes in auditory single features and feature
      conjunctions in humans as indexed by the mismatch negativity.
AB  - The mismatch negativity (MMN), an event-related potential component of the EEG,
      is elicited by violations of auditory regularities In the present study, the
      stimulus blocks contained two types of standard tones, differing from each other
      in frequency and intensity. MMNs were recorded to three different types of
      deviant stimuli: (a) feature deviants, differing from standards in their
      perceived locus of origin; (b) conjunction deviants, having the frequency of one
      of the standards and the intensity of the other; (c) double deviants, differing
      from standards in both (a) and (b). The MMN to double deviants was similar to the
      sum of the MMNs to feature and conjunction deviants. This result indicates that
      changes in simple stimulus features and conjunction of features are processed
      independently by the automatic sound change detection system indexed by MMN.

PMID- 10353340
TI  - Inhibition of nicotine-induced hippocampal norepinephrine release in rats by
      alpha-conotoxins MII and AuIB microinjected into the locus coeruleus.
AB  - Hippocampal norepinephrine (NE) is secreted by neurons projecting from the locus
      coeruleus (LC) to the hippocampus; LC nicotinic receptors (NAchRs) are involved
      in the effects of systemic nicotine on this pathway. To clarify the NAchR
      subtypes, NAchR antagonists, termed alpha-conotoxins, were microinjected into the
      LC before nicotine; MII and AuIB were used to assess the potential involvement of
      alpha3beta2 and alpha3beta4 subunit-containing NAchRs, respectively. Nicotine
      dose-dependently stimulated hippocampal NE release (P < 0.01). MII (>0.25 pmol)
      reduced the NE response to nicotine (67% decrease; P < 0.05), as did AuIB (44%
      reduction by 25 pmol; P < 0.05). Administered together, however, MII and AuIB
      were no more effective than MII. Thus, MII and AuIB are capable of interacting
      with NAchR subtypes other than those previously defined as alpha3beta2 and
      alpha3beta4, respectively. NAchRs containing both beta2 and beta4-subunits may be
      involved.

PMID- 10353341
TI  - Immunoreactivity for multiple GABA transporters (GAT-1, GAT-2, GAT-3) in the
      gerbil pineal gland.
AB  - In order to further elucidate the role of gamma-aminobutyric acid (GABA) within
      the mammalian pineal gland, an immunocytochemical study was performed aimed at
      providing information on the occurrence and localization of the plasma-lemmal
      GABA transporters GAT-1-3 in the gerbil pineal organ. Whereas all three
      transporter subtypes were regularly present in this endocrine tissue, their
      cellular distribution differed. The analysis of serial semi-thin sections showed
      that pinealocytes as well as interstitial glial cells contain
      immunocytochemically detectable amounts of GAT proteins, indicating that both
      pineal parenchymal cell types participate in GABA reuptake. These results lend
      additional support to the hypothesis that GABA serves important physiological
      functions in the pineal gland.

PMID- 10353342
TI  - The effect of alpha-phenyl-N-tert-butyl nitrone on bioenergetic state in
      substantia nigra following flurothyl-induced status epilepticus in rats.
AB  - Status epilepticus (SE), i.e. ongoing seizures of more than 30 min duration,
      gives rise to bilateral pan-necrotic lesions of the substantia nigra, pars
      reticulata (SNPR). These are known to be preceded by an initial increase,
      followed by a depression of metabolic rate, and by failure of the bioenergetic
      state, suggesting mitochondrial dysfunction. We have previously shown that the
      spin trap alpha-phenyl-N-tert-butyl nitrone (PBN) prevents the lesions caused by
      45 min of SE from occurring, in spite of ongoing seizure activity. In this
      article, we demonstrate that PBN, given 30 min before seizure induction, reduces
      or prevents the decrease in ATP concentration and adenylate energy charge,
      without significantly reducing the amount of lactate accumulated, or the decrease
      in intracellular pH (pHi). The results suggest that the spin trap nitrone
      preserves the structural and functional integrity of SNPR neurons by protecting
      the mitochondria against oxidative damage.

PMID- 10353343
TI  - Attention modulates activity in the primary and the secondary auditory cortex: a
      functional magnetic resonance imaging study in human subjects.
AB  - Using functional magnetic resonance imaging, ten healthy subjects were scanned
      whilst listening to consonant-vowel syllables under three different conditions:
      (i) a 'no-attention' condition required subjects to ignore the stimuli; (ii) an
      'attend' condition requiring attentive listening to stimuli; (iii) a 'detect'
      condition requiring detection of a specific target syllable. Hemodynamic
      responses were measured in the primary and secondary auditory cortex. These three
      conditions were associated with significantly different activations in the
      primary and secondary auditory cortex. The strongest activations were found for
      the 'detect' condition, followed by the 'attend' condition. The weakest
      activation was evident during the 'no-attention' condition. There were also
      stronger activations in the left hemisphere and within the primary auditory
      cortex. These results suggest that the primary and secondary auditory cortex play
      a main role in the selective attention.

PMID- 10353345
TI  - The distribution of substance P receptor (NK1)-like immunoreactive neurons in the
      newborn and adult human spinal cord.
AB  - Substance P receptor (i.e. NK1)-like immunoreactive (SPR-LI) neurons were
      observed in the newborn and adult human spinal cord. Substance P receptor-like
      immunoreactive neuronal cell bodies were seen most frequently in lamina I, and
      were scattered throughout the remaining laminae of the dorsal horn and the area
      around the central canal. Some neurons in the intermediolateral nucleus also
      showed weak immunoreactivity. The pattern of distribution of SPR-LI neurons in
      the adult spinal cord was essentially the same as that in the newborn spinal
      cord. However, SPR-LI neurons cell bodies were seen much more frequently in the
      newborn than in the adult dorsal horn, especially in lamina II.

PMID- 10353344
TI  - Enhancement of MTT, a tetrazolium salt, exocytosis by amyloid beta-protein and
      chloroquine in cultured rat astrocytes.
AB  - The effect of amyloid beta-protein (Abeta) on the cellular reducing activity has
      been a controversial issue. We determined the cellular reducing activity in
      cultured astrocytes using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
      bromide (MTT) and 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4
      disulfophenyl )-2H-tetrazolium (WST-8) reduction assays following Abeta
      treatment. MTT reduction was inhibited whereas WST-8 reduction was unaffected by
      the Abeta treatment. Furthermore, the early extracellular appearance of MTT
      formazan, a reduced product of MTT, was observed in association with the rapid
      disappearance of intracellular formazan granules. Notably, similar results were
      obtained in cultures treated with chloroquine, a perturbant of membrane
      trafficking. Our results suggest that MTT formazan exocytosis is enhanced in a
      similar manner by Abeta and chloroquine and that this biological activity of
      Abeta may underlie the pathogenesis of Alzheimer's disease.

PMID- 10353346
TI  - Dorsal facial area of cat medulla; 5-HT2 action on glutamate release in
      regulating common carotid blood flow.
AB  - Serotonin (5-HT) may inhibit glutamate release in the dorsal facial area (DFA) of
      the medulla and decrease common carotid arterial (CCA) blood flow. We attempted
      to clarify which subtype(s) of 5-HT receptor was involved. A microdialysis probe
      was inserted in DFA. The concentration of glutamate in dialysates were determined
      by chromatography. Glutamate concentration was dose-dependently decreased by
      perfusion of 5-HT or DOI, a 5-HT2 agonist, but not by 5-CT, a 5-HT1 agonist. The
      5-HT-induced decrease in glutamate was reversed by co-perfusion of ketanserin, a
      5-HT2 antagonist, but not by propranolol, a 5-HT1 antagonist. CCA blood flow was
      decreased when 5-HT or DOI was perfused, and was reversed by co-perfusing
      ketanserin. In conclusion, 5-HT may inhibit glutamate release via 5-HT2 receptor
      in DFA, resulting in the reduction of CCA blood flow.

PMID- 10353347
TI  - Cognitive N140 electrogenesis and concomitant 40 Hz synchronization in mid
      dorsolateral prefrontal cortex (area 46) identified in non-averaged human brain
      potentials.
AB  - The mid-dorsolateral prefrontal area 46 has working memory functions for putting
      current cognitive processing into context and for updating relevant information
      on a trial-by-trial basis. Using non-averaged human brain responses to a target
      finger stimulus attended by the subject, we identified the cognitive prefrontal
      N140 electrogenesis with the Z method which numerically assesses the detailed
      consistency between scalp topographies of any single response and a grand average
      template. The cognitive N140 was present between 100 and 180 ms at the scalp
      contralateral to the attended target finger stimulus. Control responses to
      physically identical finger stimuli that were ignored by the subject did not
      elicit a prefrontal N140. In brain mapping the N140 focus was located 30-80 mm
      from scalp midline, and 50-60 mm in front of the vertex (Cz) coronal plane of the
      head. The data were consistent with recently disclosed anatomical locations of
      area 46 and they further document its interindividual variations in brain-to
      scalp relationship. N140, is thought to manifest cortico-cortical activation from
      the posterior parietal area 7b which generates the cognitive P100 electrogenesis
      that precedes N140 in the target response. At the prefrontal site, the non
      averaged EEG showed desynchronized 40 Hz oscillations, but these became
      transiently phase-locked in conjunction with the cognitive N140 excitatory
      effect. This seems in line with the Traub model suggesting that excitation of
      certain cortical inhibitory interneurons generates doublet firings which will
      pace the spiking of pyramidal neurons so as to promote synchronization at about
      40 Hz. These results complement our recent finding that P300 inhibition
      conversely disrupts on-going 40 Hz phase-locking ('binding'). Considering the
      marked trial-to-trial variations in timing of the cortical cognitive processes,
      such physiological relationships between target response components and 40 Hz
      dynamics could only be uncovered by studying non-averaged single responses.

PMID- 10353348
TI  - Short-term reorganization of the rat somatosensory cortex following hypodynamia
      hypokinesia.
AB  - This study was performed to determine if hypodynamia-hypokinesia (HH) could
      induce a reorganization of the rat somatosensory cortex. The cortical hindpaw
      representation was determined by stimulating the limb and recording multi-unit
      cortical activity. The size of the cutaneous receptive fields was also measured.
      After 14 days of HH, the size of the cortical hindpaw representation was
      decreased. The proportion of small cutaneous receptive fields decreased while the
      large ones increased. After 7 days of HH, no change in the two studied parameters
      was noticed in five animals. In the other rats, a number of sites unresponsive to
      cutaneous stimulation or with high thresholds was observed. This study provides
      evidence of a plasticity of the somatosensory cortex induced by a situation that
      reduces both sensory and motor functions. The cortical reorganization occurs in
      two stages.

PMID- 10353349
TI  - Neurogenetic correlates of Parkinson's disease: apolipoprotein-E and cytochrome
      P450 2D6 genetic polymorphism.
AB  - Brain tissue of 50 patients with morphological confirmed Parkinson's disease
      (PD), blood samples from 149 patients with clinical parkinsonism and from 96
      healthy control subjects were collected. Apolipoprotein-E (apo E) and cytochrome
      P450 2D6 (CYP2D6) genotyping were performed by PCR followed by restriction
      fragment analysis. A significantly higher allele frequency of CYP2D6*4 was found
      in patients with PD (35%) but not with parkinsonism (14.1%) compared to control
      subjects (19.8%). The combined alleles frequency of CYP2D6*3 + apoE4 was
      significantly higher not only in the PD group (33.3%) but also in patients with
      parkinsonism (22.3%) compared to control subjects (1.6%). These results suggest
      that there is a substantial overlap not only in the clinical manifestation but
      also in the genetic risk factors between Parkinson's and Alzheimer's diseases.

PMID- 10353350
TI  - Evaluation of the baculovirus-expressed S glycoprotein of transmissible
      gastroenteritis virus (TGEV) as antigen in a competition ELISA to differentiate
      porcine respiratory coronavirus from TGEV antibodies in pigs.
AB  - The spike (S) glycoprotein of the Miller strain of transmissible gastroenteritis
      virus (TGEV) was recently cloned and expressed in baculovirus. The recombinant S
      protein was used as the coating antigen in a competition (blocking) enzyme-linked
      immunosorbent assay (ELISA) in combination with monoclonal antibodies to the S
      protein epitope A (conserved on TGEV and porcine respiratory coronavirus [PRCV])
      or epitope D (present on TGEV only) to differentiate PRCV- from TGEV-induced
      antibodies. One set (set A) of 125 serum samples were collected at different
      times after inoculation of caesarean-derived, colostrum-deprived (n = 52) and
      conventional young pigs (n = 73) with 1 of the 2 porcine coronaviruses or
      uninoculated negative controls (TGEV/PRCV/negative = 75/30/20). A second set (set
      B) of 63 serum samples originated from adult sows inoculated with PRCV and the
      recombinant TGEV S protein or with mock-protein control and then exposed to
      virulent TGEV after challenge of their litters. Sera from set A were used to
      assess the accuracy indicators (sensitivity, specificity, accuracy) of the fixed
      cell blocking ELISA, which uses swine testicular cells infected with the M6
      strain of TGEV as the antigen source (ELISA 1) and the newly developed ELISA
      based on the recombinant S protein as antigen (ELISA 2). The sera from set B
      (adults) were tested for comparison. The plaque reduction virus neutralization
      test was used as a confirmatory test for the presence of antibodies to TGEV/PRCV
      in the test sera. The accuracy indicators for both ELISAs suggest that
      differential diagnosis can be of practical use at least 3 weeks after inoculation
      by testing the dual (acute/convalescent) samples from each individual in
      conjunction with another confirmatory (virus neutralization) antibody assay to
      provide valid and complete differentiation information. Moreover, whereas ELISA 1
      had 10-20% false positive results to epitope D for PRCV-infected pigs (set A
      samples), no false-positive results to epitope D occurred using ELISA 2,
      indicating its greater specificity. The progression of seroresponses to the TGEV
      S protein epitopes A or D, as measured by the 2 ELISAs, was similar for both sets
      (A and B) of samples. Differentiation between TGEV and PRCV antibodies (based on
      seroresponses to epitope D) was consistently measured after the third week of
      inoculation.

PMID- 10353351
TI  - Analysis of ruminant respiratory syncytial virus isolates by RNAse protection of
      the G glycoprotein transcripts.
AB  - Two different respiratory syncytial virus (RSV) radiolabeled probes were used to
      characterize the genetic heterogeneity of 25 ruminant RSV isolates by the
      ribonuclease protection assay. A 32P-radiolabeled antisense RNA probe was
      transcribed from cloned ovine and bovine RSV G glycoprotein genes and then
      hybridized with total RNA isolated from infected cells with various ruminant RSV
      isolates. The results of this study, along with previously published nucleotide
      sequence data of the ovine RSV G glycoprotein gene, suggest the presence of at
      least 2 ruminant RSV subgroups. One subgroup is represented by RSV isolated from
      respiratory disease outbreaks from calves and goats, and the other is represented
      by RSV isolated from sheep.

PMID- 10353352
TI  - Experimental infection of calves with bovine viral diarrhea virus genotype II (NY
      93).
AB  - To ascertain the virulence of bovine viral diarrhea virus (BVDV) genotype II,
      isolate NY-93 was inoculated intranasally into 3 calves, 2 of which were treated
      with a synthetic glucocorticoid prior to and after virus inoculation. Anorexia,
      fever (up to 42 C), dyspnea, and hemorrhagic diarrhea developed 6 days after
      intranasal inoculation with BVDV NY-93. The condition of all calves deteriorated
      further until the end of the study on day 14 postinoculation. The most
      significant postmortem macroscopic changes in all calves were limited to the
      gastrointestinal tract and consisted of moderate to severe congestion of the
      mucosa with multifocal hemorrhages. Microscopic lesions found in the
      gastrointestinal tract were similar to those observed in mucosal disease,
      including degeneration and necrosis of crypt epithelium and necrosis of lymphoid
      tissue throughout the ileum, colon, and rectum. The basal stratum of the
      epithelium of tongue, esophagus, and rumen had scattered individual necrotic
      cells. Spleen and lymph nodes had lymphocytolysis and severe lymphoid depletion.
      Severe acute fibrinous bronchopneumonia was present in dexamethasone-treated
      calves. Abundant viral antigen was detected by immunohistochemistry in the
      squamous epithelium of tongue, esophagus, and forestomachs. BVDV antigen was
      prominent in cells of the media of small arteries and endothelial cells. The
      presence of infectious virus in tissues correlated with an absence of circulating
      neutralizing antibodies. These findings highlight the potential of BVDV genotype
      II to cause severe disease in normal and stressed cattle.

PMID- 10353353
TI  - Development and evaluation of a polymerase chain reaction assay using the 16S
      rRNA gene for detection of Eperythrozoon suis infection.
AB  - The 16S ribosomal RNA (rRNA) gene of Eperythrozoon suis was amplified using gene
      specific primers developed from GenBank sequence accession U88565. The gene was
      subsequently cloned and sequenced. Based on these sequence data, 3 sets of E.
      suis-specific primers were designed. These primers selectively amplified 1394,
      690, and 839 base-pair (bp) fragments of the 16S rRNA gene from DNA of E. suis
      extracted from the blood of an experimentally infected pig during a parasitemic
      episode. No polymerase chain reaction (PCR) products were amplified from purified
      DNA of Haemobartonella felis, Mycoplasma genitalium, or Bartonella bacilliformis
      using 2 of these primer sets. When the primer set amplifying the 690-bp fragment
      was used, faint bands were observed with H. felis as the target DNA. No PCR
      products were amplified from DNA that had been extracted from the blood of a
      noninfected pig or using PCR reagents without target DNA. The detection limits
      for E. suis by competitive quantitative PCR were estimated to range from 57 and
      800 organisms/assay. This is the first report of the utility of PCR-facilitated
      diagnosis and quantitation of E. suis based on the 16S rRNA gene. The PCR method
      developed will be useful in monitoring the progression and significance of E.
      suis in the disease process in the pig.

PMID- 10353354
TI  - Dot immunobinding assay for detection of bovine herpesvirus 4 antibodies in
      rabbits.
AB  - A dot immunobinding assay (DIA) was used for the detection of antibody against
      bovine herpesvirus 4 (BHV-4) in experimentally infected specific-pathogen-free
      male and female rabbits. A semipurified virus preparation was used as the
      antigen, and protein A/G-horseradish-peroxidase conjugate and diaminobenzidine
      tetrahydrochloride were used as the detection system. Results of the DIA
      procedure on serum samples of experimentally infected male and female rabbits
      were compared with those of a complement-dependent virus neutralization (VN)
      test. None of the tested sera (0/60 samples) from either male or female rabbits
      were positive by the complement-dependent VN test. Results of the DIA procedure
      for the same tested sera were positive in 35 of 60 samples (58%) from BHV-4
      infected rabbits, indicating higher sensitivity of DIA procedure as compared with
      the complement-dependent VN test.

PMID- 10353355
TI  - Development of an ELISA for detection of myxoma virus-specific rabbit antibodies:
      test evaluation for diagnostic applications on vaccinated and wild rabbit sera.
AB  - An enzyme-linked immunosorbent assay (ELISA) was developed and compared with 2
      reference diagnostic tests (indirect immunofluorescence [IF] and complement
      fixation) to detect myxoma virus-specific antibodies in sera from 50 rabbits
      experimentally vaccinated with an attenuated strain of myxoma virus or with a
      Shope fibroma virus. The ELISA was highly specific (100% specificity) and
      sensitive (100%, 21 days after homologous vaccination). In a comparison of the
      ELISA with the IF test in 128 wild rabbits from France, discrepant results were
      obtained in only 11 (8.6%) animals, which were positive with the ELISA and
      negative with the IF test. The higher sensitivity and the good specificity of the
      ELISA was confirmed in a serologic survey of 118 rabbits from 2 Kerguelen (Indian
      Ocean) islands, where the prevalence of myxomatosis varied considerably. The
      ELISA is an alternative serologic test for diagnosis, vaccine evaluation, and
      seroepidemiologic surveys of myxomatosis.

PMID- 10353356
TI  - Application of a nested polymerase chain reaction assay to detect Mycoplasma
      hyopneumoniae from nasal swabs.
AB  - The porcine respiratory disease complex (PRDC) is an increasingly important cause
      of decreased swine productivity and is characterized by slow growth, decreased
      feed efficiency, anorexia, cough, and dyspnea. Mycoplasma hyopneumoniae is among
      the most prevalent and important infectious agents associated with PRDC.
      Understanding of mycoplasmal pneumonia has been hindered by inadequate diagnostic
      methods. Many of the currently available tests are relatively insensitive or
      nonspecific when used in a diagnostic laboratory setting or are too costly or
      difficult for routine diagnostic use. Several polymerase chain reaction (PCR)
      assays have been described, but they are not sensitive enough to detect the
      microorganisms in live pigs, from either nasal or tracheal swabs. A nested PCR
      using 2 species-specific sets of primers from the 16S ribosomal DNA gave positive
      results with as little as 80 microorganisms and did not cross-react with other
      mycoplasma species or with other microorganisms commonly found in the respiratory
      tract of pigs. This assay was better suited for detection of M. hyopneumoniae
      from nasal swabs than was conventional PCR. Nasal swab samples were taken at
      different time periods following experimental challenge of 10 susceptible pigs.
      Only 2 of the 55 swabs examined gave a positive result with conventional PCR,
      whereas 30 of the 55 swabs gave a positive result using the nested PCR. Twenty of
      40 (50%) nasal swabs from pigs experiencing a respiratory disease outbreak where
      M. hyopneumoniae had been diagnosed also gave a positive result with the nested
      PCR. To confirm that the amplified product was specific, 4 nested PCR products
      were purified, sequences were determined and aligned, and they were confirmed to
      be from M. hyopneumoniae.

PMID- 10353357
TI  - Isolation of cilia-associated respiratory (CAR) bacillus from pigs and calves and
      experimental infection of gnotobiotic pigs and rodents.
AB  - Filamentous, gram-negative bacteria morphologically similar to cilia-associated
      respiratory (CAR) bacillus of rodents and rabbits were isolated from the tracheas
      of 5 pigs and 4 calves. All pigs but none of the calves had histologic lesions of
      chronic tracheitis. In silver-stained histologic sections, CAR bacilli were
      adhered to the tracheal epithelium of each pig but were not found in the calves.
      Like CAR bacillus of rats, the bacteria displayed gliding motility and grew only
      in cell culture or cell culture medium supplemented with fetal serum. Initially,
      all isolates were contaminated by Mycoplasma spp. This contamination was
      eliminated from 4 pig isolates by limiting dilutions, and mycoplasma-free
      isolates were used to intranasally inoculate gnotobiotic pigs and CAR bacillus
      free mice and rats and to immunize guinea pigs. The gnotobiotic pigs remained
      healthy, and when they were necropsied 4 and 7 weeks after infection no
      macroscopic or microscopic lesions were found in the respiratory tract. However,
      CAR bacillus was isolated at both times from the nasal cavities and tracheas of
      inoculated pigs, and the ciliated tracheal epithelium of infected pigs necropsied
      7 weeks after infection was colonized by low numbers of CAR bacillus-like
      bacteria. The rats and mice remained healthy through week 12 postinoculation, and
      evidence of short- or long-term colonization was not detected by histologic
      examination or culture. When used as primary antibody for immunohistochemical
      staining, sera from guinea pigs immunized with pig CAR bacillus specifically
      stained CAR bacilli colonizing the respiratory epithelium of naturally infected
      pigs, whereas sera collected prior to immunization failed to react with the
      bacteria. These results indicate that CAR bacilli are unlikely to be primary
      pathogens of pigs or cattle and that rodents do not act as reservoirs.

PMID- 10353358
TI  - Western immunoblot analysis for distinguishing vaccination and infection status
      with Borrelia burgdorferi (Lyme disease) in dogs.
AB  - Serodiagnosis of Lyme borreliosis in dogs is complicated by the use of
      commercially available Lyme disease vaccines that may cross-react with certain
      diagnostic assays. Western immunoblotting may be used to distinguish between dogs
      naturally exposed and those vaccinated against Borrelia burgdorferi. Because
      current vaccines are not 100% efficacious and dogs may be vaccinated after
      natural exposure, certain dogs may show serum antibody responses against both
      natural and vaccine exposure (dual status). In this study, samples from 17
      nonexposed, 17 B. burgdorferi-bacterin vaccinated, 13 naturally exposed, and 8
      dual-status dogs were tested by western immunoblot to determine if dual-status
      dogs could be reliably differentiated from naturally infected or vaccinated dogs.
      Reaction to outer surface protein A antigen of B. burgdorferi (31 kD) was a
      consistent marker for vaccination, appearing in all samples from vaccinate and
      dual-status dogs and in no samples from single-status naturally exposed dogs.
      Antibodies to 4 bands, at 80, 39, 29, and 28 kD, were present in all naturally
      infected and dual-status dogs. No samples from vaccinated or nonexposed dogs were
      reactive to all 4 of these bands simultaneously. Thus, vaccine and natural
      exposure produce differing antibody responses, whereas dual-status dogs produced
      the full antibody response of both types of exposure.

PMID- 10353359
TI  - A lysosomal storage disease induced by Ipomoea carnea in goats in Mozambique.
AB  - A novel plant-induced lysosomal storage disease was observed in goats from a
      village in Mozambique. Affected animals were ataxic, with head tremors and
      nystagmus. Because of a lack of suitable feed, the animals consumed an exotic
      hedge plant growing in the village that was identified as Ipomoea carnea (shrubby
      morning glory, Convolvulaceae). The toxicosis was reproduced by feeding I. carnea
      plant material to goats. In acute cases, histologic changes in the brain and
      spinal cord comprised widespread cytoplasmic vacuolation of neurons and glial
      cells in association with axonal spheroid formation. Ultrastructurally,
      cytoplasmic storage vacuoles in neurons were membrane bound and consistent with
      lysosomes. Cytoplasmic vacuolation was also found in neurons in the submucosal
      and mesenteric plexuses in the small intestine, in renal tubular epithelial
      cells, and in macrophage-phagocytic cells in the spleen and lymph nodes in acute
      cases. Residual alterations in the brain in chronic cases revealed predominantly
      cerebellar lesions characterized by loss of Purkinje neurons and gliosis of the
      Purkinje cell layer. Analysis of I. carnea plant material by gas chromatography
      mass spectrometry established the presence of the mannosidase inhibitor
      swainsonine and 2 glycosidase inhibitors, calystegine B2 and calystegine C1,
      consistent with a plant-induced alpha-mannosidosis in the goats. The described
      storage disorder is analogous to the lysosomal storage diseases induced by
      ingestion of locoweeds (Astragalus and Oxytropis) and poison peas (Swainsona).

PMID- 10353360
TI  - Odontogenic myxoma of the mandible in a filly.

PMID- 10353361
TI  - Abdominal spindle cell sarcoma of probable myofibroblastic origin in a horse.

PMID- 10353362
TI  - Prostatic leiomyosarcoma in a dog.

PMID- 10353363
TI  - Immunohistochemical detection of peste des petits ruminants viral antigen in
      formalin-fixed, paraffin-embedded tissues from cases of naturally occurring
      infection.

PMID- 10353364
TI  - Chronic experimental fumonisin intoxication of calves.

PMID- 10353365
TI  - Serodiagnosis of equine piroplasmosis, dourine, and glanders using an arrayed
      immunoblotting method.

PMID- 10353366
TI  - Cross-reactivity of an automated human haptoglobin immunoturbidimetric assay for
      detection of haptoglobin in swine serum.

PMID- 10353367
TI  - Avian sexing: an optimized protocol using polymerase chain reaction-single-strand
      conformation polymorphism.

PMID- 10353368
TI  - Contributions of prefrontal cortex to recognition memory: electrophysiological
      and behavioral evidence.
AB  - To clarify the involvement of prefrontal cortex in episodic memory, behavioral
      and event-related potential (ERP) measures of recognition were examined in
      patients with dorsolateral prefrontal lesions. In controls, recognition accuracy
      and the ERP old-new effect declined with increasing retention intervals. Although
      frontal patients showed a higher false-alarm rate to new words, their hit rate to
      old words and ERP old-new effect were intact, suggesting that recognition
      processes were not fundamentally altered by prefrontal damage. The opposite
      behavioral pattern was observed in patients with hippocampal lesions: a normal
      false-alarm rate and a precipitous decline in hit rate at long lags. The intact
      ERP effect and the change in response bias during recognition suggest that
      frontal patients exhibited a deficit in strategic processing or postretrieval
      monitoring, in contrast to the more purely mnemonic deficit shown by hippocampal
      patients.

PMID- 10353369
TI  - Mapping of semantic, phonological, and orthographic verbal working memory in
      normal adults with functional magnetic resonance imaging.
AB  - Twelve neurologically normal participants (4 men and 8 women) performed semantic,
      phonological, and orthographic working memory tasks and a control task during
      functional magnetic resonance imaging. Divergent regions of the posterior left
      hemisphere used for decoding and storage of information emerged in each working
      memory versus control task comparison. These regions were consistent with
      previous literature on processing mechanisms for semantic, phonological, and
      orthographic information. Further, working memory versus control task differences
      extended into the left frontal lobe, including premotor cortex, and even into
      subcortical structures. Findings were consistent with R. C. Martin and C.
      Romani's (1994) contention that different forms of verbal working memory exist
      and further suggest that a reconceptualization of premotor cortex functions is
      needed.

PMID- 10353370
TI  - Regional cerebral volume loss associated with verbal learning and memory in
      dementia of the Alzheimer type.
AB  - Twenty-seven research participants with dementia of the Alzheimer type were
      studied with the California Verbal Learning Test (D. C. Delis, J. H. Kramer, E.
      Kaplan, & B. A. Ober, 1987) and standardized volume measures of the mesial
      temporal cortical gray matter, neocortical gray matter, thalamus, and caudate
      nuclei, from magnetic resonance imaging. A pattern of atrophic brain changes in
      the mesial temporal lobes (MTL) and the thalamus, with relatively less severe
      atrophy in the neocortical gray matter, was associated with poorer learning of
      the word list. Similar patterns of brain atrophy were observed for measures of
      delayed recall and recognition hits. However, for delayed recall, neither
      contribution was statistically significant, and for recognition hits, MTL was
      only at the trend level for significance. These results provide evidence that the
      verbal memory deficit of Alzheimer's disease (AD) is associated not only with the
      mesial temporal limbic cortex, thought to be the site of earliest and most severe
      pathology in AD, but also with damage in the thalamus.

PMID- 10353372
TI  - Quantitative modeling of visual attention processes in patients with Parkinson's
      disease: effects of stimulus integrality on selective attention and dimensional
      integration.
AB  - Parkinson's disease (PD) patients and normal controls (NCs) were administered a
      series of visual attention tasks. The dimensional integration task required
      integration of information from 2 stimulus dimensions. The selective attention
      task required selective attention to 1 stimulus dimension while ignoring the
      other stimulus dimension. Both integral- and separable-dimension stimuli were
      examined. A series of quantitative models of attentional processing was applied
      to each participant's data. The results suggest that (a) PD patients were not
      impaired in integrating information from 2 stimulus dimensions, (b) PD patients
      were impaired in selective attention, (c) selective attention deficits in PD
      patients were not due to perceptual interference, and (d) PD patients were
      affected by manipulations of stimulus integrality and separability in much the
      same way as were NCs.

PMID- 10353371
TI  - Perceptual fluency as a cue for recognition judgments in amnesia.
AB  - This study investigated the extent to which amnesic patients use fluency of
      perceptual identification as a cue for recognition. Perceptual fluency was
      measured by having participants gradually unmask words before making recognition
      judgments. In Experiment 1, familiarity was the only possible basis for
      recognition because no words had been presented in the study phase. In Experiment
      2, recollection provided an alternative basis for recognition because words had
      appeared in the study phase. Amnesic patients were as likely as normal controls
      to use perceptual fluency as a cue for recognition in Experiment 1 but were more
      likely than controls to do so in Experiment 2. For both groups, perceptual
      fluency affected judgments for studied and unstudied items to the same extent in
      Experiment 2. These findings suggest that amnesic patients do use perceptual
      fluency cues, but reliance on perceptual fluency does not necessarily elevate
      recognition accuracy.

PMID- 10353373
TI  - Visual attention deficits in Alzheimer's disease: simple versus conjoined feature
      search.
AB  - The authors investigated selective attention in patients with Alzheimer's disease
      (AD), using a well-known visual search procedure. In simple feature search, the
      deficit observed in AD patients represented a baseline shift in the median hit
      reaction time (RT). On the conjoined feature search task, the median hit RT for
      AD patients increased disproportionately with increasing array size, indicating
      an additional cognitive impairment on this task. Of particular importance, the
      cognitive deficit observed in conjunction search was more profound than that
      predicted on the basis of previous reports of global cognitive slowing in AD.
      There was some evidence that the performance of AD patients improved more than
      the performance of controls over the duration of the experimental test session.
      Patients also had more difficulty in detecting targets on the right side of
      hemispace and in more peripheral locations.

PMID- 10353374
TI  - Redundancy gains for visual search after complete commissurotomy.
AB  - Redundant-targets effects (RTE) for visual search were investigated in 2
      commissurotomy patients (L.B., N.G.). L.B., who showed no evidence of visual
      interhemispheric transfer, exhibited a paradoxical enhancement of the redundancy
      gain in the bilateral compared with the within-hemifield redundant-targets
      conditions, whereas N.G., who showed evidence of interhemispheric transfer of
      visual information, exhibited no enhancement of the bilateral redundancy gain.
      When only uncrossed responses were considered, both bilateral and within-field
      RTE were evident only when attentional demands were high. Bilateral redundant
      targets led to stronger gains, some indicative of coactivation, in the slower
      response hand. The authors suggest that the enhancement of the bilateral RTE
      comes about by neural coactivation, which is especially pronounced when the
      slower hemisphere elicits the response.

PMID- 10353375
TI  - Spatial and semantic inhibitory processing in schizophrenia.
AB  - Two experiments assessed inhibitory mechanisms associated with the posterior and
      anterior attention networks in schizophrenia. Experiment 1 assessed the
      inhibition of return effect of the posterior network. Both healthy adults and
      schizophrenic adults showed inhibition of return, suggesting that this inhibitory
      mechanism of visual orienting is preserved in schizophrenia. Experiment 2
      assessed semantic inhibition, which supposedly taps the anterior network, in a
      lexical-decision task. Healthy adults showed semantic inhibition effects in both
      visual fields. Schizophrenic adults showed semantic inhibition effects when
      targets were presented to the left visual field, involving the right hemisphere.
      However, semantic facilitation rather than inhibition was observed when targets
      were presented to the right visual field, involving the left hemisphere. These
      results reflect left hemisphere dysfunction associated with deficits in
      attentional control in schizophrenia.

PMID- 10353376
TI  - Hemispheric and attentional contributions to perceptual organization deficits on
      the global-local task in schizophrenia.
AB  - Right and left hemisphere hypotheses have been proposed to account for cognitive
      deficits in schizophrenia. To examine these hypotheses, perception of global
      local patterns was studied in 22 patients with schizophrenia and 28 normal
      comparison participants. The patients with schizophrenia showed an abnormally
      exaggerated global processing advantage when attention was divided between global
      and local levels but not when participants were instructed to attend to either
      the local or global level. This finding suggested a local processing (left
      hemisphere) deficit, which was overcome through strategic attentional allocation
      (instructional set). When the stimulus visual angle was reduced from 9 degrees to
      3 degrees, the normal participants showed a shift from a local to a global
      processing advantage, but the patients did not. This finding suggested a more
      subtle deficit in strategic attentional processes that develop through exposure
      to stimulus context.

PMID- 10353377
TI  - The selective effects of alcohol on automatic and effortful memory processes.
AB  - Automatic and effortful memory processes were evaluated in a 2-session, within
      subjects design involving an alcohol challenge and a no-alcohol condition. Free
      recall of a 90-word list measured effortful processing. Estimation of word
      frequency from the same list measured automatic processing. Acute intoxication
      was hypothesized to diminish effortful but not automatic memory processes.
      Healthy, male volunteers (n = 36) completed the 2 conditions 1 week apart.
      Presentation frequency influenced both free recall and frequency estimation, with
      both measures increasing as presentation frequency increased. Free recall was
      significantly lower in the alcohol than in the no-alcohol condition, but
      frequency estimation was not differentially affected. The data showed that an
      alcohol challenge dissociated automatic and effortful memory processes in
      volunteers. The authors discuss potential neurobiological substrates that may
      account for alcohol's selective disruption of effortful, verbal, episodic memory
      processing.

PMID- 10353378
TI  - Functional asymmetries in the quality of handwriting movements: a kinematic
      analysis.
AB  - Writing hand preference is a prominent functional asymmetry, but biomechanical
      factors may also contribute to any kinematic differences in the quality of
      handwriting movements performed by either hand. Eighteen dextral participants
      used a noninking pen with their right or left hand to write cursive letter ls,
      inverted ls, and their mirror images (to control for biomechanical differences)
      on a graphics tablet. Kinematic analysis of the scaling, consistency, efficiency,
      and shape of writing stroke trajectories revealed functional asymmetries between
      hands. The right hand was faster and produced more efficient strokes, which were
      of more consistent length, duration, and peak velocity. Differences between hands
      do not simply reflect biomechanical factors; therefore, the documentation of any
      functional asymmetries may allow their subsequent use as markers of underlying
      pathology in conditions such as schizophrenia.

PMID- 10353379
TI  - Inaccurate prediction of retrieval in a face matrix learning task after right
      frontal lobe lesions.
AB  - This study partly supports the hypothesis that frontal lobe lesions cause
      impairment of metamemory. Fifty-nine patients with a focal brain lesion and 21
      non-brain-damaged patients memorized a 4 X 4 matrix of 16 faces in 6 consecutive
      trials and predicted the number of locations of faces they would be able to
      remember before each retrieval. When age-related impairment of learning was
      adjusted, the patients with right posterior lesions were inferior to the controls
      and to the patients with right frontal lesions on the total number of correctly
      placed faces. The patients with right frontal lesions were less accurate than the
      patients with right posterior lesions or the controls in the prediction of
      retrieval. The inaccuracy of retrieval prediction in the face test was associated
      with that in a word-list learning task.

PMID- 10353380
TI  - Computerized and traditional stroop task dysfunction in HIV-1 infection.
AB  - Controlled processing, response inhibition, and set adoption were examined in 51
      HIV-1 infected participants and 21 uninfected controls who were administered a
      vocal reaction time (RT) version of the Stroop task (Stroop-RT; J. R. Stroop,
      1935) as well as the traditional 100 item paper-and-pencil version. Response set
      expectancies on the Stroop-RT were manipulated by presenting 50% of trials in
      homogenous blocks and randomly varying the stimulus type during the remaining
      trials. As hypothesized, HIV seropositive (HIV+) participants were significantly
      slower than HIV seronegative controls on both versions of the Stroop. Significant
      interference effects were apparent on the paper-and-pencil version of the Stroop,
      but were not as prominent on the Stroop-RT. The HIV+ participants did profit from
      the blocking manipulation on the Stroop-RT, suggesting that set adoption is
      retained in HIV infection. These data suggest that HIV infection may result in
      deficient response inhibition, possibly secondary to frontostriatal dysfunction
      and dopaminergic alterations.

PMID- 10353381
TI  - The use of short-and medium-term tests for carcinogens and data on genetic
      effects in carcinogenic hazard evaluation. Consensus report.

PMID- 10353382
TI  - Mutations and altered expression of the human cancer genes: what they tell us
      about causes.
AB  - To understand the causes of cancer, it is necessary to elucidate the molecular
      basis and environmental factors that influence the carcinogenesis process.
      Cancers are progressive diseases characterized by the accumulation of defects in
      many different genes. The patterns of mutation of some genes identified in
      tumours suggest a direct action of chemicals binding to and altering DNA. Other
      cancer-associated genes may be altered as a consequence of endogenous mutagens,
      germ-line mutations, spontaneous mutations that occur during cell replication or
      increased genetic instability in precancerous cells. Recent advances in molecular
      biology and genetics have provided new tools and concepts for studying the causes
      of cancer. We know that cancers are caused by a combination of environmental and
      genetic factors, and the discovery of the molecular alterations that occur at
      various stages in different tumours is increasing our understanding of these
      causes. Thus, we are now beginning to discover which genes are involved, how they
      function normally and in tumour tissues and why cancers develop after a series of
      genetic and epigenetic changes in certain cells. As data from studies on cancer
      associated genes have accrued, the categories of genes and molecular pathways
      that have been found to play a role in carcinogenesis have also increased. Genes
      involved in development and other normal cellular processes have been implicated
      in cancer. These include genes involved in signal transduction, cell cycle
      control, DNA repair, cell growth and differentiation (growth factors and growth
      factor receptors), transcriptional regulation, senescence and apoptosis. Genes
      involved in angiogenesis, immune regulation, cellular responses to stress,
      motility, adhesion and invasion are also involved, but less is known about their
      relationship to carcinogenesis, and these processes are not discussed in this
      review. The diverse nature of these categories of cancer-related genes indicates
      the variety of processes that must be disrupted in order for tumours to develop.
      Many of the genes have several functional domains, and the functions of some have
      only recently been proposed. In this review, we describe some of the major
      classes of genes implicated in human cancers and some of the major findings on
      genetic alterations and dysfunction in human tumours. Comparisons are made with
      certain rodent models.

PMID- 10353383
TI  - Analysis of somatic mutations of the p53 gene in human cancers: a tool to
      generate hypotheses about the natural history of cancer.

PMID- 10353384
TI  - Mutations in ras genes in experimental tumours of rodents.
AB  - Studies of carcinogenesis in rodents are valuable for examining mutagenesis in
      vivo. An advantage of evaluating the frequency and spectra of ras mutations in
      chemically induced neoplasms is that the additional data at the molecular level
      indicate whether the carcinogenic effect is due to the chemical and is not a
      spontaneous event, as illustrated by the numerous examples in Appendices 1 and 2.
      In addition, data on the frequency and spectra of ras mutations in spontaneous
      and chemically induced neoplasms clearly expand the toxicological database by
      providing information helpful for understanding the pathogenesis of
      carcinogenesis. For example: (1) ozone-induced lung neoplasms had two unique
      mutations, one (codon 61 K-ras CTA mutation) consistent with a direct genotoxic
      event and a second (codon 12 K-ras G --> T transversion) consistent with an
      indirect genotoxic effect; (2) isoprene-induced Harderian gland neoplasms had a
      unique K-ras A --> T transversion at codon 61 which provided evidence that
      formation of an epoxide intermediate was involved; (3) 1,3-butadiene-induced
      neoplasms had a characteristic K-ras G --> C transversion mutation at codon 13
      which was also consistent with a chemical-specific effect; (4) methylene chloride
      induced liver neoplasms had an H-ras mutation profile at codon 61 similar to that
      of spontaneous tumours, suggesting that methylene chloride promotes cells with
      'spontaneously initiated' ras mutations and (5) oxazepam-induced liver neoplasms
      had a low frequency of ras mutations, suggesting a nonmutagenic pathway of
      carcinogenesis. By extending the evaluation of rodent tumours to include
      molecular studies on ras mutation spectra and abnormalities in other cancer genes
      with human homologues, a number of hypotheses can be tested, allowing the most
      complete understanding of carcinogenesis in rodents and in potential
      extrapolation to the human risk situation.

PMID- 10353385
TI  - Mutation patterns in non-ras oncogenes and tumour suppressor genes in
      experimentally induced tumours.

PMID- 10353386
TI  - Genetically altered mouse models for identifying carcinogens.

PMID- 10353387
TI  - Use of non-mammalian species in bioassays for carcinogenicity.
AB  - The high costs of bioassays for carcinogenicity in rodents have sparked interest
      in the use of non-mammalian species as possible alternatives. Invertebrate and
      lower vertebrate species have been used for many years in bioassays for
      teratogenicity, toxicity and carcinogenicity involving exposure to a range of
      genotoxic compounds. Carcinogenicity tests have shown that the development of
      neoplasia in non-mammalian species is predictable and reproducible and that the
      results are affected by species, age, chemical class and dose. One disadvantage
      of using these species in cancer bioassays is the absence of tissues of critical
      importance in human cancer, such as prostate, lung and breast; however, the
      similarities between mammals and lower species in basic cellular responses to
      carcinogens allow reliable correlation of many mechanisms of cancer development
      down the phylogenetic tree.

PMID- 10353388
TI  - Chemically induced preneoplastic lesions in rodents as indicators of carcinogenic
      activity.

PMID- 10353389
TI  - Short-and medium-term carcinogenicity tests: simple initiation-promotion assay
      systems.

PMID- 10353390
TI  - Medium-term bioassays in rats for rapid detection of the carcinogenic potential
      of chemicals.

PMID- 10353391
TI  - Active cell death (apoptosis) and cellular proliferation as indicators of
      exposure to carcinogens.
AB  - An excess of cell multiplication over cell death is a crucial characteristic of
      preneoplastic and neoplastic cell populations. In many tumours, the rates of both
      cell birth and cell death are increased over those in the tissue of origin. Cell
      death may occur through active mechanisms: cellular suicide or active or
      programmed cell death, often referred to as apoptosis. The term 'apoptosis' was
      originally used on morphological grounds for a type of cell death characterized
      by condensation and fragmentation of cytoplasm and chromatin; however, other
      types of active cell death exist, in which cytoplasmic degradation by lysosomal,
      autophagic or proteasomal mechanisms may dominate, e.g. in some experimental
      mammary tumours and mammary tumour cell lines. Morphological and biochemical
      differences between the types of programmed cell death should be considered when
      selecting markers for identification and quantification of cell death. There is
      still a paucity of specific, efficient methods to assay active cell death, and
      unequivocal differentiation from degenerative necrosis, especially in tumours,
      may be difficult or impossible. Active cell death is regulated by a complex
      network of survival factors and death signals. Many mitogens of exogenous or
      endogenous origin not only stimulate cell birth but at the same time may inhibit
      cell death, i.e. increase survival. Endogenous factors also exist which induce
      active cell death; these include transforming growth factor beta1, CD95 or Fas
      ligand and tumour necrosis factor. Signal pathways leading to birth or death of
      cells appear to be interconnected to allow for the fine tuning of cell numbers in
      tissues. Active cell death can be triggered in two principal ways: by toxic
      chemicals or injury leading to damage of DNA or of other important cellular
      targets, and activation or inactivation of receptors by growth-regulating signal
      factors in the organism. Increases in cell proliferation or in cell survival
      induced by a chemical do not necessarily lead to cancer, but may indicate
      carcinogenic potential. Chemicals can affect the balance between replication and
      death of cells in a number of ways. Firstly, genotoxic carcinogens induce genetic
      damage which subsequently leads to activation of the suicide machinery, involving
      genes such as p53. As a result, cells with promutational lesions and mutations
      are eliminated, thereby providing protection from potentially initiated cells.
      Secondly, toxic doses of genotoxic or nongenotoxic agents induce acute or chronic
      injury, leading to cell death and subsequent regenerative proliferation. Thirdly,
      nongenotoxic carcinogens which are primary mitogens may increase the birth and/or
      inhibit the death of cells by direct interference with growth signalling
      pathways. This group of agents includes several trophic hormones; e.g. oestradiol
      stimulates both the replication and survival of mammary tumour cells. As
      demonstrated in the rat liver model, preneoplastic and neoplastic cells may be
      over-responsive to mitogenic or survival signals and thereby undergo selective
      growth. Conversely, preneoplastic clones and even malignant tumours may still
      depend on the survival effect of mitogens and regress upon withdrawal of the
      agent. This indicates that the mitogenic action of the agent is reversible and
      underlines the principal difference between genotoxic and nongenotoxic
      carcinogens. In conclusion, studies on cell proliferation and cell death are
      useful as adjuncts to carcinogenicity assays, and the results may facilitate the
      interpretation of effects. In conjunction with other biological data, this
      information may provide an indication of potential carcinogenicity.

PMID- 10353392
TI  - DNA adducts in mammalian cells as indicators of exposure to carcinogens.

PMID- 10353393
TI  - DNA damage and repair in mammalian cells in vitro and in vivo as indicators of
      exposure to carcinogens.

PMID- 10353394
TI  - Mutation in mammalian cells in vitro and in vivo as indicators of exposure to
      carcinogens.

PMID- 10353395
TI  - Induction of mutations in transgenic animal models: BigBlue and Muta Mouse.

PMID- 10353396
TI  - Chromosomal changes.

PMID- 10353397
TI  - Use of Syrian hamster embryo and BALB/c 3T3 cell transformation for assessing the
      carcinogenic potential of chemicals.

PMID- 10353398
TI  - The results of assays in Drosophila as indicators of exposure to carcinogens.
AB  - Drosophila has fulfilled a dual function in the field of genetic toxicology: for
      use in short-term tests for identifying carcinogens and in a model for studies of
      the mechanisms of mutagenesis by chemicals. Until the mid-1980s, use of
      Drosophila in short-term tests was restricted to assays for genetic damage in
      germ cells, mostly in males. The largest database, on 700-750 chemicals, is
      available for the test for sex-linked recessive lethal (SLRL) forward mutation.
      The database for assays of the consequences of chromosomal breakage--reciprocal
      translocations and chromosome loss--is smaller, with about 100 chemicals tested.
      Comparative studies conducted within the US National Toxicology Program showed
      that SLRL is a better end-point than reciprocal translocation: of 66 chemicals
      (68 entries) that induced SLRL, only 28 (41%) induced reciprocal translocation.
      The major weakness of the SLRL assay is its low sensitivity (0.27-0.79) for
      mammalian genotoxins. A strength of the SLRL mutation test is its high
      specificity, which is close to 1. Thus, whereas a negative response in Drosophila
      provides little evidence for genotoxicity, a positive response (SLRL frequency >
      or = five times the control level) provides good evidence that a chemical is a
      trans-species mutagen and probably also carcinogenic to mammals. The poor
      performance of the SLRL test revealed in several collaborative studies led to the
      development of assays for recombination in somatic cells of Drosophila. Two of
      these tests have been evaluated for all known classes of genotoxic chemical: the
      mwh/flr wing spot test on more than 400 chemicals and the white/white+ eye spot
      test on about 220 chemicals. Of 24 carcinogens that gave negative or inconclusive
      test results in the SLRL assay, 22 gave positive results in one or both of the
      somatic systems. Their better performance in comparison with the germ-line assays
      is primarily the result of their low cost (5-10% of that needed for an SLRL
      assay), allowing use of multiple doses and protocols and the use of distinct
      tester strains with heterogeneity for activation of procarcinogens. For
      qualitative and quantitative studies on structure-activity and activity-activity
      relationship, only germ-line system have been used. In general, clear
      relationships between physico-chemical parameters (s values, O6/N7-alkylguanine
      ratios), carcinogenic potency in rodents and several descriptors of genotoxic
      activity in germ cells (from mice and Drosophila) became apparent when the
      following descriptors were used: (1) estimates of TD50 (lifetime doses expressed
      in milligrams per kilogram body weight or millimoles per kilogram body weight)
      from bioassays for cancer in rodents; (2) the degree of germ-cell specificity,
      i.e. the ability of a genotoxic agent to induce mutations at practically any
      stage of development of Drosophila and mouse spermatogenesis, as opposed to a
      more specific response in postmeiotic stages of both species; (3) the M(NER
      )/M(NER+) hypermutability ratio, determined in a repair assay in Drosophila germ
      cells; (4) the ratio of chromosomal aberrations to SLRL in postmeiotic germ cells
      of Drosophila, i.e. the comparative efficiency of a carcinogen to induce these
      two end-points; (5) mutational spectra induced at single loci, i.e. the seven
      loci used in the specific-locus test in mice and the vermilion, white and rosy
      genes of Drosophila; and (6) the doubling doses in milligrams or millimoles per
      kilogram for specific locus induction in mice. On the basis of these parameters,
      alkylating agents were classified into three categories in terms of germ-cell
      specificity, which is primarily due to stage-related differences in DNA repair,
      clastogenic efficiency, type of mutation spectra and carcinogenic potency in
      rodents. The three categories allow predictions of the genotoxicity of alkylating
      agents but not yet for other categories of genotoxic carcinogens.

PMID- 10353399
TI  - Use of tests in yeasts and fungi in the detection and evaluation of carcinogens.

PMID- 10353400
TI  - Identification of carcinogenic substances by means of short-term tests in
      bacteria.

PMID- 10353401
TI  - Short-term tests for defining mutagenic carcinogens.
AB  - The results of short-term tests for mutagenicity were first included in the IARC
      Monographs in the mid-1970s on the basis of the observation that most carcinogens
      are also mutagens, although not all mutagens are carcinogens. The experimental
      evidence at that time showed a strong correlation between mutagenicity and
      carcinogenicity and indicated that the short-term tests were useful for
      predicting carcinogenicity. Although the correlations have become weaker over the
      past 20 years, and with them the predictive value of short-term tests, such tests
      still provide vital information for identifying and understanding mechanisms
      involved in carcinogenicity. The results of short-term tests compiled in the US
      Environmental Protection Agency-IARC Genetic Activity Profile database over the
      past 12 years are summarized and reviewed here in relation to the classification
      of agents for carcinogenicity within the system used at IARC. The role of the
      information from short-term tests in making overall classifications of specific
      compounds in recent Monographs is discussed. The usefulness of data on three
      genetic end-points, gene mutation, chromosomal aberrations and aneuploidy, and
      the criteria for mutagenicity and lack of mutagenicity based on a 'defining set'
      of test results are examined. Recommendations are made for assessing chemicals on
      the basis of the strength of the evidence from short-term tests, and the
      implications of this approach for identifying putative mutational mechanisms of
      carcinogenicity are discussed.

PMID- 10353402
TI  - Angiotensin type 2 receptor is important in the normal development of the ureter.
AB  - In humans, the actions of angiotensin II are transduced through the AT1 and AT2
      receptors which have recently been implicated in renal organogenesis.
      Polymorphisms in the human angiotensin II receptor genes have been linked to
      cardiovascular and nephrological disorders. In this study we evaluated 35
      patients with either primary obstructive megaureter or posterior urethral valves.
      Each was genotyped for the A1166 AT1 polymorphism and the recently described A
      1332G AT2 transition. The incidence of these genetic variants was also evaluated
      in normal controls without any ultrasonographic urological abnormalities. Similar
      to our previous findings in congenital urological abnormalities, the AT1 receptor
      genotype distribution did not differ between patients with either primary
      obstructive megaureter or posterior urethral valves versus controls. In contrast,
      compared with normal controls, there was a dramatic increase in the occurrence of
      the AT2 A-1332G transition in patients with primary obstructive megaureter (75.0%
      vs. 41.9% in controls, P<0.025). In patients with posterior urethral valves,
      there was no difference in the occurrence of the transition versus controls
      (36.9%, P=NS). Thus, there is no correlation between the AT1 receptor gene
      polymorphism and urological abnormalities. However there is an increased
      incidence in the AT2 genetic variant in patients with primary obstructive
      megaureter.

PMID- 10353403
TI  - Anti-lymphocyte antibodies late in the course of pediatric renal transplantation.
AB  - Beyond the immediate post-transplant period, physicians are often reluctant to
      use anti-lymphocyte preparations to treat episodes of acute renal functional
      deterioration attributable to acute rejection. This is due to the perception that
      such episodes are less likely to be reversible, and to concern regarding the
      potential adverse effects of anti-lymphocyte antibodies, including opportunistic
      infections, lymphoproliferative disorders, and the development of human anti
      mouse antibodies. Records were reviewed for all 365 renal transplants performed
      in 267 patients at our center from 1971 to 1996. Anti-lymphocyte antibodies were
      used in an attempt to reverse 6 episodes of corticosteroid-resistant acute
      rejection in 5 children at a mean interval of 24.5 months following
      transplantation. The mean serum creatinine at initiation of therapy with the anti
      lymphocyte agents was 2.9 mg/dl. Following treatment, the mean serum creatinine
      decreased to 1.3 mg/dl (P=0.03, Student's t-test). Two patients developed
      uncomplicated opportunistic infections after completion of anti-lymphocyte
      therapy; none have developed lymphoproliferative disorders or antibodies to OKT3.
      We conclude that in the correct clinical setting with corticosteroid-resistant
      acute rejection, the use of anti-lymphocyte antibodies should not be withheld
      solely on the basis of length of time since transplantation.

PMID- 10353404
TI  - Vitamin E suppresses oxidative stress and glomerulosclerosis in rat remnant
      kidney.
AB  - Previous studies have shown that reduction of renal mass in the rat remnant
      kidney model induces overproduction of transforming growth factor beta1
      (TGFbeta1). We investigated whether an antioxidant, vitamin E, administered
      before the renal mass reduction, could prevent oxidative stress, reduce the
      overproduction of TGFbeta1, and mitigate against the subsequent
      glomerulosclerosis. Our results revealed that the oxidative stress, as measured
      by the change in plasma malondialdehyde, is significantly reduced by prior
      vitamin E dietary supplementation. Finally, our data show that dietary vitamin E
      supplementation ameliorates the rise in TGFbeta1 secondary to renal mass
      reduction and inhibits the glomerular sclerosis of the remnant kidney over the
      time course of this experiment.

PMID- 10353405
TI  - Up-regulation of interleukin-4 and CD23/FcepsilonRII in minimal change nephrotic
      syndrome.
AB  - Although the pathogenesis of childhood minimal change nephrotic syndrome (MCNS)
      has not been clearly defined, the current hypothesis favors an involvement of T
      cell dysfunction. The symptom onset and the relapse of MCNS are frequently
      associated with allergy and increased IgE levels in sera. Since a T cell-derived
      cytokine interleukin-4 (IL-4) plays a key role in the regulation of IgE
      production and allergic response, we investigated the role of IL-4 in the
      pathophysiology of MCNS. Using fluorescence-activated cell scanning we observed a
      significantly higher expression of CD23, the type II IgE receptor (FcepsilonRII),
      on fresh B cells from active MCNS patients (n=22) compared with age-matched
      healthy normal controls (n=12). The upregulation of CD23 correlates with greater
      IL-4 activity in the culture supernatant of MCNS peripheral blood lymphocytes
      (PBLs) than normal PBLs stimulated by mitogens, as assessed by the CD23-inducing
      effect of the PBL supernatant on tonsillar B cells. Furthermore, Northern blot
      and reverse transcription-based polymerase chain reaction analysis have revealed
      significantly elevated levels of IL-4 mRNAs both in mitogen-stimulated and
      unstimulated MCNS PBLs, compared with healthy normals or disease controls with
      other renal disorders. Together these results strongly suggest that the
      upregulation of IL-4 in T cells may be part of the T cell dysfunction involved in
      MCNS.

PMID- 10353406
TI  - Decreased intraplatelet Ca2+ release and ATP secretion in pediatric nephrotic
      syndrome.
AB  - Platelets play an important role in the natural history of idiopathic nephrotic
      syndrome (NS). Although thromboembolic events are rare, the activation of
      circulating platelets is generally considered an important factor in the
      prethrombotic state in children with NS. Platelet-activating factor (PAF), a
      potent endogenous phospholipid mediator of inflammation, stimulates intracellular
      free calcium (Ca2+) mobilization, aggregation, and release reactions in platelets
      obtained from normal donors. Platelet-related effects of PAF in children with NS
      are unknown. We studied PAF-induced intracellular Ca2+ mobilization in washed
      platelets and ATP secretion in platelet-rich plasma in 34 children with
      idiopathic NS and in 7 healthy children. There was a significant decrease in ATP
      secretion: 0.021+/-0.011 microg/10(7) cells with 20 nM PAF and 0.089+/-0.017
      microg/10(7) platelets with 200 nM PAF versus control values (0.195+/-0.004
      microg/10(7) and 0.813+/-0.09 microg/10(7), respectively). Moreover, PAF-evoked
      increase in intracellular free Ca2+ concentration was twofold lower in NS
      patients than in control subjects (230.1+/-22.4 nM versus 455.6+/-15.3 nM). Also,
      thrombin-induced intracellular free Ca2+ mobilization was diminished in children
      with NS compared with the control group. Thus, contrary to expectations, a
      decrease of platelet reactivity in response to PAF in vitro was observed in
      children with idiopathic NS. We suggest that this decreased platelet reactivity
      may reflect a period refractory to PAF and may be considered as platelet
      desensitization to PAF released in vivo in children with NS.

PMID- 10353407
TI  - Bilateral nephrectomy reverses hypothyroidism in congenital nephrotic syndrome.
AB  - A state of biochemical hypothyroidism is commonly seen in infants with congenital
      nephrotic syndrome (NS) and therefore the current recommendation is to place all
      patients with congenital NS on supplemental thyroid preparations. We report our
      experience in five children with congenital NS in whom thyroid supplementation
      was discontinued following bilateral nephrectomy and initiation of renal
      replacement therapy. Immediately after nephrectomy, thyroid function tests
      normalized, except serum thyroid-stimulating hormone (TSH) concentration, which
      initially rose, but normalized later. This observation supports the hypothesis
      that hypothyroidism in these patients is secondary to the chronic massive
      proteinuria and is not the result of a defect intrinsic to the thyroid gland
      itself. Abatement of massive proteinuria enables discontinuation of thyroid
      supplementation, and a transient rise in TSH in the early post-nephrectomy stage
      should be potentially expected.

PMID- 10353408
TI  - Furosemide in indomethacin-treated infants--systematic review and meta-analysis.
AB  - This study was designed to assess: (1) whether furosemide modifies the incidence
      of failure to close a symptomatic patent ductus arteriosus (PDA) in response to
      indomethacin in premature infants, (2) whether furosemide decreases renal and
      hydromineral side effects of indomethacin, and (3) whether the effects of
      furosemide on renal function depend on initial extracellular volume [assessed by
      blood urea nitrogen (BUN)/creatinine ratio]. We did a systematic review and meta
      analysis of all published controlled trials assessing either ductal closure or
      renal function after randomized allocation to treatment with indomethacin and
      furosemide versus indomethacin alone. All of the three studies meeting entry
      criteria were small and had methodological limitations. The number of patients
      was too small to rule out a 10% risk increase in failure of ductal closure. After
      the first dose of indomethacin, patients receiving furosemide had higher urine
      output, fractional excretion of sodium, and osmolar clearance than controls.
      Among patients with initial BUN/creatinine ratio <20, those on furosemide had a
      higher glomerular filtration rate (GFR) than controls. Among patients with
      initial BUN/creatinine of 20-30, those on furosemide had a lower GFR than
      controls. Thus, dehydration appears to be a contraindication for furosemide
      administration in premature infants treated with indomethacin for symptomatic
      PDA. The risk-benefit ratio of administering furosemide in well-hydrated patients
      treated with indomethacin for symptomatic PDA could only be assessed by a large
      randomized clinical trial.

PMID- 10353409
TI  - Comparison of ultrasound and dimercaptosuccinic acid scintigraphy changes in
      acute pyelonephritis.
AB  - The strategy for morphological investigations in children with acute
      pyelonephritis (APN) remains debatable. We studied 70 children (median age 2.0
      years) admitted with a first episode of pyelonephritis using a high-resolution
      ultrasound technique (RUS) and compared the results with 99m technetium
      dimercaptosuccinic acid (DMSA) renal scintigraphy. The DMSA scan was abnormal in
      62 children (89%). However, using a high-frequency transducer we found abnormal
      sonogram changes in 61 children (87%), consisting of an increased kidney volume
      in 42, and/or a thickening of the wall of the renal pelvis in 42, and/or a focal
      hyper- or hypoechogenicity in 36, and/or a diffuse hyperechogenicity in 31
      children. Micturating cystourethrography was performed in all children, revealing
      vesicoureteral reflux (VUR) in 22 (31%). Among those children with VUR, 4 had a
      normal DMSA scan, 2 an abnormal RUS, and 2 a normal DMSA scan and RUS. Our data
      suggest that B-mode RUS performed with a high-frequency transducer by a trained
      radiologist is nearly as sensitive as the DMSA scan in diagnosing renal
      involvement in children with unobstructed APN and in predicting VUR.

PMID- 10353410
TI  - Characterization of matrix metalloproteinases in human urine: alterations during
      adolescence.
AB  - Matrix metalloproteinases (MMPs) are a family of at least 14 zinc-dependent
      proteinases that have been implicated in matrix turnover under both normal and
      pathological conditions. Previous studies have shown that several MMPs are
      produced in various cell types in the kidney, suggesting that MMPs may be
      involved in renal morphogenesis and remodelling. Using a variety of techniques,
      including gelatin and casein zymography, gelatin affinity chromatography,
      immunoblotting, and immunoprecipitation, we have identified the major gelatinases
      in human urine as MMP-2 and MMP-9. Latent forms of both enzymes were detected in
      urine, as well as lower molecular mass species of each, consistent with activated
      forms of MMP-2 and MMP-9. MMP-2 and MMP-9 were also measured in individual human
      urine samples (n=40). No significant gender differences in MMP concentrations
      were detected. However, renal MMP expression appeared to be age dependent; the
      highest average amounts of urine MMP-2 were detected during adolescence, while
      the converse was true of urine MMP-9. Together, these findings indicate that
      under normal conditions, human urine contains MMP-2 and/or MMP-9, suggesting that
      these two MMPs are normally produced within the kidney, where they may regulate
      normal renal remodelling and matrix homeostasis in an age-specific manner.

PMID- 10353411
TI  - Prominent medial hypertrophy of renal arterioles in an infant with hyporeninemic
      hypoaldosteronism.
AB  - We describe an 11-month-old boy who presented clinically with hyperkalemic renal
      tubular acidosis due to hyporeninemic hypoaldosteronism. Persistent
      hyperchloremic acidosis and mild azotemia were present. All abnormal laboratory
      values were corrected by the administration of fludrocortisone. Renal biopsy
      showed prominent medial hypertrophy of renal arterioles and interstitial
      fibrosis, which closely resemble those of the gene-targeted mice with disruption
      of the renin angiotensin system. This is the first case report raising the
      possibility that a defective renin angiotensin system in infancy may lead to
      tubulointerstitial damage with medial hypertrophy of intrarenal arterioles.

PMID- 10353412
TI  - Apolipoprotein E epsilon 4 allele and nephrotic glomerular diseases in children.
AB  - Hyperlipidemia is a well-recognized complication of the nephrotic syndrome and is
      a factor contributing to the progression of the initial glomerular injury and the
      development of glomerulosclerosis. Apolipoprotein E (apoE) is a plasma protein
      and apoE epsilon 4 allele is associated with higher plasma cholesterol levels.
      With this in mind, we studied apoE phenotypes and alleles in children with
      nephrotic glomerular diseases (NGD, n=29), including idiopathic nephrotic
      syndrome (n=16), membranoproliferative glomerulonephritis (n=7), and focal
      segmental glomerulosclerosis (FSGS, n=6). Children with NGD had a higher epsilon
      4 allele frequency (20.7%) than controls (10.8%), and those with FSGS had both
      higher apoE4/3 (66.7%) and epsilon 4 allele (33.3%) frequencies than controls
      (20.4% and 10.8%, respectively). In IgA nephropathy (n=30, disease controls), no
      significant association with specific apoE was found. Further studies are needed
      to clarify the significance of the observed high frequencies of apoE epsilon 4
      allele in children with NGD and apoE4/3 phenotype distribution in FSGS.

PMID- 10353413
TI  - Acute renal failure due to obstruction in Burkitt lymphoma.
AB  - Acute renal failure in Burkitt lymphoma is commonly the result of tumor lysis
      syndrome. We present a 15-year-old boy who developed hypertension, seizures, and
      acute renal failure due to extrinsic compression of the bladder and ureters by a
      large retrovesical Burkitt lymphoma. The causes of acute renal failure in Burkitt
      lymphoma and the incidence of acute urinary obstruction in this disease are
      reviewed.

PMID- 10353414
TI  - Acute peritoneal dialysis in neonates: comparison of two types of peritoneal
      access.
AB  - A total of 23 sessions of peritoneal dialysis (PD) were given to 20 neonates with
      acute renal failure. Intravenous cannula (Biovalve 14G Vygon) was used for PD
      access in 13 procedures and guide wire-inserted femoral vein catheter (Medcomp
      pediatric) in 10 procedures. Intraperitoneal bleed was seen in 1 procedure each
      in both groups. Dialysate leak and catheter blockade were more common with
      intravenous cannula [3 (23.1%), 8 (61.5%)] than guide wire-inserted femoral vein
      catheter [1 (10%), 4 (40%), P-NS]. Due to repeated catheter blockade, 5 (38.4%)
      PD sessions could not be completed with intravenous cannula and had to be
      prematurely closed; this complication was not seen with guide wire-inserted
      femoral vein catheter (P<0.05). Percentage reduction of serum creatinine per PD
      session was significantly higher in neonates being dialyzed with guide wire
      inserted femoral vein catheter (51.7%+/-8.5%) than those dialyzed with
      intravenous cannula (38.3%+/-5.2%). Incidence of peritonitis was not
      significantly different [2 (15.4%) vs. 1 (10%)]. To conclude, for an effective PD
      in neonates, guide wire-inserted femoral vein catheter is safe and is associated
      with fewer access-related problems.

PMID- 10353415
TI  - Survival and complications of cuffed catheters in children on chronic
      hemodialysis.
AB  - Central venous catheters are being increasingly used as hemodialysis vascular
      access. We evaluated catheter survival, outcome predictors, and complications in
      a total of 36 catheters used in 13 children and young adults undergoing chronic
      maintenance hemodialysis through catheter for a duration of 10.4+/-5.6 months.
      Reasons for catheter failure were: thrombosis 12 of 36 (33%), infection 6 of 36
      (17%), and extrusion 2 of 36 (5.4%). Catheters were lost to infection and
      thrombosis at 1.1 and 2.2 episodes per 1,000 catheter days, respectively.
      Symptomatic infections, Gram-negative and polymicrobial sepsis increased the risk
      of catheter failure. Most of the thrombotic episodes occurred in patients with
      inherent thrombotic tendency. The survival of the 36 catheters was 62% at 1 year.
      The survival of 13 randomly chosen catheters, 1 from each patient, was 85% at 1
      year. The time from insertion to first complication correlated significantly with
      the outcome (P<0.03). We conclude that central venous catheters are still
      associated with a high rate of failure and may be a regular access choice only in
      a selected patient population with no inherent thrombotic tendency and no other
      option available for long-term hemodialysis.

PMID- 10353416
TI  - Complications of gastrostomy feeding in children receiving peritoneal dialysis.
AB  - Gastrostomy tube (g-tube) feeding is recognized to improve the nutritional
      delivery to children with end-stage renal disease. A retrospective study was
      undertaken assessing the complications of g-tube feeding in children receiving
      peritoneal dialysis (PD). Twenty-three patients, mean age 3.8+/-3.2 years
      received PD and g-tube feeding for 758 patient-months, with 127 patients
      receiving PD for 1,969 patient-months used as controls. Peritonitis occurred
      every 18.4 patient-months in controls and 7.8 patient-months in those with a g
      tube. Peritonitis occurred every 6.0 patient-months before and 8.1 patient-months
      after g-tube insertion in those undergoing g-tube insertion on PD. PD catheter
      exit site infection (PDESI) occurred every 18.7 patient-months in controls and
      16.8 patient-months in those with a g-tube. PDESI occurred every 126 patient
      months before and 16.2 patient-months following g-tube insertion. PD catheter
      replacement secondary to infection occurred every 109.4 patient-months in
      controls and 39.9 patient-months in those with a g-tube. It did not occur before
      g-tube insertion and occurred every 32.5 patient-months following insertion.
      Thirty-four episodes of g-tube exit site infection occurred, in 10 the same
      organism caused concurrent peritonitis. G-tube replacement occurred on 37
      occasions. Hemodynamically significant gastrointestinal bleeding occurred in 3
      patients, being terminal in 1. We conclude that, although not without risk, g
      tube feeding in patients receiving PD is not contraindicated.

PMID- 10353417
TI  - Dietary prescription based on estimated nitrogen balance during peritoneal
      dialysis.
AB  - Protein and energy requirements of children on automated peritoneal dialysis
      (APD) have still not been sufficiently well defined, although their adequacy is
      important to maintain a positive nitrogen (N) balance and prevent malnutrition.
      We carried out 42 studies to estimate N balance in 31 children over 3 years on
      APD for 19.8+/-15.7 months. Twenty metabolic studies were performed in patients
      dialysed for less than 1 year (7.2+/-3.3 months) and 22 in patients treated for
      more than 1 year (31.3+/-13.6 months). The mean estimated N balance of all
      metabolic studies was 57.5+/-62.8 mg/kg per day. In only 21 of 42 studies was N
      balance estimated to be over 50 mg/kg per day, which is considered adequate to
      meet N requirements for all metabolic needs and growth of uremic children.
      Estimated N balance correlated significantly with dietary protein intake
      (r=0.671, P=0.0001) and total energy intake (r=0.489, P=0.001). Using the
      equations of correlation, the values of dietary protein intake [=144% recommended
      dietary allowance (RDA)] and total energy intake (89% RDA) required to obtain an
      estimated N balance >50 mg/kg per day were calculated. Significantly lower
      estimated N balance values were obtained in the studies performed on patients on
      APD for over 1 year (36.09+/-54.02 mg/kg per day) than in patients treated for
      less than 1 year (81.11+/-64.70 mg/kg per day). In conclusion, based on the
      values of estimated N balance, we were able to establish adequate dietary protein
      and energy requirements for children on APD.

PMID- 10353418
TI  - Pediatric dialysis and renal transplantation in Kuwait over the past 11 years.
AB  - Data on end-stage renal disease (ESRD) patients and their renal replacement
      therapy (RRT) were collected retrospectively from the three dialysis centers, the
      pediatric urology unit, and the organ transplant center of Kuwait. The study
      period was from 1 January 1986 to 31 December 1996. A total of 61 children, 50 of
      whom were Kuwaiti nationals, required RRT for ESRD during those 11 years. This
      gave an average annual incidence rate of 18 per million Kuwaiti children.
      Glomerulonephritis was the most-frequent underlying disease and accounted for 44%
      of total cases, while pyelonephritis (including urinary tract anomalies and
      dysplastic kidneys) was responsible for 30%. Multisystem disease was responsible
      for ESRD in 7 patients (14%), 2 of whom had lupus nephritis, 2 vasculitis, 2
      Henoch-Schonlein purpura, and 1 hemolytic uremic syndrome. Continuous ambulatory
      peritoneal dialysis and home intermittent peritoneal dialysis, using cycler
      machines, were not favored dialysis techniques by most parents, especially for
      those <6 years old. The actuarial survival on dialysis was 75%+/-7% at 12 months.
      Of the 8 patients who died, 7 were <6 years old. Thirty-eight patients received
      46 kidney transplants, 13 of which were performed on a pre-emptive basis. The
      actuarial patient survivals at 12 months for those receiving first live and
      cadaveric kidney transplants were 90%+/-5% and 85%+/-2%, respectively, while
      those for grafts were 76%+/-8% and 66%+/-2%, respectively. This is the first
      nationwide long-term study of the incidence and etiology of pediatric ESRD in our
      area and the RRT in a country with adequate treatment facilities.

PMID- 10353419
TI  - Second International Symposium on Perinatal Nephrology, 26-27 June 1998,
      Lausanne, Switzerland.

PMID- 10353420
TI  - Clinical quiz. Cortical infarction secondary to intravascular sickling in the
      renal cortex.

PMID- 10353421
TI  - Frequency of microscopic hematuria in acute poststreptococcal glomerulonephritis.

PMID- 10353422
TI  - Renal impairment without hepatic damage after acetaminophen overdose.

PMID- 10353423
TI  - Characterizing withdrawal in rats following repeated drug administration using an
      amphetamine-vehicle-haloperidol drug discrimination.
AB  - RATIONALE: Previous research using an amphetamine (AM)-haloperidol (HA) drug-
      drug discrimination task has shown that predominant responding on the HA
      appropriate lever occurs 24 h after a single or multiple administrations of 10
      mg/kg AM. Conversely, rebound responding on the AM-appropriate lever occurs
      following single or multiple administrations of 1 mg/kg HA. HA-appropriate
      responding was also observed 24 h following a single injection of AM using a
      three-lever, AM-vehicle-HA discrimination task. However, a single administration
      of HA did not produce robust rebound responding on the AM-appropriate lever. The
      present studies seek to clarify the discrepancy between responding following HA
      in the two- and three-choice tasks. OBJECTIVE: Experiment 1 examined the extent
      of rebound responding that could be achieved following ten daily administrations
      of either 10 mg/kg AM or 1 mg/kg HA. Experiment 2 explored potential differences
      between the two- and three-choice tasks in characterizing the post-HA cue.
      METHODS: Animals were trained to discriminate 0.35 mg/kg AM, vehicle, and 0.033
      mg/kg HA. In experiment 1, animals received ten daily injections of 10 mg/kg AM,
      vehicle, or 1 mg/kg HA, and were tested 24 h after the final injection, and again
      8, 15, and 22 days post-treatment. In experiment 2, animals were retrained and
      then treated daily with either vehicle or 1.0 mg/kg HA for 10 days, and then
      tested 24 h after the final injection, and again 5 and 11 days post-treatment,
      with either all three levers or with only the AM- and HA-appropriate levers
      available. RESULTS: In experiment 1, multiple injections of AM produced robust HA
      lever responding, which is consistent with results from previous studies that
      used the two-choice, AM-HA discrimination task. However, multiple injections of
      HA did not produce predominant responding on the AM-appropriate lever. In
      experiment 2, animals treated with either vehicle or HA responded predominantly
      on the vehicle-appropriate lever when tested with all three levers present. When
      tested with the vehicle lever removed, however, animals treated with vehicle
      responded predominantly on the HA-appropriate lever, whereas those treated with
      HA responded predominantly on the AM-appropriate lever. CONCLUSIONS: These
      results suggest that the two-choice and three-choice task used here differ in how
      the post-HA withdrawal cue is characterized. This finding emphasizes the
      importance of knowing the relative locations of the agonist-, vehicle-, and
      antagonist-produced cues on the interoceptive stimulus continuum established by
      discrimination training.

PMID- 10353424
TI  - Biochemical and behavioral anxiolytic-like effects of R(+)HA-966 at the level of
      the ventral tegmental area in rats.
AB  - RATIONALE: R(+) HA-966, a weak partial agonist at the glycine/NMDA receptor
      complex, has been shown to have anxiolytic-like actions on restraint stress
      induced mesoprefrontal dopamine metabolism. OBJECTIVE: This study investigates
      the putative anxiolytic, R(+) HA-966, applied locally at the level of the
      mesocorticolimbic dopamine cell bodies in the ventral tegmental area (VTA), on
      the acquisition and expression of conditioned fear. METHODS: Ten to 14 days after
      cannula implantation, rats were subjected to the acquisition session (10x5 s tone
      paired with 0.5 s, 0.8 mA footshock) followed about 24 h later by the expression
      session (ten tones only) of a conditioned fear protocol. Rats were treated with
      R(+) HA-966 (15 microg/VTA) or saline before either the acquisition or expression
      sessions. Other rats were injected with saline or R(+) HA-966 (10 microg/side),
      intra-medial prefrontal cortex, on the expression day. RESULTS: R(+)HA-966, intra
      VTA, prevented stress-induced changes in mesoprefrontal, but not mesoaccumbal,
      dopamine metabolism and was associated with a reduction in fearful responses to
      physical (footshock) and psychological (conditioned fear) stressors.
      Additionally, rats treated with R(+)HA-966 intra-VTA before the acquisition
      session were less fearful at the beginning of the expression session. Local
      injection of R(+)HA-966 into medial prefrontal cortex did not have anxiolytic
      like behavioral or biochemical actions but diminished the expression of
      exploratory behavior in non-stress, control rats. CONCLUSIONS: These studies
      indicate that the stress-induced activation of the mesoprefrontal dopamine
      neurons is necessary for the normal expression of fearful behaviors.

PMID- 10353425
TI  - L-701,324, a selective antagonist at the glycine site of the NMDA receptor,
      counteracts haloperidol-induced muscle rigidity in rats.
AB  - RATIONALE: It has recently been suggested that the overactivity of glutamatergic
      neurotransmission may contribute to the pathophysiology of Parkinson's disease.
      Therefore, a search for new compounds which block glutamatergic receptors and
      show antiparkinsonian properties in animal models of this disease seems to be
      justified. OBJECTIVE: The aim of this study was to determine whether L-701,324 [7
      chloro-4-hydroxy-3(3-phenoxy) phenylquinoline-2-(H)-one], a selective and full
      antagonist at the glycine site of the NMDA receptor, counteracts parkinsonian
      like muscle rigidity and catalepsy induced by haloperidol in rats. METHODS: The
      muscle tone was measured as the resistance developed to passive flexion and
      extension of the hind limb. Electromyographic (EMG) activity was additionally
      recorded in the gastrocnemius and tibialis anterior muscles. RESULTS: L-701,324
      (2.5-40 mg/kg IP) dose-dependently decreased the muscle tone enhanced by
      haloperidol (1-5 mg/kg IP). Likewise, the haloperidol-enhanced resting EMG
      activity and the EMG reflex response to passive movements were diminished by
      lower and almost abolished by higher doses of L-701,324. However, up to a dose of
      20 mg/kg IP, L-701,324 did not influence haloperidol (0.5 mg/kg IP)-induced
      catalepsy. Moreover, L-701,324 (1.25-5 mg/kg IP) given alone or together with
      haloperidol (0.5-1 mg/kg IP) disturbed rotarod performance. Gross observation of
      behaviour indicated that rats injected with L-701,324 in doses equal to or higher
      than 5 mg/kg, alone or in combination with haloperidol, were markedly ataxic,
      i.e. rats showed signs of disturbed balance and loss of control over their hind
      limbs. CONCLUSIONS: The present study suggests that L-701,324 exhibits a
      beneficial action in the animal model of parkinsonian rigidity, but not that of
      parkinsonian akinesia. Nonetheless, this compound is not devoid of motor side
      effects.

PMID- 10353426
TI  - Dopaminergic mechanisms mediating the long-term expression of locomotor
      sensitization following pre-exposure to morphine or amphetamine.
AB  - The role of dopaminergic mechanisms in opiate- and psychostimulant-induced long
      term locomotor sensitization was investigated. To that aim, rats were
      behaviourally sensitized with morphine or amphetamine and 3 weeks after cessation
      of treatment challenged with various direct and indirect dopamine agonists. Both
      morphine- and amphetamine-pretreated rats displayed sensitization of the
      locomotor effects of amphetamine, cocaine, and the selective dopamine reuptake
      inhibitor GBR-12909. Sensitization of the locomotor stimulant effects of the
      dopamine D2/D3 receptor agonist quinpirole was observed in amphetamine- but not
      morphine-pretreated rats. In contrast, morphine-, but not amphetamine-pretreated
      rats appeared hyposensitive to the locomotor inhibitory effects of a low,
      presumably D2-autoreceptor selective, dose of quinpirole. Neither pretreatment
      induced sensitization to the dopamine D1/D2 agonist apomorphine or the dopamine
      D1 agonist SKF-82958. In fact, the locomotor stimulant effects of SKF-82958
      appeared to be decreased in animals pre-exposed to amphetamine. These results
      suggest that functional changes in presynaptic dopamine release mechanisms
      represent common neuroadaptations involved in the long-term expression of
      morphine- and amphetamine-induced locomotor sensitization. Presynaptic dopamine
      D2 and postsynaptic D2 and/or D3 receptors are differentially involved in the
      expression of morphine- and amphetamine-induced locomotor sensitization. In a
      parallel study, we report that all of the drugs that elicited sensitized
      locomotor responses in morphine- or amphetamine-pretreated rats caused
      reinstatement of previously extinguished heroin- or cocaine-seeking behaviour,
      respectively. Taken together, these data suggest a marked relationship between
      drug-seeking behaviour and drug sensitization.

PMID- 10353428
TI  - Antinociceptive effects of opioids following acute and chronic administration of
      butorphanol: influence of stimulus intensity and relative efficacy at the mu
      receptor.
AB  - RATIONALE: A common treatment strategy for the management of severe pain involves
      the co-administration of multiple opioid analgesics. Due to the increasing
      popularity of this practice, it is becoming increasingly important to understand
      the interactions between clinically employed opioids under a wide range of
      conditions. OBJECTIVE: The purpose of the present investigation was to examine
      the effects of opioid combinations following acute and chronic administration of
      the low-efficacy mu-opioid butorphanol, and to determine if the effects of these
      combinations are modulated by the intensity of the nociceptive stimulus. METHODS:
      In a warm-water, tail-withdrawal procedure, rats were restrained and the
      latencies to remove their tails from 50 degrees C (low temperature) and 55
      degrees C (high temperature) water were measured following both acute and chronic
      administration of butorphanol. Opioids possessing both high (etorphine,
      levorphanol, morphine) and low [dezocine, (-)-pentazocine, nalbuphine] relative
      efficacy at the mu receptor were examined. RESULTS: Under acute conditions,
      etorphine, levorphanol, morphine and dezocine increased tail-withdrawal latencies
      at both low and high temperatures, whereas (-)-pentazocine, nalbuphine and
      butorphanol increased latencies only at the low temperature. A dose of 30 mg/kg
      butorphanol increased the effects produced by these opioids at the low
      temperature, but antagonized the effects of etorphine, levorphanol, morphine and
      dezocine at the high temperature. During chronic treatment with 30 mg/kg per day
      butorphanol, tolerance was conferred to the antinociceptive effects of all the
      opioids examined, with greater degrees of tolerance conferred to those opioids
      possessing low efficacy at the mu receptor. During butorphanol treatment,
      etorphine, levorphanol and morphine increased tail-withdrawal latencies at both
      water temperatures, dezocine increased latencies at only the low temperature, and
      (-)-pentazocine, nalbuphine and butorphanol failed to increase latencies at
      either temperature. A dose of 30 mg/kg butorphanol antagonized the
      antinociceptive effects of etorphine, levorphanol, morphine and dezocine during
      chronic treatment, and these effects were observed at both water temperatures.
      CONCLUSIONS: These findings indicate that the interactions between butorphanol
      and other mu opioids vary quantitatively between low and high stimulus
      intensities, and between acute and chronic conditions. In most instances,
      however, these interactions can be predicted from the effects of the drugs when
      administered alone.

PMID- 10353427
TI  - Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin
      following long-term withdrawal of IV drug self-administration.
AB  - RATIONALE: The neurobiological mechanisms underlying the persistence of drug
      craving in detoxified addicts are still poorly understood. OBJECTIVE: The present
      study was designed to evaluate dopaminergic mechanisms in drug-seeking behaviour
      following long-term (>3 weeks) extinction of IV drug self-administration in rats.
      METHODS: To that end, we studied the effects of direct and indirect dopamine (DA)
      agonists on reinstatement of previously extinguished responding for heroin (50
      microg/kg per injection; 14-15 daily 3-h sessions) and cocaine (500 microg/kg per
      injection; 10-11 daily 2-h sessions). RESULTS: In animals with a cocaine history,
      priming with cocaine, the selective DA reuptake inhibitor GBR-12909 and the DA D2
      receptor agonist quinpirole resulted in robust and selective reinstatement of non
      reinforced nose poking behaviour in the previously drug-paired hole. In contrast,
      the D1 agonist SKF-82958 failed to reinstate responding and the non-selective DA
      agonist apomorphine even suppressed responding in these animals. In heroin
      trained rats, heroin and GBR-12909 strongly reinstated responding, whereas all
      direct DA agonists were ineffective. Again, the two highest doses of apomorphine
      decreased responding in these animals. In a parallel study, the ability of DA
      ligands to express behavioural sensitization in animals pretreated with
      amphetamine or morphine was evaluated. Interestingly, all agonists that
      reinstated responding in the present study caused expression of locomotor
      sensitization and vice versa. CONCLUSIONS: The differences between direct and
      indirect agonists indicate a clear, but complex, involvement of DA in drug
      seeking behaviour long after detoxification. Moreover, the results show an
      important role of D2 receptor activation in the persistence of cocaine- but not
      heroin-seeking behaviour. Finally, the results from both studies suggest a
      relationship between drug-induced reinstatement and drug hyperresponsiveness in
      long-term abstinent rats.

PMID- 10353429
TI  - Gonadal axis hormones in male schizophrenic patients during treatment with
      haloperidol and after switch to risperidone.
AB  - RATIONALE: The atypical neuroleptic risperidone, in addition to its dopamine
      receptor blocking activity, has a high affinity for serotonergic receptors. Since
      both dopaminergic and serotonergic neuronal activities participate in regulation
      of the pituitary gonadal axis (PGA), it is expected that a switch from treatment
      with haloperidol to treatment with risperidone should influence plasma levels of
      PGA hormones. OBJECTIVE: To study the effects of a drug with dopamine and
      serotonin receptor blocking activity on PGA hormones in patients who were on
      treatment with a dopamine receptor blocker. METHODS: Plasma levels of
      testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH), as
      well as prolactin and cortisol, were measured in 16 male schizophrenic patients
      during treatment with haloperidol (mean dose 23.3 mg daily, SD = 16.9) and 6
      weeks later after switching to treatment with risperidone (mean dose 11.8 mg
      daily, SD = 2.9). Psychopathology was assessed by BPRS. RESULTS: After switching
      to risperidone, total BPRS score and the scores in its subscales for positive,
      negative, and general symptoms were all significantly reduced in the order of 35
      45%. Prolactin levels were significantly increased from 39.5+/-22.3 to 58.9+/
      28.5 ng/ml (F= 4.61, P = 0.04), while cortisol, testosterone, LH, and FSH
      remained unchanged. No significant correlations between prolactin increases and
      reduction in BPRS or in its subscale scores were found. CONCLUSIONS: The results
      show that blocking of both dopamine and serotonin receptors does not influence
      the pituitary gonadal axis but considerably increases prolactin release.

PMID- 10353430
TI  - Little evidence that "denicotinized" menthol cigarettes have pharmacological
      effects: an EEG/heart-rate/sujective-response study.
AB  - RATIONALE: A substantial portion of cigarette smokers prefer menthol-flavored
      cigarettes. To date, however, no studies have examined whether menthol in
      cigarettes has central pharmacological effects. OBJECTIVE: We investigated
      psychophysiological and subjective effects of smoking menthol versus non-menthol
      cigarettes in both menthol and non-menthol smokers. To assess these effects
      independently of the immediate effects of nicotine, all cigarettes employed were
      "denicotinized" (FTC nicotine yield = 0.06 mg). METHODS: The psychophysiological
      measures were EEG and heart rate (HR). The subjective measures assessed mental
      alertness, muscular relaxation, anxiety/nervousness, and how much a participant
      wanted to smoke one of his usual brand of cigarettes. Menthol and non-menthol
      smokers participated in a single session in which each participant smoked both a
      menthol and a non-menthol denicotinized cigarette (order balanced across
      participants). The psychophysiological and subjective measures were recorded
      before and after smoking each cigarette. RESULTS: Out of 48 F-ratios spanning 22
      analyses of variance involving the critical interaction between pre-/post-smoking
      and menthol/non-menthol cigarette, only one unambiguously fit a "pharmacological"
      pattern, a result indistinguishable from a type-I statistical error. We report
      evidence that menthol smokers may be chronically less aroused and more sensitive
      to the effects of nicotine than non-menthol smokers. CONCLUSIONS: We found little
      evidence that menthol in cigarettes has central pharmacological effects.

PMID- 10353431
TI  - Effects of alprazolam on the acoustic startle response in humans.
AB  - In the present study, we assessed the effects of the potent benzodiazepine
      alprazolam on the human acoustic startle response in healthy volunteers. Eight
      undergraduate students received single oral doses of placebo and alprazolam 2 mg
      on 2 separate days, according to a double-blind balanced crossover design.
      Electromyographic activity of the orbicularis oculi muscle was recorded 5, 7 and
      11 h after drug administration. At each recording time, subjects received 21
      acoustic stimuli (1 KHz, 116 dB, 50 ms duration) separated by variable intervals
      (8-30 s, mean 16.5 s). Consistent with previous results obtained for diazepam in
      humans, alprazolam significantly reduced the amplitude of the startle reflex. A
      patent increase in onset latency was also observed, this being a novel effect not
      previously described for benzodiazepines in human studies. Both effects were
      maximum at 5 h after dosing, the startle response experiencing a recovery as the
      drug disappeared from systemic circulation. These results indicate a potent
      inhibitory effect of alprazolam on baseline startle at the dose used, with a
      robust time-dependent recovery of initial values effectively counteracting
      between-session habituation.

PMID- 10353432
TI  - Comparison of the effects of venlafaxine, paroxetine and desipramine on the
      pupillary light reflex in man.
AB  - RATIONALE: The time-course of the pupillary light reflex response is determined
      by the successive activation of the parasympathetic and sympathetic innervations
      of the iris, the latency and the amplitude reflecting parasympathetic and the
      recovery time mainly sympathetic activity. OBJECTIVE: To compare the effects of
      single doses of three antidepressants (venlafaxine: serotonin/noradrenaline
      reuptake inhibitor, paroxetine: selective serotonin reuptake inhibitor, and
      desipramine: tricyclic antidepressant) on resting pupil diameter and the
      pupillary light reflex response. METHODS: Fifteen healthy male volunteers
      participated in five weekly sessions, each of which was associated with one
      treatment (venlafaxine 75 mg or 150 mg, paroxetine 20 mg, desipramine 100 mg, or
      placebo) according to a double-blind, double-dummy, balanced, cross-over design.
      An infrared binocular television pupillometer was used for the recording of the
      resting pupil diameter and the pupillary light reflex in darkness, in previously
      dark-adapted eyes. Resting pupil diameter in darkness was recorded before and
      after treatment. The pupillary light reflex was elicited after treatment, with
      six light flashes (green, 565 nm peak wavelength) of 200 ms duration and of
      incremental illuminance (measured in the plane of the cornea): 3.0 x 10(-3) 8.5 x
      10(-3) 2.5 x 10(-2), 7.0 x 10(-2), 0.18, 0.43 mW cm(-2). The parameters studied
      were: latency, amplitude and 75% recovery time. RESULTS: Analyses of variance
      followed by post hoc tests (least significant difference test or Dunnett's test;
      P < 0.05) revealed that both doses of venlafaxine produced a significant increase
      in resting pupil diameter, decrease in amplitude and shortening of the 75%
      recovery time of the light reflex response; venlafaxine 150 mg prolonged the
      latency, while the other treatments had no significant effects. CONCLUSIONS: The
      increase in resting pupil diameter could be indicative of parasympathetic
      inhibition and/or sympathetic activation. The shortening of the recovery time of
      the light reflex response is consistent with sympathetic potentiation resulting
      from noradrenaline uptake blockade in the iris. The prolongation of the latency
      and decrease of the amplitude of the light reflex response are indicative of a
      parasympatholytic effect of venlafaxine. However, as venlafaxine has negligible
      affinity for muscarinic cholinoceptors, this effect cannot be attributed to the
      blockade of cholinoceptors in the iris. A possible explanation for this finding
      is that it reflects a central rather than a peripheral effect of the drug: the
      blockade of noradrenaline uptake in the brain could lead to the potentiation of
      the noradrenergic inhibition of central parasympathetic (Edinger-Westphal)
      neurones. These results demonstrate the ability of therapeutically relevant
      single doses of venlafaxine to potentiate noradrenergic responses in man,
      consistent with the blockade of noradrenaline uptake.

PMID- 10353433
TI  - Noradrenergic modulation of the discriminative-stimulus effects of
      methamphetamine in rats.
AB  - RATIONALE: Neurochemical and clinical studies indicate involvement of
      noradrenergic (NE) neurotransmitter system in the actions of methamphetamine.
      OBJECTIVE: The present study investigated NE involvement in the discriminative
      stimulus effects of methamphetamine. METHODS: In Sprague-Dawley rats trained to
      discriminate 1.0 mg/kg methamphetamine, IP, from saline under a fixed-ratio
      schedule of food presentation, effects of various NE agonists, antagonists and
      uptake inhibitors were tested. RESULTS: Desipramine (3.0-18.0 mg/kg) and
      nisoxetine (5.6-30.0 mg/kg), two selective NE-uptake inhibitors, did not
      significantly generalize to methamphetamine when administered alone, but 5.6
      mg/kg desipramine and 10.0 mg/kg nisoxetine significantly shifted the
      methamphetamine dose-response curve to the left. The beta NE agonist,
      isoproterenol (0.56-3.0 mg/kg), and antagonist, propranolol (1.0-18.0 mg/kg),
      neither generalized to methamphetamine when given alone nor altered the
      discriminative-stimulus effects of methamphetamine when administered in
      combination. The alpha- NE agonist methoxamine (1.0-5.6 mg/kg) failed to
      generalize to the methamphetamine training stimulus. When given in combination
      with methamphetamine, the alpha-1 NE antagonist, prazosin (1.0 mg/kg), shifted
      the methamphetamine dose-response curve somewhat to the right and partially
      blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of
      methamphetamine, but these changes were not significant or dose-related, with
      further increases in prazosin dose (1.8-10.0 mg/kg) either producing similar or
      smaller changes. The alpha-2 NE agonist, clonidine, partially generalized to
      methamphetamine at doses of 0.1-0.18 mg/kg and increased drug-appropriate
      responding at lower doses of methamphetamine, but it partially blocked the
      discriminative-stimulus effects of higher 0.56-1.0 mg/kg doses of methamphetamine
      over the same dose range. The alpha-2 NE antagonist, yohimbine, also partially
      generalized to methamphetamine and blocked the discriminative-stimulus effects of
      the 1.0 mg/kg training dose of methamphetamine at doses of 5.6-10.0 mg/kg. A
      lower 3.0 mg/kg dose of yohimbine increased methamphetamine-appropriate
      responding when given together with low 0.1-0.3 mg/kg doses of methamphetamine.
      CONCLUSIONS: The present data suggest that the NE system plays a modulatory role
      in the discriminative-stimulus effects of methamphetamine. These effects appear
      to be mediated through NE uptake sites and alpha-2 receptors, with limited
      involvement of alpha- receptors and beta receptors.

PMID- 10353434
TI  - Changes in aggressive behavior during withdrawal from long-term marijuana use.
AB  - RATIONALE: Even though marijuana is the most commonly abused illicit drug in the
      United States, it is still undetermined whether withdrawal after chronic use
      results in changes in aggressive behavior in humans. OBJECTIVE: The present study
      investigated the pattern and duration of changes in aggressive behavior in long
      term marijuana users during a 28-day abstinence period verified by daily urines.
      METHOD: Chronic marijuana users who had smoked marijuana on at least 5000
      occasions (the equivalent of smoking daily for approximately 14 years) and who
      were smoking regularly when recruited were studied on days 0 (when they were
      still smoking), 1 (during acute withdrawal), 3, 7 and 28 of a 28-day
      detoxification period. Aggressive behavior was measured using the Point
      Subtraction Aggression Paradigm. RESULTS: Compared to controls and to the pre
      withdrawal data, chronic marijuana users displayed more aggressive behavior on
      days 3 and 7 of marijuana abstinence. These increases in aggressive responding
      returned to pre-withdrawal levels after 28 days and were paralleled by small, non
      significant changes in depression and anxiety scores. CONCLUSIONS: Our findings
      confirm previous reports of an abstinence syndrome associated with chronic
      marijuana use and suggest that aggressive behavior should be an additional
      component of this syndrome.

PMID- 10353435
TI  - Reduced satiating effect of d-fenfluramine in serotonin 5-HT(2C) receptor mutant
      mice.
AB  - RATIONALE: d-Fenfluramine stimulates the release of serotonin (5-HT) and is a
      potent inhibitor of the re-uptake of 5-HT into nerve terminals. Administration of
      d-fenfluramine suppresses food intake in both animals and humans. OBJECTIVE: We
      have investigated the role of the 5-HT2C receptor in mediating the effect of d
      fenfluramine on mouse food intake and the behavioural satiety sequence. METHODS:
      Mutant mice lacking serotonin 5-HT2C receptors and wild-type animals were
      habituated to a daily presentation of wet mash. Animals were non-deprived and
      received d-fenfluramine (3-30 mg/kg) 30 min prior to being assessed for the
      presence of stereotypy and presented with wet mash. The behaviour of animals was
      observed for the subsequent 40 min and food intake was recorded. RESULTS: d
      Fenfluramine dose-dependently inhibited the consumption of a palatable wet mash
      by the mice. d-Fenfluramine (3 mg/kg) significantly reduced the amount of wet
      mash consumed by wild-type mice and induced a temporal advance in the behavioural
      satiety sequence consistent with an enhancement of satiety. Mutant mice were less
      sensitive to the satiating effects of 3 mg/kg d-fenfluramine. Hence, this dose of
      d-fenfluramine had a reduced effect on both food consumption and the behavioural
      satiety sequence in the 5-HT2C mutant mice. In contrast, mutant mice showed an
      increased sensitivity to the stereotypy induced by high doses of d-fenfluramine
      (10, 30 mg/kg) compared to that of wild-type littermates. CONCLUSION: These data
      demonstrate a role for the 5-HT2C receptor in mediating d-fenfluramine-induced
      satiety.

PMID- 10353436
TI  - Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors.
AB  - RATIONALE: Central cannabinoid systems have been implicated in appetite
      regulation by the respective hyperphagic actions of exogenous cannabinoids, such
      as delta9-THC, and hypophagic effects of selective cannabinoid receptor
      antagonists. OBJECTIVE: This study examined whether an endogenous cannabinoid,
      anandamide, could induce overeating, via a specific action at central (CB1)
      cannabinoid receptors. METHODS: Pre-satiated male rats (n=18), received
      subcutaneous injections of anandamide (0.5, 1.0, 5.0, 10.0 mg/kg) before 3-h,
      nocturnal food intake tests. In a second series of intake tests (n=8), anandamide
      injection (1.0 mg/kg) was preceded by injection of the specific CB1 receptor
      antagonist, SR141716 (0.1, 0.5, 1.0 mg/kg SC). RESULTS: All doses of anandamide
      induced significant overeating, with 1.0 mg/kg being most potent. Additionally,
      hyperphagia induced by 1.0 mg/kg anandamide was dose-dependently attenuated by
      SR141716 pretreatment. CONCLUSION: This first demonstration of anandamide
      induced, CB -mediated, overeating provides important evidence for the involvement
      of a central cannabinoid system in the normal control of eating.

PMID- 10353437
TI  - Plasma nicotine and cotinine levels following intravenous nicotine self
      administration in rats.
AB  - RATIONALE: The route of nicotine administration between animal models and humans
      is very different and further investigation by determining levels of nicotine
      entering into the circulatory system is warranted. OBJECTIVE: The present study
      addresses the validity of the rat self-administration procedure by comparing
      plasma levels of nicotine in the rat with levels reported in smokers following
      cigarette consumption. METHODS: Plasma levels of nicotine and its metabolite
      cotinine were measured in 17 rats following intravenous self-administration of a
      range of nicotine doses (0.015. 0.03 and 0.06 mg/kg per infusion). RESULTS: The
      two larger unit doses supported reliable self-administration behaviour with no
      overall difference in the patterns of nicotine intake. However, the total
      nicotine intake over the 2-h session was related to unit dose and this correlated
      highly with nicotine and cotinine levels measured in blood collected from the
      tail vein. On average, cotinine levels (50-200 ng/ml) were approximately 2-fold
      higher than nicotine levels (40-120 ng/ml) in plasma. Following an extinction
      test for one session in which saline was substituted for nicotine, no change in
      behaviour was observed in the two groups, while plasma levels of nicotine and
      cotinine dropped to nominal levels. CONCLUSIONS: The concentrations of nicotine
      attained following nicotine self-administration appear to be similar to levels
      reported in smokers after cigarette consumption, providing further validation of
      this procedure as an animal model of nicotine dependence.

PMID- 10353439
TI  - Alpha-1-antitrypsin and its relevance to human disease.

PMID- 10353440
TI  - The gene for X-linked anhidrotic ectodermal dysplasia encodes a TNF-like domain.

PMID- 10353438
TI  - Local administration of delta9-tetrahydrocannabinol attenuates capsaicin-induced
      thermal nociception in rhesus monkeys: a peripheral cannabinoid action.
AB  - RATIONALE: Cannabinoids can reduce nociceptive responses by acting on peripheral
      cannabinoid receptors in rodents. OBJECTIVES: The study was conducted to evaluate
      the hypothesis that local administration of delta9-tetrahydrocannabinol (delta9
      THC) can attenuate capsaicin-induced nociception in rhesus monkeys. METHODS:
      Capsaicin (100 microg) was applied locally in the tail of rhesus monkeys to evoke
      a nociceptive response, thermal allodynia, in normally innocuous 46 degrees C
      water. delta9-THC (10-320 microg) was coadministered with capsaicin in the tail
      to assess local antinociceptive effects. In addition, a local antagonism study
      was performed to confirm the selectivity of delta9-THC action. RESULTS: delta9
      THC dose-dependently inhibited capsaicin-induced allodynia. This local
      antinociception was antagonized by small doses (10-100 microg) of the cannabinoid
      CB1 antagonist, SR141716A, applied in the tail. However, 100 microg SR141716A
      injected subcutaneously in the back did not antagonize local delta9-THC.
      CONCLUSIONS: These results indicate that the site of action of locally applied
      delta9-THC is in the tail. It provides functional evidence that activation of
      peripheral cannabinoid CB1 receptors can attenuate capsaicin-induced thermal
      nociception in non-human primates and suggests a new approach for cannabinoids in
      pain management.

PMID- 10353441
TI  - Endothelin antagonism with bosentan: a review of potential applications.
AB  - Endothelin receptor antagonists have been proposed for the treatment of a variety
      of disorders in which the endothelins may act as pathogenic mediators, such as
      congestive heart failure, systemic and pulmonary hypertension, and cerebral
      vasospasm. Bosentan (Ro 47-0203) is a nonpeptide competitive antagonist, which
      can be a good tool for studying the endothelin system because it may be
      administered either acutely or chronically. It is specific for the endothelin
      system and blocks the actions of endothelin at both mammalian receptors (A and
      B). In experimental models of heart failure bosentan acts as a vasodilator and
      neurohormonal blocker that improves overall left ventricular performance and
      reduces renal dysfunction. Furthermore, in chronic studies, bosentan attenuates
      cardiac remodeling and significantly improves survival. In patients with chronic
      heart failure bosentan produces pulmonary and systemic vasodilation and may
      enhance conventional treatment with angiotensin-converting enzyme inhibitors.
      Long-term studies are being conducted to characterize the full therapeutic
      potential of bosentan in chronic heart failure. In experimental models bosentan
      reverses established pulmonary hypertension. Preclinical efficacy has also been
      demonstrated in essential hypertension, where bosentan can reduce blood pressure
      and end-organ damage. Clinical trials in hypertensive patients indicate that
      bosentan reduces blood pressure without heart rate increase or neurohumoral
      stimulation. Finally, bosentan is being considered for the treatment of cerebral
      vasospasm following subarachnoid hemorrhage. Bosentan reverses experimentally
      induced vasospasm of the basilar artery, and preliminary trials indicate that it
      can increase cerebral blood flow after aneurysmal subarachnoid hemorrhage.

PMID- 10353442
TI  - Pulmonary epithelial expression of human alpha1-antitrypsin in transgenic mice
      results in delivery of alpha1-antitrypsin protein to the interstitium.
AB  - Alpha1-antitrypsin (alpha1AT) therapy is used as a treatment for alpha1AT
      deficiency. It has also been proposed as a therapy for cigarette smoke-induced
      emphysema, although the efficacy of such therapy is as yet unproven. Moreover,
      the optimal route of delivery of alpha1AT to the lung interstitium, the crucial
      locus of action, is unknown. We created transgenic mice with expression of the
      human alpha1AT gene directed by a human surfactant protein C (SpC) promoter
      fragment or a rat Clara cell 10-kDa protein (CC10) promoter fragment in order to
      examine the ability of pulmonary epithelial cell expression of alpha1AT to
      deliver protein to the interstitium, and to produce a model that would allow
      studies on the efficacy of alpha1AT in preventing lung damage after cigarette
      smoke exposure. Four transgenic lines were studied. In situ hybridization and
      light microscopic immunohistochemistry showed that two CC10 driven lines
      expressed human alpha1AT in type 11 alveolar cells and airway epithelial cells;
      alpha1AT expression was seen in the alveolar parenchyma in two SpC driven lines,
      and in small airway epithelium in one of the SpC lines. Electron microscopic
      immunochemistry showed the presence of the human alpha1AT protein in the
      interstitium in all lines. Mean levels of human protein varied from 0.37 to 2.9
      microg/g lung protein and serum levels from 0.72 to 1.3 microg/ml, compared to
      normal human serum alpha1AT levels of 2-5 mg/ml. We conclude that transgene
      mediated expression of alpha1AT in pulmonary epithelial cells results in diffuse
      expression of the transgene in the alveolar parenchyma and reproducibly leads to
      transfer of protein to the interstitium. The present model is, however, limited
      by low levels of protein production; limited protein production may be a problem
      in other forms of gene therapy in which relatively large amounts of extracellular
      protein are needed in the lung for a therapeutic effect.

PMID- 10353443
TI  - The DNA-binding subunit p140 of replication factor C is upregulated in cycling
      cells and associates with G1 phase cell cycle regulatory proteins.
AB  - The DNA-binding subunit of replication factor C (RFCp140) plays an important role
      in both DNA replication and DNA repair. The mechanisms regulating activation of
      RFCp140 thereby controlling replication and cellular proliferation are largely
      unknown. We analyzed protein expression of RFCp140 during cell cycle progression
      and investigated the association of RFCp140 with cell cycle regulatory proteins
      in cell lines of various tissue origin and in primary hematopoietic cells.
      Western and Northern blot analyses of RFCp140 from synchronized cells showed
      downregulation of RFCp140 when cells enter a G0-like quiescent state and
      upregulation of RFCp140 in cycling cells. Translocation from the cytoplasmic
      compartment to the nucleus did not account for the significant increase in
      RFCp140 protein levels observed in cycling cells. To investigate a potential
      association of RFCp140 with cell cycle regulatory proteins coimmunoprecipitation
      assays were performed. These studies demonstrated specific binding of RFCp140 to
      cdk4-kinase in hematopoietic and fibroblast cell lines. Additional
      coimmunoprecipitation studies revealed specific association of RFCp140 with
      cyclin D1, p21, proliferating cell nuclear antigen, and retinoblastoma protein.
      These findings link DNA replication and repair factor RFCp140 to G1 phase cell
      cycle regulatory elements critically involved in cell cycle control.

PMID- 10353444
TI  - Cell therapy using microencapsulated 293 cells transfected with a gene construct
      expressing CYP2B1, an ifosfamide converting enzyme, instilled intra-arterially in
      patients with advanced-stage pancreatic carcinoma: a phase I/II study.

PMID- 10353445
TI  - New legislation on health database threatens personal autonomy and freedom of
      research.

PMID- 10353446
TI  - Dose-response relationship of phototherapy for seasonal affective disorder: a
      meta-analysis.
AB  - OBJECTIVE: The therapeutic effect of phototherapy for seasonal affective disorder
      (SAD) has been widely investigated. However, the antidepressant effect of various
      light intensities is inconclusive. The purpose of this study was to evaluate the
      dose-response relationship of phototherapy for SAD. METHOD: A meta-analytical
      methodology was applied to 39 studies of phototherapy for SAD. The studies
      collected were screened for study quality by a threats-to-validity method before
      inclusion. The fixed-effects-model analysis of variance procedures were used for
      data analysis. RESULTS: The results indicated that different light intensities
      produced different effects in reducing the typical symptoms, as measured by the
      Hamilton Depression Rating Scale, of patients with SAD. However, no significant
      differences in these effects were revealed between strong, medium and dim light
      in reducing the atypical symptoms of patients. CONCLUSION: These findings showed
      that light intensity varied positively with the antidepressant effect for typical
      but not for atypical symptoms of SAD, suggesting that light intensity tended to
      have different therapeutic effects on the typical and atypical symptoms of SAD.

PMID- 10353447
TI  - Adolescent depression: prevalence in Swedish high-school students.
AB  - A total population of high-school students aged 16-17 years in a Swedish town was
      screened for depression and previous suicide attempts, and 2300 students (93.3%)
      participated. Those with high depression scores (12.3%) and previous suicide
      attempts (2.4%), as well as controls matched for gender and education, were
      interviewed for diagnosis (DICA-R-A), and 88.8% participated. The 1-year
      prevalence of major depression was 5.8% and the lifetime prevalence was 11.4%,
      with four girls being represented for every boy. A depression lasting for at
      least 1 year was the most common type. Dysthymia was found in 2% (two girls for
      every boy). Short hypomanic episodes were present in 13.2% of those with a
      lifetime diagnosis of major depression.

PMID- 10353449
TI  - Risk factors for violence among long-stay psychiatric patients: national study.
AB  - This study identified risk factors for violence among long-stay (1 year or more)
      psychiatric patients in Israel (n = 2946) using data from a national reevaluation
      of such patients. Patients were rated as being violent if hospital staff or
      patient charts indicated an incident of physical violence at least every few
      months. The relationship between violence and patients' functioning, living
      conditions, treatment, background and hospitalization history was studied. In
      total, 22.8% of patients were violent. Based on logistic regression analysis, the
      risk factors for being violent were younger age, younger age at first
      hospitalization, poorer self-care, having more frequent visitors, and the patient
      not having his or her own clothing. The data for age and lack of gender
      differences confirm previous findings. However, the results regarding clothing,
      visitors, poor self-care and age of onset are unique. The results of this study
      suggest that the violent behaviour of in-patients is related to both individual
      and environmental variables.

PMID- 10353448
TI  - Personality disorders in dysthymia and major depression.
AB  - OBJECTIVE: The purpose of the present study was to investigate the comorbidity of
      personality disorders in patients with primary dysthymia compared to those with
      episodic major depression. METHOD: A total of 177 out-patients with primary
      dysthymia and 187 outpatients with episodic major depression were administered a
      structured diagnostic interview for DSM-III-R Axis II disorders. In addition, all
      of these patients completed the BDI, and those with the appropriate level of
      education also completed the Minnesota Multiphasic Personality Inventory (MMPI).
      RESULTS: A significantly higher proportion of dysthymic patients than patients
      with major depression met the criteria for a personality disorder, for
      borderline, histrionic, avoidant, dependent, self-defeating types and for
      personality disorders of clusters B and C. Further analysis revealed that the
      above differences were mainly due to the subgroup of patients with 'early-onset
      dysthymia'. Finally, patients with a personality disorder, both dysthymics and
      those with major depression, had significantly higher scores on the BDI and on
      the majority of the MMPI scales compared to those without a personality disorder.
      CONCLUSION: The data indicated that (i) dysthymia--mainly that of early onset--is
      associated with significantly higher personality disorder comorbidity than
      episodic major depression, and (ii) the presence of a personality disorder is
      related to more severe overall psychopathology.

PMID- 10353450
TI  - Serum testosterone levels, mental disorders and criminal behaviour.
AB  - OBJECTIVE: Although previous studies have revealed an association between
      androgens and aggression, there is a lack of knowledge of this issue in different
      mental disorders. METHOD: The associations between serum testosterone levels and
      criminal behaviour in different mental disorders were examined using data
      collected from forensic psychiatric male patients (20 schizophrenics and 42
      subjects with personality disorders). RESULTS: Male criminals with personality
      disorders had significantly higher serum levels of total and free testosterone
      than criminal schizophrenics. Among schizophrenics, total (P=0.01) and free
      testosterone (P=0.01) declined significantly more with age compared to healthy
      controls and patients with personality disorders, and also correlated with
      duration of neuroleptic drug use (r=-0.60, P=0.000 for total and r=-0.46,
      P=0.0001 for free testosterone). The recidivists with personality disorder had
      higher total (P=0.04) and free testosterone (P=0.05) levels than non-recidivists
      with personality disorder. CONCLUSION: Personality disordered criminals with
      multiple offences had high serum testosterone levels. The low testosterone
      concentrations among schizophrenics may be due either to long-term use of
      neuroleptic agents or to the mental illness itself and its possible inhibition of
      the pituitary-gonadal axis.

PMID- 10353451
TI  - Increasing rates of hospital admission for men with major mental illnesses: data
      from Scottish mental health units, 1980-1995.
AB  - OBJECTIVE: We studied first admission rates for major mental illness in order to
      explore links with an increase in psychiatric morbidity and mortality in men.
      METHOD: Patient discharge data from Scottish Mental Health Units during 1980-1995
      were analysed. RESULTS: Admission rates for schizophrenia remained constant in
      men and decreased in women. Affective disorders remained constant in men and
      decreased in women. Paranoid states increased in men and remained constant in
      women. Non-organic psychoses increased in both men and women. CONCLUSION: Further
      evidence is provided for an increase in the proportion of men, particularly
      younger age groups, admitted with major mental illness. Possible reasons include
      (i) comorbidity, (ii) biological variables, (iii) responses to and change in
      health-seeking behaviour in men and (iv) an increased prevalence of major mental
      illness in men.

PMID- 10353452
TI  - Intensive case management in Australia: a randomized controlled trial.
AB  - This study compared intensive case management (ICM) with standard clinical case
      management in a well-resourced community mental health service in Australia. A
      total of 73 severely disabled clients of an existing clinical service were
      randomly allocated to either ICM (caseload 10 clients per clinician) or standard
      case management (caseload up to 30 clients per clinician) and followed up for 12
      months. A greater proportion of clients receiving ICM showed improved social
      functioning, these clients had fewer psychiatric hospital admissions involving
      police, and were more likely to engage and remain in treatment compared to those
      who received standard case management. Clients receiving ICM did not show a
      reduction in hospitalization duration or total number of episodes. It is
      suggested that future studies of ICM should focus on which aspects of treatment
      produce positive outcomes, how they can be applied to routine clinical settings,
      and over what period of time outcomes are sustained.

PMID- 10353453
TI  - Hallucinogen, opiate, sedative and stimulant use and abuse in a population-based
      sample of female twins.
AB  - OBJECTIVE: Rates of illicit psychoactive substance use and abuse in women have
      increased substantially over the last 50 years. However, we understand little
      about the aetiology of these behaviors in women, and almost nothing about the
      role of familial-environmental and genetic factors. METHODS: We obtained, by
      means of blind telephone interviews with 1934 individual twins from female-female
      adult pairs ascertained through a population-based registry, including both
      members of 500 MZ and 326 DZ pairs, a history of lifetime illicit use, abuse and
      dependence, as defined by DSM-IV, of hallucinogens, opiates, sedatives and non
      cocaine stimulants. RESULTS: Lifetime prevalences for substance use ranged from
      3.3% for opiates to 10.4% for hallucinogens. Rates of abuse (ranging from 0.7%
      for opiates to 3.2% for stimulants) and dependence (ranging from 0.2% for
      hallucinogens to 1.4% for stimulants) were substantially lower. Significant twin
      resemblance was found for hallucinogen use, opiate use, sedative use and
      stimulant use, abuse and symptoms of dependence. The results of twin-model
      fitting suggested that twin resemblance for hallucinogen and stimulant use was
      due to both genetic and familial environmental factors, while twin resemblance
      for opiate and sedative use as well as stimulant abuse and symptoms of dependence
      was solely the result of genetic factors. Heritability of liability ranged from
      21% to 72%. Twin resemblance for substance use, abuse and dependence could not be
      explained by the similarity of the twins' environment in childhood, adolescence
      or adulthood. CONCLUSION: Although limited by the rarity in women of these forms
      of substance use and misuse, our results none the less suggest that familial
      factors, which are at least in part genetic, strongly influence the vulnerability
      to hallucinogen, opiate, sedative and stimulant use and abuse in women.

PMID- 10353454
TI  - Self-reported life satisfaction and treatment factors in patients with
      schizophrenia, major depression and anxiety disorder.
AB  - Our aim was to study the associations between life satisfaction and treatment
      factors and how depression affects these associations among patients with
      schizophrenia (n=403), major depression (n=349) and anxiety disorder (n=139) from
      a defined area. Treatment satisfaction and compliance were high, but life
      satisfaction was low regardless of diagnostic group. Patients with schizophrenia
      recorded better life satisfaction than patients with the other disorders. There
      were few independent associations between life satisfaction and treatment
      factors. Fortunately, factors amenable to treatment intervention, such as
      depression, problem-solving ability and social support, were independently
      related to life satisfaction in every diagnostic group. Depression decreased
      these associations significantly only in patients with schizophrenia. Life
      satisfaction and treatment satisfaction should be included as separate variables
      in treatment outcome studies.

PMID- 10353455
TI  - Assessment of ego state in anorexia nervosa and bulimia nervosa.
AB  - To clarify the effects of ego states on anorexia nervosa (AN) and bulimia nervosa
      (BN), the questionnaire of the Tokyo University Egogram (TEG) with critical
      parent, nurturing parent, adult, free child and adapted child scales was
      administered to 32 female AN patients aged 14 to 32 years (mean age 20 years) and
      49 female BN patients aged 14 to 33 years (mean age 23 years). The scores on the
      critical parent and adapted child scales for AN were significantly lower than
      those for BN. A multiple logistic regression analysis including all of the TEG
      scales, age, duration of illness and education showed that the adapted child
      scale significantly discriminated between AN and BN. The adaptive ego state is
      suggested for differentiating between the two disorders.

PMID- 10353456
TI  - A puzzling case of seizures and visual hallucinations during clomipramine
      treatment with a high dose but causing a low serum concentration.
AB  - We present a puzzling case of a 25-year-old depressive man suffering from
      seizures and visual hallucinations during clomipramine treatment with a high dose
      but causing a low serum concentration. We examined alleles of cytochrome P450
      (CYP) isozymes. It was revealed that he was not an ultrarapid metabolizer for
      CYP2D6, and that the genotypes were homozygous for CYP2D6J and heterozygous for
      CYP2C19m1. Throughout the treatment period, his compliance was good. Since he was
      a smoker, it seems likely that his low clomipramine level was due to smoking
      induced CYP1A2 activity. These findings suggest that smoking-induced CYP1A2
      activity overcomes the possibly inhibiting effects of homozygosity for CYP2D6J
      and heterozygosity for CYP2C19m1, and that high-dose clomipramine is not always a
      direct cause of seizures.

PMID- 10353457
TI  - The role of cognitive behavioural therapy in the treatment of unipolar
      depression.

PMID- 10353458
TI  - Mechanisms of antigen presentation.
AB  - T-lymphocytes recognize short peptide antigens bound stably to polymorphic major
      histocompatibility complex (MHC)-encoded glycoproteins expressed on the surface
      of antigen-presenting cells (APC). Two general pathways have evolved to generate
      peptide-MHC complexes. The MHC class II antigen processing pathway provides a
      mechanism for sampling proteins present in endosomal compartments. CD4+
      regulatory T-cells recognize peptides bound to MHC class II molecules, which are
      selectively expressed in specialized APC that have efficient mechanisms for
      uptake of microbial antigens, and express costimulatory molecules required for
      activating naive T-cells. CD8+ T-cells recognize peptides bound to MHC class I
      molecules. Class I molecules are widely expressed and bind peptides derived from
      the normal turnover of cellular proteins, providing a mechanism to display a
      sampling of cellular components to be monitored for abnormalities by cytotoxic T
      cells. Specialized accessory proteins influence the efficiency of antigen
      presentation and the specificity of immune responses through their roles in
      generating peptides, targeting antigen and MHC glycoproteins to selected
      intracellular compartments, and by direct participation in the peptide-loading
      mechanism. It has recently been discovered that some viruses have evolved ways to
      inhibit or subvert discrete steps in antigen processing, providing a mechanism to
      evade immune recognition.

PMID- 10353459
TI  - How to extinguish lymphocyte activation, immunotyrosine-based inhibition motif
      (ITIM)-bearing molecules a solution?
AB  - ITIM-bearing molecules represent a novel family of inhibitory receptors expressed
      widely through the hematopoietic compartment. These molecules share certain
      features such as the presence in their intracytoplasmic domain of the so-called
      motif ITIM (ImmunoTyrosine-based Inhibition Motif). These molecules are able to
      recruit phosphatases on their phosphorylated ITIM and thus mediate a localized
      inhibition of the transduction pathways. The molecular basis of this inhibitory
      pathway is discussed below.

PMID- 10353460
TI  - Association between reduced human leukocyte antigen (HLA)-DR expression on blood
      monocytes and increased plasma level of interleukin-10 in patients with severe
      burns.
AB  - Severe thermal injury causes an immune dysfunction which includes a decrease of
      monocyte human leukocyte antigen DR (HLA-DR) expression. Interleukin-10 exerts a
      negative influence on this parameter in vitro. In this study we determined the
      prognostic value of reduced monocyte HLA-DR expression with regard to infectious
      complications, and the in vivo association between monocyte HLA-DR and plasma
      interleukin-10 concentration. Both quantities were measured serially in 19
      patients with severe burns. HLA-DR expression was determined by direct
      immunofluorescence on a flow cytometer, and interleukin-10 was measured by ELISA.
      After burn trauma the percentage of HLA-DR expressing monocytes fell markedly
      (median: 53% at day 2, 36% at day 4, 31% at day 7, 28% at day 9, 35% at day 12,
      and 42% at day 14; compared to 93% for healthy volunteers). Moreover, patients
      who became septic showed lower monocyte HLA-DR expression than non-septic
      patients; the differences were significant at day 2 (p < 0.01) and day 7 (p <
      0.05). Plasma concentrations of interleukin-10 increased after thermal injury
      (median: 40 ng/l at day 2, 43 ng/l at day 4, 77 ng/l at day 7, 120 ng/l at day 9,
      63 ng/l at day 12, and 82 ng/l at day 14). Individual HLA-DR expression and
      interleukin-10 concentration were negatively correlated, the association reaching
      statistical significance at day 4 (p=0.006) and day 7 (p=0.031). Thus, after
      severe burn injury monocyte HLA-DR expression has prognostic value and is
      negatively associated with interleukin-10 plasma concentration.

PMID- 10353462
TI  - Activation and regulation of NFkappaB during acute inflammation.
AB  - During the acute inflammatory response, there is induction of a mediator cascade
      which functions to activate residential macrophages and recruit blood leukocytes
      to the site of the inflammatory insult. Dysregulation of this process can cause
      an exaggerated inflammatory response and lead to tissue injury. Recent studies
      have focused on the transcription factor NFkappaB, which controls the gene
      expression of many pro-inflammatory mediators. Under normal conditions, NFkappaB
      is retained in the cytosol by inhibitory proteins of the IkappaB family. In
      response to an inflammatory insult, IkappaB proteins are degraded and the free
      NFkappaB complex translocates to the nucleus where it initiates gene
      transcription. An understanding of the in vivo mechanisms leading to the
      activation of NFkappaB, and the regulatory mechanisms that exist to limit this
      activation, may lead to the development of novel new therapeutic options for
      inflammatory injury. In this review we will discuss the current knowledge of the
      role of NFkappaB in the development of acute inflammation, as well as the
      regulatory mechanisms that exist to prevent the activation of NFkappaB and
      resolve inflammatory tissue injury.

PMID- 10353461
TI  - Immunostimulatory CpG motifs trigger a T helper-1 immune response to human
      immunodeficiency virus type-1 (HIV-1) gp 160 envelope proteins.
AB  - Bacterial DNA sequences containing unmethylated CpG motifs have recently been
      proposed to exhibit immunostimulatory effects on B-, T- and NK cells, leading to
      the induction of humoral and cell-mediated immune responses. In the present study
      we investigated the immunomodulatory effects of a CpG-containing
      oligodeoxynucleotide (CpG ODN) to the HIV-1 gp 160 envelope (Env) protein in the
      BALB/c mouse model. Priming and boosting of mice with gp 160 adsorbed to
      aluminium hydroxide (Alum) induced a typical T helper-2 (Th2)-dominated immune
      response with high titers of gp 160-specific immunoglobulin (Ig)G1 isotypes but a
      weak IgG2a response. Specifically re-stimulated splenocytes from these mice
      predominantly secreted interleukin (IL)-5 but only minute amounts of interferon
      gamma (IFN-gamma) upon specific re-stimulation. In contrast, a boost immunisation
      of gp 160/Alum primed mice with a gp 160/Alum/CpG combination resulted in a seven
      times higher production of IgG2a antibodies, without affecting the titers of IgG1
      isotypes. Furthermore, approximately 10-fold increased levels of IFN-gamma, but
      significantly reduced amounts of IL-5, were secreted from gp 160-restimulated
      splenic cells. A further greater than 30-fold increase in the levels of specific
      IgG2a responses and a substantially elevated secretion of IFN-gamma were observed
      when the mice received gp160/Alum/CpG combinations for priming and boost
      injections. Thus, CpG ODNs are useful as an adjuvant to induce a typical Th0/Th1
      response to HIV gp 160 proteins. However, despite the induction of a more Th1
      like immune response, gp 16O/Alum/CpG combinations were not sufficient to prime
      an Env-specific cytotoxic T-cell (CTL) response.

PMID- 10353463
TI  - CD14++ monocytes, CD14+/CD16+ subset and soluble CD14 as biological markers of
      inflammatory systemic diseases and monitoring immunosuppressive therapy.
AB  - The majority of peripheral blood monocytes strongly positive for the
      lipopolysaccharides (LPS)-receptor CD14 are negative for Fcgamma receptor type
      III (CD16). However, a subset of monocytes coexpressing CD14 and CD16 accounts
      for about 8% of all monocytes. This population exhibits features of tissue
      macrophages, and is largely expanded (> 20%) during acute and chronic
      inflammatory diseases including cases with pararheumatic systemic vasculitis. In
      addition, compared to normal controls, soluble CD14 (sCD14) is elevated (> 3
      microg/ml) in serum specimens of these patients. CD14+/CD16+ monocytes show a
      higher phagocytosis rate than CD14+/CD16 negative cells, and express higher
      levels of interleukin-1 and major histocompatibility complex, such as
      histocompatibility antigens HLA-DR, -DP and -DQ antigens. Glucocorticoids
      downregulate expression of CD14 and rapidly deplete CD14+/CD16+ monocytes from
      peripheral blood. Patients under chronic immunosuppressive therapy exhibit low
      CD14/+/CD16+ rates, which may rise during infectious and non-infectious
      inflammatory complications, however. Thus, serial analyses for sCD14 and the
      proinflammatory CD14+/CD16+ subset of monocytes suggest a valuable tool
      monitoring patients under immunosuppressive and/or antiinflammatory therapy.

PMID- 10353464
TI  - A potential role of an intracellular signaling defect in neutrophil functional
      abnormalities and promotion of tissue damage in patients with localized juvenile
      periodontitis.
AB  - Localized juvenile periodontitis is a destructive form of periodontal
      inflammatory disease which has its onset at puberty. The etiopathology of the
      disease is still unclear but neutrophils have been suggested to play a major role
      both in the production and development of the disorder. About 70% of the patients
      with localized juvenile periodontitis exhibit neutrophil functional
      abnormalities, such as decreased chemotaxis and phagocytosis. Interestingly, it
      has been frequently reported that the same hypoactive cells show an enhanced
      respiratory burst response and increased adhesion. Several possible mechanisms
      explaining neutrophil anomalies in localized juvenile periodontitis have been
      proposed. These include the presence of soluble serum factors capable of
      modulating neutrophil function, altered cell-surface receptor expression and/or
      function, and a change in the post-receptor signaling events. Recently, a growing
      evidence has accumulated showing that the diacylglycerol metabolism could be
      altered in neutrophils from patients with localized juvenile periodontitis. This
      change, which may be due to a defect in a major diacylglycerol metabolizing
      enzyme, diacylglycerol kinase, results in enhanced accumulation of diacylglycerol
      in activated cells. Because diacylglycerol is an endogenous activator of protein
      kinase C, the increased and prolonged generation of diacylglycerol could lead to
      abnormal pattern of protein kinase C-regulated neutrophil functions, explaining
      the parallel hypo- and hyperactivities.

PMID- 10353465
TI  - Polymorphonuclear oxidative burst after Helicobacter pylori water extract
      stimulation is not influenced by the cytotoxic genotype but indicates infection
      and gastritis grade.
AB  - H. pylori-associated gastric mucosal inflammation is characterized by the
      presence of polymorphonuclear (PMN) leukocyte infiltrate, which is more severe
      when the infecting strain is cagA positive. After appropriate stimuli, such as
      bacterial products, PMN release large amounts of oxygen derived free radicals and
      proteases, to kill the bacterium. H. pylori seems to be particularly resistant to
      the oxidative machinery of PMN, which can in turn damage the host gastric mucosa.
      We evaluated peripheral PMN oxidative burst response after stimulation with water
      extracts from cagA positive (WEcagA+) or negative (WEcagA-) H. pylori strains in
      infected (n=31) and non-infected patients (n=32) in comparison with healthy
      controls (n=16); the influence of gastric mucosal inflammatory infiltrate and
      activity grade on PMN oxidative burst were also assessed. PMN oxidative burst was
      measured by FACS analysis. H. pylori water extracts were obtained from bacterial
      culture. H. pylori genotype was determined by means of the polymerase chain
      reaction. The PMN oxidative burst in H. pylori infected patients was
      significantly higher than that in H. pylori negative or healthy controls, no
      differences being found when the results following WEcagA+ and WEcagA-
      stimulation were compared. The difference in PMN oxidative burst obtained after
      WEcagA- and E. coli (standard stimulus for PMN oxidative burst) stimulation
      discriminated H. pylori infected from non-infected patients with a sensitivity of
      90% and a specificity of 97%. The grade of PMN oxidative burst correlated with
      PMN infiltration grade of the gastric mucosa. Our findings allow to conclude that
      PMN oxidative burst activation by H. pyloriWE is species- but not strain
      correlated. PMN priming, probably consequent to the action of soluble mediators
      released by mononuclear cells, makes PMN hyper-responsive to H. pylori products,
      thus favoring the release in the gastric mucosa of infected patients of large
      amounts of oxygen-derived free radicals, which are not enough to eliminate the
      infection, but may contribute to damaging the gastric mucosa itself. Peripheral
      PMN oxidative burst response to H. pyloriWE might furthermore be of help in
      diagnosing H. pylori infection.

PMID- 10353466
TI  - Flow cytometry of cerebrospinal fluid (CSF) lymphocytes: alterations of blood/CSF
      ratios of lymphocyte subsets in inflammation disorders of human central nervous
      system (CNS).
AB  - Flow cytometry was adapted to measure lymphocytes in human cerebrospinal fluid
      (CSF). The method was sufficiently precise, reproducible and accurate despite low
      cell counts. In lumbar CSF of controls with 500 to 3500 (10(3)/l) leukocytes,
      lymphocyte counts correlated with those in corresponding venous blood: blood/CSF
      ratios of approximately 2000 : 1 were found for total T cells (CD3+) and CD3+ HLA
      DR-, CD3+4+, CD3+8+ subsets, ratios were increased for the lymphocyte subsets
      CD3+ HLA-DR+ < or = CD3+16+56+ < CD16+56+3- < CD8+3- << CD19+; CD8+4+ ratio was
      half of CD3+ ratio. Data indicate selective barriers (blood-brain and blood-CSF
      barriers) to blood lymphocyte subsets which favor the transfer of T subsets.
      Correlation of the subset ratios to the CD3+ ratio indicates distinct barrier
      properties which changed differently with acute and subacute inflammations and
      neuroimmunological diseases of central nervous system (CNS) in lumbar or
      ventricular CSF, but not with simple protein barrier disturbance. HLA DR+ T
      ratios were higher than HLA DR- T ratios only with controls and some
      neuroimmunological diseases. Lymphocyte barrier characteristics were related to
      protein leakage situated at the same barriers, indicating for the lymphocyte
      subsets selective transfer routes in control subjects and non-selective routes in
      patients with CNS inflammation where altered ratios revealed a mixture of both
      routes.

PMID- 10353467
TI  - Effects of oxidized low density lipoprotein, lipid mediators and statins on
      vascular cell interactions.
AB  - The integrin heterodimer CDllb/CD18 (alphaMbeta2, Mac-1, CR3) expressed on
      monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b,
      fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on
      endothelium, crucially contributing to vascular cell interactions in inflammation
      and atherosclerosis. In this report, we summarize our findings on the effects of
      lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to
      oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and
      increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments
      show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate
      proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable
      oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate
      (PDTC), while 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) or
      lysophosphatidylcholine had no effect, implicating yet unidentified radicals.
      Sequential adhesive and signaling events lead to the firm adhesion of rolling PMN
      on activated and adherent platelets, which may occupy areas of endothelial
      denudation. Shear-resistant arrest of PMN on thrombin-stimulated platelets in
      flow conditions requires distinct regions of Mac-1, involving its interactions
      with fibrinogen bound to platelet alphallbbeta3, and with other platelet ligands.
      Both arrest and adhesion strengthening under flow are stimulated by platelet
      activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We
      tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of
      hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and
      survival of patients with coronary heart disease. As compared to controls,
      adhesion of isolated monocytes to endothelium ex vivo was increased in patients
      with hypercholesterolemia. Treatment with statins decreased total and low density
      lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and
      resulted in a dramatic reduction of Mac-1-mediated monocyte adhesion to
      endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but
      not LDL in vitro, indicating that isoprenoid precursors are crucial for
      adhesiveness of Mac-1. Such effects may crucially contribute to the clinical
      benefit of statins, independent of cholesterol-lowering, and may represent a
      paradigm for novel, anti-inflammatory mechanisms of action by this class of
      drugs.

PMID- 10353468
TI  - Mycophenolic acid influences T helper 2 (Th2) cytokine induced expression of
      intercellular cell adhesion molecule-1 (ICAM-1) on human endothelial cells.
AB  - A possible synergistic effect of mycophenolic acid (MPA) and the
      immunosuppressive cytokines IL-4, IL-10 and IL-13 was investigated in human
      umbilical vein endothelial cells (HUVEC). These cytokines, which are produced by
      Th2-lymphocytes, were shown to induce the expression of vascular cell adhesion
      molecule-1 (VCAM-1) and production of IL-6 in endothelial cells. In this study we
      found IL-4 to induce both intercellular cell adhesion molecule-1 (ICAM-1) and
      VCAM-1 expression, whereas IL-13 induced VCAM-1 only. The surface expression of E
      selectin was not influenced by any of the cytokines tested. MPA on its own led to
      statistically significant ICAM-1 expression on HUVEC. The combination of MPA with
      IL-4 led to a significant ICAM-1 expression in an additive manner compared to the
      cytokine alone. In contrast, MPA neither induced VCAM-1 nor did it influence the
      effects of IL-4 and IL-13 on VCAM-1 expression. A clinically relevant
      concentration of mycophenolic acid (10 micromol/l) decreased intracellular
      guanosine-5'-triphosphate (GTP) levels significantly. Since intracellular
      nucleotides are responsible for the glycosylation of proteins, a disturbance of
      the endothelial nucleotide balance could be responsible for the effects of MPA on
      ICAM-1. Guanine and guanosine prevented and partially reversed the actions of
      MPA, on both intracellular GTP and ICAM-1 expression, which strongly implies that
      MPA by interfering with nucleotide metabolism, affects the adhesive properties of
      endothelial cells, and by acting synergistically with IL-4 probably influences
      Th2 cytokine effects.

PMID- 10353469
TI  - Alterations of endothelial nucleotide levels by mycophenolic acid result in
      changes of membrane glycosylation and E-selectin expression.
AB  - The effect of the inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH),
      mycophenolic acid, on intracellular nucleotides and the synthesis of cellular
      glycoproteins was evaluated in human umbilical vein endothelial cells. A
      clinically attainable concentration (10 micromol/l) of mycophenolic acid
      decreased guanosine-5'-triphosphate (GTP) levels significantly and led to a
      strong elevation of uridine-5'-triphosphate (UTP), whereas intracellular
      adenosine-5'-triphosphate (ATP) pools remained unaffected. The staining of the
      endothelial cell membranes with lectins specific for fucose and mannose (Ulex
      europaeus- and Galanthus nivalis agglutinin, respectively) was reduced,
      reflecting an inhibition of fucose and mannose incorporation into endothelial
      glycoproteins. The surface expression of E-selectin, an important determinant for
      leuko-endothelial interactions decreased significantly. Guanine and guanosine
      prevented the actions of mycophenolic acid and reversed the drug-induced decrease
      in GTP and its associated effects. The findings that mycophenolic acid produces
      alterations in the formation of glycoproteins and in the membrane architecture
      are indicative of metabolic lesions induced by an agent that depresses guanine
      nucleotide synthesis through inhibition of IMPDH. The pronounced reduction of E
      selectin surface expression on endothelial cells accompanied by changes of
      endothelial cell fucosylation, a prerequisite for the contact with lymphocytic L
      selectin, indicates an inhibitory effect of mycophenolic acid in the rolling
      phase of leukocyte recruitment and strongly implies a new and additional
      immunosuppressive mechanism of this agent.

PMID- 10353470
TI  - C-reactive protein: structural biology and host defense function.
AB  - Human C-reactive protein is a Ca2+-binding acute phase-protein with binding
      specificity for phosphocholine. Recent crystallographic and mutagenesis studies
      have provided a solid understanding of the structural biology of the protein,
      while experiments using transgenic mice have confirmed its host-defense function.
      The protein consists of five identical protomers in cyclic symmetry. On one face
      of each protomer there is a binding site for phosphocholine consisting of two
      Ca2+ ions that ligate the phosphate group and a hydrophobic pocket that
      accommodates the methyl groups of phosphocholine. On the opposite face is a deep
      cleft formed by parts of the N and C termini and bordered by an alpha-helix.
      Mutational studies indicate that the C1q-binding site of the molecule is located
      at the open end of this cleft with Asp112 and Tyr175 representing contact
      residues. Using human C-reactive protein transgenic mice, we investigated the
      host defense functions of the protein. Transgenic mice infected with
      Streptococcus pneumoniae had increased lifespan and lowered mortality compared to
      wild-type mice. This was attributable to an up to 400-fold reduction in
      bacteremia mediated mainly by the interaction of C-reactive protein with
      complement. A complement-independent host protective effect was also
      demonstrated.

PMID- 10353471
TI  - A novel acute-phase marker: lipopolysaccharide binding protein (LBP).
AB  - Acute phase proteins are extremely helpful markers for indicating a disturbance
      of the homeostasis within the organism and for monitoring the course of a
      disease. Despite the availability of several serum acute phase markers, a better
      and more specific prediction of sepsis and related disorders, such as systemic
      inflammatory response syndrome (SIRS) is still needed, as these diseases still
      have a high mortality rate and have to be detected early and with high
      specificity. Here a novel acute-phase protein is introduced, that has certain
      biological functions in host defense and that may be a useful addition for the
      diagnosis and monitoring of sepsis. Lipopolysaccharide (LPS or endotoxin),
      binding protein (LBP) is a class 1 acute-phase protein with the ability to bind
      and transfer bacterial LPS. Changes in serum levels of LBP have profound effects
      on the host's ability to react to endotoxin stimulation and to defend itself
      against sepsis. Results obtained from in vitro studies and from an animal model
      are reviewed here and a perspective on ongoing clinical studies is given. There
      is evidence that LBP, along with other LPS-recognizing molecules, is an important
      parameter for monitoring the acute phase and the ability of the host to react to
      LPS-challenge.

PMID- 10353472
TI  - Detection of acute phase response and infection. The role of procalcitonin and C
      reactive protein.
AB  - OBJECTIVE: Established parameters, e.g. C-reactive protein (CRP), do not
      differentiate specifically enough between patients developing an infection and
      those exhibiting an acute phase response following cardiac surgery. The objective
      of this prospective study was to investigate if procalcitonin (PCT) is more
      helpful than CRP. METHODS: During a 1-year period, seven out of 563 patients
      (1.2%) developed systemic infections (group A) after cardiac operations with
      cardiopulmonary bypass (CPB), and additional eight patients (1.4%) had local
      wound infections requiring surgical therapy (group B). Blood samples for PCT and
      CRP measurements were taken preoperatively, at the onset of infection (d1), as
      well as on the third day (d3), fifth day (d5), and seventh day (d7) following
      diagnosis of infection. Forty-four randomly selected patients undergoing cardiac
      surgery with CPB without clinical signs of infection, additional intensive care
      unit (ICU) management or additional antibiotic treatment served as control (group
      C) to assess the PCT and CRP contribution to acute phase response. PCT and CRP
      levels were measured preoperatively, on the first (d1), third (d3) and fifth day
      (d5) after operation. RESULTS: At the onset of infection, PCT levels (median
      interquartile range 25%-75%) increased significantly in group A as compared to
      baseline values (10.86 (3.28-15.13) ng/ml vs. 0.12 (0.08-0.21) ng/ml), and
      decreased during treatment to still significantly elevated values on d5 (0.56
      (0.51-0.85) ng/ml). CRP levels were significantly elevated on all days
      investigated with no trend towards normalisation (d1: 164.5 (137-223) mg/l) vs.
      1.95 (1.1-2.8) mg/l preoperatively, d5: 181.1 (134-189.6) mg/l. In group B, no
      increase in PCT levels, but a significant increase of CRP from d1 (165.9 (96.6
      181.6) mg/l) vs. 3.7 (2-4.3) mg/l preoperatively) until d5 98 (92.8-226.2) mg/l
      was detected. In group C, postoperative PCT levels increased slightly but
      significantly in the absence of infection on d1 (0.46 (0.26-0.77) ng/ml vs. 0.13
      (0.08-0.19) ng/ml preoperatively), and d3 (0.37 (0.2-0.65) ng/ml and reached
      baseline on d5 (0.24 (0.11-0.51) ng/ml)). CRP levels were significantly elevated
      as compared to baseline on all postoperative days investigated (baseline: 1.75
      (0.6-2.9) mg/l, d1: 97.5 (74.5-120) mg/l), d3: 114 (83.05-168.5) mg/l, d5: 51.4
      (27.4-99.8) mg/l)). PCT showed a significant correlation to CRP in group A (r
      =0.48, p < 0.001), a weak correlation in group C (r=0.27, p=0.002) and no
      correlation in group B. Intergroup comparison revealed a significant difference
      for PCT between all groups (A>C>B) and significantly higher CRP levels in group A
      vs. C and in group B vs. C. Thus, the pattern high PCT/high CRP appears to
      indicate a systemic infection, while low PCT/high CRP indicates either acute
      phase response or local wound problems, but no systemic infection. The cost for
      PCT measurements was 5.6-fold higher as compared to CRP. CONCLUSION: Due to the
      significant differences in the degree of increase, PCT appears to be useful in
      discriminating between acute phase response following cardiac surgery with CPB or
      local problems and systemic infections, with additional CRP-measurement
      increasing the specificity.

PMID- 10353473
TI  - Lactoferrin: a multifunctional glycoprotein involved in the modulation of the
      inflammatory process.
AB  - Lactoferrin is an iron-binding glycoprotein found in exocrine secretions of
      mammals and released from neutrophilic granules during inflammation. This review
      describes the biological roles of lactoferrin in host defence. Secreted
      lactoferrin exerts antimicrobial action either by chelation of iron or by
      destabilization of bacterial membranes. Furthermore, lactoferrin modulates the
      inflammatory process, mainly by preventing the release of cytokines from
      monocytes and by regulating the proliferation and differentiation of immune
      cells. Some of these activities are related to the ability of lactoferrin to bind
      lipopolysaccharides (LPS) with high affinity. Indeed, recent in vitro studies
      indicate that lactoferrin is able to compete with the LPS-binding protein for LPS
      binding and therefore to prevent the transfer of LPS to CD14 present at the
      surface of monocytes. Moreover, the prophylactic properties of lactoferrin
      against septicemia in vivo have been demonstrated. Taken as a whole, these
      observations strongly suggest that lactoferrin is one of the key molecules which
      modulate the inflammatory response.

PMID- 10353474
TI  - Annexin V and phospholipid metabolism.
AB  - Annexins, protein kinases C and cytosolic phospholipase A2 belong to three
      families of ubiquitous cytoplasmic proteins involved in signal transduction. All
      annexins share the property of binding to phospholipids in the presence of
      calcium. Most annexins are substrates for protein kinases C except annexin V, the
      most ubiquitous and abundant annexin. Protein kinases C (PKC) belong to three
      distinct groups of kinases, conventional PKCs (cPKCs) that depend on calcium,
      diacylglycerol and negatively charged phospholipids for their activity, novel
      PKCs (nPKCs) and atypical PKCs (aPKCs), that do not require calcium for their
      activity, although they both require negatively charged phospholipids. Cytosolic
      phospholipase A2 (cPLA2) depends on calcium for its catalytic activity as well as
      on serine phosphorylation by MAP kinases. We report that annexin V modulates the
      activity of cPKCs as well as of cPLA2 by interfering with their ability to bind
      to negatively charged phospholipids and calcium. We propose that annexin V could
      interfere with the calcium and phospholipid signalling pathway.

PMID- 10353475
TI  - Regulation of leukocyte trafficking by lipoxins.
AB  - Lipoxins are lipoxygenase interaction products formed by transcellular metabolism
      during host defence and inflammation. In model systems, lipoxins modulate
      polymorphonuclear leukocytes (PMN) chemotaxis, adhesion molecule expression,
      inhibit PMN-endothelial cell adhesion, and attenuate cytokine release from
      epithelial cells. These observations raise the possibility that lipoxins are
      'stop signals' for PMN-mediated tissue injury and promote the resolution of acute
      inflammation.

PMID- 10353476
TI  - Lipoxin and aspirin-triggered 15-epi-lipoxin cellular interactions anti
      inflammatory lipid mediators.
AB  - Eicosanoids are known to play important roles in inflammation. Recent findings
      have given rise to several new concepts regulating the generation of eicosanoids,
      illustrated in Figure 1. Lipoxins (LX) are trihydroxytetraene-containing
      eicosanoids that are generated within vascular lumen by platelet-leukocyte
      interactions and at mucosal surfaces by leukocyte-epithelial cell interactions.
      During these cell-cell interactions, transcellular biosynthetic pathways are used
      as major routes, and thus, in humans, LX are formed in vivo during multicellular
      responses such as inflammation, atherosclerosis, and thrombosis. This branch of
      the eicosanoid cascade generates specific tetraene-containing products that
      appear to function as stop signals, since they inhibit key steps in leukocyte
      mediated inflammation. Of special interest, it appears that aspirin also
      functions in part via production of novel epimers of lipoxins or 15-epi-lipoxins
      (Figure 1). Here, we review recent developments on the cellular interactions of
      these novel anti-inflammatory mediators.

PMID- 10353477
TI  - Differentiation and assessment of cell death.
AB  - Three documented cell death pathways, apoptosis, necrosis, and oncosis will be
      discussed. The end result of each pathway is cell death; however, the path by
      which death is achieved and the morphological and physiological traits of each
      may be strikingly distinct. Now that well characterized models have been
      established for particularly apoptosis, the induction pathway(s) has received
      much attention and the pathway pathology is beginning to be understood. Three
      model systems were investigated: APO-1/Fas, hypoxia, and oncosis. Cell death was
      induced, and during a time course sampling, a variety of methodologies, including
      DNA fragmentation by flow cytometry and gel electrophoresis, DNA staining, flow
      cytometric light scatter, transmission electron microscopy, anti-tubulin, Trypan
      blue, annexin V, and anti-APO2.7 were employed to monitor the cell death
      progress. The apoptotic pathway in the CD95-induced Jurkat cell model was further
      investigated using caspase inhibitor peptides and analyzed for APO2.7 antigen
      expression and DNA fragmentation by flow cytometry. Time course sampling
      characterized the cell death pathway and helped to differentiate the capabilities
      of the methods. The time to response and duration of the response were dependent
      upon cell type and method of induction. The CD95-induced Jurkat cell model showed
      a classical apoptotic response; however the MDA-MB-175-VII hypoxia model and the
      anti-5A9 induced oncosis model were not as clear. Each methodology shows
      advantages and disadvantages that allow the investigator to select several
      methods to identify, monitor, and enumerate cells with respect to cell death
      progression using time course studies.

PMID- 10353478
TI  - Depending on their concentration oxidized low density lipoproteins stimulate
      extracellular matrix synthesis or induce apoptosis in human coronary artery
      smooth muscle cells.
AB  - Various lines of evidence indicate that oxidative stress resulting in lipid
      peroxidation and protein modification is involved in the pathogenesis of
      atherosclerosis and coronary heart disease. We have investigated the effect of
      modified (oxidized) low-density lipoproteins (oxLDL) on collagen and fibronectin
      synthesis in cultured human coronary artery smooth muscle cells (HCA-SMC). As
      shown by immunofluorescence microscopy and time-resolved fluorescence
      immunoassay, oxLDL dose-dependently stimulated collagen type I and fibronectin
      synthesis in cultured HCA-SMC. The effect on matrix synthesis was biphasic, with
      a maximum effect at concentrations between 1 and 10 microg/ml oxLDL. Higher oxLDL
      concentrations (>25 microg/ml) were cytotoxic. Beside oxLDL, malondialdehyde
      modified LDL also stimulated extracellular matrix synthesis. In the presence of
      100 microg/ml ascorbic acid, 25, 50 and 100 microg/ml oxLDL induced apoptosis
      within 6-8 hours (demonstrated by TUNEL-reaction, annexin-V binding and APO-2.7
      expression). Apoptosis was not induced by normal (unmodified) LDL and
      malondialdehyde-modified LDL. The radical scavengers and antioxidants TROLOX and
      probucol and the hydrogen peroxide eliminator catalase significantly reduced
      oxLDL-induced apoptosis. Our results demonstrate that low concentrations of oxLDL
      are profibrogenic by stimulating extracellular matrix synthesis, whereas higher
      oxLDL concentrations induce oxidative stress and apoptosis in coronary artery
      smooth muscle cells. The profibrogenic effect might be relevant in the formation
      of atherosclerotic plaques, and the proapoptotic effect might contribute to an
      increased plaque vulnerability.

PMID- 10353479
TI  - Apheresis of plasma compounds as a therapeutic principle in severe sepsis and
      multiorgan dysfunction syndrome.
AB  - During sepsis there is an increase in the plasma content of several compounds,
      e.g., bacterial toxins, cytokines, cell debris, free hemoglobin and myoglobin. In
      blood, these compounds activate various cascade systems, which in large amounts
      or in more vulnerable patients lead to a disseminated intra-vascular coagulopathy
      (DIC) with multiorgan dysfunction syndrome (MODS) and death, despite conventional
      intensive care unit therapy. Therapeutic attempts to reverse these conditions
      have so far been of limited benefit. These effects have mainly been focused on
      lowering the blood concentration of single substances such as tumor necrosis
      factor. By the use of low-and high-flux hemodialysis filters, usually only small
      amounts of these substances are removed. By the use of plasmapheresis or plasma
      exchange, the extent of removal is considerably increased. The efficacy varies
      between the techniques (centrifugation vs. filtration or adsorption) and has also
      different influences on e.g. the complement system. This report describes these
      techniques and the therapeutical possibilities given by them. In small trials,
      blood or plasma exchange has been used as rescue therapy in critically ill
      patients with a progressive MODS and DIC. A survival of about 80% of the patients
      has been reported in these studies and the use of combined therapy will be
      discussed. Controlled trials are required in this field.

PMID- 10353480
TI  - Supportive therapy of the sepsis syndrome.
AB  - Adequate volume loading may be the most important step in the treatment of
      patients with septic shock. Techniques allowing us to achieve and tightly control
      volume loading and regional perfusion are considered to be helpful. An elevated
      oxygen delivery may be beneficial in some patients but the increase of oxygen
      delivery should be guided by the measurement of parameters assessing global and
      regional oxygenation. Forcing an increase in oxygen delivery by the use of very
      high dosages of catecholamines can be harmful. Vasopressors should be used for
      achieving an adequate perfusion pressure. For norepinephrine, no negative effects
      on regional perfusion have been demonstrated. Epinephrine and dopamine should be
      avoided because they seem to redistribute blood flow away from the splanchnic
      region. There are no convincing data yet to support the routine use of low dose
      dopamine or dopexamine in patients with sepsis. Neither low dose dopamine nor
      dopexamine has been proven to prevent renal failure in septic patients.
      Furthermore, there is evidence that low dose dopamine may reduce mucosal
      perfusion in the gut in some patients. There is some suggestion that dopexamine
      can improve splanchnic perfusion but since these effects remain somewhat
      controversial, there is no reason for a general recommendation for dopexamine in
      septic patients.

PMID- 10353481
TI  - Supplemental immune globulins in sepsis.
AB  - Intravenous immune globulins are widely used as supplemental treatment of sepsis,
      septic shock and systemic inflammation in the critically ill, although this
      indication has at best been validated in part. Likely beneficial mechanisms of
      action may include the improvement of serum bactericidal activity due to
      neutralizing and opsonizing immunoglobulin (Ig)G- and IgM-antibodies, as well as
      stimulation of phagocytosis and neutralization of bacterial endo- and exotoxins;
      another attractive mode of action may represent immune globulin-mediated
      modification and specific suppression of proinflammatory cytokine release from
      endotoxin- and superantigen-activated blood cells. For the "entire group of
      patients with sepsis and septic shock" a reduction in mortality by intravenous
      immune globulin could not be documented; however, in the score-based
      immunoglobulin in sepsis (SBITS)-study with 653 patients included, a moderate
      improvement in sepsis morbidity and multiple organ dysfunction syndrome was
      demonstrated. In defined sepsis subgroups, a reduction in mortality by
      intravenous immune globulin has been seen in individual small, not yet confirmed
      trials. Finally, the incidence of some severe infections in well characterized
      "patients at risk" and "operations at risk" is reduced by intravenous immune
      globulin prophylaxis. Thus, intravenous immune globulin is not a "magic bullet"of
      sepsis treatment, but it may reduce morbidity and thereby represent a useful
      piece of stone in the therapeutic mosaic of sepsis treatment.

PMID- 10353482
TI  - Polymorphonuclear granulocyte stimulation by cellulose-based hemodialysis
      membranes.
AB  - Hemodialysis with cellulose-based membranes is associated with an array of
      adverse reactions, including leukopenia, pulmonary sequestration and dysfunction
      of leukocytes. Activation of the alternative pathway of complement due to direct
      contact of plasma with dialysis membrane is considered to be responsible for the
      induction of these side effects. In recent years, evidence has accumulated that
      other neutrophil effector functions such as reactive oxygen intermediate
      production play an important role as well. Here the importance of burst formation
      in cooperation with other inflammatory effector functions in the mechanisms of
      hemodialysis-related adverse effects will be discussed.

PMID- 10353483
TI  - Reduction of circulating cholesterol and apolipoprotein levels during sepsis.
AB  - Sepsis with multiple organ failure is frequently associated with a substantial
      decrease of cholesterol levels. This decrease of cholesterol is strongly
      associated with mortality suggesting a direct relation between inflammatory
      conditions and altered cholesterol homeostasis. The host response during sepsis
      is mediated by cytokines and growth factors, which are capable of influencing
      lipid metabolism. Conversely lipoproteins are also capable of modulating cytokine
      production during the inflammatory response. Therefore the decrease in
      circulating cholesterol levels seems to play a crucial role in the
      pathophysiology of sepsis. In this review the interaction between cytokines and
      lipid metabolism and its clinical consequences will be discussed.

PMID- 10353484
TI  - Outcome prediction by traditional and new markers of inflammation in patients
      with sepsis.
AB  - Patients (n=242) admitted to intensive care unit for longer than 48 hours were
      categorised for sepsis according to American College of Chest Physicians/Society
      of Critical Care Medicine (ACCP/SCCM) Consensus Conference criteria. Body
      temperature, leukocyte count, C-reactive protein (CRP) and procalcitonin (PCT) as
      well as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8, IL-10
      and HLA-DR expression on monocytes were determined. Data of one randomly chosen
      day per patient entered analysis. Immunologic mediators contributing
      significantly to outcome were determined by logistic regression analysis. Area
      under the curves (AUC) of receiver operating characteristic curves of clinical
      markers of inflammation predicting prognosis were compared with AUC of relevant
      immunologic mediators. TNF-alpha, IL-6 and HLA-DR expression on monocytes were
      significantly associated with outcome; the AUC's were 0.835, 0.844 and 0.761
      respectively. AUC's for clinical markers were 0.878, 0.811, 0.620 and 0.614 for
      PCT, CRP, leukocyte count and body temperature respectively. PCT had the highest
      AUC compared to other clinical markers. These data indicate that PCT might be a
      better marker than the classic criteria of inflammation, CRP, leukocyte count,
      and body temperature to identify patients endangered by severe infection or
      sepsis.

PMID- 10353485
TI  - Isolation of highly enriched human monocytes from ten ml samples of heparinised
      whole blood.
AB  - A detailed study of the immune dysregulation involved in systemic inflammation
      requires the analysis of the main inflammatory cells in the circulation - the
      monocytes. Blood samples available from patients are necessarily restricted so
      that a rapid and efficient method is required to isolate these cells. Here we
      present a protocol to isolate blood monocytes in high yield from small samples of
      heparinised blood. The method yields monocyte preparations with a purity greater
      than 96%.

PMID- 10353486
TI  - Endotoxin adsorbent based on immobilized human serum albumin.
AB  - Extracorporeal apheresis of endotoxins and pro-inflammatory cytokines is still a
      therapeutic option in the early hyper-inflammatory phase of gram-negative sepsis.
      There is therefore ongoing interest in adsorber materials suitable for that kind
      of clinical application. Here we describe lipopolysaccharide (LPS) and cytokine
      adsorption characteristics of a new adsorbent based on purified human serum
      albumin (HSA) covalently linked to macroporous polymer beads (iHSA). Multipoint
      attachment of HSA to acrylic beads via carboxyl groups of the protein resulted in
      an increased affinity to LPS. In adsorption experiments (adsorbent/ plasma ratio
      1:3) a 70-80% reduction of limulus amoebocyte lysate (LAL) activity from 8.59+/
      2.07 EU/ml (mean+/-SD) to 1.82+/-0.77 EU/ml (S. abortus equi; n=40) (p < 0.001)
      and from 115.13+/-53.76 EU/ml to 17.70+/-11.68 EU/ml (E. coli F583; n=6) (p <
      0.01) was achieved. iHSA-purified plasma samples showed a decreased capability of
      inducing cytokine release from peripheral monocytes. Direct haemoperfusion of LPS
      pre-stimulated whole blood over iHSA resulted in decreased tumour necrosis factor
      alpha (TNFalpha) concentrations (30-40% reduction) whereas induced levels of
      interleukin (IL)-1beta and IL-6 were not affected. Depending on the means of
      immobilization, iHSA shows higher affinity for LPS than native albumin present in
      plasma. We demonstrated an efficient removal of LPS from plasma in vitro.
      Adsorption over immobilized HSA appears to be a simple and effective means of
      removing LPS and perhaps pro-inflammatory cytokines from the circulation.

PMID- 10353487
TI  - Topographical features of cutaneous tactile hypoesthetic and hyperesthetic
      abnormalities in chronic pain.
AB  - Tactile sensory abnormalities, such as tactile hypoesthesia and mechanical
      allodynia, are frequently present in patients with chronic pain. A growing body
      of evidence indicates that hyperesthetic phenomena, like mechanical allodynia,
      are at least in part due to altered processing by neurons in the CNS. We propose
      that the hyperesthesia is associated with a functional tactile hypoesthesia that
      is similarly mediated by altered processing by CNS neurons, and that this
      association is characterized by a particular topography that may be related to
      the receptive field organization of somatosensory CNS neurons. Moreover, we
      propose that the hyperesthetic-hypoesthetic association is dynamically modulated
      in tandem by pain input.

PMID- 10353488
TI  - Acetylsalicylic acid inhibits meningeal nociception in rat.
AB  - Although acetylsalicylic acid (ASA) is one of the most commonly administered
      drugs in the treatment of acute headaches, the sites of its action and the
      mechanisms of its therapeutic efficacy are still unclear. In this study using
      extracellular recording we examined the effects of ASA on spontaneous and
      mechanically evoked activities of neurons within the medullary dorsal horn with
      input from the parietal dura mater in rat. Their dural receptive fields were
      identified by von Frey filaments and found to be mainly located at the medial
      meningeal artery. All units showed spontaneous activity and had convergent input
      from the face. Neuronal activities were recorded before and after intravenously
      applied ASA (30 mg/kg) in 13 and saline in four units. Systemic application of
      ASA inhibited spontaneous and mechanically evoked activity within 15 min after
      application. Additionally, neuronal activities were recorded before, during and
      after topical application of ASA (1 mg/ml) onto the parietal dura mater in 5
      units. Topically applied ASA inhibited the mechanically evoked activity, whereas
      the spontaneous activity remained unchanged. It is concluded, that there are
      different effects of systemic and topical ASA on trigeminal neuronal activity,
      which may be due to both central and peripheral mechanisms.

PMID- 10353489
TI  - Alteration of Na+ currents in dorsal root ganglion neurons from rats with a
      painful neuropathy.
AB  - Increased excitability of primary sensory neurons may be important for the
      generation of neuropathic pain from nerve injury. The currents underlying the
      action potentials of these neurons are largely carried by Na+, and changes in Na+
      currents have been postulated to contribute to this increased excitability. Using
      patch clamp in whole-cell mode, we recorded Na+ currents from DRG neurons freshly
      isolated from rats with a chronic constriction injury (CCI), an animal model of
      neuropathic pain. We found significant changes in Na+ currents after CCI when
      cell size and Na+ channel properties were used to segregate DRG neurons. Most
      changes were concentrated in small neurons (< or = 25 microm diameter) and in the
      slow TTX-resistant current that is predominant in these cells. CCI produced two
      principal changes in these cells: it shifted the voltage-dependence of activation
      of the TTX-resistant current to more negative potentials and it reduced the
      average density of this current. The decrease in density appears to be primarily
      due to the decrease in the number of small neurons expressing this current. The
      net result is a change in both activation and steady-state inactivation
      properties of the total Na+ current to more negative potentials without a
      significant change in the density of total Na+ current. The change in activation
      properties of the TTX-resistant Na+ current are similar to those produced by some
      hyperalgesic autacoids, and may contribute to the increase in primary afferent
      excitability and hyperalgesia that occurs after this lesion.

PMID- 10353490
TI  - The cannabinoid receptor agonist WIN 55,212-2 mesylate blocks the development of
      hyperalgesia produced by capsaicin in rats.
AB  - Although it is well known that cannabinoids produce antinociception in acute pain
      models, there is less information on the ability of cannabinoids to alleviate
      hyperalgesia. In the present study, we determined whether cannabinoids attenuated
      the development of hyperalgesia produced by intraplantar injection of capsaicin
      in rats. In normal, untreated animals, intraplantar injection of 10 microg
      capsaicin produces nocifensive behavior (elevation of the injected paw)
      suggestive of pain, an increase in the frequency of withdrawal from punctate
      mechanical stimuli applied to the paw (mechanical hyperalgesia) and a decrease in
      the latency of withdrawal from noxious heat (heat hyperalgesia). Separate groups
      of animals were pretreated intravenously with vehicle, the cannabinoid receptor
      agonist WIN 55,212-2 at doses of 1, 10, 100 or 200 microg/kg, or the enantiomer
      WIN 55,212-3 (100 microg/kg) 5 min before intraplantar injection of capsaicin
      into one paw. The duration of nocifensive behavior was measured during the first
      5 min after capsaicin injection. Withdrawal responses to mechanical and heat
      stimuli applied to the plantar surface of both hindpaws were measured before and
      at 5 and 30 min after capsaicin. Pretreatment with WIN 55,212-2 produced a dose
      dependent decrease in nocifensive behavior and in hyperalgesia to mechanical and
      heat stimuli produced by capsaicin, as compared with vehicle pretreatment. Doses
      of 100 and 200 microg/kg WIN 55,212-2 completely blocked the development of
      hyperalgesia to mechanical and heat stimuli without altering withdrawal responses
      on the contralateral control paw. Furthermore, these doses of WIN 55,212-2 had no
      effect on basal withdrawal responses to heat in animals that did not receive
      capsaicin. The inactive enantiomer WIN 55,212-3 did not alter the development of
      capsaicin-evoked pain or hyperalgesia. These data suggest that low doses of
      cannabinoids, which do not produce analgesia or impair motor function, attenuate
      chemogenic pain and possess antihyperalgesic properties.

PMID- 10353491
TI  - Psychophysical measures of sensitization to tonic heat discriminate chronic pain
      patients.
AB  - Sensitization to continued nociceptive stimulation is supposed to be involved in
      the development of chronic pain at several levels of the CNS, but experimental
      studies investigating the perceptual dynamics of sensitization in humans are
      rare, and the diagnostic validity of experimental pain models is not known. The
      present study used a tonic heat paradigm to assess early sensitization (15-100 s)
      to experimental pain in 30 chronic pain patients (15 musculoskeletal/back pain,
      15 headache) and 23 healthy controls. Change in pain sensation during prolonged
      stimulation was measured by a dual sensitization method which combines subjective
      ratings and behavioural responses in an indirect psychophysical protocol
      protected against response bias. Phasic and tonic pain thresholds were measured
      for control purposes. The degree of sensitization was linearly related to
      stimulus temperature, and groups differed significantly in this 'sensitization
      gradient': chronic pain patients sensitized earlier and stronger than healthy
      subjects, musculoskeletal pain patients showed the strongest effect. Pain
      thresholds were lowered in headache patients only. Discriminant analysis
      demonstrated good sensitivity and specificity of individual sensitization
      measures for distinguishing pain syndromes, particularly in combination with pain
      thresholds. The results are in accordance with current models of spinal
      plasticity contributing to pathological pain states. They argue for the
      diagnostic value of psychophysical measures of sensitization.

PMID- 10353492
TI  - Involvement of excitatory amino acid receptors and nitric oxide in the rostral
      ventromedial medulla in modulating secondary hyperalgesia produced by mustard
      oil.
AB  - We have recently reported a model of secondary hyperalgesia in which facilitation
      of the thermal nociceptive tail-flick reflex following topical mustard oil is
      largely dependent on descending influences from the rostral ventromedial medulla
      (RVM). The current study was designed to examine a potential role for excitatory
      amino acid receptors and nitric oxide in the RVM in modulating this hyperalgesia.
      Topical application of mustard oil (100%) to the lateral surface of the hind leg
      of awake rats produced a short-lived (60 min) facilitation of the tail-flick
      reflex that was dose-dependently attenuated by microinjection of the selective N
      methyl-D-aspartate (NMDA) receptor antagonist APV (1-100 fmol) into the RVM.
      Microinjection of a greater dose of APV (1000 fmol) into the RVM produced a
      significant inhibition of the tail-flick reflex in the presence, but not absence,
      of mustard oil. In contrast, microinjection of the non-NMDA receptor antagonist
      DNQX (10 nmol) into the RVM further enhanced the magnitude and duration of the
      hyperalgesic response, and produced a facilitation of the tail-flick reflex
      following injection into the RVM of naive animals. Similar to APV, microinjection
      of the nitric oxide synthase inhibitor L-NAME (100-1000 nmol) into the RVM
      attenuated mustard oil hyperalgesia, while the greatest dose (1000 nmol) produced
      a significant inhibition of the tail-flick reflex in the presence, but not
      absence, of mustard oil. A role for nitric oxide synthase in the RVM in mustard
      oil hyperalgesia was further demonstrated by a significant increase in the number
      of NADPH-d labeled cells in the RVM at the time of maximal hyperalgesia.
      Involvement of NMDA receptors and nitric oxide in the RVM in descending
      nociceptive facilitation was supported by the observation that microinjection of
      either NMDA or the NO* donor GEA 5024 into the RVM of naive animals dose
      dependently facilitated the tail-flick reflex. The hyperalgesia produced by NMDA
      injection into the RVM was blocked by prior intra-RVM injection of either APV or
      L-NAME. These results support the notion that secondary hyperalgesia produced by
      mustard oil involves concurrent activation of dominant descending facilitatory,
      as well as masked inhibitory systems from the RVM. Additionally, the data suggest
      that descending facilitation involves activation of NMDA receptors and production
      NO* in the RVM, whereas inhibition involves activation of non-NMDA receptors in
      the RVM.

PMID- 10353493
TI  - The role of excitatory amino acid transmission within the rostral ventromedial
      medulla in the antinociceptive actions of systemically administered morphine.
AB  - Two classes of neurons with distinct responses to opioids have been identified in
      the rostral ventromedial medulla (RVM), a region with a well-documented role in
      nociceptive modulation. 'Off-cells' are activated, indirectly, by opioids, and
      are likely to exert a net inhibitory effect on nociceptive processing. 'On-cells'
      are directly inhibited by opioids, and there is evidence that these neurons can,
      under various conditions, facilitate nociception. We showed previously that
      excitatory amino acid (EAA) neurotransmission is crucial to the nocifensor reflex
      related on-cell burst, but plays little role in maintaining the ongoing activity
      of off-cells. The aim of the present study was to determine whether EAA
      transmission contributes to the activation of off-cells and the concomitant
      behavioral antinociception that follow systemic opioid administration. The non
      selective EAA receptor antagonist kynurenate was infused into the RVM (1 nmol/200
      nl) of lightly anesthetized rats prior to administration of morphine (1.5 mg/kg
      i.v). Off-cell, on-cell and neutral cell firing, as well as, tail flick response
      (TF) latencies were recorded. Kynurenate, significantly attenuated the
      characteristic opioid activation of off-cells. As a group, off-cells in
      kynurenate-treated animals did not become continuously active, and continued to
      exhibit tail-flick related pauses in firing. On-cell and neutral cell responses
      to opioid administration were unchanged. Opioid inhibition of the TF was also
      reduced, although baseline TF latency was unaffected, by RVM kynurenate. EAA
      mediated activation of off-cells, thus has an important role in opioid analgesia.
      The present observations underscore the importance of excitatory interactions
      among opioid-sensitive nociceptive modulatory circuits for systemic morphine
      analgesia, suggesting that such interactions are a critical factor in the
      synergistic relationships which have been demonstrated among these sites.

PMID- 10353495
TI  - A comparison of diffuse noxious inhibitory controls in men and women.
AB  - Results from clinical and experimental pain studies provide consistent evidence
      of sex differences in pain perception, with women reporting more clinical pain
      and demonstrating lower pain threshold and tolerance levels than men. The present
      study was designed to assess the notion that sex differences in pain perception
      may be related to differential activation of supraspinal pain modulation systems.
      Specifically, the phenomenon of diffuse noxious inhibitory controls (DNIC) was
      examined in healthy young adult men (n = 39) and women (n = 44) using repeated
      assessment of nociceptive flexion reflex activity before, during and after
      exposure to forearm ischemia. Consistent with previous research, women exhibited
      significantly lower nociceptive flexion reflex thresholds than men, and reported
      significantly greater pain in response to both forearm ischemia and repeated
      electrocutaneous stimulation required to elicit the nociceptive flexion reflex.
      Application of forearm ischemia was associated with a significant decrease in
      nociceptive flexion reflex activity in both men and women, however, the degree of
      attenuation of nociceptive flexion reflex activity was not significantly
      different between the sexes. These findings suggest that men and women exhibit
      similar activation of diffuse noxious inhibitory controls, but they do not
      exclude the possibility of sex differences in other forms of central pain
      modulation.

PMID- 10353494
TI  - Health care utilization by older adults in response to painful orofacial
      symptoms.
AB  - The purpose of this study was to determine which specific attributes of painful
      orofacial symptoms serve as predictors of health care utilization in a population
      based sample of elderly subjects. Furthermore, we documented patterns of health
      care utilization selection by type of health care provider. To our knowledge,
      these specific utilization patterns have never before been reported in the pain
      literature. Telephone interviews were conducted with a stratified random sample
      of 1636 community dwelling older (65+) north Floridians. A total of 5860
      households were contacted and screened, with 75.3% participating to the point
      where their eligibility for the study could be determined. The percentage of
      subjects reporting health care utilization for a specific symptom ranged from 62
      to 32%. One or more health care visits were reported by at least 50% of those
      reporting symptoms of toothache pain, facial pain, jaw joint pain and burning
      mouth in the past 12 months. These rates suggest that elderly individuals are
      willing and able to seek health care for painful orofacial symptoms. We found
      that pain intensity was the best predictor of whether an elderly individual
      utilized health care or not, which suggests that some pain intensity threshold
      may exist at which health care seeking behavior is initiated. The overall number
      of visits was not predicted by pain intensity but by other qualities more
      associated with time or level of dysfunction caused by the symptom. We also found
      that elderly adults, typically seek care for toothache from a dentist and from
      physicians for painful orofacial symptoms not associated with the teeth or mouth.
      These decisions regarding the selection of a health care professional may, in
      part, be a function of financial and insurance considerations, anatomical site
      and perception of the role of dentistry in orofacial care.

PMID- 10353496
TI  - Oral ketamine is antinociceptive in the rat formalin test: role of the
      metabolite, norketamine.
AB  - The present study was designed to evaluate the oral efficacy and bioavailability
      of ketamine. Antinociceptive efficacy was determined with the rat formalin test
      and oral bioavailability by the measurement of plasma and brain concentrations of
      ketamine and its major metabolite, norketamine. Oral ketamine in a dose range
      from 30 to 180 mg/kg or saline was given prior to intraplantar formalin and the
      flinching behavior was measured. Oral ketamine dose-dependently reduced the
      flinching during phase 2, while flinching during phase 1 was reduced only with
      the highest dose given. Following oral ketamine at 100 mg/kg, blood and brain
      samples were obtained and plasma and brain ketamine and norketamine levels were
      measured using high-performance liquid chromatography (HPLC). The average
      concentration ratio of norketamine/ketamine, as expressed by the area under the
      curve (AUC) value, was 6.4 for plasma and 2.9 for brain. These results
      demonstrate that a significant amount of norketamine is formed by first pass
      biotransformation of ketamine and is distributed to the brain. Competition
      binding assays for the [3H]MK-801-labeled non-competitive site of the N-methyl-D
      aspartate receptor (NMDA) receptor revealed that both norketamine and ketamine
      displaced [3H]MK-801 at low micromolar concentrations with Ki values of 2.5 and
      0.3 mM in the forebrain, and 4.2 and 1.0 mM in the spinal cord, respectively.
      Spinal norketamine was approximately equipotent to ketamine in producing
      antinociceptive effects during phase 2 of the formalin test. Thus, norketamine
      appears to contribute to the antinociceptive effects of oral ketamine through its
      NMDA receptor antagonist activity.

PMID- 10353497
TI  - Patient beliefs predict patient functioning: further support for a cognitive
      behavioural model of chronic pain.
AB  - According to the cognitive-behavioral model of chronic pain, patient beliefs
      about their chronic pain influence their behavioral and psychological
      functioning. Previous correlational and longitudinal studies have supported this
      hypothesis. However, since previous research has relied almost exclusively on
      patient self-report to assess both beliefs and functioning, shared method
      variance may explain some of the relationships found. The aim of the current
      study was to replicate and extend previous research on the relationship between
      pain beliefs and patient functioning and behavior by assessing the latter based
      on three sources of information: patient report, spouse report and direct
      observation. A total of 121 patients with chronic pain completed self-report
      measures of beliefs and function. Their spouses completed a measure of patient
      pain behavior, and both participated in a protocol, from which patient pain
      behaviors were coded by trained observers. Previously reported relationships
      between patient beliefs about pain and patient-reported functioning were
      replicated. Measures of patient beliefs were more strongly associated with self
      report measures of pain behaviors and functioning than with spouse and observer
      ratings of patient pain behaviors. However, significant associations between
      patient beliefs and both spouse- and observer-reported frequency of patient pain
      behaviors were found. These findings argue for the generalizability of the
      relationship found between patient beliefs and patient behaviors across
      assessment domains, and for the continued application of the cognitive-behavioral
      model to the understanding of patient adjustment to chronic pain.

PMID- 10353498
TI  - Spinal manipulative therapy versus a low force mimic maneuver for women with
      primary dysmenorrhea: a randomized, observer-blinded, clinical trial.
AB  - Non-drug therapies for women with primary dysmenorrhea are primarily based on
      anecdotal evidence and small-scale clinical studies. This randomized, observer
      blinded, clinical trial evaluated the efficacy of spinal manipulative therapy
      (SMT) in the treatment of women with primary dysmenorrhea. Women were recruited
      from the Chicago metropolitan area and evaluated for inclusion through four
      screening levels. One hundred thirty eight women, ages 18-45, with primary
      dysmenorrhea diagnosed by participating gynecologists, were randomly assigned to
      either SMT or a low-force mimic (LFM) maneuver. No treatment occurred at
      menstrual cycle 1. Treatment for both groups took place on day 1 of cycles 2, 3
      and 4, and prophylactic treatment of three visits took place during the 7 days
      before cycles 3 and 4. Main outcome measures were the Visual Analog Scale (VAS)
      and plasma concentration of the prostaglandin F2alpha metabolite, 15-keto-13,14
      dihydro-prostaglandin F2alpha (KDPGF2alpha), measured 15 min before treatment and
      60 min after treatment on day 1 of four consecutive menstrual cycles. The Moos'
      Menstrual Distress Questionnaire (MDQ) was also administered after treatment on
      day 1 of each cycle. At cycle 2, the post-treatment VAS scores decreased for both
      groups, with no statistically significant difference in pre- to post-treatment
      scores between the two groups (P = 0.44). The changes in pre- to post-treatment
      KDPGF2alpha levels were not statistically different between the SMT and LFM
      groups (P = 0.15). No treatment effects were detected over the three cycles for
      VAS, KDPGF2alpha or MDQ (P = 0.65, P = 0.61 and P = 0.78, respectively). However,
      there were statistically significant linear time effects for VAS (P = 0.008), MDQ
      (P < 0.001), and borderline significance for KDPGF2alpha (P = 0.054); these
      decreases were not considered clinically meaningful. The LFM maneuver used in
      this study was designed to act as a 'placebo-like' control treatment in
      comparison with SMT. Although it is possible that the trial did not continue long
      enough for any placebo effect of the LFM to wash out, it seems more likely that
      this maneuver was indistinguishable from SMT. Therefore, the postulated superior
      benefit of high-velocity, short-lever, low-amplitude, high-force spinal
      manipulation to a low-force maneuver is not supported by the results of this
      study. 1999 International Association for the Study of Pain.

PMID- 10353499
TI  - Involvement of trigeminal subnucleus caudalis (medullary dorsal horn) in
      craniofacial nociceptive reflex activity.
AB  - We have previously shown that an increase in electromyographic (EMG) activity of
      digastric (DIG) and masseter (MASS) muscles can be reflexly evoked by injection
      into the rat's temporomandibular joint (TMJ) region of the small-fibre excitant
      and inflammatory irritant mustard oil (MO). Since the trigeminal (V) subnucleus
      caudalis (Vc, i.e. medullary dorsal horn) has traditionally been viewed as an
      essential brainstem relay site of nociceptive information from craniofacial
      tissues, an EMG study was carried out in 45 anaesthetized rats to determine if Vc
      is involved in the MO-evoked increases in jaw muscle EMG activity. The effects of
      histologically confirmed surgical or chemical lesions of Vc on this evoked EMG
      activity were tested in different groups of rats. MO injection into the left TMJ
      region of intact rats evoked bilateral increases in EMG activity of DIG and MASS
      which could be significantly reduced by surgical transection of the left caudal
      brainstem at the obex level; MO injection into the right TMJ region in these same
      rats still readily evoked increases in EMG activity. A sagittal section medial to
      Vc or transection at the level of the second cervical spinal segment did not
      produce any significant reduction in the reflexly evoked EMG activity. Neurones
      in Vc, as opposed to fibres of passage, appear to be important for the MO-evoked
      EMG activity, since injection into Vc of the neurotoxic chemical ibotenic acid
      significantly reduced the mustard oil-evoked EMG activity. The Vc also appears to
      play a role in the activation of contralateral V motoneurons, as evidenced by the
      activation of the contralateral DIG and MASS muscles by the injection of MO into
      the left TMJ region of intact rats and by the reduction of this evoked EMG
      activity in the contralateral DIG and MASS of rats with a surgical transection or
      ibotenic acid lesion of the left Vc. These findings suggest that Vc may be a
      critical element in the neural pathways underlying the reflex responses evoked
      bilaterally in DIG and MASS muscles by noxious stimulation of the TMJ region.

PMID- 10353500
TI  - Breakthrough pain: characteristics and impact in patients with cancer pain.
AB  - Few surveys have been performed to define the characteristics and impact of
      breakthrough pain in the cancer population. In this cross-sectional survey of
      inpatients with cancer, patients responded to a structured interview (the
      Breakthrough Pain Questionnaire) designed to characterize breakthrough pain, and
      also completed measures of pain and mood (Memorial Pain Assessment Card (MPAC)),
      pain-related interference in function (Brief Pain Inventory (BPI)), depressed
      mood (Beck Depression Inventory (BDI)), and anxiety (Beck Anxiety Inventory
      (BAI)). Of 178 eligible patients, 164 (92.2%) met the criteria for controlled
      background pain. The median age was 50.6 years (range 26 to 77 years), 52% were
      men, and 80.6% were Caucasian. Tumor diagnoses were mixed, 75% had metastatic
      disease, 65% had pain caused directly by the neoplasm, and a majority had mixed
      nociceptive-neuropathic pain. The median Karnofsky Performance Status score was
      60 (range 40 to 90). Eighty-four (51.2%) patients had experienced breakthrough
      pain during the previous day. The median number of episodes was six (range 1 to
      60) and the median interval from onset to peak was 3 min (range 1 s to 30 min).
      Although almost two-thirds (61.7%) could identify precipitants (movement 20.4%;
      end-of-dose failure 13.2%), pain was unpredictable in a large majority (78.2%).
      Patients with breakthrough pain had more intense (P < 0.001) and more frequent (P
      < 0.01) background pain than patients without breakthrough pain. Breakthrough
      pain was also associated with greater pain-related functional impairment
      (difference in mean BPI. P < 0.001), worse mood (mood VAS, P < 0.05; BDI, P <
      0.001), and more anxiety (BAI, P < 0.001). Multivariate analysis confirmed that
      breakthrough pain independently contributed to impaired functioning and
      psychological distress. These data confirm that cancer-related breakthrough pain
      is a prevalent and heterogeneous phenomenon. The presence of breakthrough pain is
      a marker of a generally more severe pain syndrome, and is associated with both
      pain-related functional impairment and psychological distress. The findings
      suggest the need for further studies of breakthrough pain and more effective
      therapeutic strategies.

PMID- 10353501
TI  - Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain
      sensation.
AB  - Capsaicin applied topically to human skin produces itching, pricking and burning
      sensations due to excitation of nociceptors. With repeated application, these
      positive sensory responses are followed by a prolonged period of hypalgesia that
      is usually referred to as desensitization, or nociceptor inactivation.
      Consequently, capsaicin has been recommended as a treatment for a variety of
      painful syndromes. The precise mechanisms that account for nociceptor
      desensitization and hypalgesia are unclear. The present study was performed to
      determine if morphological changes of intracutaneous nerve fibers contribute to
      desensitization and hypalgesia. Capsaicin (0.075%) was applied topically to the
      volar forearm four times daily for 3 weeks. At various time intervals tactile,
      cold, mechanical and heat pain sensations were assessed in the treated and in
      contralateral untreated areas. Skin blisters and skin biopsies were collected and
      immunostained for protein gene product (PGP) 9.5 to assess the morphology of
      cutaneous nerves and to quantify the number of epidermal nerve fibers (ENFs).
      Capsaicin resulted in reduced sensitivity to all cutaneous stimuli, particularly
      to noxious heat and mechanical stimuli. This hypalgesia was accompanied by
      degeneration of epidermal nerve fibers as evidenced by loss of PGP 9.5
      immunoreactivity. As early as 3 days following capsaicin application, there was a
      74% decrease in the number of nerve fibers in blister specimens. After 3 weeks of
      capsaicin treatment, the reduction was 79% in blisters and 82% in biopsies.
      Discontinuation of capsaicin was followed by reinnervation of the epidermis over
      a 6-week period with a return of all sensations, except cold, to normal levels.
      We conclude that degeneration of epidermal nerve fibers contributes to the
      analgesia accredited to capsaicin. Furthermore, our data demonstrate that ENFs
      contribute to the painful sensations evoked by noxious thermal and mechanical
      stimuli.

PMID- 10353502
TI  - External validation of IASP diagnostic criteria for Complex Regional Pain
      Syndrome and proposed research diagnostic criteria. International Association for
      the Study of Pain.
AB  - Recent work in our research consortium has raised internal validity concerns
      regarding the current IASP criteria for Complex Regional Pain Syndrome (CRPS),
      suggesting problems with inadequate sensitivity and specificity. The current
      study explored the external validity of these IASP criteria for CRPS. A
      standardized evaluation of signs and symptoms of CRPS was conducted by study
      physicians in 117 patients meeting IASP criteria for CRPS, and 43 patients
      experiencing neuropathic pain with established non-CRPS etiology (e.g. diabetic
      neuropathy, post-herpetic neuralgia). Multiple discriminant function analyses
      were used to test the ability of the IASP diagnostic criteria and decision rules,
      as well as proposed research modifications of these criteria, to discriminate
      between CRPS patients and those experiencing non-CRPS neuropathic pain. Current
      IASP criteria and decision rules (e.g. signs or symptoms of edema, or color
      changes or sweating changes satisfy criterion 3) discriminated significantly
      between groups (P < 0.001). However, although sensitivity was quite high (0.98),
      specificity was poor (0.36), and a positive diagnosis of CRPS was likely to be
      correct in as few as 40% of cases. Empirically-based research modifications to
      the criteria, which are more comprehensive and require presence of signs and
      symptoms, were also tested. These modified criteria were also able to
      discriminate significantly, between the CRPS and non-CRPS groups (P < 0.001). A
      decision rule, requiring at least two sign categories and four symptom categories
      to be positive optimized diagnostic efficiency, with a diagnosis of CRPS likely
      to be accurate in up to 84% of cases, and a diagnosis of non-CRPS neuropathic
      pain likely to be accurate in up to 88% of cases. These results indicate that the
      current IASP criteria for CRPS have inadequate specificity and are likely to lead
      to overdiagnosis. Proposed modifications to these criteria substantially improve
      their external validity and merit further evaluation.

PMID- 10353503
TI  - Antinociceptive effects of locally administered morphine in infant rats.
AB  - Opiates injected into a site of injury are analgesic in adult animals, but there
      are no data on the effectiveness of this route of administration in immature
      organisms. Since the biological processes that regulate the effects of locally
      administered opiates are in flux during the early postnatal life of the rat, it
      is not clear whether or not opiates given directly into local tissue would be
      effective as analgesics. To test this we injected morphine (0.12, 0.60, 3.0
      microg/injection) directly into the hindpaw (intraplantar) of infant rats at 3,
      10 and 21 days of age, and assessed the behavioral response and the induction of
      Fos like immunocytochemistry in the dorsal horn of the spinal cord in the
      formalin test. Controls included saline injections to the paw, or comparable
      doses of morphine injected subcutaneously. At 3 days of age, the two higher doses
      were behaviorally analgesic when given into the paw, but there was limited
      selectivity over the subcutaneous route. At both 10 and 21 days of age,
      intraplantar injections were effective analgesics, whereas subcutaneous
      injections were not. The number of Fos stained cells in the dorsal horn of the
      spinal cord, induced by the formalin treatment, was decreased significantly by
      the 3.0 mg dose of morphine at all three ages. The results demonstrate that local
      treatment with morphine is an effective and selective analgesic in the infant
      rat.

PMID- 10353504
TI  - Relief of postoperative pain with jaw relaxation, music and their combination.
AB  - The aim of this randomized controlled trial was to determine the effect of jaw
      relaxation, music and the combination of relaxation and music on postoperative
      pain after major abdominal surgery during ambulation and rest on postoperative
      days 1 and 2. Opioid medication provided for pain, following abdominal surgery,
      does not always give sufficient relief and can cause undesired side effects.
      Thus, additional interventions such as music and relaxation may provide more
      complete relief. Previous studies have found mixed results due to small sample
      sizes and other methodological problems. In a rigorous experimental design, 500
      subjects aged 18-70 in five Midwestern hospitals were randomly assigned by
      minimization to a relaxation, music, relaxation plus music, or control group.
      Interventions were taught preoperatively and tested postoperatively. The same
      amount of time was spent with subjects in the control group. Pain was measured
      with the visual analogue sensation and distress of pain scales. Demographic and
      surgical variables, and milligrams of parenteral or oral opioids in effect at the
      time of testing were not significantly different between the groups, nor did they
      correlate with pain scores. Controlling for pretest sensation and distress,
      orthogonal a priori contrasts and multivariate analysis of covariance indicated
      that the three treatment groups had significantly less pain than the controls, (P
      = 0.028-0.000) which was confirmed by the univariate analysis of covariance (P =
      0.018-0.000). Post hoc multivariate analysis revealed that the combination group
      had significantly less sensation and distress of pain than the control group on
      all post-tests (P = 0.035-0.000), and the relaxation and music groups had
      significantly less on all tests (P = 0.022-0.000) except after ambulation. At
      post ambulation those using relaxation did not have significantly less pain than
      the controls on both days and those using music did not on day 1, although there
      were some univariate effects. A corresponding significant decrease in mastery of
      the interventions from pre to post ambulation suggests the need for reminders to
      focus on the intervention during this increased activity. Physicians and nurses
      preparing patients for surgery and caring for them afterward, should encourage
      patients to use relaxation and music as adjuvants to medication for postoperative
      pain.

PMID- 10353505
TI  - Rheumatoid arthritis patients show weather sensitivity in daily life, but the
      relationship is not clinically significant.
AB  - While the majority of rheumatoid arthritis (RA) patients report that their pain
      is influenced by the weather, studies examining the impact of weather on RA pain
      have yielded equivocal results. It is not clear from the existing studies if the
      mixed results are due to limited statistical power (e.g. small sample sizes and
      restricted variability in weather indices) or the failure to consider individual
      differences. The current study addressed these weaknesses by having 75 RA
      patients (mean age = 52.7; 71% female) record their daily pain severity for 75
      consecutive days. Objective weather indices including temperature, barometric
      pressure, relative humidity, and percentage of sunlight were obtained for the
      same dates from a local weather service. The results indicate that for the entire
      sample, pain levels were highest on cold, overcast days and following days with
      high barometric pressure. Pain levels also increased as a function of change in
      relative humidity from one day to the next. Individual difference analyses
      revealed significant variability between patients in their weather sensitivity
      patterns. In general, patients with higher levels of self-reported pain
      demonstrated more weather sensitivity. When considering the magnitude of these
      effects, however, weather variables accounted for only a small amount of change
      in pain scores. This pattern was true even for patients with the most pronounced
      pain-weather relationships. Thus, although weather sensitivity was found, the
      effect sizes were not clinically meaningful.

PMID- 10353506
TI  - Differential effects of chemical and mechanical colonic irritation on behavioral
      pain response to intraperitoneal acetic acid in mice.
AB  - Abdominal contractions are a viscerosomatic reflex response to noxious colorectal
      irritation in rats. In this study we characterize the modulating effect of
      chemical and mechanical colonic irritation on this reflex response to peritoneal
      irritation induced by diluted acetic acid (HAc) in conscious C57BL/6N mice. Pain
      responses were scored by counting the number of abdominal contractions during the
      30-min period after intraperitoneal (i.p.) injection of either vehicle or HAc.
      Abdominal contractions were induced by 0.6% but not by 0.3% HAc. Chemical
      irritation of the colon by intraluminal 25% turpentine did not produce abdominal
      contractions by itself, but significantly increased the effect of both 0.3 and
      0.6% i.p. HAc, administered 60 min after the luminal stimulus. Mechanical
      stimulation of the anorectum and colon by insertion of a balloon did not modify
      the effect of 0.6% HAc, while the insertion plus the inflation to 0.1 and 0.2 ml
      (30 s on/30 s off for 10 min) reduced the response to i.p. HAc by 35 and 88%,
      respectively. This inhibitory effect was reversed by naloxone (5 mg/kg, s.c.)
      pretreatment, while naloxone alone did not modify the effect of 0.6% HAc. These
      results demonstrate that chemical irritation of visceral afferents in the colonic
      mucosa and peritoneum of mice interact to enhance viscerosomatic pain responses,
      while the activation of colonic mechanoreceptors inhibits peritoneal irritation
      induced pain responses and induces a freezing behavior by a naloxone-sensitive
      mechanism.

PMID- 10353507
TI  - Pain report and the relationship of pain to physical factors in the first 6
      months following spinal cord injury.
AB  - A prospective, longitudinal study of 100 people with traumatic spinal cord injury
      (SCI) was performed to determine the time of onset. prevalence and severity of
      different types of pain (musculoskeletal, visceral, neuropathic at level,
      neuropathic below level) at 2, 4, 8, 13 and 26 weeks following SCI. In addition,
      we sought to determine the relationship between physical factors such as level of
      lesion, completeness and clinical SCI syndrome and the presence of pain. At 6
      months following SCI, 40% of people had musculoskeletal pain, none had visceral
      pain, 36% had neuropathic at level pain and 19% had neuropathic below level pain.
      When all types of pain were included, at 6 months following injury, 64% of people
      in the study had pain, and 21% of people had pain that was rated as severe. Those
      with neuropathic below level pain were most likely to report their pain as severe
      or excruciating. There was no relationship between the presence of pain overall
      and level or completeness of lesion, or type of injury. Significant differences
      were found, however, when specific types of pain were examined. Musculoskeletal
      pain was more common in people with thoracic level injuries. Neuropathic pain
      associated with allodynia was more common in people who had incomplete spinal
      cord lesions, cervical rather than thoracic spinal cord lesions, and central cord
      syndrome. Therefore, this study suggests that most people continue to experience
      pain 6 months following spinal cord injury and 21% of people continue to
      experience severe pain. While the presence or absence of pain overall does not
      appear to be related to physical factors following SCI, there does appear to be a
      relationship between physical factors and pain when the pain is classified into
      specific types.

PMID- 10353508
TI  - A case of referred pain evoked by remote light touch after partial nerve injury.
AB  - An unusual case of referred pain is presented in which a 63-year-old man, who
      suffered a severe injury to his right hand and arm during young adulthood,
      describes the later development of dysesthesia and shooting pain in his arm
      subsequent to stimulation of the ipsilateral scalp, the temporal and
      infrazygomatic region of the face, and the back. Referred sensations of this type
      are usually reported following amputation of an arm. Clinical examination of the
      sensory and motor function of the arm and hand revealed partial damage to the
      radial, ulnar and median nerves as well as possible brachial plexus involvement.
      Interestingly, pain could be evoked by repeated light touches applied to the
      remote trigger areas suggesting the involvement of a 'wind-up'-like process.

PMID- 10353509
TI  - Effects of single and repeated applications of a eutectic mixture of local
      anaesthetics (EMLA) cream on spontaneous and evoked pain in post-herpetic
      neuralgia.
AB  - The analgesic effects of single and repeated applications of a eutectic mixture
      of local anaesthetics (EMLA) cream on both spontaneous and evoked pains were
      evaluated in 11 patients with post-herpetic neuralgia (PHN). Detection
      thresholds, pain thresholds and the responses to suprathreshold mechanical and
      thermal stimuli were quantitatively determined at baseline, 30 min after the
      first application and after a series of daily applications over six consecutive
      days (duration of application: 5 h/day). In the acute situation, EMLA produced an
      overall anaesthetic effect without significantly reducing spontaneous ongoing
      pain and mechanical allodynia. Repeated applications significantly reduced
      paroxysmal pain and both the dynamic and static subtypes of mechanical
      hyperalgesia. The effects on spontaneous ongoing pain were more variable. They
      were inversely correlated to the magnitude of the thermal deficit at baseline,
      and were significant only in patients with dynamic mechano-allodynia.
      Pathophysiological implications of these results are discussed.

PMID- 10353510
TI  - Pain affect without pain sensation in a patient with a postcentral lesion.
AB  - We report findings from clinical examination and cutaneous laser stimulation in a
      57-year-old male, who suffered from a right-sided postcentral stroke. In this
      patient, we were able to demonstrate (i) a dissociation of discriminative and
      affective components of pain perception and, for the first time in humans, (ii)
      the dependence of sensory-discriminative pain component and first pain sensation
      on the integrity of the lateral pain system.

PMID- 10353511
TI  - One dose ceftriaxone vs. ten days of amoxicillin/clavulanate therapy for acute
      otitis media: clinical efficacy and change in nasopharyngeal flora.
AB  - OBJECTIVE: To compare the efficacy and the safety of a single intramuscular dose
      of ceftriaxone, 50 mg/kg, vs. a 10-day course of amoxicillin/clavulanate
      (amox/clav) therapy, 80 mg/kg/day of amoxicillin: 10 mg/kg/day of clavulanate in
      three divided doses, in children with acute otitis media (AOM) and to evaluate
      the changes in nasopharyngeal flora after treatment. METHODS: In a prospective,
      comparative, open randomized, multicenter trial, children were scheduled to
      return for visits on Days 12 to 14 (main end point) and Days 28 to 42 after the
      beginning of treatment for AOM. A nasopharyngeal swab for bacterial culture was
      obtained before the treatment and at Days 12 to 14. RESULTS: Between February,
      1995, and May, 1996, 513 children with a mean age of 14.2 +/- 6.7 months were
      enrolled. All the patients were evaluable for the safety and intent-to-treat
      analyses and 463 for the per protocol efficacy. At Days 12 to 14 clinical success
      was obtained in 186 of the 235 children (79%) given ceftriaxone and in 188 of the
      228 children (82.5%) treated with amox/clav. Among the patients with clinical
      success on Days 12 to 14, the success was maintained at Days 28 to 42 for 108 of
      183 (59%) patients in the ceftriaxone group and 103 of 187 (55%) patients in the
      amox/clav group. Before the antibiotic treatment the percentages of children
      carrying Streptococcus pneumoniae (59.1%), Haemophilus influenzae (39.4%),
      Moraxella catarrhalis (55.7%) and the rate of penicillin-resistant S. pneumoniae
      (52.2%) were comparable between the 2 groups. At Days 12 to 14 the carriage of S.
      pneumoniae and M. catarrhalis was significantly different between the patients
      treated with ceftriaxone, 43.9 and 42.2, respectively, and the patients treated
      with amox/clav, 17.4 and 11.1%, respectively. Among the children carrying S.
      pneumoniae at Days 12 to 14, the percentage of penicillin-resistant strains
      reached 63.4% in the ceftriaxone treatment group and 83.0% in the amox/clav
      treatment group, (P = 0.02). Adverse events (mainly diarrhea) related to the
      study medication were reported more frequently (P < 0.0001) in the amox/clav
      treatment group. CONCLUSIONS: In an area with a high rate of penicillin-resistant
      S. pneumoniae, a single dose of ceftriaxone is as efficient as a 10-day course of
      amox/clav in the treatment of AOM in young children. There was for the two
      regimens an increased rate of penicillin-resistant strains among the pneumococci
      carried, whereas the chance for a child to carry a penicillin resistant S.
      pneumoniae did not increase after treatment.

PMID- 10353512
TI  - Methicillin-resistant and borderline methicillin-resistant asymptomatic
      Staphylococcus aureus colonization in children without identifiable risk factors.
AB  - BACKGROUND: The recent evolution in the epidemiology of methicillin-resistant
      asymptomatic Staphylococcus aureus (MRSA) infections in children, whereby
      children without traditional risk factors for MRSA have been hospitalized in
      increasing numbers, prompted us to establish whether a parallel increase in
      "asymptomatic" MRSA colonization had occurred. METHODS: We cultured the nares and
      perineum of 500 children attending our Pediatric Emergency Department. RESULTS:
      One hundred thirty-two (26.4%) of these children were colonized with S. aureus.
      Eleven (8.3%) of the S. aureus isolates were MRSA; 4 (36.4%) of the 11 subjects
      colonized with MRSA had no risk factors. Seven (5.3%) of the 132 S. aureus
      isolates were borderline methicillin-resistant S. aureus (BRSA); 5 (71.4%) of the
      7 subjects colonized with BRSA had no MRSA risk factors. CONCLUSIONS: These
      findings indicate that MRSA and BRSA isolates are circulating in the community
      and that MRSA isolates are no longer confined to children with frequent contact
      with a health care environment.

PMID- 10353513
TI  - Epidemiology and cost analysis of varicella in Italy: results of a sentinel study
      in the pediatric practice. Italian Sentinel Group on Pediatric Infectious
      Diseases.
AB  - BACKGROUND: Describing the epidemiology of varicella is relevant to the
      development of specific prevention strategies and to building up of economic
      models evaluating the cost:efficiency ratios of these strategies. AIM: Our study
      was designed to describe the epidemiology of chickenpox among Italian children
      and to assess the resulting economic and health burden on the country. METHODS:
      Thirty-nine Italian pediatricians participated in a sentinel network on pediatric
      infectious diseases representing a total pediatric population of 30 168 children.
      Each case of varicella observed from January through December, 1997, was
      recorded. Economic analysis was conducted from the societal point of view. All
      costs were broken down into two groups: direct and indirect costs. RESULTS: A
      total of 1599 cases of varicella were reported among children 0 to 14 years old.
      There were 1266 primary cases (mean age, 4.5 +/- 2 years) and 333 secondary cases
      (mean age, 3.6 +/- 3.2 years). The global incidence of chickenpox was
      51.01/1000/year. Complications were seen in 56 cases (3.5%). Drugs were
      prescribed in 672 cases. A group of adults (364 susceptible and 193 with
      uncertain status) were exposed to primary cases. Seventy (12.5%) were eventually
      infected among whom there were 4 pregnant women. For pediatric patients an
      average cost of $146.90 (250 400 lire) was estimated; this is largely accounted
      for by indirect costs. CONCLUSIONS: The epidemiology of varicella in Italy is
      consistent with that found in previous studies in industrialized countries.
      Severe complications did not occur in our population. We believe that the health
      arguments in favor of universal vaccination of children > 18 months of age do not
      differ in our own country from those of other industrialized nations. Our data
      could now be incorporated into pharmacoeconomic models to establish cost
      efficient strategies for Italy.

PMID- 10353514
TI  - Human calicivirus-associated sporadic gastroenteritis in Finnish children less
      than two years of age followed prospectively during a rotavirus vaccine trial.
AB  - BACKGROUND: Human caliciviruses (HuCV) cause outbreaks of gastroenteritis, but
      their role in sporadic diarrhea in young children is not well-established.
      METHODS: Children (n = 2398) participating in a trial of oral rhesus-human
      reassortant rotavirus tetravalent (RRV-TV) vaccine were evaluated from 2 months
      to 2 years of age. Stool specimens from 1477 episodes of acute gastroenteritis
      (788 in a placebo and 689 in a RRV-TV vaccine recipient group) were tested for
      human calicivirus (HuCV) by reverse transcriptase-PCR with the use of broadly
      reactive primers, and positive results were confirmed by Southern hybridization
      with probes specific for main genetic clusters of Genogroups I and II of HuCV.
      RESULTS: HuCV were detected in 158 (20%) and 155 (22%) cases of gastroenteritis
      in the placebo and RRV-TV vaccine groups, respectively. According to
      hybridization results, 8% of HuCV were of Genogroup I and 92% were of Genogroup
      II. The peak season of HuCV gastroenteritis was from November to February. Of the
      148 patients with pure HuCV infection in the placebo group, 89% had vomiting, 79%
      had watery diarrhea, 21% had fever, 28% needed oral rehydration and 1.4% were
      hospitalized. The diarrhea in HuCV gastroenteritis was much less severe than that
      in rotavirus gastroenteritis, but vomiting was equally severe. There was no
      effect of RRV-TV vaccine on the frequency or clinical severity of HuCV
      gastroenteritis. CONCLUSION: HuCVs are second in frequency to rotaviruses as
      causative agents in acute gastroenteritis in young children in the community.

PMID- 10353515
TI  - Long term immune response of universal hepatitis B vaccination in infancy: a
      community-based study in Taiwan.
AB  - OBJECTIVES: To evaluate the long term immunity provided by a universal hepatitis
      B vaccination program in infancy and the booster effect on school age children
      who had no protective antibody titers to hepatitis B surface antigen. METHODS: We
      conducted a community-based seroepidemiologic study of 1337 healthy 7-year-old
      children in Taiwan one decade after the implementation of a mass hepatitis B
      vaccination program. A booster vaccination was suggested for noncarrier children
      who did not have protective titers of surface antibody. Serologic responses and
      infection rates were compared with those of the nonboostered children. In a
      nonselected group of 39 volunteer noncarrier vaccinees, quantitative serologic
      response was determined before, 1 month after a booster vaccination and 1 year
      later. RESULTS: A total of 572 children (42.8%) had low concentrations of surface
      antibody, and 9 were hepatitis B surface antigen carriers (0.7%). Eighty-two
      percent of "nonprotected" vaccinees showed immunologic memory to a booster dose
      and developed protective antibody titers 1 month later; 60.6% maintained
      protective titers 1 year later. The frequency of new hepatitis B virus infection
      was similar for those who received a booster and those who did not as
      investigated by the core antibody seroconversion during 1-year follow-up.
      However, the risk was low, with annual incidences of <1% in both groups, and none
      became chronic carriers. CONCLUSION: According to these data a universal
      vaccination program in infancy provides adequate protection against hepatitis B
      virus infection for school age children and a booster vaccination is not
      recommended.

PMID- 10353516
TI  - Toxicity and efficacy of daily vs. weekly dapsone for prevention of Pneumocystis
      carinii pneumonia in children infected with human immunodeficiency virus. ACTG
      179 Study Team. AIDS Clinical Trials Group.
AB  - BACKGROUND: Dapsone is an alternative drug for Pneumocystis carinii pneumonia
      (PCP) prophylaxis in individuals intolerant to trimethoprim-sulfamethoxazole
      (T/S). There are, however, few data on the pharmacokinetics, toxicity or efficacy
      of dapsone in children. Design. Randomized, multicenter trial comparing daily (1
      or 2 mg/kg) with weekly (4 mg/kg) dapsone regimens in 94 HIV-infected children
      intolerant to T/S. METHODS: Hematologic and hepatic toxicity was monitored, as
      well as the occurrence of skin rash, PCP or death. RESULTS: Initial
      pharmacokinetic data indicated that adequate serum dapsone concentrations were
      not achieved with the daily 1-mg/kg regimen; the daily dose was then increased to
      2 mg/kg. Both short and long term hematologic toxicities were marginally greater
      in children receiving the daily 2 mg/kg compared with the weekly regimen.
      Allergic skin rashes were similar in children receiving the daily and weekly
      regimens (17% in both) and were not associated with prior history of rash with
      T/S. PCP occurred most frequently with the daily 1-mg/kg regimen (22.0 cases/100
      patient years), least frequently with the daily 2-mg/kg regimen (0 case/100
      patient years) and at intermediate frequency with the weekly regimen (9.5
      cases/100 patient years). More deaths were observed in patients receiving the
      daily than the weekly regimen (8 vs. 2, respectively), although the deaths were
      not directly attributable to dapsone treatment. CONCLUSION: Although a weekly
      dapsone regimen of 4 mg/kg produced less hematologic toxicity than a daily
      regimen of 2 mg/kg, this advantage was offset by a trend toward higher
      breakthrough rates of PCP.

PMID- 10353517
TI  - Clinical presentation of tuberculosis in culture-positive children. Pediatric
      Tuberculosis Consortium.
AB  - BACKGROUND: Because tuberculosis (TB) in children implies recent infection,
      children serve as sentinels for disease transmission within a community. Despite
      the significance of diagnosing tuberculosis in children, most cases are diagnosed
      on clinical evidence rather than laboratory findings. METHODS: We analyzed the
      demographic and clinical presentation of 156 children with culture proven
      tuberculosis using Epi-Info Version 6. RESULTS: Although the clinical
      characteristics of this population were generally consistent with those seen in
      previous studies, several unexpected results were observed. Boys were
      overrepresented in the group of very young children (72% < 1 year). Many of the
      children had coexisting diseases not known to predispose to TB (37%). Cavitation,
      usually observed in older children, was seen in four children < or = 1 year of
      age. Few children were homeless or HIV-infected, but many (42%) lived in female
      headed households. Of the adult contacts at risk for TB, many (49%) were recent
      immigrants to the US. Overall 34% of the population was either foreign born or
      the children of recent immigrants. CONCLUSIONS: This series of 156 culture
      positive children provides an understanding of the risk factors and clinical
      presentation of pediatric tuberculosis. The data emphasize the impact of the
      child's environment on the risk for tuberculosis.

PMID- 10353518
TI  - Clinical and bacteriologic correlates of the papG alleles among Escherichia coli
      strains from children with acute cystitis.
AB  - BACKGROUND: papG is the Gal(alpha1-4)Gal-specific adhesin gene of Escherichia
      coli P fimbriae. The three alleles of papG are associated with different receptor
      binding preferences, occur in different lineages of E. coli and appear
      differentially associated with specific clinical syndromes, e.g. allele II with
      pyelonephritis and allele III with cystitis. However, no data are available
      regarding associations of the papG alleles with clinical outcomes. METHODS:
      Alleles I, II and III of papG were sought among 38 E. coli urine isolates from
      children with acute cystitis by a polymerase chain reaction-based assay. The papG
      genotype was compared with other bacterial characteristics and with response to
      therapy. RESULTS: papG was detected in 13 (34%) strains. It was associated
      positively with sfa and hly (which encode S fimbriae and hemolysin) and
      negatively with afa (which encodes Dr-binding adhesins). Allele II predominated
      over allele III (29% of strains, vs. 5%; P < 0.01). Allele II was significantly
      associated with serogroups O1 and O16 and with agglutination of both human and
      sheep erythrocytes, whereas allele III was associated with sfa, hly, serogroup 06
      and preferential agglutination of sheep erythrocytes. The presence of papG
      predicted recurrent bacteriuria among children receiving 3-day treatment and
      Allele III predicted same-strain recurrence. CONCLUSIONS: These findings conflict
      with existing data associating allele III with cystitis, confirm and extend
      previous associations of papG alleles II and III with other bacterial properties
      and suggest that papG genotype may predict clinical outcomes.

PMID- 10353519
TI  - Kawasaki syndrome among American Indian and Alaska Native children, 1980 through
      1995.
AB  - BACKGROUND: Kawasaki syndrome (KS) is a leading cause of acquired heart disease
      among US children, but the epidemiologic features of KS among American Indian and
      Alaska Native (AI/AN) children have not been described. METHODS: We examined
      Indian Health Service computerized records of hospital discharges for AI/AN
      children <18 years of age with KS during 1980 through 1995. RESULTS: During 1980
      through 1995, 85 AI/AN children were reported with a hospitalization for KS; 10
      of the children had an additional KS hospitalization record within 5 months. The
      average annual KS hospitalization rate for children <5 years of age, based on
      first KS hospitalization only, was 4.3 cases per 100000 children; the rate for
      children age <1 year (n = 21) was 8.6 per 100000 and for children ages 1 to 4
      years was 3.6 per 100000. The annual rates for children < 5 years of age ranged
      from 0 to 8.5 per 100000 children. KS hospitalizations for children peaked in
      January and February; 50.6% of the children were hospitalized during January
      through April. The overall median length of hospital stay was 4 days (range, 1 to
      29 days); the median duration decreased from 8 days from 1980 through 1982 to 4
      days from 1993 through 1995. CONCLUSIONS: The overall annual hospitalization rate
      of KS among AI/AN children <5 years of age was slightly lower than rates for
      several majority white populations in the United States. (4.6 to 15.2 cases per
      100000) and much lower than rates for blacks and Asians/Pacific Islanders.

PMID- 10353520
TI  - Combination atovaquone and proguanil hydrochloride vs. halofantrine for treatment
      of acute Plasmodium falciparum malaria in children.
AB  - BACKGROUND: Malaria is a major cause of pediatric mortality in sub-Saharan
      Africa. Worldwide estimates of mortality among children with Plasmodium
      falciparum malaria range from 1 to 2 million deaths per year. Management of
      malaria is increasingly difficult because of the global spread of drug-resistant
      strains of P. falciparum. There is an urgent need for safe and effective new
      therapies to treat multidrug-resistant malaria. METHODS: This open label,
      randomized trial compared atovaquone and proguanil hydrochloride with
      halofantrine for treatment of acute, uncomplicated P. falciparum malaria in
      children age 3 to 12 years (84 patients per group). Study drug dosages were
      adjusted by weight (approximately 20 and 8 mg/kg daily for three doses for
      atovaquone and proguanil hydrochloride and 8 mg/kg every 6 h for three doses for
      halofantrine). Patients were monitored by serial clinical and laboratory
      assessments for 28 days after starting treatment. RESULTS: Both regimens were
      effective (cure rate, 93.8% for atovaquone and proguanil hydrochloride and 90.4%
      for halofantrine) and produced prompt defervescence. Mean parasite clearance
      times were 50.2 h for halofantrine and 64.9 h for atovaquone and proguanil
      hydrochloride. More adverse experiences were reported in children treated with
      halofantrine (119) than with atovaquone and proguanil hydrochloride (73).
      CONCLUSIONS: In Kenyan children the combination of atovaquone and proguanil
      hydrochloride has efficacy comparable with that of halofantrine for treatment of
      acute uncomplicated multidrug-resistant falciparum malaria and is associated with
      a lower rate of adverse events.

PMID- 10353521
TI  - IgG subclass deficiency and the day-care generation.

PMID- 10353522
TI  - Adoptive immunotherapy.

PMID- 10353523
TI  - Treatment of infection due to Mycobacterium avium complex.

PMID- 10353524
TI  - Pediatric use of quinolones.

PMID- 10353525
TI  - Multiple nodular pneumonitis in a three-week-old female infant.

PMID- 10353526
TI  - C-reactive protein levels for diagnosis of Salmonella gastroenteritis.

PMID- 10353527
TI  - Thoracic actinomycosis mimicking primary tuberculosis.

PMID- 10353528
TI  - Suppurative arthritis complicating otitis media.

PMID- 10353529
TI  - Primary acquired toxoplasmosis in a five-year-old child with perinatal human
      immunodeficiency virus type 1 infection.

PMID- 10353530
TI  - Neonatal sepsis caused by Streptococcus pyogenes: resurgence of an old etiology?

PMID- 10353531
TI  - Bordetella bronchiseptica respiratory infection in a child after bone marrow
      transplantation.

PMID- 10353532
TI  - Vancomycin-resistant Enterococcus faecium meningitis successfully treated with
      chloramphenicol.

PMID- 10353533
TI  - Agitated sleepwalking with fluoroquinolone therapy.

PMID- 10353534
TI  - Pro- and anti-inflammatory cytokine-response in abdominal aortic aneurysm repair:
      a clinical model of ischemia-reperfusion.
AB  - In traumatized and septic patients, excessive cytokine production may lead to
      organ dysfunction and death. Current understanding of cytokine kinetics with
      regard to clinical scenarios, however, is still limited by a paucity of studies
      investigating the cytokine levels in humans with inflammation-reperfusion injury
      in the absence of infection. Our hypothesis was that endotoxin is introduced into
      circulation during and after abdominal aortic aneurysm (AAA) repair and is
      associated with pro- and anti-inflammatory cytokine-response. The purpose of this
      prospective pilot study in 10 patients who underwent elective AAA repair was to
      assess organ function and immune response to systemic endotoxemia after the
      operation by measuring endotoxin, endotoxin neutralizing capacity (ENC), tumor
      necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10, and TNF-RI and II. Blood
      samples were obtained from indwelling catheters or direct venipuncture
      preoperatively, perioperatively (8 time points) until the second postoperative
      day. Endotoxin and ENC were determined by a special kinetic Limulus amoebocyte
      lysate (LAL) assay and TNF-alpha, IL-6, IL-10, and TNF-RI and II by commercial
      ELISA. Endotoxin levels were significantly elevated after declamping and 90 min
      after clamping of the aorta (2.3 + .9 pg/mL; 5.4+/-3.6 pg/mL). ENC decreased to
      the lowest levels at 90 min after clamping. TNF-alpha levels were maximal, but
      not significantly elevated, 120 min after clamping. IL-6 increased significantly
      during the operation and reached maximum levels (189.8+/-47 pg/mL) at the first
      postoperative day. Anti-inflammatory IL-10 and TNF-RI and II were elevated early
      during the operation. The changes in cytokine levels were associated with mild
      organ dysfunction. We conclude that AAA repair is associated with endotoxin,
      proinflammatory, and an almost coincidental anti-inflammatory cytokine release,
      providing baseline data about what constitutes an appropriate immune response.
      Such responses to trauma and ischemia-reperfusion need to be further investigated
      before attempting immunomodulation.

PMID- 10353535
TI  - Involvement of tyrosine protein kinase in IFN-gamma-induced human endothelial
      cell apoptosis.
AB  - Although it is well recognized that interferon-gamma (IFN-gamma) is involved in
      the development of systemic inflammatory response syndrome, a condition
      characterized by loss of endothelial barrier function, whether or not IFN-gamma
      has any direct effect on endothelial cell (EC) death is unclear. Furthermore,
      which signal transduction pathway involved in IFN-gamma-induced EC apoptosis
      remains to be elucidated. To answer these questions, we investigated the effect
      of IFN-gamma on EC death (apoptosis versus necrosis) and the underlying signal
      transduction pathway responsible for IFN-gamma-induced EC apoptosis. IFN-gamma
      resulted in a dose-dependent increase in EC apoptosis after 24 h incubation (p <
      .05). However, IFN-gamma did not induce EC necrosis. Tumor necrosis factor-alpha
      (TNF-alpha), but not lipopolysaccharide (LPS), had a augmentative effect on IFN
      gamma-induced EC apoptosis (p < .05), while both of them alone failed to induce
      EC apoptosis. These results indicate that exposure of EC to IFN-gamma can cause
      apoptosis rather than necrosis. Both calcium ionophore, A23187, and the protein
      kinase C (PKC) activator phorbol-myristate-acetate (PMA) had a synergistic effect
      on IFN-gamma-induced EC apoptosis (p < .05). However, neither the calcium
      chelator 1,2-bis 2-aminophenoxy ethane-N,N,N',N'-tetraacetic acid (BAPTA), nor
      the PKC inhibitor 1 -5-isoquinolinysulfonyl 2-methyl piperazine (H-7) attenuated
      IFN-gamma-induced EC apoptosis. Three specific tyrosine protein kinase (TPK)
      inhibitors, herbimycin A, tyrphostin, and genistein, significantly inhibited IFN
      gamma-induced EC apoptosis in a dose-dependent fashion (p < .05). Furthermore,
      the activation of TPK in EC by IFN-gamma was completely abrogated by these TPK
      inhibitors. These findings suggest that the signal transduction pathway required
      for induction of EC apoptosis by IFN-gamma is TPK dependent and is independent of
      calcium and PKC.

PMID- 10353536
TI  - Neutrophil accumulation and damage to the gastric mucosa in resuscitated
      hemorrhagic shock is independent of inducible nitric oxide synthase.
AB  - Polymorphonuclear leukocytes (PMN) and inducible nitric oxide synthase (iNOS)
      appear to play important roles in the liver and in lung injury induced by
      hemorrhagic shock. Their precise roles in hemorrhagic shock-induced acute gastric
      mucosal lesions (AGML), however, are still poorly understood. In this study, we
      investigated the effect of neutropenia on hemorrhagic shock-induced AGML. We also
      examined the roles of iNOS in PMN infiltration into the mucosa and AGML during
      hemorrhagic shock by using L-N6-(1-iminoethyl)-lysine, a potent inhibitor of
      iNOS, and by reverse transcriptase polymerase chain reaction. Remarkable gastric
      mucosal damage occurs after hemorrhagic shock. PMN depletion caused by
      Vinblastine pretreatment significantly attenuates this AGML. Although low-dose L
      N6-(1-iminoethyl)-lysine (50 microg/kg, iNOS inhibition) has no effect on AGML,
      high-dose L-N6-(1-iminoethyl)-lysine (250 microg/kg, iNOS + endothelial NOS
      inhibition) significantly exacerbates AGML without increasing PMN infiltration
      into the mucosa. The mRNA expression of iNOS in the stomach during hemorrhagic
      shock cannot be detected by reverse transcriptase polymerase chain reaction. We
      conclude that PMN play a pivotal role in hemorrhagic shock-induced AGML, iNOS
      does not regulate PMN infiltration into the mucosa, and endothelial NOS provides
      important protection against AGML during hemorrhagic shock.

PMID- 10353537
TI  - Ischemia/reperfusion induces an increase in the hepatic portal vasoconstrictive
      response to endothelin-1.
AB  - Microvascular impairment observed during reperfusion following ischemia (IR) is a
      major determinant of the development of liver injury. Previous studies have shown
      that hyper-responsiveness to endothelin-1 (ET-1) contributes to microvascular
      dysfunction following a primarily inflammatory stress induced by endotoxin. The
      present study investigates whether a similar hypercontractile response to ET-1
      occurs in the hepatic portal system of IR rats. Pentobarbital-anesthetized
      Sprague-Dawley rats underwent liver ischemia of the left and medial lobes for 60
      min (IR: n = 8) or a sham operation (n = 8). Six hours after reperfusion, the
      liver was isolated and perfused through the portal vein. Baseline portal pressure
      (Pp), portal flow (Qp), and sinusoidal diameter (Ds) were measured before and 3
      and 10 min after adding ET-1 (1 nM). In baseline, IR livers had a significantly
      greater Pp, portal resistance, and Ds than sham. ET-1 significantly increased Pp
      and portal resistance and significantly decreased Qp and Ds in IR and sham rats.
      However, these effects were significantly greater in IR. The results of the
      present study demonstrate that IR increases the porto-hepatic contractile
      response to ET-1, which may further sensitize the portal circulation to elevated
      ET-1 and may be a prominent contributor to the development of microvascular
      impairment following IR.

PMID- 10353538
TI  - Tolerance to LPS decreases macrophage G protein content.
AB  - The effects of tolerizing doses of LPS on mRNA and protein levels of three
      different G protein subunits were investigated to understand the mechanism(s)
      responsible for the reduction in Gialpha protein content in LPS tolerance.
      Tolerance was induced in rats using Salmonella enteritidis LPS (intraperitoneal
      route) with a single dose of 100 microg/kg. Peritoneal macrophages were harvested
      6 and 24 h later. In some studies, a second dose of LPS 500 microg/kg was given
      on the following day, and peritoneal macrophages were harvested 5 days after the
      first injection. Macrophage RNA or a crude membrane fraction was prepared from
      macrophages, and the mRNA level or the protein content for Gialpha3, Gialpha2,
      and Gsalpha was analyzed using Northern or Western blots, respectively. Compared
      with the control levels, the message for Gialpha3 was reduced (p < .025) at 6 and
      24 h and 5 day time periods after LPS treatment. The Gialpha2 mRNA was increased
      relative to the control levels (p < .05) at 6 h and 5 days after LPS treatment,
      respectively, and Gsalpha message was not significantly changed. The half-life of
      Gialpha3 mRNA was not significantly different in control versus tolerant
      macrophages. The Gialpha3 mRNA and membrane protein were not significantly
      changed by incubation with LPS for intervals up to 6 h in vitro. Macrophage
      membrane Gialpha3 and Gialpha1 and 2 protein content from tolerant rats were
      reduced compared with the controls at 6 and 24 h, respectively (p < .05). These
      studies are consistent with our previous observations of selective changes in
      macrophage Gialpha protein content in LPS tolerance and raise the possibility
      that this may affect signal transduction events in these cells.

PMID- 10353539
TI  - Impaired energy metabolism in hearts of septic baboons: diminished activities of
      Complex I and Complex II of the mitochondrial respiratory chain.
AB  - Recent findings support the view that the bioenergetic part of septic organ
      failure is not caused by insufficient supply of oxygen but by disturbances of the
      mitochondrial function. Therefore, the aim of the present study was to
      investigate key enzymes of energy metabolism in septic hearts to answer the
      question whether or not impairment of mitochondrial or glycolytic enzymes occur
      under these conditions. For this purpose the well established model of septic
      baboons was used. Baboons under general anesthesia were made septic by infusion
      of Escherichia coli. Single challenge with infusion of high amounts of bacteria
      was compared with a multiple challenge protocol (less bacteria infused). Some
      animals obtained no E. coli (sham). The hearts of the baboons were removed after
      72 h (survival: yes) or after death (survival: no) of the animals, frozen in
      liquid nitrogen, and stored at -80 degrees C until spectrophotometrical
      measurement of nine mitochondrial and glycolytic enzymes. A reduction of the
      activity of NADH:cytochrome-c-reductase (Complex I + III) to 67% and
      succinate:cytochrome-c-reductase (Complex II + III) to 45% was found in the
      hearts of surviving animals after infusion of high amounts of bacteria. After
      multiple challenge with lesser amounts of bacteria, no significant changes in
      enzyme activity were detectable. After lethal septic shock, activities of Complex
      I + III (12%) and Complex II + III (13%) as well as of phosphofructokinase (16%)
      were found to be strongly diminished. Decylubiquinol:cytochrome-c-reductase
      (Complex III, 59%), cytochrome-c-oxidase (51%), succinate dehydrogenase (60%),
      glucosephosphate isomerase (61%), lactate dehydrogenase (61%), and citrate
      synthase (120%) were less or unaffected. Similar but less pronounced effects were
      found after infusion of lesser amounts of bacteria. By means of inhibitor
      titrations of succinate: cytochrome-c-reductase, it was shown that the loss of
      activity is not caused by Complex III but by disturbances in Complex II. It is
      concluded that E. coli-induced sepsis causes decreased activities of Complex I
      and Complex II in baboon heart mitochondria in a dose-dependent manner.

PMID- 10353540
TI  - Prevention of the hemorrhagic hypotension-induced hepatic arterial
      vasoconstriction by L-arginine and naloxone.
AB  - The possible involvement of the L-arginine-nitric oxide pathway and endogenous
      opioid mechanisms in the hemorrhagic hypotension- (HH) induced changes of hepatic
      arterial blood flow and vascular resistance was studied in cats. During HH
      hepatic arterial blood flow was significantly higher both in L-arginine- and
      naloxone-treated animals than in controls. Furthermore, HH induced a significant
      increase of the hepatic vascular resistance in the control group, which was
      prevented by L-arginine or naloxone treatment. Because inhibition of the nitric
      oxide synthesis by N(G)-nitro-L-arginine in normotensive cats induced a similar
      increase of the hepatic vascular resistance to that observed during HH in the
      control group, our results indicate that impairment of the endothelial function
      may be responsible for the hemorrhage-induced L-arginine- and naloxone-reversible
      hepatic arterial vasoconstriction. This hypothesis is consistent with our
      previous observations demonstrating the development of endothelial dysfunction in
      the feline hepatic artery during HH.

PMID- 10353541
TI  - Hepatic gene expression and cytokine responses to sterile inflammation:
      comparison with cecal ligation and puncture sepsis in the rat.
AB  - Inflammatory stimulation of hepatic acute phase protein expression is, in part,
      modulated by tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-beta),
      and IL-6. These cytokines also may mediate some aspects of the persistent
      inflammation and metabolic dysregulation of sepsis. Cecal ligation and puncture
      (CLP) sepsis in male Sprague-Dawley rats inappropriately decreases hepatocellular
      transcription of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase
      (G6Pase), carnitine palmitoyltransferase II (CPTII), acetyl CoA acyltransferase
      (ACA), and ornithine transcarbamylase (OTC). We hypothesize that 1)
      transcriptional reprogramming does not occur after simple inflammation induced by
      subcutaneous turpentine injection, 2) the pattern of acute phase gene expression
      after CLP differs from that following turpentine injection, and 3) the different
      responses reflect differences in the intrahepatic activity of TNFalpha/IL-1beta
      or IL-6. Gene expression, transcription factor activity, and cytokine abundance
      were determined after either a subcutaneous injection of turpentine or CLP. After
      turpentine injection, PEPCK, G6Pase, CPTII, ACA, and OTC expression were
      unchanged, different from previously reported data following CLP. Both turpentine
      injection and CLP increased expression of TNFalpha/IL-1beta-regulated alpha1-acid
      glycoprotein, and IL-6-regulated alpha2-macroglobulin and decreased expression of
      transthyretin (a negative acute phase protein). However, the magnitude and
      temporal pattern of expression differed. Turpentine injection increased the
      activity of the TNFalpha/IL-1beta-linked transcription factor NF-kappaB and the
      intrahepatic abundance of TNFalpha in a manner similar to that observed after CLP
      but only slightly altered the activity of the IL-6-linked transcription factor
      Stat-3 and intrahepatic IL-6 abundance. This differed significantly from
      observations after CLP. We conclude that CLP-induced alterations in hepatic gene
      expression may reflect differences in IL-6 activity.

PMID- 10353542
TI  - Effects of immunomodulation with interferon-gamma on hepatic ischemia-reperfusion
      injury.
AB  - The development of an inflammatory response after injury depends on the
      participation of a variety of cell populations and endogenous mediators.
      Interferon-gamma (IFN-gamma) is a potent cellular immunomodulating cytokine that
      contributes to acute and chronic inflammation. In this study, the effects of
      immunomodulation on ischemia-reperfusion injury were examined using increasing
      doses of recombinant, rabbit-specific IFN-gamma in an in situ model of hepatic
      ischemia-reperfusion. Pretreatment with low dose IFN-gamma augmented injury as
      measured by histology, aminotransferase concentrations, and myeloperoxidase
      activity. By contrast, high dose IFN-gamma pretreatment, equivalent to IFN-gamma
      supplements used in clinical trials, resulted in a lack of neutrophil
      infiltration and minimal progression of late phase, neutrophil-mediated
      reperfusion injury. These results suggest that immunomodulating mediators such as
      IFN-gamma may play a regulating role in the evolution of ischemia-reperfusion,
      contributing to the development and resolution of acute hepatic injury.

PMID- 10353543
TI  - Impaired sarcoplasmic reticulum function in lipopolysaccharide-induced myocardial
      dysfunction demonstrated in whole heart.
AB  - To clarify the pathophysiological cascade leading to lipopolysaccharide- (LPS)
      induced myocardial dysfunction, we measured sarcoplasmic reticulum (SR) function,
      expression of inducible nitric oxide synthase (iNOS), and left ventricular (LV)
      function in a rat whole heart model. The LV function was evaluated by peak LV
      pressure and SR function was evaluated by the mechanical restitution (MR) curve,
      a physiological parameter of SR function. The mechanical restitution curve was
      constructed by plotting extrasystolic potentiation of LV dP/dt during
      extrasystoles (100-700 ms) under fixed pacing. Functions were evaluated using the
      perfusion apparatus at 6 or 24 h after LPS administration. In the 6 h group, LV
      pressure was depressed to 62% of the control, the SR function was impaired, and
      iNOS protein was expressed. In the 24 h group LV pressure and SR function
      remained at the control levels, iNOS was not detected. In the 6 h group
      dexamethasone co-administration normalized the LPS effect and iNOS was not
      expressed. LPS-induced myocardial dysfunction appeared to be caused by impaired
      SR function and NO expression suggesting that NO may act as a trigger.

PMID- 10353544
TI  - Videomicroscopy provides accurate in vivo assessment of pulmonary microvascular
      reactivity in rabbits.
AB  - When defining the mechanism of hypoxic pulmonary vasoconstriction (HPV),
      investigators have employed ex vivo preparations because of the belief that
      accurate, quantitative assessment of pulmonary microvessels could not be obtained
      in vivo. We hypothesize that accurate, quantitative assessment of pulmonary
      microvascular reactivity can be performed using a simple, in vivo preparation.
      Our aim was to provide this quantitative assessment in a defined animal model,
      and to confirm that the chosen preparation could discriminate changes in
      microvascular reactivity as influenced by endogenous mediators. New Zealand
      rabbits were instrumented for in vivo microscopy and direct measurement of
      subpleural arterioles. Rabbits were first randomized to either control (n = 7) or
      endotoxin (n = 5), infusion of Escherichia coli lipopolysaccharide (200 Fg/kg).
      All rabbits were then exposed to a repeated protocol of normoxia (21% O2) for 20
      min and then hypoxia (15% O2) for 10 min over 2 h. The changes in arteriole
      diameter were measured at the end of each interval. Normal pulmonary arterioles
      repeatedly constrict 15+/-3.5% during hypoxia. Altering endogenous vasoactive
      mediators, as with infusion of endotoxin, caused a loss of hypoxia-induced
      vasoconstriction. The results of our study validate this experimental preparation
      for the reliable quantification of pulmonary microvascular reactivity and
      investigation of hypoxic pulmonary vasoconstriction under both normal and
      pathologic conditions.

PMID- 10353545
TI  - Bradykinin metabolism in perfused rat kidney.
AB  - The purpose of this study was to assess the capacity of perfused rat kidney to
      inactivate bradykinin (BK), and to compare the BK degrading capacity of rat
      kidney with the BK degrading capacities of rat lung, liver, and skeletal muscle,
      which was approximated by perfusion of rat hind limbs. Radioactively labeled BK,
      with the Pro2 and Pro3 residues having been tritiated, in an asanguinous salt
      solution was perfused through the kidney of the rat, over a concentration range
      of .0028-33 microM. Rat kidney had a large capacity to degrade BK and the system
      did not appear to approach saturation until perfusate BK concentrations reached
      24 microM. A least-squares linear regression analysis and extrapolation to zero
      concentration was used to obtain values for amounts of BK degraded and BK
      fragments formed. The amount of BK cleaved was 99.9% of the administered dose.
      The major tritiated BK fragments formed, and the amount of each expressed as a
      percentage of the amount of BK degraded during transrenal passage, were the amino
      acid proline derived from the Pro2 and/or Pro3 residues of BK (Pro2,3), 60%; Pro
      Pro (BK 2-3), 12%; Arg-Pro-Pro-Gly-Phe (BK 1-5), 14%; and Arg-Pro-Pro-Gly-Phe-Ser
      Pro (BK 1-7), 14%. The formation of BK 2-3 is indicative of initial
      aminopeptidase-P cleavage of BK to yield Arg, and des-Arg1-BK. Thus in rat kidney
      the aminopeptidase-P pathway is the major route for BK degradation, as is the
      case in rat liver.

PMID- 10353546
TI  - The increased incidence of cancer of the pancreas: is there a missing dietary
      factor? Can it be reversed?
AB  - There has been a disturbing increase in the incidence of pancreas cancer,
      especially in Western countries, during the present century. The only well
      established aetiological factor of well-documented significance is the greater
      incidence of this cancer in tobacco smokers of all communities. Otherwise the
      reason for the increased incidence is not known but the pattern of increase has
      some similarities to the increased incidence of breast cancer in women and
      prostate cancer in men in Western communities. There is now well-documented
      evidence that the increase in breast and prostate cancers is at least partly
      related to diet. Typical modern Western diets have a low content of the naturally
      occurring plant hormones, the phyto-oestrogens, that are still plentiful in
      traditional diets of Asians and other communities with a low incidence of both
      breast and prostate cancer. This paper presents evidence to support the
      hypothesis that the increased incidence of pancreas cancer in Western communities
      may also be related to the relatively low dietary content and protective
      qualities of the naturally occurring plant hormones and related compounds. This
      paper presents evidence to support that hypothesis.

PMID- 10353547
TI  - Adult soft tissue sarcoma.
AB  - BACKGROUND: Soft tissue sarcomas (STS) are a group of anatomically and
      histologically diverse tumours. They account for about 1% of adult malignancies,
      and about 50% of patients diagnosed with sarcoma eventually die of the disease.
      These tumours are grouped together because of shared biological characteristics
      and treatment responses. METHODS: A review of the key literature on STS was
      undertaken, complemented by data taken from the prospectively accumulated
      database of 3442 patients treated for STS at Memorial Sloan-Kettering Cancer
      Center (MSKCC) from July 1982 to December 1997. RESULTS: Despite advances in
      knowledge of the molecular genetics of STS, the aetiology in most cases remains
      elusive. Management has been gradually refined over the last two decades. Core
      biopsy usually provides enough material for diagnosis. Computed tomography and
      magnetic resonance imaging provide a similar amount of information, which is
      usually adequate for surgical planning. Amputation as standard treatment for
      extremity lesions has been replaced by limb-sparing surgery in about 90% of
      patients. The role of adjuvant radiation has been further defined: it has been
      shown to be unnecessary for completely excised tumours less than 5 cm in
      diameter, but effective in decreasing local recurrence for others. Adjuvant
      chemotherapy has been controversial for many years. Recent meta-analysis of
      randomized trial results has found a small reduction in local and distant
      relapse, and a trend to better overall survival. Recurrent or metastatic disease
      should be completely excised if possible. CONCLUSIONS: Soft tissue sarcoma
      requires multidisciplinary care tailored to the individual patient and tumour for
      optimal results.

PMID- 10353548
TI  - Extremity soft tissue sarcoma: factors predictive of local recurrence and
      survival.
AB  - BACKGROUND: To identify risk factors for local recurrence and overall survival in
      patients with extremity soft tissue sarcoma. METHODS: A retrospective study was
      performed of all patients with extremity soft tissue sarcoma treated at the
      Combined Surgical Oncology Clinic in the Institute of Oncology at Prince of Wales
      Hospital between 1972 and 1992. Variables analysed included clinical
      presentation, patient characteristics, tumour characteristics, treatment factors
      and outcome. RESULTS: One hundred and nineteen patients were eligible for the
      study. The most common type of presentation was with a painless mass, usually in
      the thigh. Local control rates at 5 and 10 years were 75% and 73%. Local control
      was higher in patients who had more radical surgery and in those who received
      adjuvant radiotherapy. Tumour size and high grade were independent risk factors
      for poorer survival. Patients over 50 had poorer survival than younger patients
      and those who presented with recurrent tumours also tended to have poor survival
      compared to patients presenting de novo. The respective 5- and 10-year survival
      rates were 65% and 62%. CONCLUSION: This study suggests that local control of
      extremity soft tissue sarcoma is improved by radical surgery and by the addition
      of radiotherapy when more conservative procedures are used. Overall survival
      appeared to be largely determined by patient (age, recurrent presentation) and
      tumour characteristics (grade, size).

PMID- 10353549
TI  - Tumour size: the only predictive factor for 131I MIBG uptake in phaeochromocytoma
      and paraganglioma.
AB  - BACKGROUND: 131I Meta-iodobenzylguanidine (131I MIBG) scintigraphy can detect
      chromaffin tumours with a high specificity but its sensitivity remains limited.
      In this study, the influence of clinical features and tumour pathology on the
      results of 131I MIBG of patients with phaeochromocytomas and paragangliomas was
      examined. METHODS: The records of 104 patients operated on for chromaffin tumours
      who had pre-operative 131I MIBG were reviewed. Demographic data, clinical
      features, biochemical results and pathology of tumours were analysed. The size of
      the tumour was assessed by the three measured diameters of the specimen and its
      calculated volume. Univariate relationship between tumours' characteristics and
      the results of 131I MIBG were examined. RESULTS: Out of 119 tumours, 104 (87%)
      were detected by 131I MIBG. Mean +/- SD largest diameter and volume of the
      tumours were 6.0 +/- 2.4 cm (range 0.8-11.5 cm) and 68 +/- 74 cm3 (range 0.2-421
      cm3). Results of 131I MIBG were significantly correlated with both the largest
      diameter of the tumour (P < 0.01) and by its volume (P < 0.001). 131I MIBG was
      negative in 35.5% of tumours < 20 cm3 and in 2.6% of those < 20 cm3. No other
      criteria were correlated with positive 131I MIBG, including aetiology, pathology
      or catecholamine secretion pattern. CONCLUSIONS: The result of 131I MIBG scanning
      in patients with chromaffin tumours is significantly correlated with the size of
      the tumour.

PMID- 10353550
TI  - The pattern of nodal recurrence following definitive radiotherapy for
      nasopharyngeal carcinoma.
AB  - BACKGROUND: The pattern of nodal metastasis in previously untreated
      nasopharyngeal carcinoma (NPC) has been studied and reported. In order to analyse
      the pattern of recurrent nodal disease in previously treated NPC, a retrospective
      study on 68 patients who underwent radical neck dissection for regionally
      recurrent NPC was conducted. METHODS: Seventy-four neck dissections were
      performed on 68 patients who developed nodal recurrence after a mean disease-free
      interval of 39.2 months. None of the patients had evidence of local or systemic
      disease at the time of surgery. Histopathological reports of the 74 neck
      dissections were analysed with regard to the number of positive nodes as well as
      the number of involved nodal levels. RESULTS: Of the 65 neck dissection specimens
      with analysable data, 31 showed metastatic disease at a single nodal level with a
      mean number of positive nodes of 1.2, while 34 showed metastatic disease at
      multiple levels with a mean number of positive nodes of 6.6. Nodal recurrence
      occurred at level II with the greatest frequency (78.5%). Of the 31 specimens
      with single level nodal involvement, 21 (67.7%) occurred at level II. Isolated
      involvement at the other levels did occur, but was uncommon (range 3-16%). Of the
      34 specimens with multiple level nodal involvement, 30 (88.2%) showed involvement
      at level II. Once more than one level was involved, the frequency of involvement
      at any given level was at least 30%. CONCLUSION: The predominant involvement at
      level II and the high frequencies of involvement at all levels support the use of
      a classical radical neck dissection in treating recurrent nodal disease in NPC.

PMID- 10353551
TI  - Pancreatic trauma: Universities of Melbourne HPB Group.
AB  - BACKGROUND: Pancreatic trauma is uncommon, but carries high morbidity and
      mortality rates, especially when diagnosis is delayed or inappropriate surgery is
      attempted. Although the retroperitoneal position of the pancreas confers it some
      immunity to injury, the force required to do so often results in severe
      associated injuries to other organs, which may be life threatening. Diagnosis may
      be difficult and surgery can be a considerable technical challenge. METHODS: All
      patients with pancreatic trauma who attended one of three Melbourne teaching
      hospitals from 1977 to 1998 were identified. Injuries were graded and the method
      of diagnosis and treatment studied. The incidence and causation of postoperative
      morbidity and mortality was identified. RESULTS: Thirty-eight patients (26 men
      and 12 women) were studied. Blunt trauma was responsible in 30 patients, stab
      wounds in five, gunshot wounds in two and iatrogenic injury in one. Injuries to
      other organs occurred in 30 patients. Surgical procedures were undertaken in 34
      patients, resulting in the death of five and complications in 25. CONCLUSION:
      Complications and death are related to the associated injuries, as much as to the
      pancreatic injury itself. In this study, we review the experience of the
      management of pancreatic trauma in three large teaching hospitals in Melbourne
      over a 21-year period, and suggest a strategy for dealing with these difficult
      patients. Adherence to the basic concepts of control of bleeding from associated
      vascular injury, minimization of contamination, accurate pancreatic assessment,
      judicious resection and adequate drainage can diminish the risk. By approaching
      the problem in a systematic way and adopting a generally conservative management
      plan, complications and deaths can be minimized in these complex cases.

PMID- 10353552
TI  - A modification of isolated Roux loop reconstruction after
      pancreaticoduodenectomy.
AB  - BACKGROUND: Different techniques of reconstruction following
      pancreaticoduodenectomy have been described. A new modification using an isolated
      Roux-en-Y loop is reported. METHODS: The isolated loop is taken up to bile duct
      rather than pancreas as previously described. RESULTS: Seventeen patients have
      undergone this procedure. Two pancreatic fistulae developed, both following
      postoperative abscess formation. There was no operative mortality. CONCLUSION:
      This reconstruction provides separation of biliary and pancreatic fluid but adds
      two further benefits: the wide jejunal lumen allows for an easier
      pancreaticojejunal anastomosis, particularly when operating on a soft pancreas,
      and separation of gastric and biliary anastomoses prevents the efflux of bile
      into stomach.

PMID- 10353553
TI  - Laparoscopic live donor nephrectomy: the preliminary experience.
AB  - BACKGROUND: Recent improvements in video technology and surgical instrumentation
      have resulted in the application of minimally invasive techniques to many
      surgical procedures including splenectomy and adrenalectomy. Nephrectomy requires
      a long flank incision with division of abdominal musculature and possible
      subcostal nerve damage. Severe postoperative pain and a prolonged recuperative
      period may result, and the cosmetic outcome may not be satisfactory. A new
      surgical approach utilizing laparoscopic dissection and delivery of the kidney
      through a small incision was performed to circumvent these problems. The aim of
      this paper is to describe the technique of laparoscopic live donor nephrectomy
      (LLDN) and present the preliminary outcome. METHODS: Over the 12-month period
      between May 1997 and April 1998, 16 donors underwent donor nephrectomy by a
      laparoscopic approach. The procedure was assessed with regard to its safety,
      feasibility and advantages over the open method. RESULTS: All the nephrectomies
      were completed without conversion to an open procedure. The average postoperative
      pain score on a visual analogue scale of 1-10 was 2 in LLDN. The donors required
      36 mg morphine on average over 36 h postoperatively. Postoperative stay averaged
      3 days. One donor developed an infective complication along the wound drain tract
      which settled with adequate drainage and antibiotics. All the removed donor
      kidneys were transplanted with immediate good function. There were no surgical
      complications or graft losses. The recipients' serum creatinine was in the range
      of 96-181 mmol/L 3 months after transplantation. CONCLUSIONS: Significant
      potential advantages of LLDN include less postoperative pain, shorter
      hospitalization and decreased recuperative time. This preliminary experience
      indicates LLDN to be effective in terms of safety and feasibility.

PMID- 10353554
TI  - Comparative evaluation of the inflammatory mediators in patients undergoing
      laparoscopic versus conventional cholecystectomy.
AB  - BACKGROUND: Injury induces systemic inflammatory response. The degree of response
      is proportionate to the trauma. METHODS: Patients with ultrasound-proven gall
      stones posted for operation were randomized into two groups. Laparoscopic
      cholecystectomy was performed in one group while the other group underwent
      conventional cholecystectomy. Peripheral venous blood samples for inflammatory
      mediators, namely tumour necrosis factor, C-reactive protein, oxygen release from
      monocytes and polymorphonuclear leucocytes were drawn 1 day before surgery and
      repeated on the first and third days after surgery. Partial pressure of arterial
      oxygen was also measured in both groups. Only patients who met selection criteria
      and had uncomplicated postoperative courses were included in the study. There was
      a total of 40 patients for the final analysis, 20 in each group. RESULTS: There
      was no significant difference (P > 0.1) in age, sex or body mass index in both
      groups of patients. The level of all of the inflammatory mediators was elevated
      on the first postoperative day; however, the elevation was significantly less
      following laparoscopic cholecystectomy compared to conventional cholecystectomy
      (P < 0.01). Although the values came down on the third postoperative day, they
      remained above the respective controls. Postoperative hypoxaemia was
      significantly more in patients of conventional than laparoscopic cholecystectomy
      (P < 0.001). CONCLUSIONS: Trauma-induced inflammatory response is significantly
      less following laparoscopic cholecystectomy compared to conventional
      cholecystectomy. It appears to be related to degree of trauma.

PMID- 10353555
TI  - Risk factors for post-appendicectomy intra-abdominal abscess.
AB  - BACKGROUND: Appendicectomy is a common emergency operation, after which major
      complications are uncommon, however when they do occur they are a major cause of
      concern to patient and surgeon. This study aims to determine the incidence and
      risk factors for post-appendicectomy intra-abdominal abscess formation. METHOD: A
      retrospective review was undertaken of all appendicectomies undertaken in
      Christchurch Hospital between 1 January and 31 December 1995. Appendicectomies
      were identified from a database of histology. The patients' notes were reviewed
      and the surgical approach, histological diagnosis and postoperative complications
      identified. RESULTS: A total of 417 appendicectomies was identified of which 331
      were open, 66 laparoscopic, and 20 undertaken at laparotomy. Mean day stays for
      each group were 4.4, 4.2 and 11.5 days, respectively. The percentages of patients
      with acute appendicitis in each group were 87, 58 and 35%. Histologically the
      appendix was inflamed in 80% (334) of patients (acute 232, chronic 15, perforated
      56 and gangrenous 24). There were six postoperative intra-abdominal abscesses
      (1.4%), all occurring in the open appendicectomy group when the histology was
      either perforated or gangrenous appendicitis (P < 0.001). There were no cases of
      postoperative abscess formation following laparoscopic appendicectomy. All cases
      of postoperative intra-abdominal abscess were associated with perforated and/or
      gangrenous appendicitis (P < 0.001). The incidence of intra-abdominal abscesses
      was 7.5% with a perforated and/or gangrenous appendix. There were two cases of
      iatrogenic perforation following laparoscopic appendicectomy. CONCLUSION: The
      incidence of intra-abdominal abscess is 1.4% of all appendicectomies. The only
      identified risk factor for development of post-appendicectomy intra-abdominal
      abscess was the underlying pathology of gangrenous or perforated appendicitis.

PMID- 10353556
TI  - Thomas Peel Dunhill: pioneer thyroid surgeon.
AB  - Thomas Peel Dunhill, a name by now almost completely forgotten in his native
      Australia, was born in 1876 near Kerang in the State of Victoria. Although he
      qualified as a pharmacist in 1898, Dunhill had already decided to study medicine
      and graduated in 1903 from the Clinical School of the Melbourne Hospital. He was
      regarded as an outstanding student. In 1905 Dunhill was invited to join the
      Senior Medical Staff at St Vincent's Hospital by Mother Berchmans Daly, the then
      Mother Rectress. In 1906 Dunhill was awarded the MD and in 1907 he performed his
      first thyroid lobectomy under local anaesthesia for toxic goitre. As early as
      1908, Dunhill understood the essentials for successful surgery in thyrotoxicosis-
      enough thyroid had to be removed to cure the condition. To this end, he advocated
      a bilateral attack on the thyroid and advocated thyroidectomy in the thyrocardiac
      patient. He did this before Theodor Kocher, Charles Mayo, William Halsted or
      George Crile. In 1911 Dunhill visited the USA and England and communicated his
      results to the thyroid surgeons in both countries (230 cases of exophthalmic
      goitre operated on with four deaths). The English could not, or would not,
      believe his results as the mortality of surgery for exophthalmic goitre at St
      Thomas's Hospital, London in 1910 was 33%. Dunhill served with distinction in the
      Great War and his abilities favourably impressed George Gask, who was to become
      the Professor of Surgery at St Bartholomew's Hospital, London. Gask eventually
      invited Dunhill to join his Unit and Dunhill left St Vincent's Hospital in 1920.
      Between 1920 and Dunhill's retirement at the age of 60 in 1935, he became the
      outstanding general surgeon at St Bartholomew's Hospital. Dunhill and Cecil Joll,
      were regarded as the leading thyroid surgeons in the UK. Knighted in 1933,
      Dunhill was appointed surgeon to the Royal Household, serving four British
      monarchs. In addition to his brilliant surgical career, Dunhill maintained a love
      for the land. He was an expert fly fisherman. Dunhill retired from surgical
      practice in 1949 and died at the age of 80 in 1957 at his London home. Many
      eulogies were delivered, especially by Sir James Paterson Ross and Sir Geoffrey
      Keynes, his former pupils. Dunhill's exploits as a thyroid surgeon in the
      development of a safe and effective treatment for thyrotoxicosis and in operating
      on the thyrocardiac enables this modest, courteous and loyal Australian to be
      included with Theodor Kocher, Charles Mayo, William Halsted and George Crile in
      the pantheon of pioneer thyroid surgeons.

PMID- 10353557
TI  - Spray of phospholipid powder reduces peritoneal adhesions in rabbits.
AB  - BACKGROUND: The possible effects of peritoneal dialysis and a combination of two
      exogenous phospholipids, dipalmitoylphosphatidylcholine (DPPC) and
      phosphatidylglycerol (PG), on experimentally induced intraperitoneal adhesion
      formation in rabbits were compared. METHODS: Fifty New Zealand rabbits equally
      divided in five groups underwent a midline laparotomy to create a right iliac
      fossa 5 x 1 cm parietal peritoneal defect and a matching defect over the adjacent
      large bowel. In 10 control rabbits (group I) the abdominal wound was closed
      without any further intervention. Twenty rabbits forming groups II and III
      underwent two sessions of peritoneal dialysis, one following abdominal closure
      and the second 24 h later, through a catheter placed at surgery. Rabbits in group
      III received an intraperitoneal injection of DPPC and PG after each session of
      dialysis. In 10 animals (group IV) a DPPC gel was applied to the defect over the
      large bowel and in 10 animals (group V) the peritoneal cavity was sprayed with a
      'puff of DPPC:PG (7:3) powder prior to abdominal closure. All the animals were
      killed a week after the laparotomy to assess the extent of adhesion formation.
      RESULTS: The formation of adhesions was reduced in all the groups compared to the
      controls but a statistically significant difference was observed only in the
      group receiving the intraperitoneal 'puff' of DPPC:PG powder. CONCLUSION: A
      combination of DPPC and PG sprayed as a 'puff' intraperitoneally reduces
      experimentally induced peritoneal adhesions in rabbits.

PMID- 10353558
TI  - Inferior vena caval resection with autogenous peritoneo-fascial patch graft caval
      repair: a new technique.
AB  - BACKGROUND: In the course of oncological surgery, resection of the inferior vena
      cava (IVC) may be required to obtain an adequate resection margin and to offer
      the best opportunity of cure. The remaining defect in the IVC may be managed by:
      (i) primary repair which may lead to subsequent narrowing of the lumen, possibly
      leading to turbulent flow and thrombus formation; (ii) patch grafting of the
      defect, which may prevent narrowing. Several synthetic and biosynthetic materials
      are available as patch grafts and autologous pericardium has also been used.
      METHODS: The harvesting and use of the autogenous peritoneo-fascial (APF) graft
      as an alternative caval patch graft material in the management of defects in the
      caval wall is proposed. Autogenous peritoneo-fascial caval patch graft repair in
      six patients was undertaken. RESULTS: One patient with leiomyosarcoma secondaries
      in the liver eventually succumbed to the disease. The other five patients are
      clinically well with no evidence of IVC obstruction or venous aneurysms.
      CONCLUSION: Preliminary results show that this new technique of utilizing an APF
      patch graft for caval repair is clinically a suitable alternative to current
      biosynthetic and synthetic materials and may in fact be superior in many aspects.

PMID- 10353559
TI  - Gastric foreign bodies: no longer a cross to bear.
AB  - Flexible video gastroscopy can be combined with laparoscopic techniques to aid
      extraction of difficult gastric foreign bodies. A case is presented describing
      this technique.

PMID- 10353560
TI  - Reoperative surgery for recurrent or persistent primary hyperparathyroidism:
      comment.

PMID- 10353561
TI  - Breast cancer outcomes at the Strathfield Breast Centre: comment.

PMID- 10353562
TI  - Safety in laparoscopy: comment.

PMID- 10353563
TI  - Comparative experience of a simple technique for laparoscopic chronic ambulatory
      peritoneal dialysis catheter placement: comment.

PMID- 10353564
TI  - Retrieval of an extraluminal swallowed sharp foreign body.

PMID- 10353565
TI  - Check the stapler before use.

PMID- 10353566
TI  - Parathyroid cysts.
AB  - Parathyroid cysts are relatively uncommon. They may be non-functioning or
      associated with primary hyperparathyroidism. Three patients are presented,
      including one with a large mediastinal parathyroid cyst, and these cases
      illustrate the range of pathological and clinical features.

PMID- 10353567
TI  - Implantation carcinoma developing late after laparoscopic cholecystectomy for
      superficial carcinoma of the gall-bladder.

PMID- 10353568
TI  - Combination vaccines for childhood immunization.
AB  - An increasing number of new and improved vaccines to prevent childhood diseases
      are being introduced. Combination vaccines represent one solution to the problem
      of increased numbers of injections during single clinic visits. This statement
      provides general guidance on the use of combination vaccines and related issues
      and questions. To minimize the number of injections children receive, parenteral
      combination vaccines should be used, if licensed and indicated for the patient's
      age, instead of their equivalent component vaccines. Hepatitis A, hepatitis B,
      and Haemophilus influenzae type b vaccines, in either monovalent or combination
      formulations from the same or different manufacturers, are interchangeable for
      sequential doses in the vaccination series. However, using acellular pertussis
      vaccine product(s) from the same manufacturer is preferable for at least the
      first three doses, until studies demonstrate the interchangeability of these
      vaccines. Immunization providers should stock sufficient types of combination and
      monovalent vaccines needed to vaccinate children against all diseases for which
      vaccines are recommended, but they need not stock all available types or
      brandname products. When patients have already received the recommended
      vaccinations for some of the components in a combination vaccine, administering
      the extra antigen(s) in the combination is often permissible if doing so will
      reduce the number of injections required. To overcome recording errors and
      ambiguities in the names of vaccine combinations, improved systems are needed to
      enhance the convenience and accuracy of transferring vaccine-identifying
      information into medical records and immunization registries. Further scientific
      and programmatic research is needed on specific questions related to the use of
      combination vaccines.

PMID- 10353569
TI  - Current issues relating to in vitro testing for allergen-specific IgE: a workshop
      report.

PMID- 10353570
TI  - Genetics of allergy and asthma.
AB  - LEARNING OBJECTIVES: This article summarizes the latest information regarding the
      role of genetic influences in the development of allergic disorders and asthma
      and reviews our current information on some of the most likely genes responsible
      for these conditions. After reading this article, the reader will have a better
      understanding of the current molecular biologic techniques that are being used to
      understand complex genetic disorders such as allergies and asthma. The reader
      should understand the value of how this genetic insight will lead to the
      recognition of the presence of specific subtypes of these disorders that require
      unique therapeutic interventions. This information can also be used to identify
      genetically at risk children and thereby offer earlier intervention. Finally,
      understanding the genetic causes of allergies and asthma will lead to the
      development of the next--hopefully curative--generation of asthma and allergy
      therapeutics. DATA SOURCES: A detailed literature search was conducted. Studies
      considered relevant, well performed, and appropriately controlled were used. Only
      human studies are included and only the English language literature was reviewed.
      Some of the information presented is based on the author's own research
      experience. STUDY SELECTION: Material was only taken from peer-reviewed journals
      and appropriate reviews. RESULTS AND CONCLUSIONS: Asthma and allergic diseases
      are examples of disorders having an unmistakable genetic predisposition, but in
      the absence of a classic Mendelian inheritance pattern. These "complex" genetic
      disorders are caused by the interactions of multiple interacting genes some
      having protective value and some contributing to disease development and with
      each gene having its own variable tendency to be expressed. In addition, these
      disorders require the presence of appropriate environmental triggers for their
      expression. One approach to identifying the genetic basis for these conditions is
      to perform a genome-wide search in which the location of the disease-causing gene
      on a human chromosome is identified and nearby genes that may be responsible are
      subsequently identified. An alternative approach to identifying heritable
      components to asthma and allergy is to evaluate disordered structure or
      regulation within genes known to be involved in these disorders. Using these
      approaches, studies have suggested that genes within the cytokine gene cluster on
      chromosome 5 (including interleukins-3, -4, -5, -9, and -13), chromosome 11 (the
      beta chain of the high affinity IgE receptor), chromosome 16 (the IL-4 receptor),
      and chromosome 12 (stem cell factor, interferon-gamma, insulin growth factor, and
      Stat 6 [IL-4 Stat]) may contribute to asthma and allergy development. In
      addition, data support involvement of genes involved in antigen-presentation (MHC
      class II genes) and T cell responses (the T cell receptor alpha chain). Finally,
      disease-contributing alleles may be present on genes for the beta-adrenergic
      receptor, 5-lipoxygenase, and leukotriene C4 synthase.

PMID- 10353571
TI  - Advice from your allergist: pet allergies.

PMID- 10353572
TI  - Varicella immunity: persistent serologic non-response to immunization.
AB  - OBJECTIVE: Varicella-zoster (VZV) infection is an occupational hazard for health
      care workers. The "gold standard" for assessing protection is a positive antibody
      titer. We present a case of persistent serologic non-responsiveness following VZV
      immunization and discuss a management strategy. METHODS: A 29-year-old woman,
      immunocompetent pediatric resident was repeatedly removed from her clinical
      duties because of a negative history of chicken pox and the absence of a VZV
      antibody titer. She received a total of three doses of the VZV vaccine and
      continued to have a negative antibody titer as measured by a commercial ELISA
      assay (Wampole). Subsequently, she had three direct contacts with infectious
      children and did not develop clinical chicken pox. RESULTS: A lymphocyte
      proliferation assay was performed using inactivated varicella vaccine and tetanus
      antigens. The patient's varicella and tetanus stimulation index (SI) were 46.5
      and 42, respectively. The SI for the positive control (a patient recently
      recovered from a wild type infection) were 144 (varicella specific), and 114
      (tetanus). The SI secondary to VZV antigens reported in the literature is 30.5 +/
      9.1. We reassessed the varicella antibody titer using more sensitive assays:
      fluorescent antibody to membrane antigen and latex agglutination. Both tests
      verified the presence of VZV specific IgG at a titer of 1:8 in our patient.
      CONCLUSION: This case illustrates that in a subgroup of individuals the antibody
      response to VZV vaccine may be low despite an adequate cell-mediated response.
      Commercial VZV ELISA assays were designed to measure higher titers associated
      with natural infection rather than the lower titer induced by the vaccine.
      Repeated immunizations plus more sensitive measures of VZV-specific IgG should be
      used to validate protection rather than the current commonly utilized ELISA
      screening. Clinicians should be aware of the variability in VZV-specific antibody
      assays when assessing post VZV vaccine titers prior to determining protection in
      health care workers.

PMID- 10353574
TI  - Clindamycin hypersensitivity appears to be rare.
AB  - BACKGROUND: A patient developed a generalized confluent erythematous papular rash
      after a single injection of clindamycin preoperatively. The literature from two
      small studies suggested a 10% incidence of cutaneous eruptions to clindamycin
      which seemed too high. OBJECTIVE: Describe a patient with clindamycin
      hypersensitivity and determine the incidence of hospital-wide adverse drug
      reactions from clindamycin from 1995-1997. METHODS: At a tertiary care center,
      utilizing the Department of Pharmacy records, the incidence of adverse drug
      reactions was determined with (1) voluntary physician reporting, (2) Health
      Information Management chart reviews and adverse drug reaction coding, and (3)
      chart reviews by the Pharmacy and Therapeutics Committee of adverse drug
      reactions. RESULTS: (I) A 50-year-old patient developed a generalized raised,
      erythematous rash that worsened over 3.5 days until hydrocortisone was
      administered. Immediate skin tests with clindamycin were negative. (2) From 3,896
      administrations of clindamycin from April 1995 to October 1997, 14 (0.47%)
      adverse drug reactions occurred but 7 were confounded by other medications also
      being administered. CONCLUSION: (1) Adverse drug reactions to clindamycin are
      much lower than reported 25 years ago with an incidence < 1%. (2) A patient who
      previously had experienced facial edema and a generalized rash after receiving
      clindamycin and a cephalosporin 6 years ago and who was considered allergic to
      cephalosporins, was found to be clindamycin allergic when she received a
      preoperative dose of clindamycin.

PMID- 10353573
TI  - Demonstration of therapeutic equivalence of generic and innovator beclomethasone
      in seasonal allergic rhinitis. SAR Study Group.
AB  - BACKGROUND: Although generic formulations of drugs are chemically equivalent,
      they may not be bioequivalent to the innovator. Since bioequivalence of
      intranasal corticosteroids has been difficult to demonstrate by pharmacokinetic
      methods, clinical trials have been necessary to compare generic and innovator
      agents. OBJECTIVE: We therefore designed a multicenter, randomized double-blind,
      parallel-group placebo-controlled study to examine the therapeutic equivalence of
      generic beclomethasone diproprionate to the innovator. METHODS: A total of 518
      patients, ages 12 to 60, with ragweed-induced seasonal allergic rhinitis from
      eight centers were randomized to receive intranasal generic or innovator
      beclomethasone 42 microg, 84 microg or placebo twice daily for 6 weeks. Efficacy
      was assessed by means of rhinitis symptom scores as recorded in patient diaries.
      Adverse events were recorded throughout the study to assess safety. RESULTS: Mean
      rhinitis composite symptom scores (congestion, postnasal drip, runny nose, and
      sneezing) were significantly lower in patients receiving 42 microg (P = .0003) or
      84 microg (P = .0001) beclomethasone twice daily compared with placebo. Generic
      beclomethasone was equivalent therapeutically to the innovator in alleviating
      nasal congestion (42 microg and 84 microg doses), postnasal drip (84 microg
      dose), runny nose (84 microg dose), sneezing (42 microg and 84 microg doses) and
      mean composite (42 microg and 84 microg doses) symptom scores during the 6-week
      study period. Similar and equivalent efficacy was also demonstrated during the 5
      day period of peak pollen counts at each site. The type and incidence of drug
      related adverse events were similar for both beclomethasone treatment groups and
      did not differ significantly from placebo in severity and frequency. CONCLUSIONS:
      Generic beclomethasone was therapeutically equivalent to the innovator in regards
      to both efficacy and side effect profile in the treatment of ragweed-induced
      allergic rhinitis.

PMID- 10353575
TI  - How to write about pollen.
AB  - BACKGROUND: Clinicians and palynologists (pollen specialists) often have
      different ways of expressing the same thing when they write about pollen.
      OBJECTIVE: This brief paper considers the confusing use of the word pollens that
      is frequently encountered in medical literature. METHODS: Three common uses for
      the word pollens are considered citing examples from clinical literature. The
      problems associated with each case are explored. RESULTS: Words and phrases that
      can serve as suitable alternatives to the word pollens are presented. The
      advantages of these alternatives are discussed. CONCLUSION: The word pollens
      represents a vague usage that obscures the author's intended meaning. Consistent
      application of the suggested alternatives will enhance the transmission of key
      concepts in the medical literature.

PMID- 10353576
TI  - Contact reactions to fragrances.
AB  - BACKGROUND: The most common reaction to fragrances is contact dermatitis, a
      delayed hypersensitivity reaction; however, other reactions include immediate
      contact reactions (contact urticaria) and photo-allergic reactions. Fragrance mix
      (FM) and balsam of Peru (BP) are used to screen for fragrance allergy. OBJECTIVE:
      To study the different types of allergic skin reactions to fragrance compounds.
      METHODS: Delayed hypersensitivity reactions to FM and BP were studied in 4,975
      patients with suspected contact dermatitis by routine patch testing interpreted
      at 48 and 96 hours. In 664 of the patients, patch tests were read at 30 minutes
      to evaluate for immediate (wheal-and-flare) contact reactions and again at 48 and
      96 hours. Photopatch tests to FM were performed in 111 patients with suspected
      photo-allergic dermatitis. RESULTS: Delayed contact reactions to FM occurred in
      6.6% of females and 5.4% of males and to BP in 3.9% of females and 4.1% of males.
      Analysis of data over time (12 study years) showed an increased trend for
      reactions to fragrances, particularly in males. Sensitivity to other contact
      allergens (polysensitivity) was found in 62% of patients and polysensitivity
      presented more often with generalized contact dermatitis. The most sensitizing
      components of the fragrance mix that were tested in 38 patients were cinnamic
      alcohol, oak moss, and cinnamic aldehyde. There were 112 immediate patch test
      reactions to FM and 113 to BP in 664 patients. Immediate contact reactions were
      followed by delayed contact reactions in 13.4% of patients for FM and 8.8% for
      BP, representing a significant increase in the frequency of delayed contact
      reactions. Patients with immediate contact reactions to fragrances did not have a
      higher incidence of atopy (25.9%). No cases of positive photopatch test reactions
      to FM were seen. CONCLUSION: Fragrances commonly cause both delayed and immediate
      patch test reactions and patients with immediate contact reactions have an
      increase in delayed contact reactions to the same allergen.

PMID- 10353577
TI  - Corticosteroid resistance in mild asthma: markers of persistent inflammation.
AB  - BACKGROUND: Bronchial hyperresponsiveness (BHR) is an important feature of
      asthma. Glucocorticosteroids (GCS) reduce BHR, probably by suppressing allergic
      inflammation. There are, however, two groups of asthmatics with either GCS
      responsive or non-responsive BHR to methacholine. We investigated the mechanism
      of non-GCS-responsive BHR in mild asthma. METHODS: Non-GCS-responsive BHR asthma
      was defined as failure of reduction of BHR to methacholine after a 2-week course
      of oral prednisolone (30 mg/day). The expression of interleukin (IL)-4, IL-5, IFN
      gamma mRNA in peripheral blood mononuclear cells, eosinophil count, serum
      cortisol, eosinophilic cationic protein (ECP), and spirometry were measured in
      five non-GCS-responsive BHR asthmatics and six patients with GCS-responsive BHR
      asthma before and after prednisolone therapy. RESULTS: With the exception of
      serum ECP and expression of IL-5 mRNA, no significant differences were observed
      between GCS-responsive BHR and non-GCS-responsive BHR asthma. The mean ECP level
      was significantly higher in non-GCS-responsive BHR than in GCS-responsive BHR
      asthma before and after prednisolone therapy. Interleukin-5 mRNA was detected in
      all asthmatics before prednisolone therapy; however, after prednisolone therapy,
      IL-5 mRNA was only detected in non-GCS-responsive BHR asthmatics. CONCLUSIONS:
      Our findings suggest that activation of eosinophils appears to persist in some
      asthmatics with non-GCS-responsive BHR due to continuous IL-5 production by
      lymphocytes.

PMID- 10353578
TI  - Rapid onset of control with budesonide Turbuhaler in patients with mild-to
      moderate asthma.
AB  - BACKGROUND: Budesonide (Pulmicort) is an inhaled corticosteroid with high topical
      potency but low systemic activity. Turbuhaler is a novel breath-actuated, multi
      dose, dry-powder inhaler. OBJECTIVES: This study was conducted to determine the
      efficacy and safety of two different dose regimens of budesonide Turbuhaler,
      compared with placebo, in adult patients with mild-to-moderate asthma not well
      controlled with bronchodilator therapy. METHODS: This double-blind, randomized,
      placebo-controlled, parallel-group, multicenter study compared the efficacy and
      safety of 200 microg and 400 microg of budesonide, administered twice daily via
      Turbuhaler, with placebo, in 273 adult patients (aged 19 to 70 years) with mild
      to-moderate asthma (FEV1 67% of predicted normal), not well-controlled with
      bronchodilator therapy. Efficacy was assessed by pulmonary function tests and
      patient assessments of asthma symptom control. Safety was assessed in terms of
      adverse events, laboratory evaluations, and physical examinations. RESULTS: Two
      hundred and 400 microg of budesonide bid were significantly more effective than
      placebo at improving morning PEF (mean differences from placebo of 43.63 L/min
      and 40.10 L/min, respectively; P < .001) and FEV1 (mean differences from placebo
      of 0.44 L, and 0.50 L, respectively; P < .001) over the 12-week treatment period.
      Onset of action as assessed by morning PEF was within two days. Basal and
      stimulated plasma cortisol concentrations were not significantly affected by
      budesonide treatment compared with placebo. CONCLUSIONS: Treatment of adults
      suffering from mild-to-moderate asthma with budesonide Turbuhaler is well
      tolerated and results in a rapid onset of asthma control which is maintained over
      time.

PMID- 10353579
TI  - Angiotensin converting enzyme inhibitor-induced angioedema more prevalent in
      transplant patients.
AB  - BACKGROUND: Angioedema in association with angiotensin converting enzyme
      inhibitor (ACEI) use is rare, but serious. Which patients are predisposed to the
      reaction and whether it involves an immune mechanism remain unclear. OBJECTIVES:
      To determine the frequency of ACEI angioedema in immunosuppressed cardiac and
      renal transplant patients. METHODS: This was a retrospective chart review of all
      adult cardiac (n = 156) and renal (n = 341) transplant patients followed at our
      hospital (years 1985 to 1995). RESULTS: Of 105 cardiac and 91 renal transplant
      patients on a combination of immunosuppressive and ACEI therapy, 5 (4.8%) cardiac
      and 1 (1%) renal patients developed angioedema. This prevalence of ACEI
      angioedema among cardiac and renal transplant patients is 24 times and 5 times
      higher, respectively, than that observed in the general population (0.1% to
      0.2%). Reactions often appeared after prolonged ACEI use (average 19 months;
      range 3 days to 6.3 years). African-Americans were significantly more likely to
      experience ACEI-associated angioedema (P = .034), especially among the cardiac
      patients where 4 of 5 reactors were African-American. CONCLUSIONS: For unclear
      reasons, ACEI-induced angioedema (often late-onset) is more prevalent among
      immunosuppressed cardiac and renal transplant patients. Additionally, African
      Americans are over-represented among those developing the reaction.

PMID- 10353580
TI  - Reduced IL-12 level correlates with decreased IFN-gamma secreting T cells but not
      natural killer cell activity in asthmatic children.
AB  - BACKGROUND: Accessory cells such as macrophages and natural killer cells, and
      their cytokines such as IL-10, IL-12, and IFN-gamma have been suggested to play a
      critical role in the development of T helper cells. OBJECTIVE: Both natural
      killer cells and peripheral blood mononuclear cells were isolated and stimulated
      for their ability in producing cytokines. In addition, the percentage of IFN
      gamma-secreting cells was analyzed with the method of intracellular staining.
      RESULTS: The data suggested (1) no significant difference between asthmatic
      children and normal controls in number, cytotoxicity, and IFN-gamma production of
      purified NK cells; (2) decreased secretion of IL-12 by stimulated peripheral
      blood mononuclear cells in asthmatic children compared with normals (P < .05);
      (3) decreased production of IFN-gamma by PBMC from asthmatic children compared
      with normals (P < .05); and (4) intracellular expressed IFN-gamma level was lower
      in CD4+ T cells of asthmatic children (P < .05). CONCLUSION: The results
      suggested that IL-12 produced predominantly by macrophages and associated
      decreased IFN-gamma-secreting CD4+ T cells play a critical role in the
      pathogenesis of asthma.

PMID- 10353581
TI  - Comparison of the efficacy of subcutaneous and sublingual immunotherapy in mite
      sensitive patients with rhinitis and asthma--a placebo controlled study.
AB  - BACKGROUND: The efficacy of therapy with sublingual allergen extracts is
      unproven. OBJECTIVE: To evaluate the clinical and immunologic outcome of
      sublingual immunotherapy and to compare the results with subcutaneous
      immunotherapy and placebo in 36 patients with rhinitis and asthma due to mite
      allergy. METHOD: Thirty-six patients with rhinitis and asthma due to mite allergy
      were randomly divided into three groups in order to receive subcutaneous
      injections with allergenic extracts, sublingual drops with solutions of purified
      standardized allergen preparations, or sublingual placebo for a period of 1 year.
      Assessment of clinical and immunologic efficacy included symptom and medication
      scores, methacholine provocation tests, skin prick tests, and specific IgE and
      IgG4 antibody concentrations. RESULTS: Subcutaneous immunotherapy for both
      rhinitis and asthma was clinically effective. Patients treated with sublingual
      immunotherapy had decreased rhinitis symptoms (P < .01) but no change in asthma
      scores. Medication scores significantly decreased in both actively treated groups
      (P < .01) at the first year compared with baseline. When skin prick tests were
      evaluated, the subcutaneously treated group had a significant decrease in the
      wheal diameter of D. pteronyssinus (P < .01), D. farinae (P < .05), and histamine
      (P < .05) while other two groups showed no difference. There was no significant
      change in methacholine PC20 values in all groups at the end of the first year
      when compared with baseline. No change in D. pteronyssinus and D. farinae
      specific IgE levels were observed; however, specific IgG4 concentrations were
      significantly higher than baseline both in sublingual and subcutaneous
      immunotherapy groups (P < .05) after 1 year immunotherapy. No significant
      difference was obtained in any of these parameters in the placebo group.
      CONCLUSION: Sublingual immunotherapy may be effective in patients with allergic
      rhinitis. Further, we believe it is a potential therapy for allergic asthmatic
      patients. The clinical usefulness of this form of immunotherapy (when
      administered to larger study groups for a longer time) and the mechanisms
      underlying its immunologic effect deserve additional studies.

PMID- 10353582
TI  - Analysis of induced sputum to examine the effects of inhaled corticosteroid on
      airway inflammation in children with asthma.
AB  - BACKGROUND: Analysis of induced sputum can be performed safely in children with
      asthma and is useful for both cellular and biochemical markers of inflammation.
      Glucocorticosteroid inhalation has become the first line therapy for chronic
      asthma by suppressing airway inflammation, which produces the decrease of
      bronchial hyperreactivity and reduces the number of eosinophil in bronchial
      submucosa. OBJECTIVE: To determine the characteristics of the inflammatory cells
      and their markers in sputum and to examine the pharmacokinetic effects of
      glucocorticoid within 3 hours after inhalation therapy on FEV1 and sputum
      inflammatory indices in children with clinically defined chronic asthma. METHODS:
      Thirty subjects with asthma included 14 current symptomatic asthmatics and 14
      normal controls inhaled 4.5% hypertonic saline for 10 minutes by nebulizer. The
      expectorated sputum were collected from all asthmatics before and 3 hours after
      corticosteroid inhalation for children with asthma and were reduced by
      dithiotreitol. Total cell counts and differentials were determined. ECP was
      measured by CAP system. Interleukin-5, GM-CSF and albumin were measured by double
      sandwich ELISA. RESULTS: The mean eosinophil percentage and ECP in induced sputum
      of asthmatics were significantly higher than that of controls. The induced sputum
      samples obtained after glucocorticoid inhalation showed a significant reduction
      in mean eosinophil percentage, but FEV1, IL-5, GM-CSF, albumin, and ECP values
      were not significantly decreased. CONCLUSION: The present results in induced
      sputum may be interpreted to reflect direct steroid action on airways and lack of
      effect on bone marrow effectors at 3 hours after glucocorticoid inhalation.

PMID- 10353583
TI  - Two first-line therapies in the treatment of mild asthma: use of peak flow
      variability as a predictor of effectiveness.
AB  - BACKGROUND: New drug evaluations in patients with mild asthma are sometimes
      complicated by enrollment of patients whose disease is too mild to show
      improvement with therapy. A peak expiratory flow (PEF) variability criterion may
      help to more clearly define a mild asthmatic population. OBJECTIVE: To evaluate
      the effectiveness of zafirlukast (20 mg twice daily) and cromolyn sodium (1600
      microg four times daily) compared with placebo as first-line therapy for mild
      asthma using a retrospective analysis, which stratified patients by PEF
      variability (<10% or > or =10%). STUDY DESIGN: Symptomatic patients (daytime
      asthma symptoms score > or =8) were randomized to 13 weeks of treatment in a
      double-blind, double-dummy, placebo-controlled, parallel-group, multicenter
      trial. PATIENTS AND METHODS: Patients (n = 287) were nonsmokers (age > or =12
      years) with reversible airway disease, a forced expiratory volume in one second
      (FEV1) of > or = 55% of predicted, and previous treatment with beta2-agonist or
      theophylline only. Assessments included changes from baseline to endpoint in
      daytime and nocturnal asthma symptoms, beta2-agonist use, PEF, and FEV1. Response
      to treatment was assessed by predetermined diary card and FEV1 criteria. Safety
      was determined from adverse events and laboratory test results. RESULTS: No
      significant treatment effects were seen across efficacy measures for patients
      with PEF variability < 10%. For patients with PEF variability > or = 10%, both
      active treatments significantly (P < .05) decreased the daytime asthma symptoms
      score, nighttime awakenings, and beta2-agonist use, and increased morning PEF and
      FEV1 compared with placebo. Response to diary card criteria was 70% and 75% for
      zafirlukast and cromolyn, respectively; response to FEV1 criteria was 47% for
      both treatments. All treatments were tolerated well by patients. CONCLUSIONS:
      Zafirlukast and cromolyn are effective first-line therapies for mild asthma, with
      both therapies producing greater benefits in patients whose PEF variability was >
      or = 10%. In prospective trials to evaluate therapies in patients with mild
      asthma, it may be worthwhile to include PEF variability with a 10% cutoff either
      as an inclusion criteria or as a tool for subset analysis.

PMID- 10353584
TI  - Hilar adenopathy in allergic bronchopulmonary aspergillosis.
AB  - BACKGROUND: A 20-year-old male student developed allergic bronchopulmonary
      aspergillosis (ABPA). Computed tomography (CT) of the thorax done to detect
      central bronchiectasis (CB) for confirmation of diagnosis revealed, in addition,
      right hilar lymphadenopathy. Hilar adenopathy is thought to be rare in ABPA and
      has been documented only once before. Because of the finding of hilar adenopathy,
      the earlier reported patient had to undergo an invasive surgical procedure.
      OBJECTIVE: To report a case of true hilar adenopathy in ABPA. METHODS: This is a
      single case report. Contrast enhanced CT of the thorax was done. Serum
      precipitating antibodies against Aspergillus fumigatus were tested using gel
      diffusion technique, and intradermal testing with antigens of Aspergillus species
      was performed. Specific IgG antibodies against A. fumigatus and total IgE levels
      were measured by ELISA. RESULTS: A review of serial chest radiographs over a
      period of 3 years demonstrated transient pulmonary infiltrates and right hilar
      prominence. Computed tomography of the thorax revealed right hilar
      lymphadenopathy along with bilateral central bronchiectasis and patchy
      infiltrates. Strong bands of precipitins were detected against A. fumigatus.
      Intradermal testing with antigens of Aspergillus species elicited strong type I
      (immediate) and type III (Arthus-type) hypersensitivity reactions to A. fumigatus
      and A. niger. Specific IgG antibodies against A. fumigatus was positive and total
      IgE level was significantly elevated. Peripheral blood eosinophilia was also
      detected. CONCLUSIONS: Although extremely rare, ABPA should be considered in the
      differential diagnosis of hilar adenopathy.

PMID- 10353586
TI  - NMDA receptor antagonism produces antinociception which is partially mediated by
      brain opioids and dopamine.
AB  - Inhibition of nitric oxide synthase (NOS) activity results in opioid-mediated
      supraspinal analgesia in the rat, as indicated by increased reaction time in the
      hot plate test. It is documented that a relationship exists between NMDA receptor
      activation and the activity of NOS. The present investigation sought to determine
      if inactivation of the NMDA receptor produced antinociception of supraspinal
      origin, as was observed in response to inhibition of NOS, and if this response
      was mediated by brain opioids, by activation of receptors for the
      neurotransmitter, dopamine, or both. Administration of MK-801, a non-competitive
      antagonist of the NMDA receptor, produced significant antinociception as measured
      by reaction time in the hot plate test of analgesia. Antinociception resulting
      from treatment with MK-801 appeared to be mediated by brain opioids, as indicated
      by the ability of the opioid antagonist, naloxone, to partially reverse the
      effect of MK-801 administration. This analgesic response was also partially
      diminished by administration of the dopamine D1 receptor antagonist, SCH 23390
      and the dopamine D2 receptor antagonist, sulpiride. The analgesia resulting from
      NMDA receptor antagonism was found to be only partially attributable to dopamine
      and brain opioids, since co-administration of naloxone and SCH 23390 or naloxone
      and sulpiride, were unable to completely reverse the antinociceptive response to
      MK-801. The present findings suggest that inhibition of NMDA receptor activity
      produces supraspinal analgesia. Furthermore, it appears that antinociception
      induced by blockade of the NMDA receptor results, at least in part, from
      activation of endogenous brain opioids and stimulation of D1 and D2 subtypes of
      the dopamine receptor.

PMID- 10353585
TI  - Synergistic down-regulation of signal transduction and cytotoxicity by tiazofurin
      and quercetin in human ovarian carcinoma cells.
AB  - Ovarian carcinoma is one of the most common causes of cancer death in women.
      Tiazofurin, a C-nucleoside, arrests the cell cycle at S phase and reduces the
      activities of PI (phosphatidylinositol) utilizing enzymes in signal transduction
      by depleting cellular GTP concentration. Quercetin (QN), a flavonoid, attacks the
      cell cycle at the G1 and S phase boundary and mainly inhibits PI kinase (1
      phosphatidylinositol 4-kinase, EC 2.7.1.67) activity in the signal transduction
      pathway. Because tiazofurin and QN attack different biochemical targets and
      arrest different phases of the cell cycle, we tested the hypothesis that the two
      drugs might be synergistic against human carcinoma cells. In human ovarian
      carcinoma OVCAR-5 cells in growth inhibition assay, the IC50s (drug concentration
      that inhibits 50% of cell proliferation) for tiazofurin and QN were (mean +/- SE)
      13 +/- 1.2 and 66 +/- 3.0 microM; in clonogenic assays they were 6 +/- 0.5 and 15
      +/- 1.2 microM, respectively. When tiazofurin was added to cells followed 12 h
      later by QN, synergism was observed in both growth inhibition and clonogenic
      assays. The combination also yielded synergistic reduction of IP3 (inositol 1,4,5
      trisphosphate) concentration in the cells which may explain, at least in part,
      the synergistic action of tiazofurin and QN in OVCAR-5 cells. The protocols
      yielding synergism may have implications in the clinical treatment of human
      ovarian carcinoma.

PMID- 10353587
TI  - Effects of daphnodorin A, daphnodorin B and daphnodorin C on human chymase
      dependent angiotensin II formation.
AB  - We investigated whether daphnodorin A, daphnodorin B and daphnodorin C inhibited
      human chymase-dependent angiotensin II-forming activity. Although the structures
      of these compounds are very similar, daphnodorin A completely inhibited
      angiotensin II formation generated by chymase, while daphnodorin B partially
      inhibited and daphnodorin C did not. On the other hand, these daphnodorins did
      not affect angiotensin converting enzyme-dependent angiotensin II formation.
      Furthermore, these daphnodorins did not inhibit purified human tryptase, which,
      like chymase, is contained in mast cells. Therefore, daphnodorin A, but not
      daphnodorin B and daphnodorin C, may specifically inhibit the chymase-dependent
      angiotensin II formation, and such differences between inhibitory effects of
      these compounds to human chymase may be useful for the development of human
      chymase inhibitor.

PMID- 10353588
TI  - Intragastric and intraperitoneal administration of Cry1Ac protoxin from Bacillus
      thuringiensis induces systemic and mucosal antibody responses in mice.
AB  - The spore-forming soil bacterium Bacillus thuringiensis produces parasporal
      inclusion bodies composed by delta-endotoxins also known as Cry proteins, whose
      resistance to proteolysis, stability in highly alkaline pH and innocuity to
      vertebrates make them an interesting candidate to carrier of relevant epitopes in
      vaccines. The purpose of this study was to determine the mucosal and systemic
      immunogenicity in mice of Cry1Ac protoxin from B. thuringiensis HD73. Crystalline
      and soluble forms of the protoxin were administered by intraperitoneal or
      intragastric route and anti-Cry1Ac antibodies of the major isotypes were
      determined in serum and intestinal fluids. The two forms of Cry1Ac protoxin
      administered by intraperitoneal route induced a high systemic antibody response,
      however, only soluble Cry1Ac induced a mucosal response via intragastric. Serum
      antibody levels were higher than those induced by cholera toxin. Systemic immune
      responses were attained with doses of soluble Cry1Ac ranging from 0.1 to 100
      microg by both routes, and the maximal effect was obtained with the highest
      doses. High anti-Cry1Ac IgG antibody levels were detected in the large and small
      intestine fluids from mice receiving the antigen via i.p. These data indicate
      that Cry1Ac is a potent systemic and mucosal immunogen.

PMID- 10353589
TI  - Apple juice inhibits human low density lipoprotein oxidation.
AB  - Dietary phenolic compounds, ubiquitous in vegetables and fruits and their juices
      possess antioxidant activity that may have beneficial effects on human health.
      The phenolic composition of six commercial apple juices, and of the peel (RP),
      flesh (RF) and whole fresh Red Delicious apples (RW), was determined by high
      performance liquid chromatography (HPLC), and total phenols were determined by
      the Folin-Ciocalteau method. HPLC analysis identified and quantified several
      classes of phenolic compounds: cinnamates, anthocyanins, flavan-3-ols and
      flavonols. Phloridzin and hydroxy methyl furfural were also identified. The
      profile of phenolic compounds varied among the juices. The range of
      concentrations as a percentage of total phenolic concentration was: hydroxy
      methyl furfural, 4-30%; phloridzin, 22-36%; cinnamates, 25-36%; anthocyanins,
      n.d.; flavan-3-ols, 8-27%; flavonols, 2-10%. The phenolic profile of the Red
      Delicious apple extracts differed from those of the juices. The range of
      concentrations of phenolic classes in fresh apple extracts was: hydroxy methyl
      furfural, n.d.; phloridzin, 11-17%; cinnamates, 3-27%; anthocyanins, n.d.-42%;
      flavan-3-ols, 31-54%; flavonols, 1-10%. The ability of compounds in apple juices
      and extracts from fresh apple to protect LDL was assessed using an in vitro
      copper catalyzed human LDL oxidation system. The extent of LDL oxidation was
      determined as hexanal production using static headspace gas chromatography. The
      apple juices and extracts, tested at 5 microM gallic acid equivalents (GAE), all
      inhibited LDL oxidation. The inhibition by the juices ranged from 9 to 34%, and
      inhibition by RF, RW and RP was 21, 34 and 38%, respectively. Regression analyses
      revealed no significant correlation between antioxidant activity and either total
      phenolic concentration or any specific class of phenolics. Although the specific
      components in the apple juices and extracts that contributed to antioxidant
      activity have yet to be identified, this study found that both fresh apple and
      commercial apple juices inhibited copper-catalyzed LDL oxidation. The in vitro
      antioxidant activity of apples support the inclusion of this fruit and its juice
      in a healthy human diet.

PMID- 10353590
TI  - Pharmacokinetics of granisetron in rat blood and brain by microdialysis.
AB  - To characterize the pharmacokinetics of protein-free granisetron in blood and
      brain we implanted microdialysis probes into the jugular vein and cerebral
      frontal cortex of the rat. Granisetron (3 or 6 mg/kg, i.v., n=6) was then
      administered, and microdialysates from blood and brain were collected from both
      sites and assayed by a validated high-performance liquid chromatographic method.
      Pharmacokinetics parameters were calculated from the corrected dialysate
      concentrations of granisetron versus time data. The elimination half-lives of
      granisetron in blood and brain were 51.3+/-5.5 and 69.7+/-6.3 min for 6 mg/kg,
      and 50.7+/-4.3 and 74.3+/-12.5 min for 3 mg/kg, respectively. Granisetron rapidly
      entered the extracellular fluid of cerebral frontal cortex at Tmax of 24 min. The
      results suggest that simultaneous microdialysis in blood and brain can be
      usefully applied to study the pharmacokinetics of granisetron in the periphery
      and the central nervous system.

PMID- 10353591
TI  - Subcellular distribution of protein kinase C isoforms in gastric antrum smooth
      muscle of STZ-induced diabetic rats.
AB  - Contractile responses to carbachol (CCh), protein kinase C (PKC) activity and
      distribution of PKC isoforms in subcellular fractions isolated from gastric
      antrum smooth muscle of control and streptozotocin (STZ)-induced diabetic rats
      were examined. CCh induced concentration-dependent contraction in antrum smooth
      muscle from controls and diabetics, and this contraction was significantly
      greater in diabetics than in controls. In diabetics, the PKC activity in the
      nucleus fraction was significantly decreased by about 63% in the resting
      condition and that in the cytosol fraction was significantly increased by about
      135% after the treatment with 10 microM CCh for 10 min compared to controls.
      Immunoblot analysis showed that 8 PKC isoforms (-alpha, -beta, -gamma, -delta, 
      epsilon, -zeta, -iota, -lambda) were expressed in rat antrum smooth muscle. The
      PKC-beta isoform was significantly decreased by about 47% in the nucleus fraction
      in the resting condition in diabetics compared to controls. The nucleus, cytosol
      and membrane fractions of this isoform were decreased in controls after the
      treatment with 10 microM CCh for 10 min whereas these fractions were unchanged in
      diabetics. The PKC-epsilon significantly increased by about 219% in the cytosol
      fraction of diabetics in the resting condition, but the distribution of this
      isoform was unchanged in controls and diabetics after the treatment with 10
      microM CCh for 10 min. Results suggest that the diversity of PKC isoform-specific
      distribution and translocation may be related to abnormal contractility and
      intracellular signal transduction through the PKC pathway in diabetics.

PMID- 10353592
TI  - Increased permeability of primary cultured brain microvessel endothelial cell
      monolayers following TNF-alpha exposure.
AB  - TNF-alpha is a cytokine that produces increased permeability in the peripheral
      vasculature; however, little is known about the effects of TNF-alpha on the blood
      brain barrier (BBB). Using primary cultured bovine brain microvessel endothelial
      cells (BBMEC) as an in vitro model of the BBB, this study shows that TNF-alpha
      produces a reversible increase in the permeability of the brain microvessel
      endothelial cells. The BBMEC monolayers were pre-treated with 100 ng/ml of TNF
      alpha for periods ranging from 2 to 12 hours. Permeability was assessed using
      three molecular weight markers, fluorescein (376 MW), fluorescein-dextran (FDX
      4400; 4400 MW), and FDX-70000 (MW 70000). The permeability of BBMEC monolayers to
      all three fluorescent markers was increased two-fold or greater in the TNF-alpha
      treatment group compared to control monolayers receiving no TNF-alpha.
      Significant changes in permeability were also observed with TNF-alpha
      concentrations as low as 1 ng/ml. These results suggest that TNF-alpha acts
      directly on the brain microvessel endothelial cells in a dynamic manner to
      produce a reversible increase in permeability. Exposure of either the lumenal or
      ablumenal side of BBMEC monolayers to TNF-alpha resulted in similar increases in
      permeability to small macromolecules, e.g. fluorescein. However, when a higher
      molecular weight marker was used (e.g. FDX-3000), there was a greater response
      following lumenal exposure to TNF-alpha. Together, these studies demonstrate a
      reversible and time dependent increase in brain microvessel endothelial cell
      permeability following exposure to TNF-alpha. Such results appear to be due to
      TNF's direct interaction with the brain microvessel endothelial cell.

PMID- 10353593
TI  - Metabolism of modified LDL and foam cell formation in murine macrophage-like RAW
      264 cells.
AB  - The uptake of modified low density lipoprotein (LDL) by arterial macrophages is a
      key event in the atherogenesis. We studied 1) the uptake and degradation of
      modified LDL, 2) LDL recognition by specific receptors, and 3) the foam cell
      formation with murine macrophage-like RAW 264 cells in vitro. The cells took up
      and degraded effectively 125I-labeled acetylated LDL (Ac-LDL) and aggregated LDL
      (Aggr-LDL). Also oxidized LDL (Ox-LDL) was taken up but it was degraded poorly.
      The degradation of 125I-Ac-LDL was efficiently competed by both unlabeled Ac-LDL
      and Ox-LDL, whereas the degradation of 125I-Ox-LDL was partially competed by
      unlabeled Ox-LDL and Aggr-LDL but not at all by unlabeled Ac-LDL. The incubation
      with increasing concentrations of Ac-LDL, Aggr-LDL or Ox-LDL resulted in marked
      foam cell formation in the RAW 264 cells. Ox-LDL was cytotoxic at 500 to 1000
      microg/ml concentrations. The results show that RAW 264 cells have at least two
      classes of receptors for modified lipoproteins: one that recognizes both Ox-LDL
      and Ac-LDL, and is similar to the scavenger receptors, and another that
      recognizes Ox-LDL but not Ac-LDL. RAW 264 cells are a convenient model cell line
      for examining the metabolism of modified lipoproteins, not only that of Ac-LDL
      but also that of Ox-LDL and Aggr-LDL, and cellular accumulation of lipids derived
      from modified LDL.

PMID- 10353594
TI  - Prostacyclin analog prevents stress-induced expression of immediate early genes
      and gastric mucosal lesions in the rat stomach.
AB  - Water immersion-restraint induced the expression of immediate early genes (IEGs)
      in the epithelial cells and smooth muscle cells of gastric wall of rats, in
      addition to its well-known effects of mucosal erosion. Pretreatment with a
      prostacyclin analog (beraprost), a proton pump inhibitor (lansoprazole) or a
      histamine H2 receptor antagonist (famotidine) prevented formation of gastric
      mucosal erosion, while only the prostacyclin analog inhibited expression of IEGs.
      The prostacyclin analog may prevent mucosal damages as well as molecular changes
      by ameliorating the mucosal microcirculation, and may have potential therapeutic
      applications.

PMID- 10353595
TI  - Roles of 5-HT3 and opioid receptors in the ethanol-induced place preference in
      rats exposed to conditioned fear stress.
AB  - The effect of the selective 5-HT3 receptor antagonist ondansetron on the ethanol
      induced place preference in rats exposed to conditioned fear stress, which
      stimulates the release of endogenous opioid peptides (beta-endorphin and
      enkephalins), was investigated using the conditioned place preference paradigm.
      In addition, we also examined the effect of ondansetron on the ethanol-induced
      place preference enhanced by the administration of mu- and delta-opioid receptor
      agonists (exogenous opioids). The administration of ethanol (300 mg/kg, i.p.)
      induced a significant place preference in rats exposed to conditioned fear
      stress. Pretreatment with ondansetron (0.01 and 0.1 mg/kg, s.c.) effectively
      attenuated this ethanol-induced place preference. When the mu-opioid receptor
      agonist morphine (0.1 mg/kg, s.c.) or the selective delta-opioid receptor agonist
      2-methyl-4a(alpha)-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a(alpha)-octah
      ydroquinolino [2,3,3-g] isoquinoline (TAN-67; 20 mg/kg, s.c.) was administered in
      combination with 75 mg/kg ethanol (which tended to produce a place preference),
      the ethanol-induced place preference was significantly enhanced. The selective mu
      opioid receptor antagonist beta-funaltrexamine at a dose of 10 mg/kg
      significantly attenuated the enhancement of the ethanol-induced place preference
      produced by morphine. Ondansetron (0.1 mg/kg, s.c.) also significantly attenuated
      the enhancement of the ethanol-induced place preference produced by morphine.
      Furthermore, the selective delta-opioid receptor antagonist naltrindole at a dose
      of 3 mg/kg significantly attenuated the enhancement of the ethanol-induced place
      preference produced by TAN-67. Ondansetron (0.1 mg/kg, s.c.) slightly, but
      significantly, attenuated the enhancement of the ethanol-induced place preference
      produced by TAN-67. These results suggest that 5-HT3 receptors may be involved in
      the rewarding mechanism of ethanol under psychological stress, and may play an
      important role in the rewarding effect of ethanol through the activation of mu-
      and delta-opioid receptors.

PMID- 10353596
TI  - M3 muscarinic receptor activation of a delayed rectifier potassium current in
      canine atrial myocytes.
AB  - Growing body of evidence indicates that the functional responses of cells to
      muscarinic acetylcholine receptors (mAChRs) are mediated by multiple receptor
      subtypes. It is commonly thought that the M2 receptor is the only functional
      mAChR subtype in the heart and little data regarding the potential roles of other
      subtypes in cardiac tissues has been reported. In the present study, we provide
      functional evidence for the presence and physiological function of an M3 receptor
      in canine atrial myocytes. Using whole-cell patch-clamp techniques, we
      consistently found that pilocarpine, an mAChR agonist, induced a K+ current
      similar to but distinct from the classical delayed rectifier K+ current. Same
      observations were obtained when choline or tetramethylammonium (TMA) was applied
      to the bath. The currents were abolished by 1 microM atropine. Antagonists
      selective to M1 (pirenzepine, 100 nM), M2 (methoctramine 100 nM), or M4
      (tropicamide 200 nM) receptors failed to alter the currents. Conversely, three
      different M3-selective inhibitors, p-F-HHSiD (20-200 nM), 4-DAMP methiodide (2-10
      nM) and 4-DAMP mustard (4-20 nM), all produced concentration-dependent
      suppression of the currents. A cDNA fragment representing the M3 receptor was
      isolated from dog atrial RNA and the mRNA level of this construct was 0.7 +/- 0.1
      pg/microg total RNA, as quantified by the competitive RT-PCR methods. Our data
      strongly suggested that an M3 receptor exists and is coupled to a K+ channel in
      the heart.

PMID- 10353597
TI  - Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the
      mitochondrial permeability transition pore.
AB  - The molecular mode of action of lonidamine, a therapeutic agent employed in
      cancer chemotherapy, has been elusive. Here we provide evidence that lonidamine
      (LND) acts on mitochondria to induce apoptosis. LND provokes a disruption of the
      mitochondrial transmembrane potential which precedes signs of nuclear apoptosis
      and cytolysis. The mitochondrial and cytocidal effects of LND are not prevented
      by inhibitors of caspases or of mRNA or protein synthesis. However, they are
      prevented by transfection-enforced overexpression of Bcl-2, an oncoprotein which
      inhibits apoptosis by stabilizing the mitochondrial membrane barrier function.
      Accordingly, the cell death-inducing effect of LND is amplified by simultaneous
      addition of PK11195, an isoquinoline ligand of the peripheral benzodiazepine
      receptor which antagonizes the cytoprotective effect of Bcl-2. When added to
      isolated nuclei, LND fails to provoke DNA degradation unless mitochondria are
      added simultaneously. In isolated mitochondria, LND causes the dissipation of the
      mitochondrial inner transmembrane potential and the release of apoptogenic
      factors capable of inducing nuclear apoptosis in vitro. Thus the mitochondrion is
      the subcellular target of LND. All effects of LND on isolated mitochondria are
      counteracted by cyclosporin A, an inhibitor of the mitochondrial PT pore. We
      therefore tested the effect of LND on the purified PT pore reconstituted into
      liposomes. LND permeabilizes liposomal membranes containing the PT pore. This
      effect is prevented by addition of recombinant Bcl-2 protein but not by a mutant
      Bcl-2 protein that has lost its apoptosis-inhibitory function. Altogether these
      data indicate that LND represents a novel type of anti-cancer agent which induces
      apoptosis via a direct effect on the mitochondrial PT pore.

PMID- 10353598
TI  - Regulation of mRNA splicing and transport by the tyrosine kinase activity of src.
AB  - The regulation of transcription by signal transduction pathways is well
      documented. In addition, we have previously shown that src can regulate pre-mRNA
      processing. To investigate which functional domains of src are involved in the
      regulation of splicing and transport of Lymphotoxin alpha (LTalpha) transcripts,
      we have used src mutants in the catalytic, SH2 and SH3 domains in association
      with the Y527F or the E378G activating mutation. Our results establish that the
      regulation of pre-mRNA processing and transcription can occur independently of
      each other. The splicing and transport phenotypes require an intact tyrosine
      kinase domain and both are insensitive to the deletion of the SH3 domain.
      Therefore these phenotypes do not depend upon the recruitment through the SH3
      domain of src of RNA binding proteins (Sam 68, hnRNP K). By contrast, deletions
      in the SH2 domain have no effect on splicing but either abolish or exacerbate the
      transport phenotype depending upon the activating mutation (Y527F or E378G).
      These divergent responses are associated with specific changes in the pattern of
      tyrosine phosphorylated proteins. Thus, the regulation of transcription, splicing
      and mRNA transport implicate different effector pathways of src. Furthermore,
      analysis of the transport phenotype reveals the interplay between the SH2 and
      catalytic domain of the protein.

PMID- 10353599
TI  - Cyclin E dependent kinase activity in human breast cancer in relation to cyclin
      E, p27 and p21 expression and retinoblastoma protein phosphorylation.
AB  - The cell cycle machinery is regulated by cyclin dependent kinases and sets of
      activating and inhibitory proteins. The G1-S control mechanism is often
      deregulated in tumours supposedly leading to increased kinase activity,
      phosphorylation of substrates and subsequent S phase entrance. Increased kinase
      activity has been proposed to be essential in cell cycle aberrations, but few
      studies have actually shown enhanced kinase activity related to specific cell
      cycle defects in primary tumours. In the present study we have determined the
      cyclin E dependent kinase activity (cyclin E(kinase)) in 59 primary breast
      cancers, using an H1-kinase assay, and related the activity to the expression of
      cyclin E, p27 and p21. In a subgroup of 48 tumours, we further characterized the
      association between cyclin E(kinase), in vivo phosphorylation of the
      retinoblastoma protein (pRb) and proliferation. The cyclin E(kinase) correlated
      significantly with cyclin E content and inversely with p27 and p21 expression.
      P27, but not p21, was associated with low cyclin E(kinase) in specimens with
      normal/low levels of cyclin E. At elevated cyclin E levels, suppression of cyclin
      E(kinase) seemed to require high levels of both p21 and p27. The cyclin E(kinase)
      correlated with the phosphorylation status of pRb as well as with proliferation.
      Surprisingly, pRb phosphorylation did not correlate with proliferation. Our
      results support that pRb is a substrate for cyclin E(kinase) in primary breast
      cancer and that deregulation of cyclin E and p27 act through increased CDK-kinase
      activity, but cyclin E associated events beside pRb phosphorylation might be rate
      limiting for entrance into S phase.

PMID- 10353600
TI  - Regulation of NF-kappaB activity by I kappaB-related proteins in adenocarcinoma
      cells.
AB  - Constitutive NF-kappaB activity varies widely among cancer cell lines. In this
      report, we studied the expression and the role of different I kappaB inhibitors
      in adenocarcinoma cell lines. High constitutive NF-kappaB activity and low I
      kappaB-alpha expression was found in a number of these cell lines. Moreover, some
      of these cells showed a high p100 expression, responsible for the cytoplasmic
      sequestration of most of p65 complexes. Treatment of these cells with TNF-alpha
      or other NF-kappaB activating agents induced only weakly nuclear NF-kappaB
      activity without significant p100 processing and led to a very weak transcription
      of NF-kappaB-dependent reporter gene. Induction of NF-kappaB activity can be
      restored by expression of the Tax protein or by treatment with antisense p100
      oligonucleotides. In MCF7 A/Z cells stably transfected with a p100 expression
      vector, p65 complexes were sequestered in the cytoplasm by p100. These cells
      showed a reduced nuclear NF-kappaB induction and NF-kappaB-dependent gene
      transcription following TNF-alpha stimulation. As a consequence of a competition
      between I kappaB-alpha and p100, cells expressing high levels of p100 respond
      poorly to NF-kappaB activating stimuli as TNF-alpha.

PMID- 10353601
TI  - A new functional Ras antagonist inhibits human pancreatic tumor growth in nude
      mice.
AB  - Constitutively active Ras proteins, their regulatory components, and
      overexpressed tyrosine kinase receptors that activate Ras, are frequently
      associated with cell transformation in human tumors. This suggests that
      functional Ras antagonists may have anti-tumor activity. Studies in rodent
      fibroblasts have shown that S-trans, transfarnesylthiosalicylic acid (FTS) acts
      as a rather specific nontoxic Ras antagonist, dislodging Ras from its membrane
      anchorage domains and accelerating its degradation. FTS is not a
      farnesyltransferase inhibitor, and does not affect Ras maturation. Here we
      demonstrate that FTS also acts as a functional Ras antagonist in human pancreatic
      cell lines that express activated K-Ras (Panc-1 and MiaPaCa-2). In Panc-1 cells,
      FTS at a concentration of 25-100 microM reduced the amount of Ras in a dose
      dependent manner and interfered with serum-dependent and epidermal growth factor
      stimulated ERK activation, thus inhibiting both anchorage-dependent and anchorage
      independent growth of Panc-1 cells in vitro. FTS also inhibited tumor growth in
      Panc-1 xenografted nude mice, apparently without systemic toxicity. Daily FTS
      treatment (5 mg/kg intraperitoneally) in mice with tumors (mean volume 0.07 cm3)
      markedly decreased tumor growth (after treatment for 18 days, tumor volume had
      increased by only 23+/-30-fold in the FTS-treated group and by 127+/-66-fold in
      controls). These findings suggest that FTS represents a new class of functional
      Ras antagonists with potential therapeutic value.

PMID- 10353602
TI  - DEF-3(g16/NY-LU-12), an RNA binding protein from the 3p21.3 homozygous deletion
      region in SCLC.
AB  - DEF-3(g16/NY-LU-12) encodes a novel RNA binding protein isolated by positional
      cloning from an SCLC homozygous deletion region in 3p21.3 and, in parallel, as a
      differentially expressed gene during myelopoiesis from FDCPmix-A4 cells. DEF
      3(g16/NY-LU-12) is ubiquitously expressed during mouse embryogenesis and in adult
      organs while human hematopoietic tissues showed differential expression. The
      mouse and human proteins are highly conserved containing two RNA recognition
      motifs (RRMs) and other domains associated with RNA binding and protein-protein
      interactions. A database search identified related proteins in human, rat, C.
      elegans and S. pombe including the 3p21.3 co-deleted gene, LUCA15. Recombinant
      proteins containing the RRMs of DEF-3(g16/NY-LU-12) and LUCA15 specifically bound
      poly(G) RNA homopolymers in vitro. These RRMs also show similarity to those of
      the Hu protein family. Since anti-Hu RRM domain antibodies are associated with an
      anti-tumor effect and paraneoplastic encephalomyelitis, we tested sera from Hu
      syndrome patients with the RRMs of DEF-3(g16/NY-LU-12) and LUCA15. These were non
      reactive. Thus, DEF-3(g16/NY-LU-12) and LUCA15 represent members of a novel
      family of RNA binding proteins with similar expression patterns and in vitro RNA
      binding characteristics. They are co-deleted in some lung cancers and
      immunologically distinct from the Hu proteins.

PMID- 10353603
TI  - Altered phenotype of HT29 colonic adenocarcinoma cells following expression of
      the DCC gene.
AB  - On 18q, frequently deleted in late stage colorectal cancers, a gene, Deleted in
      Colon Cancer (DCC), has been identified and postulated to play a role as a tumor
      suppressor gene. DCC is retained in the majority of mucinous tumors, which
      produce high levels of mucins, and seems to be preferentially expressed in
      intestinal goblet cells. To investigate whether DCC is related to mucin
      expression and can modulate the transformed phenotype, we introduced a full
      length DCC cDNA into HT29 cells, which can be induced in vitro to express MUC2,
      the gene that encodes the major colonic mucin. Expression of DCC did not modulate
      constitutive or induced expression of MUC2, nor did DCC induce a mature goblet
      cell phenotype. However, HT29 clones expressing high and low levels of DCC
      protein showed a significant decrease in cell proliferation and tumorigenicity.
      Furthermore, increased shedding and an elevated rate of spontaneous apoptosis
      were associated with higher levels of expression of DCC. In summary, while
      restoration of DCC expression in a human colon carcinoma cell line did not
      influence expression of differentiation markers, DCC expression did affect the
      growth and tumorigenic properties of the cells suggesting that DCC can modulate
      the malignant phenotype of colon cancer.

PMID- 10353604
TI  - Characterization of a naturally occurring ErbB4 isoform that does not bind or
      activate phosphatidyl inositol 3-kinase.
AB  - Receptor tyrosine kinases regulate cell behavior by activating specific signal
      transduction cascades. Epidermal growth factor (EGF) receptor tyrosine kinases
      include ErbB1, ErbB2, ErbB3 and ErbB4. ErbB4 is a tyrosine kinase receptor that
      binds neuregulins (NRG) and several other EGF family members. Reverse
      transcriptase polymerase chain reaction (RT-PCR) analysis identified two isoforms
      of ErbB4 that differed in their cytoplasmic domain sequences. Specifically, RT
      PCR using primers flanking the putative phosphatidyl inositol 3-kinase (PI3-K)
      binding site of ErbB4 generated two specific bands when human and mouse heart and
      kidney tissues were analysed. Cloning and sequencing of these RT-PCR products
      revealed that one of the ErbB4 isoforms (ErbB4 CYT-2) lacked a 16 amino acid
      sequence including a putative PI3-K binding site, that was present in the other
      isoform (ErbB4 CYT-1). RT-PCR analysis of mouse tissues suggested that the
      expression of ErbB4 CYT-1 and ErbB4 CYT-2 was tissue-specific. Heart, breast and
      abdominal aorta expressed predominantly ErbB4 CYT-1 whereas neural tissues and
      kidney expressed predominantly ErbB4 CYT-2. To ascertain whether the absence of
      the putative PI3-K binding site in ErbB4 CYT-2 also resulted in the loss of PI3-K
      activity, NIH3T3 cell lines overexpressing ErbB4 CYT-1 or ErbB4 CYT-2 were
      produced. NRG-1 bound to and stimulated equivalent tyrosine phosphorylation of
      both isoforms. However, unlike ErbB4 CYT-1, the ErbB4 CYT-2 isoform was unable to
      bind the p85 subunit of PI3-K and to stimulate PI3-K activity in these cells.
      Furthermore, tyrosine phosphorylation of p85 or association of PI3-K activity
      with phosphotyrosine was not induced in NRG-1 treated cells expressing ErbB4 CYT
      2, indicating that this isoform was incapable of activating PI3-K even
      indirectly. It was concluded that a novel naturally occurring ErbB4 isoform
      exists with a deletion of the cytoplasmic domain sequence required for the
      activation of the PI3-K intracellular signal transduction pathway and that this
      is the only PI3-K binding site in ErbB4.

PMID- 10353605
TI  - Collagen-homology domain 1 deletion mutant of Shc suppresses transformation
      mediated by neu through a MAPK-independent pathway.
AB  - Shc proteins are implicated in coupling receptor tyrosine kinase to the mitogen
      activated protein kinase (MAPK) pathway by recruiting Grb2/SOS to the plasma
      membrane. To better understand the role of Shc in the oncogenesis by point
      mutation activated neu (p185*), we transfected a Shc mutant (ShcdeltaCHI), which
      lacks the Grb2 binding site Y317 by deletion of collagen-homology domain 1, into
      p185*-transformed NIH3T3 cells. The cellular transformation phenotypes were found
      to be largely suppressed by expression of ShcdeltaCH1. Although ShcdeltaCH1 still
      retained another Grb2 binding site (Y239/240), we did not detect its physical
      association with Grb2. We also found that ShcdeltaCH1 could associate with p185*;
      however, this association did not interfere with the endogenous Shc-p185*
      interaction or the Shc-Grb2 interaction. In addition, p185*-mediated MAPK and Elk
      activation likewise were not inhibited by ShcdeltaCH1 expression. Taken together,
      these data demonstrate that ShcdeltaCH1 suppresses the transformation induced by
      activated neu through a MAPK-independent pathway, indicating that Shc may be
      involved in other signal pathway(s) critical for cellular transformation in
      addition to the MAPK pathway.

PMID- 10353606
TI  - Analysis of the human proopiomelanocortin gene promoter in a small cell lung
      carcinoma cell line reveals an unusual role for E2F transcription factors.
AB  - The small cell lung carcinoma (SCLC) cell line DMS-79 has been used as a model
      for studying the molecular mechanism underlying the ectopic ACTH syndrome. We
      previously showed that two domains of the human Proopiomelanocortin (POMC) gene
      promoter were specifically active in DMS-79 cells. The present study focuses on
      the more distal one, Domain IV (-376/-417). DNaseI footprinting experiments
      identified a single binding site for DMS-79 cell proteins in this domain. Gel
      shift and sequence analysis indicated that E2F proteins might bind this site.
      Indeed, proteins from DMS-79 cells which bind this site (i) have in vitro DNA
      binding properties indistinguishable from those of E2F proteins (ii) form, like
      E2F proteins, multiprotein complexes which can be dissociated by sodium
      deoxycholate and (iii) are recognized by antibodies directed against E2F
      proteins. Further, we show that the rat POMC distal promoter domain contains a
      homologous sequence which constitutes a natural mutant of the human POMC E2F
      binding site, since it does not bind E2F. We show by transient transfection that
      this natural mutant, in the context of the rat POMC promoter, is not active in
      DMS-79 cells by contrast to the human POMC E2F binding site. We conclude that E2F
      binding is required for the activity of Domain IV in DMS-79 cells and contributes
      to the expression of the POMC gene in SCLC. Further studies are required to
      elucidate the role of E2F factors in POMC gene transcription in SCLC cells, but
      our results have identified mechanisms different from those in pituitary
      corticotroph cells that are used by these SCLC tumor cells.

PMID- 10353607
TI  - Human fibroblast growth factor-18 stimulates fibroblast cell proliferation and is
      mapped to chromosome 14p11.
AB  - The fibroblast growth factors (FGFs) play crucial roles in controlling embryonic
      development, cell growth, morphogenesis, and tissue repair in animals.
      Furthermore, FGFs may have a role in angiogenesis and may be involved in tumor
      invasion and metastasis. Here, we present the cloning and sequence of human FGF
      18, a novel member of the FGF family. Sequence comparison indicates that FGF-18
      is conserved with the other FGFs and most homologous to FGF-8 among the FGF
      family members. We showed that human FGF-18 was expressed primarily in the heart,
      skeletal muscle, and pancreas, and at lower levels in the other tissues. FGF-18
      was also expressed at low levels in certain cancer cell lines. FGF-18 contains a
      typical signal peptide and was secreted when it was transfected into mammalian
      cells. Recombinant FGF-18 protein stimulated proliferation in the fibroblast cell
      line NIH3T3 in a dose-dependent manner, suggesting that FGF-18 is a functional
      growth factor. Finally, the FGF-18 gene was evolutionarily conserved, and
      localized to human chromosome 14p11.

PMID- 10353608
TI  - Induced p21waf expression in H1299 cell line promotes cell senescence and
      protects against cytotoxic effect of radiation and doxorubicin.
AB  - The CDK inhibitor p21waf is a principal mediator of p53 function but can also be
      transactivated by many p53-independent stimuli leading to cell growth arrest or
      differentiation. In order to study the function of p21waf in a p53-deficient
      environment, we established an inducible expression of p21waf in the p53-null
      lung cancer cell line H1299, based on the muristerone-regulated system.
      Overexpression of p21waf led cells to growth arrest which after several days
      became irreversible and the arrested cells acquired a senescent phenotype as
      judged by cell shape, the senescence-associated beta-gal marker and inhibition of
      colony formation. The effect of p21waf overexpression, in the absence of p53, on
      the cytotoxicity caused by irradiation, doxorubicin and taxol was studied.
      Expression of p21waf provided protection against the cytotoxic effect of
      radiation and doxorubicin but not of taxol. These results are relevant to
      treatment of cancer when p53 is inactive.

PMID- 10353609
TI  - Localization of a putative tumor suppressor gene in the sub-telomeric region of
      chromosome 8p.
AB  - Several regions of chromosome arm 8p are frequently deleted in a variety of human
      malignancies including those of the prostate, head and neck, lung, and colon,
      suggesting that there is more than one tumor suppressor gene on this chromosome
      arm. Both laryngeal and oral squamous cell carcinomas exhibit three distinct and
      nonoverlapping regions of deletion on 8p. We have further refined the
      localization of the putative suppressor in 8p23 by using eight microsatellite
      loci to create a high resolution deletion map of 150 squamous cell carcinomas of
      the larynx and oral cavity. These new data demonstrate that there are two
      distinct classes of deletion within this relatively small region of the
      chromosome and suggest two possible locations for the gene within the D8S264 to
      D8S1788 interval. We also determined that there is little difference between the
      allelic loss frequencies of microsatellites mapping near the telomeric ends of
      other chromosome arms and loci mapping to more centromere proximal regions of the
      same arm. These data suggest that the high allelic loss frequencies seen at 8p23
      loci are not the result of a generalized instability of chromosome ends and are
      instead consistent with the activation of a specific suppressor gene.

PMID- 10353610
TI  - Mutation of the 9q34 gene TSC1 in sporadic bladder cancer.
AB  - Deletions involving chromosome 9 occur in more than 50% of human bladder cancers
      of all grades and stages. Most involve loss of the whole chromosome or of an
      entire chromosome arm but some small deletions are found which can be used to
      define critical regions which may contain tumour suppressor genes. We have
      localized such a critical region of deletion at 9q34 between the markers D9S149
      and D9S66, an interval which contains the Tuberous Sclerosis gene TSC1. Single
      strand conformation polymorphism (SSCP) and sequence analysis of TSC1 in bladder
      tumours and cell lines with 9q34 loss of heterozygosity (LOH) has identified five
      mutations in retained TSC1 alleles. Our results support the hypothesis that TSC1
      can act as a bladder tumour suppressor gene.

PMID- 10353612
TI  - The effect of cyclosporine administration on growth hormone release and serum
      concentrations of insulin-like growth factor-I in male rats.
AB  - The aim of this work was to study the effect of cyclosporine on the somatotropic
      axis. Accordingly, growth hormone (GH) secretion, circulating insulin-like growth
      factor I (IGF-I) and IGF binding proteins (IGFBPs) in response to cyclosporin A
      (CsA) treatment were examined in adult male Wistar rats. Cyclosporine
      administration (5, 10 or 20 mg/Kg daily) over 8 days did not modify the body
      weight, but it did decrease serum concentration of corticosterone and increased
      serum IGF-I and GH levels. Rats treated with 5 and 10 mg/Kg of cyclosporine had
      similar levels of serum IGFBPs to control rats, but there was an increase in
      circulating IGFBP-3 and IGFPB-1,2 in the group treated with 20 mg/Kg of CsA. The
      increase in circulating GH correlates with a decrease in pituitary GH content in
      CsA treated rats, with no modification in hypothalamic somatostatin content,
      suggesting an increase in pituitary GH release. In order to test this hypothesis,
      anterior pituitary cell cultures were exposed to different CsA concentrations
      during a 4 h incubation period. Cyclosporine increased GH secretion in cultured
      pituitary cells (p<0.05). These data suggest that cyclosporine increases
      circulating IGF-I and GH by stimulating pituitary GH release.

PMID- 10353611
TI  - INK4 cell cycle inhibitors direct transcriptional inactivation of NF-kappaB.
AB  - The nuclear factor kappaB, a transcription factor regulating the expression of
      multiple genes including genes essential for cell cycle control, is found in most
      cells in a dormant state in the cytoplasm bound to the inhibitory family I kappaB
      via an ankyrin repeat domain. Stimulation of cells with a variety of inducers
      inactivates I kappaB proteins. The active dimeric NF-kappaB complex, often
      composed of 50- and 65-kilodalton subunits of the Rel family, translocates into
      the nucleus, where the NF-kappaBp65 subunit stimulates transcription. Here we
      report that a family of proteins containing ankyrin repeats, the inhibitors of
      Cdk4 (INK4) is able to bind NF-kappaBp65. The association of p16INK4 with NF
      kappaBp65 is considerable in HeLa- or 293 cells, if the NF-kappaB inhibitor I
      kappaB alpha is degraded in response to TNFalpha stimulation. Overexpression of
      INK4 molecules suppresses the transactivational ability of NF-kappaB
      significantly. In contrast to INK4 proteins, the cell cycle inhibitor p27
      enhances NF-kappaB transactivation activity. Thus, the effect of INK4 proteins on
      NF-kappaB function possibly modifies NF-kappaB mediated transcriptional
      activation of cell cycle associated factors.

PMID- 10353613
TI  - Systemic effects of ingested nickel on the immune system of nickel sensitised
      women.
AB  - This study evaluates the immune response to ingestion of 10 mg of nickel (Ni) (as
      Ni sulphate) in 19 young non-atopic Ni-sensitised or 9 non-allergic women (group
      A). After Ni ingestion at 8 a.m, non-allergic and 12 Ni-sensitised women (group
      B) were non-symptomatic, while 7 Ni-sensitised women (group C) showed a flare up
      of urticaria and/or eczema. Serum and urine Ni were greatly lower before Ni
      administration than after 4 and 24 hours, without difference among the 3 groups.
      Before treatment, group B and C showed higher values of blood CD19+ and CD5-
      CD19+ cells than group A, while group C showed higher serum interleukin (IL) 2
      and lower serum IL-5. Four hours after Ni ingestion, group C showed significant
      increase in serum IL-5. Twenty-four hours after treatment, group A showed a
      significant reduction in blood CD4+-CD45RO- "virgin" cells and an increase of
      CD8+ lymphocytes, while group C showed a marked decrease in total blood
      lymphocytes and CD3+, CD4+-CD45RO-, CD4+-CD45RO+, CD8+, CD19+ and CD5--CD19+ cell
      subsets. These data may be explained with migration of lymphocytes in tissues
      with a Th0-like immune response, as shown by the elevated serum IL-2 and the
      increase of serum IL-5 during the test.

PMID- 10353614
TI  - Capacitative Ca2+ entry involves Ca2+ influx factor in rat glioma C6 cells.
AB  - Capacitative Ca2+ entry exists in rat glioma C6 cells; however, how the
      information of depletion of Ca2+ in intracellular stores transmits to the plasma
      membrane is unknown. In the present study, we examined whether Ca2+ influx factor
      (CIF) causes capacitative Ca2+ entry in C6 cells. CIF was extracted from non
      treated (Non-CIF), bombesin-treated (BBS-CIF) and thapsigargin-treated (TG-CIF)
      C6 cells by a reverse-phase silica cartridge. The addition of BBS-CIF and TG-CIF
      gradually increased cytoplasmic Ca2+ concentration ([Ca2+]i) but Non-CIF did not
      increase [Ca2+]i. Neither BBS-CIF nor TG-CIF elevated [Ca2+]i in the absence of
      extracellular Ca2+. Gd3+ inhibited the increase in [Ca2+]i induced by BBS-CIF and
      TG-CIF. Genistein abolished an elevation of [Ca2+]i induced by BBS-CIF and TG
      CIF. BBS-CIF and TG-CIF did not increase inositol 1,4,5-trisphosphate
      accumulation. The results suggest that capacitative Ca2+ entry is caused by CIF
      in rat glioma C6 cells.

PMID- 10353615
TI  - Characterization of mineralocorticoid and glucocorticoid receptors in pigs:
      comparison of Meishan and Large White breeds.
AB  - Corticosteroids receptors were characterized and compared in central and
      peripheral tissues of two pig breeds, the Meishan (MS) and the Large White (LW)
      pigs, that display differences in the basal activity and stress-induced
      reactivity of the hypothalamic-pituitary-adrenal (HPA) axis. In vitro kinetic
      experiments on kidney and liver cytosols from adrenalectomized pigs allowed to
      identify two distinct corticosteroid receptors referred to as mineralocorticoid
      (MR) and glucocorticoid (GR) receptors. The binding specificities were determined
      for kidney and hippocampal MR and for liver and hippocampal GR. In hippocampus
      and peripheral tissues, cortisol showed a greater affinity for MR than for GR. As
      already described in the dog, mouse and human, dexamethasone and progesterone
      display a moderate affinity for MR. Putative differences in corticosteroid
      receptors binding capacities and affinities were investigated by saturation
      binding studies in specific regions implicated in the regulation of HPA axis
      (hippocampus and pituitary). The MS pigs evidenced higher densities of
      hippocampal MR, while LW pigs had higher densities of pituitary GR. Thus, this
      study suggests that a difference in the MR/GR balance in hippocampus and
      pituitary could be implicated in the different HPA activity between MS and LW
      pigs.

PMID- 10353616
TI  - Moderate red wine consumption protects the rat against oxidation in vivo.
AB  - The effect of the moderate consumption of red wine on the antioxidant system in
      rat liver, kidney and plasma has been evaluated. Wistar rats were treated in
      separate groups as follows: control; red wine for 45 days or 6 months; and 13.5%
      ethanol for 45 days or 6 months. The consumption of alcoholic beverages was free
      because the rat could always choose between the alcoholic beverage and the water.
      In liver, red wine ingestion resulted in higher hepatic superoxide dismutase and
      glutathione peroxidase activities after 45 days of treatment. The data indicate
      that wine and ethanol ingestion resulted in lower hepatic malondialdehyde and
      enhanced hepatic catalase activity in both of the periods studied. In kidney, the
      reduced glutathione/oxidized glutathione ratio was higher after 45 days of wine
      consumption, and the malondialdehyde was lower after 6 months of wine
      consumption. In plasma, malondialdehyde was lower after 6 months of both
      treatments, but plasmatic vitamin E was higher after red wine consumption while
      it was lower after ethanol consumption for this period of time. The present study
      shows that the moderate and prolonged consumption of red wine is consistent with
      higher protection against oxidation in vivo.

PMID- 10353617
TI  - In vivo amifostine (WR-2721) prevents chemotherapy-induced apoptosis of
      peripheral blood lymphocytes from cancer patients.
AB  - Aim of this work was to evaluate whether in vivo amifostine (WR-2721,
      ethanethiol, 2-[(3-aminopropyl)amino]-,dihydrogen phosphate (ester), Ethyol)
      pretreatment was able to prevent the apoptosis of peripheral blood lymphocytes
      (PBLs) induced by cytotoxic drugs. The study included 19 patients with advanced
      gynaecological cancers who received neoadjuvant polychemotherapy consisting of
      three cycles of cysplatin, adriamycin, and cyclophosphamide. Five patients
      received randomly amifostine pretreatment (910 mg/m2). PBLs apoptosis was
      measured through flow-cytometry using two different methods: a) DNA fragmentation
      of PBLs cultured in vitro for one hour; b) measurement of early apoptotic cells
      through Apostain uptake by fresh PBLs. The percentage of apoptotic PBLs was
      increased in all patients 24 hr after the first chemotherapy cycle (27.1 +/- 15.6
      vs 6.3 +/- 6.2, p<.0001). A similar increase was observed in the following
      chemotherapy cycle. Amifostine pretreatment prevented the apoptosis of PBLs
      induced by chemotherapeutic drugs. Amifostine also prevented the reduction of
      lymphocyte number determined by chemotherapy. The results demonstrate that
      amifostine protects peripheral lymphocytes from the apoptotic damage induced by
      chemotherapy. This effect may explain the mechanism by which amifostine prevents
      the chemotherapy-associated reduction of leukocyte number.

PMID- 10353619
TI  - Synthesis and bioactivity of fatty acid-conjugated GnRH derivatives.
AB  - Transdermal delivery of peptidic drugs is usually inefficient, notably due to
      their hydrophilic character which makes it difficult to cross the hydrophobic
      layers of the skin. In order to obtain transdermally deliverable analogs of
      gonadotropin releasing hormone (GnRH), we have synthesized related hydrophobic
      derivatives by attaching various aliphatic acids to the N(epsilon)-amino side
      chain of [D-Lys]6GnRH, a superactive GnRH agonist. It was found that the affinity
      toward the GnRH receptor gradually decrease with increased hydrophobicity, i.e.
      increase in chain length of the attached aliphatic acid. Nevertheless, analogs
      with 12-carbon or shorter aliphatic acids were shown to be GnRH superagonists,
      with in vitro and in vivo potencies similar to that of [D-Lys]6GnRH. [D-Lys
      lauryl]6GnRH was shown to have a longer duration of action in vivo, as compared
      to [D-Lys]6GnRH. The transdermal penetration of the peptides was evaluated by in
      vivo functional experiments in rats. According to these studies the efficiency of
      penetration is gradually lowered in increasingly hydrophobic analogs. These
      results are discussed with respect to the circular dichroism spectra of the
      peptides in trifluoroethanol. The spectra of the aliphatic acid-conjugated
      superagonists examined do not express a significant tendency towards a beta-turn
      conformation, typical of GnRH and its agonists. This finding contradict previous
      publications which suggested a correlation between the conformations of GnRH
      analogs in trifluoroethanol and their biological activities.

PMID- 10353618
TI  - Cardiac atrial natriuretic peptide (ANP) in rat dams and fetuses developed in
      space (NIH-R1 and NIH-R2 experiments).
AB  - NIH-R1 and R2 missions, conducted by NASA, allowed us to study the effects of the
      microgravitational environment 1) on cardiac ANP in pregnant rats, spaceflown for
      11 days and dissected after a 2-day readaptation to Earth's gravity, after
      natural delivery, and 2) on maturation of cardiac ANP system in rat fetuses
      developed for 11 days in space and dissected on the day of landing, 2 days before
      birth. Immunocytochemical and electron microscopy analyses showed a typical
      formation of ANP-containing granules in atrial myocytes, in both dams and
      fetuses. Using competitive RT-PCR and radioimmunoassays, we observed that, after
      2 days of readaptation to Earth's gravity, cardiac ANP biosynthesis of rat dams
      flown in space was increased by about twice, when compared to Synchronous and
      Vivarium Control rats. More obviously, rat fetuses developed in space and
      dissected on the day of landing displayed an altered maturation of cardiac ANP,
      evidenced by an increased mRNA biosynthesis (by about 6 fold, p<0.05), whereas
      the cardiac ANP storage was slightly reduced (by about twice, p<0.05) in both
      Flight and Synchronous Control groups, in comparison with Vivarium Control rats.
      These last results suggest that ANP metabolism during development is impacted by
      the microgravitational environment, but also by the housing conditions designed
      for space flight.

PMID- 10353620
TI  - Intraseptal injection of scopolamine increases the effect of systemic diazepam on
      passive avoidance learning and emotionality in rats.
AB  - This experiment was designed to assess the role of the septo-hippocampal
      cholinergic (ACh) system in the deleterious effects produced by systemic
      benzodiazepine injection on learning processes in rats. Retention of a step
      through passive avoidance task was analysed after systemic injection of
      increasing doses of either scopolamine or diazepam applied alone 30 min before
      the acquisition phase. Results indicated a dose related impairment of retention
      by each drug: in addition, sub-threshold doses of scopolamine and diazepam
      applied in combination (diazepam: 2mg/kg plus scopolamine: 0.3mg/kg) produced a
      decrease of retention latencies, thus showing an additive effect of the combined
      treatment. Secondly, a sub-threshold dose of scopolamine (15microg/0.5microl) was
      also administered into the medial septal area, together with an i.p. injection of
      2mg/kg of diazepam. This combined treatment produced a severe impairment of
      retention, in parallel with a large reduction in emotionality (number of faeces).
      The data are consistent with the hypothesis that peripheral administration of
      behaviorally effective doses of diazepam on passive avoidance learning might act
      partially via a septal ACh-GABA/benzodiazepine mechanism. It is also suggested
      that this mechanism subserves both anxiety and the memorisation of contextual
      stimuli associated with passive avoidance acquisition, through the modification
      of the septo-hippocampal activity.

PMID- 10353622
TI  - In vitro and in vivo alterations of enzymatic glycosylation in diabetes.
AB  - Carbohydrate composition changes of glycoconjugates constituting the glycocalix
      of microvascular cells could be involved in the alterations of cell-cell
      interactions observed in diabetic retinopathy. In this field, we have recently
      reported that advanced glycation end products (AGEs) modify galactose, fucose and
      sialic acid contents of specific cellular glycoproteins. To better understand the
      mechanisms involved in glycoprotein modifications in diabetes, we now investigate
      whether glucose and AGEs could affect the activities of enzymes involved in
      galactose, fucose and sialic acid metabolism : glycosyltransferases (synthesis)
      and glycosidases (catabolism). For this, bovine retinal endothelial cells (BREC)
      and pericytes (BRP) were cultured in the presence of high glucose concentration
      or AGEs, and cell glycosidase and glycosyltransferase activities were measured.
      The same enzymatic activities were studied in the whole retina from
      streptozotocin-treated rats. The results show that high glucose concentration did
      not affect glycosidases and glycosyltransferases neither in BRP nor in BREC
      except for galactosyltransferase activities in BREC. Concerning BRP, only
      galactosyltransferase activities were altered by AGEs. In contrast, in BREC, AGEs
      increased beta-D galactosidase, alpha-L fucosidase and neuraminidase activities
      (+37%, +56%, 36% respectively) whereas galactosyltransferase, fucosyltransferase
      and sialyltransferase activities were decreased (-11%, -24% and -23%
      respectively). In the retina from diabetic rats, beta-D galactosidase, alpha-L
      fucosidase and neuraminidase activities increased (+70%, +57%, +78% respectively)
      whereas fucosyl and sialyltransferase decreased (-7% and -15% respectively). The
      possible consequence of these enzymatic activity changes could be a defect in the
      carbohydrate content of some glycoproteins that might participate in the
      endothelial cell dysfunctions in diabetic microangiopathy.

PMID- 10353621
TI  - Immunological responses to ultraviolet light B radiation in Black individuals.
AB  - Immunological factors are important participants in the pathogenesis of
      experimental skin tumors. We therefore studied cutaneous immune responses in
      subjects with either low natural incidence (Black individuals), or a high
      frequency rate (White individuals) of skin cancer. We performed whole body
      irradiation with a low dose of ultraviolet light B (UV-B) and evaluated
      peripheral lymphocytes. UV-B irradiation was associated with small but
      significant changes in lymphocyte phenotype frequency. In White subjects this
      consisted of an increased number of CD19 (B cells) and CD 4/29 (inducer of helper
      T cells); Black subjects had a slight decrease in CD3 (T cells). Natural killer
      activity, not affected by UV-B in White subjects, increased significantly in
      Black subjects. UV-B was devoid of immunological effects in vitro for any of the
      parameters tested. As expected, the low UV-B dose used in this study induced
      increases of serum vitamin D3 concentrations in White subjects, with lack of
      response in the Black subjects. We conclude that Black individuals selectively
      exhibit an increase in Natural Killer activity in response to irradiation with
      low dose UV-B. This race group-specific immune response to ultraviolet radiation
      appears to require mediation by the skin. Enhanced Natural Killer activity could
      underlie at least partly the resistance in Black individuals to the development
      of photodependent skin cancer.

PMID- 10353623
TI  - Modulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase activities
      by steroids and physiological conditions in hamster.
AB  - Our purpose was to examine the in vitro modulation of liver mitochondrial sterol
      27-hydroxylase (S27OHase) and microsomal cholesterol 7alpha-hydroxylase
      (CH7alphaOHase) activities by certain drugs, sterols, oxysterols and bile acids,
      and to compare the influence of sex, age, diet and cholestyramine on these
      activities, in the hamster. In vitro, 7beta-hydroxycholesterol and 5alpha
      cholestan-3beta-ol (cholestanol) were strong inhibitors (at 2 microM) of both
      enzyme activities, while 5beta-cholestan-3alpha-ol (epicoprostanol, 2 microM) and
      cyclosporin A (20 microM) inhibited S27OHase, but not CH7alphaOHase. These data
      suggest that a hydroxyl group at the 7alpha position is not required to inhibit
      CH7alphaOHase and that the presence of an aliphatic CH2-CH-(CH3)2 chain appears
      to be structurally important for S27OHase activity. Both enzyme activities
      remained unchanged by hyodeoxycholic acid (40 or 80 microM) while epicoprostanol
      inhibited only S27OHase and chenodeoxycholic acid only CH7alphaOHase. Adult (9
      week old) male or female hamsters displayed similar S27OHase activity but the
      CH7alphaOHase activity was lower in females than in males, suggesting that the
      neutral bile acid pathway has a less important role in females. In male hamsters,
      S27OHase activity did not change with age, while CH7alphaOHase activity
      significantly increased (one-year vs 9-week old). A semi-purified sucrose-rich
      (lithogenic) diet significantly lowered both enzyme activities compared to the
      commercial diet. Cholestyramine induced a stimulation of both enzymes, slightly
      more vigorously however for the key enzyme involved in the neutral pathway. Taken
      together, these data indicate that the two enzymes are separately regulated and
      that certain drugs or steroid compounds can be useful for specifically inhibiting
      or stimulating the neutral or acidic bile acid pathway.

PMID- 10353624
TI  - Dynamics of structure-function relationships in interphase nuclei.
AB  - The interphase nucleus is a topologically ordered, three-dimensional structure.
      While it remains unclear whether this structural organization also represents
      compartmentalization of function, the presence of the latter would likely be
      reflected in the spatial coupling of molecular factors involved in related
      events. This review summarizes morphological evidence, derived from in situ
      experiments, which indicates the existence of compartmentalization of both
      chromatin and non-chromatin components in the interphase nucleus. Moreover, the
      review addresses the spatial relationships of these components relative to each
      other and correlates these spatial relationships with such nuclear functions as
      transcription, splicing and nucleo-cytoplasmic transport of pre-mRNA. Given that
      it is increasingly recognized that such spatial relationships are dynamic, the
      review also addresses the emerging concept that the spatial intranuclear
      organization changes with changes in cell function, a concept which supports the
      hypothesis that the spatial organization of the interphase nucleus may represent
      one of the fundamental control mechanisms in gene expression.

PMID- 10353625
TI  - Tetracycline-controlled expression but not toxicity of an attenuated diphtheria
      toxin mutant.
AB  - Tight transcriptional regulation of transferred bacterial toxin genes represents
      a potential approach for gene therapy of cancer. We have previously shown that
      the gene for wild type diphtheria toxin A chain (DT-A) placed under
      transcriptional control of a tetracycline-responsive promoter cannot be silenced
      due to its extreme toxicity. We now have explored a tetracycline-regulated DT-A
      mutant involving the histidine-21 catalytic domain (H21A) which shows 120-fold
      reduced ADP-ribosylation activity. Cellular toxicity was determined in NIH 3T3
      fibroblasts and C6 glioma cells after triple transfections with the DT-A
      construct, the Tet transactivator gene and a luciferase plasmid as the reporter.
      Marked toxicity, i.e. reduced luciferase expression by more than 98%, was
      observed both in the absence and in the presence of tetracycline, suggesting
      leakiness of the Tet system, and absence of regulation, possibly due to
      inhibition of DT-A synthesis by activated DT-A itself. In contrast, the lacZ gene
      which was driven by the same promoter could be regulated by up to 49-fold. We
      conclude that (1) expression but not toxicity of the DT-A mutant can be
      sufficiently controlled by a tetracycline-responsive promoter, and (2) tight
      regulation of transferred genes encoding toxins remains a challenge for gene
      therapy of cancer.

PMID- 10353626
TI  - Analgesic responses to intrathecal morphine in relation to CSF concentrations of
      morphine-3,beta-glucuronide and morphine-6,beta-glucuronide.
AB  - This study was performed to determine whether variations in analgesic responses
      to intrathecal morphine could be explained by cerebrospinal fluid (CSF)
      concentrations of morphine metabolites. Twenty-four CSF samples were collected at
      the beginning, middle and end of treatment periods in seven cancer patients with
      pain of malignant origin. CSF concentrations of morphine-3,beta-glucuronide (M3G)
      and morphine-6,beta-glucuronide (M6G) metabolites were measured by gas
      chromatography/mass spectrometry. Analgesic responses to morphine were estimated
      concurrent with CSF collection using a visual analog scale representing
      percentages of pain relief. Effective analgesia was defined as > or = 75% pain
      relief. CSF concentration of M3G and M6G in the 24 samples were 722 +/- 116 ng/ml
      and 699 +/- 158 ng/ml, respectively. CSF samples were categorized into two
      groups: (1) those collected during effective analgesia (N=14), and (2) those
      collected during ineffective analgesia (N=10). M6G levels detected in group 1
      samples (effective analgesia) were significantly greater than those found in
      group 2 samples (ineffective analgesia) (978 +/- 243 ng/ml vs 309 +/- 68 ng/ml,
      P<0.05). Intergroup differences in CSF M3G concentrations and M3G/M6G ratios were
      not significant. It is concluded that CSF M6G may be indicative of effectiveness
      of analgesia in cancer patients subjected to intrathecal morphine.

PMID- 10353627
TI  - Significantly improved oral uptake of amikacin in FVB mice in the presence of CRL
      1605 copolymer.
AB  - Amikacin is an aminoglycoside which is used in the treatment of infection from
      gram negative bacteria. Amikacin is also used synergistically with penicillin
      against gram positive cocci. Amikacin cannot be delivered orally probably due to
      efflux of drug by P-glycoprotein pump in the brush border of intestine. We
      studied the possibility of delivering amikacin orally in mice using a copolymer
      (CRL-1605) as a vehicle. This copolymer inhibits P-glycoprotein pump. Two
      different doses of amikacin were used (500 mg/kg and 100 mg/kg). The
      concentration of polymer used was 132 mg/kg. The liquid formulation was fed to
      mice by gavage and serum amikacin concentrations were estimated after one hour
      and two hours using fluorescence polarization immunoassay. We observed a two fold
      increase in serum amikacin concentration when amikacin was orally delivered in
      the presence of CRL-1605 compared to controls (amikacin alone). We conclude that
      gastrointestinal absorption of amikacin is significantly increased in the
      presence of CRL-1605 in mice.

PMID- 10353628
TI  - Early alterations of polyamine metabolism induced after acute administration of
      clenbuterol in mouse heart.
AB  - An acute treatment of mice with clenbuterol, a beta-adrenergic agonist, produced
      a marked increase of polyamines levels in heart, particularly during the early
      phase of administration of the drug. A single dose of 1.5 mg/kg caused as much as
      a 10 fold induction in activity of ornithine decarboxylase (ODC) and 3 to 4 fold
      increase in levels of putrescine, spermidine and spermine in mouse heart. Maximum
      changes were observed 3 to 4 hours post-administration of clenbuterol. This
      treatment did not produce any change in S-adenosylmethionine decarboxylase
      activity. The induction of cardiac ODC by clenbuterol was also dose dependent
      with a peak at about 5 micromol/kg. Co-administration of difluoromethylornithine,
      an irreversible inhibitor of ODC, or propranolol, a nonspecific beta-antagonist,
      with clenbuterol completely prevented the induction of ODC activity as well as
      the increase in polyamine levels in heart. However, pretreatment with alprenolol
      or metoprolol, the specific beta1 and beta2-antagonists, respectively, produced
      only partial prevention. The cardiac ODC from controls as well as clenbuterol
      treated mice exhibited similar affinity (Km) for its substrate, ornithine, while
      maximum enzyme activity (Vmax) was about 14 fold higher in clenbuterol treated
      mouse heart than in the control. Clenbuterol produced no change in the level of
      specific ODC mRNA or the protein, but the enzyme from the drug-treated mouse
      heart was considerably more stable than the control. Pretreatment of mice with
      either cycloheximide or actinomycin D followed by administration of clenbuterol
      could not prevent the induction in ODC activity suggesting that de novo
      biosynthesis of the enzyme protein or ODC mRNA was not responsible for induction
      of ODC activity. Post-translational changes in ODC may be responsible for an
      early increase of ODC activity due to clenbuterol treatment.

PMID- 10353629
TI  - Increased nitric oxide synthase expression in aorta of cirrhotic rats.
AB  - The characteristic cardiovascular changes in liver cirrhosis are vasodilatation
      and increased cardiac output. Augmented activity of the vasorelaxant factor,
      nitric oxide (NO), stimulated by cytokines, have been suggested to play a role in
      the pathogenesis, but previous studies show conflicting results. We therefore
      aimed to evaluate the entire pathway from cytokines to the final metabolites,
      nitrate/nitrite. The levels of serum Tumor Necrosis Factor-alpha (TNFalpha) and
      nitrate/nitrite (NOx) were measured, and aorta content of inducible (iNOS) and
      endothelial nitric oxide synthase (eNOS) mRNA and protein were determined by
      reverse-transcription polymerase chain reaction and Western blotting in rats with
      cirrhosis due to chronic bile duct ligation and sham-operated controls. Compared
      to control rats, serum TNFalpha levels were significantly elevated in cirrhotic
      rats (48.4+/-21.1 vs 16.8+/-9.0 pg/ml, p<0.01); iNOS mRNA was detectable whereas
      it was absent in controls, and eNOS mRNA levels was significantly higher in
      aortae of cirrhotic rats. Aortic eNOS protein content was significantly higher in
      cirrhotic rats, but iNOS protein was undetectable by Western blotting in both
      groups. Serum NOx concentrations in the cirrhotic group were significantly higher
      than those in controls (3.5+/-1.0 vs 2.3+/-0.5 microM, p<0.01). These results
      suggest that NO activity in cirrhosis is increased, and is predominantly due to
      eNOS since the detectable iNOS mRNA does not seem to be expressed as protein. The
      increased NOS activity in the arterial system may play a role in the systemic
      hemodynamic changes occurring in cirrhosis.

PMID- 10353630
TI  - The binding of [3H]AF-DX 384 is reduced in the caudate-putamen of subjects with
      schizophrenia.
AB  - Clinical studies of cholinergic pharmacotherapy, together with the putative role
      of the muscarinic receptor system in the neurophysiology of human behavior,
      support a possible muscarinic cholinergic involvement in schizophrenia. The
      present study has measured the density of [3H]AF-DX 384 labelled receptors
      (muscarinic M2 and M4) in the caudate-putamen, obtained at autopsy, from 19
      subjects who had schizophrenia, and 20 subjects who did not have schizophrenia.
      [3H]AF-DX 384 binding was reduced in caudate-putamen from schizophrenic subjects
      (104 +/- 10.3 vs 145 +/- 901 fmol mg(-1) TE; mean +/- s.e.; p = 0.007).
      Preliminary analysis of patient drug data as well as rat studies suggest that the
      reduced [3H]AF-DX 384 binding in caudate-putamen of schizophrenic subjects is not
      wholly due to antipsychotic drug treatment, or anticholinergic medication for the
      treatment of extrapyramidal effects. These data suggest that the muscarinic
      cholinergic system may be involved in the pathology of schizophrenia.

PMID- 10353631
TI  - Antibodies against neurofilament subunits label retinal ganglion cells but not
      displaced amacrine cells of hamsters.
AB  - Although neurofilament (NF) antibodies have been used to visualize ganglion cells
      and their axons in the retina, it is not known, however, how many ganglion cells
      contain NF, and how the various NF subunits are distributed in the ganglion
      cells. Moreover, it is not known whether displaced amacrine cells in the ganglion
      cell layer are also labelled. In order to see whether NF antibodies can be used
      as a specific marker for ganglion cells, antibodies raised against the low (NF
      L), middle (NF-M) and high (NF-H) molecular weight subunits of NF were employed
      to stain retinal whole-mounts of adult hamsters after pre-labelling the ganglion
      cells with Granular Blue. It was found that NF-L and NF-H antibodies labelled
      38,777 and 17,750 cells in the ganglion cell layer respectively. By co
      localization with GB-labelled cells, 88% of NF-L positive cells and 91% of NF-H
      positive cells were found to be ganglion cells. In contrast, the NF-M antibody
      labelled only very few ganglion cells (418 per retina) although robust staining
      of axonal bundles was observed. Thus, NF antibodies may prove useful in studying
      this population of ganglion cells.

PMID- 10353632
TI  - Involvement of diazepam binding inhibitor and its fragment octadecaneuropeptide
      in social isolation stress-induced decrease in pentobarbital sleep in mice.
AB  - Diazepam binding inhibitor (DBI) and its fragment, octadecaneuropeptide (ODN),
      are putative endogenous ligands for benzodiazepine (BZD) receptors and have been
      shown to act as an inverse BZD receptor agonist in the brain. A previous study
      suggested that the social isolation stress-induced decrease in pentobarbital
      sleep in mice was partly due to endogenous substances with an inverse BZD
      receptor agonist-like property. In this study, we examined the effects of DBI and
      ODN on pentobarbital sleep in group-housed and socially isolated mice to test the
      possible involvement of DBI and ODN in a social isolation-induced decrease in
      pentobarbital sleep. The socially isolated mice showed significantly shorter
      durations of pentobarbital (50 mg/kg, intraperitoneally, i. p.) sleep compared to
      the group-housed animals. When injected intracerebroventricularly (i.c.v.), DBI
      and ODN (3 and 10 nmol) dose-dependently shortened the pentobarbital-induced
      sleeping time in group-housed mice at the same dose range, but these peptides had
      no effect on the sleeping time in socially isolated animals. In contrast,
      flumazenil (16.5-33 nmol, i.c.v.), a BZD receptor antagonist, reversed the
      pentobarbital sleeping time in socially isolated mice to the level of group
      housed animals without affecting the sleeping time in group-housed animals. The
      effects of DBI and ODN in group-housed mice were significantly blocked by
      flumazenil (33 nmol, i.c.v.). Moreover, the effect of flumazenil in socially
      isolated mice was significantly attenuated by DBI and ODN (10 nmol, i.c.v.).
      These results suggest that the changes in the activity of DBI and/or ODN are
      partly involved in the social isolation-induced decrease in the hypnotic action
      of pentobarbital in mice.

PMID- 10353634
TI  - Aortic endothelial cells damaged by a nitric oxide donor and protected by
      flavonoids.
AB  - Cultured porcine aortic endothelial cells (PAEC) were exposed to four
      concentrations (0.00 mM - 5.00 mM) of 3-Morpholino-sydnonimine-hydrochloride (SIN
      1, a nitric oxide donor). SIN-1 demonstrated a dose dependent cytotoxicity
      against PAEC as indicated by the thiobarbituric acid (TBA) assay. Morphologically
      and biochemically, the presence of selected flavonoids (morin, quercetin, or
      catechin) was shown to protect the PAEC from SIN-1 toxicity. Protection levels
      determined from the TBA assay were significant (p<0.05) for all flavonoids, with
      morin at 72+/-8%. Quercetin and catechin had comparable protective activities of
      54+/-6% and 43+/-3%, respectively. This study supports the contention that SIN-1
      is cytotoxic to PAEC and that antioxidants such as flavonoids may attenuate such
      toxicity.

PMID- 10353633
TI  - Human livers with cirrhosis and hepatocellular carcinoma have less mitochondrial
      DNA deletion than normal human livers.
AB  - We measured the populations of mutated mitochondrial DNAs with the 7,436 bp or
      the 4,977 bp deletion from apparently normal human liver and human livers with
      chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The amount of the
      mutated mitochondrial DNA was at the same level between normal and chronically
      hepatitic livers but was significantly lower in human livers with cirrhosis and
      hepatocellular carcinoma, especially the latter, suggesting that the mutated
      mitochondrial DNAs may be decreased with the progress of liver disease from
      chronic hepatitis to cirrhosis and hepatocellular carcinoma. This phenomenon is
      opposite to that occuring in the ageing process.

PMID- 10353635
TI  - Inhibition of human sPLA2 and 5-lipoxygenase activities by two neo-clerodane
      diterpenoids.
AB  - The inhibitory effect of two neo-clerodane diterpenoids, E-isolinaridial (EI) and
      its methylketone derivative (EIM), isolated from Linaria saxatilis var.
      glutinosa, on PLA2 and other enzyme activities involved in the inflammatory
      process was studied. Both compounds inhibited human synovial sPLA2 in a
      concentration-dependent manner with IC50 values of 0.20 and 0.49 microM,
      respectively, similar to scalaradial. Besides, these compounds decreased the cell
      free 5-lipoxygenase activity and A23187-induced neutrophil LTB4 biosynthesis.
      Another function of human neutrophils, such as receptor-mediated degranulation,
      was also significantly reduced. In contrast, none of the compounds affected
      superoxide generation in leukocytes, or cyclooxygenase-1, cyclooxygenase-2 and
      inducible nitric oxide synthase activities in cell-free assays.

PMID- 10353636
TI  - Cyclopropenone-containing cysteine proteinase inhibitors. Synthesis and enzyme
      inhibitory activities.
AB  - By focusing on the amphiphilic properties of cyclopropenone (e.g. a good
      electrophile and a precursor for a stable 2pi-aromatic hydroxycyclopropenium
      cation), a new class of cysteine proteinase inhibitors containing a
      cyclopropenone moiety was designed. For the purpose of the present research, we
      needed to devise a new method to introduce a peptide-related moiety as a
      substituent on the cyclopropenone residue. We investigated the reaction of
      metalated cyclopropenone acetal derivatives (2, R2 = metal) with N-protected
      alpha-aminoaldehydes 4 to obtain the adduct 5, and succeeded in the preparation
      of highly potentiated cysteine proteinase inhibitors 8 after several steps
      transformations. They showed strong inhibitory activities only to cysteine
      proteinases such as calpain, papain, cathepsin B, and cathepsin L and not to
      serine (e.g. thrombin and cathepsin G) and aspartic proteinases (e.g. cathepsin
      D). Kinetic studies indicated that they are competitive inhibitors, and by the
      examinations of their inhibitory mechanism it became clear that they are
      reversible inhibitors.

PMID- 10353637
TI  - Potent dipeptidylketone inhibitors of the cysteine protease cathepsin K.
AB  - Cathepsin K (EC 3.4.22.38) is a cysteine protease of the papain superfamily which
      is selectively expressed within the osteoclast. Several lines of evidence have
      pointed to the fact that this protease may play an important role in the
      degradation of the bone matrix. Potent and selective inhibitors of cathepsin K
      could be important therapeutic agents for the control of excessive bone
      resorption. Recently a series of peptide aldehydes have been shown to be potent
      inhibitors of cathepsin K. In an effort to design more selective and
      metabolically stable inhibitors of cathepsin K, a series of electronically
      attenuated alkoxymethylketones and thiomethylketones inhibitors have been
      synthesized. The X-ray co-crystal structure of one of these analogues in complex
      with cathepsin K shows the inhibitor binding in the primed side of the enzyme
      active site with a covalent interaction between the active site cysteine 25 and
      the carbonyl carbon of the inhibitor.

PMID- 10353638
TI  - Solid-phase synthesis of irreversible human rhinovirus 3C protease inhibitors.
      Part 1: Optimization of tripeptides incorporating N-terminal amides.
AB  - The optimization of a series of irreversible human rhinovirus (HRV) 3C protease
      (3CP) inhibitors is described. These inhibitors are comprised of an L-Leu-L-Phe-L
      Gln tripeptide containing an N-terminal amide moiety and a C-terminal ethyl
      propenoate Michael acceptor. Examination of approximately 500 compounds with
      varying N-terminal amides utilizing solid-phase synthesis and high-throughput
      assay techniques is described along with the solution phase preparation of
      several highly active molecules. A tripeptide Michael acceptor containing an N
      terminal amide derived from 5-methylisoxazole-3-carboxylic acid is shown to
      exhibit potent, irreversible anti-3CP activity (k(obs)/[I] = 260,000 M(-1) s(-1);
      type-14 3CP) and broad-spectrum antirhinoviral properties (average EC50 = 0.47
      microM against four different HRV serotypes).

PMID- 10353639
TI  - Structure-based design of non-peptide, carbohydrazide-based cathepsin K
      inhibitors.
AB  - Using binding models which were based on the X-ray crystal structure of an amino
      acid-based active site-spanning inhibitor complexed with cathepsin K, Cbz-leucine
      mimics have been developed, leading ultimately to the design of a potent
      cathepsin K inhibitor free of amino acid components. These mimics, which consist
      of alpha-substituted biphenylacetyl groups in place of Cbz-leucine moieties,
      effectively mimic all aspects of the Cbz-leucine moieties which are important for
      inhibitor binding. The predicted directions of binding for the inhibitors were
      confirmed by mass spectral analysis of their complexes with cathepsin K, which
      gave results consistent with acylation of the enzyme and loss of the
      acylhydrazine portion of the inhibitor which binds on the S' side of the active
      site. The binding models were found to be very predictive of relative inhibitor
      potency as well as direction of inhibitor binding. These results strengthen the
      validity of a strategy involving iterative cycles of structure-based design and
      inhibitor synthesis and evaluation for the discovery of non-peptide inhibitors.

PMID- 10353640
TI  - Synthesis and testing of azaglutamine derivatives as inhibitors of hepatitis A
      virus (HAV) 3C proteinase.
AB  - Hepatitis A virus (HAV) 3C proteinase is a picornaviral cysteine proteinase that
      is essential for cleavage of the initially synthesized viral polyprotein
      precursor to mature fragments and is therefore required for viral replication in
      vivo. Since the enzyme generally recognizes peptide substrates with L-glutamine
      at the P1 site, four types of analogues having an azaglutamine residue were
      chemically synthesized: hydrazo-o-nitrophenylsulfenamides A (e.g. 16); frame
      shifted hydrazo-o-nitrophenylsulfenamides B (e.g. 25-28); the azaglutamine
      sulfonamides C (e.g. 7, 8, 11, 12); and haloacetyl azaglutamine analogues 2 and
      3. Testing of these compounds for inhibition of the HAV 3C proteinase employed a
      C24S mutant in which the non-essential surface cysteine was replaced with serine
      and which displays identical catalytic parameters to the wild-type enzyme.
      Sulfenamide 16 (type A) showed no significant inhibition. Sulfenamide 27 (type B)
      had an IC50 of ca 100 microM and gave time-dependent inactivation of the enzyme
      due to disulfide bond formation with the active site cysteine thiol, as
      demonstrated by electrospray mass spectrometry. Sulfonamide 8 (type C) was a weak
      competitive inhibitor with an IC50 of approximately 75 microM. The haloacetyl
      azaglutamine analogues 2 and 3 were time-dependent irreversible inactivators of
      HAV 3C proteinase with rate constants k(obs)/[I] of 680 M(-1) s(-1) and 870 M(-1)
      s(-1), respectively, and were shown to alkylate the active site thiol.

PMID- 10353641
TI  - A catalytic mechanism for caspase-1 and for bimodal inhibition of caspase-1 by
      activated aspartic ketones.
AB  - We have evaluated 619 aspartic ketones with 9 different types of prime-side
      groups (acyloxymethyl, aryloxymethyl, arylthiomethyl, alkylthiomethyl, acylamino
      oxymethyl, sulfonylaminomethyl, alpha-ketoamide, alpha-(1-phenyl-3
      trifluoromethyl-pyrazol-5-yl)oxymethyl (PTP), and aliphatic ketones) as
      inhibitors of caspase-1. The inhibitory behaviors could be classified as
      reversible, inactivating, or bimodal (i.e. reversible inhibition followed by slow
      inactivation) based on the kinetically observed formation of reversible
      thiohemiketal complexes and conversion to an irreversible thioether adduct, and
      the mechanism of any given ketone was only poorly predictable on the basis of
      leaving group structure and chemistry. Among 201 bimodal inhibitors, the rate of
      conversion of the reversible thiohemiketal complex to the inactive thioether
      (k(i)) was strictly first-order, consistent with direct conversion of the
      thiohemiketal to the thioether with no intermediate collapse to free ketone and
      thiolate. We have examined 22 crystallographic structures of caspase-1 complexed
      as a thiohemiketal with the inhibitors from 8 different ketone classes, and found
      the Cys285S-C-C(alpha)-leaving group dihedral angle to be near either to 60
      degrees or to 180 degrees. Only the 180 degrees conformation was permissive for
      SN2 displacement of the leaving group and, furthermore, positioned His237Ndelta
      to stabilize developing charge on the leaving group. Among these structures and
      19 additional complexes, all showed a strong interaction between His237Ndelta and
      the ketone or thiohemiketal oxygen. We therefore propose a proteolytic mechanism
      for caspase-1 involving polarization of the scissile carbonyl by the His237
      imidazolium group. During thiohemiketal/thioether conversion (but probably not
      during peptide hydrolysis), the leaving group is stabilized by the His237
      imidazolium.

PMID- 10353642
TI  - Antimalarial effects in mice of orally administered peptidyl cysteine protease
      inhibitors.
AB  - The Plasmodium falciparum cysteine protease falcipain is required for the
      degradation of hemoglobin by erythrocytic malaria parasites. In prior studies,
      peptidyl inhibitors of falcipain blocked hemoglobin degradation and development
      by cultured parasites and one of these compounds, when administered parenterally,
      cured Plasmodium vinckei-infected mice. We now report an evaluation of orally
      administered peptidyl inhibitors of falcipain in a mouse malaria model. In
      studies with a fluoromethyl ketone, orally administered morpholine urea
      phenylalanine-homophenylalanine-fluoromethyl ketone delayed the progression of
      murine malaria. In studies of a new series of vinyl sulfones, a set of related
      compounds demonstrated marked inhibition of falcipain and of parasite biological
      activities in vitro. One of these compounds, N-methyl piperazine urea-leucine
      homophenylalanine-2-naphthalene vinyl sulfone, cured about 40% of mice when
      administered orally twice-a-day for four days. Our results suggest that peptidyl
      inhibitors of falcipain have promise as antimalarial chemotherapeutic agents.

PMID- 10353644
TI  - The influence of cyclic loading on the wear of a dental composite.
AB  - The load applied to a tooth surface during mastication is not a constant force
      and the objective of the research reported in this paper was to evaluate the
      impact of variable masticatory loads on the mechanisms involved in the wear of a
      dental composite. A new wear testing machine has therefore been developed, which
      incorporates a sine cam mechanical system to generate an alternating sine curve
      load at the wear surfaces to simulate the loading produced by masticatory
      process. The basic wear pattern is generated by positioning a disc shaped
      specimen against a rotating cylindrical ring with a normal load applied to the
      upper surface of the specimen. This approach allows different combinations of
      static and sine curve loads to be applied, thereby facilitating the study of
      different wear situations. It was found that the wear behaviour associated with
      variable loading patterns differed from that of static loading.

PMID- 10353643
TI  - Cysteine protease inhibitors as chemotherapy for parasitic infections.
AB  - Analysis of the evolution, localization and biologic function of papain family
      cysteine proteases in metazoan and protozoan parasites has provided important and
      often surprising insights into the biochemistry and cellular function of this
      diverse enzyme family. Furthermore, the relative lack of redundancy of cysteine
      proteases in parasites compared to their mammalian hosts makes them attractive
      targets for the development of new antiparasitic chemotherapy. The treatment of
      experimental models of parasitic diseases with cysteine protease inhibitors has
      provided an important 'proof of concept' for the use of cysteine protease
      inhibitors in vivo. Evidence has now accumulated that cysteine protease
      inhibitors can selectively arrest replication of a microbial pathogen without
      untoward toxicity to the host. Furthermore, this can be achieved with reasonable
      dosing schedules and oral administration of the drug. Initial studies have
      confirmed the efficacy of cysteine protease inhibitors in treatment of
      Trypanosoma cruzi, Plasmodium falciparum and Leishmania major. Work on
      Trypanosoma brucei, the agent of African trypanosomiasis, is preliminary but also
      promising. Target validation studies have shown that biotinylated or radiolabeled
      irreversible inhibitors specifically bind to the cysteine protease targets
      thought to represent the major activity within the parasite. In the case of T.
      cruzi, the effect of inhibitors appears to be predominantly in blocking protease
      processing. Transfection studies using variant constructs have supported this
      model. Finally, the generation of null mutants for the multiple protease genes in
      Leishmania mexicana has provided the first genetic support for the key role of
      this enzyme family in parasite virulence. Safety studies in rodents and analysis
      of uptake of inhibitors by parasites and host cells suggest that the selectivity
      of inhibitors for the parasite targets may reside in the lack of redundancy of
      parasite proteases, the higher concentration of host proteases in intracellular
      compartments, and differential uptake of inhibitors by parasites. Attempts to
      elicit resistance to cysteine protease inhibitors in parasite cultures suggest
      that mechanisms of induced resistance are independent of resistance to the
      traditional antiparasitic agents. This suggests that cysteine protease inhibitors
      may provide an alternative to traditional therapy in drug-resistant organisms.

PMID- 10353645
TI  - Bonelike apatite coating on organic polymers: novel nucleation process using
      sodium silicate solution.
AB  - A bonelike apatite layer was formed on organic polymers when sodium silicate was
      used as a catalyst for the apatite nucleation, and modified simulated body fluid
      was used as a medium for the apatite growth. The apatite-forming ability was the
      highest when the SiO2 concentration and SiO2/Na2O mole ratio of the sodium
      silicate solution were above 2.0 M and 1.0-1.5, respectively. It is assumed that
      particular silicate oligomers with structures such as dimer, linear trimer and
      cyclic tetramer contribute to the apatite nucleation the most. The apatite layer
      was formed not only on limited surfaces but also on the whole surfaces of fine
      PET fibers constituting a fabric. This method is expected to enable the bonelike
      apatite coating on various kinds of materials with complex shapes.

PMID- 10353646
TI  - Successive epoxy and carbodiimide cross-linking of dermal sheep collagen.
AB  - Cross-linking of dermal sheep collagen (N-DSC, T(S) = 46 degrees C, number of
      amine groups = 31 (n/1000)) with 1,4-butanediol diglycidyl ether (BDDGE) at pH
      9.0 resulted in a material (BD90) with a high T(S)(69 degrees C), a decreased
      number of amine groups of 15 (n/1000) and a high resistance towards collagenase
      and pronase degradation. Reaction of DSC with BDDGE at pH 4.5 yielded a material
      (BD45) with a T(S) of 64 degrees C, hardly any reduction in amine groups and a
      lower stability towards enzymatic degradation as compared to BD90. The tensile
      strength of BD45 (9.2 MPa) was substantially improved as compared to N-DSC (2.4
      MPa), whereas the elongation at break was reduced from 210 to 140%. BD90 had a
      tensile strength of 2.6 MPa and an elongation at break of only 93%. To improve
      the resistance to enzymes and to retain the favorable tensile properties, BD45
      was post-treated with 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) in
      the presence of N-hydroxysuccinimide (NHS) to give BD45EN. Additional cross
      linking via the formation of amide bonds took place as indicated by the T(S) of
      81 degrees C and the residual number of amine groups of 19 (n/1000). BD45EN was
      stable during exposure to both collagenase and pronase solutions. The tensile
      properties (tensile strength 7.2 MPa, elongation at break 100%) were comparable
      to those of BD45 and glutaraldehyde treated controls (G-DSC). Acylation of the
      residual amine groups of BD45 with acetic acid N-hydroxysuccinimide ester (HAc
      NHS) yielded BD45HAc with a large reduction in amine groups to 10 (n/1000) and a
      small reduction in T(S) to 62 degrees C. The stability towards enzymatic
      degradation was reduced, but the tensile properties were comparable to BD45.

PMID- 10353647
TI  - Measurement and evaluation of galvanic corrosion between titanium/Ti6A14V
      implants and dental alloys by electrochemical techniques and auger spectrometry.
AB  - The purpose of this study was to investigate, in different experimental
      conditions, the galvanic corrosion phenomena which can exist between a dental
      suprastructure and a dental implant. The electrochemical behavior of 7 alloy
      superstructures with titanium and titanium alloy (Ti6A14V) implants was
      investigated by electrochemical means in Fusayama-Meyer de-aerated saliva and
      Carter-Brugirard (AFNOR) non de-aerated saliva. Different techniques were used to
      obtain the value of the galvanic coupling current and potential for each couple.
      All showed very low corrosion rates, ranging from 10(-6) to 10(-8) A. Surface
      analysis confirmed these results.

PMID- 10353648
TI  - PDMS-based polyurethanes with MPEG grafts: synthesis, characterization and
      platelet adhesion study.
AB  - Polyurethane (PU), based on poly(dimethyl siloxane) (PDMS) as a soft segment,
      with monomethoxy poly(ethylene glycol) (MPEG) grafted onto it, was synthesized as
      a new polymeric biomaterial for coating PDMS-based biomedical devices. Two
      different chain extenders, ethylene glycol (EG) and diethyl bis(hydroxymethyl)
      malonate (DBM), were used for the synthesis of PDMS-based PUs and then MPEG was
      grafted onto them by allophanate and esterification reactions, respectively.
      Their molecular structures were confirmed qualitatively and quantitatively using
      FT-IR and 1H-NMR measurements. PDMS-based PU was more hydrophobic than
      Pellethane, which is a commercial biomedical-grade poly(ether urethane), due to
      the PDMS-rich phase at the polymeric surface. However, the incorporation of MPEG
      in PDMS-based PU induced an increase in hydrophilicity. Analyses of their
      morphology using dynamic mechanical analysis and differential scanning
      calorimetry showed that the degree of phase separation increased with the content
      of hard segments. It also showed that MPEG is compatible with a hard segment
      consisting of 4,4'-diphenylmethane diisocyanate (MDI) and DBM, while being
      incompatible with one consisting of MDI and EG. Platelet adhesions with PDMS
      based PUs were significantly reduced when compared with Pellethane. It was also
      observed from a platelet adhesion experiment that the incorportion of MPEG
      further reduced platelet adhesion. PDMS-based PUs with MPEG grafts, which have
      few hard segments and a distinct PEG phase, exhibited the least platelet adhesion
      among the polymer samples tested.

PMID- 10353649
TI  - A novel textured surface for blood-contact.
AB  - Blood-contacting surface modifications aimed at reduction of thromboembolic
      complications have included the texturing of surfaces so as to promote the
      formation of a stable pseudo-neointima. A technique has been developed whereby a
      textured surface consisting of regularly spaced micro-fibres was produced on a
      smooth base plane. Polyurethane vascular patches with and without the textured
      luminal surface were fabricated and implanted bilaterally in ovine carotid
      arteries for 1- and 3-week implantation periods (n = 6 per period). One of 6
      arteries with textured patches in the 1-week group was occluded. All other
      arteries were patent. At 1 week, all patent textured patches had adherent
      thrombus covering the entire patch surface. By 3 weeks, the thrombus had
      organised to form a stable pseudo-neointima. Non-textured patches at 1 week had
      only partial surface coverage of thrombus. At 3 weeks, 4 of 6 non-textured
      patches had significant red thrombus in the lumen. At 3 weeks, there was also
      evidence of cellular migration from artery onto both textured and non-textured
      patches. These findings suggest that the major role of the textured surface was
      as a promoter of a stabilised thrombus base onto which subsequent cellular
      migration and tissue healing occurred more rapidly than onto a smooth
      polyurethane surface.

PMID- 10353650
TI  - Preparation of poly(ethylene glycol)-polystyrene block copolymers using
      photochemistry of dithiocarbamate as a reduced cell-adhesive coating material.
AB  - This article reports a novel preparation method of poly(ethylene glycol) (PEG)
      polystyrene (PST) amphiphilic block copolymers with well-defined block lengths by
      using photopolymerization of an iniferter, benzyl N,N-diethyldithiocarbamate. PEG
      macroiniferters, which were prepared by end-capping of PEG monomethyl ethers with
      benzyl N,N-diethyldithiocarbamate group at one end, were irradiated with UV light
      in the presence of styrene (ST). NMR analyses showed that the PST block was chain
      extended from the PEG block, resulting in the preparation of PEG-PST block
      copolymers. The number-average molecular weights of the copolymers increased
      almost linearly with irradiation time, light intensity, and concentration of ST.
      The polydispersities of the copolymers remained relatively small throughout the
      reaction (Mw/Mn approximately 1.3). The composition of two PEG-PST block
      copolymers thus obtained was as follows: PEG (Mn; 1.9 x 10(3) gmol(-1))-PST (3.0
      x 10(3) gmol(-1)) and PEG (4.9 x 10(3) gmol(-1))-PST (2.6 x 10(3) gmol(-1)).
      These copolymers were coated onto a poly(ethylene terephthalate) film surface. X
      ray photoelectron spectroscopy analyses and water wettability measurements showed
      that the PST block was enriched at the outermost layer as cast in air, whereas
      upon immersion into water, the PEG block was oriented toward water. Enhanced
      wettability was observed for the diblock copolymer with a higher PEG content.
      Significantly reduced cell adhesion was observed on both the coated surfaces.
      Thus, the PEG-PST block copolymer may function as a cell adhesion-resistant
      coating which reduced cell-substrate interaction.

PMID- 10353651
TI  - Mixed oxides prosthetic ceramic ball heads. Part 1: effect of the ZrO2 fraction
      on the wear of ceramic on polythylene joints.
AB  - Although mixed oxides ceramics have been indicated in the literature as a
      promising compromise between strength and wear, to the authors' knowledge no
      reports are available on the influence of the percentage of zirconia in ceramic
      femoral heads when sliding against polyethylene cups. Two types of mixed oxides
      ceramic ball heads (alumina plus, respectively, 60 and 80% of zirconia) were
      compared to pure zirconia and pure alumina heads in terms of wear behaviour
      against UHMWPE in a hip joint simulator. Polyethylene cups and ceramic femoral
      heads were fixed on a simulator apparatus with a sinusoidal movement and load in
      presence of bovine calf serum. The experimental results did not show significant
      difference between the two experimental ceramic materials or in comparison with
      pure materials. Considering that all specimens, regardless of the material, had
      the same level of surface roughness, this roughness factor seems to have a more
      relevant role than the mix of oxides used to manufacture the ceramic head. Wear
      tests are conducted on materials used in prosthetic hip implants in order to
      obtain quality control and to acquire further knowledge of the tribological
      processes that involve joint prostheses, therefore reducing the risk of implant
      failure of innovative prostheses.

PMID- 10353652
TI  - Effects of hydroxylapatite coating crystallinity on biosolubility, cell
      attachment efficiency and proliferation in vitro.
AB  - A hydroxylapatite (HA) coating with approximately 97% crystalline HA content (MP
      1 treated HA coating, MP-HA) was tested in vitro for its biosolubility and
      cellular biocompatibility. The MP-HA coating was compared with a standard HA
      coating with approximately 63% crystallinity (SHA) and an amorphous HA coating
      with approximately 25% crystallinity (AHA), as well as a titanium (Ti) surface
      without HA coating as a control. The topographic study with scanning electron
      microscopy indicated that MP-HA appeared more coarse, with projected nodules
      which altered the shape of cells attached to the substrate. Biosolubility study
      indicated that MP-HA had the least effect on the culture medium pH, while AHA (P
      < 0.01) and SHA (P < 0.05) significantly raised the medium pH up to 8.2 and 7.75,
      respectively. X-ray diffraction (XRD) analysis showed essentially unchanged
      levels of the total soluble phases of all coatings after incubation with culture
      medium, except that the CaO phase was rapidly dissolved from AHA coatings and
      completely eliminated from SHA coatings. Cultures of human gingival fibroblasts
      on these HA coatings showed that MP-HA and SHA had about the same cell attachment
      efficiency which was relatively lower than that of AHA coatings. MP-HA generated
      significant higher cell proliferation rate relative to AHA (P < 0.01) and SHA (P
      < 0.05). This study indicated that surface chemistry and topography of lower
      crystallinity might be favorable to cell attachment, but that elevated medium pH
      might result in a cytotoxic effect that inhibits the proliferation of attached
      cells on coating surfaces.

PMID- 10353653
TI  - Meniscus cells seeded in type I and type II collagen-GAG matrices in vitro.
AB  - The objective of this study was to determine the proliferative and biosynthetic
      activity of calf meniscus cells seeded in type I and type II collagen
      glycosaminoglycan (GAG) copolymers with the overall goal to develop a cell-seeded
      implant for future investigations to improve the regeneration of the knee
      meniscus. The cell-seeded matrices were digested in protease and analyzed for GAG
      by a modification of the dimethyl-methylene blue method and assayed for DNA
      content. Other specimens were evaluated histologically after 1, 7, 14 and 21
      days. Contraction of the same types of matrices, seeded with adult canine
      meniscus cells, was measured at the same time points. After three weeks, cells
      were observed throughout the type II matrix, whereas the type I matrix was
      densely populated at the margins. The cell morphology and the cell density after
      three weeks in both matrices was consistent with the normal meniscus. DNA assay
      for the type I matrix showed a 40% decrease over the first week and a final
      amount of DNA that was not significantly different from the initial value,
      whereas the type II matrix doubled its DNA content over the same time period. The
      cells continued their biosynthesis of GAG and type I collagen. GAG content of the
      type II matrix increased by 50% more than the type I matrix after three weeks.
      Over the same time period, the type I matrix displayed a significant shrinkage to
      approximately 50% of its initial value whereas in contrast, the type II matrix
      and the unseeded controls showed no significant shrinkage. The number of cells
      and the higher GAG synthesis in the type II matrix, and its resistance to cell
      mediated contracture, commend it for future investigation of the regeneration of
      meniscus in vivo.

PMID- 10353654
TI  - Development of a calcium phosphate-gelatin composite as a bone substitute and its
      use in drug release.
AB  - This study was carried out to develop a calcium phosphate-gelatin composite
      implant that would mimic the structure and function of bone for use in filling
      voids or gaps and to release bioactive compounds like drugs, growth hormones into
      the implant site to assist healing. XDS analysis of the synthesized calcium
      phosphate revealed a calcium to phosphorus molar ratio of ca. 2.30, implying a
      less erodible material than hydroxyapatite (1.67). Release of the antibiotic
      gentamicin from the implant was with a burst, whether in situ or in vivo,
      followed by an almost constant release for about three months. It was found that
      the release rate could be decreased by increasing the density of the gelatin
      membrane. Upon implantation into rabbit tibia the release duration was
      substantially shortened (to about 4 weeks) with respect to the in situ tests
      basically due to the degradation of gelatin. In vivo studies with rabbits
      confirmed this degradation. The composite was perfectly biocompatible as shown by
      the histological studies. It, thus, has a great potential as a bone substitute
      material.

PMID- 10353655
TI  - Dimensionless analysis of swelling of hydrophilic glassy polymers with subsequent
      drug release from relaxing structures.
AB  - Two dimensionless parameters, the diffusional Deborah number, De, and the
      swelling interface number, Sw, were used as indicators of solvent and solute
      transport behavior in swellable hydrogel systems. Polymer relaxation and
      concentration-dependent diffusion led to dynamically swelling polymers which
      displayed Fickian, Case II, or anomalous transport behavior. Experimental systems
      studied included crosslinked samples of poly(vinyl alcohol), designated PVA, and
      poly(2-hydroxyethyl methacrylate-co-methyl methacrylate), designated P(HEMA-co
      MMA). Model solutes with molecular weights ranging from 200 to 17,000 were used
      to investigate release properties from these networks. Characteristic polymer
      relaxation times and swelling front velocities were determined experimentally. To
      gain an understanding of how polymer morphology and solute properties affected
      transport behavior, the calculated values of De and Sw were correlated to the
      diffusional exponent, n, used commonly to indicate the time dependence of
      sorption and release. The swelling interface number was found to correlate
      particularly with the transport kinetics, indicating anomalous and Case II solute
      transport when the Sw values were near 1.0.

PMID- 10353656
TI  - Surface corrosion of dental ceramics in vitro.
AB  - The objective of this study was to evaluate possible structural surface changes
      in different dental ceramic materials in a provocative corrosive environment in
      vitro. On the basis of compositional and microstructural differences, seven
      dental ceramic materials were selected for the test. After sintering and
      autoglazing, the surface roughness of the specimens was evaluated by confocal
      laser profilometry. A specially designed specimen holder made it possible to
      locate the same surface area before and after contact with the corrosive
      solution. The surface topography was additionally analysed using scanning
      electron microscopy. All the ceramic materials displayed evidence of surface
      structural changes on the exposed surfaces, but to varying degrees. Traditional
      leucite-containing feldspathic porcelains displayed an increase in surface
      roughness compared with baseline conditions when kept in 4% acetic acid at 80
      degrees C for 18 h. Micro-crystalline and non-crystalline ceramic materials, on
      the other hand, demonstrated a smoother surface or just a minor increase in
      surface roughness. Whether or not the smoother post-corrosion appearance of
      certain ceramic materials is indicative of a true increase in corrosion
      resistance or is merely the result of an uniformly progressive corrosive process
      will be the object of future studies.

PMID- 10353657
TI  - Dissolution of nickel and tissue response observed by X-ray scanning analytical
      microscopy.
AB  - The recently developed X-ray scanning analytical microscope (XSAM) was applied
      for the analysis of the soft tissue of rat in which Ni was implanted and serious
      inflammation occurred. Our aim is to investigate the relationship between tissue
      response and elemental distributions. The XSAM observation was conducted in air
      without pretreatment and staining of samples. Mapping images of P, S, Ca, Fe and
      Ni, which were the elements with low concentration in soft tissue, were obtained
      from the soft tissue blocks of rat where Ni was implanted. S mapping image showed
      the localization of S in muscle and in hairs. Ca mapping image showed the
      localization of Ca in muscle and hair roots. Fe distribution was also observed
      and the localized area was consistent with the hemorrhagic area. The Ni
      dissolution area was clearly detected around the Ni implant. Comparison with the
      histological observation showed that the Ni dispersed area was consistent with
      the inflammatory area and the degree of tissue damage was closely related to the
      dissolved Ni concentration.

PMID- 10353658
TI  - Study of the thermal stability and enzymatic activity of an immobilised enzymatic
      system for the bilirubin oxidation.
AB  - In this work, we have studied the immobilisation of the haemoglobin/glucose
      oxidase coupled enzymatic system in poly(vinyl alcohol) membranes. These are to
      be used as a reagent phase either in the development of an optical sensor or as
      an efficient bilirubin (BR) removal reactor. Poly(vinyl alcohol) (PVA) was chosen
      as the support for this purpose, due to its good biocompatibility, hydrophilicity
      and non-thrombogenic effects. A hydrogel containing the enzymatic system,
      consisting of PVA crosslinked with glutaraldehyde, was prepared and characterised
      by DSC, enzyme activity measurements and release tests. Investigating protein
      conformational changes as a function of temperature and the enzymatic system
      activity we have found that, in spite of the destabilizing effect of the
      glutaraldehyde in the acidic medium, the PVA insolubilisation conditions seem do
      not perturb either the conformation of the 'native state' nor the enzymatic
      system activity. Moreover, it was found that PVA/glutaraldehyde membranes offer a
      simple way to hold enzymatic system, with the possibility of controlling the
      conditions to obtain either the effective prevention of leaching of the entrapped
      proteins or the in situ delivery of the haemoglobin.

PMID- 10353659
TI  - Conjoint corrosion and wear in titanium alloys.
AB  - When considering titanium alloys for orthopaedic applications it is important to
      examine the conjoint action of corrosion and wear. In this study we investigate
      the corrosion and wear behaviour of Ti-6Al-4V, Ti-6Al-7Nb and Ti-13Nb-13Zr in
      phosphate buffered saline (PBS), bovine albumin solutions in PBS and 10% foetal
      calf serum solutions in PBS. The tests were performed under four different
      conditions to evaluate the influence of wear on the corrosion and corrosion on
      the wear behaviour as follows: corrosion without wear, wear-accelerated
      corrosion, wear in a non-corrosive environment and wear in a corrosive
      environment. The corrosion behaviour was investigated using cyclic polarisation
      studies to measure the ability of the surface to repassivate following breakdown
      of the passive layer. The properties of the repassivated layer were evaluated by
      measuring changes in the surface hardness of the alloys. The amount of wear that
      had occurred was assessed from weight changes and measurement of the depth of the
      wear scar. It was found that in the presence of wear without corrosion the wear
      behaviour of Ti-13Nb-13Zr was greater than that of Ti-6Al-7Nb or Ti-6Al-4V and
      that in the presence of proteins the wear of all three alloys is reduced. In the
      presence of corrosion without wear Ti-13Nb-13Zr was more corrosion resistant than
      Ti-6Al-7Nb which was more corrosion resistant than Ti-6Al-4V without proteins
      whereas in the presence of protein the corrosion resistance of Ti-13Nb-13Zr and
      Ti-6Al-7Nb was reduced and that of Ti-6Al-4V increased. In the presence of
      corrosion and wear the corrosion resistance of Ti-13Nb-13Zr is higher than that
      of Ti-6Al-7Nb or Ti-6Al-4V in PBS but in the presence of proteins the corrosion
      resistance of Ti-13Nb-13Zr and Ti-6Al-7Nb are very similar but higher than that
      of Ti-6Al-4V. The wear of Ti-13Nb-13Zr is lower than that of Ti-6Al-7Nb and Ti
      6Al-4V with or without the presence of proteins in a corrosive environment.
      Therefore the overall degradation when both corrosion and wear processes are
      occurring is lowest for Ti-13Nb-13Zr and highest for Ti-6Al-4V and the presence
      of proteins reduces the degradation of all three alloys.

PMID- 10353660
TI  - Microcapsules of alginate-chitosan. II. A study of capsule stability and
      permeability.
AB  - The stability of alginate-chitosan capsules was shown to depend strongly on the
      amount of chitosan bound to the capsules. When the capsules were made by dropping
      a solution of sodium alginate into a chitosan solution (one-stage procedure), all
      the chitosan was located in a thin alginate-chitosan membrane on the surface.
      These capsules were much weaker than the capsules made by reacting calcium
      alginate beads in an aqueous solution of chitosan and calcium chloride (two-stage
      procedure). Capsules with high mechanical strength were obtained after shorter
      reaction times when the number-average molecular weight of the chitosan was
      reduced to around 15,000, when the capsules were made more homogeneous and when
      the capsule diameter was reduced to around 300 microm. When these capsules were
      treated with calcium sequestrant such as citrate under conditions where calcium
      alginate gels normally dissolve, they still had a gel core indicating the
      presence of chitosan throughout the capsule matrix. The permeability of the two
      stage capsules was reduced when the chitosan molecular weight was increased and
      the degree of acetylation was increased, and when the capsules were made more
      inhomogeneous. The addition of another several layers of alginate and chitosan
      resulted in capsules virtually impermeable to IgG, suggesting an average capsule
      pore diameter less than 90 A.

PMID- 10353661
TI  - Localized corrosion behaviour in simulated human body fluids of commercial Ni-Ti
      orthodontic wires.
AB  - The corrosion performances in simulated human body fluids of commercial
      equiatomic Ni-Ti orthodontic wires having various shape and size and produced by
      different manufacturers were evaluated; for comparison purposes wires made of
      stainless steel and of cobalt-based alloy were also examined. Potentiodynamic
      tests in artificial saliva at 40 degrees C indicated a sufficient pitting
      resistance for the Ni-Ti wires, similar to that of cobalt-based alloy wire; the
      stainless steel wire, instead, exhibited low pitting potential. Potentiodynamic
      tests at 40 degrees C in isotonic saline solution (0.9% NaCl) showed, for Ni-Ti
      and stainless steel wires, pitting potential values in the range approximately
      200-400 mV and approximately 350 mV versus SCE, respectively: consequently,
      according to literature data (Hoar TP, Mears DC. Proc Roy Soc A 1996;294:486
      510), these materials should be considered potentially susceptible to pitting;
      only the cobalt-based alloy should be immune from pitting. The localized
      corrosion potentials determined in the same environment by the ASTM F746 test
      (approximately 0-200 mV and 130 mV versus SCE for Ni-Ti and stainless steel,
      respectively) pointed out that for these materials an even higher risk of
      localized corrosion. Slight differences in localized corrosion behaviour among
      the various Ni-Ti wires were detected.

PMID- 10353662
TI  - Osseo-mechanical induction of extra-cortical plates with reference to their
      surface properties and geometric designs.
AB  - The purpose of this investigation was to determine which geometric and surface
      properties encouraged optimal ingrowth and bonding of bone to an extra-cortical
      plate. Forty-eight titanium extra-cortical plates were attached onto the left and
      right femora of adult rabbits. The plates were of six different designs and the
      osseoconductive effects of four surfaces were examined. A roughened titanium
      surface, a plasma sprayed HA coating of low crystallinity (57%) and a solution
      precipitated calcium phosphate coating were compared with a plasma sprayed
      crystalline hydroxyapatite coating (crystallinity 85%). Thin sections were
      prepared by grinding and polishing. Bone formation and the interface around the
      plates were investigated histologically and computer and morphometric analyses
      were used to quantify new bone formation, bone apposition onto the plate, bone
      porosity and the condition of the HA coating. The study found that a
      hydroxyapatite coating (with the exception of the solution precipitated coating)
      had significantly greater interfacial contact with bone when compared to a
      roughened titanium surface, and that significantly more bone attached to a
      crystalline HA coating compared with the HA coating of lower crystallinity
      although significantly more bone formed in the vicinity of the lower crystalline
      HA coating. Differences in the bony reaction induced by the various geometric
      designs were evident and the optimal plate design requires either holes or slots
      along its length as this encouraged bone ingrowth into the plate.

PMID- 10353663
TI  - Lumbar sympathectomy.

PMID- 10353664
TI  - Prevention of operation related stroke: are we asking the right questions?

PMID- 10353665
TI  - Mechanical properties of abdominal aortic aneurysm and prediction of risk of
      rupture.

PMID- 10353666
TI  - Developments in diagnosis and classification of venous disorders: non-invasive
      diagnosis.
AB  - PURPOSE: This review examines the many techniques that have been used for the non
      invasive diagnosis of acute and chronic venous disease and was conducted by
      members of the Committee on Research of the American Venous Forum. It proposes to
      identify those techniques with the greatest clinical potential, to suggest
      algorithms for the clinical application of non-invasive techniques in the
      identification of acute deep venous thrombosis and chronic venous insufficiency,
      and to identify areas of deficient knowledge and potential areas for future
      research initiatives. METHODS: Review of pertinent clinical and research
      material. RESULTS: Impedance plethysmography and ultrasonic imaging are the
      primary non-invasive tools used in the diagnosis of acute deep venous thrombosis.
      At present, ultrasonic imaging techniques are recommended on the basis of greater
      diagnostic accuracy in recent comparative clinical trials. Data would suggest
      that serial evaluation should probably be viewed as the preferred option for
      symptomatic patients with a negative initial examination and the presence of risk
      factors or physical findings suggesting a proximal deep venous
      obstruction/thrombosis. Chronic venous disease is the result of valvular
      incompetence, with or without associated venous obstruction. Duplex imaging can
      be used to determine the location and extent of reflux; however, there are
      reported procedural variations in the performance and interpretation of such
      studies. Recent innovations in air plethysmography may provide a means of
      quantifying volume changes, and permit an objective characterization of venous
      reflux and calf pump efficiency. CONCLUSIONS: There are still significant
      questions that need to be answered by well-designed research initiatives.
      Research applications that incorporate non-invasive diagnostic techniques may
      involve the diagnosis, treatment and natural history of acute deep venous
      obstruction/thrombosis and chronic venous insufficiency, assessment prior to and
      following venous reconstruction, and the basic science aspects of acute and
      chronic venous disease. At present, a lack of common standards is, by far, the
      greatest impediment to an organized research approach to venous disease.

PMID- 10353667
TI  - Infection of endovascular stents: an uncommon but important complication.
AB  - In this review article, four cases of peripheral endovascular stent infection
      (including a case presented in this issue of the journal) reported in the medical
      literature are reported. While the actual incidence of endovascular stent
      infection is probably low, when it occurs it can have serious consequences. This
      complication may result in the death of a patient, as seen in two of the case
      reports. The presentation of this complication, the site of stent deployment, the
      treatment given and the outcome in each of these cases are discussed. Stent
      infection should be recognized early to avoid the high morbidity and mortality of
      this complication.

PMID- 10353668
TI  - Septic endarteritis and fatal iliac wall rupture after endovascular stenting of
      the common iliac artery.
AB  - A 52-year-old female with arterial occlusive disease underwent an uneventful
      percutaneous transluminal angioplasty and placement of a vascular metallic stent
      in the left common iliac artery. Ten days later she presented with clinical
      symptoms of septic endarteritis. Shortly after re-admittance, an emergency
      laparotomy had to be performed because of an acute retroperitoneal bleeding.
      Rupture of the common iliac artery directly overlaying the penetrating stent was
      found but control of haemorrhage was of no avail. In this report of a case,
      septic endarteritis following placement of a vascular metallic stent preceded
      fatal rupture of the common iliac artery. This up to now unknown constellation
      requires surgical intervention without undue delay.

PMID- 10353669
TI  - Argatroban as a potential anticoagulant in cardiopulmonary bypass-studies in a
      dog model.
AB  - Argatroban is a selective thrombin inhibitor synthesized in Japan. Argatroban,
      which has a high affinity for thrombin, and markedly inhibits thrombin-induced
      reactions, has been used in patients with artherosclerosis obliterans. The
      efficiency of argatroban, instead of heparin, as an anticoagulant in dog models
      of cardiopulmonary bypass was explored. In the first study, argatroban was
      administered as a bolus plus infusion for 1 h during cardiopulmonary bypass at
      doses of 1.0 mg + 10 microg/kg per min, 2.0 mg + 10 microg/kg per min and 3.0 mg
      + 10 microg/kg per min (n = 2 per group). Activated clotting time and arterial
      gas analyses were performed beforehand and 10 min thereafter. In the second
      study, there were four groups. In the first group (n = 5), no coated
      extracorporeal circuit was used and heparin (2 mg/kg) was used as an
      anticoagulant. In the second group (n = 5), a coated extracorporeal circuit was
      used and heparin was used (2 mg/kg) as an anticoagulant. In the third group (n =
      3), no coated extracorporeal circuit was used and argatroban (2.0 mg + 10
      microg/kg per min) was used as an anticoagulant. In the fourth group (n = 5), a
      coated extracorporeal circuit was used and argatroban was used (2.0 mg + 10
      microg/kg per min) as an anticoagulant. All animals were perfused for 120 min at
      40 ml/kg per minute. Platelet count, activated clotting time, thrombin
      antithrombin III complex, antithrombin III, fibrinogen, fibrinogen degradation
      products and C3a were measured to evaluate platelet, coagulofibrinolytic and the
      complement system. Activated clotting time values and the effect of argatroban
      during cardiopulmonary bypass indicated a dose-dependent response. The next
      highest dosing group (2.0 mg + 10 microg/kg per minute) had activated clotting
      time values of 250-300 seconds during cardiopulmonary bypass, and fell after
      reaching near-normal levels within 60 minutes. No clots were noted in the
      extracorporeal circuit. The argatroban group showed lower levels in their
      coagulofibrinolytic system compared with the heparin group. The platelet count
      remained at a high level in the argatroban group. It is concluded that the
      combination of heparinized cardiopulmonary bypass circuits, and the use of
      argatroban as an anticoagulant, is safe and reduces the activation of coagulation
      and fibrinolytic systems and preserves platelet count.

PMID- 10353670
TI  - Antifibrinolytic therapy with tranexamic acid in cardiac operations.
AB  - To demonstrate its antifibrinolytic effects and establish an effective regimen of
      tranexamic acid for hemostasis, the authors measured alpha2-plasmin inhibitor
      plasmin complexes, thrombin-antithrombin III complexes and postoperative blood
      loss in three groups undergoing different regimens during cardiac operations.
      Forty-six patients undergoing coronary artery bypass grafting or valve
      replacement were enrolled in this study. They were divided into three groups of
      drug administration. A bolus infusion of 50 mg/kg tranexamic acid was given to 17
      patients at the end of cardiopulmonary bypass (control group) and to 14 patients
      at the beginning of cardiopulmonary bypass (group A). In addition to the same
      bolus infusion at the beginning of cardiopulmonary bypass as group A, a
      continuous infusion of 10 mg/kg per h, starting at the time of skin incision and
      maintained for 6 h after cardiopulmonary bypass was given to 15 patients (group
      B). The marked increase in alpha2-plasmin inhibitor-plasmin complexes at the end
      of cardiopulmonary bypass in the control group was significantly reduced in group
      A (P < 0.01) and a further reduction was observed in group B (P < 0.001). The
      difference in postoperative blood loss only reached significant levels between
      the control group and group B (P < 0.05). Although a significant increase in
      thrombin-antithrombin III complexes during cardiopulmonary bypass was similarly
      observed in all groups, no thromboembolic events occurred in any group, nor was
      any difference seen in graft patency. From the tranexamic acid therapy regimens
      tested in this study, a continuous infusion of 10 mg/kg per h starting at the
      time of skin incision to 6 h after cardiopulmonary bypass, with a bolus infusion
      of 50 mg/kg at the beginning of cardiopulmonary bypass, proved to be the most
      effective.

PMID- 10353671
TI  - Lumbar sympathectomy in critical limb ischaemia: surgical, chemical or not at
      all?
AB  - The value of surgical and chemical lumbar sympathectomy was studied in patients
      with critical lower-limb ischaemia without the option of vascular reconstruction.
      Clinical success rates, defined as improvement of ischaemia stage, and limb
      salvage rates were recorded for 76 limbs of 70 consecutive patients. Chemical
      lumbar sympathectomy patients were older and had more concomitant diseases than
      surgical lumbar sympathectomy patients. The short-term (6-week) success rate in
      36 cases treated with surgical lumbar sympathectomy (44%) was better than in 40
      cases treated with chemical lumbar sympathectomy (18%) (P = 0.01). The long-term
      (1-year) success rate was 47% for surgical lumbar sympathectomy and 45% for
      chemical lumbar sympathectomy (P = NS). The 1-year limb salvage rates were 61%
      for surgical lumbar sympathectomy and 58% for chemical lumbar sympathectomy (P =
      NS). Complications were minor in both groups. Lumbar sympathectomy still has a
      limited role in the treatment of critical limb ischaemia in patients without the
      option of vascular reconstruction. Both surgical and chemical lumbar
      sympathectomy can be performed with very little morbidity and may provide a
      benefit over the natural course of the arterial insufficiency.

PMID- 10353672
TI  - Is transcranial Doppler useful in the detection of internal carotid artery cross
      clamp intolerance?
AB  - The aim of this study was to test the hypothesis that a drop in the systolic
      blood flow velocity in the middle cerebral artery of 70% or more, measured by
      transcranial Doppler, is a better criteria in the detection of cross-clamp
      intolerance than electroencephalogram (EEG) and somatosensory evoked potential
      (SSEP) monitoring. After exclusion of patients with a recent stroke, urgent
      procedures and combined procedures, a transcranial Doppler with compression test
      was scheduled in 85 patients. In 13 patients the drop was 70% or more and in
      these patients a transcranial Doppler was also performed during the
      reconstruction of the internal carotid artery (the study group) under general
      anaesthesia. A shunt was used because of EEG and SSEP abnormality in one patient.
      No changes were observed in the remaining patients and no intraoperative strokes
      were seen. The transcranial Doppler monitoring was unreliable in three patients.
      During cross-clamp, the systolic blood flow velocity in the middle cerebral
      artery dropped less than 70% in four and 70% or more in six patients. It is
      concluded that using a drop of 70% or more of the systolic blood flow velocity in
      the middle cerebral artery during internal carotid artery cross-clamp, as an
      indicator of cross-clamp intolerance, will lead to unnecessary shunting.

PMID- 10353673
TI  - The relationship between abdominal aortic aneurysm wall compliance, maximum
      diameter and growth rate.
AB  - AIM: Aortic compliance as measured by the pressure-strain elastic modulus (Ep)
      and stiffness (beta), may allow a more precise estimate of rupture risk. The aim
      of this study was to determine the relationships between compliance, maximal
      aneurysm diameter and growth rate. METHODS: Sixty abdominal aortic aneurysm
      patients of median age 73 years, were studied. Growth rate was derived from
      repeat ultrasound scans obtained over a median period of 21 months (range 6-48).
      At the end of follow-up, patients underwent measurement of maximum aortic
      diameter, Ep and beta using the Diamove echo-tracking system. RESULTS: Growth
      rate correlated positively (r = 0.6, P < 0.01) with maximum diameter on entry to
      the study There was a positive correlation between mean arterial pressure and Ep
      (r = 0.3, P = 0.03), but not between mean arterial pressure and beta (r = 0.8, P
      = 0.61). A positive correlation was found between final maximum diameter and Ep
      (r = 0.22, P = 0.04) but not beta (r = 0.16, P = 0.11). There was no significant
      relationship between growth rate and Ep or beta. CONCLUSION: Large aneurysms
      tended to be less compliant. Within a population of abdominal aortic aneurysm of
      similar maximum diameter there was a 10-fold variation in Ep and beta. Compliance
      and growth rate were not related. If aortic compliance is related to risk of
      rupture then this predictive information is likely to be largely independent of
      that currently obtained from size and growth rate.

PMID- 10353674
TI  - A prospective randomized multicentre comparison of expanded
      polytetrafluoroethylene and gelatin-sealed knitted Dacron grafts for
      femoropopliteal bypass.
AB  - PURPOSE: To compare graft patency between expanded polytetrafluoroethylene (PTFE)
      and gelatin-sealed knitted Dacron for femoropopliteal bypass. METHODS: A
      prospective, multicentre trial was performed in 108 patients randomized to
      receive either a PTFE or Dacron prosthetic graft. Distal anastomosis was above
      knee in 75 and below knee in 33 patients. RESULTS: Primary patency at 1, 2 and 3
      years was 72, 52 and 52% for PTFE, and 70, 56 and 47% for Dacron (P = 0.87).
      Secondary patency at 1, 2 and 3 years was 74, 54 and 54% for PTFE and 78, 70 and
      53% for Dacron (P = 0.39). The most significant predictors of early graft failure
      were poor vessel run-off (P = 0.04) and critical limb ischaemia (P = 0.04).
      CONCLUSION: There was no difference in graft patency between PTFE and Dacron for
      femoropopliteal bypass.

PMID- 10353675
TI  - The visceral perfusion system and distal bypass during thoracoabdominal aneurysm
      surgery: an alternative for physiological blood flow?
AB  - There are potential benefits to addition of visceral organ perfusion, by means of
      a 9-Fr. catheter system (octopus), to distal aortic perfusion during
      thoracoabdominal aneurysm surgery. However, in the literature there are reports
      of adverse effects. The authors therefore compared two groups of patients who
      underwent thoracoabdominal aneurysm surgery with and without visceral organ
      perfusion. In the group in which the visceral perfusion was applied, the use of
      platelets (26 versus 11 units; P < 0.05), fresh frozen plasma (3.4 versus 1.5
      units; P < 0.05) and packed cells (20 versus 8 units, P < 0.05) was significantly
      increased. An equal number of patients in both groups developed renal failure
      postoperatively. An explanation for this adverse effect can be found in the high
      shear rates in the catheters used, mainly as a result of the small diameter. High
      shear rates cause haemolysis. Also, the flow through the catheters is
      insufficient to maintain adequate perfusion of the visceral organs. A higher flow
      in these catheters would result in an even higher shear rate. It is therefore
      concluded that coagulopathy and insufficient bloodflow is caused by the small
      internal diameter of the catheters, which renders the device insufficient.

PMID- 10353676
TI  - Extraperitoneal laparoscopic aortic control with endovascular visualization of a
      stent-graft combination.
AB  - OBJECTIVES: to demonstrate the feasibility of minimally invasive approaches to
      the aorta using retroperitoneal laparoscopy and to clamp the aorta to give views
      for perfemoral aortic angioscopy. METHODS: using retroperitoneal laparoscopy
      facilitated by balloon dissection the authors developed a new approach to the
      infrarenal abdominal aorta, in six pigs, to allow control of aortic blood flow.
      Aortic stent-grafts were then deployed via femoral arteriotomy, and after
      flushing the blood from the aorta, the stent-grafts were visualized by
      angioscopy. RESULTS: accurate positioning and patency of the stent-grafts was
      ascertained by direct vision angioscopy in all cases. CONCLUSIONS: this series
      shows that extraperitoneal laparoscopic aortic dissection is feasible and direct
      endovascular visualization of the aortic lumen can be performed. This may find a
      role as an adjunct to endovascular techniques such as endovascular stent-graft
      placement, by aortic angioscopy following minimally-invasive aortic clamping.

PMID- 10353677
TI  - The 'primeless pump': a novel technique for intraoperative blood conservation.
AB  - PURPOSE: Hemodilution during cardiopulmonary bypass may lead to anemia requiring
      intraoperative transfusions. Prime removal from the cardiopulmonary bypass
      circuit was used to limit dilution and intraoperative transfusions. METHODS: The
      technique of prime removal consists of arterial and then venous side evacuation
      of crystalloid prior to cardiopulmonary bypass. The effectiveness of this
      technique, to maintain a higher hematocrit and reduce intraoperative
      transfusions, was studied prospectively in two consecutive groups of patients
      undergoing coronary revascularization (controls versus primeless). RESULTS:
      Intraoperative hematocrits were significantly higher (P < 0.0001) and
      transfusions lower (4%) in the primeless versus the control group (19%) (P =
      0.003). Prime removal is of particular benefit in anemic (hematocrit < or = 35%)
      and/or small patients (body surface area < or = 2 m2). CONCLUSION: The technique
      of prime removal is simple, safe and cost-effective, reducing intraoperative
      transfusions, especially in small and/or anemic patients. It could be part of
      blood conservation strategies in most adult cardiac operations.

PMID- 10353678
TI  - Color flow scan diagnosis of the carotid string may prevent unnecessary surgery.
AB  - Can the color flow scanner assist in the diagnosis and management of patients
      with preocclusive lesions of the carotid bifurcation (so-called 'string sign')?
      Twenty-three patients were identified as having a 'string' by duplex criteria.
      Seventeen patients underwent angiography, which confirmed the duplex findings in
      14 patients. In three, the angiogram was originally misread as showing an
      occluded internal carotid Artery. Six patients were managed solely on the basis
      of the duplex findings. Based on arteriography and/or duplex criteria, 12
      involved internal carotid arteries were not explored. One artery went on to
      occlude asymptomatically. The remaining 11 have remained patent and asymptomatic
      (follow-up 6-72 months). Five arteries were predicted operable and underwent
      successful endarterectomy. Six were predicted inoperable yet underwent
      exploration. All were ultimately treated by ligation +/- external carotid
      endarterectomy without subsequent neurological deficit. Duplex scans can identify
      internal carotid artery string signs, determine operability and may predict the
      functionally occluded artery that can be safely observed.

PMID- 10353679
TI  - Indications and benefits of simultaneous endoluminal balloon angioplasty and open
      surgery during elective lower limb revascularization.
AB  - Combined balloon angioplasty and conventional revascularization are occasionally
      performed but some points are still controversial: which patients are eligible
      for this associated procedure?; should the procedures be performed simultaneously
      or successively?; and in case of simultaneous procedure, which one should be
      performed first? To answer these questions, the notes of 64 patients
      consecutively submitted to this procedure at the Henri Mondor hospital were
      reviewed. Arterial dilatation was performed on the iliac artery, superficial
      femoral artery, popliteal artery or tibioperoneal trunk in 31, 26, four and four
      patients, respectively. Reasons for simultaneous procedures were multiple
      occlusive lesions in 67% of patients and inflow improvement in 14%. The others
      reasons included iliac obstruction in poor risk patients, unilateral failure of
      planned bilateral iliac balloon angioplasty, outflow improvement, local
      contraindication to arterial approach, shortness of vein graft, clamp injury
      during open surgery and inadequate patient position for both procedures.
      Complications were rare. One patient died of recurrent sepsis of the femoro
      femoral bypass. The 5-year limb salvage rate was 91%. In this study, simultaneous
      procedures were associated with three advantages: the risk of septic
      complications associated with graft implantations in a previously punctured site
      was decreased, anticoagulant and/or antiplatelet therapy did not need to be
      modified before the second procedure, hospital length of stay and cost appeared
      to be lower. On a simultaneous procedure, it is recommended that the balloon
      angioplasty be performed after the conventional procedure in order to avoid
      clamping a recently dilated artery when performing the bypass.

PMID- 10353680
TI  - Thoracoscopically-assisted thoraco-femoral bypass in a canine model.
AB  - Interest in minimally invasive procedures for vascular disease has grown
      tremendously over the past few years. Herein, we report our initial experience
      with a thoracoscopically-assisted thoraco-femoral bypass in a larger animal
      model. Included are various approaches to a final recommendation for the
      technique.

PMID- 10353681
TI  - Minimally invasive thoracoscopic thoraco-femoral bypass: a case report.
AB  - Thoracoscopic techniques have improved a variety of thoracic surgical procedures.
      Thoraco-femoral bypass is an exceptional alternative to standard thoracoscopic
      thoraco-femoral bypass. Herein we report our initial human experience with a
      thoracoscopic thoraco-femoral bypass.

PMID- 10353682
TI  - Replacement of the common carotid artery by a plastic prosthesis. Report of a
      case with forty years of follow-up.
AB  - An 18-year-old man suffered a 38 caliber gunshot wound to the right side of the
      neck on 25 September 1957. On 16 October 1957, a traumatic arteriovenous aneurysm
      between the common carotid artery and the internal jugular vein was resected. The
      jugular vein was ligated and the common carotid was replaced by a nylon
      prosthesis. On 16 October 1960. the dilated nylon graft was replaced by a dacron
      prosthesis. The patient has been followed-up during more than 40 years and his
      condition is normal. To the best of our knowledge, this operation was the first
      of its kind performed in the world and has the longest follow-up.

PMID- 10353683
TI  - Peripheral arterial occlusion in acute promyelocytic leukemia.
AB  - A 16-year-old Caucasian teenager developed fatigue, abdominal pain, pneumonia,
      and subsequently acute vascular occlusion of the left superficial femoral artery.
      Vascular assessment and heparin therapy lead to bone marrow aspiration and a
      diagnosis of acute promyelocytic leukemia. Treatment with chemotherapy prevented
      loss of limb and avoided further vascular surgery. Young patients with acute
      vascular occlusion require an in-depth assessment including attention to
      hematological disorders. Clots obtained on thromboembolectomy should be sent for
      pathological assessment and not discarded, especially in an unusual-age patient
      for arterial embolus.

PMID- 10353684
TI  - Perforation of the right ventricle by a suction drain.
AB  - Suction drains can be used as alternatives to conventional underwater seal drains
      following cardiac surgery, and may be advantageous under some circumstances. The
      authors present a case where a suction drain eroded into the right ventricle
      causing near-fatal haemorrhage following coronary artery surgery. Caution should
      be exercised in taking the decision to use suction drains, the material from
      which they are manufactured should be chosen carefully, and close attention paid
      to their positioning within the mediastinum.

PMID- 10353685
TI  - Successful repair of blunt cardiac rupture involving both ventricles.
AB  - Blunt cardiac rupture occurs infrequently and is usually lethal. Successful
      repairs of isolated atrial or ventricular ruptures have been reported when the
      diagnosis is made early. Our patient sustained blunt cardiac rupture of both
      ventricles in a motor vehicle accident. The diagnosis was made during emergency
      exploratory laparotomy when her vital signs deteriorated without obvious cause. A
      large Satinsky clamp was placed across the apices of the right and left ventricle
      to control hemorrhage while the repair was done without cardiopulmonary bypass.
      She survived and was discharged to home with a normal echocardiogram.

PMID- 10353686
TI  - Re: V. Falk, T. Walther and F.P. Mohr, Abdominal aortic aneurysm repair during
      cardiopulmonary bypass: rationale for a combined approach. Cardiovascular
      Surgery, 1997 5(3) 271-278.

PMID- 10353687
TI  - K.A. Illig et al. Value of the preoperative EEG for carotid endarterectomy 6, 490
      495.

PMID- 10353688
TI  - Regulation of mitogenesis by water-soluble phospholipid intermediates.
AB  - Many recent observations implicate choline and ethanolamine kinases as well as
      phosphatidylcholine-specific phospholipase C in the regulation of mitogenesis and
      carcinogenesis. For example, human cancers generally contain high concentrations
      of phosphoethanolamine and phosphocholine, and in different cell lines various
      growth factors, cytokines, oncogenes and chemical carcinogens were all shown to
      stimulate the formation of phosphocholine and phosphoethanolamine. In addition,
      other reports have appeared showing that both extracellular and intracellular
      phosphocholine as well as ethanolamine and its derivatives can regulate cell
      growth. This area of research has clearly arrived at a stage when it becomes
      important to examine critically the feasibility of water-soluble phospholipid
      intermediates serving as potential regulators of cell growth in vivo.
      Accordingly, the goal of this review is to summarise available information
      relating to the formation and mitogenic actions of intracellular and
      extracellular phosphocholine as well as ethanolamine and its derivatives.

PMID- 10353689
TI  - Stimulation of membrane-associated protein kinase-C activity in spleen
      lymphocytes by hPTH-(1-31)NH2, its lactam derivative, [Leu27]-cyclo(Glu22-Lys26)
      hPTH-(1-31)NH2, and hPTH-(1-30)NH2.
AB  - Human parathyroid hormone, hPTH-(1-34), stimulates adenylyl cyclase and
      phosphatidylinositol-bisphosphate-specific phospholipase-C (PIP2-PLC), as
      indicated by increased membrane-associated protein kinase C (PKC) activity in ROS
      17/2 rat osteosarcoma cells. The C-terminally truncated hPTH-(1-31)NH2 stimulates
      adenylyl cyclase as strongly as hPTH-(1-34) in these cells, but it does not
      stimulate PKC activity. Even [Leu27]-cyclo(Glu22-Lys26)-hPTH-(1-31)NH2, a 6-fold
      stronger adenylyl cyclase stimulator than hPTH-(1-34), cannot stimulate PKC
      activity in ROS cells. Therefore PTH required its 32-34 region to stimulate PIP2
      PLC/PKCs in this osteosarcoma line. In contrast, hPTH-(1-31)NH2 [Leu27]
      cyclo(Glu22-Lys26)-hPTH-(1-31)NH2 and even hPTH-(1-30)NH2 can stimulate PKC
      activity in freshly isolated rat spleen lymphocytes as strongly as hPTH-(1
      34)NH2. The difference in the ability of membrane-associated PKC activity in
      spleen lymphocytes, but not in ROS cells, to be stimulated by C-terminally
      truncated PTH fragments might be due to different receptor densities or to the
      lymphocyte's atypical PTH/PTHrP receptor.

PMID- 10353690
TI  - Differential effect of TPA on PGE2 and cicaprost-induced cAMP synthesis in UMR
      106 cells.
AB  - PGE2 and prostacyclin each enhance cAMP synthesis in the osteoblast-like cell
      line UMR-106. The amount of cAMP induced by PGE2 was 5-7-fold greater than the
      amount induced by cicaprost or iloprost, stable prostacyclin analogues. Both PGE2
      and the two prostacyclin analogues enhanced cAMP synthesis with similar time
      dependence. The EC50 values of PGE2 and cicaprost were 3 X 10(-6) and 5 x 10(-8)
      M, respectively. Short-term incubation of the cells with 12-o
      tetradecanoylphorbol 13-acetate (TPA) markedly reduced the PGE2-induced cAMP
      synthesis. In contrast, cells that were incubated with the same concentrations of
      TPA in the presence of cicaprost or iloprost showed a 1.6-fold increase in cAMP
      formation. The marked disparity between the cAMP response to cicaprost and PGE2
      in the presence of TPA suggests that the two prostanoids induce cAMP synthesis in
      the UMR-106 cells by interaction with different receptors. These observations
      support the idea that the osteoblastic UMR-106 cells may express specific
      prostacyclin receptors and suggest that prostacyclin may have a unique role in
      osteoblasts.

PMID- 10353691
TI  - Differential association of phosphatidylinositol-5-phosphate 4-kinase with the
      EGF/ErbB family of receptors.
AB  - Phosphatidylinositol-5-phosphate 4-kinase (PIP4K) is required for the production
      of phosphoinositol-4,5-hisphosphate (PIP2), which has been closely associated
      with growth factor signalling. Here we have tested the possibility that
      phosphoinositide kinases may be take part in signal transduction through
      interactions with the epidermal growth factor (EGF) receptor and the ErbB family
      of tyrosine kinase receptors. Interactions of the Type IIbeta isoform of PIP4K
      were observed with the EGF receptor family members in a number of diverse cell
      lines, including A431, PC12 and MCF7 cells but not with the N6F TrkA receptor. Co
      immunoprecipitation experiments indicate that PIP4K interacts with not only the
      EGF receptor, but also selectively with members of the ErbB tyrosine kinase
      family. These results demonstrate another enzyme substrate for EGF receptors that
      facilitates the production of phosphoinositides at the cell membrane.

PMID- 10353692
TI  - Involvement of protein kinase C and protein kinase A in the muscarinic receptor
      signalling pathways mediating phospholipase C activation, arachidonic acid
      release and calcium mobilisation.
AB  - The involvement of protein kinase C (PKC) and protein kinase A (PKA) in
      cholinergic signalling in CHO cells expressing the M3 subtype of the muscarinic
      acetylcholine receptor was examined. Muscarinic signalling was assessed by
      measuring carbachol-induced activation of phospholipase C (PLC), arachidonic acid
      release, and calcium mobilisation. Carbachol activation of PLC was not altered by
      inhibition of PKC with chelerythrine chloride, bisindolylmaleimide or chronic
      treatment with phorbol myristate acetate (PMA). Activation of PKC by acute
      treatment with PMA was similarly without effect. In contrast, inhibition of PKC
      blocked carbachol stimulation of arachidonic acid release. Likewise, PKC
      inhibition resulted in a decreased ability of carbachol to mobilise calcium,
      whereas PKC activation potentiated calcium mobilisation. Inhibition of PKA with
      H89 or Rp-cAMP did not alter the ability of carbachol to activate PLC. Similarly,
      PKA activation with Sp-cAMP or forskolin had no effect on PLC stimulation by
      carbachol. Carbachol-mediated release of arachidonic acid was decreased by H89
      but only slightly increased by forskolin. Forskolin also increased calcium
      mobilisation by carbachol. These results suggest a function for PKC and PKA in M3
      stimulation of arachidonic acid release and calcium mobilisation but not in PLC
      activation.

PMID- 10353693
TI  - Morphine and anandamide stimulate intracellular calcium transients in human
      arterial endothelial cells: coupling to nitric oxide release.
AB  - Both morphine and anandamide significantly stimulated cultured endothelial
      intracellular calcium level increases in a concentration-dependent manner in
      cells pre-loaded with fura 2/AM. Morphine is more potent than anandamide
      (approximately 275 vs. 135 nM [Ca]i), and the [Ca]i for both ligands was blocked
      by prior exposure of the cells to their respective receptor antagonist, i.e.,
      naloxone and SR 171416A. Various opioid peptides did not exhibit this ability,
      indicating a morphine-mu3-mediated process. In comparing the sequence of events
      concerning morphine's and anandamide's action in stimulating both [Ca]i and
      nitric oxide production in endothelial cells, we found that the first event
      precedes the second by 40+/-8 sec. The opiate and cannabinoid stimulation of
      [Ca]i was attenuated in cells leeched of calcium, strongly suggesting that
      intracellular calcium levels regulate cNOS activity.

PMID- 10353694
TI  - Binding of GM-CSF to adherent neutrophils activates phospholipase D.
AB  - When the hematopoietic growth factor granulocyte-macrophage colony-stimulating
      factor was incubated with neutrophils adherent to plastic tissue culture plates
      or plates coated with extracellular matrix proteins, a rapid (3 min) but
      transient formation of phosphatidic acid was observed. This stimulation was
      dependent on the dose of GM-CSF, with an EC50 of 140 pM, and was further enhanced
      (up to 350%) with the PA phosphatase inhibitor propranolol in a dose-dependent
      manner. Conversely, GM-CSF was unable to trigger any PA formation in neutrophils
      maintained in suspension, even in the presence of soluble fibronectin. However,
      GM-CSF did prime the cells for enhanced PA formation in the presence of a
      secondary stimulus (fMet-Leu-Phe or PAF). GM-CSF also caused a time-dependent
      stimulation of diacylglycerol formation in adherent, but not suspended, cells and
      elicited a time-dependent stimulation of phosphatidylethanol formation, with a
      concomitant decrease in the formation of PA only at early (< 7 min) times. These
      observations were consistent with a rapid activation of the enzyme phospholipase
      D in adherent cells stimulated with GM-CSF. Additional data indicated that the
      source of DAG was PLD coexisting with PLC, especially at later times ( > 7 min)
      of stimulation with GM-CSF. Finally, the formation of PA and PEt, and to a minor
      extent, DAG, were inhibited by the protein tyrosine kinase inhibitor erbstatin in
      conditions in which tyrosine phosphorylation occurred. Taken together the data
      indicate that GM-CSF rapidly activates PLD in adherent cells, which is
      responsible for the generation of PA. Thus, PLD activation is an early event in
      neutrophil signal transduction following exposure of adherent cells to GM-CSF.

PMID- 10353695
TI  - Prolactin-independent modulation of the beta-casein response element by Erk2 MAP
      kinase.
AB  - The MAP kinases have been suggested to play a role in intracellular signalling by
      PRL. A reporter gene construct, PRE3-CAT, which manifests PRL responsiveness
      through a Stat5-binding site (PRE), was induced by PRL in CHO cells expressing
      the PRL-R. A fusion protein (Gal4-Stat5(695)), containing the C-terminal domain
      of Stat5a (amino acids 695-794) linked to the DNA-binding domain of Gal4 (Gal4
      DBD), strongly activated transcription of a luciferase reporter gene. Therefore,
      the Stat5 C-terminus, which contains a potential MAP kinase phosphorylation site,
      exhibits a modular transactivating function. A kinase-defective mutant of Erk2
      (iMAPK) caused a dose-dependent suppression of PRL-stimulated PRE3-CAT, and also
      inhibited the induction of PRE3-CAT by Jak2 over-expression. Correspondingly,
      over-expression of the MAP kinase activator v-Src increased the PRL-stimulated
      level of PRE3-CAT. Gal4-Stat5(695) activity was not modulated by PRL or Jak2,
      consistent with the absence of the relevant tyrosine phosphorylation site at
      residue 694. Gal4-Stat5(695) was not inhibited by iMAPK, indicating that the C
      terminal transactivation region of Stat5a is not sensitive to direct modulation
      of a MAP kinase pathway. These results suggest that alteration of Erk2 activity
      by growth factors may modulate PRL-induced gene expression by a mechanism
      upstream of Stat5.

PMID- 10353696
TI  - Activation of protein kinase A by dibutyryl cAMP treatment of NIH 3T3 cells
      inhibits proliferation but fails to induce Ser-133 phosphorylation and
      transcriptional activation of CREB.
AB  - The cAMP analogue dibutyryl cAMP (dbcAMP) is often used to activate the protein
      kinase A pathway and to study the expression of cAMP-responsive genes. Here we
      show that in NIH 3T3 cells dbcAMP is able to activate PKA, but fails to stimulate
      expression of the cAMP-inducible c-fos gene. Co-expression of A-kinase anchoring
      protein 75, previously shown to amplify cAMP signalling and to stimulate c-fos
      expression, could not restore cAMP responsiveness of the c-fos promoter. DbcAMP
      induced activation of PKA may result in poor translocation of the catalytic sub
      units of PKA to the nucleus, indicated by the lack of both Ser-133
      phosphorylation of the cAMP-response element binding factor CREB and stimulation
      of the transcriptional activity of this factor. DbcAMP treatment, however,
      inhibited cell proliferation. These results suggest that cAMP-mediated inhibition
      of proliferation may be independent of translocation of the catalytic sub-units
      into the nucleus.

PMID- 10353697
TI  - FGF-2 induces surfactant protein gene expression in foetal rat lung epithelial
      cells through a MAPK-independent pathway.
AB  - Fibroblast growth factors (FGFs) play important roles in diverse aspects of
      animal development including mammalian lung epithelial cell proliferation,
      differentiation, and branching morphogenesis. We developed an in vitro lung
      epithelial cell culture system to study functions and mechanisms of FGFs in
      regulating growth and differentiation of primary foetal rat lung epithelial
      cells. In comparison with other growth factors such as IGF-I, EGF, and HGF, FGFs
      were the most potent mitogens in stimulating lung epithelial cell proliferation.
      In the presence of FGF-1, 2, or 7, the primary lung epithelial cells could be
      propagated for generations and grown for more than two mo in vitro. Among the
      three FGFs tested, FGF-7 showed the strongest stimulation in cell growth. FGF-2,
      on the other hand, is the most effective inducer of lung epithelial cell-specific
      surfactant protein gene expression (SP-A, -B, and -C). FGF-2 upregulated SP-C
      expression in a dose-dependent manner. More interestingly, the induction of
      surfactant protein gene expression by FGF-2 appeared to be independent of MAPK
      pathway, since the SP-C expression was not inhibited but rather augmented by MEK1
      inhibitor which inhibited MAPK activation and cell proliferation. Similar effects
      were observed for the expressions of surfactant protein genes SP-A and SP-B. In
      contrast to MAPK, FGF-2-induced SP-C expression was partially inhibited by PI 3
      kinase inhibitor wortmannin. These data suggest dynamic roles and complex
      signalling mechanisms of FGFs in regulating lung epithelial cell proliferation
      and differentiation. While a MAPK-dependent pathway is essential for all three
      FGFs to stimulate cell proliferation, a MAPK-independent pathway may be
      responsible for the FGF-2-induced surfactant protein gene expression. PI 3-kinase
      may play an important role in mediating FGF-2-induced lung epithelial cell
      differentiation during development.

PMID- 10353698
TI  - Membrane proteins in health and disease. Proceedings of the 8th Fisher
      Winternational Symposium of the Canadian Society of Biochemistry and Molecular
      and Cellular Biology. Banff, Alberta, Canada. April 2-5, 1998.

PMID- 10353699
TI  - A novel electron transfer mechanism suggested by crystallographic studies of
      mitochondrial cytochrome bc1 complex.
AB  - The crystal structure of bovine mitochondrial cytochrome bc1 complex, an integral
      membrane protein complex of 11 different subunits with a total molecular mass of
      242 kDa, demonstrated a tightly associated dimer consisting of three major
      regions: a matrix region primarily made of subunits core1, core2, 6, and 9; a
      transmembrane-helix region of 26 helices in the dimer contributed by cytochrome
      b, cytochrome c1, the Rieske iron-sulfur protein (ISP), subunits 7, 10, and 11;
      and an intermembrane-space region composed of extramembrane domains of ISP,
      cytochrome c1, and subunit 8. The structure also revealed the positions of and
      distances between irons of prosthetic groups, and two symmetry related cavities
      in the transmembrane-helix region upon dimerization of the bc1 complex. Extensive
      crystallographic studies on crystals of bc1 complexed with inhibitors of electron
      transfer identified binding pockets for both Qo and Qi site inhibitors. Discrete
      binding sites for subtypes of Qo site inhibitors have been mapped onto the Qo
      binding pocket, and bindings of different subtypes of Qo site inhibitors are
      capable of inducing dramatic conformational changes in the extramembrane domain
      of ISP. A novel electron transfer mechanism for the bc1 complex consistent with
      crystallographic observations is discussed.

PMID- 10353700
TI  - Complex interactions between skeletal muscle ryanodine receptor and
      dihydropyridine receptor proteins.
AB  - Evidence for functional interactions between the Ca2+ release channel in the
      skeletal muscle sarcoplasmic reticulum (the ryanodine receptor) and the L-type
      Ca2+ channel in the sarcolemma (the dihydropyridine receptor), leading to
      excitation-contraction coupling, is reviewed and experimental systems used to
      identify candidate sites of interaction are outlined.

PMID- 10353701
TI  - Spectroscopic and biophysical approaches for studying the structure and function
      of the P-glycoprotein multidrug transporter.
AB  - Multidrug resistance is a serious obstacle to the successful chemotherapeutic
      treatment of many human cancers. A major cause of multidrug resistance is the
      overexpression of a 170-kDa plasma membrane protein, known as P-glycoprotein,
      which appears to function as an ATP-driven efflux pump with a very broad
      specificity for hydrophobic drugs, peptides, and natural products. P-Glycoprotein
      is a member of the ABC superfamily and is proposed to consist of two homologous
      halves, each comprising six membrane-spanning segments and a cytosolic nucleotide
      binding domain. In recent years, P-glycoprotein has been purified and
      functionally reconstituted into lipid bilayers, where it retains both ATPase and
      drug transport activity. The availability of purified active protein has led to
      substantial advances in our understanding of the molecular structure and
      mechanism of action of this unique transporter. This review will focus on the
      recent application of fluorescence spectroscopy, infra-red spectroscopy, circular
      dichroism spectroscopy, electron microscopy, and other biophysical techniques to
      the study of P-glycoprotein structure and function.

PMID- 10353702
TI  - Anion exchangers in the red cell and beyond.
AB  - The anion exchanger genes (AE1-3) encode a family of transport proteins
      responsible for the electroneutral exchange of bicarbonate and chloride across
      membranes. These transporters are important in processes such as pH regulation
      and bicarbonate metabolism. This article reviews recent progress in this field
      based on presentations made at a satellite workshop on anion exchangers held in
      conjunction with the 8th Fisher Winternational Symposium on Cellular and
      Molecular Biology entitled "Membrane proteins in health and disease." The
      transmembrane topology of AE1 has been refined using various combinations of
      protein chemistry and site-directed mutagenesis. The use of specific inhibitors
      and novel expression systems continues to reveal fundamental features of the
      anion exchanger mechanism and its regulation. The importance of anion exchangers
      in blood and kidney diseases is underscored by the identification and
      characterization of a plethora of novel mutations in the AE1 gene. Investigations
      of anion exchanger structure and function have moved beyond studies of the red
      cell protein into the larger arenas of cellular and molecular biology.

PMID- 10353703
TI  - Mechanism of competition between chloride and stilbenedisulfonates for binding to
      human erythrocyte band 3 (AE1).
AB  - Stilbenedisulfonates (S) constitute an important class of competitive inhibitors
      of the anion exchange (AE) function found in plasma membranes of various cell
      types. I present a brief summary of recent kinetic studies that provide insight
      into the mechanism of stilbenedisulfonate-chloride competition in binding to
      human erythrocyte band 3 (AE1) (B), the chloride-bicarbonate exchanger.
      Reversible stilbenedisulfonate binding follows a two-step mechanism (S + B <-->
      SB <--> SB*). Several lines of evidence are summarized that show that chloride,
      stilbenedisulfonates, and band 3 form a ternary complex, with chloride lowering
      stilbenedisulfonate affinity allosterically, by accelerating the rate of
      stilbenedisulfonate release. Of particular significance was our evidence
      demonstrating that extracellular chloride could accelerate stilbenedisulfonate
      release from its binding site on the outer surface of band 3 in resealed ghosts
      (i.e., acceleration in the release of a bound competitive inhibitor by a cis
      substrate). I suggest that the latter result may be consistent with our earlier
      proposal that band 3 follows a two-site ordered sequential mechanism, where two
      allosterically linked chloride binding transport sites move back and forth across
      the membrane together.

PMID- 10353705
TI  - A new concept in polytopic membrane proteins following from the study of band 3
      protein.
AB  - In the present communication, we introduce a novel concept in multispanning
      polytopic membrane proteins revealed by the study of the band 3 protein. The
      transmembrane domain of such proteins can be divided into three categories, that
      is, hydrophilic loops connecting transmembrane peptides (category 1), portions
      embedded by peptide-peptide interactions (category 2), and portions embedded by
      peptide-lipid interactions (category 3). Category 2 peptides of polytopic
      membrane proteins were found to stably reside in the lipid bilayer without
      peptide-lipid interactions that had been thought to be essential for
      transmembrane segments. Category 3 peptides are equivalent to single-spanning
      segments of bitopic membrane proteins. Three different experiments, namely
      proteolytic digestion, chemical modification of the band 3 protein, and cell free
      transcription and translation, were used to categorize the transmembrane
      peptides.

PMID- 10353704
TI  - The association between familial distal renal tubular acidosis and mutations in
      the red cell anion exchanger (band 3, AE1) gene.
AB  - In distal renal tubular acidosis (dRTA) the tubular secretion of hydrogen ion in
      the distal nephron is impaired, leading to the development of metabolic acidosis,
      frequently accompanied by hypokalemia, nephrocalcinosis, and metabolic bone
      disease. The condition can be familial, when it is usually inherited as an
      autosomal dominant, though there is a rarer autosomal recessive form associated
      with nerve deafness. It has been shown that the autosomal dominant form of dRTA
      is associated with a defect in the anion exchanger (AE1) of the renal collecting
      duct intercalated cell. This transporter is a product of the same gene (AE1) as
      the erythrocyte anion exchanger, band 3. In this review we will look at the
      evidence for this association. Studies of genomic DNA from families with this
      disorder have shown, both by genetic linkage studies and by DNA sequencing, that
      affected individuals are heterozygous for mutations in the AE1 gene whilst
      unaffected family members have a normal band 3 sequence. Mutations have been
      found in the region of proposed helices 6 and 7 of the membrane domain of band 3
      and involve amino acids Arg-589 and Ser-613, and in the COOH-terminal domain of
      band 3. Studies of red cell band 3 from these families have provided information
      on the effect these mutations have on the structure and function of erythrocyte
      band 3. Expression studies of the erythroid and kidney isoforms of the mutant AE1
      proteins, in Xenopus laevis oocytes, have shown that they retained chloride
      transport activity, suggesting that the disease in the dRTA families is not
      related simply to the anion transport activity of the mutated proteins. A
      possible explanation for the dominant effect of these mutant AE1 proteins in the
      kidney cell is that these mutations affect the targeting of AE1 from the
      basolateral to the apical membrane of the alpha-intercalated cell.

PMID- 10353706
TI  - Regulation and characterization of the Na+/H+ exchanger.
AB  - The Na+/H+ exchanger is a ubiquitous protein present in all mammalian cell types
      that functions to remove one intracellular H+ for one extracellular Na+. Several
      isoforms of the protein exist, which are referred to as NHE1 to NHE6 (for Na+/H+
      exchanger one through six). The NHE1 protein was the first isoform cloned and
      studied in a variety of systems. This review summarizes recent papers on this
      protein, particularly those that have examined regulation of the protein and its
      expression and activity.

PMID- 10353707
TI  - Na+/H+ exchanger: proton modifier site regulation of activity.
AB  - The Na+/H+ exchangers (NHE1-6) are integral plasma membrane proteins that
      catalyze the exchange of extracellular Na+ for intracellular H+. In addition to
      Na+ and H+ transport sites, NHE has an intracellular allosteric H+ modifier site
      that increases exchange activity when occupied by H+. NHE activity is also
      subject to control by a variety of extrinsic factors including hormones, growth
      factors, cytokines, and pharmacological agents. Many of these factors, working
      through second messenger pathways acting directly or indirectly on NHE, regulate
      NHE activity by shifting the apparent affinity of the H+ modifier site to more
      alkaline or more acid pH. The underlying molecular mechanisms involved in the
      activation of NHE by the H+ modifier site are poorly understood at this time, but
      likely involve slow protein conformational changes within a NHE oligomer. In this
      paper, we present initial experiments measuring intracellular pH-dependent
      transition rates between active and inactive oligomeric conformations and
      describe how these transition rates may be important for overall regulation of
      NHE activity.

PMID- 10353708
TI  - Mechanisms regulating the vascular smooth muscle Na/H exchanger (NHE-1) in
      diabetes.
AB  - Vascular disease is a major component of the complications associated with
      diabetes. The pathology involves hypertrophy and proliferation of vascular smooth
      muscle cells and the production and modification of extracellular matrix. The
      sodium/hydrogen exchanger has been widely implicated in the growth of multiple
      cell types, including vascular smooth muscle. Increases in sodium/hydrogen
      exchange activity serve as an effector or at least as an indicator of vascular
      activation. This article is concerned with the role of the biochemical
      abnormalities of diabetes exerting their pathological effects on vascular smooth
      muscle cells via altering sodium/hydrogen exchange activity.

PMID- 10353709
TI  - Recent advances in the molecular biology of nucleoside transporters of mammalian
      cells.
AB  - Nucleosides are hydrophilic molecules and require specialized transport proteins
      for permeation of cell membranes. There are two types of nucleoside transport
      processes: equilibrative bidirectional processes driven by chemical gradients and
      inwardly directed concentrative processes driven by the sodium electrochemical
      gradient. The equilibrative nucleoside transport processes (es, ei) are found in
      most mammalian cell types, whereas the concentrative nucleoside transport
      processes (cit, cif, cib, csg, cs) are present primarily in specialized
      epithelia. Using a variety of cloning strategies and functional expression in
      oocytes of Xenopus laevis, we have isolated and characterized cDNAs encoding the
      rat and human nucleoside transporter proteins of the four major nucleoside
      transport processes of mammalian cells (es, ei, cit, cif). From the sequence
      relationships of these proteins with each other and with sequences in the public
      data bases, we have concluded that the equilibrative and concentrative nucleoside
      transport processes are mediated by members of two previously unrecognized groups
      of integral membrane proteins, which we have designated the equilibrative
      nucleoside transporter (ENT) and the concentrative nucleoside transporter (CNT)
      protein families. This review summarizes the current state of knowledge in the
      molecular biology of the ENT and CNT protein families, focusing on the
      characteristics of the four human (h) and rat (r) nucleoside transport proteins
      (r/hENT1, r/hENT2, r/hCNT1, r/hCNT2).

PMID- 10353710
TI  - Nucleoside transporters and liver cell growth.
AB  - Liver parenchymal cells show a wide variety of plasma membrane transporters that
      are tightly regulated by endocrine and nutritional factors. This review
      summarizes work performed in our laboratory on these transport systems,
      particularly nucleoside transporters, which are up-regulated in physiological
      situations associated with liver cell growth. Rat hepatocytes show a Na+
      dependent nucleoside transport activity that is stimulated by pancreatic
      hormones. Indeed, this biological activity appears to be the result of the co
      expression of at least two isoforms of nucleoside carriers, CNT1 and CNT2 (also
      called SPNT). These two transporters are up-regulated during the early phase of
      liver growth after partial hepatectomy, although to different extents, suggesting
      differential regulation of the two isoforms. The recent generation of isoform
      specific antibodies allowed us to demonstrate that carrier expression may also
      have complex post-transcriptional regulation on the basis of the lack of
      correspondence between mRNA and protein levels. The analysis of nucleoside
      transport systems in hepatoma cells and the comparison with those in hepatocytes
      has also provided evidence that the differentiation status of liver parenchymal
      cells may determine the pattern of nucleoside transporters expressed.

PMID- 10353711
TI  - Calreticulin, a multifunctional Ca2+ binding chaperone of the endoplasmic
      reticulum.
AB  - Calreticulin is a ubiquitous endoplasmic reticulum Ca2+ binding chaperone. The
      protein has been implicated in a variety of diverse functions. Calreticulin is a
      lectin-like chaperone and, together with calnexin, it plays an important role in
      quality control during protein synthesis, folding, and posttranslational
      modification. Calreticulin binds Ca2+ and affects cellular Ca2+ homeostasis. The
      protein increases the Ca2+ storage capacity of the endoplasmic reticulum and
      modulates the function of endoplasmic reticulum Ca2+-ATPase. Calreticulin also
      plays a role in the control of cell adhesion and steroid-sensitive gene
      expression. Recently, the protein has been identified and characterized in higher
      plants but its precise role in plant cells awaits further investigation.

PMID- 10353712
TI  - A Zn(II)-translocating P-type ATPase from Proteus mirabilis.
AB  - A mutant of Proteus mirabilis had been previously isolated as defective in
      swarming. The mutation had been found to be in a gene related to the Escherichia
      coli zntA gene, which encodes the ZntA Zn(II)-translocating P-type ATPase. In
      this study the P. mirabilis gene was expressed in an E. coli strain in which the
      zntA gene had been disrupted. The P. mirabilis gene complemented the sensitivity
      to salts of zinc and cadmium. Everted membrane vesicles from the zntA-disrupted
      strain lost ATP-driven 65Zn(II) uptake. Membranes from the complemented strain
      had restored 65Zn(II) transport. These results demonstrate that the P. mirabilis
      homologue of ZntA is a Zn(II)-translocating P-type ATPase.

PMID- 10353713
TI  - Alpha-periodicity analysis of small multidrug resistance (SMR) efflux
      transporters.
AB  - Proteins in the small multidrug resistance (SMR) family of transport proteins are
      about 110 amino acids in length and are predicted to have four transmembrane
      helices. This family is divided into a two groups, one of which we have referred
      to as small multidrug pumps (Smp) and confer resistance to a wide variety of
      quaternary ammonium compounds through a proton-drug efflux antiport mechanism.
      Members of the second group within this family have, as yet, not had their
      substrate profile characterized and are referred to as Sug proteins. Alpha
      periodicity analysis was conducted on a set of six homologous proteins of the SMR
      family consisting of three established Smp and three Sug proteins. Several amino
      acid properties were used in the analysis including hydropathy, variability, and
      a substitution matrix for lipid exposed amino acids. The scanning window was
      varied between 8 and 14 residues and the alpha-periodicity was calculated from
      the peaks in the Fourier transform power spectra in the region between 3.0 and
      4.3 residues/turn. This analysis adds to the hydropathy analysis to give a more
      confident prediction of which residues are within the lipid bilayer for each of
      the four transmembrane helices. Information was also obtained that allowed for
      the identification of zones within each transmembrane helix that face the
      interior of the helical bundle on one side and are lipid exposed on the other
      face.

PMID- 10353714
TI  - Differential inhibition of AE1 and AE2 anion exchangers by oxonol dyes and by
      novel polyaminosterol analogs of the shark antibiotic squalamine.
AB  - Oxonol and polyaminosterol drugs were examined as inhibitors of recombinant mouse
      AE1 and AE2 anion exchangers expressed in Xenopus laevis oocytes and were
      compared as inhibitors of AE1-mediated anion flux in red cells and in HL-60 cells
      that express AE2. The oxonols WW-781, diBA(5)C4, and diBA(3)C4 inhibited HL-60
      cell Cl-/Cl- exchange with IC50 values from 1 to 7 microM, 100-1000 times less
      potent than their IC50 values for red cell Cl-/anion exchange. In Xenopus
      oocytes, diBA(5)C4 inhibited AE1-mediated Cl- efflux several hundred times more
      potently than that mediated by AE2. Several novel squalamine-related
      polyaminosterols were also evaluated as anion exchange inhibitors. In contrast to
      diBA(5)C4, polyaminosterol 1361 inhibited oocyte-expressed AE2 8-fold more
      potently than AE1 (IC50 0.6 versus 5.2 microM). The 3-fold less potent desulfo
      analog, 1360, showed similar preference for AE2. It was found that 1361 also
      partially inhibited Cl- efflux from red cells, whereas neither polyaminosterol
      inhibited Cl efflux from HL60 cells. Thus, the oxonol diBA(5)C4 is >100-fold more
      potent as an inhibitor of AE1 than of AE2, whereas the polyaminosterols 1360 and
      1361 are 8-fold more potent as inhibitors of AE2 than of AE1. Assay conditions
      and cell type influenced IC50 values for both classes of compounds.

PMID- 10353715
TI  - Pre-steady state transport by erythrocyte band 3 protein: uphill countertransport
      induced by the impermeant inhibitor H2DIDS.
AB  - Pre-steady state Cl- efflux experiments have been performed to test directly the
      idea that the transport inhibitor H2DIDS (4,4'-diisothiocyanatodihydrostilbene
      2,2'-disulfonate) binds preferentially to the outward-facing state of the
      transporter. Cells were equilibrated with a medium consisting of 150 mM sodium
      phosphate, pH 6.2, N2 atmosphere, and 80-250 microM 36Cl-. Addition of H2DIDS (10
      fold molar excess compared with band 3) induces a transient efflux of Cl-, as
      expected if H2DIDS binds more tightly to outward-facing than to inward-facing
      states. The size of the H2DIDS-induced efflux depends on the Cl- concentration
      and is about 700,000 ions per cell at the highest concentrations tested. The size
      of the transient efflux is larger than would be expected if the catalytic cycle
      for anion exchange involved one pair of exchanging anions per band 3 dimer. These
      results are completely consistent with a ping-pong mechanism of anion exchange in
      which the catalytic cycle consists of one pair of exchanging anions per subunit
      of the band 3 dimer.

PMID- 10353716
TI  - Spin-label studies of lipid-protein interactions with reconstituted band 3, the
      human erythrocyte chloride-bicarbonate exchanger.
AB  - Lipid-protein interactions in reconstituted band 3 preparations were investigated
      by using spin-labeled lipids in conjunction with electron paramagnetic resonance
      (EPR) spectroscopy. Purified erythrocyte band 3 was reconstituted into egg
      phosphatidylcholine liposomes at high protein density with preservation
      predominantly of the dimeric state. Lipid-protein associations were revealed by
      the presence of a component in the EPR spectra that, when compared to spectra
      obtained from protein-free bilayers, indicated that lipid chain motions are
      restricted by interactions with the protein. From the fraction of the motionally
      restricted component obtained from the phosphatidylcholine spin-label, a value of
      64 +/- 14 annular lipids per band 3 dimer was obtained. This agrees with a value
      of 62 for the number of lipids that may be accommodated around the electron
      density map of a band 3 dimer. Selectivity of various spin-labeled lipids for the
      protein revealed that androstanol had a lower affinity for the band 3 interface,
      whereas a distinct preference was observed for the negatively charged lipids
      phosphatidylglycerol and stearic acid over phosphatidylcholine. This preference
      for negatively charged lipids could not be screened by 1-M salt, indicating that
      electrostatic lipid-protein interactions are not dominant. Estimates of annular
      lipid exchange rates from measured acyl chain segmental motions suggested that
      the rate of exchange between bilayer and boundary lipids was approximately 10(6)
      s(-1), at least an order of magnitude slower than the rate of lipid lateral
      diffusion in protein-free bilayers.

PMID- 10353718
TI  - Expression, purification, and characterization of the carboxyl-terminal region of
      the Na+/H+ exchanger.
AB  - The Na+/H+ exchanger is a pH regulatory protein that is responsible for removal
      of excess intracellular protons in exchange for extracellular Na+. It is a plasma
      membrane protein with a large cytoplasmic carboxyl terminal domain that regulates
      activity of the membrane domain. We overexpressed and purified the cytoplasmic
      domain that was produced in Escherichia coli. This region (516-815 amino acids)
      was under control of the tac promoter from the plasmid pGEX-KG and was fused with
      glutathione S-transferase. Upon induction, the fusion protein was principally
      found in inclusion bodies. Purified inclusion bodies were solubilized and
      fractionated using preparative SDS polyacrylamide gel electrophoresis. To obtain
      free Na+/H+ exchanger protein the fusion protein was dialyzed against cleavage
      buffer and cleaved at the thrombin cleavage site between glutathione S
      transferase and the Na+/H+ exchanger domain. Free Na+/H+ exchanger protein was
      obtained by rerunning the sample on preparative gel electrophoresis. The final
      yield of the purified protein was 2.15 mg protein/L of cell culture. After
      exhaustive dialysis the secondary structure of the purified protein was assessed
      using circular dichroism spectroscopy. The results indicated that the protein was
      35% alpha-helix, 17% beta-turn, and 48% random coil. They suggest that the
      cytoplasmic domain is structured and some regions may be compact in nature.

PMID- 10353717
TI  - Structural and functional consequences of an N-glycosylation mutation (HEMPAS)
      affecting human erythrocyte membrane glycoproteins.
AB  - Band 3, the human erythrocyte anion exchanger (AE1), and the glucose transporter
      (GLUT1) proteins each contain a single site of N-glycosylation that is
      heterogeneously glycosylated. Lectin binding and enzymatic deglycosylation assays
      showed that the polylactosaminyl oligosaccharide structure of these glycoproteins
      was altered to a high mannose or hybrid glycan form in three patients with
      hereditary erythroblastic multinuclearity, with a positive acidified-serum lysis
      test (HEMPAS). Offspring from one of the HEMPAS patients had intermediate levels
      of polylactosaminyl oligosaccharide associated with AE1 and GLUT1, suggesting
      they may have been heterozygous for the genetic defect. The array of
      polylactosaminyl-containing glycoproteins present in EBV-transformed lymphoblasts
      derived from fresh blood of HEMPAS patients was similar to control lymphoblasts.
      HEMPAS lymphoblasts do not therefore express the defect in polylactosamine
      synthesis found in erythroid cells, indicating that lymphoid cells are not
      deficient in the processing enzymes or contain an alternative oligosaccharide
      processing pathway. Purified HEMPAS band 3 had an unaltered oligomeric structure
      but dimers aggregated more rapidly in detergent solution than normal band 3. The
      altered oligosaccharide structure did not affect the sensitivity of band 3 to
      proteolytic digestion in intact red cells but a greater amount of HEMPAS band 3
      was associated with the cytoskeleton. The transport activities of AE1 and GLUT1
      in HEMPAS erythrocytes were similar to those in normal controls. This shows that
      the HEMPAS glycosylation defect does not impair the functional accumulation of
      these two important erythrocyte membrane transporters even though it produces
      subtle structural changes in band 3 that result in its increased cytoskeletal
      interaction and self association in detergent solution.

PMID- 10353719
TI  - Stable expression of a recombinant sodium-dependent, pyrimidine-selective
      nucleoside transporter (CNT1) in a transport-deficient mouse leukemia cell line.
AB  - Previous studies of nucleoside transport in mammalian cells have identified two
      types of activities: the equilibrative nucleoside transporters and concentrative,
      Na+-nucleoside cotransporters. Characterization of the concentrative nucleoside
      transporters has been hampered by the presence in most cells and tissues of
      multiple transporters with overlapping permeant specificities. With the recent
      cloning of cDNAs encoding rat and human members of the concentrative nucleoside
      transporter (CNT) family, it is now possible to study the concentrative
      transporters in isolation by use of functional expression systems. We report here
      the isolation of a nucleoside transport-deficient subline of L1210 mouse leukemia
      (L1210/DNC3) that is a suitable recipient for stable expression of cloned
      nucleoside transporter cDNAs. We have used L1210/DNC3 as the recipient in gene
      transfer studies to develop a stable cell line (L1210/DU5) that produces the
      recombinant concentrative nucleoside transporter with selectivity for pyrimidine
      nucleosides (CNT1) that was initially identified in rat intestine (Q.Q. Huang,
      S.Y. Yao, M.W. Ritzel, A.R.P. Paterson, C.E. Cass, and J.D. Young. 1994. J. Biol.
      Chem. 269: 17,757-17,760). L1210/DU5 was used to examine the permeant selectivity
      of recombinant rat CNT1 by comparing a series of nucleoside analogs with respect
      to (i) inhibition of inward fluxes of [3H]thymidine, (ii) initial rates of
      transport of 3H-analog, and (iii) cytotoxicity to L1210/DU5 versus the parental
      transport-deficient cell line. By all three criteria, recombinant CNT1
      transported 5-fluoro-2'-deoxyuridine and 5-fluorouridine well and cytosine
      arabinoside poorly. Although some purine nucleosides (2'-deoxyadenosinedeoxyadeno
      2'-deoxyadenosine, 7-deazaadenosine) were potent inhibitors of CNT1, they were
      poor permeants when uptake was measured directly by analysis of isotopic fluxes
      or indirectly by comparison of cytotoxicity ratios. We conclude that comparison
      of analog cytotoxicity to L1210/DU5 versus L1210/DNC3 is a reliable indirect
      predictor of transportability, suggesting that cytotoxicity assays with a panel
      of such cell lines, each with a different recombinant nucleoside transporter,
      would be a valuable tool in the development of antiviral and antitumor nucleoside
      analogs.

PMID- 10353720
TI  - A highly selective, high-affinity transporter for uracil in Trypanosoma brucei
      brucei: evidence for proton-dependent transport.
AB  - The presence of an uptake mechanism for uracil in procyclic forms of the
      protozoan parasite Trypanosoma brucei brucei was investigated. Uptake of
      [3H]uracil at 22 degrees C was rapid and saturable and appeared to be mediated by
      a single high-affinity transporter, designated U1, with an apparent Km of 0.46 +/
      0.09 microM and a Vmax of 0.65 +/- 0.08 pmol x (10(7) cells)(-1) x s(-1).
      [3H]Uracil uptake was not inhibited by a broad range of purine and pyrimidine
      nucleosides and nucleobases (concentrations up to 1 mM), with the exception of
      uridine, which acted as an apparent weak inhibitor (Ki value of 48 +/- 15
      microM). Similarly, most chemical analogues of uracil, such as 5-chlorouracil, 3
      deazauracil, and 2-thiouracil, had little or no affinity for the U1 carrier. Only
      5-fluorouracil was found to be a relatively potent inhibitor of uracil uptake (Ki
      = 3.2 +/- 0.4 microM). Transport of uracil was independent of extracellular
      sodium and potassium gradients, as replacement of NaCl in the assay buffer by N
      methyl-D-glucamine, KCl, LiCl, CsCl, or RbCl did not affect initial rates of
      transport. However, the proton ionophore carbonyl cyanide chlorophenylhydrazone
      inhibited up to 70% of [3H]uracil flux. These data show that uracil uptake in T.
      b. brucei procyclics is mediated by a single high-affinity transporter with high
      substrate selectivity and are consistent with a nucleobase-H+-symporter model for
      this carrier.

PMID- 10353721
TI  - Evidence that the transport-related proteins BAT and 4F2hc are not specific for
      amino acids: induction of Na+-dependent uridine and pyruvate transport activity
      by recombinant BAT and 4F2hc expressed in Xenopus oocytes.
AB  - Members of the BAT and 4F2hc gene family have one or, in the case of BAT, up to
      four transmembane domains and induce amino acid transport systems b(o,+) (BAT)
      and y+L (4F2hc) when expressed in Xenopus oocytes. System b(o,+) is a Na+
      independent process with a broad tolerance for cationic and zwitterionic amino
      acids, whereas y+L exhibits Na+-independent transport of cationic amino acids
      (e.g., lysine) and Na+-dependent transport of zwitterionic amino acids (e.g.,
      leucine). Mutations in the human BAT gene are associated with type I cystinuria,
      a genetic disease affecting the ability of intestinal and renal brush border
      membranes to transport cationic amino acids and cystine. An unresolved question
      is whether BAT and 4F2hc themselves have catalytic (i.e., transporting) activity
      or whether they operate as activators of other, as yet unidentified, transporter
      proteins. In this report, we have investigated the transport of representatives
      of four different classes of organic substrates in Xenopus oocytes following
      injection with rat BAT or 4F2hc RNA transcripts: leucine (a control amino acid
      substrate), uridine (a nucleoside), pyruvate (a monocarboxylate), and choline (an
      amine). Both recombinant proteins induced small, statistically significant Na+
      dependent fluxes of uridine and pyruvate but had no effect on choline uptake. In
      contrast, control oocytes injected with transcripts for conventional nucleoside
      and cationic amino acid transporters (rat CNT1 and murine CAT1, respectively)
      showed no induction of transport of either leucine or pyruvate (CNT1) or uridine
      or pyruvate (CAT1). These findings support the idea that BAT and 4F2hc are
      transport activators and minimize the possibility that they have intrinsic
      transport capability. The transport-regulating functions of these proteins may
      extend to permeants other than amino acids.

PMID- 10353722
TI  - Protein folding and maturation in a cell-free system.
AB  - Reduced cellular systems have provided important tools to study complex cellular
      processes. Here we describe the oxidation, oligomerization, and chaperone binding
      of the viral glycoprotein influenza hemagglutinin in a cell-free system. The cell
      free system, comprised of rough endoplasmic reticulum derived microsomes and a
      reticulocyte lysate, supported the complete maturation of hemagglutinin from the
      earliest oxidative intermediate to the mature homo-oligomer. Hemagglutinin
      disulfide bond formation and oligomerization were found to occur in a time- and
      temperature-dependent manner. Hemagglutinin's temporal association with the
      molecular chaperones calnexin and calreticulin was similar to that observed for
      their association with elongating ribosome-attached nascent chains in live cells.
      Furthermore, a procedure is described that permits the translocation of protein
      into microsomes that are depleted of lumenal contents. This cell-free system,
      therefore, provided an effective means to study the biological maturation
      processes of a protein that traverses the secretory pathway.

PMID- 10353723
TI  - Overexpression of calreticulin fails to abolish its induction by perturbation of
      normal ER function.
AB  - Along with other endoplasmic reticulum (ER) Ca2+-binding proteins, notably the
      glucose-response proteins grp78 and grp94, expression of calreticulin is induced
      in response to perturbation of normal ER function. It has yet to be clearly
      defined how this stress is signaled from the ER to the nucleus in mammalian
      cells, particularly with regard to its initiation. Using a GFP-calreticulin
      fusion protein, we have generated and selected stably transfected HeLa cells that
      overexpress calreticulin to investigate whether the protein might be involved in
      signaling its own induction. Basal levels of endogenous calreticulin mRNA and
      protein were unaffected in these cells, indicating that overexpression alone does
      not induce a stress response. ER stress induced calreticulin expression in
      response to either thapsigargin or tunicamycin was equivalent in these cells to
      that seen in control, nontransfected cells, leading us to conclude that
      calreticulin is unlikely be involved in its own induction. Levels of the mRNA
      encoding the fusion protein were also increased by tunicamycin, but not
      thapsigargin, suggesting that, in agreement with our previous observations,
      inhibition of N-linked glycosylation may increase the stability of calreticulin
      mRNA. This indicates that in mammalian cells, there is more than one signaling
      pathway for the ER stress response.

PMID- 10353725
TI  - Development of difluoromethylornithine (DFMO) as a chemoprevention agent.
AB  - D,L-alpha-difluoromethylornithine (DFMO) was synthesized over 20 years ago. It
      was hoped that this enzyme-activated, irreversible inhibitor of ornithine
      decarboxylase, the first enzyme in polyamine synthesis, would be effective as a
      chemotherapy for hyperproliferative diseases, including cancer and/or infectious
      processes. DFMO was generally found to exert cytostatic effects on mammalian
      cells and tissues, and its effectiveness as a therapeutic agent has been modest.
      DFMO was also found to cause treatment-limiting (but reversible) ototoxicity at
      high doses. This side effect, along with its minimal therapeutic activity,
      contributed to the loss of interest by many clinicians in further developing DFMO
      as a cancer therapeutic agent. However, DFMO was subsequently shown to inhibit
      carcinogen-induced cancer development in a number of rodent models, and interest
      in developing this compound as a preventive agent has increased. The rationale
      for the inhibition of ornithine decarboxylase as a cancer chemopreventive agent
      has been strengthened in recent years because this enzyme has been shown to be
      transactivated by the c-myc oncogene in certain cell/tissue types and to
      cooperate with the ras oncogene in malignant transformation of epithelial
      tissues. Recent clinical cancer chemoprevention trials, using dose de-escalation
      designs, indicate that DFMO can be given over long periods of time at low doses
      that suppress polyamine contents in gastrointestinal and other epithelial tissues
      but cause no detectable hearing loss or other side effects. Current clinical
      chemoprevention trials are investigating the efficacy of DFMO to suppress
      surrogate end point biomarkers (e.g., colon polyp recurrence) of carcinogenesis
      in patient populations at elevated risk for the development of specific
      epithelial cancers, including colon, esophageal, breast, cutaneous, and prostate
      malignancies.

PMID- 10353724
TI  - Calreticulin, a component of the endoplasmic reticulum and of cytotoxic
      lymphocyte granules, regulates perforin-mediated lysis in the hemolytic model
      system.
AB  - Cytotoxic lymphocytes kill virally infected cells with specialized cytotoxic
      granules containing perforin, a protein that forms toxic pores in the target cell
      membrane. These specialized cytotoxic granules also contain calreticulin, an
      endoplasmic reticulum chaperone protein. The calcium-independent association of
      perforin and calreticulin prompted our evaluation of calreticulin's potential to
      function as a regulatory molecule that protects cytotoxic lymphocytes from their
      own perforin. We report here that 10(-7) M calreticulin blocked perforin-mediated
      lysis in the hemolytic model system using erythrocytes as targets. Previously, we
      found that millimolar levels of calcium in the hemolytic assays dissociate high
      affinity perforin-calreticulin complexes, which makes it unlikely that perforin
      associates with calreticulin in solution when hemolysis is blocked. Calreticulin
      may affect perforin at the erythrocyte membrane. We observed calcium-dependent
      binding of calreticulin to erythrocyte membranes with a Kd of 2.7 x 10(-7) M and
      a saturation average of 10(5) molecules calreticulin per erythrocyte. At
      concentrations that blocked hemolysis, calreticulin occupied many of the
      calreticulin membrane-binding sites and was in molar excess of perforin. These
      observations open the possibilities that membrane-bound calreticulin prevents
      hydrophobic entry of perforin into membranes and (or) prevents perforin from
      assembling into polyperforin pores.

PMID- 10353726
TI  - Phase I study of 90Y-labeled B72.3 intraperitoneal administration in patients
      with ovarian cancer: effect of dose and EDTA coadministration on pharmacokinetics
      and toxicity.
AB  - The tumor-associated glycoprotein 72 (TAG-72) antigen is present on a high
      percentage of tumor types including ovarian carcinomas. Antibody B72.3 is a
      murine monoclonal recognizing the surface domain of the TAG-72 antigen and has
      been widely used in human clinical trials. After our initial encouraging studies
      (M. G. Rosenblum et al., J. Natl. Cancer Inst., 83: 1629-1636, 1991) of tissue
      disposition, metabolism, and pharmacokinetics in 9 patients with ovarian cancer,
      we designed an escalating dose, multi-arm Phase I study of 90Y-labeled B72.3 i.p.
      administration. In the first arm of the study, patients (3 pts/dose level)
      received an i.p. infusion of either 2 or 10 mg of B72.3 labeled with either 1,
      10, 15, or 25 mCi of 90Y. Pharmacokinetic studies demonstrated that
      concentrations of 90Y-labeled B72.3 persist in peritoneal fluid with half-lives
      >24 h after i.p. administration. In addition, 90Y-labeled B72.3 was absorbed
      rapidly into the plasma with peak levels achieved within 48 h, and levels
      declined slowly thereafter. Cumulative urinary excretion of the 90Y label was 10
      20% of the administered dose which suggests significant whole-body retention of
      the radiolabel. Biopsy specimens of bone and marrow obtained at 72 h after
      administration demonstrated significant content of the label in bone (0.015% of
      the dose/g) with relatively little in marrow (0.005% of the dose/g). The maximal
      tolerated dose was determined to be 10 mCi because of hematological toxicity and
      platelet suppression. This typically occurred on the 29th day after
      administration and was thought to be a consequence of the irradiation of the
      marrow from the bony deposition of the radiolabel. In an effort to suppress the
      bone uptake of 90Y, patients were treated with a continuous i.v. infusion of EDTA
      (25 mg/kg/12 h x 6) infused immediately before i.p. administration of the
      radiolabeled antibody. Patients (3 pts/dose level) were treated with doses of 10,
      15, 20, 25, 30, 35, 40, or 45 mCi of 90Y-labeled B72.3 for a total of 38
      patients. EDTA administration resulted in significant myeloprotection, which
      allowed escalation to the maximal tolerated dose of 40 mCi. Dose-limiting
      toxicity was thrombocytopenia and neutropenia. Studies of plasma and peritoneal
      fluid pharmacokinetics demonstrate no changes compared with patients without EDTA
      pretreatment. Cumulative urinary excretion of the radiolabel was not increased in
      patients pretreated with EDTA compared with the untreated group. However,
      analysis of biopsy specimens of bone and marrow demonstrated that bone and marrow
      content of the 90Y label was 15-fold lower (<0.001% injected dose/g) than a
      companion group without EDTA. Four responses were noted in patients who received
      15-30 mCi of 90Y-labeled B72.3 with response durations of 1-12 months. These
      results demonstrate the myeloprotective ability of EDTA, which allows safe i.p.
      administration of higher doses of 90Y-labeled B72.3 and, therefore, clearly
      warrant an expanded Phase II trial in patients with minimal residual disease
      after standard chemotherapy or for the palliation of refractory ascites.

PMID- 10353727
TI  - Centrosome abnormalities in pancreatic ductal carcinoma.
AB  - The centrosome plays an important role in microtubule nucleation and
      organization, ensuring the establishment of cell polarity and balanced chromosome
      segregation. Recent studies have suggested that the loss of cell polarity and/or
      chromosome missegregation (aneuploidy) in human malignant tumors could result
      from defects in centrosome function. Using immunofluorescence analysis with an
      antibody to gamma-tubulin (a well-characterized centrosomal component), we
      examined surgically resected human pancreatic tissues for centrosome
      abnormalities. The tissues included ductal carcinomas (n = 13), adenomas (n = 3),
      endocrine tumors (n = 3), chronic pancreatitis (n = 5), and normal pancreatic
      tissues (n = 12). We found that most (85%) carcinomas and some adenomas displayed
      abnormal centrosome profiles, characterized by an increase in size and number of
      centrosomes, and by their irregular distribution. In contrast, none of normal
      ductal and stromal tissues showed these abnormalities. These findings suggest
      that centrosome abnormalities may develop at a relatively early stage of
      pancreatic ductal carcinogenesis.

PMID- 10353728
TI  - Molecular detection of telomerase-positive circulating epithelial cells in
      metastatic breast cancer patients.
AB  - The detection of circulating tumor cells and micrometastases may have important
      therapeutic and prognostic implications. Telomerase is a hallmark of cancer and
      is absent from normal epithelial cells. The aim of this study was to use
      telomerase activity as a molecular marker for the detection of cancer cells in
      blood of patients with breast cancer. Blood samples were collected from 25 women
      with stage IV breast cancer and 9 healthy volunteers. Peripheral blood
      mononuclear cells were isolated by using Ficoll/Hypaque. Immunomagnetic beads
      coated with an epithelial-specific antibody (BerEP4) were used to harvest
      epithelial cells from peripheral blood mononuclear cells. Telomerase activity was
      detected in harvested epithelial cells (HECs) using two different telomerase-PCR
      ELISA methods. HECs from blood samples of 21 of 25 (84%) patients with breast
      cancer were telomerase positive. Telomerase activity was undetectable in HECs
      from the nine healthy volunteers, demonstrating the specificity of the
      association between telomerase activity in HECs and stage IV breast cancer. Thus,
      determination of telomerase activity in HECs appears to be a sensitive, specific,
      and noninvasive approach for detecting circulating epithelial cancer cells in
      patients with metastatic breast cancer. This method could be of great value in
      monitoring the cancer cell proliferation during chemotherapy. This study should
      be now extended to patients with early-stage breast cancer to investigate the
      role of telomerase expression by HECs and to evaluate its prognostic value.

PMID- 10353729
TI  - Overexpression of the cyclin-dependent kinase inhibitor p16 is associated with
      tumor recurrence in human prostate cancer.
AB  - The INK4A gene maps to the 9p21 region and was initially described [M. Serrano et
      al., Nature (Lond.), 366: 704-707, 1993; A. Kamb et al., Science (Washington DC),
      264: 436-440, 1994] as encoding a 148-amino-acid protein termed p16. The p16
      protein associates exclusively with Cdk4 and Cdk6, inhibiting their complexation
      with D-type cyclins and the consequent phosphorylation of pRb. This contributes
      to cell cycle arrest. The purpose of the present study was to evaluate patterns
      of p16 expression in a well-characterized cohort of prostatic adenocarcinomas
      while exploring potential associations between alterations of p16 and
      clinicopathological variables. Normal and malignant tissues from 88 patients with
      prostate carcinoma were examined. In situ hybridization and immunohistochemistry
      assays were used to determine the status of the INK4A exon 1alpha transcripts and
      levels of p16 protein, respectively. Associations between altered patterns of
      expression and clinicopathological variables, including pretreatment prostate
      specific antigen (PSA) level, Gleason grade, pathological stage, and hormonal
      status, were evaluated using the Mantel-Haenszel chi2 test. Biochemical (PSA)
      relapse after surgery was evaluated using the Kaplan-Meier method and the log
      rank test. Levels of p16 expression and INK4A exon 1alpha transcripts in normal
      prostate and benign hyperplastic tissues were undetectable. However, p16 nuclear
      overexpression was observed in 38 (43%) prostate carcinomas, whereas the
      remaining 50 (57%) cases showed undetectable p16 levels. Overexpression of p16
      protein was found to correlate with increased INK4A exon 1alpha transcripts.
      Moreover, p16 overexpression was associated with a higher pretreatment PSA level
      (P = 0.018), the use of neoadjuvant androgen ablation (P = 0.001), and a sooner
      time to PSA relapse after radical prostatectomy (P = 0.002). These data suggest
      that p16 overexpression is associated with tumor recurrence and a poor clinical
      course in patients with prostate cancer.

PMID- 10353730
TI  - Receptor for interleukin 13 is a marker and therapeutic target for human high
      grade gliomas.
AB  - Glioblastoma multiforme (GBM) is an incurable brain tumor. Due to the striking
      heterogeneity that characterizes GBM, there is no known tumor-specific antigen or
      receptor that is expressed by a majority of GBM patients. We found that virtually
      all studied human GBM specimens (23 samples) abundantly expressed a receptor for
      interleukin (IL)-13 in situ, whereas normal human brain had few, if any, IL-13
      binding sites. The GBM-associated IL-13 receptor was both quantitatively and
      qualitatively different from and, thus, more restrictive than the shared
      signaling receptor of normal tissue: it was IL-4 independent. The receptor for IL
      13 was overexpressed by a majority of cancer cells in situ. Furthermore,
      cytotoxins targeted to this more restrictive IL-13R produced cures in animals
      bearing xenografts of human high-grade gliomas. Thus, unexpectedly, the receptor
      for an immune regulatory cytokine may be a long sought marker and, concomitantly,
      a unique imaging site and therapeutic target for GBM, the most malignant and the
      most heterogeneous of brain tumors.

PMID- 10353731
TI  - Comparison of features of human lung cancer cell lines and their corresponding
      tumors.
AB  - Although human lung tumor-derived cell lines play an important role in the
      investigation of lung cancer biology and genetics, there is no comprehensive
      study comparing the genotypic and phenotypic properties of lung cancer cell lines
      with those of the individual tumors from which they were derived. We compared a
      variety of properties of 12 human non-small cell lung carcinoma (NSCLC) cell
      lines (cultured for a median period of 39 months; range, 12-69) and their
      corresponding archival tumor tissues. There was, in general, an excellent
      concordance between the lung tumor cell lines and their corresponding tumor
      tissues for morphology (100%), the presence of aneuploidy (100%),
      immunohistochemical expression of HER2/neu (100%) and p53 proteins (100%), loss
      of heterozygosity at 13 chromosomal regions analyzed (97%) using 37
      microsatellite markers, microsatellite alterations (MAs, 75%), TP53 (67%), and K
      ras (100%) gene mutations. In addition, there was 100% concordance for the
      parental allele lost in all 115 comparisons of allelic losses. Some discrepancies
      were found; more aneuploid subpopulations of cells were detected in the cell
      lines as well as higher incidences of TP53 mutations (4 of 10 mutations not found
      in the tumors) and microsatellite alterations (two cell lines with MAs not
      detected in the tumors). Similar loss of heterozygosity frequencies by
      chromosomal regions and mean fractional allelic loss index were detected between
      successfully cultured and 40 uncultured lung tumors (0.45 and 0.49,
      respectively), indicating that both groups were similar. Our findings indicate
      that the NSCLC cell lines in the large majority of instances retain the
      properties of their parental tumors for lengthy culture periods. NSCLC cell lines
      appear very representative of the lung cancer tumor from which they were derived
      and thus provide suitable model systems for biomedical studies of this important
      neoplasm.

PMID- 10353732
TI  - Prognostic significance of elevated cyclooxygenase 2 expression in primary,
      resected lung adenocarcinomas.
AB  - Recently, we demonstrated that elevated expression of cyclooxygenase 2 (COX-2) is
      frequently seen in a specific type of lung cancer, i.e., adenocarcinoma, and is
      possibly associated with its invasion and metastasis. Here, the prognostic
      significance of elevated COX-2 expression was evaluated in a cohort of 130
      adenocarcinoma patients who had consecutively undergone potentially curative
      resections. Immunohistological examination showed the presence of tumor cells
      with markedly increased COX-2 immunoreactivity in 93 of 130 (72%) cases. No
      relationship was found between the increase in COX-2 expression and clinical
      outcomes when the entire cohort was considered (P = 0.099). Reasoning that the
      influence of the increase in COX-2 expression may have been obscured by the
      clinical and molecular pathogenetic complexities in cases with an advanced
      disease, we also separately analyzed the prognostic significance of increased COX
      2 expression after stratification according to the disease stage. A significant
      relationship between elevated COX-2 expression and shortened patient survival was
      observed only in a cohort of patients with stage I disease (P = 0.034). These
      findings suggest that an increase in COX-2 expression may be clinically
      significant for the prognosis of patients undergoing surgical resection of early
      stage adenocarcinomas and, thus, warrant further conclusive studies involving a
      larger cohort.

PMID- 10353733
TI  - Cisplatin-induced activation of mitogen-activated protein kinases in ovarian
      carcinoma cells: inhibition of extracellular signal-regulated kinase activity
      increases sensitivity to cisplatin.
AB  - Cisplatin treatment activates multiple signal transduction pathways, which can
      lead to several cellular responses including cell cycle arrest, DNA repair,
      survival, or apoptosis. We investigated the response of the mitogen-activated
      protein kinases, extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun-N
      terminal kinase 1 (JNK1), and p38, to cisplatin treatment in the ovarian
      carcinoma cell line SK-OV-3. Cisplatin caused a late and prolonged induction in a
      dose-dependent manner of both ERK1/2 and JNK1 activity. ERK1/2 and JNK1
      activities continued to increase in magnitude up to 24 h following initiation of
      cisplatin treatment. In contrast, cisplatin treatment had no effect on p38
      activity. Transplatin failed to induce either ERK1/2 or JNK1 at 24 h, which
      suggests that the activation of these kinases was dependent on cisplatin-specific
      DNA damage. Treatment with cycloheximide resulted in inhibition of cisplatin
      induced ERK1/2 activation, demonstrating that ERK1/2 activity induced by
      cisplatin was dependent on de novo protein synthesis. Furthermore, inhibition of
      cisplatin-induced ERK1/2 activity by PD 98059 caused enhanced cisplatin
      cytotoxicity. Similar enhanced cytotoxic effects of cisplatin were also observed
      following treatment with PD 98059 in the ovarian carcinoma cell line UCI 101.
      These observations indicate that ERK1/2 activation induced by cisplatin partially
      protects cells from cisplatin cytotoxicity. Continued investigation into the
      mechanism by which the ERK pathway and other signal transduction pathways
      modulate the response to cisplatin may be helpful in the development of new
      strategies for improving the therapeutic use of platinum drugs.

PMID- 10353735
TI  - Locoregional regulatory peptide receptor targeting with the diffusible
      somatostatin analogue 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC): a pilot
      study in human gliomas.
AB  - Human gliomas, especially of low-grade type, have been shown to express high
      affinity somatostatin receptor type 2 (J-C. Reubi et al., Am. J. Pathol, 134: 337
      344, 1989). We enrolled seven low-grade and four anaplastic glioma patients in a
      pilot study using the diffusible peptidic vector 90Y-labeled DOTA0-D-Phe1-Tyr3
      octreotide (DOTATOC) for receptor targeting. The radiopharmakon was
      locoregionally injected into a stereotactically inserted Port-a-cath. DOTATOC
      competes specifically with somatostatin binding to somatostatin receptor type 2
      in the low nanomolar range as shown by a displacement curve of 125I-[Tyr3]
      octreotide in tumor tissue sections. Diagnostic (111)In-labeled DOTATOC
      scintigraphy following local injection displayed homogeneous to nodular
      intratumoral vector distribution. The cumulative activity of regionally injected
      peptide-bound 90Y amounted to 370-3300 MBq, which is equivalent to an effective
      dose range between 60 +/- 15 and 550 +/- 110 Gy. Activity was injected in one to
      four fractions according to tumor volumes; 1110 MBq of 90Y-labeled DOTATOC was
      the maximum activity per single injection. We obtained six disease stabilizations
      and shrinking of a cystic low-grade astrocytoma component. The only toxicity
      observed was secondary perifocal edema. The activity:dose ratio (MBq:Gy)
      represents a measure for the stability of peptide retention in receptor-positive
      tissue and might predict the clinical course. We conclude that SR-positive human
      gliomas, especially of low-grade type, can be successfully targeted by
      intratumoral injection of the metabolically stable small regulatory peptide
      DOTATOC.

PMID- 10353734
TI  - Recombinant adenovirus expressing wild-type p53 is antiangiogenic: a proposed
      mechanism for bystander effect.
AB  - Angiogenesis is required for the growth and progression of malignancies. Recent
      studies have demonstrated that genetic alterations may accompany acquisition of
      the angiogenic phenotype. The tumor suppressor gene p53 is most frequently
      mutated in human cancers and is also known to be a transcriptional regulator of a
      variety of genes. Here, we investigated the antiangiogenic effect of the wild
      type p53 (wt-p53) gene transfer on a human non-small cell lung cancer cell line.
      Mutant p53-expressing H226Br non-small cell lung cancer cells were transduced
      with the wt-p53 gene using a recombinant adenoviral vector (Ad5CMVp53) and
      applied to semiquantitative reverse transcription-PCRs for the detection of
      altered mRNA expression of angiogenic and/or antiangiogenic factors. In vivo
      neovascularization assay of Ad5CMVp53-infected cells was then performed using a
      membrane-diffusion chamber system s.c. transplanted in nu/nu mice. We also
      evaluated the effect of Ad5CMVp53-infected H226Br cells on nontransduced tumor
      cells in vivo by s.c. inoculating mixture of cells into nu/nu mice. Ad5CMVp53
      infection markedly inhibited the expression of an angiogenic factor, vascular
      endothelial growth factor, and increased the expression of a novel antiangiogenic
      factor, brain-specific angiogenesis inhibitor 1, resulting in reduced
      neovascularization in vivo. Mixing experiments showed that tumor cells transduced
      with the wt-p53 gene inhibited the in vivo tumor growth of adjacent nontransduced
      cells. Our data suggest that a recombinant adenovirus expressing the wt-p53 gene
      is antiangiogenic, which may explain, in part, the mechanism of the bystander
      effect induced by the wt-p53 gene transfer on adjacent tumor cells.

PMID- 10353736
TI  - Efficacy and safety of simultaneous immunomagnetic CD34+ cell selection and
      breast cancer cell purging in peripheral blood progenitor cell samples used for
      hematopoietic rescue after high-dose therapy.
AB  - We have established a new simultaneous positive/negative selection procedure
      using the Baxter Isolex 300i system. We tested its tumor cell (TC) purging
      efficacy by tumor contamination tests ex vivo and its safety in a group of 17
      breast cancer (BC) patients by measuring hematopoietic recovery after high-dose
      (HD) therapy and autologous stem cell rescue with the selected cells. Tumor
      contamination tests resulted in a TC depletion of 4.1-6.0 log steps. The CD34+
      cell yield in this experimental setting was 38.9-91.5%, and the CD34+ cell purity
      was 86.0-96.0%. In a group of 17 BC patients (5 high-risk adjuvant, > or = 10
      lymph nodes positive, and 12 metastatic), we processed leukapheresis products
      (LPs) by simultaneous positive/negative selection. In these clinical samples, the
      mean CD34+ cell yield was 56.2% (range, 14.0-80.1%), and the CD34+ cell purity
      was 94.5% (range, 69.0-99.8%). Additionally, we screened samples of the patients'
      LPs before and after the purging procedure for contaminating TC by
      immunocytochemistry. In 15 of 17 tested cases, TCs were detectable prior to the
      purging procedure. After the procedure, we could not detect residual TCs in 16 of
      17 cases. In one case, we found a highly reduced number of TCs. Furthermore, we
      evaluated the times for hematopoietic reconstitution in a group of five BC
      patients in the high-risk adjuvant situation who underwent HD chemotherapy and
      hematopoietic rescue with positive/negative selected stem cells and compared it
      with our own data from 10 BC patients who, after identical HD therapy, received
      only positively selected CD34+ cells and 14 patients who, after identical HD
      therapy, received autografts purged by incubation with toxic ether lipids (ET-18
      OCH3). In all groups, a leukocyte count of >2000 cells/microl was reached at day
      +10. A platelet count of > 50,000 cells/microl was reached at day +12 in the ET
      18-OCH3 group and at day +14 in the other two groups. Furthermore, 12 patients
      with metastatic disease rescued with positive/negative selected stem cells after
      HD therapy also showed fast and comparable hematopoietic recovery. The new
      simultaneous immunomagnetic positive/negative selection using a closed system is
      effective and safe. Processing LPs leads to a similar CD34+ cell yield, a higher
      TC depletion compared to standard CD34+ cell selection, and no delay in
      hematopoietic recovery.

PMID- 10353738
TI  - Paradoxical correlations of cyclin-dependent kinase inhibitors p21waf1/cip1 and
      p27kip1 in metastatic colorectal carcinoma.
AB  - The cyclin-dependent kinase inhibitors (CDIs) p27kip1 and p21waf1/cip1 are key
      cell cycle-negative regulatory enzymes. The objective of this study was to
      correlate expression of p27kip1 and p21waf1/cip1 with survival, chemotherapy
      responsiveness, and expression of the proliferation marker Ki-67 in patients with
      advanced colorectal cancer. Immunohistochemistry was performed with antibodies to
      p27kip1, p21waf1/cip1, and Ki-67 on samples from 66 patients with metastatic
      colorectal carcinoma. Interpretation was performed by visual inspection and
      automated image analysis. Patients who obtained a response to chemotherapy had
      greater p21waf1/cip1 tumor staining with a mean of 10.0 positive cells/high
      powered field, compared with 4.5 positive cells/high-powered field for
      nonresponders (P = 0.03). A positive Spearman correlation was seen between Ki-67
      and p27kip1 (r = 0.48; P = 0.0001), as well as between Ki-67 and p21waf1/cip1 (r
      = 0.48; P = 0.0001). A trend toward shorter survival was seen in patients with
      positive specimens (median survival of 10 months for patients with both p27kip1-
      and p21waf1/cip1-positive specimens, compared with 22 months for patients with
      neither p27kip1- nor p21waf1/cip1-positive specimens). In contrast to that
      previously reported in normal colonic mucosa or early-stage colorectal cancer, we
      observed positive correlations of Ki-67 with both p27kip1 and p21waf1/cip1, a
      trend toward greater CDI staining indicating worse prognosis, and greater
      p21waf1/cip1 staining in tumors that were chemosensitive. These findings suggest
      that in the metastatic setting, CDIs may show altered function, compared with
      their role in the normal cell cycle.

PMID- 10353737
TI  - Vascular stroma formation in carcinoma in situ, invasive carcinoma, and
      metastatic carcinoma of the breast.
AB  - The generation of vascular stroma is essential for solid tumor growth and
      involves stimulatory and inhibiting factors as well as stromal components that
      regulate functions such as cellular adhesion, migration, and gene expression. In
      an effort to obtain a more integrated understanding of vascular stroma formation
      in breast carcinoma, we examined expression of the angiogenic factor vascular
      permeability factor (VPF)/vascular endothelial growth factor (VEGF); the VPF/VEGF
      receptors flt-1 and KDR; thrombospondin-1, which has been reported to inhibit
      angiogenesis; and the stromal components collagen type I, total fibronectin, ED
      A+ fibronectin, versican, and decorin by mRNA in situ hybridization on frozen
      sections of 113 blocks of breast tissue from 68 patients including 28 sections of
      breast tissue without malignancy, 18 with in situ carcinomas, 56 with invasive
      carcinomas, and 8 with metastatic carcinomas. A characteristic expression profile
      emerged that was remarkably similar in invasive carcinoma, carcinoma in situ, and
      metastatic carcinoma, with the following characteristics: strong tumor cell
      expression of VPF/VEGF; strong endothelial cell expression of VPF/VEGF receptors;
      strong expression of thrombospondin-1 by stromal cells and occasionally by tumor
      cells; and strong stromal cell expression of collagen type I, total fibronectin,
      ED-A+ fibronectin, versican, and decorin. The formation of vascular stroma
      preceded invasion, raising the possibility that tumor cells invade not into
      normal breast stroma but rather into a richly vascular stroma that they have
      induced. Similarly, tumor cells at sites of metastasis appear to induce the
      vascular stroma in which they grow. We conclude that a distinct pattern of mRNA
      expression characterizes the generation of vascular stroma in breast cancer and
      that the formation of vascular stroma may play a role not only in growth of the
      primary tumor but also in invasion and metastasis.

PMID- 10353740
TI  - Expression of the hyaluronan receptor, CD44S, in epithelial ovarian cancer is an
      independent predictor of survival.
AB  - Most ovarian carcinomas present at advanced stage, principally as the result of
      dissemination to peritoneal sites. Standard CD44 (CD44S) is the principal
      receptor for hyaluronic acid, and in vitro and animal studies have suggested that
      the attachment of ovarian carcinoma cells to the peritoneal mesothelium involves
      the interaction between CD44S on ovarian carcinoma cells and hyaluronic acid on
      mesothelial surfaces. We, therefore, analyzed a series of ovarian carcinomas for
      the expression of CD44S by immunohistochemistry to see whether expression of this
      receptor by tumor cells correlated with clinicopathological factors and measures
      of patient outcome. Fifty-six fixed, paraffin-embedded primary epithelial ovarian
      tumors were immunostained with antibody to CD44S. Membrane staining was
      considered positive, and results were correlated with stage, grade, age,
      histology, and survival. Twenty-two (39%) tumors were positive for CD44S. There
      was no correlation between CD44 expression and histological type, grade, age, or
      stage. However, CD44 expression was significantly associated with survival in
      both univariate (P = 0.003) and multivariate (P = 0.006) analyses. These results
      support a role for CD44S expression in the spread of ovarian epithelial cancer
      and suggest that expression of this molecule is a significant independent
      predictor of survival in women with this disease.

PMID- 10353739
TI  - Alterations in expression of basic fibroblast growth factor (FGF) 2 and its
      receptor FGFR-1 in human prostate cancer.
AB  - Fibroblast growth factors (FGFs) play an important role in the growth and
      maintenance of the normal prostate. There is increasing evidence from both animal
      models and analysis of human prostate cancer cell lines that alterations of FGFs
      and/or FGF receptors (FGFRs) may play an important role in prostate cancer
      progression. To better define the role of FGF2 and FGF7 in human prostate cancer
      in vivo, we have quantified these two growth factors in clinically localized
      human prostate cancers and uninvolved prostate by ELISA and Western blotting and
      determined their localization by immunohistochemistry. The expression of two of
      the primary receptors for these growth factors, FGFR-1 and FGFR-2, were also
      analyzed by immunohistochemistry and Western blotting in these same samples. We
      have found that FGF2 is significantly increased in prostate cancers when compared
      with uninvolved prostate and that the FGF2 is present in the stromal fibroblasts
      and endothelial cells but not the cancer cells. In addition, we have observed
      overexpression of both FGFR-1 and FGFR-2 in the prostate cancer epithelial cells
      in a subset of prostate cancers and that such overexpression is correlated with
      poor differentiation. Thus, there is both an increase in FGF2 concentration in
      prostate cancers and an increased expression of a receptor capable of responding
      to this growth factor, establishing a potential paracrine stimulation of prostate
      cancer cells by the surrounding stromal cells, which may play an important role
      in prostate cancer progression.

PMID- 10353741
TI  - Estrogen receptor methylation is associated with improved survival in adult acute
      myeloid leukemia.
AB  - Estrogen receptor methylation (ERM) is a frequent molecular alteration in adult
      acute myeloid leukemia (AML). In this study, we sought to determine the clinical
      characteristics and prognostic significance of ERM in AML. ERM was determined for
      268 patients who had leukemic blasts available for molecular analysis. ERM was
      measured by Southern blot analysis, and results were obtained for 261 patients
      (ages 17-69). ERM ranged from 0-99.1%, with a median of 25%. One hundred sixty
      patients (61%) had ERM values over 15% and were considered ERM+. In a subset of
      patients analyzed, ERM+ samples had markedly lower ER gene expression compared
      with ERM- samples. In multiple regression analyses of patient and disease
      characteristics at diagnosis, two factors had significant independent association
      with ERM: ERM decreased with increasing age (P = 0.0001) and was significantly
      lower in patients with French-American-British classification M4 or M5 (P =
      0.0019). In regression analyses of outcome measures, ERM had no significant
      impact on complete remission rate after initial induction therapy. However, ERM+
      patients had significantly better overall survival [OS; 18% at 6 years; 95%
      confidence interval (CI), 12-24% versus 9%; CI, 3-14% for ERM- patients; P =
      0.022]. In multiple regression analyses, OS increased with increasing ERM (P =
      0.0044). Similar results were seen for relapse-free survival (23% at 6 years; CI,
      15-32% for ERM+ versus 10%; CI, 2-19% for ERM-), although the effect of ERM was
      not statistically significant (P = 0.15 in multiple regression analysis). Our
      results indicate that ERM at diagnosis may be a favorable prognostic factor for
      OS in adult AML.

PMID- 10353742
TI  - Disrupted p53 function as predictor of treatment failure and poor prognosis in B-
      and T-cell non-Hodgkin's lymphoma.
AB  - Mutation of the p53 gene has been associated with treatment failure and poor
      outcome in various malignancies. It has been suggested that immunohistochemical
      analysis of p53 and p21Waf1, a downstream target, can be used to screen for p53
      gene mutations. We determined the value of immunohistochemical screening for p53
      gene mutations as a prognostic marker in a population-based group of B- and T
      cell non-Hodgkin's lymphomas (NHLs). On the basis of p53 gene mutation status and
      immunohistochemically detected p53 and p21Waf1 expression in 34 lymphomas, we
      established an immunophenotype (delta p53) correlating with p53 gene mutation.
      The immunohistochemical analysis was extended to encompass 199 lymphomas from a
      population-based registry and was correlated with clinical parameters. Delta p53
      showed 100% concordance with p53 gene mutation and was detected in 42 cases
      (21%). Multivariate analysis of advanced stage lymphomas showed that delta p53
      was independently associated with treatment failure (relative risk, 3.8; P =
      0.001). Delta p53 predicted poor survival when analyzing all patients (P =
      0.0001), as well as B-cell (P = 0.04) and T-cell NHL (P = 0.000002). In
      multivariate analysis, delta p53 (relative risk, 2.2; P = 0.001) maintained
      prognostic significance. The impact on prognosis of delta p53 was highly
      significant in the low-intermediate-risk group (P = 0.00002). Comparing survival
      of the aggressive lymphoma patients in this group showed that the 8 delta p53
      patients died within 1 year, whereas the median survival of the 28 non-delta p53
      patients was 36 months. These results suggest that immunohistochemically assessed
      p53 status may predict treatment response and outcome in B- and T-cell NHL
      patients.

PMID- 10353743
TI  - Endothelial cell nitric oxide synthase in peritumoral microvessels is a favorable
      prognostic indicator in premenopausal breast cancer patients.
AB  - Nitric oxide (NO) is involved in tumor cell apoptosis and has additional effects
      on tumor blood flow, immune responses, and angiogenesis. We, therefore, studied
      endothelial cell NO synthase (ecNOS) protein expression in a retrospective series
      of 118 patients with primary invasive breast cancer. Immunocytochemically stained
      paraffin sections were used for determining the frequency of (a) tumor cells, (b)
      intratumoral microvessels, and (c) peritumoral microvessels that were positive
      for ecNOS. A high density of ecNOS positive microvessels in the normal tissue
      surrounding the tumor (measured by the variable PEMVD) was associated with
      significantly better recurrence-free and overall survival. The prognostic
      significance was observed in a representative series of premenopausal patients
      and was independent of other factors, including lymph node status. The counting
      procedure was highly reproducible and correlated to stereological measurements
      but was influenced by heterogeneity of the tissue samples. Analyzing two sections
      per patient improved the discriminative power by reducing the influence of tissue
      heterogeneity and produced highly significant results (recurrence-free survival,
      P < 0.001; overall survival, P < 0.0001). Immunoreactive ecNOS in microvessels is
      an independent prognostic factor in breast cancer and may reflect a mechanism of
      endothelial defense against invasion by tumor cells. Individual variations in
      ecNOS may be related to environmental, hormonal, and genetic factors and could
      represent a therapeutic target.

PMID- 10353744
TI  - Detection of melanoma cells in the blood of melanoma patients by melanoma
      inhibitory activity (MIA) reverse transcription-PCR.
AB  - The detection of tumor-specific mRNA transcripts in the blood of patients by
      reverse transcription (RT)-PCR has been used as a very sensitive technique for
      determining systemically disseminated tumor cells. On the basis of previous
      expression studies, we aimed to trace melanoma cells in the blood of melanoma
      patients by RT-PCR of melanoma-inhibitory activity (MIA) mRNA. To detect
      sensitively MIA transcripts in total RNA isolated from peripheral blood
      mononuclear cells (PBMCs), we established a sensitive PCR-ELISA system. With this
      assay, we detected one melanoma cell in 2 ml of blood by a single round of 32 PCR
      cycles. A total of 295 PBMC samples isolated from 166 patients with melanocytic
      tumors were tested with the MIA RT-PCR-ELISA: (a) 58 patients (99 samples) with
      malignant melanomas in stage I; (b) 49 patients (65 samples) with malignant
      melanomas in stage II; and (c) 47 patients (116 samples) with metastasized
      melanomas (stages III and IV), with an additional 12 patients (15 samples) with
      benign melanocytic nevi. Forty-four (26.8%) of 164 samples isolated from patients
      with melanomas in stages I and II were positive for MIA mRNA; in stages III/IV,
      33 (28.4%) of 116 samples of patients, irrespective of clinically evident
      disease, were positive. Eleven (84.6%) of 13 PBMC samples from patients with
      metastasized melanoma and clinically evident disease without treatment were MIA
      mRNA-positive in contrast to only 19 (25.7%) of 74 samples isolated from patients
      in stage IV with metastasis during chemotherapy. Furthermore, none of the 16 PBMC
      samples of patients in stage IV without clinically detectable metastases at that
      time point during chemotherapy was MIA mRNA-positive. Interestingly, of the 44
      positive samples (26.8%) isolated from patients with melanomas in stages I and
      II, 20 were still positive when retested after complete excision of the tumor.
      Our results reveal that amplification of MIA mRNA from the PBMCs of patients with
      malignant melanomas by PCR-ELISA provides a useful means to detect tumor cells in
      the systemic blood circulation. A correlation between positive blood samples and
      tumor burden in stages III and IV was detected, and, in addition, a significant
      effect of chemotherapy with respect to the reduction of the number of
      systemically spread tumor cells was observed. However, MIA amplification seems to
      be of little value as a surrogate marker for clinical staging or the detection of
      metastatic disease.

PMID- 10353745
TI  - Macrophage infiltration and heme oxygenase-1 expression correlate with
      angiogenesis in human gliomas.
AB  - Macrophages are key participants in angiogenesis. In this study on human brain
      tumors, we first investigated whether macrophage infiltration is associated with
      angiogenesis and malignant histological appearance. Immunostaining of macrophages
      and small vessels in resected glioma specimens indicated that numbers of
      infiltrating macrophages and small vessel density were higher in glioblastomas
      than in astrocytomas or anaplastic astrocytomas. Macrophage infiltration was
      closely correlated with vascular density in human gliomas. Heme oxygenase-1 (HO
      1), which is the rate-limiting enzyme in heme catabolism, was also associated
      with activated macrophages. Expression of mRNA encoding HO-1 was correlated with
      macrophage infiltration and vascular density in human glioma samples.
      Infiltrating macrophages were positively stained with anti-HO-1 antibody by
      immunohistochemical analysis, and in situ hybridization for HO-1 indicated that
      HO-1 was expressed in infiltrating macrophages in gliomas. HO-1 gene may be a
      useful marker for macrophage infiltration as well as neovascularization in human
      gliomas.

PMID- 10353747
TI  - Increased serum angiogenin concentration in colorectal cancer is correlated with
      cancer progression.
AB  - We have previously demonstrated that the increased expression of angiogenin (ANG)
      in pancreatic cancer is related to cancer aggressiveness; however, the
      relationship between ANG expression and its clinical relevance in colorectal
      cancer has not been demonstrated. We therefore investigated the correlation
      between serum ANG (sANG) concentration and colorectal cancer progression or the
      changes in sANG concentrations before and after cancer resection. To
      determination sANG concentration by ELISA, sera were obtained from colorectal
      cancer patients (the cancer group) preoperatively (n = 34) and postoperatively (n
      = 25), from hernia patients (the nonneoplastic group) preoperatively (n = 9) and
      postoperatively (n = 4), and from 23 healthy volunteers. The amount of ANG in the
      colorectal cancer tissues (n = 19) was determined by the same method. Before
      surgery, the mean sANG concentration in the cancer group (411.8 +/- 106.3 ng/ml)
      was significantly higher than that in both the nonneoplastic group (344.0 +/-
      60.7 ng/ml; P = 0.04) and in the healthy volunteers (321.7 +/- 59.7 ng/ml; P =
      0.0001). The degree of elevation of sANG concentration in the cancer group was
      more significant in the more progressed subgroups as compared with that in the
      normal group (versus T(is) + T1 + T2 cancer, P = 0.01; versus T3 + T4 cancer, P =
      0.002; versus stage 0 + I cancer, P = 0.02; versus >stage III cancer, P = 0.001;
      versus Dukes' A cancer, P = 0.02; versus Dukes' C cancer, P = 0.006). After
      cancer resection, the mean sANG concentrations in each subgroup decreased to the
      same levels as those of the normal group; the degrees of reduction were more
      significant in the more progressed subgroups. The tissue ANG amount correlated
      significantly with sANG concentration (P = 0.007). These results suggest that the
      increased concentration of sANG that is derived from colorectal cancer correlates
      with cancer progression.

PMID- 10353746
TI  - Matrix metalloproteinase production by bone marrow mononuclear cells from normal
      individuals and patients with acute and chronic myeloid leukemia or
      myelodysplastic syndromes.
AB  - The two matrix metalloproteinases (MMPs) Mr 72,000 type IV collagenase (MMP-2,
      gelatinase A) and Mr 92,000 type IV collagenase (MMP-9, gelatinase B) play key
      roles in tissue remodeling and tumor invasion by digestion of extracellular
      matrix barriers. We have investigated the production of these two enzymes as well
      as the membrane-type MMP (MT1-MMP) and the tissue inhibitors of
      metalloproteinases (TIMPs) TIMP-1 and TIMP-2 in the bone marrow mononuclear cells
      (BM-MNCs) of patients with acute myeloid leukemia (AML; n = 24), chronic myeloid
      leukemia (CML; n = 17), myelodysplastic syndromes (MDS; n = 8), and healthy
      donors (n = 5). Zymographic analysis of BM-MNC-conditioned medium showed that a
      Mr 92,000 gelatinolytic activity, identified as MMP-9 by Western blotting, was
      constitutively released from cells of all patients and healthy individuals
      examined in this study. In contrast, MMP-2 secretion was found to be absent in
      all samples from healthy donors but present in 8 of 11 (73%) of the samples from
      patients with primary AML, 7 of 8 (88%) with secondary AML, and only 1 of 5 (20%)
      cases with AML in remission, indicating MMP-2 to be produced by the leukemic
      blasts. MMP-2 release was not detected in CML cell-conditioned medium with the
      exception of two cases, both patients either being in or preceding blast crisis.
      In MDS, MMP-2 was found in three of eight (38%) of the patients, two of them
      undergoing progression of disease within 12 months. Quantitative Northern blot
      analysis in freshly isolated BM-MNCs showed a relatively low constitutive
      expression of TIMP-1 in all samples, whereas MMP-9 gene transcription was higher
      in healthy donors and CML samples, than in AML and MDS. Reverse transcriptase-PCR
      analysis revealed the presence of TIMP-2 mRNA in the majority of MMP-2-releasing
      BM-MNCs. MT1-MMP expression was present in most samples of patients with MDS or
      AML but absent in those with secondary AML and CML. Thus, we have shown that BM
      MNCs continuously produce MMP-9 and TIMP-1 and demonstrated that leukemic blast
      cells additionally secrete MMP-2 representing a potential marker for
      dissemination in myeloproliferative malignancies.

PMID- 10353748
TI  - Significance of thymidine phosphorylase as a marker of protumor monocytes in
      breast cancer.
AB  - Tumor-associated monocytic cells (TAMs) are a major component of the stroma
      responsible for tumor formation. TAMs generate various kinds of mediators for
      their function, one of which is thymidine phosphorylase (TP). TP is an angiogenic
      enzyme that is known to be up-regulated in tumor tissues. Here, we focused on the
      clinical implication of TP expression in TAMs by studying 229 primary breast
      carcinoma tissues. Immunohistochemical analysis demonstrated that monocytic TP+
      tumors had a significantly worse prognosis than did monocytic TP- tumors (P <
      0.01, log-rank test). A multivariate analysis confirmed that monocytic TP status
      provided an independent prognostic value (P < 0.0001). Furthermore, of interest
      was that monocytic TP status could categorize the CD68+ patients, who had an
      extensive accumulation of CD68+ TAMs, into two subgroups with strikingly
      contrasting prognoses: a good prognostic monocytic TP- group and a poor
      prognostic monocytic TP+ group. This indicates that there are both antitumor and
      protumor types of TAM. Subanalysis showed that microvessel density was
      significantly increased in CD68+/monocytic TP+ tumors compared with
      CD68+/monocytic TP- tumors. Experimentally, TAMs are known to function in diverse
      manners, antitumor and protumor; however, little is known about clinically
      recognizable markers to characterize the TAMs in histological sections. TP might
      be such a marker, which would be useful for identifying the character of TAMs,
      particularly the protumor phenotype.

PMID- 10353750
TI  - Detection of mutations of p53 tumor suppressor gene in pancreatic juice and its
      application to diagnosis of patients with pancreatic cancer: comparison with K
      ras mutation.
AB  - Because of the difficulty in obtaining biopsy specimens from pancreatic cancer
      patients, K-ras mutation analysis in pancreatic juice has been used for specific
      diagnosis. But recently, false positives have been obtained with this method. To
      improve the genetic diagnosis of pancreatic cancer, detection of p53 gene
      mutation in pancreatic juice was studied. Pancreatic juice was sampled
      endoscopically. Single-strand conformation polymorphism analysis was used for p53
      mutation analysis. Furthermore, K-ras mutations at codon 12 were also studied in
      the same pancreatic cancer patients. Of 26 cases of pancreatic cancer, p53
      mutations were detected in 11 (42.3%). No mutations were seen in the cases with
      mucin-producing adenoma nor with chronic pancreatitis. K-ras mutations were
      detected in 84.0% of cases by RFLP analysis, which has high sensitivity, and in
      65.3% by hybridization protection assay, which has high specificity. Using a
      combination assay with both genes, genetic abnormalities were detected in 92.0%
      by RFLP and 73.1% by hybridization protection assay including two cases in which
      p53 alone was positive by both methods. The specificity of p53 mutation for
      pancreatic cancer is very high. Therefore, simultaneous analysis of p53 and K-ras
      mutation is suggested to enhance the genetic diagnosis of pancreatic cancer.

PMID- 10353749
TI  - Prognostic significance of allelic imbalances on chromosome 9p in stage I non
      small cell lung carcinoma.
AB  - Loss of heterozygosity (LOH) on chromosomes 2q, 9p, 18q, and 22q frequently
      occurs in advanced non-small cell lung carcinoma (NSCLC). The association of p53
      mutations with prognosis is still unclear in NSCLC. Therefore, we investigated
      the prognostic significance of allelic imbalances (AI) on these chromosomes and
      p53 mutations in 108 cases of stage I NSCLC by PCR amplification of polymorphic
      dinucleotide repeat-containing sequences and PCR-single strand conformation
      polymorphism analysis. AI on 2q, 9p, 18q, and 22q was detected in 22, 38, 29, and
      15% of cases, respectively, whereas p53 was mutated in 41% of stage I NSCLC. AI
      on 9p and 22q and p53 mutations were significantly associated with shortened
      survival of the patients (P = 0.010, 0.024, and 0.022, respectively). Although
      gender and smoking history showed more significant associations with prognosis
      than other clinicopathological and molecular parameters, independent prognostic
      significance for AI on 9p was observed (P = 0.002) in male patients with a
      positive smoking history. These results indicate that clinical aggressiveness of
      early-stage NSCLC can be partly defined by the presence of AI on chromosome 9p in
      cancer cells, and that AI on 9p could be a clinically useful prognostic indicator
      for early-stage NSCLC patients.

PMID- 10353751
TI  - Telomere stability is frequently impaired in high-risk groups of patients with
      myelodysplastic syndromes.
AB  - Genomic instability induces an accumulation of genetic changes and may play a
      role in the pathogenesis of myelodysplastic syndromes (MDS). To clarify the
      possible association between genomic instability and clinical outcome in MDS
      patients, we compared telomere dynamics to the recently established International
      Prognostic Scoring System (IPSS) risk groups for MDS. We measured the terminal
      restriction fragments (TRFs) of 93 patients with MDS at the time of diagnosis,
      and telomerase activity was analyzed in 62 patients with MDS using the PCR-based
      telomeric repeat amplification protocol (TRAP) assay. A total of 53 of 93 MDS
      patients had TRFs within the age-matched normal range, and the remaining patients
      showed shortened TRFs (35 patients) or elongated TRFs (5 patients). MDS patients
      with shortened TRFs had a significantly low hemoglobin concentration (P = 0.04),
      a high percentage of marrow blasts (P = 0.02), and a high incidence of
      cytogenetic abnormalities (P < 0.05). The incidence of leukemic transformation
      was significantly high in patients with shortened TRF length (P < 0.05). In
      addition, patients with shortened TRF length were frequently seen in the IPSS
      high-risk group (P < 0.01). Most of the MDS patients had normal-to-low levels of
      telomerase activity, suggesting that changes in TRF length rather than telomerase
      activity may more accurately reflect the pathophysiology of MDS. MDS patients
      with shortened TRF length had a very poor prognosis (P < 0.01), suggesting that
      telomere dynamics may be linked to clinical outcome in MDS patients. Thus, an
      abnormal mechanism of telomere maintenance in subgroups of MDS patients may be an
      early indication of genomic instability. This study demonstrates that telomere
      stability is frequently impaired in a high-risk group of MDS patients and
      suggests that, in combination with the IPSS classification system, measurement of
      TRFs may be useful in the future to stratify MDS patients according to risk and
      manage the care of MDS patients.

PMID- 10353752
TI  - Predictive value of preclinical toxicology studies for platinum anticancer drugs.
AB  - Rodent and nonrodent toxicology studies are currently expected to support Phase I
      trials of antineoplastic drugs in the United States. To determine the predictive
      value of these studies, we initiated a project to compare preclinical and
      clinical toxicity data within various drug classes. The first class analyzed was
      the platinum anticancer drugs. Twelve platinum analogues that had both
      preclinical (mice, rats and/or dogs) and clinical data from matching drug
      administration schedules were identified. The rodent LD10 (the dose that causes
      lethality in 10% of treated animals) or dog toxic dose high (a dose that when
      doubled causes lethality in dogs) correlated well with the human maximally
      tolerated dose on a mg/m2 basis. For every platinum analogue investigated, one
      third the rodent LD10 or one-third the dog toxic dose high in mg/m2 gave a
      starting dose and a first escalation dose that did not exceed the clinical
      maximally tolerated dose. The dose-limiting toxicities in patients were
      previously observed in 7 of 7, 7 of 8, and 9 of 11 mouse, rat, and dog studies,
      respectively. Our data indicate that mice, rats, and dogs all had value in
      predicting a safe starting dose and the qualitative toxicities in humans for
      platinum anticancer compounds. The efficiency of Phase 1 trials could have been
      improved without sacrificing patient safety by allowing higher starting doses for
      this drug class than conventionally permitted.

PMID- 10353753
TI  - An improved nonisotopic test to screen a large series of new inhibitor molecules
      of poly(ADP-ribose) polymerase activity for therapeutic applications.
AB  - A reliable ELISA for screening large numbers of poly(ADP-ribose) polymerase
      (PARP) inhibitors is described. The test is based upon the drop in PARP activity
      estimated by the decrease in poly(ADP-ribose) synthesis in the presence of
      inhibitor. This ELISA is easy to perform, rapid, and specific. It is extremely
      sensitive because a clear inhibition of the total reaction could be visualized
      with molecules used in the nanomolar range. The assay uses no radioactivity, and
      automation is possible with robots for large-scale investigations. This test is
      of great interest for the screening of chemical libraries and the discovery of
      new inhibitors (and possibly activators) of PARP. Such molecules have important
      applications in all abnormal situations involving DNA damage and oxidative
      stress, such as cancer, autoimmunity, diabetes, myocardial dysfunctions, certain
      infections, aging, and radiation/chemical exposure.

PMID- 10353755
TI  - Treatment of neoplastic meningitis with intrathecal temozolomide.
AB  - Neoplastic meningitis (NM) results from leptomeningeal dissemination of cancers
      arising within the central nervous system or metastasizing to the leptomeninges
      from systemic neoplasms. The inability to produce therapeutic drug levels
      intrathecally (i.t.) with systemic administration and the minimal efficacy of
      chemotherapeutic agents currently available for direct i.t. use limit therapy.
      Temozolomide [8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4([3H])-one] is
      a novel methylating agent with proven activity against intraparenchymal malignant
      gliomas (MGs). Insolubility of the standard formulation prevents its efficacious
      use as an i.t. agent, however. To overcome this obstacle, we have developed a
      unique microcrystalline formulation of temozolomide with greatly enhanced
      solubility. Treatment of athymic rats bearing subarachnoid MER- human MG
      xenografts with four doses of i.t. microcrystalline temozolomide over a 2-week
      period produced a 142% increase in median survival at individual doses of 2.2
      micromol (P = 0.0073) and a >367% increase in median survival at individual doses
      of 6.8 micromol (P = 0.0015). At the higher dose tested, three of eight rats
      treated developed no neurological symptoms and had no evidence of residual tumor
      on histological examination after treatment. Use of this microcrystalline
      formulation in athymic rats bearing subarachnoid MER+ human MG xenografts
      increased median survival >132% (P < 0.0058) at both dose levels tested. Toxicity
      directly attributable to the i.t. administration of microcrystalline temozolomide
      was exhibited in the highest dose groups only and was limited to small patchy
      areas of focal demyelination involving <5% of spinal cord long tracks.

PMID- 10353754
TI  - Primary T-cell and activated macrophage response associated with tumor protection
      using peptide/poly-N-acetyl glucosamine vaccination.
AB  - The mode of peptide-based cancer vaccine administration critically affects the
      ability to achieve a clinically relevant tumor-specific response. We have
      previously shown (Cole et al., Clin. Cancer Res., 3: 867-873, 1997) that a
      specific formulation of the polysaccharide poly-N-acetyl glucosamine (p-GlcNAc,
      designated as F2 gel) is an effective vehicle for sustained cytokine and peptide
      delivery in vitro. The purpose of this study was to evaluate the efficacy of F2
      gel/peptide vaccination in the murine EG.7-OVA tumor model and to elucidate
      potential mechanisms involved in the observed cell-mediated response. C57BL/6
      mice were given injections of 200 microl in the base of tail/footpad using either
      F2 gel alone or 200 microg of: SIINFEKL minimal peptide (OVA) in PBS, OVA
      peptide/endoplasmic reticulum insertion signal sequence fusion (ESOVA) in PBS,
      OVA in F2 gel, or ESOVA in F2 gel. Splenocytes were tested 10 days later for a
      secondary response using a Cr51 assay as well as a primary CTL response using the
      lactate dehydrogenase cytotoxicity assay. Splenocytes from immunized mice were
      harvested at specific time points and assayed for cell surface and intracellular
      markers. On day 10 postvaccination, animals were challenged with EG.7-OVA murine
      thymoma cells. Tumor size and appearance were recorded. Vaccination with F2
      gel/peptide (either OVA or ESOVA) resulted in a primary T-cell response (up to
      25% tumor cell-specific lysis) and no tumor growth in 69% of the mice. By 48 h,
      the proportion of splenic T cells had increased 4-fold compared with B cells.
      Presence of an increased Th1 CD4 helper population was demonstrated by IFN-gamma
      production. CD4 cells were activated at 24 and 48 h as shown by IL-2 receptor
      alpha chain expression (from 2% basal expression to 15.4% at 48 h). Activated
      splenic macrophages increased from 3 to 8% within 10 h, and their level of B7-2
      expression doubled. Depletion of macrophages before vaccine injection abolished
      any tumor-specific primary CTL response. F2 gel/peptide tumor vaccine can prime
      the immune system in an antigen-specific manner by generating a measurable
      primary T-cell response with minimal peptide; this process involves macrophage
      presence and activation as well as induction of Th1 CD4 cells. This is the first
      demonstration of a primary CTL response generated with minimal peptide
      vaccination using a noninfectious delivery system. These results justify
      additional studies to better define the mechanisms involved in F2 gel/peptide
      vaccination in preparation for clinical trials.

PMID- 10353756
TI  - Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN
      38 and the diaminocyclohexane platinum derivative oxaliplatin.
AB  - CPT-11, a DNA topoisomerase I inhibitor, and oxaliplatin, a diaminocyclohexane
      platinum derivative, are cytotoxic agents that have demonstrated clinical
      antitumor activity in colorectal cancer. Given the therapeutic potential of their
      combination, we studied the cellular pharmacology of SN-38, the active metabolite
      of CPT-11, and oxaliplatin in the human colon cancer HT29 cell line. Growth
      inhibition was studied after a 1- or 24-h exposure to SN-38 or oxaliplatin, given
      alone or in combination. The cytotoxicity analysis by the isobolograms method
      elicited synergy. SN-38 delayed the reversion of oxaliplatin-induced DNA
      interstrand cross-links (ISCs), measured in cells by alkaline elution. The amount
      of detectable ISCs 15 h after a 1-h exposure to 10 microm oxaliplatin was 27% of
      the ISC peak levels and increased to 68% in the presence of 0.1 microM SN-38. The
      presence of oxaliplatin DNA adducts led to a 3.3-fold increase in the SN-38
      induced DNA elongation inhibition, as measured by pulse-labeling alkaline
      elution. Inhibition of DNA and RNA synthesis was longer after exposure to the
      combination of oxaliplatin and SN-38 than after exposure to each agent alone.
      Consistently, flow cytometry analyses revealed that preexposure to oxaliplatin
      enhanced SN-38-induced S-phase arrest. Filter binding assays indicated that the
      cells arrested in S-phase at 48 h were undergoing apoptosis. Hence, supra
      additive cytotoxicity appears related to major modifications in the cellular
      response to DNA damage rather than to changes in DNA damage formation. The
      combination of CPT-11 and oxaliplatin induced a 2-fold higher tumor growth
      reduction in vivo than did oxaliplatin alone at feasible nonlethal doses. This
      study provides a rationale for the optimal use of CPT-11 and oxaliplatin in
      combination.

PMID- 10353757
TI  - Activation of nuclear factor-kappa B in human metastatic melanomacells and the
      effect of oxidative stress.
AB  - The biological basis for the general pharmacological resistance of human melanoma
      is unknown. A unique biochemical feature of the melanocyte is the synthesis of
      melanin, which leads to the generation of hydrogen peroxide and the consumption
      of reduced glutathione. This activity produces a state of chronic oxidative
      stress in these cells. We demonstrated previously that the expression of the c
      jun family was dysregulated in metastatic melanoma cells compared with normal
      human melanocytes (D. T. Yamanishi et al., J. Invest. Dermatol., 97: 349-353,
      1991). In the current investigation, we measured the levels of two major redox
      response transcription factors, nuclear factor-kappaB (NF-kappaB) and activator
      protein-1, in metastatic melanoma cells and normal melanocytes and their response
      to oxidative stress. The basal DNA-binding activity of NF-kappaB as measured by
      the electrophoretic mobility shift assay in metastatic melanoma cells was
      increased 4-fold compared with that of normal melanocytes. This level of binding
      was paralleled by a 1.5- to 4-fold increase in the expression of p50 (NF
      kappaB1), p65 (Rel-A), and IkappaB-alpha as measured by Northern blot analysis.
      In contrast, the expression of p75 (c-rel) was markedly decreased (60%) in
      melanoma cells compared with normal melanocytes. Following oxidative stress
      produced by enzyme-generated H2O2, free H2O2, or incubation with buthionine
      sulfoximine, NF-kappaB binding activity increased 1.5- to 2.5-fold in melanoma
      cells (buthionine sulfoximine > H2O2), but only slightly in normal melanocytes.
      In contrast, activator protein-1 binding activity was unaffected or increased in
      normal melanocytes in response to oxidative stress, but was either unaffected or
      decreased in melanoma cells. These results suggest that the redox regulation of
      melanoma cells at the molecular level is fundamentally different from normal
      melanocytes and may offer a unique avenue for preventive or therapeutic
      intervention as well as new insights into the pathogenesis of melanocyte
      transformation.

PMID- 10353758
TI  - Autologous high-killing cytotoxic T lymphocytes against human lung cancer are
      induced using interleukin (IL)-1beta, IL-2, IL-4, and IL-6: possible involvement
      of dendritic cells.
AB  - Although CTLs bear main immune responses in human tumors, stable CTL clones
      against human lung cancer have rarely been generated. Our previous study
      demonstrated efficient autologous CTL induction in human gastric cancer and
      glioblastoma by cytokine combination of interleukin (IL)-1beta (167 IU/ml), IL-2
      (67 IU/ml), IL-4 (67 IU/ml), and IL-6 (134 IU/ml). In this study, we demonstrated
      successful induction of autologous stable CTLs in five of six patients with lung
      adenocarcinoma from mixed-lymphocyte tumor culture using this cytokine
      combination. All CTLs revealed potent and specific killing activity against
      autologous target cells (over 75% in CD8+ CTLs and over 50% in CD4+ CTLs at an
      E:T ratio of 10 for 24 h). Using a series of antibodies, CD8+ CTLs showed to
      recognize tumor-specific antigens of lung cancer cells through HLA class I. In
      the separate experiments, failure of CTL induction from monocyte-depleted
      peripheral blood mononuclear cells and appearance of cells with characteristics
      of dendritic cells from adherent peripheral blood mononuclear cells in the
      culture of the same concentration of IL-1beta, IL-4, and IL-6 indicated that CTLs
      can be efficiently generated by this cytokine combination via possible dendritic
      cell induction. This is the first study of an efficient and reproducible in vitro
      CTL induction against human lung cancer.

PMID- 10353759
TI  - Suppression of telomerase, reexpression of KAI1, and abrogation of tumorigenicity
      by nerve growth factor in prostate cancer cell lines.
AB  - Nerve growth factor (NGF) is expressed in the prostate, where it appears to be
      involved in the control of epithelial cell growth and differentiation. NGF
      production is decreased in prostate tumors. However, the role of this
      neurotrophin in the control of proliferation and progression of prostate cancers
      is still a matter of investigation. Prostate adenocarcinomas are telomerase
      positive tumors. Chronic exposure of DU145 and PC3 prostate tumor cell lines to
      NGF resulted in a dramatic down-regulation of telomerase activity. This effect
      was correlated in terms of concentrations and time with a remarkable down
      regulation of cell proliferation both in vitro and in vivo but was not secondary
      to NGF-induced quiescence. No down-regulation of telomerase activity was, in
      fact, detectable during serum starvation-induced quiescence. LNCaP cells, which
      do not express NGF receptors, appear to be insensitive to the actions of NGF.
      DU145 and PC3 cells do not express the KAI1 metastasis suppressor gene, which is
      present in the prostate and is progressively lost during the progression of
      prostate cancers. Chronic NGF treatment strongly induced the reexpression of this
      gene in these cell lines, and this effect was correlated with the suppression of
      their invasive potential in vitro. The data presented here suggest that NGF
      reverts two metastatic prostate cancer cell lines to slowly proliferating,
      noninvasive phenotypes characterized by a very low telomerase activity and by the
      expression of the KAI1 metastasis suppressor gene.

PMID- 10353761
TI  - Loss of heterozygosity of the Rb gene correlates with pRb protein expression and
      associates with p53 alteration in human esophageal cancer.
AB  - To understand the alterations of Rb tumor suppressor gene and the relationship
      between defects in the Rb and p53 pathways in human esophageal carcinogenesis, we
      examined the loss of heterozygosity (LOH) of the Rb gene and immunohistochemical
      staining of pRb protein in 56 esophageal squamous cell carcinoma specimens and
      related the results to the p53 gene alterations. Using four introgenic
      polymorphic markers as probes, we observed LOH of the Rb gene in 30 of the 55
      informative tumor samples. Immunohistochemical analysis revealed different
      patterns of pRb expression among the tumor samples. In the 56 cases, 16 displayed
      extensive pRb staining comparable to that of the adjacent normal epithelia,
      whereas 33 showed either significantly decreased or no pRb staining and 7 had a
      focal staining pattern reflecting heterogeneous cancer nests in the tumor with
      respect to Rb status. In the tumor samples containing Rb LOH, 90% showed low or
      no pRb expression, whereas in samples without Rb LOH, only 20% had altered pRb
      expression. There was a strong association between LOH of the Rb gene and
      alteration of pRb expression in our samples (P < 0.0001), suggesting LOH is a
      main event leading to Rb inactivation. We found that Rb LOH was more frequent in
      tumors with p53 mutations (P < 0.05), which occurred in 31 of the 49 cases
      analyzed. When the status of Rb and p53 alterations was evaluated by the combined
      results of immunohistochemical and genetic analyses, we found that alteration of
      Rb and p53 had an even stronger association in our esophageal squamous cell
      carcinoma samples (P = 0.0015). Among the 51 cases in which both the Rb and p53
      status were determined, 31 contained alterations in both genes, and only 5 and 6
      cases were altered in only Rb and only p53, respectively. Our results suggest
      that defects in the Rb and p53 pathways and their potential synergistic effect in
      deregulating cell cycle and apoptosis are major mechanisms for esophageal
      carcinogenesis.

PMID- 10353760
TI  - Mechanisms of apoptosis in T cells from patients with renal cell carcinoma.
AB  - Tumors may escape immune recognition and destruction through the induction of
      apoptosis in activated T lymphocytes. Results from several laboratories suggest
      that FasL (L/CD95L) expression in tumors may be responsible for this process. In
      this study of patients with renal cell carcinoma (RCC), we provide evidence for
      two mechanisms of T-cell apoptosis. One mechanism involves the induction of
      apoptosis via FasL expression in tumor cells. This is supported by several
      observations, including the fact that tumor cells in situ as well as cultured
      cell lines expressed FasL mRNA and protein by a variety of techniques. The FasL
      in RCC is functional because in coculture experiments, FasL+ tumors induced
      apoptosis in Fas-sensitive Jurkat T cells and in activated peripheral blood T
      cells but not in resting peripheral blood T cells. Most importantly, antibody to
      FasL partially blocked apoptosis of the activated T cells. Moreover, Fas was
      expressed by T cells derived from the peripheral blood (53% median) and tumor
      (44.3% median) of RCC patients. Finally, in situ staining for DNA breaks
      demonstrated apoptosis in a subset of T cells infiltrating renal tumors. These
      studies also identified a second mechanism of apoptosis in RCC patient peripheral
      T cells. Whereas these cells did not display DNA breaks when freshly isolated or
      after culture for 24 h in medium, peripheral blood T cells from RCC patients
      underwent activation-induced cell death after stimulation with either phorbol 12
      myristate 13-acetate/ionomycin or anti-CD3/CD28 antibodies. Apoptosis mediated by
      exposure to FasL in tumor cells or through T-cell activation may contribute to
      the failure of RCC patients to develop an effective T-cell-mediated antitumor
      response.

PMID- 10353762
TI  - Communication.

PMID- 10353763
TI  - Role of the peroneal tendons in the production of the deformed foot with
      posterior tibial tendon deficiency.
AB  - Ten patients were identified with traumatic, complete common peroneal nerve
      palsy, with no previous foot or ankle surgery or trauma distal to the knee, who
      had undergone anterior transfer of the posterior tibial tendon to the midfoot.
      Six of these patients had a transfer to the midfoot and four had a Bridle
      procedure with tenodesis of half of the posterior tibial tendon to the peroneus
      longus tendon. Average follow-up was 74.9 months (range, 18-351 months). All
      patients' feet were compared assessing residual muscle strength, the longitudinal
      arch, and motion at the ankle, subtalar, and Chopart's joint. Weightbearing
      lateral X-rays and Harris mat studies were done on both feet. In no case was any
      valgus hindfoot deformity associated with posterior tibial tendon rupture found.
      It seems that the pathologic condition associated with a posterior tibial tendon
      deficient foot will not manifest itself if peroneus brevis function is absent.

PMID- 10353764
TI  - Posterior calcaneal osteotomy with wedge: cadaver testing of a new procedure for
      insufficiency of the posterior tibial tendon.
AB  - Insufficiency of the posterior tibial tendon is challenging to treat. When the
      deformity is flexible, treatment options have included tendon transfer, often
      combined with a medial slide calcaneal osteotomy and/or a lengthening of the
      lateral column. Posterior calcaneal osteotomy has been shown to give correction,
      although not full correction. Lengthening of the lateral column also has been
      shown to give correction and has been used in the more severe flexible
      deformities, but it involves either fusion of the calcaneocuboid joint or risk of
      arthritis at this joint. An osteotomy combining the calcaneal medial slide with a
      lengthening of the lateral column at the same osteotomy site has been tested in
      the laboratory. This combined osteotomy provides a lengthening of the lateral
      column, but it is positioned away from the calcaneocuboid joint. In this study,
      the osteotomy was compared with a medial slide calcaneal osteotomy and an Evans
      lengthening of the lateral column, using a cadaver flatfoot model. Radiographic
      measurements were made to evaluate correction of the planovalgus deformity after
      each of these procedures. There was statistically significant improved correction
      with the new osteotomy compared with that in a standard medial slide, and
      correction was comparable to that in the lengthening of the lateral column. This
      combined osteotomy may be a reasonable alternative when more correction is
      desired than can be obtained from a medial slide alone and when the surgeon
      wishes to avoid an osteotomy near the calcaneocuboid joint.

PMID- 10353765
TI  - Late results of modified Mitchell procedure for the treatment of hallux valgus.
AB  - From a total of 153 patients (251 feet), 64 (41.8%) patients, who had had 105
      modified Mitchell procedures, were clinically and radiographically examined with
      follow-up periods ranging from 15 to 24 years (mean, 21 years). Mean age at
      operation was 41 years (range, 12-64 years). The classic double osteotomies,
      which diverged slightly toward the plantar surface and the distal fragment,
      shifted laterally, and angled plantarward, were fixed with a smooth Kirschner
      wire. In this way, it was possible to achieve a reduction in the first
      intermetatarsal angle from an average of 22.5 degrees preoperatively to 7.7
      degrees postoperatively, and the hallux valgus angle changed from an average of
      33 degrees to 17 degrees, with an average shortening of the first metatarsal of
      5.4 mm and an average lateral displacement of the first metatarsal head of 4.5
      mm. In 67 feet (64%), the results were graded good to excellent; in 23 feet
      (22%), satisfied; and in 15 feet (14%), poor. The results were worse than the
      results obtained on the same patient population with a follow-up ranging from 2
      to 11 years, with 97% good-to-excellent results reported. Pain over bunion caused
      by recurrence of the hallux valgus deformity was the main reason for this late
      deterioration of the results.

PMID- 10353766
TI  - Stabilization of the Mitchell first metatarsal osteotomy using an intramedullary
      K-wire.

PMID- 10353767
TI  - Modification of the Mitchell osteotomy.
AB  - This technical modification of the Mitchell osteotomy facilitates the creation of
      the "step" in the distal fragment of the osteotomy and permits accurate
      alignment.

PMID- 10353768
TI  - Chronic Achilles tendinopathy in athletic individuals: results of nonsurgical
      treatment.
AB  - We report the results of nonsurgical treatment of chronic Achilles tendinopathy
      in 22 patients with a follow-up of 33 to 72 months. Immediately after the
      treatment period, 70% of the patients were either improved or cured. At follow
      up, 65% were improved or cured, and 35% failed treatment or had a poor long-term
      result. In these patients, early surgery might have been considered, but only one
      patient received a peritendinitis operation in the follow-up period. In athletic
      individuals with chronic Achilles tendinopathy, nonsurgical treatment with
      emphasis on active training is recommended. Surgery should be considered if the
      athlete has been treated for 3 to 6 months without progress.

PMID- 10353769
TI  - Open versus closed repair of the Achilles tendon: an experimental animal study.
AB  - This experimental animal study compared the healing patterns between open and
      closed treatments of Achilles tendon tenotomies. Twenty-four male New Zealand
      rabbits underwent tenotomy of the left Achilles tendon and were randomized into
      two groups, treated with either open surgical repair or closed management. After
      the death of the animal, the retrieved tendons were submitted for biomechanical
      and histological testing. The total elongation of the open treatment group was
      9.5+/-1.0 mm compared with 21.2+/-3.4 mm for the closed treatment group (P =
      0.008), and the regain of stiffness was 67.4+/-2.0% and 48.9+/-5.3%, respectively
      (P = 0.132). Histological evaluation demonstrated similar healing patterns in
      both groups.

PMID- 10353770
TI  - Xanthomas of the Achilles tendon: report of a bilateral case and review of the
      literature.
AB  - We report a case of bilateral Achilles tendon xanthoma as the first clinical
      manifestation of familial hypercholesterolemia. We review the literature and
      stress the need for orthopaedic surgeons to be familiar with this disease. An
      early diagnosis of this metabolic disorder is important to institute medical
      therapy and to alter the course of the disease before the onset of coronary
      artery disease.

PMID- 10353771
TI  - Evaluation of ankle instability using the Biodex Stability System.
AB  - Ten patients with chronic unilateral functional lateral instability of the ankle
      were evaluated using the Biodex Stability System. This system uses a multiaxial
      testing platform which can be set at variable degrees of instability. Patients
      are then tested for their ability to "balance" the platform during single-limb
      stance, and a stability index is electronically generated. This stability index
      is believed to be an objective measurement that correlates with proprioceptive
      status of the ankle. Instability of the ankle was confirmed in all 10 patients,
      using stress radiographs. Two levels of platform stability were tested. With the
      platform in its most stable configuration, there was minimal difference between
      the previously injured and the uninjured ankle. With the platform set to permit
      up to 20 degrees of tilt in any plane, 6 of 10 patients had more difficulty
      balancing the platform with their injured ankle (higher stability index). This
      preliminary study suggests that the Biodex Stability System may be a useful tool
      in trying to objectively measure proprioceptive function.

PMID- 10353772
TI  - The efficacy of using search engines in procuring information about orthopaedic
      foot and ankle problems from the World Wide Web.
AB  - This study has attempted to demonstrate the feasibility of obtaining information
      specific to foot and ankle orthopaedics from the World Wide Web (WWW). Six search
      engines (Lycos, AltaVista, Infoseek, Excite, Webcrawler, and HotBot) were used in
      scanning the Web for the following key words: "cavus foot," "diabetic foot,"
      "hallux valgus,"and "pes equinovarus." Matches were classified by language,
      provider, type, and relevance to medical professionals or to patients. Sixty
      percent (407 sites) of the visited websites contained information intended for
      use by physicians and other medical professionals; 30% (206 sites) were related
      to patient information; 10% of the sites were not easily classifiable. Forty-one
      percent (169 sites) of the websites were commercially oriented homepages that
      included advertisements.

PMID- 10353773
TI  - Pigmented villonodular synovitis of the foot and ankle: a review of six cases.
AB  - Pigmented villonodular synovitis is a rare but well recognized proliferative
      lesion of synovial tissue. It has been most commonly described in the knee and
      hip, with most series reporting <5% occurrence in the foot and ankle. Six
      patients with pigmented villonodular synovitis of the foot and ankle that was
      treated between 1978 and 1997 were reviewed. Four of the patients had not been
      previously diagnosed, and two patients presented with recurrent disease. All six
      were women. Two patients' disease presented isolated to the ankle joint. The
      other four involved more than one joint: subtalar joint and midfoot in two, and
      the metatarsal region in two. The histology of the primary and recurrent lesions
      did not differ. The recurrent lesions were more diffuse and locally destructive.
      Five were found on magnetic resonance imaging to be a low-to-medium signal
      intensity mass on T1- and T2-weighted images. Surgical management ranged from
      simple excision to synovectomy to Lisfranc amputation. Average follow-up was 13
      months (range, 3 weeks to 51 months). One of the lesions recurred 4 years later.

PMID- 10353774
TI  - Excrescent lesion: a diagnosis of lateral talar exostosis in chronically
      symptomatic sprained ankles.
AB  - The excrescent lesion is a symptomatic anterolateral exostosis at the insertion
      of the anterior talofibular ligament. It is found in patients with chronic ankle
      pain after inversion injuries. It is most reliably diagnosed by computed
      tomography scan, but physical examination and oblique radiographs are suggestive
      in most cases. A technique for surgical excision and, in some cases, repair of
      the anterior talofibular ligament is described. Five patients having a history of
      inversion sprains of the ankle, without significant symptomatic improvement for a
      mean of 21 months after the injury, were evaluated. None had significant
      instability in the ankle or subtalar joints, clinically or with stress
      radiographs. The diagnosis of excrescent lesion was confirmed with computed
      tomography scan in all five patients. Each underwent excision of the exostosis.
      Removal of the exostosis produced laxity of the anterior talofibular ligament in
      four of the patients and required an additional modified Brostrom procedure to
      tighten the anterior talofibular ligament. Clinical results were evaluated at a
      mean of 33 months postoperatively, using the Ankle-Hindfoot scale from the
      American Orthopaedic Foot and Ankle Society. The three patients without pending
      claims for Workers' Compensation or related litigation all had excellent results
      (mean score, 93 points). Two patients with active legal claims had fair and poor
      results (mean score, 53 points).

PMID- 10353775
TI  - Avulsion fracture of the great toe: a case report.
AB  - A case involving an isolated bony avulsion fracture of the extensor insertion on
      the distal phalanx of the great toe is described. The fracture was displaced 2 mm
      with 30 degrees dorsal angulation; the joint was congruent and not subluxed. The
      patient was treated nonsurgically with a rigid-soled sandal. Bony healing at the
      fracture site was clearly evident at 16 weeks postinjury. The patient began using
      a normal shoe at 10 weeks and resumed his running activities without pain at 16
      weeks. The nonsurgical treatment of this injury, similar to that of a mallet
      finger, was successful.

PMID- 10353776
TI  - Sliding wedge local bone graft for midfoot arthrodesis.

PMID- 10353777
TI  - Support of the talus: a biomechanical investigation.

PMID- 10353778
TI  - Clinical and Molecular genetics of Stickler syndrome.
AB  - Stickler syndrome is an autosomal dominant disorder with characteristic
      ophthalmological and orofacial features, deafness, and arthritis. Abnormalities
      of vitreous gel architecture are a pathognomonic feature, usually associated with
      high myopia which is congenital and non-progressive. There is a substantial risk
      of retinal detachment. Less common ophthalmological features include paravascular
      pigmented lattice degeneration and cataracts. Non-ocular features show great
      variation in expression. Children with Stickler syndrome typically have a flat
      midface with depressed nasal bridge, short nose, anteverted nares, and
      micrognathia. These features can become less pronounced with age. Midline
      clefting, if present, ranges in severity from a cleft of the soft palate to
      Pierre-Robin sequence. There is joint hypermobility which declines with age.
      Osteoarthritis develops typically in the third or fourth decade. Mild
      spondyloepiphyseal dysplasia is often apparent radiologically. Sensorineural
      deafness with high tone loss may be asymptomatic or mild. Occasional findings
      include slender extremities and long fingers. Stature and intellect are usually
      normal. Mitral valve prolapse was reported to be a common finding in one series
      but not in our experience. The majority of families with Stickler syndrome have
      mutations in the COL2A1 gene and show the characteristic type 1 vitreous
      phenotype. The remainder with the type 2 vitreous phenotype have mutations in
      COL11A1 or other loci yet to be identified. Mutations in COL111A2 can give rise
      to a syndrome with the systemic features of Stickler syndrome but no
      ophthalmological abnormality.

PMID- 10353779
TI  - Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family
      associated with a single germline mutation in PTEN.
AB  - Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS) are two hamartoma
      syndromes with distinct phenotypic features. Although partial clinical overlap
      exists between CS and BZS, they are considered to be separate entities. PTEN has
      been identified as the susceptibility gene for both disorders, suggesting
      allelism. We have identified a germline mutation, R335X, in PTEN in a family
      consisting of two female members with the phenotypic findings of CS and two male
      members with the phenotypic findings of BZS. To our knowledge, this is the first
      report that shows the presence of separate subjects with CS and with BZS in a
      single family associated with a single germline PTEN mutation.

PMID- 10353780
TI  - Germline mutations of the LKB1 (STK11) gene in Peutz-Jeghers patients.
AB  - Germline mutations of the LKB1 (STK11) serine/threonine kinase gene (chromosome
      19p13.3) cause Peutz-Jeghers syndrome, which is characterised by hamartomas of
      the gastrointestinal tract and typical pigmentation. Peutz-Jeghers syndrome
      carries an overall risk of cancer that may be up to 20 times that of the general
      population. Here, we report the results of a screen for germline LKB1 mutations
      by DNA sequencing in 12 Peutz-Jeghers patients (three sporadic and nine familial
      cases). Mutations were found in seven (58%) cases, in exons 1, 2, 4, 6, and 9.
      Five of these mutations, two of which are identical, are predicted to lead to a
      truncated protein (three frameshifts, two nonsense changes). A further mutation
      is an in frame deletion of 6 bp, resulting in a deletion of lysine and
      asparagine; the second of these amino acids is conserved between species. The
      seventh mutation is a missense change in exon 2, converting lysine to arginine,
      affecting non-conserved amino acids and of uncertain functional significance.
      Despite the fact that Peutz-Jeghers syndrome is usually an early onset disease
      with characteristic clinical features, predictive and diagnostic testing for LKB1
      mutations will be useful for selected patients in both familial and non-familial
      contexts.

PMID- 10353781
TI  - Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in
      Ashkenazi Jewish women with breast or ovarian cancer.
AB  - We ascertained 184 Ashkenazi Jewish women with breast/ovarian cancer (171 breast
      and 13 ovarian cancers, two of the former also had ovarian cancer) in a self
      referral study. They were tested for germline founder mutations in BRCA1
      (185delAG, 5382insC, 188del11) and BRCA2 (6174delT). Personal/family histories
      were correlated with mutation status. Logistic regression was used to develop a
      model to predict those breast cancer cases likely to be germline BRCA1/BRCA2
      mutation carriers in this population. The most important factors were age at
      diagnosis, personal/family history of ovarian cancer, or breast cancer diagnosed
      before 60 years in a first degree relative. A total of 15.8% of breast cancer
      cases, one of 13 ovarian cancer cases (7.7%), and both cases with ovarian and
      breast cancer carried one of the founder mutations. Age at diagnosis in carriers
      (44.6 years) was significantly lower than in non-carriers (52.1 years) (p<0.001),
      and was slightly lower in BRCA1 than BRCA2 carriers. Thirty three percent of
      carriers had no family history of breast or ovarian cancer in first or second
      degree relatives. Conversely, 12% of non-mutation carriers had strong family
      histories, with both a first and a second degree relative diagnosed with breast
      or ovarian cancer. The predicted values from the logistic model can be used to
      define criteria for identifying Ashkenazi Jewish women with breast cancer who are
      at high risk of carrying BRCA1 and BRCA2 mutations. The following criteria would
      identify those at approximately 10% risk: (1) breast cancer <50 years, (2) breast
      cancer <60 years with a first degree relative with breast cancer <60 years, or
      (3) breast cancer <70 years and a first or second degree relative with ovarian
      cancer.

PMID- 10353782
TI  - X linked mental retardation and infantile spasms in a family: new clinical data
      and linkage to Xp11.4-Xp22.11.
AB  - In order to describe the neurological abnormalities and to identify the gene
      localisation, we re-evaluated a previously reported family with X linked mental
      retardation (XLMR). Reliable data were obtained for six of the seven affected
      males, of whom two had had infantile spasms. Profound MR (IQ<20) was found in one
      and mild MR (IQ 50-70) in five males. No dysmorphic features, except for
      macrocephaly in one male, were found. Neurological abnormalities included varying
      degrees of spinocerebellar involvement. Neuroimaging studies showed
      abnormalities, such as cerebellar atrophy or corpus callosum hypoplasia or both,
      in three of the six males. Several affected and unaffected subjects suffered from
      hyperhidrosis, which appeared to segregate independently as an autosomal dominant
      trait. Genetic linkage analysis localised the XLMR disease gene to Xp11.4-Xp22.11
      with a maximum multipoint lod score of 3.57, overlapping the candidate region
      recently found in two Belgian XLMR-infantile spasm families. Compared to the
      Belgian patients, the majority of the affected males in this report had a
      considerably milder phenotype.

PMID- 10353783
TI  - Linkage and association studies of atopy and the chromosome 11q13 region.
AB  - The clinical syndrome atopy is largely determined by genetic factors. In 1989,
      the first linkage of markers within and flanking the chromosomal region 11q13 and
      atopy was reported. In the following years, the gene coding for the beta chain of
      the high affinity IgE receptor was localised to this region and two polymorphisms
      in this gene have been shown to be associated with the atopic phenotype. We
      investigated two independent populations (population based and outpatient
      department) with different degrees of clinical symptoms. Using highly polymorphic
      markers we could find no evidence for linkage or allelic association of this
      particular genomic region to the atopic phenotype defined by enhanced IgE
      responsiveness (p>0.05). Neither did we succeed in finding either of the two
      polymorphisms described, nor could we identify any other polymorphisms within the
      gene. However, we found weak evidence for linkage in asthmatic sib pairs
      regarding maternal alleles (p=0.03). We conclude from our data that in our
      populations the gene for the beta chain of the high affinity IgE receptor is of
      minor importance for enhanced IgE responsiveness, and that it might influence
      atopy with clinical signs like asthma through maternally derived alleles.

PMID- 10353784
TI  - Connexin26 deafness in several interconnected families.
AB  - Mutations in the connexin26 gene are the basis of much autosomal recessive
      sensorineural deafness. There is a high frequency of mutant alleles, largely
      accounted for by one common mutation, 35delG. We have studied a group of
      families, who had been brought together through marriages between Deaf persons,
      in which there are more than 30 Deaf people in four generations. We show that
      many of the several cases of deafness are the result of 35delG homozygosity or
      35delG/Q57X compound heterozygosity at the connexin26 locus. A considerable range
      of audiographic phenotypes was observed. The combined effects of a high
      population frequency of mutant alleles, and of positive assortative marriage
      among the Deaf, led to an infrequently observed recessive pedigree pattern.

PMID- 10353786
TI  - The face of Smith-Magenis syndrome: a subjective and objective study.
AB  - We report a study of 55 subjects with Smith-Magenis syndrome, aged 9 months to 35
      years. Each person has been evaluated with an assessment of "gestalt" and
      detailed facial measurement, using previously published methodology, with
      compilation of Z score pattern profiles. The facial phenotype of SMS is quite
      distinctive, even in the young child. The overall face shape is broad and square.
      The brows are heavy, with excessive lateral extension of the eyebrows. The eyes
      slant upwards and appear close set and deep set. The nose has a depressed root
      and, in the young child, a scooped bridge. With time, the bridge becomes more ski
      jump shaped. The height of the nose is markedly reduced while the nasal base is
      broad and the tip of the nose is full. The shape of the mouth and upper lip are
      most distinctive. The mouth is wide with full upper and lower lips. The central
      portion of the upper lip is fleshy and everted with bulky philtral pillars,
      producing a tented appearance that, in profile, is striking. With age, mandibular
      growth is greater than average and exceeds that of the maxilla. This leads to
      increased jaw width and protrusion and marked midface hypoplasia. Craniofacial
      pattern analysis supports these subjective impressions. After mid-childhood,
      mandibular dimensions consistently exceed their maxillary counterparts.
      Craniofacial widths are greater than corresponding depths and heights. Nasal
      height is reduced while nasal width is increased. There is mild brachycephaly.
      The most marked age related changes are increased width of the nose and lower
      face (mandibular width) with reduction in nasal height and midfacial depth.

PMID- 10353785
TI  - International variation in reported livebirth prevalence rates of Down syndrome,
      adjusted for maternal age.
AB  - Reported livebirth prevalence of Down syndrome (DS) may be affected by the
      maternal age distribution of the population, completeness of ascertainment,
      accuracy of diagnosis, extent of selective prenatal termination of affected
      pregnancies, and as yet unidentified genetic and environmental factors. To search
      for evidence of the latter, we reviewed all published reports in which it was
      possible to adjust both for effects of maternal age and for selective termination
      (where relevant). We constructed indices that allowed direct comparisons of
      prevalence rates after standardising for maternal age. Reference rates were
      derived from studies previously identified as having near complete ascertainment.
      An index value significantly different from 1 may result from random
      fluctuations, as well as from variations in the factors listed above. We found 49
      population groups for which an index could be calculated. Methodological
      descriptions suggested that low values could often be attributed to under
      ascertainment. A possible exception concerned African-American groups, though
      even among these most acceptable studies were compatible with an index value of
      1. As we have reported elsewhere, there was also a suggestive increase in rates
      among US residents of Mexican or Central American origin. Nevertheless, our
      results suggest that "real" variation between population groups reported to date
      probably amounts to no more than +/-25%. However, reliable data in many human
      populations are lacking including, surprisingly, some jurisdictions with
      relatively advanced health care systems. We suggest that future reports of DS
      livebirth prevalence should routinely present data that allow calculation of an
      index standardised for maternal age and adjusted for elective prenatal
      terminations.

PMID- 10353787
TI  - Overgrowth of oral mucosa and facial skin, a novel feature of
      aspartylglucosaminuria.
AB  - Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by deficiency
      of aspartylglucosaminidase (AGA). The main symptom is progressive mental
      retardation. A spectrum of different mutations has been reported in this disease,
      one missense mutation (Cys163Ser) being responsible for the majority of Finnish
      cases. We were able to examine 66 Finnish AGU patients for changes in the oral
      mucosa and 44 of these for changes in facial skin. Biopsy specimens of 16 oral
      lesions, 12 of them associated with the teeth, plus two facial lesions were
      studied histologically. Immunohistochemical staining for AGA was performed on 15
      oral specimens. Skin was seborrhoeic in adolescent and adult patients, with
      erythema of the facial skin already common in childhood. Of 44 patients, nine
      (20%) had facial angiofibromas, tumours primarily occurring in association with
      tuberous sclerosis. Oedemic buccal mucosa (leucoedema) and gingival overgrowths
      were more frequent in AGU patients than in controls (p<0.001). Of 16 oral mucosal
      lesions studied histologically, 15 represented fibroepithelial or epithelial
      hyperplasias and were reactive in nature. Cytoplasmic vacuolisation was evident
      in four. Immunohistochemically, expression of AGA in AGU patients' mucosal
      lesions did not differ from that seen in corresponding lesions of normal
      subjects. Thus, the high frequency of mucosal overgrowth in AGU patients does not
      appear to be directly associated with lysosomal storage or with alterations in
      the level of AGA expression.

PMID- 10353788
TI  - Screening for submicroscopic chromosome rearrangements in children with
      idiopathic mental retardation using microsatellite markers for the chromosome
      telomeres.
AB  - Recently much attention has been given to the detection of submicroscopic
      chromosome rearrangements in patients with idiopathic mental retardation. We have
      screened 27 subjects with mental retardation and dysmorphic features for such
      rearrangements using a genetic marker panel screening. The screening was a pilot
      project using markers from the subtelomeric regions of all 41 chromosome arms.
      The markers were informative for monosomy in both parents at 3661902 loci (40.6%,
      95% confidence interval 37.0-44.2%) in the 22 families where DNA was available
      from both parents. In two of the 27 subjects, submicroscopic chromosomal
      aberrations were detected. The first patient had a 5-6 Mb deletion of chromosome
      18q and the second patient had a 4 Mb deletion of chromosome 1p. The
      identification of two deletions in 27 cases gave an aberration frequency of 7.5%
      without adjustment for marker informativeness (95% confidence interval 1-24%) and
      an estimated frequency of 18% if marker informativeness for monosomy was taken
      into account. This frequency is higher than previous estimates of the number of
      subtelomeric chromosome abnormalities in children with idiopathic mental
      retardation (5-10%) although the confidence interval is overlapping. Our study
      suggests that in spite of the low informativeness of this pilot screening,
      submicroscopic chromosome aberrations may be a common cause of dysmorphic
      features and mental retardation.

PMID- 10353790
TI  - Linkage disequilibrium at the SCA2 locus.
AB  - Spinocerebellar ataxia type 2 (SCA2) is caused by the expansion of an unstable
      CAG repeat encoding a polyglutamine tract. Repeats with 32 to 200 CAGs are
      associated with the disease, whereas normal chromosomes contain 13 to 33 repeats.
      We tested 220 families of different geographical origins for the SCA2 mutation.
      Thirty three were positive (15%). Twenty three families with at least two
      affected subjects were tested for linkage disequilibium (LD) between the SCA2
      mutation and three microsatellite markers, two of which (D12S1332-D12S1333)
      closely flanked the mutation; the other (D12S1672) was intragenic. Many different
      haplotypes were observed, indicating the occurrence of several ancestral
      mutations. However, the same haplotype, not observed in controls, was detected in
      the German, the Serbian, and some of the French families, suggesting a founder
      effect or recurrent mutations on an at risk haplotype.

PMID- 10353789
TI  - Feasibility of DNA based methods for prenatal diagnosis and carrier detection of
      propionic acidaemia.
AB  - Propionic acidaemia (PA) is an autosomal recessive disease caused by a genetic
      deficiency of propionyl-CoA carboxylase (PCC). Defects in the PCCA and PCCB genes
      that code for the alpha and beta subunits of PCC, respectively, are responsible
      for PA. A proband with PA was previously shown to carry the c1170insT mutation
      and the private L519P mutation in the PCCB gene. Here we report the prenatal
      diagnosis of an affected fetus based on DNA analysis in chorionic villus tissue.
      We have also assessed the carrier status in this PCCB deficient family, which was
      not possible with biochemical analysis.

PMID- 10353791
TI  - Familial pericentric inversion of chromosome 1 (p36.3q23) and Bardet-Biedl
      syndrome.

PMID- 10353792
TI  - Duplication of 8p with minimal phenotypic effect transmitted from a mother to her
      two daughters.

PMID- 10353793
TI  - Cloverleaf skull anomaly and de novo trisomy 4p.

PMID- 10353794
TI  - Study of the interaction of sulphate-reducing bacteria exopolymers with iron
      using X-ray photoelectron spectroscopy and time-of-flight secondary ionisation
      mass spectrometry.
AB  - Time-of-flight secondary ionisation mass spectrometry and X-ray photoelectron
      spectroscopy were employed to determine the interaction of crude extracellular
      polymeric substances recovered from static batch cultures of two isolates of
      marine sulphate-reducing bacteria of the genus Desulfovibrio, grown in the
      presence of and without mild steel surfaces, with Fe ions released from steel.
      The results demonstrated that exopolymers synthesised by different strains of
      sulphate-reducers varied in their ability to bind iron originating from steel.
      Based on the X-ray photoelectron spectroscopy analysis it is proposed that Fe
      released from steel was associated with bacterial exopolymers such as Fe(III)
      ion. The application of surface science techniques to study exopolymer/metal
      interaction allowed quantitative evaluation of Fe binding using small sample
      size.

PMID- 10353795
TI  - Fractal analysis to discriminate between biotic and abiotic attacks on
      chalcopyrite and pyrolusite.
AB  - In the present paper, a model describing release and mobility of copper and
      manganese in chalcopyrite and pyrolusite powders due to bacterial bioleaching,
      i.e. Thiobacillus ferrooxidans and Arthrobacter sp., is proposed. Sites where
      copper and manganese were released were examined by scanning electron microscopy
      (SEM). The resulting micrographs were scanned and submitted to a point by point
      fractal analysis to verify if a discrimination between biological and chemical
      attack could be established on the basis of the distribution of the fractional
      part of the fractal dimension over the whole surface. We demonstrate that such a
      method is able to discriminate among the different attacks.

PMID- 10353796
TI  - Use of biochemical indices in the mediterranean environment: comparison among
      soils under different forest vegetation.
AB  - In the present study, soil biomass activity, organic carbon storage, and turnover
      times were compared in adjacent mediterranean biotopes with different forest
      vegetation, to analyze the effects of litter diversity and soil management
      protocols on microbial decomposition rates. Samples of forest soil from four
      vegetation types were collected at depths of 0-20 and 20-40 cm in the 'Tenuta
      Presidenziale di Castelporziano' Reserve on the Tyrrhenian coast, near Rome
      (Italy). The samples were incubated under standard laboratory conditions (-33 kPa
      water tension, and 30 degrees C), in order to compare the microbial activity
      independently of temperature and humidity. The CO2-C accumulation curves over a
      28-d incubation period showed substantially different kinetics between the
      samples; in particular, soils with above-ground diversity were characterised by
      high mineralization activity when compared with those sampled under monospecific
      vegetation. For all the sites, statistically significant linear correlation was
      observed between nitrogen concentration and potentially mineralizable carbon (r =
      0.97), and microbial biomass carbon (Cmic) to total organic carbon (Corg) ratio
      and the microbial metabolic quotient q(CO2) (r = -0.96). The q(CO2), indicator of
      the stability of ecosystems, was enhanced by plant diversity, while the Cmic:Corg
      ratio was reduced.

PMID- 10353797
TI  - Community level physiological profile of soil bacteria unaffected by extraction
      method.
AB  - Extraction and purification of bacteria from soil by the Nycodenz gradient
      centrifugation procedure described by Bakken and Lindahl (1995; Recovery of
      bacterial cells from soil. In: van Elsas, J.D., Trevors, J.T. (Eds.), Nucleic
      Acids in the Environment: Methods and Applications. Springer Verlag, Berlin, pp.
      9-27) were compared to soil slurry extractions. Bacterial communities from four
      different soils were described by the bacterial abundance, CTC-reducing capacity,
      culturability and the community level physiological profiles (CLPP) in BIOLOG GN
      plates. A significant loss of both total and culturable number of bacteria g(-1)
      soil dry weight were found after extraction and purification of cells. The origin
      of soil influenced the yield of cells and a difference between the four soils and
      an interaction between the soils and extraction procedure were found. The
      culturability and the CLPP were different between the four soils but were
      unaffected by the extraction procedure. The bacterial community obtained after
      extraction and purification thus represented the same fraction of the indigenous
      bacterial community.

PMID- 10353798
TI  - Elevated CO2 alters community-level physiological profiles and enzyme activities
      in alpine grassland.
AB  - Plots of an alpine grassland in the Swiss Alps were treated with elevated (680
      microl l(-1)) and ambient CO2 (355 microl l(-1)) in open top chambers (OTC).
      Several plots were also treated with NPK-fertilizer. Community level
      physiological profiles (CLPPs) of the soil bacteria were examined by Biolog GN
      microplates and enzyme activities were determined through the release of
      methylumbelliferyl (MUF) and methylcoumarin (MC) from MUF- or MC-labelled
      substrates. A canonical discriminant analysis (CDA) followed by multivariate
      analysis of variance showed a significant effect of elevated CO2 on the CLPPs
      both under fertilized and unfertilized conditions. Further, the installation of
      the OTCs caused significant shifts in the CLPPs (chamber effect). Of the four
      enzyme activities tested, the beta-D-cellobiohydrolase (CELase) and N-acetyl-beta
      D-glucosaminidase (NAGase) activity were enhanced under elevated CO2. L-Leucin-7
      aminopeptidase (APEase) activity decreased, when the plots received fertilizer.
      Beta-D-glucosidase (GLUase) remained unaffected. The results suggest effects of
      elevated CO2 on specific microbial activities even under low mineral nutrient
      conditions and when bulk parameters like microbial biomass or respiration, which
      have been investigated on the same site, remain unaffected. The observed medium
      term changes point at possible long-term consequences for the ecosystem that may
      not be specified yet.

PMID- 10353800
TI  - Use of the 16S--23S ribosomal genes spacer region in studies of prokaryotic
      diversity.
AB  - The description of microbial diversity by molecular culture-independent
      techniques most often involves the amplification of the 16S rRNA by PCR gene and
      either analysis of the diversity of amplified molecules (community
      fingerprinting) that allows the simultaneous study of many samples or the cloning
      and sequencing of a significant amount of amplification products. The fact that
      between the 16S and the 23S genes in the ribosomal operon there is a spacer
      extremely variable in both sequence and length provides an excellent tool to
      simplify both approaches. The spacer can be amplified almost as easily as the 16S
      rDNA taking advantage of conserved nucleotide stretches at the 5' end of the 23S
      gene and the amplicon can contain different amounts of the 16S rDNA choosing
      primers at the different conserved areas within this gene. Identified by the
      acronym RISA (rDNA internal spacer analysis), the spacer addition provides a
      marker of highly variable size allowing standard separation of the amplification
      products and the sequence of this hypervariable region is useful in the fine
      discrimination of operational taxonomic units.

PMID- 10353799
TI  - Responses of the soil microbiota to elevated CO2 in an artificial tropical
      ecosystem.
AB  - Plants in artificial tropical ecosystems were grown under ambient (340 microl l(
      1)) and elevated (610 microl l(-1)) atmospheric CO2 for 530 d under low-nutrient
      conditions on a substrate free of organic C. At the end of the experiment a
      number of soil chemical and microbiological variables were determined. Although
      we found no changes in total soil organic matter under elevated CO2, we did find
      that after physical fractionation the amount of organic C in the supernatant (<
      0.2 microm) and the amount of water extractable organic C (WEOC) was lower under
      elevated CO2. The extractable optical density (OD) indicated a higher degree of
      humification for the elevated than for the ambient CO2 samples (P = 0.032).
      Microbial biomass C was not significantly altered under high CO2, but total
      bacterial counts were significantly higher. The microbial biomass C-to-N ratio
      was also higher at elevated (15.0) than at ambient CO2 (10.0). The number of
      mycorrhizal spores was lower at high CO2, but ergosterol contents and fungal
      hyphal lengths were not significantly affected. Changes were found neither in
      community level physiological profiles (CLPPs) nor in the structural attributes
      (phospholipid fatty acids, PLFAs) of the microbial community. Overall, the
      effects on the soil microbiota were small, perhaps as a result of the low
      nutrient supply and low organic matter content of the soil used in our study. The
      few significant results showing changes in specific, though relatively minor,
      organic matter pools may point to possible long-term changes of the more major
      pools. Furthermore, the data suggest increased competition between plants and
      microbes for N at high CO2.

PMID- 10353801
TI  - Molecular monitoring of an uncultured group of the class Actinobacteria in two
      terrestrial environments.
AB  - Previous investigations of 16S rRNA clone libraries from a wide spectrum of
      mainly terrestrial origin have shown the worldwide distribution of several as yet
      uncultivated phylogenetically deeply rooting groups of Actinobacteria. From the
      percentage of the occurrence of these clones it was concluded that these
      organisms constitute a significant part of the bacterial microflora in these
      habitats. Two of the clone groups, previously designated group II and group III,
      were shown to be phylogenetically moderately related among each other. In order
      to more exactly determine the abundance of a representative of group II, clone
      DA079, the fraction of the organism's rRNA in total extracted rRNA was determined
      in several neighboring samples from Drentse A grassland soil (The Netherlands).
      The fraction ranged from 2.6 to 9.1%, averaging 5.5%. Based upon comparison of
      total rRNA and strain DA079-specific rRNA it was concluded that on the average 2
      x 10(6) cells/g of this organism are present in the investigated soil. Attempts
      to isolate members of one of the 16S rDNA clone groups of Actinobacteria were
      made with samples from a German peat bog, in which the organisms had been
      detected previously. Molecular detection of group III organisms by a nested PCR
      approach was possible in different cultivation media. Despite the wide spectrum
      of growth media employed the isolation of group III strains failed.

PMID- 10353802
TI  - Reviewing the DA001-files: a 16S rRNA chase on suspect #X99967, a Bacillus and
      Dutch underground activist.
AB  - A variant of 'the rRNA approach' on uncultured soil bacteria is discussed, which
      is mainly based on 16S rRNA rather than on genomic 16S rDNA. While the rDNA only
      reflects the presence of bacteria, the rRNA indicates much more the activity of
      bacteria. Hence, the presented strategy can indicate the involvement of
      uncultured bacteria to the metabolic activity of the total microbial community.
      The potentials and limitations of the applied techniques will be discussed:
      isolation of ribosomes from soil, temperature gradient gel electrophoresis,
      cloning and sequencing, and the verification of these data by V6 Southern blot
      hybridization, dot blot hybridization and in situ hybridization. By this and
      another novel rRNA quantification approach, the multiple competitive RT-PCR, it
      could be found that an uncultured Bacillus, recognized as ribotype DA001,
      contributes approximately 5-10% to all bacterial ribosomes in Dutch Drentse A
      grassland soils. These bacteria should be major operators of biogeochemical
      processes in soil.

PMID- 10353803
TI  - Intra-specific diversity of Aureobasidium pullulans strains isolated from rocks
      and other habitats assessed by physiological methods and by random amplified
      polymorphic DNA (RAPD).
AB  - Intra-specific diversity of Aureobasidium pullulans strains isolated from
      environmental sources and from stones was studied by assessment of morphological,
      biochemical and physiological characters as well as random amplified polymorphic
      DNA (RAPD) using microsatellite or minisatellite DNA primers (GTG)5, (GACA)4,
      M13. The results showed that both classical and molecular techniques evidenced a
      phenotypic and genetic diversity of analysed A. pullulans strains. A different
      behaviour was observed in reference to the growth responses with D-glucosamine,
      citrate, galactitol and with different salt concentrations and range of growth
      temperature. Molecular analysis partially confirmed the data obtained with
      biochemical and physiological tests, additionally showing common fragments in all
      strains, to be used for a possible application as 'in situ' probes and for a
      rapid identification of A. pullulans strains.

PMID- 10353804
TI  - Analysis of bacterial communities on historical glass by denaturing gradient gel
      electrophoresis of PCR-amplified gene fragments coding for 16S rRNA.
AB  - The present study describes the analysis of bacterial communities on historical
      window glass by denaturing gradient gel electrophoresis of PCR-amplified 16S rDNA
      fragments. So far, only a few studies have been published in which the microflora
      and the corrosion mechanisms of glass surfaces have been investigated. Some
      microorganisms, especially fungi, have been isolated from different glass samples
      in the past. However, our results demonstrate that bacterial communities on
      biodeteriorated glass surfaces are much more complex than previously believed. In
      addition, bacteria were identified, which have never been isolated from glass
      samples before.

PMID- 10353805
TI  - Actinomycetes in Karstic caves of northern Spain (Altamira and Tito Bustillo).
AB  - A variety of isolation procedures were carried out to study the involvement of
      bacteria in the colonisation and biodeterioration of Spanish caves with
      paleolithic rock art (Altamira and Tito Bustillo). The applied techniques mainly
      aimed to isolate heterotrophic bacteria such as streptomycetes, nocardioform and
      coryneform actinomycetes, and other gram-positive and gram-negative bacteria. The
      results demonstrated that actinomycetes were the most abundant gram-positive
      bacteria in the caves. Actinomycetes revealed a great taxonomic diversity with
      the predominant isolates belonging to the genus Streptomyces. Members of the
      genera Nocardia, Rhodococcus, Nocardioides, Amycolatopsis, Saccharothrix,
      Brevibacterium, Microbacterium, and coccoid actinomycetes (family Micrococcaceae)
      were also found.

PMID- 10353806
TI  - Bacteria isolated from rock art paintings: the case of Atlanterra shelter (south
      Spain).
AB  - The Sierra de la Plata is an Aljibe yellow sandstone formation from the Acheulian
      period. There are a few shelters, some of them with rock art paintings. The most
      representative one, and subjected to anthropogenic pressure, is that of
      Atlanterra, situated in a residential area. This shelter contains some rock art
      paintings made with iron oxides. The bacteria present in these paintings were
      isolated and identified using an automatic method: fatty acid methyl esters
      profiling. Most of the bacteria belong to the Bacillus genus, B. megaterium being
      the most abundant species. The isolated strains are able to reduce hematite. This
      is significant due to the fact that Fe(III)-(hydr)oxides are the most abundant
      pigments in rock art.

PMID- 10353807
TI  - Microbiological study of the dripping waters in Altamira cave (Santillana del
      Mar, Spain).
AB  - The culturable microbial populations in dripping waters from Altamira cave were
      studied and compared with those of the ceiling rock. Water communities have low
      proportions of gram-positive bacteria, and are mainly composed of gram-negative
      rods and cocci (Enterobacteriaceae and Vibrionaceae), while those of ceiling
      rocks are mainly Streptomyces spp. The community differences are probably related
      to environmental cave conditions: high humidity, relatively low and stable
      temperature, water pH close to neutrality and nature of the organic matter. All
      these factors seem to favor colonization and long-term growth of actinomycetes
      over other heterotrophic bacteria on ceiling rocks.

PMID- 10353809
TI  - Accelerated assembly of G-quadruplex structures by a small molecule.
AB  - In the presence of alkali cations, notably potassium and sodium, DNA oligomers
      that possess two G-rich repeats associate into either a tetrameric parallel G
      quadruplex or a variety of dimeric antiparallel G-quadruplexes. The formation of
      such structures is normally a very slow process. Some proteins, such as the beta
      subunit of the Oxytricha telomere-binding protein, promote the formation of G
      quadruplex structures in a chaperone-like manner. In this report, we present data
      concerning the role of a perylene derivative, PIPER, in the assembly of G
      quadruplex structures as the first example of a small ligand behaving as a driver
      in the assembly of polynucleotide secondary structures. Gel-shift experiments
      demonstrate that PIPER can dramatically accelerate the association of a DNA
      oligomer containing two tandem repeats of the human telomeric sequence (TTAGGG)
      into di- and tetrameric G-quadruplexes. In so doing, PIPER alters the oligomer
      dimerization kinetics from second to first order. The presence of 10 microM PIPER
      accelerates the assembly of varied dimeric G-quadruplexes an estimated 100-fold
      from 2 microM oligomer. These results imply that some biological effects elicited
      by G-quadruplex-interactive agents, such as the induction of anaphase bridges,
      may stem from the propensity such compounds have for assembling G-quadruplexes.

PMID- 10353808
TI  - Bacterial bio-mediated calcite precipitation for monumental stones conservation:
      methods of evaluation.
AB  - The weathering of monumental stones is a complex process inserted in the more
      general 'matter transformation cycle' operated by physical, chemical and
      biological factors. The consequence of these combined actions is a loss of
      cohesion with dwindling and scaling of stone material and the induction of a
      progressive mineral matrix dissolution. In the case of calcareous stones, calcite
      leaching increases the material porosity and decreases its mechanical features
      with a general weakening of the superficial structural strength. Attempts to
      stop, or at least to slow down, deterioration of monumental stones has been made
      by conservative treatments with both inorganic or organic products. More recent
      studies show a new approach to hinder these phenomena by inducing a bio-mediated
      precipitation of calcite directly inside the stone porosity. This can be achieved
      either through the application of organic matrix macromolecules extracted from
      sea shells or of living bacteria. The effectiveness of the treatment using
      calcinogenic bacteria has been evaluated with laboratory tests specifically
      developed to evaluate the parameters such as : porosity, superficial strength and
      chromatic changes, influenced by the treatment itself. The results obtained seem
      to indicate that this type of treatment might not be suitable for monumental
      stone conservation.

PMID- 10353810
TI  - Identification of a unique liganded estrogen receptor complex released from the
      nucleus by decavanadate.
AB  - Unoccupied estrogen receptor (ER) can be extracted from tissues by homogenization
      with a hypotonic buffer, whereas hormone-occupied ER becomes tightly bound to the
      nuclear pellet and must be extracted with high-salt-containing buffers. The
      molecular basis for estrogen-induced tight nuclear binding of ER remains an
      important puzzle. The different subcellular fractionation behaviors of the
      occupied and unoccupied ER are presumed to be due to a difference in their
      ability to interact with nuclear components, such as DNA and proteins. The
      proteins that are the targets for interaction with the hormone-occupied ER may be
      important for transcriptional regulation. However, the salt-extracted ER is
      recovered as a homodimer, and associated proteins are presumably lost due to the
      high-salt conditions. We have discovered an alternate method of releasing the
      occupied ER from the nucleus. Inclusion of 2 mM orthovanadate, polymerized
      primarily to decavanadate, in a hypotonic buffer efficiently releases over 90% of
      estrogen-bound ER from the nuclear pellet. The recovered ER complex is fully
      functional in terms of estrogen and DNA binding and is full-length by western
      blot analysis. Our data suggest that the mechanism of ER release is by
      decavanadate competition with nuclear DNA, rather than by inhibition of a
      phosphotyrosine phosphatase. Of particular interest, the decavanadate released
      occupied ER complex shows distinct behavior by sucrose density gradient
      sedimentation analysis. It is larger than the salt-extracted transformed ER,
      suggesting that an occupied ER in complex with nuclear proteins may be released
      from the nucleus by decavanadate.

PMID- 10353811
TI  - Site-directed mutagenesis of the cysteine ligands to the [4Fe-4S] cluster of
      Escherichia coli MutY.
AB  - The Escherichia coli DNA repair enzyme MutY plays an important role in the
      recognition and repair of 7, 8-dihydro-8-oxo-2'-deoxyguanosine:2'-deoxyadenosine
      (OG:A) mismatches in DNA [Michaels et al. (1992) Proc. Natl. Acad. Sci. U.S. A.
      89, 7022-7025]. MutY prevents DNA mutations resulting from the misincorporation
      of A opposite OG by using N-glycosylase activity to remove the adenine base. An
      interesting feature of MutY is that it contains a [4Fe-4S]2+ cluster that has
      been shown to play an important role in substrate recognition [Porello, S. L.,
      Cannon, M. J., David, S. S. (1998) Biochemistry 37, 6465-6475]. Herein, we have
      used site-directed mutagenesis to individually replace the cysteine ligands to
      the [4Fe-4S]2+ cluster of E. coli MutY with serine, histidine, and alanine. The
      extent to which the various mutations reduce the levels of protein overexpression
      suggests that coordination of the [4Fe-4S]2+ cluster provides stability to MutY
      in vivo. The ability of the mutated enzymes to bind to a substrate analogue DNA
      duplex and their in vivo activity were evaluated. Remarkably, the effects are
      both substitution and position dependent. For example, replacement of cysteine
      199 with histidine provides a mutated enzyme that is expressed at high levels and
      exhibits DNA binding and in vivo activity similar to the WT enzyme. These results
      suggest that histidine coordination to the iron-sulfur cluster may be
      accommodated at this position in MutY. In contrast, replacement of cysteine 192
      with histidine results in less efficient DNA binding and in vivo activity
      compared to the WT enzyme without affecting levels of overexpression. The results
      from the site-directed mutagenesis suggest that the structural properties of the
      iron-sulfur cluster coordination domain are important for both substrate DNA
      recognition and the in vivo activity of MutY.

PMID- 10353812
TI  - The methyl-CpG binding transcriptional repressor MeCP2 stably associates with
      nucleosomal DNA.
AB  - We have investigated the interactions of the methyl-CpG binding transcriptional
      repressor MeCP2 with nucleosomal DNA. We find that MeCP2 forms discrete complexes
      with nucleosomal DNA associating with methyl-CpGs exposed in the major groove via
      the methyl-CpG-binding domain (MBD). In addition to the MBD, the carboxyl
      terminal segment of MeCP2 facilitates binding both to naked DNA and to the
      nucleosome core. These observations provide a molecular mechanism by which MeCP2
      can gain access to chromatin in order to target corepressor complexes that
      further modify chromatin structure.

PMID- 10353813
TI  - Independently melting modules and highly structured intermodular junctions within
      complement receptor type 1.
AB  - A segment of complement receptor type 1 (CR1) corresponding to modules 15-17 was
      overexpressed as a functionally active recombinant protein with N-glycosylation
      sites ablated by mutagenesis (referred to as CR1 approximately 15-17(-)). A
      protein consisting of modules 15 and 16 and another corresponding to module 16
      were also overexpressed. Comparison of heteronuclear nuclear magnetic resonance
      (NMR) spectra for the single, double, and triple module fragments indicated that
      module 16 makes more extensive contacts with module 15 than with module 17. A
      combination of NMR, differential scanning calorimetry, circular dichroism, and
      tryptophan-derived fluorescence indicated a complex unfolding pathway for CR1
      approximately 15-17(-). As temperature or denaturant concentration was increased,
      the 16-17 junction appeared to melt first, followed by the 15-16 junction, and
      module 17 itself; finally, modules 15 and 16 became denatured. Modules 15 and 16
      adopted an intermediate state prior to total denaturation. These results are
      compared with a previously published study [Clark, N. S., Dodd, I, Mossakowska,
      D. E., Smith, R. A. G., and Gore, M. G. (1996) Protein Eng. 9, 877-884] on a
      fragment consisting of the N-terminal three CR1 modules which appeared to melt as
      a single unit.

PMID- 10353814
TI  - Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent
      reaction products at the atomic level.
AB  - Organophosphorus acid anhydride (OP) nerve agents are potent inhibitors which
      rapidly phosphonylate acetylcholinesterase (AChE) and then may undergo an
      internal dealkylation reaction (called "aging") to produce an OP-enzyme conjugate
      that cannot be reactivated. To understand the basis for irreversible inhibition,
      we solved the structures of aged conjugates obtained by reaction of Torpedo
      californica AChE (TcAChE) with diisopropylphosphorofluoridate (DFP), O
      isopropylmethylphosponofluoridate (sarin), or O
      pinacolylmethylphosphonofluoridate (soman) by X-ray crystallography to 2.3, 2.6,
      or 2.2 A resolution, respectively. The highest positive difference density peak
      corresponded to the OP phosphorus and was located within covalent bonding
      distance of the active-site serine (S200) in each structure. The OP-oxygen atoms
      were within hydrogen-bonding distance of four potential donors from catalytic
      subsites of the enzyme, suggesting that electrostatic forces significantly
      stabilize the aged enzyme. The active sites of aged sarin- and soman-TcAChE were
      essentially identical and provided structural models for the negatively charged,
      tetrahedral intermediate that occurs during deacylation with the natural
      substrate, acetylcholine. Phosphorylation with DFP caused an unexpected movement
      in the main chain of a loop that includes residues F288 and F290 of the TcAChE
      acyl pocket. This is the first major conformational change reported in the active
      site of any AChE-ligand complex, and it offers a structural explanation for the
      substrate selectivity of AChE.

PMID- 10353815
TI  - Crystal structure of NAD(P)H:flavin oxidoreductase from Escherichia coli.
AB  - Flavin reductases use flavins as substrates and are distinct from flavoenzymes
      which have tightly bound flavins. The reduced flavin can serve to reduce ferric
      complexes and iron proteins. In Escherichia coli, reactivation of ribonucleotide
      reductase is achieved by reduced flavins produced by flavin reductase. The
      crystal structure of E. coli flavin reductase reveals that the enzyme structure
      is similar to the structures of the ferredoxin reductase family of flavoproteins
      despite very low sequence similarities. The main difference between flavin
      reductase and structurally related flavoproteins is that there is no binding site
      for the AMP moiety of FAD. The direction of the helix in the flavin binding
      domain, corresponding to the phosphate binding helix in the flavoproteins, is
      also slightly different and less suitable for phosphate binding. Interactions for
      flavin substrates are instead provided by a hydrophobic isoalloxazine binding
      site that also contains a serine and a threonine, which form hydrogen bonds to
      the isoalloxazine of bound riboflavin in a substrate complex.

PMID- 10353816
TI  - Structure of raw starch-digesting Bacillus cereus beta-amylase complexed with
      maltose.
AB  - The crystals of beta-amylase from Bacillus cereus belong to space group P21 with
      the following cell dimensions: a = 57.70 A, b = 92.87 A, c = 65.93 A, and beta
      =101.95 degrees. The structures of free and maltose-bound beta-amylases were
      determined by X-ray crystallography at 2.1 and 2.5 A with R-factors of 0.170 and
      0.164, respectively. The final model of the maltose-bound form comprises 516
      amino acid residues, four maltose molecules, 275 water molecules, one Ca2+, one
      acetate, and one sulfate ion. The enzyme consists of a core (beta/alpha)8-barrel
      domain (residues 5-434) and a C-terminal starch-binding domain (residues 435
      613). Besides the active site in the core where two maltose molecules are bound
      in tandem, two novel maltose-binding sites were found in the core L4 region and
      in the C-terminal domain. The structure of the core domain is similar to that of
      soybean beta-amylase except for the L4 maltose-binding site, whereas the C
      terminal domain has the same secondary structure as domain E of cyclodextrin
      glucosyltransferase. These two maltose-binding sites are 32-36 A apart from the
      active site. These results indicate that the ability of B. cereus beta-amylase to
      digest raw starch can be attributed to the additional two maltose-binding sites.

PMID- 10353817
TI  - Structural basis for antibody catalysis of a disfavored ring closure reaction.
AB  - The catalysis of disfavored chemical reactions, especially those with no known
      natural enzyme counterparts, is one of the most promising achievements of
      catalytic antibody research. Antibodies 5C8, 14B9, 17F6, and 26D9, elicited by
      two different transition-state analogues, catalyze disfavored endo-tet
      cyclization reactions of trans-epoxy alcohols, in formal violation of Baldwin's
      rules for ring closure. Thus far, neither chemical nor enzyme catalysis has been
      capable of emulating the extraordinary activity and specificity of these
      antibodies. X-ray structures of two complexes of Fab 5C8 with the original hapten
      and with an inhibitor have been determined to 2.0 A resolution. The Fab structure
      has an active site that contains a putative catalytic diad, consisting of AspH95
      and HisL89, capable of general acid/base catalysis. The stabilization of a
      positive charge that develops along the reaction coordinate appears to be an
      important factor for rate enhancement and for directing the reaction along the
      otherwise disfavored pathway. Sequence analysis of the four catalytic antibodies,
      as well as four inactive antibodies that strongly bind the transition-state
      analogues, suggests a conserved catalytic mechanism. The occurrence of the
      putative base HisL89 in all active antibodies, its absence in three out of the
      four analyzed inactive antibodies, and the rarity of a histidine at this position
      in immunoglobulins support an important catalytic role for this residue.

PMID- 10353818
TI  - Selenomethionine-substituted Thermus thermophilus cytochrome ba3:
      characterization of the CuA site by Se and Cu K-EXAFS.
AB  - We have designed a gene that encodes a polypeptide corresponding to amino acids
      44-168 of the Thermus thermophilus cytochrome ba3 subunit II [Keightley et al.
      (1995) J. Biol. Chem. 270, 20345-20358]. The resulting ba3-CuAt10 protein
      separated into two fractions (A and B) during cation exchange chromatography
      which were demonstrated to differ only by N-terminal acetylation in fraction A.
      When the gene was expressed in an Escherichia coli strain that is auxotrophic for
      methionine and grown in the presence of selenomethionine (Se(Met)), the single
      methionine of the CuAt10 protein was quantitatively replaced with Se(Met). Native
      (S(Met)) and Se(Met)-substituted proteins were characterized by electrospray
      mass, optical absorption, and EPR spectroscopies and by electrochemical analysis;
      they were found to have substantially identical properties. The Se(Met)
      containing protein was further characterized by Se and Cu K-EXAFS which revealed
      Cu-Se bond lengths of 2.55 A in the mixed-valence form and 2.52 A in the fully
      reduced form of CuA. Further analysis of the Se- and Cu-EXAFS spectra yielded the
      Se-S(thiolate) distances and thereby information on the Se-Cu-Cu and Se-Cu
      S(thiolate) angles. An expanded EXAFS structural model is presented.

PMID- 10353819
TI  - NMR solution structure of the catalytic fragment of human fibroblast collagenase
      complexed with a sulfonamide derivative of a hydroxamic acid compound.
AB  - The solution structure of the catalytic fragment of human fibroblast collagenase
      (MMP-1) complexed with a sulfonamide derivative of a hydroxamic acid compound
      (CGS-27023A) has been determined using two-dimensional and three-dimensional
      heteronuclear NMR spectroscopy. The solution structure of the complex was
      calculated by means of hybrid distance geometry-simulated annealing using a
      combination of experimental NMR restraints obtained from the previous refinement
      of the inhibitor-free MMP-1 (1) and recent restraints for the MMP-1:CGS-27023A
      complex. The hydroxamic acid moiety of CGS-27023A was found to chelate to the
      "right" of the catalytic zinc where the p-methoxyphenyl sits in the S1' active
      site pocket, the isopropyl group is in contact with H83 and N80, and the pyridine
      ring is solvent exposed. The sulfonyl oxygens are in hydrogen-bonding distance to
      the backbone NHs of L81 and A82. This is similar to the conformation determined
      by NMR of the inhibitor bound to stromelysin (2, 3). A total of 48 distance
      restraints were observed between MMP-1 and CGS-27023A from 3D 13C-edited/12C
      filtered NOESY and 3D 15N-edited NOESY experiments. An additional 18
      intramolecular restraints were observed for CGS-27023A from a 2D 12C-filtered
      NOESY experiment. A minimal set of NMR experiments in combination with the free
      MMP-1 assignments were used to assign the MMP-1 (1)H, 13C, and 15N resonances in
      the MMP-1:CGS-27023A complex. The assignments of CGS-27023A in the complex were
      obtained from 2D 12C-filtered NOESY and 2D 12C-filtered TOCSY experiments.

PMID- 10353820
TI  - The effect of O-fucosylation on the first EGF-like domain from human blood
      coagulation factor VII.
AB  - The first epidermal growth factor-like domain (EGF-1) from blood coagulation
      factor VII (FVII) contains two unusual O-linked glycosylation sites at Ser-52 and
      Ser-60. We report here a detailed study of the effect of O-fucosylation at Ser-60
      on the structure of FVII EGF-1, its Ca2+-binding affinity, and its interaction
      with tissue factor (TF). The in vitro fucosylation of the nonglycosylated FVII
      EGF-1 was achieved by using O-fucosyltransferase purified from Chinese hamster
      ovary cells. Distance and dihedral constraints derived from NMR data were used to
      determine the solution structures of both nonglycosylated and fucosylated FVII
      EGF-1 in the presence of CaCl2. The overall structure of fucosylated FVII EGF-1
      is very similar to the nonfucosylated form even for the residues near the
      fucosylation site. The Ca2+ dissociation constants (Kd) for the nonfucosylated
      and fucosylated FVII EGF-1 were found to be 16.4 +/- 1.8 and 8.6 +/- 1.4 mM,
      respectively. The FVII EGF-1 domain binds to the extracellular part of TF with a
      low affinity (Kd approximately 0. 6 mM), and the addition of fucose appears to
      have no effect on this affinity. These results indicate that the FVII EGF-1 alone
      cannot form a tight complex with TF and suggest that the high binding affinity of
      FVIIa for TF requires cooperative interaction among the four domains in FVII with
      TF. Although the fucose has no significant effect on the interaction between TF
      and the individual FVII EGF-1 domain, it may affect the interaction of full
      length FVIIa with TF by influencing its Ca2+-binding affinity.

PMID- 10353821
TI  - Human bleomycin hydrolase binds ribosomal proteins.
AB  - Bleomycin hydrolase (BH) is a cysteine proteinase that inactivates the anticancer
      drug bleomycin. Yeast BH forms a homohexameric structure that resembles a 20S
      proteasome and binds to single-stranded RNA and DNA. We now demonstrate that
      human BH (hBH) interacts and colocalizes with ribosomal proteins. Using a yeast
      two-hybrid system, we found hBH bound to human homologues of rat ribosomal
      proteins L11 and L29. The N-terminus of hBH (amino acids 14-175), which contains
      a catalytic Cys93, was critical for the binding to L11 in the two-hybrid
      environment. hBH precipitated 35S-labeled L11 and L29 in vitro, and hBH
      colocalized with L11 and L29 as determined by immunofluorescence. In addition to
      cytosolic bleomycin hydrolase, we found abundant bleomycin hydrolase activity
      associated with the ribosomal subcellular fraction by differential
      centrifugation. hBH was also detected by Western immunoblotting in a high-speed
      particulate fraction, where the majority of L11 and L29 were found. In vitro
      experiments showed recombinant hBH binds to Chinese hamster ovary cell
      microsomes. Thus, our data strongly suggest that hBH exists as both a free
      cytosolic and ribosome-associated protein.

PMID- 10353822
TI  - Mechanisms of monovalent cation action in enzyme catalysis: the first stage of
      the tryptophan synthase beta-reaction.
AB  - The tryptophan synthase bienzyme complex is activated and regulated by the
      allosteric action of monovalent cations (MVCs). The kinetic dissection of the
      first stage (stage I) in the beta-reaction of tryptophan synthase, the reaction
      of L-serine with pyridoxal 5'-phosphate at the beta-site to give the alpha
      aminoacrylate Schiff base intermediate, E(A-A), is here examined in the absence
      and presence of MVCs. This analysis reveals which of the individual steps are
      greatly affected in stage I and how the ground states and transition states are
      affected by MVCs. Kinetic studies in combination with a detailed relaxation
      kinetic analysis to determine the specific rate constants for the conversion of
      the L-Ser external aldimine, E(Aex1), to E(A-A) show that the primary kinetic
      isotope effect for proton abstraction from Calpha of the E(Aex1) species changes
      from 4.0 +/- 0.4 in the absence of MVCs to a value of 5.9 +/- 0.5 in the presence
      of Na+, indicating that the nature of the transition state for this C-H scission
      is significantly perturbed by the MVC effect. The E(A-A) species was found to
      exist in two conformations with different activities, the ratio of which is
      affected by the presence of MVCs. It is shown that changes in the rate constants
      of stage I are important in establishing the ratio of active to inactive
      conformations of the E(A-A) species. Consequently, the MVC effect alters the
      relative energies of both the transition states and the ground states for
      selected steps in stage I of the pathway. Hence, interactions at the MVC site
      give rise to a fine-tuning of the covalent bonding interactions between active
      site residues and the reacting substrate during the conformational cycle of the
      bienzyme complex.

PMID- 10353823
TI  - Mechanisms of monovalent cation action in enzyme catalysis: the tryptophan
      synthase alpha-, beta-, and alpha beta-reactions.
AB  - The alpha-subunit of the tryptophan synthase bienzyme complex catalyzes the
      formation of indole from the cleavage of 3-indolyl-D-glyceraldehyde 3'-phosphate,
      while the beta-subunit utilizes L-serine and the indole produced at the alpha
      site to form tryptophan. The replacement reaction catalyzed by the beta-subunit
      requires pyridoxal 5'-phosphate (PLP) as a cofactor. The beta-reaction occurs in
      two stages: in stage I, the first substrate, L-Ser, reacts with the enzyme-bound
      PLP cofactor to form an equilibrating mixture of the L-Ser Schiff base, E(Aex1),
      and the alpha-aminoacrylate Schiff base intermediate, E(A-A); in stage II, this
      intermediate reacts with the second substrate, indole, to form tryptophan.
      Monovalent cations (MVCs) are effectors of these processes [Woehl, E., and Dunn,
      M. F. (1995) Biochemistry 34, 9466-9476]. Herein, detailed kinetic dissections of
      stage II are described in the absence and in the presence of MVCs. The analyses
      presented complement the results of the preceding paper [Woehl, E., and Dunn, M.
      F. (1999) Biochemistry 38, XXXX-XXXX], which examines stage I, and confirm that
      the chemical and conformational processes in stage I establish the presence of
      two slowly interconverting conformations of E(A-A) that exhibit different
      reactivities in stage II. The pattern of kinetic isotope effects on the overall
      activity of the beta-reaction shows an MVC-mediated change in rate-limiting
      steps. In the absence of MVCs, the reaction of E(A-A) with indole becomes the
      rate-limiting step. In the presence of Na+ or K+, the conversion of E(Aex1) to
      E(A-A) is rate limiting, whereas some third process not subject to an isotope
      effect becomes rate determining for the NH4+-activated enzyme. The combined
      results from the preceding paper and from this study define the MVC effects, both
      for the reaction catalyzed by the beta-subunit and for the allosteric
      communication between the alpha- and beta-sites. Partial reaction-coordinate free
      energy diagrams and simulation studies of MVC effects on the proposed mechanism
      of the beta-reaction are presented.

PMID- 10353824
TI  - Thermodynamic criterion for the conformation of P1 residues of substrates and of
      inhibitors in complexes with serine proteinases.
AB  - Eglin c, turkey ovomucoid third domain, and bovine pancreatic trypsin inhibitor
      (Kunitz) are all standard mechanism, canonical protein inhibitors of serine
      proteinases. Each of the three belongs to a different inhibitor family.
      Therefore, all three have the same canonical conformation in their combining
      loops but differ in their scaffoldings. Eglin c (Leu45 at P1) binds to
      chymotrypsin much better than its Ala45 variant (the difference in standard free
      energy changes on binding is -5.00 kcal/mol). Similarly, turkey ovomucoid third
      domain (Leu18 at P1) binds to chymotrypsin much better than its Ala18 variant
      (the difference in standard free energy changes on binding is -4.70 kcal/mol). As
      these two differences are within the +/-400 cal/mol bandwidth (expected from the
      experimental error), one can conclude that the system is additive. On the basis
      that isoenergetic is isostructural, we expect that within both the P1 Ala pair
      and the P1 Leu pair, the conformation of the inhibitor's P1 side chain and of the
      enzyme's specificity pocket will be identical. This is confirmed, within the
      experimental error, by the available X-ray structures of complexes of bovine
      chymotrypsin Aalpha with eglin c () and with turkey ovomucoid third domain (). A
      comparison can also be made between the structures of P1 (Lys+)15 of bovine
      pancreatic trypsin inhibitor (Kunitz) ( and ) and of the P1 (Lys+)18 variant of
      turkey ovomucoid third domain (), both interacting with chymotrypsin. In this
      case, the conformation of the side chains is strikingly different. Bovine
      pancreatic trypsin inhibitor with (Lys+)15 at P1 binds to chymotrypsin more
      strongly than its Ala15 variant (the difference in standard free energy changes
      on binding is -1.90 kcal/mol). In contrast, turkey ovomucoid third domain variant
      with (Lys+)18 at P1 binds to chymotrypsin less strongly than its Ala18 variant
      (the difference in standard free energies of association is 0.95 kcal/mol). In
      this case, P1 Lys+ is neither isostructural nor isoenergetic. Thus, a
      thermodynamic criterion for whether the conformation of a P1 side chain in the
      complex matches that of an already determined one is at hand. Such a criterion
      may be useful in reducing the number of required X-ray crystallographic structure
      determinations. More importantly, the criterion can be applied to situations
      where direct determination of the structure is extremely difficult. Here, we
      apply it to determine the conformation of the Lys+ side chain in the transition
      state complex of a substrate with chymotrypsin. On the basis of kcat/KM
      measurements, the difference in free energies of activation for Suc-AAPX-pna when
      X is Lys+ and X is Ala is 1.29 kcal/mol. This is in good agreement with the
      corresponding difference for turkey ovomucoid third domain variants but in sharp
      contrast to the bovine pancreatic trypsin inhibitor (Kunitz) data. Therefore, we
      expect that in the transition state complex of this substrate with chymotrypsin,
      the P1 Lys+ side chain is deeply inserted into the enzyme's specificity pocket as
      it is in the (Lys+)18 turkey ovomucoid third domain complex with chymotrypsin.

PMID- 10353825
TI  - Isolation and characterization of diazoate intermediate upon nitrous acid and
      nitric oxide treatment of 2'-deoxycytidine.
AB  - The intermediate produced from dCyd by HNO2 and NO treatments was isolated and
      characterized. When 10 mM dCyd was treated with 100 mM NaNO2 in 1.0 M acetate
      buffer (pH 3.7) at 37 degrees C, a previously unidentified product was formed. By
      spectrometric measurements, the product was identified as a diazoate derivative
      of dCyd, 1-(beta-D-2'-deoxyribofuranosyl)-2-oxopyrimidine-4-diazoate. The time
      course of the concentration change of the diazoate showed a profile
      characteristic of a reaction intermediate, and the maximum yield was 37 microM at
      the reaction time of 25 min. Up to the reaction time of 10 min, the diazoate
      concentration was greater than that of dUrd, a deamination product of dCyd.
      Addition of thiocyanate increased the yield of the diazoate in HNO2 treatment,
      whereas addition of ascorbate decreased the yield. When 10 mM dCyd in 100 mM
      phosphate buffer was treated with NO at 37 degrees C under aerobic conditions
      holding the pH (7.2-7.6), the diazoate was also generated. The yield of the
      diazoate was higher than that of dUrd up to 15 mmol of NO absorption. At pH 3.7
      and 37 degrees C, the diazoate was converted to dUrd with the first-order rate
      constant k = 4.8 x 10(-)4 s-1 (t1/2 = 24 min). Under physiological conditions (pH
      7.4, 37 degrees C), however, it was fairly stable (k = 5.8 x 10(-)7 s-1, t1/2 =
      330 h). In both cases, the diazoate was converted to dUrd exclusively and no
      other intermediates were detected by HPLC analysis. Uracil-DNA glycosylase did
      not remove the diazoate residue from an oligodeoxynucleotide containing this
      damage, [d(T6DT5), D = the diazoate]. The Tm value of a duplex containing the
      diazoate, d(T6DT5).d(A5GA6), was much lower than that of a duplex containing a
      correct C:G base pair, d(T6CT5).d(A5GA6). These results show that the diazoate is
      generated as a stable intermediate in the reactions of dCyd with HNO2 and NO and
      that the major product is the diazoate but not dUrd in the initial stage of the
      reactions. Thus, once formed in vivo, the diazoate persists for long time in DNA
      and may act as a major cytotoxic and/or genotoxic lesion with biologically
      relevant doses of HNO2 and NO.

PMID- 10353826
TI  - ENDOR and special TRIPLE resonance spectroscopy of photoaccumulated semiquinone
      electron acceptors in the reaction centers of green sulfur bacteria and
      heliobacteria.
AB  - Photoaccumulation at 205 K in the presence of dithionite produces EPR signals in
      anaerobically prepared membranes from Chlorobium limicola and Heliobacterium
      chlorum that resemble the EPR spectrum of phyllosemiquinone (A1*-)
      photoaccumulated in photosystem I. We have used ENDOR and special TRIPLE
      resonance spectroscopy to demonstrate conclusively that these signals arise from
      menasemiquinone electron acceptors reduced by photoaccumulation. Hyperfine
      couplings to two protons H-bonded to the semiquinone oxygens have been identified
      by exchange of H. chlorum into D2O, and hyperfine couplings to the methyl group,
      and the methylene group of the phytyl side chain, of the semiquinone have also
      been assigned. The electronic structure of these menasemiquinones in these
      reaction centers is very similar to that of phyllosemiquinone in PSI, and shows a
      distorted electron spin density distribution relative to that of
      phyllosemiquinone in vitro. Special TRIPLE resonance spectrometry has been used
      to investigate the effect of detergents and oxygen on membranes of C. limicola.
      Triton X-100 and oxygen affect the menaquinone binding site, but n-dodecyl beta-D
      maltoside preparations exhibit a relatively unaltered special TRIPLE spectrum for
      the photoaccumulated menasemiquinone.

PMID- 10353827
TI  - The midpoint potentials for the oxidized-semiquinone couple for Gly57 mutants of
      the Clostridium beijerinckii flavodoxin correlate with changes in the hydrogen
      bonding interaction with the proton on N(5) of the reduced flavin mononucleotide
      cofactor as measured by NMR chemical shift temperature dependencies.
AB  - In the Clostridium beijerinckii flavodoxin, the reduction of the flavin
      mononucleotide (FMN) cofactor is accompanied by a local conformation change in
      which the Gly57-Asp58 peptide bond "flips" from primarily the unusual cis O-down
      conformation in the oxidized state to the trans O-up conformation such that a new
      hydrogen bond can be formed between the carbonyl group of Gly57 and the proton on
      N(5) of the neutral FMN semiquinone radical [Ludwig, M. L., Pattridge, K. A.,
      Metzger, A. L., Dixon, M. M., Eren, M., Feng, Y., and Swenson, R. P. (1997)
      Biochemistry 36, 1259-1280]. This interaction is thought to contribute to the
      relative stabilization of the flavin semiquinone and may be at least partially
      responsible for the substantial separation of the midpoint potentials of the two
      one-electron reduction steps. Through a series of amino acid substitutions, the
      above cited study demonstrated the critical role of the often conserved glycine
      residue in this process. However, it has not been directly established
      experimentally as to whether these substitutions brought about the changes in the
      midpoint potentials by altering the strength of this hydrogen-bonding interaction
      as proposed. In this study, the relative strengths of the FMN N(5)H.O57 hydrogen
      bond in wild type and the G57A, G57N, and G57T mutants were evaluated by
      measuring the temperature dependency of the chemical shift for the proton on N(5)
      of the fully reduced cofactor by 1H-15N HSQC nuclear magnetic resonance
      spectroscopy. Based on the established correlation between the temperature
      coefficient of amide protons and the strength of hydrogen bonding in small
      peptides, the apparent strength of the N(5)H.O57 interaction was found to depend
      on the properties of the side chain at position 57. The glycine residue found in
      the wild-type flavodoxin appears to provide the strongest interaction while the
      beta-branched side chain in the G57T mutant provides the weakest. A good
      correlation was noted between the temperature coefficients of N(5)H and the one
      electron reduction potential for the ox/sq couple as well as the binding free
      energy of the FMN semiquinone in this group of mutants. These results provide
      more direct quantitative evidence that support the previous hypothesis that this
      conformation change and the associated formation of the hydrogen bonding
      interaction with N(5)H of the reduced FMN represent an important means of
      stabilizing the neutral semiquinone and in modulating the oxidation-reduction
      potentials of the flavin cofactor in this and perhaps other flavodoxins.

PMID- 10353828
TI  - Localization of the binding site for modified Gb3 on verotoxin 1 using
      fluorescence analysis.
AB  - Verotoxins (VTs) from Escherichia coli elicit human vascular disease as a
      consequence of specific binding to globotriaosylceramide (Gb3) receptors on
      endothelial cell surfaces. Molecular models based on the VT1 crystal structure
      were used previously to investigate the structural basis for receptor recognition
      by VT1 and other verotoxins. Interestingly, these model-based predictions of
      glycolipid binding to VT1 differ somewhat from recently published structural data
      from cocrystals of the VT1 B-subunit (VT1B) and an analogue of the sugar moiety
      of Gb3. In this study, fluorescence spectroscopy was used to test model-based
      predictions of the location of Gb3 binding on the B-subunit pentamer of VT1.
      Resonance energy transfer was used to calculate the distance from a coumarin
      probe used to replace the acyl tail of Gb3 and the single tryptophan residue
      (Trp34) present within each VT1B monomer. The observed energy transfer efficiency
      (greater than 95%) suggests that these two moieties are approximately 13.3 A
      apart when a single distance is assumed. This distance is consistent with
      proposed models for the fit of Gb3 within the "cleft site" of the VT1 B-subunit.
      When the distances from Trp34 to the other coumarinGb3 molecules (bound to each
      of the four remaining monomers within the VT1B pentamer) are taken into
      consideration, it appears likely that the coumarin-modified Gb3 analogue used in
      this study associates with the previously proposed receptor binding site II of
      VT1. This is consistent with an observed binding preference of VT2c for
      coumarinGb3. To provide additional information on the association of Gb3 with the
      VT1 B-subunit, the influence of Gb3 glycolipid binding on the accessibility of
      Trp34 to different quenching agents in solution was then examined. Taken
      together, the data suggest that coumarin-labeled Gb3 preferentially binds to site
      II on VT1 in a position that is consistent with the previously described
      molecular models.

PMID- 10353829
TI  - Coordination of CuB in reduced and CO-liganded states of cytochrome bo3 from
      Escherichia coli. Is chloride ion a cofactor?
AB  - The ubiquinol oxidase cytochrome bo3 from Escherichia coli is one of the
      respiratory heme-copper oxidases which catalyze the reduction of O2 to water
      linked to translocation of protons across the bacterial or mitochondrial
      membrane. We have studied the structure of the CuB site in the binuclear heme
      copper center of O2 reduction by EXAFS spectroscopy in the fully reduced state of
      this enzyme, as well as in the reduced CO-liganded states where CO is bound
      either to the heme iron or to CuB. We find that, in the reduced enzyme, CuB is
      coordinated by one weakly bound and two strongly bound histidine imidazoles at Cu
      N distances of 2.10 and 1.92 A, respectively, and that an additional feature at
      2.54 A is due to a highly ordered water molecule that might be weakly associated
      with the copper. Unexpectedly, the binding of CO to heme iron is found to result
      in a major conformational change at CuB, which now binds only two equidistant
      histidine imidazoles at 1.95 A and a chloride ion at 2. 25 A, with elimination of
      the water molecule and one of the histidines. Attempts to remove the chloride
      from the enzyme by extensive dialysis did not change this finding, nor did
      substitution of chloride with bromide. Photolysis of CO bound to the heme iron is
      known to cause the CO to bind to CuB in a very fast reaction and to remain bound
      to CuB at low temperatures. In this state, we indeed find the CO to be bound to
      CuB at a Cu-C distance of 1.85 A, with chloride still bound at 2.25 A and the two
      histidine imidazoles at a Cu-N distance of 2.01 A. These results suggest that
      reduction of the binuclear site weakens the bond between CuB and one of its three
      histidine imidazole ligands, and that binding of CO to the reduced binuclear site
      causes a major structural change in CuB in which one histidine ligand is lost and
      replaced by a chloride ion. Whether chloride is a cofactor in this enzyme is
      discussed.

PMID- 10353830
TI  - Solid state 15N NMR evidence for a complex Schiff base counterion in the visual G
      protein-coupled receptor rhodopsin.
AB  - Using the baculovirus/Sf9 cell expression system, we have incorporated 99% 15N
      enriched [alpha,epsilon-15N2]-L-lysine into the rod visual pigment rhodopsin. We
      have subsequently investigated the protonated Schiff base (pSB) linkage in the
      [alpha, epsilon-15N2]Lys-rhodopsin with cross-polarization magic angle spinning
      (CP/MAS) 15N NMR. The Schiff base (SB) 15N in [alpha, epsilon-15N2]Lys-rhodopsin
      resonates with an isotropic shift sigmaI of 155.9 ppm, relative to 5.6 M 15NH4Cl.
      This suggests that the SB in rhodopsin is protonated and stabilized by a complex
      counterion. The 15N shifts of retinal SBs correlate with the energy difference
      between the ground and excited states and the frequency of maximum visible
      absorbance, numax, associated with the pi-pi transition of the polyene
      chromophore. Experimental modeling of the relation between the numax and the size
      of the counterion with a set of pSBs provides strong evidence that the charged
      chromophore in rhodopsin is stabilized by a counterion with an estimated
      effective center-center distance (deff) between the counterion and the pSB of
      0.43 +/- 0.01 nm. While selected prokaryotic proteins and complexes have been
      labeled before, this is the first time to our knowledge that a 15N-labeled
      eukaryotic membrane protein has been generated in sufficient amount for such NMR
      investigations.

PMID- 10353831
TI  - Remarkable affinity and selectivity for Cs+ and uranyl (UO22+) binding to the
      manganese site of the apo-water oxidation complex of photosystem II.
AB  - The size and charge density requirements for metal ion binding to the high
      affinity Mn2+ site of the apo-water oxidizing complex (WOC) of spinach
      photosystem II (PSII) were studied by comparing the relative binding affinities
      of alkali metal cations, divalent metals (Mg2+, Ca2+, Mn2+, Sr2+), and the oxo
      cation UO22+. Cation binding to the apo-WOC-PSII protein was measured by: (1)
      inhibition of the rate and yield of photoactivation, the light-induced recovery
      of O2 evolution by assembly of the functional Mn4Ca1Clx, core from its
      constituent inorganic cofactors (Mn2+, Ca2+, and Cl-); and by (2) inhibition of
      the PSII-mediated light-induced electron transfer from Mn2+ to an electron
      acceptor (DCIP). Together, these methods enable discrimination between inhibition
      at the high- and low-affinity Mn2+ sites and the Ca2+ site of the apo-WOC-PSII.
      Unexpectedly strong binding of large alkali cations (Cs+ >> Rb+ > K+ > Na+ > Li+)
      was found to smoothly correlate with decreasing cation charge density, exhibiting
      one of the largest Cs+/Li+ selectivities (>/=5000) for any known chelator. Both
      photoactivation and electron-transfer measurements at selected Mn2+ and Ca2+
      concentrations reveal that Cs+ binds to the high-affinity Mn2+ site with a
      slightly greater affinity (2-3-fold at pH 6.0) than Mn2+, while binding about
      10(4)-fold more weakly to the Ca2+-specific site required for reassembly of
      functional O2 evolving centers. In contrast to Cs+, divalent cations larger than
      Mn2+ bind considerably more weakly to the high-affinity Mn2+ site (Mn2+ >> Ca2+ >
      Sr2+). Their affinities correlate with the hydrolysis constant for formation of
      the metal hydroxide by hydrolysis of water: Me2+aq --> [MeOH]+aq + H+aq. Along
      with the strong stimulation of the rate of photoactivation by alkaline pH, these
      metal cation trends support the interpretation that [MnOH]+ is the active species
      that forms upon binding of Mn2+aq to apo-WOC. Further support for this
      interpretation is found by the unusually strong inhibition of Mn2+ photooxidation
      by the linear uranyl cation (UO22+). The intrinsic binding constant for [MnOH]+
      to apo-WOC was determined using a thermodynamic cycle to be K = 4.0 x 10(15) M-1
      (at pH 6.0), consistent with a high-affinity, preorganized, multidentate
      coordination site. We propose that the selectivity for binding [MnOH]+, a linear
      low charge-density monocation, vs symmetrical Me2+ dications is functionally
      important for assembly of the WOC by enabling: (1) discrimination against higher
      charge density alkaline earth cations (Mg2+ and Ca2+) and smaller alkali metal
      cations (Na+ and K+) that are present in considerably greater abundance in vivo,
      and thus would suppress photoactivation; and (2) higher affinity binding of the
      one Ca2+ ion or the remaining three Mn2+ ions via coordination to form mu-hydroxo
      bridged intermediates, apo-WOC-[Mn(mu-OH)2Mn]3+ or apo-WOC-[Mn(mu-OH)Ca]3+,
      during subsequent assembly steps of the native Mn4Ca1Clx core. In contrast to
      more acidic Me2+ divalent ion inhibitors of the high-affinity Mn2+ site, like
      Ca2+ and Sr2+, Cs+ does not accelerate the decay of the first light-induced
      intermediate, IM1, formed during photoactivation (attributed to apo-WOC
      [Mn(OH)2]+). The inability of Cs+ to promote decay of IM1, despite having
      comparable affinity as Mn2+, is consistent with its considerably weaker Lewis
      acidity, resulting in the reprotonation of IM1 by water becoming the rate
      limiting step for decay prior to displacement of Mn2+. All four different lines
      of evidence provide a self-consistent picture indicating that the initial step in
      assembly of the WOC involves high-affinity binding of [MnOH]+.

PMID- 10353832
TI  - Dynamics of carbon monoxide binding with neuronal nitric oxide synthase.
AB  - The dynamics of CO rebinding with neuronal NO synthase (nNOS) following laser
      flash photolysis have been investigated from 293 to 77 K in the absence and
      presence of its substrate L-arginine. The distribution functions of the rate
      parameters P(k) and of the activation enthalpy P(H) were determined using the
      maximum entropy method. In a fluid solvent near room temperature, bimolecular
      rebinding is biphasic, as previously reported by several groups. However,
      measurement of the rotational correlation time shows that the apparent biphasic
      rebinding is not relevant to the genuine dynamics of NOS. In addition to native
      dimeric nNOS, another species (possibly aggregated or partially unfolded
      conformation) with different hydrodynamic characteristics is responsible for the
      faster rebinding process. In a rigid environment at low temperature, the geminate
      internal rebinding is not affected by the presence of the nonnative species. nNOS
      exhibits a bimodal distribution of CO activation enthalpy with P(H) consisting of
      two distinct bands with temperature-dependent amplitudes down to 77 K. The
      similarity of these findings with those recently reported for cytochromes P-450
      suggests a common hierarchical organization of conformational substates, with a
      splitting of each conformational substate into a doublet. Thus, thiolate
      coordinated heme proteins are in clear contrast to histidine-coordinated oxygen
      transport heme proteins. The present results with nNOS provide additional support
      to previous arguments incriminating the thiolate ligand as responsible for the
      splitting of conformational substates.

PMID- 10353833
TI  - The polyelectrolyte behavior of actin filaments: a 25Mg NMR study.
AB  - Under physiological conditions, filamentous actin (F-actin) is a polyanionic
      protein filament. Key features of the behavior of F-actin are shared with other
      well-characterized polyelectrolytes, in particular, duplex DNA. For example, the
      bundle formation of F-actin by polyvalent cations, including divalent metal ions
      such as Mg2+, has been proposed to be a natural consequence of the
      polyelectrolyte nature of actin filaments [Tang and Janmey (1996) J. Biol. Chem.
      271, 8556-8563]. This recently proposed model also suggests that weak
      interactions between F-actin and Mg2+ ions reflect a nonspecific trapping of
      counterions in the electric field surrounding F-actin due to its polyelectrolyte
      nature. To test this hypothesis, we have performed 25Mg NMR measurements in F
      actin solutions. Based on the NMR data, we estimate that the rotational
      correlation times of Mg2+ are independent of the overall rotational dynamics of
      the actin filaments. Moreover, competitive binding experiments demonstrate a
      facile displacement of F-actin-bound Mg2+ by Co(NH3)63+. At higher Co(NH3)63+
      concentrations, a fraction of the magnesium ions are trapped as actin filaments
      aggregate. ATP also competes effectively with actin filaments for binding to
      Mg2+. These results support the hypothesis that magnesium ions bind loosely and
      nonspecifically to actin filaments, and thus show a behavior typical of
      counterions in polyelectrolyte solutions. The observed features mimic to some
      extent the well-documented behavior of counterions in DNA solutions.

PMID- 10353834
TI  - Molecular dissection of the C-terminal regulatory domain of the plant plasma
      membrane H+-ATPase AHA2: mapping of residues that when altered give rise to an
      activated enzyme.
AB  - The plasma membrane H+-ATPase is a proton pump belonging to the P-type ATPase
      superfamily and is important for nutrient acquisition in plants. The H+-ATPase is
      controlled by an autoinhibitory C-terminal regulatory domain and is activated by
      14-3-3 proteins which bind to this part of the enzyme. Alanine-scanning
      mutagenesis through 87 consecutive amino acid residues was used to evaluate the
      role of the C-terminus in autoinhibition of the plasma membrane H+-ATPase AHA2
      from Arabidopsis thaliana. Mutant enzymes were expressed in a strain of
      Saccharomyces cerevisiae with a defective endogenous H+-ATPase. The enzymes were
      characterized by their ability to promote growth in acidic conditions and to
      promote H+ extrusion from intact cells, both of which are measures of plasma
      membrane H+-ATPase activity, and were also characterized with respect to kinetic
      properties such as affinity for H+ and ATP. Residues that when altered lead to
      increased pump activity group together in two regions of the C-terminus. One
      region stretches from K863 to L885 and includes two residues (Q879 and R880) that
      are conserved between plant and fungal H+-ATPases. The other region,
      incorporating S904 to L919, is situated in an extension of the C-terminus unique
      to plant H+-ATPases. Alteration of residues in both regions led to increased
      binding of yeast 14-3-3 protein to the plasma membrane of transformed cells.
      Taken together, our data suggest that modification of residues in two regions of
      the C-terminal regulatory domain exposes a latent binding site for activatory 14
      3-3 proteins.

PMID- 10353835
TI  - Mechanism of interaction of different classes of cationic antimicrobial peptides
      with planar bilayers and with the cytoplasmic membrane of Escherichia coli.
AB  - Antimicrobial cationic peptides are prevalent throughout nature as part of the
      intrinsic defenses of most organisms, and have been proposed as a blueprint for
      the design of novel antimicrobial agents. They are known to interact with
      membranes, and it has been frequently proposed that this represents their
      antibacterial target. To see if this was a general mechanism of action, we
      studied the interaction, with model membranes and the cytoplasmic membrane of
      Escherichia coli, of 12 peptides representing all 4 structural classes of
      antimicrobial peptides. Planar lipid bilayer studies indicated that there was
      considerable variance in the interactions of the peptides with model phospholipid
      membranes, but generally both high concentrations of peptide and high
      transmembrane voltages (usually -180 mV) were required to observe conductance
      events (channels). The channels observed for most peptides varied widely in
      magnitude and duration. An assay was developed to measure the interaction with
      the Escherichia coli cytoplasmic membrane employing the membrane potential
      sensitive dye 3,5-dipropylthiacarbocyanine in the outer membrane barrier
      defective E. coli strain DC2. It was demonstrated that individual peptides varied
      widely in their ability to depolarize the cytoplasmic membrane potential of E.
      coli, with certain peptides such as the loop peptide bactenecin and the alpha
      helical peptide CP26 being unable to cause depolarization at the minimal
      inhibitory concentration (MIC), and others like gramicidin S causing maximal
      depolarization below the MIC. We discuss the mechanism of interaction with the
      cytoplasmic membrane in terms of the model of Matsuzaki et al. [(1998)
      Biochemistry 37, 15144-15153] and the possibility that the cytoplasmic membrane
      is not the target for some or even most cationic antimicrobial peptides.

PMID- 10353836
TI  - Flexibility of Acanthamoeba myosin rod minifilaments.
AB  - Previous electric birefringence experiments have shown that the actin-activated
      Mg2+-ATPase activity of Acanthamoeba myosin II correlates with the ability of
      minifilaments to cycle between flexible and stiff conformations. The cooperative
      transition between conformations was shown to depend on Mg2+ concentration, on
      ATP binding, and on the state of phosphorylation of three serines in the C
      terminal end of the heavy chains. Since the junction between the heavy meromyosin
      (HMM) and light meromyosin (LMM) regions is expected to disrupt the alpha-helical
      coiled-coil structure of the rod, this region was anticipated to be the flexible
      site. We have now cloned and expressed the wild-type rod (residues 849-1509 of
      the full-length heavy chain) and rods mutated within the junction in order to
      test this. The sedimentation and electric birefringence properties of
      minifilaments formed by rods and by native myosin II are strikingly similar. In
      particular, the Mg2+-dependent flexible-to-stiff transitions of native myosin II
      and wild-type rod minifilaments are virtually superimposable. Mutations within
      the junction between the HMM and LMM regions of the rod modulate the ability of
      Mg2+ to stabilize the stiff conformation. Less Mg2+ is required to induce
      minifilament stiffening if proline-1244 is replaced with alanine. Deleting the
      entire junction region (25 amino acids) results in a even greater decrease in the
      Mg2+ concentration necessary for the transition. The HMM-LMM junction does indeed
      seem to act as a Mg2+-dependent flexible hinge.

PMID- 10353837
TI  - Light chain 1 from the Chlamydomonas outer dynein arm is a leucine-rich repeat
      protein associated with the motor domain of the gamma heavy chain.
AB  - The LC1 light chain from Chlamydomonas outer arm dynein is tightly bound to the
      gamma heavy chain. Molecular cloning revealed that LC1 is a member of the SDS22+
      subclass of the leucine-rich repeat protein family and as such is likely involved
      in mediating interactions between dynein and the components of a signal
      transduction pathway. Through the combination of covalent cross-linking and
      vanadate-mediated photolysis, LC1 was found to associate with that portion of the
      gamma HC that is C-terminal to the P1 loop. This region comprises most of the
      globular head domain of the heavy chain and includes the stalk-like structure
      that is involved in microtubule binding. Attachment of LC1 to this region
      represents the only known example of an accessory polypeptide directly associated
      with a dynein motor domain. Additional cross-linking experiments revealed that
      LC1 also interacts directly in situ with an approximately 45 kDa axonemal
      component; this interaction is disrupted by the standard high salt treatment used
      to remove the outer arm from the axoneme. These data suggest that LC1 acts to
      mediate the association between this 45 kDa axonemal polypeptide and the motor
      unit of the gamma HC.

PMID- 10353838
TI  - Catalytic mechanism of nucleoside diphosphate kinase investigated using
      nucleotide analogues, viscosity effects, and X-ray crystallography.
AB  - Nucleoside diphosphate (NDP) kinases display low specificity with respect to the
      base moiety of the nucleotides and to the 2'-position of the ribose, but the 3'
      hydroxyl is found to be important for catalysis. We report in this paper the
      enzymatic analysis of a series of derivatives of thymidine diphosphate (TDP)
      where the 3'-OH group was removed or replaced by fluorine, azido, and amino
      groups. With Dictyostelium NDP kinase, kcat decreases 15-200-fold from 1100 s-1
      with TDP, and (kcat/Km)NDP decreases from 12 x 10(6) to 10(3) to 5 x 10(4) M-1 s
      1, depending on the substrate. The poorest substrates are 3'-deoxyTDP and 3'
      azido-3'-deoxyTDP, while the best modified substrates are 2',3'-dehydro-3'
      deoxyTDP and 3'-fluoro-3'-deoxyTDP. In a similar way, 3'-fluoro-2',3'-dideoxyUDP
      was found to be a better substrate than 2',3'-dideoxyUDP, but a much poorer
      substrate than 2'-deoxyUDP. (kcat/Km)NDP is sensitive to the viscosity of the
      solution with TDP as the substrate but not with the modified substrates. To
      understand the poor catalytic efficiency of the modified nucleotides at a
      structural level, we determined the crystal structure of Dictyostelium NDP kinase
      complexed to 3'-fluoro-2',3'-dideoxyUDP at 2.7 A resolution. Significant
      differences are noted as compared to the TDP complex. Substrate-assisted
      catalysis by the 3'-OH, which is effective in the NDP kinase reaction, cannot
      occur with the modified substrate. With TDP, the beta-phosphate, which is the
      leaving group when a gamma-phosphate is transferred to His122, hydrogen bonds to
      the 3'-hydroxyl group of the sugar; with 3'-fluoro-2',3'-dideoxyUDP, the beta
      phosphate hydrogen bonds to Asn119 and moves away from the attacking Ndelta of
      the catalytic His122. Since all anti-AIDS nucleoside drugs are modified at the 3'
      position, these results are relevant to the role of NDP kinase in their cellular
      metabolism.

PMID- 10353839
TI  - Probing the nucleotide-binding site of Escherichia coli succinyl-CoA synthetase.
AB  - Succinyl-CoA synthetase (SCS) catalyzes the reversible interchange of purine
      nucleoside diphosphate, succinyl-CoA, and Pi with purine nucleoside triphosphate,
      succinate, and CoA via a phosphorylated histidine (H246alpha) intermediate. Two
      potential nucleotide-binding sites were predicted in the beta-subunit, and have
      been differentiated by photoaffinity labeling with 8-N3-ATP and by site-directed
      mutagenesis. It was demonstrated that 8-N3-ATP is a suitable analogue for probing
      the nucleotide-binding site of SCS. Two tryptic peptides from the N-terminal
      domain of the beta-subunit were labeled with 8-N3-ATP. These corresponded to
      residues 107-119beta and 121-146beta, two regions lying along one side of an ATP
      grasp fold. A mutant protein with changes on the opposite side of the fold
      (G53betaV/R54betaE) was unable to be phosphorylated using ATP or GTP, but could
      be phosphorylated by succinyl-CoA and Pi. A mutant protein designed to probe
      nucleotide specificity (P20betaQ) had a Km(app) for GTP that was more than 5
      times lower than that of wild-type SCS, whereas parameters for the other
      substrates remained unchanged. Mutations of residues in the C-terminal domain of
      the beta-subunit designed to distrupt one loop of the Rossmann fold (I322betaA,
      and R324betaN/D326betaA) had the greatest effect on the binding of succinate and
      CoA. They did not disrupt the phosphorylation of SCS with nucleotides. It was
      concluded that the nucleotide-binding site is located in the N-terminal domain of
      the beta-subunit. This implies that there are two active sites approximately 35 A
      apart, and that the H246alpha loop moves between them during catalysis.

PMID- 10353840
TI  - Distribution of disulfide bonds in the two-disulfide intermediates in the
      regeneration of bovine pancreatic ribonuclease A: further insights into the
      folding process.
AB  - The distribution of one-disulfide bonds in the two-disulfide intermediates in the
      oxidative refolding of bovine pancreatic ribonuclease A has been characterized.
      These two-disulfide intermediates were formed from the fully reduced denatured
      protein by oxidation with dithiothreitol, then blocked with AEMTS, purified by
      cation-exchange chromatography, enzymatically digested, and analyzed by reversed
      phase high-performance liquid chromatography and mass spectrometry. The relative
      concentration of each of the 28 possible one-disulfide bonds in the two-disulfide
      ensemble was determined. Comparison with a statistical mechanical treatment of
      loop formation shows that the two-disulfide intermediates are probably compact.
      All 28 disulfide bonds were observed, demonstrating the absence of specific long
      range interactions in these intermediates. Thermodynamic arguments suggest that
      the absence of such specific long-range interactions in the two-disulfide species
      may elevate the concentration of kinetically important three-disulfide
      intermediates and thereby increase the folding rate. Bond [65-72] was found to
      make up approximately 27% of the disulfide bonds of the two-disulfide species,
      significantly more than all other disulfides, because of stabilization by loop
      entropy factors and an energetically favorable beta-turn. This turn may be one of
      several chain-folding initiation sites, accelerating folding by decreasing the
      dimensionality of the conformational space that has to be searched.

PMID- 10353841
TI  - Characterization of sphingolipids from mycopathogens: factors correlating with
      expression of 2-hydroxy fatty acyl (E)-Delta 3-unsaturation in cerebrosides of
      Paracoccidioides brasiliensis and Aspergillus fumigatus.
AB  - Significant differences exist between mammals and fungi with respect to
      glycosphingolipid (GSL) structure and biosynthesis. Thus, these compounds, as
      well as the cellular machinery regulating their expression, have considerable
      potential as targets for the diagnosis and treatment of fungal diseases. In this
      study, the major neutral GSL components extracted from both yeast and mycelium
      forms of the thermally dimorphic mycopathogen Paracoccidioides brasiliensis were
      purified and characterized by 1H and 13C NMR spectroscopy, ESI-MS and ESI-MS/CID
      MS, and GC-MS. The major GSLs of both forms were identified as beta
      glucopyranosylceramides (GlcCer) having (4E, 8E)-9-methyl-4,8-sphingadienine as
      long chain base in combination with either N-2'-hydroxyoctadecanoate or N-2'
      hydroxy-(E)-3'-octadecenoate. The mycelium form GlcCer had both fatty acids in a
      approximately 1:1 ratio, while that of the yeast form had on average only
      approximately 15% of the (E)-Delta 3-unsaturated fatty acid. Cerebrosides from
      two strains of Aspergillus fumigatus (237 and ATCC 9197) expressing both GalCer
      and GlcCer were also purified and characterized by similar methods. The GalCer
      fractions were found to have approximately 70% and approximately 90% N-2'-hydroxy
      (E)-3'-octadecenoate, respectively, in the two strains. In contrast, the GlcCer
      fractions had N-2'-hydroxy-(E)-3'-octadecenoate at only approximately 20 and
      approximately 50%, respectively. The remainder in all cases was the saturated 2
      OH fatty acid, which has not been previously reported in cerebrosides from A.
      fumigatus. The availability of detailed structures of both glycosylinositol
      phosphorylceramides [Levery, S. B., Toledo, M. S., Straus, A. H., and Takahashi,
      H. K. (1998) Biochemistry 37, 8764-8775] and cerebrosides from P. brasiliensis
      revealed parallel quantitative differences in expression between yeast and
      mycelium forms, as well as a striking general partitioning of ceramide structure
      between the two classes of GSLs. These results are discussed with respect to
      possible functional roles for fungal sphingolipids, particularly as they relate
      to the morphological transitions exhibited by P. brasiliensis.

PMID- 10353842
TI  - Pharmacology and cell biology of the bombesin receptor subtype 4 (BB4-R).
AB  - Recently, a fourth member of the bombesin (Bn) receptor family (fBB4-R) was
      isolated from a cDNA library from the brain of the frog, Bombina orientalis. Its
      pharmacology and cell biology are largely unknown, and no known natural cell
      lines or tissues possess sufficient numbers of fBB4-R's to allow either of these
      to be determined. To address these issues, we have used three different
      strategies. fBB4-R expression in cells widely used for other Bn receptor subtypes
      was unsuccessful as was expression in two frog cell lines. However, stable fBB4-R
      cell lines were obtained in CHO-K1 cells which were shown to faithfully
      demonstrate the correct pharmacology of the related Bn receptor, the GRP
      receptor, when expressed in these cells. [DPhe6,betaAla11,Phe13,Nle14]Bn(6-14)
      was found to have high affinity (Ki = 0.4 nM) for the fBB4 receptor and 125I
      [DTyr6,betaala11,Phe13,Nle14]Bn(6-14) to be an excellent ligand for this
      receptor. The fBB4-R had a unique pharmacology for naturally occurring Bn-related
      agonists, with the presence of a penultimate phenylalanine being critical for
      high-affinity interaction. It also had a unique profile for six classes of Bn
      antagonists. The fBB4-R was coupled to phospholipase C with activation increasing
      [3H]inositol phosphates and mobilizing Ca2+ almost entirely from cellular
      sources. There was a close correlation between agonist the receptor occupation
      and the receptor activation. Three of the five classes of Bn receptor antagonists
      that interacted with higher affinity with the fBB4-R functioned as fBB4-R
      antagonists and two as partial agonists. fBB4-R activation stimulated increases
      in phospholipase D (PLD) over the same range of concentrations at which it
      activated phospholipase C. These results demonstrate that the fBB4 receptor has a
      unique pharmacology for agonists and antagonists and is coupled to phospholipase
      C and D. The availability of these cell lines, this novel ligand, and the
      identification of three classes of antagonists that can be used as lead compounds
      should facilitate the further investigation of the pharmacology and cell biology
      of the BB4 receptor.

PMID- 10353843
TI  - Introduction of mannose binding protein-type phosphatidylinositol recognition
      into pulmonary surfactant protein A.
AB  - Pulmonary surfactant protein A (SP-A) and mannose-binding protein A (MBP-A) are
      collectins in the C-type lectin superfamily. These collectins exhibit unique
      lipid binding properties. SP-A binds to dipalmitoyl phosphatidylcholine (DPPC)
      and galactosylceramide (GalCer) and MBP-A binds to phosphatidylinositol (PI). SP
      A also interacts with alveolar type II cells. Monoclonal antibodies (mAbs PE10
      and PC6) that recognize human SP-A inhibit the interactions of SP-A with lipids
      and alveolar type II cells. We mapped the epitopes for anti-human SP-A mAbs by a
      phage display peptide library. Phage selected by mAbs displayed the consensus
      peptide sequences that are nearly identical to 184TPVNYTNWYRG194 of human SP-A.
      The synthetic peptide GTPVNYTNWYRG completely blocked the binding of mAbs to
      human SP-A. Chimeric proteins were generated in which the rat SP-A region Thr174
      Gly194 or the human SP-A region Ser174-Gly194 was replaced with the MBP-A region
      Thr164-Asp184 (rat ama4 or hu ama4, respectively). The mAbs failed to bind hu
      ama4. Rat ama4 bound to an affinity matrix on mannose-sepharose but lost all of
      the SP-A functions except carbohydrate binding and Ca2+-independent GalCer
      binding. Strikingly, the rat ama4 chimera acquired the PI binding property that
      MBP-A exhibits. This study demonstrates that the amino acid residues 174-194 of
      SP-A and the corresponding region of MBP-A are critical for SP-A-type II cell
      interaction and Ca2+-dependent lipid binding of collectins.

PMID- 10353844
TI  - The N-terminus of collagenase MMP-8 determines superactivity and inhibition: a
      relation of structure and function analyzed by biomolecular interaction analysis.
AB  - Tissue inhibitors of metalloproteinases (TIMPs) are the physiological, specific
      inhibitors of matrix metalloproteinases (MMPs) forming tight, noncovalent
      complexes. Therefore they control the proteolytic activity of MMPs toward the
      extracellular matrix. To analyze the inhibition of the "activated" and
      "superactivated" variants of human neutrophil collagenase (MMP-8) by TIMP-2, we
      determined complex dissociation constants using biomolecular interaction analysis
      (BIA). As it is known that the association rate constants can exceed the limits
      of the BIA instruments, the biomolecular interaction analysis was used to examine
      the equlibrium situation. The dissociation constants were determined by fitting
      the parameters of the mathematical term for the binding of collagenase onto the
      TIMP-coupled sensor chip surface to the saturation curve derived from individual
      sensorgrams. The resulting values are in the nanomolar range and correlate with
      the results of fluorescence kinetics. These data reveal that TIMP-2 (the
      recombinant inhibitory domain of human TIMP-2 and bovine TIMP-2 isolated from
      seminal plama) is a better inhibitor of the activated neutrophil collagenase than
      of the superactivated variant (the recombinant catalytic domain of human MMP-8).
      It has been demonstrated by X-ray analysis that the N-terminal heptapeptide only
      of superactivated MMP-8 is attached by a salt bridge and hydrophobic interaction
      to the C-terminal helix. Because these interactions have to be disrupted in the
      complex formation with TIMP we assume that the activated variant enables higher
      flexibility and a tighter induced fit in the complex formation. Therefore
      superactivation of MMP-8 correlates with weaker inhibition by TIMP-2.

PMID- 10353845
TI  - The contribution of N-terminal region residues of cystatin A (stefin A) to the
      affinity and kinetics of inhibition of papain, cathepsin B, and cathepsin L.
AB  - The affinity and kinetics of binding of three N-terminally truncated variants of
      the cysteine proteinase inhibitor cystatin A to cysteine proteinases were
      characterized. Deletion of Met-1 only minimally altered the inhibitory properties
      of the protein. However, deletion also of Ile-2 resulted in reduced affinities of
      900-, >/=3-, and 200-fold for papain and cathepsins L and B, respectively.
      Further truncation of Pro-3 substantially increased the inhibition constants to
      approximately 0.5 microM for papain and cathepsin L and to 60 microM for
      cathepsin B, reflecting additionally 2 x 10(3)-, 2 x 10(4)-, and 400-fold
      decreased affinities, respectively. The reductions in affinity shown by the
      latter mutant indicate that the N-terminal region contributes about 40% of the
      total free energy of binding of cystatin A to cysteine proteinases. Moreover, Pro
      3 and to a lesser extent Ile-2 are the residues responsible for this binding
      energy. The reduced affinities for papain and cathepsin L were due only to higher
      dissociation rate constants, whereas both lower association and higher
      dissociation rate constants contributed to the decreased affinity for cathepsin
      B. These differential effects indicate that the N-terminal portion of cystatin A
      primarily functions by stabilizing the complexes with enzymes having easily
      accessible active-site clefts, e.g., papain and cathepsin L. In contrast, the N
      terminal region is required also for an initial binding of cystatin A to
      cathepsin B, presumably by promoting the displacement of the occluding loop and
      allowing facile interaction of the rest of the inhibiting wedge with the active
      site cleft of the enzyme.

PMID- 10353846
TI  - Pro-1 of macrophage migration inhibitory factor functions as a catalytic base in
      the phenylpyruvate tautomerase activity.
AB  - Macrophage migration inhibitory factor (MIF) is an important immunoregulatory
      molecule with a unique ability to suppress the anti-inflammatory effects of
      glucocorticoids. Although considered a cytokine, MIF possesses a three
      dimensional structure and active site similar to those of 4-oxalocrotonate
      tautomerase and 5-carboxymethyl-2-hydroxymuconate isomerase. Moreover, a number
      of catalytic activities have been defined for MIF. To gain insight into the role
      of catalysis in the biological function of MIF, we have begun to characterize the
      catalytic activities in more detail. Here we report the crystal structure of MIF
      complexed with p-hydroxyphenylpyruvate, a substrate for the phenylpyruvate
      tautomerase activity of MIF. The three binding sites for p-hydroxyphenylpyruvate
      in the MIF trimer lie at the interface between two subunits. The substrate
      interacts with Pro-1, Lys-32, and Ile-64 from one subunit and Tyr-95 and Asn-97
      from an adjacent subunit. Pro-1 is positioned to function as a catalytic base.
      There is no functional group that polarizes the alpha-carbonyl of the substrate
      to weaken the adjacent C-H bond. Mutation of Pro-1 to glycine substantially
      reduces the catalytic activity. The insertion of an alanine between Pro-1 and Met
      2 essentially abolishes activity. Structural studies of these mutants define a
      source of the reduced activity and provide insight into the mechanism of the
      catalytic reaction.

PMID- 10353847
TI  - Mechanism of Salmonella typhimurium histidinol dehydrogenase: kinetic isotope
      effects and pH profiles.
AB  - L-Histidinol dehydrogenase catalyzes the biosynthetic oxidation of L-histidinol
      to L-histidine with sequential reduction of two molecules of NAD. Previous
      isotope exchange results had suggested that the oxidation of histidinol to the
      intermediate histidinaldehyde occurred 2-3-fold more rapidly than overall
      catalysis. In this work, we present kinetic isotope effects (KIE) studies at pH
      9.0 and at pH 6.7 with stereospecifically mono- and dideuterated histidinols. The
      data at pH 9.0 support minimal participation of the first hydride transfer and
      substantial participation of the second hydride transfer in the overall rate
      limitation. Stopped-flow experiments with protiated histidinol revealed a small
      burst of NADH production with stoichiometry of 0.12 per subunit, and 0.25 per
      subunit with dideuterated histidinol, indicating that the overall first half
      reaction was not significantly faster than the second reaction sequence. Results
      from kcat and kcat/KM titrations with histidinol, NAD, and the alternative
      substrate imidazolyl propanediol demonstrated an essential base with pKa values
      between 7.7 and 8.4. In KIE experiments performed at pH 6.7 or with a coenzyme
      analogue at pH 9. 0, the first hydride transfer became more rate limiting.
      Kinetic simulations based on rate constants estimated from this work fit well
      with a mechanism that includes a relatively fast, and thermodynamically
      unfavorable, hydride transfer from histidinol and a slower, irreversible second
      hydride transfer from a histidinaldehyde derivative. Thus, although the chemistry
      of the first hydride transfer is fast, both partial reactions participate in the
      overall rate limitation.

PMID- 10353848
TI  - Mutagenesis of histidinol dehydrogenase reveals roles for conserved histidine
      residues.
AB  - The dimeric zinc metalloenzyme L-histidinol dehydrogenase (HDH) catalyzes an
      unusual four-electron oxidation of the amino alcohol histidinol via the
      histidinaldehyde intermediate to the acid product histidine with the reduction of
      two molecules of NAD. An essential base, with pKa about 8, is involved in
      catalysis. Here we report site-directed mutagenesis studies to replace each of
      the five histidine residues (His-98, His-261, His-326, His-366, and His-418) in
      Salmonella typhimurium with either asparagine or glutamine. In all cases, the
      overexpressed enzymes were readily purified and behaved as dimers. Substitution
      of His-261 and His-326 by asparagine caused about 7000- and 500-fold decreases in
      kcat, respectively, with little change in KM values. Similar loss of activity was
      also reported for a H261N mutant Brassica HDH [Nagai, A., and Ohta, D. (1994) J.
      Biochem. 115, 22-25]. Kinetic isotope effects, pH profiles, substrate rescue, and
      stopped-flow experiments suggested that His-261 and His-326 are involved in
      proton transfers during catalysis. Sensitivity to metal ion chelator and
      decreased affinities for metal ions with substitutions at His-261 and His-418
      suggested that these two residues are candidates for zinc ion ligands.

PMID- 10353849
TI  - The catalytic mechanism of EPSP synthase revisited.
AB  - Recent analysis of EPSP synthase by solid-state NMR has led to the postulation of
      a new enzyme reaction pathway and raised once again the question of an
      intermediate species covalently bound to the enzyme [Studelska, D., McDowell, L.,
      Espe, M., Klug, C., and Schaefer, J. (1997) Biochemistry 36, 15555-15560].
      Therefore, we have reexamined the mechanism of the reaction catalyzed by EPSP
      synthase and analyzed the reaction products formed under the conditions used in
      preparing samples for solid-state NMR. Single-turnover experiments were carried
      out using both [1-14C]- and [32P]PEP showing the formation and decay of the
      previously proposed tetrahedral intermediate species on a time scale comparable
      with the disappearance of substrate and formation of product, thus unequivocally
      establishing the kinetic competence. The possible presence of a covalently bound
      enzyme intermediate species was also investigated, using SDS-PAGE and Centricon
      concentration analysis of the quenched reaction samples. No covalently bound
      enzyme intermediates were observed during the reaction. An enzyme assay was also
      performed repeating the conditions used in sample preparation for the solid-state
      NMR studies. We show that under these conditions, total turnover of substrates to
      products was observed within 45 s at -30 degrees C prior to freezing and
      lyophilization. Following lyophilization, the samples were stored at -20 degrees
      C and analyzed over a period of 21 days. We observed the conversion of the
      product EPSP into the side product, a cyclic EPSP ketal, and the breakdown
      product, pyruvate. Thus, the new species reported by solid-state NMR can be
      accounted for by previously characterized reaction products and side products
      formed during sample preparation and upon incubation in the solid-state. Our
      conclusions are also supported by the solution and solid-state NMR studies
      recently reported [Jakeman et al. (1998) Biochemistry 37, 12012-12019]. These
      results once again highlight the importance of kinetic competence as a criterion
      to be used in defining enzyme intermediates and point to the errors in
      interpretation of results when the time dependence of formation of the proposed
      intermediates is not considered.

PMID- 10353850
TI  - Local interactions drive the formation of nonnative structure in the denatured
      state of human alpha-lactalbumin: a high resolution structural characterization
      of a peptide model in aqueous solution.
AB  - There are a small number of peptides derived from proteins that have a propensity
      to adopt structure in aqueous solution which is similar to the structure they
      possess in the parent protein. There are far fewer examples of protein fragments
      which adopt stable nonnative structures in isolation. Understanding how nonnative
      interactions are involved in protein folding is crucial to our understanding of
      the topic. Here we show that a small, 11 amino acid peptide corresponding to
      residues 101-111 of the protein alpha-lactalbumin is remarkably structured in
      isolation in aqueous solution. The peptide has been characterized by 1H NMR, and
      170 ROE-derived constraints were used to calculate a structure. The calculations
      yielded a single, high-resolution structure for residues 101-107 that is
      nonnative in both the backbone and side-chain conformations. In the pH 6.5
      crystal structure, residues 101-105 are in an irregular turn-like conformation
      and residues 106-111 form an alpha-helix. In the pH 4.2 crystal structure,
      residues 101-105 form an alpha-helix, and residues 106-111 form a loopike
      structure. Both of these structures are significantly different from the
      conformation adopted by our peptide. The structure in the peptide model is
      primarily the result of local side-chain interactions that force the backbone to
      adopt a nonnative 310/turn-like structure in residues 103-106. The structure in
      aqueous solution was compared to the structure in 30% trifluoroethanol (TFE), and
      clear differences were observed. In particular, one of the side-chain
      interactions, a hydrophobic cluster involving residues 101-105, is different in
      the two solvents and residues 107-111 are considerably more ordered in 30% TFE.
      The implications of the nonnative structure for the folding of alpha-lactalbumin
      is discussed.

PMID- 10353851
TI  - Adenine base unstacking dominates the observed enthalpy and heat capacity changes
      for the Escherichia coli SSB tetramer binding to single-stranded oligoadenylates.
AB  - Isothermal titration calorimetry (ITC) was used to test the hypothesis that the
      relatively small enthalpy change (DeltaHobs) and large negative heat capacity
      change (DeltaCp,obs) observed for the binding of the Escherichia coli SSB protein
      to single-stranded (ss) oligodeoxyadenylates result from the temperature
      dependent adenine base unstacking equilibrium that is thermodynamically coupled
      to binding. We have determined DeltaH1,obs for the binding of 1 mole of each of
      dT(pT)34, dC(pC)34, and dA(pA)34 to the SSB tetramer (20 mM NaCl at pH 8.1). For
      dT(pT)34 and dC(pC)34, we found large, negative values for DeltaH1,obs of -75 +/-
      1 and -85 +/- 2 kcal/mol at 25 degrees C, with DeltaCp,obs values of -540 +/- 20
      and -570 +/- 30 cal mol-1 K-1 (7-50 degrees C), respectively. However, for SSB
      dA(pA)34 binding, DeltaH1,obs is considerably less negative (-14 +/- 1 kcal/mol
      at 25 degrees C), even becoming positive at temperatures below 13 degrees C, and
      DeltaCp,obs is nearly twice as large in magnitude (-1180 +/- 40 cal mol-1 K-1).
      These very different thermodynamic properties for SSB-dA(pA)34 binding appear to
      result from the fact that the bases in dA(pA)34 are more stacked at any
      temperature than are the bases in dC(pC)34 or dT(pT)34 and that the bases become
      unstacked within the SSB-ssDNA complexes. Therefore, the DeltaCp,obs for SSB
      ssDNA binding has multiple contributions, a major one being the coupling to
      binding of a temperature-dependent conformational change in the ssDNA, although
      SSB binding to unstacked ssDNA still has an "intrinsic" negative DeltaCp,0. In
      general, such temperature-dependent changes in the conformational "end states" of
      interacting macromolecules can contribute significantly to both DeltaCp,obs and
      DeltaHobs.

PMID- 10353853
TI  - Characterization of the heme and pyridoxal phosphate cofactors of human
      cystathionine beta-synthase reveals nonequivalent active sites 

PMID- 10353852
TI  - Outer membrane phospholipase A is dimeric in phospholipid bilayers: a cross
      linking and fluorescence resonance energy transfer study.
AB  - In the cell, the activity of outer membrane phospholipase A (OMPLA) is strictly
      regulated to prevent uncontrolled breakdown of the membrane lipids. Previously,
      it has been shown that the enzymatic activity is modulated by reversible
      dimerization. The current studies were carried out to define the oligomeric state
      of OMPLA in a membrane and to investigate the activation process. Three single
      cysteine variant proteins H26C, H234C, and S144C were produced and purified to
      homogeneity. Using maleimido-based homo-bifunctional cross-linking reagents, H26C
      could be efficiently cross-linked as assessed by SDS-PAGE, whereas S144C and
      H234C could not be cross-linked. These data suggest that residue 26 is located
      close to the dimer symmetry axis. H26C was specifically labeled with 5-({[(2
      iodoacetyl)amino]ethyl}amino)naphthalene-1-sulfonic acid and N,N'-dimethyl-N
      (iodoacetyl)-N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)ethylenediamine as the
      fluorescent energy donor and acceptor, respectively, and dimerization was
      investigated using fluorescence resonance energy transfer (FRET). Quenching of
      the donor in the presence of the acceptor demonstrated the dimeric nature of
      OMPLA, in agreement with cross-linking data. The observed FRET effect was
      dependent on the cofactor calcium, and the presence of substrate, indicating the
      specificity of the dimerization process. The labeled protein was reconstituted in
      phospholipid vesicles. In bilayers, OMPLA exhibited low activity and was dimeric
      as assessed by FRET. Addition of detergent resulted in a 70-fold increase in
      activity, while the protein remained dimeric. The results are discussed in terms
      of the activation of dimeric OMPLA due to changes in the physical state of the
      bilayer which occur upon perturbation of the membrane integrity.

PMID- 10353854
TI  - BK and JC viruses in patients with systemic lupus erythematosus: prevalent and
      persistent BK viruria, sequence stability of the viral regulatory regions, and
      nondetectable viremia.
AB  - A role for polyomaviruses in the pathogenesis of systemic lupus erythematosus
      (SLE) has been suggested. BK virus (BKV) and JC virus (JCV) were demonstrated in
      single urine specimens from 7 (16%) of 44 and 5 (11%) of 44 patients with SLE and
      0/88 and 18 (21%) of 88 matched healthy controls, respectively. During a 1-year
      follow-up study, episodes of polyomaviruria were detected in 16 (80%) of 20
      patients, BKV in 13, and JCV in 3 patients. A group of 12 (60%) of 20 patients
      demonstrated persistent or recurrent polyomaviruria, BKV viruria (n=9), or JCV
      viruria (n=3) in 180 (70%) of 256 specimens. Polyomaviruria was not significantly
      associated with immunosuppressive therapy. The BKV and JCV isolates revealed
      predominantly stable archetypal regulatory regions over 3 years, indicating viral
      persistence rather than reinfection as a cause for urinary shedding. The
      demonstration of nondetectable viremia and stable archetypal BKV and JCV
      noncoding control regions during persistent viruria argue against the urinary
      tract as a focus for the creation of rearranged regulatory region variants.

PMID- 10353855
TI  - Evidence for cytokine mediation of disease expression in adults experimentally
      infected with influenza A virus.
AB  - The roles of interleukin (IL)-6 and IL-8 in mediating the symptoms and signs of
      influenza A infection were examined. Adults were intranasally inoculated with a
      rimantadine-sensitive strain of influenza A HlNl virus and treated with
      rimantadine or placebo. Viral shedding, secretion weights, symptom scores, and
      concentrations of IL-6 and IL-8 in nasal lavage fluids were compared between
      treatment groups. Viral shedding was associated with increases in local and
      systemic symptoms, in expelled secretion weights, and in levels of IL-6 and IL-8.
      Compared with placebo, rimantadine treatment reduced viral shedding, systemic
      symptoms, and levels of IL-8. Days of viral shedding and IL-6 but not IL-8
      concentrations were significantly correlated with the other measures of symptoms
      and signs. These data support a causal relationship between viral replication,
      cytokine production, and symptom expression, and they suggest that IL-6 may have
      a role in mediating symptom and sign expression during influenza A infection.

PMID- 10353856
TI  - Specific vaccine therapy in chronic hepatitis B: induction of T cell
      proliferative responses specific for envelope antigens.
AB  - In a pilot study, it was established that specific therapy by standard anti
      hepatitis B virus (HBV) vaccination may be effective in reducing HBV replication
      and canceling the immune tolerance to hepatitis B surface antigen (HBsAg)
      particles in about 50% of persons with chronic active HBV replication. In the
      present study, the vaccine-induced immune responses were analyzed during an
      ongoing controlled multicenter vaccine trial. Vaccination elicited peripheral
      blood mononuclear cell proliferative responses specific for envelope antigen in 7
      of 27 subjects given HBsAg. The responses induced by the vaccines were mediated
      by CD4+ T lymphocytes, and at least three different epitopes were recognized. HBV
      specific CD4+ T lymphocytes produced high levels of interferon-gamma [corrected]
      and belonged to a T helper 1 subset. Reduction of serum HBV DNA in some of these
      persons suggests that induction of CD4+ T cell responses could be important in
      controlling viremia during vaccine therapy of chronic HBV carriers.

PMID- 10353858
TI  - A direct comparison of the activities of two humanized respiratory syncytial
      virus monoclonal antibodies: MEDI-493 and RSHZl9.
AB  - Two humanized monoclonal antibodies, MEDI-493 and RSHZ19, were developed
      independently as potential improvements over RSV-IGIV for prevention of
      respiratory syncytial virus (RSV) infection. RSV-IGIV is a polyclonal human
      antibody preparation for intravenous infusion enriched for RSV neutralizing
      activity. A phase III clinical trial showed that MEDI-493 significantly reduced
      hospitalizations due to RSV infection. In a separate trial, RSHZ19 failed to show
      significant efficacy. In new studies, the in vitro and in vivo activities of MEDI
      493 and RSHZ19 were compared to determine whether the different clinical results
      are related to differences in biologic activity. MEDI-493 was consistently 4- to
      5-fold more potent than RSHZ19 in antigen binding, RSV neutralization, and fusion
      inhibition assays. Although both MEDI-493 and RSHZ19 were effective against A and
      B subtypes of RSV in the cotton rat model of RSV infection, 2- to 4-fold higher
      doses of RSHZ19 were required for similar protection. The enhanced activity of
      MEDI-493 compared with RSHZ19 may, in part, explain its better clinical effect.

PMID- 10353857
TI  - TT virus infection in patients with hepatitis C: frequency, persistence, and
      sequence heterogeneity.
AB  - TT virus (TTV) was recently identified in the serum of a patient with hepatitis.
      The role of TTV in liver disease has not been established. Three polymerase chain
      reaction (PCR) protocols were used to detect TTV DNA in sera of persons infected
      with hepatitis C virus (HCV) and in blood donors. Sera from 11.5% of HCV-infected
      patients and 7.7% of blood donors were positive by protocols 1 or 2. In contrast,
      48.7% and 57.7% of sera, respectively, were positive when tested by protocol 3.
      There was no difference in the severity of hepatitis in persons coinfected with
      TTV and HCV when compared with those infected with HCV alone, regardless of which
      TTV PCR protocol was used. TTV DNA persisted in serum samples taken up to 6 years
      apart in individual patients. Sequence analysis indicated that most viral
      sequences were distinct between patients, and there was evidence of genetic
      heterogeneity and viral evolution within individuals.

PMID- 10353859
TI  - Severe respiratory syncytial virus disease in Alaska native children. RSV Alaska
      Study Group.
AB  - Hospitalization rates for respiratory syncytial virus (RSV) infection range from
      1 to 20/1000 infants. To determine the rate and severity of RSV infections
      requiring hospitalization for infants in the Yukon-Kuskokwim (YK) Delta of
      Alaska, a 3-year prospective surveillance study was conducted. The annual rate of
      RSV hospitalization for YK Delta infants <1 year of age was 53-249/1000. RSV
      infection was the most frequent cause of infant hospitalization. RSV disease
      severity did not differ among non-high-risk infants in the YK Delta and at Johns
      Hopkins Hospital (JHH). On average, 1/125 infants born in the YK Delta required
      mechanical ventilation for RSV infection. During the peak season, approximately
      $1034/child <3 years of age was spent on RSV hospitalization in the YK Delta. In
      YK Delta infants </=6 months old, RSV microneutralizing antibody titers <1200
      were associated with severe disease (odds ratio=6.2, P=.03). In the YK Delta and
      at JHH, newborns may be at greater risk for severe RSV illness than previously
      thought.

PMID- 10353860
TI  - Primary infection of human herpesvirus 6 in children with vertical infection of
      human immunodeficiency virus type 1.
AB  - The role of human herpesvirus 6 (HHV-6) infection in 227 children born to human
      immunodeficiency virus (HIV)-seropositive mothers was investigated. Of 41 HIV
      uninfected infants, 3 (7%) were positive for HHV-6 DNA in the first month of
      life, suggesting possible intrauterine infection. The cumulative infection rates
      of HHV-6 at 6 and 12 months of age were significantly lower in HIV-infected
      children (11% and 33%, respectively) than in uninfected children (28% and 78%,
      respectively; P<.001). There was an association between high CD4+ cell numbers
      (>15%) before HHV-6 infection and high HHV-6 infection rate. Twenty-two infants
      with HIV classed as Centers for Disease Control and Prevention stages N1 or N2
      were studied for an association of HHV-6 infection with progression of HIV
      disease. Ten of the infants had HHV-6, and 12 did not. In 5 of the infants
      without HHV-6 (42%), HIV disease had not progressed by 1 year of age; however,
      HIV disease had progressed in all 10 children with HHV-6 infection. These results
      suggest an association of HHV-6 infection and progression of HIV disease in the
      study children with vertical HIV-1 infection (P<.05).

PMID- 10353861
TI  - Efficacy of low-dose subcutaneous interleukin-2 to treat advanced human
      immunodeficiency virus type 1 in persons with </=250/microL CD4 T cells and
      undetectable plasma virus load.
AB  - The immunologic efficacy of low-dose recombinant interleukin-2 (rIL-2)
      administered subcutaneously (sc) once a day in combination with highly active
      antiretroviral therapy (HAART) was assessed in a pilot study in patients with
      advanced human immunodeficiency virus (HIV) disease. Twenty-five persons with
      </=250 CD4 cells/microL and plasma HIV-1 RNA levels </=500 copies/mL for >24
      weeks were randomly assigned to receive sc rIL-2 (3 x 10(6) IU once a day) with
      their previous antiretroviral regimen (n=13) or to continue with the same
      treatment (n=12). The level of CD4 T cells was significantly higher in the IL-2
      group at week 24 (105+/-65/microL; P<.05) but not in the control group (30+/
      78/microL). Memory T cells initially contributed to the CD4 T cell increase at
      week 4 (P<.05). Naive T cell increases (99+/-58/microL) in the IL-2 group became
      statistically significant at week 24 compared with the control group (28+/
      27/microL; P<.05). Subcutaneous rIL-2 once a day in combination with HAART was
      well tolerated and improved immunologic surface markers in patients with advanced
      HIV infection.

PMID- 10353862
TI  - Thalidomide for the treatment of esophageal aphthous ulcers in patients with
      human immunodeficiency virus infection. National Institute of Allergy and
      Infectious Disease AIDS Clinical Trials Group.
AB  - A multicenter, double-blind, randomized, placebo-controlled clinical trial was
      conducted to determine the safety and efficacy of thalidomide for treating
      esophageal aphthous ulceration in persons infected with human immunodeficiency
      virus (HIV). Twenty-four HIV-infected patients with biopsy-confirmed aphthous
      ulceration of the esophagus were randomly assigned to receive either oral
      thalidomide, 200 mg/day, or oral placebo daily for 4 weeks. Eight (73%) of 11
      patients randomized to receive thalidomide had complete healing of aphthous
      ulcers at the 4-week endoscopic evaluation, compared with 3 (23%) of 13 placebo
      randomized patients (odds ratio, 13.82; 95% confidence interval, 1.16-823.75;
      P=.033). Odynophagia and impaired eating ability caused by esophageal aphthae
      were improved markedly by thalidomide treatment. Adverse events among patients
      receiving thalidomide included somnolence (4 patients), rash (2 patients), and
      peripheral sensory neuropathy (3 patients). Thalidomide is effective in healing
      aphthous ulceration of the esophagus in patients infected with HIV.

PMID- 10353863
TI  - CD8+ anti-human immunodeficiency virus suppressor activity (CASA) in response to
      antiretroviral therapy: loss of CASA is associated with loss of viremia.
AB  - CD8+ anti-human immunodeficiency virus (HIV) suppressor activity (CASA) defines
      the noncytolytic suppression of HIV mediated by secreted soluble factors. Changes
      in CASA in patients receiving combination antiretroviral therapy have not been
      described. Thirty-two HIV-infected patients receiving mono- or dual therapy for
      52 weeks followed by highly active antiretroviral therapy (HAART) for a further
      52 weeks were analyzed. T cell number and functional subsets, cutaneous delayed
      type hypersensitivity, and plasma HIV RNA were assessed in 17 patients for CASA.
      Prior to therapy, CASA correlated inversely with HIV RNA (P<.001). Dual therapy
      yielded greater and more sustained changes in CASA than monotherapy, but HAART
      decreased CASA to levels observed in HIV-uninfected individuals. The magnitude of
      HIV RNA suppression correlated significantly with a decrease in activated CD8+ T
      lymphocytes (CD38+HLA-DR+), increases in naive CD4+ T lymphocytes (CD45RA+62L+),
      and increases in the delayed-type hypersensitivity score. However, changes in
      CASA did not correlate with changes in any T lymphocyte subset. CASA increases
      with improving immune function but appears more dependent on ongoing HIV
      replication.

PMID- 10353864
TI  - Functional T cell reconstitution and human immunodeficiency virus-1-specific cell
      mediated immunity during highly active antiretroviral therapy.
AB  - Lymphoproliferative responses (LPRs) to recall antigens (Ags) and human
      immunodeficiency virus type 1 (HIV-1) Gag and frequencies of circulating HIV-1
      specific cytotoxic T lymphocyte precursors (CTLps) were measured in 12 patients
      undergoing highly active antiretroviral therapy (HAART) after long-standing HIV-1
      infection. LPRs to at least 1 recall Ag became detectable or increased in all
      patients during HAART. No significant LPRs to Gag-p24 were observed, whereas 4 of
      8 patients tested presented with Gag-p17-specific LPRs. HIV-1-specific CTLp
      frequencies became measurable or increased early during therapy in 6 of 10
      patients tested and were maintained or decreased thereafter. Increasing HIV-1
      specific CTLp frequencies were seen only in association with partial HAART
      failure in 1 patient. In conclusion, restoration of CD4+ T lymphocyte
      responsiveness to recall Ags is achieved during HAART. The data provide evidence
      for limited HIV-1-specific CD4+ memory T cells during advanced HIV-1 infection
      and suggest that both CD4+ and CD8+ HIV-1-specific T cells are poorly stimulated
      when viral load is suppressed.

PMID- 10353865
TI  - Fever and human immunodeficiency virus infection as sentinels for emerging
      mycobacterial and fungal bloodstream infections in hospitalized patients >/=15
      years old, Bangkok.
AB  - To determine the etiology of bloodstream infections (BSIs) in hospitalized
      patients >/=15 years old in Thailand, prospectively enrolled, consecutive febrile
      (>/=38 degrees C) patients were admitted to one hospital during February-April
      1997. After a patient history was taken and a physical examination was performed,
      blood was obtained for comprehensive culture and human immunodeficiency virus
      (HIV) testing. Of 246 study patients, 119 (48%) had BSIs, and 182 (74%) were
      infected with HIV. The 2 most common pathogens were Cryptococcus neoformans and
      Mycobacterium tuberculosis (30 and 27 patients, respectively). HIV-positive
      patients were more likely than HIV-negative patients to have mycobacteremia
      (57/182 vs. 0/64, P<. 0001), fungemia (38/182 vs. 2/64, P<.001), or polymicrobial
      BSIs (19/182 vs. 0/64, P<.002). Clinical predictors of BSIs included HIV
      infection, chronic diarrhea, lymphadenopathy, or splenomegaly. Mortality was
      higher among patients with than those without BSIs (P<. 001). Cohort-based
      microbiologic studies are critically important to diagnose emerging pathogens and
      to develop algorithms for empirical treatment of BSIs in developing countries.

PMID- 10353866
TI  - Human immunodeficiency virus load in breast milk, mastitis, and mother-to-child
      transmission of human immunodeficiency virus type 1.
AB  - Human immunodeficiency virus (HIV) type 1 load in breast milk and mastitis were
      examined as risk factors for vertical transmission of HIV-1. Six weeks after
      delivery, HIV-1 load and sodium (an indicator of mastitis) were measured in
      breast milk from 334 HIV-1-infected women in Malawi. Median breast milk HIV-1
      load was 700 copies/mL among women with HIV-1-infected infants versus
      undetectable (<200 copies/mL) among those with uninfected infants, respectively
      (P<. 0001). Elevated breast milk sodium levels consistent with mastitis occurred
      in 16.4% of HIV-1-infected women and were associated with increased vertical
      transmission of HIV-1 (P<.0001). Median breast milk HIV-1 load was 920 copies/mL
      among women with versus undetectable among those without elevated breast milk
      sodium levels, respectively (P<.0001). Mastitis and breast milk HIV-1 load may
      increase the risk of vertical transmission of HIV-1 through breast-feeding.

PMID- 10353868
TI  - In vivo cytokine and neuroendocrine responses to endotoxin in human
      immunodeficiency virus-infected subjects.
AB  - The cytokine and neuroendocrine host responses to experimental challenge with
      lipopolysaccharide (LPS) were studied in human immunodeficiency virus (HIV)
      infected subjects and uninfected control subjects. Elevations in circulating
      concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8
      were significantly greater in HIV-infected subjects than control subjects after
      LPS challenge. All subjects showed a significant increase in circulating
      concentrations of adrenocorticotropin, cortisol, and norepinephrine after LPS
      challenge, but there was not a significant difference between the responses of
      these hormones in the HIV-infected and -uninfected subjects. Compared with the
      control subjects, the HIV-infected subjects had a significantly reduced IL-10
      response and a reduced IL-1 receptor antagonist response. It is concluded that
      the TNF-alpha, IL-6, IL-8, and IL-10 cytokine responses to LPS in vivo are
      disrupted in HIV subjects but that this is not related to disruption of the
      hypothalamo-pituitary-adrenal axis.

PMID- 10353867
TI  - Trends in human immunodeficiency virus (HIV) counseling, testing, and
      antiretroviral treatment of HIV-infected women and perinatal transmission in
      North Carolina.
AB  - Since 1993, trends in perinatal human immunodeficiency virus (HIV) transmission
      have been monitored by use of chart review of patients identified at a central
      diagnostic laboratory. In the population studied, either pre- or postnatal
      antiretroviral therapy to the infant increased from 21% in 1993 to 95% in 1997.
      Concurrently, the number of HIV-infected infants declined from 25 in 1993 to 4 in
      1997. The complete Pediatric AIDS Clinical Trials Group Protocol 076 regimen was
      the most effective in reducing transmission (3.1%). Twenty-two of 35 infants who
      became infected in 1995-1997 had mothers who did not receive antiretroviral
      therapy, although counseling practices improved with time. In 1995, 87% of the
      mothers of HIV-seropositive infants were counseled, whereas in 1997, 96% were
      counseled (P<.005). None of 59 infants tested had high-level phenotypic
      zidovudine resistance, although 5 (8.8%) of 57 infants had virus isolates with at
      least one mutation in the reverse transcriptase gene associated with reduced
      phenotypic susceptibility to zidovudine.

PMID- 10353869
TI  - Microbiologic findings and correlations with serum tumor necrosis factor-alpha in
      patients with severe sepsis and septic shock.
AB  - To understand the microbiology of sepsis and its relationship with tumor necrosis
      factor (TNF)-alpha, 444 septic patients were studied in a phase II clinical
      trial. In total, 270 (61%) 444 of episodes were microbiologically documented. The
      most common isolates were Escherichia coli, Staphylococcus aureus, and
      Streptococcus pneumoniae. In some patients, obligate anaerobes were isolated in
      pure culture. Data on baseline TNF-alpha (n=409) showed that the geometric mean
      TNF-alpha concentrations in patients with severe sepsis and in those with late
      shock were 41 pg/mL (range, 5-3310) and 58 pg/mL (range, 5-1870), respectively.
      Patients with a positive culture had significantly higher TNF-alpha levels (65.9
      vs. 29.2 pg/mL, P=.0001). Patients with a pure gram-negative infection had
      significantly higher TNF-alpha levels than those with a pure gram-positive or
      mixed infection, especially in the late shock group (142.6, 64.0, and 52.8 pg/mL,
      respectively, P=.004). These results provide further support for the concept that
      patients with sepsis are a heterogeneous group that require more precise
      definition.

PMID- 10353870
TI  - Nasal immunization induces Haemophilus influenzae-specific Th1 and Th2 responses
      with mucosal IgA and systemic IgG antibodies for protective immunity.
AB  - To determine the efficacy of a mucosal vaccine against nontypeable Haemophilus
      influenzae (NTHi), mice were immunized nasally, orally, intratracheally, or
      intraperitoneally with NTHi antigen together with cholera toxin. Antigen-specific
      IgA antibody titers in nasal washes and the numbers of antigen-specific IgA
      producing cells in nasal passages showed the greatest increases in mice immunized
      nasally. Cytokine analysis showed that interferon-gamma, interleukin (IL)-2, IL
      5, IL-6, and IL-10 were induced by nasal immunization, suggesting that Th2- and
      Th1-type cells were generated. Furthermore, bacterial clearance of a homologous
      strain of NTHi from the nasal tract was significantly enhanced in the nasal
      immunization group. These findings suggest that nasal immunization is an
      effective vaccination regimen for the induction of antigen-specific mucosal
      immune responses, which reduce the colonization of NTHi in the nasal tract.

PMID- 10353871
TI  - Correlation of opsonophagocytosis and passive protection assays using human
      anticapsular antibodies in an infant mouse model of bacteremia for Streptococcus
      pneumoniae.
AB  - An infant mouse assay system for assessment of protective concentrations of human
      serum pneumococcal anticapsular antibodies is described. Passive immunization of
      anticapsular antibodies was evaluated for protection of infant mice challenged
      with Streptococcus pneumoniae serotypes 1, 4, 5, 6B, 18C, and 23A, with
      bacteremia as an end point. Protection was defined as no detectable bacteremia in
      70% of mice 48 h after challenge. Type-specific anticapsular concentrations
      required for protection varied with serotype (</=0.05 to >0.4 microg/mL). Across
      serotypes, there was no significant correlation between human IgG concentration
      in mouse serum and protection from bacteremia or between IgG concentration and
      opsonophagocytic titer. Significant correlation (r=.84, P<.001) was observed
      between opsonophagocytic titer of human IgG antibody in mouse sera and protection
      from bacteremia. Thus, protective concentrations of anticapsular antibodies
      against bacteremia are serotype dependent. Opsonophagocytosis is a better
      predictor of in vivo protective capacity of pneumococcal anticapsular antibodies
      than are ELISA IgG antibody concentrations.

PMID- 10353872
TI  - Phenotypically activated gammadelta T lymphocytes in the peripheral blood of
      patients with tuberculosis.
AB  - Surface molecules with the potential relevance for resistance against
      Mycobacterium tuberculosis were investigated. The expression of lymphocyte
      function antigen-1, very late antigen (VLA)-4, l-selectin, intercellular adhesion
      molecule (ICAM)-1, major histocompatibility complex class II, Fas, and CD40 on
      alphabeta T cells, gammadelta T cells, NK cells, and monocytes of healthy donors
      and patients with tuberculosis were analyzed. A high activation status of
      gammadelta T cells and increased levels of soluble ICAM-1 in plasma of patients
      with tuberculosis versus healthy individuals was detected. Tuberculosis patients
      with and without an underlying systemic disease could be segregated by
      differential expression of VLA-4 and ICAM-1 on gammadelta T cells and on
      monocytes. The composition of peripheral blood mononuclear cells varied slightly,
      whereas the proportion of monocytes decreased significantly in patients with
      tuberculosis, compared with healthy controls. The activation phenotype of
      peripheral gammadelta T cells in patients with tuberculosis emphasizes the role
      of these T cells in controlling the inflammatory process during tuberculosis and
      perhaps other microbial infections.

PMID- 10353873
TI  - Severity of tuberculosis in mice is linked to distal chromosome 3 and proximal
      chromosome 9.
AB  - Genetic factors play a role in host response to infection with Mycobacterium
      tuberculosis, the number one infectious killer worldwide. Mice of the inbred
      strains I/St and A/Sn show significant differences in disease severity after
      intravenous injection of a lethal dose of the virulent human isolate M.
      tuberculosis H37Rv. Following challenge with H37Rv, only I/St mice have rapid
      body weight loss and short survival times. A genome wide analysis for linkage
      with body weight after M. tuberculosis H37Rv infection was done in
      (A/SnxI/St)F1xI/St mice. Among females, quantitative trait loci (QTLs) on
      chromosomes 9 and 3 were significantly linked to postinfection body weight
      (logarithm of the odds ratio [LOD] scores of 6.68 and 3.92, respectively).
      Suggestive linkages were found for QTLs on chromosomes 8 and 17 (LOD scores of
      3.01 and 2.95, respectively). For males, QTLs on chromosomes 5 and 10 showed
      suggestive linkages (LOD scores of 3.03 and 2.31, respectively). These linkages
      can be used to identify candidate regions for tuberculosis susceptibility loci in
      the human genome.

PMID- 10353874
TI  - Evidence for alphavbeta3 and alphavbeta5 integrin-like vitronectin (VN) receptors
      in Candida albicans and their involvement in yeast cell adhesion to VN.
AB  - The expression of integrin vitronectin (VN) receptors on Candida albicans yeasts
      and their involvement in the adhesion to VN were investigated. By
      immunofluorescence and cytofluorimetric analysis, several antibodies directed
      against human alphav, beta3, beta5, alphavbeta3, or alphavbeta5 integrin
      positively stained C. albicans yeasts. Biochemical analysis on yeast lysates with
      anti-human alphav, beta3, or beta5 antibody revealed molecular species of 130,
      110, 100, and 84 kDa. The 130-kDa band was identified as alphav, whereas the
      doublet of 110/100 kDa and the 84-kDa band likely correspond to the beta3 and
      beta5 subunits, respectively. Some 48%-54% of Candida yeasts specifically adhered
      to VN, and this binding was strongly inhibited by anti-human alphav, beta3,
      alphavbeta3, and alphavbeta5 antibodies and by RGD- but not RGE-containing
      peptides. In addition, VN inhibited C. albicans adherence to a human endothelial
      cell line. Thus, C. albicans in the yeast phase expresses VN receptors
      antigenically related to the vertebrate alphavbeta3 and alphavbeta5 integrins,
      which mediate its adhesion to VN.

PMID- 10353875
TI  - Longitudinal study of Cryptosporidium infection in children in northeastern
      Brazil.
AB  - A prospective, 4-year cohort study of children born in an urban slum in
      northeastern Brazil was undertaken to elucidate the epidemiology of
      Cryptosporidium infection in an endemic setting, describe factors associated with
      Cryptosporidium-associated persistent diarrhea, and clarify the importance of
      copathogens in symptomatic cryptosporidiosis. A total of 1476 episodes of
      diarrhea, accounting for 7581 days of illness (5.25 episodes/child-year), were
      recorded: of these, 102 episodes (6.9%) were persistent. Cryptosporidium oocysts
      were identified in 7.4% of all stools, and they were found more frequently in
      children with persistent diarrhea (16.5%) than in those with acute (8.4%) or no
      (4.0%) diarrhea (P<.001). Low-birth-weight children and those living in densely
      crowded subdivisions were at greater risk for symptomatic infection. Disease
      course was highly variable and was not associated with the presence of
      copathogens. Recurrent Cryptosporidium infection and relapsing diarrhea
      associated with it were moderately common. In light of these data, the
      applicability of the current World Health Organization diarrheal definitions to
      Cryptosporidium-associated diarrheal episodes may need to be reconsidered.

PMID- 10353876
TI  - Review: infectious diseases and coagulation disorders.
AB  - Infection, both bacterial and nonbacterial, may be associated with coagulation
      disorders, resulting in disseminated intravascular coagulation and multiorgan
      failure. In the last few decades a series of in vivo and in vitro studies has
      provided more insight into the pathogenetic mechanisms and the role of cytokines
      in these processes. Because of the growing interest in this field, the complexity
      of the subject, and the fact that many physicians must deal with a variety of
      infections, current data are reviewed on the association between infectious
      diseases and the coagulation system. Novel therapeutic intervention strategies
      that will probably become available in the near future are mentioned, along with
      those of special interest for infectious disorders for which only supportive care
      can be given.

PMID- 10353877
TI  - Protection after two doses of measles vaccine is independent of interval between
      doses.
AB  - The protection provided by one or two doses of measles vaccine was compared, as
      was the effect of the timing of delivery of the doses on the protection provided.
      A total of 5542 measles cases occurred in Ontario, Canada, between January 1990
      and December 1996. Three controls per case were matched for age and residence.
      Children who received a single dose at age 15 months and older were 5 times more
      likely to contract measles than were children who received two doses of vaccine
      after their first birthday. Among children given two doses of vaccines, the risk
      of measles was 3 times greater in those who had their first vaccination at age 11
      months compared with children who first received vaccine after age 1 year, but
      the protection was independent of the interval between doses. Delaying the second
      dose >6 months after the first does not increase protection.

PMID- 10353878
TI  - GB virus C infection in hemodialysis patients: molecular evidence for nosocomial
      transmission.
AB  - Studies of the prevalence and clinical relevance of GB virus C (GBV-C) infection
      in 328 hemodialysis (HD) patients were done, and the possibility of nosocomial
      GBV-C transmission was explored by molecular epidemiology methods. For GBV-C
      viremic patients in a given HD unit, nucleotide sequences of the envelope region
      were analyzed by phylogenetic tree constructions. Of 328 HD patients, active
      hepatitis B virus, hepatitis C virus (HCV), and GBV-C infection were detected in
      13%, 23%, and 17%, respectively. Except for a higher frequency of HCV
      coinfection, the demographic and clinical characteristics of patients with and
      without GBV-C infection were comparable. In contrast, patients with isolated HCV
      infection had significantly higher serum transaminase levels, longer time on HD,
      and more blood transfusions. Phylogenetic analysis showed several distinct
      clusters of closely related GBV-C isolates from one HD unit, suggesting the
      possibility of nosocomial transmission. These results suggest that GBV-C plays a
      minimal role in causing hepatitis in Taiwanese HD patients and in nosocomial
      transmission.

PMID- 10353879
TI  - Immunologic parameters as predictive factors of cytomegalovirus disease in renal
      allograft recipients.
AB  - Cytomegalovirus (CMV) disease is a major problem in renal transplant recipients,
      but few predictive markers of the disease are known. Several immunologic
      parameters of potential relevance for the defense against CMV were measured after
      renal transplantation in 25 patients before any manifestations of CMV infection
      occurred. In 10 patients who later developed CMV disease, plasma levels of
      interleukin-8 were significantly higher, whereas the levels of macrophage
      inflammatory protein-1alpha (MIP-1alpha) were significantly lower than in 15
      patients who did not develop CMV disease. Also, lower numbers of CD4+ and CD8+
      lymphocytes were observed in patients who later had CMV disease. These findings
      were independent of previous rejection therapy and were particularly pronounced
      in patients with primary CMV infection. Interleukin-8 and MIP-1alpha may be
      predictive markers of CMV disease and could be of potential use in selecting
      patients for prophylactic treatment.

PMID- 10353880
TI  - The epidemiology of neonatal herpes simplex virus infections in California from
      1985 to 1995.
AB  - Comprehensive hospital discharge data completed by the California Office of
      Statewide Health Planning and Development was used to determine whether the
      proportion of infants </=6 weeks of age who were hospitalized with a diagnosis of
      herpes simplex virus (HSV) infection changed between 1985 and 1995. During 1985,
      1990, and 1995, respectively, 11.7, 11.3, and 11.4 infants per 100,000 live
      births had a diagnosis of HSV (P=.98). The proportion of infants 1-42 days of age
      who were discharged from the hospital with a diagnosis of HSV infection did not
      change over this time period despite a decrease in deliveries by cesarean section
      and an increase in the proportion of women with a diagnosis of genital HSV
      infection who gave birth to infants by vaginal delivery. From 1985 to 1995 there
      was no decrease in the rate of secondary diagnosis of genital HSV in delivering
      women.

PMID- 10353881
TI  - The topical microbicide PRO 2000 protects against genital herpes infection in a
      mouse model.
AB  - Vaginal gel formulations containing the naphthalene sulfonate polymer PRO 2000
      are being developed as topical microbicides to protect against infection with
      sexually transmitted disease (STD) pathogens. A mouse model was used to determine
      whether PRO 2000 could protect against genital herpes in vivo. Animals received a
      single intravaginal application of 15 microL of a 10% PRO 2000 aqueous solution
      or a 4.0% or 0.5% PRO 2000 vaginal gel formulation 20 s prior to intravaginal
      challenge with 4.0 log10 pfu of herpes simplex virus type 2. Treatment with the
      4.0% gel provided complete protection against infection; treatment with the 0.5%
      gel or 10% solution provided 81% and 80% protection, respectively. Furthermore,
      the 4% gel provided significant protection even when viral challenge was delayed
      until 60 min after treatment. This is the first report to show that PRO 2000 can
      protect against infection with an STD pathogen in vivo.

PMID- 10353882
TI  - Effect of human immunodeficiency virus type 1 on intracellular activation and
      superoxide production by neutrophils.
AB  - The immunopathogenesis of AIDS is associated with the development of
      opportunistic infections by intracellular pathogens that can invade and reproduce
      freely because of impaired cellular functions. Neutrophils from asymptomatic
      human immunodeficiency virus (HIV) type 1-infected persons and from symptomatic
      patients with AIDS were found to retain normal phagocytosis activity while
      producing significantly less superoxide than neutrophils from HIV-1-negative
      subjects, when stimulated through Fc receptors or protein kinase C. After priming
      with a synthetic HIV-1 envelope peptide and stimulation via the Fc receptor, the
      neutrophils from HIV-1-negative controls had suppressed superoxide production,
      reduced phosphorylation of two unidentified cellular proteins, and increased
      expression of a third phosphoprotein. These results suggest that HIV-1 can
      produce direct functional damage of neutrophils through binding of envelope
      components to the cell membrane.

PMID- 10353883
TI  - Fas receptor up-regulation and membrane localization concurrent with apoptosis in
      idiopathic esophageal ulceration: toward a better understanding of esophageal
      injury in AIDS.
AB  - Activation of the Fas-mediated apoptotic pathway in the etiology of idiopathic
      esophageal ulcerations (IEUs) was investigated. Constitutive expression of Fas
      ligand (Fas L) was found in the basal layer of the normal esophageal mucosa and
      in IEUs and cytomegalovirus ulcerations. In addition to an altered cytokine
      environment, there was significant up-regulation of Fas antigen mRNA and membrane
      localization of the receptor in IEU specimens. Concomitant increase in the basic
      components of Fas machinery, together with elevated mucosal apoptosis, strongly
      suggests the potential role of the Fas signaling pathway in the onset of tissue
      destruction associated with IEUs.

PMID- 10353884
TI  - Protein kinase C-dependent effects on leukocyte migration of thalidomide.
AB  - Thalidomide is effective in the treatment of some tumor necrosis factor-related
      diseases, but its cellular target is not known. Effects of thalidomide were
      investigated on lymphocytes and monocytes. Cell migration was examined in a
      Boyden chamber. Effects on protein kinase C (PKC) were investigated functionally
      by use of PKC inhibitor and in purified enzyme preparations. Thalidomide itself
      showed no direct chemotactic effect on lymphocytes or monocytes. Preincubation
      with the drug significantly enhanced random migration of both cell types. This
      effect was bisindolylmaleimide-reversible, suggesting involvement of PKC.
      Preincubation with thalidomide diminished the chemotactic response of monocytes
      towards formyl peptide but failed to influence lymphocyte chemotaxis towards
      RANTES or interleukin-8. In a cell-free assay, inhibition of PKC activation by
      bisindolylmaleimide could be reversed by thalidomide, indicating direct
      interactions of thalidomide with PKC. Results suggest that effects of thalidomide
      in chronic inflammation may be related to actions on leukocyte functions.

PMID- 10353885
TI  - Rats of the genus Rattus are reservoir hosts for pathogenic Bartonella species:
      an Old World origin for a New World disease?
AB  - Bartonella species were isolated from the blood of 63 of 325 Rattus norvegicus
      and 11 of 92 Rattus rattus from 13 sites in the United States and Portugal.
      Infection in both Rattus species ranged from 0% (e.g., 0/87) to approximately 60%
      (e.g., 35/62). A 337-bp fragment of the citrate synthase (gltA) gene amplified by
      polymerase chain reaction was sequenced from all 74 isolates. Isolates from R.
      norvegicus were most similar to Bartonella elizabethae, isolated previously from
      a patient with endocarditis (93%-100% sequence similarity), followed by
      Bartonella grahamii and other Bartonella species isolated from Old World rodents
      (Clethrionomys species, Mus musculus, and Rattus species). These data suggest
      that Rattus species are a reservoir host for pathogenic Bartonella species and
      are consistent with a hypothesized Old World origin for Bartonella species
      recovered from Rattus species introduced into the Americas.

PMID- 10353886
TI  - Sequestration of T lymphocytes to body fluids in tuberculosis: reversal of anergy
      following chemotherapy.
AB  - The specificity of CD4 T lymphocytes was investigated in 6 patients affected by
      tuberculosis who had negative tuberculin purified protein derivative (PPD) skin
      tests at diagnosis. Polyclonal CD4 T cell lines from the peripheral blood failed
      to proliferate to PPD and to the 16- or 38-kDa proteins of Mycobacterium
      tuberculosis, while CD4 cell lines from the disease site responded to PPD and to
      the 16- and 38-kDa proteins and derived epitopes in vitro. Four months after
      chemotherapy, the patients became responsive to PPD. The proliferative response
      to PPD and to the 16- or 38-kDa proteins and their derived peptides decreased in
      CD4 T cell lines from the disease site and increased in lines from the peripheral
      blood. These results indicate that CD4 T cells recognizing a vast array of M.
      tuberculosis epitopes are compartmentalized at the site of disease in anergic
      patients but appear in peripheral blood after chemotherapy.

PMID- 10353887
TI  - Killing of Mycobacterium avium by neutrophils and monocytes from AIDS patients
      treated with recombinant granulocyte-macrophage colony-stimulating factor.
AB  - In this study, 30 AIDS patients without Mycobacterium avium infection were
      randomized to receive treatment with azithromycin (1200 mg), granulocyte-monocyte
      colony-stimulating factor (GM-CSF; 250 microg/m2/day for 5 days), or both agents.
      The M. avium killing capacity of neutrophils and monocytes harvested from each
      patient before intervention and during (day 4), and after therapy (day 8) was
      assessed. The mean virus load change in the groups receiving GM-CSF was +0.14 log
      human immunodeficiency virus RNA. After GM-CSF therapy, neither neutrophils nor
      monocytes could significantly reduce M. avium growth (P=.96 and.31,
      respectively). Bone pain, myalgia, presyncope, or fever occurred in 55% of
      patients receiving GM-CSF. Thus, the GM-CSF regimen used in this study did not
      affect virus load, frequently caused adverse reactions, and did not improve the
      M. avium killing capacity of neutrophils and monocytes. Future studies using a
      different GM-CSF regimen are indicated.

PMID- 10353888
TI  - Association of Chlamydia trachomatis heat-shock protein 60 antibody and HLA class
      II DQ alleles.
AB  - A total of 113 female commercial sex workers had individual alleles for HLA class
      II genes determined by using labeled sequence-specific oligonucleotide probes to
      hybridize to polymerase chain reaction products of amplified DNA. Women also had
      microimmunofluorescent (MIF) antibody titers to Chlamydia trachomatis elementary
      bodies and ELISA antibody to recombinant chlamydial heat-shock protein 60
      (Chsp60) determined. Women were prospectively followed at monthly intervals over
      2 years for incident C. trachomatis infection and acute pelvic inflammatory
      disease (PID). HLA DQA1*0401 and DQB1*0402 alleles were statistically associated
      with increased prevalence and amount of antibody to Chsp60 but not MIF antibody.
      However, these alleles did not alter the risk for chlamydial PID. The potential
      role that HLA DQ may play in chlamydial disease pathogenesis requires further
      study.

PMID- 10353889
TI  - Chlamydia pneumoniae infection accelerates the progression of atherosclerosis in
      apolipoprotein E-deficient mice.
AB  - Accumulating evidence supports an association between Chlamydia pneumoniae
      infection and atherosclerosis. To determine whether there is a causal
      relationship, the effects of chronic infection with C. pneumoniae on the
      development of atherosclerosis in apolipoprotein E (apoE)-deficient mice were
      evaluated. Eight-week-old male apoE-deficient mice were inoculated intranasally
      with C. pneumoniae three times, at 8, 9, and 10 weeks of age. The combined area
      of atherosclerotic lesions in the lesser curvature of the aortic arch was
      measured en face by computer-assisted morphometry. The lesion area was 2.4-fold
      greater (P=.05) at 16 weeks of age and 1.6-fold greater (P=.05) at 20 weeks of
      age in infected mice than in control mice. There were no differences in total
      plasma cholesterol levels between groups. This study demonstrates that C.
      pneumoniae infection accelerates the progression of atherosclerosis in the aortic
      arch of apoE-deficient mice.

PMID- 10353890
TI  - No evidence for serosubtype-restricted protection among teenagers vaccinated with
      the Norwegian group B outer membrane vesicle vaccine.

PMID- 10353891
TI  - Coccidioides immitis antigen.

PMID- 10353892
TI  - Gustave Malecot, 1911-1998. Population genetics founding father.

PMID- 10353893
TI  - Mutators, population size, adaptive landscape and the adaptation of asexual
      populations of bacteria.
AB  - Selection of mutator alleles, increasing the mutation rate up to 10, 000-fold,
      has been observed during in vitro experimental evolution. This spread is ascribed
      to the hitchhiking of mutator alleles with favorable mutations, as demonstrated
      by a theoretical model using selective parameters corresponding to such
      experiments. Observations of unexpectedly high frequencies of mutators in natural
      isolates suggest that the same phenomenon could occur in the wild. But it remains
      questionable whether realistic in natura parameter values could also result in
      selection of mutators. In particular, the main parameters of adaptation, the size
      of the adapting population and the height and steepness of the adaptive peak
      characterizing adaptation, are very variable in nature. By simulation approach,
      we studied the effect of these parameters on the selection of mutators in asexual
      populations, assuming additive fitness. We show that the larger the population
      size, the more likely the fixation of mutator alleles. At a large population
      size, at least four adaptive mutations are needed for mutator fixation; moreover,
      under stronger selection stronger mutators are selected. We propose a model based
      on multiple mutations to illustrate how second-order selection can optimize
      population fitness when few favorable mutations are required for adaptation.

PMID- 10353894
TI  - Position effect variegation at the mating-type locus of fission yeast: a cis
      acting element inhibits covariegated expression of genes in the silent and
      expressed domains.
AB  - Schizosaccharomyces pombe switches its mating type by transposing a copy of
      unexpressed genes from the respective mat2 or mat3 cassettes to mat1. The donor
      cassettes are located in a silent domain that is separated from the expressed
      mat1 cassette by the L region. We monitored the expression of ade6 from sites in
      the L region and examined the relationship between the expression state at these
      sites and at sites within the silent domain. Results indicate that: (1) the
      silent domain extends into the L region, but repression is gradually alleviated
      with increasing distance from mat2, and overexpression of swi6 enhances PEV in
      the L region; (2) a transcriptionally active chromatin state, associated with
      reporter gene expression in the L region, spreads toward the silent domain; (3) a
      cis-acting element, located at the junction between the L region and mat2-P,
      ensures repression in the silent domain, regardless of the expression state in
      the L region; and (4) repression in mat1-P cells is less stringently controlled
      than in mat1-M cells. We discuss the functional organization of the mat region
      and genetic elements that ensure separation between repressed and derepressed
      domains.

PMID- 10353895
TI  - Lesions in many different spindle components activate the spindle checkpoint in
      the budding yeast Saccharomyces cerevisiae.
AB  - The spindle checkpoint arrests cells in mitosis in response to defects in the
      assembly of the mitotic spindle or errors in chromosome alignment. We determined
      which spindle defects the checkpoint can detect by examining the interaction of
      mutations that compromise the checkpoint (mad1, mad2, and mad3) with those that
      damage various structural components of the spindle. Defects in microtubule
      polymerization, spindle pole body duplication, microtubule motors, and
      kinetochore components all activate the MAD-dependent checkpoint. In contrast,
      the cell cycle arrest caused by mutations that induce DNA damage (cdc13),
      inactivate the cyclin proteolysis machinery (cdc16 and cdc23), or arrest cells in
      anaphase (cdc15) is independent of the spindle checkpoint.

PMID- 10353896
TI  - MOD-D, a Galpha subunit of the fungus Podospora anserina, is involved in both
      regulation of development and vegetative incompatibility.
AB  - Cell death via vegetative incompatibility is widespread in fungi but molecular
      mechanism and biological function of the process are poorly understood. One way
      to investigate this phenomenon was to study genes named mod that modified
      incompatibility reaction. In this study, we cloned the mod-D gene that encodes a
      Galpha protein. The mod-D mutant strains present developmental defects.
      Previously, we showed that the mod-E gene encodes an HSP90. The mod-E1 mutation
      suppresses both vegetative incompatibility and developmental defects due to the
      mod-D mutation. Moreover, we isolated the PaAC gene, which encodes an adenylate
      cyclase, as a partial suppressor of the mod-D1 mutation. Our previous results
      showed that the molecular mechanisms involved in vegetative incompatibility and
      developmental pathways are connected, suggesting that vegetative incompatibility
      may result from disorders in some developmental steps. Our new result
      corroborates the involvement of mod genes in signal transduction pathways. As
      expected, we showed that an increase in the cAMP level is able to suppress the
      defects in vegetative growth due to the mod-D1 mutation. However, cAMP increase
      has no influence on the suppressor effect of the mod-D1 mutation on vegetative
      incompatibility, suggesting that this suppressor effect is independent of the
      cAMP pathway.

PMID- 10353897
TI  - Identification of novel Drosophila meiotic genes recovered in a P-element screen.
AB  - The segregation of homologous chromosomes from one another is the essence of
      meiosis. In many organisms, accurate segregation is ensured by the formation of
      chiasmata resulting from crossing over. Drosophila melanogaster females use this
      type of recombination-based system, but they also have mechanisms for segregating
      achiasmate chromosomes with high fidelity. We describe a P-element mutagenesis
      and screen in a sensitized genetic background to detect mutations that impair
      meiotic chromosome pairing, recombination, or segregation. Our screen identified
      two new recombination-deficient mutations: mei-P22, which fully eliminates
      meiotic recombination, and mei-P26, which decreases meiotic exchange by 70% in a
      polar fashion. We also recovered an unusual allele of the ncd gene, whose wild
      type product is required for proper structure and function of the meiotic
      spindle. However, the screen yielded primarily mutants specifically defective in
      the segregation of achiasmate chromosomes. Although most of these are alleles of
      previously undescribed genes, five were in the known genes alphaTubulin67C, CycE,
      push, and Trl. The five mutations in known genes produce novel phenotypes for
      those genes.

PMID- 10353898
TI  - Positive selection drives the evolution of the Acp29AB accessory gland protein in
      Drosophila.
AB  - Nucleotide sequence variation at the Acp29AB gene region has been surveyed in
      Drosophila melanogaster from Spain (12 lines), Ivory Coast (14 lines), and Malawi
      (13 lines) and in one line of D. simulans. The approximately 1.7-kb region
      studied encompasses the Acp29AB gene that codes for a male accessory gland
      protein and its flanking regions. Seventy-seven nucleotide and 8 length
      polymorphisms were detected. Nonsynonymous polymorphism was an order of magnitude
      lower than synonymous polymorphism, but still high relative to other non-sex
      related genes. In D. melanogaster variation at this region revealed no major
      genetic differentiation between East and West African populations, while
      differentiation was highly significant between the European and the two African
      populations. Comparison of polymorphism and divergence at synonymous and
      nonsynonymous sites showed an excess of fixed nonsynonymous changes, which
      indicates that the evolution of the Acp29AB protein has been driven by
      directional selection at least after the split of the D. melanogaster and D.
      simulans lineages. The pattern of variation in extant populations of D.
      melanogaster favors a scenario where the fixation of advantageous replacement
      substitutions occurred in the early stages of speciation and balancing selection
      is maintaining variation in this species.

PMID- 10353899
TI  - Toward reconciling inferences concerning genetic variation in senescence in
      Drosophila melanogaster.
AB  - Standard models for senescence predict an increase in the additive genetic
      variance for log mortality rate late in the life cycle. Variance component
      analysis of age-specific mortality rates of related cohorts is problematic. The
      actual mortality rates are not observable and can be estimated only crudely at
      early ages when few individuals are dying and at late ages when most are dead.
      Therefore, standard quantitative genetic analysis techniques cannot be applied
      with confidence. We present a novel and rigorous analysis that treats the
      mortality rates as missing data following two different parametric senescence
      models. Two recent studies of Drosophila melanogaster, the original analyses of
      which reached different conclusions, are reanalyzed here. The two-parameter
      Gompertz model assumes that mortality rates increase exponentially with age. A
      related but more complex three-parameter logistic model allows for subsequent
      leveling off in mortality rates at late ages. We find that while additive
      variance for mortality rates increases for late ages under the Gompertz model, it
      declines under the logistic model. The results from the two studies are similar,
      with differences attributable to differences between the experiments.

PMID- 10353901
TI  - Nipped-B, a Drosophila homologue of chromosomal adherins, participates in
      activation by remote enhancers in the cut and Ultrabithorax genes.
AB  - How enhancers are able to activate promoters located several kilobases away is
      unknown. Activation by the wing margin enhancer in the cut gene, located 85 kb
      from the promoter, requires several genes that participate in the Notch receptor
      pathway in the wing margin, including scalloped, vestigial, mastermind, Chip, and
      the Nipped locus. Here we show that Nipped mutations disrupt one or more of four
      essential complementation groups: l(2)41Ae, l(2)41Af, Nipped-A, and Nipped-B.
      Heterozygous Nipped mutations modify Notch mutant phenotypes in the wing margin
      and other tissues, and magnify the effects that mutations in the cis regulatory
      region of cut have on cut expression. Nipped-A and l(2)41Af mutations further
      diminish activation by a wing margin enhancer partly impaired by a small
      deletion. In contrast, Nipped-B mutations do not diminish activation by the
      impaired enhancer, but increase the inhibitory effect of a gypsy transposon
      insertion between the enhancer and promoter. Nipped-B mutations also magnify the
      effect of a gypsy insertion in the Ultrabithorax gene. Gypsy binds the Suppressor
      of Hairy-wing insulator protein [Su(Hw)] that blocks enhancer-promoter
      communication. Increased insulation by Su(Hw) in Nipped-B mutants suggests that
      Nipped-B products structurally facilitate enhancer-promoter communication.
      Compatible with this idea, Nipped-B protein is homologous to a family of
      chromosomal adherins with broad roles in sister chromatid cohesion, chromosome
      condensation, and DNA repair.

PMID- 10353902
TI  - Pairing-dependent mislocalization of a Drosophila brown gene reporter to a
      heterochromatic environment.
AB  - We describe the precise positioning of a reporter gene within heterochromatin
      where it may be silenced. A transposition of the 59E-60A region into pericentric
      heterochromatin ensnares distal 59E-60A via somatic pairing. The frequency with
      which a brown (bw) reporter gene in 59E is silenced is influenced by chromosomal
      configurations. Silencing occurs only when the bw+ reporter is unpaired due to
      heterozygosity with a deficiency, where the frequency of bw+ reporter expression
      is correlated with the extent of bw gene and flanking sequence present.
      Surprisingly, the frequency of pairing between the transposition in
      heterochromatin and distal 59E observed cytologically is indistinguishable from
      the frequency of pairing of homologous chromosomes at 59E in wild-type larval
      brains, regardless of configuration. Therefore, bringing a susceptible reporter
      gene into close proximity with heterochromatin does not necessarily affect its
      expression, but local pairing changes resulting from altered chromosomal
      configurations can lead to silencing. We also find that an ensnared distal copy
      of bw that is interrupted by a heterochromatic insertion enhances silencing. This
      demonstrates that bw can be simultaneously acted upon by pericentric and distal
      blocks of heterochromatin.

PMID- 10353900
TI  - The Drosophila melanogaster Suppressor of deltex gene, a regulator of the Notch
      receptor signaling pathway, is an E3 class ubiquitin ligase.
AB  - During development, the Notch receptor regulates many cell fate decisions by a
      signaling pathway that has been conserved during evolution. One positive
      regulator of Notch is Deltex, a cytoplasmic, zinc finger domain protein, which
      binds to the intracellular domain of Notch. Phenotypes resulting from mutations
      in deltex resemble loss-of-function Notch phenotypes and are suppressed by the
      mutation Suppressor of deltex [Su(dx)]. Homozygous Su(dx) mutations result in
      wing-vein phenotypes and interact genetically with Notch pathway genes. We have
      previously defined Su(dx) genetically as a negative regulator of Notch signaling.
      Here we present the molecular identification of the Su(dx) gene product. Su(dx)
      belongs to a family of E3 ubiquitin ligase proteins containing membrane-targeting
      C2 domains and WW domains that mediate protein-protein interactions through
      recognition of proline-rich peptide sequences. We have identified a seven-codon
      deletion in a Su(dx) mutant allele and we show that expression of Su(dx) cDNA
      rescues Su(dx) mutant phenotypes. Overexpression of Su(dx) also results in
      ectopic vein differentiation, wing margin loss, and wing growth phenotypes and
      enhances the phenotypes of loss-of-function mutations in Notch, evidence that
      supports the conclusion that Su(dx) has a role in the downregulation of Notch
      signaling.

PMID- 10353903
TI  - Evidence for redundancy but not trans factor-cis element coevolution in the
      regulation of Drosophila Yp genes.
AB  - In Drosophila melanogaster and the endemic Hawaiian species D. grimshawi three
      Yolk protein (Yp) genes are expressed in a similar sex- and tissue-specific
      pattern. In contrast, DNA sequence comparisons of promoter/enhancer regions show
      low levels of similarity. We tested the functional significance of these
      observations by transforming D. melanogaster with the genomic region that
      includes the divergently transcribed D. grimshawi DgYp1 and DgYp2 genes; we found
      that the introduced genes were expressed in female fat body and in ovaries but
      not in males. Moreover, we found D. grimshawi proteins in the hemolymph and
      accumulating in ovaries. Using reporter constructs we showed that the intergenic
      region from D. grimshawi was sufficient to drive accurate expression, but some
      low level of ectopic expression was seen in males. Transforming D. melanogaster
      with constructs bearing deletions within the D. grimshawi intergenic region
      revealed only subtle effects in the overall level of expression, suggesting a
      high level of redundancy. Testing mutants in the sex-specific regulator doublesex
      revealed that it is capable of repressing the DgYp genes in males. Together,
      these data show that D. melanogaster trans-acting factors can regulate the in
      vivo pattern of DgYp expression and support the notion of a redundant and complex
      system of cis-acting elements.

PMID- 10353904
TI  - Evidence for complex mutations at microsatellite loci in Drosophila.
AB  - Fifteen lines each of Drosophila melanogaster, D. simulans, and D. sechellia were
      scored for 19 microsatellite loci. One to four alleles of each locus in each
      species were sequenced, and microsatellite variability was compared with sequence
      structure. Only 7 loci had their size variation among species consistent with the
      occurrence of strictly stepwise mutations in the repeat array, the others showing
      extensive variability in the flanking region compared to that within the
      microsatellite itself. Polymorphisms apparently resulting from complex
      nonstepwise mutations involving the microsatellite were also observed, both
      within and between species. Maximum number of perfect repeats and variance of
      repeat count were found to be strongly correlated in microsatellites showing an
      apparently stepwise mutation pattern. These data indicate that many
      microsatellite mutation events are more complex than represented even by
      generalized stepwise mutation models. Care should therefore be taken in inferring
      population or phylogenetic relationships from microsatellite size data alone. The
      analysis also indicates, however, that evaluation of sequence structure may allow
      selection of microsatellites that more closely match the assumptions of stepwise
      models.

PMID- 10353905
TI  - Genetic analysis of the bone morphogenetic protein-related gene, gbb, identifies
      multiple requirements during Drosophila development.
AB  - We have isolated mutations in the Drosophila melanogaster gene glass bottom boat
      (gbb), which encodes a TGF-beta signaling molecule (formerly referred to as 60A)
      with highest sequence similarity to members of the bone morphogenetic protein
      (BMP) subgroup including vertebrate BMPs 5-8. Genetic analysis of both null and
      hypomorphic gbb alleles indicates that the gene is required in many developmental
      processes, including embryonic midgut morphogenesis, patterning of the larval
      cuticle, fat body morphology, and development and patterning of the imaginal
      discs. In the embryonic midgut, we show that gbb is required for the formation of
      the anterior constriction and for maintenance of the homeotic gene Antennapedia
      in the visceral mesoderm. In addition, we show a requirement for gbb in the
      anterior and posterior cells of the underlying endoderm and in the formation and
      extension of the gastric caecae. gbb is required in all the imaginal discs for
      proper disc growth and for specification of veins in the wing and of macrochaete
      in the notum. Significantly, some of these tissues have been shown to also
      require the Drosophila BMP2/4 homolog decapentaplegic (dpp), while others do not.
      These results indicate that signaling by both gbb and dpp may contribute to the
      development of some tissues, while in others, gbb may signal independently of
      dpp.

PMID- 10353906
TI  - Mytilus mitochondrial DNA contains a functional gene for a tRNASer(UCN) with a
      dihydrouridine arm-replacement loop and a pseudo-tRNASer(UCN) gene.
AB  - A 2500-nucleotide pair (ntp) sequence of F-type mitochondrial (mt) DNA of the
      Pacific Rim mussel Mytilus californianus (class Bivalvia, phylum Mollusca) that
      contains two complete (ND2 and ND3) and two partial (COI and COIII) protein genes
      and nine tRNA genes is presented. Seven of the encoded tRNAs (Ala, Arg, His,
      Met(AUA), Pro, Ser(UCN), and Trp) have the potential to fold into the orthodox
      four-armed tRNA secondary structure, while two [tRNASer(AGN) and a second
      tRNASer(UCN)] will fold only into tRNAs with a dihydrouridine (DHU) arm
      replacement loop. Comparison of these mt-tRNA gene sequences with previously
      published, corresponding M. edulis F-type mtDNA indicates that similarity between
      the four-armed tRNASer(UCN) genes is only 63.8% compared with an average of 92.1%
      (range 86.2-98. 5%) for the remaining eight tRNA genes. Northern blot analysis
      indicated that mature tRNAs encoded by the DHU arm-replacement loop-containing
      tRNASer(UCN), tRNASer(AGN), tRNAMet(AUA), tRNATrp, and tRNAPro genes occur in M.
      californianus mitochondria, strengthening the view that all of these genes are
      functional. However, Northern blot and 5' RACE (rapid amplification of cDNA ends)
      analyses indicated that the four-armed tRNASer(UCN) gene is transcribed into a
      stable RNA that includes the downstream COI sequence and is not processed into a
      mature tRNA. On the basis of these observations the M. californianus and M.
      edulis four-armed tRNASer(UCN) sequences are interpreted as pseudo-tRNASer(UCN)
      genes.

PMID- 10353907
TI  - Among-locus variation in Fst: fish, allozymes and the Lewontin-Krakauer test
      revisited.
AB  - Variation among loci in the distribution of allele frequencies among
      subpopulations is well known; how to tell when the variation exceeds that
      expected when all loci are subject to uniform evolutionary processes is not well
      known. If locus-specific effects are important, the ability to detect those
      effects should vary with the level of gene flow. Populations with low gene flow
      should exhibit greater variation among loci in Fst than populations with high
      gene flow, because gene flow acts to homogenize allele frequencies among
      subpopulations. Here I use Lewontin and Krakauer's k statistic to describe the
      variance among allozyme loci in 102 published data sets from fishes. As
      originally proposed, k >> 2 was considered evidence that the variation in Fst
      among loci is greater than expected from neutral evolution. Although that
      interpretation is invalid, large differences in k in different populations
      suggest that locus-specific forces may be important in shaping genetic diversity.
      In these data, k is not greater for populations with expected low levels of gene
      flow than for populations with expected high levels of gene flow. There is thus
      no evidence that locus-specific forces are of general importance in shaping the
      distribution of allele frequencies at enzyme loci among populations of fishes.

PMID- 10353908
TI  - The causes of synonymous rate variation in the rodent genome. Can substitution
      rates be used to estimate the sex bias in mutation rate?
AB  - Miyata et al. have suggested that the male-to-female mutation rate ratio (alpha)
      can be estimated by comparing the neutral substitution rates of X-linked (X), Y
      linked (Y), and autosomal (A) genes. Rodent silent site X/A comparisons provide
      very different estimates from X/Y comparisons. We examine three explanations for
      this discrepancy: (1) statistical biases and artifacts, (2) nonneutral evolution,
      and (3) differences in mutation rate per germline replication. By estimating
      errors and using a variety of methodologies, we tentatively reject explanation 1.
      Our analyses of patterns of codon usage, synonymous rates, and nonsynonymous
      rates suggest that silent sites in rodents are evolving neutrally, and we can
      therefore reject explanation 2. We find both base composition and methylation
      differences between the different sets of chromosomes, a result consistent with
      explanation 3, but these differences do not appear to explain the observed
      discrepancies in estimates of alpha. Our finding of significantly low synonymous
      substitution rates in genomically imprinted genes suggests a link between
      hemizygous expression and an adaptive reduction in the mutation rate, which is
      consistent with explanation 3. Therefore our results provide circumstantial
      evidence in favor of the hypothesis that the discrepancies in estimates of alpha
      are due to differences in the mutation rate per germline replication between
      different parts of the genome. This explanation violates a critical assumption of
      the method of Miyata et al., and hence we suggest that estimates of alpha,
      obtained using this method, need to be treated with caution.

PMID- 10353909
TI  - Evidence of selection on silent site base composition in mammals: potential
      implications for the evolution of isochores and junk DNA.
AB  - It has been suggested that mutation bias is the major determinant of base
      composition bias at synonymous, intron, and flanking DNA sites in mammals. Here I
      test this hypothesis using population genetic data from the major
      histocompatibility genes of several mammalian species. The results of two tests
      are inconsistent with the mutation hypothesis in coding, noncoding, CpG-island,
      and non-CpG-island DNA, but are consistent with selection or biased gene
      conversion. It is argued that biased gene conversion is unlikely to affect silent
      site base composition in mammals. The results therefore suggest that selection is
      acting upon silent site G + C content. This may have broad implications, since
      silent site base composition reflects large-scale variation in G + C content
      along mammalian chromosomes. The results therefore suggest that selection may be
      acting upon the base composition of isochores and large sections of junk DNA.

PMID- 10353910
TI  - Intrachromosomal recombination between well-separated, homologous sequences in
      mammalian cells.
AB  - In the present study, we investigated intrachromosomal homologous recombination
      in a murine hybridoma in which the recipient for recombination, the haploid,
      endogenous chromosomal immunoglobulin mu-gene bearing a mutation in the constant
      (Cmu) region, was separated from the integrated single copy wild-type donor Cmu
      region by approximately 1 Mb along the hybridoma chromosome. Homologous
      recombination between the donor and recipient Cmu region occurred with high
      frequency, correcting the mutant chromosomal mu-gene in the hybridoma. This
      enabled recombinant hybridomas to synthesize normal IgM and to be detected as
      plaque-forming cells (PFC). Characterization of the recombinants revealed that
      they could be placed into three distinct classes. The generation of the class I
      recombinants was consistent with a simple unequal sister chromatid exchange
      (USCE) between the donor and recipient Cmu region, as they contained the three
      Cmu-bearing fragments expected from this recombination, the original donor Cmu
      region along with both products of the single reciprocal crossover. However, a
      simple mechanism of homologous recombination was not sufficient in explaining the
      more complex Cmu region structures characterizing the class II and class III
      recombinants. To explain these recombinants, a model is proposed in which unequal
      pairing between the donor and recipient Cmu regions located on sister chromatids
      resulted in two crossover events. One crossover resulted in the deletion of
      sequences from one chromatid forming a DNA circle, which then integrated into the
      sister chromatid by a second reciprocal crossover.

PMID- 10353911
TI  - Identification of quantitative trait loci influencing traits related to energy
      balance in selection and inbred lines of mice.
AB  - Energy balance is a complex trait with relevance to the study of human obesity
      and maintenance energy requirements of livestock. The objective of this study was
      to identify, using unique mouse models, quantitative trait loci (QTL) influencing
      traits that contribute to variation in energy balance. Two F2 resource
      populations were created from lines of mice differing in heat loss measured by
      direct calorimetry as an indicator of energy expenditure. The HB F2 resource
      population originated from a cross between a noninbred line selected for high
      heat loss and an inbred line with low heat loss. Evidence for significant QTL
      influencing heat loss was found on chromosomes 1, 2, 3, and 7. Significant QTL
      influencing body weight and percentage gonadal fat, brown fat, liver, and heart
      were also identified. The LH F2 resource population originated from noninbred
      lines of mice that had undergone divergent selection for heat loss. Chromosomes 1
      and 3 were evaluated. The QTL for heat loss identified on chromosome 1 in the HB
      population was confirmed in the LH population, although the effect was smaller.
      The presence of a QTL influencing 6-wk weight was also confirmed. Suggestive
      evidence for additional QTL influencing heat loss, percentage subcutaneous fat,
      and percentage heart was found for chromosome 1.

PMID- 10353912
TI  - Hybrid zones and the genetic architecture of a barrier to gene flow between two
      sunflower species.
AB  - Genetic analyses of reproductive barriers represent one of the few methods by
      which theories of speciation can be tested. However, genetic study is often
      restricted to model organisms that have short generation times and are easily
      propagated in the laboratory. Replicate hybrid zones with a diversity of
      recombinant genotypes of varying age offer increased resolution for genetic
      mapping experiments and expand the pool of organisms amenable to genetic study.
      Using 88 markers distributed across 17 chromosomes, we analyze the introgression
      of chromosomal segments of Helianthus petiolaris into H. annuus in three natural
      hybrid zones. Introgression was significantly reduced relative to neutral
      expectations for 26 chromosomal segments, suggesting that each segment contains
      one or more factors that contribute to isolation. Pollen sterility is
      significantly associated with 16 of these 26 segments, providing a
      straightforward explanation of why this subset of blocks is disadvantageous in
      hybrids. In addition, comparison of rates of introgression across colinear vs.
      rearranged chromosomes indicates that close to 50% of the barrier to
      introgression is due to chromosomal rearrangements. These results demonstrate the
      utility of hybrid zones for identifying factors contributing to isolation and
      verify the prediction of increased resolution relative to controlled crosses.

PMID- 10353913
TI  - A mutational analysis of leaf morphogenesis in Arabidopsis thaliana.
AB  - As a contribution to a better understanding of the developmental processes that
      are specific to plants, we have begun a genetic analysis of leaf ontogeny in the
      model system Arabidopsis thaliana by performing a large-scale screening for
      mutants with abnormal leaves. After screening 46,159 M2 individuals, arising from
      5770 M1 parental seeds exposed to EMS, we isolated 1926 M2 putative leaf mutants,
      853 of which yielded viable M3 inbred progeny. Mutant phenotypes were transmitted
      with complete penetrance and small variations in expressivity in 255 lines. Most
      of them were inherited as recessive monogenic traits, belonging to 94
      complementation groups, which suggests that we did not reach saturation of the
      genome. We discuss the nature of the processes presumably perturbed in the
      phenotypic classes defined among our mutants.

PMID- 10353914
TI  - Origin of gene overlap: the case of TCP1 and ACAT2.
AB  - The human acetyl-CoA acetyltransferase 2 gene, ACAT2, codes for a thiolase, an
      enzyme involved in lipid metabolism. The human T-complex protein 1 gene, TCP1,
      encodes a molecular chaperone of the chaperonin family. The two genes overlap by
      their 3'-untranslated regions, their coding sequences being located on opposite
      DNA strands in a tail-to-tail orientation. To find out how the overlap might have
      arisen in evolution, the homologous genes of the zebrafish, the African toad,
      caiman, platypus, opossum, and wallaby were identified. In each species, standard
      or long polymerase chain reactions were used to determine whether the ACAT2 and
      TCP1 homologs are closely linked and, if so, whether they overlap. The results
      reveal that the overlap apparently arose during the transition from therapsid
      reptiles to mammals and has been retained for >200 million years. Part of the
      overlapping untranslated region shows remarkable sequence conservation. The
      overlap presumably arose during the chromosomal rearrangement that brought the
      two unrelated and previously separated genes together. One or both of the
      transposed genes found by chance signals that are necessary for the processing of
      their transcripts to be present on the noncoding strand of the partner gene.

PMID- 10353915
TI  - Using maximum likelihood to estimate population size from temporal changes in
      allele frequencies.
AB  - We develop a maximum-likelihood framework for using temporal changes in allele
      frequencies to estimate the number of breeding individuals in a population. We
      use simulations to compare the performance of this estimator to an F-statistic
      estimator of variance effective population size. The maximum-likelihood estimator
      had a lower variance and smaller bias. Taking advantage of the likelihood
      framework, we extend the model to include exponential growth and show that
      temporal allele frequency data from three or more sampling events can be used to
      test for population growth.

PMID- 10353916
TI  - Maximum-likelihood estimation of migration rates and effective population numbers
      in two populations using a coalescent approach.
AB  - A new method for the estimation of migration rates and effective population sizes
      is described. It uses a maximum-likelihood framework based on coalescence theory.
      The parameters are estimated by Metropolis-Hastings importance sampling. In a two
      population model this method estimates four parameters: the effective population
      size and the immigration rate for each population relative to the mutation rate.
      Summarizing over loci can be done by assuming either that the mutation rate is
      the same for all loci or that the mutation rates are gamma distributed among loci
      but the same for all sites of a locus. The estimates are as good as or better
      than those from an optimized FST-based measure. The program is available on the
      World Wide Web at http://evolution.genetics. washington.edu/lamarc.html/.

PMID- 10353917
TI  - Overdominant alleles in a population of variable size.
AB  - An approximate method is developed to predict the number of strongly overdominant
      alleles in a population of which the size varies with time. The approximation
      relies on the strong-selection weak-mutation (SSWM) method introduced by J. H.
      Gillespie and leads to a Markov chain model that describes the number of common
      alleles in the population. The parameters of the transition matrix of the Markov
      chain depend in a simple way on the population size. For a population of constant
      size, the Markov chain leads to results that are nearly the same as those of N.
      Takahata. The Markov chain allows the prediction of the numbers of common alleles
      during and after a population bottleneck and the numbers of alleles surviving
      from before a bottleneck. This method is also adapted to modeling the case in
      which there are two classes of alleles, with one class causing a reduction in
      fitness relative to the other class. Very slight selection against one class can
      strongly affect the relative frequencies of the two classes and the relative ages
      of alleles in each class.

PMID- 10353919
TI  - Gene genealogies in geographically structured populations.
AB  - Population genetics theory has dealt only with the spatial or geographic pattern
      of degrees of relatedness or genetic similarity separately for each point in
      time. However, a frequent goal of experimental studies is to infer migration
      patterns that occurred in the past or over extended periods of time. To fully
      understand how a present geographic pattern of genetic variation reflects one in
      the past, it is necessary to build genealogy models that directly relate the two.
      For the first time, space-time probabilities of identity by descent and
      coalescence probabilities are formulated and characterized in this article.
      Formulations for general migration processes are developed and applied to
      specific types of systems. The results can be used to determine the level of
      certainty that genes found in present populations are descended from ancient
      genes in the same population or nearby populations vs. geographically distant
      populations. Some parameter combinations result in past populations that are
      quite distant geographically being essentially as likely to contain ancestors of
      genes at a given population as the past population located at the same place.
      This has implications for the geographic point of origin of ancestral, "Eve,"
      genes. The results also form the first model for emerging "space-time" molecular
      genetic data.

PMID- 10353918
TI  - Molecular evolution of a developmental pathway: phylogenetic analyses of
      transforming growth factor-beta family ligands, receptors and Smad signal
      transducers.
AB  - Intercellular signaling by transforming growth factor-beta (TGF-beta) proteins
      coordinates developmental decisions in many organisms. A receptor complex and
      Smad signal transducers are required for proper responses to TGF-beta signals. We
      have taken a phylogenetic approach to understanding the developmental
      evolutionary history of TGF-beta signaling pathways. We were interested in
      detecting evolutionary influences among the physically interacting multigene
      families encoding TGF-beta ligands, receptors, and Smads. Our analyses included
      new ligands and Smads identified from genomic sequence as well as the newest
      published family members. From an evolutionary perspective we find that (1) TGF
      beta pathways do not predate the divergence of animals, plants, and fungi; (2)
      ligands of the TGF-beta/activin subfamily likely originated after the divergence
      of nematodes and arthropods; (3) type I receptors from Caenorhabditis elegans are
      distinct from other receptors and may reflect an ancestral transitional state
      between type I and type II receptors; and (4) the Smad family appears to be
      evolving faster than, and independently of, ligands and receptors. From a
      developmental perspective we find (1) numerous phylogenetic associations not
      previously detected in each multigene family; (2) that there are unidentified
      pathway components that discriminate between type I and type II receptors; (3)
      that there are more Smads to be discovered in Drosophila and mammals; and (4)
      that the number of C-terminal serines is the best predictor of a Smad's role in
      TGF-beta signal transduction. We discuss these findings with respect to the
      coevolution of physically interacting genes.

PMID- 10353920
TI  - Genetic variation maintained in multilocus models of additive quantitative traits
      under stabilizing selection.
AB  - Stabilizing selection for an intermediate optimum is generally considered to
      deplete genetic variation in quantitative traits. However, conflicting results
      from various types of models have been obtained. While classical analyses
      assuming a large number of independent additive loci with individually small
      effects indicated that no genetic variation is preserved under stabilizing
      selection, several analyses of two-locus models showed the contrary. We perform a
      complete analysis of a generalization of Wright's two-locus quadratic-optimum
      model and investigate numerically the ability of quadratic stabilizing selection
      to maintain genetic variation in additive quantitative traits controlled by up to
      five loci. A statistical approach is employed by choosing randomly 4000 parameter
      sets (allelic effects, recombination rates, and strength of selection) for a
      given number of loci. For each parameter set we iterate the recursion equations
      that describe the dynamics of gamete frequencies starting from 20 randomly chosen
      initial conditions until an equilibrium is reached, record the quantities of
      interest, and calculate their corresponding mean values. As the number of loci
      increases from two to five, the fraction of the genome expected to be polymorphic
      declines surprisingly rapidly, and the loci that are polymorphic increasingly are
      those with small effects on the trait. As a result, the genetic variance expected
      to be maintained under stabilizing selection decreases very rapidly with
      increased number of loci. The equilibrium structure expected under stabilizing
      selection on an additive trait differs markedly from that expected under
      selection with no constraints on genotypic fitness values. The expected genetic
      variance, the expected polymorphic fraction of the genome, as well as other
      quantities of interest, are only weakly dependent on the selection intensity and
      the level of recombination.

PMID- 10353921
TI  - Antiangiogenic therapy of a recurrent giant cell tumor of the mandible with
      interferon alfa-2a.
AB  - We report a 5-year-old girl with a large rapidly growing giant cell tumor of the
      mandible that recurred 2 months after the first surgical excision and 3 months
      after a second resection. An angiogenic protein, (bFGF), was abnormally elevated
      in her urine. The patient was treated with interferon alfa-2a for 1 year because
      this agent inhibits angiogenesis by suppressing bFGF overexpression in infantile
      hemangiomas and in other human tumors. During this time the bone tumor regressed
      and disappeared, the urinary bFGF fell to normal levels, and the mandible
      regenerated. She has remained tumor-free and has been off therapy for 3 years at
      this writing. This first successful use of interferon alfa-2a to treat a
      mandibular tumor in a child demonstrates: 1) low grade tumors that overexpress
      bFGF may respond to interferon alfa-2a, in a manner similar to life-threatening
      infantile hemangiomas; 2) antiangiogenic therapy, given without interruption for
      1 year, was safe and effective in this patient; and 3) treatment may be continued
      for 1 year without the development of drug resistance.

PMID- 10353922
TI  - Feeding strategies for premature infants: beneficial outcomes of feeding
      fortified human milk versus preterm formula.
AB  - BACKGROUND: In a large-scale study of feeding strategies in premature infants
      (early vs later initiation of enteral feeding, continuous vs bolus tube-feeding,
      and human milk vs formula), the feeding of human milk had more effect on the
      outcomes measured than any other strategy studied. Therefore, this report
      describes the growth, nutritional status, feeding tolerance, and health of
      participating premature infants who were fed fortified human milk (FHM) in
      comparison with those who were fed exclusively preterm formula (PF). METHODS:
      Premature infants were assigned randomly in a balanced two-way design to early
      (gastrointestinal priming for 10 days) versus late initiation of feeding (total
      parenteral nutrition only) and continuous infusion versus intermittent bolus tube
      feeding groups. The type of milk was determined by parental choice and infants to
      receive their mother's milk were randomized separately from those to receive
      formula. The duration of the study spanned the entire hospitalization of the
      infant. To evaluate human milk versus formula feeding, we compared outcomes of
      infants fed >50 mL. kg-1. day-1 of any human milk (averaged throughout the
      hospitalization) with those of infants fed exclusively PF. Growth, feeding
      tolerance, and health status were measured daily. Serum indices of nutritional
      status were measured serially, and 72-hour nutrient balance studies were
      conducted at 6 and 9 weeks postnatally. RESULTS: A total of 108 infants were fed
      either >50 mL. kg-1. day-1 human milk (FHM, n = 62) or exclusively PF (n = 46).
      Gestational age (28 +/- 1 weeks each), birth weight (1.07 +/- 0.17 vs 1.04 +/-
      0.19 kg), birth length and head circumference, and distribution among feeding
      strategies were similar between groups. Infants fed FHM were discharged earlier
      (73 +/- 19 vs 88 +/- 47 days) despite significantly slower rates of weight gain
      (22 +/- 7 vs 26 +/- 6 g. kg-1. day-1), length increment (0.8 +/- 0.3 vs 1.0 +/-
      0.3 cm. week-1), and increment in the sum of five skinfold measurements (0.86 +/-
      0.40 vs 1.23 +/- 0.42 mm. week-1) than infants fed PF. The incidence of
      necrotizing enterocolitis and late-onset sepsis was less in the FHM group.
      Overall, there were no differences in any measure of feeding tolerance between
      groups. Milk intakes of infants fed FHM were significantly greater than those fed
      PF (180 +/- 13 vs 157 +/- 10 mL. kg-1. day-1). The intakes of nitrogen and copper
      were higher and magnesium and zinc were lower in group FHM versus PF. Fat and
      energy absorption were lower and phosphorus, zinc, and copper absorption were
      higher in group FHM versus PF. The postnatal retention (balance) surpassed the
      intrauterine accretion rate of nitrogen, phosphorus, magnesium, zinc, and copper
      in the FHM group, and of nitrogen, magnesium, and copper in the PF group.
      CONCLUSIONS: Although the study does not allow a comparison of FHM with
      unfortified human milk, the data suggest that the unique properties of human milk
      promote an improved host defense and gastrointestinal function compared with the
      feeding of formula. The benefits of improved health (less sepsis and necrotizing
      enterocolitis) associated with the feeding of FHM outweighed the slower rate of
      growth observed, suggesting that the feeding of FHM should be promoted actively
      in premature infants.

PMID- 10353923
TI  - Epidemiology of otitis media onset by six months of age.
AB  - OBJECTIVE: Although early otitis media (OM) onset predicts later recurrent and
      chronic OM, little research has been directed at illuminating the role of
      prenatal exposures in early OM. This prospective study examined prenatal, innate,
      and early environmental exposures associated with acute otitis media (AOM) onset
      and recurrent OM (ROM) by age 6 months. DESIGN AND METHODS: Prospective study of
      596 infants from a health maintenance organization followed from birth to 6
      months. Mothers completed monthly forms on prenatal exposures (diet, medications,
      and illnesses) and infant risk factors (eg, smoke exposure and child care) during
      pregnancy and until infants were 6 months old. Urine samples were collected when
      infants were 2 months of age and analyzed for cotinine and creatinine. Physicians
      and nurse practitioners examined infants at each clinic visit and completed
      standard ear examination forms. RESULTS: Thirty-nine percent had an episode of
      AOM and 20% had ROM by age 6 months. Using Cox's regression models to control for
      confounding, respiratory tract infection (relative risk [RR] 7.5), day care (RR
      1. 7), >1 sibling (RR 1.4), maternal, paternal, and sibling OM history (RR 1.6,
      1.5, and 1.7, respectively) were significantly related to early OM onset. ROM was
      related to respiratory tract infection (RR 9. 5), day care (RR 1.9),
      conjunctivitis (RR 2.0), maternal OM history (RR 1.9), and birth in the fall (RR
      2.6). Among prenatal exposures, only high prenatal dietary vitamin C intake was
      significantly inversely related to early AOM with univariate but not multivariate
      analysis. CONCLUSION: Prenatal factors were not linked to early AOM onset with
      multivariate analysis, but environmental and innate factors play an important
      role in early AOM onset. Strategies to reduce exposure to environmental variables
      could reduce rates of early AOM, which could potentially result in declining
      rates of ROM and chronic OME.

PMID- 10353924
TI  - Access for low-income children: is health insurance enough?
AB  - OBJECTIVE: The Balanced Budget Act of 1997 authorizes $20 billion for states to
      expand health insurance coverage among uninsured low-income children. This study
      identifies lessons learned from the Medicaid Extension Demonstration, which was
      authorized by Congress to experiment with innovative approaches to providing
      health care coverage for low-income children. The three programs compare and
      contrast a variety of features that may enhance or detract from access, including
      a traditional Medicaid expansion, a private indemnity model, and a comprehensive
      managed care delivery system. METHODOLOGY: Two waves of telephone surveys were
      conducted with a sample of parents of children participating in the Medicaid
      Extension Demonstration, and a comparison group of parents of children who were
      eligible but not participating. Descriptive and multivariate analyses were
      conducted to determine the impact of the demonstration on access to care.
      RESULTS: Compared with those who were uninsured, children in the managed care
      program were more likely to have a medical home and a physician visit and were
      less likely to have an emergency room visit, and had lower levels of unmet need.
      Outcomes across the other two demonstration programs were less favorable.
      CONCLUSIONS: This study suggests that simply providing a Medicaid card or private
      indemnity insurance card is not enough to ensure access to care. Future
      initiatives also need to consider the structure of the delivery system,
      especially the availability of a medical home (with adequate after-hours care),
      as well as the impact of discontinuous insurance coverage on access to and
      continuity of care.

PMID- 10353925
TI  - The relation of overweight to cardiovascular risk factors among children and
      adolescents: the Bogalusa Heart Study.
AB  - BACKGROUND: Although overweight and obesity in childhood are related to
      dyslipidemia, hyperinsulinemia, and hypertension, most studies have examined
      levels of these risk factors individually or have used internal cutpoints (eg,
      quintiles) to classify overweight and risk factors. OBJECTIVE: We used cutpoints
      derived from several national studies to examine the relation of overweight
      (Quetelet index, >95th percentile) to adverse risk factor levels and risk factor
      clustering. DESIGN: The sample consisted of 9167 5- to 17-year-olds examined in
      seven cross-sectional studies conducted by the Bogalusa Heart Study between 1973
      and 1994. RESULTS: About 11% of examined schoolchildren were considered
      overweight. Although adverse lipid, insulin, and blood pressure levels did not
      vary substantially with the Quetelet index at levels <85th percentile, risk
      factor prevalences increased greatly at higher levels of the Quetelet index.
      Overweight schoolchildren were 2.4 times as likely as children with a Quetelet
      index <85th percentile to have an elevated level of total cholesterol. Odds
      ratios for other associations were 2.4 (diastolic blood pressure), 3.0 (low
      density lipoprotein cholesterol), 3.4 (high-density lipoprotein cholesterol), 4.5
      (systolic blood pressure), 7.1 (triglycerides), and 12.6 (fasting insulin).
      Several of these associations differed between whites and blacks, and by age. Of
      the 813 overweight schoolchildren, 475 (58%) were found to have at least one risk
      factor. Furthermore, the use of overweight as a screening tool could identify 50%
      of schoolchildren who had two or more risk factors. CONCLUSIONS: Because
      overweight is associated with various risk factors even among young children, it
      is possible that the successful prevention and treatment of obesity in childhood
      could reduce the adult incidence of cardiovascular disease.

PMID- 10353926
TI  - Sociodemographic factors identify US infants at high risk of injury mortality.
AB  - OBJECTIVES: To identify sociodemographic predictors of infant injury mortality
      and to compare trends in injury mortality rates for high- and low-risk US infants
      from 1985 to 1991. DESIGN: Historical cohort. SETTING/STUDY PARTICIPANTS: The
      National Center for Health Statistics linked US infants (<1 year) born from 1985
      to 1991 with death certificates. MAIN OUTCOME MEASURES: Multivariate regression
      was used to identify sociodemographic factors associated with injury mortality.
      The adjusted relative risks (RRs) of maternal age, education, marital status,
      number of other children, and infant birth weight were used to categorize infants
      into risk groups. We compared trends in injury rates for the highest and lowest
      risk groups. RESULTS: There were 5963 injury deaths and 18.6 million infant years
      or 32.1 injury deaths per 100 000 infant years. Highest risk infants were born to
      mothers who were younger than 20 years compared with older than 30 years (RR,
      3.25; 95% CI, 2.92-3.63), had less than a high school education compared with a
      college education (RR, 2.22; 95% CI, 1.95-2.53), had more than 2 other children
      compared with no other children (RR, 3.15; 95% CI, 2.88-3.45), were unmarried
      (RR, 1.67; 95% CI, 1.57-1.78), or had birth weights </=1500 g compared with >2500
      g (RR, 3.36; 95% CI, 2.94-3.84). Infants in the highest risk group (21.0% of the
      population) had a >10-fold increased risk of injury mortality compared with the
      lowest risk group (18.1% of the population) and there was no evidence that this
      disparity was narrowing. CONCLUSIONS: Sociodemographic predictors of infant
      injury mortality include maternal age, education, number of other children,
      marital status, and infant birth weight. Based on these factors, 1 in 5 infants
      in the United States can be identified at birth as having a >10-fold increased
      risk of injury mortality compared with infants in lowest risk group. Programs to
      reduce injuries in these high-risk groups are urgently needed.

PMID- 10353927
TI  - Impact of simple screening criteria on utilization of low-yield bacterial stool
      cultures in a Children's Hospital.
AB  - OBJECTIVE: To determine diagnostic yield of stool cultures for Salmonella,
      Shigella, Campylobacter jejuni, Yersinia enterocolitica, and Escherichia coli
      O157:H7 (SSCYE) among hospitalized children and to develop guidelines for
      appropriate use of these tests. Setting. Tertiary care pediatric hospital.
      DESIGN: Computerized records from the Microbiology Laboratory from January 1992
      to December 1996 were reviewed retrospectively to collect data on the number of
      stool cultures performed in inpatients and outpatients, the length of hospital
      stay at the time cultures were sent, and diagnostic yield of cultures in
      hospitalized patients. A detailed review of medical records of all patients with
      a stool pathogen isolated after 3 days of hospitalization was also undertaken.
      The results from this retrospective analysis were used to develop guidelines to
      reduce unwarranted stool cultures and to educate medical care providers in the
      appropriate use of these tests. The impact of these guidelines on reduction in
      the volume of stool cultures performed on hospitalized patients was measured
      prospectively from January 1998 to June 1998. RESULTS: A total of 27 110 stool
      cultures for SSCYE were performed in the 5-year study period. Of the 14 125
      cultures from inpatients, 174 (1.2%) were positive. Among the cultures from
      inpatients, 9378 (66%) were from patients hospitalized for >3 days. Only 13
      (.14%) were positive. Of these 13 cultures, 4 represented nosocomial infections,
      whereas the remaining 9 cultures either were sent to document clearance from a
      patient known previously to be infected with an enteric pathogen (7), or were
      attributed to delayed testing in individuals admitted with a diarrheal illness
      (2). Introduction of guidelines to reject all SSCYE cultures from patients
      hospitalized for >3 days who did not meet specified criteria was associated with
      an overall reduction of 689 (43%) in the volume of tests performed in the 6-month
      period evaluated. This included 497 fewer cultures ordered and 192 cultures that
      were ordered but rejected because screening criteria were not met. Only 11 (5.4%)
      of 203 cultures sent >3 days after admission were processed because they met
      clinical criteria for testing. None were positive. Estimated cost savings were
      $50 163/year. CONCLUSIONS: Stool cultures for SSCYE among hospitalized patients
      have very low diagnostic yield and are extremely overutilized. Simple guidelines,
      such as rejecting (with few exceptions) cultures from patients hospitalized for
      >3 days, can reduce substantially such unnecessary testing.

PMID- 10353928
TI  - Sleep of children with enuresis: a polysomnographic study.
AB  - OBJECTIVE: To evaluate relationships between bladder voiding and sleep in
      children with enuresis. METHODS: Polysomnographic recordings were obtained from
      25 children, aged 7 to 17 years, with monosymptomatic nocturnal enuresis. During
      52 recorded nights, 37 enuretic events were detected. Responders (n = 7) and
      nonresponders (n = 16) to desmopressin treatment were compared. RESULTS: The mean
      latency between sleep onset and the first bladder voiding was 3 hours 20 minutes
      (SD = 2 hours 5 minutes). The number of voidings were 19, 7, 10, and 1 occurring
      during stages 2, 3, and 4, and rapid-eye movement sleep, respectively.
      Desmopressin responders were found to void during the early or late part of the
      night, whereas the voidings of the nonresponders were dispersed evenly throughout
      the night (chi2 = 8.09). CONCLUSIONS: The enuretic event is a predominantly non
      rapid eye movement sleep phenomenon. Responders and nonresponders to desmopressin
      treatment void during different parts of the night.

PMID- 10353930
TI  - Highly somatizing young adolescents and the risk of depression.
AB  - OBJECTIVE: To determine if high levels of somatization symptoms in 13- to 16-year
      olds from the general population predict risk of major depression and other
      psychiatric disorders 4 years later. METHOD: Cohort study, using interview and
      self-report survey data from the 1983 Ontario Child Health Study (OCHS) and 1987
      OCHS Follow-up. The study population included 1015 13- to 16-year-olds from the
      general community within Ontario. Baseline levels of somatization and emotional
      disorder were measured by the Survey Diagnostic Instrument, a checklist based on
      DSM-III criteria. Data were also collected for a range of sociodemographic
      factors, as well as the presence of chronic health problems. Major depression,
      anxiety disorders, and substance abuse and dependency at follow-up were measured
      using a self-administered questionnaire derived from the Diagnostic Interview
      Schedule. Bivariate and multiple logistic regression techniques were used to
      assess the relationship between high levels of somatization symptoms (>90th
      percentile) and later emotional morbidity, with adjustment for potential
      confounding factors, including gender and baseline disorders. RESULTS: Highly
      somatizing adolescents are at increased risk of major depression 4 years later,
      an association that is not explained by detectable emotional disorder at baseline
      or gender differences between groups. There is an important interaction between
      somatization and emotional disorder in predicting risk of major depression. It is
      primarily the group of 13- to 16-year-olds not recognized as being emotionally
      disordered at the initial OCHS survey in which somatization symptoms increased
      risk of later depression. The young teen with high levels of somatic complaints
      had as much risk of later depression as his/her peer with more typical symptoms
      of emotional disorder. Highly somatizing adolescents were also more likely to
      describe panic attacks at 4-year follow-up. There was no increased risk of
      substance abuse/dependency in the highly somatizing group or in generalized
      anxiety. CONCLUSIONS: High levels of somatic symptoms identified in young
      adolescents in the community represent a significant risk factor for major
      depression 4 years later, particularly in those individuals who do not present
      with more typical symptoms of emotional disorder. To detect the emergence of this
      serious emotional morbidity, adequate follow-up and continuity of care for these
      challenging patients are needed.

PMID- 10353929
TI  - Cost-effective imaging approach to the nonbilious vomiting infant.
AB  - OBJECTIVE: To develop a cost- and time-effective algorithm for differentiating
      hypertrophic pyloric stenosis (HPS) from other medical causes of emesis in
      infants referred from community-based pediatricians and family practitioners to
      the imaging department of a tertiary children's care facility. METHODS: Eighty
      nine vomiting infants (22 females, 67 males) between the ages of 11 and 120 days
      (mean, 43.5 days) had received nothing by mouth for at least 1 hour before the
      study. Each child was assessed for duration of vomiting, status of body weight,
      time and volume of last ingestion, and time of last emesis. A #8 French (Sherwood
      Medical, St Louis, MO) nasogastric feeding tube was placed in the child's
      stomach. The contents were aspirated and measured to determine likelihood of HPS.
      An aspirated volume >/=5 mL implicated gastric outlet obstruction, and
      ultrasonography (US) was performed. If this study was positive for HPS, the
      patient was referred for surgery. If US was negative, an upper gastrointestinal
      series (UGI) was performed. An aspirated stomach contents volume <5 mL suggested
      a medical cause for the emesis, and UGI was performed. Pediatric surgeons with no
      knowledge of the volume results palpated the abdomens of 73 of 89 infants (82%).
      RESULTS: Twenty-three of 89 patients (25%) had HPS. The aspirate criteria for HPS
      had a sensitivity of 91%, a specificity of 88%, and an accuracy of 89%. Of the
      false-positive studies (total = 8), six were related to recent significant
      ingestion (within 2 hours of the study), and two were attributable to antral
      dysmotility. The surgeons palpated the mass in 10 of 19 patients (53%).
      Sensitivity and specificity were 53% and 93%, respectively. Only 6 of 89 infants
      (7%) required both US and UGI to determine the etiology of the nonbilious
      vomiting. By performing the UGI in 66 patients, it was also found that 14% had
      slow gastric emptying and 79% had gastroesophageal reflux. Eighty-one percent of
      the gastroesophageal reflux was significant. CONCLUSION: The volumetric method of
      determining the proper imaging study is cost- and time-effective in the
      evaluation of the nonbilious vomiting infant for pyloric stenosis. If US was
      performed initially in all patients referred for imaging, two studies would have
      been performed in 68 of 89 patients (76%) to define the etiology of the emesis.
      Because we used the volumetric method, 62 fewer imaging studies were performed,
      representing a savings of $4464 and 30 hours of physician time. If children are
      given nothing by mouth for 3 to 4 hours before gastric aspiration, the
      specificity of the volumetric method improves to 94%, and the accuracy improves
      to 96%.

PMID- 10353931
TI  - Communicating bad news: a pediatric department's evaluation of a simulated
      intervention.
AB  - OBJECTIVE: To determine if pediatric residents and emergency department (ED)
      fellows could improve their ability to counsel and inform standardized patients
      (SPs) about bad news. METHODOLOGY: A crossover, self-controlled design in which
      trainees were their own control individuals, and SPs provided feedback after the
      first interview. The setting was the consultation room in the ED of a large
      children's hospital. The outcome measures included examining the counseling and
      informing skills of study participants. RESULTS: Trainees improved their
      informing skills after being provided feedback in the broad areas of
      communication and follow-up and in the total number of content areas asked. Their
      counseling skills improved in two areas: 1) promoting more trust and 2) making
      parents feel less dependent. Those trainees who scored higher on counseling
      skills discussed more total and critical content issues with SPs in the study.
      Trainee feedback revealed a very high rating of the educational process, and the
      trainees also felt much more confident about their skills after the first and
      second sessions. CONCLUSIONS: Using SPs to teach residents and ED fellows to give
      bad news is an effective educational process that provides trainees with
      interactions that simulate real-life experience

PMID- 10353932
TI  - Assessing immunization performance of private practitioners in Maine: impact of
      the assessment, feedback, incentives, and exchange strategy.
AB  - INTRODUCTION: A provider-based vaccination strategy that has strong supportive
      evidence of efficacy at raising immunization coverage level is known as
      Assessment, Feedback, Incentives, and Exchange. The Maine Immunization Program,
      and the Maine Chapter of the American Academy of Pediatrics collaborated on the
      implementation and evaluation of this strategy among private providers. METHODS:
      Between November 1994 and June 1996, the Maine Immunization Program conducted
      baseline immunization assessments of all private practices administering
      childhood vaccines to children 24 to 35 months of age. Coverage level assessments
      were conducted using the Clinic Assessment Software Application. Follow-up
      assessments were among the largest practices, delivering 80% of all vaccines.
      RESULTS: Of the 231 practices, 58 were pediatric and 149 were family practices.
      The median up-to-date vaccination coverages among all providers for 3 doses of
      diphtheria-tetanus-pertussis vaccine and 2 doses of oral polio vaccine, and 4
      doses of diphtheria-tetanus-pertussis vaccine, 3 doses of oral polio vaccine, and
      1 dose of measles-mumps-rubella vaccine at age 12 and 24 months were 90% and 78%,
      respectively, and did not vary by number of providers in a practice or by
      specialty. Urban practices had higher coverage than rural practices at 12 months
      (92% vs 88%). The median up-to-date coverage for 4 doses of diphtheria-tetanus
      pertussis vaccine, 3 doses of oral polio vaccine, and 1 dose of measles-mumps
      rubella vaccine at 24 months of age improved significantly among those practices
      assessed 1 year later (from 78% at baseline to 87% at the second assessment). On
      average, the assessments required 21/2 person-days of effort. CONCLUSIONS: We
      document the feasibility and impact of a public/private partnership to improve
      immunization delivery on a statewide basis. IMPLICATIONS: Other states should
      consider using public/private partnerships to conduct private practice
      assessments. More cost-effective methods of assessing immunization coverage
      levels in private practices are needed.

PMID- 10353933
TI  - Association of neonatal hyperbilirubinemia with bilirubin UDP
      glucuronosyltransferase polymorphism.
AB  - OBJECTIVE: The incidence of nonphysiologic neonatal hyperbilirubinemia is twice
      as high in East Asians as in whites. We studied whether the condition was
      associated with mutations in the gene for bilirubin uridine 5'-diphosphate
      glucuronosyltransferase (UGT1A1), a key enzyme of bilirubin catabolism. DESIGN:
      We analyzed the UGT1A1 gene in 25 Japanese neonates who had nonphysiologic
      hyperbilirubinemia (serum bilirubin >257 micromol/L) with no obvious cause. They
      had all received phototherapy. The background control population consisted of 50
      Japanese neonates whose transcutaneous jaundice index was monitored during the
      first week of life. We detected mutations by direct sequencing of polymerase
      chain reaction-amplified fragments of the gene. RESULTS: We found a polymorphism
      for UGT1A1 in exon 1; a G-->A transition at nucleotide 211 caused arginine to
      replace glycine at position 71 of corresponding protein product (G71R). The
      frequency of the mutated allele in the hyperbilirubinemic group (0.34) was
      significantly higher (chi2 = 5.56) than in the control group (0.16). In the
      control group the peak transcutaneous jaundice index of the carriers of G71R was
      significantly higher than it was in the normal infants. CONCLUSIONS: The missense
      mutation causing G71R is the first reported polymorphism for UGT1A1, and the
      mutation is a risk factor for nonphysiologic neonatal hyperbilirubinemia. The
      high incidence of hyperbilirubinemia in the Japanese may be attributable to the
      high frequency of this missense mutation.

PMID- 10353934
TI  - Once-daily gentamicin dosing in newborn infants.
AB  - OBJECTIVE: We developed a simplified gentamicin dosing protocol for all neonates
      using a loading dose and once-daily dosing that would have an equal or lower
      incidence of toxicity and an equal or improved effectiveness compared with a
      regimen with no loading dose that included use of divided daily dosing. METHODS:
      All neonatal intensive care unit patients with a postnatal age </=7 days and
      started on gentamicin therapy at the discretion of the attending neonatologist
      were evaluated in this comparative cohort study. All peak and trough serum drug
      levels (SDL), pertinent demographic data, and markers of potential
      nephrotoxicity, ototoxicity, and cure were tracked prospectively during 132
      consecutive, nonrandomized courses of therapy on a new gentamicin protocol. These
      were compared with data retrieved retrospectively throughout 103 consecutive,
      nonrandomized courses of therapy in a control group. RESULTS: Initial measured
      peak SDL were higher (7.8 +/- 1.1 microgram/mL vs 6.1 +/- 1.0 microgram/mL) and
      trough SDL were lower (0.9 +/- 0.2 microgram/mL vs 2.7 +/- 0.6 microgram/mL) in
      the protocol term subset, compared with the control term subset (gestational age,
      >/=37 weeks; weight, >/=2500 g). One hundred percent of the initial and
      maintenance peak SDL in term protocol neonates were 5 to 12 micrograms/mL;
      compared with 84% of the initial and 61% of maintenance peak SDL in the term
      control group. One hundred percent of the initial and maintenance trough SDL were
      in the desired range of <2 micrograms/mL in term protocol neonates; compared with
      70% of the initial and 94% of maintenance trough SDL in the term control group.
      No significant differences were found in any SDL in low birth weight neonates
      (gestational age <37 weeks or weight <2500 g and >1500 g) in the protocol
      compared with the control group. The very low birth weight (weight <1500 g)
      protocol neonates had a significantly higher mean initial trough SDL (2.3 +/- 0.7
      micrograms/mL vs 1.5 +/- 0.6 micrograms/mL) and a lower incidence of initial
      trough SDL <2.0 micrograms/mL (30% vs 95%) than very low birth weight neonates in
      the control group. No differences were seen between groups in incidence of
      significant rise in serum creatinine or failure of hearing screen. CONCLUSION: A
      loading dose followed by once-daily dosing was shown to result in SDL in the safe
      and therapeutic range in all term neonates in this study. In low birth weight
      neonates, this regimen resulted in peak and trough SDL throughout therapy that
      were similar to those observed in the control group. Delaying the initiation of
      maintenance once-daily dosing until 36 to 48 hours after the loading dose would
      be expected to result in a higher incidence of initial trough SDL in target range
      for very low birth weight neonates.

PMID- 10353935
TI  - Employment, child care, and mental health of mothers caring for children assisted
      by technology.
AB  - OBJECTIVE: This study examines 1) the way that children with chronic conditions
      are cared for at home and assisted by technology affects maternal employment and
      child care; 2) the social and clinical factors associated with the decision of a
      mother to quit employment to care for a child at home; and 3) the way in which
      care at home and the decision of a mother to quit a job affects maternal mental
      health. DESIGN: The 6-month postdischarge status of 70 mothers of children
      assisted by technology (study group) was compared with the 6-month postdischarge
      status of 58 mothers of children (matched for age and gender) hospitalized for
      acute illnesses (comparison group). Between January and December 1993, we
      gathered information on sociodemographic status, employment status and changes in
      employment, severity of the child's condition, child care and nursing services at
      home, family support, and maternal mental health. RESULTS: One third of mothers
      in the study group reported that they quit employment to take care of a child at
      home with only 37.1% remaining employed outside the home, compared with 69.0% of
      comparison group mothers. Single caretakers were 15 times more likely to quit
      employment compared with mothers in two-parent families. Availability of child
      care had an independent effect on a mother's decision to quit a job, whereas the
      severity of the child's condition did not. Child care hours were significantly
      lower in study group families and were provided mostly by relatives compared with
      day-care facilities and regular babysitters in comparison families. Family
      support was highest among employed mothers in both the study and the comparison
      groups and lowest in study group mothers who were neither employed currently nor
      before the child's illness or who had quit employment to care for the child.
      Family income was significantly lower in families with a child assisted by
      technology. Families in the study group had 20-fold higher uncompensated health
      care costs than did the comparison group. Mothers caring for a child assisted by
      technology reported less good mental health than did comparison group mothers,
      and employment seems to mediate this relationship. CONCLUSIONS: Caring for a
      child assisted by technology seems to create barriers to maternal employment
      diminishing family resources at a time when financial needs actually may
      increase. Lack of family support and child care services increase the likelihood
      that mothers of children assisted by technology will stay out of the labor force.
      Remaining employed buffers the negative effects of care at home on maternal
      mental health. Health policies for children with chronic health problems should
      address issues of financial burdens and the labor force participation of their
      caretakers.

PMID- 10353936
TI  - Hepatitis B vaccine administered to children and adolescents at yearly intervals.
AB  - OBJECTIVE: Hepatitis B vaccines are usually administered on a schedule of 0, 1 to
      2, and 6 months. Longer intervals between the second and third doses have been
      studied, but the effectiveness of hepatitis B vaccine administered at intervals
      of >2 months between the first and second doses have not been studied. Our
      objective was to compare the antibody response in recipients of Engerix-B
      hepatitis B vaccine administered at 12-month intervals to the response to vaccine
      administered at 0-, 1-, and 6-month intervals. METHODS: A total of 389 children,
      5 through 16 years of age, were randomized to receive Engerix-B (10 mg) at a
      schedule of either 0-, 1-, and 6-month intervals or 0-, 12-, and 24-month
      intervals. Blood was drawn before and 1 month after the third dose. RESULTS:
      Immediately before the third dose of vaccine, 92.3% of children who received
      vaccine on the 0-, 1-, and 6-month schedule and 88.8% of children who received
      the 0-, 12-, and 24-month schedule had antibody to hepatitis B surface (anti-HBs)
      antigen concentrations >/=10 mIU/mL. Of the children in the 0-, 1-, and 6-month
      schedule, 95% received the third dose according to protocol versus 90% of those
      in the 0-, 12-, 24-month schedule. The geometric mean anti-HBs concentration just
      before the third dose for recipients of the 0-, 1-, and 6-month schedule (117.9
      mIU/mL) was somewhat lower than that for the children who had received vaccine on
      the 0-, 12-, and 24-month schedule (162.1 mIU/mL). One month after the third
      dose, >98% of all children had anti-HBs concentrations >/=10 mIU/mL and high
      geometric mean antibody concentrations were observed in both groups: 5687 mIU/mL
      for children on the 0-, 1-, and 6-month schedule and 3159 mIU/mL for children on
      the 0-, 12-, and 24-month schedule. Body mass index was correlated inversely with
      final antibody concentration, but age was not a factor after adjustment for body
      mass index. DISCUSSION: Engerix-B administered on a 0-, 12-, and 24-month
      schedule is highly immunogenic. Providers should consider this alternate
      immunization schedule for children who are at low risk of immediate exposure to
      hepatitis B infections.

PMID- 10353937
TI  - Prevalence of IgA-antiendomysium and IgA-antigliadin autoantibodies at diagnosis
      of insulin-dependent diabetes mellitus in Swedish children and adolescents.
AB  - OBJECTIVE: This study was conducted to investigate the prevalence of celiac
      disease (CD) in children and adolescents at diagnosis of insulin-dependent
      diabetes mellitus (IDDM) before insulin treatment was started. MATERIAL AND
      METHODS: At diagnosis of IDDM, and before treatment was started, 115 children and
      adolescents were screened for IgA- antiendomysium (EMA) and IgA-antigliadin
      antibodies (AGA). Those found to be EMA-positive and/or AGA-positive were
      investigated further with intestinal biopsy. RESULTS: Of the 115 patients, 2 had
      known CD at diagnosis of IDDM; of the remainder of patients, 6% (7/113) were
      found to be EMA-positive and 9% (10/113) were found to have AGA levels above
      normal. Of the 6 patients who underwent biopsy, 5 manifested villous atrophy. In
      addition, 2 patients with high EMA and AGA antibody titers refused biopsy, and 4
      patients with low EMA and/or AGA titers were found to have normal titers at
      control before biopsy decision. CONCLUSION: Because the prevalence of CD at
      diagnosis of IDDM would seem to be 6% to 8%, screening for CD seems to be
      justified among patients with newly diagnosed IDDM.

PMID- 10353938
TI  - Language barriers and resource utilization in a pediatric emergency department.
AB  - BACKGROUND: Although an inability to speak English is recognized as an obstacle
      to health care in the United States, it is unclear how clinicians alter their
      diagnostic approach when confronted with a language barrier (LB). OBJECTIVE: To
      determine if a LB between families and their emergency department (ED) physician
      was associated with a difference in diagnostic testing and length of stay in the
      ED. DESIGN: Prospective cohort study. METHODS: This study prospectively assessed
      clinical status and care provided to patients who presented to a pediatric ED
      from September 1997 through December 1997. Patients included were 2 months to 10
      years of age, not chronically ill, and had a presenting temperature >/=38.5
      degrees C or complained of vomiting, diarrhea, or decreased oral intake.
      Examining physicians determined study eligibility and recorded the Yale
      Observation Score if the patient was <3 years old, and whether there was a LB
      between the physician and the family. Standard hospital charges were applied for
      each visit to any of the 22 commonly ordered tests. Comparisons of total charges
      were made among groups using Mann-Whitney U tests. Analysis of covariance was
      used to evaluate predictors of total charges and length of ED stay. RESULTS: Data
      were obtained about 2467 patients. A total of 286 families (12%) did not speak
      English, resulting in a LB for the physician in 209 cases (8.5%). LB patients
      were much more likely to be Hispanic (88% vs 49%), and less likely to be
      commercially insured (19% vs 30%). These patients were slightly younger (mean 31
      months vs 36 months), but had similar acuity, triage vital signs, and Yale
      Observation Score (when applicable). In cases in which a LB existed, mean test
      charges were significantly higher: $145 versus $104, and ED stays were
      significantly longer: 165 minutes versus 137 minutes. In an analysis of
      covariance model including race/ethnicity, insurance status, physician training
      level, attending physician, urgent care setting, triage category, age, and vital
      signs, the presence of a LB accounted for a $38 increase in charges for testing
      and a 20 minute longer ED stay. CONCLUSION: Despite controlling for multiple
      factors, the presence of a physician-family LB was associated with a higher rate
      of resource utilization for diagnostic studies and increased ED visit times.
      Additional study is recommended to explore the reasons for these differences and
      ways to provide care more efficiently to non-English-speaking patients.

PMID- 10353939
TI  - Growth, puberty, and endocrine functions in patients with sporadic or familial
      neurofibromatosis type 1: a longitudinal study.
AB  - OBJECTIVE: This study prospectively evaluates parameters of growth, puberty, and
      attained adult height in children with sporadic or familial occurrence of
      neurofibromatosis type 1 (NF-1), followed up longitudinally, to define the most
      important factors affecting these parameters. PATIENTS AND METHODS: The study was
      made up of 89 patients (55 boys, 34 girls) with sporadic (n = 45) or familial NF
      1 (13 affected fathers and 31 affected mothers). The average age at referral was
      8.9 years (range 8.5-15 years), and the average follow-up period was 8.5 years (6
      15 years). A total of 28 patients attained adult height at the time of the
      report. Anthropometric measurements and bone age determinations were performed at
      6- to 12-month intervals. As indicated, central nervous system (CNS) imaging was
      performed on 60 patients. Serum levels of thyroid stimulating hormone, free T4,
      lutheinizing hormone, follicle stimulating hormone, testosterone or estradiol,
      cortisol, and prolactin were measured in all patients periodically, and the
      pituitary growth hormone reserve was assessed in 32 short patients. RESULTS: CNS
      pathology was found in 23 of the 89 patients. A total of 6 patients required
      neurosurgery, and 2 patients had cranial irradiation. Of these patients, 3 were
      receiving recombinant growth hormone and thyroxin replacement therapy and 5
      patients with precocious puberty were treated with a gonadotropin-releasing
      hormone analog. All other patients had normal endocrine tests. Precocious puberty
      was recorded in 5 patients and was more common among the familial cases. The 5
      patients with precocious puberty also had CNS pathology. Short stature (<10th
      percentile) was observed in 25.5% of the patients during the prepubertal period
      with a significant gradual reduction of their relative height for age (standard
      scores) during puberty. Short adult height was noted in 12 (43%) of 28 patients,
      and only 50% of the 28 patients attained an adult height that was appropriate for
      their respective target height. Short stature was more common among patients with
      familial NF-1, particularly if the father was affected, and among those patients
      with CNS pathology. Parental short stature was observed in 39% of the mothers and
      in 33% of the fathers (59% and 54% among the affected parents, respectively).
      Tall stature (>90th percentile) was observed in 4 of 89 patients (4.5%), who all
      had CNS tumors. A highly significant correlation was found among all adult height
      predicting parameters (r =.79), and attained adult height was best correlated
      with the target height (r =.7; n = 28). CONCLUSIONS: Short adult height is an
      important characteristic of NF-1 and deserves to be emphasized in the evaluation
      and follow-up of these patients during childhood. Short adult height is strongly
      linked with familial background of NF-1, in particular if the affected parent is
      the father, and is affected adversely by the relatively poor pubertal growth.
      Despite normal pituitary gland and thyroid function tests in most children and
      adolescents with NF-1, increased incidence of precocious puberty was observed. As
      the clinical expression in the second generation is more pronounced, the
      underlying mechanism seems to be mediated by genetic factors that are yet
      undefined.

PMID- 10353940
TI  - Assessment of neonatal encephalopathy by amplitude-integrated
      electroencephalography.
AB  - OBJECTIVE: To define normal and abnormal patterns, test interobserver
      variability, and the prognostic accuracy of amplitude-integrated
      electroencephalography (aEEG) soon after the onset of neonatal encephalopathy.
      METHODS: Consecutive cases of neonatal encephalopathy (n = 56; gestation median,
      40; range, 35-42 weeks) and healthy infants (n = 14; gestation median, 40; range,
      39-40 weeks) were studied. aEEG was recorded using a cerebral function monitor,
      at median, 0, range, 0-21 days of age. Of the infants, 24 of the 56 with
      encephalopathy and all of the normal infants were studied within 12 hours of
      birth (median, 5; range, 3-12 hours). Forty infants were suspected of having
      suffered birth asphyxia. Criteria for normal and abnormal patterns were defined
      and the interobserver variability of these classifications determined. Results
      were compared with neurodevelopmental outcome assessed at 18 to 24 months of age.
      aEEG also was compared with a standard EEG and with magnetic resonance imaging.
      RESULTS: The median upper margin of the widest band of aEEG activity in the
      control infants was 37.5 microV (range, 30-48 microV), and median lower margin
      was 8 microV (range, 6.5-11 microV). We classified the aEEG background activity
      as normal amplitude, the upper margin of band of aEEG activity >10 microV and the
      lower margin >5 microV; moderately abnormal amplitude, the upper margin of band
      of aEEG activity >10 microV and the lower margin </=5 microV; and suppressed
      amplitude, the upper margin of the band of aEEG activity <10 microV and lower
      margin <5 microV. Recordings were analyzed further for the presence of seizures,
      defined as periods of sudden increase in voltage accompanied by a narrowing of
      the band of aEEG activity. Tests of interobserver variability showed excellent
      agreement both for assessment of amplitude (kappa statistic = 0.85) and for
      identification of seizures (kappa statistic = 0.76) There was a close
      relationship between the aEEG and subsequent outcome: 19 of 21 infants with a
      normal aEEG finding were normal on follow-up at 18 to 24 months of age, whereas
      27 of 35 infants with a moderately abnormal or suppressed aEEG and/or seizures
      died or developed neurologic abnormalities. Thus, aEEG predicted outcome with a
      sensitivity of 0. 93, a specificity of 0.70, positive predictive value of 0.77,
      negative predictive value of 0.90, and the likelihood ratio of a positive result
      of 3.1 and a negative result of 0.06. For the 24 infants studied within 12 hours
      of birth, the corresponding results were sensitivity, 1.0; specificity, 0.82;
      positive predictive value, 0.85; negative predictive value, 1; likelihood ratio
      of a positive result, 5.5; and likelihood ratio of a negative result, 0.18.
      CONCLUSION: The aEEG is a simple but accurate and reproducible clinical tool that
      could be useful in the assessment of infants with encephalopathy.

PMID- 10353941
TI  - Influenza immunization of schoolchildren: can we interrupt community epidemics?

PMID- 10353942
TI  - Interferon and giant cell tumors.

PMID- 10353943
TI  - Fatal cerebral herniation after lumbar puncture in a patient with a normal
      computed tomography scan.

PMID- 10353944
TI  - Accidental hymenal injury mimicking sexual trauma.

PMID- 10353945
TI  - Hypoglycemia and propranolol in pediatric behavioral disorders.

PMID- 10353947
TI  - Thalidomide responsiveness in an infant with Behcet's syndrome.
AB  - BACKGROUND: Behcet's syndrome is a chronic relapsing vasculitis characterized by
      aphthous stomatitis, genital ulcerations, and uveitis. The disease is a
      multisystem illness, which may involve the skin, joints, gastrointestinal tract,
      blood vessels, central nervous system, and other organs. CASE STUDY: We report a
      case of an infant with features of Behcet's syndrome who did not respond to
      conventional immunosuppression with high-dose corticosteroids and cytotoxic
      agents. Thalidomide, a potent immune response-modifying drug, was used with
      marked improvement and resolution of symptoms. CONCLUSION: This finding supports
      a trial of thalidomide treatment in patients with Behcet's syndrome who are
      unresponsive to other forms of immunosuppressive therapy or develop undesirable
      side effects.

PMID- 10353946
TI  - Fatal child abuse by forced water intoxication.
AB  - BACKGROUND: Although water intoxication leading to brain damage is common in
      children, fatal child abuse by forced water intoxication is virtually unknown.
      METHODS: During the prosecution of the homicide of an abused child by forced
      water intoxication, we reviewed all similar cases in the United States where the
      perpetrators were found guilty of homicide. In 3 children punished by forced
      water intoxication who died, we evaluated: the types of child abuse, clinical
      presentation, electrolytes, blood gases, autopsy findings, and the fate of the
      perpetrators. FINDINGS: Three children were forced to drink copious amounts of
      water (over 6 L). All had seizures, emesis, and coma, presenting to hospitals
      with hypoxemia (PO2 = 44 +/- 8 mm Hg) and hyponatremia (plasma Na = 112 +/- 2
      mmol/L). Although all showed evidence of extensive physical abuse, the history of
      forced water intoxication was not revealed to medical personnel, thus none of the
      3 children were treated for their hyponatremia. All 3 patients died and at
      autopsy had cerebral edema and aspiration pneumonia. The perpetrators of all
      three deaths by forced water intoxication were eventually tried and convicted.
      INTERPRETATION: Forced water intoxication is a new generally fatal syndrome of
      child abuse that occurs in children previously subjected to other types of
      physical abuse. Patients present with coma, hyponatraemia, and hypoxemia of
      unknown etiology. If health providers were made aware of the association, the
      hyponatremia is potentially treatable.

PMID- 10353948
TI  - History of military pediatrics: fifty years of training and deploying uniformed
      pediatricians.

PMID- 10353949
TI  - The Pediatrician's role in community pediatrics. American Academy of Pediatrics.
      Committee on Community Health Services.
AB  - This policy statement offers pediatricians a concise definition of community
      pediatrics and provides a set of specific recommendations that underscore the
      critical nature of this important dimension of the profession.

PMID- 10353951
TI  - Introduction.

PMID- 10353950
TI  - Practice parameter: long-term treatment of the child with simple febrile
      seizures. American Academy of Pediatrics. Committee on Quality Improvement,
      Subcommittee on Febrile Seizures.
AB  - The Committee on Quality Improvement, Subcommittee on Febrile Seizures, of the
      American Academy of Pediatrics, in collaboration with experts from the Section on
      Neurology, general pediatricians, consultants in the fields of child neurology
      and epilepsy, and research methodologists, developed this practice parameter.
      This guideline provides recommendations for the treatment of a child with simple
      febrile seizures. These recommendations are derived from a thorough search and
      analysis of the literature. The methods and results of the literature review can
      be found in the accompanying technical report. This guideline is designed to
      assist pediatricians by providing an analytic framework for the treatment of
      children with simple febrile seizures. It is not intended to replace clinical
      judgment or establish a protocol for all patients with this condition. It rarely
      will be the only appropriate approach to the problem. The technical report
      entitled "Treatment of the Child With Simple Febrile Seizures" provides in-depth
      information on the studies used to form guideline recommendations. A complete
      bibliography is included as well as evidence tables that summarize data extracted
      from scientific studies. This report also provides pertinent evidence on the
      individual therapeutic agents studied including study results and dosing
      information. Readers of this clinical practice guideline are urged to review the
      technical report to enhance the evidence-based decision-making process. The
      report is available on the Pediatrics electronic pages website at the following
      URL: http://www.pediatrics.org/cgi/content/full/103/6/e86.

PMID- 10353952
TI  - A review of bowel and bladder control development in children: how
      gastrointestinal and urologic conditions relate to problems in toilet training.

PMID- 10353953
TI  - Instruction, timeliness, and medical influences affecting toilet training.

PMID- 10353955
TI  - Toilet Training Guidelines: Parents-The Role of the Parents in Toilet Training.

PMID- 10353954
TI  - Toilet training methods, clinical interventions, and recommendations. American
      Academy of Pediatrics.

PMID- 10353957
TI  - Toilet Training Guidelines: Day Care Providers-The Role of the Day Care Provider
      in Toilet Training.

PMID- 10353956
TI  - Toilet Training Guidelines: Clinicians-The Role of the Clinician in Toilet
      Training.

PMID- 10353959
TI  - Promoting Community Pediatrics: recommendations from the Community Access to
      Child Health Evaluation.

PMID- 10353960
TI  - Community Access to Child Health (CATCH) in the historical context of Community
      Pediatrics.
AB  - OBJECTIVES: As part of the evaluation of the American Academy of Pediatrics (AAP)
      Community Access to Child Health (CATCH), to 1) identify, retrospectively, the
      actual chronology of activities undertaken through CATCH, and 2) review its
      antecedents within the AAP, and its predecessor program-Healthy Children.
      METHODS: Key informant telephone interviews with 14 national leaders in CATCH
      were conducted. Relevant program and administrative files and other documents
      were reviewed. AAP staff assisted the authors in preparing a detailed chronology
      of Healthy Children and CATCH activities and events from spring 1988 through
      summer 1996. RESULTS AND CONCLUSIONS: A decade of change in the AAP, under the
      acronym CATCH began in the late 1980s. The formation of the AAP's Partnership for
      Children and the Access to Care for Children Initiative, combined with the
      decision by the Robert Wood Johnson Foundation to transfer the funding of Healthy
      Children to the AAP, underpinned the changes. The Foundation's decision provided
      the resources and stimulus for the expansion and increased recognition of
      Community Pediatrics at the national AAP office, culminating in the establishment
      of the Department of Community Pediatrics in mid-1994. A national program of
      pediatrician-led, community-based programs and supportive services was launched,
      other resources were attracted, and a philosophical shift in defining the role of
      the pediatrician was put forward. A responsibility toward all children within the
      community was included in the role of the pediatrician, as well as caring for the
      individual child within a community context.

PMID- 10353961
TI  - Evaluation of the Community Access to Child Health Program.
AB  - OBJECTIVE: Increasing attention is being focused on the need for pediatricians to
      promote child health in their respective communities. The objective of this study
      was to evaluate, retrospectively, the American Academy of Pediatrics' Community
      Access to Child Health (CATCH) Program. STUDY DESIGN: Case studies of 12
      Community Pediatric projects in existence from 1989 to 1995 with varying degrees
      of involvement in the CATCH Program. In-person interviews were conducted with 17
      pediatricians, 3 CATCH leaders who were not pediatricians, 27 project advisory
      committee members, 42 project staff, 47 community partners, 22 public health
      representatives, and personnel in 13 affiliated institutions. RESULTS: These
      projects established or enhanced child health services. Although most
      pediatricians' interest in community child health preceded CATCH, mentoring,
      training, and peer support contributed to ongoing involvement. Community factors
      that facilitated project development included historical collaborative efforts
      and active public health agencies. However, across sites, significant barriers
      related to attitude and resource limitations were noted. Attitudinal barriers
      included both institutional concerns (eg, competition among providers or distrust
      among community agencies and organizations) and cultural concerns (eg, general
      negative perceptions of providers about Medicaid beneficiaries or of members of
      minority population toward medical or government establishments). CONCLUSIONS: In
      an era of devolution of responsibility to local communities, there are likely to
      be more opportunities for pediatricians to work with community members to promote
      child health. Specific strategies should be refined and expanded to support
      pediatricians' involvement in community-based activities, particularly because it
      is recognized that insurance alone will not guarantee children's health.

PMID- 10353962
TI  - Pediatrician-led community child health initiatives: case summaries from the
      evaluation of the community access to child health program.
AB  - OBJECTIVES: Case study investigations of projects identified with the Community
      Access to Child Health (CATCH) Program were conducted to illustrate the range of
      achievements of CATCH and to identify those elements related to successful or
      unsuccessful implementation. METHODS: We developed a purposive sample of 12
      projects, selected based on time of initiation (1989-1995), level of intensity of
      involvement in CATCH, project locus (statewide or local), nature of program
      service(s), project setting, and target population(s). Two investigators spent
      approximately 1.5 days at each site using a preestablished case study guide that
      included document review and multiple in-person interviews. A total of 171
      interviews were conducted with project leadership and staff, community and
      institutional partners, and public health officials. In seven communities, we
      also met with individuals receiving project services (consumers). RESULTS AND
      CONCLUSIONS: The premise of CATCH that with information, support, and tools,
      pediatricians can be agents of change in their communities was confirmed. The
      CATCH pediatricians with whom we met capitalize on their status in the community
      as physicians, their expertise, and their programmatic and political connections
      to create opportunities to expand and improve health and social services for
      children. The specific leadership of these pediatricians is often key in
      overcoming political and cultural barriers to implement system changes. CATCH was
      and continues to be an effective program strategy for stimulating and enhancing
      community-based child health initiatives.

PMID- 10353963
TI  - History of Community Pediatrics.

PMID- 10353964
TI  - Community access to child health and state policy.

PMID- 10353965
TI  - Academia's role in Community Access to Child Health.

PMID- 10353966
TI  - Advisory committee perspective.

PMID- 10353967
TI  - A foundation perspective on Community Access to Child Health Program.

PMID- 10353968
TI  - Reflection from the Department of Community Pediatrics.

PMID- 10353969
TI  - The cost of medical care for patients with cystic fibrosis in a health
      maintenance organization.
AB  - BACKGROUND: Cystic fibrosis (CF) is the most common life-shortening genetic
      disorder among white individuals worldwide. Previous estimates of the costs of
      medical care have been based on expert opinion rather than observed costs.
      Accurate cost estimates are needed to enable evaluation of the cost-effectiveness
      of new interventions and prenatal genetic screening recommendations. OBJECTIVE:
      To evaluate the cost of medical care for patients (N = 136) served by a health
      maintenance organization with a CF center. METHODS: Retrospective analysis of
      data from computerized cost databases and the Cystic Fibrosis Foundation annual
      survey. Severity of disease was classified based on the percent predicted forced
      expiratory volume at 1 second. RESULTS: The annual cost of medical care in 1996
      averaged $13 300 and ranged from $6200 among patients with mild disease to $43
      300 among patients with severe disease. Of total costs, 47% were from
      hospitalization, 18% were from DNase (Pulmozyme), 12% were from clinic visits,
      and 10% were from outpatient antibiotics. When the observed costs were used to
      estimate the costs of medical care for the entire population of CF patients in
      the United States, these costs were estimated to be $314 million per year in 1996
      dollars. CONCLUSIONS: We conclude that the cost of medical care for CF varies
      greatly with severity but is substantial even among patients with mild disease.
      These findings underscore the need for strategies to ensure good health insurance
      coverage and high quality care for all individuals with this condition.

PMID- 10353970
TI  - Potential cost savings attributable to influenza vaccination of school-aged
      children.
AB  - OBJECTIVE: To analyze the costs and benefits of influenza vaccination of healthy
      school-aged children. DESIGN: The analysis was based on data from the literature.
      Total costs included direct medical costs for vaccination, physician visits, and
      treatment as well as indirect costs. Indirect costs were in the form of lost
      productivity when working parents stayed home to care for ill children or to take
      children to an office for vaccination. The total costs of vaccination strategies
      were compared with the total cost of not vaccinating. For the base case, the
      vaccine was assumed to have no effect on rates of otitis media. SETTING: Two
      hypothetical scenarios were investigated 1) individual-initiated vaccination and
      2) vaccination in a group-based setting. The former scenario required the child
      to be accompanied to a clinic by a parent during usual work hours. RESULTS:
      Vaccination resulted in a net savings per child vaccinated of $4 for individual
      initiated vaccination and of $35 for group-based vaccination. The savings were
      caused primarily by averted indirect costs. Moderate increases in the cost of
      vaccination or reductions in the rate of influenza would eliminate the savings
      for individual-initiated vaccination but not for group-based vaccination.
      Alternatively, if influenza vaccination was effective in reducing rates of otitis
      media, the net savings from vaccination would be substantially higher than the
      base case. CONCLUSION: Vaccination of school-aged children against influenza
      could have substantial financial benefits to society, especially if performed in
      a group-based setting. influenza, cost-effectiveness, vaccination, children,
      cost.

PMID- 10353971
TI  - Epidemiology and prevention of traffic injuries to urban children and
      adolescents.
AB  - OBJECTIVES: To describe the incidence of severe traffic injuries before and after
      implementation of a comprehensive, hospital-initiated injury prevention program
      aimed at the prevention of traffic injuries to school-aged children in an urban
      community. MATERIALS AND METHODS: Hospital discharge and death certificate data
      on severe pediatric injuries (ie, injuries resulting in hospital admission and/or
      death to persons age <17 years) in northern Manhattan over a 13-year period (1983
      1995) were linked to census counts to compute incidence. Rate ratios with 95%
      CIs, both unadjusted and adjusted for annual trends, were calculated to test for
      a change in injury incidence after implementation of the Harlem Hospital Injury
      Prevention Program. This program was initiated in the fall of 1988 and continued
      throughout the study period. It included 1) school and community based traffic
      safety education implemented in classroom settings in a simulated traffic
      environment, Safety City, and via theatrical performances in community settings;
      2) construction of new playgrounds as well as improvement of existing playgrounds
      and parks to provide expanded off-street play areas for children; 3) bicycle
      safety clinics and helmet distribution; and 4) a range of supervised recreational
      and artistic activities for children in the community. PRIMARY RESULTS: Traffic
      injuries were a leading cause of severe childhood injury in this population,
      accounting for nearly 16% of the injuries, second only to falls (24%). During the
      preintervention period (1983-1988), severe traffic injuries occurred at a rate of
      147.2/100 000 children <17 years per year. Slightly <2% of these injuries were
      fatal. Pedestrian injuries accounted for two thirds of all severe traffic
      injuries in the population. Among school-aged children, average annual rates (per
      100 000) of severe injuries before the intervention were 127.2 for pedestrian,
      37.4 for bicyclist, and 25.5 for motor vehicle occupant injuries. Peak incidence
      of pedestrian and bicyclist injuries occurred during the summer months and
      afternoon hours, whereas motor vehicle occupant injuries showed little seasonal
      variation and were more common during evening and night-time hours. Age-specific
      rates showed peak incidence of pedestrian injuries among 6- to 10-year-old
      children, of bicyclist injuries among 9- to 15-year-old children, and of motor
      vehicle occupant injuries among adolescents between the ages of 12 and 16 years.
      The peak age for all traffic injuries combined was 15 years, an age at which
      nearly 3 of every 1000 children each year in this population sustained a severe
      traffic injury. Among children hospitalized for traffic injuries during the
      preintervention period, 6.3% sustained major head trauma (including concussion
      with loss of consciousness for >/=1 hour, cerebral laceration and/or cerebral
      hemorrhage), and 36.9% sustained minor head trauma (skull fracture and/or
      concussion with no loss of consciousness >/=1 hour and no major head injury). The
      percentage of injured children with major and minor head trauma was higher among
      those injured in traffic than among those injured by all other means (43.2% vs
      14.2%, respectively; chi2 = 336; degrees of freedom = 1). The percentages of
      children sustaining head trauma were 45.4% of those who were injured as
      pedestrians, 40.2% of those who were injured as bicyclists, and 38.9% of those
      who were injured as motor vehicle occupants. During the intervention period, the
      average incidence of traffic injuries among school aged children declined by 36%
      relative to the preintervention period (rate ratio:.64; 95% CI:.58,.72). After
      adjusting for annual trends in incidence, pedestrian injuries declined during the
      intervention period among school aged children by 45% (adjusted rate ratio:.55;
      95% CI:.38,.79). No comparable reduction occurred in nontargeted injuries among
      school-aged children (adjusted rate ratio:.89; 95% CI:.72, 1.09) or in traffic
      injuries among younger children who

PMID- 10353972
TI  - Socioeconomic variation in asthma hospitalization: excess utilization or greater
      need?
AB  - OBJECTIVE: To assess the hypothesis that higher incidence of severe acute asthma
      exacerbation, not lower severity threshold for admission, explains the difference
      between the asthma hospitalization rates of inner-city and suburban children.
      METHODS: All 2028 asthma hospitalizations between 1991 and 1995 for children
      (aged >1 month and <19 years) dwelling in Rochester, New York, were analyzed. ZIP
      codes defined residences as inner-city, other urban, or suburban. Based
      principally on the worst oxygen saturation (SaO2) during the first 24 hours of
      hospitalization, severity was examined by hospital record review (n = 443) of
      random samples of inner-city, other urban, and suburban asthma admissions.
      RESULTS: Large inner-city/suburban differences were noted in many
      sociodemographic attributes, and there was also a distinct, stepwise gradient in
      risk factors in moving from the suburbs to other urban areas and to the inner
      city. Racial and economic segregation was particularly striking. Black
      individuals accounted for 62% of inner-city births versus <3% in the suburbs.
      Medicaid covered 65% of inner-city births, whereas Medicaid covered only 6% of
      suburban births. The overall asthma hospitalization rate was 2.04 admissions/1000
      child-years. Children <24 months old, those most commonly hospitalized for
      asthma, were fourfold more likely to be hospitalized (OR: 3.97, 95% CI: 3. 44
      4.57) than children between the ages of 13 and 18 years. The hospitalization rate
      of asthma in boys was almost twice the rate of asthma in girls. The greatest
      gender difference was observed among children who were <24 months old. For these
      children, the rate for boys was 6.10/1000 child-years compared with 2.65/1000
      child-years for girls (OR: 2.31, 95% CI: 1.95-3.03). This gender difference
      diminished gradually in older age groups to the extent that there was no
      difference among girls and boys between the ages of 13 and 18 years (males,
      1.12/1000 child-years vs females, 1.09/1000 child-years). Based on worst SaO2
      values, mild (worst SaO2 >/=95%), moderate (90%-94%), and severe (<90%)
      admissions constituted 10.3%, 41.9%, and 47.7% of all hospitalizations,
      respectively. Although rates within the community followed a distinct geographic
      pattern of suburban (1.05/1000 child-years) < other urban (2.99/1000 child-years)
      < inner-city (5.21/1000 child-years), the proportions of admissions with low
      severity did not vary among areas. Likewise, the proportions of admissions that
      were severe (SaO2 <90%) were not significantly different (44.8, 45.7, and 52.1%
      for suburban, other urban, and inner-city areas, respectively). The distributions
      of asthma severity, measured by the duration of frequent nebulized bronchodilator
      treatments and the length of hospital stay, were also similar among children from
      different socioeconomic areas. CONCLUSION: The marked socioeconomic and racial
      disparity in Rochester's asthma hospitalization rates is largely attributable to
      higher incidence of severe acute asthma exacerbations among inner-city children;
      it signals greater need, not excess utilization. Both adverse environmental
      conditions and lower quality primary care might explain the higher incidence.
      Interventions directed at the environment offer the possibility of primary
      prevention, whereas primary care directed at asthma is focused on secondary
      prevention, principally on improved medication use. Higher hospitalization rates
      cannot be assumed to identify opportunities for cost reduction. The extent to
      which our observations about asthma hold true under other conditions and in other
      communities warrants systematic attention. Knowledge of when higher rates signal
      excess utilization and when, instead, they signify greater needs should guide
      equitable national health policy.

PMID- 10353973
TI  - Preventing early-onset group B streptococcal sepsis: strategy development using
      decision analysis.
AB  - OBJECTIVE: To evaluate recommended strategies for prevention of early-onset group
      B streptococcal infections (EOGBS) with reference to strategies optimized using
      decision analysis. METHODS: The EOGBS attack rate, prevalence and odds ratios for
      risk factors, and expected effects of prophylaxis were estimated from published
      data. Population subgroups were defined by gestational age, presence or absence
      of intrapartum fever or prolonged rupture of membranes, and presence or absence
      of maternal group B streptococcus (GBS) colonization. The EOGBS prevalence in
      each subgroup was estimated using decision analysis. The number of EOGBS cases
      prevented by an intervention was estimated as the product of the expected
      reduction in attack rate and the number of expected cases in each group selected
      for treatment. For each strategy, the number of residual EOGBS cases, cost, and
      numbers of treated patients were calculated based on the composition of the
      prophylaxis group. Integrated obstetrical-neonatal strategies for EOGBS
      prevention were developed by targeting the subgroups expected to benefit most
      from intervention. RESULTS: Reductions in EOGBS rates predicted by this decision
      analysis were smaller than those previously estimated for the strategies proposed
      by the American Academy of Pediatrics in 1992 (32.9% vs 90.7%), the American
      College of Obstetricians and Gynecologists in 1992 (53.8% vs 88.8%), and the
      Centers for Disease Control and Prevention in 1996 (75.1% vs 86.0%). Strategies
      based on screening for GBS colonization with rectovaginal cultures at 36 weeks or
      on use of a rapid test to screen for GBS colonization on presentation for
      delivery, combining intrapartum prophylaxis for selected mothers and postpartum
      prophylaxis for some of their infants, would require treatment of fewer patients
      and prevent more cases (78.4% or 80.1%, respectively) at lower cost. CONCLUSIONS:
      No strategy can prevent all EOGBS cases, but the attack rate can be reduced at a
      cost <$12 000 per prevented case. Supplementing intrapartum prophylaxis with
      postpartum ampicillin in a few infants is more effective and less costly than
      providing intrapartum prophylaxis for more mothers. Better intrapartum screening
      tests offer the greatest promise for increasing efficacy. Integrated obstetrical
      and neonatal regimens appropriate to the population served should be adopted by
      each obstetrical service. Surveillance of costs, complications, and benefits will
      be essential to guide continued iterative improvement of these strategies.

PMID- 10353974
TI  - Risk factors for early-onset group B streptococcal sepsis: estimation of odds
      ratios by critical literature review.
AB  - OBJECTIVE: To identify and to establish the prevalence of ORs factors associated
      with increased risk for early-onset group B streptococcal (EOGBS) infection in
      neonates. streptococcal (EOGBS) infection in neonates. STUDY DESIGN: Literature
      review and reanalysis of published data. RESULTS: Risk factors for EOGBS
      infection include group B streptococcal (GBS)-positive vaginal culture at
      delivery (OR: 204), GBS-positive rectovaginal culture at 28 (OR: 9.64) or 36
      weeks gestation (OR: 26. 7), vaginal Strep B OIA test positive at delivery (OR:
      15.4), birth weight </= 2500 g (OR: 7.37), gestation <37 weeks (OR: 4.83),
      gestation <28 weeks (OR: 21.7), prolonged rupture of membranes (PROM) >18 hours
      (OR: 7.28), intrapartum fever >37.5 degrees C (OR: 4.05), intrapartum fever,
      PROM, or prematurity (OR: 9.74), intrapartum fever or PROM at term (OR: 11.5),
      chorioamnionitis (OR: 6.43). Chorioamnionitis is reported in most (88%) cases in
      which neonatal infection occurred despite intrapartum maternal antibiotic
      therapy. ORs could not be estimated for maternal GBS bacteriuria during
      pregnancy, with preterm premature rupture of membranes, or with a sibling or twin
      with invasive GBS disease, but these findings seem to be associated with a very
      high risk. Multiple gestation is not an independent risk factor for GBS
      infection. CONCLUSIONS: h Mothers with GBS bacteriuria during pregnancy, with
      another child with GBS disease, or with chorioamnionitis should receive empirical
      intrapartum antibiotic treatment. Their infants should have complete diagnostic
      evaluations and receive empirical treatment until infection is excluded by
      observation and negative cultures because of their particularly high risk for
      EOGBS infection. Either screening with cultures at 28 weeks gestation or
      identification of clinical risk factors, ie, PROM, intrapartum fever, or
      prematurity, may identify parturients whose infants include 65% of those with
      EOGBS infection. Intrapartum screening using the Strep B OIA rapid test
      identifies more at-risk infants (75%) than any other method. These risk
      identifiers may permit judicious selection of patients for prophylactic
      interventions.

PMID- 10353975
TI  - Antimicrobial prevention of early-onset group B streptococcal sepsis: estimates
      of risk reduction based on a critical literature review.
AB  - OBJECTIVE: To identify interventions that reduce the attack rate for early-onset
      group B streptococcal (GBS) sepsis in neonates. STUDY DESIGN: Literature review
      and reanalysis of published data. RESULTS: The rate of early-onset GBS sepsis in
      high-risk neonates can be reduced by administration of antibiotics. Treatment
      during pregnancy (antepartum prophylaxis) fails to reduce maternal GBS
      colonization at delivery. With the administration of intravenous ampicillin, the
      risk of early-onset infection in infants born to women with preterm premature
      rupture of membranes is reduced by 56% and the risk of GBS infection is reduced
      by 36%; addition of gentamicin may increase the efficacy of ampicillin. Treatment
      of women with chorioamnionitis with ampicillin and gentamicin during labor
      reduces the likelihood of neonatal sepsis by 82% and reduces the likelihood of
      GBS infection by 86%. Universal administration of penicillin to neonates shortly
      after birth (postpartum prophylaxis) reduces the early-onset GBS attack rate by
      68% but is associated with a 40% increase in overall mortality and therefore is
      contraindicated. Intrapartum prophylaxis, alone or combined with postnatal
      prophylaxis for the infants, reduces the early-onset GBS attack rate by 80% or
      95%, respectively. CONCLUSIONS: Women with chorioamnionitis or premature rupture
      of membranes and their infants should be treated with intravenous ampicillin and
      gentamicin. Intrapartum antimicrobial prophylaxis may be appropriate for other
      women whose infants are at increased but less extreme risk, and supplemental
      postpartum prophylaxis may be indicated for some of their infants. Selection of
      appropriate candidates and prophylaxis strategies requires careful consideration
      of costs and benefits for each patient. group B streptococcus, neonatal sepsis,
      early-onset sepsis, prevention, prophylaxis.

PMID- 10353976
TI  - Efficacy of parental application of eutectic mixture of local anesthetics for
      intravenous insertion.
AB  - OBJECTIVE: To demonstrate that parent application of eutectic mixture of local
      anesthetics (EMLA) results in equal reduction of the pain of intravenous (IV)
      placement compared with clinician application of EMLA, and to assess potential
      difficulties with parental application. STUDY DESIGN: A 2 x 2 randomized block
      design was used, with 41 children divided into two age groups (5-12 years vs 13
      18 years) and randomized to one of two experimental groups (parent-applied EMLA
      vs clinician-applied EMLA). METHODS: All children were scheduled to have
      outpatient gastrointestinal endoscopies with IV sedation. EMLA was placed at
      least 60 minutes before IV insertion either by the parent or a clinician,
      depending on the experimental group assignment. Outcome measures were child pain
      ratings and observed behavioral distress ratings. Parents and children were
      interviewed to determine parent and child anxiety levels in anticipation of the
      IV insertion, previous needle stick experience, and previous difficulty coping.
      Feasibility outcomes included technical difficulty with application of EMLA and
      appearance of the EMLA cream and occlusive covering. RESULTS: Pain ratings and
      behavioral distress ratings in the low to moderate range for all groups and ws
      and were consistent w previous empiric reports of EMLA outcome. There were no
      significant differences in pain or distress ratings for either the age or the
      experimental groups. Parent ratings of their child's previous difficulty coping
      was related to the level of behavioral distress exhibited before (r =.50), during
      (r =.32) and after (r =.44) the IV insertion. In addition, children's anxiety
      ratings about IV insertion seemed to differ among groups (although not
      statistically significant for post hoc comparisons), with the most anxiety
      reported by the younger children when clinicians applied the EMLA and by older
      children when parents applied the EMLA. CONCLUSION: Parent application of EMLA
      appears to be as effective as clinician application in reducing children's pain
      and distress associated with IV insertion. Permitting parents to apply the EMLA
      at home can allow children who are having procedures on an outpatient basis to
      benefit from topical anesthesia without having to arrive early to the clinic or
      hospital. Additionally, application by parents may result in less anticipatory
      anxiety for younger children.

PMID- 10353977
TI  - School start and occurrence of headache.
AB  - OBJECTIVES: The purpose of the study was to examine the occurrence of childhood
      headache at the start of school. STUDY DESIGN: An unselected population-based
      population-based questionnaire study on the occurrence of headache was conducted
      in 1433 children between the ages of 6 and 7 years old (ranging from 6 years 8
      months to 7 years 8 months) who started school in 1992. The first questionnaire
      was given within 3 months of school entry in 1992. Of 1433 children, 1290
      responded satisfactorily to the second headache questionnaire at the end of the
      second school year. The children (n = 725) who had had headache in 1994 were sent
      a more detailed questionnaire concerning risk factors of headache. RESULTS: A
      significant increase in the incidence density of overall headache in children was
      found during the first 12 school months compared with the 6 months immediately
      before school started or with the subsequent 6 school months (13th-18th month).
      The increase was attributable to occasional headache. During the first school
      months, the frequency of headache increased in 20% of children who had had
      headache before the 6 months preceding the start of school. The mothers and
      fathers of 129 children who started to have headache after school entry had a
      higher socioeconomic status than the mothers and fathers of children who had
      headache before the start of school. No significant difference in family history
      of headache or school-related factors was found among children. Predictably, the
      incidence density of recurrent headache after school start was higher than before
      school start. However, occasional headache showed a distinct peak at school start
      but regained its initial level at the end of the second school year. CONCLUSION:
      School start appears to increase the incidence of overall headache (occasional
      headache in particular) in children, independent of other factors.

PMID- 10353978
TI  - Prehospital emergency care for children at school and nonschool locations.
AB  - OBJECTIVE: The purpose of this study was to ascertain whether school-based
      emergency medical services (EMS) incidents are different from nonschool-based EMS
      incidents for school-aged children. METHODS: We examined South Dakota EMS
      incident reports involving children ages 5 to 18 years old from 1994 through 1996
      (n = 12603). Patient characteristics, dispatch reason, primary medical complaint,
      injury type, contributing factor of injury, and performed interventions were
      analyzed. RESULTS: During the study period, there were 140455 total EMS incident
      reports, of which 12603 (9.0%) were for school-aged children. EMS dispatches to a
      school represented 755 (6.0%) of all EMS incidents for school-aged children. The
      number of school-based EMS incidents was highest at the beginning of the school
      year, whereas the number of nonschool-based EMS incidents was highest during the
      summer months. School-based EMS incidents peaked at noon, whereas nonschool-based
      EMS incidents peaked after school. For both locations, the average age of the
      patient was 14 years old. The dispatch reason for school-based EMS incidents
      differed from those for nonschool-based EMS incidents. The top three school-based
      EMS dispatch reasons were falls (36.2%), other trauma (27.0%), and medical
      illness (24.5%). Motor vehicle crashes (30.8%), medical illness (26.2%), and
      other trauma (11.4%) were the leading nonschool-based EMS dispatch reasons.
      Injuries accounted for a significantly greater proportion of school-based than
      nonschool-based EMS incidents (70.7% vs 62.6%). Excluding pain, the most frequent
      type of injury was a fracture or dislocation in school-based EMS incidents and
      open soft-tissue injury in nonschool-based EMS incidents. A total of 11 students
      sustained an injury resulting in paralysis. The body region that was most
      commonly injured was a lower extremity (23%) in school-based incidents, whereas
      the head was the most commonly injured body region in nonschool-based incidents
      (20%). Sports were the largest contributing factor in school-based incidents,
      whereas alcohol/drug use was the largest contributing factor in nonschool-based
      EMS incidents among school-aged children. A medical illness was the primary
      complaint for 206 (27.3%) of the school-based incidents and 3599 (30.4%) of the
      nonschool-based incidents. The chief medical complaints were breathing difficulty
      (18.4%), seizure (16%), and other illness (12.3%) for school-based EMS incidents.
      Other illness (20.0%), breathing difficulty (13.7%), and abdominal pain (12.0%)
      were the chief complaints for nonschool-based EMS incidents. Treatment was
      rendered by the EMS provider in 11 753 (93.3%) of the incidents. Frequency of EMS
      intervention was the same for school-based incidents and nonschool-based
      incidents. Transportation to a medical facility was more frequent in school-based
      incidents than nonschool-based incidents. CONCLUSION: Compared with nonschool
      based EMS incidents, school-based EMS incidents are more often attributable to
      injury, more often related to a sports activity, and more often result in
      transport to a medical facility. Understanding the characteristics of school
      emergencies resulting in an EMS dispatch may help emergency medical providers be
      better prepared for school-based incidents. School personnel may benefit from
      increased knowledge about the EMS system and EMS programs. In addition, EMS
      incident data may provide useful information about school-based injuries and may
      provide a means for injury surveillance.

PMID- 10353979
TI  - Can pediatricians define and apply the concept of brain death?
AB  - OBJECTIVE: We sought to determine pediatric residents' and attending physicians'
      ability to define brain death, their ability to apply this standard of death to a
      clinical scenario, and their knowledge regarding the legal necessity of
      confirmatory testing when determining death by brain criteria. We compared
      resident and attending self-confidence at discussing brain death with their
      ability to define brain death and apply this concept to a clinical scenario.
      METHODOLOGY: A questionnaire was sent to 136 residents, postgraduate years 1
      through 3, at four accredited pediatric training programs in the United States.
      Participation was tracked by return address. One follow-up request for
      participation was made. A similar procedure was followed for 140 faculty
      pediatricians at two of the institutions. Demographic information including level
      of training, subspecialty training, training program, and formal ethics training
      was collected. Respondents defined brain death, interpreted a clinical scenario,
      and stated whether confirmatory testing is legally required to determine death by
      brain criteria. Respondents rated their confidence at explaining brain death to a
      patient's family on a scale from 1 to 5. RESULTS: Eighty-seven percent (118/136)
      of resident surveys were returned. Thirty-six percent (42/118) of the residents
      correctly defined brain death. Forty-three percent (51/118) of residents
      correctly interpreted the clinical scenario. Fifty-five percent (65/118) of the
      residents correctly recognized that brain death could be determined without a
      confirmatory test. Residents who correctly defined brain death were as confident
      as those who did not (2.8 +/- 1 vs 1.5 +/- 1). Residents who correctly
      interpreted the clinical scenario were as confident as those who did not (2.6 +/-
      1 vs 1.9 +/- 0.9). Eighty percent (112/140) of attending physician surveys were
      returned. Thirty-nine percent (44/112) of attending physicians correctly defined
      brain death. Fifty-three percent (59/112) correctly interpreted the clinical
      scenario. Fifty-eight percent (65/112) recognized that brain death can be
      diagnosed without confirmatory testing. All pediatric intensivists (n = 12)
      correctly answered all three questions. Their performance was significantly
      better than other pediatricians. Attendings who correctly defined brain death
      were more confident than those who did not (4.2 +/- 1 vs 1.1 +/- 0. 9).
      Attendings who correctly interpreted the clinical scenario were more confident
      than those who did not (3.8 +/- 1.2 vs 2.2 +/- 1.2). CONCLUSIONS: Pediatric
      residents and attendings have difficulty defining and applying the concept of
      brain death. This concept is difficult to grasp and internalize for many
      pediatricians. To ensure that critical decisions are made by knowledgeable
      physicians and well-informed families, more effective educational strategies need
      to be identified.

PMID- 10353980
TI  - Helicobacter pylori infection and insulin requirement among children with type 1
      diabetes mellitus.
AB  - OBJECTIVE: Helicobacter pylori induces gastric inflammation and the the
      production of cytokines in infected individuals. Theoretically, this increased
      production of cytokines could be deleterious for the control of the glycemia of
      patients with diabetes. This study aimed to describe the insulin requirement
      among patients with type 1 diabetes and H pylori infection compared with
      uninfected counterparts. METHODS: Cross-sectional design. Demographic information
      (age, gender, race, annual family income, and number of individuals per room in
      the household) and clinical information (age at diagnosis of diabetes, duration
      of illness, weight, height, compliance with clinical appointments, daily insulin
      units per kilogram of body weight [IU/kg/d], and glycosylated hemoglobin A level)
      was obtained from children and adolescents with diagnosis of type 1 diabetes
      mellitus who were seen at Children's Hospital in New Orleans. A total of 2 mL of
      blood was also collected and sera were tested for H pylori-specific
      immunoglobulin G antibodies using an enzyme immunoassay. The daily insulin
      requirement among infected and uninfected children was compared, and the effect
      of other variables was evaluated with multiple linear regression. RESULTS: Of the
      71 subjects who were evaluated (median age: 11 years), 11 (15.5%) were found to
      be infected. H pylori infection was more frequent among subjects who were older,
      who had a lower family income, and who were black. Infected children were found
      to require more insulin (1.2 vs 0.9 IU/Kg/d) and their glycosylated hemoglobin A
      level was higher (14.9 vs 11.8) than the level found in uninfected subjects.
      Multiple linear regression analysis identified H pylori infection duration of
      illness, race (black), body mass index, and gender (female), to be associated
      independently with increased daily insulin requirement (IU/kg/d). CONCLUSION: n
      our study population, children with type 1 diabetes and H pylori infection had an
      increased daily insulin requirement compared with the requirement of their
      uninfected peers. The reason for this association requires additional
      investigation.

PMID- 10353981
TI  - Flexible flat feet in children: a real problem?
AB  - OBJECTIVES: To estimate the prevalence of flexible flat feet in the provincial
      population of 4- to 13-year-old schoolchildren and the incidence of treatments
      considered unnecessary. SETTING: Province of Malaga, Spain. METHODS: We examined
      and graded by severity a sample of 1181 pupils taken from a total population of
      198 858 primary schoolchildren (CI: 95%; margin of error: 5%). The sample group
      was separated into three 2-year age groups: 4 and 5 years, 8 and 9 years, and 12
      and 13 years. The plantar footprint was classified according to Denis1 into three
      grades of flat feet: grade 1 in which support of the lateral edge of the foot is
      half that of the metatarsal support; grade 2 in which the support of the central
      zone and forefoot are equal; and grade 3 in which the support in the central zone
      of the foot is greater than the width of the metatarsal support. The statistical
      analysis for the evaluation of the differences between the groups was performed
      with Student's t and chi2 tests as appropriate. RESULTS: The prevalence of flat
      feet was 2.7%. Of the 1181 children sampled, 168 children (14.2%) were receiving
      orthopedic treatment, but only 2.7% had diagnostic criteria of flat feet. When we
      inspected the sample, we found that a number of children were being treated for
      flat feet with boots and arch supports. Most of them did not have a flat plantar
      footprint according to the criteria that we used for this work. Furthermore, in
      the group of children that we diagnosed as having flat feet, only 28.1% were
      being treated. We found no significant differences between the number of children
      receiving orthopedic treatments and the presence or absence of a flat plantar
      footprint. Children who were overweight in the 4- and 5-year-old group showed an
      increased prevalence for flat feet as diagnosed by us. CONCLUSION: The data
      suggest that an excessive number of orthopedic treatments had been prescribed in
      the province. When extrapolated to the 1997 population of schoolchildren within
      the age groups studied the figures suggested that approximately 28 167 children
      in Malaga province probably would have been receiving orthopedic treatments with
      boots and insoles at the time of our study. Consequently, the total expenditure
      on orthopedic boots and insoles that year could be estimated as 676 008 000
      pesetas ($4 447 422 in US currency).

PMID- 10353982
TI  - Influence of the home environment on the development of obesity in children.
AB  - CONTEXT: Obesity is the most common health problem facing children. The most
      recent data from the National Health and Nutrition Examination Survey III suggest
      that 22% of children and adolescents are overweight and that 11% are obese.
      OBJECTIVE: To investigate prospectively the association between the home
      environment and socioeconomic factors and the development of obesity in children.
      DESIGN: Prospective cohort study. SETTING: The National Longitudinal Survey of
      Youth. Population. A total of 2913 normal weight children between the ages of 0
      and 8 years were followed over a 6-year period. We examined the roles of race,
      marital status, maternal education, family income, and parental occupation, as
      well as standardized measures of the home environment (The Home Observation for
      Measurement of the Environment [HOME]-Short Form) on the development of childhood
      obesity. PRIMARY OUTCOME MEASURE: Incidence of obesity. Obesity was defined as a
      body mass index >95th percentile for age and gender at the 6-year follow-up.
      RESULTS: Maternal obesity was the most significant predictor of childhood obesity
      (OR: 3.62 [2. 65-4.96]). The HOME-Short Form cognitive scores and household
      income were also significant predictors of childhood obesity (OR, low HOME
      cognitive: 2.64 [1.48-4.70], medium HOME-cognitive: 2.32 [1. 39-3.88]; low
      income: 2.91 [1.66-5.08], medium income: 2.04 [1.21-3. 44]). Children who lived
      with single mothers were also significantly more likely to become obese by the 6
      year follow-up, as were black children, children with nonworking parents,
      children with nonprofessional parents, and children whose mothers did not
      complete high school. Neither the child's gender nor the HOME-emotional scores
      contributed to the development of obesity. After controlling for the child's
      initial weight-for-height z-score, maternal body mass index, race, marital
      status, occupation, education, and HOME emotional scores, only the HOME cognitive
      score and family income remained significant predictors of childhood obesity.
      CONCLUSION: Children with obese mothers, low family incomes, and lower cognitive
      stimulation have significantly elevated risks of developing obesity, independent
      of other demographic and socioeconomic factors. In contrast, increased rates of
      obesity in black children, children with lower family education, and
      nonprofessional parents may be mediated through the confounding effects of low
      income and lower levels of cognitive stimulation.

PMID- 10353983
TI  - Technical report: treatment of the child with simple febrile seizures.
AB  - OVERVIEW: Simple febrile seizures that occur in children ages 6 months to 5 years
      are common events with few adverse outcomes. Those who advocate therapy for this
      disorder have been concerned that such seizures lead to additional febrile
      seizures, to epilepsy, and perhaps even to brain injury. Moreover, they note the
      potential for such seizures to cause parental anxiety. We examined the literature
      to determine whether there was demonstrable benefit to the treatment of simple
      febrile seizures and whether such benefits exceeded the potential side effects
      and risks of therapy. The therapeutic approaches considered included continuous
      anticonvulsant therapies, intermittent therapy, or no anticonvulsant therapy.
      METHODS: This analysis focused on the neurologically healthy child between 6
      months and 5 years of age whose seizure is brief (<15 minutes), generalized, and
      occurs only once during a 24-hour period during a fever. Children whose seizures
      are attributable to a central nervous system infection and those who have had a
      previous afebrile seizure or central nervous system abnormality were excluded. A
      review of the current literature was conducted using articles obtained through
      searches in MEDLINE and additional databases. Articles were obtained following
      defined criteria and data abstracted using a standardized literature review form.
      Abstracted data were summarized into evidence tables (Tables 1 through 7).
      RESULTS: Epidemiologic studies demonstrate a high risk of recurrent febrile
      seizures but a low, though increased, risk of epilepsy. Other adverse outcomes
      either don't occur or occur so infrequently that their presence is not
      convincingly demonstrated by the available studies. Although daily anticonvulsant
      therapy with phenobarbital or valproic acid is effective in decreasing recurrent
      febrile seizures, the risks and potential side effects of these medications
      outweigh this benefit. No medication has been shown to prevent the future onset
      of recurrent afebrile seizures (epilepsy). The use of intermittent diazepam with
      fever after an initial febrile seizure is likely to decrease the risk of another
      febrile seizure, but the rate of side effects is high although most families find
      the perceived benefits to be low. Although antipyretic therapy has other
      benefits, it does not prevent additional simple febrile seizures. CONCLUSIONS:
      The Febrile Seizures Subcommittee of the American Academy of Pediatrics'
      Committee on Quality Improvement used the results of this analysis to derive
      evidence-based recommendations for the treatment of simple febrile seizures. The
      outcomes anticipated as a result of the analysis and development of the practice
      guideline include: 1) to optimize practitioner understanding of the scientific
      basis for using or avoiding various proposed treatments for children with simple
      febrile seizures; 2) to improve the health of children with simple febrile
      seizures by avoiding therapies with high potential for side effects and no
      demonstrated ability to improve children's eventual outcomes; 3) to reduce costs
      by avoiding therapies that will not demonstrably improve children's long-term
      outcomes; and 4) to help the practitioner educate caregivers about the low risks
      associated with simple febrile seizures.

PMID- 10353984
TI  - Is the role of the small intestine in first-pass metabolism overemphasized?

PMID- 10353985
TI  - Vanilloid (Capsaicin) receptors and mechanisms.

PMID- 10353986
TI  - Pharmacology of the eosinophil.

PMID- 10353987
TI  - Opioids, reward and addiction: An encounter of biology, psychology, and medicine.

PMID- 10353988
TI  - International Union of Pharmacology. XX. Current status of the nomenclature for
      nicotinic acetylcholine receptors and their subunits.

PMID- 10353989
TI  - Allometric models for interspecies extrapolation of wildlife toxicity data.

PMID- 10353990
TI  - Effects of perinatal exposure to polychlorinated biphenyls on development of
      female sexual behavior.

PMID- 10353991
TI  - Endosulfan residues in Brazilian tomatoes and their impact on public health and
      the environment.

PMID- 10353992
TI  - Comparison of gas chromatographic and ion selective electrode methods for
      measuring fluoride in urine.

PMID- 10353993
TI  - Comparison of organochlorine pesticide levels in adipose tissue and human milk of
      mothers living in Veracruz, Mexico.

PMID- 10353994
TI  - Copper, zinc, cadmium, and lead in sheep grazing in North Greece.

PMID- 10353995
TI  - Trace elements in soil and coniferous needles.

PMID- 10353996
TI  - Three digestion methods to determine concentrations of Cu, Zn, Cd, Ni, Pb, Cr,
      Mn, and Fe in mangrove sediments from Sai Keng, Chek Keng, and Sha Tau Kok, Hong
      Kong.

PMID- 10353997
TI  - Multiresidue determination of fungicides in wine.

PMID- 10353998
TI  - Estrogenic effects of organic environmental extracts with the trout hepatocyte
      vitellogenin assay.

PMID- 10353999
TI  - Recovery of acetylcholinesterase activity in the common carp (Cyprinus carpio L.)
      after inhibition by organophosphate and carbamate compounds.

PMID- 10354000
TI  - Influence of naphthalene on esterase activity during vitellogenesis of marine
      edible crab, Scylla serrata.

PMID- 10354002
TI  - Cadmium-inducible metallothionein in tilapia (Oreochromis mossambicus).

PMID- 10354001
TI  - Toxicity of metals and pesticides using the sperm cell bioassay with the sea
      urchin Arbacia spatuligera.

PMID- 10354003
TI  - Combined effects of Chlorella density and methyl parathion concentration on the
      population growth of Brachionus calyciflorus (Rotifera).

PMID- 10354004
TI  - Oxygen production rate as a test for determining toxicity of copper to Rhodomonas
      salina Hill and Wehterbee (Cryptophyceae).

PMID- 10354005
TI  - [Round Table: Severe asthma in pediatrics. Concepts and predisposing factors].
AB  - Given the clinical and functional characteristics of severe asthma, we will look
      at the factors that predispose to potentially fatal asthma. They can be divided
      into three groups: a) factors related to medical care: error of diagnosis of
      asthma and severity, deficiencies in the treatment prescribed, lack of control of
      treatment, frequent changes of doctor, lack of diagnostic tools; b) factors
      related to the patient and the environment: denial of the disease, failure to
      comply with or abandonment of treatment, underrating the severity of attacks, age
      (adolescence), coexistence of psychiatric disorder (depression); c) disease
      dependent factors: admissions to hospital, need for mechanical ventilation on
      occasion, increase of symptoms during the last year, need for substantial
      medication. Adolescence is a critical stage of life in asthma. It implicitly
      involves a number of risk factors, all of which are age-dependent: refusal to
      acknowledge the illness, resistance to treatment (in particular as regards
      continuity and frequency of doses) lack of self-esteem, lack of confidence in the
      doctor, the beginning of the smoking habit. Another key factor is the coexistence
      of depression and asthma. In addition to the low self-esteem due to the affective
      disorder (which will in itself influence any form of treatment) depression is
      associated with a higher incidence of illnesses --especially infectious illnesses
      - which can also aggravate asthma. Anxiety and stressful circumstances in general
      are factors that negatively affect the illness. Factors that influence the
      evolution of the illness are the following: factors that influence asthma
      severity: patient-dependent, sensitivization-dependent, environment-dependent,
      treatment-dependent, illness-dependent, dependent on respiratory function
      exploration.

PMID- 10354006
TI  - [Round Table: Severe asthma in pediatrics: diagnosis and prognosis].
AB  - Prevalence of asthma in children is calculated around 5-10%. In spite of this,
      severe asthma is not frequent in children (about 1% of asthmatic children), but
      its prognosis is very worrying as 90% of children with severe asthma continue
      with asthma in adulthood. The key question is if doctors dedicated to treatment
      of asthmatic children are able or not able to do something in order to modify
      this prognosis. OBJECTIVES: to evaluate the role of prevention measures in the
      evolution of severe asthma in children. METHODS: in 1995 a prospective study was
      begun with the aim of evaluating the evolution of a group of children who had
      been diagnosed as moderate or severe persistent asthma (group A; 18 patients) and
      comparing it with a control group of children with infrequent episodic asthma
      (group B, 25 patients). On the first visit we carried out anamnesis, physical
      exploration, skin tests, a lung function study and we trained the patient in the
      use of the daily diary card documenting peak expiratory flow (PEF) and asthma
      symptoms. Three (G-A) or six (G-B) month controls were programmed adjusting the
      medication dosage. Individual immunotherapy was administered, when indicated.
      RESULTS: both groups have evolved favourably. All of the patients with severe or
      moderate asthma, who had done the correct prevention measures and/or
      immunotherapy, have been able to stop the initial treatment with inhaled
      glucocorticosteroids (CGS) without lung function or clinical state deterioration.
      On the other hand the patients with poor compliance of prevention measures
      continued needing inhaled CGS. CONCLUSIONS: adequate prevention measures and/or
      immunotherapy can influence prognosis of asthmatic children. All of this, in the
      long run, could avoid or delay the remodelling process and the negative factors
      of an intensive pharmacotherapy.

PMID- 10354007
TI  - [Round Table: Severe asthma in pediatrics: treatment of acute crises].
AB  - Morbidity and mortality derived from asthma continue to be a main public health
      problem in many countries, in spite of the advances in the knowledge on the
      disease and its treatment. There are several risk factors for asthma attack which
      have to be considered in the management of patients in order to prevent
      exacerbations and mortality. Smooth bronchial muscle constriction and
      inflammation with oedema of the bronchial wall are the facts that cause airway
      flow and resistance disturbances, with hyperinflation, leading to a bigger
      respiratory work. On the other hand, the bronchial obstruction leads to a
      ventilation-perfusion disequilibrium and hypoxia. At the beginning of the process
      there is hypocarbia, but when the attack progresses muscle fatigue happens, and
      retention of CO2, being a sing of alarm (predictive of respiratory failure) a
      normal and rising PaCO2. The evaluation of an acute asthmatic patient should
      accomplish a clinical and objective assessment (peak flow rate and saturation of
      O2), in order to classify the crisis in: mild, moderate or severe. Managing acute
      asthmatic patient includes: oxygen, bronchodilator ss2 agonists at high and even
      continuous doses and systemic corticosteroids to prevent the progression and to
      control inflammation. These procedures should be promptly instituted. Although
      there is less evidence on their beneficial effects other measures as intravenous
      aminophylline, nebulized anticholynergics, magnesium sulphate and intravenous ss2
      agonists may be used when the conventional therapy is not quickly successful and
      the patient is in a critical situation, at a real risk of respiratory failure,
      and in order to avoid mechanical ventilation. If this is finally instituted,
      controlled hypoventilation with permissive hypercarbia is now recommended, to
      avoid barotrauma, which used to be a frequent complication when more aggressive
      attitude was the rule. Interaction between paralytic agents and corticosteroids
      may produce a miopathy, so the recommendation now is to try not to use paralytic
      agents, even with profound sedation of needed. Sixty four patients were treated
      on 77 occasions in the Pediatric Intensive Care Unit of our hospital. They were
      0,5 to 13,9 years old, being 50% less than 5 years old. It was the first attack
      in 9 (14%) patients. The standard management consisted of oxygen, frequently or
      continuously nebulized salbutamol and intravenous methylprednisolone (1 to 6
      mg/kg/day). Furthermore nebulized ipratropium bromide was administered 58 times
      (75%), as well as intravenous aminophylline 69 (89%), intravenous salbutamol 23
      (30%), magnesium sulphate 16 (21%) and ketamine 10 (13%). Antibiotics were given
      22 times (29%). Two 15 month old infants received mechanical ventilation in three
      occasions, and relevant complications happened (pneumothorax and myopathy, and
      pneumomediastinum and bronchiolitis obliterans respectively). Fifty six patients
      have been followed for a period of 3 to 110 months (median 48 months), and 16
      (29%) have needed high doses (equal to or move than 800 mcg of budesonide or
      equivalent). There are data on lung function in 36 of them, FEV1 is normal (> 85%
      of predicted, between 86 and 127) in 26 (78%) and < 85% (65 to 84%) of predicted
      in 8 (22%) FEV1 rises more than 15% (16 to 23%) in four patients after the
      inhalation of a ss2 agonist. Inhaled anesthetic agents and heliox have been used
      in some pediatric cases. After a severe asthma attack the strategy of management
      should be reviewed, as well as the possible risk factors.

PMID- 10354008
TI  - [Round Table: Severe asthma in pediatrics: therapeutic protocol between attacks].
AB  - The major factors contributing to asthma morbidity and mortality are
      underdiagnosis and inappropriate treatment. Consultation with an Allergy
      specialist may be appropriate for those patients with asthma who do not respond
      favorably to treatment. Effective treatments are available for controlling asthma
      symptoms, preventing exacerbations, and improving lung function so that patients
      can have active and productive lives. A comprehensive approach to treatment
      includes patient education, environmental control measures to reduce exposure to
      known risk factors, avoid adverse effects from asthma medications, establish
      individual medication plans for long-term control of asthma (especially through
      suppression and reversal of the inflammatory process), methods for monitoring
      asthma to be alert to signs of worsening, and medications for prompt reversal of
      exacerbations.

PMID- 10354010
TI  - [Round Table: Urticaria and angioedema: introduction and classification].
AB  - Urticaria and angioedema are common diseases in children and adults.
      Approximately 15-25% of the population will have urticaria or angioedema at least
      once in their life-time. Urticaria is characterized as the appearance of
      erythematous, circumscribed, elevated, pruritic, edematous swelling of the upper
      dermal tissue. Erythematous swelling of the deeper cutaneous and subcutaneous
      tissue is called angioedema. In angioedema lesions are less pruritic but pain and
      burning are common. Urticaria may occur in any part of the body, whereas
      angioedema often involves face, extremities or genitalia. In contrast to other
      forms of edema there are not symmetric distribution. Urticaria and angioedema are
      often associated. Urticaria is considered acute if symptoms are present for less
      than 6 weeks, but usually in childhood lesions disappear in a few days. In
      chronic urticaria symptoms are longer than 6 weeks; if the episodes were of
      shorter duration than the symptoms-free periods urticaria is considered
      recurrent. Acute urticaria has been reported to be the common type in childhood
      and chronic urticaria is more frequent in adults. Acute urticaria is usually a
      self-limited benign disease in young children. Nevertheless it is an
      uncomfortable nuisance, interfering daily activities and sleep, and produces
      psychosocial impact in patients and parents (an altered self-image is always an
      alarming situation). Urticaria is a frequent cause of emergency room visit but
      few patients need to be admitted. Urticaria has long been believed to be an
      allergic disease but clinically it has rare been proved to be so. The basic
      mechanism involves the release of diverse vasoactive mediators that arise from
      the activation of cells or enzymatic pathways. Histamine is the best known of
      these substances, and elicits the classic triple response consisting of
      vasodilatation (erythema), increased vascular permeability (edema) and an axon
      reflex that increases reaction. In contrast to simple symptoms and easy diagnosis
      of urticaria, etiologic factors are often difficult to establish. Urticaria can
      be classified according to the eliciting factors and the different
      pathomechanisms. According to several works, clinical history carried out by a
      trained physician can be regarded as the most valuable diagnostic tool and
      extensive screening test do not contribute to etiologic diagnosis of urticaria.
      Only a few specific tests appeared to be valuable at this respect. In different
      studies about children urticaria, the most common etiological factors have been
      identified as infection, physical urticaria, food allergy, drug adverse reaction,
      parasitic infestation and papular urticaria. The aim of this work-shop is to
      define, describe and discuss these frequent problems.

PMID- 10354009
TI  - [Round Table: Severe asthma in pediatrics: prevention].
AB  - 1. Evaluation of individual propensity to severe asthma using risk factors. 2.
      Regular follow-up at intervals of 3-4 months, regardless of the patient's
      stability in a given moment. 3. Measurements of pulmonary function at each visit
      and at home daily (PEF). 4. Monitoring evolution in relation to the need for
      specialist consultations and psychological care. 5. Factors influencing
      propensity to death should be treated specifically. 6. Designation of a person
      outside the family responsible for the patient's care. 7. Use of community
      resources. 8. Monitoring personal/family compliance with treatment programs. 9.
      Informing the patient and family about the patient's tendency to severe asthma.
      10. Developing an emergency plan for facilitating communication when asthma
      becomes unstable. The plan should emphasize eliminating any delay in obtaining
      care during an attack. The plan should include: a) A list of preventive
      medications with dosing guidelines. The simplest possible regimens should be
      established. b) Criteria for using rescue medication and emergency care in each
      specific case. c) When the physician should be called in and what to do when the
      physician cannot be contacted. d) An exact description of the signs and symptoms
      that indicate that the patient should visit the emergency room without delay.
      Advance designation of the emergency service to be used. e) Suitable vacation
      planning. 11. Mechanisms guaranteeing fluid and effective communication between
      the unit and patients with severe asthma. a) Programs for physicians, nurses and
      receptionists who take calls to establish measures for recognizing, identifying
      risk factors, and preventing complications in patients with severe asthma. b)
      Compilation of a list of patients with severe asthma. c) Patients with severe
      asthma should be identified by a medical alert card. d) Calls from patients with
      severe asthma should be taken immediately.

PMID- 10354011
TI  - [Round Table: Urticaria in relation to infections].
AB  - OBJECTIVES: 1) To study the clinical and analytic features of infectious disease
      associated to urticaria in children. 2) To look into the probable etiology of the
      infectious disease. 3) To determine atopic predisposition and previous urticarial
      episodes and to rule out the involvement of antibiotics. DESIGN: Transversal and
      observational study. SETTING: Pediatric Allergy Outpatient Clinic of a tertiary
      Hospital. PATIENTS: Forty-four children, aged 1 to 12 years with acute urticaria
      associated to clinically infectious or febrile illness attending an Emergency
      Pediatric Department. INTERVENTION: Symptoms evaluation and physical examination
      in the seventh first days and follow over 3-6 weeks by the same physician.
      MEASUREMENTS: Clinical features of urticaria (duration, angioedema associated);
      Clinic diagnosis of illness infectious (acute respiratory infection,
      gastroenteritis, febrile syndrome); white blood cells count, C-reactive protein,
      aminotransferases (AST, ALT), L-Y-glutamyl transferase; viral culture and antigen
      detection: enterovirus (EV), adenovirus, respiratory syncytial virus (RSV),
      parainfluenza 1, 2 and 3, influenza A y B and cytomegalovirus (CMV); serological
      assay: CMV, enterovirus, mycoplasma pneumoniae, Epstein-Barr, parvovirus B19.
      RESULT: 22 children (50%) are between 1-2 years old. 40 patients (90,9%) had
      symptoms of respiratory tract infection and only four patients had a pneumonia.
      The other 4 children had a gastroenteritis. The analytic was suggestive of viral
      infection in 35 (79.5%) and unknown on seven patients. In 20 children (45.4%) was
      identified a probable infection. The viral detection was positive in 3 patients:
      CMV, herpes simplex 1 and influenza A. Twenty microbiological findings for
      seventeen patients was found by serological criterion of probable infection:
      enterovirus (10); parvovirus B19 (4); Epstein-Barr (3) y mycoplasma (3). Evidence
      of a double serologic infection was found in three patients. In comparison with a
      serological control group encountered that acute urticaria during a infectious
      disease is significantly associated (p = 0.0054) to high titer to enterovirus by
      complement-fixation. The urticaria was associated with angioedema in 38.6% and 9
      children (20.4%) related an previous similar episode. Twenty-one (47.7%) had been
      treated with antibiotics before development the urticaria. All patients was given
      the suspected antibiotic and no patient developed any adverse reaction.
      CONCLUSIONS: The clinically infectious associated to urticarial rash in children,
      usually is a viral respiratory infections. Is more frequent at infant. In spite
      of antibiotic therapy is often related to development the urticaria, the
      subsequent challenge with the same antibiotic is good tolerated.

PMID- 10354013
TI  - [Round Table: Urticaria caused by arthropod bites and stings (excluding
      Hymenoptera)].
AB  - Adverse reactions to arthropod bites (hymenoptera excluded) can be faced with
      systemic reactions and local reaction. Among the numerous families of arthropods
      the species most commonly responsible are mosquitoes,. flea, horsefly and tick.
      In this article we explain the characteristics of reaction caused by arthropods
      and the mechanisms proposed. An IgE mechanism is incriminated in severe
      anaphylactic reactions. Various mechanisms have been proposed for local
      reactions. In order to know the incidence of sensitization and cross-reactivity
      with other arthropods, we have done a study where we have found that 31% of
      patients with reaction to mosquito bite had sensitization to Aedes communis and
      53% of this group also had sensitization to other arthropods, probably due to a
      cross-reactivity.

PMID- 10354012
TI  - [Round Table: urticaria with a physical cause].
AB  - Physical urticaria comprises a series of clinically differentiated conditions in
      which wheals develop as a result of physical stimuli: mechanical (friction,
      pressure), cold, heat, increased body temperature, exercise exposure to sunlight,
      vibration and contact with water. The present study reviews their clinical,
      diagnostic and treatment characteristics. Although the precise prevalence of
      physical urticaria is not know, it nevertheless represents the most common form
      of urticaria of known etiology in children. Symptomatic dermatographism is the
      most frequent presentation in children; it may be present from birth and persist
      indefinitely. In order to study the prevalence of dermatographism in our
      pediatric population, we randomly selected 238 children of both sexes (128 boys
      and 110 girls) aged 2 to 14 years, in the Paternal Health Care Center (Valencia,
      Spain). An evaluation was made of skin response 5 minutes after the application
      of pressure (3,200 g/cm2) along a 5-cm extent of skin on the back, using a
      dermatographometer. A positive response was considered when a wheal over 2 mm in
      diameter developed; in this context, the prevalence of dermatographism was 24%,
      with a significant predominance of females (33%) over males (16%). According to
      the data obtained from the anamnesis, 41% of the children with dermatographism
      referred exanthema in response to friction and pressure compatible with
      symptomatic dermatographism, versus only 5% of those who tested negatively.
      Lastly, 42% of the children with dermatographism referred intense local reaction
      (5 cm or more) in response to mosquito bites, versus only 16% of the children who
      tested negatively for dermatographism. The study of bronchial reactivity to
      metacholine in 17 children with dermatographism but no bronchial asthma (based on
      the Chatham method) proved positive in 13 cases (76%). Seven of these 17 children
      (41%) yielded positive skin tests (3 referred symptoms of rhinitis, with no
      manifestations of asthma in any case), and the metacholine challenge proved
      positive in 5 (71%). Ten of the children showed negative skin testing for
      aeroallergens - with positive metacholine testing in 8 (80%). These results
      indicate a high prevalence of bronchial hyper-responsiveness in children with
      dermatographism, suggesting the existence of an association between skin and
      bronchial hyper-reactivity. Skin tests with aeroallergens were made in 45 of the
      58 children with positive dermatographism; 38% were found to be positive for at
      least one of the allergens studied, a figure that increased to 43% when only
      considering children over the age of 7 years. This points to a high prevalence of
      atopy among children with dermatographism. In order to evaluate the prevalence of
      dermatographism in the atopic population, we studied 100 patients in the 4-14
      years age range suffering from respiratory pathology associated with
      sensitization to aeroallergens. A positive response to pressure (3,200 g/cm2) was
      observed in 47% of cases, this being significantly higher than the prevalence
      observed among the general pediatric population.

PMID- 10354014
TI  - [Round Table: Immunological urticaria mediated by IgE].
AB  - Urticaria is characterized by the appearance of hives and pruritus. Those hives
      are formed by oedema and vasodilatation and they disappear when they are pressed
      on. The acute presentation is extremely common and affects between 10 and 20% of
      the population at a determined moment. In its simplest form, urticaria is
      envisioned to represent the same sort of wheal-and-flare reaction observed when
      histamine is injected into the skin. It produces erythema because of capillary
      vasodilatation, oedema because of increased permeability in capillary and
      pruritus secondary at local specific receptors stimulation. Angioedema is caused
      by the same pathologic alterations that occur in the deep dermis and subcutaneous
      tissue. Thus, an area involved with angioedema has swelling as the prominent
      manifestation and appearance of the skin itself may be normal. Due to reduced
      nerve supply in dermis, angioedema is associated with oppression and not
      pruritus. Immunoallergological study of urticaria and/or angioedema was requested
      in 133 cases from 648 from the first patient's visits to the surgery. It supposes
      a 20.52%. The family suspicion of etiology was food in 62 cases, chemical
      products in 39 cases, other factors (physical, stings, balloons and other
      manufactured products.) in 7 cases and 25 cases without a direct relation. Out of
      100 children diagnosed of allergic urticaria-angioedema 67 was by food; the foods
      implicated in frequency order were: eggs and nuts, fruit, milk, vegetables, fish
      and shellfish. In second place, chemical products were responsible of urticaria
      in 12 children; five of them were positive in diagnosed proof (prick, oral
      challenge) for penicillin and amoxicillin, both from beta-lactamic group; two of
      them had and adverse reaction to anesthetic agents; other two cases were after
      administration of vaccination and due to tetanus toxin; and three cases were due
      to aspirin, confirmed by oral provocation test. In 10 children the etiological
      agent was latex. Other etiologies were: three cutaneous reactions after stings
      (two by wasps and one by mosquito) three reactions due to spices (paprika, cumin,
      anise, mustard) and two reactions caused by manufactures products containing
      additives as yellow-orange.

PMID- 10354016
TI  - Editor's choice

PMID- 10354015
TI  - Reply 

PMID- 10354017
TI  - Human keratin diseases: the increasing spectrum of disease and subtlety of the
      phenotype-genotype correlation.
AB  - Keratins are obligate heterodimer proteins that form the intermediate filament
      cytoskeleton of all epithelial cells. Keratins are tissue and differentiation
      specific and are expressed in pairs of types I and II proteins. The spectrum of
      inherited human keratin diseases has steadily increased since the causative role
      of mutations in the basal keratinocyte keratins 5 and 14 in epidermolysis bullosa
      simplex (EBS) was first reported in 1991. At the time of writing, mutations in 15
      epithelial keratins and two trichocyte keratins have been associated with human
      diseases which include EBS, bullous congenital ichthyosiform erythroderma,
      epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, diffuse
      and focal non-epidermolytic palmoplantar keratoderma, pachyonychia congenita and
      monilethrix. Mutations in extracutaneous keratins have been reported in oral
      white sponge naevus and Meesmann's corneal dystrophy. New subtleties of phenotype
      genotype correlation are emerging within the keratin diseases with widely varying
      clinical presentations attributable to similar mutations within the same keratin.
      Mutations in keratin-associated proteins have recently been reported for the
      first time. This article reviews clinical, ultrastructural and molecular aspects
      of all the keratin diseases described to date and delineates potential future
      areas of research in this field.

PMID- 10354018
TI  - Apoptosis and p53 protein expression increase in the process of burn wound
      healing in guinea-pig skin.
AB  - Apoptosis and the expression of p53 protein, an apoptosis-related protein, in the
      process of healing of a full-thickness burn wound in guinea-pig skin were studied
      with the terminal deoxynucleotide transferase nick-end labelling method, electron
      microscopy, and immunohistochemistry, respectively. Apoptosis was detected in the
      peripheral zone of heat-injured skin from 12 h until day 10 after the burn, with
      the peak occurring on day 2. The peripheral zone of heat-injured skin showed p53
      protein from 12 h through day 2, with the peak occurring on day 2. Apoptosis was
      also detected in tissues regenerated for covering skin defects. The peak of
      apoptosis in the regenerated epidermis occurred at days 7-10, when the epidermis
      was most acanthotic. p53 protein reactivity was also detected in the acanthotic
      regenerated epidermis, with a peak on day 7. The peak of apoptosis in the
      granulation and scar tissue took place from day 10 to 14, when the granulation
      tissue started diminishing, but p53 protein reactivity was not detected there.
      These findings suggest that apoptosis plays an important part in the elimination
      of dying and/or dead cells resulting from heat stress, the terminal
      differentiation of the regenerated epidermis, and the decrease in cellularity
      during remodelling. The apoptotic process during remodelling may be mediated by
      some p53-independent pathway.

PMID- 10354019
TI  - Genetic diversity among Trichophyton mentagrophytes isolates using random
      amplified polymorphic DNA method.
AB  - Trichophyton mentagrophytes is a common cosmopolitan dermatophyte species
      composed of two varieties: T. mentagrophytes var. interdigitale (anthropophilic
      form) and T. mentagrophytes var. mentagrophytes (zoophilic form). We used a
      random amplified polymorphic DNA (RAPD) method to study the genetic diversity of
      46 clinical isolates of the T. mentagrophytes complex collected from 38 patients
      with different geographical origins (Europe, Africa, South America). The T.
      mentagrophytes were isolated either from a unique lesion for 31 patients,
      including two patients living together, or from at least two sites for seven
      patients. Only one primer of 15 primers tested showed DNA polymorphism in the
      isolates, producing 23 distinct patterns belonging to three clusters. There was
      no specific cluster grouping isolates from the same geographical origin. The same
      pattern is shared by all the four T. mentagrophytes var. mentagrophytes and 13 of
      42 T. mentagrophytes var. interdigitale. An identity of strains responsible for
      several lesions in seven individuals suggests an homogeneous T. mentagrophytes
      population in the case of multiple lesions. In contrast, the dissimilarity of two
      strains recovered from two patients living together argues against person-to
      person transmission in that case. This study indicates that RAPD can be
      successfully applied to show genetic diversity among T. mentagrophytes isolates.

PMID- 10354020
TI  - Increased T-cell receptor vbeta2 chain expression in skin homing lymphocytes in
      psoriasis.
AB  - Studies have shown over-representation of certain T-cell receptor (TCR) Vbeta
      chains in lesional psoriatic skin, implying selection or expansion, possibly by
      bacterial superantigen. We investigated the pattern of TCR Vbeta chain usage in
      peripheral blood lymphocytes (PBL) bearing the skin homing receptor cutaneous
      lymphocyte associated antigen (CLA) in psoriasis patients. Results showed
      increased expression of TCR Vbeta2 in CLA-positive PBL in psoriasis patients (n =
      15) compared with normals (n = 10); P < 0.002. As Vbeta2 is preferentially
      expressed by lymphocytes responding to certain bacterial superantigens, this
      study could possibly indicate a role for superantigens in the pathogenesis of
      psoriasis.

PMID- 10354021
TI  - Lack of c-kit mutation in familial urticaria pigmentosa.
AB  - Somatic mutations within c-kit have been reported in individuals with
      mastocytoses, including urticaria pigmentosa (UP). We have identified three
      siblings with UP. We aimed to determine whether the c-kit proto-oncogene was
      playing a part in the aetiology of UP in these three siblings. Using seven
      microsatellite repeat markers spanning an 8-cM interval encompassing the c-kit
      gene we followed the transmission of the c-kit gene in this family. Furthermore,
      single-strand conformation polymorphism analysis was used to scan exon 17 of the
      c-kit gene for mutations in genomic DNA of all family members and somatic DNA
      extracted from skin of the eldest affected sibling, the proband. No mutations
      were found in exon 17 in either genomic DNA of all family members or somatic DNA
      of the proband. Patients with UP have been shown to possess somatic mutations of
      the c-kit gene. However, this locus has been excluded as playing a part in the
      three siblings examined here in whom a second gene locus must be determining
      their UP. Therefore, this study emphasizes genetic heterogeneity in UP. Future
      study to identify primary molecular determinants of UP should include affected
      sib-pair studies.

PMID- 10354022
TI  - Human leucocyte antigen class II associations in chronic idiopathic urticaria.
AB  - The major histocompatibility complex (MHC) acts as a marker for self during T
      cell ontogeny and is associated with the pathogenesis of many autoimmune
      diseases. Recent investigations have shown about 30% of patients with chronic
      idiopathic urticaria (CIU) have IgG autoantibodies against the high-affinity IgE
      receptor, FcepsilonRI, or IgE. A link between MHC class II alleles and CIU has
      not been reported previously. DNA was extracted from blood of 100 Caucasian
      patients with CIU, and the MHC class II type determined using the polymerase
      chain reaction with sequence-specific primers, testing for DRB and DQB1 alleles.
      The frequency of alleles in CIU patients was compared with that found in 603
      controls. Further human leucocyte antigen (HLA) typing on patient subsets,
      classified by the patients' responses to intradermal injection of autologous
      serum and their serum-induced histamine release from basophil leucocytes of
      healthy donors, was undertaken. HLA DRB1*04 (DR4) and its associated allele,
      DQB1*0302 (DQ8), are raised in CIU patients compared with a control population (P
      = 2 x 10-5 and P = 2 x 10-4, respectively). HLA DRB1*15 (DR15) and its associated
      allele, DQB1*06 (DQ6), are significantly less frequently associated with CIU. The
      HLA DRB1*04 association is particularly strong (corrected P = 3.6 x 10-6) for
      patients whose serum has in vivo and in vitro histamine-releasing activity. HLA
      class II typing is consistent with the concept that CIU is a heterogeneous
      disease, and supports an autoimmune pathogenesis in a subset of patients.

PMID- 10354023
TI  - Characterization of the antibody response in oesophageal cicatricial pemphigoid.
AB  - Cicatricial pemphigoid (CP) is a subepidermal, autoimmune bullous dermatosis. It
      is classified as a clinical subset of bullous pemphigoid (BP). However, it
      differs from BP in some significant ways: (i) in CP mucosal involvement with
      clinical scarring is prominent; (ii) there is a prominent IgA class antibody
      response alone or in addition to the IgG class antibody response; and (iii) there
      is a heterogeneous antibody response in CP, whereas in BP the majority of the
      antibodies are directed against a 180-kDa hemidesmosomal protein, bullous
      pemphigoid antigen 2 (BPAg2). Oesophageal involvement in CP is a rare, but often
      devastating manifestation. In this study we examined the humoral autoimmune
      response in oesophageal CP, in an attempt to characterize the autoantibody
      reactivity profile. We used direct and indirect immunofluorescence and Western
      immunoblotting using normal human skin and oesophagus substrates. We studied
      patient sera over time in order to search for evidence of epitope spreading in
      these patients. All patients had positive direct immunofluorescence of
      perilesional oesophageal epithelium. All patients had positive circulating
      antibasement membrane zone autoantibody titres. There was a significant IgA class
      in addition to an IgG class autoantibody response. IgA and IgG antibodies
      demonstrated significant reactivity with BPAg2 and the 97 kDa linear IgA disease
      antigen on Western immunoblot suggesting intraprotein epitope spreading. There
      was no evidence of interprotein epitope spreading over time. Our findings suggest
      that there is a heterogeneous antibody response in oesophageal CP with the
      predominant antigen being BPAg2.

PMID- 10354024
TI  - High-dose intravenous immune globulin for the treatment of autoimmune blistering
      diseases: an evaluation of its use in 14 cases.
AB  - High-dose intravenous immune globulin (IVIG) is used to treat a wide variety of
      autoimmune diseases. We report our experiences of its use in a retrospective
      study of 14 patients with autoimmune blistering diseases, namely epidermolysis
      bullosa acquisita (EBA), two; bullous pemphigoid (BP), two; pemphigoid
      gestationis (PG), one; nodular pemphigoid, two; and pemphigus vulgaris (PV),
      seven. Two patients with refractory EBA improved following regular courses of
      IVIG given as monotherapy. IVIG had a steroid-sparing effect in 10 patients with
      PV, BP and PG. However, the clinical effects were transient and of variable
      intervals, and repeated courses of IVIG were required. The rapid actions of IVIG
      were of particular benefit in two patients with extensive, rapidly progressive PV
      and in one patient with BP in whom swift disease control was required. In such
      cases, when rapid disease control is paramount, we recommend IVIG used in
      conjunction with conventional treatments as a safer and less invasive alternative
      to plasmapheresis. IVIG was ineffective in two patients with nodular pemphigoid.
      Analysis of indirect immunofluorescence (IIF) titres before and after IVIG showed
      that a fall in titre occurred after 78% of treatments and was observed in all
      disease groups. However, like the clinical improvements, the falls in IIF titres
      were transient and of variable interval, and titres rose back to pretreatment
      levels in all but one patient. IVIG appears to be beneficial under certain
      circumstances for the treatment of autoimmune blistering diseases but controlled
      trials are required to define its therapeutic role further.

PMID- 10354025
TI  - The influence of highly active antiretroviral therapy on AIDS-associated Kaposi's
      sarcoma.
AB  - To assess the clinical and biological benefit of highly active antiretroviral
      therapy on AIDS-associated Kaposi's sarcoma (KS), 13 patients with AIDS
      associated Kaposi's sarcoma (five pulmonary KS and eight cutaneous KS) were
      prospectively followed for a mean duration of 12 months. Six patients were
      treated with specific anti-KS chemotherapy before or simultaneously with the
      introduction of antiretroviral therapy. Clinical response was assessed according
      to the AIDS Clinical Trial Group (ACTG) criteria. CD4 cell counts, plasma HIV-1
      RNA and human herpesvirus 8 (HHV-8) viraemia were measured at baseline and at
      different points. Among patients with pulmonary KS, we observed three complete
      responses (CR), one partial response (PR) and one progression. The median
      survival time after the diagnosis of pulmonary KS was 15 months with a median
      duration of the response after the discontinuation of specific chemotherapy for
      KS of 8 months. Among patients with cutaneous KS, we observed four CR, three PR
      and one stable response. A complete response was significantly associated with a
      reversal in HHV-8 viraemia (five of six vs. one of six; P = 0.02, Mann-Whitney
      test).

PMID- 10354026
TI  - Long-term, intermittent treatment of chronic hand eczema with mometasone furoate.
AB  - Chronic hand eczema can be incapacitating, and there is little knowledge of the
      efficacy and safety of long-term treatment with topical corticosteroids. We
      compared the efficacy and safety of two different schedules for the treatment of
      chronic hand eczema with a potent topical corticosteroid, mometasone furoate. In
      a prospective, open, randomized trial, 120 patients with chronic hand eczema were
      treated daily with mometasone furoate fatty cream until the dermatitis cleared or
      for a maximum of 9 weeks. Those who cleared were randomized to treatment for up
      to 36 weeks with mometasone furoate on Sunday, Tuesday and Thursday (group A),
      mometasone furoate on Saturday and Sunday (group B) or no further corticosteroid
      treatment (group C). In the event of relapse, patients were permitted daily
      treatment with mometasone furoate for 3 weeks on two separate occasions. For 50
      of 106 randomized patients, daily treatment for 3 weeks controlled their
      dermatitis; 29 needed 6 weeks and 27 needed 9 weeks of treatment. During the
      maintenance phase, 29 of 35 (83%) in group A, 25 of 37 (68%) in group B and nine
      of 34 (26%) in group C had no recurrences (P = 0.001, chi2-test). Side-effects
      were minimal. It is concluded that long-term, intermittent treatment of chronic
      hand eczema with mometasone furoate fatty cream is effective and safe.

PMID- 10354027
TI  - The efficacy of narrowband ultraviolet B phototherapy in psoriasis using
      objective and subjective outcome measures.
AB  - The efficacy of narrowband ultraviolet B (UVB) was assessed in 100 consecutive
      patients with psoriasis by quantifying disease severity using objective
      (Psoriasis Area and Severity Index, PASI and Dermatologists Global Assessment,
      DGA) and subjective (Psoriasis Disability Index, PDI) measures. The median
      pretreatment PASI, DGA and PDI were 5.7 (interquartile range, IQR 4.5-8.35), 7
      (IQR 6-9) and 42 (IQR 29-63.5), respectively. At 3 month follow-up, the PASI, DGA
      and PDI had fallen to 2.7 (IQR 1.1-3.5), 3 (IQR 2-5) and 30 (IQR 21-50.5),
      respectively (P < 0.001). A small group of patients continued to score highly on
      their PDI despite being clinically clear or having minimal disease, possibly
      representing chronic disability behaviour. Patients exhibiting this may require
      more intensive supervision. In most patients, symptoms of itch and pain improved
      or disappeared (70% and 75%, respectively). Side-effects were reported in 18%.
      Narrowband UVB phototherapy is safe and effective for psoriasis. Symptoms and
      subjective quality of life measures improved significantly. Both objective and
      subjective measures should be used when evaluating the efficacy of a treatment
      for psoriasis.

PMID- 10354029
TI  - The prevalence of common skin conditions in Australian school students: 4 Tinea
      pedis.
AB  - Tinea pedis is a condition that is common, often undiagnosed and frequently
      inadequately treated. It is reported as being rare in young children, but there
      are relatively few population-based reports of prevalence. A randomized sample of
      2491 students from schools throughout the State of Victoria, Australia, were
      examined by dermatologists and dermatology registrars, who recorded clinical
      signs suggestive of tinea pedis, which were then confirmed by fungal culture. The
      age- and sex-adjusted prevalence of culture-proven tinea pedis was 5.2% [95%
      confidence interval (CI) 3.58-6.82] increasing with age from 2.1% (95% CI 0.95
      3.28) in 4-6 year olds to 9.7% (95% CI 5.21-14.26) in 16-18 year olds. A higher
      proportion of males (6.0%) had tinea pedis than females (4.3%). Trichophyton
      mentagrophytes and T. rubrum were the most common dermatophytes isolated on
      culture. Less than 40% of those with a positive diagnosis had reported on the
      questionnaire that they had tinea. Of those who reported correctly that they had
      tinea, 75% had used one or more products to treat their condition, of which more
      than 40% were classified as unlikely to have any therapeutic effect on tinea
      pedis. These data confirm that tinea pedis, a potentially transmissible disease,
      is common in Australian schoolchildren, including those in primary school. There
      is a need for education programmes in schools on the nature of tinea pedis, the
      treatment available, and the public health approach to infection control within
      the school and home environment.

PMID- 10354028
TI  - The prevalence of skin conditions in Romanian school children.
AB  - Virtually nothing is known about the prevalence of skin conditions in children in
      the general population. Although we know something about the relative frequency
      of skin conditions seen by dermatologists, we do not know how such referrals are
      influenced by factors such as social class, accessibility to medical services or
      educational and cultural background. In order to estimate the burden and relative
      frequency of dermatological disease in children in the community, we measured the
      point prevalence of skin conditions in 1114 Romanian schoolchildren aged 6-12
      years, using the British Association of Dermatologists diagnostic index. The
      overall point prevalence of children with one or more skin diseases was 22.8%,
      with no significant differences according to age group or sex, except for
      pityriasis alba which showed a male predominance (P = 0. 007). The most common
      diseases were infectious dermatoses such as viral warts and insect bites (6.3%),
      dermatitis/eczema (5.1%), pityriasis alba (5.1%), keratosis pilaris (4.0%) and
      urticaria (1. 9%). Together, these five groups accounted for more than 84% of the
      cases. Of the 1114 children, 213 (19.1%) had only one skin disease and 41 (3.7%)
      had two skin diseases. While acknowledging the limitations in defining which skin
      conditions can benefit from medical care, this study suggests that skin disorders
      are common in Romanian schoolchildren, affecting about one-quarter of 6-12 year
      olds. Such a point prevalence is likely to be conservative because of the
      tendency of prevalence estimates to exclude many other dermatoses of short
      duration. The finding that over 80% of the disorders can be grouped into fewer
      than six categories is important in informing training programmes and delivery of
      service for primary health care teams. This study provides a baseline for further
      studies into the morbidity and use of health care services by children with skin
      disease in the community.

PMID- 10354030
TI  - False negative clinical diagnoses of malignant melanoma.
AB  - The false negative rate for the clinical diagnosis (FNR) for malignant melanoma
      is reported to be of the order of 20-50%. The aim of this study was to
      investigate possible predictor variables for FNR, with particular reference to
      the features and score of the seven-point check-list within the total population
      (778) of histologically proved malignant melanomas presenting in Leicestershire
      between 1982 and 1996. The FNR was 18.5%. The check-list would have failed as a
      referral indication in only 0.8-1. 1% of the lesions. The major check-list
      features occurred more commonly than the minor features, excepting size >/= 7 mm,
      confirming the diagnostic importance of the major criteria. The FNR was
      unaffected by age or sex. More rarely involved sites had higher rates (31-42%),
      and the face was a particularly difficult diagnostic site. Clinical features of
      lesions associated with a higher FNR were lack of irregular pigmentation and
      shape, altered sensation, the presence of inflammation and size < 7 mm. The FNR
      was inversely related to the total score and major feature score, but directly
      related to the minor score. The minor features, in addition to the major
      features, are potentially valuable in avoiding false negative diagnoses and we
      suggest their retention as part of the check-list. There was only one patient, in
      whom the diagnosis of melanoma was initially missed and who was not biopsied on
      presentation to hospital, who re-presented after 1 year. However, the study
      illustrates the importance of avoiding a false negative diagnosis as there was
      marked delay in the excision of such lesions.

PMID- 10354031
TI  - Humour and alarmism in melanoma prevention: a randomized controlled study of
      three types of information leaflet.
AB  - Effectiveness of melanoma prevention depends on how it is accepted by the
      population. Humour and alarmism are often used in campaigns, but no information
      is available about how much they may improve or limit the impact of a campaign.
      Three different leaflets containing the same information about sun exposure and
      skin cancers were developed using three different tones of presentation:
      humoristic (H-leaflet), alarmist (A-leaflet) or neutral information (N-leaflet).
      In this randomized controlled study, each type of leaflet was mailed to a sample
      of 300 subjects representative of the sociodemographic population of the South of
      France. A fourth sample to whom no leaflet was sent was used as a control.
      Fifteen days after the mailing, the 1200 individuals were interviewed by phone.
      Four hundred and forty-four of the 900 who received the mail read the leaflet.
      The percentage of individuals with a good awareness of melanoma was higher in
      leaflet groups than in controls. The percentage of individuals who read a leaflet
      was lower in the A-leaflet group and the percentage of individuals knowing what a
      melanoma is tended to be lower in the H-leaflet group. There was no significant
      difference between groups with regard to ability for self-assessment of skin sun
      sensitivity, risk factors and sun exposure. The tone of presentation seems to
      have a limited impact on the effect of a campaign, but alarmism tends to reduce
      the number of people reached by the message whereas humour tends to decrease the
      impact of the message.

PMID- 10354032
TI  - Treatment of subungual exostoses by elective day case surgery.
AB  - Twenty-one patients (11 female, 10 male: mean age 21.3 years) with subungual
      exostoses were treated with elective surgery under local anaesthetic in a
      dermatology day case theatre over a period of 8 years. Fifteen (71%) tumours
      affected the great toe, four (19%) affected other toes and two (10%) affected
      fingers. All received local excision with great care to remove all tumour residue
      from the terminal phalanx. Wounds were allowed to heal by secondary intention.
      Attention was paid to preoperative antiseptic procedure and postoperative
      analgesia. During follow-up of between 6 and 36 months (mean 17 months), there
      were two relapses (10%) in the first 12 months, seen in two of the younger
      subjects aged 9 and 13 years. One required further surgery. One further case
      suffered long-term dystrophy due to perioperative damage to nail matrix.
      Conservative and thorough treatment of this pathology can be achieved using the
      appropriate tools in a dermatology day case theatre.

PMID- 10354033
TI  - Latex allergy in atopic children.
AB  - The incidence of positive circulating specific immunoglobulin E (IgE) antibodies
      to latex and evidence of clinical latex sensitivity appears to be increasing
      since its first description in 1979. Although heightened medical awareness may be
      a factor, exposure to latex products, particularly rubber gloves, has increased
      since the discovery of the human immunodeficiency virus (HIV). Atopic individuals
      are at greater risk of developing latex sensitivity. We identified seven children
      with atopic eczema who were known to have clinically significant latex allergy
      and examined the relationship of prior exposure to latex gloves. All children had
      significant serum levels of specific IgE to latex. Before developing clinical
      symptoms of latex allergy, all had been exposed to latex in the form of gloves
      during either inpatient or outpatient treatments of their skin. Exposure of
      atopic individuals to latex gloves could be a major risk factor for sensitization
      and could increase the incidence of serious reactions.

PMID- 10354034
TI  - Role of the atopy score and of single atopic features as risk factors for the
      development of hand eczema in trainee metal workers.
AB  - This study was performed as part of PROMETES (Swiss Prospective Metal Worker
      Eczema Study) to examine the role of atopy as a possible risk factor for the
      development of hand eczema in trainee metal workers. In a cohort of 201 young men
      without any skin problems at the start of their apprenticeship, 9.5% developed
      signs of dermatitis on their hands within a period of 6 months. The 2. 5-year
      incidence was 23%. We did not find a significantly increased risk for hand eczema
      in those participants with an atopic skin diathesis according to the atopy score
      of Diepgen et al. (Dermatosen 1991; 39: 79-83) Analysis of individual atopic
      signs and symptoms showed reported metal reactivity to have a significant
      influence on the onset of early skin damage within 6 months, whereas a history of
      flexural eczema appeared to be significantly related to the overall incidence
      over 2.5 years.

PMID- 10354035
TI  - Isolation of Borrelia afzelii from circumscribed scleroderma.
AB  - A 45-year-old man presented with circumscribed scleroderma (CS) on the
      extremities. Histology of lesional skin showed the typical manifestations of
      scleroderma including a perivascular and interstitial infiltrate of lymphocytes
      and plasma cells; in one of the biopsies spirochaetes could be detected. Despite
      treatment with penicillin, progression of CS was observed and spirochaetes were
      isolated from skin cultures obtained from active scleroderma lesions. These
      spirochaetes were identified as Borrelia afzelii by sodium dodecyl sulphate
      polyacrylamide gel electrophoresis of outer surface proteins and polymerase chain
      reaction (PCR) analysis of their chromosome. After two courses with ceftriaxone
      the lesions stopped expanding and sclerosis of the skin was diminished. At this
      time cultures for spirochaetes and PCR of lesional skin for Borrelia afzelii DNA
      remained negative. The pathogenetic role of Borrelia afzelii in the development
      of CS is discussed.

PMID- 10354036
TI  - HIV-associated pityriasis rubra pilaris responsive to triple antiretroviral
      therapy.
AB  - HIV-associated pityriasis rubra pilaris (PRP) or PRP type VI designates a new
      distinctive entity reported in HIV patients. It is characterized by cutaneous
      lesions of PRP and variable association with lesions of acne conglobata,
      hidradenitis suppurativa and lichen spinulosus. We report a patient with HIV
      associated PRP which was treated by triple antiretroviral therapy (zidovudine,
      lamivudin and saquinavir) with complete response. The patient has remained free
      from symptoms for 20 months of follow-up. We review the clinical features,
      pathology, evolution, treatment and possible aetiology of this recently described
      entity.

PMID- 10354038
TI  - Bowen's disease showing spontaneous complete regression associated with
      apoptosis.
AB  - Spontaneous regression is sometimes seen in malignant skin tumours. We report a
      68-year-old woman whose Bowen's disease showed spontaneous complete regression.
      Prominent infiltration of T cells and increased vascularity were found in the
      upper dermis of the regressed lesion. Strong expression of Fas (APO-1/CD95)
      antigen, an apoptosis-related tumour necrosis factor receptor family protein, in
      the primary lesion and faint expression following regression suggest the
      involvement of Fas-mediated apoptosis in the spontaneous complete regression of
      our patient's Bowen's disease.

PMID- 10354037
TI  - Epidermodysplasia verruciformis treated using topical 5-aminolaevulinic acid
      photodynamic therapy.
AB  - We describe a 65-year-old woman who had had wart-like lesions on the hands, lower
      arms and forehead for about 45 years. She had already had several basal cell
      carcinomas excised. Histological study, electron microscopy and in situ
      hybridization [human papilloma virus (HPV)-types 5/8/12/14/19-23/25/36] of skin
      biopsies confirmed a diagnosis of epidermodysplasia verruciformis (EV).
      Photodynamic therapy (PDT) was performed using a 20% 5-aminolaevulinic acid
      ointment applied for 6 h to the lesions and irradiating using an incoherent light
      source (lambda = 580-740 nm, 160 mW/cm2, 160 J/cm2). Following PDT, blistering
      and crusting of the lesions occurred, but these healed completely within 2-3
      weeks without scarring, and the cosmetic result was excellent. Six months after
      PDT a skin biopsy was taken. In situ hybridization was positive for HPV type 8 in
      skin which was clinically and histologically normal. Twelve months after PDT a
      few lesions had recurred on the hands. Although permanent cure of EV cannot be
      achieved by any therapy at present and single lesions continue to appear in this
      patient, topical PDT might result in better control of HPV-induced lesions.

PMID- 10354039
TI  - Pemphigus vulgaris localized to the vagina presenting as chronic vaginal
      discharge.
AB  - Involvement in pemphigus vulgaris of the female genital tract including the
      vulva, vagina and cervix has previously been described. In all these cases other
      cutaneous and mucosal sites have also been affected at some time. We describe a
      case of pemphigus vulgaris which only involved the vaginal mucosa. The patient
      presented with a persistent vaginal discharge and examination showed extensive
      vaginal erosions. Histology of vaginal biopsies was non-diagnostic. The
      recognition that the vaginal changes may represent an immunobullous disease led
      to further vaginal biopsies on which direct immunofluorescence studies were
      performed. These biopsies showed IgG and C3 in the intercellular epidermis,
      suggesting a diagnosis of pemphigus vulgaris. During the 3-year period that the
      patient has been under review there have never been any other cutaneous or
      mucosal lesions. To our knowledge, this is the first case of pemphigus vulgaris
      localized exclusively to the vaginal mucosa. There was considerable delay in
      diagnosis and this case highlights how important it is to recognize that chronic
      mucosal lesions at genital sites may be caused by immunobullous diseases such as
      cicatricial pemphigoid and pemphigus, and to institute appropriate
      investigations.

PMID- 10354040
TI  - Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies
      complicating long-term treatment with levamisole in children.
AB  - The cutaneous side-effects of levamisole include non-specific and lichenoid
      eruptions, fixed drug eruption and, very rarely, cutaneous vasculitis. We
      describe a distinctive clinical and histological vasculopathy with immunological
      abnormalities in children with paediatric nephrotic syndrome receiving long-term
      levamisole treatment. Four boys and one girl were identified. Their average age
      was 10 years. Levamisole had been used for an average of 24 months. Purpura of
      the ears was the most common finding corresponding histologically to a
      vasculopathic reaction pattern ranging from a leucocytoclastic and thrombotic
      vasculitis to a vascular occlusive disease without true vasculitis but with
      associated antinuclear, antiphospholipid and anticytoplasmic antibodies. The
      eruption resolved in all patients 2-3 weeks after the discontinuation of
      levamisole, but serum autoantibodies persisted for 2-14 months.

PMID- 10354041
TI  - Systemic sarcoidosis and cutaneous lymphoma: is the association fortuitous?
AB  - The association of systemic sarcoidosis and malignant lymphoma is known as the
      'sarcoidosis-lymphoma syndrome'. Cutaneous involvement is rare in this syndrome.
      We report a 52-year-old woman who was diagnosed as having tumour-stage mycosis
      fungoides. Complete remission was achieved by combination therapy consisting of
      isotretinoin, interferon (IFN) alpha, electron beam irradiation,
      photochemotherapy and topical corticosteroids. Three years later, the patient
      developed systemic sarcoidosis characterized by yellowish papules on the
      abdominal wall and the eyelids that histologically revealed non-caseating
      granulomas, multiple fine-nodular interstitial pulmonary infiltrates on chest X
      ray, hilar lymphadenopathy, decreased vital capacity and increased lymphocyte
      count in bronchoalveloar lavage fluid. As opposed to most of the reported cases,
      in our patient the manifestation of cutaneous lymphoma preceded the diagnosis of
      systemic sarcoidosis. We review the cases reported in the literature and discuss
      a possible causal and temporal relationship as well as the role of IFN alpha in
      the development of sarcoidosis.

PMID- 10354042
TI  - Familial dyskeratotic comedones.
AB  - We report a 49-year-old white woman having asymptomatic hyperkeratotic comedone
      like lesions on her legs, arms and trunk. Her sister is similarly affected, but
      less severely. The clinical and histopathological features indicated a diagnosis
      of familial dyskeratotic comedones, a rare autosomal dominant condition.

PMID- 10354043
TI  - Circumferential fingernail.
AB  - We describe a Brazilian girl with a congenital circumferential nail on her left
      ring finger associated with other bony and soft tissue abnormalities of the
      affected limb. The tubular nail plate resembling a punch biopsy has been
      described as a circumferential nail, an extremely rare congenital malformation
      that can be associated with other congenital anomalies. In our review of the
      literature, there have only been two previous reports of this unusual condition
      affecting the fingernails.

PMID- 10354044
TI  - Evidence for a single genetic locus in Clouston's hidrotic ectodermal dysplasia.

PMID- 10354046
TI  - Circulating activation markers of severe atopic dermatitis following ultraviolet
      A1 cold light phototherapy: eosinophil cationic protein, soluble interleukin-2
      receptor and soluble interleukin-4 receptor.

PMID- 10354045
TI  - Linear IgA disease with circulating IgA antibodies against the NC16A domain of
      BP180.

PMID- 10354047
TI  - Maffucci's syndrome with oral and intestinal haemangioma.

PMID- 10354048
TI  - An oculocutaneous presentation of essential progressive telangiectasia.

PMID- 10354049
TI  - Primary cutaneous CD30 (Ki-1)-positive anaplastic large cell lymphoma associated
      with renal cell carcinoma.

PMID- 10354050
TI  - Cutaneous T-cell lymphoma occurring with intestinal B-cell lymphoma.

PMID- 10354051
TI  - Dramatic postcoital vulval laceration and bruising in Ehlers-Danlos syndrome.

PMID- 10354053
TI  - Do mucin-phagocytosing histiocytes in localized lipoatrophy have any primary
      pathogenetic importance?

PMID- 10354052
TI  - Tufted folliculitis in a 10-year-old child.

PMID- 10354054
TI  - The seborrhoeic pattern of dermatomyositis.

PMID- 10354055
TI  - Cetirizine-induced urticarial reaction.

PMID- 10354056
TI  - Nevirapine-induced overlap stevens-johnson syndrome/toxic epidermal necrolysis.

PMID- 10354057
TI  - Psoriasiform drug eruption induced by fluorescein sodium used for fluorescein
      angiography.

PMID- 10354059
TI  - Minocycline for the treatment of cutaneous silicone granulomas.

PMID- 10354058
TI  - The response of rosacea to eradication of Helicobacter pylori.

PMID- 10354060
TI  - Bowen's disease of the leg treated with weekly pulses of 5% fluorouracil cream.

PMID- 10354061
TI  - The time course of phototoxicity of topical PUVA: 8-methoxypsoralen cream-PUVA
      vs. 8-methoxypsoralen gel-PUVA.

PMID- 10354062
TI  - Urticaria pigmentosa occurring with juvenile xanthogranuloma.

PMID- 10354063
TI  - The effects of ultraviolet radiation on the human immune system.
AB  - The adverse outcome of increased ultraviolet (UV) irradiation on human health is
      currently of concern. While many experiments have been carried out in rodent
      models, fewer have been designed to test the effects of UV exposure in human
      subjects. This review concentrates on the modulations induced in the human immune
      system by UV, and outlines changes in antigen presentation by Langerhans cells
      and macrophages, in the activities of natural killer cells and T cells, and in
      cytokine regulation. Precautionary measures which might be taken to help protect
      people against the immunosuppressive action of UV irradiation are considered.

PMID- 10354064
TI  - The expression of peripheral benzodiazepine receptors in human skin: the
      relationship with epidermal cell differentiation.
AB  - The peripheral benzodiazepine receptor (PBR) is a protein of mitochondrial outer
      membranes utilizing porphyrins as endogenous ligands. PBR is part of a
      heteromeric receptor complex involved in the formation of mitochondrial
      permeability transition pores and in the early events of apoptosis. PBR may
      function as an oxygen-dependent signal generator; recent data indicate that these
      receptors may preserve the mitochondria of haematopoietic cell lines from damage
      caused by oxygen radicals. To identify PBRs in human skin, we used a specific
      monoclonal antibody directed against the C-terminus fragment of the human
      receptor. PBR immunoreactivity was found in keratinocytes, Langerhans cells, hair
      follicles and dermal vascular endothelial cells. Interestingly, confocal
      microscopic examination of skin sections revealed that PBR expression was
      strongly upregulated in the superficial differentiated layers of the epidermis.
      Ultrastructurally, PBRs were distributed throughout the cytoplasm but were
      selectively expressed on the mitochondrial membranes of epidermal cells. The
      elevated level of PBRs in the spinous layer was not associated with an increased
      number of mitochondria nor with an increased amount of mRNA as assessed by in
      situ hybridization on microautoradiographed skin sections. The present work
      provides, for the first time, evidence of PBR immunoreactivity in human skin.
      This mitochondrial receptor may modulate apoptosis in the epidermis; its
      increased expression in differentiated epidermal layers may represent a novel
      mechanism of natural skin protection against free radical damage generated by
      ultraviolet exposure.

PMID- 10354066
TI  - The 0.8% ultraviolet B content of an ultraviolet A sunlamp induces 75% of
      cyclobutane pyrimidine dimers in human keratinocytes in vitro.
AB  - Tanning lamps, emitting predominantly ultraviolet (UV) A, are used widely
      throughout the U.K. and other countries, but little is known about the long-term
      risks associated with their use, especially with respect to skin cancer. We have
      exposed normal human epidermal keratinocytes to a commercial tanning lamp and
      used the comet assay in association with DNA repair enzymes T4 endonuclease V and
      endonuclease III to investigate the relative yields of directly formed
      cyclobutane pyrimidine dimers (CPDs) and indirectly formed types of oxidative DNA
      damage. To put the risk of using tanning lamps into perspective, the sunbed used
      in this study (five Philips Performance 80W-R UVA tubes at a distance of 35 cm)
      was found to be approximately 0.7 times as potent at inducing CPDs as U.K.
      natural sunlight around noon on a fine summer day. This compares with a relative
      risk for CPD induction and erythema of 0.8 and 0.7 times, respectively,
      calculated from the relevant action spectra of tanning lamps and British noontime
      sunlight. To determine the relative contribution of UVB and UVA to the induction
      of CPDs and oxidative DNA damage, we modified the spectral output of the tanning
      lamps with a series of Schott WG UVB filters. The induction of CPDs was more
      dependent on the UVB component of the sunbed than oxidative types of damage.
      Schott WG UVB filters with 50% transmission at 305 nm reduced the yield of T4
      endonuclease V sites by 42% while there was only a 17% decrease in the yield of
      endonuclease III sites. CPD induction was not completely abolished after
      irradiation through WG335 and WG345 nm filters despite there being no detectable
      UVB. From these data, it was estimated that, although the tanning lamps emitted
      only 0.8% of their total output in the UVB range, these wavelengths were
      responsible for the induction of over 75% of CPDs and 50% of the oxidative damage
      to DNA.

PMID- 10354065
TI  - Ultraviolet irradiation induces cyclooxygenase-2 expression in keratinocytes.
AB  - We examined the effect of ultraviolet (UV) irradiation on the expression of
      cyclooxygenases in cultured HaCaT keratinocytes and in human skin in vivo. UVB
      irradiation (10 and 50 mJ/cm2) and hydrogen peroxide (200 micromol/L) increased
      cyclooxygenase-2 mRNA expression in HaCaT keratinocytes. No clear expression of
      cyclooxygenase-1 mRNA was detected in either control or stimulated HaCaT cells.
      Genistein, a tyrosine kinase inhibitor, suppressed both the basal and stimulated
      expression of cyclooxygenase-2 in HaCaT cells. UVB-induced cyclooxygenase-2 mRNA
      expression was partly inhibited by the antioxidant N-acetylcysteine and by H-7, a
      non-specific inhibitor of protein kinase C. Solar-simulated irradiation (40
      mJ/cm2) was found to induce in vivo both cyclooxygenase-2 mRNA and protein
      expression in human skin, whereas the expression of cyclooxygenase-1 mRNA
      remained at the basal level. Our results show that cyclooxygenase-2 expression is
      induced by UV irradiation and suggest that tyrosine kinases and reactive oxygen
      intermediates are involved in this induction of cyclooxygenase-2.

PMID- 10354067
TI  - Higher susceptibility to apoptosis following ultraviolet B irradiation of
      xeroderma pigmentosum fibroblasts is accompanied by upregulation of p53 and
      downregulation of bcl-2.
AB  - Apoptosis plays an important part as a defence mechanism in eliminating damaged
      cells. Among the complex factors which regulate apoptosis, the p53 tumour
      suppressor protein which is induced by DNA damage has been suggested to play a
      crucial part. Cells from xeroderma pigmentosum (XP) patients, which are defective
      in nucleotide excision repair, express higher levels of p53 and are highly
      susceptible to cell death after ultraviolet (UV) irradiation. To examine the
      relationships between DNA damage, p53 and apoptosis, normal and XP group A
      fibroblasts were exposed to UVB, and expressions of molecules involved in
      apoptosis were examined. Apoptosis of XP and normal cells was clearly detected at
      48 h after irradiation with UVB at doses of 5 and 40 mJ/cm2, respectively. Cells
      were positive by terminal deoxynucleotidyl transferase-mediated deoxyuridine
      triphosphate nick end labelling (TUNEL) staining under these exposure conditions.
      At 6 h after irradiation, p53 protein expression was induced in normal and XP
      cells at minimal doses of 10 and 2.5 mJ/cm2, respectively. Bcl-2 protein, an
      inhibitor of apoptosis, was downregulated prior to cell death following UVB
      exposure at doses that induced apoptosis in both cell types. These results
      suggest that DNA damage due to UVB induces apoptosis by upregulating proapoptotic
      molecules such as p53, and by downregulating anti-apoptotic molecules such as Bcl
      2.

PMID- 10354068
TI  - A histological study of human wrinkle structures: comparison between sun-exposed
      areas of the face, with or without wrinkles, and sun-protected areas.
AB  - Wrinkles are a major topic in dermocosmetology; the purpose of this work has been
      to go deeper into the knowledge of cutaneous damage underlying these
      modifications of skin surface. Up to now, the number of published works about the
      histological structure of wrinkles is not very large. Therefore to complete the
      findings, we studied 46 subjects of both sexes, between 57 and 98-year-old,
      enabling us to obtain 157 skin biopsies of wrinkles (face) and sun-protected
      areas (abdomen). We used different histological techniques involving
      histochemistry, immunohistochemistry, electron microscopy and quantification by
      image analysis in addition to classic standard techniques. This study has allowed
      us to confirm published structural modifications of wrinkles, but also to display
      many other original alterations. The increased thinning of the epidermis
      atrophied with age is confirmed by the study of desmoplakins outlining the
      cellular contours of keratinocytes. Such a thinning is accompanied by a decrease
      in several markers of epidermal differentiation at the bottom of the wrinkles:
      filaggrin, keratohyalin granules and transglutaminase I, disturbing desquamation
      and the capacity of the horny layer to retain water. The dermoepidermal junction
      is modified by a decrease of collagen IV and VII, which, combined with fewer and
      fewer oxytalan fibres under wrinkles, weakens this interface. The deposition of
      abnormal elastotic tissue in the dermis, with an interruption of these deposits
      under wrinkles and an atrophy of dermal collagen more pronounced under wrinkles,
      boosts the magnitude and depth of wrinkles. The composition of the other dermal
      constituents is also altered with, more particularly, a marked decrease of
      chondroitin sulphates in the papillary dermis under wrinkles, combined with an
      asymmetrical variation of glycosaminoglycans on both edges of wrinkles. The
      atrophy of the hypodermis, also more marked under wrinkles, with a thickening of
      fibrous lines, also makes the depth of wrinkles more pronounced. Wrinkle
      formation appears at the same time as numerous modifications in different
      cutaneous structures, which may be mutually amplified. Such a study by pointing
      out altered elements in skin physiology, makes the development of specific
      treatments possible in order to mitigate this unwelcome cutaneous deterioration.

PMID- 10354069
TI  - All-trans retinoic acid promotes the repair of tortuosity of elastic fibres in
      rat skin.
AB  - To elucidate the repair effects of all-trans retinoic acid (t-RA) on ultraviolet
      (UV)-induced tortuosity of elastic fibres in rat skin, the hind limbs of Sprague
      Dawley rats were irradiated at a suberythemal dose of UV (three times/week for 6
      weeks) and 0.025% t-RA in ethanol was applied topically five times/week for 6
      weeks. The three-dimensional arrangement of elastic fibres with special reference
      to their linearity was quantified by image analysis using a scanning electron
      microscope following a combination of intravascular resin injection and selective
      digestion using formic acid. When t-RA was topically applied for 6 weeks on
      wrinkles formed by 6 weeks' exposure of the skin of rat hind limbs to UV
      radiation, the wrinkles disappeared to control levels, concomitant with an
      improvement in skin elasticity. The linearity of the elastic fibres was
      significantly (P < 0.01) increased compared with age-matched UV-irradiated
      controls. These findings suggest that the degeneration and deposition of elastic
      fibres accompanied by an increase in their linearity is involved in the process
      of wrinkle repair by topical application of t-RA.

PMID- 10354070
TI  - Fetal antigen 1, a member of the epidermal growth factor superfamily, in
      neurofibromas and serum from patients with neurofibromatosis type 1.
AB  - Fetal antigen 1 (FA1) is a 26-32 kDa glycoprotein containing six epidermal growth
      factor-like repeats closely related to the delta/notch/serrate proteins in
      Drosophila. FA1 has been shown to be involved in cell differentiation in a
      juxtacrine/paracrine manner. As neurofibromatosis type 1 (NF-1), also called von
      Recklinghausen disease, involves aberrant growth of tissues derived from the
      neural crest, the expression of FA1 was examined in neurofibroma skin biopsies
      and serum from patients with NF-1. FA1 was found in the spindle cells of all (n =
      10) skin tumour specimens from adult NF-1 patients, whereas normal dermis was FA1
      negative. In adults, the serum FA1 levels were significantly higher in NF-1
      patients (n = 13) than in normal healthy controls (n = 177) (P = 0.037). In the
      group of children with NF-1 (n = 9), significantly higher serum FA1 levels were
      observed in those known to have complications with cerebral or spinal involvement
      (n = 4) (P = 0.014). The presence of FA1 in neurofibroma specimens and the
      elevated serum levels in patients with NF-1 suggests that FA1 may be involved in
      the pathogenesis of NF-1, perhaps acting as a growth promoting factor.

PMID- 10354071
TI  - The detection of tyrosinase-specific mRNA in bone marrow is not more sensitive
      than in blood for the demonstration of micrometastatic melanoma.
AB  - Recent reports suggest that as a marker of progression of malignant melanoma, the
      detection of tyrosinase mRNA in blood is of limited value. In the present study,
      we investigated whether the detection of tyrosinase mRNA by reverse transcription
      polymerase chain reaction (RT-PCR) in bone marrow samples might be a more useful
      method for the detection of micrometastatic melanoma. The presence of tyrosinase
      mRNA was analysed in blood and in bone marrow samples from 20 melanoma patients
      with widespread clinical metastases. Of these 20 patients, 12 were negative for
      tyrosinase mRNA in both blood and bone marrow. The remaining eight patients had
      tyrosinase mRNA in either blood or bone marrow: six in bone marrow and blood, one
      in bone marrow but not blood, and one in blood but not bone marrow. The
      sensitivity of tyrosinase mRNA detection by RT-PCR in bone marrow samples
      apparently does not exceed that in blood samples from metastatic melanoma
      patients. This seems to be independent of prior chemotherapy or immunotherapy. In
      contrast to different solid tumours, in melanoma, bone marrow seems not to be a
      significant reservoir for micrometastatic tumour cells.

PMID- 10354072
TI  - Predictive value of serum S100B for monitoring patients with metastatic melanoma
      during chemotherapy and/or immunotherapy.
AB  - In the immunohistology of malignant melanoma the use of polyclonal antibodies
      against protein S100 is well established. Recently, it was shown that S100B, a
      subunit of the S100 protein family, is detectable in the serum of melanoma
      patients and correlates with the stage of the disease in patients with metastatic
      melanoma. In the present study, the first evaluation of a large number of
      treatment observations (n = 77) in 64 different patients during chemotherapy
      and/or immunotherapy for advanced metastatic melanoma (stage IV) is presented.
      All patients received treatment according to standardized protocols comprising 8
      weeks of treatment followed by routine staging procedures to evaluate therapeutic
      outcome. In 13 patients with tumour enlargement after first-line therapy, a
      second-line treatment was subsequently given. S100B immunoradiometric assay
      (IRMA) tests were performed before, during and after treatment at scheduled time
      points. In the interim analysis at 4 weeks 29 of 37 (78%) patients with tumour
      progression during treatment showed a raised S100B level. In the final analysis
      at 8 weeks, 31 of these 37 patients (84%) demonstrated rising S100B values (P <
      0.001). Patients who responded to treatment (stable or regressing metastatic
      disease) showed constant or declining S100B levels in 38 of 40 patients (95%) at
      the interim analysis, at 8 weeks this was further increased to 39 of 40 patients
      (98%; P < 0.001). Thus, the use of S100B for monitoring treatment is adequate in
      the majority of cases. Our observations are of great interest for therapeutic
      trials of adjuvant and palliative therapies as the rise of S100B levels might
      indicate that re-staging and/or changes in therapy strategies should be chosen.

PMID- 10354073
TI  - The role of lymphocytes, granulocytes, mast cells and their related cytokines in
      lesional skin of linear IgA bullous dermatosis.
AB  - Linear IgA bullous dermatosis (LAD) is an acquired, heterogeneous, subepidermal
      blistering disease characterized by linear IgA deposits at the dermoepidermal
      basement membrane zone (BMZ), often with circulating IgA antibodies to the BMZ.
      The pathogenetic mechanism, possibly related to the immunophenotype of
      infiltrating cells, as well as the potential role of cytokines in determining
      bullous lesions, have not yet been elucidated. An immunohistochemical study was
      performed with a large panel of monoclonal antibodies [to CD3, CD4, CD8, CD25,
      CD1a, CD30, CD54, CD50, endothelial leucocyte adhesion molecule-1, vascular cell
      adhesion molecule-1, myeloperoxidase (MPO), eosinophil cationic protein EG1 and
      EG2, tryptase, HLA-DR, human interleukin (IL)-3, human IL-5, human IL-8, human IL
      4, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma and
      granulocyte/macrophage colony-stimulating factor] using the alkaline phosphatase
      antialkaline phosphatase procedure on lesional and perilesional skin of nine
      patients (one male, eight female; age range 8 months-80 years) with clinical,
      histological and immunofluorescent proven LAD. The predominant infiltrating
      cells, distributed mostly inside and below the bullae, were neutrophils and
      eosinophils which showed intense activation (MPO +, EG1 +, EG2 +). The
      lymphocytic infiltrate, consisting principally of CD4 +, HLA-DR + and CD30 + T
      cells, had a predominantly perivascular distribution. Proinflammatory cytokines,
      such as TNF-alpha and IFN-gamma, showed a moderate focal expression on the dermal
      perivascular sites; IL-8 was found to have a particularly intense staining on all
      the epidermal cell layers and at perivascular and vascular sites. Other
      cytokines, such as IL-4 and IL-5, showed a prevalent intracytoplasmic staining on
      some cells of the dermal infiltrate (probably mastocytes and lymphocytes), and at
      the dermal-epidermal separation sites there was also an intense scattered
      distribution of IL-5. The specific tissue lesions of LAD may be the consequence
      of the IgA deposits at the BMZ and also of the release of these cytokines
      together with tissue damage enzymes derived from neutrophils or eosinophils.

PMID- 10354074
TI  - Characterization of skin cytokines in bullous pemphigoid and pemphigus vulgaris.
AB  - The purpose of this study was to determine cytokine and cell marker expression in
      perilesional skin biopsies from patients with the autoimmune blistering diseases
      bullous pemphigoid (BP, n = 21) and pemphigus vulgaris (PV, n = 7).
      Immunohistochemistry and in situ hybridization were used to detect T helper (Th)1
      [interleukin (IL)-2, interferon (IFN)-gamma] and Th2 (IL-4, IL-5, IL-13) protein
      and mRNA. Perilesional skin biopsies from patients with BP were characterized by
      the deposition of IL-4, IL-13 and IL-5. In patients with BP, IL-4 and IL-13
      localized to mononuclear cells within the dermal infiltrate while IL-5 was
      predominately expressed at the dermal-epidermal junction. BP skin sections also
      expressed vascular cell adhesion molecule 1 on endothelial cells, not seen in
      patients with PV. PV biopsies were remarkable for a mixed Th1/Th2 pattern of
      cytokine expression, including the presence of IL-2, IFN-gamma and IL-4 and the
      absence of IL-5 and IL-13. In situ hybridization detected mRNA for IL-4 and IL-5
      in the cellular infiltrate of BP patients, and IL-2 in a patient with PV. In
      vitro binding assays demonstrated that normal human eosinophils, activated by
      coculture in IL-5, bound preferentially to BP skin sections that contained
      detectable in vivo bound IL-5. The predominance of Th2 cytokines in BP, in
      association with increased binding of eosinophils in vitro, suggests that Th2
      cytokines are relevant in the recruitment and adhesion of eosinophils within the
      dermal infiltrates of patients with BP, and may play a part in the pathogenesis
      of blister formation.

PMID- 10354075
TI  - Lichen sclerosus: evidence that immunological changes occur at all levels of the
      skin.
AB  - An immunohistochemical approach was used to characterize the inflammatory
      infiltrate in vulval lichen sclerosus, using monoclonal antibodies to CD3, CD4,
      CD8, CD68 and HLA-DR. Significant numbers of CD4 + and CD8 + lymphocytes were
      observed in the dermal band of inflammatory cells in approximately equal
      proportions. Less numerous CD4 + and CD8 + lymphocytes also occurred adjacent to
      the dermoepidermal junction and occasionally in the lower epidermis. Increased
      numbers of cells staining with the monocyte/macrophage marker CD68 were also
      present in the band of inflammatory cells as well as being scattered diffusely
      throughout the sclerotic region. Expression of HLA-DR in the lichen sclerosus
      specimens was increased within the inflammatory infiltrate and around blood
      vessels in the dermis. All the vulval lichen sclerosus specimens also
      demonstrated some HLA-DR expression around the keratinocytes, suggesting that
      these keratinocytes might be involved in antigen presentation. We also studied
      the expression of CD44 and its isoforms 3G5 (marker of V3), 8G5 (marker of V6),
      3D2 (marker of V4/5) and IE8 (marker of V8/9). CD44 has been proposed to play a
      part in lymphocyte homing, cell-matrix interaction (particularly with hyaluronic
      acid), lymphocyte activation and malignant progression of certain tumours. The
      epidermis of the lichen sclerosus specimens appeared to demonstrate a greater
      intensity of staining with the pan-CD44 marker F10-44, and reduced staining with
      3G5, 3D2 and IE8 compared with normal skin. Like normal skin, the dermis of the
      lichen sclerosus specimens did not demonstrate staining with 3G5, 3D2, 8G5 or
      1E8, but did show staining with F10-44. However, the pattern of the dermal
      staining with F10-44 reflected the position of the inflammatory infiltrate and
      was sparse in the five sections where there was a prominent sclerotic zone, but
      increased in the three sections where there was a prominent band of inflammation
      cells. Our results demonstrate evidence of immunological changes at all levels of
      skin involved by lichen sclerosus, including the epidermis.

PMID- 10354076
TI  - Cellular changes in denervated tissue during wound healing in a rat model.
AB  - There is increasing evidence that innervation, possibly mediated via
      neuropeptides, promotes wound healing. This study presents data on the early
      cellular events during healing in denervated tissue. Free oblique groin flaps
      were raised on 25 adult Sprague-Dawley rats. Excisional wounds were placed within
      the flap and in two control sites, the contralateral inguinal region and the
      thorax. The absence of innervation in the free flap wounds was confirmed 10 days
      after surgery by indirect immunofluorescence with a pan-neuronal marker. The
      cellular infiltrate of the wounds was analysed immunohistochemically with a panel
      of antibodies to rat macrophages and monocytes (ED1), rat B lymphocytes (CD45R)
      and T lymphocytes (CD2). The immunostained cellular infiltrate was quantified at
      2, 4, 7 and 10 days postoperatively. Our results show that denervated wounds have
      a significantly lower macrophage and T-lymphocyte count at day 4 of wound healing
      (P < 0.05). Inflammatory cells, particularly macrophages, are known to play an
      important part in wound healing and their reduced chemotaxis in denervated tissue
      may be related to the observed delay in wound closure.

PMID- 10354077
TI  - Androgen-induced delay of hair growth in the golden Syrian hamster.
AB  - The golden Syrian hamster flank organ has been used to study the stimulatory
      effect of androgens on sebaceous glands and hair. Androgens cause the sebaceous
      glands and hair follicles in this organ to grow. We have made the novel
      observation that exogenously administered androgen, testosterone propionate (TP),
      suppresses hair growth in the area surrounding the flank organ. When given in a
      time-release (systemic) subcutaneous dosage form (pellet), 25 mg TP inhibited the
      regrowth of clipped hair in peri-flank organ skin for up to 21 days; however, by
      28 days hair grew back to the same extent as in controls. The peak serum level of
      testosterone in TP-treated animals occurred at 14 days, and declined thereafter.
      When two separate TP pellets (25 mg/pellet) were administered 14 days apart in
      order to maintain high serum levels for 28 days, the amount of hair regrowth
      after 35 days was identical to animals receiving a single TP pellet or placebo.
      This suggests that the systemic level of testosterone was not the only factor in
      hair regulation. Hair growing within the flank organ appeared to be unaffected by
      TP administration. In the golden Syrian hamster, androgen, as in humans, can
      exert stimulatory and inhibitory effects on hair growth depending on the body
      site. We conclude that this animal model could serve as a useful system to
      investigate the mechanisms responsible for the opposing effects of androgen on
      hair growth.

PMID- 10354078
TI  - Hair removal using the ruby laser: clinical efficacy in Fitzpatrick skin types I
      V and histological changes in epidermal melanocytes.
AB  - The ruby laser is effective in removing unwanted body hair. The occurrence of
      cutaneous side-effects such as blistering, hypopigmentation and
      hyperpigmentation, however, remains problematic. These side-effects are more
      commonly seen in patients with dark coloured skin, which partly explains the
      relative scarcity of information on the efficacy of ruby laser hair removal in
      such patients. The mechanisms of the occurrence of these side-effects are also
      not known. It was the aim of this study to evaluate the efficacy of ruby laser
      assisted hair removal in patients with Fitzpatrick skin type V in a retrospective
      clinical study and to evaluate the mechanism of post-treatment pigmentary change
      in a prospective clinical study. The percentage reduction in hair density in
      patients with skin type V was assessed after a variable period following
      treatment with the Chromos 694 Depilation Ruby Laser, and was compared with the
      results of those with skin types I-IV. To study the pigmentary change and
      melanocyte numbers after laser irradiation, ex-vivo scalp skin and serial patient
      biopsies were taken and stained with S-100, dopa oxidase and Masson-Fontana
      methods. Laser treatment reduced melanocyte numbers as measured by DOPA stain but
      not by S100. Laser treatment resulted in the clearance of pigment from the
      epidermis on histology. Ruby laser was shown to be effective in removing unwanted
      hair from patients with dark coloured skin, but with a higher incidence of
      cutaneous side-effects. The occurrence of hypopigmentation after laser
      irradiation was thought to be due to the suppression of melanogenesis in the
      epidermis rather than to destruction of the melanocytes.

PMID- 10354079
TI  - Pilocarpine-induced cholinergic sweat secretion compared with emotional sweat
      secretion in atopic dermatitis.
AB  - We studied pilocarpine-induced cholinergic sweating, emotional sweating and
      sympathetic reflex sweating in atopic dermatitis (AD) patients. Secreted sweat
      was measured both with equipment that continuously records sweat rate and with a
      filter paper method that measures sweat weight absorbed. Comparison of the two
      methods revealed that the filter paper method underestimated the sweat secretion
      in AD patients. While AD patients showed no significant abnormalities in
      emotional sweating and sympathetic reflex sweating, the duration of pilocarpine
      induced sweating was prolonged. The time from the maximal sweat rate until the
      sweat rate fell to half of the maximal rate was significantly longer in AD
      patients than in control subjects. In contrast, the time from the beginning of
      sweat secretion until the maximal sweat rate was not significantly different
      between AD patients and control subjects. There was no significant difference
      between AD patients and control subjects in sweat volume secreted in 20 min after
      pilocarpine iontophoresis. In AD patients, the total sweat volume secreted after
      pilocarpine iontophoresis was greater than in control subjects, although not
      significantly. These results suggest that the system of deactivation of
      pilocarpine-induced sweat secretion is impaired in AD patients whereas the
      activation system is not altered.

PMID- 10354080
TI  - The management of moderate to severe atopic dermatitis in adults with topical
      fluticasone propionate. The Netherlands Adult Atopic DermatitisStudy Group.
AB  - This study was designed to investigate a long-term therapeutic strategy for the
      management of recurring atopic dermatitis (AD) in adults using fluticasone
      propionate (FP) ointment (CutivateTM) whereby FP could help to prevent a relapse
      of AD once symptoms were under control. Adult patients with chronic, moderate to
      severe AD entered this multicentre study. All patients were initially treated
      with FP 0.005% (g/g) ointment in two different regimens. Patients whose AD had
      been completely healed by these treatments then entered a long-term treatment
      phase applying FP or placebo ointment once daily, two times per week for 16 weeks
      to 'known' healed lesions. By the end of the initial treatment period, mean
      SCORAD values had significantly (P < 0.0005) improved from baseline. Patients who
      entered the maintenance phase and were treated with intermittent FP for up to 16
      weeks, demonstrated its superior efficacy (P = 0.018) over placebo, maintaining
      the improvements achieved after the initial treatment phase, reducing risk of
      relapse and delaying time to relapse (P = 0.013). No significant changes were
      detected in either treatment group in serum cortisol levels or in skin thickness
      measurements. Intermittent FP applied two times per week maintained a significant
      level of control, and delayed relapse of AD by comparison with placebo.

PMID- 10354081
TI  - Robert Willan and the French Willanists.
AB  - In 1798, Robert Willan published the founding textbook of British dermatology. In
      adopting the elementary lesions principle previously described by Josef Plenck
      and improving the nomenclature of the skin diseases, Willan established a method
      for the diagnosis and a doctrine for the nosology of the cutaneous diseases.
      Introduced into France by Biett in the 1810s, the Willanist method, which allowed
      diagnosis on the basis of objective criteria, was adopted by the majority of the
      dermatological community. However, as a doctrine, Willanism, the use of
      elementary lesions as a framework for classifying diseases, became the subject of
      lasting debate. In fact, apart from a few, most leading French dermatologists did
      not accept Willan's doctrine and preferred classifications according to systems
      which were supposed to reflect the best understanding of the cutaneous diseases:
      physiological, aetiological and pathological. Willanism is still used by every
      dermatologist as a method for recognizing skin diseases. It constitutes a firm
      link to the founding period of modern dermatology and remains a bastion against
      uncertain hypotheses.

PMID- 10354082
TI  - The treatment of mild pemphigus vulgaris and pemphigus foliaceus with a topical
      corticosteroid.
AB  - Seven patients with mild pemphigus vulgaris (n = 3) or pemphigus foliaceus (n =
      4) were treated with a very potent topical corticosteroid alone. Clobetasol
      propionate 0.05% cream was applied to mucosal lesions and involved skin twice a
      day for at least 15 days, then progressively tapered. Pemphigus was considered to
      be controlled if healing of lesions was obtained, with a 75% decrease in the
      number of new lesions per week without addition of any systemic treatment. In all
      seven patients, the disease was controlled initially with healing of cutaneous
      lesions within 15 days, while healing of mucosal lesions took at least 1 month.
      In four patients, remission was maintained with topical corticosteroid alone for
      a mean 19-month follow-up. In three patients, relapse occurred after 2-11 months,
      requiring a systemic treatment.

PMID- 10354083
TI  - Analysis of c-kit exon 11 and exon 17 of urticaria pigmentosa that occurred in
      monozygotic twin sisters.
AB  - Genomic DNA extracted from peripheral blood mononuclear cells of monozygotic twin
      patients with urticaria pigmentosa was investigated for mutations of proto
      oncogene c-kit. Neither the patients nor their families had genomic mutations in
      exon 11 or exon 17 of c-kit. The patients did not have any systemic involvement
      or bone marrow abnormalities. There are indications that some genetic factors may
      participate in the pathogenesis of urticaria pigmentosa in monozygotic twins. In
      the present patients, factors other than genomic faults in exon 11 and exon 17 of
      c-kit may be responsible for the pathogenesis.

PMID- 10354084
TI  - A child with localized vulval pemphigoid and IgG autoantibodies targeting the C
      terminus of collagen XVII/BP180.
AB  - Localized vulval pemphigoid of childhood (LVPC) has previously been reported in
      six girls. Clinical features and immunopathological data have suggested it to be
      a morphological variant of bullous pemphigoid. Epitope targets of the
      autoantibodies of these patients have not been defined in detail. We describe a 9
      year-old girl with possible cicatricial LVPC and circulating IgG antibodies
      directed against native collagen XVII/BP180, its 120-kDa soluble ectodomain and
      against the C-terminus of collagen XVII/BP180. No reactivity was detected towards
      the NC16A domain of collagen XVII/BP180. Linear IgG and C3 deposits were found
      along the cutaneous basement membrane zone. On 1 mol/L salt-split skin, IgG
      autoantibodies were shown to bind to the epidermis, and the HLA type II allele
      DQB1*0301, a marker with significantly increased occurrence in patients with
      ocular and oral cicatricial pemphigoid, was identified in this patient. Our data
      suggest that LVPC is a variant of bullous pemphigoid in which direct
      immunofluorescence microscopy combined with immunoblot analysis can deliver
      valuable diagnostic information for differential diagnosis. However,
      differentiation between the scarring and non-scarring course of the disease
      cannot be made with the present diagnostic markers and therefore careful follow
      up of patients with LVPC is required.

PMID- 10354086
TI  - Combination treatment with extracorporeal photopheresis, interferon alfa and
      interleukin-2 in a patient with the Sezary syndrome.
AB  - Extracorporeal photopheresis is generally accepted as standard therapy for the
      leukaemic and erythrodermic variant of cutaneous T-cell lymphoma, the Sezary
      syndrome (SS). Because of the limited efficacy in some patients with SS,
      combination therapy is often necessary. We report a new combination therapy for
      an intensively treated 62-year-old woman with advanced SS (T4N1BM1, stage IVb).
      Previous treatment with PUVA, retinoids alone and in combination with
      photopheresis, chlorambucil, and chemotherapy using cyclophosphamide,
      doxorubicin, vincristine and prednisone failed and were associated with
      significant side-effects. Six cycles of combination therapy with extracorporeal
      photopheresis, low-dose interferon alfa and interleukin-2 resulted in fading of
      the erythroderma and in a decrease of Sezary cells in the white blood cell count.
      The CD4/CD8 ratio decreased from 66 to 6 and the proportion of CD4 + CD7 - cells
      from 47% to 11%. Only mild side-effects such as influenza-like symptoms, fever
      and nausea were observed. Two months after this therapy, the patient developed
      enlarged lymph nodes without erythroderma, and died 1 year later from the
      lymphoma. Combination therapy with extracorporeal photopheresis, interferon alfa
      and interleukin-2 might be useful in selected patients with SS.

PMID- 10354085
TI  - Comel-Netherton syndrome complicated by papillomatous skin lesions containing
      human papillomaviruses 51 and 52 and plane warts containing human papillomavirus
      16.
AB  - We describe a 28-year-old woman with characteristic clinical signs of Comel
      Netherton syndrome (CNS) who showed numerous plane warts on her face and forearms
      and papillomatous skin tumours affecting her groins and genitoanal skin. Using
      human papillomavirus (HPV) type-specific primers for cutaneous and mucosal HPV
      types we identified HPV 16-specific sequences in plane warts and HPV 51- and HPV
      52-specific DNA in papillomatous skin from the patient's groins, suggesting a
      pathogenetic role (cofactor) for HPV in the development of verrucous skin lesions
      in patients with CNS. Whether the susceptibility to HPV infections is due to
      decreased cellular immunity or epidermal defence mechanisms remains to be seen.

PMID- 10354087
TI  - Squamous cell carcinoma complicating chronic venous leg ulceration: a study of
      the histopathology, course and survival in 25 patients.
AB  - We have studied 25 cases of squamous cell carcinoma in chronic venous leg ulcers.
      Twenty-three of the patients were dead and two were alive. The mean age at cancer
      diagnosis was 78.5 years. The median survival was 1 year. Eleven tumours were
      well-differentiated, 10 moderately and four poorly. All patients with a poorly
      differentiated tumour died within a year. Metastases were certain in eight cases.
      The disease was lethal in 10 cases which included all poorly differentiated
      tumours. The survival of the study group was significantly shortened compared
      with a control group of patients with lower limb non-melanoma skin cancer (n =
      433) from the Swedish Cancer Registry (P = 0.0084). When diagnosed, squamous cell
      carcinoma in chronic leg ulcers merits a thorough investigation of the degree of
      differentiation and spread. Assertive treatment is indicated as poorly
      differentiated tumours and some moderately differentiated tumours may be fatal.

PMID- 10354088
TI  - Angiolymphoid hyperplasia with eosinophilia associated with arteriovenous
      malformation: a clinicopathological correlation with angiography and serial
      estimation of serum levels of renin, eosinophil cationic protein and interleukin
      5.
AB  - We present a case of angiolymphoid hyperplasia with eosinophilia (ALHE) affecting
      the auricular area of a 31-year-old man, which clinically mimicked arteriovenous
      malformation (AVM). The histology and laboratory data distinctively revealed
      ALHE, while angiography demonstrated typical findings of AVM. Although several
      reports have hitherto mentioned the relationship between ALHE and AVM, the
      aetiology of the disease remains unknown. During the 3 years treatment course, we
      performed angiography several times to assess the efficacy of the treatments and
      compared the clinical and pathological findings, based on the hypothesis that AVM
      might be a cause of ALHE. This study showed first, that the clinicopathological
      findings of ALHE correlated with the extent of AVM shown by angiography, so that
      AVM could be a primary cause of ALHE. Secondly, systemic corticosteroids and
      local irradiation therapy produced only a temporary effect on the inflammatory
      changes of ALHE; therefore, surgical resection is recommended as a curative
      treatment. Thirdly, the patient's serum levels of renin, eosinophil cationic
      protein and interleukin 5 corresponded closely with the clinical course of ALHE.

PMID- 10354089
TI  - The wide spectrum of clinical expression in Adams-Oliver syndrome: a report of
      two cases.
AB  - Two children are described with the combination of aplasia cutis congenita (ACC)
      and transverse limb defects known as Adams-Oliver syndrome. Whereas in the first
      child the typical features of ACC, syndactyly and transverse nail dystrophy were
      only mildly expressed and associated defects of the central nervous system and
      cardiac malformations were absent, the second child suffered from a very severe
      expression of the syndrome, with a combination of ACC, syndactyly, cutis
      marmorata telangiectatica congenita and multiple cardiac and central nervous
      system malformations which resulted in fatal central respiratory insufficiency.

PMID- 10354090
TI  - Lipodystrophia centrifugalis abdominalis infantilis in a 4-year-old Caucasian
      girl: association with partial IgA deficiency and autoantibodies.
AB  - We report the third case of lipodystrophia centrifugalis abdominalis outside East
      Asia. A 4-year-old Caucasian girl developed an area of bluish erythema on the
      left side of the lower abdomen which spread centrifugally to the umbilical and
      inguinal areas with depression of the skin resulting from the loss of
      subcutaneous fat, surrounded by an erythematous border. This unusual skin disease
      was characterized by clinical and histological examination. Laboratory tests
      revealed a partial IgA deficiency, antinuclear antibodies and IgG antibodies
      against gliadin.

PMID- 10354091
TI  - Paronychia associated with antiretroviral therapy.
AB  - We report six HIV patients who developed painful periungual inflammation of
      several nails during treatment with the antiretroviral drugs indinavir and
      lamivudine. The lesions appeared 2-12 months after starting treatment. The
      occurrence of paronychia in HIV patients has recently been reported in two groups
      of patients receiving either indinavir or lamivudine. Dermatologists should be
      aware of this recently reported and probably not uncommon side-effect of
      antiretroviral treatment in order to avoid an invasive approach to the nail
      lesions.

PMID- 10354092
TI  - Expression of cytokeratin antigen 20 in perianal Paget's disease.

PMID- 10354093
TI  - Proteolytic inactivation of transforming growth factor beta3 by elastase in
      venous leg ulcers: implications for clinical trials using topically-applied
      peptide growth factors.

PMID- 10354094
TI  - Light chain multiple myeloma with peripheral leucocytosis presenting as
      scleroderma amyloidosum of the Alambda-type.

PMID- 10354095
TI  - Sweet's syndrome with systemic lupus erythematosus and herpes zoster.

PMID- 10354096
TI  - Lues maligna.

PMID- 10354097
TI  - Relapsing leucocytoclastic vasculitis as the initial manifestation of acute
      brucellosis.

PMID- 10354098
TI  - Strongyloidiasis, angio-oedema and natural killer cell lymphocytosis.

PMID- 10354099
TI  - Cholangiocarcinoma associated with bullous pemphigoid.

PMID- 10354100
TI  - Postmenopausal frontal fibrosing alopecia.

PMID- 10354101
TI  - Poliosis circumscripta associated with scalp naevi: a report of four cases.

PMID- 10354102
TI  - Sarcoidosis in a child treated successfully with allopurinol.

PMID- 10354103
TI  - Sarcoidosis and HIV infection: influence of highly active antiretroviral therapy.

PMID- 10354104
TI  - Regression of metastatic angiosarcoma of the skin after systemic treatment with
      liposome-encapsulated doxorubicin and interferon-alpha.

PMID- 10354105
TI  - Autologous haematopoietic progenitor transplantation in advanced mycosis
      fungoides.

PMID- 10354106
TI  - Pseudocatalase treatment in xeroderma pigmentosum: a case report.

PMID- 10354107
TI  - Treatment of poikiloderma of Civatte with the potassium titanyl phosphate (KTP)
      laser.

PMID- 10354108
TI  - Autologous whole blood intramuscular injection as a cure for chronic urticaria:
      report of a patient in whom intradermal injection of autologous serum continued
      to cause a weal-and-flare response.

PMID- 10354109
TI  - Infective endocarditis associated with atopic eczema.

PMID- 10354110
TI  - Majocchi's granuloma caused by Trichophyton tonsurans in a cardiac transplant
      recipient.

PMID- 10354111
TI  - Terbinafine-induced neutropenia.

PMID- 10354112
TI  - Cyclosporin and pregnancy.

PMID- 10354113
TI  - Mees' lines due to cyclosporin.

PMID- 10354114
TI  - Haemophagocytosis in bone marrow rhabdomyosarcoma.

PMID- 10354115
TI  - Fetal cells in the maternal circulation: feasibility for prenatal diagnosis.

PMID- 10354116
TI  - Why do inhibitors arise in patients with haemophilia A?

PMID- 10354117
TI  - PK-LR gene mutations in pyruvate kinase deficient Portuguese patients.
AB  - In nine unrelated Portuguese patients with pyruvate kinase (PK) deficient
      anaemia, whose symptoms ranged from a mild chronic haemolytic anaemia to a severe
      anaemia presenting at birth and requiring multiple transfusions, the PK-LR gene
      mutations were identified and correlated with their phenotypes. Five different
      mutations were identified, three of them for the first time: a missense mutation
      1670G --> C on exon 12 and two 5' splice donor site (GT) mutations on intron 8
      [IVS8(+2)T --> G] and intron 10 [IVS10(+1)G --> C]. Two previously described
      missense mutations, 1456C --> T and 993C --> A, were also found. The
      genotype/phenotype correlation showed that patients with two missense mutations
      or with a missense mutation and a splicing mutation had a mild haemolytic
      anaemia. The three patients with severe anaemia, who were transfusion dependent
      until splenectomy, were homozygous for the splicing site mutations IVS10(+1)G -->
      C or IVS8(+2)T --> G.

PMID- 10354118
TI  - Identification of a novel promoter mutation in the human pyruvate kinase (PK) LR
      gene of a patient with severe haemolytic anaemia.
AB  - Using direct sequencing we analysed the pyruvate kinase (PK) LR gene of a patient
      with severe haemolytic anaemia due to PK deficiency. A novel promoter mutation 
      249delA relative to the translation initiation site and the common 1529A mutation
      in exon 11 of the gene could be identified. Reverse transcription (RT)-PCR
      analysis combined with restriction digestion revealed that the -249delA mutation
      leads to a reduction in the amount of mRNA produced from this allele to about 6%
      of normal. We assume that both mutations would account for the PK deficiency in
      the compound heterozygous patient.

PMID- 10354119
TI  - Cellular visualization of tissue prokallikrein in human neutrophils and
      myelocytes.
AB  - The vasoactive peptides bradykinin and kallidin (lysyl-bradykinin) have been
      implicated in diapedesis, a cellular process by which neutrophils migrate through
      endothelial cell gap junctions. The kinin peptides are released from their
      precursor moiety, kininogen, by the specific action of endoproteinases, the
      kallikreins. Kininogens have been demonstrated on the surface of neutrophils, and
      the presence of a competent processing enzyme such as tissue prokallikrein in
      neutrophils has been postulated, but firm evidence for this is still lacking. We
      have raised antibodies to a synthetic peptide that is a sequence copy of the
      activation segment of human TK and demonstrated that the anti-peptide antibodies
      specifically recognized the zymogen but not the active form of kallikrein. Using
      these anti-peptide antibodies, we showed by Western blotting, immunocytochemistry
      and electron microscopy that the tissue prokallikrein antigen was localized in
      neutrophils and their precursor cells, the myelocytes. We further demonstrated by
      in situ hybridization the presence of tissue kallikrein mRNA in the mature
      neutrophils and myelocytes. Our findings lend credence to the hypothesis that
      upon release and activation, neutrophil-borne TK acts on cell-associated
      kininogens to trigger the release of kinins, which may open endothelial gates for
      neutrophil diapedesis.

PMID- 10354120
TI  - High serum levels of M-CSF and G-CSF in Kawasaki disease.
AB  - To examine any role of macrophage colony-stimulating factor (M-CSF), in the
      immune responses in Kawasaki disease (KD), we serially assayed M-CSF and several
      related cytokines using ELISA. In 10 paediatric patients with KD the level of M
      CSF was significantly higher in the acute phase than in the convalescent phase
      (1476.1 +/- 443.6 v 805.0 +/- 184.7 U/ml). Higher levels of serum granulocyte
      colony-stimulating factor (G-CSF) and interleukin-6 were also found in the acute
      phase. These results suggest that M-CSF, G-CSF and interleukin-6, derived from
      monocytes as monokines or derived from vascular endothelial cells, might play an
      important role in the acute phase of KD.

PMID- 10354121
TI  - Serum G-CSF levels are not increased in patients with antibody-induced
      neutropenia unless they are suffering from infectious diseases.
AB  - By the use of a G-CSF-specific ELISA we determined the serum granulocyte-colony
      stimulating factor (G-CSF) levels in 63 patients with antibody-induced
      neutropenia including neonatal immune neutropenia, autoimmune neutropenia, and
      drug-induced immune neutropenia. In the sera of 20 patients, elevated G-CSF
      levels of 60-1006 pg/ml (normal <39 pg/ml) were observed. These patients suffered
      from infectious diseases at the time of blood collection. G-CSF levels normalized
      after successful antibiotic treatment, indicating that increased G-CSF production
      in patients with immune neutropenia may be primarily the result of infection and
      not of neutropenia.

PMID- 10354122
TI  - Thrombosis and bleeding in myeloproliferative disorders: identification of at
      risk patients with whole blood platelet aggregation studies.
AB  - Seventy-five patients with chronic myeloproliferative disorders were studied to
      investigate platelet function by simultaneous measurement of platelet aggregation
      by the impedance method and ATP dense granule release using a whole blood
      platelet lumi-aggregometer, in an attempt to identify patients at risk for
      thrombosis and bleeding. Thirty-nine patients had at least one abnormal result
      indicating platelet hyperactivity (i.e. impedance or release with one agonist
      being above the reference range); 16 patients had platelet hypoactivity (i.e. at
      least one result was below the reference range), whilst 14 had co-existence of
      hyper- and hypoactivity. Six patients had normal results. 20/53 patients with
      platelet hyperactivity (alone or mixed) had a positive history of venous and/or
      arterial thrombosis; in comparison, only two of the other 22 patients had a
      positive history. During a median follow-up of 33 months, nine patients with and
      one patient without platelet hyperactivity respectively developed new thrombotic
      events before the addition of specific therapy. A total of 50 patients with and
      eight patients without platelet hyperactivity respectively received specific
      treatment including aspirin and/or cytotoxic therapy. All but one elderly patient
      with platelet hyperactivity have remained free of new thrombotic events on
      specific therapy. Two of the 17 patients with platelet hypoactivity had major
      clinical bleeding. These observations highlight the need to test platelets for
      hyper- as well as hypo-function and suggest a useful role for routine whole blood
      platelet aggregation studies to identify the patients at risk for thrombosis or
      bleeding.

PMID- 10354123
TI  - Platelet-reactive IgG antibodies cloned by phage display and panning with IVIG
      from three patients with autoimmune thrombocytopenia.
AB  - Autoimmune thrombocytopenic purpura (AITP) is a severe disease in children with a
      still unknown aetiology. It is not known why AITP can either be transient and
      self limiting or become chronic. The beneficial use of intravenous
      immunoglobulins (IVIG) in certain groups of AITP patients has been proven. It is,
      however, not clear how IVIG functions. To analyse patient-derived monoclonal IgG
      platelet autoantibodies that interact with IVIG in an anti-idiotypic manner, the
      combinatorial antibody phage display system was applied. From three different
      patients a large number of clones specifically reacting with IVIG molecules were
      derived. Many of these IVIG binders also reacted strongly with platelets in ELISA
      and FACS, in contrast to IVIG binders derived from a healthy individual. The
      heavy and light chain variable regions were sequenced and compared with each
      other and with databases. In all three AITP patients clones with a striking
      complementarity-determining region (CDR) sequence homology to each other and to
      many of the known anti-platelet antibodies were observed. Selected Fab-phages
      representing the characteristic variable regions that occurred in the
      investigated patients with AITP may now be used to clone potentially regulatory
      anti-idiotypes from healthy donors by phage display.

PMID- 10354124
TI  - Hepatocyte growth factor in serum after injection of unfractionated and low
      molecular weight heparin in healthy individuals.
AB  - Soluble heparin displaces the cytokine hepatocyte growth factor (HGF) from
      heparan sulphate proteoglycans on the cell surface and in the extracellular
      matrix into the circulation. We examined serum HGF elevation after heparin
      injections, and whether there is a difference between unfractionated heparin (UH)
      and low molecular weight heparin (LMWH) in their ability to increase serum HGF.
      20 healthy individuals were randomized to a single injection of intravenous or
      subcutaneous UH or LMWH. There was a significant increase in HGF from
      pretreatment values. This HGF was bioactive. When these preparations were
      compared on the basis of their serum concentrations (anti-factor Xa activity or
      molar concentrations), the increase in HGF was greater in individuals receiving
      UH than LMWH. When UH or LMWH were administered over a 5 d period, the increase
      in HGF, as well as the difference between treatments to induce HGF, remained
      stable throughout the treatment. In five patients treated with continuous
      intravenous heparin infusion HGF was increased throughout the treatment period of
      5-7 d. In summary, the rise in bioactive HGF after heparin treatment was stable
      during continued treatment. UH was more potent in inducing HGF increase than
      LMWH, both after a single injection and after several days of treatment.

PMID- 10354125
TI  - The role of haematological factors in diabetic peripheral arterial disease: the
      Edinburgh artery study.
AB  - The relationship between haematological factors and peripheral arterial disease
      (PAD) among diabetics has not been widely examined. 1592 men and women aged 55-74
      years were selected from the general population. They underwent an assessment for
      PAD and a glucose tolerance test. 288 subjects (18.7%) were identified as having
      diabetes or impaired glucose tolerance (IGT). Among the diabetes/IGT group,
      median levels of fibrinogen, von Willebrand factor (VWF), tissue plasminogen
      activator (t-PA), fibrin D-dimer and plasma viscosity were higher in subjects
      with PAD than those without PAD (P </= 0.05). The prevalence of PAD was higher in
      those with diabetes/IGT (20.6%) compared to those with normal glucose tolerance
      (12.5%) (odds ratio 1.64; 95% CI 1.17, 2.31). After separate adjustment for
      fibrinogen, VWF, t-PA, fibrin D-dimer, leucocyte elastase, plasma viscosity and
      haematocrit, those with diabetes/IGT no longer had a significantly higher risk of
      PAD compared to those with a normal glucose tolerance test. Simultaneous
      adjustment for the first four of these haematological factors reduced the risk of
      PAD among subjects with diabetes/IGT to 1.11 (95% CI 0.76, 1.63). Increased
      levels of haemostatic factors may partly explain the higher prevalence of PAD in
      diabetic/IGT subjects compared to normal glucose-tolerant subjects. Future
      randomized controlled trials involving the indirect lowering of levels of
      haematological factors should help to explain whether the associations reported
      here are of causal significance.

PMID- 10354126
TI  - The effect of sample size on fresh plasma thromboplastin ISI determination.
AB  - The possibility of reduction of numbers of fresh coumarin and normal plasmas has
      been studied in a multicentre manual prothrombin (PT) calibration of high
      international sensitivity index (ISI) rabbit and low ISI human reference
      thromboplastins at 14 laboratories. The number of calibrant plasmas was reduced
      progressively by a computer program which generated random numbers to provide
      1000 different selections for each reduced sample at each participant laboratory.
      Results were compared with those of the full set of 20 normal and 60 coumarin
      plasma calibrations. With the human reagent, 20 coumarins and seven normals still
      achieved the W.H.O. precision limit (3% CV of the slope), but with the rabbit
      reagent reduction < 50 coumarins with 17 normal plasmas led to unacceptable CV.
      Little reduction of numbers from the full set of 80 fresh plasmas appears
      advisable. For maximum confidence, when calibrating the ISI of a new reagent, it
      would always seem worthwhile to use the full number of patients' and normal
      plasmas at each centre for the initial calibration, i.e. 60 fresh coumarin and 20
      fresh normal plasmas. Smaller numbers should achieve the required precision with
      the lower ISI reagent.

PMID- 10354127
TI  - Platelet glycoprotein IIIa polymorphism HPA 1b (PlA2): no association with
      platelet fibrinogen binding.
AB  - The role of the platelet glycoprotein (GP) IIIa polymorphism HPA 1b (PlA2) in the
      risk of arterial thrombosis is controversial. We investigated the effect of the
      1b allele on platelet fibrinogen binding by flow cytometry. Samples from 35
      healthy platelet and plasma donors possessing the 1b allele were compared with 35
      1a/1a donors. We found no allele-dependent difference in percentage of platelets
      binding fibrinogen (P = 0.6), nor in mean cell fluorescence (P = 0.3) following
      stimulation with ADP. These results render it unlikely that any relationship
      between the 1b polymorphism and arterial thrombosis is mediated by a significant
      effect on fibrinogen binding.

PMID- 10354128
TI  - Gly319 --> arg substitution in the dysfunctional prothrombin Segovia.
AB  - The molecular defect of a congenitally dysfunctional form of prothrombin,
      prothrombin Segovia, was identified in a patient with a severe bleeding tendency,
      reduced prothrombin coagulant activity, and normal antigen level. Nucleotide
      sequencing of amplified DNA revealed a G --> A change at nucleotide 7539 of exon
      9 of the prothrombin gene. This resulted in the substitution of Gly319 by Arg.
      The proband was homozygous for this mutation, his father and brother were
      heterozygous. We surmised that the substitution, which occurs near the site of
      cleavage of prothrombin by factor Xa (Arg320-Ile321), altered the conformation of
      the protein making the cleavage site inaccessible.

PMID- 10354129
TI  - Prothrombin carora: hypoprothrombinaemia caused by substitution of Tyr-44 by Cys.
AB  - Two members of a family from Carora, Venezuela, were found to have prothrombin
      activity levels at 4% of normal and undetectable antigen levels. All exons of the
      prothrombin gene from the proband were sequenced and a mutation at nucleotide
      1305 was identified that would result in the substitution of Cys for Tyr at
      residue 44. Residue 44 is present in the aromatic stack region of the protein.
      Substitution of a Cys in this region would result in an abnormal folding of the
      protein which could be the cause for the observed lack of secretion of the
      abnormal prothrombin.

PMID- 10354130
TI  - An improved micro-method for obtaining chromosome preparations from individual
      haemopoietic colonies.
AB  - A robust method for obtaining chromosome preparations from individual
      haemopoietic colonies in semi-solid media is described. The accumulation of
      metaphases and the hypotonic treatment of cells were carried out in the culture
      dish and individual colonies were transferred onto poly-L-lysine-treated slides
      and fixed stepwise prior to staining. The technique produced high yields of well
      spread metaphases facilitating clonal cytogenetic analysis.

PMID- 10354131
TI  - P-glycoprotein is an independent prognostic factor predicting relapse in
      childhood acute lymphoblastic leukaemia: results of a 6-year prospective study.
AB  - P-glycoprotein (P-gp), a cellular drug-efflux pump, is thought to be one of the
      major causes of multidrug resistance (MDR) in malignancies. Since therapeutic
      strategies are being developed to circumvent drug resistance by inhibiting P-gp
      function, large prospective studies evaluating the clinical relevance of P-gp in
      childhood acute lymphoblastic leukaemia (ALL) are warranted. P-gp expression was
      evaluated over a period of 6 years in 102 consecutive patients with de novo
      childhood ALL and in 35 children with relapse of ALL. Bone marrow and blood
      smears were studied immunocytochemically with two monoclonal antibodies at
      initial diagnosis and at relapse. P-gp expression was found in 14 (14%) patients
      at initial diagnosis. After induction treatment, complete remission was achieved
      in 100/102 patients (98%), of whom 19 relapsed. Cumulative event-free survival
      was significantly higher in the P-gp-negative group compared with the P-gp
      positive population (Logrank P = 0.02). Multivariate analysis showed the results
      to be independent of age, WBC count and karyotype, and concomitantly underlined
      the importance of MDR1 phenotype detection in childhood ALL. P-gp expression was
      more frequently found at relapse (34%) than at primary diagnosis (P = 0.01). In
      the relapsed patient group, P-gp-positive patients had a 2-fold greater risk for
      adverse clinical outcome than the P-gp-negative relapsed patients. P-gp
      expression was not induced by exposure to previous chemotherapy since the
      majority of P-gp-negative patients remained negative at relapse. P-glycoprotein
      expression in newly diagnosed childhood ALL is an independent adverse prognostic
      parameter with a predictive value for relapse.

PMID- 10354132
TI  - An investigation of the t(12;21) rearrangement in children with B-precursor acute
      lymphoblastic leukaemia using cytogenetic and molecular methods.
AB  - The t(12;21) is the commonest recurrent translocation in childhood acute
      lymphoblastic leukaemia (ALL), the presence of which has been suggested to be a
      good prognostic feature. We have studied 22 childhood cases of B-precursor ALL
      with this rearrangement, and have found no significant differences in event-free
      survival between these and a control group of patients with similar phenotypes.
      Using a variety of cytogenetic and molecular techniques, we have confirmed a
      strong association with co-expression of myeloid markers, frequent deletions of
      the short-arm of the untranslocated chromosome 12 homologue and duplication of
      the derivative chromosome 21. Intragenic deletion of the untranslocated ETV6 gene
      in 3/12 informative patients points to the likelihood of this gene being a target
      for deletion.

PMID- 10354133
TI  - CD99 (MIC2) expression in paediatric B-lineage leukaemia/lymphoma reflects
      maturation-associated patterns of normal B-lymphopoiesis.
AB  - We have recently shown that CD99 (MIC2) is differentially expressed during normal
      early B-cell development in the bone marrow (BM). Since immature B-cell
      precursors (BCP) are assumed to correspond to some extent to acute lymphoblastic
      leukaemia (ALL) and non-Hodgkin's lymphoma (NHL) cells with respect to patterns
      of phenotypic differentiation, we wondered whether the particular maturation
      associated expression patterns of CD99 in the normal BCP stages were conserved
      also in malignant cells. Therefore we compared malignant and physiological B
      cells from paediatric ALL/NHL and normal BM samples with respect to CD99
      expression using selective gating and semi-quantitative flow cytometry. Common
      ALLs (n = 45) were similar to their corresponding, very immature BCPs (stage 1)
      in expressing very high levels of CD99. Most pre-B ALLs (n = 16) were also CD99hi
      and thus differed from the patterns found in normal cytoplasmic mu-chain+ (cmu+)
      pre-B cells (stage 2, CD99lo). In particular, we found that those pre-B-ALL cases
      which were CD34+ also showed higher CD99 expression than the CD34- cases. This
      prompted us to investigate the levels of CD99 in those rare normal BCPs which
      also coexpress CD34 and cmu; these cells, which are transitory from stage 1 to
      stage 2, were found also CD99hi, thus precisely reflecting the patterns of CD34+
      pre-B ALLs. The blasts of Burkitt-type B-cell ALL/NHL samples (n = 13) expressed
      considerably less CD99, similarly to the more differentiated BCP stages 2 (cmu+)
      and 3 (surface mu-chain+). In summary, we found that paediatric B-lineage
      malignancies display remarkable synchrony regarding the levels of CD99 expression
      compared to their putative normal counterparts.

PMID- 10354134
TI  - Analysis of thiopurine methyltransferase variant alleles in childhood acute
      lymphoblastic leukaemia.
AB  - The role of 6-mercaptopurine (6MP) in the treatment of childhood acute
      lymphoblastic leukaemia (ALL) is well established. However, the efficacy of 6MP
      is significantly influenced by inactivation by the polymorphic enzyme thiopurine
      methyltransferase (TPMT). In the general population 89-94% have high TPMT
      activity, 6-11% have intermediate activity, and approximately 0.3% have low
      activity. Individuals with low-activity experience severe or fatal toxicity with
      standard 6MP doses. Prospective identification of this group of patients might
      prevent this problem. Recent identification of the molecular basis for low TPMT
      activity enabled rapid assessment of altered 6MP metabolism by PCR methods. This
      study evaluated the frequency of mutant TPMT alleles in 147 children with ALL.
      One patient was homozygous mutant (0.7%), and 16 patients were heterozygous for
      variant TPMT alleles (10.9%). The majority of mutant alleles were TPMT*3A. Both
      the allele frequency and the pattern of TPMT mutations were similar to that
      observed in an adult British population. The number of weeks when 6MP therapy was
      administered at full dose was determined in patients on MRC UKALL X and XI. The
      94 patients spent a median 11% of the maintenance period receiving no therapy as
      a result of haematological toxicity. There was no significant difference in the
      number of weeks when no therapy could be administered among patients with a wild
      type or heterozygous genotype. However, the one patient with a homozygous mutant
      genotype had severe haematological toxicity and no therapy could be administered
      for 53% of the maintenance period. This study demonstrates that 11.6% of the
      children had variant TPMT alleles. Prospective identification of TPMT genotype
      may be a promising tool for decreasing excessive haematological toxicity in
      individuals with low activity.

PMID- 10354135
TI  - Survival of human leukaemic B-cell precursors is supported by stromal cells and
      cytokines: association with the expression of bcl-2 protein.
AB  - We searched for cytokines with the potential to support the survival of human B
      cell precursor acute lymphoblastic leukaemia (pre-B ALL) cells. 47 patients with
      pre-B ALL were classified into four stages: stage I, CD19+CD10-CD20-; stage II,
      CD19+CD10+CD20-; stage III, CD19+CD10+CD20+cytoplasmic mu-heavy chain (cmu)-;
      stage IV, CD19+CD10+CD20+cmu. Interleukin (IL)-3 receptor alpha chain (IL
      3Ralpha) was expressed in all stages, whereas the expressions of IL-7Ralpha and
      IL-2Ralpha were pronounced in stages IV and II, respectively. Neither IL-3, IL-7
      nor IL-2 supported the survival of pre-B ALL cells. When pre-B ALL cells were
      layered on stromal, MS-10, cells, viability of the pre-B ALL cells increased.
      Addition of IL-3 to culture containing MS-10 cells enhanced the survival of pre-B
      ALL cells in all cases, whereas addition of IL-7 augmented the survival of pre-B
      ALL cells of some cases of stage III and all cases of stage IV. The survival of
      pre-B ALL cells was also supported by the conditioned media of MS-10 cells.
      Stromal-cell-derived factor 1 (SDF-1) supported the survival of pre-B ALL cells.
      Effects of the conditioned media of MS-10 cells were abrogated by an anti-SDF-1
      neutralizing antibody. The extent of survival of pre-B ALL cells supported by
      stromal cells and IL-3 and IL-7, correlated with the expression level of bcl-2
      protein. The effects of stromal cells may be in part related to SDF-1.

PMID- 10354136
TI  - Myeloid differentiation antigen and cytokine receptor expression on acute
      myelocytic leukaemia cells with t(16;21)(p11;q22): frequent expression of CD56
      and interleukin-2 receptor alpha chain.
AB  - We report the cellular characteristics of cells from three patients with de novo
      acute myelocytic leukaemia (AML) with t(16;21)(p11;q22), two M4 and one M5a
      according to the FAB classification, and two permanent cell lines with
      t(16;21)(p11;q22), TSU1621MT and YNH-1. The FUS/ERG fusion mRNA was demonstrated
      in all cases by reverse transcriptase-polymerase chain reaction (RT-PCR). The
      immunophenotypes of the AML cells, and YNH-1 and TSU1621MT cell lines with
      t(16;21) were characterized as CD34+CD33+CD13+CD11b+CD18+CD56+ HLA-DR-/+. Cells
      from all samples strongly expressed c-kit, granulocyte colony-stimulating factor
      receptor (G-CSFR), c-fms (macrophage colony-stimulating factor receptor),
      interleukin-3 receptor alpha chain (IL-3Ralpha), and granulocyte macrophage
      colony-stimulating factor receptor alpha chain (GM-CSFRalpha), and these data
      corresponded well to the growth responsiveness to the cytokines. IL-2Ralpha
      expression was also found in all t(16;21) samples, but IL-2 did not act on the
      proliferation of the leukaemic cells in in vitro cultures. G-CSF distinctly
      promoted the proliferation of leukaemic cells of t(16;21) AML, but did not
      enhance the expression of MPO and neutrophil differentiation of these cells. Our
      findings indicate that AML cells with t(16;21) preserve stem cell properties such
      as CD34 and c-kit expression, and suggest that they have the potential to
      differentiate into a monocytic lineage. The relationship between the unique
      cellular characteristics (especially CD56 and IL-2Ralpha expression) and FUS/ERG
      protein remains undetermined.

PMID- 10354137
TI  - Inhibition of p34cdc2 dephosphorylation in DNA damage- and topoisomerase II
      inactivation-induced G2 arrests in HL-60 cells.
AB  - Doxorubicin induces DNA breakage by stabilizing a cleavable topoisomerase II-DNA
      complex. In contrast, topoisomerase II catalytic inhibitor ICRF-193 and
      uncoupling inhibitor aclarubicin interfere with the cleavable complex formation.
      We analysed combination effects of these drugs using two-dimensional flow
      cytometry of DNA content and the terminal deoxynucleotidyl transferase-mediated
      dUTP-biotin nick end-labelling assay. Both ICRF-193 and aclarubicin attenuated
      the cytotoxic effect of doxorubicin on HL-60 cells (85% and 46% maximum
      reduction, respectively), which suggested that doxorubicin exerts its cytotoxic
      effect at least partially through the topoisomerase II-dependent DNA cleavage.
      Doxorubicin and ICRF-193 both induced G2 arrest in HL-60 cells, by which they may
      have reduced the cytotoxic effect of vincristine. Indeed, although ICRF-193
      inhibited doxorubicin-induced apoptosis, ICRF-193 and doxorubicin cooperated in
      arresting HL-60 cells at G2 phase. These results indicated that G2 arrest was
      caused not only by DNA damage but also through a DNA damage-free, topoisomerase
      II inactivation-induced pathway. Western blot analysis showed that both types of
      G2 arrest were mediated by the inhibition of p34cdc2 dephosphorylation.

PMID- 10354138
TI  - Clinical significance of cyclin-dependent kinase inhibitor p27Kip1 expression and
      proliferation in non-Hodgkin's lymphoma: independent prognostic value of p27Kip1.
AB  - The cyclin-dependent kinase inhibitor p27Kip1 is a negative cell cycle regulator
      linking extracellular growth-regulatory signals to the cell cycle machinery in
      G1. We investigated the pattern and prognostic value of p27Kip1 expression in a
      population-based group of 203 non-Hodgkin's lymphoma (NHL) patients. The
      expression of p27Kip1 was identified by immunohistochemistry and correlated with
      Ki-67 expression and clinical features. Correlation with outcome was determined
      using uni- and multivariate analysis stratified by clinical grade. Except for
      very aggressive NHL, there was a negative correlation between p27Kip1 and Ki-67
      expression. Low expression of p27Kip1, defined as nuclear p27Kip1 expression in
      <40% of malignant cells, was predictive of poor survival in indolent and
      aggressive NHL. However, even in this regard, very aggressive lymphomas behaved
      differently as those with low p27Kip1 expression tended to do better. Likewise, a
      high proliferation rate (Ki-67 >40%) was associated with poor survival in
      indolent and aggressive lymphomas. Multivariate analysis using the proportional
      hazards model showed that only p27Kip1, and not Ki-67, maintained independent
      prognostic significance in indolent and aggressive lymphomas (relative risk = 2.
      0; P = 0.0095). The low cost and simplicity of this standard immunohistochemistry
      analysis makes p27Kip1 a promising and suitable prognostic marker in routine
      diagnostic laboratories in a standard diagnostic panel.

PMID- 10354139
TI  - Chromosome aberrations are restricted to the CD56+, CD3- tumour cell population
      in natural killer cell lymphomas: a combined immunophenotyping and FISH study.
AB  - Natural killer (NK) cell lymphomas are a newly recognized entity of non-Hodgkin's
      lymphoma with a highly aggressive clinical course and strong association with
      Epstein-Barr virus (EBV) infection. Although no recurrent chromosome aberrations
      have been identified in NK-cell lymphoma, deletions of 6q and trisomy 7 have been
      described repeatedly in this type of lymphoma. In this study we attempted to
      determine the immunophenotypes of tumour cells with certain chromosome
      aberrations, i.e. deletions of 6q and trisomy 7, in three cases of NK cell
      lymphomas by means of combined immunophenotyping and fluorescence in situ
      hybridization (FISH). In all three cases clonal chromosome aberrations were
      detected only in CD56+ cells but not in CD3+ or CD5+ cells. However, not all
      CD56+ cells were shown to contain these chromosome aberrations. Double
      immunophenotyping combined with FISH confirmed that the chromosome aberrations
      occurred only in CD56+CD3- cells. This study indicates that chromosome
      aberrations in NK-cell lymphomas are restricted to the CD56+, CD3- and CD5- cell
      population and that NK-cell lymphomas are indeed derived from mature true NK
      cells and not from T lymphocytes.

PMID- 10354140
TI  - Semiquantitative analysis of residual disease in patients treated for adult T
      cell leukaemia/lymphoma (ATLL).
AB  - Many adult T-cell leukaemia/lymphoma (ATLL) patients who respond to induction
      treatment, then relapse. Knowing the clonality pattern of residual tumourous
      clones during treatment could help understand disease evolution and aid
      therapeutic decisions. We developed a sensitive and semi-quantitative molecular
      analysis of these clones in ATLL patients. DNA samples from PBMCs derived from
      eight ATLL patients were studied over time by quadruplicate linker mediated PCR
      (LMPCR) amplification of HTLV-1 integration sites. Patients were treated with
      combination chemotherapy, zidovudine-interferon-alpha and/or by peripheral stem
      cell transplantation or allogeneic bone marrow transplantation. Persistence of
      tumourous clones at a high frequency (>1/300 PBMCs) was frequently observed, even
      in complete responders, and was invariably correlated with relapse and/or poor
      outcome. Fluctuation in the frequency of some tumourous clones was observed with
      evidence for clonal change under treatment in one patient, indicating that
      treatment of ATLL can result in the selection of resistant clones. Finally,
      allogeneic bone marrow transplantation (BMT) using an HTLV-1 infected sibling as
      donor was found to be associated with long-lasting disappearance of tumourous
      clones and a possible cure of the disease. Long-term persistent clonal expansion
      of circulating HTLV-1 bearing T cells which derived from the donor bone marrow
      was evidenced in this patient. In conclusion, variable success in treatment of
      ATLL is probably due to the clonal heterogeneity which results in the selection
      of resistant clones. Semi-quantitative assessment of residual disease (RD)
      through LMPCR may predict treatment failure. Accordingly, additional therapy may
      be tailored to the clonality pattern observed after first-line therapy.

PMID- 10354141
TI  - Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by
      the proteasome-specific inhibitor lactacystin.
AB  - Ubiquitin-proteasome-dependent protein processing appears to be an essential
      component in the control of radiation-induced apoptosis in human lymphocytes.
      This control is altered in chronic lymphocytic leukaemia (CLL), compared to that
      of normal human lymphocytes which mainly showed high apoptotic values after
      irradiation, but in some cases no sensitivity was observed. Interestingly,
      lactacystin activated the apoptotic pathway in both radio-resistant and sensitive
      CLL cells, at doses which had no effect in normal cells where significantly
      higher concentrations were required. Therefore the resistance of some CLL cells
      to apoptosis initiation by radiation does not correlate to observed increased
      sensitivity to lactacystin. The nuclear level of the transcription factor NF
      kappaB or the cytoplasmic level of IkappaBalpha remained unaltered upon
      irradiation or lactacystin CLL cells treatment, suggesting that the activity of
      the other factors involved in apoptotic death control were altered through
      proteasomal inhibition. These results strongly suggest an essential role of the
      ubiquitin system in apoptotic cell death control in CLL lymphocytes. The
      inhibition of proteasome-ubiquitin-dependent processing could be a discriminatory
      apoptotic stimulus between normal versus malignant lymphocytes and therefore
      might potentially be of use in this specific human pathology.

PMID- 10354142
TI  - Low prevalence of flower cells in U.S.A. blood donors infected with human T
      lymphotrophic virus types I and II.
AB  - Large lymphocytes with basophilic cytoplasm and cleaved/cerebriform nuclei called
      flower cells have been described in human T-lymphotrophic virus type I (HTLV-I)
      seropositive individuals and may be precursors of adult T-cell leukaemia (ATL). A
      cohort of 546 HTLV-seropositive former blood donors, 32 HTLV-positive sexual
      partners of these donors and 799 HTLV-seronegative controls has been followed as
      part of the Retrovirus Epidemiology Donor Study. A novel methodology was
      developed to systematically review peripheral blood slides from these subjects
      for HTLV-related lymphocyte abnormalities, using an algorithm based on
      morphologic features to objectively identify flower cells. The algorithm
      included: absence of azurophil granules; nuclear chromatin condensation; cell
      size >1.5 small lymphocytes; nuclear to cytoplasmic ratio >80%; and presence of
      nuclear folding/lobulation. Peripheral slides from subjects were screened by a
      medical technologist blinded to HTLV status. 6.8% of HTLV-I subjects (P = 0.0001
      versus seronegatives), 0.9% of HTLV-II subjects and 1.1% of seronegatives were
      confirmed to have cells classified as flower cells by two haematologists using
      objective criteria, and blinded to serostatus. Despite the higher prevalence of
      flower cells in HTLV-I positives, no clinical correlations were found.
      Longitudinal follow-up may yield higher rates of cellular abnormalities as the
      sequelae of HTLV infection develop.

PMID- 10354143
TI  - Establishment of a near-triploid human B-cell lymphoma cell line with t(14;18)
      and a p53 gene point mutation.
AB  - We report a rare large B-cell non-Hodgkin's lymphoma having a characteristic near
      triploid cell population with add(17)(p22) and t(14;18)(q32;q21) translocation.
      We also established and characterized a new cell line (TK cell) derived from the
      present lymphoma. A codon 180 mutation (GAG --> GAT) in the p53 gene was
      detected. t(14;18)(q32;q21) was revealed juxtaposition of the bcl-2 and JH genes.
      Immunoprecipitation analyses of p53 and bcl-2 revealed that abnormality of the
      p53 protein and aberrant bcl-2 expression, which may protect cells from
      apoptosis, may be critical to the development of leukaemogenesis exhibiting near
      triploid chromosomes.

PMID- 10354144
TI  - Familial multiple myeloma: report of fifteen families.
AB  - To further define the frequency, clinical and biological features of familial
      multiple myeloma we performed a retrospective study of related patients who
      presented with multiple myeloma. Most cases of familial multiple myeloma were
      observed in siblings (10/15), in whom the mean age at diagnosis was similar to
      unrelated multiple myeloma. In successive generations the mean age at diagnosis
      was lower. Monoclonal component was identical (IgG kappa) in seven families.
      Familial history of monoclonal gammopathy of undetermined significance was
      observed in three families. Five other prospective studies of 1263 patients
      identified four affected families (3.2 per 1000 cases of multiple myeloma), and
      raise the question of a genetic background in multiple myeloma.

PMID- 10354145
TI  - A case of myelofibrosis with a t(4;13)(q25;q12): evidence for involvement of a
      second 13q12 locus in chronic myeloproliferative disorders.
AB  - Aberrations of 13q are frequently found in myeloproliferative disorders (MPD). In
      a case of primary proliferative polycythaemia which transformed to myelofibrosis,
      karyotype analysis at transformation revealed an acquired t(4;13)(q25;q12). FISH
      and Southern analysis demonstrated that the ZNF198 gene, disrupted in the
      t(8;13)(p11;q12) myeloproliferative syndrome, was unaffected by the t(4;13). FISH
      analysis mapped the 13q12 breakpoint to the genomic region flanked by the genetic
      markers D13S1126 and D13S1121. Physical mapping estimated this region to be <80
      kbp. Our results suggest the possibility of a novel gene, distinct from ZNF198,
      that is located at chromosome 13q12 and involved in the pathogenesis of
      myelofibrosis.

PMID- 10354146
TI  - Fludarabine-containing regimens severely impair peripheral blood stem cells
      mobilization and collection in acute myeloid leukaemia patients.
AB  - We studied the effects of an intensified induction/consolidation treatment
      containing fludarabine (ICE/FLAN/FLAN) on the mobilization and collection of
      peripheral blood stem cells (PBSC) in 31 consecutive untreated acute myeloid
      leukaemia (AML) patients. The complete remission (CR) rate was comparable to
      classic inductions (68% after ICE; 84% after ICE-FLAN I). To mobilize PBSC, 19
      patients received 10 microg/kg/d of granulocyte-colony stimulating factor (G-CSF)
      starting at day 13 after FLAN, 13 (69%) of whom were found to be nonmobilizers.
      When a second G-CSF administration was performed in 10/13 patients mobilization
      was either not achieved (8/10) or was considered insufficient (<1 x 106 CD34+
      cells/kg) (2/10) and all 13 were subsequently submitted to bone marrow harvest.
      The harvest was considered adequate in 12/13 (92%) patients and autologous BMT
      (ABMT) has so far been performed in 10/12 cases with a mean of 8.6 x 108/kg
      nucleated reinfused cells. The median times to neutrophil and platelet recovery
      after ABMT did not significantly differ from those of two previous series of
      patients treated with ABMT without fludarabine-containing regimens. Adequate
      amounts of PBSC were obtained in 6/19 (31%) patients, who were then reinfused.
      Median times for platelet recovery were significantly longer than in a previous
      series of 26 AML cases reinfused with PBSC after treatment with the ICE-NOVIA
      induction/consolidation regimen (125 v 20 d to 20 x 109 plt/l, P < 0.02; 218 v 37
      d to 50 x 109 plt/l, P < 0.02). In addition, times for platelet recovery after
      ICE/FLAN/FLAN were not significantly different from those in a previous group
      treated with ABMT performed after ICE/NOVIA,without fludarabine. We conclude that
      fludarabine-containing regimens severely impair mobilization and collection of
      PBSC in AML patients and seem unsuitable when PBSC autotransplantation is
      programmed.

PMID- 10354147
TI  - Different behaviour of fresh and cultured CD34+ cells during immunomagnetic
      separation.
AB  - In-vitro expansion of human cord blood (CB) cells could enhance peripheral blood
      recovery and ensure long-term engraftment of larger recipients in the clinical
      transplant setting. Enrichment of CD34+ cells using the MiniMACS column has been
      evaluated for the preparation of CB CD34+ cells before and after expansion
      culture. Repurification of CD34+ cells after culture would assist accurate
      phenotypic and functional analysis. When fresh CB mononuclear cells (MNC) were
      separated, the MACS positive (CD34+) fraction (90.1% pure) contained a mean (+/-
      SD, n = 5) of 93.0 +/- 8.0% of the eluted CD34+ cells, 99.6 +/- 0.7% of the CFU
      GM and all of the eluted long-term culture-initiating cells (LTC-IC). Cord blood
      CD34+ cells were then cultured for 14 d with IL-3, IL-6, SCF, G-CSF and GM-CSF,
      each at 10 ng/ml. The total cell expansion was 2490 +/- 200-fold and the CD34+
      cell expansion was 49 +/- 17-fold. The percentage of CD34+ cells present after
      expansion culture was 1.2 +/- 0.85%. When these cells were repurified on the
      MiniMACS column, the MACS positive fraction only contained 40.3 +/- 13.4% of the
      eluted CD34+ cells which was enriched for the mature CD34+ CD38+ subset, 24.4 +/-
      8.8% of the eluted CFU-GM and 79.5 +/- 11.0% of the LTC-IC. The remaining cells
      were eluted in the MACS negative fraction. In conclusion, repurification of
      cultured CD34+ cells does not yield a representative population and many
      progenitors are lost in the MACS negative fraction. This can give misleading
      phenotypic and functional data. Cell losses may be important in the clinical
      setting if cultured cells were repurified for purging.

PMID- 10354148
TI  - Peripheral blood progenitor cell (PBPC) counts during steady-state haemopoiesis
      enable the estimation of the yield of mobilized PBPC after granulocyte colony
      stimulating factor supported cytotoxic chemotherapy: an update on 100 patients.
AB  - Peripheral blood progenitor cells (PBPC) can be mobilized using chemotherapy and
      granulocyte colony-stimulating factor (G-CSF). We and others previously reported
      a correlation of steady-state PBPC counts and the PBPC yield during mobilization
      in a small group of patients. Here we present data on 100 patients (patients: 25
      non-Hodgkin's lymphoma (NHL), five Hodgkin's disease, 35 multiple myeloma (MM),
      35 solid tumour) which enabled a detailed analysis of determinants of steady
      state PBPC levels and of mobilization efficiency in patient subgroups. Previous
      irradiation (P = 0.0034) or previous chemotherapy in patients with haematological
      malignancies (P = 0.0062) led to a depletion of steady-state PB CD34+ cells. A
      correlation analysis showed steady-state PB CD34+ cells (all patients: r = 0.52,
      P < 0.0001; NHL patients, r = 0.69, P = 0.0003; MM patients: r = 0.66, P =
      0.0001) and PB colony-forming cells can reliably assess the CD34+ cell yield in
      mobilized PB. In patients with solid tumour a similar trend was observed in
      mobilization after the first chemotherapy cycle (r = 0.51, P = 0.05) but not if
      mobilization occurred after the second or further cycle of a sequential dose
      intensified G-CSF-supported chemotherapy regimen, when premobilization CD34+
      counts were 18-fold elevated (P = 0.004). When the patients with MM (r = 0.63, P
      = 0.0008) or with NHL (r = 0.65, P = 0.006) were analysed separately, a highly
      significant correlation of the steady-state PB CD34+ cell count to the mean
      leukapheresis CD34+ cell yield was found, whereas no correlation was observed for
      patients with a solid tumour. For patients with haematological malignancies
      estimates could be calculated which, at a specific steady-state PB CD34+ cell
      count, could predict with a 95% probability a defined minimum progenitor cell
      yield. These results enable recognition of patients who mobilize PBPC poorly and
      may assist selection of patients for novel mobilization regimens.

PMID- 10354149
TI  - Syngeneic stem cell transplantation for HIV-related lymphoma.
AB  - The treatment of human immunodeficiency virus (HIV)-related lymphoma is beset by
      a number of therapeutic limitations. High-dose chemotherapy followed by
      peripheral blood stem cell transplantation (PBSCT) for relapsed disease is one
      option, but may be compromised by unacceptable treatment-related morbidity and
      mortality. We describe an HIV-positive male with relapsed immunoblastic non
      Hodgkin's lymphoma (NHL) who successfully received salvage chemotherapy followed
      by a syngeneic PBSCT from his HIV-negative (hepatitis C positive) brother. At 15
      months post-transplant he remains in complete remission with low-level HIV viral
      load, an improved CD4 lymphocyte count and absent anti-hepatitis C antibodies. We
      believe selected patients with relapsed HIV-related NHL should be considered for
      high-dose therapy.

PMID- 10354150
TI  - A new preconditioning regimen with melphalan, busulphan and total body
      irradiation followed by low-dose immunosuppressant in allogeneic haemopoietic
      stem cell transplantation.
AB  - Twenty adult patients with high-risk leukaemia underwent allogeneic haemopoietic
      stem cell transplantation after melphalan, busulphan and total body irradiation
      followed by short-term methotrexate and low-dose cyclosporine or tacrolimus.
      Three patients developed veno-occlusive disease and no patient developed renal
      dysfunction. Seven patients experienced grade II-IV acute graft-versus-host
      disease (aGVHD) and five patients experienced grade III-IV. The 3-year
      probabilities of relapse and leukaemia-free survival were 22 +/- 11% (95%
      confidence interval) and 50 +/- 11%, respectively. These data suggest that this
      preconditioning regimen followed by a low-dose immunosuppressant provided a more
      anti-leukaemic effect without increased regimen-related toxicity and aGVHD.

PMID- 10354152
TI  - Synthesis of Rh Fv phage-antibodies using VH and VL germline genes.
AB  - Antibodies to the D antigen of the Rh system use a restricted set of
      immunoglobulin V and J gene segments, especially VH DP50 and DP63, JH6, Vlambda
      DPL16 and Jlambda 2/3. These gene segments may confer a natural affinity on the
      antibodies for the D antigen and this hypothesis has been tested by constructing
      two single-chain Fv phage-antibody libraries based on the germline gene segments
      DP50 and DP63; structural variability was obtained by insertion of 11 amino acids
      in random sequence in the VHCDR3. 10 anti-D antibodies were selected from these
      libraries, each with a unique VHCDR3. In contrast, selections with the CcEe
      antigens produced antibodies reacting with the Rh polypeptide molecules but
      without strict blood group specificity. One of these latter DP50-based antibodies
      was converted into 12 different antibodies with specificity for E by replacing
      the original germline light chain with chains from a rearranged L chain library.
      The CDR1 and CDR2 sequences of the DP50-based antibodies were common to both anti
      D and anti-E molecules; differentiation between D and E specificity was dependent
      on VHCDR3 sequences and their correct pairing with an appropriate L chain.

PMID- 10354151
TI  - Rapid genotyping of human platelet antigen 1 (HPA-1) with fluorophore-labelled
      hybridization probes on the LightCycler.
AB  - Genotyping of human platelet alloantigens (HPA) has become an important procedure
      in the diagnosis and prevention of disorders such as neonatal alloimmune
      thrombocytopenic purpura, post-transfusion purpura, and refractoriness to
      platelet transfusion therapy. We present a single-tube method for HPA-1
      genotyping that combines rapid-cycle PCR with allele-specific fluorescent probe
      melting profiles for product genotyping. A fragment covering the polymorphic site
      is amplified in the presence of two fluorescently-labelled hybridization probes.
      During the annealing step of the thermal cycling, both probes bind to their
      complementary sequences in the amplicon resulting in resonance energy transfer,
      thus providing real-time fluorescence monitoring of PCR. Continuous aquisition of
      fluorescence data during a melting curve analysis at the completion of PCR
      revealed that loss of fluorescence occurred in an allele-specific manner as the
      detection probe, which was fully complementary to the HPA-1b allele, melted off
      the template. By determining the temperature at which maximum melting of the
      hybrids occurred, the two alleles were readily distinguishable. Using this
      method, genotyping of 32 samples was completed within 30 min without the need for
      any post-PCR sample manipulation, thereby eliminating the risks of end-product
      contamination and sample tracking errors. The genotypes determined with the
      LightCyclerTM were identical when compared with a conventional PCR and
      restriction fragment length polymorphism technique. The genotyping of HPA-1 on
      the LightCycler is a rapid and reliable method that is suitable for typing both
      small and large numbers of samples.

PMID- 10354153
TI  - Functional lymphocyte immunophenotypes observed in thalassaemia and haemophilia
      patients receiving current blood product preparations.
AB  - Immune abnormalities have been reported in recipients of cellular and plasma
      blood products. To document the effect of current transfusion practices, we
      performed ex vivo lymphocyte immunophenotypic studies on patients with
      thalassaemia major who had received multiple (leucocyte-depleted) transfusions
      and patients with haemophilia A and B who had received heat viral-inactivated
      factor concentrates. Patients with thalassaemia major showed a significant
      lymphocytosis, with mainly B-cell changes consistent with ongoing B-cell
      stimulation associated with chronic exposure to red cell antigens. Reduced T-cell
      IL-2Ralpha expression would be consistent with inhibition by desferrioxamine
      chelation therapy. In contrast, patients with haemophilia showed predominantly T
      cell changes. Patients with haemophilia A showed significantly elevated activated
      CD8+ cytotoxic T lymphocytes whereas those with haemophilia B showed an increase
      in CD8+CD11adim and CD4+CD45RA+ suppressor T cells. Several of the immune
      abnormalities found may be due to the presence of cytokines not removed by
      leucocyte filtration or destroyed by factor concentrate production (e.g. TGF
      beta) causing a T-helper-2-like response. The extensive lymphocyte
      characterization in this study has not previously been performed and has enabled
      a closer examination of the functional lymphocyte immunophenotypes seen in
      patients treated according to current transfusion practices.

PMID- 10354154
TI  - Enhanced circulatory parameters of human platelets cryopreserved with second
      messenger effectors: an in vivo study of 16 volunteer platelet donors.
AB  - Platelet transfusion represents an important component of the therapy for
      thrombocytopenic patients. Prolonged storage capabilities for platelets would
      alleviate many problems associated with blood banking. Unfortunately, current
      cryopreservation methods are complex to implement and result in loss of cell
      number and functional activity. Previous in vitro studies have shown that the use
      of ThromboSolTM, a platelet-stabilizing formulation, in the cryopreservation of
      platelets results in significant retention of cell number and in vitro functional
      activities in addition to reducing the DMSO requirement to only 2%. We evaluated
      the in vivo circulatory parameters of platelets cryopreserved with ThromboSol.
      Single donor platelet units were obtained from healthy volunteers (n = 16); the
      units were then split and cryopreserved with either ThromboSol and 2% DMSO or 6%
      DMSO alone. Following storage at -80 degrees C for 7-10 d the samples were
      thawed, washed and radiolabelled with either 51Cr or 111In. The paired samples
      were then mixed and reinfused into the autologous volunteer. At various time
      intervals following transfusion a blood sample was drawn and the quantity of
      circulating labelled platelets was determined. The percent recovery and survival
      time was determined by multiple-hit analysis. The ThromboSol-treated platelets,
      as compared to the 6% DMSO-treated platelets, displayed statistically higher
      percent recovery (40.2% v 28.8%) and survival time (166.3 h v 152.1 h). These
      results demonstrated that platelets cryopreserved with ThromboSol displayed
      superior in vitro and in vivo characteristics as compared to the standard 6% DMSO
      method. The use of ThromboSol allowed for a 3-fold reduction in the DMSO
      concentration in conjunction with a 40% increase in circulating cell number and
      normal survival times.

PMID- 10354155
TI  - Endogenous thrombopoietin serum levels during multicycle chemotherapy.
AB  - Little is known about the behaviour of endogenous thrombopoietin (TPO) serum
      levels during rapid sequences of dose-intensified chemotherapy. To characterize
      the relationship between TPO levels and platelet counts in this setting we
      serially measured both parameters over the entire treatment period of patients
      receiving multicycle polychemotherapy. We found TPO and platelet responses to be
      generally antagonistic through all cycles. However, a cross-correlation analysis
      indicated that TPO responses preceded platelet responses by approximately one day
      in all patients. The cumulative severity of thrombocytopenia observed over
      successive cycles was accompanied by an increasing TPO response which tended to
      grow overproportionally in relation to the degree of peripheral thrombocytopenia.
      These findings are consistent with a model suggesting that both platelet and
      megakaryocyte mass contribute to a receptor-dependent consumption process
      regulating the endogenous TPO level. In order to develop optimal schedules for
      exogenous TPO administration it might be important to consider endogenous TPO
      response characteristics.

PMID- 10354157
TI  - Indolent course as presentation in t-prolymphocytic leukaemia.

PMID- 10354156
TI  - Evaluation of leptin protein levels in patients with Cooley's anaemia.

PMID- 10354158
TI  - Chronic hepatitis c virus infection and primary cutaneous B-cell lymphoma.

PMID- 10354160
TI  - Splenic irradiation as management of ITP.

PMID- 10354161
TI  - Mutation of the WT1 gene in myelodysplastic syndrome and acute myeloid leukaemia
      post myelodysplastic syndrome.

PMID- 10354159
TI  - Budd-Chiari syndrome associated with homozygous factor V Leiden mutation.

PMID- 10354162
TI  - Lipid preparations of amphotericin for the treatment of fungal infections.

PMID- 10354163
TI  - Lipid preparations of amphotericin for the treatment of fungal infections 

PMID- 10354164
TI  - Lipid preparations of amphotericin for the treatment of fungal infections 

PMID- 10354165
TI  - The role of photodynamic therapy in dermatology.
AB  - Photodynamic therapy (PDT) involves selective photosensitization of a target
      tissue by means of a topically or systemically administered agent which is then
      activated by light to effect an oxygen dependent cytotoxic reaction. The
      production of reactive oxygen intermediates, including singlet oxygen, is
      localized to where the photosensitizer accumulates and induces apoptosis and
      vascular endothelial damage. First-generation photosensitizers are
      haematoporphyrin derivatives and are effective in treating certain nonmelanoma
      skin cancers. However, they induce cutaneous photosensitization for at least 4-6
      weeks and have a limited role in dermatology. Many second-generation
      photosensitizers, such as 5-aminolaevulinic acid, are associated with less
      prolonged photosensitization. Although PDT remains largely experimental, it has
      potential applications in both benign and malignant skin disease.

PMID- 10354166
TI  - Three Hong Kong Chinese cases of pretibial epidermolysis bullosa: a
      genodermatosis that can masquerade as an acquired inflammatory disease.
AB  - Three patients in two families presented with many years' history of fragile
      skin, blisters, erosions and scars affecting almost exclusively the shin areas,
      accompanied by a variable degree of itching. Two of the patients also had toenail
      dystrophy. Skin biopsy revealed dermal-epidermal blister formation and milia but
      no immunohistochemical evidence of immunoglobulin or complement deposition.
      Electron microscopic study of the lesional and perilesional skin showed very
      sparse or absent anchoring fibrils. Immunolabelling for type VII collagen using
      LH 7.2 monoclonal antibody revealed a bright, linear staining pattern at the
      dermal-epidermal junction. The clinicopathological features were thus compatible
      with pretibial epidermolysis bullosa, a subtype of dystrophic epidermolysis
      bullosa. Of note, the inflammatory nature of the skin lesions, and their
      resemblance to nodular prurigo and hypertrophic lichen planus, had caused
      diagnostic difficulties in all cases in the past. A high degree of awareness of
      this rare subtype of epidermolysis bullosa is important to establish the correct
      diagnosis, to allow for genetic counselling and to plan clinical management.

PMID- 10354167
TI  - Recalcitrant hand and foot warts successfully treated with photodynamic therapy
      with topical 5-aminolaevulinic acid: a pilot study.
AB  - The purpose of this pilot study was to determine if photodynamic therapy with
      topical application of 5-aminolaevulinic acid followed by irradiation with
      incoherent filtered and unfiltered light (ALA-PDT) is an effective therapy for
      recalcitrant hand and foot warts. In 30 patients with recalcitrant warts, 49
      regions with a total of 250 warts were randomized to one of the following five
      treatments: (i) ALA-PDT with white light applied three times within 10 days (W3);
      (ii) ALA-PDT with white light applied once (W1); (iii) ALA-PDT with red light
      applied three times within 10 days (R3); (iv) ALA-PDT with blue light applied
      three times within 10 days (B3), and (v) cryotherapy applied up to four times
      within 2 months (CRYO). The ALA-PDT treatment modality was repeated in case of
      partially responding warts. Significantly more warts were completely healed after
      W3 and W1 than after R3, B3 and CRYO (P < 0.01): 73% of the warts treated with W3
      were completely healed, 71% after W1, 42% after R3, 23% after B3 and 20% after
      CRYO. No scars were observed in the ALA-PDT treated areas and patients treated
      for foot warts were all able to walk after the treatment. No recurrences in
      completely responding ALA-PDT treated warts were observed after 12 months of
      follow-up. In conclusion, photodynamic therapy with topical 5-aminolaevulinic
      acid followed by irradiation with white light is a promising treatment for
      recalcitrant hand and foot warts.

PMID- 10354168
TI  - Pityriasis rubra pilaris in black South Africans.
AB  - Eighteen black South African patients with pityriasis rubra pilaris were
      prospectively studied, nine adults and nine children; patients with the classical
      types (namely I and III) constituted 75% of the group. Follicular involvement was
      very prominent, especially in the children with type III, but otherwise the
      clinical and histological findings did not differ from those reported in white
      patients. This is the first series of black African patients with this condition
      to be reported.

PMID- 10354169
TI  - Dermatomyositis-like eruption and leg ulceration caused by hydroxyurea in a
      patient with psoriasis.
AB  - We report the case of an elderly woman who had been on hydroxyurea for long
      standing widespread psoriasis. After approximately 5 years's treatment with
      hydroxyurea, she developed a symmetrical dermatomyositis-like eruption on her
      hands, together with bilateral leg ulceration. Although similar skin eruptions
      have been reported after long-term hydroxyurea treatment, all of the previous
      patients were being treated for myeloproliferative disorders. A dermatomyositis
      like eruption has not previously been reported to occur as a consequence of
      hydroxyurea treatment for psoriasis. Its recognition is important to prevent
      unnecessary investigation or treatment withdrawal.

PMID- 10354170
TI  - Isoniazid induced pellagra despite pyridoxine supplementation.
AB  - Although pellagra is a recognized complication of isoniazid therapy, the
      diagnosis may be overlooked or delayed--sometimes with life-threatening
      consequences. We report a case of isoniazid-induced pellagra which occurred
      despite pyridoxine supplementation. Drug withdrawal and supplementation with
      niacin led to a rapid and sustained clinical improvement. The possible mechanisms
      of isoniazid induced pellagra are discussed.

PMID- 10354171
TI  - Small-cell carcinoma of the lung presenting as a cutaneous metastasis of the lip
      mimicking a Merkel cell carcinoma.

PMID- 10354172
TI  - Erythrokeratoderma en cocardes.
AB  - The erythrokeratodermas are a distinct but clinically variable group of rare geno
      dermatoses, characterized by circumscribed erythematous and hyperkeratotic
      lesions. All attempts to establish a valid classification have been based on
      purely clinical and morphologic criteria. Erythrokeratoderma en cocardes, also
      known as genodermatose en cocardes or Degos' syndrome, was first described by
      Degos in 1947. The condition is characterized by large round plaques with
      concentric erythema and scaling having a target configuration, which remit and
      recur, in addition to scaly plaques as seen in erythrokeratoderma variabilis. A
      case of this rare genodermatosis is described.

PMID- 10354173
TI  - Plantar hyperkeratosis due to Fusarium verticillioides in a patient with
      malignancy.
AB  - We report the case of an 82-year-old man with hyperkeratosis of the right sole
      caused by a Fusarium verticillioides infection mimicking verrucous tuberculosis;
      the infection was confirmed by direct potassium hydroxide microscopy, biopsy and
      cultures. The biopsy specimen showed an unusually deep invasion of fungal
      elements into the epidermis. This is an uncommon presentation in a localized
      cutaneous infection by Fusarium but in this case, repeated local injuries were
      the portal of entry initiating the process. Clinical patterns of cutaneous
      fusarium infections in general are also discussed.

PMID- 10354175
TI  - Milia en plaque.
AB  - Milia plaque is an unusual and rare variant of milia. We now report a Chinese man
      with numerous milia within an erythematous plaque of the upper and lower eyelids;
      histology confirmed the diagnosis and showed pericystic inflammation. All but one
      of the previous 10 reported cases affected the ear or adjacent sites, and to our
      knowledge, this is the first reported case of milia en plaque affecting the
      eyelids.

PMID- 10354174
TI  - Skin eruption as the presenting sign of Hunter syndrome IIB.
AB  - We present a case of Hunter syndrome diagnosed because of skin eruption. A 4-year
      old Japanese boy presented with a 3-4-months history of papular lesions on the
      back and extremities. His growth and development were almost normal. His face was
      not of coarse appearance. He had multiple, whitish to skin-coloured, papules and
      nodules symmetrically distributed on the scapular regions and the extensor
      aspects of the upper arms and thighs. There was no family history of similar
      symptoms. Skin biopsy showed the deposition of a considerable amount of mucin in
      the dermis. Although physical examinations failed to detect any other signs of
      Hunter syndrome, X-rays showed the characteristic features of
      mucopolysaccharidosis: deformities of the vertebral bone, ribs, and pelvis.
      Mucopolysaccharide analysis of the urine revealed a marked increase in dermatan
      sulphate and heparan sulphate. The activity of iduronate sulphatase in the
      lymphocytes was deficient, which was diagnostic for Hunter syndrome. We emphasize
      that the skin eruption can be the earliest sign of Hunter syndrome, particularly
      in the mild form presenting with normal development and growth.

PMID- 10354176
TI  - Unusual giant comedo naevus.
AB  - Comedo naevi are usually well circumscribed, and although extensive cases have
      been reported individual lesions crossing the midline are rare. Associated
      neurological, skeletal and ophthalmological abnormalities are also recognized.
      thus, the patient now reported is unusual in that she had an extensive
      systematized comedo naevus with crossing of the midline but no associated
      abnormalities. Topical tretinoin was helpful in improving the texture and
      appearance of the comedones, and various larger lesions responded to curettage.

PMID- 10354177
TI  - Severe vulval apocrine acne successfully treated with prednisolone and
      isotretinoin.
AB  - Apocrine acne, otherwise known as hidradenitis suppurativa, is a chronic
      inflammatory scarring disease affecting the apocrine gland-bearing skin. We
      present a case of a 34-year-old woman with severe vulval apocrine acne who was
      successfully treated initially with prednisolone and then maintained on long-term
      isotretinoin. This case indicates that long-term treatment with isotretinoin may
      be more successful than the usual 4-6 months treatment regime.

PMID- 10354178
TI  - Cutaneous extravascular necrotizing granuloma (Churg Strauss granuloma).
AB  - Churg Strauss granuloma (cutaneous extravascular necrotizing granuloma) is a
      distinct entity which is associated with systemic immunoreactive or autoimmune
      diseases in a majority of cases. Typically, Churg Strauss granuloma presents as
      symmetrical papules or nodules on the extremities. There are two histological
      patterns: the classic pattern reveals palisading granuloma with central
      degenerated collagen, interspersed polymorphonuclear leukocytes, and
      leukocytoclastic debris; the focal basophilic necrosis pattern does not show
      palisading granuloma. We report two cases of Churg Strauss granuloma with
      different histopathological patterns.

PMID- 10354179
TI  - Hyperpigmentation caused by hyperthyroidism: differences from the pigmentation of
      Addison's disease.
AB  - Two cases of hyperthyroidism with hyperpigmentation are presented. In both cases,
      hyperpigmentation was seen on the lower extremities, most strikingly on the
      shins, backs of the feet and the nail bed. Histology of the pigmented skin showed
      basal melanosis and heavy deposition of haemosiderin around dermal capillaries
      and sweat glands. Treatment with mercazol in both cases resulted in no
      significant waning of pigmentation. Distribution of hyperpigmentation,
      haemosiderin deposition and poor response to the treatment may be characteristic
      features of the pigmentation caused by hyperthyroidism, and may represent
      differences from the pigmentation seen in Addison's disease.

PMID- 10354180
TI  - Actinic keratoses arising only on sun-exposed vitiligo skin.
AB  - A 71-year-old woman with vitiligo developed multiple actinic keratoses only on
      the vitiligo skin of sun-exposed areas. She had worked outdoors as a farmer for a
      long period. Although actinic skin cancers arising on vitiligo skin have rarely
      been reported, the present case demonstrates that vitiligo skin is more
      susceptible to actinic damage than normal skin. Patients with vitiligo should be
      well informed about the importance of sun protection.

PMID- 10354181
TI  - Polymorphic light eruption occurring solely on an area of naevoid telangiectasia.
AB  - We report the case of a 60-year-old woman presenting with polymorphic light
      eruption occurring solely on an area of acquired naevoid telangiectasia. We have
      hypothesized that increased blood flow in the telangiectatic skin may reduce the
      threshold for expression of photosensitivity by permitting enhanced inflammatory
      cell trafficking to the overlying tissue.

PMID- 10354182
TI  - Dendritic cells: role in skin diseases and therapeutic applications.
AB  - Dendritic cells have entered the centre stage of applied immunological research.
      Dermatologists knew for quite some time about the extraordinary capacity of these
      cells to induce immune responses. Recent progress in using these cells as potent
      adjuvant for the treatment of human cancer has inaugurated an unprecedented wave
      of publications about the role of these cells for the pathogenesis and treatment
      of various types of cancers and infectious diseases. This short review attempts
      to follow some of the origins of dendritic cell research with special regard to
      dermatology and gives a perspective on newer developments such as the use of
      dendritic cells to induce antigen-specific tolerance.

PMID- 10354183
TI  - Bullous pemphigoid: correlation of mucosal involvement and mucosal expression of
      autoantigens studied by indirect immunofluorescence and immunoblotting.
AB  - Twenty patients with bullous pemphigoid were studied prospectively: sequential
      sera, in different phases of the disease, were collected over a period of
      approximately 2 years. The sera were tested using standard immunofluorescence
      techniques with salt-split and intact human tissue from different sites of the
      body (thigh, breast, oral mucosa, vagina); an early serum of each patient was
      tested by Western blotting. The concentration of circulating antibodies detected
      by the intact skin and intact mucous membranes was similar; split tissue was more
      sensitive than intact tissue. For eight of 19 patients, split vagina and
      occasionally split oral mucosa (in the same patients) were much less sensitive
      than all other tissues. Furthermore, there was a correlation between autoantibody
      reactivity with split mucous membrane tissues and clinical mucosal involvement.
      These results strongly suggest heterogeneity of antigens or epitopes expressed
      between tissues. In both split skin and mucosa all sera consistently detected an
      antigen on the epidermal side of the split regardless of the stage of the
      disease. Immunoblotting studies showed no correlation between specific antigens
      and mucosal expression or skin involvement.

PMID- 10354184
TI  - Polymorphic eruption of pregnancy and herpes gestationis: comparison of
      granulated cell proteins in tissue and serum.
AB  - Polymorphic eruption of pregnancy (PEP) and herpes gestationis (HG) are pregnancy
      related dermatoses of unknown aetiology with eosinophil infiltration which, at
      early stages, may show similar clinical and histopathological features. To
      determine the relative contributions of eosinophils, neutrophils and mast cells
      to the pathogenesis of PEP and HG through deposition of granule proteins, we
      studied tissue and serum from 15 patients with PEP and 10 with HG. Using indirect
      immunofluorescence with antibodies to human eosinophil granule major basic
      protein (MBP), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein
      (ECP), neutrophil elastase and mast cell tryptase, we determined and compared
      cellular and extracellular staining patterns in lesional skin biopsy specimens
      and, using immunoassay, measured MBP, EDN, and ECP in patients' sera. Eosinophil
      infiltration and extracellular protein deposition of all three eosinophil granule
      proteins were present in both PEP and HG indicating a pathogenic role for
      eosinophils in both diseases. Staining for eosinophil granule proteins was
      especially prominent in urticarial lesions and around blisters in HG. EDN and ECP
      serum levels in PEP and ECP serum levels in HG were significantly increased
      compared with those in normal pregnant and normal nonpregnant serum. Neutrophils
      were more prominent in HG specimens than in PEP specimens; extracellular
      neutrophil elastase was minimally present and similar in both diseases. Mast cell
      numbers and extracellular tryptase deposition did not differ between the two
      diseases and did not differ from mast cell counts in skin of normal pregnant
      women. This study shows that eosinophil granule proteins are deposited
      extracellularly in tissue and are increased in serum in both PEP and HG.
      Moreover, eosinophil involvement in the two diseases is more consistent than
      neutrophil and mast cell involvement. Comparatively, tissue eosinophil
      infiltration and extracellular protein deposition is more extensive in HG than in
      PEP, suggesting that eosinophil involvement is greater in the pathogenesis of HG
      than PEP and similar to that found in bullous pemphigoid.

PMID- 10354185
TI  - Head and neck dermatitis: the role of Malassezia furfur, topical steroid use and
      environmental factors in its causation.
AB  - The aetiology of head and neck dermatitis (HND), one subgroup of postpubertal
      atopic dermatitis (AD), is still unclear. The aim of this study was to evaluate
      the influence on HND of common environmental factors, long-term topical steroid
      use, and the role of Malassezia furfur infection. Relevant information was
      obtained from 100 patients with HND attending our dermatology clinic by means of
      both physical examinations and questionnaires. Corticosteroid-induced
      vasoconstriction was estimated by visual scoring of laser-Doppler flowmetry. and
      the following immunological studies were performed: skin prick test, measurement
      of total IgE, eosinophil cationic protein, and specific IgE antibodies to several
      fungal antigens including those of M. furfur. The questionnaire revealed that
      sweating (81%), heat (71%), dryness (70%), psychic stress (67%), and sun exposure
      (50%) were responsible for aggravation of skin lesions. The vascular response to
      topical steroid was reduced in HND patients as compared with that of normal
      healthy controls (P < 0.05). Fifty-four of 80 patients with HND (68%) had anti M.
      furfur-specific IgE antibodies and 36 of 80 patients (45%) showed positive skin
      prick tests for M. furfur. The clinical severity and serum total IgE of HND
      patients were higher in patients with positive response to anti-M. furfur
      specific IgE antibodies than in patients with negative response (P < 0.05). These
      results suggest that HND can be aggravated not only by M. furfur but also by
      environmental factors such as sweating, heat, dryness, psychic stress and sun
      exposure. Furthermore, long-term use of topical steroid might be associated with
      the development of diffuse erythematous lesions with telangiectasia on the head
      and neck areas.

PMID- 10354186
TI  - Recurrent molecular abnormalities in type VII collagen in Southern Italian
      patients with recessive dystrophic epidermolysis bullosa.
AB  - In this study we searched for mutations in the type VII collagen gene (COL7A1) in
      10 families from Southern Italy with severe generalised recessive dystrophic
      epidermolysis bullosa using PCR amplification of genomic DNA, heteroduplex
      analysis and direct nucleotide sequencing. Our principal aim was to identify any
      recurrent mutations in COL7A1 that might facilitate future mutation detection
      strategies in this population. Three recurrent COL7A1 mutations were delineated
      in six of the 10 families: a frameshift mutation in exon 4, 497insA, was detected
      in three affected individuals from three families, a deletion mutation at the
      acceptor splice site of intron 114/exon 115, 8441-14del21, was found in five
      patients in three of the families, and an intron 49 acceptor splice site
      mutation, 4783-1 G-to-A, was identified in three subjects in two families
      (GenBank accession no, L02870). Haplotype analyses showed evidence for
      propagation of common ancestral mutant COL7A1 alleles for each of these recurrent
      mutations. These results contribute significantly to understanding the nature of
      COL7A1 pathology in patients from Southern Italy and in designing future
      approaches to mutation detection.

PMID- 10354187
TI  - Multiple lentigines clearing in resolving psoriatic plaques.

PMID- 10354188
TI  - Sweet's syndrome associated with salmonella enteritidis infection.

PMID- 10354189
TI  - Treatment of pain in adiposis dolorosa (Dercum's disease) with intravenous
      lidocaine: a case report with a 10-year follow-up.

PMID- 10354190
TI  - Bullous eruption due to Cimex lecticularis.

PMID- 10354191
TI  - Secondary prevention of coronary heart disease in clinical practice: special
      considerations for intensified lifestyle modification.

PMID- 10354192
TI  - Is apoptosis an important pathogenic factor in cardiovascular disease?

PMID- 10354193
TI  - Effects of intensified lifestyle modification on the need for further
      revascularization after coronary angioplasty.
AB  - BACKGROUND: In patients with coronary artery disease (CAD), a rate of restenosis
      as high as 50% is observed after percutaneous transluminal coronary angioplasty
      (PTCA). Frequently, this results in further revascularization procedures.
      Lifestyle intervention has been shown to slow the progression of CAD and to
      reduce cardiovascular events after myocardial infarction. However, no information
      exists whether such treatment influences the rate of restenosis in patients with
      CAD. The present study was performed to investigate the effects of an intensified
      lifestyle intervention on the need for further revascularization procedures in
      patients with established CAD after successful PTCA. DESIGN: A total of 60
      patients were included and randomized to either conventional treatment by
      cardiologists and general practitioners or additional intensified lifestyle
      intervention in a diabetes and metabolism outpatient clinic for 12 months. The
      mean observation time after successful PTCA was 26 months. The primary outcome
      variable was the need for further revascularization procedures because of
      clinical restenosis. Secondary outcome variables were lifestyle-related measures.
      RESULTS: Intervention resulted in a reduction in body weight and blood pressure,
      and in increased physical activity. Furthermore, nutritional habits were changed
      towards less fat intake, and body composition changed towards a higher proportion
      of fat-free mass. The need for further revascularization procedures was reduced
      from a total of 14 out of 32 in the conventionally treated group to 3 out of 28
      in the intervention group. This resulted in an event-free survival probability of
      0.89 in the intervention group and 0.57 in the control group (P = 0.0055, log
      rank) with a resulting relative risk of 0.26 (95% CI 0.09-0.74). CONCLUSION: In
      conclusion, our data strongly suggest that intensified lifestyle modification is
      able to reduce the need for further revascularization procedures after PTCA in
      patients with CAD.

PMID- 10354194
TI  - Cardiomyocyte apoptosis and progression of heart failure to transplantation.
AB  - BACKGROUND: Cardiomyocyte apoptosis has been found in congestive heart failure,
      but its clinical significance has been difficult to study. We compared the
      occurrence of cardiomyocyte apoptosis in explanted hearts with the progression of
      severe heart failure until the need for transplantation. DESIGN: Using the TUNEL
      assay, apoptotic cardiomyocytes were quantified in explanted failing hearts from
      patients with either idiopathic dilated cardiomyopathy (n = 21) or ischaemic
      heart disease (n = 14). The percentage was compared with the clinical severity
      and progression of endstage heart failure. Samples obtained at autopsy and during
      open heart surgery served as controls. RESULTS: The number of apoptotic
      cardiomyocytes was significantly increased in failing hearts regardless of
      aetiology (medians 0.075% in ischaemic heart disease and 0.119% in dilated
      cardiomyopathy) compared with control myocardium. In patients with dilated
      cardiomyopathy, apoptotic cardiomyocytes were more numerous in subjects with a
      rapidly deteriorating clinical course (0.192%, n = 10) than in patients with
      intermediate (0.093%, n = 6, P = 0.03) or slow (0.026%, n = 5, P = 0.003)
      progression. No such association was observed in patients with ischaemic heart
      disease, in whom we found significantly increased cardiomyocyte apoptosis
      adjacent to scars of previous infarctions (0.576%) in contrast to the diffuse
      distribution seen in dilated cardiomyopathy. Expression of Bcl-2, an
      antiapoptotic protein, was increased in all failing hearts by
      immunohistochemistry. CONCLUSION: Cardiomyocyte apoptosis is a consistent feature
      of end-stage heart failure in man and appears to be quantitatively related to the
      clinical severity of deterioration in dilated cardiomyopathy. Increased
      expression of Bcl-2 in cardiomyocytes indicates activation of an antiapoptotic
      response. These observations suggest that cardiomyocyte apoptosis is a clinically
      relevant and potentially modifiable pathophysiological phenomenon in severe heart
      failure.

PMID- 10354195
TI  - Moderate red wine consumption in healthy volunteers reduced plasma clearance of
      apolipoprotein AII.
AB  - BACKGROUND: The mechanisms of the positive relationship between alcohol intake
      and plasma concentration of high-density lipoprotein (HDL) are still unclear. The
      present study shows the metabolism modifications of apolipoprotein (apo) AI and
      apoAII in normolipidaemic healthy volunteers after a period of moderate red wine
      consumption. DESIGN: Five non-smoking male subjects were studied at the end of
      two consecutive 4-week periods, one without alcohol and the other with an intake
      of 50 g per day of alcohol, in random order. The metabolic parameters of apoAI
      and apoAII in HDL were determined after endogenous labelling using amino acid
      labelled with stable isotope. Cholesterol, triacylglycerols, HDL-cholesterol,
      apoAI, apoAII, LpAI, LpAI:AII were determined in plasma at the end of the two
      study periods. RESULTS: Cholesterol and triacylglycerols did not vary
      significantly during the two periods, whereas HDL-cholesterol increased from 43.8
      to 50.0 mg dL-1 (P < 0.05). ApoAI and apoAII increased significantly (20% and 60%
      respectively) after the diet was supplemented with alcohol. LpAI:AII increased
      from 73.8 to 101.6 mg dL-1 (+32%) (P < 0.05), whereas alcohol had no effect on
      the concentration of LpAI. The alcohol treatment did not significantly alter the
      metabolism of apoAI. Conversely, the fractional catabolic rate of apoAII
      decreased significantly by 21% (P < 0.05) with alcohol, whereas the production
      rate of apoAII tended to increase by 18% (P = 0.08). CONCLUSION: The decrease in
      the fractional catabolic rate of apoAII could lead to an accumulation of apoAII
      containing lipoproteins in plasma and account for the dramatic increase in
      LpAI:AII observed in the plasma of subjects consuming alcohol.

PMID- 10354196
TI  - Elevation of plasma leptin concentrations in obese hyperinsulinaemic
      hypothyroidism before and after treatment.
AB  - BACKGROUND: Plasma leptin is considered to play a role in maintenance of energy
      balance and body weight by neuroendocrine mechanisms. Thyroid hormones are
      permissive for adrenergic activation, which in turn has been shown to decrease
      leptin expression. This study was therefore designed to test the hypothesis that
      hyperthyroidism results in lower leptin concentrations, whereas hypothyroidism
      leads to higher plasma leptin concentrations. In addition, the effects of
      normalization of thyroid function on plasma leptin were investigated. MATERIALS
      AND METHODS: Fasting plasma leptin concentrations and body fat mass (total body
      electrical conductivity) were measured in patients with overt hypothyroidism and
      hyperthyroidism before and after successful treatment. Plasma leptin, glucose,
      insulin and free fatty acid concentrations were monitored during an oral glucose
      tolerance test (OGTT 75 g). RESULTS: Fasting plasma leptin concentrations were
      similar in lean patients, independently of their thyroid function (hyperthyroid
      12.5 +/- 2 ng mL-1, hypothyroid 10.2 +/- ng mL-1, euthyroid 12.7 +/- 3 ng mL-1).
      In obese hypothyroid patients, plasma leptin was threefold higher (P < 0.0005)
      than in lean hypothyroid patients, twofold higher (P < 0.005) than in obese
      hyperthyroid patients matched for fat mass and 30% increased (P < 0.01) compared
      with obese euthyroid subjects. There were no differences between fasting and post
      prandial (OGTT) leptin concentrations in any group. Normalization of thyroid
      function did not affect plasma leptin, which remained elevated (P < 0.005) in
      formerly obese hypothyroid patients. Plasma leptin was not associated with serum
      thyroid hormones but highly correlated with body mass index and body fat mass in
      all patients (r = 0.85, P < 0.001). Plasma leptin correlated with plasma insulin
      concentration only in hyperthyroid patients (P < 0.01, r = 0.64), who presented
      with blunted stimulation of insulin release and higher plasma glucose (P < 0.05)
      than hypothyroid subjects. CONCLUSION: The results indicate that (a) the
      correlation of leptin with body fat mass is preserved in thyroid dysfunction, (b)
      plasma leptin is markedly increased in obese hypothyroid hyperinsulinaemic
      patients and (c) plasma leptin is not affected by oral glucose loading.

PMID- 10354197
TI  - Effect of inhibiting HMG-CoA reductase on 7 alpha-hydroxy-4-cholesten-3-one, a
      marker of bile acid synthesis: contrasting findings in patients with and without
      prior up-regulation of the latter pathway.
AB  - BACKGROUND: Atorvastatin is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl
      coenzyme A reductase, but its effect on bile acid synthesis is unknown. The
      objectives of the study were to determine the effect of atorvastatin on bile acid
      synthesis in patients in whom this process had not been or had been previously up
      regulated by pharmacological or surgical means. MATERIALS AND METHODS: Four
      patients with heterozygous familial hypercholesterolaemia (FH) and partial ileal
      bypass (PIB) and 19 FH heterozygotes without PIB were treated with placebo,
      atorvastatin 10 mg and atorvastatin 40 mg daily, each regimen for 4 weeks. The
      non-PIB group was subsequently treated with bile acid (BA) sequestrant 8-16 g
      daily followed by co-administration of atorvastatin 10 mg, each for 4 weeks.
      Plasma 7 alpha-hydroxy-4-cholesten-3-one (7 alpha-HCO), a well-validated marker
      of BA synthesis was measured using high-performance liquid chromatography with UV
      detection. RESULTS: The plasma 7 alpha-HCO concentration was tenfold higher with
      placebo in the PIB than in the non-PIB group (418.5 ng mL-1 vs. 39.6 ng mL-1 p =
      0.0001). Levels decreased in PIB patients treated with atorvastatin 10 mg and 40
      mg daily (350.1 ng mL-1 and 174.0 ng mL-1, P = 0.007 respectively) but did not
      change significantly in the non-PIB group (44.7 ng mL-1 and 28.3 ng mL-1
      respectively). Administration of BA sequestrant to non-PIB patients increased 7
      alpha-HCO to 197.4 ng mL-1; this decreased to 106.0 ng mL-1 during co
      administration of atorvastatin 10 mg daily (P = 0.0001). CONCLUSION: Atorvastatin
      decreases the rate of BA synthesis only if the latter is up-regulated by PIB or
      BA sequestrants, presumably by limiting the supply of newly synthesized free
      cholesterol.

PMID- 10354198
TI  - Occurrence of sialic acids in healthy humans and different disorders.
AB  - Sialic acid (SA), N-acetylated derivatives of neuraminic acid, play a central
      role in the biomedical functioning of humans. The normal range of total sialic
      acid (TSA) level in serum/plasma is 1.58-2.22 mmol L-1, the free form of SA only
      constituting 0.5-3 mumol L-1 and the lipid-associated (LSA) forms 10-50 mumol L
      1. Notably, considerably higher amounts of free SA are found in urine than in
      serum/plasma (approximately 50% of the total SA). In inherited SA storage
      diseases such as Salla's disease, SA levels are elevated many times over, and
      their determination during clinical investigation is well established.
      Furthermore, a number of reports describe elevated SA levels in various other
      diseases, tentatively suggesting broader clinical utility for SA markers.
      Increased SA concentrations have been reported during inflammatory processes,
      probably resulting from increased levels of richly sialylated acute-phase
      glycoproteins. A connection between increased SA levels and elevated stroke and
      cardiovascular mortality risk has also been reported. In addition, SA levels are
      slightly increased in cancer, positively correlating with the degree of
      metastasis, as well as in alcohol abuse, diabetes, chronic renal failure and
      chronic glomerulonephritis. Several different mechanisms are assumed to underlie
      the elevated SA concentrations in these disorders. The apparent non-specificity
      of SA to a given disease limits the potential clinical usefulness of SA
      determination. In addition, some non-pathological factors, such as aging,
      pregnancy and smoking, may cause changes in SA concentrations. The absolute
      increases in SA levels are also rather small (save those in inherited SA storage
      disorders); this further limits the clinical potential of SA as a marker.
      Tentatively, SA markers might serve as adjuncts, when combined with other
      markers, in disease screening, disease progression follow-up, and in the
      monitoring of treatment response. To become clinically useful, however, the
      existing SA determination assays need to be considerably refined to reduce
      interferences, to be specific for certain SA forms, and to be more easy to use.

PMID- 10354199
TI  - Muscle creatine phosphate in gyrate atrophy of the choroid and retina with
      hyperornithinaemia--clues to pathogenesis.
AB  - BACKGROUND: In gyrate atrophy of the choroid and retina with hyperornithinaemia
      (GA), inherited deficiency of ornithine-o-aminotransferase leads to progressive
      fundus destruction and atrophy of type II skeletal muscle fibres. Because high
      ornithine concentrations inhibit creatine biosynthesis, the ensuing deficiency of
      high-energy creatine phosphate may mediate the pathogenesis. MATERIALS AND
      METHODS: Relative concentrations of inorganic phosphate (Pi), creatine phosphate
      (PCr) and ATP in resting calf muscle were recorded in 23 GA patients and 33
      control subjects using 31P-magnetic resonance spectroscopy (MRS). Eight patients
      with autosomal recessive retinitis pigmentosa with matched control subjects
      constituted an additional reference group. RESULTS: The PCr/Pi and PCr/ATP ratios
      (means +/- SD) were lower for the GA patients than for healthy control subjects
      [4.66 +/- 0.37 vs. 9.75 +/- 2.17 (P < 0.0001) and 2.85 +/- 0.37 vs. 3.70 +/- 0.50
      (P < 0.05) respectively]. In retinitis pigmentosa the respective values were 9.12
      +/- 2.57 and 4.25 +/- 0.45. Age and stage of the disease had no effect.
      CONCLUSION: Muscle 31P-MRS spectra were markedly abnormal in all GA patients.

PMID- 10354200
TI  - Physicochemical and functional modifications induced by obesity on human
      erythrocyte membranes.
AB  - BACKGROUND: Na+,K(+)-ATPase activity was evaluated in relation to membrane
      composition and molecular organization in erythrocyte membranes from obese
      patients by the amphyphylic molecule 6-dodecanoyl-2-dimethylamino-naphthalene
      (Laurdan). Its possible relationship with fat distribution and hyperinsulinaemia
      was also investigated. DESIGN: Subjects were 10 obese men (OM), 12 women with
      subcutaneous obesity (FSO), 10 women with abdominal obesity (FAO) and 41 healthy
      lean subjects, 26 women (FC) and 15 men (MC). An oral glucose tolerance test was
      administered to all subjects to evaluate insulin secretion and glucose tolerance.
      RESULTS: Na+,K(+)-ATPase activity was increased in all obese patients. Values
      were higher in FSO and FAO than in FC (with FAO greater than FSO) and in OM than
      in MC. The erythrocyte membrane cholesterol-to-phospholipid ratio was increased
      in obese patients and was significantly different in FSO patients compared with
      FC. The erythrocyte membrane protein-to-phospholipid ratio was also increased in
      all obese subjects, reaching statistical significance only in FSO vs. FC. The
      liquid crystalline phase, as tested by Laurdan generalized polarization (GP), was
      decreased in obese patients, indicating the presence of greater molecular
      environmental order; all patients groups showed lower GP values than control
      subjects, but only FAO reached statistical significance compared with FC. There
      was no evident correlation between membrane Na+,K(+)-ATPase activity and insulin
      levels, nor did membrane composition and properties show any evident relationship
      with insulin levels. CONCLUSION: Both increased Na+,K(+)-ATPase activity and
      altered fluidity and lipid composition were observed in the erythrocyte membrane
      of all obese patients. These findings are in line with previous observations by
      our group and indicate that the changes in Na+,K(+)-ATPase activity observed in
      obese patients could be related to changes in plasma membrane organization and
      composition.

PMID- 10354201
TI  - Impaired antiplatelet effects of aspirin associated with hypoxia and ATP release
      from erythrocytes. Studies in a system with flowing human blood.
AB  - BACKGROUND: We have explored how hypoxic conditions may affect the antiplatelet
      effects of aspirin. MATERIALS AND METHODS: For this purpose, a perfusion system
      containing a damaged vessel segment was modified in order to induce hypoxia (low
      Po2) in flowing blood. Blood samples were incubated with 50 mumol L-1 aspirin and
      divided into two aliquots, one being perfused under standard conditions
      (normoxic) and the other under hypoxic conditions. The interaction of platelets
      with the subendothelium was morphometrically evaluated. RESULTS: In studies with
      untreated blood under normoxic conditions, platelet interaction with the
      subendothelium was 0.3 +/- 0.1% of contact, 5.3 +/- 1.6% of adhesion, 24.3 +/-
      3.3% of thrombus and 29.9 +/- 2.7% of total covered surface. Aspirin-treated
      blood perfused under normoxic conditions showed a marked decrease in thrombus
      with a concomitant increase in both platelet adhesion and covered surface
      percentages. However, when aspirin-treated blood was perfused under hypoxic
      conditions, platelet interaction was not significantly different from that
      observed in untreated blood. Hypoxia induced a 10-fold increase in ATP release
      from erythrocytes in the perfusates. If apyrase was added to the perfusates, ATP
      release was prevented and aspirin effects were evident again. CONCLUSION: Our
      results suggest that, under hypoxic conditions, the presence of aspirin would not
      help to inhibit further platelet activation.

PMID- 10354202
TI  - Long-term stability of human immunodeficiency virus viral load and infectivity in
      whole blood.
AB  - BACKGROUND: We intended to evaluate the stability of human immunodeficiency virus
      (HIV) type 1 virions in whole blood and in culture medium. MATERIALS AND METHOD:
      EDTA whole-blood samples taken from 12 patients were left at room temperature for
      up to 7 days, and aliquots of a laboratory virus stock spiked in EDTA, in
      heparinized or in citrated whole blood, with or without the addition of Triton X
      100, or spiked in culture medium were left at room temperature for up to 120 days
      before plasma was separated and frozen at -80 degrees C. Viral load was measured
      for all frozen plasma samples using different viral load assays. p24 antigen and
      infectivity were also measured in the spiked samples. RESULTS: The patient whole
      blood samples did not show any decrease in viral load during this 7-day period.
      The spiked samples decayed by not more than 1 log after 120 days (about 4
      months), with the fastest decay in medium. Virus infectivity decayed very slowly
      from 20,000 units mL-1 to undetectable amounts after 56 days. CONCLUSIONS: These
      results indicate that HIV-1 virions in whole blood possess a long-term stability
      in terms of viral load, p24 antigen level and infectivity, which is not
      sufficiently recognized by laboratory and health care workers.

PMID- 10354203
TI  - Invasive aspergillosis in neutropenic patients: rapid neutrophil recovery is a
      risk factor for severe pulmonary complications.
AB  - BACKGROUND: In invasive aspergillosis, the duration of neutropenia is an accepted
      risk factor, and recovery from neutropenia is generally associated with a
      favourable outcome. However, the rapidity of granulocyte recovery may rarely be
      associated with adverse sequelae. The purpose of this study was to define the
      relationship between neutrophil (polymorphonuclear, PMN) recovery after
      chemotherapy-induced bone marrow aplasia and the occurrence of severe pulmonary
      complications (haemoptysis, pneumothorax and death) in patients with
      haematological malignancies who developed invasive fungal pneumonias. METHODS:
      Twenty consecutive patients were retrospectively studied; eight of them had
      developed pulmonary events between 5 and 11 days after neutrophil recovery that
      followed deep neutropenia (PMN < 100 microL-1). RESULTS: Five patients had
      haemoptysis (one of these also had pneumothorax) and three had pneumothorax.
      According to the multiplicative logistic model, the odds of occurrence of a
      pulmonary event increased significantly with increasing PMN count on the fifth
      day (P < 0.001). Five of the eight patients who had pulmonary complications died.
      Also, the risk of death was larger in the presence of rapid neutrophil recovery,
      although the difference was not statistically significant (P = 0.111). Analysis
      of clinical and laboratory data showed that the risk of pulmonary complications
      significantly increased when the neutrophil concentration was > 4500 microL-1 on
      day 5 after deep granulocyte neutropenia (PMN < 100 microL-1). There was no
      correlation between pulmonary complications, dosage of amphotericin B and deaths.
      CONCLUSION: The occurrence of life-threatening complications in patients with
      invasive fungal pneumonia is closely related to rapid PMN recovery.

PMID- 10354204
TI  - Is measurement of endothelial dysfunction clinically useful?

PMID- 10354205
TI  - Chlamydia pneumoniae-reactive T lymphocytes in abdominal aortic aneurysms: the
      smoking gun?

PMID- 10354206
TI  - Calciotropic hormones and the skeleton in uraemia.

PMID- 10354207
TI  - Energetics and function of the failing human heart with dilated or hypertrophic
      cardiomyopathy.
AB  - BACKGROUND: Impaired energy metabolism in the failing human heart could be an
      important mechanism of functional deterioration. The purpose of this study was to
      assess the changes of myocardial energy metabolism in the human heart at end
      stage heart failure. MATERIALS AND METHODS: The left ventricular myocardium of
      patients undergoing heart transplantation due to dilated (DCM, n = 14) or
      hypertrophic cardiomyopathy (HCM, n = 5) and non-diseased donor heart samples (n
      = 4) were analysed for citrate synthase (CS), enzymes of the glycolytic pathway
      as well as concentrations of phosphocreatine (PCr), creatine (Cr), adenine and
      guanine nucleotides. RESULTS: Total creatine levels (phosphocreatine + creatine)
      were significantly decreased (P < 0.05) in both groups of diseased hearts (3.87
      +/- 0.57 in DCM, 5.09 +/- 1.23 in HCM compared with control 10. 7 +/- 3.5
      micromol g-1 wet weight). There was a trend for higher guanine nucleotide content
      in failing hearts, but no significant differences were observed in total adenine
      nucleotides and total NAD content. CS was markedly reduced (P < 0.05) in both
      groups of diseased hearts: in the DCM to 13.8 +/- 1.3 micromol min-1 g-1 wet
      weight, and in HCM to 11.9 +/- 2.4 compared with the control 29.2 +/- 2.2.
      Glycolytic enzymes were decreased compared with the control, and this decrease
      was greater in DCM than in HCM. Echocardiographic indices of contractility were
      considerably better in hypertrophic cardiomyopathy. CONCLUSION: Despite the
      different mechanisms of cardiac failure and the differences in contractility of
      the heart we have observed, metabolic changes are very similar in hypertrophic
      and dilated cardiomyopathy. Depletion of the creatine pool suggests an alteration
      in the intracellular energy reserves and transfer, whereas the decrease in
      citrate synthase activity suggests reduced oxidative capacity in both dilated and
      hypertrophic cardiomyopathy.

PMID- 10354208
TI  - An angiotensin-converting enzyme gene polymorphism suggests a genetic distinction
      between ischaemic stroke and carotid stenosis.
AB  - BACKGROUND: Ischaemic cerebrovascular disease (ICVD) is a heterogeneous syndrome
      to which different genetic factors may contribute. We have investigated the
      distribution of alleles of the angiotensin-converting enzyme (ACE) gene, which
      has been suggested to be of possible importance in ischaemic stroke or
      cardiovascular disease, in groups of patients with ischaemic stroke and carotid
      artery stenosis (CS). MATERIALS AND METHODS: One hundred and thirty patients with
      ischaemic stroke and 68 patients with more than 50% stenosis of the internal
      carotid artery were investigated and compared with age- and sex-matched healthy
      control subjects. Alleles of an insertion/deletion polymorphism of the ACE gene
      were determined by one-stage polymerase chain reaction and visualized on agarose
      gels. RESULTS: There was a significant difference (P < 0.05) in the distribution
      of ACE alleles, homozygosity for the presumed susceptibility deletion allele
      being more common in patients with CS than in healthy control subjects. There was
      also a significant difference (P < 0.05) in patients with CS in comparison with
      matched ICVD patients without CS, both in allelic frequencies and in homozygosity
      for the deletion allele. CONCLUSIONS: Our results indicate that the ACE gene
      polymorphism may be a risk factor for the development of CS. The observed
      difference in ACE allele distribution may be seen as evidence for a genetic
      distinction between ICVD and CS, two clinically related conditions, which further
      supports the hypothesis that genetic factors are of importance for this group of
      diseases.

PMID- 10354209
TI  - Echocardiographic features of primary, secondary and familial amyloidosis.
AB  - BACKGROUND: Currently recognized types of amyloidosis include primary, familial
      and secondary, each of which may affect the heart. There may be differences in
      the heart response to the deposition of amyloid fibrils in these three forms of
      the disease. MATERIALS AND METHODS: Over a period of 10 years (1985-95), 28
      consecutive patients with primary, 11 with secondary and 17 with familial
      amyloidosis were studied at the Departments of Cardiology of Laiko and
      Hammersmith Hospitals. The diagnosis of amyloidosis was confirmed by biopsies of
      subcutaneous fat, rectum, kidney, bone marrow, gum or sural nerve. Diagnosis of
      cardiac involvement was based on typical electrocardiographic and
      echocardiographic findings. RESULTS: The left ventricular fractional shortening
      (%) was reduced in primary compared with familial or secondary amyloidosis (29.8
      +/- 10.2 vs. 36.2 +/- 6.5 vs. 36 +/- 5.9, P < 0.05). The transmitral flow
      velocity pattern was compatible with abnormal relaxation in most patients in the
      three groups [primary 16 (57%), familial 11 (64. 7%), secondary 6 (54.5%), P =
      NS]. Right ventricular systolic dysfunction (right ventricular dP/dt < 220 mmHg s
      1 or tricuspid annulus systolic excursion < 10 mm) was present in 8 (28.6%), 2
      (11. 8%) and 0 patients. Patients with primary amyloidosis were followed up for
      15 +/- 6 months. There were 12 deaths, and repeat echocardiography in the
      survivors revealed a significant deterioration of left ventricular systolic
      function (fractional shortening = 23.6% +/- 8.8%, P < 0.05 vs. baseline).
      CONCLUSION: Primary amyloidosis is characterized by more severe cardiac
      involvement than the familial or secondary amyloidosis and has an ominous course.

PMID- 10354210
TI  - Lack of association between changes in plasma leptin concentration and in food
      intake during the menstrual cycle.
AB  - BACKGROUND: Changes in plasma leptin concentration and food intake occur during
      the menstrual cycle; because leptin regulates food intake, one could hypothesize
      that changes in plasma leptin concentration and in food intake are associated
      throughout the menstrual cycle. However, no data have ever been provided to
      support such a relationship. The aim of our study was to investigate, during the
      different phases of the menstrual cycle, (a) the changes in plasma leptin
      concentration and, if such changes were demonstrated, (b) the potential
      relationship between the changes in plasma leptin concentration and food intake.
      DESIGN: The study was designed as an observational study. The plasma leptin
      concentration was determined in 16 healthy, young women during different phases
      of the menstrual cycle. At the same time, the basal metabolic rate (BMR),
      respiratory quotient (RQ) and food intake (FI) were also determined. RESULTS: The
      plasma leptin concentration increased throughout the menstrual cycle (P < 0.01
      for trend) and was significantly correlated with plasma progesterone
      concentration (r = 0.55, P < 0.007, for follicular phase, r = 0.58, P < 0.02, for
      the periovulatory period and r = 0.57, P < 0.02, for the luteal phase). No
      significant differences in BMR and fasting RQ throughout the different phases of
      the menstrual cycle were found. In contrast, FI significantly declined in the
      periovulatory phase. No significant correlations between BMR, RQ and FI values
      and fasting plasma leptin concentration at all menstrual phases were found.
      CONCLUSION: Changes in plasma leptin concentration and in food intake were found
      at different phases of the menstrual cycle. Nevertheless, no correlation among
      those parameters at any phase of the menstrual cycle was observed.

PMID- 10354211
TI  - Zymogen granule alterations in caerulein-induced pancreatitis developed during
      continuous hydrocortisone administration.
AB  - BACKGROUND: The amount of enzymes stored in individual zymogen granules and the
      glycosylation of their membrane have been analysed in rats with acute
      pancreatitis induced by caerulein after hydrocortisone treatment. The
      consequences of prolonging hydrocortisone administration after pancreatitis and
      the use of the cholecystokinin (CCK) receptor antagonist, L-364,718, have also
      been evaluated. MATERIALS AND METHODS: Analysis was performed using flow
      cytometry. RESULTS: Caerulein-induced pancreatitis in rats previously treated for
      7 days with hydrocortisone (10 mg kg-1 per day) revealed alterations in enzyme
      storage in the pancreas. Significant increases in amylase and trypsinogen
      contents in zymogen granules were observed, an effect associated with a reduction
      in L-fucose glycoconjugates. Pancreatitis persists 7 days later if hydrocortisone
      treatment is prolonged. At this stage, a reduced granule fucosylation was still
      observed, and a significant decrease in the amount of trypsinogen stored in the
      granules was found. However, hydrocortisone administration led to an increase in
      intragranular amylase quantities up to normal values, even when L-364,718 was
      simultaneously administered, but it reverted to plasma as a consequence of
      pancreatitis. The amount of N-acetyl D-glucosamine in the zymogen granule
      membrane was not altered by caerulein acute pancreatitis induced under continuous
      hydrocortisone treatment, but it was decreased by the administration of L-364,718
      over 7 days after pancreatitis induction. CONCLUSIONS: The administration of
      hydrocortisone after the development of pancreatitis prevented recurrence of the
      disease. L-364,718 proved to be detrimental, not only failing to reduce the
      symptoms of pancreatitis but also altering the glycoproteins of zymogen granule
      membrane.

PMID- 10354212
TI  - Severe dietary restriction initiated in aged rats: evidence for poor adaptation
      in terms of protein metabolism and intestinal functions.
AB  - BACKGROUND: Protein energy malnutrition is a common finding in elderly people,
      increasing morbidity and mortality in aged inpatients. Investigations need to be
      developed to counteract malnutrition-induced alterations early and to avoid
      potential irreversible lesions. The aim of this experimental study was to
      evaluate time-response to severe dietary restriction (DR) initiated in aged rats
      in terms of protein metabolism and digestive trophicity. MATERIALS AND METHODS:
      After the acclimatization period, 22-month-old male rats were randomized into six
      groups: three control groups, fed ad libitum for 3, 6 or 12 weeks with a standard
      diet and three corresponding dietary-restricted groups fed for the same periods
      with only 50% of the spontaneous intake. Intestinal mucosa, liver and skeletal
      muscles (soleus, extensor digitorum longus and tibialis anterior muscle) were
      removed when the rats were killed. RESULTS: DR induced dramatic body weight loss
      (up to 50% of initial body weight after 12 weeks DR). Protein metabolism was
      affected in terms of nitrogen balance (P < 0.01) and protein content, in
      particular at the splanchnic level. Morphometrically, the intestine structure was
      altered after 12 weeks of DR (P < 0.01), and this atrophy was correlated with
      malabsorption of mannitol (P < 0. 01). Ileal hydrolase activities were decreased
      throughout the 12 weeks of DR. CONCLUSIONS: Aged rats clearly exhibit a defect of
      adaptation to long-term DR initiated at an advanced age. Severe DR leads to
      malnutrition, which becomes of major importance after 12 weeks, in particular at
      the intestine level. Hence, application of these experimental results to elderly,
      malnourished people may contribute to a better knowledge of denutrition-induced
      disorders.

PMID- 10354213
TI  - The effect of hyperglycaemia on cerebral potentials evoked by rapid rectal
      distension in healthy humans.
AB  - BACKGROUND: Acute hyperglycaemia affects the perception of sensations arising
      from the gastrointestinal tract. The mechanisms responsible for this effect are
      unknown. Recordings of cerebral evoked potentials (EPs) can be used to assess the
      integrity of visceral afferent pathways. Our aim was to determine whether
      hyperglycaemia affects EPs elicited by rectal distension in healthy humans.
      MATERIALS AND METHODS: Twelve healthy men, aged 19-31 years, were studied. A
      manometric catheter, incorporating a rectal balloon, was positioned 7-10 cm from
      the anal verge. Balloon distensions at both 'low' ( approximately 20 mL) and
      'high' ( approximately 28 mL) volumes were performed, in a single-blind,
      randomized order, during both euglycaemia (4 mmol L-1) and hyperglycaemia (12
      mmol L-1). EPs were recorded from a midline scalp electrode (Cz, International 10
      20 system) and averaged for each series of 50 distensions. EP latencies and
      interpeak amplitudes were calculated. RESULTS: Polyphasic EPs were recorded in
      all but one subject. Although the blood glucose concentration had no significant
      effect on the latencies of the EP peaks elicited by either 'low'- or 'high'
      volume balloon distension, the interpeak amplitude (P1-N1) was greater during
      hyperglycaemia than during euglycaemia at the 'low' balloon volume (6.3 +/- 1.2
      microV vs. 4.8 +/- 1.0 microV, P < 0.05). The blood glucose concentration had no
      significant effect on the perception of rectal balloon distension. CONCLUSIONS:
      We conclude that in normal subjects acute hyperglycaemia increases the amplitude
      of the cerebral EP elicited by rectal balloon distension at low balloon volumes,
      suggesting that the effects of hyperglycaemia on gastrointestinal sensation may
      be mediated by central mechanisms.

PMID- 10354214
TI  - Alpha2-macroglobulin reduces paracrine- and autocrine-stimulated matrix synthesis
      of cultured rat hepatic stellate cells.
AB  - BACKGROUND: Transforming growth factor beta1 (TGF-beta1) is considered to
      represent a major fibrogenic mediator in the liver. The aim of the present study
      was to investigate whether alpha2-macroglobulin (alpha2M) might reduce paracrine-
      and autocrine-stimulated matrix synthesis of cultured rat hepatic stellate cells
      (HSCs) by scavenging TGF-beta. METHODS AND RESULTS: Using native agarose
      electrophoresis, we demonstrated that alpha2M binds [125I]-TGF-beta1 within
      minutes. Preincubation of transiently acidified supernatants of cultured Kupffer
      cells, secondary cultured (activated) HSC and platelet lysate with, respectively,
      500 and 2000 microg mL-1 alpha2M significantly reduced the concentration of
      active TGF-beta1 in these media. As a consequence of TGF-beta scavenging by
      alpha2M, paracrine-stimulated proteoglycan synthesis of primary cultured HSCs was
      reduced significantly. Furthermore, addition of 200 microg mL-1 alpha2M to
      passaged (activated) HSCs resulted in (a) a reduction in autocrine-stimulated
      extracellular matrix synthesis (proteoglycan -52%, fibronectin -55%) and (b)
      increased cell proliferation. A similar reduction in matrix synthesis was
      observed after the addition of 5 micromol L-1 TGF-beta1 antisense oligonucleotide
      to activated HSCs. CONCLUSION: We conclude that alpha2M reduces paracrine-and
      autocrine-stimulated extracellular matrix synthesis of cultured HSCs by
      scavenging TGF-beta. These mechanisms might restrict liver fibrogenesis.

PMID- 10354215
TI  - Physiological doses of calcium regulatory hormones do not normalize bone cells in
      uraemic rats.
AB  - BACKGROUND: Low bone turnover despite normal parathyroid hormone (PTH)
      concentrations has been found in many patients with end-stage renal failure.
      Hyporesponsiveness to the calcaemic action is also a known feature of uraemia.
      Hyporesponsiveness of bone surface cells involved in bone modelling has not been
      demonstrated to date. It was the purpose of this study using a rat model of
      moderate renal failure to investigate whether doses of PTH and calcitriol that
      reverse the effect of parathyroidectomy on calcaemia also normalize bone surface
      cell activity. MATERIALS AND METHODS: Sham-operated pair-fed male Spraque-Dawley
      rats were compared with subtotally nephrectomized (SNX), parathyroidectomized
      (PTX) rats that received either solvent or calcitriol (5 pmol kg -1 h-1) + 1,34
      rat PTH (100 ng kg -1 h-1) by osmotic mini-pump. Histomorphometric measurements
      were carried out in the vertebral body (L5). RESULTS: In SNX/PTX animals,
      calcitriol + 1,34 rat PTH caused a modest increase in serum calcium (S-Ca) within
      the normal range. Osteoclast surface per cent was significantly lower in solvent
      treated SNX/PTX rats than in sham-operated controls [3.7 +/- 2.8 osteoclast
      surface/bone surface (OcS/BS%) vs. 6.3 +/- 3.9], and this was not normalized by
      PTH + calcitriol (3.3 +/- 3). In contrast, osteoblast surface per cent and
      osteoid surface per cent were increased over values in sham-operated rats; as a
      result, co-administration of calcitriol and 1,34 rat PTH caused a highly
      significant increase in fractional bone volume (BV/TV). CONCLUSIONS: The results
      show that administration of PTH and calcitriol in doses that raise serum calcium
      fails to normalize the percentage of osteoclast surface, but was effective in
      raising osteoblast number and osteoblast volume in experimental renal failure.
      The results argue for abnormal response of bone cells to calcium-regulating
      hormones and/or the action of factors other than calcium regulatory hormones in
      the genesis of skeletal abnormalities of renal failure.

PMID- 10354216
TI  - Multidrug resistance in oncology: diagnostic and therapeutic approaches.
AB  - Resistance to anticancer drugs is often mediated by the overexpression of a
      membrane pump able to extrude many xenobiotics out of the tumour cells. The most
      frequently expressed of these pumps is called P-glycoprotein and is encoded by a
      gene called MDR1 (for multidrug resistance). There could be great clinical
      interest for investigating the expression of this gene or of its product in
      patients' tumours, as well as in developing ways of circumventing this mechanism
      of resistance. Multidrug resistance can be diagnosed in tumours by molecular
      biology techniques (gene expression at the mRNA level), by immunological
      techniques (quantification of P-glycoprotein itself) or by functional approaches
      (measuring dye exclusion). Numerous studies have tried to use the MDR status of
      tumours as a predictor of response to treatment, but they have not yet reached
      definitive conclusions to allow the use of this approach in routine
      determinations. This is because no consensus has emerged concerning the optimal
      technique and the best conditions for MDR determination. Continuous efforts are
      still required for defining appropriate standardization of the techniques. The
      development of MDR modulators for the treatment of resistant tumours is a
      promising approach requiring rigorous clinical trials with successive phase I,
      phase II and phase III studies. Phase I can be omitted when the reverter is
      already being used in therapeutics; phase II should be performed using a
      sequential design, in order to prove the inefficacy of the anticancer therapy
      before combining it to a modulator; and phase III must only be undertaken after
      the demonstration that responders can be recruited by the combination. However,
      the effect of some reverters on anticancer drug pharmacokinetics may hamper rapid
      evaluation. Several drugs are good candidates for MDR modulation, but definitive
      results are still lacking for the introduction of such combinations in standard
      therapeutic protocols.

PMID- 10354217
TI  - Chlamydia pneumoniae reactive T lymphocytes in the walls of abdominal aortic
      aneurysms.
AB  - BACKGROUND: The presence of Chlamydia pneumoniae in the walls of abdominal aortic
      aneurysms (AAAs) has been demonstrated recently, but its role in the cause and/or
      maintenance of aortic wall inflammation is not known. In the present study, we
      have investigated the possible relationship between C. pneumoniae and the antigen
      specificity of T lymphocytes mediating inflammation in AAA tissue. MATERIALS AND
      METHODS: Tissue specimens were obtained from 22 consecutive AAA patients
      undergoing elective surgery (mean age 67 +/- 1 year). Immunohistochemical
      analysis of the formalin-fixed tissue was performed using the streptavidin-biotin
      peroxidase method. In vivo activated T lymphocytes were propagated from the
      specimens with interleukin (IL) 2, and antigen specificity of the established T
      cell lines was analysed in the presence of autologous antigen-presenting cells
      using radioactive thymidine labelling. RESULTS: Immunohistological staining of
      AAA tissue showed the presence of C. pneumoniae antigen in 55% (6/11) of the
      samples studied. The inflammatory cell infiltrate of the AAA tissue contained 60
      90% T (CD45RO) and 0-10% B (CD20) cells. When the tissue specimens were cultured
      without antigen in the presence of IL-2, lymphocyte propagation was achieved in
      17 out of the 22 samples. Chlamydia pneumoniae antigen was found to induce a
      positive proliferative response in 8 of the 17 lines. CONCLUSIONS: The presence
      of C. pneumoniae specific T lymphocytes among in vivo activated cells from the
      AAA tissue specimens suggests that C. pneumoniae participates in the maintenance
      of the inflammatory response in the tissue and may thus be involved in the
      progression of the disease.

PMID- 10354218
TI  - Acute-phase response patterns in isolated hepatic perfusion with tumour necrosis
      factor alpha (TNF-alpha) and melphalan in patients with colorectal liver
      metastases.
AB  - BACKGROUND: In this study, we have evaluated hepatotoxicity, secondary cytokine
      production and hepatic acute-phase response (APR) in patients who underwent
      isolated hepatic perfusion (IHP) with tumour necrosis factor (TNF) alpha and
      melphalan for irresectable colorectal liver metastases. DESIGN: An extracorporeal
      veno-venous bypass was used to shunt blood from the lower body and intestines to
      the heart. Inflow catheters were placed in the hepatic artery and portal vein,
      and an outflow catheter in the inferior caval vein. The liver was perfused for 60
      min with 0.4 mg of TNF-alpha plus 1 mg kg-1 melphalan (IHPTM group, n = 6) or 1
      mg kg-1 melphalan (IHPM group, n = 3). The liver was washed with macrodex before
      restoring vascular continuity. RESULTS: After the washout procedure, a TNF-alpha
      peak (169 +/- 38 pg mL-1) was demonstrated in the IHPTM group only. Both groups
      demonstrated peak levels of interleukin 6 (IL-6) in the perfusate as well as
      systemically. These were significantly higher in the IHPTM group. Acute-phase
      protein (APP) levels followed a similar pattern as has been demonstrated after
      major surgery, with no significant differences between both groups. The addition
      of TNF-alpha to the perfusate did not lead to a significant difference in APP
      levels and the time course between groups. CONCLUSIONS: IHP with TNF and
      melphalan is followed by a transient systemic peak of TNF directly after liver
      washout. Secondary IL-6 induction was seen in the present study after IHP with
      and without TNF, which was highest when TNF was added. This phenomenon cannot be
      extrapolated to APP induction, which appeared unaffected by the addition of TNF,
      presumably because the surgical procedure itself already causes maximal
      stimulation of APP production.

PMID- 10354219
TI  - Heat shock protein 70 (HSP70) prolongs survival in rats exposed to hyperthermia.

PMID- 10354221
TI  - Editorial 

PMID- 10354220
TI  - The role of melatonin in pathogenesis of aspirin-sensitive asthma.
AB  - BACKGROUND: Platelets are involved in the pathogenesis of bronchial asthma,
      including aspirin-sensitive asthma (ASA). The pineal hormone melatonin (MT) has
      been described as inhibiting several physiological processes in platelets. The MT
      metabolite - N-acetyl-5-methoxy-kynurenamine - has a chemical structure similar
      to that of acetylsalicylic acid. Because ASA patients usually suffer from an
      active disease, despite the avoidance of aspirin and cross-reactive drugs, it has
      been suggested that the MT synthesis may be lower and sensitivity of platelet
      reception to MT may be higher in aspirin-sensitive asthmatic subjects than in
      aspirin-tolerant ones. The objective of this study was to investigate this
      hypothesis. MATERIALS AND METHODS: We studied the urinary excretion of 6
      sulphatoxymelatonin, the major metabolite of melatonin, and the effect of
      different MT doses on ADP-induced platelet aggregation in vitro in 17 ASA
      patients, 17 patients with aspirin-tolerant asthma (ATA) and 16 healthy subjects.
      RESULTS: The results of the study have revealed a lower level of daytime aMT6s
      excretion in ASA patients (12.7 +/- 2.7 ng mL-1) than in ATA patients (32.7 +/-
      9.9 ng mL-1, P < 0.05) and control subjects (19.9 +/- 5.8 ng mL-1, P < 0.05). The
      preincubation of platelet-rich plasma with the MT in a dose of 0.01 pg mL-1
      plasma results in an increase in the intensity and the rate of the first platelet
      aggregation phase only in the ASA patients compared with the ATA patients and
      control subjects. CONCLUSION: We conclude that the reduction in MT production in
      ASA patients defines the character of ADP-induced platelet aggregation and the
      change in its first phase after the further addition of MT in vitro. The latter
      is associated with the opening of some receptor-operated channels for Ca2+ or/and
      its mobilization from the intracellular stores. The higher sensitivity of
      platelet reception and a distorted reaction not only to MT but also to its
      metabolite may be prerequisites for aspirin intolerance in ASA patients.

PMID- 10354222
TI  - The self in self-awareness.
AB  - The concepts of 'self' and 'person' are central to educational and therapeutic
      endeavours. This paper examines the emergence of 'self-awareness' as an explicit
      concern in the education of preregistration nurses. In particular, it questions
      the claims that specific experiential learning strategies are the most
      appropriate for promoting self-awareness in students, and that these strategies
      produce greater understanding of theory in students and give greater depth of
      meaning to theory for students. It argues that the long and complex history
      associated with the concepts of self, self-awareness and 'person' makes the
      unproblematic stance adopted towards them in the nursing literature untenable,
      and calls for a more rigorous and critical appraisal of experiential learning
      strategies commonly used to promote self-awareness.

PMID- 10354223
TI  - Development of basic nursing education in China and Hong Kong.
AB  - Hong Kong returned to the sovereignty of the People's Republic of China in July
      1997. In the past, Hong Kong has been greatly influenced by the British system of
      nurses' training, which was very different from that in mainland China. As Hong
      Kong is now a part of China again, there is an increased opportunity for the
      exchange of experience and ideas among nurse educators. The First China-Hong Kong
      Nursing Education Conference has provided opportunities for the authors to gain a
      deeper understanding of the development of nursing education in China and Hong
      Kong. The authors believe that it is also important for China and Hong Kong to
      increase networking with the international nursing community. This paper has been
      written largely based on the information gathered from papers presented in the
      Conference and the discussion with nurse educators who attended the Conference,
      together with a review of literature. This paper focuses on comparing the history
      and present development of basic nursing education in both places. The future
      direction for the development of nursing education in these two places will also
      be discussed.

PMID- 10354224
TI  - Students' expectations of postregistration degree programmes.
AB  - The needs of postregistration students pursuing degree-linked clinical courses
      have received little attention and there are few insights concerning their
      aspirations when they enrol on such courses. Thus the aim of this study was to
      explore postregistration students' perceptions of the specific needs of their
      patient/client group and to examine how they envisaged the course on which they
      had just enrolled might help them to meet these needs in addition to their own
      requirements for professional and personal development. Data were collected by
      group interview from 62 students enrolling on eight different postregistration
      courses, all employed in an acute hospital trust. The results were analysed
      inductively. They indicated that students had internalized the state of the
      healthcare market and were keenly aware of the need to fulfil the expectations of
      employers and the public, while fulfilling their own needs for education and
      pursuing their own professional and career trajectories. They appeared ambitious
      and yet appeared to demonstrate empathy for patients and their families and felt
      a tremendous desire to provide care of a high quality through the optimal
      development of technical expertise. Students' emphasis on the importance of
      keeping abreast of technological developments should not be lightly dismissed
      considering its prominent position within the acute areas where they were
      employed, especially as it did not replace their desire to promote the caring
      aspects of their work.

PMID- 10354226
TI  - The impact of 'Project 2000' educational reforms on the occupational
      socialization of nurses: an exploratory study.
AB  - There is much in both nursing and sociological literature concerning the
      socialization of students into health care professions. In the case of nursing,
      concern has been expressed at the disparity between the values espoused by the
      educational establishment and those in the clinical areas. This study aimed to
      explore the changes in nursing occupational socialization since the
      implementation of recent educational reforms. Ethical approval was obtained from
      the local Research and Ethics Committee. The sample (n = 18) was drawn from
      qualified nurses working in a range of departments within three Welsh hospitals,
      half had undergone traditional training and half had received Project 2000
      education. Data collection and analysis techniques were based on a grounded
      theory approach; this approach was deemed appropriate in that it allows the
      possibility of developing fresh perspectives on the subject without being too
      constrained by earlier studies. A strongly emerging theme from the data was that
      the nature of nursing socialization was related to the work contexts in which it
      was experienced; in particular respondents offered sharply contrasting accounts
      of nursing culture in 'acute' and 'chronic' areas of health work. The process of
      socialization was found to be harsher in acute areas with numerous instances of
      negative sanctions used to ensure compliance to ward culture, whilst in chronic
      areas occupational socialization was a more satisfactory process and nurses
      experienced less dissonance between ward and educational establishments. The size
      of this study mitigates against any firm conclusions; however, the early
      indications suggest that it would be a fruitful area for further research with a
      wider sample group drawn from diverse areas. This exploratory study suggests that
      the location of nursing work, in terms of whether it is in acute or chronic
      areas, is a determining factor in the experience of contemporary occupational
      socialization of nurses.

PMID- 10354225
TI  - Recording skills practice on videotape can enhance learning - a comparative study
      between nurse lecturers and nursing students.
AB  - Video recording techniques have been used in educational settings for a number of
      years. They have included viewing video taped lessons, using whole videos or
      clips of tapes as a trigger for discussion, viewing video recordings to observe
      role models for practice, and being video recorded in order to receive feedback
      on performance from peers and tutors. Although this last application has been in
      use since the 1960s, it has only been evaluated as a teaching method with health
      care professionals in the past 10 years and mostly in the areas of medical and
      counsellor education. In nurse education, however, use of video recording
      techniques has been advocated without any empirical evidence on its efficacy.
      This study has used nursing degree students and nurse educationalists to
      categorize statements from four cohorts of students who took part in a 12-day
      clinical supervision course during which their interpersonal skills were recorded
      on videotape. There were two categories: positive and negative/neutral. Analysis
      of the data showed that between 61% and 72% of the subjects gave an overall
      positive categorization to the statements in the questionnaire. Chi-square tests
      were significant for all groups in both categories. This suggests that both
      nursing students and nurse lecturers thought that course participants' statements
      expressed a positive belief that video tape recording is useful in enhancing
      students' ability to learn effective interpersonal skills in clinical
      supervision.

PMID- 10354227
TI  - A content analysis of staff nurse descriptions of job satisfaction and
      dissatisfaction.
AB  - Job satisfaction of nurses has been studied, using quantitative methodology, but
      hospital staff nurse descriptions of the source of their job satisfaction and job
      dissatisfaction have rarely been examined. This study collected information from
      30 staff nurses through semistructured, taped interviews. Using content analysis,
      interviews were coded and categories and themes were identified. Findings
      indicate that job satisfaction was derived from the following categories: patient
      care, environment, balanced workload, relations with coworkers, personal factors,
      salary and benefits, professionalism, cultural background of the nurse and career
      stage of the nurse. Themes related to patient care, the pace and variety in an
      acute care environment, relationships with coworkers and meeting personal and
      family needs were cited as particularly relevant to job satisfaction. Job
      dissatisfaction was primarily influenced by patient care, factors that interfere
      with the job and patient care, feeling overloaded, relations with coworkers,
      personal factors, organizational factors and the career stage of the nurse.
      Themes related to the following categories have the greatest influence on job
      dissatisfaction: feeling overloaded, factors that interfere with patient care,
      coworkers who do not provide good care and situations that feel unfair. The
      actual words of nurses were included to provide depth and substance to the
      categories and themes. A discussion was presented of the relationship of these
      findings to theory and to outcomes of quantitative research. These findings have
      implications for nursing practice, administration and education as the profession
      considers organizational and individual factors influencing nurses' feelings
      about their job and prepares for future nursing shortages.

PMID- 10354228
TI  - Career desirability: young people's perceptions of nursing as a career.
AB  - The majority of young people make a career choice without regard for salary, and
      base their decision on interest and enjoyment or a desire to help people. This
      paper examines students' perceptions of nursing as a career at a number of key
      stages in their education decision-making, and how this information influences
      their subsequent career decision either to choose or to reject nursing. Factors
      relating to image and status are also explored and some comparisons are made
      between nursing and young people's own choice of career, to highlight a number of
      significant issues. The findings indicate that although young people expressed
      admiration for the work of nurses, this was rarely matched by an envy of nurses,
      or a desire to become a nurse themselves.

PMID- 10354229
TI  - Emotional contagion, empathic concern and communicative responsiveness as
      variables affecting nurses' stress and occupational commitment.
AB  - Based on data gathered from registered nurses at two hospitals, this research
      examined the extent to which empathy variables contributed to nursing stress and
      occupational commitment. The empathy variables examined were emotional contagion
      (i.e. sharing the emotions of patients), empathic concern (i.e. being concerned
      for patients) and communicative effectiveness (i.e. effectively communicating
      with patients and their families). Nursing stress was explored through the
      variables of depersonalization, reduced personal accomplishment and emotional
      exhaustion. Multiple regression analyses revealed that the combination of the
      three emotional communication variables explained significant proportions of the
      variance in all three of the stress variables, as well as occupational
      commitment. The analyses further revealed that a lack of empathic concern and
      poor communicative responsiveness accounted for significant proportions of the
      variance in depersonalization. Lack of empathic concern, poor communicative
      responsiveness and high emotional contagion significantly contributed to reduced
      personal accomplishment. Emotional contagion explained a significant proportion
      of the variance in emotional exhaustion. Emotional contagion also significantly
      reduced occupational commitment. The findings are discussed in terms of nursing
      education and administration.

PMID- 10354230
TI  - Specific determinants of intrinsic work motivation, burnout and turnover
      intentions: a study among nurses.
AB  - This study of 156 Dutch general hospital nurses tested a theoretically derived
      model of specific relationships between work stressors and stress reactions. The
      model proposes four central domains of the work situation, namely work content,
      working conditions, social and labour relations, and conditions of employment. In
      addition, the model proposes three important stress reactions, namely a
      diminished intrinsic work motivation, occupational burnout and an inclination to
      leave the job. More specifically, it was hypothesized that (i) intrinsic work
      motivation is primarily determined by work content variables, (ii) burnout is
      primarily determined by both work load and limited social support, and (iii)
      propensity to leave is primarily determined by conditions of employment. All
      these relationships were simultaneously tested using a structural equations
      modelling technique. The results of a series of LISREL analyses indicate that the
      postulated model fits well to the data. The present study used conceptually
      integrated measures that cover the area of work stress and stress reactions, and
      provides directions for interventions aimed at preventing or reducing specific
      negative outcomes of work-related stress in general hospitals.

PMID- 10354231
TI  - Safeguarding care gains: a grounded theory study of organizational change.
AB  - The orientation towards a community focus of care challenges the need for
      National Health Service day hospital provision for people with dementia, thus
      forcing day hospitals to reorganize, relocate or close. Day hospitals were
      originally opened in the mid-1970s as cost-effective alternatives to the
      traditional in-patient care for the dementia sufferer. Ironically, day hospitals
      are now under threat because they are considered an expensive luxury. Advances in
      dementia care have included the move away from the mechanistic model of care
      (routines and tasks), to the development of the social psychological model of
      dementia care. This paper examines the process of changes experienced by a group
      of staff working in a day hospital for people with dementia. Where the staff
      experienced a period of prolonged change and loss, their perception of support
      differed from that of the organization. When threats to the future and low
      support were encountered, defensiveness and risk containment allowed the
      mechanistic model of care to predominate. The concept of 'safeguarding care
      gains' was contained in the actions the staff took to prevent further perceived
      erosion of their care practice.

PMID- 10354232
TI  - The new public management and the new nursing: related by rhetoric? Some
      reflections on the policy process and nursing.
AB  - The importance of health policy in terms of its effects on nursing is now
      recognized as an issue of concern for nurses; however, the essentially dynamic
      character of policy requires that consideration of its nature and consequences is
      continuous. This paper addresses the parallel development of the New Public
      Management (NPM) and the New Nursing as a means of demonstrating the perceived
      disjunction between events in nursing and the wider policy arena. The nature of
      policy is discussed and the relationship between the NPM and the New Nursing is
      explored. An examination of the unintended consequences of policy implementation
      and the role of rhetoric in the development of the NPM and the New Nursing
      demonstrates that these contrasting ideologies have emerged from a similar set of
      circumstances and have developed along a broadly similar timescale. The final
      effects of this process, however, are not yet clear. It is suggested that
      although the processes of policy formation and implementation are inherently
      complex there is an opportunity for nurses to exert some influence over them.
      Finally it is argued that if nurses become skilled in the art of rhetoric and
      combine this with a thorough understanding of the policy process they may be able
      to shape policy directly when and where it is implemented.

PMID- 10354233
TI  - Mental health nursing policy - an exploratory qualitative study of managers'
      opinions.
AB  - During the 1990s, much of the legislation and policy that pertains to mental
      health services has sought to direct them towards a virtually exclusive concern
      with the seriously mentally ill, typified by the following recommendation from a
      recent Department of Health review of mental health nursing that stated: 'The
      essential focus for the work of mental health nurses lies in working with people
      with serious or enduring mental illness'. On the other hand, pressure from the
      primary health care sector suggests the need for services to be provided for the
      less seriously mentally ill, particularly through the auspices of general
      practice fundholders. Following a review of the literature, a small-scale,
      exploratory study was initiated to seek answers to the following research
      question: How is the policy focus urging reorientation to the severely mentally
      ill viewed by nurse managers who have a responsibility through Mental Health
      Resource Centres and Community Mental Health Teams, to provide mental health
      services? The study was based within a Welsh National Health Service (NHS) Trust
      that employed six nurse managers of Community Mental Health Teams (CMHTs). Four
      of the managers additionally had responsibility for Community Mental Health
      Resource Centres (CMHRCs). Of the population of six managers, four composed the
      sample for the investigation. A qualitative research approach was employed,
      utilizing semistructured interviews as the data collection tool. Analysis of the
      data revealed that managers were finding creative solutions in order to meet the
      conflicting demands placed upon them. The research findings also indicated that
      many of the obstacles to providing a needs-led service were structural in origin,
      and could be resolved by central strategic intervention.

PMID- 10354234
TI  - Gender and perceived nurse caring in nurse-patient dyads.
AB  - The effect of nurse gender on nurse and patient perceptions of nurse caring was
      explored. Members of nurse-patient dyads (N = 145), equally distributed among the
      four possible gender combinations, completed matching forms of the Caring
      Questionnaire immediately following a shift. Perceptions of nurse caring that
      actually occurred during the preceding shift, as well as usual preferences about
      nurse caring, were measured. Results of two-factor ANOVAS showed no significant
      differences in actual caring according to nurse gender from either the nurse or
      the patient perspective. Expectations of certain nurse caring behaviours,
      however, were significantly lower for male nurses from both nurse and patient
      perspectives. The results suggest implications for nursing practice, education
      and further research.

PMID- 10354235
TI  - Self-transformation as a factor in the self-esteem and well-being of breast
      cancer survivors.
AB  - Diagnosis with a life-threatening illness can lead to many changes in one's self.
      These changes, called self-transformation, are not well understood. The present
      study used triangulation of methods and measures to (i) describe individual
      differences in self-transformation among breast cancer survivors, (ii) examine
      factors associated with self-transformation in breast cancer survivors, and (iii)
      examine the relationships between self-transformation and self-esteem and well
      being in breast cancer survivors and age-matched comparison women without cancer.
      Cancer survivors (n = 60) participated in structured interviews and both
      survivors and comparison women (n = 60) completed a set of questionnaires.
      Narrative analysis revealed three categories of transformation among breast
      cancer survivors: positive transformation, minimal transformation and feeling
      stuck. These groups differed by age, marital status and income, but not by
      disease or treatment variables. Breast cancer survivors in the positive
      transformation group had significantly higher self-esteem and well-being in
      comparison with (i) survivors grouped as feeling stuck and (ii) age-matched
      counterparts without cancer. Cancer survivors who reported feeling stuck had
      significantly lower self-esteem and well-being than the other groups of survivors
      and lower well-being in comparison with healthy women of the same age. Findings
      provide support for the concept of self-transformation and a new understanding of
      disease, demographic and treatment factors associated with the concept. Findings
      also suggest that self-transformation may be a factor in the self-esteem and well
      being of breast cancer survivors.

PMID- 10354236
TI  - Verbal communication: what do critical care nurses say to their unconscious or
      sedated patients?
AB  - The importance of using verbal communication in the care of critically ill
      patients has long been known. Both qualitative and quantitative studies have
      presented evidence of the benefits of effective communication. This non
      participant observational study aimed to explore how much and what types of
      verbal communication critical care nurses use when caring for unconscious or
      sedated patients. Sixteen critical care nurses were observed in 4-hour episodes
      and their verbal communication was transcribed and timed at source. Seven
      categories of verbal communication and a 'core concept' emerged on analysis of
      the raw data. Medical investigations/interventions performed on the patients
      increased the amount of communication used. The participants in this study were
      found to use a greater variety and amount of verbal communication than
      participants in other studies. The findings of this study highlight the need for
      formal support systems and continued education for nurses about the benefits of
      verbal communication.

PMID- 10354237
TI  - Learning to listen: serendipitous outcomes of a research training experience.
AB  - Experience gained in a qualitative research-training project led a group of
      clinical nurse specialists to discover the value of using research interview
      strategies in their clinical work. Clinical interviews, designed to garner data
      sufficient to decide on interventions, narrow the focus of the interviewer to
      information deemed relevant to that end. Research interview strategies involve a
      temporary suspension of the search for intervention, encourage a full description
      of the respondent's story and experience, and emphasise really listening to that
      story. In this case it is the respondent who decides what the story is and what
      information is relevant. This leads the interviewer to a fuller understanding of
      the context and perceptions of the respondent. The understanding and knowledge
      thus obtained comprise a better foundation for devising interventions which are
      individualised and specific to the individual and family.

PMID- 10354238
TI  - Strategies used by burns nurses to cope with the infliction of pain on patients.
AB  - The infliction of pain on patients is part of the daily routine for many nurses,
      particularly those who work in burns units, but there has been little help
      available for nurses to develop useful ways of coping with such circumstances.
      Few researchers have considered how the ways that nurses manage their feelings
      about pain may provide insights into the reasons why available pain control
      methods have not been fully practiced. The aim of this study was to identify the
      range of coping strategies used by nurses when conducting painful procedures.
      Nurses working in five burns units were interviewed about their feelings when it
      was necessary for them to inflict pain on patients in the course of giving
      patient care. Content analysis was used to identify the kinds of coping
      strategies used by nurses to manage their feelings about such situations.
      Fourteen kinds of strategy were identified and were then grouped into four
      categories: (i) distancing oneself from the patient's pain; (ii) engaging with
      the patient's pain; (iii) seeking social support and (iv) reconstructing the
      nurse's core role. The use of each of these categories of coping have
      implications for both the management of patient's pain and the nurse's emotional
      well-being. While distancing oneself from the patient's pain was the most
      prevalent way for nurses to cope with their feelings about causing pain to
      patients, all types of coping strategies had their advantages. It is possible
      that combinations of various strategies may be the most effective way for nurses
      to deal with their patients' pain.

PMID- 10354239
TI  - Nurses' perceptions of collaborative nurse-physician transfer decision making as
      a predictor of patient outcomes in a medical intensive care unit.
AB  - This prospective correlational study examined nurses' perceptions of
      collaborative nurse-physician transfer decision making as a predictor of patient
      outcomes in a medical intensive care unit, adjusting for risk. The convenience
      sample consisted of 175 patient transfer decisions. Charts and computerized
      databases were used to collect patient information, and a questionnaire developed
      by the investigator was used to obtain demographic data from the 42 medical
      intensive care nurses. An adapted version of the Decision About Transfer scale
      served to measure the nurses' perceptions of collaboration and satisfaction with
      respect to specific patient transfer decisions, as well as decision task
      complexity, and the Acute Physiology and Chronic Health Evaluation was utilized
      to adjust for patient risk. Information Processing Theory guided the study.
      Hierarchical logistic regression analyses first showed that the nurses'
      perceptions of collaboration were not a significant predictor of patient
      outcomes. Furthermore, the analysis also showed that decision task complexity and
      the nurses' years of critical care experience did not significantly moderate the
      contribution of nurses' perceptions of collaboration to patient outcome
      prediction. Finally, a Pearson product moment correlation coefficient of 0.28
      revealed a statistically significant (P = 0.000), positive relationship between
      the nurses' perceptions of collaboration and their satisfaction with the decision
      making process about decisions to transfer.

PMID- 10354240
TI  - The cooling-suit: a study of ten multiple sclerosis patients' experiences in
      daily life.
AB  - Approximately 60%-80% of all multiple sclerosis (MS) patients are heat sensitive.
      The aim of this study was to gain information on the effects of an assistive
      device, the cooling-suit, on MS-patients' self-care ability and also practical
      implications. A single-case approach was adopted in a quasi- experimental before
      and-after study. The cooling-suit was used in their own homes by 10 individuals
      with diagnosed MS in different stages from relapsing-remitting to chronic
      progressive. Data collection procedures were self-assessment through a structured
      assessment-instrument, an open-ended interview before and after the intervention
      and a diary written during one week. The selected instrument, the MS Self-Care
      ADL Scale, has been developed for persons with MS and was translated into
      Swedish. The results showed increased self-care ability during and after use of
      the cooling-suit. However, different aspects of daily life activities were
      improved and to a varying extent. It is concluded that the study participants
      were supported and empowered in different activities of daily life such as
      walking and transfer and reduced voiding problems by using the cooling-suit. Some
      difficulties in handling the cooling-suit were also reported.

PMID- 10354241
TI  - Practice nurses and the care of patients receiving depot neuroleptic treatment:
      views on training, confidence and use of structured assessment.
AB  - The movement of care into the community for the mentally ill with severe and
      enduring problems has important implications for primary care services. This
      paper reports the findings from an interview with practice nurses working in
      south-west London, United Kingdom, who had participated in a randomised control
      trial to investigate the effectiveness of training and structured assessment on
      clinical and social outcomes of patients receiving maintenance medication of
      depot antipsychotics. The aim of the interview was to explore current practice,
      attitudes, confidence and priorities for training in relation to these patients.
      Thirty-nine nurses were interviewed. The majority of practice nurses received
      scant referral information and worked without protocols. Even though these nurses
      had received the training, and as a result of the study had increased awareness
      of the problems of the severely mentally ill, there was a significant
      relationship between inadequate knowledge of schizophrenia to carry out the task
      of medication management and lack of confidence. Although the small size of the
      sample does not permit generalization, important questions are raised for further
      practice development and research, including the future training needs of
      practice nurses and partnership relationships with mental health professionals
      for supervision and support.

PMID- 10354242
TI  - Review of nursing documentation in nursing home wards - changes after
      intervention for individualized care.
AB  - Using standardized assessment instruments may help staff identify needs, problems
      and resources which could be a basis for nursing care, and facilitate and improve
      the quality of documentation. The Resident Assessment Instrument/Minimum Data Set
      (RAI/MDS) especially developed for the care of elderly people, was used as a
      basis for individualized and documented nursing care. This study was carried out
      to compare nursing documentation in three nursing home wards in Sweden, before
      and after a one-year period of supervised intervention. The review of
      documentation focused on structure and content in both nursing care plans and
      daily notes. The greatest change seen after intervention was the writing of care
      plans for the individual patients. Daily notes increased both in total and within
      parts of the nursing process used, but reflected mostly temporary situations.
      Even though the documentation of nursing care increased the most, it was the
      theme medical treatment which was the most extensive overall. A difference was
      seen between computer-triggered Resident Assessment Protocol (RAP) items,
      obtained from the RAI/MDS assessments, and items in the nursing care plans; the
      former could be regarded as a means of quality assurance and of making staff
      aware of the need for further discussions. The RAI/MDS instrument seems to be a
      useful tool for the dynamic process in nursing care delivered and as a basis for
      documentation. The documentation should communicate a patient's situation and
      progress, and if staff are to be able to use it in their everyday nursing care
      activity, it must be well-structured and freely available. The importance of
      continuing education and supervision in nursing documentation for development of
      a reliable source of information was confirmed by the present study.

PMID- 10354243
TI  - Transition in care: family carers' experience of nursing home placement.
AB  - This paper explores families' experience of nursing home placement, which emerged
      as a significant aspect of a larger hermeneutic phenomenological study of family
      caring in nursing homes. Hermeneutic analysis of 14 family carers' stories of
      nursing home placement uncovered five shared meanings: experiencing a loss of
      control; being disempowered; feeling guilt, sadness and relief simultaneously;
      possessing a sense of failure; and having to make a forced and negative choice.
      Discussion of the findings focuses upon the importance of family carer support
      during the transition period from home care to nursing home care and the
      subsequent benefits realized as a result of having received such support.
      Particular emphasis is placed upon how such support assists family carers to
      begin the process of reconstructing a valued and positive identity through which
      new possibilities for meaningful caring within a nursing home context can be
      realized.

PMID- 10354244
TI  - Health screening for people with learning disabilities by a community learning
      disability nursing service in Northern Ireland.
AB  - Over the last 30 years there has been a considerable increase in the life
      expectancy of people with learning disabilities. This has resulted in changing
      patterns of morbidity and mortality and an increasing recognition of the health
      needs of people with learning disabilities. Major strides forward have been made
      in the reduction of preventable illnesses among the general population. However,
      among people with learning disabilities such illnesses have received only limited
      health promotion attention until recently. In the last decade major gaps have
      been identified in the ability of current primary health services to respond to
      the needs of people with learning disabilities. The need to respond effectively
      to this situation has been identified as a priority by the current United Kingdom
      Government. Following an overview of the literature in relation to the changing
      health profile of people with learning disabilities and the need for health
      screening, consideration is given to some of the key difficulties which may be
      encountered when attempting to utilize current primary health services. The
      analysis of data derived from the health screening of 373 people with learning
      disabilities by a community nursing service in Down and Lisburn Health and Social
      Services Trust reveals the need for further action in relation to cardiovascular
      status, sensory deficits, mobility and aspects of sexual health.

PMID- 10354245
TI  - Can nurses learn to let go? issues arising from an intervention designed to
      improve patients' involvement in their own care.
AB  - The aim of the paper was to explore the reasons behind a perplexing observation
      that an intervention designed to alter professional behaviour in general practice
      consultations in South Wales was poorly sustained despite initial enthusiasm
      among the nurses. Nurses' baseline and continuing responses to the new approach
      with patients with non-insulin dependent diabetes are described, drawing on
      observations and interviews with the 18 practice nurses in the 15 experimental
      practices. The nurses fell into two groups: those showing greater understanding
      of the principles underlying the approach and a more reflective attitude to their
      work; and those who adapted the simple technology provided to their usual
      consultation style. This variation was related to their perception of their role
      and their attitudes to diabetic care, especially the challenge posed by the
      'difficult patient'. They were noticeably less willing to allow the patient
      freedom to decide what to do once diabetic control was deteriorating according to
      biochemical measures. It is concluded that the failure of the nurses to sustain
      behaviour change over time stems from a basic dilemma, namely, what is the extent
      of my responsibility and how ought I to discharge it? There is scope for more
      research into professional perspectives on chronic care, the strategies they use
      to manage patients and to cope with their own feelings, and the implications of
      these strategies for patients.

PMID- 10354246
TI  - Menorrhagia: women's perceptions of this condition and its treatment.
AB  - This paper reports a qualitative study of women's perceptions and experience of
      menorrhagia. Having obtained ethics committee approval, and informed written
      consent, interviews were conducted with 30 women who reported that they were
      suffering from menorrhagia. The sample included 13 women of South Asian descent.
      Some of those interviewed did not want medical treatment for menorrhagia. Other
      women were quite satisfied with the treatment they received when they consulted
      their doctors. However, it appears that some general practitioners failed to
      recognize women's need for treatment and were slow to comply with requests for
      referral to a gynaecologist. Although in the past there has been justifiable
      concern about women who undergo unnecessary treatment for perceived menorrhagia,
      this study suggests that health care professionals should be aware that some
      women may experience menorrhagia for long periods of time without receiving
      effective health care. It is possible that those who volunteered for the study
      were those most likely to have experienced problems with their treatment.
      However, the results of this study have implications for nurses, who may be in a
      position to give help and advice to women who want information about possible
      alternative treatments and sources of help for menorrhagia.

PMID- 10354247
TI  - The management of embarrassment and sexuality in health care.
AB  - In this paper, the literature on embarrassment, the related topics of delicacy
      and privacy, and the implications for nursing and medical practice are discussed,
      drawing on empirical data from an observational study of fertility clinics, plus
      other studies involving consultation and/or examination relating to sexual
      issues. It will be argued that current data are too patchy to give clear
      guidelines for professional practice, but that the issues should be explored in a
      more systematic way in (inter)professional education.

PMID- 10354248
TI  - Planning and managing research into day-surgery for cataract.
AB  - Between 1995 and 1997, a randomized controlled study, funded by the Department of
      Health, was carried out into the management of patients with cataract attending a
      peripheral ophthalmic clinic and who had been assessed as suitable for day
      surgery. The research took place in a clinical setting and it was accepted from
      the outset that, while such studies have the power to give information about the
      real clinical world, this also means that the research is potentially at the
      mercy of events within that world. The purpose of this paper is to report how the
      study was set up and integrated into the clinic. First, a literature review was
      undertaken in order to focus the aims of the study more clearly. Second, drawing
      on principles of action research, clinical and research staff worked together to
      implement the study. This strategy allowed a flexible approach to the research
      which enabled problems to be handled as they arose.

PMID- 10354249
TI  - Social support: factors to consider when designing studies that measure social
      support.
AB  - Research into the area of social support has been associated with confusion and
      concern. Much of the previous work in this area has inherent and serious
      difficulties, especially with regard to measurement issues surrounding the
      concept and with study design. However, it is paramount that social support
      research is further developed to allow effective interventions by health care
      professionals to influence positive outcomes in patient care. It is only by
      adopting a rigorous approach to social support research that its full potential
      can be achieved, that it can result in the positive promotion of recovery from
      mental and physical illness and that it can then become an important tool for the
      health care professional. This paper aims to clarify research issues relating to
      social support definition, measurement and study design, including methodology,
      selection of instruments and analysis. Guidance will be provided concerning the
      important factors to consider to achieve a well-designed study to measure social
      support.

PMID- 10354250
TI  - Attitudes to HIV/AIDS.

PMID- 10354251
TI  - Rewarding teaching faculty with a reimbursement plan.
AB  - OBJECTIVE: To develop a system for measuring the teaching effort of medical
      school faculty and to implement a payment system that is based on it. DESIGN: An
      interventional study with outcomes measured before and after the intervention.
      SETTING: A department of internal medicine with a university hospital and an
      affiliated Veterans Administration hospital. INTERVENTION: We assigned a value in
      teaching units to each teaching activity in proportion to the time expended by
      the faculty and the intensity of their effort. We then calculated total teaching
      units for each faculty member in the Division of General Internal Medicine and
      for combined faculty effort in each subspecialty division in the Department of
      Medicine. After determining the dollar value for a teaching unit, we distributed
      discretionary teaching dollars to each faculty member in the Division of General
      Internal Medicine and to each subspecialty division according to total teaching
      units. MEASUREMENTS AND MAIN RESULTS: The distribution of discretionary teaching
      dollars was determined. In the year after the intervention, there was a
      substantial redistribution of discretionary teaching dollars among divisions.
      Compared with an increase in total discretionary dollars of 11.4%, the change in
      allocation for individual divisions ranged from an increase of 78.2% to a
      decrease of -28.5%. Further changes in the second year after the intervention
      were modest. The distribution of teaching units among divisions was similar to
      the distribution of questions across subspecialties on the American College of
      Physicians In-Training Examination (r =.67) and the American Board of Internal
      Medicine Certifying Examination (r =.88). CONCLUSIONS: It is possible to measure
      the value of teaching effort by medical school faculty and to distribute
      discretionary teaching funds among divisions according to the value of teaching
      effort. When this intervention was used at our institution, there were
      substantial changes in the amounts received by some divisions. We believe that
      the new distribution more closely approximates the desired distribution because
      it reflects the desired emphasis on knowledge as measured by two of the most
      experienced professional groups in internal medicine. We also believe that our
      method is flexible and adaptable to the needs of most clinical teaching

PMID- 10354252
TI  - Validation of the pneumonia severity index. Importance of study-specific
      recalibration.
AB  - OBJECTIVE: To evaluate the predictive validity and calibration of the pneumonia
      severity-of-illness index (PSI) in patients with community-acquired pneumonia
      (CAP). PATIENTS: Randomly selected patients (n = 1,024) admitted with CAP to 22
      community hospitals. MEASUREMENTS AND MAIN RESULTS: Medical records were
      abstracted to obtain prognostic information used in the PSI. The discriminatory
      ability of the PSI to identify patients who died and the calibration of the PSI
      across deciles of risk were determined. The PSI discriminates well between
      patients with high risk of death and those with a lower risk. In contrast,
      calibration of the PSI was poor, and the PSI predicted about 2.4 times more
      deaths than actually occurred in our population of patients with CAP.
      CONCLUSIONS: We found that the PSI had good discriminatory ability. The original
      PSI overestimated absolute risk of death in our population. We describe a simple
      approach to recalibration, which corrected the overestimation in our population.
      Recalibration may be needed when transporting this prediction rule across
      populations.

PMID- 10354253
TI  - Educational and career outcomes of an internal medicine preceptorship for first
      year medical students.
AB  - OBJECTIVE: Medical educators have attempted in recent years to provide quality
      clinical experiences for medical students early in their medical training. We
      questioned whether participating in a preceptorship in internal medicine (PIM)
      resulted in better performances on subsequent clinical rotations and increased
      interest in internal medicine. PARTICIPANTS: Fifty-four students have
      participated in the PIM to date, with control groups consisting of students who
      applied for it but were not selected (n = 36), students participating in a
      preceptorship in family medicine (n = 168), and the remaining students (n = 330).
      DESIGN: Prospective cohort study. SETTING: University medical center and
      community practices. INTERVENTION: A 2-month, clinical preceptorship following
      the first year of medical school. MEASUREMENTS AND MAIN RESULTS: The following
      outcomes were assessed: scores in the introduction to clinical medicine course;
      grades in the medical ethics course; scores from the internal medicine clerkship;
      and choosing a career in internal medicine. In their second year, PIM students
      scored higher in both semesters of the introduction to clinical medicine course
      (87% and 86% vs 84% and 84%, p's <.01) and were more likely to receive honors in
      ethics (50% vs 29%, p <.01) than non-PIM students. During the internal medicine
      clerkship, PIM students' scores were significantly higher on an objective
      structured clinical examination (79% vs 76%, p =.05), ambulatory clinical
      evaluations (80% vs 76%, p <.01), and overall clerkship scores (78% vs 75%, p
      =.03) but not on inpatient clinical evaluations or on the National Board of
      Medical Examiners Subject Examination. Preceptorship students were more likely to
      receive honors grades in the medicine clerkship (33% vs 10%, p <.01), and they
      were more likely to match into internal medicine residencies than control
      students (54% vs 27%, p <.01). CONCLUSIONS: The PIM course is an intervention,
      early in students' careers, which appears to benefit them academically and
      increase their interest in internal medicine as a career.

PMID- 10354254
TI  - Student loan debt does not predict female physicians' choice of primary care
      specialty.
AB  - OBJECTIVE: There has never been a conclusive test of whether there is a relation
      between ultimately choosing to be a primary care physician and one's amount of
      student loan debt at medical school graduation. DESIGN/SETTING/PARTICIPANTS: To
      test this question, we examined data from the Women Physicians' Health Study, a
      large, nationally representative, questionnaire-based study of 4,501 U.S. women
      physicians. MEASUREMENTS AND MAIN RESULTS: We found that the youngest physicians
      were more than five times as likely as the oldest to have had some student loan
      debt and far more likely to have had high debt levels (p <.0001). However,
      younger women physicians were also more likely to choose a primary care specialty
      (p <.002). There was no relation between being a primary care physician and
      amount of indebtedness (p =.77); this was true even when the results were
      adjusted for the physicians' decade of graduation and ethnicity (p =.79).
      CONCLUSIONS: Although there may be other reasons for reducing student loan debt,
      at least among U.S. women physicians, encouraging primary care as a specialty
      choice may not be a reason for doing so.

PMID- 10354255
TI  - Improving pneumococcal vaccine rates. Nurse protocols versus clinical reminders.
AB  - OBJECTIVE: To compare the effectiveness of three interventions designed to
      improve the pneumococcal vaccination rate. DESIGN: A prospective controlled
      trial. SETTING: Department of Veterans Affairs ambulatory care clinic.
      PATIENTS/PARTICIPANTS: There were 3, 502 outpatients with scheduled visits
      divided into three clinic teams (A, B, or C). INTERVENTIONS: During a 12-week
      period, each clinic team received one intervention: (A) nurse standing orders
      with comparative feedback as well as patient and clinician reminders; (B) nurse
      standing orders with compliance reminders as well as patient and clinician
      reminders; and (C) patient and clinician reminders alone. Team A nurses
      (comparative feedback group) received information on their vaccine rates relative
      to those of team B nurses. Team B nurses (compliance reminders group) received
      reminders to vaccinate but no information on vaccine rates. MEASUREMENTS AND MAIN
      RESULTS: Team A nurses assessed more patients than team B nurses (39% vs 34%, p
      =.009). However, vaccination rates per total patient population were similar (22%
      vs 25%, p =.09). The vaccination rates for both team A and team B were
      significantly higher than the 5% vaccination rate for team C (p <.001).
      CONCLUSIONS: Nurse-initiated vaccine protocols raised vaccination rates
      substantially more than a physician and patient reminder system. The nurse
      initiated protocol with comparative feedback modestly improved the assessment
      rate compared with the protocol with compliance reminders, but overall
      vaccination rates were similar.

PMID- 10354257
TI  - Rewards and incentives for nonsalaried clinical faculty who teach medical
      students.
AB  - We surveyed the clerkship administrators of pediatrics, family medicine, and
      internal medicine at U.S. medical schools, and of pediatrics at Canadian medical
      schools to determine what rewards and incentives are being offered to nonsalaried
      faculty for office-based teaching. Monetary payment was offered by 13% to 22% of
      the programs. Nonmonetary rewards like educational opportunities were offered by
      70% to 89%; academic appointments by 90% to 95%; special recognition events by
      62% to 79%; and appreciation letters by 74% to 84% of programs. Only 3 of 338
      responders offered no rewards or incentives.

PMID- 10354258
TI  - Adhesive tape and intravascular-catheter-associated infections.
AB  - Adhesive tape is placed in close contact with intravascular catheters for
      extended periods and could theoretically contribute to local infections. We found
      that 74% of specimens of tape collected in one hospital were colonized by
      pathogenic bacteria. However, only 5% of specimens had significant growth from an
      inner layer obtained by discarding the outside layer from each roll. We suggest
      that adhesive tape is a potential source of pathogenic bacteria and that
      discarding the outer layer from a partially used roll might be a simple method
      for reducing the risk of infection to patients.

PMID- 10354256
TI  - What outcomes matter to patients?
AB  - OBJECTIVE: This study estimates the relative value to patients of physical,
      mental, and social health when making treatment decisions. Despite
      recommendations to use patient preferences to guide treatment decisions, little
      is known about how patients value different dimensions of their health status.
      DESIGN: Cross-sectional data from quasi-experimental, prospective study. SETTING:
      Forty-six primary care clinics in managed care organizations in California,
      Texas, Minnesota, Maryland, and Colorado. PATIENTS: Consecutive adult outpatients
      (n = 16,689) visiting primary care providers. MEASUREMENTS AND MAIN RESULTS:
      Medical Outcomes Study 12-Item Short Form (SF-12) health-related quality of life
      and patient preferences for their current health status, as assessed by standard
      gamble and time trade-off utility methods, were measured. Only 5% of the variance
      in standard gamble and time trade-off was explained by the SF-12. Within the SF
      12, physical health contributes substantially to patient preferences (35%-55% of
      the relative variance explained); however, patients also place a high value on
      their mental health (29%-42%) and on social health (16%-23%). The contribution of
      mental health to preferences is stronger in patients with chronic conditions.
      CONCLUSIONS: Patient preferences, which should be driving treatment decisions,
      are related to mental and social health nearly as much as they are to physical
      health. Thus, medical practice should strive to balance concerns for all three
      health domains in making treatment decisions, and health care resources should
      target medical treatments that improve mental and social health outcomes.

PMID- 10354259
TI  - Changing physician practice of physical activity counseling.
AB  - We conducted a prospective controlled trial to determine whether an educational
      intervention could improve resident physician self-efficacy and counseling
      behaviors for physical activity and increase their patients' reported activity
      levels. Forty-eight internal medicine residents who practiced at a Department of
      Veterans Affairs hospital received either two workshops on physical activity
      counseling or no intervention. All residents completed questionnaires before and
      3 months after the workshops. The 21 intervention physicians reported increased
      self-efficacy for counseling and increased frequency of counseling compared with
      the 27 control physicians. Approximately 10 patients of each resident were
      included in the study and surveyed before and 6 months after the intervention. Of
      560 patients, 465 (83%) returned both questionnaires. Following the intervention,
      there were no significant differences between patients of intervention and
      control physicians on any outcome measures. We conclude that educational
      interventions can improve physicians' reported self-efficacy of physical activity
      counseling but may not increase patient physical activity levels. Alternative
      approaches that emphasize overcoming the substantial barriers to exercise in
      chronically ill outpatients clearly will be important for facilitating changes in
      physical activity.

PMID- 10354262
TI  - Statistically derived predictive models. Caveat emptor.

PMID- 10354260
TI  - Body piercing medical concerns with cutting-edge fashion.
AB  - OBJECTIVE: To review the current information on medical complications,
      psychological implications, and legislative issues related to body piercing, a
      largely unregulated industry in the United States. METHODS: We conducted a
      MEDLINE search of English language articles from 1966 until May 1998 using the
      search terms "body piercing" and "ear piercing." Bibliographies of these
      references were reviewed for additional citations. We also conducted an Internet
      search for "body piercing" on the World Wide Web. MAIN RESULTS: In this
      manuscript, we review the available body piercing literature. We conclude that
      body piercing is an increasingly common practice in the United States, that this
      practice carries substantial risk of morbidity, and that most body piercing in
      the United States is being performed by unlicensed, unregulated individuals.
      Primary care physicians are seeing growing numbers of patients with body pierces.
      Practitioners must be able to recognize, treat, and counsel patients on body
      piercing complications and be alert to associated psychological conditions in
      patients who undergo body piercing.

PMID- 10354261
TI  - Are clinician-teachers good for anything other than teaching?

PMID- 10354263
TI  - Physicians and managed care. Challenges in the new environment.

PMID- 10354264
TI  - Circulating biochemical markers of bone remodeling in uremic patients.
AB  - Chronic renal failure is often associated with bone disorders, including
      secondary hyperparathyroidism, aluminum-related low-turnover bone disease,
      osteomalacia, adynamic osteopathy, osteoporosis, and skeletal beta2-microglobulin
      amyloid deposits. In spite of the enormous progress made during the last few
      years in the search of noninvasive methods to assess bone metabolism, the
      distinction between high- and low-turnover bone diseases in these patients still
      frequently requires invasive and/or costly procedures such as bone biopsy after
      double tetracycline labeling, scintigraphic-scan studies, computed tomography,
      and densitometry. This review is focused on the diagnostic value of several new
      serum markers of bone metabolism, including bone-specific alkaline phosphatase
      (bAP), procollagen type I carboxy-terminal extension peptide (PICP), procollagen
      type I cross-linked carboxy-terminal telopeptide (ICTP), pyridinoline (PYD),
      osteocalcin, and tartrate-resistant acid phosphatase (TRAP) in patients with
      chronic renal failure. Most of the observations made by several groups converge
      to the conclusion that serum bAP is the most sensitive and specific marker to
      evaluate the degree of bone remodeling in uremic patients. Nonetheless, PYD and
      osteocalcin, in spite of their retention and accumulation in the serum of renal
      insufficient patients, are also excellent markers of bone turnover. The future
      generalized use of these markers, individually or in combination with other
      methods, will undoubtedly improve the diagnosis and the treatment of the complex
      renal osteodystrophy.

PMID- 10354265
TI  - Hypothesis: is renal allograft rejection initiated by the response to injury
      sustained during the transplant process?
AB  - Allograft rejection can be caused by numerous factors such as damage to the donor
      kidney during surgical removal or implantation, injury sustained during the
      transport process between the donor and recipient, and suboptimal allograft
      perfusion during the intra- and post-operative period. In cadaveric allografts,
      damage can occur during cold storage, during the transit stage between donor and
      recipient, and hemodynamic instability due to the initial damage that caused its
      removal from the donor (such as brain death or trauma). We hypothesize that
      rejection requires recognition of this injury in addition to recognition of
      alloantigens. If indeed injury proves to be one factor in acute rejection
      episodes, then therapeutic efforts can be made to reduce injury during the
      transplantation process.

PMID- 10354266
TI  - Is low plasma 25-(OH)vitamin D a major risk factor for hyperparathyroidism and
      Looser's zones independent of calcitriol?
AB  - BACKGROUND: Recent reports suggest that calcitriol might not be the sole active
      metabolite of vitamin D and that plasma concentrations of 25-(OH)vitamin D
      (25OHD) are often abnormally low in hemodialysis patients. We have therefore
      evaluated plasma 25OHD as a risk factor for parathyroid hormone (PTH)
      hypersecretion and radiological bone disease. We carried out a cross-sectional
      study during the month of September in an Algerian dialysis center of 113
      patients who were not taking supplements of alphacalcidol or calcitriol. METHODS:
      Plasma 25OHD, calcitriol, PTH, calcium, phosphate, bicarbonate, and aluminum were
      measured, and x-rays of the hands and pelvis were obtained for evaluation of
      subperiosteal resorption and Looser's zones. RESULTS: The median plasma 25OHD was
      47.5 nmol/liter (range 2.5 to 170.0). Univariate analysis showed that plasma PTH
      was correlated positively with months on maintenance dialysis and negatively with
      plasma 25OHD, calcitriol, calcium, bicarbonate and aluminum, but not with that of
      phosphate. plasma 25OHD was positively correlated with calcium and calcitriol.
      Using multiple regression analysis, only plasma 25OHD (negative) and the duration
      on maintenance dialysis (positive) were independently linked to plasma PTH. The
      prevalence of isolated subperiosteal resorption (ISR) was 34%, and that of the
      combination of resorption with Looser's zones (CRLZ) was 9%; thus, only 57% of
      the patients had a normal x-ray appearance. These groups were comparable with
      regards to age, gender, and duration on dialysis. When the biochemical
      measurements of the patients with CRLZ were compared with those from patients
      without radiological lesions, plasma 25OHD was the only parameter to show a
      statistically significant difference, being significantly lower in the CRLZ group
      (26 +/- 18 vs. 57 nmol/liter, ANOVA, P < 0.004). Plasma 25OHD was also
      significantly lower in the ISR group (44, P < 0.05) than in the normal x-ray
      group, and plasma Ca (P < 0.003) and bicarbonate (P < 0.02) were lower.
      Logistical analysis showed that the presence of resorption was independently
      linked only with plasma PTH. Looser's zones and subperiosteal resorption were not
      seen in patients with plasma 25OHD of more than 40 (Looser's zones) and more than
      100 nmol/liter (subperiosteal resorption). The optimal range for intact PTH in
      hemodialysis patients with mild aluminum overload is 10 to 25 pmol/liter. We
      found that plasma PTH was inappropriately high only when plasma 25OHD was less
      than 100 nmol/liter. With a plasma 25OHD of between 100 and 170 nmol/liter,
      hypercalcemia was present with a plasma PTH of less than 10 pmol/liter in only
      one case. CONCLUSIONS: This cross sectional study shows that low plasma 25OHD is
      a major risk factor for hyperparathyroidism and Looser's zones. In dialysis
      patients, we suggest that the plasma levels of 25OHD are maintained around the
      upper limit of the reference range of sunny countries.

PMID- 10354267
TI  - Effects of interferon alpha-2b on barrier function and junctional complexes of
      renal proximal tubular LLC-PK1 cells.
AB  - BACKGROUND: Interferon alpha-2b (IFNalpha) treatment of diseases can be
      accompanied by impaired renal function and capillary leak syndrome. To explore
      potential mechanisms of IFNalpha-induced renal dysfunction, an in vitro cell
      culture model system was established to investigate the effects of IFNalpha on
      barrier function and junctional complexes. METHODS: LLC-PK1 cells were cultured
      on microporous membranes. Transepithelial resistance (TER) was measured, and the
      dose- and time-dependent effects of IFNalpha were assessed. The expression
      patterns of junctional proteins were examined by Western blot analysis and by
      confocal immunofluorescence microscopy. RESULTS: IFNalpha produced a dose- and
      time-dependent decrease in TER. The effect was reversible on removal of IFNalpha
      at doses up to 5 x 103 U/ml. Tyrphostin, an inhibitor of phosphotyrosine kinases,
      ameliorated the IFNalpha-induced decrease in TER. Increased expression of
      occludin and E-cadherin was detected by Western blot analysis after IFNalpha
      treatment. Immunofluorescence confocal microscopy revealed a broader staining of
      occludin and E-cadherin following IFNalpha treatment, with prominent staining at
      the basal cell pole in addition to localization at the junctional region. A
      marked increase in phosphotyrosine staining along the apico-lateral cell border
      was detected after IFNalpha treatment. CONCLUSIONS: These findings provide
      evidence that IFNalpha can directly affect barrier function in renal epithelial
      cells. The mechanisms involve enhanced tyrosine phosphorylation and
      overexpression and possibly displacement or missorting of the junctional proteins
      occludin and E-cadherin.

PMID- 10354268
TI  - Oxidized low-density lipoprotein stimulates monocyte adhesion to glomerular
      endothelial cells.
AB  - BACKGROUND: Abnormalities in lipid and lipoprotein metabolism have been
      implicated in the pathogenesis of glomerulosclerosis. Atherogenic lipoproteins
      [for example, low-density lipoprotein (LDL) and oxidized LDL (ox-LDL)] have been
      shown to stimulate glomerular monocyte chemoattractants involved in monocyte
      infiltration. However, the role of LDL and ox-LDL in the early monocyte adhesion
      to glomerular endothelial cells (ECs) and associated intracellular signaling
      mechanisms are not clearly understood. METHODS: In this study, we examined the
      effect of LDL and ox-LDL on intracellular signaling mechanisms associated with
      monocyte adhesion to glomerular ECs and intercellular adhesion molecule-1 (ICAM
      1) expression. RESULTS: Ox-LDL, but not LDL, stimulated EC ICAM-1 expression and
      monocyte adhesion. Ox-LDL elevated protein tyrosine kinase (PTK) activity, and
      the preincubation of ECs with specific PTK inhibitors blocked ox-LDL-induced ICAM
      1 message and monocyte adhesion. Whereas experimental maneuvers that inhibit
      either protein kinase C activation (by PKC depletion or with inhibitors) or Gi
      protein-mediated pathways (pertussis toxin sensitive) had no effect on ox-LDL
      induced monocyte adhesion and ICAM-1 expression. cAMP-elevating compounds did not
      induce ICAM-1 or monocyte adhesion. CONCLUSIONS: The data indicate that ox-LDL,
      by stimulating monocyte adhesion to the glomerular endothelium, may regulate
      monocyte infiltration within the glomerulus, supporting an early pathobiological
      role for atherogenic lipoproteins in glomerular injury. The results suggest that
      the activation of specific PTK and associated signaling may, at least in part,
      play a critical role in ox-LDL-mediated endothelial-monocyte interaction-related
      events. The data suggest that the interventions aimed at modifying associated
      intracellular signaling events within the glomerulus may provide potential
      therapeutic modalities in monocyte/macrophage-mediated glomerular disease.

PMID- 10354269
TI  - Effect of glucose on stress-activated protein kinase activity in mesangial cells
      and diabetic glomeruli.
AB  - BACKGROUND: We have reported that hyperglycemia increases c-jun mRNA levels in
      isolated glomeruli of diabetic rats. The transcriptional activity of c-jun can be
      modified by phosphorylation of serine residues in the regulatory domain of the
      protein by stress-activated protein kinases (SAPKs), but the effect of high
      glucose concentrations on SAPK expression and activity is unknown. Accordingly,
      we studied p42/44 MAPK, p38 MAPK, and SAPK expression and activity in primary
      mesangial cells exposed to high glucose concentrations, as well as SAPK
      expression and activity in glomeruli of normal and streptozotocin-induced
      diabetic rats. METHODS: Mesangial cells were incubated in 40 mM glucose for 30
      and 60 minutes and 6, 12, 24, and 48 hours, whereas glomeruli of streptozotocin
      induced diabetic rats were isolated one day and one and two weeks after the onset
      of hyperglycemia (blood glucose levels more than 15 mmol/liter), and were
      compared with age-matched normal rats. Cell lysates were subjected to Western
      blot analysis of SAPK and phosphorylated SAPK and an in vitro SAPK assay using
      recombinant c-jun. RESULTS: Western blot analysis revealed that SAPK was
      expressed, but unphosphorylated, in unstimulated mesangial cells and whole
      glomerular lysates from normal rats. In accord with these observations, no SAPK
      activity was detected in lysates from mesangial cells or whole glomeruli from
      normal rats, although mesangial cell SAPK activity was readily induced in vitro
      by sorbitol. High glucose concentrations did not increase SAPK activity or lead
      to detectable phosphorylated SAPK either in vitro or in vivo. In contrast, short
      term exposure to 40 mM of glucose activated both p42/44 MAPK and p38 MAPK.
      CONCLUSIONS: We conclude that high glucose concentrations do not activate SAPK in
      primary cultured mesangial cells or in diabetic glomeruli during the early phase
      of diabetic renal hypertrophy.

PMID- 10354271
TI  - Prior heat stress inhibits apoptosis in adenosine triphosphate-depleted renal
      tubular cells.
AB  - BACKGROUND: This study tested the following hypotheses: (a) renal tubular
      epithelial cells subjected to transient adenosine triphosphate (ATP) depletion
      undergo apoptosis, and (b) induction of heat stress proteins (HSPs) inhibits cell
      death following ATP depletion, possibly by interacting with anti-apoptotic signal
      proteins. METHODS: To simulate ischemia in vivo, cells derived from opossum
      kidney proximal tubule (OK) were subjected to ATP depletion (5 mM cyanide, 5 mM 2
      deoxy-D-glucose, and 0 mM glucose) for 1 to 1. 5 hours, followed by recovery (10
      mM glucose without cyanide). The presence of apoptosis was assessed by
      morphological and biochemical criteria. The effect of prior heat stress or
      caspase inhibition on apoptosis and cell survival were assessed. RESULTS: In the
      ATP-depleted cell, both Hoechst dye and electron microscopy revealed
      morphological features that are typical of apoptosis. On an agarose gel, a
      "ladder pattern" typical of endonucleosomal DNA degradation was observed. Prior
      heat stress reduced the number of apoptotic-appearing cells, significantly
      decreased DNA fragmentation, and improved cell survival compared with controls
      (73.0 +/- 1% vs. 53.0 +/- 1.5%; P < 0.05). Two different caspase inhibitors also
      improved survival, suggesting that apoptosis is a cause of cell death in this
      model. Compared with ATP-depleted controls, prior heat stress inhibited the pro
      apoptotic changes in the ratio of Bcl2 to BAX, proteins known to regulate the
      apoptotic set point in renal cells. HSP 72, a known cytoprotectant, co
      immunoprecipitated with Bcl2, an anti-apoptotic protein. Prior heat stress
      markedly increased the interaction between HSP 72 and Bcl2. CONCLUSIONS:
      Transient ATP depletion causes apoptosis in tubular epithelial cells. Prior HS
      inhibits apoptosis and improves survival in these cells. Novel interactions
      between HSP 72 and Bcl2 may be responsible, at least in part, for the protection
      afforded by prior heat stress against ATP depletion injury.

PMID- 10354270
TI  - Nitric oxide enhances paracellular permeability of opossum kidney cells.
AB  - BACKGROUND: Nitric oxide (NO) has been shown to be a paracrine/autocrine
      regulator of proximal tubular transport. In this study, we investigated the
      effect of NO on the paracellular permeability of opossum kidney (OK) cells, a
      proximal tubule cell line that possesses a leaky paracellular pathway resembling
      that of the in vivo proximal tubule. METHODS: Paracellular permeability of OK
      cells cultured on permeable supports was measured as the apparent paracellular
      permeability coefficient (Papp) for 3[H]-D-mannitol. Changes in cell viability,
      cellular adenosine triphosphate (ATP) content, cGMP levels, and lipid
      peroxidation were assessed. RESULTS: Incubation with 2 mM sodium nitroprusside
      (SNP), an NO donor, for 24 hours significantly enhanced the Papp of OK cell
      sheets by 30.6 +/- 7.0% (N = 8, P < 0.05). This effect was largely blunted by
      hemoglobin, a NO scavenger. Cell viability was not compromised. This effect of
      SNP was concomitant with a moderate reduction of cellular ATP content, an
      increase in lipid peroxidation, and an increase in cellular cGMP levels. The
      antioxidant superoxide dismutase (SOD) significantly attenuated the effect of SNP
      on cellular ATP content and blunted the increase in Papp caused by SNP. A soluble
      guanylate cyclase inhibitor did not affect the effect of SNP on the Papp.
      CONCLUSIONS: NO enhances the paracellular permeability of OK cells possibly via
      mechanisms involving decreases in cellular ATP content.

PMID- 10354272
TI  - Thrombospondin peptides are potent inhibitors of mesangial and glomerular
      endothelial cell proliferation in vitro and in vivo.
AB  - BACKGROUND: Thrombospondin 1 (TSP1), a multifunctional, matricellular
      glycoprotein, is expressed de novo in many inflammatory disease processes,
      including glomerular disease. Short peptide fragments derived from the type I
      properdin repeats of the TSP1 molecule mimic anti-angiogenic and/or transforming
      growth factor-beta (TGF-beta)-activating properties of the whole TSP1
      glycoprotein. We investigated the effects of D-reverse peptides derived from the
      type I domain of TSP1 in experimental mesangial proliferative glomerulonephritis
      in the rat (anti-Thy1 model), as well as their effects on cultured mesangial and
      glomerular endothelial cells. METHODS: Effects of TSP peptides on proliferation
      of mesangial or glomerular endothelial cells in culture after growth arrest or
      growth factor stimulation (fibroblast growth factor-2, platelet-derived growth
      factor-BB, 10% fetal calf serum) were measured by [3H]thymidine incorporation
      assay. Adhesion of rat mesangial cells (MCs) to a TSP-peptide matrix was assayed
      using an attachment-hexosaminidase assay. TSP peptides were intraperitoneally
      injected daily in rats that had received an intravenous injection of polyclonal
      anti-Thy1 antibody to induce mesangial proliferative glomerulonephritis. On
      biopsies from days 2, 5, and 8 of anti-Thy1 disease, mesangial and glomerular
      endothelial proliferation, matrix expansion, mesangial activation, and
      microaneurysm formation were assessed. Functional parameters such as blood
      pressure and proteinuria were also measured. RESULTS: An 18-amino acid peptide
      (type I peptide) with anti-angiogenic and TGF-beta-activating sequences decreased
      mesangial and glomerular endothelial cell proliferation in vitro and in vivo and
      reduced microaneurysm formation and proteinuria in experimental
      glomerulonephritis. Analogues lacking the TGF-beta-activating sequence mimicked
      most effects of the type I peptide. The mechanism of action of these peptides may
      include antagonism of fibroblast growth factor-2 and alteration of MC adhesion.
      The TGF-beta-activating sequence alone did not have significant effects on
      mesangial or glomerular endothelial cells in vitro or in experimental kidney
      disease in vivo. CONCLUSION: Peptides from TSP1 may be promising therapeutics in
      treating glomerular disease with mesangial and endothelial cell injury.

PMID- 10354273
TI  - IFN-gamma and LPS differentially modulate class II MHC and B7-1 expression on
      murine renal tubular epithelial cells.
AB  - BACKGROUND: We have investigated inducible class II major histocompatibility
      complex (MHC) and B7 expression on primary murine renal tubular epithelial cells,
      called F1K cells, and examined their role in activating nephritogenic T cells
      derived from kidneys of animals with autoimmune glomerulonephritis. METHODS:
      Class II MHC, class II transactivator, and costimulatory molecule expression were
      evaluated in untreated and cytokine-treated F1K cells by Northern hybridization
      and flow cytometry. Cell-surface B7-1 expression was evaluated in vitro by
      immunoprecipitation and in vivo by immunohistochemistry. T-cell activation
      studies were then performed to assess the functional significance of B7-1
      expression on F1K cells. RESULTS: Coincubation of F1K cells with interferon (IFN)
      gamma and lipopolysaccharide (LPS) significantly decreased IFN-gamma-induced
      class II MHC expression, by both fluorescence-activated cell sorting and Northern
      analyses. LPS-mediated inhibition of class II MHC in this setting was effected
      through a decrease in class II transactivator mRNA levels in treated F1K cells.
      By contrast, IFN-gamma and LPS coincubation induced B7-1 but not B7-2 expression
      in F1K cells, as detected by Northern analysis, flow cytometry, and
      immunoprecipitation. In addition, renal tubular staining for B7-1 was apparent in
      kidneys isolated from IFN-gamma+LPS-treated recipient mice, as well as mice with
      autoimmune glomerulonephritis. Further studies evaluated the interaction of F1K
      cells and MR1.3, a nephritogenic CD4+ Th2 clone derived from kidneys of animals
      with autoimmune glomerulonephritis. Cytokine production assays revealed that F1K
      cells activated MR1.3 cells if they were pretreated with both IFN-gamma and LPS
      48 hours prior to exposure to nephritogenic T cells. CONCLUSIONS: These studies
      are the first description of a differential regulation of class II MHC and B7-1
      expression in renal tubular epithelial cells mediated by IFN-gamma and LPS. Such
      findings indicate that discrete proinflammatory stimuli could potentiate antigen
      presenting capabilities of renal tubular epithelial cells in vivo and further
      suggest a direct role of such nonprofessional antigen-presenting cells in
      modulating renal immune responses.

PMID- 10354274
TI  - L-Arginine supplementation increases mesangial cell injury and subsequent tissue
      fibrosis in experimental glomerulonephritis.
AB  - BACKGROUND: Mesangial cell lysis in the antithymocyte serum (ATS)-induced model
      of glomerulonephritis is dependent on the generation of cytotoxic nitric oxide
      (NO) through transient induction of NO synthase (iNOS). We hypothesized that
      increased availability of L-arginine (L-Arg) during mesangial cell lysis might
      provide iNOS with increased substrate leading to increased lysis, and that this
      increased lysis would be reflected in more severe fibrotic disease at day 6.
      METHODS: To ensure whole body equilibration with high L-Arg at the time of
      injury, rats were pretreated with 1% L-Arg in drinking water for one week prior
      to the administration of ATS. Animals were sacrificed six hours after ATS
      injection when previous experiments had indicated iNOS induction had occurred and
      at six days. At six hours, plasma was obtained for L-Arg levels and
      nitrite/nitrate (NOx) content. Renal tissues were taken for histological
      evaluation of glomerular cell counts, macrophage infiltration (ED-1), and iNOS
      expression. Glomeruli were isolated for detection of iNOS mRNA and placed in
      culture to study the dependence of NO production on L-Arg concentration. In rats
      sacrificed at six days, L-Arg supplementation was stopped 16 hours after ATS
      injection. Fibrotic disease was evaluated by urinary protein excretion,
      histological assessment of glomerular cell number, matrix accumulation, and
      production of transforming growth factor-beta1 and matrix components fibronectin
      and plasminogen activator inhibitor type-1 (PAI-1) by isolated glomeruli in
      culture. RESULTS: At six hours, the glomerular cell number was significantly
      reduced by ATS injection (P < 0.01) and further significantly (P < 0. 05) reduced
      by L-Arg feeding [normal control (NC) = 64.2 +/- 1, ATS = 53.4 +/- 0.7, ATS + L
      Arg = 50.8 +/- 0.7]. Disease increased macrophage infiltration and iNOS protein
      and iNOS mRNA levels markedly (P < 0.01), whereas L-Arg feeding did not further
      increase these variables. Plasma L-Arg levels (nmol/ml) were reduced by disease
      (NC = 121 +/- 9, ATS = 84 +/- 13, P < 0.01) and elevated by L-Arg feeding (ATS +
      L-Arg = 166 +/- 12, P < 0.01). Plasma NOx was significantly increased by ATS and
      further increased by ATS + L-Arg (P < 0.05). Production of NOx by cultured
      glomeruli showed striking L-Arg concentration dependence in six hours but not in
      normal glomeruli. In the group sacrificed at day 6, day 2 proteinuria was higher
      in the ATS + L-Arg group compared with the ATS alone group (P < 0.05). Measures
      of fibrotic disease at day 6 all showed large increases over control with ATS
      alone (P < 0.01), and further small, but significant increases when L-Arg was
      combined with ATS (P < 0.05). CONCLUSIONS: The results indicate that if given
      during disease induction, L-Arg supplementation can enhance iNOS-dependent tissue
      injury by providing increased substrate. Although the increase in injury with L
      Arg supplementation was small, it led to increased fibrosis at day 6. These data
      predict that in diseases with repeated iNOS-dependent tissue injury, L-Arg
      supplementation may produce cumulative increases in tissue fibrosis.

PMID- 10354275
TI  - Small bowel T cells, HLA class II antigen DR, and GroEL stress protein in IgA
      nephropathy.
AB  - BACKGROUND: Previous studies suggest that intestinal mucosa may be involved in
      the pathogenesis of IgA nephropathy (IgAN). To further clarify this involvement,
      we investigated whether or not IgAN patients have small bowel mucosal findings
      suggestive of inflammation and stress. METHODS: Seventeen patients with IgAN
      underwent gastroscopic examination. Fresh small bowel biopsy specimens were
      frozen, and in cryosections, the proportion of alphabeta and gammadelta receptors
      bearing T cells and CD3+ T cells were quantitated immunohistochemically. The
      expression of HLA class II antigen DR (HLA-DR) and human GroEL stress-protein
      homologue was similarly quantitated. In an avidin-biotin peroxidase technique,
      the following monoclonal primary antibodies were used: anti-beta-chain (betaF1),
      anti-delta-chain (TCRdelta1), anti-CD3 (Leu4), anti-constant fragment of HLA-DR
      (L243), and anti-GroEL (ML30). Twenty-nine patients who had undergone gastroscopy
      because of dyspepsia served as controls. RESULTS: In all specimens, the mucosal
      architecture was normal. The amount of gammadelta T cells and the total amount of
      T cells, as indicated by CD3+ positivity, were both significantly increased in
      IgAN. The number of alphabeta T cells was also higher in the IgAN patients.
      Villous epithelium of the IgAN patients disclosed a significant increase in the
      expression of HLA-DR antigen and GroEL stress protein. CONCLUSIONS: Our results
      suggest that ongoing small bowel inflammation and stress are present in IgAN.
      Despite normal morphology, there is reason to believe that the small bowel mucosa
      is involved in the pathogenesis of IgAN.

PMID- 10354276
TI  - Effect of nitric oxide donors on renal tubular epithelial cell-matrix adhesion.
AB  - BACKGROUND: Nitric oxide (NO) and its metabolite, peroxynitrite (ONOO-), are
      involved in renal tubular cell injury. We postulated that if NO/ONOO- has an
      effect to reduce cell adhesion to the basement membrane, this may contribute to
      tubular obstruction and may be partially responsible for the harmful effect of NO
      on the tubular epithelium during acute renal failure (ARF). METHODS: We examined
      the effect of the NO donors (z)-1-[2-(2-aminoethyl)-N-(2
      ammonioethyl)amino]diazen-1- ium-1, 2-diolate (DETA/NO), spermine NONOate (SpNO),
      and the ONOO- donor 3-morpholinosydnonimine (SIN-1) on cell-matrix adhesion to
      collagen types I and IV and fibronectin using three renal tubular epithelial cell
      lines: LLC-PK1, BSC-1, and OK. RESULTS: In LLC-PK1 cells, DETA/NO (500 microM)
      had no effect, and SpNO (500 microM) had a modest effect on cell adhesion
      compared with controls. Exposure to SIN-1 caused a dose-dependent impairment in
      cell-matrix adhesion. Similar results were obtained in the different cell types
      and matrix proteins. The effect of SIN-1 (500 microM) on LLC-PK1 cell adhesion
      was not associated with either cell death or alteration of matrix protein and was
      attenuated by either the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5
      tetramethylimidazoline-1-oxyl-3-oxide, the superoxide scavenger superoxide
      dismutase, or the ONOO- scavenger uric acid in a dose-dependent manner.
      CONCLUSIONS: These results therefore support the possibility that ONOO- generated
      in the tubular epithelium during ischemia/reperfusion has the potential to impair
      the adhesion properties of tubular cells, which then may contribute to the
      tubular obstruction in ARF.

PMID- 10354277
TI  - Characterization of the rat mesangial cell type 2 sulfonylurea receptor.
AB  - BACKGROUND: Sulfonylurea receptors are classified as either high-affinity type 1
      (SUR1) or low-affinity type 2 receptors (SUR2), and the gene expression of SURs
      has recently been demonstrated in kidney. However, functional data regarding a
      renal SUR are lacking. We previously demonstrated that mesangial cell (MC) gene
      and protein expression of extracellular matrix components were up-regulated by
      the sulfonylurea, tolazamide. After noting this biological response, we next
      sought to investigate the presence of a sulfonylurea receptor in rat MCs.
      METHODS: Equilibrium binding studies employing [3H]glibenclamide as a ligand were
      performed on crude MC membrane preparations. Gene expression for SUR was explored
      by Northern analysis of cultured MCs and whole kidney tissue. The effect of
      sulfonylurea on intracellular Ca2+ in MCs was assayed by spectrofluorometry, and
      glibenclamide-induced changes in the contractility of MCs were assessed. RESULTS:
      MCs bound [3H]glibenclamide with a KD of 2.6 microM and a Bmax of 30.4 pmol/mg
      protein as determined by Scatchard analysis. Three SUR2 transcripts were detected
      in MCs. A major transcript was detected at 5.5 kb and minor transcripts at 7.5
      and 8.6 kb. Following sulfonylurea treatment of MCs, real-time videomicroscopy
      revealed intense MC contraction, coinciding with oscillatory increments of
      intracellular Ca2+ concentration. Further evidence of sulfonylurea-induced MC
      contraction was demonstrated by glibenclamide-induced deformation of a silicone
      rubber substrate. CONCLUSIONS: These results demonstrate that SUR2 resides on
      MCs. Functional activation of this receptor by sulfonylurea induces Ca2+
      transients that result in MC contraction.

PMID- 10354278
TI  - Combined administration of IgA and IgG anti-Thy-1 antibodies enhances renal
      inflammation in rats.
AB  - BACKGROUND: IgA nephropathy (IgAN) is the most common type of immunologically
      mediated glomerulonephritis (GN) and is characterized by deposition in the
      glomerular mesangium of IgA together with C3, C5b-9, and properdin. In patients,
      the codeposition of IgA together with IgG and/or IgM can lead to a more
      progressive course of disease. In Wistar rats, mesangial proliferative GN can be
      induced by the injection of mouse IgG anti-Thy-1 antibodies (ER4G). In contrast,
      the administration of mouse IgA anti-Thy-1 antibodies (ER4A) to rats results in
      isolated hematuria without detectable albuminuria and without detectable
      complement deposition. METHODS: To investigate the effect of the combination of
      IgA and IgG on glomerular injury, Wistar rats were injected with a limiting dose
      of ER4G in the presence or absence of ER4A in a dose able to induce hematuria.
      RESULTS: Although the limiting dose of ER4G or the dose of ER4A used did not
      induce significant albuminuria, the combination of ER4G and ER4A resulted in a
      synergistic increase in albuminuria. Microhematuria occurred in rats receiving
      either ER4A or ER4G alone or in combination. Although both ER4A or a limiting
      dose of ER4G induced minor increases in extracellular matrix expansion, the
      combination resulted in a pronounced, additive increased matrix expansion.
      CONCLUSION: We conclude that in this model of IgA-mediated glomerulopathy, a
      selective complement-dependent synergistic renal injury is induced in Wistar rats
      by glomerular codeposition of mouse anti-Thy-1 monoclonal isotypes.

PMID- 10354279
TI  - Heparin-binding epidermal growth factor-like growth factor is expressed in the
      adhesive lesions of experimental focal glomerular sclerosis.
AB  - BACKGROUND: In this study, we attempted to determine whether heparin-binding
      epidermal growth factor-like growth factor (HB-EGF) was up-regulated in two
      chronic models of proteinuria. METHODS: Chronic passive Heymann nephritis (PHN)
      and puromycin aminonucleoside (PAN) models were induced in Sprague-Dawley rats.
      HB-EGF expression was studied by Northern blotting, in situ hybridization, and
      immunohistochemistry. RESULTS: The chronic PAN model was associated with the
      development of glomerular lesions of focal glomerular sclerosis (FGS), severe
      interstitial fibrosis, and renal failure. Lesions of FGS were seen in
      approximately 80% of glomeruli at all time points, with a slight increase in the
      number of glomeruli showing extensive adhesion between 40 and 90 days. Northern
      blots of whole kidney tissue showed a 3- to 5.8-fold increased expression of HB
      EGF mRNA in the chronic PAN group. Increased mRNA and protein were localized by
      in situ hybridization and immunohistochemistry to tubules, glomerular epithelial
      cells (GECs), and cells of Bowman's capsule. HB-EGF mRNA and protein were
      strongly expressed by epithelial cells involved in the formation of the lesions
      of FGS. By contrast, in chronic PHN, there was a small increase in HB-EGF, and
      the extensive lesions of FGS did not develop despite continued, heavy
      proteinuria. CONCLUSIONS: These data suggest that HB-EGF may contribute to
      formation of the lesions of FGS, perhaps through stimulation of abortive
      mitogenesis in GECs or an adhesive interaction between transmembrane HB-EGF and
      the exposed glomerular basement membrane.

PMID- 10354280
TI  - Tumor necrosis factor-alpha and lipopolysaccharide induce apoptotic cell death in
      bovine glomerular endothelial cells.
AB  - BACKGROUND: The glomerular endothelial cell is a specialized microvascular cell
      type involved in the regulation of glomerular ultrafiltration. During gram
      negative sepsis, glomerulonephritis, and acute renal failure, bacterial
      lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) may cause
      severe cell damage. Our aim was to study and compare the direct effects of TNF
      alpha and LPS on the induction of apoptosis in bovine glomerular endothelial
      cells. METHODS: Primary bovine glomerular endothelial cells were stimulated with
      TNF-alpha or LPS, and apoptotic cell death was investigated by DNA fragmentation
      analysis, morphological studies, measurement of cytochrome c efflux and
      mitochondrial permeability transition, Bak, Bad, Bax, Bcl-2, Bcl-xL protein
      expression, and caspase-3-like protease activity. RESULTS: TNF-alpha, as well as
      LPS, elicited apoptotic cell death both time and concentration dependently. Along
      with DNA ladder formation, we detected the formation of 50 kbp high molecular
      weight DNA fragments, nuclear condensation, and mitochondrial permeability
      transition. Concerning all parameters, LPS signaling proved to be more rapid than
      TNF-alpha. Mechanistically, TNF-alpha-induced cell death was preceded by an
      efflux of mitochondrial cytochrome c into the cytosol and, subsequently, by a
      marked increase in the proapoptotic protein Bak and a decrease in the anti
      apoptotic Bcl-xL protein content. Comparable but more pronounced effects were
      seen with LPS. Later, caspase-3-like protease activity was first detectable after
      10 hours and was continuously increased up to 24 hours in both TNF-alpha- and LPS
      stimulated cells. Correspondingly, we detected an extended cleavage of the
      nuclear enzyme poly(ADP-ribose) polymerase. Caspase inhibitors Z-Asp-CH2-DCB and
      Z-VAD-fmk blocked both TNF-alpha- and LPS-induced apoptosis in a comparable
      manner. Only Z-Asp-CH2-DCB was able to block apoptotic cell death completely.
      CONCLUSION: Both bacterial LPS and TNF-alpha potently induced apoptotic cell
      death in glomerular endothelial cells. Direct endotoxin-induced apoptosis may
      therefore be relevant in the progression of acute renal failure, which is a
      frequent complication of gram-negative sepsis.

PMID- 10354281
TI  - Role of intron 1 in smooth muscle alpha-actin transcriptional regulation in
      activated mesangial cells in vivo.
AB  - BACKGROUND: The activation of glomerular mesangial cells is one of the early,
      important features of progressive glomerular disease. Smooth muscle alpha-actin
      (SMalphaA) is an excellent marker of activated mesangial cells. However, the
      mechanisms of SMalphaA regulation are only available from in vitro investigation.
      METHODS: We examined in vivo promoter analysis of the SMalphaA gene-utilizing
      transgenic mice harboring different promoter regions of the SMalphaA gene fused
      to chloramphenicol acetyl transferase (CAT). CAT activities were tested in
      primary cultured mesangial cells and in glomerular legions of Habu venom
      glomerulonephritis. RESULTS: The DNA sequence -891 to +3828, which contains exon
      1, intron 1, and the first 14 bp of exon 2 in addition to the 5'-flanking
      sequence of the SMalphaA gene, induced high levels of transcription in activated
      mesangial cells in in vivo habu venom glomerulonephritis and in cultured
      mesangial cells derived from transgenic mice. The DNA region -891 to -124 was a
      positive element in mesangial cells derived from transgenic mice. Deletions (3316
      or 137 bp) in intron 1 reduced transcription to undetectable levels. The 137 bp
      sequence is highly conserved among several species, containing one CArG box
      element, which is one of the key motifs for transcriptional activation of
      contractile-related proteins. In vitro transfection analysis failed to
      demonstrate these positive effects of intron 1 and region -891 to -124.
      Conclusions. In vivo promoter analysis of the SMalphaA gene provided new
      information about the transcriptional regulation of SMalphaA in activated
      mesangial cells. The DNA region -891 to -124 has a positive effect on SMalphaA
      transcription in cultured mesangial cells. The intron 1 region (+1088 to +1224)
      plays a pivotal role in SMalphaA transcription in activated mesangial cells in
      vivo. Further analysis of this conserved region in intron 1, including the CArG
      motif, will be of great value in understanding the molecular mechanisms of
      mesangial activation.

PMID- 10354282
TI  - The cyclin kinase inhibitor p21CIP1/WAF1 limits glomerular epithelial cell
      proliferation in experimental glomerulonephritis.
AB  - BACKGROUND: During glomerulogenesis, visceral glomerular epithelial cells (VECs)
      exit the cell cycle and become terminally differentiated and quiescent. In
      contrast to other resident glomerular cells, VECs undergo little if any
      proliferation in response to injury. However, the mechanisms for this remain
      unclear. Cell proliferation is controlled by cell-cycle regulatory proteins where
      the cyclin-dependent kinase inhibitor p21Cip1,WAF1 (p21) inhibits cell
      proliferation and is required for differentiation of many nonrenal cell types.
      METHODS: To test the hypothesis that p21 is required to maintain a differentiated
      and quiescent VEC phenotype, experimental glomerulonephritis was induced in p21
      knockout (-/-) and p21 wild-type (+/+) mice with antiglomerular antibody. DNA
      synthesis (proliferating cell nuclear antigen, bromodeoxyuridine staining), VEC
      proliferation (multilayers of cells in Bowman's space), matrix accumulation
      (periodic acid-Schiff, silver staining), apoptosis (TUNEL), and renal function
      (serum urea nitrogen) were studied on days 5 and 14 (N = 6 per time point). VECs
      were identified by location, morphology, ezrin staining, and electron microscopy.
      VEC differentiation was measured by staining for Wilms' tumor-1 gene. RESULTS:
      Kidneys from unmanipulated p21-/- mice were histologically normal and did not
      have increased DNA synthesis, suggesting that p21 was not required for the
      induction of VEC terminal differentiation. Proliferating cell nuclear antigen and
      bromodeoxyuridine staining was increased 4.3- and 3.3-fold, respectively, in p21
      /- mice with glomerulonephritis (P < 0.0001 vs. p21+/+ mice). At each time point,
      VEC proliferation was also increased in nephritic p21-/- mice (P < 0.0001 vs.
      p21+/+ mice). VEC re-entry into the cell cycle was associated with the loss of
      Wilms' tumor-1 gene staining. Nephritic p21-/- mice had increased extracellular
      matrix protein accumulation and apoptosis and decreased renal function (serum
      urea nitrogen) compared with p21+/+ mice (P < 0.001). CONCLUSION: These results
      show that the cyclin kinase inhibitor p21 is not required by VECs to attain a
      terminally differentiated VEC phenotype. However, the loss of p21, in disease
      states, is associated with VEC re-entry into the cell cycle and the development
      of a dedifferentiated proliferative phenotype.

PMID- 10354283
TI  - Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary
      vascular permeability.
AB  - BACKGROUND: Despite the advent of dialysis, survival with acute renal failure
      when associated with multiorgan failure is poor. The development of lung injury
      after shock or visceral ischemia has been shown; however, the effects of isolated
      renal ischemia/reperfusion injury (IRI) on the lungs are unclear. We hypothesized
      that isolated renal IRI could alter pulmonary vascular permeability (PVP) and
      that macrophages could be important mediators in this response. METHODS: Rats (N
      = 5 per group) underwent renal ischemia for 30 minutes, followed by reperfusion.
      Lung vascular permeability was evaluated by quantitation of Evans blue dye
      extravasation from vascular space to lung parenchyma at 1, 24, 48, or 96 hours
      after reperfusion. Serum was collected for blood urea nitrogen and creatinine at
      each time point. To examine the role of the macrophage, the macrophage pacifant
      CNI-1493, which inhibits the release of macrophage-derived inflammatory products,
      was administered in a blinded fashion during renal IRI. RESULTS: PVP was
      significantly (P < 0.05) increased at 24 hours and peaked at 48 hours after IRI
      compared with shams as well as baseline levels. PVP after IRI became similar to
      shams after 96 hours. This correlated with increases in blood urea nitrogen and
      creatinine at similar time points. At 48 hours, CNI-1493 significantly abrogated
      the increase in PVP compared with IRI alone. However, CNI-1493 did not alter the
      course of the acute renal failure. Pulmonary histology demonstrated interstitial
      edema, alveolar hemorrhage, and red blood cell sludging after renal IRI, which
      was partially attenuated by CNI-1493. CONCLUSIONS: Increased PVP develops after
      isolated renal IRI, and macrophage-derived products are mediators in this
      response. These findings have implications for understanding the mechanisms
      underlying respiratory dysfunction associated with acute renal failure.

PMID- 10354284
TI  - Oxygen-dependent inhibition of respiration in isolated renal tubules by nitric
      oxide.
AB  - BACKGROUND: The partial pressure (tension) of oxygen (PO2) in the kidney medulla
      has been established to be lower than that of the cortex. The kidney medulla has
      been shown to be particularly sensitive to hypoxia. However, the measured PO2 in
      the kidney medulla is sufficient to support maximal respiration. It has been
      recently shown that endogenously produced nitric oxide (NO) may inhibit oxygen
      consumption in the kidney. We studied whether NO plays a role in hypersensitivity
      of the kidney medulla to hypoxia. METHODS: We studied the effect of added NO on
      isolated cortical and outer medullary renal tubules in simultaneous oxygen
      consumption and NO measurements at different oxygen concentrations. RESULTS: We
      found that NO could potently and reversibly inhibit respiration at nanomolar
      concentrations. The inhibitory effect of NO was markedly increased at low
      physiological oxygen concentrations. The effect of NO was cGMP independent
      because the selective guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3
      a]quinoxalin-1-one (ODQ) at a 10 microM concentration had no effect on basal or
      NO-inhibited respiration. The value for half-maximal NO-mediated inhibition of
      respiration was virtually identical to that found in isolated mitochondria, and
      therefore, NO was most likely directly acting on mitochondria. Interestingly, we
      found no differences in sensitivity to NO-mediated inhibition between outer
      medullary and cortical tubules. CONCLUSIONS: We suggest that because of its low
      PO2, the renal outer medulla is more sensitive to hypoxia, not because of the low
      PO2 as such, but probably because of the competition between NO and oxygen to
      control respiration.

PMID- 10354285
TI  - Peptides derived from the human transferrin receptor stimulate endosomal
      acidification via a Gi-type protein.
AB  - Peptides derived from the human transferrin receptor stimulate endosomal
      acidification via a Gi-type protein. BACKGROUND: Acidification of the endosomal
      compartment is a prerequisite for intracellular processing of endocytosed
      complexes. Endosomal acidification is accomplished by an H+-ATPase, in parallel
      with a Cl- conductance. Previous studies from our laboratory have demonstrated
      that endosomal acidification is modulated by a pertussis toxin-sensitive
      mechanism, suggesting that endosomal acidification could be regulated through a
      self-contained signal transduction pathway. This study was designed to test this
      hypothesis using the transferrin receptor as a model. METHODS: Synthetic peptides
      corresponding to a region of the cytosolic domain of the transferrin receptor and
      containing a KPKR sequence were used to stimulate endosomal acidification in a G
      protein-dependent manner. RESULTS: Peptides activated the Gi, as evidenced by
      stimulation of the rate of GTPgammaS binding. A transferrin receptor peptide that
      lacked the KPKR sequence did not stimulate endosomal acidification and failed to
      promote GTPgammaS binding to Gi proteins. CONCLUSIONS: These results demonstrate
      that regulation of endosomal acidification can be achieved, in part, through a Gi
      mediated signal transduction pathway. These findings suggest that regulation of
      endosomal acidification through such a pathway may facilitate intracellular
      processing of the transferrin receptor.

PMID- 10354286
TI  - Insulin-dependent diabetic sibling pairs are concordant for sodium-hydrogen
      antiport activity.
AB  - Insulin-dependent diabetic sibling pairs are concordant for sodium-hydrogen
      antiport activity. BACKGROUND: Recent findings of enhanced Na+/H+ antiport
      activity in cultured fibroblasts and immortalized lymphoblasts from type 1
      diabetic patients with nephropathy support the view that a phenotypic or
      genotypic factor(s) underlies nephropathy risk. This study evaluated the kinetic
      properties of Na+/H+ antiporter in cultured fibroblasts from families with two
      siblings affected by type 1 (insulin-dependent) diabetes. METHODS: Seventeen
      diabetic sibling pairs were studied. The age was 38 +/- 10 years (mean +/- SD) in
      probands, the first to develop diabetes, and 39 +/- 7 in siblings; the duration
      of diabetes was, by definition, longer in probands (24 +/- 12 vs. 17 +/- 8 years
      in siblings). Na+/H+ antiport activity was determined using a microfluorometric
      technique with the pH sensitive dye 2', 7'-bis(2-carboxyethyl)-5(6)
      carboxyfluorescein in skin fibroblasts cultured for at least six passages.
      RESULTS: There were no significant differences between probands and siblings for
      the following parameters: glycated hemoglobin, 8.3 +/- 0.8% in probands and 8.6
      +/- 1.4% in siblings; creatinine clearance, 103 +/- 24 ml/min/1.73 m2 in probands
      and 103 +/- 25 in siblings; albumin excretion rate, 6.8 (1 to 860) microgram/min
      (median and range) in probands and 4.9 (2 to 1334) in siblings. Intracellular pH
      and buffering capacity were superimposable in the sibling pairs. The Vmax for the
      antiport was 39.2 +/- 14.7 mmol/liter cell/min in probands and 40.3 +/- 17.6 in
      siblings. The internal pH for half-maximal activation (Km) and Hill coefficient
      was also similar in probands and siblings. There were correlations between
      probands and siblings in values for intracellular pH (r = 0.51, P < 0.04), Vmax
      (r = 0.84, P < 0.0001), and buffering capacity (r = 0.53, P < 0. 03). Glycated
      hemoglobin values over five years were not significantly correlated in the
      sibling pairs (r = 0.3, P > 0.1). Vmax was related with the albumin excretion
      rate (r = +0.49, P = 0. 005) and glycated hemoglobin (r = +0.41, P = 0.017) in
      the total cohort of sibling pairs. However, multiple regression analysis, using
      Vmax as the dependent variable, found no correlations between any of the
      subjects' clinical and demographic variables. CONCLUSIONS: Familial concordance
      for Na+/H+ antiport activity in long-term cultured skin fibroblasts from type 1
      diabetic siblings suggests that at least some of the in vitro phenotypical
      characteristics of these cells are likely to be genetically determined and to be,
      at least in part, independent of in vivo metabolic control.

PMID- 10354287
TI  - Endothelin and angiotensin mediate most glomerular responses to nitric oxide
      inhibition.
AB  - BACKGROUND: Endothelin (ET) and angiotensin mediate glomerular responses to
      systemic nitric oxide (NO) inhibition. Acute systemic NO synthase (NOS)
      inhibition in the rat causes marked increases in both preglomerular (RA) and
      efferent arteriolar (RE) resistances and a fall in the glomerular capillary
      ultrafiltration coefficient (Kf). In contrast, local intrarenal NOS inhibition
      increases RA, but has no effect on RE while producing a similar Kf lowering
      effect as seen with systemic NOS inhibition. These studies were designed to
      assess whether the increase in RE during systemic NOS inhibition is mediated by
      endogenous ET and whether angiotensin II (Ang II) also contributes. METHODS:
      Micropuncture measurements were made before and during acute systemic NOS
      inhibition with N-monomethyl L-arginine (NMA) alone, NMA + the nonpeptide ETA and
      ETB receptor antagonist, bosentan, NMA + the Ang II type 1 receptor blocker,
      losartan, and NMA during combined bosentan and losartan. RESULTS: The falls in
      single nephron glomerular filtration rate (SNGFR) and glomerular plasma flow seen
      with systemic NOS inhibition were prevented by concomitant administration of
      bosentan and losartan alone and in combination. The increases in systemic blood
      pressure (BP), glomerular BP (PGC), RA, and RE and the reduction in Kf seen with
      systemic NOS inhibition were attenuated by either bosentan or losartan. An
      attenuation in the elevation in total renal vascular resistance seen with
      systemic NOS inhibition was also observed with bosentan. Combined ET and Ang II
      type 1 blockade completely prevented the increase in systemic BP, PGC, and RE and
      the fall in Kf with systemic NOS inhibition, leaving only a very attenuated rise
      in RA. CONCLUSIONS: These findings suggest that endogenous ET and Ang II
      partially mediate the glomerular hemodynamic responses (including the increased
      RE) to acute systemic NOS inhibition. The actions of ET and Ang II are mainly
      additive, and almost all of the vasoconstrictor responses to acute NOS inhibition
      are prevented when both vasoconstrictor systems are blocked.

PMID- 10354288
TI  - Essential arterial hypertension and stone disease.
AB  - BACKGROUND: Cross-sectional studies have shown that nephrolithiasis is more
      frequently found in hypertensive patients than in normotensive subjects, but the
      pathogenic link between hypertension and stone disease is still not clear.
      METHODS: Between 1984 and 1991, we studied the baseline stone risk profile,
      including supersaturation of lithogenic salts, in 132 patients with stable
      essential hypertension (diastolic blood pressure of more than 95 mm Hg) without
      stone disease and 135 normotensive subjects (diastolic blood pressure less than
      85 mm Hg) without stone disease who were matched for age and sex (controls).
      Subsequently, both controls and hypertensives were followed up for at least five
      years to check on the eventual formation of kidney stones. RESULTS: Baseline
      urine levels in hypertensive males were different from that of normotensive males
      with regards to calcium (263 vs. 199 mg/day), magnesium (100 vs. 85 mg/day), uric
      acid (707 vs. 586 mg/day), and oxalate (34.8 vs. 26.5 mg/day). Moreover, the
      urine of hypertensive males was more supersaturated for calcium oxalate (8.9 vs.
      6.1) and calcium phosphate (1.39 vs. 0.74). Baseline urine levels in hypertensive
      females were different from that of normotensive females with regards to calcium
      (212 vs. 154 mg/day), phosphorus (696 vs. 614 mg/day), and oxalate (26.2 vs. 21.7
      mg/day), and the urine of hypertensive females was more supersaturated for
      calcium oxalate (7.1 vs. 4.8). These urinary alterations were only partially
      dependent on the greater body mass index in hypertensive patients. During the
      follow-up, 19 out of 132 hypertensive patients and 4 out of 135 normotensive
      patients had stone episodes (14.3 vs. 2.9%, chi-square 11.07, P = 0.001; odds
      ratio 5.5, 95% CI, 1.82 to 16.66). Of the 19 stone-former hypertensive patients,
      12 formed calcium calculi, 5 formed uric acid calculi, and 2 formed nondetermined
      calculi. Of the urinary factors for lithogenous risk, those with the greatest
      predictive value were supersaturation of calcium oxalate for calcium calculi and
      uric acid supersaturation for uric acid calculi. CONCLUSIONS: A significant
      percentage of hypertensive subjects has a greater risk of renal stone formation,
      especially when hypertension is associated with excessive body weight. Higher
      oxaluria and calciuria as well as supersaturation of calcium oxalate and uric
      acid appear to be the most important factors. Excessive weight and consumption of
      salt and animal proteins may also play an important role.

PMID- 10354289
TI  - Cyclosporine A up-regulates angiotensin II receptors and calcium responses in
      human vascular smooth muscle cells.
AB  - BACKGROUND: The most widely used immunosuppressive drug for preventing graft
      rejection and treating autoimmune diseases is currently cyclosporine A (CsA).
      However, CsA also causes vasoconstriction, which is considered to be at the
      origin of CsA-induced nephrotoxicity and hypertension. To evaluate the cellular
      basis for these side effects, we studied the influence of CsA on the regulation
      of the free cytosolic Ca2+ concentration ([Ca2+]c) in cultured human vascular
      smooth muscle cells (SMCs). METHODS: SMCs were isolated from the medial layer of
      human aorta. [Ca2+]c regulation was studied by fluorimetry with fura 2 and by
      measuring 45Ca2+ effluxes. Angiotensin II (Ang II) receptors were detected by
      [125I]Ang II binding. RESULTS: Pretreatment of human SMCs for 24 hours with CsA
      in its therapeutic concentration range (0. 1 to 10.0 microM) had no effect on
      basal [Ca2+]c, but increased the [Ca2+]c elevation and 45Ca2+ efflux when cells
      were stimulated with Ang II. Half-maximal effects occurred at approximately 1
      microM CsA. The CsA effects on [Ca2+]c were accompanied by a nearly twofold
      increase in Ang II receptor number, whereas no change in affinity to Ang II was
      observed. CsA did not alter endothelin-1- or thapsigargin-induced 45Ca2+ efflux.
      Increases in both Ca2+ responses and [125I]Ang II binding were attenuated by the
      transcriptional inhibitor actinomycin D. The effects of CsA did not appear to be
      mediated by calcineurin inhibition because cyclosporine H, which is not
      immunosuppressive, also increased the Ang II-induced 45Ca2+ efflux. CONCLUSION:
      These data suggest that CsA preferentially up-regulates the transcription of Ang
      II receptors, which very likely leads to vasoconstriction in vivo and could be at
      the origin of CsA-induced hypertension and nephrotoxicity in humans.

PMID- 10354290
TI  - Correlation of histology to clinical rejection reversal: a thymoglobulin
      multicenter trial report.
AB  - Correlation of histology to rejection reversal: A Thymoglobulin Multicenter Trial
      report BACKGROUND: Histology may provide a link between clinical response to
      antirejection therapy and graft function. In a subset of centers, renal biopsy
      was a secondary end point for the Thymoglobulin Multicenter Trial. METHODS:
      Thirty-eight patients had a protocol biopsy one to two weeks following the end of
      therapy. Inclusion and post-treatment biopsies were graded and scored according
      to Banff criteria by a central pathologist who was blinded to the type and
      outcome of therapy and the timing of the biopsy. RESULTS: The majority of
      patients (31 of 38) had moderate rejection on their inclusion biopsy. An
      improvement of at least one Banff grade occurred in 58% of the patients. The
      treatment was clinically successful in 33 patients, but two thirds of the
      patients (25 out of 38) demonstrated residual inflammation in the graft. The
      degree of improvement of inflammation was proportionate to rejection severity (P
      = 0.006). Banff scoring indicated that residual inflammation was less in
      Thymoglobulin-treated patients than in those receiving Atgam (P < 0.05) and
      correlated with the incidence of recurrent rejection (P = 0.015). CONCLUSIONS:
      These data demonstrate a discrepancy between clinical and histological resolution
      of acute renal allograft rejection. Residual infiltrates in the graft following
      rejection therapy are common and, despite clinical improvement, may indicate an
      increased risk for recurrent rejection.

PMID- 10354292
TI  - Lipoprotein(a) levels in relation to albumin concentration in childhood nephrotic
      syndrome.
AB  - BACKGROUND: Lipoprotein(a) [Lp(a)] is a lipoprotein consisting of a low-density
      lipoprotein (LDL) particle linked to a polymorphic glycoprotein, apoprotein(a)
      [apo(a)]. Prior studies have reported high Lp(a) levels in the nephrotic
      syndrome, but it is still controversial whether this is due to the degree of
      hypoalbuminemia or proteinuria. METHODS: To investigate a model of nephrotic
      syndrome in the absence of renal failure, we studied a group of 84 children in
      different clinical stages of the disease for a period of five years. We evaluated
      the direct relationships between lipoproteins, including Lp(a), and/or plasma
      albumin and proteinuria. RESULTS: Lp(a) levels were significantly higher in the
      subjects with the active disease compared with patients in remission, and were
      also significantly different when subjects were ranked by albumin quartiles.
      Multiple regression analysis revealed that Lp(a) levels were inversely correlated
      with apo(a) isoform size and plasma albumin levels but not with the
      proteinuria/creatinine clearance ratio. Among subjects in complete remission,
      Lp(a) levels were different in patients with albumin levels below or above the
      fifth percentile. After the improvement of the clinical stage of the disease, the
      Delta% variation of albumin levels was related to the Delta% of apoB and LDL
      cholesterol (LDL-C), but not with the Delta% variation of Lp(a), whereas the
      Delta% variation of LDL-C was, in turn, related to the Delta% of Lp(a) levels.
      CONCLUSIONS: These results suggest that in the childhood nephrotic syndrome, the
      increased Lp(a) levels are mainly related to hypoalbuminemia, probably through a
      mechanism involving apoB overproduction, which leads to an increased number of
      LDL particles to be converted into Lp(a).

PMID- 10354291
TI  - Multicenter clinical trial of recombinant human insulin-like growth factor I in
      patients with acute renal failure.
AB  - BACKGROUND: Patients with acute renal failure (ARF) have high morbidity and
      mortality rates, particularly if they have serious comorbid conditions. Several
      studies indicate that in rats with ARF caused by ischemia or certain
      nephrotoxins, insulin-like growth factor-I (IGF-I) enhances the recovery of renal
      function and suppresses protein catabolism. METHODS: Our objective was to
      determine whether injections of recombinant human IGF-I (rhIGF-I) would enhance
      the recovery of renal function and is safe in patients with ARF. The study was
      designed as a randomized, double-blind, placebo-controlled trial in intensive
      care units in 20 teaching hospitals. Seventy-two patients with ARF were
      randomized to receive rhIGF-I (35 patients) or placebo (37 patients). The most
      common causes of ARF in the rhIGF-I and placebo groups were, respectively, sepsis
      (37 and 35% of patients) and hypotension or hemodynamic shock (42 and 27% of
      patients). At baseline, the mean (+/- SD) APACHE II scores in the rhIGF-I and
      placebo-treated groups were 24 +/- 5 and 25 +/- 8, respectively. In the rhIGF-I
      and placebo groups, the mean (median) urine volume and urinary iothalamate
      clearances (glomerular filtration rate) were 1116 +/- 1037 (887) and 1402 +/-
      1183 (1430) ml/24 hr and 6.4 +/- 5.9 (4.3) and 8.7 +/- 7.2 (4.4) ml/min and did
      not differ between the two groups. Patients were injected subcutaneously every 12
      hours with rhIGF-I, 100 microgram/kg desirable body weight, or placebo for up to
      14 days. Injections were started within six days of the onset of ARF. The primary
      end-point was a change in glomerular filtration rate from baseline. Other end
      points included changes from baseline in urine volume, creatinine clearance and
      serum urea, creatinine, albumin and transferrin, frequency of hemodialysis or
      ultrafiltration, and mortality rate. RESULTS: During the treatment period, which
      averaged 10.7 +/- 4.1 and 10.6 +/- 4.5 days in the rhIGF-I and placebo groups,
      there were no differences in the changes from baseline values of the glomerular
      filtration rate, creatinine clearance, daily urine volume, or serum urea
      nitrogen, creatinine, albumin or transferrin. In patients who did not receive
      renal replacement therapy, there was also no significant difference in serum
      creatinine and urea between the two groups. Twenty patients in the rhIGF-I group
      and 17 placebo-treated patients underwent dialysis or ultrafiltration. Twelve
      rhIGF-I-treated patients and 12 placebo-treated patients died during the 28 days
      after the onset of treatment. CONCLUSIONS: rhIGF-I does not accelerate the
      recovery of renal function in ARF patients with substantial comorbidity.

PMID- 10354293
TI  - HBV and proteinuria in relatives and contacts of children with hepatitis B virus
      associated membranous nephropathy.
AB  - BACKGROUND: Hepatitis B virus (HBV)-associated membranous nephropathy (HBVMN) is
      an important cause of childhood nephrotic syndrome in regions endemic for the
      virus, but little is understood of the biosocial context in which the disease
      develops. We evaluated HBV status and proteinuria in family members and household
      contacts of index children with HBVMN to test the hypothesis that HBV carriage
      and asymptomatic proteinuria are closely linked and may be causally associated.
      METHODS: Thirty-one black children with biopsy-proven HBVMN were the index cases.
      One hundred and fifty-two family members and 43 black household contacts were the
      subjects of the study. We assessed HBV carrier status by testing for HBV antigens
      and antibodies using enzyme-linked immunosorbent assays (ELISA) and for HBV DNA
      by using slot-blot hybridization and the polymerase chain reaction. Sequencing of
      the precore region of HBV was done in a subset of both index cases and subjects.
      Proteinuria was assessed by measuring the urinary protein/creatinine ratio.
      RESULTS: Seventy-two (37%) of the 195 family members and household contacts were
      HBV carriers, and 53 (27%) had a protein/creatinine ratio greater than the
      physiological limit. The frequency of abnormal proteinuria was not significantly
      different in those with [22 out of 72 (30.5%)] or without [33 out of 104 (32%)]
      HBV carriage. This lack of association remained when carriers were classified
      into those who were HBsAg positive only and those with active viral replication
      (HBsAg and/or HBeAg and/or HBV DNA; P = 0.01). Family members were more
      predisposed to HBV carriage than household contacts, but abnormal proteinuria was
      present with equal frequency (P = 0.48). Age had a significant impact on
      proteinuria, with children less than five years being more likely to have
      abnormal proteinuria (P = 0.008). The prevalence of abnormal proteinuria in
      family members and household contacts of the index cases was more than that in
      community-based controls. The 10 index HBVMN cases and the 14 family members and
      household contacts who were tested all had HBV of genotype A. CONCLUSION: These
      results suggest that the family members and household contacts of children with
      HBVMN are at very high risk of HBV carriage; they also have asymptomatic
      proteinuria at a significantly higher rate than community-based controls. The HBV
      carrier status was not associated with proteinuria, a finding supported by peak
      prevalences of proteinuria in those under five years but no corresponding peak
      for HBV carriage. Proteinuria may indicate glomerular basement membrane
      dysfunction. Environmental and social factors may underpin development of these
      two covert disorders, but are insufficient to account for the index cases of
      HBVMN. The emergence of children with HBVMN from such households additionally
      depends on unidentified and possibly genetic factors.

PMID- 10354294
TI  - Effect of hyperinsulinemia on renal function in a general Japanese population:
      the Hisayama study.
AB  - BACKGROUND: Insulin resistance and hyperinsulinemia induce glomerular
      hypertension and hyperfiltration, which may result in glomerulosclerosis.
      However, the relationship between hyperinsulinemia and renal function is
      uncertain. METHODS: To elucidate whether hyperinsulinemia plays a significant
      part in the initiation and development of renal dysfunction, we examined in 1988
      the relationship between serum insulin and renal function on data from a cross
      sectional community survey conducted among residents from Hisayama Town, Japan,
      who were aged 40 to 79 years old. A total of 1065 men (72.0% of the total
      population in the same age range) and 1381 women (79.0%) without renal failure
      (creatinine clearance of more than 30 ml/min) underwent a comprehensive
      examination, including a 75 g oral glucose tolerance test. RESULTS: The
      correlation analysis showed that serum insulin, blood pressure, total
      cholesterol, low-density lipoprotein cholesterol, triglycerides, and body mass
      index were all negatively correlated with the reciprocal of serum creatinine
      level (P < 0.01), and alcohol intake was positively correlated (P < 0.05) in both
      sexes. High-density lipoprotein cholesterol and smoking habits were positively
      correlated (P < 0.05) in men. When the subjects were divided into quartiles based
      on the sum of fasting and two-hour postloading insulin levels, the averages of
      the reciprocal of serum creatinine were significantly lower in the fourth
      quartile (0.90 +/- 0.10 for men and 1.10 +/- 0.14 for women) compared with the
      lowest quartile (0.95 +/- 0.12 and 1.13 +/- 0.13, respectively) in both sexes (P
      < 0.05). In multiple regression analysis, the correlation between the sum of
      insulin levels and the reciprocal of serum creatinine remained significant even
      after controlling for age, sex, body mass index, blood pressure, total
      cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein
      cholesterol, triglycerides, alcohol intake, and smoking habits. We could not find
      appropriate correlations of creatinine clearance calculated by the Cockcroft
      Gault formula with the covariates including serum insulin. CONCLUSIONS: The
      findings of this study suggest that hyperinsulinemia is a significant relevant
      factor of renal function in the general population.

PMID- 10354295
TI  - Cyclosporine-associated thrombotic microangiopathy in renal allografts.
AB  - BACKGROUND: The association between cyclosporine (CsA) and thrombotic
      microangiopathy (TMA) in renal allografts is well documented. However,
      predisposing factors and therapy guidelines are not adequately characterized.
      METHODS: We reviewed 188 patients with kidney or kidney-pancreas transplants who
      were treated between January 1994 and December 1996 with prednisone, CsA, or
      tacrolimus, and azathioprine or mycophenolate. We analyzed 50 patients who had
      graft biopsies: 26 with TMA and 24 with no TMA, as well as 19 patients with well
      functioning grafts who never required biopsy. RESULTS: TMA was observed in 26 of
      188 renal graft recipients (14%). TMA was confined to the allograft kidney
      without any systemic evidence in 24 of the 26 patients. At the time of the
      diagnosis of TMA, 24 of the patients were on CsA, with 19 on the microemulsion
      form. Conversely, 5 of 18 control patients with no graft dysfunction were on the
      microemulsion form of CsA (P = 0.0026). Graft loss was seen in 8 of 26 patients
      with TMA. Conversion from CsA to tacrolimus resulted in a one-year salvage of
      graft function in 13 of 16 (81%) patients. CONCLUSIONS: TMA was the cause of
      renal graft dysfunction in 14% of renal graft recipients and was associated with
      the use of the microemulsion form of CsA. Systemic signs of TMA were rare,
      underscoring the importance of the graft biopsy in making the diagnosis. The most
      successful strategy was switching from CsA to tacrolimus, with good graft
      function in 81% of the recipients one year after the TMA episode.

PMID- 10354296
TI  - Clinical and biochemical correlates of starting "daily" hemodialysis.
AB  - BACKGROUND: Daily hemodialysis has been proposed to improve outcomes for patients
      with end-stage renal disease. There has been increasing evidence that daily
      hemodialysis might have potential advantages over intermittent dialysis. However,
      despite these potential advantages, daily hemodialysis is infrequently used in
      the United States, and published accounts on the technique are few. METHODS: We
      describe patient outcomes after increasing their hemodialysis frequency from
      three to six times per week in a cohort of 72 patients treated at nine centers
      during 1972 to 1996. Analyses of predialysis blood pressure and laboratory
      parameters from 6 months before until 12 months after starting frequent
      hemodialysis used a repeated-measures statistical technique. RESULTS: Predialysis
      systolic and diastolic blood pressures fell by 7 and 4 mm Hg, respectively, after
      starting frequent hemodialysis (P = 0.02). Reductions were greatest among
      patients being treated with antihypertensive medications, despite a reduction in
      their dosage of medications. Postdialysis weight fell by 1.0% within one month of
      starting frequent hemodialysis and improved control of hypertension. After the
      initial drop, postdialysis weight increased at a rate of 0.85 kg per six months.
      Serum albumin rose by 0.29 g/dl (P < 0.001) between months 1 to 12 of treatment
      with daily hemodialysis. Hematocrit rose by 3.0 percentage points (P = 0.02)
      among patients (N = 56) not treated with erythropoietin during this period. Two
      years after the start of daily hemodialysis, Kaplan-Meier analyses showed a
      patient survival of 93%, a technique survival of 77%, and an arteriovenous
      fistula patency of 92%. Vascular access patency was excellent despite more
      frequent use of the access. CONCLUSIONS: These results suggest that in certain
      patients, daily hemodialysis might have advantages over three times per week
      hemodialysis.

PMID- 10354297
TI  - Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin
      in hemodialysis patients with hyperferritinemia.
AB  - BACKGROUND: Inadequate iron mobilization and defective iron utilization may cause
      recombinant erythropoietin (rEPO) hyporesponsiveness in hemodialysis (HD)
      patients with iron overload. We have demonstrated that intravenous ascorbic acid
      (IVAA), but not intravenous iron medication, can effectively circumvent the
      functional iron-deficient erythropoiesis associated with iron overload in HD
      patients. However, it is uncertain whether all HD patients with hyperferritinemia
      will consistently respond to IVAA and which index may indicate functional iron
      deficiency in the special entity. Therefore, a prospective study was conducted to
      establish the guidelines for IVAA adjuvant therapy. METHODS: Sixty-five HD
      patients with serum ferritin levels of more than 500 microgram/liter were
      recruited and divided into the control (N = 19) and IVAA (N = 46) groups. IVAA
      patients with a hematocrit (Hct) of less than 30% received 300 mg of ascorbic
      acid three times per week for eight weeks. Controls had a Hct of more than 30%
      and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts,
      iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the
      concentrations of plasma ascorbate and oxalate were examined before and following
      the therapy. RESULTS: Thirteen patients (four controls and nine IVAA patients)
      withdrew by the end of the study. Eighteen patients had a dramatic response to
      IVAA with a significant increase in their hemoglobin and reticulocyte index and a
      concomitant 24% reduction in rEPO dose after eight weeks. This paralleled a
      significant rise in serum iron and transferrin saturation (TS) and a fall in E
      ZPP and serum ferritin (baselines vs. 8 weeks, serum iron 68 +/- 37 vs. 124 +/-
      64 microgram/dl, TS 27 +/- 10 vs. 48 +/- 19%, E-ZPP 123 +/- 44 vs. 70 +/- 13
      micromol/mol heme, and serum ferritin 816 +/- 435 vs. 587 +/- 323
      microgram/liter, P < 0. 05). Compared with responders, mean values of hemoglobin,
      rEPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in
      controls (N = 15) and in non-responders (N = 19). Thirty-seven patients (18
      responders and 19 non-responders) were further analyzed by receiver operating
      characteristic curves to seek the criteria for prediction of a response to IVAA
      treatment. The results showed that E-ZPP at a cut-off level of more than 105
      micromol/mol heme and TS at a level of less than 25% were more specific to
      confirm the status of functional iron deficiency in iron-overloaded patients. The
      two criterion values had the highest accuracy to predict a response to treatment.
      CONCLUSIONS: Functional iron-deficient erythropoiesis plays a role in rEPO
      hyporesponsive anemia in HD patients with hyperferritinemia. IVAA may be an
      adjuvant therapy for rEPO in these patients, and E-ZPP of more than 105
      micromol/mol heme and TS of less than 25% should be used to guide the IVAA
      treatment.

PMID- 10354298
TI  - Influence of hemodialysis membrane type on pentosidine plasma level, a marker of
      "carbonyl stress".
AB  - Influence of hemodialysis membrane type on pentosidine plasma level, a marker of
      "carbonyl stress." BACKGROUND: The accumulation of advanced glycation end
      products (AGEs) in uremia has been ascribed to the retention of carbonyl
      precursors of AGEs. Pentosidine plasma level has been identified as a surrogate
      marker of carbonyl precursors ("carbonyl stress"). The influence of hemodialysis
      (HD) membrane type and residual diuresis on carbonyl stress has not been studied.
      METHODS: We measured protein-linked and free plasma pentosidine (a surrogate
      marker of carbonyl stress) by high-performance liquid chromatography in patients
      on HD with low-flux cellulose (N = 29), high-flux polysulfone (PS; N = 57),
      polymethylmethacrylate (PMMA) (N = 25), and AN69 (N = 15). RESULTS: Both protein
      linked and free pentosidine were similar on low-flux cellulose, high-flux PMMA,
      and AN69, but were lower (P < 0.01) on high-flux PS. Pentosidine levels were
      virtually identical on Fresenius and Asahi PS in Japanese and Belgian patients.
      By multivariate analysis, only the type of HD membrane and residual diuresis
      proved to be independent determinants (P < 0.001) of pentosidine levels. During a
      single HD session, the clearance of free pentosidine was similar with all
      membranes. In three patients who were switched from AN69 to PS, the protein
      linked pentosidine level dropped to the control level after resumption of the
      AN69 membrane. CONCLUSIONS: Both HD membrane type and residual diuresis are
      independent determinants of pentosidine plasma level, which is a marker of
      carbonyl stress.

PMID- 10354299
TI  - Peritoneal dialysis adequacy: a model to assess feasibility with various
      modalities.
AB  - BACKGROUND: The current standard of adequacy for peritoneal dialysis (PD) is to
      provide a weekly normalized urea clearance (Kt/V) of 2.0 or more and a creatinine
      clearance (CCr) of 60 liter/1.73 m2 or more. As native renal function is lost, it
      is important to determine the effectiveness of the available therapeutic
      modalities in achieving these goals. METHODS: A model to assess our ability to
      provide a weekly Kt/Vurea of 2.0 or more and a CCr of 60 liter/1.73 m2 or more to
      anuric patients undergoing continuous ambulatory PD (CAPD) and automated PD (PD
      Plus) was developed. The body surface area (BSA) distribution was obtained from
      38,768 patients undergoing dialysis during January 1997. The distribution of
      peritoneal transport rates (PTRs) was obtained from 2531 peritoneal equilibration
      tests performed during 1996. The weekly Kpt/Vurea was calculated for the various
      PTR groups and the range of BSA with four PD prescriptions: CAPD 8 liters, CAPD
      10 liters, PD Plus 12 liters, and PD Plus 15 liters, using a previously validated
      kinetic program (PackPD). RESULTS: The predicted percentage of patients capable
      of achieving the adequacy goals for Kt/V and CCr, respectively, were 24.8 and 11.
      2 for CAPD 8 liters, 54.2 and 33.0 for CAPD 10 liters, 77.8 and 54.9 for PD Plus
      12 liters, and 93.2 and 72.9 for PD Plus 15 liters. CONCLUSIONS: Most patients
      can attain the current adequacy standards of therapy with automated PD, but few
      (less than 25%) can do so with standard CAPD in the absence of residual renal
      function.

PMID- 10354300
TI  - Tissue engineering of a bioartificial renal tubule assist device: in vitro
      transport and metabolic characteristics.
AB  - BACKGROUND: Current renal substitution therapy for acute or chronic renal failure
      with hemodialysis or hemofiltration is life sustaining, but continues to have
      unacceptably high morbidity and mortality rates. This therapy is not complete
      renal replacement therapy because it does not provide active transport nor
      metabolic and endocrinologic functions of the kidney, which are located
      predominantly in the tubular elements of the kidney. METHODS: To optimize renal
      substitution therapy, a bioartificial renal tubule assist device (RAD) was
      developed and tested in vitro for a variety of differentiated tubular functions.
      High-flux hollow-fiber hemofiltration cartridges with membrane surface areas of
      97 cm2 or 0. 4 m2 were used as tubular scaffolds. Porcine renal proximal tubule
      cells were seeded into the intraluminal spaces of the hollow fibers, which were
      pretreated with a synthetic extracellular matrix protein. Attached cells were
      expanded in the cartridge as a bioreactor system to produce confluent monolayers
      containing up to 1.5 x 109 cells (3. 5 x 105 cells/cm2). Near confluency was
      achieved along the entire membrane surface, with recovery rates for perfused
      inulin exceeding 97 and 95% in the smaller and larger units, respectively,
      compared with less than 60% recovery in noncell units. RESULTS: A single-pass
      perfusion system was used to assess transport characteristics of the RADs.
      Vectorial fluid transport from intraluminal space to antiluminal space was
      demonstrated and was significantly increased with the addition of albumin to the
      antiluminal side and inhibited by the addition of ouabain, a specific inhibitor
      of Na+,K+-ATPase. Other transport activities were also observed in these devices
      and included active bicarbonate transport, which was decreased with
      acetazolamide, a carbonic anhydrase inhibitor, active glucose transport, which
      was suppressed with phlorizin, a specific inhibitor of the sodium-dependent
      glucose transporters, and para-aminohippurate (PAH) secretion, which was
      diminished with the anion transport inhibitor probenecid. A variety of
      differentiated metabolic functions was also demonstrated in the RAD. Intraluminal
      glutathione breakdown and its constituent amino acid uptake were suppressed with
      the irreversible inhibitor of gamma-glutamyl transpeptidase acivicin; ammonia
      production was present and incremented with declines in perfusion pH. Finally,
      endocrinological activity with conversion of 25-hydroxy(OH)-vitamin D3 to 1,25
      (OH)2 vitD3 was demonstrated in the RAD. This conversion activity was up
      regulated with parathyroid hormone and down-regulated with increasing inorganic
      phosphate levels, which are well-defined physiological regulators of this process
      in vivo. CONCLUSIONS: These results clearly demonstrate the successful tissue
      engineering of a bioartificial RAD that possesses critical differentiated
      transport, and improves metabolic and endocrinological functions of the kidney.
      This device, when placed in series with conventional hemofiltration therapy, may
      provide incremental renal replacement support and potentially may decrease the
      high morbidity and mortality rates observed in patients with renal failure.

PMID- 10354301
TI  - Survival advantage in Asian American end-stage renal disease patients.
AB  - Survival advantage in Asian American end-stage renal disease patients.
      BACKGROUND: An earlier study documented a lower mortality risk for end-stage
      renal disease (ESRD) patients in Japan compared with the United States. We
      compared the mortality of Caucasian (white) and Asian American dialysis patients
      in the United States to evaluate whether Asian ancestry was associated with lower
      mortality in the United States. METHODS: The study sample from the U.S. Renal
      Data System census of ESRD patients treated in the United States included 84,192
      white or Asian patients starting dialysis during May 1995 to April 1997, of whom
      18,435 died by April 30, 1997. Patient characteristics were described by race.
      Relative mortality risks (RRs) for Asian Americans relative to whites were
      analyzed by Cox proportional hazards regression models adjusting for
      characteristics and comorbidities. Population death rates were derived from vital
      statistics for the United States and Japan by age and sex. RESULTS: Adjusting for
      demographics, diabetes, comorbidities, and nutritional factors, the RR for Asian
      Americans was 0.75 (P = 0.0001). Race-specific background population death rates
      accounted for over half of the race-related mortality difference. For whites,
      mortality decreased as the body mass index (BMI) increased. For Asians, the
      relationship between BMI and survival was u-shaped. The ratio of Asian
      American/white dialysis death rates and the ratio of Asian American/white general
      population death rates both varied by age in a similar pattern. The population
      death rates of Asian American and Japanese were also similar. CONCLUSION: Among
      dialysis patients, Asian Americans had a markedly lower adjusted RR than whites.
      The effect of BMI on survival differed by race. Compared with the respective
      general population, dialysis patients had the same relative increase in death
      rates for both races. The difference in death rates between the United States and
      Japan does not appear to be primarily treatment related, but rather is related to
      background death rates.

PMID- 10354302
TI  - Regulation of endosomal acidification via Gi-type protein.

PMID- 10354303
TI  - Why do we have to invoke genetic susceptibility for diabetic nephropathy?

PMID- 10354304
TI  - Risky business.

PMID- 10354305
TI  - Two novel mutations in the beta subunit of the human epithelial sodium channel.

PMID- 10354306
TI  - Primary hyperoxaluria type 1.

PMID- 10354307
TI  - Renal proximal tubular cell fibronectin accumulation in response to glucose is
      polyol pathway dependent 
AB  - Thickening and reduplication of the tubular basement membrane has been reported
      as an early event in diabetic nephropathy. In the current study we have examined
      the polar requirements of proximal tubular cells for the D-glucose stimulated
      accumulation of fibronectin. We also examined the mechanism by which glucose led
      to accumulation of fibronectin, with particular emphasis on the polyol pathway.
      Incubation of confluent monolayers of LLC-PK1 cells grown on tissue culture
      inserts with 25 mM D-glucose on either their apical or basolateral aspect, led to
      fibronectin accumulation in the basolateral compartment. This reached statistical
      significance 24 h following apical addition of glucose (2.7 fold increase
      compared to 5 mM D-glucose, p = 0.007, n = 6), and 12 h after the basolateral
      addition of glucose (2.54 fold increase compared to 5 mM D-glucose, p = 0.02, n =
      6). The increase in fibronectin concentration in response to glucose was
      inhibited by the aldose reductase inhibitor sorbinil. At a dose of 100&mgr;M
      sorbinil there was 59% inhibition of fibronectin accumulation in response to
      glucose, 48 h after the addition of the inhibitor (4.76 +/- 1.4 vs 11.53 +/-
      1.41, mean +/- SD, p = 0.01, n = 3). Exposure of cells to glucose at either their
      apical or basolateral aspect lead to accumulation of intracellular glucose and
      polyol pathway activation, as assessed by sorbitol accumulation. Accumulation of
      intracellular glucose and hence subsequent polyol pathway activation occurred
      independently of transport of glucose by either apical sodium linked glucose
      transporter (SLGT) or basolateral GLUT 1. The data demonstrate that fibronectin
      generation in response to glucose was non-polar in terms application of glucose,
      but polar in terms of fibronectin accumulation. Furthermore modulation of
      fibronectin was mediated by polyol pathway activation, and more specifically
      related to the metabolism of sorbitol to fructose.

PMID- 10354308
TI  - Inflammatory cytokines induce apoptotic and necrotic cell shedding from human
      proximal tubular epithelial cell monolayers 
AB  - Acute tubular injury in sepsis is associated with proximal tubular epithelial
      cell (PTEC) detachment into the lumen leading to back-leakage of glomerular
      ultrafiltrate and tubule obstruction. Inflammatory cytokines, such as IL-1alpha,
      IFNgamma and TNFalpha, are important mediators in sepsis-induced acute renal
      failure, although their precise role is unclear. We used primary cultures of
      human PTEC to investigate the hypothesis that inflammatory cytokines exert
      cytotoxic effects and cause detachment of cells from adherent monolayers,
      possibly through the intermediate nitric oxide (NO). At 5 days post-confluence,
      PTEC monolayers were stimulated for 24 hours with IL-1alpha (10 ng/ml), IFNgamma
      (200 u/ml) and TNFalpha (10 ng/ml). Monolayer viability was assessed by a
      live/dead dual fluorescence labeling technique. Apoptosis within monolayers was
      determined by morphological examination and terminal deoxynucleotidyl transferase
      mediated dUTP nick-end labeling (TUNEL). PTEC in supernatants were counted and
      then analyzed by flow cytometry, using propidium iodide to assess cell viability
      and annexin V labeling to determine apoptosis. Results (mean +/- SEM; monolayers,
      n = 4; cell counts, n = 3; flow cytometry, n = 2) are shown below (at test, p <
      0.05). Monolayers Supernatants Viable necrotic% of cells apoptotic countsx104/ml
      viable necrotic% of cells apoptotic Unstimulated 99.0+/-0.5 1.0+/-0.5 0 8.0+/
      0.6a 64.6+/-2.5a 26.7+/-1.9a 6.2+/-0.6a Stimulated 92.4+/-3.2 7.6+/-3.2 0 14.7+/
      0.6a 37.9+/-0.05a 48.0+/-0.3a 14.1+/-0.35a Following cytokine stimulation, there
      were significantly increased numbers of shed cells in supernatants. This cell
      population demonstrated significant loss of viability with increased numbers of
      both necrotic and apoptotic cells, as compared to unstimulated PTEC supernatants.
      Cytokine-stimulated monolayers maintained viability with no significant cell
      necrosis and no evidence of apoptosis. Preliminary experiments with the NO
      synthase inhibitor L-NMMA show that it reduces the number of cytokine-induced
      shed cells to the levels found in unstimulated cells (8.0 +/- 1.0 x 104/ml),
      although the percentages of necrotic and apoptotic cells are unchanged from
      cytokine-stimulated PTEC (44% and 15%, respectively). In conclusion, inflammatory
      cytokines induce necrotic and apoptotic cell shedding from PTEC monolayers with
      maintenance of monolayer viability. Preliminary data suggest that NO plays a
      cytotoxic role in this process.

PMID- 10354310
TI  - In this issue ellipsis

PMID- 10354309
TI  - The effect of dialysate temperature on energy transfer during hemodialysis (HD) 
AB  - It is well known that the use of low temperature (T) dialysate can have a
      positive impact on hemodynamic stability during HD. However, little is known on
      the energy transfer (ET) from the extracorporeal system to the patient in
      relation to variations in dialysate T (Tdial). In this study, we assessed ET,
      body T (Tbody), and blood pressure (BP) during dialysis with normal Tdial (37.5
      degrees C) and low Tdial (35.5 degrees C). Nine patients (4 males, 5 females;
      mean age 68 +/- 10 years) were studied with the patient as his/her own control.
      Bicarbonate was used as dialysate buffer. Hemophane membranes were used. Dialysis
      contained <100 CFU/mL. Ultrafiltration volume was comparable between the 2
      treatment sessions. ET was assessed by continuous measurement of T in the
      arterial (Tart) and venous side (Tven) of the extracorporeal system (Fresenius
      BTM(R)) according to the formula: ET = (Tven - Tart) * blood flow * treatment
      time * specific thermal capacity (3.64 kJ/kg* degrees C) * blood density (1052
      kg/m3). RESULTS: Results: mean+/-SD Tdial 37.5 Tdial 35.5 p Delta Syst BP mmHg 
      43 +/-21 -22 +/-26 <0.05 Delta Dias BP mmHg -15 +/-10 0 +/-19 0.07 Tbody before
      HD ( degrees C) 36.7 +/-0.3 36.4 +/-0.6 NS Tbody after HD ( degrees C) 37.2 +/
      0.2 36.4 +/-0.3 <0.001 Tven after HD ( degrees C) 36.7 +/-0.1 35.0 +/-0.2 <0. 001
      ET (kJ) -86 +/-43 -286 +/-74 <0.001 CONCLUSION: Tbody remained stable during
      Tdial = 35.5 degrees C despite significant energy loss and increased during Tdial
      = 37.5 degrees C despite netto ET from the patient to the extracorporeal system.
      The latter suggests that HD itself leads to intrinsic heat generation in the
      patient. The removal of this excess heat in combination with the cardiovascular
      response to maintain Tbody may be responsible for the beneficial hemodynamic
      effects of low Tdial.

PMID- 10354311
TI  - Persistent attenders and heartsink.

PMID- 10354313
TI  - Face to face

PMID- 10354312
TI  - Medical school selection--fair or unfair?

PMID- 10354314
TI  - Improving senior house officer experience.

PMID- 10354315
TI  - Teaching support in the behavioural sciences for non-english speaking background
      medical undergraduates.
AB  - INTRODUCTION: This paper reports on a teaching strategy designed to support first
      year undergraduate medical students from non-English speaking backgrounds in a
      behavioural science course taught at an Australian university. METHOD: The
      strategy is described, as is the language profile of students from two successive
      cohorts who participated in the teaching programme. The effectiveness of the
      intervention in improving students' academic performance is explored, as gauged
      by summative assessment and student perceptions. CONCLUSIONS: Findings suggest
      that students disadvantaged by difficulties with language and/or knowledge of
      Australian culture were able to perform at least as well as other students on a
      number of summative criteria. Non-English speaking background students perceived
      the behavioural science course to be difficult, and indicated that they found the
      teaching support offered to them to be useful. The methodological difficulties
      and limitations involved in the evaluation of a teaching programme such as this
      are discussed and the conclusions that can be validly drawn are considered.

PMID- 10354316
TI  - The effect of problem-based learning on the academic performance of students
      studying podiatric medicine in Ontario.
AB  - OBJECTIVES: To investigate the effect of problem-based learning (PBL) on student
      achievement. DESIGN: Two cohorts of students studying podiatric medicine in
      Ontario were compared - one having undertaken the traditional lecture-based
      curriculum, and the other the problem-based learning programme. SETTING: The
      Michener Institute for Applied Health Sciences and The Toronto Hospital.
      SUBJECTS: Chiropody students. RESULTS: The performance of the students on the
      written Provincial Registration Examinations of Ontario was analysed utilizing
      independent t-tests and demonstrated that the PBL cohort of students achieved
      significantly higher overall examination scores (P < 0.005) than the traditional
      cohort. Further analysis revealed that no significant difference existed between
      student cohorts with respect to factual biomedical knowledge (P > 0.5), but that
      the PBL students performed significantly better in tests of deeper understanding
      and the cognitive skills related to patient management (P < 0.0005).
      Additionally, intragroup analysis using Spearman's rank order correlation
      indicated that there was no rank ordered association between performance on the
      multiple-choice and essay sections of the examination. CONCLUSIONS: The above
      results suggest that the PBL cohort of students was more knowledgeable than, and
      possessed superior cognitively related patient management skills, to their
      traditional counterparts.

PMID- 10354317
TI  - Education and training in the senior house officer grade: results from a cohort
      study of United Kingdom medical graduates.
AB  - INTRODUCTION: This paper shows the findings from a survey of 439 senior house
      officers undertaken as part of the British Medical Association cohort study of
      1995 medical graduates. The aim of the study was to assess the quality of senior
      house officer training in the United Kingdom. METHOD: In July 1997 a postal
      questionnaire was sent to a sample of 545 doctors who graduated from medical
      school in 1995. Responses were received from 515 (95%). Only those doctors who
      had worked as a senior house officer in the previous 12 months were included in
      the analysis (n = 439). RESULTS: Encouraging results are that 69% of the senior
      house officers surveyed had discussed their progress directly with their
      consultant, and 24% rated their supervision by their consultant as 'excellent'.
      Of concern are the findings that 47% of respondents did not receive protected
      teaching time and 16% were unable to take study leave. DISCUSSION: The study
      revealed wide variability in the quality of training received by senior house
      officers in the United Kingdom. Whilst some respondents - notably those in
      general practice, accident and emergency, paediatrics and psychiatry - had
      enjoyed a high standard of education and training, it was clear that a minority
      of posts continue to offer little if any educational value to the post holder.
      The results point to a need for a more systematic approach to maintaining
      standards in senior house officer training with greater incentives for under
      performing trusts.

PMID- 10354318
TI  - Make induction day more effective - add a few problems.
AB  - INTRODUCTION: Induction courses are important to introduce Pre-Registration House
      Officers (PRHOs) to their new place of work. Traditionally, such programmes
      employ lectures, small group discussion and demonstrations. They let PRHOs meet
      members of various hospital disciplines and services. Since 1991, an interactive
      induction programme has been held each August for new PRHOs in the Eastern Region
      of Scotland taking up posts in Dundee Teaching Hospitals NHS Trust. DESIGN:
      Feedback from participants allows the course to be refined each year. In 1995,
      three paper-based patient management problems (PMPs) were included in the
      induction programme. Response was favourable. Most of the participants (82%)
      suggested the PMPs should be used again, but that more time should be allocated
      to enable them to tackle the problems. By August 1996, we aimed to provide a
      relevant and interactive programme that encouraged PRHOs to make immediate use of
      hospital resources. Two PMPs, in print format described likely case histories,
      with tasks that mirrored the junior doctors' forthcoming responsibilities.
      Healthcare team members and laboratory staff provided support as did study boards
      displaying written sheets of relevant clinical information. RESULTS: In the
      subsequent evaluation, the PMP component was rated highly by participants. They
      effectively triggered PRHOs to interact with hospital staff. CONCLUSIONS: We
      conclude that PMPs provide a valuable learning experience for junior doctors and
      are a useful addition to an induction day programme. We plan to refine and
      increase the use of PMPs in undergraduate and postgraduate settings.

PMID- 10354319
TI  - Clinical experience of medical students in primary care: use of an electronic log
      in monitoring experience and in guiding education in the Cambridge Community
      Based Clinical Course.
AB  - OBJECTIVES: The amount of medical student teaching in the community has increased
      markedly recently, but uncertainties remain about whether there is sufficient
      clinical material to meet students' learning needs and, if so, how best to
      monitor the experience and ensure that students are benefiting from it. DESIGN:
      On the Cambridge Community Based Clinical Course, a 15-month attachment in
      primary care, the students used hand-held computers to monitor their clinical
      experience as it developed. SETTING: The General Practice and Primary Care
      Research Unit, Cambridge, UK. SUBJECTS: Medical students. RESULTS: Thirteen
      students recorded 8140 contacts over 4 years. Contacts recorded by students over
      15 months varied between 256 and 1153. Eight specialities each contributed more
      than 5% of total experience. These were general medicine, 26.9% (range 23.8%-36.
      6%), obstetrics and gynaecology, 11.3% (range 7.2%-17.1%), orthopaedics and
      rheumatology, 11.3% (range 3.7%-15.2%), paediatrics, 10.7% (range 4.1%-19.8%),
      ENT, 7.4% (range 3.3%-10.2%), dermatology, 7.1% (range 4%-10.1%), psychiatry,
      6.4% (range 5%-9.7%) and general surgery, 6.4% (range 1.1%-9.9%). CONCLUSIONS:
      The results show that it is possible to get a broad and varied exposure to
      clinical problems on a long-term community-based course. However, as a
      consequence of the opportunistic way in which clinical experience is obtained on
      a community attachment, individual students often had gaps in their experience.
      The logs provided a means for identifying these gaps so that action could be
      taken to address them. The logs themselves proved to be a practical and feasible
      way to record student experience as it unfolded.

PMID- 10354320
TI  - Psychiatric training for family doctors: what do GP registrars want and can a
      brief course provide this?
AB  - CONTEXT: About 40% of British General Practitioners (GPs) train formally in a
      psychiatric post as part of their general practice training, but such training
      may not fully meet the needs of future GPs. A specific course in psychiatry for
      family doctors has run in Manchester for more than a decade. METHOD: Semi
      structured interviews conducted with GP registrars before attending the
      Manchester course in psychiatry with questionnaire follow-up afterwards to
      ascertain (a) the training 'wants' of GP registrars and (b) whether the course
      was providing them. RESULTS: GP registrars most frequently wanted training in
      communication skills, how to access the resources that are available to GPs, the
      detection of psychiatric illness, drug treatment and the management of
      aggression. The course was successful in satisfying the first three but failed in
      the last two. There was trend for those who attended Manchester Medical School,
      which scored significantly higher on number of topics covered at undergraduate
      level, to perceive a greater need for training than those who attended other
      medical schools. However, there was no evidence to link self-perception of
      greater need with having already worked in general practice during postgraduate
      training. CONCLUSIONS: More attention needs to be paid to how to address the
      specific mental health skills training requirements of GP registrars both within
      the attachment in psychiatry and during the practice year. Preliminary research
      is required to devise teaching packages before they are entirely satisfactory for
      GP education.

PMID- 10354321
TI  - The performance of foreign medical graduates on the National Board of Medical
      Examiners (NBME) standardized patient examination prototype: a collaborative
      study of the NBME and the Educational Commission for Foreign Medical Graduates
      (ECFMG).
AB  - OBJECTIVES: The purpose of the study was to explore foreign medical graduates'
      (FMGs) performance on a clinical skills (SPX) examination. The National Board of
      Medical Examiners (NBME) is in the process of developing an SPX for potential use
      in the United States Medical Licensing Examination (USMLE). The Educational
      Commission for Foreign Medical Graduates (ECFMG) is developing the Clinical
      Skills Assessment (CSA) as an additional requirement for FMGs who wish to be
      certified by ECFMG. DESIGN: Thirty-three FMGs and 151 United States medical
      students (USMSs) took the SPX during the winter of 1996 as part of the ongoing
      pilot studies conducted by the NBME. Four clinical skill areas were assessed:
      history-taking, physical examination, communication and interpersonal skills. The
      examination used in this research consisted of 12 cases. The examination utilizes
      standardized patients (SPs) who are trained to document examinee behaviours and
      evaluate the communication component of the test. The SPs were also trained to
      evaluate the English proficiency of the candidates. Candidates were also
      administered the Test of Spoken English developed by the Educational Testing
      Services (ETS). SETTING: The examination was conducted in one medical school
      which served as an SPX centre for NBME pilot studies. SUBJECTS: Thirty-three
      foreign medical students and 151 US medical students. RESULTS: The indications
      were that the majority of candidates in both groups felt the examination was
      moderately fair but 78% of FMGs felt moderately pressed for time, vs. 80% of the
      USMSs who did not feel pressed for time. Reliabilities obtained for the various
      SPX components were somewhat higher for the FMGs reflecting the heterogeneity of
      this group. CONCLUSIONS: The NBME-ECFMG collaborative study yielded important
      information regarding the NBME SPX prototype as a performance measure for FMGs.

PMID- 10354322
TI  - Assessment of general practitioners by video observation of communicative and
      medical performance in daily practice: issues of validity, reliability and
      feasibility.
AB  - OBJECTIVES: To develop a video assessment method for General Practitioners (GPs)
      by analysing issues of validity, reliability and feasibility of observation of
      videotaped regular consultations. DESIGN: In a cross-sectional study
      consultations of 93 GPs were video recorded in the practice during 1 week. The
      GPs registered consultation and patient data in a logbook; 16 consultations per
      GP were selected using preset criteria. The quality of communicative and medical
      performance of these consultations was assessed by GP observers with a validated
      instrument. The validity of the procedure was evaluated by checking the content
      of each GP's sample using specific sample criteria. Selection bias was estimated
      by multiple regression analysis, with sample characteristics as independent
      variables and scores on communication and medical performance as dependent
      variables. The influence of observation on GPs and patients was assessed by a
      questionnaire. Generalizability theory was used to estimate reliability.
      Feasibility was assessed by conducting a questionnaire, by keeping accounts, and
      by checking the technical quality of the videotaped consultations. SETTING:
      Universities of Nijmegen and Maastricht, The Netherlands. SUBJECTS: General
      Practitioners (GPs). RESULTS: The domain of general practice was well covered in
      the samples; content validity was satisfactory. With regard to the sample
      characteristics, only the total duration of consultations appeared to correlate
      significantly with both the score on communication and the score on medical
      performance. A majority (71%) of GPs reported not being influenced by the
      observation, except in the first cases, and recognizing their usual daily
      performance in the videotaped consultations. An acceptable level of reliability
      was reached after 2.5 hours of observation, i.e. 12 cases by a single observer.
      The method was well accepted by both GPs and patients. The costs were pound250
      per GP. CONCLUSIONS: Video assessment of GPs in daily practice according to the
      procedures described is a valid and reliable method, one which is useful for
      education and quality improvement. There is a trade-off between feasibility on
      one hand and validity, reliability and credibility on the other hand. Compared to
      investments in observation methods in standardized settings, the costs of video
      observation of GPs' actual performance are acceptable.

PMID- 10354323
TI  - Selecting medical students: a case report of the need for change.
AB  - OBJECTIVES: To review the selection of medical students by academic score alone.
      SETTING: The University of Adelaide. METHODS: Surveys of students, staff, school
      counsellors and review of matriculation scores and rankings in the medical
      course. RESULTS: Staff and school counsellors both rated personal qualities such
      as problem solving ability and communication skills as highly desirable
      attributes to be sought, but not rote learning ability. School counsellors
      reported intense pressure on students and schools to achieve the required high
      scores, with educationally undesirable narrowing of subject choices and reduced
      involvement in sport and extra-curricular activities. Matriculation scores did
      not predict placings in our medical course. Only 52% of students had a clear
      ambition to do medicine, while parental pressure and a high mark featured
      strongly as other reasons for entry. Only 11% of students claimed any reasonable
      knowledge about their chosen career before entry. CONCLUSION: This case report
      confirmed that selecting medical students by academic score alone was no longer
      desirable.

PMID- 10354324
TI  - Visiting elective students at the University of Toronto from the Korea University
      Medical College.
AB  - OBJECTIVES: The main goal of the international elective programme was to provide
      the Korean students with a cross-cultural educational environment. DESIGN: This
      programme was carried out on a voluntary basis during the summer vacation,
      rotating students through various clinical divisions in the teaching hospital.
      SETTING: The University of Toronto. SUBJECTS: Medical students from the Korea
      University Medical College. RESULTS: The students found the student-teacher
      relationship to be much more open and liberal. Due to a different curricular
      structure, the Canadians have better clinical skills and problem-solving
      abilities in real clinical settings. The cultural differences perceived by the
      students during the elective programme led them to believe that educational
      reform in Korea imperatively requires curricular change, but more importantly, a
      change in our traditional psychological and behavioural traits which derive from
      Confucianism. CONCLUSIONS: Extreme politeness, passiveness and blind respect for
      teachers, which are encouraged by Confucianism, are not effective in higher
      education. All the elective students, as well as the Canadian preceptors, believe
      that this programme is an invaluable asset.

PMID- 10354326
TI  - In this issue ellipsis

PMID- 10354325
TI  - Attitudes of medical faculty physicians about taking occupational history.
AB  - OBJECTIVES: To evaluate occupational history taking, as a detailed occupational
      history is the most effective means for proper diagnosis of occupational illness.
      METHODS: In order to determine the attitudes of 66 physicians working in Dokuz
      Eylul Medical Faculty Hospital about taking occupational history, 269 patient
      records were examined. RESULTS: It was detected that 43.9% of physicians took no
      occupational history from any of their patients. Occupational history was
      obtained from 81.8% of the patients in clinics where standard examination forms
      were in regular use. CONCLUSION: We found that physicians were not in the habit
      of taking occupational histories.

PMID- 10354327
TI  - An honours degree in medicine: what does it mean?

PMID- 10354328
TI  - Portfolios--attempting to measure the unmeasurable?

PMID- 10354329
TI  - Teaching clinical reasoning--a preliminary controlled study.
AB  - BACKGROUND: The formal and explicit teaching of clinical reasoning is rarely
      undertaken in medical schools despite widespread recognition that knowledge
      acquisition alone may be insufficient to develop good clinical judgement.
      Previous work studying the effects of such teaching is inconclusive. DESIGN AND
      METHODS: A controlled observational study of 4th year medical students considered
      the effect of a brief teaching intervention on clinical reasoning skills. A
      validated measure of clinical reasoning - the diagnostic thinking inventory - was
      used as the outcome measure. RESULTS: Students participating in the teaching
      intervention performed significantly better on the diagnostic thinking inventory
      than control students. CONCLUSION: Further research is necessary to evaluate the
      long-term impact of such teaching.

PMID- 10354330
TI  - Continuing education courses in dentistry: assessing impact on practice.
AB  - INTRODUCTION: In the context of movement towards mandatory continuing dental
      education, this paper describes how a delayed postal questionnaire can be used in
      course evaluation. Specifically, the value of the questionnaire as a tool for
      assessing the impact of short course attendance on general dental practice is
      examined. METHOD: Questionnaires were distributed to all those attending three
      courses, ranging in size, in the West Midlands region. As well as reflecting on
      the course, respondents were asked their views on the usefulness of the
      questionnaire, the length of time between course attendance and assessment of
      impact, and types of courses likely to have greatest impact. RESULTS: Respondents
      thought the questionnaire an appropriate tool for assessing impact on practice,
      that an appropriate interval of time between the course and the delayed
      questionnaire is about six weeks, and that courses most likely to impact on
      practice are those which offer updates on common clinical topics and are hands-on
      in nature. DISCUSSION: A delayed questionnaire could be a useful mechanism for
      evaluating the impact on practice of some types of courses. Response rates from
      those attending large lecture courses might be low. Course evaluation is also
      limited by resources and time. Criteria for identifying which courses should be
      subject to such evaluation might include high cost per participant and links with
      review cycles. CONCLUSION: There is scope for more structured evaluation of
      continuing dental education, including the assessment of impact on practice. The
      questionnaire described is a useful component of an evaluation framework.

PMID- 10354331
TI  - Are professional attitudes related to gender and medical specialty?
AB  - OBJECTIVES: The importance of professional attitudes in medical care has long
      been recognized; however, medical training has not stressed attitude development
      until recently. In previous studies among medical students, we found that gender
      and specialty preference are important factors in attitudes. In this study,
      patient-centredness of trainees in general practice and surgery and of final-year
      clerks preferring one of these specialties was assessed in one medical school in
      The Netherlands. The effect of gender, specialty and training level on attitude
      was investigated. DESIGN: In 1995, attitudes of 37 general practice trainees, 31
      surgery trainees and 120 clerks were measured anonymously using questionnaires
      containing the Doctor-Patient Scale. This attitude scale measures patient
      centredness vs. doctor-centredness. Response rates were 78%, 58% and 84%,
      respectively. SETTING: University of Utrecht. SUBJECTS: Medical students.
      RESULTS: Attitudes were related to specialty. General practice trainees showed
      more patient-centredness than surgery trainees. In accordance with previous
      findings among younger students, no differences were found between final-year
      clerks and vocational trainees. In contrast to previous studies, gender was not
      related to patient-centredness. CONCLUSIONS: Professional attitudes, in
      particular patient-centredness, seem to be related to specialty preference in the
      final year of graduate medical training and specialty as a career choice. It
      remains unclear whether professional socialization reinforces existing attitudes
      or whether existing attitudes result in specialty preference.

PMID- 10354332
TI  - Accreditation of postgraduate medical education in the United States and Canada:
      a comparison of two systems.
AB  - The systems for accrediting residency programmes in the United States and Canada,
      although they have developed independently in the two countries, have similar
      objectives and accreditation requirements. Both have become increasingly focused
      over the past several decades on the importance of educational programmes
      structured to provide graded professional responsibility with appropriate
      guidance and supervision to residents according to their level of training,
      ability and experience. The Canadian model used by the Royal College of
      Physicians and Surgeons of Canada is a centrist one, with accreditation decisions
      on all programmes in all specialties being vested in a single, multidisciplinary
      accreditation committee. The American model developed by the Accreditation
      Council for Graduate Medical Education is a distributive one, with accreditation
      decisions being vested in each specialty Residency Review Committee. In both
      models, accreditation is based on a system of periodic on-site visits during
      which both faculty and residents are interviewed by a surveyor to provide the
      accrediting body with a first-hand evaluation of the extent to which each
      accredited programme meets the standards of accreditation. While they are similar
      in purpose, there are significant differences in the operation of the two
      systems.

PMID- 10354333
TI  - Gender, sequence of cases and day effects on clinical skills assessment with
      standardized patients.
AB  - OBJECTIVE: Clinical skills assessment using standardized patients (SPs) is an
      accepted method of professional testing, but some factors can threaten the
      validity of the scores obtained. OBJECTIVE: The main objective of this work was
      to test whether the gender of the patients, the sequence of cases and the day of
      the examination have any impact on the scores of the examinees. MATERIALS: Data
      from examinations conducted at three Medical Schools are used. Each student
      encountered 10 different SPs (5 men and 5 women). METHODS: Analysis of variance
      was used to test the existence of association between the variables. RESULTS: The
      results showed no significant differences or association between the scores and
      the three variables analysed. CONCLUSIONS: The results are coherent with the
      studies that show that performance based examination using SPs can be used
      without introducing biases into students score.

PMID- 10354334
TI  - A Delphi technique to identify and evaluate criteria for construction of PBL
      problems.
AB  - INTRODUCTION: In the process of PBL implementation, faculty members often ask
      what are the criteria for constructing problems and subsequently evaluating them.
      Although experts agree on a fundamental theoretical basis for developing
      problems, mostly prototypical, it is difficult to find specific criteria that
      could be used in constructing PBL problems. METHOD: A Delphi technique using six
      independent judges from the Rouen School of Medicine, France, answered this
      question. It took four rounds and five months. RESULTS: Nine criteria were
      identified and rank-ordered according to their relative importance: 1.
      stimulating thinking, analysis, and reasoning (openness 6.8 points); 2. assuring
      self-directed learning (autonomy 6.5); 3. using previous basic knowledge
      (richness 6.2); 4. proposing a realistic context (attractiveness 5.7); 5. leading
      to the discovery of learning objectives (coverage 5.0); 6. arousing curiosity
      (inquisitiveness 5.0); 7. choosing topics related to public health (relevance
      5.0); 8. assuring contextual breadth (comprehensiveness 4.8); and 9. choosing an
      appropriate vocabulary (medical encoding 4.7). DISCUSSION: The identification
      represents a fresh outlook on the PBL process, from judges who had recent
      experience in constructing PBL problems. Related to Barrow's dimensions, these
      criteria could be seen as a more concrete and specific level of
      conceptualization. Paired with those found in the literature, they match six out
      nine already identified, although not prioritized criteria. CONCLUSION: Judges
      from a school just having implemented PBL, found that Reasoning and Autonomy are
      the most important criteria for constructing PBL problems.

PMID- 10354335
TI  - Can medical students contribute to quality assurance programmes in day surgery?
AB  - CONTEXT AND OBJECTIVES: Health care delivery has undertaken a major shift from
      inpatient management to ambulatory surgical care with increasing emphasis on
      quality assurance (QA) processes. Educational opportunities for medical
      undergraduate programmes are being sought in the day surgery environment. Our
      study was undertaken to explore ways in which senior medical students can
      actively contribute to QA processes as part of an undergraduate day surgery
      educational programme. SUBJECTS AND METHODS: Health care delivery has undertaken
      a major shift from inpatient management to ambulatory surgical care with
      increasing emphasis on quality assurance (QA) processes. Educational
      opportunities for medical undergraduate programmes are being sought in the day
      surgery environment. Our study was undertaken to explore ways in which senior
      medical students can actively contribute to the QA processes as part of an
      undergraduate day surgery educational programme. SUBJECTS AND METHODS: Fifty-nine
      final year medical students followed allocated patients with common surgical
      conditions through all phases of the day surgery process. Students kept records
      about each case in a log book and also presented their cases at weekly Problem
      Based Learning tutorials. An audit of student log books and review of tutorial
      records was conducted for the 1996 and 1997 academic years, in order to evaluate
      student contribution to QA. RESULTS: Students followed 621 cases, representing a
      sampling of 14. 1% day surgery cases. Categories of problems highlighted by
      students included inappropriate patient and procedure selection, inadequate pain
      management, discharge, communication and resource issues. Students made a number
      of recommendations including the development of multilingual videotapes and
      patient information sheets for non-English speaking patients, avoidance of
      bilateral surgical procedures and improved links with local medical officers.
      They also developed new guidelines and protocols. CONCLUSIONS: Our study confirms
      that students are able to identify QA issues and propose solutions. We recommend
      that students have a formally recognized place in day surgery QA programmes, to
      close the QA loop and to adequately prepare them for medical practice in the 21st
      century.

PMID- 10354336
TI  - Educational portfolios in the assessment of general practice trainers:
      reliability of assessors.
AB  - OBJECTIVES: This paper reports a project that assessed a series of portfolios
      assembled by a cohort of participants attending a course for prospective general
      practice trainers. DESIGN: The reliability of judgements about individual
      'components', together with an overall global judgement about performance were
      studied. SETTING: NHSE South & West, King Alfred's College, Winchester and
      Institute of Community Studies, Bournemouth University. SUBJECTS: Eight
      experienced general practice trainers recruited from around Wessex, which
      incorporates Hampshire, Dorset, Wiltshire and the Isle of Wight. RESULTS: The
      reliability of individual assessor's judgements (i.e. their consistency) was
      moderate, but inter-rater reliability did not reach a level which could support
      making a safe summative judgement. The levels of reliability reached were similar
      to other subjective assessments and perhaps reflected individuality of personal
      agendas of both the assessed and the assessors, and variations in portfolio
      structure and content. CONCLUSIONS: Suggestions for approaches in future are
      made.

PMID- 10354337
TI  - Portfolios in continuing medical education--effective and efficient?
AB  - INTRODUCTION: A cross over comparison between 'traditional' continuing medical
      education (CME) activities and portfolio-based learning in general practice is
      described. METHOD: Thirty-two volunteer general practitioners (GPs) were divided
      into two cohorts; each cohort spent six months following a 'traditional' route to
      postgraduate educational accreditation (PGEA) and six months following a
      portfolio-based learning route supported by three CME tutors. OUTCOME MEASURES:
      These were the submission of a completed portfolio with evidence of the
      completion of learning cycles and participants reflections on the educational
      process. Qualitative and quantitative evaluation data were collected by
      questionnaire, semi-structured interview, participant observation and review of
      completed portfolios. RESULTS: The themes identified by GPs as hopes for the
      portfolios were largely fulfilled and the anxieties generally confounded. The
      flexibility of the portfolio learning process was particularly important to the
      participants. The breadth of topics covered by the portfolios was extremely wide
      and comparison with the submissions for 'traditional' PGEA showed a much smaller
      spread of learning activities and fewer subjects of study. EFFECTIVENESS: The use
      of the portfolios of critical incidents and the completion of learning cycles
      with application to practice provided evidence of the effectiveness of such
      learning. EFFICIENCY: The mean number of hours spent by GPs preparing the
      portfolios was 24.5 +/- 12 (SD) which was significantly more than the 15 hours of
      PGEA awarded. CONCLUSIONS: This study demonstrates that a portfolio-based
      learning scheme can meet the needs of GPs relevant to their professional
      practice; it can give learners control over how, what and when they learn and
      encourage active and peer-supported learning; it can build personal and
      professional confidence and be thought both valid and reliable by participants.
      Learning outcomes can also be reliably assessed by PGEA within the context of an
      individually created learning plan.

PMID- 10354338
TI  - Single-handed practices--their contribution to an undergraduate teaching network
      in the first year of the new curriculum.
AB  - OBJECTIVES: The new curriculum at King's College School of Medicine and
      Dentistry, which commenced in September 1996, requires all medical undergraduates
      to have a general practice placement throughout the 5 years of their medical
      education. DESIGN: This paper discusses recruitment, training and support of
      teaching practices for the new curriculum, reviews the distribution of single
      handed general practices in the network and, via a selection of monitoring and
      evaluation procedures, discusses the implications of a policy which is inclusive
      of single-handed practices. The findings relate to the experience of the first
      semester of the first year of the new curriculum. It also examines the
      contributions that single-handed practices have made to the teaching network and
      the kind of support needed, if single-handed practices are to continue to
      contribute to the King's teaching network. SETTING: King's College School of
      Medicine and Dentistry. SUBJECTS: Medical undergraduates. RESULTS: The findings
      of this paper revealed that over a third of general practice provision is via
      single-handed practices in South-east London. Within the undergraduate teaching
      network, 10% of practices are single-handed. Students are welcomed and receive a
      learning experience comparable to those students in larger practices. Attendance
      at training events has proved difficult for some of these tutors, but the extra
      input from the department, in order to address this deficit, has not been
      onerous. Indeed, single-handed practices have not been unique with regard to
      difficulties in attendance at training events. CONCLUSIONS: The study concludes
      that single-handed practices can make satisfactory provision for undergraduates
      in the new curriculum and there is no evidence from this study to suggest
      otherwise.

PMID- 10354339
TI  - Why? What? and How? IT provision for medical students in general practice.
AB  - OBJECTIVES: The aim of this paper is to discuss the increasing use of computers
      in undergraduate medical education and explore the why, what and how of providing
      IT facilities to undergraduate medical students when they are on placement in
      general practice. Adequate computing facilities are usually available within
      hospitals and medical schools, however, major changes are taking place in
      undergraduate education resulting in more teaching being undertaken in the
      community. Students will therefore need access to comparable facilities whilst in
      primary care settings in order for their training not to be compromised. SETTING:
      This paper describes one initiative addressing this need: the University Linked
      Practices (ULP) project in the Department of General Practice and Primary Care at
      St. Bartholomew's and the Royal London School of Medicine and Dentistry. DESIGN:
      We discuss the ways in which computers are currently being used in medical
      education and discuss some of the merits and drawbacks that are associated with
      this increasing drive to computerization.

PMID- 10354340
TI  - The patterns of small bowel motility: physiology and implications in organic
      disease and functional disorders.
AB  - The physiology and pathophysiology of small bowel motility are reviewed with
      particular focus on the motility patterns and periods that are detected by
      intraluminal manometry. Motility patterns are groups of phasic pressure waves
      resulting from contractions of the circular muscle layer of the small bowel that
      are organized by the enteric nervous system. Phase III of the migrating motor
      complex, the hallmark of the fasting motility period, thus reflects enteric
      neuromuscular function. Response to meal challenge also involves the CNS,
      reflexes beyond the gut and endocrine responses. Although specific disease
      diagnosis cannot be made by motility studies of the small bowel, the functional
      integrity is revealed. The normal occurrence of the essential patterns and
      periods of motility and the absence of distinctly abnormal patterns evidence
      preserved function, whereas the opposite indicates clinically significant
      dysmotility. Certain motility patterns are occasionally seen both in health and
      disease, and increased prevalence indicates a moderate dysfunction of yet unclear
      significance. Bacterial overgrowth with Gram-negative bacilli is the consequence
      of severe small bowel dysmotility, and a diagnosis that can be predicted by a
      motility study. Testing can be useful in the clinical management of paediatric
      and adult patients also by predicting the prognosis and response to enteral
      nutrition and medical therapy. Further studies are, however, needed to take full
      advantage of motility testing in clinical practise.

PMID- 10354341
TI  - Cortical activation during oesophageal stimulation: a neuromagnetic study.
AB  - We investigated the neuromagnetic responses to mechanical stimulation of the
      oesophagus. In six healthy right-handed volunteers (mean age 31.6 years) the
      proximal and distal oesophagus were stimulated by electronically controlled pump
      inflation of a silicone balloon once every 4.5-5.5 sec (dwell time 145 msec). The
      balloon volume was adjusted to induce different sensation levels (i) just above
      threshold of perception, (ii) strong sensation and (iii) painful sensation.
      Evoked magnetic brain responses were recorded time-locked to stimulus onset with
      a Neuromag-122TM whole-head neuromagnetometer and modelled as equivalent current
      diploe (ECD) sources. ECDs were superimposed on individual magnetic resonance
      imaging (MRI) scans. Magnetic brain responses following distal oesophageal
      stimulation were adequately explained by a time-varying 2-4 dipole model with
      unilateral or bilateral sources in second somatosensory cortex and later sources
      in the frontal cortex. With increasing stimulus intensities, latencies of the
      sources decreased and amplitudes increased. Proximal oesophageal stimulation led
      to activation of source areas spatially similar to those of distal oesophageal
      stimulation but with shorter response latencies. Both painful and nonpainful
      mechanical stimulation of the oesophagus activate the second somatosensory cortex
      (SII). Evidence for topographic organization of oesophageal afferents in SII is
      poor.

PMID- 10354342
TI  - Monitoring the lower oesophageal sphincter: sphinctometer or sleeve?
AB  - Two methods have been used to study lower oesophageal sphincter (LOS) function in
      gastro-oesophageal reflux disease: the sleeve sensor and the sphinctometer. Our
      aim was to directly compare the sleeve and sphinctometer in vivo. Ten
      asymptomatic volunteers were intubated with a perfused assembly incorporating a
      sleeve sensor, a solid-state assembly incorporating a sphinctometer and a pH
      probe. LOS function was recorded pre- and post-prandially. During basal periods
      sleeve and sphinctometer readings correlated well both within and between
      subjects (r2 = 0.89 (P < 0.0001)). However, the sphinctometer relaxed less during
      swallows (median 42 (interquartile range 27-55)% vs 73 (62-81)% (P < 0.001)),
      transient LOS relaxations (TLOSR) (50 (40-70)% vs 94 (88-100)% (P < 0.001)) and
      reflux episodes (67 (59-75)% vs 97 (91-100)% (P = 0.02)). Using criteria derived
      from 10 dry swallows, the expected relaxation of the sphinctometer during TLOSR
      was defined. The sphinctometer had an overall sensitivity ranging from 43 to 71%
      for the detection of TLOSR with 11-22 false positive relaxations, depending on
      the criteria employed. Sensitivity was particularly poor in those with low basal
      LOS pressure. The sphinctometer has a lower capacity to register LOS relaxations
      than the sleeve sensor, which limits its value in studying the pathophysiology of
      reflux disease.

PMID- 10354343
TI  - Structural relationships between immune cells and longitudinal muscle during a
      Trichinella spiralis infection in the rat intestine.
AB  - A Trichinella spiralis infection produces an acute inflammatory reaction and
      tissue damage in the mucosa, and, in addition, functional changes occur in the
      external muscle layers. The aim of the present study was to characterize
      structural changes in the musculature that occur during early infection, and to
      identify relationships between immune cells and muscle cells, as part of an
      ongoing investigation into the immune modulation of motor function in the gut.
      Rats were infected with T. spiralis larvae and the gut fixed at 12 h, 24 h, 48 h
      and 6 days post-infection for electron microscopy of the longitudinal muscle.
      Macrophages and lymphocytes penetrated the longitudinal musculature 12-24 h post
      infection. Distinct contacts were observed between specific cell types; cellular
      protrusions from macrophages or lymphocytes made close apposition contacts with
      smooth muscle cells. Resident macrophages in the subserosal space, fibroblast
      like cells as well as smooth muscle cells showed marked activation during
      inflammation. Fibroblast-like cells were frequently seen intercalated between
      lymphocytes and smooth muscle cells, hence they may mediate communication between
      immune cells and the musculature.

PMID- 10354344
TI  - Temporal distribution of neuronal and inducible nitric oxide synthase and
      nitrotyrosine during colitis in rats.
AB  - Nitric oxide (NO) has been implicated in the pathogenesis of inflammatory bowel
      disease since increased NO production is observed in this disease. NO can react
      with superoxide to generate peroxynitrite which causes and/or exacerbates
      colitis. Peroxynitrite, in turn, nitrates tyrosine residues to form nitrotyrosine
      which can be identified immunohistochemically. We investigated the distribution
      of neuronal and inducible nitric oxide synthase (iNOS) and nitrotyrosine over
      time in experimental colitis. Colitis was induced by intracolonic administration
      of trinitrobenzene sulphonic acid (TNBS) in rats. Animals were killed 1, 2, 7 and
      14 days after treatment. Myeloperoxidase activity was used as an index of
      inflammation, and tissues were examined using immunohistochemistry. Neuronal NOS
      immunoreactivity was present throughout the colon, and was only slightly reduced
      1 day after the induction of colitis. Conversely, iNOS immunoreactivity almost
      absent in controls dramatically increased in the mucosa and submucosa at the
      early stages of inflammation. iNOS was present in monocytes and macrophages and
      also another unidentified cell type. Seven and 14 days after the induction of
      colitis, iNOS was also found in nerves in the circular muscle and in the
      myenteric plexus. Nitrotyrosine immunoreactivity present in a few cells in the
      normal mucosa also increased 1 day after the induction of colitis and decreased
      thereafter. The pattern of distribution of nitrotyrosine immunoreactivity was
      distinct from that of iNOS. The increase of iNOS expression at the early stage of
      inflammation may play a role in causing tissue injury via peroxynitrite
      formation. The expression of iNOS seen in the enteric nerves in the later stage
      of inflammation correlates temporally with the beginning of tissue repair and
      with the re-innervation and compensatory growth of nerves. NO may potentially
      play a physiological as well as pathological role in experimental colitis.

PMID- 10354345
TI  - The pharmacological properties of the novel selective 5-HT3 receptor antagonist,
      alosetron, and its effects on normal and perturbed small intestinal transit in
      the fasted rat.
AB  - The purpose of this study was to investigate the pharmacological properties of
      the novel, selective 5-HT3 receptor antagonist, alosetron, and its effects on
      transit time in both the normal and perturbed small intestine of the rat.
      Alosetron concentration-dependently inhibited radioligand binding in membranes
      containing rat and human 5-HT3 receptors with estimated pKi values of 9.8 (n = 3)
      and 9.4 (n = 6), respectively. In selectivity studies alosetron had little or no
      significant affinity for any of the many other receptors and ion channels
      studied. Alosetron potently antagonized the depolarization produced by 5-HT in
      the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats,
      i. v. administration of alosetron inhibited 2-methyl-5-HT induced bradycardia
      (Bezold Jarisch index) at 1 and 3 microg kg-1, with an agonist dose ratio of
      approximately 3.0 at 1.0 microg kg-1, = 3-5). Alosetron administered via the
      duodenum also inhibited this reflex, with duration of action that was
      significantly longer than that seen with ondansetron (120-60 min, respectively, n
      = 6). Alosetron had no significant effect on normal small intestinal propulsion
      in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3)
      produced by egg albumin challenge. Alosetron is a highly selective 5-HT3
      antagonist which normalizes perturbed small intestinal propulsion. Previous
      clinical data in IBS patients together with the transit data provide a good
      rationale for further studies with alosetron in IBS patients.

PMID- 10354346
TI  - Short-chain fatty acids present in the ileum inhibit fasting gastrointestinal
      motility in conscious pigs.
AB  - Colonic compounds, primarily short-chain fatty acids (SCFAs), inhibit gastric
      tone in humans. However, since colonic compounds reflux into the ileum, SCFAs
      might act also at the ileal level. This study evaluates the effects of the
      contact of SCFAs with the ileum alone towards gastrointestinal motility in fasted
      conscious pigs. Gastrointestinal motility was recorded during ileal infusion of a
      mixture containing acetate, propionate and butyrate in intact vs ileostomized
      animals (n = 10). Ileal infusions of isomolar (500 mmol L-1) vs isocaloric (600
      kJ L-1) SCFAs were also performed. SCFA mixture reduced significantly the
      amplitude and increased the frequency of antral contractions in intact (motility
      index: 2624 +/- 503.4 vs 4077 +/- 388.2) and ileostomized pigs (motility index:
      2428 +/- 678.1 vs 4709 +/- 773.4) compared with iso-osmotic saline. SCFAs at
      isomolar concentrations inhibited equally gastric motor pattern irrespective of
      their chemical structure. On the contrary, isocaloric concentrations of SCFAs
      induced graded effects: acetic acid being the most potent to reduce gastric
      motility. In conclusion, SCFAs inhibit gastrointestinal motility by a direct
      contact with the ileum. This inhibition was concentration dependent.

PMID- 10354347
TI  - Motor activity of vascularly perfused rat duodenum. 1. Characteristics of
      spontaneous movement.
AB  - We developed an ex vivo model of arterially perfused rat duodenum to examine the
      motor activity of intestine. In this preparation, spontaneously occurring
      pressure waves with regular rhythm were observed. The oxygen consumption and
      motor activity of the intestine were compared at different arterial perfusion
      rates to determine the degree of oxygenation required to elicit spontaneous
      motility. Pressure waves with regular rhythm occurred at a frequency of 1 min-1
      when the arterial perfusion was 3-5 mL min-1, and stopped when the perfusion rate
      fell below 2 mL min-1. Atropine and hexamethonium reduced the percentage motor
      index/10 min of pressure waves in a dose-dependent manner, and tetrodotoxin
      completely blocked motor activity. Acetylcholine stimulated motor activity, and
      this effect was not antagonized by TTX. These findings suggest that spontaneous
      contraction in the ex vivo perfused rat duodenum might be mediated by a
      cholinergic mechanism via muscarinic receptors on smooth muscle, but that
      noncholinergic mechanisms may also participate in this response.

PMID- 10354348
TI  - Motor activity of vascularly perfused rat duodenum. 2. Effects of VIP, PACAP27
      and PACAP38.
AB  - We examined the mechanisms of effects of vasoactive intestinal polypeptide (VIP),
      pituitary adenylate cyclase activating polypeptide (PACAP) 27 and PACAP38 on
      spontaneously occurring pressure waves in ex vivo perfused rat duodenum. VIP and
      PACAPs dose-dependently reduced the percentage motor index of pressure waves;
      this reduction was not prevented by atropine, hexamethonium or tetrodotoxin
      (TTX). VIP and PACAPs abolished acetylcholine-induced stimulation of pressure
      waves, even in the presence of TTX. These findings suggest that VIP and PACAPs
      may exert direct inhibitory effects via VIP/PACAP receptors located on smooth
      muscle rather than via cholinergic receptors. The inhibitory effects of VIP and
      PACAPs were partially antagonized by the VIP receptor antagonists VIP(10-28),
      suggesting that VIP and PACAPs share common receptor sites on intestinal smooth
      muscle. The effects of VIP and PACAPs were completely antagonized by nitric oxide
      (NO) synthase inhibitor NG-nitro-L-arginine (L-NA), suggesting that NO mediates
      the inhibitory effects of VIP and PACAPs on duodenal motility. Furthermore,
      single injection of L-NA stimulated spontaneously occurring pressure waves, while
      VIP(10-28) did not affect them. These findings suggest that VIP/PACAPs and NO
      strongly interact as an inhibitory mediator on duodenal motility, but that their
      modes of action in doing so may differ.

PMID- 10354349
TI  - Increased tone of the rectal wall in response to feeding persists in patients
      with cauda equina syndrome.
AB  - The aim was to study fasting and postprandial rectal tone in patients with cauda
      equina injury. Electromechanical barostat measurement of rectal tone was made in
      13 healthy volunteers and in five patients during a 10 min recording, while
      fasting and for 1 h after a 1000 kCal intake. A prompt decrease of rectal volume
      was observed in all control subjects and patients. The delay between the end of
      the meal and the onset of the rectal response was always less than 3 min in the
      five patients as well as in the control group. The rapidity of the rectal
      response to feeding observed in our five patients suggests that the rectal
      response was mediated via a neural or neurohumoral pathway despite severe injury
      of the sacral parasympathetic supply.

PMID- 10354350
TI  - Biochemical characterization and localization of Fasciola hepatica 26-28 kDa
      diagnostic coproantigen.
AB  - We have previously reported the usefulness of a 26-28 kDa coproantigen of
      Fasciola hepatica for diagnosis of infection. In this study, the 26-28 kDa
      coproantigen was biochemically characterized with the aid of monoclonal
      antibodies (MoAb) in an effort to better understand the biology of the antigen.
      Differential staining of chromatographically-purified 26-28 kDa coproantigen on
      SDS-PAGE, under reducing and non-reducing conditions, indicated that the
      coproantigen was a monomeric, highly glycosylated glycoprotein. Alkaline
      treatment of the purified coproantigen resulted in an 8 kDa protein core which
      still contained the epitope recognized by the MoAb. No protease activity was
      associated with the 26-28 kDa coproantigen. The coproantigen could be cleaved by
      trypsin without altering the reactive epitope recognized by the MoAb, but was
      resistant to pepsin digestion. Further, the coproantigen was stable under several
      different storage conditions. Indirect immunofluorescence on tissue sections of
      adult flukes indicated that the coproantigen was present in gut cells and
      tegument. Taken together these results confirm the stability of the 26-28 kDa
      coproantigen and its usefulness in diagnostic tests for F. hepatica infections.

PMID- 10354351
TI  - Variability of the intestinal immunoglobulin E response of rats to infection with
      Trichinella spiralis, Heligmosomoides polygyrus or Nippostrongylus brasiliensis.
AB  - Total intestinal IgE level increased in rats infected with Trichinella spiralis
      or Heligmosomoides polygyrus (peak levels of 2.6 microg and 3.7 microg,
      respectively), but not in rats infected with Nippostrongylus brasiliensis.
      Intestinal implantation of young adult N. brasiliensis did not stimulate an
      intestinal immunoglobulin (Ig)E response, suggesting that mucosal penetration may
      be required for local intestinal IgE responses in rats. During a T. spiralis
      infection, total IgE levels in the intestinal lumen were consistently higher in
      LEWIS and LOU rats (rat strains that eliminate T. spiralis worms earlier in the
      infection) than in PVG, AO and WKA/H strain rats. There was no correlation in
      either the total level of serum IgE and IgA, or of intestinal IgA with
      differences between strains in the rate of worm elimination from the gut.
      Furthermore, the intestinal IgE immunoprecipitated from LEWIS rats 12 days after
      infection reacted with T. spiralis adult worm metabolic antigens, while
      intestinal IgE from PVG rats only became reactive with adult worm metabolic
      antigens from 14 days after infection. These data emphasize the significance of
      the intestinal IgE response and its unique features by comparison with serum IgE
      and IgA or intestinal IgA.

PMID- 10354352
TI  - Interleukin-15 enhances host protection against acute Toxoplasma gondii infection
      in T-cell receptor alpha-/-deficient mice.
AB  - A potential role for T-cell receptor (TCR)-gamma(delta) cells in response to
      Toxoplasma gondii has been described. This study was undertaken to evaluate
      whether exogenous rIL-15 can enhance the production of gamma(delta) T cells in
      response to infection with T. gondii. For this, C57BL/6 and TCR alpha-gene
      deficient mice (alpha-/-) were vaccinated with Toxoplasma lysate antigen (TLA) in
      combination with interleukin (IL)-15. The cellular and humoral immune response
      was assessed following immunization. Administration of IL-15/TLA to alpha-/-mice
      lengthened survival time post lethal challenge. Several immunological parameters
      were increased in the alpha-/-mice following immunization with IL-15/TLA
      including serum immunoglobulin (Ig)G1 and IgG2a antibody titres and splenocyte
      lymphoproliferation in response to parasite antigen. Further, the CTL response to
      parasite infected target cells as well as the production of interferon gamma was
      enhanced by IL-15/TLA administration in the alpha-/-mice. These observations
      indicate that the gamma(delta) T cells response to this parasite can be enhanced
      by the administration of exogenous IL-15 in the presence of parasite lysate
      antigen.

PMID- 10354353
TI  - Antibodies against Plasmodium falciparum vaccine candidates in infants in an area
      of intense and perennial transmission: relationships with clinical malaria and
      with entomological inoculation rates.
AB  - Serum immunoglobulin (Ig)G1, IgG3 and total IgG were assessed by immunoabsorbent
      assay in 198 infants from a Tanzanian village highly endemic for Plasmodium
      falciparum. Antibodies were measured against epitopes of the circumsporozoite
      protein (the repetitive epitope (NANP)50 and a construct of the flanking regions
      (CS27IC)), the malaria vaccine SPf66, and two constructs of the merozoite surface
      protein-1 (MSP-1), a 19-kDa fragment from the C-terminal domain (MSP-119) and an
      N-terminal fragment spanning blocks 1-6 (H6-p190 M-1/6-H6). IgG1 and total IgG
      titres showed similar age profiles, all decreasing for the first 2 months of
      life. Anti-(NANP)50 titres remained very low throughout the first year of life,
      while anti-CS27IC antibody appeared to peak around 7 months of age. Only a slight
      tendency to increase with age was observed for levels of the other antibodies
      studied. IgG3 titres except for H6-p190(1/6), were very low initially and
      remained very low throughout the first year of life. Clinical malaria incidence
      at the village dispensary was analysed prospectively in relation to antibody. No
      IgG1 or total IgG titre showed protective effects, but low IgG3 against p190(1/6)
      appeared to be a risk factor in some age groups. Given the large number of
      antibodies tested, this single indication of possible protection could merely be
      chance. There were no strong associations between antibody titres and
      entomologically assessed sporozoite exposure suggesting that transmission
      reducing interventions may have little effect on antibody levels in such
      children.

PMID- 10354354
TI  - Malaria parasite-specific Th1-like T cells simultaneously reduce parasitemia and
      promote disease.
AB  - CD4+ T cells have been implicated in immunity to the blood stages of malaria and
      cytokines associated with both monocyte and T cell activation have been
      implicated in disease. To determine whether specific T cells capable of
      inhibiting parasite growth can also mediate pathology we have transfused
      populations of Plasmodium berghei-specific T cells into normal and
      immunodeficient naive mice. We observed that they could inhibit parasite growth
      but were unable to save the animals which exhibited significantly greater anaemia
      and weight loss than control infected animals receiving either no T cells or T
      cells specific for ovalbumin. T cell-dependent tomour necrosis factor (TNF)alpha
      was a critical component in both parasite killing and disease promotion.
      Experiments with blocking antibodies demonstrated that all T-cell mediated
      antiparasitic immunity and all T-cell mediated weight loss was TNF-dependent.
      Blocking TNF-alpha in mice that received parasite-specific T cells prolonged the
      survival of the mice. Nitric oxide demonstrated no antiparasite effect, but was
      involved in the regulation of T-cell mediated weight loss. The data thus show
      that while parasite-specific CD4+ T cells can significantly limit parasite
      growth, such an effect need not be beneficial to the host, and that TNF-alpha and
      nitric oxide are critical effector molecules operating downstream of parasite
      specific T cells in both immunity and disease.

PMID- 10354356
TI  - Thematic Review Series VI: Skin Gene Therapy Introduction.

PMID- 10354355
TI  - Inhibition of in vitro growth of plasmodium falciparum field isolates mediated by
      human antibodies to Pf155/RESA and Pf332.
AB  - The capacity of antibodies to interfere with Plasmodium falciparum growth in in
      vitro cultures is considered to reflect some of their potential protective
      effects in vivo. Almost all previous analyses of antibody mediated inhibition of
      parasite growth in vitro were performed with different laboratory strains of P.
      falciparum. This study was performed to investigate if the long-term culturing of
      parasites has any effect on their susceptibility to such growth inhibition. The
      growth inhibitory effects of human antibodies to the vaccine candidate antigens
      Pf155/RESA and Pf332 on fresh field isolates from children in Burkina Faso were
      analysed and compared with their effect on an established laboratory strain of
      the parasite. Although there was variation in the inhibition titres between
      different isolates tested against one antibody preparation, the differences in
      inhibition capacity for the three different antibodies were highly significant.
      No correlation was found between serum levels of anti-Pf155/RESA or -Pf332
      antibodies and sensitivity of the corresponding parasite isolates to antibody
      mediated growth inhibition.

PMID- 10354357
TI  - Transduction of a preselected population of human epidermal stem cells:
      consequences for gene therapy.
AB  - Continuously renewing tissues, such as the epidermis, are populated by a
      hierarchy of dividing transient amplifying cells, which are maintained by stem
      cells. Transient amplifying cells divide to maintain the tissue, but they are
      limited to a finite number of cell divisions before they differentiate and are
      sloughed. Only the stem cells remain for the life of the tissue. Thus, it is
      critical to target stem cells when designing gene therapy regimes for genetically
      inherited diseases, such as epidermolysis bullosa simplex (EBS). Unfortunately,
      isolating pure epithelial stem cells has been problematic. In this study, we used
      rapid adherence to collagen type IV to successfully enrich for epidermal stem
      cells from adult human skin. These preselected stem cells were slow to
      proliferate, but they ultimately formed large colonies. When recombined with the
      dermal substrate AlloDerm, the stem cells re-formed a stratified squamous
      epidermis within 1 week after raising the AlloDerm to the air-liquid interface.
      These organotypic cultures grew continuously and, even after 6 weeks in culture,
      they maintained a proliferative basal layer. When transduced with a retroviral
      LacZ vector, preselected stem cells formed beta-galactosidase-positive clones in
      submerged and organotypic cultures. Transduced cells showed persistent expression
      through 12 weeks in organotypic culture, demonstrating the feasibility of using
      preselected stem cells for gene therapy. Currently, we are developing two models
      of EBS to test a gene therapy approach, which is based on the premise that EBS
      stem cells with a mutant keratin (K)14 gene corrected to wild type will have a
      growth advantage over noncorrected EBS stem cells.

PMID- 10354359
TI  - Biologic aspects of expression of stably integrated transgenes in cells of the
      skin in vitro and in vivo.
AB  - The observation that transgenes can be stably integrated into the genome of
      fibroblasts using recombinant retroviruses enhanced interest in using these cells
      as a vector for gene therapy. This enthusiasm has lessened during the past 8
      years, not because skin has lost the features that make it attractive for gene
      therapy, but rather because stable transgene expression in vivo has not been
      achieved. All investigators who have used genetically modified fibroblasts to
      study in vivo aspects of gene therapy have shown a decrease in transgene
      expression with time. This contrasts with transgene expression in similarly
      transduced fibroblasts in vitro, where expression is not lost or is lost very
      slowly. We have initiated an approach to bring further understanding to the
      biology of transgene expression by fibroblasts carrying stably integrated
      transgenes in an in vivo setting. Experiments described permit the following
      conclusions. Expression by and survival of genetically modified fibroblasts a)
      requires a persistent matrix scaffold in in vivo settings; b) is prolonged if the
      matrix is allowed to mature in vitro; c) is enhanced if the matrix is partially
      sequestered behind a coating of normal fibroblasts; and d) can be substantively
      prolonged in vivo by immortalizing the cells. These observations support the
      notion that prolonged expression of transgenes by fibroblasts can be achieved in
      vivo and that gene therapy utilizing fibroblasts and other cells of the skin has
      clinical utility.

PMID- 10354358
TI  - A direct in vivo approach for skin gene therapy.
AB  - In vivo gene therapy is a direct and effective way to express genes in the
      epidermis. Plasmid DNA that contains the desired gene can be injected
      intradermally, and it is rapidly absorbed and expressed by the epidermis. Because
      gene expression following plasmid injection is transient, the two principal
      therapeutic uses of this approach are genetic immunization and the expression of
      biological response modifiers to treat skin disease.

PMID- 10354360
TI  - Systemic replacement therapy from genetically modified epidermal keratinocytes.
AB  - Epidermal keratinocytes are a potential vehicle for gene transfer and systemic
      delivery. We review data showing that epidermis-secreted protein does indeed
      reach the circulation, and we discuss factors that bear upon the issue of how
      much protein epidermal keratinocytes can deliver to the circulation.

PMID- 10354361
TI  - Targeting the skin for genetic immunization.
AB  - One of the most promising applications of recent advances in gene therapy is the
      development of immunization strategies based on the delivery of antigen-encoding
      DNA. DNA-based vaccination, also referred to as genetic vaccination or
      polynucleotide vaccination, offers considerable promise for improvement over
      existing immunization strategies, and the skin offers unique potential as a
      target tissue for genetic vaccines. The expression of genetically introduced
      antigens in a cutaneous microenvironment rich in both professional antigen
      presenting cells and accessory cells, which are capable of producing
      immunostimulatory cytokines, has the potential to overcome the historical
      limitations of vaccinology and immunotherapy. Though the precise molecular
      mechanisms of genetic immunization remain unclear, a general working model of the
      events through which antigen-encoding plasmids introduced into the skin initiate
      an immune response can be constructed. The finding that Langerhans cells can be
      transfected in vivo raises the exciting possibility that these migrating
      professional antigen-presenting cells can be genetically engineered in vivo. By
      designing strategies to codeliver genes encoding antigens with genes encoding
      immunoregulatory molecules to the same antigen-presenting cell, it may be
      possible to either induce or suppress antigen-specific immune responses in the
      host. Though many aspects of the biology of cutaneous DNA immunization remain
      unknown, the skin appears to offer unique potential for the application of
      advances in gene therapy to vaccination and genetic engineering of the immune
      response.

PMID- 10354362
TI  - Activation of the plasma kallikrein/kinin system on endothelial cells.
AB  - For more than two decades, it has been known that activation of the plasma
      kallikrein/kinin system only occurs when it is exposed to artificial, negatively
      charged surfaces. The existence of physiological, negatively charged surfaces
      has, however, never been demonstrated in vivo. In this report, we describe
      current knowledge about how the proteins of the plasma kallikrein/kinin system
      interact with and become activated on cell membranes. In this model, activation
      of the plasma kallikrein/kinin system on endothelial cells is not initiated by
      factor XII autoactivation, as seen on artificial surfaces. On endothelial cells,
      plasma prekallikrein is activated by a membrane-associated cysteine protease.
      This activation is dependent on the presence of high molecular weight kininogen
      and an optimal zinc (Zn2+) concentration. Although the initiation of activation
      of plasma prekallikrein is independent of factor XII, kallikrein-mediated factor
      XIIa generation, in turn, accelerates the activation of the system. Further
      kallikrein formed on endothelial cell membranes is capable of cleaving its
      receptor and native substrate, high molecular weight kininogen, liberating
      bradykinin and terminating activation. In addition, the kallikrein formed on the
      surface of endothelial cells results in kinetically favorable activation of
      prourokinase and, subsequently, plasminogen. Activation of the plasma
      kallikrein/kinin system on endothelial cells proceeds by a physiological
      mechanism to initiate cellular fibrinolysis independent of plasmin, fibrin, and
      tissue-type plasminogen activator.

PMID- 10354363
TI  - The genes of systemic autoimmunity.
AB  - Autoimmune diseases include a wide spectrum of disorders, which have been divided
      into systemic and organ-specific disorders. Lupus, the prototypic systemic
      autoimmune disease, is characterized by female predominance, multiorgan
      pathology, and autoantibodies, primarily directed against nuclear antigens. The
      disease is heterogeneous, with variable organ involvement, serology, and clinical
      course. Susceptibility to lupus is inherited as a polygenic trait with added
      contributions from environmental and stochastic variance. Concerted efforts have
      recently been made by several laboratories to define the genetic basis of this
      disease in predisposed mice and humans. The identification of the Fas/FasL
      defects in lpr and gld lupus mice was the first example of spontaneous mutations
      of apoptosis-promoting genes being associated with systemic autoimmunity. This
      research was instrumental in clarifying the roles of these genes in tolerance and
      immunoregulation, and in extrapolating these results to other autoimmune
      diseases, as well as cancer and transplantation. To these findings have been
      added those from transgenic and gene knockout mouse studies that have helped to
      define the systemic autoimmunity-inducing or -modifying effects of specific genes
      in normal background and lupus-congenic mice. In addition, the findings from
      genome-wide searches have begun to identify predisposing loci (and ultimately
      genes) for the spontaneous lupus-like diseases in various mouse strains and in
      humans. The emerging picture is that multiple genetic contributions can
      independently lead to systemic autoimmunity in mice, which reinforces the view
      that human lupus may be similarly composed of diverse genotypes. This complexity
      underscores the importance of defining the predisposing alleles and mechanisms of
      action, an undertaking that is certainly feasible given current technologies and
      future advances in the definition of mammalian genomes.

PMID- 10354364
TI  - Free fatty acids, insulin resistance, and type 2 diabetes mellitus.
AB  - Evidence is presented that shows that free fatty acids (FFA) are one important
      link between obesity, insulin resistance, and type 2 diabetes. Plasma FFA levels
      are elevated in most obese subjects, and physiological elevations of plasma FFA
      inhibit insulin-stimulated glucose uptake into muscle. This peripheral insulin
      resistance is caused by an FFA-induced defect, which develops 3-4 hr after
      raising plasma FFA, in insulin-stimulated glucose transport or phosphorylation,
      or both. This resistance is also caused by a second defect, which develops after
      4-6 hr, consisting of inhibition of glycogen synthase activity. Whether elevated
      plasma FFA levels inhibit insulin action on endogenous glucose production (EGP),
      that is, cause central insulin resistance, is more difficult to demonstrate. On
      the one hand, FFA increase gluconeogenesis, which enhances EGP; on the other
      hand, FFA increase insulin secretion, which decreases EGP. Basal plasma FFA
      support approximately one third of basal insulin secretion in diabetic and
      nondiabetic subjects and, hence, are responsible for some of the hyperinsulinemia
      in obese, normoglycemic patients. In addition, elevated plasma FFA levels
      potentiate glucose-stimulated insulin secretion acutely and during prolonged
      exposure (48 hr). It is hypothesized that obese subjects who are genetically
      predisposed to develop type 2 diabetes will become partially "lipid blind," that
      is, unable to compensate for their FFA-induced insulin resistance with FFA
      induced insulin oversecretion. The resulting insulin resistance/secretion deficit
      will then have to be compensated for with glucose-induced insulin secretion,
      which, because of their partial "glucose blindness," will result in hyperglycemia
      and eventually in type 2 diabetes.

PMID- 10354365
TI  - Glucocorticoids augment fibroblast-mediated contraction of collagen gels by
      inhibition of endogenous PGE production.
AB  - Glucocorticoids are currently regarded as the drug of choice in the treatment of
      inflammatory airway and lung diseases, however, they are not routinely effective
      in fibrotic phases of inflammation. In the current study, glucocorticoids were
      investigated for their ability to affect fibroblast mediated contraction of a
      three dimensional collagen gel, a measure of one aspect of tissue remodeling.
      Dexamethasone, budesonide, hydrocortisone and fluticasone propionate were all
      able to significantly augment fibroblast contractility in a concentration
      dependent manner. Glucocorticoids also had an augmentative effect on collagen gel
      contraction mediated by fibroblasts from bronchi, skin and bone marrow. The
      increased contractility was not due to cell proliferation or to collagen
      degradation, since the glucocorticoids did not alter the amounts of DNA and
      hydroxyproline in the gels. The concentration of prostaglandin E2 (PGE2) in
      supernatant media was lower from glucocorticoid-treated gels compared to control
      gels. Consistent with this, addition of exogenous PGE2 to the culture system
      restored the contractile properties and indomethacin augmented contraction
      similar to the glucocorticoids suggesting that inhibition of prostaglandins or
      related eicosanoids may be the mechanism by which the increased contractility
      occurs. DBcAMP, forskolin and the long lasting beta2-agonist formoterol were able
      to reverse the effect of the glucocorticoids on fibroblast mediated collagen gel
      contraction suggesting that enhancers of cAMP can counteract the effect of
      glucocorticoids. Thus, we provide evidence that glucocorticoids have the ability
      to directly augment fibroblast contractility by inhibiting fibroblast endogenous
      PGE synthesis. The findings could be one possible mechanism to explain the poor
      therapeutic response to glucocorticoids on the later stages of fibrotic diseases.

PMID- 10354366
TI  - Lysophospholipid enhancement of human T cell sensitivity to diphtheria toxin by
      increased expression of heparin-binding epidermal growth factor.
AB  - The effects of lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) on T
      cell expression of heparin-binding epidermal growth factor-like growth factor (HB
      EGF), the diphtheria toxin (DT) receptor, were investigated in the Tsup-1
      cultured line of human CD4+ 8+ 3low T lymphoblastoma cells. Tsup-1 cells bear
      endothelial differentiation gene (edg)-2 and -4-encoded G protein-coupled
      receptors (GPCRs) for LPA and Edg-3 and -5 GPCRs for S1P. Suppression by DT of
      Tsup-1 cell protein synthesis was enhanced by LPA and S1P, with lipid structural
      specificity similar to that required for their recognition by Edg receptors. LPA
      and S1P increased the Tsup-1 cell level of immunoreactive HB-EGF, and
      neutralizing antibodies to HB-EGF inhibited LPA and S1P enhancement of Tsup-1
      cell susceptibility to DT. Stabilized transfection of Tsup-1 cells with a
      combination of plasmids encoding Edg-2 plus -4 antisense mRNA suppressed the
      levels of Edg-2 and -4, but not Edg-3 and -5, in Western blots and reduced in
      parallel the increments in HB-EGF and susceptibility to DT evoked by LPA but not
      S1P. Similar transfection with Edg-3 plus -5 antisense plasmids suppressed Tsup-1
      cell levels of immunoreactive Edg-3 and -5, but not Edg-2 or -4, and concurrently
      reduced S1P-, but not LPA-, induced Tsup-1 cell increases in both HB-EGF and
      susceptibility to DT. Edg GPCR-mediated LPA and S1P enhancement of T cell
      sensitivity to DT, thus, may be attributable to increased expression of the DT
      receptor HB-EGF.

PMID- 10354367
TI  - Alloreactive cytotoxic T-cell function, peptide nonspecific.
AB  - The recognition requirements necessary for murine alloreactive cytotoxic T-cells
      to carry out their effector function has been investigated using target cells
      that express a unique class I major histocompatibility complex (MHC)-peptide
      pair. The human cell line T2 and the murine cell line RMA-S are defective in
      peptide transport components needed to effectively express stable MHC class I
      molecules at the cell surface. When T2 cells were infected with a vaccinia virus
      that encoded the Kd gene and provided with a Kd-motif peptide from the
      nucleoprotein of influenza virus (NPP), these cells could be lysed by polyclonal
      allo Kd-reactive cytotoxic T-lymphocytes (CTL). Similar results were obtained
      with the murine RMA-S-Kd cell line, transfected with cDNA able to express some
      'empty' Kd that is heat-labile. Adding another Kd-motif peptide from influenza
      virus haemagglutinin (HAP) stabilized the surface expression of Kd and allowed
      the RMA-S-Kd cells to be lysed before or after heat shock. At 27 degrees C anti
      Kd alloreactive CTL-lysed target cells in the presence and absence of HAP
      peptide. Alloreactive CTL appear to have a more stringent requirement for a high
      density of MHC class I on cell surfaces relative to peptide-specific MHC
      restricted CTL. We conclude that while Kd-restricted CTL activity is strictly
      peptide-specific, anti-Kd-specific alloreactivity is MHC allele-specific, but
      peptide-nonspecific. This conclusion is at odds with the Standard Model of T-cell
      receptor (TCR) function, but consistent with the predictions of a Competing Model
      of TCR function.

PMID- 10354368
TI  - The standard model of T-cell receptor function: a critical reassessment.
AB  - The Standard Model of T-cell receptor (TCR) function is the distillation of many
      views. Here we provide a summary that is intended to capture the flavour of the
      whole, without assigning particular blame, or credit, to any one part. The
      Standard Model is based on the notion of a single TCR-combining site that sums
      the binding contributions of MHC and peptide to produce a single signal to the T
      cell. How this signal is interpreted can vary with the state of the T cell. A
      growing number of creaks in the tweaks needed to maintain the Standard Model
      suggest that it may be timely to make a critical reassessment of the facts and
      their interpretation. The result of this effort has been to uncover a long
      overlooked fact that T cells do not recognize hybrid class II major
      histocompatibility complex alleles; they recognize only those haplotypes directly
      associated with each alpha- or beta- subunit of class II. Our attempts to tweak
      the Standard Model to deal with lack of recognition of hybrid class II alleles
      led us, by surprise, to a quite different framework with which to view TCR
      function.

PMID- 10354369
TI  - Bacillus thuringiensis Cry1Ac protoxin is a potent systemic and mucosal adjuvant.
AB  - Recently we demonstrated that recombinant Cry1Ac protoxin from Bacillus
      thuringiensis is a potent systemic and mucosal immunogen. In this study we
      compared the adjuvant effects of Cry1Ac and cholera toxin (CT) for the hepatitis
      B surface antigen (HBsAg) and bovine serum albumin (BSA). The antibody responses
      of intestinal secretions and serum were determined by ELISA in Balb/c mice
      immunized through the intragastric (IG) or intraperitoneal (IP) routes. When
      HBsAg was administered via IG, the anti-HBsAg intestinal response was not
      enhanced by either Cry1Ac or CT, whereas via IP Cry1Ac increased the anti-HBsAg
      intestinal immunoglobulin (Ig)G response and CT increased the intestinal IgA and
      IgM responses. Serum anti-BSA antibodies increased when BSA was co-administered
      with CT or Cry1Ac by both routes. Cholera toxin and Cry1Ac co-administered via IP
      increased the IgG anti-BSA response in fluid of the large intestine and CT also
      increased the IgA and IgM responses slightly. When co-administered via IP, CT and
      Cry1Ac did not affect the IgG anti-BSA response of the small intestine
      significantly. We conclude that Cry1Ac is a mucosal and systemic adjuvant as
      potent as CT which enhances mostly serum and intestinal IgG antibody responses,
      especially at the large intestine, and its effects depend on the route and
      antigen used. These features make Cry1Ac of potential use as carrier and/or
      adjuvant in mucosal and parenteral vaccines.

PMID- 10354370
TI  - Irregular cytokine pattern of CD4+ T lymphocytes in response to Staphylococcus
      aureus in patients with Wegener's granulomatosis.
AB  - The initial stage of Wegener's Granulomatosis (WG) is often marked by symptoms of
      infection and it has been postulated that a bacterial infection could be the
      aetiologic factor of this disease. The objective of our work was to investigate T
      cell-mediated immunity in WG by testing proliferative responses on bacterial
      antigens and particularly Staphylococcus aureus. We investigated the bulk
      proliferative response of peripheral blood lymphocytes (PBL) from patients with
      clinically active WG to gram-positive bacteria and purified proteinase 3 (PR-3),
      the major target antigen of c-ANCA. We generated S. aureus-specific PBL-derived T
      cell lines and T-cell clones (TLC). In two WG patients 27 TLC were characterized
      in terms of reactivity to bacterial antigens/PR-3, phenotype, HLA class II
      restriction and pattern of cytokine secretion. Compared to coagulase-negative
      Staphylococci and beta-haemolytic Streptococci A, reactivity to S. aureus was
      significantly increased in all patients with WG. Using purified PR-3, we found a
      PBL proliferation in five out of 25 WG patients. The TLC were S. aureus-specific
      and did not cross-recognize Streptococci or coagulase-negative Staphylococci. The
      S. aureus-specific TLC were of the alphabeta-TCR+ CD4+ phenotype and HLA-DR
      restricted. These TLC predominantly showed a Th2-type of cytokine secretion.
      Interestingly, seven of the S. aureus-reactive TLC also recognized the PR-3
      antigen. From these data we conclude that Staphylococci-specific HLA-DR
      restricted CD4+ T cells may play a key role in the initial triggering of immune
      responses in WG.

PMID- 10354372
TI  - Characterization of subpopulations of T-cell receptor intermediate (TCRint) T
      cells.
AB  - CD1-autoreactive T cells of two types have been demonstrated among T cells
      expressing the T-cell receptor (TCR) alphabeta at intermediate levels (TCRint
      cells). One type constitutes a major fraction of the natural killer (NK)1.1+
      TCRint population in C57BL/6 (B6) mice and carries a restricted TCR composed of
      an alpha-chain with an invariant Valpha14-J281 rearrangement, and a beta-chain
      using Vbeta8. 2, 7 or 2. The second type utilises a variety of TCR and was
      derived from CD4+ cells in mice lacking MHC class II. To increase our
      understanding of the two different CD1-reactive subsets, we have investigated and
      compared the populations of origin: NK1.1+ and NK1. 1- TCRint subsets from MHC
      class II-deficient mice and CD4+NK1.1+ T cells from B6 mice. The three TCRint
      populations shared a phenotype indicating previous activation, and contained low
      frequencies of cells expressing NK receptors of the Ly49 family. In contrast to
      control CD4+ cells, the three TCRint subsets produced high amounts of interleukin
      (IL)-4 and interferon (IFN)-gamma after activation. Importantly, no IL-10 could
      be detected in either TCRint population, implying a distinct function for these
      cells, different from those of conventional CD8+ and CD4+ cells, including the
      typical T-helper 2 (Th2) cell. Analysis of TCR expression indicated that the
      proportion of cells using the semi-invariant Valpha14/Vbeta8.2-type TCR was lower
      in NK1.1+ cells from MHC class II-negative mice than in CD4+NK1.1+ B6 cells.
      Further, usage of the Valpha14-J281 rearrangement was also demonstrated among
      NK1.1- TCRint cells.

PMID- 10354371
TI  - Characterization of the three immunoglobulin G subclasses of macaques.
AB  - Southern blot experiments with genomic DNA samples of rhesus monkeys and crab
      eating macaques and human C gamma-specific probes indicated that the two macaque
      species studied here possessed three C gamma genes per haploid genome. By
      amplifying the cDNA from macaque-mouse hybridomas, the coding sequences of two
      different rhesus monkey immunoglobulin (Ig)G subclasses, IgG1rh (Cgamma1rh) and
      IgG2rh (Cgamma2rh), and one crab-eating macaque IgG subclass IgG1mafa
      (Cgamma1mafa), were characterized. None of the 16 rhesus monkey-mouse hybridomas
      studied here secreted IgG of the third subclass IgG3rh (Cgamma3rh). The Cgamma3rh
      gene was partly characterized at the genomic level. The cDNA of the Cgamma3rh
      gene was amplified from mRNA of rhesus monkey peripheral blood mononuclear cells
      (PBMC). The results are analysed in terms of phylogenesis of the C gamma genes.
      The cDNA sequences coding for the Cmu and the Ckappa domains of rhesus monkey Ig
      were established and compared to their human and non-human primate counterparts.

PMID- 10354373
TI  - Protein-protein interactions between native Ro52 and immunoglobulin G heavy
      chain.
AB  - Using a yeast two-hybrid system to search for proteins interacting with Ro52
      autoantigen, we identified a novel protein-protein interaction. Two different
      cDNA clones, which interacted with Ro52 in the yeast two-hybrid system, were
      identified and isolated from a human B-cell library. Surprisingly, both clones
      encoded the heavy chain of human IgG1. The expression of both HIS3 and beta
      galactosidase reporter genes in yeast suggested that the interaction between Ro52
      and IgG occurred in vivo. In vitro studies utilizing recombinant Ro52 and
      purified immunoglobulins indicated that the interaction was immunoglobulin class
      and subclass specific. Ro52 interacted with IgG1 and IgG4, but not with IgG2,
      IgG3, IgA or IgM. Ro52 could also precipitate IgG directly from serum. The
      identified cDNA clones did not include the variable region of IgG, which
      suggested a non-classical interaction independent of antibody specificity. We
      further mapped the domain of Ro52 responsible for this interaction to the C
      terminus rfp-like region. In conclusion, our data support an unusual interaction
      between native Ro52 and IgG. The potential biological significance of this
      unusual protein-protein interaction is discussed.

PMID- 10354374
TI  - Possible role of interleukin-10 in autoantibody production and in the fate of
      human cord blood CD5+ B lymphocytes.
AB  - Mononuclear cell subsets in 25 human umbilical cord blood samples and 10 healthy
      adults were studied. We found a decreased percentage of CD3+ cells, CD8+ cells
      and gammadelta T cells in cord blood compared with blood from healthy adults. The
      CD16+56+ and CD19+CD5+ phenotypes were overexpressed in cord blood. We then
      measured spontaneous gene expression and the production of interleukin-10 in
      mononuclear cells from cord blood and adult subjects. Although we found no
      difference between cord blood cells and those from healthy adults, a tendency
      towards spontaneous interleukin-10 production was observed in cord blood. Phorbol
      12-myristate 13-acetate stimulation revealed that, among lymphocytes, cord blood
      B cells are the main cellular source of interleukin-10. Finally, we found no
      evidence of augmented spontaneous apoptosis but an increased bcl-2 gene
      expression in non-T cells from cord blood. Interleukin-10 might protect CD19+CD5+
      B cells from apoptosis by inducing bcl-2 and promoting autoantibody production in
      this B-cell subpopulation.

PMID- 10354375
TI  - Interaction between B.7 and CD28 costimulatory molecules is essential for the
      activation of effector function mediating spontaneous tumour regression.
AB  - The spontaneous regression of a rat histiocytoma, AK-5, is mediated by activated
      natural killer cells through antibody-dependent cellular cytotoxicity. In
      addition to the Fc-FcR interaction between the target and the effector cells
      demonstrated previously, we show the participation of costimulatory molecules B7
      and CD28 in the efficient killing of the tumour cell. Blockade of the
      costimulatory interaction in vivo using anti-CD28 led to increased tumour growth
      and a suppressed cytokine response. Anti-CD28 antibody administration in vivo
      also diminished the cytotoxic potential of NK cells against AK-5 cells in vitro.
      Our studies also demonstrate the expression of B7.1 and B7.2 antigen on AK-5
      tumour cells. The cytotoxic activity of natural killer cells was significantly
      inhibited when the effector/target cells were cultured in the presence of
      antibodies raised against B7.1, B7.2 and CD28. Administration of anti-CD28 in
      vivo also affected the efficiency of the formation of effector/target conjugates
      in vitro. Similarly, anti-CD28 injections affected expression of the adhesion
      molecules LFA 1 and ICAM 1 by splenocytes. Administration of anti-B7.1 and B7. 2
      antibodies in AK-5 tumour-bearing animals showed a differential response. The
      cytotoxicity of natural killer cells was significantly inhibited after anti-B7.2
      administration, suggesting the preferential participation of B7.2 molecules in
      vivo. These observations suggest an important role for B7-CD28 interaction in AK
      5 tumour regression.

PMID- 10354376
TI  - Haematopathology of 'Sjogren-mice': histopathological changes in spleens after
      semiallogeneic cell transfer.
AB  - Haematopoietic transplantation chimeras may be readily produced in adult mice,
      using F1-hybrids of selected inbred strains as recipients and mice from one of
      the parental strains as donors. We transplanted spleen cells from BALB/c donors
      into nonirradiateded F1-hybrids of BALB/c and CBA/H-T6. Both female and male
      recipients developed a primary Sjogren's syndrome-like exocrinopathy without
      signs of kidney disease. At long-term follow-up, 7(1/2) months after cell
      transfer, lymph nodes were enlarged, and spleens were diminished and irregular in
      shape. In general, changes in haematopoietic organs were more prominent in males.
      The results verify that although hybrid mice of either sex develop glandular
      manifestations comparable with primary Sjogren's syndrome, when the immune system
      is stimulated by semiallogeneic immunocytes, the evoked reactions in
      haematopoietic tissues show gender difference.

PMID- 10354377
TI  - A human whole-blood assay for analysis of T-cell function by quantification of
      cytokine mRNA.
AB  - A whole blood assay was developed for T-lymphocyte analysis which allows the
      quantification of induced cytokine mRNA expression. We applied a novel kinetic
      reverse transcription polymerase chain reaction method which directly measures
      product accumulation using Taqman technology. Quantitative results were obtained
      by using beta-actin and cytokine standard curves generated from synthetic
      external standards. Since quantification relies on threshold cycles for
      fluorescence detection (Ct), this technique proved to be accurate over a dynamic
      range of at least five orders of magnitude. To evaluate the method a study was
      undertaken to find optimal conditions for whole-blood stimulation with soluble
      anti-CD3 monoclonal antibodies in the presence of a costimulatory signal mediated
      by anti-CD28 monoclonal antibody. Therefore, whole blood was taken from healthy
      individuals (n = 10) and aliquots for mRNA measurement were withdrawn after 0, 4,
      8 and 24 h of stimulation. Optimal assay conditions were reached with 1 : 10
      diluted heparinized whole blood and after stimulation with equimolar amounts of
      anti-CD3 and anti-CD28 monoclonal antibodies (1 microgram/ml). Interferon-gamma
      and tumour necrosis factor-alpha proved to be early response cytokines with peak
      expression at 4 h. In contrast, interleukin (IL)-2, IL-4 and IL-10 required 8 h
      of stimulation. This novel whole-blood assay is potentially useful for monitoring
      T-cell-specific immune functions in a variety of clinical settings. Using whole
      blood obviates the need for T-cell purification and may therefore closely
      approximate the state of responsiveness of circulating T cells in vivo.

PMID- 10354378
TI  - Interferon-gamma- and tumour necrosis factor-alpha-producing cells in humans who
      are immune to cutaneous leishmaniasis.
AB  - Individuals infected with Leishmania major usually acquire immunity to cutaneous
      leishmaniasis. In this study we have investigated peripheral blood mononuclear
      cells (PBMC) stimulated by Leishmania antigens in two groups of Sudanese
      individuals, one with a history of cutaneous leishmaniasis and one living in an
      area without the disease. The production of interferon (IFN)-gamma, tumour
      necrosis factor (TNF)-alpha and interleukin (IL)-10 was investigated in culture
      supernatants, and the cellular sources of IFN-gamma and TNF-alpha were
      identified. Cells from individuals with a history of cutaneous leishmaniasis
      produced significantly higher levels of IFN-gamma and TNF-alpha than cells from
      individuals without a history of the disease. Similar levels of IL-10 were found
      in the two groups. Flow cytometric analysis revealed high numbers of CD3+ cells
      producing IFN-gamma and TNF-alpha, and only a few CD3+ cells containing IL-10, in
      the PBMC cultures from the individuals with a history of cutaneous leishmaniasis.
      Interferon-gamma and TNF-alpha were predominantly produced by CD4+ T cells rather
      than CD8+ T cells. The results suggest that cellular immunity against cutaneous
      leishmaniasis is mediated predominantly through antigen-specific CD4+ T cells in
      individuals with a history of cutaneous leishmaniasis.

PMID- 10354379
TI  - Biological properties of interferon-alpha produced Ex vivo by whole blood of
      patients infected by human immunodeficiency virus-1.
AB  - We investigated the biological properties of interferon (IFN)-alpha produced by
      Sendai virus (SV)-activated whole blood cultures in 20 patients infected with
      human immunodeficiency virus (HIV)-1 and 24 healthy controls. Supernatants of
      cultures were assayed for IFN-alpha by using an immunological method (DELFIA),
      biological methods and an in-vitro MxA induction assay. The levels of
      intracellular MxA protein were detected by an immunochemiluminescence assay. The
      levels of IFN-alpha in patients measured by DELFIA were significantly lower than
      those in healthy controls (P < 0.0001), but the antiviral activity of IFN-alpha
      in patients infected with HIV-1 was lower than predicted from DELFIA. The IFN
      alpha produced by cells of patients infected with HIV-1 was able to induce MxA
      protein in human amnions WISH cells but was unable to protect these cells against
      Vesicular Stomatitis Virus (VSV)-induced cytopathic effects. A relative increased
      capability to induce the production of MxA protein in vitro was observed with the
      IFN-alpha contained in culture supernatant of virus-activated whole blood of HIV
      1-infected patients with increased levels of MxA in their peripheral blood. These
      data suggest that biological properties of IFN-alpha produced in the course of
      HIV-1 infection are different from those observed with IFN-alpha of healthy
      subjects.

PMID- 10354380
TI  - Prevention of transfusion-transmitted cytomegalovirus infection.
AB  - Cytomegalovirus (CMV) is a double-stranded DNA virus which can be transmitted by
      blood transfusion. Its seroprevalence in adults ranges from 40% to 100% depending
      on geographical and socioeconomic conditions. Seropositive individuals have
      latent CMV infection with viral DNA present in peripheral blood leucocytes. CMV
      can be associated with considerable morbidity and mortality in susceptible
      individuals, e.g. CMV-seronegative bone marrow allograft patients. Evidence, from
      a number of reports, suggests that provision of leucodepleted blood components
      may be as effective as the use of components from CMV-seronegative donors in
      preventing CMV infection and disease. This is relevant in the UK because Blood
      Transfusion Services are implementing universal leucodepletion of cellular blood
      components to minimize the theoretical risk of transmission of new variant
      Creutzfeldt-Jakob disease. This review examines data on the biology of CMV,
      discusses options for testing and summarizes the impact of CMV-seronegative and
      leucodepleted blood components on transfusion-transmitted CMV.

PMID- 10354382
TI  - Evaluation of iron status of Finnish blood donors using serum transferrin
      receptor.
AB  - The maximum allowable frequency of blood donations has been set so that donations
      should not cause anaemia or depletion of iron stores. However, it has not been
      determined precisely how often blood donations result in depletion of iron
      stores. In the present study we have evaluated iron status in blood donors using
      serum ferritin and transferrin receptor (TfR) concentrations. The elevation of
      serum TfR has been reported to be the most sensitive indicator of depletion of
      iron stores. On the basis of ferritin values, in men who donate frequently the
      amount of body iron is reduced to a level very close to that found in women
      donating blood for the first time. When an elevation of serum TfR above 4.0 mg L
      1 was used as a stringent definition of complete iron depletion, it was estimated
      that 17% of frequently donating women had completely lost their iron stores,
      while the corresponding value for men was 8%. The fact that a considerable
      proportion of the female blood frequent donors have completely depleted their
      iron stores raises the question whether the iron status of female frequent blood
      donors should be routinely monitored using serum transferrin receptor
      measurements.

PMID- 10354381
TI  - Inflammatory cytokines and their receptors in arterial and mixed venous blood
      before, during and after infusion of drained untreated blood.
AB  - Wound blood for postoperative autologous transfusion is drained through an area
      of damaged tissue, the surgical wound, and contains inflammatory mediators. The
      inflammatory cytokines interleukin-1-beta (IL-1beta), interleukin-6 (IL-6),
      interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) and their
      modulators interleukin-1-receptor antagonist (IL-1Ra), interleukin 6 soluble
      receptor (IL-6sR), soluble tumour necrosis factor receptor 1 (sTNF-R1) and
      interleukin 10 (IL-10), together with white cell count (WCC) and white cell
      differential count were measured in arterial and mixed venous blood before,
      during and after infusion of postoperatively drained untreated blood in nine
      patients operated for thoracic scoliosis. We found a transient increase in IL-6,
      an increase in TNF-RI, an increase in IL-8 with granulocytosis and a decrease in
      IL-10 in the systemic circulation. The increase in IL-6 was higher in mixed
      venous than in arterial blood.

PMID- 10354383
TI  - A home blood transfusion programme for beta-thalassaemia patients.
AB  - Although home transfusion programmes are relatively common in the USA (Anon,
      1990, Home Care in the 1990s. Council on Scientific Affairs. Journal of the
      American Medical Association, 263, 1241-1244), this type of treatment has only
      recently been considered in Britain and, where it is in operation, is generally
      supervised by trained nursing staff or via a hospice. North Middlesex Hospital
      now has 3 years experience of a home transfusion programme operating for beta
      thalassaemia major patients, in which relatives are trained and responsible for
      supervision of the red-cell transfusions at home. For families who request this
      service, and who are willing and able to undertake it responsibly, the scheme
      offers the advantages of improved patient comfort, reduced absences from
      education or employment and reduced hospital bed usage. Patients and their carers
      express improved satisfaction with the treatment delivered in this way.

PMID- 10354384
TI  - The swirling phenomenon in stored platelets is influenced by their endogenous
      serotonin.
AB  - The presence of the swirling phenomenon is useful to define platelet concentrates
      that are suitable for transfusion. If it is possible to identify donor-related
      factors which are related to persisting swirling during storage, it is possible
      to select platelet donors. Endogenous platelet serotonin content is stable and
      easily measured and related to agonist-induced serotonin secretion. During a 3
      month period, the swirling in 825 single donor platelet concentrates was
      controlled before issue. Endogenous serotonin, % serotonin release and swirling
      were tested in 21 concentrates with poor or no swirling during storage. Sixty
      three concentrates were randomly selected from the routinely prepared platelet
      concentrates and were routinely tested with the same analyses on days 1 and 7. To
      evaluate an obvious effect of endogenous serotonin on the swirling phenomenon,
      eight platelet concentrates prepared from buffy coat, each from four donors, were
      divided. One part was stored in the presence of 8.5 micromol serotonin L-1, and
      analysed as the control concentrates. The endogenous serotonin content in the
      'low- swirling' concentrates was significantly lower than in the control group (P
      < 0.001). PCO2 and pH were significantly lower, and PO2 and MPV significantly
      higher than in the controls. In the control group, swirling after 7 days was
      significantly correlated with serotonin release. In the eight buffy-coat
      concentrates enriched in endogenous serotonin, both swirling and the percentage
      serotonin release were improved after storage for 10 days, compared with
      nonenriched concentrates. This study suggests that endogenous serotonin content
      and serotonin release are factors that may be of significance concerning
      preservation of the swirling phenomenon in platelet concentrates during storage.

PMID- 10354385
TI  - Preanalytical requirements for flow cytometric evaluation of platelet activation:
      choice of anticoagulant.
AB  - Accurate assessment of in vivo or in vitro platelet activation requires optimal
      preanalytical conditions to prevent artefactual in vitro activation of the
      platelets. The choice of anticoagulant is one of the critical preanalytical
      conditions as anticoagulants exert different effects on the activation of
      platelets ex vivo. We tested the effectiveness of Diatube-H (also known as CTAD;
      sodium citrate, theophylline, adenosine and dipyridamole) and citrate vacutainer
      tubes in preventing artefactual activation of platelets and preserving functional
      reserve. Platelet surface expression of the CD62P (reflecting alpha granule
      release), CD63 (reflecting lysosomal release) and modulation of normal platelet
      membrane glycoproteins CD41a and CD42b, were measured in whole blood and in
      isolated platelets immediately after collection and at 6, 24 and 48 h after
      venipuncture. Samples taken into Diatube-H showed less spontaneous platelet
      activation than did those taken into citrate. To measure in vitro platelet
      functional reserve, thrombin was added as agonist to blood stored for varying
      periods up to 48 h. Although Diatube-H suppressed in vitro platelet activation
      for up to 4 h, in samples kept for 6-24 h before thrombin addition, the
      inhibitory effect was lost and platelets responded fully to agonist activation.
      Hence, Diatube-H preserved platelets and allowed for measurement of in vivo
      platelet activation as well as thrombin-induced in vitro platelet activation
      after 6-24 h, in both whole blood and isolated platelets.

PMID- 10354386
TI  - Use of a phycoerythrin-conjugated anti-glycophorin A monoclonal antibody as a
      double label to improve the accuracy of FMH quantification by flow cytometry.
AB  - The use of flow cytometry for quantifying fetomaternal haemorrhage is increasing,
      and has been shown to be more accurate than the Kleihauer-Betke test for
      evaluating larger bleeds of over 4 mL in volume. Red cells are stained with
      fluorescently labelled monoclonal anti-D. Cells for analysis are normally gated
      manually on the basis of forward and side scatter. We investigated whether the
      use of an antiglycophorin A monoclonal antibody conjugate (red cell specific) in
      a dual labelling technique would improve the gating of RBC and FMH
      quantification. Mixes of adult rr and cord R1r RBC were prepared to simulate 1,
      0.5, 0.25, 0.12 and 0.06% fetal bleeds. Phycoerythrin-conjugated BRIC 256 (mouse
      monoclonal antiglycophorin A) was used to label all RBC, and FITC-BRAD-3
      monoclonal anti-D was used to determine the proportion of D-positive cells.
      Results from the dual labelling experiments were compared to those from single
      labelling of the same mixtures with FITC-BRAD-3 alone, using gated and ungated
      data. The results showed that single labelling with manual gating gave falsely
      low FMH estimates. We conclude that use of a fluorescently labelled
      antiglycophorin A antibody improves the accuracy of the FMH measurement by flow
      cytometry, as manual subjective gating of RBC excludes a higher proportion of
      fetal than of adult RBC.

PMID- 10354387
TI  - Fine specificities of murine anti-Mg monoclonal antibodies.
AB  - The specificities of two murine anti-Mg monoclonal IgG1 antibodies, 3B10 and 2D5,
      were determined by pepscan analysis. The peptides which correspond to various
      fragments of amino-terminal portions of glycophorin A of group M (GPA-M), N (GPA
      N) and Mg (GPA-Mg), and replacement analogues of some of these peptides, were
      synthesized on plastic pins and tested for binding of the antibodies. Both
      antibodies bound strongly to the N-terminal Mg octapeptide 1LSTNEVAM8, but they
      showed different subspecificities. The essential fragment of the epitope 2D5 are
      amino acid residues 2STNEV6. Replacement of any of these amino acid residues by
      Ala, and replacement of Glu5 residue by Gly, abolished or strongly reduced the
      antibody binding, but replacement of Asn4 by Thr gave only a moderate decrease of
      peptide activity. In contrast, the Leu1 and Asn4 residues were most essential
      components of the epitope 3B10, while Ser2, Thr3 and Glu5 seemed to be less
      important. Our present results and earlier ones on the specificity of human anti
      Mg alloantibodies and monoclonal anti-M/Mg antibodies showed that antibodies
      reacting with Mg antigen recognize different fragments and/or different amino
      acid residues of the amino- terminal nonglycosylated domain of GPA-Mg. The
      knowledge of fine specificities of antibodies reacting with Mg antigen is
      interesting in view of the presence of anti-Mg alloantibodies in 1-2% of human
      sera.

PMID- 10354389
TI  - Transfusion-related acute lung injury.

PMID- 10354390
TI  - Pitted keratolysis of the palm arising after herpes zoster.

PMID- 10354388
TI  - Glycophorin A mutation Ala65 --> Pro gives rise to a novel pair of MNS alleles
      ENEP (MNS39) and HAG (MNS41) and altered Wrb expression: direct evidence for
      GPA/band 3 interaction necessary for normal Wrb expression.
AB  - We report here a novel Glycophorin A (GPA) mutation Ala65 --> Pro which gives
      rise to a low-incidence antigen HAG, lack of a high-incidence antigen ENEP and
      aberrant expression of the high-incidence Wrb antigen. Anti-ENEP was identified
      in the serum of a transfused male patient (E.H.) who was homozygous for a GPA
      Ala65 --> Pro mutation and possessed a novel low-incidence antigen which we have
      called HAG. An unrelated HAG-positive individual, heterozygous for the Ala65 -->
      Pro mutation, has also been identified. Anti-HAG was present in several
      multispecific antisera to low-incidence antigens and in one monospecific serum.
      Normal expression of the Wrb antigen depends on the presence of amino acid Glu658
      of band 3 and on the presence of GPA. However, a specific epitope on GPA has not
      previously been implicated. DNA sequence analysis of band 3 from patient E.H. was
      normal in the region of Wra/Wrb polymorphism with homozygous presence of Glu658
      and therefore the abnormal Wrb expression results from the Ala65 --> Pro mutation
      in GPA. The ENEP and HAG antigens have been assigned the MNS blood group system
      numbers 002.039 and 002.041, respectively, by the ISBT Working Party on
      Terminology for Red Cell Surface Antigens.

PMID- 10354391
TI  - Eosinophilic fasciitis associated with autoimmune thyroid disease and
      myelodysplasia treated with pulsed methylprednisolone and antihistamines.

PMID- 10354392
TI  - The common haemochromatosis mutation does not increase the risk of thrombosis in
      patients with factor V Leiden.

PMID- 10354393
TI  - Plasma membrane bound transglutaminase in the marginal zone of psoriatic skin.

PMID- 10354394
TI  - Highly potent cyclic disulfide antagonists of somatostatin.
AB  - The search for synthetic analogues of somatostatin (SRIF) which exhibit selective
      affinities for the five known receptor subtypes (sst1-5) has generated a large
      number of potent agonist analogues. Many of these agonists display good subtype
      selectivities and affinities for the subtypes 2, 3, and 5, with very few
      selective for sst1 or sst4. Until the recent report by Bass and co-workers (Mol.
      Pharmacol. 1996, 50, 709-715; erratum Mol. Pharmacol. 1997, 51, 170), no true
      antagonists of somatostatin had been discovered, let alone any displaying
      differential receptor subtype selectivity. In this present study, we further
      explore the effect of this putative L,5D6 antagonist motif on somatostatin
      octapeptide analogues with a cyclic hexapeptide core. The most potent antagonist
      found to date is H-Cpa-cyclo[DCys-Tyr-DTrp-Lys-Thr-Cys]-Nal-NH2, PRL-2970 (21),
      which has an IC50 of 1.1 nM in a rat pituitary growth hormone in vitro antagonist
      assay versus SRIF (1 nM). This analogue bound to cloned human somatostatin
      subtype 2 receptors with a Ki of 26 nM. The highest hsst2 affinity analogue was H
      Cpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2, PRL-2915 (15), with a Ki of 12 nM
      (IC50 = 1.8 nM). This analogue was also selective for hsst2 over hsst3 and hsst5
      by factors of 8 and 40, respectively, and had no agonist activity when tested
      alone at concentrations up to 10 microM. Regression analysis of the binding
      affinities versus the observed antagonist potencies revealed high correlations
      for hsst2 (r = 0.65) and hsst3 (r = 0.52) with a less significant correlation to
      hsst5 (r = 0.40). This is quite different from the somatostatin agonist analogues
      which show a highly significant correlation to hsst2 (r > 0.9). Receptor
      selective somatostatin antagonists should provide valuable tools for
      characterizing the many important physiological functions of this neuropeptide.

PMID- 10354395
TI  - [3H]Azidodantrolene: synthesis and use in identification of a putative skeletal
      muscle dantrolene binding site in sarcoplasmic reticulum.
AB  - Dantrolene sodium is a medically important hydantoin derivative that interferes
      with release of Ca2+ from intracellular stores of skeletal muscle by an unknown
      mechanism. Identification of the molecular target of dantrolene would greatly aid
      in understanding both the mechanism of action of the drug and the dynamics of
      intracellular Ca2+ release in muscle. [3H]Azidodantrolene was designed and
      synthesized as a photoaffinity analogue in order to identify a putative
      dantrolene receptor in skeletal muscle. Introduction of 1 mole-atom of tritium
      into aldehyde 5b was required during radioligand synthesis in order to ensure
      high enough specific activity for detection of photo-cross-linked proteins by
      fluorographic methods. This was accomplished by reduction of ester 3 with custom
      synthesized, 100% tritium-labeled lithium triethylborotritide, followed by
      oxidation to 5b by manganese(IV) oxide. Compound 6b was demonstrated to be >/=95%
      tritium-labeled at the imine position by NMR spectroscopy, and the specific
      radioactivity of [3H]azidodantrolene sodium was empirically determined by HPLC
      and liquid scintillation counting to be 24.4 Ci/mmol, approximately 85% of
      theoretical maximum. [3H]Azidodantrolene was found to be pharmacologically active
      in ligand-receptor binding studies with skeletal muscle sarcoplasmic reticulum
      membranes. Photo-cross-linking experiments analyzed by SDS-PAGE and tritium
      fluorography have identified a approximately 160-kDa specifically labeled protein
      as the putative, intracellular, skeletal muscle dantrolene receptor. This
      photolabeled protein comigrates with a protein in Western blots immunologically
      cross-reactive to a polyclonal anti-rabbit skeletal muscle ryanodine receptor
      antibody. Thus, the putative dantrolene receptor may be related to the skeletal
      muscle ryanodine receptor.

PMID- 10354396
TI  - 1-Benzopyran-4-one antioxidants as aldose reductase inhibitors.
AB  - Starting from the inhibitory activity of the flavonoid Quercetin, a series of 4H
      1-benzopyran-4-one derivatives was synthesized and tested for inhibition of
      aldose reductase, an enzyme involved in the appearance of diabetic complications.
      Some of the compounds obtained display inhibitory activity similar to that of
      Sorbinil but are more selective than Quercetin and Sorbinil with respect to the
      closely related enzyme, aldehyde reductase, and also possess antioxidant
      activity. Remarkably, these compounds possess higher pKa values than carboxylic
      acids, a characteristic which could make the pharmacokinetics of these compounds
      very interesting. Molecular modeling investigations on the structures of
      inhibitors bound at the active site of aldose reductase were performed in order
      to suggest how these new inhibitors might bind to the enzyme and also to
      interpret structure-activity relationships.

PMID- 10354397
TI  - Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a potential substrate for new aldose
      reductase inhibitors.
AB  - The isoxazolo-[3,4-d]-pyridazin-7-(6H)-one (2) and its corresponding open
      derivatives 5-acetyl-4-amino-(4-nitro)-6-substituted-3(2H)pyridazinones (3, 4)
      were used as simplified substrates for the synthesis of new aldose reductase
      inhibitors with respect to the previously reported 5, 6-dihydrobenzo[h]cinnolin
      3(2H)one-2 acetic acids (1). Moreover, a few derivatives lacking the 5-acetyl
      group were prepared. Several compounds derived from 2 displayed inhibitory
      properties comparable to those of Sorbinil. In this class the presence at
      position 6 of a phenyl carrying an electron-withdrawing substituent proved to be
      beneficial, independently from its position on the ring (5g,j-l). Acetic acid
      derivatives were more effective than propionic and butyric analogues. On the
      contrary, all the monocyclic compounds (6-8) were either inactive or only weakly
      active. The 3-methyl-4-(p-chlorophenyl)isoxazolo-[3,4-d]-pyridazin-7-(6H )-one
      acetic acid (5g), which proved to be the most potent derivative, was also
      investigated in molecular modeling studies, to assess possible similarities in
      its interaction with the enzyme, with respect to the model 1.

PMID- 10354398
TI  - Lamellarin alpha 20-sulfate, an inhibitor of HIV-1 integrase active against HIV-1
      virus in cell culture.
AB  - HIV-1 integrase is an attractive target for anti-retroviral chemotherapy, but to
      date no clinically useful inhibitors have been developed. We have screened
      diverse marine natural products for compounds active against integrase in vitro
      and found a series of ascidian alkaloids, the lamellarins, that show selective
      inhibition. A new member of the family named lamellarin alpha 20-sulfate (1), the
      structure of which was determined from spectroscopic data, displayed the most
      favorable therapeutic index. The site of action of lamellarin alpha 20-sulfate on
      the integrase protein was mapped by testing activity against deletion mutants of
      integrase. Inhibition of isolated catalytic domain was detectable though weaker
      than inhibition of full length integrase; possibly lamellarin alpha 20-sulfate
      binds a site composed of multiple integrase domains. Lamellarin alpha 20-sulfate
      also inhibited integration in vitro by authentic HIV-1 replication intermediates
      isolated from infected cells. Lamellarin alpha 20-sulfate was tested against wild
      type HIV using the MAGI indicator cell assay and found to inhibit early steps of
      HIV replication. To clarify the inhibitor target, we tested inhibition against an
      HIV-based retroviral vector bearing a different viral envelope. Inhibition was
      observed, indicating that the HIV envelope cannot be the sole target of
      lamellarin alpha 20-sulfate in cell culture. In addition, these single round
      tests rule out action against viral assembly or budding. These findings provide a
      new class of compounds for potential development of clinically useful integrase
      inhibitors.

PMID- 10354399
TI  - Quantitative structure-activity relationship of human neutrophil collagenase (MMP
      8) inhibitors using comparative molecular field analysis and X-ray structure
      analysis.
AB  - A set of 90 novel 2-(arylsulfonyl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxylates
      and -hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil
      collagenase (MMP-8) was designed, synthesized, and investigated by 3D-QSAR
      techniques (CoMFA, CoMSIA) and X-ray structure analysis. Docking studies of a
      reference compound are based on crystal structures of MMP-8 complexed with
      peptidic inhibitors to propose a model of its bioactive conformation. This model
      was validated by a 1. 7 A X-ray structure of the catalytic domain of MMP-8. The
      3D-QSAR models based on a superposition rule derived from these docking studies
      were validated using conventional and cross-validated r2 values using the leave
      one-out method, repeated analyses using two randomly chosen cross-validation
      groups plus randomization of biological activities. This led to consistent and
      highly predictive 3D-QSAR models with good correlation coefficients for both
      CoMFA and CoMSIA, which were found to correspond to experimentally determined MMP
      8 catalytic site topology in terms of steric, electrostatic, and hydrophobic
      complementarity. Subsets selected as smaller training sets using 2D fingerprints
      and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable
      correlation coefficients and a high predictive power. This allowed to compensate
      the weaker zinc binding properties of carboxylates by introducing optimal fitting
      P1' residues. The final QSAR information agrees with all experimental data for
      the binding topology and thus provides clear guidelines and accurate activity
      predictions for novel MMP-8 inhibitors.

PMID- 10354400
TI  - Synthesis and in vitro multidrug resistance modulating activity of a series of
      dihydrobenzopyrans and tetrahydroquinolines.
AB  - A series of dihydrobenzopyrans and tetrahydroquinolines was synthesized and
      pharmacologically tested for their ability to inhibit P-glycoprotein mediated
      daunomycin efflux in multidrug resistant CCRF-CEM vcr1000 cells. Several
      compounds exhibit activities in the range of the reference compounds verapamil
      and propafenone. Preliminary structure-activity relationship studies propose the
      importance of high molar refractivity values of the compounds and the presence of
      an additional basic nitrogen atom.

PMID- 10354401
TI  - Novel antidiabetic and hypolipidemic agents. 3. Benzofuran-containing
      thiazolidinediones.
AB  - Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2, 2,4,6,7
      pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy
      2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db
      mice. Insertion of an N-Me group into the linker between thiazolidinedione and
      substituted benzofuran pharmacophores showed considerable improvement in their
      euglycemic activity. Further improvement has been observed when a pyrrolidine
      moiety is introduced in the structure to give 5-[4-[N-[3(R/S)-5-benzyloxy-2,3
      dihydro-2,2,4,6, 7-pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidin-2-
      ylmethoxy]pheny lene]thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the
      maleate salt, compound 21a reduced the plasma glucose and triglyceride to the
      level of lean littermate, i.e. 8 +/- 1 mM, and is the most potent and efficacious
      compound reported in this series.

PMID- 10354402
TI  - 1,2,5-Oxadiazole N-oxide derivatives and related compounds as potential
      antitrypanosomal drugs: structure-activity relationships.
AB  - The syntheses of a new series of derivatives of 1,2,5-oxadiazole N-oxide,
      benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline di-N-oxide are described.
      In vitro antitrypanosomal activity of these compounds was tested against
      epimastigote forms of Trypanosoma cruzi. For the most effective drugs,
      derivatives IIIe and IIIf, the 50% inhibitory dose (ID50) was determined as well
      as their cytotoxicity against mammalian fibroblasts. Electrochemical studies and
      ESR spectroscopy show that the highest activities observed are associated with
      the facile monoelectronation of the N-oxide moiety. Lipophilic-hydrophilic
      balance of the compounds could also play an important role in their effectiveness
      as antichagasic drugs.

PMID- 10354403
TI  - Effect of A-ring modifications on the DNA-binding behavior and cytotoxicity of
      pyrrolo[2,1-c][1,4]benzodiazepines.
AB  - Several A-ring-modified analogues of the DNA-binding antitumor agent DC-81 (5)
      have been synthesized in order to study structure-reactivity/cytotoxicity
      relationships. For two molecules (23 and 30) the modifications required the
      addition of a fourth ring to give the novel dioxolo[4,5-h]- and dioxano[5,6
      h]pyrrolo[2,1-c][1, 4]benzodiazepin-11-one (PBD) ring systems, respectively.
      Another three analogues (34, 38, and 48) have the native benzenoid A-ring
      replaced with pyridine, diazine, or pyrimidine rings to give the novel
      pyrrolo[2,1-c][1,4]pyridodiazepine, pyrrolo[2,1-c][1, 4]diazinodiazepine, and
      pyrrolo[2,1-c][1,4]pyrimidinodiazepine systems, respectively. The other new
      analogues (16a,b) have extended chains at the C8-position of the DC-81 structure.
      During the synthesis of these compounds, a novel tin-mediated regiospecific
      cleavage reaction of the dioxole intermediate 18 was discovered, leading to the
      previously unknown iso-DC-81 (20). In addition, an unusual simultaneous nitration
      oxidation reaction of 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (8) was found to
      produce 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid (9), a key
      intermediate, in high yield. In general, the results of cytotoxicity and DNA
      binding studies indicated that none of the changes made to the A-ring of the PBD
      system significantly improved either binding affinity or cytotoxicity in
      comparison to DC-81. This result suggests that the superior potency of natural
      products such as anthramycin (1), tomaymycin (2), and sibiromycin (3) is due
      entirely to differences in C-ring structure, and in particular exo or endo
      unsaturation at the C2-position and C2-substituents containing unsaturation. This
      study also provided information regarding the influence of A-ring substitution
      pattern on the relative stability of the interconvertible N10-C11 carbinolamine,
      carbinolamine methyl ether, and imine forms of PBDs.

PMID- 10354404
TI  - Low-molecular-weight peptidic and cyclic antagonists of the receptor for the
      complement factor C5a.
AB  - Activation of the human complement system of plasma proteins during immunological
      host defense can result in overproduction of potent proinflammatory peptides such
      as the anaphylatoxin C5a. Excessive levels of C5a are associated with numerous
      immunoinflammatory diseases, but there is as yet no clinically available
      antagonist to regulate the effects of C5a. We now describe a series of small
      molecules derived from the C-terminus of C5a, some of which are the most potent
      low-molecular-weight C5a receptor antagonists reported to date for the human
      polymorphonuclear leukocyte (PMN) C5a receptor. 1H NMR spectroscopy was used to
      determine solution structures for two cyclic antagonists and to indicate that
      antagonism is related to a turn conformation, which can be stabilized in cyclic
      molecules that are preorganized for receptor binding. While several cyclic
      derivatives were of similar antagonistic potency, the most potent antagonist was
      a hexapeptide-derived macrocycle AcF[OPdChaWR] with an IC50 = 20 nM against a
      maximal concentration of C5a (100 nM) on intact human PMNs. Such potent C5a
      antagonists may be useful probes to investigate the role of C5a in host defenses
      and to develop therapeutic agents for the treatment of many currently intractable
      inflammatory conditions.

PMID- 10354405
TI  - Unique analogues of anandamide: arachidonyl ethers and carbamates and
      norarachidonyl carbamates and ureas.
AB  - To examine the effect of changing the amide bond of anandamide (5, AN) to a less
      hydrolyzable moiety, analogues 1a-1l, 2a-2c, 3a-3c, and 4a-4h were synthesized
      from commercially available arachidonyl alcohol or arachidonic acid and tested
      for their pharmacological activity. Arachidonyl ethers 1a-1k were obtained
      through the coupling of the arachidonyl mesylate (6) (generated from the
      mesylation of arachidonyl alcohol) with the appropriate alcohol in potassium
      hydroxide. Arachidonyl ether 1l was obtained through the phase-transfer coupling
      of arachidonyl alcohol with 2-(2-iodoethoxy)tetrahydropyran (which was generated
      from its bromide) followed by cleavage of the tetrahydropyran group with Dowex
      resin. Arachidonyl carbamates 2a-2c were obtained through the coupling of
      arachidonyl alcohol with the appropriate isocyanates. Norarachidonyl carbamates
      3a-3c and ureas 4a-4h were obtained through the coupling of the norarachidonyl
      isocyanate (generated from arachidonic acid using diphenyl phosphorazidate and
      triethylamine upon heating) with the appropriate alcohols and amines,
      respectively. AN analogues 1-3 have shown poor binding affinities to the CB1
      receptor and fail to produce significant pharmacological effect at doses up to 30
      mg/kg. Several ether analogues 1 were also evaluated in the CB2 binding assay and
      were found to be of low affinity. However, norarachidonyl urea analogues 4 have
      shown generally good binding affinities to the CB1 receptor (Ki = 55-746 nM) and
      pharmacological activity with AN-like profiles. The most potent analogue of this
      series is the 2-fluoroethyl analogue 4f which binds 2 times better than AN and
      was more active in several mouse behavioral assays. It was also observed that
      urea analogues 4a and 4g, which have weak binding affinities to the CB1 receptor
      (Ki = 436 and 347 nM, respectively), produced surprisingly potent pharmacological
      activity. These urea analogues have also shown hydrolytic stability toward the
      amidase enzymes, responsible for the primary degradation pathway of anandamide,
      in binding affinity assays in the absence of the enzyme inhibitor PMSF.

PMID- 10354407
TI  - Synthesis, calcium mobilizing, and physicochemical properties of D-chiro-inositol
      1,3,4,6-tetrakisphosphate, a novel and potent ligand at the D-myo-inositol 1,4,5
      trisphosphate receptor.
AB  - The synthesis of a novel and potent ligand at the D-myo-inositol 1,4, 5
      trisphosphate receptor (InsP3R) is described. D-chiro-Inositol 1,3, 4,6
      tetrakisphosphate (7) and L-chiro-inositol 1,3,4, 6-tetrakisphosphate (ent-7)
      have been synthesized from D-2, 5-di-O-benzyl-chiro-inositol and L-2,5-di-O
      benzyl-chiro-inositol, respectively. The potency of binding and Ca2+ release of 7
      and ent-7 were examined in L15 and Lvec cells. 7 was a full agonist at the InsP3R
      in both cells, and ent-7 was inactive. The results are compared to those from D
      myo-inositol 1,4,5-trisphosphate (1), DL-scyllo-inositol 1,2,4-trisphosphate (2),
      DL-myo-inositol 1,2,4, 5-tetrakisphosphate (3), scyllo-inositol 1,2,4,5
      tetrakisphosphate (4), D-myo-inositol 2,4,5-trisphosphate (5), and D-chiro
      inositol 1, 3,4-trisphosphate (6). The protonation processes of 7 have also been
      investigated by 31P NMR titration experiments.

PMID- 10354406
TI  - 3,7-Disubstituted-1,2,3,4-tetrahydroisoquinolines display remarkable potency and
      selectivity as inhibitors of phenylethanolamine N-methyltransferase versus the
      alpha2-adrenoceptor.
AB  - 3-Hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (4) is a more selective inhibitor
      (PNMT Ki = 1.1 microM, alpha2 Ki = 6.6 microM, selectivity (alpha2 Ki/PNMT Ki) =
      6.0) of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), with respect
      to its alpha2-adrenoceptor affinity, than is 3-methyl-1,2,3, 4
      tetrahydroisoquinoline (2; PNMT Ki = 2.1 microM, alpha2 Ki = 0.76 microM,
      selectivity = 0.36) or 1,2,3,4-tetrahydroisoquinoline (1, THIQ; PNMT Ki = 9.7
      microM, alpha2 Ki = 0.35 microM, selectivity = 0. 036). Evaluation of the O
      methyl ether derivative of 4 suggested that the 3-hydroxymethyl substituent might
      be involved in a hydrogen-bond donor-type of interaction at a sterically compact
      region in the PNMT active site. The directionality of the steric bulk tolerance
      at both the PNMT active site and the alpha2-adrenoceptor appears to be the same.
      Since the presence of a hydrophilic electron-withdrawing substituent (such as
      NO2, SO2CH3, or SO2NH2) at the 7-position of THIQ reduced the binding affinity
      toward the alpha2-adrenoceptor, we investigated the combination of both a
      hydrophilic electron-withdrawing 7-substituent and a 3-alkyl substituent on a
      THIQ nucleus. A synergistic effect in increasing the PNMT-inhibitory potency of
      the THIQ nucleus and reducing the affinity toward the alpha2-adrenoceptor was
      observed with this 3, 7-disubstitution. Remarkably, 7-aminosulfonyl-3
      hydroxymethyl-THIQ (12; PNMT Ki = 0.34 microM, alpha2 Ki = 1400 microM,
      selectivity = 4100) displayed a 23-680-fold enhanced selectivity over the parent
      compounds 27 (SK&F 29661; PNMT Ki = 0.55 microM, alpha2 Ki = 100 microM,
      selectivity = 180) and 4 (selectivity = 6.0) and is thus the most selective PNMT
      inhibitor yet reported.

PMID- 10354408
TI  - 1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent
      muscarinic M1 agonists: structure-activity relationship for 3-aryl-2-propyn-1
      yloxy and 3-aryl-2-propyn-1-ylthio derivatives.
AB  - Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes
      were synthesized and evaluated for their in vitro activity in cell lines
      transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy
      and -1-ylthio analogues substituted with halogen in the meta position showed high
      functional potency, efficacy, and selectivity toward the M1 receptor subtype. A
      quite unique functional M1 receptor selectivity was observed for compounds 8b,
      8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral
      bioavailability of about 20-30%, with the N-oxide as the only detected
      metabolite.

PMID- 10354409
TI  - New generation dopaminergic agents. 6. Structure-activity relationship studies of
      a series of 4-(aminoethoxy)indole and 4-(aminoethoxy)indolone derivatives based
      on the newly discovered 3-hydroxyphenoxyethylamine D2 template.
AB  - A series of 4-(aminoethoxy)indoles 7 and a related series of 4
      (aminoethoxy)indolones 8 were synthesized and evaluated for their affinity for
      both the high- and low-affinity agonist states (D2High and D2Low, respectively)
      of the dopamine (DA) D2 receptor. The 4-aminoethoxy derivatives (i.e., 7 and 8)
      were designed as bioisosteric analogues based on the phenol prototype 4. The
      indolones 8 were observed to have high affinity for the D2High receptor.
      Comparison of their previously reported chroman analogues with the more flexible
      4-(aminoethoxy)indoles revealed the chroman analogues to be more potent, whereas
      little loss in D2High affinity was observed when comparing the 4
      (aminoethoxy)indolones with their respective chroman analogues. Several regions
      of the phenoxyethylamine framework were modified and recognized as potential
      sites to modulate the level of intrinsic activity. A conformational analysis was
      performed and a putative bioactive conformation was proposed which fulfilled the
      D2 agonist pharmacophore criteria based on the McDermed model. Structure-activity
      relationships gained from these studies have aided in the synthesis of D2 partial
      agonists of varying intrinsic activity levels. These agents should be of
      therapeutic value in treating disorders resulting from hypo- and
      hyperdopaminergic activity, without the side effects associated with complete D2
      agonism or antagonism.

PMID- 10354410
TI  - 7alpha-Iodo and 7alpha-fluoro steroids as androgen receptor-mediated imaging
      agents.
AB  - We have synthesized several 7alpha-fluoro (F) and 7alpha-iodo (I) analogues of
      5alpha-dihydrotestosterone (5alpha-DHT) and 19-nor-5alpha-dihydrotestosterone
      (5alpha-NDHT) and tested them for binding to the androgen receptor and for their
      biological activity in an in vitro assay with cells that have been engineered to
      respond to androgens. The relative binding affinity to the androgen receptor
      determined in competition assays showed that in the androstane series the fluoro
      steroids have the highest affinity and that F-17alpha-CH3-DHT (4) has a higher
      affinity than 5alpha-DHT. All other steroids were somewhat less potent than
      5alpha-DHT with F-DHT (2) = I-17alpha-CH3-DHT (3) >/= F-NDHT (6) > F-17alpha-CH3
      NDHT (8) = I-DHT (1) >/= I-NDHT (5) > I-17alpha-CH3-NDHT (7). The relative
      biological activity in cells transfected with the androgen receptor and an
      androgen responsive reporter gene is 4 >> 5alpha-DHT > 2 > 6 > 3 >/= 1 >/= 8 >/=
      5 > 7. The iodinated compound, I-17alpha-CH3-DHT (3), with the highest binding
      activity was synthesized labeled with 125I and was shown to bind with high
      affinity, Ka = 1.9 x 10(10) L/mol, and low nonspecific binding to the androgen
      receptor in rat prostatic cytosol. However, when radiolabeled [125I]-17alpha-CH3
      DHT ([125I]3) was injected into castrated male rats, it showed very poor androgen
      receptor-mediated uptake into the rat prostate. This was unexpected in light of
      its superior receptor binding properties and its protection by the 17alpha-methyl
      group from metabolic oxidation at C-17. However, the biological potency of I
      17alpha-CH3-DHT (3) was not as high as would have been expected. When I-DHT (1)
      and I-17alpha-CH3-DHT (3) were incubated in aqueous media at 37 degrees C they
      rapidly decomposed, but they were stable at 0 degrees C. The fluorinated analogue
      4 treated similarly at 37 degrees C was completely stable. The products of the
      decomposition reaction of I-DHT (1) at 37 degrees C were identified as iodide and
      principally 17beta-hydroxy-5alpha-androst-7-en-3-one. The temperature dependence
      of this elimination reaction explains the inconsistency between the high binding
      to the androgen receptor (measured at 0 degrees C) and the low biological
      activity, as well as the poor androgen receptor mediated concentration in vivo.
      The fluorinated analogue F-17alpha-CH3-DHT (4) has both high affinity for the
      androgen receptor and high stability in aqueous media. Of the compounds tested, 4
      has the highest affinity for the androgen receptor as well as the highest
      androgenic activity. Thus it is likely that F-17alpha-CH3-DHT 4 labeled with 18F
      will be an excellent receptor-mediated diagnostic imaging agent.

PMID- 10354411
TI  - 6-Anilinouracil-based inhibitors of Bacillus subtilis DNA polymerase III:
      antipolymerase and antimicrobial structure-activity relationships based on
      substitution at uracil N3.
AB  - 6-Anilinouracils (6-AUs) are dGTP analogues which selectively inhibit the DNA
      polymerase III of Bacillus subtilis and other Gram-positive bacteria. To enhance
      the potential of the 6-AUs as antimicrobial agents, a structure-activity
      relationship was developed involving substitutions of the uracil N3 position in
      two 6-AU platforms: 6-(3,4-trimethyleneanilino)uracil (TMAU) and 6-(3-ethyl-4
      methylanilino)uracil (EMAU). Series of N3-alkyl derivatives of both 6-AUs were
      synthesized and tested for their ability to inhibit purified B. subtilis DNA
      polymerase III and the growth of B. subtilis in culture. Alkyl groups ranging in
      size from ethyl to hexyl enhanced the capacity of both platforms to bind to the
      polymerase, and with the exception of hexyl, they also significantly enhanced
      their antimicrobial potency. N3 substitution of the EMAU platform with more
      hydrophilic hydroxyalkyl and methoxyalkyl groups marginally enhanced anti
      polymerase III activity but enhanced antibacterial potency severalfold. In sum,
      the results of these studies indicate that the ring N3 of 6-anilinouracils can
      tolerate substituents of considerable size and structural variety and, thus, can
      be manipulated to significantly enhance the antibacterial potency of this novel
      class of polymerase III-specific inhibitors.

PMID- 10354412
TI  - Simplified pepstatins: synthesis and evaluation of N-terminally modified
      analogues.
AB  - The promising strategy of gastric ulcer healing with perorally administered
      epidermal growth factor (EGF) is so far strongly limited by the pepsinic
      degradation of this therapeutic polypeptide in the stomach. The incorporation of
      EGF in a bioadhesive polymer-pepsin inhibitor conjugate used as drug carrier
      matrix, however, might provide sufficient protection toward pepsinic degradation.
      The synthesis of appropriate pepsin inhibitors represents a prerequisite for the
      development of such polymer-inhibitor conjugates. The presented study
      demonstrates that modifications at the N-terminus of simplified analogues of
      pepstatin which can be synthesized in a simple and straight way result only in
      slight variations of the inhibitory activity. These analogues display only 10
      fold reduced inhibitory activity, compared to pepstatin A, when bearing a greater
      N-terminal group like isovaleryl, Boc, or Cbz. Compounds which are substituted at
      the N-terminus by a shorter N-acyl group like propionyl or cyclopropylcarbonyl
      show further reduced activity (0.01, compared to pepstatin A). The presence of an
      amide or a urethane moiety at the N-terminus has no considerable effect on enzyme
      inhibition. Therefore, the N-terminus of these analogues is able to be modified
      forming a covalent bond to various bioadhesive polymers via a suitable
      functionality.

PMID- 10354413
TI  - Thioamides: synthesis, stability, and immunological activities of thioanalogues
      of Imreg. Preparation of new thioacylating agents using fluorobenzimidazolone
      derivatives.
AB  - Imreg (Tyr1-Gly2-Gly3) is a well-known immunostimulant. However, it possesses a
      short half-life. Stabilized analogues of Imreg were prepared by a regioselective
      insertion in which peptide bonds at position 1,2 or 2,3 were replaced by
      thioamide linkages. This was achieved by using new thioacylating agents based on
      thioacyl-fluoro-N-benzimidazolone. The synthesis and properties of these reagents
      are described herein. This peptide modification enhanced significantly the half
      life of the thioanalogues relative to Imreg in blood. The thioanalogues and Imreg
      were tested in vitro in T and B cell proliferation assays and for their ability
      to stimulate cytotoxic T-lymphocytes (CTLs). Only thiotyrosyl glycyl glycine 11
      displayed some activity as evidenced by a weak stimulation of CTLs. On the basis
      of this activity and the increased stability, an in vivo immunological evaluation
      was undertaken. Immunophenotyping of 11 revealed a significant increase in
      activated CTL and NK cell populations in the spleen. This expansion was also
      accompanied by a significant stimulation of NK cells and the B cell proliferative
      response. Thioanalogues of Imreg were generally nontoxic, as exemplified by 11.
      The latter is a promising immunostimulant which may be targeted for cancer and
      viral infections, where CTLs and NK cells play an important role, or as a vaccine
      adjuvant where stimulation of antibody-producing B cells is important.

PMID- 10354414
TI  - Synthesis and pharmacology of the baclofen homologues 5-amino-4-(4
      chlorophenyl)pentanoic acid and the R- and S-enantiomers of 5-amino-3-(4
      chlorophenyl)pentanoic acid.
AB  - (RS)-5-Amino-4-(4-chlorophenyl)pentanoic acid (10) and the R-form (11) and S-form
      (12) of (RS)-5-amino-3-(4-chlorophenyl)pentanoic acid, which are homologues of
      the 4-aminobutanoic acidB (GABAB) receptor agonist (RS)-4-amino-3-(4
      chlorophenyl)butanoic acid (baclofen), were synthesized. Compound 10 was
      synthesized by homologation at the carboxyl end of baclofen using a seven-step
      reaction sequence. N-Boc-protected (4R, 5R)-4-(4-chlorophenyl)-5-hydroxy-2
      piperidone (18) was deoxygenated via a modified Barton-McCombie reaction to give
      N-Boc-protected (R)-4-(4-chlorophenyl)-2-piperidone (20), which was ring opened
      and deprotected to give 11.HCl. The corresponding S-enantiomer, 12.HCl, was
      synthesized analogously from the 4S,5S-enantiomer of 18, compound 21. The
      enantiomeric purities of 11.HCl (ee = 99.8%) and 12. HCl (ee = 99.3%) were
      determined by chiral HPLC. Compound 10 did not show detectable affinity for GABAA
      or GABAB receptor sites and was inactive as an agonist or an antagonist at GABAB
      receptors in the guinea pig ileum. Like the enantiomers of baclofen, neither 11
      nor 12 showed detectable affinity for GABAA receptor sites, and in agreement with
      the findings for (S)-baclofen, 12 did not interact significantly with GABAB
      receptor sites. Compound 11 (IC50 = 7.4 +/- 0.6 microM), a homologue of (R)
      baclofen (2), was shown to be some 50 times weaker than 2 (IC50 = 0.14 +/- 0.01
      microM) as an inhibitor of GABAB binding. Accordingly, 11 (EC50 = 150 +/- 23
      microM) was shown to be weaker than 2 (EC50 = 11 +/- 1 microM) as an inhibitor of
      electrically induced contractions of the guinea pig ileum. However, whereas this
      effect of 2 was sensitive to the GABAB antagonist, CGP35348 (4), the inhibition
      by 11 was not significantly affected. Furthermore, 12 (EC50 = 310 +/- 16 microM)
      was shown to be one-half as potent as 11 in this test system, and this effect of
      12 also was insensitive to 4. The dissimilarities of the pharmacological effects
      of 2 and compounds 11 and 12 were emphasized by the observation that whereas 2
      only inhibits the ileum contraction by 59 +/- 5%, 11 as well as 12 were shown to
      inhibit this response by approximately 94%. Neither 11 nor 12 appeared to affect
      significantly cholinergic mechanisms in the ileum, and their mechanism(s) of
      action remain enigmatic.

PMID- 10354415
TI  - An atomic model for the pleated beta-sheet structure of Abeta amyloid
      protofilaments.
AB  - Synchrotron x-ray studies on amyloid fibrils have suggested that the stacked
      pleated beta-sheets are twisted so that a repeating unit of 24 beta-strands forms
      a helical turn around the fibril axis (. J. Mol. Biol. 273:729-739). Based on
      this morphological study, we have constructed an atomic model for the twisted
      pleated beta-sheet of human Abeta amyloid protofilament. In the model, 48
      monomers of Abeta 12-42 stack (four per layer) to form a helical turn of beta
      sheet. Each monomer is in an antiparallel beta-sheet conformation with a turn
      located at residues 25-28. Residues 17-21 and 31-36 form a hydrophobic core along
      the fibril axis. The hydrophobic core should play a critical role in initializing
      Abeta aggregation and in stabilizing the aggregates. The model was tested using
      molecular dynamics simulations in explicit aqueous solution, with the particle
      mesh Ewald (PME) method employed to accommodate long-range electrostatic forces.
      Based on the molecular dynamics simulations, we hypothesize that an isolated
      protofilament, if it exists, may not be twisted, as it appears to be when in the
      fibril environment. The twisted nature of the protofilaments in amyloid fibrils
      is likely the result of stabilizing packing interactions of the protofilaments.
      The model also provides a binding mode for Congo red on Abeta amyloid fibrils.
      The model may be useful for the design of Abeta aggregation inhibitors.

PMID- 10354416
TI  - Restoring low resolution structure of biological macromolecules from solution
      scattering using simulated annealing.
AB  - A method is proposed to restore ab initio low resolution shape and internal
      structure of chaotically oriented particles (e.g., biological macromolecules in
      solution) from isotropic scattering. A multiphase model of a particle built from
      densely packed dummy atoms is characterized by a configuration vector assigning
      the atom to a specific phase or to the solvent. Simulated annealing is employed
      to find a configuration that fits the data while minimizing the interfacial area.
      Application of the method is illustrated by the restoration of a ribosome-like
      model structure and more realistically by the determination of the shape of
      several proteins from experimental x-ray scattering data.

PMID- 10354418
TI  - Spermine and arcaine block and permeate N-methyl-D-aspartate receptor channels.
AB  - Polyamines such as spermine are thought to be endogenous regulators of NMDA (N
      methyl-D-aspartate)-type glutamate receptors. Polyamine block of NMDA receptors
      was studied in excised outside-out patches from rat hippocampal neurons and
      Xenopus oocytes expressing recombinant receptors. Extracellular spermine and
      arcaine reduced NMDA single-channel conductance in a voltage-dependent manner,
      with partial relief of block evident at large inside negative membrane
      potentials. Reducing extracellular Na+ concentration increased the apparent
      affinities for spermine and arcaine, indicating strong interaction between
      spermine and permeant ions. Internal spermine also blocked NMDA channels in a
      voltage-dependent manner, with relief of block evident at large inside positive
      potentials. The Woodhull model of channel block by an impermeant ion adequately
      described the actions of external spermine from -60 to +60 mV, but failed for
      more negative potentials. Eyring rate theory for a permeable blocker with two
      barriers and one binding site adequately described the voltage-dependent block
      and relief from block by both external and internal spermine over the range of 
      120 to +60 mV. These findings indicate that polyamines block and permeate
      neuronal NMDA receptor channels from the extracellular and intracellular sides,
      although sensitivity to internal spermine is probably too low to be
      physiologically relevant.

PMID- 10354419
TI  - Crystal structure of C-phycocyanin from Cyanidium caldarium provides a new
      perspective on phycobilisome assembly.
AB  - The crystal structure of the light-harvesting protein phycocyanin from the
      cyanobacterium Cyanidium caldarium with novel crystal packing has been solved at
      1.65-A resolution. The structure has been refined to an R value of 18.3% with
      excellent backbone and side-chain stereochemical parameters. In crystals of
      phycocyanin used in this study, the hexamers are offset rather than aligned as in
      other phycocyanins that have been crystallized to date. Analysis of this
      crystal's unique packing leads to a proposal for phycobilisome assembly in vivo
      and for a more prominent role for chromophore beta-155. This new role assigned to
      chromophore beta-155 in phycocyanin sheds light on the numerical relationships
      among and function of external chromophores found in phycoerythrins and
      phycoerythrocyanins.

PMID- 10354417
TI  - The role of a conserved proline residue in mediating conformational changes
      associated with voltage gating of Cx32 gap junctions.
AB  - We have explored the role of a proline residue located at position 87 in the
      second transmembrane segment (TM2) of gap junctions in the mechanism of voltage
      dependent gating of connexin32 (Cx32). Substitution of this proline (denoted
      Cx32P87) with residues G, A, or V affects channel function in a progressive
      manner consistent with the expectation that a proline kink (PK) motif exists in
      the second transmembrane segment (TM2) of this connexin. Mutations of the
      preceding threonine residue T86 to S, A, C, V, N, or L shift the conductance
      voltage relation of wild-type Cx32, such that the mutated channels close at
      smaller transjunctional voltages. The observed shift in voltage dependence is
      consistent with a reduction in the open probability of the mutant hemichannels at
      a transjunctional voltage (Vj) of 0 mV. In both cases in which kinetics were
      examined, the time constants for reaching steady state were faster for T86N and
      T86A than for wild type at comparable voltages, suggesting that the T86 mutations
      cause the energetic destabilization of the open state relative to the other
      states of the channel protein. The structural underpinnings of the observed
      effects were explored with Monte Carlo simulations. The conformational space of
      TM2 helices was found to differ for the T86A, V, N, and L mutants, which produce
      a less bent helix ( approximately 20 degrees bend angle) compared to the wild
      type, which has a approximately 37 degrees bend angle. The greater bend angle of
      the wild-type helix reflects the propensity of the T86 residue to hydrogen bond
      with the backbone carbonyl of amino acid residue I82. The relative differences in
      propensity for hydrogen bonding of the mutants relative to the wild-type
      threonine residue in the constructs we studied (T86A, V, N, L, S, and C)
      correlate with the shift in the conductance-voltage relation observed for T86
      mutations. The data are consistent with a structural model in which the open
      conformation of the Cx32 channel corresponds to a more bent TM2 helix, and the
      closed conformation corresponds to a less bent helix. We propose that the
      modulation of the hydrogen-bonding potential of the T86 residue alters the bend
      angle of the PK motif and mediates conformational changes between open and closed
      channel states.

PMID- 10354420
TI  - Discrimination of DNA hybridization using chemical force microscopy.
AB  - Atomic force microscopy (AFM) can be used to probe the mechanics of molecular
      recognition between surfaces. In the application known as "chemical force"
      microscopy (CFM), a chemically modified AFM tip probes a surface through chemical
      recognition. When modified with a biological ligand or receptor, the AFM tip can
      discriminate between its biological binding partner and other molecules on a
      heterogeneous substrate. The strength of the interaction between the modified tip
      and the substrate is governed by the molecular affinity. We have used CFM to
      probe the interactions between short segments of single-strand DNA
      (oligonucleotides). First, a latex microparticle was modified with the sequence
      3'-CAGTTCTACGATGGCAAGTC and epoxied to a standard AFM cantilever. This DNA
      modified probe was then used to scan substrates containing the complementary
      sequence 5'-GTCAAGATGCTACCGTTCAG. These substrates consisted of micron-scale,
      patterned arrays of one or more distinct oligonucleotides. A strong friction
      interaction was measured between the modified tip and both elements of surface
      bound DNA. Complementary oligonucleotides exhibited a stronger friction than the
      noncomplementary sequences within the patterned array. The friction force
      correlated with the measured strength of adhesion (rupture force) for the tip-
      and array-bound oligonucleotides. This result is consistent with the formation of
      a greater number of hydrogen bonds for the complementary sequence, suggesting
      that the friction arises from a sequence-specific interaction (hybridization) of
      the tip and surface DNA.

PMID- 10354421
TI  - Competition between Li+ and Mg2+ in neuroblastoma SH-SY5Y cells: a fluorescence
      and 31P NMR study.
AB  - Because Mg2+ and Li+ ions have similar chemical properties, we have hypothesized
      that Li+/Mg2+ competition for Mg2+ binding sites is the molecular basis for the
      therapeutic action of lithium in manic-depressive illness. By fluorescence
      spectroscopy with furaptra-loaded cells, the free intracellular Mg2+
      concentration within the intact neuroblastoma cells was found to increase from 0.
      39 +/- 0.04 mM to 0.60 +/- 0.04 mM during a 40-min Li+ incubation in which the
      total intracellular Li+ concentration increased from 0 to 5.5 mM. Our
      fluorescence microscopy observations of Li+-free and Li+-loaded cells also
      indicate an increase in free Mg2+ concentration upon Li+ incubation. By 31P NMR,
      the free intracellular Mg2+ concentrations for Li+-free cells was 0.35 +/- 0. 03
      mM and 0.80 +/- 0.04 mM for Li+-loaded cells (final total intracellular Li+
      concentration of 16 mM). If a Li+/Mg2+ competition mechanism is present in
      neuroblastoma cells, an increase in the total intracellular Li+ concentration is
      expected to result in an increase in the free intracellular Mg2+ concentration,
      because Li+ displaces Mg2+ from its binding sites within the nerve cell. The
      fluorescence spectroscopy, fluorescence microscopy, and 31P NMR spectroscopy
      studies presented here have shown this to be the case.

PMID- 10354422
TI  - Calculation of protein form birefringence using the finite element method.
AB  - An approach based on the finite element method (FEM) is employed to calculate the
      optical properties of macromolecules, specifically form birefringence.
      Macromolecules are treated as arbitrarily shaped particles suspended in a solvent
      of refraction index n1. The form birefringence of the solution is calculated as
      the difference in its refractive index when all the particles of refractive index
      n2 are either parallel to or normal to the direction of the polarization of
      light. Since the particles of interest are small compared to the wavelength of
      light, a quasi-static approximation for the refractive index is used, i.e., that
      it is equal to the square root of the dielectric constant of the suspension. The
      average dielectric constant of the mixture is calculated using the finite element
      method. This approach has been tested for ellipsoidal particles and a good
      agreement with theoretical results has been obtained. Also, numerical results for
      the motor domains of ncd and kinesin, small arbitrarily shaped proteins with
      known x-ray structures, show reasonable agreement with the experimental data
      obtained from transient electric birefringence experiments.

PMID- 10354423
TI  - Lipid flow through fusion pores connecting membranes of different tensions.
AB  - When two membranes fuse, their components mix; this is usually described as a
      purely diffusional process. However, if the membranes are under different
      tensions, the material will spread predominantly by convection. We use standard
      fluid mechanics to rigorously calculate the steady-state convective flux of
      lipids. A fusion pore is modeled as a toroid shape, connecting two planar
      membranes. Each of the membrane monolayers is considered separately as
      incompressible viscous media with the same shear viscosity, etas. The two
      monolayers interact by sliding past each other, described by an intermonolayer
      viscosity, etar. Combining a continuity equation with an equation that balances
      the work provided by the tension difference, Deltasigma, against the energy
      dissipated by flow in the viscous membrane, yields expressions for lipid
      velocity, upsilon, and area of lipid flux, Phi. These expressions for upsilon and
      Phi depend on Deltasigma, etas, etar, and geometrical aspects of a toroidal pore,
      but the general features of the theory hold for any fusion pore that has a
      roughly hourglass shape. These expressions are readily applicable to data from
      any experiments that monitor movement of lipid dye between fused membranes under
      different tensions. Lipid velocity increases nonlinearly from a small value for
      small pore radii, rp, to a saturating value at large rp. As a result of velocity
      saturation, the flux increases linearly with pore radius for large pores. The
      calculated lipid flux is in agreement with available experimental data for both
      large and transient fusion pores.

PMID- 10354424
TI  - Ligand binding by antibody IgE Lb4: assessment of binding site preferences using
      microcalorimetry, docking, and free energy simulations.
AB  - Antibody IgE Lb4 interacts favorably with a large number of different compounds.
      To improve the current understanding of the structural basis of this vast cross
      reactivity, the binding of three dinitrophenyl (DNP) amino acids (DNP-alanine,
      DNP-glycine, and DNP-serine) is investigated in detail by means of docking and
      molecular dynamics free energy simulations. Experimental binding energies
      obtained by isothermal titration microcalorimetry are used to judge the results
      of the computational studies. For all three ligands, the docking procedure
      proposes two plausible subsites within the binding region formed by the antibody
      CDR loops. By subsequent molecular dynamics simulations and calculations of
      relative free energies of binding, one of these subsites, a tyrosine-surrounded
      pocket, is revealed as the preferred point of complexation. For this subsite,
      results consistent with experimental observations are obtained; DNP-glycine is
      found to bind better than DNP-serine, and this, in turn, is found to bind better
      than DNP-alanine. The suggested binding mode makes it possible to explain both
      the moderate binding affinity and the differences in binding energy among the
      three ligands.

PMID- 10354427
TI  - Electroreceptor model of weakly electric fish Gnathonemus petersii: II. Cellular
      origin of inverse waveform tuning.
AB  - In part I (. Biophys. J. 75:1712-1726), we presented a cellular model of the A-
      and B-electroreceptors of the weakly electric fish Gnathonemus petersii. The
      model made clear the cellular origin of the differences in the response functions
      of A- and B-receptors, which sensitively code the intensity of the fish's own
      electric organ discharge (EOD) and the variations in the EOD waveform,
      respectively. The main purpose of the present paper is to clarify the cellular
      origin of the inverse waveform tuning of the B-receptors by using the receptor
      model. Inverse waveform tuning means that B-receptors respond more sensitively to
      the 180 degrees inverted EOD than to undistorted or less distorted EODs. We
      investigated how the A- and B-receptor models respond to EODs with various
      waveforms, which are the phase-shifted EODs, whose shift angle is varied from -1
      degrees to -180 degrees, and single-period sine wave stimuli of various
      frequencies. We show that the tuning properties of the B-receptors arise mainly
      from the combination of two attributes: 1) The waveform of the stimuli (Bstim)
      effectively sensed by the B-receptor cells. This consists of a first smaller and
      a second larger positive peak, even though in the original phase-shifted EOD
      stimuli, the amplitudes of the two positive peaks are reversed. 2) The effective
      time constant of dynamical response of the receptor cells. It is on the order of
      the duration of a single EOD pulse. We also calculated the response properties of
      the A- and B-receptor models when stimulated with natural EODs distorted by
      various capacitive and resistive objects. Furthermore, we investigated the effect
      of EOD amplitude on the receptor responses to capacitive and resistive objects.
      The models presented can systematically reproduce the experimentally observed
      response properties of natural A- and B-receptor cells. The mechanism producing
      these properties can be reasonably explained by the variation in the stimulus
      waveforms effectively sensed by the A- and B-receptor cells and by time
      constants.

PMID- 10354425
TI  - Simulation of electron-proton coupling with a Monte Carlo method: application to
      cytochrome c3 using continuum electrostatics.
AB  - A new method is presented for simulating the simultaneous binding equilibrium of
      electrons and protons on protein molecules, which makes it possible to study the
      full equilibrium thermodynamics of redox and protonation processes, including
      electron-proton coupling. The simulations using this method reflect directly the
      pH and electrostatic potential of the environment, thus providing a much closer
      and realistic connection with experimental parameters than do usual methods. By
      ignoring the full binding equilibrium, calculations usually overlook the twofold
      effect that binding fluctuations have on the behavior of redox proteins: first,
      they affect the energy of the system by creating partially occupied sites;
      second, they affect its entropy by introducing an additional empty/occupied site
      disorder (here named occupational entropy). The proposed method is applied to
      cytochrome c3 of Desulfovibrio vulgaris Hildenborough to study its redox
      properties and electron-proton coupling (redox-Bohr effect), using a continuum
      electrostatic method based on the linear Poisson-Boltzmann equation. Unlike
      previous studies using other methods, the full reduction order of the four hemes
      at physiological pH is successfully predicted. The sites more strongly involved
      in the redox-Bohr effect are identified by analysis of their titration
      curves/surfaces and the shifts of their midpoint redox potentials and pKa values.
      Site-site couplings are analyzed using statistical correlations, a method much
      more realistic than the usual analysis based on direct interactions. The site
      found to be more strongly involved in the redox-Bohr effect is propionate D of
      heme I, in agreement with previous studies; other likely candidates are His67,
      the N-terminus, and propionate D of heme IV. Even though the present study is
      limited to equilibrium conditions, the possible role of binding fluctuations in
      the concerted transfer of protons and electrons under nonequilibrium conditions
      is also discussed. The occupational entropy contributions to midpoint redox
      potentials and pKa values are computed and shown to be significant.

PMID- 10354426
TI  - Molecular dynamics studies on the HIV-1 integrase catalytic domain.
AB  - The HIV-1 integrase, which is essential for viral replication, catalyzes the
      insertion of viral DNA into the host chromosome, thereby recruiting host cell
      machinery into making viral proteins. It represents the third main HIV enzyme
      target for inhibitor design, the first two being the reverse transcriptase and
      the protease. Two 1-ns molecular dynamics simulations have been carried out on
      completely hydrated models of the HIV-1 integrase catalytic domain, one with no
      metal ions and another with one magnesium ion in the catalytic site. The
      simulations predict that the region of the active site that is missing in the
      published crystal structures has (at the time of this work) more secondary
      structure than previously thought. The flexibility of this region has been
      discussed with respect to the mechanistic function of the enzyme. The results of
      these simulations will be used as part of inhibitor design projects directed
      against the catalytic domain of the enzyme.

PMID- 10354428
TI  - Biological effects due to weak electric and magnetic fields: the temperature
      variation threshold.
AB  - A large number of epidemiological and experimental studies suggest that prolonged
      (>100 s) weak 50-60-Hz electric and magnetic field (EMF) exposures may cause
      biological effects(NIEHS Working Group, NIH, 1998; Bersani, 1999). We show,
      however, that for typical temperature sensitivities of biochemical processes,
      realistic temperature variations during long exposures raise the threshold
      exposure by two to three orders of magnitude over a fundamental value,
      independent of the biophysical coupling mechanism. Temperature variations have
      been omitted in previous theoretical analyses of possible weak field effects,
      particularly stochastic resonance (Bezrukov and Vodyanoy 1997a. Nature. 385:319
      321; Astumian et al., 1997 Nature. 338:632-633; Bezrukov and Vodyanoy, 1997b.
      Nature. 338:663; Dykman and McClintock, 1998. Nature. 391:344; McClintock, 1998;.
      Gammaitoni et al., 1998. Rev. Mod. Phys. 70:223-287). Although sensory systems
      usually respond to much shorter (approximately 1 s) exposures and can approach
      fundamental limits (Bialek, 1987 Annu. Rev. Biophys. Biophys. Chem. 16:455-468;
      Adair et al, 1998. Chaos. 8:576-587), our results significantly decrease the
      plausibility of effects for nonsensory biological systems due to prolonged, weak
      field exposures.

PMID- 10354430
TI  - Hydrodynamic properties of rigid particles: comparison of different modeling and
      computational procedures.
AB  - The hydrodynamic properties of rigid particles are calculated from models
      composed of spherical elements (beads) using theories developed by Kirkwood,
      Bloomfield, and their coworkers. Bead models have usually been built in such a
      way that the beads fill the volume occupied by the particles. Sometimes the beads
      are few and of varying sizes (bead models in the strict sense), and other times
      there are many small beads (filling models). Because hydrodynamic friction takes
      place at the molecular surface, another possibility is to use shell models, as
      originally proposed by Bloomfield. In this work, we have developed procedures to
      build models of the various kinds, and we describe the theory and methods for
      calculating their hydrodynamic properties, including approximate methods that may
      be needed to treat models with a very large number of elements. By combining the
      various possibilities of model building and hydrodynamic calculation, several
      strategies can be designed. We have made a quantitative comparison of the
      performance of the various strategies by applying them to some test cases, for
      which the properties are known a priori. We provide guidelines and computational
      tools for bead modeling.

PMID- 10354429
TI  - Steric effects on multivalent ligand-receptor binding: exclusion of ligand sites
      by bound cell surface receptors.
AB  - Steric effects can influence the binding of a cell surface receptor to a
      multivalent ligand. To account for steric effects arising from the size of a
      receptor and from the spacing of binding sites on a ligand, we extend a standard
      mathematical model for ligand-receptor interactions by introducing a steric
      hindrance factor. This factor gives the fraction of unbound ligand sites that are
      accessible to receptors, and thus available for binding, as a function of ligand
      site occupancy. We derive expressions for the steric hindrance factor for various
      cases in which the receptor covers a compact region on the ligand surface and the
      ligand expresses sites that are distributed regularly or randomly in one or two
      dimensions. These expressions are relevant for ligands such as linear polymers,
      proteins, and viruses. We also present numerical algorithms that can be used to
      calculate steric hindrance factors for other cases. These theoretical results
      allow us to quantify the effects of steric hindrance on ligand-receptor kinetics
      and equilibria.

PMID- 10354431
TI  - An autoinhibitory peptide from the erythrocyte Ca-ATPase aggregates and inhibits
      both muscle Ca-ATPase isoforms.
AB  - We have studied the effects of C28R2, a basic peptide derived from the
      autoinhibitory domain of the plasma membrane Ca-ATPase, on enzyme activity,
      oligomeric state, and E1-E2 conformational equilibrium of the Ca-ATPase from
      skeletal and cardiac sarcoplasmic reticulum (SR). Time-resolved phosphorescence
      anisotropy (TPA) was used to determine changes in the distribution of Ca-ATPase
      among its different oligomeric species in SR. C28R2, at a concentration of 1-10
      microM, inhibits the Ca-ATPase activity of both skeletal and cardiac SR (CSR). In
      skeletal SR, this inhibition by C28R2 is much greater at low (0.15 microM) than
      at high (10 microM) Ca2+, whereas in CSR the inhibition is the same at low and
      high Ca2+. The effects of the peptide on the rotational mobility of the Ca-ATPase
      correlated well with function, indicating that C28R2-induced protein aggregation
      and Ca-ATPase inhibition are much more Ca-dependent in skeletal than in CSR. In
      CSR at low Ca2+, phospholamban (PLB) antibody (functionally equivalent to PLB
      phosphorylation) increased the inhibitory effect of C28R2 slightly. Fluorescence
      of fluorescein 5-isothiocyanate-labeled SR suggests that C28R2 stabilizes the E1
      conformation of the Ca-ATPase in skeletal SR, whereas in CSR it stabilizes E2.
      After the addition of PLB antibody, C28R2 still stabilizes the E2 conformational
      state of CSR. Therefore, we conclude that C28R2 affects Ca-ATPase activity,
      conformation, and self-association differently in cardiac and skeletal SR and
      that PLB is probably not responsible for the differences.

PMID- 10354432
TI  - Effects of pH on kinetic parameters of the Na-HCO3 cotransporter in renal
      proximal tubule.
AB  - The effects of pH on cotransporter kinetics were studied in renal proximal tubule
      cells. Cells were grown to confluence on permeable support, mounted in an Ussing
      type chamber, and permeabilized apically to small monovalent ions with
      amphotericin B. The steady-state, dinitrostilbene-disulfonate-sensitive current
      (DeltaI) was Na+ and HCO3- dependent and therefore was taken as flux through the
      cotransporter. When the pH of the perfusing solution was changed between 6.0 and
      8.0, the conductance attributable to the cotransporter showed a maximum between
      pH 7.25 and pH 7.50. A similar profile was observed in the presence of a pH
      gradient when the pH of the apical solutions was varied between 7.0 and 8.0
      (basal pH lower by 1), but not when the pH of the basal solution was varied
      between 7.0 and 8.0 (apical pH lower by 1 unit). To delineate the kinetic basis
      for these observations, DeltaI-voltage curves were obtained as a function of Na+
      and HCO3- concentrations and analyzed on the basis of a kinetic cotransporter
      model. Increases in pH from 7.0 to 8.0 decreased the binding constants for the
      intracellular and extracellular substrates by a factor of 2. Furthermore, the
      electrical parameters that describe the interaction strength between the electric
      field and substrate binding or charge on the unloaded transporter increased by
      four- to fivefold. These data can be explained by a channel-like structure of the
      cotransporter, whose configuration is modified by intracellular pH such that,
      with increasing pH, binding of substrate to the carrier is sterically hindered
      but electrically facilitated.

PMID- 10354433
TI  - Measurement of calcium channel inactivation is dependent upon the test pulse
      potential.
AB  - We have developed two methods to measure Ca2+ channel inactivation in Lymnaea
      neurons-one method, based upon the conventional double-pulse protocol, uses
      currents during a moderately large depolarizing pulse, and the other uses tail
      currents after a very strong activating pulse. Both methods avoid contamination
      by proton currents and are unaffected by rundown of Ca2+ current. The magnitude
      of inactivation measured differs for the two methods; this difference arises
      because the measurement of inactivation is inherently dependent upon the test
      pulse voltage used to monitor the Ca2+ channel conductance. We discuss two models
      that can generate such test pulse dependence of inactivation measurements-a two
      channel model and a two-open-state model. The first model accounts for this by
      assuming the existence of two types of Ca2+ channels, different proportions of
      which are activated by the different test pulses. The second model assumes only
      one Ca2+ channel type, with two closed and open states; in this model, the test
      pulse dependence is due to the differential activation of channels in the two
      closed states by the test pulses. Test pulse dependence of inactivation
      measurements of Ca2+ channels may be a general phenomenon that has been
      overlooked in previous studies.

PMID- 10354434
TI  - Rundown of the hyperpolarization-activated KAT1 channel involves slowing of the
      opening transitions regulated by phosphorylation.
AB  - Disappearance of the functional activity or rundown of ion channels upon patch
      excision in many cells involves a decrease in the number of channels available to
      open. A variety of cellular and biophysical mechanisms have been shown to be
      involved in the rundown of different ion channels. We examined the rundown
      process of the plant hyperpolarization-activated KAT1 K+ channel expressed in
      Xenopus oocytes. The decrease in the KAT1 channel activity on patch excision was
      accompanied by progressive slowing of the activation time course, and it was
      caused by a shift in the voltage dependence of the channel without any change in
      the single-channel amplitude. The single-channel analysis showed that patch
      excision alters only the transitions leading up to the burst states of the
      channel. Patch cramming or concurrent application of protein kinase A (PKA) and
      ATP restored the channel activity. In contrast, nonspecific alkaline phosphatase
      (ALP) accelerated the rundown time course. Low internal pH, which inhibits ALP
      activity, slowed the KAT1 rundown time course. The results show that the opening
      transitions of the KAT1 channel are enhanced not only by hyperpolarization but
      also by PKA-mediated phosphorylation.

PMID- 10354436
TI  - Membrane-pipette interactions underlie delayed voltage activation of
      mechanosensitive channels in Xenopus oocytes.
AB  - To investigate the mechanism for the delayed activation by voltage of the
      predominant mechanosensitive (MS) channel in Xenopus oocytes, currents were
      recorded from on-cell and excised patches of membrane with the patch clamp
      technique and from intact oocytes with the two-electrode voltage clamp technique.
      MS channels could be activated by stretch in inside-out, on-cell, and outside-out
      patch configurations, using pipettes formed of either borosilicate or soft glass.
      In inside-out patches formed with borosilicate glass pipettes, depolarizing
      voltage steps activated MS channels in a cooperative manner after delays of
      seconds. This voltage-dependent activation was not observed for outside-out
      patches. Voltage-dependent activation was also not observed when the borosilicate
      pipettes were either replaced with soft glass pipettes or coated with soft glass.
      When depolarizing voltage steps were applied to the whole oocyte with a two
      electrode voltage clamp, currents that could be attributed to MS channels were
      not observed. Yet the same depolarizing steps activated MS channels in on-cell
      patches formed with borosilicate pipettes on the same oocyte. These observations
      suggest that the delayed cooperative activation of MS channels by depolarization
      is not an intrinsic property of the channels, but requires interaction between
      the membrane and patch pipette.

PMID- 10354435
TI  - Ca2+-dependent gating mechanisms for dSlo, a large-conductance Ca2+-activated K+
      (BK) channel.
AB  - The Ca2+-dependent gating mechanism of cloned BK channels from Drosophila (dSlo)
      was studied. Both a natural variant (A1/C2/E1/G3/IO) and a mutant (S942A) were
      expressed in Xenopus oocytes, and single-channel currents were recorded from
      excised patches of membrane. Stability plots were used to define stable segments
      of data. Unlike native BK channels from rat skeletal muscle in which increasing
      internal Ca2+ concentration (Cai2+) in the range of 5 to 30 microM increases mean
      open time, increasing Cai2+ in this range for dSlo had little effect on mean open
      time. However, further increases in Cai2+ to 300 or 3000 microM then typically
      increased dSlo mean open time. Kinetic schemes for the observed Ca2+-dependent
      gating kinetics of dSlo were evaluated by fitting two-dimensional dwell-time
      distributions using maximum likelihood techniques and by comparing observed
      dependency plots with those predicted by the models. Previously described kinetic
      schemes that largely account for the Ca2+-dependent kinetics of native BK
      channels from rat skeletal muscle did not adequately describe the Ca2+ dependence
      of dSlo. An expanded version of these schemes which, in addition to the Ca2+
      activation steps, permitted a Ca2+-facilitated transition from each open state to
      a closed state, could approximate the Ca2+-dependent kinetics of dSlo, suggesting
      that Ca2+ may exert dual effects on gating.

PMID- 10354438
TI  - Batrachotoxin-resistant Na+ channels derived from point mutations in
      transmembrane segment D4-S6.
AB  - Local anesthetics (LAs) block voltage-gated Na+ channels in excitable cells,
      whereas batrachotoxin (BTX) keeps these channels open persistently. Previous work
      delimited the LA receptor within the D4-S6 segment of the Na+ channel alpha
      subunit, whereas the putative BTX receptor was found within the D1-S6. We mutated
      residues at D4-S6 critical for LA binding to determine whether such mutations
      modulate the BTX phenotype in rat skeletal muscle Na+ channels (mu1/rSkm1). We
      show that mu1-F1579K and mu1-N1584K channels become completely resistant to 5
      microM BTX. In contrast, mu1-Y1586K channels remain BTX-sensitive; their fast and
      slow inactivation is eliminated by BTX after repetitive depolarization.
      Furthermore, we demonstrate that cocaine elicits a profound time-dependent block
      after channel activation, consistent with preferential LA binding to BTX-modified
      open channels. We propose that channel opening promotes better exposure of
      receptor sites for binding with BTX and LAs, possibly by widening the bordering
      area around D1-S6, D4-S6, and the pore region. The BTX receptor is probably
      located at the interface of D1-S6 and D4-S6 segments adjacent to the LA receptor.
      These two S6 segments may appose too closely to bind BTX and LAs simultaneously
      when the channel is in its resting closed state.

PMID- 10354439
TI  - The effects of gramicidin on electroporation of lipid bilayers.
AB  - The effects of the channel-forming peptide gramicidin D (gD) on the conductance
      and electroporation thresholds of planar bilayer lipid membranes, made of the
      synthetic lipid 1-palmitoyl 2-oleoyl phosphatidylcholine (POPC), was studied.
      High-amplitude ( approximately 200-900 mV) rectangular voltage pulses of 15 ms
      duration were used to perturb the bilayers and monitor the transmembrane
      conductance. Electroporation voltage thresholds were found, and conductance was
      recorded before and after electroporation. Gramicidin was added to the system in
      peptide/lipid ratios of 1:10, 000, 1:500, and 1:15. The addition of gD in a ratio
      of 1:10,000 had no effect on electroporation, but ratios of 1:500 and 1:15
      significantly increased the thresholds by 16% (p < 0.0001) and 40% (p < 0.0001),
      respectively. Membrane conductance before electroporation was measurable only
      after the addition of gD and increased monotonically as the peptide/lipid ratio
      increased. The effect of gD on the membrane area expansivity modulus (K) was
      tested using giant unilamellar vesicles (GUVs). When gD was incorporated into the
      vesicles in a 1:15 ratio, K increased by 110%, consistent with the increase in
      thresholds predicted by an electromechanical model. These findings suggest that
      the presence of membrane proteins may affect the electroporation of lipid
      bilayers by changing their mechanical properties.

PMID- 10354440
TI  - Lipid-DNA complex formation: reorganization and rupture of lipid vesicles in the
      presence of DNA as observed by cryoelectron microscopy.
AB  - Cryoelectron microscopy has been used to study the reorganization of unilamellar
      cationic lipid vesicles upon the addition of DNA. Unilamellar DNA-coated
      vesicles, as well as multilamellar DNA lipid complexes, could be observed. Also,
      DNA induced fusion of unilamellar vesicles was found. DNA appears to adsorb to
      the oppositely charged lipid bilayer in a monolayer of parallel helices and can
      act as a molecular "glue" enforcing close apposition of neighboring vesicle
      membranes. In samples with relatively high DNA content, there is evidence for DNA
      induced aggregation and flattening of unilamellar vesicles. In these samples,
      multilamellar complexes are rare and contain only a small number of lamellae. At
      lower DNA contents, large multilamellar CL-DNA complexes, often with >10
      bilayers, are formed. The multilamellar complexes in both types of sample
      frequently exhibit partially open bilayer segments on their outside surfaces. DNA
      seems to accumulate or coil near the edges of such unusually terminated
      membranes. Multilamellar lipid-DNA complexes appear to form by a mechanism that
      involves the rupture of an approaching vesicle and subsequent adsorption of its
      membrane to a "template" vesicle or a lipid-DNA complex.

PMID- 10354437
TI  - Effects of outer mouth mutations on hERG channel function: a comparison with
      similar mutations in the Shaker channel.
AB  - The fast-inactivation process in the hERG channel can be affected by mutations in
      the pore or S6 domain, similar to the C-type inactivation in the Shaker channel.
      However, differences in the kinetics and voltage dependence of inactivation
      between these two channels suggest that different structural determinants may be
      involved. To explore this possibility, we mutated a serine in the outer mouth
      region of hERG (S631) to residues of different physicochemical properties and
      compared the resulting changes in the channel's inactivation process with those
      resulting from mutations of an equivalent position in the Shaker channel (T449).
      The most dramatic differences are seen when this position is occupied by a
      charged residue: S631K and S631E disrupted C-type inactivation in hERG, whereas
      T449K and T449E facilitate C-type inactivation in Shaker. S631K and S631E also
      disrupted the K selectivity of hERG pore, a change not seen in T449K or T449E of
      Shaker. To further study why there are such differences, we replaced S631 with
      cysteine. This allowed us to manipulate the properties of thiol groups at
      position 631 and correlate side-chain properties here with changes in channel
      function. S631C behaved like the wild-type channel when the thiol groups were in
      the reduced state. Oxidizing thiol groups with H2O2 or modifying them with MTSET
      or MTSES disrupted C-type inactivation and K selectivity, similar to the
      phenotype of S631K and S631E. The same thiol-modifying maneuvers did not affect
      the wild-type channel function. Our results suggest differences in the outer
      mouth structure between hERG and Shaker, and we propose a "molecular spring"
      hypothesis to explain these differences.

PMID- 10354441
TI  - Polymorphism and interactions of a viral fusion peptide in a compressed lipid
      monolayer.
AB  - With a view toward possible new insights into viral fusion mechanisms, we have
      investigated the HIV-1 gp41 fusion peptide in a monomolecular film of the
      biomembrane lipid palmitoyloleoylphosphatidylcholine. Its surface activity at an
      air/water interface was measured under equilibrium conditions, using the
      conventional Langmuir trough technique. Through a novel thermodynamic analysis,
      the partial molecular area of the peptide in the lipid moiety could be determined
      as a function of the lateral pressure and the interfacial peptide/lipid ratio.
      This indicates an orientation of the peptide backbone parallel to the lipid
      hydrocarbon tails. The molecular area decreases significantly upon monolayer
      compression, suggesting a conformational transition from a somewhat compact
      configuration to a more extended, presumably beta-strand structure when a lipid
      packing density is approached that is generally believed to mimic the physical
      state of a biological membrane. Up to a lateral pressure of approximately 15
      mN/m, practically all peptide inserts into the lipid monolayer. At higher
      compression a distinct partitioning into the aqueous subphase is observed. Under
      these conditions the data also reflect a strong aggregation of the lipid
      associated peptide. Beyond a critical peptide/lipid ratio, the peptide's area
      requirement was found to become substantially enhanced, possibly because of the
      formation of water-filled pores.

PMID- 10354442
TI  - Theoretical analysis of hydrophobic matching and membrane-mediated interactions
      in lipid bilayers containing gramicidin.
AB  - We present a quantitative analysis of the effects of hydrophobic matching and
      membrane-mediated protein-protein interactions exhibited by gramicidin embedded
      in dimyristoylphosphatidylcholine (DMPC) and dilauroylphosphatidylcholine (DLPC)
      bilayers (Harroun et al., 1999. Biophys. J. 76:937-945). Incorporating
      gramicidin, at 1:10 peptide/lipid molar ratio, decreases the phosphate-to
      phosphate (PtP) peak separation in the DMPC bilayer from 35.3 A without
      gramicidin to 32.7 A. In contrast, the same molar ratio of gramicidin in DLPC
      increases the PtP from 30.8 A to 32.1 A. Concurrently, x-ray in-plane scattering
      showed that the most probable nearest-neighbor separation between gramicidin
      channels was 26.8 A in DLPC, but reduced to 23.3 A in DMPC. In this paper we
      review the idea of hydrophobic matching in which the lipid bilayer deforms to
      match the hydrophobic surface of the embedded proteins. We use a simple
      elasticity theory, including thickness compression, tension, and splay terms to
      describe the membrane deformation. The energy of membrane deformation is compared
      with the energy cost of hydrophobic mismatch. We discuss the boundary conditions
      between a gramicidin channel and the lipid bilayer. We used a numerical method to
      solve the problem of membrane deformation profile in the presence of a high
      density of gramicidin channels and ran computer simulations of 81 gramicidin
      channels to find the equilibrium distributions of the channels in the plane of
      the bilayer. The simulations contain four parameters: bilayer thickness
      compressibility 1/B, bilayer bending rigidity Kc, the channel-bilayer mismatch
      Do, and the slope of the interface at the lipid-protein boundary s. B, Kc, and Do
      were experimentally measured; the only free parameter is s. The value of s is
      determined by the requirement that the theory produces the experimental values of
      bilayer thinning by gramicidin and the shift in the peak position of the in-plane
      scattering due to membrane-mediated channel-channel interactions. We show that
      both hydrophobic matching and membrane-mediated interactions can be understood by
      the simple elasticity theory.

PMID- 10354443
TI  - Surface binding of alamethicin stabilizes its helical structure: molecular
      dynamics simulations.
AB  - Alamethicin is an amphipathic alpha-helical peptide that forms ion channels. An
      early event in channel formation is believed to be the binding of alamethicin to
      the surface of a lipid bilayer. Molecular dynamics simulations are used to
      compare the structural and dynamic properties of alamethicin in water and
      alamethicin bound to the surface of a phosphatidylcholine bilayer. The bilayer
      surface simulation corresponded to a loosely bound alamethicin molecule that
      interacted with lipid headgroups but did not penetrate the hydrophobic core of
      the bilayer. Both simulations started with the peptide molecule in an alpha
      helical conformation and lasted 2 ns. In water, the helix started to unfold after
      approximately 300 ps and by the end of the simulation only the N-terminal region
      of the peptide remained alpha-helical and the molecule had collapsed into a more
      compact form. At the surface of the bilayer, loss of helicity was restricted to
      the C-terminal third of the molecule and the rod-shaped structure of the peptide
      was retained. In the surface simulation about 10% of the peptide/water H-bonds
      were replaced by peptide/lipid H-bonds. These simulations suggest that some
      degree of stabilization of an amphipathic alpha-helix occurs at a bilayer surface
      even without interactions between hydrophobic side chains and the acyl chain core
      of the bilayer.

PMID- 10354444
TI  - Unrestrained stochastic dynamics simulations of the UUCG tetraloop using an
      implicit solvation model.
AB  - Three unrestrained stochastic dynamics simulations have been carried out on the
      RNA hairpin GGAC[UUCG] GUCC, using the AMBER94 force field (Cornell et al., 1995.
      J. Am. Chem. Soc. 117:5179-5197) in MacroModel 5.5 (Mohamadi et al., 1990. J.
      Comp. Chem. 11:440-467) and either the GB/SA continuum solvation model (Still et
      al., 1990. J. Am. Chem. Soc. 112:6127-6129) or a linear distance-dependent
      dielectric (1/R) treatment. The linear distance-dependent treatment results in
      severe distortion of the nucleic acid structure, restriction of all hydroxyl
      dihedrals, and collapse of the counterion atmosphere over the course of a 5-ns
      simulation. An additional vacuum simulation without counterions shows somewhat
      improved behavior. In contrast, the two GB/SA simulations (1.149 and 3.060 ns in
      length) give average structures within 1.2 A of the initial NMR structure and in
      excellent agreement with results of an earlier explicit solvent simulation
      (Miller and Kollman, 1997. J. Mol. Biol. 270:436-450). In a 3-ns GB/SA simulation
      starting with the incorrect UUCG tetraloop structure (Cheong et al., 1990.
      Nature. 346:680-682), this loop conformation converts to the correct loop
      geometry (Allain and Varani, 1995. J. Mol. Biol. 250:333-353), suggesting
      enhanced sampling relative to the previous explicit solvent simulation.
      Thermodynamic effects of 2'-deoxyribose substitutions of loop nucleotides were
      experimentally determined and are found to correlate with the fraction of time
      the ribose 2'-OH is hydrogen bonded and the distribution of the hydroxyl dihedral
      is observed in the GB/SA simulations. The GB/SA simulations thus appear to
      faithfully represent structural features of the RNA without the computational
      expense of explicit solvent.

PMID- 10354445
TI  - Intrinsic conformational properties of deoxyribonucleosides: implicated role for
      cytosine in the equilibrium among the A, B, and Z forms of DNA.
AB  - Structural properties of biomolecules are dictated by their intrinsic
      conformational energetics in combination with environmental contributions.
      Calculations using high-level ab initio methods on the deoxyribonucleosides have
      been performed to investigate the influence of base on the intrinsic
      conformational energetics of nucleosides. Energy minima in the north and south
      ranges of the deoxyribose pseudorotation surfaces have been located, allowing
      characterization of the influence of base on the structures and energy
      differences between those minima. With all bases, chi values associated with the
      south energy minimum are lower than in canonical B-DNA, while chi values
      associated with the north energy minimum are close to those in canonical A-DNA.
      In deoxycytidine, chi adopts an A-DNA conformation in both the north and south
      energy minima. Energy differences between the A and B conformations of the
      nucleosides are <0.5 kcal/mol in the present calculations, except with
      deoxycytidine, where the A form is favored by 2.3 kcal/mol, leading the intrinsic
      conformational energetics of GC basepairs to favor the A form of DNA by 1.5
      kcal/mol as compared with AT pairs. This indicates that the intrinsic
      conformational properties of cytosine at the nucleoside level contribute to the A
      form of DNA containing predominately GC-rich sequences. In the context of a B
      versus Z DNA equilibrium, deoxycytidine favors the Z form over the B form by 1.6
      kcal/mol as compared with deoxythymidine, suggesting that the intrinsic
      conformational properties of cytosine also contribute to GC-rich sequences
      occurring in Z DNA with a higher frequency than AT-rich sequences. Results show
      that the east pseudorotation energy barrier involves a decrease in the furanose
      amplitude and is systematically lower than the inversion barrier, with the energy
      differences influenced by the base. Energy barriers going from the south (B form)
      sugar pucker to the east pseudorotation barrier are lower in pyrimidines as
      compared with purines, indicating that the intrinsic conformational properties
      associated with base may also influence the sugar pseudorotational population
      distribution seen in DNA crystal structures and the kinetics of B to A
      transitions. The present work provides evidence that base composition, in
      addition to base sequence, can influence DNA conformation.

PMID- 10354446
TI  - Binding of calcium ions to bacteriorhodopsin.
AB  - Adding Ca2+ or other cations to deionized bacteriorhodopsin causes a blue to
      purple color shift, a result of deprotonation of Asp85. It has been proposed by
      different groups that the protonation state of Asp85 responds to the binding of
      Ca2+ either 1) directly at a specific site in the protein or 2) indirectly
      through the rise of the surface pH. We tested the idea of specific binding of
      Ca2+ and found that the surface pH, as determined from the ionization state of
      eosin covalently linked to engineered cysteine residues, rises about equally at
      both extracellular and cytoplasmic surfaces when only one Ca2+ is added. This
      precludes binding to a specific site and suggests that rather than decreasing the
      pKa of Asp85 by direct interaction, Ca2+ increases the surface pH by binding to
      anionic lipid groups. As Ca2+ is added the surface pH rises, but deprotonation of
      Asp85 occurs only when the surface pH approaches its pKa. The nonlinear
      relationship between Ca2+ binding and deprotonation of Asp85 from this effect is
      different in the wild-type protein and in various mutants and explains the
      observed complex and varied spectral titration curves.

PMID- 10354447
TI  - Ultraviolet Raman examination of the environmental dependence of bombolitin I and
      bombolitin III secondary structure.
AB  - Bombolitin I and III (BI and BIII) are small amphiphilic peptides isolated from
      bumblebee venom. Although they exist in predominately nonhelical conformations in
      dilute aqueous solutions, we demonstrate, using UV Raman spectroscopy, that they
      become predominately alpha-helical in solution at pH > 10, in high ionic strength
      solutions, and in the presence of trifluoroethanol (TFE) and
      dodecylphosphocholine (DPC) micelles. In this paper, we examine the effects of
      electrostatic and hydrophobic interactions that control folding of BI and BIII by
      systematically monitoring their secondary structures as a function of solution
      conditions. We determine the BI and BIII secondary structure contents by using
      the quantitative UV Raman methodology of Chi et al. (1998. Biochemistry. 37:2854
      2864). Our findings suggest that the alpha-helix turn in BIII at neutral pH is
      stabilized by a salt bridge between residues Asp2 and Lys5. This initial alpha
      helical turn results in different BI and BIII alpha-helical folding mechanisms
      observed in high pH and high salt concentrations: BIII folds from its single
      alpha-helix turn close to its N-terminal, whereas the BI alpha-helix probably
      nucleates within the C-terminal half. We also used quasielastic light scattering
      to demonstrate that the BI and BIII alpha-helix formation in 0.2 M Ca(ClO4)2 is
      accompanied by formation of trimers and hexamers, respectively.

PMID- 10354448
TI  - Tryptophan rotamer distributions in amphipathic peptides at a lipid surface.
AB  - The fluorescence decay of tryptophan is a sensitive indicator of its local
      environment within a peptide or protein. We describe the use of frequency domain
      fluorescence spectroscopy to determine the conformational and environmental
      changes associated with the interaction of single tryptophan amphipathic peptides
      with a phospholipid surface. The five 18-residue peptides studied are based on a
      class A amphipathic peptide known to associate with lipid bilayers. The peptides
      contain a single tryptophan located at positions 2, 3, 7, 12, or 14 in the
      sequence. In aqueous solution, the peptides are unstructured and a triple
      exponential function is required to fit the decay data. Association of the
      peptides with small unilamellar vesicles composed of egg phosphatidylcholine
      reduces the complexity of the fluorescence decays to a double exponential
      function, with a reduced dependence of the preexponential amplitude on peptide
      sequence. The data are interpreted in terms of a rotamer model in which the
      modality and relative proportions of the lifetime components are related to the
      population distribution of tryptophan chi1 rotamers about the Calpha-Cbeta bond.
      Peptide secondary structure and the disposition of the tryptophan residue
      relative to the lipid and aqueous phases in the peptide-lipid complex affect the
      local environment of tryptophan and influence the distribution of side-chain
      rotamers. The results show that measurement of the temporal decay of tryptophan
      emission provides a useful adjunct to other biophysical techniques for
      investigating peptide-lipid and protein-membrane interactions.

PMID- 10354449
TI  - Polymer-in-a-box mechanism for the thermal stabilization of collagen molecules in
      fibers.
AB  - Collagen molecules in solution unfold close to the maximum body temperature of
      the species of animal from which the molecules are extracted. It is therefore
      vital that collagen is stabilized during fiber formation. In this paper, our
      concept that the collagen molecule is thermally stabilized by loss of
      configurational entropy of the molecule in the fiber lattice, is refined by
      examining the process theoretically. Combining an equation for the entropy of a
      polymer-in-a-box with our previously published rate theory analysis of collagen
      denaturation, we have derived a hyperbolic relationship between the denaturation
      temperature, Tm, and the volume fraction, epsilon, of water in the fiber. DSC
      data were consistent with the model for water volume fractions greater than 0.2.
      At a water volume fraction of about 0.2, there was an abrupt change in the slope
      of the linear relationship between 1/Tm and epsilon. This may have been caused by
      a collapse of the gap-overlap fiber structure at low hydrations. At more than 6
      moles water per tripeptide, the enthalpy of denaturation on a dry tendon basis
      was independent of hydration at 58.55 +/- 0.59 J g-1. Between about 6 and 1 moles
      water per tripeptide, dehydration caused a substantial loss of enthalpy of
      denaturation, caused by a loss of water bridges from the hydration network
      surrounding the triple helix. At very low hydrations (less than 1 mole of water
      per tripeptide), where there was not enough water to form bridges and only
      sufficient to hydrogen bond to primary binding sites on the peptide chains, the
      enthalpy was approximately constant at 11.6 +/- 0.69 J g-1. This was assigned
      mainly to the breaking of the direct hydrogen bonds between the alpha chains.

PMID- 10354450
TI  - Probing the energetics of dissociation of carbonic anhydrase-ligand complexes in
      the gas phase.
AB  - This paper describes the use of electrospray ionization-Fourier transform ion
      cyclotron mass spectrometry (ESI-FTICR-MS) to study the relative stabilities of
      noncovalent complexes of carbonic anhydrase II (CAII, EC 4.2.1.1) and
      benzenesulfonamide inhibitors in the gas phase. Sustained off-resonance
      irradiation collision-induced dissociation (SORI-CID) was used to determine the
      energetics of dissociation of these CAII-sulfonamide complexes in the gas phase.
      When two molecules of a benzenesulfonamide (1) were bound simultaneously to one
      molecule of CAII, one of them was found to exhibit significantly weaker binding
      (DeltaE50 = 0.4 V, where E50 is defined as the amplitude of sustained off
      resonance irradiation when 50% of the protein-ligand complexes are dissociated).
      In solution, the benzenesulfonamide group coordinates as an anion to a Zn(II) ion
      bound at the active site of the enzyme. The gas phase stability of the complex
      with the weakly bound inhibitor was the same as that of the inhibitor complexed
      with apoCAII (i.e., CAII with the Zn(II) ion removed from the binding site).
      These results indicate that specific interactions between the sulfonamide group
      on the inhibitor and the Zn(II) ion on CAII were preserved in the gas phase.
      Experiments also showed a higher gas phase stability for the complex of para-NO2
      benzenesulfonamide-CAII than that for ortho-NO2-benzenesulfonamide-CAII complex.
      This result further suggests that steric interactions of the inhibitors with the
      binding pocket of CAII parallel those in solution. Overall, these results are
      consistent with the hypothesis that CAII retains, at least partially, the
      structure of its binding pocket in the gas phase on the time scale (seconds to
      minutes) of the ESI-FTICR measurements.

PMID- 10354451
TI  - Water in actin polymerization.
AB  - We have addressed the question whether water is part of the G- to F-actin
      polymerization reaction. Under osmotic stress, the critical concentration for G
      Ca-ATP actin was reduced for six different osmolytes. These results are
      interpreted as showing that reducing water activity favored the polymerized
      state. The magnitude of the effect correlated, then saturated, with increasing MW
      of the osmolyte and suggested that up to 10-12 fewer water molecules were
      associated with actin when it polymerized. By contrast, osmotic effects were
      insignificant for Mg-ATP actin. The nucleotide binding site of the Mg
      conformation is more closed than the Ca and more closely resembles the closed
      actin conformation in the polymerized state. These results suggest that the water
      may come from the cleft of the nucleotide binding site.

PMID- 10354452
TI  - Mechanism of scaffolding-directed virus assembly suggested by comparison of
      scaffolding-containing and scaffolding-lacking P22 procapsids.
AB  - Assembly of certain classes of bacterial and animal viruses requires the
      transient presence of molecules known as scaffolding proteins, which are
      essential for the assembly of the precursor procapsid. To assemble a procapsid of
      the proper size, each viral coat subunit must adopt the correct quasiequivalent
      conformation from several possible choices, depending upon the T number of the
      capsid. In the absence of scaffolding protein, the viral coat proteins form
      aberrantly shaped and incorrectly sized capsids that cannot package DNA. Although
      scaffolding proteins do not form icosahedral cores within procapsids, an
      icosahedrally ordered coat/scaffolding interaction could explain how scaffolding
      can cause conformational differences between coat subunits. To identify the
      interaction sites of scaffolding protein with the bacteriophage P22 coat protein
      lattice, we have determined electron cryomicroscopy structures of scaffolding
      containing and scaffolding-lacking procapsids. The resulting difference maps
      suggest specific interactions of scaffolding protein with only four of the seven
      quasiequivalent coat protein conformations in the T = 7 P22 procapsid lattice,
      supporting the idea that the conformational switching of a coat subunit is
      regulated by the type of interactions it undergoes with the scaffolding protein.
      Based on these results, we propose a model for P22 procapsid assembly that
      involves alternating steps in which first coat, then scaffolding subunits form
      self-interactions that promote the addition of the other protein. Together, the
      coat and scaffolding provide overlapping sets of binding interactions that drive
      the formation of the procapsid.

PMID- 10354453
TI  - Ultrafast primary processes in photosystem I of the cyanobacterium Synechocystis
      sp. PCC 6803.
AB  - Ultrafast primary processes in the trimeric photosystem I core antenna-reaction
      center complex of the cyanobacterium Synechocystis sp. PCC 6803 have been
      examined in pump-probe experiments with approximately 100 fs resolution. A global
      analysis of two-color profiles, excited at 660 nm and probed at 5 nm intervals
      from 650 to 730 nm, reveals 430 fs kinetics for spectral equilibration among bulk
      antenna chlorophylls. At least two lifetime components (2.0 and 6.5 ps in our
      analysis) are required to describe equilibration of bulk chlorophylls with far
      red-absorbing chlorophylls (>700 nm). Trapping at P700 occurs with 24-ps
      kinetics. The multiphasic bulk left arrow over right arrow red equilibration
      kinetics are intriguing, because prior steady-state spectral studies have
      suggested that the core antenna in Synechocystis sp. contains only one red
      absorbing chlorophyll species (C708). The disperse kinetics may arise from
      inhomogeneous broadening in C708. The one-color optical anisotropy at 680 nm
      (near the red edge of the bulk antenna) decays with 590 fs kinetics; the
      corresponding anisotropy at 710 nm shows approximately 3.1 ps kinetics. The
      latter may signal equilibration among symmetry-equivalent red chlorophylls, bound
      to different monomers within trimeric photosystem I.

PMID- 10354454
TI  - Phase imaging by atomic force microscopy: analysis of living homoiothermic
      vertebrate cells.
AB  - Atomic force microscope-based phase imaging in air is capable of elucidating
      variations in material properties such as adhesion, friction, and
      viscoelasticity. However, the interpretation of phase images of specimens in a
      fluid environment requires clarification. In this report, we systematically
      analyzed atomic force microscope-derived phase images of mica, glass, and
      collagen under the same conditions as used for living cells at various tapping
      forces; the resulting data provide critical information for the interpretation of
      phase images of living cells. The peripheral regions of COS-1 cells consistently
      show a more negative phase shift than the glass substrate in phase images at set
      point amplitude: free amplitude (Asp/A0) = 0.6-0.8. In addition, at all Asp/A0
      values suitable for phase imaging, tapping frequency appears to be high enough to
      ensure that phase shifts are governed primarily by stiffness. Consequently, phase
      imaging is capable of high resolution studies of the cellular surface by
      detecting localized variations in stiffness. We demonstrate that phase imaging of
      a bifurcating fiber in COS-1 cell cytoplasm is readily capable of a lateral
      resolution of approximately 30 nm.

PMID- 10354455
TI  - A multifrequency electron spin resonance study of T4 lysozyme dynamics.
AB  - Electron spin resonance (ESR) spectroscopy at 250 GHz and 9 GHz is utilized to
      study the dynamics and local structural ordering of a nitroxide-labeled enzyme,
      T4 lysozyme (EC 3.2.1.17), in aqueous solution from 10 degrees C to 35 degrees C.
      Two separate derivatives, labeled at sites 44 and 69, were analyzed. The 250-GHz
      ESR spectra are well described by a microscopic ordering with macroscopic
      disordering (MOMD) model, which includes the influence of the tether connecting
      the probe to the protein. In the faster "time scale" of the 250-GHz ESR
      experiment, the overall rotational diffusion rate of the enzyme is too slow to
      significantly affect the spectrum, whereas for the 9-GHz ESR spectra, the overall
      rotational diffusion must be accounted for in the analysis. This is accomplished
      by using a slowly relaxing local structure model (SRLS) for the dynamics, wherein
      the tether motion and the overall motion are both included. In this way a
      simultaneous fit is successfully obtained for both the 250-GHz and 9-GHz ESR
      spectra. Two distinct motional/ordering modes of the probe are found for both
      lysozyme derivatives, indicating that the tether exists in two distinct
      conformations on the ESR time scale. The probe diffuses more rapidly about an
      axis perpendicular to its tether, which may result from fluctuations of the
      peptide backbone at the point of attachment of the spin probe.

PMID- 10354456
TI  - Dielectric properties of human leukocyte subpopulations determined by
      electrorotation as a cell separation criterion.
AB  - The separation and purification of human blood cell subpopulations is an
      essential step in many biomedical applications. New dielectrophoretic
      fractionation methods have great potential for cell discrimination and
      manipulation, both for microscale diagnostic applications and for much larger
      scale clinical problems. To discover whether human leukocyte subpopulations might
      be separable by such methods, the dielectric characteristics of the four main
      leukocyte subpopulations, namely, B- and T-lymphocytes, monocytes, and
      granulocytes, were measured by electrorotation over the frequency range 1 kHz to
      120 MHz. The subpopulations were derived from human peripheral blood by
      magnetically activated cell sorting (MACS) and sheep erythrocyte rosetting
      methods, and the quality of cell fractions was checked by flow cytometry. Mean
      specific membrane capacitance values were calculated from the electrorotation
      data as 10.5 (+/- 3.1), 12.6 (+/- 3.5), 15.3 (+/- 4.3), and 11.0 (+/- 3.2) mF/m2
      for T- and B-lymphocytes, monocytes, and granulocytes, respectively, according to
      a single-shell dielectric model. In agreement with earlier findings, these values
      correlated with the richness of the surface morphologies of the different cell
      types, as revealed by scanning electron microscopy (SEM). The data reveal that
      dielectrophoretic cell sorters should have the ability to discriminate between,
      and to separate, leukocyte subpopulations under appropriate conditions.

PMID- 10354457
TI  - Characterization of molecular mobility in seed tissues: an electron paramagnetic
      resonance spin probe study.
AB  - The relationship between molecular mobility (tauR) of the polar spin probe 3
      carboxy-proxyl and water content and temperature was established in pea axes by
      electron paramagnetic resonance (EPR) and saturation transfer EPR. At room
      temperature, tauR increased during drying from 10(-11) s at 2.0 g water/g dry
      weight to 10(-4) s in the dry state. At water contents below 0.07 g water/g dry
      weight, tauR remained constant upon further drying. At the glass transition
      temperature, tauR was constant at approximately 10(-4) s for all water contents
      studied. Above Tg, isomobility lines were found that were approximately parallel
      to the Tg curve. The temperature dependence of tauR at all water contents studied
      followed Arrhenius behavior, with a break at Tg. Above Tg the activation energy
      for rotational motion was approximately 25 kJ/mol compared to 10 kJ/mol below Tg.
      The temperature dependence of tauR could also be described by the WLF equation,
      using constants deviating considerably from the universal constants. The
      temperature effect on tauR above Tg was much smaller in pea axes, as found
      previously for sugar and polymer glasses. Thus, although glasses are present in
      seeds, the melting of the glass by raising the temperature will cause only a
      moderate increase in molecular mobility in the cytoplasm as compared to a huge
      increase in amorphous sugars.

PMID- 10354458
TI  - A new study of bacterial motion: superconducting quantum interference device
      microscopy of magnetotactic bacteria.
AB  - The recently developed "microscope" based on a high-Tc dc SQUID (superconducting
      quantum interference device) is used to detect the magnetic fields produced by
      the motion of magnetotactic bacteria, which have permanent dipole moments. The
      bacteria, in growth medium at room temperature, can be brought to within 15
      micron of a SQUID at liquid nitrogen temperature. Measurements are performed on
      both motile and nonmotile bacteria. In the nonmotile case, we obtain the power
      spectrum of the magnetic field noise produced by the rotational Brownian motion
      of the ensemble of bacteria. Furthermore, we measure the time-dependent field
      produced by the ensemble in response to an applied uniform magnetic field. In the
      motile case, we obtain the magnetic field power spectra produced by the swimming
      bacteria. Combined, these measurements determine the average rotational drag
      coefficient, magnetic moment, and the frequency and amplitude of the vibrational
      and rotational modes of the bacteria in a unified set of measurements. In
      addition, the microscope can easily resolve the motion of a single bacterium.
      This technique can be extended to any cell to which a magnetic tag can be
      attached.

PMID- 10354460
TI  - Real-time monitoring of yeast cell division by dielectric spectroscopy.
AB  - To assay cell cycle progression in synchronized culture of yeast we have applied
      dielectric spectroscopy to its real-time monitoring. The dielectric monitoring is
      based on the electromagnetic induction method, regarded as a nonelectrode method,
      which has resolved the problems encountered in measurements with metal
      electrodes, namely electrode polarization and bubble formation on electrodes. In
      the synchronized culture with temperature-sensitive cell division cycle mutants,
      the permittivity of the culture broth showed cyclic changes at frequencies below
      300 kHz. The increase and decrease in the cyclic changes of the relative
      permittivity correspond to the increase in cell length and bud size and to the
      septum formation between mother and daughter cells, respectively.

PMID- 10354459
TI  - Anomalous diffusion of major histocompatibility complex class I molecules on HeLa
      cells determined by single particle tracking.
AB  - Single-particle tracking (SPT) was used to determine the mobility characteristics
      of MHC (major histocompatibility complex) class I molecules at the surface of
      HeLa cells at 22 degrees C and on different time scales. MHC class I was labeled
      using the Fab fragment of a monoclonal antibody (W6/32), covalently bound to
      either R-phycoerythrin or fluorescent microspheres, and the particles were
      tracked using high-sensitivity fluorescence imaging. Analysis of the data for a
      fixed time interval suggests a reasonable fit to a random diffusion model. The
      best fit values of the diffusion coefficient D decreased markedly, however, with
      increasing time interval, demonstrating the existence of anomalous diffusion.
      Further analysis of the data shows that the diffusion is anomalous over the
      complete time range investigated, 4-300 s. Fitting the results obtained with the
      R-phycoerythrin probe to D = D0talpha-1, where Do is a constant and t is the
      time, gave D0 = (6.7 +/- 4.5) x 10(-11) cm2 s-1 and alpha = 0.49 +/- 0.16.
      Experiments with fluorescent microspheres were less reproducible and gave slower
      anomalous diffusion. The R-phycoerythrin probe is considered more reliable for
      fluorescent SPT because it is small (11 x 8 nm) and monovalent. The type of
      motion exhibited by the class I molecules will greatly affect their ability to
      migrate in the plane of the membrane. Anomalous diffusion, in particular, greatly
      reduces the distance a class I molecule can travel on the time scale of minutes.
      The present data are discussed in relation to the possible role of diffusion and
      clustering in T-cell activation.

PMID- 10354461
TI  - Involvement of protein tyrosine kinase in the InsP3-induced activation of Ca2+
      dependent Cl- currents in cultured cells of the rat retinal pigment epithelium.
AB  - This combined study of patch-clamp and intracellular Ca2+ ([Ca2+]i) measurement
      was undertaken in order to identify signaling pathways that lead to activation of
      Ca2+-dependent Cl- channels in cultured rat retinal pigment epithelial (RPE)
      cells. Intracellular application of InsP3 (10 microM) led to an increase in
      [Ca2+]i and activation of Cl- currents. In contrast, intracellular application of
      Ca2+ (10 microM) only induced transient activation of Cl- currents. After full
      activation by InsP3, currents were insensitive to removal of extracellular Ca2+
      and to the blocker of ICRAC, La3+ (10 microM), despite the fact that both
      maneuvers led to a decline in [Ca2+]i. The InsP3-induced rise in Cl- conductance
      could be prevented either by thapsigargin-induced (1 microM) depletion of
      intracellular Ca2+ stores or by removal of Ca2+ prior to the experiment. The
      effect of InsP3 could be mimicked by intracellular application of the Ca2+
      chelator BAPTA (10 mm). Block of PKC (chelerythrine, 1 microM) had no effect.
      Inhibition of Ca2+/calmodulin kinase (KN-63, KN-92; 5 microM) reduced Cl-
      conductance in 50% of the cells investigated without affecting [Ca2+]i.
      Inhibition of protein tyrosine kinase (50 microM tyrphostin 51, 5 microM
      genistein, 5 microM lavendustin) reduced an increase in [Ca2+]i and Cl-
      conductance. In summary, elevation of [Ca]i by InsP3 leads to activation of Cl-
      channels involving cytosolic Ca2+ stores and Ca2+ influx from extracellular
      space. Tyrosine kinases are essential for the Ca2+-independent maintenance of
      this conductance.

PMID- 10354462
TI  - Veratridine-mediated Ca2+ dynamics and exocytosis in paramecium cells.
AB  - We analyzed [Ca2+]i transients in Paramecium cells in response to veratridine for
      which we had previously established an agonist effect for trichocyst exocytosis
      (Erxleben & Plattner, 1994. J. Cell Biol. 127:935-945; Plattner et al., 1994. J.
      Membrane Biol. 158:197-208). Wild-type cells (7S), nondischarge strain nd9-28
      degrees C and trichocyst-free strain "trichless" (tl), respectively, displayed
      similar, though somewhat diverging time course and plateau values of [Ca2+]i
      transients with moderate [Ca2+]o in the culture/assay fluid (50 microM or 1 mm).
      In 7S cells which are representative for a normal reaction, at [Ca2+]o = 30 nm
      (c.f. [Ca2+]resti = approximately 50 to 100 nm), veratridine produced only a
      small cortical [Ca2+]i transient. This increased in size and spatial distribution
      at [Ca2+]o = 50 microM of 1 mm. Interestingly with unusually high yet nontoxic
      [Ca2+]o = 10 mm, [Ca2+]i transients were much delayed and also reduced, as is
      trichocyst exocytosis. We interpret our results as follows. (i) With [Ca2+]o = 30
      nm, the restricted residual response observed is due to Ca2+ mobilization from
      subplasmalemmal stores. (ii) With moderate [Ca2+]o = 50 microM to 1 mm, the
      established membrane labilizing effect of veratridine may activate not only
      subplasmalemmal stores but also Ca2+o influx from the medium via so far
      unidentified (anteriorly enriched) channels. Visibility of these phenomena is
      best in tl cells, where free docking sites allow for rapid Ca2+ spread, and least
      in 7S cells, whose perfectly assembled docking sites may "consume" a large part
      of the [Ca2+]i increase. (iii) With unusually high [Ca2+]o, mobilization of
      cortical stores and/or Ca2+o influx may be impeded by the known membrane
      stabilizing effect of Ca2+o counteracting the labilizing/channel activating
      effect of veratridine. (iv) We show these effects to be reversible, and, hence,
      not to be toxic side-effects, as confirmed by retention of injected calcein. (v)
      Finally, Mn2+ entry during veratridine stimulation, documented by Fura-2
      fluorescence quenching, may indicate activation of unspecific Me2+ channels by
      veratridine. Our data have some bearing on analysis of other cells, notably
      neurons, whose response to veratridine is of particular and continuous interest.

PMID- 10354463
TI  - Inhibition by cAMP of calcium-activated chloride currents in cultured Sertoli
      cells from immature testis.
AB  - We have characterized a Ca2+-dependent Cl- current (ClCa) in cultured Sertoli
      cells from immature rat testis by using the whole cell recording patch-clamp
      technique. Cells dialyzed with pipette solutions containing 3 mm adenoside
      triphosphate (ATP) and 1 microM free Ca2+, exhibited outward currents which were
      inhibited by 4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and
      anthracene-9-carboxylic acid (9-AC) but insensitive to tetraethylammonium (TEA).
      Dialysis of cells with pipette solutions containing less than 1 nm free Ca2+
      strongly reduced the currents indicating that they were Ca2+ dependent. With
      cells dialyzed with Cs+ glutamate-rich pipette solutions containing 0.2 mm EGTA,
      10 microM ionomycin induced outward currents having properties of Ca2+-activated
      Cl- currents. With ATP-free pipette solution, the magnitude of currents was not
      modified suggesting the direct control by Ca2+. By contrast, addition of 0.1 mm
      cAMP in the pipette solution or the superfusion of cells by a permeant analogue
      of cAMP strongly reduced the currents. These results may suggest that ClCa is
      inhibited by cAMP-dependent protein kinase. Finally, our results do not agree
      with the model of primary fluid secretion by exocrine cells, but are in agreement
      with a hyperpolarizing effect of cAMP in primary culture of Sertoli cells and the
      release of a low Cl- and bicarbonate-rich primary fluid by these cells.

PMID- 10354464
TI  - Downregulation of epithelial sodium channel (ENaC) by CFTR co-expressed in
      Xenopus oocytes is independent of Cl- conductance.
AB  - Defective regulatory interactions between the cystic fibrosis conductance
      regulator (CFTR) and the epithelial sodium channel (ENaC) have been implicated in
      the elevated Na+ transport rates across cystic fibrosis airway epithelium. It has
      recently been proposed that ENaC downregulation by CFTR depends on the ability of
      CFTR to conduct Cl- into the cell and is negligible when Cl- flows out of the
      cell. To study the mechanisms of this downregulation we have measured amiloride
      inhibitable Na+ current (Iamil) in oocytes co-expressing rat ENaC and human wild
      type CFTR. In oocytes voltage-clamped to -60 mV, stimulating CFTR with 1 mm IBMX
      reduced Iamil by up to 80%, demonstrating that ENaC is inhibited when Cl- is
      conducted out of the cell. Decreasing the level of CFTR stimulation in a single
      oocyte, decreased both the degree of Iamil downregulation and the CFTR-mediated
      plasma membrane Cl- conductance, suggesting a direct correlation. However, Iamil
      downregulation was not affected when Cl- flux across oocyte membrane was
      minimized by holding the oocyte membrane potential near the Cl- reversal
      potential (67% +/- 10% inhibition at -20 mV compared to 79% +/- 4% at -60 mV)
      demonstrating that Iamil downregulation was independent of the amount of current
      flow through CFTR. Studies with the Ca2+-sensitive photoprotein aequorin showed
      that Ca2+ is not involved in Iamil downregulation by CFTR, although Ca2+
      injection into the cytoplasm did inhibit Iamil. These results demonstrate that
      downregulation of ENaC by CFTR depends on the degree of CFTR stimulation, but
      does not involve Ca2+ and is independent of the direction and magnitude of Cl-
      transport across the plasma membrane.

PMID- 10354465
TI  - Effects of 2,3-butanedione 2-monoxime on Ca2+ release channels (ryanodine
      receptors) of cardiac and skeletal muscle.
AB  - Single channel and [3H]ryanodine binding measurements were performed to test for
      a direct functional interaction between 2,3-butanedione 2-monoxime (BDM) and the
      skeletal and cardiac muscle sarcoplasmic reticulum Ca2+ release channels
      (ryanodine receptors). Single channel measurements were carried out in symmetric
      0.25 m KCl media using the planar lipid bilayer method. BDM (1-10 mm) activated
      suboptimally Ca2+-activated (0.5-1 microM free Ca2+) single, purified and native
      cardiac and skeletal release channels in a concentration-dependent manner by
      increasing the number of channel events without a change of single channel
      conductances. BDM activated the two channel isoforms when added to either side of
      the bilayer. At a maximally activating cytosolic Ca2+ concentration of 20 microM,
      BDM was without effect on the cardiac channel, whereas it inhibited skeletal
      channel activities with IC50 approximately 2.5 mm. In agreement with single
      channel measurements, high-affinity [3H]ryanodine binding to the two channel
      isoforms was increased in a concentration-dependent manner at </=1 microM Ca2+.
      BDM was without a noticeable effect at low (</=0.01 microM) Ca2+ concentrations.
      At 20 microM Ca2+, BDM inhibited the skeletal but not cardiac channel. These
      results suggest that BDM regulates the Ca2+ release channels from the
      sarcoplasmic reticulum of skeletal and cardiac muscle in a concentration, Ca2+
      and tissue-dependent manner.

PMID- 10354467
TI  - Ten years of gene targeting: targeted mouse mutants, from vector design to
      phenotype analysis.
AB  - Gene targeting, defined as the introduction of site-specific modifications into
      the genome by homologous recombination, has revolutionarized the field of mouse
      genetics and allowed the analysis of diverse aspects of gene function in vivo. It
      is now possible to engineer specific genetic alterations ranging from subtle
      mutations to chromosomal rearrangements and more recently, even tissue-specific
      inducible gene targeting with temporo-spatial control has become feasible. This
      review tries to recapitulate what we have learned in this extremely rapidly
      expanding field during the past decade. Diverse aspects of the technique will be
      discussed starting from basic construct design to the analysis of complex
      phenotypes, including recent advances on inducible expression system. Many
      examples from different areas of biomedical research are given to illustrate the
      purpose and limitations of the employed experimental approaches.

PMID- 10354466
TI  - Distortion component analysis of outer hair cell motility-related gating charge.
AB  - The underlying Boltzmann characteristics of motility-related gating currents of
      the outer hair cell (OHC) are predicted to generate distortion components in
      response to sinusoidal transmembrane voltages. We studied this distortion since
      it reflects the mechanical activity of the cell that may contribute to peripheral
      auditory system distortion. Distortion components in the OHC electrical response
      were analyzed using the whole-cell voltage clamp technique, under conditions
      where ionic conductances were blocked. Single or double-sinusoidal transmembrane
      voltage stimulation was delivered at various holding voltages, and distortion
      components of the current responses were detected by Fourier analysis. Current
      response magnitude and phase of each distortion component as a function of
      membrane potential were compared with characteristics of the voltage-dependent
      capacitance, obtained by voltage stair-step transient analysis or dual-frequency
      admittance analysis. The sum distortion was most prominent among the distortion
      components at all holding voltages. Notches in the sum (f1+f2), difference (f2
      f1) and second harmonic (2f) components occur at the voltage where peak voltage
      dependent capacitance resides (VpkCm). Rapid phase reversals also occurred at
      VpkCm, but phase remained fairly stable at more depolarized and hyperpolarized
      potentials. Thus, it is possible to extract Boltzmann parameters of the motility
      related charge movement from these distortion components. In fact, we have
      developed a technique to follow changes in the voltage dependence of OHC motility
      and charge movement by tracking the voltage at phase reversal of the f2-f1
      product. When intracellular turgor pressure was changed, VpkCm and distortion
      notch voltages shifted in the same direction. These data have important
      implications for understanding cochlear nonlinearity, and more generally,
      indicate the usefulness of distortion analysis to study displacement currents.

PMID- 10354469
TI  - Pax2/5 and Pax6 subdivide the early neural tube into three domains.
AB  - The nested expression patterns of the paired-box containing transcription factors
      Pax2/5 and Pax6 demarcate the midbrain and forebrain primordium at the neural
      plate stage. We demonstrate that, in Pax2/5 deficient mice, the
      mesencephalon/metencephalon primordium is completely missing, resulting in a
      fusion of the forebrain to the hindbrain. Morphologically, in the alar plate the
      deletion is characterized by the substitution of the tectum (dorsal midbrain) and
      cerebellum (dorsal metencephalon) by the caudal diencephalon and in the basal
      plate by the replacement of the midbrain tegmentum by the ventral metencephalon
      (pons). Molecularly, the loss of the tectum is demonstrated by an expanded
      expression of Pax6, (the molecular determinant of posterior commissure), and a
      rostral shift of the territory of expression of Gbx2 and Otp (markers for the
      pons), towards the caudal diencephalon. Our results suggest that an intact
      territory of expression of Pax2/5 in the neural plate, nested between the rostral
      and caudal territories of expression of Pax6, is necessary for defining the
      midbrain vesicle.

PMID- 10354468
TI  - A methionine aminopeptidase and putative regulator of translation initiation is
      required for cell growth and patterning in Drosophila.
AB  - We have isolated mutations in the gene Drosophila methionine aminopeptidase 2
      (DMAP2), which encodes a homolog of the type 2 methionine aminopeptidase from
      yeast, also known as the eukaryotic initiation factor 2alpha (eIF2alpha)
      associated protein p67. Weak DMAP2 mutations cause ommatidial rotation defects
      and loss of ventral tissue in the compound eye as well as extra wing veins,
      whereas stronger alleles impair tissue growth. These limited phenotypes, in
      conjunction with the differential accumulation of DMAP2 transcripts throughout
      embryonic and larval development, suggest that a subset of proteins is spatially
      and temporally regulated at the level of post-translational processing or
      translation initiation during development. These results provide genetic evidence
      for post-transcriptional control in the development of multicellular organisms.

PMID- 10354470
TI  - The suppressor of forked gene of Drosophila, which encodes a homologue of human
      CstF-77K involved in mRNA 3'-end processing, is required for progression through
      mitosis.
AB  - The Suppressor of forked (Su(f)) protein of Drosophila melanogaster is a
      homologue of the 77K subunit of human cleavage stimulation factor required for
      cleavage of pre-mRNAs before addition of poly(A). We have previously shown that
      the Su(f) protein is not ubiquitously distributed: it accumulates in dividing
      cells at various stages of Drosophila development. In this paper, we show that
      phenotypes of su(f) temperature-sensitive mutants result from a defect in cell
      proliferation. Analysis of the mitotic phenotype of su(f) temperature-sensitive
      alleles in larval brain and in imaginal discs reveals an increase in the number
      of metaphases with overcondensed chromosomes and asymmetric or reduced mitotic
      spindles. In contrast, neural differentiation in eye imaginal discs of the same
      mutant flies does not appear to be affected. These results indicate that su(f) is
      required during cell division for progression through metaphase. Taken together,
      these data suggest that a decrease in su(f) activity preferentially affects 3'
      end formation of particular mRNAs, some of which are involved in mitosis, and are
      in agreement with a role of su(f) in the regulation of poly(A) site utilization.

PMID- 10354471
TI  - Establishment and maintenance of the border of the neural plate in the chick:
      involvement of FGF and BMP activity.
AB  - We have investigated the cell interactions and signalling molecules involved in
      setting up and maintaining the border between the neural plate and the adjacent
      non-neural ectoderm in the chick embryo at primitive streak stages. msx-1, a
      target of BMP signalling, is expressed in this border at a very early stage. It
      is induced by FGF and by signals from the organizer, Hensen's node. The node also
      induces a ring of BMP-4, some distance away. By the early neurula stage, the edge
      of the neural plate is the only major site of BMP-4 and msx-1 expression, and is
      also the only site that responds to BMP inhibition or overexpression. At this
      time, the neural plate appears to have a low level of BMP antagonist activity.
      Using in vivo grafts and in vitro assays, we show that the position of the border
      is further maintained by interactions between non-neural and neural ectoderm. We
      conclude that the border develops by integration of signals from the organizer,
      the developing neural plate, the paraxial mesoderm and the non-neural epiblast,
      involving FGFs, BMPs and their inhibitors. We suggest that BMPs act in an
      autocrine way to maintain the border state.

PMID- 10354472
TI  - Vegetal cell fate specification and anterior neuroectoderm formation by Hroth,
      the ascidian homologue of orthodenticle/otx.
AB  - To obtain insights into the mechanisms of gastrulation and neural tube formation,
      we studied the function and regulation of expression of Hroth, the ascidian
      homologue of orthodenticle/otx, during embryogenesis. Microinjection of synthetic
      Hroth mRNA into fertilized eggs led to embryos with an expanded trunk and a
      reduced tail. In these embryos, development of notochord and muscle was effected.
      Also, Hroth overexpression caused ectopic formation of anterior neuroectoderm,
      along with suppression of epidermis development, even in the absence of cell-cell
      interaction. Furthermore, we demonstrated that ectodermal expression of Hroth
      requires an inductive influence from the vegetal hemisphere cells. These data
      suggest roles of Hroth in both specification of mesoendodermal cells and anterior
      neuroectoderm formation.

PMID- 10354473
TI  - SWiP-1: novel SOCS box containing WD-protein regulated by signalling centres and
      by Shh during development.
AB  - We describe a novel chick WD-protein, cSWiP-1, expressed in somitic mesoderm and
      developing limb buds as well as in other embryonic structures where Hedgehog
      signalling has been shown to play a role. Using embryonic manipulations we show
      that in somites cSWiP-1 expression integrates two signals originating from
      structures adjacent to the segmental mesoderm: a positive signal from the
      notochord and a negative signal from intermediate and/or lateral mesoderm. In
      explant cultures of somitic mesoderm, Shh protein induces cSWiP-1, while a
      blocking antibody to Shh inhibits the induction of cSWiP-1 by the notochord.
      These results show that the positive signal from the notochord is mediated by
      Shh. We also show that in limb buds cSWiP-1 is upregulated by ectopic Shh. This
      occurs in about the same time period as upregulation of BMP2, placing cSWiP-1
      among the earliest markers for the change of limb pattern caused by ectopic Shh.
      We also describe a human homologue of cSWiP-1 and a mouse gene, mSWiP-2, that is
      more distantly related to SWiP-1, suggesting that SWiP-1 belongs to a novel
      subfamily of WD-proteins.

PMID- 10354474
TI  - Stu-7/air-2 is a C. elegans aurora homologue essential for chromosome segregation
      during embryonic and post-embryonic development.
AB  - We have isolated a new sterile uncoordinated C. elegans mutant, stu-7, which is
      defective in post-embryonic cell divisions in a regionally-specific fashion. The
      anterior of the worm is relatively unaffected whereas the mid-body and/or
      posterior are markedly thin, often resulting in worms having a central 'waist'.
      We have cloned stu-7 and found that it encodes a member of the recently expanding
      aurora sub-family of serine/threonine kinases. Elimination of maternal as well as
      zygotic stu-7 expression reveals that stu-7 is essential for mitosis from the
      first embryonic cell cycle onwards and is required for chromosome segregation
      though not for centrosome separation or for setting up a bipolar spindle.
      Multicopy expression of stu-7 also causes mitotic defects, suggesting that the
      level of this protein must be tightly controlled in order to maintain genetic
      stability during development.

PMID- 10354475
TI  - Evidence that Hoxa expression domains are evolutionarily transposed in spinal
      ganglia, and are established by forward spreading in paraxial mesoderm.
AB  - Transposition of anatomical structures along the anteroposterior axis has been a
      commonly used mechanism for changing body proportions during the course of
      evolutionary time. Earlier work (Gaunt, S.J., 1994. Conservation in the Hox code
      during morphological evolution. Int. J. Dev. Biol. 38, 549-552; Burke, A.C.,
      Nelson, C.E., Morgan, B.A., Tabin, C., 1995. Hox genes and the evolution of
      vertebrate axial morphology. Development 121, 333-346) showed how transposition
      in mesodermal derivatives (vertebrae) could be attributed to transposition in the
      expression of Hox genes along the axial series of somites. We now show how
      transposition in the segmental arrangement of the spinal nerves can also be
      correlated with shifts in the expression domains of Hox genes. Specifically, we
      show how the expression domains of Hoxa-7, a-9 and a-10 in spinal ganglia
      correspond similarly in both mouse and chick with the positions of the brachial
      and lumbosacral plexuses, and that this is true even though the brachial plexus
      of chick is shifted posteriorly, relative to mouse, by seven segmental units. In
      spite of these marked species differences in the boundaries of Hoxa-7 expression,
      cis regulatory elements located up to 5 kb upstream of the chick Hoxa-7 gene
      showed much functional and structural conservation with those described in the
      mouse (Puschel, A.W., Balling, R., Gruss, P., 1991. Separate elements cause
      lineage restriction and specify boundaries of Hox-1.1 expression. Development
      112, 279-287; Knittel, T., Kessel, M., Kim, M.H., Gruss, P., 1995. A conserved
      enhancer of the human and murine Hoxa-7 gene specifies the anterior boundary of
      expression during embryonal development. Development 121, 1077-1088). We also
      show that chick Hoxa-7 and a-10 expression domains spread forward into regions of
      somites that are initially negative for the expression of these genes. We discuss
      this as evidence that Hox expression in paraxial mesoderm spreads forward, as
      earlier found for neurectoderm and lateral plate mesoderm, in a process that
      occurs independently of cell movement.

PMID- 10354476
TI  - Dorsal and ventral retinal territories defined by retinoic acid synthesis, break
      down and nuclear receptor expression.
AB  - Determination of the dorso-ventral dimension of the vertebrate retina is known to
      involve retinoic acid (RA), in that high RA activates expression of a ventral
      retinaldehyde dehydrogenase and low RA of a dorsal dehydrogenase. Here we show
      that in the early eye vesicle of the mouse embryo, expression of the dorsal
      dehydrogenase is preceded by, and transiently overlaps with, the RA-degrading
      oxidase CYP26. Subsequently in the embryonic retina, CYP26 forms a narrow
      horizontal boundary between the dorsal and ventral dehydrogenases, creating a
      trough between very high ventral and moderately high dorsal RA levels. Most of
      the RA receptors are expressed uniformly throughout the retina except for the RA
      sensitive RARbeta, which is down-regulated in the CYP26 stripe. The orphan
      receptor COUP-TFII, which modulates RA responses, colocalizes with the dorsal
      dehydrogenase. The organization of the embryonic vertebrate retina into dorsal
      and ventral territories divided by a horizontal boundary has parallels to the
      division of the Drosophila eye disc into dorsal, equatorial and ventral zones,
      indicating that the similarities in eye morphogenesis extend beyond single
      molecules to topographical patterns.

PMID- 10354477
TI  - The acquisition of competence to respond to ecdysone in Drosophila is transcript
      specific.
AB  - The steroid hormone ecdysone induces a precise sequence of gene activity in
      Drosophila melanogaster salivary glands in late third larval instar larvae. The
      acquisition of competence for this response does not result from a single event
      or pathway but requires factors that accumulate throughout the instar. Individual
      transcripts become competent to respond at different times and their expression
      is differentially affected in ecd1, dor22 and BR-C mutants. The induction of
      early-late transcripts, originally assumed to necessarily follow early
      transcripts, is partially independent of early transcript activation. Attempts to
      inhibit the synthesis of regulatory proteins reveal transcript-specific
      superinduction effects. Furthermore these inhibitors lead to the induction of
      betaFTZ-F1 and E93 transcripts at levels normally found in prepupal glands. These
      studies reveal the complexity of the processes underlying the establishment of a
      hormonal response.

PMID- 10354478
TI  - mGCMa is a murine transcription factor that overrides cell fate decisions in
      Drosophila.
AB  - During neural development of Drosophila melanogaster, Glial Cells Missing (GCM),
      functions as a binary switch that promotes glial cell fate while simultaneously
      inhibiting the neuronal fate. Sequence similarities between GCM and the recently
      identified mouse protein mGCMa are strictly limited to the aminoterminal DNA
      binding domain. Here we show that mGCMa efficiently activates transcription in
      Drosophila cells just as Drosophila GCM activates transcription in mammalian
      cells. Transactivation potential was present in two separate regions of mGCMa
      outside the DNA-binding domain. One of them mapped to the carboxyterminal 88
      amino acids, a location corresponding exactly to the transactivation domain of
      GCM. Similarities between GCM and mGCMa were also observed in vivo.
      Overexpression of mGCMa in the developing nervous system of Drosophila embryos
      led to an increase in glial-like cells at the expense of neurons. Outside the
      neurogenic region, mGCMa interfered with epidermal development, as evident from
      changes in cell morphology and marker expression. Thus, mGCMa function is at
      least partially independent of a cell's predisposition to a neural fate. The
      potent activity of mGCMa in Drosophila and its extensive functional similarities
      to GCM make mGCMa a candidate for a regulator of mouse glial development.

PMID- 10354479
TI  - Sonic hedgehog (SHH) specifies muscle pattern at tissue and cellular chick level,
      in the chick limb bud.
AB  - Development of the musculature in chick limbs involves tissue and cellular
      patterning. Patterning at the tissue level leads to the precise arrangement of
      specific muscles; at the cellular level patterning gives rise to the fibre type
      diversity in muscles. Although the data suggests that the information controlling
      muscle patterning is localised within the limb mesenchyme and not in the somitic
      myogenic precursor cells themselves, the mechanisms underlying muscle
      organisation have still to be elucidated. The anterior-posterior axis of the limb
      is specified by a group of cells in the posterior region of the limb mesenchyme,
      called the zone of polarizing activity (ZPA). When polarizing-region cells are
      grafted to the anterior margin of the bud, they cause mirror-image digit
      duplications to be produced. The effect of ZPA grafts can be reproduced by
      application of retinoic acid (RA) beads and by grafting sonic hedgehog (SHH)
      expressing cells to the anterior margin of the limb. Although most previous
      studies have looked at changes of the skeletal patterning, ZPA and RA also affect
      muscle patterning. In this report, we investigated the role of SHH in tissue and
      cellular patterning of forearm wing muscles. Ectopic application of a localised
      source of SHH to the anterior margin of the wing, leading to complete digit
      duplication, is able to transform anterior forearm muscles into muscles with a
      posterior identity. Moreover, the ectopic source of SHH induces a mirror image
      duplication of the normal posterior muscles fibre types in the new posterior
      muscles. The reorganisation of the slow fibres can be detected before muscle mass
      cleavage has started; suggesting that the appropriate fibre type arrangement is
      in place before the splitting process can be observed.

PMID- 10354480
TI  - OTX2 homeodomain protein binds a DNA element necessary for interphotoreceptor
      retinoid binding protein gene expression.
AB  - Transcription of the human interphotoreceptor retinoid binding protein (IRBP)
      gene is strictly tissue specific, being restricted to retinal photoreceptors and
      pinealocytes. We have previously demonstrated that a sequence named A element, in
      the IRBP promoter is essential for IRBP gene transcription in vivo. Here we
      demonstrate that the human homeodomain protein OTX2 is present in nuclear
      extracts of IRBP expressing cells and specifically interacts with the IRBP A
      promoter element in vitro. OTX2, as well as CRX, a homeodomain protein very
      similar to OTX2, activates the human IRBP promoter in co-transfection
      experiments.

PMID- 10354481
TI  - Molecular genetic analysis of the Drosophila trithorax-related gene which encodes
      a novel SET domain protein.
AB  - The products of the trithorax and Polycomb groups genes maintain the activity and
      silence, respectively, of many developmental genes including genes of the
      homeotic complexes. This transcriptional regulation is likely to involve
      modification of chromatin structure. Here, we report the cloning and
      characterization of a new gene, trithorax-related (trr), which shares sequence
      similarities with members of both the trithorax and Polycomb groups. The trr
      transcript is 9.6 kb in length and is present throughout development. The TRR
      protein, as predicted from the nucleotide sequence of the open reading frame, is
      2431 amino acids in length and contains a PHD finger-like domain and a SET
      domain, two highly conserved protein motifs found in several trithorax and
      Polycomb group proteins, and in modifiers of position effect variegation. TRR is
      most similar in sequence to the human ALR protein, suggesting that trr is a
      Drosophila homologue of the ALR. TRR is also highly homologous to Drosophila
      TRITHORAX protein and to its human homologue, ALL-1/HRX. However, preliminary
      genetic analysis of a trr null allele suggests that TRR protein may not be
      involved in regulation of homeotic genes (i.e. not a member of the trithorax or
      Polycomb groups) or in position effect variegation.

PMID- 10354482
TI  - Cell-type specific modular regulation of derailed in the Drosophila nervous
      system.
AB  - The derailed (drl) gene encodes a receptor tyrosine kinase (RTK) that governs
      aspects of axon guidance and muscle-epidermal interactions in the Drosophila
      embryo. To determine the types of neurons that express drl, we have examined a
      series of drl promoter fusions to axon-targeted reporters. We have identified
      enhancers that drive reporter expression in four distinct subtypes of embryonic
      neurons, all of which project axons in the anterior commissure of the developing
      nervous system. We also identified enhancers driving expression in the drl
      expressing muscles and epidermal attachment cells. These enhancers define the
      classes of neurons projecting in the anterior commissure and can be used to
      precisely define axon pathfinding errors in drl and other mutants.

PMID- 10354483
TI  - Pattern of Brachyury gene expression in starfish embryos resembles that of
      hemichordate embryos but not of sea urchin embryos.
AB  - Echinoderms, hemichordates and chordates are deuterostomes and share a number of
      developmental features. The Brachyury gene is responsible for formation of the
      notochord, the most defining feature of chordates, and thus may be a key to
      understanding the origin and evolution of the chordates. Previous studies have
      shown that the ascidian Brachyury (As-T and Ci-Bra) is expressed in the notochord
      and that a sea urchin Brachyury (HpTa) is expressed in the secondary mesenchyme
      founder cells. A recent study by [Tagawa et al. (1998)], however, revealed that a
      hemichordate Brachyury (PfBra) is expressed in a novel pattern in an archenteron
      invagination region and a stomodaeum invagination region in the gastrula. The
      present study demonstrated that the expression pattern of Brachyury (ApBra) of
      starfish embryos resembles that of PfBra in hemichordate embryos but not of HpTa
      in sea urchin embryos. Namely, ApBra is expressed in an archenteron invagination
      region and a stomodaeum invagination region.

PMID- 10354484
TI  - Mespo: a novel basic helix-loop-helix gene expressed in the presomitic mesoderm
      and posterior tailbud of Xenopus embryos.
AB  - We have isolated a novel gene from Xenopus, called Mespo, which encodes a protein
      containing a basic helix-loop-helix (bHLH) motif characteristic of a family of
      transcriptional activators. Mespo expression begins at the gastrula stage and
      continues throughout tailbud stages; expression occurs in the presomitic mesoderm
      and the posterior tailbud. Mespo has high similarity to a subfamily of bHLH
      transcription factors involved in segmentation of the presomitic paraxial
      mesoderm.

PMID- 10354485
TI  - The genotype and epigenotype synergize to diversify the spatial pattern of
      expression of the imprinted H19 gene.
AB  - Little is known of how the genetic background effects the phenomenon of genomic
      imprinting. The H19 gene belongs to a cluster of imprinted genes on human
      chromosome 11. Here we show that the alternative splicing of a human H19
      transcript is genotype-specific. Moreover, this variant transcript, which lacks
      exon 4, is either not found at all, is widely expressed or is confined to extra
      villous cytotrophoblasts in first trimester placenta, depending on a combination
      of the genotype and the sex of the transmitting parent.

PMID- 10354486
TI  - Dynamic restricted expression of the chaperone Hsc70 in early chick development.
AB  - The non-inducible chaperone heat shock cognate 70 kDa (Hsc70) is regulated during
      development. We now characterize its dynamic expression pattern from gastrulation
      to early organogenesis. Throughout this developmental period, hsc70 transcripts
      were largely restricted to neuroectoderm- and mesoderm-derived structures. In
      stage 10 embryos, Hsc70 protein was expressed in the neural tube with increasing
      rostrocaudal and decreasing dorsoventral gradients, and in some somite cells.
      This highly regulated expression of Hsc70 is likely to reflect specific
      developmental functions, besides its well-characterized role in protein folding.

PMID- 10354487
TI  - Expression of retinoic acid 4-hydroxylase (CYP26) during mouse and Xenopus laevis
      embryogenesis.
AB  - Retinoids are important signal molecules during vertebrate embryonic development
      and their synthesis as well as catabolism should therefore be strictly regulated.
      The retinoic acid (RA) 4-hydroxylase, belonging to the cytochrome P450 family
      CYP26, is an enzyme catalyzing the 4-hydroxylation of RA, thereby regulating RA
      homeostasis. Here we describe the temporal and spatial expression patterns of
      mouse (mCYP26) and Xenopus laevis (xCYP26) homologues. In mouse, expression is
      detected in uterine crypt, around differentiating cartilage, several regions of
      the head, regions of the pharynx, the neural retina, and several regions of the
      trunk. In Xenopus, Northern blot analysis shows presence of xCYP26 transcripts
      before the MBT and an increased expression level during gastrulation. Whole-mount
      in situ hybridization shows a specific expression pattern arising at onset of
      gastrulation, with a ring around the blastopore. By mid gastrulation there is an
      anterior and a posterior expression domain, each of which gets more complex later
      in development. There are some important similarities and differences in
      expression pattern between Xenopus and mouse.

PMID- 10354488
TI  - Expression pattern of a novel hyaluronidase during Xenopus embryogenesis.
AB  - We have isolated a cDNA encoding a novel hyaluronidase, which is expressed during
      embryogenesis. The encoded protein was expressed as a fusion polypeptide with
      glutathione S-transferase, and the affinity-purified fusion protein was shown to
      possess hyaluronidase activity with a pH optimum about pH 4.0. The expression of
      the XEH1 gene was analysed by in situ hybridization, and was first apparent in
      scattered cells in a broad ventral region of late gastrula embryos. As
      development proceeded through to tailbud stages, the domain of expression became
      progressively more restricted, eventually being located in the developing liver
      rudiment near the primary hepatic cavity. The results reveal the dynamic
      regulation of the contrasting activities of hyaluronan synthesis and degradation
      during early morphogenetic movements.

PMID- 10354490
TI  - Chlorophyll a fluorescence induction1 

PMID- 10354489
TI  - Restricted expression of the receptor serine/threonine kinase BMPR-IB in
      zebrafish.
AB  - Bone morphogenetic proteins (BMPs) comprise a rapidly expanding subclass of the
      transforming growth factor-beta superfamily. They are known to regulate a diverse
      range of developmental phenomena including cell differentiation, morphogenesis
      and apoptosis. In this study, we have isolated a zebrafish homolog of BMP type IB
      receptor (BMPR-IB) and examined the localization of the transcripts during
      embryogenesis. Whole-mount in situ hybridization analysis revealed that unlike
      other type I and type II receptors that mediate BMP signal, it is expressed in
      developing somite and in mid-hind brain region in a restricted manner.

PMID- 10354491
TI  - Topographical characterization of the ubiquinone reduction site of glucose
      dehydrogenase in Escherichia coli using depth-dependent fluorescent inhibitors.
AB  - Membrane-bound glucose dehydrogenase in Escherichia coli possesses a binding site
      for ubiquinone as well as glucose, metal ion and pyrroloquinoline quinone. To
      probe the depth of the ubiquinone binding site in the membrane environment, we
      synthesized two types of fluorenyl fatty acids which bear an inhibitor mimic
      moiety (i.e., specific inhibitor capsaicin) close to the fluorene located at
      different positions in the alkyl tail chain; one close to the polar carbonyl head
      group (alpha-(3, 4-dimethoxyphenyl)acetyloxy-7-nonyl-2-fluoreneacetic acid, alpha
      DFA), and the other in the middle of the chain (theta-(3, 4
      dimethoxyphenyl)acetyloxy-7-ethyl-2-fluorenenonanoic acid, theta-DFA). Mixed
      lipid vesicles consisting of phosphatidylcholine (PC) and alpha-DFA or theta-DFA
      were prepared by sonication method, and fluorescent quenching against a
      hydrophilic quencher, iodide anion, was examined. The vesicles containing alpha
      DFA were more susceptible to quenching than those containing theta-DFA,
      indicating that the fluorene and consequently capsaicin mimic moiety are located
      at different depths in the lipid bilayer depending upon the position of
      attachment to the alkyl tail chain. The purified glucose dehydrogenase was
      reconstituted into PC vesicles which consisted of PC and alpha-DFA or theta-DFA
      with various molar ratios. For both types of reconstituted vesicles, the extent
      of inhibition of short-chain ubiquinone reduction activity increased with
      increases in the molar ratio of fluorenyl fatty acid to PC. The ubiquinone
      reduction activity was more significantly inhibited in the reconstituted vesicles
      containing alpha-DFA compared to those containing theta-DFA. Our findings
      strongly suggested that the ubiquinone reduction site in glucose dehydrogenase is
      located close to the membrane surface rather than in the hydrophobic membrane
      interior.

PMID- 10354492
TI  - Fluorescence properties of chlorophyll d-dominating prokaryotic alga,
      acaryochloris marina: studies using time-resolved fluorescence spectroscopy on
      intact cells 
AB  - Antenna components and the primary electron donor of the photosystem (PS) II in
      the Chlorophyll (Chl) d-dominating prokaryote, Acaryochloris marina, were studied
      using time-resolved fluorescence spectroscopy in the ps time range. By selective
      excitation of Chl a or Chl d, differences in fluorescence properties were clearly
      resolved. At physiological temperature, energy transfer was confirmed by a red
      shift of emission maximum among PS II antenna components, and the equilibrium of
      energy distribution among Chl a and Chl d was established within 30 ps. A
      fluorescence component that can be assigned to delayed fluorescence (DF) was
      observed at 10 ns after the excitation; however, it was not necessarily resolved
      by the decay kinetics. At -196 degrees C, a red shift of emission maximum was
      reproduced but the equilibrium of energy distribution was not detected. DF was
      resolved in the wavelength region corresponding to Chl a by spectra and by decay
      kinetics. The lifetime of the DF was estimated to be approx. 15 ns, and the peaks
      were located at 681 and 695 nm, significantly shorter wavelengths than those of
      Chl d. These findings strongly suggest that an origin of DF is Chl a, and Chl a
      is most probably the primary electron donor in the PS II reaction center (RC).
      These results indicate that the constitution of PS II RC in this alga is
      essentially identical to that of other oxygenic photosynthetic organisms.

PMID- 10354493
TI  - Cytochrome c" from the obligate methylotroph Methylophilus methylotrophus, an
      unexpected homolog of sphaeroides heme protein from the phototroph Rhodobacter
      sphaeroides.
AB  - The complete primary structure of an unusual soluble cytochrome c isolated from
      the obligate methylotrophic bacterium Methylophilus methylotrophus has been
      determined to contain 124 amino acids and to have an average molecular mass of
      14293.0 Da. The sequence has two unusual features: firstly, the location of the
      heme-binding cysteines is far downstream from the N-terminus, namely at positions
      49 and 52; secondly, an extra pair of cysteine residues is present near the C
      terminus. In both respects, cytochrome c" is similar to the oxygen-binding heme
      protein SHP from the purple phototrophic bacterium Rhodobacter sphaeroides. In
      contrast to SHP, cytochrome c" changes from low-spin to high-spin upon reduction,
      due to dissociation of a sixth heme ligand histidine which is identified as His
      95 by analogy to the class I cytochromes c. The distance of His-95 from the heme
      (41 residues) and the presence of certain consensus residues suggests that
      cytochrome c" is the second example of a variant class I cytochrome c.

PMID- 10354494
TI  - Modulation of oxidative phosphorylation of human kidney 293 cells by transfection
      with the internal rotenone-insensitive NADH-quinone oxidoreductase (NDI1) gene of
      Saccharomyces cerevisiae.
AB  - In contrast to the mitochondrial proton-translocating NADH-quinone oxidoreductase
      (complex I), which consists of at least 43 different subunits, the internal
      rotenone-insensitive NADH-quinone oxidoreductase (Ndi1) of Saccharomyces
      cerevisiae is a single polypeptide enzyme. The NDI1 gene was stably transfected
      into the human embryonal kidney 293 (HEK 293) cells. The transfected NDI1 gene
      was then transcribed and translated in the HEK 293 cells to produce the
      functional enzyme. The immunochemical and immunofluorescence analyses indicated
      that the expressed Ndi1 polypeptide was located to the inner mitochondrial
      membranes. The expression of Ndi1 did not alter the content of existing complex I
      in the HEK 293 mitochondria, suggesting that the expressed Ndi1 enzyme does not
      displace the endogenous complex I. The NADH oxidase activity of the NDI1
      transfected HEK 293 cells was not affected by rotenone but was inhibited by
      flavone. The ADP/O ratios coupled to NADH oxidation were lowered from 2.4 to 1.8
      by NDI1-transfection while the ADP/O ratios coupled to succinate oxidation (1.6)
      were not changed. The NDI1-transfected HEK 293 cells were able to grow in media
      containing a complex I inhibitor such as rotenone and 1-methyl-4-phenylpyridinium
      ion. The potential usefulness of incorporating the Ndi1 protein into mitochondria
      of human cells is discussed.

PMID- 10354495
TI  - The plasma membrane NADH oxidase of HeLa cells has hydroquinone oxidase activity.
AB  - The plasma membrane NADH oxidase activity partially purified from the surface of
      HeLa cells exhibited hydroquinone oxidase activity. The preparations completely
      lacked NADH:ubiquinone reductase activity. However, in the absence of NADH,
      reduced coenzyme Q10 (Q10H2=ubiquinol) was oxidized at a rate of 15+/-6 nmol min
      1 mg protein-1 depending on degree of purification. The apparent Km for Q10H2
      oxidation was 33 microM. Activities were inhibited competitively by the cancer
      cell-specific NADH oxidase inhibitors, capsaicin and the antitumor sulfonylurea N
      (4-methylphenylsulfonyl)-N'-(4-chlorophenyl)urea (LY181984). With coenzyme Q0,
      where the preparations were unable to carry out either NADH:quinone reduction or
      reduced quinone oxidation, quinol oxidation was observed with an equal mixture of
      the Q0 and Q0H2 forms. With the mixture, a rate of Q0H2 oxidation of 8-17 nmol
      min-1 mg protein-1 was observed with an apparent Km of 0.22 mM. The rate of Q10H2
      oxidation was not stimulated by addition of equal amounts of Q10 and Q10H2.
      However, addition of Q0 to the Q10H2 did stimulate. The oxidation of Q10H2
      proceeded with what appeared to be a two-electron transfer. The oxidation of Q0H2
      may involve Q0, but the mechanism was not clear. The findings suggest the
      potential participation of the plasma membrane NADH oxidase as a terminal oxidase
      of plasma membrane electron transport from cytosolic NAD(P)H via naturally
      occurring hydroquinones to acceptors at the cell surface.

PMID- 10354496
TI  - Inversion due to intrachromosomal recombination produced by carcinogens in a
      transgenic mouse model.
AB  - Somatic intrachromosomal recombination (SICR) can result in inversions and
      deletions in the DNA. pKZ1 mice possess an Escherichia coli (E. coli) lacZ
      transgene which is only expressed after a DNA inversion involving the transgene
      occurs. The E. coli beta-galactosidase protein can then be detected in frozen
      tissue sections using a chromogenic substrate. Therefore, pKZ1 mice can be used
      to detect SICR inversion events in vivo in different tissues. We have tested the
      pKZ1 mouse for its potential as a general mutagenesis model for detecting SICR in
      spleen in response to carcinogens which have widely different mechanisms of
      genotoxicity. Animals were given a single exposure of carcinogen and spleen cells
      were examined 3 days later for inversion events by histochemical staining of
      tissue sections. Mitomycin C, X-irradiation, etoposide and methylene chloride
      caused significant induction of inversion events in spleen tissue, ranging from
      1.6- to 4.2-fold induction with the doses used here. This is the first time that
      inversion events induced by these carcinogens have been specifically studied in
      vivo in a mouse model and the findings expand the repertoire of mutation events
      known to be caused by these agents. We suggest that the pKZ1 mouse can be used as
      a general mutagenesis model for detection of SICR events and is likely to be a
      useful model for studying the mechanism of SICR in response to DNA damaging
      agents.

PMID- 10354497
TI  - Somatic mutation in the mammary gland: influence of time and estrus.
AB  - A critical factor in the quantitation of mutation induction in vivo is the time
      interval between treatment and sampling. In order to study mutagenesis in the
      mammary epithelium, the cell type in which breast cancer arises, we have measured
      the manifestation time, the minimum time required for the maximum mutant
      frequency to be achieved, in this tissue. The F1 LacZ transgenic mice (Muta
      MousexSWR) were treated with N-ethyl-N-nitrosourea (ENU) at 50 mg/kg for five
      consecutive days and then sampled at 1, 2, 4, 6, 9, or 12 weeks after the last
      treatment. The LacZ- mutant frequency reached a maximum at 4 weeks post-treatment
      and did not vary significantly thereafter. Dlb-1- mutations in the small
      intestine reached a maximum at 2 weeks after treatment and did not vary
      significantly thereafter. Since the stage of estrus cycle during carcinogen
      exposure influences the mammary tumor incidence and latency, it was expected that
      it would also affect mutation induction. To test this, F1 LacZ mice in the estrus
      or di-estrus stage were treated with an acute dose of 250 mg/kg ENU and sampled
      10-13 weeks post-treatment. No statistical difference between the two groups was
      found, indicating that the effect of estrus on carcinogenesis is not due to
      variation in the sensitivity of the stage of the mammary gland to mutation.

PMID- 10354498
TI  - Detection of tandem CC-->TT mutations induced by oxygen radicals using mutation
      specific PCR.
AB  - DNA lesions caused by reactive oxygen species (ROS) are considered to be one of
      the major contributors to DNA damage and mutagenesis. In this study, we developed
      a modification of allele-specific PCR to detect CC-->TT mutations caused by
      oxidative damage. These tandem mutations have been previously demonstrated to be
      indicative of oxygen damage in the absence of UV-irradiation. Using a CC target
      site in the rat DNA polymerase beta (pol beta) gene and a thermostable
      restriction enzyme that cuts the wild type sequence but not the TT mutation, we
      demonstrate that the TT mutation can be preferentially amplified from plasmid DNA
      damaged by oxygen radicals but not other DNA-damaging agents. We evaluated the
      potential utility of this assay in screening for mutations in cells and in
      analyzing those that arise during clonal proliferation in carcinogenesis.

PMID- 10354499
TI  - Relationship between the kinetics of micronuclei induction and the mechanism of
      chromosome break formation by methylnitrosourea in mice in vivo.
AB  - The kinetics of micronucleated polychromatic erythrocytes (MN-PCE) induction by
      methylnitrosourea (MNU) was determined in mice with the purpose of discerning
      whether or not the kinetics reflects the mechanism of chromosome break induction.
      A very long latency period (LP) was observed which is not compatible with an
      agent that does not require metabolic activation or incorporation to DNA for
      acting, but this is consistent with the mechanism demonstrated earlier that MNU
      causes chromosome breaks throughout the repair of mismatches induced by the
      alkylation of bases in a previous division. This is also supported by the
      presence of two rates of MN-PCE induction with respect to dose, which suggests
      that MN-PCE are induced by two mechanisms, an efficient one induced with the
      lower dose, and another less efficient one induced with higher doses. A similar
      behavior was observed in the curve of LP vs. dose, the lower dose causes 8 h of
      LP and higher doses increase LP but not proportionally to dose. The lower dose
      did not cause a reduction in the proportion of polychromatic erythrocytes,
      suggesting that this dose did not produce an important cytotoxic effect that
      could explain the long LP.

PMID- 10354500
TI  - Influence of p53 zygosity on select sperm parameters of the mouse.
AB  - The influence of p53 gene zygosity on select parameters of mouse sperm was
      investigated by employing knock-out animal models. The background incidence of
      sperm shape abnormalities, total sperm count, and DNA double strand breaks were
      determined in p53 nullizygous (-/-) and heterozygous (+/-) mice and these
      estimates were compared to the corresponding measures in p53 wild-type (+/+) and
      the inbred C57Bl6 mouse strains. There were no qualitative differences in the
      incidence of sperm shape abnormalities and sperm counts regardless of p53
      zygosity. However, the number of DNA double strand breaks, as measured by the
      comet assay, were significantly lower in the p53 knock-out mice. This apparent
      decrease was interpreted to be the result of a possible change in DNA-protein
      and/or DNA-DNA cross-linking in the germ cells of the knock-out mice. These data
      show that there is no evidence of increased incidence of gross alterations in
      spermatogenesis (no significant loss in sperm production nor any increase in the
      proportion of abnormal sperm produced) in knock-out mice deficient or absent in
      p53 protein; however, there appear to be changes at the genomic level where the
      degree of cross-linking was apparently elevated in DNA from p53 nullizygous and
      heterozygous mice.

PMID- 10354501
TI  - Cell sensitivity to transplacental mutagenesis by N-ethyl-N-nitrosourea is
      greatest during early gestation in the Syrian hamster.
AB  - The extremely high rate of cell division that occurs during early embryogenesis
      is hypothesized to predispose to high rates of mutation after chemical exposure.
      We tested this supposition experimentally. To probe the variation in
      susceptibility to mutation induction as a function of gestation stage, somatic
      cells of the developing Syrian hamster were isolated after transplacental
      treatment with N-ethyl-N-nitrosourea (ENU). Mutants were quantified using either
      6-thioguanine (6-TG) or diphtheria toxin (DT) as selective agents. Several
      different approaches were used. In one, three litters were exposed on each
      gestation day and fetuses were removed on day 13. Maximum fetal sensitivity to
      ENU's genotoxic action was noted when treatment was at days 8 and 9, fewer
      mutants being obtained with earlier and later exposures. To compensate for the
      low numbers of target cells early in gestation, this experiment was repeated
      using larger numbers of litters exposed at the earlier time points, and the
      highest mutation frequency was now found to occur after treatment on gestation
      days 6 and 7. In the second approach, mutations were quantified in cells
      harvested 24 h after transplacental ENU exposure. Here again, embryos exposed at
      earlier times of gestation were more susceptible than those treated at later
      periods. Based on the total cell numbers in embryos and fetuses at each gestation
      day, we conclude that mutation frequency is maximal on day 6, corresponding to
      the primitive streak stage with extremely high rates of cell division.

PMID- 10354502
TI  - Cell sensitivity to transplacental carcinogenesis by N-ethyl-N-nitrosourea is
      greatest in early post-implantation development.
AB  - In a clear demonstration of the changing sensitivity of the developing mammal to
      transplacental carcinogenesis, Ivankovic and Druckrey [S. Ivankovic, H. Druckrey,
      Transplacentare Erzeugung maligner Tumoren des Nervensystem: I. Athyl-nitroso
      harnstoff (ANH) an BD IX-Ratten, Z. Krebsforsch. 71 (1968) 320-360] exposed
      pregnant BD IX rats to a pulse of N-ethyl-N-nitrosourea (ENU), a reactive
      carcinogen with a half-life of 20 min. No tumors were seen with ENU exposure
      before gestation day 12, but the multiplicity of neurogenic tumors increased
      steadily thereafter and was greatest with treatment on day 20, followed by a
      decline in sensitivity for the last three days of gestation. Similarly, a
      transplacental study of ENU in the Syrian hamster [B.A. Diwan, S. Rehm, J.M.
      Rice, Age- and dose-dependent transplacental carcinogenesis by N-nitrosoethylurea
      in Syrian golden hamsters, J. Cancer Res. Clin. Oncol. 122 (1996) 643-652] found
      that the numbers of tumors induced were greatest after exposure of late fetal
      stages. While these observations suggested that embryonic cells are refractory to
      carcinogenesis, an alternative explanation could be that a significant tumor
      yield was not observed because too few target cells were present in the embryo. I
      have resolved this issue by combining these published data with others on the
      numbers of neuroectodermal cells in the developing BD IX rat brain [R. Muller,
      M.F. Rajewsky, Elimination of O6-ethylguanine from the DNA of brain, liver, and
      other rat tissues exposed to ethylnitrosourea at different stages of prenatal
      development, Cancer Res. 43 (1983) 2897-2904] and total cell counts of successive
      developmental stages of the Syrian hamster fetus [P.J. Donovan, G.T. Smith, Cell
      sensitivity to transplacental mutagenesis by N-ethyl-N-nitrosourea is greatest
      during early gestation in the Syrian hamster, Mutation Res., 1999, this issue],
      allowing the risk per cell at different stages of gestation to be calculated.
      Sensitivity to carcinogenesis was found to be greatest early in gestation and to
      decrease as gestation proceeds. For the rat model, tumor frequency per cell
      changed from 1.3x10(-6) at day 12 exposure to 2.6x10(-8) at day 23 exposure, a 50
      fold decrease. For the hamster model, the tumor-initiation rate decreased 1250
      fold from 1.2x10(-5) at day 7 exposure to 9.6x10(-9) at day 13 exposure. Thus,
      two independent experiments with different rodent species demonstrate that
      sensitivity of individual cells to damage leading to transplacental
      carcinogenesis is greatest in the early fetus and lessens markedly as gestation
      proceeds, in parallel with changing sensitivity to mutation (Donovan et al.,
      Mutat. Res., this issue).

PMID- 10354503
TI  - Protein kinase C alpha protein expression is necessary for sustained
      erythropoietin production in human hepatocellular carcinoma (Hep3B) cells exposed
      to hypoxia.
AB  - Although protein kinase C (PKC) has been implicated as an effector of
      erythropoietin (EPO) production, its exact role is still uncertain. Hep3B human
      hepatocellular carcinoma cells were used for this study and were depleted of PKC
      in three different ways: long-term treatment with phorbol 12-myristate 13-acetate
      (PMA), selective inhibition with calphostin C, and treatment with PKCalpha
      antisense oligonucleotides. When EPO-producing Hep3B cells were incubated in 1%
      O2 (hypoxia) for 24 h, PMA treatment resulted in significant decreases in medium
      levels of EPO in Hep3B cell cultures at concentrations higher than 10 nM. The
      specific PKC inhibitor, calphostin C, significantly inhibited medium levels of
      EPO and EPO mRNA levels in Hep3B cells exposed to 1% O2. Western blot analysis
      revealed that Hep3B cells express the classical PKCalpha and gamma isoforms, as
      well as novel PKCepsilon and delta and the atypical zeta isoform. Preincubation
      with PMA for 6 h specifically down-regulated PKCalpha protein expression.
      Phosphorothioate modified antisense oligonucleotides specific for PKCalpha also
      decreased EPO production in Hep3B cells exposed to hypoxia for 20 h when compared
      to PKCalpha sense treatment. The translocation of PKCalpha from the soluble to
      particulate fractions was increased in Hep3B cells incubated under hypoxia
      compared with normoxia (21% O2) controls. These results suggest that the PKCalpha
      isoform plays an important role in sustaining hypoxia-regulated EPO production.

PMID- 10354504
TI  - High glucose concentrations inhibit glucose phosphorylation, but not glucose
      transport, in human endothelial cells.
AB  - Glucose uptake is autoregulated in a variety of cell types and it is thought that
      glucose transport is the major step that is subjected to control by sugar
      availability. Here, we examined the effect of high glucose concentrations on the
      rate of glucose uptake by human ECV-304 umbilical vein-derived endothelial cells.
      A rise in the glucose concentration in the medium led a dose-dependent decrease
      in the rate of 2-deoxyglucose uptake. The effect of high glucose was independent
      of protein synthesis and the time-course analysis indicated that it was
      relatively slow. The effect was not due to inhibition of glucose transport since
      neither the expression nor the subcellular distribution of the major glucose
      transporter GLUT1, nor the rate of 3-O-methylglucose uptake was affected. The
      total in vitro assayed hexokinase activity and the expression of hexokinase-I
      were similar in cells treated or not with high concentrations of glucose. In
      contrast, exposure of cells to a high glucose concentration caused a marked
      decrease in phosphorylated 2-deoxyglucose/free 2-deoxyglucose ratio. This
      suggests the existence of alterations in the rate of in vivo glucose
      phosphorylation in response to high glucose. In summary, we conclude that ECV304
      human endothelial cells reduce glucose utilization in response to enhanced levels
      of glucose in the medium by inhibiting the rate of glucose phosphorylation,
      rather than by blocking glucose transport. This suggests a novel metabolic effect
      of high glucose on cellular glucose utilization.

PMID- 10354505
TI  - Lipopolysaccharide tolerance in murine peritoneal macrophages induces
      downregulation of the lipopolysaccharide signal transduction pathway through
      mitogen-activated protein kinase and nuclear factor-kappaB cascades, but not
      lipopolysaccharide-incorporation steps.
AB  - Endotoxin/lipopolysaccharide (LPS) tolerance, a hyporesponsive state to endotoxin
      or LPS stimulation, was induced in murine peritoneal macrophages by previous
      exposure of macrophages to LPS. Expression of tumor necrosis factor (TNF)-alpha
      and interleukin (IL)-6 mRNA in response to LPS stimulation was suppressed in LPS
      tolerant macrophages. Tyrosine phosphorylations in response to LPS of 40-45-kDa
      proteins in non-tolerant macrophages were also suppressed in LPS-tolerant
      macrophages. These proteins corresponded to two members of the mitogen-activated
      protein kinase (MAPK) family, ERK and p38. In addition to these proteins, another
      MAPK family protein, JNK, was also suppressed in LPS-tolerant macrophages.
      Activation of Raf-1, located in the upstream portion of ERK cascades, was also
      suppressed by LPS-tolerance induction. These suppressions in LPS-tolerant
      macrophages were exhibited against stimulation by an LPS agonist like taxol, but
      not towards stimulation by an unrelated activator like phorbol ester (PMA).
      Activation of the transcription factor NF-kappaB, which is supposed to be one of
      the components of another important pathway for transduction of LPS-stimulated
      cytokine producing signals, was strongly suppressed and degradation of IkappaB,
      an inhibitor of NF-kappaB, was also severely diminished in LPS-tolerant
      macrophages. Although a monosaccharide lipid A analog, GLA-58, was able to
      stimulate macrophages to activate ERK proteins without cytokine production,
      pretreatment of macrophages with this compound suppressed both LPS-stimulated
      activation of ERK and cytokine production. Furthermore, downregulation of LPS
      uptake in LPS-tolerant macrophages was not observed. Based on all these findings,
      LPS tolerance might be caused by the previous activation of some components on
      LPS-signaling pathways. This may then induce a refractory state in key LPS-signal
      transducer molecules located downstream of the cell membrane LPS receptor and
      upstream of the branching point in intracellular cascades for activation of MAPK
      and NF-kappaB, probably in some initial steps of intracellular signaling.

PMID- 10354506
TI  - Identification of a gene, SOO1, which complements osmo-sensitivity and defect in
      in vitro beta1,3-glucan synthase activity in Saccharomyces cerevisiae.
AB  - The soo1-1 (for suppressor of osmo-sensitivity) mutation results in a temperature
      dependent osmo-sensitive phenotype at non-permissive temperature (37 degrees C),
      makes yeast cells more susceptible to Zymolyase and affects in vitro beta1,3
      glucan synthase activity level. Transformation of soo1-1 mutant by SOO1 gene
      reverses these effects. Nucleotide sequencing of SOO1 revealed that this gene is
      identical to the recently reported alpha-COP that is involved in the
      intracellular protein translocation from endoplasmic reticulum to Golgi and vice
      versa. Although the soo1-1 mutant strain showed osmotically remediable growth at
      37 degrees C, SOO1 disruptants could not grow in any culture conditions. Analysis
      of cell wall fractions revealed that the soo1-1 mutation causes a decrease in in
      vitro beta1,3-glucan synthase activity, and, thus, a subsequent alteration of the
      cell wall composition.

PMID- 10354507
TI  - Involvement of p38 MAPK and ERK/MAPK pathways in staurosporine-induced production
      of macrophage inflammatory protein-2 in rat peritoneal neutrophils.
AB  - Stimulation of rat peritoneal neutrophils with staurosporine (64 nM) induced
      production of macrophage inflammatory protein-2 (MIP-2) and phosphorylation of
      p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated
      kinase/MAP kinase (ERK/MAPK). The staurosporine-induced MIP-2 production at 4 h
      was inhibited by the highly specific p38 MAPK inhibitor SB 203580 and the
      MAPK/ERK kinase (MEK-1) inhibitor PD 98059 in a concentration-dependent manner.
      By treatment with SB 203580 (1 microM) or PD 98059 (50 microM), the staurosporine
      induced increase in the levels of mRNA for MIP-2 was only partially lowered,
      although the staurosporine-induced MIP-2 production was completely inhibited.
      Consistent with the inhibition by the protein synthesis inhibitor cycloheximide,
      SB 203580 and PD 98059 inhibited MIP-2 production at 4 h either when added
      simultaneously with staurosporine or 2 h after stimulation with staurosporine. In
      contrast, the DNA-dependent RNA polymerase inhibitor actinomycin D did not
      inhibit MIP-2 production at 4 h when it was added 2 h after staurosporine
      stimulation. Dot blot analysis demonstrated that treatment with SB 203580 or PD
      98059 down-regulates the stability of MIP-2 mRNA. These results suggested that
      p38 MAPK and ERK/MAPK pathways are involved in translation of MIP-2 mRNA to
      protein and stabilization of MIP-2 mRNA.

PMID- 10354508
TI  - The relationship of p53 and stress proteins in response to bleomycin and retinoic
      acid in the p53 heterozygous mouse.
AB  - A single, i.p. dose of bleomycin was administered simultaneously with
      [35S]methionine to 4-month-old p53 wild type (+/+) and p53 heterozygous (+/-)
      C57BL/6 mice. Following a period of 3.5 h from dosing, the bone marrow nuclei
      were examined by two-dimensional PAGE and fluorography for induction of stress
      proteins (sps). Eight sps ranging from 22000 to 100000 Mr were synthesized in
      p53+/- and p53+/+ mice following elicitation by bleomycin. No quantitative or
      qualitative differences were observed in sp expression in these two groups of
      animals. In a second experiment, three doses of retinoic acid were given i.p. to
      p53+/- and p53+/+ mice over a 36 h period. The p53 isoforms in bone marrow nuclei
      from these mice were analyzed by PAGE for incorporation of [35S]methionine
      following retinoic acid injections. Quantitative and qualitative alterations in
      p53 isotypes were substantially increased in p53+/+ as compared with p53+/- mice.
      The increased complexity in the synthesis patterns in both groups of dosed mice
      consisted of additional isoforms possessing more acidic isoelectric values. In an
      in vitro binding assay, individual p53 isoforms demonstrated varying degrees of
      association with sps 25a, 70i, 72c and 90 which was consistently greater in
      p53+/+ mice. Both the synthesis and binding of isoforms were greater in G1 than
      in S+G2 phase, in both groups of animals, reflecting a cell cycle regulated
      mechanism for these events. Collectively, these data implied that the synthesis
      and the binding characteristics of p53 isoforms with sps were enhanced in the
      p53+/+ mice relative to the p53+/- mouse; however, sp labeling was not affected
      by p53 genotype.

PMID- 10354509
TI  - Calcium and reactive oxygen species as messengers in endotoxin action on
      adrenocortical cells.
AB  - The effect of Escherichia coli 0111:B4 endotoxin (lipopolysaccharide, LPS) on the
      intracellular Ca2+ and reactive oxygen metabolite content of both rat isolated
      fasciculata-reticularis and glomerulosa cells was evaluated by flow cytometry to
      know the role of these mechanisms in the initiation of cell injury produced by
      LPS on adrenocortical cells during endotoxic shock. A rapid increase of
      intracellular calcium was induced by endotoxin in both cell types. In fasciculata
      reticularis cells, this [Ca2+]i increase was mainly due to an important
      mobilization of intracellular stores. Dose-dependent increases in [Ca2+]i were
      also observed when both cell types were incubated with LPS for 20 min in the
      presence of extracellular calcium. This treatment abolished the increase in
      intracellular calcium induced by ACTH and angiotensin II. On the other hand, the
      endotoxin produced a fast and dose-dependent increase in reactive oxygen species
      in both cell types, higher in glomerulosa than in fasciculata-reticularis cells.
      LPS-pretreated cells showed more susceptibility to the oxidative stress induced
      by Fe2+. These results can be related to functional alterations previously
      described showing the involvement of calcium and reactive oxygen species as
      messengers in the endotoxin action on adrenocortical cells.

PMID- 10354510
TI  - Quantitative reduction of type I adenylyl cyclase in human alcoholics.
AB  - The amounts of adenylyl cyclase type I (AC I) were examined in various parts of
      the postmortem brains from alcoholics who prior to death had been abstinent from
      alcohol for at least 6 months and compared with controls using immunoblot
      analysis with anti-AC I specific antibody. It was revealed that a significant
      reduction of AC I was observed in both frontal and temporal cortices. On the
      other hand, in other areas (occipital cortex, caudate nucleus, putamen, and
      hippocampus) the amounts were comparable between alcoholics and controls. In the
      next step, we examined two subtypes of human AC mRNA levels (AC I and AC VIII) in
      blood cells by quantitative RT-PCR using [alpha-32P]dCTP with two sets of the
      synthetic oligonucleotide primers based on the DNA sequences reported elsewhere
      (Villacres, E.C. et al., Genomics 16 (1993) 473-478; J. Parma et al., Biochem.
      Biophys. Res. Commun. 179 (1991) 455-462). The amounts of amplified DNAs of both
      AC I and AC VIII were significantly smaller in alcoholics than in controls. On
      the other hand, the amounts of amplified DNA of beta-actin DNA were almost equal
      between alcoholics and controls. It appears from these results that a reduction
      in the amount of AC subtypes may be a biological marker for alcoholics.

PMID- 10354511
TI  - Acute oxidative stress modulates secretion and repetitive Ca2+ spiking in rat
      exocrine pancreas.
AB  - The effects of the oxidant tert-butylhydroperoxide (t-buOOH) on carbachol
      stimulated pancreatic secretion in the vascularly perfused rat pancreas have been
      studied in parallel with [Ca2+]i signalling and amylase output in perifused rat
      pancreatic acinar cells. Perfusion of the pancreas with t-buOOH (0.1-1 mM) caused
      a rapid and irreversible inhibition of carbachol-stimulated (3x10-7 M) amylase
      and fluid secretion. Pre-perfusion of the pancreas with vitamin C and
      dithiothreitol or a cocktail of GSH and GSH-precursor amino acids provided only
      marginal protection against the deleterious effects of t-buOOH, even though GSH
      levels were elevated significantly. In perifused pancreatic acini, repetitive
      [Ca2+]i spikes evoked by carbachol (3x10-7 M) were sustained for 40 min. t-buOOH
      (1 mM) acutely increased the amplitude and duration of Ca2+ spikes, then
      attenuated Ca2+ spiking and subsequently caused a marked and sustained rise in
      [Ca2+]i. t-buOOH-induced alterations in carbachol-stimulated [Ca2+]i signalling
      and amylase release in perifused pancreatic acini were prevented by vitamin C.
      Although vitamin C restored impaired Ca2+ signalling and maintained amylase
      output in pancreatic acini, it seems likely that oxidative stress inhibits fluid
      secretion irreversibly in the intact pancreas, resulting in a loss of amylase
      output. Thus, perturbations in [Ca2+]i signalling may not fully explain the
      secretory block caused by oxidative stress in acute pancreatitis.

PMID- 10354512
TI  - Involvement of lipids in ferriprotoporphyrin IX polymerization in malaria.
AB  - Approximately 70% of the initial ferriprotoporphyrin IX polymerizing activity in
      cell-free preparations of erythrocytes infected with Plasmodium berghei was
      recovered in a chloroform extract. No polymerizing activity remained in the
      residue. In studies to identify substances that promote FP polymerization,
      arachidonic, linoleic, oleic, and palmitoleic acids, 1-mono- and di
      oleoylglycerol, and the detergents, SDS, Tween 80, and n-octyl-glucopyranoside,
      were active. Tri-oleoylglycerol, cholesterol, di-oleoylphosphatidylethanolamine,
      and stearic and palmitic acids were inactive. The model lipid, mono
      oleoylglycerol (250 nmol), co-precipitated with FP from a 0.09 M acetate medium
      at pH 5 and promoted the polymerization of 215 nmol (61%) of the
      ferriprotoporphyrin IX in the precipitate during a 24-h incubation at 37 degrees
      C. Polymerization was maximal at pH 5, it was approximately linear for 2 h, and
      it continued at a decreasing rate for 24 h. The polymer contained exclusively
      ferriprotoporphyrin IX (97+/-1.3%, mean+/-S.E., n=4) and exhibited the solubility
      and the electronic absorption and infrared spectral characteristics of the
      sequestered ferriprotoporphyrin IX of hemozoin. Detergents presumably promote
      polymerization in an acid medium by helping to dissolve monomeric FP. We suggest
      that unsaturated lipids co-precipitate with FP in the parasite's acidic food
      vacuole and also dissolve sufficient monomeric FP to allow polymerization.

PMID- 10354513
TI  - Incorporation of exogenous lipids modulates insulin signaling in the hepatoma
      cell line, HepG2.
AB  - The lipid content of cultured cells can be experimentally modified by
      supplementing the culture medium with specific lipids or by the use of
      phospholipases. In the case of the insulin receptor, these methods have
      contributed to a better understanding of lipid disorder-related diseases.
      Previously, our laboratory demonstrated that experimental modification of the
      cellular lipid composition of an insulin-sensitive rat hepatoma cell line (ZHC)
      resulted in an alteration in insulin receptor binding and biological action
      (Bruneau et al., Biochim. Biophys. Acta 928 (1987) 287-296/297-304). In this
      paper, we have examined the effects of lipid modification in another hepatoma
      cell line, HepG2. Exogenous linoleic acid (LA, n-6), eicosapentaenoic acid (EPA,
      n-3) or hemisuccinate of cholesterol (CHS) was added to HepG2 cells, to create a
      cellular model in which membrane composition was modified. In this model, we have
      shown that: (1) lipids were incorporated in treated HepG2 cells, but
      redistributed differently when compared to treated ZHC cells; (2) that insulin
      signaling events, such as insulin receptor autophosphorylation and the
      phosphorylation of the major insulin receptor substrate (IRS-1) were altered in
      response to the addition of membrane lipids or cholesterol derived components;
      and (3) different lipids affected insulin receptor signaling differently. We have
      also shown that the loss of insulin receptor autophosphorylation in CHS-treated
      cells can be correlated with a decreased sensitivity to insulin. Overall, the
      results suggest that the lipid environment of the insulin receptor may play an
      important role in insulin signal transduction.

PMID- 10354514
TI  - Identification of a novel substitution in the constant region of a gene coding
      for an amyloidogenic kappa1 light chain.
AB  - Current concepts regarding the association between immunoglobulin (Ig) light
      chain structure and AL amyloidosis (AL) emphasize Ig variable region amino acid
      substitutions because the majority of light chain amyloid fibrils that have been
      sequenced contain amino termini of the variable region with only small amounts of
      the constant region. In this report, we describe a patient with rapidly
      progressive AL whose amyloid deposits contained primarily monoclonal kappa light
      chain constant region fragments. We sequenced and analyzed this AL protein,
      determining that it was an O18-O8 kappa1 variant and that the constant region
      possessed an unusual Ser-->Asn substitution at position 177. Using pre-mortem
      bone marrow cells, we cloned and sequenced the cDNA for this AL protein (HCAK1)
      and, using DNA from post-mortem somatic tissue, we cloned and sequenced the
      patient's kappa germline O18-O8 donor and kappa constant region (Ckappa) gene
      segments. The cDNA that coded for HCAK1 contained a variable region that was
      derived from O18-O8, showing 96.1% homology to germline, and a Ckappa that had a
      nucleotide substitution (AGC to AAC), resulting in the 177Ser-->Asn replacement.
      Two Ckappa genes were cloned from somatic tissue DNA, one identical to a known
      Ckappa sequence and another containing this substitution which likely is a new
      Ckappa allotype. Our findings indicate that further investigation is warranted
      into the contributions genetic polymorphisms and light chain constant regions may
      make to amyloidogenesis.

PMID- 10354516
TI  - Catecholamines participate in the induction of ornithine decarboxylase gene
      expression in normal and hyperplastic mouse kidney.
AB  - In the quinazoline antifolate (CB 3717)-induced hyperplastic kidney model, a
      remarkable increase of ornithine decarboxylase (ODC) activity was paralleled by a
      smaller, but highly significant augmentation of the ODC transcript level.
      Catecholamine depletion, evoked by reserpine, strongly impaired antifolate
      induced ODC expression; the enzyme activity was almost completely abolished while
      the mRNA level decreased by 60%. Moreover, under conditions of a depleted
      catecholamine pool, kidney enlargement was significantly reduced confirming our
      earlier reports on the indispensability of ODC induction for renal hyperplasia
      (M. Manteuffel-Cymborowska et al. , Biochim. Biophys. Acta, 1182 (1993) 133
      141[1]). In normal mouse kidney catecholamines appeared to be inducers of ODC
      expression. Use of selective agonists of catecholamine receptors demonstrated the
      importance of dopamine D2 receptors, and to a lower extent beta adrenoreceptors,
      in the catecholamine mediation of induction of ODC activity and of ODC mRNA
      levels. These increases were not abolished by an antiandrogen, casodex,
      suggesting that catecholamine control of ODC expression is an androgen receptor
      independent process. The results obtained point to the critical role of renal
      catecholamines; these biogenic amines are not only involved in the regulation of
      ODC expression in normal kidney but are also required for the induction of ODC in
      hyperplastic kidney evoked by antifolate and, as shown recently (M. Manteuffel
      Cymborowska et al., Biochim. Biophys. Acta, 1356 (1997) 292-298[2]), in
      testosterone-induced hypertrophic kidney.

PMID- 10354515
TI  - Examination of the metabolic status of rat air pouch inflammatory exudate by high
      field proton NMR spectroscopy.
AB  - High field proton (1H) NMR spectroscopy was employed to investigate the metabolic
      status of rat air pouch inflammatory exudates obtained subsequent to the
      induction of inflammation with carrageenan, and the 1H NMR profiles of these
      fluids were compared and contrasted with those of inflammatory human synovial
      fluid, rat plasma and human serum. The characteristic biochemical features
      obtained from 1H NMR analysis of these exudates consisted of (1) substantially
      elevated levels of lactate (11.40+/-1.46x10-3 mol dm-3 for samples collected at a
      time point of 24 h post induction) with little or no NMR-detectable glucose, data
      consistent with a hypoxic environment and consequent anaerobic metabolism in the
      inflamed air pouch, and (2) high levels of the ketone body 3-d-hydroxybutyrate,
      providing evidence for an increased utilization of fats for energy by
      lymphocytes, the predominant leucocytes present in this environment. These
      phenomena represent a pathological extreme of the abnormal metabolic status of
      inflammatory human synovial fluids.

PMID- 10354517
TI  - Assay for reactive oxygen species-induced DNA damage: measurement of the
      formamido and thymine glycol lesions.
AB  - A 32P-postlabeling assay has been developed for the simultaneous detection of the
      thymine glycol lesion and the formamido remnant of pyrimidine bases in DNA
      exposed to reactive oxygen species (ROS). The formamido lesion is a principal
      lesion produced in X-irradiated DNA oligomers when oxygen is available to mediate
      the damage process. Production of the well-known thymine glycol lesion is less
      dependent on the concentration of oxygen. These two lesions have the common
      property that they make the phosphoester bond 3' to the modified nucleoside
      resistant to hydrolysis by nuclease P1. Our assay uses 32P-postlabeling to
      measure these lesions in the form of modified dimers obtained from DNA by
      nuclease P1 digestion. Appropriate carriers and internal standards have been
      chemically synthesized to improve the reliability and accuracy of the assay. The
      measurements were accomplished on 1-microgram samples of DNA.

PMID- 10354518
TI  - Effects of apolipoprotein E genotype on blood lipid composition and membrane
      platelet fluidity in Alzheimer's disease.
AB  - The blood lipid composition (plasma, platelets and leukocytes), platelet membrane
      fluidity, apolipoproteins A and B in the plasma of AD patients and control
      subjects with distinct Apo E genotypes were investigated. No significant
      differences were found between the Apo E genotype and the cholesterol,
      phospholipids, triglycerides and Apo B levels in the plasma; cholesterol and
      phospholipids levels in platelet and leukocyte membranes; and platelet membrane
      fluidity of AD and control groups. However, the phospholipid levels in the
      leukocyte membranes of the control subgroup with the genotypes epsilon3/epsilon3
      and epsilon3/epsilon4 and the AD subgroups with the genotypes epsilon2/epsilon3
      and epsilon3/epsilon3, epsilon3/epsilon4 and epsilon4/epsilon4 were significantly
      lower than those observed in the control subgroup with the genotype
      epsilon2/epsilon3. Moreover, the cholesterol and phospholipid levels in the
      platelet membranes of the AD subgroup with the epsilon2 allele were significantly
      higher than those in the AD subgroup without the epsilon2 allele and the control
      subgroups with and without the epsilon2 allele. A strong correlation was found
      between cholesterol and phospholipids levels in the platelet membranes of the AD
      and control subgroups without the epsilon2 allele, but the residual cholesterol
      level in the platelet membranes of the AD subgroup was twice that observed in the
      control subgroup. Furthermore, the Apo A levels in the plasma of the AD subgroup
      with the epsilon3 allele were significantly lower than those observed in the AD
      subgroup without the epsilon3 allele and the control subgroup with the epsilon3
      allele. The results are discussed in terms of involvement of lipid metabolism in
      the etiopathogenesis of AD.

PMID- 10354519
TI  - Clostridium perfringens beta-toxin is sensitive to thiol-group modification but
      does not require a thiol group for lethal activity.
AB  - The beta-toxin gene isolated from Clostridium perfringens type B was expressed as
      a glutathione S-transferase (GST) fusion gene in Escherichia coli. The purified
      GST-beta-toxin fusion protein from the E. coli transformant cells was not lethal.
      The N-terminal amino acid sequence of the recombinant beta-toxin (r toxin)
      isolated by thrombin cleavage of the fusion protein was G-S-N-D-I-G-K-T-T-T.
      Biological activities and molecular mass of r toxin were indistinguishable from
      those of native beta-toxin (n toxin) purified from C. perfringens type C.
      Replacement of Cys-265 with alanine or serine by site-directed mutagenesis
      resulted in little loss of the activity. Treatment of C265A with N-ethylmaleimide
      (NEM), which inactivated lethal activity of r toxin and n toxin, led to no loss
      of the activity. The substitution of tyrosine or histidine for Cys-265
      significantly diminished lethal activity. In addition, treatment of C265H with
      ethoxyformic anhydride which specifically modifies histidyl residue resulted in
      significant decrease in lethal activity, but that of r toxin with the agent did
      not. These results showed that replacement of the cysteine residue at position
      265 with amino acids with large size of side chain or introduction of functional
      groups in the position resulted in loss of lethal activity of the toxin.
      Replacement of Tyr-266, Leu-268 or Trp-275 resulted in complete loss of lethal
      activity. Simultaneous administration of r toxin and W275A led to a decrease in
      lethal activity of beta-toxin. These observations suggest that the site essential
      for the activity is close to the cysteine residue.

PMID- 10354520
TI  - Synthesis of adenine and guanine nucleotides at the 'inosinic branch point' in
      lymphocytes of leukemia patients.
AB  - The synthesis of purine nucleotides has been studied in human peripheral blood
      lymphocytes from healthy subjects and patients affected by B-cell chronic
      lymphocytic leukemia (B-CLL). The rate of the synthesis was measured by following
      the incorporation of 14C-formate into the nucleotides of lymphocyte suspensions.
      The whole sequence AMP-->ADP-->ATP was found reduced in B-CLL lymphocytes; in the
      case of guanylates only the last step of the sequence GMP-->GDP-->GTP was
      significantly lower in the same cells. From the analysis of these results,
      combined with previous data, we conclude that purine metabolism undergoes an
      imbalancement during CLL, which is partially compensated, and point out the
      importance of studying concomitantly purine metabolism and nucleic acid synthesis
      in leukemia cells.

PMID- 10354521
TI  - The mechanism of inhibition of beta-oxidation by aspirin metabolites in skin
      fibroblasts from Reye's syndrome patients and controls.
AB  - The effects of aspirin metabolites on beta-oxidation were studied in skin
      fibroblasts from eight typical Reye's syndrome (RS) patients and controls. RS
      patients' cells did not differ from controls in rates of palmitate oxidation or
      in the three component activities of the mitochondrial trifunctional enzyme
      (MTE), indicating no inherited beta-oxidation defect. Aspirin metabolites
      salicylate, hydroxyhippurate and gentisate, but not aspirin, directly inhibited
      palmitate oxidation in control and RS cells. RS cells were significantly more
      sensitive to inhibition than controls at 0.5 to 5 mM salicylate. Inhibition was
      concentration-dependent and reversible. Inhibition did not occur in fibroblasts
      lacking activity of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
      activity of MTE. Salicylate was therefore inhibiting beta-oxidation at this step.
      Hydroxyhippurate and salicylate reversibly inhibited HAD activities in extracts
      of control and RS cells. Studies with pure short-chain HAD and LCHAD (MTE) showed
      hydroxyhippurate and salicylate were competitive inhibitors of the former but
      mixed (not competitive) inhibitors of the latter. Both compounds inhibited the
      combined, three-step, MTE reaction measured in the physiological direction. We
      conclude that (1) salicylate and hydroxyhippurate decrease beta-oxidation in
      intact cells by reversible inhibition of LCHAD activity of the MTE, and (2) beta
      oxidation in RS cells is inherently more sensitive to inhibition by low
      concentrations of salicylate than controls.

PMID- 10354523
TI  - ICH-harmonised guidances on genotoxicity testing of pharmaceuticals: evolution,
      reasoning and impact.
AB  - The International Conference on Harmonisation of Technical Requirements for
      Registration of Pharmaceuticals for Human Use (ICH) has convened an expert
      working group which consisted of the authors of this paper and their respective
      committees, consulting groups and task forces. Two ICH guidances regarding
      genotoxicity testing have been issued: S2A, 'Guidance on Specific Aspects of
      Regulatory Genotoxicity Tests' and S2B, 'Genotoxicity: A Standard Battery for
      Genotoxicity Testing of Pharmaceuticals.' Together, these guidance documents now
      form the regulatory backbone for genotoxicity testing and assessment of
      pharmaceuticals in the European Union, Japan, and the USA. These guidances do not
      constitute a revolutionary new approach to genotoxicity testing and assessment,
      instead they are an evolution from preexisting regional guidelines, guidances and
      technical approaches. Both guidances describe a number of specific criteria as
      well as a general test philosophy in genotoxicity testing. Although these
      guidances were previously released within the participating regions in their
      respective regulatory communiques, to ensure their wider distribution and better
      understanding, the texts of the guidances are reproduced here in their entirety
      (see Appendix A) and the background for the recommendations are described. The
      establishment of a standard battery for genotoxicity testing of pharmaceuticals
      was one of the most important issues of the harmonisation effort. This battery
      currently consists of: (i) a test for gene mutation in bacteria, (ii) an in vitro
      test with cytogenetic evaluation of chromosomal damage with mammalian cells or an
      in vitro mouse lymphoma tk assay, (iii) an in vivo test for chromosomal damage
      using rodent hematopoietic cells. A major change in testing philosophy is the
      acceptance of the interchangeability of testing for chromosomal aberrations in
      mammalian cells and the mouse lymphoma tk assay. This agreement was reached on
      the basis of the extensive review of databases and newly generated experimental
      data which are in part described in this publication. The authors are fully aware
      of the fact that some of the recommendations given in these ICH guidances are
      transient in nature and that the dynamic qualities and ongoing evolution of
      genetic toxicology makes necessary a continuous maintenance process that would
      serve to update the guidance as necessary.

PMID- 10354522
TI  - Molecular cloning and expression of a novel human cDNA related to the diazepam
      binding inhibitor.
AB  - In order to isolate the unidentified autoantigens in autoimmune diabetes, a human
      pancreatic islet cDNA library was constructed and screened with the sera from the
      diabetic patients. From the library screening, one clone (DRS-1) that strongly
      reacted with the sera was isolated. Subsequent sequence analysis revealed that
      the clone was a novel cDNA related to the diazepam binding inhibitor. DRS-1 was
      expressed in most tissues including liver, lung, tonsil, and thymus, in addition
      to pancreatic islets. DRS-1 was in vitro translated and the recombinant DRS-1
      protein was expressed in Escherichia coli and purified. The size of the in vitro
      translated or bacterially expressed DRS-1 protein was in agreement with the
      conceptually translated polypeptide of DRS-1 cDNA. Further studies are required
      to test whether or not DRS-1 is a new autoantigen in autoimmune diabetes.

PMID- 10354524
TI  - Drug metabolism polymorphisms as modulators of cancer susceptibility.
AB  - Recently, several molecular genetic bases of polymorphic enzyme activities
      involved in drug activation and detoxification have been elucidated. Many
      molecular epidemiology studies based on these premises have sought to gather
      information on the association of genetically determined metabolic variants with
      different risks of environmentally induced cancer. While rare alterations of
      tumor suppressor genes dramatically raise cancer risk for the single affected
      subjects, far more common and less dramatic differences in genes encoding for
      drug metabolism enzymes can be responsible for a relatively small, but rather
      frequent increase of cancer risk at the population level. This increase could be
      especially important in specific cases of occupational, pharmacological or
      environmental exposure. Examination of the current literature reveals that the
      most extensively investigated metabolic polymorphisms are those of P450 1A1 and
      P450 2D6 cytochromes, glutathione S-transferases (GSTs; M1 and, to a lesser
      extent, M3, P1 and T1) and N-acetyltransferases (NATs; NAT1 and NAT2). Making
      reference to these enzymes, we have assayed the current knowledge on the
      relations among polymorphisms of human xenobiotic-metabolizing enzymes and cancer
      susceptibilities. We have found intriguing models of susceptibility toward
      different types of cancer. We have reviewed and commented these models on light
      of the complex balance among different enzyme activities that, in each
      individual, determines the degree of each cancer susceptibility. Moreover, we
      have found techniques of molecular genetic analysis, more suitable than previous
      ones on phenotypic expression, now allowing better means to detect individuals at
      risk of cancer. According to the models presently available, a systematic
      screening of individuals at risk seems to make sense only in situations of well
      defined carcinogenic exposures and when performed by the polymorphism analysis of
      coordinated enzyme activities concurring to the metabolism of the carcinogen(s)
      in question. Genetic polymorphism analysis can allow for the detection of
      patients more prone to some types of specific cancers, or to the adverse effects
      of specific pharmaceutical agents. Considering the increasingly confirmed double
      edged sword nature of metabolism polymorphism (both wild-type and variant alleles
      can predispose to cancer, albeit in different situations of exposure), individual
      susceptibility to cancer should be monitored as a function of the nature, and
      mechanism of action, of the carcinogen(s) to which the individual under study is
      known to be exposed, and with reference to the main target organ of the
      considered type of exposure.

PMID- 10354525
TI  - Mutagenicity, carcinogenicity, and teratogenicity of acrylonitrile.
AB  - Acrylonitrile (AN) is an important intermediary for the synthesis of a variety of
      organic products, such as artificial fibres, household articles and resins.
      Although acute effects are the primary concern for an exposure to AN, potential
      genotoxic, carcinogenic and teratogenic risks of AN have to be taken seriously in
      view of the large number of workers employed in such industries and the world
      wide population using products containing and possibly liberating AN. An
      understanding of the effect of acrylonitrile must be based on a characterization
      of its metabolism as well as of the resulting products and their genotoxic
      properties. Tests for mutagenicity in bacteria have in general been positive,
      those in plants and on unscheduled DNA synthesis doubtful, and those on
      chromosome aberrations in vivo negative. Wherever positive results had been
      obtained, metabolic activation of AN appeared to be a prerequisite. The extent to
      which such mutagenic effects are significant in man depends, however, also on the
      conditions of exposure. It appears from the limited data that the ultimate
      mutagenic factor(s), such as 2-cyanoethylene oxide, may have little opportunity
      to act under conditions where people are exposed because it is formed only in
      small amounts and is rapidly degraded. The carcinogenic action of AN has been
      evaluated by various agencies and ranged from 'reasonably be anticipated to be a
      human carcinogen' to 'cannot be excluded', the most recent evaluation being
      'possibly carcinogenic to humans'. Animal data that confirm the carcinogenic
      potential of AN have certain limitations with respect to the choice of species,
      type of tumors and length of follow up. Epidemiological studies which sometimes,
      but not always, yielded positive results, encounter the usual difficulties of
      confounding factors in chemical industries. Exposure of workers to AN should
      continue to be carefully monitored, but AN would not have to be considered a
      cancer risk to the population provided limitations on releases from consumer
      products and guidelines on AN in water and air are enforced. AN is teratogenic in
      laboratory animals (rat, hamster) at high doses when foetal/embryonic (and
      maternal) toxicity already is manifest. Pregnant workers should not be exposed to
      AN. In view of the small concentrations generally encountered outside plants,
      women not professionally exposed would appear not to be at risk of teratogenic
      effects due to AN. Future research should concentrate on the elucidation of the
      different degradation pathways in man and on epidemiological studies in workers
      including pregnant women, assessing also, if possible, individual exposure by bio
      monitoring.

PMID- 10354526
TI  - [The evaluation of the drug situation: the need for a comprehensive and rigorous
      information strategy].

PMID- 10354527
TI  - [Discrepancies in the number of deaths from an acute reaction to psychoactive
      substances recorded in Spain].
AB  - OBJECTIVE: The National Mortality Register (NMR) is used to monitor and
      prioritize health problems, but it may underestimate deaths from external causes,
      among which are deaths from acute reaction to psychoactive substances (ARPS). To
      evaluate the discrepancies between death from ARPS collected in the NMR and those
      collected in the specific register of the State Information System for Drug
      Addiction (SEIT). METHODS: We evaluated the discrepancy between ARPS deaths in 15
      49 years olds registered in the NMR (code E850-858) and deaths from acute
      reaction to opium and cocaine in the SEIT, in Barcelona, Bilbao, Madrid, Sevilla,
      Valencia and Zaragoza, between 1984-93. RESULTS: 3,491 ARPS deaths were
      registered in SEIT, 1,285 in NMR. Varying degrees of discrepancies appeared
      between the two registers in all six cities. The NMR in Madrid showed 92% fewer
      deaths than the SEIT, while in Barcelona the NMR figure was 23% lower. Between
      1984 and 1993 the differences between registers in all cities, except Madrid and
      Seville, narrowed (p < 0.01). CONCLUSIONS: Even though detection of ARPS deaths
      in the NMR has been improving, it still underestimates the real situation, and is
      therefore not a useful tool in the evaluation of temporal-spatial variations. To
      improve detection of ARPS deaths (and those from other external causes) a
      systematic linkage with data from the coroners' registers must be done.

PMID- 10354528
TI  - [The characteristics of opiate users seen in an emergency service].
AB  - INTRODUCTION: Despite of the fact that it was reported for years that emergency
      rooms are the first health services where drug users attend, there are very few
      direct studies of this population. In most emergency room studies, the
      information was obtained from data available in the clinical records, and in very
      few drug users were interviewed. With the aim of having a deeper knowledge of
      opiate users who attend the emergency room it was planned to carry out a cross
      sectional study interviewing them. The aims of this paper are to describe
      demographic characteristics, patterns of drug use and to know whether they
      contact first to an emergency room or to a treatment centre. METHODS: The sample
      included all patients detected and referred by the doctor as being current opiate
      users, defined as any use in the 30 days prior the interview. A descriptive
      bivariate analysis with simple stratification was carried out. RESULTS: Of the
      subjects referred by the doctor 383 opiate users were interviewed and 76 were not
      interviewed. The male/female ratio for the 383 interviewed opiates users was 2.
      Women were younger than men (25.8 vs 28.3, p (3/4) 0.001). Heroin or cocaine ever
      injected was reported by 93% and 76% reported injecting in the last 30 days. The
      mean age at the first use of heroin was higher for those who started use during
      1989 or after (21.6) than those who started before 1989 (17.9) (p (3/4) 0.0001).
      Patients attending the emergency room for organic pathology were older (28.5)
      than those who attended for withdrawal (26.2) and those who attended for overdose
      (27.3) (p (3/4) 0.05). Thirty eight percent reported to attend first an emergency
      room for a drug related problem since they started drug use, and 47% to contact
      first with a treatment centre for drug dependence. CONCLUSION: Drug users
      interviewed seem to be more heavy users than those who started drug treatment in
      the public centres of Barcelona in 1992. Also, the hypothesis that emergency
      rooms are for this population the first contact point with health services is not
      supported by this study.

PMID- 10354529
TI  - [The consistent use of condoms among intravenous drug users and their regular
      partners].
AB  - OBJECTIVE: To describe consistent condom use between drug injectors and their
      regular sexual partners and to identify factors associated to its use which may
      be amenable to intervention. METHODS: Information was collected by personal
      interviews of drug injectors in 13 sampling points of the city of Granada, Spain.
      A bivariate analysis of factors identified in the literature was carried out and
      a multivariate logistic regression was fitted to the data to test the
      hypothesized associations. RESULTS: The proportion of drug injectors who report
      consistent condom use with their regular partners was 26. 4%. Talking about
      condoms with other injectors and with their regular sexual partners, professional
      sources of information and counselling when receiving results of HIV testing are
      independently associated with the use of condoms. In terms of social indicators,
      those with the highest and lowest levels of social integration use condoms less
      than those who belong to the middle social group. Sociodemographic
      characteristics and history of drug injection are not associated with consistent
      condom use with the regular partner. CONCLUSION: The use of condoms between drug
      injectors and their regular sexual partners is associated with communication with
      other drug injectors, the sexual partner and hearth professionals, on this topic.
      Promoting consistent condom use with regular partners among intravenous drug
      users is best accomplished through peer groups and during HIV counseling.

PMID- 10354530
TI  - [The users of centers for AIDS information and prevention in the Comunidad
      Valenciana, Spain: a study based on cluster analysis].
AB  - OBJECTIVE: To measure the usefulness of multiple correspondence analysis (MCA)
      and cluster analysis applied to the epidemiological research of HIV infection.
      The specific are to explore the relationships between the different variables
      that characterize the users of the AIDS Information and Prevention Center (CIPS)
      and to identify clusters of characteristics which in terms of the attendance to
      these centers, could be considered similar. METHODS: The clinical history the
      CIPS in the Valencian region in Spain was used as data source. The target
      population target were intravenous drug users (IDUSs) attending these centers
      between 1987 and 1994 (n = 6211). Information about socio-demographic and HIV
      type I infection-related variables (drug use and sexual behaviour) was collected
      by means of a semistructured questionnaire. A MCA was carried out to obtain a
      group of quantitative factors that were used in a cluster analysis. RESULTS: A
      44.8% HIV type I prevalence was found. Five factors were detected by MCA that
      explain 51.14% of the total variability, of which sex, age and the usual sexual
      partner were the variables best explained. Cluster analysis allowed to describe 5
      different subgroups of CIPS users according to their socio-demographics
      characteristics, risk behaviours and serologic status. It is necessary to
      highlight the categories 1 and 2, which collect the serologic status and the most
      relevant characteristics of HIV infection. Category I contains users with a
      negative serology and characterized by being mainly single adolescent men, with a
      low educational level; they stated that they have no steady sexual partner, do
      not share syringes and have been intravenous drug users between 3 and 10 years.
      They mainly come from the city of Alicante. Category 2 contains mainly people
      that are HIV positive and older. They also share syringes and have been
      intravenous drug users for a longer time; they have a higher education level and
      most of them come from the city of Valencia. CONCLUSIONS: The proposed method of
      analysis was able to characterise the CIPS users, identifying those socio
      demographic variables and risk behaviours that are more related to the serologic
      status. The applicability of these techniques to epidemiologic studies of HIV
      type I infection is discussed.

PMID- 10354531
TI  - [AIDS patients with an unclassified risk factor for HIV].
AB  - OBJECTIVES: In the surveillance of the AIDS epidemic via registries there is a
      small proportion of cases whose route of HIV transmission is unknown (5% for
      Catalonia, Spain). For reclassification purposes, the aim of this study is to
      detect similarities between these cases with "not qualified risk" (NQR) with the
      other main HIV transmission groups. METHODS: All Aids cases (> 12 years) resident
      in Catalonia and reported between 1988 and 1996 to the AIDS registry (n = 8,559)
      were compared according to their distribution of "age at diagnosis" and "first
      indicative AIDS disease". ANOVA and log-linear regression models were applied
      separately by sex. RESULTS: Evidence of similarity with the NQR group was only
      found for men; in terms of age at diagnosis, the NQR group was similar to both
      groups of sexual transmission whilst in terms of Aids indicative disease it was
      similar to the heterosexual transmission group. As from 1994, a reduction in the
      incidence of NQR cases was observed and coincided with an increase in the
      heterosexual group. CONCLUSIONS: According to the characteristics of the NQR
      cases, it can be concluded that all cases acquired HIV via one of the classic
      routes of infection, primarily through heterosexual contacts. For this reason, it
      is advisable that the criteria that define heterosexual HIV transmission be
      relaxed.

PMID- 10354532
TI  - [The sociodemographic determinants of the tobacco habit and its cessation in the
      population of Cornella de Llobregat].
AB  - OBJECTIVE: To assess the relationship between socio-demographic factors and
      smoking status in a population of Barcelona metropolitan area. METHODS: The study
      included 2,074 questionnaires from the health interview survey carried out in a
      representative sample of Cornella during december 1993-november 1994. Only
      questionnaires of respondents older than 15 were included. A politomic logistic
      regression was used. Smoking status, classified as never smoker, actual smoker
      and former smoker, was considered the dependent variable and the sociodemographic
      factors, the independent variables. Socio-economic status was measured by
      educational level. RESULTS: The percentage of smokers in men was 46% while in
      women was only 22%. In men, the probability of smoking was higher in those men
      whose educational levels were lower (OR: 2.97); in women, no association was
      found between smoking and education. Unemployment increased the likelihood of
      being a smoker in both men and women (OR: 1.80). Women did smoke less than men in
      all age groups and educational levels except for women aged 15-44 with EGB or
      higher educational level. Educational level was not a significant factor in
      quitting smoking in either men or women. For both sexes, the greater the age the
      more likelihood there was of being an ex-smoker. Quitting was not associated with
      gender in any age or educational group. CONCLUSION: A similar prevalence of
      smoking in younger women and men of higher educational level suggests that gender
      differences are diminishing. In men, smoking was associated with educational
      level. Age is the principal determinant of quitting and neither educational
      achievement nor gender play a significant role in our study.

PMID- 10354533
TI  - [The mortality trend in suicides in Andalucia from 1976 to 1995].
AB  - OBJECTIVE: To describe trends in mortality from suicide among people older then
      14 years of age in Andalucia, Spain, from 1976 to 1995, with reference to age,
      sex, marital status and method of suicide. METHODS: With deaths from suicide and
      the populations of Andalucia, the following indicators were computed: crude and
      age-adjusted rates by gender, year of death and marital status; age-adjusted
      rates of years of potential life lost by year of death and marital status.
      Poisson regression models were obtained to analyze time trends. RESULTS:
      Mortality from suicide has experienced an important increase, mainly in men,
      changing from rates of 13,66 to 18,19 deaths per 100,000 person-years. In women,
      the increase has been much slighter, from 3,81 to 4,36 deaths per 100,000 person
      years. The largest increase has occurred among young males and, to a lesser
      extent, in the oldest groups, both in males and females, although the rates
      increase with age. The two main methods of suicide, both in males and females,
      were hanging and jumping, with the highest frequency occurring among widowers,
      followed by single and divorced persons, while married people were in the last
      position. CONCLUSIONS: In a situation of generalized increase in mortality from
      suicide in Andalucia in the study period, important differences were found by
      sex, age and marital status.

PMID- 10354534
TI  - [The libraries of the public hospitals in Spain. An economic analysis. The
      Research Group on Libraries].
AB  - BACKGROUND: The continuous increase in scientific knowledge in the health field,
      the development of new technologies and the rising cost of publications means
      that libraries are essential for patient care, medical education and research. In
      Spain some deficiencies have been seen in hospital libraries, and their cost is
      unknown. OBJECTIVE: To analyze the cost of public hospital libraries in Spain and
      to estimate the cost of adapting them to international standards. METHODS: Cross
      sectional survey of public hospitals larger than 100 beds, or smaller public
      hospitals with teaching accreditation. Information on the variables of interest
      was collected by questionnaire mailed to the libraries and followed up by
      telephone. Data collection was completed in 1996. The information on costs is for
      1994. A sensitivity analysis was done to examine the effects of imprecise
      estimates and assumptions. RESULTS: Of the 314 hospitals identified, 211 (67.2%)
      had libraries. The 1994 cost of the of the 211 libraries was 3,060 million
      pesetas (mean cost: 14.5 million pesetas). Personnel costs were the most
      important item (38% of the total), followed by the cost of subscriptions (29%).
      The cost of hospital libraries represented 0.08% of national public expenditures
      on health. The cost of correcting inadequacies in accordance with international
      standards would increase spending by about 400 million pesetas the first year
      (0.01% of public spending on health). CONCLUSIONS: The cost of hospital libraries
      represents only a small fraction of public spending on health. Correction of the
      observed deficiencies and the importance of libraries in the health system would
      require increasing spending to about 0.1% of public spending on health.

PMID- 10354536
TI  - A Boston T party.

PMID- 10354537
TI  - Single enzyme may hold key to cancer treatment.

PMID- 10354538
TI  - High-throughput screening: new frontiers for the 21st century.

PMID- 10354539
TI  - Eukaryotic antibiotic peptides: not only a membrane business.

PMID- 10354535
TI  - [AIDS prevention among adolescents in school: a systematic review of the efficacy
      of interventions].
AB  - BACKGROUND AND AIMS: Preventive interventions are considered useful although
      poorly evaluated. Since 1990 there are growing evidences of effective school aids
      prevention interventions. This paper aims to identify school aids prevention
      programs among youngsters aged 13 to 19, published between 1990 and 1995, to
      analyze each evaluation and intervention quality, to assess their effectiveness
      as well as identifying the possible contributing factors. METHODS: Location of
      reports by means of a Medline computerized search of published articles and
      reviews, which should include the following criteria: school aids prevention
      programs, addressed to youngsters aged 13 to 19, published in Spanish, French or
      English between 1990 and 1995 in scientific literature, and evaluating changes in
      behavior or its determinants through quantitative measures. Analysis of the
      evaluation quality through the assessment of the sample size, the use of a
      control group, the groups comparability, the drop out analysis and the time
      between the pretest and the posttest. Intervention quality analysis through the
      use of a psychological behavioral change model and the number of sessions. The
      effectiveness of the high quality interventions in changing behaviors,
      intentions, attitudes and knowledge was assessed. RESULTS: 29 studies were
      selected. Of these studies, relating the quality of evaluation criteria, a 28%
      was considered a high quality study, a 14% an intermediate quality study and a
      58% a low quality one. In relation to intervention quality criteria, a 27% was
      found to be a high quality study, a 41% an intermediate quality study and 32% a
      low quality one. 38% (11 studies) showed high or intermediate quality criteria at
      the same time in intervention and in evaluation. All these studies modified
      knowledge and attitudes, an 80% modified the intention to behave and a 86%
      modified behavior. The increase in knowledge and attitudes was in general quite
      important, greater than 10%, and changes in intentions and behaviors were smaller
      than 10%, although relevant. CONCLUSIONS: Only 38% of the studies may be
      considered of high or intermediate quality. Preventive interventions correctly
      evaluated which rely on a theoretical model and offer 4 or more sessions show
      evidence of moderate but relevant reduction of aids risk practices, and important
      changes of the future behavior determinants.

PMID- 10354540
TI  - Molecular diversity and its analysis.
AB  - We have recently developed a novel strategy for the rational design of compounds.
      This 'in silico screening' approach is based on the design and screening of
      virtual combinatorial libraries. Screening is performed using defined rules
      derived from a comprehensive description of active and inactive molecules in a
      relevant learning set. This strategy allows the development of potential ligands
      without the necessity of any knowledge of the 3D-structure of the target
      receptor. Key to the success of such methods is the quality of the information
      being processed, in particular, the diversity of the data in the context of the
      molecular population in the libraries concerned. Here, we review the problem of
      data diversity, its definition and its analysis using a new software tool, named
      Diverser.

PMID- 10354541
TI  - Automated synthesis: new tools for the organic chemist.
AB  - Routine automation of organic chemistry had proved an elusive goal until the
      arrival of combinatorial chemistry and the economic pressures of increased drug
      discovery throughput. Now, several approaches have been used to automate chemical
      synthesis, resulting in a range of new tools, both large and small, to support
      the process of compound production. The availability of these tools to the
      organic chemist heralds the change from the traditional 'hand-crafted' philosophy
      to a more mechanized view of compound synthesis in drug discovery groups.

PMID- 10354542
TI  - Anti-inflammatory substances - a new therapeutic option in Alzheimer's disease.
AB  - Among several pathogenetic elements underlying Alzheimer's disease (AD), a brain
      specific inflammatory response has recently attracted attention as a cause of
      neurodegeneration and progressive cognitive decline. Markers of inflammation in
      AD are activated microglial cells, synthesis of cytokines, acute-phase proteins
      and complement proteins in areas of brain destruction. Epidemiological studies
      point to a reduced risk of AD among users of anti-inflammatory drugs. Influencing
      inflammatory parameters has become the focus of several new treatment strategies
      and a clinical trial with indomethacin shows promising results. The results from
      current clinical trials with steroidal and non-steroidal anti-inflammatory drugs
      will be available in the near future.

PMID- 10354543
TI  - Recent developments in oral hypoglycemic agents.
AB  - Recent large-scale studies in patients with type 2 diabetes have suggested that
      improved glycemic control will reduce the incidence and severity of chronic
      complications. However, it is difficult to maintain the blood glucose levels of
      diabetic patients within a narrow range. Since insulin resistance and impaired
      insulin secretion cause hyperglycemia in type 2 diabetes, both improvement of
      insulin resistance and compensation for defective insulin secretion are
      necessary. Recently, the first insulin sensitizer was released, and a short
      acting insulinotropic agent, which should be more convenient for strict glycemic
      control than sulfonylureas, has also been launched. This review focuses on these
      two new classes of hypoglycemic agents.

PMID- 10354544
TI  - Monitor: molecules and profiles.
AB  - Monitor provides an insight into the latest developments in drug discovery
      through brief synopses of recent presentations and publications together with
      expert commentaries on the latest technologies. There are two sections: Molecules
      summarizes the chemistry and the pharmacological significance and biological
      relevance of new molecules reported in the literature and on the conference
      scene; Profiles offers commentary on promising lines of research, emerging
      molecular targets, novel technology, advances in synthetic and separation
      techniques and legislative issues.

PMID- 10354545
TI  - Combinatorial chemistry.

PMID- 10354546
TI  - Contribution of oxidative stress to excitotoxicity-induced deleterious iNOS in
      the CNS.

PMID- 10354547
TI  - Immune correlates of protection from HIV and AIDS - more answers but yet more
      questions.

PMID- 10354548
TI  - Delivery of DNA vaccines by attenuated intracellular bacteria.

PMID- 10354549
TI  - The chemokine system: redundancy for robust outputs.
AB  - Chemokines are redundant in their action on target cells and promiscuous in
      receptor usage. Moreover, certain cells concomitantly produce several chemokines
      with an overlapping spectrum of action. Here, Alberto Mantovani argues that such
      robustness provides a conceptual framework to understand these intriguing aspects
      of the chemokine system.

PMID- 10354550
TI  - Novel mechanism for the impairment of cell proliferation in HIV-1 infection.
AB  - The synthesis of ribonucleotides is essential to cell proliferation. Defects in
      the relevant metabolic pathways have been demonstrated in stimulated T cells from
      AIDS patients and are associated with lymphocyte necrotic death. Here, Margarita
      Bofill and colleagues discuss the possibility that an impaired ribonucleotide
      metabolism might be common to all rapidly dividing cells and thus contribute to
      other recognized symptoms of HIV-1 infection.

PMID- 10354551
TI  - T-cell clonality in immune responses.
AB  - Recent methodological advances allow the analysis of clonal composition within T
      cell subsets. Here, Mala Maini and colleagues review the available data on
      clonality in acute immune responses and steady-state situations. They highlight
      and explore reasons for the striking differences in clonality between the CD4+
      and CD8+ T-cell subsets.

PMID- 10354552
TI  - Regional specialization in the mucosal immune system: primed cells do not always
      home along the same track.
AB  - According to the current paradigm of lymphocyte trafficking, primed B and T cells
      extravasate in the intestinal lamina propria chiefly by means of the mucosal
      homing receptor alpha4beta7, which interacts with the vascular addressin MAdCAM
      1. However, as discussed here, this mechanism cannot explain the preferential
      homing of B cells with a high level of J-chain expression to mucosal effector
      sites outside the gut.

PMID- 10354553
TI  - ADAM family proteins in the immune system.
AB  - CD156 is a member of a family proteins characterized by a disintegrin and a
      metalloprotease domain (ADAM). These molecules are phylogenically conserved but
      have individual roles in a variety of cells. Here, Shunsuke Yamamoto and
      colleagues discuss data suggesting that ADAM family proteins have important roles
      in the immune system.

PMID- 10354554
TI  - Structure and evolution of the extended B7 family.
AB  - Here, Joelle Henry and colleagues explore structural and evolutionary
      relationships between the B7 costimulator molecules and a growing number of
      molecules encoded within the major histocompatibility complex. They propose that
      B7 and MHC genes are derived from a common ancestor, with several members of this
      large gene family possibly having pivotal influences on T-cell activation.

PMID- 10354555
TI  - Langerhans cells, nitric oxide, keratinocytes and psoriasis.

PMID- 10354556
TI  - Microarrays: their origins and applications.

PMID- 10354557
TI  - Sustainable development: how can biotechnology contribute?
AB  - Sustainable development has become a priority for the world's policy makers.
      Among the broad range of technologies with the potential to reach the goal of
      sustainability, biotechnology could take an important place, especially in the
      fields of food production, renewable raw materials and energy, pollution
      prevention, and bioremediation. However, technical and economic problems still
      need to be solved. In some cases, the environmental impact of biotechnological
      applications has been misjudged; in other cases, expectations cannot yet be
      matched.

PMID- 10354558
TI  - Towards electronic Petri dishes and picolitre-scale single-cell technologies.
AB  - Microsensors have traditionally been made as one-off, hand-crafted probes.
      Recently, however, there has been a concerted drive to exploit the
      microfabrication methods developed within the semiconductor industry in order to
      mass produce cheap, planar microsensing arrays. Such devices might be 'electronic
      Petri dishes' for the direct stimulation of, and measurement from, a variety of
      single cells, including neurones. In addition, micromachining has been used to
      construct picolitre-scale analytical sensors to extend the range of single-cell
      analyses.

PMID- 10354560
TI  - The biotechnological potential and design of novel carotenoids by gene
      combination in Escherichia coli.
AB  - Carotenoids are antioxidants with considerable pharmaceutical potential. More
      than 600 carotenoid structures are known but their availability is limited owing
      to practical difficulties associated with chemical synthesis and isolation from
      microorganisms or plant tissue. To overcome some of these problems, heterologous
      expression of carotenoid genes in Escherichia coli can be used for the synthesis
      of rare derivatives or even of novel carotenoids. Novel and rare carotenoids can
      be obtained by combining carotenoid genes from different host species in E. coli.

PMID- 10354561
TI  - Engineering baker's yeast: room for improvement.
AB  - Bread making is one of the oldest food-manufacturing processes. However, it is
      only in the past few years that recombinant-DNA technology has led to dramatic
      changes in formulation, ingredients or processing conditions. New strains of
      baker's yeast that produce CO2 more rapidly, are more resistant to stress or
      produce proteins or metabolites that can modify bread flavour, dough rheology or
      shelf-life are now emerging.

PMID- 10354562
TI  - An enzyme controlled by light: the molecular mechanism of photoreactivity in
      nitrile hydratase.
AB  - Extensive studies have revealed the molecular mechanism of the photoreactivity of
      nitrile hydratase from Rhodococcus sp. N-771. In the inactive enzyme, nitric
      oxide is bound to the non-heme ferric iron at the catalytic center, stabilized by
      a claw-like structure formed by two post-translationally modified cysteines and a
      serine. The inactive nitrile hydratase is activated by the photoinduced release
      of the nitric oxide. This result might provide a means of designing novel
      photoreactive chemical compounds or proteins that would be applicable to biochips
      and light-controlled metabolic systems.

PMID- 10354563
TI  - Elastic molecular machines in metabolism and soft-tissue restoration.
AB  - Elastic protein-based machines (bioelastic materials) can be designed to perform
      diverse biological energy conversions. Coupled with the remarkable energy
      conversion capacity of cells, this makes possible a tissue-restoration approach
      to tissue engineering. When properly attached to the extracellular matrix, cells
      sense the forces to which they are subjected and respond by producing an
      extracellular matrix that will withstand those forces. Elastic protein-based
      polymers can be designed as temporary functional scaffoldings that cells can
      enter, attach to, spread, sense forces and remodel, with the potential to restore
      natural tissue.

PMID- 10354564
TI  - All aboard the cyclin train: subcellular trafficking of cyclins and their CDK
      partners.
AB  - Progression through the cell cycle is governed by the periodic activation and
      inactivation of cyclin-dependent kinase complexes (CDK-cyclins). Although the
      enzymatic activity of these complexes is regulated tightly, it has recently been
      demonstrated that an additional facet of cell-cycle control involves the
      modulation of CDK-cyclin subcellular localization. Recent discoveries include the
      identification of nuclear transport factors responsible for ferrying some of the
      CDK-cyclins in and out of the nucleus, the demonstration that phosphorylation can
      regulate these transport processes and the establishment of potential links
      between cell-cycle checkpoints and the control of CDK-cyclin subcellular
      localization.

PMID- 10354565
TI  - PH domains in WASP - a bug in the system? Wiskott-Aldrich syndrome protein.

PMID- 10354566
TI  - PH domains in WASP - a bug in the system? reply 

PMID- 10354567
TI  - AKAPs: from structure to function.
AB  - Compartmentalization of signalling molecules through association with anchoring
      proteins ensures specificity in signal transduction by placing enzymes close to
      their appropriate effectors and substrates. For example, 'A-kinase anchoring
      proteins' (AKAPs) bind to the regulatory subunit of cAMP-dependent protein kinase
      (PKA) to direct the kinase to discrete intracellular locations. Recently,
      functional studies aimed at disrupting AKAP-PKA complexes have demonstrated a
      role for anchored PKA in various cellular processes, including gene
      transcription, hormone-mediated insulin secretion and ion-channel modulation. By
      binding to additional signalling molecules, AKAPs might function to coordinate
      multiple components of signal-transduction pathways.

PMID- 10354568
TI  - Protein import into chloroplasts.
AB  - Chloroplasts have evolved an elaborate system of membrane and soluble
      subcompartments to organize and regulate photosynthesis and essential aspects of
      amino acid and lipid metabolism. The biogenesis and maintenance of organellar
      architecture rely on protein subunits encoded by both nuclear and plastid
      genomes. Import of nuclear-encoded proteins is mediated by interactions between
      the intrinsic N-terminal transit sequence of the nuclear-encoded preprotein and a
      common import machinery at the chloroplast envelope. Recent investigations have
      shown that there are two unique membrane-bound translocation systems, in the
      outer and inner envelope membranes, which physically associate during import to
      transport preproteins from the cytoplasm to the internal stromal compartment.
      This review discusses current understanding of these translocation systems and
      models for the way in which they might function.

PMID- 10354569
TI  - Cytoskeletal rearrangement during migration and activation of T lymphocytes.
AB  - T lymphocytes have an inherent ability to migrate along a chemotactic gradient,
      which enables them to exit the bloodstream and reach different tissues. Motile T
      cells display a polarized morphology with two distinct cell compartments: the
      leading edge and the uropod. During cell polarization, chemoattractant receptors,
      cell-adhesion molecules and cytoskeletal proteins are redistributed within these
      cellular compartments. The polarity of T lymphocytes changes during the
      establishment of antigen-specific cell-cell interactions, and this involves
      rearrangement of cytoskeletal proteins. This article discusses the regulation of
      these cytoskeletal rearrangements, and their role in the activation, migration
      and effector function of T cells.

PMID- 10354571
TI  - Editorial: useful URLs 

PMID- 10354570
TI  - Homing and mobilization in the stem cell niche.
AB  - All mature blood cells are derived from the haemopoietic stem cell (HSC). In
      common with all other haemopoietic cells, stem cells are mobile, and it is this
      property of mobility that has allowed bone marrow transplantation to become a
      routine clinical option. Successful transplantation requires haemopoietic stem
      cells to home to the bone marrow, leave the peripheral circulation and become
      stabilized in regulatory niches in the extravascular space of the bone marrow
      cavity. This homing and tethering process is reversible - haemopoietic stem cells
      can be released from their bone marrow tethering through changes in molecular
      interactions, which are also important in homing following transplantation. The
      molecular mechanisms regulating this two-way flow of stem cells are beginning to
      be elucidated, and much recent data has emerged that sheds light on the processes
      and molecules involved in these complex physiological events. This article
      reviews current knowledge of the adhesive, homing and proliferative influences
      acting on HSCs and progenitor cells.

PMID- 10354572
TI  - Careers perspective interview: Norka Ruiz Bravo.

PMID- 10354573
TI  - Spatial and temporal limits in cognitive neuroimaging with fMRI.
AB  - A large body of research in human perception and cognition has been concerned
      with the segregation of mental events into their presumed hierarchical processing
      stages, the temporal aspect of such processing being termed 'mental chronometry'.
      Advances in single-event functional magnetic resonance imaging (fMRI) have
      allowed the extraction of relative timing information between the onset of
      activity in different neural substrates as well as the duration of cognitive
      processing during a task, offering new opportunities in the study of human
      perception and cognition. Single-event fMRI studies have also facilitated
      increased spatial resolution in fMRI, allowing studies of columnar organization
      in humans. Important processes such as object recognition, binocular vision and
      other processes are thought to be organized at the columnar level; thus, these
      advances in the spatial and temporal capabilities of fMRI allow a new generation
      of cognitive and basic neuroscience studies to be performed, investigating the
      temporal and spatial relationships between these cortical sub-units. Such
      experiments bear a closer resemblance to single-unit or evoked-potential studies
      than to classical static brain activation maps and might serve as a bridge
      between primate electrophysiology and human studies. These advances are initially
      demonstrated only in simple visual and motor system tasks and it is likely to be
      several years before the techniques we describe are robust enough for general
      use.

PMID- 10354574
TI  - Autism: cognitive deficit or cognitive style?
AB  - Autism is a developmental disorder characterized by impaired social and
      communicative development, and restricted interests and activities. This article
      will argue that we can discover more about developmental disorders such as autism
      through demonstrations of task success than through examples of task failure.
      Even in exploring and explaining what people with autism find difficult, such as
      social interaction, demonstration of competence on contrasting tasks has been
      crucial to defining the nature of the specific deficit. Deficit accounts of
      autism cannot explain, however, the assets seen in this disorder; for example,
      savant skills in maths, music and drawing, and islets of ability in visuospatial
      tests and rote memory. An alternative account, reviewed here, suggests that
      autism is characterized by a cognitive style biased towards local rather than
      global information processing - termed 'weak central coherence'. Evidence that
      weak coherence might also characterize the relatives of people with autism, and
      form part of the extended phenotype of this largely genetic disorder, is
      discussed. This review concludes by considering some outstanding questions
      concerning the specific cognitive mechanism for coherence and the neural basis of
      individual differences in this aspect of information processing.

PMID- 10354575
TI  - Models of word production.
AB  - Research on spoken word production has been approached from two angles. In one
      research tradition, the analysis of spontaneous or induced speech errors led to
      models that can account for speech error distributions. In another tradition, the
      measurement of picture naming latencies led to chronometric models accounting for
      distributions of reaction times in word production. Both kinds of models are,
      however, dealing with the same underlying processes: (1) the speaker's selection
      of a word that is semantically and syntactically appropriate; (2) the retrieval
      of the word's phonological properties; (3) the rapid syllabification of the word
      in context; and (4) the preparation of the corresponding articulatory gestures.
      Models of both traditions explain these processes in terms of activation
      spreading through a localist, symbolic network. By and large, they share the main
      levels of representation: conceptual/semantic, syntactic, phonological and
      phonetic. They differ in various details, such as the amount of cascading and
      feedback in the network. These research traditions have begun to merge in recent
      years, leading to highly constructive experimentation. Currently, they are like
      two similar knives honing each other. A single pair of scissors is in the making.

PMID- 10354576
TI  - Corrigendum.

PMID- 10354577
TI  - Is imitation learning the route to humanoid robots?
AB  - This review investigates two recent developments in artificial intelligence and
      neural computation: learning from imitation and the development of humanoid
      robots. It is postulated that the study of imitation learning offers a promising
      route to gain new insights into mechanisms of perceptual motor control that could
      ultimately lead to the creation of autonomous humanoid robots. Imitation learning
      focuses on three important issues: efficient motor learning, the connection
      between action and perception, and modular motor control in the form of movement
      primitives. It is reviewed here how research on representations of, and
      functional connections between, action and perception have contributed to our
      understanding of motor acts of other beings. The recent discovery that some areas
      in the primate brain are active during both movement perception and execution has
      provided a hypothetical neural basis of imitation. Computational approaches to
      imitation learning are also described, initially from the perspective of
      traditional AI and robotics, but also from the perspective of neural network
      models and statistical-learning research. Parallels and differences between
      biological and computational approaches to imitation are highlighted and an
      overview of current projects that actually employ imitation learning for humanoid
      robots is given.

PMID- 10354578
TI  - Deafness genes: expressions of surprise.
AB  - Recent rapid progress in identifying genes involved in deafness has suggested
      that a wide range of different types of gene products can result in hearing
      impairment, which, given the complexity of the auditory system, is not
      surprising. However, what has given some surprises are the unexpected expression
      patterns within the ear of some of these genes, which suggests that cochlear
      physiologists need to look again at some of the cell types involved.

PMID- 10354579
TI  - The small, the large and the wild: the value of comparison in plant genomics.
AB  - Studies of the model plant Arabidopsis are providing knowledge about the function
      of plant genes with an unprecedented clarity and quantity. A major challenge now
      is to apply this new information to the improvement of crop plants in a
      systematic manner. Sequence comparisons between Arabidopsis and rice can define
      potential functional relationships, and conserved gene order among cereals can
      then be used to ascribe functions to genes in many cereals.

PMID- 10354580
TI  - Pax genes in Caenorhabditis elegans: a new twist.

PMID- 10354581
TI  - A potential imprint control element: identification of a conserved 42 bp sequence
      upstream of H19.

PMID- 10354582
TI  - The origin of the genetic code: amino acids as cofactors in an RNA world.
AB  - The genetic code, understood as the specific assignment of amino acids to
      nucleotide triplets, might have preceded the existence of translation. Amino
      acids became utilized as cofactors by ribozymes in a metabolically complex RNA
      world. Specific charging ribozymes linked amino acids to corresponding RNA
      handles, which could basepair with different ribozymes, via an anticodon hairpin,
      and so deliver the cofactor to the ribozyme. Growing of the 'handle' into a
      presumptive tRNA was possible while function was retained and modified
      throughout. A stereochemical relation between some amino acids and cognate
      anticodons/codons is likely to have been important in the earliest assignments.
      Recent experimental findings, including selection for ribozymes catalyzing
      peptide-bond formation and those utilizing an amino acid cofactor, hold promise
      that scenarios of this major transition can be tested.

PMID- 10354583
TI  - NF-kappaB to the rescue: RELs, apoptosis and cellular transformation.
AB  - The REL/NF-kappaB/IkappaB superfamily of signal transducers and transcription
      factors are paradigmatic of molecular mechanisms by which rapid responses in the
      immune system can be achieved. NF-kappaB proteins have been implicated in diverse
      processes such as the ontogeny of the immune system, immune responses to
      pathogens and, importantly, in contributions to the multistage processes of
      oncogenesis, as described in this review. NF-kappaB and its regulators, the
      IkappaBs, are linked to pro- and anti-apoptotic events as well as signaling
      systems contributing to cellular transformation. How are these disparate events
      controlled to effect normal and abnormal processes in cells? Here we explore a
      few of the many events in which NF-kappaB appears to participate and processes
      that integrate signals to control important stages of oncogenesis.

PMID- 10354584
TI  - Early steps in pituitary organogenesis.
AB  - Significant advances have been made in defining the transcription cascade that is
      responsible for the early steps of pituitary formation and the environmental
      signals that induce, pattern and specify the pituitary gland and its cell types.
      It is now possible to outline the molecular mechanisms underlying the formation
      of the pituitary gland, as well as the initial development of organ-specific cell
      types.

PMID- 10354585
TI  - Mouse autosomal trisomy: two's company, three's a crowd.
AB  - Autosomal trisomy causes a large proportion of all human pregnancy loss and so is
      a significant source of lethality in the human population. The autosomal trisomy
      syndromes each have a different phenotype and are probably caused by the effects
      of specific genes that are present in three copies, rather than the normal two.
      Identifying these genes will require the application of classical genetic and new
      genome-manipulation approaches. Recent advances in chromosome engineering are now
      allowing us to create precisely defined autosomal trisomies in the mouse, and so
      provide new routes to identifying the critical, dosage-sensitive genes that are
      responsible for these highly deleterious, yet very common, syndromes.

PMID- 10354586
TI  - Zebrafish in the Net.

PMID- 10354587
TI  - Online access to 

PMID- 10354591
TI  - T-cell choice 

PMID- 10354592
TI  - The latest on budding 

PMID- 10354593
TI  - Pathoadaptive mutations: gene loss and variation in bacterial pathogens.
AB  - Pathogenicity-adaptive, or pathoadaptive, mutations represent a genetic mechanism
      for enhancing bacterial virulence without horizontal transfer of specific
      virulence factors. Pathoadaptive evolution can be important within single
      infections and for defining the population structure of a pathogenic species.

PMID- 10354594
TI  - Kaposi's sarcoma-associated herpesvirus: a new human tumor virus, but how?
AB  - Kaposi's sarcoma-associated herpesvirus, or human herpesvirus 8, the most
      recently discovered human tumor virus, is involved in the pathogenesis of
      Kaposi's sarcoma, primary effusion lymphoma and some cases of multicentric
      Castleman's disease. It is non-pathogenic in the majority of otherwise healthy
      individuals but highly oncogenic in the context of HIV-1 infection and iatrogenic
      immune suppression, and other cofactors might exist. Several viral genes can
      interfere with normal cell growth and differentiation, but their precise role in
      oncogenesis is still under investigation.

PMID- 10354595
TI  - When the going gets tough: survival strategies and environmental signaling
      networks in Bacillus subtilis.
AB  - Regulatory pathways involving two-component histidine kinase/response regulator
      proteins of Bacillus subtilis are highly interconnected and form a signal
      transduction network controlling stationary-phase adaptive responses. These
      include chemotaxis and motility, degradative enzyme synthesis, antibiotic
      production, natural competence for DNA uptake, and sporulation. Many of these
      responses are mutually exclusive, with different control levels involving protein
      environment, protein-protein and protein-DNA interactions, allowing the bacteria
      to adapt rapidly to environmental changes.

PMID- 10354596
TI  - Families of arsenic transporters.
AB  - Bacterial arsenic resistance (ars) operons encode an arsenite-efflux system that
      can be a secondary carrier protein (ArsB) or an anion-translocating ATPase
      (ArsAB). Yeasts extrude arsenite using Acr3p, a plasma membrane carrier protein,
      or sequester it in vacuoles as the glutathione conjugate using Ycf1p, an ABC
      transporter.

PMID- 10354597
TI  - Gene transfer systems for the Archaea.
AB  - The recent focus on exobiology and the potential for life in extreme environments
      has generated a great deal of interest in the Archaea because of their adaptation
      to extremes of temperature, salinity and anaerobicity. Recent advances in the
      development of genetic transfer systems for the Archaea provide the first glimpse
      of their genetic mechanisms and have the potential to serve as powerful tools for
      studying their unique adaptive strategies.

PMID- 10354598
TI  - Vectors, routes and maps: new discoveries about navigation in insects.

PMID- 10354599
TI  - The evolution of visual cortex: where is V2?
AB  - A comparative analysis of the area of the cortex that is adjacent to the primary
      visual area (V1), indicates that the lateral extrastriate cortex of primitive
      mammals was likely to contain only a single visuotopically organized field, the
      second visual area (V2). Few, if any, other visual areas existed. The opposing
      hypothesis, that primitive mammals had a 'string' of small visual areas in the
      cortex lateral to V1 (as in some rodents), is not supported by studies of the
      organization of extrastriate cortex in other mammals, nor by the variability in
      this organization among extant rodents. A critical re-analysis of published
      evidence on the presence of multiple areas adjacent to V1 in some rodents has led
      to alternative interpretations of the organization of the areas in these regions.

PMID- 10354600
TI  - Recent advances in understanding the pathogenesis of Huntington's disease.
AB  - Huntington's disease (HD) is an autosomal, dominantly inherited neurodegenerative
      disorder that is characterized by abnormal involuntary movements (chorea),
      intellectual impairment and selective neuronal loss. The expansion of a
      polymorphic trinucleotide repeat (the sequence CAG that codes for glutamine) to a
      length that exceeds 40 repeat units in exon 1 of the gene, HD, correlates with
      the onset and progression of the disease. The protein encoded by HD, huntingtin,
      is normally localized in the cytoplasm, whereas the mutant protein is also found
      in the nucleus, suggesting that its translocation to this site is important for
      the pathogenesis of HD. Although several proteins that interact with huntingtin
      have been identified in vitro, the significance of these interactions with the
      mutant protein in the pathogenesis of HD has yet to be determined. Recent
      progress in the development of cellular and animal models for the disease have
      provided invaluable insights and resources for studying the disease mechanisms
      underlying HD, and will be useful for screening and evaluating possible
      therapeutic strategies.

PMID- 10354602
TI  - Tagging the hebb synapse: reply 

PMID- 10354601
TI  - Tagging the Hebb synapse.

PMID- 10354603
TI  - FAK and PYK2/CAKbeta in the nervous system: a link between neuronal activity,
      plasticity and survival?
AB  - A major aim of neurobiology today is to improve understanding of the signaling
      pathways that couple rapid events, such as the action potential and
      neurotransmitter release, to long-lasting changes in synaptic strength and
      increased neuronal survival. These adaptations involve interactions of neurons
      with other cells and with the extracellular matrix. They use, in part, the same
      molecular machinery that controls adhesion, motility or survival in non-neuronal
      cells. This machinery includes two homologous non-receptor tyrosine kinases, FAK
      and PYK2/CAKbeta, and the associated SRC-family tyrosine kinases. Specific brain
      isoforms of FAK with distinct properties are regulated by neurotransmitters,
      whereas PYK2/CAKbeta is highly sensitive to depolarization. The multiplicity of
      the pathways that can be activated by these tyrosine kinases indicates their
      importance in signal transduction in the adult brain.

PMID- 10354604
TI  - Development of the vertebrate ear: insights from knockouts and mutants.
AB  - The three divisions of the ear (outer, middle and inner) each have an important
      role in hearing, while the inner ear is also crucial for the sense of balance.
      How these three major components arise and coalesce to form the peripheral
      elements of the senses of hearing and balance is now being studied using
      molecular-genetic approaches. This article summarizes data from studies of
      knockout and mutant animals in which one or more divisions of the ear are
      abnormal. The data confirm that development of all three divisions of the ear
      depends on the genes involved in hindbrain segmentation and segment identity.
      Genes that are regionally expressed in the inner ear can, when absent or mutated,
      yield selective ablation of specific inner-ear structures or cell types.

PMID- 10354605
TI  - Factors intrinsic to the neuron can induce and maintain its ability to promote
      axonal outgrowth: a role for BCL2?
AB  - The adult CNS provides a poor environment for axonal growth and regeneration. The
      question of to what extent the loss of axonal growth occurring as the brain
      matures is dependent on factors intrinsic or extrinsic to the growing neuron is
      still unanswered. Examination of axonal growth from neural transplants provides
      insight into the roles of growth factors, inhibitory molecules, growth-promoting
      substrates and the differences between CNS and PNS environments in the regulation
      of neurite extension. The data that imply a role for BCL2 and related molecules
      in such processes are reviewed in this article, which analyzes the factors
      intrinsic to the neuron that control its capacity for axonal growth.

PMID- 10354608
TI  - Online access to 

PMID- 10354606
TI  - Acetylcholine in mind: a neurotransmitter correlate of consciousness?
AB  - The cholinergic system is one of the most important modulatory neurotransmitter
      systems in the brain and controls activities that depend on selective attention,
      which are an essential component of conscious awareness. Psychopharmacological
      and pathological evidence supports the concept of a 'cholinergic component' of
      conscious awareness. Drugs that antagonize muscarinic receptors induce
      hallucinations and reduce the level of consciousness, while the nicotinic
      receptor is implicated as being involved in the mechanism of action of general
      (inhalational) anaesthetics. In degenerative diseases of the brain, alterations
      in consciousness are associated with regional deficits in the cholinergic system.
      In Alzheimer's disease (AD), there is a loss of explicit (more than implicit)
      memory and hypoactivity of cholinergic projections to the hippocampus and cortex,
      while the visual hallucinations experienced by subjects with Dementia with Lewy
      bodies (DLB) are associated with reductions in neocortical ACh-related activity.
      In Parkinson's disease, the additional loss of pedunculopontine cholinergic
      neurones, which control REM (rapid eye movement) sleep or dreaming, is likely to
      contribute to REM abnormalities, which also occur in DLB. Widespread basal
      forebrain and rostral brainstem cholinergic pathways, which include converging
      projections to the thalamus, appear to be located strategically for generating
      and integrating conscious awareness. Alleviation of a range of cognitive and non
      cognitive symptoms by drugs that modulate the cholinergic system, which are being
      developed for the treatment of AD and related disorders, could be caused by
      changes in consciousness.

PMID- 10354609
TI  - RAMPs: accessory proteins for seven transmembrane domain receptors.

PMID- 10354610
TI  - NMDA receptor-dependent and -independent behavioural sensitization.

PMID- 10354612
TI  - Tzschentke and schmidt reply 

PMID- 10354611
TI  - NMDA receptors and behavioural sensitization: beyond dizocilpine.

PMID- 10354613
TI  - Stroke therapy in traditional Chinese medicine (TCM): prospects for drug
      discovery and development.
AB  - Brain injuries resulting from stroke are a major and increasing public health
      problem in both developed and developing countries worldwide. China's extensive
      experience in the use of traditional Chinese medicines (TCMs) in stroke therapy
      indicates that TCM preparations are effective, with few or no side-effects. There
      are more than 100 traditional medicines in use for stroke therapy in China. Some
      of their therapeutic effects in stroke have been confirmed by recent clinical
      studies. A large number of compounds have been isolated from TCMs and most of
      these resources have not yet been characterized for pharmacological purposes.
      Here, this article explains how TCM provides an extensive and knowledge-rich
      foundation for implementing a strategically focused pharmacological research
      programme aimed at the development of new drugs.

PMID- 10354614
TI  - Medicines from nature: are natural products still relevant to drug discovery?
AB  - Historically, most drugs have been derived from natural products, but there has
      been a shift away from their use with the increasing predominance of molecular
      approaches to drug discovery. Nevertheless, their structural diversity makes them
      a valuable source of novel lead compounds against newly discovered therapeutic
      targets. Technical advances in analytical techniques mean that the use of natural
      products is easier than before. However, there is a widening gap between natural
      product researchers in countries rich in biodiversity and drug discovery
      scientists immersed in proteomics and high-throughput screening.

PMID- 10354615
TI  - Artemisinin drugs in the treatment of malaria: from medicinal herb to registered
      medication.
AB  - Registration in Europe of several artemisinin drugs for the treatment of malaria
      can soon be expected. Artemisinin is isolated from the herb Artemisia annua, in
      use in China more than 2000 years as a herbal tea against fever. Artemisinin
      drugs are being used extensively in South-East Asia and increasingly in Africa.
      Active derivatives have been synthesized - artemether, arteether and artesunate -
      which are used for oral, intramuscular, rectal and intravenous administration.
      The origin, mechanism of action, efficacy and safety in patients, the
      pharmacokinetics and the position of this group of compounds among existing
      antimalarials are discussed in this review.

PMID- 10354616
TI  - The interactions of adenylate cyclases with P-site inhibitors.
AB  - Recent kinetic, binding and crystallographic studies using P-site inhibitors of
      mammalian adenylate bases provide new insights into the catalytic mechanism of
      these highly regulated enzymes. Here, Carmen Dessauer and colleagues discuss the
      conformational states of adenylate cyclase, the structural determinants of
      inhibitor binding and the potential uses of these inhibitors as pharmacological
      agents.

PMID- 10354617
TI  - Heart failure and endothelin receptor antagonists.
AB  - Cardiac myocytes and vascular endothelial cells produce endothelin-1, which
      increases the contractility of cardiac muscles and of vascular smooth muscles.
      Endothelin-1 also exerts long-term effects, such as myocardial hypertrophy, and
      causes cellular injury in cardiac myocytes. In heart failure, the production of
      endothelin-1 is markedly increased in the failing heart. Here, evidence that an
      endothelin receptor antagonist is a useful new drug for the treatment of heart
      failure is discussed. Long-term treatment with an endothelin receptor antagonist
      greatly improves the survival rate of animals (rat, hamster, etc.) with chronic
      heart failure. This beneficial effect is accompanied by amelioration of left
      ventricular dysfunction. The myocardial endothelin system appears to be a novel
      and important target for therapeutic intervention in heart failure.

PMID- 10354618
TI  - Uridine and its nucleotides: biological actions, therapeutic potentials.
AB  - There are many disorders of pyrimidine metabolism and those that involve an
      alteration in uridine metabolism have neurological and systemic effects, which
      provide insights into the biological activity of uridine and its analogues.
      Studies of the metabolism and actions of pyrimidines have uncovered a wealth of
      information on how these endogenous metabolites modulate cell physiology. In this
      article, the roles for the pyrimidine nucleoside uridine and its nucleotide
      derivatives in the regulation of a number of biological systems are examined and
      benefits of further studies are outlined. An understanding of how uridine and its
      nucleotides modulate such vastly complicated biological systems should ultimately
      lead to the development of new ways for modulating human physiology in both
      normal and diseased states. Likely targets for therapy include the respiratory,
      circulatory, reproductive, and nervous systems, and the treatment of cancer and
      HIV infection.

PMID- 10354619
TI  - Do animal mitochondrial genomes recombine?

PMID- 10354621
TI  - Further endosymbiont diversity: a tree hiding in the forest?

PMID- 10354620
TI  - How old are animals?

PMID- 10354622
TI  - The importance of cloud and fog in the maintenance of ecosystems.

PMID- 10354623
TI  - Landscape approaches to historical and contemporary gene flow in plants.
AB  - Growing interest in metapopulation dynamics and dispersal at a landscape level is
      promoting new approaches to the study of contemporary gene flow. These approaches
      have been fostered by the development of new genetic markers and statistical
      methods, as well as an awareness that contemporary gene flow cannot be reliably
      estimated by conventional methods based on genetic structure. Estimation of the
      spatial and temporal dynamics of pollen and seed movement with respect to extant
      landscape features can aid evolutionary and conservation biologists in predicting
      the demographic and genetic responses of species to naturally occurring or human
      mediated population subdivision.

PMID- 10354624
TI  - Nematode community structure as a bioindicator in environmental monitoring.
AB  - Four of every five multicellular animals on the planet are nematodes. They occupy
      any niche that provides an available source of organic carbon in marine,
      freshwater and terrestrial environments. Nematodes vary in sensitivity to
      pollutants and environmental disturbance. Recent development of indices that
      integrate the responses of different taxa and trophic groups to perturbation
      provides a powerful basis for analysis of faunal assemblages in soil as in situ
      environmental assessment systems.

PMID- 10354626
TI  - Reply from I.C.W. Hardy and P.J. Mayhew.

PMID- 10354625
TI  - Successful sons or advantaged daughters? The Trivers-Willard model and sex-biased
      maternal investment in ungulates.
AB  - The Trivers-Willard model predicts that in polygynous species, given certain
      assumptions, mothers with extra resources should bias investment towards sons by
      adjusting sex ratio at birth and/or by differential provisioning of sons and
      daughters. Evidence for facultative adjustment of the birth sex ratio from recent
      empirical studies on ungulates is equivocal at best. However, studies on maternal
      input and reproductive costs suggest that ungulate mothers do discriminate
      against daughters during maternal investment in the most polygynous, dimorphic
      species. Better data on the relationship between maternal input and fitness
      returns for producing sons or daughters are needed to interpret patterns of sex
      biased maternal investment.

PMID- 10354627
TI  - Sexual selection and the Y chromosome.

PMID- 10354628
TI  - Kin recognition: function and mechanism in avian societies.
AB  - Cooperative behaviour resulting from kin selection is widespread among animals
      and the ability to recognize and discriminate between kin and non-kin is a
      critical element in kin selection theory. Current evidence suggests that
      associative learning is the most likely mechanism of kin discrimination. However,
      surprisingly, there have been no experimental studies of the putative
      'associative-learning period', the likely recognition mechanisms enabling fine
      discrimination between close and distant kin of similar familiarity, whether
      generic or individual cues are employed in kin recognition, and how recognition
      ability varies at different stages of a species' life history. Comparative
      studies of kin recognition and discrimination in cooperative and noncooperative
      species are also needed to shed light on the adaptive value of helping behaviour
      and to identify key factors in the evolution of cooperation.

PMID- 10354629
TI  - Extinction risk in the sea.
AB  - Jean Baptiste de Lamarck and Thomas Huxley, two of the foremost thinkers of the
      18th and 19th centuries, believed that humanity could not cause the extinction of
      marine species. Their opinions reflected a widespread belief that the seas were
      an inexhaustible source of food and wealth of which people could barely use a
      fraction. Such views were given weight by the abundant fisheries of the time.
      Additionally, the incredible fecundity and wide distributions of marine fishes,
      combined with limited exploitation, provided ample justification for optimism.
      The ideas of Huxley and Lamarck persist to this day, despite a sea change in the
      scale and depth of our influence on the oceans. Marine species could be at a far
      greater risk of extinction than we have assumed.

PMID- 10354630
TI  - Ecosystem metabolism and the global carbon cycle.

PMID- 10354631
TI  - Soil exposure no protection against atopy.

PMID- 10354633
TI  - 1918 and all that 

PMID- 10354632
TI  - Landing on lipid rafts.

PMID- 10354634
TI  - The big picture 

PMID- 10354635
TI  - Microbial genomics 

PMID- 10354636
TI  - Local mating and sex ratios.

PMID- 10354637
TI  - The structure of carotenoids.

PMID- 10354638
TI  - Conserving biological resources.

PMID- 10354639
TI  - [Pathologic-anatomic investigations in laying hens in various housing systems].
AB  - Gross pathologic and histologic changes were investigated in a total of 1000 end
      of-lay hens. Thirty animals were drawn from free range stocks, 270 from deep
      litter stocks, and 700 from caging systems. The following changes were evaluated
      with regards to housing systems: Pododermatitis, deformation of the keel bone and
      amputated beaks occurred primarily in free range hens. Deep litter hens also
      suffered from pododermatitis, keel bone deformation and amputated beaks in
      addition to pecking wounds. In caged hens severe fatty liver syndromes, injuries
      of the claws and inflammation of the feather follicles were mainly found.
      Furthermore, injuries and fractures due to handling and transport were almost
      exclusively found in caged hens. It has to be concluded that all of the
      investigated housing systems can predisposed hens to certain lesions. The
      documented changes--e.g. chronic inflammation, skelettal deformities and injuries
      -are painful and may lead to permanent alterations. Therefore, these changes
      should be condemned as conflicting with animal protection regulations.

PMID- 10354640
TI  - [Amendment of the Animal Welfare Act and other topical questions in animal
      welfare legislation].
AB  - A report on the amendment of the German Animal Welfare Act as well as on other
      questions relevant to animal welfare legislation in the Federal Republic of
      Germany is given.

PMID- 10354641
TI  - [Voluntary testing procedures of farm animal housing equipment according to the
      Animal Welfare Act of 1998].
AB  - Before its broad application in practice, housing equipment should be tested, in
      particular with regard to animal welfare. The differing positions of the German
      Federal Council (Bundesrat) and the German Federal Parliament (Bundestag),
      whether such testing should be mandatory or voluntary, have been conciliated in
      the amended animal welfare act by empowering the Federal Ministry of Food,
      Agriculture and Fisheries (BML) to fix official standards for voluntary testing
      procedures by regulation. On request of the BML, a report as scientific basis for
      a draft regulation is currently prepared by the scientific animal welfare
      committee of the German Agricultural Society (DLG). The scientific animal welfare
      committee has been appointed by the DLG in order to provide support in the effort
      to strengthen animal welfare aspects in the DLG-utility testing procedure of
      housing equipment, which is in place since 1953. The committee elaborates
      standards concerning testing methods, assessment criteria and the necessary size
      of investigations. As required, the scientific animal welfare committee may
      support the DLG-testing bodies in the implementation of the animal welfare part
      of the testing procedure. It will, moreover, be involved in the welfare
      assessment based on the testing results. The amendments of the already
      established testing procedure will help to fulfill the general requirements on an
      acceptable animal welfare testing procedure. While keeping in mind that there are
      certain limits in what can be achieved by a voluntary testing procedure, the
      enhanced consideration of animal welfare aspects within the DLG-utility testing
      procedure has the advantage to be relatively unbureaucratic and in line with EU
      legislation, and is, therefore, an appropriate tool for a contibrution to
      improved animal welfare in livestock housing.

PMID- 10354642
TI  - [Transgenic pigs for xenotransplantation for humans].
AB  - Transgenic livestock have been generated via microinjection of DNA-constructs
      into pronuclei of zygotes. However, efficiency is low and only 1-3% transgenic
      offspring are to be obtained. Integration of the transgene occurs at random and
      expression is independent from the number of integrated copies but can be
      affected by the integration site. To overcome the shortage of human organs,
      transgenic pigs have been generated that express human complement regulatory
      genes. This approach enables to overcome the hyperacute rejection response as
      shown by an average survival rate (40-90 days) of the immunosuppressed primate
      recipients receiving a heart from a transgenic pig. It is expected that
      transgenic pigs would be available as organ donors in the next 5-10 years. A
      major prerequisite, however, is the prevention of the potential transfer of
      pathogenic microorganisms, in particular porcine endogenous retroviruses (PERV).
      Improvements of the efficiency in the generation of transgenic pigs will be
      achieved by the use of genetically modified donor cells in nuclear transfer
      technology (cloning).

PMID- 10354644
TI  - [Ethical reflections on xenotransplantation].
AB  - The success of transplantation and the increasing demand for donor organs have
      led to an increasingly acute shortage of human organs and tissue for
      transplantation. In this situation xenotransplantation (cross-species
      transplantation from animals to humans) is discussed as a possible alternative to
      allotransplantation. Therefore the animal plays an important role in the
      discussions on xenotransplantation. Currently, a lot of research is being done on
      xenotransplantation. Cross-species transplantation involves many biological and
      medical problems and risks which may affect not only the individual patient but
      also the wider community and population. These problems give rise to important
      ethical questions about xenotransplantation. Apart from them other ethical issues
      are involved, concerning the human being as well as the animal. Animals are
      raised, genetically modified (transgenic animals) and kept under SPF-conditions
      before they can be used as organ sources. At the moment they are used as models
      in xenotransplantation research. My aim is to discuss some of the major ethical,
      medical and biological problems of xenotransplantation.

PMID- 10354643
TI  - [Porcine endogenous retroviruses (PERV): in vitro artifact or a big problem for
      xenotransplantation?].
AB  - The pig is the favorized donor species for clinical xenotransplantation. However,
      PATIENCE et al. could show, that porcine endogenous retroviruses (PERV), released
      by a porcine kidney cell line, are capable of infecting human cell lines in
      vitro. Based on this discovery there is an ongoing discussion concerning the
      risks of zoonosis combined with xenotranplantation, which culminated in the
      demand for a moratorium on clinical transplantation of porcine organs. Recent
      findings exclude the possibility of an artifact due to the use of an immortalized
      cell line: Release of infectious PERV was also shown for mitogenic stimulated
      primary porcine peripheral blood mononuclear cells and, even more important, for
      primary porcine endothelial cells. In contrast, none of the recent retrospective
      in vivo studies showed evidence for PERV transmission, neither in patients after
      transplantation of porcine pancreas islet cells or after extracorporal perfusion
      of porcine kidneys, nor in baboons after transplantation of porcine endothelial
      cells. Currently it is not known, whether impairments of the immunological
      responses against foreign pathogens, which are associated with different
      xenotransplantation strategies, could enable PERV in vivo infection. Only in vivo
      experiments, if possible in suitable subhuman primate models, offer the prospect
      for a final risk assessment.

PMID- 10354645
TI  - [Practice report: corrective education for misbehaving dogs].
AB  - A report on practical experiences with the education of aggressive dogs is given.
      Attention is payed to the instruction of the owners who ought to understand the
      nature and the behavioural needs of the animals. Positive results of the use of
      the electrical education aid Teletakt are reported.

PMID- 10354646
TI  - [Laying hen maintenance in the future--the Proposal of the Commission for a
      Council Directive setting minimum standards for the protection of laying hens
      under various rearing systems].
AB  - A prognostic of the keepingsystems of laying hens in the future is done on the
      basis of the conclusions in the Report on the Welfare of Laying Hens made by the
      Scientific Veterinary Committee of the European Commission and the Commission's
      Proposal for a Council Directive laying down minimum standards for the protection
      of laying hens kept in various systems of rearing. The present discussions in the
      Councils are reported. It is quite evident, that various keepingsystems will also
      exist in the future, but the predominant position of battery cages will not stay
      at that level.

PMID- 10354647
TI  - [Domestic animal welfare--practice oriented solutions].
AB  - Examples for practical solutions of animal welfare questions in poultry and pig
      holdings are described: A new inspection trolley for laying hens in battery cages
      with 8 floors, rearing conditions for laying hens in alternative housing systems
      including outdoor areas, improvement of hen-runs with plantation and mobile
      shelters, incidence of day-light in broiler houses, use of an automatic broiler
      catching machine, straw-racks and structured pens for fattening turkeys, outdoor
      husbandry of "Kelleyturkeys", kennelled system with "bungalows" for weaners
      (Nurtinger System), "Straw-Flow" systems with a sloping floor and straw provided
      from a freely accessible dispenser, outdoor areas with solid surface for
      fattening pigs, straw-racks, animal friendly construction of farrowing pens as
      well as an outdoor system for breeding sows.

PMID- 10354648
TI  - [Humane killing of animals in agricultural management].
AB  - The special problem of handling weak, chronically ill, injured farm animals or
      those not sellable for slaughter is described. Farmers generally do not have
      sufficient knowledge in killing animals. They need external help or they must
      take specific training courses to get the necessary knowledge. Solutions how to
      improve animal welfare in this field are given.

PMID- 10354649
TI  - [Housing of dogs and cats in animal shelters].
AB  - The results of an examination of 10 animal shelters was, that anyone was unical.
      The everyday and fundamental problems in administration, housing animals and
      animal care were the same: Most of them employ laity, which do their job with a
      lot of commitment but without knowledge. Therefore they come into conflict with
      the demands of animal protection. Veterinary surgeons, responsible authorities
      and communities are strongly asked to take steps against the situation. The
      reason for the fact, that such steps are missed, is, that there is no guideline
      or recommendation available for these persons, which handles animal shelters
      relative to "animal justice" and the right housing of animals. The results of the
      survey helps to make a guideline for animal home owners and builders, veterinary
      surgeons, veterinary authorities and communities, which gives suggestions to
      build, equip and run animal shelters for cats and dogs responsible regarding the
      individual circumstances and in the best way for animals.

PMID- 10354650
TI  - [Effect of common head gear on horses].
AB  - The functions of the most common head-gears for horses are analysed from a
      biomechanical point of view. With the exception of the stable halter are all of
      them designed to enlarge the tensile forces transmitted through the reins or the
      longe, and to concentrate the enlarged forces on sensitive parts of the horse's
      head: the nose, or the lips, mandible and tongue. Since the direction, duration
      and size of these tensile forces are the essential factors to modulate signals
      for controlling the horse, a device has been developed to measure, or at least
      roughly quantify these forces. The mechanical characteristics of bosal, cavecon,
      serreta, kappzaum and hackamore are demonstrated and compared with those of the
      two major types of bits: those with and without levers.

PMID- 10354651
TI  - [Equipment and aids in trotting races].
AB  - During the last years, trotting races met with massive criticism, because some of
      the numerous items of equipment were not to be reconciled with animal protection.
      In March 1998, the Trotting Association (HVT), as well as the list of authorized
      equipment. The so-called "positive list" includes harnesses, bridles, bits,
      auxiliary reins, driving reins, whips and other aids, among other things brushing
      boots, ear-muffs and head-pole. Especially criticized items are submitted to an
      assessment according to the present animal protection law. Moreover,
      possibilities are shown to make positive conditions in the surrounding area of
      the trotter more transparent, for instance horse keeping and training management,
      and to underline them in order to improve the reputation of the trotting sport.

PMID- 10354652
TI  - [Equipment, methods of constraint and other aids in horse racing].
AB  - After a brief introduction to the most important aspects of the current sport of
      horse-racing the equipment and tack will be described with respect to the horses
      wellbeing: bridles, tonguestrap, blinkers, saddle and girth. With reference to
      incorrect equipment for the rider, the wip and its misuse will be discussed.
      Problems with saddling and at the starting gate are often indicators of the
      incorrect application of aids. Then the misuse of the automatic horse trainer,
      treadmills and swimmingpools will be explained. Finally, the three most important
      requirements for improving the protection of racehorse are summarized: the racing
      regulations should conform to animal welfare laws and the application of these
      laws should be in the hands of an independent veterinary surgeon, who has the
      authority to enforce its requirement.

PMID- 10354653
TI  - Mood disorders in children and adolescents: coming of age.

PMID- 10354654
TI  - Psychopharmacogenetics and psychiatric genetics: similar methodological
      challenges.

PMID- 10354655
TI  - Lithium dosage and leukocyte counts in psychiatric patients.
AB  - OBJECTIVE: To evaluate differences in leukocyte counts among patients treated
      with either lithium alone, antipsychotic medications alone, or a combination of
      both. DESIGN: Retrospective study. SETTING: Long-stay psychiatric hospital.
      PATIENTS: Patients admitted between 1990 and 1993, and treated with lithium for
      at least 1 week and/or with antipsychotic medication for at least 2 weeks.
      Excluded from the study were those patients for whom complete blood counts at
      baseline and during therapy were not available, and those patients whose blood
      picture could primarily be accounted for by extraneous factors. Included in the
      study were 38 patients treated with lithium alone, 207 patients receiving
      antipsychotic medications alone, and 71 patients receiving both. OUTCOME
      MEASURES: Leukocyte, lymphocyte and granulocyte counts. RESULTS: Patients treated
      with lithium alone had significantly higher mean leukocyte and granulocyte counts
      than those treated with antipsychotic medication alone (analysis of variance, p <
      0.05). None of the patients receiving lithium alone showed leukopenia. The dosage
      of lithium was significantly correlated with leukocyte count (r = 0.25, 95%
      confidence interval [CI] 0.14 to 0.35, p < 0.001,) and granulocyte count (r =
      0.27, 95% CI 0.16 to 0.38, p < 0.001), but not with lymphocyte count (r = 0.06, p
      = 0.286, 95% CI -0.05 to 0.17). CONCLUSIONS: Lithium therapy is associated with
      higher leukocyte and granulocyte levels in psychiatric patients. This
      leukocytotic effect of lithium may be dose dependent.

PMID- 10354656
TI  - Lithium does not alter the choline/creatine ratio in the temporal lobe of human
      volunteers as measured by proton magnetic resonance spectroscopy.
AB  - OBJECTIVE: To study the effect of lithium administration on brain
      choline/creatine (Cho/Cr) ratios in healthy volunteers. DESIGN: Double-blind,
      placebo-controlled, prospective study. SETTING: The Nuclear Magnetic Resonance
      Research Unit at the University of Alberta. PARTICIPANTS: Sixteen healthy
      volunteers, recruited through advertisements. Subjects were excluded if they had
      a physical illness, or a personal or family history of psychiatric illness. The
      study period was from Feb. 6, 1996, to Mar. 21, 1996. INTERVENTIONS: Subjects
      received a baseline proton magnetic resonance spectroscopy (1H MRS) scan, and
      then were instructed to take either lithium (1,200 mg) or placebo at night for 7
      days. On Day 8, the subjects returned for a second 1H MRS scan. Study
      participants were seen by a physician at the beginning and at the end of the
      experiment, and had access to the physician throughout the study period. OUTCOME
      MEASURES: Ratios of Cho/Cr measured in the temporal lobes by 1H MRS. RESULTS:
      There were no significant differences in the Cho/Cr ratios between the 2 groups
      on the test day (placebo 0.748 [standard deviation 0.29] versus lithium 0.811 [SD
      0.25]; F = 0.147, p = 0.72), and there was no significant change from baseline in
      either group (0.003 above baseline for placebo; 0.056 above baseline for lithium;
      F = 1.21, p = 0.32). CONCLUSIONS: Lithium administration to healthy volunteers
      does not alter the Cho/Cr ratio in temporal lobe as measured by 1H MRS. The
      result concurs with reports that differences in Cho/Cr ratios observed in
      patients with bipolar disorder are likely specific to the illness, and are not
      the result of lithium therapy. Hence, alterations in choline function are not
      involved in the clinical effectiveness of lithium.

PMID- 10354657
TI  - Effect of lithium maintenance therapy on thyroid and parathyroid function.
AB  - OBJECTIVES: To assess changes induced by lithium maintenance therapy on the
      incidence of thyroid, parathyroid and ion alterations. These were evaluated with
      respect to the duration of lithium therapy, age, sex, and family history (whether
      or not the patient had a first-degree relative with thyroid disease). DESIGN:
      Prospective study. SETTING: Affective Disorders Clinic at St. Mary's Hospital,
      Montreal. PATIENTS: One hundred and one patients (28 men and 73 women) with
      bipolar disorder receiving lithium maintenance therapy ranging from 1 year's to
      32 years' duration. The control group consisted of 82 patients with no
      psychiatric or endocrinological diagnoses from the hospital's out-patient
      clinics. OUTCOME MEASURES: Laboratory analyses of calcium, magnesium and thyroid
      stimulating hormone levels performed before beginning lithium therapy and at
      biannual follow-up. RESULTS: Hypothyroidism developed in 40 patients, excluding 8
      patients who were hypothyroid at baseline. All patients having first-degree
      relatives affected by thyroid illness had accelerated onset of hypothyroidism
      (3.7 years after onset of lithium therapy) compared with patients without a
      family history (8.6 years after onset of lithium therapy). Women over 60 years of
      age were more often affected by hypothyroidism than women under 60 years of age
      (34.6% versus 31.9%). Magnesium levels in patients on lithium treatment were
      unchanged from baseline levels. After lithium treatment, calcium levels were
      higher than either baseline levels or control levels. Thus, lithium treatment
      counteracted the decrease in plasma calcium levels associated with aging.
      CONCLUSIONS: Familial thyroid illness is a risk factor for hypothyroidism and
      hypercalcemia during lithium therapy.

PMID- 10354658
TI  - Selegiline in the treatment of Alzheimer's disease: a long-term randomized
      placebo-controlled trial. Czech and Slovak Senile Dementia of Alzheimer Type
      Study Group.
AB  - OBJECTIVE: To evaluate the efficacy and adverse effects of the type B monoamine
      oxidase inhibitor selegiline (also known as I-deprenyl) in the treatment of
      Alzheimer's disease. DESIGN: Long-term, double-blind, placebo-controlled trial.
      SETTING: Seven cities (1 or 2 nursing homes in each city) in the Czech and Slovak
      Republics. PATIENTS: A total of 173 nursing-home residents fulfilling the DSM-III
      criteria for mild to moderate Alzheimer's disease. INTERVENTIONS: Selegiline (10
      mg per day) or placebo (both including 50 mg ascorbic acid) administered for 24
      weeks. OUTCOME MEASURES: Clinical Global Impressions scale and Nurses Observation
      Scale for Inpatient Evaluation at baseline and at weeks 6, 12 and 24; Clock
      Drawing Test at baseline and 24 weeks, results of which were evaluated as normal
      or pathologic, and quantitatively on a modified 6-point scale; Sternberg's Memory
      Scanning test at baseline and at weeks 6, 12 and 24; Mini Mental State
      Examination, and electroencephalogram at baseline and 24 weeks; Structured
      Adverse Effects Rating Scale; physical, laboratory, hematological and
      electrocardiographic examinations at baseline and weeks 12 and 24. RESULTS: A
      total of 143 subjects completed enough of the trial to be entered in the
      analysis. Subjects were analyzed by 2 subgroups depending on whether they had a
      normal or pathologic result of the Clock Drawing Test. Analysis of variance
      showed significant improvement with selegiline versus placebo among those with a
      normal result of the Clock Drawing Test on the Mini Mental Status Examination
      (total score and orientation-place subscale) and among those with a pathologic
      result of the Clock Drawing Test of Sternberg's Memory Scanning test (for both
      speed and accuracy), on the Clinical Global Impressions scale as well as in terms
      of the dominant frequency on electroencephalograms. CONCLUSION: Selegiline has a
      long-term beneficial effect in Alzheimer's disease on memory modalities that
      reflect the function of the prefrontal areas of the brain, which are rich in
      dopamine receptors. The delayed appearance of differences between selegiline and
      placebo supports the notion that the mechanism of action is through neuronal
      rescue or neuroprotection. The differential response of patients with normal and
      pathologic results of the Clock Drawing Test may reflect the fact that the
      evaluation methods' sensitivity to change depends on the severity of dementia.

PMID- 10354659
TI  - Is atypical depression a moderate severity depression? A 536-case study.
AB  - OBJECTIVE: To determine if atypical depression is less common among outpatients
      with severe depression than among those with nonsevere depression. DESIGN: Case
      series. SETTING: Private practice. PATIENTS: Five hundred and thirty-six
      consecutive outpatients presenting for treatment of unipolar or bipolar II
      depression. OUTCOME MEASURES: Prevalence of atypical depression among patients
      with severe depression (Global Assessment of Functioning Scale [GAF] score of 50
      or less) and nonsevere depression. RESULTS: There was no significant difference
      in the prevalence of atypical depression between patients with severe and
      nonsevere depression. CONCLUSIONS: Results do not support previous studies that
      atypical depression is usually of moderate severity. A rating scale like the GAF,
      which assesses both symptom severity and impairment of functioning, may give a
      more complete assessment of depression severity than a symptoms rating scale
      (used in previous studies), which does not cover atypical features and does not
      assess functioning.

PMID- 10354660
TI  - Pimozide augmentation in a patient with drug-resistant psychosis previously
      treated with olanzapine.

PMID- 10354661
TI  - Light-therapy-induced hot flushes in a patient with seasonal affective disorder.

PMID- 10354662
TI  - Clozapine and sialorrhea: a new intervention for this bothersome and potentially
      dangerous side effect.

PMID- 10354663
TI  - Is psychopharmacological treatment effective for the symptoms of borderline
      personality disorder (BPD)?

PMID- 10354664
TI  - [Global network to catch up with the new infections is planned. Continuous
      watchfulness concerning the "classic" diseases is needed].

PMID- 10354665
TI  - [Is euthanasia legal now?].

PMID- 10354666
TI  - [What will happen to the Rh prophylaxis?].

PMID- 10354667
TI  - [Why are parents of children with autism and DAMP/ADHD blamed?].

PMID- 10354668
TI  - [Early discovery of "hidden" disabilities is questioned].

PMID- 10354669
TI  - [Life of more people with heart arrest outside hospital can be saved. Improved
      organization and education is required].

PMID- 10354670
TI  - [Midazolam (Dormicum) in terminal anxiety and agitation. The last choice
      alternative in palliative care].
AB  - Although midazolam has been proposed for the treatment of a variety of conditions
      such as anxiety, dyspnoea, hiccups and status epilepticus, terminal agitation is
      the only condition where its use is based on a reasonably large number of
      published clinical studies. A causal approach is generally recommended. Whenever
      possible, the aetiological condition (pain, fever, constipation, etc.) should be
      corrected. Such general measures as ensuring a peaceful, familiar environment,
      and the use of a night light, fluid therapy to counteract dehydration, and
      antipyretics for fever are beneficial. When symptomatic treatment is needed,
      drugs with little anticholinergic effect are to be recommended. The use of
      benzodiazepines as single drug treatment may exacerbate the condition.
      Haloperidol or risperidone (which has fewer side effects) are recommended. If the
      agitation is marked, a common strategy is to add lorazepam. Chlormethiazole is an
      alternative. Subcutaneous midazolam should be reserved for refractory cases.
      Attention should be paid to dosage, reduced doses being given to the elderly,
      patients on opioid medication, and patients with impaired liver or renal
      function. Overdosage may induce deep sedation, and result in carbon dioxide
      retention and subsequently heart failure and pulmonary oedema which may be fatal.

PMID- 10354671
TI  - [New aspects of the pathogenesis of hantavirus infections. A systemic disease
      with general vascular changes].

PMID- 10354672
TI  - [Travels, risks and advice. Certain health recommendations to travellers abroad
      are not necessary; the non-medical risks are often underestimated].

PMID- 10354673
TI  - [HTLV-1 induced adult T-cell leukemia. The first case now documented in Sweden].

PMID- 10354674
TI  - [Training and sports competition during pregnancy and after childbirth. Physical
      training is beneficial for mother and child].
AB  - Physical training and activity during pregnancy is very common today, and many
      women even continue training after the 25th week of gestation. Irrespective of
      its level of intensity, training has not proved to be associated with manifest
      risk. Moderate training seems to be beneficial, by increasing the peripheral
      effect of insulin among those possibly at risk of gestational diabetes. Gravidae
      who train not only tend to be characterised by better health and self-esteem, and
      a lower incidence of depression during pregnancy, but also find delivery less
      strenuous. The offspring of women who train during pregnancy manifest fewer signs
      of stress during delivery, and are usually characterised by better general
      condition (e.g., higher Apgar scores).

PMID- 10354675
TI  - [New documentation routines in psychiatry in Vasterbotten: unified structure for
      better quality of care].
AB  - During recent decades psychiatric health care has become increasingly complex due
      to substantial clinical improvements and to the growing need of integrating
      psychiatric services with other health and welfare services in the community. The
      traditional psychiatric record format is incompatible both with these
      requirements and with the practical advantages and difficulties of modern
      computer technology. In a collaborative effort involving most professional
      categories at three psychiatric units in the county of Vasterbotten in northern
      Sweden, a new structured format for medical records was developed. The basic
      feature is a structured summary of background factors, social situation, drug
      habits, and general health, which is reviewed and updated as necessary. The
      psychiatric condition is described in some detail, including onset and course,
      symptomatology, personality factors, diagnosis, treatment results, suicidality,
      etc. Day to day treatment is outlined in in- and out-patient treatment plans,
      which are evaluated and revised at regular intervals. The new record format,
      which is used by all categories of health care professionals, is intended to
      promote goal-directed treatment and professional collaboration, and is easily
      adapted to computer technology.

PMID- 10354676
TI  - [Health care within the research program of the EU for 1999-2002: age-related
      diseases and public health are prioritized].

PMID- 10354677
TI  - Choices in health care: what are they and what are they worth?
AB  - This overview article provides a conceptual introduction to this special issue on
      health care choices, containing four main papers originally commissioned in 1997
      for a conference titled "The Power of Choice in the Health Care Marketplace and
      Its Consequences," sponsored by the Robert Wood Johnson Foundation under its
      Changes in Health Care Financing and Organization (HCFO) program and conducted by
      the Alpha Center on November 19, 1997. Drawing on information from these four
      papers, the authors discuss what factors affect the different choices we face,
      highlighting the fact that different players in the health care system face
      diverse and often conflicting choices and trade-offs. The authors then examine
      the consumer choice model and its premise that when consumers are presented with
      adequate information about these different choices, they will make selections
      about plans, providers, and health insurance that will move the health care
      system toward a higher quality/lower cost equilibrium.

PMID- 10354678
TI  - Health care consumers: choices and constraints.
AB  - This article summarizes the research and data currently available on different
      dimensions of consumer choice. These dimensions include not only whether to
      participate in a health care plan and which plan to select if given a choice but
      also the decisions that lead to having a choice and the implications of making
      the choice. Data are presented on what choices consumers face, how many are given
      what kinds of choices, what constraints they face, what we know about how they
      make these choices, and what information they are given and what they use. The
      majority of Americans are offered some kind of health insurance plan either
      through their place of employment or as a dependent on someone else's employer
      sponsored health plan. About half of those offered health insurance are offered a
      choice, usually of only two or three plans. The majority elect to participate in
      one of those plans.

PMID- 10354679
TI  - What do consumers want and need to know in making health care choices?
AB  - This article assesses the presumption that consumer choice in health care is
      based on a rational weighing of alternatives--that information consumers about
      plan or provider performance, when coupled with information on cost plus service
      scope and limitation, will lead consumers to select high-quality, low-priced
      plans or providers. The authors review research on what health care consumers
      know, what they want to know, and what others think they should know. They also
      consider how people use information in making decisions and what this implies for
      what consumers really need to know to make effective decisions. The article
      concludes that assuming a rational consumer does not account for choice among
      options in the increasingly complex health care context facing consumers today.
      Based on this review, the article identifies gaps in the knowledge and sketches
      out a prospective research agenda in the area of consumer health care decision
      making.

PMID- 10354680
TI  - Choice and representation in health care.
AB  - Choice is often thought to be critical in health care, especially to foster
      quality improvements and lower costs. However, it is also recognized that in the
      current system there is significant representation of consumers, members, and
      patients by physicians, employers, and health plans. Consent, accountability, and
      protections against conflicts of interest are necessary to ensure legitimate and
      effective representation. This article discusses the roles and responsibilities
      of physicians, employers, and other parties with respect to serving as
      representatives of health care consumers. The author concludes that to make
      representation more legitimate and effective in health care will require
      significant changes, which include (1) changing business to a stakeholder theory,
      (2) involving employees in health care coverage decisions, and (3) involving
      members of health plans in policy decisions.

PMID- 10354681
TI  - Commentary: the new paternalism.

PMID- 10354682
TI  - Management by objection? Public policies to protect choice in health plans.
AB  - Consumer choice is a watchword of the market reforms now sweeping the U.S. health
      care system. Policy makers, however, must grapple with an important ambiguity; is
      the objective to expand choice or protect choosers, and what should be done if
      the two goals conflict? Concerns about health care market malfunctions trigger a
      politics of consumer protection that may emphasize regulatory standards over
      market flexibility. To complicate matters further, hopes that deluging consumers
      with information can ensure that choices are at once ample and prudent are likely
      to be disappointed.

PMID- 10354683
TI  - [Levels of eosinophil cationic protein in serum of infants with wheezy
      bronchitis].
AB  - Wheezy bronchitis is one of the most important problems in pediatric
      pneumonology. Characteristic of bronchial inflammatory response during acute
      episode of wheezy bronchitis is not well known. The aim of our study was to
      examine eosinophil activation marker--eosinophil cationic protein(s-ECP) in
      infants with wheezy bronchitis. The study group consisted of 69 infants. Mean s
      ECP level was 12.51 ug/l. Increased concentration was found in 13 children
      (18.8%). s-ECP level depended on age (the lowest value in the first three month
      of life), severity of symptoms and atopic status (higher value in case of severe
      course of disease and in group with higher IgE level)). There was no difference
      in s-ECP value between group of children presenting recurrent symptoms and
      children without respiratory problems in follow-up observation. However in group
      with frequent episodes of wheezing results of ECP level on first examination were
      higher than in group with only one or two episodes. Our observation suggests that
      in infants suffering from wheezy bronchitis eosinophils are activated and s-ECP
      correlate with severity of symptoms and atopic predisposition.

PMID- 10354684
TI  - [Use of a video questionnaire for assessment of asthma prevalence in school
      children as part of the ISAAC epidemiological study].
AB  - The aim of this publication is the comparison of the data characterizing asthma
      prevalence obtained from standardized questionnaire (SQ) and video-questionnaire
      (VQ) used in epidemiological study ISAAC--Poznan. Number of positive answers to
      questions concerning wheezing ever, current wheezing, night symptoms were lower
      in VQ. The percentage of children reporting exercise induced asthma didn't differ
      in both methods. Severe asthma attacks were reported more frequently in VQ. VQ
      may eliminate the differences in perception and interpretation of asthma
      symptoms, but presentation of severe symptoms leads to underestimation of asthma
      problem.

PMID- 10354685
TI  - [Diagnostic standard for differentiation between bronchial asthma and chronic
      obstructive pulmonary disease].
AB  - The aim of this study was to work out the simplified standard for distinguishing
      COPD from bronchial asthma. An overall sample of 150 individuals was used for
      statistical analysis. Sixty one were diagnosed as having COPD and 89 as suffering
      from asthma. For each patient the modified ATS-DLD-75-C questionnaire was filled
      out, and laboratory tests results were collected. Laboratory findings included:
      basic spirometry and flow-volume curve parameters, diurnal PEF variation, tests
      with bronchodilators (salbutamol, ipratropium bromide and corticosteroids),
      challenges with histamine and exercise, blood gas analysis, skin tests, chest X
      ray, ECG, blood cell count, blood and sputum eosinophilia. Continuous variables
      were transformed into discrete (dichotomous) ones using commonly accepted
      threshold values. Then, sensitivity, specificity and accuracy indexes were
      calculated for each variable and for all possible sets of 2, 3 and 4 variables.
      Finally, 2 sets of 4 signs and symptoms were selected as the most characteristic
      of the diseases of interest. Asthma was diagnosed if 3 out of 4 following
      conditions were present: 1) episodes of shortness of breath and wheezing, 2)
      smoking index (cigarettes number per day x years of smoking) < or = 200, 3) PC20
      < or = 8 mg/ml or delta FEV1 after bronchodilator > or = 15% predicted, 4)
      diurnal PEF variation > or = 20% predicted. COPD was recognised in the same way
      on the basis of: 1) productive cough, 2) smoking index > 200, 3) signs of
      emphysema on the chest X-ray, 4) maximal FEV1 < 80% predicted (after treatment).
      Diagnosis established using this model was correct in 76% and false (what was
      very important) in only 2.6% of cases. In the remaining 21% of patients it was
      uncertain (e.g. both of the diseases confirmed).

PMID- 10354686
TI  - [Specificity and sensitivity of some signs, symptoms and basic laboratory
      findings for differentiation between bronchial asthma and chronic obstructive
      pulmonary disease].
AB  - The aim of this study was to asses the importance of the most frequently observed
      signs and symptoms, as well as commonly used laboratory tests for differentiation
      between bronchial asthma and chronic obturative pulmonary disease (COPD).
      Sensitivity(Se) and specificity (Sp) indices were calculated for 140 analysed
      variables. Sixty one patients diagnosed as having COPD and 89 as suffering from
      asthma were analysed. For each patient the modified ATS-DLD-75-C questionnaire
      was filled out, and laboratory tests results were collected. Laboratory findings
      included: basic spirometry, diurnal PEF variation, bronchodilator tests with
      salbutamol, ipratropium bromide and corticosteroids, challenges with histamine
      and exercise, blood gas analysis, skin tests, chest X ray, ECG, blood cell count,
      blood and sputum eosinophilia. The results obtained have shown that there is no
      single parameter characterised by specificity and sensitivity that enable to
      differentiate between the diseases of interest with sufficient accuracy. Sputum
      expectoration for et least 3 months of the year (Se = 84%, Sp = 69%), smoking
      index (cigarettes number per day x years of smoking) > or = 200 (Se = 89%, Sp =
      74%), have appeared to have the highest sensitivity and specificity for COPD.
      Most typical of asthma are: intermittent episodes of wheezing (Se = 89%, Sp =
      69%), positive bronchodilator tests: with salbutamol (Se--73%, Sp--93%), with
      ipratropium bromide and with corticosteroids (Se--66%, Sp--94%) and diurnal
      variation of PEF > or = 20% predicted (Se--64%, Sp--92%). Challenge test with
      histamine is of limited value for differentiation bronchial asthma from COPD (Se-
      96%, Sp--40%), while blood eosinophilia, resting spirometry or blood gases are
      useless for this purpose.

PMID- 10354687
TI  - [Evaluation of a new model for a Polish continuous positive airway pressure
      device (POL-CPAP 2)].
AB  - The aim of the study was to compare physical and technical features of a new,
      improved, model of polish CPAP device (POL-CPAP2). The new model is smaller and
      lighter than the previous one. The new model produces higher flow and maximal
      working pressures 335 L/min and 19 mbar respectively. Device is also less noisy
      at usually applied pressures. Important novelty is a 20 minutes ramp pressure
      increase facilitating patient to fall asleep.

PMID- 10354688
TI  - [Deaths from tuberculosis among permanent residents of Torun in the years 1990
      1993].
AB  - The aim of this was to verify the cases of death from tuberculosis (TB) in Torun
      province in the years 1990-1993. The data of the official register of death were
      compared, with the hospital records and with the autopsy reports. Tuberculosis
      was accepted as the cause of death in all patients treated for sputum positive
      tuberculosis and also in those in whom pathological proof of tuberculosis
      existed. In addition tuberculosis was accepted as the cause of death in patients
      in whom no bacteriological examination was done, but who were tuberculosis
      contacts and who had the radiological picture of the lung compatible with
      tuberculosis. Those patients were admitted to the hospital in terminal state and
      the permission for autopsy was refused. Tuberculosis was excluded as the cause of
      death in those who were treated for tuberculosis but were considered cured and
      also in those in whom a proof of other severe disease existed. 72 cases of
      tuberculosis death were officially registered in the above-mentioned time. In 23
      of those 72 causes tuberculosis was excluded. On the other hand 26 patients who
      died of tuberculosis were officially registered as death from other causes. After
      verification we have found that 75 patients died of tuberculosis. Thus the real
      number of death from tuberculosis was similar to the registered one although the
      errors in registered deaths from tuberculosis are in two directions.

PMID- 10354689
TI  - [Analysis of tuberculosis mortality in the Torun province in the years 1990
      1993].
AB  - There were 75 deaths from tuberculosis in Torun Vojevodship province in 1990
      1993. In 26 of them the diagnosis was made only after death during the autopsy
      examination and/or by positive culture for tubercle bacilli. In 27 patients
      diagnosis of tuberculosis was made very late, 15 days before death in 12, and 30
      days in other 15 patients. In 19 patients the diagnosis was made 30 days or more
      before death. In majority of them, however, the treatment was interrupted or
      taken irregularly. We conclude that the main cause of death from tuberculosis in
      Torun province in the years 1990-1993 was the late diagnosis. The late diagnosis
      of tuberculosis was established mainly in those who died at home and also in
      those who were admitted to hospital in critical state and died during the first
      two weeks of hospitalization.

PMID- 10354690
TI  - [Influence of food on the bioavailability of isoniazid in health volunteers].
AB  - From the theoretical point of view, food intake exerts a complex influence on the
      bioavailability of drugs. It may interfere with tablet disintegration, drug
      dissolution and drug transit through the gastrointestinal tract, may also affect
      the metabolic transformation of drugs in the gastrointestinal wall and the liver.
      The knowledge about the influence of food is very important in treatment of
      tuberculosis, where the drugs are taken once daily or even less frequently. We
      studied the isoniazid concentrations in blood serum of 20 volunteers (12 slow and
      8 fast acetylators of INH) both sexes, after the drug intake 2 hours before
      breakfast and immediately after breakfast. Concentrations of INH were tested by
      biological method with Mycobacterium aurum REB as a standard strain. The results
      have shown, that Cmax (3.55 +/- 0.29 versus 2.56 +/- 0.49 in fast acetylators and
      4.34 +/- 0.2 versus 3.67 +/- 0.37 in slow acetylators), tmax (0.75 +/- 0.26
      versus 1.31 +/- 0.37 in fast acetylators and 0.87 +/- 0.31 versus 1.79 +/- 0.62
      in slow acetylators and AUC0-t (6.6 +/- 1.34 versus 5.47 +/- 1.5 in fast
      acetylators and 21.82 +/- 2.57 versus 18.61 +/- 2.57 in slow acetylators) are
      significantly decreased after ingestion of INH with breakfast.

PMID- 10354691
TI  - [A case of eosinophilic granuloma localized in the bronchial wall].
AB  - A case of eosinophilic granuloma of the lung in a 24 years old male is presented.
      The initial manifestations were hemoptysis and cough. During hospitalization the
      bronchoscopy was performed, which revealed granuloma in the right bronchus.
      Computer tomography showed tumour in the right bronchus, without pulmonary
      changes characteristic for histiocytosis X. The granuloma was removed by
      bronchoscopy, but control examination performed after three months showed the
      residue. Once again residual tumor was removed by bronchoscopy and oral steroids
      were ordered. Unfortunately the next local residue was observed and the residual
      tumour was finally removed by thoracotomy. Now patient is free of symptoms.

PMID- 10354692
TI  - [The respiratory system of workers employed in the casting and processing of
      copper].
AB  - The aim of the study was to examine the influence of work in exposure to copper
      on the respiratory system. The study was carried out in 267 men aged (x +/- SD)
      40.6 +/- 7.2 yrs, workers of a colour metal mill. 134 of them dealt with casting
      and processing of copper (the mean weighed concentration of copper on work posts
      was below 0.05 mg x m-3) and 133, not employed in a contaminated environment,
      comprised the control group. The subjects were divided into five groups according
      to the degree of energy expenditure at work and, additionally cigarette smoking
      was taken into account. All subjects underwent medical examination and
      spirometry. However the mean values of the ventilatory parameters in the compared
      groups did not significantly differ (p > 0.05), the multivarious regression
      analysis has shown a decreasing trend of FEV1 and FVC with relation to the
      exposition to copper and tobacco smoking. The frequency of chronic bronchitis as
      well as of radiological changes was not increased. The authors conclude: 1. At
      copper concentration not exceeding the MAC, and an advantageous microclimate,
      this exposition only slightly diminishes the pulmonary ventilation and does not
      cause other comprehensible pulmonary pathological sequelae, especially chronic
      bronchitis. 2. Tobacco smoking is a favourable factor for the occurrence of
      chronic bronchitis.

PMID- 10354693
TI  - [The effect of salmeterol on specific and non-specific bronchial response in
      allergic asthma patients].
AB  - The effect of a single dose of salmeterol, long-term, regular treatment with
      salmeterol and a termination of the therapy on specific and non-specific
      bronchial reactivity were evaluated. The effect of the therapy on serum ECP level
      was studied too. The studies were carried out in a group of 16 mild asthmatics
      sensitive to mite allergens. Both types of bronchial challenges were performed
      according to Ryan's method. Blood samples to evaluate the ECP level were
      collected before treatment and on the day before the last day of the study. The
      single dose of 50 micrograms of salmeterol taken 3 hours before bronchial
      challenge significantly decreased the bronchial response to histamine (the
      average PC20FEV1 value increased about a four fold after salmeterol) and to the
      Dpt allergen (PD20FEV1 increased 3.5 fold). No effect of salmeterol on LAR was
      observed. Bronchial reactivity to histamine was significantly lower in the period
      of the therapy and did not differ from the baseline 12 hours after stopping the
      treatment. PD20FEV1 Dpt during the therapy was about 3 fold higher than the
      baseline but 36 hours after stopping the treatment did not differ from the
      baseline. Although the patients had inhaled a 3-fold higher dose of allergen to
      induce EAR, the frequency of LAR did not change. No anti-inflammatory effect of
      salmeterol was observed.

PMID- 10354694
TI  - [Clinical evaluation of 12 week salmeterol therapy in allergic asthma patients].
AB  - The purpose of the study was to evaluate the efficacy of salmeterol in asthma
      therapy. The study was performed on a group of 16 allergic asthma patients
      sensitive to house dust mite allergens. After a run-in period the patients were
      treated with salmeterol, 2 x 50 micrograms, for a period of 12 weeks. They noted
      an intensity of asthma symptoms, morning and evening PEF, beta 2-agonist
      consumption and adverse in their diary cards. On the visit to the clinic
      spirometry was performed. During the treatment a significant reduction in the
      symptom score, PEF variation, beta-agonist consumption and an increase in the
      value of morning and evening PEF were noted. The above results indicate the great
      efficacy of salmeterol in asthma therapy.

PMID- 10354695
TI  - [Assessment of answer repeatability in a questionnaire evaluation of respiratory
      tract symptoms in children].
AB  - Repeatability of parental answers to questions concerning respiratory symptoms
      and environmental exposure was examined in 250 children. Repeatability of
      answers, given two times with a 6 week interval, in 250 questionnaires was
      assessed with two methods: by accounting the percentage of the same answers and
      with the use of the Kappa test. It was demonstrated that answers concerning
      respiratory tract symptoms were characterized by the agreement rate of 77-99% and
      the Kappa values ranging from 0.44 to 0.76. The answers to questions concerning
      environmental factors were more satisfactory, with the agreement rate: 89-95% and
      the Kappa values: 0.68-0.93. The above results correspond to the literature data
      on repeatability of results of the standard questionnaire investigation; this
      testifies to credibility of the questionnaire investigation of the prevalence and
      risk factors in respiratory disorders in children.

PMID- 10354696
TI  - [Comparison of 14-day rehabilitation and oxygen therapy on exercise tolerance and
      percutaneous oxygen saturation in patients with advanced COPD].
AB  - Whether rehabilitation may be as beneficial as oxygen therapy (T) in the
      management of chronic obstructive pulmonary disease (COPD) is still not known.
      The aim of the was to compare the effects of T or R on exercise tolerance (ET)
      and percutaneous oxygen saturation (SO2) at rest and at the peak exercise in 21
      patients with COPD (FEV1, 1.29 L +/- 0.5) Eleven patients with COPD were treated
      with oxygen (17 hour per day) for 14 days and 10 patients were rehabilitated.
      Both groups did not differ in age 63.7 vs 69.3 years, in the baseline values of
      FEV1, PaCO2 and PaO2 and resting SO2%. Before the study patients R and T had
      similar resting SO2 values and ET (4.5 +/- 1 vs 3.4 +/- 2 METs, p = NS), but
      those in the R group revealed higher drop in SO2 at peak exercise test (10.9 vs
      3.4%, p = 0.007). RESULTS: We found no significance impact of 14- day R and 14-
      day T on results of exercise test and exercise pulse oximetry in studied
      patients. However, rehabilitated patients, as opposite to patients on oxygen
      therapy had tendency to increase number of Mets and to diminish maximal drop in
      pulse oximetry during exercise. As a result, when we compared group R i T after
      study patients of R group differed from T patients with number of METs achieved
      (4.6 vs 3.0, p = 0.02), whereas maximal drop in SO2 at the peak exercise test in
      R and T patients equalized (7.9 +/- 7 vs 3.2 +/- 3%, p = NS). We conclude that
      the results of our short term study may suggest better effects of rehabilitation
      than oxygen therapy on exercise tolerance and oxygen saturation during exercise
      in COPD patients and justify further studies.

PMID- 10354697
TI  - [Diagnosis of chronic pulmonary embolism in patients with advanced chronic
      obstructive pulmonary disease].
AB  - The coexistence of chronic obstructive pulmonary disease (COPD) and chronic
      pulmonary embolism (PE) worsens prognosis and requires complex therapeutic
      procedures. However, the diagnosis COPD + PE is difficult because of similar
      clinical symptomatology. Pulmonary angiography was performed in 20 patients aged
      60.9 (37-75) years with COPD and with clinical suspicion of chronic pulmonary
      embolism (PE). Of 13 patients with PE 8 had proximal PE and in 5 patients
      peripheral PE was found. Both groups of patients did not differ with regard to
      their age 60.2 +/- 7 vs 59 +/- 10 years (NS), FEV1 0.9 +/- 0.3 vs 1.1 +/- 0.4 l
      (NS) as well as platelet cells count, fibrinogen, hematocrit and hemoglobin.
      Patients with COPD + PE compared to patients with COPD had higher pH 7.38 +/-
      0.05 vs 7.32 +/- 0.03 (p = 0.01), and tendency to lower PaCO2 44.3 +/- 12 vs 52.0
      +/- 7 mmHg(NS), and higher mean pulmonary artery pressure 48 +/- 17 vs 36.3 +/- 9
      mmHg(NS). Patients with COPD+ proximal PE compared to COPD patients had higher pH
      7.4 +/- 0.05 vs 7.3 +/- 0.03 (p = 0.004) and lower paCO2 39.6 +/- 10 vs 52 +/- 7
      mmHg (p = 0.03).

PMID- 10354698
TI  - [Use of pleuro-peritoneal shunt in the treatment of chronic chylothorax].
AB  - Persistent chylothorax is usually treated by frequent aspirations or intercostal
      tube drainage with interpleural installation of chemical or mechanical irritants.
      In 1986 Denver pleuroperitoneal shunt has been introduced. This is a single-unit
      silicone rubber conduit consisting of unidirectional valved pumping chamber
      located between pleural and peritoneal catheters. Manual compression of the shunt
      is required to achieve active pumping. The described unit is implanted
      subcutaneously in the lover thoracic and upper abdominal region in the anterior
      axillary line. We present a 38 year old patient with persistent chylothorax
      treated successfully by implantation of the described device.

PMID- 10354699
TI  - [Chronic obstructive pulmonary disease and lung cancer].

PMID- 10354700
TI  - [Etiology and treatment of bronchial fistula after pneumonectomy].

PMID- 10354701
TI  - [From the history of thoracic surgery--effective method of bronchus closure
      following pneumonectomy].

PMID- 10354702
TI  - The catalytic subunit of cAMP-dependent protein kinase: prototype for an extended
      network of communication.
AB  - The protein kinase catalytic core in essence comprises an extended network of
      interactions that link distal parts of the molecule to the active site where they
      facilitate phosphoryl transfer from ATP to protein substrate. This review defines
      key sequence and structural elements, describes what is currently known about the
      molecular interactions, and how they are involved in catalysis.

PMID- 10354704
TI  - Recognition and regulation of primary-sequence motifs by signaling modular
      domains.

PMID- 10354703
TI  - Structural analysis of receptor tyrosine kinases.
AB  - Receptor tyrosine kinases (RTKs) are single-pass transmembrane receptors that
      possess intrinsic cytoplasmic enzymatic activity, catalyzing the transfer of the
      gamma-phosphate of ATP to tyrosine residues in protein substrates. RTKs are
      essential components of signal transduction pathways that affect cell
      proliferation, differentiation, migration and metabolism. Included in this large
      protein family are the insulin receptor and the receptors for growth factors such
      as epidermal growth factor, fibroblast growth factor and vascular endothelial
      growth factor. Receptor activation occurs through ligand binding, which
      facilitates receptor dimerization and autophosphorylation of specific tyrosine
      residues in the cytoplasmic portion. The phosphotyrosine residues either enhance
      receptor catalytic activity or provide docking sites for downstream signaling
      proteins. Over the past several years, structural studies employing X-ray
      crystallography have advanced our understanding of the molecular mechanisms by
      which RTKs recognize their ligands and are activated by dimerization and tyrosine
      autophosphorylation. This review will highlight the key results that have emerged
      from these structural studies.

PMID- 10354705
TI  - Regulation of antigen receptor function by protein tyrosine kinases.

PMID- 10354706
TI  - Adaptor proteins and T-cell antigen receptor signaling.

PMID- 10354707
TI  - The STAT family of proteins in cytokine signaling.
AB  - It has now been well established that the STAT family of proteins play important
      roles in cytokine-mediated specific gene activation. Although significant
      progress has been made toward the understanding of the structure and function of
      STATs as well as the regulation of STAT signaling pathways, many important
      questions remain to be answered. STAT PTPase(s) and STAT serine kinase(s) which
      play important roles in regulating STAT activity have not been identified. In
      addition, the molecular mechanisms of the negative regulation of STAT signaling
      by recently discovered protein inhibitors and the crosstalk between STAT and
      other signal transduction pathways have not been understood. The JAK/STAT field
      remains to be challenging and exciting.

PMID- 10354708
TI  - The role of SHIP in growth factor induced signalling.
AB  - The recently cloned, hemopoietic-specific, src homology 2 (SH2)-containing
      inositol phosphatase, SHIP, is rapidly gaining prominence as a potential
      regulator of all phosphatidylinositol (PI)-3 kinase mediated events since it has
      been shown both in vitro and in vivo to hydrolyze the 5' phosphate from
      phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P3). Thus SHIP, and its more
      widely expressed counterpart, SHIP2, could play a central role in determining PI
      3,4,5-P3 and PI-3,4-P2 levels in many cell types. To explore the in vivo function
      of SHIP further we recently generated a SHIP knock out mouse and in this review
      we discuss experiments carried out with bone marrow derived mast cells (BMMCs)
      from these animals.

PMID- 10354709
TI  - Signaling through focal adhesion kinase.
AB  - Integrin receptor binding to extracellular matrix proteins generates
      intracellular signals via enhanced tyrosine phosphorylation events that are
      important for cell growth, survival, and migration. This review will focus on the
      functions of the focal adhesion kinase (FAK) protein-tyrosine kinase (PTK) and
      its role in linking integrin receptors to intracellular signaling pathways. FAK
      associates with several different signaling proteins such as Src-family PTKs,
      p130Cas, Shc, Grb2, PI 3-kinase, and paxillin. This enables FAK to function
      within a network of integrin-stimulated signaling pathways leading to the
      activation of targets such as the ERK and JNK/mitogen-activated protein kinase
      pathways. Focus will be placed on the structural domains and sites of FAK
      tyrosine phosphorylation important for FAK-mediated signaling events and how
      these sites are conserved in the FAK-related PTK, Pyk2. We will review what is
      known about FAK activation by integrin receptor-mediated events and also non
      integrin stimuli. In addition, we discuss the emergence of a consensus FAK
      substrate phosphorylation sequence. Emphasis will also be placed on the role of
      FAK in generating cell survival signals and the cleavage of FAK during caspase
      mediated apoptosis. An in-depth discussion will be presented of integrin
      stimulated signaling events occurring in the FAK knockout fibroblasts (FAK-) and
      how these cells exhibit deficits in cell migration. FAK re-expression in the FAK-
      cells confirms the role of this PTK in the regulation of cell morphology and in
      promoting cell migration events. In addition, these results reinforce the
      potential role for FAK in promoting an invasive phenotype in human tumors.

PMID- 10354710
TI  - MAP kinase pathways.
AB  - MAP kinases help to mediate diverse processes ranging from transcription of
      protooncogenes to programmed cell death. More than a dozen mammalian MAP kinase
      family members have been discovered and include, among others, the well studied
      ERKs and several stress-sensitive enzymes. MAP kinases lie within protein kinase
      cascades. Each cascade consists of no fewer than three enzymes that are activated
      in series. Cascades convey information to effectors, coordinates incoming
      information from other signaling pathways, amplify signals, and allow for a
      variety of response patterns. Subcellular localization of enzymes in the cascades
      is an important aspect of their mechanisms of action and contributes to cell-type
      and ligand-specific responses. Recent findings on these properties of MAP kinase
      cascades are the major focus of this review.

PMID- 10354711
TI  - Applications of mass spectrometry to signal transduction.
AB  - Advances in mass spectrometry instrumentation, protocols for sample handling, and
      computational methods provide powerful new approaches to solving problems in
      analytical biochemistry. This review summarizes recent work illustrating ways in
      which mass spectrometry has been used to address questions relevant to signal
      transduction. Rather than encompass all of the instruments or methodologies that
      might be brought to bear on these problems, we present an overview of commonly
      used techniques, promising new methodologies, and some applications.

PMID- 10354712
TI  - The protein kinase resource and other bioinformation resources.
AB  - The Internet, especially the World Wide Web has transformed how today's
      researchers communicate, share information, and analyze their data.
      Unfortunately, the vast number of online databases, information resources and
      analytical tools, some of them masked by unfamiliar titles and Internet
      addresses, has hindered their universal and effective use by the research
      community. To overcome these hurdles, subject- and function-specific compendiums
      are now available which organize information and online tolls in a manner
      familiar to the biological researcher. The Protein Kinase Resource and the CMS
      Molecular Biology Resource are two excellent examples of web compendia.

PMID- 10354713
TI  - [Postoperative wound infections. IV. Flora and clinical course of postoperative
      wound infection].
AB  - Each wound infection may be coursed in few clinical manifestations and may
      concern either skin with subcutaneous tissue (superficial infection) or deeper
      layers-fascias, muscles (deep infection). The aim of this study was to evaluate
      the form of infection and its clinical course, and moreover, to find the specific
      flora of infected wounds. The material was 1527 surgically treated patients in
      the 3rd Surgical Department of the Collegium Medicum of the Jagiellonian
      University during one year. 66 patients with wounds of the head and 7 patients
      who died within first three days after surgery without wound infection signs were
      excluded from the study population. The healing of each wound was observed during
      the patient's hospitalisation and 30 days after discharge from hospital, and in
      orthopedic patients 6 months after discharge. The total number of 132 infected
      wounds was identified. The population of 1352 wounds healed without any
      complications was a control group. All the data were recorded in a Wound
      Infection Register Card and were collected in the computer database. The data
      were statistically analysed. Relationships between single factors and
      postoperative wound infection were evaluated using chi-square statistics and in
      the small number Fisher's exact probability test. Analysis of variance was used
      for continuous variables. Odds ratios and corresponding 95% confidence intervals
      were computed for all variables. Postoperative wound infection was found in 132
      (8.9%) cases, including 76 (57.6%) in males and 56 (42.4%) in females. The
      average age was 50.9 years. The period of hospitalisation ranged from 3 to 119
      days, with the mean of 31.9 days in comparison to 16.3 days in the control group.

PMID- 10354714
TI  - [Interleukin-8 (IL-8) and lipid disorders in chronic renal graft rejection].

PMID- 10354715
TI  - [Crucial evaluation of medical management in patients with cranial and brain
      injuries from the moment of the accident to the end of the diagnostics].
AB  - The aim of the research was to verify the procedures of first-aid and treatment
      in 100 patients with cranial and brain injuries, admitted to the Intensive Care
      Unit. Material was estimated using Ambulance and Surgical Ambulatory data and
      Intensive Care Unit case records. Medical procedure at the place of accident and
      during transport, duration of the transport to the hospital, duration of the
      diagnostics and morbidity in studied groups were estimated. Considering the
      analysed material, it seems that following procedures have significant influence
      on the final outcome: 1. full resuscitation of the patient at the place of
      accident; 2. correct protection of the injured person during transport and
      duration of the transport; 3. time necessary for full and correct diagnostics.

PMID- 10354716
TI  - [Extracellular components of broncho-alveolar lavage fluid (BALF) as markers of
      interstitial pulmonary disease activity. II. Phospholipid concentration].
AB  - Phospholipids found in the alveolar space come from the surfactant which is
      produced by type II pneumocytes and whose surplus is eliminated from lungs by
      macrophages. In 188 patients with interstitial pulmonary diseases bronchoalveolar
      lavage was performed. Phospholipids from the supernatant of BALF were extracted
      using of Folch method and their concentration was measured colorimetrically
      assaying inorganic phosphorus after prior mineralization by Fiske-Subbarov
      method. The persons were divided into 7 groups: active sarcoidosis, inactive
      sarcoidosis, avian fancier's lung in the period of contact with the antigen, and
      after stopping the contact with the antigen, advanced idiopathic pulmonary
      fibrosis, moderate idiopathic pulmonary fibrosis, and a control group of healthy
      persons. Apart from that, the patients were divided into untreated and treated
      with corticosteroids. In every group of patients we have noticed increased
      concentration and total amount of phospholipids in BALF. Particularly distinct
      increase of the total number of phospholipids in BALF in pulmonary fibrosis was
      observed. However, this parameter does not permit to estimate disease activity in
      interstitial lung disease. Corticotherapy increases phospholipids concentration
      in BALF in patients with idiopathic pulmonary fibrosis and avian fancier's lung
      but decreases in sarcoidosis patients.

PMID- 10354717
TI  - [Glutamine--its metabolic role and possibilities for clinical use].
AB  - Glutamine has been the point of interest of many nutritional studies concerning
      parenteral and enteral nutrition. Advantages from glutamine support have been
      observed previously in animal models. It was shown that glutamine is the energy
      source for rapidly dividing cells e.g. immune cells, gut mucosa. Recent molecular
      and protein chemistry studies have begun to define metabolic mechanism of
      glutamine action, and clinical trials suggest its safe and positive influence on
      catabolic patients. Parenteral and enteral nutrition enriched with glutamine
      improves gut integrity and function, decreases infection rate and improves
      function of immune cells. However, the indications for glutamine enriched
      nutrition and appropriate protocol of administration need determination. Taken
      together the data suggest that this amino-acid is an important dietary nutrient
      and is probably conditionally essential in certain catabolic conditions.

PMID- 10354718
TI  - [Mammography screening for breast cancer].
AB  - Principles of the population-based mammography screening for breast cancer have
      been presented. Methodology, results and limitations of this method have been
      discussed.

PMID- 10354719
TI  - [Present day opinion about beta block treatment of congestive heart failure].
AB  - The congestive heart failure is an important clinical problem because of its
      frequency of appearance and poor prognosis. A new groups of drugs are to be found
      to change the negative natural course of this disease. Beta adrenolytic agents
      are on focus now because of promising results of small and great clinical trials
      and wider knowledge about the pathophysiology of congestive heart failure. This
      paper presents the present day knowledge about the role of the beta blockers
      therapy in the congestive heart failure treatment.

PMID- 10354720
TI  - [Thrombus of the right ventricle simulating a cardiac tumor--case report].
AB  - A nine day infant with Down syndrome and congenital heart disease is presented in
      whom the course of neonatal sepsis was complicated by the presence of difficult
      to diagnose pathological masses in the right ventricle. The etiology of
      pathological masses was difficult to establish in survival investigations.
      Histopathological examinations revealed the presence of thrombus in the right
      heart and foci of granulation on a muscle of right ventricle outflow, probably
      after a septic embolus.

PMID- 10354721
TI  - [Cognitive impairment and cardiovascular disease risk factors. Project CASCADE
      Krakow. I. Project to test exposure to risk factors for cardiovascular disease in
      the studied sample].
AB  - Dementia is found in a small percent of general population but remains a
      significant problem in the elderly population. Little is known whether prevention
      of dementia in the elderly is possible. Some evidence exists that both vascular
      dementia and Alzheimer's type dementia are related to cardiovascular disease risk
      factors. The main goal of the CASCADE Krakow Project is to study the relation
      between the exposure to cardiovascular disease risk factors in the middle age and
      cognitive impairment and cerebral white matter lesions in old age. Project
      CASCADE Krakow is an independent part of the international project CASCADE, which
      is carried out in 11 research centres from 9 countries. Polish part of the study
      includes a longitudinal observation of the sample screened earlier in POL-MONICA
      Krakow Project, which was selected from population of residents of rural province
      (Tarnobrzeg Voivodship). Studied sample are 1318 persons, for whom cardiovascular
      disease risk factors were measured in 1983-84 and who completed at least 64 years
      in 1997. Two-stage examination was designed. In the first stage collection of the
      following data was designed: socio-economic factors, history of cardiovascular
      disease, perceived health, blood pressure and cognitive function assessment using
      Mini-Mental State Examination (MMSE) procedure. In the second stage (sub-sample
      of 300 persons included) the following procedures were designed: detailed neuro
      psychological testing, neurolo-gical examination, MRI, determination of total-
      and HDL-cholesterol and determination of apoE isoforms. There were 625 (47%) men
      and 693 (53%) women selected for the first stage. Out of them 128 (43%) men and
      172 (57%) women were selected for the second stage. There were no important
      differences in age, education, health status and exposure to cardiovascular
      disease risk factors between the studied groups in the baseline assessment.
      However, there were important differences between men and women. Compared to men,
      women had lower education (higher than elementary education in 17% and 9%
      respectively), more frequent obesity (respectively 12% and 36%), hypertension
      (respectively 57% and 71%) and hyperlipoproteinemia (respectively 17% and 30%)
      but lower smoking rate (respectively 53% and 4%). Integration of
      neuropsychological testing and neuroimaging with the epidemiological approach to
      risk factors could contribute to better understanding of the mechanisms on which
      the disease affects the brain morphology and functions. The results of CASCADE
      and CASCADE Krakow projects will contribute also to the development of the
      strategies of medical care and management of the cognitive impairment in the
      elderly.

PMID- 10354722
TI  - [Cognitive impairment and cardiovascular disease risk factors. Project CASCADE
      Krakow. II. Agreement of Mini-Mental State Examination (MMSE) obtained by nurses
      and by psychologists from the same persons at age 67-78 years of age].
AB  - Mini-Mental State Examination (MMSE) can be used for screening procedures by
      personnel with no university training in psychology. However, little is known on
      the reliability of the results of MMSE obtained by medical personnel with little
      experience in cognitive function assessment. The goal of the paper was to assess
      the agreement between the results of MMSE obtained by trained community nurses
      and by psychologists, and to study whether the agreement depends on age, sex and
      education of examined persons. Studied group were 92 women and 90 men at age 65
      78 years. Most of them (81.3%) had only elementary education. There was no
      significant difference between the distribution of the results obtained by nurses
      and obtained by psychologists. Individual difference < or = 2 points was found in
      63.1% participants and difference < or = 3 points in 78.4% participants. There
      was a significant correlation between the results obtained by nurses and by
      psychologists (r = 0.64, p < 0.001). The correlation was also significant within
      the age, sex and education strata. Variation of the results obtained by nurses
      was explained in 42% by variation of the results obtained by psychologists. The
      best agreement in classification in cognitive function was found for the MMSE cut
      off point < or = 19 (kappa = 0.75 in women and kappa = 0.58 in men). The worst
      agreement was found for the cut-off point < or = 25. Also weak agreement was
      found for the cut-off point < or = 23. There was a significant agreement between
      the results of MMSE obtained by nurses and results obtained by psychologists on
      the population level. However at the level of individuals the agreement in
      classification of cognitive function depended of cut-off point used. The
      agreement was only fair if cut-off point < or = 23 and < or = 25 were used.

PMID- 10354724
TI  - [Cognitive impairment and cardiovascular disease risk factors. Project CASCADE
      Krakow. IV. Prevalence of cognitive impairment in relation to age, sex, education
      and history of myocardial infarction in men and women at age 65-78, residents of
      a rural province in Poland (Tarnobrzed)].
AB  - Decrease in cardiovascular disease mortality below age of 65 years, which has
      been observed in Poland since 1992, is followed by increasing number of elderly
      people. One of the typical problems of ageing is deterioration of cognitive
      function. Little is known on prevalence of cognitive impairment and its
      correlates in Polish population. The goal of this paper was to assess the
      prevalence of cognitive impairment in the elderly Polish rural population and to
      study the differences in the distribution of cognitive function and frequency of
      cognitive impairment by age, sex, education and by history of previous MI.
      Studied group were 943 men and women at age 65-78 from the cohort representing
      the population of Polish rural province (Tarnobrzeg Voivodship). Participants
      were visited at their homes. Interview and cognitive function assessment by Mini
      Mental State Examination (MMSE) procedure were carried out according to the
      standard questionnaire. Participation rate was 94%--882 persons were examined.
      There were 58% women and 17% persons at age 75 or older in the examined group.
      87% had only elementary (7 years of schooling) education or less. History of
      previous myocardial infarction was found in 15% of participants. In almost half
      of participants the result of MMSE < or = 25 points suggested cognitive
      impairment. More severe impairment (MMSE < or = 21 points) was found in 15% of
      examined persons. In participants at age 75 years or older and in those with low
      education, per cent of persons with cognitive impairement function was higher.
      Sex and history of previous myocardial infarction were not related to frequency
      of cognitive impairment. Results indicate the high prevalence of the cognitive
      impairment in elderly men and women in Polish rural population with low average
      level of education.

PMID- 10354723
TI  - [Cognitive impairment and cardiovascular disease risk factors. Project CASCADE
      Krakow. III. Assessment of cognitive function in elderly women and men (65-78
      years old)].
AB  - There are commonly used simple tests for cognitive function that allow for rather
      superficial assessment in population based study. The goal of the paper was to
      present the results of cognitive function assessment in elderly men and women
      recruited from Polish rural population obtained using the battery of tests
      designed for the CASCADE Project and to assess the relations between the results
      of tests included in the battery. Studied group were 182 persons at the age of 65
      78 years. The battery of tests included: MMSE, Stroop Test, Test Purdue Pegboard
      (TPP), letter-digit substitution test, word recall test (3 word lists including
      one with distraction), word fluency test and prospective memory test. The battery
      allowed for the assessment of short, semantic and prospective memory, attention,
      speed of perception and processing, word fluency and motoric function. The
      results of all tests were strongly correlated and indicated for a decreased
      cognitive function in men and women at the age of 65-78 years with low level of
      education. Decreased level of cognitive function could be related both to
      physiological ageing of the brain and to the presence of pathological process.

PMID- 10354725
TI  - [Cognitive impairment and cardiovascular disease risk factors. Project CASCADE
      Krakow. V. Disorders of higher cerebral functions in elderly people (65-78 years
      old)].
AB  - Higher cortical dysfunctions, like dysphasia, dysgnosia and dyspraxia, relatively
      frequent in the elderly, are related to progressive neurodegenerative or vascular
      disorders with dementia. The aim of the study was to assess the prevalence and
      the intensity of higher cerebral dysfunctions in the population over 65 years and
      to investigate the association between these disorders and the presence of other
      neurological abnormalities, i.e. extrapyramidal signs, primitive reflexes as well
      as cognitive impairment assessed by Mini-Mental State Examination (MMSE). There
      were 92 women and 90 men, aged from 65-78 years included in the study. All
      patients were interviewed for the presence of vascular risk factors. The battery
      of 21 detailed test of higher cerebral functions testing speech, calculation,
      reading, writing, praxia and gnosia were performed in each person. Extra
      pyramidal signs and primitive reflexes were also examined. Among the disorders of
      higher cortical functions, slight dyspraxia was the most frequent (33.7%). Finger
      dysgnosia, dyscalculia and dysgraphia were found less frequently. 25.4% of
      studied group abnormally performed at least two tests assessing higher cortical
      functions and when compared with normal persons, they presented significantly
      more frequent the extrapyramidal signs (63.9% vs. 46.9%, respectively) and had
      significantly frequent impaired cognitive functions (p < 0.05). Patients with
      higher cortical dysfunction, when compared with other persons, had more frequent
      primitive reflexes (p < 0.05). The results of the study showed that slight
      disorders of higher cortical functions were found in about 25% of studied
      population; they were more frequent in people with cognitive impairment,
      primitive reflexes and extrapyramidal signs.

PMID- 10354726
TI  - [Cognitive impairment and cardiovascular disease risk factors. Project CASCADE
      Krakow. VI. Magnetic resonance imaging of the aging brain in elderly persons (65
      78 years old)].
AB  - Magnetic resonance imaging (MRI) is the most sensitive non-invasive method for
      the detection of brain lesions. The aim of the study was to examine the
      prevalence of brain abnormalities (white matter lesions, atrophy, and infarction)
      on MRI in an elderly population. Sample of 174 men and women, aged from 65 to 78
      years, was examined. MRI scans were made using a mobile MRI 1.0 Tesla machine
      (Siemens). Imaging was performed with standard spin-echo sequences (slice
      thickness 5-6 mm thick and 20% gap): proton density, T1 and T2 images. All MRI
      scans were read using standardized methodology of assessment of deep white matter
      lesions, periventricular lesions, cortical atrophy and infarction. Medium
      subcortical white matter lesions (4-10 mm) were present in 55% participants.
      Large subcortical white matter lesions (> or = 10 mm) were observed in 27%
      people, 24% had periventricular white matter lesions (score > or = 3), 83% had
      cortical atrophy (score > or = 4) and 18% had at least 1 infarct. Frequency of
      cortical atrophy increased gradually by age group (p < 0.01). The cortical
      atrophy, deep and periventricular white matter lesions were more frequent only in
      the oldest group (75-78 years).

PMID- 10354727
TI  - [Cognitive impairment and cardiovascular disease risk factors. Project CASCADE
      Kradow. VII: Prevalence of apoprotein E isoforms in women and men at age 65-78
      years of age].
AB  - There is a growing evidence on the relations between apoprotein E (apo E), in
      particular apoE4, cardiovascular disease and Alzheimer's disease. However, little
      is known on the prevalence of apoE in Polish population. The goal of this paper
      was to assess the frequency of apoE phenotypes and isoforms in the sample of
      elderly people. Studied group were 90 men and 92 women, residents of Polish rural
      province (Tarnobrzeg Voivodship) at age 65-78 years. Identification of apoE
      isoforms was done using the immunoblotting method. The most frequent phenotype
      was apoE3/3, which was found in 70% of men and 73% of women. Phenotype apoE3/2
      was identified in 20% men and 15% women. Both in men and in women phenotypes
      apoE4/2 and apoE4/3 were more rare-in total 10% and 12% participants,
      respectively. There was nobody with phenotype apoE4/4. In women there was also
      nobody with phenotype apoE4/2, but in men phenotype apoE4/2 was found in 4% of
      participants. No person was found with phenotype apoE2/2. Frequency of
      homozygotes apoE4/4 was low in studied population and could little contribute to
      the epidemy of cardiovascular disease and dementia in the elderly. However, the
      10% frequency of heterozygotes with isoform apoE4 could have more impact.

PMID- 10354728
TI  - [Selected forms of health in the Polish Kingdom and Galicia during the First
      World War].
AB  - The forms of health care instituted during the First World War by medical
      organizations set up as a form of self-defense by the society have been
      presented. The health care was organised--in Galicia by Cracow Bishop Committee
      for assistance to war casualties (CBC) in Cracow and by Central Civic Committees
      in Warsaw (CCC). Sanitary sections organised by both Committee were engaged in
      health protection, specially in medical treatment of contagious diseases, its
      fighting down, prophylaxis and vaccination. The works on territory of Galicia
      were mainly located in presbyteries (network) and on territory of Polish Kingdom-
      in sanitary sections of local committees. The sanitary and medical activities of
      CBC and CCC were only part of their overall preoccupation. Flying sanitary
      medical squads, mobile hospitals, vaccination points (kolumny) were among the
      basic forms of the work in the region. Committees provided sanitary and medical
      assistance to all citizens regardless of their nationality, paid special
      attention to protection of the children, and very often carried out prophylactic
      activities under the protection of the police. Committees were partly financed by
      Russia and Austria which gave their consent to formation of Committees, in that
      way solving the problems of underdeveloped at those times medical care with the
      hands of citizens themselves. Simultaneously these provided prophylcatic measures
      for the Austrain and the Russian armies against contagious diseases transmitted
      within the society. Despite some elements of social medical care put into
      practice by CCK at that time, one must admit that the system was bearing traces
      of alms and charity (CBC).

PMID- 10354729
TI  - [And is research on the prognosis of Hodgkin's still justified?].

PMID- 10354730
TI  - [The outlook in the treatment of obesity in adults].

PMID- 10354731
TI  - [Juvenile obesity: the pathogenetic aspects and therapeutic outlook].

PMID- 10354733
TI  - [The therapy of metastatic renal carcinoma].
AB  - Nowadays, renal cell carcinomas (RCC) are mostly detected incidentally, following
      abdominal ultrasound performed for non-urological complaints. These asymptomatic
      tumors are often small and with low stage. However, about 25% of the RCC are
      still detected in advanced stage, with synchronous metastasis. Since few years
      ago, there was no effective treatment for the advanced RCC that shows resistance
      to the traditional systemic chemotherapy and radiotherapy. Today, two different
      treatments, either alone or in association, have provided interesting results in
      these setting, mostly in term of stabilization of the disease. Continuous
      systemic chronobiological chemotherapy with Floxuridine and immunotherapy with
      recombinant Interleukin-2 administered intravenously or subcutaneously, represent
      the treatment of choice of advanced RCC. Both treatment are well tolerated by the
      patients (except the intravenous Interleukin-2) and do not preclude radical
      nephrectomy. This paper reports a review of recent literature and the results of
      the authors' experience.

PMID- 10354732
TI  - [The diagnosis of new cases of HIV infection: a reversal of the trend?].
AB  - In order to assess the trend of new cases of HIV infection, spontaneous requests
      of HIV counseling and testing made at our outpatient Center since 1993 were
      retrospectively evaluated. During the considered 6-year period, 7,492 subjects
      had voluntary HIV testing, and 225 proved HIV-positive (3.0%). While the overall
      number of spontaneous requests of HIV serology did not show remarkable variations
      over time, a tendency towards a significant increase of newly diagnosed HIV
      disease was observed during the past two years (1997 and 1998). In particular,
      among the 57 subjects with HIV infection disclosed in 1998, a predominance of
      young adults and a relatively elevated frequency of females compared with males
      was demonstrated, while heterosexual (38 cases) and homo-bisexual contacts (18
      cases) accounted for the great majority of newly identified retroviral
      infections, and 66.1% out of the 56 patients who acquired HIV infection by sexual
      route were stable partners of individuals with known HIV disease. Although
      epidemiological estimates foresaw a progressive reduction of cases of HIV
      infection since 1990, a surprising increase of newly diagnosed HIV disease among
      patients who spontaneously asked for HIV testing was observed in our experience.
      The apparent temporal coincidence of this phenomenon with the remarkable advances
      obtained in both diagnostic and therapeutic strategies of HIV disease just since
      1996, could not be a fortuitous event. The non-decline of newly diagnosed cases
      of HIV infection should re-orient strategies of communication and prophylaxis
      dealing with HIV disease, and involving the general population and people with
      persisting high-risk behavior.

PMID- 10354734
TI  - [Chronic erythremic myelosis (or the chronic form of Di Guglielmo's disease). A
      case report].
AB  - The chronic erythromyelosis (or chronic type of Di Guglielmo's disease) is a rare
      illness of uncertain classification. This illness shows characteristics that
      remember on the one hand the myeloproliferative and on the other hand the
      myelodysplastic diseases. The therapy is quite unsatisfactory. As a presence of
      erythrocytic antibodies has been detected, a therapy with steroids, danazol,
      splenectomy, immunosuppressive agents, plasmapheresis is advised. We have tried a
      cycle of therapy with high doses of intravenous gammaglobulin (0.4 g/kg/day for 4
      days) also in the attempt of reduce, even if temporarily, the hemolytic component
      due to the reticuloendothelial system's hyperplasia. We conclude that this
      therapy, in our patient, has not yielded good outcomes immediately but carried
      out settled levels of haemoglobin as well as reduction of bilirubin and LDH after
      a month.

PMID- 10354735
TI  - [Pneumocystosis in a nonimmunodepressed cocaine addict].

PMID- 10354736
TI  - ["Pollution" of the Italian language?].

PMID- 10354737
TI  - [The symptoms in HIV disease: prevalence and control].

PMID- 10354738
TI  - [Obesity in children: a behavioral approach and programs of family treatment].

PMID- 10354739
TI  - [The articular damage of hemochromatosis. A little known aspect].
AB  - Genetic haemochromatosis is a HLA-linked disease characterized by a high and
      inappropriate gastrointestinal iron absorption; the excess iron is stored in
      parenchymal cells, provoking the failure of the involved organs. The common
      target organs of genetic haemochromatosis are liver, heart, pancreas, pituitary,
      joints and skin. The disease is inherited in an autosomal recessive manner with
      predilection for male sex and penetration conditioned by age, sex and food
      habits. The first clinical manifestation of genetic haemochromatosis, whose onset
      is typically between ages 40 and 60, is represented by arthropathy in 45% of the
      cases; the articular features are unfortunately often misdiagnosed and it is
      known that the diagnosis delay heavily compromises the outcome; vice-versa the
      early identification of the disease, and the consequent suitable treatment give
      back a normal life expectancy to these patients. The articular features of
      genetic haemochromatosis are of two types: 1) progressive degenerative
      arthropathy, characterized by pain without inflammatory signs, morning stiffness
      and functional impairment involving hands, wrists, shoulders, hips, knees and
      feet; 2) chondrocalcinosis with its typical proteiform clinical manifestations.
      The aim of this report is to underline that the patients with premature
      osteoarthritis or unexplained chondrocalcinosis must be screened for genetic
      haemochromatosis in order to formulate the correct diagnosis before the
      development of severe internal organ involvement.

PMID- 10354740
TI  - [Polyomavirus infections in exotic birds in Switzerland].
AB  - Polyomavirus infections in budgerigars, in other parrots as well as in
      passeriformes have been described in many countries, but not in Switzerland so
      far. This paper reports on cases of polyomavirus infections in three different
      bird collections in Switzerland. The first outbreak occurred in a mixed
      collection of passeriformes, the second in a collection of parrotlets (Genus
      Forpus), and the third in a large groups of parrots (Psittaciformes), of which
      only one recently acquired Kea (Nestor notabilis) was affected. The clinical
      symptoms, gross necropsy changes and histopathologic findings are described. The
      presence of avian polyomavirus was confirmed by the polymerase chain reaction
      (PCR).

PMID- 10354741
TI  - [Clinical, epidemiologic and therapeutic aspects of idiopathic epilepsy in 25
      golden retrievers: results of a long term study].
AB  - The records of 25 Golden Retrievers with idiopathic epilepsy were reviewed. One
      goal was to identify objective aspects enabling a realistic prognosis prior to
      treatment. In half the dogs seizures occurred for the first time at the age of
      one to three years and were mostly generalised. The character, feeding habits and
      confinement of the dogs played a minor role in the clinical manifestation of the
      fits, but they were seen mostly during sleep in two thirds of the dogs. Because
      of the long follow-up period some important findings were made. At the beginning
      of the standardized long-term therapy with phenobarbital a success was observed
      in two thirds of the dogs, while after four years the symptoms worsened
      significantly in about half the dogs. We found no better success rate in
      castrated dogs. Dogs responded well to therapy if treated as early as possible.

PMID- 10354742
TI  - [Effects of mitotane therapy in dogs with pituitary dependent Cushing syndrome on
      the adrenal gland size--an ultrasonographic study].
AB  - The effect of mitotane therapy on adrenal gland size was evaluated in 13 dogs
      with pituitary dependent hyperadrenocorticism. Ultrasonographic measurements were
      obtained before and during mitotane therapy. During therapy both adrenal glands
      were shorter and thinner (median during therapy: left adrenal gland 19.4 mm long,
      5.4 mm thick, right adrenal gland 18.1 mm long, 6.1 mm thick) than before
      mitotane therapy (median before therapy: left adrenal gland 23.6 mm long, 8.3 mm
      thick, right adrenal gland 21.6 mm long, 8.1 mm thick). Statistical evaluation
      showed a significant reduction in size. But ultrasonographic measurement of
      adrenal gland size is not useful in the evaluation of adrenal reserve during
      mitotane therapy. Inadequate adrenal reserve was not identified and adrenal size
      measurement by ultrasonography was not helpful to differentiate adequate and
      inadequate control of adrenal cortisol secretion during mitotane therapy.

PMID- 10354743
TI  - [Community medicine after the disintegration of the Soviet Union].

PMID- 10354745
TI  - [Return of virtues].

PMID- 10354744
TI  - [Small groups--creative thinking or babbling talk-clubs?].

PMID- 10354746
TI  - [Variation in hospital mortality should be seriously considered].

PMID- 10354747
TI  - [Acute stroke--who dies in a stroke unit?].
AB  - Stroke unit care increases the proportions of patients able to live at home,
      improves functional outcome, reduces the need for institutional care, and reduces
      mortality. We have evaluated the data on the 69 patients who died in our stroke
      unit with an acute stroke, among the first 1,000 patients treated. The patients
      who died were older and had lower functional scores (median Barthel Index score 0
      versus 70) and neurological scores (median Scandinavian Stroke Scale score 6
      versus 48) at admittance. Early progression of the stroke was also more frequent
      in the group of patients who died. No differences in blood pressure, heart rate
      and body temperature were found between the groups, aside from increased
      diastolic pressure and heart rate in patients who died with an embolic infarction
      and increased systolic pressure in patients who died with an intracerebral
      haemorrhage.

PMID- 10354748
TI  - [Tonsillectomy--day surgery or hospitalization?].
AB  - Most current studies show that adenotonsillectomies can be performed safely as
      day case surgery. We wanted to evaluate patient acceptability of ambulatory
      surgery. A prospective study was undertaken in order to compare
      (adeno)tonsillectomies performed on an inpatient and outpatient basis. 104
      patients underwent day surgery (adeno)tonsillectomy. 88 patients were treated as
      inpatients, but would have met the selection criteria for ambulatory surgery if
      an exception had been made in relation to travel distance. Tonsillectomy is an
      operation with high postoperative morbidity. Our study shows that patients
      undergoing day case surgery had better sleep, better oral intake and had less
      pain during the first postoperative night. The majority of the inpatients
      considered tonsillectomy performed as day case surgery less tolerable. With
      adequate information and patient selection, our study showed that most patients
      prefer day surgery. Questioned two weeks postoperatively, 92% of the patients
      preferred tonsillectomy performed as a day case procedure. Use of day surgery may
      improve health care efficiency. At the same time, it may improve quality of care
      for the patients.

PMID- 10354749
TI  - [Coccygectomy for coccygodynia].
AB  - Treatment of coccygodynia is primarily conservative and symptomatic. Operative
      treatment is controversial and the results are confusing. A thorough examination
      including X-rays is recommended in order to exclude other diseases. We undertook
      a follow-up of 26 patients 1-16 years after coccygectomy for coccygodynia. The
      aim was to elucidate the long term result including rate of patient satisfaction.
      We used patients records and questionnaires. 25 patients answered. The answers
      revealed that 20 of the patients were completely free of symptoms or had
      improved. Three had suffered aggravation of the symptoms. Patient opinion varied
      widely; 18 were satisfied with the long-term result, and five regretted the
      procedure. The importance of preoperative information and patient selection
      before surgery is emphasized.

PMID- 10354750
TI  - [Fatal coronary heart disease in a young woman 20 years after radiotherapy for
      Hodgkin disease].
AB  - We present a case in which a 37-year-old female died of acute myocardial
      infarction. The patient was 20 years earlier successfully treated with radiation
      therapy against the mediastinum for Hodgkin's disease. Nearly half of the
      patients with Hodgkin's disease are younger than 40 years at the time of
      diagnosis. Most of them are successfully treated with radiation therapy.
      Radiation against mediastinum including parts of the heart can induce fibrotic
      changes in the coronary arteries. We conclude that the radiation therapy was the
      main etiologic factor behind the patient's coronary artery disease. It is
      important to use techniques with the lowest possible risk for damaging the
      coronary arteries under chest radiation therapy. It is also important to perform
      early checks for coronary artery disease in this category of patients when they
      present with chest pain.

PMID- 10354751
TI  - [Should the community pay for hospitalized patients waiting for transfer to
      nursing homes?].
AB  - Many hospital patients are on waiting lists for transferral to nursing homes. In
      a retrospective study, all patients (n = 75) hospitalised at the Department of
      Oncology, University Hospital of Tromso until their death and all patients (n =
      20) transferred to nursing homes from the same department during a 23-month
      period were registered. The duration of hospitalisation was 1-111 days (median 10
      days) for the first group and 1-39 days (median 8 days) for the second group. 23
      out of 32 patients (72%) hospitalised more than 14 days were from the city of
      Tromso. This city and other municipalities should be required by law to pay the
      hospital for patients on waiting list for nursing homes. Today, 4 out of 16 major
      Norwegian hospitals have such arrangements.

PMID- 10354753
TI  - [Patient treatment in radiation accidents].
AB  - Accidental human injury due to ionizing radiation is rare. Industrial accidents
      are comparatively the most common. Life saving procedures should always have
      priority to any concern about radiation injury or contamination. The personal
      risks for emergency medical personnel is negligible when simple measures are
      taken. Repeated clinical examinations and blood lymphocyte counts should be
      performed on all patients with suspected radiation injury to allow a diagnosis.
      The radiation syndrome develops within days or weeks depending on total radiation
      dose, dose rate and dose distribution. Damage to the bone marrow and gut are the
      most important. Local radiation injuries to the hands are common in industrial
      accidents. The Norwegian Radiation Protection Authority should always be called
      when a potential ionizing radiation accident takes place within Norway.

PMID- 10354752
TI  - [Current viewpoints on etiology and physiopathology of migraine].
AB  - Migraine is an inheritable disease, and the mutation causing a rare variant of
      migraine (familial hemiplegic migraine) has now been demonstrated. The mutated
      gene encodes a subunit of a brain-specific calcium channel in cell membranes.
      Brains of patients with recurrent migraine attacks seem to behave differently
      from other brains, also when examined outside attacks, in that they commonly
      demonstrate lack of habituation when exposed to serial stimuli. The patho
      physiological process of the attack might well consist of a spreading cortical
      depression starting in the occipital region and gradually involving other parts
      of the cortex. It is primarily a cerebral process secondarily accompanied by
      reduced cerebral blood flow, later converting into increased flow. The pain of
      migraine probably is mediated by way of the trigeminal nerve which releases
      vasoactive peptides leading to dilatation of the greater blood vessels. During an
      attack there is increased metabolism in cranial parts of the brain stem,
      demonstrated as areas of increased blood flow in PET studies. This increased
      metabolism persists even when the symptoms of migraine have disappeared after
      drug treatment, perhaps because the migraine attacks may be generated in this
      region. The primary dysfunction in migraine probably is located in the brain
      rather than in blood vessels.

PMID- 10354754
TI  - [Monotherapy with antiandrogens for prostatic cancer].
AB  - Bicalutamide (Casodex) is a new antiandrogen, so far approved for the treatment
      of prostate cancer in combinations with a GnRH agonist. Results from large, well
      controlled studies show that monotherapy with bicalutamide is an interesting
      alternative to surgical or medical castration for patients with advanced prostate
      cancer. The efficacy generally appears to be similar to that of castration, but
      without the well known side effects of castration such as hot flushes, reduced
      sexual interest and functioning, and reduced physical capacity. Bicalutamide is
      well tolerated, but some patients will experience gynaecomastia and/or breast
      tenderness, and they should be informed about this before treatment is started.
      Monotherapy with bicalutamide is an attractive first line treatment for these
      patients in order to maintain optimal quality of life for as long as possible.
      Studies show that many patients will respond to second line treatment with
      castration if bicalutamide has failed.

PMID- 10354755
TI  - [Rheumatic fever and rheumatic heart disease in Northwest Russia].
AB  - 296 patients who were operated between 1965 and 1993 with mitral commissurotomy,
      were included in this retrospective study of rheumatic heart disease in North
      West Russia. There were 117 (39.5%) reported cases of acute rheumatic fever, with
      either polyarthritis (n = 88), carditis (n = 23), or Sydenham's chorea (n = 6).
      There were no reported cases of erythema marginatum and subcutaneous nodules. The
      first case of acute rheumatic fever in our patients was in 1924. More than 50% of
      the patients (164) did not get the diagnosis acute rheumatic fever, and became
      aware of their rheumatic heart disease only when symptoms of mitral stenosis
      appeared. 15 patients had a subclinical attack of rheumatic fever, i.e. not all
      of Jones' criteria were fulfilled. At onset of acute rheumatic fever, the mean
      age was 15 years, when valvular disease was confirmed 24 years, and 33 years at
      mitral surgery. Dyspnea (n = 293) was the most common symptom of mitral stenosis,
      followed by atrial fibrillation (n = 105). 15 patients developed cerebral stroke.
      The Archangel Health Region has one of the highest prevalences of rheumatic heart
      disease in Europe (3.7/1,000 in those above 16 years of age, 1993). There is high
      mortality and the disease develops rapidly.

PMID- 10354756
TI  - [Spontaneous abortion with complications].

PMID- 10354757
TI  - [Patient rights and the physician-patient relationship].
AB  - Although in Norway the patient's freedom to influence medical decisions has so
      far been restricted to the right to refuse treatment, patient rights is an issue
      of increasingly importance in medical practice. One reason is the (paradoxically)
      increased awareness that public health care is unable to meet the public's need
      for basic health care. Another reason is the declining confidence in physicians'
      ability and commitment to meeting the need of the individual patient. High
      technology medicine (diagnostical and therapeutic) reduces the close and personal
      bonds between physician and patient. Medicine as a market also increases the need
      for patient rights to secure the quality of the services paid for. More people
      are being considered in need of health care as a consequence of modern medicine's
      strong emphasis on risk and early diagnosis for an increasing number of
      conditions. This leaves fewer people free to remain non-patients. This new limit
      to personal freedom is rarely problematized. Rights may be powerful tools for the
      strongest groups of patients, but the most valuable aspects of the art of
      medicine--trust, empathy and understanding, cannot be enhanced through legal
      rights, only through increased emphasis on the humanistic aspect of medicine.

PMID- 10354758
TI  - [Freedom in a little box].
AB  - What are the implications for health of freedom as a community value? This
      article focuses on the fact that both health and freedom are complex concepts
      that elude a concise definition. Depending on how you define them, the answer to
      the question above will vary. Different conceptions of health and freedom are
      described initially, and then their interdependence is illustrated by means of
      examples. One issue examined is how the breakdown of the communist regime in the
      former Soviet Union influenced life expectancy, another the positive and negative
      aspects of the Cuban health system. Finally, the importance of a questioning
      attitude to the two concepts is underlined.

PMID- 10354759
TI  - [Equality and brotherhood--values worth preserving in the health services].
AB  - This article is the last in a series on virtues and values in medicine and health
      care. Its point of departure relates to the heritage of the great French 1789
      revolution. Equality in society is hardly attainable, but equity in health care,
      providing health care according to need rather than according to wealth, has been
      a highly valued aim for the post-war Norwegian health services. The political
      ideas of this development came from the socialist labour movement as well as from
      Christian ideas of charity, merging to form the institutions of the post-war
      welfare states. Fraternity, brotherhood, or in its modern version solidarity, is
      based on the very nature of man as a social being, but has also been a tool to
      create political power necessary to achieve equity. Mounting research evidence on
      inequality and health shows that what makes a difference to health is more a
      matter of people's relative income and status in society rather than their
      absolute material standard of living. The values of equity and solidarity are
      challenged by recent neo-liberalist and populist movements. Market models in the
      health services tend to turn health services into commodities and patients into
      consumers. This has implications for medicine beyond the financial impact.
      Utilitarian arguments tend to favour more user fees for medical services and
      drugs, the emergence of private services and health insurance, the result being a
      drift towards greater inequality in health and access to health services.
      However, recent research on value preferences suggests that issues related to
      equality are gaining support in several European countries.

PMID- 10354761
TI  - [Communicable diseases in the countries of the former Soviet Union].
AB  - The reasons for the breakdown of control of communicable diseases in the
      countries of the former Soviet Union are discussed. The national and
      international response to the threat to public health is outlined. The factors
      behind the breakdown are complex and related both to inherent features of the old
      system and a failure on the part of the public health authorities to respond
      quickly in a situation of financial and societal unrest. In collaboration with
      the international community, the Russian authorities have managed to prevent some
      560,000 new cases of diphtheria and 15,000 probable deaths from 1994 to 1998 by
      concerted action through the Interagency Immunization Coordination Committee.

PMID- 10354760
TI  - [Mortality trends in Russia].
AB  - Mortality statistics were sparse during the last two decades of the Soviet Union.
      Official spokesmen claimed that life expectancy increased after the Second World
      War, but reconstruction of mortality data after the downfall of the union
      revealed that mortality rates during the 1980s were far higher than in Western
      countries. During the 1990s, Russia has experienced a dramatic increase in
      mortality rates particularly in men aged 20-64 years. The major cause for this
      increase is the steep upturn of cardiovascular deaths which has been associated
      with high prevalence of smoking as well as high-fat diet. The increasing
      consumption of alcohol and the Russian habit of binge drinking is thought to be
      directly associated with an increased mortality of cardiovascular diseases. This
      is reflected in the excess number of cardiovascular deaths during weekends
      compared to weekdays.

PMID- 10354762
TI  - [Gonorrhea and syphilis from Russia to Norway].
AB  - In the 1990s, Russia has experienced a rapidly increasing incidence of syphilis
      and gonorrhoea. There are concerns of a spread of the epidemics to neighbouring
      Norway. From 1993 to 1998, 1,335 cases of gonorrhoea and 62 cases of syphilis
      were reported to the Norwegian notification system for infectious diseases. We
      studied cases with a Russian patient or source partner and cases acquired in
      Russia. 28 (2.1%) of gonorrhoea cases and 12 (19%) of syphilis cases had links to
      Russia. There was no time trend over the period. Ten gonorrhoea and three
      syphilis cases were from Finnmark, a sparsely populated county neighbouring
      Russia. Most patients were males over 30 years of age. So far, the gonorrhoea and
      syphilis epidemics in Russia have had minor impact in Norway. Thorough
      surveillance is still needed.

PMID- 10354763
TI  - [Health aid for Eastern Europe--the Eurohealth program and Norwegian
      contribution].
AB  - Europe has changed considerably during the last 10 years. 20 new member states
      have joined WHO's Regional Office for Europe. These new member states had
      delegates and representatives appearing in international meetings who were not
      used to international representation. Such representation had previously been
      taken care of from Moscow. WHO's office in Europe has a Norwegian, Dr. Jo Asvall,
      as regional director. His team started a comprehensive plan for the development
      of health systems in the newly independent states, called the Eurohealth
      programme. Norway has been very active in this programme. We have supported it in
      the governing bodies of WHO. We have funded part of the programme, and we have
      seconded Norwegian doctors to work actively in the Eastern European countries as
      part of the Eurohealth programme. Armenia and Georgia plus the Aral Sea region
      have been the prioritised countries. In addition to the Eurohealth programme,
      Norway has been active in the most neighbouring eastern European countries. The
      resources have mainly been used in North-West Russia in Archangel and Murmansk.
      The plan is to increase the funding for work in this region.

PMID- 10354764
TI  - [The creative atmosphere in the meeting of patient and physician].

PMID- 10354765
TI  - [Reconstruct university hospitals as educational institutions].

PMID- 10354766
TI  - [Primary prevention in osteoporosis?].

PMID- 10354768
TI  - [Hospital without patients?].

PMID- 10354767
TI  - [Injuries among children and little more].

PMID- 10354769
TI  - [Easily won arm-chair solutions of the tobacco problem].

PMID- 10354770
TI  - [Research combined with clinical practice--think if it were like that!].

PMID- 10354771
TI  - [Medical students out of and interns in the regional hospitals].

PMID- 10354772
TI  - [About Nordisk Medicin].

PMID- 10354773
TI  - [Increasing student capacity in Oslo?].

PMID- 10354774
TI  - [Therapeutic results in acute myeloid leukemia. Is there any progress?].

PMID- 10354775
TI  - [Is health of the Danes ailing?].

PMID- 10354776
TI  - [Neovascularization of tumors. New therapeutic possibilities].

PMID- 10354777
TI  - [Why research?].

PMID- 10354778
TI  - [Mild intraoperative hypothermia. Another risk factor for postoperative
      complications].
AB  - Intraoperative mild hypothermia (core temperature 35-36 degrees) is common during
      major surgical procedures. Recent studies have shown that hypothermia may be
      related to the development of postoperative serious complications such as
      impaired platelet function with increased blood loss and transfusion
      requirements, postoperative morbid cardiac events, impaired wound healing, and
      prolonged hospitalization. Core hypothermia during surgery should therefore
      receive more attention as a risk factor for postoperative complications. The most
      effective prevention of intraoperative hypothermia is forced air warming combined
      with the infusion of warm fluids. The paper gives clinical guidelines for
      monitoring and prevention of intraoperative core hypothermia.

PMID- 10354779
TI  - [Contrast media in ultrasonography].
AB  - Microbubbles of air or other gases are ideally suited as echo-enhancers because
      of the high difference in acoustic impedance of gas/fluid interfaces. The
      microbubbles are 1-7 microns in diameter and capable of surviving pulmonary
      passage to produce enhancement of especially the Doppler signal after intravenous
      injection. The main clinical role of ultrasound (US)-contrast is to enhance the
      Doppler signals (up to 20 dB) in inconclusive Doppler examinations. Experience
      with US-contrast agents comes mainly from use of the galactose based agent
      Levovist (Schering AG, Germany). The US-contrast agents have further properties:
      a) Air bubbles in the sound fields will reverberate and return sound with
      harmonic frequencies. This phenomenon can be used in "harmonic imaging". B) Short
      intense sound impulses will destroy the bubbles resulting in a mosaic of colours
      (stimulated acoustic emission). This phenomenon may be used in tumour diagnostics
      in the liver.

PMID- 10354780
TI  - [Acute myeloid leukemia. Therapeutic results 1985-1994].
AB  - In a retrospective study we evaluate the treatment and outcome of 421 adults
      admitted to our department with acute myeloid leukemia (AML) during the 10 year
      period from 1985-1994. Younger patients (< or = 55 years) had a significantly
      better prognosis than elderly patients (> 55 years), partly because more younger
      patients had remission-induction therapy (81% versus 39%) and their complete
      remission (CR) rate was higher (69% versus 41%). In patients achieving CR the
      long-term survival (five years) was 40% for younger and 26% for elderly patients.
      Nineteen patients received autologous bone marrow transplantation (BMT) and eight
      an allogeneic BMT in first CR. Five patients treated with allogeneic BMT are
      still relapse-free, whereas autologous BMT, in comparison to conventional
      chemotherapy alone, did not improve the five-year relapse-free survival (29
      versus 27%). Our data illustrate that in a non-selected material of AML patients
      the long-term survival (five years) has only slightly improved. The effect of
      autologous BMT cannot be evaluated in this retrospective setting.

PMID- 10354781
TI  - [Self-reported health and morbidity among adult Danes 1987-1994].
AB  - Developments in morbidity among adult Danes were studied by means of
      representative national health interview surveys conducted in 1987, 1991, and
      1994. Each health interview survey was based on personal interviews with a sample
      of 6000 Danes. Response rates were about 80%. From 1987 to 1994 prevalence of
      long-standing illness increased from 33 to 38%, prevalence of health-related
      restrictions of daily activities increased from 11 to 14%, while prevalence of
      perceived poor health decreased slightly and prevalence of not feeling well
      enough to do what you want to do decreased from 22 to 19%. In 1994 16% reported
      reduced psychological well-being within a four week period, and 23% had due to
      emotional problems accomplished less than they desired at work or in other daily
      activities. The prevalence of self-reported morbidity and ill-health increased
      with increasing age, and for most of the indicators prevalence was higher among
      women than among men.

PMID- 10354782
TI  - [Charcot foot. A serious complication of diabetes mellitus].
AB  - The Charcot foot is a destructive disease seen in patients with peripheral
      neuropathy due to diabetes mellitus. I present a case where a man aged 52 years
      contracted bilateral Charcot foot with total destruction of the mid feet one and
      a half years after initial symptoms. The case illustrates how rapidly the
      destruction occurs and the importance of early diagnosis.

PMID- 10354783
TI  - [Extracerebral stereotactic radiotherapy--a new therapeutic principle].

PMID- 10354784
TI  - [Consensus conference. "Depression--a public disease to be treated?"].

PMID- 10354785
TI  - [Molecular biology examinations of dopa-responsive dystonia].

PMID- 10354786
TI  - [Differences between the utilization of invasive cardiologic procedures in the
      different counties].

PMID- 10354787
TI  - [Poisoning among children: development within two decades].

PMID- 10354788
TI  - [Diagnosis and check up of bladder tumors].

PMID- 10354789
TI  - [Coordination of the treatment of cancer patients].

PMID- 10354790
TI  - [How to optimize the research at universities?].

PMID- 10354791
TI  - [Neuronal growth factors--neurotrophins].
AB  - Neurotrophic factors are polypeptides primarily known to regulate the survival
      and differentiation of nerve cells during the development of the peripheral and
      central nervous systems. The neurotrophic factors act via specific receptors
      after retrograde axonal transport from the nerve fibre target areas back to the
      cell bodies, and locally through autocrine and paracrine mechanisms linked to
      nerve cell activity. In the mature nervous system, neurotrophic factors maintain
      morphological and neurochemical characteristics of nerve cells and promote
      activity-dependent dynamic/plastic changes in the synaptic contacts between nerve
      cells by strengthening functionally active synaptic connections. Induction and
      increased production of neurotrophic factors in relation to neural injuries are
      thought to serve protective and reparative purposes. Specific neurotrophic
      factors have thus been shown to protect nerve cells in a number of experimental
      models for neurodegenerative diseases, such as Parkinson disease, Alzheimer
      disease, and amyotrophic lateral sclerosis, just as specific neurotrophic factors
      have been shown to stimulate regenerative growth of both peripheral and central
      nerve fibres. Today, problems with continuous and localized delivery of specific
      neurotrophins or combinations thereof into the nervous system appear to be the
      most important obstacle for more widespread clinical application.

PMID- 10354792
TI  - [Bladder tumor antigen test versus urinary cytology in patients with bladder
      tumors].
AB  - The value of the BARD bladder tumour antigen (BTA) test for the diagnosis of
      bladder tumour was compared to urinary cytology. A total of 60 patients with
      bladder tumours (Category Ta: 39 patients and Category T1-4: 21 patients) were
      investigated. Urinary cytology was found to be more sensitive than the BTA test.
      The overall sensitivity of cytology was 0.63 compared to 0.27 for the BTA test.
      The sensitivity of both tests improved with increasing tumour severity. For Ta
      tumours and T1-4 tumours the sensitivity of cytology was 0.46 and 0.95
      respectively, and for the BTA test it was 0.13 and 0.53 respectively. We conclude
      that urinary cytology is superior to the BTA test. The BTA test cannot be
      recommended either for bladder tumour screening or monitoring for recurrence
      because of too many false negative results. Because of its high specificity
      (0.93), a positive BTA test might reduce the number of flexible cystoscopies, and
      prepare the patient directly for tumour resection.

PMID- 10354793
TI  - [Cross-sectorial cooperation regarding cancer patients in a recently started care
      program. Ideas and themes based on focus group interviews with general
      practitioners and oncologists].
AB  - This study identified ideas for an improved collaboration between general
      practitioners and oncologists regarding patients with cancer. A qualitative
      research-method with focused group interviews was chosen. The results
      demonstrated that both oncologists and general practitioners would like the
      general practitioners to take more active part in the total care programme for
      cancer patients. Some of the needed improvements were more detailed referral
      letters including description of treatment plans, information about what the
      patient had been told and general information about the specific cancer disease.
      Both parts desire bilateral information exchange and a dialogue about the
      distribution of tasks. Both parts are willing to collaborate but this is at
      present restricted due to lack of knowledge of each others' working areas and the
      oncologists' impression that general practitioners need more medical knowledge
      regarding specific aspects of cancer. A randomized intervention study using ideas
      from this study may clarify if it is possible to improve the collaboration and
      thereby the cancer patients' satisfaction with care.

PMID- 10354794
TI  - [Risk of cancer among Danish electricity workers. A cohort study].
AB  - We report the incidence of cancer in a large cohort of employees identified from
      all 99 Danish utility companies. Personal data, and information on employment and
      exposure to magnetic fields and asbestos were obtained from manual files at the
      companies, the Danish Supplementary Pension Fund and the public payroll
      administration. A total of 32,006 individuals with more than three months of
      employment were linked with the files of the Danish Cancer Registry. Overall,
      3008 cancers were observed, with 2825 expected, yielding a small but
      significantly increased risk of 1.06 (95% CI, 1.03-1.10). No excess was observed
      for all leukemias or for cancers of the brain or breast among men or women. There
      was no association of electromagnetic field exposure with risk of these cancers
      even when the level and length of exposure to magnetic fields were taken into
      account. Increased risks for cancers of the lung and pleural cavity were seen
      mainly for workers whose jobs involve exposure to asbestos. Our results do not
      support the hypothesis of an association between occupational exposures to
      magnetic fields in the electric utility industry and the risk for cancer.

PMID- 10354795
TI  - [A method for quality assurance of surgical urologic training. Decentralized
      registration with centralized statistical processing].

PMID- 10354796
TI  - [Treatment of delirium in a psychogeriatric university hospital department.
      Etiology, treatment concept and outcome].
AB  - The purposes of the study were to account for aetiology, treatment concept,
      outcome of treatment, and discharge destination of delirious elderly inpatients.
      During one year all patients in a psychogeriatric university department were
      assessed on admission and at discharge with a selection of assessments measuring
      psychopathology, behavioural disorders, depressive symptoms, intellectual
      functioning, activities of daily living, and gait. Diagnoses were made according
      to the ICD-10 criteria for research. All patients with a principal diagnosis of
      delirium (n = 26) are accounted for. Delirious patients improved their health
      status significantly in all the assessments, and 86% of patients admitted from
      independent living were discharged to independent living. It is concluded that
      elderly inpatients with severe or prolonged delirium profit significantly from
      the treatment concept in all of the rated health aspects.

PMID- 10354797
TI  - [Spigelian hernia. A case of typical Spigelian hernia in an elderly man].
AB  - A case of typical Spigelian hernia in an elderly patient successfully treated
      with operation is reported. A Spigelian hernia, protrusion of preperitoneal fat
      and peritoneal sac through the Spigelian aponeurosis, may present with
      uncharacteristic abdominal pain and a palpable mass along the Spigelian
      aponeurosis. Patients who complain of pain but have no visible or palpable lump
      present the greatest difficulty in diagnosis. Ultrasound examination is a
      valuable diagnostic tool both in palpable and nonpalpable Spigelian hernias. The
      treatment is surgical, with excellent results and low risk of recurrence.

PMID- 10354798
TI  - [Tinea capitis. Increased occurrence and changed etiology].

PMID- 10354799
TI  - [Influenza and mortality].

PMID- 10354800
TI  - [MTV--back pain].

PMID- 10354801
TI  - [Pulmonary edema after anesthesia with sevoflurane].

PMID- 10354802
TI  - Adolescent storm and stress, reconsidered.
AB  - G. S. Hall's (1904) view that adolescence is a period of heightened "storm and
      stress" is reconsidered in light of contemporary research. The author provides a
      brief history of the storm-and-stress view and examines 3 key aspects of this
      view: conflict with parents, mood disruptions, and risk behavior. In all 3 areas,
      evidence supports a modified storm-and-stress view that takes into account
      individual differences and cultural variations. Not all adolescents experience
      storm and stress, but storm and stress is more likely during adolescence than at
      other ages. Adolescent storm and stress tends to be lower in traditional cultures
      than in the West but may increase as globalization increases individualism.
      Similar issues apply to minority cultures in American society. Finally, although
      the general public is sometimes portrayed by scholars as having a stereotypical
      view of adolescent storm and stress, both scholars and the general public appear
      to support a modified storm-and-stress view.

PMID- 10354803
TI  - Eye movements of younger and older drivers.
AB  - This 2-part study focuses on eye movements to explain driving-related visual
      performance in younger and older persons. In the first task, participants' eye
      movements were monitored as they viewed a traffic scene image with a numeric
      overlay and visually located the numbers in their sequential order. The results
      showed that older participants had significantly longer search episodes than
      younger participants, and that the visual search of older adults was
      characterized by more fixations and shorter saccades, although the average
      fixation durations remained the same. In the second task, participants viewed
      pictures of traffic scenes photographed from the driver's perspective. Their task
      was to assume the role of the driver and regard the image accordingly. Results in
      the second task showed that older participants allocated a larger percentage of
      their visual scan time to a small subset of areas in the image, whereas younger
      participants scanned the images more evenly. Also, older participants revisited
      the same areas and younger participants did not. The results suggest how aging
      might affect the efficacy of visual information processing. Potential
      applications of this research include training older drivers for a more effective
      visual search, and providing older drivers with redundant information in case
      some information is missed.

PMID- 10354805
TI  - Double trade-off curves with different cognitive processing combinations: testing
      the cancellation axiom of mental workload measurement theory.
AB  - The accomplishment model of average mental workload--a formal axiomatic
      measurement theory--was used as a basis for developing and testing secondary task
      indices of mental workload (H. A. Colle & G. B. Reid, 1997). Its cancellation
      axiom implies global sensitivity, which is an important theoretical and practical
      criterion for mental workload indices. Performance levels of different secondary
      tasks were empirically equated in mental workload and then used to test the
      cancellation axiom. Cognitive processing similarity--including orthographic,
      phonemic, and semantic processing of pairs of operator and secondary tasks--was
      manipulated in three experiments. Equivalencies between secondary tasks were
      independent of secondary-operator task similarity, consistent with the
      cancellation axiom and the global sensitivity of these secondary tasks. The
      results suggest that standardized secondary task techniques can be developed for
      the practical measurement of mental workload. Actual or potential applications of
      this research include the development of functionally useful and realistic
      secondary task measures of mental workload.

PMID- 10354804
TI  - Age-related performance in a multiple-task environment.
AB  - Younger and older adult participants performed a dynamic multiple-task requiring
      concurrent processing of 4 independent tasks. Component-task performance emphasis
      (i.e., task priorities) was biased by differential point allocations across task
      components. After training, the point structure was modified. Older adults
      exhibited larger multiple-task performance deficits compared with younger adults;
      however, the age-related gap in multiple-task performance decreased with
      practice. The age-related performance difference increased again when task
      emphasis was changed, but not when demands were changed. Consistent with the
      training data, the age-related differences diminished again with additional
      experience on this new task-component emphasis. The data suggest that higher
      order, strategic processing may be an important source of age-related differences
      in complex multiple-task performance. Actual or potential applications of this
      research include the facilitation of techniques for age-related comprehensive
      usability testing for products of even moderate complexity.

PMID- 10354806
TI  - The effect of personality type on muscle coactivation during elbow flexion.
AB  - A great deal of interest has been generated recently regarding the influence that
      psychosocial factors may have on the reporting of and disability associated with
      work-related musculoskeletal disorders. The current study considers the potential
      influence of one psychosocial factor--personality type--on basic neuromuscular
      control strategies and biomechanical loading. The study investigated the
      hypothesis that Type A people exhibit increased muscular antagonism relative to
      their Type B counterparts. Volunteers participated in an EMG-based biomechanical
      study to investigate the coactivation patterns of the major muscles that span the
      elbow joint during elbow flexion exertions. Results showed that, averaging across
      all conditions, the antagonist muscle activity was significantly higher for Type
      A individuals than for their Type B counterparts (10% of maximum for Type A, 5.5%
      of maximum for Type B). Although the study was somewhat limited in its size and
      scope, the results indicate that certain psychosocial factors may be more than a
      filter in postinjury response and may directly influence biomechanical loading. A
      potential application of this research is an increased awareness that certain
      individuals may be at greater risk of developing work-related musculoskeletal
      disorders.

PMID- 10354808
TI  - Impairment of driving performance caused by sleep deprivation or alcohol: a
      comparative study.
AB  - A study was conducted to assess the relative impact of partial sleep deprivation
      (restriction to 4 h sleep before testing) and full sleep deprivation (no sleep on
      the night before testing) on 2 h of simulated driving, compared with an alcohol
      treatment (mean blood alcohol content = 0.07%). Data were collected from the 64
      male participants on the primary driving task, psychophysiology (0.1 Hz heart
      rate variability), and subjective self-assessment. The results revealed that the
      full sleep deprivation and alcohol group exhibited a safety-critical decline in
      lane-keeping performance. The partial sleep deprivation group exhibited only
      noncritical alterations in primary task performance. Both sleep-deprived groups
      were characterized by subjective discomfort and an awareness of reduced
      performance capability. These subjective symptoms were not perceived by the
      alcohol group. The findings are discussed with reference to the development of
      systems for the online diagnosis of driver fatigue. Potential applications of
      this research include the formulation of performance criteria to be encompassed
      within a driver impairment monitoring system.

PMID- 10354807
TI  - Designing an interface to optimize reading with small display windows.
AB  - The extent of electronic presentation of text in small display windows is
      mushrooming. In the present paper, 4 ways of presenting text in a small display
      window were examined and compared with a normal page condition: rapid serial
      visual presentation (RSVP), RSVP with a completion meter, sentence-by-sentence
      presentation, and sentence-by-sentence presentation with a completion meter.
      Dependent measures were reading efficiency (speed and comprehension) and
      preference. For designers of hardware or software with small display windows, the
      results suggest the following: (a) Though RSVP is disliked by readers, the
      present methods of allowing self-pacing and regressions in RSVP are efficient and
      feasible, unlike earlier tested methods; (b) slower reading in RSVP should be
      achieved by increasing pauses between sentences or by repeating sentences, not by
      decreasing the presentation rate within a sentence; (c) completion meters do not
      interfere with performance and are usually preferred; (d) the space-saving
      sentence-by-sentence format is as efficient and as preferred as the normal page
      format.

PMID- 10354809
TI  - The discrimination, acquisition, and retention of aiming movements made with and
      without elastic resistance.
AB  - Two experiments were conducted to compare the discrimination, acquisition, and
      retention of movements made with and without elastic resistance. Using methods
      from psychophysics, Experiment 1 revealed that a discrete 800-mm movement could
      be discriminated equally precisely when it was performed with and without elastic
      resistance. Similarly, there was no difference in the spatial accuracy of a
      discrete aiming movement made with and without elastic resistance when extended
      practice with knowledge of results (KR) was provided in Experiment 2. Contrary to
      expectation, when KR about the outcome of the movement was removed on a retention
      test given 24 h after practice, the accuracy of the movements made with elastic
      resistance declined much more rapidly than those made without resistance. These
      findings question the common assumption that elastic resistance is a desirable
      characteristic of a control mechanism. Actual or potential applications of this
      research include the design of control mechanisms that facilitate performance
      under a variety of task and environmental conditions.

PMID- 10354811
TI  - Applied studies of plant meridian system: I. The effect of agri-wave technology
      on yield and quality of tomato.
AB  - Agri-wave technology is a new agricultural technology based on the plant meridian
      system, that focuses on measurement of plant sound characteristics. The basic
      principle of agri-wave technology is to improve the yield and quality of plants
      such as vegetables, flowers, and fruit trees by broadcasting sound waves of
      certain frequencies and spraying a compound microelement fertilizer on the
      leaves. The application of agri-wave technology on tomatoes remarkably stimulates
      growth of their seedlings. Fresh weight of the branch, stems, and leaves of the
      treated tomatoes is significantly (59.53%, P < 0.0001) higher than that of the
      control group. Sampling survey results indicate that agri-wave technology
      accelerates the ripeness of tomatoes. The fresh weight of ripe tomatoes treated
      with this technique is 30.73% higher than that of the untreated (P = 0.0018),
      while the fresh weight of the treated unripe tomatoes is 27.29% lower than that
      of the untreated unripe group (P = 0.0020). Yield surveys show that the yield of
      treated plants is 13.89% (p < 0.0001) higher than that of the control group.
      Moreover, with agri-wave technology treatment the storage period of tomatoes is
      almost doubled. Analysis of tomato nutrition shows that agri-wave technology has
      increased their sugar content by 26.19%, vitamin A and niacin (an antifavours
      vitamin) by 55.39% and 92.31% respectively. There is no difference concerning
      vitamin B1, B2, and D content between the two groups, and vitamin C and E
      contents decreased by 2.10% and 12.69%, respectively. Among the analyzed 33
      minerals of tomatoes, 26 increased in content, while 7 decreased. In conclusion,
      agri-wave technology has promoted the growth of the tomato, increased its yield,
      and improved its quality.

PMID- 10354810
TI  - Predicting optimal accommodative performance from measures of the dark focus of
      accommodation.
AB  - Leibowitz and his colleagues found that accommodation rests at an intermediate
      distance that shows wide interindividual variation. They proposed that this
      intermediate dark focus is useful for correcting anomalous refractive errors, but
      this proposal was later questioned when different measurement techniques yielded
      discrepant dark focus values. The present study measured dark focus under two
      levels of visual attentiveness: (a) when performing an open-loop, active viewing
      task (aDF); and (b) when looking passively into darkness (pDF). These dark focus
      measures were then compared with an optimal accommodation distance that was
      derived from accommodative response functions in bright and dim luminance. The
      aDF measures were found to be more myopic (nearer) than the pDF measures and
      highly correlated with the optical accommodation distance. No significant
      relationship was found between pDF and optical accommodation distance. These
      findings confirm that measures of dark focus are affected by nonoptical aspects
      of the measurement technique; they also suggest that techniques that demand
      visual attention (aDF) yield dark focus values that are more useful for
      optimizing accommodation and potentially reducing fatigue in difficult
      situations.

PMID- 10354812
TI  - Changes of pulse rate and skin temperature evoked by electroacupuncture
      stimulation with different frequency on both Zusanli acupoints in humans.
AB  - The purpose of this study was to investigate the effect of electroacupuncture
      stimulation (EA) of different frequency on pulse rate and skin temperature.
      Sixteen healthy male medical student volunteers received EA of 2 Hz, and 100 Hz,
      respectively on the both Zusanli acupoints (St-36) while resting. Their pulse
      rates were measured on the middle finger, and skin temperature was taken between
      the thumb and index finger before, during, and after EA stimulation. Each test
      took 35 minutes. The initial 10 min were defined as baseline period (no EA), the
      following 15 min as the EA period and the last 10 min as the post-EA period.
      Three assessments were performed on each subject as follows: A) control
      assessment: no EA was done throughout the test; B) 2 Hz EA assessment: 2 Hz EA
      was applied to both Zusanli acupoints during the EA period; and C) 100 Hz EA
      assessment: 100 Hz EA was applied to both Zusanli acupoints during the EA period.
      Our results indicate that both 2 Hz EA and 100 Hz EA decreased pulse rates during
      the EA period, and these changes remained throughout the post-EA period in 2 Hz
      EA assessment, but not in 100 Hz EA assessment. Both 2 Hz and 100 Hz EA resulted
      in decreases of skin temperature during the EA period. Our conclusions are that 2
      Hz EA and 100 Hz EA applied to both Zusanli acupoints resulted in the decrease of
      pulse rate, which possibly evoked greater parasympathetic nerve activity on heart
      beats. 2 Hz EA had a more sustained effect on heart beats than 100 Hz EA.
      Decreased skin temperatures in the EA period may have resulted from cutaneous
      vasoconstriction caused by EA induced sympathetic stress response, suggesting EA
      at least remains for 15 min in clinical application.

PMID- 10354813
TI  - The effect of auricular acupuncture on olfactory acuity.
AB  - The modulation of olfactory thresholds by auricular acupuncture at a specific
      auricular acupuncture point was examined. The Lung Point, supplied by the
      auricular branch of the vagus nerve, was employed in a controlled single blind
      study of a randomized population of 23 healthy volunteers. Two odorous
      substances, beta-Phenyl ethyl alcohol and Methyl cyclopentenolone were used to
      evaluate the modulation of olfactory thresholds after acupuncture. A significant
      decrease in the olfactory recognition threshold by acupuncture in comparison with
      controls (P < 0.05) for two standard odors was observed. Our findings suggest
      that auricular acupuncture stimulation can decrease the recognition threshold of
      olfactory sensitivity.

PMID- 10354814
TI  - The association between postmenopausal osteoporosis and kidney-vacuity syndrome
      in traditional Chinese medicine.
AB  - The aim of this study was to evaluate the association between postmenopausal
      osteoporosis and kidney-vacuity syndrome. Eighty-one postmenopausal women were
      enrolled; their age were between 40 to 65 years old. The mean ages of the non
      osteoporosis group and osteoporosis group were 54.0 +/- 4.8 and 58.9 +/- 5.9
      years old, respectively. Bone density examination was performed by DEXA technique
      and the diagnosis of osteoporosis was made by finding 2.5 standard deviations
      below the bone density of healthy youths. Kidney-vacuity syndrome was deduced
      according to the diagnostic criteria developed in the National Congress on
      Chinese Medicine and Sino-Western Combined Geriatric Medicine held in the
      People's Republic of China in 1986. The results showed that patients with kidney
      qi-vacuity and kidney-yin-vacuity were more likely to have osteoporosis than
      those who were not. No significant difference in the rates of osteoporosis
      between the kidney-yang-vacuity group and non-kidney-yang-vacuity group was
      found. The kidney-qi-yin-vacuity group had a higher probability of developing
      osteoporosis than the kidney-qi-vacuity or kidney-yin-vacuity group. By logistic
      regression analysis, patients with kidney-qi-vacuity or kidney-yin-vacuity were
      more likely to develop osteoporosis than those who were not. In conclusion, a
      marked association between kidney-vacuity syndrome and postmenopausal
      osteoporosis was observed. Patients with kidney-qi-yin-vacuity syndrome were more
      likely to get osteoporosis than those with kidney-qi-vacuity syndrome or kidney
      yin-vacuity syndrome.

PMID- 10354815
TI  - MMPI manifestations of Chinese migraine syndromes: a control study.
AB  - The investigation of personality traits of patients suffering from migraine
      headache with the Minnesota Multiphasic Personality Inventory (MMPI) is an
      important line of research, and differentiating syndromes in treating this
      disease is one of the characteristics of Chinese Medicine (CM). This study
      presents the MMPI-(Chinese edition) responses of 80 Chinese subjects with
      migraine and 40 non-headache healthy control subjects. Among them, migraine fire
      syndrome (MF) group consisted of 45 subjects (10 men, 35 women); migraine Qi
      stasis syndrome (MQ) group, 35 subjects (8 men, 27 women). The healthy control
      group was divided into healthy Qi stasis syndrome (HQ) group, 9 subjects (2 men,
      7 women); and healthy normal (HN) group, 31 subjects (7 men, 24 women) according
      to CM diagnostic criteria. Statistical analysis was performed by pairs among four
      groups. The results revealed that both MF and MQ groups' MMPI profiles were
      significantly higher than that of the Normal (HN) group, and formed a 1.2.3.7
      type slope. Profile deviation in the MQ group was slight, but in the MF group was
      serious and accompanied by a significant rising scores in F, paranoia (6),
      schizophrenia (8) and social introversion (0) subtests; HQ group's MMPI profile
      had a similar deviation as in the MQ group. The results suggest that CM migraine
      syndromes have an exact expression on MMPI profile, and that MMPI as an effective
      diagnostic method could be applied for CM syndrome discrimination. The "deviation
      of migraineurs' personality" may not be a special characteristic held only by
      migraineurs. The existence of different syndromes in migraine is one of the
      reasons that different scholars have reported different results on migraine by
      means of MMPI.

PMID- 10354816
TI  - Studies on the psychosomatic functioning of ill-health according to Eastern and
      Western medicine. 1. Visual observation of the sublingual vein for early
      detection of vital energy stagnation and blood stasis.
AB  - Computer-assisted image analyses were performed on the tongue color of 95 medical
      students without previous history of blood stasis-related condition to clarify
      the mutual relationship of the color of the tongue proper, the coating, and
      sublingual vein. The location of the measurement for the tongue proper was the
      underside of the tongue, and location of the measurement for the tongue coating
      was the upper surface of the tongue. A linear correlation analysis showed a
      correlation for each of the different positions for the non-normalized red value
      and normalized blue value. This analysis also demonstrated a statistically
      significant relationship between the tongue proper and the sublingual vein using
      Red-Green-Blue components and normalized Red-Green-Blue components (r = +0.670 -
      0.817, p < 0.0001). The most significant correlation between the tongue proper
      and the sublingual vein was the normalized red value and the normalized Red-Green
      Blue values for minimizing the range of the standard error of the mean (r =
      +0.745, p < 0.0001), although non-normalized blue had the highest correlation
      coefficient. Therefore, it seems reasonable to select those normalized red values
      for the comparison in the tongue color analysis. Correlation of the color between
      the sublingual vein and the tongue proper strongly suggests that inspection with
      the naked eye of the sublingual vein is useful for the early detection of vital
      energy stagnation and blood stasis. Also, because of its close relation to
      sustained chronic stress, changes in the sublingual vein might be available as
      one physiological parameter of a stress reaction.

PMID- 10354817
TI  - Antiviral effect of gingyo-san, a traditional Chinese herbal medicine, on
      influenza A2 virus infection in mice.
AB  - Gingyo-san is a crude drug containing extracts from 7 medicinal plants and
      fermented soybeans in a specific ratio. It has been used clinically in China as a
      therapeutic agent for the common cold. In the present study, we examined the
      antiviral effect of this agent on influenza virus infection in mice. Gingyo-san
      and its components were administered orally to mice 1 day before, then 1 and 4
      days after the inhalation of a mouse-adopted strain of influenza A2 (H2N2) virus.
      After infection with a 10 LD50 of the virus, 100% of mice treated with 10 mg/kg
      of the agent survived as compared with a 0% survival of control mice treated with
      saline. Also, the mean survival days were increased and consolidation scores were
      decreased in treated mice as compared with those of control mice. Two components
      contained in the agent, extracts from Glycyrrhizae radix and Arctii fructus,
      expressed antiviral activities in mice infected with influenza virus. However, in
      vitro growth of influenza virus in MDCK cells or viability of the virus was not
      affected by these extracts or Gingyo-san. From these results Gingyo-san was shown
      to be an antiviral agent in mice infected with a lethal amount of a mouse-adopted
      strain of influenza A2 virus.

PMID- 10354818
TI  - The evaluation of antianaphylactic effect of Oryza sativa L. in rats.
AB  - This study was carried out to examine the effect of methanol extract of Oryza
      sativa L. (Dong-Jin in Korean, abbreviate as Os-DJ hereafter) on anaphylaxis. Os
      DJ (10(-5) to 1 g/kg) dose-dependently inhibited systemic anaphylaxis induced by
      compound 48/80 in rats. When Os-DJ was pretreated at concentration ranging from
      10(-5) to 1 g/kg, the serum histamine levels were reduced in a dose-dependent
      manner. Os-DJ (1 g/kg) also significantly inhibited local anaphylaxis activated
      by anti-dinitrophenyl (DNP) IgE. Moreover, Os-DJ dose-dependently inhibited the
      histamine release from rat peritoneal mast cells (RPMC) activated by compound
      48/80 or anti-DNP IgE. These results indicate that Os-DJ possess antianaphylactic
      activity by inhibition of histamine release from mast cells in vivo and in vitro.

PMID- 10354819
TI  - Ameliorative effect of an urinary preparation on acetaminophen and D
      galactosamine induced hepatotoxicity in rats.
AB  - The effect of oral administration of a preparation of human urine (PHU) on acute
      liver injury was examined in rats intoxicated with acetaminophen and D
      galactosamine. The results indicated that PHU protected the liver from
      acetaminophen and D-galactosamine-induced injury as judged by morphological and
      biochemical observation. An increase in lipid peroxide concentrations and
      decrease in protein concentrations occurred in the liver by D-galactosamine
      injection, PHU administration significantly prevented these changes.

PMID- 10354820
TI  - The influence of propolis ethanol extract on liver microsomal enzymes and
      glutathione after chronic alcohol administration.
AB  - Propolis designates a series of gums, resins and balms of viscous consistency,
      which are gathered by honeybees from certain parts, mainly the buds and barks of
      plants, especially those found on coniferous trees. Bees bring propolis back to
      the hive, where it is modified and mixed with other substances including the
      bees' own wax and salivary secretions. In this study, the influences of propolis
      ethanol extract on chronic alcohol induced liver microsomal enzyme changes were
      investigated. Three grams of alcohol was added to rats' daily diet for four weeks
      to induce chronic alcohol liver injuries, and two different doses of propolis
      ethanol extract were p.o. administrated three times per day on the 28th, 29th,
      and 30th day. During the period of propolis administration, the ethanol diet was
      continued. After sacrifice, the rat livers were excised for assay of microsomal
      enzymes activity, glutathione (GSH) concentration, glutathione-S-transferase
      (GSTase) and gamma-glutamylcysteine synthetase (gamma-GCSase) activity. It was
      found that 30 mg/kg of propolis ethanol extract significantly prevented the
      elevations of total cytochrome P-450 enzymes, NADPH-dependent cytochrome C
      reductase, aniline hydroxylation, 7-ethoxyresorufin hydroxylation (7-ERH), 7
      penthoxyresorufin hydroxylation (7-PRH), and lipid peroxidation induced by
      chronic ethanol administration. Additionally, propolis ethanol extract (100
      mg/kg) also induced GSTase and gamma-GCSase activities and decreased glutathione
      levels in the liver.

PMID- 10354821
TI  - Effect of garlic active principle, diallyl disulfide, on cell viability, lipid
      peroxidation, glutathione concentration and its related enzyme activities in
      primary rat hepatocytes.
AB  - This study investigated the effects of various concentrations and incubation time
      intervals of diallyl disulfide (DADS), the active principle of garlic, on: 1.
      cell viability, 2. lipid peroxidation, and 3. glutathione (GSH) concentration and
      its related enzyme activities of rat hepatocytes. According to the results of LDH
      leakage and microscopic examination, 0.5 and 1 mM DADS did not significantly
      affect the viability of hepatocytes. However, significant decrease in cell
      viability according to increased LDH leakage and significant changes in
      morphology of hepatocytes were observed at 2 mM DADS (P < 0.05). Lipid
      peroxidation was also detected when the hepatocytes were treated with 2 mM DADS.
      At 0.5 mM DADS, a higher GSH content was found in the hepatocytes although not at
      a statistically significant level. 0.5 and 1 mM DADS has little effect on the
      activities of glutathione-S-transferase (GST) and glutathione peroxidase (GPx);
      however a significant decrease in GST, GPx and glutathione reductase (GRd)
      activities was observed at 2 mM DADS. Once the media of 2 mM DADS was replaced
      with fresh medium at 24 hr treatment, the activities of GST, GRd and GPx were
      recovered, although they were still lower than the control values.

PMID- 10354822
TI  - Efficacy of shitei-to, a traditional Chinese medicine formulation, against
      convulsions in mice.
AB  - The anticonvulsant effects of Shitei-To and its components on maximal
      electroshock seizures and chemical convulsions were examined. Shitei-To
      significantly prolonged the latency to bicuculline (2.0 mg/kg, s.c.)-induced
      clonic convulsions. Repeated treatment with Shitei-To also significantly
      prolonged the latency to strychnine (1.5 mg/kg, i.p.)- and pentylenetetrazol (90
      mg/kg, i.p.)-induced clonic convulsions. On the other hand, Shitei-To had no
      effect on maximal electroshock seizures. Of the components of Shitei-To, Shitei
      had almost the same effect as Shitei-To against the clonic convulsions induced by
      the three chemical agents tested. These findings suggest that Shitei-To has
      anticonvulsant effects.

PMID- 10354823
TI  - Evaluation of the antioxidant activities of Erycibe obtusifolia.
AB  - Free radicals may be involved in various pathogenesis processes. Tissue damage
      and cellular toxicity of some chemicals mediated by oxygen free radicals can be
      monitored by studying the levels of lipid peroxidation in the tissues. The study
      reported here is to investigate the MDA concentrations in different tissues after
      various doses of Erycibe obtusifolia (EO) treatments. EO given at doses of 10, 20
      and 30 mg/kg body weight is experimentally tested through oral administration.
      The antioxidant effect of EO extract is assessed by the measurements of hepatic,
      renal and splenic lipid peroxides (measured as malondialdehyde; MDA) after
      treatments. The results show no significant time-related and dose-dependent
      increase or decrease of MDA concentrations in the liver, kidney and spleen after
      EO administrations, respectively. The peak of antioxidant activities is found on
      the first day and the 6 hrs after treatments for liver and kidney, respectively.
      In contrast, the MDA concentrations in spleen after EO administrations remained
      above the normal values. This result suggests that a high dose of EO
      administration may contribute a little antioxidant activity in both liver and
      kidney.

PMID- 10354824
TI  - Effect of panax notoginseng extracts on inferior sperm motility in vitro.
AB  - The purpose of this study was to investigate the effects of Panax notoginseng
      extracts on inferior sperm motility in vitro. Semen samples were collected from
      23 patients with sperm motility between 20% and 40%. The sperm count was over 20
      x 10(6)/ml in accordance with the World Health Organization standard. 1.0 mg/ml
      and 2.0 mg/ml of Panax notoginseng extracts including aqueous extract, n-butanol
      extract, and polysaccharide fraction on sperm motility and progression were
      evaluated by computer assisted semen analysis. The results demonstrated that
      sperm motility as well as progression on inferior sperm motility were enhanced at
      1 hour and 2 hours after incubation with all three types of extracts.

PMID- 10354825
TI  - [Tilidine retard--a new option for pain therapy].

PMID- 10354826
TI  - [Intensive care today: different clinical picture--different sedation method].

PMID- 10354827
TI  - [New strides in surgery].

PMID- 10354828
TI  - [Preventive surgery: cost-efficiency relationship--an introduction].
AB  - The problems of financial costs in our health care system have led to preventive
      surgery being criticized as well, since valid data regarding the value for
      patients are often missing. The decrease in resources should induce the physician
      to check the efficacy of his therapy in comparative studies, especially when
      taking preventive measures. To reach an optimum for the benefit of the patient it
      is ethically justifiable to also mention economic aspects in these studies in
      order to gain financial resources further on.

PMID- 10354829
TI  - [Preventive surgery of inherited colorectal cancer identified through molecular
      diagnosis].
AB  - Numerous inherited genetic changes predisposing to cancer have already been
      identified and the number is increasing. Accurate prediction of individual risk
      by means of molecular diagnosis implies clinical consequences in the treatment of
      cancer-predisposing syndromes. Using familial adenomatous polyposis (FAP) and
      hereditary non-polyposis colorectal cancer (HNPCC) as an example, we present here
      the underlying genetic changes that contribute to tumor development. These
      genetic alterations can be efficiently identified through molecular diagnostic
      techniques. Identification of the familial germline mutation permits one to
      distinguish mutation carriers from non-mutation carriers within affected families
      and results in individually tailored surveillance and prevention. Therefore,
      molecular diagnosis is making a contribution to the advances in preventive
      surgical therapy. The indications are discussed.

PMID- 10354830
TI  - [Carotid surgery for prophylaxis of ischemic stroke].
AB  - Every year more than 250,000 patients suffer from ischemic (80%) or hemorragic
      (20%) stroke. Some 40,000 of these strokes are induced by stenosis or occlusion
      of the extracranial carotid artery. Several randomized studies (NASCET, ECST,
      ACAS, etc.) have proved that operative removal of high-grade carotid stenoses is
      an effective method in the primary and secondary prophylaxis of ischemic stroke.
      Operative therapy is significantly better than medical therapy with thrombocyte
      aggregation inhibitors. The prerequisite for effective operative prophylaxis is a
      low perioperative stroke rate. Even though the prophylactic value of carotid
      thrombarterectomy (TEA) is obvious, only about 5% of all carotid-related strokes
      are prevented by this operation. Essential conditions for increased efficiency in
      carotid surgery are close cooperation with the neurologist and the internist,
      screening of patients with a high risk for ischemic stroke, sophisticated, mainly
      non-invasive diagnostics, and more operative capacity. Interventional methods
      (stent, PTA) have not yet been proved safe and effective. These methods should be
      employed only in special cases after interdisciplinary discussions or in
      randomized studies.

PMID- 10354831
TI  - [Prophylactic surgery of the musculoskeletal system].
AB  - Prophylactic surgery on the musculoskeletal system has a wide range of
      indications, for example posttraumatic or non-traumatic malalignment of the lower
      extremities, joint instabilities or bony lesions with the risk of fracture and
      secondary malignant change. The goals of treatment include pain relief, improved
      function and redistribution of the physiological mechanical forces. Clinical
      experience over the past three decades has defined the current role of
      realignment of the lower limbs. Recent technological advances have further
      improved the surgical ability to assess and select patients who are candidates
      for realignment osteotomy or joint stabilization.

PMID- 10354833
TI  - [Mammographic screening starting in the fifth or sixth decade of life].
AB  - Mammography is an established diagnostic procedure for breast cancer. Data
      concerning screening mammography are available from nine prospectively controlled
      trials, the largest series being presented from Sweden. Mammographic screening
      leads to a significant reduction of breast cancer of 30% in women ages 50-59
      years. In younger women (40-49 years) the benefit accounts to only 20% and has
      not proven to be statistically significant. Nevertheless, the major advantage of
      mammographic screening is detection of the non-palpable tumor < or = 10 mm in
      size. The treatment of these small breast carcinomas leads to long-term survival
      rates of > or = 90%. Mammographic screening programs have been introduced in the
      USA, Canada, Iceland and Sweden for women in their 5th decade of life. Starting
      yearly lifelong mammography-screening at the age of 40, the theoretical cancer
      induction by radiation exposure does not exceed 0.1%. Under highly qualified
      conditions, it should be possible to minimize false-positive and false-negative
      screening results. In Germany, screening-mammography is only introduced in
      patients at high risk for breast cancer. Based on medical data, mammography must
      be a part of screening for women with an average risk--starting at the age of 40,
      although there are still open questions needing further clinical research.

PMID- 10354832
TI  - [BRCA1 and BRCA2: mutations and other genetic changes--practical relevance].
AB  - Genetic predisposition is responsible for 5-10% of all breast cancer. Within the
      past 10 years the major susceptibility genes for breast cancer, BRCA1 and BRCA2,
      have been identified. Both genes are considered to be tumor-suppressor genes, but
      their function is poorly understood. Current genetic testing for mutated BRCA1
      and BRCA2 is the basis for estimating disease risk for women with a strong family
      history of breast cancer and will provide important information on the prevention
      and treatment of familial breast cancer.

PMID- 10354834
TI  - [Three-dimensional breast biopsy and surgery].
AB  - For the histological verification of suspicious non-palpable small breast tumors,
      the three-dimensional breast biopsy applied as cylindrical extirpation using the
      ABBI system is the optimal solution at present. Because of the possibility of
      performing mammography during the operation, errors of localization can be
      corrected and incorrect incisions avoided. Taking the three radiomorphologically
      leading symptoms into consideration--suspicious microcalcification, focal shadow
      and structural irregularity--it can be stated that the digital mammography of the
      ABBI system is more sensitive than the conventional one for detecting
      microcalcification, but focal shadow and structural irregularity are detected
      less well by digital technique. These structures should be preoperatively marked
      by using sonography. After the complete removal of suspicious microcalcification
      checked by digital mammography during the operation, residual tumor might be
      found in a second excision when histologically invasive or intraductal tumor
      terminations reach the excision margin (R1 resection). Thirteen invasive and 8
      intraductal carcinomas were found in 80 cases of cylindrical extirpation using
      the ABBI system. In 7 procedures carried out to exclude an in-breast recurrence,
      3 intraductal carcinomas and 1 invasive carcinoma were observed. In 8 of 12
      invasive carcinomas and in 1 of 5 intraductal carcinomas, breast-conserving
      therapy was indicated. Two cases of invasive carcinoma fulfilled the criteria
      applied (minimal tumor-free margin > 2 mm, no extensive intraductal component) to
      use the ABBI cylinder as lumpectomy without a second excision to follow.

PMID- 10354835
TI  - [Indications and contraindications for breast preservation in patients with
      breast cancer].
AB  - Roughly 70% of all patients with breast cancer can be treated by breast
      preserving procedures under optimal circumstances. Risk factors for the
      development of local recurrences are age, angioinvasion, poor differentiation of
      the tumor, negative steroid hormone receptors, extensive intraductal component
      and positive margins. Contraindications for breast preservation are large tumors
      without remission after preoperative chemotherapy, multicentricity, extensive
      intraductal component, large ductal carcinoma in situ, inflammatory breast cancer
      after preoperative chemotherapy, Paget disease and local recurrence after breast
      conserving surgery. Preoperative needle biopsy allows determination of nearly all
      of the risk factors. To further increase the rate of breast conservation,
      preoperative chemotherapy should be used more extensively.

PMID- 10354836
TI  - [The situation of oncological surgery in Germany in 1998: results of a current
      survey].
AB  - The situation of oncological surgery in Germany was evaluated by sending a
      questionnaire in January 1998 to 1979 registered surgical clinics. A total of 938
      responded and stated that they are involved in that field. In 72% of the
      departments oncological surgery adds up to 10-30% of their overall work. The
      proportion of oncological surgery correlated to hospital size and is highest in
      university clinics. Colorectal surgery is 93% and is the leading topographical
      field in oncological surgery. 73% of the hospitals regularly perform gastric
      tumor surgery. The proportion of hospitals with breast surgery is surprisingly
      high (45%). Many hospitals (54.6%) report neoadjuvant treatment regimens.
      Together with adjuvant therapy this rate amounts to 85.2%. The diagnostic
      spectrum of the hospitals involved in the inquiry is satisfactory. However, the
      modern possibilities of network and telecommunication are not sufficiently used.
      A second opinion is required predominantly in their own department or clinic, but
      not between centers. The surgeon's position concerning the speciality "surgical
      oncology" is ambivalent: only 35.3% of the department chiefs support this
      speciality--and over 90% of the departments reject the structural independence of
      "surgical oncology" from "visceral surgery".

PMID- 10354837
TI  - [Comparative study of oncological outcome quality in colorectal carcinoma-
      ranking by surrogate endpoint?].
AB  - The data of the German Prospective Multicenter Study of the Study Group
      Colorectal Carcinoma (SGCRC) were analyzed with regard to interinstitutional
      differences in 5-year survival by statistical methods adequate for ranking and
      observing anonymity. Furthermore, possible so-called surrogate endpoints that
      allow an assessment of definite outcome after surgical treatment earlier than
      after 5 years were also analyzed. This requires a separate analysis for rectal
      and colon carcinoma patients. For rectal carcinoma, the combination of the
      frequency of local tumor cell spillage during tumor resection (iatrogenous tumor
      perforation and/or incision into or through tumor tissue) and the rate of
      locoregional recurrences (within 2 years after surgery) could be demonstrated as
      reliable surrogate endpoint. For colon carcinoma, no reliable surrogate endpoint
      could be found. Surgical morbidity is not an indicator of definite outcome. A
      very low rate of surgical mortality does not ensure satisfactory long-term
      results in colorectal cancer surgery.

PMID- 10354838
TI  - [Diagnosis and therapy of second aortoenteric fistulas: results of 16 patients].
AB  - From January 1977 to July 1997, 16 patients with aorto/iliac-enteric fistulas
      underwent repair. The fistula became apparent at a mean of 51 months.
      Gastrointestinal bleeding was the main symptom in 11 cases, 4 patients had a
      cutaneous fistula, and 1 developed retroperitoneal bleeding. The preoperative
      diagnosis was established in one-half of the cases. Three patients had to be
      treated surgically on an emergency basis without a preoperative diagnosis because
      of bleeding, 7 patients were semi-urgent and 6 had elective surgery. In 3 cases
      treatment consisted only of local repair. In 6 patients we performed extra
      anatomic revascularization and in 7 patients we achieved restoration by in situ
      replacement after removal of all infected prosthetic material. Eight of 16
      patients survived the perioperative period. Local repair alone cannot be
      recommended. All 3 patients died. The mortality rates between extra-anatomic
      revascularization and in situ reconstruction are comparable.

PMID- 10354839
TI  - [Minimized polypropylene mesh for preperitoneal net plasty (PNP) of incisional
      hernias].
AB  - Repair of incisional hernias requires the extensive implantation of alloplastic
      materials. The extent of the scar tissue is markedly regulated by the amount and
      structure of the incorporated material and is responsible for the increased rate
      of local wound complications. Correspondingly, minimization of the alloplastic
      implants should be favorable. In a randomized, prospective clinical study, the
      early results were compared after implantation of either a minimized, low-weight
      (26.8 g/m2) mesh with a pore size of 5 mm or a common, heavy-weight (90.2 g/m2
      polypropylene) mesh with a pore size of 0.8 mm. Indicators for clinical
      suitability were the rate and volume of seroma, subjective paraesthesia, physical
      capability, abdominal wall compliance, and the histologically analyzed tissue
      reaction of samples removed on the occasion of revision operations. As result,
      the optimized, low-weight mesh showed a remarkable decrease in the rate of
      seroma, patient complaints, less restriction of abdominal wall mobility, and
      improved abdominal wall compliance as verified by 3D stereography. These clinical
      findings corresponded to a pronounced decrease in inflammation and scar reaction,
      indicating improved incorporation of the alloplastic material. No other major
      complications except for one recurrence have been found.

PMID- 10354840
TI  - [Photodynamic ablation and argon-plasma coagulation of premalignant and early
      stage malignant lesions of the oesophagus--an alternative to surgery?].
AB  - Eleven patients with high-grade mucosal dysplasia in a columnar-lined oesophagus
      and 2 patients with a squamous carcinoma (uT1) underwent photodynamic therapy
      (PDT) and argon-plasma coagulation (APC). For PDT, 5-aminolevulinic acid (5-ALA)
      was given orally (60 mg/kg) and treated endoscopically with a light dose of 150
      J/cm2 (100 mW/cm2) at 635 nm 4-6 h later. A second PDT was performed under the
      same conditions 2-3 weeks later. Patients who received APC were treated 4 times
      on average to reach radical Barrett mucosa eradication. All patients were
      consistently given medication to suppress acid production. No complications
      occurred in either group. Follow-up endoscopies and multiple biopsies for 3-42
      months showed squamous regeneration in the dysplastic columnar-lined oesophagus
      in all 11 patients. Two patients with squamous carcinoma were found to have a
      recurrence 9 and 12 months later. PDT with 5-ALA-induced endogenous prophyrins,
      as well as APC combined with omeprazole protection, can eradicate superficial
      high-grade dysplastic mucosa in Barrett's oesophagus. However, we did not succeed
      in destroying a manifest carcinoma.

PMID- 10354841
TI  - [Medical treatment and research on humans: ethical fundamentals of physicians'
      concerns].

PMID- 10354842
TI  - [Public health system in the United States].

PMID- 10354843
TI  - [Liver resection for non-colorectal, non-neuroendocrine hepatic metastases].
AB  - Over a period of 11 years a total of 140 liver resections for non-colorectal, non
      neuroendocrine hepatic metastases were performed in 127 patients (73 women, 54
      men; median age 53 years). There were 120 first, 14 second and 6 third liver
      resections. Primary tumors were: breast cancer (n = 34), leiomyosarcoma (n = 20),
      pancreatic cancer (n = 16), renal cell carcinoma (n = 13), melanoma (n = 9),
      gastric cancer (n = 9), lung cancer (n = 6) and adrenal cancer (n = 6) and
      miscellaneous tumors (n = 14). Extrahepatic tumor manifestation (including
      synchronous primary tumors) was found in 69/140 cases (49%); 61 of 120 patients
      with a first liver resection had extrahepatic tumor (51%). In the 120 first liver
      resections, 82 (68%) R0, 13 (11%) R1 and 25 (21%) R2 excisions were possible.
      Median survival after first liver resection was 20 months; after R0 resection a
      median survival of 28 months and after R1/2 resection of 8 months was achieved.
      The 5-year survival rate was 16% for the total group, 24% in patients with R0
      resection and 0% for R1/2 resections. After a second liver resection (n = 14)
      there was a median survival of 28 months (5-year-survival-rate of 21%) for all
      patients and of 41 months (5-year survival rate 38%) after R0 resection.
      Morbidity and mortality after the first liver resection were 32.5% and 5.8%,
      respectively. In patients without extrahepatic tumor at the time of the first
      liver resection a median survival of 32 months (5-year survival rate 25%) and 7
      months was achieved after R0 resection and R1/2 resection, respectively. In case
      of extrahepatic tumor the median survival was 24 months (5-year survival rate
      23%) for R0 resection compared to 8 months after R1/2 resection. These data
      suggest that not the presence of extrahepatic tumor but rather the possibility of
      a R0 resection is most decisive for the prognosis after liver resection. We
      conclude that patients with liver metastases of non-colorectal, non
      neuroendocrine tumors may benefit from liver resection. Similar to colorectal
      metastases, a second or third liver resection can be worthwhile in selected
      cases. Even in more unfavorable tumor entities, several cases of long-term
      survival were observed after surgical therapy. Therefore, the indication for
      liver resection should be considered carefully in every single case.

PMID- 10354844
TI  - Surgery for portal hypertension and transjugular intrahepatic portosystemic
      shunts in Germany: results of a national survey.
AB  - A national survey was conducted to determine the role of portosystemic shunt
      surgery and transjugular intrahepatic portosystemic shunt (TIPS) in Germany. A
      questionnaire was mailed to 1324 surgical units at 1273 hospitals, and 941
      responses (74%) were received. Interventional endoscopy for variceal bleeding is
      carried out predominantly (73%) in medical departments. From 1992 to 1997 the
      annual number of surgical shunts dropped from 253 to 120, whereas the respective
      numbers of TIPS increased from 202 to 920. In this 6-year period a total of 1042
      shunts and 3575 TIPS were reported by 109 and 64 centers, respectively. TIPS was
      applied mainly in university hospitals (88.9%), whereas shunt surgery was more
      broadly used in non-university hospitals (58.8%). Clearly, prospective randomized
      comparisons of TIPS and surgical shunts are needed to reveal which treatment is
      best in patients with variceal bleeding stratified for mortality risk and stage
      of liver disease. However, the decreasing number and experience with shunt
      surgery may impede such studies. Probably, liver transplant centers which
      currently do only 41.2% of shunt procedures are most familiar with surgery in
      portal hypertension and are therefore most appropriate to maintain quality and
      expertise in this palliative and demanding branch of surgery.

PMID- 10354845
TI  - [Long-term results after laparoscopic resection of colorectal carcinoma].
AB  - BACKGROUND: Laparoscopic techniques are currently used for curative resection of
      colorectal cancer although long-term results from controlled clinical trials are
      not available yet that prove laparoscopic procedures are adequate. METHODS: All
      patients who under-went a curative resection of a colorectal tumor from 1995 to
      1997 were included in a prospective cohort study to evaluate the short- and long
      term results. RESULTS: Laparoscopic colorectal resections were accomplished in 68
      patients. In only 3 patients was an adenoma (stage 0) found, and 10 patients had
      multiple liver metastases at the time of palliative resection. An oncological
      resection was performed in 55 patients. The average age was 62.8 +/- 14.6 years
      (29 female and 26 male patients). Eleven right colectomies, 1 left colectomy, 21
      sigmoid resections, 16 proctosigmoidectomies and 6 abdominoperineal resections
      were carried out. Two patients (3.6%) were lost during follow-up. The median
      follow-up was 27.1 months (range 9.1-45.1 months). No port-site metastases were
      found. Two patients who are still alive after sigmoid resection suffered from a
      recurrence. The first patient underwent only limited lymphadenectomy because of
      synchronous malignant lymphoma. The second patient developed bilateral lung
      metastases. Only one patient died during the follow-up period because of
      myocardial infarction. CONCLUSION: Although the follow-up is short, it seems that
      the recurrence rate is low. Controlled multicenter clinical trials are currently
      performed to evaluate whether laparoscopic surgery is really adequate to treat
      colorectal cancer.

PMID- 10354846
TI  - [Laparoscopic antireflux surgery for gastroesophageal reflux disease: report on a
      4-year experience].
AB  - In a period of 4 years between March 1994 and March 1998, 143 patients with
      gastroesophageal reflux disease (GERD) underwent laparoscopic antireflux surgery.
      According to manometric studies 76 patients had a short-floppy Nissen
      fundoplication, patients with impaired motility or paraesophageal hernias
      received a hemifundoplication (Toupet = 42, Dor/Thal = 25). Recurrent reflux
      symptoms appeared in 6.3% after mean 16.7 months follow-up (Nissen = 2.6%, Toupet
      = 2.3%, Dor/Thal = 24%, P < 0.01). Persistent dysphagia with reoperation occurred
      in 2.1% (Nissen = 2.6%, Toupet = 2.3%, Dor/Thal = 0%, n.s.). The assessment of
      Visick's score at the latest control showed the following: Visick I = 63.6%,
      Visick II = 30.1%, Visick III = 6.3%, Visick IV = 0%. The outcome of the
      operation was rated "excellent" or "good" by 91.6% of the patients.

PMID- 10354847
TI  - [Video-assisted thoracoscopic access in pleural empyema compared with mere chest
      tube drainage].
AB  - Video-assisted thoracoscopic (VAT) debridement is gaining importance in the
      fibrino-purulent phase of empyema thoracis. However, evaluation of this access
      compared with mere chest tube drainage or thoracotomy remains unsatisfactory. A
      total of 356 parapneumonic empyemas from 1986 to 1997 were retrospectively
      analyzed concerning the results after primary treatment (chest tube 225,
      thoracotomy 80, VAT 51). The three groups did not differ significantly for gender
      and associated diseases. Median age of the chest tube drainage group (54 years)
      was higher than for thoracotomy (43.5 years) or VAT (39 years). Median duration
      of chest tube treatment after thoracotomy (7 days) was shorter than after VAT (13
      days) or chest tube drainage (20 days) (P < 0.0001). The more invasive procedures
      were also superior to the lesser invasive treatment concerning duration of
      postoperative hospitalization, recurrence rate and treatment failures. In spite
      of its better results thoracotomy will be pushed back by VAT in the treatment of
      empyema thoracis. Acceptance of VAT is reflected in rising numbers of admissions.
      Based on these retrospective results we are planning a prospective multicenter
      trial to evaluate the indication for VAT in empyema thoracis.

PMID- 10354848
TI  - [Anal sphincter restoration using dynamic graciloplasty--results of 50 patients].
AB  - During the period from 1992 to 1998, 50 patients underwent anal sphincter
      restoration by dynamic graciloplasty for primary (n = 26) or secondary (n = 6)
      total anorectal reconstruction (TAR) following abdominoperineal rectal resection
      (APR) or acquired (n = 9) or congenital (n = 9) fecal incontinence, respectively.
      Forty-seven patients were operated on by a single-stage procedure using a
      modified technique for the muscle wrap ("split sling"). Muscle fiber
      transformation by controlled stimulation was achieved at the beginning of the
      learning curve within 8 weeks and in the meantime within 4 weeks. Rectal injury
      (n = 10) turned out to be the most serious postoperative complication and was
      observed mainly in patients following TAR (n = 8). As the most prominent
      functional problem constipation in patients following TAR hampered the
      postoperative functional result; however, this was overcome by regular enemas. An
      improvement in the continence status was observed in 80% of the patients treated
      for fecal incontinence, and following APR 66% of the patients had acceptable
      results without a permanent colostomy.

PMID- 10354849
TI  - [Mesentericoportal Rex-shunt as a treatment for extrahepatic portal vein
      thrombosis].
AB  - The most common cause of portal hypertension in children with healthy livers is
      the prehepatic block. A 7-year-old girl had presented with portal vein thrombosis
      after umbilical vein catheterization in the newborn period. She suffered from
      collateral circulation with recurrent bleeding episodes due to esophageal varices
      (stage III-IV) and developed hypersplenism. Ultrasound demonstrated an open
      branch of the left portal vein. Direct splenoportography showed an open and
      communicating superior mesenteric vein. Liver biopsy was normal. An autologous
      left jugular vein graft was used to create a bypass from the superior mesenteric
      vein to the umbilical portion of the left intrahepatic portal vein
      (mesentericoportal Rex-shunt). Postoperatively, normal intrahepatic portal vein
      flow was demonstrated by ultrasound. After 2 years of follow-up, the patient is
      asymptomatic with no signs of portal hypertension. In contrast to classic
      portosystemic shunt operations, this bypass restores physiological portal vein
      flow, thus avoiding the possible consequences of longterm portosystemic shunting
      and low-grade encephalopathy.

PMID- 10354850
TI  - [The wound care center in surgery: an interdisciplinary concept for diagnostic
      and treatment of chronic wounds].
AB  - In Germany there is no standardized wound care for patients with chronic wounds
      in specialized centers. We have established a wound care unit for the past 6
      years. The principal concept of therapy was characterized by standardized local
      surgery, moist wound dressings and concomitant treatment of the underlying
      disease. We performed local therapy, coordinated the interdisciplinary treatment
      and developed a new wound documentation system for quality control. We
      established a close network, integrating general practitioners and home care
      organizations to realize a mainly outpatient treatment supported by short
      hospital therapy. Exclusive outpatient treatment was performed in 42% of all
      patients. According to our prospective data, we achieved an improvement in wound
      care: 69% of the wounds resistant to therapy for a mean of 30 months healed
      within 12 months after therapy according to our protocol. Our data strongly
      supported the importance of local surgery: neither wound depth nor wound
      infection had any influence on the healing rate, presumably due to radical
      excisional debridement of necrotic tissue. The presented data justify on medical
      and economic grounds the establishment of such wound care centers in Germany.

PMID- 10354851
TI  - [Life-cycle assessment of single-use versus reusable surgical drapes
      (cellulose/polyethylene-mixed cotton system)].
AB  - Surgical drapes made of cotton are under increasing competition with various
      disposable products and reusable draping systems (e.g., made of synthetic fabrics
      like polyester). When making a choice to use one of these medical devices in
      practical surgery, major aspects like handling, hygienic safety and costs, but
      also environmental effects have to be taken into account. In this study a mixed
      system for patient drapes (reusable cotton drapes combined with a reduced set of
      impermeable single-use drapes made of cellulose/polyethylene) was compared to a
      system that is only based on single-use drapes with regard to ecology [life-cycle
      assessment (LCA)]. The medical literature was reviewed to assess important
      medical aspects of the use of patient drapes, resulting in the statement that
      there are no conclusive arguments to support a clear hygienic superiority of one
      of these alternatives. Based on the conditions assumed and stated, the results of
      the LCA indicate that the mixed draping system is associated with two times more
      total energy consumption. In addition, more water is needed and more CO2
      emissions are produced. However, draping with the single-use product results in
      more clinical waste. Regarding water pollution no system proved superior. It is
      difficult to compare and weigh various environmental aspects like the polluting
      cultivation of cotton in distant countries (reusable drapes) and the higher
      figure of transportation necessary to deliver the single-use product within
      Germany. It is an important disadvantage of the mixed system that it combines the
      ecological burden of both cotton drapes and the single-use alternative.

PMID- 10354852
TI  - [The struggle with the ego: the assessment center in the selection of physicians
      in-chief].
AB  - The assessment center (AC), which played an important role in the recruitment of
      officers at the beginning of the century, nowadays is used in the business for
      the selection of managers. Also in the medical institutions the AC is of
      increasing significance, since the accentuation of economic aspects have led to a
      change in the qualities expected of a physician in chief. Usually the AC in the
      classic form is not applied; more often, hospitals take advantage of professional
      counselors who obviously use the basic elements of the AC. Physicians who are
      concerned are recommended to study the essence of the AC.

PMID- 10354853
TI  - [How expensive are thoracic surgical procedures? Comment on letter to the editor
      from Kraus T in Chirurg 1999 70:78)].

PMID- 10354854
TI  - [Oncologic principles associated with colon carcinoma. Diagnosis, therapy and
      follow-up].

PMID- 10354855
TI  - Detection of ileS-2 gene encoding mupirocin resistance in methicillin-resistant
      Staphylococcus aureus by multiplex PCR.
AB  - The presence of the ileS-2 gene, responsible for mupirocin resistance, in
      clinical isolates of methicillin-resistant Staphylococcus aureus was determined
      by multiplex polymerase chain reaction. Three pairs of primers were used, which
      yielded specific fragments of femA (encoding a unique feature of S. aureus), mecA
      (encoding resistance to methicillin) and ileS-2 genes. The multiplex polymerase
      chain reaction system is an easy and time-saving technique that, together with a
      rapid method for DNA extraction by boiling, may be incorporated as a routine
      analysis in clinical diagnostic laboratories.

PMID- 10354856
TI  - Rapid detection of the mecA gene in methicillin resistant staphylococci using a
      colorimetric cycling probe technology.
AB  - A Cycling Probe Technology (CPT) assay was developed for the detection of the
      mecA gene from methicillin resistant staphylococcal cultures. The assay is based
      on a colorimetric enzyme-immuno-assay (EIA) and uses a mecA probe (DNA-RNA-DNA)
      labeled with fluorescein at the 5'-terminus and biotin at the 3'-terminus. The
      reaction occurs at a constant temperature that allows the target DNA to anneal to
      the probe. RNase H cuts the RNA portion, allowing the cut fragments to dissociate
      from the target, making it available for further cycling. CPT-EIA uses
      streptavidin-coated microplate wells to capture uncut probe followed by detection
      with horseradish-peroxidase conjugated anti-fluorescein antibody. The assay was
      compared to PCR and shown to accurately detect the presence or absence of the
      mecA gene in 159 staphylococcal clinical isolates. The CPT-EIA assay takes two
      hours starting from cultured cells compared with the 24-48 h required for
      detection of methicillin resistance by conventional susceptibility tests.

PMID- 10354857
TI  - Comparative antimicrobial activity of gatifloxacin tested against Streptococcus
      spp. including quality control guidelines and etest method validation. Quality
      Control Study Group.
AB  - Gatifloxacin (formerly AM-1155 or CG 5501) is a new 8-methoxy fluoroquinolone
      with enhanced activity against Gram-positive cocci, especially Streptococcus
      pneumoniae and other streptococci. Recent clinical strains (599 isolates) were
      tested against gatifloxacin, three comparison fluoroquinolones, and penicillin by
      the reference broth microdilution, Etest (AB BIODISK, Solna, Sweden) and
      standardized disk diffusion methods (5 micrograms gatifloxacin disk).
      Gatifloxacin (MIC90, 0.5 microgram/ml) activity was generally comparable to that
      of trovafloxacin (MIC90, 0.25 microgram/ml), or sparfloxacin (MIC90, 0.5
      microgram/ ml) and markedly superior to ofloxacin (MIC90, 2-4 micrograms/ml)
      against the streptococci. Rates of penicillin non-susceptibility were 41.9, 38.0,
      and 16.2% for S. pneumoniae (301 strains), viridans group streptococci (150
      strains), and beta-haemolytic streptococci (148 strains). Etest results
      correlated well (95.7-100.0% +/- one log2 dilution) with the reference MIC
      results, but Etest tended to have elevated gatifloxacin MIC results compared to
      the broth microdilution method for the highly resistant isolates (MICs, > 2
      micrograms/ml). Gatifloxacin disk zone diameters correlate well to reference MICs
      for all streptococci and proposed interpretive criteria (susceptible at < or = 1
      microgram/ml or > or = 18 mm, and resistant at > or = 4 micrograms/ml or < or =
      14 mm) did not produce discords between method results (absolute agreement). A
      nine laboratory quality control (QC) study conforming to the National Committee
      for Clinical Laboratory Standards (NCCLS) Guideline M23-T3 studied S. pneumoniae
      ATCC 49619 and gatifloxacin. Proposed ranges for QC of NCCLS tests were 0.12-0.5
      microgram/ml for the broth microdilution test and 24-31 mm for the disk diffusion
      method. These reported results indicate that gatifloxacin was a potent
      fluoroquinolone with extensive activity against streptococcal isolates. In vitro
      test methods to measure this activity appear accurate and comparable; and QC
      guidelines have been established for routine clinical laboratory use pending
      approval by the NCCLS and the Food and Drug Administration (FDA).

PMID- 10354858
TI  - Comparative antimicrobial activity of gatifloxacin tested against Campylobacter
      jejuni including fluoroquinolone-resistant clinical isolates.
AB  - Campylobacter jejuni is an important pathogen that causes gastroenteritis, as
      well as other disease states such as meningitis and septic arthritis. In this
      study, the Etest (AB BIODISK, Solna, Sweden) results were compared to a reference
      agar dilution method using gatifloxacin, a new 8-methoxyfluoroquinolone. A total
      of 53 strains of C. jejuni initially isolated from patients in California and
      Mexico were tested. Results demonstrated a high correlation (r = 0.88) between
      the two utilized in vitro dilution methods. In addition, gatifloxacin activity
      was compared to that of ciprofloxacin, metronidazole, amoxicillin, erythromycin,
      chloramphenicol, gentamicin, tetracycline, and trimethoprim/sulfamethoxazole
      using the Etest. Gatifloxacin (MIC90, 4 micrograms/ml) was approximately eight-
      to 16-fold more potent than ciprofloxacin (Mic90, > 32 micrograms/ml), a commonly
      used fluoroquinolone for Campylobacter infections. Eight strains highly resistant
      to ciprofloxacin (MIC90, > 32 micrograms/ml) were tested for cross resistance
      against the newer fluoroquinolones (gatifloxacin, levofloxacin, trovafloxacin)
      and the rank order of potency was: gatifloxacin (MIC50, 16 micrograms/ml) >
      trovafloxacin = levofloxacin (MIC50, > 32 micrograms/mL). However, only 25%
      ciprofloxacin-resistant strains were inhibited by < or = 1 microgram/mL of
      gatifloxacin or trovafloxacin. These results for gatifloxacin against C. jejuni
      strains must be further assessed in the context of in vivo trials before the
      clinical role of this new fluoroquinolone can be determined. The Etest appears to
      be a simple and precise susceptibility test method for testing C. jejuni isolates
      against fluoroquinolones and other alternative therapeutic agents.

PMID- 10354859
TI  - Antimicrobial activity and spectrum of SCH27899 (Ziracin) tested against gram
      positive species including recommendations for routine susceptibility testing
      methods and quality control. Quality Control Study Group.
AB  - SCH27899 is an oligosaccharide, everninomicin antibiotic with activity primarily
      against Gram-positive pathogens. The activity of SCH27899 was evaluated against
      360 routine clinical isolates by the broth microdilution (BMD), agar dilution
      (AD), disk diffusion (DD), and Etest (AB BIODISK, Solna, Sweden) methods. In
      addition, results from a nine center SCH27899 quality control (QC) trial were
      used to establish QC ranges. SCH27899 MICs for 330 Gram-Positive strains,
      including multiply-resistant staphylococci and enterococci, ranged from 0.015 to
      1 microgram/ml with MIC90s of 0.12 to 0.5 microgram/ ml. SCH27899 had no
      measurable activity against the 30 selected Gram-negative strains tested (MICs, >
      256 micrograms/ml), with the exception of Moraxella catarrhalis MICs, 0.12
      microgram/ ml). Etest MICs for SCH27899 correlated well with AD and BMD results
      with > 90% of MICs within +/- one log2 dilutions of the reference test results.
      Three disk concentrations (2.5-, 5-, 10-microgram) of SCH27899 were evaluated,
      but minimal difference of zone diameters between disk drug contents was observed
      (+/- 2 mm). SCH27899 disk zone diameters correlated poorly with reference MICs
      due to small zone diameters (range, 11 to 22 mm) attributed to poor diffusion
      through agar mediums, a product of this compound's high molecular weight and
      solubility. The use of the DD method for SCH27899 was not recommended. The
      proposed MIC quality assurance limits for SCH27899 using Staphylococcus aureus
      ATCC 29213 and Enterococcus faecalis ATCC 29212 was 0.06 to 0.25 microgram/ml for
      both QC strains and methods. SCH27899 appears to be a eveminomicin-derivative
      widely active against important Gram-positive cocci, and in vitro dilution
      testing methods would be preferred for clinical use, validated by the recommended
      MIC control ranges cited in this report.

PMID- 10354860
TI  - Use of cerebrospinal fluid shunt for the management of elevated intracranial
      pressure in a patient with active AIDS-related cryptococcal meningitis.
AB  - Persistently elevated intracranial pressure (ICP) is one of the most accurate
      predictors of a poor prognosis in patients with AIDS-related cryptococcal
      meningitis. We present a severe case of persistent cryptococcal meningitis in a
      patient with advanced AIDS, complicated by elevation of ICP. A
      ventriculoperitoneal shunt was placed that successfully lowered the ICP and
      alleviated the associated symptoms. The elevated ICP secondary to AIDS-related
      cryptococcal meningitis should be treated aggressively. Despite the risk of shunt
      complications, cerebrospinal fluid shunts can be considered in these patients if
      they do not respond to other treatment.

PMID- 10354861
TI  - Actinomyces viscosus postoperative endophthalmitis.
AB  - Endophthalmitis, attributable to Actinomyces viscosus, developed in a 78-year-old
      man after cataract surgery. Postoperative endophthalmitis with this organism is a
      rare occurrence. This report emphasizes the importance of the Actinomyces species
      as potential eye pathogens and presents antimicrobial susceptibility data for the
      isolate.

PMID- 10354862
TI  - In vitro activity of linezolid against vancomycin-resistant enterococci,
      methicillin-resistant Staphylococcus aureus and penicillin-resistant
      Streptococcus pneumoniae.
AB  - We report the activity of the new oxazolidinone antimicrobial agent linezolid
      against 37 clinical isolates of vancomycin-resistant enterococci (including
      organisms carrying the vanA, vanB, vanC-1, and vanC-2/3 genes), 26 clinical
      isolates of methicillin-resistant S. aureus and 20 clinical isolates of high
      level penicillin-resistant S. pneumoniae. All isolates of vancomycin-resistant
      enterococci were inhibited by < or = 4 ug/ml of linezolid. All isolates of
      methicillin-resistant S. aureus were inhibited by < or = 8 ug/ml of linezolid.
      All isolates of penicillin-resistant S. pneumoniae were inhibited by < or = 2
      ug/ml of linezolid. Linezolid inhibits strains of multidrug resistant Gram
      positive cocci in vitro at concentrations < or = 8 ug/ml.

PMID- 10354864
TI  - The return of tuberculosis.
AB  - At the end of the 20th century, tuberculosis remains a major public health issue.
      In developing countries tuberculosis is a leading cause of morbidity and
      mortality, and the spread of the HIV epidemic contributes significantly to the
      worsening of the situation. Coinfection with tuberculosis and HIV results in
      special diagnostic and therapeutic problems and uses up larger amounts of medical
      resources in developing countries. Outbreaks of multidrug resistant tuberculosis
      (MDR-TB) were first reported from US-American centers caring for HIV patients,
      but have now been observed in many other countries. In Western Europe the
      tuberculosis epidemic is under control, but increasing incidence rates in
      migrants raise new problems in these countries. Tuberculosis is uncontrolled in
      large parts of the former Soviet Union due to the socio-economic break-down in
      these countries. Only rigorous infection control measures on a world-wide scale
      will prevent further detoriation of this situation. Therefore, the extension of
      surveillance systems, and sufficient funding for the prevention, diagnosis, and
      treatment of tuberculosis by national governments and international organizations
      are all urgently needed.

PMID- 10354863
TI  - Evaluation of the in vitro activity of six broad-spectrum beta-lactam
      antimicrobial agents tested against over 2,000 clinical isolates from 22 medical
      centers in Japan. Japan Antimicrobial Resistance Study Group.
AB  - Numerous broad-spectrum beta-lactam antimicrobial agents have been introduced
      into medical practice since 1985. Although several of these compounds have
      advanced, infectious disease therapy resistances to them has also emerged world
      wide. In 1997, a Japanese 22 medical center investigation was initiated to assess
      the continued utility of these agents (oxacillin or piperacillin, ceftazidime,
      cefepime, cefpirome, cefoperazone/sulbactam [C/S], imipenem). The participating
      medical centers represented a wide geographic distribution, and a common protocol
      and reagents were applied. Three control strains and a set of challenge organisms
      were provided to participant centers. Etest (AB BIODISK, Solna, Sweden) strips
      were used in concurrent tests of these organisms and a qualitative determination
      of participant skills in the identification of resistant and susceptible
      phenotypes was established. The quantitative controls demonstrated 97.7-99.2% of
      MIC values within established QC limits, and the qualitative (susceptibility
      category) controls documented a 97.3% agreement of participant results with that
      of reference values (1,320 total results). Only 0.2% of values were false
      susceptible errors. After the participant quality was assured, a total of 2,015
      clinical strains were tested (10 strains from 10 different organism groups
      including methicillin-susceptible Staphylococcus aureus and coagulase-negative
      staphylococci [CoNS], Escherichia coli, Klebsiella spp., Citrobacter freundii,
      Enterobacter spp., indole-positive Proteae, Serratia spp., Acinetobacter spp.,
      and Pseudomonas aeruginosa). The staphylococci were uniformly susceptible to all
      drugs tested except ceftazidime (MIC90, 24 micrograms/ml) that had a potency six-
      to 12-fold less than either cefepime or cefpirome. Only 3.7 and 45.1% of S.
      aureus and CoNS were susceptible to ceftazidime, respectively. Among E. coli and
      Klebsiella spp. the rank order of antimicrobial spectrum was imipenem = "fourth
      generation" cephalosporins > ceftazidime > C/S > piperacillin. Possible extended
      spectrum beta-lactamase phenotypes were identified in 2.9-8.6% of these isolates.
      Isolates of C. freundii, Enterobacter spp., Proteae, and Serratia spp. that were
      resistant to ceftazidime and piperacillin remained susceptible to imipenem (0.0
      4.5% resistance) and cefepime (0.0-5.0%). Acinetobacters were inhibited best by
      C/S (99.5% susceptible) and least susceptible to piperacillin (MIC90, > 256
      micrograms/ml; 21.7% susceptible) activity. P. aeruginosa isolates were most
      susceptible to cefepime (83.6%) and this zwitterionic cephalosporin also had the
      lowest level of resistance (9.1% of MICs at > or = 32 micrograms/ml). Several
      multi-resistant organisms were identified in participant medical centers
      including S. marcescens strains resistant to cefepime, imipenem, or both observed
      in six hospitals. Clonal spread was documented in two medical centers; one
      hospital having two distinct epidemic clusters. Also a multi-resistant E. cloacae
      was found in two patients in the same hospital. Evaluations of carbapenem
      resistance in four species discovered only two strains (in same hospital) among
      40 P. aeruginosa isolates (5.0%) with a metallo-enzyme, with nearly all of the
      remaining strains inhibited by an Ambler Class C enzyme inhibitor (BRL42715)
      indicating a hyperproduction of a chromosomal cephalosporinase. These results
      indicate that most newer beta-lactams remain widely useable in medical centers in
      Japan, but emerging often clonal, resistances have occurred. The overall rank
      order of antimicrobial spectrum against all ten tested bacterial groups favors
      the "fourth-generation" cephalosporin, cefepime (96.4% susceptible) as an equal
      to imipenem (95.9%) > C/S (90.9%) = cefpirome (90.0%) > ceftazidime (75.1%) =
      penicillins, either oxacillin or piperacillin (76.4%).

PMID- 10354865
TI  - Immunological defense mechanisms in tuberculosis and MAC-infection.
AB  - Protective immunity to mycobacterial infections develops in immunocompetent hosts
      after activation of alpha beta- and gamma delta-T cells in association with the
      generation of a protection-specific cytokine profile that stimulates the
      bactericidal potential of the macrophages. The maintenance of a delicate balance
      between Th1 and Th2 response is decisive for infection control and prevention of
      exacerbation of disease. Mycobacterial infection in the immunocompromised host is
      mainly due to the diminished cellular immune function. In addition,
      nontuberculous mycobacteria isolated from AIDS patients have special virulence
      factors that promote development of disease by further compromising the function
      of an already damaged cytokine network.

PMID- 10354866
TI  - Malnutrition in tuberculosis.
AB  - Tuberculosis has a dramatic effect on nutritional state and this has been borne
      out in all the studies that have investigated body composition in affected
      patients. I have included some of the key studies in this review; those I have
      not cited generally reach the same conclusions. Such malnutrition undoubtedly
      contributes to the morbidity of the disease and may also contribute to mortality,
      particularly in resource-poor settings where nutritional state, even in the
      "healthy," may be parlous. The extent to which such malnutrition also contributes
      to pathology remains unclear. Certainly, in other models, nutritional depletion
      has a major impact on immune function (Chandra, 1997) and depression of
      lymphocyte function cannot be a desirable commodity in an individual fighting
      invasive mycobacterial infection. Considering the reverse relationship, there is
      good evidence, both at the population level and at the clinical level, for the
      effect of primary malnutrition on tuberculosis, both to increase frequency of
      occurrence and to exacerbate clinical manifestations. It has not been possible to
      explore this relationship within the context of this paper but it is clearly an
      important aspect of the bi-directional relationship between tuberculosis and
      malnutrition. There is still more to be understood about the pathophysiology of
      the wasting seen in chronic infections such as tuberculosis but it is clear that,
      in addition to good anti-tuberculous therapy, such patients need a good supply of
      nutrition during the treatment/recovery phase. In the developed world, this may
      include medical measures to achieve nutritional support whereas in resource-poor
      settings, nutritional intake may have more to do with equitable resource
      distribution and community involvement in health care.

PMID- 10354867
TI  - Nipple discharge disorders: current diagnostic management and the role of fiber
      ductoscopy.
AB  - Nipple discharge disorders is a field in which there has been both increasing
      awareness on the part of patients and advances in management. Today secretion
      from nipples can be classified according to its color, cellularity and biology.
      To be significant a discharge should be true, spontaneous, persistent and non
      lactational. Moreover there are methods to differentiate patients who require
      surgical intervention from those who do not. Surgically significant nipple
      discharges are watery, serous (yellow), serosanguineous and bloody. Cytology
      smears of discharge material have helped to classify the cellular material,
      providing information about normality, atypia and malignancy and also about
      papillary formation of the exfoliated cells. Tests such as Hemoccult help to
      discover occult blood in the secreted fluid. Modern immunological tests can be
      performed on cytology smears where occurrence of high levels of carcinoembryonic
      antigen could indicate a latent malignancy. Galactography investigation is today
      the state-of-the-art approach to investigate patients with nipple discharge
      disorders and this examination can demonstrate the size, location and extent of
      an intraductal abnormality. Modern high-resolution ultrasound techniques are
      helpful in visualizing intraductal disorders and are becoming a good
      complementary approach if not an alternative to traditional radiology techniques.
      Recently even MR galactography has been shown to be of diagnostic value, but not
      as informative as regular galactography. The most sophisticated investigation
      method, which can also be used therapeutically, is fiber-ductoscopy of the
      concerned duct in a breast. This technique, although expensive and in its
      infancy, is a fascinating and promising approach for inspecting the intraductal
      lumina. In this article the background, current investigation methods and
      possibilities of the technique are described, as well as the most sophisticated
      ways to deal with nipple discharge disorders in human breasts.

PMID- 10354868
TI  - Storage phosphor and film-screen mammography: performance with different
      mammographic techniques.
AB  - The aim of this study was to compare the image quality of storage phosphor plates
      with that in screen-film radiograms in mammography. Two anode/filter combinations
      were also compared--Mo/Mo and W/Rh. S Storage phosphor plates, generation IIIN
      (Fuji, Tokyo, Japan) and a conventional screen-film system (Kodak, Rochester, N.
      Y.) were evaluated using two mammographic units. One unit had a 0.6-mm focal
      spot, an anode/filter combination of Mo/Mo and no grid (AMo); the other had a 0.3
      mm focal spot, a grid, and two possible combinations of anode/filter Mo/Mo (BMo)
      and W/Rh (BW). Simulated tumours and microcalcifications were randomly positioned
      in an anthropomorphic breast phantom (RMI model 165, no. 210-009, Radiation
      Measurements Inc., Middleton, Wisconsin). The image quality was evaluated using a
      modified version of receiver operating characteristics analysis. Five observers
      evaluated 300 films and 300 hard copy images each. Radiation doses were also
      determined. The image quality of the conventional screen-film images was
      significantly better than that for the storage phosphor plate mammograms. The BMo
      system rated best, for the detection of both tumours and microcalcifications,
      although it was not significantly different from the BW system. Systems BMo and
      BW rated significantly better than the AMo system for both image receptors
      studied. The mean absorbed dose was twice as high for the BMo system as for the
      AMo and BW systems for both conventional and digital technique. The mammograms
      produced with the screen-film combination gave a significantly better
      detectability than the storage phosphor plates used in this study. Substantial
      dose reduction could be achieved using an anode/filter combination of W/Rh
      instead of Mo/Mo with no significant loss of information in the images.

PMID- 10354869
TI  - Von Hippel-Lindau disease: strategies in early detection (renal-, adrenal-,
      pancreatic masses).
AB  - Von Hippel-Lindau disease (VHL) is a hereditary syndrome characterized by a
      predisposition for bilateral and multicentric retinal angiomas, hemangioblastomas
      in the central nervous system (CNS), renal cell carcinomas, pheochromocytomas,
      islet cell tumors of the pancreas, and endolymphatic sac tumors, as well as cysts
      in the kidney, pancreas, and epididymis. This review focuses on developments in
      imaging of renal, adrenal, and pancreatic masses in VHL. Radiology still has a
      central place in managing of VHL. Radiologists should therefore be aware of the
      importances of MRI, CT, and US compared with other radiodiagnostic tools for
      these three organs. Since a conservative approach to the treatment of VHL lesions
      is now becoming more widely accepted, ongoing follow-up by careful radiological
      screening with US, and especially with MRI, will play a central role in managing
      the disease. We also give an overview of recent advances in the molecular biology
      of VHL, because the combination of imaging with (presymptomatic) DNA analysis has
      made early detection and screening of lesions possible and led to a reduction in
      morbidity and mortality.

PMID- 10354870
TI  - Renal trauma in occult ureteropelvic junction obstruction: CT findings.
AB  - The aim of this study was to present CT findings of occult ureteropelvic junction
      obstruction in patients with renal trauma and to describe the clinical signs and
      singular CT features that are characteristically observed with trauma and are
      relevant to management of these patients. We retrospectively reviewed 82 helical
      CT studies in patients with renal trauma referred to our institution. We found 13
      cases of occult preexisting renal pathology, six of which were occult
      ureteropelvic junction obstructions. The clinical presentation, radiologic
      findings of trauma according to the Federle classification, and CT findings of
      obstructed ureteropelvic junction are presented. We found three category-I
      lesions (one in horseshoe kidney), two of them treated with nephrostomy because
      of increased ureteropelvic junction obstruction due to pelvic clots; two category
      II lesions (parenchymal and renal pelvis lacerations) that had presented only
      with microhematuria; and one category-IV lesion (pelvic laceration alone). Pelvic
      extension was demonstrated in all the cases with perirenal collections. The CT
      studies in all the cases with suspected ureteropelvic junction obstruction showed
      decreased parenchymal thickness and enhancement, and dilatation of the renal
      pelvis and calyx, with a normal ureter. Computed tomography can provide
      information to confidently diagnose underlying ureteropelvic junction obstruction
      in renal trauma, categorize the traumatic injury (at times clinically silent) and
      facilitate proper management according to the singularities observed, such us
      rupture of the renal pelvis alone (Federle category IV) and increasing
      ureteropelvic obstruction due to clots which can be decompressed by nephrostomy.

PMID- 10354871
TI  - Multiple renal aspergillus abscesses in an AIDS patient: contrast-enhanced
      helical CT and MRI findings.
AB  - Renal insufficiency or allergic reactions for X-ray contrast agents are frequent
      limitations in immunocompromised hosts such as neutropenic or AIDS patients. Due
      to a better tolerance of contrast agents in MRI, this technique is well suited
      for investigation of parenchymal organs. We demonstrate an allergic AIDS patient
      who presented with fever and flank pain. At sonography, anechoic renal lesions
      were supposed to be non-complicated cysts; however, on T2-weighted MRI, the
      center was of high signal. Dynamic contrast-enhanced MRI of the kidneys
      demonstrated an enhancing rim with ill-defined margins. The lesions were supposed
      to be multiple bilateral abscesses. Due to the multiple dynamic contrast series,
      a delayed enhancement of renal parenchyma was detectable adjacent to the lesion.
      This was suggested as accompanying local pyelonephritis and an infectious
      etiology became more reliable. Aspergillus fumigatus was identified by CT-guided
      biopsy as the underlying microorganism. The MR appearance of this manifestation
      has not been described previously.

PMID- 10354872
TI  - Detection and quantification of coronary artery calcification with electron-beam
      and conventional CT.
AB  - To identify patients with increased risk of having coronary artery disease (CAD),
      electron-beam computed tomography (EBCT) was used for years for quantifying
      calcifications of the coronary arteries. The first direct comparison between EBCT
      and conventional CT was performed to determine the reliability of widely
      available conventional CT for the assessment of the coronary calcium score. Fifty
      male patients with suspected CAD were investigated with both modalities, EBCT and
      conventional 500-ms non-spiral partial scan CT. Scoring of the coronary
      calcification was performed according to the Agatston method. Forty-two of these
      patients underwent coronary angiography for the assessment of significant luminal
      narrowing. The correlation coefficient of the score values of both modalities was
      highly significant (r = 0.982, p < 0.001). The variability between the two
      modalities was 42%. Mean calcium score in patients with significant coronary
      luminal narrowing (n = 37) was 1104 +/- 1089 with EBCT and 1229 +/- 1327 with
      conventional CT. In patients without luminal narrowing (n = 5) mean calcium score
      was 73 +/- 57 with EBCT and 26 +/- 35 with conventional CT. Although images of
      the heart from conventional CT may suffer from cardiac motion artifacts,
      conventional CT has the potential to identify patients with CAD with accuracy
      similar to EBCT.

PMID- 10354873
TI  - First results of computerised tomographic angiography using electron beam
      tomography.
AB  - The aim of this study was to evaluate the suitability of electron beam tomography
      (EBT) with fast continuous volume scanning for CT angiography (CTA) in chest and
      abdomen. An Evolution XP EBT scanner with a new software version (12.34) was
      used. One hundred forty images per study can be acquired in 17 s using 3-mm
      collimation and overlapping image reconstruction. Study protocols for five
      different clinical applications of EBT CTA were established and evaluated. The
      EBT CTA technique was performed in 155 patients. High- and homogeneous density
      values were achieved along the whole course of the vessels; the mean density in
      the aorta was > 240 HU. Coeliac axis, superior and inferior mesenteric artery,
      renal and lumbar arteries were visualised in all cases. Maximum intensity
      projection and shaded surface display reconstruction demonstrated the relation
      between aneurysm and aortic branches very well due to an excellent resolution
      along the z-axis. In large scan volumes overlapping image reconstruction
      demonstrated better resolution along the z-axis than is available with helical
      CT. The EBT CTA technique proved to be very well suited excellent suitability for
      evaluation of pulmonary vessels. Compared with helical CT, EBT CTA offers a
      shorter scan time, which allows higher contrast enhancement in pulmonary vessels.
      The identification of intraluminal emboli and mural thrombi has improved. The EBT
      CTA technique is a very reliable tool for evaluation of aortic disease and
      pulmonary vessels.

PMID- 10354874
TI  - Intimal hyperplasia within biliary Wallstents: failure of recanalisation by
      insertion of a second endoprosthesis.
AB  - We report two patients with benign biliary strictures in whom we attempted
      recanalisation of metallic biliary endoprostheses, occluded by intimal
      hyperplasia, by the insertion of further endoprostheses within the occluded
      stents. Initial technical success was achieved in deploying the stents and
      restoring patency with elimination of mural filling defects. However, we found
      the intimal hyperplasia to be restrained for less than 48 h. From our initial
      results it appears that biliary metallic stent occlusion by intimal hyperplasia
      is not effectively treated by insertion of a second endoprosthesis.

PMID- 10354875
TI  - Cardiac rhabdomyosarcoma: diagnosis by MR imaging.
AB  - We report a case of cardiac rhabdomyosarcoma the initial clinical features of
      which were pericardial effusion, clinical symptoms of congestive heart failure
      and probable pulmonary thromboembolism, in which echocardiography constituted the
      first approach to the diagnosis of cardiac tumor and MRI confirmed it, precisely
      delimiting the tumoral extension and possible infiltration of pericardiac
      structures. A brief literature review of this entity is given, the MRI findings
      obtained in our case are described, and we discuss the advantages and limitations
      of this technique as compared with other alternatives of image diagnosis.

PMID- 10354876
TI  - Diagnostic and therapeutic impact of MRI and arthrography in the investigation of
      full-thickness rotator cuff tears.
AB  - Investigation of shoulder pain is important before surgical treatment. The
      presence or absence of a full-thickness rotator cuff tear (FTRCT) may determine
      the type of surgical treatment. Both MRI and conventional arthrography can be
      used, but little is known about their relative diagnostic and therapeutic impact.
      We performed a prospective trial assessing: (a) the influence of MRI and
      arthrography results on the clinician's diagnostic thinking (diagnostic impact);
      (b) the influence of the results on the clinician's therapeutic thinking
      (therapeutic impact); and (c) the diagnostic performance of the two techniques in
      patients with surgical confirmation. A total of 104 consecutive patients with
      shoulder problems referred to a specialist orthopaedic shoulder clinic underwent
      pre-operative investigation with MRI and arthrography. The surgeon's diagnosis,
      diagnostic confidence and planned treatment were measured before the
      investigation, and then again after the results of each investigation. Before the
      presentation of the investigation, results, the patients were randomised into two
      groups. In one group MRI was presented first; in the other group, arthrography.
      The MRI results led to fewer changes in diagnostic category (14 of 46, 30%) than
      arthrography (20 of 54, 37%), but the difference was not significant (P > 0.5).
      Magnetic resonance imaging led to slightly more changes in planned management (17
      of 47, 36%) than arthrography (14 of 55, 25%), but again the difference was not
      statistically significant (P > 0.3). The results of the second investigation
      always had less diagnostic and therapeutic impact than the first. The accuracy of
      MRI for FTRCT in 38 patients with surgical confirmation was 79%, sensitivity 81%
      and specificity 78%; the accuracy of arthrography was 82%, sensitivity 50% and
      specificity 96%. The clinical diagnosis and management plan can be adequately
      defined by a single radiological investigation. Magnetic resonance imaging and
      arthrography had fairly similar diagnostic and therapeutic impact and comparable
      accuracy, although MRI was more sensitive and less specific. Magnetic resonance
      imaging may be the preferred investigation because of its better demonstration of
      soft tissue anatomy.

PMID- 10354877
TI  - Orientation of trabecular bone in human vertebrae assessed by MRI.
AB  - The aim of the study was to assess the relative number of bone trabeculae in
      different orientations by using magnetic inhomogeneity measurements by MR
      imaging. Twelve defatted human vertebrae (L2-L4) were studied by MR imaging and
      CT. In the MR measurements the reversible transaxial decay rate, R2', was
      determined using the GESFIDE sequence. The relative contribution to R2' of bone
      trabeculae oriented along the x (R2'x), y (R2'y) and z (R2'y) axes was assessed,
      by rotation of the specimen in the magnetic field. The results were validated by
      CT measurements of trabecular structure at a resolution of 0.2 x 0.2 x 1 mm.
      using custom-made software. R2' ranged from 4.9 to 32 s-1. After separation,
      theoretical R2'x ranged from 2.3 to 10.7 s-1, R2'y ranged from 2.6 to 14.0 s-1
      and R2'z ranged from 4.7 to 17.9 s-1. The number of bone trabeculae per
      millimeter identified in axial CT images ranged from 0.15 to 0.38 and from 0.039
      to 0.22 per millimeter in sagittal images. The difference between axial and
      sagittal CT images was statistically significant and due to anisotropic voxels.
      The correlation between R2' and the number of bone trabeculae per millimeter was
      statistically significant (r = 0.83, p < 0.001 for x orientation: r = 0.63 for y
      orientation, and r = 0.59 for z orientation, p < 0.05 for both). The relative
      amount of bone trabeculae in different orientations can be assessed in vitro
      using R2' measurements.

PMID- 10354878
TI  - Bone mineral density in adults with Down's syndrome.
AB  - The objective of the study was to elucidate if individuals with Down's syndrome
      (DS) are likely to experience an increased risk of osteoporosis with advancing
      age, in addition to precocious aging and their skeletal anomalies. Bone mineral
      density (BMD) was measured in 22 home-reared adults (9 males and 13 females; age
      26.22 +/- 4.45 and 23.65 +/- 3.23 years, respectively) by dual energy X-ray
      absorptiometry (DXA). The BMD of the second to fourth lumbar vertebrae was
      measured in posteroanterior projection and the mean density expressed as grams
      per square centimetre. The BMD of DS individuals was compared with 27 control
      subjects (12 males and 15 females) of the same age (age 24.16 +/- 3.46 and 23.86
      +/- 2.92 years, respectively). The results showed that the BMD of the lumbar
      spine in the males as well as in the females with DS was significantly lower than
      that in their control counter-parts (p < 0.001). Comparing the DS males with the
      females, the BMD was lower in the males at a level of 9%. Factors that contribute
      to this disorder may be mainly the muscular hypotonia, the sedentary life-style
      and the accompanying diseases which frequently observed in the syndrome. Future
      studies must be focused on the biochemistry of bone metabolism, the evaluation of
      gonadal, thyroid and parathyroid function, and the genes of the extra chromosome
      21.

PMID- 10354879
TI  - MRI of bone marrow: opposed-phase gradient-echo sequences with long repetition
      time.
AB  - Signal intensity for opposed-phase gradient-echo (GE) sequences of tissues
      composed of fat- and water-equivalent cells such as red bone marrow is extremely
      sensitive to variation of the ratio of both cell populations (fat-to-water ratio
      QF/W). Because most bone marrow pathology results in variation of QF/W, GE
      sequences are characterized by high-contrast imaging of pathology. The aim of
      this study was to evaluate the influence of TR, TE, FA, QF/W and histology on
      signal intensity. Signal intensity of opposed-phase GE sequences as a function of
      TR, TE, FA, and QF/W was measured for a fat-water phantom and cadaver specimens
      of normal bone marrow (red and yellow) and pathological bone marrow (tumors). All
      specimens were correlated to histology. Opposed-phase GE imaging of red bone
      marrow pathology results in low-signal-intensity imaging of intact red bone
      marrow and high-signal-intensity positive contrast imaging of pathology
      associated with a change in QF/W. In first-order approximation the signal
      intensity of pathology is linearly correlated to the change in QF/W. Opposed
      phase GE imaging is a sensitive imaging technique for red bone marrow pathology.
      Relative contrast of red bone marrow pathology is similar to fat-suppressed
      imaging techniques. Acquisition time is identical to T1-weighted SE sequences.

PMID- 10354880
TI  - Cervical myositis ossificans traumatica: a rare location.
AB  - An unusual case of myositis ossificans traumatica lesion located in the
      paraspinal region is reported. Despite the contiguity of the lesion with the
      cervical vertebrae and ominous appearance of the biopsy material, the history of
      antecedent trauma and computed tomography findings allowed preoperative accurate
      diagnosis. To our knowledge, myositis ossificans traumatica located in the
      cervical paraspinal region is very rare.

PMID- 10354881
TI  - MRI and CT features of hyperplastic callus in osteogenesis imperfecta tarda.
AB  - We describe the MRI and CT findings of hyperplastic callus formation simulating a
      tumour of pelvis in patient with osteogenesis imperfecta tarda. Possible
      differential diagnoses and the impact of different imaging techniques on the
      correct diagnosis are discussed.

PMID- 10354882
TI  - Pathological fracture in non-ossifying fibroma with histological features
      simulating aneurysmal bone cyst.
AB  - A 12-year-old-girl presented with a fracture of an osteolytic lesion of the
      distal radius. A 7-year-old girl presented with a fracture of an osteolytic
      lesion of the femoral shaft. In both cases it was a non-ossifying fibroma with
      fracture misdiagnosed at pathology as aneurysmal bone cyst. Fractures through non
      ossifying fibromas may alter the histological pattern of the initial lesion in
      two ways: firstly, by the presence of blood pigments due to the fracture, and
      secondly, by formation of new bone. Radiological-pathological correlation is
      essential to avoid histological errors after pathological fracture in a non
      ossifying fibroma.

PMID- 10354883
TI  - Lemierre's syndrome.
AB  - Postanginal sepsis, or Lemierre's syndrome, is rare but with life-threatening
      potential involving mainly infants and adolescents. The morbidity or mortality is
      caused mainly by lack of knowledge of the syndrome. The 18-year-old boy described
      here developed a jugular thrombosis 7 days after an angina. Fusobacterium
      necrophorum was isolated from the culture of the excised jugular vein. Secondary
      embolism involved the lungs, associated with an iliac osteomyelitis and
      sacroiliitis. Computed tomography was used for diagnosis and follow-up.

PMID- 10354884
TI  - Liver metastases: interventional therapeutic techniques and results, state of the
      art.
AB  - The liver is the most common site of metastatic tumour deposits. Hepatic
      metastases are the major cause of morbidity and mortality in patients with
      gastrointestinal carcinomas and other malignant tumours. The rationale and
      results for interventional therapeutic techniques in the treatment of liver
      metastases are presented. For the treatment of patients with irresectable liver
      metastases, alternative local ablative therapeutic modalities have been
      developed. Technique and results of local interventional therapies are presented
      such as microwave-, radiofrequency (RF)- and ultrasound ablation, and laser
      induced interstitial therapy (LITT), cryotherapy and local drug administration
      such as alcohol injection, endotumoral chemotherapy and regional
      chemoembolisation. In addition to cryotherapy, all ablative techniques can be
      performed percutaneously with low morbidity and mortality. Cryotherapy is an
      effective and precise technique for inducing tumour necrosis, but it is currently
      performed via laparotomy. Percutaneous local alcohol injection results in an
      inhomogeneous distribution in liver metastases with unreliable control rates.
      Local chemotherapeutic drug instillation and regional chemoembolisation produces
      relevant but non-reproducible lesions. Laser-induced interstitial thermotherapy
      (LITT) performed under MRI guidance results in precise and reproducible areas of
      induced necrosis with a local control of 94%, and with an improved survival rate.
      Interventional therapeutic techniques of liver metastases do result in a
      remarkable local tumour control rate with improved survival results.

PMID- 10354885
TI  - Transjugular intrahepatic portosystemic stent-shunt (TIPSS): technique and
      indications.

PMID- 10354886
TI  - CT appearances of mucosa-associated lymphoid tissue (MALT) lymphoma.
AB  - Mucosa-associated lymphoid tissue (MALT) lymphoma is a low-grade lymphoma that
      differs from high-grade non-Hodgkin lymphoma both clinically and histologically.
      The CT appearances of MALT lymphoma are described. Of 40 patients referred with
      biopsy-proven MALT lymphoma, only seven had not had gastrectomy or chemotherapy
      prior to CT examination. The CT scans of these seven cases were analysed for the
      degree and extent of gastric wall thickening, enlargement of abdominal and extra
      abdominal lymph nodes, and presence of extra-nodal disease. In all patients the
      stomach was distended with oral contrast medium and scans performed at narrow
      collimation, after intravenous administration of 20 mg hyoscine butylbromide. In
      six patients focal thickening of the gastric wall was 1 cm or less. One patient
      had thickening of over 4 cm. There was no enlargement of abdominal or extra
      abdominal lymph nodes or extension to adjacent organs. Thus on CT, at
      presentation, MALT lymphoma results in minimal gastric wall thickening, unlike
      high-grade non-Hodgkin lymphoma, which typically causes bulky gastric disease,
      nodal enlargement and extension into adjacent organs. CT is therefore of limited
      value in monitoring response to treatment. With disease greater than minimal
      thickening, transformation to a higher grade should be considered.

PMID- 10354887
TI  - Appendicular involvement in perforated sigmoid disease: US and CT findings.
AB  - We describe four patients in whom ultrasound (US) and/or computed tomography (CT)
      demonstrated a thickened appendix, secondarily enlarged due to perforated sigmoid
      diverticulitis (n = 2) or carcinoma (n = 2). The underlying pathology was
      correctly recognized in all cases. Secondary thickening of the appendix due to
      perforated sigmoid disease provides a potential pitfall mainly on US and may lead
      to an incorrect diagnosis and thus to unnecessary surgery or a wrong surgical
      intervention. Although US alone is enough to diagnose periappendicitis and
      sigmoid disease, combined use of US and CT may improve assessment of its origin
      and extension.

PMID- 10354888
TI  - Gastric cancer screening in selected population of Moscow region: retrospective
      evaluation.
AB  - The aim of the study was to evaluate the efficacy of photofluorographic gastric
      cancer screening in selected population of Moscow Region (Russia) during a 15
      year period. Thirty-five thousand patients were examined annually with
      photofluorography (tight filling and double contrast) of the stomach. Gastroscopy
      with multiple biopsies was performed in suspicious or inconclusive cases. Dynamic
      CT scan with air distention of the stomach was made before the operation for
      precise determination of tumor size as well as in some inconclusive cases. The
      final diagnosis was made by histologic examination of resected stomach. A total
      of 4286 patients dropped out of the study. In 25,392 patients no pathology was
      found. Gastric cancer was diagnosed in 680 (1.94%) of patients. In the study 170
      (25%) "early" gastric cancers and 510 (75%) advanced gastric cancers were found.
      Among 170 early gastric cancers 120 (70%) were type-IIb (flat carcinoma) lesions
      in which endoscopy had low positive predictive value due to nonspecific picture
      and negative biopsy. On the contrary, dynamic CT scan with air distention of the
      stomach revealed local thickening of stomach wall in 118 of 120 (98.3%) of the
      tumors and correctly determined their sizes in 106 of 120 (89.9%). Gastric cancer
      screening by means of photofluorography in selected groups of patients is
      efficient and cost-effective. In doubtful cases with negative biopsies and
      nonspecific endoscopic image, dynamic CT scan with air distention of the stomach
      can be a method of choice.

PMID- 10354889
TI  - The use of non-ionic water-soluble contrast agents for small bowel follow-through
      examination.
AB  - In certain situations it is preferable to perform small bowel examination using
      water-soluble contrast agents. Generally, ionic agents are used, but non-ionic
      agents may be an alternative in certain circumstances. We retrospectively
      reviewed a consecutive series of small bowel examinations using non-ionic media
      in order to determine their efficacy. A total of 52 water-soluble non-ionic small
      bowel follow-through examinations were performed in 42 patients using 100 ml
      iohexol. Indications for the study and the reasons why barium sulphate
      suspensions were contraindicated were established. Studies were assessed for
      radiographic quality and clinical findings were noted, and comparison was made
      with operative findings and clinical outcome. Obstruction was diagnosed in 12
      examinations and the radiological findings were confirmed in all 7 patients
      surgically treated. Fistulae were identified in 11 examinations and the
      radiological findings were confirmed in all 8 patients who were treated by
      laparotomy. Additionally, at laparotomy no obstruction or fistula was found in
      the 5 patients in whom prior contrast examination had been negative. Non-ionic
      water-soluble follow-through examination is easily performed and well tolerated,
      allowing accurate diagnosis of obstruction and fistula when barium suspensions
      are contraindicated.

PMID- 10354890
TI  - US and CT findings of multicentric leiomyosarcomatosis.
AB  - This article presents a case of leiomyosarcomatosis with widespread lesions
      involving the soft tissues and the most unlikely organs such as thyroid and
      salivary glands, pancreas, ligamentum teres, bladder wall, and bones without
      lymph node or distant metastasis. The CT and US findings of this rare phenomenon
      are discussed with regard to the literature.

PMID- 10354891
TI  - Amyloidosis presenting as a perforated giant colonic diverticulum.
AB  - Colonic amyloidosis is frequent, although rarely radiographically evident. The
      radiological findings are varied and unspecific. We report a case of perforated
      giant colonic diverticulum (GCD) diagnosed by helical CT in which amyloid
      deposition was pathologically demonstrated. The patient was a renal transplant
      recipient who previously had undergone hemodialysis for 10 years. A possible role
      of amyloidosis in the pathogenesis of this case is discussed. Giant colonic
      diverticulum must be included in the spectrum of gastrointestinal manifestations
      of amyloidosis.

PMID- 10354892
TI  - US and CT findings of rectal amebian abscess.
AB  - An interesting case of rectal amebic abscess is presented. Ultrasound and CT
      images provided the diagnosis of a cystic intramural mass at the rectal wall of a
      young man, who complained of pelvic pain, constipation, and fever. His clinical
      history of amebiasis and the finding of trophozoids and cysts at the stool swap
      confirmed the diagnosis. Intravenous metronidazole therapy cured the disease and
      led to total disappearance of the mass, and clinical well-being.

PMID- 10354893
TI  - Clinical utility of chest roentgenograms.
AB  - Because chest roentgenograms are the most common radiological procedure, they
      represent a considerable use of resources. Because the usefulness of chest
      radiography is frequently disputed, it is mandatory to investigate whether or not
      this use of resources can be defended in terms of clinical utility. The current
      study was performed as an outcome analysis to assess the clinical utility of
      chest radiography for monitoring patients in general practice (GP). One year of
      chest radiography referrals from a municipality practice, comprising a total of
      55 patients, were prospectively studied. Prior to the referrals, questionnaires
      were filled in with indications and expected results. After the examination, the
      radiological results were assessed regarding clinical utility. All 55 patients
      were carefully monitored by the same GP. The most frequent reason for referral
      was infectious disease. Only in 5 patients was the radiology report without
      value. In the 29 patients with a negative report, it was considered of value. In
      7 of these 29 patients the ongoing treatment was altered. The subjective value of
      the radiology reports were considered to be high. The clinical utility was good,
      both when receiving positive and negative answers. Of special interest was the
      negative answers as 7 patients actually changed treatment. The clinical utility
      was considered high enough to justify the costs. Good access to radiology for GPs
      is both cost-saving and cost-effective.

PMID- 10354894
TI  - Spontaneous pneumomediastinum.
AB  - In this paper two cases of spontaneous pneumomediastinum, occurring in a patient
      with diabetic ketoacidosis and in a patient with bronchial asthma, are presented.
      We describe the radiological findings, the differential diagnosis and the
      important radiographic considerations in establishing the diagnosis. In addition,
      we discuss the anatomical pathways and review the pathophysiological mechanisms
      responsible for the development of respiratory spontaneous pneumomediastinum.

PMID- 10354895
TI  - CT features of a pericardial gossypiboma.
AB  - We report a case of surgically retained pericardial sponge as a cause of
      paracardiac mass in a woman who had thoracotomy 3 weeks prior for replacement of
      mitral valve prosthesis. Computed tomography examination showed a thin-walled
      mass containing relatively high-density material in the central part with low
      density rim at the periphery suggesting a haematoma with clot formation at first.
      Surgically removed mass was a retained sponge between right atrium and
      pericardium. Gossypiboma should be included in the differential diagnosis of an
      intrathoracic mass besides haematoma and abscess formation in any patient who has
      had previous thoracotomy.

PMID- 10354896
TI  - Bilateral optic neuritis in a child diagnosed with Gd-enhanced MR imaging using
      fat-suppression technique.
AB  - A 4-year-old boy developed bilateral optic neuritis. Although precise neuro
      ophthalmological evaluation was difficult, the diagnosis was made with gadolinium
      enhanced MR imaging using fat-suppression technique in the initial stage of the
      disease. Enhancement and enlargement of the intraorbital and intracanalicular
      optic nerve were demonstrated bilaterally as well as protrusion of the optic
      nerve head. The disease responded dramatically to intravenous steroid therapy.
      The etiologies in children usually differ from those in adolescent and adult
      patients.

PMID- 10354897
TI  - Rupture of a cervical spinal cord arteriovenous malformation: a rare complication
      of endovascular embolization.
AB  - Patients suffering from a cervical spinal cord arteriovenous malformation (SCAVM)
      run high risk of devastating subarachnoid hemorrhage and hematomyelia. Therefore,
      cervical SCAVMs represent a compelling indication for surgical or endovascular
      therapy. The authors report on an acute life-threatening subarachnoid hemorrhage
      from a cervical SCAVM that ruptured during an embolization procedure. Causality
      and therapeutic management are discussed.

PMID- 10354898
TI  - Contrast media and metformin: guidelines to diminish the risk of lactic acidosis
      in non-insulin-dependent diabetics after administration of contrast media. ESUR
      Contrast Media Safety Committee.
AB  - The purpose of this study was to establish guidelines on how to avoid metformin
      induced lactic acidosis following intravascular use of contrast media. We
      reviewed articles published in international journals. No conclusive evidence was
      found to indicate that the intravascular use of contrast media precipitated the
      development of metformin-induced lactic acidosis in patients with normal S
      creatinine (< 130 mumol/l). The complication was almost always observed in non
      insulin-dependent diabetic patients with decreased renal function before
      injection of contrast media. Guidelines for the use of contrast media in this
      group of patients are proposed.

PMID- 10354899
TI  - Turf battles in radiology: how to avoid/how to fight/how to win.
AB  - Turf battles have always existed in radiology although recently, we have observed
      an increase in their numbers and sometimes in their virulence. The main reasons
      for this increase include the relative plethora of physicians especially in
      industrialized areas, and the rapid progress and development of medical
      technology and minimally invasive techniques. These turf battles risk interfering
      with the over-all medical costs of local health care systems as they will
      inevitably lead to an increase in the concentration of complex medical devices
      controlled by different specialties which, in turn, will lead to an increase in
      number of invasive and noninvasive, diagnostic and therapeutic examinations. The
      only way that radiologists can hope to maintain control of today's techniques
      will be if they are willing to offer qualitative expertise in their procedures
      with full clinical, academic and technological backing similar, or superior to
      that presented by our respective clinical and surgical colleagues. Furthermore,
      they should be fully involved in the decisional process and actual purchase of
      the technological equipment of their entire institution.

PMID- 10354900
TI  - X-ray diagnostic without medical indication and bodily harm: decision of the
      Supreme Court of Germany 3/12/97--2StR 397/97.
AB  - An orthopedic surgeon had been condemned for different offences to 2 years and 6
      months imprisonment by the superior court in Frankfurt/Main. One point of the
      ruling had been the use of X-rays without medical indication, which the superior
      court of Frankfurt/Main finally did not assess as bodily harm. The supreme court
      of Germany overruled this interpretation and referred the case back for a new
      trial and ruling.

PMID- 10354901
TI  - Para-anastomotic pseudoaneurysm of the supracoeliac abdominal aorta: late effect
      of aortic surgery.

PMID- 10354902
TI  - Renal amyloidosis masquerading as renal cell carcinoma.

PMID- 10354903
TI  - Percutaneous embolization of a splenic arteriovenous fistula related to acute
      necrotizing pancreatitis.

PMID- 10354904
TI  - Imaging diagnosis of mesenteric cystic lymphangioma: a case report in a newborn.

PMID- 10354905
TI  - Quiz case of the month. Biliary cystadenoma.

PMID- 10354906
TI  - The penetration characteristic of radio wave frequencies from oral cavities.
AB  - Recently many radio telemetry systems have been inserted into oral cavities and
      have been used to send data to receivers. Although various frequencies were used
      in those systems, there has been no report about the most effective penetrative
      frequency in the human body. In this study, we observed the penetration of radio
      waves from oral cavities and compared the efficiency of different frequencies. We
      selected 11 edentulous persons as subjects and the frequencies ranged from 1 to
      150 MHz. Although the attenuation gradually increased with the increase of
      frequency in most cases, we observed that there were effective resonance-like
      frequencies in three subjects and the frequency differed from person to person.
      This phenomenon was only observed when receiving antennas were set beside the
      mouth and not observed when the antennas were set about 1 m away from subjects.
      Therefore, it is considered that this phenomenon was produced by the relationship
      between the transmitting antenna and the receiving antenna. This result suggested
      that there were effective resonance-like frequencies in the case of radiation
      from edentulous oral cavities.

PMID- 10354907
TI  - Suitable location and optimum bladder width for the occluding cuff used for
      indirect arterial blood pressure measurements at the wrist.
AB  - Using a finite element method (FEM) and a volume oscillometric method with a
      photo-electric plethysmograph, we tried to determine which location(s) and which
      bladder width(s) of the occluding cuff would allow the most accurate indirect
      blood pressure measurements at the human wrist. Nuclear magnetic resonance
      imaging of the wrist allowed us to determine the geometry of two-dimensional (2D)
      finite element models. FEM analysis showed that the pressure transmission ratio
      (calculated tissue pressure: externally applied pressure) from the cuff to the
      radial artery (RA) was 100% when the cuff was placed over the site (L1) at which
      the RA crosses the most protuberant spot on the volar aspect of the distal end of
      the radius. In fact, the mean blood pressure (BPM) measured at this site in human
      subjects coincided with that measured at the upper arm (BPMA). In addition, a
      three-dimensional (3D) FEM was constructed by extending the 2D FEM at site L1 in
      the longitudinal direction to investigate the relation between pressure
      transmission to the RA and cuff bladder width. FEM analysis using the 3D finite
      element model showed that for all cuff widths greater than 0.25 times the
      diameter of the wrist, the external pressure was transmitted almost completely to
      the RA beneath the cuff center. Moreover, when the cuff width was as large as
      0.45 times the diameter of the wrist, the BPM measured at site L1 in human
      subjects was similar to the BPMA. The theoretical and experimental results in the
      present study both suggest that for accurate indirect blood pressure measurements
      at the wrist, the L1 site is a suitable location for the occluding cuff and a
      cuff whose bladder width is more than one-third but less than one-half the wrist
      diameter can be used.

PMID- 10354908
TI  - Reliability of measurement of muscle fiber conduction velocity using surface EMG.
AB  - Cross-correlating two surface EMG signals detected at two different locations
      along the path of flow of action potential enables the measurement of the muscle
      fiber average conduction velocity in those active motor units monitored by the
      electrodes. The position of the peak of the cross-correlation function is the
      time delay between the two signals and hence the velocity may be deduced. The
      estimated velocity using this technique has been observed previously to depend on
      the location of the electrodes on the muscle surface. Different locations
      produced different estimates. In this paper we present a measurement system,
      analyze its inherent inaccuracies and use it for the purpose of investigating the
      reliability of measurement of conduction velocity from surface EMG. This system
      utilizes EMG signals detected at a number of locations on the biceps brachii,
      when under light tension, to look for any pattern of variations of velocity as a
      function of location and time. It consists of a multi-electrode unit and a set of
      eight parallel on-line correlators. The electrode unit and the parallel
      correlators ensure that these measurements are carried out under the same
      physical and physiological conditions of the muscle. Further, the same detected
      signals are used in different measurement configurations to try to understand the
      reasons behind the observed variations in the estimated velocity. The results
      obtained seem to suggest that there will always be an unpredictable random
      component superimposed on the estimated velocity, giving rise to differences
      between estimates at different locations and differences in estimates with time
      at the same location. Many factors contribute to this random component, such as
      the non-homogeneous medium between the muscle fibers and the electrodes, the non
      parallel geometry and non-uniform conduction velocity of the fibers, and the
      physical and physiological conditions of the muscle. While it is not possible to
      remove this random component completely from the measurement, the user must be
      aware of its presence and how to reduce its effects.

PMID- 10354909
TI  - New on-line methods for analysis of walking foot pressures in diabetic
      neuropathy.
AB  - In this paper, studies are performed on a large number of diabetic patients
      belonging to different classes, using new on-line foot pressure parameters, i.e.
      normalized peak pressure (NPP) and pressure contact ratio (PCR), which include
      effects of the weight of the subject, velocity of walking and duration of high
      pressures in any region of the foot. A statistical study of the mean maximum
      value of these parameters in different plantar areas of the feet, for different
      classes of diabetic subjects, indicates distinguishing trends and hence could aid
      the clinician in better diagnosis and therapy planning. The NPP and PCR
      transforms calculated on-line (using specially developed software) help the
      clinician to quickly determine the heavily loaded foot areas that are potential
      sites of ulceration in insensitive feet and take the necessary action to prevent
      further damage to the foot sole.

PMID- 10354910
TI  - Respiratory impedance during positive expiratory airway pressure in patients with
      chronic obstructive pulmonary disease.
AB  - The effect of positive airway pressure (5.0 hPa) on airway impedance (Za) and
      tissue impedance (Zt) during the expiratory phase in chronic obstructive
      pulmonary disease (COPD) patients was evaluated using random noise oscillation
      and a body box method. The results were then compared with those obtained from
      normal subjects. In normal subjects, there was no significant difference between
      non-expiratory positive pressure (NPEP) and positive expiratory pressure (PEP)
      for the Zar (real part) and Zai (imaginary part) at 10 Hz (Zar NPEP: 2.14 +/-
      0.76, PEP: 1.96 +/- 0.79; Zai NPEP: 1.42 +/- 0.66, PEP: 1.40 +/- 0.70 hPa l-1 s).
      However, in COPD patients, Zar decreased significantly and the Zai increased
      significantly during PEP as compared to the values during NPEP (Zar NPEP: 7.10 +/
      1.88, PEP: 5.97 +/- 1.67, P < 0.05; Zai NPEP: -4.10 +/- 2.27, PEP: -2.99 +/-
      2.62 hPa l-1 s, P < 0.05). These results suggested that both central and
      peripheral airway resistance decreased during PEP in COPD patients. Tissue
      compliance (Ct) calculated from the Zt increased significantly during PEP as
      compared to during NPEP, in both normal subjects and in COPD patients (normal
      NPEP: 0.024 +/- 0.004, PEP: 0.021 +/- 0.003, P < 0.05; COPD NPEP: 0.024 +/-
      0.004, PEP: 0.014 +/- 0.004 l hPa-1, P < 0.001). This may have been indicative of
      the stiffened chest wall during PEP.

PMID- 10354912
TI  - Three new diseases listed for Japanese research on their treatment.

PMID- 10354911
TI  - A circle map model of human circadian rhythms.
AB  - Peculiar relationships between the sleep-wake cycle and temperature rhythm have
      been found during free-run situations, i.e. internal synchronization, internal
      desynchronization and phase trapping. The periods of both rhythms and the phase
      relationships between them could well characterize the above behavioral states.
      In this paper, firstly, our mathematical interpretations for them are proposed.
      According to these interpretations, a new circadian system model is developed.
      Our model consists of two circle maps, one for the dynamics of sleep-onset phase
      and the other wake-onset phase in reference to the temperature rhythm. The model
      dynamics is controlled mainly by the map for sleep-onsets which simultaneously
      determines behavior of wake-onsets. The model parameters are uniquely estimated
      based on the experimental results. The diverse behavior of the sleep-wake cycle
      associated with the synchronized and desynchronized states is suggested to be
      understood as bifurcation phenomena of the model dynamics. The bifurcation of the
      model dynamics is controlled by a single parameter, whose quantitative
      characteristics are investigated in detail. The results shown here could provide
      a novel framework to understand the human circadian rhythms systematically.

PMID- 10354913
TI  - Food and Drug Administration approves lamivudine for hepatitis B.

PMID- 10354914
TI  - Gen-Probe, Chiron and US Red Cross to investigate new technology to provide an
      extra layer of safety to the blood supply.

PMID- 10354915
TI  - [Cosmetics: definition and legal aspects of the term].
AB  - Classification of cosmetics, which are more and more similar to topical
      therapeutic agents, is getting increasingly difficult for dermatologists. Their
      definition within the EU and the respective European directives, replacing
      national laws step by step, will be briefly presented. The problems of
      distinguishing cosmetics from medicinal products will be discussed in detail by
      examples from clinical practice. Finally, we will review the various active
      substances which tend to be added to cosmetics following the global trend in the
      cosmetic industry towards developing "medicinally" active cosmetics, and in the
      pharmaceutical industry towards "cosmetically" oriented medicinal products as
      part of a current "life-style" ideology. In some clinical dermatological fields
      these active substances may allow the dermatologists to use cosmetics as topical
      therapeutic agents.

PMID- 10354917
TI  - [Ehlers-Danlos syndrome].
AB  - The Ehlers-Danlos syndrome (EDS) comprises a heterogenous group of nine
      hereditary connective tissue disorders, characterized by hyperelasticity of skin
      and hypermobility of joints to differing extents. The skin is easily injured and
      wound healing is delayed. The majority of EDS patients belong to EDS-types I-III.
      The pathogenesis in these cases is not known, although recent data suggest a role
      for collagen V. In contrast, the etiology of EDS-types IV, VI and VII has been
      found. While EDS IV is caused by a mutation in the collagen III gene, in EDS VI a
      mutation in the lysyl hydroxylase gene is present. In EDS VII, the underlying
      defect is a mutation in the collagen I gene. The EDS-types V, VII and X are very
      rare; their symptoms resemble those of EDS-type II.

PMID- 10354916
TI  - [S-100 beta protein in serum, a tumor marker in malignant melanoma-- current
      state of knowledge and clinical experience].
AB  - S100 is an acidic-calcium-binding protein, composed as a heterodimer of two
      isomeric subunits alpha and beta and was first described in cells of
      neuroendocrine origin. It plays an important role in various cellular processes
      such as cell differentiation and proliferation and interacts with the tumour
      suppressor gene p53.S100 is also present in melanoma cells and its
      immunhistochemical detection is widely used in the histopathological diagnosis of
      malignant melanoma. S100 has been detected in the serum of patients with
      malignant melanoma and many clinical studies have been performed to establish
      this protein as a tumor marker in different stages of the disease. The data
      suggest that S-100 beta-protein in serum of patients with malignant melanoma
      could be an independent prognostic marker and an additional clinical parameter
      for progression of metastatic disease and serological monitoring during systemic
      therapy. However there are patients in stage of lymph node- or systemic
      metastasis with negative S-100 beta-serum levels and no correlation to the course
      of disease. Our results confirm the findings for patients in stage III/IV.
      However, the percentage of S-100 beta-positive patients in stage III/IV is lower
      than reported in the literature, if repeatedly positive samples are excluded from
      statistical analysis. For monitoring in stage I and II it seems to be not
      helpful.

PMID- 10354918
TI  - [Depression and suicidal intentions as a side effect of high dosage interferon
      alpha therapy--two cases].
AB  - Adjuvant therapy with interferon for malignant melanoma causes neurotoxic side
      effects such as depression. The biochemical mechanisms are unknown. We report two
      cases with both depression and amnesia. In one case, attempted suicide was
      accompanied by 7 h of amnesia. The diagnostic classification and possible
      explanations for the amnesia secondary to interferon therapy are reviewed.

PMID- 10354919
TI  - [Palpable migratory acriform erythema and lymphocytic infiltration of the skin-
      different presentations of the same entity?].
AB  - Palpable arciform migratory erythema of Clark (PAME) has been described as a rare
      member in the group of T-cell pseudolymphoma. The clinical picture of infiltrated
      annular erythema developing into large migrating lesions with the trunk as
      predilection site is distinctive from other pseudolymphomas. Because of the very
      similar histology and immunohistochemistry in comparison to the more frequent
      lymphocytic infiltration of the skin of Jessner and Kanof (LIS) doubts have been
      raised about the existence of PAME as an unique entity. A 46-year old patient
      presented with the typical picture of PAME on his trunk while showing typical
      lesions of LIS on his neck and face. Both diseases showed synchronous
      intermittent remissions in response to different therapeutic modalities. Multiple
      biopsies were subsequently performed and histological, immunohistochemical and
      molecular biological examinations did not reveal relevant differences between
      PAME and LIS in this patient. We conclude that the findings in this key case
      suggest that the T-cell pseudolymphoma PAME is not an unique entity, but a
      special clinical presentation of LIS.

PMID- 10354920
TI  - [Bath-PUVA therapy of granuloma annulare].
AB  - Sixteen patients with generalized granuloma anulare and two patients with
      localized granuloma anulare received bath-PUVA therapy. Their lesions previously
      had not responded to conventional therapy. After an average of 55 (11 to 61)
      treatments and a mean cumulative dose of 69.5 (7.1 to 261.5) J/cm2, complete
      remission was observed in 5 patients and a clear improvement in 10 patients.
      Three patients stopped therapy after few treatments. Recurrent lesions appeared
      in 4 patients; in three of them reinitiation of the bath-PUVA-therapy again led
      to complete remission. Maintenance therapy for several months may be useful for
      patients suffering from relapsing granuloma anulare. Potential risks of long
      lasting bath-PUVA therapy should be taken into consideration.

PMID- 10354921
TI  - [Drug-induced papular-purpuric gloves and socks syndrome].
AB  - The papular-purpuric "gloves and socks" syndrome (PPGSS) was first described in
      1990 by Harms et al. The syndrome is characterised by fever, an itchy erythema
      with edema, confluent papules and purpura of the hands and feet in a "gloves and
      socks" distribution. The skin lesions may be associated with purpura and
      superficial erosions of the oral mucosa. Viral infections, in particular
      parvovirus B19, are the most likely trigger. In the present case PPGSS developed
      after taking trimethoprim/sulfamethoxazole. Since the patient developed identical
      symptoms after accidental re-challenge with the same drug, this case strongly
      suggests medications as another factor in the pathogenesis of PPGSS.

PMID- 10354922
TI  - [Painful ischemia of the extremities with T-cell lymphoma].
AB  - Two years after the diagnosis of Sezary syndrome, a 50-year old female patient
      experienced attacks of painful ischemia of both hands and feet, leading to acral
      necrosis. Another 59-year old patient presented with severe pain in his feet,
      secondary to ischemia. This was the first symptom of a T-cell-chronic lymphocytic
      leukemia. Similar cases have only occasionally been described. The relationship
      between acral ischemia and T-cell-lymphoma is not clear but is discussed in this
      article.

PMID- 10354923
TI  - [Linear IgA dermatosis in an adult with clinical signs of Stevens-Johnson
      syndrome].
AB  - Immunohistologically linear IgA disease presents with unambiguous features,
      whereas clinical manifestations are variable. It sometimes shows similarity to
      other bullous dermatoses such as bullous pemphigoid and dermatitis herpetiformis.
      A 73 year old female patient was referred with the diagnosis of bullous
      pemphigoid. One day after admission clinical examination revealed the classical
      features of Stevens-Johnson syndrome (SJS): widespread confluent atypical target
      lesions, partly raised, partly flat with central blisters, and erythematous
      spots, but few typical targets, as well as blisters and large areas of skin
      detachment on her back and buttocks, accompanied by erosions of the oral and
      genital mucosa. Direct immunofluorescence performed on peri-lesional skin showed
      linear deposition of IgA along the basement membrane zone, leading to the
      diagnosis of linear IgA disease of adults. Our case report shows that linear IgA
      disease may present with the clinical pattern of SJS.

PMID- 10354924
TI  - [Trichophyton rubrum syndrome with axillary tinea infection].
AB  - Trichophyton rubrum infections occur worldwide. In the last few years
      Trichophyton rubrum has increasingly often been isolated from other parts of the
      body besides the soles of the feet, toenails and the groin. Our patient's
      infection spread from the feet, to the inguinal region, to the thighs, to the
      hips, to the abdominal wall, to the left forearm and even the axillae. Such skin
      lesions have recently been called chronic dermatophytosis syndrome. We describe
      this new entity for the first time in the German literature and discuss it in
      relation to commonly found Trichophyton rubrum infections.

PMID- 10354925
TI  - [Keratosis follicularis spinulosa decalvans associated with patent ductus
      arteriosus and hypospadia in an Asiatic patient].
AB  - Keratosis follicularis spinulosa decalvans (KFSD) appeared sporadically in an
      Asian boy, who also presented with naevus teleangiectaticus lateralis, patent
      ductus arteriosus (Botalli) and hypospadia. The association of these findings
      raises the question of a new syndrome. In addition, this is the first report of
      KFSD in a patient of Asian origin.

PMID- 10354926
TI  - [History of clinical dermatology and venereology in Magdeburg 1906-1997].
AB  - The report gives an overview on the history and the development of clinical
      dermatology and venereology from a small department at the medical clinic of the
      city-hospital "Magdeburg-Altstadt" (1906) to the University Department of
      dermatology and venereology at the Medical Faculty of the "Otto von Guericke"
      University (1997).

PMID- 10354927
TI  - [Comment on the work of E. Kosler: "Transitory acantholytic dermatosis (Grover's
      disease) with Sarcoptes scabiei infection". Hautarzt (1997) 48:915-7].

PMID- 10354928
TI  - [Legal aspects of the publication of patients' photographs].

PMID- 10354930
TI  - [New findings for pathogenesis and therapy of venous ulcers. Interview with Dr.
      Johannes Norgauer, Freiburg].

PMID- 10354929
TI  - [Alopecia areata. Part 2: Therapy].

PMID- 10354931
TI  - [High viral content in men's semen during highly active antiretroviral therapy].

PMID- 10354932
TI  - [Dermatology and the threshold to the third millennium. Interview with Prof. Dr.
      E. Schopf, president of the German Dermatologic Society].

PMID- 10354933
TI  - [Angiology].

PMID- 10354935
TI  - [Hematology and internal medicine oncology].

PMID- 10354934
TI  - [Endocrinology].

PMID- 10354936
TI  - [Infectiology].

PMID- 10354937
TI  - [Cardiology].

PMID- 10354938
TI  - [Nephrology].

PMID- 10354939
TI  - [Pneumology].

PMID- 10354940
TI  - [Rheumatology].

PMID- 10354941
TI  - [Digestive and metabolic diseases].

PMID- 10354942
TI  - [1,25(OH)2-vitamin D3. The vitamin D hormone].

PMID- 10354943
TI  - [Unusual tachycardia in a 27-year-old roofer].

PMID- 10354945
TI  - [Medical autopsy].

PMID- 10354944
TI  - [29-year-old patient with gynecomastia and small testis].

PMID- 10354946
TI  - [Multi-resistant Staphylococcus aureus strains].

PMID- 10354947
TI  - [Bisphosphonates. A neu therapy principle in calcium and bone metabolism
      disorders].

PMID- 10354950
TI  - Suicide inactivation of peroxidase by H2O2: kinetic equations for peroxidatic
      oxidation reaction of guaiacol and determination of the kinetic parameters.
AB  - The kinetics of horseradish peroxidase (HRP) in oxidation reaction of guaiacol
      (AH) by hydrogen peroxide was studied, taking into account the inactivation of
      enzyme during reaction by its suicide substrate, H2O2. Those ranges of
      concentrations were selected in which: 1) the reaction was first-order in
      relation to [AH] and 2) [H2O2] >> [AH]. By combination of rate equations of the
      two concurrent reactions, consumption of AH and suicide inactivation of HRP, the
      overall kinetic equations were obtained which define the progress curve of
      reactions. The compatibility between equations and kinetic behaviour of reaction
      were evaluated in different ways. A close match was found between equations and
      experimental data. These equations can be used for determining 1) intact value of
      enzyme activity at start time of reaction and 2) apparent rate constant of
      suicide inactivation (ki') in a given concentration of H2O2, by processing of the
      data of the progress curve. The ki' value was found to be 0.178 +/- 0.003 min.-1
      at 10 mM of H2O2 and 0.04 +/- 0.002 at 3 mM H2O2, at 27 degrees C and sodium
      phosphate buffer, pH = 7.0.

PMID- 10354952
TI  - [Decreased plasma soluble P-selectin level in coronary sinus after successful
      coronary angioplasty in patients with unstable angina].
AB  - P-selectin, an adhesion molecule, is involved in the alpha-granules of platelets
      with several factors such as platelet factor 4 (PF-4) and in Weibel-Parade bodies
      of endothelial cells with von Willebrand factor. The levels of the soluble form
      of P-selectin increase after angina episodes in patients with unstable angina,
      indicating that soluble P-selectin is associated with platelet activation and
      thrombogenesis in the coronary circulation. To evaluate the effect of successful
      coronary angioplasty on platelet activation or thrombogenesis in the coronary
      circulation, plasma soluble P-selectin, PF-4 and von Willebrand factor antigen
      levels were measured in blood obtained from the coronary sinus before and after
      successful coronary angioplasty in 15 patients with unstable angina. Fifteen
      patients with normal coronary angiograms served as controls. Plasma P-selectin,
      PF-4 and von Willebrand factor antigen levels were determined by sandwich enzyme
      linked immunosorbent assays. Increased plasma soluble P-selectin (159.7 +/- 74.5
      vs 78.7 +/- 26.4 ng/ml, p < 0.01) and PF-4 (456.5 +/- 87.0 vs 118.7 +/- 62.3
      IU/ml, p < 0.01) levels were found in patients with unstable angina compared with
      those in controls, and were significantly decreased after angioplasty (147.8 +/-
      69.6 ng/ml, p < 0.05; 401.6 +/- 108.5 IU/ml, p < 0.05), whereas von Willebrand
      factor antigen was unchanged. The ratio of plasma soluble P-selectin levels after
      and before angioplasty correlated with the corresponding ratio of plasma PF-4
      levels (r = 0.53, p < 0.05), but not with the ratio of plasma von Willebrand
      factor antigen levels. The plasma levels of soluble P-selectin, which increase in
      the coronary circulation in patients with unstable angina, decrease after
      successful coronary angioplasty. Such data indicate that soluble P-selectin is
      associated with platelet activation and the therapeutical procedure improves the
      thrombogenic state in the coronary circulation.

PMID- 10354953
TI  - [Assessment of left ventricular function by electrocardiogram-gated myocardial
      single photon emission computed tomography using quantitative gated single photon
      emission computed tomography software].
AB  - Electrocardiogram (ECG)-gated myocardial single photon emission computed
      tomography (SPECT) can assess left ventricular (LV) perfusion and function easily
      using quantitative gated SPECT (QGS) software. ECG-gated SPECT was performed in
      44 patients with coronary artery disease under post-stress and resting conditions
      to assess the values of LV functional parameters, by comparison to LV ejection
      fraction derived from gated blood pool scan and myocardial characteristics. A
      good correlation was obtained between ejection fraction using QGS and that using
      cardiac blood pool scan (r = 0.812). Some patients with myocardial ischemia had
      lower ejection fraction under post-stress compared to resting conditions,
      indicating post-stress LV dysfunction. LV wall motion and wall thickening were
      significantly impaired in ischemic and infarcted myocardium, and the degree of
      abnormality in the infarcted areas was greater than in the ischemic area. LV
      functional parameters derived using QGS were useful to assess post-stress LV
      dysfunction and myocardial viability. In conclusion, ECG-gated myocardial SPECT
      permits simultaneous quantitative assessment of myocardial perfusion and
      function.

PMID- 10354954
TI  - [Development and evaluation of a new target heart rate formula for the adequate
      exercise training level in healthy subjects].
AB  - Little data is available recommending the adequate exercise level for physical
      fitness, so we hypothesized that the anaerobic threshold (AT) point is an ideal
      exercise level. We aimed to determine a new target heart rate formula for the
      adequate exercise training level in healthy subjects. This study first developed
      a new formula in 405 subjects (221 males, 184 females, mean age 48.9 +/- 12.3
      years). The AT was determined during cycle ergometer exercise with continuous
      respiratory gas measurements. The correlation of heart rate at the AT to resting
      heart rate, age and gender was analyzed by the multiple regression method. Based
      on this correlation, a new formula calculating target heart rate was established
      as 74.8 + 0.76 x (resting heart rate) - 0.27 x (age) + 7.3 x S (male: 0 or
      female: 1). This formula was then compared to Blackburn's method in 210 subjects
      (139 males, 71 females, mean age 44.5 +/- 14.4 years). The difference between the
      new target heart rate and the heart rate at the AT was significantly lower than
      that between the target heart rate by Blackburn's method [(220 - age) x 0.7] and
      the heart rate at the AT (8.8 +/- 6.3 vs 12.7 +/- 8.2 beat/min, p < 0.001). The
      resting heart rate and gender are important factors in determining the target
      heart rate for exercise. This new formula indicates the adequate exercise
      training level more accurately in healthy subjects.

PMID- 10354955
TI  - Isolated effect of partial left ventriculectomy for dilated cardiomyopathy: a
      case report.
AB  - A 38-year-old man underwent the Batista operation to treat end-stage dilated
      cardiomyopathy. There was no associated mitral regurgitation, so only partial
      left ventriculectomy was performed. The patient recovered successfully. His New
      York Heart Association (NYHA) class improved from IV to I, ejection fraction
      increased from 8% to 37% and left ventricular diastolic dimension decreased from
      89 to 68 mm. Cardiac output and stroke volume increased from 3.8 to 6.7 l/min and
      from 52 to 85 ml/min, respectively. This case shows the isolated positive effect
      of partial left ventriculectomy without mitral valve reconstruction.

PMID- 10354956
TI  - [A 30-year-old woman suffering from orthopnea immediately after caesarian
      section].

PMID- 10354957
TI  - [A 70-year-old woman with left atrial mass].

PMID- 10354958
TI  - Practical considerations of the pharmacology of angiotensin receptor blockers.
AB  - A review of the drug class of angiotensin receptor blockers (ARBs) as well as the
      ARBs currently available by prescription in the United States is presented. The
      importance of angiotensin II production by non-angiotensin-converting enzyme (non
      ACE) pathways, particularly human chymase, is discussed. Emphasis is placed on
      the mechanism of action of ARBs and the different binding kinetics of these
      agents. Although all ARBs, as a group, block the AT1 receptor, they may differ in
      the pharmacological characteristics of their binding and be classified as either
      surmountable or insurmountable antagonists. Mechanisms of surmountable and
      insurmountable antagonism as well as possible benefits of these blocking
      characteristics are discussed in relation to the various ARBs. The cardiovascular
      effects of activation of the two main subtypes of angiotensin receptors (AT1 and
      AT2) are presented. In addition to their treatment of hypertension, ACE
      inhibitors are recognized as being effective in the management of heart failure,
      left ventricular hypertrophy, recurrent myocardial infarctions, and renal
      disease. ARBs are currently indicated only for the treatment of hypertension;
      however, in vitro and in vivo pharmacological studies as well as preliminary
      clinical data suggest that ARBs, like ACE inhibitors, may also provide effective
      protection against end-organ damage in these conditions.

PMID- 10354959
TI  - First time in human for GV196771: interspecies scaling applied on dose selection.
AB  - The utility of interspecies scaling in early drug development has been
      extensively debated. The authors discuss the dose selection strategy for a first
      time into man (FTIM) study for GV196771, a new glycine antagonist, using
      techniques of interspecies scaling. The FTIM dose selection strategy was based on
      predicted plasma profiles of GV196771 in humans using allometric scaling and
      considerations of safety and pharmacological activity in animals. Allometric
      techniques were first retrospectively applied to data obtained in humans and
      animals for GV150526, a glycine antagonist with similar pharmacokinetic
      characteristics to GV196771. GV196771 and GV150526 are extensively protein bound;
      thus, protein binding differences among species were considered in the scaling.
      Using the scaled pharmacokinetic parameters, compartmental modeling was performed
      to prospectively simulate concentration profiles for the oral administration of
      GV196771. This article will discuss the outcome of the prospective dose selection
      strategy for GV196771 compared to the actual concentration profiles observed in
      the FTIM study.

PMID- 10354960
TI  - Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high
      affinity) and CYP3A4 (low affinity): implications for interactions with enzyme
      inducing drugs.
AB  - The human cytochrome P450 (CYP) isoforms mediating nortriptyline 10-hydroxylation
      have been identified using kinetic studies on heterologously expressed human CYPs
      and chemical inhibition studies on human liver microsomes. Nortriptyline was
      metabolized to E-10-hydroxynortriptyline by human lymphoblast-expressed CYPs 2D6
      (Km 2.1 microM) and 3A4 (Km 37.4 microM) with high and low affinity,
      respectively, whereas CYPs 1A2, 2A6, 2B6, 2C9, 2C19, and 2E1 had no detectable
      activity. Human liver microsomal nortriptyline E-10-hydroxylation displayed
      biphasic kinetics. The high-affinity component (Km 1.3 +/- 0.4 microM, n = 11
      livers) was selectively inhibited by the CYP 2D6 inhibitor quinidine, whereas the
      CYP3A4 inhibitor ketoconazole selectively inhibited the low-affinity component
      (K(m) 24.4 +/- 7 microM, n = 11 livers). Inhibition by ketoconazole increased
      with increasing substrate concentration, whereas the reverse was true for
      quinidine. The Vmax of the low-affinity component in human liver microsomes was
      significantly correlated (r2 = 0.84) with the relative activity factor for
      CYP3A4, a measure of the amount of catalytically active enzyme. A simulation of
      the relative contribution of CYPs 2D6 and 3A4 to net nortriptyline hydroxylation
      rate suggested that the relative contribution of CYP3A4 is only 20% even at the
      higher end of the therapeutic range. Induction of CYP3A4 will increase its
      importance and increase the net metabolic rate, whereas inhibition of CYP3A4 will
      be of little importance due to its minimal relative contribution under uninduced
      conditions. The identification of CYP3A4 as a low-affinity nortriptyline E-10
      hydroxylase explains the ability of poor metabolizers of debrisoquin to
      hydroxylate nortriptyline, as well as the increased in vivo clearance via this
      pathway caused by CYP3A4-inducing drugs such as pentobarbital, carbamazepine, and
      rifampin.

PMID- 10354962
TI  - Pharmacokinetic and pharmacodynamic analysis of subcutaneous recombinant human
      granulocyte colony stimulating factor (lenograstim) administration.
AB  - A total of 72 adult healthy volunteers were administered 1 microgram/kg of rhG
      CSF. There was no correlation between Cmax and an increase in peripheral
      neutrophil count, and there was a negative correlation between AUC and this
      increase. The mechanism of this is probably based on the correlation between the
      elimination rate constant (ke) and neutrophil increase. The ke probably has a
      close relationship with uptake by neutrophil and its progenitor via the G-CSF
      receptor. An individual with higher ke should therefore show a greater increase
      in neutrophil count. Therefore, AUC is proportional to the rhG-CSF remainder,
      that is, the proportion that is not consumed in the course of increasing the
      neutrophil count. In such a situation, the bioavailability calculated from the
      AUC is unlikely to indicate the absorbed amount. The authors also analyzed the
      pharmacokinetics using a two-compartment model with zero-order absorption and
      first-order elimination. This model was sufficient to obtain a good curve fit,
      and this demonstrates that the absorption process is not a first-order but a zero
      order process. Therefore, there might be an upper limit to the rhG-CSF transfer
      rate from subcutaneous tissue to blood.

PMID- 10354961
TI  - Differences in the urinary excretion of 6-beta-hydroxycortisol/cortisol between
      Asian and Caucasian women.
AB  - The urinary ratio of 6-beta-hydroxycortisol/cortisol has been used as a
      noninvasive probe for human cytochrome P450 3A4 isoforms (CYP3A4). Ethnic-related
      differences in the ratio have not been evaluated. The aim of this study was to
      determine if there are differences in the ratio between Asian and Caucasian women
      over a menstrual cycle. First-morning urine samples were collected every other
      day starting from the second day of menstruation for a complete menstrual cycle
      from 15 Asians and 16 Caucasian women who were 18 to 40 years old, healthy,
      nonsmoking, and alcohol and drug free, including oral contraceptives. Urine
      concentrations of 6-beta-hydroxycortisol and cortisol were measured by high
      pressure liquid chromatography (HPLC). For statistical analysis, three phases of
      the menstrual cycle were evaluated: menstruation (days 1-4), follicular or
      postmenstruation (days 6-10), and the luteal phase (days 21-24) based on the
      average menstrual cycle (28 days). Statistical analysis was performed by an
      independent sample t-test using the Bonferroni correction for repeated measures.
      Large intersubject and intrasubject variations of the 6-beta
      hydroxycortisol/cortisol ratios were observed during the menstrual cycles in both
      ethnic groups. Asian women had a statistically significant lower ratio than
      Caucasian women did for all three phases of the menstrual cycle: 2.2 +/- 1.1
      versus 5.1 +/- 3.5, 2.1 +/- 1.1 versus 6.0 +/- 4.9, and 2.8 +/- 1.6 versus 5.6 +/
      3.0 for the menstruation, follicular, and luteal phases, respectively. The two-
      to threefold lower 6-beta-hydroxycortisol/cortisol ratios in Asian women suggest
      that Asian women may have a lower CYP3A activity compared with Caucasian women.
      Differences in ethnicity may mask potential gender-related effects if ethnic
      background is not evaluated as a contributing factor.

PMID- 10354963
TI  - Lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared
      with lamivudine and zidovudine administered concurrently and the effect of food
      on absorption.
AB  - A single-center, open-label, three-way crossover study was conducted in 24
      healthy subjects to assess (1) the bioequivalence of a combined lamivudine 150
      mg/zidovudine 300 mg tablet relative to the separate brand-name components
      administered concurrently and (2) the effect of food on the bioavailability of
      the drugs from the combination tablet. The subjects were randomly assigned to
      receive each of the following three treatments, separated by a 5- to 7-day
      washout period: one lamivudine/zidovudine combination tablet after an overnight
      fast, one lamivudine 150 mg tablet and one zidovudine 300 mg tablet
      simultaneously after an overnight fast, or one lamivudine/zidovudine combination
      tablet 5 minutes after completing a standardized high-fat breakfast (67 g fat, 58
      g carbohydrate, and 33 g protein). Serial blood samples were collected up to 24
      hours postdose for the determination of lamivudine and zidovudine plasma
      concentrations. Standard pharmacokinetic parameters were estimated. Treatments
      were considered bioequivalent if 90% confidence intervals for the ratio of least
      squares (LS) means for the lamivudine and zidovudine area under the plasma
      concentration-time curve (AUC infinity) and maximum observed plasma concentration
      (Cmax) fell entirely within 0.80 to 1.25 for log-transformed parameters. The
      combined lamivudine/zidovudine tablet was bioequivalent in the extent (AUC
      infinity) and rate of absorption (Cmax and time of Cmax [tmax]) to the individual
      brand-name drug components administered concurrently under fasted conditions.
      Geometric LS mean ratios and 90% confidence intervals for AUC infinity and Cmax
      were 0.97 (0.92, 1.03) and 0.94 (0.84, 1.06), respectively, for lamivudine and
      0.99 (0.91, 1.07) and 0.97 (0.82, 1.15), respectively, for zidovudine. The extent
      of absorption of lamivudine and zidovudine from the combination tablet was not
      altered by administration with meals, indicating that this formulation may be
      administered with or without food. However, food slowed the rate of absorption,
      delayed the tmax, and reduced the Cmax of lamivudine and zidovudine. These
      changes were not considered clinically important. All formulations were well
      tolerated under fasted and fed conditions.

PMID- 10354964
TI  - Feasibility and functionality of OROS melatonin in healthy subjects.
AB  - OROS (melatonin), an oral osmotic system for controlled drug delivery, was
      evaluated in an open-label, two-way crossover study to test the feasibility of
      continuous overnight melatonin delivery. Twelve healthy subjects with no sleep
      disorders, ranging from 60 to 73 years of age, were enrolled in the study. Two
      doses of melatonin (1 x 110 micrograms and 4 x 110 micrograms) were administered
      on two separate occasions. Endogenous baseline nighttime serum melatonin
      concentrations were measured the night before each treatment. Following treatment
      at 2100 hours, the lights were extinguished at 2200 hours and remained so, except
      during blood sample collection, which was performed under dim light (< 50 lux) at
      specified times. Serum samples were analyzed for melatonin by an LC/MS/MS method.
      In addition, safety measurements such as vitals and serum samples for endocrine
      functions were measured both prior to and after melatonin dosing. The serum
      melatonin concentration profile following OROS (melatonin) dosing mimicked the
      normal endogenous serum melatonin concentration-time profile. The mean maximal
      melatonin concentration occurred at 3 a.m. The mean AUCs of endogenous melatonin
      before the two treatment days were 248 and 234 pg.h/mL, respectively. Serum
      concentrations of melatonin corrected for endogenous production increased
      proportionally with dose, with AUCs of 288 and 1069 pg.h/mL, respectively.
      Deconvolution of the serum concentration data showed good correlation between the
      in vitro amount released and the in vivo amount absorbed, suggesting continuous
      absorption throughout the gastrointestinal tract. Less than 5% residual content
      was observed in the recovered OROS system. Minimal changes in serum hormone
      concentrations (luteinizing hormone, follicular stimulating hormone, and
      prolactin) and no serious adverse events were observed following OROS treatment
      in these subjects. Delivery of melatonin with OROS formulation may result in a
      physiologic nocturnal profile in elderly subjects.

PMID- 10354965
TI  - Single oral dose escalation pharmacokinetics of pleconaril (VP 63843) capsules in
      adults.
AB  - Pleconaril is an orally active broad-spectrum antipicornaviral agent with
      excellent penetration into the central nervous system and nasal epithelium. The
      authors report the results of a randomized, placebo-controlled, dose escalation
      study of pleconaril oral capsules following single-dose administration of 50 to
      1000 mg. Fifty-six healthy adults (ages 19-55) participated in the study. Each
      subject received a single dose of pleconaril oral capsule(s) or an identically
      matched placebo. Blood samples (n = 19) were obtained over 36 hours postdose, and
      pleconaril was quantified from plasma by gas chromatography. Pleconaril
      disposition was best characterized using a two-compartment open-model with first
      order absorption. Fifty-five subjects completed the study (31 +/- 10 years, 77.6
      +/- 11 kg). The administration of pleconaril was well tolerated. There was no
      difference in tmax, lambda z, ka, t1/2elim, Cl/F, or Vdss/F among the various
      dose groups. A significant difference in both Cmax and AUC was observed between
      study groups; however, this difference became insignificant when the parameters
      were corrected for dose. Cmax and AUC were dose proportional between 50 and 1000
      mg (r2 > 0.97 and 0.90, respectively). Pleconaril demonstrates a favorable safety
      and pharmacokinetic profile following single-dose administration.

PMID- 10354967
TI  - Pharmacokinetic and adrenal interactions of IL-10 and prednisone in healthy
      volunteers.
AB  - The pharmacokinetic and adrenal interactions of recombinant human interleukin-10
      and prednisolone were examined in this open-label, randomized, four-way crossover
      study in 12 healthy adult male volunteers. Single doses of IL-10 (8 micrograms/kg
      s.c.), IL-10 with prednisone (15 mg p.o.), placebo with prednisone, or placebo
      were administered on four separate occasions with at least 3-week interceding
      washout periods. Measurements included plasma prednisone, prednisolone and
      cortisol, unbound prednisolone, and serum IL-10 concentrations. Pharmacokinetic
      parameters were determined using noncompartmental and model-fitting analysis,
      while area analysis and an indirect response model were used to assess cortisol
      dynamics. IL-10 exhibited prolonged serum concentrations owing to dual-absorption
      processes that were largely unaffected by prednisone. The Cmax values were about
      3 ng/mL, while the tmax occurred at 7 to 9 hours. Prednisolone exhibited rapid
      systemic kinetics with a Cmax of 235 ng/mL, tmax at 1.11 hours, and t1/2 of 2.54
      hours with no significant alterations owing to IL-10. Both prednisolone and
      prednisolone/IL-10 caused marked suppression of cortisol concentrations with
      similar magnitude and IC50 values; however, IL-10 alone significantly increased
      the 24-hour AUC of cortisol by 20%. Thus, IL-10 and prednisolone do not interact
      in disposition or adrenal suppression to a clinically significant degree.

PMID- 10354966
TI  - Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and
      liquid formulations.
AB  - Buprenorphine is an effective new treatment for opiate dependence. This study
      compared the bioavailability of buprenorphine from a tablet to that from a
      reference solution. Six men experienced with, but not dependent on, opiates (DSM
      III-R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in
      tablet form 1 week apart in a balanced crossover design. Plasma levels were
      measured by electron capture capillary gas chromatography (GC), and concentration
      time curves were constructed. Pharmacokinetic data were analyzed by analysis of
      variance. The bioavailability from the tablet was approximately 50% that from the
      liquid and was not affected by saliva pH. Lower bioavailability from the tablet
      may be due to slow dissolution.

PMID- 10354968
TI  - Effect of indinavir on the single-dose pharmacokinetics of theophylline in
      healthy subjects.
AB  - The effect of multiple doses of indinavir on the pharmacokinetics of a single
      dose of theophylline was investigated in 16 healthy male subjects using a
      randomized, double-blind, placebo-controlled, parallel-group study design. On
      days 1 and 7, all of the subjects received a single oral 250 mg dose of
      theophylline. From days 2 to 7, the subjects received orally administered 800 mg
      doses of indinavir or a matched placebo every 8 hours. On day 7, theophylline and
      indinavir (or a placebo) were coadministered. The geometric mean AUC(0-24 h) of
      theophylline increased 18% when coadministered with indinavir compared to when
      theophylline was administered alone. This small increase in AUC(0-24 h), although
      considered statistically significant, did not meet the prespecified criterion for
      clinical significance. The geometric mean Cmax of theophylline, when
      coadministered with indinavir, was within 8% of theophylline when administered
      alone. The mean tmax (+/- SD) value for theophylline, when coadministered with
      indinavir (0.9 +/- 0.5 h), was comparable to that observed for theophylline alone
      (1.0 +/- 0.5 h). In conclusion, the administration of multiple doses of indinavir
      followed by a single dose of theophylline did not appear to result in a
      clinically significant pharmacokinetic interaction for theophylline.

PMID- 10354969
TI  - Bracing for change: how American practice of interventional electrophysiology is
      being irrevocably altered.

PMID- 10354970
TI  - Genetics of cardiovascular disease with emphasis on atrial fibrillation.
AB  - Cardiology has embraced the techniques of molecular genetics later than other
      medical disciplines but is now completely submerged in the genetic mapping of
      cardiac diseases. The techniques of molecular biology, and in particular, their
      application to the genetics of inherited diseases, have brought the clinician and
      the scientist together in an unparalleled dependence. The chromosomal mapping of
      genes responsible for disease requires the identification of families with
      inherited diseases. This step involves the cooperation of the clinician. In order
      to continue improving our understanding of the molecular basis, it is imperative
      to raise the clinician awareness of the role of genetics in cardiac diseases.
      Arrhythmias can also have a familial origin and it is not generally appreciated
      that atrial fibrillation could be inherited. In the last two years, we have
      identified more than 100 families all over the world with individuals affected by
      the familial form of the disease. With the techniques of genetic mapping we have
      identified an area on chromosome 10 that carries a gene causing the disease in
      some of the families and there is ongoing research to identify the specific
      mutation. The clinician/scientist relationship has just started and the
      application of the discoveries in molecular genetics will probably have a direct
      role on how to approach medicine in the future, from prevention of diseases in
      patients carrying the susceptibility genes to gene therapy in those individuals
      with the disease.

PMID- 10354971
TI  - Nonpharmacologic validation of the intrinsic heart rate in cardiac transplant
      recipients.
AB  - BACKGROUND: The maximum sinus rate during exertion in humans is inversely related
      to age. However, the sinus rate at rest is quite variable. The intrinsic heart
      (IHR) following pharmacologic blockade of autonomic tone with propranolol and
      atropine has been proposed as a test of sinus node function and is related to age
      by the linear regression equation: IHR = 118.1 - (0.57 x age). Whether this
      relationship exists for transplanted hearts for which the donor sinus node is
      denervated has not been determined. METHODS: The relationship between the resting
      heart rate and the age of the donor heart was examined in 103 patients 1 year
      following orthotopic cardiac transplantation in the absence of rejection or
      intercurrent illness. Patients receiving beta-blockers, calcium blockers,
      antiarrhythmic drugs, digitalis, theophylline, or with biopsy evidence of
      rejection or abnormal coronary arteriograms were excluded from analysis. RESULTS:
      The recipient age, left ventricular ejection fraction, pulmonary capillary
      pressure, cardiac index, donor heart ischemic time and cardiopulmonary bypass
      time did not correlate with the rate of the resting donor sinus node. The resting
      heart rate was inversely related to age of the donor heart by the linear
      regression equation: HR = 112.0 - (046 x age). CONCLUSION: The resting rate of
      the denervated sinus node is related to donor age with a regression equation that
      is similar, though slightly slower, than that predicted after pharmacologic
      autonomic blockade.

PMID- 10354972
TI  - Prospective clinical evaluation of a programmed atrial stimulation protocol for
      induction of sustained atrial fibrillation and flutter.
AB  - We sought to define a minimum standardized protocol for induction of atrial
      fibrillation [AF] and/or atrial flutter. In contrast to ventricular stimulation
      protocols, a stimulation protocol for induction of AF or atrial flutter has not
      been critically evaluated. Since suppression of inducible AF or atrial flutter is
      used as one of the endpoints of success of pharmacologic and ablation therapies,
      there is an obvious need to define a minimally appropriate electrical stimulation
      protocol for induction of AF or atrial flutter. We prospectively evaluated 70
      patients, 44 with spontaneous atrial flutter or AF and 26 controls without
      documented atrial arrhythmias. A standardized programmed stimulation protocol,
      which employed up to three atrial extrastimuli delivered at two atrial sites at
      two atrial drive pacing lengths, was used in attempt to reproduce sustained AF
      and atrial flutter. The study endpoint was induction of sustained (> 30 s) AF or
      atrial flutter. Sustained AF or atrial flutter was induced in 39/44 (89%)
      patients and 2/26 (7%) of controls (p < 0.01). The arrhythmia induced was atrial
      flutter in 19/21 (91%) of atrial flutter patients, AF in 17/18 (94%) AF patients,
      both atrial flutter and AF in 5 AF/atrial flutter patients (100%). Two patients
      with atrial flutter had both AF/atrial flutter and 1 patient with AF had atrial
      flutter induced. The arrhythmia was induced from first stimulation site in 37
      patients (85%) using a single extrastimuli in 9 (20%) patients, double
      extrastimuli 18 (41%) patients and triple extrastimuli in 10 (23%) patients. Two
      patients (5%) required stimulation from second site with two and three
      extrastimuli, respectively. The overall sensitivity and specificity of this
      stimulation protocol were 89% and 92%, respectively with a positive predictive
      accuracy of 95%. CONCLUSIONS: 1. Up to three atrial extrastimuli and two atrial
      sites are needed to increase yield of AF/atrial flutter induction at
      electrophysiologic study. 2. Induction of either AF or atrial flutter correlates
      well with the presence of a similar spontaneous arrhythmia. 3. A baseline
      determination of the induction mode may be desirable prior to evaluation of
      interventions directed at AF or atrial flutter.

PMID- 10354973
TI  - "Rate-drop response" cardiac pacing for vasovagal syncope. Rate-Drop Response
      Investigators Group.
AB  - Recent reports suggest that cardiac pacing incorporating a rate-drop response
      algorithm is associated with a reduction in the frequency of syncopal episodes in
      patients with apparent cardioinhibitory vasovagal syncope. The detection portion
      of the algorithm employs a programmable heart rate change-time duration "window"
      to both identify abrupt cardiac slowing suggestive of an imminent vasovagal event
      and trigger "high rate" pacing. The purpose of this study was to develop
      recommendations for programming the rate-drop response algorithm. Pacemaker
      programming, symptom status, and drug therapy were assessed retrospectively in 24
      patients with recurrent vasovagal syncope of sufficient severity to warrant
      consideration of pacemaker treatment. In the 53 +/- 19 months prior to pacing,
      patients had experienced an approximate syncope burden of 1.2 events/month.
      During follow-up of 192 +/- 160 days, syncope recurred in 4 patients (approximate
      syncope burden, 0.3 events/month, p < 0.05 vs. pre-pacing), and pre-syncope in 5
      patients. In these patients, rate-drop response parameters were initially set
      based on electrocardiographic and/or tilt-table recordings, and were re
      programmed at least once in 14 (58%) individuals. A 20 beat/min window height
      (top rate minus bottom rate), a window width of 10 beats (61% of patients), and 2
      or 3 confirmation beats (79% of patients) appeared to be appropriate in most
      patients. Treatment intervention rate was set to > 100 beats/min in 89% of
      patients, with a duration of 1 to 2 min in 79%. In conclusion, a narrow range of
      rate-drop response parameter settings appeared to be effective for most
      individuals in this group of highly symptomatic patients.

PMID- 10354974
TI  - Interatrial septum pacing: a new approach to prevent recurrent atrial
      fibrillation.
AB  - BACKGROUND: There are a variety of approaches to the prevention of atrial
      fibrillation (AF) with pacing. Aim of this study was to test the safety and
      feasibility of interatrial septum pacing at the posterior triangle of Koch for AF
      prevention and to exclude potential arrhythmic effects. MATERIAL AND METHODS:
      Interatrial septum pacing was performed in 34 patients (21 males, 13 females,
      mean age 69 +/- 12 years): 9 without a history and clinical evidence of atrial
      fibrillation (AF) (6 with sinus bradycardia, 2 with second-degree AV block, and 1
      with carotid sinus hypersensitivity) and 25 with sinus bradycardia and paroxysmal
      atrial fibrillation (PAF) (mean symptomatic episodes/month 6.2 +/- 10). In all
      patients a screw-in bipolar lead was positioned in the interatrial septum
      superiorly to the coronary sinus. RESULTS: At implant the mean P wave amplitude
      was 2.5 +/- 1.5 mV, the pacing threshold was 1 +/- 0.6 V and the impedance was
      907 +/- 477 Ohm. Mean P wave duration was 118 +/- 17 ms in sinus rhythm and 82 +/
      15 during interatrial septum pacing (p < 0.001). During a mean follow-up period
      of 10 +/- 7 months, no patients without atrial tachyarrhythmias before
      implantation experienced AF. During a 9 +/- 6 months follow-up we observed only 2
      symptomatic arrhythmia recurrences between AF patients (mean symptomatic
      episodes/month 0.006 +/- 0.0022) (p < 0.01 vs before implant period).
      CONCLUSIONS: Our data indicate that interatrial septal pacing is safe and
      feasible. A significant less incidence of arrhythmic episodes has been observed
      during follow-up. Further controlled randomized prospective studies are necessary
      to establish the exact role of this technique respect to conventional or
      multisite stimulation when patients with paroxysmal AF need to be permanently
      paced.

PMID- 10354976
TI  - Optimizing atrial defibrillation.

PMID- 10354975
TI  - Single shock endocavitary low energy intracardiac cardioversion of chronic atrial
      fibrillation.
AB  - BACKGROUND: Discomfort related to low-energy internal cardioversion (LEIC)
      represents a real problem in patients (pts) with atrial fibrillation (AF). The
      aim of our study was to verify if a single shock could restore sinus rhythm (SR)
      with a lower discomfort for the pt. METHODS: Thirty pts with chronic AF were
      randomized to receive a single 350 V shock (15 pts) or multiple shocks of
      increasing energy (15 pts). Three leads were positioned, respectively, in the
      coronary sinus and in the lateral right wall for shock delivery, and in the right
      ventricular apex for R wave synchronization. Truncated, biphasic shocks were
      used. In the first group a single 350 V shock was directly delivered and a second
      400 V shock was given only if SR has not been restored. In the second group,
      beginning at 50 volts the voltage was increased in steps of 50 volts until SR
      restoration. No patient was sedated. After each shock the pts were asked to rate
      their discomfort on a scale of 1 to 5 (1 = not perceived, 5 = severe discomfort).
      RESULTS: SR was restored in all the subjects. In group 1 SR was obtained in 12/15
      (80%) pts with the first 350 V (8.1 +/- 0.8 joules) shock, while the remaining 3
      patients required the second 400 V (10.2 +/- 0.3 joules) shock. In group 2 the
      mean atrial defibrillation threshold was 346.7 +/- 1029.7 volts (8.0 +/- 101.5
      joules). Then discomfort score was 2.5 +/- 0.6 in group 1 and 3.3 +/- 10.6 in
      group 2 (p < 0.01). CONCLUSIONS: A single shock of 350 V restores SR in the
      majority of pts with chronic AF; by use this new approach, LEIC is tolerated
      better than the multiple shocks step-up protocol.

PMID- 10354977
TI  - The middle cardiac vein--a novel pathway to reduce the defibrillation threshold.
AB  - Defibrillation energy requirements of epicardial implantable cardioverter
      defibrillator systems are generally lower than endovascular systems currently
      used. The former has the disadvantage of requiring a thoracotomy and so has a
      greater morbidity and mortality than an endovascular procedure. The middle
      cardiac vein (MCV) is an epicardial structure that is accessible by a non
      thoracotomy approach. This study investigated the merits of ventricular
      defibrillation from the middle cardiac vein. METHODS AND RESULTS. Defibrillation
      thresholds (DFT) were measured in 10 anesthetized pigs, weighing 34.5 +/- 44.1 kg
      (mean 39 kg). An Angeflex electrode (1.7 mm x 50 mm) was introduced via the left
      external jugular vein to the right ventricular apex. The MCV was identified with
      standard angiography techniques and a 4080 (Angeion Corp.) defibrillation
      electrode (1.6 mm x 65 mm) introduced into the vein. An active can was implanted
      in the left subpectoral region. The defibrillation thresholds (DFT) of the
      following defibrillation configurations were assessed using a modified four
      reversal binary search: RV-->Can, RV + MCV-->Can and MCV-->Can. The DFT's for the
      three configurations were 15.5 +/- 2.8 J, 10.8 +/- 3.4 J and 13.7 +/- 2.4 J.
      Analysis of variance showed that the DFT with the RV + MCV combination was
      significantly less than the RV alone (p < 0.05) CONCLUSIONS: Defibrillation is
      possible through the MCV and that incorporating an electrode in the MCV with RV
      Can configuration can reduce the DFT by 30%.

PMID- 10354978
TI  - Azimilide decreases defibrillation voltage requirements and increases spatial
      organization during ventricular fibrillation.
AB  - INTRODUCTION: Drugs with class III antiarrhythmic properties generally decrease
      defibrillation threshold (DFT). However, the concentration effect relation for
      this effect and drug effects on ventricular fibrillation (VF) itself are not well
      understood. The objectives of this study were to determine the effect of
      azimilide (NE-10064), a new class III agent, on DFT, and on spatial organization
      during VF. METHODS: Defibrillation patch electrodes were sutured to the right and
      left ventricular epicardium in 12 open-chest anesthetized dogs. The delayed up
      down algorithm was used to measure DFT and to estimate the shock strength
      (voltage) with a 50% probability of successful defibrillation (V50). The
      magnitude squared coherence (MSC), which measures the spatial relation in the
      frequency domain, was measured during VF between two unipolar epicardial
      electrodes 3 mm apart. The V50, MSC, electrophysiologic parameters, and plasma
      concentrations were determined before and after four cumulative i.v. doses of
      azimilide (2, 7, 17, and 30 mg/kg). RESULTS: Azimilide elicited a dose dependent
      reduction of V50 and increase in MSC. Compared with baseline, azimilide lowered
      mean V50 by 2 +/- 9%, 10 +/- 18%, 11 +/- 14% and 19 +/- 5%, and increased MSC by
      17 +/- 20%, 32 +/- 31%, 20 +/- 44% and 27 +/- 20% (p < 0.05 for dose effect) at
      2, 7, 17 and 30 mg/kg, respectively. Mean increases in monophasic action
      potential duration at 90% repolarization (3-11%), ventricular effective
      refractory period (6-13%) at 400 msec paced cycle length, and VF cycle length (5
      37%) (p < 0.01 for dose effect) were observed with the 4 increasing doses of
      azimilide, respectively. CONCLUSION: Azimilide significantly decreases DFT and
      increases coherence in VF in a dose dependent manner.

PMID- 10354979
TI  - Bio-battery signal predicts myocardial lesion formation and depth in vitro.
AB  - AIMS: The aim of this study was to determine if the bio-battery signal can
      predict myocardial lesion formation and depth. METHODS: Fresh bovine ventricular
      myocardium was immersed in a temperature-controlled bath of circulating blood. RF
      energy was delivered with a custom generator to a catheter electrode. RF energy,
      electrode temperature, bio-battery signal and tissue impedance were displayed and
      recorded. A copper return plate was placed in the bath. RESULTS: When 50 volts of
      constant RF energy was terminated at a 20, 40, or 60% decline from the maximum
      bio-battery signal, the lesion depth was 4 +/- 0.4 mm. When RF energy application
      was terminated later, at a point characterized by a brief change of slope of the
      bio-battery signal, the lesions measured 7.8 +/- 1.4 mm in depth. This "bump"
      occurred before a rapid impedance rise. CONCLUSION: The depth of lesions created
      at the "bump" point was almost two-fold deeper than those at the termination
      points of 20, 40 and 60% bio-battery decrease (p = 0.0001). When RF energy was
      terminated at the rapid impedance rise the lesions were similar in depth, 8.2 +/-
      0.9 mm, to those obtained when RF energy was stopped at the "bump" (p = 0.28).
      The bio-battery signal provides a unique marker that might be useful to obtain
      maximum lesion depth while avoiding rapid impedance rise.

PMID- 10354980
TI  - Radiofrequency ablation in older children and adolescents by an adult
      electrophysiology team.
AB  - BACKGROUND: Radiofrequency (RF) catheter ablation has been widely and
      successfully employed to cure adult patients of a variety of arrhythmias. Only a
      few centers have a pediatric electrophysiology (EP) service available and have
      presented similar results in children. The aim of this study was to investigate
      the efficacy and safety of RF ablation in pediatric patients performed by an
      adult EP team. PATIENTS AND METHODS: The study group included 33 consecutive
      pediatric patients, aged 7-18 years (mean 14.1 +/- 3.1), with symptomatic
      supraventricular tachyarrhythmias, who underwent RF ablation during the last 3
      years. All but two patients underwent a full EP study during the same session.
      Procedures were performed in all but five patients with use of local anesthesia
      and deep or light sedation. The left heart was approached with use of transaortic
      (n = 3) or transseptal (n = 7) techniques. RF ablation was performed for manifest
      (n = 11) or concealed (n = 9) (9 left, 4 anteroseptal, 3 midseptal, and 4
      posteroseptal) or right atriofascicular (Mahaim) (n = 1) accessory pathways in 19
      patients, 12 slow AV nodal pathways and 2 atrial tachycardia foci in the other 14
      patients. RESULTS: RF ablation was successful in all patients (100%) with 1-27 RF
      applications (mean: 10 +/- 7). There was one complication in a patient with 2
      accessory pathways; after RF ablation of a posteroseptal accessory pathway,
      complete heart block occurred during successful ablation of a second midseptal
      accessory pathway. Fluoroscopy time averaged 35 +/- 23 min and procedure duration
      2.8 +/- 1.4 hours. During long-term follow-up of 19 +/- 10 months, there was one
      AV nodal tachycardia recurrence at 2.5 months, successfully treated with repeat
      RF ablation. CONCLUSION: RF ablation in pediatric patients performed by an adult
      EP team is efficacious and safe offering cure of symptomatic cardiac
      tachyarrhythmias in this patient population.

PMID- 10354981
TI  - A nationwide survey of financing health-related services for special education
      students.
AB  - The Individuals with Disability Education Act (IDEA) requires state educational
      systems to provide school-based, health related services (RS). This survey
      determined the financing arrangements used by states for health-related services
      for school-aged children with disabilities. A survey was sent to directors of
      special education, Medicaid, and public health departments in each of the 50
      states. Financial patterns for RS were sought at the state level for children
      ages 3-21 with disabilities for the 1993-1994 school year, the most recent year
      for which complete financial data were available. Univariate analyses probed the
      relationship between systems' variables and the extent of Medicaid usage by local
      education agencies. Respondents reported that schools tapped traditional health
      resources to supplement educational dollars in paying for related services in
      schools. Medicaid was by far the most common source with 29 states reporting
      established mechanisms for recouping Medicaid dollars and 10 states reporting
      phase-in activities. Seventeen states reported that departments of public health
      played some role in administration, training, and demonstrations, but only six
      states provided specific dollars for related services through the department. Use
      of private insurance was reported sporadically with only one state indicating a
      specific state-level program. Correlates of increased Medicaid usage were
      presence of interagency agreements (IAAs) (OR 11.1, p = 0.002), having specific
      personnel for school-based medical assistance (OR 17.7, p = 0.001), and utilizing
      school nursing services as a Medicaid optional service (OR 4.2, p = 0.048).

PMID- 10354982
TI  - Assessment of an itinerant medical evaluation program for school dysfunction.
AB  - This paper describes an itinerant medical evaluation (IME) project and reports on
      the outcome of 108 consecutive referrals made in the first year. Subjects were of
      ages 5 to 17 years. Most students had been evaluated by the schools but were not
      receiving special education or related services. IME led to clinical diagnosis of
      ADHD in 70% of the sample, and specific learning disabilities were diagnosed in
      26%. Several other clinically significant and educationally relevant diagnoses
      were made. As a result of the IME, many students were placed in special education
      and/or began to receive related services. At three-month follow-up, classroom
      accommodations were being made for 97% of the students. Teachers reported they
      felt more capable of teaching challenging students as a result of the IME.
      Significant improvements occurred in hyperactivity, conduct problems, and
      inattention, and grades improved in 31% of the sample. Reasons for the project's
      success are discussed.

PMID- 10354983
TI  - Using puppetry in a coordinated school health program.
AB  - Educators and clinicians are continually searching for innovative methodologies
      that promote positive health behaviors, that are age and developmentally
      appropriate, and that are fun. Puppetry meets these criteria. Puppetry is a
      creative learning methodology that stimulates learning through play. Various
      types of puppets are identified and a summary of the ways in which puppets may be
      used in a coordinated school health program to enhance positive health behaviors
      is presented. While many individuals attest to the value of using puppets,
      research should be conducted to assess effectiveness of puppetry on health
      knowledge, attitudes, skills, and behaviors.

PMID- 10354984
TI  - Adolescent weight management and perceptions: an analysis of the National
      Longitudinal Study of Adolescent Health.
AB  - Researchers investigated contemporary weight management activities and weight
      perceptions among adolescents and determined the effects of school health
      education on these perceptions and activities. This national, random sample of
      more than 6,500 adolescents (grades 7-12) measured perceived weight, weight
      change efforts, weight change activities, Body Mass Index, and health education
      for weight management. Results indicate that most adolescents: 1) take part in
      efforts to manage their weight, although many struggle with perceiving their
      weight; 2) engage in appropriate weight change efforts; and 3) report receiving
      school health education that positively effects some aspects of their weight
      management behavior. Thus, adolescents are concerned about weight and perceptions
      of weight and are engaging in a variety of weight change activities for weight
      maintenance and weight change. School health education appears to have some
      effect in improving adolescent health behavior, and discussion centers on this
      topic.

PMID- 10354985
TI  - School nurses' perceptions of and experiences with head lice.
AB  - Researchers examined school nurses' perceptions of head lice, perceived self
      efficacy in dealing with head lice, and personal experience in reducing head lice
      problems. Survey data from a two-wave mailing from 382 school nurses found most
      nurses supported a "no-nit" rule of forced absenteeism of any child with nits in
      their hair (60%). They perceived OTC treatments for head lice as very effective
      in killing adult lice (66%), and 9% perceived them as not effective. Nurses had a
      high efficacy expectation regarding their ability to control head lice (63%), and
      they had high outcome expectations regarding the results of their work with
      students and families of students (66%). Most nurses received their information
      about head lice from professional journals (76%) and professional
      conferences/conventions (62%).

PMID- 10354986
TI  - Fifteen prevalent myths concerning adolescent suicide.

PMID- 10354987
TI  - Bright smiles, shining futures.

PMID- 10354988
TI  - Perceptions of alcoholics: the impact of personal characteristics.

PMID- 10354989
TI  - [Immunotherapy of multiple sclerosis. Consensus and controversies].

PMID- 10354990
TI  - [Neurocysticercosis. Current review of the literature based on a long-term study
      of 2 clinically distinct German cases].
AB  - Neurocysticercosis, caused by Taenia solium larvae (cysticerci), is the most
      common parasitic infection of the human CNS Worldwide. In Germany its appearance
      is rare. Here we report two cases of neurocysticercosis which we followed over a
      period of 4-6 years. The first patient acquired neurocysticercosis in Germany. On
      admission he suffered from papilledema, partial seizures and a mild psychotic
      disorder. MR-tomography showed an internal hydrocephalus and multiple contrast
      enhancing parenchymal cysts. In the course of the disease a giant cyst within the
      left temporal pole developed and was exstirpated neurosurgically. The persistent
      internal hydrocephalus required ventriculoperitoneal shunting. Therapy with
      Praziquantel led to a clinical improvement, however, repeated analysis of the
      cerebrospinal fluid documented persistent inflammation. With the aid of a
      contrast enhanced three-dimensional (3D) ultrasound imaging technique we
      demonstrated increased cerebral perfusion surrounding one cyst. This may be
      interpreted as evidence for persistent disease activity. The second patient
      presented with repeated episodes of cysticercotic encephalitis, which is rarely
      described in the literature (incidence 1%). Clinical features, laboratory
      findings, diagnosis, and therapy of neurocysticercosis will be presented together
      with the pitfalls of the two described cases. Our cases will be compared to
      previous reports on clinical findings in neurocysticercosis.

PMID- 10354992
TI  - [Percutaneous transluminal angioplasty (PTA) and stenting in internal carotid
      artery stenoses. Combined position of the German Society of Neurology, the German
      Society of Neuroradiology and the German Society of Vascular Surgery].

PMID- 10354991
TI  - [Polyneuropathy and encephalopathy caused by organic solvents and mixed solvent
      solutions. Occupational medicine and neurologic aspects of a new occupational
      disease].
AB  - Solvent induced polyneuropathy and encephalopathy have been acknowledged quite
      recently as occupational diseases in Germany. For compensation first of all the
      diagnosis has to be proven. For differential diagnosis other known causes as well
      as non-organic mental diseases must be taken into consideration. The causality
      between proven exposures and diagnosed disease has at least to be probable. To
      evaluate causation extensive experience of the experts is needed. In this context
      scientific criteria regarding neurotoxicity of the solvent, duration of exposure,
      individual aspects of non-occupational influences, time course of the disease are
      important within a through synoptic evaluation. Possibilities and limitations of
      sensitive diagnostic measures such as neurographic, neuropsychologic and
      neuroimaging examinations are discussed. The prognosis of toxic polyneuropathy
      and encephalopathy is in general favorable if exposure has stopped. Additionally,
      adequate therapy and rehabilitation measures are supportive for a good prognosis.

PMID- 10354993
TI  - [Cocaine-induced acute CNS diseases].
AB  - Drug-associated/-induced neurological complications are well known in the
      literature. Cocaine is of major interest due to its widespread use. On the basis
      of a case report, we discuss the broad spectrum of medical and, in particular,
      neurological complications. The risk of cerebrovascular damage and epileptic
      seizures is indicated. The pathophysiological mechanisms of cerebrovascular
      complications are not well understood.

PMID- 10354994
TI  - [Rehabilitation treatment after stroke. An assessment of current status].
AB  - A standardized postacute inpatient rehabilitation program
      (Anschlussheilbehandlung) after stroke is well established in Germany. Yet the
      needs of patients being admitted to an Anschlussheilbehandlung (AHB) are not
      completely known. Therefore sociodemographic data, handicap, impairment and
      neuropsychologic deficits in 200 stroke patients were evaluated before admission
      to an AHB with different scores (Barthel, modified Rankin Score, NIHSS, HAWIE-R,
      Wilde, etc.). About half of the patients were still working prestroke. Most
      patients suffered from several vascular risk factors, which were insufficiently
      treated, and about a third of the patients had cerebrovascular disease prior to
      this stroke. At admission to the rehabilitation program the group of patients
      with severe neurological deficits was small. In average the disability was rather
      moderate (Rankin = 2.6). Mainly gait and finger dexterity were handicapped.
      Functional impairment was outweighed by neuropsychological deficits.

PMID- 10354995
TI  - [Systemic thrombolytic therapy with rt-PA in acute medial territory infarct.
      Experiences in routine clinical practice].
AB  - BACKGROUND AND PURPOSE: Only a few clinical reports about the routine use of
      intravenous rt-PA for the treatment of acute ischemic stroke have been published.
      Wether the perfusion of the extracranial parts of the internal carotid artery
      influences the outcome of the patients is still unknown, because the two major
      studies about systemic thrombolytic therapy with rt-PA in stroke (ECASS and
      NINDS) did not formally assess the status of the extracranial vessels. METHODS:
      56 Patients were treated with intravenous rt-PA within 6 h of acute ischemic
      stroke between January 1995 and May 1998. Before and within 24 h after the
      thrombolytic therapy usually a neurovascular diagnostic with extra- und
      transcranial Doppler-ultrasound or CT-angiography was performed. Occlusions of
      the intracranial parts of the internal carotid artery (Carotid-T) were excluded
      from thrombolytic therapy. The outcome was assessed using the Rankin-scale at
      least 3 month after the therapy. RESULTS: The average time from stroke onset to
      administration of treatment was 3.7 h.A parenchymal hemorrhage with clinical
      deterioration was found in four patients (7.1%). Eight patients died until the
      follow-up (14.3%), four within 14 days. 39 patients showed a clinical
      improvement. Outcome and recanalization rate of the medial cerebral artery was
      not influenced by stenoses or occlusions of the extracranial internal carotid
      artery. CONCLUSIONS: Routine intravenous use of rt-PA for acute ischemic stroke
      shows safety comparable to the results of the NINDS study even in 6 h time
      window. The outcome and recanalization rate depends not on the perfusion of the
      extracranial parts of the internal carotid artery.

PMID- 10354996
TI  - [Complex regional pain syndrome. Clinical and autonomic disorders during acute
      and chronic illness stages].
AB  - In order to describe autonomic dysfunction and clinical outcome in complex
      regional pain syndrome (CRPS) 20 patients were followed-up. First investigation
      was performed in the acute stage of CRPS and the second investigation two years
      later after therapy (individual, not standardized). Skin temperature and
      sudomotor function (thermoregulatory sweating (TST) and quantitative sudomotor
      axon reflex (QSART)) were assessed, and a clinical follow-up was performed
      carefully. Skin temperature was warmer on the affected side at first
      investigation (p < 0.001) and colder at follow-up (p < 0.02). Sudomotor output
      was enhanced on the affected side both after TST (p < 0.005) and QSART (p < 0.05)
      at first investigation. At follow-up, however, while thermoregulatory sweating
      was still increased (p < 0.04) QSART was not different. While autonomic failure
      improves as assessed by clinical examination, therapy failed to alleviate pain
      significantly. But patients' self-assesment of therapy was mostly positive (16 of
      20, p < 0.001). The present study has shown that the autonomic failure may be
      probably the result of central disturbances of thermoregulation, but secondary
      peripheral mechanisms also contribute to our findings. Individual based therapy
      seems to be efficacious for long term treatment, but for final judge controlled
      studies are required.

PMID- 10354998
TI  - [Marchiafava-Bignami syndrome. Extrapontine myelinolysis in chronic alcoholism].
AB  - Until now, the pathogenesis of Marchiafava-Bignami disease, an extrapontine
      myelinolysis, is unknown. Accept an abuse of alcohol for many years additional
      metabolic and vascular disturbances are supposed. The early performance of
      magnetic resonance imaging in patients with a sudden encephalopathy and history
      of alcoholism is essential for an assessment of the diagnosis. The bilateral lack
      of transcallosal inhibition--a parameter for the integrity of the transcallosal
      connections between motor cortices--is the consequence of the axonal degeneration
      of transcallosal fibers. Clinical and neuroradiological features of three
      patients with extrapontine myelinolysis are reported and possible etiologies of
      the complex disease are discussed. In two cases a severe alcohol abuse was
      present with the typical picture of the Marchiafava-Bignami disease. In a third
      patient an intoxication with methanol was present with a similar clinical
      picture. Although severe neurological disturbances were initially apparent in the
      patients, during the follow-up there was a significant amelioration of the
      clinical course under a high-dose vitamin B supplementation.

PMID- 10354997
TI  - [Cerebral ischemia as initial manifestation of neoplastic low-malignancy changes.
      2 case reports and review of the literatures].
AB  - Thrombembolic events as paraneoplastic complications in malignant disease account
      for severe morbidity and mortality in these patients. In some cases disturbance
      in hemostasis is the first manifestation of a neoplastic process. We report the
      cases of two patients with cerebral and extracerebral vessel occlusions, in whom
      epithelial tumors of low malignant potential (borderline-tumors) of ovary and
      peritoneum were diagnosed later on. In one case the removal of the tumor stopped
      the coagulation problems. The second patient died a few days after the first
      symptoms with devastating multiple vessel occlusion. In stroke of unknown
      aetiology a paraneoplastic process should be kept in mind. The diagnosis is more
      probable with recurrent thrombembolism in different body regions and when
      warfarin therapy was ineffective. Thoughtful coagulation studies and a tumor
      search program is recommended in these cases.

PMID- 10354999
TI  - [Bilateral hypoglossal nerve paralysis as isolated neurological symptom after
      craniocerebral trauma].
AB  - We report a 72-year-old patient who developed an isolated bilateral hypoglossal
      nerve paralysis following head trauma with complete recovery after three months.
      Since the CT scan did not show any fractures of the posterior skull base, we
      discuss a traction nerve injury as a possible mechanism.

PMID- 10355000
TI  - [Spontaneous vertebral arteriovenous fistula. Detection and treatment follow-up
      with color-coded duplex ultrasound].
AB  - Spontaneous or traumatic arteriovenous fistulae between vertebral artery and the
      surrounding venous plexus may cause vertebrobasilar hypoperfusion by steal
      effects. We report on a 71-year-old man presenting with vertigo. Duplex
      sonography revealed a vertebral arteriovenous fistula at the C4/5 level with the
      typical perivascular color Doppler artifact and hyperperfusion in the supplying
      arteries and draining veins. Angiography confirmed the findings; the consequently
      performed endovascular embolization using platin coils and silicon balloon
      removed the symptoms immediately. Ultrasonographic follow-up examinations within
      5 months demonstrated the success of therapy showing only low-flow fistula yet.
      This case demonstrates that early detection of a vertebral arteriovenous fistula
      by duplex sonography is highly beneficial because efficient treatment modalities
      are available.

PMID- 10355001
TI  - [Leptomeningeal dissemination of chronic lymphatic leukemia. Molecular genetic
      detection in cerebrospinal fluid].
AB  - The diagnosis of leptomeningeal dissemination of chronic lymphatic leukemia (CLL)
      by conventional cytology is unreliable because cytomorphologic criteria of
      malignancy are often lacking. Immunophenotyping of leukocyte differentiation
      antigens may also be of limited diagnostic value due to the small number of cells
      in cerebrospinal fluid (CSF) samples. Molecular methods may support the specific
      diagnosis of leptomeningeal infiltration of CLL. We present an 54 old patient who
      was diagnosed with CLL five years ago. Despite clinical signs of leptomeningeal
      involvement neither magnetic resonance imaging (MRI) nor conventional CSF
      analysis were suggestive of lymphomatous meningitis. Using PCR we selectively
      amplified the highly variable and clone-specific CDR3 region of the locus
      encoding the immunoglobulin heavy chain (IgH) in DNA obtained from both CSF and
      peripheral blood cells. Analysis of PCR products by high resolution gel
      electrophoresis revealed a single DNA fragment respectively indicating the
      presence of a monoclonal cell population in both compartments. DNA sequence
      analysis of the amplified CDR3 segments confirmed the clonal identity of cells
      and the leptomeningeal dissemination of CLL.

PMID- 10355002
TI  - [Secondary prevention after ischemic cerebral infarct. The ESPRIT Study: low dose
      anticoagulation, combined therapy with acetylsalicylic acid/dipyridamole or
      monotherapy with acetylsalicylic acid?].
AB  - The European and Australian Stroke Prevention in Reversible Ischaemia Trial
      (ESPRIT) is a randomised clinical trial in which patients with cerebral ischaemia
      of arterial origin will be randomised between oral anticoagulation (international
      normalized ratio (INR): 2.0-3.0), the combination of acetylsalicylic acid (in any
      dose between 30 and 325 mg per day) plus dipyridamole (400 mg daily) and
      acetylsalicylic acid only (in any dose between 30 and 325 mg per day). It is
      planned to enroll 4500 patients with a mean follow-up of three years. Primary
      outcome is the composite event of vascular death, stroke, myocardial infarction,
      or major bleeding complication; outcome assessment will be blinded. ESPRIT is an
      international, multi-center study in which 60-80 hospitals in the Netherlands and
      other countries in Europe and Australia will participate.

PMID- 10355003
TI  - [MS Therapy Consensus Group. Immunomodulating staged therapy of multiple
      sclerosis].
AB  - The positive results of several multi-center studies significantly improved the
      immunomodulatory treatment of multiple sclerosis over the last few years. It was
      demonstrated that different compounds are capable to reduce the number of
      relapses and to modulate the progression of disease. To improve the transition of
      results obtained in these studies into daily clinical practice, a consensus group
      started to prepare a report on the current treatment options for the German
      speaking European countries. The aim of this paper is to summarize the current
      knowledge, compare the results of recent clinical trials with the experience from
      other therapeutic options and assess their clinical evidence.

PMID- 10355004
TI  - Topical antimicrobial therapy.

PMID- 10355005
TI  - Failure of intense preventive efforts to arrest early childhood and rampant
      caries: three case reports.
AB  - This report presents the first three children who developed dental caries despite
      being enrolled in a randomized, control trial to test methods to prevent early
      childhood caries. The children's caretakers received education on decreasing
      frequent and prolonged feeding with a nursing bottle and other sugar containing
      foods, as well as brushing the children's teeth daily with 0.4% SnF2 gel. One of
      the child's caretaker additionally received training sessions to improve
      confidence in eliminating the child's nursing bottle habit and in performing
      daily tooth brushing. The two other children received monthly topical fluoride
      treatments with 2% NaF. Despite these intensive preventive efforts, these three
      children developed dental caries. Two of the children had mutans streptococci
      colonization at the time of initial visit, (12 and 14 months of age,
      respectively). All had high mutans streptococci levels at the time that caries
      was detected. Incorrigible, high-frequency sugar consumption from a bottle or
      from solid foods was suggested in all three cases. In one case, dental caries was
      associated with defects of the tooth enamel. Conceivably, the cariogenic
      challenge and harmful behaviors in certain children may be so extreme that they
      can overwhelm even extraordinary preventive efforts.

PMID- 10355006
TI  - Continuous effect of pit and fissure sealing on S. mutans presence in situ.
AB  - PURPOSE: The effect of sealants on S. mutans presence in situ was investigated.
      METHODS: Four intact, fully erupted first permanent molars in each of 74
      children, aged 6-8 years were required for inclusion in the study. Baseline
      examination included deft and plaque index. S. mutans presence on occlusal
      surfaces of the molars was evaluated, using a microbial replica method.
      Immediately after sealing the first permanent molars on one side, S. mutans
      presence in situ was re-evaluated, as well as three and six months thereafter.
      Three months after the initiation of the study, S. mutans presence was evaluated
      on the molars of the unsealed side, which were consequently sealed and re
      evaluated immediately, and three months later. RESULTS: Positive correlation was
      found between deft scores, plaque indices and microbial replica values, at
      baseline. Sealing caused a significant reduction in S. mutans levels on the
      treated occlusal surfaces, in vivo (P < 0.001), which lasted, in most cases, up
      to six months. CONCLUSIONS: The data suggest that sealants enable a prolonged
      reduction of S. mutans presence in situ, indicating an additional prevention
      effect, by reducing one source of dissemination.

PMID- 10355007
TI  - Effect of chlorhexidine varnish mouthguards on the levels of selected oral
      microorganisms in pediatric patients.
AB  - PURPOSE: The effect of a chlorhexidine varnish delivery system on the levels of
      selected oral microorganisms was evaluated in caries active pediatric patients,
      ages 4 to 12 years old. METHODS: Forty-six patients were enrolled into the study
      when they had multiple carious surfaces and salivary mutans streptococci (MS)
      levels higher than 10(4) colony forming units (CFUs) per milliliter. This study
      incorporated a double-blind design and patients were randomly assigned to either
      the chlorhexidine treatment group or the placebo group. Complete-arch, vacuum
      adapted mouthguards (0.02 in. polypropylene coping material) were custom
      fabricated and coated internally with either a 3.0% chlorhexidine varnish or a
      placebo varnish. Two pretreatment paraffin-stimulated saliva samples were
      obtained for culturing prior to varnish treatment. Saliva samples were also
      obtained immediately after treatment and once a month for up to three months
      after wearing the mouthguard appliances. Dental restorations were placed at most
      of these saliva collection visits. Mouthguards were reportedly worn for an
      average of 9.7 hours per night for approximately seven nights by 40 subjects
      (87%). RESULTS: After two months, and after three months, there was a significant
      reduction in MS levels immediately after the chlorhexidine varnish treatment.
      Total anaerobic and total facultative bacteria levels were not significantly
      affected. CONCLUSION: One week of nightly use of the chlorhexidine varnish
      mouthguard system is effective at reducing the number of MS in caries-active
      pediatric patients in the mixed and primary dentition for at least three months.

PMID- 10355008
TI  - Effects of four anticaries agents on lesion depth progression in an in vitro
      caries model.
AB  - PURPOSE: This study compares four chemotherapeutic regimens used for inhibiting
      carious lesion progression: silver nitrate (AgNO3); silver fluoride/stannous
      fluoride (AgF/SnF2); silver diammine fluoride (SDF); and chlorhexidine (CHX).
      METHODS: For this study, a bacterial model system containing Mutans streptococci
      (MS) and Lactobacilli casei (L) was used to generate carious lesions on 85
      extracted sound permanent third molars which were randomly assigned to four test
      groups and one control group. At week two, the four treatment regimens were
      applied to the lesions (one treatment per test group). RESULTS: Six weeks later,
      lesions treated with a single AgF/SnF2 or AgNO3 application demonstrated 29% and
      19% less lesion progression, respectively, than did the control group (P < 0.05).
      SDF and CHX did not differ significantly from the control. CONCLUSION: AgF/SnF2
      and AgNO3 may be useful in slowing down carious lesion depth progression.

PMID- 10355010
TI  - Growth and development considerations in the diagnosis of gingivitis and
      periodontitis in children.
AB  - Increasing information emphasize the relevance of the prevention, early diagnosis
      and early treatment of periodontal diseases in children. In order to avoid
      erroneous diagnosis and unnecessary treatments, the pediatric dentist is required
      to differentiate between pathologic processes and normal changes that take place
      in the periodontum with age. The present review outlines structural and
      functional changes of the periodontal structures, the establishment and
      maturation of the oral microflora and immune defense reactions to periodontal
      pathogens in children and adolescents. The age-related tendency to develop
      gingivitis, that is evident in children and adolescents, may be related to
      changes in the bacterial composition of the dental plaque, the inflammatory cell
      response, hormonal changes, morphological differences, tooth eruption and
      shedding. The hormonal influence on the gingival tissues and the composition of
      the dental plaque are of particular relevance during puberty. Large ranges for
      the prevalence of attachment loss, periodontitis or destructive periodontal
      disease in children and adolescents have been reported. The variance in values
      may be related to population characteristics, method of examination or diagnostic
      criteria that may include measurements of attachment loss and distances from the
      cementoenamel junction to the alveolar bone crest, both of which may be either
      physiological or pathological. The pediatric dentist should be able to diagnose
      gingival inflammation, attachment loss or distances from the cementoenamel
      junction to the alveolar crest which are out of proportion to the child's age and
      the amount of dental plaque. These may be indicative of a high susceptibility to
      periodontal diseases or reflect systemic conditions that affect the periodontum.

PMID- 10355009
TI  - Emergence of antibiotic resistant Streptococcus sanguis in dental plaque of
      children after frequent antibiotic therapy.
AB  - PURPOSE: In the pediatric population, several different antibiotic regimens are
      currently recommended for the treatment of otitis media. This study investigated
      whether therapy for otitis media was associated with the emergence of antibiotic
      resistant oral bacteria. METHODS: Streptococcus sanguis (S. sanguis) was isolated
      from supragingival dental plaque of children after a recent course of antibiotic.
      The isolated strains were tested for resistance to penicillin, amoxicillin,
      trimethoprim-sulfamethoxazole, and erythromycin and compared to isolated strains
      from age- and sex-matched control subjects, who had received no antibiotics
      within two years before sampling. RESULTS: While control subjects harbored no
      resistant strains of S. sanguis, about 60% of children who had received
      antibiotics harbored S. sanguis which were resistant to at least one of the
      tested antibiotics. Nearly half of these strains were resistant to two or more
      antibiotics. Resistance to penicillin and amoxicillin decreased with the age of
      the child and with the length of time since exposure to the antibiotic. However,
      resistance to trimethoprim-sulfamethoxazole or erythromycin showed no
      relationship to the age of the child or the length of time since exposure to the
      antibiotic. CONCLUSION: The data show that children who had been treated for
      otitis media with common antibiotic protocols do harbor antibiotic-resistant oral
      streptococci which may complicate prophylactic and therapeutic regimens for
      bacterial endocarditis.

PMID- 10355011
TI  - Orofacial injuries in youth soccer.
AB  - PURPOSE: The purpose of this study was to estimate the incidence of orofacial
      injuries in youth soccer in the 1995 fall and 1996 spring seasons for eight
      Dallas, Texas metropolitan area YMCA youth soccer leagues. METHOD: Surveys
      requesting orofacial injury as well as game and practice information were sent to
      all soccer coaches of children 3 to 12 years of age in eight cooperating YMCA
      leagues in the Dallas metropolitan area. RESULTS: The incidence of orofacial
      injury was low. In 47,772 hours of games and practice only 17 orofacial injuries
      were reported by the 122 coaches who responded. All reported injuries were to
      soft tissue and none required professional attention. CONCLUSION: The reported
      incidence of orofacial injury was very low suggesting that at the age and skill
      levels represented by these YMCA teams, soccer appears to be relatively safe to
      the maxillofacial complex.

PMID- 10355013
TI  - Parents' attitudes toward behavior management techniques during dental treatment.
AB  - PURPOSE: This study investigated the attitudes of parents toward behavior
      management techniques used during dental treatment of children. METHODS: One
      hundred and four parents who accompanied their children to the Department of
      Pediatric Dentistry at the Hebrew University, Hadassah Faculty of Dental Medicine
      in Jerusalem, Israel, participated in the study. The techniques for managing the
      children's behavior were explained to the parents prior to treatment and parents
      were present in the operatory during dental treatment. At the end of the second
      appointment, parents completed a questionnaire requesting demographic,
      behavioral, and dental information as well as the parents' attitudes toward the
      management techniques. RESULTS: Most parents preferred an explanation as to the
      proper approach for treating their children. Voice control was totally accepted
      by most parents, Papoose Board by one-third of the parents and physical restraint
      by nearly one-fourth of the parents. Of the parents who were in favor of
      restraint, most children did not cooperate. CONCLUSION: Detailed explanations and
      witnessing children during dental treatment may raise parents' tolerance level to
      firm techniques.

PMID- 10355012
TI  - Evaluating the efficacy of commonly used topical anesthetics.
AB  - PURPOSE: This study compared the efficacy of commonly used topical anesthetics
      using an objective measuring scale. METHODS: The following were tested: 5% EMLA
      cream, 10% cocaine, 10% lidocaine, 10% benzocaine, 1% dyclonine, and a placebo. A
      special instrument was designed to serve the purpose of pressure application on
      the gingiva to obtain a threshold discomfort level in grams before and after the
      topical delivery. The medicaments, in the quantity of 20 microL (2-3 drops) were
      placed on the maxillary anterior region using Beckman paper wicks in the form of
      discs. The topical anesthetics were left on the gingiva for 3 min and off for
      another 3 min. The instrument applied pressure progressively, and the pressure
      application was stopped when the subjects reported the initial feeling of
      discomfort. RESULTS: 5% EMLA cream significantly reduced the pain threshold level
      followed by 1% dyclonine and 10% benzocaine. However, there was no significant
      difference between 10% cocaine, 10% lidocaine, and the placebo. The placebo
      effect was observed. CONCLUSIONS: 5% EMLA cream was superior in performance to
      all other topical anesthetics. The remainder of the agents had no statistically
      different effect than the saline.

PMID- 10355014
TI  - Unerupted second primary mandibular molar positioned inferior to the second
      premolar: case report.
AB  - This report is a clinical case of a 7-year-old child who presented right impacted
      second primary mandibular molar. This tooth was positioned inferior to the second
      premolar successor and a supernumerary tooth superior to the second premolar.
      Clinical examination did not reveal systemic diseases ot trauma in the facial
      region. Treatment consisted of the extraction of the impacted second primary
      molar and the supernumerary tooth. Periodic examination was indicated for follow
      up.

PMID- 10355015
TI  - Lip biting in a patient with Chiari type II malformation: case report.
AB  - Self mutilation of lips and tongue is considered a common type of Self-Injurious
      Behavior (SIB). Treatment of SIB in the form of Lip-Biting in developmentally
      disabled individuals has been the focus of several related reports using
      different oral appliances preventing or inhibiting the SIB. In this paper we
      report a case of SIB in the form of Lip-Biting on an infant with Chiari Type II
      Malformation which was treated with a Lip-bumper. The Lip-bumper demonstrated to
      be a viable option in treating transient and acute episodes of SIB involving the
      lower lip and buccal mucosa.

PMID- 10355016
TI  - Localized deficient root development associated with taurodontism: case report.
AB  - Dentinal dysplasia type I (DDI) is a rare disturbance in dentin formation. This
      case report illustrates different radiographic features from other reported DDI
      cases in that only one quadrant (lower right posterior teeth) has the
      characteristic of DDI and both right and left upper molars exhibit taurodontism.
      This finding might be a variation of DDI. However, it is possible that this type
      of developmental defect could occur because of regionalized abnormalities in
      cellular function and proliferation as occurs in regional odontodysplasia.

PMID- 10355017
TI  - Diuretics and renal cell carcinoma--what the practicing physician needs to know.

PMID- 10355018
TI  - [Prevalence of Helicobacter pylori infection in asymptomatic 5-7-year-old
      children of St. Gallen canton].
AB  - The prevalence of Helicobacter pylori infection in asymptomatic Swiss children is
      not known. The aim of this study was to determine the rate of Helicobacter pylori
      infection in preschool children of the Canton of St. Gallen, eastern Switzerland.
      A 13C-urea breath test was performed in 432 randomly selected 5- to 7-year-old
      children from February to September 1998. A total prevalence of 6.5% was found,
      with 3.9% for Swiss children and 19.2% for children of parents immigrated from
      countries or regions with a high prevalence of Helicobacter pylori infection.
      Children born in these countries and who immigrated later were Helicobacter
      pylori positive in 70%. In 20/21 brother and sister pairs, the status of
      Helicobacter pylori infection was concordant. The amount of living space per
      person and the educational level of parents were comparable for all Helicobacter
      pylori positive children (Swiss and immigrants). In conclusion, total prevalence
      of Helicobacter pylori infection in preschool children aged 5 to 7 is low in the
      eastern part of Switzerland, with a significantly higher rate in children of
      immigrant parents.

PMID- 10355019
TI  - [Experience of surgical treatment for primary lung cancer in Geneva 1977-1996].
AB  - INTRODUCTION: In Switzerland, primary lung carcinoma is the leading cause of
      cancer death among males and the third cause of cancer death after carcinomas of
      the breast and colon in females. Surgical resection is the only potentially
      curative treatment but only in 20-25% of the patients. METHODS: Between January
      1, 1977 and December 31, 1996, 1079 consecutive patients (877 males, 202 females)
      underwent surgery for primary lung carcinoma at the University Hospital of
      Geneva. RESULTS: Lobectomy was performed in the majority of patients (n = 558,
      51.7%), followed by pneumonectomy (n = 319, 29.6%), exploratory thoracotomy (n =
      73, 6.8%), segmentectomy (n = 68, 6.3%), and bilobectomy (n = 61, 5.6%). Most
      tumours were squamous cell carcinomas (n = 613, 57%) and adenocarcinomas (n =
      327, 30.3%). Small cell lung carcinomas were diagnosed in 33 patients (3%). The
      overall operative mortality rate was 6.6%. However, over the period studied, the
      operative mortality decreased from 9% in 1977-1980 to 4% in 1993-1996. Survival
      according to the new staging system was 61% at 5 years in stage IA, 43% in stage
      IB, 37% in stage IIA, 19% in stage IIB, 14% in stage IIIA, 0% in stage IIIB, and
      4% in stage IV. CONCLUSIONS: In future, improvement in long-term survival will
      require earlier detection of lung carcinomas and better adjuvant and neoadjuvant
      therapies for advanced tumours.

PMID- 10355020
TI  - [Breast cancer and hormone replacement therapy].
AB  - There are more than 50 studies and at least 6 metaanalyses with varying results
      concerning breast cancer risk related to hormone replacement therapy. According
      to the literature the breast cancer risk in hormone replacement therapy may be
      slightly increased, especially after long-term treatment. After discontinuing
      hormone therapy the risk decreases and reaches baseline 5 years later. Since
      prospective randomised studies are lacking, it is still unclear whether hormone
      replacement therapy really promotes breast cancer or if the increase is due to
      methodological biases such as more frequent breast examination or mammography.
      According to the literature there is no evidence that under hormone replacement
      therapy the risk of relapse is elevated or the prognosis less favourable in women
      treated for breast cancer. Since prospective randomised studies with long-term
      follow-up are lacking, we recommend the use of the guidelines of the "Deutsche
      Gesellschaft fur Senologie", based on oestrogen receptor levels and lymph node
      involvement. Risks and benefits of hormone replacement therapy should be
      discussed with the well-informed patient and alternative therapy modalities
      evaluated.

PMID- 10355021
TI  - [Young man with a conspicuous EKG].

PMID- 10355022
TI  - Introduction: fat metabolism and adipose homeostasis.

PMID- 10355024
TI  - An adipocyte-central nervous system regulatory loop in the control of adipose
      homeostasis.
AB  - Mounting evidence supports a 'lipostatic' model for the regulation of adipose
      mass. In such a model, signals are generated in the periphery in proportion to
      adipose mass that act on hypothalamic control centers in the brain to regulate
      food intake and energy expenditure. Two such signals, leptin and insulin, have
      been identified and found to dramatically lower food intake and body weight.
      Several signalling molecules in the effector pathways that mediate the response
      to these signals in the brain have also been identified. The regulation of these
      factors and the nature of the adipose-CNS regulatory loop will be discussed.

PMID- 10355023
TI  - Molecular regulation of adipocyte differentiation.
AB  - Significant advances have been made recently toward understanding the molecular
      events that regulate adipocyte differentiation. In vitro models of adipogenesis,
      such as the 3T3-L1 and F-442A preadipocyte cell lines have proven to be an
      invaluable resource in elucidating mechanisms of adipocyte differentiation.
      Subject to modulation by hormonal, dietary, and genetic influences, the
      differentiation program now appears to be distinctly controlled through the
      coordinate regulation of transcription factors that predominantly include members
      of the C/EBP and PPAR families. Increased understanding of these critical factors
      and how they are regulated will provide insights into adipose tissue development
      as well as treatment of obesity.

PMID- 10355025
TI  - The role of TNF alpha in adipocyte metabolism.
AB  - Tumor necrosis factor-alpha (TNF alpha) is a multifunctional cytokine which
      exerts a myriad of biological actions in different tissues and species. Many of
      these actions can perturb the normal regulation of energy metabolism. In adipose
      tissue, in particular, TNF alpha has been demonstrated to regulate or interfere
      with adipocyte metabolism at numerous sites including transcriptional regulation,
      glucose and fatty acid metabolism and hormone receptor signaling. The
      implications of these perturbations in disease states and the current
      understanding of the molecular mechanisms utilised by TNF alpha are discussed
      herein.

PMID- 10355026
TI  - Acylation stimulating protein (ASP), an adipocyte autocrine: new directions.
AB  - Acylation stimulating protein (ASP) is an adipocyte-derived protein which has
      potent anabolic effects on human adipose tissue for both glucose and free fatty
      acid (FFA) storage. Our hypothesis is that: (i) ASP is produced by adipocytes in
      specific response to stimuli that initiate efficient fat storage; (ii) ASP
      interacts with a specific adipocyte receptor triggering an intracellular
      signalling pathway which activates triglyceride synthesis and fat storage; and
      (iii) that absence (ASP knockout mouse) or excess (in normal or obese mice) of
      ASP will result in physiological changes of plasma fat clearance and adipose
      tissue metabolism. The present review focuses on advances in ASP within the last
      2 years with particular emphasis on these three aspects of ASP.

PMID- 10355027
TI  - Fatty acid trafficking in the adipocyte.
AB  - The insolubility of fatty acids in cellular environments requires that specific
      trafficking mechanisms be developed to vectorally orient and deliver lipids for
      cellular needs. The roles of putative membrane bound fatty acid transporters and
      soluble carrier proteins are discussed in terms of mechanisms of fatty acid
      trafficking. The numerous roles for fatty acids as an energy source, as
      structural elements for membrane synthesis, as bioregulators and as prohormones
      with the potential to regulate gene expression, are discussed in terms of the
      necessity to regulate their intracellular location and concentration.

PMID- 10355028
TI  - Perilipins, ADRP, and other proteins that associate with intracellular neutral
      lipid droplets in animal cells.
AB  - Although all animal cells package and store neutral lipids in discrete
      intracellular storage droplets, there is little information on the molecular
      processes that govern either the deposition or catabolism of the stored lipid
      components. Studies on adipocytes have uncovered the perilipins and ADRP, related
      proteins that appear to be intrinsic to the surfaces of intracellular lipid
      storage droplets. We discuss the properties, distribution, localization, and
      potential functions of these proteins, as well as those of vimentin and the
      recently-described 'capsular' proteins, in lipid storage and metabolism.

PMID- 10355029
TI  - Heart developmental biology. Introduction.

PMID- 10355030
TI  - Intersecting signalling and transcriptional pathways in Drosophila heart
      specification.
AB  - The Drosophila heart, also called the dorsal vessel, is a linear tube consisting
      of two major cell types, namely cardioblasts which serve as cardiomyocytes and
      pericardial cells which surround its outer surface. This organ is derived from
      segmental clusters of cells in the dorsal mesoderm during early embryonic
      development. During the past few years, genetic and molecular studies have led to
      significant advances in our understanding of the regulatory mechanisms that
      pattern the early mesoderm by defining these cell clusters and ultimately
      specifying individual cells within them as heart progenitors. These studies
      established that the patterning events involve specific combinations of localized
      inductive signals that act in concert with mesoderm-autonomous transcription
      factors to achieve a progressive subdivision of the mesoderm. Some of the
      synergistic interactions between mesodermal transcription factors and external
      signalling molecules have been defined at the molecular level. With respect to
      the pericardial cells, the final specification steps were found to employ cell
      intrinsic lineage mechanisms. Because of the many striking similarities between
      Drosophila and early vertebrate heart development, which appear to extend to the
      molecular level, these insights will be of significant help in defining related
      events during vertebrate cardiogenesis.

PMID- 10355031
TI  - Vertebrate tinman homologues and cardiac differentiation.
AB  - In Drosophila, the homeobox gene tinman is required for specification of dorsal
      vessel and a number of mesodermal subtypes. Six tinman homologues have now been
      found in diverse vertebrate species: Nkx2-3, 2-5, 2-6, 2-7, 2-8 and 2-9. Of
      these, Nkx2-5 appears to be the mostly highly conserved among species, in terms
      of both primary protein sequence and mRNA expression pattern. Of the others, some
      have been found as yet only in a single species. Although expression patterns of
      vertebrate tinman homologues indicate that they may play a role in the
      specification of several mesodermal or endodermal tissues, to date most attention
      have been focussed on their role in cardiac development. Results of these studies
      indicate that, as for Drosophila tinman, vertebrate tinman homologues may be
      required for heart formation, but may not be sufficient. Studies in Drosophila
      are defining other pathways which are required in concert with tinman for dorsal
      vessel formation. Circumstantial evidence suggests that similar pathways may be
      operative in vertebrate heart formation. This review summarizes recent advances
      in our understanding of vertebrate tinman homologues and interacting genetic
      pathways.

PMID- 10355032
TI  - GATA transcription factors and cardiac development.
AB  - Three members of the GATA family of transcription factors, GATA-4, -5, and -6,
      are expressed in the developing heart. One family member, GATA-5, is restricted
      to the endocardium while the other two, GATA-4 and -6, are present in the
      myocardium where they apparently fulfil distinct functions. The mechanisms
      underlying GATA factor specificity are not fully understood but may involve
      interaction with other tissue-restricted or ubiquitous co-factors. Thus,
      combinatorial interaction among GATA factors or between GATA factors and other co
      factors may differentially control various stages of cardiogenesis.

PMID- 10355033
TI  - Patterning during organogenesis: genetic analysis of cardiac chamber formation.
AB  - A classical genetic approach, in which mutagenized organisms are screened for
      phenotypes of interest, is appealing for the analysis of developmental processes.
      Here, we describe the advantages of zebrafish genetics for the study of heart
      development. As an example of the utility of this strategy, we discuss its
      potential to illuminate the molecular mechanisms of cardiac chamber formation.
      The signals that specify ventricular and atrial lineages and the differentiation
      pathways that produce distinct chambers are poorly understood. Recently
      identified zebrafish mutations that disrupt ventricular or atrial development
      promise to reveal genes essential for these processes.

PMID- 10355034
TI  - Seeking a regulatory roadmap for heart morphogenesis.
AB  - Despite descriptive studies spanning centuries, we are still lacking an
      integrated concept of how molecular patterning information is developed in the
      heart, and how this information guides morphogenesis. With an increasing number
      of regionally-expressed cardiac genes and transgenes being identified, along with
      new animal models of cardiac dysmorphogenesis and an exciting array of genetic
      tools for further dissection, the need for an integrated morphogenetic concept is
      acute. Models invoking a linear array of cardiac segments are difficult to
      reconcile with the observation that those segments are evident only on the outer
      curvature of the heart tube. Molecular and anatomical evidence supports the view
      that chamber specification is achieved by interpretation of dorso-ventral (inner
      curvature/outer curvature), as well as anterior-posterior patterning information
      in the primary heart tube. In this essay, I examine some of the issues
      influencing and perhaps confusing our view of cardiac morphogenesis and briefly
      discuss regulatory genes in the context of an evolving morphogenetic model.

PMID- 10355035
TI  - Embryological basis for cardiac left-right asymmetry.
AB  - Asymmetric heart tube looping and chamber morphogenesis is a complex process that
      is just beginning to be understood at the genetic level. Rightward looping is the
      first embryological manifestation of consistently oriented, left-right asymmetric
      development of nearly all visceral organs. Intuitively, invariant anatomical
      asymmetry must derive from a novel mechanism capable of integrating dorsoventral
      and anteroposterior information. The details of this process are emerging for
      several vertebrates and reveal that overall left-right asymmetry, once polarized
      with respect to dorsoventral and anteroposterior axes, unfolds through distinct
      left- and right-sided programs of gene expression. These, in turn, regulate
      expression of cardiac and chamber-specific genes which guide heart morphogenesis
      and differentiation.

PMID- 10355036
TI  - Tea--a potent agent to prevent disease?

PMID- 10355037
TI  - [Angiogenesis in gynecology and obstetrics].
AB  - In current scientific discussion, increasing importance is being given to the
      clinical significance of the new formation of vessels (angiogenesis) in the
      course of physiological, inflammatory and neoplastic processes. Angiogenesis is
      best studied in the growth of malignant tumors, since cancer may be regarded as
      the most important angiogenesis-dependent disease in terms of social and economic
      aspects. The significance of angiogenesis in gynecological oncology is as
      follows: 1) Intratumoral vessel density is an indicator for the emergence and
      growth of malignant tumours and their precursor lesions, 2) intratumoral vessel
      density is an independent prognostic factor for solid malignancies and 3) the
      inhibition of tumor angiogenesis by means of anti-angiogenetic substances causes
      tumor growth to be suppressed. Angiogenesis also plays an important role in the
      regulation of the female menstrual cycle. Proliferation of the endometrium and
      the formation of the corpus luteum in the second half of the menstrual cycle are
      examples of angiogenesis in the physiological field. The function of angiogenetic
      factors in the emergence of endometriosis and in female and male infertility are
      currently under study. In obstetrics, the new formation of blood vessels is
      significant for the implantation of impregnated blastocysts and for the
      development and growth of the placenta. Preeclempsia (gestational toxicosis), for
      instance, is a typical pregnancy-related disease whose pathophysiological
      mechanism is attributed to a disturbed development and function of small
      placental vessels. The present paper is an overview of current knowledge and
      current approaches of research concerning angiogenesis in the field of gynecology
      and obstetrics. The paper is focused on the clinical significance of
      angiogenesis.

PMID- 10355038
TI  - The green tea extract epigallocatechin gallate is able to reduce neutrophil
      transmigration through monolayers of endothelial cells.
AB  - Green tea is widely used in Asia and has also become popular in Western
      countries. The influence of green tea extracts on leukocytes is not well
      understood. Leukocytes play a crucial role in the process of inflammation. They
      migrate from the intravascular space into the tissue to attack micro-organisms.
      The aim of the current study was to investigate the influence of epigallocatechin
      gallate on leukocyte transmigration through endothelial cell monolayers and
      thereby evaluate its potential role in the inflammatory process. Human umbilical
      vein endothelial cells were cultured on microporous membranes to achieve a
      monolayer. Freshly isolated neutrophils from healthy subjects were measured with
      a migration assay. The amount of untreated neutrophils migrating through
      untreated endothelial cell monolayers was used as control and set as 100%.
      Neutrophils and/or endothelial cell monolayers were pre-treated with
      epigallocatechin gallate using relevant, as well as higher and lower
      concentrations. The relevant plasma concentration of epigallocatechin gallate was
      able to significantly inhibit neutrophil migration through endothelial cell
      monolayers (69 +/- 6.4% SD; p < 0.05 compared to control), when both cell types
      (leukocytes and endothelial cell monolayer) were treated. This is similar to the
      situation after resorption in-vivo. Treating either neutrophils or endothelial
      cell monolayers alone led to significant reductions in migratory response (only
      neutrophils treated: 86 +/- 8.1% SD, p < 0.05; only endothelial cell monolayers:
      77 +/- 6.1%, p < 0.05). In conclusion, epigallocatechin gallate was identified as
      a potent inhibitor of leukocyte migration through endothelial cell monolayers.
      The treatment of both cell types showed an additive effect. Endothelial cells
      seem to be more affected than neutrophils. Further clinical investigations are
      necessary to understand the potential clinical consequences.

PMID- 10355039
TI  - [Effectiveness and tolerance of a gonadotropin releasing hormone (goserelin) in
      treatment of symptomatic endometriosis].
AB  - Endometriosis is one of the most common benign gynecological diseases, affecting
      an estimated 10-15% of all premenopausal women. In this open multicentric
      prospective study, we investigated the effectiveness and tolerance of a
      gonadotropin releasing hormone agonist (goserelin) for the treatment of
      symptomatic endometriosis. One hundred and thirteen patients were included in the
      study. During the treatment, we documented a relevant reduction in the rAFS score
      and in the additive diameter of the implants. In addition, we noted a reduction
      in pelvic pain and an improvement of symptoms on pelvic examination. These
      effects were also reported during the follow up visits (24 weeks). Only 12
      patients had intolerable side effects (hot flushes, sweating during the night,
      vaginal dryness, depression), which could be managed with transdermal 17 beta
      estradiol, without reducing therapeutic effectiveness. In conclusion,
      gonadotropin releasing hormone analogs proved to be an excellent treatment for
      symptomatic endometriosis and are generally well tolerated.

PMID- 10355040
TI  - [Ambulatory hysteroscopy in evaluation of postmenopausal bleeding].
AB  - INTRODUCTION: Diagnostic hysteroscopy is the most precise procedure to evaluate
      diseases involving the uterine cavity. There is, however, only limited data
      concerning the use of hysteroscopy carried out as an outpatient procedure in
      patients with postmenopausal bleeding. MATERIALS AND METHODS: In this study we
      report on 360 postmenopausal patients with erratic bleeding, who were referred to
      our outpatient hysteroscopy clinic. 185 women had frank postmenopausal bleeding
      (PMB) and another 175 had abnormal uterine bleeding while taking hormone
      replacement therapy (AUB). The mean age was 57.9 years (range: 42-86). All
      hysteroscopies were performed using a standard 5-mm hysteroscope with a 30
      degrees fore-oblique lens; the uterine cavity was generally distended with normal
      saline. RESULTS: Outpatient hysteroscopy was performed successfully in 339
      patients (94.2%). In 166 cases (46.1%) cervical dilatation was necessary, and 138
      required (38.3%) intracervical anaesthesia. Intrauterine pathology was diagnosed
      in 49.6% of cases, with endometrial polyps (20.9%) and fibroids (15.9%) being the
      most common abnormalities. While there was no difference in the incidence of
      intrauterine lesions between patients with AUB and those with PMB, endometrial
      carcinoma was more common in the latter group (PMB: n = 11 vs. AUB: n = 1; p <
      0.002). CONCLUSION: Due to its high accuracy and patient acceptance, outpatient
      diagnostic hysteroscopy should become a first line investigation in
      postmenopausal patients with bleeding disorders.

PMID- 10355041
TI  - [Long central apnea as the chief symptom of aseptic meningoencephalitis in a 6
      week-old infant].
AB  - Viral infections can cause apnoea, bradycardia, and desaturation events in
      preterm and new born infants. These symptoms do not always occur in older
      infants. A link between virus infection, apnoea, apparent life threatening events
      (ALTE) and sudden infant death (SID) is speculated. We report a 6-week-old infant
      with long central apnoea as the first and main symptom of meningoencephalitis
      caused by enterovirus.

PMID- 10355042
TI  - [Carl Adolph von Basedow--on the 200th anniversary of his birth].
AB  - Carl Adolph von Basedow was the son of an aristocratic family and was born 1799
      in Dessau. He was the grandson of the famous pedagogue Johann Bernhard Basedow.
      He studied medicine at the university of Halle and spent two years in the
      surgical service of Paris hospitals--the Charite and the Hotel Dieu. In 1822, he
      settled in Merseburg as a physician. He was soon acclaimed as a genial and
      skilled helper in all branches of medical practice. He performed his own post
      mortem examinations and published findings on a number of different diseases. His
      famous contribution in the thyroid field appeared in 1840 entitled "Exophthalmos
      due to hypertrophy of the cellular tissue in the orbit". Exophthalmos, goiter and
      palpitation of the heart have become known as the Merseburg Triad. In 1848, he
      published the autopsy findings on a patient who died from "exophthalmic
      cachexia". In Germany and some other countries, the disease was named as Morbus
      Basedow since 1858. In 1854 he pricked in his finger in the postmortem room when
      examining a patient who had died of typhus and he succumbed to septicemia at the
      early age of fifty-five. The date of his death was April 11, 1854. On April 14,
      he was laid in the Sixtus Cemetery in Merseburg. Basedow postulated that a wrong
      mixing of the blood manifested in cell tissue congestion and glandular vegetation
      cause the manifestations of disease. If we abstract our modern knowledge and
      accept circulating antibodies and disturbance of the immune balance as a
      dyscrasia as well as the proliferation of lymphocytic clones and local cellulary
      infiltration in terms of immune thyroiditis and autoimmune orbitopathy as cell
      tissue congestion and glandular vegetations, then doubt arise whether we have
      indeed made much progress in the last 150 years. At least, respect for the genius
      of the general physician Carl Adolph von Basedow is becoming greater. We may all
      hope that in the contributions and the discussions, we shall learn where we stand
      at the end of the century and what new avenues of research are appearing on the
      horizon.

PMID- 10355043
TI  - [Genetic risk markers in Graves' disease].
AB  - Graves' disease is exceptional as a disorder of stimulatory autoimmunity in
      comparison with all other endocrine autoimmunopathies. Research into its
      pathogenesis has so far focussed on the genetics next to characterisation of
      antibody-antigen as well as T-lymphocyte interactions. A multigenic
      predisposition similar to other autoimmune diseases has been proposed. Such
      polygenic disorders are frequent in the population and require special genetic
      epidemiological tools to dissect the many gene loci, where polymorphisms are
      readily detectable by several molecular typing assays. This review presents these
      tools and methods as well as the currently identified main susceptibility loci in
      the Human Leukocyte Antigen (HLA DQA1*0501), cytotoxic T-lymphocyte antigen 4
      (CTLA4-ala17) as well as interferon-gamma (IFN-gamma *2) regions. Most of these
      predisposing alleles are shared risk factors in several endocrine autoimmune
      diseases. Further research is required to identify those gene variants that
      determine the individual course of thyroid stimulation or destruction.

PMID- 10355044
TI  - [The sodium-iodide-symporter (NIS): function, regulation and clinical
      importance].
AB  - Cloning, functional characterisation, and diagnostic proof of the expression of
      sodium-iodide-symporter (NIS) in the thyroid are essential steps for a better
      understanding of function and regulation of thyroid hormone synthesis, which is
      limited by the availability of the trace element iodide. The physiological or
      pharmacological modulation of NIS function can now be used for a rational
      functional diagnosis and therapy of thyroid diseases. Diagnostic procedures based
      on analysis of the this gene or its expression are already in use for the
      analysis of benign and malignant alterations of the thyroid. Experimental
      protocols aiming at the functional expression of NIS in thyroid tumors or their
      metastases which lost capability for iodide uptake are currently developed.
      Furthermore, techniques are under investigation to express functional NIS by gene
      transfer in those benign or malignant tissues, tumors, metastases, which normally
      do not accumulate iodide. This would allow application of radioiodide therapy, a
      save and established technique to non-thyroid-related fatal diseases.

PMID- 10355045
TI  - Non-autoimmune hyper- and hypothyroidism due to mutations in the thyrotropin
      receptor gene.

PMID- 10355046
TI  - [Mutations in the thyrotropin receptor gene in the pathogenesis of toxic thyroid
      adenomas, toxic goiter nodules and autosomal dominant hyperthyroidism].
AB  - In iodine deficiency regions such as Germany, more than 50% of toxic thyroid
      adenomas and some toxic goiter nodules harbor activating mutations in the TSH
      receptor or Gs-alpha gene. These mutations cause cellular hyperfunction and
      hyperthyroidism but are not sufficient to generate thyroid adenomas and nodules.
      In the pathogenesis of these tumors, other primary and secondary molecular
      mechanism are operative, including overexpression of growth factors, their
      receptors and of signaling proteins. Expression of some of these growth factors
      is regulated by TSH-dependent pathways. However, iodine deficiency and its effect
      on thyroid growth remains the most important pathogenetic factor for these
      diseases. Therefore, toxic adenomas as well as the majority of nonfunctioning and
      eufunctioning thyroid nodules and adenomas are relatively rare in regions with
      high iodide intake of the population.

PMID- 10355047
TI  - [Etiology and pathophysiology of Graves' disease].
AB  - Infectious agents are considered as etiologic factors for the onset of Graves'
      disease, while psychosocial stress and smoking may amplify the pathogenic
      cascade. Furthermore, smoking increases the risk of developing Graves'
      ophthalmopathy. Occasional evidence indicates that the autoimmune process may
      primarily be induced by foreign antigens, leading to the synthesis of antibodies
      which, in part, cross-react with thyrocytic TSH receptors. Once initiated,
      autoimmunity appears sustained within the thyroid by the cooperation of
      immunomodulated thyrocytes and antigen-presenting dendritic cells, which may,
      moreover, cause humoral responses against further thyrocytic antigens. Owing to a
      local increase in cytokine and integrin expression, lymphocytes and monocytes are
      attracted to the organ. The synthesis of autoantibodies is mainly propagated by T
      helper-2 cells, while, at the same time, T-suppressor cells appear to be
      functionally deficient. Proof for this hypothetical scenario may allow for novel
      immunotherapeutic onsets in the near future.

PMID- 10355048
TI  - [Pathogenesis of Graves' ophthalmopathy].
AB  - Ophthalmopathy, the most frequent extrathyroidal manifestation of Graves'
      disease, results from an increased volume of the orbital tissues (connective and
      adipose tissue, interstitial enlargement of extraocular muscles) within the
      enclosed space of the bony orbits. While the primary antigen is still uncertain,
      the thyrotropin receptor has recently become a prime candidate because it is
      expressed both by thyroid epithelial cells and by orbital preadipocyte
      fibroblasts. Tolerance towards the thyroidal and orbital TSH receptor may be
      disrupted by bacterial or viral antigens through a "molecular mimicry"-type
      mechanism. In the context of appropriate costimulatory signals, this would prompt
      antigen presentation by local dendritic cells and macrophages followed by the
      recruitment of TSH receptor-specific T cells to the orbital space. As a result,
      orbital T cells, fibroblasts, adipocytes and perhaps other residential cells
      would release numerous cytokines, growth factors and inflammatory mediators, many
      of which act as potent stimulators of glycosaminoglycan accumulation and edema
      formation. Once initiated, the orbital immune process frequently takes on a
      momentum of its own, leading to non-specific but nonetheless harmful consequences
      such as tissue hypoxia, oxygen free radical damage and fibrogenic tissue
      remodeling. The clinical signs and symptoms of GO reflect the mechanical
      consequences of increased orbital tissue volume and pressure within the confines
      of the bony orbits.

PMID- 10355049
TI  - [Hyperthyroidism in Graves' disease--antithyroid drug treatment].
AB  - In patients with the first manifestation of hyperthyroidism of Graves' disease,
      antithyroid drug treatment is the therapy of first choice. Treatment has to be
      carried out depending on iodine supply of the individual patient with the lowest
      possible drug dose. Controls of treatment have to be done in short intervals
      (every 2 weeks) until euthyroidism is reached, afterwards controls of thyroid
      function have to be done every three months. After euthyroidism is established,
      the combination of antithyroid drug therapy with thyroid hormones may be useful
      to avoid hypothyroidism or goiter development during treatment in contrast to a
      monotherapy with antithyroid drugs. Antithyroid drug treatment has to be carried
      out for one year. The remission rate of patients is not increased with higher
      doses of antithyroid drugs or a longer treatment duration. By means of the
      established methods the determination of TSH receptor antibodies does not help
      predicting a relapse of hyperthyroidism of Graves' disease in the individual
      patient at the end of or after treatment. Clinical studies using the human TSH
      receptor have to elucidate whether these new methods to measure TSH-receptor
      antibodies are of prognostic relevance. Regular follow-up controls after
      antithyroid drug treatment are necessary to recognize relapse of Graves' disease
      in time.

PMID- 10355050
TI  - [Administration of levothyroxine in the treatment of Basedow disease].
AB  - Current therapy of Graves' disease is symptomatically effective in eliminating
      hyperthyroidism but is not directed towards the immunological cause of the
      disease. As a result, the majority of patients experience relapse of
      hyperthyroidism after antithyroid drugs have been discontinued and need to
      undergo radioiodine treatment or surgery. Improvement of efficacy of antithyroid
      drug therapy in inducing longlasting remission of Graves' disease has therefore
      been an elusive goal. A number of recent experimental and clinical trials have
      addressed the issue of improving and optimizing modalities of antithyroid
      therapy. In-vitro studies demonstrating direct immunosuppressive effects of
      thionamide drugs and encouraging results from a Japanese clinical trial suggested
      that maximum thyroid blockade and supplementation with levothyroxine might be
      effective in preventing relapse of disease. The superior efficacy of this
      approach could not be confirmed by others studies. On the other hand, these
      studies so far lack statistical power to prove a lack of effect of this approach.
      The issue of levothyroxine supplementation during antithyroid drug treatment
      should be separated from another issue of levothyroxine prophylaxis following
      successful treatment outcome. The latter question is currently addressed by a
      prospective randomized multicenter study.

PMID- 10355051
TI  - Antithyroid drug therapy: predictive parameters.
AB  - Antithyroid drugs have mainly been used to obtain euthyroidism in patients with
      chronic hyperthyroidism independent from its etiology and for long-term medical
      treatment of hyperthyroidism due to Graves' disease. Endocrinologists are faced
      with the problem of potential side-effects and a high relapse rate (30-50%) after
      an apparently successful treatment course. Several studies have therefore been
      undertaken to find parameters for the prediction of outcome of antithyroid drug
      therapy. Most of the investigated variables have proven rather disappointing as
      predictors. The strongest investigated predictors are goitre size and the level
      of thyrotropin receptor antibodies. It may be concluded that patients with very
      large goitres and high levels of thyrotropin receptor antibodies are unlikely to
      obtain permanent euthyroidism by treatment with antithyroid drugs, and therefore
      might benefit from a more destructive therapy (radioiodine or surgery) at an
      early stage of the disease. For all other patients prediction of outcome is not
      possible at present and choice of therapy should be based on available studies on
      high versus low dose antithyroid drug therapy, optimal length of therapy, in all
      cases with careful consideration of risk of side-effects.

PMID- 10355052
TI  - [Surgical treatment of Graves' disease].
AB  - In the surgical treatment of Graves' disease, there are several concepts
      established. The methods of bilateral subtotal resection, hemithyreoidectomy
      combined with contralateral subtotal resection, near-total resection and total
      thyreoidectomy all have there rightful placement in the surgical treatment of
      Graves' disease. The method of choice should be selected according to the
      activity of the disease. To avoid a recurrence of the disease, the more
      aggressive resections have proven to be more successful and there's evidence of
      preference of these techniques lately. Despite the more refined surgical
      techniques, the radical resections are still burdened with higher complication
      rates, specifically recurrent nerve palsy and hypoparathyroidism. Due to the
      excellent long lasting results of total thyreoidectomy, this concept appears to
      be the most convincing when technically well administered as it reliably cures
      the disease. The further development and regular use of technical aid such as
      surgical magnification lenses and neuromonitoring are expected to eventually help
      improve the more radical surgical concepts in the future. The prospect of
      combining surgical therapy with radioiodine-therapy may represent a chance to
      cure Graves' disease effectively and minimize complications from different sides.

PMID- 10355053
TI  - [Radioiodine therapy of Graves' disease--quality assurance and radiation
      protection].
AB  - Radioiodine (I-131) is used successfully since more than 50 years for treatment
      of hyperthyroidism in Graves' disease. In the USA, more than half of the patients
      with a Graves' hyperthyroidism are treated primarily with radioiodine, whereas in
      Europe the frequency is less than a quarter of the patients. In Germany consensus
      could be achieved, the antithyroid drugs are indicated in patients with manifest
      hyperthyroidism to induce euthyroidism before radioiodine treatment. Typical
      indications for radioiodine treatment are: Treatment with antithyroid drugs
      without success for more than one year, drug-incompatibility and increased risk
      for surgery. In relation to the radiation dose applied, hyperthyroidism is
      eliminated after radioiodine treatment; in 80-100% of the patients the incidence
      of hypothyroidism ranges between 50 and 100%. In Germany, for reasons of quality
      assurance and radiation protection, radioiodine treatment is carried out in
      hospitals with wards equipped with radiation protection facilities; fractionated
      treatment with radioiodine is not allowed. Due to recent changes in radiation
      protection regulations, patients can be dismissed earlier from the wards than
      before; the mean duration of stay could be decreased from 10-12 to 3-4 days.
      Radioiodine treatment is safe and has only few side effects. However, patients
      have to be followed-up for life. Considering the cost-benefit-relation,
      radioiodine treatment has advantages especially in patients with small goiters as
      compared to surgery.

PMID- 10355054
TI  - Treatment of endocrine ophthalmopathy.

PMID- 10355055
TI  - [Transplantation immunology].

PMID- 10355056
TI  - [Transplantation immunology].
AB  - Allogeneic grafts can be immunologically attacked by different rejection types:
      hyperacute, accelerated, acute, and chronic rejection. The introduction of the
      "crossmatch" before transplantation into the clinical routine completely prevents
      the hyperacute rejection. The development of new immunosuppressive agents, which
      are just approved, will make the management of accelerated rejection more
      efficient, too. Modern immunosuppressive agents are very efficient in the
      prevention of early acute rejection. In order to delay or even to prevent
      development of chronic rejection, the diagnostic of early and late acute
      rejection has to be improved. The clinically symptomless CMV infection is a very
      important risk factor of chronic rejection and an antiviral therapy can prevent
      acceleration of chronic rejection by CMV. We had to learn that CMV and other
      viral infection are not only a problem of the early post-transplant course.
      Another approach for prevention of chronic rejection is the reduction and control
      of unspecific inflammatory processes triggered peri-operatively by
      ischemia/reperfusion injury.

PMID- 10355057
TI  - [Immunosuppressive therapy in autoimmune diseases].
AB  - Autoimmune diseases play an increasing role in daily practise. Advanced
      understanding of the pathogenesis and pathophysiology enables an outcome
      orientated therapy leading to a far better prognosis. Immunosuppressive drugs are
      essential for the treatment. The therapeutical concepts are adopted to the
      individual character and stage of the disease. In the meantime, therapeutical
      regimes combine certain drugs. Although it is not possible to cure these
      autoimmune diseases, a remission can be achieved in most cases. Further
      developments will concentrate on more selective strategies and the potentials of
      gene therapy.

PMID- 10355058
TI  - [Treatment of rheumatoid arthritis with cytokine antagonists].
AB  - The blockade of proinflammatory cytokines is an interesting experimental approach
      for the therapy of rheumatoid arthritis. Various biological inhibitors are
      currently being tested in a number of large clinical studies with encouraging
      results. This review summarizes the existing data and discusses potential future
      developments.

PMID- 10355059
TI  - [Treatment with immunoglobulins].
AB  - The application of various formulations of immunoglobulins has become feasible
      for an impressive array of indications, and the number of available preparations
      is quite considerable. Nevertheless aside from immunologic/haematologic routine
      the relation of promise, cost and risk is hard to estimate. This presentation
      will try to review these factors for certain groups of diseases.

PMID- 10355060
TI  - [The DEGAM-concept--development, dissemination, implementation and evaluation of
      guidelines for general practice].
AB  - The German Society for General Practice/Family Medicine (DEGAM) has launched a
      project to develop and implement national guidelines for general practice
      accordingly to international models. Guidelines are seen as statements to assist
      practitioners and patients in deciding about appropriate, effective and efficient
      health care. They should be evidence-based, feasible for primary care practices,
      and purposefully addressing to physicians as well as practice staff and patients.
      The development follows a comprehensive and well-structured programme (10 stages)
      which requires the appraisal of medical evidence, the involvement of experienced
      general practitioners on various stages (primary review, feasibility testing),
      and comments of concerned specialists, before a guideline is promulgated.
      Implementation of each guideline is promoted by at least five tools (full text,
      quick reference guide, telephone card for practice staff; patient leaflet, and
      information-prescription--"infozept"). Methodological quality is checked for the
      first time in Germany according to the standards of the German Agency for Quality
      Assurance. Different targets and criteria for evaluation of guidelines in primary
      care are mandatory part of the DEGAM-concept.

PMID- 10355061
TI  - [Quality assessment of medical care--a standardized scheme for the development of
      quality indicators].
AB  - A reliable and valid assessment of the quality of medical interventions is an
      indispensable prerequisite for any initiatives targeting at quality improvement
      in the health system. Quality indicators are well suited tools for such tasks,
      e.g. in the setting of a continuous monitoring. In the German health system,
      previous experiences concerning the use of quality indicators are limited.
      Available knowledge from medical services of other nations is mainly focused on
      the hospital sector. Therefore, it appears to be desirable to be able to provide
      a highly universal and standardized way for the definition of indicators of
      quality, enabling measurements of performance in any kind of health sector or
      disease treatment. Based on the demand for continuous quality monitoring in the
      sector of outpatient care recognized by the Central Institute of Panel
      Physicians, an indicator development scheme is demonstrated.

PMID- 10355062
TI  - [Quality assurance regarding cooperation between general practitioners and
      psychiatric services].
AB  - Although evaluation of client satisfaction is of great importance in quality
      assurance of psychiatric care, general practitioners' cooperation with
      psychiatric services was rarely investigated until now. The referral to a
      psychiatric hospital is a substantial problem area. Apart from length of waiting
      lists, competence of hospital and quality of cooperation, particularly general
      practitioner's role perception regarding mental illness determines referral
      policy. The need of general practitioners should be taken into consideration in
      planning psychiatric care to improve the treatment of patients with mental
      disorders.

PMID- 10355063
TI  - [Comprehensive quality management in hospitals--experience and recommendations].
AB  - Total quality management concepts, increasingly being introduced into hospitals,
      offer opportunities for integrative leadership concepts because of their
      multidimensional character viewed from the aspects of results and from the
      standpoint of organisational design. Customized for leadership and organisation
      of hospitals in Germany, questions of introduction strategies as well as
      recommendations for the integration of total quality understanding into the daily
      practice of management and employees are discussed. The active support of top and
      middle management and a combination of radical change in selected problem areas
      and continual incremental improvements on a broad base have been proven as
      significant factors for the success in the introductory phase. For a lasting
      integration of the principles of a comprehensive quality management concept in a
      hospital, it will be necessary to carry out regularly relevant measurements of
      success. The results become an important part of agreements with management.

PMID- 10355064
TI  - [Quality assurance in rheumatology].
AB  - Coming from a collection of letters for quality assurance in rheumatology, a
      provisional program by the Commission for Quality Assurance of the German Society
      for Rheumatology is introduced. The completion and supplementation of the manual
      has been started already. The necessary continuation of this process shall be
      undertaken via internet. Contacts with other medical societies are planned to
      improve the consensus of the guidelines and to work on comprehensive topics of
      global interest. General practitioners and self-help groups for patients should
      be consulted to optimize this project. Specific controversially discussed
      procedures for diagnosis and therapy have to be clarified by prospective studies.
      Finally, the result of this project has to be reviewed by using the criteria for
      the assessment of guidelines developed by the Society of Physicians of Germany
      resulting in evidence based guidelines. The most important aspects of a
      comprehensive quality management in practices for rheumatology, rheuma- and
      rehabilitation hospitals are pointed out.

PMID- 10355065
TI  - [Quality assurance in geriatric medicine].
AB  - This article describes the peculiarities of geriatric quality assurance from the
      view of a clinical setting. Description of structural elements of quality are
      well known. Improvements in process quality of individual patient care have been
      sustained by controlled studies on comprehensive geriatric assessment. However,
      implementation of results from comprehensive assessment into external rating
      systems for hospital accreditation/certification still needs further research.
      The documentation of product quality depends on the measurement of patients'
      independency, activities of daily living and subjective well being.

PMID- 10355066
TI  - [Hypertrophic cardiomyopathy (HCM). Surgical versus drug therapy].
AB  - Hypertrophic cardiomyopathy (HCM) is a disease with different etiological,
      morphological, functional, clinical and therapeutic aspects. Recent
      investigations indicate that HCM is considerably widespread in the population
      (1:500). The causes seem to generate from familial or sporadic abnormalities
      (mutations). Depending on the clinical aspect, the complaints, and on the basis
      of morphologic and hemodynamic investigational results, we mainly have to
      consider two types of medical and surgical management. 1. Hypertrophic
      nonobstructive cardiomyopathy (HNCM) Patients may have no hemodynamic or
      morphologic deviations, but may be identified by familial moleculargenetic
      investigations. Others may have different types of rhythm disturbances which may
      indicate a higher risk of sudden death. Depending on the degree of hypertrophy,
      the clinical impairment indicates medical therapy with beta-blockers, Ca
      antagonists, and antiarrhythmic drugs. In the case of clinical deterioration and
      manifestation of myocardial insufficiency diuretics, digitalis, ACE inhibitors,
      and catecholamines are indicated. Further impairment may lead to heart
      transplantation or as a bridging procedure to implantation of a left ventricular
      or biventricular assist device until a suitable donor heart is available. 2.
      Hypertrophic obstructive cardiomyopathy (HOCM) Symptomatic patients may have
      different localizations of the left ventricular outflow tract obstruction (LVOTO)
      in the subaortic area (typical form) and in midventricular position of the LV
      (atypical form). The first therapeutic step is always medical therapy with beta
      blockers, Ca antagonists, and antiarrhythmic drugs. Further deterioration toward
      clinical class III (NYHA) despite long-term medication until recently was
      generally accepted as indication for transaortic subvalvular myectomy (TSM).
      Today mostly two other techniques are preferred--if possible Double chamber
      pacing (DCP) (atrial triggered ventricular pacing), Transcoronary ablation of
      septal hypertrophy (TASH) (by selective injection of alcohol, 95%, into the first
      septal branch). Especially in younger patients, after syncope, life-threatening
      tachyarrhythmias, and after resuscitation, the implantation of a cardioverter
      defibrillator may be necessary. Comparative prospectively randomized studies
      between different therapeutic regimens for HOCM are not available. Retrospective
      analyses of patients after TSM show a considerable clinical improvement. The risk
      of sudden death is relatively low, but not excluded. Patients after TSM
      demonstrate advantages concerning the survival rate despite the more deteriorated
      condition against those after medical therapy only. According to the new
      interventional techniques, long-term results are not yet available, of course.
      However, the long-term results after TSM may serve as a comparative standard
      which have at least to be reached by DCP and/or TASH.

PMID- 10355067
TI  - [Therapy of acute heart failure--surgical possibilities].
AB  - Acute heart failure represents a severe complication of several cardiac
      disorders. Coronary artery disease, acute bacterial endocarditis or acute
      decompensation of preexisting heart valve disease as well as endstage
      cardiomyopathies are the most frequent underlying causes. Because of the high
      mortality, surgical therapy should be always considered in addition to medical
      treatment. However, any therapeutical intervention must be based on an immediate
      diagnosis to evaluate type and severity of the disease. Surgical options comprise
      coronary revascularization, valve replacement or--reconstruction as well as a
      temporary support by means of mechanical assist devices.

PMID- 10355068
TI  - [Changes in heart surgical strategies: a word of caution].
AB  - The introduction of minimally invasive coronary artery bypass surgery has
      expanded the technical armementarium for operative treatment of coronary artery
      disease. Minimal access surgery using partial sternotomy or anterior intercostal
      minimal thoracotomy can be combined with videoscopic techniques or port-access
      methods. Either atrio-aortal cannulation, femoro-femoral or jugular-femoral
      connections to the pump are possible for extracorporal circulation (ECC). Even
      endoluminar occlusion of the aorta and application of cardioplegia into the
      aortic root can be considered and applied. Extracorporal circulation has
      developed into a safe standardized method. As far as pathophysiology is
      concerned, the decision to use ECC or not is of much more importance than the
      grade of invasiveness. Fundamentally we therefore need to distinguish between
      minimally invasive methods with and without ECC. Video-assisted coronary surgery
      in hearts under hypothermia and fibrillation with ECC is also recommended
      occasionally. Minimally invasive coronary artery procedures on beating hearts
      without ECC have to be done in a stabilized and bloodless operative field to
      allow the construction of high standard anastomoses between bypass grafts and
      coronary arteries. In practice, silicon occluders, epicardial and myocardial
      suture occlusion and fixation, mechanical stabilization devices, and
      pharmacologic induction of bradycardia are used. In principle a skilled surgeon
      should be familiar with all these methods to select the most suitable solution
      for the special clinical problem. A final judgement about each method is not
      possible up to now. High patients numbers have to be recruited in the groups and
      subgroups due to low mortality (1%) and morbidity (5%), otherwise statistical
      significance of the results cannot be gained.

PMID- 10355069
TI  - [Medicamentous prevention of symptomatic paroxysmal atrial fibrillation/flutter
      onset. Goals and design of the SOPAT Study. Executive committee of the
      investigators representing trial physicians].
AB  - The indication to treat symptomatic paroxysmal atrial fibrillation is discussed
      controversely. Successful medical treatment may result in the reduction of
      symptoms by improving hemodynamics in a reduction of thromboembolic events.
      However, several antiarrhythmic drugs are also known to increase the risk of
      proarrhythmic events. A randomized, double-blind, and placebo-controlled
      multicenter trial with 1000 patients to be recruited was designed to compare the
      effects of two antiarrhythmic drugs frequently used in Germany for the treatment
      of atrial fibrillation, Sotalol and the fixed combination of chinidin and
      verapamil (Cordichin). Patients with symptomatic paroxysmal atrial
      fibrillation/atrial flutter will be observed for a period of one year. The
      occurrence of paroxysmal atrial fibrillation is documented by transtelephonic ECG
      monitoring. Patients with document an ECG once daily, and recording is mandatory
      in case of symptoms. ECGs are transmitted to a central data base for analysis.
      This clinical trial is designed to answer the following questions: (1) What is
      the average rate of spontaneous events of symptomatic atrial fibrillation? (2) Is
      it possible to reduce the frequency of symptomatic events by chronic
      antiarrhythmic drug administration? (3) What is the long-term frequency for the
      occurrence of severe side-effects under antiarrhythmic medication? The primary
      endpoint is defined as the time to first recurrence of symptomatic arrhythmia
      after reaching steady-state plasma concentrations of the study medication. The
      trial started in November 1997 and is planned to be finished by the end of 1999.

PMID- 10355070
TI  - [Medicamentous prevention after electric cardioversion of chronic atrial
      fibrillation. Goals and design of the PAFAC Study].
AB  - Atrial fibrillation (AF) is the most frequent cardiac arrhythmia. However,
      despite manifold publications reflecting numerous clinical trials about treatment
      of AF, the management of this arrhythmia is still under controversial discussion,
      in daily clinical work as well as in research. The present study concentrates on
      three major questions: 1. How frequent are recurrences of AF in long-term follow
      up? Most of the previous studies used the occurrence of symptoms as a surrogate
      parameter for recurrences of AF, despite the expected high rate of asymptomatic
      relapses. In the present study a daily transtelephonic ECG transmission enables a
      rhythm monitoring independent of symptoms. 2. Is the frequency of AF recurrences
      significantly reduced by antiarrhythmic medication? A direct comparison of class
      I and III antiarrhythmic drugs, which still are most frequently used for this
      indication, and of placebo will answer this question. 3. How safe is the long
      term treatment for the prevention of AF recurrences with special respect to
      proarrhythmic effects? The daily transtelephonic ECG transmission enables a
      quantitative and qualitative monitoring of tachy- and bradyarrhythmias
      independent of symptoms. Additionally, the daily analysis of ECG measures may
      detect parameters predicting subsequent life threatening arrhythmias. The study
      design provides a prospective, randomised, double-blind, placebo controlled,
      multicenter parallel group comparison. In Germany and in the Czech Republic about
      90 hospitals will include 900 patients with documented chronic AF, age 18 to 80
      years, if they are eligible for electrical cardioversion without concomitant
      antiarrhythmic drug therapy and if they are anticoagulated for at least three
      weeks prior to inclusion. Neither the size of the left atrium nor the duration of
      chronic AF are exclusion criteria. A few hours after successful electrical
      cardioversion the patients are randomised either to sotalol (2 x 160 mg) or
      quinidine + verapamil (3 x 160 mg + 3 x 80 mg) or placebo. Starting at the day
      after cardioversion, the patient is asked to record and transmit
      electrocardiograms of one minute duration at least once a day using his personal
      transtelephonic ECG recording unit (Tele-ECG recorder, credit card size), in case
      of symptoms as often as necessary. The ECGs can be transmitted at any time by any
      regular phone without additional equipment using a toll free number. A custom
      made, computer based, fully automated receiving centre is handling the patient
      calls interactively with voice control, including a voice recording of the
      patient's symptoms. The ECG tracings and the patient's voice messages are
      subsequently computer based analysed by experienced technicians. All ECG measures
      are stored in a database. In case of AF recurrence, any other relevant arrhythmia
      or additional abnormalities (e.g. QT prolongation) the correspondent hospital is
      immediately informed by fax. In case of AF recurrence, a subsequent Holter
      recording discriminates in paroxysmal and permanent AF. Study medication is ended
      if either permanent AF or the third episode of paroxysmal AF are detected or
      after 12 months of follow-up. Regular follow-up visits are performed monthly.
      Major endpoints are the time to first recurrence of AF or the time to death,
      secondary parameters are the number of AF recurrences, the time to end of
      medication and AF related symptoms. The recruitment started in the last days of
      1996. Until the end of June 1998, 424 patients have been randomised. It is
      expected to end recruitment in spring 1999 and to close the study in spring 2000.
      Final results will be available in summer 2000.

PMID- 10355071
TI  - [Sublingual nitroglycerin or intravenous enalaprilat in preclinical treatment of
      hypertensive patients with pulmonary edema].
AB  - In a prospectively designed randomized study, we compared the efficacy of
      sublingual nitroglycerine and intravenous enalaprilat in the out-of-hospital
      treatment of 46 hypertensive patients with pulmonary edema (defined as rales over
      both lungs and systolic blood pressure > 200 mm Hg and diastolic blood pressure >
      100 mg). The out-of-hospital treatment consists of oxygen (6 Ll/min) via a face
      mask, furosemide 80 mg i.v., opioids 10 mg s.c., and either sublingual
      nitroglycerine (n = 23; initial dose: 0.8 mg; repetitive application of 0.8 mg
      every 10 min until a cumulative dose of 3.2 mg) or intravenous enalaprilat
      (initial dose: 2.5 mg; repetitive application of 2.5 mg every 30 min until a
      cumulative dose of 10 mg). The aim of the antihypertensive treatment was a
      reduction of systolic blood pressure below 160 mm Hg and diastolic blood pressure
      below 90 mm Hg until admission to the emergency department. In the emergency
      room, an arterial and venous blood sample was taken to determine the respiratory
      (pO2, pCO2) and metabolic status (pH value; base-excess; serum lactate) of the
      patient. Successful antihypertensive treatment was observed in 13/23 (57%)
      patients of the enalaprilat group and 15/23 (65%) patients of the nitroglycerine
      group (p = 0.54). Systolic and diastolic blood pressure on admission were similar
      in both treatment groups (systolic RR: enalaprilat: 179 [31] mm Hg;
      nitroglycerine: 184 [38] mm Hg; p = 0.59; diastolic RR: enalaprilat: 96 [14] mm
      Hg; nitroglycerine: 101 [14] mm Hg; p = 0.12). No significant differences were
      observed between the enalaprilat and the nitroglycerine groups concerning
      respiratory and metabolic parameters on admission (pO2: 67 [15] vs. 64 [17] mm
      Hg; p = 0.50; pCO2: 46 [9] vs. 47 [13]; p = 0.75; pH value: 7.27 [0.12] vs. 7.27
      [0.09]; p = 0.98; BE: -4.2 [3.7] vs. -5.7 [4.1]; p = 0.23; lactate: 4.2 [3.3] vs.
      4.2 [2.7]; p = 0.98). Intravenous enalaprilat did not exhibit any advantage
      compared to nitroglycerine in terms of blood pressure reduction or respiratory
      and metabolic parameters on admission to the emergency room. We conclude that
      enalaprilat is no substitute for nitroglycerine in the out-of-hospital treatment
      of hypertensive patients with pulmonary edema.

PMID- 10355073
TI  - [Papillary muscle rupture during stress ECG after myocardial infarct].
AB  - The case of a 57 year old patient is reported, who suffered from an acute
      myocardial infarction with maximum CK and CKMB values of 821 and 84 U/l,
      respectively. The patient underwent bicycle exercise testing 9 days after a
      myocardial infarction in 25 W steps every 2 min starting with 50 W. The ergometry
      was interrupted at 125 W because of ST segment depression of 0.28 mV in V6.
      Systolic blood pressure dropped to 55 mm Hg, combined with severe angina and
      shock. Volume substitution and catecholamines did not elevate blood pressure.
      Immediate M-mode and Doppler echo revealed a "stiletto"-shaped mitral
      regurgitation profile typical of acute mitral valve insufficiency. The
      transesophageal echocardiogram showed a distinct mass moving between the left
      ventricle and left atrium, diagnostic of papillary muscle rupture. Despite of
      shock, mitral valve replacement was performed successfully. To our knowledge,
      this is the first report of a papillary muscle rupture during exercise testing
      after myocardial infarction. Papillary muscle rupture can be induced by exercise.
      This fateful event may not be predicted by the course of the ergometry. In case
      of hypotension during exercise, papillary muscle rupture should be considered.
      The diagnosis is to be established by transesophageal echocardiography.

PMID- 10355072
TI  - [The heart and metabolic syndrome].
AB  - Most people with the Metabolic Syndrome die from thrombotic complications
      superimposed to degenerative arterial vascular lesions, mostly myocardial
      infarction. Type-2-Diabetes is a risk factor per se for such complications, but
      often clusters with dyslipoproteinemia, hypertension and obesity. This is
      referred to as "Metabolic Syndrome" and often operates on a genetically
      programmed susceptibility which accelerates the pathogenesis of coronary artery
      disease in front of a much wider diabetes specific cardiopathy. From a
      pathophysiological point of view none of these associated risk factors explains
      the pathogenetic series of events leading to the precipitation of an occlusive
      thrombus at sites of complicated coronary plaques. In patients with the Metabolic
      Syndrome the coagulation system is switched towards a prethrombotic state,
      involving increased plasmatic coagulation, diminished fibrinolysis, decreased
      endothelial thromboresistance and predominantly platelet hyperreactivity
      ("diabetic thrombocytopathy"). Some of these factors are associated with an
      increased coronary risk (e.g. fibrinogen, PAI-1, platelets), but are also
      directly linked to the pathogenesis of "atherothrombosis". Altered cardiac
      remodelling together with adhesion and coagulation mechanisms appears suitable to
      explain decreased functional performance of infarcted organs, decreased success
      of acute (reduced fibrinolytic response, no reflow phenomenon) and longterm
      intervention strategies for vessel patency (PTCA, CABG) in Diabetes. Glucose
      adjustment alone will not adequately neutralize these complex mechanisms, but in
      the situation of myocardial infarction eumetabolization with parenteral glucose
      insulin-potassium infusion appears mandatory similar to non-diabetics. On the
      longterm a multidimensional interventional repertoire is required particularly in
      patients with the Metabolic Syndrome including antihypertensive,
      antidyslipoproteinemic and antithrombotic drugs, customized according to the
      individual patients needs as assessed by early diagnostic measures ("early
      secondary prevention").

PMID- 10355074
TI  - [Transesophageal imaging of a coronary fistula in simultaneous endocarditis
      lenta].
AB  - A 61 year old diabetic patient with bacterial endocarditis probably caused by a
      congenital coronary fistula is presented. The fistula was already detected by
      transthoracic echocardiography. Transesophageal color-Doppler echocardiography
      identified the precise localization and course of the fistula. Additionally, in
      some parts of the fistula echogenic material could be seen that decreased in size
      after antibiotic treatment. Therefore, it was considered as corresponding to
      bacterial vegetations. Coronary angiography disclosed an ectopic aneurysmatic and
      elongated circumflex coronary artery. Thus, even in rare conditions such as
      coronary fistulas transesophageal echocardiography may be helpful to allow
      detection of morphological substrate of associated infective endocarditis.

PMID- 10355075
TI  - [Report on the structure and performance statistics of the heart catheterization
      laboratories in Germany. Results of a survey by the Committee of Clinical
      Cardiology of the German Society of Cardiology--Heart and Cardiovascular research
      throughout 1997].

PMID- 10355076
TI  - [Plaque inhibition with the GPIIb/IIIa antagonist Tirofiban].

PMID- 10355078
TI  - [Gaseous oxygen for protection and conditioning of organs during ischemia].
AB  - During organ ischemia, oxygen (O2) is the first "substrate", which is depleted.
      However, during ischemic storage in hypothermia (0-4 degrees C), a sufficient
      oxygenation is attainable by means of gaseous O2. The results of organ
      preservation were (mostly) better than those obtained with other methods at the
      respective times. O2 can be supplied via organ surfaces: Applying high O2
      pressures (3040-15,200 hPa), ileum and lungs or hearts had some functions after
      48 and 72 h storage, respectively; life-supporting functions regained kidneys and
      pancreas after 48 and 22 h storage, respectively. At normobaric conditions,
      intestine supplied with O2 via its lumen had during ischemic storage an aerobic
      metabolism and a better post-ischemic function. Using the "two-layer-method"
      (TLM), pancreas was stored for 96 h and after 90 min anaerobic warm ischemia
      (aWI) for 48 h with life-supporting functions after transplantation (Tx).
      Ischemic organs can be persufflated normobarically with gaseous O2 via their
      vessels. Hearts, skeletal muscles and kidneys in normothermia or frogs' spinal
      cords-remained viable for many hours. In hypothermia, kidneys damaged by 30 or 60
      min aWI could be preserved for 48 and 24 h, respectively, with life-supporting
      functions after Tx. Hearts subjected to several hours of aerobic ischemia
      performed post-ischemically better. Livers aerobically stored for 48 h, or for 24
      or 4 h after 30 or 60 min aWI, respectively, exhibited greatly improved post
      ischemic functions. After 60 min aWI and 2 h persufflation for reconditioning,
      livers could be stored for another 22 h period of anaerobic ischemia. With
      normobaric O2-persufflation or TLM during ischemia, energy supply in form of ATP
      and its demand-meeting utilisation during hypothermia are apparently guaranteed,
      so that even longer periods of ischemia for Tx-related measures can be overcome.
      Not only the maintenance of cell and organ integrity or of cellular functions,
      but also the repair of damaged structures and functions have become possible with
      less expenditures and risks than with perfusion. The composition of the solutions
      for preservation or reconditioning of the ischemic organs is pivotal.

PMID- 10355079
TI  - [Artificial oxygen carriers. Alternatives to homologous blood transfusion?].
AB  - The expected explosion of costs in transfusion medicine due to the shortfall of
      healthy donors and the more frequent treatment of transfusion-associated
      complications (chronic hepatitis, cirrhosis, wound infection, tumor recurrence)
      increases the socio-economic importance of the development of safe and effective
      synthetic oxygen carriers as an alternative to the transfusion of homologous red
      blood cells. Currently two types of artificial oxygen carriers are experimentally
      and clinically investigated for their capacity to ensure adequate tissue
      oxygenation in the case of severe anemia. In addition to their oxygen transport
      capacity solutions based on free human or bovine hemoglobin provide
      vasoconstrictor properties. Their hyperoncotic properties make them particularly
      attractive for the treatment of severe hemorrhagic shock. Perfluorocarbon (PFC)
      emulsions allow an increase of the physically dissolved portion of arterial
      oxygen content. Due to their particulate nature (emulsion droplets) PFC may only
      be infused in low doses. Otherwise there is risk of overload and malfunction of
      phagocytic cells of the reticulo-endothelial system. In the case of an
      intraoperative blood-loss in preoperatively hemodiluted patients, bolus infusion
      of PFC represents an effective means to avoid immediate retransfusion of
      autologous blood and allows for further, extreme hemodilution without risking
      tissue hypoxia.

PMID- 10355080
TI  - [Erythrocytes after cryopreservation with HES: molecular, structural and
      functional characteristics].
AB  - The use of hydroxyethylstarch (HES) as an alternative to glycerol for
      cryopreservation of erythrocytes is presented. Immediately after thawing
      erythrocytes showed alterations in the membrane skeleton and a lowered rigidity
      of their membrane. However, a few minutes after resuspension in a physiological
      salt solution the initial poicilocytosis changed back to normocytotic forms.
      Intravital microscopy of the dog's mesentery revealed a homogeneous distribution
      of labeled previously cryopreserved erythrocytes in the capillary bed. The
      lowering of the ATP-level in the erythrocyte by about 20 to 40% was seen to be
      harmless, because the ATP-turn over rate was unchanged and the glucose support by
      the GluT 1 carrier was seen to be guaranteed. There was no decrease in the 2,3
      DPG level on one hand, but a shift to the right in the O2-association as well as
      dissociation functions; the saturation capacity of hemoglobin with O2 on the
      other hand was constant. Free radical oxygen species, generated as a consequence
      of the freezing/thawing process, were inactivated by the erythrocyte's own
      antioxidation system. The 24-hour post-transfusion survival in dog amounted to
      about 95% and the in vivo-life time was normal. The hemolysis of human
      erythrocytes after thawing was about 5%. Most methodological and scientific
      problems concerning erythrocyte cryopreservation are considered to be solved.
      After official permission for use in humans, major benefits to many fields in
      surgery are expected: no more short-cuts in blood supply, practically complete
      exclusion of infectious risks, even unlimited use of autologous blood.

PMID- 10355081
TI  - [Predictive molecular diagnosis and preventive surgical treatment of hereditary
      colorectal carcinoma: a new field of interest for surgical research].
AB  - Colorectal cancer is one of the most frequent cancers in the Western hemisphere.
      It seems to be well established that colorectal tumors develop as a result of an
      accumulation of inherited and/or acquired somatic mutational events in tumor
      suppressor genes and oncogenes. An increasing understanding of the molecular
      basis of the most prevalent colorectal cancer syndromes, such as hereditary
      nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP),
      is reflected by modifications in diagnosis and therapy. Therefore, strategies
      have been developed for predictive molecular diagnosis and preventive surgical
      treatment of colorectal cancer syndromes. In the future surgical research will
      participate in research and development in the field of molecular diagnosis of
      colorectal cancer and will then evaluate the clinical management concepts as a
      result.

PMID- 10355082
TI  - [Immunocytochemical and molecular proof of disseminated tumor cells in bone
      marrow, peritoneal lavage, blood and regional lymph nodes. A review of the
      literature and own results].
AB  - Immunocytochemical or molecular detection of disseminated tumor cells in
      different compartments (bone marrow, abdomen, venous blood, lymph nodes) is
      becoming more and more important in determining the complete extent of the tumor
      at the time of primary therapy. However, their prognostic relevance is not clear
      up to now. Whereas their appearance in bone marrow revealed a poor prognosis in
      some studies, contradictory results have been obtained from examinations of lymph
      nodes. Moreover peritoneal lavage and venous blood have seldom been examined with
      these methods. Because standardization of the immunocytochemical or molecular
      techniques does not exist, therapeutical conclusions can not be drawn from their
      detection at this time.

PMID- 10355083
TI  - [Significance of the absorption of macromolecules for the immune response of an
      organism].
AB  - Numerous antigens are offered to the living organism by the daily food. With
      these investigations the influence of orally administered human gammaglobulin
      (HGG) on the immunity of sensitized animals after systemic immunization should be
      clarified. Experiments were performed in rabbits. Changes of the circulation were
      measured by bloodpressure registration and measurements of the organ flow.
      Simultaneous investigations of the antibody content, complement C3 and histamin
      were performed in the peripheral blood. In orally fed animals as well as in non
      fed controls an i.v. antigen challenge was performed. The level of circulating
      antibodies could be significantly decreased (60%) by the oral administration of
      HGG. In control animals the parenteral antigen challenge resulted in a mortality
      rate of 50%. In these animals the bloodpressure decreased significantly and long
      lasting, whereas antigen fed animals showed only a slight change in bloodpressure
      with normalization after a short period. During oral absorption of antigen
      complement factor C3 remained unchanged. In the first hour after the oral antigen
      administration a significant increase of histamin in the peripheral blood could
      be observed. Investigation with regard to the fate of the antibodies which were
      decreased by antigen feeding showed a storage in the layers of the gut which was
      depending on the dosage. It could be demonstrated that it is possible to
      influence the systemic immune response by the enteral application of
      macromolecules and this is also relevant for reactions of the circulation.

PMID- 10355084
TI  - [Vaccine development for P. aeruginosa: based on antigen cloning of clinical
      vaccines][.
AB  - For the development of a clinical vaccine against P. aeruginosa infections we
      cloned the genes for the main outer membrane proteins F and I of P. aeruginosa
      and characterized protective epitopes by monoclonal antibodies. A recombinant
      hybrid protein (OprFaa190-342-OprIaa21-83) was expressed in E. coli which
      represents the protective epitopes. The vaccine showed to be highly protective in
      mice against experimental P. aeruginosa infections. A phase I trial in human
      volunteers showed that the vaccine is well tolerated and that high antibody
      titers against P. aeruginosa were induced.

PMID- 10355085
TI  - [Prognostic importance of preclinically evaluated biochemical mediators in
      polytrauma].
AB  - There is compelling data from several clinical studies on the impact of various
      anti- and proinflammatory mediators on traumatized patients. Immediate trauma
      related results, however, are only available from animal experiments so far.
      Therefore, in this prospective clinical study the following questions were
      addressed: (I) Is there any marker in the preclinical phase that give information
      independent of and better than conventional studies conducted so far, (II) does
      this possible factor prove to be a (significant) predictor of late complications
      and/or poor overall outcome, and (III) does this mediator provide information
      that can alter treatment decisions? METHODS: Upon approval of the local IRB/IEC,
      85 patients (pts) were enrolled who suffered from multiple injuries. The pts were
      rescued by the helicopter-based service of the German Army Hospital in Ulm. The
      first blood samples were drawn at the site of accident and at admission, then in
      hourly to daily intervals. The plasma concentrations of following mediators were
      analyzed: Prostanoids, products of O2-radicals, soluble adhesion molecules,
      various cytokines, C-reactive protein, creatinine kinase, and neopterin. All
      values were calculated in relation to the actual plasma protein content to
      eliminate fluid-induced dilution effects. Subsets of patients were performed
      according to the severity of trauma (ISS < 9; 9-17; 18-31; > 32), based on the
      different injury pattern, and survivors versus nonsurvivors as well. RESULTS: As
      early as at the scene of accident, all patients revealed a severity-dependent
      increase in most mediators' plasma levels. There was, however, also a pattern
      related inflammatory response that was most pronounced in pts who had suffered
      from thoracic trauma irrespective of whether it was associated with multiple
      trauma. In a total, 15 pts died within 72 h after the accident. In those
      casualties, the plasma concentrations of prostaglandin E2 (P < 0.03), glutathione
      (P < 0.01) as well as creatinine kinase (P < 0.05) were more markedly elevated
      when compared with survivors. CONCLUSION: Although there were severity-dependent
      as well as pattern-related releases of various mediators, which in part were more
      apparent in nonsurviving patients, we failed in proving any predictive marker to
      specifically discriminate outcome.

PMID- 10355086
TI  - [Laparoscopic-transperitoneal and lumboscopic-retroperitoneal surgery of the
      spine. Developments from animal experiments for use in clinical practice].
AB  - With the use of an in vivo porcine training model we established the
      transperitoneal laparoscopic approach for the instrumentation of anterior lumbar
      spine fusion with Bagby-and-Kuslich (BAK) interbody implants as well as
      "Brantigan" cages. The transperitoneal laparoscopic approach caudally from the
      aortic bifurcation allows the spine fusion procedure of the caudal but not of the
      cranial part of the lumbar spine. Because ventral stabilization of the upper
      lumbar spine is frequently necessary, in particular in trauma patients with spine
      body fractures, an additional retroperitoneal minimal-invasive (lumboscopic)
      approach was established using again the in vivo porcine training model. We
      demonstrate that via this approach spine fusion can easily be performed including
      the Th12 segment after fenestration of the diaphragm. With the experience from
      the in vivo experiments, both techniques could safely and successfully be
      transferred to clinical practice with the advantage of markedly reducing the
      extent of operative trauma compared with the corresponding open approaches.

PMID- 10355087
TI  - [Clinical guidelines as part of total quality management. Analysis of
      heterogenous treatment concepts of sepsis in various clinics with computer
      assisted generation, logical testing and complexity assessment of clinical
      algorithms].
AB  - Generation, local tailoring, implementation and evaluation of clinical guidelines
      is an integral part of quality management. Clinical guidelines are intimately
      related to the independency of physicians' decisions. By this the physicians
      should be responsible for guideline development and guarantee the use of adequate
      methods of total quality management and outcome assessment. Formal consensus
      finding and transparency of evidence are necessary to guarantee the use of
      guidelines. Clinical algorithms are highly formalized and they are well suited
      for generation and analysis by the software ALGO. Determination of complexity and
      comparison of the clinical contents of algorithms is done by the scores CASA
      (Clinical Algorithm Structural Analysis) and CAPA (Clinical Algorithm Patient
      Abstraction). In a study of 22 clinical departments on treatment management
      concepts in sepsis following anastomotic insufFiciency in colorectal carcinoma a
      considerable heterogeneity was shown using this program.

PMID- 10355088
TI  - [Breast cancer screening in surgical patients].
AB  - Between January and August 1996, 304 patients of the Department of General and
      Abdominal Surgery of the University of Mainz who were at least 40 year old, were
      interviewed about their breast cancer screening behavior. The aim of our
      investigation was to evaluate the attitude of the target population to breast
      screening and the value of breast palpation, completed with mammography, during
      the women's treatment in hospital. 168 (55%) of the interviewed women reported
      that they had a yearly clinical breast examination in the past. All patients
      underwent a clinical breast examination. 185 (60%) did not have a mammography in
      the past or within the past 2 years. These women were offered a mammographic
      examination during their treatment in the hospital. The investigation revealed
      one invasive breast cancer. 13 patients had abnormal mammographic or sonographic
      findings. Our investigation shows, that the compliance of the target population
      for breast cancer screening is low. Therefore it is necessary to point out the
      value of breast cancer prevention with clinical examination and mammography also
      for patients treated in the hospital for an other disease. Every female patient
      should undergo breast examination. But early detection of breast cancer before
      micrometastases have occurred is only possible by mammography.

PMID- 10355089
TI  - [Age and sex distribution of primary thyroid cancer in relation to histological
      type].
AB  - METHOD: Data of all (239) patients suffering from thyroid carcinoma and operated
      on between January 1st, 1982, and December, 31st, 1997 in our center, were
      analyzed retrospectively with respect to age- and sex-distribution in relation to
      the histological type of cancer. The change of frequency in the histological
      groups was observed over a 16 years period. RESULTS: From all 239 cases, 202
      (84.5%) were females and 37 (15.5%) males. The most common histological type with
      70.3% in both male and female was the papillary carcinoma, followed by follicular
      carcinoma with 21.6% of male and 17.8% of female patients. A medullary carcinoma
      was seen in 8.1% and 5.9%, respectively and an anaplastic carcinoma in only 5.9%
      of female patients. There was no significant gender difference regarding the
      histological type. In male patients there was also no influence of age on
      histological groups. Females with papillary and medullary cancer were
      significantly younger than those suffering from follicular and anaplastic cancer.
      Beside, we observed an increase in papillary and a decrease in anaplastic
      carcinoma during the examination period. CONCLUSIONS: Although the relation of 1
      male to 5 females with thyroid carcinoma shows a clear dependence on sex, the
      histological type distribution is identical in both male and female. Therefore,
      several different factors seem to influence the development of thyroid carcinoma.
      One of these factors depends on sex and supports an increased development of
      carcinoma in female patients. Another factor doesn't depend on sex and causes
      different histological types. Causes for that could be as well hormonal and
      reproductive ones as regional differences in iodine availability.

PMID- 10355090
TI  - [Controlled reperfusion of ischemic extremity musculature to prevent free radical
      induced lesions].
AB  - Tissue injury following reperfusion represents an essential problem of
      reconstructive vascular surgery. Pathogenetically toxic oxygen radicals are
      considered to play a pivotal role. Pharmacotherapeutical approaches are based
      particularly on antioxidants and vasodilators. However, a standardized regimen is
      not yet clinically introduced. In 48 adult Lewis-rats lower limb ischemia was
      induced by aortal cross-clamping. Following 3.5 hours of ischemia intravascular
      flushing perfusion via the distal aorta with a heparinized electrolyte solution
      (group B). Group C received additionally oxypurinol, group D alprostadil and
      group E sodium selenite into the flushing solution. At 4 hours recirculation was
      established. After 10 min, 30 min and 24 hours of reperfusion we determined
      lactate, creatine kinase, lactate dehydrogenase, urea, malondialdehyde and the
      laser Doppler flux. At the end of the experiments biopsies were taken from M.
      tibialis anterior. In comparison to control animals (group A) we observed an
      attenuation of reperfusion injury in the groups treated with flushing perfusion.
      Free oxygen radical reactions measured by malondialdehyde release were
      significantly reduced (30 min: A-209.1 +/- 45.4, B-127.3 +/- 36.9, C-113.2 +/-
      14.1, D-99.6 +/- 24.5, E-123.6 +/- 11.2 mmol/l, p < 0.05). The laser Doppler flux
      measurements corresponded with the biochemical analyses (30 min: A-52.4 +/- 11.1,
      B-48.0 +/- 11.0, C-72.6 +/- 12.0, D-74.4 +/- 13.3, E-62.6 +/- 10.8% of baseline).
      Histologically, treatment with alprostadil (PGE1) and oxypurinol revealed
      superior results. Standardized intraarterial flushing perfusion with antioxidants
      and vasodilators reduces reperfusion injury. Clinical trials are urgently
      required to confirm the experimental findings and to optimize the therapy of
      extremity ischemia/reperfusion injury in humans.

PMID- 10355092
TI  - [Initial experience with laparoscopic gastrectomy in benign and malignant
      tumors].
AB  - From May 1993 to May 1998 at our hospital 12 classic gastric resections were
      operated on by laparoscopic procedure. A 2/3 distal Billroth resection was
      performed in 5 patients, for gastric ulcer (2) and for GIST (3). Other 7 patients
      were curatively operated on for a malignant disease. Any case was resected by
      oncosurgical gastrectomy including a D2-lymphadenectomy. The histological
      diagnoses were an adenocarcinoma in 6 cases, and one highly malignant maltoma.
      The mean operating time was 230 min in Billroth I resections and 295 min in total
      gastrectomies. As a complication, we saw postoperatively a duodenal leakage in
      one case, we could successfully manage also laparoscopically on the day after the
      operation. All the courses were extremely uncomplicated, connected with rapid
      mobility, early gut motility, little pain, and a comfortable cosmetic result. The
      resection result in any case of malignoma was R0, the mean lymphonode amount was
      34. Tumour cell dissemination and trokar site metastases we could'nt note either.
      Oncosurgically, there are no disadvantages in comparison to the open approach.

PMID- 10355091
TI  - [Ascaridiasis as an incidental finding after intraoperative cholangiography
      during a laparoscopic cholecystectomy].
AB  - We report a case of biliary ascariasis which was detected fortuitously during a
      routine intraoperative cholangiography following laparoscopic cholecystectomy.
      The diagnosis was confirmed by the finding of worm eggs in the faeces. We were
      able to discharge the patient on the 15th postoperative day after antihelmintic
      treatment.

PMID- 10355093
TI  - [Hemotherapy in operative medicine (part 2)].

PMID- 10355094
TI  - [Practical value of immunotherapy in gynecologic oncology].

PMID- 10355095
TI  - [Combined aspects of pregnancy and tumor immunology].

PMID- 10355096
TI  - [Monoclonal anti-idiotype antibodies in immunotherapy of ovarian carcinoma (MAb
      ACA125) and breast carcinoma (MAb ACA14C5)].
AB  - Anti-idiotypic antibodies, which imitate a tumor-associated antigen by their
      variable region, offer an elegant method for the induction of a specific immune
      response, when used as a surrogate antigen for immunization. We generated anti
      idiotypic antibodies imitating 2 different tumor-associated antigens. I. CA125
      for ovarian carcinomas and II. 14C5, a tumor-associated cell substrate adhesion
      molecule on breast cancer cells, whereas the first approach could be introduced
      in a first clinical trial and the second was evaluated in an immunocompetent
      animal model. For the induction of an immune response against CA125, 18 patients
      with advanced ovarian cancer (n = 6) or heavily pretreated recurrences (n = 12)
      were immunized with the anti-idiotypic antibody MAb ACA125. Patients were treated
      with 2 mg anti-idiotype antibody every two weeks for 4 injections i.m. and then
      monthly. 12 of 18 patients demonstrated an anti-anti-idiotypic (Ab3) response,
      which was to a lower extent also directed against CA125 and 9 of 18 patients
      developed a CA125 specific cellular immune response by their peripheral blood
      lymphocytes. Based on this data a follow-up clinical trial in advanced ovarian
      cancer patients with minimal residual disease in an adjuvant approach after
      primary therapy was started to evaluate the effect of the immune response on the
      progression free survival. For immunotherapy of breast cancer, we generated a
      murine monoclonal anti-idiotypic antibody (MAb ACA14C5), which imitates a cell
      substrate adhesion molecule on breast cancer cells. The anti-idiotype was
      introduced in an immunocompetent animal to prove his capability on induction of
      an immune and tumor response. The results showed a highly significant difference
      in the tumor growth of the ACA14C5 treated group in contrast to the controls
      starting the immunization on day 6 after tumor cell application with 10 of 12
      animals being cured from their tumor burden. Prophylactic immunization against
      the invasion antigen of breast cancer by anti-idiotypic antibodies showed
      protection against increasing tumor burden. However, in the situation of
      established tumors only minor responses could be detected. Vaccination with anti
      idiotypic antibodies comprises an effective method for induction of a specific
      immune response against non-immunogenic tumor-associated antigens and should be
      therefore considered in immunological approaches to tumor therapy, where the
      primary structure and sequence of the antigen, e.g. CA125, is up to now not
      available.

PMID- 10355097
TI  - [Endothelial lesions in pregnancy--detection of serum adhesion molecules (sVCAM
      1)].

PMID- 10355098
TI  - [Genetic techniques to overcome antitumor anergy].
AB  - Immunotherapy of malignant tumors is often hampered by "immune escape"
      phenomenons of tumor cells. Both active (e.g. induction of T-cell apoptosis,
      secretion of immunomodulators, -downregulators) and passive (e.g. antigen
      shedding, loss of MHC-class I/II molecules on the tumor cell surface) mechanisms
      are involved in this process. Another reason are inborn or acquired
      immunodeficiency syndromes. Gene technology tries to reconstitute the
      immunocompetent status by genetic compensation or modulation of the defect. Some
      of these trials have been performed already in phase I studies of different kinds
      of tumors and will be shortly presented here.

PMID- 10355099
TI  - [Maternal anti-paternal reactivity--depends on etiology].
AB  - Since TH1-cytokines compromise pregnancy and TH2-cytokines are produced at the
      maternal-fetal interface one can hypothesize that TH2-cytokines improve fetal
      survival. Cytotoxic T- or NK-cells are unable to recognize MHCI/II-negative
      trophoblast or become inactivated by HLA-G expression, respectively. Normal
      delivery at term might be assisted by a rapid reversal of the TH2 cytokine bias.
      Thus, the maternal immune state is most beneficial to reproductive fitness.

PMID- 10355100
TI  - [Immunologic and tumor biology aspects of placentation in humans].
AB  - In this survey, findings relating to the control of infiltration by the
      cytotrophoblast during human placentation are reviewed, with particular reference
      to immunology and tumour biology. Possible effects on pregnancy and parturition
      due to failure of the regulatory processes involved in placentation are
      discussed.

PMID- 10355101
TI  - A sub-boiling distillation method for the preparation of low carbon content water
      from urine samples for tritium measurement by liquid scintillation counting.
AB  - A new preparation method was developed for obtaining low carbon content water
      from urine samples for the measurement of tritium by a liquid scintillation
      counter. The method uses a simple and convenient subboiling distillation bottle.
      Many urine samples have been purified by this method and the change of tritium
      level in a tritium-handling radiation-worker was observed.

PMID- 10355102
TI  - Multielement analysis of human hair and kidney stones by instrumental neutron
      activation analysis with the k0-standardization method.
AB  - This paper focuses on the evaluation of the k0 method of instrumental neutron
      activation analysis in biological materials. The method has been applied in
      multielement analysis of human hair standard reference materials from IAEA, No.
      085, No. 086 and from NIES (National Institute for Environmental Sciences) No. 5.
      Hair samples from people resident in different parts of Malaysia, in addition to
      a sample from Japan, were analyzed. In addition, human kidney stones from members
      of the Malaysian population have been analyzed for minor and trace elements. More
      than 25 elements have been determined. The samples were irradiated in the rotary
      rack (Lazy Susan) at the TRIGA Mark II reactor of the Malaysian Institute for
      Nuclear Technology and Research (MINT). The accuracy of the method was
      ascertained by analysis of other reference materials, including 1573 tomato
      leaves and 1572 citrus leaves. In this method the deviation of the 1/E1+ alpha
      epithermal neutron flux distribution from the 1/E law (P/T ratio) for true
      coincidence effects of the gamma-ray cascade and the HPGe detector efficiency
      were determined and corrected for.

PMID- 10355103
TI  - Evaluation of radioiodination of meta-iodobenzylguanidine (MIBG) catalysed by in
      situ generated Cu(I) and directly added Cu(II).
AB  - A reliable method of labelling MIBG with 131I is reported. Radioiodination
      involved nucleophilic exchange reaction (160 degrees C, 30 min) catalysed by
      directly added Cu(II) or by Cu(I) generated in situ by addition of Na2S2O5 to
      CuSO4. An additional step of purification of the radiolabelled MIBG by anion
      exchange chromatography is recommended. The radiochemical (RC) yield was over
      90%, while the typical RC purity of 131I-MIBG was not less than 98%. Higher
      labelling yield was achieved with Cu(I) than when using Cu(II), and with 125I
      (commercial product) than with 131I obtained by wet radiochemical processing
      method in-house. The purity and stability of MIBG-131I was confirmed by
      biodistribution studies in monkeys with 0.03% and 0.8% uptake in adrenals and
      myocardium, respectively. It is concluded that Cu(I) or Cu(II) catalysed
      radioiodination method is well suited for production of MIBG-131I.

PMID- 10355104
TI  - Manufacture of strontium-82/rubidium-82 generators and quality control of
      rubidium-82 chloride for myocardial perfusion imaging in patients using positron
      emission tomography.
AB  - We describe a protocol to manufacture 82Sr/82Rb generators and 82RbCl for
      myocardial imaging with PET. The generators are manufactured in 3 stages: (1)
      preparation of a tin oxide column, (2) leak test of the generator column and (3)
      loading of the generator with 82Sr. The generators produced sterile and non
      pyrogenic 82RbCl for i.v. injection. No significant 82Sr/85Sr breakthroughs were
      observed after elution with 20 1 of saline. The automated system delivered human
      doses of 82RbCl accurately.

PMID- 10355105
TI  - Procedures for the determination of 222Rn exhalation and effective 226Ra activity
      in soil samples.
AB  - Two methods for measuring 222Rn exhalation and effective 226Ra in soil samples
      were studied. In the first determination, the method employed was based on the
      adsorption of radon onto activated charcoal and subsequent measurement of the
      activity of its daughters with an HPGe (high-purity germanium) detector. In the
      second, vials containing an aqueous suspension of the sample, mixed with an
      insoluble high efficiency mineral oil scintillation cocktail, were measured using
      a low-level liquid scintillation counter. Studies of optimum sampling time,
      efficiency in both procedures, variation of 226Ra efficiency with quenching, as
      well as the effect of sample amount and granulometry upon the quenching
      parameter, were carried out. The two methods were applied to the determination of
      222Rn exhalation and effective 226Ra in environmental samples.

PMID- 10355106
TI  - Radioactivity in bottled mineral waters.
AB  - Consumption of bottled mineral water is a growing practice and is sometimes a
      necessity rather than a choice. In this work, a study of the radioactive content
      of a wide selection of commercial bottled mineral waters for human intake was
      carried out. The origins of the analyzed waters were very different, coming from
      various locations in France, Portugal and Spain. Their total alpha and beta
      activity concentrations were determined and also gamma spectrometry was used to
      detect some radionuclides. In some cases, the waters presented high values of the
      total alpha and beta activity concentrations surpassing the reference levels
      established by the CSN, the Spanish. Regulatory Organization. In these cases, a
      determination of uranium and 226Ra was also performed by using low-level liquid
      scintillation counting. The results revealed a strong correlation between
      radioactive content and dry residue, and lead one to conclude that high
      radioactive content is mainly related to the mineralization in waters of
      underground origin.

PMID- 10355107
TI  - Air concentration of radiocaesium in Tsukuba, Japan following the release from
      the Tokai waste treatment plant: comparisons of observations with predictions.
AB  - On March 11, 1997 a fire and explosion accident occurred at the bituminization
      facility of the Power Reactor and Nuclear Fuel Development, Tokai, Japan. As a
      result of this accident, 134,137Cs was detected in an air filter sample collected
      at the Meteorological Research Institute, Tsukuba during March 10 to 12. The
      134,137Cs air concentration was about 100 and 10 muBq m-3, respectively. This
      result suggests that there was little radiation exposure of the residents in the
      area. The average 137Cs air concentration during this period was about two orders
      of magnitude higher than "baseline" air (sub-muBq m-3) during February to April,
      1997, measured by ultra-low background gamma-spectrometry. By a simple
      calculation using a Gaussian plume model with the measured data, we estimated the
      minimum emission of the radioactivity by the PNC accident to be in the range 60
      MBq to around 600 MBq. The meteorological condition during the week of the
      accident are also described.

PMID- 10355108
TI  - Retention level of Cs-137 and K-40 in some users of an Egyptian nuclear research
      center.
AB  - Body burden activities of Cs-137 and K-40 of about 120 humans, of composite sex,
      were measured using Inshas whole body counter facilities. The contained body
      burden activity in such distribution is found to be 3.5-10 Bq l-1 for Cs-137 and
      3.39 x 10(-3) kg l-1 as well as 3.69 x 10(-3) kg l-1 for K-40 respectively for
      females and males. It was found, that the amount of Cs Kg l-1 K increases
      significantly with increase of either the body volumes and/or the total body
      potassium. It seemed reasonably to conjecture that, from the results of this
      study, the retention time of Cs-137 in body is closely connected to the amount of
      K-40. The discrimination factor related to the body burden content of Cs-137 to K
      40 is also experimentally predicted. Moreover, the burden activities of Cs-137
      and K-40 over a period of two years are scanned monthly. The results show a
      slight continuous increase in body burden activity of both elements. The net
      daily intakes of Cs-137 and K-40 are calculated using a formula developed from
      ICRP. The calculated results for K-40 show a variation ranging from 30 to 40 Bq
      per day for females and from 45 to 55 B per day for males. While for Cs-137 show
      a slight variation ranged from 5.2 to 6.8 Bq per day for a composite sex. The
      authors emphasise the importance of the periodic measurement of human population
      since both the consumed food chain and the environmental enclosure contained both
      radio elements. Accumulation of the daily ingested activity of Cs-137 and K-40,
      and of food eaten, showed that the predicted body burden retained activity is
      relatively higher by a range of 5-25% for Cs-137 and 3-15% for K-40 when compared
      with that detected by the whole body counter over the 24-month scanning course.

PMID- 10355109
TI  - 137Cs contamination of Techa river flood plain in Brodokalmak settlement.
AB  - 137Cs contamination of the Techa river flood plain inside the Brodokalmak
      settlement has been mapped. The collimated scintillated detector technique was
      used for 137Cs deposit measurements. The 137Cs contamination is very
      heterogeneous. A comparison of this technique with the traditional sample method
      was performed at selected locations. The sampling data are in good agreement with
      in-situ data. Soil surface activity of 90Sr was determined from the samples. It
      was shown that 137Cs contamination correlates with 90Sr contamination within the
      flood plain of the settlement.

PMID- 10355110
TI  - Modeling and measuring the indoor randon concentrations in high-rise buildings in
      Hong Kong.
AB  - A newly constructed, uninhabited high-rise building has been measured for its
      indoor and outdoor radon concentrations at similar locations on each of the 18
      floor levels. Grab sampling technique has been used so that many locations can be
      measured within short period of time to minimize the variations due to
      temperature, pressure and humidity. Air exchange rates inside rooms were obtained
      by tracer gas method. Standard concrete samples were manufactured in laboratory
      to simulate the concrete used in the construction of the high-rise building. The
      concrete samples were measured for their radon exhalation rates by calculating
      the initial growth rates of radon inside an airtight container. The air exchange
      rates have been found to increase with floor levels, whilst the indoor and
      outdoor radon concentrations decreased with floor levels. Using a model utilizing
      a simple mass balance equation, the indoor radon concentration inside a room on
      each of the 18 floor levels has been calculated and the results agreed very well
      with measurements.

PMID- 10355111
TI  - Radon-222 and related activities in surface waters of the English Lake District.
AB  - Activities of radon-222 in selected surface waters of the English Lake District
      have been determined. Very wide variations were observed. The activity present in
      lakes and streams depends on the nature of the bedrock or sediment, the presence
      of faulting, the degree of turbulence, and the supply of fresh water from
      tributaries and ground waters. Radium-226 and uranium-238 activities were found
      to be comparable but in no case was it found that radon-222 is significantly
      supported by dissolved radium-226.

PMID- 10355112
TI  - Experimental infection of mice with Yersinia enterocolitica serotype O9 by oral
      and parenteral routes: spreading and enterotropism of virulent yersiniae.
AB  - An isogenic pair of Yersinia enterocolitica serotype O9 strains, with and without
      virulence plasmid, was used to study the plasmid role in the infection of BALB/c
      mice by oral, intraperitoneal, and intravenous routes. The plasmid-bearing
      strain, but not its plasmid-less derivative, caused enteric infection after
      challenge by all three routes. The virulence plasmid did not influence the
      peritoneal clearance of yersiniae, but only the plasmid-bearing yersiniae were
      able to move from the peritoneal cavity to the bloodstream, and thus they spread
      to spleen and liver. Moreover, plasmid-bearing yersiniae were able to move from
      the liver to the gallbladder, and they shed in bile into the intestine. Western
      blot analysis of antibody responses to chromosomally encoded outer membrane
      proteins revealed similar patterns with sera from mice challenged with each one
      of two strains by intraperitoneal route. In contrast, only the plasmid-bearing
      strain elicited an antibody response to these antigens in mice challenged by oral
      route. Although mice experimentally infected with plasmid-bearing O9 yersiniae
      developed an enteric infection, irrespective of the inoculation route,
      differences between the first steps in infection by oral and parenteral routes
      may be important, especially when the infection model is used as an approach to
      study the yersinia-host interactions.

PMID- 10355113
TI  - Distribution of the rubredoxin gene among the Clostridium butyricum species.
AB  - With PCR methods, the rubredoxin gene was systematically identified among 11
      strains of Clostridium butyricum; this ubiquity means major functions in the
      metabolism of the Clostridia. The 11 PCR products allowed deduction of a sequence
      of 26 amino acids corresponding to positions 11-36 of the rubredoxin. They all
      contained the tyrosines at positions 11 and 13 and the phenylalanine at position
      30 characteristic of the rubredoxin, but differed at positions 14-17, 20, 25, 29,
      and 31, allowing determination of three types of rubredoxins among these 11
      strains of C. butyricum.

PMID- 10355114
TI  - Derivation of extracellular polysaccharide-deficient variants from a serotype A
      strain of Pasteurella multocida.
AB  - The production of serotype A extracellular polysaccharide is thought to be
      associated with expression of an approximately 40-kDa lipoprotein (P1p-40)
      present on the outer surface of Pasteurella multocida strains of avian origin.
      The tendency of certain strains to undergo colonial dissociation concomitantly
      with serial passaging on laboratory growth media was exploited to derive two
      variant strains exhibiting the capsule-deficient phenotype from a heavily
      capsulated parental strain. Assessments of colonial consistency, iridescence,
      gentian violet binding, and hyaluronidase sensitivity were consistent with
      cellular observations indicating little or no capsulation of derivative strains.
      Fluorographic analysis of electrophoretically resolved cellular lipoproteins
      labeled with [3H]-palmitate revealed capsular loss occurred with a concomitant
      diminution of P1p-40 production in the variant strains. In contrast, a
      phenotypically stable strain that did not undergo colonial dissociation under
      identical conditions exhibited no decrease in P1p-40 content. This work provides
      a model system for investigating the role of extracellular polysaccharide in the
      cell surface physiology and pathogenicity of P. multocida. The present results
      strongly support the notion that P1p-40 is associated with serotype A capsular
      material and suggest coordinate regulation of their biosynthesis.

PMID- 10355115
TI  - Release of outer membrane vesicles from Bordetella pertussis.
AB  - The aim of the study reported here was to investigate the production of
      Bordetella pertussis outer membrane vesicles (OMVs). Numerous vesicles released
      from cells grown in Stainer-Scholte liquid medium were observed. The formation of
      similar vesicle-like structures could also be artificially induced by sonication
      of concentrated bacterial suspensions. Immunoblot analysis showed that OMVs
      contain adenylate cyclase-hemolysin (AC-Hly), among other polypeptides, as well
      as the lipopolysaccharide (LPS). Experiments carried out employing purified AC
      Hly and OMVs isolated from B. pertussis AC-Hly- showed that AC-Hly is an integral
      component of the vesicles. OMVs reported here contain several protective
      immunogens and might be considered a possible basic material for the development
      of acellular pertussis vaccines.

PMID- 10355116
TI  - Selection of vaginal H2O2-generating Lactobacillus species for probiotic use.
AB  - Lactobacilli are believed to contribute to the control of the vaginal microflora
      by different mechanisms such as production of antagonistic substances like lactic
      acid, bacteriocins, and H2O2. This paper describes the selection of H2O2
      generating lactobacilli among 35 hydrophobic isolates from the human vagina.
      Lactobacillus crispatus F117, which generated the highest H2O2 level, was chosen
      to study: (a) the kinetics of H2O2 production considering different culture
      conditions, and (b) the effect of this metabolite on the growth of urogenital
      tract pathogens. The levels of H2O2 in L. crispatus supernatant increased during
      its growth and were maximum at the early stationary phase (3.29 mmol H2O2 L-1)
      under aerated conditions (agitated cultures). In nonagitated cultures there were
      no detectable levels of H2O2. L. crispatus F117 spent supernatant inhibited
      Staphylococcus aureus growth in plaque assay. Inhibition was due to H2O2 since
      catalase treatment of the supernatant suppressed inhibition. In mixed cultures
      performed with L. crispatus and S. aureus a significant decrease in pathogen
      growth was observed. The inhibitory effect depended on the initial inoculum of S.
      aureus. Further evaluation of the properties of L. crispatus F117 will be
      performed to consider its inclusion in a probiotic for local use in the vaginal
      tract.

PMID- 10355117
TI  - The Saccharomyces cerevisiae mevalonate diphosphate decarboxylase (erg19p) forms
      homodimers in vivo, and a single substitution in a structurally conserved region
      impairs dimerization.
AB  - The wild-type ERG19 gene of the yeast Saccharomyces cerevisiae encoding
      mevalonate diphosphate decarboxylase (MVD) and the mutated recessive erg19-34
      allele leading to a decrease of sterol production and to a thermosensitive
      phenotype have been characterized [2]. The mutated erg19-34 allele bears a single
      amino acid leucine 79-to-proline (L79P) substitution. It was shown that this
      mutation does not affect the level of production of the enzyme. We performed a
      two-hybrid assay to show that the yeast Saccharomyces cerevisiae MVD forms
      homodimers in vivo and that the single point mutation drastically impairs the
      oligomerization of the protein, thereby explaining the deficiency of MVD activity
      observed in the temperature-sensitive strain.

PMID- 10355118
TI  - Kinetic behavior of some polyphosphate-accumulating bacteria isolates in the
      presence of nitrate and oxygen.
AB  - This paper studies the phosphate uptake by pure cultures of Aeromonas hydrophila,
      Klebsiella oxytoca, Agrobacterium tumefaciens, and Aquaspirillum dispar in the
      presence of both nitrate and oxygen. It is shown that species were able to
      respire both electron acceptors for phosphate accumulation. A. tumefaciens and A.
      dispar accumulated overall phosphate both in oxic and anoxic culture conditions,
      whereas A. hydrophila and K. oxytoca eliminated overall phosphate only in oxic
      conditions. A. dispar was able to remove phosphate by reducing oxygen and nitrate
      simultaneously with the production of dinitrogen gas. The anoxic denitrification
      observed in the cultures of adapted and nonadapted cells to nitrate showed that
      only A. dispar have a denitrification rate superior when the cells were adapted
      to nitrate.

PMID- 10355119
TI  - RNA editing site recognition in higher plant mitochondria.
AB  - RNA editing is a process by which genomically encoded cytidines are converted to
      uridines in plant mitochondrial transcripts. This conversion usually changes the
      amino acid specified by a codon and converts an "aberrant" residue to the
      evolutionarily conserved amino acid. The selection of the edited cytidine is
      highly specific. The cis-acting sequences for editing site recognition have been
      examined in ribosomal protein S12 (rps12) transcripts and in transcripts for a
      second copy of an internal portion of the ribosomal protein S12 (rps12b). rps12b
      was created by recombination at 7 and 9 nucleotide sequences that included
      editing sites I and IV of rps12, thus affording an opportunity to study the
      editing of chimeric transcripts with rearrangement very near C to U editing
      sites. Rearrangements downstream of editing site IV did not affect the editing of
      that sequence, while rearrangement upstream of editing site I ablated editing at
      that cytidine residue. Secondary structure predictions indicated that RNA
      structure did not correlate with the editing of these substrates. These results
      taken together with other studies in the literature suggest that RNA editing site
      recognition is primarily dependent on the 5' flanking RNA sequence.

PMID- 10355120
TI  - Transcription signals of mitochondrial and nuclear genes for mitochondrial
      proteins in dicot plants.
AB  - Mitochondria contain several large multisubunit enzyme complexes that are
      composed of proteins encoded in the nuclear and mitochondrial genomes.
      Particularly for correct assembly of these enzyme complexes, expression of the
      respective mitochondrial and nuclear genes has to be coordinated to ensure
      correct stoichiometries of the protein subunits. Part of this control and the
      response to specific demands is exercised at the level of transcription. To
      determine the respective transcription signals we have analyzed the mitochondrial
      promoters in dicot plants and the promoter structure for nuclear-encoded genes of
      the respiratory chain complex I. We summarize the results of these investigations
      and extend the mitochondrial promoter survey to the mitochondrial genome in
      Arabidopsis thaliana.

PMID- 10355121
TI  - Mitochondrial gene organization and expression in petunia male fertile and
      sterile plants.
AB  - In cytoplasmic male-sterile Petunia lines, NADH dehydrogenase subunit 3 (nad3)
      and ribosomal protein S12 (rps12) are cotranscribed with the chimeric gene pcf
      and located in the region of the mitochondrial genome associated with cytoplasmic
      male sterility (CMS) in Petunia. In fertile Petunia line 3704, the genes for nad3
      and rps12 are cotranscribed with an unidentified open reading frame (orf143). In
      the homologous region of fertile line 3699, there is an ORF that lacks a genomic
      DNA-encoded stop codon; instead an RNA editing event creates a stop codon,
      resulting in an ORF of 161 codons. While expressed sequences homologous to this
      open reading frame can be detected in sterile lines, a contiguous orf143/orf161
      gene does not exist in the CMS-encoding mitochondrial genome. Transcription at
      the CMS-associated pcf locus and the fertile orf143/nad3/rps12 locus is complex,
      with multiple 5' and 3' termini. The presence of the nuclear fertility restorer
      gene affects the abundance of a transcript class with 5' termini--121 nucleotides
      before the pcf start codon, and greatly reduces the abundance of a pcf gene
      product with apparent molecular mass of 25 kDa which is present in both
      vegetative and reproductive tissues of CMS plants. In addition to the 25 kDa
      protein product, small amounts of precursor and processed pcf products with
      higher molecular mass have been detected; their possible role in the CMS
      phenotype is unknown. Current hypotheses for the mechanism of action of CMS
      associated and fertility restorer genes are discussed.

PMID- 10355122
TI  - Mitochondrial transcript processing and restoration of male fertility in T
      cytoplasm maize.
AB  - Cytoplasmic male sterility (CMS) systems have been useful in the production of
      hybrid seed in a number of crops. The Texas or T-cytoplasmic male-sterile (cms-T)
      system was used extensively in the 1960s to eliminate the need for hand
      detasseling in hybrid maize production. As a consequence of the 1970 epidemic of
      southern corn leaf blight, cms-T is no longer widely used commercially. However,
      it has been developed as a model system to study the genetic and molecular
      mechanisms underlying male sterility and fertility restoration. Male sterility in
      T-cytoplasm maize results from the action of a T-cytoplasm-specific mitochondrial
      gene, T-urf13. Full (or partial) fertility restoration of T-cytoplasm maize is
      mediated by the Rf2 nuclear restorer in combination with one of three other
      restorers: Rf1, Rf8, or Rf*. Rf2 encodes a protein highly similar to
      mitochondrial aldehyde dehydrogenases; Rf1, Rf8, and Rf* each mediate discrete T
      urf13 mitochondrial transcript processing events. To test the functionality of
      Rf1, Rf8, or Rf*, a T-cytoplasm transformation system is under development. AFLP
      bulk-segregant analysis has been used to identify DNA markers closely linked to
      the Rf8 locus. These tools will provide a foundation for determining mechanisms
      of nuclear-directed mitochondrial RNA processing and fertility restoration.

PMID- 10355123
TI  - A unique two-gene gametophytic male sterility system in sorghum involving a
      possible role of RNA editing in fertility restoration.
AB  - The sorghum line IS1112C carries a male sterility-inducing cytoplasm when
      introduced into nuclear backgrounds that do not include fertility restoration
      genes. An mtDNA chimeric configuration resulting from recombination/duplication
      with atp9 resulted in the formation of orf107, a chimeric open reading frame.
      Transcription of orf107 is driven by three promoters, and abundant whole-length
      transcripts are detected in male-sterile lines. Fertility restoration is exacted
      through a unique two-gene gametophytic system requiring complementary action of
      genes designated Rf3 and Rf4. In male-sterile lines carrying Rf3, or lines
      restored to fertility, an enhanced nucleolytic transcript processing activity is
      targeted within orf107, cleaving 75% of whole-length transcripts. Rf3 thus
      confers or regulates the nucleolytic processing activity. A correlation between
      the frequency of RNA editing at two sites in orf107 and transcript processing
      suggests that processing may be dependent on templates edited at these sites. In
      addition, editing of atp6 transcripts is specifically reduced in anthers/pollen
      of male-sterile lines. Partially restored F1s and segregating F2s exhibit atp6
      editing frequencies consistent with the possibility that Rf4 may confer the
      restitution of normal editing frequency. Thus RNA editing may be involved in
      features of fertility restoration in this unusual system.

PMID- 10355124
TI  - Cryptic species of rockfishes (Sebastes: Scorpaenidae) in the southern hemisphere
      inferred from mitochondrial lineages.
AB  - We used mitochondrial DNA sequence variation of Sebastes from the southeastern
      Pacific and three localities in the South Atlantic to address long-standing
      systematic and evolutionary issues regarding the number of species in the
      Southern Hemisphere. Sequences of the hypervariable mitochondrial control region
      were obtained from 10 specimens of S. capensis from South Africa (n = 5) and from
      Tristan da Cunha Island (n = 5) and 27 of S. oculatus from Valparaiso, Chile (n =
      10), and the Falkland Islands (n = 17). Results of the study include (1)
      significant levels of genetic differentiation among the sampled populations (phi
      ST = 0.225, P < .000001), thus indicating limited gene flow; (2) corroboration of
      the existence of two different lineages of austral Sebastes corresponding to S.
      capensis and S. oculatus; (3) finding that S. capensis is not restricted to
      Tristan da Cunha and South Africa, but is widespread across the South Atlantic;
      (4) the position of S. capensis as the ancestral lineage of the austral Sebastes;
      (5) the existence of a third evolutionary lineage with high levels of genetic
      divergence, particularly abundant in the south-western Atlantic, which may be
      recognized as a third austral species of Sebastes.

PMID- 10355125
TI  - Genetics of gamma-irradiation-induced mutations in Arabidopsis thaliana: large
      chromosomal deletions can be rescued through the fertilization of diploid eggs.
AB  - Despite the demonstrated value of chromosomal deletions and deficiencies as tools
      in plant and animal genome research, in the genetic model plant species
      Arabidopsis thaliana, such mutations have not been extensively studied. For
      example, it is not known whether large deletions in different regions of the
      genome can be tolerated in diploid plants that are heterozygous for such
      mutations. Similarly the viability or inviability of monosomics has not been
      examined in detail. To investigate these questions, we have used gamma-irradiated
      haploid wild-type pollen to pollinate diploid and tetraploid multimarker lines of
      Arabidopsis. Examination of M1 progenies revealed that chromosome loss mutations
      and large deletions were induced in the irradiated pollen. Such mutations were
      eliminated in diploid M1 plants due to dominant lethality but could be rescued in
      triploid M1 progeny. The use of irradiated pollen and tetraploid marker lines of
      Arabidopsis is a convenient way of generating deletions and modified chromosomes
      and provides a genetic tool for deletion mapping and for analysis of chromosomal
      regions essential for chromosome maintenance.

PMID- 10355126
TI  - Characterization and chromosomal distribution of satellite DNA sequences of the
      water buffalo (Bubalus bubalis).
AB  - Satellite DNA sequences were isolated from the water buffalo (Bubalus bubalis)
      after digestion with two restriction endonucleases, BamHI and StuI. These
      satellite DNAs of the water buffalo were classified into two types by sequence
      analysis: one had an approximately 1,400 bp tandem repeat unit with 79%
      similarity to the bovine satellite I DNA; the other had an approximately 700 bp
      tandem repeat unit with 81% similarity to the bovine satellite II DNA. The
      chromosomal distribution of the satellite DNAs were examined in the river-type
      and the swamp-type buffaloes with direct R-banding fluorescence in situ
      hybridization. Both the buffalo satellite DNAs were localized to the centromeric
      regions of all chromosomes in the two types of buffaloes. The hybridization
      signals with the buffalo satellite I DNA on the acrocentric autosomes and X
      chromosome were much stronger than that on the biarmed autosomes and Y
      chromosome, which corresponded to the distribution of C-band-positive centromeric
      heterochromatin. This centromere-specific satellite DNA also existed in the
      interstitial region of the long arm of chromosome 1 of the swamp-type buffalo,
      which was the junction of the telomere-centromere tandem fusion that divided the
      karyotype in the two types of buffaloes. The intensity of the hybridization
      signals with buffalo satellite II DNA was almost the same over all the
      chromosomes, including the Y chromosome, and no additional hybridization signal
      was found in noncentromeric sites.

PMID- 10355127
TI  - Thawing of foods in a microwave oven: I. Effect of power levels and power
      cycling.
AB  - Microwave thawing is faster than other methods, but it can produce significant
      non-uniformity of heating. The objective of this study was to perform
      comprehensive experimentation and heat transfer modeling to relate the time to
      thaw and the non-uniformity of thawing to power cycling, power level and the
      surface heat transfer coefficient. The governing energy equation was formulated
      with an exponential decay of the microwave flux from the surface. Surface
      microwave flux was obtained from the measured temperature rise using inverse heat
      transfer analysis. Gradual phase change was formulated as an apparent specific
      heat, and was obtained for the experimental material tylose from differential
      scanning calorimetry (DSC) measurements. The temperatures were measured
      immediately following heating with a fast response thermocouple. Dielectric
      properties were measured above freezing. Results show that the microwave flux at
      the surface and its decay are affected by the changes in the power level. Power
      cycling has an almost identical effect as continuous power at the reduced level
      of the average cycled power. As power level increases, the surface flux increases
      by the same fraction. At higher power levels, however, the outside thaws
      relatively faster. A "shield" develops due to a much reduced microwave
      penetration depth at the surface. This thawing time at higher power levels is
      reduced considerably. Temperature increases initially are non-uniform since the
      surface is heated at a faster rate than the interior. In keeping with the
      assumption that once the temperature reaches 100 degrees C, all energy absorbed
      goes into evaporation, and subsequent temperature is maintained at 100 degrees C.
      Thus, eventually, non-uniformity starts to decrease.

PMID- 10355128
TI  - Thawing of foods in a microwave oven: II. Effect of load geometry and dielectric
      properties.
AB  - Non-uniformity of temperatures in thawing of food and biological materials inside
      a microwave oven is affected by size, shape, and dielectric properties of the
      load (food). The objective of this study was to relate the time to thaw and the
      non-uniformity of heating to the shape, size, and the dielectric properties of
      the load. The details of the heat transfer analysis, experimental measurement of
      thermal and dielectric properties, and temperature measurements are described in
      a companion paper. Results show that both the aspect ratio and the volume have a
      significant effect on the heating rates, time to thaw and the non-uniformity of
      temperatures during thawing. A "shield" develops from surface thawing and leads
      to reduced microwave penetration. This "shield" develops more readily at higher
      dielectric loss, thereby effectively increasing the thawing time even more for a
      lossy material at higher power levels. Thawing time increases linearly with
      volume. As the load aspect ratio decreases (it is made flatter), it thaws faster
      since the energy decays relatively less in a thinner material. These new results
      could provide a more rational and quantitative approach to development of frozen
      food products to be heated in a microwave oven.

PMID- 10355129
TI  - [Recent challenges and progress in AIDS therapy--emergence of drug resistant HIV
      1 variants].

PMID- 10355130
TI  - [Treatment strategies for childhood acute leukemia and their effectiveness:
      message to internists from a pediatrician].

PMID- 10355131
TI  - [The molecular mechanism of hematopoietic stem cell development in the AGM
      region].

PMID- 10355132
TI  - [Hematopoietic stem cells and stromal cells in AGM region of mouse embryo].

PMID- 10355133
TI  - [Role of cytokines and SDF-1 in the regulation of hematopoietic cell localization
      in microenvironment].

PMID- 10355134
TI  - [Functional roles of signaling molecules in cytokine-induced cell growth].

PMID- 10355135
TI  - [The role of NF-E2 related transcription factors in hematopoiesis].

PMID- 10355136
TI  - [Generation and analysis of mouse models for leukemia].

PMID- 10355137
TI  - [Decrease serum erythropoietin level induced by iron replacement therapy in
      patients with iron deficiency anemia].
AB  - The relationship between serum erythropoietin (EP) and hemoglobin (Hb)
      concentrations was investigated in patients of iron deficiency anemia (IDA) in
      the course of iron replacement therapy to elucidate how the therapy induced
      changes in that relationship. At first Hb-dependent EP levels were determined in
      123 IDA patients prior to the treatment by the third-degree logarithmic
      regression of EP on the Hb deficit (d-Hb). Following the start of iron supply,
      the deviation of observed EP values from the predicted level (EPc), i.e., delta
      EP, was most obvious at the next phase of the onset of reticulocyte crisis;
      however, this deviation reduced with the alleviation of IDA. The value in maximum
      phase (delta-EPmx), as individually defined for each of 95 patients, correlated
      significantly with the severity of the pretreatment ID state (r = 0.502, p <
      0.01). Partial correlation analysis revealed that about 80% of this gap was
      attributable to the ID state. Also, it was assumed that EP upregulation was twice
      that attributable to the Hb-deficit factor alone. The phase sequence of the delta
      EP versus d-Hb relationship in 21 relapsed patients demonstrated a different rout
      from that observed in their improvement phase. The ID state-induced upregulation
      of EP, i.e., EPc, was followed by a therapy-induced overshooting drop that was
      attributable to acute uptake of EP by shifted erythroid precursors. From the
      viewpoint of erythropoietic regulation, the subsequent down-regulation of EP in
      the mid to late phases was considered appropriate for the prevention of Hb over
      production.

PMID- 10355138
TI  - [Diagnosis of malaria by allele-specific PCR].
AB  - Malaria is relatively rare in Japan. Of 13 patients referred to our laboratory
      for malarial screening in the past 4 years, malarial parasites were detected in
      8. Conventional screening procedures commonly detect hepatic dysfunction,
      thrombocytopenia, elevated LDH activity, and increased CRP levels in malaria
      patients. More notably, the 8 malaria patients identified by our laboratory also
      demonstrated reactive lymphocytosis. In the absence of additional clinical
      information, reactive lymphocytosis alone may be enough to warrant laboratory
      blood smear tests on the suspicion of malaria. Conventional microscopic methods
      have often proved inconclusive in identifying malarial parasite species or
      detecting mixed infections. However, by combining the methods of DNA analysis
      with those of microscopy, we were able to conclusively diagnose all cases of
      suspected malaria. As a test of their skills, 9 laboratory technicians relatively
      inexperienced with malarial parasites were asked to screen 6 samples: 3
      containing malarial parasites, and 3 that were malaria-free. Although none of the
      technicians were able to accurately identify the samples without additional
      clinical information, 4 accurately identified all malarial samples when that
      information was provided. Experience is a crucial determinant of ability to
      detect malarial parasites by microscopic methods alone. Nonetheless, the findings
      of our study suggested the diagnostic accuracy of laboratory screening procedures
      for malaria can be significantly improved if combined with minimal clinical data
      and the techniques of DNA analysis.

PMID- 10355139
TI  - [Discrimination of leukoencephalopathy from leukemic cell invasion by MR
      spectroscopy in a patient with acute lymphoblastic leukemia].
AB  - A 58-year-old man was admitted to our hospital in November 1992 because of fever
      and arthralgia. He was given a diagnosis of acute lymphoblastic leukemia and
      treated with an Ad-VP regimen, which resulted in complete remission. After two
      courses of consolidation therapy and intrathecal (IT) injections of methotrexate,
      Ara-C, and prednisolone the patient received high-dose Ara-C plus VP-16 followed
      by recombinant human G-CSF for the collection of peripheral blood stem cells.
      However, he relapsed with the appearance of leukemic cells in cerebrospinal fluid
      (CSF), and was accordingly given IT injections 8 more times. After the
      disappearance of leukemic cells from CSF, the patient received a peripheral blood
      stem cell transplant (PBSCT) and achieved rapid hematopoietic recovery. However,
      he suffered mental aberrations and loss of consciousness 9 days after PBSCT.
      Proton magnetic resonance spectroscopy (1H-MRS) disclosed severe necrosis due to
      leukoencephalopathy in the frontal lobe and invasion of leukemic cells around the
      lateral ventricles. The patient did not receive any therapy for neurological
      symptoms because of severe necrosis in the frontal lobe, and died of bone marrow
      relapse in April 1995. MRS is useful for the discrimination of
      leukoencephalopathy from leukemic cell invasion.

PMID- 10355140
TI  - [Disappearance of residual disease confirmed by RT-PCR following induction
      chemotherapy in two hypoplastic leukemia patients with t(8;21)].
AB  - Reverse transcriptase-polymerase chain reaction (RT-PCR) methods often detect the
      AML1/MTG8 fusion transcript even in acute myelogenous leukemia (AML) patients
      with t(8;21) who have been in long-term remission. We encountered 2 hypoplastic
      leukemia patients with t(8;21) who achieved cytogenetic remission with short-term
      conventional chemotherapy. Patient 1 was a 42-year-old woman. Chromosomal
      analysis detected t(8;21) (q22;q22) and PCR analysis (35 cycles PCR
      amplification; detection limit 1 x 10(-5) cells) detected the AML1/MTG8 fusion
      transcript. Complete remission was obtained with 1 course of chemotherapy
      consisting of low-dose cytarabine (20 mg x 14 days) and etoposide (50 mg x 14
      days). After 2 courses of consolidation chemotherapy consisting of conventional
      dose cytarabine and mitoxantrone, the RT-PCR findings were negative for the
      AML1/MTG8 fusion transcript. Patient 2 was a 67-year-old man. Cytogenetic
      analysis detected t(8;21) (q22;q22), and was positive for the AML1/MTG8 fusion
      transcript. After 2 courses of induction chemotherapy comprising low-dose
      cytarabine (20 mg x 14 days) and etoposide (50 mg x 14 days), and 3 courses of
      conventional consolidation chemotherapy, RT-PCR analysis confirmed the
      disappearance of the AML1/MTG8 fusion transcript.

PMID- 10355141
TI  - [Marked thrombocytopenia after high-dose intravenous gamma globulin in a pregnant
      woman with idiopathic thrombocytopenic purpura].
AB  - A 35-year-old pregnant woman had thrombocytopenia with a platelet count of 6.3 x
      10(4)/microliter. After her third normal delivery, peripheral blood studies
      revealed that the patient had a normal Hb concentration and leukocyte count, with
      mild thrombocytopenia. A diagnosis of idiopathic thrombocytopenic purpura (ITP)
      was made based on the high megakaryocyte count of 338/microliter and PAIgG of
      40.8 ng/10(7) cells in January 1995. The patient was followed without treatment.
      She was 9 weeks pregnant on June 7, 1996, and desired an abortion. Her platelet
      count was 6.3 x 10(4)/microliter, leukocyte count 8,600/microliter, and Hb 13.7
      g/dl at the time. She was given high-dose intravenous gammaglobulin (Globenin-I)
      at 400 mg/kg/day for 5 consecutive days. The platelet count was found to have
      decreased markedly, to 0.9 x 10(4)/microliter on June 11. The percentage
      reduction in the Hb concentration, leukocyte count, and platelet count after
      gammaglobulin treatment was 11.7%, 46.6%, and 85.8%, respectively. The PAIgG
      titer had increased to 181.2 ng/10(7) cells on June 17, but
      hypergammaglobulinemia was suspected. The patient was started on prednisolone on
      June 24, and an abortion was performed on July 29. The mechanism of
      thrombocytopenia after infusion of Globenin-I was unknown. We suspect that
      Globenin-I treated with polyethylene glycol was one of the possible causes of
      myelosuppression in this case.

PMID- 10355142
TI  - [Development of cyroglobulinemia and polyneuropathy in a chronic myeloid leukemia
      patient during interferon-alpha treatment].
AB  - Neurological side effects and complications of cryoglobulinemia were observed
      during interferon-alpha (IFN-alpha) therapy in a patient with chronic myeloid
      leukemia (CML). A 50-year-old man was hospitalized because of leukocytosis and
      extramedullary tumors in the lumbar spine. In addition, the patient complained of
      dysesthesia in his feet. A diagnosis of accelerated phase CML was made.
      Administration of prednisolone, vincristine, hydroxyurea, and Ara-C and
      irradiation of the lumbar spine were started. Two months later, the patients
      achieved hematologic response and the size of his tumors decreased. Thereafter,
      we started IFN-alpha treatment (3-6 x 10(6) units daily) by intramuscular
      injection. After 8 weeks of this treatment, the patient complained of worsening
      dysesthesia in his feet. An axonal form of peripheral neuropathy was diagnosed by
      electrophysiological examination. Immunological studies revealed decreased
      complement levels and type III mixed cryoglobulinemia. Methylprednisolone pulse
      therapy alleviated the neurological symptoms and lowered the cryoglobulin levels.
      The clinical course suggested that mixed cryoglobulinemia was associated with CML
      and that the increase in cryoglobulin levels was caused by IFN-alpha and played a
      causative role in the worsening peripheral neuropathy. Therefore, to prevent
      these side effects, careful clinical assessment is necessary before starting IFN
      alpha therapy.

PMID- 10355143
TI  - [Splenic lymphoma with villous lymphocytes expressing chromosomal abnormalities].
AB  - An 88-year-old Japanese woman with splenomegaly, but without lymphadenopathy, was
      admitted because of epigastric distress. Laboratory data disclosed an RBC of 310
      x 10(4)/microliter, Hb of 10.1 g/dl, Ht of 30.6%, Plt count of 9.8 x
      10(4)/microliter, and WBC of 4,470/microliter with 38% abnormal lymphocytes.
      Peripheral blood films revealed lymphocytes with thin, short cytoplasmic villi,
      condensed nuclear chromatin, and small nucleoli. The lymphocytes stained negative
      for tartrate-resistant acid phosphatase. Also, immunophenotyping was positive for
      expression of the cell surface markers CD19, CD20, IgG, kappa and HLA-DR, but not
      for CD5, CD10, CD11c, CD23, CD25, CD38, or CD103 antigens. Chromosomal analysis
      of peripheral blood cells disclosed the 46, XX, del(7), (q32) aberration. A
      splenectomy was performed simultaneously with partial colon resection because of
      a mucinous carcinoma found in the transverse colon. Histologic examination of
      resected spleen tissues revealed a distinctive pattern of white pulp infiltration
      by lymphoma cells. The histologic findings and clinical data were consistent with
      the features of splenic lymphoma with circulating villous lymphocytes. Our
      patient exhibited a relatively benign clinical course, and was being followed on
      an outpatient basis with no additional therapy.

PMID- 10355144
TI  - [Neuroendocrine regulation of the mucosal immune system].

PMID- 10355145
TI  - [The proliferative response and immunoglobulin production in peripheral blood
      lymphocytes stimulated with Japanese cedar pollen antigens].
AB  - Peripheral blood mononuclear cells taken from 38 normal subjects and 50 Japanese
      cedar pollinosis patients were cultured with or without mitogens or Japanese
      cedar pollen antigens to study the proliferative response and immunoglobulin
      production in periphral blood lymphocytes. When stimulated with Con A or anti-CD
      40 mAb, the proliferative responses in the patient group were significantly
      higher than those in the normal group, and when stimulated with anti-CD 40 mAb,
      the IgG 2 production was markedly dominant among the IgE and IgG subclass
      productions in both groups. When stimulated with Japanese cedar pollen antigens,
      the proliferative responses in the patient group were markedly augmented in
      comparison with the normal group, and showed a correlation with the serum anti
      cedar IgE antibody titers in the patient group. In regard to the immunoglobulin
      production in peripheral blood lymphocytes stimulated with Japanese cedar pollen
      antigens, the IgE productions in the patient group were significantly higher than
      those in the normal group, and showed a weak correlation with the serum anti
      cedar IgE antibody titers in the patient group. The IgG productions were,
      however, slightly enhanced by the stimulation with Japanese cedar pollen antigens
      in both of the normal and patient groups. While it could not be clearly
      demonstrated which subclass of IgG was responsible for the enhancement of IgG
      production, there were some cases of relatively higher responses of IgG 2 or IgG
      4 production. Though the IgG 4 productions in the patient group were
      significantly higher than those in normal group, there was no clear correlation
      with the serum anti-cedar IgE antibody titers in the patient group. On the other
      hand, it seems to be noteworthy that a weak negative correlation was recognized
      between the IgG 2 productions and the IgG 4 productions, and between the IgG 4
      productions and the IgE productions. Considering these results in the present
      study, it was concluded to be difficult to identify a IgG 4 high responder in a
      course of clinical immunotherapy through the in vitro IgG 4 production or other
      related reactions as attempted in this study.

PMID- 10355146
TI  - [The relapse rate in patients with bronchial asthma remission and the risk
      factors of relapse].
AB  - To investigate the relapse rate in patients with bronchial asthma remission, a
      questionnaire study was performed. The answer sheets from 450 of 865 patients who
      first visited Saitama Medical School Hospital before the age of 16 were obtained.
      281 patients had been in asthma remission more than one year after the last their
      attack. Among them, 31 patients (14 males and 17 females) relapsed. Their average
      age of last attack was 15.1 +/- 3.6 years old. While the average age of the last
      attack in patients who did not relapse was 12.9 +/- 4.1. The average age of
      relapse was 20.8 +/- 4.2 and their duration of remission was 5.8 +/- 2.9 years.
      No relapse was observed after 14 years of remission. The most of the patients
      relapsed within 10 years. The relapse rate calculated by life table method was
      13.5%. Relapse retes were calculated in various characteristics: females; 24.9%,
      patients who had severe symptoms at the first visit and moderately severe; 22.4%,
      23.1%, respectively, positive history of steroid therapy; 25.1%, IgE level of
      more than 500 IU/ml; 19.7%, patients whose last attack was after the age of 13;
      21.2%. Those figures are significantly higher than the opposite characteristics.
      The environmental factors significantly contribute to the relapse of remitted
      asthmatics. They are apartment house, ferroconcrete and aluminum-framed house,
      carpet in bedroom, pets, maternal or self-smoking. The asthmatic children who
      have those risk factors should be followed to prevent relapse and their
      environment controls should be adequately stressed even in asthma remission.

PMID- 10355147
TI  - [Change in prevalence of allergic diseases in primary school children in Fukuoka
      City for the last fifteen years].
AB  - We have been investigating the yearly change of prevalence rate of childhood
      allergic diseases using same method and in same region in five primary schools in
      Fukuoka City for the last fifteen years. From 1981 to 1995, revised ATS-DLD
      questionnaire had been administered yearly to the first graders of primary school
      children (6-7 yrs). The total number of subjects for fifteen years were 8000. The
      average number of children in each year was 533. 1. The cumulative prevalence of
      bronchial asthma statistically increased from 5.7% (average of 1981 to 1983) to
      7.7% (1993 to 1995). It was 1.7 times higher on boys. 2. The cumulative
      prevalence of atopic dermatitis did not change yearly and its average was 36.3%.
      The boys/girls ratio was 1.2. Remission rate of atopic dermatitis statistically
      increased from 14.3% (average of 1987 and 1988) to 19.6% (1994 and 1995). 3. The
      cumulative prevalence of allergic rhinitis did not change yearly and its average
      was 17.6%. It was 1.5 times higher on boys. 4. The cumulative prevalence of
      allergic conjunctivitis statistically increased from 8.4% (average of 1987 and
      1988) to 11.1% (1994 and 1995).

PMID- 10355148
TI  - [Inhibition of antigen-specific T helper type 2 responses by Perilla frutescens
      extract].
AB  - Perilla frutescens leaf extract (PFE) is known as a natural medicine with anti
      allergic activities, although its mechanism of action remains unclear. In this
      study, we examined the effect of PFE on antigen-specific antibody and on cytokine
      production. Mice were immunized three times (weekly) with sugi basic protein
      (SBP), a major allergen of Japanese cedar pollen, in alum adjuvant. PFE was
      injected intraperitoneally into mice on day 2 before and on the day of each
      immunization with SBP in alum adjuvant. Serum anti-SBP IgE and IgG 1 antibody
      levels were significantly suppressed in mice injected with PFE. Furthermore, the
      production of interleukin (IL)-4, IL-5 and IL-10 by SBP-stimulated splenocyses
      also decreased in PFE-injected mice in a dose-dependent manner. However, PFE had
      no effect on either the serum anti-SBP IgG 2 a antibody levels or on interferon
      (INF)-gamma production by splenocytes. When splenocytes were stimulated with
      concanavalin A, there was no difference in cytokine production between mice
      injected with PFE and control mice injected with vehicle. SBP-specific T cell
      line established in the presence of PFE from the lymph node cells of mice
      immunized with SBP showed reduced IL-4, IL-5 and IL-10 production compared with
      that established in the absence of PFE. In contrast, comparable levels of IFN
      gamma production were observed between these two T cell lines. These data suggest
      that PFE down-regulates Th 2-type cytokine production and prevents the Th 1/Th 2
      balance from polarizing toward Th 2-type immune responses.

PMID- 10355149
TI  - [Peripheral blood dendritic cell dysfunction in patients with Sjogren's
      syndrome].
AB  - The function of dendritic cell (DC), that has the strongest antigen-presenting
      ability, was investigated for the purpose of clarifying immune abnormalities in
      Sjogren's syndrome (SS) from the point of view of antigen-presenting cells. DCs
      were separated from peripheral blood of SS patients, and mixed lymphocyte
      reaction (MLR) with DCs was observed to examine the function of DC. Autologous
      MLR (AMLR), which was induced by mixed culture of DCs with autologous T cells,
      significantly decreased in SS patients (p < 0.01). Allogeneic MLR (alloMLR),
      which was induced by mixed culture of DCs with allogeneic T cells, also decreased
      in SS patients, suggesting the presence of DC dysfunction. Cell surface
      expression rates of HLA-DR, CD 80, and CD 83, which are a first signal of cell
      surface antigen presentation, a second signal, and a specific antigen of DC,
      respectively, were then examined. Among HLA-DR-positive cells, CD 80-positive
      cells and CD 83-positive cells increased in SS patients, compared with normal
      subjects (p < 0.0003 and p < 0.00009, respectively). From these results, it was
      inferred that SS patients have not only DC dysfunction, but abnormalities in cell
      surface antigens as well.

PMID- 10355150
TI  - [Pranlukast allows reduction of inhaled steroid dose without deterioration in
      lung function in adult asthmatics].
AB  - We undertook a community based case-control study to measure the effect of
      pranlukast on the reduction of inhaled steroid in adult asthmatics. Forty-one
      adults completed a run-in period of 4 weeks on 800 microgram of beclomethasone
      dipropionate (BDP) documenting twice daily peak expiratory flow (PEF) and symptom
      score and therapeutic score on a standard diary. Forced expiratory volume in one
      second (FEV1.0), V50, V25 was measured once during the run-in period. Patients
      were then randomized to receive either pranlukast with 400 microgram of BDP or
      400 microgram alone for 8 weeks. There was no difference in the symptom score and
      therapeutic between the two groups at any time point. However, morning and
      evening % PEF run-in expressed as a % of the PEF average during the run-in period
      was significantly lower at 8 weeks in the groups without pranlukast. There were
      subjects in the group without pranlukast (35.3%) compared to those with (20.8%)
      who had a 10% or more reduction in % PEF from the run-in period. The patients
      with an FEV1.0 < 80% predicted who were randomized to the control group were more
      likely (5 of 7) to have a fall in % PEF run-in and those randomized to received
      pranlukast were less likely to have a fall in % PEF run-in though this was not
      significant (2 of 6). In this study, pranlukast has demonstrated steroid sparing
      effect. Severe asthmatics (FEV1.0 < 80%) who deteriorate after reduction of
      inhaled steroid may benefit most from pranlukast. Larger studies are now required
      to explore this important effect.

PMID- 10355151
TI  - [Exhaled nitric oxide of childhood asthma].
AB  - Chronic airway inflammation is a central feature of pathology of bronchial
      asthma. In order to evaluate inflammatory status in asthma, examinations such as
      bronchoscope or induced sputum test can be done. Because of difficulty of those
      examinations we need non-invasive and simple measures for childhood asthma. Here
      we investigated eNO in childhood asthma. Twenty-six of atopic asthma, 13 non
      asthmatic atopic children and 12 normal children were enrolled in this study. eNO
      was measured by chemiluminescence analyzer. eNO was significantly collerated with
      % FEV 1.0 and blood eosinophil counts (R = -0.494, R = 0.416, respectively).
      Geometrical mean of eNO in normal, non-asthmatic atopic, asthma without inhaled
      corticosteroid (ICS) and asthma with ICS was 16.3, 23.7, 71.6, 43.6 ppb,
      respectively. eNO was significantly higher in asthma than in normals. eNO in
      patients without ICS were significantly higher than in non-asthmatic atopic. We
      concluded that eNO might be useful marker for evaluation of airway inflammation
      in asthmatic children.

PMID- 10355152
TI  - [Nebulised budesonide is effective for severe infantile asthma--a report of two
      clinical cases].

PMID- 10355153
TI  - [A case with hereditary angio-neurotic edema treated effectively by danazol].

PMID- 10355154
TI  - [Effects of immunotherapy on cytokine production from peripheral blood
      mononuclear cells in patient with house dust mite allergic rhinitis].
AB  - We studied effects of immunotherapy on mite antigen-induced cytokine production
      from peripheral blood mononuclear cells in patient with house dust mite allergic
      rhinitis. In good response group, IL-4 production were lower than that of poor
      response group. In contrast, IFN-gamma production and the ratio of IFN-gamma to
      IL-4 synthesis were significant higher than that of poor response group. The
      production of IFN-gamma significantly correlated with the periods of
      immunotherapy. These results suggest that the changes of cytokine synthesis have
      a close relationship to clinical effects of immunotherapy.

PMID- 10355155
TI  - Branch retinal artery occlusion in systemic diseases: a case report.
AB  - Although branch retinal artery occlusion (BRAO) is a relatively benign disease in
      terms of permanent visual impairment, the associated systemic diseases confer
      significant morbidity and mortality. The following systemic disorders can be
      found among patients presenting with a retinal artery occlusion: hypertension
      (59%), significant atherosclerotic cardiovascular disease (21%), diabetes
      mellitus (15% to 21%), left-sided valvular heart disease (5%), and
      cerebrovascular accidents (5%). These underlying systemic diseases are often
      responsible for a significant reduction in life expectancy and are in many cases
      potentially treatable conditions. A thorough cardiovascular examination
      (including a carotid duplex ultrasonography) may identify these occult diseases,
      and a prompt and effective treatment may improve the quantity and quality of
      patients' lives by reducing the risk of further arterial occlusive events.

PMID- 10355157
TI  - Adenocarcinoma of the nonpigmented ciliary body epithelium: report of a rare
      case.
AB  - Acquired tumours of the nonpigmented ciliary body epithelium are rare. We present
      herein a case of low-grade adenocarcinoma in order to stress the problems related
      to the clinical diagnosis. The tumour in our case was circumscribed, localised on
      the ciliary body, and nonpigmented. The height of the tumour, measured with
      ultrasound biomicroscopy, was 3.5 mm. The internal reflectivity of the tumor was
      homogeneous with low attenuation. The tumour was surgically excised with an
      uneventful iridocyclectomy. Both clinical presentation and preoperative
      examinations allowed to circumscribe the correct diagnosis which could be
      confirmed only with histology.

PMID- 10355156
TI  - Acute unilateral visual loss due to a single intranasal methamphetamine abuse.
AB  - An otherwise healthy 35 year old male with insulin-dependent diabetes mellitus
      (IDDM) presented himself three days after a single intranasal methamphetamine
      abusus. Directly upon awakening the day after the recreational use of this drug,
      he discovered an acute and severe visual loss of his right eye. This unilateral
      loss of vision was permanent and eventually lead to a pale and atrophic optic
      nerve head. The characteristics of this visual loss, together with the aspect of
      the optic nerve head was very similar to the classical non-arteritic ischemic
      optic neuropathy (NAION). We suggest a direct ischemic episode to the short
      posterior ciliary arteries due to this single intranasal abuse of methamphetamine
      as the underlying pathogenesis of this acute and permanent visual loss.

PMID- 10355158
TI  - Neuro-ophthalmic complication after maxillary surgery.
AB  - We report an unusual case of ophthalmoplegia after maxillofacial surgery. A
      thirteen year old girl with unilateral left cleft lip and palate underwent
      maxillary advancement by distraction osteogenesis. Postoperatively she developed
      diplopia. The diplopia was not due to orbital lesions, most often seen after
      maxillofacial surgery, but to a haemorrhage posterior to the cavernous sinus.

PMID- 10355159
TI  - Long-term results of wagon wheel packed acrylic intra-ocular lenses (AcrySof).
AB  - To evaluate long-term results of Wagon Wheel packed AcrySof intraocular lenses
      (IOLs), 88 and 39 patients (115 and 55 eyes respectively) were examined at 14 and
      28 months respectively. Visual acuity increased from an average of 0.324
      preoperatively to about 0.722 one week post-operatively. A YAG capsulotomy had to
      be performed in two eyes only. Vacuoles, as described with the Acry Pak system,
      were also detectable in our Wagon Wheel packed lenses. They increased
      significantly in incidence and number with time.

PMID- 10355160
TI  - Severe subconjunctival haemorrhage associated with malaria.
AB  - PURPOSE: To describe a patient with sudden onset of subconjunctival haemorrhage
      related to malaria. METHODS: A case report. RESULTS: The patient, who had a
      history of malaria, had bilateral subconjunctival haemorrhages. General
      examination showed no abnormality except malaria. All signs of conjunctival
      haemorrhages resolved later. CONCLUSION: Ocular malaria should be considered in
      the differential diagnosis of subconjunctival haemorrhages.

PMID- 10355161
TI  - [Progressive deterioration of episcleral Miragel explants].
AB  - Miragel (TM) episcleral explants undergo deterioration with the passing years, so
      that their ablation becomes necessary in a growing number of cases because of
      progressive discomfort and/or diplopia. The present study deals with 13 eyes
      undergoing the removal of an episcleral Miragel explant between 10/1/96 and
      10/15/98. The Miragel explant ablation, which is tedious because of the material
      alterations, gives excellent functional and cosmetic results. The risk of retinal
      detachment recurrence seems low.

PMID- 10355162
TI  - Late side-effects of radiotherapy for subfoveal choroidal neovascularization.
AB  - Radiation therapy for subfoveal neovascularization has not yet proved its
      efficiency, but, to our knowledge, no exudative complication of this treatment
      has been reported. We describe a late side effect observed in 16 eyes after a
      mean follow up of 33 months, characterized by major extension and exudation of
      the choroidal new vessels. In several cases, development of elongated, club like
      new vessels was observed at the border of the neovascular membrane. At the end of
      the follow-up, 4 eyes had an exudative retinal detachment affecting half of the
      retina or more and visual acuity was < or = 1/50 in 94% of the cases (including a
      case with no light perception and 2 cases with only light perception).

PMID- 10355163
TI  - Subfoveal choroidal neovascularization: radiotherapy or perifoveal
      photocoagulation? A fellow eye study.
AB  - Perifoveolar photocoagulation is advised for subfoveal choroidal
      neovascularization responding to the MPS eligibility criteria. Recently,
      radiation therapy has been proposed but has not yet proved its efficacy. We
      compared these two treatments. We retrospectively reviewed 27 patients with age
      related macular degeneration and subfoveal choroidal neovascularization in both
      eyes. The first eye was treated with perifoveolar photocoagulation and the second
      eye with radiotherapy. In case of simultaneous diagnosis, radiotherapy was
      performed in the eye with the best visual acuity. Although the follow up is two
      times longer and the initial visual acuity is lower in the group of the
      photocoagulated eyes, both groups have similar results at the end of their
      respective follow up. However, in the eyes treated with radiotherapy the lesions
      are still active and edematous while in the eyes treated with perifoveolar
      photocoagulation, the lesions are stable and dry. The percentage of patients who
      subjectively prefer the photocoagulated eye has increased progressively from 0%
      to 71.5% along the 20 months of follow-up post radiotherapy. The perifoveolar
      photocoagulation of the subfoveal choroidal neovascularization seems, at median
      term, to give better objective and subjective results than the radiation therapy.

PMID- 10355164
TI  - [Craniopharyngioma: ophthalmological manifestations and prognosis after
      treatment].
AB  - The craniopharyngioma is a benign tumor located at least in part in the
      suprasellar cistern. The symptoms are determined not only by the position of the
      tumor but also by its size and the age of the patient. The goal of our study is
      to analyse retrospectively the manifestations of craniopharyngioma and their
      prognosis after treatment in function of the age.

PMID- 10355165
TI  - Unusual combination of night blindness and optic neuropathy after biliopancreatic
      bypass.
AB  - Night blindness and optic neuropathy were the presenting symptoms of an
      iatrogenic malabsorption syndrome in a 64-year old female. This case illustrates
      the necessity of lifelong vitamin supplementation after biliopancreatic bypass
      for morbid obesity.

PMID- 10355167
TI  - Benign prostatic hyperplasia: an appraisal of the indications for transurethral
      prostatectomy.

PMID- 10355166
TI  - The long-term effect of Yag laser posterior capsulotomy on intraocular pressure
      after combined glaucoma and cataract surgery.
AB  - In order to evaluate the long-term effect of Yag laser posterior capsulotomy on
      intraocular pressure (IOP) after combined cataract and glaucoma surgery, we
      retrospectively studied 20 patients who underwent posterior capsulotomy after
      single-site combined phacoemulsification and trabeculectomy. We assessed mean IOP
      and number of glaucoma medications. The mean follow-up was 3 months (range 1 to 6
      months). Mean IOP's remained almost unchanged, and were 13.9 +/- 2.7 before and
      14.8 +/- 3 mmHg after capsulotomy (p = 0.115). The mean number of medications
      (0.4) remained unchanged. We conclude that Yag laser posterior capsulotomy does
      not significantly affect bleb function or glaucoma medication use in patients who
      underwent combined phacoemulsification and trabeculectomy.

PMID- 10355168
TI  - Chronic peripheral occlusive arterial disease in Sri Lanka.

PMID- 10355170
TI  - Street children--a preliminary study.
AB  - OBJECTIVE: To study the background, life styles, health and prevalence of abuse
      of street children in Colombo. STUDY SAMPLE: 50 street children receiving
      temporary day care or night shelter from community service centres were serially
      recruited. DESIGN: A retrospective descriptive survey. Demographic, experiential
      and clinical data were collected by an interviewer, based on a semistructured
      questionnaire, followed by physical examination and laboratory investigation.
      RESULTS: The children were aged between 4 and 17 years. (Mean 10.5 years.) 64%
      were males and 18% belonged to ethnic minorities. The majority (84%) had family
      ties. Family disintegration was mentioned as the cause for life on the streets by
      36%. Child labour was reported in 38%. 16% admitted to being sexually abused. 20%
      were tobacco smokers. Respiratory and skin infections, and injuries incurred in
      road traffic accidents were the main causes of morbidity. CONCLUSION: Street
      children in Colombo are an abused and exploited group. Road traffic accidents,
      and physical and sexual abuse are the main hazards of the street they are exposed
      to.

PMID- 10355169
TI  - User satisfaction with child psychiatry outpatient care: implications for
      practice.
AB  - INTRODUCTION: Satisfaction with outpatient care is determined by the extent to
      which the expectations of users are met. Obtaining the opinion of users is
      considered a reliable method of assessing the quality of service. The objective
      of our study was to assess the degree of satisfaction expressed by users of a
      child psychiatry outpatient service and to match degree of satisfaction with the
      dropout rate. METHOD: A questionnaire was used to assess the users' expectation
      of the service and degree of satisfaction. Dropout rate was determined from the
      clinical records. RESULTS: 165 new referrals to the outpatient service were
      recruited for the study. 41.2% expected a cure for the child's mental health
      problem. 65.5% expressed satisfaction with the treatment intervention and time
      provided at the first consultation. Positive free text comments supported this
      opinion, but were incongruent with the 32.8% dropout rate after the first and
      second visits to the clinic. Behaviour problems in children and serious social
      problems in the families increased the risk of dropout from treatment.
      CONCLUSIONS: Initial expression of satisfaction with the service by the users
      does not guarantee continued co-operation with follow up care. Sensitivity in the
      approach to treatment is needed where there is a higher risk of dropout.

PMID- 10355171
TI  - Retinopathy of prematurity in Sri Lanka.

PMID- 10355172
TI  - Can group A beta haemolytic streptococcal sore throats be identified clinically?
AB  - OBJECTIVE: To differentiate the clinical manifestations of a Group A beta
      haemolytic streptococcal throat infection from viral and other bacterial
      infections. SETTING: Outpatients' department, Lady Ridgeway Hospital, Colombo.
      PATIENTS AND METHODS: Children aged 3 to 12 years attending with a sore throat.
      Throat swabs were taken and relevant details were obtained using a questionnaire.
      They were examined for significant cervical lymphadenopathy and tonsillar
      exudate. RESULTS: Group A beta haemolytic streptococci were isolated from 61
      (44.5%) throat swabs. Clinical differentiation of Group A beta haemolytic
      streptococcal sore throats was not possible as none of the symptoms or signs were
      significantly associated with the presence of this organism. CONCLUSIONS: Group A
      beta haemolytic streptococcal sore throats cannot be identified clinically, so
      that throat swabs for culture are necessary in children with sore throat. In the
      absence of this facility, it is reasonable to treat sore throats in children as
      for beta haemolytic streptococci.

PMID- 10355173
TI  - Reliable and easy identification of bacterial acute respiratory infections of
      childhood.
AB  - OBJECTIVES: To identify the causative bacteria in childhood acute respiratory
      infections (ARI) and to determine the usefulness of pus cell counts in
      differentiating between pathogenic and commensal bacteria, cultured from
      nasopharyngeal aspirates. DESIGN: Case control prospective study. SETTING:
      Outpatients' department and the paediatric unit at General Hospital, Colombo
      South. SUBJECTS: 200 children under 5 years with cough and difficulty in
      breathing for less than one week who had no history of antibiotic therapy for the
      current illness, and 50 healthy controls matched for age and sex. RESULTS: 56.5%
      of cases had bacterial infections. Branhamella catarrhalis (25%), Haemophilus
      influenzae (12.5%) and Streptococcus pneumoniae (10.5%) were the major pathogens
      identified. Pus cell counts were found to be significantly higher in cases than
      in controls (X2 58.28 df = 1 p < 0.001), and the pathogens were more often
      associated with pus cell counts of more than 10/field. CONCLUSIONS: 56.5% of
      children with ARI had bacterial infections. B catarrhalis seems to play a major
      role in childhood ARI. Examination of nasopharyngeal aspirates is a useful way to
      identify pathogens, provided microscopic examination for pus cells is performed
      together with culture.

PMID- 10355174
TI  - Exfoliative cytology in screening for malignant and premalignant lesions in the
      buccal mucosa.
AB  - OBJECTIVE: To test the efficacy of exfoliative cytology in the detection of oral
      premalignant and malignant lesions. DESIGN: Cytological diagnosis of lesions of
      the buccal mucosa assessed using histopathological diagnosis of the same lesions
      as the gold standard. SUBJECTS: Patients with buccal lesions clinically diagnosed
      as leukoplakia (n = 91) and squamous cell carcinoma (SCC, n = 59), and healthy
      subjects (n = 40) in whom buccal mucosa appeared clinically normal. SETTING: Oral
      and Maxillo-facial Unit, General Hospital, Kandy and Department of Pathology,
      Faculty of Medicine, University of Peradeniya. RESULTS: A sensitivity of 77%,
      specificity of 100% and accuracy of 92% were obtained for leukoplakia. SCC gave a
      sensitivity of 94%, specificity of 100% and an accuracy of 95%. CONCLUSIONS: Oral
      exfoliative cytology is a useful method for detecting oral premalignant and
      malignant lesions. Anucleated squames in a smear is non-diagnostic.

PMID- 10355177
TI  - Cardiovascular disease and hormonal contraceptives: latest results.

PMID- 10355175
TI  - Heart attacks: exploring new preventive strategies.
AB  - Ischaemic heart disease is an emerging public health problem in Sri Lanka.
      Implementation of programs for lifetime control and prevention of established
      coronary risk factors such as smoking, hyperlipidaemia, hypertension, diabetes
      and hereditary risk are costly and unaffordable in countries such as Sri Lanka
      with limited resources for health care. Other potential risk factors which are
      less expensive with regard to prevention require investigation. This paper
      summarises several studies done over the past decade at Peradeniya, to
      investigate three such potential coronary risk factors of IHD, namely
      homocysteine, vitamin C and dietary fat.

PMID- 10355178
TI  - A single pathological grading system for breast carcinoma should be adopted in
      Sri Lanka.
AB  - INTRODUCTION: Histologic grading of breast cancer is related to prognosis and
      management of patients. The grading systems used are the initially formulated
      subjective methods, and the more recently described objective Nottingham system.
      In Sri Lanka there is lack of uniformity in histopathology reporting of breast
      cancer. All methods used employ 3 grades. If histologic grading is to be of
      clinical relevance, it is important that the grades of different systems
      correlate with one another. OBJECTIVE: To determine if the three grades of the
      Nottingham system correlate with those of the other systems. SETTING: Department
      of Pathology, Faculty of Medicine, Colombo. METHOD: 54 breast carcinomas were
      graded using the Nottingham system by reviewing histology slides. The Nottingham
      grading was compared with the original grading mentioned in the histology report.
      RESULTS: The original reports included 35 tumours graded with systems other than
      Nottingham. 45.7% of these tumours did not correspond with the subsequent
      Nottingham grade. 40% had to be upgraded from grade II to III. When the 19
      tumours originally graded using the Nottingham system were re-evaluated using the
      same system, there was concurrence in 89.5% of the cases. CONCLUSION: Our results
      indicate a failure of other grading systems to correlate with the corresponding
      Nottingham grade in a high proportion of cases. We recommend the adoption of a
      single, objective grading system such as the Nottingham method by all clinicians
      in Sri Lanka.

PMID- 10355179
TI  - Massive ascites and bilateral hydrothorax complicating severe pre-eclampsia.
AB  - Massive ascites and hydrothorax as additional complications of pre-eclampsia are
      rare. The case reported is one of ascites and bilateral hydrothorax in a patient
      with severe pre-eclampsia. Careful antenatal assessment may help in detecting
      more cases with this complication, which is often misunderstood and the diagnosis
      missed.

PMID- 10355180
TI  - Serum folic acid levels of adolescent schoolgirls in a rural area.

PMID- 10355181
TI  - Is it HNPCC or HMRDS?

PMID- 10355182
TI  - Solitary rectal ulcer syndrome (SRUS) masquerading as a carcinomatous stricture.

PMID- 10355183
TI  - Carcinoma of the large bowel in persons under 20 years of age.

PMID- 10355184
TI  - An appendiceal skip lesion in ulcerative colitis.

PMID- 10355186
TI  - Primary PTCA for acute myocardial infarction in Sri Lanka.

PMID- 10355185
TI  - Two cases of Creutzfeldt-Jakob disease.

PMID- 10355187
TI  - Hypertension in a general medical clinic in the National Hospital of Sri Lanka.

PMID- 10355188
TI  - Cluster of cases of Legionnaires' disease associated with a Bangkok hotel.

PMID- 10355189
TI  - Communicable disease hazards facing refugees from Kosovo.

PMID- 10355190
TI  - Extensive tympanosclerosis with a fixed malleus.

PMID- 10355191
TI  - The surgical significance of the agger nasi cell.

PMID- 10355192
TI  - Reinke's edema.

PMID- 10355193
TI  - Hearing loss in siderosis.

PMID- 10355195
TI  - Lingual thyroid gland: clinical evaluation and comprehensive management.
AB  - Although lingual thyroid gland is the most common benign mass found at the
      junction of the anterior two-thirds and the posterior one-third of the tongue, it
      is still a rare clinical entity. This developmental anomaly is the result of an
      arrested descent of the gland anlage early in the course of embryogenesis.
      Patients may have symptoms of dysphagia due to obstruction or even hemorrhage.
      These symptoms can occur at any time from infancy through adulthood. The clinical
      findings, laboratory tests, and radiographic imaging studies employed in
      confirming the diagnosis and in planning appropriate treatment have been
      evaluated. The primary therapeutic goal is to restore thyroid function. We
      describe a case of lingual thyroid gland and summarize the current management
      principles for this condition.

PMID- 10355194
TI  - Simultaneous binaural bithermal; normal alternate binaural bithermal.

PMID- 10355196
TI  - Combined infratemporal fossa and transfacial approach to excising massive tumors.
AB  - Massive tumors of the infratemporal and pterygopalatine fossa are usually
      resected via the Fisch type C infratemporal fossa approach. This approach
      provides the surgeon with wide enough access to safely remove massive tumors, and
      it allows excellent control of the internal carotid artery without leaving facial
      scars. The disadvantages of this approach include a total loss of hearing on the
      affected side and the risk of damage to the facial nerve. The Fisch type D
      infratemporal preauricular approach provides a limited access to tumors, but it
      does preserve hearing. We studied the practice of combining the Fisch type D
      approach with a transfacial, transmaxillary approach. This allows the removal of
      massive tumors of the area without the necessity of resorting to the type C
      approach and the resultant loss of hearing and the possibility of facial
      paralysis. The flexibility of the type D infratemporal fossa approach allows the
      surgeon to combine it with transmaxillary, transmandibular, and periorbital
      approaches to remove tumors of all sizes from the infratemporal fossa,
      pterygopalatine fossa, parapharyngeal space, and orbit.

PMID- 10355197
TI  - Initial report of primary sinusitis caused by an atypical pathogen (Mycobacterium
      chelonae) in an immunocompetent adult.
AB  - Primary sinonasal infections caused by atypical mycobacteria are rare. In fact,
      only four examples of a primary nontuberculous mycobacterial etiology of
      paranasal sinusitis have been cited in the literature. The patients in all these
      cases were infected with the human immunodeficiency virus and, by definition,
      they all had acquired immunodeficiency syndrome. We present a report of an
      immunocompetent adult with a history of chronic sinusitis who consistently and
      repeatedly manifested a fast-growing, nonpigmented, atypical mycobacterium of the
      Runyon group IV category: Mycobacterium chelonae. The patient was successfully
      treated over a 3-year period with a combination of antimicrobial agents, multiple
      limited endoscopic sinus surgeries, and eventually a total globe-sparing
      maxillectomy. At this time, the patient is disease-free and has received no
      further treatment. This case represents the first report of an immunocompetent
      adult host with a primary atypical mycobacterial infection of the paranasal
      sinuses. It also demonstrates the multimodal nature of the treatment of atypical
      mycobacterial infections. We also discuss the Byzantine classification scheme
      relative to atypical mycobacteria, the disease process in the immunocompromised
      host, and the various treatment options.

PMID- 10355198
TI  - The use of low-dose histamine therapy in otolaryngology.
AB  - Low-dose histamine therapy has been prescribed by otolaryngologists primarily to
      treat Bell's palsy, vestibular disorders, vascular headache, Meniere's attacks,
      and urticaria vasculitis. The scientific explanations for the usefulness of this
      once-empiric treatment are becoming more apparent. Two methods of establishing
      the appropriate dosages have emerged: the empiric, optimum-dosage approach and
      the objective, endpoint-titration approach. In this article, the author describes
      and recommends the latter approach. The author also reports on a 100-patient
      retrospective clinical study that revealed that the objective, endpoint-titration
      approach was effective in treating 80% of patients. In light of such success and
      the ease and economy of this treatment, low-dose histamine therapy appears to be
      a valuable clinical tool.

PMID- 10355199
TI  - Head and neck mucosal melanoma: a 32-year review.
AB  - Because mucosal melanoma of the head or neck is uncommon, retrospective data are
      of value in defining its natural history, response to treatment, and patterns of
      recurrence. We analyzed the medical records of 28 patients who had been treated
      for a mucosal melanoma of the head or neck between 1961 and 1993. We found that
      their cumulative 5-year survival rate was 20%. Patients who had primary tumors of
      the nasal cavity had significantly better 5-year survival than other patients.
      Early stage at presentation was another predictor of a more favorable outcome.
      Only 2 of the 17 patients (12%) who underwent surgery died with local disease.
      However, 13 of these 17 surgical patients (76%) eventually died of distant
      metastases. There were 3 long-term (> 5 yr) survivors: 2 who were treated by
      surgery alone, and 1 who was treated with surgery and radiation therapy. We found
      that aggressive resection of the primary tumor and of any local recurrence can
      achieve local control in most patients with mucosal melanoma of the head or neck.
      Distant metastasis is the limiting factor for long-term survival.

PMID- 10355200
TI  - Endodermal sinus tumor of the maxillary sinus: a case report.
AB  - Endodermal sinus tumor is an uncommon malignant germ cell tumor that occurs in
      both gonadal and extragonadal tissues. Endodermal sinus tumors of the head and
      neck, exclusive of the central nervous system, are rare. We report a case of
      endodermal sinus tumor arising from the maxillary sinus in a 4-year-old boy.
      Combined treatment with radiation therapy and chemotherapy resulted in complete
      tumor regression.

PMID- 10355201
TI  - General assembly adopts changes in HIV/AIDS statute.

PMID- 10355202
TI  - RUOK 4 Y2K?

PMID- 10355203
TI  - Malpractice risks in cyperspace.

PMID- 10355204
TI  - Effective advocacy never ends.

PMID- 10355205
TI  - Is your fee schedule compliant?

PMID- 10355206
TI  - Medicaid reimbursement top priority.

PMID- 10355207
TI  - Subcutaneous hydration with no hyaluronidase in patients with advanced cancer.

PMID- 10355208
TI  - Query "wind-down, switch-off".

PMID- 10355209
TI  - Board certification in palliative care for U.S. physicians. Officers and Trustees
      of the American Board of Hospice and Palliative Medicine.

PMID- 10355210
TI  - Fatigue and quality of life in breast cancer patients undergoing autologous stem
      cell transplantation: a longitudinal comparative study.
AB  - As more individuals are being treated for cancer with high-dose therapy and
      autologous stem cell rescue (ASCR), there is growing interest in treatment side
      effects and their impact on quality of life. The primary aim of this study was to
      determine if the severity of fatigue and its impact on quality of life is
      significantly greater in women undergoing ASCR for breast cancer than in women of
      similar age with no history of cancer. A group of women being treated with ASCR
      for breast cancer (n = 31) and a group of women of similar age with no history of
      cancer (n = 49) participated in this study. Patients completed measures of
      fatigue and psychosocial functioning prior to treatment, midway through
      treatment, and toward the end of treatment. Healthy comparison subjects completed
      the same measures three separate times. Breast cancer patients undergoing ASCR
      reported significantly more frequent fatigue and more severe fatigue than women
      with no cancer history. In addition, fatigue had a significantly greater impact
      on daily functioning and quality of life in patients than in women with no cancer
      history. Fatigue during ASCR for breast cancer was related to both medical
      factors (i.e., time since transplant) and psychosocial factors. During ASCR for
      breast cancer, women experience fatigue which is worse than what is "normally"
      experienced and which interferes with daily functioning and quality of life.
      Future research should focus on identifying the biological correlates of fatigue,
      psychological and physiological mechanisms by which fatigue is produced, and
      interventions to alleviate fatigue.

PMID- 10355211
TI  - Pain, fatigue, and sleep disturbances in oncology outpatients receiving radiation
      therapy for bone metastasis: a pilot study.
AB  - Pain and fatigue are two of the most common problems experienced by oncology
      patients. This study evaluated 24 oncology patients who were receiving radiation
      therapy for bone metastases to (1) describe the patterns of pain intensity and
      fatigue severity over a 48-hour period; (2) evaluate for sleep disturbances; (3)
      describe the relationships between these symptoms and various treatment
      characteristics; and (4) describe the self-care strategies used by patients to
      manage pain and fatigue. Patients reported moderate amounts of pain and fatigue.
      Average pain scores did not vary significantly over a 48-hour period. However,
      patients reported significantly lower fatigue scores in the morning compared to
      the evening. In addition, patients experienced significant sleep disturbances,
      with a mean sleep efficiency index of 70.7% (estimated using wrist actigraphy).
      Patients with lower Karnofsky Performance Status scores reported more sleep
      disturbances. In addition, patients who had received a higher percentage of their
      radiation treatment reported more sleep disturbances. Patients used a variety of
      self-care strategies to manage pain and fatigue. Additional research is warranted
      to describe more completely the patterns of pain, fatigue, and sleep disturbances
      in oncology outpatients receiving radiation therapy.

PMID- 10355212
TI  - The treatment of chronic cancer pain in a cancer hospital in The Netherlands.
AB  - In a prospective study of 313 Dutch cancer patients with chronic pain, the
      practice of pain treatment was evaluated by means of Donabedian's structure
      process-outcome framework. The practice of pain treatment was assessed by: (1)
      structural resources, describing the setting in which pain treatment is provided;
      (2) process components, which describe the clinical practice; and (3) outcome
      measures, which refer to patients' pain intensity, patient satisfaction, or
      composite pain management index scores. Results showed that 31.4-59.8% of the
      cancer pain patients received less than optimal pain treatment. Although pain
      education and refresher courses for health care providers are scarce, structural
      resources were not the major cause of the suboptimal level of pain treatment.
      Rather, the major cause was the process components. Only 36.4% of the patients
      received strong opioids; 23.1% received analgesics "as needed." Patients' pain
      knowledge was far from optimal (54.8 on a 0-100 scale), and written pain
      information was given to only 15.8% of the patients. After discharge, only 36.8%
      of the district nurses were informed about patients' pain. These results
      emphasize that continuing efforts to improve the practice of pain treatment are
      needed.

PMID- 10355214
TI  - The Symptom Checklist-90 Revised questionnaire: no psychological profiles in
      complex regional pain syndrome-dystonia.
AB  - Complex regional pain syndrome (CRPS) is a syndrome usually localized in the
      extremities, mostly occurring after a preceding trauma or operation. Dystonia is
      present in a minority of CRPS patients, but, when present, leads to severe
      disability. Various pathological factors have been postulated to present in CRPS
      dystonia, such as involvement of the sympathetic system, reorganization of the
      central nervous system, and psychological distress. In the present study, we
      investigated the involvement of psychological distress in CRPS-dystonia with the
      aid of the Symptom Checklist-90 Revised (SCL-90R) questionnaire. The SCL-90R is a
      multidimensional self-report inventory covering various dimensions of
      psychological distress. In a population of 1006 CRPS patients, we analyzed the
      SCL-90R scores of 27 patients with CRPS-dystonia (23 female and 4 male) and
      compared the scores to sample scores of a control female (n = 577) and a control
      rehabilitation population (n = 56). Insomnia scored significantly higher in the
      female CRPS-dystonia population, as compared to the control female population (P
      < 0.001), and in the total CRPS-dystonia population, as compared to the
      rehabilitation population (P < 0.01). Remarkable was the significantly higher
      score of somatization in the rehabilitation population, as compared to the CRPS
      dystonia population (P = 0.006). For the other dimensions of psychological
      distress of the SCL-90R, the scores of the CRPS-dystonia and control populations
      were similar. With regard to the SCL-90R scores, we conclude that specific
      psychological profiles are not present in CRPS-dystonia.

PMID- 10355213
TI  - Analgesic effects of nonsteroidal anti-inflammatory drugs in cancer pain due to
      somatic or visceral mechanisms.
AB  - The role of nonsteroidal anti-inflammatory drugs (NSAIDs) is well established in
      the treatment of cancer pain. This class of drugs is considered particularly
      effective in pain due to somatic mechanisms, although proof of this observation
      is lacking. To ascertain whether NSAIDs are more effective in specific
      nociceptive forms of cancer pain, they were administered alone or added to
      opioids in 32 patients with a sole pain mechanism, somatic pain due to bone
      metastases (17 patients) or visceral pain (15 patients), respectively. Pain
      intensity, mean doses of opioids used, and symptoms were recorded after starting
      NSAID. A significant reduction in pain intensity was found at 3, 7, and 14 days.
      No differences in pain intensity between the two groups were observed. However,
      patients with a visceral mechanism required higher opioid doses after a week of
      treatment. No differences in adverse effects were reported. NSAIDs may be useful
      drugs in the management of cancer pain, regardless of the mechanism of pain
      involved. The incidence of adverse effects during prolonged administration should
      be assessed in future studies.

PMID- 10355215
TI  - The use of phenobarbitone in the management of agitation and seizures at the end
      of life.
AB  - This study investigated the role of phenobarbitone at the end of life by
      retrospective analysis of case notes. During a 3-year period, of the 748 patients
      who died in a 32-bed palliative care unit, 60 received phenobarbitone during the
      last week of life. Fifty-nine patients had advanced cancer, 16 of whom had
      cerebral involvement. Phenobarbitone was used to control agitation and seizures.
      It was administered via subcutaneous infusion at a dose of 600-2400 mg/day. The
      mean time from starting phenobarbitone to death was 34.1 hours. Phenobarbitone
      was well tolerated and effective, controlling physical and psychological
      agitation. No further seizures occurred. This study suggests that phenobarbitone
      has a useful role in the management of distressing symptoms in the last few days
      of life.

PMID- 10355216
TI  - Opioids for managing patients with chronic pain: community pharmacists'
      perspectives and concerns.
AB  - Previous studies of pharmacists have suggested poor availability of opioids and
      apprehension about dispensing these drugs. This pilot study surveyed 52 randomly
      selected New Jersey community pharmacists (response rate = 69%). Reluctance to
      stock opioids was attributed to concerns about robbery by 14% and to concerns
      about federal or state investigation by 17%. No correlation was found between
      respondents who had a high degree of concern about robbery and those who had
      incurred previous robbery. Of the 20% of respondents who had incurred a prior
      federal or state investigation, none expressed more than minimal concern about
      opioid regulatory issues. Pharmacist confidence in the acceptability of opioids
      for chronic pain was 75% for malignant pain in patients with no history of opioid
      abuse and declined to 3% for nonmalignant pain in patients with a history of
      opioid abuse.

PMID- 10355217
TI  - The development and impact of a chronic pain support group: a qualitative and
      quantitative study.
AB  - To study the process of establishment, and evaluate the outcome of participation,
      in a self-help support group for people with chronic nonmalignant pain, members
      of a newly-established, consumer-led group participated in two interviews 5
      months apart and a researcher observed group meetings. Participants reported
      significant benefits from participating in the group. They had a significant
      increase in functional ability and activity, and reported decreased recourse to
      health professionals, particularly family physicians. This study indicates that
      pain support groups can play a valuable role for people in pain, assisting with
      support and rehabilitation, and meeting needs that health professionals are often
      not appropriate or able to provide.

PMID- 10355218
TI  - Clinical experience with oral ketamine.
AB  - Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist used
      recently for analgesia in patients with chronic pain. Twenty one patients with
      chronic neuropathic pain were treated with oral ketamine starting at a divided
      dose of 100 mg/day and titrating upwards by 40 mg/day until efficacy was reached,
      or until side effects became limiting. A retrospective chart review was conducted
      to evaluate the analgesic efficacy and side effects of the treatment. Nine
      patients discontinued ketamine because of intolerable side effects, four patients
      experienced few or no side effects but had no discernible benefit, four others
      had equivocal responses. Four patients have continued oral ketamine for long
      periods. One patient has had no significant benefit or side effects but continues
      to use ketamine 500 mg/day and three people have used doses ranging from 100-240
      mg day for over 1 year duration and have reported improvements in pain and
      decreased use of analgesics. The analgesic benefits of ketamine appeared to be
      most pronounced in, but not limited to, patients with pain histories of less than
      5 years.

PMID- 10355219
TI  - [A study of factors relating to aggravation of patients with pulmonary
      Mycobacterium avium complex disease--with special reference to malnutrition].
AB  - We examined physical and blood statuses of 24 patients with pulmonary M. avium
      complex disease who entered our hospital from April 1993 to March 1997. Ten
      patients (41.7%) were diagnosed as primary infection type and 14 patients (58.3%)
      as secondary infection type. Twenty-four patients were classified to the
      following two groups: Group A was 14 patients who converted to MAC negative
      within six months after the admission and group B was 10 patients who continued
      to excrete MAC for more than six months after the admission. We made a comparison
      between group A and group B as to the results of physical and blood examinations
      on admission. Mean value of %IBW in group B was significantly lower (group B:74.4
      +/- 8.9%, group A:82.9 +/- 12.7%, p < 0.05) than that of group A. The level of
      serum albumin in group B was significantly lower (group B: 3.39 +/- 0.53 g/dl,
      group A: 3.99 +/- 0.45 g/dl, p < 0.01) than that of group A. ChE in group B was
      significantly lower (group B: 321.2 +/- 94.5 IU/l, group A: 442.9 +/- 148.4 IU/l,
      p < 0.05) than that of group A. Group B was nutritionally depleted than group A.
      In conclusion, these findings suggested that nutritional support should be taken
      into consideration in combination with conventional chemotherapy in treating
      chronic, intractable MAC disease.

PMID- 10355220
TI  - [Clinical investigation on endobronchial tuberculosis].
AB  - In order to assess the clinical features and clinical courses of endobronchial
      tuberculosis, which included trachea to segmental bronchus, we studied 34 cases
      of patients who were admitted to TB ward of International Medical Center of Japan
      from 1994 to 1997. We noticed a higher incidence in females and in the main
      bronchus. Cough was the most common complaint seen in 97% of cases. The duration
      of symptoms before the initiation of antituberculous chemotherapy was long (on
      the average 6 months), and they were often treated as bronchial asthma or
      bronchitis. Bronchoscopic examination is necessary for diagnosis. The scars
      sometimes gave rise to severe stenosis, especially when the lesion developed to
      an advanced stage or circumscribed the lumen before treatment. We tried INH
      inhalation with systemic chemotherapy. Although rapid improvement was suggested
      by this method, yet no significant difference was seen in the results for the
      efficacious prevention of stenosis. Five cases required surgical intervension
      (bronchoplasty and lobectomy) in order to avoid atelectasis or secondary
      infection. Early diagnosis and appropriate treatment are most important, and
      bronchoscopic examination is essential in early diagnosis.

PMID- 10355221
TI  - [Six-months chemotherapy (2HRZS or E/4HRE) of new cases of pulmonary tuberculosis
      -six year experiences on its effectiveness, toxicity, and acceptability].
AB  - The incidence of tuberculosis in Japan, 33.7 per 100,000 in 1997, is very high
      compared with USA or Western European countries. The decrease in the incidence
      has slowed down from the early 1980s, and the average annual rate of decrease has
      been 3.8% in the last 5 years. About 9 percent of tuberculosis patients defaulted
      from the nine-month regimen (6HRS or E/3HR) in urban areas. Regimens shorter than
      nine-month are needed to achieve high effectiveness of tuberculous chemotherapy.
      Out of 1128 new pulmonary tuberculosis patients, six-hundred twenty started
      treatment with six-month (2HRZS or E/4HRE) in Fukujuji Hospital, JATA, in Tokyo
      from January 1991 to December 1996. Out of 620, four-hundred twenty eight were
      both smear and culture positive, 136 were smear negative and culture positive and
      56 were bacilli negative. Out of 564 bacilli positive cases, 530 were susceptible
      to INH and RFP. Out of 530 drug susceptible cases three hundred ninety-three
      patients completed the regimen. Ninety-three percent of these patients had
      converted to negative at two months of chemotherapy and all of them at five
      months. Out of 450, two-hundred ninety five completed 6-month regimen, one
      hundred fifty-five were changed their regimen or prolonged duration of
      chemotherapy. Out of 295, nine patients (3.1%) relapsed after the completion of 6
      month chemotherapy. Mean follow-up period was 17.2 months and the median was 15.5
      months. The relapse rate was 2.2 per 100 person-years. Six of the relapsed cases
      were complicated with Diabetes Mellitus. Relapse rate was higher in patients with
      Diabetes Mellitus than in patients without (6/54, 7.9 per 100 person-years vs
      3/237, 0.8 per 100 person-years) (p < 0.001). Drug-induced hepatotoxicity was
      defined as elevated serum transaminase level with clinical symptoms of hepatitis
      or elevated serum transaminase level more than 5 times of upper limit of normal
      range with or without symptoms. Drug-induced hepatotoxicity developed in 43
      (8.0%) of 535 with initial normal liver function test results, this rate was
      similar to that in patients treated with nine-month regimen (34/420, 8.1%). But
      the frequency of hepatotoxicity of more than 400 IU/ml of serum transaminase
      level was higher in patients treated with PZA-containing regimen than with nine
      month regimen (16/536, 3.0% vs 4/420, 1.0%), but this deference was not
      statistically significant. Hepatotoxicity developed in 13/85 (15.3%) of patients
      treated with PZA-containing regimen with abnormal liver function tests at the
      beginning of chemotherapy, and this frequency was similar to 7/65 (10.8%) in
      patients with nine-month regimen. The relapse rate in patients with Diabetes
      Mellitus was statistically higher than in without Diabetes Mellitus (7.9 vs 0.8
      per 100 person-years). We concluded that the six-month regimen was highly
      effective, but the frequency of severe hepatotoxicity was relatively higher than
      in nine-month regimen and the duration of chemotherapy was not enough for
      patients complicated with Diabetes Mellitus. Further study is needed for
      sufficient chemotherapy in patients with Diabetes Mellitus.

PMID- 10355222
TI  - [A case of pulmonary tuberculosis case with pancytopenia accompanied to bone
      marrow gelatinous transformation].
AB  - A 45-year-old man did not visit a doctor in spite of his complains, cough and
      sputum lasting, for six months, and he finally could not eat without beer, and as
      a result, he lost his body weight and currently 52 kg. He became unconsciousness,
      was carried to a hospital, and was referred to our hospital. His sputum
      examination for acid fast bacilli was smear positive, Gaffky 6, for M.
      tuberculosis. His chest roentogenogram revealed large cavitary lesions in
      bilateral lung fields. On blood examination, WBC was 1100/microL, RBC was 256 x
      10(4)/microL, and PLT was 13.4 x 10(4)/microL. Total protein was 4.7 g/dl,
      albumin was 1.9 mg/dl, and total cholesterol was 65 mg/dl. We tried to aspirate
      bone marrow from his sternum, but it was impossible. Hence we did biopsy of his
      ilium. The pathology of his bone marrow revealed gelatinous transformation. It
      was thought that the marked delay in visiting a doctor caused general consumption
      and loss of apetite, thus led to gelatinous transformation and finally
      pancytopenia.

PMID- 10355223
TI  - [The current situation and treatment of childhood tuberculosis].
AB  - We performed a retrospective analysis of 394 patients who were treated for active
      tuberculosis (TB) at our hospital from 1976 to 1997. The diagnosis criteria for
      establishing TB were history of direct contact with TB patients, tuberculin skin
      test reactivity, positive bacteriology and radiographic findings compatible with
      TB. There were 192 males and 202 females (age range 1 month to 18 years of age,
      mean 6.3 years of age). Fifty-four percent of the cases were under 5 years of
      age. Primary pulmonary TB was presented in 200, post primary pulmonary TB in 97,
      pleural effusion in 53, endbronchial TB in 4, TB meningitis (TBM) in 28, miliary
      TB in 28 and other extra-pulmonary TB in 31. A history of contact with the
      patients was obtained in 72.8% of cases. Two hundred and thirty (58.4%) had
      received BCG, 134 (34%) no BCG, 30 (7.6%) were unclear. Especially, under 5 years
      of age, only 29 (13.6%) had received BCG. TBM is not disappeared in Japan and
      there were 28 cases with TBM. Fifteen patients out of them recovered completely,
      8 patients recovered with severe neurological sequelae which included mental
      retardation, motor weakness, seizures and hydrocephalus and 5 patients died.
      Twenty-six had no BCG. Particularly in 1990s, we had experienced 4 dead TBM
      cases, 1 multi-drug resistant (MDR) TBM case and 1 TBM case due to nosocomial
      infection. Children with TBM should received 12-month regimen using initial daily
      treatment with isoniazid, rifampin, pyrazinamide, and streptmycin, followed by
      isoniazid and rifampin administered daily. Pulmonary TB in children is
      successfully treated with 6-month standard chemotherapy using isoniazid,
      rifampin, and pyrazinamide daily for 2 months, followed by isoniazid and rifampin
      daily for 4 months. In order to promote TB control and eliminate childhood TB,
      especially in infants, the following is necessary; 1) early detection and
      treatment of adult TB patients, source of infection, 2) prompt and appropriate
      contact examination and chemoprophylaxis, 3) BCG vaccination during early
      infancy, 4) protection from MDR TB are most important in Japan.

PMID- 10355224
TI  - [Nontuberculous mycobacteriosis; the present status of epidemiology and clinical
      studies].
AB  - In Japan, The Mycobacteriosis Research Group at the Japanese National Chest
      Hospitals has continuously made the clinico-epidemiological study of
      nontuberculous mycobacteriosis (NTM) since early 1970s. The prevalence rate was
      determined as 0.82, 0.91, 1.22, 1.74 and 2.43 per 100,000 population per year in
      1971, 1975, 1980, 1985 and in 1990 respectively. The newest datum in 1997 was
      3.52. These data indicates the prevalence rate has continuously increased and
      became 3.8 times than 25 years ago. While on the other hand, the prevalence rate
      of lung tuberculosis has decreased from 133.1 to 15.2, becoming one nines in the
      same period. The numbers of newly detected patients of lung mycobacteriosis in
      1996 were also studied at 12 hospitals in Kinki district. The rate of NTM was
      16.6% in 4 sanatorium hospitals, being about the same to the datum of The
      Mycobacteriosis Research Group. The rate of NTM in 8 general hospitals was
      surprisingly high, 40.0%. The 70% of NTM patients were infected with
      Mycobacterium avium complex (MAC). The 24% were with M. kansasii, and the only 6%
      were with other miscellaneous species. That is, the about one thirds or more of
      total NTM patients were female MAC desease patients, another one thirds or less
      were male MAC patients, and the more than 90% of M. kansasii patients (about one
      fourth of total patients) were male. These 3 groups took the most part of NTM
      patients. The rate of female MAC patients with small non-cavitary lesion without
      underlying diseases showed a tendency to increase, and the rate of male MAC
      patients with cavitary lesions with underlying lung or systemic diseases
      decreased. In 1997, American Thoracic Society (ATS) published the official
      statement about the diagnosis and treatment of NTM disease. The table-1 in that
      statement showed the new criteria for diagnosis of NTM pulmonary disease. It is
      useful for precise diagnosis of lung NTM disease, and the old criteria made by
      The Mycobacteriosis Research Group of the Japanese National Chest Hospitals is
      also useful for rough diagnosis. In the ATS statement, for adult HIV-negative MAC
      patients, minimum three drug regimen of clarithromycin (or azithromycin),
      rifabutin (or rifampin) and ethambutol, with intermittent streptomycin which is
      option for extensive disease, is recommended. This regimen is the same that most
      of the Japanese specialists for NTM disease recommended. The follow-up study of
      47 Japanese MAC patients treated by the regimen contained clarithromycin with
      other anti-tuberculous drugs revealed that 80% of cases converted into bacilli
      negative and that the regimen had durable effect for at least 24 months. The
      resectional surgery may be considered for localized disease, and supportive
      nutritional treatment must also be considered for the MAC patients to whom the
      drug therapy was not effective, as if for the tuberculosis patients of multi-drug
      resistant.

PMID- 10355225
TI  - [Tuberculosis among health care workers in Okinawa Prefecture].
AB  - In health care setting, transmission of M. tuberculosis (TB) is considerable risk
      not only to patients but to health care workers (HCWs). The total number of
      registered TB cases in Okinawa prefecture was 1,202 in 1993-1995 (incidence rate
      28.3 per 100,000 in 1995) and that of HCWs was 23. Using data from TB
      registration system, relative risk of tuberculous disease of nurses was estimated
      to be 2.3 higher than general population. Nosocomial transmission of TB to HCWs
      in a general hospital was occurred in 1993. After 2 nurses in the same ward were
      diagnosed as active pulmonary TB by routine screening chest X-ray, a contact
      investigation was performed in their family, friends and the ward staffs. On the
      result of initial evaluation of PPD test, 22 of 26 HCWs were suspected to be
      infected and preventive therapy with isoniazid were given to 16 HCWs. Follow-up
      chest radiographs for 3 years revealed 5 HCWs were active TB. According to RFLP
      analysis of M. tuberculosis isolates, 3 HCWs and 1 patient had identical RFLP
      pattern to 65-year-old female SLE patient, who was admitted for fever in Nov.
      1993 and was diagnosed as miliary tuberculosis after 2 weeks admission. As she
      had no cough and sputum, the infectiousness of the case was suspected to be
      increased by cough-inducing procedure. The following TB infection control
      measures were conducted in the hospital; (1) Education and training to all HCWs
      for early identification of TB patient and adequate treatment (2) Surveillance
      and reporting system of TB patient from laboratory and ward to infection-control
      committee (3) Introduction of PPD test program for HCWs (4) Use of HEPA masks as
      personal respiratory protection. We need further evaluation of engineering
      controls e.g. ventilation and isolation room.

PMID- 10355226
TI  - [Tuberculosis outbreak among inpatients].
AB  - The Index case, 22 year-old pregnant woman, was admitted for threatened abortion
      among obstetric ward in X Hospital for 17 days. Two months later, she was
      admitted for delivery among perinatal ward in another Y Hospital for 5 days. She
      produced persistent cough and sputum, when she had diagnosed pulmonary
      tuberculosis (TB) with sputum smear-positive and cavity on 2nd Y hospital day. By
      2 years after the detection, 15 TB patients were newly diagnosed. Seven of 15 TB
      patients were culture positive cases and RFLP analysis of the 7 Mycobacterium TB
      strains demonstrated an identical banding pattern, thus confirming the spread of
      a unique strain. Of the 15 TB patients, seven were patients on the obstetric
      ward. Three were visitors. Two were infants with TB meningitis and miliary TB
      were not confirmed direct contact with the index case. Another two were family
      member and one was employee. The present outbreak emphasizes the high risk of TB
      transmission on obstetric and perinatal ward when the diagnosis of smear-positive
      pulmonary TB was delayed.

PMID- 10355227
TI  - [The present status and the task of nosocomial tuberculosis infection in Japan].
AB  - The present study aimed to assess the status of preventive measures for
      nosocomial tuberculosis infection and the incidence of tuberculosis among
      hospital workers in Japan. Data were collected using two types of questionnaires
      submitted to 333 hospitals with tuberculosis beds and 247 hospitals without
      tuberculosis beds. The incidence of tuberculosis among hospital workers was
      assessed for the period from 1992 to 1996. Handling of the tuberculin test and
      BCG vaccination at the time of employment was inadequate. Environmental
      management of the workplace in laboratories and tuberculosis wards was also in
      adequent. Regarding the incidence of tuberculosis among hospital workers, nurses
      at hospitals with tuberculosis beds had the highest incidence especially those in
      their twenties to thirties. Considering these findings, improvement of the
      prevention of tuberculosis infection in hospitals is important.

PMID- 10355228
TI  - [Tuberculosis infection control practice in hospitals from the viewpoint of
      occupational health].
AB  - Several outbreaks of tuberculosis (TB) among health care workers were reported
      recently in Japan. To assess the current situation of TB infection control
      practice in hospitals in Japan from the viewpoint of occupational health, we
      carried out a cross sectional survey by mail-questionnaires. The questionnaires
      with closed and open-ended questions to ask situation of TB infection control
      program in hospital were mailed to 542 hospital chiefs in and around Tokyo,
      Kantoh district. 269 replies were received. We analyzed them especially focussing
      on the prevention of TB among health care workers. Out of 269 hospitals replied,
      39 of them had wards and/or beds designated for tuberculosis patients, 223 did
      not have, and 7 were unknown. 102 (38.9%) had set written tuberculosis infection
      control programs or guidelines, only 21 (53.8%) have set them even in hospitals
      with TB beds. 110 (42.0%) hospitals had triage system for identifying patients
      with active TB in the outpatient setting. Although, most health care workers
      underwent annual health check programs including chest X-rays, only 67 (25.6%) of
      the hospitals provide tuberculin skin test to their new recruits. 165 (63.0%) of
      hospitals admit that undiagnosed patients with respiratory symptoms may stay with
      immuno-compromised patients in the same room. Since administrative management,
      staff education, environmental control in work place, personal infection control
      and individual health care should be carried out from the viewpoint of
      occupational health, we showed concrete steps of these in this paper. We
      recommend that a TB infection control manager in each hospital should be
      designated, and that TB infection control program and/or guideline should be
      made. Environmental control in work place to prevent infection should be more
      prioritized in Japan.

PMID- 10355229
TI  - [Tuberculin skin testing in students of school of nursing].
AB  - Tuberculin skin testing in students of the School of Nursing Attached to National
      Hiroshima Hospital was analyzed. On initial test using 0.05 microgram of PPDs,
      diameter of erythema in 26.7% of 300 new students were less than 9 mm. Twelve of
      24 who were tested by two-step method reacted more than 10 mm on the second test.
      Twenty-seven non-reactors who were vaccinated with BCG all reacted more than 10
      mm after 9 to 16 weeks after vaccination. They might be vaccinated in the past by
      insufficient technique and better be revaccinated. Thirty-one of 49 students who
      graduated in 1998 were tested and their reactions were compared with those on
      entrance or after BCG vaccination. The two tests were spaced 31 to 34 months
      apart. The reactions were weakened in the cases after BCG vaccination, and in
      those who were not vaccinated on entrance, only a little booster effect were
      observed, except in 3 graduates whose reactions were significantly boosted and
      thought to be infected while in school. As there is considerable variation in
      tuberculin reactivity after BCG vaccination, diameter of reaction should be kept
      on personal health record as base line reaction to diagnose tuberculous infection
      henceforce.

PMID- 10355230
TI  - Context effects in lexical access: a meta-analysis.
AB  - The modularity hypothesis was evaluated in this review of 25 studies that
      investigated context effects in early lexical processing. Selection criteria
      restricted the review to priming studies and to studies that presented the target
      word before or at the end of the prime word. Meta-analysis was used to provide
      summary information about the 17 studies in the review for which effect sizes
      could be calculated. Overall, the analysis revealed a small effect of context on
      lexical access. Results provide a disconfirmation of the modularity hypothesis;
      although multiple interpretations of a word were sometimes accessed, the
      contextually appropriate interpretation was consistently more strongly activated.
      The lack of significant heterogeneity of variance suggests that the variability
      observed across studies was due to sampling error; however, task, timing of
      target presentation, meaning frequency, type of target, and type of context were
      identified as potential moderator variables.

PMID- 10355231
TI  - Masked priming of words and nonwords in a naming task: further evidence for a
      nonlexical basis for priming.
AB  - Masked priming effects in word identification tasks such as lexical decision and
      word naming have been attributed to a lexical mechanism whereby the masked prime
      opens a lexical entry corresponding to the target word. Two experiments are
      reported in which masked repetition priming effects of similar magnitude were
      obtained with word and nonword targets in a naming task. Masked orthographic
      priming was more stable for word than for nonword targets, although morphological
      primes produced no advantage beyond that achieved by matched orthographic primes.
      These results, taken together with the recent finding that repetition priming of
      nonwords can be obtained in the lexical decision task, support the view that
      masked priming of words and nonwords has a nonlexical component. We suggest that
      masked primes can enhance target identification by contributing to the
      construction of an orthographic or a phonological representation of the target,
      regardless of the target's lexical status.

PMID- 10355232
TI  - Lexical access of resyllabified words: evidence from phoneme monitoring.
AB  - Resyllabification is a phonological process in which consonants are attached to
      syllables other than those from which they originally came. In four experiments,
      we investigated whether resyllabified words, such as "my bike is" pronounced as
      "mai.bai.kis," are more difficult to recognize than nonresyllabified words. Using
      a phoneme-monitoring task, we found that phonemes in resyllabified words were
      detected more slowly than those in nonresyllabified words. This difference
      increased when recognition of the carrier word was made more difficult. Acoustic
      differences between the target words themselves could not account for the
      results, because cross-splicing the resyllabified and nonresyllabified carrier
      words did not change the pattern. However, when nonwords were used as carriers,
      the effect disappeared. It is concluded that resyllabification increases the
      lexical-processing demands, which then interfere with phoneme monitoring.

PMID- 10355233
TI  - Phonological and semantic priming: evidence for task-independent effects.
AB  - The questions asked in the present experiments concern the generality of semantic
      and phonological priming effects: Do these effects arise automatically regardless
      of target task, or are these effects restricted to target tasks that specifically
      require the retrieval of the primed information? In Experiment 1, subjects
      produced faster color matching times on targets preceded by a masked rhyming
      prime than on targets preceded by an orthographic control or an unrelated prime.
      This result suggests that automatic priming effects on the basis of phonological
      similarity can be obtained even when the target task does not make use of
      phonological information. This claim was reinforced in Experiment 2 in which a
      rhyme priming effect and a semantic priming effect were found in a semantic
      categorization task. In Experiment 3, the target task was phonological (rhyme
      detection), and, again, both phonological and semantic priming effects were
      observed. Finally, in Experiments 4 and 5, in a replication and an extension of
      Experiment 1, phonological and semantic priming effects were found in a color
      matching task, a task involving neither phonological nor semantic processing.
      These results are most straightforwardly interpreted by assuming that both
      semantic and phonological priming effects are, at least in part, due to automatic
      activation of memorial representations.

PMID- 10355234
TI  - Lexical integration: sequential effects of syntactic and semantic information.
AB  - Both semantic and syntactic context constraints can influence word processing at
      the level of lexical integration. In event-related brain potentials (ERPs),
      semantic integration is reflected by a negativity around 400 msec (N400), whereas
      phrase structure assignment and syntactic integration are assumed to be reflected
      by an early left anterior negativity and a late positivity (P600), respectively.
      An ERP study is presented in which participants read different types of sentences
      whose terminal verb was either congruent with the preceding context or
      incongruent due to a phrase structure violation, a semantic violation, or both.
      The main finding was that only the pure semantic violation condition, but not the
      combined semantic and syntactic violation condition, elicited a large N400. The
      two conditions containing phrase structure violations were predominantly
      characterized by a P600. Both semantic violation conditions, moreover, displayed
      a late negativity around 700 msec that overlapped with the P600 in the double
      violation condition. The absence of an N400 effect for elements that are
      syntactically as well as semantically incongruent with prior context suggests an
      early influence of phrase structure information on processes of lexical-semantic
      integration. The present data are discussed in comparison to previous ERP
      findings, and a new view of lexical integration processes is proposed.

PMID- 10355236
TI  - Cue set size effects: sampling activated associates or cross-target interference?
AB  - Previous findings indicate that test cues linked to more associates (more
      knowledge) produce lower levels of recall than cues with fewer associates. One
      hypothesis attributes this effect to cross-target interference arising during
      retrieval on the assumption that cues with more associates are more likely to be
      indirectly connected to studied words other than the target. Another attributes
      the effect to sampling associates of the cue on the assumption that the
      probability of sampling the target declines as more associates are activated.
      Findings from four experiments showed that recall varied with cue set size, and,
      more importantly, that cue set size affected recall independently of the
      interference produced by cross-target connections. These results were interpreted
      as supporting a model that attributes cue set size effects to sampling processes
      associated with the intersection of the test cue and its associates with the
      target and its associates.

PMID- 10355235
TI  - Associative priming in color naming: interference and facilitation.
AB  - In Experiment 1, color-naming interference for target stimuli following
      associated primes was greater in a group making a lexical decision to the prime
      than in a group reading the prime silently. High-frequency targets were responded
      to more quickly than low-frequency targets. In Experiment 2, with subjects naming
      the prime, there was evidence of associative interference when the prime and the
      target were grouped temporally but not when the intertrial interval was
      comparable with the prime-target interval. Associative primes presented at a
      short (120-msec) prime-target stimulus onset asynchrony facilitated color naming
      in Experiment 3. Taken together, the results suggest that the effect of faster
      processing of the base word in a color-naming task is facilitatory and that color
      naming priming interference arises when associative prime processing increases
      conflict between word and color responses by enhancing phonological or
      articulatory activation of the base word.

PMID- 10355237
TI  - Facilitation and impairment of event memory produced by photograph review.
AB  - Selectively reviewing some items from a larger set of previously learned items
      increases memory for the items that are reviewed but may also be accompanied by a
      cost: Memory for the nonreviewed items may be impaired relative to cases where no
      review occurs at all. This cost to nonreviewed items has primarily been shown in
      contexts of verbal list learning and in situations where the reviewed and
      nonreviewed items are categorically or semantically related. Using a more
      naturalistic impetus to selective review--photographs relating to previously
      experienced events--we assessed whether the memory of older and younger adults
      for unrelated complex activities that they themselves had performed was also
      impaired due to nonreview. Both younger and older adults showed impaired memory
      for nonreviewed activities when tested with free recall (Experiment 1), but not
      when tested with recognition or cued recall (Experiment 2). If mitigating
      retrieval cues are unavailable, selective review may impair memory for
      nonreviewed everyday events.

PMID- 10355238
TI  - Norms for word lists that create false memories.
AB  - Roediger and McDermott (1995) induced false recall and false recognition for
      words that were not presented in lists. They had subjects study 24 lists of 15
      words that were associates of a common word (called the critical target or
      critical lure) that was not presented in the list. False recall and false
      recognition of the critical target occurred frequently in response to these
      lists. The purpose of the current work was to provide a set of normative data for
      the lists Roediger and McDermott used and for 12 others developed more recently.
      We tested false recall and false recognition for critical targets from 36 lists.
      Despite the fact that all lists were constructed to produce false remembering,
      the diversity in their effectiveness was large--60% or more of subjects falsely
      recalled window and sleep following the appropriate lists, and false recognition
      for these items was greater than 80%. However, the list generated from king led
      to 10% false recall and 27% false recognition. Possible reasons for these wide
      differences in effectiveness of the lists are discussed. These norms serve as a
      useful benchmark for designing experiments about false recall and false
      recognition in this paradigm.

PMID- 10355240
TI  - Effects of divided attention on perceptual and conceptual memory tests: an
      analysis using a process-dissociation approach.
AB  - In two experiments, the nature of the relation between attention available at
      learning and subsequent automatic and controlled influences of memory was
      explored. Participants studied word lists in full and divided encoding
      conditions. Memory for the word lists was then tested with a perceptually driven
      task (stem completion) in Experiment 1 and with a conceptually driven task
      (category association) in Experiment 2. For recall cued with word stems,
      automatic influences of memory derived using the process-dissociation procedure
      remained invariant across a manipulation of attention that substantially reduced
      conscious recollection for the learning episode. In contrast, for recall cued
      with category names, dividing attention at learning significantly reduced the
      parameter estimates representing both controlled and automatic memory processes.
      These findings were similar to those obtained using indirect test instructions.
      The results suggest that, in contrast to perceptual priming, conceptual priming
      may be enhanced by semantic processing, and this effect is not an artifact of
      contamination from conscious retrieval processes.

PMID- 10355239
TI  - Relaxing decision criteria does not improve recognition memory in amnesic
      patients.
AB  - An important question about the organization of memory is whether information
      available in non-declarative memory can contribute to performance on tasks of
      declarative memory. Dorfman, Kihlstrom, Cork, and Misiaszek (1995) described a
      circumstance in which the phenomenon of priming might benefit recognition memory
      performance. They reported that patients receiving electroconvulsive therapy
      improved their recognition performance when they were encouraged to relax their
      criteria for endorsing test items as familiar. It was suggested that priming
      improved recognition by making information available about the familiarity of
      test items. In three experiments, we sought unsuccessfully to reproduce this
      phenomenon in amnesic patients. In Experiment 3, we reproduced the methods and
      procedure used by Dorfman et al. but still found no evidence for improved
      recognition memory following the manipulation of decision criteria. Although
      negative findings have their own limitations, our findings suggest that the
      phenomenon reported by Dorfman et al. does not generalize well. Our results agree
      with several recent findings that suggest that priming is independent of
      recognition memory and does not contribute to recognition memory scores.

PMID- 10355241
TI  - Feature centrality: naming versus imagining.
AB  - Being white is central to whether we call an animal a "polar bear," but it is
      fairly peripheral to our concept of what a polar bear is. We propose that a
      feature is central to category naming in proportion to the feature's category
      validity--the probability of the feature, given the category. In contrast, a
      feature is conceptually central in a representation of the object to the extent
      that the feature is depended on by other features. Further, we propose that
      naming and conceptual centrality are more likely to disagree for features that
      hold at more specific levels (such as is white, which holds only for the specific
      category of polar bear) than for features that hold at intermediate levels of
      abstraction (such as has claws, which holds for all bears). In support of these
      hypotheses, we report evidence that increasing the abstractness of category
      features has a greater effect on judgments of conceptual centrality than on
      judgments of name centrality and that other category features depend more on
      intermediate-level category features than on specific ones.

PMID- 10355242
TI  - Age differences in accuracy and choosing in eyewitness identification and face
      recognition.
AB  - Studies of aging and face recognition show age-related increases in false
      recognitions of new faces. To explore implications of this false alarm effect, we
      had young and senior adults perform (1) three eye-witness identification tasks,
      using both target present and target absent lineups, and (2) and old/new
      recognition task in which a study list of faces was followed by a test including
      old and new faces, along with conjunctions of old faces. Compared with the young,
      seniors had lower accuracy and higher choosing rates on the lineups, and they
      also falsely recognized more new faces on the recognition test. However, after
      screening for perceptual processing deficits, there was no age difference in
      false recognition of conjunctions, or in discriminating old faces from
      conjunctions. We conclude that the false alarm effect generalizes to lineup
      identification, but does not extend to conjunction faces. The findings are
      consistent with age-related deficits in recollection of context and relative age
      invariance in perceptual integrative processes underlying the experience of
      familiarity.

PMID- 10355243
TI  - The object-based representation of partially occluded surfaces in short-term
      visual memory: evidence from image combination.
AB  - Distinct short-term and longer term visual representations of form allow people
      to combine mental images of separately presented pictures in order to identify a
      novel object (see, e.g., Brandimonte, Hitch, & Bishop, 1992; Hitch, Brandimonte,
      & Walker, 1995; Walker, Hitch, Dewhurst, Whiteley, & Brandimonte, 1997). The
      present study focuses on the short-term representation and asks whether it
      describes the 2-D features in a picture or the depicted surfaces in 3-D space
      (see Nakayama, He, & Shimojo, 1995). To-be-combined figures were sometimes
      partially occluded by irrelevant forms, and it was determined whether image
      combination was contingent on the directly visible regions of the figures or on
      the perceptually completed figures. Results showed that image combination was not
      impeded by partial occlusion, though it was impeded if an occluder was removed
      from a picture and only the previously visible regions of the figure were
      presented. It is concluded that the short-term visual representation supporting
      image combination is not a pictorial code, but is an object-based description of
      completed surfaces in 3-D space.

PMID- 10355244
TI  - Implicit motor sequence learning is not purely perceptual.
AB  - Many reports have indicated that implicit learning of sequences in a choice
      response time task is primarily perceptual; subjects learn the sequence of
      stimuli rather than the sequence of motor responses. Three experiments tested
      whether implicit motor sequence learning could be purely perceptual: no support
      was found for that hypothesis. Subjects who merely watched stimuli did not learn
      the sequence implicitly (Experiment 1), and sequence learning transferred
      robustly to a different set of stimulus cues (Experiment 2). In the final
      experiment, the stimulus-response mapping was changed at transfer so that one
      group of subjects pushed the same sequence of keys but saw new stimuli, whereas
      another group pushed a different sequence of keys but saw the same stimuli.
      Transfer to the new mapping was shown only if the motor sequence was kept
      constant, not the perceptual sequence. It is proposed that subjects learn a
      sequence of response locations in this and similar tasks.

PMID- 10355245
TI  - [The concept of "gateway drug"].
AB  - To develop drug abuse prevention for adolescents in Japan, the author reviewed
      concepts of "gateway drug" and "stepping-stone hypothesis". Firstly, results
      obtained from high school students in New York State (Kandel, D., 1975) were
      introduced as a standard model of "stepping-stone hypothesis". Secondly, results
      obtained from serious drug abusers in New York City (Golub, A. et al., 1994) were
      introduced as an example that shows the importance of defining clearly which
      cohort a study refers to when we use "gateway drug". Thirdly, results of a junior
      high school students survey in Japan were introduced and discussed to consider
      whether alcohol and cigarette for junior high school students in Japan are
      "gateway drugs" to solvent. The author concluded: 1) that cigarette smoking in
      junior high school students in Japan has a strong relationship with solvent
      inhalation, and 2) that drinking alcohol, however, depends on the presence of
      adults. Lastly, the author emphasized the need for doing more research on drug
      abuse in Japan.

PMID- 10355246
TI  - [Ethanol-induced hepatic microcirculatory disturbance].
AB  - Alcoholic liver injury predominates in the pericentral region, in which oxygen
      tension is physiologically lowest. The enhanced injurious effect of ethanol at
      this site is postulated to be due to hypoxia, resulting from an enhanced oxygen
      demand of hepatocytes for the oxidative metabolism of ethanol. Moreover, we found
      that ethanol at higher concentrations induces hypoxia in the liver by causing
      microcirculatory disturbance. Upon initiation of ethanol infusion into the portal
      vein of isolated perfused rat liver at concentrations ranging from 25 to 100 mM,
      portal pressure began to increase in a concentration-dependent manner and reached
      maximal levels in 2-5 min (initial phase), followed by a gradual decrease over
      the period of ethanol infusion (escape phase). Sodium nitroprusside, a known
      vasodilator, diminished the ethanol-induced increase in portal pressure,
      increased oxygen consumption leading to inhibition of the reduction of the
      respiratory cytochromes of the liver, and diminished liver injury. The data
      indicate that the ethanol-induced hepatic vasoconstriction disturbs hepatic
      microcirculation, leading to hepatic hypoxia and hepatocellular injury.
      Endothelin-1 antiserum inhibited significantly hepatic vasoconstriction induced
      by ethanol. Cessation of infusion of endothelin-1 antiserum was followed by a
      subsequent increase in portal pressure. On the other hand, when a nitric oxide
      synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA), was infused into the
      portal vein simultaneously with ethanol, the initial phase of the response of
      portal pressure to ethanol was not altered and the peak values of portal pressure
      remained unchanged. However, following the peak increase in portal pressure, the
      rate of decrease was less than in the absence of L-NMMA. Thus, L-NMMA diminished
      the escape phase the sustained the vasoconstriction. Based on the current
      results, we propose that the sinusoidal tone in the presence of ethanol is
      regulated predominantly by the actions of the two endothelium-derived vasoactive
      factors, endothelin-1 and nitric oxide.

PMID- 10355247
TI  - [Relationship between ALDH2 genotypes and choice of alcoholic beverages].
AB  - There are obviously individual differences in the choice for many kinds of
      alcoholic beverages such as beer, wine, whisky, sake, cocktail and so on. It is
      generally believed that these differences are related to acquired preferences in
      taste and smell, in addition to life style. However, the basis of these acquired
      preferences is not yet understood. It has been shown that around half of Japanese
      show a marked sensitivity to alcoholic beverages because of aversive reactions
      due to a catalytic deficiency in ALDH2 isozyme. Therefore, differences in ALDH2
      genotypes may possibly influence the choice of alcoholic beverages because the
      individuals possessing the ALDH2*2 gene may prefer the alcoholic beverages
      containing lower concentrations of alcohol. A large population survey (320 males,
      132 females) was conducted using questionnaires to investigate the relationship
      between ALDH2 genotypes and the choice of alcoholic beverages. Individuals with
      the homozygote of ALDH2*1 generally showed more preference for alcoholic
      beverages containing a higher concentration of alcohol than those with the
      heterozygote or the homozygote of ALDH2*2. It was noted that the latter groups
      preferred whisky and water, and sweet cocktails. Also, the choices for beer,
      whisky, and sake were significantly different between both genders. Our data
      suggested that individuals with ALDH2*2 prefer beverages with lower
      concentrations of alcohol due to an aversive reaction after drinking, and that
      there are obvious gender differences in the consumption as well as the choice for
      many alcoholic beverages.

PMID- 10355248
TI  - [A case report of organic solvent abuse with amotivational syndrome].
AB  - We investigated an organic solvent abuser who developed amotivational syndrome
      employing neuropsychological examination (Rorschach test, Bender Gestalt test and
      Benton visual retention test), electroencephalography, magnetic resonance imaging
      (MRI) and single photon emission computed tomography (SPECT). The patient
      manifested a disability to maintain a goal-orient mental activity, immature
      reality testing and poor set shifting, which suggest frontal lobe dysfunction, as
      we have reported before in neuropsychological examination. In this case, single
      photon emission computed tomography (SPECT) also revealed a decrease of regional
      cerebral blood flow (rCBF) in the medial frontal lobe. These results may suggest
      a contribution of frontal lobe (especially medial frontal lobe) dysfunction to
      the pathogenesis of amotivational syndrome due to organic solvent abuse.

PMID- 10355249
TI  - [A clinical study on renal pelvic and ureteral tumor associated with bladder
      tumor with special reference to risk factors of subsequently recurrent bladder
      tumor].
AB  - PURPOSE: The purpose of this report is to analyze the clinical feature of renal
      pelvic and/or ureteral tumor (RUT) associated with bladder tumor (BT) with
      special reference to risk factors of subsequently recurrent BT. METHODS: Of the
      49 patients with RUT who underwent surgery and were diagnosed pathologically as
      transitional cell carcinoma at the Department of Urology, Osaka National Hospital
      from April 1986 to October 1996, 20 patients (40.8%) had associated BTs. These
      patients were categorized to the following 4 groups, Group 1: 5 patients with BT
      preceding RUT, Group 2: 5 patients with concomitant BT, Group 3: 10 patients with
      subsequent BT following RUT operation and Group 4: 29 patients without any
      associated BT. The clinical course of these 4 groups were studied and compared
      with each other retrospectively. RESULTS: In group 1, the first BTs preceded RUTs
      by 19 to 81 months (mean 54.6 months). And during this relatively long period,
      the preceding BTs were treated by TUR for each recurrence, 1 to 9 times (mean 5.2
      times). Two of 5 were bilateral RUT cases, which were observed only in this
      group. In group 2, the prognosis were relatively poor (5-year survival rate: 0%),
      because all RUTs of this group were high stage. And also the concomitant BTs were
      showing invasive feature during the observation period, despite they were
      superficial at first. Thus 3 of 5 underwent radical cystectomy. On the other
      hand, in group 3, the subsequent BTs, which developed at 2 to 26 month (mean 13.4
      month) after RUT operation, were all superficial and resectable by TUR. The 5
      year disease specific survival rate was 50% in group 1, 0% in group 2, 63.5% in
      group 3, 64.9% in group 4. Group 2 had the most poor prognosis. However there was
      no significant difference in prognosis among the 4 groups. Incidence of
      preoperative urine positive cytology was significantly higher in group 3, than in
      group 4 (87.5% vs. 44.8%). CONCLUSIONS: These results indicated that the RUTs
      with associated BTs have distinct clinical features depending on the sequence of
      association with the BTs. Especially the RUTs with concomitant BTs should be
      watched carefully as a high risk group with poor prognosis and possible
      development of invasive BTs. Positive urine cytology prior to RUT operation may
      reflect biological activity of tumor cell for dissemination in the lower urinary
      tract and we suggested preoperative urine cytology was possible predictor of
      subsequently recurrent BTs after RUT operation in this study.

PMID- 10355250
TI  - [p53 tumor suppressor gene mutation and prognosis in 105 cases of bladder cancer-
      the relationship between mutation of the p53 gene with clinicopathological
      features and smoking].
AB  - PURPOSE: Alterations of the p53 tumor suppressor gene are the most common genetic
      change detected in human cancers. The incidence of p53 gene mutation in bladder
      tumor patients were studied and were compared with clinicopathological findings,
      smoking history and prognosis. MATERIALS AND METHODS: Polymerase chain reaction
      single-strand conformation polymorphism (PCR-SSCP) was used for analysis from
      exon 4 to 9 of p53 gene in 105 cases of primary bladder tumors. RESULT: p53
      matations were detected in 38 or 105 patients (36.2%). Kaplan-Meier Survival
      curves fo groups wit or without p53 gene mutation show a statistically
      significant difference (p = 0.0098). The mutation of p53 gene in stages pT 1 pT
      1. pT 2, pT 3, pT 4 was found in 2 of 12 (16.7%), 8 of 32 (25.0%), 10 of 25
      (40.0%), 12 of 20 (60.0%), 6 of 16 (37.5%) and in grades I, II, III, was noted in
      1 of 17 (5.9%), 16 of 49 (32.7%), 21 of 39 (53.8%) cases, respectively.
      Significant differences were found for groups with grade I and grade II-III (p =
      0.0045) cancers and in cases of superficial (stage pTa-1) and muscle-invasive (pT
      2-4) tumors (p = 0.0148). However, mutation of p53 was not related to either age
      or sex in 105 patients. Recurrence rates in stage pTa-1 superficial tumor group
      with or without p53 mutation showed a statistically significant difference (p =
      0.0419). No statistically significant difference was noted between p53 mutation
      and habitual smoking as well as durations of smoking. CONCLUSIONS: p53 mutations
      occur more commonly in higher grades and later stages of bladder tumors. Our
      results suggest that the prognostic factor is linked to not only histological
      findings but also to the presence of p53 mutation. The mutations of the p53 gene
      may be involved in the late events of tumorigenesis and might be used as good
      molecular markers for prognosis in bladder tumor.

PMID- 10355251
TI  - [The use of predeposited autologous blood transfusion for radical prostatectomy
      and total cystectomy].
AB  - BACKGROUND: To avoid homologus blood transfusion, we performed the operation for
      intra-pelvic malignancy with predeposited autologus blood using recombinant human
      erythropoietin (rH-EPO). MATERIALS AND METHODS: The seven cases of radical
      prostatectomy and the 15 cases of total cystectomy were analyzed retrospectively.
      All cases were given ferrons sulfate/200 mg of iron orally every day to the day
      before the operation and treated with 24,000 unit of rH-EPO subcutaneously every
      week. The target volumes of preoperative autologus blood collection were 800 to
      1,000 ml and 800 to 1,200 ml for radical prostatectomy and total cystectomy,
      respectively. For each case, 400 ml blood was collected once a week. RESULTS: In
      cases of radical prostatectomy, the preserved blood volume was 885.7 +/- 157.4 ml
      and 6 out of 7 operations were successfully performed without additional
      homologus blood transfusion (85.7%). In total cystectomy, the preserved blood
      volume was 1,033.3 +/- 167.6 ml and 14 out of 15 operations were successfully
      performed without additional homologus blood transfusion (93.3%). The bleeding
      volume during operation showed no significant difference compared to control
      group where used homologus blood transfusion. Postoperative courses were
      uneventful and there encountered no severe side effects and complications in all
      our procedures. CONCLUSIONS: Our study indicates that in cases of radical
      prostatectomy and total cystectomy, the operation with predeposited autologus
      blood using rH-EPO is possible to be performed in safe. The effect on long term
      prognosis of malignancy is not clear, however, this technique is helpful able to
      avoid hazardous issues related to homologus blood transfusion during the
      operation.

PMID- 10355252
TI  - [Elevation of serum and urine tumor necrosis factor levels after transurethral
      resection of the prostate].
AB  - BACKGROUND: Recent studies have suggested that inflammatory cytokines are major
      mediator of the acute phase protein response after surgery. The aim of the
      present study is to investigate the relationship between the degree of surgical
      trauma and the change of serum and urine cytokine levels after transurethral
      resection of the prostate (TUR-P). METHOD: Serum and urine concentrations of
      tumor necrosis factor-alpha (TNF), interleukin-6 (IL 6), and interleukin-1 (IL 1)
      were evaluated in 55 patients who underwent TUR-P and in 23 patients who
      underwent abdominal surgery. The samples were collected periodically before and
      after an intervention, and the concentrations of cytokines were measured by
      enzyme-linked immunosorbent assay. RESULTS: The concentration of serum TNF was
      significantly increased 6 hours after TUR-P. Since serum TNF level was not
      increased after abdominal surgery, serum TNF level was significantly higher after
      TUR-P than after abdominal surgery. Serum IL 6 and IL 1 levels were not increased
      after TUR-P. Urine levels of TNF, IL 6 and IL 1 were significantly increased
      after TUR-P, meanwhile no significant elevation of urine cytokine levels was
      recognized in the patients who underwent abdominal surgery. The elevation of
      urine cytokine levels was thought to be caused by the increased production of
      cytokines at the surgically resected sites. The urine TNF level after TUR-P was
      increased related to the resected tissue volume and irrigation fluid volume. The
      preoperative urinary tract infection caused excessive elevation of the urine TNF
      level after TUR-P. The urine TNF level after TUR-P also tended to be increased
      depending on the degree of postoperative pyrexia. CONCLUSION: These results
      indicate the unique response of TNF to TUR-P. Measurement of serum and urine TNF
      levels after TUR-P can be a useful index for evaluating the perioperative
      condition of the patients undergoing TUR-P.

PMID- 10355253
TI  - [Double cancer observed from bladder cancer].
AB  - BACKGROUND: In recent years, despite of the improvement of treatment results for
      cancer and long life, the occurrence of second primary cancer was increased. In
      this paper, we analyzed present condition of double cancer observed with bladder
      cancer in our hospital. METHOD: Last 21 years, we have treated 969 cases (828
      male and 141 female) of primary bladder cancer. For those cases, we analyzed in
      term of frequency, involved organ, age, interval between two cancer occurrence,
      risk factor and prognosis of double cancer patients. RESULT: Of 969 cases with
      bladder cancer, 81 cases (8.36%) had double cancer involving 6 cases (0.61%) of
      triple cancer. In sex, 70 males (9.78%) and 11 females (7.80%) had double cancer.
      As involved organs, 25 cases (3.02%) had in prostate, 23 cases (2.37%) in
      stomach, 3 case (2.13%) in breast, 14 cases (1.44%) in colon and rectum. In
      diagnosis timing of complicated cancer from bladder cancer, 28 cases (34.6%) were
      diagnosed previously to bladder, 28 cases (34.6%) were simultaneously and 31
      cases (38.3%) were secondary. An average interval of diagnosis of two cancer were
      49 +/- 42.5 months. An average age of occurrence of second cancer was 70.3 +/-
      8.8 years. Actual survival rate from diagnosis of bladder cancer were 90.8%,
      68.6%, 53.3% and 30.3%, after 1, 3, 5 and 10 years, respectively. Ten cases were
      dead by bladder cancer, 21 cases by complicated cancer and 16 cases by another
      cause. CONCLUSION: The incidence of double cancer with bladder cancer were
      increased. Prostate cancer, colorectal cancer and breast cancer were gradually
      increased as complicated organs in Japan. The prognosis of double cancer patients
      with bladder cancer was poor than single bladder cancer patients.

PMID- 10355254
TI  - [Clinical studies on inverted papilloma of the urinary tract].
AB  - BACKGROUND: Inverted papilloma of the urinary tract is believed to be a benign
      neoplasm based on its histologic morphology and clinical behavior. In recent
      years, however, several investigators have warned against too optimistic an
      approach, emphasizing the possibility of malignant cellular transformation within
      the lesion, or its eventual association with other urothelial tumors such as
      transitional cell carcinoma or carcinoma in situ. We here report on 35
      clinicopathologically diagnosed cases of inverted papilloma, and present the
      clinical significance attributed to these lesions in view of the current
      literature. PATIENTS AND METHODS: From 1976 to 1997, 35 cases of inverted
      papilloma of the urinary tract were treated at our hospital. This report presents
      the clinical features of these cases, the results of prognosis research, an
      investigation of the cases in which inverted papilloma and transitional cell
      carcinoma were found to co-exist, and a discussion of the recurrent cases of
      inverted papilloma found in previous literature. RESULTS: The patients ranged
      from 24 to 77 years of age, with a mean of 54 years, and included 4 women and 31
      men. The most frequently occurring symptom was grosshematuria, and more than 90%
      of the 35 cases occurred in the bladder. In 2 of the 35 cases, transitional cell
      carcinoma coexisted with the inverted papilloma, at a different location in the
      bladder in one case and within the same neoplasm in the ureter in the other case.
      Clinical courses after treatment were followed in 29 of the 35 cases, with a
      follow-up period of from 8 months to 19 years (mean follow-up, 5 years and 4
      months). Of these 29 cases, 2 showed recurrence, one at 16 and one at 30 months
      after the initial resection. Many previous reports show that the association of
      inverted papilloma and transitional cell carcinoma is stronger in the upper
      urinary tract and recurrence of inverted papilloma almost always happens with 2
      years. CONCLUSION: This study suggests that some cases of urinary inverted
      papilloma show recurrence or malignant potential. Our results indicate that all
      cases of urinary inverted papilloma should be treated and followed as cases of
      low-grade transitional cell carcinomas. Consequently, all cases must be followed
      for two years or more after the initial operation.

PMID- 10355255
TI  - [High-dose chemotherapy followed by peripheral blood stem cell transplantation in
      advanced extragonadal germ cell tumor--a case report].
AB  - We reported the experience of high-dose chemotherapy (HDC) combined with
      peripheral stem cell transplantation (PBSCT) in 29 years-old man with advanced
      retroperitoneal germ cell tumor accompanied with left supraclavicular lymph node
      metastases, who obtained complete remission after comprehensive treatment. The
      initial levels of serum AFP, hCG and beta-hCG were high at 30.2 ng/ml, 14,000
      mIU/ml and 66 ng/ml, respectively. After 3 courses of chemotherapy (BEP regimen),
      while left supraclavicular lymph node swelling was disappeared, the
      retroperitoneal mass lesion persisted on CT scan. Not all of 3 markers fell to
      the normal range. After myelosuppressive chemotherapy (etoposide 500 mg/m2 Day 1
      3), PBSCs were collected by two consecutive apheresises on Day 17 and 18. In
      total, 19.5 x 10(6)/kg CD 34 positive cells were obtained. The patient underwent
      PBSCT (all CD 34 positive cells were infused) on Day 0 following HDC (CBDCA 250
      mg/m2/day, etoposide 300 mg/m2/day, IFM 1.5 g/m2/day, Day-7(-)-3, respectively).
      He became severely leukopenic and thrombopenic with nadir of 200/microliter on
      Day 6 and 2 x 10(4)/microliter on Day 2, respectively. By administration of
      platelet transfusion and G-CSF, the white blood cell counts and thrombocyte
      counts recovered to 6,400/microliter and 4.1 x 10(4)/microliter on Day 10,
      respectively. Microbiologically enterocolic and respiratory tract infections
      occurred with elevated body temperature (> 40 degrees C). Antibiotic and
      antimycotic treatments were continued until disappearance of all clinical and
      microbiological evidence. He was kept for 10 days in clean room. After HDC, all
      markers fell to the normal range, but the retroperitoneal residual mass still
      persisted. Resection of the residual mass and retroperitoneal lymph node
      dissection were performed with pathological examination revealing tissue necrosis
      without viable cell. The patient has survived with no sign of the disease for 9
      months.

PMID- 10355256
TI  - [A case of metachronous bilateral testicular tumors with burned-out histology in
      one side].
AB  - A 22-year-old man with a history of left radical orchiectomy due to a testicular
      tumor had bilateral pulmonary tumors. Transbronchial biopsy specimens revealed
      them to be germ cell tumors. The serum levels of AFP and hCG-beta were elevated.
      The right testis was free from a palpable mass but showed a small hyperechoic
      lesion on scrotal ultrasonography. We excised the echogenic focus, which was a
      whitish nodule under the tunica albuginea. By pathological findings it was
      diagnosed as a burned-out testicular tumor. This was a case with metachronous
      bilateral testicular tumors.

PMID- 10355257
TI  - [Application of SPECT to child neurology].
AB  - SPECT is a noninvasive functional neuroimaging method widely used even in child
      neurology because it can be easily implemented in routine clinical studies.
      Normal brain perfusion SPECT images in children change with brain maturation and
      differ from those in adults; for example, the blood flow is lower in the
      cerebellum than in the cerebrum. New methods have been developed to measure the
      cerebral blood flow without blood sampling and to perform statistical parametric
      mapping after spatial normalization of SPECT images to standard brain. They are
      applied to functional disorders such as autism and learning disorders.
      Neurotransmission imagings using SPECT are also available to visualize the
      benzodiazepine and dopamine systems; an early application of insurance is
      expected.

PMID- 10355258
TI  - [MR analysis of brain function].
AB  - Magnetic resonance (MR) is a remarkably versatile technology applicable to
      various aspects of medical science. Currently, there are three categories of MR
      techniques available for probing human brain function in detail. The first
      category comprises the most widely utilized techniques which make use of the
      metabolic effects of brain activation, represented by BOLD functional magnetic
      resonance imaging (fMRI). The second category of techniques deals with apparent
      diffusion tensor in probing the cellular aspects of brain function and is
      represented by three dimensional anisotropy contrast (3DAC) axonograpy. The third
      category of techniques is the oldest and as yet the most underutilized. These
      techniques which include MR spectroscopy (MRS) and spectroscopic imaging (SI),
      are based on classical nuclear magnetic resonance (NMR) spectroscopy and are
      capable of providing biochemical information in vivo. Because of its inherently
      non-invasive nature, MR technologies are especially important for the field of
      pediatric neurology and developmental neuroscience.

PMID- 10355259
TI  - [Problems surrounding absence seizures].
AB  - The diagnosis, treatment, and prognosis of childhood absence epilepsy (CAE) and
      juvenile absence epilepsy (JAE) were reviewed with reference to 94 patients with
      typical absence seizures (82 with CAE, 12 with JAE) and the literature. The
      patients were separated into two groups based on clinical features, age at onset
      of seizures, and EEG findings. There has been much discussion on the age that
      represents the borderline between CAE and JAE. My view is that JAE begins with
      puberty, i.e. at around 10 years old. The treatment of choice for CAE is valproic
      acid (VPA). If the seizures are not controlled with VPA, add-on therapy with
      ethosuximide is recommended. For patients who respond poorly to these drugs,
      clonazepam in often effective. Lamotrigine, which is not yet commercially
      available in Japan, is effective when combined with VPA. As for school
      performance, some patients showed excellent results. However, about half of them
      performed weakly. Patients followed beyond 20 years were free of absence seizures
      in both groups, but suffered from GTCS with occurred sporadically in CAE as well
      as in JAE. The social prognosis in CAE and JAE may not be as good as we believed
      it to be.

PMID- 10355260
TI  - [What has medical science resolved learning disabilities (LD) into?: introductory
      remarks].
AB  - What can medicine contribute to learning disabled (LD) children? In this
      symposium, most distinguished speakers in Japan discuss the following issues: the
      incidence of LD in children with preterm birth, biochemical aspect in LD children
      neurophysiological examinations for LD and speech therapy for specific reading
      disorders. Brain dysfunctions in LD children should be clarified to facilitate
      remedial interventions. It is expected that medical insurance supports LD
      children and their family.

PMID- 10355261
TI  - [Why should LD be discussed now?].
AB  - The term learning disability was first used in 1962 by Kirk S A in his textbook.
      In Japan the term was adopted as a substitute term for MBD in the 1970s. At
      present many professionals, especially on education and psychology, are
      interested with LD. The role of child neurologist is discussed here from three
      viewpoint: the term and definition, LD as a brain dysfunction, and LD in the
      child neurology. For collaboration with education and psychology, child
      neurologist should know more about LD and make efforts to find the etiology and
      mechanism of LD.

PMID- 10355262
TI  - [Basic patterns of learning disability: follow-up study of very low birth weight
      children].
AB  - The purpose of this study was to characterize learning disability (LD) in low
      birth weight children (VLBW). Longitudinal mental development of VLBW without
      major handicap was investigated using several neuropsychological tests (ITPA,
      BGT, WISC-R) suitable for their ages. The tests at ages of 5-6 years demonstrated
      delays in visual perception and visual motor integration. In the school-age,
      impairments of language understanding and abstraction were suggested. The process
      of mental development in VLBW with LD was reported in detail on the cases
      requiring special education. Some cases with a pervasive developmental disorder
      (PDD) were also presented to show difference from LD.

PMID- 10355263
TI  - [Neuropsychological approach to the learning disability: the correlation between
      neuropsychological findings and rCBF].
AB  - We investigated the relationship between a disorder of higher brain function and
      the area of reduced regional cerebral blood flow (rCBF) in learning disabled (LD)
      children. Subjects consisted of two LD children with a specific Kanji writing
      disorder, one with dyslexia and dysgraphia and two with a specific verbal
      semantic disorder. Neuropsychological assessment batteries were used to detect
      higher brain disorders, and single photon emission tomography to measure rCBF. We
      found that the area of reduced rCBF in LD children correspond to that in adults
      with an acquired brain damage showing similar symptoms. These results suggest
      that LD is caused by a localized brain dysfunction.

PMID- 10355264
TI  - [Neurochemical and neurotransmitter studies in patients with learning
      disabilities].
AB  - To clarify the pathophysiology of learning disability (LD), we measured the
      urinary levels of 3-methoxy-4-hydroxyphenyl glycol (MHPG), and phenylethylamine
      (PEA) in urine samples collected in a 24 hour period. Findings were compared with
      those obtained in age-matched controls and diseased controls including patients
      with attention deficit-hyperactivity disorder (ADHD), infantile autism, and
      mental retardation. The mean urinary level of MHPG in LD (n = 6) were not
      significantly different from those in ADHD (n = 16), mental retardation (n = 4),
      infantile autism (n = 5), and the controls (n = 6), while the mean urinary levels
      of PEA were significantly lower in LD (n = 6, 91 +/- 17.3 micrograms/mg) and in
      ADHD (n = 5, 65 +/- 53.6 micrograms/mg) as compared to age-matched controls (n =
      3, 340 +/- 264.5 micrograms/mg) ANOVA, (p < 0.05). PEA is considered to play an
      important role for the pathogenesis of LD and ADHD.

PMID- 10355265
TI  - [Neurophysiological correlates of learning disabilities in Japan].
AB  - In the present study, we developed a new event-related potentials (ERPs)
      stimulator system applicable to simultaneous audio visual stimuli, and tested it
      clinically on healthy adults and patients with learning disabilities (LD), using
      Japanese language task stimuli: hiragana letters, kanji letters, and kanji
      letters with spoken words. (1) The origins of the P300 component were identified
      in these tasks. The sources in the former two tasks were located in different
      areas. In the simultaneous task stimuli, a combination of the two P300 sources
      was observed with dominance in the left posterior inferior temporal area. (2) In
      patients with learning disabilities, those with reading and writing disability
      showed low amplitudes in the left hemisphere in response to visual language task
      stimuli with kanji and hiragana letters, in contrast to healthy children and LD
      patients with arithmetic disability. (3) To evaluate the effect of
      methylphenidate (10 mg) on ADD, paired-associate ERPs were recorded.
      Methylphenidate increased the amplitude of P300.

PMID- 10355266
TI  - [Learning disabilities; toward adequate treatment and education].
AB  - The medical staff can serve learning disabled (LD) children by ruling out
      progressive and regressive diseases, and by treating concurrent disorders, such
      as attention deficit hyperactivity disorders (ADHD). Teachers and even some
      medical members in Japan have confused ADHD with LD. Although looking similar,
      these two disorders are completely different. We should further clarify the brain
      dysfunction in LD children, thereby contributing to remedial education.

PMID- 10355267
TI  - [Efficacy of zonisamide in West syndrome].
AB  - The efficacy of zonisamide (ZNS) was studied in 16 patients (11 males, 5 females)
      with West syndrome (WS), symptomatic in 13 and cryptogenic in 3. They did not
      respond to pyridoxal phosphate (12 cases) or valproate (16 cases). The mean age
      of onset of WS was 4.4 (2-9) months. ZNS was administered from 3 to 9 months of
      age (mean 6.1). Four cases (2 cryptogenic and 2 symptomatic) became seizure free.
      Two had more than 50% seizure reduction. Ten infants remained unchanged or showed
      less than 50% seizure reduction. In the 4 responders, the effective dose was 4-8
      mg/kg (mean 5.8), and the serum ZNS concentration was 10-21 micrograms/ml (mean
      13.8). One had relapse of WS after 4 months. Three with normalized EEG remained
      seizure-free during the follow-up period (12-26 months). One case developed a
      transient drowsiness, but no serious side effects were observed. These data
      suggest ZNS may be regarded as a therapy of choice before synthesized ACTH
      therapy in the management of WS.

PMID- 10355268
TI  - [Lissencephaly type I: electroencephalographic findings and neuroradiological
      classification].
AB  - Lissencephaly type I is a diffuse type of migration disorder that contains agyria
      and/or pachygyria on the brain surface. We experienced 5 cases of this disease
      and evaluated their electroencephalographic findings and seizure types based on
      the neuroradiological classification of lissencephaly. Ages at seizure onset
      ranged from 2 months to 4 months (mean 3.2 months). The patients with complete
      agyria had generalized tonic seizures, and those with pachygyria partial seizures
      or tonic spasms. The characteristic findings of complete agyria in
      electroencephalogram were high-voltage alfa activity. The amount of high-voltage
      slow waves increased with the ratio of pachygyria on the brain surface. The
      appearance of multifocal spikes and sharp waves suggested irregular arrangement
      of pachygyria on the brain surface.

PMID- 10355269
TI  - [Auditory brainstem responses in group A xeroderma pigmentosum].
AB  - Xeroderma pigmentosum has been known to result from disturbance in the repair of
      injured DNA caused by the ultra violet light. According to cell fusion studies,
      this disease is classified into 8 groups. Among these groups, group A (A-XP)
      shows the most severe type of neurological disturbance. Slowly progressive
      diffuse impairment both in the central and the peripheral nervous systems has
      been reported. Although hearing loss occurs in all the patients, few papers have
      described the chronological changes of this disability. This study aimed to
      clarify the development of audiological abnormalities in A-XP patients. We
      recorded auditory brainstem evoked responses (ABRs) in 20 Japanese children with
      A-XP. All patients had homozygous intron 3 splicing mutations of xeroderma
      pigmentosum group A complementing gene, the most common type mutations in Japan.
      ABR threshold, peak latency of 5th wave and the peak interval latency between the
      1st and 5th waves (I-V interpeak latency) were measured, and were compared with
      those obtained from age-matched controls. ABRs were well detected in all patients
      examined under 4 years old. The I-V interpeak latencies became shorter with age
      as in the controls. In 3 ears, the 5th wave was recorded without 1st wave. In 4
      ears which no ABRs were detected with 90 dBHL stimulation, the only 5th wave was
      detected. No waves were obtained from the patients aged over 10 years. The
      current study revealed that ABR disturbance in A-XP patients became obvious after
      4 years of age. In addition, no ABR was found to be identified after 10 years of
      age. During 4 to 10 years of age, some patients showed the elevation of the
      threshold of the 5th wave. In A-XP patients, the peripheral nerve was
      hypothesized to be affected earlier than the central pathway involved in ABR.

PMID- 10355270
TI  - [Lidocaine induced seizure following topical application of local anesthetics:
      case report].

PMID- 10355271
TI  - [Marked efficacy of steroid pulse therapy in an infant with acute encephalopathy
      having elevated cerebrospinal fluid level of neopterin].

PMID- 10355272
TI  - Domestic violence: fueled by alcohol?

PMID- 10355274
TI  - When I was younger. Looking back at my residency 66 years ago.

PMID- 10355273
TI  - Serendipity and opportunism. Building a pathology department in mid-century
      America.

PMID- 10355276
TI  - The North Carolina Medical Journal finds itself in the vanguard of progressive
      medical journalism or, the deputy editor finds his fifteen minutes of fame.

PMID- 10355275
TI  - The physician's voice in North Carolina. Thomas Fanning Wood and the beginnings
      of the North Carolina Medical Journal.

PMID- 10355277
TI  - Truth-telling and hope. The dilemma of modern medicine.

PMID- 10355278
TI  - Hospitalization for hip fractures among North Carolina's Medicare population.

PMID- 10355279
TI  - 'Do not resuscitate' orders. The right to refuse cardiopulmonary resuscitation.

PMID- 10355280
TI  - Domestic violence and South Asian women.

PMID- 10355281
TI  - [Cross-talk between signal transduction pathways in the cell-- the role of G
      proteins in these processes].
AB  - Family of heterotrimeric G proteins plays an essential role in transducing
      signals across the plasma membrane in animal cells. Members of G protein family
      have been grouped into four subtypes: Gs, Gi, Gq and G12. A cross-talk between Gi
      and Gq-; Gs- and Gi-; and Gs- and Gi-coupled receptors are presented.
      Interactions between G protein coupled receptors and receptor tyrosine kinases
      and between G12 protein and the small molecular weight guanosine trisphosphate
      protein Rho are also described.

PMID- 10355283
TI  - [Signal transduction in the cell by phosphoinositide-specific phospholipase C
      isozymes].
AB  - This article reviews recent studies on phosphoinositide-specific phospholipase C
      species named beta, gamma and delta. The localization of PLC isozymes in the
      cell, structural organization, regulation of PLC activity and the interaction
      with various receptors is presented.

PMID- 10355284
TI  - [Regulation of protein S100 expression during transcription].
AB  - The S100 protein family is a group of homologous, small, calcium-binding proteins
      expressed in a cell specific manner. In man, the genes coding the majority of
      these proteins are localized in a cluster on chromosome 1. The cell specific
      expression of these proteins is mainly attained at the transcriptional level. It
      appears that the promoters of some S100 genes (rat S100A4, mouse and human S100B
      and rat CALB3) contain inhibitory sequences which reduce transcription level.
      Their effect may be counteracted by an interaction with cell specific
      transcription factor(s), which allows transcription in certain cell types. In
      other cases (human S100A2, mouse S100A4 and human S100A6), the main mechanism
      controlling cell specific expression seems to be methylation of the promoter or
      intronic sequences leading to gene silencing in some cells. The level of protein
      expression might be further modulated by different regulatory sequences that
      respond, via interactions with specific transcription factors, to various
      extracellular stimuli.

PMID- 10355282
TI  - [Adenylyl cyclase--isoforms, regulation and function].
AB  - Since its discovery in 1956, cyclic AMP (cAMP) has been shown to be a ubiquitous
      second messenger. It functions as one of many signaling molecules enabling cells
      to respond to external signals. cAMP is synthesized by adenylyl cyclases (ACs),
      enzymes that convert adenosine triphosphate (ATP) to cAMP. Three classes of ACs
      have been cloned based on the conservation of their catalytic domains; they
      include: class I-ACs from Enterobacteria, including Escherichia coli; class II
      "toxic" ACs, including calmodulin-activated enzymes from Bordetella pertussis and
      Bacillus anthracis; class III-ACs homologues from bacteria to human; they include
      nine isoformes found in mammals, and designated AC-1 to AC-9. Although ACs can
      exist in particulate and soluble forms, the former form predominates-at least in
      mammals. Nine (AC-1-AC-9) mammalian enzymes are stimulated by an "alpha" subunit
      of Gs-protein (Gs alpha) and by the diterpene forskolin, albeit to varying
      degrees (with AC-9 being least sensitive to forskolin). In addition to their core
      signaling capability in response to signals from Gs alpha, the different ACs are
      capable of receiving signals from a variety of sources, including other G-protein
      subunits, such as Gi alpha (inhibitory) or G beta gamma (stimulatory or
      inhibitory, depending on the enzyme), protein kinases (protein kinase A, PKA;
      protein kinase C, PKC; and calmodulin kinase, Ca(2+)-CaM), and Ca2+ by itself.
      The effects of activators are often highly synergistic or conditional, suggesting
      function of ACs as coincidence detectors. The plethora of G-protein-coupled
      receptors, together with functional differentiation among G-protein subunits and
      many AC isoforms, permits assembly of a very complex signaling systems with a
      wide variety of integrative characteristics. This survey presents basic facts on
      ACs classification and characteristics, and gives a brief review of the recent
      developments in this important and rapidly growing field of cyclic AMP research.

PMID- 10355285
TI  - [Signal transmission by Fc gamma receptors].
AB  - Fc gamma receptors are present on cells involved in the immune response. Although
      there are many reports concerning the mechanism of interaction of the receptors
      with the immunoglobulin ligands, expression of the receptors on cells and their
      effector functions and genes encoding the receptor chains, information concerning
      Fc gamma R signalling is rather limited. This review presents data on Fc gamma R
      mediated signal transduction.

PMID- 10355286
TI  - Nitric oxide signaling in the cardiovascular system--physiology and pathology.

PMID- 10355287
TI  - [Guanylyl cyclases].
AB  - Guanylyl cyclases constitute still growing family of enzymes, which catalyze
      synthesis of cGMP and can be activated in several ways. This review describes
      activation mechanisms for different forms of guanylyl cyclases. Possible
      signalling pathways mediated by cGMP are also indicated.

PMID- 10355288
TI  - NO/cGMP/VASP pathway is involved in integrin activation.

PMID- 10355289
TI  - [Interaction between guanylate cyclases in the kidney glomerulus].
AB  - Cyclic GMP mediates regulation of the basic functions in the kidney. The membrane
      and cytosolic (soluble) guanylate cyclase systems in the kidney glomeruli
      modulate reciprocally their activities. In physiological conditions, this
      compensatory regulation results in maintaining the stable cGMP level.

PMID- 10355290
TI  - [Cascade of biochemical events triggered by stimulation of adrenergic receptors
      in the rat pineal gland--from cell membrane to nucleus].
AB  - Pineal glands of various vertebrate species synthesize melatonin in a circadian
      rhythm generated by an endogenous pacemaker. The levels of melatonin and activity
      of serotonin N-acetyltransferase (AA-NAT: a penultimate and key regulatory enzyme
      in melatonin biosynthesis) are low during the light phase and high during the
      dark phase of any natural or imposed light-dark illumination cycle. The
      expression of AA-NAT gene in rat pineal gland is regulated by a photoneural
      system that acts through the adrenergic-cAMP-related mechanisms in pinealocytes.
      Concomitant stimulation by noradrenaline of beta 1- and alpha 1-adrenergic
      receptors, in a mechanism of "AND gate" activation, results in a large, 60-100
      fold increase in intrapinealocyte cAMP level. The role of cAMP-dependent
      transcription factors CREB, ICER and Fra-2 in turning on and off the AA-NAT gene
      expression is discussed.

PMID- 10355291
TI  - [Electric signals as universal mechanisms for fast information transfer between
      cells. Mechanisms of modulation in physiological and pathological conditions].
AB  - The scope of this work is to make a brief presentation of the
      electrophysiological recordings employed in the studies on ionic channel
      properties in physiological and pathological conditions. A number of examples are
      made on how electrophysiological recording contributed to understand the
      pathogenesis of certain diseases such as myasthenia gravis, myothonia congenita,
      cystic fibrosis and degradation of neurons in CA1 hippocampal region following
      ischaemia.

PMID- 10355292
TI  - [Mechanisms of selective vulnerability of cholinergic neurons to neurotoxic
      stimuli].
AB  - Preferential loss of cholinergic neurons in course of several encephalopathies
      may result from the fact that they utilize acetyl-CoA not only for energy
      production, but also for acetylcholine synthesis. Changes in activities of acetyl
      CoA metabolizing enzymes and shifts in acetyl-CoA compartmentalization, found in
      different animal models of brain pathologies and in human post mortem brain, are
      discussed in therms of their impact on cholinergic system integrity.

PMID- 10355294
TI  - [The role of MAP kinases and inducible transcription factors in the regulation of
      cell death and survival].
AB  - Cell growth and survival are constantly promoted and modulated by a variety of
      extracellular stimuli. Modules of sequentially activating protein kinases serve
      as important routes for the intracellular transmission of signals from diverse
      stimuli to nucleus. The Raf signaling involving Mitogen-Activated Protein (MAP)
      kinases is a key element of mitogenic stimulation. The c-Jun N-terminal kinases
      (JNKs) are activated in cells in response to cytokines, stress or proapoptotic
      stimuli, indicating that this signaling pathway may contribute to inflammatory
      and cell death phenomena. Cross-talk between different MAP kinase signaling
      pathways determines cellular responses in stress, apoptosis and normal
      physiological processes.

PMID- 10355293
TI  - [Activation of the cell proliferation program by acidic fibroblast growth factor
      (aFGF)].
AB  - Acidic fibroblast growth factor belongs to the fibroblast growth factor family.
      It is a potent mitogenic agent. The growth factor acts through activation of
      specific cell-surface receptors leading to intracellular tyrosine phosphorylation
      cascade. In addition to its extracellular action, however, there are reports
      indicating that aFGF enters cells and that it has an intracellular function as
      well. Using different experimental approaches it was found that: 1) aFGF can
      stimulate DNA synthesis in cells without specific receptors when is translocated
      into cells as a fusion protein with diphtheria toxin, 2) the growth factor as
      such is able to enter cells expressing FGF receptors and localize in nuclei, and
      3) an intracellular protein, which specifically binds only to mitogenic aFGF was
      found as well. Therefore it might be concluded, that transport of the growth
      factor from the cell-surface into the nucleus is an important event in the
      mechanism of stimulation of DNA synthesis and activation the proliferation
      program during aFGF treatment.

PMID- 10355295
TI  - [Does the universal "signal transduction pathway of differentiation" exist?
      Comparison of different cell differentiation experimental models with
      differentiation of HL-60 cells in response to 1,25-dihydroxyvitamin D3].
AB  - The comparison of distinct cell-differentiation models can help to answer the
      question whether there are common signalling pathways activated in the cells
      during the differentiation process or not. The differentiation of PC12
      pheochromocytoma cells in response to NGF, the differentiation of melanoma B16
      cells triggered by alpha-MSH, the formation of myotubes by L6E9 skeletal muscle
      myoblasts deprived of FCS or differentiation of HL-60 cells in response to
      steroid hormone 1,25-dihydroxyvitamin D3 share some similarities in the
      activation of signal transduction pathways. Differentiation-inducing agents
      stimulate sustained activation and nuclear translocation of MAP kinases (ERK1 and
      ERK2). Some of differentiation-inducing agents activate PI3-kinase as well, and
      the inhibition of the PI3K/p70S6K pathway blocks the process of differentiation
      in the cells.

PMID- 10355296
TI  - [Signal transduction mechanisms induced by epidermal growth factor receptor
      (EGFR) and their role in apoptosis regulation].
AB  - Stimulation of epidermal growth factor receptor (EGFR) leads to cell
      proliferation and plays an important role in cancerogenesis. It seems that these
      effects are a consequence of triggering of various signal transduction pathways
      involving PI-3K and MAP kinase activation. Surprisingly, under certain
      circumstances stimulation of EGFR may also result in cell growth arrest and
      apoptosis induction. It is possible that anti-proliferative effect of EGF depends
      on STAT protein activation. It has been reported, that STAT upregulates
      expression of cyclin-dependent kinase inhibitor, which blocks the cell cycle.
      Additionally, STAT may increase caspase 1 (ICE) expression, which seems to be
      necessary for apoptosis induced by EGF. Intracellular mechanisms involved in EGFR
      proapoptotic activity still remains poorly understood and, because of their
      potential clinical significance, require further investigation.

PMID- 10355297
TI  - [Antigen peptide/MHC complex as an initiator of a signal for lymphocyte T
      activation].
AB  - T lymphocytes recognize antigens in the form of oligopeptides bound by major
      histocompatibility complex (MHC) molecules. This recognition is specific due to
      clonally distributed receptors (T cell receptors, TCRs) that are specific for a
      given peptide/given MHC combination. Recognition of appropriate (agonist) peptide
      bound to appropriate (usually self) MHC molecule results in conformational change
      in the TCR that is transmitted to TCR-associated CD3 gamma, delta, epsilon and
      zeta polypeptide chains. These chains then undergo a series of tyrosine
      phosphorylations which, in turn, cause transmission of the activation signal
      further along the intracellular signaling pathway. However, there are peptides
      (partial agonists or antagonists) that induce only incomplete signal
      transmission, leading to the expression of only some, but not the other, T cell
      functions, to the anergy, or to the apoptosis. All these situations might be
      exploited in future for specific immunotherapy of different pathologic
      conditions. Advantages and disadvantages of this approach are briefly discussed.

PMID- 10355298
TI  - [Signal suppression of gene recombination with beta chain T-cell antigen receptor
      -mechanism for allelic exclusion].

PMID- 10355299
TI  - [Disturbance of signalling pathways for apoptosis in thymic lymphomas from TCR
      transgenic mice].
AB  - The abrogation of apoptosis during development of thymocytes could contribute to
      the lymphomagenesis of immature thymocytes which otherwise would be deleted. In
      agreement with this possibility it was found that cells of thymic lymphomas from
      TCR anty H-Y transgenic mice were resistant to TCR mediated apoptosis. Molecular
      mechanism responsible for resistance to TCR/Nur77-mediated apoptosis in these
      lymphomas is discussed.

PMID- 10355301
TI  - [Impaired signal transduction in T-lymphocytes of the aged].
AB  - An age-related dysfunction of the immune system, and especially of the T
      lymphocytes, is the most common feature observed during aging. It is well
      recognized by now that changes in the molecular mechanisms connecting the antigen
      receptor of the T cell with its nuclear machinery, commonly called 'signal
      transduction pathways' are the basis for this dysfunction. This paper is an up-to
      date review of current literature of the problem, describing age-related changes
      in the functioning of three major, complementary pathways of signal transduction
      in murine and human T cell: IP3/Ca2+/calcineurin, DAG/protein kinase C (PKC) and
      Ras/MAP kinases, discovered so far.

PMID- 10355300
TI  - [Induction of apoptosis by receptors for factors from the TNF family].
AB  - Mechanisms leading to induction of apoptosis by TNF family receptors involve
      intracellular activation of cysteinyl-aspartate-specific proteases (caspases).
      Caspase activation requires engagement of adaptor proteins. It is plausible, that
      caspase activation is sufficient for cell death in course of receptor-dependent
      induction of apoptosis. However, there are some data that programmed cell death
      involves also generation of ceramides, arachidonic acid metabolism, or MAP kinase
      (SAPK/JNK) activation. On the other hand, TNF receptor family triggers some
      protective, anti-apoptotic mechanisms, i.e. protein kinase C (PKC) and NF-kappa
      B. The outcome of induction of apoptosis by TNF receptor family depends on the
      cell type, its physiological condition and influence of environmental factors.

PMID- 10355302
TI  - [The function of voltage-gated potassium canals in T-lymphocytes under
      physiological and pathologic conditions].
AB  - This review focuses on biophysical properties and physiological role of voltage
      gated potassium channels (named as Kv1.3) in T lymphocytes. In the first section
      basic electrophysiological and pharmaceutical properties of the channels have
      been described. Then the data on the role of the channels in setting the cell
      resting membrane potential, cell mitogenesis and volume regulation has been
      reviewed. Finally, results on patch-clamp studies on the changes in the channel
      expression in TL in patients suffering from chronic renal failure have been
      presented.

PMID- 10355303
TI  - Effects of environmental factors on child survival in Bangladesh: a case control
      study.
AB  - The need for further studies on relationships between deaths and environmental
      variables has been reported in the literature. This case-control study was,
      therefore, carried out to find out the associations between several social and
      environmental variables and deaths of children due to infectious diseases such as
      those leading to diarrhoea, acute respiratory infection, measles and other
      diseases. Six hundred and twenty-five deaths (cases) and an equal number of
      matched living children (controls) aged 1-59 months, were studied in rural
      Matlab. An analysis of crude and adjusted odds ratio showed differential
      associations. Sources of drinking water, amount of stored water, conditions of
      latrines, number of persons sleeping with the child and the type of cooking site
      were statistically significantly associated with deaths due to infectious
      diseases after controlling for breast feeding, immunization, and the family size.
      Significant associations were also observed between: (i) the sources of drinking
      water and deaths due to ARI, and (ii) conditions of latrines and deaths due to
      diarrhoeal diseases, after controlling for the confounding variables. Several
      other environmental factors also showed associations with these various death
      groups, but they were not statistically significant. The size of the samples in
      death groups (small) and the prevalence of more or less homogeneous environmental
      health conditions probably diminished the magnitude of the effects. The results
      of the study reconfirm the importance of environmental health intervention in
      child survival, irrespective of breast-feeding, immunization, and selected social
      variables.

PMID- 10355304
TI  - Prolonged breastfeeding in Bangladesh: indicators of inadequate feeding practices
      or mothers' response to children's poor health?
AB  - The association between breastfeeding and diarrhoeal morbidity was examined in a
      prevalence study of 5502 children aged 6-71 months from rural and urban
      Bangladesh. Breastfeeding was found to be associated with reduced prevalence of
      diarrhoea. This association was most pronounced at the age of six months and
      declined linearly to zero at approximately 30 months of age; thereafter,
      breastfeeding was increasingly associated with diarrhoeal illness. The linear
      association was found only among those children who have no access to modern
      health services and information, when controlling for urban and rural
      differences. The literature provides two opposing explanations for the positive
      association of prolonged breastfeeding with diarrhoeal illness. The first
      explanation suggests that breastfeeding can be seen as mothers' response to
      children's poor health. The second explanation incriminates sub-optimal child
      feeding practices, characterised by prolonged breastfeeding and inadequate
      quality and quantity of complementary foods, as the cause of malnutrition and
      diarrhoea. Further studies are needed to identify which explanation is correct,
      given the public health implications in terms of children's survival, growth and
      development.

PMID- 10355305
TI  - Vitamin A intake and xerophthalmia among Indian children.
AB  - OBJECTIVE: To estimate prevalence of xerophthalmia and to assess dietary intake
      of vitamin A in Indian children aged under 6 y. DESIGN: Cross sectional study.
      STUDY SETTING: Urban slums under Urban Health Centre affiliated to Department of
      Preventive and Social Medicine, Government Medical College, Nagpur, India.
      PARTICIPANTS: The study included 1094 all children under 6 y of age, from two
      randomly selected urban slums. METHODS: Xerophthalmia was diagnosed on the basis
      of ocular signs and symptoms (WHO recommendations). Dietary intake of vitamin A
      was assessed by using one year recall method recommended by International Vitamin
      A Consultative Group. RESULTS: Prevalence of xerophthalmia was estimated to be
      8.7%. Nine hundred and ninety-five (90.9%) study subjects were identified as
      inhabitants consuming dietary vitamin A at below recommended levels. (UPF score <
      210). Five hundred and ninety-three (54.2%) study subjects were consuming dietary
      vitamin A at approximately less than 200 RE/d (UPF score < 120) while 402 (36.2%)
      were consuming approximately 200-300 RE/d (UPF score 120-210). The prevalence of
      xerophthalmia was found to be decreasing as the score of usual pattern of food
      consumption (UPF) increased. CONCLUSIONS: Children with a dietary intake
      represented by a UPF score of less than 120 were at high risk of developing
      xerophthalmia, whereas, those consuming vitamin A equal to a UPF score greater
      than 120 were at comparatively less risk despite being below the recommended
      levels.

PMID- 10355306
TI  - Prevalence and consequences of low back problems in The Netherlands, working vs
      non-working population, the MORGEN-Study. Monitoring Project on Risk Factors for
      Chronic Disease.
AB  - OBJECTIVE: To study the burden of illness of low back problems--prevalence and
      consequences--in the working and the non-working population. METHODS: Data from
      the Monitoring Project on Risk factors for Chronic Diseases, the MORGEN-study,
      were used. This project provided data on a probability sample of the general
      population aged 20-59 y in the Netherlands. Cross-sectional questionnaire data on
      6317 men (24% non-working) and 7505 women (47% non-working) gathered over the
      period 1993-1995 were analysed. RESULTS: The 12 month period prevalence of low
      back problems for the working and non-working population was 44.4% and 45.8% for
      men, and 48.2% and 55.0% for women. Larger differences were found for chronic low
      back problems, and activity limitation and use of health services due to low back
      problems. More than one-third of those who were disabled were so because of low
      back problems. When those unable to work because of disability (work disabled)
      were excluded, the prevalence and consequences of low back pain were still higher
      in the non-working group in comparison with the working population. Most of the
      non-working women were housewives and this group was both large in size and had a
      high prevalence of low back problems. CONCLUSIONS: Among the men studied, more
      than a quarter of the total burden of low back problems in those aged 20-59 y
      were found in the non-working population, among women this was 50%. Both research
      on causes and determinants of low back pain and the development of preventive
      actions--now being extensively focused on the working population--should also be
      translated to the non-working population.

PMID- 10355307
TI  - Effects of morbidity, age, gender and region on percutaneous transluminal
      coronary angioplasty (PTCA) utilisation.
AB  - OBJECTIVES: To investigate changes in the use of PTCA application in respect to
      morbidity, gender, region and age, and to investigate the morbidity as related to
      geographical variation. STUDY DESIGN: Retrospective record linkage study.
      SETTING: All hospitals and cardiological centres (n = 156) which performed the
      Minimum Basic Data Set (MBDS). PATIENTS: All Austrian residents who were
      diagnosed for myocardial infarction, coronary heart disease or angina pectoris in
      1993-1995 (1993: n = 73.077; 1994: n = 80.173; 1995: n = 84.896). MEASUREMENTS
      AND MAIN RESULTS: The intervention rate (IR = PTCA/indication) increased from
      0.03-0.04 (33%) between 1993 and 1995 with differences in genders (males: 24%,
      females: 27.7%) and regions (Vorarlberg: -7.5%, Burgenland: 65.3%). Male
      morbidity started to increase at about 60 y and female morbidity at about 70 y.
      Morbidity as a demand factor did not correlate with PTCA application. The
      intervention rate was significantly lower for females in Austria in general (P <
      0.001) as it was in every Federal State (P < 0.001). This pattern was constant
      during 1993-1995 with the highest difference in Salzburg and the lowest in
      Styria. Austrian men were about three times more likely to have received PTCA
      application than women (crude Odds Ratio = 2.8, 95% CI = 2.6-3, P-value < 0.001).
      Logistic regression modelling revealed age as main confounder (adjusted Odds
      Ratio = 1.36, 95% CI = 1.31-1.42, P < 0.001). The > or = 5% intervention rate
      peak was between 30-75 y for males and between 30-65 y for females whereas
      morbidity of > or = 1% started for males at about 50 y and for females at about
      60 y. Marked geographical differences of the intervention rate were observed
      (Upper Austria, Salzburg IR = 0.07, Styria IR = 0.02) but could not be explained
      by the demand factor morbidity (Pearson's correlation coefficients 1993: 0.039, P
      = 0.71; 1994: 0.155, P = 0.133; 1995: 0.087, P = 0.399). CONCLUSIONS: The highest
      intervention rates were in the age groups with the lowest morbidity. Women
      received significantly fewer interventions than men by age and region. The
      demographic strata with lowest use rate were women aged 64 y and more. Marked
      geographical differences of PTCA application were stated but could not be
      explained by the demand factor morbidity. Further studies on supply factors as
      well as on economic and social factors are needed in order to develop public
      health strategies to guarantee equal utilisation rates for the whole Austrian
      population.

PMID- 10355308
TI  - Body mass index and distribution of body fat in female Bosnian refugees--a study
      in primary health care.
AB  - Between 1992 and 1996 more than one million refugees, mostly women, received
      asylum in the USA, Canada and Germany and about 47,000 of them sought refuge in
      Sweden. Little is known about their cardiovascular health. Using data from a
      cross-sectional study of a simple random sample of non-patients, female Bosnian
      refugees (n = 98) aged 18-59 and Swedish-born controls (n = 95) we examined six
      primary diet cardiovascular risk factors: S-triglycerides, S-cholesterol, high
      density lipoprotein cholesterol, body mass index (BMI), waist circumference, and
      sagittal diameter of the abdomen. Bosnian women aged 42-59 y had substantially
      higher levels of BMI, larger waist and sagittal diameter of the abdomen
      measurements, higher levels of S-triglycerides, and lower HDL cholesterol
      indicating a more disadvantaged diet (CVD risk profile) than Swedish women.
      Younger Bosnian women aged 18-41 y had a higher sagittal diameter of the abdomen
      and lower high-density lipoprotein cholesterol than Swedish women. In conclusion
      this is the first study to report large differences in blood lipids, obesity and
      abdominal obesity after adjustment for socioeconomic status between Bosnian and
      Swedish women. These findings underscore the critical need to improve early
      detection obesity-related conditions in Bosnian women in exile.

PMID- 10355309
TI  - Parenting challenges in the Millenium.

PMID- 10355310
TI  - Community participation in international health: practical recommendations for
      donor and recipient organizations.
AB  - This article discusses the need for donor agencies and recipient organizations to
      involve target communities in the conceptualization, development, monitoring, and
      implementation of health services and programs in international health. This
      paper assumes that most donor organizations are based in industrialized
      countries. Given that resources are finite in both developing and developed
      countries, the article briefly reviews the current trend of declining public
      funds for health systems and an increasing role for privately funded health
      services worldwide. The article calls for community-based international health
      services that reflect the priorities of target populations, and it also discusses
      practical steps to involve local populations in community-based health planning
      and management in international health.

PMID- 10355311
TI  - [Prevalence of infections by hepatitis B, C, D and E viruses in Bolivia].
AB  - In Bolivia, no studies have been carried out specifically on hepatitis viruses.
      Thus, their prevalence and circulation patterns are virtually unknown. A
      seroepidemiologic study was performed from 1992 to 1996 to generate a preliminary
      idea of the overall prevalence of infection from hepatitis B, C, D, and E viruses
      (HBV, HCV, HDV, and HEV, respectively) in different Bolivian population groups.
      Prompted by the data obtained in other areas of Latin America, the study focused
      on indigenous communities in the Amazon region. In rural areas of the high Andean
      plateau, HBV infection showed an overall prevalence compatible with medium to low
      endemicity (11.2%), and no carriers of HCV or HDV antibodies were found. In two
      high-risk groups in the city of Cochabamba (homeless children and sexual
      workers), the prevalence of HBV infection was similar (11.6%) and could be
      considered low by comparison to that of similar population groups in Latin
      American urban centers. The prevalence of HCV (one positive case, or 0.5%) was
      similar to that found in similar population groups, although the small number of
      samples precludes drawing more definite conclusions. As has been noted previously
      with similar communities in tropical areas of South America, HBV infection is
      highly endemic in indigenous populations of the Bolivian Amazon (with an overall
      prevalence of 74.0%), but circulation of HCV has not been detected. It is a well
      known fact that HBV is horizontally transmitted and that transmission can take
      place very early in life, but the mechanisms involved are unknown. By 10 years of
      age, more than half the population has already had the natural infection that, in
      approximately 10 more years will have affected virtually the entire population.
      The very low rate of positivity to HBsAg (1.6%), the absence of viral DNA in
      samples showing isolated positivity to anti-HBc, and the high prevalence of anti
      HBs among individuals who show markers for natural infection (92.4%) suggest
      vertical transmission plays no role in persistent endemicity. So far, no outbreak
      of HDV infection has been documented in these communities, but the high
      endemicity shown by HBV points to the possibility of future outbreaks. Results
      obtained with tests for the detection of antibodies against HEV suggest that this
      virus is circulating widely in Bolivia and that it could have caused recent
      outbreaks in Cochabamba state. Vaccination against HBV in endemic populations is
      recommended as a short-term measure. Also recommended are actively searching for
      outbreaks and sporadic cases of hepatitis E in the entire country and performing
      additional research that will help in assessing the public health consequences of
      the situation described in this article.

PMID- 10355312
TI  - Barriers to early detection of breast cancer among women in a Caribbean
      population.
AB  - The purpose of this descriptive study was to identify and describe barriers to
      early detection of breast cancer, as well as current breast cancer screening
      behaviors and attitudes regarding the disease, among women aged 20 and older on
      the Caribbean island of Tobago. Tobago is the smaller of the two islands that
      make up the nation of Trinidad and Tobago. Between February and June 1996, 265
      women fitting the age criteria completed a structured survey questionnaire. Women
      of African descent made up 89% of the respondents. In terms of age, 48% of those
      surveyed were between 20 and 39, 40% were between 40 and 59, and 12% were 60 or
      older. Barriers to early detection identified were a low level of breast self
      examination, infrequent clinical breast examinations as part of regular care,
      unavailability of mammography services on Tobago, cost of screening, and
      difficulty of traveling to Trinidad for mammography. Furthermore, only a minority
      of the study participants had ever attended early detection or public awareness
      programs. The results were nearly the same for individuals with a family history
      of breast cancer, who would have a higher risk of occurrence of the disease. In
      addition, the majority of the respondents reported what can be considered a
      cultural barrier to early detection practices, a belief that no matter what they
      did, if they were to get breast cancer, they would get it. The authors recommend
      that mammography services be made available on Tobago. The authors also intend to
      use the findings to help develop an appropriate, culturally sensitive breast
      cancer awareness and early detection program for women on the island.

PMID- 10355314
TI  - Nutrition of Honduran mothers/caretakers.
AB  - In 1996, the Honduran Ministry of Health conducted a national micronutrient
      survey of children 12-71 months old, which also included an assessment of the
      nutrition status of their mothers/caretakers. The 1,126 mothers/caretakers who
      participated in the survey tended to be short and plump. About 15% of them were
      at obstetric risk by virtue of their short stature and/or low body weight. About
      9% had chronic energy deficiency (CED), but 27% were at least 20% overweight. CED
      was associated with socioeconomic indicators of poverty. Risk factors for being
      at least 20% overweight included being over 30 years old, not breast-feeding,
      having attended no higher than grade 4, 5, or 6 of primary school, coming from a
      wealthier household, and living in San Pedro Sula or medium-sized cities. Among
      the women surveyed, 26% of nonpregnant and 32% of pregnant mothers/caretakers
      were anemic. The likely principal cause of anemia was the low intake of
      bioavailable iron from food and, in some cases, excessive iron loss associated
      with intestinal parasites, especially hookworm. Only 50% of the
      mothers/caretakers participating in this study had received iron during their
      last pregnancy, and just 13% had received postpartum vitamin A. The results
      highlight the need to develop and implement an effective program to control iron
      deficiency anemia in women of reproductive age, including by fortifying such
      widely consumed foods as processed wheat and maize flour and by routinely
      administering iron supplements to high-risk groups. Postpartum vitamin A
      supplementation should be encouraged to protect both the mother and newborn
      infant against vitamin A deficiency.

PMID- 10355315
TI  - [Health communication as a curriculum at United States universities].
AB  - This article analyzes the state of development of communications related to
      health in universities of the United States of America. This specialty is
      essential for people's well-being, and it involves interpersonal, organizational,
      and mass communications. In the United States, communications for health
      promotion is an area of applied communications with social relevance and
      generally performed in interdisciplinary settings. A number of universities in
      the United States offer communications master's degree programs with an emphasis
      on health. However, so far, the only program with a formal graduate degree in
      health and communications is one jointly offered by the Emerson University
      Department of Communications and the Tufts School of Medicine. Developing and
      including this specialization in the schools of communications in Latin America
      is crucial to improving the quality of life of the peoples of the continent.

PMID- 10355313
TI  - [Susceptibility to antimicrobial agents in isolates from invasive Streptococcus
      pneumoniae in Colombia].
AB  - A study was done to determine the patterns of susceptibility to antimicrobial
      agents in isolates of Streptococcus pneumoniae that caused invasive disease
      diagnosed in children under the age of 5 in Colombia between 1994 and 1996, as
      well as to establish the distribution of the capsular types of the resistant
      isolates. The analysis was done using 324 isolates obtained during the
      performance of the National Serotyping Protocol for S. pneumoniae carried out in
      Bogota, Medellin, and Cali, Colombia, between July 1994 and March 1996. Of the
      324 isolates, 119 (36.7%) showed diminished susceptibility to at least one
      antimicrobial agent, including 39 (12%) that showed diminished susceptibility to
      penicillin. Of these 39 resistant to penicillin, 29 showed intermediate
      resistance and 10 showed high resistance. Nine isolates (2.8%) showed resistance
      to ceftriaxone, 80 (24.7%) to the combination of trimethoprim and
      sulfamethoxazole (TMS), 49 (15.1%) to chloramphenicol, and 31 (9.6%) to
      erythromycin. Resistance to two antimicrobial agents was observed in 31 isolates
      (9.6%); multiple resistance was found in 22 (6.7%). These 22 multiresistant
      isolates all showed resistance to TMS. The most frequent associations were
      penicillin, TMS, and erythromycin (5 cases); penicillin, chloramphenicol, TMS,
      and erythromycin (4 cases); penicillin, ceftriaxone, chloramphenicol, and TMS (3
      cases); and penicillin, ceftriaxone, chloramphenicol, TMS, and erythromycin (3
      cases). The most frequent serotypes in the penicillin-resistant isolates were:
      23F (53.8%), 14 (25.6%), 6B (7.7%), 9V (5.1%), 19F (5.1%), and 34 (2.6%). The
      most frequent serotypes in the isolates resistant to antimicrobial agents other
      than penicillin were: 5 (37.5%), 23F (7.5%), 14 (18.8%), and 6B (13.8%). This
      difference in the distribution of the serotypes was statistically significant (P
      < 0.0001). The study results indicate the need to maintain active surveillance of
      antibiotic susceptibility patterns in order to avoid resistance in S. pneumoniae
      and to provide timely information to change practices regarding prescribing and
      consuming antimicrobial agents.

PMID- 10355317
TI  - [Introduction of a conjugate vaccine against Hib in Chile and Uruguay].
AB  - In some countries, the invasive disease caused by Haemophilus influenzae type b
      (Hib) has been practically eliminated thanks to vaccination. However, in much of
      the developing world, meningitides and pneumonias caused by these bacteria
      continue to be a major cause of childhood morbidity and mortality, as well as
      high hospitalization costs. Because safe and effective conjugate vaccines are now
      available, the Special Program for Vaccines and Immunization of the Pan American
      Health Organization has recommended introducing them into the regular vaccination
      regimen of as many countries as possible. This has been done in Chile and
      Uruguay, where the Hib vaccine now forms part of the regular vaccination routine.
      When the vaccine was being introduced, both countries had difficulties they could
      have avoided if they had known of the experiences of other nations. Therefore,
      these two countries now offer the lessons they learned to other nations
      considering introducing the vaccine into their immunization programs. The most
      important lessons were to: strengthen the epidemiological surveillance system
      sufficiently in advance of introducing the vaccine; with the support of
      scientific societies, present the technical information that justifies
      introducing the vaccine; seek community backing and acceptance; precisely
      establish in advance the presentation and dosage of the vaccine that is most
      appropriate for the country; and be certain to have the political and legal
      decisions needed to ensure the continuity of Hib vaccination in the future.

PMID- 10355318
TI  - HIV/AIDS research priorities among aboriginal people in Canada.

PMID- 10355316
TI  - [Vaccination against Haemophilus influenzae type b in Uruguay: experience and
      impact].
AB  - Between 1979 and 1994, epidemiological surveillance of meningitides in Uruguay
      showed a progressive increase in suppurative meningitides due mainly to Neisseria
      meningitidis and Haemophilus influenzae type b (Hib). The cases were concentrated
      in children under 5; however, among the cases caused by Hib, 70% affected
      children from 1 to 11 months old. Facing this situation, the Ministry of Public
      Health resolved, as of August 1994, to include the Hib vaccine in the country's
      Expanded Program on Immunization, which has been in place since 1982. The Hib
      vaccination is done without charge and is obligatory for all children under 5
      years of age. It is done using the following series of vaccinations: a) three
      doses, given at 2, 4, and 6 months, with a booster dose at age 1; b) children
      from 7 to 11 months old receive two doses two months apart and a booster dose a
      year later; and c) a single dose for children 12 months to 4 years old. Between
      August and December 1994 a coverage rate of 76.6% was reached among children
      between 2 months and 4 years old, and the coverage has remained above 80% in the
      new cohorts. In Uruguay, this vaccination strategy had a spectacular impact on
      morbidity and mortality due to meningitides caused by Hib. One of the results was
      that the incidence of 15.6 per 100,000 registered in children under 5 in the
      prevaccination years declined to 0.03 per 100,000 in 1996.

PMID- 10355319
TI  - Preventing violence: a commitment by the organization.

PMID- 10355320
TI  - Violence: from knowledge to prevention.

PMID- 10355321
TI  - [Violence and public health].

PMID- 10355322
TI  - [Multicenter Study on Cultural Attitudes and Norms towards Violence (ACTIVA
      project): methodology].
AB  - The purpose of this article is to describe the conceptual bases and methods used
      in the ACTIVA multicenter study, as well as the process employed in the different
      stages of the research. General information is given on the approach, design, and
      methods that were applied in the cities that participated in the study: San
      Salvador, El Salvador; San Jose, Costa Rica; Cali, Colombia; Caracas, Venezuela;
      Salvador, Bahia, Brazil; Rio de Janeiro, Brazil; Santiago, Chile; and Madrid,
      Spain. The objectives of the study were to: (1) analyze and compare among cities
      the prevalence of verbal and physical aggressive behaviors toward children, the
      spouse or other partner, and persons outside the family; and (2) identify
      personal, environmental, and socioeconomic factors associated with these violent
      behaviors. The purpose of the ACTIVA project was to generate information to help
      guide violence-prevention policies and programs in the cities and to provide
      criteria for decision-making, as well as to obtain baseline data to use in
      evaluating prevention policies and programs. To achieve the proposed objectives,
      a single, common questionnaire was prepared and validated. The questionnaire was
      used in face-to-face interviews with residents of private urban homes who were
      between 18 and 70 years old. The sample was selected in each city through
      stratified multistage sampling of clusters proportionate to the socioeconomic
      strata of the general population and without any substitutions. The final sample
      consisted of 10,821 people. In general, the response rates were within the
      established limits. Exceptions included San Jose, Rio de Janeiro, and Madrid,
      where the size of the final sample was slightly smaller than anticipated. More
      young men of higher socioeconomic strata declined to participate, so that the
      samples had an overrepresentation of women from medium and lower strata. The
      article concludes with a description of the scope and limitations of the study,
      in terms of both the approach and methods. With their comparative analyses,
      studies of this type can contribute to identifying the differences and
      similarities between cities. The article shows that with this method it is
      possible to analyze how violent behaviors are associated with different risk
      factors and individuals' characteristics, at a point in time. However, this
      design is limited in terms of establishing causal relationships, and it did not
      allow an evaluation of the context of every specific instance of violence.

PMID- 10355324
TI  - [Violence between couples].
AB  - This article describes variables related to different forms of violence in
      couples. These variables have been organized in a theoretical model that takes
      into account cultural factors, sociodemographic and family characteristics,
      attitudes, and other variables defined as inhibitors and facilitators of violence
      in conflict situations. For the ACTIVA project, a representative sample
      consisting of 10,821 people was interviewed in eight cities. For this research on
      couples, 6,184 of those responses were taken into consideration, from persons who
      were in a marriage or an unmarried relationship during the year before the
      interview. The data were obtained from verbal responses to a questionnaire
      completed in the interviewees' residences. The variables that were clearly
      associated with couples violence were: socioeconomic level (the fewer the
      economic resources, the greater the violence), gender (women reported both using
      and receiving more violence than men did, although the actual level of violence
      was similar), age (there was more violence between younger people), marital
      status (there was more violence between unmarried persons), childhood abuse
      (those most abused in childhood), excessive alcohol consumption (those who have
      gotten drunk), holding attitudes justifying violence, and having fewer skills to
      deal with conflicts. Acts of violence, which both men and women commit in
      relationships, originate in the socialization process, both through the practice
      of abuse as well as the transmission of values that lead to attitudes justifying
      violence. A number of things could help markedly reduce the levels of couples
      violence, including a balance of power between the two persons in the
      relationship, a modification of attitudes, an improvement in conflict-resolution
      skills, and a reduction in stress-producing factors.

PMID- 10355323
TI  - Who is violent?: factors associated with aggressive behaviors in Latin America
      and Spain.
AB  - The main purpose of this paper was to evaluate the strength of the association
      between: 1) aggressive behaviors and 2) attitudes and self-efficacy for
      alternatives to violence, in different cities of the Region of the Americas and
      Spain. Results were based on a cross-sectional house-hold survey of a sample of
      the population aged 18 to 70 years. The survey was conducted in eight
      metropolitan areas of Latin America and Spain: Rio de Janeiro, Brazil; Salvador,
      Bahia, Brazil; Santiago, Chile; Cali, Colombia; San Jose, Costa Rica; San
      Salvador, El Salvador; Caracas, Venezuela; and Madrid, Spain. Each sample of
      approximately 1,200 respondents per city was stratified by clusters and was
      proportional in terms of socioeconomic position and population density. In all
      cities and for all targets of aggression studied, people who reported using
      aggression were less likely to feel confident that they could solve conflicts
      without violence, and they were more likely to hold attitudes supporting
      violence. Young persons were also more likely to commit aggression against all
      the targets. In addition, aggression toward nonfamily members was found most
      frequently among young men who reported binge drinking, who either carried a
      firearm or would have liked to carry one, or who perceived the police as
      inefficient. Additional studies need to be done in each country to describe more
      specific attitudes associated with aggression within each subculture. Future
      prevention programs should focus on modifying attitudes that support violence,
      increasing self-efficacy in solving problems without using violence, supporting
      the development of a police system that people can trust, regulating firearms and
      access to alcohol, and raising people's education levels.

PMID- 10355325
TI  - [Victimization by urban violence: incidence and associated factors in cities in
      Latin America and Spain].
AB  - This article looks at eight cities in Latin America and Spain and compares the
      chances of and variables associated with being a victim of various kinds of urban
      violence. The analysis was done using data from the ACTIVA Multicenter Study,
      which was coordinated by the Pan American Health Organization in 1996. The study
      sample consisted of 10,821 persons who were representative of residents between
      the ages of 18 and 70 in eight metropolitan areas of Latin America and Spain: Rio
      de Janeiro, Brazil; Salvador, Brazil; Santiago, Chile; Cali, Colombia; San Jose,
      Costa Rica; San Salvador, El Salvador; Caracas, Venezuela; and Madrid, Spain. The
      results show that the likelihood of being a victim of different types of violence
      varies from city to city. The variables associated with a greater likelihood of
      being a victim in most--though not all--of the cities are sex, age, and
      consumption of alcohol.

PMID- 10355326
TI  - [Violence, ethnic groups and skin color: a study on differences in the
      metropolitan region of Salvador, Bahia, Brazil].
AB  - The objective of this study was to analyze the distribution of various forms of
      violence--structural, institutional, interpersonal, and crime-related--in the
      three most common color groups of Bahian society: mulattos, whites, and blacks.
      The study compared the levels of victimization of mulatto, white, and black
      individuals with their assessments of the efficiency of crime-control
      institutions, in order to ascertain how that relates to those same citizens'
      acceptance of authoritarian attitudes and norms. The data analyzed came from the
      multicenter project on Attitudes and Cultural Standards about Violence (ACTIVA)
      project, from a sample of 1,384 residents of the Salvador metropolitan region.
      The study was designed as a cross-sectional survey, with interviews done in the
      people's homes between September and December of 1996. The sample selection was
      done in three stages: first, residential areas were chosen at random; then, a
      systematic selection was made from the homes in each of the selected areas;
      finally, the persons to be interviewed were chosen at random. To collect the data
      the researchers used a pretested questionnaire that had been designed for the
      ACTIVA study. The results showed an unequal distribution of structural violence
      that mainly affected blacks. There were no differences by color group for
      interpersonal and institutional violence. Criminal violence impacted whites and
      blacks to the same degree. Distrust in the efficiency of the civil and military
      police and in the justice and penal systems was very high among all three color
      groups. Moreover, few differences were found among the groups with regard to
      authoritarian attitudes and norms. Based on the results, it is possible to
      conclude that public order is threatened if the dissatisfaction with institutions
      for crime prevention and reduction continues at a high level at the same time
      that individuals tend to support violence to resolve conflicts.

PMID- 10355327
TI  - [Santiago, a terror-stricken city].
AB  - The general purpose of this article is to determine how citizens' fear of lack of
      safety affects the use of public spaces. In an evaluation such as this, it is
      necessary to analyze two types of relationships pertaining to violence: the one
      between victimization and a perception of being unsafe, and the one that exists
      between social attitudes and the peaceful resolution of national conflicts. To
      this end, an analysis was performed of different variables--victimization,
      feeling unsafe, use of physical spaces, attitudes toward the established
      political and social institutions and toward the resolution of national conflicts
      -and of potential associations between these variables. The data for the study
      came from a survey of 1,200 persons between 18 and 70 years old who were
      residents of Santiago. Results show that Santiago's citizens live in fear and
      that their perception of a lack of safety has grown more intense, despite the
      fact that victimization rates remained relatively stable over the years preceding
      the survey. Fear is associated with an abandonment of both physical and
      sociopolitical public spaces, as well as with seeking refuge in private spaces
      and private life. There is a widespread attitude in favor of resolving conflicts
      through non-peaceful means, and such an attitude is more often associated with
      feeling unsafe, having negative attitudes toward democracy, and lacking hope in
      the nation's future. The results of this study support the notion that, in order
      to overcome their fear, people tend to adapt to reality by adopting a conformist
      attitude, taking on standard beliefs and behaviors, and overestimating the use of
      force as a way of resolving their differences.

PMID- 10355328
TI  - [Authoritarian attitudes and violence in Madrid].
AB  - One of the objectives of the Multicentric Study on Cultural Norms and Attitudes
      Toward Violence (Estudio Multicentrico sobre Actitudes y Normas Culturales frente
      a la Violencia, the ACTIVA project) is to analyze the relationship between those
      attitudes that foster violence and the violent behaviors themselves. This article
      examines the relationship between attitudes and two components of violence: its
      justification and its actual occurrence. Data were collected in Madrid between
      October and December 1996 from a representative sample of 1,219 people, who were
      interviewed at home with the common questionnaire used for the ACTIVA project,
      with some additional questions. Overall, the sample respondents scored low on the
      authoritarianism scale. Persons who most strongly justified the use of violence
      scored higher on authoritarianism, along with those who customarily displayed a
      higher level of aggression. Attitudes that were more strongly authoritarian were
      found in low-income neighborhoods, in people who were not part of the workforce,
      in people with less education, and in those persons who described themselves as
      having a right-wing ideology. If people who are more authoritarian justify and
      practice violence more than others, it becomes necessary to encourage criticism
      of those who abuse their power and tolerance toward differences, in order to
      prevent such behaviors without disregarding the influence of the social variables
      previously mentioned.

PMID- 10355329
TI  - [Psychosocial impact of violence in San Salvador].
AB  - This study had two objectives: (1) to describe the levels of victimization of
      Salvadorians due to criminal violence, and the population groups most affected by
      it; (2) to learn if these levels of victimization are related to the presence of
      norms, attitudes, and behaviors that encourage the occurrence of violence. For
      this purpose data from the ACTIVA project of El Salvador were used. The project
      was carried out by the University Institute of Public Opinion during October and
      November 1996, with a sample of 1,290 personal interviews that were presumed to
      be representative of people between 18 and 70 years of age living in the
      Metropolitan Area of San Salvador. The sample was obtained through multistage
      probability sampling. The results show that the level of victimization from
      violence is quite high in San Salvador and that it especially affects adult and
      young men. The results also indicate that persons who have been victims of
      serious aggression tend to show, more frequently than average, norms justifying
      and approving the use of violence, a tendency to use weapons, and aggressive
      behaviors toward other people.

PMID- 10355330
TI  - [Promotion of public health research: attempting to balance relevance and
      excellence].
AB  - Those in charge of directing scientific research face a daunting task: finding a
      proper balance between excellence in research and that research's relevance to
      people's health problems. In developing countries, this task is further hampered
      by deficient scientific and technological infrastructure, the lack of
      competitiveness of its research community, and the shortage of research funds.
      This article explains some of the mechanisms that have been put in place in Latin
      America to achieve a balance between excellence and relevance, especially by
      promoting research that targets pertinent public health problems. Within this
      context, the multicenter studies being conducted under the auspices of the Pan
      American Health Organization's Program for the Support of Research are described.
      The article also lays out the fundamental features of a new model for
      international cooperation to generate knowledge to help resolve the public health
      problems of the countries of the Americas.

PMID- 10355331
TI  - Behavioral sciences concepts in research on the prevention of violence.

PMID- 10355332
TI  - [Epidemiologic surveillance for the prevention and control urban violence].
AB  - Violence prevention policies should be based on information, follow-up, research,
      and analysis, all of which increase the chances of success and make it easier to
      evaluate interventions. This implies, in turn, that there is a need to create
      surveillance, research, and prevention models for violence within the sphere of
      public health and epidemiology, a task that constitutes an integral part of the
      Pan American Health Organization's Regional Plan of Action Health and Violence.
      This article describes the objectives of epidemiologic surveillance systems and
      explains their purpose and scope, along with the barriers that stand in the way
      of their implementation. It also examines a number of variables and their
      definitions, the types of analyses and reports that should be generated, and the
      decisions that can be made on the basis of these reports. Finally, it discusses
      ethical criteria and describes the experiences of the program known as
      Desarrollo, Seguridad y Paz (DESEPAZ) in Cali and Santa Fe de Bogota, Colombia,
      where an epidemiologic surveillance system against violence has been implemented.

PMID- 10355333
TI  - [Violence in the family: Ecuadorian experience in the formulation of policies for
      health services].
AB  - Since 1995, PAHO has been carrying out in Bolivia, Ecuador, and Peru a project
      known as "Violence against Women and Girls: Proposal to Establish Community
      coordinated Interventions in Three Countries of the Andean Subregion." Its
      purpose is to support initiatives being conducted by various nongovernmental
      organizations (NGOs), government agencies, and social institutions in an attempt
      to improve the status of women. One of its objectives is to formulate public
      policies and local services aimed at preventing and combating violence against
      women and girls through local action networks, data-gathering systems, and legal
      proposals. This article examines what the initiative has achieved so far in
      Ecuador, in efforts conducted in Quito, Guayaquil, and Sigsig with the support of
      three national NGOs and in conjunction with the Ministry of Health and the
      National Women's Council.

PMID- 10355334
TI  - Youth violence in Latin America: current situation and violence prevention
      strategies.

PMID- 10355335
TI  - [Regulatory control of new medicines: help or hindrance?].
AB  - To answer the question of the benefit and the cost/benefit ratio of the
      activities of a drug regulatory agency, the most important, clinically relevant
      "products" of a licensing authority in general, and the Swiss licensing authority
      (IKS) in particular are discussed. The activities of the medicines licensing
      authority assure that: For all new substances the efficacy and a positive
      benefit/risk ratio have been demonstrated before a marketing authorisation. For
      all marketed medicines an information for professionals and patients is available
      that has been evaluated and approved by an independent and competent reviewer. An
      independent post marketing surveillance of the side effects profile continues
      after a medicine has been put on the market. All clinical trials investigating
      medicinal products are performed according to GCP rules corresponding to
      international ethical and scientific standards. An international comparison of
      the time needed for the evaluation of a marketing authorisation application for a
      new medicine reveals that the IKS is one of the most efficient agencies. This is
      illustrated with an example showing the evaluation times of the EMEA and the IKS
      for products approved in 1997.

PMID- 10355336
TI  - [Me too's and generics].
AB  - Generics are pharmaceutical products containing the same active substance as an
      original branded medication. Generics are used in order to reduce the cost of
      pharmacotherapy. They have to be bioequivalent to the original drug-their mean
      "area under the curve" (AUC) should not deviate from the AUC of the original by
      more than 20 per cent. One generic is not necessarily bioequivalent to another
      generic. It is therefore highly questionable whether an original drug should be
      replaced by a no-name generic. From a medical point of view only branded generics
      should be prescribed. "Generics-related" conflicts can be minimized through tight
      cooperation between hospitals, physicians in ambulatory practice and pharmacies.
      Generic drugs should never be used if a better but non-generic medication is
      available.

PMID- 10355337
TI  - [Interactions and adverse drug reactions: how to obtain information].
AB  - Adverse drug reactions (ADR) are common. They may mimick many other diseases. It
      is therefore important to consider always ADR as possible causes for new
      complaints. Interactions are less common but they may also be the source of
      serious problems. First informations on both topics are commonly found in the
      Swiss Drug Compendium ("Arzneimittel-Kompendium der Schweiz") and in the
      accompanying "Grundlagen der Pharmakotherapie". Further information is found in
      several standard text books, on new substances eventually also via the internet.
      Rare side-effects require a Medline-search or eventually consultation of the WHO
      database on ADR. Several institutions in Switzerland provide information on ADR
      (an index is found in an annex of the "Arzneimittel-Kompendium der Schweiz"). It
      is essential for drug safety monitoring that every physician communicates
      observation of ADR.

PMID- 10355338
TI  - [The medical advisor: a friend to count on?].
AB  - The medical advisor can be helpful for the practitioner as a source of
      information on drugs. However, the physician has to learn how to obtain basic
      rational information on therapy, how to identify whether the given information is
      relevant or not for the clinical decision, to distinguish between rational and
      irrational information during presentation and to validate all given information.

PMID- 10355339
TI  - [Newer antibiotics--missed efficacy in false indications].
AB  - Various reports indicate conclusively that antibiotics are used much too
      frequently and physicians often prefer broad spectrum compounds for "safety
      reasons". Symptoms of viral infections of the respiratory tract such as fever,
      cough and runny nose are often reason enough to start antibiotic regimens leading
      to increased costs and finally to development of resistance. Some newly developed
      antibiotics, often with unique properties will be discussed in this paper
      emphasizing potential problems associated with their uncritical use.

PMID- 10355340
TI  - [Life sciences on the march].

PMID- 10355341
TI  - [Relevance of life sciences for traumatologic and orthopedic surgery].
AB  - During the last 15 years biology and life science underwent a dramatic
      development. Daily we hear about new discoveries in this area of research. There
      is for example the identification of new genes, which are responsible for
      different phenomena: cancer genes, adipositas genes and suicide genes.
      Furthermore there are reports of human ears growing on the back of a mice or
      cloning of complex organisms (i.e. Dolly). This kind of research is mostly
      summarized under terms like: genetic engineering, life science, genetics,
      molecular biology, biochemistry, bioanalytics, tissue engineering and
      reproduction medicine. Because of the indiscriminate use of these terms and the
      complexity of the single discipline only specialists are able to understand and
      to assess the relevance of results. Aim of this article is to explain some of
      these terms and to clarify the principles of some important techniques. By this
      we want to show the relevance of life science for traumatology which possibly
      leads to new diagnostic and therapeutic concepts.

PMID- 10355342
TI  - [The significance of intracompartmental pressure values for the diagnosis of
      chronic functional compartment syndrome. A meta-analysis of research studies of
      pressures in anterior M. tibialis during exercise stress].
AB  - INTRODUCTION: The chronic exertional compartment syndrome of the musculus
      tibialis anterior is thought to be responsible for a major part of complaints of
      the lower leg among active sportsmen. There is an important role of tissue
      pressure measurement in diagnosing chronic anterior compartment syndrome during
      muscular activity. However, there is a controversial debate about the relevant
      parameters. METHODS: Metaanalysis of all the 21 studies (1979-1998) measuring
      intracompartmental pressures during muscular activity. Parameters of analysis:
      type of exercise, catheter technique, recommendations of diagnostic criteria.
      RESULTS: Analysis of literature shows that there has been no standardisation
      concerning the type of muscular exertion (isometrics for 5-10 min, exercise on
      the treadmill between 3.2 and 12 km/h). In 8 of the 21 studies the results have
      been attained through the unsuitable Wick-catheter-technique. In the overall view
      none of the suggested criterions for diagnosis is taken up by other teams. There
      are considerable variations up to 500% regarding the recommended parameters.
      CONCLUSIONS: From all studies no uniform recommendation for parameters of
      diagnostic relevance can be derived. On this background it should be demanded
      that future research is conducted by a uniform regimen for examination and modern
      technique of measuring with a high temporal resolution. Under these standardised
      conditions the investigated parameters of the intracompartmental pressure curve
      should be reconsidered once more regarding diagnostic predictability by
      calculations of specifity and sensitivity.

PMID- 10355343
TI  - [Treatment of acromioclavicular joint separations. Central Kirschner- wire and
      PDS-augmentation].
AB  - Beside the basic question wether a separation of the acromioclavicular joint
      should be treated operatively or not, the method of operation is discussed in
      particular. For that reason we investigated our own method of a temporary
      transfixation of the joint by a centrally drilled K-wire combined with a PDS
      augmentation of the coracoclavicular and a suture of the acromioclavicular
      ligament. Follow up examinations were possible in 57 out of 82 patients which
      were operated during 5 years. Patients subjective rating and objective follow up
      and sonographically evaluated joint conditions were scored together. Looking for
      the range of motion of the shoulder only 5.5% of the patients had a reduction of
      more than 20 degrees. Out of 12 complications in particular three infections only
      resulted satisfying by influencing the subjective rating negatively. In 28.1% of
      patients no durable anatomic reconstruction of the joint was achieved. Score
      achieved by these patients was significantly lower compared to those with a
      lasting anatomic reconstruction of the acromioclavicular joint. In conclusion the
      results confirm our operative regime for separations of the acromioclavicular
      joint. In literature survey the here described method of operation belongs to the
      better ones without showing a clear advantage. Nevertheless the method should be
      modified to decrease the rate of subluxations.

PMID- 10355344
TI  - [Surgical embolectomy after reanimation in central pulmonary embolism].
AB  - Central pulmonary embolism represents one of the most threatening complications
      in surgical patients. In most cases deep vein thrombosis of the lower extremities
      is the source of emboli. Despite the introduction of hypocoagulative drugs in
      standard surgical concepts the incidence of deep vein thrombosis remains about
      10% in trauma patients. Estimated numbers of unknown cases of pulmonary embolism
      are supposed to be rather high too. In haemodynamically symptomatic pulmonary
      embolism events and especially when the patient has to be reanimated, mortality
      rates of up to 93% are reported in literature. After introduction of the heart-
      and lung-machine in the surgical concept of therapy, survival rates have
      increased significantly. We report on three cases of successful surgical
      embolectomy after CPR. In a review of literature current concepts of treatment in
      central pulmonary embolism are discussed.

PMID- 10355345
TI  - [Complex hand injuries. Importance of primary repair with free flaps].
AB  - BACKGROUND: The treatment of large and complex hand injuries is particularly
      challenching concerning the functional and cosmetic outcome. In this kind of
      injuries the primary defect cover is of paramount importance and so the initial
      situation for secondary reconstructive options may be evidently improved.
      MATERIAL & METHODS: Between October 1986 and Mai 1996 43 patients with large
      complex and combined hand injuries were primarily treated with 49 free flaps. The
      mean follow-up was 39 (6 to 92) months, the mean hospital stay was 19 (8 to 40)
      days. Depending on the time of the reconstruction and based on a classification
      established in our clinic, the patients were distributed among three groups:
      primarily (within 24 hours), delayed (between 2 and 7 days), and late (after 7
      days till 3 weeks posttraumatically) reconstruction. RESULTS: Within the group of
      primary reconstruction the best results could be achieved, since radical
      debridement and primary defect cover by healthy tissue (free flap) led to
      physiological wound healing. That caused reduced hospital stay thus decreased
      costs, since flap failure, infection and multiple secondary surgical
      interventions could be diminished. Also earlier rehabilitation and reintegration
      into social life and profession was achievable. CONCLUSION: Due to the obtained
      results a primary treatment of large and complex hand injuries through radical
      debridement and reconstruction with free flaps seems to be effective and should
      already be considered in the emergency room.

PMID- 10355346
TI  - [Management of pancreatic injuries].
AB  - This is a retrospective analysis of the treatment of 18 patients with pancreatic
      injuries at our institution. 13 were victims of blunt abdominal trauma. 17
      sustained a polytrauma and had an ISS > 15. They had 2.4 associated
      intraabdominal and 2.7 associated extraabdominal injuries. The mean pancreatic
      organ injury scale was II. A partial duodenopancreatectomy was performed in one
      case. In 5 cases a distal pancreatic resection was necessary. In the remaining
      patients drainage procedures were applied. 3 additional injured organs had to be
      treated during the first operation. 2 of them were situated intraabdominally. The
      primary operative procedure was performed in 13 cases during the first 6 hours
      after the trauma. 7 patients (39%) died during the hospitalisation. None deceased
      during an operation. 5 patients (28%) died because of abdominal complications. 4
      of 5 patients with injuries to the great vessels died. 12 had abdominal
      complications. The mean hospitalisation time was 49 days. The mean drainage time
      was 26 days. The patients sustained parenteral nutrition for 21 days. The
      priority in the primary operative approach is damage control. This consists of
      bleeding control, control of enteral spillage, assessment of pancreatic damage,
      especially recognition of any ductal injury and generous drainage of the injured
      pancreas. Definitive treatment in the severely injured patient has to be
      performed after hemodynamic stabilisation without delay by an experienced
      surgeon.

PMID- 10355347
TI  - [Clinical examination of accident victims].

PMID- 10355348
TI  - [Revocation of operating privileges is against the law! Bavarian Administrative
      Court decides in favor of the assistant medical director].

PMID- 10355349
TI  - [Os trigonum syndrome].
AB  - The os trigonum syndrome is an entity causing posterior ankle pain and occurs
      mostly with typical sports activities. Diagnosis and differential diagnosis are
      presented. Typical complaints and therapeutic procedure are demonstrated in one
      case. Therapy includes different non-operative methods, resistance to non
      operative procedures is an indication for excision of this ossicle.

PMID- 10355350
TI  - [Nosocomial infections with methicillin-resistant Staphylococcus aureus (MRSA)
      and epidermidis (MRSE) strains. Their importance, prophylaxis and therapy in
      orthopedic surgery].
AB  - MRSA/MRSE infections are a major problem in hospitals and although in orthopaedic
      units the incidence is low awareness of this problem is necessary. Once a MRSA
      strain has been isolated the strict use of the hygiene precautions has to be
      applied to avoid epidemic spread of the strain. The patient has to be isolated.
      The staff has to use gloves and gowns whilst treating the patient. A
      antimicrobiel hand wash solution has to be used after taking off the gloves and
      before leaving the isolation room. Patient and staff have to be informed about
      the pathogenicity and the way of infection spread so that infection precaution
      rules are fulfilled. Antibiotics should only be used in clinically well defined
      cases and the overall use of antibiotics should be reduced to lower the incidence
      of MRSA/E isolates. The problems of an MRSA case and its successful treatment are
      demonstrated.

PMID- 10355351
TI  - [Closed elbow dislocation with rupture of the brachial artery].
AB  - The case of a closed elbow dislocation with complete rupture of the brachial
      artery and its veins is described. This combination of injuries is rather rare
      and only 25 cases were found in the literature. The sharp lesion of the vessels
      was remarkable, probably due to the edge of the distally ruptured capsule.
      Immediate revision with suture of the vessels and an immobilization for three
      weeks gave a good result.

PMID- 10355352
TI  - [Laws governing irregular systems?].

PMID- 10355353
TI  - [The inherent tear resistance of the tendon of M. supraspinatus in humans. A
      biomechanical study. A response to a letter by E. Ludolph, Emergency surgery
      (1999) 102.77-78].

PMID- 10355354
TI  - Pertussis vaccines.

PMID- 10355355
TI  - Viral haemorrhagic fever/Marburg, Democratic Republic of the Congo.

PMID- 10355356
TI  - Child and adolescent health and development.

PMID- 10355357
TI  - New frontiers in the development of vaccines against enterotoxinogenic (ETEC) and
      enterohaemorrhagic (EHEC) E. coli infections. Part III.

PMID- 10355358
TI  - Enigmatic relationship of Pleckstrin homology domain with phospholipid breakdown
      mediated signal transduction.
AB  - Research into phospholipid signaling continues to flourish, as more and more
      bioactive lipids and proteins are being identified and their actions
      characterised. The Pleckstrin homology (PH) domain is one such newly recognized
      protein module thought to play an important role in intracellular signal
      transduction. The tertiary structures of several PH domains have been determined,
      some of them complexed with ligands and on the basis of structural similarities
      between PH domains and lipid binding proteins it has been suggested that PH
      domains may be binding to lipophilic molecules. In fact many of the proteins that
      contain this domain can interfere with the membrane association. This review
      examines the specificity of this binding and illustrates the importance of charge
      charge interactions in PIP2-PH domain complex formation. The precise
      physiological functions of PH domain in vivo remains to be explored therefore
      this review examines the biochemical aspects of the interaction of PH domains
      with phospholipid breakdown mediated products and proto-oncogenic serine
      threonine kinase (Akt), protein tyrosine kinases, which have been found to be a
      target of phospholipid second messengers. Thus, number of cellular processes
      mediated by this way, ranging from insulin signaling and protein synthesis to
      differentiation and cell survival are regulated by this intracellular signaling
      protein module.

PMID- 10355359
TI  - Recent trends in drug delivery systems: intranasal drug delivery.
AB  - Nasal route of drug delivery is commonly known for treatment of local ailments
      like-cold, cough, rhinitis etc. Recently, efforts have been made to deliver
      various drugs, specially peptides and proteins, through nasal route for systemic
      use; utilizing the principles and concepts of rate controlled drug delivery and
      various polymers and absorption promoters. Considering the large number of
      problems associated with oral, parenteral, rectal and other routes of drug
      administration and gradual increase in interest of pharmaceutical scientists
      towards exploring the possibilities of intranasal delivery of various drugs, this
      article aims at giving an insight into nasal cavity, consideration of factors
      affecting and strategies to improve drug absorption through nasal route,
      pharmaceutical dosage forms and delivery systems with examples of some peptides
      for intra nasal delivery, its advantages and limitations.

PMID- 10355360
TI  - Comparative effects of prenatal and postnatal undernutrition on learning and
      memory in rats.
AB  - Effects of pre- and post-natal undernutrition on learning and memory parameters
      were studied in albino rats. Prenatal undernutrition was induced in rat pups by
      restricting the mother's diet by 50% during the entire gestation period, whereas
      postnatal undernutrition was induced in rat pups by restriction of their diet by
      rotating them between lactating and non-lactating maternalised females for 12 hr
      each day during suckling period from 2nd day to 18th day after birth. At 2.5 to 3
      months of age all the rat offsprings were subjected to (i) original and reversal
      discrimination learning, (ii) passive avoidance, and (iii) active avoidance and
      its retention tests. The results indicate that both pre- and post-natal
      undernutrition in rat pups caused significant deficits in original and reversal
      discrimination learning, retention of passive avoidance after one week retention
      interval, and retention of active of avoidance learning. However, both pre- and
      post-natal undernutrition did not show significant effect on acquisition of
      active avoidance and retention of passive avoidance after 24 hr retention
      interval.

PMID- 10355361
TI  - Effect of "rasayanas" a herbal drug preparation on cell-mediated immune responses
      in tumour bearing mice.
AB  - Administration of herbal preparation, Rasayanas has been found to enhance the
      natural killer cell activity in normal as well asin tumour bearing animals.
      Brahma Rasayana (BR) was found to have the maximum activity. BRand Aswagandha
      Rasayana (AR) were found to activate antibody-dependent cellular cytotoxicity
      significantly. AR was also found to activate macrophages. All the Rasayanas were
      found to stimulate antibody dependent complement mediated tumour cell lysis. The
      results of these studies indicate usefullness of Rasayanas for immunostimulation
      in normal and in disease state.

PMID- 10355363
TI  - Hepatic pyridine nucleotides content in rat--a better indicator for determining
      available niacin values of food.
AB  - After 10 days depletion period with niacin free diet, weanling rats were repleted
      with either reference diets containing niacin at four levels (2, 4, 8 and 12
      mg/kg diet) or test diets containing test material at two levels as source of
      niacin. Gains in body weight and hepatic pyridine nucleotides content increased
      with increase in niacin intake. The correlation coefficient for hepatic pyridine
      nucleotides content and niacin intake was 0.98, whereas for weight gain and
      niacin intake was 0.89. Dried skim milk and pearl millet were taken as test
      materials. Dried skim milk with most of its niacin in free form showed 98% niacin
      equivalent to be bioavailable whereas in pearl millet niacin was in bound form
      and bioavailability equivalent was only 48 per cent.

PMID- 10355362
TI  - Effect of "rasayanas", a herbal drug preparation on immune responses and its
      significance in cancer treatment.
AB  - Rasayanas are considered to be immunostimulating preparations used extensively in
      indigenous medical practice. However there are only very few reports to
      substantiate this claim, and this paper gives preliminary evidence for the
      potentiation of immunity by Rasayanas given to mice orally. Administration of
      Rasayanas were found to enhance the proliferation of spleen cells significantly
      especially in the presence of mitogen. Similar result was also seen with bone
      marrow cells; however mitogenic stimulation could not be observed. Esterase
      activity was found to be enhanced in bone marrow cells indicating increased
      maturation of cells of lymphoid linkage. Rasayanas also enhanced humoral immune
      response as seen from the increased number of antibody forming cells and
      circulating antibody titre. These results indicate the usefulness of Rasayana as
      immunostimulating agent.

PMID- 10355364
TI  - Absence of in vivo mutagenic potency of heated and fried oils in mice.
AB  - The mutagenic potency of heated and fried oils (under laboratory conditions),
      viz. peanut, sesame and coconut oils were studied employing two well validated in
      vivo mammalian assays, viz. bone marrow micronucleus assay and the sperm
      morphology assay in albino mice. In the bone marrow micronucleus assay oral doses
      of fresh, heated and fried oils (7.5 ml and 30.0 ml/kg body weight) did not
      induce any increase in the incidence of micronucleated polychromatic
      erythrocytes. Intragastric administration of oils at the highest dose (30.0 ml/kg
      body weight/day) for 5 consecutive days in male mice did not produce any
      morphological effect either on the testicular or epididymal weights and
      histology. No significant alterations were observed in the caudal sperm counts at
      any of the sampling intervals and also there was no treatment related increase in
      the incidence of sperm head abnormalities. It is concluded that controlled
      thermal treatment as well frying of these oils did not produce appreciable amount
      of mutagens which could be detected under in vivo situations.

PMID- 10355365
TI  - Human spermatozoal motility and lipid peroxidation.
AB  - Correlation between human spermatozoal motility and lipid peroxidation is worked
      out following their suspension in native seminal plasma and in Biggers, Whitten
      and Whittengham (BWW) medium. Spermatozoa suspended in BWW showed higher motility
      and lesser degree of lipid peroxidation than those suspended in seminal plasma.
      Further, higher activities of antioxidant enzymes are recorded in the BWW
      suspended spermatozoa vis a vis those suspended in native seminal plasma.

PMID- 10355366
TI  - Effect of ciprofloxacin on steady state pharmacokinetics of phenytoin in rabbits.
AB  - Present study was undertaken to determine if an interaction exists during co
      administration of ciprofloxacin with phenytoin. Eight healthy male rabbits
      received oral phenytoin, 40 mg/kg, od, for 7 days. On day 7, phenytoin blood
      sampling was done at times 0, 0.1, 1, 2, 3, 4, 5, 6, 8 and 24 hr. From day 8 to
      14, phenytoin was co-administered with oral ciprofloxacin, 70 mg/kg, od. On day
      14, blood samples were collected as previously described. Pharmacokinetic
      analysis revealed significant decrease in steady state maximum concentration
      (Cmax), through concentration (Cmin), elimination half life (t 1/2 e) and the
      area under plasma time concentration curve (AUC0-24) of phenytoin when co
      administered with ciprofloxacin. It warrants close monitoring of levels when
      these two agents are given simultaneously.

PMID- 10355367
TI  - Gallotannin hydrolysis by immobilized fungal mycelia in a packed bed bioreactor.
AB  - Hydrolysis of gallotannin to gallic acid by immobilized mycelia of Aspergillus
      niger MTCC 282, Aspergillus fischerii MTCC 150, Fusarium solani MTCC 350 and
      Trichoderma viride MTCC 167 in a packed bed bioreactor was studied. Fungal
      mycelia preinduced with 5 g L-1 gallotannin were immobilized in calcium alginate
      gel (1.5%) and the resultant beads were packed in a column to a bed volume of 175
      mm3. Gallotannin dissolved in distilled water was passed through the column and
      the eluate was recycled after adjusting pH to 6 with ammonium hydroxide (10%).
      Maximum hydrolysis of gallotannin was recorded by immobilized mycelia of F.
      solani and T. viride at 35 degrees and 45 degrees C after 175 and 60 min of
      residency period respectively. Optimum substrate concentration required for
      maximum hydrolysis was 10 g L-1 at pH 5 for both the fungi. Immobilized mycelia
      of A. niger and A. fischerii revealed maximum operational stability. Loss of
      activity after eighth run was in the order of-A. niger (no loss), A. fischerii
      (7.5%), F. solani (18%) and T. viride (18%). Stability in terms of retention of
      enzyme activity after 150 days of storage at 4 degrees C was A. niger (58%), A.
      fischerii (26.8%), F. solani (83%) and T. viride (85.1%).

PMID- 10355368
TI  - Subgroup-A Rous sarcoma virus-induced growth stimulation of chick embryos
      infected via the chorioallantoic membrane.
AB  - Chicks that hatch from eggs containing group specific antigen (gs antigen) of
      lymphoid leukosis virus (LLV) subgroups, grow poorly. In our laboratory for more
      precise identification of LLV-of subgroup A (LLV-A) resistant and susceptible
      genotypes by progeny testing, the chorioallantoic membrane (CAM) assay in
      complemented by liver tumour (LT) assay, wherein Rous sarcoma virus (RSV) of
      subgroup A (homologous to LLV-A) was used. The present study was conducted in a
      light breed (White Leghorn) and also in a heavy breed (Rhode Island Red) to
      ascertain the effect of infection on embryonic growth by RSV subgroup A. Mean
      relative body weight (rbw) of infected LT negative chicks of either breed
      exceeded the control highly significantly (P < 0.01) by 2%. However, neither the
      dose of virus inoculated per embryo, nor egg size influenced the relative body
      weight of day old chicks (P > 0.05). No difference in relative body weight of LT
      positive and control chicks was observed.

PMID- 10355369
TI  - Response to wing-web challenge of Rous sarcoma virus subgroups in some chicken
      breeds.
AB  - Response to wing-web challenge (WWC) of Rous sarcoma virus (RSV) subgroups was
      studied in 4-8 weeks old chicks of a light breed, a heavy breed and a cross
      between an indigenous black plumage Bantam fowl and Australorp breed. Wing-web
      tumor (WWT) began to develop within one week in response to virus subgroups A (BS
      RSV) and C [RSV (RAV-49)] challenge. In chicks challenged with subgroup D [RSV
      (RAV-50)] virus it took a minimum of 4 weeks for development of WWT. Positive
      response to WWC by subgroups A, C and D virus was 84%, 100% and 52%,
      respectively. The duration of exhibition of positive response was maximum for
      subgroup A virus, followed by subgroup D and minimum for subgroup C virus.

PMID- 10355370
TI  - Generosity: a psychological and interpersonal motivational factor of therapeutic
      relevance.
AB  - This paper examines the role of generosity in analysis. Generosity represents a
      complex constellation of cognitions and affects that is antithetical to those
      states of super-ego harshness that characterize many forms of human
      psychopathology. In development, generosity is evoked by idealization, and a
      dynamic axis of idealization-generosity promotes relational proximity between the
      child and its caretakers, and eventually fosters separation and individuation.
      Generosity is highly sensitive to adverse conditions, and requires environmental
      conditions that are conducive to psychosomatic well-being. The imaginal basis of
      generosity is rooted in the myth of the 'hero and the return', which is the
      mythic foundation of the analyst's role as psychopomp. It is argued that the
      generosity of the analyst is a cardinal therapeutic factor in treatment.

PMID- 10355371
TI  - The Embryonics Project: a machine made of artificial cells.
AB  - It is possible to trace the origins of biological inspiration in the design of
      electronic circuits to the very dawn of the field of computer engineering, with
      the work of John von Neumann in the 1940s. To his brilliance we owe not only the
      first methodical attempts to define the electronic equivalents of many
      fundamental biological process, but also the development of the first self
      replicating computing machines. Unfortunately, the electronic technology of the
      time would not allow a physical realization of von Neumann's machines, and it was
      not until the introduction of new programmable circuits in the 1980s that the
      field of bio-inspired machines gained new momentum. In this article, we describe
      the Embryonics (embryonic electronics) Project, an attempt to draw inspiration
      from the ontogenetic processes that determine the growth of multicellular
      organisms in the design of new, massively parallel arrays of processors (the
      artificial cells). Our cells are simple processors, all based on an identical
      hardware structure and all containing the same program (our artificial genome),
      but executing different parts of the genome depending on their spatial
      coordinates within the array. As in living beings, the presence of the genome in
      every cell allows the introduction of features such as self-replication and self
      repair (cicatrization). In addition, the cells are implemented using an array of
      programmable elements (the artificial molecules), which allows their structure to
      be adapted to a given application. Through the parallel operation of many of
      these simple processors, we hope to realize highly complex systems, the
      equivalent of multicellular organisms in the natural world.

PMID- 10355372
TI  - Confounding by indication: an example of variation in the use of epidemiologic
      terminology.
AB  - Confounding by indication is a term used when a variable is a risk factor for a
      disease among nonexposed persons and is associated with the exposure of interest
      in the population from which the cases derive, without being an intermediate step
      in the causal pathway between the exposure and the disease. However, in the
      literature, the term confounding by indication is not always used consistently.
      The authors found three different situations in which the term has been applied
      or might have been used but was not: confounding by indication as protopathic
      bias, as confounding by severity, or as a form of selection bias. It might be
      helpful to limit use of the term confounding by indication to the situation in
      which the disease that forms the indication acts as a confounder irrespective of
      its severity and to apply the term confounding by severity if the severity of
      this disease acts as a confounder. Protopathic bias and selection bias should not
      be confused with these terms. The use of appropriate terms ultimately will
      improve communication among researchers and contribute to the clarity of their
      papers.

PMID- 10355373
TI  - Logistic regression analysis for more than one characteristic of exposure.
AB  - When more than one characteristic of an exposure is under study, it is easy to
      misinterpret the results of a logistic regression analysis that incorporates
      terms for each characteristic. For example, in a study of the risk of endometrial
      cancer in relation to the duration and the recency of use of estrogen replacement
      therapy (ERT), simultaneously including terms for duration and recency of
      exposure to ERT in a logistic model may leave the mistaken impression that it is
      possible to adjust for recency when a given duration of ERT use is compared with
      no use. In this article, the authors show why such an adjusted comparison is
      impossible, and they discuss several pitfalls in the interpretation of logistic
      regression coefficients when two or more characteristics of exposure are under
      study. They also suggest a method for avoiding these pitfalls.

PMID- 10355374
TI  - Alcohol intake, beverage preference, and risk of hip fracture in men and women.
      Copenhagen Centre for Prospective Population Studies.
AB  - The authors prospectively studied the association between quantity and type of
      alcohol intake and risk of hip fracture among 17,868 men and 13,917 women.
      Analyses were based on pooled data from three population studies conducted in
      1964-1992 in Copenhagen, Denmark. During follow-up, 500 first hip fractures were
      identified in women and 307 in men. A low to moderate weekly alcohol intake (1-27
      drinks for men and 1-13 drinks for women) was not associated with hip fracture.
      Among men, the relative risk of hip fracture gradually increased for those who
      drank 28 drinks or more per week (relative risk (RR) = 1.75, 95% confidence
      interval (CI) 1.06-2.89 for 28-41 drinks; RR = 5.28, 95% CI 2.60-10.70 for 70 or
      more drinks) as compared with abstainers. Women who drank 14-27 drinks per week
      had an age-adjusted relative risk of hip fracture of 1.44 (95% CI 1.03-2.03), but
      the association weakened after adjustment for confounders (RR = 1.32, 95% CI 0.92
      1.87). The risk of hip fracture differed according to the type of alcohol
      preferred: preferrers of beer had a higher risk of hip fracture (RR = 1.46, 95%
      CI 1.11-1.91) than preferrers of other types of alcoholic beverages. The
      corresponding relative risks for preferrers of wine and spirits were 0.77 (95% CI
      0.58-1.03) and 0.82 (95% CI 0.58-1.14), respectively. In conclusion, an alcohol
      intake within the current European drinking limits does not influence the risk of
      hip fracture, whereas an alcohol intake of more than 27 drinks per week is a
      major risk factor for men.

PMID- 10355375
TI  - Association of race and other potential risk factors with nonvertebral fractures
      in community-dwelling elderly women.
AB  - This study determined potential associations of sociodemographic, lifestyle,
      health, and drug use factors known to affect bone metabolism with incident
      nonvertebral fractures. The baseline sample consisted of 2,590 female, nonproxy
      subjects from the Duke Established Populations for Epidemiologic Studies of the
      Elderly, which focuses on five adjacent counties in the Piedmont area of North
      Carolina. Information about potential risk factors was collected during a
      baseline in-home interview during 1986-1987. Subsequent nonvertebral fractures
      were reported at follow-up interviews during the annual follow-up periods (1988
      1993). The authors used multivariate analyses in which weighted data were
      adjusted for sampling design. After controlling for other potential confounding
      sociodemographic, lifestyle, health, and drug use factors, they found that
      African American race (adjusted odds ratio (OR) = 0.43, 95% confidence interval
      (CI) 0.31-0.58), age (adjusted OR = 1.04, 95% CI 1.01-1.06), alcohol consumption
      (adjusted OR = 1.61, 95% CI 1.01-2.57), being underweight (adjusted OR = 1.63,
      95% CI 1.13-2.34), cognitive impairment (adjusted OR = 1.67, 95% CI 1.12-2.48),
      impaired mobility (adjusted OR = 1.15, 95% CI 1.03-1.29), and phenytoin use
      (adjusted OR = 2.93, 95% CI 1.04-8.30) were associated with first fracture
      occurrence. Similar findings were observed for nonhip, nonvertebral fractures.
      African Americans were less likely than Whites to have nonvertebral fractures,
      and these differences were not related to lifestyle or health factors examined in
      this study.

PMID- 10355376
TI  - Primary liver cancer, other malignancies, and mortality risks following
      porphyria: a cohort study in Denmark and Sweden.
AB  - Cancer incidence and mortality risks were evaluated in a combined cohort of
      patients who were hospitalized for porphyria in Denmark (1977-1989) and Sweden
      (1965-1983). Patients were identified by using population-based hospitalization
      registries. The unique individual identification numbers of 530 patients with
      porphyria cutanea tarda (PCT) and 296 with acute intermittent porphyria (AIP)
      were linked to the nationwide cancer and death registries. Among patients with
      both types of porphyria, the authors found small but significantly elevated risks
      of all cancers combined (PCT: standardized incidence ratio (SIR) = 1.7, 95%
      confidence interval (CI) 1.3-2.2; AIP: SIR = 1.8, 95% CI 1.1-2.8) due to
      pronounced excesses of primary liver cancer (PCT: SIR = 21.2, 95% CI 8.5-43.7;
      AIP: SIR = 70.4, 95% CI 22.7-164.3) and moderate increases in lung cancer (PCT:
      SIR = 2.9, 95% CI 1.5-5.2; AIP: SIR = 2.8, 95% CI 0.3-10.2). PCT patients had a
      significantly increased risk of mortality from liver cirrhosis (standardized
      mortality ratio (SMR) = 8.4, 95% CI 3.1-18.4) or chronic obstructive pulmonary
      disease (SMR = 3.1, 95% CI 1.1-6.7). The increased risk of primary liver cancer
      and the increased risk of mortality from cirrhosis of the liver are consistent
      with findings from previous clinical surveys, but the new observations of excess
      lung cancer and chronic obstructive pulmonary disease require confirmation.

PMID- 10355377
TI  - Estimating the prevalence of multiple sclerosis in the United Kingdom by using
      capture-recapture methodology.
AB  - The geographic distribution of multiple sclerosis is nonrandom, as the disease is
      more prevalent in temperate than in tropical regions. Surveys conducted between
      1970 and 1996 suggest that multiple sclerosis is more prevalent in the northern
      part of the United Kingdom than in the southern part. This north-south gradient
      ("the latitudinal gradient") might be a methodological artifact, because high
      prevalence figures from serial surveys of the northern part of the United Kingdom
      might have been the result of better ascertainment. By using capture-recapture
      methods, the authors found that case ascertainment was similar in the northern
      and southern parts of the United Kingdom. When prevalence figures for multiple
      sclerosis in the southern United Kingdom were increased to account for the number
      of unobserved cases, the difference persisted: The prevalence of multiple
      sclerosis in the northern part of the United Kingdom appeared to be at least 180
      cases per 100,000 persons, whereas the maximum prevalence in the southern part of
      the United Kingdom was less than 160 cases per 100,000 persons. The distribution
      of multiple sclerosis in the United Kingdom is not uniform and is consistent with
      the hypothesis that populations with a high prevalence of multiple sclerosis may
      be genetically predisposed to the disease.

PMID- 10355378
TI  - Estimates of the annual number of clinically recognized pregnancies in the United
      States, 1981-1991.
AB  - The authors estimated the number of clinically recognized pregnancies that
      occurred annually from 1981 to 1991 in the United States by type of outcome and
      by race. Estimates of the numbers of livebirths, induced abortions, ectopic
      pregnancies, and fetal deaths were obtained by using data from the Centers for
      Disease Control and Prevention in Atlanta, Georgia. The number of spontaneous
      abortions was estimated by using previously published, age-specific rates. More
      than 67 million pregnancies occurred during the study period. Overall, 62.5% of
      these pregnancies resulted in livebirths, 21.9% in legal induced abortions, 13.8%
      in spontaneous abortions, 1.3% in ectopic pregnancies, and 0.5% in fetal deaths.
      These data can be used to provide denominators for the calculation of a variety
      of pregnancy outcome-specific rates.

PMID- 10355379
TI  - Influence of parental smoking on respiratory symptoms during the first decade of
      life: the Tucson Children's Respiratory Study.
AB  - Compelling evidence suggests a causal relation between exposure to parental
      cigarette smoking and respiratory symptoms during childhood. Still, the roles of
      prenatal versus postnatal parental smoking need clarification. In this study, the
      authors assessed the effects of passive smoking on respiratory symptoms in a
      cohort of over 1,000 children born during 1980-1984. The children were enrolled
      in the Tucson Children's Respiratory Study in Tucson, Arizona, and were followed
      from birth to age 11 years. The population was generally middle class and
      consisted of two main ethnic groups, non-Hispanic Whites (75%) and Hispanics
      (20%), reflecting Tucson's population. Information on parental smoking and on
      wheeze and cough in their children was elicited from parents by using
      questionnaires at five different surveys. Data were analyzed both cross
      sectionally and by using the generalized estimation equation approach, a
      longitudinal mixed-effects model. The best-fitting model indicated that maternal
      prenatal but not postnatal smoking was associated with current wheeze (odds ratio
      = 2.3, 95% confidence interval 1.4-3.8) independently of a family history of
      asthma, socioeconomic factors, and birth weight. This effect was time dependent
      and significant only below age 3 years; although independent of gender, the
      association was stronger for girls (odds ratio = 3.6, 95% confidence interval 1.6
      8.0). Cough was not associated with parental smoking during the first decade of
      life. This transitory effect of maternal prenatal smoking on wheezing could be
      due to changes that affect the early stages of lung development.

PMID- 10355380
TI  - Serum dioxin and immunologic response in veterans of Operation Ranch Hand.
AB  - The authors studied immune response and exposure to 2,3,7,8-tetrachlorodibenzo-p
      dioxin (dioxin) among veterans of Operation Ranch Hand, the US Air Force unit
      responsible for the aerial spraying of herbicides in Vietnam from 1962 to 1971. A
      comparison group of Air Force veterans who served in Southeast Asia but were not
      involved in spraying herbicides was included. The authors studied delayed-type
      hypersensitivity skin test responses to Candida albicans, mumps, Trichophyton,
      and a bacterial antigen made from lysed Staphylococcus aureus. Lymphocyte
      measurements included total lymphocyte counts; T-cell (CD3, CD4, CD5, and CD8), B
      cell (CD20), and NK-cell (CD16 and CD56) subsets; and expression of the
      activation antigen CD25 on CD3 T cells. The authors quantitated the serum
      concentrations of immunoglobulin (Ig)A, IgG, and IgM; examined sera for the
      presence of monoclonal immunoglobulins (M proteins); and looked for a broad range
      of autoantibodies (rheumatoid factor, antinuclear antibody, smooth muscle
      autoantibody, mitochondrial autoantibody, parietal cell autoantibody, and thyroid
      microsomal autoantibodies). They measured the level of dioxin in 1987 or 1992,
      extrapolated the result to the time of service in Vietnam, and assigned each
      veteran to one of four exposure categories: Comparison and three Ranch Hand
      groups (Background, Low, or High). Overall, the authors found no evidence of a
      consistent relation between dioxin exposure category and immune system
      alteration.

PMID- 10355381
TI  - Diabetes and hypertension in Mexican American families: relation to
      cardiovascular risk.
AB  - There is a strong familial predisposition to type 2 diabetes, hypertension, and
      cardiovascular disease. The authors evaluated the association between a family
      history of these diseases and a large panel of cardiovascular risk factors in
      1,431 Mexican American subjects who were enrolled in the San Antonio Family Heart
      Study in San Antonio, Texas. The baseline phase of the study covered 1992-1996.
      Diabetes and hypertension were diagnosed according to standard clinical criteria,
      while cardiovascular disease was defined as a history of heart attack or heart
      surgery. The prevalence of diabetes, hypertension, and cardiovascular disease in
      this population was 15%, 12%, and 3%, respectively. For each unaffected subject,
      the authors computed a family history score based on the presence or absence of
      disease in parents and older siblings, and correlations between cardiovascular
      risk factors and family history scores were estimated by using likelihood-based
      variance component methods. Diabetes family history score was significantly
      correlated with a broad panel of cardiovascular risk factors, including glucose
      and insulin, obesity, blood pressure, triglycerides, and total cholesterol.
      Hypertension family history score was significantly correlated with glucose,
      blood pressure, body mass index, waist circumference, total cholesterol, and
      triglycerides. These results support the idea that genes that confer a risk for
      diabetes, and to a lesser extent hypertension, adversely alter the cardiovascular
      risk profile long before the manifestation of clinical disease.

PMID- 10355382
TI  - Increasing response rates for mailed surveys of Medicaid clients and other low
      income populations.
AB  - Mailing surveys to low-income populations is often avoided because of concern
      about low response rates. In this study, the authors used a mailed survey of a
      low-income population to test whether $1.00 or $2.00 cash-response incentives
      were worth the expense and whether 2-day priority mail ($2.90 postage) would
      yield a sufficiently higher response rate than certified mail ($1.52 postage) to
      justify its cost. In 1994, 2,243 randomly selected families in subsidized health
      care programs in Pierce County, Washington, were randomly sent no incentive,
      $1.00, or $2.00 in the first of three mailings. For the third mailing,
      nonrespondents were randomly assigned to receive either certified or 2-day
      priority mail. After 4 weeks, the response rates were 36.7%, 48.1%, and 50.3% for
      the no-incentive, $1.00, and $2.00 groups, respectively. After three mailings,
      the cost per response was the lowest for the group that received $1.00. The
      response rate for the certified mailing (28.1%) was significantly higher than the
      rate for the more expensive priority mailing (21.7%). No incentive-related bias
      was detected. The authors concluded that the most efficient protocol for this low
      income population was to use a $1.00 incentive in the first mailing and a
      certified third mailing.

PMID- 10355383
TI  - Comparison of methods for classifying Hispanic ethnicity in a population-based
      cancer registry.
AB  - The accuracy of ethnic classification can substantially affect ethnic-specific
      cancer statistics. In the Greater Bay Area Cancer Registry, which is part of the
      Surveillance, Epidemiology, and End Results (SEER) Program and of the statewide
      California Cancer Registry, Hispanic ethnicity is determined by medical record
      review and by matching to surname lists. This study compared these classification
      methods with self-report. Ethnic self-identification was obtained by surveying
      1,154 area residents aged 20-89 years who were diagnosed with cancer in 1990 and
      were reported to the registry as being Hispanic or White non-Hispanic. Predictive
      value positive, sensitivity, and relative bias were used to assess the accuracy
      of Hispanic classification by medical record and surname. Among those persons
      classified as Hispanic by either or both of these sources, only two-thirds agreed
      (predictive value positive = 66%), and many self-identified Hispanics were
      classified incorrectly (sensitivity = 68%). Classification based on either
      medical record or surname alone had a lower sensitivity (59% and 61%,
      respectively) but a higher predictive value positive (77% and 70%, respectively).
      Ethnic classification by medical record alone resulted in an underestimate of
      Hispanic cancer cases and incidence rates. Bias was reduced when medical records
      and surnames were used together to classify cancer cases as Hispanic.

PMID- 10355384
TI  - Re: "The legacy of epidemiology in the Department of Social and Preventive
      Medicine: a commemoration of the sesquicentennial of the State University of New
      York at Buffalo School of Medicine and Biomedical Sciences," "Current problems
      that are likely to affect the future of epidemiology," and "Toward an integrated
      approach to molecular epidemiology".

PMID- 10355385
TI  - Re: "Sex differences in risk factors for clinical diabetes mellitus in a general
      population: a 12-year follow-up of the Finnmark study".

PMID- 10355386
TI  - Re: "Eating patterns and risk of colon cancer".

PMID- 10355387
TI  - Ralph D. Alley lecture. Medical leadership and the future of health care.

PMID- 10355389
TI  - Clinical experience with 111 thoratec ventricular assist devices.
AB  - BACKGROUND: Ventricular assist devices (VADs) have gained wider acceptance due to
      refinements in patient selection and management and device availability. METHODS:
      To evaluate early and late results, we reviewed our first 111 patients with the
      Thoratec VAD. RESULTS: Forty-four patients were supported for myocardial
      recovery. The mean age in the recovery group was 51.9 years. There were 18 left
      VADs (LVADs), 17 biventricular VADs (BVADs), and nine right VADs (RVADs).
      Complications included bleeding in 20 patients (45%) and device-related infection
      in 1 patient (2%). Nineteen were weaned from the VAD, with 12 survivors. Sixty
      seven patients were supported as a bridge to cardiac transplantation. The mean
      age was 41.5 years. There were 39 LVADs and 28 BVADs. Complications included
      bleeding in 21 patients (31%) and device-related infection in 12 (18%). Three
      patients were weaned and 39 patients were transplanted from the assist device,
      for a total of 42 bridge survivors. Device-related thromboembolism occurred in 9
      patients (8.1%), 7 of whom were bridge to transplantation. The duration of VAD
      support ranged from 0.1 to 27 days (mean 4.5 days) in the recovery group and 0.2
      to 184 days (mean 40.7 days) in the bridge to transplantation group. The 10-year
      actuarial survival was 16% for the recovery group, 22%, for the bridge group, and
      33% for transplanted patients. CONCLUSIONS: Despite advances, VAD support remains
      associated with significant morbidity and operative mortality.

PMID- 10355388
TI  - The NFkappaB inhibitory peptide, IkappaBalpha, prevents human vascular smooth
      muscle proliferation.
AB  - BACKGROUND: Vessel injury results in an inflammatory response characterized by
      the elaboration of cytokines and growth factors, which ultimately influence
      vascular smooth muscle cell (VSMC) growth and contribute to atherogenesis.
      Nuclear factor-kappa B (NFkappaB) is a central transcription factor important in
      mediating stress and inflammatory-induced signals. We hypothesized that
      strategies aimed at inhibiting NFkappaB would abrogate mitogen-induced human VSMC
      proliferation. METHODS: Human aortic VSMC were stimulated with basic fibroblast
      growth factor (FGF) and tumor necrosis factor-alpha (TNF), and proliferation was
      quantified by a colormetric assay. The influence of NFkappaB on VSMC
      proliferation was examined by both nonspecific NFkappaB blockade with calpain
      inhibitor-1 (CI-1) and dexamethasone (Dex) and specific NFkappaB blockade with
      liposomal delivery of the NFkappaB inhibitory peptide, IkappaBalpha. RESULTS: FGF
      and TNF induced concentration-dependent VSMC proliferation (p < 0.002). Neither
      CI-1, Dex, nor liposomal IkappaBalpha influenced proliferation of unstimulated
      VSMC. However, both FGF- and TNF-stimulated VSMC proliferation was inhibited to
      the level of control with CI-1, Dex, and liposomal IkappaBalpha (p < 0.001).
      CONCLUSION: The mitogenic effect of FGF and TNF on human arterial VSMC may be
      prevented by inhibiting NFkappaB. Furthermore, liposomal delivery of endogenous
      inhibitory proteins such as IkappaBalpha may represent a novel, therapeutically
      accessible method for selective transcriptional suppression in the response to
      vascular injury.

PMID- 10355390
TI  - Coronary artery bypass grafting with an expanded polytetrafluoroethylene graft.
AB  - BACKGROUND: We report our experience with the Perma-Flow aortocoronary-right
      heart graft in 15 patients in whom autologous conduits were not available.
      METHODS: Fifteen patients received 39 coronary anastomoses--10 to left anterior
      descending coronary artery branches, 15 to circumflex coronary artery branches,
      and 14 to branches of the right coronary artery. Early angiography was done in 11
      patients. RESULTS: One patient died on postoperative day 17 of multiorgan
      failure. The graft was patent at postmortem examination. Of 30 coronary
      anastomoses at risk, 24 were patent. Three connections to the left anterior
      descending system were occluded in patients with an additional internal mammary
      artery graft to the same coronary system, and three connections to the circumflex
      system were occluded in patients with a history of major posterior infarction.
      Three of five distal anastomoses to the right atrial appendage were occluded,
      whereas all six connections to the superior vena cava were patent. None of the
      patients had shown recurrent angina at a mean follow-up of 10.9 months (range, 2
      39 months). CONCLUSIONS: The synthetic Perma-Flow coronary graft appears to be a
      safe alternative in patients in whom arterial or venous conduits are not
      available. Competitive flow may lead to anastomotic occlusions. The appropriate
      site for the distal arteriovenous fistula seems to be the superior vena cava.

PMID- 10355391
TI  - Individualized surgical strategy for the reduction of stroke risk in patients
      undergoing coronary artery bypass grafting.
AB  - BACKGROUND: This study was designed to evaluate the efficacy of a protocol of
      systematic screening of the ascending aorta and internal carotid arteries and
      individualization of the surgical strategy to the ascending aorta and internal
      carotid arteries status in reducing the stroke incidence among patients
      undergoing coronary artery bypass grafting. METHODS: On the basis of a pre- and
      intraoperative screening of the ascending aorta and internal carotid arteries,
      2,326 consecutive patients undergoing coronary artery bypass grafting were
      divided in low, moderate, and high neurologic risk groups. In the high-risk group
      dedicated surgical techniques were always adopted and the reduction of the
      neurologic risk was considered more important than the achievement of total
      revascularization. RESULTS: The incidence of perioperative stroke in the high
      risk group was similar to those of the other two groups (1.1 versus 1.3 and 1.1%,
      respectively; p = not significant); however, angina recurrence was significantly
      more frequent in the high-risk group. CONCLUSIONS: The described strategy allows
      a low rate of perioperative stroke in high-risk patients undergoing coronary
      artery bypass grafting. Whether the reduction of the neurologic risk outweighs
      the benefits of complete revascularization remains to be determined.

PMID- 10355392
TI  - Endothelium-derived nitric oxide enhances the effect of intraaortic balloon
      pumping on diastolic coronary flow.
AB  - BACKGROUND: High shear rate with pulsation is one of the major stimuli for the
      release of endothelium-derived nitric oxide leading to coronary arteriolar
      dilation. Intraaortic balloon pumping mechanically enhances shear rate and
      diastolic-to-systolic flow oscillation. We aimed to evaluate whether or not
      coronary blood flow augmentation during intraaortic balloon pumping is mediated
      by coronary arteriolar dilation through endothelium-derived nitric oxide release.
      METHODS: Using a charge-coupled device intravital videomicroscope, we observed
      epicardial coronary arterioles (40 to 220 microm in diameter) in anesthetized
      open-chest dogs (n = 10) during 2:1 mode of intraaortic balloon pumping.
      Endothelium-derived nitric oxide-mediated vasodilatory effects of intraaortic
      balloon pumping were evaluated by comparing end-diastolic arteriolar diameters
      between the coupled beats of on and off intraaortic balloon pumping before and
      after intracoronary endothelium-derived nitric oxide synthesis inhibition with
      Nomega-nitro-L-arginine (L-NNA, 2 micromol/min) administration. RESULTS:
      Intraaortic balloon pumping increased coronary arteriolar diameters and coronary
      blood flow by 11.4%+/-1.8% (p < 0.0001) and 33.4%+/-4.1% (p < 0.001),
      respectively. Vasodilation was greater in small arterioles (<110 microm; 15.4%+/
      2.2%) than in large arterioles (> or =110 microm; 4.2%+/-1.2%, p < 0.0001). L-NNA
      attenuated the intraaortic balloon pumping-induced vasodilation and augmentation
      of coronary blood flow to 4.6%+/-1.0% (p < 0.001) and to 20.8%+/-2.1%, (p <
      0.05), respectively. Attenuation of vasodilatory effect by L-NNA was observed
      mainly in small arterioles (from 15.4%+/-2.2% to 5.9%+/-1.2%). CONCLUSIONS:
      Intraaortic balloon pumping augmented coronary blood flow by dilating coronary
      arterioles in diastole, more significantly in small arterioles than in large
      arterioles. Endothelium-derived nitric oxide inhibition markedly attenuated these
      effects. We conclude that, in a canine model, endothelium-derived nitric oxide
      contributes to mechanical enhancement of the coronary blood flow with diastolic
      arteriolar vasodilation during intraaortic balloon pumping.

PMID- 10355393
TI  - Quality of life in survivors of thoracic aortic surgery.
AB  - BACKGROUND: The results of surgical repair of thoracic aortic lesions are
      improving. Still, mortality and morbidity are considerable. Outcomes need to be
      studied in greater detail. We studied quality of life in survivors of thoracic
      aortic surgery, which has not been reported before. METHODS: During a 5-year
      period, 115 patients underwent thoracic aortic repair. All mid- to long-term
      survivors (n = 81; median follow-up time, 26 months) received the Short Form-36
      (SF-36) health questionnaire plus specific questions related to surgery. Five
      patients were lost to follow-up. RESULTS: Scores for the eight dimensions of SF
      36 (range, 0 to 100, 100 reflecting best function) were compared with a normal
      population. The mean deficits from the norm were bodily pain, 0.1 (95% confidence
      interval, -3.4 to 3.6) points below norm; mental health, 8.3 (5.7 to 10.9);
      vitality, 9.5 (6.7 to 12.3); social functioning, 10.1 (6.9 to 13.3); general
      health, 11.1 (8.5 to 13.7); physical functioning, 16.6 (13.4 to 19.8); role
      emotional, 20.6 (15.3 to 25.9); and role physical, 30.2 (24.7 to 35.7). Subgroup
      scores for acute versus elective cases, ascendens versus arch versus descendens
      procedures, and major complication versus no major complication were not
      significantly different. Sixty-six percent (50 of 76) stated a general health
      perception improvement. In 82% (62 of 76), the quality of life improved or was
      preserved. Ninety-one percent (69 of 76) considered the operation successful.
      CONCLUSIONS: Considering the seriousness of the conditions, quality-of-life
      scores after thoracic aortic surgery were acceptable, although lower than in a
      normal population, except for bodily pain. Postoperative quality of life
      justifies thoracic aortic surgical repair.

PMID- 10355394
TI  - A prospective randomized trial of Duraflo II heparin-coated circuits in cardiac
      reoperations.
AB  - BACKGROUND: Heparin-coated circuits in cardiopulmonary bypass have been shown to
      decrease the systemic inflammatory responses associated with cardiopulmonary
      bypass. Previous clinical studies on low-risk patients who had coronary artery
      bypass grafting (CABG) and received full-dose systemic heparin did not have
      clearly improved clinical outcomes. We hypothesized that the beneficial effects
      of heparin-coated circuits might be seen in patients who had cardiac
      reoperations. METHODS: Three hundred fifty patients who had reoperation with CABG
      only (58%), or with valve operations (42%) were randomly assigned to receive
      either a heparin-coated (Duraflo II; study group) or uncoated (control group)
      circuit. Clinical outcomes were compared and the variables were analyzed using
      the following three groups: entire populations of study group and control group,
      subgroup of patients who had CABG reoperation only, and a subgroup who had valve
      reoperation or combined valve and CABG reoperation. RESULTS: Preoperative
      variables were the same in both groups. No difference in clinical outcomes could
      be demonstrated except that the percentage of patients with major bleeding
      episodes was significantly lower in the study group (1.2% versus 5.4%, p =
      0.035). In the subgroup analysis of patients who had valve reoperations, lower
      blood transfusion requirements in the intensive care unit (p = 0.013) were found
      in the study group. When the subgroup of patients who had CABG reoperations was
      analyzed separately, there was a trend toward less reoperation for bleeding in
      the study group (0% versus 4.0%, p = 0.058). CONCLUSIONS: We conclude that the
      use of heparin-coated circuits was safe and imparted protection from reoperations
      for bleeding and major bleeding episodes. Material-independent blood activation
      (eg, blood-air interface and cardiotomy suction) blunted the total effect of the
      heparin-coated surface.

PMID- 10355395
TI  - Blunt cardiac rupture: the utility of emergency department ultrasound.
AB  - BACKGROUND: Rupture of the heart is usually a fatal injury in patients sustaining
      blunt trauma. Those arriving in the emergency department alive can be saved with
      prompt diagnosis and treatment. METHODS: We describe the cases of 4 consecutive
      patients with rupture of the free cardiac wall whom we treated at Grady Hospital.
      Two had a tear of the right ventricle, 1 had a tear of the right atrium, and 1
      had two tears of the left atrium. All patients were involved in motor vehicle
      accidents. The diagnosis was made by ultrasound in 3 patients and during
      exploratory surgical intervention in the other. All tears were repaired primarily
      without the aid of cardiopulmonary bypass. RESULTS: Three of the patients
      survived, and 1 died. CONCLUSIONS: Rarely are patients with rupture of the free
      cardiac wall seen in an emergency department. The improvements in the prehospital
      care and the transportation may result in an increase in the numbers of such
      patients. Physicians treating patients with blunt trauma must suspect the
      presence of cardiac rupture. Immediate use of ultrasonography will establish the
      diagnosis and prompt repair of the injury may improve overall survival.

PMID- 10355396
TI  - Inhibition by dipyridamole of neutrophil adhesion to vascular endothelium during
      coronary bypass surgery.
AB  - BACKGROUND: Release of reactive oxygen radicals by activated neutrophils and
      neutrophil adhesion to endothelial cells have been observed after cardiopulmonary
      bypass. The aim of the present study was to evaluate the effects of preoperative
      dipyridamole treatment on neutrophil superoxide anion generation and endothelial
      cell-neutrophil interactions. METHODS: Two groups of patients scheduled for
      elective coronary artery bypass grafting were randomized to receive oral
      dipyridamole or a placebo. Nitro blue tetrazolium scores of circulating
      neutrophils, neutrophil CD11b/CD18 expression, and their adhesion to human
      umbilical vein endothelial cells were assayed before anesthesia, 30 minutes after
      the beginning of cardiopulmonary bypass, at the end of bypass, and 60 minutes
      postoperatively. RESULTS: In both groups, cardiopulmonary bypass resulted in a
      significant increase in nitro blue tetrazolium scores in circulating neutrophils
      as well as a significant increase in both neutrophil CD11b/CD18 expression and
      neutrophil adhesion to endothelial cells. The extent of neutrophil superoxide
      anion generation was higher in the control group; a significant (p < 0.01)
      reduction in neutrophil adhesion to endothelial cells was observed 1 hour
      postoperatively in the dipyridamole group. In 5 patients treated with
      dipyridamole, the incubation of activated polymorphonuclear leukocytes with
      adenosine deaminase significantly increased their adhesion to endothelial cells
      (p < 0.05). CONCLUSIONS: Our study demonstrated that preoperative treatment with
      oral dipyridamole significantly reduces both neutrophil superoxide anion
      generation and extent of neutrophil adhesion to endothelial cells after coronary
      bypass grafting procedures with cardiopulmonary bypass. The mechanism is probably
      mediated by endogenous adenosine.

PMID- 10355397
TI  - Epsilon-aminocaproic acid administration and stroke following coronary artery
      bypass graft surgery.
AB  - BACKGROUND: Epsilon-aminocaproic acid is routinely used to reduce bleeding during
      cardiac surgery. Anecdotal reports of thrombotic complications have led to
      speculation regarding this drug's safety. We investigated the association between
      epsilon-aminocaproic acid administration and postoperative stroke. METHODS: Six
      thousand two hundred ninety-eight patients undergoing isolated coronary artery
      bypass graft surgery between 1989 and 1995 were studied. Data was obtained from
      the Duke Cardiovascular Database as well as from an automated intraoperative
      anesthesia record keeper. Patients identified as having postoperative stroke were
      reviewed and confirmed by a board certified neurologist blinded to epsilon
      aminocaproic acid administration. RESULTS: Postoperative stroke occurred in 97
      patients (1.5%). Three thousand one hundred thirty-five (49.8%) patients received
      epsilon-aminocaproic acid. Increased age was associated with a higher incidence
      of postoperative stroke (p = 0.0001). In contrast, there was no significant
      difference (p = 0.7370) in the incidence of stroke between use of epsilon
      aminocaproic acid (1.3%) and nonuse (1.7%). Multivariable logistic regression
      found no significant effect of epsilon-aminocaproic acid use on stroke after
      accounting for age, date of surgery, and history of diabetes. CONCLUSIONS: This
      series suggests that epsilon-aminocaproic acid administration does not increase
      the risk of postoperative stroke.

PMID- 10355398
TI  - Management of exsanguinating hemoptysis during cardiopulmonary bypass.
AB  - BACKGROUND: Large-volume hemoptysis during cardiopulmonary bypass is an
      infrequent, but life-threatening event. Rapid airway clearance and control are
      the primary prerequisites for successful management. METHODS: The cases of 3
      patients with different sources of exsanguinating hemoptysis during
      cardiopulmonary bypass managed initially with rigid bronchoscopy were reviewed.
      RESULTS: In all patients, airway control was rapidly established and weaning from
      cardiopulmonary bypass CPB was accomplished. Two patients survived the operative
      procedure. The other patient died in the operating room of unremitting bilateral
      pulmonary hemorrhage. CONCLUSIONS: Major hemoptysis during cardiopulmonary bypass
      is best dealt with initially by rapid airway control and cessation of bypass in
      an expeditious manner. An algorithm for suggested management is provided. The
      rigid bronchoscope is the optimal tool for initial management and it should
      always be available. Definitive treatment is determined by the cause and the
      persistence of hemorrhage once these maneuvers have been performed.

PMID- 10355399
TI  - Identification of P waves after the Cox-maze procedure: significance of right
      precordial leads V3R through V6R.
AB  - BACKGROUND: The maze circuit lengthens the period of atrial depolarization and
      may lead to small or absent P waves, which may not be readily apparent in a
      standard 12-lead electrocardiogram. In this prospective study, we investigate if
      the right precordial leads V3R through V6R can improve detection of P waves and
      identification of atrial electrical activity. METHODS: Standard 12-lead
      electrocardiograms (with leads I through III, aVR, aVL, aVF, and V1 through V6)
      and right precordial electrocardiograms (V3R through V6R) were recorded in 30
      consecutive patients during the first 5 postoperative days and 1, 3, 6, 12, and
      24 months after combined Cox-maze III procedure and mitral valve surgery. The P
      wave identification as an indication of atrial electrical activity and atrial
      contraction was proved by transesophageal echocardiographic identification of
      atrial contractions. RESULTS: Despite echocardiographically identifiable atrial
      contractions, the P waves were not visible on standard 12-lead electrocardiograms
      in 7 (23%) patients after 1 and 3 months, and in 4 patients after 6 months. In
      contrast, right precordial electrocardiograms showed P waves in all of these
      patients that were best seen in lead V4R. Twelve and 24 months postoperatively,
      only 2 patients had no visible P waves in the standard leads that were still
      present in the right precordial leads. However, if P waves were easily
      identifiable in standard 12-lead electrocardiograms (23 patients at 1 and 3
      months after surgery), the right precordial leads showed P waves only in 15
      patients. CONCLUSIONS: Right precordial electrocardiogram with leads V3R through
      V6R is a helpful tool for visualizing P waves after the Cox-maze procedure.
      Standard 12-lead electrocardiogram should be combined with right precordial
      electrocardiogram in all patients after the Cox-maze procedure.

PMID- 10355400
TI  - Effect of topical vasodilators on gastroepiploic artery graft.
AB  - BACKGROUND: Mobilization of the gastroepiploic artery (GEA) often results in a
      vasospasm with reduction of early graft flow. In order to prevent or suppress
      this highly reactive artery's spasm, we have compared the effect of 4
      vasodilators, used in external application to prepare the GEA graft, prior to
      myocardial revascularization. METHODS: WE performed a double-blind clinical study
      to compare the effects of external application of vasodilators on gastroepiploic
      artery grafts. Fifty patients, whose gastroepiploic artery was used for coronary
      artery bypass grafting, were randomized into 5 groups of 10 patients.
      Gastroepiploic artery free flow and hemodynamic measurements were evaluated
      immediately after harvesting, before any pharmacological manipulation, and 10
      minutes after the topical application of vasodilators, respectively: papaverine,
      linsidomine, nicardipine, glyceryl trinitrate, and normal saline solution.
      RESULTS: A significant increase in free flow occurred in all groups except for
      the normal saline solution group with measurements from 26.1+/-3.6 mL/min to
      26.4+/-6.5 mL/min; p = 0.9. The most important increase in flow before and after
      local application occurred with glyceryl trinitrate and papaverine: from 25.5+/-2
      mL/min to 50+/-6.1 mL/min (p < or = 0.01) and from 36.8+/-3.2 mL/min to 62+/-7.8
      mL/min (p < 0.01) respectively. Nicardipine and linsidomine produced a less
      significant increase in flow: from 33.1+/-3.6 mL/min to 47.7+/-8.9 mL/min (p <
      0.05) and from 28+/-3.8 mL/min to 39.8+/-7.5 mL/min (p < 0.05) respectively. When
      comparing percentage of flow increase, glyceryl trinitrate appeared to be
      significantly more efficient than nicardipine and linsidomine (p < 0.01 versus
      both groups). Although papaverine was more efficient than nicardipine and
      linsidomine, it did not reach statistical significance. CONCLUSIONS: During
      intraoperative preparation of the GEA graft, glyceryl trinitrate and papaverine
      to a lesser extent, used as topical vasodilators, appear to be more efficient in
      external application to increase the free flow of the GEA.

PMID- 10355401
TI  - The CarboMedics "Top-Hat" supraannular prosthesis.
AB  - BACKGROUND: The CarboMedics "Top-Hat" supraannular prosthesis was designed to
      permit the implantation of a larger prosthesis. METHODS: Between June 1993 and
      November 1996, 127 patients (average age, 61.8+/-10.2 years) received a
      CarboMedics "Top-Hat" supraannular aortic prosthesis. The average follow-up was
      15.7 months, and all surviving patients underwent echocardiographic study. This
      group is compared with 656 patients in whom a standard CarboMedics prosthesis was
      implanted and also with 2,927 patients who received other aortic prostheses.
      RESULTS: Using the standard and the supraannular sizers, there was an average
      increase of one size in favor of the supraannular prosthesis: 18.9+/-2.8 mm
      standard versus 20.8+/-2.6 mm supraannular (p < 0.005). For each prosthesis size
      (19 to 23 mm), the body surface area of the patients in whom a CarboMedics
      supraannular prosthesis was implanted was significantly smaller than that in
      those who received a CarboMedics standard prosthesis or any other model. Hospital
      mortality was 3.9%, and late mortality was 5.5%. The actuarial survival was
      86.5%+/-3.9% at 42 months. CONCLUSIONS: Using the CarboMedics supraannular
      prosthesis allows implantation of a larger prosthesis compared with the standard
      CarboMedics prosthesis or other models. This advantage is especially important in
      patients with a small aortic root.

PMID- 10355402
TI  - Vascular delay of the latissimus dorsi provides an early hemodynamic benefit in
      dynamic cardiomyoplasty.
AB  - OBJECTIVES: Dynamic cardiomyoplasty (CMP) as a surgical treatment for chronic
      heart failure improves functional class status for most patients. However,
      significant hemodynamic improvement with latissimus dorsi muscle (LDM)
      stimulation has not been consistent. The current protocols do not allow early LDM
      stimulation after CMP surgery. We hypothesized that vascular delay of LDM would
      increase myocardial assistance after CMP and allow early (48-h) LDM stimulation
      after CMP. METHODS: Mongrel dogs (n = 24) were divided in four groups: 1)
      controls (n = 6), single-stage CMP; 2) Group ES (n = 6), single-stage CMP with
      early LDM stimulation beginning 48 h, postoperatively; 3) Group VD (n = 6),
      vascular delay of the LDM followed by CMP without early LDM stimulation, and 4)
      Group VDES (n = 6), vascular delay of LDM (14-18 days), followed by CMP with
      early stimulation (48 h postoperatively). Two weeks after CMP, global cardiac
      dysfunction was induced by injecting microspheres into the left coronary artery.
      LDM-assisted (S) beats were compared with nonstimulated beats (NS) by measuring
      aortic pressure (AoP), LV pressure, aortic flow, and by calculating first
      derivative of LV contraction (+/-dP/dt), stroke volume (SV), and stroke work
      (SW). RESULTS: In ES, LDM stimulation had no effect on the hemodynamic
      parameters. In the other groups, LDM stimulation significantly (p < 0.05)
      increased AoP, LVP, dP/dt, SV, and SW. However, these increases were much larger
      in VD and VDES. In VD, LDM stimulation increased peak AoP by 21.5+/-3.8 mm Hg,
      LVP by 22.1+/-4.1 mm Hg, dP/dt by 512+/-163 mm Hg/sec, SV by 10.4+/-2.3 mL, and
      SW by 22.1+/-5.4 g/m(-1). Similarly, in VDES, LDM stimulation increased peak AoP
      by 24.1+/-4.7 mm Hg, LVP by 26.2+/-4.3 mm Hg, dP/dt by 619+/-47 mm Hg/sec, SV by
      6.5+/-0.7 mL, and SW by 16.7+/-4.1 g/m(-1). CONCLUSIONS: In dogs with global LV
      dysfunction, CMP after vascular delay resulted in a significant improvement in
      hemodynamic function measured 2 weeks after surgery. This improvement was not
      provided by single-stage CMP with or without early stimulation. Vascular delay of
      the LDM before surgery may play an important role for early benefit after CMP,
      shorten the overall muscle training period, as well as increase hemodynamic
      response to LDM stimulation.

PMID- 10355403
TI  - Perinatal mitral valve interventions: a report of 10 cases.
AB  - BACKGROUND: Rheumatic mitral valve stenosis is still an endemic disease in some
      parts of the world and may complicate pregnancy and perinatal period. During the
      10-year period between January 1988 and December 1997, 10 pregnant women with
      mitral stenosis were operated on. METHODS: Combined cesarean delivery and closed
      mitral valvulotomy (CMV) were performed on 6 patients, combined cesarean delivery
      and Mitral Valve Replacement (MVR) were performed on 1 patient, and 3 patients
      had CMV during their third trimester. RESULTS: There was 1 stillbirth. All other
      patients and delivered babies were healthy. MVR was necessary for mitral
      restenosis in one patient 5 years after her CMV. Three of the remaining patients
      had some degree of restenosis but did not require reoperation. CONCLUSION: CMV
      when indicated during pregnancy can be performed with low risk. For symptomatic
      patients responding to medical therapy, a combined approach of cesarean section
      and CMV will prevent possible complications that may arise on perinatal period
      due to hemodynamic fluctuation.

PMID- 10355404
TI  - Biocompatibility of a silicone-coated polypropylene hollow fiber oxygenator in an
      in vitro model.
AB  - BACKGROUND: A silicone-coated microporous hollow-fiber membrane oxygenator has
      been developed to prevent plasma leakage during long-term use. The objective of
      this study was to evaluate the biocompatibility of the oxygenator. METHODS: A
      silicone-coated oxygenator was compared with an uncoated oxygenator in an in
      vitro model of cardiopulmonary bypass. Simulated circulation was maintained for 6
      h at 37 degrees C. RESULTS: Platelet counts decreased significantly (p < 0.05)
      and leukocyte counts tended to decline; however, the differences between groups
      were not significant. Concentrations of C3a increased significantly in both
      groups (p < 0.05), but levels were significantly less in the silicone-coated
      oxygenator (p = 0.008). In contrast, concentrations of C4a, beta-thromboglobulin,
      and granulocyte elastase increased significantly (p < 0.05), but the differences
      between groups were not significant. CONCLUSIONS: Silicone coating over a
      microporous hollow-fiber membrane may improve biocompatibility by reducing C3a
      activation.

PMID- 10355405
TI  - Cardiopulmonary bypass and oxygen consumption: oxygen delivery and hemodynamics.
AB  - BACKGROUND: This study was undertaken to investigate the relations between whole
      body oxygen consumption (VO2), oxygen delivery (DO2), and hemodynamic variables
      during cardiopulmonary bypass. METHODS: One hundred one patients were studied
      during cooling, hypothermia, and rewarming. Oxygen consumption, DO2,
      hemodynamics, and DO2crit were measured at these times. RESULTS: There was a
      direct linear relation between DO2 and VO2 during all three times. No relation
      between VO2 and hemodynamics was detected during cooling; during hypothermia, an
      inverse linear relation with peripheral arterial resistance was found. Finally,
      during rewarming, there was a direct relation with pump flow rate, and an inverse
      relation with arterial pressure and arterial resistance. The same relations among
      the variables were found at delivery levels above or below DO2crit. CONCLUSIONS:
      During cardiopulmonary bypass there is a direct linear relation between DO2 and
      VO2; the relations with hemodynamic variables depend on the phases of
      cardiopulmonary bypass. This suggests that increasing delivery levels may recruit
      and perfuse more vascular beds, and higher delivery levels are advisable during
      perfusion. During rewarming and hypothermia, lower arterial resistances are also
      desirable to optimize VO2.

PMID- 10355406
TI  - Minimally invasive mitral valve surgery: the subxiphoid approach.
AB  - BACKGROUND: This report describes mitral valve replacement using a unique
      subxiphoid approach with a lower ministernotomy and a skin crease incision and
      compares the operative and echocardiographic results to patients undergoing
      mitral valve replacements using previously described strategies. METHODS: Fifty
      four patients underwent mitral valve replacement using a subxiphoid approach
      (group 1); 32 patients underwent mitral valve replacement, 11 patients underwent
      mitral valve replacement + tricuspid reconstruction, 2 patients underwent mitral
      valve replacement + tricuspid valve replacement, and 9 patients underwent mitral
      reconstruction. This group of patients was compared to 11 patients who underwent
      mitral valve replacement through a superior ministernotomy (group 2) and 29
      patients who underwent mitral valve replacement with full median sternotomy
      (group 3, 22 mitral valve replacements, 2 mitral valve replacements + tricuspid
      reconstruction, 2 mitral reconstructions, and 3 mitral reconstructions +
      tricuspid reconstruction). RESULTS: There was no operative mortality in all
      groups. The operation lasted significantly longer in group 2 patients compared to
      group 1 and 3 patients (p < 0.01). Postoperative mediastinal drainage was
      significantly lower in groups 1 and 2 (p < 0.001). Pain assessment revealed no
      difference between the groups. Three patients in group 1 presented with
      pericardial effusion. Except for this complication, early postoperative
      echocardiographic findings of the patients were similar in all three groups. All
      patients were in New York Heart Association functional class I or II at the
      second postoperative month, irrespective of the surgical technique used.
      CONCLUSIONS: There was no prominent superiority of the ministernotomy approaches
      over the standard median sternotomy approach. However, the reliability of the
      subxiphoid approach is documented echocardiographically and any type of mitral
      replacement can be performed with this approach.

PMID- 10355407
TI  - Early and late outcome after elective cardiac surgery in patients with cirrhosis.
AB  - BACKGROUND: A prospective study was performed to evaluate the early and late
      outcome after elective cardiac surgery in patients with cirrhosis. METHODS: All
      patients who underwent elective cardiac surgery between 1995 and 1997, and were
      suspected of having a history of cirrhosis, were followed in the intensive care
      unit (ICU), during hospitalization and after hospital discharge. All patients
      received high doses of aprotinin during surgery. RESULTS: Ten patients of Child
      Pugh class A and 2 patients of Child-Pugh class B were studied. All patients had
      signs of portal hypertension, and 11 of 12 patients had thrombocytopenia. In the
      first 24 h after operation, the median chest tube output was 810 mL (range 350 to
      1,500 mL). Median ICU and hospital stays were 3 and 15 days, respectively (range
      2 to 10 and 7 to 36 days, respectively). Seven patients experienced postoperative
      morbidity and 7 patients had significant complications after their hospital
      discharge. One death occurred in the ICU. Two deaths occurred after hospital
      discharge and were related to further hepatic damage. CONCLUSIONS: These results
      suggest that, in patients with mild or moderate cirrhosis, the incidence of
      significant complications was high after elective cardiac surgery, increasing the
      length of stay in ICU and overall hospitalization time and compromising the
      health status, even well after the operation.

PMID- 10355408
TI  - A new method of double cardiomyoplasty: "contractile muscular sling".
AB  - BACKGROUND: In several experimental studies, double cardiomyoplasty using both
      latissimus dorsi muscles did not provide sufficient assist to the failing heart
      and did not clearly show improvement compared with single cardiomyoplasty. This
      study demonstrated the superior efficacy of our method of double cardiomyoplasty
      compared with single cardiomyoplasty. METHODS: In 16 dogs, the two latissimus
      dorsi muscles were crossed in front of the heart and directly sutured to each
      other behind the heart. Control hemodynamic measurements were obtained, and acute
      heart failure was induced by intravenous administration of propranolol. After the
      hemodynamic changes with bilateral latissimus dorsi muscle assistance were
      measured, single cardiomyoplasty was done in the same dog, and the hemodynamic
      variables were measured. RESULTS: With our double cardiomyoplasty, aortic
      systolic pressure increased by 25% (p < 0.001); pulmonary artery systolic
      pressure, by 40% (p < 0.001); end-systolic elastance, by 155% (p < 0.001); and
      cardiac output, by 55% (p < 0.001). There were significant increases in aortic
      pressure, pulmonary artery pressure, end-systolic elastance, stroke volume, and
      cardiac output with our double cardiomyoplasty compared with single
      cardiomyoplasty. CONCLUSIONS: In this study, our double cardiomyoplasty provided
      significant hemodynamic improvement compared with single cardiomyoplasty.

PMID- 10355409
TI  - Effects of cardioplegic flushing, storage, and reperfusion on coronary
      circulation in the pig.
AB  - BACKGROUND: The aim of the study was to investigate how flush-perfusion of the
      heart with cold cardioplegic solution, 2 or 12 hours of cold ischemic storage,
      and 24 hours of reperfusion affect coronary endothelial function and coronary
      vascular resistance. METHODS: Porcine coronary arterial endothelial and smooth
      muscle function was studied in organ baths. An adult porcine working heart model
      was used to investigate coronary vascular resistance after 24 hours of
      reperfusion. RESULTS: Flushing the heart with 1 L of St. Thomas' cardioplegic
      solution, using a perfusion pressure of 60 to 65 mm Hg, significantly reduced
      endothelium-dependent relaxation. Flushing followed by 12 hours of storage
      gravely impaired endothelium-dependent relaxation, and 24 hours of reperfusion
      worsened it still more. CONCLUSIONS: Flushing the heart with cold cardioplegic
      solution impairs endothelium-dependent relaxation, as does prolonged cold
      ischemic storage. Reperfusion of injured coronary endothelium may injure it still
      more. A correlation was found (p < 0.001) between high coronary vascular
      resistance and low endothelium-dependent relaxation.

PMID- 10355410
TI  - Thoracic and cardiovascular interventions after orthotopic heart transplantation.
AB  - BACKGROUND: The long-term outcome of orthotopic heart transplantation is limited
      by the development of cardiac allograft vasculopathy, rejection, infection, and
      malignancy. METHODS: After heart transplantation, we treated patients with
      thoracic and cardiovascular diseases: preexisting coronary artery sclerosis in 2
      patients, cardiac allograft vasculopathy in 19, valvular disease in 3, mycotic
      ascending aortic aneurysm in 2, superior vena cava stenosis in 2, and lung
      neoplasm in 10 patients. RESULTS: We successfully performed coronary artery
      bypass grafting for preexisting coronary artery sclerosis, valve replacement for
      valvular disease, and patch enlargement for superior vena cava stenosis.
      Percutaneous transluminal coronary angioplasty for cardiac allograft vasculopathy
      achieved excellent initial results, but the incidence of restenosis was high
      (67%). One patient who underwent coronary artery bypass grafting for cardiac
      allograft vasculopathy died immediately after operation. Graft replacement was
      performed for mycotic aortic aneurysm, but 1 patient required reoperation because
      of recurrent aneurysm. The long-term survival rate in patients undergoing
      surgical resection for lung neoplasm was poor (50%). CONCLUSIONS: The need for
      thoracic and cardiovascular interventions in patients after heart transplantation
      was low (4.7%). Use of the appropriate procedures can improve the long-term
      survival after heart transplantation.

PMID- 10355412
TI  - Myocardial revascularization with the left internal thoracic artery Y graft
      configuration.
AB  - BACKGROUND: The proved long-term patency of the left internal thoracic artery
      (LITA) has made it the conduit of choice for myocardial revascularization.
      Maximal utilizable LITA length can be achieved by using a semiskeletonizing
      harvest technique. Expanded LITA use with sequential and Y graft techniques
      allows for a wider territory of myocardial revascularization. METHODS: A
      retrospective analysis of 30 patients undergoing coronary artery bypass surgery
      with a LITA-Y graft between December 1994 and November 1996 was performed. In
      selected patients the LITA was cut to length and anastomosed to the left anterior
      descending artery (LAD), with the redundant length of LITA used as a free graft
      to the lateral circumflex and diagonal systems. The proximal end of the free LITA
      was anastomosed to the in situ LITA to form the Y graft. Selection criteria
      included: a) minimal distal disease in the LAD and circumflex systems; and b)
      graftable circumflex branches proximal to the mid free wall of the left
      ventricle, allowing total revascularization of the left coronary system with the
      Y graft. RESULTS: Thirty patients (22 male, 8 female) underwent the LITA-Y graft
      procedure. There were no deaths or episodes of myocardial infarction. One patient
      required inotropic and intraaortic balloon pump support. Two patients with
      isolated coronary ostial stenosis developed recurrence of angina due to occlusion
      of the free limb of the LITA. CONCLUSIONS: In patients with suitable coronary
      artery anatomy, the LITA-Y graft can be successfully performed with good short
      term outcome, but may be contraindicated in the management of isolated coronary
      ostial stenosis.

PMID- 10355411
TI  - The Ross operation: mid-term results.
AB  - BACKGROUND: The Ross operation, although more demanding, is now widely accepted
      as an alternative solution for aortic valve replacement in young adults and
      children. A review of our experience to assess the mid-term results with the Ross
      operation is presented. METHODS: From June 1991 through October 1997, 80 patients
      (mean age, 31 years) underwent aortic valve or root replacement with pulmonary
      autografts. Indications for operation were predominant aortic stenosis in 38
      patients, aortic incompetence in 42 patients including endocarditis in 3
      patients. Congenital lesions were present in 57 patients, either at pediatric (27
      patients) or adult age (30 patients). Transthoracic echocardiography was
      performed preoperatively in all patients and serially after operation with the
      aims of measuring aortic and pulmonary annuli, evaluating transvalvular gradients
      and incompetence, and studying the left ventricular function. Intraoperative
      transesophageal echocardiography was used routinely. Complete root replacement
      was performed in 52 patients, intraluminal cylinder in 25 patients, and
      subcoronary implantation in 3 patients. RESULTS: One patient died in the early
      postoperative period (1.2%). There was no late death. The actuarial survival at 5
      years was 98%+/-1%. All survivors remained in New York Heart Association
      functional class I and were free of complications and medications. No gradient or
      significant aortic incompetence could be demonstrated in 73 patients. One patient
      developed late aortic incompetence grade 3 and reoperation is considered. On the
      pulmonary outflow tract, 6 patients had gradients between 20 and 40 mm Hg as
      calculated on echocardiography. CONCLUSIONS: The pulmonary autograft gives
      excellent mid-term results with low mortality and no morbidity. It completely
      relieves the abnormal loading conditions of the left ventricle, resulting in a
      complete recovery of left ventricular function in most patients.

PMID- 10355413
TI  - Selective protection of gray and white matter during spinal cord ischemic injury.
AB  - BACKGROUND: Ischemic injury in the gray matter is associated with excitatory
      amino acid neurotransmitters (EAA) release, and in the white matter is associated
      with intracellular sodium accumulation. We investigated the protective effect
      during spinal ischemia of the EAA antagonist, 2-carboxypiperazinyl
      propylphosphonic acid (CPP), and the sodium channel blocker (2,6
      dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX). METHODS: Sprague
      Dawley rats were randomized in four groups, received intrathecally 10 microL of
      saline, CPP, QX, or QX/CPP, and underwent balloon occlusion of the aorta.
      Proximal pressure was lowered by exsanguination. In the acute protocol, 28 rats
      were used to calculate the length of occlusion, resulting in paraplegia in 50% of
      animals (P50). In the chronic study, 60 rats underwent 11' occlusion. The chronic
      animals were scored daily for 28 days and submitted to cord histology. RESULTS:
      The P50 of QX (11'22") and QX/CPP (11'54") were longer than saline (10'39"),
      suggesting a beneficial effect. Neurologic scores of all treatment groups (p =
      0.0001) and histologic scores of CPP (p = 0.003) and QX/CPP (p = 0.002) were
      better than saline. CONCLUSIONS: Protection of spinal cord during ischemia can be
      achieved with intrathecal administration of selective agents directed to the gray
      and white matter.

PMID- 10355415
TI  - Repair of aortic coarctation in patients more than 50 years of age.
AB  - BACKGROUND: Most patients with uncorrected coarctation of the aorta die before
      reaching age 50 years. In those who survive, the beneficial effect of surgical
      repair on systolic hypertension has been questioned. METHODS: Surgical repair of
      aortic coarctation was performed in 8 patients aged 51 to 73 years (mean, 58+/-9
      years). Preoperative mean systolic pressure was 185+/-34 mm Hg and systolic
      gradient, 70+/-11 mm Hg. In addition, 3 patients had significant coronary artery
      disease. Severe calcification of the aortic arch and left subclavian artery was
      found in 3 patients. The surgical technique involved bypass of the coarctation
      with a Dacron tube graft (16 or 18 mm) in all patients. One patient underwent
      concomitant coronary artery bypass grafting. RESULTS: There were no operative or
      late deaths during a mean follow-up of 4.3 years. Mean systolic blood pressure
      decreased significantly in the postoperative period to 128+/-16 mm Hg (p <
      0.001). At the last visit, systolic blood pressure was a mean of 127+/-9 mm Hg.
      Five patients were not taking antihypertensive medication. CONCLUSIONS: Surgical
      repair of aortic coarctation in patients more than 50 years of age with a Dacron
      tube bypass graft reduces systolic hypertension and the need of antihypertensive
      medication.

PMID- 10355414
TI  - Procoagulant activity after off-pump coronary operation: is the current
      anticoagulation adequate?
AB  - BACKGROUND: Hemostasis is preserved after off-pump coronary operations compared
      with conventional coronary procedures. However, this preserved hemostasis may
      result in a procoagulant activity. METHODS: We prospectively studied coagulation
      in 22 patients who underwent off-pump coronary operation either through a midline
      sternotomy (n = 14) or with minimally invasive anterolateral thoracotomy (n = 8).
      RESULTS: Procoagulant activity, represented by prothrombin factor 1 and 2,
      remained at baseline levels during operation but increased significantly on
      postoperative day 1. Factor VII remained at baseline levels during the operation
      but decreased significantly on postoperative day 1. Fibrinolysis was increased as
      indicated by the fibrin degradation products on postoperative day 1. A promoted
      hemostasis attributable to endothelial activation was indicated by the increase
      in von Willebrand factor on postoperative day 1. Platelets counts and platelet
      activation (beta-thromboglobulin) remained at baseline levels after the
      operation. No adverse clinical events occurred. CONCLUSIONS: Patients undergoing
      off-pump coronary operation show an increased procoagulant activity in the first
      postoperative 24 hours regardless of the surgical approach (midline sternotomy or
      anterolateral thoracotomy). This procoagulant activity is not mediated by
      platelet-related factors. Therefore, a specific perioperative prophylactic
      pharmacologic regimen is advisable.

PMID- 10355416
TI  - Cardiovascular effects of inhaled nitric oxide in a canine model of
      cardiomyopathy.
AB  - BACKGROUND: The inhalation of nitric oxide (NO) in patients with heart failure
      decreases pulmonary vascular resistance (PVR) and is associated with an increase
      in pulmonary artery wedge pressure (PAWP). The mechanism for this effect remains
      unclear. METHODS: In dogs rapid-paced for 8 weeks to induce cardiac dysfunction,
      we performed left ventricular pressure-volume analysis of unpaced hearts in situ
      to determine whether during NO inhalation (80 ppm), the mechanism for the rise in
      PAWP is due to: 1) primary pulmonary vasodilation; 2) a direct negative inotropic
      effect; or 3) impairment of ventricular relaxation. RESULTS: Inhalation of NO
      decreased PVR by 51%+/-3.8% (257+/-25 vs 127+/-18 dynes x sec x cm(-5) [NO 80
      ppm]; p < 0.001) and increased PAWP (15.4+/-2.4 vs 18.1+/-2.6 mm Hg [NO 80 ppm];
      p < 0.001). Calculated systemic vascular resistance remained unchanged. Left
      ventricular (LV) end-diastolic pressure rose (16.4+/-1.9 vs 19.1+/-1.8 mm Hg [NO
      80 ppm]; p < 0.001), as did LV end-diastolic volume (83.5+/-4.0 vs 77.0+/-3.4 mL
      [NO 80 ppm]; p = 0.006). LV peak +dP/dt was unchanged by NO (1,082+/-105 vs
      1,142+/-111 mm Hg/sec [NO 80 ppm]; p = NS). There was a trend toward a stroke
      volume increase (17.4+/-1.2 vs 18.8+/-1.3 mL; p = NS), but the relaxation time
      constant and end-diastolic pressure-volume relation were both unchanged.
      CONCLUSIONS: In this canine model of cardiomyopathy, inhaled NO decreases
      pulmonary vascular resistance. The associated increase in left ventricular
      filling pressure appears to be secondary to a primary pulmonary vasodilator
      effect of NO without primary effects on the contractile or relaxation properties
      of the left ventricle.

PMID- 10355417
TI  - Operation of mid-arch coarctation.
AB  - BACKGROUND: Coarctation occurring within the aortic arch is rare and may present
      difficulties during surgical repair. We describe the operative technique and
      outcome in 6 patients with this unusual anomaly. METHODS: Five patients had
      antegrade perfusion with circulatory arrest. Three patients with presubclavian
      narrowing (one presenting with type B dissection) were operated through extended
      left thoracotomy. Two precarotid and paracarotid lesions were approached through
      a median sternotomy. All patients were perfused antegradely from the ascending
      aorta and operated with hypothermic circulatory arrest. One patient who had a
      complex presubclavian coarctation after two previous repairs received an
      ascending aorta to abdominal aorta bypass graft without cardiopulmonary bypass.
      RESULTS: All patients survived operation and are well at a mean follow-up of 3.3
      years after the procedure. None had cerebral problems or spinal cord injury.
      Renal function was unchanged. The mean (+/- standard error of the mean) resting
      gradient across the coarctation decreased from 42+/-4.0 mm Hg to 6+/-1.2 mm Hg (p
      = 0.0004). CONCLUSIONS: Hypothermic circulatory arrest using antegrade ascending
      aortic perfusion allows safe and effective repair of mid-arch coarctation.
      Complicated reoperations can be managed safely using ascending-to-abdominal
      aortic bypass.

PMID- 10355418
TI  - Outcome after repair of tetralogy of Fallot with absent pulmonary valve.
AB  - BACKGROUND: Tetralogy of Fallot with absent pulmonary valve (TOF/APV) is
      associated with pulmonary artery dilatation and airway compression. METHODS:
      Since January 1, 1984, 28 patients with TOF/ APV have undergone complete repair
      (median age 11 days, range 1 day to 16 years). RESULTS: Thirteen patients were
      ventilated for respiratory failure preoperatively and extracorporeal membrane
      oxygenation was used in 3. Twenty-six patients underwent pulmonary artery
      plication (11 anterior, 15 anterior/ posterior). The right ventricular outflow
      tract (RVOT) was reconstructed with a patch (19), valved conduit (5), or monocusp
      valve (4). Early mortality was 21.4% (6/28), with 1 late death. All early deaths
      occurred in infants intubated preoperatively. Survival was 77% (95% confidence
      limit [CL] 56%, 89%) at 1 year and 72% (95% CL 50%, 86%) at 10 years. After
      surgery, 3 patients underwent reoperation for persistent respiratory symptoms,
      which resolved after repeat plication and placement of a valved conduit. Freedom
      from death or reoperation was 68% (95% CL 46%, 83%) at 1 year and 52% (95% CL
      29%, 71%) at 10 years. In a multivariable analysis, only preoperative intubation
      was associated with a worse outcome (p = 0.04). CONCLUSIONS: Long-term outcome
      for patients with TOF/APV who survive the initial repair is good. Repeat
      plication and pulmonary valve implantation may improve outcome in patients with
      persistent airway compression.

PMID- 10355419
TI  - Does the modified Blalock-Taussig shunt cause growth of the contralateral
      pulmonary artery?
AB  - BACKGROUND: Although some pediatric cardiology departments have a policy of
      adopting primary correction of tetralogy of Fallot in all symptomatic infants, we
      and others still palliate neonates and infants. Effective palliation should
      ameliorate symptoms and allow growth of the pulmonary arteries. Although studies
      on the growth of the ipsilateral and contralateral pulmonary arteries after a
      classic Blalock-Taussig shunt have been reported, pulmonary artery growth after a
      modified Blalock-Taussig shunt has not been studied as thoroughly. Therefore, we
      examined whether there is equal growth of the contralateral pulmonary artery
      after a modified Blalock-Taussig shunt. METHODS: We retrospectively analyzed the
      records of 140 patients with symptomatic tetralogy of Fallot who had a modified
      Blalock-Taussig shunt between October 1985 and October 1995. The median age at
      the time of the Blalock-Taussig shunt was 1.6 months. All patients had corrective
      procedures at a median age of 1.7 years. Cineangiography was done before the
      corrective procedure. From the angiograms the diameter of the right and left
      pulmonary arteries before their first lobar branches and the diameter of the
      descending thoracic aorta at the level of the diaphragm were measured. For each
      patient the ratios of right pulmonary artery to descending thoracic aorta and
      left pulmonary artery to descending thoracic aorta were determined and compared
      using Student's t test. RESULTS: Of the 140 patients, 114 had a left-sided
      Blalock-Taussig shunt, 20 had a right-sided shunt, and 6 patients had bilateral
      shunts. The mean right pulmonary artery to descending thoracic aorta ratio was
      1.10 and the mean left pulmonary artery to descending thoracic aorta ratio was
      0.98. This difference was not significant. CONCLUSION: We showed equal growth of
      the right and left pulmonary arteries with no distortion after a modified Blalock
      Taussig shunt. If palliation is considered, the modified Blalock-Taussig shunt
      remains our choice.

PMID- 10355420
TI  - Cardiac pacing in premature infants and neonates: steroid eluting leads and
      automatic output adaptation.
AB  - BACKGROUND: Appropriate generator and lead selection as well as techniques of
      implantation are most important aspects of cardiac pacing in the extremely young
      patient. Here we report the clinical results using a new technique with automatic
      output adaptation based on evoked response in combination with steroid-eluting
      epicardial leads in small children. METHODS: One neonate and 2 premature infants
      underwent permanent pacemaker implantation because of congenital high-degree
      atrioventricular block or postoperative complete heart block, respectively.
      Steroid-eluting epicardial leads and a multiprogrammable pacemaker with automatic
      output adaptation were used. RESULTS: Intermuscular abdominal generator placement
      and epicardial suture-fixation of the bipolar lead through a subcostal approach
      was without complications. Serial follow-up examinations revealed safe and
      consistent pacemaker function up to 12 months after operation. CONCLUSIONS: The
      technique represents an excellent alternative for permanent cardiac pacing in
      extremely small patients. We believe that it provides an increase in functional
      lifetime of the devices and delays the need for battery replacement with its
      associated complications in this young patient population.

PMID- 10355421
TI  - Ventricular morphology and coronary arterial anatomy in hearts with isometric
      atrial appendages.
AB  - BACKGROUND: Knowledge of the precise anatomy can be advantageous when striving to
      improve surgical results in patients with visceral heterotaxy. METHODS: We
      studied the ventricular mass, and its coronary arterial supply, in 125 specimens
      with isomeric right and 58 with isomeric left appendages. RESULTS: The situation
      in which each atrium connected to its own ventricle was the most common
      arrangement in hearts with isomeric left appendages. The pattern with both
      atriums connecting to the same ventricle was more frequently seen in those with
      isomeric right appendages. Concordant ventriculoarterial connections were seen in
      only 4% of cases with isomeric right appendages, but were seen in 45% of those
      with isomeric left appendages. Abnormal patterns in branching of the coronary
      arteries were commonly associated with abnormal ventricular architecture. The
      morphologically right or left ventricular arteries were frequently lacking in
      those hearts with a dominant ventricle and a rudimentary and incomplete
      ventricle. A solitary coronary artery was seen in 13%. CONCLUSIONS: Recognition
      of these abnormalities is of clinical importance if optimal surgical strategies
      are to be established for patients with visceral heterotaxy.

PMID- 10355422
TI  - Repair of partial atrioventricular septal defect in children less than five years
      of age: late results.
AB  - BACKGROUND: Presently, surgical correction of partial atrioventricular septal
      defects is an extremely viable option giving good results. An aggressive approach
      toward operating on these patients at an early age may be warranted given the
      otherwise unfavorable natural history. METHODS: A retrospective study was done in
      38 consecutive patients from 3 to 58 months of age, who underwent correction
      between 1981 and 1997. Preoperatively, moderate to severe mitral regurgitation
      was present in 45% of the patients. Congestive cardiac failure was noted in 41%
      of the cases. Closure of the left atrioventricular valve cleft was performed in
      92% of the cases. A need for mitral annuloplasty was felt in 28% of the cases.
      Majority of the ostium primum defects in our series were closed by a pericardial
      patch. RESULTS: The early, 30 day mortality was 7.9%. A significantly low
      incidence of late mitral regurgitation (0.9%) was noted on a follow-up extending
      up to 14 years. There was only one reoperation during late follow-up. On their
      last follow-up, 87% of the patients are asymptomatic. CONCLUSION: An aggressive
      approach toward operating at an early age on children with this malformation is
      safe, effective, and yields excellent long term results.

PMID- 10355423
TI  - Intraaortic balloon pumping in children.
AB  - BACKGROUND: Intraaortic balloon pump (IABP) usage in young children remains a
      rarity because, first, there is a widespread misconception that the greater
      elasticity of the aorta in children may prevent effective augmentation, and
      second, children in low cardiac output states are more likely to have associated
      right ventricular failure and pulmonary problems. We report our experience with
      the use of IABP in children undergoing cardiac surgery in whom mechanical support
      was necessary for the treatment of refractory cardiac failure. METHODS: Over a 3
      year period, 14 children were identified as requiring IABP support after cardiac
      surgery. Their median age was 3 years (range 7 days to 13 years) and their median
      weight was 13.3 kg (range 3.5-51 kg). Indications for IABP use were: failure to
      wean from cardiopulmonary bypass (5 patients), sudden deterioration in intensive
      therapy unit (ITU) (3 patients), progressive deterioration in ITU (4 patients),
      and prophylactic therapy for known poor preoperative ventricular function (2
      patients). RESULTS: Ten of 14 patients (71%) were successfully weaned from the
      IABP, of whom 8 became long-term survivors (57%). Among the survivors, the mean
      duration of IABP usage was 127 h (range 12-260 h), while for those who died while
      on IABP, the mean duration was 15 h (range 8-24 h). The most major IABP-related
      complication encountered was mesenteric ischemia, which had a fatal outcome.
      CONCLUSIONS: IABP therapy, used as an adjunct to conventional medical treatment,
      can give properly selected young children in refractory low cardiac output states
      after heart surgery a greater than 50% chance of long-term survival.

PMID- 10355424
TI  - Gene transfer of heat shock protein 70 protects lung grafts from ischemia
      reperfusion injury.
AB  - BACKGROUND: We recently demonstrated that heat stress induction of heat shock
      protein 70 (HSP70) in donor animals before harvest decreases posttransplant
      ischemia-reperfusion injury in preserved rat lung isografts. The purpose of this
      study was to investigate the feasibility of HSP70 gene transfection into rat lung
      isografts using an adenoviral vector, and to study the effects of gene expression
      on subsequent ischemia-reperfusion injury. METHODS: In preliminary studies to
      determine the optimal titer, animals were injected with various titers of
      adenovirus-HSP70 (saline, 5 x 10(9), 1 x 10(10), and 2 x 10(10) plaque forming
      units [pfu]) and sacrificed 5 days after injection. To determine the optimal
      exposure time, animals were sacrificed at different times (0, 6, 24, and 72
      hours) after intravenous injection of adenovirus-HSP70. In a subsequent series of
      transplant experiments, donors were allocated to three groups according to
      transfection strategy. Group 1 (n = 8) donors received 5 x 10(9) pfu adenovirus
      HSP70 intravenously, group 2 (n = 7) donors received 5 x 10(9) pfu adenovirus
      beta-galactosidase (as a virus control), and group 3 (n = 7) donors received
      saline and served as a negative control. Twenty-four hours after treatment all
      grafts were harvested and stored for 18 hours before orthotopic left lung
      transplantation. Twenty-four hours after implantation animals were sacrificed for
      assessment. The expression of HSP70 was assessed by Western blot analysis.
      RESULTS: In preliminary studies, HSP70 was detectable even at low titers (5 x
      10(9) pfu) of adenovirus-HSP70, and was detectable at low levels as early as 6
      hours after intravenous administration. Heat shock protein 70 expression was
      maximal at 24 hours. In transplant experiments, Western blot analysis showed that
      overexpression of HSP70 occurred in the HSP70-transfected lungs. The mean
      arterial oxygenation 24 hours after reperfusion in group 1 was superior in
      comparison with other groups (p < 0.05). Wet to dry weight ratio (p < 0.05) and
      myeloperoxidase activity (p < 0.05) were also significantly less in group 1
      grafts compared with the other groups. CONCLUSIONS: This study demonstrates that
      in vivo, donor adenovirus-mediated gene transfer of HSP70 decreases subsequent
      ischemia-reperfusion injury in rat lung isografts.

PMID- 10355425
TI  - Reduced neutrophil infiltration protects against lung reperfusion injury after
      transplantation.
AB  - BACKGROUND: There is evidence that lung ischemia reperfusion injury is a result
      of the activation of components of the inflammatory cascade. However, the role of
      neutrophils in lung reperfusion injury continues to be a source of controversy.
      METHODS: Using an isolated, whole blood-perfused, ventilated rabbit lung model,
      we sought to characterize the pattern of reperfusion injury and investigate the
      contribution of neutrophils to this injury. Donor rabbits underwent lung harvest
      after pulmonary arterial prostaglandin E1 injection and Euro-Collins preservation
      solution flush. Group I lungs (n = 8) were immediately reperfused without
      ischemic storage. Group II lungs (n = 8) were stored for 18 h at 4 degrees C
      before reperfusion. Group III lungs (n = 10) underwent 18 h of ischemic storage
      and were reperfused with whole blood that was first passed through a leukocyte
      depleting filter. All lungs were reperfused for 2 h. RESULTS: Arterial
      oxygenation in group III progressively improved, and was significantly higher
      than that of group II after 2 h of reperfusion (272.58+/-58.97 vs 53.58+/-5.34 mm
      Hg, p = 0.01). Both pulmonary artery pressure and pulmonary vascular resistance
      were significantly reduced in group III when compared with group II (27.85+/-1.45
      vs 44.15+/-4.77 mm Hg, p = 0.002; and 30,867+/-2,323 vs 52,775+/-6,386 dynes x
      sec x cm(-5), p = 0.003, respectively). Microvascular permeability in group III
      lungs was reduced to 73.98+/-6.15 compared with 117.16+/-12.78 ng Evans blue
      dye/g tissue in group II (p = 0.005). Group III myeloperoxidase activity was
      56.92+/-6.31 deltaOD/g/min compared with 102.84+/-10.41 delta0d/g/min in group II
      (p = 0.002). CONCLUSIONS: Leukocyte depletion of the blood reperfusate protects
      against microvascular permeability and significantly improves pulmonary graft
      function. The neutrophil plays a major role in amplifying lung injury later
      during reperfusion, and this lung ischemia reperfusion injury may be reversed
      through the interruption of the inflammatory cascade and the interference with
      neutrophil infiltration.

PMID- 10355426
TI  - Prognostic value of positive pleural lavage in patients with lung cancer
      resection.
AB  - BACKGROUND: Despite an early stage, lung cancer patients often have a poor
      survival, suggesting inaccurate staging. A pleural lavage demonstrating malignant
      cells at the time of operation may predict a poorer survival, particularly in
      patients with otherwise early disease. METHODS: Patients, with no preoperative
      evidence of pleural effusions and undergoing a surgical resection with curative
      intent, had a preresectional and postresectional lavage to be evaluated by
      cytology. RESULTS: Fourteen percent of patients with stage I disease had
      malignant cells in their preresectional lavage and had a significantly shorter
      survival than stage I patients with a negative lavage. Positivity of
      preresectional lavage was not correlated with nodal status, pleural or lymphatic
      involvement, or histologic findings. CONCLUSIONS: Preoperative pleural lavage
      should become a standard technique intraoperatively to better characterize and
      stage patients undergoing lung cancer resections. Patients with malignant cells
      in their preoperative lavage should be upstaged.

PMID- 10355427
TI  - Initial experience with two sequential anterolateral thoracotomies for bilateral
      lung transplantation.
AB  - BACKGROUND: Bilateral transsternal thoracotomy (clamshell incision) is the
      standard approach used for bilateral sequential lung transplantation (BLTX). The
      morbidity of this large incision can be considerable. Two separate sequential
      anterolateral thoracotomies represent a less invasive approach. METHODS: The
      value of this approach was investigated in a prospective series of 13 consecutive
      patients with the underlying diagnosis of COPD or cystic fibrosis (group A).
      Results were compared to 8 consecutive patients with similar indications who had
      undergone BLTX via clamshell incision during the last year prior to this new
      technique (group B). RESULTS: No intraoperative complications occurred in either
      group. The difference between the cold ischemic time of the 1st and 2nd
      transplanted lung was comparable between the 2 groups (81 min+/-17 min in group A
      vs 79 min+/-14 min in group B, p = 0.783). Postoperative restriction was
      significantly less in the group operated through 2 separate thoracotomies, as
      proven by the vital capacity in the first spirometry performed during the 3rd
      postoperative week (VC group A 55%+/-16% predicted vs 41%+/-11% predicted in
      group B; p = 0.043). CONCLUSION: The bilateral sequential anterolateral
      thoracotomy represents a safe and less invasive approach for BLTX in patients
      with large chest volumes. It minimizes the operative trauma, improves
      postoperative functional recovery and prevents the potential spread of unilateral
      complications to the other pleural cavity.

PMID- 10355428
TI  - Assessment of pulmonary complications after lung resection.
AB  - BACKGROUND: We assessed the utility of maximum oxygen consumption during exercise
      (MVO2) and diffusing capacity for carbon monoxide (DL(CO)) in the prediction of
      postoperative pulmonary complications, and the effect of such complications on
      postoperative length of hospital stay and the cost of hospitalization. METHODS:
      Candidates for lung resection were prospectively studied by preoperative
      measurement of DL(CO) (expressed as a percentage of predicted [DL(CO)%]) and
      MVO2. Postoperative pulmonary complications, duration of postoperative
      hospitalization, and the cost of hospitalization were assessed. RESULTS: Forty
      patients had lung resection with no operative mortality. The postoperative length
      of hospitalization was longer for the 13 patients who developed pulmonary
      complications compared with the 27 patients who did not (7.7+/-0.8 vs 5.0+/-0.4
      days, respectively; p = 0.007), and the cost of hospitalization in the former
      group was higher ($11,530+/-$1,959 vs $6,578+/-$406, respectively; p = 0.031).
      Diffusing capacity was higher in patients without than in patients with pulmonary
      complications (DL(CO)% 90.1+/-5.0 vs 65.3+/-5.9; p = 0.0034). The mean MVO2 did
      not differ between the groups (17.8+/-0.9 vs 16.3+/-1.2). DL(CO)% predicted
      pulmonary complications (p = 0.006). CONCLUSIONS: DL(CO)% predicts the likelihood
      of pulmonary complications after major lung resection, which are associated with
      increased length of hospital stay and cost.

PMID- 10355429
TI  - Temporary tracheobronchial stenting in malignant lymphoma.
AB  - BACKGROUND: Temporary stenting is a new strategy in the treatment of malignant
      airway stenoses. Patients receive stents as primary palliation followed by tumor
      specific therapy in order to reduce the stenosis and subsequently remove the
      stent. METHODS: We investigated this strategy of temporary airway stenting in 5
      consecutive patients with malignant lymphoma (Non-Hodgkin's lymphoma, n = 3;
      Hodgkin's lymphoma, n = 2) who presented with severe dyspnoea. Nine stents (six
      Strecker, three Dumon stents) were implanted into the trachea or main bronchi.
      After stenting, patients underwent tumor-specific therapy (chemotherapy, n = 4;
      percutaneous radiotherapy, n = 1). RESULTS: Clinical improvement of dyspnoea and
      stridor was observed in each patient after stent implantation. In 4 patients
      (80%), stents could easily be removed after successful tumor-specific therapy,
      which led to reduction of stenosis after a mean interval of 26 days (14 to 52
      days). One patient died during chemotherapy 6 days after stenting. CONCLUSIONS:
      The results show that temporary stenting is a valuable strategy in chemo- and
      radiosensitive malignancies, as it ameliorates the patients' respiratory
      condition until tumor-specific therapy is effective, and prevents poststenotic
      complications. It integrates stent implantation in a multi-therapy concept.

PMID- 10355430
TI  - Young lung cancer patients in Japan: different characteristics between the sexes.
AB  - BACKGROUND: Lung cancer in younger people is uncommon and has characteristics
      that distinguish it from cancer in older patients. The percentage of smokers
      among younger patients ranges from 40% to 50% in Asia to 90% in Western
      countries. The prognosis for young patients with this disease is controversial.
      METHODS: Medical records of 91 young (40 years of age or younger) and 3,221 older
      (more than 40 years of age) Japanese patients with lung cancer were reviewed to
      compare smoking habits, distribution of histopathologic types, clinical stage,
      and survival. RESULTS: Among female patients, only 39% were smokers in both age
      groups, whereas smokers were less common among the young male patients (84%) than
      the older male patients (95%) (p < 0.0001). Adenocarcinomas were diagnosed in 92%
      of the young and 73% of the older female patients (p = 0.021) versus only 71% and
      42% of the corresponding male patients (p < 0.0001). There was no difference in
      tumor extent or survival between the two groups of female patients. In the male
      groups, advanced disease (stages IIIB and IV) was more common in the young
      patients (75%) than in the older patients (54%) (p = 0.0031), but there was no
      survival difference between the two groups. CONCLUSIONS: Young male and female
      lung cancer patients in Japan have different characteristics from each other and
      from older patients of the same sex. Their survival did not differ from that of
      older patients.

PMID- 10355431
TI  - Clinical behavior of solitary fibrous tumors of the pleura.
AB  - BACKGROUND: Solitary fibrous tumors of the pleura are rare and present
      unpredictable clinical behavior. METHODS: Between 1981 and 1998, 11 solitary
      fibrous tumors of the pleura were resected in 10 patients at the University
      Hospital of Geneva. Their clinical behavior and outcome were reviewed. RESULTS:
      Seven tumors arose from the visceral pleura, and three arose from the parietal
      pleura. Tumors arising from the parietal pleura were revealed to be more
      difficult to resect than those from the visceral pleura because of their size and
      adhesion to the chest wall requiring extrapleural resection. Eight tumors showed
      benign features, whereas two showed distinct features of malignity. One
      additional patient presented marked pleomorphism that could represent an
      intermediate form before frank malignity. Four tumors had been followed
      expectantly for 2 to 10 years before surgery. Although three enlarged rapidly, no
      signs of malignity were observed on histological examination. All patients are
      alive, from 2 months to 14 years after surgery (mean 55 months). In one case,
      however, a malignant tumor recurred 6 years after resection of a benign variant.
      CONCLUSIONS: Although histologically benign, solitary fibrous tumors of the
      pleura may enlarge rapidly and occasionally transform into malignant variants
      after several years. Therefore, complete surgical resection and long-term follow
      up is recommended for all patients.

PMID- 10355432
TI  - Prediction of hypoxemia and mechanical ventilation after lung resection for
      cancer.
AB  - BACKGROUND: Hypoxemia usually occurs after thoracotomy, and respiratory failure
      represents a major complication. METHODS: To define predictive factors of
      postoperative hypoxemia and mechanical ventilation (MV), we prospectively studied
      48 patients who had undergone lung resection. Preoperative data included, age,
      lung volume, force expiratory volume in one second (FEV1), predictive
      postoperative FEV1 (FEV1ppo), blood gases, diffusing capacity, and number of
      resected subsegments. RESULTS: On postoperative day 1 or 2, hypoxemia was
      assessed by measurement of PaO2 and alveolar-arterial oxygen tension difference
      (A-aDO2) in 35 nonventilated patients breathing room air. The other patients (5
      lobectomies, 9 pneumonectomies) required MV for pulmonary or nonpulmonary
      complications. Using simple and multiple regression analysis, the best predictors
      of postoperative hypoxemia were FEV1ppo (r = 0.74, p < 0.001) in lobectomy and
      tidal volume (r = 0.67, p < 0.01) in pneumonectomy. Using discriminant analysis,
      FEV1ppo in lobectomy and tidal volume in pneumonectomy were also considered as
      the best predictive factors of MV for pulmonary complications. CONCLUSIONS: These
      results suggest that the degree of chronic obstructive pulmonary disease in
      lobectomy and impairment of preoperative breathing pattern in pneumonectomy are
      the main factors of respiratory failure after lung resection.

PMID- 10355434
TI  - Acute cardiovascular changes of partial left ventriculectomy without mitral valve
      repair.
AB  - We assessed the acute cardiovascular changes of partial left ventriculectomy
      (PLV) in a patient with idiopathic dilated cardiomyopathy (IDCM) without mitral
      regurgitation. Acutely, PLV reduced left ventricular (LV) end-diastolic dimension
      and volume while increasing LV ejection fraction and cardiac output due to
      increased HR and SV. Substantial increases in LV filling pressure, possibly due
      to high LV end-systolic and diastolic elastances, were of concern clinically and
      the mechanism(s) of change remain unclear. However, one year follow-up showed
      remarkable improvements in NYHA and VO2 max while maintaining reduced LV volume,
      increased LVEF, and trivial MR.

PMID- 10355433
TI  - Endoscopic ultrasonography in the staging of esophageal carcinoma after
      preoperative radiotherapy and chemotherapy.
AB  - BACKGROUND: In past years multimodal neoadjuvant treatment for carcinoma of the
      esophagus has been used with increased frequency. Staging of the neoplasm still
      remains fundamental in evaluating the response to therapy and in planning
      operation. The aim of the present study was to assess the accuracy of endoscopic
      ultrasonography (EUS) in a group of patients with squamous cell carcinoma of the
      thoracic esophagus after undergoing radiotherapy and chemotherapy. METHODS: Among
      a group of 111 patients with squamous cell carcinoma of the thoracic esophagus
      and treated with preoperative radiotherapy and chemotherapy, 87 were operated. In
      these patients it was possible to compare the results of EUS, with regard to
      depth of invasion of esophageal wall (T) and lymph node involvement (N), with the
      results of operation and histopathologic study. RESULTS: Feasibility of EUS
      before and after neoadjuvant treatment was 71.2% and 83.9%, respectively. The
      overall accuracy of EUS regarding the wall invasion was 47.9%. The more frequent
      error was overstaging, especially in patients with complete response and in
      patients with minimal residual disease. In the assessment of lymph node
      involvement, EUS showed an overall accuracy of 71.2% with a moderate kappa value.
      Sensitivity for N1 and NO was 73.7% and 68.6%, respectively. CONCLUSIONS:
      Endoscopic ultrasonography was feasible in most patients after preoperative
      radiotherapy and chemotherapy, but our study documented a worsening of accuracy
      of EUS in the evaluation of T attributable to the confounding presence of
      radiation fibrosis and soft tissue reaction after radiotherapy and chemotherapy.

PMID- 10355435
TI  - Right aortic arch, right ligamentum, absent left pulmonary artery: a rare
      vascular ring.
AB  - A 5-month-old infant presented with respiratory failure secondary to severe right
      bronchial compression. Diagnostic imaging revealed a right aortic arch and absent
      left pulmonary artery. Surgical relief was obtained via median sternotomy by
      dividing a right ligamentum and pexing the enlarged right pulmonary artery to the
      ascending aorta.

PMID- 10355436
TI  - Intraosseous neurilemoma of the sternum.
AB  - Sternal benign bone tumor is uncommon. We report a very rare case of intraosseous
      neurilemoma in the sternum. A girl, 10 years of age, was diagnosed as having a
      sternal tumor. Computed tomographic scan disclosed a mushroom-shape tumor in the
      region from inside of the sternum to the ventral soft tissues. Surgical resection
      was performed. Histopathologic findings showed a typical neurilemoma with Antoni
      type A and B patterns. No recurrence has been found.

PMID- 10355437
TI  - Mobilization of the anterior mitral leaflet for excision of a left ventricular
      myxoma.
AB  - Left ventricular myxomas are extremely rare. We report use of a left atrial
      approach with mobilization of the anterior mitral valve leaflet to enhance
      exposure of the subvalvar region and facilitate excision of a left ventricular
      myxoma entangled within the chordal apparatus, lying between the anterolateral
      papillary muscle and the left ventricular wall. The detached mitral leaflet was
      reattached to the annulus with a continuous suture. The tumor was completely
      excised, thus avoiding a separate transventricular or transaortic approach.

PMID- 10355438
TI  - Coronary ostial patch angioplasty in children.
AB  - Patch angioplasty for coronary artery ostial stenosis was first reported in
      adults in 1952 and only sparsely used until 1983 when Hitchcock reviewed the
      technique in adults. We present two cases that highlight our use of this
      technique in inflammatory diseases of the aorta in children. Patch angioplasty
      restores physiologic perfusion of the coronary artery tree, preserves conduit
      material for further procedures later in life, and allows subsequent percutaneous
      transluminal coronary angioplasty of stenosis. For these reasons we believe that
      patch angioplasty holds undoubted advantage over the available alternatives.

PMID- 10355439
TI  - Spontaneous chylothorax associated with primary lymphedema and a lymphangioma
      malformation.
AB  - Spontaneous chylothorax associated with primary lymphedema is an exceedingly rare
      clinical entity. We report a case of chylothorax in a 38-year-old woman with a
      history of primary lymphedema of the right leg and an inguinal lymphangioma.
      Pathophysiology, diagnosis, treatment, as well as literature review are
      presented.

PMID- 10355440
TI  - Expanding mesh stent in the emergency treatment of Boerhaave's syndrome.
AB  - Boerhaave's syndrome, or spontaneous esophageal perforation, is a life
      threatening condition demanding early diagnosis and rapid aggressive management
      to prevent fulminant mediastinitis and death. We describe a patient treated in an
      emergency situation with an expanding esophageal mesh stent to bridge the
      esophageal rent together with chest and mediastinal drainage, resulting in
      complete recovery and return to the community. We also describe the partial
      recovery of the stent in the convalescent period.

PMID- 10355441
TI  - Stuck valve leaflet detected by intraoperative transesophageal echocardiography.
AB  - We encountered a rare complication of mitral valve replacement with the
      CarboMedics prosthesis: a "stuck" leaflet detected by transesophageal
      echocardiography even though weaning from cardiopulmonary bypass had been
      uneventful. The patient was immediately managed without significant problems. We
      emphasize the importance of performing routine intraoperative transesophageal
      echocardiography in valve replacement as well as in valve repair, from the
      initial phase of operation.

PMID- 10355442
TI  - Extrathoracic subclavian internal thoracic artery bypass grafting.
AB  - Interval development of a significant stenosis at the origin of the left internal
      thoracic artery (LITA) after this vessel has been used to revascularize the
      anterior descending coronary artery may be an indication for reoperation. We
      present an extrathoracic approach to bypass the proximal segment of the LITA that
      allows patients with this lesion a quick recovery, short hospital stay, and early
      resumption of normal activity.

PMID- 10355443
TI  - Severe aortic regurgitation immediately after mitral valve annuloplasty.
AB  - We report a case of severe aortic regurgitation occurring immediately after the
      insertion of a mitral annuloplasty ring. On transesophageal echocardiography,
      regurgitation was found to originate from the retracted left coronary cusp. On
      direct examination, part of the aortic wall was folded, but no suture could be
      identified. It was reasoned that tension created by the ring caused the
      retraction. The problem was corrected by releasing three sutures on the ring.
      Postoperative course was uneventful.

PMID- 10355444
TI  - Inverted left atrial appendage presenting as a left atrial mass after cardiac
      surgery.
AB  - Inversion of the left atrial appendage can masquerade as a new left atrial mass.
      Failure to be aware of this entity can result in unnecessary diagnostic and
      therapeutic procedures. If the entity is diagnosed intraoperatively, treatment is
      simple with external reduction and ligation.

PMID- 10355445
TI  - Inverted left atrial appendage: an unusual complication in cardiac surgery.
AB  - Two patients with an inverted left atrial appendage after cardiac surgery were
      presented. Magnetic resonance imaging is one of the useful methods to establish
      an accurate diagnosis of this complication. In 1 patient, it repaired
      spontaneously without surgical intervention.

PMID- 10355446
TI  - Intrahepatic venovenous shunting to an accessory hepatic vein after Fontan type
      operation.
AB  - Because there are various types of systemic venous connections in patients with
      visceral heterotaxy, unanticipated abnormal systemic venous channels may pose
      additional problems after a Fontan type operation. We report a case of severe
      cyanosis caused by anomalous intrahepatic venovenous fistula to an accessory
      hepatic vein early after total cavopulmonary anastomosis.

PMID- 10355447
TI  - Atraumatic lung hernia.
AB  - Lung hernia is a distinctly rare event, regardless of its location and cause.
      Most lung hernias are acquired traumatic thoracic hernias. All previously
      reported cases of acquired spontaneous lung hernia involve some aspect of trauma,
      most commonly caused by vigorous coughing with a subsequent rib fracture. We
      report a case of totally atraumatic, acquired spontaneous lung hernia.

PMID- 10355448
TI  - Combined coronary artery bypass grafting and repair of aneurysm of the descending
      aorta.
AB  - The outcome of patients with thoracic or thoracoabdominal aortic aneurysm is
      often determined by the concomitant coronary artery disease. Two patients with
      thoracic and thoracoabdominal aortic aneurysm and concomitant single-vessel
      coronary artery disease underwent combined myocardial revascularization and
      repair of aortic aneurysm. The operations were performed through a left
      thoracotomy and thoracoabdominal incision with distal aortic perfusion using a
      partial femoro-femoral bypass and selective right lung ventilation. Coronary
      anastomoses were performed on the beating heart, and the aneurysm was replaced
      with a woven Dacron tube graft.

PMID- 10355449
TI  - Traumatic paramediastinal air cysts.

PMID- 10355450
TI  - Replacement of the ascending aorta and aortic valve with a valved stentless
      composite graft.
AB  - A technique of total aortic root replacement with a stentless porcine composite
      graft is described. This graft is assembled during surgery using a woven
      polyester vascular prosthesis and a stentless aortic bioprosthesis.

PMID- 10355451
TI  - "Mini-sternotomy" for bilateral pulmonary wedge resections.
AB  - A mini-sternotomy is described that allows access to both thoracic cavities. This
      technique offers excellent exposure for lung resections from chest cavities
      without the invasiveness of a formal thoracotomy.

PMID- 10355452
TI  - Reversed-J inferior sternotomy for beating heart coronary surgery.
AB  - Median sternotomy or combined multiple minimally invasive approaches are
      currently used to revascularize patients with multivessel coronary artery disease
      on the beating heart. We present here a new alternative approach for minimally
      invasive coronary surgery on the beating heart: the reversed-J inferior
      sternotomy. Through this approach, the left anterior descending, diagonal, and
      right coronary arteries can be revascularized via a single minimally invasive
      approach.

PMID- 10355453
TI  - Split pectoralis major muscle flap reconstruction after clavicular-manubrial
      resection.
AB  - Resection of the clavicular head and clavicular-manubrial junction is required in
      cases of chronic osteomyelitis or tumor. This article describes a technique for
      soft tissue coverage in an infected or irradiated area after resection using a
      split pectoralis major rotational muscle flap.

PMID- 10355454
TI  - Lateral thoracotomy closure technique.
AB  - A pericostal closure technique is described that is effective, quick, and surgeon
      friendly.

PMID- 10355455
TI  - Glue containment and anastomosis reinforcement in repair of aortic dissection.
AB  - In operations for aortic dissection anastomotic bleeding or secondary anastomosis
      dehiscence are common problems. The advent of Gelatin-resorcin-formaldehyde
      glutaraldehyde (GRF) biologic glue has ameliorated type A dissection operative
      management. Glue containment is mandatory since detrimental effects of glue
      migration are described. We herein present a simple technique of anastomosis
      reinforcement and glue containment that helps in overcoming these complications.

PMID- 10355456
TI  - William Carlos Williams (1883-1963): physician-writer and "godfather of avant
      garde poetry".
AB  - William Carlos Williams, Pulitzer Prize-winning physician-writer, was born in
      Rutherford, New Jersey, where he practiced medicine until he was incapacitated by
      a stroke at age 68. After graduating from the University of Pennsylvania School
      of Medicine, Williams trained in New York City and Leipzig, Germany, settling in
      Rutherford in 1909. Doctor Williams revolutionized American poetry by rejecting
      traditional conventions of rhyme and meter, and he masterfully used "American"
      English-brusque, colloquial, and incisive-in his poetry. Williams is recognized
      as one of the most original poets of the 20th century. His medical life sometimes
      trivialized, Williams was a serious student of medicine and considered himself
      "in the front lines, in the trenches." He regarded art and medicine as "two parts
      of a whole," and the intimate doctor-patient interface proved a powerful
      inspiration for his writing. Dr Williams was a physician of immense integrity and
      dedication; he regarded allegiance to humanism as important as excellence in
      medical science. Prolific in various genre, Dr William Carlos Williams attained
      belated recognition in spite of astonishing productivity and originality. His
      stature and influence has steadily increased since his death in 1963, and Dr
      Williams is now considered "the most important literary doctor since Chekhov."

PMID- 10355458
TI  - The Fontan operation.

PMID- 10355457
TI  - Thoracic complications of peritoneal dialysis.
AB  - Approximately 20% of the 100,000 patients in the United States currently
      undergoing dialysis therapy for end-stage renal disease use the technique of
      peritoneal dialysis. We present a patient on peritoneal dialysis who developed a
      large posterior mediastinal mass, which on surgical exploration was found to be a
      paraesophageal hernia sac filled with omentum and dialysis fluid. We use this
      case as an introduction to review the thoracic complications of peritoneal
      dialysis.

PMID- 10355459
TI  - As originally published in 1992: coronary artery bypass without cardiopulmonary
      bypass. Updated in 1999.

PMID- 10355460
TI  - Endoaortic occlusion for the calcified thoracic aorta.

PMID- 10355461
TI  - Adjustment of faulty graft length in aortocoronary bypass.

PMID- 10355462
TI  - Advancement flaps for superficial sternal wound infection.

PMID- 10355463
TI  - Aprotinin-enhanced lung preservation solutions: is it worthwhile.

PMID- 10355464
TI  - Ongoing prospective study of extended segmentectomy for small lung tumors.

PMID- 10355465
TI  - Why does partial left ventriculectomy work on dilated cardiomyopathy?

PMID- 10355466
TI  - An unexplained cluster of thrombosed bileaflet mechanical heart valve prostheses.

PMID- 10355467
TI  - Small aortic valve prostheses in octogenarians.

PMID- 10355468
TI  - Cerebrospinal fluid drainage.

PMID- 10355469
TI  - Optimizing mitral valve exposure with azygous vein ligation.

PMID- 10355470
TI  - Abnormal urinary protein excretion in African Americans with type 2 diabetes
      mellitus.
AB  - The purpose of this investigation was to determine the prevalence and correlates
      of abnormal urinary albumin excretion and to examine the possible additive
      effects of cardiovascular risk factors on urinary albumin excretion in African
      Americans with type 2 diabetes mellitus. One hundred fifty-one African-American
      subjects who met WHO criteria for type 2 diabetes were included in this cross
      sectional analysis. Subjects were identified through computerized medical records
      from a family medicine clinic and a community health center. Urinary albumin
      excretion ratios (UAER) were determined from overnight samples. The prevalence of
      abnormal urinary protein excretion was 51%. Of those with abnormal protein
      excretion, 36% had microalbuminuria and 15% had macroalbuminuria. Diabetes
      duration, waist to hip ratio, blood pressure, and total- and LDL cholesterol were
      significantly higher in subjects with macroalbuminuria. Regression analysis
      indicated that mean arterial blood pressure, diabetes duration and total
      cholesterol were independently associated with UAER. Mean UAER significantly
      increased with the addition of one or more syndrome X risk factors to pure
      diabetes. Our results indicate that African Americans with type 2 diabetes
      mellitus have a high prevalence of abnormal urinary protein excretion, which is
      associated with a clustering of additional cardiovascular risk factors. The fact
      that this increased risk was associated with hypertension indicates that
      screening for albuminuria in this population is essential and that a majority of
      African Americans with diabetes may be at risk for developing cardiovascular
      complications.

PMID- 10355471
TI  - Cultural sensitivity in public health: defined and demystified.
AB  - There is consensus that health promotion programs should be culturally sensitive
      (CS). Yet, despite the ubiquitous nature of CS within public health research and
      practice, there has been surprisingly little attention given to defining CS or
      delineating a framework for developing culturally sensitive programs and
      practitioners. This paper describes a model for understanding CS from a public
      health perspective; describes a process for applying this model in the
      development of health promotion and disease prevention interventions; and
      highlights research priorities. Cultural sensitivity is defined by two
      dimensions: surface and deep structures. Surface structure involves matching
      intervention materials and messages to observable, "superficial" characteristics
      of a target population. This may involve using people, places, language, music,
      food, locations, and clothing familiar to, and preferred by, the target audience.
      Surface structure refers to how well interventions fit within a specific culture.
      Deep structure involves incorporating the cultural, social, historical,
      environmental and psychological forces that influence the target health behavior
      in the proposed target population. Whereas surface structure generally increases
      the "receptivity" or "acceptance" of messages, deep structure conveys salience.
      Techniques, borrowed from social marketing and health communication theory, for
      developing culturally sensitive interventions are described. Research is needed
      to determine the effectiveness of culturally sensitive programs.

PMID- 10355472
TI  - Ethnic variation in the health burden of self-reported diabetes in adults aged 75
      and older.
AB  - OBJECTIVE: The health burden of self-reported diabetes was compared across three
      ethnic groups of older adults. METHODS: Analysis of variance and logistic
      regression were used to compare ethnic differences in the rates of co-morbid
      chronic health conditions, complications, and disability for older diabetics vs
      non-diabetics, in a sample of 173 Mexican Americans, 201 African Americans, and
      181 non-Hispanic whites, all aged 75 and older. RESULTS: The prevalence of self
      reported diabetes was significantly higher in older Mexican Americans (17.6%) and
      African Americans (16.4%) than in non-Hispanic whites (8.5%). In all three ethnic
      groups, and after controlling for sociodemographic characteristics, diabetics
      were found to be generally at higher risk for chronic conditions such as heart
      disease, stroke, and hypertension, circulation and foot problems, obesity, and
      impaired vision and activities of daily living. Multivariate analyses indicated
      that the burden of diabetes appeared to be greatest among non-Hispanic white
      diabetics. We suggest that this is the result of higher diabetes-mortality rates
      among minority diabetics at earlier ages. CONCLUSIONS: Diabetes is known to be
      increasing in prevalence and incidence, particularly among the elderly, the
      fastest growing segment of the population. Our findings indicate that regardless
      of ethnicity, diabetes carries an increased burden that affects both the
      functioning and the quality of life of older adults.

PMID- 10355473
TI  - Examination of factor structure of the cognitive representations of hypertension
      scale for ethnic equivalence.
AB  - The major purpose of this analysis was to examine the factor structure of
      separate interpretive dimensions of the Cognitive Representation of Hypertension
      Scales (CRHTN) for ethnic equivalence. The CRHTN is a theoretically derived
      measurement of individualized experience of hypertension assessed along three
      cognitive interpretive dimensions: perceptions, preferences and possibilities.
      The sample for this study was recruited from a university-based hypertension
      clinic, a Veterans Administration ambulatory service, and a large urban-based
      HMO. Analysis of data through confirmatory factor analysis techniques across both
      samples provided evidence for construct validity of a five-factor model along
      three dimensions: perceptions, preferences and possibilities. However, multigroup
      analyses suggest the model may not equally describe cognitive representations of
      hypertension for different ethnic groups. Differences in fit of the theoretical
      model to data from two different ethnic groups is discussed. Findings from this
      study provide a basis for development of culturally sensitive and appropriate
      cognitive strengthening strategies to influence behavioral outcomes for
      hypertension management.

PMID- 10355474
TI  - Diabetes and obesity in the Louisiana Coushatta Indians.
AB  - OBJECTIVE: In order to assist their community in planning intervention and
      prevention programs, prevalence rates for diabetes and obesity were examined
      among the Louisiana Coushatta. RESEARCH DESIGN AND METHODS: Coushatta individuals
      participated in a health survey (questionnaires and physical examinations). Those
      without known diabetes underwent oral glucose tolerance testing and were
      classified as having normal glucose tolerance (NGT), impaired glucose tolerance
      (IGT), or diabetes mellitus (DM). Those with known DM had the diagnosis confirmed
      by history and/or elevated hemoglobin A1c. Waist-to-hip ratio (WHR), body mass
      index (BMI), and percent body fat (%BF) were determined as measures of central
      adiposity and obesity. Prevalence rates of diabetes and obesity among those
      examined were calculated. The prevalence of those with more than one
      anthropometric index positive for obesity was also determined. RESULTS: The
      prevalence of DM was 30% and IGT was 17% among the first 151 Coushatta
      participants. For males, the prevalence of obesity was 62%, 57%, and 52%, and for
      females, 59%, 54%, 45%, as determined by the BMI, %BF, and WHR, respectively.
      Obesity was more prevalent among those with glucose intolerance (IGT + DM) than
      those with NGT, and those who were obese had the highest prevalence of glucose
      intolerance. A greater percentage of those with glucose intolerance had more than
      one positive obesity measure as compared to those with NGT, and those with more
      than one index consistent with obesity had a greater prevalence of IGT + DM.
      CONCLUSIONS: Prevalence rates of DM and obesity are high among the Louisiana
      Coushatta, and obesity is associated with glucose intolerance. Clustering of the
      three obesity measures occurs in a high percentage of individuals. Data from the
      current survey are providing information that is being used by the Coushatta
      community for health planning and development of intervention and prevention
      programs.

PMID- 10355475
TI  - Knowledge, attitudes and behaviors related to physical activity among Native
      Americans with diabetes.
AB  - OBJECTIVE: Native Americans (NA) have higher diabetes morbidity and mortality
      compared to other ethnic groups. Although exercise plays an important role in
      diabetes management, little is known about exercise among Native Americans with
      diabetes. Our goal was to describe knowledge, attitudes and behaviors related to
      exercise in Native American participants in New Mexico. DESIGN: Bilingual
      community members administered a questionnaire to assess knowledge, stage of
      change (a measure of exercise readiness), and physical activity behavior.
      Hemoglobin A1c (HbA1c) was measured by DCA 2000 analyzer. Height and weight were
      measured to calculate body mass index (BMI). Average random blood glucose (RBS)
      levels and diabetes duration were assessed through chart audit. SETTING:
      Questionnaires were completed in offices in or near the communities.
      PARTICIPANTS: 514 Native Americans with diabetes were identified as potential
      participants, 40% (142 women, 64 men) participated. RESULTS: 37% of participants
      knew exercise lowers blood sugar. 82% reported they were in the preparation,
      action, or maintenance stage of change for exercise behavior. Seventy seven
      percent of this population did not meet the Surgeon General's recommendation for
      accumulating 30 minutes of leisure time endurance exercise on most days of the
      week. However, 67% of participants fell within the "high activity" category for
      all moderate and vigorous activities. Average age, BMI and HbA1c were 58.5 yrs.,
      30.5 kg/m2, 8.6%, respectively. CONCLUSIONS: Interventions to increase physical
      activity awareness and participation could improve diabetes management and
      overall health for Native Americans. When evaluating physical activity,
      researchers need to consider usual activities of daily living and leisure time
      activities specific to that population. Failure to do so would be ethnocentric
      and could lead to inappropriate conclusions.

PMID- 10355476
TI  - Workplace discrimination and alcohol consumption: findings from the San Francisco
      Muni Health and Safety Study.
AB  - OBJECTIVE: There is evidence of an association between occupational stress and
      alcohol consumption. This study investigates the association between workplace
      racial discrimination and alcohol consumption in a sample of urban transit
      operators. METHODS: During 1993-1995, after undergoing a medical exam, 1,542
      transit operators completed an interview. Depending on the outcome, we used
      logistic or linear regression models to examine the cross-sectional relationship
      between discrimination experience and alcohol consumption. RESULTS: Operators who
      reported discrimination in at least one situation, out of a possible four, were
      more likely to have had negative life consequences as a result of drinking
      (adjusted OR = 1.97; 95% CI, 1.20-3.83) and were more likely to be classified as
      having an alcohol disorder (OR = 1.56 [0.96-2.54]), compared to those who
      reported no instances of workplace discrimination. Results adjusted
      simultaneously for age, sex, race/ethnicity, education, income, marital status,
      and seniority. There was no association between workplace discrimination and
      heavy drinking or drinks per month. CONCLUSIONS: Cross-sectional data from a
      sample of urban transit operators indicates an association between workplace
      racial discrimination and some measures of alcohol consumption.

PMID- 10355477
TI  - Perceptions and knowledge of breast cancer among African-American women residing
      in public housing.
AB  - OBJECTIVE: The purpose of this study, theoretically based on the Health Belief
      Model, was to assess breast cancer perceptions, knowledge, and screening behavior
      of low-income, African-American women residing in public housing. METHODS: One
      hundred twenty (120) randomly selected women were interviewed to determine their
      perceived susceptibility to breast cancer, perceived severity of the disease,
      perceived barriers to breast cancer screening, and perceived benefits of
      mammography. Knowledge about breast cancer causes, risk factors, symptoms, and
      screening was also assessed. Contingency tables and Student's t test were used to
      analyze the data. RESULTS: The results demonstrated that 80.7% of women aged 40
      and older had a previous mammogram. Approximately 92% of women reported having a
      clinical breast examination, and 75.8% performed breast self-examination.
      Knowledge of breast cancer was poor among the women in this study. Most women did
      not perceive themselves or a particular racial or economic group to be more
      susceptible to breast cancer. Moreover, the women in the sample did not perceive
      breast cancer as a fatal disease. Overall, women in the sample endorsed the
      benefits of mammography and denied the relevance of commonly cited barriers to
      breast cancer screening. The constructs of the Health Belief Model were not
      significantly related to mammography or breast self-examination. However,
      perceived severity and perceived barriers were found to be significantly related
      to clinical breast examination. CONCLUSIONS: Rates of early detection behaviors
      in this sample are commendable. Future research should focus on actual
      determinants and facilitators of regular screening behavior within a theoretical
      framework that incorporates cultural, ethnic, and socioeconomic diversity.

PMID- 10355478
TI  - Ethnic differences in cancer risk behaviors through the transition out of high
      school.
AB  - Differences were assessed by ethnic group in the performance of cancer risk
      related lifestyle behaviors through the transition out of high school. Data were
      obtained from a nationally representative probability sample survey, the 1992
      National Health Interview Survey-Youth Risk Behavior Survey. A cross-sectional
      sub-sample included adolescents with an age range from high school freshmen to
      young adults within four years after high school. Self reported indicators of
      diet, physical activity, cigarette smoking, smokeless tobacco use, alcohol use,
      and sexual practices were the primary dependent measures. Cancer risk increased
      at the transition out of high school through changes in cancer related behaviors.
      Hispanic-American males experienced somewhat higher risks after the transition
      for chewing tobacco and snuff. African Americans experienced somewhat higher
      risks after the transition for physical activity, chewing tobacco, and number of
      sexual partners. Further research needs to verify these findings with
      longitudinal designs, assessment of tracking of behaviors through the transition,
      and of the ecological, social and psychosocial correlates that may explain why
      these changes occurred.

PMID- 10355479
TI  - Aerobic exercise attenuates blood pressure reactivity to cold pressor test in
      normotensive, young adult African-American women.
AB  - Exaggerated blood pressure reactivity to behavioral stress has been observed in
      the African-American population, and such a pressor response is believed to play
      a role in hypertension. Regular aerobic exercise has been shown to exert an anti
      hypertensive effect, and this may alter the blood pressure hyperreactivity
      observed in African Americans. To test the hypothesis that aerobic exercise
      attenuates pressor reactivity in African Americans, we studied eight healthy
      aerobically-trained normotensive African-American females and five similar
      sedentary females. The stress stimuli consisted of the cold pressor test with the
      foot immersed in ice water for two minutes. The aerobic exercise training
      protocol consisted of six weeks of jogging at 60-70% of peak oxygen uptake
      (VO2peak), three days/week for 35 min/exercise session. Systolic blood pressure,
      diastolic blood pressure, mean arterial blood pressure, heart rate, cardiac
      output, total peripheral resistance, and forearm blood flow were measured.
      Manifestation of a training effect was illustrated by a 24.1 +/- 0.2% increase in
      VO2peak (26.9 +/- 1.2 mL x kg(-1) min(-1) vs 35.4 +/- 1.6 mL x kg(-1) min(-1))
      (P<.05). Within the exercise-trained group there was a 6.3 +/- .15% decrease in
      systolic pressure (129 +/- 4.6 mm Hg vs. 121 +/- 5.4 mm Hg) (P<.05), and a 5.0 +/
      .05% decrement in mean arterial blood pressure (99 +/- 3.3 mm Hg vs 94 +/- 3.6
      mm Hg) (P<.05) during the cold pressor test. Pressor reactivity to cold stress
      did not change in the untrained group. Measures of heart rate, cardiac output,
      total peripheral resistance, and forearm blood flow were unaltered during
      conditions of the cold pressor test. We conclude that aerobic exercise attenuates
      the blood pressure reactivity to behavioral stress in young, adult normotensive
      African-American females. A lifestyle change such as exercising may play a role
      in reducing the risk of hypertension in African-American women.

PMID- 10355480
TI  - The relationship of socio-economic status and access to minimum expected therapy
      among female breast cancer patients in the National Cancer Institute Black-White
      Cancer Survival Study.
AB  - Black women are more likely to be diagnosed with later stage breast cancer and
      have higher mortality rates from breast cancer than white women. To determine
      whether cancer treatment varies for white and black women, we analyzed data from
      the National Cancer Institute (NCI) Black-White Cancer Survival Study (BWCSS).
      Data from hospital medical records, central review of histology slides, and
      patient interviews on 861 breast cancer cases (in situ and invasive) were
      examined. Minimum expected therapy was defined for each disease stage as a basic
      minimum course of treatment that incorporated current practice, state-of-the-art
      knowledge, and recommendations advanced by NIH Consensus Conferences up to and
      including the one held in 1985. Patients in this study were diagnosed during 1985
      1986. Using logistic regression techniques, those who received at least the
      minimum expected therapy were compared to those who did not. Thirty-six percent
      of the patients with late stage disease did not receive minimum expected therapy
      compared to four percent of the patients with early stage disease. Older women
      and women with no usual source of care were significantly less likely to receive
      minimum expected therapy. Overall, 21% of black women did not receive minimum
      expected therapy compared to 15% of white women.

PMID- 10355481
TI  - Sun protection behaviors among African Americans.
AB  - The anatomic distribution of some skin cancers suggests that sun exposure may be
      an etiologic factor for skin cancer among African Americans. Yet little is known
      about sun protection behaviors among African Americans. We analyzed data from the
      1992 National Health Interview Survey (N = 1,583) to determine the prevalence of
      sun protection behaviors and sun sensitivity. About 6% of African Americans
      reported being extremely sensitive to the sun and severe sunburning, and 9%
      reported mild burns. Overall, 53% of respondents (47% of men and 57% of women)
      reported that they were very likely to wear protective clothing, seek shade, or
      use sunscreen lotion. Women were more likely than men to report seeking shade and
      using sunscreen. Sun protection behaviors were more frequently reported by those
      who sunburn more easily and were positively associated with age. Use of sunscreen
      was positively associated with income and education. Education about sun
      protection and early detection may help reduce the morbidity and mortality of
      skin cancer among African Americans.

PMID- 10355482
TI  - Do patients' ethnic and social factors influence the use of do-not-resuscitate
      orders?
AB  - OBJECTIVES: To determine whether ethnic and other social factors affect how
      frequently do-not-resuscitate (DNR) orders are written, the timing of DNR orders,
      or patient involvement in the DNR decision. DESIGN: Retrospective cohort.
      METHODS: Patients who died in one urban teaching hospital on the medicine,
      cardiology, or family practice service during 1988 were eligible; 288 were
      included in the analyses. Chi-square tests and logistic regression were used to
      examine frequency of DNR orders and patient involvement; analysis of variance and
      linear regression were used to examine timing of the DNR orders. RESULTS: Non
      whites were more likely than whites to have DNR orders (OR 1.76; 95% CI, 1.09
      2.84) but timing of the DNR order did not vary significantly by race/ethnicity.
      Patients who spoke English fluently were more likely to be involved in the DNR
      decision than those who did not (OR 1.28; 95% CI, 1.01-1.61). Patients with
      documented human immunodeficiency virus were more likely than uninfected patients
      to have DNR orders (OR 3.51; 95% CI, 1.36-9.02), to be involved in the decision
      (OR 10.11; 95% CI, 4.87-21.00); and to have DNR orders written earlier (P =
      0.02). Alcoholic patients were more likely than non-alcoholics to have DNR orders
      (OR 1.17; 95% CI, 1.04-1.33). CONCLUSIONS: Ethnic and other social factors do
      appear to play a role in DNR decisions. It needs to be determined if these
      differences are due to patient preferences or clinician characteristics.

PMID- 10355483
TI  - Differential provision or acquisition of health care is related to one's race or
      gender.

PMID- 10355484
TI  - Norepinephrine uptake modifications in circumventricular organs, pons and
      myelencephalic areas and nuclei in prehepatic portal hypertensive rats.
AB  - Peripheral noradrenergic activity is enhanced in portal hypertension and
      correlates with the progression of the disease. However, little is known about
      the status of central norepinephrine (NE) in portal hypertension. The aim of the
      present work was to study the uptake of NE in several areas rich in NE in
      experimental prehepatic portal hypertension. The experiments were performed in
      vitro in several encephalic areas and nuclei, obtained according to the 'punch
      out technique'. Results showed that in portal hypertensive rats NE uptake
      enhanced in all areas and nuclei studies (subfornical organ, organum vasculosum
      lamina terminalis, area postrema, locus coeruleus and nucleus tractus
      solitarius). The present results suggest that these encephalic areas and
      brainstem nuclei may be related to the development and/or maintenance of portal
      hypertension in this animal model.

PMID- 10355485
TI  - Corticotropin-releasing factor and vasoactive intestinal polypeptide activate
      gene transcription through the cAMP signaling pathway in a catecholaminergic
      immortalized neuron.
AB  - Corticotropin-releasing factor (CRF) and vasoactive intestinal polypeptide (VIP)
      are neuropeptides displaying a variety of short-term effects in the nervous
      system. It is shown here in transfection experiments of an immortalized
      noradrenergic locus coeruleus-like cell line that both CRF and VIP also trigger a
      signaling cascade capable of activating gene transcription. To elucidate the
      signaling pathway leading to transcriptional induction, cells were transfected
      with an inhibitor for cAMP-dependent protein kinase, targeted to the nucleus via
      a nuclear-localization signal. Transcriptional induction of a reporter gene by
      CRF and VIP was blocked in these cells, indicating that the cAMP-dependent
      protein kinase is required for transducing CRF and VIP generated signals into the
      nucleus. Additionally, transfection experiments with a reporter gene containing
      cAMP response elements in its regulatory region demonstrate that CRF and VIP
      receptor activation induce transcription through this genetic regulatory element.
      We conclude that long-term effects of CRF and VIP in neurons are likely to be
      mediated by the transcriptional regulation of CRF and VIP-responsive genes via
      the cAMP signaling pathway.

PMID- 10355487
TI  - Analysis of hyposmolarity-induced taurine efflux pathways in the bullfrog
      sympathetic ganglia.
AB  - Hyposmolarity-induced taurine release was dependent on the decrease in medium
      osmolarity (5-50%) in the satellite glial cells of the bullfrog sympathetic
      ganglia. Release of GABA induced by hyposmolarity was much less than that of
      taurine. Omission of external Cl- replaced with gluconate totally suppressed
      taurine release, but only slightly suppressed GABA release. Bumetanide and
      furosemide, blockers of the Na+/K+/2Cl- cotransport system, inhibited taurine
      release by about 40%. Removal of external Na+ by replacement with choline, or
      omission of K+, suppressed taurine release by 40%. Antagonists of the Cl-/HCO3
      exchange system, SITS, DIDS and niflumic acid, significantly reduced taurine
      release. The carbonic anhydrase inhibitor, acetazolamide, reduced the taurine
      release by 34%. Omission of external HCO3 by replacement with HEPES caused a 40%
      increase in the hyposmolarity-induced taurine release. Hyposmolarity-induced GABA
      release was not affected by bumetanide or SITS. Chloride channel blockers, 5
      nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and N-phenylanthranilic acid
      (DPC), practically abolished taurine release. Blockers of K+ channels, clofilium
      and quinidine, had no effect on the taurine release. The hyposmolarity-induced
      taurine release was considerably enhanced by a simultaneous increase in external
      K+. GABA was not mediated by the same transport pathway as that of taurine. These
      results indicate that Cl- channels may be responsible for the hyposmolarity
      induced taurine release, and that Na+/K+/2Cl- cotransporter and Cl-/HCO3
      exchanger may contribute to maintain the intracellular Cl- levels higher than
      those predicted for a passive thermodynamic distribution in the hyposmolarity
      induced taurine release.

PMID- 10355486
TI  - Preventive effects of exogenous phospholipases on inhibition by ferrous ions of
      [3H]MK-801 binding in rat brain synaptic membranes.
AB  - Prior treatment with ferrous chloride led to marked inhibition of [3H](+)-5
      methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (MK-801) binding to
      an open ion channel associated with the N-methyl-D-aspartate (NMDA) receptor in a
      concentration-dependent manner at concentrations of higher than 1 microM in rat
      brain synaptic membranes. Both phospholipases A2 and C significantly prevented
      the inhibition when treated before the treatment with ferrous chloride, while
      neither superoxide dismutase nor alpha-tocopherol affected the inhibition even
      when treated simultaneously with ferrous chloride. Of various saturated and
      unsaturated free fatty acids, moreover, both oleic and arachidonic acids
      exclusively decreased the potency of ferrous chloride to inhibit binding when
      membranes were first treated with fatty acids, followed by the second treatment
      with ferrous chloride. These results suggest that membrane phospholipids may be
      at least in part responsible for interference by ferrous ions with opening
      processes of the native NMDA channel through molecular mechanisms associated with
      the liberation of unsaturated free fatty acids in rat brain.

PMID- 10355488
TI  - Effects of guanine nucleotides on adenosine and glutamate modulation of cAMP
      levels in optic tectum slices from chicks.
AB  - Glutamate and adenosine both modulate adenylyl cyclase activity through
      interaction of their specific receptors with stimulatory or inhibitory G
      proteins. Guanine nucleotides (GN), which modulate G-protein activity
      intracellularly, are also involved in the inhibition of glutamate responses,
      acting from the outside of the cells. We had previously reported that glutamate
      inhibits adenosine-induced cyclic AMP (cAMP) accumulation in slices obtained from
      the optic tectum of chicks. In the present study we investigated the interaction
      of GN with these two neurotransmitters and found that GN inhibit the inhibitory
      effect of glutamate on adenosine-induced cAMP accumulation and potentiate
      adenosine-induced cAMP accumulation. These effects were observed with 5'
      guanylylimidodiphosphate (GppNHp) or GMP, but not with guanosine (the
      nucleoside). Besides, these interactions of GN occur via a metabotropic glutamate
      receptor (mGluR) sensitive to (1 S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid
      (1 S,3R-ACPD) but not to L-2-amino-4-phosphonobutyrate (L-AP4). These effects
      were partially modulated by a mGluR antagonist, (RS)-alpha-methyl-4
      carboxyphenylglycine ((RS)M-CPG), and by an adenosine receptor antagonist, 8
      phenyltheophylline. GN only potentiated the adenosine response when adenosine was
      acting through its receptor positively linked to adenylyl cyclase. Therefore, the
      data show that guanine nucleotides not only inhibit glutamate-induced responses,
      but also stimulate adenosine-induced responses, a fact that may contribute to the
      understanding of the physiological functions of guanine nucleotides.

PMID- 10355489
TI  - Regulation of calcium-dependent [3H]noradrenaline release from rat
      cerebrocortical synaptosomes by protein kinase C and modulation of the actin
      cytoskeleton.
AB  - The effects that active phorbol esters, staurosporine, and changes in actin
      dynamics, might have on Ca2+ -dependent exocytosis of [3H]-labelled
      noradrenaline, induced by either membrane-depolarizing agents or a Ca2+
      ionophore, have been examined in isolated nerve terminals in vitro.
      Depolarization-induced openings of voltage-dependent Ca2+ channels with 30 mM KCl
      or 1 mM 4-aminopyridine induced limited exocytosis of [3H]noradrenaline,
      presumably from a readily releasable vesicle pool. Application of the Ca2+
      ionophore calcimycin (10 microM) induced more extensive [3H]noradrenaline
      release, presumably from intracellular reserve vesicles. Stimulation of protein
      kinase C with phorbol 12-myristate,13-acetate increased release evoked by all
      secretagogues. Staurosporine (1 microM) had no effect on depolarization-induced
      release, but decreased ionophore-induced release and reversed all effects of the
      phorbol ester. When release was induced by depolarization, internalization of the
      actin-destabilizing agent DNAase I into the synaptosomes gave a slight increase
      in [3H]NA release and strongly increased the potentiating effect of the phorbol
      ester. In contrast, when release was induced by the Ca2+ ionophore, DNAase I had
      no effect, either in the absence or presence of phorbol ester. The results
      indicate that depolarization of noradrenergic rat synaptosomes induces Ca2+ 
      dependent release from a releasable pool of staurosporine-insensitive vesicles.
      Activation of protein kinase C increases this release by staurosporine-sensitive
      mechanisms, and destabilization of the actin cytoskeleton further increases this
      effect of protein kinase C. In contrast, ionophore-induced noradrenaline release
      originates from a pool of staurosporine-sensitive vesicles, and although
      activation of protein kinase C increases release from this pool, DNAase I has no
      effect and also does not change the effect of protein kinase C. The results
      support the existence of two functionally distinct pools of secretory vesicles in
      noradrenergic CNS nerve terminals, which are regulated in distinct ways by
      protein kinase C and the actin cytoskeleton.

PMID- 10355490
TI  - Adenosine and dopamine receptor antagonist binding in the rat ventral and dorsal
      striatum: lack of changes after a neonatal bilateral lesion of the ventral
      hippocampus.
AB  - There is experimental evidence from radioligand binding experiments for the
      existence of strong antagonistic interactions between different subtypes of
      adenosine and dopamine receptors in the striatum, mainly between adenosine A1 and
      dopamine D1 and between adenosine A2A and dopamine D2 receptors. These
      interactions seem to be more powerful in the ventral compared to the dorsal
      striatum, which might have some implications for the treatment of schizophrenia.
      The binding characteristics of different dopamine and adenosine receptor subtypes
      were analysed in the different striatal compartments (dorsolateral striatum and
      shell and core of the nucleus accumbens), by performing saturation experiments
      with the dopamine D1 receptor antagonist [125I]SCH-23982, the dopamine D2-3
      receptor antagonist [3H]raclopride, the adenosine A1 receptor antagonist
      [3H]DPCPX and the adenosine A2A receptor antagonist [3H]SCH 58261. The
      experiments were also performed in rats with a neonatal bilateral lesion of the
      ventral hippocampus (VH), a possible animal model of schizophrenia. Both dopamine
      D2-3 and adenosine A2A receptors follow a similar pattern, with a lower density
      of receptors (40%) in the shell of the nucleus accumbens compared with the
      dorsolateral caudate-putamen. A lower density of adenosine A1 receptors (20%) was
      also found in the shell of the nucleus accumbens compared with the caudate
      putamen. On the other hand, dopamine D1 receptors showed a similar density in the
      different striatal compartments. Therefore, differences in receptor densities
      cannot explain the stronger interactions between adenosine and dopamine receptors
      found in the ventral, compared to the dorsal striatum. No statistical differences
      in the binding characteristics of any of the different adenosine and dopamine
      receptor antagonists used were found between sham-operated and VH-lesioned rats.

PMID- 10355491
TI  - Chronic exposure to aluminium impairs the glutamate-nitric oxide-cyclic GMP
      pathway in the rat in vivo.
AB  - Aluminium is neurotoxic and is considered a possible etiologic factor in
      Alzheimer's disease, dialysis syndrome and other neurological disorders. The
      molecular mechanism of aluminium-induced impairment of neurological functions
      remains unclear. We showed that aluminium impairs the glutamate-nitric oxide-cGMP
      pathway in cultured neurons. The aim of this work was to assess by in vivo brain
      microdialysis whether chronic administration of aluminium in the drinking water
      (2.5% aluminium sulfate) also impairs the glutamate-nitric oxide-cGMP pathway in
      the cerebellum of rats in vivo. Chronic exposure to aluminium reduced NMDA
      induced increase of extracellular cGMP by ca 50%. The increase in extracellular
      cGMP induced by the nitric oxide generating agent S-nitroso-N-acetylpenicillamine
      was higher (240%) in rats treated with aluminium than in controls. Immunoblotting
      experiments showed that aluminium reduced the cerebellar content of calmodulin
      and nitric oxide synthase by 34 and 15%, respectively. Basal activity of soluble
      guanylate cyclase was decreased by 66% in aluminium-treated rats, while the
      activity after stimulation with S-nitroso-N-acetylpenicillamine was similar to
      controls. Basal cGMP in the cerebellar extracellular space was decreased by 50%
      in aluminium-treated rats. These results indicate that chronic exposure to
      aluminium reduces the basal activity of guanylate cyclase and impairs the
      glutamate-nitric oxide-cGMP pathway in the animal in vivo.

PMID- 10355492
TI  - Age changes in some somatometric characters of the Assamese Muslims of Kamrup
      district, Assam.
AB  - Growth in weight, stature, sitting height, lower extremity length, head
      circumference and girth of biceps, chest and calf were studied in a cross
      sectional sample of Assamese Muslims in Kamrup district, Assam, India. The sample
      comprised 835 boys and 894 girls, aged 3-20 years. The average growth pattern for
      the linear body dimensions was analysed by fitting Preece Baines model I to the
      mean values. The other dimensions were analysed in terms of simple line charts.
      Average final size and age at peak velocity of the linear dimensions were derived
      from the fitted curves. The data for height and weight were compared with other
      samples of the same district, with national urban and rural growth data for
      India, and with the NCHS growth standards. Mean height and weight of Assamese
      Muslim children fluctuates between the 5th and 10th centile of the NCHS standards
      up to approximately 15 years in boys and 13 years in girls. Thereafter, average
      length and weight lags behind the American standards, ending up below the 5th
      centile. The differences between the growth of Assamese Muslims and other
      populations are discussed.

PMID- 10355493
TI  - Income, educational level and body height.
AB  - The relation between adult body height and two socio-economic factors (income and
      educational level) was studied in a large, ethnically homogenous population. In
      the period 1980-1983 all persons aged 40-54 years (born 1926-1941) in two
      Norwegian counties were invited to a cardiovascular screening. Ninety per cent
      (or 38162 persons) of those invited attended and had their height measured.
      Information concerning income and education was available at an individual level
      from the 1980 national census. Strong, positive relations were found between mean
      body height and the socio-economic factors, relations that probably are due to
      conditions during growth influencing both height, attained education and income
      abilities. The difference between highest and lowest educational class was 3.3 cm
      in men and 3.2 cm in women, and between highest and lowest income group 3.5 cm in
      men and 4.2 cm in women. These differences could not be explained by the strong
      cohort effect of increasing height in the successive birth cohorts from 1926 to
      1941 which also was evident. It should be emphasized that height only could
      explain a small fraction of the variance in the socio-economic factors and is
      thus not a usable indicator of an individual's socio-economic status. However, it
      might contribute with important information concerning social inequalities in
      groups or population.

PMID- 10355494
TI  - An investigation of ethnic differences in bone mineral, hip axis length, calcium
      metabolism and bone turnover between West African and Caucasian adults living in
      the United Kingdom.
AB  - The aim of the study was to investigate factors relating to calcium and bone
      metabolism which might explain the low incidence of osteoporotic fracture among
      Africans. Adult bone mineral status, hip axis length and biochemical indices were
      investigated in 20 Caucasians (10 male, 10 female) and 19 Gambians (12 male, 7
      female) living in the UK. Bone mineral content (BMC), bone mineral density (BMD)
      and BMC adjusted for bone area, body weight and height (size-adjusted BMC) were
      measured for the whole-body, lumbar spine, femoral neck, trochanter, radius shaft
      and radius wrist using dual-energy X-ray absorptiometry. There were no
      significant differences in whole body or regional BMC; values tended to be lower
      in the Gambians. Gambian men had higher size-adjusted BMC at the femoral neck
      (Gambian-British = 21%, 95% CI = 6 to 36%, p < 0.01), associated with a smaller
      bone area (Gambian-British = -11%, 95% CI = -20 to -2%, p = 0.02). BMD was
      affected similarly. No other significant differences in BMD or size-adjusted BMC
      were observed. Gambians had shorter hip axis length (Gambian British, after
      accounting for sex, = -5%, 95% CI = -9 to -1%, p = 0.02). There were no
      significant differences in bone turnover (osteocalcin, bone isoenzyme of alkaline
      phosphatase, urinary deoxypyridinoline) or calciotropic hormone levels
      (parathyroid hormone, 1,25-dihydroxyvitamin D, calcitonin). Gambian men had lower
      25-hydroxyvitamin D concentrations (Gambian = 26.3 SD 12.0 nmol/L, British = 55.5
      SD 13.9 nmol/L, p < 0.0001), a difference not seen among the women. Gambian men
      and women excreted significantly less phosphate and potassium than British
      subjects by 30-60%; urinary calcium and sodium excretion were similar in the two
      groups. This study revealed few ethnic differences that could account for the
      disparity in osteoporotic fracture rates between Africans and Caucasians, with
      the possible exception of anatomical differences in the hip.

PMID- 10355495
TI  - Characteristics of menstrual cycles in Moroccan girls: prevalence of dysfunctions
      and associated behaviours.
AB  - Population studies on normal and dysfunctional characteristics of menstrual
      cycles are scarce for western populations and practically non-existent for non
      western ones. Recent data suggest that the type of menstrual cycle can be
      relevant for later gynaecological problems in several ways. The type of menstrual
      cycle is related to menarcheal age in a way that those with early maturation show
      more menstrual disorders which are the largest diagnosis category accounting for
      hysterectomies in adult women. On the other hand menstrual pain is often cited as
      the main single cause of school absenteeism among adolescent girls. The aim of
      this study is to describe characteristics of menstrual cycles, prevalence of main
      dysfunctions and their relationship to the age of maturity. The sample comprises
      495 adolescent girls from Marrakech (Morocco) aged 12-19 years. At 13 years, 40%
      of these girls had reached menarche. The median age at menarche is 13.04. The
      prevalences of abdominal pain, premenstrual symptoms and irregularity are 69.60,
      51.20 and 23.03 respectively. Abdominal pain is significantly more frequent in
      girls with early menarche.

PMID- 10355496
TI  - Secular trends in stature in Poland: national and social class-specific.
AB  - Mean statures of Polish 19-year-old males, as estimated from large national
      random samples of conscripts examined at 10-year intervals, increased from
      170.5cm in 1965 to 176.9cm in 1995. The average statural gain of 2.1 cm per
      decade is rather high compared to other European countries, although not
      exceptionally so. In addition, secular trends were analysed separately for each
      of seven selected social groups, each group comprising subjects equated for three
      social criteria. The rank-order of the seven groups on the statural scale has
      remained identical throughout the period considered, although the group-specific
      trends have not been strictly parallel. During the period 1965 1986 there has
      been a tendency for the groups lowest on the social and statural scale to
      diminish their statural distance from the social elite, the sons of the large
      city intelligentsia, a social group consistently the tallest of all the seven
      groups considered. However, that tendency for the social gaps to narrow came to a
      halt during the last, 1986-1995, decade. The present time-lag, in stature, of the
      group lowest on the social scale, the peasants, behind the social elite amounts
      to almost 30 years. These findings assume special significance in view of: (1)
      the high ethnic homogeneity of the population of Poland; (2) the absence in that
      population of any social-class differences in gene frequencies; and (3) certain
      peculiarities of Poland's post-war economic and political history.

PMID- 10355497
TI  - Validation of a newly developed mini-knemometer for premature infants.
AB  - A newly developed knemometric device for lower leg length measurement in
      premature and newborn infants is presented and validated. The present study was
      performed to establish a standardized method of use of this instrument. Two
      independent observers obtained 10 subsequential readings per measurement in three
      infants over 43 days, after which analysis showed that 5 subsequential readings
      per measurement gave comparable technical errors. Thirty-one premature infants
      were assessed by knemometry by two independent observers. The correlation
      coefficient of all measurements was 0.998. The acquired technical error (mean
      Standard Deviation (SD) of 5 sequential readings) over a total observation period
      of 294 days in all studied infants was 0.06 and 0.05 mm, respectively. By a mean
      lower leg length growth velocity of 0.52 mm per day the technical error amounted
      to 11% of daily bone growth. The described mini-knemometer is an accurate device
      for the detection of daily individual growth. A learning period of 21 days is
      necessary to obtain reliable results.

PMID- 10355498
TI  - Identifying population differences in lung function: results from the Allied
      Dunbar national fitness survey.
AB  - In order to identify valid population differences in lung function (e.g.
      occupational, ethnic), it is necessary to adjust for known confounding variables
      (e.g. age, body size). The present paper proposes appropriate methods for
      analysing forced expiratory volume (FEV1), forced vital capacity (FVC) and
      maximum oxygen uptake (VO2 max), recorded as part of the Allied Dunbar national
      fitness survey (ADNFS). The ADNFS randomly selected subjects from 30 regional
      sites throughout England. Measurements of FEV1, FVC and complete records of other
      relevant information were available on 2672 subjects. Traditional analyses of co
      variance (ANCOVA) were found to be inappropriate to investigate population
      differences in FEV1 and FVC, due to a significant increase in error variance with
      age. However, by fitting a multiplicative model with allometric body size
      components to the FEV1 and FVC measurements using weighted log-linear regression,
      valid and plausible associations with body size, age, smoking, and physical
      activity, together with 'gender specific' regional differences in lung function
      were identified. Further insight was obtained when FEV1 and FVC were included
      into the multiplicative model to predict VO2 max. The apparent advantage of being
      taller when predicting VO2 max, was explained more accurately by the subjects'
      superior FVC. In summary, by fitting the multiplicative 'allometric' model using
      weighted log-linear regression, valid population differences in lung function
      were identified. Regions containing a higher proportion of working-class,
      unemployed or less affluent subjects were found to be associated with below
      average lung function performances.

PMID- 10355499
TI  - Secular trends in male adult height 1904-1996 in relation to place of residence
      and parent's educational level in Portugal.
AB  - The records of height of 22841 18-year-old Portuguese males were analysed as well
      as their parents educational level and localities of subject's residence
      (districts). The sample includes all the Portuguese 18-year-old males, born in
      1978 and examined in 1996, in central and southern Portugal, representing all the
      social strata. Statistically significant differences (p < or = 0.001) among the
      districts were found: males from Setubal (172.75 cm) and Lisboa (172.64 cm), the
      most developed districts, are the tallest, and those from C. Branco (170.79cm)
      and Coimbra (171.19 cm) are the shortest. Comparing to published data from 1904,
      a positive secular trend in height was found. The average increase was 8.99 cm,
      which yields a rate of 0.99 cm per decade. This positive trend must be related to
      the general improvement in the population's standard living conditions, as the
      striking drop of post-neonatal mortality rate shows after the 1960s and 1970s.
      Despite this positive trend, great social difference still exists: the gap
      between the two extremes of parents' educational level is almost 4 cm for height.
      Analysis of variance (ANOVA) showed significant effects of father's and mother's
      educational level as well as subject's locality of residence, but the influence
      of parents' educational level was stronger than that of geographic residence.
      These results suggest that the secular trend in height will continue for the
      Portuguese population in the future decade.

PMID- 10355500
TI  - Utility of genotyping in diagnosis of genetic haemochromatosis.

PMID- 10355501
TI  - Recommendations of the International Association for the Study of the Liver
      Subcommittee on nomenclature of acute and subacute liver failure.

PMID- 10355502
TI  - Molecular aspects of organic compound transport across the plasma membrane of
      hepatocytes.
AB  - Many organic compounds are taken up from the blood by membrane transporters,
      taken across the sinosuidal membrane of hepatocytes and then excreted into bile
      via the bile canalicular membrane. The hepatic uptake of conjugated bile acids is
      mediated by the sodium taurocholate cotransporting polypeptide. Many organic
      anions and bulky organic cations are incorporated into hepatocytes by the organic
      anion transporting polypeptide, while small organic cations are transported by
      the organic cation transporter. At the canalicular membrane, organic compounds
      are excreted into bile by ATP-binding cassette transporters which hydrolyse ATP
      to ADP. Excretion of monovalent bile acids is mediated by the canalicular bile
      salt transporter and that of organic anions, including divalent bile acid,
      conjugates, are mediated by the multi-drug resistance-associated protein 2, also
      termed canalicular multi-specific organic anion transporter. Organic cations are
      excreted into bile by the multi-drug resistance gene product (MDR) 1 and
      phospholipids are excreted by MDR3 (mdr2 in mice and rats). The clinical
      syndromes associated with alterations of these transporters are also discussed.

PMID- 10355503
TI  - Effect of ursodeoxycholic acid on autoimmune-associated chronic hepatitis C.
AB  - BACKGROUND: Hypergammaglobulinaemia and various auto-antibodies which are
      commonly seen in autoimmune hepatitis are also found in patients with chronic
      hepatitis C. We recently reported that ursodeoxycholic acid (UDCA) improved liver
      function tests and immunoserological markers in patients with type I autoimmune
      hepatitis. The aim of this study was to prospectively evaluate the efficacy of
      UDCA on autoimmune-associated chronic hepatitis C. METHODS: Immunoglobulin G
      (IgG), anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA)
      were determined in 95 patients with chronic hepatitis C. All patients were
      positive for hepatitis C virus RNA. Autoimmune-associated chronic hepatitis C (C
      AIH) was defined by elevated serum IgG level (> or = 2.0 g/dL) and high titres of
      ANA and/or ASMA (> or = 1 : 160). Nine (9%) of 95 patients were diagnosed as C
      AIH. All the C-AIH patients and 30 of the remaining 86 chronic hepatitis C
      patients without autoimmune features (CHC) were treated with UDCA (600 mg/day)
      for 1 year. RESULTS: Autoimmune-associated chronic hepatitis C patients included
      one man and eight women and their AIH scores, as defined by the International
      Autoimmune Hepatitis Group, were significantly higher than the CHC patients.
      Before UDCA therapy, there were no significant differences in aspartate
      aminotransferase (AST), alanine aminotransferase (ALT) and y-glutamyl
      transpeptidase (gamma-GTP) levels between C-AIH and CHC patients. However, after
      1 year UDCA therapy, AST, ALT and gamma-GTP were significantly lower in C-AIH
      patients (P< 0.05) than in CHC patients. In C-AIH, ANA titres in seven of nine
      patients and ASMA titres in five of seven patients were reduced after 1 year UDCA
      treatment. CONCLUSIONS: These results suggest that UDCA is a useful therapeutic
      agent for autoimmune-associated chronic hepatitis C.

PMID- 10355504
TI  - Low-titre auto-antibodies predict autoimmune disease during interferon-alpha
      treatment of chronic hepatitis C.
AB  - BACKGROUND: In this study, we determined whether low-titre auto-antibodies are a
      risk factor for the development of autoimmune disease during interferon-alpha
      (IFNalpha) therapy for chronic hepatitis C (CHC) infection. METHODS: Eighty-three
      patients with circulating hepatitis C virus RNA and chronic viral hepatitis on
      liver biopsy, who had not received IFNalpha, were assessed for serum auto
      antibodies (anti-nuclear antibodies (ANA), anti-smooth muscle antibodies, thyroid
      microsomal antibodies, thyroglobulin antibodies) and thyroid function tests.
      RESULTS: Thirty-five patients had one or more pre-existing auto-antibody. The
      majority were low titre ANA. Seven of the 35 patients had clinical autoimmune
      disease or immune-mediated disorders, predominantly thyroid disease. Twenty
      patients with low titre auto-antibodies received treatment with IFNalpha and of
      these 20 patients, six patients developed adverse effects with a possible auto
      immune basis. In comparison, only five of the 48 patients without auto-antibodies
      had immune-mediated disorders and no patient developed autoimmune complications
      during therapy with IFNalpha. CONCLUSIONS: These results suggest that the
      presence of low-titre auto-antibodies may be a risk factor for the development of
      autoimmune dysfunction during IFNalpha therapy for chronic hepatitis C. Patients
      with no detectable auto-antibodies have a low risk for developing autoimmune
      complications during treatment with IFNalpha.

PMID- 10355505
TI  - Comparison of two methods for quantification of hepatitis B viral DNA.
AB  - BACKGROUND: Quantitation of serum hepatitis B virus (HBV) DNA has proven useful
      in assisting with patient management and treatment and several commercially
      available assays have been developed to quantify serum HBV-DNA levels. METHODS:
      The performance of the cross-linking assay and the branched-DNA signal
      amplification (bDNA) assay for the quantitative measurement of HBV-DNA was
      studied in 99 hepatitis B surface antigen-positive and viraemic patients.
      RESULTS: Of these samples, 82 (83%) were positive for HBV-DNA by both assays and
      four (4%) were below the cut-off for both assays. Of the remaining 13 samples, 10
      contained measurable levels of HBV-DNA by the cross-linking assay alone and three
      other samples contained measurable levels of HBV-DNA by the bDNA assay alone. The
      sensitivity gain of the cross-linking assay relative to bDNA assay in this study
      population was 10/92 (11%). In addition, a linear regression analysis showed that
      the HBV-DNA levels obtained from both assays was significantly correlated
      (gamma=0.974, P< 0.0001). CONCLUSIONS: These findings suggest that the recently
      developed cross-linking assay is more sensitive than the bDNA assay for the
      quantitative determination of HBV-DNA.

PMID- 10355506
TI  - Genotyping as a diagnostic aid in genetic haemochromatosis.
AB  - BACKGROUND: Two mutations in a newly described gene, HFE, have been proposed as
      genetic markers for the inherited iron overload disease, genetic
      haemochromatosis. METHODS: We assessed the frequency of both mutations in a
      cohort of genetic haemochromatosis patients and compared these with a control
      population. The patients were genetic haemochromatosis patients from Western
      Australia whose diagnosis met strict criteria for phenotypic expression. Control
      patients had other liver disease where iron overload was excluded. RESULTS:
      Genomic DNA of 72 genetic haemochromatosis patients and 69 controls was examined
      for the C282Y and H63D mutations of the HFE gene using polymerase chain reaction
      amplification and restriction enzyme digestion. In genetic haemochromatosis
      patients, the C282Y mutation was homozygous in 64 of 72, giving a sensitivity of
      89% (95% confidence interval 82-96%), heterozygous in five (7%) and absent in
      another three (4%), whereas none of the control subjects were homozygous. The
      H63D mutation was present in one genetic haemochromatosis patient and was not
      useful as a diagnostic marker. In this cohort of Western Australian patients with
      phenotypic expression of genetic haemochromatosis, the specificity of a
      homozygous C282Y mutation for genetic haemochromatosis was 100%. CONCLUSIONS: The
      results indicate that genotyping for the C282Y mutation is a useful test for the
      diagnosis of genetic haemochromatosis in clinical practice.

PMID- 10355507
TI  - Case report: a rare association of primary biliary cirrhosis and systemic lupus
      erythematosus and review of the literature.
AB  - We report a rare occurrence of systemic lupus erythematosus in a patient known to
      have had well-documented primary biliary cirrhosis for 10 years. The presentation
      was dramatic with pericardial tamponade, but responded well to high dose
      corticosteroid. There are only five such definite associations reported in the
      literature. In the present case, other possible causes were considered, such as
      drug-induced cholestasis, drug-induced lupus, autoimmune chronic active hepatitis
      and the overlap syndrome.

PMID- 10355508
TI  - Highly enhanced fucosylation of serum glycoproteins in patients with
      hepatocellular carcinoma.
AB  - BACKGROUND: We recently reported that the measurement of Lens culinaris
      agglutinin-reactive species of alpha-fetoprotein (AFP), alpha-1-antitrypsin (AAT)
      and transferrin (TF) is useful for the diagnosis of hepatocellular carcinoma
      (HCC) and that the molecular basis for this reactivity is fucosylation at the
      innermost N-acetylglucosamine residue of a biantennary sugar chain. However, the
      precise relationship of the fucosylation of AFP, AAT and TF in patients with HCC
      and liver cirrhosis is not fully understood. The aim of this study is to
      delineate the relationship of the fucosylation between these three glycoproteins
      in HCC. METHODS: Three hundred and thirty-four patients with HCC were referred to
      our university hospital from 1987 to 1997. An increase in serum AFP (> 20 ng/mL)
      was observed in 233 (69.8%) patients with HCC. From these 233 patients with AFP
      producing HCC, 60 serum samples were randomly selected and used in the present
      study. As a reference, samples from 60 patients with liver cirrhosis, in which 30
      had increased AFP, were used. Lens culinaris agglutinin (LCA)-reactive species
      were determined by crossed immunoaffinoelectrophoresis (CIAE). The contents of
      the fucosylated biantennary chain of purified AAT and TF samples were determined
      as pyridylamino derivatives of each oligosaccharide with high-performance liquid
      chromatography (HPLC). RESULTS: There was a highly significant correlation
      between LCA-reactive species by CIAE and pyridyl-amino-fucosylated biantennary
      sugar chain by HPLC in both AAT and TF. Lens culinaris agglutinin-reactive
      species of AFP, AAT and TF in HCC were significantly higher than those in liver
      cirrhosis. A highly statistically significant positive correlation of fucosylated
      glycans was observed between AAT and TF in both HCC and liver cirrhosis, but not
      between AFP and AAT or between AFP and TF. Accordingly, the present results
      indicate that highly enhanced fucosylation of serum glycoproteins was found in
      HCC compared with liver cirrhosis and that the combination of measurements of
      fucosylated AFP with AAT or TF were useful for the diagnosis of HCC.

PMID- 10355509
TI  - Apolipoprotein A-I in bile inhibits cholesterol crystallization and modifies
      transcellular lipid transfer through cultured human gall-bladder epithelial
      cells.
AB  - BACKGROUND: Apolipoprotein A-I (Apo A-I), conventionally purified by several
      steps including organic solvent-delipidation from plasma, inhibits cholesterol
      crystallization in bile. To observe a significant effect in vitro, however,
      supraphysiological concentrations above 100 microg/mL are required. For this
      reason, this protein has not been considered to play a physiological role in
      vivo. In the present study, we examined the cholesterol crystal growth-inhibiting
      effect of biliary Apo A-I at its physiological concentration, the modification of
      transcellular transfer of biliary lipids through cultured human gall-bladder
      epithelial cells (GBEC) by Apo A-I at its physiological concentration and the
      binding and secretion of Apo A-I by GBEC. METHODS AND RESULTS: We purified
      biliary Apo A-I to near homogeneity using immobilized artificial membrane
      chromatography. At 5 microg/mL, biliary Apo A-I reduced cholesterol crystal mass
      by 50%, whereas plasma-derived, solvent-delipidated Apo A-I had no effect. Using
      an antibody-capture enzyme-linked immunosorbent assay, we found reduced Apo A-I
      concentrations in bile samples from gallstone patients when compared with bile
      samples from gallstone-free controls (medians, 2.35 and 9.4 microg/mL,
      respectively). In a GBEC line, Apo A-I (5 microg/mL) enhanced transfer of
      phospholipid and cholesterol from the mucosal to the serosal side of cell
      monolayers by approximately 50%. These cells appear to bind Apo A-I reversibly in
      a dose- and time-dependent manner, compatible with receptor-type binding.
      Cultured human gall-bladder epithelial cells also showed basal secretion of Apo A
      I, which was greatly increased by exposure to model bile solutions. CONCLUSIONS:
      Apolipoprotein A-I in bile, thus, has both a direct effect on cholesterol crystal
      formation and enhances lipid removal from gall-bladder bile by GBEC. This effect
      may be specific and receptor mediated. These observations support two separate
      roles for human biliary Apo A-I and suggest that this protein may be important in
      preventing the formation of cholesterol crystals (the initial step in gallstone
      formation) in supersaturated bile.

PMID- 10355510
TI  - Increased neutrophil chemotaxis in obstructive jaundice: an in vitro experiment
      in rats.
AB  - BACKGROUND AND AIMS: Changes in neutrophil functions in obstructive jaundice have
      been poorly understood. An in vitro experimental study was performed to evaluate
      the effect of obstructive jaundice on the functions of macrophages (secretion of
      neutrophil chemoattractants) and neutrophils (chemotaxis and superoxide anion
      generation). METHODS: Obstructive jaundice was produced in rats by 7 day bile
      duct ligation. Peripheral neutrophils and peritoneal macrophages were harvested
      from either normal, sham-ligated or bile duct-ligated rats and supernatants of
      the monolayers of the respective macrophages were prepared after stimulation with
      lipopolysaccharide. Neutrophil chemotaxis was evaluated with a modified Boyden
      method. RESULTS: The supernatant of the bile duct-ligated rat macrophages showed
      a chemotactic effect on normal rat neutrophils with insignificant difference from
      the supernatant of the sham-ligated rat macrophages. Chemotaxis of the bile duct
      ligated rat neutrophils towards the supernatant of the normal rat macrophages was
      significantly increased, compared with that of sham-ligated rat neutrophils.
      Similarly, neutrophils from bile duct-ligated rats showed significantly greater
      chemotaxis to formyl-methionyl-leucyl-phenylalanine than the sham-ligated rat
      neutrophils. Superoxide anion generation in response to formyl-methionyl-leucyl
      phenylalanine or phorbol myristate acetate was significantly increased in the
      bile duct-ligated rats compared with the sham-ligated rats. CONCLUSIONS: The
      results suggest that the neutrophil is primed in terms of chemotaxis and
      superoxide anion generation in obstructive jaundice. How these activated
      neutrophils play a role in the inflammatory response to obstructive jaundice
      should be evaluated.

PMID- 10355511
TI  - Case report: two cases of biliary papillomatosis with unusual associations.
AB  - Papillomatosis arising from the biliary tree is a well recognized but rare
      entity. We encountered two patients with this condition. However, one of them had
      associated hepatocellular carcinoma and cirrhosis and the other had concomitant
      recurrent pyogenic cholangitis. To our knowledge, these associations have not
      been reported before. We, therefore, present these clinical problems and
      highlight the added difficulty in the management of these patients.

PMID- 10355512
TI  - Efficacy of 7 day lansoprazole-based triple therapy for Helicobacter pylori
      infection in elderly patients.
AB  - BACKGROUND: The prevalence of Helicobacter pylori increases with age. However,
      data regarding the effects of anti-H. pylori treatments in the elderly are very
      scarce. METHODS: To evaluate the effect of three lansoprazole-based, 7 day,
      triple-therapy regimens on H. pylori eradication rates, symptomatology, chronic
      gastritis activity and serological markers of H. pylori infection in elderly
      subjects, we studied 150 symptomatic patients over 60 years of age with H. pylori
      positive duodenal ulcer (DU, n = 34), gastric ulcer (GU, n= 19) or chronic
      gastritis (CG, n = 97). Patients were consecutively treated with one of the
      following regimens: (A) lansoprazole (LNS) 30 mg b.i.d. + clarithromycin (CLR)
      250 mg b.i.d. + metronidazole (MTR) 250 mg q.i.d.; (B) LNS 30mg b.i.d. +
      amoxycillin (AMOX) 1 g b.i.d. + MTR 250 mg q.i.d.; and (C) LNS 30 mg b.i.d. + CLR
      250 mg b.i.d. + AMOX 1 g b.i.d. RESULTS: Two months after therapy, the
      eradication rates of the three treatments, expressed using both intention-to
      treat and per-protocol analyses were, respectively; group A, 86 and 91.5%; group
      B, 80 and 87%; group C, 82 and 89.1%. After therapy, a significant reduction in
      epigastric pain (P<0.001), heartburn (P=0.02), dyspepsia (P<0.001) and vomiting
      (P< 0.005) was observed independently of the success of H. pylori eradication. A
      significantly higher percentage of asymptomatic patients were in the GU-DU group
      than in CG group (87.7 vs 70.0%, P= 0.032). After therapy, 33 subjects still
      suffered from symptoms. Persistence of symptoms was significantly associated with
      an endoscopic diagnosis of oesophagitis and not with H. pylori infection.
      Patients cured of H. pylori infection showed a significant decrease in the
      histological activity of both antral and body gastritis (P< 0.0001), a
      significant drop in immunoglobulin (Ig) G anti-H. pylori antibodies (P< 0.0001)
      and pepsinogen (PG) C (P<0.0001) and an increase in the PGA/PGC ratio (P<0.0001).
      CONCLUSIONS: The 7 day, lansoprazole-based triple therapy was well tolerated and
      highly effective in the cure of H. pylori infection, the reduction of symptoms,
      chronic gastritis activity and serum levels of IgG anti-H. pylori antibodies and
      PGC. Persistence of symptoms after therapy was significantly higher in CG than GU
      and DU patients and was significantly associated with oesophagitis.

PMID- 10355513
TI  - High prevalence of cagA-positive strains in Helicobacter pylori-infected,
      healthy, young Chinese adults.
AB  - BACKGROUND: Cytotoxin-associated gene A (cagA) has been implicated as a potential
      pathogenic marker for Helicobacter pylori-induced severe gastroduodenal diseases.
      Although the prevalence of cagA-positive strains has been reported in patient
      populations from developed countries, only limited information from developing
      countries is available. METHODS: Polymerase chain reaction (PCR) in combination
      with immunoblot analysis was used to determine the prevalence of cagA and its
      adjacent cagE genes and to evaluate the expression of CagA protein in 55 H.
      pylori clinical isolates from China. RESULTS: The expected PCR products derived
      from H. pylori cagA and cagE genes were identified in all Chinese H. pylori
      clinical isolates. Similarly, the CagA protein was detected in all 40 isolates
      tested. CONCLUSIONS: These results demonstrated that the presence of the cagA
      gene correlated well with expression of the CagA protein in all surveyed Chinese
      H. pylori isolates and that infection with cagA-positive H. pylori strains is
      highly common in China and independent of clinical presentation.

PMID- 10355514
TI  - A sclerosant with astringent properties developed in China for oesophageal
      varices: comparison with ethanolamine oleate and polidocanol.
AB  - BACKGROUND: Xiao zhi ling (XZL), which consists of Chinese nutgalls and aluminium
      potassium sulphate, is used as a local injection for the treatment of internal
      haemorrhoids in China. It is also used for endoscopic sclerotherapy of
      oesophageal varices. To date, however, it has not been compared with other
      sclerosants with regard to its safety and efficacy. METHODS: In the present
      study, the effect on the endothelium and the haemolytic and thrombosing effects
      of XZL were compared with those of 5% ethanolamine oleate and 1% polidocanol,
      using an endothelial cell line and red blood cells taken from rats and the dorsal
      marginal ear vein of rabbits. In addition, XZL was injected into the area
      surrounding varices in rats and its efficacy was studied endoscopically and
      histologically. RESULTS: Xiao zhi ling reduced the size of varices in rats after
      causing severe damage in the injected region. Compared with the other two
      sclerosants, however, XZL had little effect on the endothelium and was the least
      haemolytic compound. Furthermore, XZL did not cause thrombosis in the injected
      vein of a rabbit. CONCLUSIONS: These results suggest that XZL is another type of
      sclerosant with astringent rather than detergent properties. This compound should
      be used to treat oesophageal varices by paravariceal injection in smaller doses
      than 5% ethanolamine oleate and 1% polidocanol.

PMID- 10355515
TI  - Effect of temperature and mechanical strain on gastric epithelial cell line GSM06
      wound restoration in vitro.
AB  - BACKGROUND: The influence of the degree of cell differentiation and of physical
      stimulation on gastric mucosal wound healing is not completely understood.
      METHODS: A gastric mucosal cell line, GSM06, derived from the gastric mucosal
      cells of transgenic mice harbouring the simian virus 40 large T antigen, was
      cultured at 33 degrees C to make a confluent cell sheet. Artificial wounds of
      constant size were created. Wound healing was monitored at different temperatures
      (33, 37 and 39 degrees C), which altered the degree of differentiation. Cell
      proliferation was detected by bromodeoxyuridine staining. Mechanical strain was
      applied to adherent GSM06 cells after wounding in order to increase their length
      by an average of 5 or 10% at 5 cycles/min for 60 h. Repair of the wound was
      monitored every 12 h. RESULTS: Differentiated gastric epithelial cells showed a
      higher speed of migration. The number of proliferating cells around the wound was
      greatest at 33 degrees C and barely detectable at 39 degrees C. Under conditions
      of mechanical strain, the migration speed of differentiated cells (at 39 degrees
      C) slowed in a strain strength-dependent manner. CONCLUSIONS: It is suggested
      that cell differentiation status and physical stimulants might play a role in
      gastric wound healing in vivo by modifying cellular migration.

PMID- 10355517
TI  - Increased intestinal non-substance P tachykinin concentrations in malignant
      midgut carcinoid disease.
AB  - BACKGROUND: Diarrhoea is an important feature of the carcinoid syndrome, and
      various agents which may be released from carcinoid tumours have been considered
      to contribute pathophysiologically. The aim of the present study was to determine
      luminal concentrations of possible chemical mediators in an uninvolved small
      intestinal segment using a two-balloon six-channel tube in nine patients with
      malignant midgut carcinoid disease. METHODS: All patients were treated with
      interferon and/or octreotide to alleviate the most severe flush. Ion transport
      was measured during luminal perfusion and luminal perfusate concentrations of
      calcitonin gene-related peptide, neurotensin, prostaglandin E (PGE)2,
      neuropeptide Y, somatostatin, vasoactive intestinal polypeptide, substance P and
      other tachykinins (neurokinin A, neurokinin B, neuropeptide K, eledoisin) were
      determined by separate assays. RESULTS: Carcinoid patients showed decreased
      absorption of Cl-, Na+, K+ and water and increased luminal content of non
      substance P tachykinins to 424.5 fmol/cm per h, compared with 255.5 fmol/cm per h
      in control subjects. There were also increased luminal concentrations of PGE2,
      commonly claimed as a more general mediator of diarrhoea. CONCLUSIONS: The
      observed increase in intestinal tachykinins may involve extended activity from
      tachykinin-containing intrinsic neurones in the enteric nervous system,
      contributing to enhanced intestinal motility and secretory diarrhoea in patients
      with carcinoid syndrome.

PMID- 10355518
TI  - Images of interest. Gastrointestinal: intraluminal duodenal diverticulum.

PMID- 10355519
TI  - Images of interest. Hepatobiliary and pancreatic: a man with an amoebic liver
      abscess.

PMID- 10355516
TI  - Rebamipide prevents occurrence of gastric lesions following transcatheter
      arterial embolization in the hepatic artery.
AB  - BACKGROUND: Transcatheter arterial embolization (TAE) of the hepatic artery is a
      common treatment method for hepatocellular carcinoma (HCC), but it often induces
      gastric mucosal injury. We examined whether or not rebamipide administration,
      beginning 1 week before and ending 2 weeks afterTAE, can prevent worsening of
      gastric mucosal disorders. METHODS: The subjects were 73 chronic hepatitis C or
      type C liver cirrhosis patients who concomitantly had HCC and received TAE in our
      hospital. The patients were randomly allocated to the rebamipide group (oral, 300
      mg/day for 3 weeks starting 1 week before TAE) or the non-rebamipide group.
      Gastric endoscopy was performed 1 week before and 2 weeks afterTAE and the
      presence of erythema, erosion and/or submucosal haemorrhagic spots was monitored.
      Based on the findings, gastric mucosal disorder before and after TAE was
      quantitatively evaluated using the modified Lanza score (MLS). RESULTS: Overall,
      MLS after TAE increased significantly (P< 0.05). However, in the rebamipide
      group, MLS did not change. The MLS after TAE increased significantly in patients
      who had either liver cirrhosis, oesophageal varices or gastropathy (P< 0.01 or <
      0.05). In the non-rebamipide group, a significant increase in MLS after TAE was
      observed in patients who had one of the above-mentioned three diseases (P< 0.01
      or < 0.05). CONCLUSIONS: Gastric lesions which were present before TAE were
      significantly worsened after TAE. Rebamipide administration prevents TAE-induced
      aggravation of gastric lesions.

PMID- 10355520
TI  - Drosophila conditioned courtship: two ways of testing memory.
AB  - In Drosophila, courtship reduction in male flies that have previous experience of
      courting a mated female is a result of the counterconditioning of an attractive
      unconditioned stimulus (US)--the aphrodisiac--which becomes an aversive
      conditioned stimulus (CS) after being paired with an aversive US--the
      antiaphrodisiac. In a retention test with a virgin female lacking the
      antiaphrodisiac, males retain a lower level of courtship for 3 hr after training.
      However, a measure of courtship suppression, the learning index (LI), decreases
      significantly after only 1 hr. In contrast, in the retraining test with a mated
      female, the LI shows no decrease for 8 hr but falls below significance 16 hr
      after training. These results are discussed in terms of the transfer of training.
      Nonspecific transfer and nonassociative behavioral modifications play little, if
      any, role in the transfer of training. The retraining test is recommended as a
      new protocol for studying conditioned courtship. According to the model proposed
      here, in tests with a virgin female, the duration of memory retention is limited
      by the retention of the direct association between the CS and the aversive
      motivational system or by the retention of an internal representation of the US.
      In retraining tests, the CS-US association seems to be the only factor involved
      in transfer 3 or more hours after training.

PMID- 10355521
TI  - Separate effects of a classical conditioning procedure on respiratory pumping,
      swimming, and inking in Aplysia fasciata.
AB  - We examined whether swimming and inking, two defensive responses in Aplysia
      fasciata, are facilitated by a classical conditioning procedure that has been
      shown to facilitate a third defensive response, respiratory pumping. Training
      consisted of pairing a head shock (UCS) with a modified seawater (85%, 120%, or
      pH 7.0 seawater--CSs). Animals were tested by re-exposing them to the same
      altered seawater 1 hr after the training. For all three altered seawaters, only
      respiratory pumping is specifically increased by conditioning. Swimming is
      sensitized by shock, and inking is unaffected by training, indicating that the
      conditioning procedure is likely to affect a neural site that differentially
      controls respiratory pumping. Additional observations also indicate that the
      three defensive responses are differentially regulated. First, different noxious
      stimuli preferentially elicit different defensive responses. Second, the three
      defensive responses are differentially affected by shock. Inking is elicited only
      immediately following shock, whereas swimming and respiratory pumping are
      facilitated for a period of time following the shock. Third, swimming and
      respiratory pumping are differentially affected by noxious stimuli that are
      delivered in open versus closed environments. These data confirm that neural
      pathways exist that allow Aplysia to modulate separately each of the three
      defensive behaviors that were examined.

PMID- 10355522
TI  - Rapid, labile, and protein synthesis-independent short-term memory in conditioned
      taste aversion.
AB  - Short-term memory is a rapid, labile, and protein-synthesis-independent phase of
      memory. The existence of short-term memory in conditioned taste aversion (CTA)
      learning has not been demonstrated formally. To determine the earliest time at
      which a CTA is expressed, we measured intraoral intake of sucrose at 15 min, 1
      hr, 6 hr, or 48 h after contingent pairing of an intraoral infusion of 5% sucrose
      (6.6 ml over 6 min) and toxic lithium chloride injection (76 mg/kg). Rats were
      implanted with intraoral catheters to allow presentation of taste solutions at
      arbitrary times. Intraoral intake was measured under conditions of long-delay,
      single-trial learning typical of CTA. Rats decreased intraoral intake of sucrose
      at 15 min after contingent pairing of sucrose and LiCl, but not after
      noncontingent LiCl or sucrose. Thus CTA learning can be expressed rapidly. To
      determine if short-term CTA memory is labile and decays in the absence of long
      term memory, we measured intraoral intake of sucrose after pairing sucrose with
      low doses of LiCl. Rats received an intraoral infusion of 5% sucrose (6 ml/6
      min); 30 min later LiCl was injected at three different doses (19, 38, or 76
      mg/kg). A second intraoral infusion of sucrose was administered 15 min, 1 hr, 3
      hr, 4.5 hr, 6 hr, or 48 hr later. The formation of long-term CTA memory was
      dependent on the dose of LiCl paired with sucrose during acquisition. Low doses
      of LiCl induced a CTA that decayed within 6 hr after pairing. Central
      administration of the protein synthesis inhibitor cycloheximide prior to LiCl
      injection blocked long-term CTA expression at 6 and 48 hr, but not short-term CTA
      expression at 1 hr. Thus, short-term memory for CTA learning exists that is
      acquired rapidly and independent of protein synthesis, but labile in the absence
      of long-term memory formation.

PMID- 10355523
TI  - Prism adaptation and aftereffect: specifying the properties of a procedural
      memory system.
AB  - Prism adaptation, a form of procedural learning, is a phenomenon in which the
      motor system adapts to new visuospatial coordinates imposed by prisms that
      displace the visual field. Once the prisms are withdrawn, the degree and strength
      of the adaptation can be measured by the spatial deviation of the motor actions
      in the direction opposite to the visual displacement imposed by the prisms, a
      phenomenon known as aftereffect. This study was designed to define the variables
      that affect the acquisition and retention of the aftereffect. Subjects were
      required to throw balls to a target in front of them before, during, and after
      lateral displacement of the visual field with prismatic spectacles. The diopters
      of the prisms and the number of throws were varied among different groups of
      subjects. The results show that the adaptation process is dependent on the number
      of interactions between the visual and motor system, and not on the time spent
      wearing the prisms. The results also show that the magnitude of the aftereffect
      is highly correlated with the magnitude of the adaptation, regardless of the
      diopters of the prisms or the number of throws. Finally, the results suggest that
      persistence of the aftereffect depends on the number of throws after the
      adaptation is complete. On the basis of these results, we propose that the system
      underlying this kind of learning stores at least two different parameters, the
      contents (measured as the magnitude of displacement) and the persistence
      (measured as the number of throws to return to the baseline) of the learned
      information.

PMID- 10355524
TI  - Landmark discrimination learning in the dog.
AB  - Allocentric spatial memory was studied in dogs of varying ages and sources using
      a landmark discrimination task. The primary goal of this study was to develop a
      protocol to test landmark discrimination learning in the dog. Using a modified
      version of a landmark test developed for use in monkeys, we successfully trained
      dogs to make a spatial discrimination on the basis of the position of a visual
      landmark relative to two identical discriminanda. Task performance decreased,
      however, as the distance between the landmark and the "discriminandum" was
      increased. A subgroup of these dogs was also tested on a delayed nonmatching to
      position spatial memory task (DNMP), which relies on egocentric spatial cues.
      These findings suggest that dogs can acquire both allocentric and egocentric
      spatial tasks. These data provide a useful tool for evaluating the ability of
      canines to use allocentric cues in spatial learning.

PMID- 10355526
TI  - Cancer departments as a source of resistant bacteria and fungi?
AB  - Antimicrobial resistance increases worldwide. Among many factors, such as clonal
      spread of genes of resistance among and intra species, local epidemiology,
      nosocomial transmission, also consumption of antimicrobials may be responsible.
      Cancer departments, mainly in centers treating hematologic malignancies and
      organizing bone marrow transplantation (BMT) are known to have extensive
      consumption of either prophylactically or therapeutically administered
      antibiotics and antifungals. It is worthy to remember, that first strains of
      quinolone resistant E. coli, vancomycin resistant enterococci and staphylococci
      and fluconazol-resistant Candida albicans appeared in the patients treated for
      cancer with antineoplastic chemotherapy, resulting in profound granulocytopenia.
      Therefore, assessment of risks of antibiotic prophylaxis with quinolones and
      azoles and extensive use of empiric therapy with glycopeptides and polyenes needs
      to be considered. Intensive prophylactic strategies should be limited to group of
      high risk, leukemic patients or BMT recipients.

PMID- 10355527
TI  - Small cell carcinoma of the esophagus.
AB  - Small cell carcinoma of the esophagus (SCEC) is a rare tumor with its particular
      biologic features, distinct from squamous and glandular carcinoma of esophagus.
      Although initial symptoms can be similar (with metastatic dissemination and
      paraneoplastic syndromes at presentation more frequent in SCEC), differences in
      age and sex distribution, tumor location, radiological and endoscopic findings,
      clinical course and prognosis have been observed between SCEC and other
      esophageal malignancies. SCEC should be considered a systemic disease, and by
      analogy to bronchogenic small cell carcinoma, multimodality approach including
      chemotherapy is recommended. In patients with limited disease, irradiation or
      surgery should be offered after induction chemotherapy to manage local disease.
      However, optimal treatment schedule has not yet been defined. In the future,
      registration of all SCEC cases and careful analysis of prognostic factors in the
      larger multi-institutional series could contribute to further progress in
      treatment outcome.

PMID- 10355525
TI  - On the respective roles of nitric oxide and carbon monoxide in long-term
      potentiation in the hippocampus.
AB  - Perfusion of hippocampal slices with an inhibitor nitric oxide (NO) synthase
      blocked induction of long-term potentiation (LTP) produced by a one-train tetanus
      and significantly reduced LTP by a two-train tetanus, but only slightly reduced
      LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme
      for carbon monoxide (CO), significantly reduced LTP by either a two-train or four
      train tetanus. These results suggest that NO and CO are both involved in LTP but
      may play somewhat different roles. One possibility is that NO serves a phasic,
      signaling role, whereas CO provides tonic, background stimulation. Another
      possibility is that NO and CO are phasically activated under somewhat different
      circumstances, perhaps involving different receptors and second messengers.
      Because NO is known to be activated by stimulation of NMDA receptors during
      tetanus, we investigated the possibility that CO might be activated by
      stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this
      idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by
      inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also
      blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or
      cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in
      hippocampal slices. However, biochemical assays indicate that whereas heme
      oxygenase is constitutively active in hippocampus, it does not appear to be
      stimulated by either tetanus or tACPD. These results are most consistent with the
      possibility that constitutive (tonic) rather than stimulated (phasic) heme
      oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest
      that mGluR activation stimulates guanylyl cyclase phasically through some other
      pathway.

PMID- 10355528
TI  - Cell surface immunophenotype and gelatinase activity of the human breast
      carcinoma cell line (MCF-7/6) with functionally defective E-cadherin.
AB  - Expression of differentiation and adhesion cell surface antigens (LewisX - CD15,
      CD44, syndecan 1 - CD138 and basigin/EMMPRIN - CD147) were determined on the cell
      surface of human breast carcinoma MCF7 cells in vitro with the aid of flow
      cytometry and compared with that of MCF-7/6 cells, with functionally defective E
      cadherin system and increased biological aggressiveness. The major cell surface
      alterations in MCF-7/6 cells compared with the parental MCF-7 cell line were a
      markedly increased CD15 (LewisX) and CD44 antigen cell surface expression on MCF
      7/6 cells. There were no major differences between parental MCF-7 and MCF-7/6
      cells in cell surface syndecan 1, basigin/EMMPRIN, E-cadherin and high affinity
      non-integrin laminin receptor expression. The constitutive cell surface
      gelatinase A and B activities were absent on MCF-7 and faint in MCF-7/6 cells.
      Both phorbol ester TPA and tumor necrosis factor TNF-alpha induced a marked up
      regulation of gelatinase B only in MCF-7/6 cells. No marked differences in
      penetration of MCF-7 vs. MCF-7/6 cells into collagen/fibroblast matrix in vitro
      were observed. The increased expression of CD15 (LewisX), CD44 antigen and TNF
      alpha-inducible gelatinase B on MCF-7/6 cells may represent auxiliary factors
      contributing to the increased biological aggressiveness of MCF-7/6 cells.

PMID- 10355529
TI  - Study of in vitro conditions modulating expression of MN/CA IX protein in human
      cell lines derived from cervical carcinoma.
AB  - In an effort to better understand the biological significance of MN/CA IX human
      tumor-associated protein, we have investigated its expression in human cervical
      carcinoma cell lines in vitro. SiHa cells that naturally express MN/CA IX were
      used as a model for expression study at the protein level. In addition, we have
      transfected MN/CA9 gene-negative but transcription-competent C33A cells with a
      plasmid carrying CAT reporter gene under a control of MN/CA9 promoter. By this
      way, we have generated a stable cell line C33A/MNP-CAT that was employed in
      analysis of MN/CA9 regulation at the level of promoter activity as estimated by
      CAT protein abundance. For the purpose of our study, we have chosen experimental
      conditions relevant to growth characteristics and phenotypic features of
      malignantly transformed cells. Both the level of MN/CA IX protein and the gene
      promoter activity were found to be substantially elevated either in culture of
      high density or when the adherent carcinoma cells grew in suspension, but were
      not markedly affected by diminished serum concentration and in the cell cycle
      progression. These observations support the involvement of MN/CA IX protein in
      aberrant cell-cell and cell-matrix interactions that facilitate loss of contact
      inhibition and anchorage independence of cancer cells.

PMID- 10355530
TI  - Expression of bcl-2 protein in non-small cell lung cancer: correlation with
      clinicopathology and patient survival.
AB  - Molecular genetic studies have revealed mutations in a number of oncogenes and
      tumor suppressor genes in lung cancer. The bcl-2 gene product (bcl-2 protein) is
      implicated in oncogenesis by its ability to prolong cell death through the
      inhibition of apoptosis. We investigated expression of bcl-2 in 84 resected human
      non-small cell lung cancers (NSCLC) and correlated this phenomena with
      clinicopathology and survival. Immunohistochemical analysis with a monoclonal
      antibody specific for bcl-2 (Clone 124; Dako) was used to detect the protein in
      tumor samples. Overall, bcl-2 was detectable in 39 of 84 (46%) NSCLC. The
      percentage of bcl-2 positive cases varied according to the histological type.
      Positive bcl-2 immunostaining was observed in 27 of the 46 squamous cell
      carcinomas (59%), 7 of the 25 adenocarcinomas (28%) and 5 of the 13 large cell
      carcinomas (38%). The frequency of positive bcl-2 expression in squamous cell
      carcinomas was significantly higher than that in other histological two types (p
      = 0.037). Statistical comparisons between the patients' clinical characteristics
      and bcl-2 status revealed no significant differences in the frequency of bcl-2
      expression with respect to sex, T and N factors, as well as TNM stage. The
      relationship between bcl-2 protein expression and postoperative survival was
      analyzed in 84 patients. Patients with bcl-2 negative tumors showed significantly
      shorter survival times than those with bcl-2 positive tumors. In univariate
      analysis of various potential prognostic factors only TNM stage and bcl-2 test
      were significant prognostic factors (p < 0.009 and p < 0.008, respectively). In
      multivariate analysis (Cox proportional hazard model), bcl-2 status (negative
      test) was independent unfavorable prognostic factor (p = 0.017). In conclusion,
      this set of observations suggests that assessment of the expression status of bcl
      2 by tumors may provide prognostic information on the clinical behavior of NSCLC.

PMID- 10355531
TI  - Positive staining for p53 and expression of c-erbB-2 in endosalpinx hyperplasia:
      analysis of 48 cases and review of literature.
AB  - To establish the diagnostic value of p53 and c-erbB-2 expression, forty-eight
      cases of endosalpinx hyperplasia were analyzed. p53 protein and c-erbB-2
      oncoprotein expression was examined using an avidin-biotin peroxidase complex
      method. The accumulation of p53 protein and c-erbB-2 oncoprotein was used as
      objective evidence to support morphologic differential diagnosis of endosalpinx
      hyperplasia and early cancer. In all cases various forms of endosalpinx
      hyperplasia were seen. Only in 4 cases staining for p53 showed positive reaction
      without staining for c-erbB-2. In one case positive reaction for c-erbB-2 was
      showed and no expression of p53 protein was detected. It is concluded that
      immunohistochemical detection of the mutant p53 protein and c-erbB-2 oncoprotein
      might be useful tools in differential diagnosis among various forms of
      hyperplastic changes of endosalpinx. The presence of these markers may be
      associated with the risk of malignant transformation in various forms of the
      tubal hyperplasia.

PMID- 10355532
TI  - Soluble IL-6 and TNF receptors release by polymorphonuclear and mononuclear cells
      in cancer patients.
AB  - Immune response of the host to tumor is regulated by soluble mediators, such as
      cytokines. Data including the release of soluble mediators by polymorphonuclear
      cells (PMNs) are controversial. In the present investigation we studied the
      ability of spontaneous and LPS-stimulated PMNs derived from the patients with
      oral cavity cancer to the release of soluble IL-6 receptor (sIL-6R) and soluble
      TNF receptors (sTNF-Rs). Obtained results were compared to the release of sIL-6R
      and sTNFRs by peripheral blood mononuclear cells (PBMC) as well as the serum
      levels. The culture supernatants of spontaneous and LPS-stimulated PMNs derived
      from the patients with oral cavity cancer contained unchanged concentrations of
      sIL-6R and higher concentrations of sTNFRp55 and sTNFRp75 in comparison with the
      control. The amounts of sIL-6R and sTNF-Rs released by PBMC were higher than
      those released by PMNs in both control and patient groups. Demonstrated results
      indicate that PMN contribution in the immune response is mediated by TNF-alpha,
      via the release of sTNFRp75 mainly. Profile measurement of the soluble cytokine
      receptors in the culture supernatants of PMNs and PBMC and the serum levels may
      be useful for estimation of the actual immunity in patients with oral cavity
      cancer.

PMID- 10355533
TI  - Radiosensitivity of human lymphocytes in vitro correlates more with proliferative
      ability of cells than with the incidence of radiation-induced damages of the
      genome.
AB  - The purpose of this study was the estimate the extent of individual variability
      in radioresponse of human lymphocytes in vitro and to establish the reasons of
      variability. Individual variability in radiation-response was evaluated using the
      cytochalasin B micronucleus test among 82 healthy individuals (36 men and 46
      women), of mean age 38 (range 30-48). Blood samples were irradiated with gamma
      (60Co) rays at a dose of 2 Gy in vitro. The yield of radiation-induced
      micronuclei (MN), cytochalasin blocked proliferation index (CBPI), fraction of
      micronucleated binucleate (BN) cells and mean incidence of MN per micronucleated
      BN cells at a sampling time of 72 hours were scored. Our results brought out a
      significant effect of gender on the level of spontaneously occurring micronuclei,
      the lack of statistical differences between gender in the yield of radiation
      induced micronuclei and marked variability in radiation response among
      individuals. Likelihood of expressing hypersensitivity was correlated with
      ability of cells to proliferate in vitro (beta = 0.41, p < 0.000) more than with
      the incidence of radiation-induced micronuclei per micronucleated cell (beta =
      0.20, p < 0.000).

PMID- 10355534
TI  - Crosslinking of cellular DNA by nitracrine and furocoumarin derivatives.
AB  - The anticancer drug, nitracrine, a 1-nitro-9-aminoalkyl derivative of acridine
      exhibits potent cytotoxic effects which are due to its metabolic activation,
      followed by covalent binding to macromolecules--DNA being the target for the
      drug. The renaturable fraction of DNA from L-1210 cells pretreated with
      nitracrine is assayed by means of ethidium bromide fluorescence assay and
      chromatography on hydroxyapatite column. The effect of the drug was compared with
      furocoumarins of different DNA crosslinking potencies. The existence of
      crosslinks in DNA upon incubation of cells with nitracrine (1-4 microM) have been
      confirmed with two different methods under the conditions where 8
      methoxypsoralen, a classic crosslinking agent induced the renaturation. The DNA
      preparation isolated from the drug pretreated cells exhibited decreased
      transcriptional template activity with E. coli DNA-dependent RNA polymerase.

PMID- 10355535
TI  - The influence of surgery and anesthesia on lymphocyte functions in breast cancer
      patients: in vitro effects of indomethacin.
AB  - Surgical trauma and anesthesia may lead to the postoperative immunosuppression,
      the exact mechanism of which is still unresolved. Among various factors, the role
      of prostaglandine PGE2-mediated suppression was also proposed. We investigated
      the influence of surgery and two anesthetic regimes on lymphoproliferative
      response (LPR) to PHA and on NK cell activity (MTT) in breast cancer patients, as
      well as the effect of indomethacin, a PGE2 synthesis inhibitor, on these
      lymphocyte functions in vitro. In 36 previously untreated patients the lymphocyte
      functions were assayed before, 24 hours and seven days after the surgery. In
      regard to LPR, three distinct response patterns were observed: a) significant (p
      < 0.05) increase of initially lowered LPR; b) significant (p < 0.001) decrease of
      initially normal LPR 24 hours after operation, followed by normalization after
      seven days; c) no change of initially normal LPR. Indomethacin in vitro
      significantly (p < 0.05) enhanced the diminished LPR only before surgery, no
      effect being seen after the operation. The NK cell function was unaffected by
      surgery regardless the initial level of activity. Indomethacin had no effect on
      this lymphocyte function. There was no difference between the patient groups
      submitted to the different anesthetic regimes. In conclusion, our results show
      that surgical trauma variably affect the lymphocyte functions of cancer patients,
      the effect not being related to the particular anesthetic regime used. The PGE2
      mediated suppression is not likely to be involved in postoperative immune
      function impairment.

PMID- 10355536
TI  - Sequential standard dose mitoxantrone and cytosine arabinoside for newly
      diagnosed adult acute myeloblastic leukemia.
AB  - Twenty one adult patients with previously untreated acute myeloblastic leukemia
      (AML) were treated with sequential mitoxantrone and standard dose cytosine
      arabinoside remission induction therapy. The median age was 33 years (range 17-56
      years). Complete remission (CR) was achieved in 80% (17/21 cases) and 76% (16/21
      cases) achieved CR after one course of induction therapy. The median duration of
      disease free survival was 9 months with an actuarial disease free survival of 22%
      at 43 months. The non-hematological toxicity was acceptable. We conclude that
      sequential mitoxantrone and cytosine arabinoside combination therapy is an
      effective antileukemic regimen which produces high CR rates in previously
      untreated adult patients with AML.

PMID- 10355537
TI  - Comparative estimation of cure rates for supraglottic and glottic cancer in
      radiotherapy.
AB  - There are some clinical evidences, that the same types of tumors originated from
      neighboring anatomical structures can significantly differ in their response to
      radiation therapy. Squamous cell cancer of supraglottis and glottis could be good
      examples of this phenomenon. The purpose of the study was to compare the
      radiocurability of cancers localized in the upper and medium level of the larynx.
      From 1985 to the end of 1989, 544 patients with squamous cell cancer of the
      larynx were treated by radiotherapy alone. There were 388 patients with
      supraglottic cancer and 156 patients with glottic cancer. The total dose was in
      the range of 59-74 Gy. The end-point criteria were overall (OS) and disease-free
      survival (DFS). Generally, 5-year overall and disease-free survival rates were
      significantly more favorable for glottic cancer patients than for supraglottic
      cancer (67 and 63% vs. 40 and 36%, respectively). Significant differences in both
      disease-free and overall survival between supraglottic and glottic cancer in
      aspect of several analyzed clinical prognostic factors were found for: male sex,
      age, pattern of tumor growth, clinical performance status, radiation total dose
      lower than 70 Gy, fraction doses and overall treatment time. In all these
      prognostic categories 5-year survival rates were lower for supraglottic cancer
      patients. This tendency disappeared when the treatment results were compared in
      aspect of tumor stage (T). Tumor cure doses for 50% probability of local control
      (TCD50) in supraglottic cancer were estimated as: 61 Gy (T(1+2)) and 66 Gy (T3).
      In glottic cancer the lower TCD50 values of 54.5 Gy (T(1+2)) and 61 Gy (T3) were
      found in comparable treatment time. The comparative estimation of cure rates
      (i.e. OS and DFS) of laryngeal cancer treated by radiation alone showed that in
      aspect of almost all analyzed prognostic factors the greater risk of treatment
      failure was significantly associated with supraglottic origin.

PMID- 10355538
TI  - Reversal of impaired calcium homeostasis in the rat diaphragm subjected to
      Monocrotaline-induced pulmonary hypertension.
AB  - Monocrotaline (MCT) pneumotoxicity is known to alter the structure of pulmonary
      vascular wall and impairs endothelial cell function resulting in pulmonary
      hypertension. Its effect on the diaphragm muscle has not yet been elucidated.
      This study examines the effect of MCT pneumotoxicity on calcium transport in the
      rat diaphragm. Pulmonary hypertension induced by MCT pneumotoxicity caused a
      significant increase (P < 0.001) in calcium accumulation in strips isolated from
      rat diaphragms. Treatment of rats having received MCT with Indapamide reduced
      calcium uptake by diaphragmatic strips to levels that are not significantly
      different from the control (P > 0.05). Treatment with Indapamide alone did not
      elicit any change in calcium accumulation in the diaphragmatic strips. Treatment
      of the animals with MCT, Indapamide or both did not produce any significant
      change (P > 0.05) in the cell volume of the diaphragmatic strips. Pulmonary
      hypertension increased calcium uptake by the muscle cells in the rat diaphragm
      which may alter diaphragmatic contractility; an effect that was prevented by
      Indapamide.

PMID- 10355539
TI  - Mercuric chloride-induced apoptosis is dependent on protein synthesis.
AB  - Apoptosis is a mode of cell death with morphologic and biochemical features that
      distinguish it from necrosis. Recent studies demonstrating that mercury compounds
      initiate apoptosis in cultured cells did not elucidate if the biochemical
      mechanism of apoptosis involved a dependence on macromolecular synthesis post
      insult, i.e. programmed cell death. The objectives of this in vitro study were
      (1) to determine if HgCl2 cytotoxicity includes an apoptotic component, and (2)
      to determine if apoptosis is dependent on protein synthesis, i.e. proceeds by an
      inducible mechanism. Suspensions of mouse lymphoma (L5178Y-R) cells were exposed
      to 0, 1, 5, or 10 microM HgCl2 and apoptosis was evaluated utilizing qualitative
      and quantitative methods. At 24 h after exposure, transmission electron
      microscopy revealed a concentration-related increase in morphologic changes
      typical of apoptosis: margination of condensed chromatin to the nuclear membrane,
      dilation of the rough endoplasmic reticulum, cytoplasmic condensation and
      vacuolation, nuclear dissolution, and plasma membrane blebbing. An increase in Hg
      induced DNA fragmentation (DNA 'ladder') was observed using agarose gel
      electrophoresis. Time- and concentration-dependent increases in the percent of
      apoptotic cells were observed at 1, 6, 12, and 24 h after HgCl2 exposure using a
      flow cytometric method that discriminates between cells according to size and
      granularity. Pretreatment of cells with cycloheximide (CHX), an inhibitor of
      translation, prior to HgCl2 exposure resulted in a 25-50% reduction in apoptotic
      cells 24 h after exposure to 10 and 20 microM HgCl2, and concomitantly reduced
      the overall cytotoxicity compared to HgCl2 alone. These results, although limited
      to a single cell line, support the hypothesis that HgCl2 induces apoptosis that
      is dependent, at least in part, upon protein synthesis.

PMID- 10355540
TI  - Lipid peroxidative damage on pyrethroid exposure and alterations in antioxidant
      status in rat erythrocytes: a possible involvement of reactive oxygen species.
AB  - Pyrethroid pesticides are used preferably over organochlorines and
      organophosphates due to their high effectiveness, low toxicity to non-target
      organisms and easy biodegradibility. However, it is possible that during the
      pyrethroid metabolism, there is generation of reactive oxygen species (ROS) and
      pyrethroids may produce oxidative stress in intoxicated rats. The present study
      was therefore, undertaken to determine pyrethroid-induced lipid peroxidation
      (LPO) and to show whether pyrethroid intoxication alters the antioxidant system
      in erythrocytes. A single dose of cypermethrin and/or fenvalerate (0.001% LD50)
      was administered orally to rats and the animals were sacrificed at 0, 1, 3, 7 and
      14 days of treatment. The results showed that lipid peroxidation (LPO) in
      erythrocytes increased within 3 days of pyrethroid treatment. The increased
      oxidative stress resulted in an increase in the activity of antioxidant enzymes
      such as superoxide dismutase (SOD) and catalase (CAT). The increase in reduced
      glutathione (GSH) content in erythrocytes may probably be an initial adaptive
      response to increased oxidative stress in pyrethroid intoxicated rats.
      Erythrocytes and serum acetylcholinesterase (AChE) activity was measured in
      pyrethroid-induced oxidative stress as it may mimic inhibition in target tissues
      such as muscle and brain. The inhibition in erythrocytes and serum AChE activity
      was partially relieved over a period of time indicating recovery from pyrethroid
      intoxication. The increase in erythrocyte LPO correlated with the inhibition in
      erythrocyte AChE activity and so erythrocyte AChE can be a marker enzyme in
      pyrethroid toxicity. The results show oxidative stress and alteration in
      antioxidant enzymes in erythrocytes of pyrethroid intoxicated rats.

PMID- 10355541
TI  - Expression of MT-3 protein in the human kidney.
AB  - The objective of the present study was to determine the expression of MT-3 in the
      human kidney. To accomplish this, an antibody was generated against a unique 8
      amino acid sequence present in MT-3 that is not shared by any other MT family
      member. Western analysis demonstrated that the resulting antibody reacted with a
      protein band of approximately 6 kDa, corresponding to the known molecular weight
      of MT-3. Immunohistochemical staining using this antibody demonstrated reactivity
      with several epithelial components of the nephron. In the glomerulus, moderate
      intensity was demonstrated in parietal epithelial cells of Bowman's capsule and
      in visceral epithelial cells of the glomerular tuft. Proximal convoluted tubule
      cells exhibited moderate cytoplasmic MT-3 reactivity. Distal tubules showed
      strong cytoplasmic staining for MT-3, particularly in the medullary rays. In the
      medulla, MT-3 staining was the most variable, with weak to moderate staining in
      the medullary collecting ducts and a general absence of staining in the thin
      loops of Henle and in the transitional epithelium of the renal pelvis. The
      finding that MT-3 is constitutively expressed in several glomerular and tubular
      epithelial elements of the human kidney warrants consideration of an expanded
      role for this protein family in maintaining renal homeostasis.

PMID- 10355542
TI  - Inhibition of cytochrome P450 2E1 expression by oleanolic acid: hepatoprotective
      effects against carbon tetrachloride-induced hepatic injury.
AB  - The protective effects of oleanolic acid on carbon tetrachloride-induced
      hepatotoxicities and the possible mechanisms involved in this protection were
      investigated in mice. Pretreatment with oleanolic acid prior to the
      administration of carbon tetrachloride significantly prevented the increase in
      serum alanine aminotransferase and lactate dehydrogenase activity and liver lipid
      peroxidation in a dose-dependent manner. Hepatic glutathione levels and
      glutathione-S-transferase activities were not affected by treatment with
      oleanolic acid alone but pretreatment with oleanolic acid protects carbon
      tetrachloride-induced depletion of hepatic glutathione levels. The effects of
      oleanolic acid on the cytochrome P450 (P450) 2E1, the major isozyme involved in
      carbon tetrachloride bioactivation were investigated. Treatment of mice with
      oleanolic acid resulted in a significant decrease of P450 2E1-dependent p
      nitrophenol and aniline hydroxylation in a dose-dependent manner. Consistent with
      these observations, the P450 2E1 expressions were also decreased, as determined
      by immunoblot analysis. These results show that the protective effects of
      oleanolic acid against the carbon tetrachloride-induced hepatotoxicity may, at
      least in part, be due to its ability to block bioactivation of carbon
      tetrachloride mainly by the inhibition of expression and activities of P450 2E1.

PMID- 10355543
TI  - Additive inhibitory action of chlorpyrifos and polycyclic aromatic hydrocarbons
      on acetylcholinesterase activity in vitro.
AB  - This study tested the hypothesis that the inhibition of acetylcholinesterase is
      greater when the insecticide chlorpyrifos (CPF) is in the presence of several
      polycyclic aromatic hydrocarbons (PAHs) found in house dust. CPF-oxon (CPFO)
      inhibition curves of purified AChE (electric eel) were generated in the presence
      or absence of different concentrations of the PAHs pyrene, benzo(a)pyrene,
      anthracene, and fluoranthene. Without CPF-oxon, all four PAHs themselves
      inhibited AChE activity with IC50 values in the range 8.2-17 microM. The IC50 for
      benzo(a)pyrene with human recombinant AChE was 1.5 microM. When AChE was
      incubated with CPF-oxon together with the PAHs, the inhibitory effect on AChE was
      additive. This was exemplified by large (60-80%) and significant (P<0.01)
      inhibition in AChE activity by the PAHs when combined with nanomolar
      concentrations of CPF-oxon. Kinetic studies indicated that benzo(a)pyrene
      inhibited AChE in a noncompetitive manner, and the reduction in maximal velocity
      (Vmax) by benzo(a)pyrene and CPFO together was the sum of the inhibitory effect
      of the two inhibitors alone, further supporting an additive effect. These data
      suggest that some PAHs have anticholinesterase activity, and contribute in an
      additive manner to the inhibitory effect of CPFO on AChE in vitro. Further
      research is needed to determine the toxicological relevance of these findings.

PMID- 10355544
TI  - Tri-isobutylphosphate: a prenatal toxicity study in rats.
AB  - To assess the prenatal toxicity to rats of the anti-foaming agent, tri
      isobutylphosphate (CAS 126-71-6), a study was conducted in which daily dosages of
      0, 100, 300 and 1000 mg/kg were administered to different treatment groups by
      gavage from day 6 to 15 of pregnancy. Dams were killed and foetuses examined on
      day 20 of pregnancy. Maternal effects during the dosing period included a dosage
      related increase in the frequency, persistence and severity of post dosing
      salivation in all test groups and significantly increased water consumption at
      1000 mg/kg. Bodyweight gain at 1000 and 300 mg/kg was lower than that of controls
      but the differences were not statistically significant. The lowest dosage of 100
      mg/kg could be considered as the maternal 'lowest observed adverse effect level'
      (LOAEL) or 'no observed adverse effect level' (NOAEL) according to whether
      increased salivation is perceived to be a true toxic effect or simply a reaction
      to the taste of the test material. Neither litter values nor the prevalence of
      foetuses with abnormalities indicated any embryotoxic effects (including
      teratogenicity) at any dosage. The most notable feature of the results was the
      occurrence of a cluster of foetuses with the congenital abnormality referred to
      as 'hunched posture syndrome' or 'squat foetus syndrome'. However, the incidence
      of this finding was similar to that noted among background data for the same
      strain and, in the absence of any other embryotoxic findings, was considered
      likely to have arisen coincidentally.

PMID- 10355545
TI  - Effects of prenatal exposure to styrene on neurochemical levels in rat brain.
AB  - Styrene was evaluated to determine its neurochemical effects in the offspring of
      rats exposed during the gestation period. Maternal Wistar rats were exposed to 0,
      50 or 300 ppm styrene during gestation days 6 to 20 and the neurochemical effects
      on their offspring were compared with their pair-feeding and ad lib. feeding
      controls. The cerebrum weights at birth on day 0 were significantly lower than
      those for an ad lib. feeding control group. Neurotransmitter analyses showed
      decreases of neuroamines, especially 5-hydroxytryptamine and homovanillic acid in
      the cerebrum of newborn offspring of dams receiving a 300 ppm styrene exposure
      compared with the ad lib. fed control group and homovanillic acid was also
      decreased compared to the pair-feeding control. On postnatal day 21, the styrene
      exposure pups showed a significant decrease of 5-hydroxyindoleacetic acid in the
      frontal neocortex compared with the ad lib. control group. In the hippocampus a
      significant decrease of 5-hydroxyindoleacetic acid was observed compared with
      both control groups. Moreover, the ratio of 5-HIAA/5-HT in the hippocampus was
      significantly decreased among the styrene-exposure groups. The 50 ppm styrene
      exposed group induced increase of concentrations of 5-hydroxytryptamine in the
      striatum. These results suggest that prenatal styrene exposure affects the
      developing fetal brain in terms of a few signs of neurochemical alteration.

PMID- 10355546
TI  - Competitive inhibition by inducer as a confounding factor in the use of the
      ethoxyresorufin-O-deethylase (EROD) assay to estimate exposure to dioxin-like
      compounds.
AB  - The ethoxyresorufin-O-deethylase (EROD) assay has been extensively used in whole
      animals and in cell culture as a biomarker of exposure to environmental
      contaminants such as dioxin-like compounds (DLCs). This paper addresses two
      controversial phenomena that arise when DLCs are examined by the EROD assay.
      Firstly, the maximum level of induced EROD activity varies with the identity of
      the inducing compound; secondly, the induced EROD activity reaches a
      concentration-dependent maximum level that is followed by an apparent reduction
      in activity when the concentration of inducer is further increased. These
      phenomena are completely explained by competitive inhibition of the EROD enzyme
      substrate reaction by the dioxin-like compound. A kinetic model explains the
      biphasic appearance of EROD induction curves as a function of a compound's
      binding affinity with the Ah receptor (Kd) and its binding affinity to CYP 1A1
      (Ki) which results in inhibition of the EROD enzyme-substrate reaction. These
      results limit the reliability of the information obtained from calibration curves
      of EROD activity versus concentration of a standard DLC such as 2,3,7,8
      tetrachlorodibenzo-p-dioxin.

PMID- 10355547
TI  - Role of O2 in regulation of lactate dynamics during hypoxia: mathematical model
      and analysis.
AB  - The mechanistic basis of the relationship between O2 and lactate concentration in
      muscle is not fully understood. Although hypoxia can cause lactate (LA)
      accumulation, it is possible for LA accumulation to occur without hypoxia.
      Nevertheless, during conditions of low O2 availability, blood and tissue LA
      accumulation are used as indicators of hypoxia. To provide a framework for
      analyzing changes in energy metabolism and its regulation, we developed a
      mathematical model of human bioenergetics that links cellular metabolic processes
      to whole-body responses. Our model is based on dynamic mass balances and
      mechanistic kinetics in muscle, splanchnic and other body tissues for many
      substrates (glycogen, glucose, pyruvate, LA, O2, CO2, etc.) and control
      metabolites (e.g., ATP) through coupled reaction processes. Normal substrate
      concentrations in blood and tissues as well as model parameters are obtained
      directly or estimated indirectly from physiological observation in the
      literature. The model equations are solved numerically to simulate substrate
      concentration changes in tissues in response to disturbances. One key objective
      is to examine and quantify the mechanisms that control LA accumulation when O2
      availability to the muscle is lowered. Another objective is to quantify the
      contribution of different tissues to an observed increase in blood lactate
      concentration. Simulations of system responses to respiratory hypoxia were
      examined and compared to physiological observations. Model simulations show
      patterns of change for substrates and control metabolites that behave similarly
      to those found experimentally. From the simulations, it is evident that a large
      decrease can occur in muscle O2 concentration, without affecting muscle
      respiration (Um,O2) significantly. However, a small decrease in Um,O2 (1%-2%) can
      result in a large increase in LA production (50%-100%). The cellular rate of
      oxygen consumption, Um,O2, which is coupled to ATP formation and NADH oxidation,
      can regulate other processes (e.g., glycolysis, pyruvate reduction) with high
      sensitivity through its effects on ADP/ATP and NADH/NAD. Thus, although LA
      metabolism does not depend directly on O2 concentration, it is indirectly
      affected by Um,O2, through changes in ADP/ATP, and NADH/NAD. Arterial LA
      concentration (Ca,LA) follows the pattern of change of muscle LA concentration
      (Cm,LA). Nevertheless, changes in Ca,LA, due to Cm,LA, are unlikely to be
      detected experimentally because changes in Cm,LA are small relative to the total
      LA concentrations in other tissues.

PMID- 10355548
TI  - A computational analysis of FXa generation by TF:FVIIa on the surface of rat
      vascular smooth muscle cells.
AB  - A computational model was developed to investigate the contribution of classical
      mass transport and flow parameters to factor X (FX) activation by the tissue
      factor-factor VIIa complex (TF:VIIa) on one wall of a parallel-plate flow
      chamber. The computational results were compared to previously obtained
      experimental data for the generation of factor Xa (FXa) by TF:VIIa on the surface
      of cultured rat vascular smooth muscle cells. In this study, the complete steady
      state convection-diffusion equation was solved using the commercial software
      package, FLUENT (Fluent Inc., Lebanon, New Hampshire). A user-defined subroutine
      interfaced with FLUENT implemented the surface reaction which was modeled using
      classical Michaelis-Menten reaction kinetics. The numerical solutions were
      obtained for 12 cases which used combinations of three wall shear rates and four
      reaction rates. The numerically obtained fluxes for a given reaction rate
      displayed a wall shear rate dependence which ranged from classical kinetic
      reaction control (no dependence) to pure diffusional control (maximum
      dependence). The experimental data, however, were not represented by numerical
      data generated using a single reaction rate. The three numerically obtained
      fluxes which corresponded most closely to the experimental fluxes were determined
      using three different Vmax values. This finding supports the hypothesis that
      there may be a direct effect of flow on the TF:VIIa complex or the cell membrane.

PMID- 10355549
TI  - A field-compatible method for interpolating biopotentials.
AB  - Mapping of bioelectric potentials over a given surface (e.g., the torso surface,
      the scalp) often requires interpolation of potentials into regions of missing
      data. Existing interpolation methods introduce significant errors when
      interpolating into large regions of high potential gradients, due mostly to their
      incompatibility with the properties of the three-dimensional (3D) potential
      field. In this paper, an interpolation method, inverse-forward (IF)
      interpolation, was developed to be consistent with Laplace's equation that
      governs the 3D field in the volume conductor bounded by the mapped surface. This
      method is evaluated in an experimental heart-torso preparation in the context of
      electrocardiographic body surface potential mapping. Results demonstrate that IF
      interpolation is able to recreate major potential features such as a potential
      minimum and high potential gradients within a large region of missing data. Other
      commonly used interpolation methods failed to reconstruct major potential
      features or preserve high potential gradients. An example of IF interpolation
      with patient data is provided to illustrate its applicability in the actual
      clinical setting. Application of IF interpolation in the context of noninvasive
      reconstruction of epicardial potentials (the "inverse problem") is also examined.

PMID- 10355550
TI  - An analysis of hypoxia in sheep brain using a mathematical model.
AB  - Cerebral blood flow (CBF) increases as arterial oxygen content falls with hypoxic
      (low PO2), anemic (low hemoglobin) and carbon monoxide (CO) (high
      carboxyhemoglobin) hypoxia. Despite a higher arterial PO2, CO hypoxia provokes a
      greater increase in CBF than hypoxic hypoxia. We analyzed published data using a
      compartmental mathematical model to test the hypothesis that differences in PO2
      in tissue, or a closely related vascular compartment, account for the greater
      response to CO hypoxia. Calculations showed that tissue, but not arteriolar, PO2
      was lower in CO hypoxia because of the increased oxyhemoglobin affinity with CO
      hypoxia. Analysis of studies in which oxyhemoglobin affinity was changed
      independently of CO supports the conclusion that changes in tissue PO2 (or
      closely related capillary or venular PO2) are predictive of alterations in CBF.
      We then sought to determine the role of tissue PO2 in anemic hypoxia, with no
      change in arterial and little, if any, change in venous PO2. Calculations predict
      a small fall in tissue PO2 as hematocrit decreases from 55% to 20%. However,
      calculations show that changes in blood viscosity can account for the increase in
      CBF in anemic hypoxia over this range of hematocrits.

PMID- 10355551
TI  - O2-Hb reaction kinetics and the Fahraeus effect during stagnant, hypoxic, and
      anemic supply deficit.
AB  - We modified our previous computer model of O2 and CO2 transport in the cerebral
      microcirculation to include nonequilibrium O2-Hb kinetics and the Fahraeus effect
      (reduced tube hematocrit in small microvessels). The model is a steady-state
      multicompartmental simulation which includes three arteriolar compartments, three
      venular compartments, and one capillary compartment. Three different types of
      oxygen deficits (stagnant, hypoxic, and anemic conditions) were simulated by
      respectively reducing blood flow, arterial O2 saturation, and systemic hematocrit
      to one half of normal. Microcirculatory distributions for PO2, PCO2, O2
      saturation and deviations from equilibrium, and the O2 and CO2 fluxes for each
      compartment were predicted for the three O2 supply deficits. Differences were
      found for O2 extraction ratios and relative contributions of arteriolar, venular,
      and capillary gas fluxes for each type of deficit. The Fahraeus effect and O2-Hb
      kinetics reduced O2 extraction in all cases and altered microcirculatory gas
      distributions depending on the specific type of O2 supply deficits. The modified
      model continues to predict that capillaries are the major site where gas exchange
      takes place, and demonstrates that the Fahraeus effect and nonequilibrium O2-Hb
      kinetics are important mechanisms that should not be neglected in O2 and CO2
      transport modeling. While this model provides useful insight regarding the
      influence of the Fahraeus effect and O2-Hb kinetics under steady state, the
      addition of a distributed and dynamic simulation should further elucidate the
      effects of the brain's heterogeneous properties and transient behavior.

PMID- 10355552
TI  - Imaging epicardial oxygen.
AB  - Measurements of oxygen concentration and metabolic status in the heart are
      important to understanding the mechanisms that control cardiac respiration and
      its response to changing workload and substrate delivery. This paper presents
      images, recorded from a perfused rat heart, that reveal regional changes in
      concentrations of epicardial oxygen and of mitochondrial NADH in response to
      local ischemia, heterogeneous perfusion, and barbiturate inhibition. A
      fluorescence/ phosphorescence imaging system was developed to acquire digital
      images of oxygen concentration and NADH fluorescence from the epicardium of
      perfused hearts. The oxygen imaging technique is based upon quenching of Pd(II)
      meso-tetra(p-sulfonatophenyl)porphin phosphorescence by dissolved oxygen. Images
      of oxygen and NADH fluorescence provided complimentary information about oxygen
      supply and demand in the heart. The utility of two-dimensional measurements of
      the mitochondrial bioenergetic status is illustrated by the comparison of
      gradients for NADH and oxygen across the boundary separating locally ischemic
      tissue from normoxic epicardium. Images of oxygen concentration provide a
      powerful means for studying the dynamics of regional oxygen supply/ demand
      relationships in cardiac muscle.

PMID- 10355553
TI  - Changes in the organization of the smooth muscle cells in rat vein grafts.
AB  - Mechanical tensile stress in vein grafts increases suddenly under the influence
      of arterial blood pressure. In this study, we examined the influence of increased
      tensile stress on the organization of the smooth muscle cells (SMCs) in the
      neointima and media of the rat vein grafts. An autogenous jugular vein was
      grafted into the abdominal aorta of the rat, and changes in the organization of
      the vein graft SMCs were studied by observing the distribution of SMC actin
      filaments and nuclei at 3 min and 1, 5, 10, and 30 days after surgery. In a
      normal jugular vein, the average wall circumferential tensile stress was
      approximately 3 kPa at an internal pressure of 3 mm Hg. The SMCs, that contained
      long, slender actin filamentous bundles, were oriented mainly in the
      circumferential direction of the vessel, and constituted a 2- to 3-cell-thick
      medial layer underneath the endothelium. In a vein graft, the wall
      circumferential tensile stress suddenly increased by approximately 140 times
      compared with the control level. In response to this suddenly increased stress,
      the SMC layer was stretched into a structure with scattered pores and disrupted
      SMC actin filamentous bundles within 3 min. This initial change was followed by a
      rapid reduction in the density of the SMC nuclei and actin filaments within 1 day
      and progressive SMC proliferation, that was associated with medial thickening and
      a change in the SMC orientation from 5 to 30 days. Further studies showed that a
      local inflation of normal jugular veins to 120 mm Hg for 3 min induced a similar
      change as found in the vein grafts, whereas the organization of the SMCs was not
      significantly changed in vein-vein grafts, that did not experience a change in
      tensile stress. These results suggested that increased tensile stress contributed
      to the initial damage of the SMCs and played a role in the regulation of medial
      SMC remodeling in vein grafts.

PMID- 10355554
TI  - Measurement of articular cartilage thickness in the articulated knee.
AB  - A radiographic and image analysis method was developed and applied in porcine
      knees for the measurement of articular cartilage thickness in articulated joints.
      The feasibility of the approach was assessed by implementing the method for the
      lateral femoral condyle from harvested limbs. Measurement of the undeformed
      cartilage thickness with this method was found to have a great degree of
      precision, with approximately a 1.0% (14 microm) mean variation. Accuracy was
      also high when compared to an optical method for measuring the true cartilage
      thickness. An excellent linear correlation (r2>0.99) between the thickness
      determined optically and that obtained from the radiographic images was
      demonstrated. No significant differences were found between these two measures of
      cartilage thickness. This method, which minimizes disturbance to the structures
      of the knee to maintain its physiologic environment, also has promise to measure
      the changes in cartilage thickness as the tissue is deformed during joint
      loading. Information about the undeformed and deformed cartilage thicknesses can
      be combined with finite element models to examine cartilage behavior from both
      experimental and theoretical perspectives.

PMID- 10355555
TI  - Factors affecting Volterra kernel estimation: emphasis on lung tissue
      viscoelasticity.
AB  - The goal of this study is to quantitatively investigate how the memory length,
      order of nonlinearity, type of input, and measurement noise can affect the
      identification of the Volterra kernels of a nonlinear viscoelastic system, and
      hence the inference on system structure. We explored these aspects with emphasis
      on nonlinear lung tissue mechanics around breathing frequencies, where the memory
      length issue can be critical and a ventilatory input is clinically demanded. We
      adopted and examined Korenberg's fast orthogonal algorithm since it is a least
      squares technique that does not demand white Gaussian noise input and makes no
      presumptions on the kernel shape and system structure. We then propose a memory
      autosearch method, which incorporates Akaike's final production error criterion
      into Korenberg's fast orthogonal algorithm to identify the memory length
      simultaneously with the kernels. Finally, we designed a special ventilatory flow
      input and evaluated its potential for the kernel identification of the nonlinear
      systems requiring oscillatory forcing. We found that the long memory associated
      with soft tissue viscoelasticity may prohibit correct identification of the
      higher-order kernels of the lung. However, the key characteristics of the first
      order kernel may be revealed through averaging over multiple experiments and
      estimations.

PMID- 10355557
TI  - Estimation of organ transport function for recirculating indicator dilution
      curves.
AB  - The transport function of an indicator through an organ allows the calculation of
      important physiological parameters, but its estimation, especially in the
      presence of recirculation, can be difficult. In this paper, we estimate the
      transport function of 3H-mannitol (an extracellular tracer of glucose) in the
      human leg skeletal muscle. To do so, an indicator bolus is administered into the
      femoral artery and its recirculating dilution curves are nonuniformly sampled in
      both the femoral artery and the femoral vein. A new deconvolution-based method is
      used to simultaneously estimate the indicator transport function and the organ
      plasma flow. Subsequently, the indicator mean transit time and distribution
      volume are calculated. The reliability of the method is assessed by Monte Carlo
      simulation. The ability to estimate parameters, like mean transit time and
      extracellular distribution volume, is critical to the study of pathophysiologic
      states such as diabetes, insulin resistance, and hypertension.

PMID- 10355556
TI  - Kinetics of plasma membrane electron transport in a pulmonary endothelial cell
      column.
AB  - Thiazine dyes such as toluidine blue O (TBO) are reduced at the luminal
      endothelial surface. The purpose of this study was to determine the rate of this
      reaction in endothelial cells in culture. A multiple indicator dilution method
      was used to measure the reaction kinetics during transient passage of a TBO
      containing bolus through a chromatographic column filled with bovine pulmonary
      arterial endothelial cells grown on microcarrier beads (cell-column). A bolus
      containing TBO and an inert extracellular reference indicator (FITC-Dextran) was
      injected upstream of the cell-column, and the indicator concentrations were
      measured downstream using on-line photodetection. The effects of column flow
      rate, PO2, and TBO concentration were studied. The fraction of TBO reduced upon
      passage through the cell-column decreased with increasing flow indicating that
      the reaction rate rather than TBO delivery controlled TBO reduction. The fraction
      of TBO reduced did not change with PO2 or dose in the ranges studied. TBO
      reduction was about 10 times that for steady state TBO sequestration by these
      cells which, along with the lack of a PO2 effect indicates that the rapid rate of
      reduction is not the rate-limiting step in steady state sequestration.

PMID- 10355558
TI  - Localization of a fluorescent object in highly scattering media via frequency
      response analysis of near infrared-time resolved spectroscopy spectra.
AB  - Frequency response analysis via pulse testing for engineering systems and near
      infrared (NIR) time resolved spectroscopy (TRS) for biological system
      characterization involve identical principles: the system of interest is
      disturbed by an input pulse and the output response is observed. Since a sharp
      pulse, such as the Dirac delta function, contains the information of
      multimodulation frequencies (theoretically from 0 to infinity in frequency) a
      narrow pulse TRS input can produce a wide range frequency response for
      identifying any system of interest. Currently used NIR-TRS spectral analyses
      either fit the spectra with a known theoretical solution or use photon mean time
      of-flight. Transforming the system time domain representation to the frequency
      domain generates five system parameters that can be valuable for process
      identification utility: steady state gain, time constant, system order, and
      magnitude ratio and phase shift over a wide frequency range. Optical contrast
      agents or fluorescent agents can be used to enhance the capability of optical
      instruments in detecting biological heterogeneities. In this article, magnitude
      ratio, phase shift, and other system parameters derived from the transfer
      function of systems with both a fluorescent absorber and a regular absorber are
      correlated with the position of the absorber. This technique is important in that
      ultimately it can be used to enhance optical medical imaging.

PMID- 10355559
TI  - Mean velocity and Reynolds stress measurements in the regurgitant jets of tilting
      disk heart valves in an artificial heart environment.
AB  - Laser Doppler velocimetry, with a high temporal resolution (1 ms time windows),
      was used to measure the flow field in two regions (major and minor orifices) near
      the aortic and mitral valves (Bjork Shiley monostrut Nos. 25 and 27,
      respectively) of the Penn State artificial heart. The motion of each valve was
      also investigated using a 1000 frame/s video camera in order to estimate the
      valve's closing velocity. Fluid velocities in excess of and opposite to valve
      closing velocity were detected near the valve, providing evidence of "squeeze
      flow." Maximum Reynolds shear stresses of approximately 20,000 dyn/cm2 and time
      averaged Reynolds shear stresses of approximately 2000 dyn/cm2 were observed
      during the regurgitant flow phase. These elevated Reynolds shear stresses suggest
      that regurgitant jets play a role in the hemolysis and thrombosis associated with
      tilting disk heart valves in an artificial heart environment.

PMID- 10355560
TI  - Elastic properties of the composite outer hair cell wall.
AB  - We propose a mathematical model for analyses of the elastic properties of the
      wall of the outer hair cell (OHC) in the inner ear. The model reflects the
      properties of the major components of the OHC wall: the subsurface cisternae, the
      cortical lattice, the plasma membrane, and the radial pillars. The wall is
      treated as a composite consisting of three elastic cylindrical shells. Two inner
      shells, isotropic and orthotropic/ are adjacent to each other, and the outermost
      isotropic shell is connected to the combined inner shell by elastic springs. We
      derive Flugge-type equations for the composite wall and apply the model to the
      interpretation of the experiments with axial loading and with inflation of the
      OHC. We derive expressions for the axial stiffness and the wall strains measured
      in these experiments in terms of the elastic properties of the wall components.
      We also consider a conceivable experiment with torsion of the OHC and obtain
      relations between the torque (the axial reaction) and the angle of torsion. These
      solutions provide necessary information for the future determination of the OHC
      elastic properties.

PMID- 10355561
TI  - A mathematical model of gas exchange in an intravenous membrane oxygenator.
AB  - Acute respiratory distress syndrome (ARDS) is a pulmonary edemic condition which
      reduces respiratory exchange in 150,000 people per year in the United States. The
      currently available therapies of mechanical ventilation and extracorporeal
      membrane oxygenation are associated with high mortality rates, so intravenous
      oxygenation represents an attractive, alternative support modality. We are
      developing an intravenous membrane oxygenator (IMO) device intended to provide
      50% of basal oxygen and carbon dioxide exchange requirements for ARDS patients. A
      unique aspect of the IMO is its use of an integral balloon to provide active
      mixing. This paper describes a mathematical model which was developed to quantify
      and optimize the gas exchange performance of the IMO. The model focuses on
      balloon activated mixing, uses a lumped compartment approach, and approximates
      the blood-side mass transfer coefficients with cross-flow correlations. IMO gas
      exchange was simulated in water and blood, for a variety of device geometries and
      balloon pulsation rates. The modeling predicts the following: (1) gas exchange
      efficiency is reduced by a buildup of oxygen in the fluid near the fibers; (2)
      the IMO gas exchange rate in blood is normally about twice that in water under
      comparable conditions; (3) a balloon diameter of about 1.5 cm leads to optimal
      gas exchange performance: and (4) in vivo positioning can affect gas exchange
      rates. The numerically predicted gas transfer rates correlate closely with those
      experimentally measured in vitro for current IMO prototypes.

PMID- 10355562
TI  - Role of complementary medicine in the US.

PMID- 10355563
TI  - Private company wins Icelandic gene database.

PMID- 10355564
TI  - Problems and advantages for oncology in the new German Landern.

PMID- 10355565
TI  - Sacking of JAMA's editor-in-chief.

PMID- 10355566
TI  - Treatment for poor prognosis metastatic germ-cell tumours: much heat but, as yet,
      little light.

PMID- 10355567
TI  - What is the role of radiation therapy in locally advanced non-small-cell lung
      cancer?

PMID- 10355568
TI  - Cytokine gene therapy: hopes and pitfalls.
AB  - Transduction of a cytokine gene into neoplastic cells elicits a strong
      inflammatory host reaction that impairs tumor growth, and a long-lasting immune
      memory is established following their rejection. These findings have aroused
      great enthusiasm and expectations. Despite their enhanced immunogenicity,
      however, the immune reaction provoked by repeated injections of these engineered
      cells can do little more than inhibit the growth of initial tumors and metastases
      and is only minimally effective against established forms. Better therapeutic
      activity is thus being sought by combining such cells with tumor cells engineered
      with other genes.

PMID- 10355569
TI  - Selecting computer-based evidence sources.

PMID- 10355570
TI  - Controversies and consensus in the diagnosis, work-up and treatment of gastric
      lymphoma: an international survey.
AB  - BACKGROUND: Variations in diagnostic criteria and staging procedures in cancer
      patients have important consequences for patient selection and often preclude
      meaningful comparison of published series. In gastric lymphoma, these effects
      will play a role, since diagnostic criteria are controversial. Moreover, staging
      procedures and therapeutic choices are influenced by insights from different
      clinical specialisms. METHODS: To review the management of gastric lymphoma,
      formatted questionnaires were mailed to leading institutes with a special
      interest in this field in Europe, the United States and Japan. RESULTS: Nineteen
      centers agreed to contribute. Minimum histological criteria varied among
      pathologists with a notable influence of the classification system used in the
      different countries. Detailed evaluation of the lymphoma distribution in the
      gastric wall and routine staging of the GI-tract differed between groups leaded
      by medical oncologists and gastroenterologists. This results in basically
      different patient selections and bias in treatment outcome. Similar effects were
      recorded for the role of gastric resection and radiotherapy. CONCLUSIONS: This
      study gives insight in the basis of the decisions that result in different
      approaches in the management of gastric MALT-NHL and in the effects for patient
      selection and treatment results and may help in the design of future clinical
      trials.

PMID- 10355571
TI  - Third International Conference on Biology, Prevention and Treatment of
      Gastrointestinal Malignancies. Cologne, 23-26 September 1998.
AB  - R. Mayer (USA), summarizing the data presented during the three-day conference,
      stressed the importance of the development of new cytotoxic drugs and --
      particularly -- biological therapies as forms of treatment for patients with
      gastrointestinal malignancies. He also acknowledged the increasing application of
      molecular biology to gastrointestinal cancer through the identification of
      genetically-defined high-risk patients who merit costly screening techniques and
      the increased use of molecular 'markers' to serve as prognostic indicators and
      criteria for stratification in future clinical trials. Dr Mayer cautioned against
      allowing long-term frustration over poor surgical outcomes in patients with T3-4
      esophageal cancer and enthusiasm derived from uncontrolled (i.e., phase II)
      trials to lead to the premature acceptance of preoperative chemoradiation therapy
      as standard treatment for such patients in the absence of properly controlled,
      adequately powered randomized studies. Dr Mayer reinforced the progress that has
      been made in the adjuvant treatment of colon cancer and noted the increasing
      number of new randomized studies that have been proposed to further enhance the
      likelihood for cure, particularly in patients with stage III disease. Dr Mayer
      concluded by presenting a series of hypothetical agenda items for the Fourth
      International Conference on Biology, Prevention, and Treatment of
      Gastrointestinal Malignancies to be held in the new millennium which he hoped
      would demonstrate the incorporation of biological agents into clinical trials,
      would document more concerted efforts to study the biology and improve the
      treatment for pancreatic cancer, and would begin to consider the use of 'risk
      adapted' management strategies into clinical trials, based on such preclinical
      biological markers as intratumoral thymidylate synthase levels, apoptotic
      indices, allelic deletions, and the like.

PMID- 10355572
TI  - BOMP/EPI intensive alternating chemotherapy for IGCCC poor-prognosis germ-cell
      tumors: the Spanish Germ-Cell Cancer Group experience (GG)
AB  - BACKGROUND: Patients with poor-prognosis germ-cell tumors according to the IGCCC
      have a poor long-term survival. This study evaluates the efficacy and toxicity of
      the intensive alternating chemotherapy regimen BOMP/EPI in these patients.
      PATIENTS AND METHODS: Patients with IGCCC poor-prognosis germ-cell tumors treated
      at 13 centres were studied. Treatment consisted of bleomycin 30 mg, vincristine 2
      mg, methotrexate 300 mg/m2 and cisplatin 100 mg/m2 (BOMP), alternating after a 14
      day interval with etoposide 120 mg/m2 day 1-4, ifosfamide 1.3 g/m2 day 1-4 and
      cisplatin 25 mg/m2 day 1-4 (EPI). BOMP was administered 21 days after the EPI.
      Bleomycin was administered weekly per 12 weeks. RESULTS: Thirty-eight patients
      were treated. The median number of cycles administered was 7 (1-10 cycles).
      Eighteen patients achieved complete responses with chemotherapy alone (12 had
      necrosis and 2 mature teratoma at postchemotherapy resection), and four achieved
      complete responses with chemotherapy and surgical resection of viable cancer.
      Thus, an overall favorable response was achieved in 22 patients (60%). Four
      additional patients had marker-negative non-resected residual masses. Eleven
      patients were considered treatment failures, including one who died early and
      another who succumbed to granulocytopenic sepsis and renal failure. Hematologic
      toxicity was the most common, with 26 patients (70%) having grade 4
      granulocytopenia. After a median follow-up of 41 months, the actuarial two-year
      overall survival and progression-free survival were 64% and 58%, respectively.
      CONCLUSION: BOMP/EPI is active in poor-prognosis germ-cell tumors according to
      the IGCCC criteria. The results obtained compare favorably with those expected
      with conventional chemotherapy, and justify further studies.

PMID- 10355574
TI  - Combined sequential approach in locally advanced breast cancer.
AB  - BACKGROUND: The interaction between primary and adjuvant chemotherapy is a
      crucial point in the treatment of locally advanced breast cancer. OBJECTIVE: To
      evaluate the therapeutic efficacy of a sequential treatment with primary
      anthracyclines and adjuvant CMF in this patient subset. DESIGN: Prospective
      cohort study. PATIENTS: Eighty-eight breast cancer patients, stage T3b-T4 abc, N0
      2, M0. RESULTS: From February 1991 to July 1994, 88 consecutive patients with
      locally advanced breast cancer were treated at the Istituto Nazionale Tumori,
      Milano, with full-dose doxorubicin (75 mg/m2) or epirubicin (120 mg/m2) for three
      cycles followed by surgery, adjuvant chemotherapy with i.v. CMF for six cycles
      and local radiotherapy +/- Tamoxifen. A high rate of objective responses (70%),
      but a low incidence of pathologic complete remission (2%), were observed
      following primary treatment with single-agent anthracyclines. Frequency of
      responses was not associated with tumor estrogen or progesterone receptors
      status, Mib-1 or grading. In 28 patients (32%) conservative surgery could be
      performed. At a median follow-up of 52 months, relapse free survival and overall
      survival are 52% and 62%, respectively. A multivariate analysis demonstrated a
      significant favorable prognosis in patients with limited nodal involvement at
      surgery and negative Mib-1 values. This drug sequence failed to significantly
      ameliorate the long term results in this unfavorable patient subset and more
      effective drug regimens and innovative therapeutic strategies are needed.

PMID- 10355573
TI  - A randomised phase III trial comparing consolidation treatment with further
      chemotherapy to chest irradiation in patients with initially unresectable
      locoregional non-small-cell lung cancer responding to induction chemotherapy.
      European Lung Cancer Working Party.
AB  - PURPOSE: A phase III randomised trial was conducted in patients with non
      metastatic unresectable non-small-cell lung cancer in order to compare, in
      responders to induction chemotherapy, consolidation treatment by further
      chemotherapy to chest irradiation. PATIENTS AND METHODS: A total of 462 untreated
      NSCLC patients were eligible for three courses of induction chemotherapy (MIP)
      consisting of cisplatin (50 mg/m2), ifosfamide (3 g/m2) and mitomycin C (6
      mg/m2). It was proposed that objective responders be randomised to either three
      further courses of MIP or to chest irradiation (60 Gy; 2 Gy per fraction given
      over six weeks). RESULTS: An objective response rate of 35% was achieved; 115
      patients (including 52% with initial stage IIIA and 44% with initial stage IIIB)
      were randomised to consolidation treatment, 60 of them to further chemotherapy
      and 55 to chest radiotherapy. There was no significant difference in survival
      between the two arms, with a respective median and two-year survival of 42 weeks
      (95% confidence intervals (95% CI: 35-51) and 18% (95% CI: 8-28) for chemotherapy
      and 54 weeks (95% CI: 43-73) and 22% (95% CI: 11-33) for irradiation. There was
      also no statistical difference for response duration between the two arms but
      chest irradiation was associated with a significantly greater duration of local
      control than chemotherapy (median duration times: 158 vs. 31 weeks, P = 0.0007).
      CONCLUSIONS: For non-metastatic unresectable NSCLC treated by an induction
      chemotherapy regimen containing cisplatin and ifosfamide, if an objective
      response is obtained, consolidation treatments by further chemotherapy or by
      chest irradiation result in non-statistically different survival distributions,
      although a better local control duration is observed with radiotherapy.

PMID- 10355575
TI  - Double-blind, randomised, placebo-controlled, dose-finding study of oral
      ibandronate in patients with metastatic bone disease.
AB  - BACKGROUND: Bisphosphonates are an important component of the treatment of
      metastatic bone disease but more potent, oral formulations are required to
      improve the effectiveness and convenience of treatment. An oral formulation of
      the new bisphosphonate, ibandronate (BM 21.0955) has recently been developed.
      PATIENTS AND METHODS: One hundred ten patients with bone metastases (77 breast,
      16, prostate, 3 myeloma, 14 others) were recruited from a single institution to
      this double blind placebo-controlled evaluation of four oral dose levels (5, 10,
      20 and 50 mg) of ibandronate. No changes in systemic anti-cancer treatment were
      allowed in the month before commencing treatment or during the study period.
      After an initial four-week tolerability phase, patients could continue on
      treatment for a further three months without unblinding; patients initially
      allocated to placebo received ibandronate 50 mg. The primary endpoint was urinary
      calcium excretion (UCCR). Bone resorption was also assessed by measurement of
      pyridinoline (Pyr), deoxypyridinoline (Dpd), and the N-terminal (NTX) and C
      terminal (Crosslaps) portions of the collagen crosslinking molecules. RESULTS:
      Two patients did not receive any trial medication thus, 108 patients were
      evaluable for safety. Ninety-two patients were evaluable for efficacy. A dose
      dependent reduction was observed in both UCCR and collagen crosslink excretion.
      At the 50 mg dose level, the percentage reductions from baseline in UCCR, Pyr,
      Dpd, Crosslaps and NTX were 71%, 28%, 39%, 80% and 74% respectively. One or more
      gastrointestinal (GI) adverse events occurring in the first month of treatment
      were reported by six (30%), seven (33%), nine (39%), nine (41%) and eleven (50%)
      patients at the placebo, 5, 10, 20 and 50 mg dose levels respectively. One
      patient (20 mg dose) developed radiographically confirmed oesophageal ulceration.
      GI tolerability may have been adversely affected by concomitant administration of
      non-steroidal anti-inflammatory agents. Nine (8%) patients stopped treatment
      within the first month due to GI intolerability but these patients were evenly
      distributed across the five treatment groups. There was no difference in non-GI
      adverse events between groups. CONCLUSIONS: Oral ibandronate has potent effects
      on the rate of bone resorption at doses which are generally well tolerated.
      Further development is appropriate to evaluate the effects of long-term
      administration in the prevention of metastatic bone disease and the management of
      established skeletal metastases.

PMID- 10355576
TI  - Incidence of second neoplasms in patients with MALT lymphoma: no increase in risk
      above the background population.
AB  - BACKGROUND: Lymphomas of mucosa associated lymphoid tissue (MALT) are a special
      type of extranodal lymphoma, possibly related to chronic antigenic stimulation.
      Increased cancer susceptibility may also contribute to the development of MALT
      lymphoma (MALToma). It has been suggested that patients with MALToma have an
      increased incidence of other malignancies. PATIENTS AND METHODS: We
      retrospectively reviewed the histology and clinical records of 147 patients with
      MALToma, including 51 cases of gastric MALToma. The incidence of any second
      malignancy was confirmed with a provincial registry. The relative rates of
      cancer, excluding MALToma, were calculated relative to the background population
      of the same age group and secular year. RESULTS: A total of 41 tumors occurred in
      32 patients (21%), including 22 solid tumors. The incidence of solid tumors in
      the gastric MALToma group was 15%. Seven patients had two or more second
      malignancies. Cancer occurred before diagnosis of MALToma in 29 cases, concurrent
      with MALToma in three, and after MALToma in nine. Follow-up of the surviving
      patients is short (median 17.6 months). The relative rate from birth of a second
      malignancy was 0.86 in the whole group (90% confidence interval (CI): 0.62-1.16)
      and 0.95 (90% CI: 0.55-1.54) in the gastric MALToma group. The rates were roughly
      the same if skin cancers were excluded. CONCLUSIONS: The incidence of second
      cancers in this series is similar to previous reports. However, when compared to
      an age-matched population followed for the same period of time, MALToma patients
      do not appear to have a statistically significant increased rate of cancers.

PMID- 10355577
TI  - Bone marrow derived dendritic cells from patients with multiple myeloma cultured
      with three distinct protocols do not bear Kaposi's sarcoma associated herpesvirus
      DNA.
AB  - BACKGROUND: An association between Kaposi's sarcoma associated herpesvirus (KSHV)
      and the pathogenesis of multiple myeloma (MM) was postulated recently. The
      dendritic cells of patients with MM were proposed to be infected with the virus.
      PATIENTS AND METHODS: Bone marrow mononuclear cells (MNC) of 23 patients, 22 with
      MM and one with MGUS, were cultured according to three distinct protocols for the
      generation of dendritic cells. One was essentially the stromal cell culture
      protocol described by Rettig et al. (Science 1997; 276: 1851-4), while the two
      other protocols comprised growth factors. Cultured cells were characterised by
      FACS analysis and assessed for the presence of KSHV DNA with a highly sensitive
      and specific nested PCR assay detecting the KS 330233 sequence of the virus
      genome followed by hybridisation with a KSHV specific oligonucleotide. RESULTS:
      FACS analysis of the cells with the specific markers CD1a, CD86 and HLA-DR,
      characteristic for dendritic cells, revealed differences in the expression
      pattern depending on the protocol used. The proportion of CD1a+ cells was very
      low in the stromal cell cultures (median 0.4%), while a higher percentage of
      CD14+ cells could be observed (median 37.8%). Growth factor containing cultures
      revealed a distinctly higher median percentage of CD1a+ cells of 32.5%. The
      proportion of CD86+ cells varied between 10.4% and 78.5% and HLA-DR+ cells
      between 26% and 94.4%. Examination of those cells with PCR did not reveal
      positivity for KSHV in any of the 34 samples assessed. Amplification of seven
      samples revealed PCR products of approximately the size of the KS 330(233),
      which, however, could not be confirmed as KSHV specific after hybridisation.
      CONCLUSION: We have no evidence that bone marrow derived dendritic cells from
      patients with MM are infected with KSHV.

PMID- 10355578
TI  - Pharmacokinetically guided dose escalation of carboplatin in epithelial ovarian
      cancer: effect on drug-plasma AUC and peripheral blood drug-DNA adduct levels.
AB  - BACKGROUND: Platinum based drugs are active agents in epithelial ovarian cancer
      and increased platinum drug dose intensity is thought to lead to improved
      survival, because of the largely untested assumption that increased dose
      intensity results in an increased interaction of the platinum drug with its
      target, DNA. In a previously reported phase I trial (Lind et al., J Clin Oncol
      1996; 14: 800-5), carboplatin dose intensity was increased by the use of G-CSF to
      support the bone marrow and using pharmacokinetically-guided carboplatin dosing.
      The objectives of this study were to validate the carboplatin dosing formula
      during high dose intensity therapy and evaluate the relationship between systemic
      carboplatin exposure and Pt-DNA adduct levels in peripheral blood leucocytes.
      PATIENTS AND METHODS: A total of 17 patients were studied over four levels of
      dose intensification. The carboplatin dose was calculated using the 'Calvert
      formula'. Levels of drug-target interaction in peripheral blood leukocytes were
      measured using an immunoassay based on a monoclonal antibody that recognises DNA
      platinum adducts. Pharmacokinetic measurements were carried out using a
      previously validated single sample method. RESULTS: The area under the curve of
      concentration of unbound carboplatin in plasma versus time (AUC) for target AUC
      values of 5, 7 and 9 mg/ml x min were: 5.6 +/- 1.0, 7.3 +/- 0.7 and 9.8 +/- 0.5
      mg/ml x min (mean +/- S.D.). There was a good correlation between target and
      achieved dose intensities (r2 = 0.899) and the slope of the linear regression
      line was 0.95 (+/- 0.09 SD) not significantly different to 1.0 (P > 0.6). The
      levels of immunoreactive DNA adducts were not detectable at a target AUC of 5
      mg/ml x min but increased progressively at the higher AUC levels. Accumulation of
      adducts between courses was not detected. CONCLUSIONS: Pharmacokinetically-based
      carboplatin dosing during high intensity therapy accurately predicted the dose
      required to achieve a target AUC and resulted in consistent patient exposure to
      active drug. During the dose escalation study, peripheral blood leucocyte DNA
      platinum-DNA adduct levels were positively related to drug dose and drug AUC.

PMID- 10355579
TI  - All-trans-retinoic acid increases cytosine arabinoside cytotoxicity in HL-60
      human leukemia cells in spite of decreased cellular ara-CTP accumulation.
AB  - BACKGROUND: Accumulation of the cytosine arabinoside (ara-C) metabolite ara-C
      triphosphate (ara-CTP) in leukemic blast cells is considered to be the main
      determinant of ara-C cytotoxicity in vitro and in vivo. Retinoids such as all
      trans-retinoic acid (ATRA) have been shown to increase the sensitivity of acute
      myelogenous leukemic (AML) blast cells to ara-C. To investigate the mechanism of
      this sensitisation, the hypothesis was tested that ATRA augments cellular ara-CTP
      levels in human-derived myelogenous leukemia HL-60 cells. MATERIALS AND METHODS:
      The effect of ATRA and 13-cis-retinoic acid on ara-CTP accumulation and ara-C
      induced apoptosis was studied. Ara-CTP levels were measured by high-performance
      liquid chromatography (HPLC), cytotoxicity by the tetrazolium (MTT) assay, and
      apoptosis by occurrence of DNA fragmentation (gel electrophoresis), cell
      shrinkage and DNA loss (flow cytometry). RESULTS: Pretreatment of HL-60 cells
      with ATRA (0.01-1 microM) caused a significant decrease in intracellular ara-CTP
      levels; e.g., incubation for 72 hours with ATRA 1 microM prior to one hour ara-C
      10 microM reduced ara-CTP levels to 41% +/- 4% of control. Similar results were
      obtained after preincubation with 13-cis-retinoic acid. In spite of decreased ara
      CTP levels, the cytotoxicity of the combination was supraadditive and ATRA
      augmented ara-C-induced apoptosis. CONCLUSION: At therapeutically relevant
      concentrations ATRA increased ara-C cytotoxicity and ara-C induced apoptosis but
      this augmentation is not the corollary of elevated ara-CTP levels. The
      feasibility of ara-C treatment optimisation via strategies other than those
      involving elevation of ara-CTP levels should be investigated further.

PMID- 10355580
TI  - Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered
      as a 21-day continuous infusion.
AB  - BACKGROUND: Preclinical results support a prolonged schedule of administration
      for topoisomerase I inhibitors, and we have previously demonstrated the safety
      and activity of the novel water-soluble topoisomerase I inhibitor GG211 when
      given as a 72-hour continuous infusion to cancer patients. PATIENTS AND METHODS:
      In a three-center international phase I trial, 38 patients received GG211 doses
      from 0.3 to 0.5 mg/m2/day by continuous intravenous infusions for seven, 14, and
      21 days. Patients' median performance status was 1; nearly half had colorectal
      cancer, and 35 patients had prior chemotherapy. RESULTS: The first patient cohort
      received 0.3 mg/m2/day for seven days with no significant toxicities. Subsequent
      cohorts received continuous infusions for 14 and 21 days at this dose level with
      only mild myelosuppression noted. Dose-escalation on the 21-day schedule was then
      performed. No dose-limiting toxicity occurred at the 0.4 mg/m2/day dose level.
      Thrombocytopenia was dose-limiting with 0.5 mg/m2/day dosing but was not
      cumulative. Other grade 3 4 toxicities included neutropenia, nausea, vomiting,
      diarrhea, and fatigue. Partial responses occurred with 21-day infusion in two
      patients with breast and ovarian cancer at the 0.3 and 0.4 mg/m2/day dose levels,
      respectively. Mean GG211 lactone Css ranged from 0.17 to 0.64 ng/ml. CONCLUSION:
      The maximum tolerated dose of GG211 administered as a 21-day continuous infusion
      is 0.4 mg/m2/day with antitumor activity noted at tolerable doses.

PMID- 10355581
TI  - Management of cancer in pregnancy: a case of Ewing's sarcoma of the pelvis in the
      third trimester.
AB  - Ewing's sarcoma of the pelvic bones was diagnosed in a 21-year childbearing
      woman, raising major medical and ethical problems. The diagnostic and therapeutic
      approaches during the sixth month of gestation were tailored in order to cure the
      patient and avoid unnecessary toxicity to the fetus. Ancillary tests included
      ultrasound and MRI studies of the pelvis. Ifosfamide and adriamycin, premedicated
      by granisetron, were administered during gestation, and were found to be safe.
      Cesarean section was the preferred way of delivery since the tumor involved the
      pelvic bones. The outcome was a disease-free patient and a small healthy baby who
      is now two years of age.

PMID- 10355582
TI  - Preliminary results on the activity of oxaliplatin (L-OHP) in
      refractory/recurrent non-Hodgkin's lymphoma patients.
AB  - BACKGROUND: Many patients with advanced NHL ultimately relapse and require
      salvage treatment. Oxaliplatin, a diaminocyclohexane (DACH) platinum, has shown a
      differential spectrum of cytotoxicity with cisplatin, with activity in primary or
      secondary cisplatin-resistant solid tumors (colon and ovarian cancer). We report
      the tolerance/activity of this platinum derivate in previously-treated NHL
      patients. PATIENTS AND METHODS: From July 1988 to February 1994, 22 patients (11
      men, 11 women) with recurrent NHL received single-agent oxaliplatin (100-130
      mg/m2 i.v. over two hours with antiemetic premedication, q three weeks). All had
      been previously treated (median number of prior chemotherapy regimens 2, range 1
      7) > or = 1 alkylating agent: 22 patients, anthracyclines: 18 patients,
      cisplatin: four patients, and radiation: 11 patients. Fourteen patients (63%) had
      progressive disease as best response to their last chemotherapy, and were
      considered treatment-refractory. All histologies were centrally reviewed in
      accord with the R.E.A.L. Classification; they were: eight follicular, five MCL,
      three diffuse large cell, two MALT, one lymphoplasmocytoid, and three other.
      RESULTS: A total of 144 cycles were administered for a median number of 6 (range
      1-30) per patient. The objective response rate was 40% (95%, CI: 21-64),
      including one CR (MCL) and eight PRs (four follicular, two MCL, two MALT). The
      median response duration was 27 months (range 5-44). Treatment-related toxicity
      was limited to grade 1-2 nausea/vomiting and reversible grade 1-2 peripheral
      neuropathy in most of the patients. CONCLUSION: Oxaliplatin is an active agent in
      relapsed/refractory NHL, including the MCL type. Its safety profile makes this
      agent a good candidate for the development of combined salvage regimens. Further
      phase II studies are needed to confirm these preliminary results.

PMID- 10355584
TI  - Radiotherapy for oesophageal cancer.

PMID- 10355583
TI  - Cisplatin-topotecan-paclitaxel weekly administration with G-CSF support for
      ovarian and small-cell lung cancer patients: a dose-finding study.
AB  - PURPOSE: Paclitaxel (PTX) and topotecan (TPT) have shown promising antitumor
      activity in both ovarian cancer (OC) and small-cell lung cancer (SCLC) patients.
      This phase I study was aimed at determining the maximum tolerable dose (MTD) of
      TPT given weekly over 30 min in combination with fixed doses of cisplatin (CDDP)
      and (PTX), and with G-CSF support. PATIENTS AND METHODS: Forty-four patients with
      OC (19) or SCLC (25), either chemo-naive (20) or pretreated (24) received CDDP 40
      mg/m2, PTX 85 mg/m2 (one-hour infusion) and escalating TPT doses (starting from
      0.75 mg/m2) in a 30-min infusion in weekly administration. Filgrastim 5 mg/kg was
      administered on days 3 to 5 of each week. RESULTS: Eight different dose levels
      were tested for a total of 295 delivered cycles. The dose escalation was
      interrupted at the TPT dose of 2.50 mg/m2. No toxic deaths occurred in this
      study. Grade 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 15
      patients (36 cycles), seven patients (15 cycles), and four patients (five
      cycles), respectively. Severe vomiting and diarrhoea occurred in seven and four
      patients. Peripheral neuropathy was recorded in 11 patients (42 cycles), but it
      was never severe. An overall 11 of 19 (58%) OC and 11 of 25 (44%) SCLC patients
      obtained objective responses. Eight patients showed complete responses (three OC
      and three SCLC). Among the 20 chemo-naive patients, 9 of 11 (82%) OC and seven of
      nine (78%) SCLC responded. CONCLUSIONS: The CDDP/TPT/PTX weekly administration
      with filgrastim support represents a well-tolerated and active therapeutic
      approach in both chemo-naive and pretreated OC and SCLC patients. A weekly dose
      of TPT of 2.25 mg/m2 is recommended for the phase II study.

PMID- 10355585
TI  - Epirubicin in a breast cancer patient with Gilbert's syndrome: apparent lack of
      major pharmacokinetic alterations.

PMID- 10355586
TI  - Has the PSA wave already crashed upon us? Changes in the epidemiology of prostate
      cancer from 1985 to 1994 in central Italy.

PMID- 10355587
TI  - Acute myeloid leukemia and myelodysplasia in patients with chronic lymphocytic
      leukemia receiving fludarabine as initial therapy.

PMID- 10355588
TI  - 3-Isobutyl-1-methylxanthine inhibits basal mu-opioid receptor phosphorylation and
      reverses acute morphine tolerance and dependence in mice.
AB  - Phosphorylation of the mu-opioid receptor may play a role in opioid tolerance and
      dependence. 3-Isobutyl-1-methylxanthine (IBMX) was found to inhibit basal mu
      opioid receptor phosphorylation (IC50 < or = 10 microM) either upon acute
      treatment or after 8 h pre-treatment in HEK293 cells transfected with the mu
      opioid receptor. In mice made acutely tolerant to and dependent on morphine, IBMX
      (30-100 nmol, i.c.v.) significantly attenuated the naloxone-induced withdrawal
      jumping and partially reversed morphine antinociceptive tolerance. IBMX also
      blocked changes to mu-opioid receptor signaling associated with chronic morphine
      treatment, specifically, the inverse agonist effect elicited by naloxone, in
      which naloxone paradoxically elevated the cAMP levels in cells previously exposed
      to morphine for > or = 12 h. These results suggest a new effect of IBMX in
      inhibiting basal mu-opioid receptor phosphorylation, and provide additional
      evidence for the involvement of receptor phosphorylation in the development of
      opioid tolerance and dependence.

PMID- 10355589
TI  - Chronic hypoxia differentially alters the responses of pulmonary arteries and
      veins to endothelin-1 and other agents.
AB  - The effects of chronic hypoxia on the responses of rat large pulmonary arteries
      and veins to vasoactive agents have been examined. Endothelin-1-induced
      contractions of pulmonary arteries and pulmonary veins were reduced by chronic
      hypoxia. In contrast, chronic hypoxia augmented sarafotoxin 6c-induced
      contractile responses in pulmonary veins but not in pulmonary arteries. Chronic
      hypoxia augmented the constrictor effect of phenylephrine in pulmonary arteries,
      but not in pulmonary veins. The thromboxane receptor agonist, U46619 (9,11
      dideoxy-9alpha,11alpha-epoxy-methanoprostaglandin++ + f2alpha) contracted
      pulmonary arteries and pulmonary veins, and although maximal responses were not
      altered in chronically hypoxic preparations, the EC50 value in pulmonary arteries
      was increased following chronic hypoxia. The relaxant effects of acetylcholine
      and isoprenaline on pulmonary arteries were potentiated by chronic hypoxia. In
      contrast, ionomycin-mediated relaxations of pulmonary arteries and pulmonary
      veins were reduced, while sodium nitroprusside-induced relaxation of pulmonary
      arteries and veins were not altered by chronic hypoxia. Previous studied have
      looked primarily at the effects of chronic hypoxia on pulmonary arteries. This
      data provides evidence that chronic hypoxia also causes selective changes in the
      reactivity of large pulmonary veins.

PMID- 10355590
TI  - Modulatory effect of imetit, a histamine H3 receptor agonist, on C-fibers,
      cholinergic fibers and mast cells in rabbit lungs in vitro.
AB  - The pharmacological mechanisms involved in the interactions between C-fibers,
      cholinergic fibers and mast cells were investigated in tracheally perfused rabbit
      lungs by measuring the simultaneous release of substance P and histamine in lung
      effluents. The amounts of substance P and histamine released in lung superfusates
      were measured by radioimmunoassay (RIA) after administration of capsaicin and
      carbachol. Capsaicin (10(-4) M) induced a simultaneous increase in substance P
      (273 +/- 56% of baseline) and histamine (460 +/- 138%) release. Similarly,
      carbachol (10(-4) M) caused an increase in the release of both substance P (367
      +/- 111%) and histamine (1379 +/- 351%). The effect of capsaicin was prevented by
      pretreating the lungs with the tachykinin NK1 receptor antagonist SR 140333 (10(
      7) M), and atropine (10(-6) M). SR 140333 prevented the carbachol-induced release
      of substance P but not of histamine. Exogenous substance P induced an increase in
      histamine release (136 +/- 7%) which was significantly greater in lungs perfused
      with the neutral endopeptidase inhibitor, thiorphan (10(-5) M) (272 +/- 35%).
      This effect was prevented by atropine (10(-6) M). Pretreatment of lungs with
      imetit (5 x 10(-8) M), a selective H3 receptor agonist, prevented the capsaicin
      induced release of both mediators. Imetit also blocked the carbachol-induced
      release of substance P but not of histamine. Exogenous substance P-evoked
      histamine release was inhibited by imetit. Therefore, it can be concluded that
      substance P released through the action of capsaicin can activate cholinergic
      fibers, leading to cholinoceptor stimulation with subsequent activation of C
      fibers and mast cells. While the presence of presynaptic H3 receptors modulating
      substance P-induced acetylcholine release was only surmised, the existence of
      modulating histamine H3 receptors on C-fibers was confirmed.

PMID- 10355591
TI  - Characterisation of the functional alpha-adrenoceptor subtype in the isolated
      female pig urethra.
AB  - The aim of the present study is to characterise the contraction-mediating
      functional alpha-adrenoceptor of the female pig urethra. Alpha-adrenoceptor
      reference agonists were used to contract the isolated female pig urethra. The
      relative intrinsic activity was noradrenaline (1.0), phenylephrine (0.91),
      methoxamine (0.74), (+/-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethane
      sulfonanilid e hydrochloride (NS-49) (0.68), oxymetazoline (0.60), dopamine
      (0.50), clonidine (0.43), midodrine (0.32), ephedrine (0.30), 5-bromo-N-(4,5
      dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304) (0.11), and
      phenylpropanolamine (0.11). The 21 competitive antagonists used caused parallel
      rightward shifts in the alpha-adrenoceptor agonist concentration-response curves,
      giving linear Schild-plots with slopes not significantly different from unity,
      suggesting that contraction was mediated by a single receptor. The antagonist
      pK(B) values calculated were R(-)-tamsulosin (9.68), risperidone (9.19), 2-[2-[4
      (2-methoxyphenyl)-1-piperazinyl]ethyl]-4,4-dimethyl-1,3(2H,4H)-+
      ++isoquinolinedione (AR-C 239) (9.09), 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)
      1,4-benzodioxane (WB-4101) (8.87), N-[3-[4-(2-methoxyphenyl)-1
      piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl- 4H-1-benzopyran-8-carboxamide
      monomethanesulfonate (Rec 15/2739/3) (8.81), 5-methylurapidil (8.59), prazosin
      (8.57), benoxathian (8.56), S(+)-tamsulosin (8.27), indoramin (8.11), doxazosin
      (7.96), alfuzosine (7.82), phentolamine (7.70), terazosin (7.52), spiperone
      (7.48), oxymetazoline (7.40), 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8
      azaspiro[4,5]deca ne-7,9-dione dihydrochloride (BMY 7378) (7.05), corynanthine
      (6.98), rauwolscine (6.40), yohimbine (6.22), and N-[2-(2
      cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha,alpha-dime thyl-1H-indole-3
      ethanamine hydrochloride (RS 17053) (6.07). Correlation of subtype-selective
      antagonist pK(B) values was best with published values for the alpha1a/1A
      adrenoceptor subtype. Therefore, the present results suggest that contraction of
      the female pig urethra is caused by activation of the alpha1A-adrenoceptor.

PMID- 10355592
TI  - Antitussive effect of K+ channel openers.
AB  - The effect of the K(ATP) channel openers, pinacidil and cromakalim, on coughing
      was studied in guinea pigs exposed to a nebulized aqueous solution of citric acid
      (0.50 M). Both pinacidil and cromakalim, subcutaneously administered 45 min
      before the test, inhibited coughing. The D50 (95% CI) were 0.95 +/- 0.90 mg/kg
      for cromakalim and 3.25 +/- 0.92 mg/kg for pinacidil. Under our experimental
      conditions, the D50 (95% CI) of codeine was 1.74 +/- 0.75 mg/kg. The combination
      of cromakalim and pinacidil with codeine produced an additive effect. An additive
      effect was also produced by the combination of pinacidil with the selective
      tachykinin NK2 receptor antagonist MEN 10,627 = [cyclo(Met-Asp-Trp-Phe-Dap
      Leu)cyclo(2beta-5beta)]. The antitussive effect of pinacidil and cromakalim was
      not a consequence of a bronchodilating effect, which was absent at these dose
      levels under our experimental conditions. These results indicate that K(ATP)
      channel openers have an opioid-like antitussive effect and may suggest a novel
      approach to the symptomatic treatment of coughing.

PMID- 10355593
TI  - Participation of the opioid system in the regulation of prolactin secretion in
      androgenized rats: effect of ovarian steroids.
AB  - We examined the role of the opioid system on the regulation of prolactin
      secretion in neonatally androgenized rats and evaluated the participation of
      ovarian steroids in this regulation. Androgenized rats exhibited an increase of
      prolactin secretion with higher serum circulating levels in the afternoon (1800)
      than in the morning (1000). The administration of the opioid antagonist naloxone
      (2 mg/kg, 30 min before decapitation) reduced serum prolactin levels in both
      groups. To identify the opioid receptor subtypes involved in this regulation,
      opioid agonists were administered i.c.v. 15 min before the decapitation (1000).
      The mu-opioid receptor agonist DAMGO ([D-Ala2, NMe-Phe4, Gly5-ol]-enkephalin)
      caused a significant increase in serum prolactin concentration. The selective
      kappa-opioid receptor agonist U-50, 488H (trans-(+/-)-3,4-dichloro-N-[2(1
      pyrrolidinyl)-cyclohexyl]-benzene acetamide methane sulfonate salt) induced a
      small but significant increase in serum prolactin levels but no effect was
      observed after administration of the delta-opioid agonist DPDPE ([D-Pen2, D-Pen5]
      enkephalin). The role of oestradiol and the opioid system in the continuous
      secretion of prolactin was also study. Chronic gonadectomy (3-4 weeks) reduced
      serum prolactin concentrations measured at 1000 but the administration of
      naloxone had no effect. Three days of oestrogen treatment (2 microg/rat in oil)
      restored serum prolactin levels compared with ovariectomized animals and this
      effect was abolished by naloxone treatment. Interestingly, acute ovariectomy or
      administration of tamoxifen to intact androgenized rats did not prevent the
      continuous secretion of prolactin observed in these animals and naloxone
      treatment reduced serum prolactin levels in both groups of rats. We also examine
      the participation of adrenal progesterone and the endogenous opioid peptides on
      the regulation of prolactin levels in androgenized rats. After adrenalectomy, no
      changes in serum prolactin levels (1000) were observed compared with the control
      animal and naloxone treatment significantly reduced circulating prolactin levels.
      Progesterone treatment to intact androgenized rats significantly increased
      prolactin levels and the administration of naloxone blocked the stimulatory
      effect of the steroid. These results suggest that the opioid system play a role
      in the regulation of prolactin secretion in androgenized rats modulated by the
      persistence of oestrogen action. Moreover, the presence or absence of
      progesterone did not modify the regulation of prolactin secretion by the opioids.
      The mu- and kappa-opioid receptor subtypes are the ones involved in the
      modulation of pituitary prolactin secretion.

PMID- 10355594
TI  - Glucose-dependent insulinotropic effects of JTT-608, a novel antidiabetic
      compound.
AB  - The effects of JTT-608 [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid], a novel
      antidiabetic compound, on insulin secretion were investigated using mouse
      insulinoma cell line (MIN6 cells) and isolated, perfused rat pancreas. JTT-608
      enhanced insulin secretion in MIN6 cells in a dose dependent (10-300 microM) and
      glucose concentration-dependent (2.8-16.7 mM) manner. Unlike sulphonylureas, JTT
      608 minimally stimulated insulin secretion at low glucose concentrations but
      potently enhanced insulin secretion at high glucose concentrations. In isolated,
      perfused pancreas of normal rats, JTT-608 (100-300 microM) dose-dependently
      enhanced insulin secretion in the first and second phases at high glucose
      concentrations but minimally stimulated insulin secretion at a basal glucose
      concentration. In isolated, perfused pancreas of neonatally streptozotocin
      induced non-insulin-dependent diabetes mellitus rats (nSTZ rats), JTT-608 (200
      microM) normalized the first phase and doubled the second phase of insulin
      secretion. In MIN6 cells, JTT-608 did not inhibit the binding of
      [3H]glibenclamide to membrane fractions but enhanced K+-ATP channel-independent
      insulin secretion. These results suggest that JTT-608 enhances insulin secretion
      in a different manner and via a different mechanism from hypoglycemic
      sulphonylureas.

PMID- 10355595
TI  - Inhibition of tumor necrosis factor-alpha induced neutrophil apoptosis by cyclic
      AMP: involvement of caspase cascade.
AB  - Treatment of neutrophils with tumor necrosis factor-alpha (TNF-alpha) in the
      presence of cycloheximide induced apoptosis within 3 h, as evaluated by the
      occurrence of morphological nuclear changes characteristic of apoptosis.
      Pretreatment of neutrophils with dibutyryl cyclic AMP (dbcAMP) suppressed the TNF
      alpha/cycloheximide-induced apoptosis in neutrophils in a concentration-dependent
      manner, while dbcAMP by itself did not induce any morphological changes.
      Forskolin, or a phosphodiesterase inhibitor, also produced a concentration
      dependent inhibition on apoptosis. This inhibition by dbcAMP was completely
      reversed by pretreatment with the protein kinase A inhibitor, N-[2-(p
      bromocinnamylamino) ethyl]-5-isoquinoline sulphonamide (H-89). DbcAMP also
      inhibited the TNF-alpha/cycloheximide-induced activation of caspase-3, but it had
      no effect on the activation of caspase-8 in human neutrophils. Furthermore,
      dbcAMP did not directly inhibit activated caspase-3 activity. Inhibitor of
      protein kinase C, phosphatidylcholine-specific phospholipase C, tyrosine kinase,
      nitric oxide synthase, or granulocyte colony-stimulating factor or granulocyte
      monocyte colony-stimulating factor did not affect apoptosis. These results
      indicate that the elevation of levels of endogenous intracellular cyclic AMP and
      subsequent activation of protein kinase A play a crucial role in the prevention
      of apoptosis triggered by TNF-alpha/cycloheximide in human neutrophils, and that
      the possible target of cyclic AMP is a product in the metabolic pathway between
      caspase-8 and caspase-3.

PMID- 10355596
TI  - Differential regulation of Na+/H+ exchange and DNA synthesis in vascular smooth
      muscle cells.
AB  - Na+/H+ exchange has been proposed to be involved in the regulation of cell
      growth. However, little is known about the regulatory pathway and relationship
      between Na+/H+ exchange and DNA synthesis. In vascular smooth muscle cells,
      platelet-derived growth factor (a tyrosine kinase-coupled receptor agonist) and
      thrombin (a G protein-coupled receptor agonist) stimulate both activation of
      Na+/H+ exchange and DNA synthesis. In this study, we compared the effect of
      platelet-derived growth factor (PDGF) and thrombin on the signal transduction
      pathway leading to the activation of these responses in A10 cells, clonal rat
      thoracic aortic smooth muscle cells. To investigate the role of mitogen-activated
      protein kinase (MAPK) and phosphatidylinositol-3-kinase as potential mediators,
      we examined the effect of pharmacological kinase inhibitors on these responses.
      The Na+/H+ exchange activity induced by thrombin was inhibited by a specific
      inhibitor of MAPK kinase, 2'-amino-3'-methoxyflavone (PD98059), but was not
      affected by a specific phosphatidylinositol-3-kinase inhibitor, 2-(4-morpholinyl)
      8-phenyl-4H-1-benzopyran-4-one (LY294002). Thrombin-induced DNA synthesis was
      inhibited by LY294002, but not by PD98059. In contrast, the Na+/H+ exchange
      activity induced by PDGF was inhibited by neither LY294002 nor PD98059, but PDGF
      induced DNA synthesis was inhibited by both LY294002 and PD98059. These data
      suggest that, in A10 cells, Na+/H+ exchange activation and DNA synthesis are
      differently regulated by the two extracellular stimuli.

PMID- 10355597
TI  - SB203580 reverses adrenomedullin's effect on proliferation and apoptosis in
      cultured mesangial cells.
AB  - Adrenomedullin is a potent vasodilatory peptide that has a variety of effects in
      a number of different systems including kidney. In cultured rat glomerular
      mesangial cells adrenomedullin increases cAMP, decreases proliferation and
      increases apoptosis. Associated with the anti-proliferative and apoptotic
      effects, adrenomedullin also causes a decrease in extracellular signal-regulated
      kinase2 (ERK2) and an increase in cJun N-terminal kinase 1 (JNK1) and P38 mitogen
      activated protein kinase (P38 MAPK) activities. The purpose of the present study
      was to examine the role of P38 MAPK on adrenomedullin-mediated inhibition of
      [3H]thymidine incorporation (an index of proliferation) and on adrenomedullin
      stimulated nucleosome-associated cytoplasmic DNA fragmentation (an index of
      apoptosis) in mesangial cells, using a selective inhibitor of P38 MAPK, SB203580
      [[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-im idazole], and
      also to characterize the proximal signal transduction pathways of the three MAPKs
      in relation to [3H]thymidine incorporation and cytoplasmic DNA fragmentation
      using a phosphotidyl inositol-3-kinase inhibitor, wortmannin [[1S-(1alpha,6b
      alpha,9alphabeta,11alpha,11b beta)]-11-(acetyloxy)-1,6b,7,8,9a,10,11,11b
      octahydro-1-(methoxyme thyl)-9a,11b-dimethyl-3H-furo[4,3,2-de]indeno[4,5-h]-2
      benzopyran-3,6,9- trione]. SB203580 significantly reversed the effects of
      adrenomedullin on [3H]thymidine incorporation and cytoplasmic DNA fragmentation,
      and inhibited only P38 MAPK activity. It had no effect on ERK2 and JNK1
      activities. Wortmannin, on the other hand, inhibited only adrenomedullin
      stimulated cytoplasmic DNA fragmentation and did not affect adrenomedullin
      mediated inhibition of [3H]thymidine incorporation. Wortmannin also inhibited
      adrenomedullin-stimulated P38 MAPK activity without affecting ERK2 and JNK1
      activities. These results indicate that: (a) In rat mesangial cells
      adrenomedullin-mediated inhibition of [3H]thymidine incorporation and stimulation
      of nucleosome-associated cytoplasmic DNA fragmentation are sensitive to SB203580,
      and (b) adrenomedullin activates a P38 MAPK through a wortmannin-sensitive
      kinase. The data using SB203580 suggest an important physiological role for P38
      MAPK in rat mesangial cell proliferation and apoptosis.

PMID- 10355598
TI  - Adenosine and cerebral ischemia: therapeutic future or death of a brave concept?
AB  - Numerous studies have consistently shown that agonist stimulation of adenosine A1
      receptors results in a significant reduction of morbidity and mortality
      associated with global and focal brain ischemia in animals. Based on these
      observations, several authors have suggested utilization of adenosine A1
      receptors as targets for the development of clinically viable drugs against
      ischemic brain disorders. Recent advent of adenosine A1 receptor agonists
      characterized by lowered cardiovascular effects added additional strength to this
      argument. On the other hand, although cardioprotective, adenosine A3 receptor
      agonists proved severely cerebrodestructive when administered prior to global
      ischemia in gerbils. Moreover, stimulation of adenosine A3 receptors appears to
      reduce the efficacy of some of the neuroprotective actions mediated by adenosine
      A1 receptors. The review discusses the possible role of adenosine receptor
      subtypes (A1, A2, and A3) in the context of their involvement in the pathology of
      cerebral ischemia, and analyzes putative strategies for the development of
      clinically useful strategies based on adenosine and its receptors. It also
      stresses the need for further experimental studies before definitive conclusions
      on the usefulness of the adenosine concept in the treatment of brain ischemia can
      be made.

PMID- 10355599
TI  - The influence of interleukin-1 receptor antagonist transgene on spiral ganglion
      neurons.
AB  - The cytokine interleukin-1beta (IL-1) has been shown to induce the secretion of
      NGF and GDNF in several types of neuronal populations. IL-1 has also been shown
      to mediate immune response following trauma or presence of foreign antigens. We
      investigated the influence of an IL-1 antagonist on the survival of spiral
      ganglion neurons in inner ears in which hair cells have been eliminated. We used
      a replication-deficient adenoviral vector containing the human IL-1 receptor
      antagonist (IL-1ra) cDNA. Guinea pigs were bilaterally deafened with ototoxic
      drugs. One week later their left cochleae were inoculated with the IL-1ra vector,
      designated Ad.IL-1ra. The vector was delivered by injection through the cochlear
      round window. IL-1ra protein levels within the perilymph of Ad.IL-1ra-injected
      animals were measured with ELISA and found to be significantly elevated compared
      to our controls. Spiral ganglion cell counts in experimental ears revealed a
      lower density of neurons after Ad.IL-1ra inoculation. Taken together, the data
      suggest that the Ad.IL-1ra-infected cochlear cells synthesized the transgenic
      human IL-1ra protein, which was then secreted by the cells into the perilymph,
      resulting in an accelerated neuronal degeneration in hair cell-depleted ears.

PMID- 10355601
TI  - Ultrastructural pathology in the stria vascularis of the MRL-Fasl(lpr) mouse.
AB  - The MRL-Fas(lpr) mouse, a model of multisystemic, organ nonspecific autoimmune
      disease, has been proposed as a model of immune-mediated inner ear disease. A
      preliminary study employing light microscopy indicated that it develops cochlear
      pathology that appeared most striking in the stria vascularis, where cells
      underwent edema and degeneration. However, other structures, including the inner
      and outer hair cells and the supporting cells, also appeared to display
      pathology. The current study analyzed cochlear ultrastructure using transmission
      electron microscopy to better delineate the cochlear lesions found in these
      animals. MRL-Fas(lpr) animals were allowed to develop systemic disease (20 weeks
      old) and then had auditory brainstem response (ABR) thresholds determined.
      Animals were then killed and their cochleas prepared for electron microscopy. Age
      matched MRL-+/+ and BALB/c mice served as controls. Results indicated that MRL
      Fas(lpr) mice demonstrated elevated ABR thresholds. In contrast to a preliminary
      report, the cochlear pathology was observed exclusively in the stria vascularis,
      where cells demonstrated hydropic degeneration. Strial capillary structure was
      normal as were the rest of the cellular cochlear constituents. No inflammatory
      infiltrate was noted. These studies confirm that the MRL-Fas(lpr) mouse develops
      cochlear abnormalities focused in the stria vascularis. Whether the mechanism of
      the cellular degeneration involves autoimmune, genetic, or uremic processes has
      yet to be determined.

PMID- 10355600
TI  - Structural basis for mechanical transduction in the frog vestibular sensory
      apparatus: III. The organization of the otoconial mass.
AB  - The saccule and the utricle of the vestibular system detect linear acceleration
      and gravity. Sensory transduction in these organs depends on myriads of calcium
      carbonate crystals of high specific gravity, called otoconia, embedded in a
      filament matrix that overlies the sensory epithelium. The coexistence of hard
      crystals and slender filaments in this complex extracellular matrix makes it
      difficult to analyze by conventional electron microscopy. We have now examined
      this structure in the bullfrog saccule using the quick-freeze, deep-etch replica
      technique. The otoconia in their typical aragonite polymorph shape exhibit smooth
      surfaces and are embedded in a loose matrix made of two types of filaments. The
      regular surface of the otoconia forms a natural smooth background against which
      we could observe with unprecedented detail the network organization and
      substructure of the filaments. One type of filament is 8 nm in diameter, while
      the other, which has a characteristic beaded appearance, is 15 nm in diameter.
      Both types of filaments either make lateral connections with or end directly on
      the surface of the otoconia. A consistent observation was the presence of short
      filaments that directly cross-link adjacent otoconia. Very few otoconia were
      fractured in an orientation that would allow the study of their internal
      architecture. These otoconia presented a typical conchoidal cleavage of
      aragonite. Although crystallites were not clearly apparent, thin lamellar
      microstructures appeared oriented both perpendicularly and longitudinally to the
      major otoconial axis. This structural study establishes a framework for the
      identification of the molecular components present in this unique extracellular
      matrix and may also help elucidate their role in mechanical transduction.

PMID- 10355602
TI  - Stereociliary anomaly in the guinea pig: effects of hair bundle rotation on
      cochlear sensitivity.
AB  - Histological analysis of cochleas from 100 albino guinea pigs (Hartley strain)
      obtained from Charles River Laboratories revealed an apparently congenital
      anomaly in 24% of animals, with roughly equal prevalence in males and females. In
      affected animals, 15-50% of the first-row outer hair cells (OHCs) showed
      distinctly abnormal orientation of the W-shaped stereociliary array. These
      abnormal hair bundles could be rotated by up to 180 degrees from the normal quasi
      radial orientation. Second- and third-row OHCs appeared normal in all cases.
      Cochlear sensitivity was assayed in a subset of animals via compound action
      potentials (CAPs): CAP thresholds in affected animals were, on average, elevated
      by 5-10 dB with respect to normal controls. If the contributions of individual
      OHCs to cochlear 'amplification' add linearly, and if the total OHC contribution
      corresponds to approximately 45 dB of 'gain', a quantitative correlation of the
      degree of stereociliary rotation and the degree of threshold shift in these ears
      suggests that first-row OHCs make a larger contribution to the cochlear amplifier
      than either of the other OHC rows.

PMID- 10355603
TI  - The radial pattern of basilar membrane motion evoked by electric stimulation of
      the cochlea.
AB  - Electric current applied to the cochlea can evoke in situ electromotile responses
      of the organ of Corti. These nonsound-generated responses can give insight into
      the mechanics of the organ as the putative forces produced by outer hair cells
      (OHC) must couple to the modes of vibration of the basilar membrane (BM). In this
      study, platinum-iridium wire electrodes were positioned into the scala vestibuli
      and scala tympani of the first cochlear turn in the guinea pig. Current (1.5 ms
      rectangular-shaped pulses) was applied to these electrodes at levels to 500
      microA peak. A laser Doppler velocimeter was used to record the velocity or
      displacement of the basilar membrane at the tonotopic 18 kHz place via an opening
      into the scala tympani of the first cochlear turn. Beads were positioned across
      the width of the BM so that the velocity or displacement of the BM could be
      studied in the radial direction. It was found that the current pulses evoked
      linear displacements of up to 2 nm for current levels of 500 microA (higher
      levels were damaging to the organ of Corti). The pattern of motion across the
      width of the BM was such that maximum displacement and velocity was located near
      the first row of OHCs and the position of the outer pillar cell footplate. The BM
      motion was biphasic in that the zona arcuata moved in the opposite direction to
      that of the zona pectinata. The results of this study demonstrate that the level
      of force produced by OHCs is effective in moving the BM and that the distribution
      of force within the organ of Corti leads to a multimodal motion pattern of the BM
      for this experimentally artificial means of evoking OHC motion.

PMID- 10355604
TI  - Ensemble responses of the auditory nerve to normal and whispered stop consonants.
AB  - Whispered syllables lack many of the frequency and voicing cues of normally
      voiced speech, but these two acoustically distinct forms of speech are placed
      into the same linguistic categories. To examine how whispered and voiced speech
      are encoded in the auditory system, the responses to speech sounds were recorded
      from 132 single auditory nerve fibers in 20 ketamine anesthetized chinchillas.
      Stimuli were the naturally produced syllables /da/ and /ta/ presented in
      whispered and normal voicing. The results for each syllable presented at a fixed
      intensity were analyzed by pooling the responses from individual auditory nerve
      fibers across animals to create a global average peri-stimulus time (GAPST)
      histogram. For each word-initial consonant, the pattern of peaks in the GAPST was
      the same for both normal and whispered speech. For the vowel the GAPSTs for the
      whispered speech sounds did not display the synchronization observed in the
      responses to the voiced syllables. The temporal pattern of the peaks was constant
      over a 40 dB intensity range, although peak sizes varied. Grouping fibers within
      different frequency ranges created local averages (LAPST) that revealed the
      significant contribution of high frequency fibers in the response to the
      whispered consonants. Responses of individual fibers varied with both the
      syllable and the voicing. These findings suggest that the encoding of either a
      whispered or a normal stop consonant results in the same temporal pattern in the
      ensemble response.

PMID- 10355605
TI  - Cyclic GMP-dependent protein kinase-I in the guinea pig cochlea.
AB  - Recent studies have begun to characterize the nitric oxide/cyclic GMP/protein
      kinase G pathway in the mammalian cochlea by demonstrating the presence of both
      the enzyme that produces nitric oxide (NO), nitric oxide synthase, and the NO
      receptor, soluble guanylate cyclase. The present study investigated protein
      kinase G (cyclic GMP-dependent protein kinase-I, cGK-I), the downstream enzyme of
      this pathway that frequently mediates its physiological effects. A commercial
      antibody to a human cGK-I sequence recognized a protein of appropriate molecular
      weight in Western blots of guinea pig aorta. Immunostaining of guinea pig aorta
      was consistent with the expected distribution of cGK-I. In lateral wall tissues
      of the cochlea, pericytes lining the blood vessels of the spiral ligament were
      strongly immunoreactive. In the organ of Corti, cGK-I was detected in Hensen's,
      Deiters', and pillar cells, but not in inner and outer hair cells. This
      distribution coincides with the localization of soluble guanylate cyclase
      activity and suggests that cGK-I mediates the effects of the NO/cyclic GMP
      pathway in the cochlea. It reinforces the hypothesis that the NO/cyclic GMP/cGK-I
      pathway is involved in regulation of cochlear blood flow and supporting cell
      physiology.

PMID- 10355606
TI  - Avian species differences in susceptibility to noise exposure.
AB  - Previous studies of hair cell regeneration and hearing recovery in birds after
      acoustic overstimulation have involved relatively few species. Studies of the
      effects of acoustic overexposure typically report high variability. Though it is
      impossible to tell, the data so far also suggest there may be considerable
      species differences in the degree of damage and the time course and extent of
      recovery. To examine this issue, we exposed four species of birds (quail,
      budgerigars, canaries, and zebra finches) to identical conditions of acoustic
      overstimulation and systematically analyzed changes in hearing sensitivity,
      basilar papilla morphology, and hair cell number. Quail and budgerigars showed
      the greatest susceptibility to threshold shift and hair cell loss after
      overstimulation with either pure tone or bandpass noise, while identical types of
      overstimulation in canaries and zebra finches resulted in much less of a
      threshold shift and a smaller, more diffuse hair cell loss. All four species
      showed some recovery of threshold sensitivity and hair cell number over time.
      Canary and zebra finch hearing and hair cell number recovered to within normal
      limits while quail and budgerigars continued to have an approximately 20 dB
      threshold shift and incomplete recovery of hair cell number. In a final
      experiment, birds were exposed to identical wide-band noise overstimulation under
      conditions of artificial middle ear ventilation. Hair cell loss was substantially
      increased in both budgerigars and canaries suggesting that middle ear air
      pressure regulation and correlated changes in middle ear transfer function are
      one factor influencing susceptibility to acoustic overstimulation in small birds.

PMID- 10355607
TI  - Monaural response properties of single neurons in the chinchilla inferior
      colliculus.
AB  - The responses of 274 inferior colliculus (IC) central nucleus neurons from 20
      chinchillas were studied. Characteristic frequency (CF) increased as the IC was
      traversed in the dorsal-ventral direction. Most units had little or no
      spontaneous activity, with a mean threshold for response of about 30 dB SPL
      across all units. Tuning curve width varied between units, with a significant
      increase in Q20, with increasing CF. Peri-stimulus time histogram (PSTH) types
      were similar to those reported for cat inferior colliculus units. Transient,
      sustained, pauser, and buildup types were observed, with transient responses
      predominating. Response area (RA) types were also similar to those of cat IC
      units, with most units displaying stable best frequencies across a range of
      stimulus intensity levels. For a few units, excitatory RA regions were surrounded
      by inhibitory sidebands. Nonmonotonic discharge rate vs. stimulus intensity level
      functions were common in all CF ranges and for all PSTH and RA types. Mean first
      spike latencies, however, differed across PSTH groups, owing to the temporal
      definitions of these PSTH shapes. Latencies of sustained units were significantly
      longer than those of transient units, and buildup PSTHs showed significantly
      longer latencies than any other group.

PMID- 10355608
TI  - Reversed tonotopic map of the basilar papilla in Gekko gecko.
AB  - A published model of the frequency responses of different locations on the
      basilar papilla of the Tokay gecko Gekko gecko (Authier and Manley, 1995. Hear.
      Res. 82, 1-13) had implied that (a) unlike all other amniotes studied so far, the
      frequency map is reversed, with the low frequencies at the base and the high
      frequencies at the apex, and (b) the high-frequency area is split into two
      parallel-lying hair cell areas covering different frequency ranges. To test these
      hypotheses, the frequency representation along the basilar papilla of Gekko gecko
      was studied by recording from single auditory afferent nerve fibers and labelling
      them iontophoretically with horseradish peroxidase. Successfully labelled fibers
      covered a range of characteristic frequencies from 0.42 to 4.9 kHz, which
      extended from 78% to 9% of the total papillar length, as measured from the apex.
      The termination sites of labelled fibers within the basilar papilla correlated
      with their characteristic frequency, the lowest frequencies being represented
      basally, and the highest apically. This confirms the first prediction of the
      model. The map indicates, however, that one of the two high-frequency papillar
      regions (the postaxial segment) represents the full high-frequency range, from
      about 1 to 5 kHz. No functionally identified labelling was achieved in the
      preaxial segment. Thus the assumptions underlying the proposed model need
      revision. A good mathematical description of the frequency distribution was given
      by an exponential regression with a mapping constant in the living state of
      approximately 0.4 mm/octave.

PMID- 10355609
TI  - Effect of 4-methylthiobenzoic acid on cisplatin-induced ototoxicity in the rat.
AB  - The purpose of this study was to investigate the effectiveness of 4
      methylthiobenzoic acid (MTBA) as a protection agent against cisplatin (CDDP)
      induced changes in organ of Corti surface structure, compared to
      electrophysiological changes. Electrophysiological change was assessed using
      auditory brainstem response (ABR) and morphological changes were assessed using
      scanning electron microscopy (SEM). Male Wistar rats underwent pre-treatment ABRs
      in response to clicks, and tone bursts at 2, 4, 8, 16, and 32 kHz. The three
      groups of rats were injected as follows: (1) MTBA (250 mg/kg, i.p.), (2) CDDP (16
      mg/kg, i.p.), (3) CDDP+MTBA (16 mg/kg, i.p. + 250 mg/kg, i.p.). Post-treatment
      ABRs were performed 3 days after drug administration and rats were sacrificed.
      Their cochleae were harvested and SEM was used to examine the surface of the
      organ of Corti, specifically the number of inner hair cells (IHCs) and outer hair
      cells (OHCs) in the apical, middle and basal turns of the cochlea. Animal weight
      was measured on the first and final days. There was a good correlation between
      ABR threshold changes and hair cell loss in the high frequency region of the
      cochlea (basal turn), while threshold changes in the lower test frequencies
      (middle turn) appeared to be the result of more subtle changes in the cochlea.
      MTBA provided effective protection against cisplatin-induced ABR threshold
      changes at all test frequencies as well as hair cell loss. MTBA also protected
      against body weight loss.

PMID- 10355610
TI  - The influence of pneumococcal otitis media on the cochlear lateral wall.
AB  - The cochlear influence of otitis media was investigated in order to identify
      damaged regions causing cochlear malfunction. BALB/c mice were challenged with
      viable Streptococcus pneumoniae into the middle ear cavity and were killed 1 day
      to 1 month later for immunohistochemical analysis. Otitis media was induced in
      all of the animals, and some showed inflammatory cells in the cochlea. Although
      other changes were not obvious by hematoxylin and eosin staining,
      immunohistochemistry showed the presence of fibrinogen in the cochlea, mainly in
      the lower portion of the spiral ligament and in the spiral limbus. Immunostaining
      for connexin 26 was decreased in the spiral ligament, accompanied by marked
      fibrinogen staining. Immunostaining for sodium-potassium-adenosine triphosphatase
      in the stria vascularis and in the type II fibrocytes of the spiral ligament was
      not affected obviously. The presence of fibrinogen in the cochlea suggests
      disruption of the blood-labyrinth barrier caused by the middle ear inflammation.
      Changes in connexin 26 staining suggest the possibility that the spiral ligament
      could be among the regions responsible for the cochlear malfunction.

PMID- 10355611
TI  - Do auditory responses recorded from awake animals reflect the anatomical
      parcellation of the auditory thalamus?
AB  - Previous studies performed in anesthetized animals have shown differences between
      the acoustic responses of neurons recorded from the different divisions of the
      medial geniculate body (MGB). This study aimed at determining whether or not such
      differences are also expressed when neurons are recorded from awake animals. The
      auditory responses of 130 neurons of the auditory thalamus were determined in
      awake, restrained guinea pigs while the state of vigilance of the animals was
      continuously monitored. There were significantly more 'on' phasic evoked
      responses and significantly fewer 'non-responsive' or 'labile' cells in the
      ventral division of the MGB (MGv) than in the other divisions. The response
      latencies and the variability of the latencies were smaller in the MGv than in
      the other divisions. The tuning of the neurons obtained from MGv and from the
      lateral part of the posterior complex were significantly sharper than those
      coming from the dorsal division of the MGB and the medial division. The mean
      threshold and the percentage of monotonic vs. non-monotonic intensity functions
      were not different in the subdivisions of the auditory thalamus. When compared
      with previous studies, the quantifications of the acoustic responses obtained in
      the present study gave values that differed from those reported under deep
      anesthesia, but were close to those reported under light anesthesia. Lastly, even
      if none of the physiological characteristic makes it possible, by itself, to
      determine the locus of recordings in the auditory thalamus, we conclude that the
      physiological characteristics of the evoked responses obtained in MGv differ from
      those of other divisions.

PMID- 10355612
TI  - Responses of auditory nerve fibers innervating regenerated hair cells after local
      application of gentamicin at the round window of the cochlea in the pigeon.
AB  - Hair cells in the basilar papilla of birds have the capacity to regenerate after
      injury. There is also functional recovery of hearing after regeneration of the
      hair cells. The present study was undertaken to determine the effect of local
      aminoglycoside application on the physiology of auditory nerve fibers innervating
      regenerated hair cells. Collagen sponges loaded with gentamicin were placed at
      the round window of the cochlea in adult pigeons. The local application of
      gentamicin-loaded collagen sponges resulted in total hair cell loss over at least
      the basal 62% of the basilar papilla. According to the pigeon cochlear place
      frequency map (Smolders, Ding-Pfennigdorff and Klinke, Hear. Res. 92 (1995) 151
      169), frequencies above 0.3 kHz are represented in this area. Physiological data
      on single auditory nerve fibers were obtained 14 weeks after gentamicin
      treatment. The response properties showed the following characteristics when
      compared to control data: CF thresholds (CF = characteristic frequency) were
      elevated in units with CF above 0.15 kHz, sharpness of tuning (Q10dB) was reduced
      in units with CF above 0.38 kHz, low-frequency slopes of the tuning curves were
      reduced in units with CF above 0.25 kHz, high frequency slopes of the tuning
      curves were reduced in units with CF above 0.4 kHz, spontaneous firing rate was
      reduced in units with CF above 0.38 kHz, dynamic range of rate-intensity
      functions at CF was reduced in units with CF above 0.4 kHz and the slopes of
      these rate-intensity functions were elevated in units with CF above 0.4 kHz.
      Maximum discharge rate was the only parameter that remained unchanged in
      regenerated ears. The results show that the response properties of auditory nerve
      fibers which innervate areas of the papilla that were previously devoid of hair
      cells are poorer than the controls, but that action potential generation in the
      afferent fibers is unaffected. This suggests that despite structural regeneration
      of the basilar papilla, functional recovery of the auditory periphery is
      incomplete at the level of the hair cell or the hair cell-afferent synapse.

PMID- 10355613
TI  - Mechano-electrical transduction in mice lacking the alpha-subunit of the
      epithelial sodium channel.
AB  - Sensory hair cells of the vertebrate inner ear use mechanically gated transducer
      channels (MET) to perceive mechanical stimuli. The molecular nature of the MET
      channel is not known but several findings suggested that the amiloride-sensitive
      epithelial Na+ channel, ENaC, might be a candidate gene for this function. In
      order to test this hypothesis, we examined knockout mice deficient in the alpha
      subunit of ENaC, and therefore in ENaC function. First, neonatal alphaENaC(-/-)
      mice exhibited vestibular reflexes not different from wildtype littermates thus
      indicating normal vestibular function. We used organotypic cultures of cochlear
      outer hair cells from newborns to rescue the hair cells from the perinatal death
      of alphaENaC(-/-) mice. When hair bundles of cochlear outer hair cells of
      alphaENaC(-/-) mice were mechanically stimulated by a fluid jet in whole cell
      voltage clamp experiments, transducer currents were elicited that were not
      significantly different from those of alphaENaC(+/-) or (+/+) cochlear outer hair
      cells. These results suggest that the vertebrate mechano-electrical transducer
      apparatus does not include the alpha-subunit of the epithelial Na+ channel.

PMID- 10355614
TI  - Post-stimulatory suppression, facilitation and tuning for delays shape responses
      of inferior colliculus neurons to sequential pure tones.
AB  - Temporal changes in the excitability of inferior colliculus (IC) neurons will
      shape their responses to complex stimuli. Single-unit responses of rat IC neurons
      to the second (probe) of a pair of tones exhibited suppression, facilitation and
      delay tuned effects. Responses to probe tones were markedly suppressed (by 76%
      for contralateral stimulation with equal intensity tone pairs) during
      contralateral and binaural stimulation in 60% of IC neurons. Suppression
      developed rapidly as a function of the duration of the initial tone, and
      approached maximum for tones of less than 200 ms. Suppression decreased as the
      interval between tones increased, and this recovery of responsiveness was often
      exponential (time constants: mean: 271.4 ms; median: 72.8 ms; n = 47), and
      independent of the duration and intensity of preceding stimulation. Facilitation
      of responses to probe tones was observed chiefly in neurons with 'pauser/buildup'
      response patterns, and decreased as the intertone interval increased. The
      greatest suppression of responses to probe tones occurred only after intertone
      intervals of 32 ms (delayed minimum; n = 8) in 11% of IC neurons. Other IC
      neurons exhibited an increased excitability to probe tones presented 128 ms after
      stimulation (delayed maximum; n = 7). The latencies of the later neurons'
      responses were longer (mean: 29.5 ms) than other IC neurons. The role of
      suppression in sound localization and echo suppression, and the relationship
      between 'delay tuning' effects and encoding of complex stimuli are discussed.

PMID- 10355616
TI  - Gingival recession and toothbrushing in an Italian School of Dentistry: a pilot
      study.
AB  - The aim of this pilot study was to evaluate the prevalence of gingival recession
      at buccal tooth surfaces in a student population of Bologna University Dental
      School. A total of 55 subjects, attending the 1st and 5th year of the course were
      examined. The clinical examination involved assessment of plaque, calculus, width
      of keratinized gingiva, buccal probing depth and buccal gingival recession.
      Information about toothbrushing behavior was collected in an interview. The
      multiple regression analysis showed that level of education (p=0.002),
      toothbrushing technique (p=0.013) and toothbrushing frequency (p=0.016) are
      significant contributors to gingival recession. Notwithstanding the limits of a
      preliminary study, a higher prevalence of buccal recession is observed in the
      final year students, which have also a significantly lower % of buccal surfaces
      with calculus (p=0.014). In addition, it clearly appears that there is the
      necessity to investigate other factors connected with toothbrushing (pressure,
      time, toothpaste quantity) in order to provide an oral hygiene education without
      undesired effects.

PMID- 10355615
TI  - Salivary lactoferrin and low-Mr mucin MG2 in Actinobacillus actinomycetemcomitans
      associated periodontitis.
AB  - Concentrations and output of lactoferrin and of low-Mr mucin MG2 were determined
      in saliva of subjects suffering from Actinobacillus actinomycetemcomitans
      associated periodontal disease and healthy subjects. Periodontal patients were
      clinically examined and a microbiological sample was taken from the deepest
      bleeding pockets in each quadrant. The number of viable A. actinomycetemcomitans
      was determined in the sampled sites of each patient. The MG2 output in the
      diseased subjects (13.6 microg protein/min) was decreased at least by a factor
      three compared to periodontal healthy subjects (44.3 microg protein/min). On the
      other hand, output of lactoferrin was not significantly different in healthy (9.5
      microg/min) and diseased subjects (7.6 microg/min). Western analyses demonstrated
      a higher iron-saturation of lactoferrin in diseased subjects in comparison with
      the healthy subjects. Lactoferrin degrading enzymes, probably derived from
      microbial sources, could be detected in saliva of the periodontally diseased
      subjects, but not in saliva of healthy subjects. The combination of iron
      saturation and degradation of lactoferrin suggests that anti-microbial properties
      of lactoferrin are diminished in periodontitis patients. Moreover, the low
      concentration of mucin MG2 suggests a decline in mucin defence and consequently a
      higher susceptibility for oral infection. A negative correlation (r= -0.4, p <
      0.05) between the number of subgingival A. actinomycetemcomitans and lactoferrin
      in saliva suggested that low concentrations of lactoferrin favour the growth of
      the bacterium. These data indicate that a decline in the salivary defence system
      might increase the risk for oral infection by A. actinomycetemcomitans.

PMID- 10355617
TI  - Clinical study on the plaque-removing ability of a new triple-headed toothbrush.
AB  - The aim of this study was to determine the plaque removing ability of a new
      toothbrush with a u-shaped head (Superbrush) compared to a conventional manual
      toothbrush (Elmex) and an electric toothbrush with a rotating head (Braun Plak
      control). 36 healthy volunteers, aged 6-60 years, participated in this single
      blind cross-over study. They were randomly assigned to 3 groups (A, B, C) with 12
      participants each. To obtain a plaque-free condition at the baseline,
      professional toothcleaning was performed in each participant. After instructions
      on how to use the toothbrushes, each group started the experiment with a
      different type of toothbrush. After 1 week of application, the Quigley-Hein
      plaque index (QHI) and the proximal plaque index (API) were used to assess the
      oral hygiene status of each participant. This was followed by 1 week of recess
      before each group switched to the next type of toothbrush. The duration of the
      study was 5 weeks. All examinations were performed by 1 examiner. Compared to the
      2 other brushes, the Superbrush was more effective in removing plaque (medians of
      QHI: 0.84 versus 1.56 (Elmex) and 1.56 (Braun); p<0.001; medians of API: 0.69
      versus 0.94 (Elmex) and 0.87 (Braun); p<0.001). The study indicated that the new
      toothbrush may be an effective alternative to commonly used toothbrushes.

PMID- 10355618
TI  - A 24-h regrowth study to evaluate the plaque inhibitory properties of a
      proprietary liquid dentifrice.
AB  - Dentifrices have typically been formulated as pastes. Recently however, a number
      of liquid products have become available. The chemical plaque inhibitory activity
      of such products has so far received little attention. The aim of this study was
      to determine the plaque inhibitory effect of a proprietary liquid dentifrice by
      comparison to a negative control (water) and a conventional fluoride toothpaste.
      The study design was a randomised single centre, single blind 3-way cross-over
      trial with the objective of validating claims of plaque inhibition for the liquid
      dentifrice. Volunteers were rendered plaque free then asked to brush for one
      minute with one of the three test products, following which they abstained from
      oral hygiene for the subsequent 24 h. The plaque area was recorded and then
      measured planimetrically. The results showed that more plaque accumulated with
      water and the liquid dentifrice compared with the fluoride toothpaste. Thus,
      there was a statistically significant difference between the fluoride toothpaste
      and water and between the fluoride toothpaste and the liquid dentifrice. There
      was no significant difference between the liquid dentifrice and water. It is
      concluded that in this particular model system, the liquid dentifrice provided
      little chemical plaque inhibitory action.

PMID- 10355619
TI  - An evaluation of video instruction for an electric toothbrush. Comparative single
      brushing cross-over study.
AB  - Instructions on the use of electric toothbrushes are usually derived from the
      written and/or diagrammatic leaflets provided with the device or perhaps less
      often instruction from a professional. Videos are now widely used for information
      transfer and the direction of physical activities. The aim of this study was to
      determine whether video instruction in the use of an electric toothbrush could
      promote efficient use of the device. The 2-min video demonstrated the use of an
      oscillating, rotating electric toothbrush used by a hygienist for 15 s in each
      buccal and lingual quadrant. A voice-over directed the observer to follow the
      hygienist's movements. The study was planned as a 2-phase, single-examiner blind,
      randomised, cross-over study accepting there would be confounding of the 2nd
      period by carry-over from the 1st. A group of 24 healthy volunteers participated
      who had average oral hygiene and never used an electric toothbrush. 12 subjects
      received the video first (VN) and 12 subjects the instructional leaflet with the
      device (NV). Single brushings were performed after suspending tooth cleaning for
      48 h. Plaque was scored before and after brushing. A 2-week washout period was
      permitted before the crossover. In period 1, plaque removal with the video was
      overall significantly greater than with written instructions. The effects for
      posterior teeth were greater than anterior and comparison between groups for
      posterior minus anterior differences were highly significant in favour of the VN
      group. In period 2, the effect of period was dominant with both groups achieving
      greater plaque removal in period 2 than period 1. Plaque removal by group VN
      remained considerably greater than group NV Despite the confounding influences of
      carry-over in this particular design of study, the results support the idea that
      video instruction for electric toothbrushes could be a simple and efficient way
      of improving plaque removal by these devices. The methodology needs to be
      verified in a home-use type of investigation.

PMID- 10355621
TI  - Prevalence and serotyping of Porphyromonas gingivalis in an Indonesian
      population.
AB  - In this study, the prevalence and serotype distribution of Porphyromonas
      gingivalis in an Indonesian population (n=158) is described. The relationship
      between subgingival P. gingivalis and periodontal attachment loss was
      investigated. The serotype distribution and periodontal parameters were studied.
      Serotyping was also used to study person-to-person transmission between siblings
      and between spouses. Approximately 50% of the subjects had periodontal attachment
      loss > or =3 mm at 1 or more recorded sites. The population was divided into 2
      subgroups based on the presence or absence of P. gingivalis. No differences in
      plaque index, pocket depth, clinical attachment loss, bleeding upon probing, % of
      sites with > or =3 mm clinical attachment loss and % of sites with probing pocket
      depth > or =5 mm, were observed between both sub-populations. All known 6
      capsular serotypes were found in the study population, with the exception of the
      K1 type. Detection of 1 of the known P. gingivalis serotypes was not related with
      the amount of clinical attachment loss. In 3 out of 29 sibships with more than
      one member positive for P. gingivalis, an identical P. gingivalis serotype was
      found. None of the 15 couples in the study shared an identical P. gingivalis
      serotype, indicating that transmission is probably not a common phenomenon in
      this population.

PMID- 10355620
TI  - Digital radiography of interproximal bone loss; validity of different filters.
AB  - The aim of the present study was to compare linear measurements of interproximal
      bone loss on digitized radiographic images after application of different filters
      to the gold standard of intrasurgical measurements. Immediately before surgery,
      50 radiographs of 50 periodontally-diseased teeth exhibiting interproximal bone
      loss, were obtained by a standardized technique in 33 patients. Intrasurgically,
      the distances from the cementoenamel junction (CEJ) to the alveolar crest (AC)
      and from the CEJ to the deepest extension of the bony defect (BD) were assessed.
      All radiographs were digitized with a flatbed scanner (resolution: 600x1200 dpi).
      Using the FRIACOM-soft-ware, the linear distances CEJ to AC and CEJ to BD were
      measured at 50 interproximal lesions from the digitized but unchanged
      radiographic images and also after use of 7 different basic image-processing
      modes (enhancement of contrast [dynamics], inversion, high-pass, enhancement of
      gray-level differences, mean value, histogram correction, spreading of grey
      values) with 11-fold magnification. Neither the measurement of the distance CEJ
      to AC on the unchanged images nor assessments with any of the filters revealed
      significant differences from the gold standard. Multivariate analysis of variance
      showed the respective filter (p=0.009), intrasurgical and radiographic
      assessments (p<0.0001), to statistically significantly, influence the difference
      between intrasurgical and radiographic measurements of the distance CEJ to BD.
      The underestimation of the intra-surgically assessed distance CEJ to BD by
      radiographic measurements ranged from 0.3+/-2.0 to 0.8+/-1.9 mm. The filter "mean
      value" underestimated interproximal bone loss statistically significantly more
      than the digitized but unchanged radiograph (p=0.05). In this study, basic
      digital manipulations (filters) of radiographic images failed to result in
      statistically significantly more valid measurements of interproximal bone loss
      when compared to the unchanged but digitized images. All radiographic assessments
      on the digitized images except for use of one filter (mean value) came close to
      the intrasurgical gold standard.

PMID- 10355622
TI  - Substance removal on teeth with and without calculus using 308 nm XeCl excimer
      laser radiation. An in vitro investigation.
AB  - It was the aim of this in vitro study to determine the potential effects of 308
      nm XeCl excimer laser radiation on root surfaces when used for removing calcified
      deposits. The source of laser radiation was a XeCl-excimer laser (MAX 10, Fa.
      Medolas, Germany) emitting ultraviolet radiation at a wavelength of 308 nm with a
      pulse duration of 60 ns. Subjects of irradiation were 60 extracted teeth which
      were divided into 2 groups of 30 samples each with (group 1) and without calculus
      (group 2). Specimens were irradiated with 800 laser pulses at 5 different energy
      densities per pulse of 1.0 J/cm2, 2.0 J/cm2, 3.0 J/cm2, 4.0 J/cm2 and 5.0 J/cm2.
      For each parameter 6 samples (n=6) were exposed to 308 nm excimer-laser
      radiation. The ablation of hard tissue on the treated root surfaces was measured
      3-dimensionally with a laser scanning device (100,000 surface points per sample;
      accuracy: 5 microm) and evaluated with a special image analyzing software
      (volume, mean, median, standard deviation). In addition, a scanning electron
      microscopic (SEM) evaluation of the irradiated root surfaces was performed.
      Statistical analysis was done using ANOVA with the Scheffe-test. The lowest
      amount of ablation on teeth without calculus was induced with 14.01 (+/-5.86)
      microm using laser radiation at an energy density of 2.0 J/cm2. Maximum tissue
      removal in this sample group was obtained with 56.67 (+/-21.05) microm with laser
      treatment at an energy density of 5.0 J/cm2. While no ablation of dental cementum
      was detectable after irradiating root surfaces without calculus at 1.0 J/cm2, a
      strong removal of calculus with a mean value of 31.91 (+/-4.2) microm was
      observed under these conditions. The results seem to indicate that a selective
      removal of subgingival calculus creating a homogenous shape of the root surface
      with 308 nm excimer laser radiation is possible. Furthermore, no signs of the
      formation of a smear layer nor the induction of thermal side-effects were
      observed.

PMID- 10355623
TI  - Severe, rapidly progressing peri-implantitis.
AB  - The replacement of teeth by means of titanium implants is a safe and predictable
      procedure in most patients. Some studies show that a small number of patients
      lose the majority of their implants. Unfortunately, it is impossible to identify
      these patients prior to surgery. It is important to report such cases so that we
      may, in the future, be able to identify them before surgery. The present case
      showed a severe and rapid exfoliation of titanium implants. Out of 8 implants
      inserted in the anterior lower jaw of this patient, only two maintained
      osseointegration over a 2-year period.

PMID- 10355624
TI  - Presence of oxytalan fibers in human regenerated periodontal ligament.
AB  - The aim of the present study was to investigate whether oxytalan fibers are
      formed in the regenerated human periodontal ligament. 6 patients, each of them
      exhibiting an advanced intrabony defect, were treated with a bioresorbable
      membrane according to the GTR-principle. Following a healing period of 6 months,
      the teeth were extracted together with their surrounding soft and hard tissues
      and subsequently fixed in 10% buffered formalin. Following decalcification in
      EDTA, the specimens were embedded in paraffin and 8-microm histological sections
      were cut in the mesio-distal direction, parallel to the long axes of the teeth.
      The sections were stained with hematoxylin and eosin, or with the oxone-aldehyde
      fuchsin-Halmi staining method and examined in the light microscope. A regenerated
      periodontal ligament containing newly-formed oxytalan fibers was observed in all
      specimens. Many of them inserted into the newly formed cementum on the root
      surface. It is concluded that oxytalan fibers are formed de novo in human
      regenerated periodontal ligament tissue.

PMID- 10355625
TI  - The effect of periodontal therapy on the number of cariogenic bacteria in
      different intra-oral niches.
AB  - Several publications have reported an increased susceptibility for root caries
      after periodontal therapy. It has been suggested that newly exposed roots were
      less resistant to cariogenic species. This study examined the hypothesis that the
      increased susceptibility could also be related to an intra-oral microbial shift
      during the initial phase of the periodontal therapy from a perio-pathogenic to a
      more cariogenic flora. 10 patients with severe periodontitis were followed for 8
      months after thorough scaling and root planing in combination with optimal plaque
      control. At baseline and after 4 and 8 months, samples were taken from the
      saliva, the tongue dorsum and the supragingival interdental spaces. These samples
      were cultured both aerobically and anaerobically in order to determine the total
      number of colony forming units (CFU) per sample as well as the number of CFU of
      Streptococcus mutans and Lactobacillus species. Oral hygiene parameters were
      recorded at the same visits. Finally, at baseline and at the 8 months follow-up,
      changes in caries activity and periodontal health were registered. Although the
      total number of aerobic and anaerobic CFU in samples from the tongue and the
      saliva remained nearly constant over the entire observation period (variations
      within 0.5 log), significant (p< or =0.05) increases in the number of S. mutans
      could be detected, especially at month 8. The significant decrease in the total
      number of anaerobic CFU in samples from the teeth was not associated with a
      reduction in the number of S. mutans, so that also for this niche the relative
      proportion of the latter increased. The number of lactobacilli species for the
      different niches showed only negligible changes (within 0.5 log values), except
      for samples from the teeth for which a small (1 log), but statistically
      significant (p<0.01), reduction could be detected. The periodontal conditions
      improved for all patients, but the caries activity could not be arrested. These
      findings seem to indicate that the increased caries susceptibility after
      periodontal therapy might partially be explained by a significant increase in the
      number of S. mutans due to ecological changes within the oral cavity. The
      clinical consequence of this observation would be to advocate a more strict
      caries preventive program during initial periodontal therapy.

PMID- 10355626
TI  - Protein kinase C-alpha produces reciprocal effects on the phorbol ester
      stimulated tyrosine phosphorylation of a 50 kDa kinase in Jurkat cells.
AB  - A detergent extract isolated from the enriched fraction of integral membrane
      proteins of Jurkat cells showed an enhanced tyrosine phosphate level when
      phosphorylated in the presence of phorbol 12-myristate 13-acetate (TPA) and
      phorbol 12,13-dibutyrate (PDBu). The enhanced tyrosine phosphorylation was
      observed when the reaction time exceeded 6 min; at shorter incubation times,
      however, TPA inhibited tyrosine phosphorylation. When the reaction proceeded for
      a constant time period longer than 6 min and phorbol esters were added at
      different times after the start of the reaction, two phases of an enhanced
      tyrosine phosphorylation of a 50 kDa protein were observed. An increased
      phosphorylation of the 50 kDa protein was correlated with an enhanced
      phosphorylation of poly(Glu4,Tyr1). The two phases of enhanced phosphorylation
      differed in their TPA and PDBu requirement and in the proteins that were tyrosine
      phosphorylated. Studies with protein kinase C (PKC) inhibitors showed a
      negatively correlated effect on the enhanced tyrosine phosphorylation in phase I;
      tyrosine phosphorylation was further augmented. In phase II the regulation of
      tyrosine phosphorylation correlated with the efficiency of the PKC inhibitors on
      the alpha-isoform of PKC which was found in the cell extract. Separation of the
      proteins present in the investigated cell extract by gel filtration revealed a co
      migration of the alpha-PKC and the 50 kDa protein. The metabolic labeling of
      intact Jurkat cells with 32Pi indicated that phorbol esters are also able to
      induce tyrosine phosphorylation of the 50 kDa protein underin vivo conditions.
      These data suggest an activation of two different tyrosine phosphorylation
      pathways by phorbol esters involving tyrosine phosphorylation/autophosphorylation
      of a 50 kDa kinase, as confirmed by 5'-p-fluorosulfonylbenzoyladenosine (FSBA)
      labeling, that are accurately regulated by alpha-PKC.

PMID- 10355627
TI  - Growth- and development-dependent expression of gangliosides in rat hepatocytes
      and liver tissues.
AB  - Expression of gangliosides in the liver was examined in primary cultures of
      hepatocytes from adult rats and liver tissues from rats of different ages.
      Hepatocytes were isolated from 7-week-old rat liver and cultured in L-15 medium
      containing insulin, dexamethasone and 10% fetal bovine serum. Hepatocytes
      proliferated only on the first day, and then ceased proliferation. The content of
      GD3 and GD1a increased during the period of active proliferation and reached a
      nearly constant level, whereas GM1, GD1b, GT1b, and GQ1b gradually increased
      throughout culture. Addition of EGF to the culture medium caused significant
      increases in the content of GD3, and to a lesser degree of GM3, but exhibited
      little effect on the expression of other ganglioside species. The specific
      induction of GD3 and GM3 expression by EGF was reproduced under serum-free
      conditions, despite the lack of hepatocyte proliferation. Expression of
      gangliosides in cultured hepatocytes was also modulated by cell density; higher
      cell density brought about increased content of GM1, GD1a, GD1b, GT1b, and GQ1b
      with concomitant reduction of GM3 in cells. The composition of gangliosides in
      liver tissues demonstrated a unique developmental pattern. GD3 and GD1a were
      strongly expressed in E-16 embryonic tissue and rapidly decreased with increasing
      age. GD1b, GT1b, and GQ1b were found only in postnatal liver tissues. These
      findings suggest that the expression of gangliosides in rat hepatocytes and liver
      tissues are regulated by growth- and development-dependent factors.

PMID- 10355628
TI  - Regulated phosphorylation of the Gal4p inhibitor Gal80p of Kluyveromyces lactis
      revealed by mutational analysis.
AB  - The yeast Gal80 protein inhibits the transcription activation function of Gal4p
      by physically interacting with the activation domain (Gal4-AD). Gal80p
      interaction with Gal1p or Gal3p is required to relieve Gal4p inhibition in
      response to galactose. Gal80p orthologs of Saccharomyces cerevisiae and
      Kluyveromyces lactis, ScGal80p and KIGal80p, can also inhibit the heterologous
      Gal4p variants; however, heterologous Gal3p/Gal1p only regulate ScGal80p but not
      KIGal80p. To compare KIGal80p and ScGal80p, point mutations known to affect
      ScGal80p function were introduced at corresponding positions in KIGal80p, and
      Gal4p regulation in vivo and KIGal80p-binding to Gst-Gal1p and Gst-Gal4-AD in
      vitro were analysed. The in vitro binding properties of the KIGal80p mutants were
      similar to those of ScGal80p, but two out of four mutants differed in Gal4p
      regulation. E. g. KIGAL80s-0(G302R) but not ScGAL80s-0 (G301R) alleviates Gal4p
      inhibition. Possibly, this difference is related to a role of phosphorylation in
      the regulation of Gal80p function in K. lactis. Wild-type and mutant forms of
      KIGal80p are shown to be subject to carbon source regulated phosphorylation
      whereas no evidence for ScGal80p phosphorylation exists. (Hyper-)phosphorylation
      of KIGal80p is strongly reduced in galactose-containing medium. This reduction
      requires KIGal1p but no interaction with KIGal4p. The inhibition deficient
      KIGal80s-0p (G302R) variant is under-phosphorylated. We thus propose that
      phosphorylation of Gal80p in Kluyveromyces lactis contributes to the regulation
      of Gal4p mediated transcription.

PMID- 10355629
TI  - The WW domain of dystrophin requires EF-hands region to interact with beta
      dystroglycan.
AB  - Skeletal muscle dystrophin is a 427 kDa protein thought to act as a link between
      the actin cytoskeleton and the extracellular matrix. Perturbations of the
      dystrophin-associated complex, for example, between dystrophin and the
      transmembrane glycoprotein beta-dystroglycan, may lead to muscular dystrophy.
      Previously, the cysteine-rich region and first half of the carboxy-terminal
      domain of dystrophin were shown to interact with beta-dystroglycan through a
      stretch of fifteen amino acids at the carboxy-terminus of beta-dystroglycan. This
      region of dystrophin implicated in binding beta-dystroglycan contains four
      modular protein domains: a WW domain, two putative Ca2+-binding EF-hand motifs,
      and a putative zinc finger ZZ domain. The WW domain is a globular domain of 38-40
      amino acids with two highly conserved tryptophan residues spaced 20-22 amino
      acids apart. A subset of WW domains was shown to bind ligands that contain a Pro
      Pro-x-Tyr core motif (where x is any amino acid). Here we elucidate the role of
      the WW domain of dystrophin and surrounding sequence in binding beta
      dystroglycan. We show that the WW domain of dystrophin along with the EF-hand
      motifs binds to the carboxy-terminus of beta-dystroglycan. Through site-specific
      mutagenesis and in vitro binding assays, we demonstrate that binding of
      dystrophin to the carboxy-terminus of beta-dystroglycan occurs via a beta
      dystroglycan Pro-Pro-x-Tyr core motif. Targeted mutagenesis of conserved WW
      domain residues reveals that the dystrophin/beta-dystroglycan interaction occurs
      primarily through the WW domain of dystrophin. Precise mapping of this
      interaction could aid in therapeutic design.

PMID- 10355630
TI  - Purification and MALDI-MS characterization of stressin, a stress-associated
      glycoprotein.
AB  - Glycoconjugates have a whole spectrum of biological roles, from those that appear
      trivial to those that are crucial. Results accumulated in the past years indicate
      they might also play an important role in the response to stress, a complex
      physiological response of the human organism to various threats. We have recently
      identified stressin, a human serum glycoprotein, which was found to be increased
      under stress conditions. Here we report the purification of stressin from sera of
      professional soldiers and partial characterization of its protein and
      carbohydrate parts using lectin blotting and matrix assisted laser
      desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Stressin
      was purified using a combination of ammonium sulfate precipitation, ion exchange
      chromatography, preparative gel electrophoresis and reverse-phase HPLC. It was
      found to be a highly glycosylated protein. Only 21.9 kDa (out of 36.7 kDa) was
      the protein part, whereas the remaining 40% of the mass originated from N-linked
      oligosaccharides. The carbohydrate part contained 12 sialic acids moieties,
      nearly 90% of which were lost due to post-source decay in the field-free tube.
      Tryptic fragments were produced from glycosylated and deglycosylated stressin,
      separated by reverse-phase HPLC and their exact molecular masses were determined
      using MALDI-MS. Comparison with tryptic maps of other proteins in computer
      databases indicated that stressin does not correspond to any already described
      protein.

PMID- 10355631
TI  - Direct selection of EGF mutants displayed on filamentous phage using cells
      overexpressing EGF receptor.
AB  - Understanding receptor-ligand interactions, and the signal transduction pathways
      they activate, is of great interest for the discovery of novel antagonists and
      agonists. In this report we describe a rapid and efficient procedure to evaluate
      the importance of several different epidermal growth factor (EGF) residues for
      the binding and activation of its receptor (EGFR). We constructed an EGF mutant
      library randomized at positions 13, 15 and 16 and expressed them on filamentous
      phages. Phage display is a powerful system, allowing rapid isolation of binding
      mutants. Since many of the most pharmacologically interesting receptors cannot be
      produced in a soluble form, we developed a technique to rapidly select receptor
      binding molecules directly on cells. A luciferase assay, simple to perform, was
      then used to test their biological transduction activity and to rapidly detect
      mutants of interest. Analysis of the resulting sequences revealed that the wild
      type amino acids at positions 13, 15 and 16 are optimized for binding and
      activity. EGF mutants with agonist properties were also isolated and tolerated
      substitutions were identified.

PMID- 10355632
TI  - Refolding studies on the tetrameric loop deletion mutant RM6 of ROP protein.
AB  - Previous DSC and X-ray studies on RM6, a loop deletion mutant of wtROP protein,
      have shown that removal of five amino acids from the loop causes a dramatic
      reorganization of the wild-type structure. The new tetrameric molecule exhibits a
      significantly higher stability (Lassalle, M.W. et al., J. Mol. Biol., 1998, 279,
      987-1000) and unfolds in a second order reaction (Lassalle, M.W. and Hinz, H.-J.,
      Biochemistry, 1998, 37, 8465-8472). In the present investigation we report
      extensive refolding studies of RM6 at different temperatures and GdnHCl
      concentrations monitored by CD and fluorescence to probe for changes in secondary
      and tertiary structure, respectively. The measurements permitted us to determine
      activation parameters as a function of denaturant concentration. The results
      demonstrate convincingly that the variation with GdnHCl concentration of the
      activation parameters deltaH#, deltaS# and deltaG# is very similar for unfolding
      and refolding. For both processes the activation properties approach a maximum in
      the vicinity of the denaturant concentration, c(K=1), where the equilibrium
      constant equals 1, i.e. deltaG0 equals zero. CD and fluorescence refolding
      kinetics are described by identical constants suggesting that the formation of
      secondary and tertiary structure occurs simultaneously. Refolding is, however,
      characterized by a more complex mechanism than unfolding. Although the general
      pattern is dominated by the sequence monomers to dimers to tetramers, parallel
      side reactions involving dimers and monomers have to be envisaged in the initial
      folding phase, supporting the view that the native state of RM6 can be reached by
      several rather than a single pathway.

PMID- 10355633
TI  - Secretion of protease nexin-II/amyloid beta protein precursor by human colorectal
      carcinoma cells and its modulation by cytokines/growth factors and proteinase
      inhibitors.
AB  - Trypsin inhibitors secreted by human colorectal adenocarcinoma cell lines were
      analyzed by reverse zymography. Among eleven cell lines analyzed, the major
      inhibitor secreted was protease nexin-II (PN-II), a secreted form of amyloid beta
      protein precursor (APP) containing a Kunitz-type serine proteinase inhibitor
      domain. Expression of the APP gene was also confirmed in the cell lines and the
      main APP mRNA species were PN-II types. The APP gene expression was constant
      during cell growth in vitro. On the other hand, the rate of extracellular PN-II
      accumulation markedly increased after long-term serum-free maintenance of the
      confluent culture. The extracellular accumulation of PN-II was also strongly
      stimulated either by interleukin-1beta (IL-1beta) treatment or to a lesser extent
      by basic fibroblast growth factor, tumor necrosis factor-alpha, hepatocyte growth
      factor or epidermal growth factor. Neither serum depletion- nor IL-1beta-induced
      stimulation of extracellular PN-II accumulation were accompanied by obvious
      alteration of the levels of APP mRNA and cellular APP holoprotein, suggesting
      that the enhanced extracellular accumulation of PN-II might result from up
      regulation of the secretory pathway of APP. The IL-1beta-induced PN-II secretion
      was significantly inhibited by relatively high concentrations (50-200 microg/ml)
      of aprotinin, a serine proteinase inhibitor, in a dose-dependent manner without
      obvious cell-toxic effects.

PMID- 10355634
TI  - Isolation and primary structure of the CCI papain-like cysteine proteinases from
      the latex of Carica candamarcensis hook.
AB  - The dried latex of the mountain papaya, Carica candamarcensis, was
      chromatographed on CM-Sephadex C50, giving rise to three peaks (CCI, CCII and
      CCIII) with amidase activity on N-alpha-benzoyl-DL-arginine-4-nitroanilide. The
      less basic, most active, peak, CCI, was separated into two components, CCIa and
      CCIb, by reverse-phase HPLC under denaturing conditions. The primary structures
      of CCIa and CCIb are presented. They were deduced from sequence analysis of the
      whole proteins and peptides resulting from enzymatic digestions. Both proteinases
      are made of 213 amino acid residues, CCIb sharing 88-89% similarity with the
      three subvariants (G90/R212, E90/R212, E90/K212) of CCIa. 139-140 amino acid
      residues (65.8%) of CCIa and 141 residues (66.5%) of CCIb are common to papain.
      The seven cysteine residues are aligned with those of papain and the catalytic
      triad (Cys25, His159, Asn175) of all cysteine peptidases of the papain family is
      conserved. The similarity with the other cysteine proteases from Carica papaya is
      discussed.

PMID- 10355635
TI  - Identification of SLPI (secretory leukocyte protease inhibitor) in human mast
      cells using immunohistochemistry and in situ hybridisation.
AB  - Recently interest has been focused on secretory leucocyte protease inhibitor
      (SLPI) and its role in immediate hypersensitive reactions, possibly by inhibiting
      mast cell chymase. The purpose of this investigation was to show whether or not
      SLPI is produced in mast cells. Double-immunolabelling revealed that SLPI
      coexists with mast cell tryptase (60%) and chymase (37%). On the other hand, in
      situ hybridisation studies demonstrated the expression of SLPI mRNA in all mast
      cells. The differences in results can be attributed to the fact that in situ
      hybridisation is a more sensitive method than immunohistochemistry. Hence, we
      conclude that SLPI is produced in human tonsillar mast cells.

PMID- 10355636
TI  - Stereochemistry of the interaction between methionine sulfur and the protein
      core.
AB  - The stereochemical features of the interaction between the sulfur atom of
      methionine residues and surrounding atoms are examined on a large set of known
      protein crystal structures. It appears that the minimum energy conformations
      observed in small molecule crystals are not observed within the protein core.
      This suggests that these interactions are either of little intensity, though they
      might contribute to regulate the protein physiological behavior, or
      physicochemically different from their counterpart in small molecule crystals.

PMID- 10355637
TI  - Trypsin from Pacifastacus leniusculus hepatopancreas: purification and cDNA
      cloning of the synthesized zymogen.
AB  - Trypsin was purified from crayfish, Pacifastacus leniusculus, hepatopancreas, and
      the gene that encoded this enzyme was cloned from a hepatopancreas cDNA library.
      Crayfish trypsin is synthesized as a zymogen according to the sequence of the
      putative precursor peptide. The authenticity of the trypsinogen is supported by
      the deduced amino acid sequence and confirmed by the N-terminal amino acid
      sequence of the mature protein. The enzyme has features characteristic of a
      trypsin, such as a specific binding pocket. Sequence comparison shows that
      crayfish trypsin is similar to those of other species, with the exception that
      six cysteine residues present in vertebrates are missing. Some structural
      characteristics, such as the length of the signal peptide and a calcium binding
      site, are similar to bacterial trypsin.

PMID- 10355638
TI  - Analyses of prosthetic episodes in trans-tibial amputees.
AB  - The prosthetic episodes, i.e. actual processes of provision, identifying number
      of prostheses, their maintenance, repairs and replacements were analysed for 104
      trans-tibial amputees aged 16 and over, over a 10 year period. The purpose of
      this investigation was to identify how frequently a new prosthesis is actually
      required for this group of amputees and what are their maintenance requirements.
      Variations of requirement between the amputee groups of aged 16-60 and over 60
      years are also addressed. In the 10 years period of the study the amputees needed
      an average of 5.04 new prostheses, 6.25 refits, 2.28 major repairs and 17.04 day
      repairs. The younger amputees, i.e. below the age of 60 years, required
      significantly more new prostheses (p=0.003), more refit of sockets (p=0.0012) and
      more day repairs (p=0.01). Traumatic amputees below the age of 60 years needed
      significantly more day repairs compared to the non-traumatic amputees in the
      older age group (p=0.003).

PMID- 10355639
TI  - Relaxed versus activated stump muscles during casting for trans-tibial
      prostheses.
AB  - In prosthetic practice, the question often arises as to whether the hand cast
      should be made from a contracted or from a non-contracted amputation stump. To
      elucidate this question, the authors have performed a study to quantify the
      volume difference between these 2 conditions, and to relate the differences to
      prosthetic fitting. Sixteen (16) trans-tibial amputees participated in the study.
      All of them were fitted with an ICEROSS silicone socket. Electromyographic
      studies, with electrodes attached to the anterior tibial and medial gastrocnemius
      muscles, were carried out to determine muscle contraction levels. Volume
      determinations were made with the CAPOD laser scanning system. Measurements were
      performed with and without the silicone liner on the stump. Without a silicone
      liner, the volume of the stump increased by 5.8% (SD=5.3) as the muscles
      contracted. This increase was statistically significant. With the liner donned
      the volume increased 3.5% (SD=3.3). This increase was also statistically
      significant. The volume of the prosthetic socket was also compared with the stump
      volume with a silicone liner on. For the relaxed stump, the difference was 1.8%
      (SD=10.1), and for the contracted stump -1.7% (SD=11.3). Neither difference was
      statistically significant. The importance of these volume changes and how they
      influence stiffness of the coupling between the stump and the socket are
      discussed. It is concluded, that the observed difference in volume between a
      contracted and a non-contracted stump are large enough to be considered by the
      prosthetist in his decision on how to make a hand cast.

PMID- 10355640
TI  - Interface pressures and shear stresses: sagittal plane angular alignment effects
      in three trans-tibial amputee case studies.
AB  - Interface pressures and shear stresses at different sagittal plane angular
      alignment settings were measured on 3 trans-tibial amputee subjects ambulating
      with patellar-tendon-bearing total contact prostheses. Substantial socket-shank
      angular alignment modifications in the sagittal plane had minimal effect on
      stance phase peak interface pressures, though more substantial effects on stance
      phase peak resultant shear stresses. No consistent trend of a greater stress at
      misaligned vs nominally aligned settings was identified. Changes in interface
      stresses from session to session tended to be greater than those for different
      alignment settings, suggesting that subjects compensated well for misalignments
      but less well for session differences.

PMID- 10355641
TI  - Validation of a quantitative method for defining CAD/CAM socket modifications.
AB  - A quantitative method was developed for defining manual socket modifications,
      averaging these modifications over a series of amputees, and using the average
      modifications as a template in commercial CAD/CAM systems. The CADVIEW programme
      (i.e. software for viewing and analysing CAD sockets) was rewritten to provide
      comparison functions for aligning sockets to a common axis, visualising the
      differences between sockets, generating modification outlines, assigning apex
      point values, and averaging the modification outlines. A CAD template generated
      in this manner should be the best general representation of a prosthetist's
      modification style. To test this hypothesis, 13 people with trans-tibial
      amputations were fitted with both a manual and a CAD/CAM socket. Questionnaires
      were completed by the subjects and by the prosthetist to obtain information on
      prosthetic comfort, function, and overall satisfaction. Ground reaction force and
      stride parameter data were also collected for each prosthesis during gait
      laboratory testing. No significant differences were found between the manually
      designed socket and the CAD/CAM designed socket for all data except the vertical
      peak forces on the amputated side. These results support the clinical application
      of this quantitative technique for making the transition from manual to CAD/CAM
      prosthetic modification procedures.

PMID- 10355642
TI  - The efficacy of physiological cost index (PCI) measurement of a subject walking
      with an Intelligent Prosthesis.
AB  - The Intelligent Prosthesis may enable lower limb amputees to walk faster than
      with conventionally damped prostheses and as a result the physical burden
      involved in walking could be expected to be considerably higher. The aim of this
      study was to investigate whether or not physiological cost index (PCI) is
      applicable as an indicator for monitoring the amount of exercise load involved in
      walking with an Intelligent Prosthesis. The method used a treadmill and monitored
      gas exchange, ventilation and heart rate (HR) in 6 unilateral trans-femoral
      amputees, ages were between 17 and 34 with an average age of 23.1. The exercise
      protocol was as follows: for each person speeds at 0.8 times the subject's free
      level walking speed, 1.0 times, 1.2 times, 1.4 times and for some 1.6 times were
      applied. In each case the index of correlation between PCI and oxygen uptake in
      response to walking speed was calculated. A significant correlation was observed
      between PCI and oxygen uptake in each case, which indicated a close relationship
      between cardiopulmonary factor and energy consumption while walking. These
      results suggest that PCI is of use as an indicator for ascertaining the amount of
      exercise load in walking with an Intelligent Prosthesis.

PMID- 10355643
TI  - Bilateral lower limb amputations as a result of landmine injuries.
AB  - Landmine explosions cause most of the war injuries in the battlefield.
      Amputations resulting from severe injuries reveal serious problems despite the
      improvements in surgery. Bilateral lower limb amputations have more impact than
      unilateral on social life. Some 29 cases with lower limb amputations due to
      landmine injuries were treated in the Department of Orthopaedics and
      Traumatology, Gulhane Military Medical Academy between January 1992 and December
      1996. Amputation levels were as follows: 1 case had hip disarticulation and a
      trans-femoral amputation, 6 had bilateral trans-femoral amputations, 6 had trans
      femoral and trans-tibial amputations, 12 had bilateral trans-tibial amputations,
      1 had trans-femoral and Chopart amputations and the remaining 3 cases had trans
      tibial and Chopart amputations. The initial treatment was done for all cases in
      the first 6-8 hours after injury at the field hospitals. Aggressive debridement,
      excision and primary closure were performed. None of the stumps required
      reamputations and/or revision. No case had gas gangrene or tetanus.
      Postoperative, pre-prosthetic training programme which ranged between 30-120 days
      with an average 48 days; and prosthesis fitting and adequate post-prosthetic
      training programme which ranged 32-126 (average 94) days was applied. All the
      cases were followed-up with a mean of 38.5 months (14-72 months). Nine (9) cases
      (31%) returned to their previous occupation, while 20 (69%) cases had to change
      their jobs.

PMID- 10355644
TI  - Save that arm: a study of problems in the remaining arm of unilateral upper limb
      amputees.
AB  - A study has been made by questionnaire, personal examination and telephone
      interview of unilateral upper limb amputees seen at the Prince Henry Hospital,
      Australia between 1994 and 1997. There were 60 questionnaires posted. Replies
      were received from 46. Problems were noted in the remaining arm of 23 (50%). The
      respondents' problems not only consisted of overuse symptoms, but also of an
      exacerbation of pre-existing arthritis and injury due to trauma to the remaining
      arm during the accident. Case histories are given in 3 typical cases. Treating
      professionals are warned about the hazards that one arm amputations present to
      the remaining arm.

PMID- 10355645
TI  - Patient compliance and effect of orthopaedic shoes.
AB  - Orthopaedic shoes are individually handmade after a prescription from an
      orthopaedic surgeon, hence relatively expensive. Bad compliance is mentioned in
      the literature but not investigated. In order to evaluate patient compliance and
      the effect of orthopaedic shoes, 85 patients who were prescribed orthopaedic
      shoes at the authors' department during a 3 year period received a questionnaire
      concerning relief of symptoms and daily use of the shoes. The answers from 74
      patients were correlated to the prescription procedure and the degree of medical
      follow-up. Only 60 of 74 patients used their shoes. Some 51 patients had some
      benefit while 23 had no effect or even worse symptoms. Some patients even used
      their shoes despite no symptomatic relief. However, patients who felt they were
      well informed about the purpose and function of their shoes had more benefit than
      the rest. Only 12 patients of the 74 were checked by the orthopaedic surgeon
      after delivery of the shoes. In conclusion the authors believe there is a great
      need for information to be given to the patients about the functions and
      limitations of orthopaedic shoes and that every patient should be offered a
      control check-up by the surgeon. Further investigations of the effect of
      orthopaedic shoes should be carried out to optimise the use of these expensive
      devices.

PMID- 10355646
TI  - Comparison of bending stiffness of six different colours of copolymer
      polypropylene.
AB  - This paper compares the bending stiffness of 5 different colours of copolymer
      polypropylene (CCP) with that of natural copolymer polypropylene (NCP). Flesh
      coloured and natural sheets are supplied thicker than other pigmented sheet. The
      bending stiffness of a specimen may be defined as EI, i.e. the product of E,
      Young's modulus of elasticity and I, the 2nd moment of area. Strips of "as
      supplied" (AS) and "post-draped" (PD) specimen were clamped and subjected to
      bending to assess the effect of pigmentation on bending characteristics. The
      gradient of the graph of bending deflection delta versus bending moment enables
      EI to be estimated. The process of thermoforming polypropylene reduces EI, the
      bending stiffness. However, the manual draping and vacuum procedure introduces so
      many variables that it is difficult to quantify the effect of pigmentation. The E
      of a bent specimen may be estimated from the gradient of the graph of deltaI
      versus bending moment. In the case of AS sheet, the effect of pigmentation on E
      is inconclusive. PD specimens indicate a significant reduction in E due to
      thermoforming. This was verified by an electron-microscope study of AS and PD
      specimens. Draping an ankle-foot orthosis (AFO) results in a non-uniform wall
      thickness. The results of this study with respect to the effects of pigmentation
      on the bending stiffness of AFOs are inconclusive. More detailed studies require
      to be completed in order to confirm which factors are responsible for this non
      uniformity in wall thickness and consequent variation in bending stiffness.

PMID- 10355647
TI  - Creating a model for fabricating a partial hand glove prosthesis using the
      realigned casts of the contralateral digits.
AB  - A method for creating a model for fabricating a partial hand glove prosthesis is
      described. The realigned casts of the corresponding digits of the contralateral
      uninjured hand were used to substitute for the lost digits on a cast of the
      stump. The technique allows an exact reproduction of the anatomical and fine
      surface details of the digits. It has the advantage of customisation, allowing a
      close match in the size, shape and surface characteristics of the prosthesis to
      that of the remaining digits of the hand.

PMID- 10355648
TI  - Analysis of body-device interface forces in the sagittal plane for patients
      wearing ankle-foot orthoses.
AB  - An ankle-foot orthosis (AFO) is employed principally to treat musculoskeletal
      disorders of the ankle and/or subtalar joints although, occasionally, it may be
      prescribed to provide stance phase control of the knee. In order to function
      satisfactorily, an AFO must apply appropriate forces to the lower leg in a manner
      which does not cause local tissue damage or discomfort. Equally the leg will
      apply forces to the AFO which it must be capable of withstanding without breakage
      or loss of function. Thus it is useful to know where the body-device interface
      forces act during walking and to be able to estimate their magnitudes. This is
      not well understood and has not been satisfactorily documented. This paper
      explains the force actions between the AFO and the leg, in the sagittal plane,
      where there is absence of muscle power. Furthermore, it explores the possibility
      of estimating the magnitudes of these forces. It is found that the forces are
      greatest when orthotic assistance is needed to compensate for plantar flexor
      insufficiency in late stance phase. On the other hand, where the AFO is used to
      support the foot, in the absence of dorsiflexion power in swing phase, the forces
      are relatively small. Understanding these force levels is relevant to the design
      of the AFO in terms of choice and use of materials and components.

PMID- 10355649
TI  - Use of a gas spring contracture correction orthosis for the management of a fixed
      flexion contracture of the elbow.
AB  - This paper describes the application of low level controlled torque to an elbow
      contracture through the use of an active orthosis. Over a period of twenty months
      the lack of elbow extension range was reduced from 105 degrees to 57 degrees. A
      description of the important orthotic design factors which led to significant
      functional improvement is provided.

PMID- 10355650
TI  - Primary thymic epithelial neoplasms: spectrum of differentiation and histological
      features.
AB  - Primary thymic epithelial neoplasms have been the source of much controversy over
      the years because of difficulties in their histopathologic classification and
      prognostication of clinical behavior. Despite recent advances in our
      understanding of the immunopathology and molecular pathology of these neoplasms,
      no universally accepted system of classification is yet available for these
      tumors. A variety of classification schemes have been proposed in the past based
      on either morphological, histogenetic, or immunophenotypic considerations. For
      the most part, the majority of such classifications have been merely descriptive
      with little value for prognostication, or have proven cumbersome and difficult to
      apply in clinical practice. Recent studies have shown that primary thymic
      epithelial neoplasms, rather than representing several discrete, separate
      entities constitute part of a continuous spectrum of differentiation ranging from
      well-differentiated neoplasms to poorly-differentiated neoplasms. Based on these
      observations, a novel classification of primary thymic epithelial neoplasms has
      been proposed that divides these tumors into three easily reproducible diagnostic
      categories based on their degrees of differentiation: thymoma, atypical thymoma,
      and thymic carcinoma (corresponding to well-differentiated, moderately
      differentiated, and poorly-differentiated neoplasms, respectively). The
      histopathologic features and diagnostic criteria for these tumors is the subject
      of this review.

PMID- 10355651
TI  - Primary carcinomas of the thymus gland.
AB  - Carcinomas of the thymus are now well recognized as distinctive but rare
      entities, and several clinicopathologic variants of such neoplasms have been
      described. These include keratinizing squamous cell carcinoma, nonkeratinizing
      squamous cell carcinoma, lymphoepithelioma-like carcinoma, neuroendocrine
      carcinoma, adenosquamous carcinoma, mucoepidermoid carcinoma, clear-cell
      carcinoma, papillary adenocarcinoma, adenocarcinoma not otherwise specified,
      basaloid carcinoma, and sarcomatoid carcinoma. The application of electron
      microscopy, immunohistology, and other adjunctive pathological techniques is
      effective in refining the differential diagnosis between primary thymic carcinoma
      (PTC) and several other histological simulators. However, the distinction between
      PTC and carcinomas that involve the thymic region by metastasis from other sites
      is a difficult one, and ultimately must be predicated on detailed clinical and
      radiographic information. Well-differentiated squamous carcinoma, low-grade
      mucoepidermoid carcinoma, and basaloid carcinoma of the thymus usually are
      associated with a favorable prognosis, but other variants are aggressive and
      require multimodality treatment approaches.

PMID- 10355652
TI  - Primary neuroendocrine carcinomas of the thymus.
AB  - Primary neuroendocrine carcinomas of the thymus are rare and comprise a wide
      spectrum of lesions ranging from well-differentiated to poorly-differentiated
      neoplasms. The classification of such tumors in the thymus is still
      controversial. By convention, the better-differentiated examples have been
      traditionally designated as thymic carcinoids and thought to represent the
      mediastinal counterpart of carcinoid tumors in other foregut locations. However,
      recent studies have shown that such neoplasms, when arising in the thymus,
      exhibit a much more aggressive behavior than those originating at other
      locations. We therefore consider these lesions to represent fully malignant
      neoplasms that fall within the spectrum of neuroendocrine carcinomas. The
      designation of well-, moderately-, or poorly-differentiated thymic neuroendocrine
      carcinoma is therefore favored for these tumors in the present review. Because
      such tumors may often adopt unusual morphological appearances, it is important to
      distinguish them from other more common conditions presenting at this location
      that may exhibit similar histological features. The clinicopathologic,
      immunohistochemical, and differential diagnostic features of these tumors in the
      mediastinum are discussed.

PMID- 10355653
TI  - Germ-cell tumors of the mediastinum.
AB  - Mediastinal germ-cell tumors (GCTs) usually occur within the anterior
      mediastinum, accounting for about 15% of all mediastinal cysts and tumors. They
      are associated with the thymus, presumably arising from extragonadal germ cells
      or thymic cells with germ-cell potential. Mediastinal seminoma develops primarily
      in young males with rare cases reported in females; likewise, embryonal
      carcinoma, endodermal sinus tumor or yolk-sac tumor, choriocarcinoma, and
      malignant mixed or combined GCTs also overwhelmingly affect males. Mature cystic
      teratoma affects males and females equally. The prognosis for mediastinal mature
      cystic teratoma and seminoma is very good. Nonseminomatous malignant GCTs of the
      mediastinum often present with advanced disease and do not respond as well to
      chemotherapy as their gonadal counterparts. Nonetheless, it is important to
      separate mediastinal GCTs from other undifferentiated malignant tumors,
      especially thymic carcinoma, which has a poor prognosis. Clearly, some patients
      with mediastinal GCTs respond very well to modern therapies.

PMID- 10355654
TI  - Primary large-cell lymphomas of the mediastinum.
AB  - The mediastinum is a frequent site of involvement for malignant lymphoma. The
      most common types encountered in this location include Hodgkin's and non
      Hodgkin's lymphoma and lymphoblastic lymphoma. With the exception of
      lymphoblastic lymphoma in children and adolescents, most cases of mediastinal
      involvement by lymphoma represent part of systemic disease and do not generally
      pose difficulties for diagnosis. However, a relatively small group of tumors have
      become increasingly recognized in recent years that are primarily localized in
      the anterior mediastinum and show features of nonlymphoblastic/non-Hodgkin's
      large-cell lymphoma. Because such tumors are capable of adopting unusual
      morphological appearances, they can often pose difficulties for diagnosis and be
      frequently mistaken for other conditions. This review discusses this group of
      neoplasms collectively known as diffuse large-cell lymphoma of the mediastinum.
      The clinicopathologic, immunohistochemical, and molecular genetic aspects of
      these tumors appear to indicate that a significant proportion of them may
      correspond to a distinctive type of lymphoproliferative process most likely
      arising from a native B-cell population of the thymus, thus representing, in
      essence, a primary extranodal large-B-cell lymphoma of the thymus.

PMID- 10355655
TI  - Mediastinal tumors of peripheral nervous system origin.
AB  - A wide spectrum of benign and malignant tumors of peripheral nervous system
      origin can arise in the mediastinum. These neoplasms are more frequent in the
      posterior mediastinum and can develop from peripheral nerves, sympathetic and
      parasympathetic ganglia, and neural tube embryonic remnants. The
      clinicopathologic features of mediastinal schwannomas, melanotic schwannomas,
      neurofibromas, ganglioneuromas, granular cell tumors, malignant tumors of
      peripheral nerve sheath origin, malignant melanocytic tumors of peripheral nerve
      sheath origin, neuroblastomas, ganglioneuroblastomas, and pigmented
      neuroectodermal tumors of infancy are reviewed.

PMID- 10355656
TI  - Predictable recovery from myasthenia gravis crisis with plasma exchange: thirty
      six cases and review of current management.
AB  - Adult, acquired, idiopathic, autoimmune myasthenia gravis has a well
      characterized IgG anti-acetylcholine striated-muscle receptor antibody. Removal
      by plasma exchange is effective, established therapy to augment anti
      cholinesterase and immunosuppressive therapy and is the treatment of choice for
      myasthenia gravis crisis. We report 36 consecutive patients referred and accepted
      for plasma exchange, 32 of whom were in or entering myasthenia crisis, over a 10
      year period. An average of 7.8 (range 1 to 16) plasma exchange procedures were
      done, with uniform, significant improvement, including extubation of 13 in
      myasthenic crisis and discharge from hospital in all. We conclude that this is
      the best treatment for myasthenia gravis crisis in hospital. From recent cases,
      most, if not all, crises can be prevented by IVIgG or plasma exchange as out
      patients with use of corticosteroid and or azathioprine.

PMID- 10355657
TI  - Thrombotic thrombocytopenia purpura: a single institution experience.
AB  - TTP is a disease with protean manifestations leading to errors in diagnosis.
      Critical reevaluation of a single observer's experience at LIJMC over a 7-year
      period is compared to that in published literature. We retrospectively analyzed
      presentation, clinical course, treatment, and outcome of 15 patients treated for
      TTP between 1990 and 1997 by one of the authors (V.C.). Minimal diagnostic
      criteria for TTP were unexplained moderate to severe thrombocytopenia (platelet
      count <100,000/cmm), microangiopathic hemolytic anemia, with or without low grade
      fever, and no other attributable etiologies. Neurologic and/or renal dysfunction
      constituted severe grade. Age range was 5-86 years, with one patient age 5, the
      youngest yet to date reported with classic TTP. Female to male ratio was 2:1.
      Overall survival rate was 87%; 40% of patients experienced immediate relapse
      within the first 4 weeks of presentation; and predisposing causes for immediate
      relapse appear to be intercurrent infections and severity of presentation. There
      was a 40% incidence of late relapses of TTP. Two patients with an unusually high
      number of late recurrences (6 and 16) were HCV-Ab positive and the possible role
      of persistent HCV infection in recurrent TTP was explored.

PMID- 10355658
TI  - Electrolyte monitoring in patients undergoing peripheral blood stem cell
      collection.
AB  - In recent years peripheral blood stem cell (PBSC) collection for allogeneic or
      autologous transplantation has experienced an increased use in the onco
      hematological setting. The latest generation cell separators allow a satisfactory
      and safe PBSC collection. Nevertheless, as in all therapeutic apheresis
      procedures, patients may experience procedure-related side-effects, mainly
      vasovagal reactions or symptoms related to hypocalcemia and/or hypomagnesemia. We
      investigated electrolyte changes in 18 patients, with a median age of 46 years
      (range 7-62), undergoing PBSC collection from January to April 1998. A
      significant decrease in total calcium in the final sample (9.65 +/- 0.7 mg/dL)
      with respect to the basal one (9.2 +/- 0.6 mg/dL, P < 0.05) was observed; also
      ionized calcium decreased markedly from the first sample drawn at +30 minutes:
      1.22 +/- 0.14 vs. 1.03 +/- 0.15 mmol/L (P < 0.05), and a highly significant
      difference emerged when basal value were compared to the final value: 1.22 +/-
      0.14 vs. 0.94 +/- 0.13 mmol/L (P < 0.0001). Similar findings affected potassium
      concentration: 4.1 +/- 0.4 vs. 3.3 +/- 0.3 mEq/L (P < 0.0001). Three out of
      eighteen patients (16.7%) reached a final potassium level <3.0 mEq/L, and eight
      out of eighteen (44.5%) showed a potassium concentration decrease >20% with
      respect to the basal value. A mild metabolic alkalosis occurred during the
      procedure: pH increased from 7.35 +/- 0.02 to 7.43 +/- 0.028 (P < 0.001), and
      plasma bicarbonate concentration increased from 27.48 +/- 2.21 to 32.44 +/- 2.52
      mmol/L (P < 0.01). Sodium and chloride did not differ in the final sample with
      respect to the basal sample. None of our patients experienced clinically relevant
      side effects related to severe electrolyte changes (i.e., >20% with respect to
      the basal value). Because our current therapeutic schedules include patients
      older than 50 years in the PBSC collection and transplantation program and since
      it is well known that subclinical myocardial disease may occur in up to 4% of
      middle-aged males, we suggest that patients aged 50 or older undergoing PBSC
      collection procedures be carefully monitored in order to identify significant
      electrolyte variation, especially if they present with low serum potassium
      levels. However, further investigation of larger patient series are needed to
      determine the clinical relevance of serum potassium changes during apheresis.

PMID- 10355659
TI  - Kinetic study of CD34+ cells during peripheral blood stem cell collections.
AB  - The impact of the separated volume on the yield of CD34+ cells during peripheral
      blood stem cell collections (PBSCC) remains controversial. We therefore studied
      the CD34+ cell concentration in the peripheral blood of patients (pts) during
      PBSCC as well as the total amount of CD34+ cells collected after each blood
      volume (BV) processed and engraftment data for each cycle of high dose
      chemotherapy (HD Ctx). A total of 21 PBSCC from 20 patients with different
      malignancies were analyzed. Stem cells were mobilized by chemotherapy and G-CSF
      (14 pts) or GM-CSF (6 pts). Samples from the pts peripheral blood and the
      collection bag were taken after each BV processed and analyzed for CD34+ cells,
      WBC, platelets (plt), and hemoglobin (Hb). The total volume processed was two to
      five times the pts calculated BV (mean value 17.4 L, range 9.0-24.0 L). Sixteen
      pts could be evaluated for engraftment. The mean peripheral blood CD34+ cell
      count was 116+/-103.5/microl at the start of PBSCC and decreased to 57+/
      61.6/microl after processing of four times the pts BV. The mean number of CD34+
      cells collected after each BV was 2.3+/-2.4, 5.8+/-5.2, 8.5+/-7.2, and 11.8+/
      10.3x10(6) per kg body weight, respectively. The mean plt count decreased by 53+/
      40.2/nl, Hb by 1.+/-0.5 g/dl and WBC by 0.+/-6.1/nl after separation of 4 BV. All
      but two pts reached the target value of 1.5x10(6) CD34+ cells/kg body weight and
      planned cycle of HD Ctx with 1 PBSCC. All pts engrafted and reached
      neutrophils>500/microl and plt>20,000/microl at a median of 11 and 13 days,
      respectively. We could demonstrate, that the yield of CD34+ cells during PBSCC
      increased continuously with the volume of the separated BV and that up to 5x the
      patients' BV could be processed safely without serious side effects. Most pts had
      to undergo only 1 PBSCC to collect sufficient numbers of CD34+ cells to support
      sequential courses of HD Ctx without delayed engraftment.

PMID- 10355660
TI  - Comparison of COBE Spectra software version 4.7 PBSC and version 6.0 auto PBSC
      program.
AB  - Until recently, the collection of peripheral blood progenitor cells (PBPC) has
      been semi-automated by using the COBE Spectra, with the operator manually
      maintaining the position of the white cells being collected. The COBE Spectra
      Version 6.0 apheresis device offers the user an automated program for the
      collection of PBPC. In this study, we compared the new software Version 6.0 to
      that of Version 4.7. Patients (n = 46) undergoing PBPC collection were allocated
      to cell processing with either Version 4.7 (n = 24) or Version 6.0 (n = 22). The
      CD34+ cell count, mononuclear cell (MNC) count, white cell count (WCC),
      hemoglobin (Hb), and platelet content in the autograft product by using the two
      versions were compared. We divided the analysis into three subsets according to
      peripheral blood (PB) CD34 content: <10x10(6)/L, 10-50x10(6)/L and >50x10(6)/L.
      Analysis of the three subsets showed no statistical difference between results
      obtained when the starting PB CD34+ cell count was 10-50x10(6)/L (P=0.08) or
      >50x10(6)/L (P=0.4065). At lower starting PB CD34+ cell counts of <10x10(6)/L,
      Version 4.7 was superior (P=0.0167). However, autograft platelet contamination of
      the autograft was significantly higher using Version 4.7 (P=<0.0001).

PMID- 10355661
TI  - Timing of platelet recovery is associated with adequacy of leukapheresis product
      yield after cyclophosphamide and G-CSF in patients with lymphoma.
AB  - A subgroup of patients with refractory Hodgkin's (HD) or non-Hodgkin's (NHL)
      lymphoma may be cured with high-dose chemotherapy and peripheral blood progenitor
      cell rescue. To investigate the relationship of adequate leukapheresis yield and
      time course of platelet recovery after mobilization chemotherapy, we
      retrospectively analyzed the leukapheresis yields in seven patients with
      Hodgkin's disease and fifteen patients with non-Hodgkin's lymphoma undergoing
      high-dose chemotherapy. Our goal was to develop a rule to determine when to
      initiate leukapheresis and then to prospectively validate this rule. All patients
      were mobilized with cyclophosphamide and G-CSF (granulocyte-colony stimulating
      factor). A total of 144 leukaphereses were completed and analyzed. Based on the
      CD34 content in the initial harvest product, fifteen patients were defined as
      poor mobilizers (CD34 < 0.15 x 10(6)/kg) and seven were good mobilizers. The
      platelet count on the first day of harvesting was significantly associated with
      the poor mobilizers (P = .03). Age, sex, marrow involvement, disease (HD vs.
      NHL), prior radiation, time since last chemotherapy, and total number of cycles
      of prior chemotherapy were not predictive of poor mobilizers. By using a platelet
      count cut off of 35 x 10(9)/L, we retrospectively analyzed 144 individual
      leukapheresis products, to test whether CD34 yield was predicted by the
      peripheral blood platelet count on the day of leukapheresis. This rule had an
      excellent sensitivity, 91%, and a specificity of 67%. Subsequently, we validated
      this rule with the next twenty-four patients undergoing leukapheresis of which
      there were 143 leukaphereses. The prediction rule exhibited a sensitivity of 72%
      and a specificity of 68% in the validation set. There does appear to be utility
      in using the platelet count to guide the initiation of leukapheresis after
      chemotherapy and G-CSF mobilization.

PMID- 10355662
TI  - Shorter turn-around-time and improved patient care in peripheral blood progenitor
      cell collection procedures.
AB  - The collection of peripheral blood progenitor cells (PBPC) requires the combined
      efforts of the Transfusion Medicine/Hemapheresis and Hematology/Oncology services
      and HLA/Progenitor Cell and Immunology laboratories. Coordination and
      communication among these different services and laboratories are key to
      attaining an optimal collection in a timely manner for the patient undergoing
      PBPC collection. In an effort to improve patient care by same-day decision to
      cease or continue collections avoiding unnecessary collections, needless patient
      trips to the hospital and ultimately increasing patient satisfaction, a flow
      chart was used to capture the sequence of events. The flow chart served as a
      powerful tracking tool that defined system process and steps to attain
      enumeration of CD34+ cells the same day of collection. It provided documentation
      of work flow from each of the independent operations involved in progenitor cell
      collection and enumeration turn-around-time including attending and staff time
      involvement. By using the flow chart, potential and actual problem areas were
      demonstrated and this allowed for creative thinking and problem solving by
      individual sections rather than recriminations. Finally, it focused all the staff
      involved in the common goal of a shorter turn-around-time for CD34+ cell
      enumeration the same day of collection. This allowed a prompt decision for
      subsequent leukapheresis as improved service to oncology patients and their
      physicians.

PMID- 10355663
TI  - Management of chronic myeloid leukemia during pregnancy with leukapheresis.
AB  - We describe the successful treatment of a pregnant patient with chronic
      myelogenous leukemia in chronic phase by using only leukapheresis. Following 20
      leukapheresis procedures initiated during the 13th week of gestation and
      performed over approximately 7 weeks, the patients white blood cell count dropped
      from 242,000/microl to 19,300/microl. The WBC remained stable over the ensuing 17
      weeks until the time of delivery. The patient gave birth by cesarean section to a
      healthy 2,640 g boy at 37.5 weeks of gestation. This is the second report of the
      successful use of leukapheresis alone for chronic myelogenous leukemia in chronic
      phase during the first half of pregnancy. We conclude that where leukapheresis is
      available, it may provide an alternative treatment to chemotherapy or alpha
      interferon, especially in light of their potential teratogenic and leukemogenic
      side-effects.

PMID- 10355665
TI  - Facts and fallacies on anti-GM1 antibodies: physiology of motor neuropathies.

PMID- 10355664
TI  - Use of nonmyeloablative preparative regimens for allogeneic blood stem cell
      transplantation: induction of graft-vs.-malignancy as treatment for malignant
      diseases.

PMID- 10355666
TI  - Surgical outcome in patients with epilepsy and dual pathology.
AB  - High-resolution MRI can detect dual pathology (an extrahippocampal lesion plus
      hippocampal atrophy) in about 5-20% of patients with refractory partial epilepsy
      referred for surgical evaluation. We report the results of 41 surgical
      interventions in 38 adults (mean age 31 years, range 14-63 years) with dual
      pathology. Three patients had two operations. The mean postoperative follow-up
      was 37 months (range 12-180 months). The extrahippocampal lesions were cortical
      dysgenesis in 15, tumour in 10, contusion/infarct in eight and vascular
      malformation in five patients. The surgical approach aimed to remove what was
      considered to be the most epileptogenic lesion, and the 41 operations were
      classified into lesionectomy (removal of an extrahippocampal lesion); mesial
      temporal resection (removal of an atrophic hippocampus); and lesionectomy plus
      mesial temporal resection (removal of both the lesion and the atrophic
      hippocampus). Lesionectomy plus mesial temporal resection resulted in complete
      freedom from seizures in 11/15 (73%) patients, while only 2/10 (20%) patients who
      had mesial temporal resection alone and 2/16 (12.5%) who had a lesionectomy alone
      were seizure-free (P < 0.001). When classes I and II were considered together
      results improved to 86, 30 and 31%, respectively. Our findings indicate that in
      patients with dual pathology removal of both the lesion and the atrophic
      hippocampus is the best surgical approach and should be considered whenever
      possible.

PMID- 10355667
TI  - Anti-ganglioside antibodies can bind peripheral nerve nodes of Ranvier and
      activate the complement cascade without inducing acute conduction block in vitro.
AB  - The neurophysiological effects of nine neuropathy-associated human anti
      ganglioside antisera, three monoclonal antibodies to ganglioside GM1 (GM1) and of
      the cholera toxin B subunit (a GM1 ligand) were studied on mouse sciatic nerve in
      vitro. GM1 antisera and monoclonal antibodies from patients with chronic motor
      neuropathies and Guillain-Barre syndrome, and GQ1b/ disialosyl antisera and
      monoclonal antibodies from patients with chronic ataxic neuropathies and Miller
      Fisher syndrome were studied. In vitro recording, for up to 6 h, of compound
      nerve action potentials, latencies, rise times and stimulus thresholds from
      isolated desheathed sciatic nerve was performed in the presence of
      antiganglioside antibodies and fresh human serum as an additional source of
      complement. No changes were observed over this time course, with 4-6 h values for
      all electrophysiological parameters being within 15% of the starting values for
      both normal and antibody containing sera and for the cholera toxin B subunit.
      Parallel experiments on identically prepared desheathed nerves performed with 0.5
      nM saxitoxin led to complete conduction block within 10 min of application. Under
      identical conditions to those used for electrophysiological recordings,
      quantitative immunohistological evaluation revealed a significant increase in IgM
      (immunoglobulin M) deposition at nodes of Ranvier from 5.3+/-3.1% to 28.7+/-8.4%
      (mean+/-SEM) of desheathed nerves exposed to three normal and three antibody
      containing sera, respectively (P < 0.03). Complement activation was seen at 100%
      of normal and 79% of disease-associated IgM positive nodes of Ranvier. These data
      indicate that anti-ganglioside antibodies can diffuse into a desheathed nerve,
      bind to nodes of Ranvier and fix complement in vitro without resulting in any
      overt physiological deterioration of the nerve over 4-6 h. This suggests that the
      node of Ranvier is relatively resistant to acute antiganglioside antibody
      mediated injury over this time scale and that anti-ganglioside antibodies and the
      cholera toxin B subunit are unlikely to have major direct pharmacological effects
      on nodal function, at least in comparison with the effect of saxitoxin. This in
      vitro sciatic nerve model appears of limited use for analysing
      electrophysiologically the effects of anti-ganglioside antibodies on nerve
      function, possibly because its short-term viability and isolation from
      circulating systemic factors do not permit the evolution of an inflammatory
      lesion of sufficient magnitude to induce overt electrophysiological
      abnormalities. In vivo models may be more suitable for identifying the effects of
      these antibodies on nerve conduction.

PMID- 10355668
TI  - A novel mutation in the human voltage-gated potassium channel gene (Kv1.1)
      associates with episodic ataxia type 1 and sometimes with partial epilepsy.
AB  - Episodic ataxia type 1 (EA1) is a rare autosomal dominant disorder characterized
      by brief episodes of ataxia associated with continuous interattack myokymia.
      Point mutations in the human voltage-gated potassium channel (Kv1.1) gene on
      chromosome 12p13 have recently been shown to associate with EA1. A Scottish
      family with EA1 harbouring a novel mutation in this gene is reported. Of the five
      affected individuals over three generations, two had partial epilepsy in addition
      to EA1. The detailed clinical, electrophysiological and molecular genetic
      findings are presented. The heterozygous point mutation is located at nucleotide
      position 677 and results in a radical amino acid substitution at a highly
      conserved position in the second transmembrane domain of the potassium channel.
      Functional studies indicated that mutant subunits exhibited a dominant negative
      effect on potassium channel function and would be predicted to impair neuronal
      repolarization. Potassium channels determine the excitability of neurons and
      blocking drugs are proconvulsant. A critical review of previously reported EA1
      families shows an over-representation of epilepsy in family members with EA1
      compared with unaffected members. These observations indicate that this mutation
      is pathogenic and suggest that the epilepsy in EA1 may be caused by the
      dysfunctional potassium channel. It is possible that such dysfunction may be
      relevant to other epilepsies in man.

PMID- 10355669
TI  - Focal ictal direct current shifts in human epilepsy as studied by subdural and
      scalp recording.
AB  - In order to clarify further the characteristics of ictal direct current (DC)
      shifts in human epilepsy, we investigated them by subdural and scalp recording in
      six and three patients, respectively, both having mainly neocortical lobe
      epilepsy (five with frontal lobe epilepsy, two with parietal lobe epilepsy and
      two with temporal lobe epilepsy). By using subdural electrodes made of platinum,
      ictal DC shifts were observed in 85% of all the recorded seizures (89 seizures)
      among the six patients, and they were localized to just one or two electrodes at
      which the conventional initial ictal EEG change was also observed. They were
      closely accompanied by the electrodecremental pattern in all patients except for
      one in whom 1 Hz rhythmic activity was superimposed on clear negative slow
      shifts. Seizure control after resection of the cortex, including the area showing
      DC shifts, was favourable irrespective of histological diagnosis. Scalp-recorded
      ictal slow shifts were observed in 23% of all the recorded seizures (60 seizures)
      among the three patients. They were, like the subdurally recorded ones, mainly
      surface-negative in polarity, closely related to the electrodecremental pattern
      and consistent in their location. It seems that scalp-recorded DC shifts were
      detected particularly when seizures were clinically intense, while no slow shifts
      were observed in small seizures. It is concluded that at least subdurally
      recorded ictal slow shifts are clinically useful before epilepsy surgery to
      delineate more specifically an epileptogenic area as well as to further confirm
      the conventional initial ictal EEG change, and that scalp-recorded ictal slow
      shifts also have high specificity although their low sensitivity is to be taken
      into account.

PMID- 10355670
TI  - Electrophysiological manifestations of open- and closed-class words in patients
      with Broca's aphasia with agrammatic comprehension. An event-related brain
      potential study.
AB  - This paper presents electrophysiological data on the on-line processing of open-
      and closed-class words in patients with Broca's aphasia with agrammatic
      comprehension. Event-related brain potentials were recorded from the scalp when
      Broca patients and non-aphasic control subjects were visually presented with a
      story in which the words appeared one at a time on the screen. Separate waveforms
      were computed for open- and closed-class words. The non-aphasic control subjects
      showed clear differences between the processing of open- and closed-class words
      in an early (210-375 ms) and a late (400-700 ms) time-window. The early
      electrophysiological differences reflect the first manifestation of the
      availability of word-category information from the mental lexicon. The late
      differences presumably relate to post-lexical semantic and syntactic processing.
      In contrast to the control subjects, the Broca patients showed no early
      vocabulary class effect and only a limited late effect. The results suggest that
      an important factor in the agrammatic comprehension deficit of Broca's aphasics
      is a delayed and/or incomplete availability of word-class information.

PMID- 10355671
TI  - Functional coupling of human cortical sensorimotor areas during bimanual skill
      acquisition.
AB  - Bimanual co-ordination of skilled finger movements is a high-level capability of
      the human motor system and virtually always requires training. Little is known
      about the physiological processes underlying successful bimanual performance and
      skill acquisition. In the present study, we used task-related coherence (TRCoh)
      and task-related power (TRPow) analysis of multichannel surface EEG to
      investigate the functional coupling and regional activation of human sensorimotor
      regions during bimanual skill acquisition. We focused on changes in
      interhemispheric coupling associated with bimanual learning. TRCoh and TRPow were
      estimated during the fusion of two overlearned unimanual finger-tapping sequences
      into one novel bimanual sequence, before and after a 30-min training period in 18
      normal volunteers. Control experiments included learning and repetition of
      complex and simple unimanual finger sequences. The main finding was a significant
      increase in interhemispheric TRCoh selectively in the early learning stage (P <
      0.0001). Interhemispheric TRCoh was also present during the unimanual control
      tasks, but with lower magnitude, even if learning was involved. Training improved
      bimanual sequence performance (from 58.3+/-24.1 to 83.7+/-15.3% correct
      sequences). After training, interhemispheric (bimanual) TRCoh decreased again,
      thereby approaching levels similar to those in the unimanual controls. We propose
      that the initial increase in TRCoh reflects changes in interhemispheric
      communication that are specifically related to bimanual learning and may be
      relayed through the corpus callosum. The present data might also offer a
      neurophysiological explanation for the clinical observation that patients with
      lesions of the corpus callosum may show deficits in the acquisition of novel
      bimanual tasks but not necessarily in the execution of previously learned
      bimanual activities.

PMID- 10355672
TI  - Development of a multiple sclerosis functional composite as a clinical trial
      outcome measure.
AB  - The primary clinical outcome measure for evaluating multiple sclerosis in
      clinical trials has been Kurtzke's expanded disability status scale (EDSS). New
      therapies appear to favourably impact the course of multiple sclerosis and render
      continued use of placebo control groups more difficult. Consequently, future
      trials are likely to compare active treatment groups which will most probably
      require increased sample sizes in order to detect therapeutic efficacy. Because
      more responsive outcome measures will be needed for active arm comparison
      studies, the National Multiple Sclerosis Society's Advisory Committee on Clinical
      Trials of New Agents in Multiple Sclerosis appointed a Task Force that was
      charged with developing improved clinical outcome measures. This Task Force
      acquired contemporary clinical trial and historical multiple sclerosis data for
      meta-analyses of primary and secondary outcome assessments to provide a basis for
      recommending a new outcome measure. A composite measure encompassing the major
      clinical dimensions of arm, leg and cognitive function was identified and termed
      the multiple sclerosis functional composite (MSFC). The MSFC consists of three
      objective quantitative tests of neurological function which are easy to
      administer. Change in this MSFC over the first year of observation predicted
      subsequent change in the EDSS, suggesting that the MSFC is more sensitive to
      change than the EDSS. This paper provides details concerning the development and
      testing of the MSFC.

PMID- 10355673
TI  - Dissociable neural responses to facial expressions of sadness and anger.
AB  - Previous neuroimaging and neuropsychological studies have investigated the neural
      substrates which mediate responses to fearful, disgusted and happy expressions.
      No previous studies have investigated the neural substrates which mediate
      responses to sad and angry expressions. Using functional neuroimaging, we tested
      two hypotheses. First, we tested whether the amygdala has a neural response to
      sad and/or angry facial expressions. Secondly, we tested whether the
      orbitofrontal cortex has a specific neural response to angry facial expressions.
      Volunteer subjects were scanned, using PET, while they performed a sex
      discrimination task involving static grey-scale images of faces expressing
      varying degrees of sadness and anger. We found that increasing intensity of sad
      facial expression was associated with enhanced activity in the left amygdala and
      right temporal pole. In addition, we found that increasing intensity of angry
      facial expression was associated with enhanced activity in the orbitofrontal and
      anterior cingulate cortex. We found no support for the suggestion that angry
      expressions generate a signal in the amygdala. The results provide evidence for
      dissociable, but interlocking, systems for the processing of distinct categories
      of negative facial expression.

PMID- 10355674
TI  - Voluntary movement after pallidotomy in severe Parkinson's disease.
AB  - The mechanisms of improvement in parkinsonian bradykinesia after posteroventral
      pallidotomy were investigated in 17 patients undergoing unilateral pallidotomy
      for severe Parkinson's disease. Clinical ratings of 'off' period bradykinesia
      demonstrated a maximal improvement of 22% 3 months postoperatively. Kinematic
      assessments of rapid repetitive finger and sequential arm movements were
      performed after overnight withdrawal of antiparkinsonian medications. There was a
      bilateral reduction in the inter-onset latency of a two-stage sequential arm
      movement and a contralateral increase in speed of arm movement after pallidotomy.
      There was no significant improvement postoperatively in the rhythm, amplitude or
      speed of repetitive finger movements. The results confirm the clinical impression
      that pallidotomy improves bradykinesia. This was more evident for complex limb
      movements, which used attentional strategies and external (visual and auditory)
      cues, than for repetitive fingertapping movements, which were largely internally
      generated. Since ablation of the pallidum can only reduce inhibitory pallidal
      outflow, it is unlikely to restore the normal pallidal influence on
      thalamocortical motor circuits. Therefore, any improvement in bradykinesia after
      pallidotomy must be related to mechanisms other than restoration of
      pallidothalamocortical connectivity. Based on the above observations, we suggest
      that some of the changes in motor control may be explained by the greater
      efficacy of external cues in facilitating movement after withdrawal of the
      abnormal pallidal discharge.

PMID- 10355675
TI  - Auditory stream segregation in dyslexic adults.
AB  - Developmental dyslexia is often associated with problems in phonological
      processing based on, or accompanied by, deficits in the perception of rapid
      auditory changes. Thirteen dyslexic adults and 18 control subjects were tested on
      sequences of alternating tones of high (1000 Hz) and low (400 Hz) pitch, which at
      short stimulus onset asynchronies (SOAs) led to perceptual separation of the
      sound sequence into high- and low-pitched streams. The control subjects perceived
      the tone sequence as connected down to SOAs of 130 ms, with segregation of the
      streams at shorter SOAs; in dyslexic subjects the segregation occurred already at
      210 ms. Auditory stream segregation has previously been shown to impair the
      detection of phoneme order in segments of speech sounds. The observed aberrant
      segregation of sound streams in dyslexic subjects might thus contribute to their
      difficulties in achieving awareness of phonemes or phoneme order and in the
      acquisition of literacy.

PMID- 10355676
TI  - Cognitive motor control in human pre-supplementary motor area studied by subdural
      recording of discrimination/selection-related potentials.
AB  - To clarify the functional role of human pre-supplementary motor area (pre-SMA) in
      'cognitive' motor control as compared with other non-primary motor cortices (SMA
      proper and lateral premotor areas) and prefrontal area, we recorded epicortical
      field potentials by using subdural electrodes in five epileptic patients during
      presurgical evaluation, whose pre-SMA, SMA-proper, prefrontal and lateral
      premotor areas were defined by electric cortical stimulation and recent
      anatomical orientations according to the bicommissural plane and callosal grid
      system. An S1-Go/NoGo choice and delayed reaction task (S1-choice paradigm) and a
      warned choice Go/NoGo reaction task (S2-choice paradigm) with inter-stimulus
      intervals of 2 s were employed. The results showed (i) transient potentials with
      onset and peak latencies of about 200 and 600 ms, respectively, after S1 in the
      S1-choice paradigm mainly at pre-SMA and to a lesser degree at the prefrontal and
      lateral premotor areas, but not in the S2-choice paradigm. At SMA-proper, a
      similar but much smaller potential was seen after S1 in both S1- and S2-choice
      paradigms and (ii) slow sustained potentials between S1 and S2 in both S1- and S2
      choice paradigms in all of the non-primary motor areas investigated (pre-SMA, SMA
      proper and lateral premotor areas) and prefrontal area. It is concluded that pre
      SMA plays a more important role in cognitive motor control which involves sensory
      discrimination and decision making or motor selection for the action after
      stimuli, whereas SMA-proper is one of the main generators of
      Bereitschaftspotential preceding self-paced, voluntary movements. In the more
      general anticipation of and attention to the forthcoming stimuli, non-primary
      motor cortices including pre-SMA, SMA-proper and lateral premotor area, and the
      prefrontal area are commonly involved.

PMID- 10355677
TI  - Conduction block in carpal tunnel syndrome.
AB  - Wrist extension was performed in six healthy subjects to establish, first,
      whether it would be sufficient to produce conduction block and, secondly, whether
      the excitability changes associated with this manoeuvre are similar to those
      produced by focal nerve compression. During maintained wrist extension to 90
      degrees, all subjects developed conduction block in cutaneous afferents distal to
      the wrist, with a marked reduction in amplitude of the maximal potential by >50%.
      This was associated with changes in axonal excitability at the wrist: a
      prolongation in latency, a decrease in supernormality and an increase in
      refractoriness. These changes indicate axonal depolarization. Similar studies
      were then performed in seven patients with carpal tunnel syndrome. The patients
      developed conduction block, again with evidence of axonal depolarization prior to
      block. Mild paraesthesiae were reported by all subjects (normals and patients)
      during wrist extension, and more intense paraesthesiae were reported following
      the release of wrist extension. In separate experiments, conduction block was
      produced by ischaemic compression, but its development could not be altered by
      hyperpolarizing currents. It is concluded that wrist extension produces a
      'depolarization' block in both normal subjects and patients with carpal tunnel
      syndrome, much as occurs with ischaemic compression, but that this block cannot
      be altered merely by compensating for the axonal depolarization. It is argued
      that conduction slowing need not always be attributed to disturbed myelination,
      and that ischaemic compression may be sufficient to explain some of the
      intermittent symptoms and electrodiagnostic findings in patients with carpal
      tunnel syndrome, particularly when it is of mild or moderate severity.

PMID- 10355678
TI  - A functional neuroimaging study of the variables that generate category-specific
      object processing differences.
AB  - Brain damage can cause remarkably selective deficits in processing specific
      categories of objects, indicating the high degree of functional segregation
      within the brain. The neuroimaging study presented here investigates differences
      in the neural activity associated with two categories of natural objects (animals
      and fruit) and two categories of man-made objects (vehicles and tools). Stimuli
      were outline drawings and the tasks were naming and word-picture matching. For
      man-made objects, the only category-specific effect was in the left posterior
      middle temporal cortex, which was most active for drawings of tools, as
      previously reported. For natural objects, drawings of animals and fruit (relative
      to drawings of man-made objects) enhanced activity in bilateral anterior temporal
      and right posterior middle temporal cortices. Critically, these effects with
      natural objects were not observed when the stimuli were coloured appropriately to
      facilitate identification. Furthermore, activation in the same right hemisphere
      areas was also observed for viewing and matching unfamiliar non-objects relative
      to naming and matching man-made objects. These results indicate that, in the
      right hemisphere, differences between processing natural relative to man-made
      objects overlap with the effects of increasing demands on object identification.
      In the left hemisphere, the effects are more consistent with functional
      specialization within the semantic system. We discuss (i) how category-specific
      differences can emerge for multiple reasons and (ii) the implications of these
      effects on the interpretation of functional imaging data and patients with
      category-specific deficits.

PMID- 10355679
TI  - Context-dependent, neural system-specific neurophysiological concomitants of
      ageing: mapping PET correlates during cognitive activation.
AB  - We used PET to explore the neurophysiological changes that accompany cognitive
      disability in ageing, with a focus on the frontal lobe. Absolute regional
      cerebral blood flow (rCBF) was measured in 41 healthy volunteers, evenly
      distributed across an age range of 18-80 years, during two task paradigms: (i)
      the Wisconsin Card Sorting Test (WCST), which depends heavily on working memory
      and is particularly sensitive to dysfunction of the dorsolateral prefrontal
      cortex (DLPFC); and (ii) Raven's Progressive Matrices (RPM), which may also have
      a working memory component, but depends more on visuo-spatial processing and is
      most sensitive to dysfunction of postrolandic regions. We used voxel-wise
      correlational mapping to determine age-related changes in WCST and RPM activation
      and developed a method to quantitate and localize statistical differences between
      the correlation maps for the two task paradigms. Because both WCST and RPM
      performance declined with age, as expected, correlational analyses were performed
      with and without partialling out the effect of task performance. Task-specific
      reductions of rCBF activation with age were found in the DLPFC during the WCST
      and in portions of the inferolateral temporal cortex involved in visuo-spatial
      processing during the RPM. We also found reduced ability to suppress rCBF in the
      right hippocampal region during the WCST and in mesial and polar portions of the
      prefrontal cortex during both task conditions. Task-dependent alterations with
      age in the relationship between the DLPFC and the hippocampus were also
      documented; because the collective pattern of changes in the hippocampal-DLPFC
      relationship with ageing was opposite to that seen in a previous study using
      dextroamphetamine, we postulated a dopaminergic mechanism. These results indicate
      that, despite some cognitive overlap between the two tasks and the age-related
      cognitive decline in both, many of the changes in rCBF activation with age were
      task-specific, reflecting functional alteration of the different neural circuits
      normally engaged by young subjects during the WCST and RPM. Reduced activation of
      areas critical for task performance (i.e. the DLPFC during the WCST and posterior
      visual association areas of the inferolateral temporal cortex during the RPM), in
      conjunction with the inability to suppress areas normally not involved in task
      performance (i.e. the left hippocampal region during the WCST and mesial polar
      prefrontal cortex during both the WCST and RPM), suggest that, overall, reduced
      ability to focus neural activity may be impaired in older subjects. The context
      dependency of the age-related changes is most consistent with systems failure and
      disordered connectivity.

PMID- 10355680
TI  - Common inhibitory mechanism in human inferior prefrontal cortex revealed by event
      related functional MRI.
AB  - Inhibition of an ongoing reaction tendency for adaptation to changing
      environments is a major function of the human prefrontal cortex. This function
      has been investigated frequently using the go/no-go task and set-shifting tasks
      such as the Wisconsin Card Sorting Test (WCST). Studies in humans and monkeys
      suggest the involvement of the dorsolateral prefrontal cortex in the two task
      paradigms. However, it remains unknown where in the dorsolateral prefrontal
      cortex this function is localized, whether a common inhibitory mechanism is used
      in these task paradigms and how this inhibitory function acts on two different
      targets, i.e. the go response in the go/no-go task and the cognitive set in the
      WCST. In the go/no-go task of this study, subjects were instructed to either
      respond (go trial) or not respond (no-go trial), depending on the cue stimulus
      presented. The signals of functional MRI (fMRI) related to the inhibitory
      function should be transient by nature. Thus, we used the temporal resolution of
      fMRI (event-related fMRI) by which transient signals in go and no-go trials can
      be analysed separately and compared with each other. We found a focus that showed
      transient no-go dominant activity in the posterior part of the inferior frontal
      sulcus in the right hemisphere. This was true irrespective of whether the
      subjects used their right or left hands. These results suggest that the transient
      activation in the right inferior prefrontal area is related to the neural
      mechanism underlying the response inhibition function. Furthermore, this area was
      found to be overlapped spatially with the area that was activated transiently
      during cognitive set shifting in the WCST. The transient signals in the go/no-go
      task peaked 5 s after the transient expression of the inhibitory function, and
      the transient signals in the WCST peaked 7s after the transient expression,
      reflecting different durations of neuronal activity in the two inhibitory task
      paradigms. These results imply that the right inferior prefrontal area is
      commonly involved in the inhibition of different targets, i.e. the go response
      during performance of the go/no-go task and the cognitive set during performance
      of the WCST.

PMID- 10355681
TI  - Biochemical parameters regulating forward motility initiation in vitro in goat
      immature epididymal spermatozoa.
AB  - An investigation was carried out to analyse the biochemical parameters
      influencing forward motility (FM) initiation in vitro in the goat caput
      epididymal immature spermatozoa. Forward motility was induced in approximately
      55% of caput-sperm upon incubation in an alkaline (pH 8.0) modified Ringer's
      solution containing theophylline (30 mM) (an inhibitor of cyclic AMP
      phosphodiesterase), dialysed epididymal plasma (EP) and bicarbonate. Both EP and
      bicarbonate induced sperm motility in a dose-dependent manner, and at saturating
      doses EP (0.6 mg protein mL(-1)) and bicarbonate (25 mM) induced FM in
      approximately 38% and 44% of the cells, respectively. The motility-promoting
      efficacy of EP was attributed to a heat-stable protein termed 'forward motility
      protein' (FMP). Bicarbonate served as an initiator as well as a stabilizer of FM
      and its action was not dependent on FMP. FMP can induce FM in the caput-sperm,
      but it is not essential for sperm motility initiation. Alteration of the medium
      pH from 6.60 to 8.00 caused a marked increase in the EP or bicarbonate-dependent
      sperm FM initiation, as well as intrasperm pH. At the physiological pH,
      bicarbonate served as a much more potent motility activator than FMP, although
      both the motility promoters showed maximal efficacy at alkaline pH (approximately
      7.8). EP as well as bicarbonate elevated the intrasperm cyclic AMP level. Unlike
      EP, bicarbonate is capable of increasing intrasperm pH. The intrasperm pH
      increased from 6.54 +/- 0.02 to 6.77 +/- 0.03 during sperm transit from caput to
      cauda. The data are consistent with the view that FMP activates sperm forward
      motility by enhancing the intrasperm cyclic AMP level and that extracellular
      bicarbonate and pH play a vital role in the initiation of sperm FM during the
      epididymal transit.

PMID- 10355682
TI  - The proteolysis of insulin-like growth factor binding proteins in ovine uterine
      luminal fluid.
AB  - During days 12-15 after oestrus (day 0), the uterine luminal fluid (ULF) of both
      pregnant and non-pregnant ewes contains only two prominent insulin-like growth
      factor binding proteins (IGFBPs) of 16-18 kDa and 22-24 kDa which preferentially
      bind IGF-2. Immunoblotting with an IGFBP-3 antibody revealed these to be
      proteolytic fragments of IGFBP-3. In contrast, the ULF from anoestrus and
      ovariectomized ewes contained intact IGFBP-3 (40-44 kDa) and IGFBP-2 (34 kDa). Co
      incubation of ULF from an anoestrus ewe with that from a day 12 cycling ewe
      cleaved the IGFBP-3 present into the two lower molecular weight IGFBPs
      characteristic of ewes in the late luteal phase of the oestrous cycle. The
      variation in proteolytic activity both during the year and during the cycle
      suggested an influence of progesterone. Supplementation of progesterone to long
      term ovariectomized ewes via a CIDR-G breeding device for 5, 10 or 15 days
      induced marked proteolytic activity in all 10-day treated sheep. The ULF from the
      15-day treated ewes showed reduced activity and could inhibit the activity
      present in 10-day ULF, suggesting the induction of an inhibitor after prolonged
      exposure to progesterone treatment. A possible role of IGFBP-3 proteolysis in the
      ovine ULF may be to selectively increase the bioavailability of IGF-1 in the
      uterine microenvironment, which may be crucial for the rapid elongation of
      trophoblast that begins during days 12-15 after mating.

PMID- 10355683
TI  - Ultrastructural features of bovine cumulus-corona cells surrounding oocytes,
      zygotes and early embryos.
AB  - Integrated transmission and scanning electron microscopic (TEM and SEM)
      techniques have provided the first detailed description of the ultrastructural
      features of the bovine cumulus-corona (CC) cells surrounding oocytes at the time
      of final maturation, zygotes and early cleaving embryos (2/4 to 6/8 blastomeres).
      TEM revealed the presence of rough endoplasmic reticulum and Golgi complexes in
      the cytoplasm of CC cells surrounding immature, mature and fertilized eggs, and
      also revealed an increasing amount of smooth endoplasmic reticulation membranes,
      lipid droplets and mitochondria with villiform and/or tubular cristae in the
      cytoplasm of CC cells during maturation and fertilization of the oocyte. In
      addition, a loss of cell-to-cell junctions between CC cells was evident. TEM also
      demonstrated that a few residual CC cells were still associated with early
      embryos and that these cells showed rather degenerative or apoptotic patterns,
      the latter pattern also observed on cells associated with fertilized eggs. SEM
      revealed that the complex of CC cells of immature oocytes was compact with narrow
      intercellular spaces, which progressively enlarged in size around mature oocytes.
      This phenomenon is mostly due to the production of abundant extracellular matrix.
      Immature CC cell complexes possessed characteristic long and filiform microvilli
      whereas the surface of CC cells surrounding mature oocytes showed numerous blebs
      and occasional large cytoplasmic protrusions as well as microvilli. Zygotes and
      early embryos were covered with a few polyhedral CC cells possessing scarce and
      short microvilli and a large amount of pleomorphic blebs. This study demonstrated
      a precocious luteinization occurring in bovine CC cells at ovulation until zygote
      segmentation, and this process was associated with a progressive apoptotic
      mechanism that ended in the complete denudation of the zona pellucida covering
      the early embryo. The presence of CC cells around the maturing oocyte and
      fertilized egg could have important functions related to the microenvironmental
      requirements of ovum maturation as well as facilitating activities related to
      fertilization.

PMID- 10355684
TI  - Exogenous protein affects developmental competence and metabolic activity of
      bovine pre-implantation embryos in vitro.
AB  - The role of exogenous protein during bovine pre-implantation embryo development
      in two in vitro production systems was investigated. Morphological development,
      survival after vitrification and metabolic activity before and after
      vitrification were recorded in blastocysts generated in vitro in synthetic
      oviduct fluid (SOF) medium in the presence of either bovine serum albumin (BSA)
      or polyvinyl-alcohol (PVA). Metabolic activity was determined by measuring oxygen
      consumption, glucose and pyruvate uptake as well as lactate production.
      Development to blastocysts and survival after vitrification were reduced
      significantly in medium lacking protein. Of the metabolic parameters measured,
      only pyruvate uptake was increased significantly in embryos cultured in medium
      supplemented with PVA. Whereas in BSA-supplemented medium pyruvate uptake was
      correlated with lactate production, in PVA-supplemented medium glucose uptake was
      correlated with lactate production. Lactate production increased significantly
      after vitrification as compared with fresh embryos. Thus, exogenously added
      protein significantly alters oxidative metabolism. In medium lacking protein, the
      additional pyruvate may be used for the maintenance of intracellular amino acid
      pools. Vitrification appears to alter glycolytic metabolic profiles indicating a
      stress-response. In conclusion, the perturbed metabolism corresponding to reduced
      developmental capacity of embryos produced under protein-free conditions
      emphasizes the ambiguity between maximum development, technical and hygienic
      requirements and physiological demands of the early bovine embryo in vitro. The
      use of well-defined recombinant proteins might assist in closing this gap.

PMID- 10355685
TI  - Influence of maternal bodyweight on adaptation after birth in near-term lambs
      delivered by Caesarean section.
AB  - The present study investigated the influence of maternal bodyweight on adaptation
      after birth in near-term lambs delivered by caesarean section. One twin lamb from
      a heavy (>60 kg) or light ewe (<55 kg) was randomly taken and immediately placed
      into a warm (30 degrees C) ambient temperature and its twin then delivered into a
      cool (15 degrees C) ambient temperature. Continuous recordings of colonic
      temperature were then made followed by measurements of thermoregulation and brown
      adipose tissue function up to 6 h of life. Following caesarean section delivery
      colonic temperature rapidly declined over the first 30 min of life, a response
      that was greater in lambs at 15 degrees C. Irrespective of ambient temperature
      all lambs born to heavy ewes commenced shivering within 15 min of birth and were
      able to restore body temperature. These adaptations were only observed in warm
      delivered lambs born to light ewes, as cool-delivered lambs failed to shiver,
      became hypothermic and 4 out of 6 lambs exhibited respiratory failure. Umbilical
      vein plasma thyroid hormone concentrations were lower in lambs born to light
      compared with heavy ewes. Plasma T3 concentrations remained lower in warm
      delivered lambs born to light ewes until 2 h after birth when heat production and
      colonic temperature were not significantly different from warm delivered lambs
      born to heavy ewes. Lambs born to light ewes possessed less brown adipose tissue
      than those born to heavy ewes. In conclusion, maternal bodyweight has a critical
      influence on survival following caesarean section birth that is dependent on the
      ambient temperature into which a lamb is delivered.

PMID- 10355686
TI  - Glucocorticoid activity in the fetal spontaneously hypertensive rat.
AB  - Fetal exposure to high concentrations of corticosteroids in the rat is associated
      with elevated blood pressure in postnatal life. In this study we have
      investigated indicators of corticosteroid activity in fetal spontaneously
      hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in order to determine whether
      fetal corticosteroid exposure is increased in the SHR. Placental 11beta
      hydroxysteroid dehydrogenase (11beta-HSD) activity, which prevents maternal
      steroids from crossing the placenta, was not impaired in the SHR. Concentrations
      of amniotic fluid corticosterone were significantly decreased in the SHR compared
      with the WKY at fetal Day 20, but were not significantly different on fetal Days
      16 or 22. This suggests that rather than increased exposure to corticosteroids in
      the SHR fetus corticosteroid exposure may be reduced. Expression of lung
      surfactant protein A (Sp-A), a gene induced in late gestation by corticosteroids,
      was decreased in the SHR. In addition, differences in amniotic fluid electrolyte
      concentrations were observed which may reflect delayed renal maturation in the
      fetal SHR. These data suggest that the SHR fetus is exposed to low concentrations
      of corticosteroids and that the late gestation rise in fetal corticosteroid may
      be delayed in the SHR.

PMID- 10355687
TI  - Effect of compatible solutes and diluent composition on the post-thaw motility of
      ram sperm.
AB  - The effect of the compatible solutes proline, glycine betaine and trehalose in
      Tris-based diluents at varying pH, concentrations of egg yolk or glycerol on the
      post-thaw motility characteristics and fertility of ram sperm was examined. In
      addition, the amino acid glycine was compared with proline, glycine betaine and a
      standard Tris-based diluent. Post-thaw motility was assessed using a Hamilton
      Thorn motility analyser. In the presence of glycerol and egg yolk, proline and
      glycine betaine improved the post-thaw motility characteristics of ram sperm.
      Regardless of the pH of the diluent at which semen was frozen, the percentage of
      motile sperm was higher when frozen in the presence of proline or glycine betaine
      than in their absence, whereas proline and glycine betaine only improved the
      progressive and rapid percentages of sperm for semen frozen in diluents at pH
      lower than 7.0. When semen was frozen in the absence of egg yolk or glycerol all
      the motility characteristics were reduced. Increasing the concentration of egg
      yolk in the diluent from 5% to 10, 15 or 20% had no effect on the post-thaw
      motility of sperm. The addition of 27 mM of proline or glycine betaine to the
      diluent also improved post-thaw motility. However, at a concentration of 81 mM,
      proline and glycine betaine had a detrimental effect on the percentage of motile
      sperm. Trehalose had no effect on the motility of sperm frozen in glycerol
      containing diluents, but motility was lower after cryopreservation in glycine
      than in Tris-, proline- or glycine betaine-based diluents. There were no
      differences in the fertility of sperm frozen in Tris-, proline or glycine betaine
      diluents after cervical or laparoscopic insemination of ewes.

PMID- 10355688
TI  - The effects of intrafetal ACTH administration on the outcome of pregnancy in the
      mare.
AB  - Enhanced adrenocortical activity in the fetus is related to the onset of
      parturition in many species. The aim of this study was to determine the effect of
      injection of fetal ACTH on gestational length and fetal viability in the horse.
      Pony mares (n=23) were studied from 300 days gestation. Seven control mares
      (Group 1) received three consecutive intrafetal injections of sterile water,
      while fetuses of a further 16 mares received Depot ACTH1-24. These mares were
      either allowed to foal spontaneously (Group 2, n=4) or delivery was induced
      within 3 days of the last fetal injection (Group 3, n=7); 5 mares aborted within
      48 h of intrafetal ACTH injection. Maternal plasma progestagen concentrations
      increased significantly (P<0.05) in Groups 2 and 3 mares following intrafetal
      ACTH injection, compared with Group 1 mares. All Group 1 mares delivered live
      foals at a median gestational age of 327 days (interquartile range, 323 334),
      except one that aborted 16 days after the last fetal injection. Gestational
      length was significantly (P<0.05) shortened in Group 2 mares (median 314 [312
      314]) days compared with controls. Group 1 and Group 2 foals showed normal
      postnatal adaptive responses and endocrine (plasma cortisol/progestagens)
      patterns. Group 3 mares delivered live foals at 306 (306-308) days gestation
      except one that aborted. Their foals were less mature compared with Groups 1 and
      2 foals. Eight ACTH-injected fetuses were meconium-stained at delivery, including
      four that were aborted. Eight mares had thickened placentae, including three that
      aborted. The data show that both precocious maturation of the equine fetus and a
      significant reduction in gestational length compared with controls may be
      achieved in pony mares by intrafetal ACTH injections. This is probably mediated
      via adrenal regulation of fetal maturation and production of maternal
      progestagens.

PMID- 10355689
TI  - Adult somatic cell nuclear transfer is used to preserve the last surviving cow of
      the Enderby Island cattle breed.
AB  - To preserve the female genetics of an endangered breed of cattle, adapted to sub
      Antarctic conditions, adult somatic cell nuclear transfer was used to clone the
      last surviving Enderby Island cow from mural granulosa cells. Embryos
      reconstructed with metaphase II cytoplasts and quiescent cells were either
      activated and fused simultaneously (AFS) at 24 or 30 hours post maturation (hpm)
      or alternatively, fused 4-6 h before activation at 26-30 hpm (FBA). A
      significantly higher proportion of fused embryos developed in vitro to grade 1-3
      blastocysts on Day 7 with FBA (39.8+/-2.8%) compared to AFS with activation
      either at 24 hpm (10.6+/-3.9%, P<0.01) or at 30 hpm (18.6+/-4.1%, P<0.01).
      Following the transfer of 74 embryos from the FBA treatment over two experiments,
      survival rates on Days 30, 55, 85, 150 and 190 of pregnancy were 38%, 30%, 23%,
      16% and 15%, respectively. Of 22 embryos transferred in the first experiment, two
      calves were born alive with one calf surviving. DNA analyses confirmed that the
      calves were genetically identical to the Enderby Island cow. Additional
      pregnancies are currently ongoing. These data show that embryo development is
      increased by prolonged exposure of quiescent somatic cell nuclei to oocyte
      cytoplasm before artificial activation, possibly facilitating nuclear
      reprogramming. The successful demonstration of somatic cell nuclear transfer in
      animal conservation extends the applications of the technology beyond the main
      agricultural and biomedical interests.

PMID- 10355690
TI  - Differential effects of adenosine on focal and macroreentrant atrial tachycardia.
AB  - INTRODUCTION: The effects of adenosine on atrial tachycardia (AT) remain
      controversial, and the mechanistic implications of adenosine termination have not
      been fully established. The purpose of this study was to elucidate the
      differential effects of adenosine on focal and macroreentrant AT and describe the
      characteristics of adenosine-sensitive AT. METHODS AND RESULTS: Thirty patients
      received adenosine during AT. Tachycardia origins were identified as focal or
      macroreentrant during invasive electrophysiologic studies. Responses to adenosine
      were analyzed and characterized as tachycardia termination, transient
      suppression, or no effect. Electrophysiologic studies demonstrated a focal origin
      of tachycardia in 17 patients. Adenosine terminated focal tachycardias in 14
      patients (dose 7.3 +/- 4.0 mg) and transiently suppressed the arrhythmias in
      three others (dose 10.0 +/- 6.9 mg). A macroreentrant mechanism was demonstrated
      in 13 patients; adenosine terminated only one of these tachycardias and had no
      effect on the remaining 12 patients (dose 10.2 +/- 2.9 mg). Four classes of
      adenosine-sensitive AT were identified. Class I consisted of nine patients with
      tachycardia arising from the crista terminalis; these tachycardias also
      terminated with verapamil (4/4). Class II consisted of four patients with
      repetitive monomorphic AT arising from diverse sites in the right atrium; these
      either slowed or terminated in response to verapamil (2/2). Class III consisted
      of the three patients with transient suppression and demonstrated
      electropharmacologic characteristics consistent with an automatic mechanism,
      including insensitivity to verapamil (2/2). In the one patient with
      macroreentrant AT that was comprised of decremental atrial tissue, adenosine
      terminated tachycardia in a zone of decremental slow conduction (Class IV); this
      tachycardia slowed with verapamil. CONCLUSIONS: Adenosine-sensitive AT is usually
      focal in origin and arises either from the region of the crista terminalis
      (inclusive of the sinus node) or from diverse atrial sites with an incessant
      nonsustained repetitive pattern. Although most forms of macroreentrant AT are
      insensitive to adenosine, rarely macroreentrant AT with zones of decremental slow
      conduction can demonstrate adenosine sensitivity.

PMID- 10355691
TI  - The activation of platelet function, coagulation, and fibrinolysis during
      radiofrequency catheter ablation in heparinized patients.
AB  - INTRODUCTION: Catheter ablation may be complicated by clinical thromboembolism in
      about 1% of patients. METHODS AND RESULTS: We studied the activation of
      coagulation (prothrombin fragment 1+2 [PF1+2]), platelets (beta-thromboglobulin
      [beta-TG])) and fibrinolysis (plasmin-antiplasmin complexes [PAP] and D-dimer)
      during radiofrequency (RF) ablation in 13 patients. They received heparin 100
      U/kg intravenously after the initial electrophysiologic study, prior to the
      delivery of RF current; thereafter 1,000 U/hour throughout the procedure. PF1+2
      increased fourfold (P < 0.001) during the diagnostic study, but gradually
      declined to upper reference value during heparin administration. There was a
      strong correlation between procedure duration prior to heparin bolus (range 39 to
      173 min); and (a) the maximal rise of PF1+2 (r = 0.83, P < 0.001) and (b) the
      increase of PF1+2 from baseline to end of the procedure (r = 0.74, P = 0.004).
      There was no correlation between postheparin changes of PF1+2 and (a) postheparin
      procedure duration (range 40 to 317 min), (b) number of RF pulses (range 1 to
      16), or (c) RF current duration (range 46 to 687 sec). Plasma beta-TG
      concentration showed similar trends. Fibrinolytic activity increased moderately
      from baseline until heparin administration; then remained around the upper
      reference values. PAP at the end of procedure and D-dimer at the time of heparin
      administration both correlated with preheparin procedure duration (r = 0.70, P =
      0.007 and r = 0.69, P = 0.01, respectively). All parameters were normal the next
      morning. CONCLUSION: Procedure duration prior to heparin administration, and not
      the delivery of RF current per se, determines activation of hemostasis and
      fibrinolysis during RF ablation.

PMID- 10355692
TI  - Atrial sensing and AV synchrony in single lead VDD pacemakers: a prospective
      comparison to DDD devices with bipolar atrial leads.
AB  - INTRODUCTION: Single lead VDD pacing has offered an alternative to DDD systems in
      patients with isolated AV block. Up to now, however, the relative performance of
      these pacemaker systems was not systematically compared. METHODS AND RESULTS:
      Three hundred sixty patients who received either a VDD pacemaker (n = 180) or a
      DDD device (n = 180) with a bipolar atrial lead were investigated prospectively
      for a mean period of 30 +/- 13 months. Pacemaker function was analyzed by
      telemetry, Holter monitoring, and exercise ECG. Time of implantation and
      fluoroscopy was significantly lower with VDD devices (44.3 +/- 5.1 min vs 74.4 +/
      13.5 min and 4.6 +/- 2.5 min vs 10.3 +/- 5.6 min in DDD pacemakers,
      respectively). Intermittent atrial undersensing occurred in 23.3% of patients
      with a VDD pacemaker and in 9.4% with DDD devices (NS). The incidence of atrial
      tachyarrhythmias did not differ between the VDD (6.7%) and the DDD group (6.1%).
      Sinus node dysfunction developed in 1.9% of patients, but the vast majority
      (85.7%) of patients were asymptomatic. There was a tendency for a higher rate of
      operative revisions in the DDD group (6.1% vs 3.3% in VDD pacemakers, P = 0.15).
      Cumulative maintenance of AV-synchronized pacing mode was 94.9% in patients with
      VDD pacemakers and 92.1% with DDD devices (NS). CONCLUSION: With the benefit of a
      simpler implant procedure, long-term outcome of single lead VDD pacing is
      equivalent to DDD pacing in patients with AV block and preoperative normal sinus
      node function.

PMID- 10355693
TI  - Wavelength and conduction inhomogeneity in each atrium in patients with isolated
      mitral valve disease and atrial fibrillation.
AB  - INTRODUCTION: Patients with mitral valve disease frequently have atrial
      fibrillation (AF), and the left atrium is presumed to be the primary atrium that
      develops AF. However, it is still not clear whether the electrophysiologic
      abnormalities responsible for AF are confined to the left atrium in this subset
      of patients. METHODS AND RESULTS: To examine the AF vulnerability of each atrium,
      we measured the wavelength and inhomogeneity of the conduction at the lateral
      right atrium, lateral left atrium, and Bachmann's bundle after defibrillation of
      AF in seven patients undergoing the maze procedure and mitral valve surgery for
      AF and isolated mitral valve disease, respectively (AF group). The data were
      compared with five coronary surgery patients in sinus rhythm (SR group). The
      wavelength in the AF group was significantly shorter (P < 0.05) than in the SR
      group not only at the lateral left atrium (225 +/- 62 vs 285 +/- 36 mm) but also
      at the lateral right atrium (214 +/- 54 vs 254 +/- 34 mm). The variation
      coefficient of the local maximum activation phase difference in the AF group (1.9
      +/- 0.8 at the right atrium, 2.1 +/- 0.8 at the lateral left atrium, and 2.0 +/-
      0.6 at Bachmann's bundle) was significantly greater (P < 0.05) than in the SR
      group at all atrial regions. CONCLUSION: AF vulnerability was not confined to the
      left atrium immediately after defibrillation in AF patients with isolated mitral
      valve disease. Electrical remodeling resulting from perpetuation of AF,
      pathological changes extending to the right atrium, geometric changes caused by
      the atrial interactions occurring across the interatrial septum, or a combination
      of these may explain the results.

PMID- 10355694
TI  - Optimal target site for slow AV nodal pathway ablation: possibility of
      predetermined focal mapping approach using anatomic reference in the Koch's
      triangle.
AB  - INTRODUCTION: Although a variety of ablation techniques have been developed in
      the treatment of atrioventricular nodal reentrant tachycardia (AVNRT), there have
      been few reports discussing the location of the optimal target site. Based on our
      early experiences, we hypothesized that radiofrequency (RF) current applied
      around the upper margin of the coronary sinus ostium (UCSO) results in the most
      effective and safe treatment of AVNRT. METHODS AND RESULTS: To confirm our
      hypothesis, the efficacy of RF currents applied around the UCSO guided by local
      electrograms in 59 patients (group B: predetermined focal mapping approach) were
      compared with the outcomes in 60 other patients previously treated with the
      standard electrogram-guided mapping method starting around the lower margin of
      the coronary sinus ostium (group A). The precise location of ablation catheters
      at successful sites (S) was also evaluated. All the patients were successfully
      treated without complications. Significantly fewer RF pulses and lower energies
      were needed in group B patients (mean RF applications: 4.3 vs 1.4 applications,
      mean total energy delivered: 4,699 vs 2,236 J in groups A and B, respectively, P
      < 0.01). Detailed analyses of the anatomical locations of S using CS venography
      in group B patients who received only a single RF application (46 patients)
      revealed that the distance between His and S varied according to the length of
      Koch's triangle, while that between S and UCSO was relatively constant. In 85 %
      of these 46 patients, S was located within 5 mm above and below the level of the
      UCSO. CONCLUSION: RF applications around the UCSO guided by local electrograms
      yielded excellent outcomes in AVNRT patients with wide varieties in the size of
      Koch's triangle. The optimal target site was located within 5 mm above and below
      the level of UCSO along the tricuspid annulus.

PMID- 10355695
TI  - Electroanatomic mapping for radiofrequency ablation of cardiac arrhythmias.
AB  - Radiofrequency catheter ablation is the current treatment of choice for several
      cardiac arrhythmias. The conventional approach utilizing intracardiac
      electrograms during sinus rhythm and during tachycardia has inherent limitations
      including limited two-dimensional fluoroscopic imaging and the ability to
      evaluate several potential sites for ablation and to go precisely to the most
      suitable site. Recently, a nonfluoroscopic three-dimensional electroanatomic
      system has been developed for mapping arrhythmias. We describe in this report the
      advantage of utilizing the system in facilitating a successful outcome in three
      patients with different arrhythmias.

PMID- 10355696
TI  - A role for the renin-angiotensin system in the evolution of cardiac memory.
AB  - INTRODUCTION: We studied the role of the cardiac renin-angiotensin II system in
      the genesis of cardiac memory, in which T wave changes induced by ventricular
      pacing (VP) accumulate and persist during subsequent sinus rhythm. METHODS AND
      RESULTS: Anesthetized dogs were instrumented via a thoracotomy and three 20
      minute runs of VP were interspersed with periods of normal sinus rhythm
      sufficient to permit T wave recovery to 90% of control. Memory was quantified as
      the change (delta) in T wave vector angle showing accumulation over the three
      monitoring periods. In five control dogs T wave vector = -27 +/- 49 degrees, and
      this shifted by 104 degrees (P < 0.05) over the three postpacing recovery
      periods. In seven dogs infused with the receptor blocker saralasin, five infused
      with the angiotensin-converting enzyme inhibitor captopril, and four infused with
      the tissue protease inhibitor chymostatin, there were significant reductions in
      the incidence and the accumulation of memory. In four other experiments, we used
      isolated, blood-perfused canine hearts to demonstrate that VP used to induce
      memory alters the contractile pattern of the left ventricle. CONCLUSIONS: We
      propose that the alteration in myocardial stretch induced by pacing activates
      angiotensin II synthesis by cardiac cells. We propose, further that the
      endogenous cardiac renin-angiotensin II system (blocked by saralasin, captopril
      and by chymostatin) is an important contributor to the induction of memory.

PMID- 10355698
TI  - Biventricular shocking leads improve defibrillation efficacy.
AB  - INTRODUCTION: A single lead active can configuration has been widely used in
      patients with life-threatening ventricular arrhythmias. Occasionally, however,
      such a defibrillation lead configuration may not achieve adequate defibrillation
      threshold (DFT). The purpose of this study was to determine whether addition of a
      left ventricular (LV) lead can improve defibrillation efficacy. METHODS AND
      RESULTS: Three transvenous defibrillation leads (8.3-French with a 5-cm long
      unipolar coil) were placed in the right ventricle (RV), LV, and superior vena
      cava (SVC), along with an active can (92 cm2) in the left subpectoral area. The
      DFT stored energy of seven combinations of these defibrillation leads were
      compared in a pig ventricular fibrillation model using a biphasic defibrillation
      waveform (125 microF, 6.5/3.5 msec). A biventricular leads active can
      configuration in which the RV and LV leads were of the same polarity reduced the
      DFT stored energy by approximately 35% when compared to a single RV lead active
      can configuration (9.6 +/- 3.0 J vs 15.0 +/- 7.2 J, respectively, P = 0.02).
      Moreover, adding a SVC lead further reduced the DFT energy (8.4 +/- 3.3 J).
      CONCLUSION: A biventricular leads active can configuration can significantly
      improve defibrillation efficacy as compared to a single lead active can
      configuration. In such a defibrillation lead configuration, the polarity of RV
      and LV leads should be the same.

PMID- 10355697
TI  - Alterations in gene expression of proteins involved in the calcium handling in
      patients with atrial fibrillation.
AB  - INTRODUCTION: Atrial fibrillation (AF) leads to a loss of atrial contraction
      within hours to days. During persistence of AF, cellular dedifferentiation and
      hypertrophy occur, eventually resulting in degenerative changes and cell death.
      Abnormalities in the calcium handling in response to tachycardia-induced
      intracellular calcium overload play a pivotal role in these processes. METHODS
      AND RESULTS: The purpose was to investigate the mRNA expression of proteins and
      ion channels influencing the calcium handling in patients with persistent AF.
      Right atrial appendages were obtained from 18 matched controls in sinus rhythm
      (group 1) and 18 patients with persistent AF undergoing elective cardiac surgery.
      Previous duration of AF was < or = 6 months in 9 (group 2) and > 6 months in 9
      patients (group 3). In a single semiquantitative polymerase chain reaction, the
      mRNA of interest and of glyceraldehyde-3-phosphate dehydrogenase, were
      coamplified and separated by gel electrophoresis. L-type calcium channel alpha1
      subunit mRNA content was inversely related to the duration of AF: -26% in group 2
      compared to group 1 (P = 0.2), and -49% in group 3 compared to group 1 (P =
      0.01). Inhibitory guanine nucleotide binding protein ialpha2 mRNA content was
      reduced in group 3 compared to group 1 (-30%, P = 0.01). Sarcoplasmic reticulum
      calcium ATPase, phospholamban and sodium-calcium exchanger mRNA contents were not
      affected by AF. CONCLUSIONS: AF-induced alterations in mRNA contents of proteins
      and ion channels involved in the calcium handling seem to occur in relation to
      the previous duration of AF. In the present patient population, these changes
      were significant only if AF lasted > 6 months.

PMID- 10355699
TI  - Catheter mounted coaxially moveable ablation electrode for the creation of linear
      transmural endocardial lesions.
AB  - INTRODUCTION: Use of a novel ablation catheter for the creation of linear
      transmural endocardial lesions, which uses a coaxially moving ablation electrode
      mounted on the terminal portion of a catheter shaft and able to move axially for
      a distance of up to 4 cm, is reported. METHODS AND RESULTS: The coaxially moving
      ablation electrode is moved by a sliding mechanism in the catheter handle. The
      distal portion of the catheter shaft is steerable. Bipolar or unipolar
      electrograms can be recorded from electrodes on the catheter tip and the
      coaxially moving ablation. Radiofrequency (RF) current is delivered to the
      coaxially moving ablation electrode with thermocouple temperature control. This
      ablation catheter was evaluated in five (30 to 65 kg) anesthetized pigs and
      introduced via the venous/arterial systems into the right and left atrium (1
      lesion) (using the retrograde aortic approach). The catheter was maneuvered to
      bring the slide range into apposition with atrial endocardium. The coaxially
      moving ablation electrode was deployed to the terminal portion of the catheter's
      slide range and then withdrawn in 2-mm steps. RF current was delivered to the
      coaxially moving ablation electrode at each point (maximum temperature 70 degrees
      C). Postmortem examination of eight endocardial linear lesions (2.2 to 4.1 cm
      length) was made 1 to 3 hours after creation. Histopathologic examination
      confirmed transmural myocyte necrosis along the length of the lesion, that
      included the trabeculated right atrium. CONCLUSION: We conclude that a catheter
      using a moveable electrode creates continuous linear transmural lesions and could
      find clinical application in the therapy of a variety of reentry tachycardia
      mechanisms.

PMID- 10355700
TI  - Quatrefoil reentry in myocardium: an optical imaging study of the induction
      mechanism.
AB  - INTRODUCTION: The "critical point hypothesis" for induction of ventricular
      fibrillation has previously been extended to infer the coexistence of four
      critical points, and hence four simultaneous spiral reentries or a quatrefoil
      reentry, resulting from only one premature stimulus delivered to the same
      location as the pacing stimulus. An optical imaging technique was used to explore
      its existence and to study the induction mechanism of this peculiar reentry
      pattern. METHODS AND RESULTS: In 16 isolated, Langendorff-perfused rabbit hearts,
      high-speed optical imaging at 133 or 267 frames/sec was performed to observe the
      induced response with a unipolar point electrode. A novel quatrefoil-shaped
      reentry pattern consisting of two pairs of opposing rotors was created by
      delivering long stimuli during the vulnerable phase. Successful induction
      occurred in a narrow range of coupling intervals. A dogbone pattern of virtual
      electrodes was established during the premature stimulus. Propagating wavefronts
      launched from the virtual anodes immediately after the termination of S2. The
      alternating blocking and conducting effects of the virtual electrodes, as well as
      the boundary between virtual cathode and virtual anode, provided the necessary
      pathways for quatrefoil reentry. Propagation directions of the reentrant spiral
      wavefronts reversed with a reversal in S2 polarity. Quatrefoil reentries were not
      sustained and lasted 1 to 4 complete cycles. CONCLUSION: The initiation of
      quatrefoil reentry followed anodal- or cathodal-break stimulation as a result of
      local symmetrical enhancement of the dispersion of tissue excitability. The
      "critical point hypothesis" provides the minimum topology required for this type
      of reentry; the "graded response hypothesis" can be viewed as providing a more
      detailed explanation of how this topology is actually realized. Triggering
      mechanisms due to the "break" mode of stimulation also posits a new mechanism for
      defibrillation.

PMID- 10355701
TI  - Effects of 17beta-estradiol on tachycardia-induced changes of atrial
      refractoriness and cisapride-induced ventricular arrhythmia.
AB  - INTRODUCTION: Gender difference is known to be associated with the occurrence of
      arrhythmia. However, the effects of female sex hormone on atrial
      electrophysiology, and on the occurrence of torsades de pointes (TdP) induced by
      cisapride have been unclear. METHODS AND RESULTS: Two experiments were included
      in this study. In experiment 1, effective refractory periods (ERPs) from five
      epicardial atrial sites were measured before and after rapid atrial pacing at 800
      beats/min for 30 minutes in dogs with pretreatment of verapamil (n = 10), 17beta
      estradiol (n = 10), or without pretreatment (n = 10, control group). In
      experiment 2, limb-lead ECG and monophasic action potentials in the left and
      right ventricles were recorded before and after each dose of cisapride (2 to 6
      mg/kg) during different ventricular rates in dogs with (n = 9) and without (n =
      14) concomitant administration of 17beta-estradiol (0.3 microg/kg). After 17beta
      estradiol administration, there were greater atrial ERPs in the study dogs than
      in the control group. The atrial ERPs were shortened significantly after rapid
      atrial pacing, but the degree was greater in the control group than in the dogs
      pretreated with verapamil or 17beta-estradiol. Moreover, the recovery of atrial
      ERPs was faster in dogs pretreated with verapamil or 17beta-estradiol than in the
      control group. In experiment 2, cisapride prolonged the QT interval and
      biventricular APD90 and induced early afterdepolarizations (EADs) in a dose
      dependent manner. However, dogs receiving cisapride combined with 17beta
      estradiol had a greater increase of ventricular repolarization and a higher
      incidence of EADs than those receiving cisapride only. Moreover, dogs receiving
      cisapride combined with 17beta-estradiol (3/9, 33%) had a greater incidence of
      TdP than those receiving cisapride only (0/14, 0%, P < 0.05). CONCLUSIONS: 17beta
      estradiol has a significant effect on atrial electrophysiology, which may be
      related to the prevention of atrial fibrillation. However, the high incidence of
      TdP in dogs receiving cisapride combined with 17beta-estradiol suggests that the
      female sex hormone is an important risk factor of cisapride-induced
      proarrhythmia.

PMID- 10355702
TI  - Human histopathologic findings following radiofrequency ablation of the tricuspid
      inferior vena cava isthmus.
AB  - Radiofrequency (RF) ablation of the tricuspid valve-inferior vena cava isthmus is
      now the first line of treatment in the management of typical atrial flutter.
      Successful ablation is associated with conduction block in this region, although
      the histopathologic changes following this procedure have never been reported. We
      describe the pathologic changes following RF ablation of this region in an
      explanted heart of a patient undergoing heart transplantation 4 months after
      successful atrial flutter ablation. The findings confirm the ability of RF
      ablation to create in the isthmus a chronic full thickness fibrosis, which
      represents the histopathologic counterpart of the conduction block demonstrated
      at the end of procedure.

PMID- 10355703
TI  - Radiofrequency ablation of a concealed nodoventricular Mahaim fiber guided by a
      discrete potential.
AB  - INTRODUCTION: We present the case of a 17-year-old woman who underwent an
      electrophysiological study and radiofrequency (RF) ablation of supraventricular
      tachycardia refractory to medical treatment. Two right-sided, concealed,
      nondecremental atrioventricular accessory pathways (AV-APs) involved in
      orthodromic circus movement tachycardias were identified. After RF ablation of
      both AV-APs, evidence of bidirectional dual AV nodal conduction was demonstrated
      and regular narrow complex tachycardia was induced. METHODS AND RESULTS: During
      the tachycardia, retrograde slow and fast AV nodal pathway conduction with second
      degree ventriculoatrial (VA) block and VA dissociation were observed. During the
      tachycardia with second-degree VA block, ventricular extrastimuli elicited during
      His-bundle refractoriness advanced the next His potential or terminated the
      tachycardia. Mapping the right atrial mid-septal region, a distinct high
      frequency activation P potential was recorded in a discrete area, two thirds of
      the way from the His bundle toward the os of the coronary sinus. Detailed
      electrophysiologic testing with the recordable P potential demonstrated that the
      tachycardia utilized a concealed nodoventricular AP arising from the proximal
      slow AV nodal pathway. CONCLUSION: The tachycardia with slow 1:1 VA conduction
      could be reset by ventricular extrastimuli elicited during His-bundle
      refractoriness advancing the subsequent activation P potential and atrial
      activation. RF ablation guided by recording of the activation P potential
      resulted in elimination of both the slow AV nodal pathway and the nodoventricular
      connection with preservation of the normal AV conduction system.

PMID- 10355704
TI  - Thromboembolic complications of cardiac radiofrequency catheter ablation: a
      review of the reported incidence, pathogenesis and current research directions.
AB  - INTRODUCTION: Radiofrequency catheter ablation (RFCA) has become established as
      an effective therapy for the treatment of many cardiac tachyarrhythmias. The
      principle limitation of conventional RFCA continues to be the risk of
      thromboembolism. This risk is of particular concern for the ongoing development
      of the catheter maze procedure for the treatment of atrial fibrillation, which
      currently involves the creation of extensive linear lesions in the left atrium.
      METHODS AND RESULTS: A Medline search of the literature over the last ten years
      was performed. Focused review of the reported thromboembolic complications of
      RFCA indicates an overall incidence of 0.6%. However, the risk is increased when
      ablation is performed in the left heart (1.8% to 2%) and for ventricular
      tachycardia (2.8%). It is of concern that intravenous heparin and the use of
      temperature feedback to control radiofrequency current do not eliminate the risk
      of thromboembolic events. CONCLUSION: The thromboembolic complications of RFCA
      are not eliminated by the treatment of intravenous herapin and mode of
      temperature control during ablation. Potential approaches to further reduce the
      risk of thromboembolism include the adjunctive administration of specific
      inhibitors of platelet activation and aggregation, intraprocedural intracardiac
      echocardiography, irrigated radiofrequency ablation, and cryoablation catheter
      systems.

PMID- 10355705
TI  - Functional reentry: leading circle or spiral wave?

PMID- 10355706
TI  - A regular, wide-QRS complex tachycardia: what is the tachycardia mechanism?

PMID- 10355707
TI  - Macroscopic T wave alternans as a harbinger of sudden death.

PMID- 10355708
TI  - T wave alternans and left ventricular ejection fraction, but not QT variability
      index, predict appropriate ICD discharge.

PMID- 10355709
TI  - Anterior cruciate ligament and intercondylar notch in the coronal oblique plane:
      anatomy complemented by magnetic resonance imaging in cruciate ligament-intact
      knees.
AB  - We assessed the anatomy of the anterior cruciate ligament (ACL) and femoral
      intercondylar notch on cryosections from one cadaveric knee specimen in the
      coronal oblique plane oriented parallel to the intercondylar roof. We determined
      the course of the ACL, the widths of the cruciate ligaments at intersection, and
      the intercondylar notch configuration on coronal oblique plane magnetic resonance
      images in 51 adult cruciate ligament-intact knees (25 women, 26 men; age range,
      16 to 47 years). The intercondylar notch widths were measured at the notch
      entrance, at the intersection of the ACL and posterior cruciate ligament (PCL),
      and at the notch outlet. In the coronal oblique plane, the ACL exhibited a
      diagonal course from the central and medial part of the anterior intercondylar
      area of the tibia distally, across the lateral third of the intercondylar notch,
      to the intercondylar surface of the lateral femoral condyle proximally. At the
      cruciate ligament intersection, the absolute widths of the ACLs measured on
      average 6.1+/-1.1 mm in men and 5.2+/-1.0 mm in women representing 31.9% and
      31.1% of the ACL/central intercondylar notch width ratios. The absolute widths of
      the PCLs measured on average 9.6+/-1.3 mm in men and 8.5+/-1.3 mm in women
      representing 50.4% and 51.4% of PCL/central intercondylar notch width ratios. On
      average for both groups, men and women, the absolute widths of the PCLs were
      significantly larger than the absolute widths of the ACLs. However, the relative
      widths of the cruciate ligaments with respect to corresponding intercondylar
      notch widths were not significantly different. In the coronal oblique plane, the
      intercondylar notch widths showed on average a significant decrease from
      posterior to intersection and from intersection to anterior. At notch outlet, the
      mean notch width measured 21.4 mm in men and 18.5 mm in women. At intersection,
      the mean notch width measured 19.1 mm in men and 16.6 mm in women. At notch
      entrance, the notch width measured 14.6+/-1.8 mm in men and 12.7+/-2.1 mm in
      women. We recommend magnetic resonance tomography of the knee in the coronal
      oblique plane oriented parallel to the intercondylar roof as the imaging modality
      of choice to visualize accurately the anatomic diagonal course of the ACL and its
      relation to the intercondylar notch and posterior cruciate ligament complex.

PMID- 10355710
TI  - Tripled semitendinosus-cancellous bone anterior cruciate ligament reconstruction
      with bioscrew fixation.
AB  - A prospective evaluation of a tripled semitendinosus-autologous cancellous bone
      plug ACL reconstruction, secured with bioabsorbable interference screws
      (Bioscrew; Linvatec, Largo, FL) made of polyL-lactic acid, was undertaken from
      July 1994 through August 1995. A total of 21 patients with 22 anterior cruciate
      ligament (ACL) reconstructions were followed-up an average 29 months (range, 20
      to 45). The average age was 38 years (range, 24 to 48 years). Tegner and Lysholm
      scores were 2.1 and 46, respectively, preoperatively and increased
      postoperatively to 4.4 and 90. KT tests at 24 months follow-up showed an average
      20-lb laxity of 1.4 mm, an average 30-lb laxity of 2.1 mm, and an average KT
      maximum manual side-to-side difference of 2.9 mm. A pivot shift was absent in all
      but two patients at final follow-up. Full extension was rapidly achieved in all
      cases and flexion averaged 135 degrees at follow-up. No problems with the poly L
      lactic acid interference screws occurred. These data support the effectiveness of
      Bioscrew fixation of the tripled semitendinosus-cancellous bone graft ACL
      reconstruction, which achieves both anatomic graft position and anatomic graft
      fixation.

PMID- 10355711
TI  - Arthroscopic treatment of popliteal cyst and associated intra-articular knee
      disorders in adults.
AB  - We describe a surgical arthroscopic treatment for popliteal cyst in a series of
      30 patients, with a mean follow-up of 32 months. The treatment consists of a cure
      for the intra-articular pathology of the knee associated with popliteal cysts,
      and the contemporaneous correction of the valvular mechanism responsible for the
      formation and reoccurrence of popliteal cyst. The popliteal cyst in adults was
      found to be almost invariably associated with other knee disorders. In all of the
      cases studied, a connection between joint space and cyst was found. Arthroscopy
      allowed the treatment of almost all of the associated knee disorders and the
      removal of anatomic structures imposing the one-way passage of fluid from the
      joint space into the cyst. Two years after the treatment, we observed optimal or
      good clinical results in 95% of the patients treated.

PMID- 10355712
TI  - Intra-articular ganglion cysts of the knee.
AB  - A ganglion is a cystic mass with myxoid matrix that occasionally occurs within
      muscles, tendons, and menisci. A ganglion cyst within the knee is very rare, with
      few reports to be found. We are reporting eight cases of a ganglion within the
      knee joint. Our cases include two ganglia in the infrapatellar fat pad which have
      not been previously reported. Ganglion cysts do not have specific symptoms. We
      hypothesize that symptoms of a ganglion cyst may correlate with the size and the
      location within the knee joint. The diagnosis of ganglia within the knee was
      established by magnetic resonance imaging study and confirmed by pathological
      testing. All the patients were treated successfully using the arthroscopic
      technique.

PMID- 10355713
TI  - Contributions of femoral fixation methods to the stiffness of anterior cruciate
      ligament replacements at implantation.
AB  - One purpose of this study was to determine the stiffness of three femoral
      fixation methods used commonly in anterior cruciate ligament (ACL) reconstruction
      to secure a double-looped semitendinosus and gracilis (DLSTG) graft and then
      assess how the stiffness of these methods affects the stiffness of the young
      human femur-fixation method-graft complex at the time of reconstruction. A second
      purpose was to define principles for adjusting the stiffness of the ACL
      replacement (defined as the femoral fixation method plus DLSTG graft plus tibial
      fixation method) to match that of the native ACL. The stiffness of a DLSTG graft
      and the stiffness of the femur-fixation method-DLSTG graft complex for three
      endoscopic fixation methods were measured. Fixations of the DLSTG graft to a
      button, anchor, and post, both with and without compaction of bone, were tested
      in young, human femur. The stiffness of each fixation was calculated by modeling
      the DLSTG graft and fixation method as a series of springs. The stiffness of the
      DLSTG graft averaged 954+/-292 N/mm. The stiffness of the DLSTG graft-fixation
      complex was lowered fourfold to 40-fold by adding fixation. The method of
      fixation determined the reduction in stiffness. The stiffness of the femur-button
      DLSTG graft complex averaged 23+/-2 N/mm, the femur-anchor-DLSTG graft complex
      averaged 25+/-3 N/mm, and the femur-post with bone graft-DLSTG graft complex
      averaged 225+/-23 N/mm (P = .0001). The knot in the suture loop was the least
      stiff component and determined the stiffness when the DLSTG graft was fixed with
      both the button and anchor. Compaction of bone significantly increased stiffness
      by an average of 41+/-14 N/mm (P = .027). Because the stiffness of femoral
      fixation methods are 4 to 40 times less than the stiffness of the graft,
      increasing the stiffness of an ACL replacement would be best achieved by
      selecting fixation methods with higher stiffness and not by either shortening the
      graft or increasing the cross-sectional area of the graft.

PMID- 10355714
TI  - A statistical analysis of the accuracy of sonography of the patellar tendon.
AB  - The purpose of this study was to evaluate the accuracy of sonography in measuring
      the dimensions of the cadaveric patellar tendon to determine whether sonography
      might have future applications in the preoperative assessment of autograft
      tissues before anterior cruciate ligament (ACL) reconstruction. Eleven lower
      extremity human cadaveric limbs, with an average donor age of 75 years (range, 67
      to 87 years), underwent patellar sonography with a 7.5-MHz transducer. Patellar
      tendon thickness, width, and length were measured sonographically. After skin
      removal, the patellar tendon dimensions were measured manually. Sonographic and
      manual measurements were compared statistically. Sonographic and manual
      measurements showed good agreement for thickness. There was poor agreement for
      width and length. Because of its limited accuracy, sonography cannot be
      recommended for the measurement of the patellar tendon before ACL reconstruction.

PMID- 10355715
TI  - Initial fixation strength of modified patellar tendon grafts for anatomic
      fixation in anterior cruciate ligament reconstruction.
AB  - Recently it has been shown that anatomic tibial graft fixation in anterior
      cruciate ligament (ACL) reconstruction is preferable in order to increase
      isometry and knee stability. To facilitate anatomic patellar tendon graft
      fixation, customized graft length shortening is necessary. The purpose of this
      study was to compare the initial fixation strength of four different shortened
      patellar tendon grafts including three bone plug flip techniques and direct
      patellar tendon-to-bone interference fit fixation in a model with standardized
      bone density. Ninety calf tibial plateaus (22 to 24 weeks old) with adjacent
      patella and extensor ligaments were used. Tendon grafts were shortened by
      flipping the bone plug over the tendon leaving a tendon-tendon-bone (TTB)
      construct and, as the first modification in the opposite direction resulting in a
      tendon-bone-tendon (TBT) construct. The second modification consisted of the TBT
      construct with interference screw position at the lateral aspect of the bone plug
      (TBTlat). As the fourth modification the tendon graft was directly fixed
      (Tdirect) with an interference screw. In addition, a round-threaded titanium
      (RCI; Smith & Nephew DonJoy, Carlsbad, CA), a round-threaded biodegradable screw
      (Sysorb; Sulzer Orthopedics, Munsingen, Switzerland), and a conventional titanium
      interference screw (Arthrex Inc, Naples, FL) were compared. We found that TTB
      (mean 441 N for biodegradable screw, 357 N for RCI screw, 384 N for conventional
      screw) and TBT (mean 407 N for biodegradable screw, 204 N for RCI screw, 392 N
      for conventional screw) construct fixation achieves comparable fixation strength,
      although failure in the TTB was due to tendon strip off at its ligamentous
      insertion. The highest failure load was found in TBTlat fixation (mean 610 N for
      biodegradable screw, 479 N for RCI screw). Therefore, this technique should be
      recommended when using a tendon flip technique. The failure load for Tdirect
      fixation (mean 437 N for biodegradable screw, 364 N for RCI screw) was similar to
      that of TTB and TBT fixation, which may indicate that a patellar-tendon graft
      harvested without its patellar bone plug and directly fixed with an interference
      screw is equivalent to a flipped graft. This may additionally reduce harvest site
      morbidity and eliminates the risk of patellar fracture. The fixation strength of
      round-threaded biodegradable and conventional titanium interference screws was
      similar, whereas that of round-threaded titanium screws was significantly lower
      in the patellar tendon flip-techniques. However, it should be taken into
      consideration that round-threaded titanium screws are proposed for direct tendon
      to-bone fixation.

PMID- 10355716
TI  - Modified Caspari technique for traumatic anterior shoulder instability:
      comparison of absorbable sutures versus absorbable plus nonabsorbable sutures.
AB  - The efficacy of the Caspari technique using a combination of absorbable and
      nonabsorbable sutures was compared with that of using only absorbable sutures.
      Forty-four patients (45 shoulders) underwent our modified Caspari technique for
      traumatic anterior shoulder instability and were followed-up for 2 to 3 years
      postoperatively. The average age at operation was 22 years. Among 27 patients
      treated using all absorbable PDS sutures, 7 patients had recurrent instability
      (success rate, 74%). Among 18 patients treated using both PDS and nonabsorbable
      polypropylene sutures, only one showed apprehension after a direct blow to the
      shoulder sustained by falling from a height (success rate, 94%). The mean
      stability score according to Rowe's criteria was significantly higher in the
      combination of absorbable and nonabsorbable group (P = .0412). External rotation
      increased more slowly in the combination of absorbable and nonabsorbable group
      than in the absorbable group. The mean limitation of external rotation was 8.4
      degrees and 2.7 degrees, respectively (P = .0129). The modified Caspari technique
      using both absorbable and nonabsorbable sutures achieved excellent stability
      according to Rowe's criteria and external rotation showed more gradual
      improvement compared to repair with absorbable sutures alone.

PMID- 10355717
TI  - Glenohumeral motion after complete capsular release.
AB  - The range of glenohumeral motion is primarily limited by the joint capsule. If
      the capsule is contracted, greater restriction in glenohumeral motion is
      exhibited. Release of a tight capsule has been an effective means of managing
      refractory stiffness of the glenohumeral joint. The effect of a complete capsular
      release on glenohumeral kinematics has not been previously studied in a cadaver
      model. Elevation, rotation, and translation of eight cadaveric glenohumeral
      preparations were studied before and after complete capsular release. As the
      intact joint was positioned near the limits of motion, glenohumeral torque rose
      rapidly with relatively small concomitant increases in elevation and rotational
      angles. Notable torque, due to tension in the capsule or cuff, ensued only after
      glenohumeral elevation reached approximately 80% of maximal range. After complete
      capsular release, maximal elevation increased on average 15%, yet retained
      definitive endpoints due to residual tension in the rotator cuff. Axial humeral
      rotation with an intact capsule decreased as maximum elevation approached,
      especially at elevation angles greater than 60 degrees. Maximum internal rotation
      was less than external, for all planes except +90 degrees. After complete
      capsular release, the greatest net gains for external rotation tended to be in
      the posterior scapular planes, whereas gains for internal rotation tended to be
      in the anterior scapular planes. Maximal translation in an intact vented capsule
      was 21 mm, 14 mm, and 15 mm in the anterior, posterior, and inferior directions,
      respectively. After complete capsular release, translation increased in all
      positions with maximal anterior, posterior, and inferior translations of 28 mm,
      25 mm, and 28 mm, respectively. In general, relative gains in translation were
      greater in planes posterior to the scapula and at extremes of the range of
      motion. Although large glenohumeral translations were measured, no preparation
      could be dislocated before or after complete capsular release. Complete capsular
      release significantly increased glenohumeral range of motion and translation. The
      intact rotator cuff myotendinous units serves to limit the range of motion and
      translation after all capsuloligamentous attachments are rendered incompetent by
      complete capsular release.

PMID- 10355718
TI  - Endoscopic release of the carpal ligament for carpal tunnel syndrome: long-term
      results using the Chow technique.
AB  - This report presents the author's experience with the Chow method for endoscopic
      release of the carpal ligament for carpal tunnel syndrome, with a minimum follow
      up of 5 years. The report includes 116 cases (wrists) of 84 patients. The success
      rate for these cases is 93.3% and the recurrence rate is 0.96%. One temporary
      ulnar neuropraxia was reported in this group with spontaneous recovery. There
      were no permanent nerve injuries. Results of 5-year follow-up nerve conduction
      velocity tests are also included. This report shows that endoscopic release of
      the carpal ligament for carpal tunnel syndrome, using the Chow method, is a
      reliable alternative to the open procedure and has produced good, long-term,
      results.

PMID- 10355719
TI  - The ligament augmentation device: an historical perspective.
AB  - Anterior cruciate ligament (ACL) injury is the most common ligament injury in the
      knee, and a significant number of patients may develop progressive instability
      and disability despite aggressive rehabilitation. Various materials have been
      used for its reconstruction. These include autografts, allografts, prosthetic
      ligaments, and synthetic augmentation of the biological tissue. The concept of
      ligament augmentation device (LAD) arose from the observation that biological
      grafts undergo a phase of degeneration and loss of strength before being
      incorporated. The LAD is meant to protect the biological graft during this
      vulnerable phase. However, it provokes an inflammatory reaction in the knee, and
      has been found to delay maturation of autogenous graft in humans. In experimental
      situations, the LAD has been found to share loads in a composite graft. It has
      also been found to be substantially stronger than the biological graft. However,
      in clinical situations no significant advantages have been observed with the use
      of LAD to augment patellar tendon or hamstring reconstruction of the chronic ACL
      deficient knee or in the acute setting to augment repair of the torn ACL. There
      are very few reports of the use of LAD in reconstruction of the posterior
      cruciate ligament, and again these do not suggest any advantage in its use.
      Insertion of the LAD implies the introduction of a foreign material into the
      knee, has been associated with complications such as reactive synovitis and
      effusions, and may also be associated with an increased risk of infection. At
      present, there is no evidence that its routine use should be advocated in
      uncomplicated reconstructions of the ACL using biological grafts.

PMID- 10355720
TI  - A novel surgical procedure for osteonecrosis of the humeral head: reposition of
      the joint surface and bone engraftment.
AB  - A novel surgical procedure was performed on a 33-year-old woman with idiopathic
      osteonecrosis of the head of the left humerus. The operation involved
      repositioning of the joint cartilage and bone engraftment through her humeral
      head from under the greater tuberosity with shoulder arthroscopy. The patient
      wore an abduction brace for 8 weeks after the operation to hold the joint surface
      in its new position. This surgical procedure resulted in considerable improvement
      of the functional status of the shoulder by relieving pain and increasing range
      of-motion. A preoperative radiograph showed stage IV osteonecrosis of the humeral
      head. However, at follow-up, repositioning of the joint surface and improvement
      of the necrotic bone were observed by radiography and magnetic resonance imaging.

PMID- 10355721
TI  - Chronic compartment syndrome of the lower leg: a new diagnostic method using near
      infrared spectroscopy and a new technique of endoscopic fasciotomy.
AB  - A 19-year-old female basketball player had chronic compartment syndrome. During
      basketball playing, she complained of bilateral lower leg pain that disappeared
      after several minutes of rest. The intracompartmental pressure in the anterior
      compartment was 41 mm Hg on the right side and 29 mm Hg on the left side
      immediately after playing. Prolonged ischemia of the anterior compartment was
      observed in comparison with four normal controls using near-infrared
      spectroscopy. Magnetic resonance imaging also revealed that the anterior
      compartment was mainly affected. Endoscopic fasciotomy was performed using an
      arthroscope, a transparent outer tube, and a retrograde blade. After the
      operation, her symptoms disappeared. Three months postoperatively, the anterior
      compartment pressure decreased and prolonged tissue ischemia improved. Endoscopic
      fasciotomy allowed us to cut the fascia safely and less invasively. We concluded
      that this technique is useful in treating chronic compartment syndrome in the
      anterior compartment of the lower leg.

PMID- 10355722
TI  - How to switch posts without rethreading when tying half-hitches.
AB  - Arthroscopically tied stacked half-hitch knots and sliding knots are best locked
      with half-hitches on alternating posts. It is possible to switch posts without
      rethreading the suture through the knot tier by flipping the half-hitch. This
      article describes extra- and intra-articular techniques for flipping half-hitches
      to switch posts. The post switching is most easily accomplished by transforming
      the half-hitch to an intermediate flat knot with symmetrical throws. This
      intermediate step is imperceptible when the sequence of actions is rapid. An over
      under half-hitch becomes an under-over half-hitch when the post is switched.

PMID- 10355723
TI  - The giant knot: a new one-way self-locking secured arthroscopic slip knot.
AB  - A secure slip knot is very important in the field of arthroscopy. The new giant
      knot, developed by the first author, has the properties of being a one-way self
      locking slip knot, which is secured without additional half hitches and can
      tolerate higher forces to be untied.

PMID- 10355724
TI  - A new, all-inside technique for meniscus repair.
AB  - A new method for arthroscopic meniscal repair using sutures with multiple knots
      was developed, and its mechanical strength was evaluated. Sutures are passed
      arthroscopically through the torn meniscus using a needle with a cleft in its
      tip, and when the needle is withdrawn, knots are placed both in the meniscus and
      the joint capsule. Our method does not require additional skin incisions and can
      be performed for repair of posterior tears. Furthermore, this all-inside
      technique minimizes the risk of popliteal neurovascular injury. Biomechanical
      analysis using bovine menisci showed that the maximum frictional force between
      the suture and meniscus was greater than the maximum strength of a suture itself.
      Our method is simple and rapid, making it easy to insert multiple sutures to
      achieve adequate stability.

PMID- 10355725
TI  - A posteromedial working portal for arthroscopic subacromial decompression and
      acromioclavicular joint arthroplasty.
AB  - Arthroscopic subacromial decompression is traditionally performed through a
      posterolateral viewing portal and a lateral working portal. We describe the same
      procedure by using a posterolateral viewing portal and a posteromedial working
      portal. Because this portal is in the same sagittal plane as the ipsilateral
      acromioclavicular joint, it allows performing an arthroscopic excision
      arthroplasty of this joint.

PMID- 10355726
TI  - Trans-section of a peroneal nerve as a complication of routine knee arthroscopy.

PMID- 10355727
TI  - Xenogeneic islet transplantation.

PMID- 10355728
TI  - Comparative analysis of three genetic modifications designed to inhibit human
      serum-mediated cytolysis.
AB  - Hyperacute rejection (HAR) remains a critical immunologic hurdle in the
      development of xenogeneic organs for human transplantation. Strategies that
      simultaneously eliminate both natural antibody reactivity and complement
      activation on the xenogeneic cell surface may be the best approach to achieve
      clinical application of xenogeneic vascularized organ transplantation. We have
      developed multiple lines of genetically manipulated mice to evaluate the
      combination of different genetic approaches aimed at inhibiting antibody and
      complement-mediated cell lysis. We utilized transgenic mice expressing the human
      complement inhibitor, CD59, the human 1,2-fucosyltransferase (H-transferase, HT)
      and the alpha1,3-galactosyltransferase (alpha1,3-GT) knock-out mouse line (Gal
      KO). Our data show that expression of hCD59 in combination with HT expression or
      the null phenotype of alpha1,3-GT are equally effective at preventing human serum
      mediated cytolysis. Interestingly, the triple combination affords no additional
      protective effect. Therefore, coexpression of HT and a complement inhibitor is
      the most immediate strategy to genetically engineer transgenic pigs to be used as
      xenogeneic donors.

PMID- 10355729
TI  - Effect of pig-specific cytokines on mobilization of hematopoietic progenitor
      cells in pigs and on pig bone marrow engraftment in baboons.
AB  - Mixed hematopoietic chimerism has been found to be a requirement for achieving
      specific immunologic hyporesponsiveness. Some of the requirements for in vitro
      and in vivo coexistence of discordant hematopoietic systems in the pig-to-baboon
      (or human) model have been investigated. We have tested the efficacy of pig
      specific cytokines (PSC) (IL3, SCF, GM-CSF) in the mobilization of porcine bone
      marrow (BM) progenitors in vivo (i) in the pig and (ii) in baboons that underwent
      a conditioning regimen and porcine BM transplantation. In a preliminary in vitro
      study, porcine BM cells were incubated in various media to assess the effect of
      human plasma on pig progenitors in a colony-forming unit (CFU) assay. In in vivo
      studies, four pigs received PSC and one control pig did not. Six baboons
      underwent natural antibody removal, with subsequent pig BM transplantation. Four
      of these six underwent nonmyeloablative (n=2) or myeloablative (n=2) conditioning
      and all received PSC treatment. Two baboons did not receive PSC, one of which
      underwent a nonmyeloablative regimen. Sequential blood samples and BM biopsies in
      pigs and baboons were analyzed by CFU assay for the detection of porcine cells.
      Baboon samples were analyzed by polymerase chain reaction (PCR) to detect porcine
      DNA. In the case of the in vitro tests, colony forming by porcine progenitors was
      not inhibited by media containing human plasma and for the in vivo tests, PSC
      increased the number of progenitors in pig BM; mobilization of progenitors into
      the peripheral blood was observed. PSC-treated baboons which experienced
      transient depletion of leukocytes < 1,000/ml (as an effect of the conditioning
      regimen) had porcine BM cells detectable by PCR for as long as day 316 after BM
      transplantation. In conclusion we found that: (i) under the conditions of these
      studies, in vitro porcine progenitor cell growth was not inhibited by human
      plasma containing natural antibody and complement; (ii) PSC treatment led to an
      increased number of progenitors in pig BM and peripheral blood; (iii) the
      combination of an effective conditioning regimen and treatment with PSC was
      capable of inducing long-term survival of pig progenitors in baboons, although
      only a low level of engraftment was achieved.

PMID- 10355730
TI  - Rat-to-mouse small bowel xenotransplantation: a novel model for studying acute
      vascular and hyperacute xenograft rejection and xenogenic cell migration.
AB  - The present study was undertaken to establish a rat-to-mouse vascularized small
      bowel xenotransplantation model to study acute vascular and hyperacute xenograft
      rejection, and xenogenic cell migration. Lewis rat small bowel grafts were
      transplanted heterotopically to group 1, Balb/c mice, and group 2, Balb/c mice
      pre-sensitized with a donor spleen cell injection. The grafts were examined by
      serial pathology and flow cytometry. In group 1, acute vascular rejection was
      present by the 5th post-operative day (POD). Immunohistology showed a strong
      endothelial deposition of IgG, IgM and C3, associated with a minimal lymphocytic
      infiltrate. There was a vigorous cell migration from the recipient to the graft,
      in which recipient origin cells comprised 80.1+/-6.9% of the graft mesenteric
      lymph node by POD 3. However, there was almost no cell migration from the graft
      to the recipient. The intestinal xenografts in the group 2 showed massive
      hemorrhage, fibrin deposition, vascular congestion and thrombosis 60 min after
      transplantation. IgG and C3 were present on the endothelium as early as 1 min
      after reperfusion. The vigorous humorally-mediated vascular damage and rapid
      elimination of donor cells seen with intestinal xenograft rejection are distinct
      from the usual picture of allograft rejection. Hyperacute rejection can be
      induced by recipient pre-sensitization with donor spleen cells. The potential
      advantages of studying xenotransplantation in this model include: (1) the wide
      range of immunologic reagents available for mice; (2) the opportunity to study
      the progression of vascular damage easily by performing serial biopsies in the
      same animal; and (3) the opportunity to study, in vivo, two-way cellular response
      by examining cell trafficking in the mesenteric lymph nodes.

PMID- 10355731
TI  - Intravenous synthetic alphaGal saccharides delay hyperacute rejection following
      pig-to-baboon heart transplantation.
AB  - Several oligosaccharides containing the terminal structure Gal(alpha)1-3Gal
      (alphaGal) and different side chains were tested in vitro for their ability to
      block natural anti(alpha)Gal antibodies. A di-and a trisaccharide (di(alpha)Gal
      and tri(alpha)Gal) were selected. A blood group B baboon, having IgG and IgM
      natural antipig titers of 1:256 and 1:1024 and a hemolytic titer (to pig red
      blood cells, RBCs) of 1:8, was chosen to measure pharmacokinetic parameters of
      the saccharides and to assess the extent of in vivo neutralization of the
      antibodies. Three grams each of the di(alpha)Gal and the tri(alpha)Gal dissolved
      in saline were administered by bolus intravenous (i.v.) injection. Blood samples
      were collected at various times and urine was collected at 8 and 24 h. Plasma and
      urine concentrations of the alphaGal saccharides were estimated by an ELISA
      specially developed for this study. A fast distribution phase followed by
      equilibrium and excretion phases were observed, indicating a T1/2 in the order of
      1 h. Fifty-eight per cent of the saccharides were recovered in the urine within
      24 h. Determination of antipig antibody binding by FACS analysis and of serum
      cytotoxicity titers for pig endothelial cells demonstrated that a 70% reduction
      in binding and cytotoxicity could be achieved with plasma saccharide levels of
      300-400 microg/ml. Six months later, a pig heart was transplanted heterotopically
      into the baboon. A 3-g bolus of the saccharide mixture (1.5 g of each saccharide)
      was given i.v. before allowing blood reperfusion of the transplanted heart,
      followed by an i.v. infusion of 1 g/hr for 1 hr and 0.5 g/hr for the 3 succeeding
      hours. Blood concentrations of the saccharides, CH50, hematology and cytotoxicity
      for PK15 cells were estimated in blood samples taken at various times. Heart
      function was observed to be satisfactory for 8 h, but was found to have ceased at
      18 h. Myocardial biopsies taken at 3 and 5 h showed congestion only, suggestive
      of minimal vascular rejection, but by 18 h demonstrated severe vascular
      rejection. In conclusion, alphaGal saccharide therapy given for a period of 4 h
      delayed, but did not totally prevent, the development of vascular rejection in
      the pig-to-baboon heart transplant model. alphaGal saccharide therapy may be one
      of several useful approaches for the prevention of hyperacute rejection in pig-to
      primate organ transplantation.

PMID- 10355732
TI  - Lack of variation in alphaGal expression on lymphocytes in miniature swine of
      different genotypes.
AB  - BACKGROUND: Gal(alpha)1-3Gal epitopes (alphaGal) have been demonstrated to be
      present on tissues of all pig breeds tested to-date and are the major target for
      human anti-(alpha)galactosyl (alphaGal) antibodies. We investigated members of an
      MHC-inbred miniature swine herd to assess whether there was an association
      between genotype and expression of alphaGal. Identification of a low expressor
      genotype would potentially enable selective breeding of pigs that might prove
      beneficial as donors in clinical xenotransplantation. METHODS: we measured
      alphaGal expression on various pig cells by use of fluorescent-activated cell
      sorter (FACS) using (i) purified human anti-alphaGal antibody and (ii) the
      isolectin GS-I-B4. Initial studies were on porcine peripheral blood mononuclear
      cells (PBMCs) and subsequent studies on lymphocytes, platelets, and T cell
      subsets (CD4+ and CD8+ cells). RESULTS: there was considerable day-to-day
      variation in alphaGal expression on PBMCs from the same pig. When only
      lymphocytes were examined, there was a high degree of reproducibility, and no
      significant difference in alphaGal expression was detected between representative
      pairs of animlas of three different genotypes. Purified anti-alphaGal antibody
      bound to different sites on the alphaGal epitope than did Griffonia (Bandeiraea)
      simplicifolia I-B4 (GS-I-B4). Lectin binding was significantly reduced in the
      absence of divalent cations. When CD4+ and CD8+ T cells were examined for
      alphaGal expression, two distinct populations of each type of cell were observed,
      with larger cells expressing a higher level of alphaGal. CONCLUSIONS: although
      the number of pigs of different genotypes studied was small, on the basis of this
      limited study, pigs of a low alphaGal expressor genotype that could be
      selectively bred for use in clinical xenotransplantation were not identified.

PMID- 10355734
TI  - Literature update 1998, part 3.

PMID- 10355733
TI  - Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused pig
      xenografts.
AB  - Compstatin, a newly described C3-binding peptide, inhibits complement activation
      by blocking C3 convertase-mediated cleavage of C3. As the complement activation
      is an essential part of the rejection reaction, we evaluated the ability of
      Compstatin to delay or prevent hyperacute rejection in an ex vivo xenograft
      model. Pig kidneys were perfused with fresh human blood containing either
      Compstatin (n=6) or a control agent (n=6). Graft survival and activation of
      complement, leukocytes and platelets both in the fluid-phase and in the tissue
      were examined. The survival of the Compstatin-perfused kidneys (median, 380 min)
      was significantly (P=0.0036) longer than that of the controls (median, 90 min).
      The classical complement pathway (C1rs-C1inhibitor and C4bc) was significantly
      and equally activated in both groups during the first 60 min. C3 activation
      products increased fivefold and terminal complement complex eightfold in the
      control group, but no increase occurred in the Compstatin group during this
      period. Immunohistochemistry showed less C3 and fibrin deposition and immune
      electron microscopy showed less terminal SC5b-9 complement complex deposition in
      the Compstatin group. A significant change in total white cells, neutrophils,
      myeloperoxidase, and expression of the surface activation markers CD11b (CR3) and
      CD35 (CR1) and CD62L (L-selectin) was observed in both groups. Leukocyte
      activation was lower in the Compstatin group but the difference was not
      statistically significant. There were no differences in platelet counts,
      thrombospondin, soluble P-selectin or beta-thromboglobulin between the groups. We
      conclude that Compstatin prolongs graft survival and suggest that it may be a
      useful agent for attenuating hyperacute rejection by inhibiting C3 and thus
      terminal complement pathway activation.

PMID- 10355735
TI  - Sample size calculations when outcomes will be compared with an historical
      control.
AB  - The usual formulae for calculating sample size are not valid when a treated
      cohort will be compared with an historical control population. Methods
      appropriate for a single group study may greatly underestimate the required
      sample size because they, in effect, assume a control population of infinite
      size. Methods appropriate for a two-group study require specification of the
      proportions of patients in the two groups--a requirement that can not be met when
      the size of the historical control group is fixed. An easily programmed iterative
      solution is presented and simulations indicating the validity of the method are
      performed.

PMID- 10355736
TI  - Evaluation of linear diaphragm-chest expansion models for magnetic resonance
      imaging motion artifact correction.
AB  - The efficacy of Fourier analysis, autoregressive with exogenous input (ARX) and
      adaptive models to estimate diaphragm position from respiratory belt signal (a
      measure of chest expansion) was evaluated for the purpose of correcting
      respiratory motion artifacts in magnetic resonance imaging (MRI). Respiratory
      belt signal and diaphragm position data were obtained simultaneously during one
      dimensional MRI scans with sampling intervals of 100 ms for 128 s (1280 samples).
      The models were trained using the first 512 data samples for the Fourier method
      and the first 640 samples for the ARX and adaptive methods. The remaining samples
      were used as a test set for evaluating the models. Both ARX and adaptive methods
      produced more accurate results than the Fourier method as reflected by the
      normalized mean square error (NMSE) and correlation coefficient (R) between the
      estimated and actual diaphragm position during normal breathing (P < 0.05).
      However, all three models had difficulty modeling diaphragm positions during
      breathing plateaus.

PMID- 10355737
TI  - Gain optimized cosine transform domain LMS algorithm for adaptive filtering of
      EEG.
AB  - The most common adaptive filtering method is based on the least mean square (LMS)
      algorithm, which updates the filter coefficients by a gradient based method. The
      convergence properties of the LMS algorithm can be improved by updating the
      filter coefficients in the frequency domain. This work presents a new LMS
      algorithm, which updates the filter coefficients in the cosine transform domain.
      Instead of a constant gain factor in the coefficient updating the present method
      uses a time-varying optimized gain factor. This yields a considerably improved
      convergence performance. The algorithm was applied to the EEG activity analysis
      of freely behaving rats.

PMID- 10355738
TI  - An edge-sensitive noise reduction algorithm for image processing.
AB  - An edge-sensitive noise reduction algorithm for digital image processing is
      proposed. It is designed as C-DLL to run as a macro command under Image-Pro Plus.
      Its properties are compared to the median filter and a simple smoothing kernel.

PMID- 10355739
TI  - Automated morphometric analysis in peripheral neuropathies.
AB  - We describe a three-step algorithm for the morphometric analysis of color images
      of nerve specimens, currently used in the diagnosis of peripheral neuropathies.
      The algorithm first segments the images by applying a clustering method in the
      color space. It then identifies and eliminates irrelevant regions and, in the
      final step, calculates the diagnostic parameters required for clinical analysis.
      The results obtained on 25 images are reported and compared with corresponding
      measurements made by neurologists.

PMID- 10355740
TI  - Tumor-initiating activity of the (+)-(S,S)- and (-)-(R,R)- enantiomers of trans
      11,12-dihydroxy-11,12-dihydrodibenzo[a,l]pyrene in mouse skin.
AB  - A single administration of enantiomerically pure 11,12-dihydrodiols of
      dibenzo[a,l]pyrene (DB[a,l]P) on the back of NMRI mice and subsequent chronic
      treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) (initiation/promotion
      assay) revealed strikingly different carcinogenic activities of both enantiomers.
      Tumor-initiating activity of (-)-(11R,12R)-DB[a,l]P-dihydrodiol, which is the
      metabolic precursor of the (-)-anti-(11R,12S)-dihydrodiol (13S,14R)-epoxide, was
      exceptionally higher than the corresponding effect of (+)-(11S,12S)-DB[a,l]P
      dihydrodiol, the metabolic precursor of (+)-syn-(11S,12R)-dihydrodiol (13S,14R)
      epoxide. After topical application of 10 nmol (-)-11,12-dihydrodiol and promotion
      with TPA twice weekly for a further 18 weeks 93% of treated animals exhibited
      four to five tumors. In contrast, no neoplasms were observed after treatment with
      10 nmol (+)-11,12-dihydrodiol, whereas in the group exposed to 20 nmol of this
      enantiomer only 13% of mice developed neoplasms (0.1 tumors/survivor). For
      DB[a,l]P, considered as the most potent carcinogenic polycyclic aromatic
      hydrocarbon to date, stereoselective formation of (+)-syn- and (-)-anti-11,12
      dihydrodiol 13,14-epoxides via the corresponding enantiomeric 11,12-dihydrodiols
      has been found to be the principal metabolic activation pathway leading to DNA
      adducts and mutagenicity. Our study demonstrates that the striking difference in
      carcinogenic activity in mouse skin of (+)-(11S,12S)- and (-)-(11R,12R)-DB[a,l]P
      dihydrodiol convincingly reflects the different genotoxicity, i.e. DNA binding
      and mutagenicity, of both enantiomers observed earlier.

PMID- 10355741
TI  - Cytotoxic analogs of luteinizing hormone-releasing hormone bind with high
      affinity to human breast cancers.
AB  - Recently, we developed two new cytotoxic analogs of luteinizing hormone-releasing
      hormone (LH-RH), AN-152 in which doxorubicin (DOX) is linked to [D-Lys6]LH-RH,
      and AN-207 which consists of 2-pyrrolino-DOX coupled to [D-Lys6]LH-RH. In this
      study, we examined binding of AN-152 and AN-207 to membranes of human breast
      cancer specimens and MCF-7 and MDA-MB-231 human breast cancer lines. Both
      cytotoxic analogs displayed IC50 values in the nanomolar concentration range
      (IC50 = 2-13 nM). Using radioligand binding studies, we characterized the
      receptors for LH-RH on membranes of breast cancers. In addition, the expression
      of mRNA for LH-RH receptors in MCF-7 and MDA-MB-231 cell lines was demonstrated
      by reverse transcription-polymerase chain reaction (RT-PCR). These highly active
      cytotoxic analogs of LH-RH have been designed as targeted chemotherapeutic agents
      for the treatment of various cancers expressing receptors for LH-RH.

PMID- 10355742
TI  - DNA adduct formation by secondary metabolites of cyclopenta[cd]pyrene in vitro.
AB  - In this study, calf thymus DNA was reacted in vitro with cyclopenta[cd]pyrene 3,4
      epoxide (CPPE) or its metabolites, 3,4-dihydroCPP-3,4-diol (CPP-3,4-diol) and 4
      hydroxy-3,4-dihydroCPP (4-OH-DCPP), activated with sulfotransferase. The adducts
      formed were analyzed by HPLC with fluorescence detection following enzymatic
      digestion of DNA to deoxynucleosides. We have shown previously that the major
      CPPE-reacted DNA adducts are cis-3-(deoxyguanosin-N2-yl)-4-hydroxy-3,4
      dihydroCPP. Sulfotransferase activation of trans-CPP-3,4-diol yielded two adducts
      that were identical to the products resulting from the reaction of CPPE with DNA,
      while cis-CPP-3,4-diol gave very low covalent binding. Two adducts formed by
      sulfotransferase activation of 4-OH-DCPP were identical to the products of the
      reaction of synthetic 4-NaO3S-O-DCPP or sulfotransferase-activated 4-OH-DCPP with
      deoxyguanosine. These results indicate that guanine is the predominant site of
      CPP adduct formation in DNA, and that the 4-hydroxy-3-dGuo adducts can arise by
      reaction of DNA with either CPPE or sulfotransferase-activated trans-CPP-3,4
      diol.

PMID- 10355744
TI  - Low antibody responsiveness is found to be associated with resistance to chemical
      skin tumorigenesis in several lines of Biozzi mice.
AB  - High and low antibody responder lines of mice from Selections I, III and G were
      assayed for two-step skin tumorigenesis using a protocol consisting in initiation
      with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O
      tetradecanoylphorbol-13-acetate (TPA). Concordant results were obtained in the
      three selections: low antibody responder mice were shown to be significantly more
      resistant to tumor induction than the high responder counterparts. The difference
      was observed for all parameters: kinetics and percentages of tumor incidence and
      tumor multiplicity. The three bidirectional selective breeding experiments
      differed in several respects namely, the origin of the foundation populations,
      the antigens and immunization protocols used during the selection, as well as the
      breeding unit environments. Therefore, the consistent results relative to
      tumorigenesis strongly suggest that some of the alleles relevant to multispecific
      'low' antibody production could contribute to the resistance to cutaneous
      chemical tumorigenesis.

PMID- 10355743
TI  - Differential distribution of protein phosphatase 2A in human breast carcinoma
      cell lines and its relation to estrogen receptor status.
AB  - Protein phosphatase 2A (PP2A) acts as a growth suppressor and is negatively
      influenced by oncogenic signals. We determined its activity in various human
      breast carcinoma (HBC) cell types to understand its relationship to estrogen
      receptor (ER) expression as well as to the distribution of protein kinase C
      (PKC), an opposing enzyme. PP2A activity was measured using a preferred
      substrate, histone H1 phosphorylated by PKC. PP2A activity was higher in both the
      soluble and nuclear fractions of ER-positive cell lines (MCF-7, T47D and ZR-75-1)
      than in the ER-negative cell lines (MDA-MB-231, Hs578T and BT-20). PP2A multiple
      forms (2A0, 2A1, 2A2), separated by DEAE-cellulose chromatography and immunoblot
      analysis of PP2A catalytic subunit, also showed similar differences in these two
      HBC cell types. In all cases, PP2A distribution was inversely correlated with the
      PKC activity profile. Moreover, PP2A activity in MCF-7 cells maintained in
      estrogen-depleted medium was low. Nonetheless, it was induced by a prolonged
      treatment with 17beta-estradiol, this induction being blocked by the
      antiestrogens, tamoxifen and ICI-182,780. Studies in both MCF-7 transfectants
      stably overexpressing ras and MDA-MB-231 transfectants stably expressing ER,
      suggested that a low PP2A distribution in ER-negative HBC cell types may be
      related to tumor progression rather than the loss of ER. Conceivably, the
      presence of high PP2A along with low PKC in ER-positive HBC cell types may be
      related to the restricted cell growth associated with the retention of a certain
      degree of differentiation or hormonal control. Conversely, the presence of low
      PP2A along with high PKC in ER-negative cell types may be related to hormone
      independent enhanced cell growth.

PMID- 10355745
TI  - Inhibition of focus formation of transformed cloned cells by contact with non
      transformed BALB/c 3T3 A31-1-1 cells.
AB  - When transformed cells were co-cultured with various densities of non-transformed
      BALB/c 3T3 A31-1-1 cells, the number of transformed cell foci decreased as the
      density of the A31-1-1 cells was increased. Under the condition of separate co
      cultivation in which transformed cloned cells could not make contact with A31-1-1
      cells, no inhibitory effect was induced. We examined with a dye-transfer assay
      the formation of heterologous gap-junctional intercellular communication (GJIC),
      links between the transformed cells and A31-1-1 cells before and after focus
      formation. Heterologous GJIC was observed almost always before, but almost never
      after, focus formation. Using time-lapse photography to record the fate of
      transformed cloned cells that did not form foci in the co-cultivation, it was
      noted that most of them were living, but did not proliferate. These results
      suggested that focus formation of transformed cloned cells was inhibited by
      contact with non-transformed A31-1-1 cells.

PMID- 10355746
TI  - Involvement of NO, H2O2 and TNF-alpha in the reduced antitumor activity of murine
      peritoneal macrophages by aflatoxin B1.
AB  - Aflatoxin B, (AFB1), a potent hepatocarcinogen, has been known to impair non
      specific and specific immune responses. Nitric oxide (NO), hydrogen peroxide
      (H2O2), superoxide anion (O2-) and tumor necrosis factor-alpha (TNF-alpha)
      produced by macrophages play an important role in host defense against tumors and
      microorganisms. In the present studies, we investigated the involvement of those
      products in the reduced antitumor activities by AFB1. When macrophages are
      stimulated with LPS after AFB1-pretreatment, the cytolytic activities decrease in
      a dose-dependent manner. The addition of N(G)-monomethyl arginine (NMMA), anti
      TNF-alpha antibodies, catalase and peroxidase decreases antitumor activities
      further. In contrast, superoxide dismutase (SOD) does not change the antitumor
      activities. NO and TNF-alpha production was reduced by the addition of NMMA and
      anti-TNF-alpha antibodies, respectively. Taken together, these data indicate that
      the reduced antitumor activities in murine peritoneal macrophages are mediated by
      the suppressed production of NO, TNF-alpha and H2O2 by AFB1 pretreatment,
      suggesting that the inhibitory effect of AFB1 on those materials may provide the
      tumors with readily growing condition in vivo.

PMID- 10355747
TI  - Effects of bombesin on methadone-induced apoptosis of human lung cancer cells.
AB  - The therapeutic opioid methadone, used to treat cancer pain and opioid addiction,
      is also a potent inducer of apoptosis in human lung cancer cells, thereby
      inhibiting their growth. However, in contrast to its central nervous system (CNS)
      actions, this effect appears to be mediated through a non-opioid mechanism
      involving bombesin, an autocrine growth-stimulatory factor that plays a central
      role in the early events of pulmonary carcinogenesis. Exposure of 'variant' small
      cell lung carcinoma (SCLC) and non-SCLC cells, which secrete low concentrations
      (< 0.01 pmol/mg protein) of bombesin, to nanomolar concentrations of methadone
      resulted in increased levels of mitogen-activated protein (MAP) kinase
      phosphatases and inactivation of MAP kinase, suppression of the bcl-2 protein,
      and induction of apoptosis. These effects of methadone were reversed by the
      addition of bombesin to the culture medium, at concentrations of < 1 microM, and
      'classic' SCLC cells, which secrete high concentrations of bioactive bombesin (>
      6 pmol/mg protein), were found not to respond to methadone. Thus, methadone's
      effectiveness is dependent upon the concentration of bioactive bombesin secreted
      by lung cancer cells. Methadone treatment suggests a novel therapeutic approach
      for patients presenting 'variant' SCLC and non-SCLC morphologies, since they
      respond less to conventional therapy.

PMID- 10355748
TI  - Identification and characterization of the putative retinoblastoma control
      element of the rat insulin-like growth factor binding protein-2 gene.
AB  - The authors previously identified a silencer of the rat IGFBP-2 gene. Sequence
      examination of the silencer has revealed that it contains the target sequence for
      the pRb (retinoblastoma) tumour suppressor gene, referred to as the
      retinoblastoma control element (RCE) which is frequently found in the regulatory
      element of cellular oncogenes and growth factors. The presence of RCE suggests
      that the IGFBP-2 gene may be regulated by the pRb tumour suppressor gene. An in
      vitro gel retardation assay has shown that the putative RCEs from the IGFBP-2
      gene are complexed with multiple nuclear factors from the rat liver BRL-3A cells.
      These DNA-protein complexes were not detected with the nuclear extracts from the
      cells that were growth arrested at the G1/S border of the cell cycle by high cell
      density. Using specific antibodies, Sp1 was shown to be one of the components for
      the multiple DNA-protein complex while pRb does not appear to be directly
      involved in the formation of the complex.

PMID- 10355749
TI  - The inhibitory effect of genistein on the growth and metastasis of a
      transplantable rat accessory sex gland carcinoma.
AB  - BACKGROUND: A cell line (K1) derived from a carcinogen-induced accessory sex
      gland carcinoma was used to examine the effects of the soybean extract,
      genistein, on tumor growth and metastasis. METHODS: Male Lobund-Wistar rats were
      injected s.c. with 20 million K1 cells; genistein (50 mg/kg BW) or the vehicle
      was administered s.c. every 12 h for 31 days. RESULTS: Genistein significantly
      inhibited tumor growth. Compared with controls, fewer genistein-treated rats
      developed invasive tumors (11% vs. 44%) or lymph node metastases (44% vs. 89%).
      No lung metastases were found in genistein-treated animals in contrast to
      controls (0% vs. 44%). Estrogenic side effects were precipitated in genistein
      treated rats, including decreased accessory sex gland complex weight, increased
      pituitary weight, decreased testis weight, and decreased (BW). Serum testosterone
      was undetectable and serum prostate-specific acid phosphatase activity was 38%
      lower in genistein-treated rats compared with controls. Genistein concentrations
      in the solid tumors (2 nmol/g) were one-third those in blood. CONCLUSIONS: These
      data suggest that genistein may be a useful chemotherapeutic agent to inhibit the
      growth and metastasis of accessory sex gland cancers, such as those derived from
      the prostate.

PMID- 10355750
TI  - Inhibition of vascular endothelial growth factor induced mitogenesis of human
      endothelial cells by a chimeric anti-kinase insert domain-containing receptor
      antibody.
AB  - The kinase insert domain-containing receptor (KDR) is the human vascular
      endothelial growth factor (VEGF) receptor responsible for the mitogenic and
      angiogenic effects of VEGF. There is much experimental evidence to suggest that
      the VEGF/KDR pathway plays an important role in tumor angiogenesis, a process
      essential for tumor growth and metastasis. Here we produced a chimeric anti-KDR
      antibody (IgG1), c-p1C11, from a single chain (scFv) antibody isolated from a
      phage display library. C-p1C11 binds specifically to the extracellular domain of
      soluble as well as cell-surface expressed KDR. It effectively blocks VEGF-KDR
      interaction and inhibits VEGF-stimulated activation of KDR and MAP kinases
      p44/p42 of human endothelial cells. Furthermore, c-p1C11 efficiently neutralizes
      VEGF-induced mitogenesis of human endothelial cells. Our results suggest that
      antibodies against KDR have potential clinical applications in the treatment of
      cancer and other diseases where pathological angiogenesis is involved.

PMID- 10355752
TI  - Cytofluorometric DNA ploidy analysis in giant cell tumor of bone: histologic and
      prognostic value.
AB  - DNA ploidy analysis by DNA cytofluorometry was performed on 41 tumors obtained
      from 37 patients with primary giant cell tumor of bone (GCT). Histologically, 26
      of the tumors from primary or recurrent lesions were evaluated as grade I, and 13
      tumors as grade II. Among the 33 primary GCT patients, 4 patients had local
      recurrence or pulmonary metastasis. The DNA ploidy pattern and the percentage of
      hyperdiploid cells showing a greater DNA content than diploid cells, were
      obtained from DNA cytofluorometry. All of the 33 primary tumors were diploid. Of
      6 recurrent tumors, 4 were diploid and 2 were euploid-polyploid. One of the two
      pulmonary metastatic tumors was diploid, but another that demonstrated a
      malignant transformation to malignant fibrous histiocytoma was aneuploid. The
      percentage of hyperdiploid cells was significantly different between primary and
      recurrent tumors (P = 0.0188) and between grade I and grade II tumors (P =
      0.0052), while there was no difference between primary tumors in the cases that
      recurred or metastasized and those that did not. Thus, these data indicate that
      cell proliferative activity is closely correlated with biological aggressiveness
      and histological grading, although DNA ploidy is not useful for predicting
      prognosis.

PMID- 10355751
TI  - p53/p21(WAF1/CIP1) expression and its possible role in G1 arrest and apoptosis in
      ellagic acid treated cancer cells.
AB  - Ellagic acid is a phenolic compound present in fruits and nuts including
      raspberries, strawberries and walnuts. It is known to inhibit certain carcinogen
      induced cancers and may have other chemopreventive properties. The effects of
      ellagic acid on cell cycle events and apoptosis were studied in cervical
      carcinoma (CaSki) cells. We found that ellagic acid at a concentration of 10(-5)
      M induced G arrest within 48 h, inhibited overall cell growth and induced
      apoptosis in CaSki cells after 72 h of treatment. Activation of the cdk
      inhibitory protein p21 by ellagic acid suggests a role for ellagic acid in cell
      cycle regulation of cancer cells.

PMID- 10355753
TI  - Methylation of p16INK4A in primary gynecologic malignancy.
AB  - The p16INK4A gene mapped on band p21 of chromosome 9 can be inactivated via
      multiple mechanisms including homozygous deletion, point mutation and promoter
      hypermethylation in various human tumors. A polymerase chain reaction (PCR) based
      analysis was performed to examine methylation of the p16INK4A gene promoter in
      196 primary gynecologic malignancies including 98 cervical, 49 endometrial and 49
      ovarian carcinomas. Methylation of p16INK4A was detected in 31% of cervical, 20%
      of endometrial, and 4% of ovarian carcinomas, respectively. The incidence of
      p16INK4A methylation in patients with cervical and endometrial carcinomas at
      advanced stages (stages III-IV) was statistically higher than those at early
      stages (stages I-II). There were also significant differences in the incidence of
      p16INK4A methylation in both cancers between the patients who had died of their
      disease or were alive with evidence of disease, and those without evidence of
      disease. The results indicate that methylation of the p16INK4A gene is present in
      a proportion of primary gynecologic malignancies and this alteration may be
      associated with poor outcome in cervical and endometrial carcinomas.

PMID- 10355754
TI  - Alfalfa mosaic virus and ilarviruses: involvement of coat protein in multiple
      steps of the replication cycle.

PMID- 10355755
TI  - Subcellular localization and in vivo identification of the putative movement
      protein of olive latent virus 2.
AB  - The gene encoding the 36.5 kDa ('36K') nonstructural protein located on RNA3 of
      olive latent virus 2 (OLV-2) was cloned, expressed with the Escherichia coli pGEX
      2T system and the purified protein used to raise a polyclonal antiserum.
      Immunoblot analysis of OLV-2-infected Nicotiana benthamiana plants showed that
      the 36K protein accumulated in the early stages of infection and was associated
      with a subcellular fraction enriched in cytoplasmic membranes. In infected cells
      there were tubular structures, some containing virus-like particles, scattered in
      the cytoplasm or protruding from or penetrating the cell wall at the
      plasmodesmata. Immunogold labelling localized the 36K protein in the
      plasmodesmata of OLV-2-infected cells and showed it to be associated with virus
      containing tubules. Leaf trichome cells of N. tabacum plants, transformed with a
      36K-green fluorescent protein (GFP) fusion construct, revealed localized
      fluorescence in the cell walls, possibly due to association of the fusion protein
      with plasmodesmata. When the same 36K-GFP fusion protein was expressed in N.
      tabacum protoplasts, long tubular fluorescent structures protruded from the
      protoplast surface, suggesting that the 36K protein is responsible for tubule
      induction. The conclusion is drawn that this protein is likely to be the OLV-2
      movement protein, mediating cell-to-cell virus movement, and that movement is by
      a tubule-guided mechanism.

PMID- 10355756
TI  - Lettuce infectious yellows virus: in vitro acquisition analysis using partially
      purified virions and the whitefly Bemisia tabaci.
AB  - Virions of lettuce infectious yellows virus (LIYV; genus Crinivirus) were
      purified from LIYV-infected plants and their protein composition was analysed by
      SDS-PAGE and immunoblotting. Virion preparations contained the major capsid
      protein (CP), but the minor capsid protein (CPm), p59 and the HSP70 homologue
      were also identified by immunoblot analysis. Immunogold labelling analysis showed
      that CP constituted the majority of the LIYV virion capsid, but CPm was also part
      of the capsid and localized to one end of the virion, similar to the polar
      morphology seen for viruses in the genus Closterovirus. p59 and the HSP70
      homologue were not detected on virions by immunogold labelling, but were always
      detected in virion preparations by immunoblot analysis. Purified LIYV virions
      were used for in vitro acquisition analysis with Bemisia tabaci whiteflies and
      were efficiently transmitted to plants. Infectivity neutralization analyses were
      done using antisera to the LIYV-encoded CP, CPm, p59 and HSP70 homologue. Only
      antiserum to the CPm effectively neutralized LIYV transmission by B. tabaci.
      These data suggest that the LIYV-B. tabaci transmission determinants are
      associated with purified virions, and that the LIYV virion structural protein CPm
      is involved in transmission by B. tobaci.

PMID- 10355757
TI  - Identification of the RNA-binding sites of the triple gene block protein 1 of
      bamboo mosaic potexvirus.
AB  - The triple gene block protein 1 (TGBp1) encoded by open reading frame 2 of bamboo
      mosaic potexvirus (BaMV) was overexpressed in Escherichia coli and purified in
      order to test its RNA-binding activity. UV crosslinking assays revealed that the
      RNA-binding activity was present mainly in the soluble fraction of the refolded
      TGBp1. The binding activity was nonspecific and salt concentration-dependent:
      activity was present at 0-50 mM NaCl but was almost abolished at 200 mM. The RNA
      binding domain was located by deletion mutagenesis to the N-terminal 3-24 amino
      acids of TGBp1. Sequence alignment analysis of the N-terminal 25 amino acids of
      the TGBp1 homologues of potexviruses identified three arginine residues. Arg-to
      Ala substitution at any one of the three arginines eliminated most of the RNA
      binding activity, indicating that they were all critical to the RNA-binding
      activity of the TGBp1 of BaMV.

PMID- 10355758
TI  - Self-association and mapping of interaction domains of helper component
      proteinase of potato A potyvirus.
AB  - Potyviral helper component-proteinase (HC-Pro) is a multifunctional protein
      involved in aphid transmission, long-distance movement, polyprotein processing,
      genome amplification and symptom expression. It has been proposed that the active
      form of HC-Pro is a dimer and that coat protein (CP)-HC-Pro interaction is
      required for aphid transmission. To test these proposed interactions between CP
      and HC-Pro of potato A potyvirus (PVA), the yeast two-hybrid system was used. HC
      Pro was shown to interact with itself in vivo in yeast cells, as did CP. Taken
      together with previous observations, we conclude that the functional HC-Pro is a
      homodimer. Deletion analysis showed that a 24 aa domain in the N-terminal half
      and the C-terminal proteinase part of HC-Pro were required for the interaction
      between HC-Pro molecules. No interactions were found between HC-Pro and CP using
      the genes of aphid-transmissible as well as aphid non-transmissible strains of
      PVA.

PMID- 10355759
TI  - Potyvirus helper component-proteinase and coat protein (CP) have coordinated
      functions in virus-host interactions and the same CP motif affects virus
      transmission and accumulation.
AB  - Amino acid differences between helper component-proteinase (HC-Pro) and coat
      protein (CP) that are putatively associated with biological differences between
      isolates PVA-B11 and PVA-U of potato A potyvirus (PVA) were studied using an
      infectious cDNA clone of PVA-B11. Replacement of the entire CP gene of PVA-B11
      with the CP gene of PVA-U reduced virus accumulation in tobacco 5-fold, to the
      level of PVA-U. In contrast, four simultaneous amino acid substitutions made in
      PVA-B11 HC-Pro (according to PVA-U HC-Pro) increased virus accumulation 2- to 4
      fold. A single substitution (S7G) at the CP N terminus reduced virus accumulation
      10-fold, but restored aphid-transmissibility of PVA-B11. Simultaneous mutation of
      HC-Pro and replacement of CP in B11 delayed systemic movement in tobacco and
      limited cell-to-cell movement in potato. These results imply coordinated
      functions of HC-Pro and CP in accumulation and movement of PVA, because the
      phenotypic effects caused by simultaneous mutation of the two genes were
      different from the expected 'sum' of phenotypic changes observed following
      mutation of only one gene at a time.

PMID- 10355760
TI  - Complete sequence and genome properties of Chinese wheat mosaic virus, a new
      furovirus from China.
AB  - The complete nucleotide sequence of a virus infecting winter wheat in Shandong
      province, China has been determined. This was previously thought to be soil-borne
      wheat mosaic virus but, while the two viruses are related, they are only 75%
      (RNA1) and 63% (RNA2) identical at the nucleotide level, while the amino acid
      sequences share from 62% (19 kDa RNA2 product) to 84% (RNA1 replicase) identity.
      The analysis shows that the Chinese virus should be considered a new member of
      the genus Furovirus and has been named Chinese wheat mosaic virus (CWMV). A Cys
      Gly ... Cys-Gly-X-X-His amino acid pattern was identified in the cysteine-rich
      protein of CWMV and those of several other plant virus genera, which seems likely
      to have some functional significance.

PMID- 10355761
TI  - Oxidative stress in cells infected with bovine viral diarrhoea virus: a crucial
      step in the induction of apoptosis.
AB  - Bovine viral diarrhoea virus (BVDV) belongs to the genus Pestivirus of the family
      Flaviviridae. Both a noncytopathic (ncp) and an antigenically related cytopathic
      (cp) BVDV can be isolated from persistently infected animals suffering from
      mucosal disease. In every case studied so far, the genomic changes leading to the
      cp biotype correlate with the production of the NS3 nonstructural protein, which,
      in the ncp biotype, is present in its uncleaved form, NS23. This report shows
      that, in contrast to ncp BVDV, the cp biotype induces apoptosis in cultured
      embryonic bovine turbinate cells. Early in the process of apoptosis, cells show a
      rise in the intracellular level of reactive oxygen species, which is indicative
      of oxidative stress. This precedes two hallmarks of apoptosis, caspase activation
      as shown by cleavage of the caspase substrate poly(ADP-ribose) polymerase, and
      DNA fragmentation. Cells were protected from apoptosis only by certain
      antioxidants (butylated hydroxyanisole and ebselen), whereas others (N
      acetylcysteine, pyrrolidine dithiocarbamate, lipoic acid, dihydrolipoic acid and
      tiron) turned out to be ineffective. Antioxidants that protected cells from
      apoptosis prevented oxidative stress but failed to block virus growth. These
      observations suggest that oxidative stress, which occurs early in the interaction
      between cp BVDV and its host cell, may be a crucial event in the sequence leading
      to apoptotic cell death. Hence, apoptosis is not required for the multiplication
      of the cp biotype of BVDV.

PMID- 10355762
TI  - Localization of pestiviral envelope proteins E(rns) and E2 at the cell surface
      and on isolated particles.
AB  - The glycoproteins E(rns) of classical swine fever virus (CSFV) and E(rns) and E2
      of bovine viral diarrhoea virus (BVDV) are shown to be located at the surface of
      infected cells by the use of indirect immunofluorescence and by cytofluorometric
      analysis. The positive immunostaining of the cell surface was further analysed by
      immunogold electron microscopy and it could be shown that only extracellular
      virions were labelled. Gold granules were not seen at the cellular plasma
      membrane. In contrast to BVDV E2, the CSFV E2 of virions sticking to the plasma
      membrane was not accessible to the respective monoclonal antibodies. However,
      CSFV particles isolated from culture supernatant were able to bind both
      monoclonal anti-E(rns) and anti-E2 antibodies. For CSFV and BVDV, binding of anti
      E(rns) antibodies to the virions was more pronounced than that of anti-E2. This
      finding was unexpected since E2 is considered to be the immunodominant
      glycoprotein.

PMID- 10355763
TI  - Homology model of the dengue 2 virus NS3 protease: putative interactions with
      both substrate and NS2B cofactor.
AB  - The crystal structure coordinates of the hepatitis C virus NS3 protease (HCVpro)
      were used to develop an homology model of the dengue 2 virus NS3 protease
      (DEN2pro). The amino acid sequence of DEN2pro accommodates the same alpha
      helices, beta-sheets and protein-binding domains as its HCVpro counterpart, but
      the model predicts a number of significant differences for DEN2pro and its
      interactions with substrates and cofactor. Whereas HCVpro contains a Zn2+-binding
      site, there is no equivalent metal-binding motif in DEN2pro. It is possible that
      the structural role played by the zinc ion may be provided by a salt bridge
      between Glu93 and Lys145. The two-component viral protease comprises NS3 and a
      virus-encoded cofactor, NS4A for HCV and NS2B for DEN2. Previous studies have
      identified a central 40 amino acid cofactor domain of the dengue virus NS2B that
      is required for protease activity. Modelling of the putative interactions between
      DEN2pro and its cofactor suggests that a 12 amino acid hydrophobic region within
      this sequence (70GSSPILSITISE81) may associate directly with NS3. Modelling also
      suggests that the substrate binds in an extended conformation to the solvent
      exposed surface of the protease, with a P1-binding site that is significantly
      different from its HCV counterpart. The model described in this study not only
      reveals unique features of the flavivirus protease but also provides a structural
      basis for both cofactor and substrate binding that should prove useful in the
      early design and development of inhibitors.

PMID- 10355764
TI  - Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes
      cell growth.
AB  - The phosphoprotein NS5A of hepatitis C virus has recently been suggested to
      control PKR protein kinase for resistance to interferon. To investigate other
      functions of NS5A, studies were initiated on the regulation of transcription of
      important cellular genes and of cell growth by this protein. The results
      suggested that NS5A protein represses transcription of the cell cycle regulatory
      gene p21WAF1, while it activates the human proliferating cell nuclear antigen
      gene in murine fibroblasts and human hepatoma cells. Furthermore, introduction of
      NS5A into murine fibroblasts (NIH3T3) promoted anchorage-independent growth and
      tumour formation in nude mice. Thus, NS5A appears to exhibit a role in cell
      growth regulation.

PMID- 10355765
TI  - Only the non-glycosylated fraction of hepatitis E virus capsid (open reading
      frame 2) protein is stable in mammalian cells.
AB  - Hepatitis E virus (HEV) is a non-enveloped, positive-strand RNA virus, with the
      genome encoding three open reading frames (ORFs) of which ORF 2 directs
      translation of the capsid protein, PORF2. Following pulse-labelling and cell
      fractionation of PORF2 expressed in mammalian cells using the Semliki Forest
      virus replicon, the capsid protein was detected as three major species of 78
      (PORF2), 82 and 86 kDa, with P82 and P86 being N-glycosylated (gPORF2 and
      ggPORF2, respectively). Although gPORF2 and ggPORF2 species represented 79% of
      total PORF2 after 20 min metabolic labelling and were largely membrane
      associated, the glycosylated PORF2 species were much less stable than non
      glycosylated PORF2, which was present in the cytosol and represented the major
      product accumulated in the cell. In the absence of detectable surface expression
      or export of PORF2, this suggests that glycosylated ORF 2 proteins may not be
      intermediates in HEV capsid assembly.

PMID- 10355766
TI  - Recombinant Semliki Forest virus particles encoding the prME or NS1 proteins of
      louping ill virus protect mice from lethal challenge.
AB  - Recombinant Semliki Forest virus (rSFV) vaccines encoding louping ill virus (LIV)
      genes prME and NS1 were examined. Cells transfected with rSFV-prME RNA showed
      correct processing of the precursor prME and the release into the medium of M and
      E proteins in particulate form, whilst rSFV-NS1-transfected cells secreted
      glycosylated, heat-labile NS1 dimers. Mice immunized with rSFV particles produced
      antibodies against prME and NS1 that were mainly of the IgG2a subtype, indicating
      that a T-helper 1 immune response was induced. Immunization with prME- or NS1
      encoding particles induced T-cell proliferation. Mice vaccinated
      intraperitoneally (i.p.) with rSFV-prME and/or rSFV-NS1 were significantly
      protected from lethal i.p. challenge by two strains of LIV, the virulent LI/31
      strain, from which the commercial LIV vaccine is derived, and the less-virulent
      LI/I antibody-escape variant. Intranasal (i.n.) vaccination was protective for
      rSFV-prME only against LI/31 challenge and not against challenge with LI/I.
      Immunization with rSFV-NS1 was protective against i.p. and i.n. challenge with
      both virus strains when given i.p., but was not protective when given i.n. For
      unvaccinated mice infected with LIV, all animals showing clinical signs had
      severe degenerative and inflammatory lesions in the central nervous system. None
      of the rSFV-vaccinated mice that survived challenge showed central nervous system
      pathology, with the exception of mild leptomeningitis in a minority of LI/31
      infected mice. This suggests that protection following immunization with rSFV
      must occur at early stages of LIV infection.

PMID- 10355767
TI  - Human parainfluenza virus type 1 phosphoprotein is constitutively phosphorylated
      at Ser-120 and Ser-184.
AB  - RNA-dependent RNA polymerases of single-stranded, negative-sense RNA viruses
      comprise a phosphoprotein (P) and a large protein. The constitutive
      phosphorylation of the P protein in these viruses is highly conserved, yet the
      functional significance of phosphorylation is enigmatic. To approach this
      problem, phosphorylation sites were determined in two closely related
      paramyxovirus P proteins. Sendai virus (SV) is a prototypic paramyxovirus.
      Previously, using a phosphopeptide mapping technique, the primary constitutive
      phosphorylation site of SV P protein was mapped to Ser-249. Phosphorylation at
      Ser-249 is dependent on the presence of Pro-250. Human parainfluenza virus type 1
      (HPIV-1) P protein has 66% similarity to SV P protein and its predicted secondary
      structure is highly similar to that of SV P protein. However, there is no obvious
      conserved phosphorylation site in HPIV-1 P protein. Using the phosphopeptide
      mapping strategy, the constitutive phosphorylation sites of HPIV-1 P protein were
      mapped. The HPIV-1 P protein is primarily phosphorylated at Ser-120.
      Phosphorylation at Ser-120 is dependent on the presence of Pro-121. It also has a
      minor phosphorylation site at Ser-184. The sequence at Ser-184 does not match any
      consensus phosphorylation target site for the known kinases. Significantly, the P
      proteins from both viruses are constitutively and primarily phosphorylated at one
      serine and the phosphorylation of that serine is dependent on the presence of a
      proline on its carboxyl side.

PMID- 10355768
TI  - Deduced structural model for animal rhabdovirus glycoproteins.
AB  - The G protein sequences of fourteen animal rhabdoviruses, representing all four
      recognized genera (Vesiculovirus, Lyssavirus, Ephemerovirus and Novirhabdovirus)
      and the ungrouped sigma virus, were aligned using CLUSTAL W and adjusted to
      account for obvious sequence similarities not detected by the algorithm. Analysis
      of the alignment indicated remarkable preservation of G protein structural
      features including cysteine residues, antigenic sites and significant elements of
      secondary structure (alpha-helices, beta-strands and loops). Twelve highly
      conserved cysteine residues were assigned numbers (C(I) to C(XII)) according to
      their location in the alignment. Other cysteine residues were assigned numbers
      (C0 to C(XIIe)) according to their position relative to the conserved cysteines.
      The pattern of conservation of cysteine residues and the structural
      characteristics of identified discontinuous antigenic sites were used to deduce a
      model for G protein structure. Six absolutely conserved cysteines are predicted
      to associate in three disulphide bridges (C(I)-C(XII); C(VIII)-C(XI); C(IX)-C(X))
      that form the core of the G protein structure and define the common discontinuous
      antigenic site. The associations of six other highly conserved cysteines (C(II)
      C(IV); C(III)-C(V); C(VI)-C(VII)) are predicted by the absence of a specific pair
      in all viruses within a genus. Of the other cysteines, one pair occurs only in
      ephemeroviruses and novirhabdoviruses (C0-C(XIIa)); two pairs occur only in
      ephemeroviruses (C(Ib)-C(VIIIa); C(XIIb)-C(XIIe)); and two pairs occur only in
      lyssaviruses (C(Ia)-C(VIIIb); C(XIIc)-C(XIId)). The structures predicted by the
      model account for the preservation of conformational antigenic sites, accommodate
      genus-specific variations, and are generally consistent with previous
      observations of G protein structure.

PMID- 10355769
TI  - Mutations in the glycoprotein of viral haemorrhagic septicaemia virus that affect
      virulence for fish and the pH threshold for membrane fusion.
AB  - To study the molecular basis of virulence of viral haemorrhagic septicaemia virus
      (VHSV), we used a cross-reactive neutralizing MAb to select MAb-resistant (MAR)
      mutants with reduced pathogenicity for fish. From sequence determination of the G
      gene of MAR mutants, attenuated laboratory variant and avirulent field strains,
      we identified two distant regions of the glycoprotein associated with virulence:
      region I (aa 135-161), homologous to the putative fusion peptide of both rabies
      virus (RV) and vesicular stomatitis virus (VSV), and region II (surrounding aa
      431-433), homologous to RV and VSV domains controlling the conformational changes
      necessary for the fusion process to take place. Simultaneous mutations in both
      regions resulted in the most attenuated phenotype and we obtained genetic
      evidence that regions I and II may be structurally linked. As the MAR mutants had
      mutations in or near domains involved in fusion, the fusion properties of VHSV
      and its variants were analysed. This work allowed us to postulate that the fusion
      domain of VHSV is probably constituted of two distinct regions of the protein
      connected through a disulfide bridge between cysteines 110 and 152. Finally, we
      obtained evidence suggesting that the pH threshold for fusion is a determinant
      for virulence: restriction of fusion to a more acidic pH was associated with
      attenuation for the variant tr25 which had a shift of the threshold for maximal
      fusion from pH 6.30 (for the parental strain) to pH 6.00; conversely, two field
      strains which had maximal fusion at pH 6.60 were the most virulent.

PMID- 10355770
TI  - A highly pathogenic simian/human immunodeficiency virus with genetic changes in
      cynomolgus monkey.
AB  - A highly pathogenic simian/human immunodeficiency virus (SHIV), designated C2/1,
      was obtained by serum passages in cynomolgus monkeys of p-SHIV, an SHIV strain
      that contains the env gene of pathogenic human immunodeficiency virus type 1
      89.6. CD4+ lymphocyte depletion was induced within 1 week of the SHIV-C2/1
      infection in peripheral blood as well as in various lymphoid organs in all the
      animals tested, with symptoms of diarrhoea and no increase in body weight,
      followed by intense viraemia. Serum antibody against Env protein was detected
      from 4 weeks after the virus infection, while the anti-Gag antibody response was
      absent in the SHIV-C2/1-infected animals. In contrast, both anti-Gag and anti-Env
      antibody responses were present in animals infected with p-SHIV or the non
      pathogenic SHIV-MN. Sequencing of the env gene of isolates of SHIV-C strains
      showed conserved amino acid changes in the Env C2 and V3 regions that included
      changes to negatively charged amino acids, in the cytoplasmic region of gp41 that
      included a 42 amino acid deletion, and in the Nef protein. The pathogenic SHIV
      C2/1-monkey model suggests that virus-specific pathogenicity in SHIV infection
      may be associated with the absence of anti-Gag antibody responses in animals and
      may be caused by genetic changes during serum passage in vivo.

PMID- 10355771
TI  - Coreceptor usage of BOB/GPR15 and Bonzo/STRL33 by primary isolates of human
      immunodeficiency virus type 1.
AB  - Primary isolates of human and simian immunodeficiency viruses (HIV and SIV) use
      the chemokine receptor CCR5, in association with CD4, as coreceptor. During AIDS
      progression, HIV-1 and HIV-2 often adapt to use additional cofactors,
      particularly CXCR4. In contrast, SIV isolates do not use CXCR4, but other
      coreceptors such as BOB/GPR15 and Bonzo/STRL33. Only limited information is
      currently available on usage of BOB/GPR15 and Bonzo/STRL33 by HIV-1. Therefore,
      we investigated a panel of gp160 clones from 15 primary isolates, representing 5
      different subtypes, for utilization of these cofactors. The majority of HIV-1
      envelopes mediated entry into BOB/GPR15-expressing cells, albeit often with low
      efficiency. Usage of Bonzo/STRL33 was less common and usually inefficient. To
      investigate if HIV-1 entry via these orphan receptors is sufficient to allow
      virus replication, 15 uncloned primary HIV-1 isolates and 7 molecular clones were
      used to infect target cells expressing CD4 and Bonzo/STRL33 or BOB/GPR15. Three
      primary isolates and two molecular clones replicated efficiently in cells
      expressing BOB/GPR15. Two of these isolates were X4-tropic, two were R5X4-tropic
      and one was R5-tropic. In contrast, none of the HIV-1 variants showed significant
      levels of replication in Bonzo/STRL33-expressing cells. Our data show that some
      HIV-1 isolates of different genetic subtype and of different biological phenotype
      use BOB/GPR15 for productive infection and suggest that this cofactor may play a
      role in HIV-1 pathogenesis and transmission.

PMID- 10355772
TI  - Inhibition of interferon-inducible MxA protein expression by hepatitis B virus
      capsid protein.
AB  - Chronic hepatitis B treatment has been significantly improved by interferon (IFN)
      treatment. However, some studies have suggested that hepatitis B virus (HBV)
      might have a direct effect on the resistance to IFN. Defective particles,
      generated by spliced HBV RNA and associated with chronic hepatitis B, have been
      previously characterized; expression of these particles leads to cytoplasmic
      accumulation of the capsid protein. The aim of this study was to investigate the
      role of these defective genomes in IFN resistance. The global antiviral activity
      of IFN was studied by virus yield reduction assays, the expression of three IFN
      induced antiviral proteins was analysed by Western blotting and confocal
      microscopy, and the regulation of MxA gene expression was studied by Northern
      blotting and the luciferase assay, in Huh7 cells transfected with a complete or
      the defective HBV genome. Results showed that the expression of the defective
      genome reduces the antiviral activity of IFN and that this modulation involves a
      selective inhibition of MxA protein induction by the HBV capsid protein. Our
      results also show the trans-suppressive effect of the HBV capsid on the MxA
      promoter, which might participate in this phenomenon. In conclusion, this study
      shows a direct interplay between the IFN-sensitive pathway and the capsid protein
      and might implicate this defective HBV genome in virus persistence.

PMID- 10355774
TI  - An analysis of herpes simplex virus gene expression during latency establishment
      and reactivation.
AB  - In order to facilitate an analysis of the pattern of herpes simplex virus gene
      expression during latency establishment and reactivation, recombinant viruses
      containing the lacZ reporter gene under control of either the immediate early 110
      (IE110) promoter or the latency-associated promoter have been constructed.
      Histochemical staining of ganglia taken from mice infected with these viruses
      allows for the rapid identification and quantification of sensory neurones in
      which these two promoters are active. Using the mouse ear model, this study
      demonstrates that, during the establishment of latency in vivo, IE110 promoter
      activity is only detectable in ganglia which provide innervation to the site of
      virus inoculation. Latency, however, is efficiently established not only in these
      ganglia, but also in adjacent ganglia whose neurones do not innervate the ear,
      and in which there was no evidence of IE110 expression during the acute phase of
      infection. This implies that replication-competent virus can efficiently
      establish latency in the absence of detectable IE110 expression. In addition, it
      has been possible to investigate viral gene expression in neurones following
      ganglionic explant culture by monitoring IE110 promoter-driven lacZ expression
      within reactivating neurones. This study shows that virus can be reactivated from
      all latently infected ganglia, but that reactivation appears to be more efficient
      from ganglia which provide innervation to the site of infection. The implications
      of these results for the mechanisms involved in latency establishment and
      reactivation are discussed.

PMID- 10355773
TI  - Mucosal immunization of calves with recombinant bovine adenovirus-3: induction of
      protective immunity to bovine herpesvirus-1.
AB  - To determine the potential of replication-competent (E3-deleted) bovine
      adenovirus-3 (BAV-3) as a delivery system for vaccine antigens in calves, we
      evaluated the ability of recombinant BAV-3 expressing different forms of of
      bovine herpesvirus-1 (BHV-1) glycoprotein gD to protect against BHV-1 infection
      in calves that had pre-existing BAV-3 specific antibodies. Three- to four-month
      old calves, vaccinated intranasally with recombinant BAV-3 expressing full-length
      gD (BAV3.E3gD) or a truncated version of gD (gDt) (BAV3.E3gDt), or with E3
      deleted BAV-3 (BAV3.E3d; control), were challenged with BHV-1 strain 108.
      Vaccination with BAV3.E3gD or BAV3.E3gDt induced gD-specific antibody responses
      in serum and nasal secretions, and primed calves for gD-specific
      lymphoproliferative responses. In addition, all calves developed complement
      independent neutralizing antibodies against BHV-1. Protection against viral
      challenge was observed in calves vaccinated with recombinant BAV3.E3gD or
      BAV3.E3gDt as shown by a significant reduction in body temperature and clinical
      disease, and a partial reduction in the amount and duration of virus excretion in
      nasal secretions. These results indicate that replication-competent BAV-3-based
      vectors can induce protective immune responses in calves (the natural host) that
      have pre-existing BAV-3-specific antibodies.

PMID- 10355775
TI  - Antibody-induced endocytosis of viral glycoproteins and major histocompatibility
      complex class I on pseudorabies virus-infected monocytes.
AB  - Purified porcine monocytes, the natural carrier cells of pseudorabies virus (PrV)
      in the pig, were inoculated in vitro with PrV. At different time-points post
      inoculation (p.i.) (from 7 to 17 h p.i.), the cells were washed and incubated
      with fluorescein isothiocyanate-labelled porcine PrV-specific polyclonal
      antibodies (IgG) at 37 degrees C. At all time-points tested p.i., 1 h of antibody
      incubation induced passive patching and subsequent internalization of the plasma
      membrane-anchored viral glycoproteins in approximately 65% of the infected
      monocytes. This endocytosis process is antibody-dependent, since biotinylated
      glycoproteins did not undergo spontaneous endocytosis. The process is fast and
      efficient, since only very low amounts of viral glycoproteins on the plasma
      membrane (7 h p.i.) and a minimal concentration of antibodies (0.04 mg IgG/ml)
      were needed to induce endocytosis. Experiments with PrV strains carrying
      deletions in the genes encoding the 11 different viral glycoproteins showed that
      viral glycoproteins gB and gD play a very important role in endocytosis (80%
      reduction with deletion mutants, P < 0.001), while the gE:gI Fc receptor complex,
      but not gE or gI alone, has a significant but lesser effect (45% reduction, P <
      0.05). Double staining of viral glycoproteins and major histocompatibility
      complex class I (MHC I) showed a clear co-localization and co-endocytosis of MHC
      I with the viral glycoproteins, suggesting a possible role of the process in
      immune evasion of the virus.

PMID- 10355777
TI  - Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) ORF54 encodes a
      functional dUTPase expressed in the lytic replication cycle.
AB  - The complete ORF54 of the Kaposi's sarcoma-associated herpesvirus (KSHV) (human
      herpesvirus-8; HHV-8) was cloned and expressed in E. coli. The results show that
      KSHV/HHV-8 ORF54 encodes a functional dUTPase which specifically hydrolyses dUTP
      to dUMP. Monoclonal antibodies against the HHV-8 dUTPase detected a protein with
      the expected molecular mass of 35 kDa in HHV-8-infected BCBL-1 cells. Induction
      of the lytic replication cycle of HHV-8 by treatment of BCBL-1 cells with the
      phorbol ester TPA resulted in an increased expression of the protein which was
      not inhibited by phosphonoacetic acid, indicating that the protein is expressed
      early in the lytic replication cycle. Moreover, the sporadic expression of the
      HHV-8 dUTPase in tissue sections of Kaposi's sarcoma was detected by
      immunohistochemistry.

PMID- 10355776
TI  - Domain mapping of the human cytomegalovirus IE1-72 and cellular p107 protein
      protein interaction and the possible functional consequences.
AB  - Our previous work demonstrated that following human cytomegalovirus (HCMV)
      infection of fibroblasts, there was a protein-protein interaction between the
      HCMV IE1-72 immediate-early (IE) protein and the cellular p107 protein which
      resulted in the alleviation of p107-mediated transcriptional repression of E2F
      responsive promoters. In a further characterization of this interaction, we now
      show that IE1-72 binds to the N-terminal portion of p107, not the C-terminal
      'pocket' region that binds E2F-4, and where a number of other viral gene products
      bind. Additionally, we show that exons 2 and 3 of IE1-72 are required for binding
      to p107. After mapping the binding domains, we next wanted to address the
      additional functional consequences of this interaction. It is well known that
      p107 can negatively regulate cell growth. To examine whether IE1-72 can also
      overcome this growth suppression, we transfected and infected or cotransfected
      various constructs into SAOS-2 cells. We showed that infection of SAOS-2 cells
      was capable of alleviating p107-mediated growth suppression. Additionally, we
      showed that IE1-72 alone is capable of overcoming p107-mediated growth arrest.
      Alleviation of this repression by IE1-72 is dependent on the protein-protein
      interaction between p107 and IE1-72 as deletion mutants of either protein which
      lack the identified binding domains fail to achieve this effect. These data
      indicate that the IE1-72 protein is capable of overcoming p107-mediated blocks in
      cellular proliferation, events that occur in both productive and non-productive
      HCMV infections.

PMID- 10355778
TI  - The gene product encoded by ORF 57 of herpesvirus saimiri regulates the
      redistribution of the splicing factor SC-35.
AB  - The herpesvirus saimiri (HVS) gene product encoded by ORF 57 shares limited C
      terminal similarity with herpes simplex virus 1 ICP27, a protein that has been
      demonstrated to be involved in the inhibition of host-cell splicing and is
      responsible for the redistribution of components of the spliceosome. It has
      previously been shown that ORF 57 can either activate or repress viral gene
      expression by a post-transcriptional mechanism. Furthermore, repression of gene
      expression by ORF 57 is dependent on the presence of an intron within the target
      gene coding region. In this report, it is shown that HVS infection results in the
      redistribution of the SC-35 splicing factor in the infected cell nucleus.
      Furthermore, the redistributed SC-35 colocalized with the ORF 57 protein product
      and expression of the protein alone was sufficient to cause the redistribution of
      the spliceosome components. These results suggest that the mechanism by which ORF
      57 down-regulates expression of intron-containing genes involves the
      redistribution of the spliceosome complex.

PMID- 10355779
TI  - Purification and partial genome characterization of a herpes-like virus infecting
      the Japanese oyster, Crassostrea gigas.
AB  - First observed in 1972 in Crassostrea virginica, herpes-like viruses of bivalves
      were more recently found to be associated with high mortality rates in other
      cultured oyster species, such as Crassostrea gigas and Ostrea edulis. The
      diagnosis of herpes-like virus infections is performed currently by laborious
      histological and transmission electron microscope examinations. Preparation of
      specific reagents for use in more amenable diagnostic techniques prompted
      purification of virus particles and investigation of the viral genome. This paper
      is the first description of the purification of a virus pathogen from a bivalve
      mollusc. A procedure was developed which facilitated purification of large
      amounts of virus particles on the 40-50% interface of sucrose gradients.
      Transmission electron microscopy showed that a purified virus suspension
      contained capsids and enveloped virus particles. High molecular mass viral DNA
      was extracted, and the genome size was estimated by the summation of the sizes of
      restriction endonuclease fragments to be approximately 180 kbp. Partial cloning
      of the virus genome was achieved and the specificity of certain cloned fragments
      was established by dot blot hybridization.

PMID- 10355780
TI  - Sequence analysis of the genome of Bombyx mori nucleopolyhedrovirus.
AB  - The genome of the nucleopolyhedrovirus (NPV) (T3 strain) pathogenic for Bombyx
      mori (Bm) was sequenced and analysed. The BmNPV genome was 128,413 nucleotides
      long with a G+C content of 40% and contained 136 open reading frames (ORFs)
      encoding predicted proteins of over 60 amino acids. Although phenotypically
      different, the genome organizations of BmNPV and Autographa californica
      multinucleocapsid NPV (AcMNPV) were closely related. The BmNPV genome was over
      90% identical to about three-quarters of the genome of AcMNPV. The relatedness of
      predicted amino acid sequences of corresponding ORFs between BmNPV and AcMNPV was
      about 90%. However, the BmNPV genome lacked homologues of the following AcMNPV
      ORFs: Ac3 (conotoxin), Ac7 (orf603), Ac48 (etm), Ac49 (pcna), Ac70 (hcf-1), Ac86
      (pnk/pnl) and Ac134 (p94). In addition, BmNPV contained five ORFs related to Ac2.
      A high frequency of multiple 3 bp insertions was also found within BmNPV and
      AcMNPV coding sequences.

PMID- 10355781
TI  - Lessons from a large outbreak of Escherichia coli O157:H7 infections: insights
      into the infectious dose and method of widespread contamination of hamburger
      patties.
AB  - Between November 1992 and February 1993, a large outbreak of Escherichia coli
      O157:H7 infections occurred in the western USA and was associated with eating
      ground beef patties at restaurants of one fast-food chain. Restaurants that were
      epidemiologically linked with cases served patties produced on two consecutive
      dates; cultures of recalled ground beef patties produced on those dates yielded
      E. coli O157:H7 strains indistinguishable from those isolated from patients,
      confirming the vehicle of illness. Seventy-six ground beef patty samples were
      cultured quantitatively for E. coli O157:H7. The median most probable number of
      organisms was 1.5 per gram (range, < 0.3-15) or 67.5 organisms per patty (range,
      < 13.5-675). Correlation of the presence of E. coli O157:H7 with other bacterial
      indicators yielded a significant association between coliform count and the
      presence of E. coli O157:H7 (P = 0.04). A meat traceback to investigate possible
      sources of contamination revealed cattle were probably initially colonized with
      E. coli O157:H7, and that their slaughter caused surface contamination of meat,
      which once combined with meat from other sources, resulted in a large number of
      contaminated ground beef patties. Microbiological testing of meat from lots
      consumed by persons who became ill was suggestive of an infectious dose for E.
      coli O157:H7 of fewer than 700 organisms. These findings present a strong
      argument for enforcing zero tolerance for this organism in processed food and for
      markedly decreasing contamination of raw ground beef. Process controls that
      incorporate microbiological testing of meat may assist these efforts.

PMID- 10355782
TI  - Temporal and geographical distributions of reported cases of Escherichia coli
      O157:H7 infection in Ontario.
AB  - The distribution of 3001 cases of verocytotoxigenic Escherichia coli (VTEC)
      reported in the Province of Ontario, Canada, were examined to describe the
      magnitude of this condition geographically and to evaluate the spatial
      relationship between livestock density and human VTEC incidence using a
      Geographical Information System. Incidence of VTEC cases had a marked seasonal
      pattern with peaks in July. Areas with a relatively high incidence of VTEC cases
      were situated predominantly in areas of mixed agriculture. Spatial models
      indicated that cattle density had a positive and significant association with
      VTEC incidence of reported cases (P = 0.000). An elevated risk of VTEC infection
      in a rural population could be associated with living in areas with high cattle
      density. Results of this study suggested that the importance of contact with
      cattle and the consumption of contaminated well water or locally produced food
      products may have been previously underestimated as risk factors for this
      condition.

PMID- 10355783
TI  - Salmonellosis in North Thames (East), UK: associated risk factors.
AB  - We assessed the rate of salmonella infections and risk factors associated with
      infection in North East Thames in 1993. Cases of culture confirmed infection were
      identified through microbiology laboratories and environmental health officers in
      the North East Thames. A total of 1730 cases were reported and 209 of these
      individuals (those who could be contacted within a 3-week interval after onset of
      symptoms) and matched controls were interviewed by telephone. In addition
      randomly selected controls were interviewed over a 4-month period about recent
      gastric acid lowering medication and antimicrobial ingestion. Sixty-six serotypes
      were identified: S. enteritidis was isolated from 1179 (69%) cases, S.
      typhimurium from 221 (13%), S. virchow from 77 (4%) and S. newport 25 (1%).
      Infections were more frequent in summer months. Highest rates were documented in
      children under 2 years of age for S. enteritidis (108/100,000) and under 1 year
      for S. typhimurium (36/100,000). Using the Townsend score, highest isolation
      rates of S. enteritidis were in more prosperous areas (36/100,000 vs. 27/100,000;
      odds ratio (OR) 1.3, 95% confidence intervals (CIs) 1.2-1.6, P < 0.0001), while
      for S. typhimurium, there was no relation between deprivation index and isolation
      rates areas (6.4/100,000 vs. 6.1/100,000; OR 1.1, 95% CIs 0.8-1.5, P = 0.77). The
      case control study showed a significant association between ingestion of products
      containing raw eggs and S. enteritidis infection (8/111 cases vs. 0/110 controls;
      OR undefined, lower 95% CIs 3.4). Individuals with salmonella infection were
      significantly more likely to have travelled abroad in the week before the onset
      of illness [42/186 (23%) vs. 1/182 (0.5%); OR 40, 95% CIs = 5.5-291, P < 0.001]
      and to report gastroduodenal disease [11/143 (7%) vs. 3/143 (2%); OR 5.0, 95% CIs
      = 1.1-23, P = 0.04]. There was an association between illness and gastric acid
      lowering medications [unmatched controls OR 22.3 (95% CIs 1.5-3.7, P = 0.0002),
      matched controls OR 3.7 (95% CIs 1.0-3.8, P = 0.07)], but no association with
      antimicrobial ingestion.

PMID- 10355784
TI  - A Mexican restaurant-associated outbreak of Salmonella Enteritidis type 34
      infections traced to a contaminated egg farm.
AB  - In May 1996, the Georgia Division of Public Health was notified about a cluster
      of persons with Salmonella Enteritidis (SE) infections in Waycross, Georgia. A
      matched pair case-control study to determine risk factors for illness found a
      statistically significant association of SE infection with a history of having
      eaten at Restaurant A during the 5 days before onset of illness (relative risk =
      13 [95% confidence interval (CI) = 3-62, P < 0.01]). In a second case-control
      study, to determine specific food exposures, consumption of a deep-fried Mexican
      dish (chile relleno) (4 of 21 cases vs. 0 of 26 controls, odds ratio undefined,
      95% CI > 1.46, P = 0.034) was found to be significantly associated with SE
      infection. An environmental investigation found evidence of suboptimal food
      storage and cooking temperatures at Restaurant A; cross contamination of foods
      may have contributed to the low attributable risk identified for chile rellenos.
      Five of 37 Restaurant A food and environment specimens yielded SE strains. All
      five positive specimens were from chiles rellenos. Of the seven outbreak
      associated strains (six patient isolates and one food isolate from Restaurant A)
      for which phage typing was conducted, all were phage type 34. A FDA traceback
      investigation through Restaurant A's single-egg supplier identified the potential
      source as three interrelated farms in South Carolina. Environmental culture from
      one of these farms yielded SE phage type 34. As a result of this outbreak, FDA
      helped institute a statewide egg quality-assurance programme in South Carolina to
      minimize SE contamination of eggs.

PMID- 10355786
TI  - Phages for methicillin-resistant Staphylococcus aureus: an international trial.
AB  - An internationally agreed and validated set of phages is used worldwide for the
      typing of strains of Staphylococcus aureus of human origin. However, because of
      the sometimes reduced susceptibility of methicillin-resistant strains (MRSA) to
      these phages, some of the national typing centres use locally isolated and
      characterized sets of experimental phages. In this trial, 42 such phages were
      distributed to 6 centres and tested against 744 isolates of MRSA with the
      intention of defining a phage set to augment the international set. The use of
      these experimental phages increased the percentage typability from 75% with the
      international set to 93% and the number of identifiable lytic patterns from 192
      to 424. A subset of 10 experimental phages was selected. When this subset was
      compared with the experimental panel, the typability rate was 91% and 370
      distinct patterns were obtained. This subset of phages has been distributed for
      international trial.

PMID- 10355785
TI  - A high proportion of Vibrio cholerae strains isolated from children with
      diarrhoea in Bangkok, Thailand are multiple antibiotic resistant and belong to
      heterogenous non-O1, non-O139 O-serotypes.
AB  - Results of a surveillance on cholera conducted with patients seen at the Children
      Hospital in Bangkok, Thailand from August 1993 to July 1995 are presented.
      Annually, isolation rates for Vibrio cholerae varied between 1.7 and 4.4% of
      patients with diarrhoea. V. cholerae O1 serotype Ogawa accounted for between 31
      and 47% of patients cultured positive for V. cholerae, whereas the O139 serotype
      dominated in early 1994 after which it disappeared. Non-O1, non-0139 strains were
      isolated at similar rates as serotype O1 in 1993 and 1994, but accounted for 69%
      of V. cholerae culture positive specimens in 1995. However, the annual proportion
      of the isolation of non-O1, non-O139 strains showed little variation and remained
      low between 1.0 and 1.3%. Serotyping of 69 epidemiological unrelated non-O1, non
      O139 strains produced 37 different O-serotypes. BglI ribotyping of serotypes
      containing more than two strains demonstrated a high degree of heterogeneity
      within and between serotypes, except seven serotype O37 strains which showed an
      identical ribotype suggesting clonality. None of the 69 strains hybridized with a
      cholera toxin probe and only two strains hybridized with a heat-stable
      enterotoxin probe. Susceptibility testing to 12 antibiotics showed that 40 of 69
      (58%) non-O1, non-O139 strains were resistant to colistin, streptomycin and
      sulphisoxazole and 28 of 69 (41%) were multiple antibiotic resistant (MAR; > or =
      4 antibiotics). Although 26 of 69 (38%) strains contained one or more plasmids,
      the plasmids were of low molecular weights and did not seem to encode antibiotic
      resistance. The results of the present study showed that a high proportion of
      heterogenous MAR V. cholerae non-O1, non-O139 strains were isolated from children
      at the hospital. With reference to the emergence of V. cholerae O139 in 1992, we
      suggest that non-O1, non-O139 strains should be monitored carefully to detect new
      serotypes with a possible epidemic potential, but also to determine the
      development and mechanism of antibiotic resistance.

PMID- 10355787
TI  - Consequences of MRSA carriage in nursing home residents.
AB  - A prospective cohort study with 1 year follow-up evaluated the relation between
      MRSA carriage and mortality, likelihood of hospitalization and functional status
      in residents of a nursing home for the elderly. Included were all 447 residents
      living in the home in early June 1994. From all patients, swabs were taken from
      nose, throat and perineum. Additional swabs (sputum, urine or wounds) were taken
      when indicated. The relative risk (RR) of dying within 6 months in MRSA carriers
      compared to non-carriers was 2.29 (95% CI = 1.04-5.04). This RR remained stable
      (1.57-2.40) after adjustment for co-variables using Mantel-Haenszel stratified
      analysis. After I year, the RR was reduced to 1.30 (95% CI = 0.65-2.58).
      Univariate survival analysis confirmed a difference in survival between carriers
      and non-carriers after 6 months (log-rank P = 0.04) and no difference after 1
      year. Cox regression analysis resulted in a hazard ratio for dying within 6
      months of 1.73 (95% CI = 0.72-4.17). No relation was found between carriage and
      either likelihood of hospitalization or indicators of functional status. These
      results are compatible with a possible relation between 6 months mortality and
      MRSA carriage in nursing home patients. It calls for a large scale, multicentre
      cohort study in order to either confirm or refute these findings.

PMID- 10355788
TI  - Analysis of genomic diversity within the Xr-region of the protein A gene in
      clinical isolates of Staphylococcus aureus.
AB  - Protein A of Staphylococcus aureus contains a polymorphic Xr-region characterized
      by a tandem repeat of eight amino acid units. In this study, the diversity of
      genes encoding the repeat regions and their relatedness among S. aureus strains
      was analyzed. Ten different protein-A types characterized by repeat numbers 4-13
      were identified in a total of 293 clinical isolates. The protein-A type with 10
      repeat units (10 repeats) in the Xr-region was most frequently detected in
      methicillin-resistant S. aureus, whereas the majority of methicillin-susceptible
      strains were distributed almost evenly into protein-A types with 7-11 repeats.
      Strains that belonged to a single coagulase type were classified into multiple
      protein-A types, e.g. strains with the common coagulase types II and VII were
      differentiated into 7 and 8 protein-A types, respectively. Nucleotide sequence
      analysis of the Xr-region of 42 representative strains revealed the presence of
      37 different genotypes (spa types), which were constituted by a combination of
      several of 24 different repeat unit genotypes. Based on the similarity in
      arrangement of repeat unit genotypes, 34 strains with different repeat numbers
      were classified into 5 genetic clusters (C1-C5). The clusters C1, C2 and C3
      consisted exclusively of strains with identical coagulase types II, III, and IV,
      respectively. These findings suggested that the protein-A gene of S. aureus has
      evolved from a common ancestral clone in individual clusters independently.

PMID- 10355789
TI  - Epidemiology of Streptococcus pneumoniae infections at the Edinburgh City
      Hospital: 1980-95.
AB  - We present data on pneumococcal isolates collected from deep and superficial
      sites over a 16-year period at the Edinburgh City Hospital. The 10 most frequent
      serotypes overall were 6, 19, 11, 9, 3, 14, 1, 15 and 18 in children and 19, 23,
      6, 6, 9, 11 3, 15, 14, 22 and 4 in adults. Over 88% (2588/2932, 88.3%) of these
      pneumococci were of serotypes represented in the 23-valent polysaccharide
      pneumococcal vaccine. Within the 20-45 years age group, 228/434 (52.5%) of
      specimens were from HIV-infected individuals. The isolations showed a seasonal
      distribution with peaks in February and troughs in September. The annual numbers
      of blood culture isolates showed an upward trend. Recurrent isolations were more
      frequent in HIV-infected individuals (49/132, 37%) than in non-HIV-infected
      individuals (218/2421, 9.9%) (relative risk = 5.05, 95% confidence interval, 3.46
      7.03). The prevalence of resistance to penicillin and erythromycin was lower than
      that reported in other parts of the UK.

PMID- 10355790
TI  - Needlestick and sharps injuries among health-care workers in Taiwan.
AB  - Sharps injuries are a major cause of transmission of hepatitis B and C viruses
      and human immunodeficiency virus in health-care workers. To determine the yearly
      incidence and causes of sharps injuries in health-care workers in Taiwan, we
      conducted a questionnaire survey in a total of 8645 health care workers,
      including physicians, nurses, laboratory technicians, and cleaners, from teaching
      hospitals of various sizes. The reported incidence of needlestick and other
      sharps injuries was 1.30 and 1.21 per person in the past 12 months, respectively.
      Of most recent episodes of needlestick/sharps injury, 52.0% were caused by
      ordinary syringe needles, usually in the patient units. The most frequently
      reported circumstances of needlestick were recapping of needles, and those of
      sharps injuries were opening of ampoules/vials. Of needles which stuck the health
      care workers, 54.8% had been used in patients, 8.2% of whom were known to have
      hepatitis B or C, syphilis, or human immunodeficiency virus infection. Sharps
      injuries in health-care workers in Taiwan occur more frequently than generally
      thought and risks of contracting blood-borne infectious diseases as a result are
      very high.

PMID- 10355791
TI  - Non-participation bias in unlinked anonymous HIV-prevalence surveys in England
      and Wales.
AB  - The objective was to assess the potential bias in unlinked anonymous HIV
      seroprevalence surveys from objections to specimens being included. Objection
      rates in seroprevalence surveys were examined. Statistically large clusters of
      objections were considered to be the result of health care worker behaviour, and
      were disregarded. Underlying objection rates were estimated from remaining data
      and compared to seroprevalence. Overall objection rates approached or exceeded
      seroprevalence in many participating centres. However, underlying objection rates
      declined with time while prevalences were generally unchanging. Also, underlying
      rates correlated poorly with observed seroprevalences. Findings were therefore
      consistent with processes producing the clusters of objections and underlying
      objection rates independently of serostatus of individuals. Although national
      seroprevalence estimates produced by the surveys are reasonably free from
      objection bias, regional seroprevalence estimates outside London remain
      vulnerable to bias as a result of some centres returning data whose quality
      cannot be guaranteed.

PMID- 10355792
TI  - Transplacental transfer of measles and total IgG.
AB  - This study was conducted to evaluate factors affecting the levels of total IgG
      (tIgG) and measles specific IgG (mIgG) in mother and cord sera, and the
      efficiency of transplacental transport of tIgG and mIgG. The study was conducted
      in four hospitals in Oporto, Portugal, where 1539 women and their newborns were
      enrolled. Measles IgG levels were lower among vaccinated mothers and respective
      cord sera than among vaccinated counterparts. Cord mIgG was strongly correlated
      with maternal levels in both vaccinated and unvaccinated groups. Transplacental
      transport efficiency (TTE) of mIgG decreased with increasing maternal levels,
      although almost one third of the observed effect was due to measurement error.
      The TTE was not affected by vaccination status. Monitoring maternal measles
      antibody levels and maternal vaccination status could be useful to determine when
      the age for measles vaccination can be reduced.

PMID- 10355793
TI  - Molecular and serological characterization of adenovirus genome type 7h isolated
      in Japan.
AB  - In 1996, three adenovirus type 7 (Ad7) strains were isolated from children with
      fever and upper respiratory diseases in Japan. Restriction endonucleases (REs)
      analysis and PCR amplification of the E3 7.7 kDa ORF revealed that these strains
      were genotype Ad7h and closely related to an Argentine Ad7h strain, which has
      been reported to be highly virulent and so far predominant only in South America.
      These strains showed weak cross-neutralizing activity and specific
      haemagglutination-inhibition activity to Ad3 antiserum. The present findings
      suggest that Ad7h in South America has spread to other parts of the world. Since
      the seroprevalence to Ad7 in the current Japanese population is very low due to
      the absence of Ad7 circulation in Japan for decades, Ad7 outbreak as a typical
      case of re-emerging infectious diseases is a cause for serious concern.

PMID- 10355794
TI  - A variant of variola virus, characterized by changes in polypeptide and
      endonuclease profiles.
AB  - A variant of variola virus is described which produces a late polypeptide of 25
      kDa instead of one of 27 kDa and which has an additional endonuclease cleavage
      site for SalI in the viral DNA. These markers were shown to be genetically
      independent and to characterize 14 of the 48 variola strains which were examined.
      The variant strains were isolated from smallpox outbreaks originating in or from
      Pakistan between 1961 and 1974 and also from two cases at a Mission Hospital in
      Vellore, India in 1964. No variant strains were found among 9 other isolates from
      cases of variola major occurring in other parts of India or in Bangladesh, nor
      among 4 isolates from Indonesia, 15 from Africa or 6 isolates of variola minor.

PMID- 10355795
TI  - Determinants of antibodies to Cryptosporidium infection among gay and bisexual
      men with HIV infection.
AB  - A cross-sectional serosurvey for markers of prior Cryptosporidium infection was
      conducted among homosexual or bisexual males infected with human immunodeficiency
      virus (HIV); of 262 individuals approached, 236 (90%) agreed to participate.
      Serological response to two Cryptosporidium antigens was measured using a Western
      blot assay. The intensity or detection of serological responses to two
      Cryptosporidium antigens was not associated with CD4 cell counts or tap water
      consumption. A number of sexual practices were related to increased serological
      response for only the 27-kDa marker, including having had sex within the past 2
      years, having anal sex and having had a larger number of sex partners during the
      past 2 years. Attending a spa or sauna was related to serological response to
      both the 27-kDa and 17-kDa markers. Based on these results, activities related to
      sexual activity appear to be a significant risk factors for prior Cryptosporidium
      infection.

PMID- 10355796
TI  - The relationship between ocular toxoplasmosis and levels of specific toxoplasma
      antibodies.
AB  - The relationship between ocular toxoplasmosis and levels of toxoplasma specific
      antibodies was examined in 195 patients. Using clinical information collected by
      questionnaires, patients were divided into: 97 with ocular toxoplasmosis (group
      1) and 98 with ocular lesions not due to toxoplasma (group 2). The geometric mean
      of dye test titres (+/-S.D. natural log titre) in group 1 was 53.2 (+/-0.95)
      compared with 24.6 (+/-1.11) in group 2 (P < 0.001). Young females tended to have
      more active lesions compared with young males (P < 0.05). There was an age
      dependent difference in dye test titres between the groups (P < 0.001). Group 1
      showed a decline in titre with age compared with an increase in group 2. Ocular
      toxoplasmosis was diagnosed most frequently among 21-30 year olds. More group 1
      patients had dye test titres > or = 65 iu/ml than group 2 (P < 0.05). Dye test
      titres > or = 65 iu/ml support a diagnosis of ocular toxoplasmosis whereas lower
      titres suggest other causes for eye lesions.

PMID- 10355797
TI  - Potential contamination of drinking water with Toxoplasma gondii oocysts.
AB  - The world's first documented toxoplasmosis outbreak associated with a municipal
      water supply was recognized in 1995 in Victoria, British Columbia, Canada. It was
      hypothesized that domestic cat (Felis catus) or cougar (Felis concolor) faeces
      contaminated a surface water reservoir with Toxoplasma gondii oocysts. An
      extensive investigation of the Victoria watershed 1 year following the outbreak
      documented the presence of an endemic T. gondii cycle involving the animals
      inhabiting the area. Cats and cougars were observed throughout the watershed.
      Serological evidence of T. gondii infection was demonstrated among domestic cats
      living in the Victoria area. Cougars were found to shed T. gondii oocysts.
      Serological evidence of T. gondii infection in deer mice living in the riparian
      environments of the watershed suggested that T. gondii oocysts were being shed
      near the water edge. Contamination of Victoria's water supply with T. gondii
      oocysts potentially occurred during the study period and future waterborne
      toxoplasmosis outbreaks in this and other communities are possible.

PMID- 10355798
TI  - Amoebiasis among institutionalized psychiatric patients in Taiwan.
AB  - Although information on amoebiasis among institutionalized psychiatric patients
      is available, reports on the relationship between behaviour and this infection
      are not abundant. From July 1995 to June 1996, stool and blood samples were
      collected from 565 patients in three psychiatric hospitals of North Taiwan. Stool
      samples were examined using the direct smear and formalin-ethyl acetate
      sedimentation techniques as well as ProSpecT Entamoeba histolytica Microplate
      Assay kit. Blood samples were examined by the Amebiasis Serology Microwell ELISA
      kit. Among these patients, 14 (2.5%) harboured one or two species of intestinal
      parasites. There were 6 (1.1%) E. histolytica/E. dispar cyst passers: 5 positive
      in stool ELISA test and 2 with antibodies against E. histolytica. Among
      demographic factors, type of psychiatric disorder and disability, only a
      significant sexual difference in seropositivity of E. histolytica was observed.
      These findings indicate that the infected patients acquired the infections before
      they entered the hospitals.

PMID- 10355799
TI  - Evaluation of 16S, map1 and pCS20 probes for detection of Cowdria and Ehrlichia
      species.
AB  - A panel of 16S ribosomal RNA gene probes has been developed for the study of the
      epidemiology of heartwater; five of these detect different cowdria genotypes, one
      detects five distinct genotypes; one detects any Group III Ehrlichia species
      other than Cowdria and one detects any Group II Ehrlichia species. These probes
      have been used on PCR-amplified rickettsial 16S rRNA genes from over 200
      Amblyomma hebraeum ticks. Control ticks were laboratory-reared and either
      uninfected or fed on sheep experimentally infected with different cowdria
      isolates, field ticks were collected from animals in heartwater-endemic areas.
      All tick-derived DNA samples were also examined by PCR amplification and probing
      for two other cowdria genes (map1 and pCS20) which have previously been used for
      heartwater epidemiology. This paper describes the first direct comparison of all
      currently available DNA probes for heartwater-associated organisms.

PMID- 10355800
TI  - Coagulase gene polymorphism of Staphylococcus aureus isolates from dairy cattle
      in different geographical areas.
AB  - The objectives of this study were to investigate the coagulase gene polymorphism
      of Staphylococcus aureus isolates obtained from bovine mastitic milk and to
      determine the resistance of predominant and rare coagulase genotypes to bovine
      blood neutrophil bactericidal activities. A total of 453 isolates were collected
      from four countries: the Czech Republic, France, Korea and the United States. The
      isolates were subtyped into 40 types by restriction fragment length polymorphism
      (RFLP) of the coagulase gene. Twenty-three strains from predominant and rare
      genotypes were evaluated for their ability to resist neutrophil bactericidal
      activities. There were significant (P < 0.01) differences in the average percent
      neutrophil killing of the predominant (16.7%) and rare (39.7%) genotypes when
      bacteria were opsonized with antiserum. The results indicate that the profiles of
      coagulase genotype differ among geographic locations, and only a few genotypes
      prevail in each location. In addition, the predominant genotypes were more
      resistant to neutrophil bactericidal activities than rare genotypes.

PMID- 10355801
TI  - Molecular typing of Escherichia coli O157:H7 (H-) isolates from cattle in Japan.
AB  - A total of 77 Escherichia coli O157:H7 (H-) isolates from cattle in Japan were
      investigated by molecular biological methods. Most of these isolates (43
      isolates) possessed the stx-2 gene, but not stx1. Fifteen bacteriophage types and
      50 pulsed-field gel electrophoresis (PFGE) profiles were observed. One isolate
      was indistinguishable from the human outbreak strain by these methods. This
      indicates that cattle must be considered as a possible source of human E. coli
      O157:H7 infection in Japan.

PMID- 10355802
TI  - The shift of genetic subtypes of Escherichia coli O157:H7 isolates from cattle.
AB  - A total of 46 Escherichia coli O157:H7 isolates were obtained from sequential
      faecal samples from seven cattle collected over periods of 2 months. Nine closely
      related genetic subtypes, determined by pulsed-field gel electrophoresis types
      using three kinds of restriction endonuclease were observed among the isolates.
      Distinguishable, but closely related genetic subtypes can be isolated from one
      farm, or from one cow, should be considered when undertaking an epidemiological
      survey.

PMID- 10355803
TI  - Basic neurosciences.

PMID- 10355804
TI  - The relation between intracranial pressure and outcome in non-accidental head
      injury.
AB  - The aim of this retrospective study was to ascertain whether physiological
      derangement and potential secondary brain insult from raised intracranial
      pressure (ICP) or reduced cerebral perfusion pressure (CPP) in non-accidental
      head injury (NAHI) influences outcome. Any child who had a diagnosis of NAHI and
      had ICP monitoring or measurements during the acute illness was entered in the
      study. Seventeen children with an average age 5.1 months (range 1 to 20 months)
      were identified. Details of the acute encephalopathy, lowest mean arterial blood
      pressure (MAP), mean of maximum ICP measured, lowest CPP, and neurodevelopmental
      outcome at follow up were obtained from the hospital case notes. Seshia's (1994)
      outcome classification scale was used. The lowest CPP was very significantly
      related to outcome (P=0.0047, tau=-0.544). Mean of maximum ICP did not correlate
      with outcome. The lowest MAP was significantly related to outcome (P=0.039). It
      was concluded that the degree of secondary brain insult from reduced CPP
      influences outcome.

PMID- 10355805
TI  - The effect of botulinum toxin A on gastrocnemius length: magnitude and duration
      of response.
AB  - Thirty-nine ambulant children (22 with hemiplegia, 17 with diplegia) with spastic
      cerebral palsy receiving isolated gastrocnemius muscle injection with botulinum
      toxin A were studied prospectively. The children had a mean age of 6 years (range
      3 to 13 years). Measurement of gastrocnemius muscle length was used to estimate
      the dynamic component of each child's spasticity and to quantify the response.
      There was a strong correlation between the dynamic component of spasticity before
      injection and the corresponding magnitude of the response after injection.
      Children undergoing repeated injections showed similar correlations. A strong
      correlation was found between the duration of response and the dynamic component.
      Children with hemiplegia showed twice the duration for a given dynamic component
      compared with those with diplegia when injected with the same total dose per unit
      body weight. Long-term lengthening did not occur for the cohort, although some
      patients showed a response at a 12-month follow-up. By delaying shortening, the
      injections may have a role in delaying the need for surgery. Injections were well
      tolerated with few side effects.

PMID- 10355806
TI  - Aetiological findings and associated factors in children with severe mental
      retardation.
AB  - The purpose of this study, through a retrospective epidemiological survey carried
      out over three geographical areas in France, was to characterize the aetiological
      factors involved in severe mental retardation (SMR) within a geographically
      defined population of children with disabilities aged between 7 and 16 years. The
      inclusion criteria for SMR (IQ<50) were met by 1150 children born between 1976
      and 1985. Of these children, aetiology was known in 25%, suspected (or unclear)
      in 26%, and unknown in 49%. These rates of known and suspected aetiology varied
      between the groups of children with CP and those without CP. An analysis of
      factors associated with SMR was undertaken among the 144 subjects with SMR, of
      suspected or unknown aetiology, who had been referred to a neonatal care unit
      with or without intensive care (NCU) during their neonatal period. These subjects
      with SMR were compared with 864 children without SMR (control children) who were
      also referred to an NCU during their neonatal period. The main specific
      associated factors were a prolonged intubation of more than 24 hours, a very low
      birthweight (<1500 g) for children with an associated clinical feature of CP, and
      the presence of isolated neonatal fits and a time of transfer to the NCU of more
      than 4 hours after birth for children without an associated clinical feature of
      CP. Although common associated factors were encountered in the children with SMR
      with CP and the children with SMR without CP, the results of this study suggest
      differences in the underlying pathogenic factors.

PMID- 10355807
TI  - Sequential neuromotor examination in children with intrauterine cocaine/polydrug
      exposure.
AB  - Data are presented on 157 newborn infants followed sequentially in a randomized
      home-based nursing-intervention trial for drug-exposed infants with follow up at
      3 (N=118), 6 (N=124), and 12 months (N=77). The objectives of this study were to
      describe the longitudinal neurodevelopmental status of a cohort of children with
      intrauterine exposure to illicit drugs during their gestation, characterize the
      evolution of early tone abnormalities in a polydrug-exposed cohort, and determine
      whether neuromotor outcome is associated with drug-exposure patterns. For
      analysis, infants were grouped based on maternal drug-use pattern and the
      presence of drug metabolites in the neonatal drug screen. The sequential
      neuromotor examination was used at each age to define the neuromotor status of
      six domains and define categorical classifications as either normal, suspect, or
      abnormal. Multiple patterns of neuromotor abnormalities were observed during the
      neonatal period; most resolved over time. Axial hypotonia was a prominent finding
      in the neonatal period; however, it was infrequent in abnormal examinations at 12
      months. Increased lower-extremity tone was a less frequent finding during the
      neonatal period. Infants whose neonatal urine drug screen was positive for both
      cocaine and opiates, were more likely than infants with negative urine drug
      screens, cocaine only, or opiate only drug screen results to have abnormal
      neuromotor examinations; while positive maternal drug screens for concurrent
      cocaine and opiate use were associated with peripheral hypertonia. Persistence of
      increased leg-extensor tone was found in 67% of the abnormal examinations at 12
      months. Acquisition of rolling and walking was delayed in the drug-exposed
      cohort.

PMID- 10355808
TI  - Visual-proprioceptive mapping in children with developmental coordination
      disorder.
AB  - Developmental coordination disorder (DCD) occurs in a small but significant
      proportion of children who present with impaired body-eye coordination and show
      poor acquisition of motor skills. This study investigated the visual
      proprioceptive mapping ability of children with DCD from a small selected group,
      with particular reference to the use of vision in matching tasks. The children
      with DCD in this study were significantly poorer than control children on all
      matching tasks. They seemed to have particular difficulty in cross-modal
      judgements that required the use of visual information to guide proprioceptive
      judgements of limb position. A distinction is drawn between tasks that can be
      achieved purely through sensory matching and those that require body-centred
      spatial judgements, suggesting that it is the latter that posits a particular
      difficulty for children with DCD.

PMID- 10355810
TI  - Cognitive functioning in Lesch-Nyhan syndrome: a 4-year follow-up study.
AB  - Lesch-Nyhan syndrome (LNS) is a rare disorder of metabolism caused by a defective
      gene on the X chromosome. It is typically characterized by choreoathetosis,
      hypertonia, hyperreflexia, and self-mutilation. The present study is a 4-year
      follow-up investigation of the cognitive status of six subjects with a mean age
      of 17 years 10 months (range 14 years 9 months to 23 years). The Stanford-Binet
      Intelligence Scale: IV was used. Each of the four domains assessed by this
      battery (verbal reasoning, abstract/visual reasoning, quantitative, and short
      term memory) was compared with previous findings of the same subjects at their
      initial test and 2-year follow up; the aim being to gain further insight into the
      clinical course of LNS over time. The results suggest that while the subjects
      generally continued to acquire new information and skills over time, their
      standardized scores declined, indicating that a plateau was reached in their
      skill levels relative to their peers, as also seen in other developmental
      disabilities. Deficits were noted in working memory, particularly on tasks that
      involve considering multiple features simultaneously.

PMID- 10355809
TI  - Melatonin treatment of non-epileptic myoclonus in children.
AB  - Oral melatonin (MLT) has been used by our Vancouver research group in the
      treatment of paediatric sleep disorders since 1991; slightly over 200 children,
      mainly with multiple disabilities, who frequently had seizures, have been
      treated. Three children with markedly delayed sleep onset due to recurring
      myoclonus were also referred for MLT treatment: two had non-epileptic, and one
      had epileptic and non-epileptic myoclonus. Low doses of oral MLT (3 to 5 mg)
      unexpectedly abolished their myoclonus and allowed them to sleep. There were no
      adverse effects. It appears that certain types of myoclonus, which might be
      resistant to conventional anticonvulsant medications, may respond to MLT but the
      mechanism of action is unclear. Further research on this novel treatment is
      urgently needed.

PMID- 10355811
TI  - Cognitive functioning in children with typical cri du chat (5p-) syndrome.
AB  - This study is the first attempt to assess systematically the cognitive
      functioning in children diagnosed with typical cri du chat syndrome (CDCS) using
      neuropsychological test measures. Twenty-six children aged between 6 years 4
      months and 15 years 5 months (mean 8 years 3 months) completed a battery of tasks
      measuring IQ level, receptive and expressive language skills, and articulation.
      Twenty-four children were in the severe learning-disability range with no
      specific verbal or performance profile. Using more finely tuned measures of
      cognition, however, a clear discrepancy in the pattern of language functioning
      was found with better receptive than expressive language skills. One implication
      of these findings is that parents and professionals should be more optimistic
      about the capacities of children with CDCS to understand more complex verbal
      commands than their expressive language skills would suggest.

PMID- 10355812
TI  - Carbamazepine hypersensitivity and the use of lymphocyte proliferation responses.
AB  - This report describes a case of multisystem failure in a 5-year-old boy who was
      being treated with carbamazepine for a seizure disorder. Carbamazepine
      hypersensitivity was diagnosed from the combination of the clinical constellation
      and the results of the patient's peripheral blood monocyte proliferation
      responses to both carbamazepine and a panel of other medications.

PMID- 10355813
TI  - Autistic disorders in children with CHARGE association.
AB  - Three children with CHARGE association (coloboma, heart defect, atresia of the
      choanae, retarded growth and development, genital hypoplasia, ear anomalies and
      hearing defects) as well as concomitant autistic disorder are reported. Two of
      the children also had mental retardation. Several types of cerebral
      maldevelopment/dysfunction have been reported in CHARGE association. With regard
      to aetiology, involvement of the neural crest has been suggested. Autism in
      CHARGE association may represent a neuro-endocrine dysfunction. Children with a
      CHARGE association have many medical problems and therefore autistic behaviour
      can easily be overlooked. A multidisciplinary approach with respect to
      assessment, treatment, and habilitation is of vital importance.

PMID- 10355814
TI  - Congenital paraplegia following maternal hypotension.
AB  - Congenital paraplegia, with partial improvement over the first months of life,
      occurred in a female neonate born at 35 weeks' gestation, whose mother had
      suffered hypotension and hypoxaemia due to anaphylaxis 12 weeks earlier. Our
      patient subsequently had an acute encephalopathy during a respiratory illness
      with later developmental delay. We speculate that the baby's paraplegia resulted
      from spinal-cord ischaemia in utero. The aim of this report is to describe the
      spinal presentation.

PMID- 10355815
TI  - Significance of oral health in persons with Down syndrome: a literature review.

PMID- 10355816
TI  - 'Improved hand function remains after upper-limb tendon transfer and muscle
      release in children with hemiplegia'.

PMID- 10355817
TI  - 'Paresis of facial and abducens nerves in a patient with growth-hormone receptor
      deficiency treated with insulin-like growth factor I'.

PMID- 10355818
TI  - Cytotoxic hammerhead ribozymes.
AB  - Small catalytic RNA molecules of the hammerhead ribozyme type were found to have
      cytotoxic effects unrelated to their intended activity. An expression library of
      ribozyme sequence variants was constructed in a recA-deficient strain of
      Escherichia coli such that individual library members differed in regions
      designed to form base pairs with human immunodeficiency virus-1 (HIV-1) tat mRNA.
      The parental ribozyme and many variants exhibited a bacteriostatic effect. One
      variant studied in detail was also bactericidal. When its expression was induced,
      ribozyme-dependent inhibition of bacterial growth was not observed in recA+ or
      recA+ lexA3 (Ind-) cells, suggesting that the recombination function of the RecA
      protein, not the absence of the SOS response, is sufficient to alleviate the
      cytotoxic effect. These data document the need for careful testing for toxic
      effects during intracellular studies of ribozyme action.

PMID- 10355819
TI  - Transient transfection of a synthetic hammerhead ribozyme targeted against human
      MGMT gene to cells in culture potentiates the genotoxicity of the alkylation
      damage induced by mitozolomide.
AB  - Unmodified and chemically modified forms of a synthetic hammerhead ribozyme with
      the mRNA of methylguanine-DNA methyltransferase (MGMT) gene as substrate were
      characterized for their in vitro and in vivo activities. The unmodified ribozyme
      efficiently cleaved in vitro a short synthetic substrate, and it was rapidly
      degraded in fetal bovine serum (FBS). The introduction of phosphorothioates and
      the substitution of uridine with thymidine at probable nuclease-sensitive sites
      slightly increased the nuclease resistance of the ribozyme. Conversely,
      pyrimidine nucleoside substitution with 2'NH2 and 2'F nucleosides strongly
      enhanced nuclease resistance. The in vivo activity was determined by measuring
      the genotoxicity induced by the alkylating drug mitozolomide, the damage of which
      is repaired by MGMT enzyme. CHO/47 cells, temporarily depleted of the MGMT
      protein, were first transfected with the various synthetic ribozymes and
      subsequently treated with mitozolomide. At equivalent concentration of the drug,
      the induction of sister chromatid exchanges was higher in ribozyme-transfected
      than in untransfected cells, indicating that the synthetic ribozymes potentiated
      the genotoxicity of mitozolomide. Moreover, the concomitant occurrence of
      messenger RNA reduction in ribozyme-transfected cells indicated that the
      inhibition of MGMT resynthesis was the basis of the enhanced genotoxicity.

PMID- 10355820
TI  - Antisense oligodeoxynucleotides targeting internal exon sequences efficiently
      regulate TNF-alpha expression.
AB  - ABSTRACT Exon sequences upstream of splice sites play a critical role in mRNA
      processing, which is dependent on spliceosome interactions with these sites.
      Using antisense oligodeoxynucleotides (ODN), we targeted these and other
      sequences of the proinflammatory tumor necrosis factor-alpha (TNF-alpha) gene
      because it is multiply spliced and has been difficult to regulate with ODN in the
      past. ODN targeting exon sequences upstream of the donor splice sites of internal
      exons 2 (ORF4) and 3 (ORF6) significantly reduced TNF-alpha levels in stimulated
      U937 cells by 62%+/-7% and 51%+/-9%, respectively, in a dose-dependent manner but
      did not affect interleukin-6 (IL-6) levels. In contrast, ODN targeting the exon
      sequences downstream of the acceptor splice sites of exons 1, 2, and 3 failed to
      reduce TNF-alpha levels significantly under the same conditions. End
      phosphorothioated ORF4 (ORF4-PE) significantly reduced TNF-alpha mRNA levels by
      greater than 80% (p < 0.001) and protein levels by 60% (p < 0.001) in U937 cells.
      ORF4-PE reduced newly synthesized TNF-alpha protein levels by >80% in
      lipopolysaccharide (LPS)-stimulated human macrophages, by greater than 60% in
      phorbol myristate acetate/phyto-hemagglutinin (PMA/PHA)-stimulated human
      peripheral blood mononuclear cells (PBMC), and by approximately 50% in LPS
      stimulated murine monocytes. These results suggest that exon sequences flanking
      donor splice sites are highly susceptible target domains for antisense inhibition
      of TNF-alpha gene expression.

PMID- 10355821
TI  - Inhibition of translation of hepatitis C virus RNA by 2-modified antisense
      oligonucleotides.
AB  - Inhibition of hepatitis C virus (HCV) gene expression by antisense
      oligonucleotides was investigated using both a rabbit reticulocyte lysate in
      vitro translation assay and a transformed human hepatocyte cell expression assay.
      Screening of overlapping oligonucleotides complementary to the HCV 5' noncoding
      region and the core open reading frame (ORF) identified a region susceptible to
      translation inhibition between nucleotides 335 and 379. Comparison of 2'-deoxy-,
      2'-O-methyl-, 2'-O-methoxyethyl-, 2'-O-propyl-, and 2'-fluoro-modified
      phosphodiester oligoribonucleotides demonstrated that increased translation
      inhibition correlated with both increased binding affinity and nuclease
      stability. In cell culture assays, 2'-O-methoxyethyl-modified oligonucleotides
      inhibited HCV core protein synthesis with comparable potency to phosphorothioate
      oligodeoxynucleotides. Inhibition of HCV core protein expression by 2'-modified
      oligonucleotides occurred by an RNase H-independent translational arrest
      mechanism.

PMID- 10355822
TI  - Decreased bone resorption, osteoclast differentiation, and expression of vacuolar
      H+-ATPase in antisense DNA-treated mouse metacarpal and calvaria cultures ex
      vivo.
AB  - Expression and function of vacuolar H(+)-ATPase, a key enzyme in bone resorption,
      were monitored in antisense DNA-treated bone organ cultures ex vivo. A novel
      fluoroimmunoassay was used to quantitate mRNA levels after treatment with various
      antisense, sense, or random DNA oligonucleotides. Conventional slot blots and in
      vitro translation experiments were used to monitor the efficiency of the
      antisense molecules. In cell cultures, the used antisense molecules were
      transported into osteoclasts and a population of mononuclear cells. A significant
      decrease in bone resorption and in the expression of the 16 kDa, 31 kDa, 42 kDa,
      60 kDa, 70 kDa, and 116 kDa subunits of V-ATPase was seen after antisense
      treatment. Also, osteoclast differentiation was decreased in antisense-treated
      mouse metacarpal cultures. These data show that the proper function of V-ATPase
      in osteoclasts requires expression of the 16 kDa, 31 kDa, 42 kDa, 60 kDa, 70 kDa,
      and 116 kDa subunits of V-ATPase. Antisense DNA molecules can be used to inhibit
      osteoclast differentiation and function in tissue cultures, in which the physical
      and chemical cellular environment resembles that in vivo. However, more studies
      are needed to learn if antisense DNA molecules can be used for inhibiting bone
      resorption also in vivo.

PMID- 10355823
TI  - Enzymatic assignment of diastereomeric purity of stereodefined phosphorothioate
      oligonucleotides.
AB  - Enzymatic hydrolysis of stereoregular oligodeoxyribonucleoside phosphorothioates
      (PS-oligos) synthesized via the oxathiaphospholane method has been used for
      assignment of their diastereomeric purity. For this purpose, two well-known
      enzymes of established diastereoselectivity, nuclease P1 and snake venom
      phosphodiesterase (svPDE) have been used. However, because of some
      disadvantageous properties of svPDE, a search for other [Rp]-specific
      endonucleases was undertaken. Extracellular bacterial endonuclease isolated from
      Serratia marcescens accepts PS-oligos as substrates and hydrolyzes
      phosphorothioate bonds of the [Rp] configuration, whereas internucleotide [Sp]
      phosphorothioates are resistant to its action. Cleavage experiments carried out
      with the use of unmodified and phosphorothioate oligonucleotides of different
      sequences demonstrate that the Serratia nuclease is more selective in recognition
      and hydrolysis of oligodeoxyribonucleotides than previously reported. The
      substrate specificity exhibited by the enzyme is influenced not only by the
      nucleotide sequence at the cleavage site but also by the length and base sequence
      of flanking sequences. The Serratia nuclease can be useful for analysis of
      diastereomeric purity of stereodefined phosphorothioate oligonucleotides, but
      because of its sequence preferences, the use of this enzyme in conjunction with
      svPDE is more reliable.

PMID- 10355824
TI  - Stable antisense RNA expression neutralizes the activity of low-density
      lipoprotein receptor-related protein and promotes urokinase accumulation in the
      medium of an astrocytic tumor cell line.
AB  - Low-density lipoprotein receptor-related protein (LRP) binds and internalizes
      multiple ligands that are structurally and functionally diverse. However, the
      effects of LRP on cellular phenotype remain unclear. To study LRP in human
      astrocytic tumor cells, we designed LRP antisense RNA expression constructs in
      which the antisense cDNA fragment was expressed under the control of the
      cytomegalovirus (CMV) promoter. U-1242 MG astrocytic tumor cells were transfected
      with the antisense constructs and cloned from single cells to yield multiple cell
      lines with decreased LRP expression. Further studies were performed with two cell
      lines in which LRP antigen was completely eliminated (L(alpha)42) or
      substantially decreased (Lalpha47), as determined by Western blot analysis.
      Untransfected U-1242 MG cells and cells that were stably transfected with empty
      vector (pBK-CMV) bound activated alpha2-macroglobulin (alpha2M) in a specific and
      saturable manner. The Bmax was about 5000 receptors/cell. Lalpha42 cells did not
      bind alpha2M, and binding was decreased by >60% in Lalpha47 cells. Lalpha42 and
      Lalpha47 cells also demonstrated reduced susceptibility to the cytotoxin,
      Pseudomonas exotoxin A, and accumulated greatly increased levels of urokinase
      type plasminogen activator (uPA) in conditioned medium. The accumulation of uPA
      demonstrates a major role for LRP in the catabolism of this protein in astrocytic
      tumor cells. The LRP-deficient cell lines, developed using antisense technology,
      represent a new model system for studying LRP function in astrocytes.

PMID- 10355825
TI  - Antisense raf oligodeoxyribonucleotide is a radiosensitizer in vivo.
AB  - Raf-1, a cytosolic protein serine/threonine kinase, plays important roles in cell
      growth, proliferation, transformation, and cell survival. The aim of the present
      study was to evaluate the radiotherapeutic efficacy of a fully phosphorothioated
      and well-characterized antisense raf oligodeoxyribonucleotide (ODN) corresponding
      to the 3'-untranslated region of human c-raf-1 mRNA (ISIS 5132/5132). Using our
      recently developed liposome encapsulation of ODN approach, we first compared the
      pharmacokinetic parameters of a liposomal formulation of 5132 (LE-5132) and 5132.
      The peak plasma concentrations 5 minutes after ODN administrations (30 mg/kg
      i.v.) were 28.5 microg/ml and 13.5 microg/ml for LE-5132 and 5132, respectively.
      The decrease in plasma concentration of LE-5132 and 5132 followed a biexponential
      pattern, with initial distribution half-lives (t1/2alpha) of 34.8 minutes and
      21.6 minutes, respectively. The terminal half-lives (t1/2beta) with LE-5132 and
      5132 were 14.5 hours and 4.3 hours, respectively. The area under the plasma
      concentration-time curve (AUC) was 5.8 times higher with LE-5132 than with 5132.
      Significantly higher intact ODN levels could be measured in most organs within 48
      hours of administration of LE-5132 compared with 5132 (liver 18.4-fold, spleen,
      31-fold, heart 3-fold, lungs 1.5-fold). In kidneys, the level was lower with LE
      5132 (0.77-fold). LE-5132 composition, unlike 5132, did not affect clotting time
      in vitro. Significant decline in the level of Raf-1 protein was observed in vitro
      in relatively radioresistant human laryngeal squamous cell carcinoma cells (SQ
      20B) treated with LE-5132 compared with SQ-20B cells treated with equimolar
      concentration of 5132 or liposome-encapsulated mismatched 5132 (0.5 microM LE
      5132, 71.3%+/-22.5%; 1.0 microM LE-5132, 79.6%+/-16.7%). In addition, LE-5132
      appeared to be a more potent antitumor compound than 5132 (p < 0.001). These data
      established the suitability of LE-5132 for in vivo radiotherapeutic efficacy
      studies. Intravenous administration of LE-5132 into SQ-20B tumor-bearing athymic
      mice inhibited Raf-1 expression in tumor tissue compared with blank liposome
      treated or untreated control groups. LE-5132 or ionizing radiation (IR) treatment
      alone caused significant but transient inhibition of SQ-20B tumor growth but not
      tumor regression. Remarkably, a combination of LE-5132 and IR treatments led to
      significant and sustained tumor regression for at least 27 days after the last
      treatment (< 0.001). Histopathologic examination of tumor samples revealed a
      significant proportion of cells containing fragmented chromatin in the LE-5132 +
      IR treatment group as compared with single agent and untreated control groups.
      These in vivo data support the notion that Raf-1 has proliferative and survival
      functions and advance the scientific and technologic bases for the use of
      antisense raf ODN in the management of radioresistant malignancies.

PMID- 10355827
TI  - Antisense morpholino oligonucleotide analog induces missplicing of C-myc mRNA.
AB  - A 28-mer morpholino oligonucleotide analog was designed to hybridize to 8 bases
      of intron 1 and extend 2 bases beyond the translation initiation codon in exon 2
      of the unspliced c-myc RNA transcript. Delivery of this compound into human
      chronic myeloid leukemia KYO1 cells, by streptolysin O permeabilization, resulted
      in almost total ablation of the 65 kDa c-MYC protein expression for at least 24
      hours after treatment. An unexpected band with SDS-PAGE electrophoretic mobility
      indicating a protein of about 47 kDa was apparent on the 24-hour western blots
      that were developed using antibodies that recognize MYC protein C terminal
      epitopes. No inhibition of the approximately 2400 nt c-myc mRNA expression was
      observed by northern hybridization, a result of the inability of morpholino
      analogs to direct the activity of ribonuclease H. In fact, high molecular weight
      c-myc RNA species were found to have accumulated in antisense-treated KYO1 cells.
      Control sense and scrambled antisense morpholino analogs did not inhibit MYC
      protein expression or induce the appearance of the anomalous RNA and protein
      bands. Molecular analyses by RT-PCR and sequencing revealed that the morpholino
      antisense effector had (1) inhibited splicing of the c-myc pre-mRNA, (2) induced
      missplicing of the pre-mRNA, and (3) inhibited translation of normal spliced c
      myc mRNA. Identical results were obtained with acute promyelocytic leukemia,
      acute lymphoblastic leukemia, and histiocytic lymphoma cell lines.

PMID- 10355826
TI  - Differential knockdown of delta-opioid receptor subtypes in the rat brain by
      antisense oligodeoxynucleotides targeting mRNA.
AB  - Two antisense oligodeoxynucleotides (A-ODN), targeting delta-opioid receptor mRNA
      (DOR) and two mismatch ODN sequences (mODN) were continuously infused for 24 days
      into the lateral brain ventricles of Wistar rats. The density of delta-opioid
      receptors in rat brain homogenates was measured by saturation binding experiments
      using four selective ligands, two agonists ([D-Ala2, Glu4]-deltorphin and DPDPE)
      and two antagonists (Dmt-Tic-OH and naltrindole), and by immunoblotting SDS
      solubilized receptor protein. In brain membranes of mODN or saline-infused rats,
      the rank order of delta-opioid receptor density, calculated by Bmax values of the
      four delta-opioid receptor ligands, was: [D-Ala2, Glu4]deltorphin approximately
      Dmt-Tic-OH approximately naltrindole (86-118 fmo/mg protein) > DPDPE (73.6+/-6.3
      fmol/mg protein). At the end of the 24 day infusion of A-ODN targeting DOR
      nucleotide sequence 280299 (A-ODN280-299), the Bmax of DPDPE (62.4+/-3.2 fmol/mg
      protein) was significantly higher than that of Dmt-Tic-OH (31.5+/-3.9 fmol/mg
      protein). Moreover, both the Kd value for DPDPE saturation binding and the Ki
      value for Dmt-Tic-OH displacement by DPDPE were halved. In contrast, an A-ODN
      treatment targeting exon 3 (A-ODN741-760) decreased the specific binding of [D
      Ala2, Glu4]deltorphin and Dmt-Tic-OH significantly less (67%-81%) than the
      binding of DPDPE (53%), without changes in DPDPE Ki and KD values. No A-ODN
      treatment modified the specific binding of the micro-opioid agonist DAMGO and of
      the k-selective opioid receptor ligand U69593. On the Western blot of solubilized
      striatum proteins, A-ODN(280-299) and A-ODN(741-760) downregulated the levels of
      the DOR protein, whereas the corresponding mODN were inactive. The 24-day
      infusion of A-ODN(280-299) inhibited the rat locomotor response to [D-Ala2,
      Glu4]deltorphin but not to DPDPE. Intracerebroventricular (i.c.v.) infusion of A
      ODN(741-760) reduced the locomotor responses to both delta-opioid receptor
      agonists, whereas mODN infusion never affected agonist potencies. In conclusion,
      these results demonstrate that 24-day continuous i.c.v. infusion of A-ODN
      targeting the nucleotide sequence 280-299 of DOR can differentially knockdown
      delta1 and delta2 binding sites in the rat brain.

PMID- 10355828
TI  - Selectivity of spermine homologs on triplex DNA stabilization.
AB  - We synthesized seven homologs of spermine (H2N(CH2)3NH(CH2)nNH(CH2)3NH2, where n
      = 2-9; n = 4 for spermine) and studied their effects on melting temperature (Tm),
      conformation, and precipitation of poly(dA).2poly(dT). The triplex DNA melting
      temperature, Tm1 was 34.4 degrees C in the presence of 150 mM KCl. Addition of
      spermine homologs increased Tm1 in a concentration-dependent and structure
      dependent manner, with 3-6-3 (n = 6) exerting optimal stabilization. The
      dTm1/dlog[polyamine] values were 9-24 for these compounds. The duplex melting
      temperature, Tm2 was insensitive to homolog concentration and structure,
      suggesting their ability to stabilize triplex DNA without altering the stability
      of the underlying duplex. Circular dichroism spectral studies revealed psi-DNA
      formation in a concentration-dependent and structure-dependent manner. Phase
      diagrams were constructed showing the critical ionic/polyamine concentrations
      stabilizing different structures. These compounds also exerted structural
      specificity effects on precipitating triplex DNA. These data provide new insights
      into the ionic/structural determinants affecting triplex DNA stability and
      indicate that 3-6-3 is an excellent ligand to stabilize poly(dA).2poly(dT)
      triplex DNA under physiologic ionic conditions for antigene therapeutics.

PMID- 10355830
TI  - 'Eye-catching' dermatitis for the skin surgeon.

PMID- 10355829
TI  - Phosphorothioate oligodeoxynucleotides inhibit basic fibroblast growth factor
      induced angiogenesis in vitro and in vivo.
AB  - Angiogenesis is regulated by heparin-binding growth factors, such as basic
      fibroblast growth factor (bFGF). We investigated the effects of phosphorothioate
      mediated oligodeoxynucleotides (PS-ODN) on bFGF-induced angiogenesis. Because PS
      ODN are polyanions, they can also bind many heparin-binding proteins. On a
      basement matrix using a Matrigel matrix, we observed <50% tube formation by human
      umbilical endothelial cells with 10 microM bFGF, vascular endothelial growth
      factor, or nuclear factor-kappaB (NF-kappaB) antisense and sense PS-ODN, while
      phosphodiester oligodeoxynucleotides (PO-ODNs) were not affected. The PS-ODN, but
      not the PO-ODN, inhibited the bFGF-induced rabbit corneal neovascularization. In
      albino rats, the NF-kappaB antisense PS-ODN showed a low rescue score for bFGF
      dependent photoreceptor rescue because of their degradation by constant light
      exposure. However, antisense PS-ODN active against bFGF inhibited angiogenesis
      more strongly than did the antisense NF-kappaB PS-ODN. Because of the important
      role bFGF plays in angiogenesis, some PS-ODN may serve as potent antiangiogenic
      compounds that act through a combination of polyanionic phosphorothioate effects
      and a sequence-specific antisense mechanism.

PMID- 10355831
TI  - Elective surgery and the patient with human immunodeficiency virus.

PMID- 10355832
TI  - The 1998 Pan American Lecture. Intraocular invasion of conjunctival squamous cell
      carcinoma in five patients.
AB  - PURPOSE: To report five patients with intraocular invasion of conjunctival
      squamous cell carcinoma and to make recommendations regarding clinical
      recognition and treatment of this condition. METHODS: The authors reviewed the
      clinical records and pathology slides on five patients who had intraocular
      invasion of conjunctival squamous cell carcinoma, and they describe the
      presenting features and histopathology in these cases. RESULTS: Intraocular
      invasion of conjunctival squamous cell carcinoma occurred in older patients who
      had one or more recurrences of a previously excised conjunctival epithelial tumor
      located near the comeoscleral limbus. The intraocular recurrence often was
      heralded by the onset of low-grade inflammation and secondary glaucoma,
      simulating a granulomatous iridocyclitis. A white mass generally was observed in
      the anterior chamber angle. Histopathologic examination revealed an ingrowth of
      malignant epithelial cells through the limbus with diffuse involvement of the
      anterior segment of the eye. The reported patients were managed by modified
      enucleation (standard enucleation with excision of affected conjunctival tissue).
      Metastatic disease did not develop in any of the patients. CONCLUSIONS: The onset
      of signs of uveitis and glaucoma and a white mass in the anterior chamber angle
      in a patient with prior excision of a conjunctival squamous cell neoplasm tumor
      should raise suspicion of intraocular recurrence of conjunctival squamous cell
      carcinoma. Most affected patients require enucleation or subtotal orbital
      exenteration. The prognosis is good.

PMID- 10355834
TI  - Removal of orbital apex hemangioma using new transorbital craniotomy through
      suprabrow approach.
AB  - PURPOSE: To describe a technique combining the expertise of the oculoplastic
      orbital surgeon and the neurosurgeon which allows access to the posterior orbit,
      anterior fossa, cavernous sinus and suprasellar region with minimal brain
      manipulation. METHODS: A transorbital craniotomy through a suprabrow incision is
      performed removing part of the frontal bone and orbital roof as a single piece.
      This allows wide access with only minimal, if any, brain retraction. The
      superior, lateral and medial orbit is clearly visualized, as well as the apex of
      the orbit. The bone flap is replaced at the end of the case with Tantalum plates.
      RESULTS: A cavernous hemangioma at the orbital apex was removed without
      complications. The exposure was superb and allowed identification and
      preservation of orbital structures. CONCLUSIONS: Transorbital craniotomy allows
      for wide access to the posterior orbit and parasellar region and anterior fossa
      of the brain with minimal brain manipulation. The use of a suprabrow incision
      results in an excellent cosmetic result. There is minimal postoperative
      morbidity, which decreases hospitalization time.

PMID- 10355833
TI  - Repair of orbital floor fractures with hydroxyapatite block scaffolding.
AB  - PURPOSE: To determine the efficacy of using a scaffold of hydroxyapatite blocks
      within the maxillary sinus to treat patients with large orbital floor fractures
      and secondary vertical globe dystopia. METHODS: Case series of five patients.
      Hydroxyapatite blocks were stacked within the maxillary antrum to support the
      reconstructed orbital floor. RESULTS: All patients had good results, though mild
      residual enophthalmos persisted in three patients. The orbital floor implants and
      globe positions remained stable during follow-up intervals ranging from 46 to 65
      months. No adverse postoperative complications, such as sinusitis, developed.
      CONCLUSIONS: Hydroxyapatite block scaffolding is a useful alternative to metallic
      floor implants and autologous bone grafts in the reconstruction of large
      traumatic orbital floor defects associated with vertical globe dystopia.

PMID- 10355835
TI  - Ocular-adnexal lymphoid tumors: a clinicopathologic and molecular genetic study
      of 77 patients.
AB  - PURPOSE: To determine whether molecular genetic analysis of ocular-adnexal
      lymphoid tumors, combined with histopathology and tumor location, is helpful in
      predicting which patients will develop systemic lymphoma. METHODS: A combined
      retrospective and prospective study of 77 patients with ocular-adnexal lymphoid
      tumors was performed. The tumors were subdivided into conjunctival, orbital, and
      eyelid lesions, and all were studied using both routine histopathology and
      molecular genetic analysis. RESULTS: Most lesions (70%) were small cell lymphomas
      of the mucosa-associated lymphoid tissue type, and the majority of tumors (90%)
      contained monoclonal or oligoclonal populations of lymphocytes discovered on
      molecular genetic analysis. Additionally, 72% of tumors exhibiting clonality had
      more than one gene rearrangement. Fifty-three percent of patients developed
      extraocular lymphoma sometime during the course of their disease. Patients with
      gene rearrangements on Southern blot hybridization had a 52% incidence of
      nonocular disease, compared with 63% of those without rearrangements. Patients
      with conjunctival tumors had a 37.5% incidence of nonocular disease, those with
      orbital tumors had a 54% incidence, and those with eyelid tumors had a 100%
      incidence of nonocular lymphoma. Only two patients died as result of systemic
      lymphoma. CONCLUSIONS: Most ocular-adnexal lymphoid tumors are lymphomas of the
      mucosa-associated lymphoid tissue type. The majority of tumors exhibit gene
      rearrangements on molecular genetic analysis, and this technique was not helpful
      in predicting which patients would develop nonocular lymphoma. Tumor location did
      have predictive value: Conjunctival lesions had the lowest incidence of nonocular
      lymphoma, and lid lesions had the highest incidence. Even with disseminated
      disease, most patients have a favorable prognosis with treatment.

PMID- 10355836
TI  - Gallium scanning in the diagnosis and management of orbital lymphoma: a case
      report.
AB  - PURPOSE: To illustrate the utility of gallium scintigraphy in the diagnosis and
      management of orbital lymphoma. METHODS: A patient with an orbital lymphoma is
      reported. The results of the computed tomography scan and gallium scan are
      reviewed. RESULTS: Although the orbital lymphoma was readily visible on the
      gallium scan, it was poorly visualized on the computed tomography scan, which was
      interpreted as normal. CONCLUSION: Gallium scanning is a valuable adjunct in the
      diagnosis and management of orbital and systemic lymphoma.

PMID- 10355837
TI  - Pilomatrixoma of the eyelids and eyebrows in children and adolescents.
AB  - PURPOSE: To review the clinical features of pilomatrixomas of the eyelids and
      eyebrows in children and adolescents. METHODS: The authors reviewed the medical
      records of 95 patients, all of whom were 20 years old or younger and had the
      histopathologic diagnosis of pilomatrixoma made from 1976 through 1995. Special
      attention was given to that subgroup of patients with tumors involving the
      eyelids and eyebrows. Data analyzed included age at diagnosis, patient sex,
      location and size of tumor, preoperative diagnosis, and clinical description of
      tumor. RESULTS: Eleven (12%) of 95 patients had lesions involving the eyelid or
      eyebrow. Six of those patients (55%) were female. Eight patients (73%) were 10
      years old or younger, and three were 11 to 20 years old. The tumor occurred on
      the upper lid or in the brow in eight patients, the lower eyelid in two patients,
      and the medial canthus in one patient. Tumor diameter was 1 cm or less in all 11
      patients. Pilomatrixoma was included in the preoperative differential diagnosis
      in only four of the 11 patients. The most common misdiagnoses were epidermoid and
      dermoid cyst. Three patients had pink or blue discoloration of the overlying
      skin, two had visible yellow-white patches in the tumor, and two had dilated
      vessels on the tumor surface. CONCLUSIONS: Pilomatrixoma is an uncommon tumor
      that can occur on the eyelids and in the brow region of children and adolescents.
      It is commonly misdiagnosed preoperatively as an epidermoid or dermoid cyst.
      Distinctive clinical features, however, suggest the correct diagnosis.

PMID- 10355838
TI  - Medpor Motility Coupling Post: a rabbit model.
AB  - PURPOSE: To verify if a Medpor porous polyethylene orbital implant (PPOI) (Porex
      Surgical, Atlanta, GA, U.S.A.), once vascularized, will tolerate a partially
      exposed titanium screw on its anterior surface. METHODS: Ten New Zealand white
      rabbits were enucleated and given Medpor PPOIs. Eight weeks postoperatively,
      Medpor Motility Coupling Posts (MCPs) (Porex Surgical) were placed into the
      orbital implants. Clinical tissue tolerance and histologic response to the new
      device were noted. RESULTS: The titanium screws were well tolerated by the
      animals. No case of post-operative infection, conjunctival inflammation,
      conjunctival erosion, MCP dislocation, or PPOI fragmentation was noted. A fibrous
      tissue growth over the titanium head was noted in all screws with a head height
      of 2.5 mm. The fibrous tissue overgrowth was not observed in screws with a head
      height of 4 mm or more. CONCLUSION: During the 6-month observation period, all
      implanted Medpor MCPs demonstrated favorable tissue tolerance and stable
      interfaces between the MCP and the conjunctiva and between the MCP and the PPOI.

PMID- 10355839
TI  - Hard palate mucosal grafts in the treatment of the contracted socket.
AB  - PURPOSE: The treatment of the traumatic contracted anophthalmic socket is
      challenging. The ability to wear an ocular prosthesis may require multiple
      operations to replace orbital volume, mucosa, or both. Hard palate mucosal grafts
      are a logical choice to augment mucosa and volume in the reconstruction of a
      contracted socket. METHODS: Ten patients with severely contracted sockets
      underwent socket reconstruction using hard palate mucosal grafts. The mucosal
      surface lining the contracted sockets was undermined and recessed toward the lid
      margins. Hard palate mucosal grafts that were harvested freehand and by using a
      radiofrequency instrument were placed in the socket fundus and sutured to the
      recessed mucosal edges. Forniceal sutures were placed full thickness through the
      lids, and custom conformers were placed in the sockets. In six patients, fixation
      sutures were passed through the conformer, fornices, and full thickness through
      the lid. In four patients, temporary tarsorrhaphies were placed for a minimum of
      4 weeks postoperatively. RESULTS: Postoperatively, 8 of the 10 patients were able
      to wear an ocular prosthesis comfortably. Cosmesis was acceptable. Two patients
      had recurrent socket contracture and were unable to wear a prosthesis.
      CONCLUSIONS: Hard palate mucosal grafts are a useful option in the surgical
      rehabilitation of contracted sockets. A mucosal surface, resistance to
      contracture, ease of harvesting, and ability for additional harvesting are
      advantages over other graft materials.

PMID- 10355840
TI  - Use of isobutyl cyanoacrylate tissue adhesive to stabilize mucous membrane grafts
      in total socket reconstruction.
AB  - PURPOSE: To describe a technique to secure a mucous membrane graft to a custom
      conformer during reconstruction of the conjunctival fornices and socket. METHODS:
      A cyanoacrylate-based tissue glue was used instead of sutures to secure the
      mucous membrane graft to the conformer. RESULTS: The adhesion between the graft
      and the conformer weakens over time, permitting easy removal of the conformer
      from the socket 6 to 12 weeks postoperatively. No complications were encountered
      in six patients in whom this technique was used. CONCLUSION: Using a
      cyanoacrylate-based tissue glue is simpler and quicker than suturing a mucous
      membrane graft.

PMID- 10355841
TI  - Nasolacrimal tuberculosis in a patient with conjunctivodacryocystorhinostomy.
AB  - PURPOSE: To present an unusual case of nasolacrimal tuberculosis that was
      diagnosed with polymerase chain reaction (PCR) and to discuss the role of PCR as
      a diagnostic aid. METHODS: Case presentation with diagnostic modalities including
      PCR, cytopathologic, and histopathologic examinations with special stains.
      RESULTS: A 40-year-old woman with bilateral lacrimal drainage system obstruction
      underwent a right dacryocystorhinostomy with stents and left
      conjunctivodacryocystorhinostomy with Jones bypass tube. Although the findings of
      direct and endoscopic examinations of the nasal cavity were within normal limits,
      the tissue removed during surgery from the middle turbinate revealed caseating
      granulomatous lesions on histopathologic examination. Acid-fast organisms were
      demonstrated in postoperative nasal washings, and Mycobacterium tuberculosis
      infection was confirmed with PCR. CONCLUSION: Primary tuberculosis of the
      nasolacrimal mucosa is rare, and its occurrence without any symptoms, as in this
      patient, is even less frequent. The most interesting aspect of this case was the
      identification of the M. tuberculosis DNA in the mucosa of anterior turbinate and
      fibrous tissue within the previous surgical site. Histopathologically, the
      presence of caseating granulomas was seen only in the nasal mucosa, indicating
      that PCR may be of use in identifying the causative organism even in the absence
      of typical histopathologic features.

PMID- 10355842
TI  - Computed tomography of the lacrimal drainage system: retrospective study of 107
      cases of dacryostenosis.
AB  - PURPOSE: To evaluate the role of computed tomography in patients with
      dacryostenosis. METHODS: One hundred seven cases of dacryostenosis (94 patients)
      were assessed by thorough clinical and lacrimal history and examination, and
      lacrimal region computerized tomography (CT). The lacrimal drainage system
      examination included the state and position of the puncta; Jones testing;
      lacrimal syringing; and, in the latter half of the study, telescopic nasal
      endoscopy. The patients were drawn from the hospital outpatients and private
      office of the operating lacrimal surgeon in this series (I.C.F.). Of the 107
      cases, 79 either underwent dacryocystorhinostomy surgery or had this planned.
      RESULTS: In 14 of the 107 cases (12 patients), preoperative CT led to an
      alteration of patient management, usually referral to an otolaryngologist for
      further evaluation or treatment. In addition to the detection of two tumors
      extrinsic to the sac, conditions such as ethmoiditis, lacrimal sac mucoceles,
      soft tissue opacity in the nasolacrimal duct, gross nasal polyposis, fungal
      sinusitis, and a dacryolith were observed by CT. CONCLUSION: Similar to the role
      of functional endoscopic sinus surgery in otolaryngology, CT imaging will become
      increasingly important in the assessment of many patients with symptoms of
      lacrimal drainage obstruction.

PMID- 10355843
TI  - Prevention of lacrimal stent prolapse using a silicone sleeve.

PMID- 10355844
TI  - The effects of pyruvate supplementation on body composition in overweight
      individuals.
AB  - A 6-wk, double-blinded, placebo-controlled study was done to ascertain the
      effects of pyruvate supplementation (6 g/d) on body weight, body composition, and
      vigor and fatigue levels in healthy overweight Caucasian men and women. Twenty
      six individuals were randomly assigned to a placebo group (seven men, seven
      women) and a pyruvate-supplemented group (three men, nine women). In addition,
      all subjects participated in a 3 d/wk exercise program, which consisted of a 45
      60 min aerobic/anaerobic routine. After 6 wk of treatment, there was a
      statistically significant decrease in body weight (-1.2 kg, P<0.001), body fat (
      2.5 kg, P<0.001), and percent body fat (23.0% pre versus 20.3% 6 wk post) in the
      pyruvate group. Furthermore, Profile of Mood States fatigue and vigor scores
      improved significantly for the pyruvate group (P<0.05) at 6 wk (vigor) and 4 and
      6 wk (fatigue). There was no significant change in total lean body mass in the
      pyruvate group. The placebo group demonstrated a significant increase (P<0.05)
      for POMS vigor at 2 and 4 wk with no changes occurring in any of the remaining
      parameters measured. Thus, the ingestion of 6 g of pyruvate for 6 wk, in
      conjunction with mild physical activity, resulted in a significant decrease in
      body weight and fat mass.

PMID- 10355845
TI  - Fat emulsion administration in the early postoperative period in patients
      undergoing esophagectomy for carcinoma depresses arachidonic acid metabolism in
      neutrophils.
AB  - The aim of this study was to evaluate the effect of fat emulsion administration
      on neutrophil arachidonic acid and leukotriene B4 (LTB4) generation in surgically
      stressed patients. Total parenteral nutrition was administered to 17 patients for
      2 wk after esophagectomy for carcinoma. Eight patients received fat with glucose
      (fat group, 30% of total calories) and 9 patients received glucose (glucose
      group) as a non-protein calorie source from the day of the operation to the
      seventh postoperative day (POD), and they gradually were converted to enteral
      nutrition during the second postoperative week. The arachidonic acid in the fat
      group decreased in the serum from POD 4 to 14. and in neutrophils from 12 h after
      the beginning of surgery to POD 14, compared to preoperative levels. LTB4
      production by A23187-stimulated neutrophils was highest 6 h after the beginning
      of surgery, when neutrophil arachidonic acid concentration was decreasing, and
      then fell below the preoperative value from POD 4 to 14 in both groups. LTB4
      production on POD 14 was lower in the fat group than in the glucose group.
      Biosynthesis of arachidonic acid from linoleic acid is inhibited in surgically
      stressed patients receiving fat emulsion, resulting in the diminished synthesis
      of LTB4 by neutrophils. The decrease in LTB4 may diminish chemotactic and
      chemokinetic signals to other leukocytes.

PMID- 10355846
TI  - Nasogastric tubes and dietary advancement after laparoscopic and open colorectal
      surgery.
AB  - Historically, all patients having abdominal procedures routinely awoke with a
      nasogastric tube, which remained until the resolution of the postoperative ileus
      as defined by the passage of flatus or feces per rectum. Dietary advancement was
      accomplished in a stepwise fashion, starting with clear liquids, progressing to
      full liquids, and finally a regular diet. Recently, the postoperative nutritional
      management of elective colorectal surgical patients has undergone several
      modifications and advancements. With the advent of the laparoscopic technique,
      attention was focused on the reported benefits of decreased postoperative pain,
      length of ileus, and consequently faster return to tolerance of diet. Surgeons
      then began to wonder if these benefits were really unique to laparoscopic
      surgery, or if laparotomy patients were merely treated differently than
      laparoscopy patients during the postoperative course. The next logical question
      was whether, after laparotomy, patients could be treated in the same manner as
      laparoscopic patients and enjoy the same postoperative benefits. The avoidance of
      a nasogastric tube and hence the subsequent rapid advancement of diet may shorten
      the length of hospitalization.

PMID- 10355847
TI  - Differences between men and women as regards the effects of protein-energy
      malnutrition on the hypothalamic-pituitary-gonadal axis.
AB  - Although protein-energy malnutrition (PEM) affects 50% of hospitalized patients,
      its effects on the hypothalamic-pituitary-gonadal (HPG) axis have not been
      extensively investigated. To investigate the effects of PEM on the HPG axis in
      hospitalized patients, 62 inpatients ages 18-91 y (35 men and 27 women) had a
      nutritional and hormonal evaluation. Hormones were determined in blood samples
      obtained between 0700 and 1200 h. Patients were divided into two subgroups: those
      with body mass index (BMI) <18.5 kg/m2 (low body mass index [LBMI]; 16 men, 13
      women) and those with BMI >20 kg/m2 (normal-high body mass index [NHBMI]; 19 men,
      14 women). The nutritional parameters of LBMI patients were inferior to those of
      NHBMI patients. Total and free testosterone levels were subnormal, 31.4% and
      17.2% respectively, in all men; free testosterone was subnormal in 31.25% of LBMI
      versus 5.3% of NHBMI male patients and total testosterone concentration was
      subnormal in 43.8% of LBMI versus 21.1% of NHBMI male patients. Luteinizing
      hormone (LH) level was higher in LBMI men than in NHBMI men, whereas the reverse
      was the case for women, for whom follicle-stimulating hormone (FSH) also was
      lower in the LBMI group than the NHBMI group. The HPG axis hormones which best
      discriminated between the LBMI and NHBMI groups were free testosterone for men
      and LH and FSH for women, which were all lower in the LBMI than in the NHBMI
      group. LH was correlated with BMI and midupper arm muscle circumference (AMC)
      (women positively and men negatively) but not with triceps skin-fold thickness
      (TSF). Total testosterone level was positively correlated with AMC and free
      testosterone with TSF. Hypogonadism is common among hospitalized patients with
      PEM. Men with PEM have low testosterone levels with normal or high gonadotropin
      levels, which suggests impairment of Leydig cell function. Women with PEM suffer
      hypogonadotropic hypogonadism. AMC correlates positively with total serum
      testosterone concentration in men and with LH levels in women, suggesting that
      satisfactory function of the HPG axis requires a functional (protein) reserve as
      well as an energy (fat) reserve.

PMID- 10355848
TI  - Phagocyte-induced lipid peroxidation of different intravenous fat emulsions and
      counteractive effect of vitamin E.
AB  - Unsaturated fatty acids, a major component of fat emulsions used in parenteral
      nutrition, are prone to peroxidation which is an important feature of oxygen
      associated tissue damage. We used the nitroblue tetrazolium (NBT) reduction test
      to measure the production of superoxide radicals by stimulated polymorphonuclear
      neutrophils (PMN) in the presence of different fat emulsions: Intralipid
      (containing 100% long-chain triacylglycerols, LCT), Vasolipid (a physical mixture
      of 50% LCT and 50% medium-chain triacylglycerols, MCT) and Structolipid
      (structured triacylglycerols containing 63% LCT and 37% MCT). We measured the
      amount of malonaldehyde (MDA) and 4-hydroxyalkenal to determine the lipid
      peroxidation of the three fat emulsions in the presence of stimulated
      neutrophils. Further, we investigated the role of vitamin E (alpha-tocopherol) in
      preventing lipid peroxidation in vitro. The results showed that the values of NBT
      reduction of PMN were significantly decreased in each of the three fat emulsions
      and that increasing concentrations of fat emulsions were associated with
      decreased values of NBT reductions, in a dose-dependent way (P<0.001). There
      were, however, no statistically significant differences between the values of the
      three different types of fat emulsions (P>0.05). Lipid peroxidation increased
      significantly in the presence of all three types of fat emulsions, and was more
      pronounced for Intralipid than for Vasolipid and Structolipid after 1 and 2 h of
      incubation with resting as well as with stimulated phagocytes. The increased
      lipid peroxidation of the fat emulsions was markedly reduced by vitamin E, and
      the inhibition was concentration dependent. In conclusion, lipid peroxidation in
      vitro is more pronounced when PMNs are incubated with fat emulsions. This
      increase in lipid peroxidation can be reduced by adding vitamin E to the fat
      emulsions.

PMID- 10355849
TI  - Effect of operative stress on food intake and feeding pattern in female rats.
AB  - Effects of operative stress on food intake, meal size, and meal number were
      measured in 15 female rats before and after jugular vein catheterization. All
      rats had 5-d estrous cycles which correlated with cyclical feeding patterns that
      were most prominent during dark phase eating. In proestrous, meal number peaked
      (30.3+/-1.32), and meal size reached a nadir (0.33+/-0.02 g) with some
      corresponding change in food intake (9.8+/-0.38 g). Following operation on day
      11, the cyclical variation of food intake, meal number, and meal size with
      estrous cycle was lost for the first 3 d, as was the diurnal rhythm in food
      intake. Eight rats recovered their dark phase feeding pattern by day 17
      (recovered group), while 7 had not done so even by day 24 (non-recovered group).
      Food intake decreased to 40% of baseline in the recovered group and to 25% in the
      non-recovered group on day 11, increasing to 70% by day 14 in both groups and
      matching preoperative levels by day 17. Similar postoperative decreases were
      observed in meal number and meal size. Light phase feeding was increased, the
      ratio of day to night food intake being three times preoperative levels even at
      day 24. Preoperatively, non-recovered rats were similar to the recovered rats in
      all feeding indexes and continued to have estrous cycling in vaginal smears
      postoperatively. In the non-recovered rats, meal size more than doubled and meal
      number was depressed by 47% of preoperative levels and remained low until the end
      of the study. We conclude that operative stress disrupted cyclical and diurnal
      rhythms in food intake. In female rats, meal size is the first index to recover,
      increasing temporarily to maintain food intake.

PMID- 10355850
TI  - Effects of a mixture of organisms, Lactobacillus acidophilus or Streptococcus
      faecalis on delta6-desaturase activity in the livers of rats fed a fat- and
      cholesterol-enriched diet.
AB  - The effect of a mixture of organisms (a probiotic mixture) comprising Bacillus,
      Lactobacillus, Streptococcus, Clostridium, Saccharomyces, and Candida (10(7-8)
      colony-forming units/g rice bran of each component) on delta6-desaturase activity
      in liver microsomes was compared with those of Lactobacillus acidophilus and
      Streptococcus faecalis. There were four treatment groups. Each group of these
      rats received rice bran (control), the mixture of organisms, L. acidophilus, or
      S. faecalis (30 g/kg) along with a fat- and cholesterol-enriched diet for 4 wk.
      The serum total cholesterol concentration of the group fed the mixture of
      organisms was reduced by 15-33% compared with the other groups at the end of the
      4-wk feeding period (P<0.05). The proportion of palmitic acid in the serum
      phosphatidylcholine (PC) for the control group was significantly higher than
      those of the other groups. The proportion of arachidonic acid in the serum PC for
      the mixed-organism group was also significantly higher than those of the other
      groups. The proportion of arachidonic acid in the liver PC for the mixed-organism
      group was significantly higher than those of the control and S. faecalis groups.
      The ratio of arachidonic acid/linoleic acid was significantly higher in the liver
      PC of rats fed the mixed organisms compared with the control group (P<0.05). The
      delta6-desaturase activity in the liver microsomal fraction of the mixed-organism
      group was significantly higher than those of the other groups. The delta6
      desaturase activity correlated positively with the ratio of arachidonic
      acid/linoleic acid of liver PC, the correlation coefficient (r) being 0.819
      (P<0.001). The results indicate that the effect of the mixture of organisms was
      to increase delta6-desaturase activity and serum arachidonic acid and decrease
      cholesterol compared to the other organisms and control, but the mechanism
      whereby the enzyme activity was related to serum cholesterol does not appear to
      have been explored.

PMID- 10355851
TI  - Ornithine alpha-ketoglutarate counteracts the decrease of liver cytochrome P-450
      content in burned rats.
AB  - The effect of ornithine alpha-ketoglutarate (OKG) on cytochrome P-450 enzyme
      activities was studied in a well-defined model of injury (burn followed by
      fasting then subsequent hypocaloric diet) administered to young rats for 3 d.
      Hepatic microsomes were prepared by ultracentrifugation and levels of cytochromes
      P-450 were determined spectrophotometrically. The activities of ethoxy-resorufin
      O-deethylase (EROD), benzyloxy-resorufin-O-dealkylase (BROD), and erythromycin
      demethylase were measured as markers of P-450 1A, 2A, and 3A isotypes
      respectively. The level of total hepatic microsomal proteins (8 mg/mL) remained
      constant. The level of cytochrome P-450 (1.14+/-0.08 nmol/mg microsomal proteins)
      was decreased by a hypocaloric diet (23%, P = 0.003) and burn further enhanced
      this phenomenon (15%, P = 0.03). Both healthy and burned rats receiving OKG
      showed the same level of cytochrome P-450 as the rats fed ad libitum. OKG
      supplementation counteracted the enhancement (40%) of EROD activity induced by
      hypocaloric diet but did not influence BROD and erythromycin demethylase
      activities. OKG sustained cytochrome P-450 levels in rats fed a hypocaloric diet,
      even after burning. These findings indicate that OKG may favor drug metabolism in
      this injured population.

PMID- 10355852
TI  - An evaluation of resting energy expenditure in hospitalized, severely underweight
      patients.
AB  - A prospective trial was conducted with 14 hospitalized patients who were severely
      underweight with a mean weight of 40.9+/-5.1 kg and 70.7+/-7.8% of ideal body
      weight, to compare estimates of resting energy expenditure (REE) with measured
      values. The 9 women and 3 men, whose mean age was 66.5+/-13.9 y, underwent
      nutritional assessment and measurement of their REE by indirect calorimetry using
      the Sensormedics Deltatrac MBM100 indirect calorimeter. Their REE was also
      estimated by the Harris-Benedict formula (mean 1032+/-66 kcal/d) as well as a
      previously established empirical formula where REE = 25 x body weight in kg (mean
      1023+/-129 kcal/d). Results by both estimates were significantly lower than the
      measured resting energy expenditure (MREE) in this group of patients (P<0.0001).
      The percentage difference between MREE and estimated REE by the Harris-Benedict
      formula was 18.4+/-9.4% and 20.9+/-7.5% by the empirical formula. The MREE
      exceeded the estimated REE in each individual. The correlation between MREE and
      body weight (r2 = 0.558, r = 0.005) was better than that between MREE and
      estimated REE by Harris-Benedict formula (r2 = 0.275, P = 0.08) suggesting that
      weight was the principal determinant rather than the other components (height,
      age, sex) of the Harris-Benedict formula. Our data shows that commonly employed
      formulae routinely underestimate the energy needs of severely underweight
      patients below 50 kg in body weight. The Harris-Benedict equation had limited
      predictive value for the individual, explaining approximately 25% of the variance
      in energy expenditure. Given the particular importance of matching energy intake
      to needs in this group of patients with limited reserves, many of whom are
      critically ill, we suggest an empirical equation using 30-32 kcal/kg be used to
      estimate the energy requirements of severely underweight patients when direct
      measurements are unavailable or clinically less imperative.

PMID- 10355853
TI  - Celiac disease and hypoprothrombinemia.

PMID- 10355854
TI  - The influence of maternal diet on breast cancer risk among female offspring.
AB  - The induction of breast cancer is a long process, containing a series of
      biological events that drive a normal mammary cell towards malignant growth.
      However, it is not known when the initiation of breast cancer occurs. One
      hypothesis is that a high estrogenic environment during the perinatal period
      increases subsequent breast cancer risk. There are many sources of extragonadal
      estrogens, particularly in the diet. The purpose of this paper is to review the
      evidence that a high maternal intake of dietary fats increases serum estrogens
      during pregnancy and increases breast cancer risk in daughters. Our animal
      studies show that a high maternal consumption of corn oil consisting mainly of
      linoleic acid (omega-6 polyunsaturated fatty acid, PUFA), increases both
      circulating estradiol (E2) levels during pregnancy and the risk of developing
      carcinogen-induced mammary tumors among the female rat offspring. A similar
      increase in breast cancer risk occurs in female offspring exposed to injections
      of E2 through their pregnant mother. Our data suggest that the mechanisms by
      which an early exposure to dietary fat and/or estrogens increases breast cancer
      risk is related to reduced differentiation of the mammary epithelial tree and
      increased number of mammary epithelial cell structures that are known to the
      sites of neoplastic transformation. These findings may reflect our data of the
      reduced estrogen receptor protein levels and protein kinase C activity in the
      developing mammary glands of female rats exposed to a high-fat diet in utero. In
      summary, a high dietary linoleic acid intake can elevate pregnancy estrogen
      levels and this, possibly by altering mammary gland morphology and expression of
      fat- and/or estrogen-regulated genes, can increase breast cancer risk in the
      offspring. If true for women, breast cancer prevention in daughters may include
      modulating the mother's pregnancy intake of some dietary fats.

PMID- 10355855
TI  - Lymphocytic gastritis, Helicobacter pylori, and gastric cancer: is vitamin C the
      common link?

PMID- 10355856
TI  - Enteral nutrition in the critically ill: is the gut working properly?

PMID- 10355857
TI  - Beta-carotene and immune function: is it a case of defining the right intake?

PMID- 10355858
TI  - Footprint of fish: docosahexaenoic acid (DHA) in adipose tissue.

PMID- 10355859
TI  - Safe practices in parenteral nutrition compounding--an international consensus?

PMID- 10355860
TI  - The nutritional dimension of physical assessment.

PMID- 10355861
TI  - Nutrition: neglected nursing business.

PMID- 10355862
TI  - Application of methionine-free nutrition as an anticancer treatment.

PMID- 10355863
TI  - Medical costs of treating venous stasis ulcers: evidence from a retrospective
      cohort study.
AB  - Venous stasis ulcers (VSU) account for approximately 80-90% of lower extremity
      ulcerations. Given their prevalence and chronic nature, VSU are thought to impose
      a significant economic burden on Medicare (the USA's largest health insurance
      program) and other third party payers. However, comprehensive studies on the
      costs of VSU treatment are lacking. The objective of this study therefore was to
      examine comprehensively the direct medical costs of treating patients with a VSU
      in routine clinical practice. A cohort of 78 patients who presented with a VSU to
      the Cleveland Clinic Foundation (CCF), a large primary and tertiary referral
      center, was studied retrospectively. All inpatient and outpatient costs related
      to VSU treatment that were incurred during the year following VSU presentation or
      until the ulcer healed, whichever occurred first, were quantified. A total of 71
      (91%) patients healed during the study. The average duration of follow-up was 119
      days (median: 84 days). The average number of visits per patient was seven
      (range: 2 to 57). A total of 14 (18%) patients underwent 18 hospitalizations for
      VSU care. The average total medical cost per patient was $9685 (median: $3036).
      Home health care, hospitalizations and home dressing changes accounted for 48%,
      25% and 21% of total costs, respectively. Total costs were related to duration of
      active therapy, ulcer size and the presence of at least one comorbidity (p<0.05).
      VSU are costly to manage, especially when time to healing is prolonged. The
      present findings reflect an underestimate of VSU costs since indirect costs were
      not examined. Time absent from work, forced early retirement, loss of functional
      independence and unquantifiable suffering may be additional factors that
      contribute to the overall burden of VSU.

PMID- 10355865
TI  - Quantitative and qualitative progression of peripheral arterial disease by non
      invasive testing.
AB  - There is little information on the progression of peripheral arterial disease
      (PAD) over time. A series of 508 patients with a prior examination for PAD were
      contacted and brought in for follow-up to evaluate the natural history of PAD. A
      total of 85 patients were excluded because they had interventions in both limbs
      prior to their return visit. Progression was assessed in the remaining 423
      patients for a total of 755 limbs, both quantitatively and qualitatively using
      six categories of PAD severity. There was a modest overall categorical
      progression of disease: 228 limbs (30.2%) displayed categorical progression,
      while 172 limbs (22.8%) improved over a 4.6-year average follow-up. Through
      analysis of quantitative change, it was determined that more quantitative
      progression occurred than was evident from categorical progression. Two of the
      three non-invasive tests employed, the ankle/brachial index (ABI) and posterior
      tibial peak forward flow velocity (peak PT), showed statistically significant
      progression during follow-up: mean ABI change = -0.019, 95% confidence interval
      (CI)= -0.031 to -0.007; mean peak PT change = -2.32 cm/s, 95% CI = -3.20 to 
      1.44. The toe/brachial index (TBI) also suggested progression: mean change= 
      0.013, but the 95% CI included no change. Standard scores (sum of the Z-scores
      for ABI, peak PT and TBI) were calculated. The standard score progressed
      approximately 0.34 units (standard deviations), p-value <0.001, over 4.6 years;
      or about 0.07 standard deviations per year. There were independent and
      statistically significant (p<0.05) associations between the rate of PAD
      progression (standard score change) and age, diabetes, classic ('Rose')
      intermittent claudication, moderate to severe PAD in the same limb, moderate to
      severe PAD in the contralateral limb and future therapeutic intervention. There
      were independent and suggestive associations (0.05<p-value<0.15) between PAD
      progression and pain at rest, mild PAD in the same limb, and mild PAD in the
      contralateral limb. PAD progression was not associated with gender, atypical
      claudication, or amputation status. Thus, in this cohort of PAD patients, PAD on
      average progressed significantly over 4.6 years. This progression was
      independently related to age, diabetes and several markers of disease severity.

PMID- 10355864
TI  - Venous thrombus stability during acute phase of therapy.
AB  - The purpose of this study was to use serial venous duplex scans to document the
      status of deep venous thrombi during the early phase of therapy for acute, deep
      vein thrombosis (DVT). A total of 71 consecutive participants treated for a first
      episode of acute DVT were monitored for new venous thrombosis using serial venous
      duplex scans. An average of 4.6 duplex scans were performed per patient (range,
      three to seven) during the 3-week study period. The cumulative incidence of
      contiguous/non-contiguous extension of the DVT at 3 weeks was 26% (95% CI = 14%
      to 38%). Nine of the 15 (60%) occurrences were asymptomatic. None of the
      classical risk factors for DVT was significantly associated with the development
      of new thrombi. The fraction of time during which the level of anticoagulation
      was considered 'adequate' (international normalized ratio > or =2.0 and/or
      heparin concentration > or =0.2 IU/ml) was inversely associated with the risk of
      extension/new thrombi (p = 0.01, Cox proportional hazards analysis). It was
      concluded that: (1) the frequency of contiguous/non-contiguous extension of
      venous thrombosis detectable during the first 3 weeks of therapy was higher than
      previously reported; (2) the majority of the occurrences were asymptomatic; and
      (3) the risk of developing this complication was inversely associated with the
      level of anticoagulation achieved.

PMID- 10355866
TI  - Decrease in P-selectin levels in patients with hypercholesterolaemia and
      peripheral arterial occlusive disease after lipid-lowering treatment.
AB  - At sites of thrombosis and vascular injury, interactions occur among platelets,
      leucocytes and endothelial cells. Patients with peripheral arterial occlusive
      disease (PAOD) have been shown to have raised total serum cholesterol and serum
      triglycerides and increased sP-selectin levels when compared with controls. A
      total of 31 patients with PAOD and hypercholesterolaemia took part in this three
      staged study. Soluble P-selectin (sP-selectin) levels were significantly lowered
      after 12 weeks of fluvastatin treatment (157.0 ng/ml versus 113.77 ng/ml, p =
      0.01), whereas 12 weeks of placebo treatment had no statistically significant
      effect on sP-selectin levels (150.0 ng/ml versus 139.4 ng/ml). An unpaired t-test
      almost reached statistical significance (p = 0.051) when the levels by which sP
      selectin fell after 12 weeks of active or placebo treatment were compared. The
      placebo group was then put onto long-term, active treatment and sP-selectin
      levels were significantly lowered by fluvastatin when compared to pre-treatment
      levels (150.0 ng/ml versus 110.0 ng/ml, p = 0.03). By lowering the levels of P
      selectin, fluvastatin may not only attenuate atherosclerotic progression but may
      also decrease the platelet activation associated with PAOD.

PMID- 10355867
TI  - L-arginine and nitric oxide-related compounds in plasma: comparison of normal and
      arginine-free diets in a 24-h crossover study.
AB  - The amino acid L-arginine is the precursor of nitric oxide (NO), a powerful
      vasodilator with antiplatelet properties. The availability of L-arginine has been
      suggested to be a rate-limiting factor in the production of NO in conditions such
      as hypercholesterolemia. It was speculated that fluctuations in plasma
      concentrations of L-arginine during the day may be dependent upon dietary intake
      of the amino acid, or other variables, and might modify the elaboration of
      endogenous NO. Over a 24-h period, the plasma concentrations of L-arginine and NO
      related compounds (NOx) were measured during an L-arginine and nitrate/nitrite
      free diet (diet A) or a nitrate/nitrite-free diet with a fixed amount of L
      arginine intake (3.8 g/d) (diet B) in eight healthy volunteers during a 2-day
      crossover study. Subjects were randomly selected to begin with diet A or diet B
      and consumed the other diet on the second day. During diet A, plasma L-arginine
      decreased significantly from 09.00 to 16.00 (21.4+/-2.0 to 11.9+/-1.1 microg/ml),
      rose slightly in the evening (to 16.6+/-1.7 microg/ml) and gradually increased
      during the night. During diet B, plasma L-arginine showed a peak after each meal
      (approximately 23 microg/ml). Plasma NOx concentrations measured by
      chemiluminescence did not show any circadian variation on either diet. Plasma L
      arginine concentrations change during the day and are influenced by dietary
      intake. Importantly, plasma NOx do not seem to vary with this pattern in healthy
      individuals.

PMID- 10355868
TI  - Relief of sleep apnea after intravascular stenting for superior vena cava
      syndrome.
AB  - A rarely reported association of sleep apnea and superior vena cava stenosis from
      mediastinal fibrosis is described. A case is presented where substantial
      improvement in the sleep parameters and the symptoms of sleep apnea occurred
      subsequent to superior vena cava thrombolysis and stent angioplasty.

PMID- 10355869
TI  - Antiphospholipid antibody syndrome in a patient with neurosarcoidosis.
AB  - The case of a 56-year-old woman who developed neurosarcoidosis and was discovered
      to have inferior vena cava and lower extremity thromboses is described. She was
      found to have anticardiolipin antibodies. This newly described association of
      antiphospholipid antibody syndrome with sarcoidosis is discussed and the relevant
      literature reviewed.

PMID- 10355870
TI  - Circadian variation and triggering of cardiovascular events.
AB  - Myocardial infarction and sudden cardiac death demonstrate a marked circadian
      variation with an increased risk during the morning after awakening and arising.
      The recognition of the morning increase of acute cardiovascular events has
      convinced many that they may be triggered by morning activities. It is of note,
      however, that cardiovascular events occur throughout the day--even if at lower
      frequency compared with the morning. There is a strong association between
      external triggers and the onset of myocardial infarction and sudden cardiac death
      beyond what is to be expected by chance alone. The magnitude of this association
      (relative risk two- to threefold) is comparable with the known long-term risk
      factors of cardiac disease. Trigger factors occur relatively frequently and may
      play a causative role in up to 20% of cases of acute coronary syndromes. Physical
      exertion, bursts of anger and sexual activity have been proved to have triggering
      potential. Other possible triggers include external and environmental events such
      as earthquakes, war threat and climatic factors. The pathophysiological links
      between external triggers and the onset of cardiovascular events are important in
      addressing the question of a causal relationship between triggers and disease
      onset and in perhaps improving preventive strategies.

PMID- 10355871
TI  - Images in vascular medicine. Arteriovenous fistula from the common carotid artery
      to the internal jugular vein.

PMID- 10355872
TI  - Transient up-regulation of myotonic dystrophy protein kinase-binding protein,
      MKBP, and HSP27 in the neonatal myocardium.
AB  - Myotonic dystrophy protein kinase (DMPK)-binding protein, MKBP, has high homology
      with a small heat shock protein, HSP27. Western blotting analyses showed that
      MKBP level in rat heart rapidly increased, with a sharp peak at one week after
      birth (3-fold the level at the fetus), but that it rapidly decreased (1/10 of
      peak value at 13 weeks). Human myocardium also showed similar age-dependency.
      Similar but small increase of HSP27 was observed in the neonatal rat myocardium,
      but not in constitutive and inducible forms of HSP70. Immunofluorescence analysis
      localized MKBP at the Z lines and intercalated discs in the rat myocardium. MKBP
      may protect actin cytoskeleton or other proteins of heart muscle against
      oxidative stress in the neonate.

PMID- 10355873
TI  - Transferrin synthesized in cultured human fibroblasts is associated with tubulins
      and has iron binding capacity.
AB  - In a previous report (13), using immunocytochemical and fluorescence-labeling
      techniques, we demonstrated that transferrin is synthesized in cultured human
      fibroblasts and that it is associated with tubulins in the cells. These
      morphological findings led us to attempt to elaborate those issues in more detail
      by biochemical methods. In this report, we were able to prove the association of
      transferrin produced in cells with tubulins. In addition, the transferrin
      associated with tubulins was found to bind to iron. These results suggest that
      endogenous transferrin plays a role in preventing damage caused by free radicals
      which can be induced by the interaction of iron with the hydrogen peroxide
      produced in cells.

PMID- 10355874
TI  - Disruption of circumferential actin filament causes disappearance of occludin
      from the cell borders of rat hepatocytes in primary culture without distinct
      changes of tight junction strands.
AB  - We investigated the relationship of actin filament organization to occludin and
      tight junction strands in primary cultured rat hepatocytes using an actin
      depolymerizing agent, mycalolide B. In control cultures, well-developed
      circumferential actin filaments and occludin immunoreactivity were observed on
      the most subapical plasma membrane of the cells, and tight junction strands
      formed well-developed networks in freeze-fracture replicas. In hepatocytes
      treated with 3 microM mycalolide B for 6 h, circumferential actin filaments and
      occludin immunoreactivity disappeared from the cell borders. However, there were
      no marked abnormalities of tight junction strands in freeze fracture replicas.
      Similar results were obtained from cells cultured in medium with 0.05 mM Ca2+ for
      6 h. The close association of occludin with actin and the existence of intact
      tight junction strands that are virtually free of both occludin and actin suggest
      a physiological role of occludin, but not the other proteins forming the tight
      junction strands, in the linkage between actin cytoskeleton and tight junction.

PMID- 10355876
TI  - Direct measurement of inter-doublet elasticity in flagellar axonemes.
AB  - The outer doublet microtubules in ciliary and flagellar axonemes are presumed to
      be connected with each other by elastic links called the inter-doublet links or
      the nexin links, but it is not known whether there actually are such elastic
      links. In this study, to detect the elasticity of the putative inter-doublet
      links, shear force was applied to Chlamydomonas axonemes with a fine glass needle
      and the longitudinal elasticity was determined from the deflection of the needle.
      Wild-type axonemes underwent a high-frequency, nanometer-scale vibration in the
      presence of ATP. When longitudinal shear force was applied, the average position
      of the needle tip attached to the axoneme moved linearly with the force applied,
      yielding an estimate of spring constant of 2.0 (S.D.: 0.8) pN/nm for 1 microm of
      axoneme. This value did not change in the presence of vanadate, i.e., when dynein
      does not form strong cross bridges. In contrast, it was at least five times
      larger when ATP was absent, i.e., when dynein forms strong cross bridges. The
      measured elasticity did not significantly differ in various mutant axonemes
      lacking the central-pair microtubules, a subset of inner-arm dynein, outer-arm
      dynein, or the radial spokes, although it was somewhat smaller in the latter two
      mutants. It was also observed that the shear displacement in an axoneme in the
      presence of ATP often took place in a stepwise manner. This suggests that the
      inter-doublet links can reversibly detach from and reattach to the outer doublets
      in a cooperative manner. This study thus provides the first direct measure of the
      elasticity of inter-doublet links and also demonstrates its dynamic nature.

PMID- 10355875
TI  - Expression of extracellular matrix components fibronectin and laminin in the
      human fetal heart.
AB  - It has been well documented that the extracellular matrix components fibronectin
      and laminin promote or regulate morphogenesis of the myocardial cells in
      mammalian heart. However, their chronological change of expression (or
      localization) in the human heart remains elusive. In this study, fibronectin and
      laminin in the left ventricle of forty-two human fetuses aged from 8 to 26 weeks
      gestation and left ventricular tissues obtained from a 2-week old infant and two
      adults were investigated by Western blot analyses and indirect immunofluorescence
      technique with monoclonal antibodies. In the fetal heart, fibronectins were
      present along the endocardium, epicardium, and linings of larger blood vessels.
      In 14-16 weeks gestation, fibronectin immunofluorescence became stronger but not
      evenly dispersed in the interstitium. After 24 weeks gestation, they were
      strongly positive only in the relatively larger blood vessels, as well as those
      in the infant and adult cardiac tissues. Laminins were strongly positive along
      the endocardium and basement membrane of the myocardial cells and fibroblasts
      during fetal life. After birth, laminins formed fine fibrillar network along the
      basement membrane in association with the transverse tubules of myocardial cell;
      these morphological characteristics remained in the adult cardiac tissues. These
      results indicate that fibronectin expression is relatively constant during fetal
      life but decreases after birth; in contrast, laminin expression is not age
      dependent and constant throughout the life.

PMID- 10355877
TI  - SV40LT highly mutates and immortalizes two fibroblast strains from patients with
      Wilms' tumor.
AB  - In order to analyze in detail the process of immortalization of human cells,
      SV40LT was introduced into two chromosome 11p- fibroblast strains from Wilms'
      tumor patients. Both fibroblasts, hereafter referred to as CM1 and CM2, displayed
      the mutant phenotype in the crisis stage of cellular aging. In comparison to a
      control fibroblast, the density of the CM1 strain was abnormally high while the
      crisis period of the CM2 strain was abnormally long. The CM1 immortalization was
      7 times greater than the control and the CM2 strain had the highest frequency of
      immortalization, 7 times greater than the CM1. These findings indicate that genes
      associated with chromosome 11p- may be involved in the immortalization of human
      cells. During their abnormal crisis periods, the cells derived from the patients
      with Wilms' tumor showed an extremely high frequency of chromosomal aberrations
      and mutations (6TGs --> 6TGr). These results indicate that when the growth
      arrested cells from Wilms' patients are induced to grow with the introduction of
      SV40LT at the crisis stage they are highly mutable, resulting in their
      immortalization in vitro.

PMID- 10355878
TI  - Effects of the central pair apparatus on microtubule sliding velocity in sea
      urchin sperm flagella.
AB  - To produce oscillatory bending movement in cilia and flagella, the activity of
      dynein arms must be regulated. The central-pair microtubules, located at the
      centre of the axoneme, are often thought to be involved in the regulation, but
      this has not been demonstrated definitively. In order to determine whether the
      central-pair apparatus are directly involved in the regulation of the dynein arm
      activity, we analyzed the movement of singlet microtubules that were brought into
      contact with dynein arms on bundles of doublets obtained by sliding
      disintegration of elastase-treated flagellar axonemes. An advantage of this new
      assay system was that we could distinguish the bundles that contained the central
      pair apparatus from those that did not, the former being clearly thicker than the
      latter. We found that microtubule sliding occurred along both the thinner and the
      thicker bundles, but its velocity differed between the two kinds of bundles in an
      ATP concentration dependent manner. At high ATP concentrations, such as 0.1 and 1
      mM, the sliding velocity on the thinner bundles was significantly higher than
      that on the thicker bundles, while at lower ATP concentrations the sliding
      velocity did not change between the thinner and the thicker bundles. We observed
      similar bundle width-related differences in sliding velocity after removal of the
      outer arms. These results provide first evidence suggesting that the central pair
      and its associated structures may directly regulate the activity of the inner
      (and probably also the outer) arm dynein.

PMID- 10355879
TI  - Mechanisms of attention in touch.
AB  - A series of experiments demonstrated the role of higher level cognitive
      processes, such as attention, in tactile perception. The first series of
      experiments demonstrated that automatic orienting to a tactile stimulus resulted
      in inhibition of subsequent stimuli at that body site--inhibition of return
      (IOR). A possible explanation suggests that inhibition of saccades to a body site
      can cause the inhibition of subsequent stimuli presented to that same site. In
      contrast, when the subjects strategically oriented attention to the stimulus, the
      processing of subsequent stimuli at that body site was facilitated. In both of
      these experiments the skin received exactly the same test stimuli, (100 Hz sine
      wave presented for 50 ms), but very different effects were observed depending
      upon attentional strategy. Experimental manipulations showed that this cannot be
      due to a peripheral masking of the receptors after cue presentation to the
      target. Rather the results may be explained centrally by cognitive, particularly
      attentional mechanisms. Cross-modal interactions suggest that tactile processes
      are facilitated when vision is oriented to the body site receiving stimulation.
      Possible explanations come from recent findings of spatiotopic maps of different
      sensory modalities in the superior colliculus of the midbrain and in the parietal
      lobe. These are integrated with motor systems that control saccades and head
      orientation towards sensory inputs. Excitatory links among these maps could be
      the source of the observed facilitation effects.

PMID- 10355880
TI  - Proprioceptive control of wrist extensor motor units in humans: dependence on
      handedness.
AB  - The effectiveness of the monosynaptic proprioceptive assistance to the wrist
      extensor motoneurone activity was investigated during voluntary contraction in
      relation to the subjects' handedness. The reflex responses of 411 single motor
      units to homonymous tendon taps were recorded in the wrist extensor carpi
      radialis muscles in both arms of five right-handed and five left-handed subjects.
      In the right-handed subjects, the motor unit reflex responses were clearly
      lateralized in favour of their right arm, whereas no side-related differences
      were observed in the left-handed subjects, whatever the motor units' mechanical
      properties and firing rates. When the muscle spindle sensitivity was by-passed by
      electrically stimulating the primary afferents in both arms of three right-handed
      and three left-handed subjects, no side-related differences were observed in the
      Hoffmann reflex (H-reflex) amplitude in either of the two lateralization groups.
      The effectiveness of the primary afferent synapses on to the motoneurones
      therefore does not seem to depend on the subject's handedness. Without excluding
      the possibility of structural changes being involved at the periphery, the
      comparisons carried out on the data obtained using electrical vs mechanical
      stimulation suggest that the asymmetrical effectiveness of the proprioceptive
      assistance observed in favour of the right arm in the right-handed subjects might
      result from either the gamma or beta drive being more efficient. This asymmetry
      might result from the preferential use of the right hand in skilled movements. In
      a predominantly right-handed world, however, left-handed people might tend to
      develop the ability to use their right arm almost as skillfully as their
      preferred left arm, which could explain the symmetrical effectiveness of the
      proprioceptive assistance observed here in the left-handers' wrist extensor
      muscles.

PMID- 10355881
TI  - Changes in substance P and calcitonin gene-related peptide binding in the dorsal
      horn of rat spinal cord following pronase-induced deafferentation.
AB  - Quantitative receptor autoradiography was used to evaluate potential alterations
      in substance P (SP) and calcitonin gene-related peptide (CGRP) binding in the L4
      spinal segment of rats following unilateral poisoning of the sciatic nerve with
      pronase. Ten days after pronase-induced deafferentation there was a significant
      increase in SP and CGRP binding in the superficial (I-II) and deeper (II-IV)
      laminae of the dorsal horn ipsilaterally. Densitometric measurements revealed a
      50% return towards normal values for SP binding by 90 days postpronase injection
      in all laminae examined, while the density of CGRP binding showed a partial
      return towards normal values for laminae III-IV only. These differential
      responses may be indicative of the mechanisms underlying pronase-induced
      peripheral neuropathy.

PMID- 10355882
TI  - Deafferentation-induced regulation of AMPA receptors in the spinal cord of the
      adult rat.
AB  - Glutamate released from primary afferents is thought to be involved in mediating
      spinal reflexes, nociception, and the development and consequent maintenance of
      hyperalgesia. The role of glutamate is dependent on the distribution and
      regulation of glutamate receptors in the spinal cord. Due to the numerous
      glutamate receptor subtypes and their differential physiological profiles, the
      system is quite complex. Understanding the regulation of the various glutamate
      receptor subunits may aid in the elucidation of the role of glutamate in
      somatosensory processing. In this study we found a transient reduction in delta
      amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptors in the dorsal
      horn following partial deafferentation. The time course for the alterations of
      spinal AMPA receptors may correspond to the functional consequence of
      deafferentation.

PMID- 10355883
TI  - Inverted pyramidal neurons in chimpanzee sensorimotor cortex are revealed by
      immunostaining with monoclonal antibody SMI-32.
AB  - We used the monoclonal antibody SMI-32 to label pyramidal cells of sensorimotor
      cortex in two chimpanzees. The majority of the pyramidal cells had typical
      vertically oriented apical dendrites that extended towards the pial surface. A
      small population of pyramidal cells varied from this orientation, so that the
      apical dendrites were 20 degrees or more from radial, and were often inverted,
      extending away from the pial surface. When numbers of non-inverted and inverted
      pyramidal cells were compared, less than 1% were found to be inverted.

PMID- 10355884
TI  - Sex differences in heat pain thresholds as a function of assessment method and
      rate of rise.
AB  - Studies of sex differences in the responses to experimentally induced pain
      demonstrate greater pain sensitivity among females than males. However, studies
      investigating heat pain responses have produced inconsistent results. Differences
      in stimulus characteristics and assessment methods probably account for this
      variability. This study examined sex differences in the heat pain threshold as a
      function of two different assessment methods and varying rates of rise. Nineteen
      female and 18 male healthy volunteers underwent heat pain threshold assessment
      via the method of levels and the method of limits. In addition, both fast (4.0
      degrees C/s) and slow (0.5 degrees C/s) rates of rise were used for the method of
      levels assessments. In order to examine the reliability of threshold values, each
      subject participated in two sessions, separated by approximately 8 days. Females
      evinced lower thresholds than males for the method of levels assessments with
      both slow and fast rates of rise (ps < 0.05), while no sex differences emerged
      for the threshold assessed via the method of limits. Test-retest reliability
      coefficients were relatively high. However, thresholds generally increased
      significantly from session 1 to session 2. Between method correlations were
      generally low to moderate. These findings indicate that the method of levels may
      be more sensitive to sex differences than the more commonly used method of
      limits. Also, thresholds appear to increase from session 1 to session 2, and
      thresholds assessed via different methods are not strongly correlated. Potential
      implications of these results for experimental pain assessment are discussed.

PMID- 10355885
TI  - Radiofrequency thermal ablation of liver tumors.
AB  - Chemotherapy and radiation therapy are ineffective against primary and secondary
      malignant hepatic tumors. Surgical resection has been considered the only
      potentially curative option, but few patients with hepatic tumors are candidates
      for surgery. Recent results suggest that radiofrequency thermal ablation may be
      an effective, minimally invasive technique for treating malignant hepatic tumors.
      Sonography is the primary technique for guiding percutaneous ablative procedures.
      We review the current research and clinical experience with radiofrequency
      thermal ablation for treating malignant hepatic tumors.

PMID- 10355886
TI  - Evaluation of solid breast lesions with power Doppler sonography.
AB  - PURPOSE: We compared the abilities of power and conventional color Doppler
      sonography to depict the vascularity of solid breast lesions and evaluated the
      usefulness of power Doppler sonography in differentiating between benign and
      malignant breast lesions. METHODS: One hundred two solid breast lesions (59
      benign and 43 malignant lesions) were studied with power and color Doppler
      sonography. Power and color Doppler sonograms were retrospectively compared for
      the depiction of blood flow signals. Power Doppler images were also reviewed for
      the amount of Doppler signals, pattern of vascularity, and morphology of vessels.
      The sensitivity, specificity, and accuracy of the 2 techniques were calculated.
      RESULTS: Compared with color Doppler sonography, power Doppler sonography
      depicted flow superiorly in 61 cases (60%) and equally in 41 cases (40%). On
      power Doppler sonography, the incidence of marked blood flow in malignant lesions
      (65%) was higher than that in benign lesions (39%). The pattern of vascularity
      was predominantly central (86%) and/or penetrating (65%) more often in malignant
      lesions than in benign lesions (51% and 34%, respectively). Branching (56%) and
      disordered vessels (42%) were seen more often in malignant lesions than in benign
      lesions (22% and 8%, respectively). The sensitivity, specificity, and accuracy in
      diagnosing malignancy were 64%, 76%, and 71%, respectively, for power Doppler
      sonography and 77%, 76%, and 76% for color Doppler sonography. CONCLUSIONS: Power
      Doppler sonography was more sensitive than color Doppler sonography in the
      detection of flow in solid breast lesions. Although power Doppler sonography was
      not more effective in diagnosing malignant lesions, central and penetrating
      vascularity patterns and branching and disordered vessels seem to be helpful
      findings in predicting malignancy.

PMID- 10355887
TI  - Hepatic arterial resistance after mixed-meal ingestion in healthy subjects and
      patients with chronic liver disease.
AB  - PURPOSE: This study investigated hemodynamic changes in the resistance index of
      the hepatic artery after mixed-meal ingestion. METHODS: We used color Doppler
      sonography to measure hemodynamic changes in the right hepatic artery in response
      to mixed-meal ingestion (225 ml, 69 g, 300 kcal) in 9 healthy subjects, 15
      patients with chronic hepatitis with low-grade fibrosis (no bridging), 10
      patients with chronic hepatitis with moderate-grade (bridging) fibrosis, and 18
      patients with cirrhosis. RESULTS: After mixed-meal ingestion, the mean (+/
      standard error) maximum increase in the resistance index of the right hepatic
      artery in healthy subjects was 31+/-2%. These changes were significantly greater
      than those in patients with chronic hepatitis with low-grade fibrosis (22+/-2%;
      p<0.05), patients with chronic hepatitis with moderate-grade fibrosis (11+/-2%;
      p<0.01), and cirrhotic patients (5+/-2%; p<0.01). Mixed-meal ingestion produced
      significantly smaller increases in the resistance index in cirrhotic patients
      than in patients with chronic hepatitis with low-grade fibrosis (p<0.01). A
      postprandial increase in the resistance index of 15% or less was associated with
      100% sensitivity, 72% specificity, and 84% accuracy in distinguishing patients
      with cirrhosis from patients with chronic hepatitis. CONCLUSIONS: The response of
      the resistance index after mixed-meal ingestion decreases as the severity of
      hepatic fibrosis increases. Doppler evaluation of postprandial increases in the
      resistance index of the right hepatic artery may be useful in differentiating
      between patients with chronic hepatitis and those with cirrhosis.

PMID- 10355888
TI  - In vitro sonographic evaluation of common bile duct stones and fragments with a
      high-frequency microprobe.
AB  - PURPOSE: This study was conducted to evaluate the sonographic characteristics of
      common bile duct (CBD) stones and stone fragments scanned in vitro with a high
      frequency (20-MHz) microprobe. METHODS: We sonographically examined 4 whole CBD
      stones (1 cholesterol stone with radiant cross section, 1 cholesterol stone with
      lamellar cross section, 1 black pigment stone, and 1 brown pigment stone), 44
      fragments of a cholesterol stone (diameter range, 1.1-3.0 mm; mean diameter, 2.0
      mm), and 75 fragments of a black pigment stone (diameter range, 1.1-3.0 mm; mean
      diameter, 2.0 mm). The chemical composition of all stones was analyzed by
      infrared absorption spectroscopy. All stones and fragments were placed in a
      plastic box filled with physiologic saline solution for scanning with a 20-MHz
      microprobe and a 5-MHz probe. Echogenic foci and acoustic shadows revealed at
      each frequency were compared. RESULTS: At 5 MHz, the 4 CBD stones showed
      different sonographic characteristics. The cholesterol stone with radiant cross
      section showed an echogenic focus but no definite acoustic shadow, whereas the
      cholesterol stone with lamellar cross section showed an echogenic line, several
      echogenic spots, and a definite acoustic shadow. The black pigment stone showed
      an echogenic line with a vague acoustic shadow, and the brown pigment stone
      showed echogenicity of the whole stone and a definite acoustic shadow. At 20 MHz,
      the 4 stones showed an echogenic line with a definite acoustic shadow. All
      fragments appeared as echogenic foci at 20 and 5 MHz. Seventy-seven percent (34)
      and 5% (2) of 44 cholesterol stone fragments cast a definite acoustic shadow at
      20 and 5 MHz, respectively. Sixty-nine percent (52) and 15% (11) of 75 black
      pigment stone fragments cast a definite acoustic shadow at 20 and 5 MHz,
      respectively. Among fragments 1.5 mm in diameter and smaller, only 45% (5 of 11)
      from a cholesterol stone and 30% (6 of 20) from a black pigment stone showed a
      definite acoustic shadow at 20 MHz. CONCLUSIONS: High-frequency (20-MHz)
      sonography demonstrates a definite acoustic shadow more frequently among CBD
      stones and fragments 1.6 mm in diameter or larger than does low-frequency (5-MHz)
      sonography, but it does not discriminate the chemical composition.

PMID- 10355889
TI  - Role of color Doppler imaging in interventional sonography.

PMID- 10355890
TI  - Prenatal sonographic diagnosis of persistent right umbilical vein with varix.
AB  - Persistence of the right umbilical vein is variably associated with life
      threatening malformations of the fetal genitourinary, gastrointestinal, cardiac,
      and skeletal systems. Varices of the intraabdominal umbilical vein, although not
      necessarily associated with other malformations, do seem to carry a risk of fetal
      mortality, especially if they are large or appear early during the pregnancy. We
      report the prenatal diagnosis of the rare combination of persistence and varix of
      the right umbilical vein in an otherwise healthy infant.

PMID- 10355891
TI  - First-trimester sonographic diagnosis of Cantrell's pentalogy with exencephaly.
AB  - We report a case of Cantrell's pentalogy with exencephaly detected by sonography
      at 11 weeks 4 days' menstrual age and confirmed at autopsy. Cantrell's pentalogy
      consists of defects of the lower sternum, anterior diaphragm, midline
      supraumbilical abdominal wall, and diaphragmatic pericardium with ectopia cordis.
      Exencephaly involves acrania with a disorganized mass of brain tissue. Both
      conditions are rare; the combination of the 2 has been reported only twice
      before. To our knowledge, this is the earliest reported diagnosis of the 2
      conditions by prenatal sonography.

PMID- 10355893
TI  - Sonographic diagnosis of mesenteric hematoma.
AB  - Blunt abdominal trauma is common in children. Handlebar injuries may produce
      duodenal hematoma and pancreatic injuries, but mesenteric hematoma is relatively
      uncommon. We report a mesenteric hematoma resulting from a handlebar injury in a
      4-year-old boy. Abdominal sonography showed a heterogeneous hypoechoic mass with
      an echogenic wall in the central portion of the abdomen. Color Doppler study
      revealed vascularity at the periphery of the lesion, suggesting mesenteric
      hematoma. CT, upper gastrointestinal endoscopy, and a small bowel x-ray series
      confirmed the diagnosis.

PMID- 10355892
TI  - Preoperative sonographic diagnosis of midgut malrotation with volvulus in adults:
      the "whirlpool" sign.
AB  - Midgut malrotation and volvulus, found mostly in children, are rare and difficult
      to diagnose preoperatively in adults. We report 2 cases in which a 68-year-old
      man and a 75-year-old woman presented with intermittent cramping abdominal pain,
      abdominal distention, and vomiting. Abdominal sonography demonstrated wrapping of
      the superior mesenteric vein and bowel loops around the superior mesenteric
      artery (the "whirlpool sign") in both patients. Abdominal CT revealed similar
      findings. The diagnoses of midgut volvulus and mesenteric malrotation were made,
      and the patients underwent laparotomy. The man was confirmed to have
      duodenojejunal malrotation and volvulus, and the woman had cecal volvulus. The
      whirlpool sign is valuable for the preoperative diagnosis of mesenteric vessel
      malrotation and midgut volvulus.

PMID- 10355894
TI  - Neuroblastoma with spermatic cord metastasis in a child: sonographic findings.
AB  - We report a case of neuroblastoma in a patient who had no involvement of the
      spermatic cord at diagnosis but who developed spermatic cord metastasis 2 months
      later. The metastasis appeared on sonography as a hypoechoic, highly vascular,
      fusiform, hard, 14x10x7 mm mass located in the right inguinal canal and extending
      into the scrotum. The diagnosis of spermatic cord metastasis was confirmed by
      resection and histopathologic examination. We recommend that the scrotum and
      spermatic cord be evaluated by high-resolution sonography in children with
      neuroblastoma, both at the time of diagnosis and during follow-up.

PMID- 10355895
TI  - Peroxynitrite scavenging by different antioxidants. Part I: convenient assay.
AB  - A convenient "tube" assay to quantify relative antioxidant activities in aqueous
      solutions has been developed. Peroxynitrite was employed as a biologically
      relevant source of radicals with Pyrogallol Red as a detecting molecule. A
      variety of compounds have been examined, namely polyphenols, uric acid,
      glutathione, and ascorbic acid. Competition kinetics were observed for the
      majority of examined compounds, except thymol and ascorbic acid. Pyrogallol Red
      was fully protected by ascorbic acid against the bleaching by peroxynitrite until
      its total consumption. The deviation from competition kinetics in the case of
      thymol was due to the formation of radicals from thymol and their subsequent
      reaction with Pyrogallol Red. Quercetin was the most efficient scavenger of free
      radicals. The measurements of relative antioxidant activities using Pyrogallol
      Red and other detecting molecules, such as gallocyanine and carminic acid, were
      in fair agreement. The assay was successfully used for a screening of antioxidant
      activity of plant extracts of unknown composition.

PMID- 10355896
TI  - Generation and characterization of a stable soluble guanylate cyclase
      overexpressing CHO cell line.
AB  - A stably transfected soluble guanylate cyclase (sGC, alpha1 and beta1 subunits of
      the rat lung enzyme)-overexpressing CHO cell line was generated for the
      characterization of different types of activators of the soluble guanylate
      cyclase. Polyclonal antibodies directed against both subunits of the rat enzyme
      were used to detect both subunits in the cytosol of the transfected CHO cells. We
      studied the effects of different nitric oxide (NO) donors like SNP and DEA/NO
      and, in particular, the direct, NO-independent stimulator of the soluble
      guanylate cyclase 3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole (YC-1), on
      intracellular guanosine 3',5'-cyclic monophosphate (cGMP) production. DEA/NO
      (0.01-3 microM), SNP (1-10 microM), and YC-1 (1-10 microM) induced a
      concentration-dependent intracellular cGMP increase with maximal effects of 16
      fold (3 microM DEA/NO), 8-fold (10 microM SNP), and 6-fold (10 microM YC-1)
      stimulation compared to controls, respectively. In addition, a synergistic effect
      of the combination of the NO donor and YC-1 could be observed with a maximal
      stimulation of 64-fold by SNP (10 microM) and YC-1 (10 microM). 1H-(1,2,4)
      Oxadiazolo-(4,3-a)-6-bromo-quinoxazin-1-one (ODQ, 10 microM), a potent and
      selective inhibitor of sGC, inhibited both the single effects of NO donors
      [DEA/NO (3 microM), 77%; SNP (3 microM), 83%] and YC-1 [YC-1 (3 microM), 82%],
      but moreover the synergistic effects between NO donors and YC-1 [DEA/NO (3
      microM) + YC-1 (3 microM), 81%; SNP (3 microM) + YC-1 (3 microM),89%] on
      intracellular cGMP production. In summary,we have generated a simple, sensitive,
      and useful bioassay method to characterize all types of sGC activators on the
      cellular level without the need of primary cell culture, several transfections,
      or purifying enzyme from biological materials.

PMID- 10355897
TI  - Trifluoroacetic anhydride-catalyzed nitration of toluene as an approach to the
      specific analysis of nitrate by gas chromatography-mass spectrometry.
AB  - The nitration of aromatic compounds by electrophilic substitution is often
      utilized in analyses of nitrate concentrations in physiological samples by gas
      chromatographic methods. Problems associated with the use of concentrated
      sulfuric acid, which is normally used to catalyze this reaction, led us to
      investigate an alternative method. We describe here a facile GC/MS assay for
      nitrate in plasma or urine samples which takes advantage of the ability of
      trifluoroacetic anhydride (TFAA) to catalyze the nitration of aromatics. Toluene,
      utilized as both reaction solvent and electrophile, was shown to react with
      nitrate in the presence of TFAA to quantitatively produce the three nitrotoluene
      isomers (ratio o-:m:p-, approx 57:3:40). Following the incorporation of 15N
      labeled nitrate as internal standard, nitrotoluene was quantified using GC/MS by
      analysis of the selected the ion pairs m/z 120 and 121 (M+ -OH) for the o-isomer
      or m/z 137 and 138 (molecular ion, M+) for the p-isomer. The limit of detection
      for nitrate after TFAA-catalyzed conversion to nitrotoluene was less than 100
      fmol on column (s/n; 40:1). The TFAA-based GC/MS assay was compared with that
      utilizing the usual catalyst, concentrated sulfuric acid. With the exception of
      samples containing nitroarginine analogues, good correlation was found for urine
      or plasma samples analyzed using either a standard sulfuric acid-catalyzed method
      or the TFAA-catalyzed procedure. Nitroarginine analogues, which can be present in
      samples following their use as nitric oxide synthase inhibitors, did not
      decompose under the conditions of the TFAA-catalyzed assay and, hence, do not
      give rise to significant interference with nitrate analysis in this procedure. In
      contrast, catalytic sulfuric acid caused nitroarginine analogues to decompose
      (essentially quantitatively) and cause spuriously high nitrate levels in samples.
      The use of TFAA as a catalyst for the nitration of toluene enables a facile and
      sensitive GC/MS analysis for nitrate which offers improved safety and sample
      integrity.

PMID- 10355898
TI  - Nitric oxide synthase-independent generation of nitric oxide in rat skeletal
      muscle ischemia-reperfusion injury.
AB  - We have used electron paramagnetic resonance to investigate the time course of
      nitric oxide (NO) generation and its susceptibility to inhibitors of nitric oxide
      synthase (NOS) in ischemia-reperfusion (IR) injury to rat skeletal muscle in
      vivo. Significant levels of muscle nitroso-heme complexes were detected 24 h
      postreperfusion, but not after at 0.05, 3, and 8 h of reperfusion. The levels of
      muscle nitroso-heme complexes were not decreased by the NOS inhibitor N-nitro-L
      arginine methyl ester as a single dose (30 mg/kg) prior to reperfusion or as
      multiple doses continued throughout the reperfusion (total administered, 120
      mg/kg) or by the potent NOS inhibitor S-methylisothiourea (3 mg/kg). In contrast,
      nitroso-heme levels were reduced by the glucocorticoid dexamethasone (2.5 mg/kg).
      Muscle necrosis in vitro did not result in the formation of nitroso-heme
      complexes. The finding that reperfusion after ischemia is necessary for NO
      formation suggests that an inflammatory pathway is responsible for NOS
      independent NO formation in IR injury to skeletal muscle.

PMID- 10355899
TI  - Relaxant effects of sodium nitroprusside and NONOates in goat middle cerebral
      artery: delayed impairment by global ischemia-reperfusion.
AB  - Global cerebral ischemia and subsequent reperfusion induce early impairment of
      the vasodilator responses to hypercapnia and vasoactive substances. Nitric oxide
      (NO) is involved in the regulation of cerebral blood flow (CBF) in both health
      and disease. The present study was designed to assess possible changes in the
      cerebrovascular reactivity to NO donors induced by cerebral ischemia-reperfusion
      in goats. Female goats (n = 9) were subjected to 20 min global cerebral ischemia
      under halothane/N2O anesthesia. Sixteen additional goats were sham-operated as a
      control group. One week later the effects of ischemia-reperfusion on relaxations
      to NO donors sodium nitroprusside (SNP), diethylamine/NO (DEA/NO),
      diethylenetriamine/NO (DETA/NO), and spermine/NO (SPER/NO) were studied in rings
      of middle cerebral artery (MCA) isolated in an organ bath for isometric tension
      recording. SNP, DEA/NO, DETA/NO, and SPER/NO induced concentration-dependent
      relaxations of MCA precontracted with KCl (DEA/NO > SPER/NO > SNP > DETA/NO) or
      with endothelin-1 (DEA/NO > SNP > SPER/NO > DETA/NO). Relaxations were always
      higher in endothelin-1-precontracted arteries. One week after cerebral ischemia
      concentration-response curves to SNP and DEA/NO were displaced to the right,
      indicating a reduction in relaxant potency of NO donors. The classical
      nitrovasodilator SNP and NONOates induce relaxation of isolated goat MCA which is
      partially inhibited by arterial depolarization. Global cerebral ischemia followed
      by reperfusion induces delayed impairment of the relaxant effects of NO on
      cerebrovascular smooth muscle, which results in reduced vasodilatory potency of
      NO donors in large cerebral arteries.

PMID- 10355900
TI  - Spatial view cells in the primate hippocampus: allocentric view not head
      direction or eye position or place.
AB  - Hippocampal function was analysed by making recordings from hippocampal neurons
      in monkeys actively walking in the laboratory. 'Spatial view' cells, which
      respond when the monkey looks at a part of the environment, were analysed. It is
      shown that these cells code for the allocentric position in space being viewed
      and not for eye position, head direction or the place where the monkey is
      located. This representation of space 'out there' would be an appropriate part of
      a primate memory system involved in memories of where in an environment an object
      was seen, and more generally in the memory of particular events or episodes, for
      which a spatial component normally provides part of the context.

PMID- 10355901
TI  - From perception to action: temporal integrative functions of prefrontal and
      parietal neurons.
AB  - The dorsolateral prefrontal cortex (DPFC) and the posterior parietal cortex (PPC)
      are anatomically and functionally interconnected, and have been implicated in
      working memory and the preparation for behavioral action. To substantiate those
      functions at the neuronal level, we designed a visuomotor task that dissociated
      the perceptual and executive aspects of the perception-action cycle in both space
      and time. In that task, the trial-initiating cue (a color) indicated with
      different degrees of certainty the direction of the correct manual response 12 s
      later. We recorded extracellular activity from 258 prefrontal and 223 parietal
      units in two monkeys performing the task. In the DPFC, some units (memory cells)
      were attuned to the color of the cue, independent of the response-direction it
      connoted. Their discharge tended to diminish in the course of the delay between
      cue and response. In contrast, few color-related units were found in PPC, and
      these did not show decreasing patterns of delay activity. Other units in both
      cortices (set cells) were attuned to response-direction and tended to accelerate
      their firing in anticipation of the response and in proportion to the
      predictability of its direction. A third group of units was related to the
      determinacy of the act; their firing was attuned to the certainty with which the
      animal could predict the correct response, whatever its direction. Cells of the
      three types were found closely intermingled histologically. These findings
      further support and define the role of DPFC in executive functions and in the
      temporal closure of the perception-action cycle. The findings also agree with the
      involvement of PPC in spatial aspects of visuomotor behavior, and add a temporal
      integrative dimension to that involvement. Together, the results provide
      physiological evidence for the role of a prefrontal-parietal network in the
      integration of perception with action across time.

PMID- 10355902
TI  - Partial blocking of NMDA receptors reduces plastic changes induced by short
      lasting classical conditioning in the SI barrel cortex of adult mice.
AB  - The effect of blockade of N-methyl-D-aspartate (NMDA) receptors in the barrel
      cortex upon the learning-induced changes of the cortical body map was examined in
      adult mice. We have previously found that three sensory conditioning sessions, in
      which stimulation of a row of vibrissae was paired with a tail shock, produced an
      enlargement of the functional representation of a row of vibrissae stimulated
      during training. Implantation of the slow release polymer Elvax, containing 2
      amino-5-phosphonovalerate (APV, 50 mM), in the vicinity of the barrel cortex was
      performed 1 day before conditioning to block NMDA receptors. The cortical
      representation of a trained row of vibrissae was visualized with 2-deoxyglucose
      (2DG) functional brain mapping 1 day after the completion of the conditioning
      procedure. The partial blockade of NMDA receptors within the barrel cortex
      reduced (by half) the expansion of the cortical representation of a trained row
      of vibrissae as compared to the enlargement of the cortical representation of a
      trained row found in untreated (60%) and Elvax-PBS implanted (47%) mice. The
      results provide evidence that the learning-induced processes of cortical map
      reorganization involve mechanisms that depend on NMDA receptor activation.

PMID- 10355903
TI  - Some temporal and parietal cortical connections converge in CA1 of the primate
      hippocampus.
AB  - Large sectors of polymodal cortex project to the hippocampal formation via
      convergent input to the entorhinal cortex. The present study reports an
      additional access route, whereby several cortical areas project directly to CA1.
      These are parietal areas 7a and 7b, area TF medial to the occipitotemporal sulcus
      (OTS), and a restricted area in the lateral bank of the OTS that may be part of
      ventromedial area TE. These particular cortical areas are implicated in
      visuospatial processes; and their projection to and convergence within CA1 may be
      significant for the elaboration of 'view fields', for the postulated role of the
      hippocampal formation in topographic learning and memory, or for the snapshot
      identification of objects in the setting of complex visuospatial relationships.
      Convergence of vestibular and visual inputs (from areas 7b and 7a respectively)
      would support previous physiological findings that hippocampal neurons respond to
      combinations of whole-body motion and a view of the environment. The direct
      corticohippocampal connections are widely divergent, especially those from the
      temporal areas, which extend over much of the anteroposterior axis of the
      hippocampal main body. Divergent connections potentially influence large
      populations of CA1 pyramidal neurons, consistent with the suggestion that these
      neurons are involved in conjunctive coding. The same region of ventromedial TE,
      besides the direct connections to CA1, also gives rise to direct projections to
      area V1, and may correspond to a functionally specialized subdivision, perhaps
      part of VTF.

PMID- 10355904
TI  - Molecular correlates of topographic reorganization in primary visual cortex
      following retinal lesions.
AB  - Adult visual cortex undergoes substantial functional change as a result of
      alterations in visual experience. Binocular retinal lesions lead to a
      reorganization of the visuotopic map in primary visual cortex. Associated with
      this change is a strengthening of an existing plexus of long-range horizontal
      connections by sprouting of axon collaterals and synaptogenesis. To explore the
      molecular substrate of this change, we studied the expression of potential
      factors involved in neural plasticity in the area of reorganization. We found
      elevation in a number of factors as early as 3 days following the lesion,
      including neurotrophins BDNF, NT3, NGF and the insulin-like growth factor IGF-1.
      Associated with the changes in neurotrophin levels was an elevation in their
      receptors. We also measured elevation of transcription factors, CaMKII, MAP2 and
      synapsins. These experiments provide evidence for a signal transduction cascade
      associated with cortical reorganization.

PMID- 10355905
TI  - Impaired experience-dependent plasticity in barrel cortex of mice lacking the
      alpha and delta isoforms of CREB.
AB  - The transcription factor cyclic-AMP response element binding protein (CREB) has
      been implicated in long-term plasticity processes in vertebrate and invertebrate
      species. In the absence of the alpha/delta CREB isoforms, performance is impaired
      in long-term memory tasks and the long-term maintenance of long-term potentiation
      (LTP) is impaired in the hippocampus. However, it is not known whether CREB plays
      a role in neocortical plasticity. Antibodies to CREB revealed that CREB
      immunoreactive nuclei are present in all cortical layers but are more numerous in
      layers II/III, where they composed at least two-thirds the total population of
      cells. CREB-immunopositive cells were therefore present and densest in the very
      cortical layers that exhibit experience-dependent plasticity at this age. In
      order to assess the role of CREB in neocortical plasticity, we studied the effect
      of vibrissae deprivation on receptive field plasticity in the barrel cortex of
      mutant mice lacking the alpha/delta isoforms of CREB. A single vibrissa was
      spared and the others removed for 18 days. In wild-types this caused potentiation
      of the spared vibrissa response. However, in adult mutants (>6 months) spared
      vibrissa responses from homozygotes were potentiated less than in any adolescent
      animals or in adult wild-type littermates. Surround receptive field responses
      were abnormally large in homozygotes and failed to increase by the same amount as
      they did in wild-types. In contrast, the alpha/delta CREB mutation had no
      discernible effect on plasticity in cortical layers II/III of the younger
      adolescent age group (1-2 months), suggesting that different plasticity processes
      may operate at this age. Further tests showed that the beta isoform of CREB was
      up-regulated in the barrel cortex of the alpha/delta CREB knock-outs, suggesting
      that this subunit may have compensated partly for the loss of the alpha/delta
      isoforms. These studies suggests that CREB plays a role in experience-dependent
      plasticity in the adult neocortex.

PMID- 10355906
TI  - An fMRI version of the Farnsworth-Munsell 100-Hue test reveals multiple color
      selective areas in human ventral occipitotemporal cortex.
AB  - Studies of patients with cerebral achromatopsia have suggested that ventral
      occipitotemporal cortex is important for color perception. We created a
      functional magnetic resonance imaging (fMRI) version of a clinical test commonly
      used to assess achromatopsia, the Farnsworth-Munsell 100-Hue test. The test
      required normal subjects to use color information in the visual stimulus to
      perform a color sequencing task. A modification of the test requiring ordering by
      luminance was used as a control task. Subjects were also imaged as they passively
      viewed colored stimuli. A limited number of areas responded more to chromatic
      than achromatic stimulation, including primary visual cortex. Most color
      selective activity was concentrated in ventral occipitotemporal cortex. Several
      areas in ventral cortex were identified. The most posterior, located in posterior
      fusiform gyrus, corresponded to the area activated by passive viewing of colored
      stimuli. More anterior and medial color-selective areas were located in the
      collateral sulcus and fusiform gyrus. These more anterior areas were not
      identified in previous imaging studies which used passive viewing of colored
      stimuli, and were most active in our study when visual color information was
      behaviorally relevant, suggesting that attention influences activity in color
      selective areas. The fMRI version of the Farnsworth-Munsell test may be useful in
      the study of achromatopsia.

PMID- 10355907
TI  - Representational plasticity in cortical area 3b paralleling tactual-motor skill
      acquisition in adult monkeys.
AB  - The representations of the surfaces of the hand in the primary somatosensory
      cortical field, area 3b, were reconstructed in detail in seven owl monkeys and
      two squirrel monkeys trained to pick up food pellets from five wells of different
      sizes. From an early clumsy performance in which several to many retrieval
      attempts were required for each successful pellet retrieval, the monkeys
      exhibited a gradual improvement in digital dexterity as shown by significant
      decreases in mean numbers of grasp attempts/successful retrieval and
      corresponding standard deviations (e.g. 5.8 +/- 4.5 and 4.8 +/- 3.1 respectively,
      for the smallest well) between the first and last training sessions. All monkeys
      commonly used alternative, specific retrieval strategies involving various
      combinations of digits for significant time epochs before developing a highly
      successful strategy, which, once achieved, was rapidly stereotyped. For example,
      the numbers of digit combinations used during the first five versus the last five
      training sessions decreased from 3.3 +/- 0.7 to 1.8 +/- 0.6 for the smallest
      well. In both owl and squirrel monkeys, as the behavior came to be stereotyped,
      monkeys reliably engaged limited surfaces of the glabrous tips of two digits (in
      eight monkeys), or of three digits (in one monkey) in the palpation and
      manipulation of these small pellets for their location, capture, and
      transportation to the mouth. In cortical area 3b, the magnification of
      representation of these differentially engaged glabrous fingertip surfaces was
      nearly 2x larger than for the corresponding surfaces of other hand digits, or for
      the contralateral cortical representations of the same digit surfaces on the
      opposite hand. In parallel, cutaneous receptive field for area 3b neurons
      representing crucial digital tip surfaces were less than half as large as were
      those representing the corresponding surfaces of control digits. Receptive field
      overlaps were smaller on the trained fingertips than on control fingers.
      Moreover, the proportion of small overlaps was greater for the trained digits (76
      +/- 7%) than for the other digits of the same hand (49 +/- 5.4%). There was still
      a simple, single--but apparently topologically expanded--representation of these
      differentially engaged skin surfaces in these monkeys. Thus, with very limited
      manual exercise over a total period of a few hours of practice at a skill played
      out in brief daily sessions over a several week long training period, the
      representations of skin surfaces providing information crucial for successfully
      performing a small-object retrieval behavior appeared to be substantially
      remodeled in the most 'primary' of the SI somatosensory cortical fields, cortical
      area 3b. By that remodeling, behaviorally important skin surfaces were
      represented in a much finer representational grain than normal. Some implications
      of these findings for motor skill acquisition are discussed.

PMID- 10355908
TI  - The connectional organization of the cortico-thalamic system of the cat.
AB  - Data on connections between the areas of the cerebral cortex and nuclei of the
      thalamus are too complicated to analyse with naked intuition. Indeed, the
      complexity of connection data is one of the major challenges facing neuroanatomy.
      Recently, systematic methods have been developed and applied to the analysis of
      the connectivity in the cerebral cortex. These approaches have shed light on the
      gross organization of the cortical network, have made it possible to test
      systematically theories of cortical organization, and have guided new
      electrophysiological studies. This paper extends the approach to investigate the
      organization of the entire cortico-thalamic network. An extensive collation of
      connection tracing studies revealed approximately 1500 extrinsic connections
      between the cortical areas and thalamic nuclei of the cat cerebral hemisphere.
      Around 850 connections linked 53 cortical areas with each other, and around 650
      connections linked the cortical areas with 42 thalamic nuclei. Non-metric
      multidimensional scaling, optimal set analysis and non-parametric cluster
      analysis were used to study global connectivity and the 'place' of individual
      structures within the overall scheme. Thalamic nuclei and cortical areas were in
      intimate connectional association. Connectivity defined four major thalamo
      cortical systems. These included three broadly hierarchical sensory or
      sensory/motor systems (visual and auditory systems and a single system containing
      both somatosensory and motor structures). The highest stations of these
      sensory/motor systems were associated with a fourth processing system composed of
      prefrontal, cingulate, insular and parahippocampal cortex and associated thalamic
      nuclei (the 'fronto-limbic system'). The association between fronto-limbic and
      somato-motor systems was particularly close.

PMID- 10355909
TI  - Blockade and disruption of neocortical long-term potentiation following
      electroconvulsive shock in the adult, freely moving rat.
AB  - Although the neocortex has been considered to be highly resistant to the
      induction of long-term potentiation (LTP), we have recently shown that spaced and
      repeated stimulation of white matter afferents reliably induces neocortical LTP
      in the freely moving rat. The following study examined the effects of maximal
      electroconvulsive shock (MES) stimulation on the induction of LTP in the
      chronically prepared rat. MES stimulation was applied at different intervals
      following LTP-inducing trains over a 10 day period. High-frequency LTP-inducing
      stimulation resulted in amplitude changes in both early (9.28 ms to peak) and
      late (20.81 ms to peak) components of the evoked EPSP, as well as of the
      population spikes. There was a window of time following high-frequency
      stimulation within which MES could interrupt the induction of LTP MES stimulation
      applied immediately, or 1 h after, LTP-inducing trains prevented the induction of
      LTP LTP was not blocked, however, when the MES stimulation was applied 6 h after
      the LTP-inducing trains. MES stimulation applied to a fully potentiated animal
      transiently attenuated both the population spike and polysynaptic measures, but
      both components recovered within 24 h. These data support the idea of a
      consolidation gradient for neocortical LTP similar to that seen in behavioural
      studies.

PMID- 10355911
TI  - Isolated Dandy-Walker malformation: prenatal diagnosis in two consecutive
      pregnancies.
AB  - We report a family with recurrent Dandy-Walker malformation (DWM). The first
      offspring was found prenatally to have isolated DWM at 30 weeks' gestation.
      Ultrasonography at 19 weeks' gestation in the subsequent pregnancy revealed
      isolated DWM in both dizygotic twins. Chromosome analysis was normal in all three
      infants, and autopsy confirmed that no other congenital abnormalities were
      present. Evidence suggests that rare families transmit the disorder in an
      autosomal or X-linked recessive pattern, with a high recurrence risk.

PMID- 10355910
TI  - Does perinatal phenobarbital exposure affect developmental outcome at age 2?
AB  - The objective of this paper is to determine if phenobarbital exposure during
      pregnancy affects developmental outcome at age 2 years. Between 1991 and 1994,
      401 pregnant patients at risk for delivery prior to 34 weeks' gestation were
      invited to participate; 48 mothers declined entry. Before delivery, pharmacy
      randomized the pregnant women to receive phenobarbital and vitamin K or
      identically appearing placebo in a blinded fashion. Developmental follow-up at
      age 2 years was performed. Children from the treatment group scored significantly
      lower on the Bayley Mental Developmental Index (mean MDI +/- 1 SD) than children
      whose mothers were randomized to the placebo group [104 +/- 21 (n = 59) vs. 113
      +/- 22 (n = 62), p = 0.023]. Of 36 independent variables, randomization group was
      one of five that individually contributed to the prediction of the Bayley MDI
      score (p < 0.05). It was concluded that perinatal phenobarbital therapy may
      impair developmental outcome.

PMID- 10355913
TI  - Amnioreduction in emergency cerclage with prolapsed membranes: comparison of two
      methods for reducing the membranes.
AB  - To evaluate the effectiveness of amnioreduction in pregnancies requiring
      emergency cerclage placement, we performed a retrospective case-control study of
      all consecutive pregnant women with cervical dilation and effacement with
      prolapse of the fetal membranes in vagina between 16 and 26 weeks' gestation, who
      required placement of a McDonald emergency cerclage during the period January
      1991-December 1997. Duration of pregnancy prolongation, rate of delivery before
      32 weeks, and duration of neonatal hospital stay were compared between women in
      whom amniochorionic membranes were reduced at the time of cerclage placement
      using only intracervical Foley balloon catheter (controls; n = 7) and those who
      in addition underwent amnioreduction to facilitate cerclage placement (n = 9).
      Statistical analysis utilized Fisher's exact test and Wilcoxon rank sum test. A p
      value <0.05 was considered significant. There were no procedure-related ruptures
      of membranes. Gestational age at cerclage and rate of positive cervico-vaginal
      cultures were not different between the two groups. Gestation was prolonged for a
      median of 100 days (range 4 to 144 days) in the amnioreduction group and 10 days
      (2 to 133) among controls (p = 0.3). The rate of delivery before 32 weeks was
      significantly lower (1/7 vs. 6/8, p = 0.03) and the duration of neonatal hospital
      admission significantly shorter (median 3 vs. 37 days, p = 0.001) in the
      amnioreduction group than among controls. The amount of amniotic fluid withdrawn
      ranged from 220 to 340 mL. These findings suggest that amnioreduction at the time
      of emergency cerclage placement is associated with a lower rate of extreme
      prematurity and related neonatal morbidity.

PMID- 10355912
TI  - Pregnancy complications and neonatal outcomes in multifetal pregnancies reduced
      to twins compared with nonreduced twin pregnancies.
AB  - Our objective was to compare the pregnancy complications and neonatal outcomes of
      multifetal pregnancies reduced to twins to those in twin pregnancies without
      multifetal pregnancy reduction (MPR). A cohort study was performed in patients
      with dichorionic twin pregnancies who reached 24 weeks' gestation and delivered
      at the Mount Sinai Medical Center between 1986 and 1997. A study population of 77
      multifetal pregnancies reduced to twins were compared with 140 dichorionic twin
      pregnancies without MPR regarding pregnancy complications and neonatal outcomes.
      Statistical analysis was performed with Chi-square and two-tailed Student's t
      tests. Multifetal pregnancies reduced to twins were similar to nonreduced twins
      in all parameters studied except the cesarean section rate and neonatal
      polycythemia. Increased cesarean section rate in MPR group was attributed to
      elective indications. Pregnancy-induced hypertension was found to be higher only
      in a subgroup of patients (i.e., 4-2). Multifetal pregnancies reduced to twins do
      not differ from the twin pregnancies without MPR in the overwhelming majority of
      pregnancy complications and neonatal outcomes.

PMID- 10355914
TI  - Neonatal platelet counts in fetal brain injury.
AB  - The objective of this study was to determine whether neonatal platelet counts can
      be used in fetal brain injury. The initial platelet counts, expressed as 1000 per
      mm3, of singleton term infants with and without permanent asphyxial brain injury
      were compared. Neonates with encephalopathy were divided into 3 groups: I-
      nonreactive fetal heart rate (FHR) pattern from admission until delivery; II-
      reactive FHR pattern on admission followed by nonreactivity, tachycardia, a loss
      of variability and repetitive FHR decelerations; and III--acute: reactive FHR
      pattern followed by a sudden prolonged FHR deceleration that lasted until
      delivery. The neonates and platelet counts for each group were as follows:
      CONTROL: 104 neonates, mean 281 +/- 56, range 154 to 411; I: 60, mean 185 +/- 80,
      range 28 to 365; II: 34, mean 251 +/- 66, range 100 to 375; and III: 35, mean 267
      +/- 93, range 86 to 569. Platelet counts were significantly lower in neonates
      with encephalopathy (p <0.001). Group I differed statistically from both Groups
      II and III (p <0.001). These data suggest an association between the FHR pattern,
      fetal asphyxial brain injury, and the initial platelet count in singleton term
      neonates. Further investigation should be pursued to clarify the physiological
      processes leading to this result.

PMID- 10355916
TI  - Prenatal diagnosis and perinatal management of fetal sacrococcygeal teratoma.
AB  - Sacrococcygeal teratoma is the most common fetal neoplasm, with an incidence of 1
      in 40,000 births. Fetuses with this malformation are at risk for significant
      perinatal morbidity and mortality. We identified nine fetuses with sacrococcygeal
      teratomas that were diagnosed antenatally and managed at the University of North
      Carolina Hospitals over a 7-year period. We retrospectively reviewed the charts
      of mothers and infants and recorded data concerning perinatal and surgical
      management. Six infants survived the neonatal period. All infants diagnosed after
      20 weeks' gestation survived. Fetal hydrops developed in three fetuses, all of
      whom died. Inadequate ventilation secondary to prematurity was a contributing
      factor in each lethal case. Diagnosis at an early gestational age, development of
      fetal hydrops, and premature delivery predicted a poor prognosis. When possible,
      we recommend that delivery be delayed to allow for fetal development.
      Stabilization of the infant should be attempted before resection of the teratoma.

PMID- 10355915
TI  - Helicobacter pylori infection and persistent hyperemesis gravidarum.
AB  - Hyperemesis gravidarum is the most severe spectrum of gastrointestinal complaints
      in pregnant women. Our purpose is to describe an association of Helicobacter
      pylori with hyperemesis gravidarum. Three pregnant women are described with the
      working diagnoses of hyperemesis gravidarum unresponsive to standard therapy. The
      medical management used to treat Helicobacter pylori in these women are
      elaborated. The persistence of the symptomatology and/or hematemesis resulted in
      Helicobacter pylori testing of these women. A 2-week course of antibiotics and a
      proton pump inhibitor or H2 receptor antagonist resulted in resolution of the
      hyperemesis. A discussion of the incidence, diagnosis, and management of
      Helicobacter pylori in pregnancy is described. When the symptoms of hyperemesis
      gravidarum are persistent into the second trimester, active peptic ulcer disease
      from Helicobacter pylori should be included in the differential diagnoses.

PMID- 10355917
TI  - Leukemoid reaction in extremely low-birth-weight infants.
AB  - The objective of this paper was to determine the incidence of leukemoid reaction
      and to evaluate its relationship with maternal and neonatal factors in extremely
      low-birth-weight (ELBW) infants. The design a case-controlled retrospective study
      of all live-born ELBW infants (<1000 g) over a period of 2 years, from July 1994
      to June 1996. A total of 60 preterm infants were born during the study period,
      and are included in this report. The infants who demonstrated leukemoid reaction
      formed the study group, while the remainder formed the control group. Leukemoid
      reaction was defined as a white blood cell (WBC) count > or = 50,000/mm3. The
      relationship between maternal and neonatal variables and WBC counts was studied.
      Nine of the 60 infants studied demonstrated counts >50,000/mm3, with an incidence
      of 15%. There was no significant association demonstrated between maternal or
      neonatal variables and leukemoid reaction. Patients with leukemoid reaction had a
      better overall survival. Leukemoid reaction in ELBW infants is a rare and
      recently documented phenomenon. In our study the incidence was 15%. Although many
      factors have been postulated as a cause of this phenomenon, we could not
      demonstrate any relationship between these factors and high WBC counts, including
      sepsis and the use of antenatal steroids, the two most likely variables. It was
      interesting to note that the infants who were able to mount a leukemoid response
      had a better chance of survival than those who did not.

PMID- 10355918
TI  - Electrophysiologic characteristics of accessory atrioventricular connections in
      an inherited form of Wolff-Parkinson-White syndrome.
AB  - INTRODUCTION: A familial form of Wolff-Parkinson-White syndrome (WPW) occurs in
      association with hypertrophic cardiomyopathy and intraventricular conduction
      abnormalities. This syndrome, demonstrating autosomal dominant inheritance and
      segregating with a high degree of penetrance but variable expressivity, has been
      genetically linked to chromosome 7q3. The purpose of this study is to detail the
      electrophysiologic characteristics of accessory atrioventricular connections (AC)
      in four members of a kindred with this syndrome. METHODS AND RESULTS: We
      clinically evaluated 32 members of a single kindred and identified 20 individuals
      with ventricular preexcitation, abnormal intraventricular conduction including
      complete AV block and/or ventricular hypertrophy. Genetic linkage analysis mapped
      the disease gene in this kindred to the chromosome 7q3 locus (maximum logarithm
      of the odds score = 6.88, theta = 0); recombination events in affected
      individuals reduced the genetic interval from 7 centimorgans (cM) to 5 cM.
      Electrophysiologic study of four individuals with preexcitation, identified seven
      AC (1 right sided, 3 septal, and 3 left sided). All four individuals had
      inducible orthodromic tachycardia; while three had multiple AC. Bidirectional
      conduction was demonstrated in 6 of 7 AC. Successful ablation was accomplished in
      5 of 7 AC. CONCLUSION: The electrophysiologic characteristics and location of AC
      in family members having this complex cardiac phenotype are similar to those seen
      in individuals with isolated WPW. Identification of WPW in more than one family
      member should prompt clinical evaluation of relatives for additional findings of
      ventricular hypertrophy or conduction abnormalities.

PMID- 10355919
TI  - Idiopathic paroxysmal atrial fibrillation induced by a focal discharge mechanism
      in the left superior pulmonary vein: possible roles of the ligament of Marshall.
AB  - INTRODUCTION: The origin of double potentials inside the left superior pulmonary
      vein and their relation to the mechanisms of idiopathic paroxysmal focal atrial
      fibrillation (AF) are unclear. METHODS AND RESULTS: A total of 40 patients were
      studied. Group I included 15 patients who underwent radiofrequency catheter
      ablation of accessory pathway. Double potentials were found inside the left
      superior pulmonary vein during sinus rhythm in 10 patients and during premature
      atrial contractions in the remaining five patients. Group II included 25 patients
      with idiopathic paroxysmal AF. Double potentials were also identified in the left
      superior pulmonary vein. In 15 patients (Group IIA), the earliest automatic
      discharge during premature atrial contractions and at the onset of AF was within
      the left superior pulmonary vein. AF was ablated by radiofrequency energy
      application at the site registering double potentials. Radiofrequency ablation in
      the remaining 10 patients failed to terminate AF (Group IIB). The patients in
      Group IIA had significantly more male patients and more frequent premature atrial
      contractions and atrial tachycardia on 24-hour Holter recordings prior to the
      procedure than patients in Group IIB. CONCLUSIONS: Double potentials are present
      at the left superior pulmonary veins in patients with and without a history of
      AF. The first potential is due to the activation of atrial myocardium and the
      second is due to the activation of a different muscular structure. Rapid
      discharge of this structure triggers episodes of paroxysmal AF. Patients with
      focal AF originating from the left superior pulmonary vein can be identified by
      Holter recordings.

PMID- 10355920
TI  - The effect of procainamide on T wave alternans.
AB  - INTRODUCTION: The measurement of microvolt level T wave alternans (TWA) is a
      technique for detecting arrhythmia vulnerability. Previous studies demonstrated
      that the magnitude of TWA is dependent on heart rate. However, the effects of
      antiarrhythmic drugs on TWA are unknown. METHODS AND RESULTS: This was a
      prospective evaluation of intravenous procainamide on TWA in 24 subjects with
      inducible sustained ventricular tachycardia (VT). Measurements of TWA were
      performed at baseline in the drug-free state and after procainamide loading
      (1,204+/-278 mg). Recordings were made in normal sinus rhythm, and during atrial
      pacing at 100 beats/min and 120 beats/min. The magnitude of TWA in the vector
      magnitude lead was decreased by procainamide at all heart rates: 0.6+/-0.8 to
      0.3+/-0.4 microV in sinus rhythm, 2.0+/-1.6 to 0.7+/-0.7 microV at 100 beats/min,
      and 3.0+/-2.0 to 1.7+/-1.8 microV at 120 beats/min (P<0.001 by analysis of
      variance). The sensitivity of TWA for the induction of VT at baseline was 5% in
      sinus, 60% at 100 beats/min, and 87% at 120 beats/min, while it decreased with
      procainamide to 5%, 19%, and 60%, respectively. Decreases in TWA in response to
      procainamide were independent of the antiarrhythmic effects on VT inducibility.
      CONCLUSIONS: These results indicate that the magnitude of TWA decreases with
      acute procainamide loading and this effect decreases the sensitivity of TWA for
      the induction of sustained VT.

PMID- 10355921
TI  - Entrainment of typical AV nodal reentrant tachycardia using para-Hisian pacing:
      evidence for a lower common pathway within the AV node.
AB  - INTRODUCTION: Despite the ability to cure atrioventricular nodal reentrant
      tachycardia (AVNRT) by radiofrequency catheter ablation with a high success rate,
      the exact localization of the tachycardia circuit is still not well established.
      The presence of AV nodal tissue between the typical AVNRT circuit and the His
      bundle, constituting a lower common pathway (LCP), remains controversial. METHODS
      AND RESULTS: Entrainment of AVNRT during para-Hisian stimulation allows accurate
      measurement of the His- to- atrial (HA) interval which is part of the same
      circuit as that of the tachycardia. With an LCP, during tachycardia, there is
      simultaneous conduction from the low turnaround of the circuit to the atrium (via
      the fast pathway) and to the His bundle (via the LCP). However, during
      entrainment by para-Hisian pacing, the impulse has to retrogradely depolarize
      sequentially the LCP and the fast pathway. Therefore, in the presence of an LCP,
      the HA interval duration during tachycardia (HAt) should be shorter than that of
      during entrainment by para-Hisian stimulation (HAe). We considered an LCP present
      when Hae - HAt was > or = 10 msec. Entrainment of typical AVNRT with para-Hisian
      stimulation was performed in 23 consecutive patients (21 females) with a mean age
      of 45+/-17 years. LCP was considered to be present in 18 of 23 patients (78%). In
      addition, transient His-bundle dissociation from the ongoing tachycardia occurred
      in seven patients (30%). CONCLUSION: These results support the presence of a LCP
      during typical AVNRT.

PMID- 10355922
TI  - Local electrogram-based criteria of cavotricuspid isthmus block.
AB  - INTRODUCTION: The efficacy and outcome of cavotricuspid isthmus ablation guided
      by local electrogram-based criteria of linear block were prospectively assessed.
      METHODS AND RESULTS: In 40-consecutive patients (age 65+/-11 years) with typical
      right atrial (RA) flutter (cycle length = 255+/-31 msec), radiofrequency (RF)
      energy was delivered at electrograms in the isthmus coinciding with the center of
      the ECG plateau until termination of flutter, followed by local assessment of
      isthmus conduction during slow rate low-lateral RA pacing. 'Gaps' in the ablation
      line were located in the form of single or fractionated potentials centered on
      the isoelectric intervals of adjacent double potentials and ablated. Complete
      linear isthmus block was defined by the achievement of a complete corridor of
      parallel double potentials from the right ventricle to the inferior vena cava
      edge. Applications of 11+/-7 RF applications were required in all patients to
      achieve a complete line of double potentials separated by an isoelectric interval
      of 120+/-26 msec (range 60 to 190). After 6+/-3 RF applications, 6 (15%) patients
      had evidence of isthmus block using indirect RA activation sequence mapping
      without a complete line of double potentials. 5+/-5 further RF applications of
      eliminated local conduction and achieved complete linear block without altering
      descending septal RA activation. Conduction recovery occurred in 20 (50%)
      patients--1.85 times per patient-indicated by reversed changes in local
      electrograms eliminated by further ablation of the recovered gaps. After
      discharge, two recurrences (5%) occurred during a follow-up of 16+/-2 months.
      CONCLUSION: Double potential mapping is an effective assessment modality for
      local isthmus conduction. Slow conduction limited to the ablation line is
      observed during ablation in 15% of patients.

PMID- 10355923
TI  - Dispersion of filtered P wave duration by P wave signal-averaged ECG mapping
      system: its usefulness for determining efficacy of disopyramide on paroxysmal
      atrial fibrillation.
AB  - INTRODUCTION: Although it is desirable to know drug efficacy before initiating
      antiarrhythmic therapy, there have been no methods for this evaluation. P wave
      signal-averaged ECG (P-SAECG) is useful to detect subtle changes in disturbance
      of atrial conduction. The purpose of this present study was to test whether P
      SAECG mapping system would give any information on the efficacy of disopyramide
      on the prevention of paroxysmal atrial fibrillation (PAF). METHODS AND RESULTS: P
      SAECG was performed before disopyramide treatment, at 3 hours after a single dose
      of oral disopyramide (200 mg), and after 4 weeks of disopyramide treatment (300
      mg/day). After measuring the filtered P wave duration by the vector magnitude and
      mapping methods, we calculated filtered P wave duration dispersion, difference
      between the maximal and minimal filtered P wave duration within 16 chest leads at
      these three time points. Filtered P wave duration and filtered P wave duration
      dispersion before treatment were longer in 32 patients with symptomatic PAF than
      in 31 healthy volunteers. Disopyramide was effective for suppression of PAF in 17
      patients and ineffective in 15 patients after 4 weeks of treatment. Filtered P
      wave duration was similarly prolonged at 3 hours in the two groups, whereas
      filtered P wave duration dispersion at 3 hours after the disopyramide
      administration behaved differently; it decreased in all of the effective group
      and increased in all of the ineffective group. The effective patients were
      prospectively followed with the same treatment for 6 months. In 16 (94%) of these
      17 effective patients, no PAF was documented and they remained to be
      asymptomatic. CONCLUSIONS: Thus, measuring filtered P wave duration dispersion
      with the P-SAECG mapping method after a single administration may predict the
      long-term efficacy of disopyramide in patients with PAF.

PMID- 10355924
TI  - Low-power radiofrequency application and intracardiac echocardiography for
      creation of continuous left atrial linear lesions.
AB  - INTRODUCTION: Continuity of radiofrequency (RF) lesions for a catheter-based cure
      of atrial fibrillation is essential in order to avoid reentrant tachycardias. In
      the present study, we assessed the value of intracardiac echocardiography and
      preablation electrode-tissue interface parameters for creation of left atrial
      linear lesions. METHODS AND RESULTS: In six healthy dogs, two left atrial linear
      lesions (lesion 1, along the inferior posterior left atrium; lesion 2, from the
      appendage to the left atrial roof) were attempted via a transseptal approach
      using a deflectable catheter with six 7-mm coil electrodes. In a randomized
      fashion, one lesion was performed under echocardiographic guidance and one with
      blinded echocardiographic monitoring. The following preablation parameters were
      assessed for every coil electrode: (1) mean atrial electrogram amplitude of six
      consecutive sinus beats; (2) diastolic pacing threshold; and (3) temperature
      response to application of 5 W for 10 seconds. After ablation (target temperature
      70 degrees C, maximum power 50 W, duration 60 sec), the excised left atrium was
      examined macroscopically and histologically for lesion length, continuity, and
      presence or absence of lesions associated with each coil. Out of 12 attempted RF
      lesions, 7 were continuous (length, 47+/-5 mm, lesion 2, n = 6) and 5 were
      discontinuous (lesion 1, n = 5). Fifty-two of 70 coil electrodes (74%) had
      pathologic evidence of lesion creation. Intracardiac echocardiography was
      superior to fluoroscopy with respect to the actual number of coil electrodes
      creating lesions, and lesion continuity was correctly predicted in 9 of 12
      lesions. Intracardiac echocardiography was 85% sensitive and 54% specific in
      predicting lesions created by individual coils. The correlation between the mean
      60-second ablation temperature and the preablation parameters was 0.45 for the
      electrogram amplitude, -0.67 for the pacing threshold, and 0.81 for the
      temperature response to low-power application. Sensitivity and specificity for
      prediction of lesions created by individual coils, respectively, were 84% and 48%
      for the electrogram amplitude, 90% and 68% for the pacing threshold, and 96% and
      76% for the low-power RF application. CONCLUSION: Long linear lesions can be
      safely and effectively performed in the canine left atrium, using a tip
      deflectable multielectrode catheter. Intracardiac echocardiography may be helpful
      for positioning the ablation catheter in some parts of the left atrium, and
      preablation parameters, especially a nontraumatic low-power RF application, are
      able to predict ultimate lesion creation with high accuracy.

PMID- 10355925
TI  - Unitary current analysis of L-type Ca2+ channels in human fetal ventricular
      myocytes.
AB  - INTRODUCTION: L-type calcium channels were studied in cell-attached patches from
      ventricular cell membranes of human fetal heart. METHODS AND RESULTS: Experiments
      were performed in the presence of 70 mM Ba2+ as the charge carrier at 22 degrees
      C to 24 degrees C. Unitary current sweeps were evoked by 300-msec depolarizing
      pulses to 0 mV from a holding potential of -50 mV at 0.5 Hz. Recorded currents
      were blocked by nisoldipine (1 microM) and stimulated by (-)Bay K 8644 (1
      microM). During control, channel activity was seen in 13.9%+/-4.2% of the total
      200 sweeps. Ensemble average current amplitude was 0.03+/-0.01 pA (n = 6) and
      average conductance was 20.4+/-0.2 pS (n = 5). Analysis of single channel
      kinetics showed open time and closed time histograms were best fit by one and two
      exponentials, respectively. Mean open time was tau(o) = 0.99+/-0.05 msec (n = 6).
      Mean closed time fast (tau(cf)) and slow (tau(cs)) component values were tau(cf)
      = 0.85+/-0.09 msec and tau(cs) = 8.0+/-0.94 msec (n = 6), respectively. With
      intrapipette (-)Bay K 8644 (1 microM), mean open time was best fit by two
      exponentials, tau(of) = 0.9+/-0.2 msec (n = 10) and tau(os) = 13.4+/-2.6 msec (n
      = 10); mean close time values were tau(cf) = 0.6+/-0.1 msec (n = 10) and tau(cs)
      = 9.8+/-1.9 msec (n = 10), respectively. With (-)Bay K 8644, channel activity was
      66.5%+/-7.4%, the ensemble average current was 0.52+/-0.04 pA (n = 10) and the
      conductance 20.7+/-0.5 pS (n = 5). CONCLUSION: (1) the data establishes the
      characteristics of L-type Ca channels of human fetal hearts and their modulation
      by dihydropyridines; (2) the open time kinetics differ from those of avian
      embryonic and rat fetal hearts; and (3) the findings provide new and relevant
      information for understanding the physiologic behavior of unitary Ca2+ channels
      in the developing human heart and the baseline comparison for diseases that
      implicate Ca2+ channels in their etiology, such as autoimmune-associated
      congenital heart block.

PMID- 10355926
TI  - Effects of electroporation on the transmembrane potential distribution in a two
      dimensional bidomain model of cardiac tissue.
AB  - INTRODUCTION: Defibrillation shocks, when delivered through internal electrodes,
      establish transmembrane potentials (Vm) large enough to electroporate the
      membrane of cardiac cells. The effects of such shocks on the transmembrane
      potential distribution are investigated in a two-dimensional rectangular sheet of
      cardiac muscle modeled as a bidomain with unequal anisotropy ratios. METHODS AND
      RESULTS: The membrane is represented by a capacitance Cm, a leakage conductance
      g(l) and a variable electroporation conductance G, whose rate of growth depends
      exponentially on the square of Vm. The stimulating current Io, 0.05-20 A/m, is
      delivered through a pair of electrodes placed 2 cm apart for stimulation along
      fibers and 1 cm apart for stimulation across fibers. Computer simulations reveal
      three categories of response to Io: (1) Weak Io, below 0.2 A/m, cause essentially
      no electroporation, and Vm increases proportionally to Io. (2) Strong Io, between
      0.2 and 2.5 A/m, electroporate tissue under the physical electrode. Vm is no
      longer proportional to Io; in the electroporated region, the growth of Vm is
      halted and in the region of reversed polarity (virtual electrode), the growth of
      Vm is accelerated. (3) Very strong Io, above 2.5 A/m, electroporate tissue under
      the physical and the virtual electrodes. The growth of Vm in all electroporated
      regions is halted, and a further increase of Io increases both the extent of the
      electroporated regions and the electroporation conductance G. CONCLUSION: These
      results indicate that electroporation of the cardiac membrane plays an important
      role in the distribution of Vm induced by defibrillation strength shocks.

PMID- 10355927
TI  - Separation between virtual sources modifies the response of cardiac tissue to
      field stimulation.
AB  - INTRODUCTION: While it is now understood that the tissue geometry and the
      electric field distribution are important in generating virtual electrodes, the
      effects of interaction between a collection of electrodes have not been examined.
      To develop a basis for understanding such interactions, we have studied a single
      pair of oppositely polarized virtual sources. Although such oppositely polarized
      pairs of virtual electrodes can be generated by a variety of field distributions
      and tissue geometries, we examine one simple system that incorporates the salient
      features of source interaction. METHODS AND RESULTS: Our model system is a
      homogeneous tissue strip stimulated by a uniform extracellular field. To clarify
      virtual source interaction, we show that field stimulated tissue can be
      equivalently polarized by a set of intracellular current sources with magnitude
      and distribution defined by the generalized activating function. In our model
      system, an intracellular current source is produced at one edge of the tissue and
      an intracellular current sink at the other. Therefore, the tissue length acts to
      modulate the overlap, or interaction, between the polarizations arising from each
      source. To quantify the effects of source interaction, the chronaxie and rheobase
      values of the strength-duration relation were determined for source separations
      varying between 1.0 cm and 100 microm (active membrane dynamics were modeled with
      the Luo-Rudy phase I formulation). At all separations >3.0 mm, the chronaxie was
      constant at 3.09 msec and the rheobase was 0.38 V/cm. Under 0.2 mm, the chronaxie
      decreased to 0.55 msec while the rheobase increased linearly with the inverse of
      source separation. The dependence of these parameters on separation primarily
      reflects passive electrotonic interactions between the two virtual electrodes.
      However, the exact values are strongly dependent upon active tissue properties
      largely the inward rectifier potassium channel and activation of the sodium
      current. CONCLUSION: Tissue excitation in response to field stimulation is
      strongly modulated by the proximity of, and therefore the interaction between,
      oppositely polarized virtual electrode sources.

PMID- 10355928
TI  - Electrophysiologic study and radiofrequency catheter ablation of isthmus
      independent atrial flutter.
AB  - INTRODUCTION: We report the electrophysiologic study and radiofrequency catheter
      ablation of isthmus-independent atrial flutter in 2 patients. The isthmus
      independent atrial flutter in these 2 patients had similar ECG and
      electrophysiologic findings. Both were reproducibly induced by rapid atrial
      pacing. The atrial activation sequence and entrainment study proved that these
      atrial flutters were not isthmus-dependent. A high-right atrial site was
      identified as the critical site of the slow conduction zone of the tachycardia in
      both. This site showed double potentials and mid-diastolic potentials.
      Radiofrequency catheter ablation at this site successfully eliminated the isthmus
      independent atrial flutter in both patients.

PMID- 10355929
TI  - Coexisting preexcitation syndrome and intermittent heart block presenting as
      neonatal seizures.
AB  - An infant presented with neonatal syncope and seizures. An ECG showed a
      preexcitation pattern, most compatible with Wolff-Parkinson-White (WPW) syndrome.
      Rhythm monitoring during an event demonstrated prolonged periods of complete AV
      block with no ventricular escape mechanism. We postulated that ventricular
      asystole was initiated by mechanical or autonomic influences on the accessory
      pathway and sustained by electrophysiologic interactions between the accessory
      pathway and the junctional escape focus. This is the first case report of a
      newborn having coexisting congenital AV block and WPW syndrome.

PMID- 10355930
TI  - Signal transduction in ischemic preconditioning: the role of kinases and
      mitochondrial K(ATP) channels.
AB  - Ischemic preconditioning is a phenomenon whereby exposure of the myocardium to a
      brief episode of ischemia and reperfusion markedly reduces tissue necrosis
      induced by a subsequent prolonged ischemia. Therefore, it is hoped that
      elucidation of the mechanism of preconditioning will yield therapeutic strategies
      capable of reducing myocardial infarction. In the rabbit, the brief period of
      preconditioning ischemia and reperfusion releases adenosine, bradykinin, opioids,
      and oxygen radicals that summate to induce the translocation and activation of
      protein kinase C (PKC). PKC appears to be the first element of a complex kinase
      cascade that is activated during the prolonged ischemia in preconditioned hearts.
      Current evidence indicates that PKC activates a tyrosine kinase that leads to the
      activation of p38 mitogen-activated protein (MAP) kinase or JNK, or possibly
      both. The stimulation of these stress-activated protein kinases ultimately
      induces the opening of mitochondrial K(ATP) channels that may be the final
      mediator of protection by ischemic preconditioning.

PMID- 10355931
TI  - Antiarrhythmic drugs and ion channels: have we made the connection?

PMID- 10355932
TI  - An irregular, narrow QRS complex tachycardia with ventriculoatrial block: what is
      the tachycardia mechanism?

PMID- 10355933
TI  - Arrhythmogenic right ventricular cardiomyopathy with regional left ventricular
      involvement.

PMID- 10355934
TI  - Osteotomy site healing following mandibular sagittal split osteotomy and rigid
      fixation with polylactide biodegradable screws.
AB  - Follow-up of 47 patients, treated using mandibular bilateral sagittal split
      osteotomy and self-reinforced poly-L-lactide acid (SR-PLLA) screws for rigid
      internal fixation, is presented. The focus was on clinical and radiological
      osteotomy healing. The average follow-up time was 2.1 years (range 0.5-5 years).
      Clinical recovery and radiological osteotomy healing during follow-up were
      uneventful. Osteolytic changes were seen around the SR-PLLA screws in 27% of
      cases. The majority of the screw canals remained as radiolucent shadows without
      bony filling.

PMID- 10355936
TI  - Full-thickness skin graft in the secondary repair of bilateral cleft lip. A case
      report.
AB  - A 13-week-old boy with bilateral complete cleft lip and palate is presented. He
      had three attempted repairs of his lip elsewhere over a period of four weeks, and
      all of these broke down. Consequently, a substantial amount of his prolabium
      became necrotic. After a preoperative orthodontic realignment of the cleft
      segments, a secondary lip/nose repair was performed. The mucosa was reconstructed
      by advancement flaps. The orbicularis muscle was dissected out from its abnormal
      insertion and reconstructed in the midline. The philtrum was reconstructed with a
      full-thickness skin graft from the right postauricular area. The six-month
      postoperative result was satisfactory. This technique could be considered as an
      alternative to primary Abbe flap in secondary reconstruction of the cleft lip,
      although long-term follow-up must be obtained.

PMID- 10355935
TI  - Computer-aided surgery in distraction osteogenesis of the maxilla and mandible.
AB  - When using unidirectional intraoral distraction devices, it is desirable to be
      able to determine the final position of the bone fragment after the distraction
      procedure. However, additional constraining forces from adjacent tissues render
      the prediction of the distraction direction difficult. We have utilised computer
      aided surgery in three patients for intraoperative control of the distraction
      direction. In one cleft palate patient, suffering from maxillary hypoplasia and
      anterior open bite, a modified Le Fort I osteotomy and maxillary distraction was
      performed. Despite a ventrocaudal position of the distraction device,
      intraoperative computer visualisation showed an unfavourable caudal vector of
      distraction without any anterior movement. The final result confirmed the
      direction indicated by the computer. Maxillary advancement remained insufficient.
      In two patients suffering from mandibular hypoplasia, intraoperative assessment
      revealed a favourable direction of distraction. The distraction procedure led to
      a satisfactory result in both cases. Computer-aided surgery is helpful in
      assessing the vector of distraction intraoperatively, making the result of the
      distraction procedure more predictable and allowing instant correction by
      adequate reapplication of the device.

PMID- 10355937
TI  - Frontal sinus pneumocele. A case report.
AB  - A pneumocele refers to an aerated sinus with either focal or generalized thinning
      of the bony sinus wall. Although the pathogenesis of a pneumocele is not yet
      known, it is presumed that increased intrasinusal pressure, due to a one-way
      valve between the nasal cavity and the affected sinus, is responsible for this
      condition. A 37-year-old man with frontal bossing, who underwent surgery for
      cosmetic reasons, is presented.

PMID- 10355938
TI  - Oral implants in combination with bone grafts. A 3-year retrospective multicenter
      study using the Branemark implant system.
AB  - A retrospective, multicenter, Scandinavian study of bone grafting of alveolar
      processes of severely atrophic jaws in combination with implant insertion was
      conducted with 150 patients. Five different grafting techniques were assessed:
      local or full onlay; inlay; combination of onlay/inlay grafts; and LeFort I
      osteotomies. The majority of the patients were treated using a one-stage approach
      (n = 125) and all had autogenous bone grafts. A total of 781 Branemark implants
      were inserted, of which 624 were placed in bone grafts and alveolar bone. Twenty
      five patients (17%) dropped out during the follow-up period of three years.
      Within the remaining patients, 77% of the inserted implants (n = 516) were still
      in function at the end of the follow-up period. A further ten implants were kept
      mucosa-covered, resulting in an overall implant survival rate of around 80%.
      Onlays, inlays and LeFort I osteotomies showed almost the same success rates (76
      84%), whereas the onlay/inlay technique gave rise to less favourable results
      (60%). Most of the observed losses (n = 131) took place during healing and the
      first year of loading. More implants were lost when they were inserted
      simultaneously with the grafting (23%) than when they were placed in a second
      stage (10%). The latter technique was used mainly in combination with local onlay
      grafting (16/25). The failure percentage for implants inserted in non-grafted
      bone (11%) was lower than for those inserted in bone grafts and alveolar bone
      (25%). The surviving implants of treated and followed patients served, in 88% of
      the cases (n = 110), to support fixed bridges or overdentures, albeit, in some
      instances (n = 23), after additional implant placement. In only 15 patients was
      it necessary to fall back on conventional removable prostheses or fixed partial
      bridges.

PMID- 10355939
TI  - Mountainbiking--a dangerous sport: comparison with bicycling on oral and
      maxillofacial trauma.
AB  - The popularity of bicycling is reflected in the number of cycling-related oral
      and maxillofacial injuries. Five hundred and sixty-two injured bicyclists (10.3%
      of all trauma patients) were registered at the Department of Oral and
      Maxillofacial Surgery, University of Innsbruck, Austria, between 1991 and 1996,
      accounting for 31% of all sports-related accidents and 48.4% of all traffic
      accidents. A review of the patient records revealed more severe injury profiles
      in sixty mountainbikers, with 55% facial bone fractures, 22% dentoalveolar trauma
      and 23% soft tissue injuries, compared to 502 street cyclists showing 50.8%
      dentoalveolar trauma, 34.5% facial bone fractures and 14% soft tissue lesions.
      The dominant fracture site in bicyclists was the zygoma (30.8%), whereas
      mountainbikers sustained an impressive 15.2% LeFort I, II and III fractures.
      Condyle fractures were more common in bicyclists, with 18.8% compared to 10.8% in
      mountainbikers. Reduction of facial injuries due to cycling-related accidents
      needs appropriate design of helmets with faceguards and compulsory helmet use for
      all cyclists, and particularly mountainbikers.

PMID- 10355940
TI  - Complications after apicoectomy in maxillary premolar and molar teeth.
AB  - This study was designed to enumerate the number of perforations to the maxillary
      sinus while performing apicoectomy on maxillary premolar and molar teeth and to
      evaluate possible complications as a result of these perforations. A total of 472
      apicoectomies were performed in 440 patients; perforations occurred in 10.4% of
      teeth, 23% in molars, 13% in second premolars and 2% in first premolars. No cases
      of acute or chronic sinusitis were recorded. It was concluded that apicoectomy,
      carried out using a meticulous surgical technique and proper postoperative care,
      should be considered as a treatment option before contemplating extraction.

PMID- 10355941
TI  - Bilateral reflex fracture of the coronoid process of the mandible. A case report.
AB  - Bilateral fractures of the coronoid process of the mandible occurred following a
      blow to the left temporal region in an assault. There was no evidence of direct
      trauma and the zygoma and other facial bones were intact. The probable cause was
      acute reflex contraction of the temporalis muscles leading to bilateral stress
      coronoid fractures. Conservative management was followed by complete resolution
      of symptoms.

PMID- 10355942
TI  - Comparison between hockey stick and reversed hockey stick incision: gently curved
      single linear neck incisions for oral cancer.
AB  - Hockey stick incision (HSI) and reversed-HSI are known to be useful incisions for
      lymph node dissections of the neck. Both are gently curved single linear
      incisions without three-point suture line junctions, but are different at the
      base of the skin flap. The HSI allows the elevation of a superiorly-based single
      cervical skin flap and the reversed-HSI allows for an inferiorly-based flap. We
      compared the viability of the skin flaps, exposure of the operation field and
      cosmetic results to evaluate the characteristics of each incision. HSI appeared
      to be the suitable incision for radical neck dissection due to adequate exposure
      of the operation field while rendering excellent cosmetic results. Reversed-HSI
      was applied in combination with block resection of parts of the oral cavity
      because it provided much better exposure of the operation field than HSI, while
      still achieving acceptable cosmetic results. Using this technique, a small area
      of marginal necrosis was occasionally seen at the apex of the skin flap due to
      poor blood supply.

PMID- 10355944
TI  - Usefulness of fluorescence photography for diagnosis of oral cancer.
AB  - This study was carried out to evaluate the validity of fluorescence photography
      as an adjunctive diagnostic method for oral cancer. Fluorescence photography was
      performed on 130 oral lesions in 130 patients. Lesions showing red, orange or
      pink fluorescence on the photographs were defined as positive, while all other
      lesions were considered negative. Seventy-two (91.1%) of 79 carcinomas and 6
      (85.7%) of 7 epithelial dysplasias were judged as positive, whereas two (4.5%) of
      44 benign lesions that were not dysplasias showed positive fluorescence. Sixty
      nine (94.5%) of 73 squamous cell carcinomas showed positive fluorescence. These
      results suggest that fluorescence photography is useful as an adjunctive
      diagnostic method for oral squamous cell carcinoma.

PMID- 10355943
TI  - Is the new TNM (1997) the best system for predicting prognosis?
AB  - In 1997, the U.I.C.C. (International Union against Cancer) modified the previous
      TNM stage grouping published in 1987. In the present study, TANIS and TNM '97
      systems were compared in order to evaluate their prognostic ability. Data from
      164 patients affected by primary squamous cell carcinoma cancers of the oral
      cavity (n=100) and oropharynx (n=64) were analyzed by means of survival analyses.
      Both systems showed a significant correlation with survival rate. TANIS yielded
      better results in association with the survival rate as compared with TNM '97.

PMID- 10355945
TI  - A comparison of one hundred and fifty consecutive parotidectomies for tumours and
      inflammatory disease.
AB  - The demographic profile and complications are compared and contrasted for 150
      consecutive parotidectomies. All patients were under the care of one surgeon
      (JDL) over a twenty-year period (1977-1997). The case records and contemporaneous
      database were analysed retrospectively. 111 (74%) procedures were performed for
      tumours and 39 (26%) for inflammatory disease. The incidence of unexpected
      permanent facial nerve palsy was 1.8% in the tumour group and zero in the
      inflammatory group. The overall unexpected palsy rate was 1.3%. Transient
      paralysis was more common in the inflammatory group than the tumour group (61.5%
      compared with 33.3%, P<0.02) and was more likely to be panfacial (48.7% compared
      with 17.1%, P<0.0002). The overall incidence of Frey's syndrome was less than 20%
      and both salivary fistulae and sialocoeles were infrequent.

PMID- 10355947
TI  - The influence of simultaneous versus delayed placement on the stability of
      titanium implants in onlay bone grafts. A histologic and biomechanic study in the
      rabbit.
AB  - A rabbit model was used to study the healing and stability of titanium implants
      in free bone grafts, placed simultaneously or after 8 weeks of healing and
      followed for 24 weeks. The skull bone was used as donor site and the tibial
      metaphysis as recipient site. Stability measurements were performed by using
      resonance frequency analysis (RFA) at implant placement and after 4, 8, 16 and 24
      weeks of healing. Statistically significant higher resonance frequencies were
      measured at all time points for the delayed approach implants. Removal torque
      tests after 24 weeks revealed no differences between the two procedures.
      Histologic ground sections were prepared on specimens taken after 8, 16 and 24
      weeks of healing. More bone-implant contacts were observed in the bone graft for
      the implants inserted in a delayed fashion, while there was no statistically
      significant difference in the degree of total bone-implant contact between the
      two groups. It is concluded that delayed implant placement in autogenous onlay
      bone grafts results in a better integration and stability of the implants.

PMID- 10355946
TI  - Nevoid basal cell carcinoma syndrome: molecular biology and new hypotheses.
AB  - To understand the molecular biology of the nevoid basal cell carcinoma syndrome,
      the hedgehog signaling network is explained. The syndrome is caused by mutations
      in patched, a tumor suppressor gene. A single point mutation in one patched
      allele may be responsible for the malformations found in the syndrome.
      Inactivation of both patched alleles results in the formation of tumors and cysts
      (basal cell carcinomas, odontogenic keratocysts, and medulloblastomas). Several
      new hypotheses are proposed to account for a minority of nevoid basal cell
      carcinoma syndrome patients. Evidence is provided to suggest that these
      hypotheses deserve to be investigated.

PMID- 10355948
TI  - Bone augmentation by recombinant human BMP-2 and collagen on adult rat parietal
      bone.
AB  - A composite of recombinant human bone morphogenetic protein-2 (rhBMP-2) and
      collagen was implanted beneath the cranial periosteum of 10-month-old rats to
      observe bone development and absorbent change of carrier collagen. The rhBMP
      2/collagen onlay implant resulted in active bone formation and the augmented bone
      was connected directly with the original bone, whereas the collagen alone
      resulted in neither bone nor cartilage. The ossification process in the rhBMP
      2/collagen occurred directly through bone formation, similar to intramembranous
      ossification. The carrier collagen fibers were found in the woven bone and were
      completely absorbed at 8 weeks in the presence of rhBMP-2, while the collagen
      alone implant remained encapsulated by a thin, fibrous connective tissue. Our
      results indicate that rhBMP-2/collagen is an effective material as a biological
      onlay implant, showing osteoinductive properties and being completely replaced by
      new bone. Carrier collagen not only plays a role in rhBMP-2 delivery, but also
      provides a cell anchorage for cell differentiation and remains as an artificial
      matrix in woven bone.

PMID- 10355949
TI  - Technetium-99m-tetrofosmin imaging of lung cancer: relationship with
      histopathology.
AB  - Tc-99m-tetrofosmin is an agent to delineate cancer. To elucidate the usefulness
      of Tc-99m-tetrofosmin scintigraphy, we analyzed the relationship between the
      uptake of Tc-99m-tetrofosmin and histopathology in patients with lung cancer.
      SPECT studies were conducted twice: 15 minutes (early scan), and 60 minutes
      (delayed scan), after intravenous injection of 740 MBq Tc-99m-tetrofosmin. We
      calculated the retention index in order to evaluate the degree of Tc-99m
      tetrofosmin retention in the primary tumor. The retention indices were
      significantly lower in squamous cell carcinoma than those of small cell carcinoma
      or adenocarcinoma. As the retention indices of Tc-99m-tetrofosmin were different
      in each histopathology, the index might play a part as a tumor marker of lung
      cancer.

PMID- 10355950
TI  - Prediction of response to revascularization in patients with renal artery
      stenosis by Tc-99m-ethylenedicysteine captopril scintigraphy.
AB  - The aim of the present study was to assess the predictive value of captopril
      scintigraphy with the new renal agent 99mTc-ethylenedicysteine (99mTc-EC) for
      post-interventional improvement in blood pressure. Twelve patients who had
      persistently high blood pressure with previous demonstration of various degrees
      of renal artery lesion on angiography were included into the study. Baseline and
      captopril scintigraphies were performed on the same day at 4 hour intervals after
      the injection of 74 and 296 MBq of 99mTc-EC, respectively. All patients had
      percutaneous transluminal angioplasty (PTA), and improvement in blood pressure
      was evaluated 3-6 months after the intervention. 99mTc-EC captopril scintigraphy
      successfully predicted a positive or negative outcome in 11 of 12 patients. In
      one patient with captopril induced renal function deterioration, scintigraphy
      failed to predict post-interventional response. Our preliminary findings showed
      that 99mTc-EC captopril scintigraphy can be used to determine patients who will
      benefit from revascularization.

PMID- 10355951
TI  - Relationship between the biodistributions of radioactive metal nuclides in tumor
      tissue and the physicochemical properties of these metal ions.
AB  - This study was undertaken to elucidate the relationship between the
      biodistribution of radioactive metal nuclides in tumor tissue and its
      physicochemical properties. Potassium analogs (86Rb, 134Cs, 201Tl) were taken up
      into viable tumor tissue, although 22Na concentrated in necrotic tumor tissue.
      67Ga and 111In were more predominant in inflammatory tissue than in the viable
      and necrotic tumor tissue. 169Yb and 167Tm accumulated in viable tumor tissue and
      tissue containing viable and necrotic tumor tissue. 67Ga, 111In, 169Yb and 167Tm
      were bound to the acid mucopolysaccharide with a mol. wt. of about 10,000 daltons
      in the tumor tissue. 46Sc, 51Cr, 95Zr, 181Hf, 95Nb, 182Ta, and 103Ru were highly
      concentrated in inflammatory tissue and were bound to the acid
      mucopolysaccharides with a mol. wt. exceeding 40,000 daltons. 65Zn and 103Pd
      concentrated in viable tumor tissue and were bound to the protein in the tissue.
      The results suggest that the difference in intra-tumor distribution of these
      elements is caused by a difference in the binding substances (or status) of these
      elements in the tissues, and the binding substance is determined by
      physicochemical properties of the elements. We therefore conclude that the
      biodistribution of radioactive metal ions in tumor tissue is determined by its
      own physicochemical properties.

PMID- 10355952
TI  - Washout rate of 123I-metaiodobenzylguanidine increased by posture change or
      exercise in normal volunteers.
AB  - 123I-metaiodobenzylguanidine (MIBG) imaging detects sympathetic nerve function in
      the heart. The present study was conducted to clarify whether posture change or
      exercise affects 123I-MIBG kinetics in normal volunteers. Seven subjects
      underwent three 123I-MIBG studies, i.e., supine protocol, sitting protocol and
      exercise protocol. Planar 123I-MIBG images were obtained at 15 minutes, 1 hour
      and 4 hours after injection of 123I-MIBG. The washout rate (WR) from 15 minutes
      to 1 hour in the supine position in all subjects was similar for all three
      protocols, whereas the WR from 1 hour to 4 hours was significantly augmented in
      the sitting protocol and the exercise protocol as compared to the supine protocol
      (p < 0.05 and p < 0.01). The serum concentration of noradrenaline was
      significantly increased from the baseline to the 4 hour sampling in the sitting
      protocol and the exercise protocol (both p < 0.01), but was not altered in the
      supine protocol. The WR from 1 hour to 4 hours significantly correlated with the
      noradrenaline concentration in 4 hour sampling (r = 0.59, p < 0.01). It also
      significantly correlated with an increase in the noradrenaline concentration from
      the baseline to the 4 hour sampling (r = 0.53, p < 0.05). It is concluded that
      posture change or exercise affects the WR of 123I-MIBG in normal healthy
      subjects.

PMID- 10355953
TI  - Diabetic cardiac autonomic dysfunction: parasympathetic versus sympathetic.
AB  - BACKGROUND: Diabetic cardiac autonomic dysfunction often causes lethal arrhythmia
      and sudden cardiac death. 123I-Metaiodobenzylguanidine (MIBG) can evaluate
      cardiac sympathetic dysfunction, and analysis of heart rate variability (HRV) can
      reflect cardiac parasympathetic activity. We examined whether cardiac
      parasympathetic dysfunction assessed by HRV may correlate with sympathetic
      dysfunction assessed by MIBG in diabetic patients. METHODS AND RESULTS: In 24
      hour electrocardiography, we analyzed 4 HRV parameters: high-frequency power
      (HF), HF in the early morning (EMHF), rMSSD and pNN50. MIBG planar images and
      SPECT were obtained 15 minutes (early) and 150 minutes (late) after injection and
      the heart washout rate was calculated. The defect score in 9 left ventricular
      regions was scored on a 4 point scale (0 = normal approximately 3 = severe
      defect). In 20 selected diabetic patients without congestive heart failure,
      coronary artery disease and renal failure, parasympathetic HRV parameters had a
      negative correlation with the sum of defect scores (DS) in the late images (R = 
      0.47 approximately -0.59, p < 0.05) and some parameters had a negative
      correlation with the washout rate (R = -0.50 approximately -0.55, p < 0.05). In a
      total of 64 diabetic patients also, these parameters had a negative correlation
      with late DS (R = -0.28 approximately -0.35, p < 0.05) and early DS (R = -0.27
      approximately -0.32, p < 0.05). CONCLUSIONS: The progress of diabetic cardiac
      parasympathetic dysfunction may parallel the sympathetic one.

PMID- 10355954
TI  - Effect of tracer metabolism on PET measurement of [11C]pyrilamine binding to
      histamine H1 receptors.
AB  - The present study was carried out to investigate the time course of
      [11C]pyrilamine metabolism and the degree of entry of metabolites into the brain.
      PET studies were performed in seven healthy volunteers and arterial plasma
      concentrations of [11C]pyrilamine and its labeled metabolites were determined.
      After intravenous injection, [11C]pyrilamine metabolized gradually in the human
      body, with less than 10% of plasma activity being original radioligand at 60 min.
      Tracer metabolism markedly affected the input function and the calculated impulse
      response function of the brain. Rat experiments demonstrated that although
      metabolites of [11C]pyrilamine might enter the brain, they were not retained for
      prolonged periods of time. At 30-90 min after injection of [11C]pyrilamine, less
      than 1% of the radioactivity in the brain was originating from metabolites of
      [11C]pyrilamine. Based on the rat data, the contribution of 11C-labeled
      metabolites to total [11C]pyrilamine radioactivity in the human brain was
      estimated and found to be negligible. These results suggest that the metabolites
      of [11C]pyrilamine do not accumulate within the cerebral extravascular space and
      that there is minimal metabolism of [11C]pyrilamine by brain tissue itself.
      Therefore, [11C]pyrilamine metabolites can be neglected in kinetic analysis,
      using either a compartmental or a noncompartmental model, of the [11C]pyrilamine
      binding to histamine H1 receptors.

PMID- 10355955
TI  - Cerebral blood flow-SPECT in a patient with Sneddon's syndrome.
AB  - We report a 50-year-old woman diagnosed with Sneddon's syndrome and examined by
      CBF scintigraphy several times for follow-up of the disease. There were no
      significant changes in her CBF scintigraphic findings or neurological status
      during the 6-year follow-up period. Sneddon's syndrome is a slowly progressive
      disorder in which livedo reticularis precedes cerebrovascular accidents. Because
      small cortical arteries are predominantly affected in Sneddon's syndrome, MR and
      conventional angiography often fail to show any abnormal findings, and MR imaging
      may not visualize decreased CBF in the early stage. Therefore, CBF scintigraphy
      should be performed in patients who have or are suspected of having Sneddon's
      syndrome.

PMID- 10355956
TI  - Technetium-99m pertechnetate uptake in ectopic parathyroid adenoma.
AB  - A 37-year-old male with a persistent increased parathyroid hormone level, after
      subtotal thyroidectomy and parathyroidectomy, was referred for scintigraphic
      localization of a possible ectopic parathyroid adenoma. Tc-99m pertechnetate and
      Tc-99m MIBI scintigraphy were performed on separate days. There was marked uptake
      of both tracers in the mediastinum, which at surgery was confirmed to be an
      extrathyroidal parathyroid adenoma. Hypervascularity was suggested as a possible
      explanation for rare cases of pertechnetate avid parathyroid adenomas. And Tc-99m
      MIBI scintigraphy proved to be a successful imaging procedure for ectopic
      parathyroid tissue.

PMID- 10355957
TI  - Gallium-67 uptake in Bellini duct carcinoma of the kidney.
AB  - Bellini duct carcinoma is a rare variant of renal cell carcinoma and usually has
      a poor prognosis. In this article, we report the Gallium-67 citrate (Ga-67)
      uptake in Bellini duct carcinoma. To our knowledge, this is the second reported
      case of Bellini duct carcinoma in which Ga-67 uptake was positive. We suggest
      that Ga-67 scintigraphy has potential utility in detecting Bellini duct carcinoma
      of the kidney. And if a hypovascular tumor of the kidney shows Ga-67 uptake,
      Bellini duct carcinoma should be included in the differential diagnosis.

PMID- 10355958
TI  - Simultaneous assessment of function and perfusion during dipyridamole-handgrip Tc
      99m sestamibi imaging in chronic coronary artery disease.
AB  - The main goal of this work was to know the value of ventricular function in
      addition to perfusion Tc-99m sestamibi images in the assessment of coronary
      artery disease (CAD) when using dipyridamole (DIP) associated to isometric
      exercise. We analyzed 52 patients with suspected CAD; 40 of them had coronary
      lesions > or = 50% and 12 patients without CAD, conforming study and control
      groups, respectively. Twenty-eight patients had prior myocardial infarction. A
      two-day sestamibi protocol was employed with i.v. DIP-handgrip and rest
      injections, acquiring ECG-gated first pass and planar perfusion images.
      Sensitivity for perfusion images was 85% and specificity was 91.7%. There was no
      change between rest and DIP ejection fraction (EF) in controls. CAD patients
      presented a significant EF decrease with DIP (p: 0.0015). Patients with ischemia
      in perfusion images had larger EF decrease (p: 0.0001). For the analysis, an EF
      drop > or = 5% and any wall motion abnormality (WMA) were considered as having an
      abnormal response to DIP. CAD sensitivity improved significantly to 92.5% when
      adding EF drop and to 90% when adding WMA parameters, but specificity decreased
      to 75% with EF drop, and to 58.3% with WMA. In conclusion, first pass parameters
      from DIP-isometric exercise in addition to perfusion images are not a significant
      help in the assessment of CAD.

PMID- 10355959
TI  - Technetium-99m complex of N-(2-pyridylmethyl)iminodiacetic acid as a new renal
      radiopharmaceutical.
AB  - A tetradentate chelating agent constituting of an iminodiacetic acid group and a
      nitrogen atom of pyridine, N-(2-pyridylmethyl)iminodiacetic acid (PMIDA), was
      coordinated with 99mTc and evaluated as a renal functional agent. The complex of
      PMIDA with 99mTc was prepared by using a stannous chloride solution as a reducing
      agent. The chelating efficiency was analyzed by thin layer chromatography and
      electrophoresis. Chelation with 99mTc resulted in a single radiochemical product.
      Biological studies were performed in mice and rats. 99mTc-PMIDA was removed from
      the circulation solely by the kidneys. Clearance of 99mTc-PMIDA from the blood
      and the kidneys was as rapid as that of 99mTc-diethylenetriaminepentaacetic acid.
      The rate of blood clearance was unaffected by the administration of probenecid (a
      test for tubular secretion by the weak-acid mechanism), so that the glomerular
      filtration rate could be estimated by measuring its clearance from the blood. The
      results in animals with myohemoglobinuric acute renal failure suggested that
      99mTc-PMIDA might be a useful renal function radiopharmaceutical.

PMID- 10355960
TI  - Re: I-123 iomazenil SPECT in patients with mental disorders.

PMID- 10355961
TI  - Reactive oxygen species-induced molecular damage and its application in
      pathology.
AB  - Recent studies have clarified that reactive oxygen species (ROS) are involved in
      a diversity of biological phenomena including radiation damage, carcinogenesis,
      ischemia-reperfusion injury, diabetes mellitus and neurodegenerative diseases.
      The breakthrough of these fruitful accomplishments was the discovery of an
      enzyme, superoxide dismutase, by McCord and Fridovich in 1968. In the 1970s and
      80s, biochemists and radiation biologists were attracted by the role of ROS in
      its irreversible damage to biological molecules. In the 1990s, ROS were further
      found to be a reversible modulator of protein structure as well, and this led to
      a recent rapid data accumulation on the association of ROS and transcription
      factors. At the same time, methods to localize ROS-induced damage in paraffin
      embedded tissues have been established. This owes to a successful production of
      antibodies against covalently modified structures specific for ROS-induced
      damage. The epitopes include 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal
      modified proteins. The present article reviews histochemical and
      immunohistochemical methods to localize ROS-induced damage in tissues and cells,
      further comments on the association of ROS with transcription factors, and shows
      a prospective view of ROS-induced carcinogenesis.

PMID- 10355962
TI  - CD95 ligand is expressed in Reed-Sternberg cells of Hodgkin's disease.
AB  - Reed-Sternberg (RS) cells and their mononuclear variants, Hodgkin's (H) cells,
      are considered to be the neoplastic cells of Hodgkin's disease (HD). The cellular
      origin of H-RS cells remains the subject of considerable controversy, although
      most recent papers have claimed that H-RS cells are of B cell origin. Recently,
      however, it has been reported that some H-RS cells express granzyme B, as
      observed in cytotoxic T cells and/or natural killer cells, which also express
      CD95 ligand (FasL/APO-1L). In the present study, the expression of CD95L and
      granzyme B in H-RS cells of HD was investigated. CD95L was detected in H-RS cells
      in five of nine HD cases (one case of lymphocyte-rich classical HD, two of these
      cases of nodular sclerosis type, and two of four cases of mixed cellularity
      type). All three examined HD cell lines expressed CD95L in the cytoplasm,
      although cell surface expression was seen only in L428 cells. Three HD cases
      expressed both CD95L and granzyme B. It was concluded that CD95L is frequently
      expressed in H-RS cells, which is one of their notable characteristics; albeit it
      seems to be irrespective of cell lineage.

PMID- 10355964
TI  - Pathological changes of the spinal cord in centenarians.
AB  - In order to study the changes that occur in the spinal cords of the aged, 19
      centenarian spinal cords from two men and 17 women (age range, 100-116 years at
      death; mean, 103 years) were pathologically examined. Cross-sections at each
      segmental level of the 19 autopsied spinal cords were examined for
      histopathological changes. The cross-sectional area and flattening ratio at the
      level of the C7 segment were measured. The size of the cords had some negative
      correlation with age, but the individual variation was considerably large. Among
      the 19 centenarians, macroscopic anteroposterior flattening appeared in the lower
      cervical cords in six individuals. In these cases, various degrees of neuron loss
      were observed in the anterior horn. White matter degeneration appeared
      frequently, especially in the posterior column. In 12 cases, myelin loss in the
      fasciculus of Goll at the cervical level was observed. The degeneration of the
      fasciculus of Goll was considered to be upward wallerian degeneration secondary
      to posterior root damage at the lumbosacral level. These changes seemed to be
      produced by disorders in the spinal canal or surrounding tissue, such as cervical
      spondylosis, degeneration of the intervertebral disk and spinal canal stenosis.
      Argyrophilic structures such as neurofibrillary tangles and neuropil threads were
      observed in 16 cases; however, this incidence was less than in the brain. Medial
      thickening of the anterior spinal artery was found in four cords.
      Amyloidangiopathy was noted in only one cord. Necrosis and hemorrhage due to
      vascular disturbance were not found.

PMID- 10355963
TI  - Polymerase chain reaction screening of immunoglobulin heavy chain and T cell
      receptor gamma gene rearrangements: a practical approach to molecular DNA
      analysis of non-Hodgkin's lymphoma in a surgical pathology laboratory.
AB  - Characterization of the clonality of non-Hodgkin's lymphoma (NHL) by the
      rearranged segments of immunoglobulin heavy chain (Ig(H)) or T cell receptor
      (TCR) genes is not only useful in the confirmation of the diagnosis but also for
      the future assessment of how a secondary lymphoma, such as a recurrence or
      another primary lymphoma, occurs. As a practical approach to obtaining and
      registering this information in a surgical pathology laboratory, FR3 and FR1
      regions of Ig(H) gene and TCRgamma gene were concurrently amplified by polymerase
      chain reaction (PCR) using each pair of consensus primers and the same PCR
      protocol. Examined samples consisted of 134 primary NHL (phenotypically, 108 B
      cell and 26 T cell NHL), 19 reactive lymphadenopathies, as well as five secondary
      lymphomas whose primary lesions were included in this study. Among the primary
      NHL, the combined PCR analysis disclosed the clonality in 103 of 134 NHL (77%),
      by FR3 PCR in 77 B cell and two T cell NHL, by FR1 PCR in 59 B cell and one T
      cell NHL, and by TCRgamma PCR in 11 B cell and 17 of 26 T cell NHL, but in none
      of the reactive lymphadenopathies. Among the secondary lymphomas, the same
      pattern of PCR analysis was obtained in two cases (the durations between first
      and second lymphomas; 6 and 10 months), which suggested recurrence. In contrast,
      different results were obtained in three cases (17-37 months), which indicated
      another primary or emergence of the subclones. The results of Southern blot
      analysis were concordant with the PCR results of the first and the secondary
      lymphomas. Although the combined PCR analysis cannot replace Southern blot
      hybridization because of its lower detection rate, it can select those cases
      suitable for further Southern blot analysis thus reducing the number of
      unnecessary examinations by nearly 75%. This approach may also be useful in the
      comparative evaluation of primary and secondary lymphomas.

PMID- 10355965
TI  - Distribution of cadmium and metallothionein in CdCl2-exposed rat kidney:
      relationship with apoptosis and regeneration.
AB  - Male Sprague-Dawley rats were injected subcutaneously with 0.6 mg cadmium/kg
      bodyweight per day for 6 weeks. In each week of exposure, rats were killed and
      the localization of cadmium and metallothionein in the kidney was studied by
      histochemical and immunohistochemical methods. Although cadmium was localized
      throughout the proximal tubules during exposure, apoptosis and subsequent
      regeneration were observed mainly in the straight portion of the proximal tubules
      after 4 weeks of exposure. The distribution of tubular injury may thus not
      necessarily coincide with that of cadmium. Expression of metallothionein was also
      detected in the cytoplasm and nuclei of the convoluted and the straight portion
      of the proximal tubules, but the latter became positive in accordance with
      apoptosis and regeneration. These results suggest a close relationship between
      metallothionein distribution and tubular cell regeneration.

PMID- 10355966
TI  - Sjogren's syndrome in mice carrying the Ipr(cg) gene and the therapeutic efficacy
      of an immunosuppressive agent FK506.
AB  - The influence of the Ipr(cg) gene on the development of Sjogren's syndrome was
      followed up to 5 months of age in male and female mice of MRL, CBA and C3H
      strains. In MRL-Ipr(cg) mice, focal mononuclear cell infiltration started at 2
      months and became conspicuous after 3 months of age in the lacrimal and
      submandibular glands but was minimal in the parotid and sublingual glands, even
      at 5 months of age, without any apparent sex effects found. In CBA and C3H mice
      carrying the Ipr(cg) gene, this manifestation of Sjogren's syndrome was much less
      prominent, indicating that the participation of some genes of the MRL strain may
      be indispensable for the development of Sjogren's syndrome in mice carrying this
      gene. In MRL-Ipr(cg) mice, an immunosuppressive agent, FK506, improved the
      serological abnormalities (decreased levels of anti-double-stranded DNA antibody
      of IgG2a and IgG3 subclasses) and proteinuria. It also reduced the manifestations
      of Sjogren's syndrome when it was intraperitoneally administered three times
      weekly at a dose of 2 mg/kg from 6 weeks (before disease onset) until 5 months of
      age (the termination of the experiment). Although VP8.2+ T cells have been
      demonstrated to be responsible for causing several autoimmune diseases, the
      selective deletion of Vp8.2+ T cells with the superantigen encoded by mouse
      mammary tumor virus did not affect the disease severity at all, suggesting that
      this T cell repertoire may not play a crucial role in induction of Sjogren's
      syndrome.

PMID- 10355967
TI  - Subversion of antigenic expression in neoplasia: lessons from immunohistology of
      teratomas.
AB  - Many examples of inappropriate expression of intermediate filaments and other
      cell identity markers are known to occur in diagnostic tumor pathology. In the
      present study, this subversion of antigenic differentiation in tumors has been
      investigated using teratomas as a model, as these unique tumors not only mimic
      developing tissues but also show carcinomatous elements. Ten cases of teratoma
      (eight immature, two mature) were studied immunohistochemically using a panel of
      13 commonly used cell identity markers, including intermediate filaments.
      Examples of antigenic coexpression and transbarrier expression in various
      morphologically mature and immature tissues were noted to be similar to those
      seen in various tumors. Carcinomatous elements in teratomas were non-reactive
      rather than showing antigenic aberrations. Hence, this study strengthens the
      proposition that antigenic subversion in neoplasia is related to the process of
      maturation and differentiation, rather than malignant transformation.

PMID- 10355968
TI  - Expression pattern of a newly recognized protein, LECT2, in hepatocellular
      carcinoma and its premalignant lesion.
AB  - Leukocyte cell-derived chemotoxin 2 (LECT2) is a recently isolated protein and
      has been shown to be synthesized by human hepatocytes. All hepatocytes show
      diffuse immunostaining for LECT2 within the cytoplasm. In the present study, an
      attempt was made to clarify the expression pattern of LECT2 in nine cases of low
      grade malignant hepatocellular carcinoma (LGM-HCC) and five cases of advanced HCC
      and 19 cases of premalignant lesion, termed atypical hyperplasia (AH), using the
      indirect immunoperoxidase technique. Variable spotty to coarsely diffuse staining
      in the majority of cells, a mixture of positively staining and negatively
      staining areas, and essentially negative staining was observed within the
      cellular cytoplasm of AH, LGM-HCC and advanced HCC, respectively. The expression
      of LECT2 became weaker with the progression of multistep hepatocarcinogenesis.
      The data clearly demonstrate that LECT2 becomes essentially negative in full
      blown HCC cells and that the histological distinction between AH and LGM-HCC is
      valid. It also seems likely that LECT2 is related to hepatocyte growth.

PMID- 10355969
TI  - Retroperitoneal bronchogenic cyst: report of a case and literature review.
AB  - A large cystic mass was found in the subdiaphragmatic region of a 46-year-old
      woman who had complained of continuous pain in the left flank . The cyst was
      located in the retroperitoneum just below the diaphragm and was adhered to the
      diaphragmatic skeletal muscle and abdominal aorta, but was separate from the
      spleen, pancreas, left adrenal gland and left kidney. The surgically resected
      cyst measured 8 x 8 x 7 cm and was filled with protein-rich fluid, which
      contained amylase and embryonal proteins such as carcinoembryonic antigen, CA125
      and CA19-9. Histologically, the cyst wall was composed of a fibrovascular
      connective tissue containing thin smooth muscle layers and mucus-secreting glands
      and was lined by a ciliated pseudostratified or tall columnar epithelium without
      dysplastic changes. Thus, a diagnosis of bronchogenic cyst, which is usually
      discovered in the posterior part of the mediastinum, was made. A rare case of
      bronchogenic cyst and a literature review is presented.

PMID- 10355970
TI  - Esophageal adenocarcinoma that probably originated in the esophageal gland duct:
      a case report.
AB  - A case of primary esophageal adenocarcinoma in a 64-year-old man is reported. An
      ulcerating tumor was located in the middle intrathoracic esophagus.
      Histopathological examination revealed a moderately differentiated
      adenocarcinoma, which had invaded down to the adventitia. The cancerous tubuli
      were lined by flattened cuboidal cells with eosinophilic cytoplasm, which were
      analogous with the esophageal gland ducts and syringoma of the skin. The
      carcinoma was spread widely in the lamina propria mucosae without intraepithelial
      neoplastic elements. An immunohistochemical profile of individual cytokeratins
      and other epithelial markers in the carcinoma was similar to that of the
      esophageal gland ducts. Barrett's metaplastic epithelium or ectopic gastric
      mucosa was not found around the tumor. It is strongly suggested that this unique
      carcinoma is derived from the esophageal gland ducts.

PMID- 10355971
TI  - Poorly differentiated adenocarcinoma with extensive rhabdoid differentiation:
      clinicopathological features of two cases arising in the gastrointestinal tract.
AB  - This paper describes the pathological features of two cases of composite extra
      renal rhabdoid tumor; that is, poorly differentiated carcinoma with extensive
      rhabdoid differentiation, arising in the small intestine of a 64-year-old man and
      in the pancreas of a 77-year-old woman. In both cases the tumor behaved
      aggressively and the patients died from disseminated malignancy within 3 months
      of original presentation and diagnosis. To the best of our knowledge these are
      the first examples of such tumors in the small intestine and pancreas.

PMID- 10355972
TI  - An autopsy case of hepatoid carcinoma of the ovary with PIVKA-II production:
      immunohistochemical study and literature review.
AB  - A case of hepatoid carcinoma of the ovary in a 61-year-old Japanese woman, who
      showed high serum levels of alpha-fetoprotein and CA125, is reported. Grossly,
      the left ovarian tumor, which measured 12 x 9 cm, was solid and multinodular.
      Histologically, the tumor resembled hepatocellular carcinoma by its architectural
      and cytological features. Liver cell differentiation was indicated functionally
      by the immunohistochemical detection of alpha-fetoprotein and protein induced by
      vitamin K absence or antagonist II (PIVKA-II) and by positive bile production,
      and the hepatocellular differentiation was structurally in accord with keratin 7,
      8 and 18 expression. CA125 expression, commonly present in ovarian surface
      epithelial carcinomas, suggested that this neoplasm originated from ovarian
      common epithelial cells. There are only nine such cases in the literature. A
      review of these cases reveals that hepatoid carcinoma of the ovary occurs
      exclusively in postmenopausal women (mean age, 62.7 years) and that the prognosis
      is poor.

PMID- 10355973
TI  - Pseudovascular squamous cell carcinoma of the uterine cervix: a lesion that may
      simulate an angiosarcoma.
AB  - A case of pseudovascular squamous cell carcinoma in the uterine cervix of a 64
      year-old woman was examined. Histologically, the lesion consisted of atypical,
      large, non-keratinizing squamous cells that exhibited not only acantholytic
      changes but also pseudovascular changes. Immunohistochemically, these tumor cells
      were positive for cytokeratin, epithelial membrane antigen and carcinoembryonic
      antigen, but none of them were positive for Factor VIII-related antigen or CD34.
      To our knowledge, pseudovascular carcinoma of the uterine cervix has not been
      described in the literature. Pathologists should be aware of this unusual form of
      cervical squamous cell carcinoma, particularly in the differential diagnosis of
      angiosarcoma.

PMID- 10355974
TI  - Intravascular fasciitis of the forearm vein: a case report with
      immunohistochemical characterization.
AB  - Intravascular fasciitis is a very unusual variant of nodular fasciitis. A unique
      case of this lesion occurring in the proximal portion of the superficial vein of
      the forearm in an otherwise healthy 26-year-old man is reported. The
      intravascular polypoid lesion grew longitudinally along the vascular lumen, was
      loosely attached to the intimal layer, and was partly anchored beyond the
      internal elastic lamina into the medial smooth muscle layer. However,
      extravascular involvement was absent. The histological features were identical to
      those observed in ordinary cellular nodular fasciitis. Because of its
      myofibroblastic phenotype exhibited by highly proliferative spindle cells,
      certain intimomedial myofibroblasts are thought to be the indigenous source of
      this unique fibroproliferative lesion. Unless the diagnosis of intravascular
      fasciitis is considered and appropriate differential markers examined, it may be
      confused with other intravascular lesions, such as intravascular leiomyoma,
      intravenous pyogenic granuloma, organized thrombus and, even, fibromuscular
      dysplasia if it arises in the arteries. A simple excision is considered curable.
      Even so, two recurrent cases have been documented to date.

PMID- 10355975
TI  - Amyloid deposition in renal angiomyolipoma.
AB  - An irregular tumor shadow, seen on the left kidney in a 48-year-old woman by
      computed tomography, was pathologically diagnosed as 'angiomyolipoma'. HMB-45
      immunoreactivity distinguished angiomyolipoma from renal cell carcinoma of
      sarcomatoid type. The amyloid deposition was limited to the tumor. M-protein and
      Bence-Jones protein were negative. For amyloid protein characterization,
      immunohistochemical studies were performed with antiamyloid A, anti-kappa, anti
      lambda, anti-prealbumin and anti-beta-2 microglobulin, but none reacted with the
      amyloid. This is the first documented case of amyloid deposition in
      angiomyolipoma and may represent a novel precursor protein of amyloid.

PMID- 10355976
TI  - Primary pure intratesticular fibrosarcoma.
AB  - Testicular sarcoma appears to be a rare stromal tumor usually of indolent course
      with potential for distant metastases. A pure primary intratesticular
      fibrosarcoma in a 71-year-old male is presented. By the time the tumor became
      evident metastases had already occurred widely. The course was rapidly fatal. A
      review of the literature yielded only one case reported previously. The present
      case illustrates that pure fibrosarcoma occurs occasionally as a stromal tumor
      and may be associated with a dismal prognosis. The diagnosis of pure fibrosarcoma
      should be made only after extensive sampling of the testicular tumor to rule out
      an associated germ cell component. The differential diagnosis also includes the
      fibroma of gonadal stroma origin and the unclassified sex cord-stromal tumor with
      a predominance of spindle cells.

PMID- 10355981
TI  - Reducing the risk of recurrent coronary heart disease. We know a bit more about
      what doesn't work.

PMID- 10355982
TI  - Angiogenic revascularisation in ischaemic disease. Molecular techniques hold
      promise, though they are still some way off.

PMID- 10355983
TI  - Same information, different decisions: format counts. Format as well as content
      matters in clinical information.

PMID- 10355984
TI  - The coroner service. A relic in need of reform.

PMID- 10355985
TI  - Managing drug misuse in general practice. New department of health guidelines
      provide a benchmark for good practice.

PMID- 10355986
TI  - Minimising the impact of visual impairment. Low vision aids are a simple way of
      alleviating impairment.

PMID- 10355987
TI  - Sale of prescription data breaches confidentiality.

PMID- 10355988
TI  - Cycle helmets should not be compulsory.

PMID- 10355989
TI  - In brief 

PMID- 10355991
TI  - Gonads are the key to a long life 

PMID- 10355990
TI  - Moratorium on GM food would perpetuate world hunger.

PMID- 10355992
TI  - Doctors demand AIDS drugs for women who have been raped.

PMID- 10355994
TI  - EU supports delay in reducing doctors' hours 

PMID- 10355993
TI  - Canada sends patients with cancer to United States.

PMID- 10355995
TI  - Scotland appoints health minister 

PMID- 10355996
TI  - Scare tactics cut smoking rates in Australia to all time low.

PMID- 10355998
TI  - Carvedilol seems no better than metoprolol for heart failure 

PMID- 10355999
TI  - Viagra guidance declared unlawful.

PMID- 10355997
TI  - Most deaths related to abortion occur in the developing world.

PMID- 10356001
TI  - Report finds no evidence of ethnic bias in GMC 

PMID- 10356000
TI  - Liver cancer toll high in Japan.

PMID- 10356002
TI  - GP loses libel action 

PMID- 10356003
TI  - Congenital toxoplasmosis: systematic review of evidence of efficacy of treatment
      in pregnancy.
AB  - OBJECTIVE: To summarise the evidence that treating toxoplasmosis in pregnancy
      reduces the risk of congenital toxoplasma infection and improves infant outcomes.
      DESIGN: Systematic review of studies comparing at least two concurrent groups of
      pregnant women with proved or likely acute toxoplasma infection in which
      treatments were compared with no treatment and outcomes in the children were
      reported. SUBJECTS: Studies were identified from Medline (1966-97), Pascal (1990
      7), Embase (1993-7), and Biological abstracts (1993-5) plus contact with experts
      in the field, including the European Research Network on Congenital
      Toxoplasmosis. MAIN OUTCOME MEASURE: Proportion of infected children at 1 year
      born to infected pregnant women who were or were not treated. RESULTS: Out of
      2591 papers identified, nine met the inclusion criteria. There were no randomised
      comparisons, and control groups were generally not directly comparable with the
      treatment groups. Congenital infection was common in treated groups. five studies
      showed that treatment was effective and four that it was not. CONCLUSION: It is
      unclear whether antenatal treatment in women with presumed toxoplasmosis reduces
      congenital transmission of Toxoplasma gondii. Screening is expensive, so the
      effects of treatment and impact of screening programmes need to be evaluated. In
      countries where screening or treatment is not routine, these technologies should
      not be introduced outside carefully controlled trials.

PMID- 10356005
TI  - Trends in the use of the Mental Health Act: England, 1984-96.

PMID- 10356004
TI  - Explaining differences in English hospital death rates using routinely collected
      data.
AB  - OBJECTIVES: To ascertain hospital inpatient mortality in England and to determine
      which factors best explain variation in standardised hospital death ratios.
      DESIGN: Weighted linear regression analysis of routinely collected data over four
      years, with hospital standardised mortality ratios as the dependent variable.
      SETTING: England. SUBJECTS: Eight million discharges from NHS hospitals when the
      primary diagnosis was one of the diagnoses accounting for 80% of inpatient
      deaths. MAIN OUTCOME MEASURES: Hospital standardised mortality ratios and
      predictors of variations in these ratios. RESULTS: The four year crude death
      rates varied across hospitals from 3.4% to 13.6% (average for England 8.5%), and
      standardised hospital mortality ratios ranged from 53 to 137 (average for England
      100). The percentage of cases that were emergency admissions (60% of total
      hospital admissions) was the best predictor of this variation in mortality, with
      the ratio of hospital doctors to beds and general practitioners to head of
      population the next best predictors. When analyses were restricted to emergency
      admissions (which covered 93% of all patient deaths analysed) number of doctors
      per bed was the best predictor. CONCLUSION: Analysis of hospital episode
      statistics reveals wide variation in standardised hospital mortality ratios in
      England. The percentage of total admissions classified as emergencies is the most
      powerful predictor of variation in mortality. The ratios of doctors to head of
      population served, both in hospital and in general practice, seem to be critical
      determinants of standardised hospital death rates; the higher these ratios, the
      lower the death rates in both cases.

PMID- 10356007
TI  - Medical practitioners and the plague duty in india 

PMID- 10356006
TI  - Aseptic meningitis after treatment with amoxicillin.

PMID- 10356009
TI  - A neglected but prevalent tragedy 

PMID- 10356008
TI  - Effect of postal prompts to patients and general practitioners on the quality of
      primary care after a coronary event (POST): randomised controlled trial.
AB  - OBJECTIVES: To determine whether postal prompts to patients who have survived an
      acute coronary event and to their general practitioners improve secondary
      prevention of coronary heart disease. DESIGN: Randomised controlled trial.
      SETTING: 52 general practices in east London, 44 of which had received
      facilitation of local guidelines for coronary heart disease. PARTICIPANTS: 328
      patients admitted to hospital for myocardial infarction or unstable angina.
      INTERVENTIONS: Postal prompts sent 2 weeks and 3 months after discharge from
      hospital. The prompts contained recommendations for lowering the risk of another
      coronary event, including changes to lifestyle, drug treatment, and making an
      appointment to discuss these issues with the general practitioner or practice
      nurse. MAIN OUTCOME MEASURES: Proportion of patients in whom serum cholesterol
      concentrations were measured; proportion of patients prescribed beta blockers (6
      months after discharge); and proportion of patients prescribed cholesterol
      lowering drugs (1 year after discharge). RESULTS: Prescribing of beta bockers
      (odds ratio 1.7, 95% confidence interval 0.8 to 3.0, P>0.05) and cholesterol
      lowering drugs (1.7, 0. 8 to 3.4, P>0.05) did not differ between intervention and
      control groups. A higher proportion of patients in the intervention group (64%)
      than in the control group (38%) had their serum cholesterol concentrations
      measured (2.9, 1.5 to 5.5, P<0.001). Secondary outcomes were significantly
      improved for consultations for coronary heart disease, the recording of risk
      factors, and advice given. There were no significant differences in patients'
      self reported changes to lifestyle or to the belief that it is possible to modify
      the risk of another coronary event. CONCLUSIONS: Postal prompts to patients who
      had had acute coronary events and to their general practitioners in a locality
      where guidelines for coronary heart disease had been disseminated did not improve
      prescribing of effective drugs for secondary prevention or self reported changes
      to lifestyle. The prompts did increase consultation rates related to coronary
      heart disease and the recording of risk factors in the practices. Effective
      secondary prevention of coronary heart disease requires more than postal prompts
      and the dissemination of guidelines.

PMID- 10356010
TI  - Influence of data display formats on physician investigators' decisions to stop
      clinical trials: prospective trial with repeated measures.
AB  - OBJECTIVE: To examine the effect of the method of data display on physician
      investigators' decisions to stop hypothetical clinical trials for an unplanned
      statistical analysis. DESIGN: Prospective, mixed model design with variables
      between subjects and within subjects (repeated measures). SETTING: Comprehensive
      cancer centre. PARTICIPANTS: 34 physicians, stratified by academic rank, who were
      conducting clinical trials. INTERVENTIONS: PARTICIPANTS were shown tables, pie
      charts, bar graphs, and icon displays containing hypothetical data from a
      clinical trial and were asked to decide whether to continue the trial or stop for
      an unplanned statistical analysis. MAIN OUTCOME MEASURE: Percentage of accurate
      decisions with each type of display. RESULTS: Accuracy of decisions was affected
      by the type of data display and positive or negative framing of the data. More
      correct decisions were made with icon displays than with tables, pie charts, and
      bar graphs (82% v 68%, 56%, and 43%, respectively; P=0.03) and when data were
      negatively framed rather than positively framed in tables (93% v 47%; P=0.004).
      CONCLUSIONS: Clinical investigators' decisions can be affected by factors
      unrelated to the actual data. In the design of clinical trials information
      systems, careful consideration should be given to the method by which data are
      framed and displayed in order to reduce the impact of these extraneous factors.

PMID- 10356012
TI  - Ideas must be comforting 

PMID- 10356011
TI  - General practitioners' perceptions of effective health care.
AB  - OBJECTIVES: To explore general practitioners' perceptions of effective health
      care and its application in their own practice; to examine how these perceptions
      relate to assumptions about clinicians' values and behaviour implicit in the
      evidence based medicine approach. DESIGN: A qualitative study using
      semistructured interviews. SETTING: Eight general practices in North Thames
      region that were part of the Medical Research Council General Practice Research
      Framework. PARTICIPANTS: 24 general practitioners, three from each practice. MAIN
      OUTCOME MEASURES: Respondents' definitions of effective health care, reasons for
      not practising effectively according to their own criteria, sources of
      information used to answer clinical questions about patients, reasons for making
      changes in clinical practice. RESULTS: Three categories of definitions emerged:
      clinical, patient related, and resource related. Patient factors were the main
      reason given for not practising effectively; others were lack of time, doctors'
      lack of knowledge and skills, lack of resources, and "human failings." Main
      sources of information used in situations of clinical uncertainty were general
      practitioner partners and hospital doctors. Contact with hospital doctors and
      observation of hospital practice were just as likely as information from medical
      and scientific literature to bring about changes in clinical practice.
      CONCLUSIONS: The findings suggest that the central assumptions of the evidence
      based medicine paradigm may not be shared by many general practitioners, making
      its application in general practice problematic. The promotion of effective care
      in general practice requires a broader vision and a more pragmatic approach which
      takes account of practitioners' concerns and is compatible with the complex
      nature of their work.

PMID- 10356013
TI  - Therapeutic angiogenesis.

PMID- 10356015
TI  - X marks the spot 

PMID- 10356014
TI  - Evidence based cardiology: Prevention of ischaemic stroke.

PMID- 10356017
TI  - What a rotten job you've got 

PMID- 10356016
TI  - ABC of intensive care. Criteria for admission.

PMID- 10356018
TI  - Numbers needed to treat derived from meta-analyses--sometimes informative,
      usually misleading.

PMID- 10356019
TI  - Economic Notes: opportunity cost.

PMID- 10356020
TI  - The one neither of us saw 

PMID- 10356021
TI  - Use of renal transplants from living donors. Practice is essential to alleviate
      shortage of organs.

PMID- 10356022
TI  - Call to needle times after acute myocardial infarction. Paramedics in Derbyshire
      can admit direct to coronary care unit when they diagnose myocardial infarction.

PMID- 10356023
TI  - Emerging tobacco hazards in China. Is assumption of no association between
      smoking and other causes of death valid?

PMID- 10356024
TI  - I don't want to be invited to invest in the tobacco trade.

PMID- 10356025
TI  - Women must be given fully informed information about cervical screening.

PMID- 10356027
TI  - Few patients with prostate cancer are willing to be randomised to treatment.

PMID- 10356026
TI  - Cancer patients should be offered semen cryopreservation.

PMID- 10356028
TI  - Trial of prophylactic mastectomy is needed.

PMID- 10356029
TI  - Article on Colombia should have been more objective.

PMID- 10356030
TI  - Behaviour described in scenario in paper would be unethical.

PMID- 10356031
TI  - Teaching patients with bipolar disorder to identify early symptoms of relapse.
      When were outcomes separated?

PMID- 10356032
TI  - Recognition of depression and anxiety in primary care. Patients' attributional
      style is important factor.

PMID- 10356033
TI  - Authors' words foster stigmatisation of commercial sex workers in India.

PMID- 10356034
TI  - Careers article on psychotherapy was not balanced.

PMID- 10356035
TI  - Vulvodynia is important cause of vulval pain.

PMID- 10356036
TI  - Medical examiners employed by health authorities should audit death certificates.

PMID- 10356037
TI  - Trauma related shin splints. Shin splints are symptoms, not a diagnosis.

PMID- 10356039
TI  - Saadi hussain Al-roumani 

PMID- 10356038
TI  - All GPs have problems when they first start in practice.

PMID- 10356040
TI  - Artists for Medecins du monde 

PMID- 10356041
TI  - Inherited susceptibility to cancer: clinical, predictive and ethical perspectives

PMID- 10356042
TI  - Our NHS: A celebration of 50 years 

PMID- 10356044
TI  - Website of the week 

PMID- 10356043
TI  - Skin cancer: in your face 

PMID- 10356046
TI  - New england journal 

PMID- 10356045
TI  - Iceland's database is ethically questionable.

PMID- 10356047
TI  - The mysterious and the prosaic 

PMID- 10356048
TI  - Evidence for antenatal toxoplasmosis screening is poor 

PMID- 10356049
TI  - Numbers of hospital doctors and GPs affect inpatient mortality 

PMID- 10356050
TI  - Compulsory admissions have risen as psychiatric beds have fallen 

PMID- 10356051
TI  - Postal prompts do not improve secondary prevention of coronary events 

PMID- 10356052
TI  - Why doctors don't always apply effective health care 

PMID- 10356053
TI  - The way data are presented affects the conclusions drawn 

PMID- 10356054
TI  - Hippocampal sclerosis and temporal lobe epilepsy: cause or consequence?

PMID- 10356055
TI  - Forebrain ischaemia with CA1 cell loss impairs epileptogenesis in the tetanus
      toxin limbic seizure model.
AB  - There is a long-standing controversy as to whether Ammon's horn sclerosis is the
      result or the cause of severe limbic epilepsy. In the tetanus toxin model of
      limbic epilepsy, rats have intermittent spontaneous fits over a period of 3-6
      weeks after injection of tetanus toxin into the hippocampus. The fits then
      usually remit and the EEG returns to normal. In a few rats, however, the fits
      recur some weeks to months later, and it was previously found that in these rats
      there was gross cell loss in area CA1 of the dorsal hippocampus (distant from the
      injection site in ventral hippocampus). Such cell loss might either promote
      recurrence of fits or be the result of the recurrence. In the present experiment,
      the effect of previous induction of CA1 cell loss by transient 4-vessel occlusion
      cerebral ischaemia on the subsequent development of the tetanus toxin-induced
      epilepsy was studied, using continuous time-lapse video monitoring to assess the
      number of fits. The hypothesis that the previous forebrain ischaemia would
      predispose rats to reoccurring fits was not supported: no rats in the ischaemia
      group had reoccurring fits and additionally fits were delayed and fewer occurred
      than in the control groups.

PMID- 10356056
TI  - Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100
      consecutive cases.
AB  - Nocturnal frontal lobe epilepsy (NFLE) has been delineated as a distinct syndrome
      in the heterogeneous group of paroxysmal sleep-related disturbances. The variable
      duration and intensity of the seizures distinguish three non-rapid eye movement
      related subtypes: paroxysmal arousals, characterized by brief and sudden
      recurrent motor paroxysmal behaviour; nocturnal paroxysmal dystonia, motor
      attacks with complex dystonic-dyskinetic features; and episodic nocturnal
      wanderings, stereotyped, agitated somnambulism. We review the clinical and
      polysomnographic data related to 100 consecutive cases of NFLE in order to define
      the clinical and neurophysiological characteristics of the different seizure
      types that constitute NFLE. NFLE seizures predominate in males (7:3). Age at
      onset of the nocturnal seizures varies, but centres during infancy and
      adolescence. A familial recurrence of the epileptic attacks is found in 25% of
      the cases, while 39% of the patients present a family history of nocturnal
      paroxysmal episodes that fit the diagnostic criteria for parasomnias. A minority
      of cases (13%) have personal antecedents (such as birth anoxia, febrile
      convulsions) or brain CT or MRI abnormalities (14%). In many patients, ictal
      (44%) and interictal (51%) EEGs are uninformative. Marked autonomic activation is
      a common finding during the seizures. NFLE does not show a tendency to
      spontaneous remission. Carbamazepine completely abolishes the seizures in
      approximately 20% of the cases and gives remarkable relief (reduction of the
      seizures by at least 50%) in another 48%. VideoEEG recordings confirm that NFLE
      comprises a spectrum of distinct phenomena, different in intensity but
      representing a continuum of the same epileptic condition. We believe that the
      detailed clinical and videoEEG characterization of patients with NFLE represents
      the first step towards a better understanding of the pathogenic mechanisms and
      different clinical outcomes of the various seizure types that constitute the
      syndrome.

PMID- 10356057
TI  - Language related brain potentials in patients with cortical and subcortical left
      hemisphere lesions.
AB  - The role of the basal ganglia in language processing is currently a matter of
      discussion. Therefore, patients with left frontal cortical and subcortical
      lesions involving the basal ganglia as well as normal controls were tested in a
      language comprehension paradigm. Semantically incorrect, syntactically incorrect
      and correct sentences were presented auditorily. Subjects were required to listen
      to the sentences and to judge whether the sentence heard was correct or not.
      Event-related potentials and reaction times were recorded while subjects heard
      the sentences. Three different components correlated with different language
      processes were considered: the so-called N400 assumed to reflect processes of
      semantic integration; the early left anterior negativity hypothesized to reflect
      processes of initial syntactic structure building; and a late positivity (P600)
      taken to reflect second-pass processes including re-analysis and repair. Normal
      participants showed the expected N400 component for semantically incorrect
      sentences and an early anterior negativity followed by a P600 for syntactically
      incorrect sentences. Patients with left frontal cortical lesions displayed an
      attenuated N400 component in the semantic condition. In the syntactic condition
      only a late positivity was observed. Patients with lesions of the basal ganglia,
      in contrast, showed an N400 to semantic violations and an early anterior
      negativity as well as a P600 to syntactic violations, comparable to normal
      controls. Under the assumption that the early anterior negativity reflects
      automatic first-pass parsing processes and the P600 component more controlled
      second-pass parsing processes, the present results suggest that the left frontal
      cortex might support early parsing processes, and that specific regions of the
      basal ganglia, in contrast, may not be crucial for early parsing processes during
      sentence comprehension.

PMID- 10356058
TI  - Callosal and cortical contribution to procedural learning.
AB  - Acallosal and callosotomized subjects usually show impairments on tasks requiring
      bilateral interdependent motor control. However, few studies have assessed the
      ability of these subjects to learn a skill that requires the simultaneous
      contribution of each hemisphere in its acquisition. The present study examined
      whether acallosal and callosotomized subjects could learn a visuomotor skill that
      involved a motor control from either both or a single hemisphere. Eleven adult
      patients, six acallosal and five callosotomized, participated in this study.
      Seven of these patients had epileptic foci located in the frontal and/or temporal
      areas and one of the acallosal patients showed bilateral prefrontal atrophy
      following surgical removal of an orbitofrontal cyst. The performance of the
      experimental subjects was compared with that of 11 matched control subjects, on a
      modified version of a serial reaction time task developed by Nissen and Bullemer
      (Cogn Psychol 1987; 19: 1-32). This skill acquisition task involved bimanual or
      unimanual key-pressing responses to a sequence of 10 visual stimuli that was
      repeated 160 times. A declarative memory task was then performed to assess
      explicit knowledge of the sequence. None of the experimental subjects learned the
      task in the bimanual condition. Patients with frontal epileptic foci or
      orbitofrontal damage also failed to learn the task in the unimanual condition
      when they were using the hand contralateral to the damaged hemisphere. All other
      subjects, including the acallosal and callosotomized patients with temporal foci,
      learned the visuomotor skill as well as their controls in the unimanual
      condition. In spite of the absence of transfer and interhemispheric integration
      of procedural learning, some of the acallosal and callosotomized patients were
      able to learn the sequence explicitly. These findings indicate that the corpus
      callosum and the frontal cortical areas are important for procedural learning of
      a visuomotor skill. They also confirm the dissociation described by Squire
      (Science 1986; 232: 1612-9 and J Cogn Neurosci 1992; 4: 232-43) between the
      declarative and procedural memory systems and extend this dissociation to
      processes involving simultaneous bihemispheric co-operation.

PMID- 10356059
TI  - Classification learning in Alzheimer's disease.
AB  - Previous research has demonstrated that explicit recognition of dot patterns is
      impaired in amnesic patients with damage to the limbic-diencephalic memory
      system, while implicit categorization of the same kind of stimuli is preserved.
      The aim of the present study was to investigate the relationship between
      recognition and categorization performances in patients with Alzheimer's disease.
      Consistent with the findings in amnesic subjects, our results revealed that the
      explicit recognition of dot patterns was significantly impaired in Alzheimer's
      disease. However, implicit categorization functions were also disrupted. This was
      selective for the prototype stimuli; the categorization of non-prototype dot
      patterns was spared. The impaired category learning is likely to reflect the
      damage of modality-specific neocortical areas in Alzheimer's disease.

PMID- 10356060
TI  - Direct comparison of the neural substrates of recognition memory for words and
      faces.
AB  - For the purpose of identifying the relatively specific brain regions related to
      word and face recognition memory on the one hand and the regions common to both
      on the other, regional cerebral blood flow associated with different cognitive
      tasks for recognition memory was examined using [H215O]PET in healthy volunteers.
      The tasks consisted of recognizing two types of stimuli (faces and words) in two
      conditions (novel and familiar), and two baseline tasks (reading words and gender
      classification). The statistical analyses used to identify the specific regions
      consisted of three subtractions: novel words minus novel faces, familiar words
      minus familiar faces, and reading words minus gender classification. These
      analyses revealed relative differences in the brain circuitry used for
      recognizing words and for recognizing faces within a defined level of
      familiarity. In order to find the regions common to both face and word
      recognition, overlapping areas in four subtractions (novel words minus reading
      words, novel faces minus gender classification, familiar words minus reading
      words, and familiar faces minus gender classification) were identified. The
      results showed that the activation sites in word recognition tended to be
      lateralized to the left hemisphere and distributed as numerous small loci, and
      particularly included the posterior portion of the left middle and inferior
      temporal gyri. These regions may be related to lexical retrieval during written
      word recognition. In contrast, the activated regions for face recognition tended
      to be lateralized to the right hemisphere and located in a large aggregated area,
      including the right lingual and fusiform gyri. These findings suggest that
      strikingly different neural pathways are engaged during recognition memory for
      words and for faces, in which a critical role in discrimination is played by
      semantic cueing and perceptual loading, respectively. In addition, the
      investigation of the regions common to word and face recognition indicates that
      the anterior and posterior cingulate have dissociable functions in recognition
      memory that vary with familiarity, and that the cerebellum may serve as the co
      ordinator of all four types of recognition memory processes.

PMID- 10356061
TI  - Mutant channels contribute <50% to Na+ current in paramyotonia congenita muscle.
AB  - An important question in the pathophysiology of dominantly inherited diseases,
      such as channelopathies, is the level of expression of the mutant protein. In our
      study, we address this issue by comparing the gating defects of two human muscle
      Na+ channel mutants (R1448C and R1448P) causing paramyotonia congenita in native
      muscle specimens from two patients with those of the same mutant recombinant
      channels expressed in human embryonic kidney (HEK-293) cells. Patch-clamp
      recordings of transfected HEK-293 cells revealed a pronounced slowing of the Na+
      current decay, a left-shifted and decreased voltage dependence of steady-state
      inactivation, and an increased frequency of channel reopenings for mutant
      compared with wild-type channels. For R1448P channels, inactivation was almost
      six-fold and for R1448C it was three-fold slower than for wild-type channels. The
      same defects, though less pronounced, as expected for a disorder with dominant
      inheritance, were observed for muscle specimens from paramyotonia congenita
      patients carrying these mutations. Quantitative kinetic analysis of Na+ channel
      inactivation in the paramyotonic muscle specimens separating wild-type from
      mutant channels suggested that no more than 38% of the channels in the
      paramyotonia congenita muscle specimen were of the mutant type. Our data raise
      the possibility that variability in the ratio of mutant to wild-type Na+ channels
      in the muscle membrane has an impact on the clinical severity of the phenotype.

PMID- 10356062
TI  - A large-scale distributed network for covert spatial attention: further
      anatomical delineation based on stringent behavioural and cognitive controls.
AB  - Functional MRI was used to examine cerebral activations in 12 subjects while they
      performed a spatial attention task. This study applied more stringent behavioural
      and cognitive controls than previously used for similar experiments: (i) subjects
      were included only if they showed evidence of attentional shifts while performing
      the task in the magnet; (ii) the experimental task and baseline condition were
      designed to eliminate the contributions of motor output, visual fixation,
      inhibition of eye movements, working memory and the conditional (no-go) component
      of responding. Activations were seen in all three hypothesized cortical
      epicentres forming a network for spatial attention: the lateral premotor cortex
      (frontal eye fields), the posterior parietal cortex and the cingulate cortex.
      Subcortical activations were seen in the basal ganglia and the thalamus. Although
      the task required attention to be equally shifted to the left and to the right,
      eight of 10 subjects showed a greater area of activation in the right parietal
      cortex, consistent with the specialization of the right hemisphere for spatial
      attention. Other areas of significant activation included the posterior temporo
      occipital cortex and the anterior insula. The temporo-occipital activation was
      within a region broadly defined as MT+ (where MT is the middle temporal area)
      which contains the human equivalent of area MT in the macaque monkey. This
      temporo-occipital area appears to constitute a major component of the functional
      network activated by this spatial attention task. Its activation may reflect the
      'inferred' shift of the attentional focus across the visual scene.

PMID- 10356063
TI  - A pure case of Gerstmann syndrome with a subangular lesion.
AB  - The four symptoms composing Gerstmann's syndrome were postulated to result from a
      common cognitive denominator (Grundstorung) by Gerstmann himself. He suggested
      that it is a disorder of the body schema restricted to the hand and fingers. The
      existence of a Grundstorung has since been contested. Here we suggest that a
      common psychoneurological factor does exist, but should be related to
      transformations of mental images rather than to the body schema. A patient (H.P.)
      was studied, who presented the four symptoms of Gerstmann's syndrome in the
      absence of any other neuropsychological disorders. MRI showed a focal ischaemic
      lesion, situated subcortically in the inferior part of the left angular gyrus and
      reaching the superior posterior region of T1. The cortical layers were spared and
      the lesion was seen to extend to the callosal fibres. On the basis of an
      extensive cognitive investigation, language, praxis, memory and intelligence
      disorders were excluded. The four remaining symptoms (finger agnosia, agraphia,
      right-left disorientation and dyscalculia) were investigated thoroughly with the
      aim of determining any characteristics that they might share. Detailed analyses
      of the tetrad showed that the impairment was consistently attributable to
      disorders of a spatial nature. Furthermore, cognitive tests necessitating mental
      rotation were equally shown to be impaired, confirming the essentially
      visuospatial origin of the disturbance. In the light of this report, the common
      cognitive denominator is hypothesized to be an impairment in mental manipulation
      of images and not in body schema.

PMID- 10356064
TI  - Sequential bilateral transplantation in Parkinson's disease: effects of the
      second graft.
AB  - Five parkinsonian patients who had received implants of human embryonic
      mesencephalic tissue unilaterally in the striatum 10-56 months earlier were
      grafted with tissue from four to eight donors into the putamen (four patients) or
      the putamen plus the caudate nucleus (one patient) on the other side, and were
      followed for 18-24 months. After 12-18 months, PET showed a mean 85% increase in
      6-L-[18F]fluorodopa uptake in the putamen with the second graft, whereas there
      was no significant further change in the previously transplanted putamen. Two
      patients exhibited marked additional improvements after their second graft: 'on
      off' fluctuations virtually disappeared, movement speed increased, and L-dopa
      could be withdrawn in one patient and reduced by 70% in the other. The
      improvement in one patient was moderate. Two patients with atypical features, who
      responded poorly to the first graft, worsened following the second
      transplantation. These findings indicate that sequential transplantation in
      patients does not compromise the survival and function of either the first or the
      second graft. Moreover, putamen grafts that restore fluorodopa uptake to normal
      levels can give improvements of major therapeutic value.

PMID- 10356065
TI  - From off-period dystonia to peak-dose chorea. The clinical spectrum of varying
      subthalamic nucleus activity.
AB  - The effect of chronic bilateral high-frequency stimulation of the subthalamic
      nucleus (STN) on levodopa-induced dyskinaesias was investigated in eight patients
      with fluctuating Parkinson's disease complicated by functionally disabling off
      period dystonia. All of the patients also had severe diphasic and peak-dose
      chorea, so that it was possible to study the effect of high-frequency stimulation
      on the different types of levodopa-induced dyskinaesias. Off-period fixed
      dystonia was reduced by 90% and off-period pain by 66%. After acute levodopa
      challenge, high-frequency stimulation of the STN reduced diphasic mobile dystonia
      by 50% and peak-dose choreic dyskinaesias by 30%. The effect of bilateral high
      frequency stimulation of the STN on the Unified Parkinson's Disease Rating Scale
      motor score had the same magnitude as the preoperative effect of levodopa. This
      allowed the levodopa dose to be reduced by 47%. The combination of reduced
      medication and continuous high-frequency stimulation of the STN reduced the
      duration of on-period diphasic and peak-dose dyskinaesias by 52% and the
      intensity by 68%. Acute high-frequency stimulation of the STN mimics an acute
      levodopa challenge, concerning both parkinsonism and dyskinaesias, and suppresses
      off-period dystonia. Increasing the voltage can induce repetitive dystonic
      dyskinaesias, mimicking diphasic levodopa-induced dyskinaesias. A further
      increase in voltage leads to a shift from a diphasic-pattern dystonia to a peak
      dose pattern choreodystonia. Chronic high-frequency stimulation of the STN also
      mimics the benefit of levodopa on parkinsonism and improves all kinds of levodopa
      induced dyskinaesias to varying degrees. Off-period dystonia, associated with
      neuronal hyperactivity in the STN is directly affected by stimulation and
      disappears immediately. The effect of chronic high-frequency stimulation of the
      STN on diphasic and peak-dose dyskinaesias is more complex and is related
      directly to the functional inhibition of the STN and indirectly to the
      replacement of the pulsatile dopaminergic stimulation by continuous functional
      inhibition of the STN. Chronic high-frequency stimulation of the STN allows a
      very gradual increase in stimulation parameters with increasing beneficial effect
      on parkinsonism while reducing the threshold for the elicitation of stimulation
      induced dyskinaesias. In parallel with improvement of parkinsonism, the levodopa
      dose can be gradually decreased. As diphasic dystonic dyskinaesias are improved
      to a greater degree than peak-dose dyskinaesias, both direct and indirect
      mechanisms may be involved. Peak-dose choreatic dyskinaesias, associated with
      little evidence of parkinsonism and thus with low neuronal activity in the STN,
      are improved, mostly indirectly. Fixed off-period dystonia, mobile diphasic
      dystonia and peak-dose choreodystonia seem to represent a continuous clinical
      spectrum reflecting a continuous spectrum of underlying activity patterns of STN
      neurons.

PMID- 10356066
TI  - Visual evoked potentials in migraine patients: alterations depend on pattern
      spatial frequency.
AB  - Visual information is conducted by two parallel pathways (luminance- and contour
      processing pathways) which are thought to be differentially affected in migraine
      and can be investigated by means of pattern-reversal visual evoked potentials
      (VEPs). Components and habituation of VEPs at four spatial frequencies were
      compared between 26 migraineurs (13 without aura, MO; 13 with aura, MA) and 28
      healthy volunteers. Migraineurs were recorded in the headache-free interval (at
      least 72 h before and after an attack). Five blocks of 50 responses to
      chequerboards of 0.5, 1, 2 and 4 cycles per degree (c.p.d.) were sequentially
      averaged and analysed for latency and amplitude. Differences in VEPs were
      dependent on spatial frequency. Only when small checks were presented, i.e. at
      high spatial frequency (2 and 4 c.p.d.), was the latency of N2 significantly
      prolonged in MA and did it tend to be delayed in MO subjects. Habituation
      behaviour was not significantly different between groups under the stimulating
      conditions employed. Prolonged N2 latency might be explained by the lack or
      attenuation of a contour-specific component N130 in migraineurs, indicating an
      imbalance of the two visual pathways with relative predominance of the luminance
      processing Y system. These results reflect an interictally persisting dysfunction
      of precortical visual processing which might be relevant in the pathophysiology
      of migraine.

PMID- 10356067
TI  - Impaired grip-lift synergy in children with unilateral brain lesions.
AB  - Children with spastic hemiplegia have impaired dexterity in the affected
      extremity. The purpose of the present study was to investigate whether the force
      co-ordination pattern during precision grip in 13 children between 4 and 10 years
      of age with predominant unilateral brain lesions is related to manual dexterity
      and to the location and size of the brain lesion. The force co-ordination pattern
      was investigated by means of a specially designed object that monitored the
      isometric fingertip forces applied to the contact surfaces during precision grip.
      Hand function was measured by means of neurological examination, functional hand
      grips and dexterity. Brain lesions were identified by series of ultrasound and
      MRI scans. Normally, the fingertip forces are applied to the object in the
      initial phase of the lift in an invariant force co-ordination pattern (i.e. grip
      lift synergy), in which the grip and load forces are initiated simultaneously and
      increase in parallel with unimodal force rate trajectories. A majority of
      children with unilateral brain lesions had not developed the force co-ordination
      pattern typical for their age, but produced an immature or a pathological
      pattern. The developmental level of the grip-lift synergy was determined and
      quantified according to criteria derived from earlier studies on normally
      developed children. There was a clear relationship between the developmental
      level of the grip-lift synergy and impaired dexterity, indicating that proper
      development of the force co-ordination pattern is important for skilled hand
      function. The grip-lift synergy correlated with the total extent of lesions in
      the contralateral cortex and white matter and with lesions in the thalamus/basal
      ganglia, while no correlation was found for isolated cortical lesions. The
      results suggest that the neural circuits involved in the control of the precision
      grip are organized in a parallel and distributed system in the hemispheres, and
      that the basal ganglia are important during the formation of these circuits.
      Perinatal lesions in specific cortical motor areas may be compensated for by
      circuits elsewhere in the grip-lift motor system, while large lesions exclude
      this possibility.

PMID- 10356068
TI  - Spatial deficits in ideomotor limb apraxia. A kinematic analysis of aiming
      movements.
AB  - Ideomotor limb apraxia is a classic neurological disorder manifesting as a
      breakdown in co-ordinated limb control with spatiotemporal deficits. We employed
      kinematic analyses of simple aiming movements in left hemisphere-damaged patients
      with and without limb apraxia and a normal control group to examine
      preprogramming and response implementation deficits in apraxia. Damage to the
      frontal and parietal lobes was more common in apraxics, but neither frontal nor
      parietal damage was associated with different arm movement deficits. Limb apraxia
      was associated with intact preprogramming but impaired response implementation.
      The response implementation deficits were characterized by spatial but not
      temporal deficits, consistent with decoupling of spatial and temporal features of
      movement in limb apraxia. While the apraxics' accuracy was normal when visual
      feedback was available, it was impaired when visual feedback of either target
      location or hand position was unavailable. This finding suggests that ideomotor
      limb apraxia is associated with disruption of the neural representations for the
      extrapersonal (spatial location) and intrapersonal (hand position) features of
      movement. The non-apraxic group's normal kinematic performance demonstrates that
      the deficits demonstrated in the apraxic group are not simply a reflection of
      left hemisphere damage per se.

PMID- 10356069
TI  - Visual perception of motion, luminance and colour in a human hemianope.
AB  - Human patients rendered cortically blind by lesions to V1 can nevertheless
      discriminate between visual stimuli presented to their blind fields. Experimental
      evidence suggests that two response modes are involved. Patients are either
      unaware or aware of the visual stimuli, which they are able to discriminate.
      However, under both conditions patients insist that they do not see. We
      investigate the fundamental difference between percepts derived for the normal
      and affected hemifield in a human hemianope with visual stimuli of which he was
      aware. The psychophysical experiments we employed required the patient, GY, to
      make comparisons between stimuli presented in his affected and normal hemifields.
      The subject discriminated between, and was allowed to match, the stimuli. Our
      study reveals that the stimulus parameters of colour and motion can be
      discriminated and matched between the normal and blind hemifields, whereas
      brightness cannot. We provide evidence for associations between the percepts of
      colour and motion, but a dissociation between the percepts of brightness, derived
      from the normal and hemianopic fields. Our results are consistent with the
      proposal that the perception of different stimulus attributes is expressed in
      activity of functionally segregated visual areas of the brain. We also believe
      our results explain the patient's insistence that he does not see stimuli, but
      can discriminate between them with awareness.

PMID- 10356070
TI  - Hazel Metz Fox (1921-1989).

PMID- 10356071
TI  - Jasmine green tea epicatechins are hypolipidemic in hamsters (Mesocricetus
      auratus) fed a high fat diet.
AB  - These studies were designed to test the hypolipidemic activity of green tea
      epicatechins (GTE) isolated from jasmine green tea. In Experiment 1, three groups
      of hamsters were given a semisynthetic diet containing 200 g lard/kg and 1 g
      cholesterol/kg for 4 wk. The control group received distilled water, and the
      other two groups received either 15 g/L green tea water extract (GTWE) or 5.0 g/L
      GTE solution. Both the GTWE and GTE groups had lower concentrations of serum
      total cholesterol (TC) and triacylglycerols (TG) than the controls (P < 0.05). In
      Experiment 2, four groups of hamsters received tap water as the drinking fluid,
      but they were given the same high fat and cholesterol diet supplemented with 0
      (control), 1.1, 3.4 or 5.7 g GTE/kg diet. The hypolipidemic effect of jasmine GTE
      was dose dependent. In Experiment 3, the time-course of changes in serum TC and
      TG was monitored in hamsters given the high fat diet supplemented with 5.7 g
      GTE/kg in comparison with that of controls. The hypolipidemic effects of dietary
      GTE were evident after feeding for 2 wk. Dietary supplementation of GTE did not
      affect liver fatty acid synthase. However, GTE-supplemented hamsters had higher
      fecal excretions of total fatty acids, neutral sterols and acidic sterols
      compared with the control group. In Experiment 4, hamsters were fed nonpurified
      diet; the control group drank distilled water, and the GTE group drank distilled
      water containing 5.0 g GTE/L. No differences in activities of 3-hydroxy-3-methyl
      glutaryl coenzyme A reductase and intestinal acyl CoA:cholesterol acyltransferase
      were observed. This study suggests that the hypolipidemic activity of GTE is not
      due to inhibition of synthesis of cholesterol or fatty acid but is most likely
      mediated by its influence on absorption of dietary fat and cholesterol.

PMID- 10356072
TI  - Leucine supplementation enhances skeletal muscle recovery in rats following
      exercise.
AB  - This study was designed to determine the ability of leucine to enhance muscle
      recovery after exercise. Male rats (200 g) were divided into five groups:
      sedentary, food-deprived (SF); exercised, food-deprived (EF); exercised, fed a
      carbohydrate meal (EC); exercised, fed a leucine meal (EL); and exercised, fed a
      combination of carbohydrate and leucine (ECL). All meals were administered by
      oral gavage immediately following exercise. EC and ECL meals were isocaloric and
      provided 15% of daily energy intake. EL and ECL meals each provided 270 mg
      leucine. Rats ran on a motor-driven treadmill for 2 h at 36 m/min and were killed
      1 h postexercise. Plasma glucose and insulin were measured, and the gastrocnemius
      and plantaris muscles were excised as a unit to determine glycogen levels and the
      fractional rate of skeletal muscle protein synthesis (Ks). Exercise did not alter
      plasma glucose or insulin. In contrast, prolonged exercise reduced muscle
      glycogen (-51%) and Ks (-18%). Refeeding a combination of carbohydrate and
      leucine increased plasma insulin relative to the EF and SF groups and produced
      complete recovery of muscle Ks and glycogen to values not different from those in
      SF rats. Feeding leucine alone restored Ks to that in the SF group without
      affecting plasma glucose or insulin concentrations. Feeding carbohydrate alone
      enhanced the rate of glycogen repletion compared to the EF group, concomitant
      with increases in plasma glucose and insulin. The degree of glycogen recovery
      correlated with plasma insulin concentrations (r = 0.58, P < 0.05). These data
      suggest that leucine stimulates muscle protein synthesis following exercise,
      independent of increased plasma insulin. This is the first demonstration that
      orally administered leucine stimulates recovery of skeletal muscle protein
      synthesis after exercise.

PMID- 10356073
TI  - Lactase-phlorizin hydrolase and sucrase-isomaltase genes are expressed
      differently along the villus-crypt axis of rat jejunum.
AB  - Lactase-phlorizin hydrolase (LPH) and sucrase-isomaltase (SI) are two
      disaccharidases specifically expressed in small intestinal absorptive cells. We
      previously showed that the transcripts of both genes are elevated within 12 h of
      carbohydrate intake. To examine at which locus of villus-crypt axis this response
      to dietary carbohydrate occurs, 6-wk-old rats were fed a low-carbohydrate diet
      (5% energy) for 7 d, and then force-fed either the low-carbohydrate diet or a
      sucrose (40% energy) diet during the last 6 h. Cryostat sectioning of jejunal
      segments followed by RNA blot hybridizations of the transcripts revealed that,
      unlike SI mRNA which was expressed maximally in the lower villus, maximal LPH
      mRNA level was attained at the upper villus. The distribution of the respective
      immunoreactive protein and the enzymatic activity was shifted more toward the
      villus tips for LPH than for SI. Force-feeding the sucrose diet caused an abrupt
      increase in SI mRNA level in the lower villus within 3 h, while the rise in LPH
      mRNA level occurred in the mid- and upper-villus. The diet-induced increases in
      the LPH mRNA and SI mRNA levels were abolished along the entire villus by the
      administration of actinomycin D. These results suggest that LPH gene is maximally
      expressed in more apical villus cells than SI gene, and that dietary sucrose
      elicits enhancement of the gene expressions in the villus cells which are
      accumulating the respective transcripts.

PMID- 10356074
TI  - Aleurone flour is a rich source of bioavailable folate in humans.
AB  - With the use of novel milling technology, it has become commercially viable to
      isolate the aleurone layer of cells from wheat grain and to prepare a novel flour
      from this fraction that has a natural folate concentration of approximately 500
      microgram/100 g. The aim of this study was to determine the relative
      bioavailability of natural folate from aleurone flour when ingested as a cereal.
      Using a series of randomized, short-term intervention trials with a cross-over
      involving eight men and eight women aged between 29 and 50 y, we compared the
      increment of plasma folate following ingestion of 1) 100 g wheat bran cereal (low
      folate control), 2) 100 g aleurone cereal, and 3) a tablet containing 500
      microgram folic acid taken together with 100 g wheat bran cereal (high folate
      control). Folate absorption was measured by estimating the area under the plasma
      folate concentration versus time curve. The extent of increase in plasma folate
      over the 7-hour period following ingestion of aleurone cereal was more than
      fourfold greater than that observed following the wheat bran cereal (P < 0.0001)
      and not different from that observed following the 500 microgram folic acid
      tablet taken with wheat bran cereal. Differences were significant when data for
      males and females were analyzed separately (P < 0.001). This study has shown that
      cereal made from wheat aleurone flour is a good source of bioavailable, natural
      folate.

PMID- 10356075
TI  - Fish oil-enriched nutritional supplement attenuates progression of the acute
      phase response in weight-losing patients with advanced pancreatic cancer.
AB  - The presence of an acute-phase protein response (APPR) has been suggested to
      shorten survival and contribute to weight loss in patients with pancreatic
      cancer. Fatty acids derived from fish oil have been shown to alter
      proinflammatory cytokine production and acute-phase protein synthesis in vitro.
      The present study was designed to determine the effects of a fish oil-enriched
      nutritional supplement on the concentrations of a range of individual acute-phase
      proteins (APP) in patients with advanced pancreatic cancer. In a sequential
      series, 18 patients with pancreatic cancer received the supplement (providing 2 g
      eicosapentaenoic acid and 1 g docosahexaenoic acid/d) for 3 wk while another 18
      received full supportive care alone. Six healthy subjects served as additional
      controls. Acute-phase proteins were measured before and after the 3-wk
      intervention period in cancer patients. At baseline, albumin, transferrin and pre
      albumin were significantly reduced and fibrinogen, haptoglobin, alpha-1-acid
      glycoprotein, alpha-1-antitrypsin, ceruloplasmin and C-reactive protein (CRP)
      were significantly elevated in the cancer patients compared with healthy
      controls, reflecting their roles as negative and positive acute phase proteins,
      respectively. In the supplemented cancer group, the only significant change in
      APP concentrations over the 4-wk study period was an increase in transferrin. In
      the control cancer group there were further significant reductions in albumin,
      transferrin and pre-albumin, and a significant increase in CRP concentration.
      These results suggest that many positive and negative APP are altered in advanced
      pancreatic cancer. The APPR tends to progress in untreated patients but may be
      stabilized by the administration of a fish oil-enriched nutritional supplement.
      This may have implications for reducing wasting in such patients.

PMID- 10356076
TI  - (n-3) fatty acid supplementation in moderately hypertriglyceridemic adults
      changes postprandial lipid and apolipoprotein B responses to a standardized test
      meal.
AB  - The effects of (n-3) fatty acids on the postprandial state were investigated by
      monitoring the alimentary responses to identical test meals fed to adults [n =
      11; fasting triacylglycerol (TG) 2.55 +/- 0.24 mmol/L; mean +/- SEM] after a self
      selected diet baseline period (BLP) and then after a 6-wk (n-3) fatty acid period
      (FOP) [ approximately 5.2 g (n-3) fatty acids] and a 6-wk control oil period
      (COP) administered in random order. Samples were drawn immediately prior to the
      test meal (time 0) and then hourly from 2 to 6 h postmeal. Postprandial plasma
      triacylglycerol (TG) and TG-rich lipoprotein (TRL) TG apo B48, and B100 absolute
      concentrations were significantly lower after FOP than after COP or BLP, while
      plasma cholesterol was unchanged. Normalizing the results as increments over time
      0 eliminated the diet effect on all but plasma TG. Time remained a significant
      effect for plasma TG, TRL TG, and TRL TC. Finally, only absolute TRL B48 and
      absolute and incremental plasma TG concentrations displayed significant time-diet
      interactions. These results suggest that postprandial TRL apo B reductions are
      likely caused by (n-3) fatty acid suppression of both hepatic and intestinal apoB
      secretion/synthesis. Altered TRL metabolism, i.e. changes in postprandial TG,
      cholesterol, apo B48, and increase in LDL particle size, may represent an
      additional mechanism for the reduced heart disease risk associated with fish [(n
      3) fatty acid] consumption.

PMID- 10356077
TI  - Dietary folate from vegetables and citrus fruit decreases plasma homocysteine
      concentrations in humans in a dietary controlled trial.
AB  - Elevated total plasma homocysteine (tHcy) concentrations are considered a risk
      factor for neural tube defects (NTD) and cardiovascular disease. Supplementation
      with folic acid decreases the risk of women having children with NTD. In both
      sexes, it decreases tHcy levels. We investigated the efficacy of natural dietary
      folate in improving folate and homocysteine status. We performed a 4-wk dietary
      controlled, parallel design intervention trial with 66 healthy subjects (18-45 y)
      divided into 3 treatment groups: the dietary folate group, the folic acid group
      and the placebo group. Each day each group was fed a different diet. The dietary
      folate group received a diet high in vegetables and citrus fruit (total folate
      content approximately 560 microgram) plus a placebo tablet. The folic acid group
      received a diet naturally low in folate (approximately 210 microgram) plus 500
      microgram folic acid and placebo tablet on alternate days, i.e., 250 microgram
      folic acid/d. And the placebo group received the same low-folate diet as the
      folic acid group plus a placebo tablet. After 4 wk of intervention, folate status
      improved, and tHcy concentrations decreased in both the dietary folate and the
      folic acid groups. From the amount of additional folate (350 microgram/d) and
      folic acid (250 microgram/d) consumed, the relative bioavailability of dietary
      folate compared to folic acid was calculated to be 60-98%, depending on the
      endpoint used. In conclusion, increasing the consumption of vegetables and citrus
      fruit, both good sources of folate, will improve folate status and decrease tHcy
      concentrations. This may contribute to the prevention of cardiovascular disease
      and NTD in the general population

PMID- 10356078
TI  - Filipino children exhibit catch-Up growth from age 2 to 12 years.
AB  - Potential for catch-up growth among stunted children is thought to be limited
      after age 2 y, particularly when they remain in poor environments. We explored
      the extent to which there were improvements in height status from age 2 to 12 y
      in a cohort of >2, 000 children from the Cebu (The Philippines) Longitudinal
      Health and Nutrition Survey. At age 2 y, about 63% of sample children were
      stunted as defined by height-for-age (HAZ) <-2 based on the WHO reference. Of
      children stunted at age 2, 30% were no longer stunted at 8.5 y, and 32.5% were no
      longer stunted at 12 y. The mean increase in HAZ among those with such
      improvements was 1.14 units. The likelihood that children stunted at age 2 y
      would no longer be stunted at 8.5 y was estimated using logistic regression. Low
      birth weight, which was associated with more severe stunting in the first 2 y of
      life, significantly reduced likelihood of catch-up growth in later childhood. In
      contrast, children with taller mothers, who were first born, longer at birth,
      less severely stunted in early infancy and those with fewer siblings were more
      likely to increase HAZ from <-2 to >-2 between ages 2 and 8.5 y. Similar factors
      predicted the improvement in linear growth from 8.5 to 12 y. These results
      suggest that there is a large potential for catch-up growth in children into the
      preadolescent years.

PMID- 10356079
TI  - Dietary phospholipids rich in long-chain polyunsaturated fatty acids improve the
      repair of small intestine in previously malnourished piglets.
AB  - Malnourished piglets were studied to establish how a diet containing long-chain
      polyunsaturated fatty acids (LC-PUFA) of the (n-6) and (n-3) series, esterified
      in the form of phospholipids, affects intestinal recovery after severe
      malnutrition. Piglets (7-d-old) were randomly assigned to two groups. One group
      was fed a piglet milk formula and the other was malnourished by protein-energy
      restriction for 30 d. Healthy and malnourished piglets were then divided into two
      subgroups fed for 10 d either an adapted milk formula (C and M) or the same diet
      supplemented with LC-PUFA phospholipids (C-P and M-P). The M-P group had greater
      protein, DNA, cholesterol and phospholipid levels and a lower triglyceride level
      in the jejunal segment than did the M group. The fatty acid composition of the
      jejunal mucosa and microsomes of the M-P piglets did not differ from that of
      healthy piglets (C). However, in jejunal mucosa, microsomes and phospholipids
      from malnourished piglets that did not receive LC-PUFA (group M) had
      significantly lower percentages of (n-6) LC-PUFA than those in healthy piglets
      (C). The (n-3) LC-PUFA percentages of jejunal mucosa were also lower in the M
      group than in the C group. The small intestine of piglets fed the LC-PUFA
      supplemented formula recovered more completely from histologic lesions and
      biochemical alterations caused by the malnutrition process than the small
      intestine of piglets fed the control formula without LC-PUFA.

PMID- 10356080
TI  - Nutritionally-directed compensatory growth enhances mammary development and
      lactation potential in rats.
AB  - A nutritionally-regulated compensatory growth regimen imposed during a growing
      period from prepuberty to gestation can significantly affect mammary development
      and subsequent lactation performance. The objectives of this study were as
      follows: 1) to determine whether a compensatory nutrition regimen enhances
      lactation potential for the first and second lactation cycles and 2) to determine
      the extent to which a compensatory nutrition regimen modulates cell
      proliferation, differentiation, and apoptosis and expression of genes in mammary
      tissues of female rats. Female Sprague-Dawley rats (n = 122, 35 d of age) were
      randomly assigned either to the control group, with free access to diet, or to a
      stair-step compensatory nutrition feeding regimen, with an alternating 2-2-3-3-wk
      schedule. The regimen began with an energy-restricted diet (40% restriction) for
      2 wk, followed by the control diet for 2 wk; this step was then repeated at 3-wk
      intervals. Pups of dams from the compensatory nutrition regimen group gained more
      during mid-lactation than did control group pups. Mammary tissues were obtained
      from early (d 2) and late (d 19) lactating rats. Mammary tissue from the
      compensatory nutrition group exhibited increased cell proliferation and greater
      gamma-glutamyltranspeptidase and ornithine decarboxylase gene expressions than
      did tissue from the control group during early lactation of both cycles. Mammary
      tissue from the compensatory nutrition group also had fewer apoptotic cells than
      tissue from the control group during late lactation of the first lactation cycle.
      These results suggest that the compensatory nutrition regimen imposed during the
      peripubertal developmental phase stimulated mammary growth and enhanced lactation
      performance by affecting the expression of genes that regulate the cell cycle.

PMID- 10356081
TI  - Aromatic amino acids are utilized and protein synthesis is stimulated during
      amino acid infusion in the ovine fetus.
AB  - The purpose of this study was to determine whether the ovine fetus is capable of
      increased disposal of an amino acid load; if so, would it respond by increased
      protein synthesis, amino acid catabolism or both? A further purpose of the study
      was to determine whether the pathways of aromatic amino acid catabolism are
      functional in the fetus. Late gestation ovine fetuses of well-nourished ewes
      received an infusion of Aminosyn PF alone (APF), and Aminosyn PF + glycyl-L
      tyrosine (APF+GT) at rates estimated to double the intake of these amino acids.
      The initial study, using APF, was performed at 126 +/- 1.4 d; the APF+GT study
      was performed at 132 +/- 1.7 d (term = 150 d). Phenylalanine and tyrosine
      kinetics were determined using both stable and radioactive isotopes. Plasma
      concentrations of most amino acids, but not tyrosine, increased during both
      studies; tyrosine concentration increased only during the APF+GT study.
      Phenylalanine rate of appearance and phenylalanine hydroxylation increased during
      both studies. Tyrosine rate of appearance increased only during the APF+GT study;
      tyrosine oxidation did not increase during either study. Fetal protein synthesis
      increased significantly during both studies, producing a significant increase in
      fetal protein accretion. Fetal proteolysis was unchanged in response to either
      amino acid infusion. These results indicate that the fetus responds to an acute
      increase in amino acid supply primarily by increasing protein synthesis and
      accretion, with a smaller but significant increase in amino acid catabolism also.
      Both phenylalanine hydroxylation and tyrosine oxidation are active in the fetus,
      and the fetus is able to increase phenylalanine hydroxylation rapidly in response
      to increased supply.

PMID- 10356082
TI  - Low intensity exercise and varying proportions of dietary glucose and fat modify
      milk and mammary gland compositions and pup growth.
AB  - Exercise during pregnancy or lactation may create a competition for glucose
      between the exercising muscle and either the developing fetus or the lactating
      mammary gland. To test these two hypotheses, pregnant rats were randomly assigned
      to isoenergetic diets with varying levels of glucose (20, 40 or 60% by weight)
      and fat (30, 22 or 14%, respectively, by weight) and were rested (R) or exercised
      (E) on a motorized treadmill at 20 m/min, 60 min/d (low intensity), 7 d/wk
      throughout pregnancy and lactation. Main effects and selected interactions of
      diet and exercise during pregnancy and diet, exercise and litter size during
      lactation were tested using 3 x 2 and 3 x 2 x 2 factorial designs, respectively.
      Neither diet nor exercise affected pregnancy outcomes. In contrast, during
      lactation, milk and mammary gland compositions and pup growth were altered.
      Exercise produced higher milk protein concentrations (40% glucose diet) and lower
      milk lactose concentrations (20% glucose diet). Exercise also lowered mammary
      gland fat content and produced higher milk fat concentrations. The 60% glucose
      diet resulted in the highest milk fat concentrations, but pups of dams fed the
      40% diet were heavier on lactation d 15 than pups of dams fed the 60% diet. Taken
      together, these results support the claim of decreased availability of glucose to
      the mammary gland for lactose synthesis during chronic low intensity exercise.
      Additionally, the best lactation performance was not supported by a high
      carbohydrate (60% glucose), lower fat (14%) intake. A more moderate carbohydrate
      (40% glucose), higher fat (22%) intake promoted greater pup weights at weaning,
      suggesting an overlooked role for macronutrient composition in optimizing
      lactation performance.

PMID- 10356083
TI  - Cis-lycopene is more bioavailable than trans-lycopene in vitro and in vivo in
      lymph-cannulated ferrets.
AB  - Lycopene is the predominant carotenoid in tomatoes and tomato-based foods and is
      also a predominant carotenoid in human serum and tissues. Intake of lycopene-rich
      foods was recently associated with decreased risk for several chronic diseases.
      The observation that serum and tissue lycopene is more than 50% cis-lycopene,
      whereas tomatoes and tomato-based foods contain mainly all-trans-lycopene, has
      led to the hypothesis that cis-isomers of lycopene are more bioavailable. We
      tested this hypothesis both in vitro (study 1) and in vivo (study 2). In study 1,
      bile acid micelles containing crystalline lycopene were prepared. The crystalline
      lycopene used for these analyses was 54.4% cis-lycopene. The optically clear
      micelle preparation contained 75.9% cis-lycopene in repeated analyses. In study
      2, mesenteric lymph duct cannulated ferrets were used to study the in vivo
      absorption of lycopene from LycoredTM (an ethyl acetate extract of tomatoes
      containing 5% lycopene by weight; of which 91% was all-trans lycopene). Before
      being anesthetized, male ferrets (n = 7) were dosed orally with 40 mg lycopene
      per kg body weight in soybean oil. Lymph secretions were collected, on ice, for 2
      h. The residual stomach and small intestinal contents, mucosa lining, lymph
      secretion and serum were analyzed by HPLC. Whereas the dose, stomach and
      intestinal contents contained 6.2-17.5% cis-lycopene, the mesenteric lymph
      secretions contained significantly more, 77.4%, cis-lycopene (P < 0.01). These
      studies demonstrate that in ferrets, cis-isomers of lycopene are more
      bioavailable than trans-lycopene probably because cis-isomers are more soluble in
      bile acid micelles and may be preferentially incorporated into chylomicrons.

PMID- 10356084
TI  - Plasma and hepatic cholesterol and hepatic activities of 3-hydroxy-3-methyl
      glutaryl-CoA reductase and acyl CoA: cholesterol transferase are lower in rats
      fed citrus peel extract or a mixture of citrus bioflavonoids.
AB  - The cholesterol-lowering effects of tangerine peel extract and a mixture of two
      citrus flavonoids were tested. Male rats were fed a 1 g/100 g high-cholesterol
      diet for 42 d with supplements of either tangerine-peel extract or a mixture of
      naringin and hesperidin (0.5 g/100 g) to study the effects of plasma and hepatic
      lipids, hepatic enzyme activities, and the excretion of fecal neutral sterols.
      Both the tangerine-peel extract and mixture of two flavonoids significantly
      lowered the levels (mean +/- SE) of plasma (2.44 +/- 0. 59 and 2.42 +/- 0.31
      mmol/L, vs. 3.80 +/- 0.28 mmol/L, P < 0.05), hepatic cholesterol (0.143 +/- 0.017
      and 0.131 +/- 0.010 mmol/g vs. 0.181 +/- 0.003 mmol/g, P < 0.05), and hepatic
      triglycerides (0.069 +/- 0.007 and 0.075 +/- 0.006 mmol/g vs. 0.095 +/- 0.002
      mmol/g, P < 0.05) compared to those of the control. The 3-hydroxy-3-methyl
      glutaryl-CoA (HMG-CoA) reductase (1565.0 +/- 106. 0 pmol. min-1. mg protein-1 and
      1783.0 +/- 282 pmol. min-1. mg protein-1 vs. 2487.0 +/- 210.0 pmol. min-1. mg
      protein-1, P < 0.05) and acyl CoA: cholesterol O-acyltransferase (ACAT)
      activities (548.0 +/- 65.0 and 615.0 +/- 80.0 pmol. min-1. mg protein-1 vs. 806.0
      +/- 105.0 pmol. min-1. mg protein-1, P < 0.05) were significantly lower in the
      experimental groups than in the control. These supplements also substantially
      reduced the excretion of fecal neutral sterols compared to the control (211.1 +/-
      26.7 and 208.2 +/- 31.6 mg/d vs. 521.9 +/- 53.9 mg/d). The inhibition of HMG-CoA
      reductase and ACAT activities resulting from the supplementation of either
      tangerine-peel extract or a combination of its bioflavonoids could account for
      the decrease in fecal neutral sterol that appears to compensate for the decreased
      cholesterol biosynthesis in the liver.

PMID- 10356085
TI  - Natural copepods are superior to enriched artemia nauplii as feed for halibut
      larvae (Hippoglossus hippoglossus) in terms of survival, pigmentation and retinal
      morphology: relation to dietary essential fatty acids.
AB  - Replicate groups of halibut larvae were fed to d 71 post-first feeding (PFF)
      either the marine copepod, Eurytemora velox, or Artemia nauplii doubly enriched
      with the marine chromist or golden algae, Schizochytrium sp., (Algamac 2000) and
      a commercial oil emulsion (SuperSelco). The fatty acid compositions of eyes,
      brains and livers from larvae fed the two diets were measured, and indices of
      growth, eye migration and skin pigmentation were recorded along with histological
      examinations of eye and liver. The docosahexaenoic acid [22:6(n-3);
      DHA]/eicosapentaenoic acid [20:5(n-3); EPA] ratios in Artemia nauplii enriched
      with the SuperSelco and Algamac 2000 were 0.4 and 1.0, respectively. The E. velox
      copepods were divided into two size ranges (125-250 and 250-400 microm) with the
      smaller size range containing the highest level of (n-3) highly unsaturated fatty
      acids (HUFA). The DHA/EPA ratios for the two size ranges of copepods were 2.0 and
      0.9, respectively. The total lipids of eyes, brains and livers of larvae fed
      copepods had higher levels of DHA and lower levels of EPA than those of larvae
      fed enriched Artemia. The percentage of survival of the halibut larvae was
      significantly higher when copepods rather than enriched Artemia nauplii were fed,
      but larval specific growth rates did not differ. The indices of eye migration
      were high and not significantly different in larvae fed the two diets, but the
      percentage of larvae undergoing successful metamorphosis (complete eye migration
      and dorsal pigmentation) was higher in larvae fed copepods (40%) than in larvae
      fed enriched Artemia (4%). The rod/cone ratios in histological sections of the
      retina were 2.5 +/- 0.7 in larvae fed copepods and 1.3 +/- 0.6 in larvae fed
      enriched Artemia (P < 0.01). Histological examination of the livers and
      intestines of the larvae were consistent with better assimilation of lipid from
      copepods than lipid from Artemia nauplii up to 46 d post-first feeding. Thus,
      marine copepods are superior to enriched Artemia as food for halibut larvae in
      terms of survival, eye development and pigmentation, and this superiority can be
      related to the level of DHA in the feed.

PMID- 10356087
TI  - Comparison of phylloquinone bioavailability from food sources or a supplement in
      human subjects.
AB  - Phylloquinone (K) absorption was assessed in 22- to 30-y-old human subjects
      consuming a standard test meal [402 kcal (1682 kJ), 27% energy from fat]. The
      absorption of phylloquinone, measured over a 9-h period as the area under the
      curve (AUC), was higher (P < 0.01) after the consumption of a 500- microgram
      phylloquinone tablet [27.55 +/- 10.08 nmol/(L. h), n = 8] than after the
      ingestion of 495 microgram phylloquinone as 150 g of raw spinach [4.79 +/- 1.11
      nmol/(L. h), n = 3]. Less phylloquinone (P < 0.05) was absorbed from 50 g of
      spinach (AUC = 2.49 +/- 1.11 nmol/(L. h) than from 150 g of spinach. Absorption
      of phylloquinone from fresh spinach (165 microgram K), fresh broccoli (184
      microgram K) and fresh romaine lettuce (179 microgram K) did not differ. There
      was no difference in phylloquinone absorption from fresh or cooked broccoli or
      from fresh romaine lettuce consumed with a meal containing 30 or 45% energy as
      fat.

PMID- 10356086
TI  - High dietary lipid levels enhance digestive tract maturation and improve
      dicentrarchus labrax larval development.
AB  - This study was designed to determine the nutritional lipid requirement of seabass
      larvae and to understand the effects of dietary fat concentration on their
      digestive tract maturation. Seabass (Dicentrarchus labrax) larvae were fed, from
      d 15 to 38 of life, one of five isonitrogenous compound diets with different
      lipid levels, ranging from 10 to 30 g/100 g. The higher the lipid level, the
      greater the growth and survival of the larvae (P < 0.05). The lipolytic enzymes
      assayed, lipase and phospholipase A2, were stimulated by the increase in their
      respective dietary substrates, triglycerides and phospholipids, in 38-d-old
      larvae (P < 0.05). Nevertheless, a plateau in the activity of these two lipolytic
      enzymes was observed from 20% dietary lipids onwards. The similar mRNA levels of
      phospholipase A2 in the three groups fed the highest lipid levels suggested that
      the maximal synthesis level of lipolytic enzyme was reached at 20% dietary fat.
      Pancreatic secretion of trypsin and amylase were positively affected by the
      dietary lipid level; a possible involvement of a cholecystokinin-releasing factor
      is discussed. Diets containing >20% lipids led to the increase in activities of
      brush border membrane enzymes to the detriment of a cytosolic enzyme in
      enterocytes, leucine-alanine (Leu-Ala) peptidase. This enzymatic change reveals
      the earlier maturation of enterocytes in larva groups fed high lipid levels.

PMID- 10356088
TI  - High dietary folate supplementation affects gestational development and dietary
      protein utilization in rats.
AB  - There is new evidence that good folate status may play a critical role in the
      prevention of neural tube defects and in the maintenance of adequate homocysteine
      levels, an amino acid recently identified as a risk factor for cardiovascular
      disease. This has led to different folate recommendations, all of them much
      higher than the present dietary recommendations. Folic acid is a water-soluble
      vitamin with a low potential toxicity. However, the possible consequences of long
      term, high folate intakes are unknown. Therefore, the present study was
      undertaken to determine the effects of long-term, high dietary folate
      supplementation on gestational and nutritional markers in pregnant and virgin
      rats. Four groups of Wistar rats were classified on the basis of physiological
      status (virgin or pregnant) and the experimental diets administered (folic acid
      supplemented, 40 mg/kg diet; or control diet, 2 mg folic acid/kg diet). Rats were
      fed their respective diets for 3 wk. Two critical periods were used for metabolic
      balance studies (experimental d 1-5 and 17-21), which involved the determination
      of fat and protein digestibilities as well as metabolic protein utilization (MPU)
      and net protein utilization (NPU). Gestational development (number of live
      fetuses) was adequate in both diet groups regardless of folate supplementation.
      However, body weight and vertex-coccyx length in fetuses from supplemented dams
      were less than (P < 0.0001) in fetuses of control dams. Fat and nitrogen
      digestibilities were not affected by supplementation, but MPU and NPU
      coefficients were significantly lower (P < 0.05) in the folic acid-supplemented
      groups, irrespective of physiological status, compared to control rats. These new
      findings of macro-micronutrient interactions caused by high folate
      supplementation are discussed on the basis that the vitamin may act as a
      xenobiotic more than as a nutrient.

PMID- 10356089
TI  - Chronic fluoride ingestion decreases 45Ca uptake by rat kidney membranes.
AB  - High exposures to fluoride (F-) may occur in environments rich in F- from natural
      or industrial sources and from misuse of F--containing dental care products,
      particularly by children. Both acute and chronic exposures to elevated levels of
      F- have negative effects on several calcium-dependent processes, including kidney
      glomerular and tubular function. We examined the effect of chronic F- ingestion
      on ATP-dependent 45Ca uptake by rat kidney membrane vesicles to characterize the
      mechanism by which high F- alters Ca++ transport in the kidney. Twenty weanling
      female Sprague-Dawley rats were raised on low-F- (0.9 mg/L), semi-purified diet
      with a Ca++ concentration of 400 mg/100g diet. Rats were divided into four groups
      and were fed ad libitum deionized water containing F- at 0, 10, 50, or 150 mg/L
      added as NaF for 6 wk. This consumption produced plasma F- levels of <0.4, 2, 7,
      or 35 micromol/L, respectively. ATP-dependent 45Ca uptake was significantly lower
      in the 150 mg F-/L exposure group than in the 0 mg F-/L controls (P < 0.05).
      Studies with thapsigargin, a specific inhibitor of the endoplasmic reticulum Ca++
      pump, showed that the lower uptake was associated with significantly lower
      activities of both the plasma membrane Ca++-pump (P < 0.05, 150 mg F-/L group
      versus control) and endoplasmic reticulum Ca++-pump (P < 0.05 for both the 50 and
      150 mg F-/L groups versus control). Slot blot analysis of kidney homogenates with
      specific Ca++-pump antibodies showed less (P < 0.05) endoplasmic reticulum Ca++
      pump protein and plasma membrane Ca++-pump protein in all treatment groups than
      controls. Both Ca++-pumps are transport molecules of great importance in the
      regulation of Ca++ homeostasis. Our study suggests that chronic, high F-
      ingestion producing high plasma F- levels may occur in humans and may affect Ca++
      homeostasis by increasing the turnover or breakdown or decreasing the expression
      of plasma membrane and endoplasmic reticulum Ca++-pump proteins.

PMID- 10356090
TI  - Fecal steroid excretion is increased in rats by oral administration of gymnemic
      acids contained in Gymnema sylvestre leaves.
AB  - Gymnemic acids are the saponins with a triterpenoid structure contained in
      Gymnema sylvestre leaves and have the hypoglycemic effects. In spite of the
      cholesterol-binding properties of saponins, the effect of gymnemic acids on
      cholesterol metabolism has not been elucidated to date. We investigated the
      effects of gymnemic acids on fecal steroid excretion in rats. Three kinds of
      extracts from Gymnema sylvestre leaves, extract (GSE), acid precipitate (GSA) and
      column fractionate (GSF), of which the gymnemagenin (an aglycone of gymnemic
      acids) concentrations are 58.87, 161.6, and 363.3 mg/g respectively, were used
      for the experiments. These were administered to rats orally at the dose of 0.05
      1.0 g/kg for 22 d. Rats were given free access to water and nonpurified diet
      without cholesterol, and the differences in fecal excretion of steroids and
      gymnemic acids were investigated. Although there were no significant effects of
      GSE, GSA and GSF decreased body weight gain and food intakes in a dose-dependent
      manner (P < 0.01). GSF (1.0 g/kg) significantly increased fecal excretion of
      neutral steroids and bile acids in a dose-dependent manner (P < 0.05), especially
      those of cholesterol and cholic acid (CA)-derived bile acids. The increases in
      fecal steroid excretion of cholesterol, total neutral steroids, total bile acids
      and CA-related bile acids were acute and significantly correlated with fecal
      gymnemagenin levels (r2 = 0.2316-0.9861, P < 0. 05). These results demonstrated
      for the first time that a high dose of gymnemic acids increases fecal cholesterol
      and CA-derived bile acid excretion. Further studies are needed to clarify the
      effect of gymnemic acids on cholesterol metabolism.

PMID- 10356091
TI  - Iron deficiency in young rats alters the distribution of vitamin A between plasma
      and liver and between hepatic retinol and retinyl esters.
AB  - We assessed whether iron deficiency alters the concentration of vitamin A (VA) in
      plasma or liver and the chemical distribution between hepatic unesterified and
      esterified retinol. Weanling male Sprague-Dawley rats (n = 10/group) were
      allocated to one of four diet groups: low iron (ID3, 3 mg of elemental iron/kg
      diet), marginal iron (ID15, 15 mg/kg), control diet food-restricted to the ID3
      group (FR, 35 mg/kg), and control diet ad libitum consumption (AD, 35 mg/kg).
      Both ID3 and FR rats grew less than AD and ID15 rats. At the end of 5.5 wk,
      plasma retinol concentrations of the ID3 and FR rats were reduced >40% compared
      to ID15 and AD rats [Kruskal-Wallis test (K-W), P < 0.0042)]. Paradoxically, the
      hepatic VA concentration was greater in FR rats, with accumulation of more
      retinyl esters and retinol compared to the other dietary groups. Concentrations
      of hepatic retinyl esters and retinol did not differ among the other groups, but
      the molar ratio of hepatic retinyl esters to retinol was greater in ID3 rats
      (20.1 +/- 1.4) compared to ID15 rats (13.8 +/- 1.6, P = 0.02), AD (11.3 +/- 2.1,
      P < 0.0042) and FR (9.5 +/- 1.1, P < 0.0042). Iron deficiency may cause changes
      in liver and plasma VA that are refractory to VA intake, and thus a benefit may
      be derived from combining iron and VA supplements during nutrition interventions.

PMID- 10356092
TI  - Decreasing ascorbate intake does not affect the levels of glutathione, tocopherol
      or retinol in the ascorbate-requiring osteogenic disorder shionogi rats.
AB  - Levels of glutathione in liver and kidney, and other nutrients in plasma were
      evaluated in male and female ascorbate-requiring osteogenic disorder Shionogi
      (ODS) rats fed semipurified diets in which the concentrations of ascorbate were
      gradually decreased from 1965 to 180 mg/kg. Plasma ascorbate levels in ODS rats
      were unaffected when ascorbate levels in the diet were decreased from 1965 to 768
      mg/kg. However, plasma ascorbate levels decreased progressively when levels of
      ascorbate in the diet were decreased from 527 to 180 mg/kg. Plasma ascorbate
      levels decreased up to 77% when the dietary ascorbate concentration decreased
      from 1965 to 180 mg/kg. Ascorbate levels in liver and kidney fell as much as 60
      70% when the dietary ascorbate levels were reduced from 1965 to 180 mg/kg.
      However, the glutathione levels in these tissues were not affected. Plasma
      retinol and vitamin E levels were not affected by decreasing dietary ascorbate
      intake. Total cholesterol levels increased significantly in female rats as
      dietary ascorbate intake declined. Levels of glycated hemoglobin decreased
      significantly when dietary ascorbate levels decreased from 1965 to 527 mg/kg.
      This study suggests that levels of vitamin E, retinol and glutathione are not
      affected by decreased dietary intake of ascorbate under nonscorbutic conditions,
      whereas elevated ascorbate intake is associated with a decrease in levels of
      plasma cholesterol in female ODS rats. However, excessive intake of ascorbate may
      be associated with elevated glycation of hemoglobin. To achieve the maximal
      health benefit of ascorbate supplementation, further studies are necessary to
      define optimal ascorbate intakes.

PMID- 10356093
TI  - Clinical stroke trials: guarding against bias.

PMID- 10356094
TI  - Progression of mass effect after intracerebral hemorrhage.
AB  - BACKGROUND AND PURPOSE: While the evolution of mass effect after cerebral
      infarction is well characterized, similar data regarding intracerebral hemorrhage
      (ICH) are scant. Our goal was to determine the time course and cause for
      progression of mass effect after ICH. METHODS: Patients with spontaneous
      supratentorial ICH who underwent >/=2 CT scans were identified in our
      prospectively collected database. CT lesion size and midline shift of the pineal
      and septum pellucidum were retrospectively measured and correlated with clinical
      and CT characteristics. Causes for increased midline shift were determined by 2
      independent observers. RESULTS: Seventy-six patients underwent 235 scans (3.1+/
      1.3 per patient). Initial CT was obtained within 24 hours of ICH in 66. Twenty
      five scans were repeated on day 1, 80 on days 2 through 7, 31 on days 8 through
      14, and 24 >14 days after ICH. Midline shift was present on 88% of the initial
      scans. There were 17 instances of midline shift progression: 10 occurred early
      (0.2 to 1.7 days) and were associated with hematoma enlargement, and 7 occurred
      late (9 to 21 days) and were associated with edema progression. Progression of
      mass effect due to edema occurred with larger hemorrhages (P<0.05). Of 65 scans
      repeated for clinical deterioration, only 10 were associated with increased mass
      effect. CONCLUSIONS: Progression of mass effect after ICH occurred at 2 distinct
      time points: within 2 days, associated with hematoma enlargement, and in the
      second and third weeks, associated with increase in edema. The clinical
      significance of later-developing edema is unclear.

PMID- 10356095
TI  - Diffusion MRI in patients with transient ischemic attacks.
AB  - BACKGROUND AND PURPOSE: Diffusion MRI has established value in patients with
      ischemic stroke but has not been systematically investigated in patients with
      transient ischemic attack (TIA). METHODS: Clinical, conventional MRI, and
      diffusion MRI data were collected on 42 consecutive patients with symptoms of
      cerebral TIA. TIA imaging data were compared with those from a contemporaneous
      group of 23 completed stroke patients. RESULTS: Twenty of the 42 TIA patients
      (48%) demonstrated neuroanatomically relevant focal abnormalities on diffusion
      weighted imaging (DWI) and apparent diffusion coefficient (ADC) imaging. When
      present, DWI/ADC signal changes in TIA patients were less pronounced and smaller
      in volume than those in completed stroke patients. TIA symptom duration was
      significantly longer for DWI-positive than for DWI-negative patients, 7.3 versus
      3.2 hours. Diffusion MRI information changed the suspected anatomic and vascular
      TIA localization and the suspected etiologic mechanism in over one third of
      patients with diffusion MRI abnormalities. Of the 20 TIA patients with
      identifiable lesions on diffusion MRI, 9 had follow-up imaging studies; of these,
      4 did not show a relevant infarct on follow-up imaging. CONCLUSIONS: Diffusion
      MRI demonstrates ischemic abnormalities in nearly half of clinically defined TIA
      patients. The percentage of patients with a DWI lesion increases with increasing
      total symptom duration. In nearly half, the diffusion MRI changes may be fully
      reversible, while in the remainder the diffusion MRI findings herald the
      development of a parenchymal infarct despite transient clinical symptoms.
      Finally, diffusion imaging results have significant clinical utility, frequently
      changing the presumed localization and etiologic mechanism.

PMID- 10356096
TI  - Risk of subarachnoid hemorrhage after surgical treatment of unruptured cerebral
      aneurysms.
AB  - BACKGROUND AND PURPOSE: Recent progress in noninvasive imaging techniques has
      resulted in increased detection of unruptured aneurysms. Although many
      neurosurgeons advocate surgical intervention for such unruptured aneurysms, the
      long-term results of surgery for unruptured aneurysms have not been carefully
      investigated. METHODS: We analyzed 173 consecutive patients who had unruptured
      intracranial saccular aneurysm(s) detected by angiography that was performed for
      reasons other than subarachnoid hemorrhage (SAH). Of those, 115 cases were
      surgically treated and studied. All patients were followed up for either SAH,
      repeat treatment of aneurysms, or death. The median follow-up period was 8.8
      years. RESULTS: Four of the 115 patients suffered SAH either from a de novo
      aneurysm (2) or from regrowth of clipped aneurysm (1), or from regrowth after
      wrapping (1). Additionally, 1 patient also suffered SAH from an unstudied basilar
      aneurysm. One patient was incidentally found to have de novo aneurysm and
      underwent reoperation 14 years after the first operation. The cumulative risk for
      SAH for the 114 cases excluding the basilar aneurysm case was 1.4% in 10 years
      and 12.4% in 20 years. CONCLUSIONS: Although this study confirmed the long-term
      efficacy of clipping unruptured aneurysms, the risk of SAH was high compared with
      that in the general population, even after treatment. Considering the high
      mortality rate of SAH, long-term follow-up by angiography may be warranted for
      patients with surgically treated unruptured aneurysms.

PMID- 10356097
TI  - Prospective randomized trial of bilateral carotid endarterectomies: primary
      closure versus patching.
AB  - BACKGROUND AND PURPOSE: Although several studies have compared the results of
      carotid endarterectomy (CEA) with primary closure (PC) versus patch closure, none
      have compared the outcome of bilateral CEAs with patch versus PC performed on the
      same patient. This prospective randomized study compares the clinical outcome and
      incidence of recurrent stenosis (>/=80%) for CEA with PC versus patch closure in
      patients with bilateral CEAs. METHODS: This study includes 74 patients with
      bilateral CEAs with PC on one side and patching on the other. Patients were
      randomized to sequential operative treatment of either patching/PC or
      PC/patching. Postoperative duplex ultrasounds and clinical follow-up were done at
      1, 6, and 12 months and every year thereafter. A Kaplan-Meier analysis was used
      to estimate the risk of significant restenosis (>/=80%). RESULTS: Demographic
      characteristics and the mean operative diameter of the internal carotid artery
      were similar for both PC and patching. The mean follow-up was 29 months (range, 6
      to 65 months). The incidence of ipsilateral stroke was 4% for PC versus 0% for
      patching. PC had a significantly higher incidence of neurological complications
      (transient ischemic attacks and stroke combined) than patching (12% versus 1%;
      P=0.02). Operative mortality was 0%. PC had a higher incidence of recurrent
      stenosis (22% versus 1%; P<0.003) and total internal carotid artery occlusion (8%
      versus 0%; P=0.04) than patching. Restenoses necessitating a repeated CEA were
      also higher for PC (14%) than for patching (1%; P=0.01). The Kaplan-Meier
      analysis showed that patching had a significantly better cumulative patency rate
      than PC (P<0.01). This analysis also showed that freedom from recurrent stenosis
      at 24 months was 75% for PC and 98% for patching. CONCLUSIONS: Patch closure is
      less likely than PC to cause ipsilateral stroke, transient ischemic attacks, and
      recurrent carotid stenosis. The higher rate of unilateral recurrent stenosis may
      suggest that local factors play a more significant role than systemic factors in
      the etiology of recurrent carotid stenosis.

PMID- 10356098
TI  - Early neurobehavioral outcome after stroke is related to release of
      neurobiochemical markers of brain damage.
AB  - BACKGROUND AND PURPOSE: The study aimed to investigate the predictive value of
      neurobiochemical markers of brain damage (protein S-100B and neuron-specific
      enolase [NSE]) with respect to early neurobehavioral outcome after stroke.
      METHODS: We investigated 58 patients with completed stroke who were admitted to
      the stroke unit of the Department of Neurology at Magdeburg University. Serial
      venous blood samples were taken after admission and during the first 4 days, and
      protein S-100B and NSE were analyzed by the use of immunoluminometric assays. In
      all patients, lesion topography and vascular supply were analyzed and volume of
      infarcted brain areas was calculated. The neurological status was evaluated by a
      standardized neurological examination and the National Institutes of Health
      Stroke Scale (NIHSS) on admission, at days 1 and 4 on the stroke unit, at day 10,
      and at discharge from the hospital. Comprehensive neuropsychological examinations
      were performed in all patients with first-ever stroke event and supratentorial
      brain infarctions. Functional outcome was measured with the Barthel score at
      discharge from the hospital. RESULTS: NSE and protein S-100B concentrations were
      significantly correlated with both volume of infarcted brain areas and NIHSS
      scores. Patients with an adverse neurological outcome had a significantly higher
      and significantly longer release of both markers. Neuropsychological impairment
      was associated with higher protein S-100B release, but this did not reach
      statistical significance. CONCLUSIONS: Serum concentrations and kinetics of
      protein S-100B and NSE have a high predictive value for early neurobehavioral
      outcome after acute stroke. Protein S-100B concentrations at days 2 to 4 after
      acute stroke may provide valuable information for both neurological status and
      functional impairment at discharge from the acute care hospital.

PMID- 10356099
TI  - Reasons for variability in the reported rate of occurrence of unilateral spatial
      neglect after stroke.
AB  - BACKGROUND AND PURPOSE: We sought to determine the frequency of occurrence of
      contralesional unilateral spatial neglect (USN) after stroke and to investigate
      the effect of side of lesion, nature of assessment tool used, and timing of
      assessment relative to stroke onset. METHODS: We performed a systematic review of
      published reports, identified by a search of electronic databases (MEDLINE 1966
      1997, PSYCHLIT 1974-1996, and CINAHL 1982-1997) and by searching reference lists
      of the reports selected. Excluded were unpublished, non-English language, and
      nonhuman studies. RESULTS: Thirty published reports met the selection criteria,
      17 of which directly compared right brain damage (RBD) and left brain damage
      (LBD). Contralesional USN appeared to occur more frequently after RBD than LBD in
      16 of these. Both the assessment tool used and the time of assessment relative to
      stroke onset affected the reported rate of occurrence, although recovery rate
      data were inadequate (4 reports). CONCLUSIONS: The clinical belief that USN
      occurs more frequently after RBD than LBD was apparently supported by a
      systematic review of published data. However, an accurate estimate of the rates
      of occurrence and recovery after stroke could not be derived. Four reasons for
      the variability among studies were discussed, including subject selection, lesion
      localization, and nature and timing of assessment. Different USN disorders may
      exist, which may require type-specific rehabilitation approaches. This may have
      implications for epidemiological studies and for the development of new
      treatments. Theoretically driven epidemiological studies are required before
      adequately powered randomized controlled trials of rehabilitation can be
      conducted.

PMID- 10356100
TI  - Assessing the laryngeal cough reflex and the risk of developing pneumonia after
      stroke: an interhospital comparison.
AB  - BACKGROUND AND PURPOSE: We sought to evaluate the efficacy of testing the
      laryngeal cough reflex in identifying pneumonia risk in acute stroke patients.
      METHODS: We performed a prospective study of 400 consecutive acute stroke
      patients examined using the reflex cough test (RCT) compared with 204 consecutive
      acute stroke patients from a sister facility examined without using the RCT. The
      binary end point for the study outcome was the development of pneumonia. RESULTS:
      Of the 400 patients examined with the RCT, 5 developed pneumonia. Of the 204
      patients examined without the RCT, 27 developed pneumonia (P<0.001). Three of the
      27 patients died in the rehabilitation hospital of respiratory failure secondary
      to pneumonia. Seven others were transferred to the emergency department with
      acute respiratory distress. Power analysis for this comparison was 0.99. There
      were no other significant differences between the 2 groups. CONCLUSIONS: A normal
      RCT after an acute stroke indicates a neurologically intact laryngeal cough
      reflex, a protected airway, and a low risk for developing aspiration pneumonia
      with oral feeding. An abnormal RCT indicates risk of an unprotected airway and an
      increased incidence of aspiration pneumonia. Alternate feeding strategies and
      preventive measures are necessary with an abnormal RCT. Clinical treatment
      algorithm and prescription of food, fluids, and medications are discussed on the
      basis of RCT results.

PMID- 10356101
TI  - Progression in acute stroke: value of the initial NIH stroke scale score on
      patient stratification in future trials.
AB  - BACKGROUND AND PURPOSE: The objective was to determine the occurrence of
      neurological changes during the first 48 hours after acute stroke as it relates
      to initial stroke severity. METHODS: The National Institutes of Health Stroke
      Scale (NIHSS) was performed serially for the first 48 hours on 127 consecutive
      ischemic stroke patients (129 strokes) admitted to the neuroscience intensive
      care unit. Incidence of stroke progression (a >/=3-point increase on the NIHSS)
      was recorded and analysis performed to determine its association with initial
      stroke severity and other demographic and physiological variables. Deficit
      resolution by 48 hours, defined as an NIHSS score of 0 or 1, measured the
      frequency of functional recovery predicted by the initial deficit. RESULTS:
      Overall progression was noted in 31% of events (40/129). Applying Bayes' solution
      to the observed frequency of worsening, the greatest likelihood of predicting
      future patient progression occurs with stratification at NIHSS scores of </=7 and
      >7. Patients with an initial NIHSS of </=7 experienced a 14.8% (13/88) worsening
      rate versus a those with a score of >7 with a 65.9% (27/41) worsening rate
      (P<0.000005). Forty-five percent (40/88) of those with an initial score of </=7
      were functionally normal at 48 hours, whereas only 2.4% (1/41) of those with
      scores of >7 returned to a normal examination within this period (chi2,
      P<0.000005). CONCLUSIONS: This study suggests that the early clinical course of
      the neurological deficit after acute stroke is dependent on the initial stroke
      severity and that a dichotomy in early outcome exists surrounding an initial
      NIHSS score of 7. These findings may have significant implications for the design
      and patient stratification in treatment protocols with respect to primary
      clinical outcome.

PMID- 10356102
TI  - Replicability of SF-36 summary scores by the SF-12 in stroke patients.
AB  - BACKGROUND AND PURPOSE: The replicability of the physical and mental component
      summary scores of the Short Form (SF)-36 has been established using the SF-12 in
      selected patient populations but has yet to be assessed in stroke patients. If
      the summary scores of the SF-12 are highly correlated with those of the SF-36,
      the benefits of using a shorter health-status measure may be realized without
      substantial loss of information or precision. Both self-reported and proxy
      assessments were evaluated for replicability. METHODS: Intraclass correlation
      coefficients (ICCs) and linear regression were used to assess the ability of the
      SF-12 physical component summary (PCS-12) scores to predict PCS-36 scores and the
      SF-12 mental component summary (MCS-12) scores to predict MCS-36 scores.
      Multivariate regression was used to explore the relationship between SF-12 and SF
      36 scores. RESULTS: The MCS-12 and PCS-12 scores were strongly correlated with
      the corresponding SF-36 summary scores for surveys completed by proxy or self
      report (ICCs ranged from 0.954 to 0.973). Regression analysis of the proxy
      assessments indicated that patient age was an important effect modifier in the
      relationship between MCS-12 and MCS-36 scores. CONCLUSIONS: The SF-12 reproduced
      SF-36 summary scores without substantial loss of information in stroke patients.
      Accordingly, the SF-12 can be used at the summary score level as a substitute for
      the SF-36 in stroke survivors capable of self-report. However, the mental health
      summary scores of proxy assessments are influenced by patient age, thereby
      limiting the replicability of the SF-36 by the SF-12 under these conditions.

PMID- 10356103
TI  - Risk assessment and anticoagulation for primary stroke prevention in atrial
      fibrillation.
AB  - BACKGROUND AND PURPOSE: Risk assessment before anticoagulation is important for
      effective stroke prevention in atrial fibrillation (AF). METHODS: A study was
      undertaken in patients with AF to investigate the contribution of clinical and
      echocardiography (ECHO) criteria to treatment decisions on anticoagulation.
      Patients were stratified by age and stroke risk; contraindications to
      anticoagulation and warfarin use were assessed. The value of ECHO in treatment
      decisions, effect of age, and existing anticoagulation practice were evaluated.
      RESULTS: The mean+/-SD age of 234 patients was 67.1+/-11.8 years, and 122 (52%)
      were women. Clinical risk factors were present in 74 of 80 patients (92%) aged
      >75 years compared with 99 of 154 patients (64%) </=75 years (P<0.01). ECHO risk
      was identified in 94 of 154 patients (61%) </=75 years, 16 (17%) of whom had no
      clinical risk factors. ECHO risk was present in 71 patients (88%) >75 years of
      age, and was associated with clinical risk factors in all patients. Eligibility
      for anticoagulation was seen in 72 of 154 (47%) to 105 of 154 (68%) patients aged
      </=75 years, depending on the criteria used, and in 66 of 80 patients (83%) >75
      years, regardless of criteria used (P<0.01). Warfarin was being used in 55 of 105
      patients (51%) </=75 years and 8 of 66 patients (12%) >75 years (P<0.001).
      Anticoagulation was being undertaken in 7 of 49 patients (14%) </=75 years
      despite no clinical or ECHO risks. CONCLUSIONS: Accurate assessments of
      eligibility and appropriateness of anticoagulation in AF can be made on clinical
      criteria alone, especially in older people. The value of ECHO in treatment
      decisions is limited to patients </=75 years of age with no clinical risk
      factors.

PMID- 10356105
TI  - The natural history of CADASIL: a pooled analysis of previously published cases.
AB  - BACKGROUND AND PURPOSE: Although numerous families with cerebral autosomal
      dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
      have been reported, our understanding of the disease remains incomplete. Thus, we
      performed this study to investigate the phenotypic range and natural history of
      CADASIL. METHODS: We performed a pooled analysis of previously published cases.
      RESULTS: We identified 105 symptomatic patients in 33 families. Vascular risk
      factors were uncommon, with hypertension reported in only 8 patients. The mean
      age of symptom onset was 36. 7+/-12.9 years. Stroke or transient ischemic attack
      was an initial symptom in 45 patients, with a mean age of onset of 41.2+/-9.2
      years. Migraine was also a common initial symptom, reported by 42 patients at a
      younger mean age of 28.3+/-11.7 years. Other initial symptoms included depression
      in 9 patients, cognitive impairment in 6 patients, and seizures in 3 patients.
      Regarding clinical course, 71 patients experienced a stroke or transient ischemic
      attack, and 52 of those patients had 1 or more recurrent ischemic events.
      Dementia was reported in 44 patients. Only 3 additional patients experienced
      migraine at a later time, while 13 additional patients developed depression. Six
      patients had seizures. Twenty-two of the 105 patients had died, with a mean age
      of death of 54.8+/-10.6 years. Nineteen of those 22 patients had experienced a
      stroke or transient ischemic attack and 19 patients were demented. CONCLUSIONS:
      CADASIL typically becomes evident in early or middle adulthood with migraine or
      an ischemic event, later manifests itself through recurrent subcortical ischemic
      strokes leading to a stepwise decline and dementia, and results in reduced
      survival.

PMID- 10356104
TI  - Factors associated with ischemic stroke during aspirin therapy in atrial
      fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials.
      The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators.
AB  - BACKGROUND AND PURPOSE: Nonvalvular atrial fibrillation (AF) is a strong,
      independent risk factor for stroke, but the absolute rate of stroke varies widely
      among AF patients, importantly influencing the potential benefit of
      antithrombotic prophylaxis. We explore factors associated with ischemic stroke in
      AF patients taking aspirin. METHODS: We performed multivariate logistic
      regression analysis of 2012 participants given aspirin alone or in combination
      with low, inefficacious doses of warfarin in the Stroke Prevention in Atrial
      Fibrillation I-III trials followed for a mean of 2.0 years, during which 130
      ischemic strokes were observed. RESULTS: Age (relative risk [RR]=1.8 per decade,
      P<0.001), female sex (RR=1.6, P=0.01), history of hypertension (RR=2.0, P<0.001),
      systolic blood pressure >160 mm Hg (RR=2.3, P<0.001), and prior stroke or
      transient ischemic attack (RR=2.9, P<0.001) were independently associated with
      increased stroke risk. Regular consumption of >/=14 alcohol-containing drinks per
      week was associated with reduced stroke risk (adjusted RR=0.4, P=0.04). Among
      SPAF III participants, estrogen hormone replacement therapy was associated with a
      higher risk of ischemic stroke (adjusted RR=3.2, P=0.007). With the use of these
      variables, a risk stratification scheme for primary prevention separated
      participants into those with high (7.1%/y, 22% of the cohort), moderate (2.6%/y,
      37% of the cohort), and low (0.9%/y, 41% of the cohort) rates of stroke. Ischemic
      strokes in low-risk participants were less often disabling (P<0.001).
      CONCLUSIONS: Patients with AF who have high and low rates of stroke during
      treatment with aspirin can be identified. However, validation of our risk
      stratification scheme is necessary before it can be applied with confidence to
      clinical management. Postmenopausal estrogen replacement therapy and moderate
      alcohol consumption may additionally modify the risk of stroke in AF, but these
      findings require confirmation.

PMID- 10356106
TI  - Methodological parameters influence the detection of right-to-left shunts by
      contrast transcranial Doppler ultrasonography.
AB  - BACKGROUND AND PURPOSE: Contrast transcranial Doppler ultrasonography is a new
      method to detect intracardiac right-to-left shunts, such as the patent foramen
      ovale. However, the methodology of the procedure varies considerably among
      investigators. This study was undertaken to assess the influence of
      methodological parameters on the results of the contrast transcranial Doppler
      examination in the detection of right-to-left shunts. METHODS: A total of 72
      patients (mean age, 58.2+/-14.7 years) had a contrast transcranial Doppler
      ultrasonography examination. To study the influence of methodological factors,
      patients with evidence of a right-to-left shunt underwent repeated examinations
      with modified procedures. Parameters under investigation were the timing of the
      Valsalva maneuver, the dose of the contrast medium, and the patient's posture
      during the examination. RESULTS: The median contrast signal count was 58.5 and
      48.0 (P<0.001) and the median latency of the first intracranially detected
      contrast signal was 12.5 and 8.5 seconds (P=0.05) when the Valsalva maneuver was
      performed 5 and 0 seconds after the start of the injection, respectively.
      Reducing the contrast medium dose from 10 to 5, 2.5, and 1.2 mL resulted in a
      decline of the median signal count from 54.5 to 28.5, 20.5, and 12.0 (P<0.01),
      respectively, while the latency of the first contrast signal increased from 13.3
      to 14.0, 14.6, and 15.0 seconds (P<0.05). The sitting position also produced a
      lower signal count than the supine position (P<0.02). CONCLUSIONS: This study
      demonstrates that several essential methodological parameters influence the
      results of the contrast transcranial Doppler ultrasonography examination.
      Therefore, it is necessary to standardize the procedure to permit comparable
      quantitative assessments of the shunt volume. The findings of the present study
      suggest that 10 mL of contrast medium be injected with the patient in the supine
      position and that the Valsalva maneuver be performed 5 seconds after the start of
      the injection.

PMID- 10356107
TI  - Ischemic preconditioning in 18- to 20-month-old gerbils: long-term survival with
      functional outcome measures.
AB  - BACKGROUND AND PURPOSE: In young animals, ischemic preconditioning protects CA1
      hippocampal neurons against global ischemia. However, cerebral ischemia occurs
      most frequently in individuals aged >/=65 years. This study examined the
      protection provided by ischemic preconditioning in a population of aged (18- to
      20-month-old) gerbils. METHODS: One group of animals was exposed to two 1.5
      minute episodes of global ischemia separated by 24 hours and followed 72 hours
      later by a 5-minute occlusion of both carotid arteries. A second group was given
      2 episodes of preconditioning only. Two other groups were exposed to 5 minutes of
      ischemia or sham surgery. The animals survived 10, 30, or 60 days. Functional and
      histological assessments were used to determine the extent of protection.
      RESULTS: Ten days after ischemia there was >80% protection of CA1 neurons in
      ischemic preconditioned animals compared with 6% in ischemic gerbils.
      Nevertheless, these preconditioned animals were impaired in open-field tests of
      habituation. In addition, CA1 dendritic field potentials were smaller in
      amplitude compared with those in sham animals. While there was a complete loss of
      staining for CA1 microtubule-associated protein-2 in ischemic animals, staining
      in ischemic preconditioned animals was normal. This suggests that dendritic
      abnormalities per se were not responsible for the observed functional deficits.
      CA1 cell survival declined to approximately 75% of sham values (P<0.05) at 60
      days after ischemia. CONCLUSIONS: Ischemic preconditioning provided substantial
      neuroprotection in aged gerbils. Nonetheless, the striking dissociation between
      histological and functional protection provided by ischemic preconditioning in
      aged animals emphasizes the need to use functional end points and long-term
      survival when assessing neuroprotection. Although functional recovery was evident
      with increasing survival time, CA1 cell death continued, thereby raising the
      possibility that the level of neuroprotection attained was not permanent.

PMID- 10356109
TI  - Primary hypoxic tolerance and chemical preconditioning during estrus cycle in
      mice.
AB  - BACKGROUND AND PURPOSE: Exogenous application of estrogens or progesterone
      ameliorates hypoxic/ischemic cell damage. This study investigates whether values
      of primary and induced hypoxic tolerance vary endogenously during the estrus
      cycle in female mice. METHODS: Population spike amplitude (PSA) and NADH were
      measured during hypoxic hypoxia and recovery in hippocampal slices from untreated
      control animals (C slices) and slices prepared from animals pretreated in vivo
      with a single intraperitoneal injection of 3-nitropropionate (3NP) (3NP slices)
      or acetylsalicylate (ASA) (ASA slices). RESULTS: Posthypoxic recovery of PSA was
      dose dependent in 3NP slices from males, with maximal recovery on pretreatment
      attained with 20 mg/kg 3NP (82+/-32% [mean+/-SD]; C slices, 38+/-29%; P<0.01).
      PSA recovered to 17+/-12% in C slices during proestrus, 43+/-23% during estrus,
      and 63+/-44% during diestrus. In 3NP slices, recovery of PSA increased to 57+/
      36% (P<0. 05) during proestrus. Hypoxic tolerance was not increased in other
      stages of the estrus cycle. Hypoxic NADH increase during proestrus declined from
      212+/-76% in C slices to 133+/-11% in 3NP slices (P<0. 05). Recovery of PSA in
      ASA slices was 75+/-36% (P<0.01 versus control) in males and 48+/-34% during
      proestrus (P<0.05 versus ASA slices from males). CONCLUSIONS: Primary and induced
      hypoxic tolerance are endogenously modulated during the estrus cycle. Differences
      in hypoxic oxidative energy metabolism mediate part of the differential
      tolerance. Experimental and clinical therapeutic strategies against cerebral
      ischemia/hypoxia need to consider sex-related dependence.

PMID- 10356108
TI  - Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning.
AB  - BACKGROUND AND PURPOSE: Edema formation after intracerebral hemorrhage has been
      linked to thrombin toxicity induced by the clot. However, thrombin at low
      concentrations actually protects neurons and astrocytes in culture from
      hypoglycemic and ischemic cell death. It is also known that a brief episode of
      brain ischemia increases neuronal tolerance to a subsequent severe ischemic
      episode. The objective of this study was to investigate whether pretreatment of
      the brain with low-dose thrombin induces tolerance to a subsequent large dose of
      thrombin injected into brain parenchyma. METHODS: The rat brain was
      preconditioned with 1 U thrombin by direct infusion into the right caudate
      nucleus. After thrombin pretreatment, the effects of a large dose (5 U) of
      thrombin on brain edema formation were studied at different intervals. We
      examined whether heat-shock protein (HSP) 27, HSP32, and HSP70 were induced by
      Western blot analysis, immunocytochemistry, and immunofluorescent double
      staining. RESULTS: Thrombin pretreatment significantly attenuated the brain edema
      that normally follows the infusion of a large dose of thrombin (79.2+/-0.4 versus
      84.0+/-0.3; P<0.01). This effect was abolished by the thrombin inhibitor hirudin.
      Time course studies showed that the maximal effect of thrombin preconditioning
      (TPC) on brain edema formation was 7 days after pretreatment. This time course
      corresponded to marked upregulation of HSP27 in the ipsilateral brain. TPC also
      induced HSP32, but this effect occurred earlier than the effect on edema
      formation. TPC had no effect on HSP70. Immunocytochemistry and immunofluorescent
      double labeling showed that HSP27 and HSP32 were expressed in astrocytes after
      TPC. CONCLUSIONS: OFF phenomenon of thrombin-induced tolerance of the brain to
      edema formation may be related to HSP27 induction.

PMID- 10356110
TI  - Reperfusion in a gerbil model of forebrain ischemia using serial magnetic
      resonance FAIR perfusion imaging.
AB  - BACKGROUND AND PURPOSE: Existing methods for the quantitative measurement of the
      changing cerebral blood flow (CBF) during reperfusion suffer from poor spatial or
      temporal resolution. The aim of this study was to implement a recently developed
      MRI technique for quantitative perfusion imaging in a gerbil model of
      reperfusion. Flow-sensitive alternating inversion recovery (FAIR) is a
      noninvasive procedure that uses blood water as an endogenous tracer. METHODS:
      Bilateral forebrain ischemia of 4 minutes' duration was induced in gerbils (n=8).
      A modified version of FAIR with improved time efficiency was used to provide CBF
      maps with a time resolution of 2.8 minutes after recirculation had been
      initiated. Quantitative diffusion imaging was also performed at intervals during
      the reperfusion period. RESULTS: On initiating recirculation after the transient
      period of ischemia, the FAIR measurements demonstrated either a symmetrical,
      bilateral pattern of flow impairment (n=4) or an immediate side-to-side
      difference that became apparent with respect to the cerebral hemispheres in the
      imaged slice (n=4). The flow in each hemisphere displayed a pattern of recovery
      close to the preocclusion level or, alternatively, returned to a lower level
      before displaying a delayed hypoperfusion and a subsequent slow recovery. The
      diffusion measurements during this latter response suggested the development of
      cell swelling during the reperfusion phase in the striatum. CONCLUSIONS: The CBF
      during the reperfusion period was monitored with a high time resolution,
      noninvasive method. This study demonstrates the utility of MRI techniques in
      following blood flow changes and their pathophysiological consequences.

PMID- 10356111
TI  - Differential time-course decreases in nonselective, mu-, delta-, and kappa-opioid
      receptors after focal cerebral ischemia in mice.
AB  - BACKGROUND AND PURPOSE: Neuroprotection studies have demonstrated the involvement
      of opioids in ischemia, and we have previously demonstrated alterations in Bmax
      of opioidergic receptors after 2 post-MCAO time points in mice. METHODS: In the
      present study, we have investigated in a detailed manner the postischemic time
      course of variations in [3H]diprenorphine (nonselective), [3H]DAMGO (mu),
      [3H]DADLE (delta), and [3H]U69593 (kappa) relative binding densities after focal
      cerebral ischemia (0 to 48 hours) in mice. RESULTS: In frontoparietal cortices,
      our results demonstrate decreases in (1) delta receptor densities at 1 to 3 hours
      after MCAO, (2) mu and nonselective binding sites at 6 to 12 hours after MCAO,
      and (3) kappa receptor densities between 6 and 24 hours after MCAO. In the
      rostral part of the infarct border zone, a decrease in delta-receptors was found
      concomitant with the extension of the infarct core; conversely, the decrease in
      delta-receptors appeared before (6 to 12 hours) macroscopic histological damage,
      which occurred between 12 hours and 24 hours after MCAO in the caudal part of
      this area. In this frontier, mu- and especially kappa-binding sites were
      decreased later (12 to 48 hours after MCAO). CONCLUSIONS: These differential
      alterations in opioidergic receptors could be due to the selective
      sublocalization of receptors, postsynaptically on cortical interneurons for mu-
      and delta-receptors versus presynaptically on cortical afferent pathways for the
      kappa subtype. Further, our results suggest that delta- and mu-opioidergic
      receptors could be markers of infarct extension and neuronal death; the study of
      [3H]diprenorphine and selective binding sites argues in favor of the use of
      receptor-specific ligands. Finally, the relative preservation of kappa-receptors
      might be correlated with the neuroprotective role of kappa-agonists, as
      previously reported.

PMID- 10356113
TI  - Standardization of carotid ultrasound.

PMID- 10356114
TI  - Standardization of carotid ultrasound.

PMID- 10356112
TI  - Neuroprotective FK506 does not alter in vivo nitric oxide production during
      ischemia and early reperfusion in rats.
AB  - BACKGROUND AND PURPOSE: Previous studies have demonstrated that the
      immunosuppressant FK506 provides neuroprotection in experimental brain injury and
      suggest that this action may be mediated by suppression of neuronal nitric oxide
      synthase activation that occurs after ischemic depolarization. We sought to
      determine whether FK506 reduces histological injury after middle cerebral artery
      occlusion (MCAO) in the rat and whether the neuroprotective effect is mediated
      via suppression of in vivo nitric oxide (NO) production during ischemia or early
      reperfusion. METHODS: Under controlled conditions of normoxia, normocarbia, and
      normothermia, halothane-anesthetized male Wistar rats were subjected to 2 hours
      of MCAO by the intraluminal occlusion technique in a blinded, randomized
      experimental trial. Ipsilateral parietal cortical laser-Doppler flowmetry was
      monitored throughout ischemia. Animals were randomly assigned to 4 pretreatment
      groups: intravenous FK506 0.3 mg/kg or 1. 0 mg/kg, vehicle (cremaphor), or an
      equivalent volume of saline administered 30 minutes before MCAO. Infarction
      volume was assessed by a triphenyltetrazolium chloride staining at 22 hours of
      reperfusion. In separate experiments, microdialysis probes were placed
      bilaterally into the striatum. Rats were perfused with artificial cerebrospinal
      fluid containing 3 micromol/L [14C]- L-arginine for 3 hours and then subjected to
      2 hours of right MCAO. Intravenous 0.3 mg/kg FK506 or cremaphor was given 30
      minutes before right MCAO. Right-left differences between [14C]-L-citrulline in
      the effluent were assumed to reflect differences in NO production. RESULTS: All
      values are mean+/-SE. FK506 at 0.3 mg/kg reduced infarction volume in cortex:
      40+/-12 mm3 compared with saline (109+/-15 mm3) and cremaphor vehicle (148+/-23)
      (P<0.05). Striatal infarction was also reduced by low-dose FK506: 16+/-4 mm3
      versus 36+/-4 mm3 and 34+/-4 mm3 in saline and vehicle groups, respectively
      (P<0.05). High-dose treatment reduced infarction volume in cortex (61+/-14 mm3,
      P<0.05 from saline and vehicle groups) and in striatum (22+/-5 mm3, P<0.05 from
      saline and vehicle groups). [14C]-L-citrulline recovery via microdialysis was
      markedly enhanced in ischemic compared with nonischemic striatum. However,
      ischemia-evoked [14C]-L-citrulline recovery was not different in FK506-treated
      rats compared with vehicle-treated animals. CONCLUSIONS: These data demonstrate
      that FK506 provides robust neuroprotection against transient focal cerebral
      ischemia in the rat. The mechanism of protection in vivo is not through
      attenuation of ischemia-evoked NO production during MCAO and early reperfusion.

PMID- 10356115
TI  - Transcranial Doppler monitoring of carotid artery occlusion during
      endarterectomy.

PMID- 10356117
TI  - Surgery for cerebral amyloid angiopathy-related hemorrhage.

PMID- 10356116
TI  - Early ischemic recurrence and microembolic signals detected by transcranial
      Doppler.

PMID- 10356118
TI  - Should we screen for familial intracranial aneurysm?

PMID- 10356119
TI  - Using pathophysiology in acute stroke trials.

PMID- 10356120
TI  - Influence of arterial blood pressure on cerebrovascular reactivity.

PMID- 10356127
TI  - Abstracts of literature 

PMID- 10356128
TI  - Major ongoing stroke trials.

PMID- 10356130
TI  - Is there an epidemic of cardiovascular disease on the horizon?

PMID- 10356129
TI  - [The persistence of risky conduct for HIV transmission among intravenous drug
      users in Madrid, Seville, and Valencia. The Working Group of the Medicos del
      Mundo for the Monitoring of HIV Infection and the Risk Practices of Intravenous
      Drug Users].
AB  - OBJECTIVE: To determine the prevalence of HIV infection and risk-taking behavior
      for infection among intravenous drug users in Madrid, Seville, and Valencia
      (Spain). To study the main factors associated with such behavior. MATERIAL AND
      METHODS: Personal interviews were carried out with 821 intravenous drug users
      recruited in 1994 and 1995 among recent participants in three needle-exchange
      programs. Subjects were asked about their risk-taking behavior in the 30 days
      preceding the interview. Bivariate statistical methods and logistical regression
      techniques were used. RESULTS: In the month before the interview, 13.8% of the
      subjects in Valencia, 18.1% in Madrid, and 26.9% in Seville used needles that had
      been used by other people, usually (73-88%) without disinfecting them
      effectively. Condom use during the reference period was 50% in Seville, 42.5% in
      Madrid, and 34.2% in Valencia. The prevalence of HIV infection ranged from 30.1%
      in Seville to 43. 2% in Madrid. Multivariate analysis showed that the factors
      most closely associated with accepting used needles were: needle sharing (OR =
      12.2), residence in Seville (OR = 6.6), and HIV positivity (OR = 4.6). The
      factors most closely associated with not using condoms systematically were:
      ignorance of personal HIV serological state (OR = 4.1), needle sharing (OR =
      3.7), and HIV negativity (OR = 3.3). CONCLUSIONS: The risk of HIV transmission
      among intra-venous drug users in Spain is high (infection and risk-taking
      behavior have a high prevalence), so programs designed to reduce this risk should
      be increased quickly.

PMID- 10356131
TI  - Newborn screening for inborn errors of metabolism is going to expand: are we
      ready?

PMID- 10356132
TI  - Secular trends of blood pressure and body size in a multi-ethnic adolescent
      population: 1986 to 1996.
AB  - OBJECTIVES: To determine the levels and time trends of blood pressure and body
      size in a healthy population of youth. STUDY DESIGN: Minneapolis, Minnesota,
      fifth through eighth grade public school children (aged 10 to 14 years) were
      surveyed in 1986 and 1996. Blood pressure, height, and weight were measured by
      technicians trained to the same rigorous protocol at each time period, and
      comparisons were made between the 2 groups (1986 and 1996). RESULTS: In 1986 and
      1996, 8222 and 10,241 children, respectively, were measured with participation
      rates of over 93%. African American, Hispanic, Native American, Asian, and non
      Hispanic white groups were all represented. Systolic blood pressure was
      significantly higher and diastolic blood pressure lower in 1996 than in 1986 in
      all ethnic and gender groups. Weight and body mass index (wt/ht2) were
      significantly higher in all groups in 1996. Adjustment for body size largely
      eliminated the systolic blood pressure differences but had no effect on measured
      diastolic blood pressure. CONCLUSIONS: Body size and systolic blood pressure are
      rising among school children. Weight and body mass index show substantial
      increases over 10 years (1986-1996). Diastolic blood pressure fell for unclear
      reasons. These changes may have future health implications for cardiovascular
      disease, as these youth move into adulthood.

PMID- 10356133
TI  - Outcome of individuals with low-moderate methylmalonic aciduria detected through
      a neonatal screening program.
AB  - BACKGROUND: The clinical spectrum of methylmalonic aciduria (MMAuria) ranges from
      severe, neonatal acidosis to benign asymptomatic organic aciduria. In 1975,
      screening for MMAuria was established in the province of Quebec. Although newborn
      screening programs facilitate presymptomatic detection and treatment and also
      detect asymptomatic variants, uncertainties about potential long-term hazards of
      mild to moderate elevations of MMA create concern. The objective of this study
      was to examine the outcome of individuals excreting low to intermediate
      quantities of MMA, ascertained by a newborn screening program. RESULTS AND STUDY
      DESIGN: One hundred and thirty-six individuals with elevations of urinary MMA
      were initially identified by the screening program; 122 individuals were noted to
      have excretion of urinary MMA <1400 micromol/mmol creatinine. At follow-up
      assessment at 1 year of age, in 65 of these 122 individuals, the MMA excretion
      had resolved. Of the remaining individuals, 9 were lost to follow-up, 13 had
      symptoms, and the remaining 35 were free of symptoms. Among the 35 individuals
      with asymptomatic persistent MMAuria, MMA excretion has resolved in 13 over 1
      year; 22 individuals exhibit persistent low-moderate MMAuria (range, 210 to 1133
      micromol/mmol creatinine). CONCLUSION: Follow-up examination of individuals in
      the latter asymptomatic cohort with persistent low-moderate MMAuria indicates
      normal somatic and cognitive outcomes.

PMID- 10356134
TI  - Leukocyte adhesion deficiency II syndrome, a generalized defect in fucose
      metabolism.
AB  - Leukocyte adhesion deficiency II has been described in only 2 patients; herein we
      report extensive investigation of another patient. The physical stigmata were
      detected during prenatal ultrasonographic investigation. Sialyl-Lewis X (sLex)
      was absent from the surface of polymorphonuclear neutrophils, and cell binding to
      E- and P-selectin was severely impaired, causing an immunodeficiency. The
      elevation of peripheral neutrophil counts occurred within several days after
      birth. A severe hypofucosylation of glycoconjugates bearing fucose in different
      glycosidic links was present in all cell types investigated, demonstrating that
      leukocyte adhesion deficiency II is not only a disorder of leukocytes but a
      generalized inherited metabolic disease affecting the metabolism of fucose.

PMID- 10356135
TI  - Maternal uniparental disomy 14 as a cause of intrauterine growth retardation and
      early onset of puberty.
AB  - Uniparental disomy for particular chromosomes is increasingly recognized as a
      cause of abnormal phenotypes in humans either as a result of imprinted genes or,
      in the case of isodisomy, homozygosity of mutated recessive alleles. We report on
      the occurrence of maternal uniparental disomy for chromosome 14 (matUPD 14) in a
      25-year-old woman with a normal karyotype, normal intelligence but low birth
      weight, short stature, small hands, and early onset of puberty. Comparison of her
      phenotype with those of 15 previously described liveborn patients with matUPD14
      gives further evidence for an imprinted gene region on chromosome 14 and
      highlights the necessity to consider this cause in children with intrauterine
      growth retardation and early onset of puberty caused by acceleration of skeletal
      maturation.

PMID- 10356136
TI  - Infantile encephalopathy associated with the MELAS A3243G mutation.
AB  - MELAS syndrome is typically characterized by normal early development and
      childhood-onset recurrent neurologic deficits (stroke-like episodes), seizures,
      short stature, lactic acidosis, and ragged red fibers on muscle biopsy specimens.
      It is usually, but not invariably, associated with the A3243G point mutation in
      the mitochondrial DNA tRNALeu(UUR) gene. We report 3 unrelated children with the
      A3243G mutation who presented with severe psychomotor delay in early infancy. One
      patient's clinical picture was more consistent with Leigh syndrome, with apneic
      episodes, ataxia, and bilateral striatal lesions on brain magnetic resonance
      imaging (MRI). The second patient had generalized seizures refractory to
      treatment and bilateral occipital lesions on brain MRI. The third child had
      atypical retinal pigmentary changes, seizures, areflexia, and cerebral atrophy on
      brain MRI. All patients had several atypical features in addition to early onset:
      absence of an acute or focal neurologic deficit, variable serum and cerebrospinal
      fluid lactate levels, lack of ragged red fibers in muscle biopsy specimens. The
      proportion of mutant mtDNA in available tissues was relatively low (range, 5% to
      51% in muscle; 4% to 39% in blood). These observations further extend the
      phenotypic expression of the A3243G "MELAS" mutation. Our findings confirm
      previous observations that there is poor correlation between abundance of mutant
      mtDNA in peripheral tissues and neurologic phenotype. This suggests that other
      factors contribute to the phenotypic expression of this mutation.

PMID- 10356137
TI  - Single-dose dexamethasone treatment of hypotension in preterm infants.
AB  - OBJECTIVE: To test the efficacy of single-dose dexamethasone (DXM) in the
      management of severe arterial hypotension of newborn infants. Our hypothesis was
      that epinephrine infusions could be discontinued in 70% of patients within 12
      hours after DXM administration compared with 10% in the placebo group. STUDY
      DESIGN: Twenty preterm infants (median birth weight 690 g, gestational age 28
      weeks, age at intervention 2 days) who did not respond to a standardized
      treatment protocol (blood/colloid followed by dopamine infusion stepwise
      increased to 15 micrograms/kg and minute) were started on an epinephrine infusion
      and were randomly allocated to receive either DXM (0.25 mg/kg) or placebo
      intravenously. The primary outcome criterion was the need for an epinephrine
      infusion 12 hours after treatment. RESULTS: Three infants were excluded.
      Epinephrine infusion was discontinued in 5 of 8 infants with DXM but in only 1 of
      9 infants in the control group. The duration of epinephrine infusion was
      significantly shorter in the DXM group (exact log-rank test, P =. 023).
      CONCLUSIONS: DXM was effective for the management of severe arterial hypotension
      in preterm infants not responding to standardized treatment.

PMID- 10356138
TI  - Hypothyroxinemia of prematurity and the risk of cerebral white matter damage.
AB  - OBJECTIVE: Infants with hypothyroxinemia of prematurity (HOP) are at increased
      risk for neurodevelopmental dysfunction. Infants born near the end of the middle
      trimester are also at increased risk for an echolucency (EL) in the cerebral
      white matter, which reflects white matter damage and is the cranial ultrasound
      abnormality that best predicts neurodevelopmental dysfunction. We postulated that
      some of the increased risk of neurodevelopmental problems associated with HOP
      reflects an increased risk of EL. STUDY DESIGN: We studied 1414 infants weighing
      500 to 1500 g who were born at 4 medical centers between 1991 and 1993. The
      infants had thyroxine blood levels measured during the first weeks of life, at
      least 1 of 3 cranial ultrasound scans performed at specified postnatal intervals,
      and their own and their mother's hospital charts reviewed. Infants were
      classified by whether or not their first thyroxine level placed them in the
      lowest quartile among all infants in this sample (ie, <67.8 nmol/L, our
      definition of HOP, equivalent to <5.3 micrograms/dL). RESULTS: After adjusting
      for such potential confounders as low gestational age and measures of illness
      severity, infants with HOP had twice the risk of EL as their peers with higher
      thyroxine levels. CONCLUSION: Our findings are consistent with the hypothesis
      that a "normal" blood thyroxine level protects infants born near the end of the
      middle trimester against the risk of cerebral white matter damage.

PMID- 10356139
TI  - Sternocleidomastoid pseudotumor and congenital muscular torticollis in infants: a
      prospective study of 510 cases.
AB  - OBJECTIVES: Congenital muscular torticollis is a common and controversial
      condition in infancy. We studied prospectively a group of infants with clearly
      defined sternomastoid tumor treated with a well-defined protocol. STUDY DESIGN: A
      total of 510 cases of sternomastoid tumor in infants over a 10-year period were
      studied prospectively with a mean follow-up of 3.5 years and a range from 1. 5
      years to 13 years. The clinical presentations, associated abnormalities,
      treatments, and outcomes of the overall group and subgroups were evaluated to
      determine the most important prognostic factors. RESULTS: The mean age of
      presentation was day 24, with most (92.7%) presenting before the age of 3 months.
      There was a high correlation with breech presentation and assisted delivery.
      Clinical subgroups according to the deficit in passive rotation of the neck
      correlated with the incidence of hip dysplasia (up to 11.6%), mode of delivery,
      time of presentation, degree of craniofacial asymmetry, head tilt, and the size
      and extent of the pseudotumor (P <.05). With an early and prolonged manual
      stretching program, 90.7% had excellent and good overall results. The 6.7% of
      patients in the poor outcome group requiring surgical treatment all belonged to
      the more severe rotation limitation groups. CONCLUSIONS: Subgrouping patients
      with sternomastoid tumor according to the passive limitation of rotation of the
      neck has prognostic significance, with good overall results of conservative
      treatment with manual stretching.

PMID- 10356140
TI  - The effects of zidovudine in the subset of infants infected with human
      immunodeficiency virus type-1 (Pediatric AIDS Clinical Trials Group Protocol
      076).
AB  - OBJECTIVE: To describe the effect of zidovudine on human immunodeficiency virus
      type 1 (HIV-1) and on the course of disease in infants who became infected while
      they and their mothers received zidovudine preventive therapy or placebo in
      Pediatric AIDS Clinical Trials Group Protocol 076. STUDY DESIGN: Observational
      substudy of a multicenter, randomized, double-blind, placebo-controlled trial.
      METHODS: We compared the progression of disease, timing of HIV-1 transmission,
      and the plasma HIV-1 RNA level in infected infants of mother-infant pairs who
      were randomly assigned to receive zidovudine (n = 14) or placebo (n = 43). The
      development of genotypic zidovudine resistance was assessed among infected
      infants in the zidovudine treatment group. RESULTS: In this limited study,
      zidovudine therapy during pregnancy and labor and in the neonatal period for 6
      weeks failed to have a major effect on rapid progression of disease, timing of
      transmission, and viral replication in HIV-infected infants. When the zidovudine
      treatment regimen failed to prevent maternal-infant transmission of HIV-1,
      resistance to zidovudine did not develop during study treatment. CONCLUSIONS: Our
      study supports the safety of zidovudine use in pregnancy and in the newborn
      period but demonstrates the continued need for more potent antiretroviral
      treatment of the infected infant.

PMID- 10356141
TI  - C-reactive protein is useful in distinguishing Gram stain-negative bacterial
      meningitis from viral meningitis in children.
AB  - OBJECTIVE: To clarify to what extent Gram stain-negative bacterial meningitis can
      be distinguished from viral meningitis by assessment of cerebrospinal fluid (CSF)
      and blood indices and serum C-reactive protein (CRP) in children over 3 months of
      age. DESIGN: Common CSF indices, blood leukocyte counts, and serum CRP values
      were compared between patients with bacterial meningitis who had a positive CSF
      bacterial culture but a negative Gram stain and patients with viral meningitis.
      POPULATION: Three hundred twenty-five consecutive patients with CSF culture
      proven bacterial meningitis, for whom Gram stain was negative in 55 cases, and
      182 children with proven or presumed viral meningitis. RESULTS: Significant
      differences between patients with bacterial and viral meningitis were found in
      all indices with large overlap in all except serum CRP. In patients with
      bacterial meningitis, the mean CSF glucose concentration, protein concentration,
      leukocyte count, blood leukocyte count, and serum CRP were 2.9 mmol/L (52 mg/dL),
      1.88 g/L, 4540 x 10(6)/L, 18.0 x 10(9)/L, and 115 mg/L; and in those with viral
      meningitis, mean values were 3.3 mmol/L (59 mg/dL), 0.52 g/L, 240 x 10(6)/L, 10.6
      x 10(9)/L, and <20 mg/L, respectively. Of the tests investigated in this study,
      only serum CRP was capable of distinguishing Gram stain-negative bacterial
      meningitis from viral meningitis on admission with high sensitivity (96%), high
      specificity (93%), and high negative predictive value (99%). CONCLUSION:
      Exclusion of bacterial meningitis with only the conventional tests is difficult.
      Combined with careful physical examination and CSF analyses, serum CRP
      measurement affords substantial aid.

PMID- 10356142
TI  - Lung function in infants with chronic pulmonary disease after severe adenoviral
      illness.
AB  - OBJECTIVE: To evaluate pulmonary function and bronchodilator responses in young
      children with chronic pulmonary disease (CPD) after a severe adenoviral lower
      respiratory tract infection. METHODS: Pulmonary function tests were performed in
      13 patients (mean age, 1.32 +/- 0.8 years) with CPD and were compared with a
      control group of 13 healthy infants (mean age, 1.16 +/- 0.4 years). RESULTS:
      Respiratory rate, peak tidal expiratory flow (PTEF), PTEF/tidal volume, absolute
      time up to PTEF, time percentage to PTEF, volume percentage for PTEF, and
      compliance and resistance of the respiratory system were significantly affected
      in the CPD group. Similarly, maximal flow at functional residual capacity
      (V'maxFRC) was 56.0 +/- 42 mL/s and 373 +/- 107 mL/s in the CPD and control
      groups, respectively (P =.001). No within-group differences with baseline values
      or between-group differences were noted in response to treatment with ipratropium
      bromide or albuterol. CONCLUSION: Young children with CPD caused by adenovirus
      have pulmonary function changes characterized by severe obstruction and
      diminished lung distensibility not responsive to the administration of inhaled
      ipratropium bromide or albuterol.

PMID- 10356143
TI  - Estimating effectiveness in an observational study: a case study of dornase alfa
      in cystic fibrosis. The Investigators and Coordinators of the Epidemiologic Study
      of Cystic Fibrosis.
AB  - Patients with cystic fibrosis (CF) receiving dornase-alfa had improved pulmonary
      function relative to a control group in a large randomized phase III controlled
      study. We reviewed data from a large observational phase IV study to estimate the
      observed drug effect in patients receiving dornase alfa as part of their routine
      care. Patients 6 years or older and with a baseline forced expiratory volume in 1
      second (FEV1) of at least 40% predicted who had been enrolled for at least 18
      months were included (n = 283). The control group consisted of 2382 patients who
      had never received dornase alfa. Patients in the study had a baseline spirometry
      and a second spirometry recorded 12 months later; a baseline observation period
      of 6 months preceded the initial spirometry, and dornase alfa had to have been
      started after the baseline spirometry (within 3 months) and to have continued
      through the 12-month follow-up spirometry. Patients treated with dornase alfa had
      lower pulmonary functions, more bacterial colonization, and more exacerbations at
      baseline (FEV1 : 76.0% vs 87.6%, Pseudomonas aeruginosa : 64.1% vs 46.7%,
      pulmonary exacerbations during the previous 6 months: 56.4% vs 22. 2%). Mean
      values of FEV1 for patients treated with dornase alfa improved by 3.9% of
      predicted compared with a decline of 1.6% in the untreated cohort. Covariate
      adjustment provided an estimated benefit of dornase alfa of 4.3% predicted FEV1
      (SE = 0.9, P <.0001). This analysis provides evidence for the effectiveness of
      dornase alfa therapy in clinical practice.

PMID- 10356144
TI  - Influence of severe combined immunodeficiency phenotype on the outcome of HLA non
      identical, T-cell-depleted bone marrow transplantation: a retrospective European
      survey from the European group for bone marrow transplantation and the european
      society for immunodeficiency.
AB  - We analyzed the outcomes of 214 HLA non-identical T-cell-depleted bone marrow
      transplantations (BMTs), performed in 178 consecutive patients for treatment of
      severe combined immunodeficiencies (SCID). Patients were treated in 18 European
      centers between 1981 and March 1995. SCID variants, that is, absence of T and B
      lymphocytes (B-) or absence of T cells with presence of B lymphocytes (B+) were
      found to have a major influence on outcome. The disease-free survival was
      significantly better for patients with B+ SCID (60%) as compared with patients
      with B- SCID (35%) (P =.002), with a median follow-up of 57 months and 52 months,
      respectively. Other factors associated with a poor prognosis were the presence of
      a lung infection before BMT (odds ratio = 2.47 [1.99-2.94]) and the use of
      monoclonal antibodies for T-cell depletion of the graft (odds ratio = 1.67 [1. 18
      2.15]). Additional factors influencing outcome were age at BMT (<6 months) and
      period during which BMT was performed. Better results were achieved after 1991.
      Reduced survival of patients with B- SCID was associated with a higher incidence
      of early deaths from infection, a diminished rate of marrow engraftment, a trend
      to a higher incidence of chronic graft-versus-host disease, and slower kinetics
      of T/B immune function development. In both groups of patients, the use of
      busulfan (8 mg/kg total dose) and cyclophosphamide (200 mg/kg total dose) as a
      conditioning regimen provided the best cure rate (74% for patients with B+ SCID
      and 43% for patients with B- SCID, respectively), although results were not
      statistically significantly different from other regimens. This retrospective
      analysis should lead to the design of adapted measures to the performance of HLA
      non-identical BMT in patients with distinct SCID conditions.

PMID- 10356145
TI  - Temporal course of the development of obesity in Japanese school children: a
      cohort study based on the Keio Study.
AB  - OBJECTIVE: To demonstrate the temporal course of obesity development in Japanese
      school children by conducting a school-site cohort study over 12 years. METHODS:
      From 1981 to 1984, height and weight of 479 subjects (343 boys and 136 girls)
      were measured every year from entrance into primary school until graduation from
      high school in Tokyo. Obese children were defined as those with a body mass index
      (BMI) at or above the age-sex-specific standard value, derived from Japanese
      nationwide data. RESULTS: Approximately 50% of the children who were obese in the
      primary school period were obese at age 17. Likewise, 40% who were obese in the
      junior high school period and 70% who were obese in the high school period were
      obese at age 17. Among 44 children who were obese at age 17, 14 showed tracking
      of obesity from the preschool period, 14 showed tracking from ages 7 to 11 years,
      10 showed tracking from the junior high school period, and 6 showed tracking from
      the high school period. CONCLUSIONS: Among children who were obese at age 17,
      most tracked from the primary school age or earlier. The earlier the tracking
      commenced, the greater the BMI at age 17. This indicates the importance of
      conducting health education for school children at an early age.

PMID- 10356146
TI  - Sleep characteristics in children with Down syndrome.
AB  - BACKGROUND: Obstructive sleep apnea syndrome is common in children with Down
      syndrome (DS). Little is known about sleep patterns, especially arousals,
      awakenings, and movements during sleep in children with DS. OBJECTIVE: To
      determine the characteristics of sleep disorders in children with DS and to
      define the associations between respiratory disturbance and arousals, awakenings,
      and movements. METHODS: The study included 23 children with DS, compared with 13
      children with primary snoring. All underwent a 6- to 8-hour sleep study. RESULTS:
      The respiratory disturbance index was significantly higher in the children with
      DS (2.8 +/- 2.3 events/h vs 0.6 +/- 0.4 events/h; P <.05). Sleep was
      significantly fragmented in children with DS, who had a significantly higher
      arousal/awakening (A/Aw) index (24.6 +/- 7.9 events/h) compared with the
      comparison group (17.6 +/- 4.0 events/h) (P <.02). A higher percentage of jerks
      associated with A/Aw and respiratory event-associated A/Aw was observed in
      patients with DS (45.2% +/- 25% and 8.6% +/- 6.4%, respectively) compared with
      the control patients (10.2% +/- 4.5% and 1.5% +/- 2.1%) (P <.02). The median
      length of occurrences of stage 2 sleep was 27% shorter in the DS group (P <.03).
      The number of shifts from "deeper" to "lighter" stages of non-rapid eye movement
      sleep was 30% greater (P <.02) in the DS group. CONCLUSION: Children with DS have
      significant sleep fragmentation, manifested by frequent awakenings and arousals,
      which are only partially related to obstructive sleep apnea syndrome.

PMID- 10356147
TI  - Excessive infantile growth and early pubertal growth spurt: typical features in
      patients with aspartylglycosaminuria.
AB  - Rapid infantile growth was the first clinical sign in patients (n = 51) with
      aspartylglycosaminuria, a lysosomal storage disorder. Even if young children with
      aspartylglycosaminuria were tall for their age, an early but weak pubertal growth
      spurt in both sexes resulted in reduced adult heights.

PMID- 10356148
TI  - Multiple acyl-coenzyme A dehydrogenase deficiency: diagnosis by acyl-carnitine
      analysis of a 12-year-old newborn screening card.
AB  - We report a family who experienced an unexplained neonatal death. Twelve years
      after the death, we retrospectively diagnosed multiple acyl-coenzyme A
      dehydrogenase deficiency by demonstrating an abnormal acyl-carnitine profile in
      the child's archived newborn screening card, using tandem mass spectrometry.

PMID- 10356150
TI  - Pain and the Guillain-Barre syndrome in children under 6 years old.
AB  - During a 15-year period, 29 children, under the age of 6 years, with acute
      Guillain-Barre syndrome were seen at our institution. A review of their charts
      revealed that pain was a symptom in all patients and was present on admission in
      79% of cases. Pain was often the most important symptom and led to misdiagnosis
      in 20 patients (69%). In 11 of these children, symptoms were present for more
      than a week before the correct diagnosis was made. The most common pain syndrome
      was back and lower limb pain, present in 83% of patients. Pediatricians should
      consider Guillain-Barre syndrome in their differential diagnosis when faced with
      a child who has lower limb pain and areflexia.

PMID- 10356149
TI  - Social and emotional problems in children with neurofibromatosis type 1: evidence
      and proposed interventions.
AB  - OBJECTIVE: To describe social and emotional problems in children and adolescents
      with neurofibromatosis type 1 (NF1) and propose interventions. Our hypothesis is
      that children with NF1 will have significantly more social and emotional
      problems, compared with their unaffected siblings and children in the general
      population. STUDY DESIGN: Forty-three children with NF1 and 22 unaffected
      siblings (ages 5 to 18 years) were assessed with a standardized test completed by
      parents and teachers (the Child Behavior Checklist). RESULTS: As with other
      aspects of NF1, there was variable expressivity. However, when rated by parents,
      children with NF1 had significantly more problems in comparison with test norms
      or unaffected siblings on 7 of 8 scales: Social Problems, Attention Problems,
      Anxiety/Depression, Withdrawal, Thought Problems, Somatic Complaints, and
      Aggressive Behavior. Children with NF1 also scored lower than unaffected siblings
      on measures assessing sports and other activities. Teachers reported fewer
      differences. CONCLUSIONS: We propose interventions in the form of information for
      parents; early screening and treatment for speech, motor, and cognitive problems;
      and an increased level of intervention to prevent and treat psychologic problems,
      including systematic screening with standardized tests.

PMID- 10356151
TI  - Prothrombin G20210A mutation in a child with spinal cord infarction.
AB  - Prothrombin G20210A is a newly described common mutation that is associated with
      an increased risk of arterial and venous thrombosis. We describe a healthy child
      heterozygous for this prothrombin mutation who had a spinal cord infarct with no
      other prothrombotic risk factors.

PMID- 10356152
TI  - Chorioretinal lesions in patients and carriers of chronic granulomatous disease.
AB  - OBJECTIVE: To investigate the frequency of retinal lesions in patients with
      chronic granulomatous disease (CGD) and to seek such lesions in carriers. STUDY
      DESIGN: Seventy-four individuals from 33 families were recruited; 38 had CGD (30
      X-linked and 8 autosomal recessive inheritance). All participants (including 33
      control subjects) underwent measurement of visual acuity, anterior segment
      examination by slit lamp, and dilated funduscopy. RESULTS: Nine of 38 (23.7%) of
      the affected children had chorioretinal lesions compared with 0 of 33 control
      subjects. All 9 were known to have X-linked CGD and absent gp91(phox). The
      "typical" retinal abnormality consisted of "punched out" chorioretinal lesions
      associated with pigment clumping lying along major retinal vessels. Unexpectedly,
      3 XL-CGD asymptomatic carriers also had typical chorioretinal lesions.
      CONCLUSION: Retinal lesions are relatively common in patients with XL-CGD and may
      interfere with vision and thus should be sought in such patients.

PMID- 10356153
TI  - Hepatitis A vaccination in chronic carriers of hepatitis B virus.
AB  - Because hepatitis A infection may be more severe in patients with chronic liver
      disease, we vaccinated 33 children who were chronic HBsAg carriers against
      hepatitis A virus. Anti-hepatitis A virus seroconversion rates after the first,
      second, and third doses were 90.9%, 96.9%, and 100%, respectively.

PMID- 10356154
TI  - Hepatic veno-occlusive disease in ataxia-telangiectasia.
AB  - Existing descriptions of liver abnormalities in ataxia-telangiectasia have been
      associated with co-existent hepatitis virus infection. Here we report veno
      occlusive disease of the liver in 2 patients with ataxia telangiectasia that is
      not attributable to bone marrow transplantation or coincidental hepatitis
      infection.

PMID- 10356155
TI  - Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune
      Albright syndrome.
AB  - McCune-Albright syndrome consists of fibrous dysplasia of bone, cafe-au-lait skin
      pigmentation, and endocrine dysfunction (usually precocious puberty). Other
      endocrine abnormalities occur in a minority of patients, and of these, Cushing's
      syndrome is the least often recognized. We present 5 children (4 girls) with
      features of McCune-Albright syndrome who had Cushing's syndrome in the infantile
      period (<6 months). In 2 children spontaneous resolution occurred, but the
      remaining 3 required bilateral adrenalectomy. In addition, all 4 girls have
      experienced precocious puberty, and 3 children demonstrated radiologic evidence
      of nephrocalcinosis. Understanding of the underlying defect causing McCune
      Albright syndrome emphasizes the importance of searching for other endocrine
      dysfunction in these children.

PMID- 10356156
TI  - Dorsal dermal sinus and dermoid cysts in occult spinal dysraphism.

PMID- 10356157
TI  - Transient hypokalemic metabolic alkalosis in a newborn mimicking Bartter's
      syndrome.

PMID- 10356158
TI  - Transient neonatal cholestasis and perinatal asphyxia.

PMID- 10356160
TI  - Reply 

PMID- 10356159
TI  - Rebound bilirubin-bounces back.

PMID- 10356161
TI  - Managing Adolescents and Their Parents: Avoiding Pitfalls and Traps.
AB  - The author proposes an effective set of physician-adolescent-parent interactions
      or transactions-that flexibly integrates the patient's current level of cognitive
      and psychosocial development with two significant variables: the nature of the
      condition involved and the status of adolescent-parent communication.

PMID- 10356162
TI  - Stress and the Modern Adolescent.
AB  - The purposes of this chapter are to increase physicians' awareness of the effect
      of stress on adolescents, to assist physicians in recognizing the manifestations
      of stress, to review issues important in assessing stress and its effects, and to
      assist professionals in devising management strategies to help alleviate the
      effects of stress on their adolescent patients.

PMID- 10356163
TI  - Access to Psychosocial Care for Adolescents.
AB  - This discussion addresses obstacles to adolescents' receiving care for
      psychosocial problems, such as behavioral issues by both adolescent and
      physician, inadequate insurance coverage, and confidentiality issues. Approaches
      designed to improve access to care are described.

PMID- 10356164
TI  - Depressive Mood Disorders in Adolescents.
AB  - The authors discuss the two major classifications of mood disorders in detail and
      make specific recommendations for diagnosis, medical evaluation, differentiation
      from other disorders, and psychopharmacologic treatment of adolescent mood
      disorders.

PMID- 10356165
TI  - Adolescent Suicide: Assessment of Risk, Prevention, and Treatment.
AB  - The enormity of the problem of adolescent suicide-attempts and completions
      mandates that each attempt be evaluated with the context of the adolescent's
      social, psychological, and biological history. The assessment of risk, including
      the mental status exam, and prevention and treatment are covered.

PMID- 10356166
TI  - Current Perspectives on Adolescent Conduct Disorder.
AB  - Conduct disorder is a common biopsychosocial problem in children and adolescents.
      It is important for clinicians to recognize this condition in their patients so
      that timely evaluation and treatment strategies can be initiated.

PMID- 10356167
TI  - Adolescent Violence: Can It Be Curbed?
AB  - The dramatic increase in the amount of violence in the United States,
      particularly among minority youth and young adults, has produced a flurry of
      activity in the area of violence prevention. The dynamics of youth violence, the
      relationship of violence to poverty, approaches to violence reduction, and
      violence prevention programs are discussed.

PMID- 10356168
TI  - Psychosomatic Problems in Adolescents.
AB  - Many adolescents see physicians for diagnosis and treatment of symptoms that are
      found to have little or no organic basis. Definition, epidemiology, diagnosis,
      and management of psychosomatic symptoms are presented, with special attention to
      recurrent abdominal pain, which is one of the most common somatoform syndromes.

PMID- 10356169
TI  - Attention Deficit Hyperactivity Disorder in Adolescents.
AB  - There has been a decided shift in overall concepts regarding the diagnosis,
      presentation, therapy, and outcomes of attention deficit hyperactivity disorder
      (ADHD) in the adolescent and young adult populations. These concepts are explored
      and a multimodal approach to treatment is emphasized.

PMID- 10356170
TI  - Use of Psychometric with Adolescent Patients.
AB  - This chapter describes and critiques instruments that are appropriate for
      psychometric assessment of adolescents. Content areas include cognitive
      assessment (intelligence, neuropsychological, and educational tests), personality
      assessment (projective tests and structured interviews), and behaviorally based
      measures (direct observation, rating scales, and checklists). Guidelines are
      provided for evaluating both the utility of a psychometric measure and the
      adequacy of a psychoeducational report.

PMID- 10356171
TI  - What Pediatricians Should Know About Adolescent Psychiatry.
AB  - The authors review the most common psychiatric disorders in adolescents in order
      to familiarize pediatricians with techniques for recognizing, treating, and, when
      necessary, referring adolescents with a psychiatric disorder.

PMID- 10356172
TI  - Role of the Primary Care Pediatrician in Adolescent Psychosocial Assessment and
      Intervention.
AB  - The author believes that the pediatrician is in a position to counsel adolescents
      and parents. Some pediatricians are uncomfortable with the idea of offering
      separate office hours to counsel adolescents, but once the interest is there and
      the physician is well versed in dealing with adolescent care, the counseling
      aspect of patient care becomes a natural consequence. Common areas of adolescent
      turmoil are addressed, including the depressed adolescent, the adolescent who is
      failing in school, the adolescent who is not functioning well at home, the
      adolescent who is using drugs, and the adolescent who is having a sexual problem.

PMID- 10356173
TI  - Determinants of Adolescent Initiation of Coitus.
AB  - This article reviews selected studies that document social and biological
      correlates of adolescent sexual behavior and describes the ongoing search for
      biosocial determinants of initiation of coitus in adolescents.

PMID- 10356174
TI  - Delaying the Start of Intercourse Among Adolescents.
AB  - A high proportion of today's parents do not know how to help their school-age
      children avoid early sexual involvement. Interventions to delay the start of
      sexual intercourse are explored, and the goals and results of several abstinence
      intervention programs are described.

PMID- 10356175
TI  - Sexuality Education for Adolescents.
AB  - There is ample evidence that sexuality education programs increase adolescents'
      knowledge, and the better programs show significant positive effects on
      adolescent sexual behavior. The goals of such education should not be limited to
      preventing pregnancy and disease, but should teach young people how to identify,
      evaluate, communicate, and, if necessary, modify their own thoughts, feelings and
      actions.

PMID- 10356176
TI  - Role of Hormonal Contraceptives in Prevention of Pregnancy and Sexually
      Transmitted Diseases.
AB  - The high rates of both unintended pregnancy and sexually transmitted diseases
      among adolescents mandate appropriate preventive efforts by providers of
      adolescent health care. Hormonal contraceptives offer the most effective and
      acceptable method of pregnancy prevention. The efficacy, risks, and benefits of
      low-dose combined oral contraceptive pills, injectable or implantable progestins,
      hormone-containing intrauterine devices, and vaginal rings are discussed. The
      effects of hormonal contraception on the acquisition of sexually transmitted
      diseases are also addressed.

PMID- 10356177
TI  - The Role of Barrier Contraceptives in Prevention of Pregnancy and Disease in
      Adolescents.
AB  - The advent of HIV infection and a greater understanding of the effects of other
      viral sexually transmitted diseases have brought condoms back to the forefront in
      discussions of contraception in both the general press and the medical
      literature. Development of several newer barrier methods and improved
      understanding of use of the older methods by adolescents have occurred during the
      past few years.

PMID- 10356178
TI  - School- and Community-Based Pregnancy Prevention Programs.
AB  - The author reviews what works and what does not work in pregnancy prevention
      programs in schools and community agencies. Various prevention strategies, such
      as condom distribution in schools, are assessed, and a number of specific
      programs with excellent potential for success are described.

PMID- 10356179
TI  - Legal Issues in Adolescent Sexual Health.
AB  - Legal issues involving adolescent sexuality must be understood in the context of
      the general right of minors to health care of any sort. In keeping with the trend
      toward greater adolescent autonomy in all areas of their lives, adolescents have
      more rights to make health care decisions than they did a generation ago.

PMID- 10356180
TI  - Involving Adolescent Males in Pregnancy and STD Prevention Programs.
AB  - The principal barriers responsible for lack of male involvement in sexuality
      programs and in STD and pregnancy prevention programs are discussed and
      strategies are offered to help attract and keep males in sexual and reproductive
      health programs.

PMID- 10356181
TI  - Adolescent Abortion: Correlates and Consequences.
AB  - This chapter is organized into five sections that discuss the characteristics of
      adolescent aborters, the decision-making process, preabortion counseling, medical
      management, and postabortion adjustment. The purpose of the chapter is to help
      clinicians differentiate aborters from childbearers, to become informed
      participants in adolescents' pregnancy-resolution decision making, to manage
      medical aspects of the procedure, and to prepare patients for a healthy
      adjustment afterward.

PMID- 10356182
TI  - Reducing the Adverse Consequences of Adolescent Pregnancy and Parenting: The Role
      of Service Programs.
AB  - The optimal way to reduce the adverse consequences of adolescent childbearing and
      child rearing is to prevent conception or birth. However, no country has been
      able to prevent all such births, and it is likely that the U.S. will continue to
      experience high rates of teenage childbearing. Services such as those described
      herein must be provided to reduce the hazard to the mother and child, encourage
      adequate parenting by both parents, and reduce the burdens on welfare and other
      social services caused by adolescent parenting.

PMID- 10356184
TI  - Sexually Related Health Care for Developmentally Disabled Adolescents.
AB  - The authors elucidate the role of parents, educators, and health care providers
      in assisting adolescents with physical disabilities and/or mental retardation in
      understanding their sexuality and related issues such as contraception,
      gynecologic care, and sterilization.

PMID- 10356183
TI  - Sexual Behavior and Related Health Care for Adolescents with Chronic Medical
      Illness.
AB  - The authors review physical and psychosocial development in adolescents with
      chronic medical illness and the available data with regard to their sexual
      behavior. The relationship of various chronic diseases and their therapies to
      health-related outcomes of sexual behavior and the management of sexuality in
      adolescents with chronic illness are discussed.

PMID- 10356185
TI  - Inappropriate Sexual Behaviors: One Gynecologist's Viewpoint.
AB  - Sexual abuse, rape, date rape, prostitution, and pornography are discussed in
      terms of epidemiology, cultural and research issues, social and legal responses,
      physical and psychological consequences, treatment considerations, and
      prevention.

PMID- 10356186
TI  - Special Health Needs of Homosexual Youth.
AB  - The authors provide a developmental framework for understanding the psychosocial
      and medical problems that threaten the health of homosexual adolescents. Their
      special health needs are described and the role of health professionals in
      reaching and caring for them is outlined.

PMID- 10356187
TI  - Great Expectations: Overview of Adolescent Nutrition for the Year 2000 and
      Beyond.
AB  - Although in many respects American adolescents have never been healthier than
      they are today, expectations for future improvements must take into account
      cultural factors such as socioeconomic status, rural residence, and ethnic
      identity as well as specific issues associated with pregnancy, chronic illness,
      and eating disorders. Public health policy must address these concerns on the
      local, state, and federal levels.

PMID- 10356188
TI  - Adolescent Fitness.
AB  - Physical fitness testing and programs should address such basic elements as body
      composition, aerobic power, and strength. Current trends that encourage a
      sedentary lifestyle among adolescents (from entertainment to cutbacks in
      government physical education programs) must also be considered, with particular
      attention to populations suffering from chronic illness and disability, such as
      mental retardation, blindness, motor disabilities, and extreme obesity.

PMID- 10356189
TI  - Cultural Aspects of Nutrition in Adolescents.
AB  - By the year 2010, as many as 38% of American adolescents may belong to ethnic
      minorities. Nutritional education and counseling programs must take into account
      the diverse cultural patterns of Asian, Pacific Islander, Black, and Hispanic
      populations, all of whom may be divided into subgroups with varying dietary
      habits.

PMID- 10356190
TI  - The Vegetarian Adolescent.
AB  - Ecologic and philosophic as well as health concerns have led to an increasing
      number of adolescent vegetarians. The various types of vegetarianism differ
      substantially in dietary composition. Benefits of the vegetarian diet must be
      balanced by careful attention to ensuring adequate intake of protein and amino
      acids as well as certain vitamins and minerals that tend to be less available in
      plant foods.

PMID- 10356191
TI  - Nutrition for the Pregnant Adolescent.
AB  - In the U.S., 1 out of 10 women between the ages of 15 and 19 becomes pregnant.
      Maternal as well as infant health demands careful attention to adequate nutrition
      during pregnancy. But counseling programs must take into account both
      psychological and socioeconomic factors if optimal weight gain and other crucial
      factors are to be successfully managed in this growing population.

PMID- 10356192
TI  - Obesity in the Adolescent.
AB  - Obesity in childhood and adolescence represents a significant health problem.
      Factors involved may include social environment, genetic effects, and individual
      physiology. Effects on growth and pathophysiologic consequences such as
      hypertension and abnormal glucose tolerance must be addressed in diagnosis and
      treatment.

PMID- 10356193
TI  - Hyperlipidemia.
AB  - In the industrialized world coronary artery disease associated with high plasma
      cholesterol levels accounts for more death and disability than any other disease
      group. The various disorders that lead to hyperlipidemia often begin in childhood
      or adolescence. Early attention to these problems can reduce risk for mortality
      and morbidity in later life.

PMID- 10356194
TI  - Medical Complications of Anorexia and Bulimia Nervosa.
AB  - Medical complications of anorexia and bulimia nervosa may include metabolic,
      renal, gastrointestinal, cardiovascular, pulmonary, endocrinologic, neurologic,
      hematologic, immunologic, dental, and/or dermatologic effects. Patient evaluation
      and differential diagnosis must keep all of these possibilities in mind if the
      adolescent with an eating disorder is to be successfully treated.

PMID- 10356195
TI  - Amenorrhrea in Anorexia Nervosa: Etiology and Implications.
AB  - Amenorrhea is one of the necessary criteria for diagnosis of anorexia nervosa in
      female adolescents, but its exact pathophysiology remains controversial.
      Involvement of hyperthalamic dysfunction may be due to malnutrition or to an
      underlying neurotransmitter abnormality. The association of anorexia nervosa with
      both osteopenia and hypoestrogenemia gives clinical and therapeutic significance
      to an understanding of the underlying pathophysiology. The authors base
      recommendations for intervention on the current state of knowledge.

PMID- 10356196
TI  - Treatment and Outcome of Adolescents with Anorrexia Nervosa.
AB  - Primary care providers need to be aware of the therapeutic partnership required
      for successful treatment of adolescents with anorexia nervosa. This partnership,
      based on a biopsychological model, addresses multiple aspects of the disorder
      rather than isolated goals, such as weight gain. Early, established, and severe
      anorexia are discussed, as well as options for outpatient care and
      hospitalization and possible outcome.

PMID- 10356197
TI  - Nutrition Management in Adolescents with Eating Disorders.
AB  - Nutritional education and rehabilitation of the adolescent with an eating
      disorder is based on dietary history and analysis of eating behavior as well as
      laboratory tests and metabolic and anthropometric assessments. Treatment as well
      as diagnosis must take into account the distinctions between anorexia and bulimia
      nervosa.

PMID- 10356198
TI  - Adolescents in the Emergency Department: An Overview.
AB  - Because of their often multiple, complex, and time-consuming problems,
      adolescents often receive less than optimal care in the emergency room and
      represent for the physician a frustrating experience. This problem is compounded
      by the fact that for many adolescents visits to the emergency room are their only
      contact with the health-care system. An understanding of the psychosocial and
      developmental issues that characterize adolescence helps staff to respond more
      effectively and makes the emergency room "use-friendly" for the adolescent.

PMID- 10356199
TI  - Adolescent Trauma: Epidemiologic Approach.
AB  - Trauma caused by all types of injury is the leading reason for visits to the
      emergency department, hospital admission, and death among adolescents in the
      United States. Injury related to motor vehicles is the predominant killer,
      followed by homicide, suicide, drowning, and firearm accidents. In addition, the
      rate of injuries resulting from sports (both organized and unsupervised) and
      recreational activity increases throughout adolescence. The task for the
      physician in the emergency setting is not only to treat bodily damage but also to
      introduce the subject of prevention and to assess other injury risks for a given
      patient.

PMID- 10356200
TI  - Adolescent Chest Pain and Cardiac Emergencies.
AB  - Chest pain is a common problem among adolescents and often leads them to seek
      medical care. Although studies have shown that the complaint is rarely associated
      with severe illness, symptoms must be carefully assessed because they
      occasionally can be secondary to serious pathology and often cause major stress
      for the adolescent and his or her family.

PMID- 10356201
TI  - A Practical Approach to Nontraumatic, Nongynecologic Abdominal Pain in the
      Adolescent Patient.
AB  - Abdominal pain is a frequent complaint among adolescents presenting to the
      emergency department. Complete history, physical examination, and appropriate
      screening tests are the physician's major tools for differentiating the various
      etiologies. Although the physician often must be prepared to deal with
      uncertainty, the first priority is to recognize potentially life-threatening
      conditions and to institute appropriate consultations or therapies.

PMID- 10356202
TI  - Adolescent Urologic Emergencies.
AB  - The vast majority of adolescent genitourinary problems are treated effectively by
      a general urologist once the problem is recognized by the primary care or
      emergency physician. Male adolescents may present with acute scrotal pain, often
      accompanied by swelling, which constitutes one of the few true urologic
      emergencies. The first step is to rule out testicular torsion because gonadal
      salvage depends on rapid restoration of blood flow. Other urologic problems in
      male and female adolescents are also addressed.

PMID- 10356203
TI  - Adolescent Gynecologic Conditions Presenting in Emergency Settings.
AB  - What an adolescent patient and her parents define as a gynecologic emergency
      often proves to be merely a prolonged period. Nevertheless, because gynecologic
      complaints can be serious, each patient must be thoroughly evaluated. Common
      problems include dysfunctional uterine bleeding (mild, moderate, or severe),
      ectopic pregnancy, pelvic inflammatory disease, spontaneous abortion, and
      abdominal pain. Diagnosis and management of each of these conditions are
      discussed in detail.

PMID- 10356204
TI  - Adolescent Head and Neck Trauma.
AB  - Head injuries in adolescents, which often result from motor vehicle accidents,
      sports injuries, falls, burns, or trauma due to violence, may range from mild to
      severe to fatal. One of the most useful initial scoring systems is the Glasgow
      Coma Scale. Proper care of the injured adolescent begins at the scene of the
      incident, with an emphasis on management of the airways, breathing, and
      circulation (the ABCs) and prevention of secondary injury, which may result from
      hypoxia, hypercarbia, rapid swings in blood pressure, hypovolemia, seizures, and
      poor or improper immobilization. Monitoring and management of intracranial
      pressure become a priority on arrival at the emergency department. Imaging
      techniques, such as CT scan, may be necessary. Injuries to the neck (cervical
      spine), which may result in quadriplegia, should be suspected in the presence of
      neurologic deficits.

PMID- 10356205
TI  - Emergency Care of the Asthmatic Adolescent.
AB  - Asthma affects an estimated 5-10% of children in the United States. The incidence
      is highest in the first several years of life. Few new cases are diagnosed during
      adolescence, and many children with asthma improve during the teenage years.
      Likelihood of remission, however, is related to severity of disease; thus asthma
      remains a major cause of morbidity in affected adolescents. Almost 30% of
      adolescents with asthma experience some limitation of activity. The authors focus
      on differential diagnosis, pathophysiology, evaluation of the acute episode,
      treatment, and related issues such as smoking, pregnancy, and the effects of
      chronic illness on the developmental tasks of adolescence. A special emphasis is
      placed on asthma mortality, which has increased dramatically in the United States
      since 1979, primarily among nonwhite children of lower socioeconomic status. An
      estimated 1-2% of patients with severe asthma die from the disease.

PMID- 10356206
TI  - Adolescents with Insulin-Dependent Diabetes.
AB  - Although the basic pathophysiology of insulin-dependent diabetes remains
      unchanged, regardless of age, diabetes among adolescents is affected by certain
      biologic and psychosocial developments, such as reduced insulin sensitivity and
      compliance with treatment regimens. Emergent and urgent conditions associated
      with adolescent diabetes include hypoglycemia, ketoacidosis, abdominal pain,
      painful foot syndrome, eating disorders, and ophthalmologic problems. Diagnosis,
      etiology, and treatment of each are discussed in detail.

PMID- 10356207
TI  - Drug-related Coma in the Adolescent.
AB  - The poisoned and comatose adolescent presents numerous diagnostic and management
      problems. Often interventions must be performed before a specific diagnosis is
      made. A history may be impossible to obtain, thus forcing the physician to rely
      on physical findings, rapid diagnostic testing, and expectant supportive care.
      The first stage of treatment is stabilization, which involves basic and advanced
      life support, rapid assessment, presumptive substrate and antidotal therapy, and
      gastrointestinal decontamination. The second stage, definitive care, requires a
      careful history, detailed physical examination, and diagnostic studies tailored
      to narrow the possible etiologies. The authors describe each stage in detail,
      including evaluation and treatment, as well as discuss common toxic causes of
      coma in adolescents.

PMID- 10356208
TI  - Emergency Care of the Substance-abusing Adolescent.
AB  - Adolescents and young adults seem to be a particularly high risk for substance
      abuse, which is a problem of increasing significance in the United States. The
      most frequently used substances are tobacco and alcohol. The authors discuss
      intoxication, withdrawal, associated trauma, and medical complications. The final
      section focuses on emergent problems associated with other specific substances,
      including cocaine, phencyclidine, amphetamines, and volatile substances.
      Diagnosis and treatment are the major concerns, along with an emphasis on
      prevention.

PMID- 10356209
TI  - Emergencies in Adolescents: Life- and Limb-threatening Injuries.
AB  - This chapter focuses on life- and limb-threatening injuries that result from
      involvement in sports. Emphasis is on diagnosis and initial management of both at
      the playing site and in the emergency room. Life-threatening injuries include
      head and spinal cord trauma, cardiac emergencies, abdominal trauma, and heat
      stroke. Far more common are the limb-threatening emergencies that involve the
      elbow or knee.

PMID- 10356210
TI  - Psychological and Psychiatric Emergencies: Strategies for Providers.
AB  - Given the recent increase in suicide rate among adolescents, mental health
      concerns constitute an area in need of systematic evaluation. Common sources of
      psychological stress include family conflict, depression, sexual abuse and
      assault, and eating disorders. Any of these problems may result in visits to the
      emergency department. Important ingredients for successful diagnosis and referral
      include careful screening, basic family therapy skills, and sensitivity to
      treating adolescents with respect.

PMID- 10356211
TI  - Adolescent Medicine and Law.
AB  - The body of law governing the rights of adolescents and the corresponding duties
      of their physicians cannot be understood apart from the general body of health
      care law, upon which it is based. Obligations to young patients, however, are
      applied with special strictness. Federal, state and local legislation must be
      taken into account. Basic concepts include the right to medical care, creation
      and duration of the physician-patient relationship, abandonment by the physician,
      criteria for legally mandated quality of care, the right of consent, and
      confidentiality. Also included is a discussion of ethical standards imposed by
      professional organizations.

PMID- 10356212
TI  - Adolescent Substance Use and Addictions: Epidemiology, Current Trends, and Public
      Policy.
AB  - Although the proportion of high school seniors who use illicit drugs has declined
      from 54% in 1979 to 29% in 1991, substance use and addiction are still major
      problems among adolescents. The authors examine epidemiologic and demographic
      data for each of the major illicit drugs, focusing on relevant factors such as
      age, gender, educational plans, socioeconomic status, geographic region,
      population density, race, and ethnicity. This analysis leads to a discussion of
      policies that may further decrease the use of illicit drugs.

PMID- 10356213
TI  - Risk Factors and Risk Behaviors in Prevention of Adolescent Substance Abuse.
AB  - Although substance abuse is both preventable and treatable, few primary care
      physicians include its prevention or assessment in their routine practice. The
      authors examine strategies for identifying risk factors in adolescents, such as
      family history, persistent behavioral problems, failure at school, interpersonal
      alienation, and peer pressure. Also analyzed are both the opportunities and the
      barriers faced by physicians in the treatment of adolescent substance abuse.

PMID- 10356215
TI  - Office Assessment of Substance Abuse and Addiction.
AB  - Various factors prevent the primary care physician from implementing effective
      diagnosis, evaluation, and treatment of substance abuse among adolescents,
      including time constraints, practice styles, inadequate reimbursement, and
      physician discomfort. The author examines the positive outcomes of physician
      involvement as well as the negative consequences of noninvolvement and recommends
      strategies and resources to aid the primary care physician in coping with
      adolescents suspected of substance abuse.

PMID- 10356216
TI  - Alcohol and Adolescents.
AB  - Multiple studies show that 45-50% of adolescent victims of violent death have
      been drinking alcohol before the fatal incident. The authors examine the acute
      effects of alcohol on the brain and on behavior, discuss the types of teenage
      alcoholism, and then focus on specific issues such as patterns of inheritance,
      alcohol use during pregnancy, and fetal alcohol syndrome.

PMID- 10356214
TI  - Ethnic and Cultural Factors in Substance Abuse.
AB  - Health care providers must recognize the importance of multicultural training in
      any effective diagnostic, treatment, or prevention service for substance abuse
      among adolescents. Current estimates indicate that by the year 2020, minorities
      will constitute 40% of all school-age Americans. The authors examine the cultural
      differences among the four major ethnic groups-African Americans, Hispanic
      Americans, Asian/Pacific Islanders, and Native/Alaskan Americans-and then discuss
      the design of programs targeted at each.

PMID- 10356217
TI  - Adolescent Nicotine Use and Dependence.
AB  - Because regular, compulsive smoking usually begins in childhood or adolescence,
      pediatricians and other clinicians with adolescent patients have a unique
      opportunity to treat and prevent nicotine addiction before it causes lasting harm
      or death. The author examines the pharmacology, toxicity, and natural history of
      nicotine addiction as well as its relationship to other drug problems and methods
      of clinical management.

PMID- 10356218
TI  - Illicit Drugs of Abuse.
AB  - The authors discuss in detail the pharmacology and toxicity of illicit drugs that
      pose a major threat to adolescent health, including marijuana, cocaine,
      hallucinogens, opiates, inhalants, and designer drugs. The discussion of each
      drug concludes with guidelines for clinical management of adolescent users.

PMID- 10356219
TI  - Anabolic Steroid and Ergogenic Drug Use by Adolescents.
AB  - Enhancement of body image and improvement of athletic performance, with
      anticipated gains in self-esteem, are the major motives underlying adolescent use
      of anabolic steroids and ergogenic drugs. The authors discuss prevalence and
      availability, side effects and monetary cost, dependency and withdrawal
      syndromes, and clinical management of adolescent abusers.

PMID- 10356220
TI  - Testing for Drugs of Abuse: Controversies and Techniques.
AB  - Testing for drugs of abuse involves screening tests, designed for maximal
      sensitivity, and confirming tests, designed for maximal specificity. The author
      offers practical suggestions for testing, examines various procedures, reviews
      legal and ethical issues, and warns against common pitfalls.

PMID- 10356221
TI  - Treatment Issues in Adolescent Substance Use and Addictions: Options, Outcome,
      Effectiveness, Reimbursement, and Admission Criteria.
AB  - Cost-reduction strategies and a lack of overall perspective have created a
      potentially dangerous climate for the treatment of the various forms of
      adolescent substance abuse. The authors argue for a holistic approach that
      focuses on demographics, family issues, school functioning, and other related
      problems as well as on careful evaluation of treatment outcome and criteria for
      admission, continued stay, and discharge from treatment programs.

PMID- 10356222
TI  - Adolescents, Drugs, and the Media.
AB  - Although tobacco and alcohol involve a high rate of morbidity and mortality, both
      remain widely advertised in the media. After a review of research into the
      influence of television and advertisements and an overview of the policies of the
      tobacco and alcohol industries, the author proposes ten specific steps to
      minimize detrimental effects on adolescents, including a total ban on tobacco
      advertising in all media and on beer and wine advertising in the broadcast media.

PMID- 10356223
TI  - Influence of Drug Use on Adolescent Sexual Activity.
AB  - Because of the biopsychosocial events associated with adolescence, young people
      are at increased risk for engaging in risky behaviors that help them to cope with
      the transition into adulthood. The concept of covariation suggests that
      adolescents at risk for substance abuse are also at risk for unsafe sexual
      activity; both behaviors greatly compromise future well-being. The author
      examines the specific effects of various drugs on sexual behavior.

PMID- 10356224
TI  - Substance Misuse and Trauma: Clinical Issues and Injury Prevention in
      Adolescents.
AB  - This chapter explores the common ground shared by substance abuse specialists and
      clinicians involved in the treatment of physical injury and highlights the role
      of prevention initiatives in reducing adolescent trauma. Motor vehicle accidents,
      interpersonal violence, and suicide are related to substance abuse, and case
      studies are used to illustrate the potential efficacy of prevention strategies.

PMID- 10356225
TI  - Adolescent Children of Alcoholics.
AB  - Children from families with an alcoholic member are at increased risk of
      emotional, cognitive, behavioral, social, medical, and substance abuse problems.
      The authors review the characteristics of such children and the factors that
      increase their vulnerability; discuss the problems of codependency and enabling;
      and explore clinical presentations and treatment issues for both adolescent
      children of alcoholics and their families.

PMID- 10356226
TI  - Psychiatric, Developmental, and Adolescent Medicine Issues in Adolescent
      Substance Use and Abuse.
AB  - After an overview of the developmental goals of early, middle, and late
      adolescence, the authors discuss the demographics and patterns of comorbidity.
      The high incidence both of psychiatric symptoms in the substance-abusing
      population and of drug abuse in the psychiatric population complicates diagnosis
      and treatment of both disorders, especially when treatment services are separate,
      as in the public sector. The adolescent medicine physician can perform a valuable
      role in bridging the gap.

PMID- 10356227
TI  - Children, Adolescents, and the Media: Five Crucial Issues.
AB  - Television and other media represent the single most important modifiable
      influence on children and adolescents in the 1990s. Five issues are examined in
      this context: the extent to which the media influence children and adolescents;
      the varying susceptibility of children and adolescents to media influence; the
      validity of relevant research; strategies to improve the quality of the media;
      and the role of the primary-care physician.

PMID- 10356228
TI  - Media Violence: Q & A.
AB  - In a question-and-answer format, the authors survey the problem of violence in
      American television and movies. Central themes include the extent of violent
      content, the manner in which violence is portrayed, research methodology for
      studying the effects of violent content on children and adolescents, common myths
      related to the issue, and strategies for effecting change.

PMID- 10356229
TI  - Mass Media, Sex, and Sexuality.
AB  - The average age of first sexual intercourse, the high rate of teenage
      pregnancies, and the spread of sexually transmitted diseases indicate the extent
      to which sex and sexuality have created major threats to adolescent health. A
      crucial factor is the highly sexual content of the media. The authors examine
      factors that determine selection of and reaction to sexual content in the media,
      including gender and racial differences and family structure.

PMID- 10356230
TI  - Effects of Media Alcohol Messages on Adolescent Audiences.
AB  - Research into the effects of the media on teenage alcohol consumption has
      concentrated on positive portrayals of beer drinking in advertising, depiction of
      alcohol in movies and television programs, and public service announcements that
      warn against abuse and drunk driving. After examining each of these areas, the
      author focuses on the future role of messages related to alcohol consumption.

PMID- 10356231
TI  - Television, Obesity, and Eating Disorders.
AB  - Two national survey from the early 1960s indicate that the prevalence of obesity
      is directly related to the amount of time spent in viewing television in young
      people aged 6 to 17 years. The author discusses the mechanisms by which
      television affects obesity and other eating disorders.

PMID- 10356232
TI  - Sex Roles and Stereotyping on Television.
AB  - Gender-role images on television emphasize ideal body types and stereotypical
      patterns of behavior that influence the way in which adolescents view their peers
      of both sexes as well as themselves. The degree of change in society is not
      reflected in the content of television commercials or programs, which continue to
      reinforce traditional concepts of physical appearance, marriage, power, and
      occupational roles.

PMID- 10356233
TI  - Pornography's Impact on Male Adolescents.
AB  - Although some male adolescents may be harmed by exposure to pornography, little
      research addresses this issue directly, partly because of ethical and political
      restraints. The author discusses definitions of both pornography and harm as well
      as the extent and effect of exposure among male adolescents.

PMID- 10356234
TI  - Rock Music and Music Videos.
AB  - Sex, violence, sexual violence, drugs, suicide, satanic worship, and racism are
      common themes in modern rock lyrics. The authors examine their effect on
      adolescent development and identity, concluding with a discussion of the roles of
      parents and health care professionals in addressing the problem.

PMID- 10356235
TI  - Video Games.
AB  - The emergence of video games as a preferred leisure activity has spurred concern
      about their effect on adolescent behavior. After reviewing the available
      research, the author outlines prosocial applications of video games, considers
      future developments, and presents practical recommendations for players.

PMID- 10356236
TI  - Adolescents, Parenting, and the Media in the Twenty-First Century.
AB  - After analyzing the role of the media in perceptions of adolescence and
      parenting, the author contrasts the traditional concept of adolescent immaturity
      with the postmodern concept of adolescent sophistication. Ramifications for
      family structure and family ties are explored, along with recommendations for the
      future.

PMID- 10356237
TI  - Television and School Performance.
AB  - Although the question of whether television harms, helps, or has no effect on
      school performance has engaged researchers for many years, the answer remains
      elusive. Before-after studies and survey studies are controversial in terms of
      both interpretation and methodology. The author argues for integration of
      television into the curriculum to take advantage of its unique potential for
      democratization.

PMID- 10356238
TI  - Alcohol and Cigarette Advertising: A Legal Primer.
AB  - Legal precedent for the regulation of commercial speech makes clear that the
      First Amendment does not prohibit government control of alcohol and cigarette
      advertising. A review of federal legislation suggests that the problem lies with
      the political process rather than with constitutional prohibition.

PMID- 10356239
TI  - Killing Us Softly: Gender Roles in Advertising.
AB  - Recent years have brought an increasing awareness that advertising sells images
      of success, normalcy, sexuality, and love as well as specific products.
      Stereotypes of gender roles, reinforced through ideal images of physical beauty
      and body language, have negative effects on both men and women. The author
      concludes with a discussion of strategies for effecting change.

PMID- 10356241
TI  - Reply 

PMID- 10356240
TI  - Demographics and diagnosis of pyridoxine-dependent seizures.

PMID- 10356242
TI  - Reply 

PMID- 10356243
TI  - Respiratory effort with airway closure during mixed apneas.

PMID- 10356244
TI  - Functional genomics: An opportunity for bioengineers 

PMID- 10356245
TI  - Toward metabolic phenomics: analysis of genomic data using flux balances.
AB  - Small genome sequencing and annotations are leading to the definition of
      metabolic genotypes in an increasing number of organisms. Proteomics is beginning
      to give insights into the use of the metabolic genotype under given growth
      conditions. These data sets give the basis for systemically studying the genotype
      phenotype relationship. Methods of systems science need to be employed to
      analyze, interpret, and predict this complex relationship. These endeavors will
      lead to the development of a new field, tentatively named phenomics. This article
      illustrates how the metabolic characteristics of annotated small genomes can be
      analyzed using flux balance analysis (FBA). A general algorithm for the
      formulation of in silico metabolic genotypes is described. Illustrative analyses
      of the in silico Escherichia coli K-12 metabolic genotypes are used to show how
      FBA can be used to study the capabilities of this strain.

PMID- 10356246
TI  - Metabolic pathway analysis: basic concepts and scientific applications in the
      post-genomic era.
AB  - This article reviews the relatively short history of metabolic pathway analysis.
      Computer-aided algorithms for the synthesis of metabolic pathways are discussed.
      Important algebraic concepts used in pathway analysis, such as null space and
      convex cone, are explained. It is demonstrated how these concepts can be
      translated into meaningful metabolic concepts. For example, it is shown that the
      simplest vectors spanning the region of all admissible fluxes in stationary
      states, for which the term elementary flux modes was coined, correspond to
      fundamental pathways in the system. The concepts are illustrated with the help of
      a reaction scheme representing the glyoxylate cycle and adjacent reactions of
      aspartate and glutamate synthesis. The interrelations between pathway analysis
      and metabolic control theory are outlined. Promising applications for genome
      annotation and for biotechnological purposes are discussed. Armed with a better
      understanding of the architecture of cellular metabolism and the enormous amount
      of genomic data available today, biochemists and biotechnologists will be able to
      draw the entire metabolic map of a cell and redesign it by rational and directed
      metabolic engineering.

PMID- 10356247
TI  - Functional genomic technologies: creating new paradigms for fundamental and
      applied biology.
AB  - New technologies that analyze the behavior of thousands of genes in parallel are
      creating, for the first time, a foundation of data for building integrated models
      of cellular processes. This review discusses the general issues of utilizing
      genomic methods in fundamental and applied research settings, using the study of
      stress responses and improvement of secondary metabolite production as examples.
      A fusion of concepts from biological and nonbiological disciplines, including
      mathematics, computer science, physics, chemistry, and engineering, is required
      to address the theoretical and experimental challenges facing the field of
      genomics, and together promise great breakthroughs in our understanding and
      engineering of cellular systems.

PMID- 10356248
TI  - Proteomics: theoretical and experimental considerations.
AB  - Cellular engineering relies on the ability to decipher the genetic basis of
      various phenotypes. Emerging technologies for analyzing the biological function
      of the information encoded in the genome of particular organisms and/or tissues
      focus on the monitoring of transcription (mRNA) and translation (protein)
      processes. Elementary theoretical considerations presented in this article
      strongly suggest that a combination of mRNA and protein expression patterns
      should be simultaneously considered to fully develop a conceptual understanding
      of the functional architecture of genomes and gene networks. We propose a
      framework of experimental and mathematical methods for acquiring and analyzing
      quantitative proteomic information and discuss recent developments in proteome
      analytical technology.

PMID- 10356249
TI  - Design of mixing systems for plant cell suspensions in stirred reactors 
AB  - The properties of dense plant cell suspensions, such as high viscosity, shear
      sensitivity, cell aggregation, and tendency to foam, present significant
      technical challenges for bioreactor design and operation. As in all fermentation
      processes, reactors used for large-scale plant cell culture must provide adequate
      mixing and mass transfer at nondamaging levels of hydrodynamic shear. In stirred
      vessels, this means that the impeller must be operated with restricted power
      input and speed, while still achieving complete gas dispersion and solids
      suspension. Although many experimental studies of conventional and novel
      impellers have been carried out, no clear guidelines for impeller choice have
      emerged. In this paper, an engineering analysis is used to identify which
      agitators and operating regimes have greatest potential for high-density plant
      culture applications, irrespective of whether they have been tested
      experimentally. Ways of improving impeller performance by modifying internal
      reactor geometry are also discussed.

PMID- 10356250
TI  - Stable production of a human growth hormone antagonist from CHO cells adapted to
      serum-free suspension culture.
AB  - Human growth hormone (hGH) is a polypeptide with 191 amino acids and a molecular
      mass of 22 kDa. An hGH analogue was created with a single amino acid substitution
      (glycine[G] 120 to arginine[R]) in the third alpha-helix of the hGH molecule.
      This hGH analogue, named hGHG120R, was found to be an hGH antagonist. It is a
      parenteral drug candidate for treating conditions in which hGH levels are
      abnormally high, as found in type I diabetics. Previously, a genetically
      engineered anchorage-dependent mouse L cell line was created that produced and
      secreted hGHG120R in culture media (Dulbecco's modified Eagle's medium, DMEM)
      supplemented with 5% NuSerum IV. A multistep downstream process was developed to
      purify hGHG120R. The process consisted of cell clarification, salt precipitation,
      membrane ultrafiltration, size exclusion chromatography, reversed phase high
      performance liquid chromatography, phase separation, and lyophilization. Here, we
      present the development of a superior eukaryotic system using a proper
      combination of genetic elements, cell line, and media formulation. This system is
      suitable for the large-scale production of the recombinant protein and is
      superior to the previously developed system in that it increases the specific
      production rate and at the same time eases the burden of the purification
      process, in both time and efficiency. Dihydrofolate reductase mutant (DHFR-)
      Chinese hamster ovary (CHO) cells were used that were stably transfected with an
      expression vector in which the hGHG120R gene is driven by the relatively strong
      human cytomegalovirus-early gene regulatory region. The hGHG120R tested to be
      biologically active. These cells were then adapted to grow in suspension in CHO-S
      SFM (serum-free media). High cell densities, typically 2.0 x 10(6) cells/mL were
      obtained from spinner flask cultures. Partial purification of hGHG120R from CHO
      cell cultured media revealed that the level of impurities in SFM was
      significantly lower than the serum-supplemented DMEM. This suggests that the salt
      precipitation and the SEC step need not be employed in the purification of
      hGHG120R from SFM. This would result in a reduction of the operating time by 50 h
      and boost the recovery yield of hGHG120R to 75%.

PMID- 10356251
TI  - High-rate treatment of terephthalate in anaerobic hybrid reactors.
AB  - The anaerobic degradation of terephthalate as sole substrate was studied in three
      anaerobic upflow reactors. Initially, the reactors were operated as upflow
      anaerobic sludge bed (UASB) reactors and seeded with suspended methanogenic
      biomass obtained from a full-scale down-flow fixed film reactor, treating
      wastewater generated during production of purified terephthalic acid. The
      reactors were operated at 30, 37, and 55 degrees C. The terephthalate removal
      capacities remained low in all three reactors (<4 mmolxL-1xday-1, or 1 g of
      chemical oxygen demand (COD)xL-1xday-1) due to limitations in biomass retention.
      Batch experiments with biomass from the UASB reactors revealed that, within the
      mesophilic temperature range, optimal terephthalate degradation is obtained at 37
      degrees C. No thermophilic terephthalate-degrading culture could be obtained in
      either continuous or batch cultures. To enhance biomass retention, the reactors
      were modified to anaerobic hybrid reactors by introduction of two types of
      reticulated polyurethane (PUR) foam particles. The hybrid reactors were operated
      at 37 degrees C and seeded with a mixture of biomass from the UASB reactors
      operated at 30 and 37 degrees C. After a lag period of approximately 80 days, the
      terephthalate conversion capacity of the hybrid reactors increased exponentially
      at a specific rate of approximately 0.06 day-1, and high removal rates were
      obtained (40-70 mmolxL-1xday-1, or 10-17 g of CODxL-1xday-1) at hydraulic
      retention times between 5 and 8 h. These high removal capacities could be
      attributed to enhanced biomass retention by the development of biofilms on the
      PUR carrier material as well as the formation of granular biomass. Biomass
      balances over the hybrid reactors suggested that either bacterial decay or
      selective wash-out of the terephthalate fermenting biomass played an important
      role in the capacity limitations of the systems. The presented results suggest
      that terephthalate can be degraded at high volumetric rates if sufficiently long
      sludge ages can be maintained, and the reactor pH and temperature are close to
      their optima.

PMID- 10356252
TI  - Biotransformation and biodegradation of selected nitroaromatics under anaerobic
      conditions 
AB  - The fate of four nitroaromatic compounds (5-nitrosalicylate, 5NSA; 4
      nitrobenzoate, 4NBc; 2,4-dinitrotoluene, 2,4DNT; nitrobenzene, NB) was studied in
      160 mL laboratory-scale upward-flow anaerobic sludge bed reactors supplied with a
      mixture of volatile fatty acids and/or glucose as electron donors. All the
      nitroaromatics were transformed stoichiometrically to their corresponding
      aromatic amines. After prolonged reactor operation, 5NSA and 4NBc were completely
      mineralized to CH4 and CO2, whereas 2,4DNT was partially transformed to a
      nonidentified and nondegradable metabolite. Batch nitro-reduction experiments
      indicated that the position of the nitro group in relation to the other
      substituents in the aromatic ring plays a key role in the rate of the nitro-group
      reduction. The results obtained indicate that certain nitroaromatic compounds can
      be completely mineralized and serve as a carbon and energy source for anaerobic
      bacteria.

PMID- 10356253
TI  - Immobilization of highly concentrated cell suspensions using the laminar jet
      breakup technique 
AB  - The controlled breakup of a disturbed jet is a well-known technique for
      monodisperse particle production and has been well-investigated for Newtonian and
      viscoelastic fluids. For the immobilization of cells in beads of a hydrogel it
      has been observed that there is a maximum cell concentration beyond which a
      monodisperse bead distribution cannot be reached. Higher concentrations lead to
      irregular jet breakup and thus to droplet coalescence forming beads with double
      or triple volume. This maximum cell concentration has been investigated for
      different operating conditions using latex beads of different diameters as a
      model substance for cells and baker's yeast as a comparison. The maximum cell
      concentration where a monodisperse size distribution could still be achieved was
      increased using an electrostatic droplet dispersion system.

PMID- 10356254
TI  - Model simulation and analysis of perfusion culture of mammalian cells at high
      cell density.
AB  - Rate equations recently proposed by the authors for growth, death, consumption of
      nutrients, and formation of lactic acid, ammonium, and monoclonal antibody of
      hybridoma cells are used to simulate and analyze the behavior of perfusion
      cultures. Model simulations are in good agreement with experimental results from
      three different cell lines under varied perfusion and cell bleed rates except for
      cultures with very low viability. Analysis of simulations and experimental
      results indicates that in perfusion cultures with a complete cell separation cell
      bleed rate is a key parameter that strongly affects all the process variables,
      whereas the perfusion rate mainly affects the total and viable cell
      concentrations and the volumetric productivity of monoclonal antibody. Growth
      rate, viability, and specific perfusion rate of cells are only a function of the
      cell bleed rate. This also applies to cultures with partial cell separation in
      the permeate if the effective cell bleed rate is considered. It is suggested that
      the (effective) cell bleed rate of a perfusion culture should be carefully chosen
      and controlled separately from the perfusion rate. In general, a low cell bleed
      rate that warrants a reasonable cell viability appears to be desirable for the
      production of antibodies. Furthermore, model simulations indicate the existence
      of an optimum initial glucose concentration in the feed. For the cell lines
      considered, the initial glucose concentration used in normal cell culture media
      is obviously too high. The initial glutamine concentration can also be reduced to
      a certain extent without significantly impairing the growth and antibody
      production but considerably reducing the ammonia concentration. The mathematical
      model can be used to predict these optimum conditions and may also be used for
      process design.

PMID- 10356255
TI  - Construction of a thread coater and use of azocasein release To characterize the
      sealant coat porosity of fibers coated with latex biocatalytic coatings 
AB  - A single-stage annular fiber coating method with co-current dry-air drying at 30
      degrees C has been developed for multilayer coating of 128 &mgr;m diameter
      polyester thread (yarn) with latex films as a model for enzyme immobilization and
      development of a filament biocatalytic filter. Acrylic vinyl acetate polymer
      coatings were sequentially metered onto the fibers by the combination of a
      flexible squeegee and a red rubber annulus. The thread coater can operate over a
      range of 0.07-1.37 m/min thread velocities while delivering a nearly constant and
      reproducible polymer loading of 30. 8 +/- 1.3 mg/m. A 100% polyester, 278.9
      denier thread was precoated with latex to generate an approximately 369 denier
      sealed filament. The filament was then coated with a latex + sulfanilamide
      azocasein mixture and sealed with a polymer top coat. The permeability of the
      polymer sealant top coat was characterized using entrapped azocasein as a tracer
      molecule and monitoring the azocasein release upon rehydration of the coated
      threads. Azocasein release rate decreased with curing time at 30 degrees C until
      2 days and was invariant after 2-3 days of curing. A 282 mOsm rehydrating
      solution was sufficient to suppress increased azocasein release due to top coat
      blistering. No enhancement in the permeability of the top coat was observed when
      high molecular weight water soluble polymers (WSPs) were used as fillers. This
      probably results from the low WSP to latex ratio used (0.05-0.1) and the slow
      rate of WSP leaching compared to the release of azocasein. A method using 60-120
      mesh silica was also developed to study the effect of mechanical abrasion of the
      coated threads as measured by azocasein release kinetics.

PMID- 10356256
TI  - Constrained cell recognition peptides engineered into streptavidin.
AB  - Streptavidin is widely used as an adaptor molecule in diagnostics, separations,
      and laboratory assay applications. We have here engineered cell adhesive peptides
      into the three-dimensional scaffolding of streptavidin to convert streptavidin
      into a functional protein. The mutations did not alter refolding or tetramer
      assembly and the slow biotin dissociation rate of wild-type streptavidin was
      retained. The peptide targets were hexapeptide sequences derived from osteopontin
      and fibronectin that contain the RGD cell adhesion sequence. Cell binding assays
      directly demonstrated that rat aortic endothelial cells and human melanoma cells
      adhered to surfaces coated with either of the two RGD streptavidin mutants in a
      dose-dependent fashion. Wild-type streptavidin displayed no significant cell
      binding activity. Inhibition studies with soluble RGD peptides confirmed that the
      cell adhesion was RGD mediated. Further inhibition studies with antibodies
      directed against alphavbeta3 demonstrated that the RGD-streptavidin interaction
      was primarily mediated by this integrin with melanoma cells. These results
      demonstrate that peptide recognition sequences can be engineered into accessible
      surface regions of streptavidin without disrupting biotin binding properties.
      This approach to introducing secondary functional activities into streptavidin
      may improve streptavidin's utility in existing applications or provide new
      technology opportunities.

PMID- 10356258
TI  - Metabolic engineering from a cybernetic perspective. 1. Theoretical preliminaries
AB  - The theoretical basis of a cybernetic metabolic network design and analysis
      framework, which has been subsequently successfully applied to predict system
      response to genetic alteration, is presented. This conceptual methodology
      consists of three main branches, namely, a model realization framework, a
      representation of genetic alteration, and lastly, a metabolic design component.
      These concepts are introduced as a series of postulates that describe the basic
      tenets of the approach. Each branch is discussed in turn, starting with the
      cybernetic representation of arbitrarily complex metabolic networks. A set of
      postulates is put forth that affords the modular construction of cybernetic
      models of metabolic networks using as a base a library of elementary pathways.
      This is followed by a discussion of the representation of genetic alterations
      within the cybernetic framework. It is postulated that the objective of the base
      network and the altered system are identical (at least on the time scale required
      for the organism to "learn" new objectives). This implies, with respect to
      resource allocation, that the base network and its genetically altered
      counterpart may still be treated as optimal systems; however, the set of
      competing physiological choices open to the altered network expands or contracts
      depending upon the nature of the genetic perturbation. Lastly, to add a
      predictive design aspect to the methodology, we present a set of postulates that
      outline the application of metabolic control analysis to cybernetic model
      systems. We postulate that sensitivity coefficients computed from a cybernetic
      model, although still local in scope, have the added benefit of a systematic
      representation of regulatory function as described by the cybernetic variables.
      Thus, information gained from sensitivity measurements stemming from a cybernetic
      model include the explicit input of metabolic regulation, a component that is
      lacking in a purely kinetic representation of metabolic function. The sensitivity
      results can then be employed to develop qualitative strategies for the rational
      alteration of metabolic function, which can be evaluated by simulation of an
      appropriately modified cybernetic model of the base network.

PMID- 10356257
TI  - Differential inhibition of retrovirus transduction by proteoglycans and free
      glycosaminoglycans.
AB  - We have previously shown that the efficiency of retrovirus-mediated gene transfer
      is limited in part due to the presence of chondroitin sulfate proteoglycans in
      virus stocks. In this study, we have used a model recombinant retrovirus encoding
      the Escherichia coli lacZ gene, bovine aorta chondroitin sulfate proteoglycan
      (CSPG), various free glycosaminoglycan chains (GAGs), and quantitative assays for
      retrovirus transduction to explore the mechanism by which proteoglycans and
      glycosaminoglycans inhibit retroviruses. We found that CSPG and GAGs block an
      early step in virus-cell interactions but do not act by inactivating viruses or
      by reducing the growth rate of the target cells. CSPG and most of the GAGs tested
      (chondroitin sulfate A, chondroitin sulfate B, heparin, heparan sulfate, and
      hyaluronic acid) inhibited transduction, but with widely varying degrees of
      activity. The chemical structure of GAGs was found to be an important determinant
      of their inhibitory activity, which suggests that GAGs do not inhibit
      transduction simply because they are highly negatively charged polymers. When
      GAGs were used in combination with a cationic polymer (Polybrene), however, their
      inhibitory activity was neutralized, and interestingly, at optimal doses of GAG
      and Polybrene, transduction efficiency was actually enhanced by as much as 72%.
      In contrast, the inhibitory activity of CSPG, due to the influence of its core
      protein, was not substantially reduced by Polybrene. The importance of these
      findings to our understanding of retrovirus-cell interactions and to the
      development of more efficient retrovirus gene transfer protocols is discussed.

PMID- 10356259
TI  - Metabolic engineering from a cybernetic perspective. 2. Qualitative investigation
      of nodal architechtures and their response to genetic perturbation 
AB  - A cybernetic representation of the branch point development of Stephanopoulos and
      Vallino is formulated. The model systems are employed to translate the
      qualitative properties of the nodal control architectures characterized by
      Stephanopoulos and Vallino into a mathematical context. It is shown that a
      cybernetic model in which the objective is the independent maximization of the
      levels of branch point products is consistent with the characterization of a
      flexible node. In contrast, the rigid control architecture is shown to be
      equivalent to the maximization of the mathematical product of the branch point
      products. It has been demonstrated subsequently that cybernetic metabolic network
      models are capable of predicting the system response to enzymatic amplification.
      However, given the complicated nature of the subsequent models, a clear
      illustration of the basic mechanism by which such predictions are manifested is
      not forthwith. Thus, a second objective of the present work is the examination of
      the response of the flexible and rigid control architectures to genetic
      perturbation, specifically enzymatic overexpression, with the expressed aim of
      elucidating the mechanism by which a cybernetic model predicts metabolic network
      responsiveness. It is shown that the ramifications of genetic perturbation are
      transmitted through the cybernetic representation of a metabolic network via the
      resource allocation structure which acts as the conduit by which regulatory
      signals are transmitted to seemingly unconnected portions of the network. It is
      postulated that enzymatic overexpression under an artificial promoter represents,
      from the perspective of the microorganism, an uncontrollable resource drain that
      forces the metabolic network control architecture to reevaluate the standing
      resource allocation policy as implemented via the cybernetic control variables.
      In biological terms, the reevaluation of allocation policy implies a shift in the
      level and activity of network enzymes yielding, in some cases, qualitatively
      different network function. It is our position that, conceptually, this is
      equivalent to the conventional wisdom that genetic manipulation of a metabolic
      network is the impetus for shifts in the network functionality, i.e., enzyme
      levels as well as activity. Thus, this development provides a necessary
      intellectual precursor for the formulation and analysis of the model systems that
      follow.

PMID- 10356260
TI  - Effect of SecB chaperone on production of periplasmic penicillin acylase in
      Escherichia coli.
AB  - The effect of SecB chaperone on production of periplasmic penicillin acylase
      (PAC) in Escherichia coli was investigated. It appears that formation of PAC
      required the function of SecB chaperone and the amount of SecB required was at a
      basal level. The secB mutant was defective in production of PAC, and the
      impairment could be complemented by extrachromosomally supplementing SecB in
      trans. The function of SecB might be primarily stabilizing the cytoplasmic PAC
      precursors. Overproduction of SecB chaperone usually resulted in an increase in
      the amount of PAC precursors without enhancing PAC activity. In addition, most of
      the PAC precursors were located in the periplasm, suggesting that formation of
      active PAC was likely limited by periplasmic processing steps.

PMID- 10356261
TI  - Effect of the nitrogen source on pyruvate content and rheological properties of
      xanthan 
AB  - Batch and fed batch cultivations of Xanthomonas campestris with varying amounts
      of the N source (NH4Cl) yield xanthan polymers which differ in pyruvate content.
      Analyzing the rheological properties of the xanthans produced exhibits that it is
      not only the molecular mass but also the pyruvate content that affects the
      viscosity of xanthan solutions. However, there is obviously no simple functional
      dependency but rather a step increase in viscosity when going from below 2 to
      above 3 wt % of pyruvate.

PMID- 10356262
TI  - Enhanced conversion rate of L-phenylalanine by coupling reactions of
      aminotransferases and phosphoenolpyruvate carboxykinase in Escherichia coli K-12.
AB  - In Escherichia coli, aspartate aminotransferase (encoded by aspC) and aromatic
      amino acid aminotransferase (encoded by tyrB) share overlapping substrate
      specificity in the syntheses of aromatic amino acids. Through the transamination
      reactions catalyzed by AspC or TyrB, L-phenylalanine (L-Phe) can be produced from
      phenylpyruvate with aspartic acid as the amino donor. To modulate and enhance the
      production levels of proteins, both aspC and tyrB were subcloned into a runaway
      replication vector. As a result, the specific activities of AspC and TyrB
      obtained showed 65-fold and 50-fold increases, respectively, compared with the
      wild-type level. Employing resting cells of AspC- and TyrB-overproducing E. coli
      K-12 strains for L-Phe productions resulted in molar conversion yields of 70% and
      55%, respectively. With an additional introduction of phosphoenolpyruvate
      carboxykinase (encoded by pck) into the transamination reactions, the conversion
      yields were improved to 93% from 70% and to 75% from 55% in a relatively short
      time. These results account for more than an 8-fold increase in productivity, as
      compared to the previous report (Calton et al., 1985). In addition, a four-run
      reuse of the recombinant cells for L-Phe production gave a total yield of 91 g/L
      with a 93% conversion.

PMID- 10356263
TI  - Stable high-copy-number integration of Aspergillus oryzae alpha-AMYLASE cDNA in
      an industrial baker's yeast strain.
AB  - The Aspergillus oryzae alpha-amylase cDNA was placed under the control of the
      Saccharomyces cerevisiae actin promoter (pACT1) and introduced into the ribosomal
      DNA locus of an industrial baker's yeast strain. To obtain a strain eligible for
      commercial use, we constructed an integrative cassette lacking bacterial DNA
      sequences but containing the alpha-amylase cDNA and ribosomal DNA sequences to
      target the integration to this locus. High-copy-number integrants were obtained
      including a defective TRP1d promoter in the integrative cassette. We selected one
      transformant, Rib-AMY (CECT10872), in which the multi-integrated sequences were
      stable even after 200 generations of growth in nonselective medium. This
      transformant also expressed and secreted high levels of alpha-amylase. Bread made
      with this strain had a higher volume, lower density, and softer crumbs than bread
      made with a control strain. The Rib-AMY transformant also was useful in retarding
      bread firming. This new strain fulfills all the requirements for commercial
      utilization and should reduce or eliminate the requirement for addition of
      exogenous alpha-amylase to the flour, reducing allergenic work-related symptoms
      due to this enzyme.

PMID- 10356264
TI  - Functional expression of horseradish peroxidase in E. coli by directed evolution.
AB  - In an effort to develop a bacterial expression system for horseradish peroxidase
      (HRP), we inserted the gene encoding HRP into the pET-22b(+) vector (Novagen) as
      a fusion to the signal peptide PelB. A similar construct for cytochrome c
      peroxidase (CcP) leads to high CcP activity in the supernatant. Expression of the
      wild-type HRP gene in the presence of isopropyl-beta-D-thiogalactopyranoside
      (IPTG) yielded no detectable activity against ABTS (azinobis(ethylbenzthiazoline
      sulfonate)). However, weak peroxidase activity was detected in the supernatant in
      the absence of IPTG. The HRP gene was subjected to directed evolution: random
      mutagenesis and gene recombination followed by screening in a 96-well microplate
      format. From 12 000 clones screened in the first generation, one was found that
      showed 14-fold higher HRP activity than wild-type, amounting to approximately 110
      microg of HRP/L, which is similar to that reported from laborious in vitro
      refolding. No further improvement was obtained in subsequent generations of
      directed evolution. This level of expression has nonetheless enabled us to carry
      out further directed evolution to render the enzyme more thermostable and more
      resistant toward inactivation by H2O2. These results show that directed evolution
      can identify mutations that assist proteins to fold more efficiently in
      Escherichia coli. This approach will greatly facilitate efforts to "fine-tune"
      those many enzymes that are promising industrial biocatalysts, but for which
      suitable bacterial or yeast expression systems are currently lacking.

PMID- 10356265
TI  - Effects of added yeast on protein transmission and flux in cross-flow membrane
      microfiltration 
AB  - Microfiltration membranes may be used to separate valuable proteins from
      suspensions containing cells or cell debris. Although a clean microfiltration
      membrane allows for complete protein transmission and high flux, both of these
      quantities decline in time due to membrane fouling. Using bovine serum albumin
      (BSA) as a model protein, flux and protein transmission during cross-flow
      microfiltration were studied with and without added yeast cells. Cross-flow
      microfiltration of BSA-only solutions results in a BSA fouling layer with low
      permeability forming on the membrane surface. Due to this layer, the long-term
      BSA transmission is typically only 25-40%. In contrast, during microfiltration of
      yeast-BSA mixtures, the yeast forms a cake layer on the membrane surface. The
      yeast cake acts as a dynamic or secondary membrane, allowing BSA monomers to pass
      through but preventing protein aggregates from fouling the membrane. The result
      is slower flux decline and higher long-term BSA transmission of typically 60-90%.
      For filtration of yeast-BSA mixtures at low yeast concentrations (<1 g/L), 50
      100% higher BSA recovery is obtained than for BSA-only solutions with the same
      BSA concentration. At high yeast concentrations (>5 g/L), the protein
      transmission remains high, but the recovery may be lower due to reduced flux.

PMID- 10356266
TI  - Oxidative refolding of Denatured/Reduced lysozyme utilizing the chaperone-like
      function of liposomes and immobilized liposome chromatography 
AB  - Oxidative refolding of the denatured/reduced lysozyme was examined in the
      presence of small unilamellar vesicles (SUVs) essentially composed of 1-palmitoyl
      2-oleoyl-sn-glycero-3-phosphocholine (POPC). SUVs facilitated the recovery of the
      enzymatic activity of lysozyme like molecular chaperones through the interaction
      with the refolding intermediate of lysozyme. The highest reactivation yield (87%)
      was obtained by delaying oxidation time (15-30 s) after dilution of the
      denaturant concentration was initiated in the presence of SUVs. SUVs supplemented
      with 1 mol % phosphatidylethanolamine were covalently coupled to gel beads, and
      then the interactions of SUVs with lysozyme at the various conformations were
      quantitatively examined with immobilized liposome chromatography (ILC). The
      reduced lysozyme lacking disulfide bonds was found to have a property similar to
      that of the molten globule state in terms of its local hydrophobicity, which was
      determined with the aqueous two-phase partitioning method. The reduced lysozyme
      was more clearly retarded on the ILC column than the native and 1 M guanidinium
      hydrochloride (GuHCl)-treated lysozymes with intact disulfide bonds. Similar
      results were obtained for alpha-lactalbumin, which has three-dimensional
      structure closely similar to that of lysozyme, regarding the membrane-protein
      interaction. These results can be interpreted as follows. In the early stage of
      the oxidative refolding, liposomes bound to the refolding intermediate of
      lysozyme lacking disulfide bonds. Then, liposomes assisted the formation of the
      tertiary structure of lysozyme by reducing protein intermolecular interactions,
      which usually cause the formation of the inactive aggregates. Consequently, the
      correct formation of the disulfide bonds was promoted. On the basis of the above
      results, the chromatographic oxidative refolding was also examined with ILC. The
      denatured/reduced lysozyme (9 mg/mL, 10 &mgr;L) was passed through the ILC column
      with a flow rate of 1 mL/min, which corresponds to the retention of lysozyme
      about 1 min in the ILC column. Subsequent oxidation of the eluted lysozyme
      resulted in the almost complete recovery (100%) of the original enzymatic
      activity of lysozyme.

PMID- 10356267
TI  - Strategies for recombinant protein recovery from canolaby precipitation 
AB  - Transgenic plants may prove to be one of the most economical systems for the
      large-scale production of proteins and peptides. Our goal is to develop an
      approach for protein recovery from canola that will be adaptable to a wide
      variety of recombinant proteins. For recombinant protein recovery, the two
      downstream processes considered were extraction of target protein and
      purification of recombinant protein from host proteins and other impurities. In
      these experiments, T4 lysozyme has been added to the canola extracts as an
      example protein to simulate recovery of recombinant proteins while evaluating the
      merits of several candidate precipitation strategies to understand selectivity
      behavior and how it might be affected by the presence of canola components. The
      ability of precipitating agents, such as acid and the polyelectrolytes Glass H
      and poly(acrylic acid) (PAA), was investigated. Approximately 70% of extracted
      canola proteins were precipitated by acid addition to pH 5, leaving about 90% of
      T4 lysozyme still in solution. Targeting T4 lysozyme for the precipitate phase by
      addition of oppositely charged polyelectrolyte was not successful in the presence
      of canola components. Addition of 2.5 times the PAA dosage required to
      precipitate pure T4 lysozyme to the spiked canola extract brought down only 40%
      of the T4 lysozyme. For the comparable result with Glass H, a 9 times higher
      dosage was required.

PMID- 10356269
TI  - Protein adsorption onto tentacle cation-exchange hollow-fiber membranes 
AB  - A sulfonic group (up to 200 &mgr;mol/mL) membrane was incorporated to epoxy
      activated microporous hollow fibers to obtain high-capacity convective ion
      exchangers. The pure water flux through the membrane decreased exponentially with
      sulfonic group density and protein binding capacity increased accordingly. At
      sulfonic group density of 70 &mgr;mol/mL, the membrane lysozyme maximum binding
      capacity was 84 +/- 9 mg/mL in comparison with its theoretical monolayer maximum
      binding capacity of 20 mg/mL, thus evidencing tentacle formation. After a cycle
      of adsorption in a 30 mM sodium phosphate buffer, pH 7. 0, adsorbed lysozyme
      could be quantitatively recovered following elution with 0.5 M NaCl in the same
      buffer. Dynamic capacity for lysozyme was 67% of maximum binding, and this value
      did not change at space velocities ranging from 10 to 40 min-1 as shown by the
      superimposition of the corresponding breakthrough curves. A cartridge assembled
      with 21 fibers showed a dynamic-to-static capacity ratio for lysozyme of 0.60
      with 1 mg/mL pure lysozyme solution, and 0.42 with a particulate feed composed of
      1 mg/mL lysozyme and 0.1 mg/mL yeast.

PMID- 10356268
TI  - Aqueous two-phase systems containing urea: influence on phase separation and
      stabilization of protein conformation by phase components.
AB  - During recombinant Escherichia coli fermentation with high expression levels,
      inclusion bodies are often formed. Aqueous two-phase systems have been used in
      the presence of urea for the initial recovery steps. To investigate phase
      behavior of such systems we determined phase diagrams of poly(ethylene glycol)
      (PEG)/sodium sulfate/urea/water and PEG/dextran T-500 (DEX)/urea/phosphate
      buffer/water at different concentrations of urea and different molecular weight
      of PEG. PEG/Na2SO4 aqueous two-phase systems could be obtained including up to
      30% w/w urea at 25 degrees C and PEG/dextran T-500 up to 35% w/w urea. The
      binodial was displaced toward higher concentrations with increasing urea
      concentrations. The partition coefficient of urea was near unity. An unstable
      mutant of T4-lysozyme with an amino acid replacement in the core (V149T) was used
      to analyze the effect of phase components on the conformation of the enzyme. We
      showed that partitioning of tryptophan was not dependent on the concentration of
      urea in the phase system.

PMID- 10356270
TI  - Protein separation using affinity-based reversed micelles 
AB  - Reversed micellar two-phase extraction is a developing technique for protein
      separation. Introduction of an affinity ligand is considered to be an effective
      approach to increase the selectivity and capacity of reversed micelles. In this
      article, Cibacron Blue F3G-A (CB) as an affinity ligand was immobilized to
      reversed micelles composed of soybean lecithin by a two-phase reaction. The
      affinity partitioning of lysozyme and bovine serum albumin (BSA) to the CB
      lecithin micelles was studied. Formation of mixed micelles by additionally
      introducing a nonionic surfactant, Tween 85, to the CB-lecithin micelles was
      effective to increase the solubilization of lysozyme due to the increase of W0
      (water/surfactant molar ratio)/micellar size. The partitioning isotherms of
      lysozyme to the CB-lecithin micelles with and without Tween 85 were expressed by
      the Langmuir equation. The dissociation constants in the Langmuir equation
      decreased on addition of Tween 85, indicating the increase of the effectiveness
      of lysozyme binding to the immobilized CB. On addition of 20 g/L Tween 85 to 50
      g/L lecithin/hexane micellar phase containing 0.1 mmol/L CB, the extraction
      capacity for lysozyme could be increased by 42%. Moreover, the CB-lecithin
      micelles with or without Tween 85 showed significant size exclusion for BSA due
      to its high molecular weight. Thus, lysozyme and BSA were separated from
      artificial solutions containing the two proteins. In addition, the affinity-based
      reversed micellar phase containing Tween 85 was recycled three times for lysozyme
      purification from crude egg-white solutions. Lysozyme purity increased by 16-18
      fold, reaching 60-70% in the recycled use.

PMID- 10356272
TI  - Organophosphorus hydrolase-based assay for organophosphate pesticides 
AB  - We report a rapid and versatile organophosphorus hydrolase (OPH)-based method for
      measurement of organophosphates. This assay is based on a substrate-dependent
      change in pH at the local vicinity of the enzyme. The pH change is monitored
      using fluorescein isothiocyanate (FITC), which is covalently immobilized to the
      enzyme. This method employs the use of poly(methyl methacrylate) beads to which
      the FITC-labeled enzyme is adsorbed. Analytes were then measured using a
      microbead fluorescence analyzer. The dynamic concentration range for the assay
      extends from 25 to 400 &mgr;M for paraoxon with a detection limit of 8 &mgr;M.
      Organophosphorus insecticides measured using this technique included
      ethylparathion, methylparathion, dursban, fensulfothion, crotoxyphos, diazinon,
      mevinphos, dichlorvos, and coumaphos. This technique was used to measure
      coumaphos in biodegradation samples of cattle dip wastes and showed a high
      correlation (r2 = 0.998) to an HPLC method.

PMID- 10356271
TI  - Purification of recombinant proteins based on the interaction between a
      phenothiazine-derivatized column and a calmodulin fusion tail.
AB  - A method to purify proteins by fusing them to the Ca2+-dependent protein
      calmodulin is described by using glutathione-S-transferase (GST) from Schistosoma
      japonicum as a model. Glutathione-S-transferase was genetically fused to
      calmodulin (CaM). The designed GST-CaM fusion protein has a selective factor Xa
      cleavage site located between the C-terminus of GST and the N-terminus of CaM.
      The recombinant fusion protein was expressed in Escherichia coli, and the crude
      cell extract was loaded onto a phenothiazine affinity column in the presence of
      Ca2+. Calmodulin was used as an affinity tail to enable binding of the fusion
      protein to the phenothiazine column. Removal of Ca2+ with a calcium-complexing
      solution causes elution of the fusion protein. The GST-CaM fusion protein was
      then digested with factor Xa, and the target protein GST was isolated. The purity
      of the isolated GST was verified by sodium dodecyl sulfate polyacrylamide gel
      electrophoresis (SDS-PAGE).

PMID- 10356273
TI  - Quartz crystal microbalance measurement of self-assembled micellar tubules of the
      amphiphilic decyl ester of D-tyrosine and their enzymatic polymerization.
AB  - Amphiphilic decyl derivatives of D-tyrosine self-assemble into long rodlike or
      tubular aggregate structures in aqueous buffered solution. In this report we
      demonstrate the novel use of the quartz crystal microbalance (QCM) to measure the
      presence in solution, and subequent enzymatic polymerization, of long rodlike
      monomer aggregates of the decyl ester of D-tyrosine (DEDT) as a function of their
      formation and increasing surface binding level as pH values increase from 3 to 7.
      From these data, using the Sauerbray equation to calculate the effective elastic
      mass surface binding of deprotonated DEDT aggregates, a pKapp of 8.3 is obtained
      for the DEDT alpha-NH2 group protonation-deprotonation and subsequent aggregation
      equilibrium. Furthermore, once aggregates are bound to the QCM surface, we
      initiate and subsequently monitor enzymatic polymerization of the DEDT monomers
      by horseradish peroxidase through the measurement of significant changes in the
      quartz crystal frequency and motional resistance. Following the onset of
      polymerization, the viscoelastic properties of the bound monomer aggregates
      change. A final polymerized state is achieved in which the altered physical
      properties of the polymerized rodlike aggregates make the solution immediately
      above the QCM surface-solution interface behave as a Newtonian fluid, producing a
      nearly pure viscosity-density energy dissipative effect on the measured crystal
      frequency and motional resistance values.

PMID- 10356274
TI  - In situ monitoring of an escherichia coli fermentation using a diamond
      composition ATR probe and mid-infrared spectroscopy 
AB  - A diamond composition ATR probe was used in situ to obtain IR spectra on
      replicate Escherichia coli fermentations involving a complex medium. The probe
      showed excellent stability over a 6-month operating period and was unaffected by
      either agitation or aeration. The formation of an unknown was observed from IR
      spectra obtained during the sterilization; subsequent experiments proved this to
      be a reaction product between yeast extract and the phosphates used as buffer
      salts. Partial-least-squares-based calibration/prediction models were developed
      for both glucose and acetate using in-process samples. The resulting models had
      prediction errors of +/-0.26 and +/-0.75 g/L for glucose and acetic acid,
      respectively, errors which were statistically equivalent to the estimated
      experimental errors in the reference measurements. Relative concentration
      profiles for the unknown formed during sterilization could be generated either by
      tracking peak height at an independent wavelength or by self-modeling curve
      resolution of the spectral region overlapping that of glucose. These profiles
      indicated that this compound was metabolized simultaneously with glucose; upon
      depletion of the glucose, when the microorganism switched to consumption of
      acetic acid, utilization continued but at a lower rate. The data presented
      provide an extensive characterization of the performance characteristics of this
      in situ analysis and clearly demonstrate its utility not just in the quantitative
      measurement of multiple known species but in the qualitative evaluation of
      unknown species.

PMID- 10356275
TI  - Use of in vitro data for construction of a physiologically based pharmacokinetic
      model for naphthalene in rats and mice to probe species differences.
AB  - A physiologically based pharmacokinetic (PBPK) model with five tissue groups
      (lung, liver, fat, richly perfused, and poorly perfused tissues plus venous and
      arterial blood compartments) has been developed from in vitro data and models of
      primary cell cultures for naphthalene toxicity in mice and rats. It extends a
      previous naphthalene PBPK model (Sweeney et al., 1996) and demonstrates a
      possible approach to a predictive mathematical model that requires minimal animal
      data. Naphthalene metabolism was examined after four exposure routes
      (intraperitoneal injection (ip), intravenous injection (iv), ingestion (po), and
      inhalation). Naphthalene and its primary metabolite, naphthalene oxide, are
      consumed by enzymes in pulmonary and hepatic tissues (cytochrome P450
      monooxygenases, epoxide hydrolase, and glutathione-S-transferase). Additionally,
      the nonenzymatic reactions of naphthalene oxide in all tissues and in blood are
      included in the model. Kinetic constants for the model were derived primarily
      from cell fraction and primary cell culture incubations presented in the
      literature. The mouse model accurately predicts glutathione (GSH) and covalent
      naphthalene oxide-protein binding levels after a range of ip doses, and the rat
      model provides excellent estimates for mercapturate excretion following po doses;
      but neither model simulates well naphthalene blood concentrations after low iv
      doses. Good prediction of in vivo response using only in vitro data for parameter
      estimation (except for epoxide-protein binding rates) suggests that the assumed
      molecular description is a plausible representation of the underlying mechanisms
      of toxicity. Mice and rats show significant species differences in response to
      naphthalene. The model results suggest that species differences in toxicity may
      be explained, in part, by the lower overall rate of enzyme activities in the rat
      cells. Lower enzyme activities in the rat result in out-of-phase GSH minima in
      hepatic and lung compartments, while the simultaneous occurrence of these minima
      in mice results in higher naphthalene oxide concentrations, thereby allowing
      formation of more metabolites (e.g., covalent binding to proteins) that may be
      toxic.

PMID- 10356276
TI  - Control of a nonsquare drug infusion system: A simulation study.
AB  - A model predictive control strategy was developed and tested on a nonlinear
      canine circulatory model for the regulation of hemodynamic variables under
      critical care conditions. Different patient conditions such as congestive heart
      failure, post-operative hypertension, and sepsis shock were studied in closed
      loop simulations. The model predictive controller, which uses a different linear
      model depending on the patient condition, allowed constraints to be explicitly
      enforced. The controller was initially tuned on the basis of a linear plant
      model, then tested on the nonlinear physiological model; the simulations
      demonstrated the ability to handle constraints, such as drug dosage
      specifications, commonly desired by critical care physicians.

PMID- 10356277
TI  - Development of a novel methodology To validate optimal sterilization conditions
      for maximizing the texture quality of white beans in glass jars 
AB  - Optimal thermal processes were designed for white beans in glass jars heated in a
      still and end-over-end rotary pilot water cascading retort. For this purpose,
      isothermal kinetics of thermal softening of white beans were studied in detail
      using a tenderometer and a texturometer. The fractional conversion model was
      applied in both cases to model the texture degradation. The Arrhenius equation
      described well the temperature dependence of the reaction rate constant. With
      regard to the heat transfer, heat penetration parameters (fh and jh) were
      experimentally determined from 100 containers under static as well as rotational
      (end-over-end) conditions at 4, 7, 10, and 15 rpm. Theoretical optimal
      temperatures, maximizing volume average quality retention, were calculated using
      a computer program valid for conduction heating foods. Experimental verification
      of the calculated results was conducted. Considering the finite surface heat
      transfer coefficient, theoretical and experimental optimal temperatures were of
      the same order of magnitude, around 130 degrees C, while for an infinite surface
      heat transfer coefficient the calculated optimum temperature was much lower than
      the experimental value. The type of reaction kinetic model, fractional conversion
      or first-order models, does not significantly affect optimal sterilization
      temperatures. Although some differences were found, the developed theoretical
      approach was successfully applied to convective and mixed heating mode products.
      The use of the correct surface heat transfer coefficient is crucial to design
      optimal processing conditions.

PMID- 10356278
TI  - Thermoreactive displacers for anion exchange and hydroxyapatite displacement
      chromatography 
AB  - A set of copolymers was prepared via radical copolymerization of N, N
      dimethylacrylamide and 7-hydroxy-3-methyl-4-vinylindanone. While poly(N,N
      dimethylacrylamide) is water-soluble at all temperatures, the copolymers showed a
      lower critical solution temperature (LCST), which depended on the composition.
      Independent of this LCST all copolymers can be used in the dissolved state as
      protein displacers in combination with anion exchange stationary phases. The
      indanone group of the polymers is known the chelate calcium ions. It was
      therefore also possible to use the polymers to displace acidic (i.e., C-site
      interacting) proteins from hydroxyapatite. The major advantage of the described
      displacers over existing agents stems from the fact that they can be almost
      quantitatively recovered by thermoprecipitation from the carrier but also from
      any given protein zone. Lowering of the temperature renders the polymers again
      fully soluble and ready for use. No unspecific protein coprecipitation was
      observed under these conditions within our analytical means.

PMID- 10356279
TI  - DSC confirmation that vitrification is not necessary for stabilization of the
      restriction enzyme EcoRI dried with saccharides 
AB  - The glass transition temperature (Tg) of preparations of the restriction enzyme
      EcoRI, vacuum-dried in the presence of sucrose, trehalose, or raffinose, was
      determined using differential scanning calorimetry. Tg values were well below
      those expected for low-moisture sucrose, trehalose, or raffinose, and this was
      attributed to the presence of glycerol (a plasticizer), which was a main
      component of the restriction enzyme preparation. This was verified by determining
      the glass transition temperature of glycerol, which was found to be (onset value)
      -77 degrees C. Present results confirmed that vitrification (i.e., glass
      formation) was not necessary for enzyme protection in present low-moisture
      saccharide systems. As shown in previous work, enzyme EcoRI was very stable
      stored at 37/45 degrees C in spite of the fact that sugar matrices were
      completely rubbery, as unequivocally demonstrated in the present work.

PMID- 10356280
TI  - Recovery of thuringiensin with cetylpyridinium chloride using micellar-enhanced
      ultrafiltration process 
AB  - A cationic cetylpyridinium chloride (CPC) surfactant-based micellar-enhanced
      ultrafiltration (MEUF) process was used to recover thuringiensin from the
      supernatant of Bacillus thuringeinsis fermentation broth. Several different
      strategies of manipulating process variables, such as ionic strength, pH, CPC
      concentration, micelle formation temperature, and membrane pore size, were
      investigated. It was found that CPC concentration and membrane pore size were two
      major factors to the increase of thuringiensin recovery, while the ionic strength
      and pH adjustments were not necessary and micelle formation temperature was not
      important within the temperature range studied. Finally, a novel two-step MEUF
      processing scheme was developed which includes microfiltration and two-step
      ultrafiltration (UF) processes. The thuringiensin recovery up to 94.6% was
      attained when an initial CPC concentration of 4% (w/v) and UF membrane of
      molecular weight cutoff (MWCO) of 3000 was used in conjunction with the previous
      UF process using a MWCO 30 000 membrane. The bioassay results showed that the
      spray-dried thuringiensin with CPC was more toxic to fly larvae than without CPC.
      This research demonstrated that CPC not only facilitated thuringiensin recovery
      but also improved the insecticidal effect.

PMID- 10356281
TI  - Crystal structure of myotoxin II, a monomeric Lys49-phospholipase A2 homologue
      isolated from the venom of Cerrophidion (Bothrops) godmani.
AB  - Lys49-Phospholipase A2 (Lys49-PLA2) homologues damage membranes by a Ca2+
      independent mechanism which does not involve catalytic activity. With the aim of
      determining the structural basis for this novel activity, we have solved the
      crystal structure of myotoxin-II, a Lys49-PLA2 isolated from the venom of
      Cerrophidion (Bothrops) godmani (godMT-II) at 2.8 A resolution by molecular
      replacement. The final model has been refined to a final crystallografic residual
      (Rfactor) of 18.8% (Rfree = 28.2%), with excellent stereochemistry. godMT-II is
      also monomeric in the crystalline state, and small-angle X-ray scattering results
      demonstrate that the protein is monomeric in solution under fisicochemical
      conditions similar to those used in the crystallographic studies.

PMID- 10356282
TI  - High-affinity folate receptor in human ovary, serous ovarian adenocarcinoma, and
      ascites: radioligand binding mechanism, molecular size, ionic properties,
      hydrophobic domain, and immunoreactivity.
AB  - High-affinity folate receptors are expressed in normal ovaries and ovarian
      carcinomas. Binding of [3H]folate in human ovary, serous ovarian carcinoma
      tissue, and ascites is a complex process that has not been well characterized.
      This study shows changes in binding affinity and mechanism of binding with
      decreasing receptor concentration, inhibition by folate derivatives, and a slow
      radioligand dissociation at pH 7.4 becoming rapid and complete at pH 3.5. The
      receptor seems to be positively charged since it elutes in the front effluent of
      a DEAE-Sepharose CL-6B ion-exchange column at pH 6.3. The gel filtration profile
      of Triton X-100-solubilized tissue and ascites contained two peaks of radioligand
      bound receptor (25 and 100 kDa). Exposure of ascites to cleavage by
      phosphatidylinositol-specific phospholipase C resulted in a partial conversion of
      the 100-kDa peak to a 25-kDa peak. This suggests that the receptor may be
      anchored to the membrane by a glycosylphosphatidyl residue that inserts into
      Triton X-100 micelles, resulting in a large molecular size on gel filtration. The
      receptor in ovarian carcinoma tissue immunoreacts with antibodies against
      purified human milk folate receptor protein as shown by enzyme-linked
      immunosorbent assay, immunoprecipitation, sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis immunoblotting (a single band of 45 kDa), and
      immunohistochemistry. In only three of seven ovarian carcinomas did expression of
      radioligand-bound receptors exceed levels found in five normal ovaries. However,
      only receptors in ovarian carcinoma specimens showed a high degree of
      immunoreactivity. Hence, even without elevations of the total receptor level, a
      folate receptor isoform homologous to human milk folate receptor protein seemed
      to prevail in serous ovarian carcinomas.

PMID- 10356283
TI  - P450BM-3: absolute configuration of the primary metabolites of palmitic acid.
AB  - P450BM-3, a catalytically self-sufficient, soluble bacterial P450, contains on
      the same polypeptide a heme domain and a reductase domain. P450BM-3 catalyzes the
      oxidation of short- and long-chain, saturated and unsaturated fatty acids. The
      three-dimensional structure of the heme domain both in the absence and in the
      presence of fatty acid substrates has been determined; however, the fatty acid in
      the substrate-bound form is not adequately close to the heme iron to permit a
      prediction regarding the stereoselectivity of oxidation. In the case of long
      chain fatty acids, the products can also serve as substrate and be metabolized
      several times. In the current study, we have determined the absolute
      configuration of the three primary products of palmitic acid hydroxylation (15-,
      14-, and 13-OH palmitic acid). While the 15- and 14-hydroxy compounds are
      produced in a highly stereoselective manner (98% R, 2% S), the 13-hydroxy is a
      mixture of 72% R and 28% S. We have also examined the binding of these three
      hydroxy acids to P450BM-3 and shown that only two of them (14-OH and 13-OH
      palmitic acid) can bind to and be further metabolized by P450BM-3. The results
      indicate that in contrast to the flexibility of palmitoleic acid bound to the
      oxidized enzyme, palmitic acid is rigidly bound in the active site during
      catalytic turnover.

PMID- 10356284
TI  - Unique properties of purified, Escherichia coli-expressed constitutive cytochrome
      P4504A5.
AB  - Cytochromes P450 of the 4A family metabolize a variety of fatty acids,
      prostaglandins, and eicosanoids mainly at the terminal carbon (omega
      hydroxylation) and, to a lesser extent, at the penultimate carbon [(omega-1)
      hydroxylation]. In the present study, cytochrome P4504A5 (4A5) has been
      successfully expressed in Escherichia coli, with an average yield of enzyme of
      approximately 80 nmol/liter of cells. Spectroscopic characterization of the
      purified enzyme, using electron paramagnetic resonance and absolute and substrate
      perturbed optical difference spectroscopy, showed that the heme of resting 4A5 is
      primarily low spin, but is converted primarily to high spin by substrate binding.
      The kcat and Km values for laurate omega-hydroxylation were 41 min-1 and 8.5
      microM, respectively, in the absence of cytochrome b5, and 138 min-1 and 38
      microM, respectively, in the presence of cytochrome b5. Hydroxylation of
      palmitate was dependent on the presence of cytochrome b5; kcat and Km values were
      48 min-1 and 122 microM, respectively. Hydroxylation of arachidonic acid was
      barely detectable and was unchanged by the addition of cytochrome b5.

PMID- 10356285
TI  - Phosphorylation of tyrosine hydroxylase by cGMP-dependent protein kinase in
      intact bovine chromaffin cells.
AB  - The phosphorylation of the enzyme tyrosine hydroxylase by the cGMP pathway was
      investigated in chromaffin cells from the bovine adrenal medulla. The nitric
      oxide donor, sodium nitroprusside, and the natriuretic peptide, C-type
      natriuretic peptide, which are able to increase cGMP levels and cGMP-dependent
      protein kinase activity, produced significant increases in the phosphorylation
      level of tyrosine hydroxylase in a time- and concentration-dependent manner. The
      pretreatment of the cells with the soluble guanylyl cyclase inhibitor, 1H
      [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one blocked the effect of sodium
      nitroprusside. This result indicates that cGMP production by this enzyme mediated
      this effect. Experiments performed with a cGMP-dependent protein kinase
      inhibitor, the Rp-isomer of 8-(4-chlorophenylthio)-cyclic guanosine
      monophosphorothioate, which blocked the effects of both sodium nitroprusside and
      C-type natriuretic peptide, demonstrated that the phosphorylation increases
      evoked by both compounds were mediated by the activation of cGMP-dependent
      protein kinase. In cells incubated with the adenylyl cyclase activator,
      forskolin, an increase in the phosphorylation level of the tyrosine hydroxylase
      was also found. When cells were treated simultaneously with forskolin and sodium
      nitroprusside or C-type natriuretic peptide, an additive effect on tyrosine
      hydroxylase phosphorylation was not observed. This suggests that cAMP- and cGMP
      dependent protein kinases may phosphorylate the same amino acid residues in the
      enzyme. Western blot analysis of soluble extracts from chromaffin cells detected
      specific immunoreactivity for two different commercial antibodies raised against
      cGMP-dependent protein kinase (both Ialpha and Ibeta isoforms). Electrophoretic
      mobility correlates with that of purified PKG Ialpha. Because the phosphorylation
      of the tyrosine hydroxylase correlates with increases in its enzymatic activity
      and thus with augmentation in the cell capacity to synthesize catecholamines, our
      results indicate that a cGMP-based second messenger pathway participates in
      catecholamine biosynthesis regulation in chromaffin cells, a mechanism which may
      be widespread in other catecholamine-synthesizing cells.

PMID- 10356286
TI  - Stimulation of ouabain binding to Na,K-ATPase in 40% dimethyl sulfoxide by a
      factor from Na,K-ATPase preparations.
AB  - In 40% dimethyl sulfoxide (Me2SO) high-affinity ouabain (O) binding to Na,K
      ATPase (E) is promoted by Mg2+ in the absence of inorganic phosphate (Pi) (Fontes
      et al., Biochim. Biophys. Acta 1104, 215-225, 1995). Furthermore, in Me2SO the EO
      complex reacts very slowly with Pi and this ouabain binding can therefore be
      measured by the degree of inhibition of rapid phosphoenzyme formation. Here we
      found that, unexpectedly, the ouabain binding decreased with the enzyme
      concentration in the Me2SO assay medium. We extracted the enzyme preparation with
      Me2SO or chloroform/methanol and demonstrated that the extracted (depleted)
      enzyme bound ouabain poorly. Addition of such extracts to assays with low enzyme
      concentration or depleted enzyme fully restored the high-affinity ouabain
      binding. Dialysis experiments indicated that the active principle had a molecular
      mass between 3.5 and 12 kDa. It was highly resistant to proteolysis. It was
      suggested that the active principle could either be a low-molecular-weight,
      proteolysis-resistant-peptide (e.g., a proteolipid) or a factor with a
      nonproteinaceous nature. A polyclonal antibody raised against the C-terminal 10
      amino acids of the rat kidney gamma-subunit was able to recognize this low
      molecular-weight peptide present in the extracts. The previously depleted enzyme
      displayed lower amounts of the gamma-proteolipid in comparison to the native
      untreated enzyme, as demonstrated by immunoreaction with the antibody.

PMID- 10356287
TI  - Tyrosine kinase-independent inhibition of cyclic-AMP phosphodiesterase by
      genistein and tyrphostin 51.
AB  - The phosphodiesterase activity in the HT4.7 neural cell line was
      pharmacologically characterized, and phosphodiesterase isozyme 4 (PDE4) was found
      to be the predominant isozyme. The Km for cAMP was 1-2 microM, indicative of a
      "low Km" phosphodiesterase, and the activity was inhibited by PDE4-selective
      inhibitors rolipram and Ro20-1724, but not PDE3- or PDE2-selective inhibitors.
      Calcium, calmodulin, and cGMP, regulators of PDE1, PDE2, and PDE3, had no effect
      on cAMP hydrolysis. The protein tyrosine kinase inhibitor, genistein, inhibited
      HT4.7 cAMP phosphodiesterase activity by 85-95% with an IC50 of 4 microM; whereas
      daidzein, an inactive structural analog of genistein, had little effect on
      phosphodiesterase activity. This is a common pharmacological criterion used to
      implicate the regulation by a tyrosine kinase. However, genistein still inhibited
      phosphodiesterase activity with a mixed pattern of inhibition even when ion
      exchange chromatography was used to partially purify phosphodiesterase away from
      the tyrosine kinase activity. Moreover, tyrphostin 51, another tyrosine kinase
      inhibitor, was found to also inhibit partially purified phosphodiesterase
      activity noncompetitively. These data suggest that HT4.7 phosphodiesterase
      activity is dominated by PDE4 and can be regulated by genistein and tyrphostin 51
      by a tyrosine kinase-independent mechanism.

PMID- 10356288
TI  - Activation of several MAP kinases upon stimulation of rat alveolar macrophages:
      role of the NADPH oxidase.
AB  - Zymosan-activated serum (ZAS), a source of C5a, stimulates the rat alveolar
      macrophages (AM) to release superoxide anion. Here we show that treatment of rat
      AM with ZAS induced a time-dependent increase in the tyrosine phosphorylation of
      several proteins (116, 105-110, 82-78, 66-72, 62, 45, 42, and 38 kDa). This
      increase was sensitive to genistein, a tyrosine kinase inhibitor. ZAS stimulated
      the tyrosine phosphorylation and activation of three members of a family of
      serine/threonine kinases known as the mitogen-activated protein kinases (MAPK),
      i.e., ERK1 and ERK2, as assessed by immunoblotting, immunoprecipitation, and
      phosphotransferase activity, and p38 MAPK, as determined by immunoblotting with
      phospho-specific antibodies. In addition, ZAS induced the tyrosine
      phosphorylation of the SHC proteins and their association with GRB2, suggesting a
      role for this complex in the activation of the ERK pathway. Addition of
      extracellular catalase during ZAS stimulation significantly reduced the tyrosine
      phosphorylation response and the activation of ERK1 and ERK2 and their activator
      MEK1/2 while it did not affect that of p38 MAPK and MKK3/MKK6. Superoxide
      dismutase marginally increased the response to ZAS, supporting a role for
      hydrogen peroxide. In contrast to the results with AM, stimulation of human
      neutrophils with ZAS in the presence of catalase minimally altered the activation
      of ERK1 and ERK2. These data show that, in ZAS-stimulated rat AM, activation of
      the respiratory burst and production of hydrogen peroxide via superoxide
      dismutation are largely responsible for the activation of the ERK pathway through
      an upstream target.

PMID- 10356289
TI  - Nitric oxide prevents anoxia-induced apoptosis in colonic HT29 cells.
AB  - Apoptosis is a critical determinant of tissue mass homeostasis and may play a
      role in carcinogenesis. The aim of the present study was to investigate anoxia
      induced cell death in colon-derived HT29 cells and the effect of nitric oxide on
      this phenomenon. It was found that HT29 cells subjected to anoxia undergo
      apoptosis in a time dependent manner, as determined by DNA fragmentation and
      Hoechst-33258 dye staining. Cytochrome c release from mitochondria to cytosol is
      a key step in this process and this release precedes DNA fragmentation. NO
      inhibits anoxia induced apoptosis in these cells by inhibiting the release of
      cytochrome c and thus may play a role in modulating the apoptotic cell death of
      colon-derived epithelial cells.

PMID- 10356290
TI  - Identification, characterization, and partial purification of 4 alpha
      carboxysterol-C3-dehydrogenase/ C4-decarboxylase from Zea mays.
AB  - A microsomal preparation from seedlings of Zea mays catalyzed the NAD+-dependent
      oxidative decarboxylation of several substrates, including 4alpha-carboxy-cholest
      7-en-3beta-ol, synthesized according to a new procedure, giving the first in
      vitro evidence for this enzymatic activity in a higher plant. A GC assay has been
      developed to detect the Delta7-cholestenone produced and the kinetic parameters
      of the microsomal system have been established. 4alpha-Carboxysterol
      decarboxylation shows an exclusive requirement for an oxidized pyridine
      nucleotide, with NAD+ being more efficient than NADP+. The decarboxylation
      reaction is independent of molecular oxygen. 4alpha-Carboxysterol-C3
      dehydrogenase/C4-decarboxylase (4alpha-CD) is a microsome-bound protein which can
      be efficiently solubilized by detergents, including Brij W-1 and sodium cholate.
      The Brij W-1-solubilized enzyme was partially purified 290-fold by a combination
      of DEAE anion-exchange chromatography, Cibacron blue 3GA-agarose dye
      chromatography, and gel permeation. The apparent molecular mass of 4alpha-CD in
      sodium cholate was estimated to be 45 kDa. These results support the contention
      that demethylation at C4 of plant sterols is composed of two separate processes:
      an oxygen- and NAD(P)H-dependent oxidation of the 4alpha-methyl group to produce
      the 4alpha-carboxysterol metabolite (S. Pascal et al., J. Biol. Chem. 268, 11639,
      1993) followed by oxygen-independent dehydrogenation/decarboxylation to produce
      an obligatory 3-ketosteroid.

PMID- 10356292
TI  - Lucigenin is a mediator of cytochrome C reduction but not of superoxide
      production.
AB  - The relevance of lucigenin (bis-N-methylacridinium nitrate)-amplified
      chemiluminescence (CL) as a specific assay for superoxide ion has recently been
      disputed (S. I. Liochev and I. Fridovich, Arch. Biochem. Biophys. 337, 115-120,
      1997). These authors suggested that the redox cycling of lucigenin can lead to
      the formation of additional amount of superoxide ion. However, thermodynamic
      consideration shows that the equilibrium for the reaction O*-2 + Luc2+ if O2 +
      Luc*+ is completely shifted to the right (Keq = 10(6)); therefore, the redox
      cycling of lucigenin is of no importance. This conclusion is supported by the
      study of the effects of lucigenin on cytochrome c reduction by xanthine oxidase.
      It was found that lucigenin did enhance the rate of cytochrome c reduction with
      xanthine as a substrate, but it did not increase the rate of xanthine oxidation.
      When NADH was used as a substrate, lucigenin inhibited the SOD-dependent
      component of cytochrome c reduction and enhanced both the SOD-independent
      cytochrome c reduction and NADH oxidation, being a sole acceptor of an electron
      from the enzyme. All these findings indicate the extremely low probability of
      lucigenin redox cycling. In our opinion, lucigenin-amplified CL remains the most
      sensitive and highly specific test for superoxide formation in biological
      systems.

PMID- 10356291
TI  - Sodium-dependent uptake of [3H]scyllo-inositol by Tetrahymena: incorporation into
      phosphatidylinositol, phosphatidylinositol-linked glycans, and
      polyphosphoinositols.
AB  - [3H]Scyllo-inositol was taken up by Tetrahymena cells through a sodium-dependent
      pathway wherein unlabeled scyllo- and myo-inositol competed for uptake. d-Glucose
      was a competitor of [3H]myo-inositol uptake, but did not appear to compete for
      [3H]scyllo-inositol uptake. Transport of [3H]scyllo- and [3H]myo-inositol was
      inhibited when sodium was removed from the labeling buffer and by phlorizin, an
      inhibitor of sodium-dependent transporters. Cytochalasin B, an inhibitor of
      facilitated glucose transporters, had no significant effect on inositol
      transport. Internalized [3H]scyllo-inositol was readily incorporated intact into
      phosphatidylinositol, phosphatidylinositol-linked glycans, and
      polyphosphoinositols. Distribution of [3H]scyllo- and [3H]myo-inositol
      radioactivity into individual polyphosphoinositols was found to differ.

PMID- 10356293
TI  - Oxalate oxidase from Ceriporiopsis subvermispora: biochemical and cytochemical
      studies.
AB  - The enzyme oxalate oxidase was identified in mycelial extracts of the
      basidiomycete Ceriporiopsis subvermispora and thereafter purified to homogeneity.
      The purification procedure included only three steps: Q-Sepharose chromatography,
      precipitation at pH 3.0, and phosphocellulose chromatography. The enzyme is a 400
      kDa homohexamer, as determined by gel permeation in Sephadex G-200 and SDS
      polyacrylamide gel electrophoresis. Isoelectrofocusing revealed a pI of 4.2.
      Optimal activity was obtained at pH 3.5 and at 45 degrees C. The purified enzyme
      has Km and kcat values of 0.1 mM and 88 s-1, respectively. It is highly specific
      for oxalate, although it is inhibited at concentrations of this substrate above
      2.5 mM. Hystochemistry studies conducted over mycelium slices showed reactions
      products in both endocellular and periplasmic associated elements. A possible
      connection between the intracellular metabolism of oxalate and the extracellular
      ligninolytic activity of the fungus is proposed.

PMID- 10356294
TI  - GDNF family neurotrophic factor signaling: four masters, one servant?

PMID- 10356295
TI  - Neuroprotective utility and neurotrophic action of neurturin in postnatal motor
      neurons: comparison with GDNF and persephin.
AB  - Neurturin and persephin are recently discovered homologs of glial cell line
      derived neurotrophic factor (GDNF). Here, we report that neurturin, like GDNF,
      increases the choline acetyltransferase activity of normal postnatal motor
      neurons, induces neurite outgrowth in spinal cord, and potently protects motor
      neurons from chronic glutamate-mediated degeneration. Persephin, in contrast,
      does not appear to have neurotrophic or neurite-promoting effects on mature motor
      neurons and may instead worsen the glutamate injury of motor neurons. This
      pattern in the TGF-beta family suggests certain receptor specificities, requiring
      at least the Ret/GFRalpha-1 receptor complex. The results predict potential
      benefit of neurturin, but not persephin, in the treatment of motor neuron
      disorders and spinal cord diseases.

PMID- 10356296
TI  - Isolation and characterization of Dek, a Drosophila eph receptor protein tyrosine
      kinase.
AB  - We have isolated a Drosophila receptor protein tyrosine kinase (RTK) of the Eph
      subfamily. Dek, for Drosophila Eph kinase, possesses all the domains
      characteristic of the Eph subfamily of RTKs and is equally similar in sequence to
      both the EphA and the EphB subclasses. Antibody staining and promoter fusions to
      axon-targeted reporters reveal that Dek is expressed by a large subset of
      developing embryonic interneurons and is targeted to their axons and growth cones
      at the time of axon pathfinding. Dek is also expressed by photoreceptor cells of
      third-instar larvae as they project axons into the optic brain lobe.
      Misexpression and overexpression of full-length Dek or kinase-inactive Dek do not
      grossly affect axon pathfinding.

PMID- 10356297
TI  - Modulation of early but not later stages of programmed cell death in embryonic
      avian spinal cord by sonic hedgehog.
AB  - Sonic hedgehog (Shh) is a secreted glycoprotein expressed by the notochord and
      floor plate that is involved in the induction and specification of ventral
      phenotypes in the vertebrate neural tube. Recently, Shh has also been shown to
      promote the survival of cultured rat embryo ventral brain and spinal cord cells.
      We have examined whether Shh can promote the survival of chick embryo neurons in
      vivo or in vitro. In the chick, Shh is expressed in notochord, floor plate, and
      ventral neural tube/spinal cord at several stages at which programmed cell death
      (PCD) occurs. However, the administration of exogenous Shh to embryos in vivo or
      to motoneuron cultures at these stages failed to promote the survival of several
      different neuronal populations, including spinal motoneurons, spinal
      interneurons, sympathetic preganglionic neurons, sensory neurons, and neuronal
      precursor cells. Rather, at the earliest stage of PCD examined here (embryonic
      day 3) Shh selectively induced the death of ventral neuronal precursors and floor
      plate cells, resulting in a net loss of cells in the neural tube. Altered
      concentrations of Shh induce aberrant phenotypes that are removed by PCD.
      Accordingly, normal PCD in the early neural tube may play a role in dorsal
      ventral patterning.

PMID- 10356299
TI  - Neurons depend on astrocytes in a coculture system for protection from glutamate
      toxicity.
AB  - Glutamate can be toxic to neurons although it is a neurotransmitter. Regulation
      of extracellular glutamate levels is essential for prevention of glutamate
      neurotoxicity. Astrocytes play a major role in clearance of glutamate released by
      neurons. A coculture system combining cerebellar cells and astrocytes was
      employed to investigate the astrocytic control of glutamate toxicity. Coculture
      of astrocytes with cerebellar neurons enhanced uptake of glutamate by astrocytes.
      Inhibition of glutamate uptake in a coculture system led to death of cerebellar
      cells. This toxicity could be inhibited by MK801. However, in the presence of the
      glutamate uptake inhibitor, there was no increase in glutamate in the cultures
      compared to when the neurons were not cocultured. This indicated that neurons
      become more susceptible to glutamate toxicity in the presence of astrocytes and
      thus become dependent on astrocytes for prevention of glutamate toxicity.
      Astrocytes treated with conditioned medium from cerebellar cells did not show an
      increase in glutamate uptake but medium from astrocytes exposed to neuron
      conditioned medium was toxic to cerebellar cells. This toxicity was due to
      glutamate present in the medium. This suggests that a soluble factor released by
      neurons signals to astrocytes that neurons are present and stimulates a signal
      back to neurons which causes an increased sensitivity to glutamate toxicity.

PMID- 10356298
TI  - Distinct neurite outgrowth signaling pathways converge on ERK activation.
AB  - Several distinct classes of proteins positively regulate axonal growth; some of
      these are known to activate the mitogen-activated protein kinase
      (MAPK)/extracellular signal-regulated kinase (ERK) signaling cascade, at least in
      nonneuronal cells. We have found that N-cadherin, as well as laminin (LN) and
      basic fibroblast growth factor (bFGF), can activate ERK in embryonic chick
      retinal neurons. Additionally, adhesion of retinal neurons to LN or N-cadherin
      substrates induced a redistribution of ERK from the cytoplasm toward the plasma
      membrane. Neurite outgrowth induced by bFGF, LN, or N-cadherin was strongly
      inhibited by treatment with inhibitors of ERK kinase activation, but not by an
      inhibitor of p38 MAPK. We conclude (1) that N-cadherin and LN can activate ERK in
      retinal neurons and (2) that activation of ERK is required for full neurite
      outgrowth induced by these proteins. Our results suggest that ERK activation is
      one point of convergence for signaling pathways generated by a variety of axon
      growth inducers.

PMID- 10356301
TI  - Self-learning fuzzy control with temporal knowledge for atracurium-induced
      neuromuscular block during surgery.
AB  - Self-learning fuzzy logic control has the important property of accommodating
      uncertain, nonlinear, and time-varying process characteristics. This intelligent
      control scheme starts with no fuzzy control rules and learns how to control each
      process presented to it in real time without the need for detailed process
      modeling. In this study we utilize temporal knowledge of generated rules to
      improve control performance. A suitable medical application to investigate this
      control strategy is atracurium-induced neuromuscular block of patients in the
      operating theater where the patient response exhibits high nonlinearity and
      individual patient dose requirements may vary fivefold during an operating
      procedure. We developed a computer control system utilizing Relaxograph (Datex)
      measurements to assess the clinical performance of a self-learning fuzzy
      controller in this application. Using a T1 setpoint of 10% of baseline in 10
      patients undergoing general surgery, we found a mean T1 error of 0.28% (SD =
      0.39%) while accommodating a 0.25 to 0.38 mg/kg/h range in the mean atracurium
      infusion rate. This result compares favorably with more complex and
      computationally intensive model-based control strategies for atracurium infusion.

PMID- 10356302
TI  - Spatial and temporal distribution enhancement of movement-related brain
      macropotentials.
AB  - Conventional brain maps suffer from severe limitations due to both the spatial
      blur of potential distributions and the dependence on electrical reference. The
      surface Laplacian (SL) has been used to deblur movement-related brain
      macropotentials (MRBM) since it acts as a high-pass spatial filter that reduces
      the head volume conductor effects. Moreover, the method usually employed to
      improve the signal-to-noise ratio (SNR) is the well-known synchronized average.
      However, this method is no longer valid when the object of the study is the sweep
      by-sweep variability. In this case, the SNR of original and Laplacian-transformed
      single-sweep MRBM can be improved by autoregressive with exogenous input (ARX)
      filtering. In our study, isolated or combined ARX and SL are applied to enhance
      the spatial distributions of single-sweep MRBM associated with unilateral
      voluntary self-paced finger movements in humans. It shows that single-sweep brain
      mappings are more coherent to physiological findings when ARX is first used
      followed by SL.

PMID- 10356303
TI  - Estimation of latency changes and relative amplitudes in somatosensory evoked
      potentials using wavelets and regression.
AB  - Changes in onset latency and relative amplitudes of somatosensory evoked
      potentials (SEP) may be a convenient and reliable neurophysiological indicator of
      depth of anesthesia. However, to derive the components is very difficult
      mathematically and visual inspection or alternatively the peak-latency estimation
      is usually employed. A methodology for estimating the components was developed
      for both real-time and off-line applications based on the combination of the
      wavelet transforms (WT), geometric analysis, artificial intelligence (AI), and
      mathematical analysis of the first positive wave of SEPs. The WT together with AI
      constitutes a feature extraction engine for localizing the first positive peak
      and negative valley and hence relative amplitudes. The latency change between two
      averages is obtained by shifting one average toward another to achieve a best
      match along the positive inflections. The inflection, based on the peak, is
      modeled as a regression line and is refined using a steepness inference
      algorithm. Results from simulation and anesthetized rats show that it is reliable
      in comparison with visual inspection, robust to amplitude variation and signal
      distortion, and efficient in computation, and hence it is suitable for
      automation. Comparisons of interobserver variability and analysis of method
      agreement suggest that the method can be used as a substitute for estimations by
      visual inspection.

PMID- 10356304
TI  - A computer program to calculate indicators of descriptive epidemiology.
AB  - Comparison of incidence and mortality data between areas is useful for monitoring
      the health status of a population, for exploring quality of health care, and for
      planning studies on determinant(s) of heterogeneous patterns. Common statistical
      indicators involved, together with their confidence intervals, are age-specific
      and cumulative rates, age-standardized rates and ratios, and expected numbers.
      The data required for calculations include information of event distribution
      according to age and residence, and corresponding population at risk. The
      calculations of these indicators, although conceptually simple, can be a
      cumbersome task to carry out with available statistical packages; lack of
      flexibility to suit the need of specific researches represents another problem.
      In order to facilitate descriptive epidemiological studies, we developed a set of
      Statistical Analysis System macros to compute indicators but, also, to read and
      write data from/to some standard file formats. Important features of these macros
      are their flexibility, expandability, and ability to be transferred to various
      computer platforms. Moreover, macros give an added value to raw data. The method
      is illustrated using published incidence data from Italy.

PMID- 10356305
TI  - On the human left ventricular shape.
AB  - The geometry of the heart plays a major role in cardiac function. The purpose of
      this study was to characterize analytically the geometric properties of the left
      ventricular (LV) three-dimensional (3D) shape, while excluding the effects of
      aspect ratio and size. Two groups of human hearts were studied by Cine-CT. The
      first group was composed of 10 healthy volunteers and the second of 9
      pathological hearts. The hearts were scanned from apex to base. The endocardial
      borders of each LV scan were traced and used to reconstruct the 3D LV at end
      diastole (ED) and end-systole (ES). Using a special normalized helical shape
      descriptor, denoted "geometrical cardiogram" (GCG), the typical 3D normal ED and
      ES shapes were determined. These typical shapes were then analytically
      approximated via a discrete cosine transform (DCT). The shape of each LV was then
      investigated for its correspondence to five analytically defined shapes: (i) a
      cone, (ii) a sphere, including all ellipsoidal shapes, (iii) a cylinder, (iv) a
      truncated ellipsoid, and (v) the DCT approximation of the normal LV shape. The
      results indicate that the normal LV shape can be well approximated by using only
      seven coefficients of the DCT. Conicity was the only geometrical feature which
      did not change from ED to ES in the normal group of hearts. The most prominent
      shape difference between normal and abnormal hearts was the significantly reduced
      conicity of the latter. Conicity is an important feature of LV geometry. The
      possible contribution of the conical shape to LV ejection efficiency is also
      discussed.

PMID- 10356306
TI  - Automatic segmentation of lung fields on chest radiographic images.
AB  - In this work we have implemented a system for the automatic segmentation of lung
      fields in chest radiographic images. The image analysis process is carried out in
      three levels. In the first one we perform operations on the image that are
      independent from domain knowledge. This knowledge is implicitly and not very
      elaborately used in the intermediate level and used in an explicit manner in the
      high level block, globally corresponding to the idea of progressive segmentation.
      The representation of knowledge in the high level block is in the form of
      production rules. The control structure is in general bottom-up but there are
      certain hybrid control stages, in which the control is driven by the region model
      (main organs) we are seeking. We have applied the global system to a set of 45
      posteroanterior (PA) chest radiographs, obtaining a mean degree of overlap with
      contours drawn by radiologists of 87%.

PMID- 10356307
TI  - Functional regulative pathways for p53, a protein of basic importance for the
      integrity of the cell genome.

PMID- 10356308
TI  - Glutamine, as a precursor of glutathione, and oxidative stress.
AB  - Oxidative stress is related to several pathologies and it is also associated with
      surgical operations. Reactive oxygen species generated during oxidative stress
      can induce severe damage to biomolecules. To prevent this damage, cells are
      endowed with both enzymatic and nonenzymatic defenses. One of the most important
      antioxidant molecules is glutathione. Since glutamine is a precursor of
      glutathione, its supplementation in the clinical diet can be used to maintain
      high levels of glutathione and to avoid oxidative stress damage. Here, recent
      literature concerning this recurrent topic is critically reviewed.

PMID- 10356309
TI  - Identification and characterization of the molecular lesion causing
      mucopolysaccharidosis type I in cats.
AB  - Mucopolysaccharidosis Type I (MPS I) is the lysosomal storage disease caused by
      the deficient activity of alpha-L-iduronidase (IDUA). In man, MPS I can occur in
      severe, mild, or intermediate forms known as the Hurler, Scheie, or Hurler/Scheie
      syndromes, respectively. MPS I also has been described in cats, dogs, and mice.
      This manuscript reports the identification and characterization of the mutation
      causing MPS I in cats. To obtain wild-type feline IDUA cDNAs, two PCR-based
      strategies were used. PCR primers were constructed from a conserved region of the
      published human and dog sequences and used to amplify a 224-bp IDUA fragment from
      normal cat genomic DNA. This fragment was then used to screen a feline uterus
      cDNA library. PCR also was used to directly amplify IDUA fragments from the same
      cDNA library. Two overlapping feline IDUA cDNAs encoding 466 amino acid residues
      of the feline IDUA polypeptide ( approximately 85% of the mature protein based on
      comparison to the human, dog, and mouse sequences) were obtained by these
      strategies. To identify the mutation causing MPS I in cats, DNA sequencing was
      carried out on the corresponding IDUA region from several affected animals. A 3
      bp deletion was found on both IDUA alleles in each of the MPS I animals,
      predicting the deletion of a single aspartate residue from the feline IDUA
      polypeptide. To confirm the authenticity of this mutation, heteroduplex, SSCP,
      and transient expression studies were carried out. Over 100 animals from the MPS
      I colony were screened for the presence of the mutation by heteroduplex and SSCP
      analyses-in all cases the presence of the 3-bp deletion was 100% concordant with
      the disease phenotype. For transient expression studies, the two partial,
      overlapping feline cDNAs were combined and joined in-frame to the 5' end of the
      canine IDUA cDNA. This wild-type, hybrid cDNA expressed IDUA activity up to
      sixfold over endogenous levels after transfection into COS-1 cells. A modified
      full-length IDUA cDNA containing the 3-bp deletion did not express IDUA activity
      in a transient expression system, providing proof that this lesion was the cause
      of feline MPS I.

PMID- 10356310
TI  - Regulation of erythropoietin gene expression depends on two different oxygen
      sensing mechanisms.
AB  - Erythropoietin (Epo), a glycoprotein hormone produced principally in the fetal
      kidney and in the adult liver in response to hypoxia, is the prime regulator of
      growth and differentiation in erythroid progenitor cells. The regulation of Epo
      gene expression is not fully understood, but two mechanisms have been proposed.
      One involves the participation of a heme protein capable of reversible
      oxygenation and the other depends on the intracellular concentration of reactive
      oxygen species (ROS), assumed to be a function of pO2. We have investigated the
      production of Epo in response to three stimuli, hypoxia, cobalt chloride, and the
      iron chelator desferrioxamine, in Hep3B cells. As expected, hypoxia caused a
      marked rise in Epo production. When the cells were exposed to the paired stimuli
      of hypoxia and cobalt no further increase was found. In contrast, chelation of
      iron under hypoxic conditions markedly enhanced Epo production, suggesting that
      the two stimuli act by separate pathways. The addition of carbon monoxide
      inhibited hypoxia-induced Epo production, independent of desferrioxamine
      concentration. Taken together these data support the concept that pO2 and ROS are
      sensed independently.

PMID- 10356311
TI  - Human HKR isozyme: organization of the hexokinase I gene, the erythroid-specific
      promoter, and transcription initiation site.
AB  - We previously described a cDNA for the human HKR isozyme, whose sequence is
      identical to that of the ubiquitous HKI isozyme, except for a unique 5' end
      sequence. Screening a human genomic library with a DNA fragment containing an
      erythroid-specific sequence we found one clone including 5' ends for both HKR and
      HKI genes. The first HKR exon was located 3 kb 5' of the first HKI exon. These
      results confirmed that HKR is produced from the HKI gene by alternate promoter
      and splicing. The HKI gene consisted of 19 exons. All exon-intron boundaries are
      conserved among the genes for hexokinase and glucokinase. The HKI gene length was
      estimated at over 67 kb. The initiation site for the HKR was identified by primer
      extension. Its promoter did not have a canonical TATA box, but an inverted GATA
      at nt -177 (i.e., 36 nt 5' to the transcription initiation site). In the HKR
      promoter a DNA fragment spanning nt -275 to nt -107 exhibited erythroid-specific
      activity. However, this was absent in shorter promoter fragments (nt -206 to -107
      or nt -229 to -107). The sequence nt -275 to -229, which appeared critical for
      the erythroid-specific expression of the HKR gene, contained a consensus motif
      for Sp-1 and GATA, CCAAT, and GGAA motifs. The electrophoretic mobility shift
      assay (EMSA) suggested erythroid-specific cooperative protein-protein interaction
      in this region. Deletion of the GATA sequence as well as reaction with a specific
      antibody identified GATA-1 as one of the interacting proteins.

PMID- 10356312
TI  - Sialuria in a Portuguese girl: clinical, biochemical, and molecular
      characteristics.
AB  - Sialuria, a disorder of sialic acid (NeuAc) metabolism characterized by increased
      free NeuAc in the cytoplasm of cells, is due to failure of CMP-Neu5Ac to feedback
      inhibit UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase. We now describe the
      fifth patient in the world with sialuria, a 7-year-old Portuguese girl with
      developmental delay, hepatomegaly, coarse facies, and urinary excretion of 19
      micromol of free NeuAc/mg creatinine. The patient's fibroblasts stored excess
      free NeuAc in the cytosolic fraction, and fibroblast UDP-GlcNAc 2-epimerase
      activity was only 26% inhibited by 100 microM CMP-Neu5Ac (normal, 79%). The
      patient's UDP-GlcNAc 2-epimerase gene displayed an R266Q mutation in only one
      allele, consistent with known sialuria mutations and with the proposed dominant
      nature of this disorder. Extensive description of sialuria patients will help to
      define the clinical and biochemical spectrum of this disease.

PMID- 10356313
TI  - A polymorphic variant in the human electron transfer flavoprotein alpha-chain
      (alpha-T171) displays decreased thermal stability and is overrepresented in very
      long-chain acyl-CoA dehydrogenase-deficient patients with mild childhood
      presentation.
AB  - The consequences of two amino acid polymorphisms of human electron transfer
      flavoprotein (alpha-T/I171 in the alpha-subunit and beta-M/T154 in the beta
      subunit) on the thermal stability of the enzyme are described. The alpha-T171
      variant displayed a significantly decreased thermal stability, whereas the two
      variants of the beta-M/T154 polymorphism did not differ. We wished to test the
      hypothesis that these polymorphisms might constitute susceptibility factors and
      therefore determined their allele and genotype frequencies in (i) control
      individuals, (ii) medium-chain acyl-CoA dehydrogenase-deficient patients
      homozygous for the K304E mutation (MCAD E304), (iii) a group of patients with
      elevated urinary excretion of ethylmalonic acid (EMA) possibly due to decreased
      short-chain acyl-CoA dehydrogenase activity, and (iv) in patients with proven
      deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD). No significant
      overrepresentations or underrepresentations were found in the first two patient
      groups, suggesting that the polymorphisms studied are not significant
      susceptibility factors in either the MCAD E304 or the EMA patient group. However,
      in the VLCAD deficient patients the alpha-T171 variant (decreased thermal
      stability) was significantly overrepresented. Subgrouping of the VLCAD patients
      into three phenotypic classes (severe childhood, mild childhood, and adult
      presentation) revealed that the overrepresentation of the alpha-T171 variant was
      significant only in patients with mild childhood presentation. This is compatible
      with a negative modulating effect of the less-stable alpha-T171 ETF variant in
      this group of VLCAD patients that harbor missense mutations in at least one
      allele and therefore potentially display residual levels of VLCAD enzyme
      activity.

PMID- 10356314
TI  - Long-term beneficial effects of the phenylalanine-restricted diet in late
      diagnosed individuals with phenylketonuria.
AB  - The potential benefits to society of treating late-diagnosed mentally retarded
      persons with phenylketonuria were investigated. In order to ascertain the effects
      of late dietary intervention, the charts of 124 adults with PKU seen in the
      metabolic service at the Childrens Hospital of Los Angeles were reviewed. Fifty
      nine were diagnosed later than 3 months of age and were over the age of 18 years.
      They were followed up with medical, psychological, and nutritional assessments.
      Genotyping was also performed. Twenty-eight have remained on a phenylalanine
      restricted diet during the intervening years. All but 3 of the 28 late-diagnosed
      PKU persons who remained on a restricted diet showed significant intellectual
      improvement. Seven are able to attend college, 9 are employed, and 12 are
      attending workshops and/or day care programs. The result of treatment with the
      phenylalanine-restricted diet was that these individuals could participate in
      society and were able to arrest the neurodegenerative course characteristic of
      persons with mutations classified as severe in the phenylalanine hydroxylase
      gene. We conclude that society could benefit substantially by providing a
      phenylalanine-restricted diet for late-diagnosed mentally retarded persons with
      phenylketonuria. Eighteen of 28 such persons who otherwise would have required
      residential care are living independently.

PMID- 10356315
TI  - Biochemical phenotype and its relationship with genotype in hyperphenylalaninemia
      heterozygotes.
AB  - The molecular detection of heterozygotes for hyperphenylalaninemia is difficult
      due to the large number of mutations in the PAH gene. For this reason, various
      indexes that measure plasma concentrations of phenylalanine (Phe) and tyrosine
      (Tyr), as an expression of Phe metabolizing capacity, have been used for the
      detection of carriers for mutations in the PAH gene. In this study, we contrast
      the biochemical and the molecular data in order to know if this is an accurate
      method. Familial genetic analysis of the PAH gene in 93 parents of
      hyperphenylalaninemia patients allows the study of the biochemical expression of
      the different mutant alleles. Molecular study was performed by SSCP and DGGE
      analyses of PAH genes, and plasma amino acid analysis by ion-exchange
      chromatography. Then the biochemical and molecular data were compared by the
      Student t test. The results found show a relationship between the severity of
      PKU/HPA mutations in the PAH gene and their biochemical phenotype (Phe/Tyr,
      Phe2/Tyr) as an expression of the residual enzymatic activity. The study adds
      further information about the prevalent Mediterranean allele mutations.

PMID- 10356316
TI  - Late infantile neuronal ceroid lipofuscinosis is due to splicing mutations in the
      CLN2 gene.
AB  - Late infantile neuronal ceroid lipofuscinosis, LINCL, is one of the most common
      pediatric neurodegenerative disorders. It is caused by mutations in the CLN2
      gene, which encodes a lysosomal pepstatin-insensitive peptidase (LPIP). We have
      identified a novel mutation, T523-1G --> A, by molecular analyses of three
      unrelated LINCL cases. The mutation was found to affect a 3' intronic splicing
      acceptor site, resulting in an aberrant mRNA with an insertion of 146 bp of
      intronic sequence. This causes a frame shift, produces a nonfunctional truncated
      protein, and results in LINCL.

PMID- 10356318
TI  - Studies on human porin XIX: zinc ions reduce the voltage-dependence of human type
      1 porin integrated in artificial planar lipid bilayers; barium ions do not.
AB  - We report on the first data concerning the effects of ionic zinc or barium on
      human type-1 porin. The channel enriched as mature protein from B-lymphocyte
      crude membranes was integrated into artificial planar lipid bilayers and both
      agonists were applied as their chloride salts at 100 microM. Relative conductance
      was measured from -80 to 80 mV. The presence of Zn2+ resulted in a distinct
      reduction of the voltage dependence of the channel, the effect appearing to be
      symmetric. The addition of Ba2+ did not produce any measurable effect on human
      porin. According to our knowledge we present the first results on the interaction
      of bivalent metal ions and eukaryotic type-1 porin. The putative physiological
      relevance of the data is discussed.

PMID- 10356317
TI  - Splicing variants in sheep CLN3, the gene underlying juvenile neuronal ceroid
      lipofuscinosis.
AB  - Mutations in different genes underlie different forms of the neuronal ceroid
      lipofuscinoses (NCLs, Batten disease). Subunit c of mitochondrial ATP synthase
      specifically accumulates in most of them, including the juvenile CLN3 form and a
      sheep form orthologous to CLN6. Products of these genes are likely to be
      components of a complex or pathway for subunit c turnover, and their expression
      may be cross-regulated. Different bands, some with different subcellular
      distributions, were detected by antisera against different regions of CLN3 on
      Western blots of sheep tissues. Affected liver blots were the same as controls
      but a specific 50-kDa band was at higher concentration in affected brain
      homogenates than in controls. Others have also reported bands reacting
      differently to different CLN3 antibodies. When the 3' end of sheep CLN3 cDNA was
      amplified by RT-PCR, four mRNA splicing variants were found. Different CLN3
      splicing variants at the 5' end of the human cDNA have been reported. These mRNA
      splicing variants may account the variation of epitope distribution and the
      different subcellular locations of the CLN3 gene product(s). The predicted size
      of the unmodified CLN3 protein is 48 kDa. Significantly higher molecular weight
      bands may correspond to oligomers of a CLN3 isoform or to a CLN3 isoform tightly
      bound to another protein.

PMID- 10356319
TI  - Identification of a nuclear transport inhibitory signal (NTIS) in the basic
      domain of HIV-1 Vif protein.
AB  - The HIV-1 auxiliary protein Vif contains a basic domain within its sequence. This
      basic region,90RKKR93, is similar to the prototypic nuclear localization signal
      (NLS). However, Vif is not a nuclear protein and does not function in the
      nucleus. Here we have studied the karyophilic properties of this basic region. We
      have synthesized peptides corresponding to this positively charged NLS-like
      region and observed that these peptides inhibited nuclear transport via the
      importin pathway in vitro with IC50values in the micromolar range. Inhibition was
      observed only with peptides derived from the positively charged region, but not
      from other regions of the Vif protein, showing sequence specificity. On the other
      hand, the Vif inhibitory peptide Vif88-98 did not confer karyophilic properties
      when conjugated to BSA. The inactive Vif conjugate and the active SV40-NLS-BSA
      conjugate both contained a similar number of peptides conjugated to each BSA
      molecule, as was determined by amino acid analysis of the peptide-BSA conjugates.
      Thus, the lack of nuclear import of the Vif peptide-BSA conjugate cannot be
      attributed to insufficient number of conjugated peptide molecules per BSA
      molecule. Our results suggest that the HIV-1 Vif protein carries an NLS-like
      sequence that inhibits, but does not mediate, nuclear import via the importin
      pathway. We have termed such signals as nuclear transport inhibitory signals
      (NTIS). The possible role of NTIS in controlling nuclear uptake, and specifically
      during virus infection, is discussed herein. Our results raise the possibility
      that NLS-like sequences of certain low molecular weight viral proteins may serve
      as regulators of nucleocytoplasmic trafficking and not neccessarily as mediators
      of nuclear import.

PMID- 10356320
TI  - Solution structure of the SH2 domain of Grb2 complexed with the Shc-derived
      phosphotyrosine-containing peptide.
AB  - The solution structure of growth factor receptor-bound protein 2 (Grb2) SH2
      complexed with a Shc-derived phosphotyrosine (pTyr)-containing peptide was
      determined by nuclear magnetic resonance (NMR) spectroscopy. The pTyr binding
      site of Grb2 SH2 was similar to those of other SH2 domains. In contrast, the
      amino acid residues C-terminal to pTyr did not form an extended structure because
      of steric hindrance caused by a bulky side-chain of Trp121 (EF1). As a result,
      the peptide formed a turn-structure on the surface of Grb2 SH2. The asparagine
      residue at the pTyr+2 position of the Shc-peptide interacted with the main-chain
      carbonyl groups of Lys109 and Leu120. The present solution structure was similar
      to the crystal structure reported for Grb2 SH2 complexed with a BCR-Abl-derived
      phosphotyrosine-containing peptide. Finally, the structure of Grb2 SH2 domain was
      compared with those of the complexes of Src and phospholipase C-gamma1 with their
      cognate peptides, showing that the specific conformation of the peptide was
      required for binding to the SH2 domains.

PMID- 10356321
TI  - Mechanism of DNA gyrase-mediated illegitimate recombination: characterization of
      Escherichia coli gyrA mutations that confer hyper-recombination phenotype.
AB  - To study the mechanism of DNA gyrase-mediated illegitimate recombination in
      Escherichia coli, we isolated temperature-sensitive gyrA mutants that confer
      spontaneous illegitimate recombination and spontaneous induction of lambda
      prophage at higher frequencies than that in the wild-type. After reconstruction
      of single mutations by targeted mutagenesis, we confirmed that two single
      mutations, gyrAL492P and gyrAL488P, and a double mutation, gyrAI203V+gyrAI205V,
      show the same properties as those described above. With respect to the phenotypes
      of hyper-recombination and higher induction of lambda prophage, these mutations
      were dominant over the wild-type. Analysis of recombination junctions of
      lambdabio transducing phages formed spontaneously in these mutants showed that
      the parental E. coli bio and lambda recombination sites have a homologous
      sequence of only 0. 7 base-pair on average, indicating that homology is not
      required for this illegitimate recombination. Analysis of nucleotide sequences of
      mutant gyrA genes revealed that the gyrAL492P and gyrAL488P mutations contain
      amino acid substitutions of Leu492-->Pro and Leu488-->Pro, respectively, which
      correspond to the alpha18 helix in the breakage-reunion domain of DNA gyrase A
      subunit. The gyrAI203V and gyrAI205V mutations contain Ile203-->Val and Ile205-
      >Val, respectively, which correspond to the alpha10' helix, also in the breakage
      reunion domain of DNA gyrase A subunit. Biochemical analysis indicated that the
      GyrA63 protein that contains the L492P mutation has an apparently normal
      supercoiling activity, but it also produces a small amount of linear DNA in the
      absence of DNA gyrase inhibitor during the supercoiling reaction, suggesting that
      the mutant DNA gyrase may have a defect at the step of religation or a defect in
      the subunit interaction. These results suggest that the recombination is induced
      by defects of religation and/or dimer formation in the mutant DNA gyrases,
      implying that two alpha helices, alpha10' and alpha18, of DNA gyrase A subunit
      have crucial roles in subunit interaction and/or resealing of DNA.

PMID- 10356322
TI  - Interaction of interferon regulatory factor-1 and nuclear factor kappaB during
      activation of inducible nitric oxide synthase transcription.
AB  - We investigated the molecular mechanism for the synergistic induction of
      inducible nitric oxide synthase transcription by TNF-alpha and IFN-gamma. Since
      TNF-alpha and IFN-gamma stimulate cells in part by activating NF-kappaB and IRF
      1, we hypothesized that these two transcription factors interact with each other.
      IRF-1 and NF-kappaB co-localize in the nucleus of stimulated macrophages. Co
      immunoprecipitation experiments show that IRF-1 and NF-kappaB interact in
      stimulated but not resting cells. Super-shift experiments show that IRF-1 and NF
      kappaB interact while binding to their respective DNA binding sites. These
      results demonstrate the existence of a physical interaction between IRF-1 and NF
      kappaB proteins in vivo. We next suggested that this interaction between IRF-1
      and NF-kappaB bends the DNA of the iNOS promoter region. Using a cyclization
      assay, we demonstrate that nuclear extracts from stimulated cells accelerate the
      rate of conversion of a linear to circular DNA, compared to extracts from resting
      cells. However, stimulated nuclear extracts cannot affect the rate of cyclization
      of a promoter with a mutant IRE or kappaB site. Furthermore, stimulated nuclear
      extracts depleted of IRF-1 and NF-kappaB cannot induce cyclization. We conclude
      that IRF-1 and NF-kappaB interact in vivo, and that this interaction physically
      bends the indicible nitric oxide synthase promoter DNA. This interaction may
      explain the mechanism by which IFN-gamma synergistically augments inducible
      nitric oxide synthase transcription.

PMID- 10356324
TI  - Pseudouridine synthetase Pus1 of Saccharomyces cerevisiae: kinetic
      characterisation, tRNA structural requirement and real-time analysis of its
      complex with tRNA.
AB  - Pseudouridine synthetase Pus1 from Saccharomyces cerevisiae is a multisite
      specific enzyme that catalyses the formation of pseudouridine residues at
      different positions in several tRNA transcripts. Recombinant Pus1, tagged with
      six histidine residues at its N terminus was expressed in Escherichia coli and
      purified. Transcripts of yeast tRNAValand intronless yeast tRNAIlewere used as
      substrates to measure pseudouridine formation at position 27. The catalytic
      parameters Kmand kcatfor tRNAValand tRNAIlewere 420(+/-100) nM and 0.4(+/-0.1)
      min-1, 740(+/-100) nM and 0.5(+/-0.1) min-1, respectively. Pus1 possesses a
      general affinity for tRNA, irrespective of whether they are substrates. Its
      equilibrium dissociation constant ranges from 15 nM for the substrate yeast
      tRNAValand non-substrate yeast intronless tRNAPhe, to 150 nM for the substrate
      yeast intronless tRNAIle. The difference in the affinity for the different tRNA
      species is not reflected in the specific activity of the enzyme, indicating that
      the binding of Pus1 to tRNA is not the kinetically limiting step. The importance
      of tertiary base-pairs was investigated with several variants of yeast tRNAs.
      Although dispensable for activity, both the presence of a D-stem-loop and the
      presence of a G26.A44 base-pair, near the target uridine U27, are important
      elements for Pus1 tRNA high affinity recognition. The presence of a G26.A44 base
      pair in tRNA increases its association constant rate with Pus1 (ka) by a factor
      of approximately 100, resulting in a decrease of the overall equilibrium
      dissociation constant (Kd). The dissociation rate (kd) is the same, independent
      of the presence of a G26.A44 base-pair in the tRNA. A model describing the
      interaction of Pus1 with tRNA is proposed.

PMID- 10356323
TI  - Group II intron reverse transcriptase in yeast mitochondria. Stabilization and
      regulation of reverse transcriptase activity by the intron RNA.
AB  - Group II introns encode reverse transcriptases that function in both intron
      mobility and RNA splicing. The proteins bind specifically to unspliced precursor
      RNA to promote splicing, and then remain associated with the excised intron to
      form a DNA endonuclease that mediates intron mobility by target DNA-primed
      reverse transcription. Here, immunoblotting and UV cross-linking experiments show
      that the reverse transcriptase activity encoded by the yeast mtDNA group II
      intron aI2 is associated with an intron-encoded protein of 62 kDa (p62). p62 is
      bound tightly to endogenous RNAs in mitochondrial ribonucleoprotein particles,
      and the reverse transcriptase activity is rapidly and irreversibly lost when the
      protein is released from the endogenous RNAs by RNase digestion. Non-denaturing
      gel electrophoresis and activity assays show that the aI2 reverse transcriptase
      is associated predominantly with the excised intron RNA, while a smaller amount
      is associated with unspliced precursor RNA, as expected from the role of the
      protein in RNA splicing. Although the reverse transcriptase in wild-type yeast
      strains is bound tightly to endogenous RNAs, it is regulated so that it does not
      copy these RNAs unless a suitable DNA oligonucleotide primer or DNA target site
      is provided. Certain mutations in the intron-encoded protein or RNA circumvent
      this regulation and activate reverse transcription of endogenous RNAs in the
      absence of added primer. Although p62 is bound to unspliced precursor RNA in
      position to initiate cDNA synthesis in the 3' exon, the major template for target
      DNA-primed reverse transcription in vitro is the reverse-spliced intron RNA, as
      found previously for aI1. Together, our results show that binding to intron
      containing RNAs stabilizes and regulates the activity of p62.

PMID- 10356325
TI  - Duplex opening by primosome protein PriA for replisome assembly on a
      recombination intermediate.
AB  - PriA and other primosome assembly proteins of Escherichia coli recruit the major
      replicative helicase DnaB for replisome assembly during bacteriophage Mu
      transposition and replication. MuA transposase catalyzes the transfer of Mu ends
      to target DNA, forming a potential replication fork that provides the assembly
      site for the replisome. However, this fork lacks the single-stranded DNA needed
      to load DnaB. Although no pre-existing primosome assembly sites that bind PriA
      were found within the Mu end sequences, PriA was able to bind to the forked DNA
      structure created by MuA. The helicase activity of PriA could then open the
      duplex to create the DnaB binding site. In a tightly coupled reaction on
      synthetic forked substrates, PriA promoted both the unwinding of the lagging
      strand arm and preprimosome assembly to load DnaB onto the lagging strand
      template. PriA apparently translocated 3' to 5' along the lagging strand template
      until sufficient single-stranded DNA was exposed for binding of DnaB, which then
      translocated 5' to 3' in the opposite direction. Mutant PriA lacking helicase
      activity was unable to promote this process, and loss of PriA helicase impaired
      Mu DNA replication in vivo and in vitro. This suggests that the opening of the
      duplex by PriA helicase is a critical step in the initiation of Mu DNA
      replication. Concerted helicase and primosome assembly functions would allow PriA
      to act as initiator on recombination intermediates and stalled replication forks.
      As part of the replisome, PriA may act as a mobile initiator that minimizes
      interruptions in chromosomal replication.

PMID- 10356326
TI  - A newly identified, essential catalytic residue in a critical secondary structure
      element in the integrase family of site-specific recombinases is conserved in a
      similar element in eucaryotic type IB topoisomerases.
AB  - The integrase family of site-specific recombinases catalyzes conservative
      rearrangements between defined segments of DNA. A highly conserved tetrad (RHRY)
      of catalytic residues is essential for this process. This tetrad is dispersed in
      two motifs in the linear sequence, but is configured appropriately in the
      catalytic pocket to execute the strand cleavage and rejoining reactions. A third
      conserved motif has been identified in the Xer subgroup of the integrase family.
      Mutational analysis of 12 conserved residues in this motif in the XerD protein
      from Salmonella typhimurium led to the identification of an essential fifth
      catalytic residue (lysine 172) which is implicated in strand cleavage or
      exchange. This lysine residue occupies part of the turn of an antiparallel beta
      hairpin which forms one side of the catalytic cleft in XerD, and is found at
      similar positions among evolutionarily diverse integrase family members. Related
      antiparallel beta-hairpins are present in eucaryotic type IB topoisomerase
      enzymes which also contain a critical lysine residue in the turn of the hairpin.
      In both the integrase family and eucaryotic type IB topoisomerases, the catalytic
      lysine residues are in close contact with the substrates and may play similar
      roles in influencing the reactivity of the phosphotyrosine intermediates formed
      during reactions catalyzed by both enzymes.

PMID- 10356327
TI  - The three-dimensional structure of the vnd/NK-2 homeodomain-DNA complex by NMR
      spectroscopy.
AB  - The three-dimensional solution structure obtained by NMR of the complex formed
      between the uniformly singly15N and doubly13C/15N-labeled vnd/NK-2 homeodomain
      and its consensus 16 base-pair DNA binding sequence was determined. This work was
      carried out using the accepted repertoire of experiments augmented with a novel
      implementation of the water flipback technique to enhance signals from
      exchangeable amide protons. The results using this new technique confirm the
      existence of hydrogen bonding between the invariant Asn51 and the second adenine
      of the DNA binding sequence, as seen in crystal structures of other homeodomain
      DNA complexes, but never before detected by NMR. Hydrogen bonding by Arg5 and
      Lys3 in the minor groove of the DNA appears to be responsible for two unusually
      upfield-shifted ribose H1' resonances. The DNA duplex is nearly straight and its
      structure is primarily that of B -DNA. A detailed comparison is presented for all
      available homeodomain-DNA structures including the vnd/NK-2 DNA complex, which
      demonstrates that homology is maintained in the protein structure, whereas for
      the orientation of the homeodomain relative to DNA, small but significant
      variations are observed. Interactions are described involving certain residues in
      specific positions of the homeodomain, namely Leu7, Thr41, and Gln50 of vnd/NK-2,
      where single amino acid residue mutations lead to dramatic developmental
      alterations. The availability of our previously determined three- dimensional
      structure of the vnd/NK-2 homeodomain in the absence of DNA allows us to assess
      structural changes in the homeodomain induced by DNA binding.

PMID- 10356328
TI  - Large-scale networks of hydration water molecules around bovine beta-trypsin
      revealed by cryogenic X-ray crystal structure analysis.
AB  - The hydration structure of bovine beta-trypsin was investigated in cryogenic X
      ray diffraction experiments. Three crystal forms of the enzyme inhibited by
      benzamidine with different molecular packing were selected to deduce the
      hydration structure for the entire surface of the enzyme. The crystal structures
      in all three of the crystal forms were refined at the resolution of 1.8 A at 100
      K and 293 K. The number of hydration water molecules around the enzyme at 100 K
      was 1.5 to two times larger than that at 293 K, indicating that the motion of
      hydration water was quenched by cooling. In particular, the increase in the
      number of hydration water molecules was prominent on flat and electrostatically
      neutral surface areas. The water-to-protein mass ratio and the radius of gyration
      of a structural model of hydrated trypsin at 100 K was consistent with the
      results obtained by other experimental techniques for proteins in solution.
      Hydration water molecules formed aggregates of various shapes and dimensions, and
      some of the aggregates even covered hydrophobic residues by forming oligomeric
      arrangements. In addition, the aggregates brought about large-scale networks of
      hydrogen bonds. The networks covered a large proportion of the surface of trypsin
      like a patchwork, and mechanically linked several secondary structures of the
      enzyme. By merging the hydration structures of the three crystal forms at 100 K,
      a distribution function of hydration water molecules was introduced to
      approximate the static hydration structure of trypsin in solution. The function
      showed that the negatively charged active site of trypsin tended to be easily
      exposed to bulk solvent. This result is of interest with respect to the solvent
      shielding effect and the recognition of a positively charged substrate by
      trypsin.

PMID- 10356329
TI  - Engineered mutants in the switch II loop of Ran define the contribution made by
      key residues to the interaction with nuclear transport factor 2 (NTF2) and the
      role of this interaction in nuclear protein import.
AB  - Nuclear protein import requires a precisely choreographed series of interactions
      between nuclear pore components and soluble factors such as importin-beta, Ran,
      and nuclear transport factor 2 (NTF2). We used the crystal structure of the
      GDPRan-NTF2 complex to design mutants in the switch II loop of Ran to probe the
      contribution of Lys71, Phe72 and Arg76 to this interaction. X-ray crystallography
      showed that the F72Y, F72W and R76E mutations did not introduce major structural
      changes into the mutant Ran. The GDP-bound form of the switch II mutants showed
      no detectable binding to NTF2, providing direct evidence that salt bridges
      involving Lys71 and Arg76 and burying Phe72 are all crucial for the interaction
      between Ran and NTF2. Nuclear protein accumulation in digitonin-permeabilzed
      cells was impaired with Ran mutants deficient in NTF2 binding, confirming that
      the NTF2-Ran interaction is required for efficient transport. We used mutants of
      the yeast Ran homologue Gsp1p to investigate the effect of the F72Y and R76E
      mutations in vivo. Although neither mutant was viable when integrated into the
      genome as a single copy, yeast mildly overexpressing the Gsp1p mutant
      corresponding Ran F72Y on a centromeric plasmid were viable, confirming that this
      mutant retained the essential properties of wild-type Ran. However, yeast
      expressing the Gsp1p mutant corresponding to R76E to comparable levels were not
      viable, although strains overexpressing the mutant to higher levels using an
      episomal 2micrometers plasmid were viable, indicating that the R76E mutation may
      also have interfered with other interactions made by Gsp1p.

PMID- 10356330
TI  - Determination of the MurD mechanism through crystallographic analysis of enzyme
      complexes.
AB  - UDP -N- acetylmuramoyl- L -alanine: D -glutamate (MurD) ligase catalyses the
      addition of d -glutamate to the nucleotide precursor UDP -N- acetylmuramoyl- L 
      alanine (UMA). The crystal structures of three complexes of Escherichia coli MurD
      with a variety of substrates and products have been determined to high
      resolution. These include (1) the quaternary complex of MurD, the substrate UMA,
      the product ADP, and Mg2+, (2) the quaternary complex of MurD, the substrate UMA,
      the product ADP, and Mn2+, and (3) the binary complex of MurD with the product
      UDP - N- acetylmuramoyl- L -alanine- D -glutamate (UMAG). The reaction mechanism
      supported by these structures proceeds by the phosphorylation of the C-terminal
      carboxylate group of UMA by the gamma-phosphate group of ATP to form an acyl
      phosphate intermediate, followed by the nucleophilic attack by the amino group of
      D-glutamate to produce UMAG. A key feature in the reaction intermediate is the
      presence of two magnesium ions bridging negatively charged groups.

PMID- 10356331
TI  - High resolution crystal structure of a Mg2+-dependent porphobilinogen synthase.
AB  - Common to the biosynthesis of all known tetrapyrroles is the condensation of two
      molecules of 5-aminolevulinic acid to the pyrrole porphobilinogen catalyzed by
      the enzyme porphobilinogen synthase (PBGS). Two major classes of PBGS are known.
      Zn2+-dependent PBGSs are found in mammals, yeast and some bacteria including
      Escherichia coli, while Mg2+-dependent PBGSs are present mainly in plants and
      other bacteria. The crystal structure of the Mg2+-dependent PBGS from the human
      pathogen Pseudomonas aeruginosa in complex with the competitive inhibitor
      levulinic acid (LA) solved at 1.67 A resolution shows a homooctameric enzyme that
      consists of four asymmetric dimers. The monomers in each dimer differ from each
      other by having a "closed" and an "open" active site pocket. In the closed
      subunit, the active site is completely shielded from solvent by a well-defined
      lid that is partially disordered in the open subunit. A single molecule of LA
      binds to a mainly hydrophobic pocket in each monomer where it is covalently
      attached via a Schiff base to an active site lysine residue. Whereas no metal
      ions are found in the active site of both monomers, a single well-defined and
      highly hydrated Mg2+is present only in the closed form about 14 A away from the
      Schiff base forming nitrogen atom of the active site lysine. We conclude that the
      observed differences in the active sites of both monomers might be induced by
      Mg2+-binding to this remote site and propose a structure-based mechanism for this
      allosteric Mg2+in rate enhancement.

PMID- 10356332
TI  - Backbone dynamics and energetics of a calmodulin domain mutant exchanging between
      closed and open conformations.
AB  - Previous studies have suggested that the Ca2+-saturated E140Q mutant of the C
      terminal domain of calmodulin exhibits equilibrium exchange between "open" and
      "closed" conformations similar to those of the Ca2+-free and Ca2+-saturated
      states of wild-type calmodulin. The backbone dynamics of this mutant were studied
      using15N spin relaxation experiments at three different temperatures.
      Measurements at each temperature of the15N rate constants for longitudinal and
      transverse auto-relaxation, longitudinal and transverse cross-correlation
      relaxation, and the1H-15N cross-relaxation afforded unequivocal identification of
      conformational exchange processes on microsecond to millisecond time-scales, and
      characterization of fast fluctuations on picosecond to nanosecond time-scales
      using model-free approaches. The results show that essentially all residues of
      the protein are involved in conformational exchange. Generalized order parameters
      of the fast internal motions indicate that the conformational substates are well
      folded, and exclude the possibility that the exchange involves a significant
      population of unfolded or disordered species. The temperature dependence of the
      order parameters offers qualitative estimates of the contribution to the heat
      capacity from fast fluctuations of the protein backbone, revealing significant
      variation between the well-ordered secondary structure elements and the more
      flexible regions. The temperature dependence of the conformational exchange
      contributions to the transverse auto-relaxation rate constants directly
      demonstrates that the microscopic exchange rate constants are greater than
      2.7x10(3)s-1at 291 K. The conformational exchange contributions correlate with
      the chemical shift differences between the Ca2+-free and Ca2+-saturated states of
      the wild-type protein, thereby substantiating that the conformational substates
      are similar to the open and closed states of wild-type calmodulin. Taking the
      wild-type chemical shifts to represent the conformational substates of the mutant
      and populations estimated previously, the microscopic exchange rate constants
      could be estimated as 2x10(4)to 3x10(4)s-1at 291 K for a subset of residues. The
      temperature depen dence of the exchange allows the characterization of apparent
      energy barriers of the conformational transition, with results suggesting a
      complex process that does not correspond to a single global transition between
      substates.

PMID- 10356333
TI  - NOE data demonstrating a compact unfolded state for an SH3 domain under non
      denaturing conditions.
AB  - The N-terminal SH3 domain of drk (drkN SH3) is unstable, existing in equilibrium
      between a folded state (Fexch) and an unfolded state (Uexch) under non-denaturing
      buffer conditions. Using a15N/2H-labeled sample, long range amide NOEs can be
      observed in the Uexchstate as a result of reduced relaxation, in some cases
      correlating protons over 40 residues apart. These long range NOEs disappear upon
      addition of 2 M guanidinium chloride, demonstrating that there are substantial
      differences between the Uexchand the guanidine denatured states. Calculations
      using the long range NOEs of the Uexchstate yield highly compact structures
      having non-native turns and a non-native buried tryptophan residue. These
      structures agree with experimental stopped-flow fluorescence data and analytical
      ultracentrifugation results. Since protein stability depends on the structural
      and dynamic properties of both the folded and unfolded states, this study
      provides insights into the stability of the drkN SH3 domain. These results
      provide the first strong NOE-based evidence for compact unfolded states of
      proteins and suggest that some unfolded states under physiological conditions
      have specific interactions leading to compact structures.

PMID- 10356334
TI  - Partially formed native tertiary interactions in the A-state of cytochrome c.
AB  - Considerable insight into protein structure, stability, and folding has been
      obtained from studies of non-native states. We have studied the extent of native
      tertiary contacts in one such molecule, the A-state of yeast iso-1
      ferricytochrome c. Previously, we showed that the interface between the N and C
      terminal helices is completely formed in the A-state. Here, we focus on
      interactions essential for forming the heme pocket of eukaryotic cytochromes c.
      To determine the extent of these interactions, we used saturation mutagenesis at
      the evolutionarily invariant residue leucine 68, and measured the free energy of
      denaturation for the native states and the A-states of functional variants. We
      show that, unlike the interaction between the terminal helices, the native
      interactions between the 60s helix and the rest of the protein are not completely
      formed in the A-state.

PMID- 10356335
TI  - High-throughput mass spectrometric discovery of protein post-translational
      modifications.
AB  - The availability of genome sequences, affordable mass spectrometers and high
      resolution two-dimensional gels has made possible the identification of hundreds
      of proteins from many organisms by peptide mass fingerprinting. However, little
      attention has been paid to how information generated by these means can be
      utilised for detailed protein characterisation. Here we present an approach for
      the systematic characterisation of proteins using mass spectrometry and a
      software tool FindMod. This tool, available on the internet at
      http://www.expasy.ch/sprot/findmod.html , examines peptide mass fingerprinting
      data for mass differences between empirical and theoretical peptides. Where mass
      differences correspond to a post-translational modification, intelligent rules
      are applied to predict the amino acids in the peptide, if any, that might carry
      the modification. FindMod rules were constructed by examining 5153 incidences of
      post-translational modifications documented in the SWISS-PROT database, and for
      the 22 post-translational modifications currently considered (acetylation,
      amidation, biotinylation, C-mannosylation, deamidation, flavinylation,
      farnesylation, formylation, geranyl-geranylation, gamma-carboxyglutamic acids,
      hydroxylation, lipoylation, methylation, myristoylation, N -acyl diglyceride
      (tripalmitate), O-GlcNAc, palmitoylation, phosphorylation, pyridoxal phosphate,
      phospho-pantetheine, pyrrolidone carboxylic acid, sulphation) a total of 29
      different rules were made. These consider which amino acids can carry a
      modification, whether the modification occurs on N-terminal, C-terminal or
      internal amino acids, and the type of organisms on which the modification can be
      found. We illustrate the utility of the approach with proteins from 2-D gels of
      Escherichia coli and sheep wool, where post-translational modifications predicted
      by FindMod were confirmed by MALDI post-source decay peptide fragmentation. As
      the approach is amenable to automation, it presents a potentially large-scale
      means of protein characterisation in proteome projects.

PMID- 10356336
TI  - Assembly of the type II secretion machinery of Erwinia chrysanthemi: direct
      interaction and associated conformational change between OutE, the putative ATP
      binding component and the membrane protein OutL.
AB  - Erwinia chrysanthemi secretes, by the type II secretory pathway, a large number
      of enzymes, including cellulases and pectinases. This process requires the
      products of the out genes, which are widely conserved in Gram-negative bacteria.
      The Out proteins are thought to form a membrane-associated multiprotein complex.
      Here, we investigated interaction between OutE, the putative ATP binding
      component, and OutL, an inner membrane protein. We showed, by limited
      proteolysis, genetic suppression and the yeast two-hybrid system, that OutE and
      OutL interact directly. Analysis of truncated forms of OutE demonstrated that the
      N terminus of OutE (residues 1-97) is important for the OutE/OutL interaction.
      Moreover, results from the yeast two-hybrid system suggested that OutE and OutL
      are each able to form homomultimers. The region required for homomultimerisation
      of OutE is located in its C terminus. Limited proteolysis assay indicated that
      OutE induces a conformational change in OutL, in both its cytoplasmic and
      periplasmic domains. Moreover, the secretion process requires a conformational
      change in OutE which depends on both the interaction with OutL and on the
      presence of an intact Walker A motif in OutE. Our results support the view that
      interaction occurring on the cytoplasmic side influences the events occurring in
      the outer membrane. We discuss a model in which OutE uses ATP to control the
      assembly of the type II secretion machinery.

PMID- 10356337
TI  - Editorial 

PMID- 10356338
TI  - Electrophysiological recording from brain slices.
AB  - This article discusses several of the currently used methodologies for recording
      from brain slices. Aspects of slice preparation as well as appropriate uses for
      the various slice models (i.e., thin or thick slices) are considered. The merits
      of extracellular and intracellular electrophysiological recording and their uses
      are discussed. In addition, mechanisms of neuronal circuit activation and
      stimulation are presented.

PMID- 10356339
TI  - Use of intrinsic optical signals to monitor physiological changes in brain tissue
      slices.
AB  - Optical imaging techniques have the potential to bring a combination of high
      spatial and temporal resolution to studies of brain function. Many optical
      techniques require the addition of a dye or fluorescent marker to the tissue, and
      such methods have proven extremely valuable. It is also known that the intrinsic
      optical properties of neural tissue are affected by certain physiological changes
      and that these intrinsic optical signals can provide information not available by
      other means. Most authors attribute the intrinsic optical change to alterations
      in cell volume and concomitant change in the concentration of the cytosol. In
      this article we review the literature on intrinsic optical signals, covering both
      the mechanisms of the optical change and its use in various branches of
      neurophysiology. We also discuss technical aspects of the technique as used with
      hippocampal slices, including illumination methods, cameras, experimental
      methods, and data collection and analysis procedures. Finally we present data
      from investigations in which we used intrinsic optical signals in hippocampal
      slices to study the extent of spread of synaptic activation, propagation of
      spreading depression, extent and severity of the response to hypoxia, and tissue
      response to osmotic challenges. We conclude that (1) at least two processes
      generate intrinsic optical signals in hippocampal slices, one of which causes
      light scattering to change inversely with cell volume and is related to dilution
      of the cytoplasm, while the other, opposite in sign, may be due to mitochondrial
      swelling; and (2) the intrinsic optical signal can be a useful tool for spatial
      mapping of relatively slow events, but is not suitable for study of fast
      physiological processes.

PMID- 10356340
TI  - Optical methods for probing mitochondrial function in brain slices.
AB  - Brain slice preparations have become useful tools for studying multiple facets of
      normal brain function and for investigations of brain pathophysiology. Recently,
      a variety of neurological disorders have been linked to dysfunction of brain
      mitochondria. In this report we discuss optical methods for probing mitochondrial
      function in brain slices. Absorption spectrophotometric and spectrofluorometric
      techniques are described for measuring changes in the redox activity of
      mitochondrial cytochromes and the primary respiratory chain substrate
      nicotinamide adenine dinucleotide (NADH), respectively. A spectrofluorometric
      method is described also for measuring changes in mitochondrial membrane
      potential using the potential-sensitive fluorescent indicator JC-1. These methods
      used together have proven to be useful for studying dysfunction of mitochondria
      following in vitro ischemia in hippocampal slices, and might also be valuable for
      investigations of mitochondrial involvement in other neurological disorders.

PMID- 10356341
TI  - Use of brain slices to study long-term potentiation and depression as examples of
      synaptic plasticity.
AB  - Brain slices have been responsible for the majority of advances in our
      understanding of the cellular aspects of altered synaptic strength underlying
      memory, long-term potentiation (LTP) and long-term depression (LTD), and
      increases and decreases, respectively, in synaptic strength at glutamatergic
      synapses. Our current understanding of LTP and LTD has come largely from studies
      in hippocampal slices. We consider the strengths and limitations of brain slice
      technology applied to this subject and conclude that they will continue to have
      an important role in future studies into the cellular machinery underlying
      changes in synaptic strength.

PMID- 10356342
TI  - Study of cerebral energy metabolism using the rat hippocampal slice preparation.
AB  - This article describes methods and experimental paradigms used in combination
      with the rat hippocampal slice preparation in an attempt to better understand
      cerebral energy metabolism under the following conditions: normal resting
      conditions, conditions of oxygen and/or glucose deprivation, and conditions of
      activation (excitation). The outcome of this attempt, as described herewith,
      demonstrates the unmatched usefulness of the brain slice preparation as an in
      vitro tool in the field of neuroscience.

PMID- 10356343
TI  - Autoradiographic measurements of protein synthesis in hippocampal slices from
      rats and guinea pigs.
AB  - Protein synthesis is an extremely important cell function and there is now good
      evidence that changes in synthesis play important roles both in neuronal cell
      damage from ischemic insults and in neural plasticity though the mechanisms of
      these effects are not at all clear. The brain slice, and particularly the
      hippocampal slice, is an excellent preparation for studying these effects
      although, as with all studies on slices, caution must be exercised in that
      regulation in the slice may be different from regulation in vivo. Studies on
      neural tissue need to take into account the heterogeneity of neural tissue as
      well as the very different compartments within neurons. Autoradiography at both
      the light and electron microscope levels is a very powerful method for doing
      this. Successful autoradiography depends on many factors. These include correct
      choice of precursor amino acid, mechanisms for estimating changes in the specific
      activity of the precursor amino acid pool, and reliable methods for quantitation
      of the autoradiographs. At a more technical level these factors include attention
      to detail in processing tissue sections so as to avoid light contamination during
      exposure and developing and, also, appropriate choices of the various parameters
      such as exposure time and section thickness. The power of autoradiography is
      illustrated here by its ability to discern effects of ischemia and of plasticity
      related neural input on distinct cell types and also in distinct compartments of
      neurons. Ischemia inhibits protein synthesis in principal neurons but activates
      synthesis in other cell types of the brain slice. Plasticity-related neural input
      immediately enhances protein synthesis in dendrites but does not affect cell
      bodies.

PMID- 10356344
TI  - Use of ascorbate in the preparation and maintenance of brain slices.
AB  - Ascorbate and glutathione (GSH) are normally concentrated in brain cells at
      millimolar levels. However, both of these low-molecular-weight antioxidants are
      washed out of mammalian brain tissue during slice preparation and subsequent
      incubation. Ascorbate, which is not synthesized in the brain, can be added back
      to slices by active uptake from the incubation medium. Levels of GSH, on the
      other hand, are regulated by synthesis rather than uptake, and cannot be readily
      maintained in slices. Importantly, maintenance of brain slice ascorbate content
      at at least 50% of that in vivo, prevents the increase in slice water content
      that normally occurs during incubation. Slices with maintained ascorbate levels
      also have better histological characteristics than ascorbate-depleted tissue. The
      medium concentration of ascorbate sufficient to maintain content and inhibit
      edema formation is 400 microM, which is the normal concentration in brain
      extracellular fluid. This paper describes methods to maintain ascorbate levels in
      brain slices, including procedures to minimize oxidation in oxygenated incubation
      media. Also described is an HPLC analysis for ascorbate and GSH that is based on
      direct injection rather than extraction of samples.

PMID- 10356345
TI  - Using hippocampal slices to study how aging alters ion regulation in brain
      tissue.
AB  - Aging alters ion regulation in brain tissue. This article describes methods
      useful for studying such age-related changes in the rat hippocampal slice
      preparation. Topics considered include (a) selection of appropriate age groups of
      rats for aging studies, (b) a description of methods for preparing and
      maintaining hippocampal slices, (c) measurement of intracellular pH with the H+
      sensitive dye carboxy-SNARF-1, and (d) measurement of extracellular pH and K+
      with cation-selective microelectrodes.

PMID- 10356347
TI  - Optical imaging in living brain slices 

PMID- 10356346
TI  - Coupling of organotypic brain slice cultures to silicon-based arrays of
      electrodes.
AB  - Fetal or early postnatal brain tissue can be cultured in viable and healthy
      condition for several weeks with development and preservation of the basic
      cellular and connective organization as so-called organotypic brain slice
      cultures. Here we demonstrate and describe how it is possible to establish such
      hippocampal rat brain slice cultures on biocompatible silicon-based chips with
      arrays of electrodes with a histological organization comparable to that of
      conventional brain slice cultures grown by the roller drum technique and on
      semiporous membranes. Intracellular and extracellular recordings from neurons in
      the slice cultures show that the electroresponsive properties of the neurons and
      synaptic circuitry are in accordance with those described for cells in acutely
      prepared slices of the adult rat hippocampus. Based on the recordings and the
      possibilities of stimulating the cultured cells through the electrode arrays it
      is anticipated that the setup eventually will allow long-term studies of defined
      neuronal networks and provide valuable information on both normal and
      neurotoxicological and neuropathological conditions.

PMID- 10356348
TI  - Color plates 

PMID- 10356349
TI  - Optical imaging of living brain slices.

PMID- 10356350
TI  - Potential sources of intrinsic optical signals imaged in live brain slices.
AB  - Changes in how light is absorbed or scattered in biological tissue are termed
      intrinsic optical signals (IOSs). Imaging IOSs in the submerged brain slice
      preparation provides insight into brain activity if it involves significant water
      movement between intracellular and extracellular compartments. This includes
      responses to osmotic imbalance, excitotoxic glutamate agonists, and
      oxygen/glucose deprivation, the latter leading to spreading depression. There are
      several misconceptions regarding these signals. (1) IOSs are not generated by
      glial swelling alone. Although neuronal and glia sources cannot yet be directly
      imaged, several lines of evidence indicate that neurons contribute significantly
      to the changes in light transmittance. (2) Excitotoxic swelling and osmotic
      swelling are physiologically different, as are their associated IOSs. Hyposmotic
      swelling involves no detectable neuronal depolarization of cortical pyramidal
      neurons, only the passive drawing in of water from a dilute medium across the
      cell membrane. In contrast excitotoxic swelling involves sustained membrane
      depolarization associated with inordinate amounts of Na+ and Cl- entry followed
      by water. IOSs demonstrate substantial damage in the latter case. (3) Osmotic
      perturbations do not induce volume regulatory mechanisms as measured by IOSs. The
      osmotic responses measured by IOSs in brain slices are passive, without the
      compensatory mechanisms that are assumed to be active on a scale suggested by
      studies of cultured brain cells under excessive osmotic stress. (4) Spreading
      depression (SD) can cause neuronal damage. Innocuous during migraine aura, SD
      induces acute neuronal damage in brain slices that are metabolically compromised
      by oxygen/glucose deprivation, as demonstrated by IOSs. Neighboring tissue where
      SD does not spread remains relatively healthy as judged by a minimal reduction in
      light transmittance. IOSs show that the metabolic stress of SD combined with the
      compromise of energy resources leads to acute neuronal damage that is resistant
      to glutamate antagonists. (5) While hyperosmotic conditions reduce LT by causing
      cells to shrink, excitotoxic conditions reduce LT by causing dendritic beading.
      This conformational change increases light scattering even as the tissue
      continues to swell.

PMID- 10356351
TI  - Fluorescence imaging of changes in intracellular chloride in living brain slices.
AB  - In brain slice preparations, chloride movements across the cell membrane of
      living cells are measured traditionally with 36Cl- tracer methods, Cl--selective
      microelectrodes, or whole-cell recording using patch clamp analysis. We have
      developed an alternative, noninvasive technique that uses the fluorescent Cl- ion
      indicator, 6-methoxy-N-ethylquinolinium iodide (MEQ), to study changes in
      intracellular Cl- by epifluorescence or UV laser scanning confocal microscopy. In
      brain slices taken from rodents younger than 22 days of age, excellent cellular
      loading is achieved with the membrane-permeable form of the dye, dihydro-MEQ.
      Subsequent intracellular oxidation of dihydro-MEQ to the Cl--sensitive MEQ traps
      the polar form of the dye inside the neurons. Because MEQ is a single-excitation
      and single-emission dye, changes in intracellular Cl- concentrations can be
      calibrated from the Stern-Volmer relationship, determined in separate
      experiments. Using MEQ as the fluorescent indicator for Cl-, Cl- flux through the
      gamma-aminobutyric acid (GABA)-gated Cl- channel (GABAA receptor) can be studied
      by dynamic video imaging and either nonconfocal (epifluorescence) or confocal
      microscopy in the acute brain slice preparation. Increases in intracellular Cl-
      quench MEQ fluorescence, thereby reflecting GABAA receptor activation. GABAA
      receptor functional activity can be measured in discrete cells located in
      neuroanatomically defined populations within areas such as the neocortex and
      hippocampus. Changes in intracellular Cl- can also be studied under various
      conditions such as oxygen/glucose deprivation ("in vitro ischemia") and
      excitotoxicity. In such cases, changes in cell volume may also occur due to the
      dependence of cell volume regulation on Na+, K+, and Cl- flux. Because changes in
      cell volume can affect optical fluorescence measurements, we assess cell volume
      changes in the brain slice using the fluorescent indicator calcein-AM.
      Determination of changes in MEQ fluorescence versus calcein fluorescence allows
      one to distinguish between an increase in intracellular Cl- and an increase in
      cell volume.

PMID- 10356352
TI  - Simultaneous optical recording of membrane potential and intracellular calcium
      from brain slices.
AB  - Optical recording techniques provide a constantly evolving and increasingly
      powerful set of tools for investigations of cellular physiology. These techniques
      rely on the use of optical indicators, molecules that change their optical
      properties depending on the cellular parameter of interest. In this paper we
      discuss some of the general considerations involved in recording optical signals
      from multiple indicators. Specifically, we describe a technique for
      simultaneously recording transients of membrane potential and intracellular
      calcium concentration, two parameters that have a very complex interrelationship
      in neuronal functioning. This technique relies on the use of two fluorescent
      indicators (the voltage-sensitive dye RH-414 and the calcium-sensitive dye
      Calcium Orange) that have overlapping excitation spectra but separable emission
      spectra. This fact, in combination with the use of fast, spatially resolving
      photodetectors (10 x 10-element photodiode matrices), allows for truly
      simultaneous recording of these transients from brain slices with high spatial (
      approximately 200 x 200 microm with a 10x microscope objective) and temporal (
      approximately 500 micros) resolution. Furthermore, the quality of the signals
      obtained is sufficient to allow for recording of spontaneous synchronized
      activity such as epileptiform activity induced by the potassium channel blocker 4
      aminopyridine. The nature of the signals obtained by these indicators recorded
      from guinea pig hippocampal slices and some applications of this technique are
      discussed.

PMID- 10356353
TI  - Detecting action potentials in neuronal populations with calcium imaging.
AB  - The study of neural circuits requires methods for simultaneously recording the
      activity of populations of neurons. Here, using calcium imaging of neocortical
      brain slices we take advantage of the ubiquitous distribution of calcium channels
      in neurons to develop a method to reconstruct the action potentials occurring in
      a population of neurons. Combining calcium imaging with whole-cell or perforated
      patch recordings from neurons loaded with acetoxymethyl ester or potassium salt
      forms of calcium indicators, we demonstrate that each action potential produces a
      stereotyped calcium transient in the somata of pyramidal neurons. These signals
      are detectable without averaging, and the signal-to-noise is sufficient to carry
      out a reconstruction of the spiking pattern of hundreds of neurons, up to
      relatively high firing frequencies. This technique could in principle be applied
      systematically to follow the activity of neuronal populations in vitro and in
      vivo.

PMID- 10356354
TI  - Confocal imaging of microglial cell dynamics in hippocampal slice cultures.
AB  - Methods are described for imaging the cellular dynamics of microglia in live
      mammalian brain slice cultures. Brain slices prepared from developing rat
      hippocampus are cultured for up to 2 weeks by the roller tube or static filter
      culture technique, stained with one or more fluorescent dyes, and imaged by
      scanning laser confocal microscopy. One of several cell type-specific or
      nonspecific fluorescent dyes can be used independently or in combination to label
      cells in live brain tissues. The fluorescently conjugated plant isolectin GSA-IB4
      is useful for identifying microglia and for following their structure, movement,
      and proliferation. Live and dead neurons and glia can be distinguished using
      membrane-permeant and -impermeant fluorescent nucleic acid dyes. Nonspecific
      fluorescent lipids such as DiIC18 can be used as a vital stain to label
      populations of endocytic and phagocytic cells. Using multichannel confocal
      imaging, tissue slices that are single-, double-, or triple-labeled can be imaged
      in the living state in two or three spatial dimensions as well as in time. This
      provides a means for investigating the cell-cell interaction and dynamic behavior
      of microglia and other cell types in live brain tissues cultured under various
      physiological conditions.

PMID- 10356356
TI  - The role of rho family GTPases in development: lessons from Drosophila
      melanogaster.
AB  - It has become increasingly clear in the last few years that the Rho family
      GTPases regulate cytoskeleton rearrangements that are essential for a variety of
      morphogenetic events associated with the development of multicellular organisms.
      In particular, Drosophila has provided an excellent in vivo system for
      deciphering the signaling pathways mediated by Rho GTPases, as well as
      establishing the role of these pathways in numerous developmental processes.
      Continued use of this system will undoubtedly lead to the identification of
      additional Rho signalling components and information regarding the function and
      organization of the Rho signaling pathways in tissue morphogenesis. The striking
      similarity between Drosophila and mammalian Rho signaling components identified
      thus far indicates that the Rho pathways are highly conserved in evolution.
      Therefore, the findings from the Drosophila system can be extrapolated to higher
      organisms, including humans. Combined with the rapid progress in the human and
      Drosophila genome projects, these findings should contribute greatly to our
      understanding of mammalian Rho GTPase signaling pathways and their roles in
      normal development and pathological conditions.

PMID- 10356355
TI  - Two-photon imaging in living brain slices.
AB  - Two-photon excitation laser scanning microscopy (TPLSM) has become the tool of
      choice for high-resolution fluorescence imaging in intact neural tissues.
      Compared with other optical techniques, TPLSM allows high-resolution imaging and
      efficient detection of fluorescence signal with minimal photobleaching and
      phototoxicity. The advantages of TPLSM are especially pronounced in highly
      scattering environments such as the brain slice. Here we describe our approaches
      to imaging various aspects of synaptic function in living brain slices. To
      combine several imaging modes together with patch-clamp electrophysiological
      recordings we found it advantageous to custom-build an upright microscope. Our
      design goals were primarily experimental convenience and efficient collection of
      fluorescence. We describe our TPLSM imaging system and its performance in detail.
      We present dynamic measurements of neuronal morphology of neurons expressing
      green fluorescent protein (GFP) and GFP fusion proteins as well as functional
      imaging of calcium dynamics in individual dendritic spines. Although our
      microscope is a custom instrument, its key advantages can be easily implemented
      as a modification of commercial laser scanning microscopes.

PMID- 10356357
TI  - Activation of a functionally distinct 80-kDa STAT5 isoform by IL-5 and GM-CSF in
      human eosinophils and neutrophils.
AB  - Interleukin-5 (IL-5), IL-3, and granulocyte macrophage colony-stimulating factor
      (GM-CSF) are hematopoietic cytokines which signal through a common beta subunit
      (betac) of a heterodimeric receptor. Among the intracellular signaling pathways
      activated via betac is the JAK/STAT pathway. We show that different STAT5
      isoforms are activated by IL-5 and GM-CSF in eosinophils, neutrophils, and
      differentiated eosinophilic HL-60 cells. Whereas IL-5 activated the wild-type
      STAT5A and STAT5B proteins in HL60-eos cells, a carboxyl-terminally truncated 80
      kDa STAT5 isoform was activated in mature eosinophils and neutrophils.
      Surprisingly, while both isoforms bind strongly to an element from the beta
      casein promoter, only p80 STAT5 binds to the ICAM1-IRE. Consequently, a carboxyl
      terminal truncated STAT5 is capable of blocking STAT3-mediated transcription of
      an IREtkCAT reporter construct. The cell type-specific expression of these
      functionally distinct STAT5 isoforms might contribute to the pleiotropic effects
      of IL-5 and GM-CSF on different target cells.

PMID- 10356358
TI  - Cell adhesion properties and effects on receptor-mediated insulin endocytosis are
      independent properties of pp120, a substrate of the insulin receptor tyrosine
      kinase.
AB  - pp120 undergoes phosphorylation by the tyrosine kinase of the insulin, not the
      insulin-like growth factor 1 (IGF-1), receptor. Moreover, pp120 stimulates
      receptor-mediated insulin, but not IGF-1, endocytosis, suggesting that pp120
      phosphorylation underlies its effect on insulin endocytosis. pp120
      phosphorylation also underlies its bile acid transport and tumor suppression
      functions. In addition to depending on the intracellular tail, the cell adhesion
      property of pp120 depends on Arg98 in the N-terminal IgV-like ectoplasmic domain.
      To investigate whether this domain mediates the effect of pp120 on insulin
      endocytosis, we mutated Arg98 to Ala and examined whether this mutation altered
      pp120 phosphorylation and its effect on ligand endocytosis in transfected NIH 3T3
      cells. This mutation did not modify either pp120 phosphorylation or its effect on
      receptor-mediated ligand endocytosis. These findings support the hypothesis that
      stimulation of insulin endocytosis by pp120 is not mediated by Arg98 in the N
      terminal IgV-like ectoplasmic domain of pp120.

PMID- 10356359
TI  - Activation of Jak-Stat and MAPK2 pathways by oncostatin M leads to growth
      inhibition of human glioma cells.
AB  - Oncostatin M (OSM) is a cytokine of the IL-6 family that modulates the growth of
      various cell types, at least in vitro. We have recently described that OSM
      inhibits growth and changes cell morphology of human glioma cell lines. Although
      leukemia inhibitory factor (LIF) receptor components are also expressed by these
      cells, the response to LIF was significantly weaker compared to OSM. We have
      therefore analyzed the signal transduction pathways induced by these cytokines.
      While OSM induces a number of strong tyrosine phosphorylations, including Janus
      tyrosine kinases (Jak) and the signal transducer and activator of transcription
      (Stat) proteins, LIF induces only minor tyrosine phosphorylation of Tyk2 and
      Stat3. Specific activation of the tyrosine phosphatase SHP-2 as well as the
      mitogen-activated kinase 2 (MAPK2) was found in glioma cells upon OSM treatment.
      MAPK2 turns out to be a crucial mediator of the OSM effect in glioma cells since
      inhibition of MAPK activity by the Mek1 inhibitor PD98059 blocks the OSM-induced
      inhibition of DNA synthesis by about 70%.

PMID- 10356360
TI  - Homeobox proteins as signal transduction intermediates in regulation of NCAM
      expression by recombinant human bone morphogenetic protein-2 in osteoblast-like
      cells.
AB  - The role of homeobox genes in signaling of recombinant human bone morphogenetic
      protein-2 (rhBMP-2) was studied in osteoblast-like cells. Expression of several
      homeobox genes was decreased by rhBMP-2. The finding that this regulation of
      homeobox gene expression by rhBMP-2 was not dependent on protein synthesis
      suggests that homeobox proteins can act as direct intermediates in signal
      transduction of BMPs. Therefore, we studied the regulation of neural cell
      adhesion molecule (NCAM), which has previously been described as a target gene of
      both rhBMP-2 and homeobox proteins. We now show that in osteoblast-like cells,
      rhBMP-2 inhibits NCAM expression, while HOXC6 increases its expression, both
      acting via the same region of the promoter. As overexpression of HOXC6 could
      abolish effects of rhBMP-2 on NCAM promoter activity, these data show for the
      first time that members of the homeobox gene family may form direct functional
      intermediates in the signaling mechanism of the TGF-beta superfamily.

PMID- 10356361
TI  - Transcriptional activation of the cyclin-dependent kinase inhibitor p21 by
      PML/RARalpha.
AB  - Acute promyelocytic leukemia (APL) is a result of clonal expansion of
      hematopoietic precursors blocked at the promyelocytic stage and is associated
      with a t(15;17) chromosomal translocation and the expression of the PML/RARalpha
      fusion protein. Treatment of APL cells with retinoic acid (RA) leads to complete
      remission by inducing growth arrest and differentiation of these cells into
      granulocytes. The cyclin-dependent kinase inhibitor p21WAF1/CIP1 may be involved
      in terminal differentiation associated growth arrest. We showed in this study
      that PML/RARalpha increased the transcription of p21WAF1/CIP1 gene and the
      activation was further induced by RA treatment. Deletion analysis revealed a
      region upstream of the p21WAF1/CIP1 promoter that is required for transactivation
      by PML/RARalpha. Transient transfection of PML/RARalpha in cells increased the
      endogenous p21WAF1/CIP1 protein levels. These results suggest that the induction
      of APL cells differentiation by RA may be a result of the activation of
      p21WAF1/CIP1 by PML/RARalpha.

PMID- 10356362
TI  - Compartmentalization of the mitogen-activated protein kinase (MAPK) in hepatic
      endosomes: association with the internalized epidermal growth factor (EGF)
      receptor.
AB  - A pool of MAPK was found in hepatic plasma membrane (PM) and endosomes (ENs).
      After injection of a single dose of EGF (10 microg/100 g body weight), MAPK was
      detected in EGF receptor (EGFR) immunoprecipitates prepared from ENs. MAPK was
      detected in a time-dependent manner in EGFR immunoprecipitates that was
      coincident with the progressive concentration of the EGFR. The EGFR-associated
      MAPK was also detected by using an anti-phospho-MAPK suggesting that it was
      active. MAPK was present in wheat-germ agglutinin (WGA) eluates prepared from ENs
      and was maximally tyrosine-phosphorylated at the time peak of EGFR
      internalization. MAPK therefore is compartmentalized in PM and ENs of rat liver.
      A fraction of the endosomal MAPK was found to be associated with the internalized
      EGFR complexes, suggesting that it plays a role in the control of the EGFR
      activity at this locus.

PMID- 10356363
TI  - Human glomerular epithelial cell express CD4 and interaction with gp120 protein
      promotes PYK2 tyrosine phosphorylation.
AB  - Focal segmental glomerulosclerosis (FSGS) is the predominant glomerular lesion in
      patients with HIV infection. Visceral glomerular epithelial cell (vGEC) injury is
      a key feature of this glomerular lesion. However, the exact mechanism of HIV-1
      induced vGEC injury is not clear. We studied the presence of CD4 (HIV-1 receptor)
      in vGECs. vGECs were cultured from human kidneys and used during the 5th to 10th
      passages. Immunocytochemical studies were carried out to visualize CD4 receptors
      in these cells. Protein and RNA were extracted from vGECs and renal cortical
      tissues. Western and Northern blots were generated and probed for the expression
      of CD4. To determine the downstream effect of ligand receptor interaction, vGECs
      were treated either with variable concentrations of HIV-1 gp120 protein (0.001 to
      0.1 microg/ml) for 1 min or with a fixed dose of gp120 protein (0.01 microg/ml)
      for variable time periods (0 to 10 min), and at the end of the incubation period,
      tyrosine phosphorylation of pyk2 was studied. Immunocytochemical studies showed
      the presence of CD4 receptors in vGECs. Western and Northern blot studies
      confirmed the presence of CD4 expression in these cells. gp120 protein promoted
      vGEC tyrosine phosphorylation of pyk2 in a dose- and time-dependent manner. The
      present study provides a mechanistical insight for the role of HIV-1 in the
      development of glomerular injury in patients with HIV infection.

PMID- 10356365
TI  - The SH3 and BH domains of the p85alpha adapter subunit play a critical role in
      regulating class Ia phosphoinositide 3-kinase function.
AB  - We have investigated the role of the SH3 and BH domains in the function of the
      p85alpha adapter/regulatory subunit of PI 3-kinase. In these studies epitope
      tagged adapter subunit constructs containing wild-type p85alpha, p85alpha lacking
      the SH3 domain (deltaSH3-p85alpha), or p85alpha lacking the Rac-GAP/BCR homology
      (BH) domain (deltaBH-p85alpha) were coexpressed with either the p110alpha or
      p110beta PI 3-kinase catalytic subunit in HEK293 cells. The deletion of either BH
      or SH3 domains had no effect on the intrinsic activity of the PI 3-kinase
      heterodimers. However, the ability of activated Rac to stimulate PI 3-kinase
      activity was only observed in heterodimers containing the p85alpha and deltaSH3
      p85alpha, indicating that rac binding to the BH domain is responsible for rac
      induced stimulation of class Ia PI 3-kinase. We also investigated the effect of
      SH3 and BH domain deletion on the ability of insulin to induce recruitment of
      these constructs into phosphotyrosine-containing signaling complexes. We find
      that p85alpha expressed alone is poorly recruited into such signaling complexes.
      However, when coexpressed with catalytic subunit, the p85alpha adapter subunit is
      recruited to an extent similar to that of endogenous p85alpha. Maximal insulin
      stimulation caused a similar level of recruitment of p85alpha, deltaSH3-p85alpha,
      and deltaBH-p85alpha to signaling complexes when these adapter subunits were
      coexpressed with catalytic subunit. However, there was a higher level of basal
      association of the deltaSH3-p85alpha and deltaBH-p85alpha with tyrosine
      phosphorylated proteins, meaning that the insulin-induced fold increase in
      recruitment was lower for these forms of the adapter. These results indicate that
      the N-terminal domains of p85alpha play a critical role in the way the adapter
      subunit responds to growth factor stimulation.

PMID- 10356364
TI  - Expression of a Y559F mutant CSF-1 receptor in M1 myeloid cells: a role for Src
      kinases in CSF-1 receptor-mediated differentiation.
AB  - We have established two M1 myeloid cell lines, M1/WT cells overexpressing the
      wild-type CSF-1 receptor and M1/Y559F cells expressing a specific tyrosine
      mutant. M1/WT cells differentiated in response to CSF-1, with a reduction in
      their proliferative capacity. CSF-1-mediated differentiation was partially
      abrogated in the M1/Y559F cells, with a less marked reduction in proliferative
      capacity. The Src tyrosine kinases c-Src, c-Yes, c-Fyn, and c-Hck were tyrosine
      phosphorylated in the M1/WT cells in response to CSF-1 and bound to the WT CSF-1R
      through their SH2 domains. Binding of the Src kinases to the CSF-1 receptor was
      greatly reduced in the M1/Y559F cells. CSF-1-mediated activation of STAT3 was
      also abrogated in the M1/Y559F cell line. Treatment of M1/WT cells with the Src
      family inhibitor PP2 resulted in an inhibition of CSF-1-mediated differentiation,
      equivalent to that observed in the M1/Y559F cells. These data suggest that the
      reduced Src binding observed in the M1/Y559F cells may contribute to their
      reduced ability to differentiate.

PMID- 10356366
TI  - GAL4 is a substrate for caspases: implications for two-hybrid screening and other
      GAL4-based assays.
AB  - Yeast two-hybrid technology as well as mammalian reporter assays use fusions
      between a protein of interest and the GAL4 DNA-binding domain (GAL4DB). We
      demonstrate that expression of a GAL4DB/caspase-1 chimeric protein in yeast leads
      to autoproteolytic cleavage of GAL4DB. Moreover, recombinant GAL4DB is a good in
      vitro substrate for recombinant caspase-1 and several other caspases. Cleavage
      sites map at the C-terminus of GAL4DB and result in release of the fused protein.
      The finding that GAL4DB can be cleaved by caspases has important implications for
      the use of caspases in two-hybrid analysis and in the interpretation of mammalian
      assays based on GAL4-dependent reporter gene expression.

PMID- 10356367
TI  - Localization of a class II phosphatidylinositol 3-kinase, PI3KC2alpha, to
      clathrin-coated vesicles.
AB  - We have analysed phosphatidylinositol 3-kinase activity associated with
      subcellular fractions prepared from rat brains. Phosphatidylinositol 3-kinase
      activity is not markedly enriched with synaptic vesicle purification; whilst the
      activity associated with the most pure fractions is inhibited at low
      concentrations of wortmannin (IC50 approximately 4-5 nM). In contrast, clathrin
      coated vesicle (CCV) fractions showed increased enzyme activity compared to light
      membrane fractions from which they are purified. In addition to a wortmannin
      sensitive activity, we also detected an activity that could only be inhibited at
      higher concentrations of wortmannin (IC50 approximately 400 nM), characteristic
      of certain class II enzymes (including phosphatidylinositol 3-kinase C2alpha) to
      be highly enriched in CCV fractions. Immunoblotting with an antibody raised
      against phosphatidylinositol 3-kinase C2alpha, confirmed that this enzyme is
      highly enriched in CCVs and displays an enrichment profile during the
      purification that mirrors enrichment of the low nanomolar wortmannin-insensitive
      activity. If the CCV purification protocol is adapted to favour nerve terminally
      derived vesicles, we find reduced levels of the C2alpha enzyme in the CCV
      fractions, suggesting that the enzyme may principally reside on vesicles
      associated with the cell body.

PMID- 10356368
TI  - Gender difference in management of epilepsy-what women are hearing.
AB  - This study reports the results of a questionnaire survey of female members of the
      British Epilepsy Association (BEA). The women were asked about their concerns
      about their epilepsy with respect to being female, and, in particular, asked
      about the information they had been given on important topics such as
      contraception and pregnancy. A questionnaire was sent to 6000 BEA female members
      of whom 1855 (31%) replied. Forty-six percent of the women (mainly aged between
      26 and 45) stated that they currently used some form of contraception. The most
      frequently used method was the condom (34%). Twenty-two percent of the women
      using contraception were taking the oral contraceptive pill whilst a further 4%
      were using a hormonal contraceptive injection. Fifty-one percent of the women
      aged between 16 and 55 claimed not to have received any advice about possible
      interactions between contraception and antiepileptic drug therapy. With regards
      to pregnancy, 34% claimed they had not received any advice and 25% had not
      discussed pregnancy with anyone. The women planning to have children over the
      subsequent 2 years received the greatest amount of advice about epilepsy and
      pregnancy, although 20% still claimed not to have received any information.
      Thirty-four percent of the women in the study stated that they were either
      menopausal or post-menopausal. Twenty-nine percent of women who had taken hormone
      replacement therapy in the past reported an increase in seizure frequency
      compared with 18% amongst current users. This survey has shown that women with
      epilepsy want, and need, more information and counselling about issues relating
      to contraception, pregnancy and the menopause.

PMID- 10356369
TI  - Observations on the misdiagnosis of generalized epilepsy as partial epilepsy:
      causes and consequences.
AB  - More therapeutic options (surgical and pharmacologic) are available for partial
      than for generalized epilepsies. This report describes and analyzes a possible
      bias to diagnose focal epilepsies. Data were prospectively collected on patients
      who underwent noninvasive prolonged EEG-video monitoring over a 2-year period at
      an epilepsy program. Cases where the diagnosis of 'partial seizures' (after
      monitoring) was questionable were identified and the data reviewed. Sixteen cases
      were identified. (a) Six had an idiopathic generalized epilepsy. All had
      generalized tonic-clonic (GTC) seizures, two had myoclonic seizures, and three
      had typical absences. All patients had generalized spikes and spike-wave
      complexes. All had normal IQs and normal brain imaging. One patient underwent
      invasive EEG. (b) Ten patients had a symptomatic or cryptogenic generalized
      epilepsy. IQs ranged from 49 to 74 (mean: 63). All patients had diffuse EEG
      slowing, and generalized ictal EEG patterns. Interictal EEG showed generalized
      spike-wave complexes in nine, and multifocal spikes in five. Seizures included
      GTC in all, generalized tonic in four, and atypical absences in two. Two of the
      10 patients underwent invasive EEG. The misdiagnosis of generalized epilepsy as
      partial epilepsy occurs for both idiopathic and cryptogenic or symptomatic
      generalized epilepsies, more often in the latter case. Risk factors may include:
      asymmetry in EEG or seizure semeiology, the eagerness to enroll in drug studies
      or surgical programs, and the lack of team thinking involving several
      epileptologists. This problem is almost certainly under-reported and may
      occasionally result in unwarranted invasive procedures.

PMID- 10356370
TI  - Follow-up of psychogenic, non-epileptic seizures: a pilot study - experience in a
      Dutch special centre for epilepsy.
AB  - A follow-up study was performed in 33 patients with proven (ictal EEG-CCTV)
      psychogenic, non-epileptic seizures (PNES). These patients received a
      questionnaire to evaluate seizures, treatment and rehabilitation. The response
      group consisted of 21 females (80% response) and seven males (100% response).
      Follow-up after diagnosis varied from 23-67 months. Seven patients (25%) reported
      that seizures had ceased and of the patients not seizure-free seven did report a
      seizure-free period after diagnosis of an average 6.7 months. Eight patients were
      on antiepileptic drugs again. Of 13 patients referred for psychotherapy, who also
      did receive treatment, six became free of seizures and seven did not. Of seven
      patients also referred, but who did not receive psychotherapy, all continued to
      have seizures. On a self-rating scale to compare "overall function" at the time
      of diagnosis and follow-up, 75% considered themselves to have "improved", but no
      improvement could be detected in psychosocial functioning.

PMID- 10356371
TI  - Postictal symptoms help distinguish patients with epileptic seizures from those
      with non-epileptic seizures.
AB  - The aim of the study was to assess whether post-ictal symptoms can help
      distinguish patients who have epileptic seizures from those with non-epileptic
      seizures (NES). We reviewed the spontaneous responses to the question 'What
      symptoms do you have after a seizure?' in 16 patients with epileptic seizures
      (predominantly focal with secondary generalization or generalized tonic-clonic)
      and 23 NES patients. Six of the 16 patients (38%) vs. only one of 23 NES patients
      (4.3%) noted post-ictal headache (P = 0.008). Nine epilepsy patients (56%) vs.
      three NES patients (13%) reported post-ictal fatigue (P = 0.004). Confusion or
      other symptoms did not distinguish epilepsy patients from those with NES. All
      epilepsy patients had at least one post-ictal symptom while 12 NES patients (52%)
      had none (P = 0.001). Therefore, patients evaluated for epileptic vs. non
      epileptic seizures who have post-ictal fatigue or headache, are more likely to
      have epileptic seizures. Patients with a diagnosis of NES who note post-ictal
      fatigue or headache should be investigated further.

PMID- 10356372
TI  - The value of provocation methods in patients suspected of having non-epileptic
      seizures.
AB  - Non-epileptic seizures (NES) are reported in 18-23% of patients referred to
      comprehensive epilepsy centres. Non-epileptic seizures may also be present in 5
      20% of the patients who are diagnosed as having refractory seizures. Because of
      their prevalence, financial and psychosocial outcomes cannot be ignored and
      accurate diagnosis is of the utmost importance. Various methods of seizure
      induction have been developed with the aim of differentiating epileptic from non
      epileptic seizures. However, recording the attacks by video-EEG monitoring is the
      gold standard. In our outpatient EEG laboratory we try to induce seizures with
      verbal suggestion or IV saline infusion in patients who are referred by a
      clinician with the diagnosis of probable non-epileptic seizures. In this study we
      investigated the results of 72 patients who were referred between January 1992
      June 1996. Non-epileptic seizures were observed in 52 (72.2%) patients. Thirteen
      of these patients still had risk factors for epilepsy. We could not decide
      whether all of their previous attacks were non-epileptic because 10-30% of the
      patients with NES also have epileptic seizures. For a more accurate diagnosis it
      was decided that these 13 patients, together with the 20 patients who did not
      have seizures with induction, needed video-EEG monitoring. Thirty-nine patients
      who had NES and no risk factors for epilepsy were thought to have pure non
      epileptic seizures. We claim that not all patients suspected of having NES need
      long-term video-EEG monitoring and almost half (54.2%) of the cases can be
      eliminated by seizure induction with some provocative techniques.

PMID- 10356373
TI  - Meeting the educational needs of general practitioners for epilepsy.
AB  - Epilepsy care in general practice has been criticized, but what do GPs feel they
      deal with most and complete satisfactorily? If criticism is justified, education
      should be useful in improving epilepsy care, but what do general practitioners
      want to learn and how do they want to learn it? Questionnaires about these issues
      were sent to randomly chosen general practitioners throughout the United Kingdom.
      One hundred and twenty-four out of 200 (62%) responded. They were not biased by
      age, sex, type of practice or previous interest in epilepsy. Drug treatment and
      regular review were the two areas of care GPs said they dealt with most, but only
      half felt they dealt with them well. Sixty-six percent wanted to learn more about
      drug treatment, 46% about lifestyle advice, 45% about non-drug treatment, 44%
      about diagnosis and only 16% did not want to learn more about any aspect of care.
      Weekdays and evenings were the preferred times for study. Courses up to one full
      day away from practices were popular, distance learning and personal education
      plans were not, except for a group of younger GPs. When attending courses multi
      disciplinary lectures rated highly and nearly three-quarters preferred to attend
      courses where epilepsy was covered in conjunction with other conditions. Future
      epilepsy education for GPs should recognize these findings if attendance and
      positive outcomes are to be maximized.

PMID- 10356374
TI  - Acute symptomatic seizures - incidence and etiological spectrum: a hospital-based
      study from South India.
AB  - We analysed the incidence and etiological spectrum of acute symptomatic seizures
      in 2531 patients with seizure disorder, both in-patients and out-patients, seen
      in a university hospital in South India. Seizure(s) occurred in close temporal
      association with an acute systemic, metabolic, or toxic insult or in association
      with an acute central nervous system (CNS) insult in 22.5% of patients. Of the
      572 patients, 8% could be grouped under the International League Against Epilepsy
      (ILAE) category 4.1 and 92% under category 1.2. The seizure type was generalized
      in all the patients included in category 4.1 and 78% of patients grouped in
      category 2.1 had simple or complex partial seizure(s) with or without secondary
      generalization. Sixteen (3%) patients developed status epilepticus during the
      acute phase of illness and 7% of patients had only single seizure. Infections of
      the central nervous system (CNS) and single CT enhancing lesions (SCTEL) together
      accounted for 77% of the provoking factors in patients grouped under category
      2.1. These two etiological factors together accounted for 95% of etiologies in
      patients aged under 16 years. SCTEL and neurocysticercosis together accounted for
      67% of the provoking factors. In 14% of patients cerebrovascular diseases were
      the etiological factors and 60% of the patients were aged over 40 years. In
      patients with cerebrovascular diseases, aged under 40 years, cortical sinovenous
      thrombosis accounted for 37%. SCTEL was the provoking factor in 61% of patients
      with isolated seizure. Infections of CNS and SCTEL together accounted for 62.5%
      of etiological factors for status epilepticus. This study illustrates that the
      etiological spectrum of acute symptomatic seizures in this part of the world is
      different from that described from developed countries and CNS infections account
      for a significant number of cases.

PMID- 10356375
TI  - An audit of admissions of patients with epilepsy to a district general hospital.
AB  - The results of an audit of the admission of epilepsy sufferers in a UK District
      General Hospital are presented. The results strongly suggest that most admissions
      were due to potentially mutable problems including poor compliance with
      medication rather than to difficult epilepsy per se. It is suggested that
      consistent support of these patients, for example by an epilepsy nurse
      specialist, would have perhaps prevented many of these admissions. Care of these
      patients in hospital failed to achieve standards set by various guidelines for
      epilepsy management.

PMID- 10356376
TI  - The effect of acupuncture in chronic intractable epilepsy.
AB  - We examined the effect of acupuncture on epileptic seizures in humans in a
      controlled clinical setting. Treatment was administered by two Chinese professors
      of acupuncture. Effect was measured by change in seizure frequency. Twenty-nine
      patients with chronic intractable epilepsy completed the study. They were
      randomized in two groups; 15 were given classical acupuncture and 14 were given
      sham acupuncture. There was a reduction in seizure frequency in both groups,
      which did not reach a level of statistical significance. There was also an
      increase in the number of seizure-free weeks in both groups, which reached a
      level of significance in the sham group. Thus, we have not been able to prove a
      beneficial effect of acupuncture in chronic intractable epilepsy.

PMID- 10356377
TI  - The management of epilepsy in a hospital for people with a learning disability.
AB  - The study examined changes in the use of antiepileptic drugs (AEDs) in a large
      hospital for people with a learning disability over a 2 year period, the use of
      investigations, and the presence of medication side-effects. The surveys were
      carried out in 1993 and 1995/6. In 1993, 27% of patients were being treated for
      epilepsy and in 1995/6, 30.1%. Ninety percent and 82.4% of patients,
      respectively, were receiving one or two AEDs. In the second survey there were
      fewer prescriptions for phenobarbitone (5.8% vs. 12.5%) and an increase in the
      use of lamotrigine (21.6% vs. 5%), gabapentin (5.8% vs. 0) and vigabatrin (3.9%
      vs. 2.5% in 1993). Side-effects were recorded in 6 (11.8%) patients. Seven
      (21.2%) patients receiving carbamazepine were found to have hyponatraemia. Of the
      54 electroencephalograms (EEGs) requested, 41 (76%) were reported as abnormal.
      Six CT brain scans had been conducted, of which five were abnormal. People
      receiving antipsychotic drugs had fewer seizures than average.

PMID- 10356378
TI  - Long-term treatment with vigabatrin - 10 years of clinical experience.
AB  - This report describes the long-term follow-up of 56 patients with refractory
      partial epilepsy who, within 3 months of vigabatrin add-on therapy (3 g/day),
      showed a reduction in monthly seizure frequency of more than 50%. The short-term
      (6 months) and long-term (5 years) effects of vigabatrin on seizure frequency in
      this patient cohort have been published separately. The reduction in seizure
      frequency appeared to be long-lasting in the patients followed-up (n = 36) and,
      importantly, a significant number of the patients (n = 7) became seizure-free,
      especially during long-term treatment. Thus, the efficacy of vigabatrin appears
      to be progressive, at least in patients who show an early response to treatment.
      These results are consistent with experimental findings that suggest that
      vigabatrin may have anti-epileptogenic and neuroprotective effects.

PMID- 10356379
TI  - Accurate diagnosis of convulsive syncope: role of an implantable subcutaneous ECG
      monitor.
AB  - Convulsive syncope due to transient bradycardia is recognized as a cause of
      treatment-resistant seizures. However, the diagnosis may be difficult to make
      with conventional electrocardiographic devices if attacks are infrequent. We
      present a case of apparent epilepsy in which a new implantable
      electrocardiographic event recorder (the 'Reveal' insertable loop recorder) was
      used to show that attacks were caused by prolonged asystole of up to 36 s in
      duration. The insertable loop recorder may have an important role in the
      investigation of patients with treatment-resistant seizures, particularly where
      there is a strong suspicion of an underlying cardiac arrhythmia.

PMID- 10356380
TI  - A case of fever following antiepileptic treatment.
AB  - A 23-year-old female patient treated with 900 mg oxcarbazepine for complex
      partial seizures is presented. Good seizure control and slight fever were noted a
      few weeks after drug administration. Reduction of oxcarbazepine and replacement
      with valproate resulted in a transient normothermia. Because of fever
      reappearance, vigabatrin was added and valproate was gradually reduced. Seizures
      reappeared, but the body temperature fell below 37 degrees C. Substitution of
      valproate for lamotrigine resulted in seizure control but abnormal body
      temperature (37- 37.6 degrees C) was noted again. Repeated hospital admission for
      clinical and laboratory investigation before any change of treatment revealed no
      other abnormal findings. The patient's abnormal temperature possibly reflects a
      derangement of high-level temperature control.

PMID- 10356381
TI  - Successful treatment with gabapentin in the presence of hypersensitivity syndrome
      to phenytoin and carbamazepine: a report of three cases.
AB  - We report three consecutive patients with hypersensitivity syndrome (HSS) due to
      phenytoin and carbamazepine and successful treatment with gabapentin. HSS is a
      rare but potentially fatal reaction to multiple drugs including several
      anticonvulsants. Cross-reactivity among drugs may occur. Immediate withdrawal of
      the offending drug is the most important step in treatment. Benzodiazepines
      acutely and, after resolution of the hepatitis, valproic acid have been
      successfully used for seizure control in patients with HSS. Our cases indicate
      that gabapentin is also a safe anticonvulsant in HSS.

PMID- 10356383
TI  - Paediatric epilepsy syndromes and their surgical treatment 

PMID- 10356382
TI  - Epilepsy and other neurological disorders in coeliac disease 

PMID- 10356384
TI  - Global warming and performance of antiepileptic therapeutics.

PMID- 10356386
TI  - Announcements 

PMID- 10356385
TI  - Clinical and EEG findings in complex partial status epilepticus with tiagabine.

PMID- 10356387
TI  - Selfish sentinels in cooperative mammals.
AB  - Like humans engaged in risky activities, group members of some animal societies
      take turns acting as sentinels. Explanations of the evolution of sentinel
      behavior have frequently relied on kin selection or reciprocal altruism, but
      recent models suggest that guarding may be an individual's optimal activity once
      its stomach is full if no other animal is on guard. This paper provides support
      for this last explanation by showing that, in groups of meerkats (Suricata
      suricatta), animals guard from safe sites, and solitary individuals as well as
      group members spend part of their time on guard. Though individuals seldom take
      successive guarding bouts, there is no regular rota, and the provision of food
      increases contributions to guarding and reduces the latency between bouts by the
      same individual.

PMID- 10356388
TI  - Current-induced insulator-metal transition and pattern formation in an organic
      charge-transfer complex 
AB  - Organic molecular Mott insulators, in which carriers are localized as a result of
      the electron correlation, showed nonlinear electric conduction upon application
      of a high electric field along the molecular stacking axis. The current-driven
      low-resistive state of potassium 7,7,8,8-tetracyanoquinodimethanane was
      stabilized down to 2 kelvin, where a metallic path was visible with a microscope.
      The current flow caused a stripe-like periodic phase-segregation into the carrier
      rich and carrier-poor regions along the current path.

PMID- 10356389
TI  - Enhanced reactivity of highly vibrationally excited molecules on metal surfaces 
AB  - The chemical dynamics of highly vibrationally excited molecules have been studied
      by measuring the quantum state-resolved scattering probabilities of nitric oxide
      (NO) molecules on clean and oxygen-covered copper (111) surfaces, where the
      incident NO was prepared in single quantum states with vibrational energies of as
      much as 300 kilojoules per mole. The dependence of vibrationally elastic and
      inelastic scattering on oxygen coverage strongly suggests that highly excited NO
      (v = 13 and 15) reacts on clean copper (111) with a probability of 0.87 +/- 0.05,
      more than three orders of magnitude greater than the reaction probability of
      ground-state NO. Vibrational promotion of surface chemistry on metals (up to near
      unit reaction probability) is possible despite the expected efficient relaxation
      of vibrational energy at metal surfaces.

PMID- 10356390
TI  - Adsorbed layers and the origin of static friction 
AB  - Analytic results and experiments in ultrahigh vacuum indicate that the static
      friction between two clean crystalline surfaces should almost always vanish, yet
      macroscopic objects always exhibit static friction. A simple and general
      explanation for the prevalence of static friction is proposed. "Third bodies,"
      such as small hydrocarbon molecules, adsorb on any surface exposed to air and can
      arrange to lock two contacting surfaces together. The resulting static friction
      is consistent with experimental behavior, including Amontons' laws.

PMID- 10356391
TI  - Experimental evidence for the source of excess sulfur in explosive volcanic
      eruptions 
AB  - The amounts of sulfur released in explosive volcanic eruptions are often orders
      of magnitude larger than those expected to result from the degassing of the
      erupted SiO2-rich magma. Experimentally measured fluid/melt partition
      coefficients of sulfur ranged from 47 under oxidizing conditions (where SO2 is
      the dominant sulfur species in the fluid) to 468 under reducing conditions (where
      H2S dominates). Therefore, a few weight percent of hydrous fluid accumulated in
      the top of a magma chamber may extract most of the sulfur out of the entire magma
      reservoir and generate sulfur excesses upon eruption.

PMID- 10356392
TI  - A mid-european decadal isotope-climate record from 15,500 to 5000 years B.P 
AB  - Oxygen-isotope ratios of precipitation (delta18OP) inferred from deep-lake
      ostracods from the Ammersee (southern Germany) provide a climate record with
      decadal resolution. The record in detail shows many of the rapid climate shifts
      seen in central Greenland ice cores between 15,000 and 5000 years before the
      present (B.P.). Negative excursions in the estimated delta18OP from both of these
      records likely reflect short weakenings of the thermohaline circulation caused by
      episodic discharges of continental freshwater into the North Atlantic. Deviating
      millennial-scale trends, however, indicate that climate gradients between Europe
      and Greenland changed systematically, reflecting a gradual rearrangement of North
      Atlantic circulation during deglaciation.

PMID- 10356393
TI  - Topography of the lunar poles from radar interferometry: a survey of cold trap
      locations.
AB  - Detailed topographic maps of the lunar poles have been obtained by Earth-based
      radar interferometry with the 3.5-centimeter wavelength Goldstone Solar System
      Radar. The interferometer provided maps 300 kilometers by 1000 kilometers of both
      polar regions at 150-meter spatial resolution and 50-meter height resolution.
      Using ray tracing, these digital elevation models were used to locate regions
      that are in permanent shadow from solar illumination and may harbor ice deposits.
      Estimates of the total extent of shadowed areas poleward of 87.5 degrees latitude
      are 1030 and 2550 square kilometers for the north and south poles, respectively.

PMID- 10356394
TI  - Contribution of gular pumping to lung ventilation in monitor lizards.
AB  - A controversial hypothesis has proposed that lizards are subject to a speed
      dependent axial constraint that prevents effective lung ventilation during
      moderate- and high-speed locomotion. This hypothesis has been challenged by
      results demonstrating that monitor lizards (genus Varanus) experience no axial
      constraint. Evidence presented here shows that, during locomotion, varanids use a
      positive pressure gular pump to assist lung ventilation. Disabling the gular pump
      reveals that the axial constraint is present in varanids but it is masked by
      gular pumping under normal conditions. These findings support the prediction that
      the axial constraint may be found in other tetrapods that breathe by costal
      aspiration and locomote with a lateral undulatory gait.

PMID- 10356395
TI  - Purification and cloning of aggrecanase-1: a member of the ADAMTS family of
      proteins.
AB  - We purified, cloned, and expressed aggrecanase, a protease that is thought to be
      responsible for the degradation of cartilage aggrecan in arthritic diseases.
      Aggrecanase-1 [a disintegrin and metalloproteinase with thrombospondin motifs-4
      (ADAMTS-4)] is a member of the ADAMTS protein family that cleaves aggrecan at the
      glutamic acid-373-alanine-374 bond. The identification of this protease provides
      a specific target for the development of therapeutics to prevent cartilage
      degradation in arthritis.

PMID- 10356396
TI  - Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed.
AB  - Matrix metalloproteinases (MMPs) catalyze extracellular matrix degradation.
      Control of their activity is a promising target for therapy of diseases
      characterized by abnormal connective tissue turnover. MMPs are expressed as
      latent proenzymes that are activated by proteolytic cleavage that triggers a
      conformational change in the propeptide (cysteine switch). The structure of
      proMMP-2 reveals how the propeptide shields the catalytic cleft and that the
      cysteine switch may operate through cleavage of loops essential for propeptide
      stability.

PMID- 10356397
TI  - Genetics of mouse behavior: interactions with laboratory environment.
AB  - Strains of mice that show characteristic patterns of behavior are critical for
      research in neurobehavioral genetics. Possible confounding influences of the
      laboratory environment were studied in several inbred strains and one null mutant
      by simultaneous testing in three laboratories on a battery of six behaviors.
      Apparatus, test protocols, and many environmental variables were rigorously
      equated. Strains differed markedly in all behaviors, and despite standardization,
      there were systematic differences in behavior across labs. For some tests, the
      magnitude of genetic differences depended upon the specific testing lab. Thus,
      experiments characterizing mutants may yield results that are idiosyncratic to a
      particular laboratory.

PMID- 10356398
TI  - Crystal structure of the human papillomavirus type 18 E2 activation domain.
AB  - The papillomavirus E2 protein regulates viral transcription and DNA replication
      through interactions with cellular and viral proteins. The amino-terminal
      activation domain, which represents a protein class whose structural themes are
      poorly understood, contains key residues that mediate these functional contacts.
      The crystal structure of a protease-resistant core of the human papillomavirus
      type 18 E2 activation domain reveals a novel fold creating a cashew-shaped form
      with a glutamine-rich alpha helix packed against a beta-sheet framework. The
      protein surface shows extensive overlap of determinants for replication and
      transcription. The structure broadens the concept of activators to include
      proteins with potentially malleable, but certainly ordered, structures.

PMID- 10356399
TI  - The fourth dimension of life: fractal geometry and allometric scaling of
      organisms.
AB  - Fractal-like networks effectively endow life with an additional fourth spatial
      dimension. This is the origin of quarter-power scaling that is so pervasive in
      biology. Organisms have evolved hierarchical branching networks that terminate in
      size-invariant units, such as capillaries, leaves, mitochondria, and oxidase
      molecules. Natural selection has tended to maximize both metabolic capacity, by
      maximizing the scaling of exchange surface areas, and internal efficiency, by
      minimizing the scaling of transport distances and times. These design principles
      are independent of detailed dynamics and explicit models and should apply to
      virtually all organisms.

PMID- 10356401
TI  - Delayed-type hypersensitivity reactions to nominal protein antigens and to
      environmental allergens: similarities and differences.
AB  - Tuberculin-induced delayed type hypersensitivity and allergen-induced late phase
      responses are two types of cutaneous inflammatory reactions mediated by antigen
      specific T cells and involving distinct pathophysiological mechanisms. In humans,
      different types of cellular infiltration as well as cytokine profiles have been
      ascribed to each reaction. A more precise analysis of these reactions shows that
      in fact they are complementary, intricated, and cross regulatory, and that they
      represent interesting models to evaluate the regulation of some pathological
      disorders.

PMID- 10356400
TI  - The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation.
AB  - The two members of the atypical protein kinase C (aPKC) subfamily of isozymes
      (zetaPKC and lambda/iotaPKC) are involved in the control of nuclear factor kappaB
      (NF-kappaB) through IKKbeta activation. Here we show that the previously
      described aPKC-binding protein, p62, selectively interacts with RIP but not with
      TRAF2 in vitro and in vivo. p62 bridges the aPKCs to RIP, whereas the aPKCs link
      IKKbeta to p62. In this way, a signaling cascade of interactions is established
      from the TNF-R1 involving TRADD/RIP/p62/aPKCs/IKKbeta. These observations define
      a novel pathway for the activation of NF-kappaB involving the aPKCs and p62.
      Consistent with this model, the expression of a dominant-negative mutant
      lambda/iotaPKC impairs RIP-stimulated NF-kappaB activation. In addition, the
      expression of either an N-terminal aPKC-binding domain of p62, or its C-terminal
      RIP-binding region are sufficient to block NF-kappaB activation. Furthermore,
      transfection of an antisense construct of p62 severely abrogates NF-kappaB
      activation. Together, these results demonstrate that the interaction of p62 with
      RIP serves to link the atypical PKCs to the activation of NF-kappaB by the
      TNFalpha signaling pathway.

PMID- 10356402
TI  - Ultraviolet light and dendritic cells.
AB  - The ultraviolet (UV) spectrum is divided into UVC (200-280 nm), UVB (280-320 nm)
      and UVA (320-400 nm). Of these only UVB and UVA are of environmental significance
      since UVC is effectively absorbed by ozone in the earth's atmosphere. UVB
      wavelengths penetrate the epidermis and are almost completely absorbed in the
      upper dermis while UVA penetrates to the deep dermis.

PMID- 10356403
TI  - Tufted hair folliculitis: response to topical therapy with nadifloxacin.
AB  - Tufted hair folliculitis (THF) is a relatively rare disorder. We report two
      typical cases of THF, which are the first cases from Japan reported in the
      international literature and we discuss a new effective treatment for this
      condition.

PMID- 10356404
TI  - Marie Unna hereditary hypotrichosis.
AB  - Hereditary congenital hypotrichosis is an autosomal dominant pilar dysplasia
      first described by Marie Unna in an extended German family. The diffuse hair
      defect typically occurs as an isolated phenomenon and the ultrastructural hair
      findings consist of both torsion and longitudinal grooving of the hair shaft. A
      large pedigree comprising 6 generations with 20 members affected by Marie Unna
      hypotrichosis from Italy is reported.

PMID- 10356405
TI  - Heat shock protein HSP 27 is expressed in all types of basal cell carcinoma in
      low and high risk UV exposure groups.
AB  - HSP 27, a marker of differentiation and proliferation, helps the cell in repair
      processes after environmental stress such as heat, UV-irradiation and oxidative
      stress. So far, its role on carcinogenesis is not yet understood. HSP 27 was
      studied immunohistochemically in different types of primary, untreated basal cell
      carcinoma (BCC) in two populations with different UV exposure habits: descendents
      from Germany, "Pommern", living in Brazil (Pommeranos, n = 15), rural workers
      with high UV exposure and Germans from the region Baden-Wurttemberg with indoor
      jobs (n = 14). Age distribution and type of BCC were similar between the
      Pommeranos and the Germans. Specimens of BCC (n = 15 solid, n = 6 keratotic, n =
      4 adenoid, n = 4 fibrotic) were evaluated in cryostat and paraffin sections for
      HSP 27, HSP 72 and bcl-2. In Pommeranos in Brazil (UV high risk group) versus
      (vs) inhabitants from Baden-Wurttemberg (UV low risk group), HSP 27 was expressed
      in 93% vs 79% in all histological subclasses, HSP 72 in 20% vs 21% and bcl-2 in
      93 % in both groups. Antibodies against HSP 27, but not HSP 72, labeled BCC of
      all types. In contrast to the lack of HSP 27 in squamous cell carcinoma reported
      in the literature, we found HSP 27 and bcl-2 positive cells in BCC which might
      characterize the tumour as relatively benign and slow progressing.

PMID- 10356406
TI  - Twisted collagen fibrils in acrocyanosis.
AB  - Essential acrocyanosis (EA) present as a dusky discoloration of the hands as the
      sole symptom without any other abnormal results from laboratory investigation.
      Previously, the authors have found twisted collagen fibrils (TCF) in the normal
      skin of an EA patient. This study was intended to evaluate the significance of
      TCF in EA. Thirteen patients showing dusky discoloration were randomly selected
      and studied for TCF in normal skin by routine electron microscopy. TCF were found
      in 10 of 13 patients; 3 patients with only the discoloration (EA), 3 with the
      mild symptoms which were supposed to be Ehlers-Danlos syndrome (EDS), 1 with
      definite symptoms of EDS, 1 with Raynaud's disease and 2 with hyperglobulinemia.
      TCF were the ultrastructural sign for inherited malformation of collagen fibrils.
      EA was probably elucidated as a vascular disorder in TCF-carrying people. EA
      could be included in the disease category of EDS but it seems unreasonable to
      force EA patients into one of the subtypes of EDS. For pathogenesis, the
      inherited dysfunction in the hypertrophic pericytes of the subpapillary vascular
      plexus was presumed.

PMID- 10356407
TI  - Triterpenes from Centella asiatica stimulate extracellular matrix accumulation in
      rat experimental wounds.
AB  - Titrated Extract from Centella asiatica (TECA) is a drug which has been used for
      many years in Europe for the treatment of wound healing defects. It is a
      reconstituted mixture of 3 triterpenes extracted from the plant, asiatic acid,
      madecassic acid and asiaticoside. In this report, we studied the effects of TECA
      and its separated components in the wound chamber model described by Schilling et
      al. Stainless steel wound chambers were surgically inserted under the skin of
      rats and received serial injections of either TECA or its purified components.
      Chambers were collected at days 7, 14, 21 or 28 for biochemical analysis or
      histological examination. TECA-injected wound chambers were characterized by
      increased dry weight, DNA, total protein, collagen and uronic acid contents.
      Peptidic hydroproline was also increased, showing an increased remodeling of the
      collagen matrix in the wound. The 3 purified components of TECA were all able to
      reproduce the effects of the complete drug, with some differences depending on
      the product. Asiatic acid and asiaticoside were the most active of the 3
      triterpenes. Asiaticoside exerted a preferential stimulation of collagen
      synthesis and was active at low doses only. In addition to collagen, the 3
      components were also able to stimulate glycosaminoglycan synthesis.

PMID- 10356409
TI  - Two recent cases of tertiary syphilis.
AB  - Tertiary syphilis is now a rare disease in Europe, mainly as a result of
      occasional antibiotherapy for concomitant infections. However early syphilis is
      rising in USA and Germany, and it is necessary to maintain an high level of
      knowledge and suspicion to achieve a diagnosis in the tertiary stage of the
      disease. In this report two patients with benign tertiary syphilis are described.
      The first one is a 55-year-old female with erythemato-violaceous annular scaling
      plaques on the right buttock and scapula and on both thighs, which had a negative
      and then a low VDRL titer. The second case is a 33-year-old mentally handicapped
      female with erythematous plaques, with psoriasiform scaling in the trunk and well
      defined crusted ulcers on the face, which also had negative VDRL. Biopsy of the
      skin lesions revealed plasmocytic infiltrate with endothelial swelling without
      granulomas and with negative silver stains in both patients. The investigation
      for cardiovascular and neurological involvement was negative in both patients.
      Diagnosis of tertiary syphilis can be difficult as clinical pictures can be
      misleading, similar to other granulomatous diseases, and serological titers can
      be low or negative. We recall the necessity of ruling out neurological and
      cardiac involvement in this stage of syphilis. These cases are reported as a
      reminder of the possibility of syphilis, so that new cases are not misdiagnosed
      and mistreated as other diseases.

PMID- 10356408
TI  - Dendritic mast cells in prurigo nodularis skin.
AB  - Mast cells are traditionally recognized as round or oval connective tissue cells
      containing many specialized cytoplasmic granules. During recent years, more and
      more mast cell functions and properties have been clarified, and it is now
      evident that the mast cells are of different subtypes. The present study,
      utilizing chymase and tryptase immunofluorescence double-labelling and
      conventional electron microscopy techniques, has identified a kind of mast cells
      with obvious dendritic features in the lesional dermis of prurigo nodularis skin.
      This group of mast cell have enlarged cell bodies and contain fewer cytoplasmic
      granules, especially within certain dendrites. The morphological identification
      of such subgroups of mast cells could contribute to the understanding of mast
      cell heterogeneity.

PMID- 10356410
TI  - The seven features for melanoma: a new dermoscopic algorithm for the diagnosis of
      malignant melanoma.
AB  - The clinical diagnosis of melanoma has a mean sensitivity of 67%, dermoscopy or
      dermatoscopy is a non invasive technique which improves this sensitivity. Our
      purpose was to create a simple dermoscopic method for the diagnosis of melanoma
      useful in daily office practice. For this reason a training set of 218 cutaneous
      pigmented lesions was used and scored for 16 dermoscopic features: for each
      feature sensitivity, specificity and statistical significance were evaluated. The
      results were used to create a simple dermoscopic diagnostic method of only seven
      dermoscopic features (7FFM). The method was used to evaluate a test set of 713
      pigmented skin lesions consecutively observed. The diagnostic dermoscopic method
      developed gave a sensitivity of 94.6%, a specificity of 85.5% and an efficiency
      of 87.6%. Our method improves the sensitivity in the diagnosis of melanoma and
      can be used for the screening of pigmented skin lesions.

PMID- 10356411
TI  - Multiple piloleiomyomas associated with solitary angioleiomyoma.
AB  - A 58 year-old male had reddish scattered papules strictly confined to the right
      side of his upper back and neck, right shoulder, and right upper arm.
      Additionally, he also noticed a subcutaneous nodule on his left thigh.
      Histopathological examinations revealed that the papules on the back, nape of the
      neck, shoulder, and arm were multiple piloleiomyomas, as shown by the
      proliferation of bundles of smooth muscles in the dermis. The subcutaneous nodule
      of the thigh was angioleiomyoma with a well-circumscribed lesion composed of
      smooth muscles and blood vessels. Ipsilaterality and segmentality of the
      distribution of the papules of piloleiomyomas and probable family history that
      his mother had similar papules with a similar distribution suggest the nevoid
      character of our case. Piloleiomyomas are often reported to be associated with
      leiomyoma of the uterus or other organs. This is the first reported case of
      multiple piloleiomyomas with solitary angioleiomyoma in the literature.

PMID- 10356412
TI  - Hydroa vacciniforme persistent in a 60-year-old man.
AB  - Hydroa vacciniforme (HV) is an idiopathic photodermatosis with onset in
      childhood, a chronic-recurrent course, and spontaneous resolution in adolescence
      or early adulthood. We present a patient with typical HV in whom lesions began in
      childhood and continued until 60 years of age.

PMID- 10356413
TI  - Multiple rheumatoid papules characteristic of the early stage of rheumatoid
      vasculitis.
AB  - The rheumatoid papule has recently been described as the skin manifestation of
      rheumatoid arthritis (RA). The papules represent leukocytoclastic vasculitis and
      necrobiosis clinicopathologically. We report a 59-year-old Japanese woman with
      multiple recurrent rheumatoid papules located on the bilateral extensor forearms
      in correlation with the level of RA activity and as a cutaneous manifestation of
      rheumatoid vasculitis. These papules appeared prior to other cutaneous
      manifestations. It was suggested that rheumatoid papules represent the early
      stage of rheumatoid vasculitis and that they are a reliable early clinical marker
      of rheumatoid vasculitis.

PMID- 10356414
TI  - Ofuji's papuloerythroderma. An association with early gastric cancer.
AB  - A case of Ofuji's papuloerythroderma in an 88-old man, affected by early gastric
      cancer, is reported. The association noticed in our case with early visceral
      malignancy is the starting point for the consideration of pathological
      relationships, nosological and prognostic evaluations in regard to this rare
      dermatosis which is distinctive of elderly people, and underlines the importance
      of a long-term follow-up of these patients.

PMID- 10356415
TI  - Pro and contra of specific hyposensitization.
AB  - Specific hyposensitization is the practice of administering gradually increasing
      quantities of a specifically relevant allergen to allergic patients until
      reaching a maintenance dose or loss of symptoms. The most important hypothesis
      regarding the mechanism is a switch from a Th 2- into a Th 1 reaction pattern in
      the T cell regulation. The efficacy of specific hyposensitization has been
      assessed in controlled studies. Allergen extracts are obtained by extraction of
      the active constituents from animal or vegetable substances with a suitable
      menstruum. There is a great assortment of different allergen extracts available,
      but only standardized extracts should be used. Specific hyposensitization is a
      causal treatment for patients with IgE-mediated allergies like seasonal or
      perennial allergic rhino-conjunctivitis, asthma or hymenoptera venom allergy. The
      principal and most effective route of allergen application is the subcutaneous
      injection. The risk of side effects, especially life threatening anaphylaxis must
      be considered and can be minimized by careful allergology practice.
      Oral/sublingual application of allergen extracts is still discussed
      controversially. Specific hyposensitization requires the high motivation and
      cooperation of an informed patient.

PMID- 10356416
TI  - The role of crystals in osteoarthritis.
AB  - The deposition of calcium-containing crystals in articular tissues is probably an
      under-recognized event. Clinical observations indicate that an exaggerated and
      uniquely distributed cartilage degeneration is associated with these deposits.
      Measurements of putative markers of cartilage breakdown suggest that the presence
      of these crystals magnifies the degenerative process. In vitro studies indicate
      two potential mechanisms by which crystals cause degeneration. These involve the
      stimulation of mitogenesis in synovial fibroblasts and the secretion of proteases
      by cells that phagocytose these crystals. Approaches that might ameliorate the
      degenerative process may ensue from new information about how crystals form and
      how they exert their biologic effects.

PMID- 10356417
TI  - The role of nitric oxide in articular cartilage damage.
AB  - The production of large amounts of NO in vitro by cytokine-activated chondrocytes
      has been established. In vitro studies suggest that NO compromises chondrocyte
      survival. The role of NO in regulating matrix biosynthesis and degradation has
      received much attention. Most studies indicate that NO is at least partly
      responsible for IL-1-induced suppression of glycosaminoglycan and collagen
      synthesis. NO also may be involved as a mediator of IL-1-induced expression of
      MMP, mRNA, and protein and may contribute as an activator of the latent forms of
      the enzymes. Although the interaction of NO and prostaglandins is of considerable
      interest, current data are inconclusive with respect to the role of NO in the
      regulation of prostaglandin synthesis, although it seems clear that prostaglandin
      is not involved in NO synthesis. It is important to note that NO does have
      protective effects in cartilage and other tissues. Under certain conditions, NO
      may have anabolic and anticatabolic effects in cartilage. In other tissues,
      notably in skin and muscle, NO has been found to have a stimulatory role in
      extracellular matrix repair. In antimicrobial defense, in general, and in
      bacterial arthritis specifically, NO is an important protective molecule.
      Production of NO in arthritis-affected cartilage and synovium is a consistent
      feature of human and experimentally induced arthritis. The production of NO is
      associated with matrix degradation and chondrocyte apoptosis. The administration
      of NO synthase inhibitors in experimentally induced arthritis has resulted in
      reduction of synovial inflammation and destruction of cartilage and bone.

PMID- 10356418
TI  - The role of muscle weakness in the pathogenesis of osteoarthritis.
AB  - To date, very few studies have investigated the role of muscle dysfunction in the
      pathogenesis of osteoarthritis (OA). Using largely indirect evidence, this
      article hypothesizes that motor and sensory dysfunction of muscle may be
      important factors in the pathogenesis of articular damage and are not simply a
      consequence of joint damage. A new paradigm is constructed to better describe the
      complex interrelationship between muscle sensorimotor dysfunction, joint damage,
      and disability in OA. If the hypothesis is correct, because muscle is a
      relatively plastic tissue, maintaining well-conditioned muscles may delay or
      prevent the onset of OA, and rehabilitation exercise therapy that reverses muscle
      sensorimotor dysfunction may ameliorate the effects of OA.

PMID- 10356419
TI  - Proprioceptive impairment in knee osteoarthritis.
AB  - Proprioception, the perception of limb position in space, is derived from
      afferent signals originating primarily from musculotendinous and joint receptors.
      Proprioception is critical to the maintenance of joint stability. Studies have
      demonstrated that proprioception is less accurate in patients with knee
      osteoarthritis versus elderly control subjects, in healthy older versus younger
      subjects, and in the setting of other conditions affecting the knee including
      anterior cruciate ligament deficiency and hypermobility syndrome. Possible
      pathways between proprioceptive inaccuracy, knee osteoarthritis, and related knee
      disorders are described.

PMID- 10356420
TI  - Vitamins and arthritis. The roles of vitamins A, C, D, and E.
AB  - There are at least four mechanisms whereby the nutrient vitamins A, C, D, and E
      may be related to the processes that impede or give rise to OA. These nutrient
      vitamins have major roles in modulating oxidative stress, participating in immune
      responses, and contributing to cell differentiation. There is a substantial need
      to understand the contribution of these nutrients to OA, because they may provide
      important insight into ameliorating the initiation and progression of the
      disease. Simultaneously, greater understanding will add rationality to an area of
      potential intervention that is often based on anecdote. Investigation will be
      complex; there is the need to select appropriate systems. Typical animal model
      systems used in the study of OA are inappropriate because most animals can
      synthesize ascorbic acid. There is the need to disaggregate, as much as possible,
      the numerous subsets of OA and the plethora of processes that contribute to that
      heterogeneity. Certainly, there is the need to recognize the interdependency of
      the actions of each of these nutrients at the cellular level. Furthermore, humans
      rarely consume these nutrients as independent products. For example, watermelon
      is a primary source of both ascorbic acid and beta-carotene. Failure to address
      these complexities denies the scientist the opportunity to advance our
      understanding of health and disease processes. More importantly, failure to
      address these complexities denies the person with OA the opportunity to address
      his or her own health.

PMID- 10356421
TI  - Potential treatment of osteoarthritis by gene therapy.
AB  - OA is common, debilitating, costly, incurable, and, in many cases, resistant to
      treatment. Novel approaches to therapy are clearly required. Progress in
      understanding the biology of cartilage and OA have led to our suggestion of a
      gene therapy approach to treatment. Genes whose products stimulate chondrogenesis
      or inhibit breakdown of the cartilaginous matrix are obviously candidates for
      therapeutic use. These genes may be transferred to the synovium or cartilage of
      affected joints by in vivo or ex vivo means using a variety of vectors. Transfer
      of such genes to chondroprogenitor cells is a particularly attractive approach.

PMID- 10356422
TI  - Viscosupplementation therapy with intra-articular hyaluronic acid. Fact or
      fantasy?
AB  - Pharmacologic therapy for osteoarthritis is presently only palliative and is
      based on the use of analgesic or anti-inflammatory agents. Simple analgesics,
      however, do not provide enough of an effect to satisfy the needs of many OA
      patients, and anti-inflammatory drugs that are currently available do not have
      favorable risk-to-benefit ratio in typical patients with OA. A need remains,
      therefore, for therapies that will be analgesic, appropriately anti-inflammatory
      when necessary, and that may favorably alter the natural history of the disease.
      The development of intra-articular hyaluronic acid (HA) supplementation was
      thought to fulfill these criteria. This therapy has been shown to modulate pain
      in OA of the knee and investigators have attempted to show that it have positive
      effects on articular cartilage biology. This article considers these claims for
      HA supplementation as an important therapy for the treatment of OA.

PMID- 10356423
TI  - Selective cyclooxygenase-2 inhibitors.
AB  - The identification of COX-2 less than a decade ago has been followed by an
      unprecedented period of discovery and drug development. An awareness of the
      existence of two COX isoforms has led to potential novel insights into disease
      pathogenesis (arthritis, Alzheimer's disease, cancer) and the regulation of
      normal physiology (brain, kidney). The preliminary in vivo experience with COX-2
      selective inhibitors has provided evidence for proof of concept for the COX-1 and
      COX-2 hypothesis, namely that the selective inhibition of COX-2-derived
      prostaglandins is sufficient to inhibit inflammation and is nonulcerogenic. It
      may be that we have moved closer to the "better aspirin" envisioned by Sir John
      Vane for the treatment of degenerative and inflammatory arthritides; however,
      caution is still warranted. Some toxicities of current NSAIDs may result from COX
      2 inhibition, as in the kidney and brain; such side effects may be shared by the
      selective compounds. In addition, unexpected toxicities may arise simply because
      new chemical compounds will be widely prescribed. Finally, since the efficacy of
      traditional NSAIDs derives largely from their capacity to inhibit COX-2, it may
      be that the COX-2 selective drugs will not prove to be therapeutically superior
      to available agents. Given the well-recognized toxicity of NSAIDs, however, the
      availability of COX-2-selective agents promises to provide significant advantage
      to patients with chronic diseases, such as RA and OA.

PMID- 10356425
TI  - Exercise in the treatment of osteoarthritis.
AB  - Exercise, both therapeutic and recreational, is an effective therapy in
      successful management of osteoarthritis. Exercise is integral in reducing
      impairment, improving function, and preventing disability. Benefits of
      flexibility, muscular conditioning, and cardiovascular exercise and the role of
      regular physical activity in maintaining general health are discussed. Exercise
      recommendations and safety considerations are provided.

PMID- 10356424
TI  - Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine,
      chondroitin sulfate, and collagen hydrolysate.
AB  - There are a sufficient number of short-term studies with these agents suggesting
      efficacy equal to that seen in the symptomatic treatment of OA using NSAIDs. Two
      recent meta-analyses by McAlindon and colleagues and Towheed et al reviewed
      clinical trials of glucosamine and chondroitin in the treatment of
      osteoarthritis. The study by McAlindon and co-workers included all double-blind
      placebo-controlled trials of greater than 4 weeks' duration, testing oral or
      parenteral glucosamine or chondroitin for treatment of hip or knee
      osteoarthritis. Thirteen trials (six with glucosamine, seven with chondroitin)
      met eligibility criteria. The authors used global pain score or the Lequesne
      index in the index joint as the primary outcome measure and considered the trial
      positive if improvement in the treatment group was equal to or greater than 25%
      compared with the placebo group, and was significant (P < or = .05). All 13
      studies reviewed were classified as positive, demonstrating large effects,
      compared with placebo (39.5% [S.D. 21.9] for glucosamine, 40.2% [S.D. 6.4] for
      chondroitin). The authors concluded that clinical trials of these two agents
      showed substantial benefit in the treatment of osteoarthritis but provided
      insufficient information about study design and conduct to allow definitive
      evaluation. Towheed and colleagues reviewed nine randomized, controlled trials of
      glucosamine sulfate in osteoarthritis. In seven of the randomized controlled
      trials, in which they compared glucosamine with placebo, glucosamine was always
      superior. In two randomized controlled trials comparing glucosamine to ibuprofen,
      glucosamine was superior in one and equivalent in one. Methodologic problems,
      including lack of standardized case definition of osteoarthritis and lack of
      standardized outcome assessment led the authors to conclude that further studies
      are needed to determine if route of administration is important and whether the
      therapeutic effect is site specific. A meta-analysis of chondroitin sulfate
      trials has also been published. Of the 12 published trials, 4 randomized double
      blind placebo or NSAID-controlled trials with 227 patients on chondroitin sulfate
      were entered into the analysis. All four studies showed chondroitin sulfate to be
      superior to placebo, with respect to Lequesne index, visual analog scale for pain
      and medication consumption. Significant changes (P < or = .05) were seen in those
      treated from day 60 to the study endpoints (150 to 180 days). Pooled data
      demonstrated at least 50% improvement in the study variables in the chondroitin
      treated group. Discrepancies in some of the study findings reported in the
      literature may relate to the composition of the nutritional supplements used.
      Studies in the United States have revealed that a number of preparations claiming
      to contain certain doses of glucosamine or chondroitin sulfate have significantly
      less (or none) of the dosages described. Accordingly, it is essential that
      studies performed with these agents use preparations that are carefully defined
      in manufacture. The amounts generally administered are glucosamine, 1500 mg, and
      chondroitin sulfate, 1200 mg, daily. Although glucosamine has been described as
      effective when used alone, it is probably reasonable to use the combination
      pending further studies. The average cost is approximately $30 to $45 per month.
      In the interim, what should physicians tell their patients when they ask whether
      these agents are effective, or whether they should or should not take them? The
      authors emphasize that these agents are not FDA-evaluated or recommended for the
      treatment of OA. They are available as health food supplements, and the number of
      studies of toxicity, particularly with respect to long-term evaluations, is
      limited. The pros and cons of these agents and the published data are described
      so that patients can make a reasonably informed decision as to whether they wish
      to proceed with use of these agents in therapy. (ABSTRACT TRUNCATED)

PMID- 10356426
TI  - Serum markers of articular cartilage damage and repair.
AB  - Joint cartilage is a dynamic tissue that reacts to trauma, inflammation, and
      other insults by attempting to repair its matrix. This reaction results in the
      release of cartilage macromolecules into the body fluids. Analysis of these
      fluids has identified a limited number of at least somewhat tissue-specific
      markers of altered cartilage metabolism. Analyses of serum are less specific and
      less sensitive than analyses of synovial fluid, but their use as research tools
      in clinical studies, drug development, and experimental work in animal models is
      increasing.

PMID- 10356427
TI  - Synovial fluid markers in osteoarthritis.
AB  - Exploration of the mechanisms responsible for breakdown and repair of articular
      cartilage in osteoarthritis has promoted interest in the potential use of
      cartilage-derived molecules as markers of cartilage metabolism in this disease.
      Many of the macromolecules detectable in synovial fluid have been evaluated as
      possible surrogate markers of the severity or activity of disease processes.
      Measurements of the synovial fluid concentration of any marker without due
      consideration of the fate of the molecule in the joint cavity are likely to be
      misleading and insufficient to cement a relationship between marker concentration
      and the severity of articular pathology.

PMID- 10356428
TI  - Magnetic resonance imaging of osteoarthritis.
AB  - Considering the plethora of imaging protocols, joint-specific orientations, and
      potential artifacts, the design and interpretation of MR imaging examination is
      difficult. Like a physical examination, these considerations must be tailored to
      the specific tissue, joint, and clinical question under consideration.
      Shortcomings of MR imaging include the lack of consensus among radiologists with
      respect to which protocols best image articular joints. To date, few prospective
      studies have been undertaken to assess osteoarthritis by MR imaging. Diagnostic
      imaging is central to staging the severity of osteoarthritis and assessing the
      efficacy of therapeutic osteoarthritis. Plain film radiography is insensitive for
      identifying early changes of osteoarthritis. Tailored MR imaging, producing high
      spatial and or contrast resolution images, is proving to be an important tool in
      the early detection and surveillance of osteoarthritis progression. Future
      therapeutic techniques, such as chondrocyte transplantation, use of growth
      factors, or cartilage protease inhibitors requires high resolution and volumetric
      MR imaging studies for accurate identification of focal articular cartilage
      defects and generalized cartilage loss. Creation of cartilage models by three
      dimensional MR image rendering may be helpful for preoperative planning of
      orthopedic surgical procedures in advanced cases of osteoarthritis. More work
      needs to be done in high resolution and volumetric MR imaging of articular
      cartilage. Given the availability of new disease-modifying treatments designed to
      prevent, delay the progression of, or reverse osteoarthritis, additional
      prospective MR imaging studies need to be undertaken to improve the
      reproducibility of MR imaging as a primary outcome measure in the evaluation of
      osteoarthritis. Interinstitutional standardization of specific MR imaging magnet
      strengths, surface coils, joint orientations, sequences used, scoring systems and
      quality assurance methodologies are needed to establish the reproducibility of MR
      imaging and interpretation for assessment of patients with osteoarthritis.

PMID- 10356430
TI  - Good drugs and bad drugs: what's the difference?

PMID- 10356429
TI  - Plain radiography as an outcome measure in clinical trials involving patients
      with knee osteoarthritis.
AB  - The identification of pharmacologic agents that inhibit matrix metalloproteinase
      activity and may serve as effective disease-modifying osteoarthritis drugs
      (DMOADs) in humans has led to interest in the ability of plain radiographic
      methods to detect early cartilage damage and assess progressive cartilage changes
      of knee osteoarthritis (OA). Conventional knee radiography lacks sufficient
      standardization of key elements of the radioanatomic positioning of the knee to
      avoid significant, probably insurmountable, error variation in the measurement of
      tibiofemoral joint space width (JSW), the surrogate for the thickness of
      articular cartilage in radiographic images. Recently, several protocols for the
      use of fluoroscopy to standardize the radioanatomic position of the knee in a
      plain radiograph have been shown to afford notably more precise measurement of
      medial tibiofemoral JSW than can be derived from unstandardized, conventional
      techniques. A field test of one of these protocols suggests that DMOAD trials
      with respect to sample size or duration of treatment necessary to detect true OA
      progression and demonstrate a drug effect may be more feasible.

PMID- 10356431
TI  - Comparison of oral chloral hydrate with intramuscular ketamine, meperidine, and
      promethazine for pediatric sedation--preliminary report.
AB  - Fifteen consecutive pediatric patients ranging from 3 to 5 years old were
      selected to receive one of three sedative/hypnotic techniques. Group 1 received
      oral chloral hydrate 50 mg/kg, and groups 2 and 3 received intramuscular ketamine
      2 mg/kg and 3 mg/kg, respectively. In addition to ketamine, patients in groups 2
      and 3 received transmucosal intramuscular injections of meperidine and
      promethazine into the masseter muscle. Sedation for the satisfactory completion
      of restorative dentistry was obtained for over 40 min on average in the chloral
      hydrate group, but completion of dental surgery longer than 40 min was achieved
      in groups 2 and 3 only by intravenous supplements of ketamine.

PMID- 10356432
TI  - Illinois Dental Anesthesia and Sedation Survey for 1996.
AB  - Dentists in the state of Illinois who possess a permit to administer sedation or
      general anesthesia were surveyed. A 71% response rate was achieved. Of the
      respondents, 86% held permits for deep sedation/general anesthesia and 14% held
      permits for parenteral conscious sedation. By practice specialty, 84% were oral
      and maxillofacial surgeons, 11% were general dentists, 5% were periodontists, and
      fewer than 1% were dental anesthesiologists. Advanced Cardiac Life Support
      training was possessed by 85% of the respondents. The most common anesthesia team
      configuration (82%) was a single operator-anesthetist and two additional
      assistants. Only 4% reported use of a nurse anesthetist, and 2% used an
      additional MD or DDS anesthesiologist. The vast majority (97%) of the
      practitioners do not intubate in the office on a routine basis. Supplemental
      oxygen was used by 81% of the respondents whenever intravenous agents were used.
      A total of 151,335 anesthetics were administered during the year. One mortality
      occurred in a patient with an undisclosed pre-existing cardiac condition. Four
      other events were reported that required medical intervention or hospital
      evaluation; however, no permanent injuries were reported. Other practice
      characteristics were described.

PMID- 10356433
TI  - Who should determine the medical necessity of dental sedation and general
      anesthesia? A clinical commentary supported by Illinois patient and practitioner
      surveys.
AB  - Many third-party payers try to deny benefits for dental sedation and general
      anesthesia. The term "not medically necessary" is often applied to these services
      by third-party payers. The label is poorly defined and varies from payer to
      payer. This paper uses original practitioner and patient opinion surveys to
      support the position that the definition of medical necessity is solely the joint
      responsibility of the patient and his/her physician. These surveys also support
      the argument that both patients and practitioners view dental sedation and
      general anesthesia as a medically necessary procedure if it allows a patient to
      complete a medically necessary surgical procedure that he/she might otherwise
      avoid.

PMID- 10356435
TI  - Dental anesthetic management of a patient with ventricular arrhythmias.
AB  - During routine deep sedation for endodontic therapy, a dentist-anesthesiologist
      observed premature ventricular contractions (PVCs) on a 62-yr-old woman's
      electrocardiogram (EKG) tracing. The dentist was able to complete the root canal
      procedure under intravenous (i.v.) sedation without any problems. The dentist
      anesthesiologist referred the patient for medical evaluation. She was found to be
      free from ischemic cardiac disease with normal ventricular function. The patient
      was cleared to continue her dental treatment with deep sedation. She subsequently
      continued to undergo dental treatment with deep intravenous sedation without
      incident, although her EKG exhibited frequent PVCs, up to 20 per minute,
      including couplets and episodes of trigeminy. This article will review
      indications for medical intervention, antiarrhythmic medications, and anesthetic
      interventions for perioperative PVCs.

PMID- 10356434
TI  - Dental fear among university students: implications for pharmacological research.
AB  - University students are often subjects in randomized clinical trials involving
      anxiolytic and analgesic medications used during clinical dental and medical
      procedures. The purpose of this study was to describe a typical university
      student population available for research by using data from a mail survey.
      Subjects were 350 students chosen randomly from all enrolled, full-time,
      traditional students on the main campus at the University of Washington in
      Seattle, WA. The aim was to determine the extent and nature of dental anxiety in
      this population. In addition, the relationships between subject willingness to
      receive dental injections and general and mental health and medical avoidance and
      medical fears were examined. The Dental Anxiety Scale (DAS) was used to measure
      dental anxiety. Dental anxiety was prevalent in this population; 19% of students
      reported high rates of dental fear. Thirteen percent of students had never had a
      dental injection. Students with no experience with dental injections were more
      reluctant than those with experience to receive an injection if one were needed.
      DAS scores were correlated with injection reluctance. Students who were reluctant
      to go ahead with a dental injection also reported poorer general and mental
      health than those who were less reluctant. These students also reported higher
      medical avoidance and medical anxiety scores. University students provide a rich
      source of potential subjects for clinical research. The student population, like
      the community at large, contains people with high levels of dental and medical
      fear.

PMID- 10356436
TI  - Intraoperative spasm of coronary and peripheral artery--a case occurring after
      tourniquet deflation during sevoflurane anesthesia.
AB  - A 68-yr-old man with a 9-yr history of hypertension presented for
      hemiglossectomy, segmental resection of the mandible, and the radial forearm free
      flap grafting. Intraoperatively, facial artery spasm was observed during
      microvascular suturing of the radial artery to the facial artery. Simultaneously,
      systolic blood pressure decreased from 100 to 80 torr and the ST segment elevated
      to 15 mm from the base line. The possible mechanisms responsible for vasospasm in
      coronary as well as in peripheral arteries under sevoflurane anesthesia are
      discussed.

PMID- 10356437
TI  - CDS members speak.

PMID- 10356439
TI  - The survival of fee-for-service dentistry.

PMID- 10356438
TI  - Jump-start your entry into cyberspace.

PMID- 10356440
TI  - Tooth whitening project raises $1.5 million for children's hospital.

PMID- 10356441
TI  - Overhead control.

PMID- 10356442
TI  - New 'make-over' every year.

PMID- 10356443
TI  - Esthetics. Feel guilty about your fees?

PMID- 10356444
TI  - Esthetics. Esthetic dentistry fuels growth.

PMID- 10356445
TI  - Esthetics. Give your practice a high profile.

PMID- 10356446
TI  - Is there such a thing as an 'effective' meeting?

PMID- 10356447
TI  - What your staff needs to know about marketing your practice.

PMID- 10356448
TI  - Comdex '98: a window to technology in the future.

PMID- 10356450
TI  - Lean, strong, and unperturbed.

PMID- 10356449
TI  - Keeping in touch.

PMID- 10356451
TI  - When should you sell?

PMID- 10356452
TI  - The far reaching stature of the ICOI. International Congress of Oral
      Implantologists.

PMID- 10356453
TI  - Professional cooperation between dentist and laboratory technician.
AB  - This case points out the importance of professional cooperation between the
      dentist and the technician because of the concept that implantology means
      specialized prosthetics including a surgical component. Success of any implant
      treatment depends on the professionally trained technician as a partner of the
      team. Clinical and technical treatment steps are intertwined. The dentist is
      responsible for the surgical procedure and must use his or her utmost skills and
      learning. In cases of proposed sinus elevation on both sides of the maxilla, the
      dentist must not necessarily collect autologous bone from the iliac crest because
      appropriate bone substitutes are available; also, tuber blades may be used to
      avoid sinus elevation. Unfortunately, at this time, the universities in Germany
      have not endeavored to pursue intensive scientific research concerning this
      important topic.

PMID- 10356454
TI  - Maxillary sinus membrane repair: report of a technique for large perforations.
AB  - Maxillary sinus membrane perforation is the most common complication that occurs
      with the sinus elevation augmentation procedure. Repair of relatively small (5-10
      mm) tears is commonly done using fast resorbing collagen membranes and/or by
      allowing the sinus membrane to overlap on itself. A technique using a cross
      linked type I collagen membrane for predictable repair of large perforations (>
      10 mm) as well as for circumstances in which no membrane is found is described.
      This technique has several advantages because of its inherent biologic
      properties.

PMID- 10356455
TI  - Augmentation grafting of the maxillary sinus for placement of dental implants:
      anatomy, physiology, and procedures.
AB  - In patients with an inadequate amount of bone for implant placement, sinus lift
      surgery can be performed to restore a sufficient amount of alveolar bone to allow
      for successful implant placement and subsequent prosthetic reconstruction. In
      this article, the anatomy and physiology of the maxillary sinus, the mechanisms
      of bone grafting, bone grafting material, preoperative evaluation, surgical
      technique, and the grafting procedure, as well as intraoperative bleeding and
      postoperative complications, are discussed.

PMID- 10356456
TI  - New bone formation after a sinus lift procedure using demineralized freeze-dried
      bone and tricalcium phosphate.
AB  - A mixture of demineralized freeze-dried bone and beta-tricalcium phosphate was
      used for bone augmentation in a sinus lift procedure. Hydroxyapatite-coated
      implants were placed in the newly formed bone-like material before prosthetic
      reconstruction. A biopsy specimen taken at 16 months showed that the bone-like
      material was composed of normal lamellar and woven bone.

PMID- 10356457
TI  - Classification and treatment modalities for immediate implantation. Part I: Hard
      and soft tissue status.
AB  - Clinical and experimental studies related to immediate implantation have focused
      on the significance of the osseous defects and soft tissue status in the
      achievement of a predictable outcome. This article describes a new three
      dimensional classification of the osseous defects around immediate implants and a
      new grading of the soft tissue. A simplified staging of the severity of
      horizontal and vertical defects is proposed. Factors affecting the degree of
      defect are discussed.

PMID- 10356458
TI  - Esthetic considerations in anterior single-tooth replacement.
AB  - Anterior single-tooth replacement is the ultimate challenge facing the
      prosthodontist or the restorative dentist. Use of dental implants as a modality
      of treatment has overcome the disadvantages of conventional restorative
      techniques. Implantologists aim at creating an implant-supported restoration that
      replicates natural teeth. This article focuses on the different techniques that
      enhance maximum esthetic outcome of implant-supported anterior tooth restorations
      at the different stages of treatment. In addition, it discusses one of the
      problems in esthetic implant dentistry, prosthetic-driven implant placement
      versus available-bone-driven implant placement.

PMID- 10356459
TI  - Classification system for implant-supported overdentures.
AB  - A classification system for implant-supported overdentures is proposed in this
      article. Various types of implant-supported overdentures have been described in
      the literature, but there is considerable difference in the function of these
      designs. For example, an overdenture supported by freestanding implants does not
      have the retentive elements provided by a bar and, therefore, is less retentive
      than an overdenture supported by a straight bar. If more than two implants are
      configured in an arch, and if indirect retention is incorporated into the bar and
      overdenture design, function is improved over that of a straight-bar design.
      Another classification of overdenture is one that receives all of its support
      from an implant-supported bar with tissue contact to provide a mucosal seal. This
      tissue contact does not provide any actual support. By accepting and using this
      classification system, the clinician can design an overdenture that is
      appropriate for the functional requirements of the patient being treated.

PMID- 10356460
TI  - Implant support for removable partial overdentures: a case report.
AB  - Functional stability and the preservation of remaining alveolar bone are primary,
      and often elusive, goals when restoring the partially edentulous arch. The
      incorporation of dental implants for the partial support of removable prostheses
      offers a practical adjunct in the fulfillment of these objectives. Planning for
      complex courses of treatment that include dental implants requires close
      coordination between the surgeon and the restorative dentist. Decisions that deal
      with type, location, size, number of implant fixtures, and design of the
      prosthesis are critical. All of these areas must be discussed and established as
      acceptable to the patient and each clinician before the initiation of treatment.
      In this report, we present a course of patient treatment in which a removable
      partial denture is supported by natural remaining teeth in conjunction with
      osseointegrated implants.

PMID- 10356461
TI  - Osseointegration of titanium metal implants in erbium-YAG laser-prepared bone.
AB  - Titanium screws were implanted in rat calvarial defects of identical size using
      either a laser or bur. The aims of this study were to determine whether the
      screws were able to osseointegrate in a laser-prepared bone defect and to compare
      the pattern of bone healing around these screws. The optimal laser settings to
      produce a 0.7-mm-diameter hole in the rat calvaria were determined. A 0.7-mm
      diameter hole was prepared on the left calvaria with the erbium-YAG laser to
      receive a 1-mm-diameter self-threading titanium screw. Each animal also received
      a 0.7-mm-diameter hole prepared on the right calvaria with a conventional metal
      bur, and a 1-mm-diameter self-threading screw implant was placed. Rats were
      killed humanely either 3 weeks or 3 months after surgery, and the skulls were
      processed in paraffin wax for histological analysis. Laser-prepared defects: At 3
      weeks, the screw was surrounded by vital woven bone. The dura mater was
      perforated, and cystic change was present in the underlying brain tissue. There
      was active bone formation adjacent to the screw surface, deposited on a thin zone
      of necrotic bone. At 3 months, the screws were osseointegrated, and the brain
      tissue was healed by gliosis. Bur-prepared defects: At 3 weeks, there was
      extensive remodeling around the prepared defect. The dura mater was intact, and
      there was no damage to the underlying brain. At 3 months, the screws were
      successfully osseointegrated with bone adjacent to the screw. Osseointegration of
      titanium screws can be achieved using an erbium-YAG laser to prepare the implant
      bed.

PMID- 10356462
TI  - Chemical modification of pure titanium surfaces for oral implants.
AB  - A technique that achieves different pure titanium surfaces depending on acid
      concentration and exposure time is described. It is possible to obtain, with the
      same chemical treatment, both large pits and small rugosities. This technique may
      have interesting applications in oral implants.

PMID- 10356463
TI  - External and internal macromorphology in 3D-reconstructed maxillary molars using
      computerized X-ray microtomography.
AB  - AIM: The aim of this study was to perform a qualitative analysis of the
      relationship between the external and internal macromorphology of the root
      complex and to use fractal dimension analysis to determine the correlation
      between the shape of the outer surface of the root and the shape of the root
      canal. METHODOLOGY: On the basis of X-ray computed transaxial microtomography, a
      qualitative and quantitative analysis of the external and internal
      macromorphology of the root complex in permanent maxillary molars was performed
      using well-defined macromorphological variables and fractal dimension analysis.
      Five maxillary molars were placed between a microfocus X-ray tube with a focal
      spot size of 0.07 mm, a Thomson-SCF image intensifier, and a CCD camera
      compromising a detector for the tomograph. Between 100 and 240 tomographic 2D
      slices were made of each tooth. Assembling slices for 3D volume was carried out
      with subsequent median noise filtering. Segmentation into enamel, dentine and
      pulp space was achieved through thresholding followed by morphological filtering.
      Surface representations were then constructed. A useful visualization of the
      tooth was created by making the dental hard tissues transparent and the pulp
      chamber and root-canal system opaque. On this basis it became possible to assess
      the relationship between the external and internal macromorphology of the crown
      and root complex. RESULTS: There was strong agreement between the number,
      position and cross-section of the root canals and the number, position and degree
      of manifestation of the root complex macrostructures. Data from a fractal
      dimension analysis also showed a high correlation between the shape of the root
      canals and the corresponding roots. CONCLUSIONS: It is suggested that these types
      of 3D volumes constitute a platform for preclinical training in fundamental
      endodontic procedures.

PMID- 10356464
TI  - Formaldehyde release from root-canal sealers: influence of method.
AB  - AIM: To examine formaldehyde release from three different root-canal sealers: one
      phenol resin, one epoxy resin and one paraformaldehyde containing zinc oxide
      eugenol cement. METHODOLOGY: Formaldehyde was measured from freshly mixed
      material and from specimens allowed to set for 2 days or 2 weeks. Different
      mixing ratios and sample sizes were tested. Analysis was performed by reacting
      formaldehyde with acetylacetone and ammonia to form diacetyldihydrolutidine,
      which was revealed by spectrophotometry. RESULTS: Analysis revealed that mixing
      ratio, time after mixing and surface:weight ratios of specimens had different
      influences on the formaldehyde release from different materials. CONCLUSIONS:
      From the results of this study it is difficult to define a standardized in-vitro
      test that can be applied universally for the definitive determination of
      formaldehyde release from endodontic sealers. Prediction of in-vivo formaldehyde
      release from endodontic sealers is difficult.

PMID- 10356465
TI  - Obturation of root canals with different sealers using non-instrumentation
      technology.
AB  - AIM: To evaluate and compare the sealing quality of hand- or vacuum-obturated
      root canals after hand preparation or hydrodynamic cleansing of root canals,
      respectively. METHODOLOGY: After assessing root curvature, 96 single-rooted deep
      frozen teeth were divided into eight comparable groups. The root canals of four
      groups were instrumented with the balanced force technique. The remaining
      uninstrumented teeth were connected to a reduced-pressure device (NIT) and the
      root-canal system perfused with 2.5% NaOCl under alternating pressure fields.
      This dissolved the pulpal tissues and removed debris from the root-canal system.
      The canals of the hand-instrumented groups were obturated using the cold lateral
      condensation method with guttapercha and one of four different sealers (AH26, AH
      Plus, Apexit and Pulp Canal Sealer EWT). The teeth treated with the alternating
      pressure device (NIT) were obturated by a vacuum obturation method (NIT) with the
      same four sealers. The quality of the coronal seal was assessed using a dye
      penetration method. In order to minimize errors the roots were perfused with
      water before exposure to the dye, under vacuum. The teeth were then rendered
      transparent and the depth of penetration of the dye between the wall of the canal
      and the obturating material was measured with a stereomicroscope. RESULTS: The
      canals cleaned and filled by NIT showed statistically significantly less dye
      penetration than those obturated by lateral condensation (P < 0.05). Within the
      NIT group, Pulp Canal Sealer EWT exhibited significantly more dye penetration
      than Apexit. Amongst the control lateral condensation groups no significant
      differences were found between the various sealers. CONCLUSIONS: The present
      investigation demonstrated the validity of the NIT obturation method in
      combination with commonly used root-canal sealers.

PMID- 10356466
TI  - Analysis of forces developed during mechanical preparation of extracted teeth
      using Profile NiTi rotary instruments.
AB  - AIM: The aim of this study was to analyse the vertical forces and torque
      developed in the root canal system of extracted teeth during mechanical
      preparation using ProFile NiTi instruments. METHODOLOGY: Instrument wear and
      fracture is in great part due to the repeated application of forces and torque
      during the course of root-canal preparation but research into the direct
      relationship has been hampered by the lack of adequate measuring devices.
      Measurements of these forces and torque were made with a new force analyser
      device, the Endographe, that was equipped with a holder to record and generate
      graphs of the vertical forces and torque exerted during the preparations. These
      preparations was performed by endodontists or students either with a series of
      instruments of increasing size or with the crown-down pressureless technique.
      RESULTS: The mean values for the endodontists of the generated vertical forces
      and torque varied, respectively, from 4 to 6N and from 7.105 to 12.105 Nm for the
      step-back technique and from 2.9 to 4.2 N and from 18.105 to 20.105 Nm for the
      crown-down technique. This suggested that the crown-down technique generated
      lower stresses (lower torque and lower vertical forces), although these findings
      also depend on the shape of individual canals. The students initially showed wide
      variations in generated forces, with significantly lower vertical force the
      torque values. By the end of the experimental sessions their values were similar
      to those of the endodontists, which indicated improvement in the efficiency of
      manipulation. CONCLUSIONS: Further work is needed to investigate the relationship
      between the force and the torque data from this study and the incidence of
      instrument fracture with the two techniques, as the clinical implications are
      considerable. It must be noted, however, that the Endographe is unable to take
      into account the cutting efficiency of the instruments. The use of graphs
      provides a new approach to the analysis of mechanical preparation.

PMID- 10356467
TI  - A comparative study of the removal of smear layer by three endodontic irrigants
      and two types of laser.
AB  - AIM: The effects of three endodontic irrigants and two types of laser on a smear
      layer created by hand instrumentation were evaluated in vitro in the middle and
      apical thirds of root canals. METHODOLOGY: Sixty human mature extracted
      mandibular premolar teeth with a single root canal and a closed apex were
      distributed randomly into five groups of 12 teeth each. Whilst cleaning and
      shaping up to a size 60 master apical file with a step-back technique, the root
      canals were irrigated with 3 mL of 5.25% NaOCL and 3% H2O2, alternately, between
      each file size. Group 1 (G1) were control specimens that were irrigated with a
      final flush of 17% EDTA. The teeth in group 2 (G2) were irrigated with a final
      flush of 6% phosphoric acid, and group 3 (G3) with 6% citric acid. In the
      specimens of group 4 (G4) the root canals were irradiated with a carbon dioxide
      (CO2) laser, and specimens of group 5 (G5) were irradiated using an Er:YAG laser.
      The teeth were split longitudinally and prepared for examination by scanning
      electron microscopy. RESULTS: Control specimens (G1) showed clean root-canal
      walls with open dentinal tubules in the middle one-third, but in some specimens
      thick smear layer was observed in the apical one-third. Specimens irrigated with
      a final flush of 6% phosphoric acid (G2) or 6% citric acid (G3) were cleaner than
      with 17% EDTA, showing very clean root canal surfaces in the middle one-third but
      in the apical one-third the smear layer was not completely removed, especially at
      the openings of the dentinal tubules. The specimens irradiated with the CO2 laser
      (G4) showed clean root-canal walls with the smear layer absent, charred, melted,
      recrystallized and glazed in both middle and apical thirds. The root-canal walls
      of the specimens irradiated with the Er:YAG laser (G5) revealed an absent smear
      layer with open dentinal tubules in the middle and apical thirds. Statistical
      analysis showed no significant difference in the cleanliness of root-canal wall
      between G1 and G2, and G1 and G3. However, there were statistically significant
      differences (P < 0.01) between G1 and G4, and G1 and G5 in the cleanliness of the
      middle and apical one-thirds of the root canals. CONCLUSIONS: Irrigation with 17%
      EDTA, 6% phosphoric acid and 6% citric acid did not remove all the smear layer
      from the root-canal system. In addition, these acidic solutions demineralized the
      interbular dentine around tabular openings, which became enlarged. The CO2 laser
      was useful in removing and melting the smear layer on the instrumented root-canal
      walls and the Er:YAG laser was the most effective in removing the smear layer
      from the root-canal wall.

PMID- 10356469
TI  - Incidence of four canals in root-canal-treated mandibular first molars in a Saudi
      Arabian sub-population.
AB  - AIM: The aim of this in-vivo study was to assess the incidence of three roots and
      four root canals in clinical cases of root-treated mandibular first molars in a
      Saudi Arabian population. METHODOLOGY: A clinical study of 251 root-canal treated
      permanent mandibular first molars was conducted. The teeth were examined
      clinically and radiographically. RESULTS: The results showed that 5.97% of the
      examined teeth had three roots, 57.76% had four root canals (two mesial and two
      distal) and 42.3% had three root canals (two mesial and one distal). CONCLUSIONS:
      The occurrence of four root canals in the mandibular first molar of a Saudi
      Arabian subpopulation was high.

PMID- 10356468
TI  - Human teeth with periapical pathosis after overinstrumentation and overfilling of
      the root canals: a scanning electron microscopic study.
AB  - AIM: The aim of this study was to determine whether overinstrumentation followed
      by immediate overfilling could be a potential risk in the treatment of infected
      root canals. METHODOLOGY: Thirty-five human teeth with infected root canals were
      overinstrumented and overfilled approximately 45 min after their extraction. The
      experimental teeth were enlarged up to size 40 and the overinstrumentation and
      overfilling were checked with the aid of a magnifying glass. The specimens were
      fixed in glutaraldehyde plus sodium cacodylate solution and prepared for scanning
      electron microscope examination. RESULTS: Bacteria were detected on the flute of
      the files and mostly at the root apices around the main foramen, remaining firmly
      attached to resorptive lacunae despite the fact that the apices had undergone
      great changes, including fracture or zipping. A control group consisting of 10
      human teeth root canals containing vital pulps were also overinstrumented and
      overfilled. No bacteria were detected on the flutes of the files, at the apices
      or on the extruded master cone overfilling these samples. CONCLUSIONS: The high
      percentage of bacteria adhering to the resorptive lacunae or in the flutes of
      files used in overinstrumented human teeth with infected root canals carry a
      potential risk for postoperative pain, clinical discomfort and flare-ups. The
      hazards observed in these circumstances do not support the one-visit treatment of
      teeth having acute or chronic periapical abscesses.

PMID- 10356470
TI  - A method of adapting gutta-percha master cones for obturation of open apex cases
      using heat.
AB  - CLINICAL TECHNIQUE: It is generally accepted that the success of root-canal
      treatment is mainly dependent on the proper cleaning, shaping and hermetic
      obturation of root canals. Obturation of the root canal is of importance as 60%
      of endodontic failures are attributable to incomplete obliteration of the root
      canal system. The clinical application of many obturation techniques used today
      demands the preservation of the natural apical construction or the preparation of
      an artificial equivalent during chemo-mechanical preparation. However, in
      clinical practice there are cases where the apical foramen is wide because of
      over-instrumentation, root-end resection during periradicular surgery, root
      resorption or because the apex of the root is incompletely formed. Thus the
      preparation of an artificial apical stop is very difficult to achieve. It is a
      common experience that performing usual gutta-percha condensation techniques in
      such canals often results in overfilling and therefore special obturation
      techniques are needed. Some clinical cases of teeth with wide apical foramen
      treated by a special obturation method are presented in this paper. In this
      method the end point of the primary gutta-percha cone is elasticized with a
      heated instrument and inserted into the root canal to record the internal
      morphology of the apical portion.

PMID- 10356472
TI  - Why we still have to bend wires.

PMID- 10356471
TI  - Herpes zoster of the trigeminal nerve third branch: a case report and review of
      the literature.
AB  - LITERATURE REVIEW AND CASE REPORT: A literature review of Herpes zoster of the
      trigeminal nerve is presented. Included are differential diagnosis and treatment
      modalities that will enable the dental practitioner to identify and manage this
      disease. A case report is provided to amplify this timely information.

PMID- 10356473
TI  - The flip-lock Herbst appliance.

PMID- 10356474
TI  - Computer-aided fabrication of bonded lingual retainers.

PMID- 10356475
TI  - Band cementation with a no-mix, light-cured glass ionomer cement.

PMID- 10356476
TI  - Simplified repositioning splint construction.

PMID- 10356477
TI  - Use of disclosing material to detect fixed retainer bond failures.

PMID- 10356478
TI  - Orthodontists' fees and bracket recycling.

PMID- 10356479
TI  - An easy method of checking archform and canine width.

PMID- 10356480
TI  - Class II combination therapy.

PMID- 10356481
TI  - Orthodontic uprighting of horizontally impacted mandibular second molars.

PMID- 10356482
TI  - Modified quad helix for Class III treatment.

PMID- 10356483
TI  - Air-rotor stripping with the Essix anterior anchor.

PMID- 10356485
TI  - Low-profile, double-tube bracket for indirect bonding.

PMID- 10356484
TI  - The distal jet for upper molar distalization.

PMID- 10356486
TI  - Correcting malaligned mandibular incisors with removable retainers.

PMID- 10356487
TI  - Treatment of deep bite with bonded biteplanes.

PMID- 10356488
TI  - Managing without managed care.

PMID- 10356489
TI  - 1996 JCO Study of Orthodontic Diagnosis and Treatment Procedures. Part 1. Results
      and trends.

PMID- 10356490
TI  - Thomas D. Creekmore, DDS on treatment mechanics. Interview by Dr. Larry W. White.

PMID- 10356491
TI  - Lip retractor for occlusal photography.

PMID- 10356492
TI  - Uprighting of lower molars.

PMID- 10356493
TI  - Disinfection of permanent markers.

PMID- 10356494
TI  - Customized indirect bonding method for lingual orthodontics.

PMID- 10356495
TI  - How about four-to-six-month treatment?

PMID- 10356496
TI  - A new locking facebow.

PMID- 10356497
TI  - Bending spooled nickel titanium wire.

PMID- 10356498
TI  - 1996 JCO Study of Orthodontic Diagnosis and Treatment Procedures. Part 3. More
      breakdowns of selected variables.

PMID- 10356499
TI  - Site planning.

PMID- 10356500
TI  - Seven clinical principles of interactive twin mechanisms.

PMID- 10356501
TI  - People, product, and profit.

PMID- 10356502
TI  - Use of an impacted post for anchorage.

PMID- 10356503
TI  - Organic polymer wire for esthetic maxillary retainers.

PMID- 10356504
TI  - Molar rotation and beyond.

PMID- 10356505
TI  - Correction of posterior single-tooth crossbite.

PMID- 10356506
TI  - A new look at indirect bonding.

PMID- 10356508
TI  - On second thought.

PMID- 10356507
TI  - Fixed biteplanes for treatment of deep bite.

PMID- 10356509
TI  - A new molar band.

PMID- 10356510
TI  - Molar intrusion with a removable appliance.

PMID- 10356511
TI  - Dr. Anthony Gianelly on current issues in orthodontics. Interview by Dr. Larry W.
      White.

PMID- 10356512
TI  - Removable Nance appliance.

PMID- 10356513
TI  - Protection of exposed dentin.

PMID- 10356514
TI  - Non-surgical treatment of facial asymmetry with mandibular protrusion.

PMID- 10356515
TI  - What do you mean by that?

PMID- 10356516
TI  - Direct-bonded lingual button retainer.

PMID- 10356517
TI  - The speed positioner.

PMID- 10356518
TI  - Modified edgewise-Herbst appliance.

PMID- 10356520
TI  - Innovative staff marketing.

PMID- 10356519
TI  - 1996 JCO Study of Orthodontic Diagnosis and treatment procedures. Part 2.
      Breakdowns of selected variables.

PMID- 10356521
TI  - The Distal Jet for uprighting lower molars.

PMID- 10356522
TI  - Old tricks for new dogs.

PMID- 10356523
TI  - Orthopedic correction of Class III malocclusion: retention and phase II therapy.

PMID- 10356524
TI  - Comparison of tooth movements using Friction-Free and preadjusted edgewise
      bracket systems.

PMID- 10356525
TI  - A light-cured hybrid compomer for bonding to impacted canines.

PMID- 10356526
TI  - Disconnectable rapid palatal expander.

PMID- 10356527
TI  - A new paradigm of motivation.

PMID- 10356528
TI  - Protection of enamel from ceramic bracket wear.

PMID- 10356529
TI  - Treatment of adult midline deviation by condylar repositioning.

PMID- 10356530
TI  - Failing to win.

PMID- 10356532
TI  - Creating the compliant patient.

PMID- 10356531
TI  - Inverted labial bow appliance for Class III treatment.

PMID- 10356533
TI  - Treatment outcome assessment.

PMID- 10356534
TI  - New types of elastic functional appliances.

PMID- 10356535
TI  - Frictional characteristics of a modified ceramic bracket.

PMID- 10356536
TI  - Asymmetric mandibular space closure.

PMID- 10356537
TI  - Improving patient comfort with lingual sheaths.

PMID- 10356539
TI  - Revision of accreditation standards for dental hygiene education programs.

PMID- 10356538
TI  - A national survey of dental hygiene education administrators: demographics,
      characteristics, and academic profile.
AB  - PURPOSE: The purpose of this study was to develop a comprehensive demographic
      database of dental hygiene education administrators and to examine their academic
      professional profile. METHODS: On April 1, 1996, a survey was mailed to all
      dental hygiene education administrators in the U.S. The survey requested
      participants to respond to specific questions regarding demographic
      characteristics, professional academic profile, and extent of management theory
      background. The results were analyzed using descriptive statistics, including
      frequencies and percentages. Cross-tabulations and chi-square tests were
      calculated for type of institution, type of program, extent of management theory
      background, highest degree earned, and rank. RESULTS: One hundred thirty-eight
      valid surveys (63%) were returned. The demographic profile determined the
      majority of administrators were Caucasian (95.6%), female (87.6%), dental
      hygienists (87.6%), with a mean age of 47. The highest degree earned was a
      master's degree (64.5%) with a specialization in education (47.7%). Additionally,
      87.5 percent had some form of educational management theory background, and 22.6
      percent held the rank of full professor. Professional experience ranged from one
      to 30 years, with a mean of 10 years. The majority of participants worked in
      public (95.7%) institutions, primarily community and technical colleges (67.4%)
      that awarded associate's degrees (72.5%). Cross-tabulations and chi-square tests
      for type of institution, type of program, extent of management theory background,
      and rank were calculated. Significance was found between rank and type of
      institution, type of program, highest degree earned, and gender. Additionally, a
      relationship was found between gender and highest degree earned. CONCLUSION:
      These findings help develop a demographic database and professional academic
      profile of dental hygiene education administrators that can be used for future
      research and theory development, trends identification, problem solving, decision
      making, and policy formation. When compared to past studies, Caucasian females
      still dominate the profession. Also, dental hygiene faculty/administrators have
      increased in percentage of earned master's and doctoral degrees, and in
      advancement of academic rank to full professor. Furthermore, administrators are
      comparable to other full-time faculty in health-related programs and two-year
      institutions in regard to academic rank and highest degree earned. Thus, this
      population reflects individuals who can be considered highly dedicated and
      educationally prepared for their administrative role. However, compared to
      faculty across all disciplines in higher education, this population did not
      reflect advanced professional preparation or academic rank. It is recommended
      that dental hygiene administrators and faculty continue their scholarly endeavors
      to help advance the field to full professionalization and build academic
      legitimacy.

PMID- 10356540
TI  - What hurts during dental hygiene treatment.
AB  - PURPOSE: The purpose of this study was to examine clients' pain reports for
      routine clinical procedures during dental hygiene treatment, and to examine the
      degree to which physical and psychological variables contribute to pain. METHODS:
      A convenience sample consisting of 53 (18 male, 35 female) undergraduate students
      enrolled at Dalhousie University participated as dental hygiene clients. Before
      treatment, the demographics, dental anxiety, and pain catastrophizing of students
      were measured. During procedures, dental status was measured. Following
      procedures, the amount of pain associated with procedures was recorded. Data was
      analyzed using an SPSS/PC statistical package. RESULTS: Most procedures were
      associated with little or no pain. However, probing and scaling were associated
      with greater pain. Furthermore, 25 percent of the sample reported their pain was
      > or = 7/10 on at least one dental hygiene procedure. Dental status measures and
      treatment difficulty did not correlate with pain. Individuals higher in dental
      anxiety and pain catastrophizing reported greater pain. Multiple regression
      showed that all predictor variables combined to account for approximately 1/3 of
      the variance in pain reports. CONCLUSION: On average, clinical dental hygiene
      treatment is associated with low levels of pain, but approximately 25 percent of
      subjects experienced at least one of the seven procedures as being moderately to
      severely painful. Findings illustrate the need for effective pain management that
      may be physiologically or psychologically based. Interventions geared toward
      reducing anxiety and pain catastrophizing may be useful additions to the
      curriculum of dental hygiene programs.

PMID- 10356542
TI  - Current trends in dental hygiene education and practice.

PMID- 10356541
TI  - Guidelines for nutrition screening, assessment, and intervention in the dental
      office.
AB  - Patients with complicated disease and medication histories are being seen with
      increasing frequency in the dental office. Many are at high nutritional risk,
      which can impact their oral health status. Nutrition is an integral part of
      health promotion and prevention, but it often is a poorly utilized component of
      preventive dentistry. This article provides the dental hygienist with a
      systematic approach to determining which patients are in need of nutrition
      intervention, and discusses screening, assessment, counseling, and referral.
      Dental hygienists, as part of a multidisciplinary healthcare team, are in an
      ideal position to identify patients at nutritional and oral health risk, help
      them attain optimal oral and general health, and improve overall quality of life.

PMID- 10356543
TI  - Expression and localization of HGF mRNA in monkey submandibular gland.
AB  - We investigated the characteristics and mRNA expression of hepatocyte growth
      factor (HGF) in the adult female monkey submandibular gland using Western blot
      analysis and the reverse-transcriptase PCR (RT-PCR) technique, and observed HGF
      mRNA localization using the in situ RT-PCR technique. HGF was extracted with PBS
      containing protease inhibitors, and purified partially by heparin affinity
      chromatography. With Western blot analysis, the HGF fraction showed an
      immunopositive protein band of 69-kDa corresponding to the alpha-subunit of HGF.
      The gene expression for HGF was revealed in the monkey submandibular gland using
      RT-PCR, and the PCR products showed high homology to cDNA for human HGF.
      Furthermore, the mRNA signal for HGF was localized in the striated and excretory
      ductal cells. These results unequivocally confirmed both the synthesis and
      existence of HGF in monkey submandibular glands.

PMID- 10356544
TI  - Correlation of lining thickness and expression of alpha 2 and alpha 3 integrins
      within the epithelial lining of odontogenic cysts.
AB  - Using monoclonal antibodies, we performed immunohistochemical investigations of
      the expression of alpha 2, alpha 3 and beta 4 integrin subunits within the
      squamous epithelial linings of odontogenic cysts. Tissue samples consisted of
      both follicular cysts and odontogenic keratocysts from 15 patients. It was found
      that beta 4 integrin was expressed on the basement membrane regardless of the
      histological type of the cyst. The degree of immunostaining for alpha 2 and alpha
      3 integrin expression corresponded to the thickness of the epithelial cyst wall.
      We found that the thickness of the epithelial lining of odontogenic cysts had a
      direct correlation with the expression of integrin molecules.

PMID- 10356545
TI  - Effect of impression material on surface reactive layer when casting pure
      titanium in phosphate investment.
AB  - We evaluated the effect of impression materials used in preparation of pure
      titanium castings on the surface reactive layer. Surface roughness of the
      refractory models before and after firing was smaller when silicone rather than
      agar impression material was used. The surface roughness of castings prepared
      with T-invest varied little with the impression material. However, the surface
      roughness of the castings prepared with CD Titaninvest was less when silicone
      impression material was used. Surface hardness of the castings was slightly
      greater when agar impression material was used, and metallic texture analysis of
      the surface of the castings showed a chill layer and a columnar crystal layer
      extending from the surface toward the interior. A relatively non-corroded white
      layer and a markedly corroded black layer were observed in the chill layer, and
      their thickness was smaller when silicone impression material was used. Use of
      the Electron Probe Micro Analyzer (EPMA) to determine distribution of various
      elements in the superficial layer of the casting plates showed that the reactive
      layer contained less P and Si when silicone impression material was used rather
      than agar. NH4H2 PO4, which is a component of the bonding material in the
      investment, was present at a high concentration in the superficial layer of the
      agar impression material. This shows the importance of preparing refractory
      models with a non-water-absorbing impression material to obtain pure titanium
      casting plates with a smaller reactive layer.

PMID- 10356546
TI  - Adsorption of salivary proteins and serum proteins to titanium.
AB  - Titanium (Ti) is very effective as a dental implant material owing to its low
      toxicity and high biocompatibility. I carried out in vitro experiments on the
      adsorption of salivary proteins and serum proteins to Ti to better understand how
      this material reacts in the oral cavity. I found that when Ti that had adsorbed
      serum proteins was exposed to salivary proteins, there was an exchange of the
      proteins on the Ti surface. The same thing happened when Ti that had adsorbed
      salivary proteins was exposed to serum proteins. These results suggest that both
      human salivary proteins and serum proteins adsorb to Ti with different affinity,
      and that protein already adsorbed to Ti might mask binding sites for other
      proteins.

PMID- 10356547
TI  - Setting time and sealing ability of alpha-tricalcium phosphate cement containing
      titanic oxide.
AB  - We developed a new type of calcium phosphate cement for clinical use in
      endodontics as a root canal sealer or pulp cupping agent. The solid phase of the
      sealer is composed of 70% of alpha-tricalcium phosphate (alpha-TCP) and 30% of
      titanic oxide (TiO2), and the liquid phase is 37% citric acid, 5% tannic acid and
      58% distilled water. TiO2 was added to control setting time and handling of the
      cement. We used commercially available calcium phosphate root canal sealer as a
      control. ISO standards specify that new endodontic products should be examined
      thoroughly before clinical use. It is important to carry out in vitro
      cytotoxicity and in vivo histocompatibility tests. We first did in vitro test of
      setting time and root canal sealing ability of the cement. We found that this
      developed calcium phosphate cement had an appropriate setting time and excellent
      sealing ability as a root canal sealer, and concluded that it was suitable for
      clinical use as a root canal sealer.

PMID- 10356548
TI  - Academia: for me, the best of all worlds.

PMID- 10356549
TI  - Dental cutting with diamond burs: heavy-handed or light-touch?
AB  - PURPOSE: The cutting efficiency of diamond dental burs using different handpiece
      loads was evaluated against simulated enamel, a machinable glass ceramic (Macor).
      MATERIALS AND METHODS: An ultra-high-speed dental handpiece was mounted in a
      frictionless bearing so that the pressure applied at the contact interface
      between the dental bur and the cutting substrate was controlled. One type of
      coarse- and two types of medium-grit diamond burs were studied. Handpiece loads
      of 44, 91.5, and 183 g were applied at the bur/Macor interface, and cutting
      efficiency was determined as the amount of Macor removed in ten 30-second
      duration cuts that were 4 mm in length. The data were analyzed by one-way ANOVA
      and a post-hoc Scheffe test at an a priori alpha = 0.05. RESULTS: Cutting
      efficiency depended on both the diamond grit of the bur and the load applied to
      the handpiece. CONCLUSIONS: The pressure used by most dentists, about 100 g at
      the bur tip, appears to be optimal for medium-grit burs. If the pressure applied
      to the handpiece is markedly increased, there was no increase in cutting
      efficiency for medium-grit burs. In contrast, an increased handpiece pressure
      raises the cutting efficiency of coarse-grit burs but the effect of this enhanced
      rate of cutting on the pulpal tissues is uncertain. Cutting efficiency also
      appeared to be dependent on debris accumulation between the diamond chips.

PMID- 10356551
TI  - Reinforcement of denture base resin with glass fillers.
AB  - PURPOSE: This study evaluated the effect of short glass fibers on the transverse
      strength of a heat-polymerized acrylic resin denture base material. MATERIALS AND
      METHODS: Four groups of specimens (n = 10) were fabricated according to the ISO
      standard for the transverse strength test. E-glass fibers were triturated to
      produce short fibers of different lengths. Specimens for Group 1 (control) were
      made of unfilled polymethylmethacrylate (PMMA). For group 2, the PMMA powder was
      modified with 0.1 g of dry glass fibers. For group 3, the PMMA powder was
      modified with 0.1 g of silanized glass fibers. For group 4, the PMMA powder was
      modified with 0.2 g of silanized glass fibers. A three-point loading test was
      used to determine the transverse strength of the tested specimens. The fracture
      surface of each specimen was evaluated using SEM. RESULTS: The addition of
      untreated glass fibers increased the transverse strength by 11% but produced some
      porosity in the polymeric matrix. The addition of silane-treated glass fibers
      increased the transverse strength of PMMA by 28% for group 3 and by 26% for group
      4, and produced a dense structure for the polymer-fiber composite. CONCLUSION:
      The transverse strength of PMMA can be slightly increased by the addition of
      short glass fibers.

PMID- 10356550
TI  - A pilot study to evaluate different palate materials for maxillary complete
      dentures with xerostomic patients.
AB  - PURPOSE: The hypothesis tested in this pilot study was that materials used for
      the palatal region of a maxillary denture affect the comfort of the maxillary
      denture in xerostomic patients. MATERIALS AND METHODS: Xerostomic complete
      denture wearers were selected to test three different maxillary dentures that
      were made with different palatal materials. Each denture was worn for a period of
      2 weeks. The Kapur Index was used to measure retention. The Oral Health Index
      Profile (OHIP) was used to determine the patient's perception of each denture
      after the 2-week period. At the end of the study, the patients were asked to
      select which of the three dentures they would like as their primary denture.
      RESULTS: All participants chose the metal-palate dentures, and 4 of 5 selected
      the titanium-palate denture as their primary denture. Statistical analysis of the
      OHIP demonstrated that the metal-palate dentures were perceived as being more
      comfortable than the acrylic-resin dentures. CONCLUSION: This pilot study
      suggests that for xerostomic patients who have worn complete dentures, their
      selection of a metal-palate denture as their primary prosthesis strongly suggests
      that these dentures have properties that make them more comfortable to the
      patient than acrylic dentures. Subjective patient measurements supported this
      conclusion that the metal-palate dentures were preferable, while the evaluation
      method available to the clinician failed to discriminate among the prostheses.

PMID- 10356552
TI  - Classification system for complete edentulism. The American College of
      Prosthodontics.
AB  - The American College of Prosthodontists has developed a classification system for
      complete edentulism based on diagnostic findings. These guidelines may help
      practitioners determine appropriate treatments for their patients. Four
      categories are defined, ranging from Class I to Class IV, with Class I
      representing an uncomplicated clinical situation and a Class IV patient
      representing the most complex and higher-risk situation. Each class is
      differentiated by specific diagnostic criteria. This system is designed for use
      by dental professionals who are involved in the diagnosis of patients requiring
      treatment for complete edentulism. Potential benefits of the system include: 1)
      better patient care, 2) improved professional communication, 3) more appropriate
      insurance reimbursement, 4) a better screening tool to assist dental school
      admission clinics, and 5) standardized criteria for outcomes assessment.

PMID- 10356554
TI  - A technique to replicate soft tissues around fixed restoration pontics on working
      casts.
AB  - When missing maxillary incisors are replaced, the patient's primary concern is
      usually esthetics. Depending on the patient's smile line and the display of the
      incisors, the esthetic zone may extend to the entire clinical crown and include
      the surrounding soft tissue. For these patients, the appearance and form of the
      soft tissue at the base of the pontics is as critical as the esthetics of the
      incisal edges of the restoration. A technique is presented to precisely transfer
      the soft tissue morphology of the pontic area to the working cast. This modified
      master cast allows the laboratory technician to fabricate restorations that will
      harmonize precisely with the soft tissues of the patient.

PMID- 10356553
TI  - Dental implant materials: commercially pure titanium and titanium alloys.
AB  - Manufacturers use six different titanium-based biomaterials to fabricate dental
      implants. Each of these materials, including four grades of commercially pure
      titanium and two titanium alloys, has distinct mechanical and physical
      properties. Clinicians should recognize these differences for optimal treatment
      planning and patient care.

PMID- 10356555
TI  - Use of a surgical template for autologous bone grafting of alveolar defects.
AB  - This article describes the fabrication of a surgical template for planning and
      performing the harvest and placement of autologous bone grafts for the
      reconstruction of alveolar defects before implant placement. A diagnostic cast is
      altered to replicate the anticipated bone anatomy. The ideal bony contours for
      implant placement are then created on the cast to form the template. This
      template may then be used for treatment-planning donor sites for the harvest of
      corticocancellous bone grafts. The template is sterilized and used by the surgeon
      in procuring and placing the bone graft. This template allows communication of
      the prosthetic requirements of the ridge augmentation, as well as ensuring
      adequate volume and proper positioning of the block graft for eventual implant
      placement.

PMID- 10356556
TI  - Facilitated cement removal technique between splinted crowns.
AB  - A technique for facilitating cement removal between splinted crowns is described.
      The technique involves tying dental floss with the large-diameter yarn portion
      around the embrasure of the splinted crown before cementing, and pulling it
      through before the cement has reached a final set. This simple, quick technique
      achieves removal of cement without damage to the interproximal crown surface.

PMID- 10356558
TI  - Centric relation registration using an anterior deprogrammer in dentate patients.
AB  - A technique is described for registering centric relation in dentate patients
      using an anterior deprogrammer to prevent muscle splinting. Properly executed,
      the patient is able to close into centric relation unassisted, eliminating the
      possibility of operator-induced error associated with commonly accepted
      manipulative techniques. Verification is possible visually when articulating
      casts by confirming the precise alignment of the mandibular incisors with
      occlusal markings on the deprogrammer attached to the maxillary cast.

PMID- 10356557
TI  - Fabricating a gold occlusal platform on a removable partial denture to help
      prevent extrusion of mandibular incisors.
AB  - A clinical procedure is presented in which a maxillary removable partial denture
      (RPD) replacing anterior teeth was fabricated with a cast gold anterior occlusal
      platform. This treatment is indicated to correct abrasion caused by extruded
      mandibular anterior teeth on the maxillary RPD. The advantages compared with
      prosthetic teeth supported by an acrylic resin base or metal-backed facings are
      discussed. This technique allows for development of optimal esthetics, strength,
      and durability, while preventing further extrusion and excessive wear of the
      teeth occluding against prosthesis.

PMID- 10356559
TI  - Why patients do not accept treatment.

PMID- 10356560
TI  - Invasive cervical resorption: an analysis of potential predisposing factors.
AB  - OBJECTIVE: An investigation was undertaken to assess potential predisposing
      factors to invasive cervical resorption. METHOD AND MATERIALS: A group of 222
      patients with a total of 257 teeth displaying varying degrees of invasive
      cervical resorption were analyzed. Potential predisposing factors, including
      trauma, intracoronal bleaching, surgery, orthodontics, periodontal root scaling
      or planing, bruxism, delayed eruption, developmental defects, and restorations
      were assessed from the patients' history and oral examination. RESULTS: Of the
      potential predisposing factors identified, orthodontics was the most common sole
      factor, constituting 21.2% of patients and 24.1% of teeth examined. Other factors
      were present in an additional 5.0% of orthodontically treated patients (4.3% of
      teeth), and these consisted principally of trauma and/or intracoronal bleaching.
      Trauma was the second most frequent sole factor (14.0% of patients and 15.1% of
      teeth). Trauma in combination with intracoronal bleaching, orthodontics, or
      delayed eruption constituted an additional 11.2% of patients (10.6% of teeth).
      Intracoronal bleaching was found to be the sole potential predisposing factor in
      4.5% of patients and 3.9% of teeth, and an additional 10.4% of patients and 9.7%
      of teeth showed a combination of intracoronal bleaching with trauma and/or
      orthodontics. Surgery, particularly involving the cementoenamel junction area,
      was a sole potential predisposing factor in 6.3% of patients and 5.4% of teeth.
      Periodontal therapy, including deep root scaling and planing, showed a low
      incidence, as did other factors, such as bruxism and developmental defects. The
      presence of an intracoronal restoration was the only identifiable factor in 15.3%
      of patients and 14.4% of teeth, while 15.0% of patients and 16.4% of teeth showed
      no identifiable potential pedisposing factors. CONCLUSION: These results
      indicated a strong association between invasive cervical resorption and
      orthodontic treatment, trauma, and intracoronal bleaching, either alone or in
      combination.

PMID- 10356561
TI  - Treatment of invasive cervical resorption: an analysis of results using topical
      application of trichloracetic acid, curettage, and restoration.
AB  - OBJECTIVE: The purpose of this study was to carry out a clinical evaluation of
      the treatment of invasive cervical resorption. METHOD AND MATERIALS: Topical
      application of a 90% aqueous solution of trichloracetic acid, curettage,
      nonsurgical root canal treatment where necessary, and restoration with glass
      ionomer cement were performed on 94 patients with a total of 101 affected teeth.
      A minimum of 3 years' follow-up was required, unless failure occurred before that
      time, in which case that treatment was included. Teeth were divided into four
      classes, depending on the extent of the resorptive process. Class 1 represented
      the least invasive resorptive lesion, near the cervical area with shallow
      penetration into dentin, while class 4 represented the most invasive resorptive
      process, which had extended beyond the coronal third of the root. RESULTS: In all
      class 1 and class 2 cases, the results showed complete success, judged by an
      absence of resorption or signs of periapical or periodontal pathosis. When
      overall success was judged by absence of resorption and periapical or
      periradicular pathosis, the success rate in class 3 lesions was 77.8%. Only 12.5%
      of teeth in class 4 were free of resorption and deemed to be clinically sound.
      CONCLUSION: The treatment regimen was successful in class 1 and class 2 cases,
      reasonably successful in class 3 cases, and generally unsuccessful in class 4
      resorptions, where alternative treatment is recommended. Diagnosis of lesions at
      an early stage is, therefore, highly desirable.

PMID- 10356562
TI  - Cemental tear treated with guided tissue regeneration: a case report 3 years
      after initial treatment.
AB  - Cemental tear is a rare but probably underdiagnosed condition that may be a
      factor in rapid periodontal breakdown. The present case report describes the
      regenerative treatment of a periodontal lesion around a mandibular canine in a 50
      year-old woman. The preoperative radiograph revealed a small cemental tear within
      an intrabony lesion. The three-wall bony lesion was treated with a barrier
      membrane and followed for 3 years. Periodontal pocket reduction was 5.5 mm, and
      attachment gain amounted to 3.5 to 4.5 mm Standardized radiographs showed
      remarkable, 1.6-mm bone fill of the intrabony lesion. Also, a band of keratinized
      tissue had formed.

PMID- 10356563
TI  - Volumetric microleakage assessment of glass-ionomer-resin composite hybrid
      materials.
AB  - OBJECTIVE: This study was intended to quantify the marginal leakage of three
      glass-ionomer-resin composite hybrid materials and compare it with the leakage
      exhibited by a glass-ionomer cement and a bonded resin composite system. METHOD
      AND MATERIALS: Standardized Class V cavities were prepared on root surfaces of
      105 extracted human teeth, randomly assigned to five groups of 21 each, and
      restored with either Ketac-Fil Aplicap, Z100/Scotchbond Multi-Purpose Plus,
      Vitremer, Photac-Fil Aplicap, or Dyract. The teeth were thermally stressed for
      500 cycles and stained with methylene blue. The microleakage was quantified
      spectrophotometrically, and the data were statistically analyzed with Friedman's
      test. RESULTS: There were no significant differences in microleakage among the
      five groups. Restorations of all tested materials showed some marginal leakage in
      Class V cavities. CONCLUSION: The microleakage performance of glass-ionomer-resin
      composite hybrid materials was similar to those of a conventional glass-ionomer
      and a bonded resin composite system.

PMID- 10356564
TI  - In vitro comparison of 10-minute versus 24-hour shear bond strengths of six
      dentin bonding systems.
AB  - OBJECTIVE: Early bond strengths produced by dentin bonding systems should be
      sufficient to resist the polymerization shrinkage of resin composite. This study
      compared the 10-minute and 24-hour shear bond strengths of six dentin bonding
      systems: One-Step (OS), PermaQuik (PQ), Prime & Bond 2.1 (PB), Scotchbond Multi
      Purpose (SBMP), Single Bond (SB), and Tenure Quik with Fluoride (TQ). METHOD AND
      MATERIALS: Each bonding system was used to bond composite to visibly moist dentin
      at 34 degrees C +/- 2 degrees C. The specimens were debonded at 37 degrees C +/-
      1 degree C 10 minutes after the start of light curing of the bonding system, and
      the results were compared with the 24-hour bond strengths. The mode of failure
      was recorded. RESULTS: The 10-minute mean shear bond strengths were: OS, 16.4;
      PQ, 14.3; SB, 14.0; PB, 12.7; TQ, 10.7; and SBMP, 9.3 MPa. The 24-hour mean shear
      bond strengths were OS, 23.3; PB, 20.8; SB, 20.3; PQ, 19.4; TQ, 11.2; and SBMP,
      10.0 MPa. The 10-minute mean shear bond strengths of OS, PQ, PB, and SB bonding
      systems were significantly less than the 24-hour values. More dentinal fractures
      and mixed failures were observed with OS, PQ, and PB. Systems with higher bond
      strengths had more resin penetration into the lateral dentinal branches.
      CONCLUSION: The 10-minute mean shear bond strengths were all less than 17 MPa,
      and the 10-minute bond strengths were less than the 24-hour values.

PMID- 10356565
TI  - Bulimia-induced dental erosion in a male patient.

PMID- 10356566
TI  - Improving dentist-patient relations.

PMID- 10356567
TI  - Carbamide peroxide whitening of nonvital single discolored teeth: case reports.
AB  - Patients who present with a single discolored tooth represent a significant
      restorative challenge. These case reports describe an economic and conservative
      treatment option for these patients. The situations presented demonstrate
      techniques for bleaching with carbamide peroxide in a traditional nightguard or
      with an inside-outside technique to achieve acceptable esthetic results on
      isolated nonvital discolored teeth. Although these techniques may not be
      effective in all cases, they do not compromise or eliminate any future treatment
      options.

PMID- 10356568
TI  - A clinical comparison of resin composite inlay and onlay posterior restorations
      and cast-gold restorations at 7 years.
AB  - OBJECTIVE: The purpose of this study was to evaluate the clinical performance of
      Concept indirect posterior heat- and pressure-polymerized restorative material
      and compare it to the performance of cast gold. METHOD AND MATERIALS: Inlays and
      onlays placed in a standardized manner as part of a clinical study were evaluated
      at 7 years. Eighteen patients (45%) who had received 36 Concept restorations
      returned and were evaluated using the US Public Health Service criteria.
      Restorations were evaluated in seven categories as the percentage receiving Alfa
      (ideal), Bravo (clinically acceptable), or Charlie (clinically unacceptable)
      scores or as restoration no longer present. Fourteen of the restorations were
      cemented with Heliobond bonding resin and 13 were cemented with Special Bond
      bonding resin. Each patient also received a cast-gold restoration for comparison.
      RESULTS: Concept restorations received scores of Alfa at the following rates:
      color match, 64%; interfacial staining, 47%; secondary caries, 75%; wear, 58%;
      marginal integrity, 64%; surface texture, 72%; and axial contour, 58% (in 14%
      this category was not applicable because they were Class I restorations). Nine
      Concept restorations (25%) were no longer present. Fifteen of 18 gold
      restorations were present at this recall. Statistical analysis indicated no
      significant differences in any categories between the two bonding resins used
      with Concept restorative material and the gold restorations. CONCLUSION: At 7
      years in vivo, the Concept indirect posterior restorative system yields
      clinically acceptable restorations, particularly in premolars.

PMID- 10356569
TI  - Surface finish produced on resin composites by new polishing systems.
AB  - OBJECTIVE: There is a demand for more efficient and finer polishing of resin
      composite restorations. This study compared the use of some new systems, with new
      or reduced numbers of abrasive instruments, to polish representative resin
      composites. METHOD AND MATERIALS: Super-Snap Rainbow Technique Kit, Sof-Lex Pop
      On System, and Enhance Finishing and Polishing System were used to prepare the
      surfaces of blocks of seven different hybrid or microfilled resin composites. For
      each system, three instruments were used for 30 seconds each in a standard
      manner. The average surface roughness of the polished surfaces was determined by
      profilometer. RESULTS: Visually, all surfaces were of clinically acceptable
      luster. By profilometer ranking, the Super-Snap Rainbow Kit produced the
      smoothest surfaces, followed by the Sof-Lex Pop-On System disks (which were not
      statistically different), and the Enhance System. CONCLUSION: The Super-Snap
      Rainbow Technique Kit and Sof-Lex Pop-On System provided the smoothest surfaces
      for all the composites tested. For several composites, the Enhance System
      provided less smooth surfaces, but these were also clinically acceptable.

PMID- 10356570
TI  - Occlusal caries: diagnosis and noninvasive treatments.
AB  - The diagnosis of occlusal caries and the initiation of more effective treatment
      present a considerable challenge. Caries not only has decreased in prevalence,
      but also has changed in pattern and in progression because of the increased use
      of fluorides. Correct diagnosis is crucial, distinguishing lesions that can be
      arrested by noninvasive treatment from those that may justify restorative
      treatment. For incipient lesions, it is necessary to improve the patient's home
      care preventive methods, to apply fluoride or other prophylactic agents, or even
      to seal fissures, preserving the maximum amount of sound tooth structure. This
      article discusses the diagnosis of occlusal caries and noninvasive treatments for
      the management of early caries.

PMID- 10356571
TI  - Comparative radiopacity of flowable resin composites.
AB  - OBJECTIVE: This in vitro investigation aimed to determine the radiopacity of
      eight recently introduced "flowable" restorative resin composites and to compare
      their radiodensities to those of enamel, dentin, and a widely used composite
      marketed for universal application in anterior and posterior teeth. METHOD AND
      MATERIALS: A total of 45 composite specimens were fabricated in cylindrical molds
      and exposed to a curing light for 120 seconds. Two methods were used to determine
      radiopacity: a transmission densitometer and a computer-assisted densitometric
      image analysis station. RESULTS: Of the eight flowable resin composites tested,
      only three exhibited a radiopacity equal to or greater than that of enamel, a
      widely followed guideline for clinicians' diagnostic ability. The radiopacity of
      the remaining five materials was not statistically significantly greater than
      that of dentin. CONCLUSION: The level of radiopacity of the tested flowable
      composites was variable; those with low radiodensity should be avoided in Class
      II restorations, where a clear determination of recurrent caries by the examining
      clinician could be compromised.

PMID- 10356572
TI  - Photoelastic assessment of the expansion of direct-placement gallium restorative
      alloys.
AB  - OBJECTIVE: The purpose of this study was to assess, via a photoelastic resin, the
      expansion of gallium restorative alloys under conditions similar to those found
      in the clinical situation. METHOD AND MATERIALS: Two gallium alloys, Galloy and
      Gallium GF II, were tested, along with a high-copper amalgam, Dispersalloy, and a
      low-copper alloy, New True Dentalloy. The gallium alloys were tested as (1)
      uncontaminated, (2) contaminated with water, Ringer's solution, or a cell culture
      medium, and (3) immersed in these fluids at times ranging from 5 minutes to 3
      days. The gallium and amalgam alloys were condensed in a hole drilled in a block
      of photoelastic resin and observed for 3 months. The amount of stress was
      recorded on color slides taken through polarized light at regular intervals. The
      photographs of the color bifringen stress patterns at 1 and 3 months were ranked
      by two independent evaluators for least to greatest observed stress. RESULTS:
      Dispersalloy had the least expansion, followed by uncontaminated Galloy and
      Galloy contaminated with water. Next came Galloy contaminated with cell culture
      medium, Galloy contaminated with Ringer's solution, contaminated New True
      Dentalloy, and Gallium GF II. The last group was Gallium GF II contaminated with
      any of the three solutions. Both gallium alloys immersed in the three fluids
      showed a strong edge effect, and by 6 weeks many of the gallium alloys had
      extruded from the mold. CONCLUSION: These results corroborate the findings of
      some clinical studies that have shown that these gallium alloys can potentially
      cause catastrophic failures.

PMID- 10356573
TI  - Solubility and fluoride release in ionomers and compomers.
AB  - OBJECTIVE: The degree of solubility and the fluoride release of glass-ionomer
      cements and "compomers" were determined as a function of time. METHOD AND
      MATERIALS: Three conventional glass-ionomer cements, three hybrid ionomers, and
      two compomers were included in the study. Disk-shaped specimens were prepared and
      immersed in a lactic acid solution. Solubility was evaluated from determinations
      of loss of mass as a function of time. To evaluate fluoride release, similar
      specimens were immersed in 50 mL of deionized water to which 50 mL of buffer
      solution was added. A fluoride ion detector was used to read the concentration of
      fluoride ion in the overall solution at different times after immersion. RESULTS:
      Material and time factors had a significant influence on results. The compomers
      showed less corrosion and fluoride release than the ionomers. Some correlation
      was found between solubility and fluoride leakage values. CONCLUSION: Components
      of both the ionomers and compomers that were studied can dissolve in water. The
      materials leak fluoride ions in amounts that differ according to the
      characteristics of the individual products.

PMID- 10356575
TI  - Royal Australasian College of Surgeons annual scientific congress. Auckland,
      Australia, 9-14 May 1999. Abstracts.

PMID- 10356574
TI  - Two-body sliding wear of a direct-filling silver alternative to amalgam.
AB  - OBJECTIVE: This study investigated the wear resistance of a mercury-free silver
      direct-filling material and a dental amalgam. METHOD AND MATERIALS: A
      precipitated silver powder was rinsed with dilute fluoboric acid and consolidated
      into a cohesive solid. For tooth cavity restoration and flexural testing, the
      silver was consolidated with a dental amalgam plugger at a load of 15 N. For wear
      testing, because of the relatively large specimen size, the silver was pressed at
      a pressure of 150 MPa, yielding a density similar to that obtained by hand
      consolidation. RESULTS: The silver had a flexural strength twice that of amalgam.
      Pin-on-disk wear resulted in a smooth surface and hardening in silver, as
      measured by indentation inside the wear tracks, in contrast to the damage that
      was found in amalgam. The wear track cross-sectional area (n = 12) at 10(6)
      revolutions was not statistically significantly different among amalgam, polished
      silver, and burnished silver. CONCLUSION: The consolidated silver exhibited work
      hardening and surface densification during wear and, as a result, was more
      resistant to wear-induced damage than amalgam.

PMID- 10356576
TI  - [Infectiology during change: prospects and controversies].

PMID- 10356577
TI  - [HIV infections: mortality reduced only in developed countries].

PMID- 10356578
TI  - [Is cancer an infectious disease too?].

PMID- 10356579
TI  - [Clinical research on human subjects. (2) Preclinical].

PMID- 10356580
TI  - [Can diagnostic scoring systems help decision making in primary care of patients
      with suspected acute appendicitis?].
AB  - BACKGROUND AND OBJECTIVE: To assess two recently developed scoring systems with
      respect to making or excluding the diagnosis of acute appendicitis. PATIENTS AND
      METHODS: Data on 2359 patients with typical signs of acute appendicitis (AA) were
      analysed, the results of two diagnostic scoring systems being compared with the
      diagnosis made by an experienced surgeon. RESULTS: AA was confirmed in 662 of the
      22,359 patients (prevalence 28%). Sensitivity, specificity, positive and negative
      predictive values and overall accuracy for diagnosis with the Ohmann scoring
      system were 0.63, 0.93, 0.77, 0.86 and 0.84; with the Eskelinen score the values
      were 0.79, 0.85, 0.68, 0.81 and 0.835; and by the surgeon they were 0.90, 0.94,
      0.85, 0.96 und 0.93. The negative appendectomy or laparotomy rate was 14.3 an
      12.3 respectively with the Ohmann score, 29.5 and 26.6 with the Eskelinen score.
      The numbers of potential and of nondiagnosed perforations were 41% and 37%
      respectively with the Ohman score and 26.6% and 16.3% with the Eskelinen score.
      The number of missed cases of AA was lowest with the Ohman scoring system,
      compared with 1.8% for the surgeon. After excluding AA, both scoring systems had
      a specificity of -0.99, with a positive probability rate of at least 27
      (Eskelinen score) up to 87 (Ohman score). CONCLUSION: Both diagnostic scoring
      systems are better for excluding than correctly diagnosing AA; the decision to
      exclude could be made with a high degree of accuracy. Either scoring system may
      therefore be used in primary care of patients suspected of AA to help decide on
      referral to hospital.

PMID- 10356581
TI  - [A 63-year-old patient with worsening general condition, bone demineralization,
      hypocalcemia and excess parathyroid hormone: late manifestations of
      pseudohypohyperparathyroidism].
AB  - HISTORY AND CLINICAL FINDINGS: A 63-year-old man was hospitalized because of his
      worsening general condition and weight loss. Physical examination revealed marked
      thoracic kyphosis with impaired mobility of his back and restricted walking
      because of pain in the right hip. He also had other bone pains. INVESTIGATIONS:
      Serum calcium was reduced (1.60 mmol/l) and there was generalized bone
      demineralization. Subsequently an increased parathormone (PTH) level was noted
      (499.0 ng/l) as well as markedly increased activity of enzymes involved in bone
      metabolism, decreased renal excretion of phosphates (4.76 mmol/24 h) and multiple
      pathological fractures. TREATMENT AND COURSE: The listed abnormalities indicated
      the diagnosis of pseudohypoparathyroidism (PHP), type 1 b. After treatment had
      been started with vitamin D (calcitriol 2 x 0.25 micrograms/d) and calcium
      (calcium gluconate, 3 x 500 mg/d), the levels of calcium, PTH and enzymes in bone
      metabolism gradually became normal. A cataract operation had to be performed
      because of calcification of the lens. CONCLUSION: The level of PTH should be
      determined in patients with extensive bone demineralization and hypocalcaemia. If
      PTH is raised, PHP should be included in the differential diagnosis.
      Normalization of serum calcium by calcium substitution and vitamin D
      administration will normalize PTH and improve mineralization of the skeleton. In
      this way the debilitating effects of osteodystrophia cystica generalisata (OCG)
      (Engel von Recklinghausen syndrome) can be prevented. Also, the consequences of
      extraosseous calcification, such as extrapyramidal symptoms of calcification of
      the brain-stem ganglia can be avoided if treated in time.

PMID- 10356582
TI  - [Percutaneous transvenous mitral valvuloplasty in a pregnant patient. Successful
      treatment of severe mitral stenosis].
AB  - HISTORY AND CLINICAL FINDINGS: A 31-year-old woman presented in the 25th week of
      pregnancy with ankle and pretibial oedema and increasing dyspnoea, ultimately in
      class IV (New York Heart Association classification). There were fine rales on
      auscultation and dullness on palpation over both lung bases. The heart rate was
      regular at 110/min. The first heart sound was very loud, and there was a mitral
      opening snap and a loud diastolic murmur maximal, over the cardiac apex.
      INVESTIGATIONS: The ECG showed sinus rhythm at a rate of 110/min, left axis
      deviation, incomplete right bundle branch block and P biatriale, but no other
      abnormalities. Echocardiography revealed biatrial enlargement and an enlarged
      right ventricle as well as pulmonary systolic hypertension of 100 mm Hg. Doppler
      sonography demonstrated severe mitral stenosis with a calculated mitral opening
      area of 0.9 cm2. DIAGNOSIS, TREATMENT AND COURSE: The symptoms improved only
      slightly under conservative drug treatment. The mitral valve changes, as noted
      sonographically, met the criteria for percutaneous transluminal balloon mitral
      valvoplasty (PTBMV), which was successfully performed. Afterwards the mitral
      opening area was 2.6 cm2 and pulmonary artery pressure gradually became normal.
      She was delivered without complication of a healthy child in the 39th week of
      pregnancy. CONCLUSION: PTBLMV is a relatively low-risk treatment in pregnant
      women with symptomatic mitral stenosis.

PMID- 10356583
TI  - [Clinical counseling and care of women with genetic predisposition to breast and
      ovarian carcinoma].

PMID- 10356584
TI  - [Epilepsy and epileptic seizures in the elderly].

PMID- 10356585
TI  - [Physician's liability during team work in surgery. Decision of the Federal Court
      on January 26, 1999].

PMID- 10356586
TI  - [Alcohol and myocardial infarct].

PMID- 10356587
TI  - [Muscle pain after travel to the tropics].

PMID- 10356588
TI  - [Muscle pain after travel to the tropics].

PMID- 10356589
TI  - [Neurologic cause of respiratory insufficiency].

PMID- 10356590
TI  - [DNA demonstration of Chlamydia trachomatis and Neisseria gonorrhoeae in urine
      specimens of medical students].

PMID- 10356591
TI  - Association for Research in Vision and Ophthalmology annual meeting. Fort
      Lauderdale, Florida, USA. May 9-14, 1999. Abstracts.

PMID- 10356592
TI  - International Association for Dental Research Divisional meetings, 1998-1999.
      Abstracts.

PMID- 10356593
TI  - Clinical importance of coronary endothelial vasodilator dysfunction and
      therapeutic options.
AB  - The vascular endothelium plays a key role in the control of vasomotor tone, local
      haemostasis and vascular wall proliferation processes. These responses are
      mediated by a variety of substances released from the endothelium in response to
      physiological stimuli, including prostacyclin, endothelin, and most importantly
      nitric oxide (NO). NO mediates vasodilation and furthermore inhibits platelet
      aggregation, expression of adhesion molecules for monocytes and adhesion of
      neutrophils, and it impairs growth of vascular smooth muscle cells. Risk factors
      for coronary atherosclerosis, such as hypercholesterolaemia, impair NO
      bioactivity, mainly due to an oxidative stress by superoxide radicals (O2-),
      which are able of rapidly inactivating endothelium-derived NO. Impaired NO
      bioactivity leads to unopposed paradoxical vasoconstriction of epicardial
      conductance vessels in response to physiological stimuli such as sympathetic
      activation as well as impaired vasodilator function of coronary resistance
      vessels. Therefore, endothelial dysfunction contributes to ischaemic
      manifestation of coronary artery disease. In addition, enhanced paradoxical
      vasoconstriction and a loss of endothelial antithrombotic activities might
      unfavourably modulate the course of acute coronary syndromes. Thus, the aim of
      therapeutic interventions is to increase NO bioavailability by either increasing
      NO production or decreasing O2- production in the endothelium. This goal can be
      reached, for example by ACE inhibitors, lipid-lowering drugs, increased shear
      stress by physical exercise, oestrogens, and L-arginine, which have already been
      shown to improve endothelial vasodilator function. Nevertheless, it has to be
      determined whether ameliorated endothelial function will contribute to improved
      patients prognosis.

PMID- 10356594
TI  - Urinary albumin excretion rate is independently related to autonomic neuropathy
      in type 2 diabetes mellitus.
AB  - OBJECTIVE: To evaluate if urinary albumin excretion rate (UAER) is independently
      related to subclinical autonomic neuropathy in type 2 diabetes. DESIGN: A
      controlled cross-sectional study. SETTING: Primary health care centre. SUBJECTS:
      Consecutive recently diagnosed (< 1 year) type 2 diabetic patients (group A, n =
      150) and patients with long-standing (median 11 years) type 2 diabetes (group B,
      n = 146) chosen at random. A nondiabetic control group (group C, n = 150) matched
      for age and gender to group A. MAIN OUTCOME MEASURES: Neuropathy by
      cardiovascular reflex tests and UAER by nephelometry. METHODS: Univariate
      statistics in group A + B (t-test chi 2- or McNemars test) with Valsalva and
      breathing ratios as categorical grouping variables and the independent variables
      gender, smoking, systolic and diastolic blood pressure, fasting serum
      cholesterol, HDL cholesterol, triglycerides, haemoglobin A1c, glucagon stimulated
      C-peptide, fasting and postload 1 and 2 h blood glucose and serum insulin, UAER,
      coronary heart disease and congestive heart failure. Logistic regression analyses
      in group A + B with Valsalva and breathing ratios as dependent categorical
      variables and age, systolic blood pressure, congestive heart failure, coronary
      heart disease, fasting blood glucose, serum triglycerides and UAER as independent
      variables. RESULTS: Compared to nondiabetic subjects the diabetic patients of
      both groups were at increased risk of neuropathy as judged by the Valsalva ratio
      (P < 0.01). In known diabetic patients with a UAER > or = 30 mg 24-1 h neuropathy
      was more common than amongst their normoalbuminuric counterparts (Valsalva test P
      = 0.007, breathing test P = 0.02). In logistic regression analysis UAER
      independently explained abnormal Valsalva (P = 0.015) and breathing tests (P =
      0.04) in the group A + B. CONCLUSIONS: UAER is independently related to
      subclinical autonomic neuropathy in type 2 diabetes.

PMID- 10356595
TI  - Under-reporting of dietary intake by smoking and non-smoking subjects counselled
      for hypercholesterolaemia.
AB  - OBJECTIVES: We asked whether under-reporting of energy and cigarette smoking were
      associated with choice of foods and dietary composition amongst subjects with
      hypercholesterolaemia who had received dietary instruction to lower serum
      cholesterol. DESIGN, SETTING AND SUBJECTS: Dietary intake was assessed with a 4
      day weighed food record in 205 women and 141 men, aged 20-73 years, being treated
      at a lipid clinic (tertiary referral centre). Under-reporting was assessed by
      calculating the ratio of energy intake (EI) to estimated basal metabolic rate
      (BMR). RESULTS: The median EI/BMR was 1.1 for both men and women. EI/BMR did not
      differ according to smoking status, but correlated negatively with body mass
      index (Spearman's rho = -0.32, P = 0.0001). EI/BMR was inversely associated with
      energy-adjusted intakes of potatoes, vegetables, fish and low-fat meats, and
      positively associated with intakes of nuts, potato crisps, chocolate, sour and
      ice cream, oils, fatty meat spreads, cakes and biscuits, and with alcohol. Thus,
      low EI/BMR was associated with increased energy-adjusted intakes of protein,
      thiamine, riboflavin, niacin, iron and cholesterol and with decreased intakes of
      sugar, poly- and monounsaturated fats and vitamin E (all P < 0.05). Cigarette
      smokers had a higher energy percentage (E%) from fat than non-smokers (29 +/- 6
      vs. 26 +/- 6), a lower E% from carbohydrates (50 +/- 7 vs. 54 +/- 7) and a lower
      intake of vitamin C (11 +/- 7 vs. 16 +/- 9 mg MJ-1; all P = 0.0001), reflecting
      an increased intake of fatty meats and a decreased intake of skimmed cheese,
      fruit, rice and pasta, and cakes and biscuits (all P < 0.05). CONCLUSION: Weighed
      dietary records reflected a 'healthier' intake of fat, protein, sugar, alcohol
      and some micronutrients amongst under-reporters, suggesting that self-reported
      dietary intakes are biased in patients with hypercholesterolaemia. Lack of
      responsiveness to the diet should not be assumed when dietary data are based on
      self-report. Smokers report a higher intake of fat and lower intake of vitamin C
      than non-smokers, even after dietary counsel, and may require more intensive
      interventions to optimize the diet.

PMID- 10356596
TI  - Adrenal steroid dysregulation in dystrophia myotonica.
AB  - OBJECTIVE: To evaluate circulating adrenal steroid hormones, cortisol diurnal
      rhythm and the negative feedback function of the cortisol axis in patients with
      dystrophia myotonica (DyM), a disease where metabolic disturbances, peripheral
      insulin insensitivity and cognitive dysfunction are common features. DESIGN:
      Morning serum levels of dehydroepiandrosterone sulphate, androstenedione, 17
      alpha-hydroxy progesterone and cortisol; morning serum levels of testosterone and
      insulin; diurnal rhythm of saliva cortisol; and an overnight dexamethasone
      suppression test, together with a cognitive screening test in men with DyM and in
      controls. SETTING: Outpatient clinic in co-operation with Umea University
      Hospital. SUBJECTS: Fifteen men with DyM and 13 age-matched controls. MAIN
      OUTCOME MEASURES: Adrenal steroid hormone levels, diurnal rhythm of saliva
      cortisol, dexamethasone suppression test and Mini Mental State Examination
      scores. RESULTS: Morning serum levels of dehydroepiandrosterone sulphate,
      androstenedione and 17 alpha-hydroxy progesterone were significantly decreased in
      DyM after inclusion of age and body mass index in multiple regression analyses
      (48, 26 and 32% decreases, respectively). An abnormal diurnal rhythm of saliva
      cortisol was present in all patients, mean saliva cortisol levels being
      significantly increased (33%) in DyM patients. Dexamethasone suppressibility did
      not differ between groups. DyM patients scored significantly lower on the Mini
      Mental State Examination (P < 0.001). CONCLUSIONS: These results indicate an
      abnormal adrenal steroid hormone secretion in DyM, which may contribute to
      peripheral insulin sensitivity as well as cognitive impairment in these patients.

PMID- 10356597
TI  - Bronchoalveolar lavage cells from sarcoidosis patients and healthy controls can
      efficiently present antigens.
AB  - OBJECTIVES: The interaction between antigen-presenting cells (APC) and T
      lymphocytes, that recognize the antigen-HLA complex using its T cell-receptor for
      antigen, is of crucial importance for a subsequent specific immune response. In
      patients with pulmonary sarcoidosis, the local antigen-presenting capacity in the
      lungs has been suggested to be abnormally enhanced, and implicated in the
      immunopathogenesis of the disease. This study was aimed at increasing the
      understanding of the capacity to present antigens by APC in the lung compartment.
      DESIGN AND SUBJECTS: We used bronchoalveolar lavage (BAL) cells and paired
      peripheral blood mononuclear cells (PBMC) of six sarcoidosis patients and two
      healthy controls to stimulate in total eight well characterized T-cell clones
      with known HLA and antigen specificities. All subjects were HLA typed. RESULTS:
      BAL cells of sarcoidosis patients as well as of healthy controls efficiently
      induced proliferation of the relevant T-cell clone in an HLA-restricted manner
      when adding either intact antigen or antigenic peptides. CONCLUSIONS: BAL cells
      have the capacity to process and present antigens adequately, irrespective of
      whether they are derived from healthy individuals or from patients with
      sarcoidosis, implying the alveolar space as an important location for active
      immune reactions.

PMID- 10356598
TI  - QT dispersion and late potentials during doxorubicin therapy for non-Hodgkin's
      lymphoma.
AB  - OBJECTIVES: To investigate effects of doxorubicin therapy on cardiac
      electrophysiology, with special emphasis on QT dispersion and late potentials, in
      lymphoma patients. DESIGN: Prospective study. SETTING: University hospital.
      SUBJECTS: Twenty-eight adult non-Hodgkin's lymphoma patients who received
      doxorubicin to a cumulative dose of 400-500 mg m-2. MAIN OUTCOME MEASURES:
      Standard 12-lead electrocardiogram (ECG) and signal-averaged ECG (SAECG)
      recordings were performed at baseline and after cumulative doxorubicin doses of
      200, 400 and 500 mg m-2. RESULTS: Heart rate-corrected QT interval (QTc)
      increased from 402 +/- 4 to 416 +/- 5 ms (P = 0.002) during the study period. QT
      dispersion (variability in QT interval duration amongst the different leads of
      the standard 12-lead ECG) increased from 24.1 +/- 2.5 to 35.0 +/- 2.8 ms (P =
      0.041) and QTc dispersion increased from 26.5 +/- 2.5 to 39.0 +/- 3.5 ms (P =
      0.039). Five patients (18%) developed QT dispersion exceeding 50 ms. In addition,
      two patients (7%) developed late potentials during doxorubicin therapy. The
      changes in QTc duration, QT dispersion and late potentials occurred independently
      of the impairment of left ventricular function. CONCLUSIONS: Prolongation of QTc,
      increased QT dispersion and development of late potentials are indicative of
      doxorubicin-induced abnormal ventricular depolarization and repolarization. QT
      dispersion and late potentials are both known to be associated with increased
      risk of serious ventricular dysrhythmias and sudden death in various cardiac
      diseases. Thus, follow-up of these parameters might also be useful in assessing
      the risk of late cardiovascular events in cancer patients treated with
      anthracyclines.

PMID- 10356599
TI  - Oral anticoagulant treatment in patients with mechanical heart valves: how to
      reduce the risk of thromboembolic and bleeding complications.
AB  - Patients with mechanical heart valves have a high risk of thrombus formation on
      the valve and subsequent systemic embolism. These patients therefore need to
      receive life-long oral anticoagulation (OAC). Despite this treatment, the overall
      incidence rate of major thromboembolic complications is still about 1-2 per 100
      patient-years. Additionally, these patients have an increased risk of bleeding
      complications, ranging between 1 and 7 per 100 patient-years. To reduce both
      types of often very serious complications, the optimal intensity of
      anticoagulation needs to be established. We found a fairly wide optimal range
      between 2.5 and 4.9 INR (international normalized ratio) at which the incidence
      of both untoward events was minimal. As a target intensity, we recommend opting
      for the middle of this range (INR 3.0-4.0), thereby providing a safe margin at
      both ends. In order to further reduce thromboembolic and bleeding complications,
      two approaches can be considered: first of all, the management of OAC treatment
      needs to be optimized in order to achieve a stable therapeutic effect in as many
      patients as possible. Secondly, patient characteristics need to be identified
      that increase the thromboembolic or bleeding risk. Subsequently, the optimal
      intensity may need to be adjusted accordingly, at an individual level. Possible
      risk factors for an increased thromboembolic risk are position and type of the
      prosthesis. Age may increase both the risk of thromboembolism and the risk of
      haemorrhage.

PMID- 10356601
TI  - Oral anticoagulants are effective long-term after acute myocardial infarction.
AB  - Three long-term studies on oral anticoagulation, the Sixty Plus trial, the WARIS
      study, and the ASPECT trial all meet the methodological requirements for modern
      stand alone clinical trials: large number of patients, double-blinded, placebo
      controlled design, and intention to treat analysis. All demonstrate significant
      reduction in recurrent myocardial infarction, and all show reduction in the risk
      of total stroke. The WARIS study, however, is the only study demonstrating
      efficacy in terms of statistically significant reduction of all-cause mortality.
      These findings are confirmed by a recent meta-analysis. The overall benefit of
      oral anticoagulation after myocardial infarction suggests avoidance of 4-26
      events per 100 patients treated for 2-3 years. Given the results from the trials
      applying the most adequate control of anticoagulation, avoidance of 10-14 events
      per 100 patients treated seems to be a realistic benefit. Provided there is sound
      management of the anticoagulant therapy, especially employment of suitable
      control methods, the incidence of bleeding may be kept at a low level.

PMID- 10356600
TI  - Oral anticoagulation in nonvalvular atrial fibrillation.
AB  - Chronic nonvalvular atrial fibrillation is associated with an overall risk of
      thromboembolic complications of 4.5% per year. Advancing age, prior stroke or
      transient cerebral ischaemia, diabetes, hypertension, and impaired function of
      the left ventricle are known risk factors. Placebo-controlled trials have
      demonstrated that oral anticoagulant therapy with warfarin is effective for
      primary and secondary prevention of ischaemic stroke, reducing the risk by 68%.
      The effect of aspirin is still controversial, reducing the risk by 18-44%. Recent
      clinical trials have investigated the effect of warfarin given at a very low
      intensity alone or combined with aspirin. The results from the SPAF III study
      demonstrated that a combination of mini-intensity warfarin plus aspirin was
      insufficient for stroke prevention in atrial fibrillation. More trials have now
      confirmed that oral anticoagulation at INR-values below 2.0 is not effective for
      prevention of thromboembolic events in these patients. It is currently
      recommended that patients at a high risk of stroke are treated with warfarin at
      an intensity of INR 2.0-3.0. Patients younger than 65 years without other risk
      factors can be given aspirin 325 mg day-1.

PMID- 10356602
TI  - Oral anticoagulation in peripheral vascular surgery: how intense, for how long,
      or at all?
AB  - To evaluate the influence of postoperative pharmacotherapy (antiplatelet therapy
      with acetylsalicylic acid (ASA) or oral anticoagulation) following various
      peripheral vascular surgical interventions (femoro-popliteal reconstruction,
      femoro-popliteotibial venous bypass;) two clinical series of patients were
      analysed (A1-2) and we made the hypothesis that adjuvant therapy may be
      beneficial. Thereafter two clinical trials were carried out (B1-2), to assess the
      value of postoperative antiaggregant and anticoagulant treatment. It was not
      possible to demonstrate any influence of ASA on improving patency at the iliaco
      popliteal level or on patient survival. It was concluded that the ASA dosage of
      1500 mg daily was too high, and produced severe side-effects, probably leading to
      insufficient patient compliance to therapy. In the B2 trial 130 patients received
      a femoro-popliteal above- or below-knee vein bypass, and were assigned to the
      therapy group (n = 66) and treated with anticoagulants or to the control group (n
      = 64) which received no therapy. During the follow-up, for a maximum of 10 years,
      the probability of bypass function, limb salvage and patient survival were
      significantly in favour of the treatment. The described single centre clinical
      trial B-2 produced in accordance with other trials a level II evidence in favour
      of postoperative pharmacotherapy. Level 1 trials assessing the direct comparison
      of antiaggregant versus anticoagulant therapy are underway, but results are
      unavailable yet, similarly the results of the Antithrombotic Trialist's
      Collaboration (ATT) are currently unknown.

PMID- 10356603
TI  - Oral anticoagulation in venous thromboembolism: decisions based on more than mere
      feelings.
AB  - Although there is a very limited scientific basis for the recommendation to
      target the intensity of oral anticoagulation after venous thromboembolism at an
      international normalized ratio (INR) of 2.0-3.0, this has been widely adopted. It
      seems possible from the DURAC I and II trials that a slight lowering of the upper
      limit could further reduce the risk of major haemorrhage. The optimal duration of
      anticoagulation in this group of patients has been extensively investigated. For
      the majority of patients a treatment duration of 6 months eliminates the high
      risk of relatively early recurrences without yielding an increase in the
      incidence of major haemorrhages. Patients with a distal deep vein thrombosis and
      a temporary risk factor or those with poor compliance should have a shorter
      treatment duration, whereas further prolongation is warranted in patients with
      certain biochemical abnormalities or recurrent thromboembolic episodes. The
      optimal treatment regimen is individualized, taking into account a variety of
      risk factors, and re-evaluated regularly in case of prolonged therapy.

PMID- 10356604
TI  - Relapsing pneumonia due to a migrating intrathoracic foreign body in a World War
      II veteran shot 53 years ago.
AB  - In the great majority of cases of long-standing intrathoracic foreign bodies,
      patients are asymptomatic. However, symptoms may occur years later from the
      migration of the foreign body. We report on a 70-year-old patient who developed
      relapsing pneumonia due to obstruction of a bronchial branch of the left apical
      group by a migrating infantry bullet impacting 53 years ago. This was not
      diagnosed until the second attack of pneumonia in 1998. The bullet remains were
      removed bronchoscopically and the pneumonia resolved completely without further
      complications.

PMID- 10356605
TI  - Cortisol deficiency may account for elevated apoptotic cell population in
      patients with chronic fatigue syndrome.

PMID- 10356606
TI  - Single aetiological agent may not be feasible in CFS patients.

PMID- 10356607
TI  - Intestinal endocrine cells in myotonic dystrophy: an immunocytochemical and
      computed image analytical study.
AB  - OBJECTIVES: To study intestinal endocrine cell types in patients suffering from
      myotonic dystrophy (MD) and diarrhoea. DESIGN: Comparative study between MD
      patients and matched controls. SETTING: Departments of Medicine, Central
      Hospital, Boden, and University Hospital, Umea, Sweden. SUBJECTS: Ten patients
      with MD (four males and six females) and suffering from diarrhoea. Ten healthy
      volunteers served as controls for the duodenal study and 13 patients under
      investigation for rectal bleeding and with endoscopically normal mucosa were
      controls for the rectal study. MEASUREMENTS: The duodenal and rectal endocrine
      cell types were identified by immunohistochemical investigation and quantified by
      computed image analysis. RESULTS: The total endocrine cell area in the duodenum
      as demonstrated by chromogranin A-immunoreactivity was significantly increased in
      MD as compared with the controls (126 +/- 58 vs. 48 +/- 22 x 10(3) micron 2 mm-2
      in crypts and 230 +/- 183 vs. 28 +/- 22 in villi, respectively, P < 0.01). The
      increase included all types of endocrine cells studied, namely those positive for
      serotonin, cholecystokinin (CCK)/gastrin, secretin, gastric inhibitory peptide
      (GIP) and somatostatin. In the rectum, the total endocrine cell area as
      determined by chromogranin A-immunoreactivity was also significantly increased,
      but there was no statistical difference between the controls and patients with
      respect to the area of serotonin-, peptide YY (PYY)-, pancreatic polypeptide (PP)
      or somatostatin-immunoreactive cells. CONCLUSIONS: The increase in endocrine
      cell area indicates a disturbed endocrine regulation of the gastrointestinal
      tract that may contribute to the development of gastrointestinal symptoms
      encountered in MD patients.

PMID- 10356608
TI  - [Inverse radiotherapy planning].
AB  - BACKGROUND: In clinical practice it sometimes happens that with currently
      available conformal radiotherapy techniques no satisfactory dose distribution can
      be achieved. In these cases inverse radiotherapy planning and intensity modulated
      radiotherapy may give better solutions. METHOD: Inverse planning is a technique
      using a computer program to automatically achieve a treatment plan which has an
      optimal merit. This merit may either depend on dose or dose-volume constraints
      like minimum and maximum doses in the target region or critical organs,
      respectively, or biological indices like the complication free tumor control
      rate. As the result of inverse planning the inhomogeneous intensity fluence of
      the beams is calculated. These fluence distributions may be generated by beam
      compensators or multi-leaf collimation. RESULTS: Clinical studies to prove the
      advantage of inverse planning are already on the way. It has been shown that this
      technology is safe and that the dose distributions which can be achieved are
      superior to conventional methods. CONCLUSIONS: Inverse treatment planning and
      intensity modulated radiation therapy will almost certainly come to be the
      technique of choice for selected clinical cases.

PMID- 10356609
TI  - The accuracy of dose determination during total body irradiation.
AB  - AIM: The aim of this work was to estimate the error in dose calculations, to
      check the agreement between the measured and calculated doses and to analyse dose
      discrepancies in the group of patients undergoing total body irradiation.
      PATIENTS AND METHODS: A combination of lateral and anterior-posterior fields was
      used in 8 fractions and on 4 consecutive days. Doses were preliminarily
      calculated and then measured in vivo by thermoluminescent, semiconductor and
      ionization dosimeters attached to the body in 10 representative transverse cross
      sections. Calculations and measurements were carried out for the beam at the body
      entry and exit. The error in dose calculations was estimated for each reference
      point. Dose deviations between calculations and measurements were analysed using
      the Student's t-test. RESULTS: The error in preliminary dose calculations ranged
      from 3% to 15% (Table 1). Standard deviations of the measurements and percent
      deviations from the calculations exceeded 10% only for the lung and neck exits
      (Table 3). Average thermoluminescent readings were 6% higher than the
      corresponding semiconductor readings. The measured doses fitted the calculated
      values within the limit of error, except for the lung, head and neck exits for
      the whole group, depending on the type of fields used (Table 4).

PMID- 10356610
TI  - [Simultaneous radiochemotherapy with carboplatin in patients with inoperable
      advanced stage III and IV head and neck tumors].
AB  - BACKGROUND: The results of treating advanced tumors in the head and neck region
      with radiotherapy alone are disappointing. Concurrent radiotherapy and
      chemotherapy may improve this situation. The treatment results of concurrent
      radiochemotherapy at the University of Rostock were analyzed retrospectively.
      PATIENTS AND METHODS: From 1991 to 1996 92 patients with head and neck tumors
      were treated with concurrent radiochemotherapy (1.8 to 63 Gy; 70 mg/m2
      carboplatin day 1 to 5 and 29 to 33) with palliative tumor resection (n = 37) or
      without surgical treatment (n = 55). Remission rate, overall survival and disease
      free survival, local control and acute toxicity were analyzed. RESULTS: Six weeks
      after radiochemotherapy 56.5% of patients had a complete remission, 36% a partial
      remission and 7.5% "no change". With a median follow-up of 42 months (6 to 74
      months) overall survival, disease-free survival and local control were 24.3%,
      28.9%, 18.0% 5 years after treatment. All these criteria were significantly
      better in patients with palliative tumor resection compared to no surgical
      treatment (uni- and multivariate) and in patients with Stage III than in patients
      with Stage IV carcinomas (univariate), overall survival was significantly better
      in patients with Stage III (multivariate). A pretherapeutic Hb level below 7.0
      mmol/l (11.27 g/dl) reduced the local control significantly (uni- and
      multivariate). Grade III and IV mucositis was detected in 10%, Grade III
      leucopenia in 12% of treated patients. Grade IV leucopenia and Grade III
      thrombopenia were observed in 1 patient each. CONCLUSION: The toxicity of this
      treatment is tolerable. However, additional trials must be conducted before
      considering the palliative tumor resection as standard therapy.

PMID- 10356611
TI  - [Palliative radiation oncologic therapy: is patient's age a determining factor of
      feasibility? A 1-year analysis (1997) at a radiotherapy clinic of an academic
      teaching hospital].
AB  - BACKGROUND: Radiotherapy is a successfully proven, feasible and appropriate
      antineoplastic treatment for the palliation of tumor symptoms. Clinicians
      sometimes use the argument of the burden of advanced age and limited tolerance to
      withhold this modality of treatment from older patients. PATIENTS AND METHODS:
      All cancer patients (n = 827) who presented for the first time to the Department
      of Radiation Oncology during 1997 were used as a base to analyze if age was a
      factor with regard to the feasibility and the effectiveness of palliative
      radiation treatment in patients with measurable tumor burden. The following
      treatment end-points were analyzed in 440 (53%) patients who were treated
      palliatively: reduction or management of pain; neurological impairment; superior
      vena cava syndrome; dysphagia; dyspnea; bleeding or ulceration of the tumor or
      metastasis as well as prevention from clinically but not yet symptomatic tumor
      progression, while controlling for age (< 70 years: n = 293, 70 to 75 years: n =
      79, > 75 years: n = 68); treatment status (in- or out-patient), range of
      treatment modalities (radiation and/or chemotherapy, no cancer specific
      treatment). The frequency of not reaching these treatment goals is a criterium of
      treatment feasibility and a measure of the effect of the variables. RESULTS: When
      comparing primarily palliative and non-palliative treated patients, there were
      similar frequencies in the defined age groups, which points to the effect of
      other mechanisms of selection, e.g. effect of comorbidity. In an analysis of the
      relevant reasons for the discontinuation of treatment in palliatively treated
      patients (reduction of general condition: n = 31 [7%], comorbidity: n = 1 [0%],
      treatment toxicity: n = 3 [1%], tumor progression: n = 15 [3%], therapy
      associated death: n = 11 [3%], at patients own request: n = 8 [2%]) age was not a
      discernible factor. Frequencies of discontinuation of treatment according to age
      of patients and treatment status defined as in- vs out-patient are relatively
      small (< 70 years: 5/85 vs 42/208; 70 to 75 years: 2/29 vs 11/50; > 75 years:
      4/29 vs 13/39). There are similarities in the lower age groups and these seem to
      be independent from the treatment modalities used in each of the age groups.
      CONCLUSIONS: This presents an example of how one can analyze and present the
      treatment results of radiotherapy as part of quality management in a department
      of radiation oncology. The results confirm that it is not justified to withhold
      radiation therapy based on advanced age alone.

PMID- 10356612
TI  - [Possibilities of an open magnetic resonance scanner integration in therapy
      simulation and three-dimensional radiotherapy planning].
AB  - PURPOSE: A system for digital integration of an open MR scanner (0.23 T, Figure
      1) in therapy simulation and 3D radiation treatment planning is described.
      METHOD: MR images were acquired using the body coil and various positioning and
      immobilization aids. A gradient echo sequence (TR/TE 320 ms/24 ms) was used to
      create axial and coronal data sets. Image distortions were measured and corrected
      using phantom measurements (Figure 2) and specially developed software. RESULTS:
      Maximal and mean distortions of the MR images could be reduced from 19 mm to 8.2
      mm and from 2.7 mm to 0.7 mm, respectively (Figure 3 to 5, Table 1). Coronal MR
      images were recalculated in fan beam projection for use at the therapy simulator.
      Tumor and organ contours were transferred from the MR image to the digitally
      acquired and corrected simulator image using a landmark matching algorithm
      (Figure 6 and 7). For 3D treatment planning, image fusion of axial MR images with
      standard CT planning images was performed using a landmark matching algorithm, as
      well (Figure 8). Representative cases are shown to demonstrate potential
      applications of the system. CONCLUSION: The described system enables the
      integration of the imaging information from an open MR system in therapy
      simulation and 3D treatment planning. The low-field MR scanner is an attractive
      adjunct for the radio-oncologist because of the open design and the low costs.

PMID- 10356613
TI  - [Significance of a rectal balloon as internal immobilization device in conformal
      radiotherapy of prostatic carcinoma].
AB  - BACKGROUND: As known from the literature, prostate motion depends on different
      bladder and/or rectum fillings. The aim of this study was to analyze the
      influence of a rectum balloon catheter, used as an internal immobilization
      device, on prostate and rectum motion during the treatment course. Moreover we
      have analyzed if the balloon enables an increase of the distance between the
      prostate and the posterior rectum wall. PATIENTS AND METHODS: Ten patients with
      localized prostate cancer (T1 to T3) underwent computed tomographic examinations
      with and without rectal balloon (filled with 40 ml air) at 3 times during
      treatment course (at the start, middle and end of treatment). Edges of prostate,
      rectum and bladder were measured in relation to bony reference structures and
      compared for both examination series (with and without balloon). RESULTS: An
      increase of the distance between the prostate and the posterior rectal wall of 8
      mm was observed at the base of the prostate when using the rectum balloon
      (Figures 1a,b and 2). Moreover prostate motion in the ventrodorsal direction > or
      = 4 mm (1 SD) was reduced from 6/10 patients (60%) to 1/10 patients (10%) using
      the rectal balloon (Table 3, Figure 3). In general, deviations in the latero
      lateral and cranio-caudal directions were less (mean < or = 2 mm, 1 SD), no
      difference between both examination series (with and without balloon) was
      observed. CONCLUSION: Rectal balloon catheter offers a possibility to reduce
      prostate motion and rectum filling variations during treatment course. In
      addition it enables an increase in the distance between prostate and posterior
      rectal wall, which could enable an improved protection of the posterior rectal
      wall.

PMID- 10356616
TI  - [Surgery with postoperative radiotherapy compared with primary radiotherapy in
      mouth and oropharyngeal carcinomas].

PMID- 10356614
TI  - Differential proliferation dependence of alpha and beta damage in X-irradiated
      Chinese hamster cells.
AB  - PURPOSE: To determine quantitatively the influence of altering proliferation
      rates on clonal survival of asynchronously growing Chinese hamster (CHO) cells
      after X-irradiation and to evaluate the related contribution of alpha and beta
      damage. MATERIAL AND METHODS: Cell cycle distributions at the time of X
      irradiation of CHO cells were assessed by flow cytometry. Clonal radiation
      survival was established by colony forming assay. Survival data were fitted to
      the linear-quadratic model and analyzed on the basis of the mean inactivation
      dose, D. RESULTS: Increased S-phases were associated with increased resistance to
      X-rays. Radiosensitivity as expressed by D differed by a factor of 1.6 between
      the most sensitive and the most resistant populations. Separately analyzing the
      alpha and beta coefficients of survival curves revealed that the proliferation
      dependent effect was correlated only with beta. The major determinant of D was
      alpha, but its substantial interexperimental variations were independent of the
      cell cycle. CONCLUSIONS: Due to altering cell cycle distributions, considerable
      changes of radiosensitivity can occur. They can in part be understood as a
      consequence of S-phase dependent alterations of DNA damage repair. Reasons for
      the changes of a damage dependent lethality remain to be discovered by further
      research.

PMID- 10356615
TI  - [HIT'91: Precision and acute maximal side effects of radiotherapy of craniospinal
      axis. Concerning the contribution by R.D. Kortmann et al., Strahlenther Onkol
      1999;175:162-9 (No.4)].

PMID- 10356617
TI  - [Improving prognosis by simultaneous but not sequential radiochemotherapy:
      results of 2 randomized studies on nasopharyngeal carcinoma].

PMID- 10356618
TI  - [No improvement of prognosis by neoadjuvant chemotherapy alone in operable
      esophageal carcinoma].

PMID- 10356619
TI  - [Electropotential measurements as a new diagnostic modality in breast carcinoma].

PMID- 10356620
TI  - Schizotypal personality disorder and MRI abnormalities of temporal lobe gray
      matter.
AB  - BACKGROUND: Structural MRI data indicate schizophrenics have reduced left-sided
      temporal lobe gray matter volumes, especially in the superior temporal gyrus
      (STG) and medial temporal lobe. Our data further suggest a specificity to
      schizophrenia spectrum disorders of STG volume reduction. Interpretation of
      research studies involving schizophrenics may be complicated by the effects of
      exposure to neuroleptics and chronic illness. Sharing the same genetic diathesis
      of schizophrenics, subjects with schizotypal personality disorder (SPD) offer a
      unique opportunity to evaluate commonalities between schizophrenia and SPD,
      particularly as SPD subjects are characterized by cognitive and perceptual
      distortions, an inability to tolerate close friendships, and odd behavior, but
      they are not psychotic and so have generally not been prescribed neuroleptics nor
      hospitalized. Evaluation of brain structure in SPD may thus offer insight into
      the "endophenotype" common to both disorders. In addition, differences between
      groups may suggest which are the brain structures of schizophrenics that
      contribute to the development of psychosis. METHODS: To test the hypothesis of
      whether SPD subjects might show similar STG abnormalities, STG and medial
      temporal lobe regions of interest (ROI) were manually drawn on high resolution
      coronal MRI 1.5 mm thick slices. Images were derived from 16 right-handed male
      SPD subjects, without regard to family history, and 14 healthy, right-handed,
      comparison males who did not differ from the SPD group on parental socio-economic
      status, age, or verbal IQ. RESULTS: As predicted, SPD subjects showed a reduction
      in left STG gray matter volume compared with age and gender matched comparison
      subjects. SPD subjects also showed reduced parahippocampal left/right asymmetry
      and a high degree of disordered thinking. Comparisons with chronic schizophrenics
      previously studied by us showed the SPD group had a similarity of left STG gray
      matter volume reduction, but fewer medial temporal lobe abnormalities.
      CONCLUSIONS: These abnormalities strengthen the hypothesis of a temporal lobe
      abnormality in SPD, and the similarity of STG findings in schizophrenia and SPD
      suggest that STG abnormalities may be part of the spectrum "endophenotype." It is
      also possible that presence of medial temporal lobe abnormalities may help to
      differentiate who will develop schizophrenia and who will develop the less severe
      schizophrenia spectrum disorder, SPD.

PMID- 10356621
TI  - A short echo proton magnetic resonance spectroscopy study of the left mesial
      temporal lobe in first-onset schizophrenic patients.
AB  - BACKGROUND: Past 1H magnetic resonance spectroscopy (MRS) studies of the temporal
      lobe in schizophrenic patients have shown decreased levels of N-acetylaspartate
      (NAA) suggesting reduced neuronal density in this region. However, the measured
      volumes have been large and included contributions from mostly white matter.
      METHODS: Short echo 1H MRS was used to measure levels of NAA and other
      metabolites (i.e., glutamate and glutamine) from a 6 cm3 volume in the left
      mesial-temporal lobe of 11 first-episode schizophrenic patients and 11 healthy
      control subjects of comparable age, gender, handedness, education, and parental
      education levels. Spectra were quantified without operator interaction using
      automated software developed in our laboratory. Metabolite levels were normalized
      to the internal water concentration of each volume studied. Images were also
      obtained to determine temporal lobe gray and white matter volumes. RESULTS: No
      significant differences were found between levels of NAA or other metabolites, or
      gray and white matter volumes, in first-episode schizophrenic patients and
      comparison subjects. CONCLUSIONS: Since the volume studied was small compared to
      previous studies and contained mostly gray matter, this result suggests
      consequential NAA decreases may be restricted to regions of white matter.

PMID- 10356622
TI  - Treatment of nonpsychotic relatives of patients with schizophrenia: four case
      studies.
AB  - BACKGROUND: Substantial evidence now shows that the genetic vulnerability to
      schizophrenia can be manifested clinically in first-degree relatives of people
      with schizophrenia, even without the full manifestations of the disorder. One
      pattern of problems observed involves the combination of negative symptoms and
      neuropsychological deficits. We have investigated whether a low dose of a novel
      antipsychotic medication, risperidone, could attenuate these clinical problems in
      non-psychotic, first-degree relatives, and report here findings from our first 4
      cases. METHODS: Twelve adults who were first-degree relatives of patients with
      schizophrenia were evaluated for the presence of negative symptoms and
      neuropsychological deficits (in attention and working memory, long-term verbal
      memory and executive functions). Four subjects who met our predetermined
      criteria, and who did not demonstrate medical contraindications, were enrolled in
      a 6-week trial of risperidone. Clinical and medical measures were assessed
      before, during and after treatment. Doses of risperidone started at 0.25 mg and
      were increased to 1.0-2.0 mg/day. RESULTS: These subjects showed substantial
      reductions in negative symptoms, and one subject showed modest reductions. All
      four subjects showed substantial improvements on some tests of attention and
      working memory. Side effects of risperidone were temporary and mainly mild.
      CONCLUSIONS: These initial findings support two conclusions. First, clinical
      deficits in non-psychotic first-degree relatives of people with schizophrenia are
      identifiable, and to a significant extent, reversible. Second, risperidone may
      eventually serve as an effective treatment for people whose lives are impaired by
      similar or related problems.

PMID- 10356623
TI  - Olfactory identification and psychosis.
AB  - BACKGROUND: Olfactory identification performance has been investigated in several
      psychiatric populations, with deficits most commonly reported in patients with
      schizophrenia. In this study, olfactory identification performance was
      investigated in a more homogenous group of treatment-refractory patients with
      schizophrenia (T-RS) and in two additional psychiatric groups who demonstrate
      some similarities to the patients with schizophrenia in terms of symptomotology
      and medication regime. METHODS: The olfactory identification performance of 16 T
      RS patients was assessed using the University of Pennsylvania Smell
      Identification Test (UPSIT) and compared to that of 16 normal control subjects
      and two other psychiatric patient groups: 19 affective disorder patients
      requiring maintenance antipsychotic medication and 20 affective disorder patients
      not receiving antipsychotic medication. RESULTS: The olfactory identification
      performance of T-RS patients was significantly lower than that of normal controls
      but not significantly different from either affective disorder group. The
      olfactory identification performance of affective disorder patients receiving
      antipsychotic medication was significantly lower than that of affective disorder
      patients not receiving antipsychotic medication. DISCUSSION: Results are
      discussed in the context of a possible link between psychotic symptomotology and
      olfactory identification performance.

PMID- 10356624
TI  - Sleep-disordered breathing and periodic limb movements in sleep in older patients
      with schizophrenia.
AB  - BACKGROUND: Since the prevalence of both sleep-disordered breathing (SDB) and
      periodic limb movements in sleep (PLMS) increase with age, we explored whether
      older schizophrenia patients would have a high incidence of SDB and PLMS.
      Correlations between sleep and clinical variables were also examined. METHODS:
      Fifty-two patients (mean age = 59.6 years, SD = 8.9) had their sleep/wake,
      respiration, and leg movements recorded using a modified Medilog/Respitrace
      portable recording system plus oximetry. A battery of clinical, psychosocial, and
      motor disturbance variables were collected by research center staff. RESULTS:
      Forty-eight percent of these patients had at least 10 respiratory events per hour
      of sleep. These patients reported more symptoms of daytime sleepiness than
      patients with fewer than 10 events per hour. The relatively high prevalence of
      SDB in this group may contribute to overall sleep disturbances, and does not
      appear to be a result of high body mass index. Only 14% of the patients had at
      least five limb movements per hour of sleep, suggesting the prevalence of PLMS is
      much lower than expected in this age group. The number of leg jerks was inversely
      related to symptoms of tardive dyskinesia. CONCLUSIONS: The disturbance of sleep
      in these patients may be due, in part, to SDB, but is unlikely due to PLMS.

PMID- 10356625
TI  - Platelet serotonin, plasma cortisol, and dexamethasone suppression test in
      schizophrenic patients.
AB  - BACKGROUND: Serotonin (5-HT) regulates hypothalamic-pituitary-adrenal (HPA) axis
      activity. Abnormal response to the dexamethasone suppression test (DST) and
      altered platelet 5-HT concentration have been shown in some schizophrenic
      patients. METHODS: Platelet 5-HT and plasma cortisol concentrations were
      determined simultaneously in 86 male schizophrenic patients before and after DST.
      Basal plasma cortisol and platelet 5-HT levels were also determined in 69 healthy
      male persons. RESULTS: Schizophrenic patients had higher plasma cortisol and
      platelet 5-HT concentrations than healthy persons. An abnormal escape from
      dexamethasone suppression was observed in 50% of patients. In these patients
      predexamethasone cortisol and platelet 5-HT concentrations were higher than in
      patients with normal DST. CONCLUSIONS: This study demonstrates that schizophrenic
      patients have the HPA axis dysregulation that could be connected with a
      disturbance in the 5-HT system.

PMID- 10356626
TI  - Effects of left frontal transcranial magnetic stimulation on depressed mood,
      cognition, and corticomotor threshold.
AB  - BACKGROUND: The pathophysiology of depression may include synaptic hypoactivity
      of left prefrontal cortex. Several groups of investigators have described
      improved mood associated with rapid transcranial magnetic stimulation (rTMS) but
      have not looked for possible cognitive side effects associated with left
      prefrontal magnetic stimulation. METHODS: We measured the effects of left
      prefrontal rTMS on mood, cognition, and motor evoked potential threshold in 10
      patients with medication-resistant major depression. RESULTS: In a 2-week open
      trial of left prefrontal rTMS off antidepressant medications, scores on the
      Hamilton Rating Scale for Depression and the Beck Depression Inventory decreased
      by 41% and 40%, respectively. After resuming pre-rTMS antidepressant medication,
      improvement in mood was still significant at 1 and 3 months later. rTMS had no
      adverse effects on neuropsychological performance. rTMS treatments were
      associated with significant decreases in motor evoked potential threshold in the
      9 of 10 patients who remained off psychotropic medications during the 2-week
      treatment period. CONCLUSIONS: These preliminary data suggest that left
      prefrontal rTMS is safe and improves mood in patients with medication-resistant
      major depression. Changes in motor evoked potential threshold suggest that
      prefrontal rTMS may alter brain activity at sites remote from the stimulation.
      Double-blind, sham-controlled studies are needed.

PMID- 10356627
TI  - Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing
      hormone in subjects with chronic fatigue syndrome and in healthy volunteers.
AB  - BACKGROUND: Corticotropin-releasing hormone (CRH) and vasopressin (VP) are the
      two principal neuropeptide regulators of the hypothalamic-pituitary-adrenal axis
      in man, with VP serving to augment CRH-induced adrenocorticotropic hormone (ACTH)
      release. Unlike VP, desmopressin (DDAVP), which is a synthetic analogue of VP,
      when administered alone, has not been shown in healthy subjects to have
      consistent ACTH-releasing properties. It has been suggested that chronic fatigue
      syndrome (CFS), characterized by profound fatigue and a constellation of other
      symptoms, may be caused by a central deficiency of CRH. METHODS: We administered
      100 micrograms ovine CRH (oCRH) and 10 micrograms DDAVP, both alone and in
      combination, to a group of subjects with CFS, and to a group of healthy
      volunteers. Our aim was to establish the effect of DDAVP on CRH-induced ACTH
      release in these two groups. RESULTS: The delta-ACTH responses to oCRH were
      attenuated in the CFS (21.0 +/- 4.5 ng/L) compared to the control subjects (57.8
      +/- 11.0 ng/L; t = 3.2, df = 21, p < .005). The delta-cortisol responses were
      also reduced in the CFS (157.6 +/- 40.7 nmol/L) compared to the healthy subjects
      (303.5 +/- 20.9 nmol/L; t = 3.1, df = 21, p < .01). The delta-ACTH and delta
      cortisol responses to DDAVP alone did not differ between the two groups. On
      administration of both CRH and DDAVP no response differences between the two
      groups for either ACTH (p = .3) or cortisol output (p = .87) were established.
      Comparing the ACTH and cortisol responses to CRH and CRH/DDAVP in only those
      individuals from each group who had both tests, the cortisol output to the
      combination was significantly greater in the CFS compared to the healthy group.
      The ACTH output was also increased in the former group, though this was not
      significant. CONCLUSIONS: DDAVP augments CRH-mediated pituitary-adrenal
      responsivity in healthy subjects and in patients with CFS. That DDAVP was capable
      of normalizing the pituitary-adrenal response to oCRH in the CFS group suggests
      there may be increased vasopressinergic responsivity of the anterior pituitary in
      CFS and/or that DDAVP may be exerting an effect at an adrenal level.

PMID- 10356628
TI  - Prepulse inhibition of startle and the neurobiology of primary nocturnal
      enuresis.
AB  - BACKGROUND: Children with primary nocturnal enuresis (PNE) wet the bed during all
      stages of sleep and irrespective of state of arousal, suggesting that during
      sleep, when voluntary, i.e., cortical control, is not available, the signal from
      the distended bladder is not registered in the subcortical centers inhibiting
      micturition. Deficient prepulse inhibition (PPI) of startle has been reported in
      PNE. This study evaluates the association of this PPI deficit in PNE with
      comorbidity with attention-deficit hyperactivity disorder (ADHD) and with
      intelligence. METHODS: Prepulse modulation of startle was studied in 96 boys with
      PNE and 105 nonenuretic boys using intervals of 60, 120, and 4000 msec between
      the onset of a 75-dB 1000-Hz tone and a 104-dB noise burst. Thirty-one percent of
      the enuretic and 36% of the nonenuretic boys were diagnosed with ADHD. RESULTS:
      After adjustment for presence or absence of ADHD, lower or higher IQ, age, and
      unmodulated startle amplitude, there was a significant association between PNE
      and deficient PPI of startle following the 120-msec prepulse interval. Those
      enuretic boys who also were ADHD or had higher performance IQs (> or = 110)
      showed the greatest PPI deficit. CONCLUSIONS: A common deficiency of inhibitory
      signal processing in the brain stem may underlie both deficient PPI and the
      inability to inhibit micturition in PNE. Strong familiarity for PNE, ADHD, and
      intelligence suggests a possible genetic mediation of these effects.

PMID- 10356629
TI  - Glucocorticoid receptors in anorexia nervosa and Cushing's disease.
AB  - BACKGROUND: Patients with anorexia nervosa do not display cushingoid features in
      spite of elevated cortisol plasma levels. Whether a cortisol resistance or a
      reduced availability of the metabolic substrates necessary to develop the effect
      of glucocorticoids is responsible for this has not been established. METHODS:
      Twenty-two patients with severe restrictive anorexia nervosa, 10 patients with
      active Cushing's disease, and 24 healthy volunteers without psychiatric disorders
      or mood alterations were investigated. Glucocorticoid receptor characteristics
      were examined on mononuclear leukocytes by measuring [3H]dexamethasone binding
      and the effect of dexamethasone on [3H]thymidine incorporation, which represents
      an index of DNA synthesis. RESULTS: The number of glucocorticoid receptors on
      mononuclear leukocytes (MNL) was comparable in patients with anorexia nervosa,
      patients with active Cushing's disease, and normal subjects (binding capacity 3.3
      +/- 0.23 vs. 3.7 +/- 0.30 and 3.5 +/- 0.20 fmol/10(6) cells). Conversely,
      glucocorticoid receptor affinity was significantly decreased in anorexia nervosa
      as well as in Cushing's patients compared to control subjects (dissociation
      constant 4.0 +/- 0.31 and 4.1 +/- 0.34 vs. 2.9 +/- 0.29 nmol/L, p < .001) and
      inversely correlated with the levels of urinary free cortisol in both groups of
      patients. Basal [3H]thymidine incorporation in MNL was significantly reduced in
      anorexia nervosa as well as in Cushing's patients compared to control subjects (p
      < .001) and was diminished by dexamethasone to an extent similar to control
      subjects in patients with anorexia nervosa, but significantly (p < .001) less in
      those with Cushing's disease. In patients with anorexia nervosa, the
      incorporation of [3H]thymidine into the MNL was inversely correlated with urinary
      free cortisol levels. CONCLUSIONS: These data indicate that the lack of
      cushingoid features in patients with anorexia nervosa is not ascribable to a
      reduced sensitivity to glucocorticoids but is more likely due to the paucity of
      metabolic substrates.

PMID- 10356630
TI  - Further evidence on the effects of vitamin B12 and folate levels on episodic
      memory functioning: a population-based study of healthy very old adults.
AB  - BACKGROUND: The relationship between vitamin status and cognitive functioning has
      been addressed in several recent studies with inconclusive results. The purpose
      of this study was to examine separate and combined effects of serum vitamin B12
      and folic acid on episodic memory functioning in very old age. METHODS: Four
      study groups were selected from a population-based sample of healthy very old
      adults (90-101 years of age): normal B12/normal folic acid, low B12/normal folic
      acid, normal B12/low folic acid, and low B12/low folic acid. Cutoff levels were
      set at 180 pmol/L for vitamin B12 and at 13 nmol/L for folic acid. Subjects
      completed two episodic recall tasks (objects and words) and two episodic
      recognition tasks (faces and words). RESULTS: Neither vitamin affected
      recognition or primary memory. Most interesting, although B12 was unrelated to
      recall performance, subjects with low folic acid levels showed impairment in both
      word recall and object recall. CONCLUSIONS: These results replicate and extend
      previous findings that folic acid may be more critical than B12 to memory
      functioning in late life. The selective effects of folic acid on episodic recall
      were discussed in terms of encoding and retrieval mechanisms, as well as in
      relation to brain protein synthesis.

PMID- 10356631
TI  - Neurochemical adaptation to cocaine abuse: reduction of N-acetyl aspartate in
      thalamus of human cocaine abusers.
AB  - BACKGROUND: The aim of this study was to determine the existence of, and possible
      mechanisms for, chronic cocaine use-induced neurotoxicity in the human brain.
      Because in vivo magnetic resonance spectroscopy (MRS) provides a noninvasive way
      to detect biochemical and physiological changes in the brain, we sought to
      specifically determine the neurochemical adaptations in chronic cocaine-dependent
      subjects. METHODS: Twenty-one cocaine users and 13 non-drug-using, age-matched
      normal volunteers were recruited for an in vivo proton MRS study. Following
      screening that included physical examination, histories, and blood testing,
      cocaine group subjects received a spectral scan on a 1.5-T GE Signa scanner.
      Spectra were obtained from the left basal ganglia and/or the left thalamus from
      subjects in both groups using an rf bird-cage type head coil with single-voxel
      localization. RESULTS: The level of N-acetyl aspartate in the region of left
      thalamus was lower (17%) in the chronic cocaine user group but not in the region
      of left basal ganglia, compared with the control group. CONCLUSIONS: These
      results suggest that chronic cocaine use may induce abnormal neurochemical
      activity and a state of neuronal dysregulation and/or neurotoxicity. It will now
      be important to determine if these alterations are reversible during withdrawal
      and what the functional implications of this observation are with respect to
      cognitive function and drug relapse.

PMID- 10356632
TI  - Event-related potential indices of auditory selective attention in dependent
      amphetamine users.
AB  - BACKGROUND: The aim of the present study was to further investigate a previously
      reported attention-related impairment in dependent amphetamine users using event
      related potential (ERP) indices of selective attention. METHODS: ERPs were
      recorded during an auditory selective attention task (SAT) that involved
      detecting infrequent long-duration target tones presented among short-duration
      tones that varied in location (left vs. right ear) and pitch (low vs. high).
      Amphetamine users (n = 19) were divided into two groups, high dependence (n = 10)
      and low dependence (n = 10), based on amphetamine Severity of Dependence Scale
      scores, and compared to an age-matched control group (n = 9). RESULTS: The high
      dependence group showed slowed reaction time and reduced early processing
      negativity and peak N1 amplitude to location-relevant nontarget stimuli. Poor
      performance on the SAT was highly correlated with deficits in early processing,
      which were also related to poor performance on the Wechsler Memory Scale
      Attention/Concentration index. CONCLUSIONS: It is suggested that severely
      dependent users suffer an inability to selectively enhance the sensory processing
      of relevant auditory information. This may produce poor automatic preferential
      processing of relevant information and increase load on limited attentional
      resources.

PMID- 10356633
TI  - Reduced P300 responses in criminal psychopaths during a visual oddball task.
AB  - BACKGROUND: Clinicians have long recognized that psychopaths show deficits in
      cognitive function, but there have been few experimental studies exploring these
      deficits. We present here the first in a series of event-related potential (ERP)
      experiments designed to elucidate and characterize the neural correlates of
      cognitive processes of psychopaths. METHODS: We recorded ERPs from a topographic
      array from 11 psychopathic and 10 nonpsychopathic prison inmates, assessed with
      the Hare Psychopathy Checklist-Revised, during performance of a visual oddball
      task. ERPs to target (25% of trials) and nontarget (75% of trials) visual stimuli
      were analyzed. RESULTS: Consistent with previous research, there were no group
      differences in the latency or amplitude of the ERPs for the nontarget stimuli.
      For nonpsychopaths, the P300 amplitude was larger when elicited by the target
      stimuli than when elicited by the nontarget stimuli. In contrast, psychopaths
      failed to show reliable P300 amplitude differences between the target and
      nontarget conditions. Psychopaths had a smaller amplitude P300 to target stimuli
      than did nonpsychopaths. In addition, the amplitude of the P300 was less
      lateralized in psychopaths than in nonpsychopaths. Psychopaths also had a larger
      centrofrontal negative wave (N550) during the target condition than did
      nonpsychopaths. CONCLUSIONS: The results of this study indicate that there are
      substantial differences between psychopaths and others in the processing of even
      simple cognitive tasks and provide support for information processing models of
      psychopathy.

PMID- 10356634
TI  - Elevated plasma levels of S-100b protein in schizophrenic patients.
AB  - BACKGROUND: In this study, we examined the possibility that structural damage to
      the brain may play a role in the pathogenesis of schizophrenia. METHODS: We
      compared plasma levels of S-100b protein in 20 patients with schizophrenic
      psychosis and 20 age- and gender-matched healthy blood donors. Concentrations of
      S-100 protein were determined by microtiter-based immunofluorometric assay
      detecting predominantly S-100b. RESULTS: Mean concentrations of S-100b protein in
      blood were significantly (p < or = .001) higher in schizophrenic patients (0.165
      +/- 0.138 microgram/L) compared to control subjects (0.054 +/- 0.031
      microgram/L). Levels did not correlate with age of onset or duration of
      psychosis. CONCLUSIONS: Our findings indicate that patients with schizophrenia
      may suffer ongoing structural damage to cells of the central nervous system, and
      that the concentration of S-100b protein in plasma may help to identify clinical
      subgroups in schizophrenia.

PMID- 10356635
TI  - Human plasma glutathione peroxidase and symptom severity in schizophrenia.
AB  - BACKGROUND: Previous studies have shown impaired antioxidant defense system in
      schizophrenia, including alterations in glutathione peroxidase (GSH-Px) activity
      in erythrocytes. There exists a related enzyme, human plasma GSH-Px (hpGSH-Px),
      that has not been previously examined in schizophrenia. METHODS: An enzyme-linked
      immunoassay was used to determine hpGSH-Px levels in male schizophrenic patients
      (n = 39), using a within-subject, on-off haloperidol (HD) treatment design,
      compared with age- and gender-matched normal control subjects (n = 37). RESULTS:
      hpGSH-Px was not significantly different between normal control subjects and
      patients, consistent with our previous findings in erythrocyte GSH-Px. There were
      no significant treatment effects. hpGSH-Px was significantly and positively
      correlated with psychosis rating scores in patients both on and off HD treatment.
      CONCLUSIONS: Although not different from normal controls, hpGSH-Px levels in
      patients may reflect oxidative stress associated with greater psychosis severity.
      The present findings thus suggest that schizophrenic patients, without obvious
      increase of endogenous antioxidant enzymes (e.g., hpGSH-Px), may be at risk for
      oxidative damage.

PMID- 10356636
TI  - Menstrual cycle synchronized changes in brain stem auditory evoked potentials and
      visual evoked potentials.
AB  - BACKGROUND: Several studies have reported changes in the spontaneous
      electroencephalogram of women across the menstrual cycle (MC), raising questions
      on whether sensory or cognitive evoked potentials would change with MC as well.
      Some of these studies have found changes synchronized with MC in visual event
      related brain potentials (ERPs) and brain stem auditory evoked potentials
      (BAEPs), whereas others have reported none. METHODS: In the present study, we
      attempted to study the changes in P300 component of visual ERPs, and in BAEPs
      across the MC in healthy women. RESULTS: The latency of P300 was longer during
      the ovulatory phase. Decrease across the MC phases was found for the amplitude of
      BAEP waves I and III, and for the wave V latency and the III-V interpeak latency.
      CONCLUSIONS: The results indicate that there may be a small relationship between
      visual ERP or BAEP and MC phase.

PMID- 10356637
TI  - Salivary gland enlargement and elevated serum amylase in bulimia nervosa.
AB  - BACKGROUND: Clinical reports have described salivary gland enlargement in bulimia
      nervosa, particularly in patients with elevated serum amylase concentration. The
      goal of the current study was to provide a controlled comparison of salivary
      gland size in patients with bulimia nervosa and healthy volunteers. METHODS:
      Subjects included 17 women with bulimia nervosa and 21 healthy female control
      subjects. Dimensions of the parotid and submandibular salivary glands were
      estimated by ultrasonography. Blood samples for amylase measurement were obtained
      after overnight fast. RESULTS: Parotid gland size was enlarged 36% in patients
      with bulimia nervosa in comparison to control subjects (p < .01). For the patient
      group, salivary gland size was significantly correlated with frequency of bulimic
      symptoms and with serum amylase concentration. CONCLUSIONS: These results provide
      new quantitative data demonstrating increased salivary gland size in bulimia
      nervosa. Further studies are needed to evaluate factors responsible for salivary
      gland enlargement and hyperamylasemia in this disorder.

PMID- 10356638
TI  - Alcohol-induced depersonalization.
AB  - BACKGROUND: A case of alcohol-induced depersonalization disorder is presented.
      The subject had experienced several depersonalization states following the
      consumption of alcohol rather than from a psychogenic etiology, and the episodes
      were transient, not chronic. METHODS: Three quantitative EEG (QEEG) studies were
      performed on the subject, one during the index depersonalization episode and two
      subsequent studies when the subject was clinically asymptomatic. RESULTS: Slow
      wave activity (relative theta power) was significantly increased when
      symptomatic. This slowing was still present over the occiput 3 days after the
      symptoms had remitted but was absent 17 days after symptoms had ameliorated.
      CONCLUSIONS: The time course of EEG slowing suggests a metabolic encephalopathy,
      a condition which likely contributes to the manifestations of depersonalization
      syndrome.

PMID- 10356639
TI  - Cerebrospinal fluid dynorphin A[1-8] and beta-endorphin levels in Tourette's
      syndrome are unaltered.

PMID- 10356640
TI  - A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic
      depressives.

PMID- 10356641
TI  - Cell orientation induced by extracellular signals.
AB  - Cells like fibroblasts and osteoblasts are oriented by different extracellular
      guiding signals like an electric field, a bent surface, and a periodically
      stretched surface. An automatic controller is responsible for the cell alignment.
      The controller contains both a deterministic and a stochastic signal. The
      following machine properties were determined: (1) The angle dependence of the
      cellular signal transformer is cos 2(psi 0 - psi). (2) The set point of the
      automatic controller is psi 0 = +/- 90 degrees. The cells like to orient their
      long axis perpendicular to the direction of the applied guiding signal. (3) The
      signal transformer measures the extracellular signal in a quadratic fashion. The
      cells cannot register the sign of the guiding field. (4) The stochastic signal in
      the automatic controller can be quantified by a characteristic time
      (approximately 130 min for fibroblasts). (5) The extracellular signal is
      registered in cell-made standards (ratio of the deterministic and stochastic
      signal equals one): 0.3 +/- 0.05 V/mm for human fibroblasts (electric field) and
      85 +/- 3 microns for human fibroblasts and osteoblasts (cyclindrically bent
      surface). (6) The lag-time in the signal transduction system of fibroblasts is
      approximately 4 min.

PMID- 10356642
TI  - The yeast pheromone-responsive G alpha protein stimulates recovery from chronic
      pheromone treatment by two mechanisms that are activated at distinct levels of
      stimulus.
AB  - The pheromone response of Saccharomyces cerevisiae is mediated by a receptor
      coupled heterotrimeric G protein. The beta gamma subunit of the G protein
      stimulates a PAK/MAP kinase cascade that leads to cellular changes preparatory to
      mating, while the pheromone-responsive G alpha protein, Gpa1, antagonizes the G
      beta gamma-induced signal. In its inactive conformation, Gpa1 sequesters G beta
      gamma and tethers it to the receptor. In its active conformation, Gpa1 stimulates
      adaptive mechanisms that downregulate the mating signal, but which are
      independent of alpha-beta gamma binding. To elucidate these potentially novel
      signaling functions of G alpha in yeast, epistasis analyses were performed using
      N388D, a hyperadaptive mutant form of Gpa1, and null alleles of various loci that
      have been implicated in adaptation. The results of these experiments indicate the
      existence of signaling thresholds that affect the yeast mating reaction. At low
      pheromone concentration, the Regulator of G Protein Signaling (RGS) homologue and
      putative guanosine triphosphatase (GTPase) activating protein, Sst2, appears to
      stimulate sequestration of G beta gamma by Gpa1. Throughout the range of
      pheromone concentrations sufficient to cause cell cycle arrest, Gpa1 stimulates
      adaptive mechanisms that are partially dependent on Msg5 and Mpt5. Gpa1-mediated
      adaptation appears to be independent of Afr1, Akr1, and the carboxy-terminus of
      the pheromone receptor.

PMID- 10356643
TI  - A growing family of receptor genes for lysophosphatidic acid (LPA) and other
      lysophospholipids (LPs).
AB  - A missing component in the experimental analysis of cell signaling by
      extracellular lysophospholipids such as lysophosphatidic acid (LPA) or
      sphingosine-1-phosphate (S1P) has been cloned receptors. Through studies on the
      developing brain, the first such receptor gene (referred to as vzg-1) was
      identified, representing a member of the G-protein coupled receptor (GPCR) super
      family (1). Here we review the neurobiological approach that led to both its
      cloning and identification as a receptor for LPA, along with related expression
      data. Summarized sequence and genomic structure analyses indicate that this
      first, functionally identified receptor is encoded by a member of a growing gene
      family that divides into at least two subgroups: genes most homologous to the
      high-affinity LPA receptor encoded by vzg-1, and those more homologous to an
      orphan receptor gene edg-1 that has recently been identified as a S1P receptor. A
      provisional nomenclature is proposed, based on published functional ligand
      actions, amino acid composition and genomic structure whereby the receptors
      encoded by these genes are referred to as lysophospholipid (LP) receptors, with
      subgroups distinguished by letter and number subscripts (e.g., LPA1 for Vzg-1,
      and LPB1 for Edg-1). Presented expression data support the recently published
      work indicating that members of the LPB1 subgroup are receptors for the
      structurally-related molecule, S1P. The availability of cloned LP receptors will
      enhance the analysis of the many documented LP effects, while their prominent
      expression in the nervous system indicates significant but as yet unknown roles
      in development, normal function, and neuropathology.

PMID- 10356644
TI  - Expression, regulation, and function of the SPR family of proteins. A review.
AB  - The small, proline-rich (SPR) genes consist of three subclasses closely linked on
      human chromosome 1, a region referred to as the epidermal differentiation
      complex. SPR genes consist of two exons, with the second exon containing the
      entire open reading frame. SPRs are expressed in all squamous tissues of the
      skin, scalp, footpad, vaginal epithelia, and most of the epithelial lining of the
      digestive tract, including the lip, tongue, esophagus, and forestomach. Although
      SPR1 is absent in normal mucociliary epithelium of the respiratory tract,
      epithelia that undergo squamous differentiation in response to vitamin-A
      deficiency or to injury owing to exposure to environmental toxicants express
      SPR1. High levels of SPR1 are detected in various diseases and cancers of the
      skin or respiratory epithelia and in nonkeratinizing papillary adenocarcinomas.
      SPR expression can be regulated by transcriptional factors, by
      posttranscriptional factors, or by factors that affect SPR1 mRNA translation or
      protein turnover. Furthermore, regulation can be affected by the state of cell
      proliferation. The presence of SPR1 in most of these epithelia, and the absence
      of SPR3 in normal skin, suggest that these subclasses have distinct functions.
      Various approaches to the study of the cross-linked envelope (CE) components in
      identifying SPR1 and SPR2 and in suggesting that SPRs are one of the precursor
      proteins of the CE. However, expression of SPR1 in nonsquamous tissues and cell
      lines indicates a function not associated with squamous differentiation. Several
      studies have demonstrated that SPR1 antibodies react with nuclear proteins and
      that SPR1 is expressed in cells before entering the G0 phase of the cell cycle.
      Future studies should clarify the role of SPRs by modifying their contents in CE,
      and should identify SPR-associated proteins to clarify the cell growth-related
      role of SPR1.

PMID- 10356645
TI  - Regulatory and spatial aspects of inositol trisphosphate-mediated calcium
      signals.
AB  - Hormones that act to release Ca2+ from intracellular stores initiate a signaling
      cascade that culminates in the production of inositol 1,4,5-trisphosphate
      (InsP3). The Ca2+ response mediated by InsP3 is not a sustained increase in the
      cytosolic Ca2+ concentration, but rather a series of periodic spikes that
      manifest as waves in larger cells. In vitro studies have determined that the key
      positive feedback parameter driving spikes and waves is a highly localized direct
      Ca(2+)-activation of InsP3-gated Ca2+ channels. Advances in fluorescent Ca2+
      imaging have facilitated the resolution of individual positive feedback units.
      These studies have revealed that there are several modes of channel coupling
      underlying global Ca2+ signals; single channel openings or Ca2+ "blips,"
      synchronized clusters of channels or Ca2+ "puffs," and cell wide calcium waves.
      It appears that the channel clusters that produce Ca2+ puffs are synchronized by
      the highly localized positive feedback that was predicted by the in vitro studies
      of channel regulation. Localization of InsP3-induced Ca2+ signals has been shown
      to be important for activation of several cellular processes including uni
      directional salt flow and mitochondrial activation.

PMID- 10356646
TI  - Tyrosine kinase activation in LPS stimulated rat Kupffer cells.
AB  - Kupffer cells, a majority of the body's fixed macrophages, are a major site of
      bacterial lipopolysaccharide (LPS) metabolism and are mediators in the body's
      response to sepsis. Uptake of LPS is different in Kupffer cells than other
      macrophages. Signal transduction in other macrophages in response to LPS involves
      phosphorylation of proteins in the 50-60 kDa range. We hypothesized that Kupffer
      cells may have unique signal transduction pathways in response to LPS. Rat
      Kupffer cells were exposed to LPS (1 microgram/mL) for varying times ranging from
      15 to 90 min. Cell lysates were Western blotted using an anti-phosphotyrosine
      antibody. The blots showed an increase in the amount of tyrosine phosphorylation
      on two proteins of 119 kDa and 83 kDa. The effects of varying LPS concentration
      (1 ng/mL-1 microgram/mL) showed an increasing amount of phosphorylation with
      increasing LPS concentration. To associate the importance of tyrosine
      phosphorylation in the response of Kupffer cells to LPS, the tyrosine kinase
      inhibitors, tyrphostin, lavendustin, and genisten were used to study the effects
      of inhibiting phosphorylation on TNF-alpha production. Kupffer cells were
      preincubated in the presence of the inhibitor and exposed to LPS (1
      microgram/mL). TNF-alpha was measured in the conditioned media by ELISA. A 70% or
      greater decrease in TNF-alpha production was observed. When phagocytosis of latex
      beads by rat Kupffer cells was measured in vivo using intravital video
      microscopy, LPS treatment significantly increased uptake. This increase in
      phagocytosis was inhibited by tyrphostin. These results show what may be unique
      phosphorylation events in Kupffer cells that are related to LPS induced
      production of TNF-alpha.

PMID- 10356647
TI  - Relationship between panic and schizophrenia.
AB  - Although panic attacks and schizophrenic symptoms are common comorbid conditions,
      little is known about the reason for this association. A critical review of the
      literature on the association between panic attacks and schizophrenic symptoms is
      presented. The findings reported in the literature are discussed as evidence for
      one of four competing hypotheses: 1) the reported association is due to a
      methodological artifact, 2) panic attacks cause schizophrenic symptoms, 3)
      schizophrenic symptoms cause panic attacks, and 4) panic attacks and
      schizophrenic symptoms share common etiologic factors. No firm conclusions can be
      drawn due to insufficient empirical data. The best preliminary explanation for
      the association is that the two disorders share common etiologic factors.

PMID- 10356648
TI  - International study of expert judgment on therapeutic use of benzodiazepines and
      other psychotherapeutic medications: VI. Trends in recommendations for the
      pharmacotherapy of anxiety disorders, 1992-1997.
AB  - OBJECTIVE: To assemble expert clinical experience and judgment regarding the
      treatment of anxiety disorders in a systematic, quantitative manner, particularly
      with respect to changes during the preceding five years. METHOD: A panel of 73
      internationally recognized experts in the pharmacotherapy of anxiety and
      depression was constituted by multistage peer nomination. Sixty-six completed a
      questionnaire in 1992, and 51 of those completed a follow-up questionnaire in
      1997. This report focuses on the experts' responses to questions about
      therapeutic options relevant to seven vignettes describing typical cases of
      different anxiety disorders. RESULTS: The preferred initial treatment strategy in
      1992 was a combination of medication with a psychological therapy for all
      vignettes except simple phobia, where a psychological procedure alone was
      favored. There was little change in 1997, primarily some decrease in the choice
      of psychological therapy and some increase in the choice of medication for social
      phobia. Experts recommending a medication in 1992 most often chose as first-line
      treatment a benzodiazepine anxiolytic (BZ) for panic disorder (PD), generalized
      anxiety disorder (GAD), simple phobia, and adjustment disorder. They recommended
      a beta-blocker most often for social phobia and a tricyclic anti-depressant (TCA)
      for agoraphobia and obsessive-compulsive disorder (OCD). Nearly a fourth chose a
      combination of medications, usually a TCA plus a BZ. In 1997, the expert panel's
      most frequent recommendation for agoraphobia, PD, and OCD changed to a specific
      serotonin reuptake inhibitor (SSRI); and they also recommended these compounds
      more often for GAD, social phobia, and simple phobia. Fewer experts chose BZs or
      TCAs. However, in 1997 many again chose a combination of medications, often a BZ
      plus a SSRI, so that, overall, there was only a small decline in recommendations
      for BZs. As second-line medications (1997 only), the experts recommended SSRIs
      most often for most vignettes, but a TCA for PD and GAD. Recommendations for a
      combination of medications rose substantially for most vignettes, usually a BZ
      plus an antidepressant. CONCLUSIONS: Combined cognitive-behavioral therapy plus
      medication was highly favored by the experts as the initial treatment strategy
      for anxiety disorders. During the preceding five years, SSRIs displaced older
      antidepressants as the experts' first-line choices for the pharmacotherapy of
      anxiety disorders. In case of an unsatisfactory response, the experts' second
      line choices more often were an older antidepressant or a combination of an
      antidepressant plus a BZ. According to the experts' judgements, the BZs,
      especially combined with an antidepressant, remain mainstays of pharmacotherapy
      for anxiety disorders.

PMID- 10356649
TI  - Confirmatory factor analysis of the Fear Questionnaire in injured workers with
      chronic pain.
AB  - In an effort to extend the validity of the Fear Questionnaire (FQ) in a sample of
      patients with high levels of blood/injury phobia, the FQ responses of 255 injured
      workers with chronic pain were subjected to confirmatory factor analysis. Results
      indicated that an intercorrelated three-factor model of the FQ provided a better
      fit to the data than unidimensional, two-factor, hierarchical three-factor, or
      categorical three-factor models. These findings provide further support for the
      factorial validity of the FQ and the corresponding multidimensional theory of
      fear.

PMID- 10356650
TI  - Reduced sensory gating of the P1 potential in rape victims and combat veterans
      with posttraumatic stress disorder.
AB  - The P1 midlatency auditory evoked potential was studied in female rape victims
      with Posttraumatic Stress Disorder (PTSD) and compared to an age-matched female
      control group; and in male combat veterans with PTSD and compared to three groups
      of age-matched male control subjects. Sensory gating of the P1 potential was
      determined using a paired click stimulus paradigm in which the stimuli were
      presented at 250, 500 and 1000 msec interstimulus intervals (ISI). Results showed
      that sensory gating of the P1 potential was significantly decreased at the 250
      msec ISI, and that there was a numerical, but not a statistically significant,
      decrease in sensory gating at the other intervals tested in both male and female
      PTSD subjects compared to all control groups. Since the P1 potential may be
      generated, at least in part, by the reticular activating system, dysregulation of
      sensory processing by elements of this system may be present in PTSD.

PMID- 10356651
TI  - Meta-analysis of the safety and tolerability of two dose regimens of buspirone in
      patients with persistent anxiety.
AB  - Buspirone is an azapirone with 5-HT1A partial agonist activity which has
      demonstrated efficacy in the treatment of generalized anxiety disorder, commonly
      referred to as persistent anxiety. In this meta-analysis report, safety results
      from two studies comparing buspirone 15 mg twice daily (BID) with buspirone 10 mg
      three times daily (TID) in patients with persistent anxiety are presented. In the
      study protocols, qualified patients completed a 7-day placebo lead-in phase and
      were randomized to receive buspirone 30 mg per day, as either a BID or TID
      regimen, for 6-8 weeks. A total of 289 patients received buspirone 15 mg BID (n =
      144) or 10 mg TID (n = 145) at 15 sites. The incidence of adverse events was
      similar between the two treatment groups, except for a significantly greater
      incidence of palpitations in patients receiving buspirone BID (5%) compared to
      buspirone TID (1%). The most frequently reported adverse events for both
      buspirone BID- and TID-treated patients were dizziness, headache, and nausea. No
      appreciable differences between treatments were observed for vital signs,
      physical exam, ECG, or clinical laboratory results. A change to BID dosing for
      buspirone may offer convenience and possibly higher compliance in patients with
      persistent anxiety without compromising the excellent safety and tolerability
      profile of the medication.

PMID- 10356652
TI  - Further psychometric assessment of the TOP-8: a brief interview-based measure of
      PTSD.
AB  - The TOP-8 scale was developed as a brief, clinician-administered scale for use in
      assessing responses to treatment in patients with post-traumatic stress disorder.
      Further psychometric evaluation of the scale has now been undertaken and is
      reported and discussed here.

PMID- 10356653
TI  - Progression of limited symptom attacks.
AB  - To study the progression of limited symptom attacks (LSAs) to panic attacks, we
      screened a community sample for LSAs using the Structured Clinical Interview of
      the DSM-IIIR initially and one year thereafter. Of 21 subjects with LSAs
      initially, 4 (19%) reported progression of their LSAs to panic attacks after one
      year.

PMID- 10356654
TI  - Nocturnal panic and trauma.
AB  - We examined the recollection of traumas in panic disorder patients with and
      without history of nocturnal panic attacks. From a sample of 154 patients seeking
      treatment for panic disorder, almost 85% of those with nocturnal panic reported a
      history of traumatic events in comparison to only 28% without nocturnal panic.
      Fear of loss of vigilance is considered as a potential mediator of the
      relationship between nocturnal panic and traumatic events.

PMID- 10356655
TI  - Nefazodone treatment and dream reports in chronic PTSD.

PMID- 10356656
TI  - The molecular basis of von Willebrand disease.
AB  - von Willebrand disease (VWD) is a clinically heterogeneous bleeding disorder that
      reflects a wide array of defects. Quantitative subtypes of the disorder,
      including types 1 and 3 VWD, result in bleeding due to reduced levels of
      circulating von Willebrand factor (VWF) protein. Qualitative subtypes, defined as
      type 2 VWD, act through altered VWF function. A range of molecular defects are
      responsible for many of these subtypes, including missense, nonsense, splicing,
      insertion, and deletion mutations, resulting in either dominant or recessive
      inheritance. While many mutations correspond to selected variants, the basis for
      variation in expression and the imperfect correlations between genotype and
      phenotype remain to be understood.

PMID- 10356657
TI  - Takayasu's arteritis: a cell-mediated large-vessel vasculitis.
AB  - Takayasu's arteritis is an idiopathic, systemic inflammatory disease, typically
      involving the aorta and its main branches. Cell-mediated autoimmunity has been
      strongly implicated in its pathogenesis. Early or active-stage pathology consists
      of continuous or patchy granulomatous inflammation, which progresses to intimal
      and adventitial fibrosis and scarring of the media. Multiple focal or segmental
      stenoses result and aneurysms may occasionally occur. Clinical presentation is
      heterogeneous, ranging from asymptomatic to catastrophic. In some patients,
      constitutional signs and symptoms indicating a systemic inflammatory response are
      observed, usually in the early stages. Specific features reflect arterial
      involvement, and result from end-organ or limb ischemia; they include vascular,
      neurological, cardiac, and pulmonary manifestations. The course of Takayasu's
      arteritis usually extends for many years with varying degrees of activity.
      Takayasu's arteritis has a worldwide distribution, with the greatest prevalence
      in eastern countries. Women of reproductive age are preferentially affected, but
      the illness is being recognized with increasing frequency in males. Variable
      phenotypes are recently emerging in different ethnic groups. Diagnosis is based
      on clinical features and vascular imaging studies that document typical patterns
      of stenoses or aneurysms of the aorta and its primary branches. Assessment of the
      activity of Takayasu's arteritis is imprecise, in that clinical features and
      acute-phase reactants do not accurately reflect active blood vessel inflammation.
      High-dose corticosteroids alone or a cytotoxic agent in addition to a
      corticosteroid may be effective in treating active disease. Critical lesions may
      require correction by surgery or interventional radiology.

PMID- 10356658
TI  - Introduction of the human PLTP transgene suppresses the atherogenic diet-induced
      increase in plasma phospholipid transfer activity in C57BL/6 mice.
AB  - The human plasma phospholipid transfer protein (PLTP) has been shown to
      facilitate the transfer of phospholipids between lipoproteins and convert high
      density lipoproteins into larger and smaller particles in vitro. To explore the
      lipid transport function in vivo, transgenic C57BL/6 mice that express the human
      PLTP gene, driven by its natural promoter, were generated. Little difference in
      PLTP activity and lipoprotein lipids was observed between transgenic mice and non
      transgenic control mice fed the chow diet. In response to an atherogenic high
      fat, high-cholesterol, cholic acid containing diet, the PLTP activity increased
      significantly with time in control mice (62% in males and 34% in females after
      the high-fat diet for 18 weeks). In contrast, the PLTP activity did not change
      appreciably in the transgenic mice fed the atherogenic diet. Thus, the
      introduction of the human transgene suppressed the diet-induced increase in
      plasma PLTP activity, as evidenced by a decrease in PLTP mRNA in a variety of
      tissues. High-density lipoprotein levels decreased in mice fed the atherogenic
      diet, but there was a proportionally greater decrease in transgenic animals than
      in controls. After 18 weeks on the atherogenic diet, the transgenic animals had
      high-density lipoprotein-cholesterol and PLTP activity approximately one-half of
      that of control animals. Non-denaturing gradient gel electrophoresis of plasma
      indicated that the atherogenic diet decreased the high-density lipoprotein size
      distribution in control mice. However, high-density lipoprotein particle size
      distribution of the transgenic mice was shifted to smaller particles compared
      with control animals (P < 0.001). These findings suggest that PLTP activity can
      modulate the effects of an atherogenic diet on high-density lipoproteins.

PMID- 10356659
TI  - Joint effects of HMG-CoA reductase inhibitors and eicosapentaenoic acids on serum
      lipid profile and plasma fatty acid concentrations in patients with
      hyperlipidemia.
AB  - HMG-CoA reductase inhibitors reduce serum total cholesterol concentrations and
      the risk of coronary heart disease in patients with hypercholesterolemia.
      Recently, it has been reported that patients with combined hyperlipidemia are
      also at risk of coronary heart disease. However, HMG-CoA reductase inhibitor
      therapy alone does not sufficiently reduce serum triglyceride concentrations.
      Epidemiological and clinical evidence has shown that fish oil can lower plasma
      lipid levels, especially triglycerides. Consequently, we investigated the effects
      of the combination of HMG-CoA reductase inhibitors and eicosapentaenoic acid, a
      major component of fish oil, on hyperlipidemia. We administered 900-1,800 mg/day
      of the ethyl ester of eicosapentaenoic acid to patients with hyperlipidemia who
      had been treated with HMG-CoA reductase inhibitors for 30 +/- 6 months (means +/-
      SE). Serum total cholesterol and triglyceride concentrations were significantly
      decreased 3 months after the administration of eicosapentaenoic acid (from 5.63
      +/- 0.23 mmol/l to 5.02 +/- 0.20 mmol/l, P < 0.05; from 2.07 +/- 0.41 mmol/l to
      1.08 +/- 0.17 mmol/l, P < 0.01, respectively). Serum high-density lipoprotein
      cholesterol concentrations were significantly increased after the treatment (from
      1.23 +/- 0.12 mmol/l to 1.34 +/- 0.13 mmol/l, P < 0.05). Plasma eicosapentaenoic
      acid concentrations and the ratio to arachidonic acid in plasma were also
      significantly increased 3 months after the treatment (from 101.9 +/- 8.1 mg/l to
      181.8 +/- 23.9 mg/l, P < 0.001; from 0.640 +/- 0.075 to 1.211 +/- 0.170, P <
      0.001, respectively). These results suggested that the combination therapy of HMG
      CoA reductase inhibitors and eicosapentaenoic acid was effective for patients
      with hyperlipidemia.

PMID- 10356660
TI  - Evaluation of serum laminin as a tumor marker in breast cancer.
AB  - Laminin is a noncollagenous constituent of the extracellular matrix (basement
      membrane). Increased serum concentrations were recorded in patients with a
      variety of cancers. The clinical usefulness of serum laminin as a marker for
      breast cancer was investigated in 60 female patients with malignant breast tumors
      (30 metastatic, 30 non-metastatic). Subjectively healthy age-matched women (n =
      30) served as a control group. Laminin was significantly higher in breast cancer
      patients than in normal controls. Serum laminin levels were also significantly
      higher in patients with metastasis than in those without metastasis. A positive
      correlation was observed between serum laminin and the breast cancer-associated
      antigen CA 15-3 in the tumor patients. The sensitivity and specificity values of
      laminin for cancer detection at the optimum decision level [mean + 2 SD (1.4
      U/ml)] were 75% and 97% respectively, with a 98% positive predictive value, 66%
      negative predictive value, and 82% diagnostic efficiency. For the detection of
      metastasis, serum laminin exhibited 77% sensitivity and 100% specificity [best
      decision level: mean + 2 SD (1.9 U/ml)], with a 100% positive predictive value,
      81% negative predictive value, and 88% diagnostic efficiency. The latter
      specificity and positive predictive value were superior to those obtained with
      serum CA 15-3. These results suggest that serum determination of laminin could be
      a useful diagnostic tool in breast cancer and a valuable parameter in the
      prediction of metastasis.

PMID- 10356661
TI  - Increased levels of lactoferrin in synovial fluid but not in serum from patients
      with rheumatoid arthritis.
AB  - Lactoferrin is a multifunctional immunoregulatory protein, stored in specific
      granules of neutrophil granulocytes, from which it is released following cell
      activation. As activated neutrophils play a crucial role in the destruction of
      synovial joints in rheumatoid arthritis, we evaluated lactoferrin concentration
      in synovial fluid and sera from 21 patients with rheumatoid arthritis and 11
      patients with osteoarthritis. We also measured lactoferrin levels in sera from 12
      healthy controls. Lactoferrin was measured by a solid-phase inhibition
      immunoassay. Median lactoferrin levels were significantly higher in synovial
      fluid from rheumatoid arthritis than from osteoarthritis patients (P = 0.0002).
      In contrast, no significant difference was found between serum lactoferrin from
      patients with rheumatoid arthritis or osteoarthritis compared with normal
      controls. In patients with rheumatoid arthritis, lactoferrin concentrations were
      higher in synovial fluid than in sera (P = 0.036). In both rheumatoid arthritis
      and osteoarthritis no correlation was found between serum and synovial fluid
      lactoferrin (P = 0.51 and P = 0.5, respectively). In synovial fluid from patients
      with rheumatoid arthritis, lactoferrin concentrations correlated with neutrophil
      granulocyte count (P < 0.0001), but neither serum nor synovial lactoferrin levels
      correlated with disease activity (P = 0.32 and P = 0.25, respectively). In
      conclusion, lactoferrin is a reliable marker of neutrophil activation at sites of
      inflammation in rheumatoid synovitis, but does not represent a marker of disease
      activity.

PMID- 10356662
TI  - Carnitine deficiency and hyperammonemia in children receiving valproic acid with
      and without other anticonvulsant drugs.
AB  - Plasma ammonia and total and free carnitine were measured in 84 children
      requiring anticonvulsant drugs: 32 patients (group A) on valproic acid alone, 28
      children (group B) on polytherapy including valproic acid, and 24 patients (group
      C) on polytherapy without valproic acid. The other anticonvulsant drugs used in
      groups B and C were carbamazepine and phenobarbital. Plasma ammonia
      concentrations were elevated in both group A and B compared with controls. Group
      B patients showed significantly higher hyperammonemia than group A (59.9 +/- 16.3
      micrograms/dl vs. 36.7 +/- 12.4 micrograms/dl; P < 0.05). Group C patients had
      plasma ammonia levels similar to those of controls (31.1 +/- 14.7 micrograms/dl
      vs. 29.7 +/- 12.1 micrograms/dl; NS). In both group A and group B patients,
      plasma ammonia levels were correlated with the valproic acid dosage (r = 0.32, P
      < 0.01) and with serum concentrations of valproic acid (r = 0.41, P < 0.001).
      Moreover, a significant correlation between plasma ammonia and duration of
      valproic acid therapy was found in the patients as a whole (r = 0.31, P < 0.01).
      Plasma total and free carnitine concentrations were significantly reduced in
      groups A and B (total carnitine 36.9 +/- 6.9 mumol/l vs. 32.9 +/- 9.7 mumol/l;
      free carnitine 28.9 +/- 5.1 mumol/l vs. 25.7 +/- 4.3 mumol/l, respectively)
      compared with group C patients who did not receive valproic acid and in whom
      values were similar to controls (total carnitine 46.1 +/- 9.0 mumol/l vs. 47.7 +/
      10.1 mumol/l; free carnitine 40.1 +/- 7.1 mumol/l vs. 42.9 +/- 8.0 mumol/l,
      respectively). Twenty-eight patients (18 of group A and 10 of group B) were re
      evaluated and showed a complete normalization of plasma ammonia, and total and
      free carnitine levels which were similar to controls. Our data suggest that
      hyperammonemia is an important problem in patients receiving valproic acid,
      particularly in association with other anticonvulsant drugs. This increase of
      plasma ammonia and the concomitant reduction of carnitine seem to be transient
      and completely reversible.

PMID- 10356664
TI  - Biliary bile acid composition in gastric cancer.
AB  - Bile reflux into the stomach has been considered carcinogenic. Secondary bile
      acids, and in particular deoxycholic acid, have been shown to act experimentally
      as co-carcinogens in the colon and are increased in patients with colorectal
      adenocarcinoma. No information is available with respect to biliary bile acid
      composition in patients with gastric cancer. We studied biliary bile acid
      composition in 11 patients with gastric cancer and 23 healthy controls. Bile
      acids were measured using high-performance liquid chromatography. The site of
      gastric cancer was the antrum in 6 patients and body in 5. There were 6
      intestinal-type and 5 diffuse adenocarcinomas. Only 2 patients had Helicobacter
      pylori infection. Deoxycholic acid constituted 24% +/- 2% of biliary bile acid in
      gastric cancer patients versus 22% +/- 2% in healthy controls (NS). Similarly, no
      differences were found between the two groups for all other bile acids.
      Deoxycholic acid constituted 23% +/- 3% of biliary bile acid (NS vs. controls) in
      patients with antral adenocarcinoma and 25% +/- 2% (NS vs. controls) in patients
      with intestinal-type gastric adenocarcinoma. Gastric adenocarcinoma is not
      associated with an increase in the more-toxic secondary bile acids, and
      deoxycholic acid in particular. This reduces the importance of bile acid
      composition as a promotor in gastric carcinogenesis.

PMID- 10356663
TI  - Analysis of the Bak protein expression in human polymorphonuclear neutrophils.
AB  - In this study, we investigated the expression of Bak, a member of the Bcl-2
      protein family, in human polymorphonuclear neutrophils. Northern blot and Western
      blot analyses revealed that Bak messenger RNA and protein were constitutively
      expressed in peripheral polymorphonuclear neutrophils and mononuclear cells, as
      well as in several hematopoietic cell lines. Remarkably, culturing neutrophils
      for 24 h in the presence or absence of interferon-gamma or tumor necrosis factor
      alpha, which have been described to modulate the survival rate of these cells,
      did not influence the expression of antigenic Bak. Taken together, our data
      indicate that the expression of the pro-apoptotic protein Bak in
      polymorphonuclear neutrophils is constitutive, is not subject to modulation, and
      does not correlate with the neutrophil life span in culture.

PMID- 10356665
TI  - The process of care model for evaluation and treatment of erectile dysfunction.
      The Process of Care Consensus Panel.
AB  - This paper addresses pertinent issues concerning the role of physicians in the
      assessment and treatment of men with complaints of erectile dysfunction. With the
      availability of safe and effective oral drug therapy, the field of erectile
      dysfunction has expanded rapidly to encompass multiple disciplines and
      specialties. Recognizing the need for evidence-based standards and guidelines in
      the management of this common disorder, a multidisciplinary panel of experts was
      convened to examine existing literature and practice standards. This panel
      employed a modified Delphi methodology to develop consensus on definition and
      classification, rational utilization of diagnostic and therapeutic options, and
      clinical guidelines for the management of erectile dysfunction in a primary care
      setting. A 'Process of Care Model for Erectile Dysfunction' was thus developed,
      incorporating a step-wise decision making approach, defined in terms of relevant
      processes, actions and outcomes. According to this method, initial assessment
      should include a careful clinical history, focused physical examination and
      selected laboratory tests. Subsequent management should be goal-oriented, taking
      into account patient and partner needs and preferences. The step-wise treatment
      algorithm is based on the selection criteria of ease of administration,
      reversibility, relative invasiveness and cost. In addition, common referral
      indications for specialized diagnostic testing and treatment are provided. By
      assisting the primary physician in selecting appropriate assessment tools and
      treatment interventions, the proposed guidelines are intended to optimize care of
      the patient with erectile dysfunction. The panel strongly recommends further
      research into the causes and associated risk factors for erectile dysfunction,
      prevention and the role of lifestyle modification, and the critical issue of
      partner-related sexual dysfunction. Considering the strong relationship between
      sexual dysfunction and overall quality of life, it is incumbent upon physicians
      to address the sexual needs of their patients in a sensitive and informed manner.

PMID- 10356666
TI  - Surgical treatment of Peyronie's disease with incision and venous patch
      technique.
AB  - Peyronie's patients are candidates for surgical treatment when the acute phase
      has resolved. The choice of surgical treatment modality, either reconstructive
      procedure or implantation of penile prosthesis, largely depends on the type and
      degree of the deformity and the penile vascular status of the patient. We present
      the results of ou1Effects of inhibitors and rmTNF-alpha on FMLP-induced O2
      production by mouse leukocytesr experience with incision and venous patch
      technique in Peyronie's disease. Incision and venous patch technique was
      performed in 20 patients with a mean duration of the disease of 26.1 +/- 19.8
      months. Complete straightening was achieved in 15 (75%) patients after a mean
      followup of 13.2 +/- 9.4 (3-27) months. Postoperative residual curvature (< 20
      degrees) was observed in 4 (20%) patients. Bulging at the graft site was noted in
      1 (5%) patient. Potency was preserved in all patients except one. Incision and
      venous patch technique, with its satisfactory results, should be considered in
      Peyronie's patients having an adequate penile vascular system during chronic
      stable phase of the disease.

PMID- 10356667
TI  - Clinical value of pelvic and penile magnetic resonance angiography in
      preoperative evaluation of penile revascularization.
AB  - Penile angiography is invasive, costly and requires postinterventional
      surveillance. The aim of this pilot study was to determine whether three
      dimensional magnetic resonance (3D-MR)-angiography may replace conventional
      penile angiography in preoperative planning of penile revascularization. Twelve
      patients with a mean age of 39 (21-59) y were evaluated. All patients underwent
      evaluation with intracavernous pharmacotesting, color Doppler sonography (CDS),
      digital subtraction angiography (DSA) and pelvic MR-angiography with gadolinium
      diethylene-triaminepentaacetic acid (Gd-Dota) 0.2-0.3 mmol/kg body weight. MR
      angiography demonstrated the anatomy of the internal iliac arteries in 9 out of
      12 patients. Intrapenile vessels were visible in 7 out of 12 patients. In
      comparison DSA provided complete visualization of all pelvic and penile vessels.
      Relevant arterial obstruction was found in 10 out of 12 patients. CDS revealed a
      mean maximal arterial flow of 27 (22-40) cm/s and showed in accordance to
      angiography arterial insuffiency in 10 out of 12 cases. Indication for
      revascularization could have been based on MR-angiography alone in only one
      patient. Therefore, selective penile angiography remains the 'gold standard' for
      preoperative planning of revascularization procedures.

PMID- 10356668
TI  - Diabetes and vascular impotence: does insulin dependence increase the relative
      severity?
AB  - AIM OF THE STUDY: Diabetes is a well documented risk factor for vascular erectile
      dysfunction (ED). We evaluated the relative roles of insulin dependence (IDDM) vs
      oral agent controlled diabetes (NIDDM) in predicting the etiologies and severity
      of ED: arterial insufficiency (AI), venous leakage (CVOD), and mixed vascular
      disease. The impact of additional risk factors were also analyzed: hypertension
      (HTN), coronary artery disease (CAD), and smoking (SM). METHODS: Retrospective
      data on 105 patients complaining of impotence who underwent pharmacotesting with
      PGE1 (Caverject) and color duplex Doppler was reviewed. Penile blood flow study
      (PBFS) data following a period of privacy and self-stimulation was compared. PBFS
      diagnostic criteria were: AI for peak systolic velocity (PSV) < 25 cm/s; CVOD for
      PSV > or = 35 cm/s and resistive index (RI) < 0.9; mixed vascular disease for PSV
      > or = 25 cm/s, PSV < 35 cm/s and RI > 0.9. Consistent dosing of PGE1 was used; 6
      mcg for age < 60 y and 10 mcg for age > or = 60 y. Patients were NIDDM (79 out of
      105) and IDDM (26 out of 105). Mean ages for NIDDM and IDDM were respectively 60,
      and 55 y. The relative significance of insulin dependence was assessed by
      Student's t-test. RESULTS: The most common etiology of ED was arterial
      insufficiency: mean PSV's did not significantly vary and were: 23.5 cm/s for
      NIDDM, and 21.6 cm/s for IDDM. PBFS parameters did not vary significantly for the
      risk factors of SM or HTN and diabetes. Mean peak systolic velocities were
      significantly different among diabetics with coronary artery disease: NIDDM/CAD,
      22.9 cm/s compared to IDDM/CAD, 14.8 cm/s (P = 0.006). CONCLUSIONS: We found
      among the 105 diabetics the most common etiology of vascular ED based on Doppler
      criteria was arterial insufficiency, 64%. Statistical analysis of additional risk
      factors (SM, HTN, CAD) suggested that patients with IDDM and CAD have more severe
      cavernosal arterial insufficiency than patients with NIDDM and CAD. This data
      tends to support the theory that microangiopathy is the predominant factor in
      diabetic impotence, and that insulin dependent diabetes with 'large vessel'
      coronary heart disease have a similar pathology in the 'small vessels' regulating
      penile inflow which is unfortunately worse than their non-insulin dependent
      counterparts.

PMID- 10356669
TI  - A double blind, placebo controlled study of intracavernosal vasoactive intestinal
      polypeptide and phenotolamine mesylate in a novel auto-injector for the treatment
      of non-psychogenic erectile dysfunction.
AB  - Three hundred and four patients with non-psychogenic erectile dysfunction (ED)
      completed a dose assessment phase with intracavernosal injection utilizing 25
      micrograms vasoactive intestinal polypeptide (VIP) combined with phentolamine
      mesylate 1.0 mg (VIP/P-1) or 2.0 mg (VIP/P-2) in an auto-injector for a response
      rate of 83.9%. In a sub-group of 183 patients who withdrew from one or more
      previous ED therapies, 82% responded with an erection suitable for intercourse.
      One hundred and ninety-five patients were subsequently treated in a placebo
      controlled phase. 75.1% responded to VIP/P-1, 12% to placebo (P < 0.001); 66.5%
      responded to VIP/P-2, 10.3% to placebo (P < 0.001), with the median duration of
      erection of 54 min. The principal adverse event was transient facial flushing in
      2770 injections (33.9%). There was no pain post injection and two episodes of
      priapism (0.05%). Only nine patients withdrew because of adverse events. Over 85%
      and 95% of patients were satisfied with the drug and auto-injector, respectively.
      Over 81% of patients and 76% of partners reported an improved quality of life.

PMID- 10356670
TI  - Ultra-structural changes in collagen of penile tunica albuginea in aged and
      diabetic rats.
AB  - Tunica albuginea (TA) of the penis, which has an important role in mechanism of
      erection, is composed mainly of collagen bundles. Both aging and diabetes
      mellitus (DM) were reported to be associated with many alterations in collagen
      content and architecture in several body tissues. So, the aim of this work was to
      evaluate the effects of both conditions on the collagen bundles of penile TA in
      rats. Our diabetic models were three groups of Zucker Diabetic Fatty (ZDF) rats
      with non-insulin-dependent DM (NIDDM) aged 15, 40 and 75 weeks. Their age-matched
      controls were Zucker Fatty (ZF) rats. TA were excised from the side of mid-penile
      shaft and were examined by scanning electron microscopy using chemical digestion
      to extract collagen components. With aging, only the (70 w) ZF rats showed a
      significant increase in both thickness (P < 0.005) and loss of undulation of its
      bundles (P < 0.005) compared with the younger animals. In ZDF animals, a
      significant gradual increase in bundle thickness (P < 0.005) and loss of its
      undulation (P < 0.005) were found as the disease progressed to 40 w duration.
      Comparing these two parameters between both study groups showed that DM animals
      had significantly higher bundle thickness (P < 0.005) with loss of its undulation
      (P < 0.005) than controls starting from 40 w old. In conclusion, with progress of
      both aging and NIDDM, an increase in both thickness and loss of undulation of
      collagen bundles of penile TA was appreciated. The association of DM with aging
      could represent a cofactor effect that ultimately led to a greater impact on
      architecture of the bundles. The resulting changes may explain the compromised
      rigidity of the penis during erection under both conditions.

PMID- 10356671
TI  - Sexual dysfunction related to antihypertensive agents: results from the animal
      model.
AB  - The present investigation elucidates the deleterious effects of three
      prototypical antihypertensive drugs namely, propranolol, clonidine and captopril
      on the erectile physiology. In order to delineate the direct drug effects from
      vascular insufficiency inherent in hypertensive states, the study was conducted
      on a normotensive animal model. The adverse effects of these drugs were estimated
      as changes in sexual behaviour and intracavernous pressure response of electrical
      stimulation in the treated rats compared to normal age-matched controls (n = 10,
      each group). Copulation studies indicated significant impairment of sexual
      function in the groups on propranolol and clonidine. The cavernous pressure
      response to nerve stimulation at the end of sixteen weeks further reinforced the
      gross compromise on sexual function in these two treated groups. In contrast, the
      captopril administration produced only marginal alterations to the responses
      recorded. The results from this study clearly indicate that propranolol and
      clonidine interfere with sexual behaviour and nerve mediated response to erection
      whereas captopril which is devoid of significant effects on these parameters, may
      be a better therapeutic option.

PMID- 10356672
TI  - Complete resolution of post-traumatic high-flow priapism with conservative
      treatment.
AB  - The most frequent cause of high-flow priapism is penile or perineal closed trauma
      with laceration of the cavernous artery and the formation of an arterial-lacunar
      fistula. We present the case of a high-flow priapism due to closed perineal
      trauma and damage to the left cavernous artery which completely resolved
      following conservative treatment. The case was documented by duplex Doppler
      ultrasound and selective pudendal arteriogram before and after resolution.

PMID- 10356673
TI  - Fluid balance modelling in patients with kidney failure.
AB  - In patients with kidney failure, adequate control of fluid status remains one of
      the most difficult routine issues to be addressed in the modern style of
      dialysis. This is primarily due to the lack of quantitative methods for the
      assessment of fluid status and the reliance on subjective criteria. Fluid is
      removed from the blood during dialysis treatments using a process called
      ultrafiltration. The last decade has seen considerable developments in blood
      volume monitoring (BVM) technology which has enabled responses to ultrafiltration
      to be continually monitored on an individual basis. This has enabled feedback
      control of patients' blood volume to be applied with partial success, reducing
      the number of symptoms. The feedback control algorithms employed have been
      relatively unsophisticated, using simple proportional control with no attempt to
      include models of the patient fluid dynamics. This paper describes the
      development of some prototype fluid kinetic models which may be used in a more
      advanced control system. Initial results demonstrate the importance of active
      control processes in the patients' physiological compensatory mechanisms.

PMID- 10356674
TI  - The biomechanical evaluation of polyester as a tension band for the internal
      fixation of patellar fractures.
AB  - We use a braided polyester suture in place of cerclage wire in tension band
      fixations. The objective of this study was to test the biomechanical properties
      of this technique. Sixteen cadaveric patellae were fractured and repaired by
      modified tension band fixation. Eight were fixed using eighteen gauge stainless
      steel wire as a tension band and eight using braided polyester. All specimens
      were subjected to tensile testing. Polyester was 75.0% as strong as wire. For
      dynamic testing, the patellae of seven cadaveric knees were fractured and then
      fixed with polyester tension bands. These were mounted in a device capable of
      extending the knees from 90 degrees to neutral against an applied force. None of
      the fixations failed. Three of the specimens fixed using 18 gauge stainless steel
      wire were compared with three fixed using polyester over 2000 cycles of knee
      flexion and extension. Polyester performed as well as wire. We conclude that
      polyester is an acceptable alternative to wire in tension band fixation.

PMID- 10356675
TI  - An electrical impedance index to distinguish between normal and cancerous
      tissues.
AB  - Bioimpedance measurements have previously shown that cancerous tissues in many
      cases have a higher characteristic frequency than normal tissues. This paper
      tries to find an index which is sensitive to variation in the characteristic
      frequency but is independent of the impedance value itself. Calculated indexes
      from several publications in most cases show values larger than one for cancerous
      tissues and less than one for normal tissues.

PMID- 10356676
TI  - Analysis of regurgitation, mean systolic pressure drop and energy losses for two
      artificial aortic valves.
AB  - The work reported here is related to the hydrodynamic performance of a Jellyfish
      valve and St Vincent valve in terms of total energy losses, mean systolic
      pressure drop and regurgitation. The in vitro experimental investigation was
      conducted at cardiac outputs of 3.5, 4.5 and 6.51 min-1 across the two valves and
      under pulsatile flow condition. It was found that the closure volume of the St
      Vincent valve was about 2.5 times higher than that of the Jellyfish valve. The
      total back flow losses on the other hand were found to be in the range of 36.5 to
      107.1 and 85.5 to 192.5 mJ for the Jellyfish valve and St Vincent valve
      respectively. Moreover, the mean systolic pressure drop of the St Vincent valve
      was found to be higher than that of the Jellyfish valve. However, for all the
      operating conditions tested here, the Jellyfish valve showed superior
      hydrodynamic performance in terms of backflow and mean systolic pressure as well
      as energy losses.

PMID- 10356677
TI  - Tensile properties of relaxed excised skin exhibiting striae distensae.
AB  - Tensile properties of skin determine some important physical attributes of skin.
      They may be conveniently assessed using recent technologies. The aim of the study
      was to compare ex vivo the tensile properties of normal looking skin and striae
      distensae. The Cutometer was used with 2 and 4 mm diameter probes. Skin
      distensibility values were dependent on the suction force and area of the skin
      tested. Conversely, tensile ratios yielding elasticity parameters were not
      affected by the same variables. Although tensile properties of excised normal
      skin resembled those previously reported in vivo, striae distensae showed
      markedly different properties in vivo and ex vivo. The ex vivo and in vivo
      evaluations of the tensile properties and functions of skin are complementary
      particularly when the connective tissue is abnormal.

PMID- 10356678
TI  - Prediction of olfactory response based on age, gender and smoking habits.
AB  - The measurement of olfaction has been neglected compared with the other senses.
      Recently, some progress has been made in the search for an instrument to
      objectively measure olfaction. This article outlines the early test results of a
      low cost, computer-based olfactometer which uses the frequency content of evoked
      potentials to quantify a subject's response to an olfactory stimulus. Clinical
      trials have been undertaken to establish the validity of the olfactometer and
      several thousand tests have been carried out using patients with olfactory
      dysfunctions as well as normals for norm referencing. The paper discusses a
      theoretical model for olfaction based on the age, gender and smoking habits of a
      subject. The validity of the model is then compared with the experimental data.
      The correlation between the model and the experimental results is strong.

PMID- 10356679
TI  - A new method for the automatic mesh generation of bone segments from CT data.
AB  - A new procedure for the automatic generation of finite element meshes of bone
      segments from computed tomography (CT) data sets is described. The new method
      allows a direct automatic generation from the CT data and produces a very
      accurate unstructured hexahedral mesh. The accuracy of the method was established
      using the CT images of an artificial femur showing range of attenuation values
      comparable to those of a human femur. To establish the optimal values for the
      parameters controlling the mesh a sensitivity analysis was carried out using mesh
      conditioning indicators. Some of the best meshes, with increasing levels of
      refinement, were used to analyse the stresses induced in the proximal femur by
      single leg stance posture. The accuracy of the meshes was evaluated using an
      implicit a posteriori residual-based error estimates. The number of elements with
      stress residuals larger than 10% of the peak stress was 7.8% using the coarsest
      mesh and only 1.8% with the finest mesh. The proposed method has been proved able
      to conjugate full automation with high-quality finite element meshes. The stress
      predictions obtained using these hexahedral-only meshes have been more accurate
      than those obtained by any other automatic mesh generation algorithm. Once
      properly integrated in an easy-to-use application, the described method could
      finally make feasible many clinical applications of finite element analysis.

PMID- 10356680
TI  - Cancer outreach programs for African-Americans.

PMID- 10356681
TI  - Photodynamic therapy for palliation of locally advanced lung cancer.

PMID- 10356682
TI  - Increased NIH funding needed to combat cancer in minorities, medically
      underserved.

PMID- 10356684
TI  - ASCO urges passage of bill to guarantee Medicare coverage of cancer clinical
      trials.

PMID- 10356683
TI  - Reinventing bone marrow transplantation. Nonmyeloablative preparative regimens
      and induction of graft-vs-malignancy effect.
AB  - The therapeutic benefit of allogeneic hematopoietic transplantation is due
      largely to an immune graft-vs-malignancy effect. Most of the evidence for such an
      effect has come from studies of allogeneic transplantation in leukemia. In
      patients with susceptible malignancies who relapse following an allogeneic
      transplant, infusion of donor lymphocytes can induce durable remissions. Use of
      less toxic, nonmyeloablative preparative regimens permits engraftment and
      generation of graft-vs-malignancy effects. This strategy permits allogeneic
      transplantation to be used in older patients and those with comorbidities who
      cannot tolerate conventional high-dose preparative regimens. The long-term
      efficacy of nonmyeloablative preparative regimens and induction of graft-vs
      malignancy effects remains to be determined. Also, further clinical trials are
      required to address various unresolved issues and to compare this strategy with
      standard, myeloablative transplantation regimens.

PMID- 10356685
TI  - Update on the management of advanced breast cancer.
AB  - Recent trials comparing single-agent vs combination therapy in metastatic breast
      cancer suggest that it may be time to reconsider the belief that combination
      chemotherapy is the gold standard of treatment. Based on the limited randomized
      trial data available to date, high-dose chemotherapy with stem-cell rescue should
      not be viewed as "state-of-the art" treatment for metastatic disease and should
      be used only in the context of clinical trials. Recent trials have explored the
      optimal dosing and scheduling of the taxanes, as well as the possible role of
      these agents in combination regimens. Capecitabine (Xeloda), a new oral
      fluoropyrimidine, appears to be comparable in efficacy to CMF (cyclophosphamide,
      methotrexate, and fluorouracil), and preclinical data suggest possible synergy
      between this agent and the taxanes. Other promising agents under study include
      liposome-encapsulated doxorubicin (TLCD-99), an immunoconjugate linking a
      chimeric human/mouse monoclonal antibody to doxorubicin molecules; MTA
      (LY231514), a multitargeted antifolate; and marimistat, a broad-spectrum matrix
      metalloproteinase inhibitor. Tamoxifen (Nolvadex) remains the most important
      hormonal agent, but new antiestrogens and selective estrogen receptor modulators
      (SERMs) may provide alternatives. The potential role of new aromatase inhibitors
      as first-line hormonal agents requires further study. Finally, the possible
      synergy between trastuzumab (Herceptin), a recombinant humanized monoclonal
      antibody to the HER-2/neu protein, and paclitaxel (Taxol) is being studied in two
      clinical trials.

PMID- 10356686
TI  - Clinical trials referral resource. Clinical trials with gadolinium-texaphyrin and
      lutetium-texaphyrin.

PMID- 10356687
TI  - Surgical staging of lung cancer.
AB  - The staging of lung cancer defines the extent of disease. Accurate staging is
      important to define operability, select treatment regimens, and predict survival.
      Nonsurgical and surgical techniques are used to stage patients. The most
      important nonsurgical techniques used currently are the chest x-ray and computed
      tomographic (CT) scan of the chest and upper abdomen. In the future, positron
      emission tomography (PET) may become the single most important nonsurgical
      investigation. Surgical staging involves histologic assessment of the primary
      tumor and potential sites of metastases. At present, the standard for surgical
      staging is cervical mediastinotomy. Other minimally invasive surgical procedures
      used to stage patients with lung cancer are scalene lymph node biopsy,
      bronchoscopy with transbronchial biopsy, anterior mediastinoscopy, and video
      assisted thoracoscopy. The different surgical staging options and their
      indications will be discussed in depth.

PMID- 10356688
TI  - Current imaging techniques for head and neck tumors.
AB  - Modern head and neck imaging has led to advances in both the diagnosis and
      treatment of head and neck cancers. Both computed tomography (CT) and magnetic
      resonance imaging (MRI) studies provide important information about the location
      and extent of neoplasm, particularly with respect to the interface of tumor with
      bone, fat, muscles and other soft tissues, air, blood vessels, dura, and brain.
      Conventional angiography can be used to assess tumor blood supply and vascularity
      and to perform therapeutic embolization. Magnetic resonance angiography (MRA) and
      CT angiography (CTA) are new tools for the noninvasive evaluation of blood
      vessels. Positron emission tomography (PET) shows promise for differentiating
      tumor from scar, edema, and other nonneoplastic soft tissues.

PMID- 10356689
TI  - Treatment of estrogen deficiency symptoms in women surviving breast cancer. Part
      5: Selective estrogen receptor modulators and hormone replacement therapy.
      Proceedings of a conference. Charlottesville, Virginia, USA. September 21-23,
      1997.
AB  - There are several million breast cancer survivors worldwide. In the United
      States, 180,000 women were diagnosed with breast cancer in 1997, and
      approximately 97,000 of these women have an extremely low chance of suffering a
      recurrence of their cancer. With an average age at diagnosis of 60 years and a 25
      year expected duration of survival, the current number of breast cancer survivors
      in the United States may approach 2.5 million women. Since breast cancer is now
      being detected at an earlier stage than previously and since adjuvant
      chemotherapy may cause ovarian failure, an increasing number of women are
      becoming postmenopausal at a younger age after breast cancer treatment. This
      conference was convened in September 1997 to consider how menopausal breast
      cancer survivors should be treated at the present time and what future studies
      are needed to develop improved therapeutic strategies. A total of 47 breast
      cancer experts and 13 patient advocates participated. The proceedings of the
      conference are being published in six installments in successive issues of
      ONCOLOGY. This fifth part examines the potential role of antiestrogens and
      selective estrogen receptor modulators (SERMs) in breast cancer patients being
      treated for estrogen deficiency symptoms.

PMID- 10356690
TI  - Thalidomide shows promising results in patients with multiple myeloma.

PMID- 10356691
TI  - Managing pain in patients with advanced cancer: the role of neuraxial infusion.

PMID- 10356692
TI  - Pain control in patients with cancer.
AB  - Pain is the most common symptom of advanced cancer. For most cancer patients,
      pain can be controlled with systemic analgesic and coanalgesic therapy in concert
      with treatment of their underlying cancer. Analgesic therapy for pain involves
      choosing the right drug and giving it at the proper dose and interval via the
      best route of administration. The goal of pain prevention requires around-the
      clock dosing and aggressive titration of long-acting opioids with as--needed
      supplements of short-acting opioids for breakthrough pain. Sequential trials of
      alternative opioids plus the early use of pain-specific coanalgesics can further
      optimize patient comfort and function. Most clinicians should be able to control
      most of the pain in most of their cancer patients. Collaboration with pain and
      palliative care experts can help the rest. No cancer patient should live or die
      with unrelieved pain.

PMID- 10356693
TI  - Patient and family caregiver perspectives.
AB  - The introduction of any new analgesic agent or delivery system is often focused
      on efficacy of the agent or on considerations of use by health care
      professionals. Introduction of novel pain technologies should also consider the
      ultimate recipients of the treatments, i.e., patients and family caregivers at
      home. This article reviews four frequently ignored issues in the integration of
      new pain treatments. These are 1) recognizing that pain is managed by patients
      and family caregivers at home; 2) acknowledging patient and family caregivers'
      knowledge and beliefs about pain; 3) recognizing cost considerations; and 4)
      identifying common ethical dilemmas in managing pain at home. Attention to these
      considerations will ensure optimum pain relief and support of patients and their
      family caregivers.

PMID- 10356694
TI  - A 15-year-old boy with primitive neurectodermal tumor.

PMID- 10356695
TI  - Managing cancer pain poorly responsive to systemic opioid therapy.
AB  - Large surveys of populations with cancer pain indicate that as many as 90% of
      patients can attain adequate relief of pain using optimal, systemic, opioid-based
      pharmacotherapy. Skilled clinicians should be able to achieve this benchmark and
      should also be knowledgeable about the variety of clinical strategies that may be
      used to manage pain in those patients who are poorly responsive to routine
      measures. These strategies can be conceptualized in four broad categories: 1)
      opening the "therapeutic window" by more aggressive side effect management, 2)
      identifying an opioid with a more favorable balance between analgesia and side
      effects through "opioid rotation," 3) introducing a pharmacologic technique that
      reduces the systemic opioid requirement (either treatment with a systemic
      coanalgesic or a trial of intraspinal therapy), or 4) offering a trial of a
      nonpharmacologic intervention that may reduce the systemic opioid requirement
      (e.g., nerve block). In the absence of comparative trials, the selection of a
      specific approach depends on an informed risk/benefit evaluation based on
      information from a comprehensive clinical assessment.

PMID- 10356696
TI  - Neuraxial infusion in the management of cancer pain.
AB  - Pain due to malignancy can be controlled through simple means in most patients.
      In certain refractory cases, however, the chronic delivery of analgesics to the
      epidural or subarachnoid space may be appropriate. This review will discuss
      criteria for patient selection for neuraxial drug delivery, the technologic
      systems available for neuraxial drug delivery, and criteria for selection of the
      appropriate technology in the individual patient.

PMID- 10356697
TI  - Practical issues when using neuraxial infusion.
AB  - The pharmacologic tailoring guidelines of the World Health Organization represent
      the accepted treatment algorithm for the management of cancer-related pain
      syndromes. Unfortunately, the guidelines are only effective in 70% to 90% of
      patients, leaving a substantial population with intractable pain. In fact, recent
      surveys have shown that, in the United States, only 50% of hospitalized
      terminally ill patients die comfortably. When patients do not respond to the WHO
      guidelines, practitioners should abandon the therapy and not the patient.
      Interventional pain management approaches including intraspinal delivery of
      analgesics may be an effective alternative. Before a more permanent system for
      intraspinal therapy is implemented, a trial must be performed to assure efficacy,
      rule out toxicity, and establish that the positive response to the intrathecal
      agent trialed is not due to placebo effects. An external drug delivery system is
      appropriate if the patient has less than 3 months to live. If the patient is
      expected to survive more than 3 months, a totally implanted system is appropriate
      and cost-effective. Although morphine remains the gold standard for intrathecal
      pain therapy, other opioids such as fentanyl, hydromorphone, sufentanil, and
      meperidine are now being used in patients who do not tolerate morphine. Nonopioid
      agents for intrathecal use in patients who have pain syndromes that are poorly
      responsive to opioids include local anesthetics, such as bupivacaine, and
      clonidine.

PMID- 10356698
TI  - Complications of neuraxial infusion in cancer patients.
AB  - Intraspinal drug delivery systems can be effective in controlling intractable
      pain. However, before these invasive pain therapies are initiated and to avoid or
      minimize any complications associated with their use, there must be a thorough
      understanding of the etiology of the pain, the underlying cancer, and
      antineoplastic therapy. For example, the assumption that intraspinal cannulation
      is contraindicated in all patients with known vertebral metastatic lesions is not
      supported in clinical practice. A majority of spinal metastatic lesions involve
      the vertebral body, which is distant from the dorsal position of the intraspinal
      catheter. Based on extensive experience, the only pragmatic contraindications to
      neuraxial infusion device implantation are those also revelant to surgical
      intervention. Careful patient selection may help avoid some complications and
      constant vigilance may be the best defense against errors.

PMID- 10356699
TI  - A 38-year-old man with pancreatic cancer.

PMID- 10356700
TI  - Neuraxial infusion for pain control: when, why, and what to do after the implant.
AB  - Neuraxial infusion therapy is an excellent option for selected patients with
      severe pain. Both epidural and intrathecal systems can be effective for multiple
      pains and are titratable, nondestructive, and very safe. Intraspinal therapy
      requires low opioid doses, has no motor, sensory, or sympathetic effects, and may
      have a lower side-effect liability than systemic therapy. Although most
      oncologists do not refer patients for intrathecal therapy, a recent study
      indicated that more oncologists would if they knew more about the therapy and if
      patients requested it. When permanent systems are used, close follow-up is
      essential. To obtain the maximum benefit from intraspinal therapy, pain
      management physicians and oncologists must communicate with each other and work
      together as partners.

PMID- 10356701
TI  - Cost modeling for alternate routes of administration of opioids for cancer pain.
AB  - The economic considerations relative to neuraxial infusion can be looked at with
      different types of economic models, including cost-minimization, cost
      effectiveness, and cost-benefit analyses. A theoretical predictive model was
      developed about 2 years ago using a computer spreadsheet and based on four levels
      of supportive data. The model shows that the breakeven point at which it becomes
      less expensive to administer opioids with an intrathecal/implanted pump, rather
      than an epidural/external pump, is between 3 and 6 months after the start of pain
      management. In addition, the break even point between systemic treatment and
      spinal delivery with an implanted system is between 1 1/2 and 2 1/2 years from
      start of pain treatment.

PMID- 10356703
TI  - Chronic toxicity/oncogenicity evaluation of 60 Hz (power frequency) magnetic
      fields in B6C3F1 mice.
AB  - A 2-yr whole-body exposure study was conducted to evaluate the chronic toxicity
      and possible oncogenicity of 60 Hz (power frequency) magnetic fields in mice.
      Groups of 100 male and 100 female B6C3F1 mice were exposed to pure, linearly
      polarized, transient-free 60 Hz magnetic fields at flux densities of 0 Gauss (G)
      (sham control), 20 milligauss (mG), 2 G, and 10 G; an additional group of 100
      male and 100 female B6C3F1 mice received intermittent (1 hr on/1 hr off) exposure
      to 10 G fields. A small but statistically significant increase in mortality was
      observed in male mice exposed continuously to 10 G fields; mortality patterns in
      all other groups of mice exposed to magnetic fields were comparable to those
      found in sex-matched sham controls. Body weight gains and the total incidence and
      number of malignant and benign tumors were similar in all groups. Magnetic field
      exposure did not increase the incidence of neoplasia in any organ, including
      those sites (leukemia, breast cancer, and brain cancer) that have been identified
      in epidemiology studies as possible targets of magnetic field action. A
      statistically significant decrease in the incidence of malignant lymphoma was
      observed in female mice exposed continuously to 10 G fields, and statistically
      significant decreases in the incidence of lung tumors were seen in both sexes
      exposed continuously to 2 G fields. These data do not support the hypothesis that
      chronic exposure to pure, linearly polarized 60 Hz magnetic fields is a
      significant risk factor for neoplastic development in mice.

PMID- 10356702
TI  - Chronic toxicity/oncogenicity evaluation of 60 Hz (power frequency) magnetic
      fields in F344/N rats.
AB  - A 2-yr whole-body exposure study was conducted to evaluate the chronic toxicity
      and possible oncogenicity of 60 Hz (power frequency) magnetic fields in rats.
      Groups of 100 male and 100 female F344/N rats were exposed continuously to pure,
      linearly polarized, transient-free 60 Hz magnetic fields at flux densities of 0
      Gauss (G) (sham control), 20 milligauss (mG), 2 G, and 10 G; an additional group
      of 100 male and 100 female F344/N rats received intermittent (1 hr on/1 hr off)
      exposure to 10 G fields. Mortality patterns, body weight gains throughout the
      study, and the total incidence and number of malignant and benign tumors in all
      groups exposed to magnetic fields were similar to those found in sex-matched sham
      controls. Statistically significant increases in the combined incidence of C-cell
      adenomas and carcinomas of the thyroid were seen in male rats chronically exposed
      to 20 mG and 2 G magnetic fields. These increases were not seen in male rats
      exposed continuously or intermittently to 10 G fields or in female rats at any
      magnetic field exposure level. No increases in the incidence of neoplasms, which
      have been identified in epidemiology studies as possible targets of magnetic
      field action (leukemia, breast cancer, and brain cancer), were found in any group
      exposed to magnetic fields. There was a decrease in leukemia in male rats exposed
      to 10 G intermittent fields. The occurrence of C-cell tumors at the 2 lower field
      intensities in male rats is interpreted as equivocal evidence of carcinogenicity;
      data from female rats provides no evidence of carcinogenicity in that sex. These
      data, when considered as a whole, are interpreted as indicating that chronic
      exposure to pure linearly polarized 60 Hz magnetic fields has little or no effect
      on cancer development in the F344/N rat.

PMID- 10356704
TI  - Rodent carcinogenicity studies on magnetic fields.

PMID- 10356705
TI  - Disseminated thrombosis and bone infarction in female rats following inhalation
      exposure to 2-butoxyethanol.
AB  - Groups of 10 male and 10 female F344/N rats were exposed to 0, 31, 62.5, 125,
      250, and 500 ppm of 2-butoxyethanol (BE) by inhalation, 6 hr/day, 5 days/wk, for
      13 wk. Four moribund female rats from the 500 ppm group were sacrificed during
      the first 4 days of exposure, and 1 moribund female from the same group was
      sacrificed during week 5. Dark irregular mottling and/or loss of the distal tail
      were noted in sacrificed moribund rats. Similar gross lesions were noted in the
      terminally sacrificed females exposed to 500 ppm BE. Histologic changes noted in
      the day 4 sacrificed moribund rats included disseminated thrombosis involving the
      coccygeal vertebrae, cardiac atrium, lungs, liver, pulp of the incisor teeth, and
      the submucosa of the anterior section of the nasal cavity. Alterations noted in
      coccygeal vertebrae from the 500 ppm sacrificed moribund rats included ischemic
      necrosis and/or degeneration of bone marrow cells, bone-lining cells, osteocytes
      (within cortical and trabecular bone), and chondrocytes (both articular and
      growth plate), changes that are consistent with an infarction process. The
      moribund female rat that was sacrificed during week 5 and those female rats
      treated with 500 ppm and sacrificed following 13 wk of treatment lacked thrombi,
      but they had coccygeal vertebral changes consistent with prior infarction and
      transient or complete bone growth arrest. No bone lesions or thrombi were noted
      in the male rats treated with the same doses of BE. In conclusion, exposure to
      500 ppm BE vapors caused acute disseminated thrombosis and bone infarction in
      female rats. Possible pathogenic mechanisms are discussed.

PMID- 10356706
TI  - Renal changes associated with naproxen sodium administration in cynomolgus
      monkeys.
AB  - Naproxen sodium was administered to cynomolgus monkeys (Macaca fascicularis) by
      oral gavage at daily doses of 44, 88, or 176 mg/kg for 2 wk (2 monkeys/gender) or
      of 44 mg/kg for 13 wk (4 monkeys/gender). Body weight loss occurred in at least
      one monkey in all naproxen sodium-dosed groups in the 2-wk (up to 16% loss) and
      13-wk (up to 22% loss) studies. Increases in plasma naproxen concentrations were
      dose proportional between 44 and 88 mg/kg but were less than dose proportional
      between 88 and 176 mg/kg. Up to 2-fold increases in creatinine and/or serum urea
      nitrogen values as well as higher renal weights occurred in monkeys receiving 176
      mg/kg for 2 wk or 44 mg/kg for 13 wk. Microscopically, renal changes were
      observed in all naproxen sodium-dosed groups. Renal findings after 2 wk of
      exposure included increased interstitial ground substance, tubular dilatation,
      and tubulointerstitial nephritis; in the 13-wk study, cortical tubular atrophy
      and interstitial fibrosis were also observed. These studies identify the kidney
      as the target organ of naproxen sodium in cynomolgus monkeys.

PMID- 10356707
TI  - Evaluation of the renal effects of an antisense phosphorothioate
      oligodeoxynucleotide in monkeys.
AB  - Antisense phosphorothioate oligodeoxynucleotides are therapeutic agents that
      provide target specificity resulting from Watson-Crick base pairing. However,
      there are nonspecific effects that in some instances result in toxicity. These
      compounds accumulate in the kidney and induce renal proximal tubular degeneration
      at high doses. The relationship between accumulation of phosphorothioate
      oligodeoxynucleotides in the kidney, indicators of renal toxicity, and
      histomorphology were investigated in rhesus monkeys. Monkeys received vehicle or
      an escalating dose regimen of 3, 10, 40, and 80 mg/kg of ISIS 2105 and were then
      evaluated for changes in clinical pathology indices, urinalysis parameters, and
      renal histopathology. Urinalysis revealed an increase in protein levels and a
      slight increase in blood content following the third 40 mg/kg dose and continuing
      through the 80 mg/kg doses, whereas other urinary markers of renal toxicity were
      unchanged. Creatinine clearance was slightly decreased in monkeys during the 80
      mg/kg dose cycle. Granulation in the cytoplasm of proximal tubular epithelial
      cells was evident by microscopic examination of kidney and was present at all
      doses examined and increased with dose. Immunohistochemical staining localized
      the oligodeoxynucleotide within these granules. Histopathologic changes
      consisting of minimal to moderate tubular degeneration were present only at the
      higher doses of 40 and 80 mg/kg and at high tissue concentrations, and these
      changes occurred concurrent with functional alterations, whereas lower doses (<
      or = 10 mg/kg) did not affect a pathologic or functional change.

PMID- 10356708
TI  - Eosinophilic gastroenterocolitis in iron lactate-overloaded rats.
AB  - Eosinophilic gastroenterocolitis with peripheral eosinophilia was induced in rats
      fed a diet containing 2.5% or 5.0% iron lactate for 3 mo. Additional findings
      consistent with iron overload were also observed. Microscopically, the lesions
      consisted of eosinophilic infiltrations in the mucosa and submucosa along the
      whole length of the gastrointestinal tracts, increased surface area of the
      gastric mucosal propria covered with mucous cells, and increased apoptotic bodies
      in the gastric glandular neck of rats in the 2.5% and 5.0% groups. An increased
      number of intraepithelial globule leukocytes in the gastric and intestinal lamina
      propria was also observed in the 5.0% group. Globule leukocytes in the gastric
      mucosa contained obviously enlarged granules in their cytoplasm in these rats.
      The granules of the globule leukocytes were positive for rat mast cell protease
      II, suggesting the mastocyte origin of these cells. Although severe infiltration
      of eosinophils and globule leukocytes suggested a type-1 hypersensitivity
      reaction, other features such as an increasing vascular permeability were not
      detected. Serum IgE levels in the 5.0% and control groups were < 3 ng/ml. Final
      body weights of male and female rats of the 5.0% group were suppressed to 70% and
      90%, respectively, of those of the control rats, whereas food consumption was
      comparable to that of the control group. The morphologic characteristics of the
      gastrointestinal lesions and peripheral eosinophilia induced in rats fed iron
      lactate were very similar to those in some cases of eosinophilic
      gastroenterocolitis in humans and other animals.

PMID- 10356709
TI  - Effects of neonatal diethylstilbestrol (DES) exposure on morphology and growth
      patterns of endometrial epithelial cells in CD-1 mice.
AB  - The effects of neonatal diethylstilbestrol (DES) exposure on the morphology and
      proliferating patterns of endometrial epithelial cells were investigated at
      various stages of development in mice. Female CD-1 mice were given daily
      subcutaneous injections of 2 micrograms of DES in corn oil or corn oil alone
      (control) at 1-5 days of age and were killed at 5, 6, 7, 8, 15, and 22 days of
      age. At 5 days of age, the uteri of DES-treated mice had expanded lumina and
      undulated luminal surfaces lined by slightly elongated epithelial cells. At 6-8
      days of age, marked infolding of clusters of hypertrophic elongated luminal
      epithelial cells was present; uteri had disorganized endometrial stromal and
      myometrial layers. At 15 and 22 days of age, the tissues from DES-treated mice
      had decreased numbers of endometrial glands, minimal stromal fibrosis, and
      smaller uterine horns than did the controls. Ultrastructurally, the endometrial
      epithelial cells of DES-treated mice at 5 and 8 days of age had distorted nuclei
      with condensed matrix and abundant secretory granules associated with rough
      endoplasmic reticulum and Golgi apparatus. At 8 days of age, an accumulation of
      fingerlike cytoplasmic processes that extended into the separated intercellular
      spaces and along the basal aspects of the endometrial epithelial cells were also
      observed. At 5-8 days of age, the proliferative activity of endometrial
      epithelial cells in DES-treated mice, identified by bromodeoxyuridine labeling,
      was significantly lower (10.5-1.7%) than that of the controls (25.5-19.8%). In
      situ analysis of endometrial luminal epithelial cells for DNA fragmentation
      representing apoptosis revealed < or = 0.1% and > 10% in the DES-treated and
      control mice at 5-8 days of age, respectively. The data show that cell cycle
      kinetics, in addition to changes in morphology, are altered in the developing
      mouse uterus following neonatal exposure to DES.

PMID- 10356711
TI  - Hepatoprotection by dimethyl sulfoxide. I. Protection when given twenty-four
      hours after chloroform or bromobenzene.
AB  - Dimethyl sulfoxide (DMSO) has previously been reported to protect against
      hepatotoxicity resulting from chloroform (CHCl3) or bromobenzene (BB) when given
      10 hr after the toxicant. The object of these studies was to further demonstrate
      the latent protective ability of DMSO by administering it at a much later time
      (24 hr) following toxicant exposure. In addition, a more detailed evaluation of
      the lesions was performed to better characterize the lesion progression and
      resolution. Male Sprague-Dawley rats received a hepatotoxic oral dose of either
      CHCl3 (1.0 ml/kg) or BB (0.5 ml/kg) and then received 2 ml/kg DMSO
      intraperitoneally 24 hr later. With both toxicants, limited centrilobular lesions
      were already present by the time DMSO was administered. Without treatment, liver
      injury rapidly progressed so that by 48 hr it occupied 40-50% of the liver, with
      accompanying large increases in plasma alanine aminotransferase (ALT) activity.
      Administration of DMSO greatly attenuated lesion development for both toxicants;
      the area injured was reduced by more than 4-fold, accompanied by a decrease in 48
      hr ALT activity of 8-16-fold. The ability of DMSO to intervene in the development
      of liver injury at such a late time appears to be unique and may provide insight
      into therapies for acute xenobiotic-induced hepatitis.

PMID- 10356710
TI  - Early alterations of lung injury following acute smoke exposure and 21
      aminosteroid treatment.
AB  - In a simulated fire-related smoke exposure protocol, New Zealand white rabbits
      were utilized to investigate the potential effects of the 21-aminosteroid
      (lazaroid) analog U75412E on the early events of acute lung injury. Inhalation of
      a total of 1.6 mg/kg U75412E aerosolized at a rate of 1.53 mg/min at 0.5 hr after
      smoke exposure significantly attenuated the extent of lung injury at 1 hr, as
      evidenced by decreased bronchoalveolar lavage (BAL) concentration of total
      protein, 6-keto-prostaglandin F1-alpha, and blood gas defect. Histopathologic
      examination demonstrated that the lazaroid significantly attenuated smoke-induced
      lung injury as evidenced by a decrease in wet lung/body weight ratio, necrosis,
      and sloughing of airway epithelial cells. Electron microscopy showed that the
      lazaroid decreased smoke-induced interstitial edema and the vacuolization of
      alveolar type II epithelium (21.6 +/- 9.7 vs 8.5 +/- 3.6 vacuoled blebs/cell,
      smoke only vs smoke + lazaroid). However, U75412E did not attenuate smoke-induced
      changes in BAL concentration of tumor necrosis factor-alpha, total cell count,
      and granulocyte percentage. These observations suggest that U75412E may exert its
      action through cooperative mechanisms, such as the modulation of arachidonic acid
      metabolism, in addition to its characterized antioxidative effects.

PMID- 10356712
TI  - Neurotoxic effects of 2,5-hexanedione on normal and neurofilament-deficient
      quail.
AB  - The neurotoxic effects of 2,5-hexanedione (2,5-HD) were investigated using
      neurofilament (NF)-deficient (Quv) Japanese quail in comparison with normal
      Japanese quail. Both Quv and normal Japanese quail were inoculated
      intraperitoneally with 350 mg/kg/day 2,5-HD for 6 consecutive wk. The results of
      2,5-HD exposure differed substantially between the 2 strains of Japanese quail.
      The 2,5-HD-exposed normal quail showed leg paralysis about 4 wk after initiation
      of dosing. Some treated normal quail fell into dysstasia and died of nutritional
      disturbances. Histologically, 2,5-HD-treated normal quail had NF-rich axonal
      swellings and degeneration in the distal parts of the peripheral nerves, spinal
      cord, and cerebellar peduncles. In contrast, 2,5-HD-injected Quv quail showed
      tonic convulsion, ataxia gait, severe quivering, and excitation about 2-3 days
      after administration. Some treated Quv birds died immediately after systemic
      tonic convulsion, probably because of asphyxia. Although all treated Quv quail
      showed neurologic signs, there were no recognizable 2,5-HD-induced lesions in the
      nervous system. After about 4-6 wk of dosing, 2,5-HD induced distal axonopathy in
      normal quail and acute neurotoxicity in Quv quail.

PMID- 10356713
TI  - "Mesenchymal tumor" or "decidual-like reaction"?
AB  - For more than 40 yr, an unusual urinary bladder lesion has been known to occur in
      certain strains of mice, but no consensus has been obtained regarding its
      etiology, pathogenesis, biology, or classification. The lesion was first assumed
      to be epithelial and non-neoplastic, then it was called a smooth muscle cell
      tumor or leiomyosarcoma because of ultrastructural characteristics for smooth
      muscle cells. Later, the nonspecific term "mesenchymal tumor" was introduced due
      to histomorphologic differences from all smooth muscle tumors known. Recently, a
      proposal was made to name it "decidual-like reaction" because of the
      histomorphologic similarity to the rare spontaneous decidual reaction in the
      uterus of aging mice. Both lesions are characterized by spindle and large
      pleomorphic epithelioid cells with large bizarre nuclei; these characteristics
      mimic anaplasia of malignant tumors and led pathologists to assume a neoplastic
      nature. The decidual hypothesis is supported by the regular presence of nuclear
      progesterone receptors, the occasional occurrence of eosinophilic cytoplasmic
      granules, the rare finding of cells morphologically resembling granulated metrial
      gland cells (all also observed in the uterine decidual reaction), and the
      reproducibility through long-term feeding of combinations of estrogens and
      progestogens. It appears that the new decidual hypothesis can explain many
      detailed facets of the lesion, with the exception of the reported smooth muscle
      cell characteristics. The controversy of "mesenchymal tumor versus decidual-like
      reaction" should be resolved soon, not only as a scientific issue, but also
      because of consequences for risk assessment.

PMID- 10356714
TI  - Mesenchymal tumors of mouse urinary bladder: neoplasm or reactive change?

PMID- 10356715
TI  - Ito cell tumor: immunohistochemical investigations of a rare lesion in the liver
      of mice.
AB  - In 2 lifespan transgeneration experiments using a total of 4,682 CBA/J mice, we
      observed uncommon lipomatous lesions in the livers of 8 mice independent of the
      treatment. Macroscopically, the lesions were described as pale white areas (2) or
      nodules (6) during necropsy. The lesions ranged from 1 to 15 mm in diameter.
      Microscopically, the lesions consisted of nodular aggregations of round to
      spindle-shaped cells that partly caused distinct compression of the adjacent
      hepatic parenchyma. The tumor cells were smaller than hepatocytes and had dark
      oval nuclei. Many of the more spherical cells contained clear vacuoles of various
      sizes, which were shown to be lipid droplets by oil red O staining. In addition
      to Gomori's silver and Masson's trichrome staining, several immunohistochemical
      stains were used to characterize the origin of the proliferating cells. Tumor
      cells were labeled by vimentin, actin, desmin, and proliferating cell nuclear
      antigen. The 2 cell phenotypes showed similar staining characteristics. Increased
      amounts of laminin and tenascin, 2 extracellular matrix proteins of the liver,
      were detected within these neoplasms. Summarizing, we suggest that these tumors
      are of Ito cell origin.

PMID- 10356716
TI  - Changes in clinical pathology parameters during gestation in the New Zealand
      white rabbit.
AB  - Hematology and serum chemistry parameters were analyzed in 2 groups of pregnant
      rabbits to assess changes in these parameters over the course of gestation. These
      data were used to generate a historical control reference range for embryofetal
      development regulatory toxicology studies. During the 28-day gestation period,
      the following major changes were observed. Red blood cell counts, hemoglobin, and
      hematocrit increased slightly up to day 13 and subsequently decreased
      progressively to a nadir for all parameters on day 25. Reticulocyte counts
      increased maximally by day 16 and then decreased to a minimum value on day 28.
      White blood cell counts progressively declined after day 7. Platelet counts
      increased slightly by day 10, were relatively stable until day 13, then
      progressively decreased to a nadir on day 25. Aspartate aminotransferase and
      alanine aminotransferease values increased steadily throughout the study to reach
      a maximum value on day 25. Triglycerides increased to their maximum value by day
      19 and then steadily decreased until day 28, whereas cholesterol decreased
      progressively to reach a nadir on day 25. Urea and total protein decreased
      steadily from day 13 onward. Calcium values decreased throughout the study to
      reach a minimum value on day 28. Phosphorus values increased slightly on days 7
      and 13 and then progressively decreased to reach a nadir on day 28. With a few
      exceptions, changes that occur in clinical pathology parameters during pregnancy
      in the rabbit are similar to those observed in pregnant women. Therefore, the
      rabbit can be considered a suitable species for embryofetal development toxicity
      studies with regard to clinical pathology.

PMID- 10356717
TI  - "Have you seen this?" Progression of drug-induced testicular toxicity.

PMID- 10356718
TI  - [Endovascular therapy of cerebral aneurysms and vasospasm].
AB  - Major improvements have been achieved in endovascular treatment of cerebral
      aneurysms during the last twenty years. Initial techniques of selective balloon
      occlusion were progressively replaced by controlled packing of the aneurysmal sac
      with soft detachable platinum-coils (GDC). In some patients with large or giant
      aneurysms of the cavernous portion of the internal carotid artery endovascular
      parent vessel occlusion therapy with balloons is still necessary. In aneurysms of
      the proximal paraclinoidal segment of the internal carotid artery a combined
      endovascular and microneurosurgical approach, the "evacuation-trapping"-technique
      might be helpful. In patients with symptomatic cerebral vasospasm in whom
      conservative therapy has failed or is not possible balloon angioplasty and or the
      intra-arterial infusion of papaverine has become a valuable therapeutic
      alternative. Further follow-up studies are necessary to assess the value and long
      term results of endovascular strategies.

PMID- 10356719
TI  - [Keratocysts of the jaws with an expansion to the skull base].
AB  - Ceratocysts prefer attaint the jaws solitarily or multiply. Familiar heapings are
      described in connection with the naevoid basal cell carcinoma syndrome (Gorlin
      Goltz-Syndrome). In most of the patients they are removable simply by
      enucleation. The histological typing as a cyst suggests a harmlessness of the
      disease. There is a significant higher amount of recurrent cysts compared to
      other odontogenous cysts, whereas clinical symptoms are absent for a long time.
      That give reasons for findings of breakthrough to the skull base. There are no
      real alternatives for the impairing operation procedures. It is reported about 69
      patients with ceratocysts. In 6.9% a breakthrough to the skull base was found.
      Therefore a radical operation procedure and a close meshed postoperative checking
      management with regular MRI and conventional x-ray will be demanded.

PMID- 10356720
TI  - Pericallosal artery aneurysm originating from a "supreme anterior communicating
      artery".
AB  - Report on the rare case of a ruptured pericallosal aneurysm originating from an
      atypic communicating segment between both distal A2 arteries, called the 'supreme
      anterior communicating artery'. The neurosurgeon should be aware of this rare
      vascular anomaly that might be angiographically occult and raise unexpected
      intraoperative difficulties.

PMID- 10356721
TI  - [Cerebral and basilar artery thrombosis following cervical spinal injury].
AB  - Vertebral artery injury may complicate cervical spine injury and may result in
      severe neurological impairment. We present a case of a 54 year-old male who
      sustained a hyperextension injury of the neck during horse-back riding with
      cervical spine dislocation of C3/4. As a consequence of right-sided traumatic
      vertebral artery thrombosis and extension of the thrombus into the basilar artery
      the patient developed a brainstem and bilateral cerebellar infarction with fatal
      outcome. In a review of the literature the characteristics of 33 cases with
      vertebral artery injuries following cervical spine trauma and with associated
      neurological complications are described. The problems of vertebral artery injury
      are discussed concerning diagnosis and therapy.

PMID- 10356722
TI  - [Radiation-induced meningioma 20 years after operation and high-dose irradiation
      of an ependymoma].
AB  - We report the case of a 30 year old female patient who had got high-dose
      irradiation at the age of 10 after subtotal removal of an ependymoma in the
      fourth ventricle. 20 years later a meningioma of the tuberculum sellae was
      diagnosed and removed surgically. In this case the following meningioma fulfills
      the criteria for a radiation-induced tumor. There exist many reports about tumors
      of the central nervous system which have developed after radiotherapy in the
      irradiated field after a latency period. But after a thorough review of the
      international literature about radiation-induced tumors of the CNS is this the
      third case in which a benign meningioma has followed a radiotherapy for an
      ependymoma.

PMID- 10356723
TI  - [Borrelia species new to Russia--possible causative agents of ixodid tick-borne
      borreliosis].
AB  - 18 Borrelia isolates, obtained in 1996-1997 from adult Ixodes ricinus collected
      from plants in the environs of Stavropol', were identified with the use of the
      polymerase chain reaction and the analysis of the polymorphism of the length of
      restriction fragments. Among them, in addition to B. garinii and B. afzelii,
      widely spread in Eurasia, 2 recently described species, B. valaisiana and B.
      lusitaniae, were found in Russia for the first time. Their possible spread and
      their importance in infectious pathology are described.

PMID- 10356724
TI  - [The pathogenicity enzymes of clinical strains of Klebsiella pneumoniae].
AB  - In 108 K. pneumoniae clinical strains isolated in pneumonia (32 strains),
      inflammatory processes of the urinary tracts (36 strains) and toxicoseptic states
      (40 strains) caseinolytic, gelatinase, phosphatase, lecithinase activities and
      the capacity for producing DNAase and RNAase were studied. The presence of
      caseinolytic activity was found in 38 cultures (35.1%), gelatinase activity in 37
      cultures (34.2%) and lecithinase activity in 13 cultures (12.0%). The production
      of RNAase was noted in 74 strains (68.5%), DNAase in 56 strains (51.8%) and
      acidic phosphatase in 33 strains (30.5%). The role of the above-mentioned enzymes
      in the development of purulent inflammatory processes, as well as the importance
      of further studies, including those aimed at establishing the nature of the
      genetic control of the already known properties of the pathogen, are discussed.

PMID- 10356725
TI  - [The use of minipigs to produce diagnostic sera for the serological
      identification of bacteria in the genus Morganella].
AB  - Mini-pigs of the Svetlogorsk breed were immunized with vaccine prepared from of
      M. morganii culture; the culture had been grown in a liquid nutrient medium,
      obtained from casein hydrolysate, in flasks placed in a thermostatically
      controlled shaker to the phases of exponential growth and cell growth
      deceleration. O-agglutinating sera thus obtained were specific. The highest
      antibody level was detected in the serum obtained as the result of the
      immunization of guinea pigs with the vaccine prepared from the culture on the
      phase of exponential growth. This serum retained its properties after storage for
      9 months. Heterologous antibodies occurred in the sera under study not more
      frequently than in rabbit sera and practically in the same titers.

PMID- 10356726
TI  - [The effect of an artificial magnetic field on Salmonella infection in mice].
AB  - Experimental Salmonella infection in mice, developing simultaneously with the
      prolonged action of an artificial constant magnetic field with induction equal to
      3 x 10(-4) T, was found to induce a pronounced decrease in nonspecific resistance
      in the animals. The study of Salmonella population structure revealed that the
      cells selected the animals subjected to the action of the artificial magnetic
      field had mostly a lesser number of signs of antibiotic resistance. By the end of
      the experiment Salmonella cultures isolated from the mice subjected to the action
      of the artificial magnetic field were characterized by greater virulence and
      resistance to the bactericidal action of blood serum. The use of sodium
      nucleinate under the conditions of the action of the artificial magnetic field
      enhanced the level of anti-infectious protection in the animals, which changed
      the direction of cell selection in Salmonella population towards cells with a
      greater number of markers of antibiotic resistance.

PMID- 10356727
TI  - [Interferon incorporated into liposomes. A method for the design of homologous
      and heterologous liposomes and the control of their in-vivo permeability].
AB  - The specific features of the fatty acid composition of phospholipid carriers
      obtained from raw materials of vegetable and animal origin were studied.
      Differences in the enrichment of phospholipids of different origin with polyene
      fatty acids were shown. The method for obtaining fluoroliposomes incorporating
      such components as phospholipids of mouse organs, egg yolk, etc. were proposed.
      The study proved that the homology of the lipid base of liposomes facilitated
      their binding by tropic organs and more rapid liberation of the blood stream from
      them. The selection of lipid carriers and their sources was determined by their
      uniformity, morpho-functional importance, phospholipid and fatty acid
      composition, as well as their homology as regards their composition features.

PMID- 10356728
TI  - [The isolation of monoclonal antibodies to the hemolysin of noncholerigenic
      vibrios].
AB  - The results of the work on obtaining monoclonal antibodies (McAb) to hemolysin of
      noncholerigenic vibrios and the study of hemolysin preparations and Vibrio
      cholerae strains are presented. As established with the use of McAb, hemolysin
      preparations proved to be complex compounds containing, in addition to hemolytic
      protein, some lipopolysaccharide determinants, which had not been detected with
      the use of traditional biochemical tests. The study revealed that V. cholerae non
      01 and V. cholerae eltor hemolysins have common antigenic determinants, which was
      confirmed by the data of literature on the homogeneity of these substances. McAb
      obtained in this study interacted with V. cholerae avirulent hemolytic strains,
      not interacting with V. cholerae classical strains.

PMID- 10356729
TI  - [The role of the structural parts of bacterial lipopolysaccharide in its direct
      immunosuppressive activity].
AB  - The direct immunosuppressive activity of lipopolysaccharides (LPS) and their
      structural parts (O-chains, R-core, lipid A), obtained from Salmonella,
      Pseudomonas and Burkholderia, was studied. LPS preparations were extracted by the
      phenol-water method. Structural parts of LPS were obtained by acetic acid
      hydrolysis and gel filtration. The study demonstrated that all these
      preparations, when injected intraperitoneally into mice, did not affect the level
      of delayed-type hypersensitivity (DTH) to the test antigen in the animals. After
      redox treatment all LPS preparations became capable of suppressing DTH. After
      redox treatment such immunosuppressive activity could be observed in lipid A,
      while O-specific chains and R-core remained inactive. After phenol treatment
      immunosuppressive activity disappeared. Chemical groups capable of activation
      were likely to be located in lipid A or in lipid A-associated protein.

PMID- 10356730
TI  - [Streptococcus pneumoniae adhesion to mouse tracheal explants and its inhibition
      by carbohydrate preparations].
AB  - The method for the cultivation of tracheal explants of non-inbred mice was
      developed. The adhesive capacity of 34 S. pneumoniae strains belonging to 15
      serotypes was studied. The geometric mean of S. pneumoniae concentrations
      attached to the organ culture was 8.93 x 10(4) CFU/ml. D-galactose blocked
      adhesion, on the average, 4.35 x 10(4) (95.5%) CFU/ml. The level of S. pneumoniae
      adhesion and the degree of its inhibition were dose- and strain-dependent. The
      use of different variants of the combination of D-galactose and S. pneumoniae
      made it possible to come to the conclusion that this monosaccharide blocked the
      receptors of epithelial cells and bacterial adhesins.

PMID- 10356731
TI  - [The interrelationship of biomass and toxin accumulation to the dynamics of the
      physicochemical parameters of Corynebacterium diphtheriae PW8 cultivation].
AB  - As established in the process the controlled cultivation of C. diphtheriae PW8,
      the rate of the accumulation of biomass and antigenic material increases with
      higher values of the redox potential of the nutrient medium (exceeding 11.0 mV).
      The data obtained in this study are indicative of the expediency of using the
      value of redox potential as an additional criterion in the evaluation of the
      quality of the nutrient media. The direct relationship between the productivity
      of the process of C. diphtheriae PW8 cultivation as regards the accumulation of
      biomass and antigenic material and the economic coefficients of the accumulation
      of biomass and antigenic material as determined by the utilized substrate has
      been established. The above relationship may facilitate the prognostication of
      the course of the process of microbial cultivation and the accumulation of
      diphtheria toxin, evaluated by antigenic activity.

PMID- 10356732
TI  - [The estimation of the amount of diphtheria toxin and its activity by various
      tests in the dynamic cultivation of Corynebacterium diphtheriae PW8].
AB  - Direct correlation between the results of tests for the biological activity of
      diphtheria toxin, carried out in vivo guinea pigs and in vitro in the
      microcytotoxicity test in CHO cell culture, has been established, which makes it
      possible to use the latter as one of the methods for the rapid, reproducible and
      economic evaluation of diphtheria toxin. The qualitative and quantitative
      evaluation of diphtheria toxin in the enzyme immunoassay with the use of
      monoclonal antibodies and in the microcytotoxicity test demonstrates that these
      two tests, when used for controlling cultivation processes, have essential
      advantages over the flocculation test as regards their specificity and
      information content.

PMID- 10356733
TI  - [Food poisonings caused by halophilic vibrios in the city of Vladivostok: their
      epidemiological characterization].

PMID- 10356734
TI  - [The epidemiological aspects of viral hepatitides in Estonia].
AB  - The etiological structure of viral hepatitides among the adult population of
      Tallinn and the occurrence of markers of hepatitis B and hepatitis C virus
      infections in medical workers, addict introducing drugs intravenously and
      hemodialysis patients were studied. Changes in the etiological structure of viral
      hepatitides were established: they took the form of a decrease in the level of
      hepatitis A morbidity and the considerable growth of the role of hepatitides B
      and C, as well as the newly detected circulation hepatitis D virus. About one
      third in the structure of morbidity in viral hepatitides were hepatitis cases
      without markers of hepatitis A, B or C viruses (non-A, non-B, non-C). The highest
      rates of hepatitis B virus infection (78.9%) and hepatitis C virus infection
      (82.5%) were detected among drug addicts. Their level of HBsAg was 8.8%. In the
      group of medical workers, 25% of the examinees, i.e. every fourth person, had
      markers of hepatitis B virus, while antibodies to hepatitis C virus were detected
      in 5% of cases. Among hemodialysis patients these rates were 21.4% and 10.7%
      respectively.

PMID- 10356735
TI  - [The etiological structure of acute intestinal infections in children in the
      Republic of Tajikistan].
AB  - The Republic of Tajikistan belongs to the territories, traditionally hyperendemic
      with respect to acute enteric diseases (AED). The problem of AED still remains
      topical in recent years, especially among child population. The study of the
      etiological structure of AED in children has made it possible to establish that
      more than 70% of these diseases are of infectious nature. The leading role in the
      etiological structure of these diseases belongs to Shigella infections (32.4%),
      enterovirus diarrhea (12.1%) and Escherichia infections (8.9%). No significant
      differences in the character of the etiological structure of AED in children of
      urban and rural areas have been detected with the exception of enterovirus
      diarrhea, found to occur 2.7 times more frequently on children of urban areas
      (15.9%) than in those of rural areas (5.8%). The ascertaining of the etiological
      structure of AED in Tajikistan will make it possible to essentially increase
      epidemiological surveillance on AED and render it more concrete.

PMID- 10356736
TI  - [The results of the registration clinical trials of the Act-Hib vaccine
      manufactured by the firm of Pasteur Merieux Connaught, France].
AB  - The results of the field trials of the vaccine "Act-Hib" against Haemophilus
      influenzae of type b, presented for registration by Pasteur Merieux Connaught
      (France), are summarized. The vaccine was found to have low reactogenicity and
      high immunological effectiveness. A single injection of the vaccine induced the
      formation of the protective level of anti-PRP antibodies in 94% of the immunized
      children aged 1-4 years. After immunization the mean geometric titers of specific
      antibodies increased sixfold in comparison with the initial level and were equal
      to 3.4 mu/ml. On the basis of the data of laboratory control and field clinical
      trials the vaccine "Act-Hib" was registered in the Russian Federation and
      permission and its practical use in the public health service of the country was
      permitted.

PMID- 10356737
TI  - [The efficacy and outlook for the study of live vaccines for the prevention of
      melioidosis].
AB  - The effect of immunization with Burkholderia pseudomallei, (Pur- and Ts),
      heterologous vaccines and the recombinant culture of Francisella tularensis RM2,
      carrying a plasmid with fragments of B. pseudomallei chromosome, was studied on
      four species of experimental animals, essentially differing by their sensitivity
      to melioidosis. B. pseudomallei mutants formed the statistically significant
      level of protection in subcutaneously challenged animals, moderately sensitive to
      melioidosis, but were not effective when tested, under the same conditions, in
      animals, highly sensitive to melioidosis. The effect produced by the experimental
      vaccines under study in animals of all species, subjected to aerogenic challenge,
      was leveled. The study showed good prospects for the use of tularemia vaccine
      with a view to create heterologous immunity to melioidosis and the possibility of
      its use as the basis of bivalent gene engineering vaccine.

PMID- 10356738
TI  - [The need for a review of the procedure for the preventive vaccination of
      researchers working with Rickettsia prowazekii].
AB  - The analysis of the results of prolonged observations on the prophylactic
      immunization of employees working with R. prowazekii is presented. The necessity
      of the differentiated approach to the determination of the immunization schedule
      and the choice of vaccine is shown. The presence of specific antibodies (Ab) and
      the level of their titers have been found to be related to the degree of anti
      infectious protection. The following characteristics indicate the presence of
      profound immunological transformation in vaccinees: complement-fixing Ab in
      titers 1:10 and more and/or immunofluorescent Ab in titers not below 1:180, Ab to
      protein in the hemagglutination test in titers not below 1:1000. These specific
      Ab and the level of their titers can be registered after the second injection of
      live combined typhus vaccine E and the third injection of chemical typhus
      vaccine. Cases of laboratory infection and their relationship to the character of
      immunization and the intensity of contacts with R. prowazekii virulent strains
      are discussed. Attention is drawn to the strict observance of professional safety
      rules.

PMID- 10356739
TI  - [The antidiphtheria and antitetanus immunities of children of the Maritime
      Territory after the use of adsorbed DTP vaccine and adsorbed DT-m anatoxin].
AB  - The state of collective immunity to diphtheria and tetanus in children of
      preschool age, depending on the kind of vaccine preparation used for
      immunization, was studied. The immunological potency of adsorbed DPT vaccine
      (i.e. its capacity of forming prolonged and stable basic immunity) was shown to
      be higher in comparison with the potency of adsorbed DT toxoid with reduced
      antigen content (DT-R). The study revealed that in all groups of children the
      level of antitetanus immunity was higher than the level of antidiphtheria
      immunity, and 3 years later its decrease was less pronounced. A stricter approach
      to giving medical grounds for the use of low-reactive adsorbed DT-R in the
      immunization of children belonging to groups of risk is recommended.

PMID- 10356740
TI  - [Vaccinal prophylaxis in Bashkortostan: the results, problems and outlook].

PMID- 10356741
TI  - [The characteristics of the humoral antibacterial immunity of young children with
      respiratory organ diseases].
AB  - The state of antibacterial humoral immunity in young children with acute
      bronchitis, acute obstructive bronchitis and bronchial asthma at the period of
      exacerbation has been shown with the use of the enzyme immunoassay. The
      concentration of antibodies to endotoxin positively correlates with the severity
      of clinical manifestations of the endogenic intoxication of the body. As the
      inflammatory process in the bronchial tree increases, the spectrum bacterial
      agents to which elevated concentrations of specific antibodies can be detected
      becomes wider, and this finds its maximum reflection in bronchial asthma.

PMID- 10356742
TI  - [The assessment of the parallelism in the results of measuring an analyzable
      substance and the calibrator in immunological assays].
AB  - The method for checking the results of measurements of the analyzed substance and
      the calibrator for parallelism the immunological testing kit ABICAP-test
      DIPHTHERIA, produced by ABION (Germany), is described. The international standard
      sample of diphtheria antitoxin human serum was used as calibrator, and human
      serum No. 18, obtained from the Biomed Group (Russia), was used as the substance
      to be analyzed. The described method made it possible to detect the parallelism
      of "dose-response" curves with the relative error not exceeding 20%. Such
      accuracy proved to be sufficient for practical purposes and was in agreement with
      the amplitude of oscillations in measured optical densities. The shift of graphs
      along the abscissa made it possible to estimate the concentration of the serum as
      exceeding the concentration of the standard sample 2.3 times. The use of
      analytical approximation for the standard seems to be an important feature in the
      described method.

PMID- 10356743
TI  - [The prospects for the diagnosis of bacterial meningitis].
AB  - The samples of spinal fluid arriving to the Clinical Infectious Hospital in 1994
      1996 with the clinical diagnosis "generalized form of meningococcal infection" or
      "purulent meningitis of unclear etiology" were studied. The etiological agent was
      bacteriologically identified in 35% of 487 patients (in 25% of cases Neisseria
      meningitidis, in 7% of cases Streptococcus pneumoniae and in 2% of cases
      Haemophilus influenzae, type b, were detected). The method of latex
      agglutination, used in this study, was highly specific (100%) and moderately
      sensitive (67%); this method made it possible to diagnose 25% of cases
      additionally (N. meningitidis in 15% of cases, S. pneumoniae in 5% of cases and
      H. influenzae in 3% of cases). Diagnostics with the use of PCR was characterized
      by high specificity (> 97%) and sensitivity (> 85%) relatively to the "golden
      standard" of microbiological diagnostics. There were few false positive results
      (3 samples), caused probably by contamination at the moment of taking the
      samples. For this reason the results obtained by PCR could be used for diagnostic
      purposes even in cases of negative results given by other methods. Tests with the
      use of PCR made it possible to diagnose 29% more cases additionally (in 26% of
      cases N. meningitidis DNA and in 3% of cases S. pneumoniae DNA were detected.
      Thus the complex of methods used in this study permitted the detection of the
      etiological agent altogether in 87% of cases.

PMID- 10356744
TI  - [Combined antibacterial and probiotic therapy of Helicobacter-associated diseases
      in children].
AB  - On the basis of microbiological monitoring and clinico-morphological criteria,
      the use of probiotics containing lacto- and bifidobacteria, simultaneously with
      "triple" antibacterial therapy (antibiotics of choice, metronidazole and bismuth
      salts), has been found to produce curative effect in the treatment of
      Helicobacter-associated gastroduodenal pathology in children. The influence of
      "triple" antibacterial therapy on the microecology of the gastrointestinal tract
      and the state of the immunobiological status of patients was studied. The
      combined scheme for correcting damaged microbiocenosis with probiotics in
      accordance with the concept of microecological adequacy is proposed. The scheme
      includes modern antibacterial therapy in combination with the probiotic
      preparations of lactobacteria. The prescription of bifidobacteria-containing
      probiotics is recommended at early stages from the beginning of etiotropic
      therapy. The effectiveness of the therapy may be dynamically evaluated, starting
      from week 5 after the end of the complex therapy, in EIA with the use of specific
      anti-Helicobacter antibodies.

PMID- 10356745
TI  - [Monoclonal antibodies to Mycoplasma pneumoniae antigens].
AB  - Approaches to obtaining stable mouse hybridomas, capable of producing monoclonal
      antibodies (McAb) to M. pneumoniae key antigens, were developed. As the result of
      hybridization experiments, 7 clones were obtained; of these, 4 clones stably
      synthesized IgG McAb. Clones H1/H9 and H9/B2 synthesized antibodies to
      thermolabile, proteinase-sensitive K protein, produced by cytoplasmic membranes
      of M. pneumoniae cells. The molecular weight of this protein was found to be 90
      kD. McAb of clone H1/H9, labeled with horse-radish peroxidase and fluorescein
      isothiocyanate, specifically reacted with M. pneumoniae antigens in the
      immunofluorescence test and the enzyme immunoassay (EIA). The sensitivity of EIA
      was 0.25 ng/ml of antigen protein. These data are prerequisites for the
      development of diagnostic test systems for the detection of M. pneumoniae
      antigens in different biological substances obtained from patients with
      respiratory pathology.

PMID- 10356746
TI  - [The effect of the vaccinal strain of Yersinia pestis on the expression of Fc
      gamma receptors on macrophage surfaces].

PMID- 10356747
TI  - [The isolation and comparative characteristics of sera to the enterotoxin of
      Vibrio cholerae of the serogroups O139 and O1].

PMID- 10356748
TI  - [Patterns in the epidemic process of respiratory streptococcal infections in
      Vladivostok].

PMID- 10356749
TI  - [Immunoenzyme screening for bacterial antibodies in the blood sera of workers of
      the Moscow subway].

PMID- 10356750
TI  - [The quantitative determination of diphtheria antitoxin by a color test method].

PMID- 10356751
TI  - [The lessons of diphtheria].

PMID- 10356752
TI  - [Prion terminology].

PMID- 10356753
TI  - [The poly(hetero)morphic forms of pathogenic bacteria in infectious pathology].

PMID- 10356754
TI  - [The potentials and prospects for the use of computer systems for the
      surveillance of hospital bacterial infections].

PMID- 10356756
TI  - [An outbreak of acute intestinal infections of unknown etiology in a preschool
      institution (1)].

PMID- 10356755
TI  - [Pyrazinamidase as a p6rker of Yersinia pathogenicity].

PMID- 10356757
TI  - [A small outbreak of rotavirus gastroenteritis in a preschool institution].

PMID- 10356758
TI  - [An outbreak of acute intestinal infections of unknown etiology in a preschool
      institution (2: answers to questions and the authors' commentary)].

PMID- 10356759
TI  - Effect of dietary fish oil (active EPA-30) on liver phospholipids in young and
      aged rats.
AB  - We explored the uses of fish oil (active EPA-30) as a source of eicosapentaenate
      (EPA; 20:5 n-3), to young and old rats. We treated three subgroups of rats each
      comprising 20 young or old rats, respectively. The first group was kept on the
      basal ration (lab-pellet) as control diet, the second group was fed semi-purified
      diets contained 5% pig-fat (n-3 fatty acids deficient diet). The third group was
      fed a modified diet in which 50% of pig-fat was replaced by active EPA-30. Livers
      of young rats fed pig-fat had a drastic decrease in the amount of
      phosphatidylethanolamine (PE) and omega-3 polyunsaturated fatty acids (EPA, 20:5
      n-3 and docosahexaenoic, DHA, 22:6 n-3) and compensatory increase of
      phosphatidylcholine, saturated fatty acids and n-6 polyunsaturated fatty acids in
      the liver phospholipids. In contrast, the liver of young rats fed active EPA-30
      had large amounts of PE and concomitant enrichment in polyunsaturated fatty
      acids. The liver of old rats, fed on active EPA-30 supplemented diet had lower
      amounts of PE and there were no significant changes in the phospholipid fatty
      acid composition.

PMID- 10356761
TI  - Tissue sequestration of C-labelled bicarbonate [HCO3-] in fed and fasted young
      sheep.
AB  - Carbon dioxide entry rates (CER) based on isotopic activities in either expired
      air or blood following a 24-h intravenous infusion of [13C]- and [14C] sodium
      bicarbonate were compared with CO2 production quantified by respiration hood in
      young sheep (28-30 kg) either fed (three animals) or fasted (three animals). CO2
      production increased with intake (5.2 vs 10.3 mol/day; P < 0.001) as did CER
      values based on expired air (9.9 vs 18.6 mol/day; P < 0.001) or blood (7.5 vs
      16.5 mol/day; P < 0.001). The differences between air and blood CER values were
      significant (P < 0.001). There were no differences, however, when data were
      compared between [13C] and [14C] measurements. How much of these differences
      could be attributed to sequestration of label in body tissues was examined at the
      end of the infusion. The highest specific radioactivities (dpm/g dry matter) in
      acid-fast tissue material were observed for the more metabolically active
      tissues, liver, jejunum and kidney, with the lowest values for fat and muscle.
      When tissue mass was taken into account, however, the largest proportions of the
      dose sequestered were in bone muscle, skin and fat with significantly more
      retained for the former three (P < 0.01) during fasting. Separately, losses as
      urinary urea were also quantified. Total measured sequestration of label only
      accounted for approximately 24-44% of the difference between CER and CO2
      production.

PMID- 10356762
TI  - Vanadium inhibition of serine and cysteine proteases.
AB  - A study was made on the effect of vanadium, in both the tetravalent state in
      vanadyl sulphate and in the pentavalent state in sodium meta-vanadate, and ortho
      vanadate, on the proteolysis of azocasein by two serine proteases, trypsin and
      subtilisin and two cysteine proteases bromelain and papain. Also the proteolysis
      of bovine azoalbumin by serine proteases was considered. An inhibitory effect was
      present in all cases, except meta-vanadate with subtilisin. The oxidation level
      of vanadium by itself did not determine the inhibition kinetics, which also
      depended on the type and composition of the vanadium containing molecule and on
      the enzyme assayed. The pattern of inhibition was similar for proteases belonging
      to the same class. The highest inhibition was obtained with meta-vanadate on
      papain and with vanadyl sulphate on bromelain.

PMID- 10356763
TI  - The effect of isovolemic anaemia on blood O2 affinity and red cell triphosphate
      concentrations in the painted turtle (Chrysemys picta).
AB  - The blood oxygen affinity of vertebrates is regulated, in part, through changes
      in red cell phosphate levels and increased oxygen affinity during reductions in
      inspired oxygen and is a well-described and common feature. However, during
      anaemia, when oxygen delivery is compromised by a reduction in blood oxygen
      carrying capacity, a lowering of blood oxygen affinity will facilitate oxygen
      unloading in the tissues, while oxygen loading at the gas exchange organ is not
      impaired. The present study investigated the effects of artificially induced
      anaemia in vivo on the blood oxygen affinity and red cell nucleoside triphosphate
      (NTP) concentrations in the turtle, Chrysemys picta. Blood was obtained from
      conscious animals through an arterial catheter and oxygen equilibrium curves were
      determined using the Tucker method while NTP concentrations were analyzed
      spectrophotometrically. Before induction of anaemia haematocrit averaged 23% and
      P50 was 18.5 +/- 0.7 with a NTP/Hb of 0.20 +/- 0.01 (mmol/mmol). After the
      haematocrit had been reduced to approximately 10% by bleeding (48-96 h) (blood
      volume was maintained by re-infusion of plasma and Ringer) there were no effects
      on P50 or red cell NTP concentrations. Thus, in contrast to fish and mammals,
      turtles do not exhibit a change in blood oxygen affinity during anaemia.

PMID- 10356764
TI  - On-line measurement of adenosine triphosphate and catecholamine released from
      adrenal chromaffin cells.
AB  - Adenosine triphosphate (ATP) and catecholamine (CA) released from cultured
      porcine adrenal chromaffin cells were continuously measured with an ATP
      photometer (luciferin-luciferase method) and electrochemical detector,
      respectively. Application of acetylcholine (ACh, 0.1 mM) or high K+ (60 mM)
      caused increases of ATP and CA in perfused effluent with the same time course.
      The peak molar ratio of CA to ATP in the effluent was about 10 for ACh and high
      K+ stimulation. The high-performance liquid chromatographic (HPLC) analysis of
      adenine nucleotides in the collected effluent revealed that the relative amounts
      of ATP, ADP and AMP were almost the same throughout the period of stimulation,
      suggesting that ATP breakdown in the effluent was constant. Changes in the peak
      molar ratio of CA to ATP appearing in the effluent did not occur with repetitive
      high K+ or sustained Ba2+ stimulation (5 mM). The similarity between the time
      courses of ATP and CA appearing in the effluent suggests that releasable
      chromaffin granules have a constant molar ratio of CA to ATP. The on-line system
      developed is a simple and rapid method for examining ATP and CA secretion,
      simultaneously.

PMID- 10356766
TI  - The life cycle of Amblyomma neumanni Ribaga, 1902 (Acari: Ixodidae) in the
      laboratory.
AB  - A colony of Amblyomma neumanni was started with engorged females collected from
      cattle in the province of Salta (24 degrees 51'S, 65 degrees 33'W), Argentina.
      The larvae and nymphs were fed on rabbits and the adults on calves. The non
      parasitic stages were maintained in darkness at 27 +/- 1 degrees C and 83-86% RH.
      The life cycle (pre-feeding period not tested) had a mean duration of 205.7 days.
      The mean time (days) for the different phases of the cycle were as follows:
      feeding of females 8.8, pre-oviposition 23.8, oviposition 41.4, minimum egg
      incubation 76.1, feeding of larvae 8.5, pre-moult to nymphs 16.4, feeding of
      nymphs 7.9 and pre-moult to adults 22.8. The mean recovery rates of larvae,
      nymphs and females were 83.8, 85.6 and 89.3%, respectively. The nymphs moulting
      to females were heavier (8.1 +/- 2.34 mg) than those moulting to males (6.0 +/-
      2.34 mg; p < 0.01), but their range of engorgement weight showed overlap (2.3
      16.2 versus 2.2-12.8 mg, respectively). Two gynandromorphs were detected between
      the nymphs. A comparison of biological parameters of A. neumanni with other
      American Amblyomma species from mammals is presented.

PMID- 10356765
TI  - Regulation of squid visual phospholipase C by activated G-protein alpha.
AB  - Phospholipase C (PLC) is the key enzyme in the phototransduction cascade of
      invertebrate rhabdomeric photoreceptors. In addition to 130 kDa PLC, a 95 kDa
      protein recognized by antibody against the catalytic site of PLC was found in the
      squid retina. The PLC-like 95 kDa protein (95 kDa PLC) was produced from 130 kDa
      PLC by an intrinsic protease in the presence of calcium. The 130 kDa PLC was
      stimulated by the active form of Gq-class G-protein alpha (Gq alpha), but the 95
      kDa PLC was not, although their PLC activity was similar. A 35 kDa fragment, the
      counterpart of 95 kDa PLC, was not recognized by antibodies against catalytic
      site or N-terminal site of the 130 kDa PLC, indicating that the cleavage site is
      on the C-terminal side beyond the catalytic site. In the presence of a large
      excess of the 35 kDa fragment, 95 kDa PLC was stimulated by Gq alpha to a similar
      extent as intact 130 kDa PLC. These results indicate that the C-terminal
      polypeptide of PLC is necessary for regulation of its enzyme activity by Gq
      alpha. The uncoupling of PLC from Gq alpha, caused by limited proteolysis, is
      therefore a candidate regulatory mechanism of the phototransduction cascade in
      rhabdomeric photoreceptors.

PMID- 10356767
TI  - Sexual transmission of Borrelia garinii by male Ixodes persulcatus ticks (Acari,
      Ixodidae).
AB  - We investigated the transmission of Borrelia garinii and Borrelia afzelii between
      male and female Ixodes persulcatus ticks. For this purpose the infection rate of
      partners from tick couples was determined by polymerase chain reaction and
      reverse line blot. In couples, where the male tick was infected with B. garinii,
      four out of nine female partners carried B. garinii. In eight couples, male ticks
      had a dual infection of B. afzelii and B. garinii and three female partners were
      infected by Borrelia spirochetes. Two female ticks carried B. garinii, and one
      female tick had a dual infection. No evidence for transmission of B. afzelii from
      male to female ticks was found among seven couples. In 45 couples where the
      female tick was infected, not one male tick carried spirochetes. The difference
      in the B. garinii infection rate between male and female ticks among these
      couples is highly significant. Our data suggest that transmission of B. garinii
      from male ticks to female ticks does occur. Sexual transmission of this pathogen
      may play an important role in the maintenance of B. garinii in I. persulcatus.

PMID- 10356768
TI  - Anti-tick effects of Stylosanthes humilis and Stylosanthes hamata on plots
      experimentally infested with Boophilus microplus larvae in Morelos, Mexico.
AB  - The anti-tick effects of the tropical pasture legumes Stylosanthes humilis and
      Stylosanthes hamata were evaluated and compared with two common grasses,
      Cenchurus ciliaris and Andropogon gayanus, in the state of Morelos, Mexico, on
      plots experimentally infested with larvae of the tick Boophilus microplus. The
      effect was evaluated by recovery of larvae from the experimental plots by
      flagging during a 4 week period. The anti-tick effect due to Stylosanthes was
      significantly higher for S. humilis and S. hamata (p < 0.05) and slightly better
      for S. humilis (3% survival) than for S. hamata (12% survival). Further studies
      are required to determine the potential role of Stylosanthes plants for tick
      control in Mexico.

PMID- 10356770
TI  - Seasonal distribution of Rhipicephalus sanguineus ticks (Acari: Ixodidae) on dogs
      in an urban area of Morelos, Mexico.
AB  - Between 1993 and 1995, we examined 1742 dogs at two veterinary clinics in
      Cuernavaca City in Mexico for the presence of Rhipicephalus sanguineus ticks. The
      overall tick infestation prevalence was 20% and there were no significant
      differences (p > 0.05) between different years. The prevalence was somewhat
      higher in spring, summer and autumn (20% or more) than in winter (13.7%). A
      positive correlation (p < 0.01) was found between prevalence of ticks and
      rainfall in spring, summer and autumn, whereas in winter there was only a
      correlation with temperature. Different stages of the tick were found and it was
      calculated that 2.5 generations could be completed each year. It is concluded
      that the environmental conditions of Cuernavaca City favour development and
      maintenance of R. sanguineus ticks throughout the year and that its role as a
      vector of diseases poses a threat to dogs and may have potential zoonotic risks.

PMID- 10356769
TI  - Density of deer in relation to the prevalence of Borrelia burgdorferi s.l. in
      Ixodes ricinus nymphs in Rambouillet forest, France.
AB  - The Rambouillet Forest, a Lyme disease-endemic area near Paris, France, was
      surveyed from September 1994 to October 1995 to determine the risk periods and
      zones for humans. Firstly, during the period of Ixodes ricinus activity,
      abundance of nymphs is greater in spring than in autumn. Secondly, we observed
      significant variation in nymphal abundance between zones according to the density
      of cervids. The polymerase chain reaction (PCR) was used to detect DNA of
      Borrelia burgdorferi sensu lato in 461 unfed nymphs. DNA was detected in 38
      nymphs (8.2%). By genospecific PCR based on the OspA gene, we detected the three
      pathogenic spirochetes with occurrences of 10.3, 31.1 and 58.6 for B. burgdorferi
      s.s., Borrelia garinii and Borrelia afzelii, respectively, indicating that B.
      afzelii is probably the main Borrelia species in the Rambouillet Forest. Finally,
      11.5% of positive nymphs exhibited a double infection. Infection rates of I.
      ricinus nymphs by B. burgdorferi s.l. were not significantly different throughout
      the year for a given area, indicating that the risk periods of acquiring Lyme
      disease are mainly linked to nymph activity and correspond to spring and autumn.
      Likewise infection rates of nymphs were not significantly different between zones
      with a high density of deer (more than 100 animals per 100 ha) and zones with
      lower deer density (less than 20 animals per 100 ha). In addition to the role of
      deer as an amplifier of tick populations, these data indicate that zones with a
      high density of cervids should be considered as higher risk areas.

PMID- 10356771
TI  - Validation of short tandem repeat analysis for the investigation of cases of
      disputed paternity.
AB  - This study details validation of two separate multiplex STR systems for use in
      paternity investigations. These are the Second Generation Multiplex (SGM)
      developed by the UK Forensic Science Service and the PowerPlex 1 multiplex
      commercially available from Promega Inc. (Madison, WI, USA). These multiplexes
      contain 12 different STR systems (two are duplicated in the two systems).
      Population databases from Caucasian, Asian and Afro-Caribbean populations have
      been compiled for all loci. In all but two of the 36 STR/ethnic group
      combinations, no evidence was obtained to indicate inconsistency with Hardy
      Weinberg (HW) proportions. Empirical and theoretical approaches have been taken
      to validate these systems for paternity testing. Samples from 121 cases of
      disputed paternity were analysed using established Single Locus Probe (SLP) tests
      currently in use, and also using the two multiplex STR systems. Results of all
      three test systems were compared and no non-conformities in the conclusions were
      observed, although four examples of apparent germ line mutations in the STR
      systems were identified. The data was analysed to give information on expected
      paternity indices and exclusion rates for these STR systems. The 12 systems
      combined comprise a highly discriminating test suitable for paternity testing.
      99.96% of non-fathers are excluded from paternity on two or more STR systems.
      Where no exclusion is found, Paternity Index (PI) values of > 10,000 are expected
      in > 96% of cases.

PMID- 10356772
TI  - Medicolegal anthropology in France.
AB  - Medicolegal anthropology has a very long history in France. Basic studies on
      human skeletal remains started as early as the 18th century. The 19th century
      produced many medical theses and research papers on age, sex, as well as stature
      estimation. The research proliferated in the first 60 years of the 20th century,
      much of which is still in use in France and abroad. The later half of the 20th
      century, however, was dormant in research on human skeletal biology at a time
      when forensic anthropology was becoming an active field worldwide. In the last
      decade, medicolegal anthropology took a different perspective, independent of its
      traditional roots. Research and practice have both been in the professional
      domain of forensic physicians unlike the situation in many other countries.
      Population based studies requiring large databases or skeletal collections have
      diminished considerably. Thus, most research has been on factors of
      individualization such as trauma, time since death, crime scene investigation,
      and facial reconstruction. It is suggested that there is a need for cooperation
      between the forensic physician and anthropologist to further research. This also
      encourages anthropologists to carry out research and practice that can fulfill
      the needs of the medicolegal system of the country.

PMID- 10356773
TI  - Crime scene analysis and the escalation of violence in serial rape.
AB  - The current study examines the crime scene behavior manifest by 108 serial
      rapists responsible for the perpetration of 565 rapes across various cities
      within the US. The goal of the current study is to identify which aspects of
      crime scene behavior reported to law enforcement by the victim are most useful in
      predicting, early in a series of offenses, which rapists are most likely to
      escalate into higher and, at times, life threatening levels of violence. Using 58
      scales that quantify the verbal, physical, and sexual behavior manifest by a
      rapist in his interaction with his victim during his first reported rape and 36
      modal variables that summarized approach, timing, demographics, and weapon usage
      across the series of rapes, the study attempts to differentiate between those
      rapists who escalate in their use of blunt force (Increasers) from those who do
      not (Non-Increasers). A logistic regression indicates that rapists who are white
      rather than of minority status and who, at the time of their first reported rape,
      rape their victims for longer periods of time and use more profanity are more
      likely to escalate in their level of blunt force than those rapists who do not
      exhibit these behaviors. The relevance of this type of predictive framework for
      law enforcement in its attempts to prioritize particular investigations is
      discussed.

PMID- 10356774
TI  - Inquiries on intraspousal transmission of hepatitis C virus: benefits and
      limitations of genome sequencing and phylogenetic analysis.
AB  - During recent years, courts had to decide in some notable cases whether or not
      defendants infected the plaintiffs with HIV. Lawsuits on the transmission of
      other viral pathogens up to now have hardly become known. We report here on the
      use of genome sequencing and phylogenetic analysis to investigate possible
      intraspousal transmission of hepatitis C virus (HCV). The high degree of genetic
      relatedness observed in phylogenetic analysis among the HCV strains isolated from
      the couple demonstrates that the man and the woman are infected with the same
      isolate of the virus. After other plausible routes of infection have been
      virtually excluded by anamnestic and conventional epidemiological evaluation we
      could infer that the man most probably has infected his girlfriend with HCV. This
      conclusion was further supported by the finding that both are also infected with
      closely related isolates of GB virus C (GBV-C). Thus, the results from molecular
      biological investigations and epidemiological evaluation are complementary pieces
      of evidence in inquiries on possible intraspousal transmission of HCV.

PMID- 10356775
TI  - Genetic variation at six STR loci (HUMTH01, HUMTPOX, HUMCSF1PO, HUMF13A01,
      HUMFES/FPS, HUMVWFA31) in Aragon (north Spain).
AB  - The STR loci HUMTH01, HUMPTPOX, HUMCSF1PO, HUMF13A01, HUMFES/FPS and HUMVWFA31
      are widely used in forensic casework analyses and population data are necessary
      to estimate the frequency of a DNA profile. This paper presents the results of a
      survey aimed to investigate the allele frequency distribution of these loci in an
      important Spanish population (Aragon, North Spain). Statistical analysis to
      determine whether allele frequencies were in Hardy-Weinberg Equilibrium was
      carried out and also to obtain some parameters of medico-legal interest. There
      was no evidence of association between the alleles of the loci. The Aragonese
      sample does not differ substantially from other Caucasian populations.

PMID- 10356776
TI  - Population distribution of six PCR-amplified loci in Madeira Archipelago
      (Portugal).
AB  - Frequency data of the short tandem repeat (STR) loci HUMTH01, HUMVWA31/A,
      HUMF13A1, HUMFES/FPS, D12S391 and HUMFIBRA/FGA were determined in blood stains
      obtained from a population of unrelated individuals from the Madeira Archipelago.
      The observed genotype distribution showed no significant deviation from the Hardy
      Weinberg equilibrium and there was no evidence for association of alleles among
      the six loci. Population data showed a combined discrimination power of 0.9999998
      and a chance of exclusion of 0.99597. The frequencies are similar to those of
      other compared caucasian populations but significant differences were found
      between the Madeira population and Japanese, Chinese, Greenland Eskimos and
      Quechua Amerindians. The six loci studied, together proved to be highly
      discriminating and valuable for forensic cases.

PMID- 10356777
TI  - Chemical burn from alkaline batteries--a case report.
AB  - A 2-year-old male was found to have a third degree (full thickness) burn on his
      rear right thigh. The father discovered the burn at a physician's office where
      the child was being treated for an ear infection. The physician notified
      authorities of suspected physical child abuse.

PMID- 10356778
TI  - Drowning due to cyclobenzaprine and ethanol.
AB  - The deceased was a 35 year old female who was found by her husband in the bathtub
      with her head and face submerged in the water. Autopsy findings were
      unremarkable. Toxicological analysis revealed the presence of ethanol (215 mg/dL)
      and cyclobenzaprine (1.786 mg/l) in the blood. This high concentration of
      cyclobenzaprine (Flexeril) in combination with alcohol proved to be fatal.

PMID- 10356779
TI  - Fatal combined intoxication with new antidepressants. Human cases and an
      experimental study of postmortem moclobemide redistribution.
AB  - Three cases are presented in which death was caused by suicidal intoxication with
      moclobemide in combination with a selective serotonin reuptake inhibitor. Both
      antidepressant drug types are considered to be relatively safe with regard to
      lethal overdose. However, the combination may cause the serotonin syndrome, a
      condition with a high mortality rate. In one of the cases, there was clinical
      information consistent with the serotonin syndrome, in the two other cases, there
      was no information of the clinical course. Postmortem redistribution of the
      selective monoamine oxidase inhibitor moclobemide was investigated in a rat
      model. Postmortem concentrations in blood from the vena cava and the heart were
      found to be in good accordance with antemortem concentrations. Postmortem
      concentrations in vitreous humour and various tissues were also measured. The
      apparent volume of distribution was calculated to be 0.95 +/- 0.10 l/kg, which is
      in the same range as that reported in man.

PMID- 10356780
TI  - Paraquat myopathy: report on two suicide cases.
AB  - We describe two suicide cases in which old paraquat was ingested. In conjunction
      with lung involvement a pronounced degeneration was observed in skeletal muscle
      of one who died on the 14th day after the ingestion. The following sarcoplasmic
      or endoplasmic reticulum Ca2+ ATPase (SERCA) monoclonal antibodies were used for
      skeletal muscle fiber typing by an immunohistochemical method: NCL-SERCA1,
      reactive with type 2 fiber (fast-twitch), and NCL-SERCA2, reactive with type 1
      fiber (slow-twitch). The examination revealed that the remarkably degenerated
      fibers belonged to type 1 muscle fibers. This case showed an abrupt increase of
      plasma CK levels (1796 mU/ml) on the fifth day after the ingestion. The authors
      presume that the damage to the skeletal muscle had occurred in this period. The
      degeneration of the muscle seemed to be attributable to the long retention of
      paraquat in the tissue because these findings were not observed in the other case
      who died on the fifth day. Paraquat-induced myopathy may develop in prolonged
      paraquat poisoning. The examination of CK levels in plasma will be useful for
      diagnosis of damage of skeletal muscle.

PMID- 10356781
TI  - Unexpected death in persons with symptomatic epilepsy due to glial brain tumors:
      a report of two cases and review of the literature.
AB  - Two cases of unexpected death in persons with epileptic seizures due to a brain
      tumor are presented which encompassed an astrocytoma WHO grade II and an
      anaplastic astrocytoma WHO grade III. A 35-year-old man was found somnolent and
      disoriented at home. A computed tomography (CT) scan revealed a tumor of the
      right frontal lobe suggestive for an oligodendroglioma. During an angiographic
      examination the patient experienced an epileptic seizure. Some weeks later, the
      man was found dead in front of his house with a fresh bite mark of the tongue.
      Neuropathological examination revealed an astrocytoma WHO grade II of the right
      frontal lobe. A 47-year-old man plunged into a swimming-pool and was found
      submerged some minutes later. After resuscitation he survived comatose for 8 days
      but finally died due to severe hypoxic brain damage. He had been operated on a
      brain tumor of the temporal lobe 1 year before the accident. Neuropathological
      examination revealed residual tumor tissue at the operation site corresponding to
      an anaplastic astrocytoma WHO grade III. Although rare, death in persons with
      epileptic seizures due to brain tumors is an important mechanism of death
      encountered by the forensic pathologist.

PMID- 10356782
TI  - Fatal anaphylactic shock during a fluorescein angiography.
AB  - The Authors describe an extremely rare fatal case (sixth case in the literature)
      of anaphylactic shock following a fluorescein angiography. This is the first
      report in which the diagnosis of anaphylactic reaction to the dye was made
      through laboratory analyses. The diagnosis of fatal shock due to sodium
      fluorescein was made based on clinical, laboratory and immunohistochemical data.
      Mast-cell tryptase was dosed in serum and a pulmonary immunohistochemical
      evaluation was performed. Tryptase, a neutral protease of human mast-cells is a
      potentially important indicator of mast-cell involvement in anaphylactic events.

PMID- 10356783
TI  - Positive- and negative-ion mass spectrometry of non-steroidal antiinflammatory
      agents and their clean-up with Bond Elut Glass C18 from biological samples.

PMID- 10356784
TI  - Comments on "An unusual case of sexual assault on an infant: an intraperitoneal
      candle in a 20-month old girl".

PMID- 10356785
TI  - Cell-cell organization and functions of 'sinusoids' in liver microcirculation
      system.
AB  - Following much controversy through the first three decades in this century
      structure and function of hepatic sinusoids have been elucidated. The sinusoidal
      wall consists of endothelial cells, Kupffer cells, dendritic cells, NK cells (pit
      cells) and stellate cells. Using classic staining methods, immunocytochemistry,
      fluorescence microscopy, TEM and SEM, cell-cell organizations and functions of
      sinusoids have been studied. Based on observations, a new definition of the space
      of Disse was proposed.

PMID- 10356786
TI  - Electron microscopic observation on the parathyroid gland of the cardiomyopathic
      hamster (UM-X7.1 Syrian hamster).
AB  - The ultrastructure of the parathyroid gland (PTG) of the UM-X7.1 cardiomyopathic
      hamster (the UM-X7.1) was qualitatively and quantitatively compared with that of
      the normal hamster. In the UM-X7.1, the Golgi apparatus and rER were well
      developed compared with those of the control hamster. Morphometric analysis
      revealed that the mean values of the Golgi apparatus, rER and large vacuolar
      bodies were significantly greater in the UM-X7.1 than in the normal hamster and
      the mean value of lipid droplets was significantly less in the UM-X7.1 than in
      the normal hamster. Ultrastructurally, we consider that in the UM-X7.1, the
      synthesis and release of the parathyroid hormone may be activated by an excessive
      amount of circulating catecholamine, and the functional activity of the PTG may
      be higher than that in the normal hamster.

PMID- 10356787
TI  - Cellular roles in relapse processes of experimentally-moved rat molars.
AB  - This histological study was designed to clarify the relapse processes of rat
      molars following orthodontic tooth movement by the Waldo method. An elastic band
      was inserted between the upper first and second molars, and removed either 7 or
      21 days later. The relapse processes of first molars were examined at 1 or 4 days
      after completing the 7-day-insertion and at 5 or 10 days after the end of the 21
      day-insertion. At the end of the 7-day-insertion period, the mean interdental
      space was 158 microns, but decreased rapidly, reaching 44 microns by 1 day after
      removal, and 16 microns by day 4. In the periodontal ligament (PDL) compressed by
      elastic band insertion, partial hyalinization and/or mineralization occurred. The
      stretched PDL consisted of irregularly-distributed, thin principal fibres,
      approximately 2.4 microns in diameter. On days 1 and 4 after removal,
      osteoclasts, macrophage-like cells and fibroblast-like cells were localized
      around hyalinized tissues, but thick principal fibres, approximately 3.8 microns
      in diameter, were regularly distributed throughout the PDL proper. The mean
      interdental space after the 21-day-insertion was 536 microns, but this had
      decreased to 108 microns by day 5, and 71 microns by day 10. On day 5 after
      removal, numerous osteoclasts were evenly distributed in the compressed PDL,
      while thick principal fibres, approximately 3.5 microns, were present in the
      stretched PDL. These results suggest that, during relapse of experimentally-moved
      rat molars, (i) rapid remodelling of the PDL and surrounding alveolar bones is
      the main cause of tooth relapse and (ii) hyalinized and/or mineralized tissues
      occurred by compression are rapidly resorbed by osteoclasts, macrophage-like
      cells and fibroblast-like cells.

PMID- 10356788
TI  - Ultrastructural studies demonstrate that epithelial polarity is established in
      cultured mouse pre-Sertoli cells by extracellular matrix components.
AB  - The effect of three different substrates, laminin, fibronectin and reconstituted
      basement membrane, on isolated mouse pre-Sertoli cells maintained in vitro has
      been investigated. Cultures were monitored on a daily basis by phase contrast
      microscopy, and processed for light and electron microscopy at the end of the
      culture period. Extra-cellular matrix components have been found to influence
      Sertoli cell differentiation: both fibronectin and laminin promoted cell adhesion
      and differentiation, though laminin cultures showed poor viability. Pre-Sertoli
      cells cultured on reconstituted basement membrane showed the highest degree of
      differentiation, developing a polarized epithelial phenotype and forming cord
      like aggregates; such cultures provide a model system for the investigation of
      factors involved with gonadal differentiation.

PMID- 10356789
TI  - Abrasion of human enamel by brushing with a commercial dentifrice containing
      hydroxyapatite crystals in vitro.
AB  - Automatic toothbrushing with a commercial dentifrice containing hydroxyapatite
      (HAP) crystals was performed on the tangential polished surfaces of sound human
      enamel, mainly consisting of biological apatite similar to HAP, for 10 min in
      vitro. The X-ray diffraction peaks of HAP, brushite (DCPD), and monetite (DCP)
      crystals were detected from the dentifrice. After brushing, the enamel surfaces
      were observed with a scanning electron and a confocal scanning laser microscope.
      The brushing caused larger abrasive loss and more remarkable roughness of the
      enamel surfaces following the broad traces of brush bristles and the exposure of
      prism structures than brushing with a dentifrice containing only DCPD, which we
      previously reported. We claim that the fine granular-shaped HAP crystals of the
      dentifrice indicated as an active ingredient for preventing enamel caries possess
      stronger abrasivity of sound enamel than the DCPD and DCP as abrasives on account
      of their Mohs hardness values rather than sizes and shapes. The HAP crystals of
      dentifrices may not occlude the small defects of early caries enamel, but erode
      them more strongly as an abrasive than the other abrasives.

PMID- 10356790
TI  - Three-dimensional analysis of protein aggregate body in Saccharomyces cerevisiae
      cells.
AB  - Modified genes of peroxisomal isocitrate lyase of Candida tropicalis (CT-ICL)
      were constructed and expressed in Saccharomyces cerevisiae cells. We observed
      subcellular localization of expressed products of the mutant CT-ICL genes by
      immunoelectron microscopy. An unknown structure termed a protein aggregate body
      (PAB) storing the expressed product was observed in cytoplasm in various mutants
      (Kamasawa et al. (1996) J. Electron Microsc. 45: 491-497). We chose two typical
      cells harbouring the mutant ICL genes delta 550 and delta 237-339 to analyse the
      ultrastructure and three-dimensional (3D) structure of PABs. The PABs had a
      homogeneous matrix with a wavy periphery in the cell image using a high-pressure
      freezing fixation method. Although PABs could not be separated from the cytoplasm
      or mitochondria under a confocal fluorescence microscope, 3D reconstruction of
      serial electron micrographs clearly showed the PAB was an independent structure
      of varying size and had the shape of an incomplete sphere. A cell was sometimes
      observed to have multiple PABs.

PMID- 10356791
TI  - Highly specific detection of H2O2-dependent luminol chemiluminescence in
      stimulated human leukocytes using polyvinyl films.
AB  - When human polymorphonuclear leukocytes (PMN) were attached to glass coverslips,
      cells always spread and formed reactive oxygen species prior to any experimental
      stimulation. To avoid this, a polyvinylidine chloride film was used as an
      inactive substance to place the cells. Cells engaged in phagocytosis on the film
      exhibited a specific H2O2-mediated luminol chemiluminescence (LCL) at the cell
      particle interface; the cells stimulated with 12-O-tetradecanoylphorbol-13
      acetate became aggregated and the LCL was observed at the cell-cell contact.
      These results corresponded well with those obtained by an electron microscopic
      H2O2-demonstration method.

PMID- 10356792
TI  - Survival of Enterobacter cloacae and Pseudomonas paucimobilis in yoghurts
      manufactured from cow's milk and soymilk during storage at different
      temperatures.
AB  - The survival of two microbial contaminants, Enterobacter cloacae and Pseudomonas
      paucimobilis, in yoghurts manufactured from cow's milk and soymilk was
      investigated during storage for 45 days at 4 and 12 degrees C. Sensory panel
      tests performed before microbiological investigation, showed that the flavor of
      soy-yoghurts made with cocoa powder or malt added did not have the beany taste of
      soy beans. Both contaminants were significantly resistant to low pH values during
      storage for 32 days at 4 degrees C. The survival at 4 degrees C was remarkable in
      both plain and flavored yoghurts and a population close to 10(2) C.F.U./ml was
      observed after 38 days of storage. Experiments performed with soymilk yoghurts
      showed an enhanced survival of P. paucimobilis at 4 degrees C compared to the
      storage in cow's milk yoghurts; microbial values were close to 7-8 x 10(6)
      C.F.U./ml after 16 days. Soymilk exhibited a protective effect on L. delbrueckii
      subsp. bulgaricus and S. thermophilus at 12 degrees C and, compared to the
      survival in cow's milk yoghurts, a larger number of viable cells of both
      probiotic microorganisms (10(6) and 10(8) C.F.U./ml, respectively) were observed
      after 36 days of storage.

PMID- 10356793
TI  - Identification of bacteria using two degenerate 16S rDNA sequencing primers.
AB  - Two degenerate 16S rDNA primers have been designed for broad-range identification
      of eubacteria by PCR and automated sequencing. Using a simple method, the primers
      have proven useful in identification of proteobacteria (Campylobacter,
      Enterobacter, Escherichia, Helicobacter, Klebsiella), gram-positive bacteria
      (Mycobacterium, Staphylococcus, Streptococcus) and spirochetes (Borrelia) derived
      from clinical samples. In several cases, the samples could be identified at the
      species level.

PMID- 10356794
TI  - Co-operative effects of protein engineering and vector optimization on high yield
      expression of functional bivalent miniantibodies in Escherichia coli.
AB  - The volumetric yield of functional phosphocholine-binding miniantibodies could be
      increased in E. coli fermentations by the combination of the following
      approaches: Firstly, miniantibody mutants with amino acid exchanges in the VH
      chain leading to improved folding were expressed. Secondly, the expression vector
      was stabilized by an efficient suicide system to prevent plasmid loss. Thirdly,
      the cells were grown to high cell densities in a stirred tank reactor.

PMID- 10356795
TI  - Efficiency of a novel non-Shine-Dalgarno and a Shine-Dalgarno consensus sequence
      to initiate translation in Escherichia coli of genes with different downstream
      box composition.
AB  - The efficiency of a novel non-Shine-Dalgarno translational initiator
      (ACCUACUCGAGUUAG, denoted PL) to promote translation in Escherichia coli was
      compared with that of the Shine-Dalgarno (SD) consensus sequence (AAGGAGGU) using
      four reporter genes. The obtained results showed that the genes of pokeweed
      antiviral protein (PAP I) and human calcitonin (CT) were poorly expressed under
      the conventional SD and were better expressed under the PL sequence. On the
      contrary, the genes of human interferon gamma (hIFN gamma) and chloramphenicol
      acetyltransferase (CAT) were highly expressed under SD and poorly expressed under
      the PL sequence. Computer search revealed a great diversity between the four
      reporter genes in respect to their complementarity to E. coli 16S rRNA. PAP I and
      CT genes were rich in nucleotides matching 16S rRNA (called downstream boxes)
      whereas the complementary domains in the other two (hIFN-gamma and CAT) genes
      were much shorter. The different behavior of the four reporter genes when placed
      under the translational control of SD and PL sequences was explained by the
      different binding energy of their mRNAs to the 30S ribosomal subunit.

PMID- 10356796
TI  - Inducers of nod genes of Rhizobium ciceri.
AB  - Induction of nodABC genes of R. ciceri was studied by constructing nodABC-lacZ
      fusion. The root exudates of the homologous hosts induced the expression of
      nodABC genes but those of heterologous hosts failed to do so. The HPLC analysis
      of the root exudates of C. arietinum showed the presence of 6-7 compounds with
      retention times matching to flavonoids like naringenin, hesperetin, daidzein,
      naringin, 7 OH coumarin and luteolin. Induction studies using the standard
      flavonoids showed naringenin, followed by daidzein, as most potent inducer of the
      nodABC genes of R. ciceri. Naringenin in combination with daidzein showed a
      synergistic effect on the expression of nodABC genes.

PMID- 10356797
TI  - Mineralization of benzo[a]pyrene by Marasmiellus troyanus, a mushroom isolated
      from a toxic waste site.
AB  - Mycelia from the mushroom Marasmiellus troyanus were grown in the presence of
      radiolabeled benzo[a]pyrene in liquid culture. After 15 days, 8.1% of the label
      from M. troyanus cultures was recovered in CO2 as compared to 1.1% for
      Phanerochaete chrysosporium and 0.2% for Aspergillus niger. M. troyanus
      efficiently transformed B[a]P into water soluble metabolites with 64% of the
      label recovered in the water soluble fraction as compared to 11.7% for P.
      chrysosporium and 4.1% for A. niger. Glucuronic acid and sulfate conjugates of
      B[a]P were identified from the aqueous fraction of cultures of M. troyanus, after
      17 days.

PMID- 10356798
TI  - Mode of action of pesticides on aflatoxin biosynthesis and oxidase system
      activity.
AB  - The effects of nine pesticides on the biosynthesis of aflatoxin and oxidase
      activity in wild-type Aspergillus flavus and mutant strains of A. parasiticus avr
      1 (w 49) and A. parasiticus ver-1 (wh 1) were investigated. In A. parasiticus,
      phosphonic acid derivative (lancer) reduced the formation of aflatoxin B2 but B1,
      G1 and G2 and anthraquinones (versicolorin A, versiconal hemiacetal acetat and
      averufin) accumulated. Phosphorothioic acid derivatives (pirimiphos-methyl and
      pyrazophos) reduced the formation of aflatoxin B2 and G2 but B1 and G1 and
      anthraquinones accumulated. Phosphorodithioic acid derivatives (dimethoate and
      malathion) blocked aflatoxin B2, reduced B1 and G2 but G1 and anthraquinones
      accumulated. Phosphoric acid derivative (profenfos) inhibited the formation of
      all aflatoxins, versicolorin A and versiconal hemiacetal acetate but averufin
      accumulated. The phenylurea derivatives (linuron and pencycuron) at
      concentrations of 500 and 1000 ppm inhibited all aflatoxin but anthraquinones
      accumulated. On the other hand, the dicarboximide derivative (iprodione)
      inhibited the whole pathway in the mutant strains of A. parasiticus. The oxidase
      system in wild-type A. flavus was active in the conversion of averufin and
      versicolorin A into aflatoxin B1. Most organophosphate and phenylurea derivatives
      may competitively increase or decrease the oxidase enzymes, however, profenfos
      and iprodione blocked the enzymes between averufin and versicolorin A.

PMID- 10356799
TI  - cDNA cloning of a sorghum pathogenesis-related protein (PR-10) and differential
      expression of defense-related genes following inoculation with Cochliobolus
      heterostrophus or Colletotrichum sublineolum.
AB  - A sorghum cDNA clone was isolated by differential screening of a cDNA library
      prepared from mesocotyls (cultivar DK18) inoculated with fungal pathogenes. The
      deduced translation product shows sequence similarity to a family of
      intracellular pathogenesis-related proteins (PR-10) with a potential ribonuclease
      function. We studied the accumulation of PR-10 and chalcone synthase (CHS)
      transcripts in mesocotyls following inoculation with Cochliobolus heterostrophus
      or Colletotrichum sublineolum. CHS is involved in phytoalexin synthesis in
      sorghum. Coordinate expression of PR-10 and CHS genes was localized in the area
      of inoculation along with the accumulation of phytoalexins. C. heterostrophus is
      a nonpathogen of sorghum and cytological studies indicated that cultivar DK18 is
      resistant to C. sublineolum, a sorghum pathogen. We demonstrated that the two
      fungi triggered different time courses of plant defense reactions. Inoculation
      with C. heterostrophus resulted in rapid accumulation of PR-10 and CHS
      transcripts after appressoria had become mature. Accumulation of these
      transcripts was delayed in plants inoculated with C. sublineolum until
      penetration of host tissue had been completed and infection vesicles had formed.
      Results suggest that different recognition events are involved in the expression
      of resistance to the two fungi used or that C. sublineolum suppresses the
      nonspecific induction of defense responses.

PMID- 10356800
TI  - Polygalacturonase and polygalacturonase inhibitor protein: gene isolation and
      transcription in Glycine max-Heterodera glycines interactions.
AB  - The cell wall acts as the first line of defense during pathogen invasion.
      Polygalacturonases (PGs) are a class of cell-wall-modifying enzymes with precise
      temporal and organ-specific expression. A 350-bp fragment with high homology to
      PGs was identified by differential display (DD) analysis of soybean cyst nematode
      (SCN) race 3 resistant PI 437654 and susceptible cultivar Essex. The fragment was
      strongly expressed in Essex, 2 days after inoculation (DAI). Complete coding
      sequences of two PG cDNAs, PG1 and PG2, were isolated by 3' and 5' rapid
      amplification of cDNA ends polymerase chain reaction (RACE PCR). PI 437654 and
      Essex had identical PG1 and PG2 sequences. A transversion from A to C created a
      PstI restriction site in the PG2 cDNA that was used to distinguish the two PG
      cDNAs by cleaved amplified polymorphic sequence (CAPS) analysis. A cDNA encoding
      a polygalacturonase-inhibitor protein (PGIP) that is 89% identical to the
      Phaseolus vulgaris PGIP was isolated from soybean roots by reverse transcription
      (RT)-PCR. Steady-state levels of PG and PGIP were investigated by RNA gel blot
      analysis in roots 1 to 5 DAI and in hypocotyls and leaves. Differences in the
      constitutive levels of PG mRNAs were observed in roots of different soybean
      genotypes. Steady-state levels of PG mRNAs were enhanced during compatible
      interactions with SCN and reduced in incompatible interactions and in
      mechanically wounded roots. Enhanced PGIP transcription was observed in response
      to mechanical wounding in both PI 437654 and Essex, but only in compatible
      interactions with SCN, suggesting uncoupling of PGIP functions in developmental
      and stress cues. Constitutive expression in incompatible interactions shows PGIP
      is not a factor in SCN resistance. Thus, the up-regulation of endogenous PG
      transcription in soybean roots early after SCN infection could facilitate
      successful parasitism by SCN.

PMID- 10356802
TI  - The early nodulin gene MtN6 is a novel marker for events preceding infection of
      Medicago truncatula roots by Sinorhizobium meliloti.
AB  - MtN6 belongs to a series of cDNA clones representing Medicago truncatula genes
      transcriptionally activated during nodulation by Sinorhizobium meliloti (P.
      Gamas, F. de Carvalho Niebel, N. Lescure, and J. V. Cullimore, Mol. Plant-Microbe
      Interact. 9:233-242, 1996). We show here by in situ hybridization that MtN6
      transcripts specifically accumulate first at very localized regions in the outer
      root cell layers, corresponding to outer cortical cells containing preinfection
      threads. At later stages, MtN6 expression is observed ahead of growing infection
      threads, including in the infection zone of mature root nodules. Interestingly,
      regulation of MtN6 is clearly distinct from that of other early nodulins
      expressed in the same region of the nodule, in terms of response to bacterial
      symbiotic mutants and to purified Nod factors. We thus suggest that MtN6
      represents the first specific marker of a pathway involved in preparation to
      infection, which is at least partly controlled by Nod factors. Finally, we
      discuss the intriguing sequence homology shown by MtN6 to a protein from
      Emericella (Aspergillus) nidulans, FluG, that plays a key role in controlling the
      organogenesis of conidiophores (B. N. Lee and T. H. Adams, Genes Dev. 8:641-651,
      1994).

PMID- 10356801
TI  - Mutation in a gene required for lipopolysaccharide and enterobacterial common
      antigen biosynthesis affects virulence in the plant pathogen Erwinia carotovora
      subsp. atroseptica.
AB  - Spontaneous bacteriophage-resistant mutants of the phytopathogen Erwinia
      carotovora subsp. atroseptica (Eca) SCRI1043 were isolated and, out of 40, two
      were found to exhibit reduced virulence in planta. One of these mutants, A5/22,
      showed multiple cell surface defects including alterations in synthesis of outer
      membrane proteins, lipopolysaccharide (LPS), enterobacterial common antigen
      (ECA), and flagella. Mutant A5/22 also showed reduced synthesis of the exoenzymes
      pectate lyase (Pel) and cellulase (Cel), major virulence factors for this
      pathogen. Genetic analysis revealed the pronounced pleiotropic mutant phenotype
      to be due to a defect in a single gene (rffG) that, in Escherichia coli, is
      involved in the production of ECA. We also show that while other enteric bacteria
      possess duplicate homologues of this gene dedicated separately to synthesis of
      LPS and ECA, Eca has a single gene.

PMID- 10356803
TI  - Post-exposure prophylaxis: a new form of prevention?

PMID- 10356804
TI  - Disclosure of HIV status.
AB  - A significant proportion of HIV-infected persons choose not to disclose their
      status to sexual partners. Healthcare providers may play a role in motivating
      patients to disclose despite powerful forces working in favor of secrecy.

PMID- 10356805
TI  - Will the immune system ever recover?

PMID- 10356806
TI  - Ethical issues in AIDS vaccine development.

PMID- 10356807
TI  - An effective AIDS prevention program and why it is not enough.

PMID- 10356808
TI  - Unusual distributions of body fat in AIDS patients: a review of adverse events
      reported to the Food and Drug Administration.
AB  - This report summarizes postmarketing adverse events reported to the Food and Drug
      Administration (FDA) that describe unusual or abnormal fat distribution in
      association with anti-retroviral therapies. Reports associated will protease
      inhibitors were compared to those associated with non-protease inhibitor
      antiretroviral therapies. The Spontaneous Reporting System (SRS) and Adverse
      Event Reporting System (AERS) of the FDA MEDWATCH post-marketing surveillance
      system served as the database. Four protease inhibitors (saquinavir, indinavir,
      nelfinavir, and ritonavir) and seven nonprotease inhibitors (zidovudine,
      didanosine, zalcitabine, stavudine, lamivudine, nevirapine, and delavirdine) were
      searched for reports relating to: weight increase, unusual fat deposition,
      Cushing's syndrome, or Cushingoid appearance. Each drug was searched for its
      "life" from time of initial approval through a uniform database cutoff of March
      18, 1998. A total of 62 cases of abnormal fat accumulation were reported in
      association with one or several of the four approved protease inhibitors compared
      to three cases reported in association with the seven non-protease inhibitor
      based therapies. Case descriptions varied, and included abdominal fat
      accumulation, breast enlargement, thick necks, buffalo humps, multiple lipomatous
      growths, Cushingoid features, centralized fat redistribution, and mesenteric,
      omental, and retroperitoneal fat accumulation. Some subjects switched or stopped
      their antiretroviral therapy, others underwent surgery to remove the fat, and
      many considered their symptoms disabling. The pathophysiologic mechanism for
      these events remains unclear and a causal link to a specific drug or drug class
      is uncertain. Patients and clinicians reporting to the MEDWATCH system, however,
      have clearly associated the development of abnormal body fat with protease
      inhibitors as opposed to other antiretroviral therapies.

PMID- 10356810
TI  - HIV/AIDS case histories: diagnostic problems. Myelodysplasia in AIDS.

PMID- 10356809
TI  - Boosting social support in caregivers of children with HIV/AIDS.
AB  - Providing care for a child that is infected with human immunodeficiency virus
      (HIV) is challenging for the child's caregiver and affects the entire family
      system. Research has demonstrated that social support has the potential to buffer
      caregiver stress and facilitate caregiver coping. A two-group experimental study
      was implemented to test the effect of a social support boosting intervention on
      caregiver stress, coping and social support among caregivers of children with
      HIV/acquired immune deficiency syndrome (AIDS). The subjects in the study were
      caregivers of children with HIV/AIDS. The sample strata included seropositive
      caregivers (biological parents) and seronegative caregivers (foster parents and
      extended family members). The measures for the study included the Derogatis
      Stress Profile, The Family Crisis Oriented Personal Evaluation Scale, and the
      Tilden Interpersonal Relationship Inventory. These data were then analyzed
      descriptively and then with a repeated measure MANOVA. Initially, there were no
      statistically significant differences found between the control and intervention
      groups. However, when subject HIV status was included in the analysis, the
      combined dependent variables of stress, coping, and social support were
      significantly related to the interactions of group by HIV status over time. F
      values were then computed and no statistically significant differences were found
      for stress or coping. There were, however, significant differences in measures of
      social support between groups when adjusting for HIV status of caregivers. In
      this study, social support levels over time for seronegative caregivers were
      significantly different from those of seronegative caregivers in the control
      group. Three case studies are presented that illustrate differences between
      seronegative and seropositive caregivers. The case studies describe the problems
      identified by caregivers and the effectiveness of problem solving using the
      social support boosting intervention. Finally, the mobilization of social support
      is discussed. Contrasts between the problems of caregivers are made relative to
      their HIV status. The potential for the effectiveness of the social support
      boosting intervention is discussed within the context of the caregiver's HIV
      status.

PMID- 10356811
TI  - Updated data on amprenavir.

PMID- 10356812
TI  - Twice daily saquinavir.

PMID- 10356814
TI  - Stopping HAART.

PMID- 10356813
TI  - Aldesleukin shows promise.

PMID- 10356815
TI  - New nucleoside analog.

PMID- 10356817
TI  - First AIDS vaccine trial begins in Africa.

PMID- 10356816
TI  - Gel approved for KS.

PMID- 10356818
TI  - Clinical trial web site updated.

PMID- 10356819
TI  - Rates of unsafe sex and rectal gonorrhea rise.

PMID- 10356820
TI  - College survey reveals more wary attitude toward casual sex.

PMID- 10356821
TI  - CDC recommends procedures to reduce spread of TB from HIV-infected prisoners to
      the community.

PMID- 10356822
TI  - [Meningococcal infection. Immunologic aspects].

PMID- 10356823
TI  - [Technical report on breast feeding in Spain. Breast Feeding Committee of the
      Spanish Association of Pediatrics].

PMID- 10356824
TI  - [Antibody titer, immunologic memory and protective efficiency of the vaccine
      against Haemophilus influenzae type B. Vaccine Committee of the Spanish
      Association of Pediatrics].

PMID- 10356825
TI  - [Meningococcal sepsis and septic shock: efficient measures and controversial
      treatments].

PMID- 10356826
TI  - [Diagnosis of acute hematogenous osteomyelitis by ultrasound in pediatric
      patients].
AB  - OBJECTIVE: The objective of this study was to evaluate the efficacy of ultrasound
      in the diagnosis of acute hematogenous osteomyelitis of long bones in pediatric
      patients. PATIENTS AND METHODS: A prospective study was performed in a tertiary
      care pediatric hospital. During 12 months we prospectively studied 46 patients
      with the clinical diagnosis of acute hematogenous osteomyelitis (AHO) of long
      bones at the Hospital Nacional de Ninos in Costa Rica. In all patients ultrasound
      (US) was performed within 24-36 hours of admission, before any invasive diagnosis
      or therapeutic procedure was begun. RESULTS: In those without US findings, but
      with strongly suspected (AHO), a bone scan was done. Of these patients, 26/46
      (57%) was female. The mean age was 6.8 years. Sixty-five percent (30/46) had US
      findings compatible with AHO affecting the tibia (13), femur (11), humerus (4),
      and radius (2). The findings included subperiostic fluid (10), periosteal
      thickening (14), subperiostic abscess (6) and thickening of subcutaneous tissues
      (26). Patients were surgically drained and puss was obtained from the bone in all
      30. Two patients with negative US, but strongly suspected AHO had a bone scan
      that was negative. Patients with AHO were followed with US within 5-7 days of
      surgery and all 30 showed marked improvement. CONCLUSIONS: In this study, US
      showed 100% sensitivity and specificity for the diagnosis of AHO of long bones in
      pediatric patients. US are a sensitive and non-invasive procedure for the
      diagnosis and follow-up of AOH of long bones.

PMID- 10356827
TI  - [Prospective study with auditory evoked potentials of the brain stem in children
      at risk].
AB  - OBJECTIVE: The aim of this study was to evaluate methods of hypoacusis screening.
      PATIENTS AND METHODS: The early detection of audition problems is vital for quick
      rehabilitation. For this reason, resting on the criteria of the Comision Espanola
      para la Deteccion Precoz de la Hipoacusia (Spanish Commission for the Early
      Detection of Hypoacusis), we have carried out a prospective study, from January
      to May 1998, evaluating patients at risk of suffering from hypoacusis. The study
      included 151 patients with ages between birth and 14 years. Medical records and
      brainstem auditory evoked responses (BAER) were carried out. RESULTS: The most
      common reason for requesting a consultation for the 151 patients included in our
      study was the suspicion of hypoacusis. Seventy-one (47%) presented pathological
      BAER, 37 of them were bilateral. In most cases the loss of audition was of
      cochlear origin, with 11 patients having a serious deafness, 4 with bilateral
      affection (3 suspicious of hypoacusis and 1 of hyperbilirubinemia) and 7
      unilateral deafness. CONCLUSIONS: BAER is a good screening method for children at
      risk. It is an innocuous, objective and specific test that does not require the
      patient's collaboration. The level of positives is high (47%).

PMID- 10356828
TI  - [Urinary excretion of mucopolysaccharides in pediatric and adolescent patients].
AB  - OBJECTIVE: Lysosomal enzyme deficiency results in an accumulation of undegraded
      material producing structural and functional disorders. Mucopolysaccharidosis is
      a group of disorders caused by an increase in glycosaminoglycans (GAG)
      (mucopolysaccharides). Mucopolysaccharidosis, while showing a low incidence, has
      some clinical manifestations that warrant early diagnosis in order to establish
      immediate therapeutical action. Although definitive diagnosis is based on
      quantification of the involved enzymatic activity, it is necessary to have easy
      to use analytical methods available when there is clinical suspicion of the
      disease. PATIENTS AND METHODS: This study was made on a population of 632
      clinically normal adolescents and children (one month to 18 years of age). In all
      cases a partial sample of urine to quantify glycosaminoglycans and creatinine
      expressed as the index GAG/creatinine (mg/mmol) was collected. In a reduced group
      of 27 people a 24-hour urine sample was collected. Determination of
      glycosaminoglycan levels was performed with a colorimetric reaction with 1,9
      dimethylmethylene blue (DMB). Optimal condition of pH, wavelength and reaction
      time were established. The values found to be optimal for quantification were
      defined as pH 4.0, wavelength 528 nm and a reaction time of five minutes. Intra-
      and inter-assay coefficients of variation were less than 5%. RESULTS: Validity of
      the partial urine sample was established by obtaining a linear correlation
      between the 24 hour urine sample and the partial urine sample with a correlation
      coefficient of r = 0.89 (p < 0.0001). The results obtained have allowed the
      establishment of normal values ranging from an index GAG/creatinine of 8.70
      mg/mmol in the group aged 1 to 2 years to 1.34 mg/mmol in the group 17 to 18
      years of age, with a distribution of intermediate ages adjusted to a logarithmic
      function. There was a clear difference in the values obtained in urine of
      patients with clinical suspicion of mucopolysaccharidosis. CONCLUSIONS:
      Modifications in the spectrophotometric method using DMB as a colorant for
      quantification of glycosaminoglycans are presented. The feasibility, easy
      application and sensibility of this method, condition required for its widespread
      use, are confirmed. Normal reference values from a healthy population have been
      obtained and shown to be age dependent.

PMID- 10356829
TI  - [Effects of physical exercise on the cardiorespiratory system in children].
AB  - OBJECTIVE: Our aim was to perform a prospective study to evaluate the effects of
      competitive sports on the cardiorespiratory system and physical performance in
      children. PATIENTS AND METHODS: Male children aged 6 and 7 years were selected
      from a public school (PS) and from a soccer sports school (SS). They underwent
      anthropometrical measurement. Those boys who were further than one standard
      deviation from the 50th percentile were excluded from the study. A total of 74
      boys were selected with 41 being from the PS and 33 from the SS. Three different
      physical competitive activities were performed by the children. Hemodynamic
      measurements [heart rate (HR), systolic, mean and diastolic blood pressure (SBP,
      MBP and DBP)] and respiratory measurements [respiratory rate (RR), arterial
      oxygen saturation (SatO2), peak expiratory flow (PEF), forced expiratory volume
      in one second (FEV1), forced vital capacity (FVC), and the FEV1/FVC relationship]
      were taken before and after the physical activity. RESULTS: Overall we found a
      significantly higher physical performance in the SS group (p < 0.001). The HR
      before and after exercise was significantly lower in the SS group. The comparison
      between constants before and after physical activity in each group showed a
      significant increase in HR, SBP, MBP and DBP in the PS group, but there was no
      difference between the SBP before and after physical activity in the SS group.
      The SS group had a significantly lower RR and better SatO2 in the basal
      measurement. The relationship between constants before and after physical
      activity showed a rise in the PEF in the PS group and a decrease in the SatO2 in
      the SS group. CONCLUSIONS: We recommend controlled physical competitive activity
      in children because of its benefits on cardiorespiratory function and the absence
      of adverse effects.

PMID- 10356830
TI  - [Is it necessary to hospitalize so many children for so many days? Unnecessary
      pediatric hospitalization].
AB  - OBJECTIVE: A tendency exists towards an increase in hospital admissions of
      children whereas evidence shows that some of the admissions could have been
      avoided or the length of stays reduced. The aim of this study was to identify the
      proportion of unnecessary pediatric stays and the motive behind them. PATIENTS
      AND METHODS: Three hundred eighty-eight hospital stays of 151 children between 6
      months and 14 years of age which were discharged by the local pediatric hospital
      service have been reviewed. Patients and stays were selected at random.
      Admissions were stratified by age group and stays by episode length. The
      Pediatric Appropriateness Evaluation Protocol (PAEP) was used to evaluate the
      necessity of the hospital stay. RESULTS: Of the admissions, 27.8% (42/151) were
      evaluated as unnecessary, as were 48.7% (189/388) of the hospital stays. Long
      stays (except for hospitalizations longer than 9 days), programmed admissions
      (93.5%), first admissions to a hospital (59.9%) and admissions evaluated as
      unnecessary (80.6%) were significantly associated with unnecessary stays.
      Hospital organization and doctors' style of practice accounted for 74.1% of the
      unnecessary stays and children familiar circumstances for 21.7%. CONCLUSIONS: The
      high proportion of unnecessary stays and the motives, which explained them,
      justify the great concern about the criteria for the hospitalization of children
      and early discharge planning. To improve coordination among hospitals, central
      services, primary health care services and social services is probably required.

PMID- 10356831
TI  - [Clinical epidemiological study of lower respiratory tract illness with wheezing
      in children under 2 years of age and its risk factors].
AB  - OBJECTIVE: The objective of this study was to improve our knowledge of the main
      clinical and epidemiological characteristics of the lower respiratory tract
      illnesses with wheezing (LRTIW) in children under 2 years of age and its
      associated risk factors. PATIENTS AND METHODS: The clinical records of children
      born between January 1, 1988 and December 31, 1995 and controlled in a primary
      care center were reviewed. Two types of studies were carried-out: 1) A
      descriptive and retrospective study was performed where children diagnosed with
      LRTIW were selected and studied. Those patient meeting the criteria for
      McConnochie's bronchiolitis were also identified. 2) A case-control study was
      carried out where children affected with LRTIW were the cases and the rest
      controls. RESULTS: From 476 clinical records, 259 were included in the study.
      LRTIW was diagnosed in 101 children, with 261 episodes of illness and a median of
      2 (P25-75 = 1-4). Of this group, 96 had bronchiolitis and a mean age of 7.5 +/-
      4.7 months with ten 10 being hospitalized (mean age 2.7 +/- 1.4 months). The odds
      ratio for risk factors were as follows: premature birth (6.3), family history of
      asthma (4.1) or atopia (2.3), atopic dermatitis (3.4), older siblings (2.6), born
      in the second semester of the year (2), maternal smoking (2) and both parents
      smoking (2.4). No statistically significant differences were found for sex,
      breast-feeding or day-care attendance. CONCLUSIONS: Lower respiratory tract
      illnesses are frequent in children who are 0 to 2 years of age and have a
      positive relationship with some risk factors.

PMID- 10356832
TI  - [Anthropometric and nutritional study of full-term newborns. Evaluation of the
      submandibular adipose skinfold].
AB  - OBJECTIVE: We performed an anthropometric study in a series of normal full-term
      newborns to evaluate the discriminatory capabilities of the submandibular
      skinfold compared to other anthropometric parameters. MATERIAL AND METHODS: We
      studied 794 consecutive Caucasian newborns, 377 males and 471 females, with a
      mean gestational age of 39.5 +/- 0.9 weeks and adequate weights for age.
      Anthropometric variables analyzed included weight, length, left arm circumference
      and bicipital, tricipital, subscapular, suprailiac and submandibular skinfolds.
      Statistical analysis was performed by using the Student's t-test to evaluate
      differences between the different parameters and by Pearson's test to look for
      correlations among them. RESULTS: The weight and lengths of male newborns were
      significantly higher than those of female newborns (p < 0.005) These parameters
      showed differences with other series of newborns studied. Measurements of the
      tricipital, subscapular and suprailiac skinfolds were significantly different
      between males and females (p < 0.005); however, bicipital and submandibular
      skinfolds were not. The submandibular skinfold measurement highly correlated with
      the other skinfold measurements, especially with the bicipital measurement, in
      both males (0.536; p < 0.0001) and females (0.578; p < 0.001). Submandibular
      skinfold measurements also correlated with weight and arm circumference in both
      sexes. CONCLUSIONS: Some somatometric measurements in normal term newborns differ
      significantly between the sexes, especially weight, length and tricipital,
      subscapular and suprailiac skinfolds. The submandibular skinfold correlates well
      with weight, arm circumference and the four routinely measured skinfolds. This
      finding suggests that measurement of the submandibular skinfold should be
      included in the evaluation of the newborn's nutritional status.

PMID- 10356833
TI  - [Hyperbilirubinemia in full-term newborns. Predictive factors].
AB  - OBJECTIVE: Nowadays economical criteria lead to early maternal hospital
      discharge, even before 48 hours after labor, producing an increase in neonatal
      readmissions for hyperbilirubinemia. We tried to predict the healthy term
      newborns that may develop a significant hyperbilirubinemia (> or = 17 mg/dl in
      the first 4 days of life). METHODS: Bilirubin in umbilical cord blood,
      transcutaneous measurements of bilirubin at 24, 48 and between 60 and 96 hours of
      life and bilirubin in blood obtained from heel-sticks at 96 hours was analyzed in
      610 newborns. Moreover, serum bilirubin was determined at the same time-points in
      169 newborns submitted to blood extractions for different reasons. The
      transcutaneous bilirubinometer used was a Minolta/Air-Shields JM-102. RESULTS: A
      significant hyperbilirubinemia was present in 2.95% of the newborns. The
      correlation between serum and transcutaneous bilirubin was high (r = 0.92; p <
      0.0001). Umbilical cord blood bilirubin with a cut-off point of 2.2 mg/dl was not
      an useful predictor of neonatal jaundice. At 24 and 48 hours of life serum
      bilirubin levels > or = 6 mg/dl and > or = 9 mg/dl, respectively, predicted a
      subsequent hyperbilirubinemia with a sensitivity of 100% at both time-points,
      specificity of 47.5% and 64.3%, positive predictive value of 7.3% and 16.4%,
      respectively, and a negative predictive value of 100% for both. Transcutaneous
      measurement at 48 hours with a cut-off point of 13 (equivalent to a bilirubinemia
      of 9 mg/dl) predicts hyperbilirubinemia with a sensitivity of 94.4%, specificity
      of 51.7%, positive predictive value of 6.0% and negative predictive value of
      99.6%. CONCLUSIONS: If the newborn presents a bilirubinemia > or = 6 mg/dl at 24
      hours and > or = 9 mg/dl or a transcutaneous measurement > or = 13 at 48 hours a
      new bilirubin measurement must be performed between 48 and 72 hours of life.

PMID- 10356834
TI  - [Combined hereditary coagulation factor deficiencies: familial study of two type
      I cases (familial multiple coagulation factor deficiency type I)].

PMID- 10356835
TI  - [Results of treatment with oral citrate and pyridoxine in patients with primary
      hyperoxaluria type 1].

PMID- 10356836
TI  - [Ectopic pancreas associated with antropyloric membrane].

PMID- 10356837
TI  - [Microcephaly and severe brain atrophy in a monochorionic twin pregnancy].

PMID- 10356838
TI  - [Non-ketotic hyperglycinemia: clinical and therapeutic course in three patients].

PMID- 10356839
TI  - [What is your diagnosis? Midline thoracic defect].

PMID- 10356840
TI  - [Anisakiasis in incarcerated epigastric hernia].

PMID- 10356841
TI  - Comparison of two methods for destruction of biological material for
      determination of selenium.
AB  - The purpose of the study was to compare two methods for destruction of biological
      material for selenium (Se) analysis: wet digestion by conductive heating in
      programmed digestion block and digestion in microwave oven. In both methods
      samples were prepared in a closed system using nitric acid. Selenium was analysed
      by electrothermal atomic absorption spectrometry. The results have shown that
      both methods are convenient for complete mineralisation and are accurate in
      determining selenium in a variety of foodstuffs. Microwave digestion, however,
      has the advantage of speed and simplicity over the conventional heating
      procedure.

PMID- 10356842
TI  - Development in harmonisation of proficiency testing (for vapours, gasses, and
      dusts) in the European Union.
AB  - A network has been established of the 11 major proficiency schemes in the
      European Union concerned with the occupational hygiene and environmental analyses
      of chemicals and dusts in the air. A comparison of all the schemes was carried
      out and a compendium is being produced. This will allow users of the schemes such
      as testing laboratories, customers, and regulatory bodies to choose the scheme
      that is most suited to their purpose. All schemes have been compared with the
      revised ISO Guide 43, published in 1997. The performance statistics in most
      schemes conform to the criteria in European Standard EN 482 that define the
      acceptability limits for overall uncertainty in measurement. However, the
      performance statistics and assessment strategies of the different schemes vary.
      While many of the schemes supply similar sample material such as lead on filters
      and benzene on charcoal, there are a number of sample types that many schemes
      would like to introduce. However, it would be uneconomic to do this on a national
      basis and the network is developing procedures to introduce them throughout the
      member countries. Additionally, there are countries that have no schemes at
      present and may wish to introduce them. The network will provide a framework to
      help set up schemes in these areas.

PMID- 10356843
TI  - Significance of the quality of Florisil in organochlorine pesticide analysis.
AB  - During the analysis of chlorinated pesticides in animal fat tissue applying the
      matrix solid-phase dispersion method, and notwithstanding the use of a gas
      chromatograph with a highly selective capillary column, two peaks occur: one with
      a retention time very similar to that of lindane, and the other almost identical
      to that of dieldrin. Repeated analyses of the same sample with a GC/MS system
      revealed that neither lindane nor dieldrin were present. It was proven that those
      peaks resulted from florisil of local origin used for analysis, but not from the
      original Florisil. The removal of the first peak ("lindane") was possible through
      heating of florisil of local origin at 680 degrees C for 4 hours, whereas some
      other method would be required for the removal of the other peak ("dieldrin").
      The incident proved that, in such demanding analyses, it is extremely important
      to use original, high quality substances to avoid possible interference and
      misinterpretation of results.

PMID- 10356844
TI  - Comparison of two extraction procedures for determination of trace metals in soil
      by atomic absorption spectrometry.
AB  - The study compares nitric acid and ethylenediaminetetraacetic acid (EDTA)
      extraction of forest soils for the analysis of trace metals Fe, Mn, Zn, Cu, Pb,
      and Cd. Fifty forest soil samples from ten different locations were extracted
      using both methods. The two extraction procedures were compared through
      regression analysis for each element. All elements were analysed by flame atomic
      absorption spectrometry method (AAS). The results show that both extracting
      procedures are only partially effective for most of the measured trace elements
      in soil. The extraction with diluted HNO3 was incomplete, as large amounts of
      siliceous material remained undigested. Recoveries obtained by this method for
      Fe, Mn, Zn, Cu, Pb, and Cd on certified reference material (San Joaquin Soil)
      were 34, 79, 47, 56, 71, and 102%, respectively. EDTA extraction was even less
      effective and is considered to reflect the quantity of bioavailable metals. The
      respective recoveries were 2, 45, 7, 20, 38 and 74%. The regression analyses
      performed for EDTA-extractable vs. HNO3-extractable metals of forest soils showed
      high and significant correlation for all examined metals, except Fe.

PMID- 10356845
TI  - Validation of microwave digestion method for determination of trace metals in
      mushrooms.
AB  - A microwave digestion method for mushrooms, developed in the study, allows fast
      preparation of samples and reduces the contamination risk in the process of
      determining trace metals. Concentrations of six trace elements, Fe, Mn, Cu, Zn,
      Pb, and Cd were measured in 50 samples of different species of edible mushrooms
      (fam. Boletaceae) using atomic absorption spectrometry after microwave and dry
      ashing procedure. The methods were validated through certified Standard Reference
      Material SRM 1577b (Bovine Liver) which was treated and analysed using the same
      procedures as for the mushrooms. The samples were either digested with
      concentrated HNO3 in closed Teflon PFA vessels in a microwave oven, or ashed in
      quartz crucibles at 450 degrees C. The respective recoveries of Fe, Mn, Zn, Cu,
      Pb, and Cd obtained by measuring SRM were 112, 107, 104, 115, 111 and 95% after
      microwave digestion procedure and 86, 101, 109, 111, 98, and 110% after dry
      ashing procedure. The correlation between concentrations obtained by the two
      different methods of sample preparation was high for all metals.

PMID- 10356847
TI  - Standardised methods--tools for mutual understanding and integration into global
      society.
AB  - The paper presents basic concepts, terms, and their definitions in the field of
      standardisation--standard, international standard, national standard, testing
      standard, test report, and proficiency testing according to the ISO/IEC Guide
      2:1996. The paper also explains the role of voluntary standards in the process of
      technical harmonisation. National adoption and implementation of international
      testing standards facilitates testing, comparison of test reports, and any
      proficiency testing, and can promote their global recognition. This can be
      recognised as a step toward creation of the global society. The Croatian
      "approach" to these activities is given attention in the light of globalisation
      and efforts made in establishment of Croatian standardisation infrastructure.

PMID- 10356846
TI  - Decomposition of fish samples for determination of mercury.
AB  - The aim of the study was to compare the efficiency of acid and alkaline
      decomposition of biological materials using an open and a closed system for total
      mercury determination. Acid digestion was performed with concentrated HNO3 in
      tubes at 80 degrees C and lasted five hours. Alkaline digestion was performed
      with a 45% NaOH and a 1% cysteine, heated at 120 degrees C for 20 minutes. Total
      mercury was measured by atomic absorption spectrometry using the cold vapour
      technique (CVAAS). The average recovery obtained for analysis of certified
      reference material in closed tubes for acid digested sample was superior to the
      alkaline one, 103 +/- 4% vs. 70 +/- 3%, respectively. In addition, the recoveries
      through the open system acid digestion (90 +/- 8%) and the open system alkaline
      digestion (57 +/- 2%) were lower than through the respective closed system
      digestions. Reproducibility of the acid decomposition method was superior to the
      alkaline one.

PMID- 10356848
TI  - Validation of analytical methods and laboratory procedures for chemical
      measurements.
AB  - Method validation is a key element in the establishment of reference methods and
      in the assessment of a laboratory's competence in producing reliable analytical
      data. Hence, the scope of the term "method validation" is wide, especially if one
      bears in mind the role of Quality Assurance/Quality Control (QA/QC). The paper
      puts validation in the context of the process generating chemical information,
      introduces basic performance parameters included in the validation processes, and
      evaluates current approaches to the problem. Two cases are presented in more
      detail: the development of European standard for chlorophenols and its validation
      by a full scale collaborative trial and the intralaboratory validation of a
      method for ethylenethiourea by using alternative analytical techniques.

PMID- 10356850
TI  - New audiology certification standards: what they mean to you.

PMID- 10356849
TI  - Quality assurance in aquatic biology--a user's perspective.
AB  - The essential elements of developing biological quality assurance systems are
      presented in terms of the 4M principles. These relate to methods, manpower,
      materials, and machines. The use of international or European standards is
      recommended where such standards exist. Users must be sure that these are
      appropriate to their specific needs as standardisation can require considerable
      compromise. Examples of limitations in international standards are given with
      reference to the coliform isolation by membrane filtration, Daphnia magna acute
      toxicity test and the luminescent bacteria test. The criteria for the selection
      and use of national methodologies are considered using macroinvertebrate,
      macrophytes, imposex, and the oyster embryo bioassay as examples. In recognising
      that the main resource in science is the skill, training, and dedication of the
      scientists themselves, the United Kingdom has developed a quality initiative
      aimed at best utilising the human resource, the so-called Investors in People
      (IIP) initiative. This contains the essential elements of any quality system:
      commitment, planning, action, and evaluation. Quality aspects of the materials
      and the machines used in biological analyses are briefly considered.

PMID- 10356852
TI  - Why can't my computer count? And other questions for Y2K.

PMID- 10356851
TI  - New & emerging technologies. Going where we've never gone before.

PMID- 10356853
TI  - Pediatric audiology: poised for the future. Interview by Susan Boswell.

PMID- 10356854
TI  - Earliest intervention: speech-language pathology services in the neonatal
      intensive care unit.

PMID- 10356855
TI  - The System for Augmenting Language (SAL) and Project FACTT: a two-way
      partnership.

PMID- 10356856
TI  - Hearing aids for children.

PMID- 10356857
TI  - Ethical issues in randomized clinical trials.

PMID- 10356858
TI  - [Passive smoking].

PMID- 10356859
TI  - [Giving women the floor].

PMID- 10356860
TI  - [Italian Cystic Fibrosis Registry: 10 years of activity].
AB  - Cystic Fibrosis (CF) is a recessive autosomic genetic disease with an incidence
      in mediterranean countries of about 1:3500 born alive. In Italy the considerable
      genetic variability makes it difficult to identify all the homozygous subjects
      and, consequently, to estimate the incidence of the disease in healthy carriers.
      The disease is evolutive and affects various systems, most of all the respiratory
      and gastrointestinal systems. Not many years ago, when the clinical definition of
      CF was first introduced, average survival did not exceed the pediatric age.
      Nowadays with ever advancing diagnostic and therapeutical techniques many CF
      patients survive until an adult age. It is therefore necessary to plan adequate
      health service interventions so as to satisfy as much as possible the needs of
      both the patients and their families. To this end data collected since 1.1.1988
      by the Italian registry for CF (year of birth, sex, region of birth and
      residence, diagnosis procedures, results of sweat test, pancreatic insufficiency,
      DNA analysis, status: alive, dead, lost to follow up) of all the patients,
      diagnosed in the 18 Reference Centres and the 3 local Centres for CF, have proved
      to be extremely useful. Since the birth of the Registry on 31.12.1997, data
      relating to 2458 patients alive on 1.1.1988 and 1159 born during the last ten
      years, for a total of 3617 subjects (1756 females and 1861 males), have been
      recorded. As already mentioned a considerable increase in life expectancy of CF
      patients (from 1988 to 1990 the average age of death was 14 years, from 1994 to
      1997 it was 19) and a consequent increase in the percentage of adult patients
      have been observed.

PMID- 10356861
TI  - [Differences in in-hospital mortality in patients treated with aortocoronary
      bypass for cardiopathic ischemia, Rome 1996].
AB  - Data from Health Information Systems (HIS) have been used in recent years to
      evaluate effectiveness and quality of care. We analyzed in-hospital mortality
      occurring within 30 days following operation among 1984 patients (age > or = 35
      yrs, males 84%) who underwent Coronary Artery Bypass Graft (CABG) surgery in
      seven hospitals in Rome in 1996. Data were extracted from the Lazio HIS run by
      the Regional Health Authority. The HIS database includes up to four diagnoses and
      surgical procedures (ICD-9); the following variables were considered a priori
      risk factors: type of ischemic disease, comorbidities, and others surgical
      interventions during the same admission. Logistic regression was performed in
      order to evaluate the association between hospital and risk of mortality after
      adjusting for potential confounders (ORs and 95% CI). The overall in-hospital
      mortality was 4.7% (ranged from 0.0 to 14.7%). Predictors of outcome included:
      older age, acute myocardial infarction, chronic myocardial ischemia, other heart
      diseases, chronic renal diseases, peripheral vascular diseases, other heart and
      vascular interventions. Statistically significant variability in mortality was
      observed across hospitals; taking hospital A as reference, hospitals D and E
      showed the highest risks (OR = 6.36 and OR = 3.12, respectively). We conclude
      that the observed differences in mortality rates among hospitals cannot be
      explained by differences in case mix, nor by varying coding styles. They are
      likely to reflect differences in currently unknown aspects of patient care.

PMID- 10356862
TI  - [Tuberculosis in Italy: available data and open questions].
AB  - OBJECTIVES: To describe the epidemiological trend of tuberculosis (TB) in Italy.
      DESIGN: Descriptive study on the basis of routine information sources: TB deaths
      (1955-1993) and TB notifications (1955-1995). To identify persons with AIDS
      (PWAs) among notified TB cases, a record linkage with the National AIDS Registry
      was performed. RESULTS: From 1955 to 1993, the TB mortality constantly decreased
      by a mean of 7.6% per year. From 1955 to 1995, the crude annual total incidence
      of TB decreased from 25.26 to 9.12 per 100,000. The trend of decrease of
      pulmonary TB ceased in 1980, whereas the incidence of extrapulmonary TB began to
      markedly increase in 1980. Between 1992 and 1995, the average annual meningitis
      notification rate in children < five years was 0.045 per 100,000. In 1995, the
      curve of incidence rates by age shows two peaks (> 75 years and 25-34 years).
      Persons with AIDS and foreigner-born persons represented in total 11.3% of TB
      cases (1992-1995); in the age class 25-34 years, this proportion was 32.5% (34.1%
      in 1995). A considerable undernotification of TB among PWAS was detected.
      CONCLUSION: The TB incidence is no longer decreasing due to the changes of TB
      case definition in 1987 and the.

PMID- 10356863
TI  - [Evaluation of the impact of guidelines for rationalizing the prescription of
      preop tests for patients ASA 1 and 2 undergoing elective surgery].
AB  - OBJECTIVES: To evaluate the impact of implementation of guidelines aimed at
      reducing the use of laboratory and diagnostic preoperative tests in patients with
      low anesthesiologic risk, admitted to six public hospital of Ente Ospedaliero
      Cantonale in Cantone Ticino (Switzerland). DESIGN: Observational study. METHODS:
      Time series analysis of patterns of use of preoperative tests, on 14,585 patients
      admitted to public hospitals form March 1996 to June 1998. PRINCIPAL OUTCOME
      MEASURE: Proportion of patients undergoing a laboratory or other diagnostic tests
      during three six months periods before guidelines implementation (baseline),
      during the six months of the implementation phase and during the following four
      months of adoption of the guidelines in the participating centres. RESULTS:
      During the four months following the implementation, we observed a reduction of
      15% (95% CI: 1%-27%) in the use of azotemia, and a reduction of 34% (95% CI: 18%
      50%) for coagulation tests. Corresponding figures for glycemia and chest x-ray
      indicated a reduction of 44% (95% CI: 32%-54%) and of 22% (95% CI: 8%-34%),
      respectively. As for other tests (creatinine, ECG), no statistically significant
      reduction was observed. Most of the observed effect was explained by a reduction
      in use in patients at a low risk (ASA 1 and 2). In addition, guidelines appeared
      to have a greater impact in the four small (i.e. < 200 beds) hospitals, as
      compared with the two centres of greater size. CONCLUSIONS: Consistently with the
      empirical evidence available in this area, this study suggests that guidelines
      can change clinical practice, when they are implemented through a strategy taking
      into account adaptation of the recommendations to local circumstances and
      involvement of health professionals.

PMID- 10356864
TI  - [How have opinions of medical oncologists changed regarding compared guidelines?
      Findings from two surveys conducted in 1993-1997].
AB  - OBJECTIVES: To assess changes in physicians' attitudes toward practice guidelines
      and towards the role of empirical evidence in the development of recommendations
      for clinical practice. DESIGN: Comparison of findings from two surveys carried
      out in Italy in 1993 and 1997 on the same random sample of 300 physicians from
      two specialty societies dealing with cancer care. RESULTS: As for goals, the only
      change was the increasing (from 26% in 1993 to 40% in 1997; p = 0.010) number of
      physicians indicating cost containment. More clinicians (43% in 1993 vs 58% in
      1997; p < 0.01) stated that guidelines should be based primarily on empirical
      evidence, rather than on clinical experience, and that the Ministry of Health
      should have a role in issuing guidelines (from 21% in 1993 to 46% in 1997; p <
      0.001). Physicians supporting the participation of representatives from outside
      the medical profession in developing guidelines increased from 6% in 1993 to 26%
      in 1997 (p < 0.001) for consumers, from 24% to 38% (p = 0.015) for patients, and
      from 16% to 33% (p = 0.003) for health care administrators. CONCLUSIONS: Overall,
      these changes indicate that an increasing number of clinicians acknowledge the
      role of empirical evidence and the need for a confrontation with other
      professional and societal components as to what should be done in clinical
      practice.

PMID- 10356865
TI  - [Body weight as a predictor of bone mass in women].

PMID- 10356866
TI  - [Establishment of "epidemiological statistics" as a discipline in the national
      health sector. Opinions: Italian Epidemiological Association].

PMID- 10356867
TI  - COS, case-only-study on breast cancer before the age of 40. Announcement of a new
      study on gene-environment interaction in breast cancer.

PMID- 10356868
TI  - A stochastic model of the electrically stimulated auditory nerve: single-pulse
      response.
AB  - Most models of neural response to electrical stimulation, such as the Hodgkin
      Huxley equations, are deterministic, despite significant physiological evidence
      for the existence of stochastic activity. For instance, the range of discharge
      probabilities measured in response to single electrical pulses cannot be
      explained at all by deterministic models. Furthermore, there is growing evidence
      that the stochastic component of auditory nerve response to electrical
      stimulation may be fundamental to functionally significant physiological and
      psychophysical phenomena. In this paper we present a simple and computationally
      efficient stochastic model of single-fiber response to single biphasic electrical
      pulses, based on a deterministic threshold model of action potential generation.
      Comparisons with physiological data from cat auditory nerve fibers are made, and
      it is shown that the stochastic model predicts discharge probabilities measured
      in response to single biphasic pulses more accurately than does the equivalent
      deterministic model. In addition, physiological data show an increase in
      stochastic activity with increasing pulse width of anodic/cathodic biphasic
      pulses, a phenomenon not present for monophasic stimuli. These and other data
      from the auditory nerve are then used to develop a population model of the total
      auditory nerve, where each fiber is described by the single-fiber model.

PMID- 10356869
TI  - A stochastic model of the electrically stimulated auditory nerve: pulse-train
      response.
AB  - The single-pulse model of the companion paper [1] is extended to describe
      responses to pulse trains by introducing a phenomenological refractory mechanism.
      Comparisons with physiological data from cat auditory nerve fibers are made for
      pulse rates between 100 and 800 pulses/s. First, it is shown that both the shape
      and slope of mean discharge rate curves are better predicted by the stochastic
      model than by the deterministic model. Second, while interpulse effects such as
      refractory effects do indeed increase the dynamic range at higher pulse rates,
      both the physiological data and the model indicate that much of the dynamic range
      for pulse-train stimuli is due to stochastic activity. Third, it is shown that
      the stochastic model is able to predict the general magnitude and behavior of
      variance in discharge rate as a function of pulse rate, while the deterministic
      model predicts no variance at all.

PMID- 10356870
TI  - Analog circuits for modeling biological neural networks: design and applications.
AB  - Computational neuroscience is emerging as a new approach in biological neural
      networks studies. In an attempt to contribute to this field, we present here a
      modeling work based on the implementation of biological neurons using specific
      analog integrated circuits. We first describe the mathematical basis of such
      models, then present analog emulations of different neurons. Each model is
      compared to its biological real counterpart as well as its numerical computation.
      Finally, we demonstrate the possible use of these analog models to interact
      dynamically with real cells through artificial synapses within hybrid networks.
      This method is currently used to explore neural networks dynamics.

PMID- 10356871
TI  - Theory of multichannel magnetic stimulation: toward functional neuromuscular
      rehabilitation.
AB  - Human excitable cells can be stimulated noninvasively with externally applied
      time-varying electromagnetic fields. The stimulation can be achieved either by
      directly driving current into the tissue (electrical stimulation) or by means of
      electro-magnetic induction (magnetic stimulation). While the electrical
      stimulation of the peripheral neuromuscular system has many beneficial
      applications, peripheral magnetic stimulation has so far only a few. This paper
      analyzes theoretically the use of multiple magnetic stimulation coils to better
      control the excitation and also to eventually mimic electrical stimulation.
      Multiple coils allow electronic spatial adjustment of the shape and location of
      the stimulus without moving the coils. The new properties may enable unforeseen
      uses for peripheral magnetic stimulation, e.g., in rehabilitation of patients
      with neuromuscular impairment.

PMID- 10356872
TI  - Quantification of force abnormalities during passive and active-assisted upper
      limb reaching movements in post-stroke hemiparesis.
AB  - We evaluated a method for measuring abnormal upper-limb motor performance in post
      stroke hemiparetic subjects. A servomechanism (MIME) moved the forearm in simple
      planar trajectories, directly controlling hand position and forearm orientation.
      Design specifications are presented, along with system performance data during an
      initial test of 13 stroke subjects with a wide range of impairment levels.
      Performance of subjects was quantified by measuring the forces and torques
      between the paretic limb and the servomechanism as the subjects relaxed
      (passive), or attempted to generate force in the direction of movement (active).
      During passive movements, the more severely impaired subjects resisted movement,
      producing higher levels of negative work than less-impaired subjects and
      neurologically normal controls. During active movements, the more severely
      impaired subjects produced forces with larger directional errors, and were less
      efficient in producing work. These metrics had significant test-retest
      repeatability. These motor performance metrics can potentially detect smaller
      within-subject changes than motor function scales. This method could complement
      currently used measurement tools for the evaluation of subjects during recovery
      from stroke, or during therapeutic interventions.

PMID- 10356874
TI  - Enhancement of spectral analysis of myoelectric signals during static
      contractions using wavelet methods.
AB  - In this paper, we introduce wavelet packets as an alternative method for spectral
      analysis of surface myoelectric (ME) signals. Both computer synthesized and real
      ME signals are used to investigate the performance. Our simulation results show
      that wavelet packet estimate has slightly less mean square error (MSE) than
      Fourier method, and both methods perform similarly on the real data. Moreover,
      wavelet packets give us some advantages over the traditional methods such as
      multiresolution of frequency, as well as its potential use for effecting time
      frequency decomposition of the nonstationary signals such as the ME signals
      during dynamic contractions. We also introduce wavelet shrinkage method for
      improving spectral estimates by significantly reducing the MSE's for both Fourier
      and wavelet packet methods.

PMID- 10356873
TI  - Innovative ambulatory drug delivery system using an electrolytic hydrogel
      infusion pump.
AB  - This report describes an ambulatory infusion device developed to provide
      parenteral drug delivery at a precisely controlled rate. The device is based on
      the innovative and unique concept of utilizing electrohydrolysis of a negatively
      charged hydrogel. The system consists of two modules: a pump unit and an
      electronic control unit. The pump module, which can be a disposable unit,
      contains medication separated by a flexible membrane from a gas generating
      chamber; this latter is an electrolytic cell comprising a hydrogel block and two
      platinum electrodes. The microcontroller-based control module is constructed with
      a user interface which includes input keys and a liquid crystal display, as well
      as a control to alter driving current level, depending on the infusion rate
      required. A microprocessor instantaneously calculates the current level required;
      this is based on operator-selected infusion rate, ambient pressure, and
      temperature sensor output. The accuracy and precision of the device were verified
      for all flow rates and for different environmental conditions; in vitro test
      results showed acceptable accuracy with less than +/- 5% error over the whole
      operating range of 0.1-100 [ml/h]. The device is small, lightweight, simple and
      easy to manufacture, and is also designed to be comfortably and conveniently worn
      by patients. It can be used for a variety of regimens including, for example,
      chemotherapy, insulin delivery, and pain management, antibiotic and AIDS therapy.

PMID- 10356875
TI  - Decomposition of multiunit electromyographic signals.
AB  - We have developed a comprehensive technique to identify single motor unit (SMU)
      potentials and to decompose overlapped electromyographic (EMG) signals into their
      constituent SMU potentials. This technique is based on one-channel EMG recordings
      and is easily implemented for many clinical EMG tests. There are several distinct
      features of our technique: 1) it measures waveform similarity of SMU potentials
      in the wavelet domain, which gives this technique significant advantages over
      other techniques; 2) it classifies spikes based on the nearest neighboring
      algorithm, which is less sensitive to waveform variation; 3) it can effectively
      separate compound potentials based on a maximum signal energy deduction
      algorithm, which is fast and relatively reliable; and 4) it also utilizes the
      information on discharge regularities of SMU's to help correct possible
      decomposition errors. The performance of this technique has been evaluated by
      using simulated EMG signals composed of up to eight different discharging SMU's
      corrupted with white noise, and also by using real EMG signals recorded at levels
      up to 50% maximum voluntary contraction. We believe that it is a very useful
      technique to study SMU discharge patterns and recruitment of motor units in
      patients with neuromuscular disorders in clinical EMG laboratories.

PMID- 10356876
TI  - Parametric model derivation of transfer function for noninvasive estimation of
      aortic pressure by radial tonometry.
AB  - Aortic pressure can be estimated noninvasively by applying a transfer function
      (TF) to radial tonometry signals. This study compares the performance of prior
      approaches, based on Fourier transform and inverted aortic-to-radial model, with
      direct radial-to-aortic autoregressive exogenous (ARX) model. Simultaneous
      invasive aortic pressure and radial tonometry pressure were recorded during rest
      in 39 patients in the supine position. Individual radial-aortic TF's were
      estimated from 20 patients, and the average TF was used to predict aortic
      pressures in the remaining 19 patients. The direct average TF yielded accurate
      aortic systolic pressure estimation (error 0.4 +/- 2.9 mmHg) and good
      reproduction of the aortic pressure waveform (root mean squared error 2.2 +/- 0.9
      mmHg). The inverted reverse TF (aortic radial) yielded comparable results, while
      the Fourier-based TF had worse performance. Individual direct TF provided
      improved predictive accuracy only for indexes which are based on higher frequency
      components of the waveform (augmentation index, systolic time period). An ARX
      average TF can be used to accurately estimate central aortic pressure waveform
      parameters from noninvasive radial pulse tracings, and its performance is
      superior to previous techniques.

PMID- 10356877
TI  - Enhancement of deep epileptiform activity in the EEG via 3-D adaptive spatial
      filtering.
AB  - The detection of epileptiform discharges (ED's) in the electroencephalogram (EEG)
      is an important component in the diagnosis of epilepsy. However, when the
      epileptogenic source is located deep in the brain, the ED's at the scalp are
      often masked by more superficial, higher-amplitude EEG activity. A noninvasive
      technique which uses an adaptive "beamformer" spatial filter has been
      investigated for the enhancement of signals from deep sources in the brain
      suspected of containing ED's. A forward three-layer spherical model was used to
      relate a dipolar source to recorded signals to determine the beamformer's spatial
      response constraints. The beamformer adapts, using the least-mean-squares (LMS)
      algorithm, to reduce signals from sources distant to some arbitrarily defined
      location in the brain. The beamformer produces three outputs, being the
      orthogonal components of the signal estimated to have arisen at or near the
      assumed location. Simulations were performed by using the same forward model to
      superimpose realistic ED's on normal EEG recordings. The simulations show the
      beamformer's ability to enhance signals emanating from deep foci by way of an
      enhancement ratio (ER), being the improvement in signal-to-noise ratio (SNR) to
      that observed at any of the scalp electrodes. The performance of the beamformer
      has been evaluated for 1) the number of scalp electrodes, 2) the recording
      montage, 3) dependence on the background EEG, 4) dependence on magnitude, depth,
      and orientation of epileptogenic focus, and 5) sensitivity to inaccuracies in the
      estimated location of the focus. Results from the simulations show the
      beamformer's performance to be dependent on the number of electrodes and
      moderately sensitive to variations in the EEG background. Conversely, its
      performance appears to be largely independent of the amplitude and morphology of
      the ED. The dependence studies indicated that the beamformer's performance was
      moderately dependent on eccentricity with the ER increasing as the dipolar source
      and the beamformer were moved from the center to the surface of the brain (1.51
      2.26 for radial dipoles and 1.17-2.69 for tangential dipoles). The beamformer was
      also moderately dependent on variations in polar or azimuthal angle for radial
      and tangential dipoles. Higher ER's tended to be seen for locations between
      electrode sites. The beamformer was more sensitive to inaccuracies in both polar
      and azimuthal location than depth of the dipolar source. For polar locations, an
      ER > 1.0 was achieved when the beamformer was located within +/- 25 degrees of a
      radial dipole and +/- 35 degrees of a tangential dipole. Similarly, angular
      ranges of +/- 37.5 degrees and +/- 45 degrees, respectively, for inaccuracies in
      azimuthal locations. Preliminary results from real EEG records, comprising 12
      definite or questionable epileptiform events, from four patients, demonstrated
      the beamformer's ability to enhance these events by a mean 100% (52%-215%) for
      referential data and a mean 104% (50%-145%) for bipolar data.

PMID- 10356878
TI  - Electromyogram amplitude estimation with adaptive smoothing window length.
AB  - Typical electromyogram (EMG) amplitude estimators use a fixed window length for
      smoothing the amplitude estimate. When the EMG amplitude is dynamic, previous
      research suggests that varying the smoothing length as a function of time may
      improve amplitude estimation. This paper develops optimal time-varying selection
      of the smoothing window length using a stochastic model of the EMG signal.
      Optimal selection is a function of the EMG amplitude and its derivatives.
      Simulation studies, in which EMG amplitude was changed randomly, found that the
      "best" adaptive filter performed as well as the "best" fixed-length filter.
      Experimental studies found the advantages of the adaptive processor to be
      situation dependent. Subjects used real-time EMG amplitude estimates to track a
      randomly-moving target. Perhaps due to task difficulty, no differences in
      adaptive versus fixed-length processors were observed when the target speed was
      fast. When the target speed was slow, the experimental results were consistent
      with the simulation predictions. When the target moved between two constant
      levels, the adaptive processor responded rapidly to the target level transitions
      and had low variance while the target dwelled on a level.

PMID- 10356879
TI  - Probability density of the surface electromyogram and its relation to amplitude
      detectors.
AB  - When the surface electromyogram (EMG) generated from constant-force, constant
      angle, nonfatiguing contractions is modeled as a random process, its density is
      typically assumed to be Gaussian. This assumption leads to root-mean-square (RMS)
      processing as the maximum likelihood estimator of the EMG amplitude (where EMG
      amplitude is defined as the standard deviation of the random process). Contrary
      to this theoretical formulation, experimental work has found the signal-to-noise
      ratio [(SNR), defined as the mean of the amplitude estimate divided by its
      standard deviation] using mean-absolute-value (MAV) processing to be superior to
      RMS. This paper reviews RMS processing with the Gaussian model and then derives
      the expected (inferior) SNR performance of MAV processing with the Gaussian
      model. Next, a new model for the surface EMG signal, using a Laplacian density,
      is presented. It is shown that the MAV processor is the maximum likelihood
      estimator of the EMG amplitude for the Laplacian model. SNR performance based on
      a Laplacian model is predicted to be inferior to that of the Gaussian model by
      approximately 32%. Thus, minor variations in the probability distribution of the
      EMG may result in large decrements in SNR performance. Lastly, experimental data
      from constant-force, constant-angle, nonfatiguing contractions were examined. The
      experimentally observed densities fell in between the theoretic Gaussian and
      Laplacian densities. On average, the Gaussian density best fit the experimental
      data, although results varied with subject. For amplitude estimation, MAV
      processing had a slightly higher SNR than RMS processing.

PMID- 10356880
TI  - In vivo high-frequency ultrasonic characterization of human dermis.
AB  - The aim of this study is in vivo skin tissue characterization of young and old
      human cutaneous tissues by estimating the slope of the attenuation coefficient.
      The method used is the centroid algorithm with a second-order autoregressive
      model to perform the spectral analysis. Backscattered signals are acquired with a
      40-MHz transducer fixed on a three-dimensional robot. Diffraction phenomena are
      eliminated via an axial translation of the transducer that allows the acquisition
      of the signal in the focal zone. The slope of the attenuation coefficient is
      estimated on phantoms of known attenuation, in order to validate the method.
      Preliminary measurements of the slope of the attenuation coefficient are
      subsequently performed in the echographic mode on abdominal human skin samples in
      vitro at 40 MHz. After assessing the reproducibility of the measurement of the
      attenuation coefficient slope in human dermis at 40-MHz in vivo, this is carried
      out on the volar face of the forearm of 150 healthy subjects aged 14-85 yr. The
      values measured range from 0.7 to 3.6 dB/cm.MHz. The main result of this study is
      the decrease with advancing age of the attenuation coefficient slope, which may
      reflect structural modifications of human dermis with age.

PMID- 10356881
TI  - The electric field induced in the human body when exposed to electromagnetic
      fields at 1-30 MHz on shipboard.
AB  - The electric field induced in the body of a man standing on the metal deck of a
      ship near a vertical antenna is determined analytically. Typical antennas for
      radio communication in the 1-30 MHz band are described and their near fields are
      calculated. The current induced in the man is determined by solving the relevant
      integral equation. Explicit formulas are obtained for the total axial current and
      the associated current densities and electric fields.

PMID- 10356882
TI  - Electroporation therapy: a new approach for the treatment of head and neck
      cancer.
AB  - Electroporation can deliver exogenous molecules like drugs and genes into cells
      by pulsed electric fields through a temporary increase in cell membrane
      permeability. This effect is being used for the treatment of cancer by
      intratumoral injection of low dosage of an otherwise marginally effective
      chemotherapeutic drug, bleomycin. Application of a pulsed electric field results
      in substantially higher uptake of the drug and enhanced killing of the cancer
      cells than is possible by conventional methods. The MedPulser, a new treatment
      system for local electroporation therapy (EPT) of head and neck tumors was
      developed and is described in this paper. EPT with bleomycin has been found to be
      very effective in killing cancer cells in vitro, in mouse tumor xenografts in
      vivo, and in tumors in humans. Ten head and neck cancer patients with recurring
      or unresponsive tumors were enrolled in a Phase I/II clinical trial. Treatment of
      the entire tumor mass in each of eight patients resulted in five complete
      responses confirmed by biopsy and MRI, and three partial responses (> or = 50%
      shrinkage). Two additional patients who received partial treatment of their tumor
      mass had local response where treated, but no overall lesion remission. Duration
      of the complete responses ranges from 2-10 months to date. All patients tolerated
      the treatment well with no significant local or systemic adverse effects.

PMID- 10356883
TI  - Comments on "Fields and currents in the organs of the human body when exposed to
      power lines and VLF transmitters".

PMID- 10356884
TI  - An artefact suppressing fast-recovery myoelectric amplifier.
AB  - An amplifier for recording myoelectric signals using surface electrodes has been
      developed. The special features are suppression of stimulation artefacts and
      motion artefacts from electrodes. It is designed for recording of myoelectric
      signals from a muscle that is being stimulated with short impulses. The artifact
      suppression is achieved by using fast-recovery instrumentation amplifiers and
      having a nonlinear feedback loop for automatic compensation of changes in DC
      offset.

PMID- 10356886
TI  - [An outbreak of parainfluenza 3 virus infection in the elderly in a ward].
AB  - In the D ward of Nagoyashi-Koseiin geriatric hospital (36-beds), upper
      respiratory illnesses were recognized in all the inpatients between July and
      August in 1995, and we studied 7 elderly subjects with parainfluenza 3 infection
      diagnosed by serology and viral culture. The outbreak of upper respiratory
      illnesses occurred in the ward during the 17 days from July 21 through August 6,
      1996. Fifteen of the 18 elderly persons with upper respiratory illnesses were
      tested by serology; parainfluenza 3 infection was identified in 7. One of the 7
      patients, parainfluenza 3 virus was isolated. Seven elderly subjects with
      parainfluenza 3 infection were 2 males and 5 females and five of them (71.4%)
      were bedridden. The most common complaint was fever and coughing in 7/7 (100%),
      followed by sputum in 5/7 (71.4%), wheezing in 4/7 (42.9%). The pyrexial period
      in the parainfluenza-infected group ranged from 1 to 4 days (average 3.1 days),
      and was significantly shorter than that of the influenza group. The maximum
      recorded temperature in the parainfluenza-infected group ranged from 37.0 to 39.2
      degrees C (average 38.1 degrees C), and was significantly lower than that of the
      influenza group. Two of the 7 patients with parainfluenza 3 virus infection had
      pneumonia, but nobody died, and all 7 patients recovered without sequele. It is
      possible that parainfluenza 3 virus infection among elderly subjects cause
      secondary bacterial infection, so we think that prevention of nosocomial
      parainfluenza infection should be a high priority in the case of outbreak of such
      an infection in a ward.

PMID- 10356885
TI  - [Combination effect of fosfomycin otic solution and norfloxacin against chronic
      otitis media].
AB  - Studies on a combination therapy of fosfomycin (FOM) and norfloxacin (NFLX)
      against chronic otitis media were performed, and the following results were
      obtained. 1. The fractional inhibitory concentration index (FIC index) < or = 0.5
      between FOM and NFLX showed 66.7% (4/6) against S. aureus isolated from chronic
      otitis media and 80.5% (4/5) against P. aeruginosa. 2. Clinical effects was
      excellent in 2 cases (18.2%), good in 6 cases (54.5%) and poor in 3 cases
      (27.3%). 3. Bacteriologically 9 strains out of 11 patients were eradicated after
      the combination treatment; 5/6 in S. aureus and 4/5 in P. aeruginosa. 4. No
      adverse effect and abnormal laboratory findings were observed in this study. It
      is suggested that the combination of FOM otic solution and NFLX is useful for the
      treatment of chronic otitis media.

PMID- 10356887
TI  - [Trial of oral administration of Bifidobacterium breve for the prevention of
      rotavirus infections].
AB  - It was investigated that Bifidobacterium breve YIT4064 (B. breve YIT4064), Which
      had augmented IgA production and prevented rotavirus-induced diarrhea in mice,
      prevented rotavirus infection in infants. The effect of B. breve YIT4064 was
      evaluated in ten infants from an infants home who received 50 mg of the bacterium
      every day for 28 days (the B. breve group). Nine infants did not receive this
      (the control group). Though rotavirus shedding in the control group was detected
      from 2 (a total of 5 stool samples) of 9 infants (a total of 112 stool samples),
      it was not detected in any infants (a total of 133 stool samples) in the B. breve
      group during the administration period. From day 8 to day 14 of the test,
      rotavirus shedding was detected from 4 of 32 stool samples in the control group,
      but was not detected at all from 38 stool samples in the B. breve group. The
      frequency of rotavirus shedding in the B. breve group was significantly lower
      than that in the control group. Further, the frequency in appearances of anti-IgA
      in stool samples in the B. breve group showed a tendency to increase in
      comparison with the control group from day 8 to 14 of the test. The oral
      administration of B. breve YIT4064 significantly decreased rotavirus shedding in
      stool samples and prevented rotavirus infection.

PMID- 10356888
TI  - [Recurrent respiratory tract infection caused by Moraxella catarrhalis in
      patients with pneumoconiosis].
AB  - Moraxella catarrhalis is recognised as a major pathogen in chronic respiratory
      diseases. Patients with pneumoconiosis have repeated respiratory infections, and
      the control is very important for good prognosis. From 1988 to 1993, fifty
      strains of Moraxella catarrhalis were obtained from 9 patients with
      pneumoconiosis attended at Nagasaki Rosai Hospital. Restriction enzyme analysis
      of chromosomal DNA by Hind III. Hae III, Cla I was performed on 50 strains of M.
      catarrhalis. Twelve strains (56%) out of 23 isolates with interval of less than 5
      months had identical bacterial restriction endonuclease digestion patterns with
      three different enzymes, and all isolates with interval more than 6 months had
      different patterns. Tweny out of 13 episodes by the same strains occurred during
      3 months. The acquisition and clearance of M. catarrhalis from the respiratory
      tract is a dynamic process.

PMID- 10356889
TI  - [Basic study of Beutin's washed sheep blood agar plate used for selective
      screening of verocytotoxin-producing/enterohemorrhagic Escherichia coli
      (VTEC/EHEC)].
AB  - Enterohemolysin production of Beutin's washed sheep blood agar plate has been
      used as an epidemiological marker for selective screening of Verocytotoxin
      producing/Enterohemorrhagic Escherichia coli (VTEC/EHEC). In this study, we
      examined about the component of Beutin's washed sheep blood agar for further
      improvement of hemolysin production media. The following items were studied: the
      numbers of washings of sheep blood with phosphate buffered saline (PBS) (pH 7.2),
      concentration of sheep blood, kind and concentration of divalent metal ion (Ca2+,
      Mg2+) and basal medium. Twenty-seven strains of VT-producing E. coli of 7
      different O-serotypes, 74 strains of VT-nonproducing E. coli of 24 different O
      serotypes and one strain of O157 coded Escherichia hermanii were used for this
      basic study. In comparison of washing times of sheep blood with PBS, 5 times
      washing was better than 3 times, the original. In sheep blood concentration,
      supplement with 4% sheep blood was best for hemolysis observation. In experiment
      of addition of 2 divalent metal ions, Ca2+ and Mg2+, supplement with Ca2+ was
      more suitable than Mg2+ for hemolysis, and the supplement with 10 mM CaCl2, the
      original, was the best concentration. On the basal medium used in Beutin's sheep
      washed blood agar, 4 kinds of media were compared. In addition to Soybean-Casein
      Digest (SCD) agar, the original, Nutrient agar, Heart Infusion (HI) agar and
      Brain Heart Infusion (BHI) agar were examined, HI agar was the best blood agar
      base in the four media. As the above experimental results, the composition of the
      better Beutin's washed sheep blood agar may be summarize as follows: Heart
      Infusion agar 'Eiken' used for blood agar base, supplemented with 10 mM CaCl2 and
      4% defibrinated sheep blood (Japan biosupp. Center) washed five times in
      phosphate-buffered saline, pH 7.2.

PMID- 10356890
TI  - [Soluble proteins from Staphylococcus aureus can change expression of CD11b and
      CD62L, but not H2O2 production by human blood granulocytes].
AB  - We examined the production of CD11b, CD62L and H2O2 by human peripheral blood
      granulocytes after treatment with soluble proteins prepared from five different
      pressure-disrupted strains of Staphylococcus aureus (SaSP) by flow cytometory.
      Peripheral blood was treated with final SaSP concentrations of 0.05, 0.5 and 5.0
      micrograms for 20 min at 37 degrees C. The ratio of CD11b positive granulocytes
      did not increase at concentrations from 0.05 to 5.0 micrograms, but fluorescence
      intensity showed about two and three-fold increase, respectively, at
      concentrations of 0.5 and 5.0 micrograms, in comparison with that of control
      cells. The ratio CD62L positive cells decreased as follows: 0.5 microgram, 53.8%
      and 5.0 micrograms, 19.0%, respectively, whereas the control value was 79.8%.
      Fluorescence intensity also decreased as follows: 0.5 microgram, 10.4 and 5.0
      micrograms, 9.2, respectively, whereas the control value was 46.8. Slight
      induction of H2O2 was found at 5.0 micrograms concentration only. In addition,
      SaSP treatment granulocytes that stimulated with PMA (1 ng) increased H2O2
      production. Thus, SaSP has no beneficial effect against H2O2 production by
      granulocytes. All of the SaSP preparations indicated similar results for the
      production of CD11b, CD62L and H2O2 by granulocytes. SaSP effects activation of
      granulocytes, and the activation may occur independently of protein kinase C.

PMID- 10356891
TI  - [Usefulness of rapid antigen detection for the diagnosis of systemic infections
      due to Haemophilus influenzae].
AB  - Twenty-eight cases of systemic infections due to Haemophilus influenzae diagnosed
      from October 1988 to December 1998 were analyzed retrospectively. The clinical
      manifestations were 13 meningitis (15 episodes), 9 septic arthritis, 4 acute
      epiglottitis, 1 septicemia and 1 lung abscess. In the 15 meningitis episodes, 13
      had positive CSF culture results, and the other 2 episodes of pretreated with
      antibiotics were diagnosed by H. influenzae type b (Hib) antigen detection by
      using concentrated urine specimens. In the 9 septic arthritis cases, 6 had
      positive synovial fluid culture results. Of the 3 cases with negative results on
      Gram stain and on synovial fluid and blood cultures, etiological diagnosis was
      established by Hib antigen detection in synovial fluid. Results of Hib antigen
      detection were positive in all 8 cases (100%). In 6 of these 8 cases,
      antimicrobial therapy was started by the results of antigen detection. In the 4
      acute epiglottitis, 2 had positive blood culture results, and the other 1 case
      was diagnosed by Hib antigen detection by using concentrated urine specimen. In 3
      of these 4 cases, H. influenzae strains isolated from nasopharyngeal swab or
      aspirated sputum were serotyped as type b. In this study, rapid antigen detection
      has several advantages in the rapid laboratory diagnosis of systemic infections
      due to Haemophilus influenzae. 1. The detection of Hib antigen is the only way to
      diagnose bacterial etiology of infection in patients who had received partially
      treatment with antimicrobials. Urine is as an appropriate specimen for antigen
      testing as CSF in patients with suspected Hib meningitis. Moreover, to detect Hib
      antigen in synovial fluid is clinically useful in septic arthritis. 2. Both the
      antigen detection and Gram stain made the rapid presumptive identifications and
      effected therapeutic decision making. 3. Antigen detection methods have also been
      used in serotyping of clinical isolates. We conclude that rapid antigen detection
      is a very useful tool for the rapid etiological diagnosis and guideline for the
      choice of antimicrobials in systemic infections due to Hib. It is necessary to
      diagnose bacterial etiology as a routine procedure using not only Gram stain and
      culture but also rapid antigen detection technique in patients with suspected Hib
      systemic infection.

PMID- 10356892
TI  - [Non-Hodgkin's lymphoma complicated by recurrent intractable generalized herpes
      zoster responsive to long-term acyclovir therapy].
AB  - A 34-year-old male with a history of chickenpox developed primary abdominal non
      Hodgkin's lymphoma (diagnosed in August 1995). Treatment with cyclophosphamide,
      doxorubicin, vincristine, and prednisolone achieved a partial remission. In July
      1996, the disease recurred, and the patient received chemotherapy with
      carboplatine, etoposide, mitoxantrone, and prednisolone, but no response was
      noted. Involvement of the central nervous system and meninges was diagnosed on
      September 12, 1997. Blast cells were detected in the peripheral blood on
      September 26. Based on these findings, he was diagnosed as having leukemia. On
      September 27, painless vesicles developed on the left gluteal region. On October
      13, the patient was hospitalized because the vesicles had spread over his entire
      body. Pathologic examination of the roofs of the blisters showed masses of
      inclusion bodies. Based on this, a diagnosis of varicella-zoster infection was
      made. Treatment with acyclovir (750 mg/day) for seven days failed to form crusts.
      New vesicles developed after the drug was discontinued, but crusts formed after
      acyclovir therapy was resumed. He died of interstitial pneumonia on December 21.
      Autopsy could not be performed. Histopathologic examination of pulmonary tissue
      obtained by necropsy did not reveal the presence of inclusion bodies
      characteristic of herpes simplex or varicella-zoster infection. Varicella-zoster
      virus (VZV) antigen was negative by an immunochemical staining method using
      monoclonal antibodies against VZV. Continuous long-term administration of
      acyclovir has been reported to be effective for non-Hodgkin's lymphoma
      complicated by recurrent intractable herpes zoster.

PMID- 10356893
TI  - [Case of varicella-zoster pneumonia with bronchioalveolar lavage confirmed by the
      detection of VZV DNA in the bronchial washing by the polymerase chain reaction].
AB  - A 32-year old male was admitted to our hospital complaining of cough, fever, and
      skin eruptions. He was coctacted with a child who had chickenpox 3 weeks before
      the onset. He showed the elevating of antibody to varicella-zoster virus. Despite
      of the administration of Acyclovir for four days, cough was not relieved and a
      chest X-ray film showed infiltrative shadow in right middle lobe of the lung.
      Bronchoscopic examination revealed vasicle and edema, and the varicella-zoster
      virus (VZV) DNA was detected in the bronchoalveolar lavage by the polymerase
      chain reaction. The patient in first case confirmed by the virus DNA in the
      bronchial washing by the PCR.

PMID- 10356894
TI  - [An autopsy case of AIDS complicated with cytomegalovirus infection and multiple
      Kaposi's sarcoma].
AB  - Cutaneous Kaposi's sarcoma (KS) is a well-known complication of the acquired
      immunodeficiency syndrome. KS in the internal organs, however, is rare in Japan.
      We present here a 33-years-old Japanese homosexual man who had AIDS complicated
      with cytomegalovirus (CMV) infection and KS. He was found to be HIV-seropositive,
      when he was 31-years-old. He visited our hospital in June 1996 because of high
      fever. The peripheral blood CD4+ lymphocyte counts were 2 per cubic millimeter,
      and CMV antigenemia was noted (p65 antigen positive cells; 240/50,000 white blood
      cells). Thereafter he was successfully treated with parental ganciclovir. On
      admission, some brown-colored flat nodules were found on the skin, and the
      diagnosis of KS was made by skin biopsy. We administrated human chorionic
      gonadotropin (hCG) for the treatment of KS, but had no clinical response. In
      September 1996, he complained of severe cough, shortness of breath, and vomiting.
      A chest radiogram showed nodular lesions and pleural effusion in bilateral lungs.
      A computed tomography of his chest also revealed nodular and linear densities
      distributed along the bronchovascular bundles. The ultrasonic examination of his
      abdomen revealed a duodenal nodule. Both nodules in the lungs and duodenum were
      proved to be KS based on the autopsy findings. Intranuclear inclusionbodies
      pathognomonic for CMV infections were detected in the stomach and the colon.

PMID- 10356895
TI  - [Clinical analysis on an outbreak of SRSV-gastroenteritis with 644 patients
      emerged in Shizuoka Prefecture].
AB  - Small round structured viruses (SRSV) are the major cause of acute non-bacterial
      enterogastritis and have a characteristic of breaking out with mass victims as
      food poisoning. The outbreak usually occurs among school children from school
      lunches in Japan. A case in adults is relatively rare. The SRSV food poisoning
      with 644 adult victims carried through lunch box broke out, which may be the
      biggest number in adult cases in the world. This is the report describing its
      outlines, analytical result of clinical symptoms and fecal microbial examination.
      The average latent period was 37 hours, the time was mostly (47%) between 24-36
      hours. The most emerged symptom was diarrhea and followed nausea, abdominal pain,
      vomiting and high fever. The older patients showed a higher rate of diarrhea and
      fewer one of nausea and fever. 15 patients complained of eye symptom. This number
      should not be neglected. It may be a characteristic of the disease. SRSV
      detection test with PT-PCR method of feces was done on 36 patients and 24
      patients were positive. The most sensitive primer was Yuri/nested/22F/R. In
      Japan, lunch-service has become a industry advancing monopolization and wide
      areazation. SRSV make easily contamination to food, therefore if mass victim food
      poisoning occurs, this should be considered initially.

PMID- 10356896
TI  - [A nosocomial outbreak of Moraxella catarrhalis confirmed by restriction enzyme
      analysis].

PMID- 10356897
TI  - [Albumin, transport of saturated fatty acids, and metabolic stress-syndrome
      (literature review)].

PMID- 10356898
TI  - [Biochemical indicators of metabolic disorders in bone tissue. I. Bone
      formation].

PMID- 10356899
TI  - [Quantitative assay of autoantibodies against low density lipoproteins].
AB  - The task of this study was to develop a solid-phase enzyme immunoassay (EIA) for
      measuring autoantibodies to low-density lipoproteins. The sandwich variant of
      solid-phase EIA was used. Parameters of the test were selected. Test system was
      calibrated for high-affinity autoantibodies obtained on an immunoadsorbent from a
      serum pool of coronary patients with hyperlipidemia. Normal values of
      autoantibodies in human serum (45.32 +/- 4.25) x 10(-3) g/liter and in
      circulating immune complexes (0.52 +/- 0.07) x 10(-3) g/liter for this method are
      determined. In coronary patients with angiographically documented atherosclerosis
      the level of autoantibodies was significantly higher: (115-175) x 10(-3) g/liter
      (p < 0.001) in the blood serum and (1.1-5.2) x 10(-3) g/liter (p < 0.01) in
      circulating immune complexes.

PMID- 10356900
TI  - [Immunoenzyme assay for detection of natural antibodies against vasopressin in
      systemic lupus erythematosus].
AB  - A solid-phase enzyme immunoassay procedure for detecting natural antibodies to
      vasopressin (VP) is developed. For this purpose, a VP antigen is synthesized on
      polymer matrix. Optimal conditions of enzyme immunoassay for detecting antibodies
      to this antigen in the sera of donors and patients with systemic lupus
      erythematosus (SLE) are selected. The level of anti-VP antibodies is constant in
      donors and shifted in SLE patients. Changes in the level of natural antibodies to
      VP correlate with immunochemical parameters.

PMID- 10356902
TI  - [Possibilities, failures and prospects of studies on tumor markers in oncological
      clinics. 1. (lecture)].

PMID- 10356901
TI  - [Anti-inflammatory cytokine in early diagnosis of endometritis after Cesarean
      section].
AB  - Antiinflammatory cytokines IL-1 alpha, IL-1 beta, IL-8, and TNF-alpha are
      measured and clinical course of the postoperative period is analyzed in 30 women
      after cesarean section. Postoperative endometritis can be predicted from an
      increase in the concentrations of IL-8 and TNF-alpha on days 2-3 after delivery.
      Early (preclinical) treatment of endometritis improves the treatment efficacy and
      decreases hospital stay of the patients.

PMID- 10356903
TI  - [Novel method for calculation of hemostatic potential and its clinical
      applications. 2].
AB  - A formula for calculating the hemostatic potential is proposed: HV = -{Ig[(APTT +
      PTTIS)/(WBCT.Hct)] + IgPF/PT}, where APTT is activated partial thromboplastin
      time, sec; PTT prothrombin time, sec; IS index of sensitivity of thromboplastin
      reagent used; WBCT whole blood clotting time after Lee-White, sec; Het
      hematocrit; PF probability of liquid blood preservation: and PT probability of
      thrombotic complications. The aim of the study was to evaluate the probability of
      practical use of the method and its practical potentialities. Statistical
      analysis (1014 specimens from 402 patients) confirmed the correctness
      (plausibility) of our concept and of the model of hemostatic potential. Despite
      the difficulties of calculation, the resultant hemostatic potential value
      represents the actual conditions of hemostasis in vivo. The physiological norm is
      represented as small-positive values of hemostatic potential, reflecting the
      constant "readiness" of blood to coagulation. Time course of hemostatic potential
      demonstrates the hemostasis status and its stability during various exposures.
      The homeostatic potential is a value highly sensitive to hemostatic status and
      outer exposures. Its changes can be used as a criterion of therapy efficacy.

PMID- 10356904
TI  - [Platelet adhesion to collagen in whole blood: a simple and rapid quantitative
      method].
AB  - A simple, rapid, and easily reproducible method for quantitative assessment and
      graphic representation of platelet adhesion of whole blood specimens is proposed.
      It is based on registration (by means of impedance aggregometer) of changes in
      the module of complex resistance of an EDTA-stabilized blood specimen by
      collagen. The amplitude of the process initiated under such conditions directly
      depends on collagen concentration, weakly decreases if blood is incubated with
      high concentrations of acetylsalicylic acid (500 micromol/liter), and
      significantly decreases in the presence of RGD-containing peptides in a
      concentration of 20-40 micromol/liter). A relatively higher collagen adhesion
      capacity of blood platelets from coronary patients correlates with their high
      aggregation activity.

PMID- 10356905
TI  - [Complex interpretation of aggregatograms for assessing the functional activity
      of platelets in patients with hypertension].

PMID- 10356906
TI  - [Status and measures of improvement of laboratory support in diagnosis and
      treatment of patients at the Public Health Institutions of the Russian
      Federation].

PMID- 10356907
TI  - [Treatment of rheumatic arthritis: role of glucocorticoids].

PMID- 10356908
TI  - [Methemoglobinemia: pathogenetic and clinical features].

PMID- 10356909
TI  - [Clinical effect of prostenon in patients with resistant arterial hypertension
      and target organs complications].

PMID- 10356910
TI  - [Mitral valve prolapse and respiratory diseases].
AB  - Respiratory function was studied in 9 patients with mitral prolapse because of
      myxomatous degeneration of valvular cusps. Respiratory disorders were diagnosed
      in 7 of them. Respiratory organ abnormalities in cusp prolapses result from
      hereditary deficiency of the connective tissue with visceral manifestations.
      Valvular cusp prolapse and their myxomatous degeneration may serve as markers of
      impairment of the respiratory organs and other viscera related to "weakness" of
      the connective tissue.

PMID- 10356911
TI  - [Cardiolipin antibodies in pregnancy of high risk].
AB  - Cardiolipin IgG and IgM antibodies (CAb) were studied in 116 cases of high-risk
      pregnancy. All the women were undergoing examination or treatment in regional
      perinatal center. CAb occurred more frequently in antenatal fetal death (50%). In
      blood hypertension, habitual abortions, history of infertility, gestational
      gestosis, CAb were encountered in 21.4, 20, 20 and 15.2% of cases, respectively.
      Intrauterine growth retardation was associated with CAb in 33.3% of cases. CAb
      occurred in pregnant women of different groups who had high uterine vascular
      resistance. The above findings indicate CAb contribution to genesis of
      gestational complications in high risk pregnancy.

PMID- 10356912
TI  - [Immunological characteristics of patients with acute coronary syndrome (unstable
      angina and myocardial infarction)].
AB  - Admission and discharge values of rosette formation, adhesive and phagocytic
      ability of neutrophils, exercise tests with calculation of the tension index
      (TI), serum concentrations of IgG, IgA and IgM, circulating immune complexes
      (CIC) and cardiolipin antibodies (CAB) were studied in 48 males with unstable
      angina pectoris and acute myocardial infarction. Acute coronary syndrome is shown
      to be associated with marked immune alterations, primarily, with elevated levels
      of CIC and CAB, reduced TI. These alterations persisted for 3-5 weeks of the
      hospital stay and provoked the risk of repeated infarctions and thrombotic
      complications after relief of clinical symptoms of acute coronary failure.

PMID- 10356913
TI  - [Vitamin supply in patients with non-insulin-dependent diabetes mellitus].
AB  - Concentrations of vitamins C, A, E, B2, B6 and carotinoids were measured in
      patients with non-insulin-dependent diabetes mellitus (NIDDM). Most of the
      examinees had deficiency of both group B vitamins and carotinoids, some of the
      patients were vitamin C deficient. Vitamin-enriched drink Zolotoi shar (Golden
      Ball) and beta-carotene in oil were included in regular diet of NIDDM and taken
      for 4 weeks. As a result, supply of the vitamins C and beta-carotene has improved
      significantly. There was a positive trend in the levels of vitamin B6, while
      vitamins A and E reached optimal values.

PMID- 10356914
TI  - [Cardio-hemodynamic effects of domestic adrenergic beta-antagonist proxodolol in
      hypertension in patients with pacemaker].
AB  - 59 patients with mild and moderate essential hypertension have received a course
      treatment with beta-adrenoblocker proxodolol. The latter was studied for a
      hypotensive action and cardiohemodynamic effects as regards baseline type of
      circulation and pacing regimen. Proxodolol hypotensive action in hyperkinetic
      circulation is attributed primarily to a fall in the ejection (beta-adrenoblock),
      in hypo- and eukinetic circulation type--to reduction in cardiac postload (alpha
      adrenoblock). In isolated ventricular stimulation proxodolol cardiodepressive
      effect was more pronounced than in atrial stimulation. An overall hypotensive
      effect of proxodolol in mild arterial hypertension made up 77.2%, in moderate-
      66.5%.

PMID- 10356915
TI  - [Prognosis in meningococcal disease: methodology and practice].
AB  - 78 patients with systemic meningococcal disease admitted to the Intensive Care
      Unit of the 2nd Moscow Hospital for Infectious Diseases were studied and the
      composite prognostic score was developed to estimate the risk of lethal outcome.
      The stepwise variable selection procedure for the multiple logistic regression
      was applied to 30 potential clinical and laboratory risk factors and markers.
      Five factors were selected for the score, namely the platelet count (< 150 x
      10(6)/ml), the presence of hemorrhages into the eye or mucosal tissue, the
      interval from the last urination before admission (> 4 h), the respiration rate
      (> 170% of age-adjusted normal value) and age (< 2 or > 65 years) with regression
      coefficients 0.3, 0.2, 0.2 and 0.1, respectively. Both for the source clinical
      group and for the additional test group (64 patients), the scale was able to
      classify correctly 95% of cases using the data collected at admission. Ten
      prognostic scores proposed previously by foreign investigators were tested in the
      same patients and the best four scores were selected (GMSPS, Gedde-Dahl,
      Niklasson, Kahn); the scores classified correctly 85-90% of cases. This study is
      an example of methodological approaches to prognostic score construction in
      medicine.

PMID- 10356916
TI  - [Response to metabolic therapy with amino acid complex in aged patients with
      ischemic heart disease].
AB  - Aged patients with IHD were randomised into two groups (45 patients each). Mean
      age of the patients was 65.8 +/- 0.8 years. Control patients received standard
      treatment, test subjects received the same standard therapy plus metabolic
      complex of amino acids. The comparison of the groups was made by clinical
      evidence, data obtained at ECG, echo-CG, Holter ECG monitoring, exercise test.
      Those patients who had been given adjuvant amino acid composition in a dose 100
      mg 3 times a day for 20 days exhibited stronger antianginal, hemodynamic effects,
      higher exercise tolerance.

PMID- 10356918
TI  - [Differential diagnosis in pulmonary infiltrates].

PMID- 10356917
TI  - [Cortexin effectiveness in circulatory encephalopathy].
AB  - A clinical trial of cortexin, a new peptide bioregulator of cerebral functions,
      in combined therapy of dyscirculatory encephalopathy (DE) stage I-II was made in
      76 patients. They were divided into two groups: a control group of 31 patients on
      standard therapy and the study group of 45 patients on standard therapy with
      adjuvant cortexin delivered via nasal electrophoresis (NE). The effect was
      estimated by clinical symptoms, psychophysiological tests, computed EEG,
      quantitative parameters of rehabilitation. Cortexin NE produced a positive effect
      on psychoemotional state, neurological status, intellectual-mnestic and CNS
      functions. Adjuvant cortexin aroused efficiency of rehabilitation in DE stage I
      and II by 22.7%. The response of intellectual-mnestic and CNS functions was the
      highest. Cortexin improves attention, perception, memory, thinking, cortical
      neurodynamic processes. It is well tolerated and has no side effects. Cortexin is
      recommended as a drug of choice in combined treatment of patients with DE stage I
      II.

PMID- 10356919
TI  - [Combined use of tumor markers and MRI tomography in differential diagnosis of
      ovarian neoplasms].
AB  - 15 women with indeterminate diagnosis of ovarian lesion have undergone a standard
      examination, NMR tomography and enzyme immunoassay for tumor markers (KA-125, KA
      19-9, CEA). NMR-tomography appeared highly informative in differentiating benign
      and malignant tumors of the ovaries, effective in staging. The oncomarkers are
      effective in screening for cancer risk groups, control of treatment efficacy and
      the disease prognosis. Carbohydrate (tumor-associated) antigen KA-125 is most
      specific for ovarian cancer. Combined use of the tumor markers and NMR-tomography
      provides a reliable diagnosis.

PMID- 10356921
TI  - [Initial steps of therapy in St. Petersburg in th first half of 19th century].

PMID- 10356920
TI  - [Difficulties in differential diagnosis of peptic ulcer and ischemic heart
      disease].

PMID- 10356922
TI  - [Diazepam-induced chromosome aberrations in human lymphocytes in vitro].
AB  - This paper reports results of the research of genotoxic effects of anxiolitic
      benzodiazepine diazepam in the culture of lymphocytes of human periphery blood.
      It has been found out that diazepam reduces lymphocytes mitotic activity, causes
      numeric chromosomal aberrations (mostly hypodiploidy), and shows cytotoxic
      reactions. Frequency and expressiveness of perceived effects are in correlation
      with the intensity of concentrations tested.

PMID- 10356923
TI  - [The role of BRCA1 and BRCA2 genes in hereditary breast cancer].
AB  - From 5% to 10% of breast cancer cases result from an inherited predisposition.
      The majority of hereditary breast and ovarian cancer can be accounted for by
      mutation in BRCA1 and BRCA2 in transcription regulation. Although this role could
      be consistent with the reported localisation of the BRCA1/BRCA2 protein to the
      nucleus. The BRCA1 and BRCA2 may play an as yet undefined protective role in
      cells, as it is expressed in epithelial cells undergoing high levels of
      proliferation associated with differentiation.

PMID- 10356924
TI  - [Modern methods in the diagnosis of tuberculosis: PCR--polymerase chain
      reaction].
AB  - The diagnosis of tuberculosis depends on many factors but essentially on the
      detection of mycobacteria, their identification to the species level, and their
      susceptibility to major antituberculous drugs. The classic tests (direct
      examination-Ziehl-Neelsen, conventional culture and antibiotic susceptibility
      tests) are combined with modern tests (the molecular tests such as genomic
      amplification /PCR/ direct from clinical samples). By Polymerase Chain Reaction
      (PCR) over a billion identical bacteria could be multiplied from a single DNA
      molecule. These modern tests shortened diagnostics duration from several weeks to
      one or two days. The sensitivity of PCR test was 97% for Z-N positive, 68% for Z
      N negative samples while specificity was 99% either for Z-N positive or negative
      samples.

PMID- 10356925
TI  - [Effect of hemodialysis on functional parameters of the left ventricle].
AB  - Many cardiac functional disorders are developed in chronic renal failure. The aim
      of our work was the echocardiographic assessment of left ventricular functional
      parameters in patients on haemodialysis. We observed that left ventricular end
      diastolic volume, left ventricular end-systolic volume and stroke volume
      significantly decreased after haemodialysis. Left ventricular ejection fraction
      increased after haemodialysis, but not significantly. Systolic and diastolic
      blood pressure decreased significantly after haemodialysis while heart rate
      increased significantly. During the haemodialysis, many haemodynamic changes are
      observed. Analysis of cardiac functional status is essential before the
      haemodialysis starts.

PMID- 10356926
TI  - [Echocardiographic changes in patients with chronic renal insufficiency on
      hemodialysis].
AB  - Cardiovascular diseases cause death in 40% patients on the chronic haemodialysis
      program. Our aim was to assess the heart changes in these patients by
      echocardiography. We have tested 40 patients, but 34 of them accomplished
      criteria for this study. There were 19 (55.88%) females and 15 (44.12%) males.
      The average age was 44 years and average duration of haemodialysis treatment was
      4.72 years. The research was made with ultrasound device TOSHIBA SSH 65 A
      SONOLAYER and transducers 3.5 and 2.75 MHz. Twenty patients (58.82%) have had
      pathological echocardiogram. Ten patients (29.42%) have had conditionally normal
      echocardiogram while four patients (11.76%) have had completely normal
      echocardiogram. In patients with pathological echocardiogram, some of the left
      ventricle hypertrophy forms dominated. Echocardiography is a useful method in
      morphologic and functional cardiac assessment at the last stage renal disease
      patients on the chronic haemodialysis program. Using the aforementioned method we
      are able to select the patients who need intensive cardiac care.

PMID- 10356927
TI  - [Reasons for conversion in the first 200 laparoscopic cholecystectomies].
AB  - In this paper, the authors analyzed the reasons for conversion of laparoscopic
      cholecystectomy (LH) into an open method (OH) in the group of 200 patients. In 8
      (4%) patients the conversion of laparoscopic procedure was done. Reasons for
      conversion were the following: growth in abdomen (1.5%), empyema of gallbladder
      (1%), bleeding (0.5%), injuries of gallbladder tract (0.5%), and complications in
      pneumoperitoneum (0.5%). All complications because of which the conversion was
      performed were treated with classic surgical methods, and there were no death
      cases. The incidence of complications which required conversion of LH among our
      subjects is close to the reports of other authors with significantly larger
      number of patients.

PMID- 10356928
TI  - [Converting enzyme inhibitors in acute myocardial infarct and heart failure].
AB  - Inhibitors of angiotensin converting enzyme (ACE inhibitors) have been introduced
      more than fifteen years ago into the treatment of hypertension, congestive heart
      failure, myocardial infarction and diabetic nephropathy. The therapeutic success
      is related to their action in reduction of plasma and tissue angiotensin II
      concentrations and potentiation of endogenous kinins. They are able to improve
      myocardium metabolic status, prevent cardiac hypertrophy, limit myocardial
      infarct size, and thus prevent heart failure. Since 1987 ACE inhibitors are
      introduced in the clinical practice in our clinic. We introduced the therapy with
      lisinopril (Lopril), in 70% of patients among 2855 patients that were admitted in
      Coronary Care Unit in 1997 and 1998. Lisinopril was introduced as soon as the
      patient was admitted, together with fibrinolitic, Heparin and Aspirin therapy.
      Since that time we noticed decrease in postinfarction heart failure in comparison
      to previous years. We recommend permanent therapy with a small doses of ACE
      inhibitors in patients with heart infarction.

PMID- 10356929
TI  - [Myocardial infarct in a young man with angiographically normal coronary arteries
      and atrial septal defect].
AB  - The paper is a case report of a 34 year old man with an inferior wall myocardial
      infarction, episodes of ventricular tachycardia, normal coronary arteries and a
      large atrial septal defect. Coronary atherosclerosis causes 95% of all myocardial
      infarcts and 75% in the age group under 35 years. Other possible causes are
      coronary arteritis, trauma, valuvlopathy, systemic diseases, infective and non
      infective endocarditis, polycithemia, thrombocytosis, cocaine abuse. These can be
      usually excluded by history, physical or laboratory examination. The existence of
      a large atrial septal defect with dominantly left to right shunting, but
      occasional right to left shunting, is an indication and a justification for
      surgical treatment aiming to prevent recurrence by closure of the atrial septal
      defect. Paradoxical emboli have been recognised in the recent literature as an
      important cause of cerebral infarction, more rarely of emboli to other locations.
      The etiology remains difficult to confirm with certitude except when an embolus
      is seen by echocardiography in transit through a patent foramen ovale. We have
      also reviewed previously published cases of paradoxical emboli in literature.

PMID- 10356930
TI  - [Arrhythmogenic dysplasia of the right ventricle].
AB  - This paper is a case report of 58 years old patient with arrhytmogenic right
      ventricular dysplasia (ARVD), very rare cardiomyopathy of unknown cause who was
      in jeopardy because of recurrent ventricular tachycardia. ARVD is caused by
      abnormality in the development of the right ventricular musculature. In the right
      ventricular wall there are areas with a reduced number of myofibrils which are
      replaced by fatty and fibrous tissue. Therapy consists of drugs administration
      and DC cardioversion while surgical treatment is required in refractory cases.

PMID- 10356931
TI  - Refugees, returnees and rehabilitation.
AB  - Health and social security services are the basic elements which people have the
      right to ask for from their community. Strong efforts are made to reform the
      function of this support system all over Bosnia-Hercegovina. With a mutual effort
      made by Ministry of Health and mental health professionals the Community Mental
      Health Centres might be an excellent support for people with mental health
      problems in the society. This is true even for the heavy influx of returnees. The
      Community Mental Health Centres are expected to handle about 80% of people with
      mental health problems in the society where people live, or in the new
      establishments for returnees. However there is a great need for Ministry of
      Health to design the policy and edict precise rules. The same is true for
      Ministry of Social Affairs which in co-operation with social workers and other
      professionals have to reform the Centres for Social Work. However, even if
      resources are slowly growing, there still seems to lack in communication of the
      two basic elements, health and social security. Respective ministries in The
      Federation of Bosnia-Hercegovina need to co-operate and the Ministry of Health
      and Social Affairs in Republika Srpska needs to strong in developing a co
      operation between the centres in the field.

PMID- 10356932
TI  - [Diabetes mellitus and Candida albicans].
AB  - According to Salomon, diabetes mellitus is a chronic disease caused by inadequate
      insulin action. As a syndrome, it could come in practice in many different forms.
      This disease, from genetic aspect presents a very heterogeneous phenomenon. For
      that reason a research of oral cavity tissue in diabetic patients presents a very
      complex problem from the scientific point of view. Truly, in the research today
      there are controversial cognition about relationship between diabetes mellitus
      and oral cavity diseases: diabetic stomatopathy, oral candidiasis, alterations of
      oral mucosa and periodontia. In this paper a special aspect is given to the
      research of incidence of candidiasis which is the result of contamination of all
      other pathological alterations in oral cavity.

PMID- 10356933
TI  - [Oral complications of chemotherapy of malignant neoplasms].
AB  - Function and integrity disorders of the oral cavity fall into the most frequent
      complication of the chemotherapy of leucemias, malignant lymphomas and solid
      tumors. Complications associated with cancer chemotherapy can be direct ones,
      resulting from the toxic action of antineoplastic agents on the proliferative
      lining of the mouth, or indirect, as a result of myelosuppression and
      immunosuppression. The most frequent oral complications associated with cancer
      chemotherapy are mucositis, infection and bleeding. The principles of prevention
      and management of oral complications during cancer chemotherapy are considered in
      this paper.

PMID- 10356934
TI  - [Physicists in medicine: Johann Christian Doppler].
AB  - It is impossible, nowadays, to imagine modern medical diagnostic without devices
      that work on the basis of "Dopplers Effect". Within medicine (in medical
      diagnostic as well as in medical therapy" "Dopplers Effect" is mainly used
      indirectly, in other words, using the devices based on "Dopplers Effect", due the
      the gathering of some useful results, but their physics background or direct
      usage and understanding of this scientific theory are usually left outside. The
      physical nature of "Dopplers Effect", biographical facts on J.C. Doppler and main
      ways of "Dopplers Effect" usage are mentioned in the following thesis.

PMID- 10356935
TI  - Redefining critical limb ischaemia.

PMID- 10356936
TI  - Revascularization of the ischemic diabetic foot by popliteal-to-distal bypass.
AB  - BACKGROUND: Diabetic foot revascularization by popliteal-to-distal bypass is a
      procedure for limb salvage spread in the last decade. METHODS: The authors report
      their experience with a consecutive series of 15 ischemic feet (mean
      transcutaneous oxygen 5.3 +/- 4.1 mmHg) with gangrenous lesions due to extensive
      tibial arteries occlusive disease beginning at the popliteal artery trifurcation
      (9 cases) or involving the distal popliteal artery (6 cases). Limb salvage was
      achieved by popliteal-to-distal bypass with autogenous inverted saphenous vein.
      RESULTS: No operative death was observed. At a mean follow-up of 35 +/- 23 months
      (range 3-84 months) 4 bypasses were occluded and two were surgically revised
      after 4 and 50 months from surgery and subsequently remained patent. One patient
      was submitted to a major amputation. By life table analysis the cumulative
      primary and secondary patency and limb salvage rates for this group of diabetic
      patients were at 2 years 79.3%, 86.2% and 93.1% respectively (SE < 10%).
      CONCLUSIONS: This small experience and a review of the literature confirm the
      validity of the popliteal-to-distal bypass and the need for a more aggressive
      vascular surgical attitude to treat the ischemic diabetic foot.

PMID- 10356937
TI  - Ultrasound characterization and quantification of carotid atherosclerosis
      lesions.
AB  - The development of ultrasonography in vascular applications has entailed research
      of ultrasound parameters leading to precise the diagnosis and quantification of
      carotid lesions in routine. The use of recent colour Doppler imaging techniques
      (velocity or power encoding) is recommended as they allow a better definition of
      the lesions and recesses. At present, features of plaque that could be related to
      increased incidence of stroke are: echogenicity, with a more frequent observation
      of anechoic or hypoechoic lesions in the case of clinical signs; texture, with
      frequent haemorrhage; surface contour, with a high rate of ulcerations which were
      accompanied by stroke; plaque motion, with a significant alteration in plaque
      motility in symptomatic patients; progression or regression in size, with a
      faster progression of anechoic and hypoechoic plaques; an increase in plaque
      volume is associated with a greater risk of stroke; a significant relationship
      between the presence of "ulcers" and embolic activity. The quantification of
      stenosis degree could be made using velocity criteria and/or morphological
      criteria. Velocity criteria could be obtained at the site of the stenosis (direct
      criteria) or downstream the carotid stenosis using Duplex systems. Morphological
      criteria could be obtained using B-mode imaging or colour Doppler but this
      quantification remains difficult in case of diffuse carotid stenoses or very
      severe stenoses.

PMID- 10356938
TI  - [Carotid atherosclerosis and thrombotic stroke. Diagnostic and therapeutic
      perspectives].
AB  - Carotid atherosclerotic lesions can be studied with color-Doppler ultrasonography
      vascular systems. Ultrasonography of the carotid plaques at major risk for the
      development of cerebrovascular ischemic events showed the following
      characteristics: irregular surface, degree of stenosis > 70%, intimal hemorrhage
      and ulceration. The plaques with these ultrasonography patterns have to be
      considered for surgical approach (TEA). The other patients with carotid
      atherosclerotic lesions will be initially treated with diet and changes of life
      style to obtain the correction of cardiovascular risk factors (i.e. hypertension,
      hypercholesterolemia, diabetes). Furthermore, medical therapy with antithrombotic
      agents will be instituted which, used with good results also in acute cerebral
      stroke, proved to be effective in the reduction of vascular events in patients
      with extracranial atherosclerotic plaques. However, it has not been clarified if
      the positive effect of antiaggregation therapy in carotid atherosclerosis is due
      to the inhibition of the progression and plaque growth or if other
      hemorheological factors are involved.

PMID- 10356939
TI  - Salmonella mycotic aneurysms: traditional and "alternative" surgical repair with
      arterial homograft.
AB  - Salmonella infection of the abdominal aorta with formation of mycotic aneurysm is
      rare, but associated with a high mortality and morbidity. Prompt surgical
      treatment and selective and prolonged antibiotic therapy are required because of
      its rapid and impredictable evolution in a short period of time, even if an
      infectivous etiology is only suspected. Methods of revascularization can be
      different: the traditional two are in situ or extraanatomic bypass using
      synthetic graft. Both these solutions are subject to complications. An
      "alternative" method of revascularization with low risk of infection and good
      patency is the use of arterial homograft in situ. We report two cases of
      Salmonella mycotic aortic aneurysms successfully treated with revascularization
      respectively by extraanatomic bypass using synthetic graft and in situ arterial
      homograft. The reasons for our choice are also discussed.

PMID- 10356940
TI  - [Clinical and capillaroscopic evaluation of chronic uncomplicated venous
      insufficiency with procyanidins extracted from vitis vinifera].
AB  - BACKGROUND: The pharmacological treatment of non-complicated chronic venous
      insufficiency is a current and well-debated topic. The introduction of new
      products with action on the venous system, improved knowledge on the
      physiopathology of venous insufficiency and the possibility provided by new
      analytical instruments, have given new impulse to the consolidation of the
      clinical value of phlebotonics in this indication. METHODS: In light of this, 24
      patients with non-complicated chronic venous insufficiency were treated with oral
      administration of Oligomeric Proanthocyanidins (Pycnogenols-OPC) 100 mg/day. To
      evaluate the therapeutic efficacy of the treatment, an instrumental evaluation by
      optical probe capillaroscope was employed in addition to the traditional
      subjective clinical parameters: swelling, itching, heaviness and pain. The
      videocapillaroscope examination was performed at the lower third of the leg and
      the first toe. Edema in the capillaroscopic field, the number of observable
      capillaries and the capillary dilatation were the parameter chosen to evaluate
      the efficacy of treatment. All patients completed the study with no reports of
      adverse events during the period of observation. RESULTS: The results obtained
      show a positive clinical response (improved or absent symptoms) in over 80% of
      patients, with significant improvement of symptoms already evident after the
      first 10 days of treatment. The mechanism of action of the OPCs explains the
      rapid reduction of the swelling of the lower limbs and correlated with this are
      the other evaluable symptoms: heaviness and itching. Particularly striking
      results were observed for itching and pain which completely disappeared during
      the course of therapy in 80% and 53% of the patients respectively. Noteworthy is
      the good correlation between the clinical and instrumental data, with improvement
      in a total of 70% of patients. CONCLUSIONS: The results obtained in the course of
      this clinical experience, with evident improvement already during the first weeks
      of treatment, the absence of adverse events added to the benefit of a once-a-day
      administration, justify the use of OPC in the treatment of non-complicated
      chronic venous insufficiency.

PMID- 10356941
TI  - [Use of natural vitamin supplements in children during convalescence and in
      children with athletic activities].
AB  - BACKGROUND AND AIMS: Sporting activities and periods of convalescence call for an
      added intake of nutrients in children. This study aimed to evaluate the effect of
      a natural vitamin supplement on diet, food intake, body composition and muscular
      strength in children during convalescence and in children practising sports.
      METHODS: A comparative study was performed in two different groups of subjects:
      20 children aged between 6 and 12 years old during convalescence following
      infections of upper airways, and 20 9-year-old children forming part of a
      football team. All subjects were randomly subdivided into two groups who were
      respectively given a vitamin supplement (Vitality Roeder 2000 Junior) or a
      placebo for 4 weeks. Weight, body composition using and muscolar strength using
      dynamometer measured before and after the study and a food diary was kept for 3
      days before each visit. RESULTS: No significant differences in body mass and
      strength emerged from the data collected in the athletic group, whereas an
      increase was observed in appetite, calorie intake, weight and muscular strength
      in the convalescent group (p < 0.05). A significant increase in vitamin B12, B3,
      B5 and D levels was observed in both groups. CONCLUSIONS: The supplement to
      provides an adequate intake for those categories at risk of vitamin deficiency or
      in conditions of increased requirements.

PMID- 10356942
TI  - [Hematuria in pediatric clinical practice].
AB  - Haematuria, which was known at the time of Hippocrates, is defined as the
      presence of an anomalous number of red globules in the urine. It may present
      itself in a macroscopic or microscopic form. The latter is frequently found and
      is present in 1-2% of children. The pathogenesis of haematuria has been the
      object of recent acquisitions. The diagnosis is based in the first instance on
      the association of a positive urinary stick and confirmation of the presence of
      red globules in an assay of the sediment. The study of erythrocytic morphology is
      still the most useful test to identify the site of bleeding, even if more
      recently other markers, such as an excessive presence of acanthocytes or reduced
      mean corpuscle volume, together with the traditional study of cylindruria may
      represent elements to differentiate between glomerular and non-glomerular
      haematuria. Both family and personal medical history as well as objective
      examination play an important role in the definition of haematuria. Abdominal
      ultrasonography and biohumoral tests may, in association with the earlier data,
      allow a rapid and correct diagnosis of children with haematuria. A more detailed
      diagnosis using biopsy should be taken into consideration in selected cases, for
      example in familial forms that are not clearly defined and forms associated with
      altered renal function tests, as well as in persistent microhaematuria lasting
      for more than one year.

PMID- 10356943
TI  - [Measures to prevent injuries related to bicycle seats].
AB  - Injuries related to the use of bicycle seats are increasing due to the more
      frequent use of bicycles, mostly in metropolis. Several cases of children who
      suffered lesions to the lower limbs are reported from which we may summarize the
      most frequent clinical features, characterized by a foot swelling caused by the
      crushing between the wheel spokes, with different degrees of skin injuries.
      Fractures of the lower part of the leg bones are frequent as well. A greater
      number of cases was reported in summertime and, in all the bicycles, there was no
      spoke cover and the seats did not provide any protection to the feet. So far no
      precise rules for the marketing approval of bicycle seats have been fixed by UE,
      contrary to what has been already set for cars. Therefore, we suggest that such
      rules should soon be enforced. We also recommend the compulsory use of the
      helmet, as in other countries. We underline the usefulness of a more detailed
      epidemiological monitoring to better understand the dynamic of such traumatic
      events and, consequently, achieve some further improvements in the seats design,
      for an increased safety. The critical factor in prevention, however, will always
      remain a proper sanitary education. In the general chapter of accidents
      prevention, pediatrics should provide the parents with all the indications and
      cautions concerned with bicycle seat safety.

PMID- 10356944
TI  - [Medical care for children in the late middle ages].

PMID- 10356945
TI  - Extent of the odontoblastic process. Analysis by SEM and confocal microscopy.
AB  - BACKGROUND: Towards the middle of the eighteenth century, Tomes described
      membranous structures of cellular origin inside the dentinal tubules. Subsequent
      studies of the terminal segment of the odontoblasts have been controversial.
      According to Fusayama, this cellular process reaches as far as the junction;
      others, including Brannstrom, affirm that this process is present only in the
      inner third of the dentin. AIMS: The aim of the present study was to verify the
      exact length of the odontoblastic terminal segment with the aid of advanced
      confocal microscopy (CLSM) and high resolution field-emission scanning electron
      microscopy (FE-SEM). METHODS: Premolars due for extraction for orthodontic
      reasons, were used for this study; vestibular class V cavities about 2 mm in
      diameter and 3 mm in depth prepared and subsequently filled with IRM (Caulk
      Dentsply). All teeth were extracted after four weeks fixed and prepared for
      examination under SEM and CLSM. RESULTS: CLSM revealed cylindrical structures
      inside the tubules even in the absence of odontoblasts. SEM evidenced the
      presence tubular structures only in the inner third of the dentin (towards the
      pulp). CONCLUSIONS: Structures previously described as cellular processes can be
      identified as the lamina limitans of the peritubular dentin.

PMID- 10356946
TI  - [Percutaneous maxillary nerve block anesthesia in maxillofacial surgery].
AB  - BACKGROUND: Personal experience in percutaneous maxillary nerve block anesthesia
      in association with transmucosal anesthesia of the sphenopalatine ganglion in
      oral and maxillofacial surgery, is presented. METHODS: Six Caldwell-Luc, 9
      anthrotomies and biopsies of maxillary sinus, 8 removals of extensive odontogenic
      cysts and 12 surgical maxillary expansions were performed from 1994 to 1996 at
      our Department. Maxillary transcutaneous nerve block in association with
      transmucosal anesthesia of the sphenopalatine ganglion were performed. Carbocaine
      without adrenaline in association with NaCO3 1/10 for maxillary nerve block
      anesthesia and lidocaineoprilocaine cream (EMLA) for transmucosal anesthesia were
      employed. Intra- and post-operative pain were evaluated by visual analogue scale
      in all the patients. RESULTS: Anesthesiological procedures revealed to be
      effective in all surgical interventions and postoperative analgesia allowed
      easier pain control. CONCLUSIONS: The simplicity of execution, the effective pre-
      and postoperative anesthesia and the absence of side effects make this procedure
      particularly indicated in oral and maxillofacial surgery.

PMID- 10356947
TI  - [Maxillofacial trauma in pediatric age].
AB  - The different incidence of various kinds of maxillofacial fractures in children
      are examined and the causes of such differences are analyzed. The most
      significant are the variations in morphology of the maxillofacial skeleton during
      the children's growth and the physical-statistic problems strictly connected.
      Attention is drawn on the diagnostic difficulties of traumas due to fractures
      during childhood, sometimes unknown, especially with regard to the heavy
      functional and aesthetic exits which may occur.

PMID- 10356948
TI  - Giant cervico-mediastinal lipoma. A clinical case.
AB  - The lipoma is a circumscribed mesenchymal tumour originating from adipose tissue.
      The lesion is usually small and asymptomatic, and is most frequently located in
      the neck region. The case of a 77-year-old woman with chronic extrasystolic
      arrhythmia caused by a non-specified ischemic cardiopathy is reported. The woman
      presented a swelling at the front of her neck, observed for the first time about
      6 months previously. This swelling progressively increased in size, provoking
      dysphagia, dysphonia, persistent cough, dyspnea, light jugular turgor and
      palpitations. Chest X-rays showed and opaque area at the front of the neck, which
      extended beyond the jugular incisure by about 2 cm. NMR of the neck showed a
      gross lipomatous formation at the front, mainly of the left, continuing in the
      front mediastinal region; the trachea was dislocated to the right and compressed
      at the back; the vasculo-nervous fasciculus, especially on the left, was
      compressed and enveloped by the adipose formation. The Holter test confirmed the
      presence of ventricular and supra-ventricular extrasystoles. Surgery was carried
      out under local anaesthesia because the displacement of the laryngo-tracheal axes
      precluded intubation. Histological analysis of the 9 x 4 x 2.2 cm mass confirmed
      the diagnosis of lipoma. After removal of the mass all the symptoms, which had
      been provoked by compression, as well as the cardiac arrhythmias disappeared. The
      prompt disappearance of the latter was particularly surprising. The possibility
      of the external compression of the nervous structures of the neck should be taken
      into consideration in cases of ventricular arrhythmia of unknown origin, and
      systematic study of the region carried out.

PMID- 10356949
TI  - [Evaluation of two root canal preparation and obturation methods: the Mc Spadden
      method and the use of ProFile-Thermafil].
AB  - BACKGROUND: In endodontic field different instruments and techniques have been
      suggested for the preparation and filling or radicular bent canals. The purpose
      of this study is to compare two different cleaning and canal filling methods:
      preparation and filling technique, according to Mc Spadden's method, instrument
      technique and the closing of the canal system according to ProFile-Thermafil
      method. METHODS: In this study ten molars divided into two groups of five
      elements each were used. The five molars of the first group were prepared
      according to the "crown-down" technique with nickel-titanium instruments by NT
      Engine Files Quantec 2000 series. The 18 canals found out in the five molars have
      been filled with Pac Mac and gutta-percha preheated. The five molars of the
      second group have 17 radicular canals which, firstly, have been cleaned with
      ProFile .04 and .06 taper fitted to a manipulator at 220 revolutions per minute
      and then filled by Thermafil n. 30 with plastic carrier. All ten molars were X
      rayed first, during and after the treatment. All teeth were soaked into
      polymerised resin, dissected into three different points and observed through
      Optical Microscope. RESULTS: Both cleaning techniques succeed in being efficient
      in bent canals. The instruments made by Mc Spadden highlight a greater
      preservation of canal dentine than the ProFile. In samples of the first group
      there is an excellent adaptation of multiphase gutta-percha to the canal walls
      and a correct relationship between the filling material and the apical foramen.
      In filling with Thermafil the adaptation of gutta-percha inside the radicular
      canal shows outstanding differences in relation to sections taken into account.
      Actually, while in portion of the crown the filling can be considered
      satisfactory towards the canal walls, in apical sections there is a decrease in
      the quantity of gutta-percha step by step, while a contact of plastic carrier
      with dentine walls is highlighted. CONCLUSIONS: Wheter in the shaping or in the
      canal filling phase, the two methods are efficient and conservative towards
      dental structure at the same time. These methods, have an outstanding reduction
      in dental weakening and in times of the endodontic treatment performance.

PMID- 10356950
TI  - [Anesthetic efficacy of an eutectic mixture of lidocaine and prilocaine (EMLA) on
      the oral mucosa: prospective double-blind study with a placebo].
AB  - BACKGROUND AND AIMS: The aim of this study was to evaluate the topical analgesic
      efficacy of an eutectic mixture of lignocaine and prilocaine (EMLA) cream on oral
      mucosa. METHODS: The study evaluated a total of 52 patients of legal age to give
      their informed consent, requiring the removal of metal maxillary and/or
      mandibular splints used to contain fractures. A double-blind prospective study
      was carried out using EMLA cream and placebo during the removal of metal splints.
      The placebo cream contained the eccipients of EMLA cream without the active
      ingredients. After the removal of the metal clips, patients were invited to
      quantify the pain using a visual analog scale of 100 mm. Patients were then
      evaluated using an objective examination to identify the possible presence of
      alterations to the oral mucosa. RESULTS: The analysis of results highlighted a
      statistically significant difference (p < 0.01) between EMLA cream (23 mm) and
      placebo (35.3 mm) in reducing pain consequent to the removal of metal splints and
      the relative pericoronal bindings. As shown by the results of this study, the
      analgesic effect of EMLA cream on oral mucosa allow the application of contact
      anesthesia to be broadened to oral surgery and dentistry, limiting it to those
      procedures that do not involve deep tissues and only require short-term
      anesthesia.

PMID- 10356951
TI  - [Diarrheagenic toxins produced by Escherichia coli].

PMID- 10356953
TI  - [Molecular biology of dimorphism in Candida albicans].

PMID- 10356952
TI  - [Studies on the receptor for Clostridium botulinum neurotoxin].

PMID- 10356954
TI  - [Enzyme-linked immunosorbent assay for rapid detection of Clostridium perfringens
      alpha toxin].

PMID- 10356955
TI  - [Yet, the name Salmonella choleraesuis does not be used].

PMID- 10356956
TI  - N-methyl-D-aspartate (NMDA) receptor: friend or foe?

PMID- 10356958
TI  - Prevalence of serum antibodies to LA-1 oncoprotein, herpes simplex virus type-2
      glycoprotein and human papillomavirus type 16 transactivator (E2) protein among
      Indian women with cervical neoplasia.
AB  - Prevalence of serum antibodies to synthetic peptide to oncoprotein of LA-1 known
      as oncogene of herpes simplex virus type-2, herpes simplex virus type-2
      glycoprotein-D as an determinant of viral pathogenicity and human papillomavirus
      type 16 transactivator E2 protein was studied among 46 Indian women with cervical
      neoplasia using immunoblot assay for HSV-2 gD glycoprotein and LA-1 antibodies as
      well as peptide ELISA assay to detect HPV16 E2 antibodies. The seropositivity to
      LA-1 oncoprotein was found to be high (61%) among patients with invasive cervical
      carcinoma as compared to 35% in various grades of cervical intraepithelial
      neoplasia (CIN) and 36% in normal control women. In contrast to this, a uniformly
      high frequency of antibody to HPV 16 E2 was observed among women with CIN (68%),
      normal healthy controls (50%) and invasive cervical carcinoma (43%). However, a
      low frequency of seropositivity (13%) to recombinant vaccinia virus HSV-2 gD
      protein was found among 15 tested sera each from group of women with various
      grades of CIN as well as invasive cervical carcinoma as compared to 28% among
      seven normal healthy control. A negative correlation of LA-1 and HPV16 E2
      seropositivity on patient by patient comparison among CIN and invasive cervical
      carcinoma group was observed which is statistically significant (P = 0.019 for
      CIN; P = 0.038 for invasive cervical carcinoma). However, a positive correlation
      (P = 0.144) was found among normal control women. The study has shown a desirable
      serological marker of cervical neoplasia. This serological marker could be
      employed as a screening tool in conjunction with cytopathological screening to
      diagnose women harbouring LA-1 oncogene associated cervical lesions.

PMID- 10356957
TI  - Purification of catalytically active hepatic NADPH cytochrome P450 oxidoreductase
      from the rhesus monkey, Macaca mulatta.
AB  - Hepatic NADPH cytochrome P450 oxidoreductase capable of supporting polysubstrate
      monooxygenase (PSMO) reactions was purified from microsomes obtained from
      phenobarbitone (PB) pretreated rhesus monkey. Two preparations of the enzyme
      purified by affinity and molecular exclusion chromatographic techniques
      demonstrated specific content of 19.5 and 37.9 nmol cytochrome c reduced/min/mg
      protein and subunit molecular weight of 66 and 80 kDa, respectively. Both forms
      supported oxidation of NADPH and reduction of cytochrome c and DCIP but only 80
      kDa preparation supported PSMO reactions. The reconstituted system consisted of
      hepatic P450, NADPH cytochrome P450 oxidoreductase, cytochrome b5 all purified
      from PB pretreated rhesus monkey and dilauroyl phosphatidylcholine or microsomal
      lipid. Eighty kDa preparation supported the metabolism of aminopyrine and
      tolbutamide by hepatic P4502C and erythromycin, ethylmorphine and nifedipine by
      hepatic P450 3A, respectively. The turnover of these substrates increased in the
      presence of partially purified cytochrome b5 from the rhesus monkey. To best of
      our knowledge this is the first report on the purification of monkey hepatic
      NADPH cytochrome P450 oxidoreductase capable of supporting in vitro PSMO by
      different isozymes of P450.

PMID- 10356959
TI  - Antinociceptive effect of sumatriptan in mice.
AB  - Antinociceptive effect of the antimigraine drug sumatriptan (5-HT1A agonist) was
      studied against acetic acid-induced writhing in mice. Sumatriptan produced the
      effect in a dose-dependent manner (1, 5, 10 and 20 mg/kg, s.c.). Naloxone (1
      mg/kg i.p.) an opiate antagonist failed to reverse sumatriptan-induced
      antinociception. Cholinomimetic physostigmine (0.05 mg/kg, i.p.) potentiated and
      the muscarinic antagonist atropine (5 mg/kg, i.p.) blocked the antinociceptive
      effect of sumatriptan, respectively. The antinociceptive effect of sumatriptan
      was compared with an another 5-HT agonist (5-HT1A) buspirone which also produced
      antinociception. Like sumatriptan-analgesia, the buspirone response was also
      potentiated by physostigmine in atropine sensitive way. Further, buspirone
      potentiated the analgesic effect of sumatriptan. These observations suggest that
      5-HT1A agonists produce antinociception possibly by modulating central
      cholinergic activity.

PMID- 10356960
TI  - Antiinflammatory activity of Muktashukti bhasma.
AB  - Muktashukti bhasma (MSB), an Ayurvedic compound, consisting of pearl, Aloe vera
      and vinegar, inhibited acute and subacute inflammation in albino rats as induced
      by subplanter injection of carrageenan, histamine, 5-HT, nystatin and
      subcutaneous implant of cotton pellets. In all the test procedures the
      antiinflammatory response of 1000 mg/kg MSB was comparable to the response
      observed with 300 mg/kg acetylsalicylic acid (ASA). Oral premedication with MSB
      delayed castor oil-induced diarrhoea in rats, indicating its prostaglandin
      inhibitory activity. The antiinflammatory activity of the compound is attributed
      to its ability to cause inhibition of prostaglandins, histamine and 5-HT and also
      by stabilization of the lysosomal membranes. The antiinflammatory activity of MSB
      seems one third to half as potent as ASA.

PMID- 10356961
TI  - Experimental analysis of gossypol and chloroquine interaction in serum and in
      liver of rat.
AB  - Interactive effects of gossypol and chloroquine as determined by activities of
      serum alanine transaminase (ALT), aspartate transaminase (AST) and liver lactate
      dehydrogenase (LDH), alkaline phosphatase (ALK-pase), glucose-6-phosphatase (G-6
      pase) and cholesterol level were investigated in rats. Administration of gossypol
      for eight weeks, at a concentration of 20 mg per kg body wt. per day with or
      without chloroquine had no effect on the serum enzymes and glucose-6-phosphatase
      activities. When chloroquine at a concentration of 5 mg per kg body wt. thrice a
      week was administered alone, there was a marked decrease in total protein content
      and ALK-pose activities, while a significant increase in LDH activity was
      observed. Administration of either gossypol or chloroquine decreased the level of
      cholesterol. A greater decrease was recorded when both were given together. It is
      suggested that gossypol can be employed as a male contraceptive among malaria
      infected populations.

PMID- 10356962
TI  - Effect of prenatal diazepam, phenobarbital, haloperidol and fluoxetine exposure
      on foot shock induced aggression in rats.
AB  - Different groups of pregnant rats were treated with diazepam (10 mg/kg),
      phenobarbital (10 mg/kg), haloperidol (0.1 mg/kg), fluoxetine (10 mg/kg) and
      vehicle (normal saline) intraperitoneally once a day during gestation days 13 to
      21. After birth these pups were culled to 8 pups/dam and foster-nursed by
      lactating mothers for 3 weeks and were reared in colony cages thereafter. Sex and
      weight matched pairs of rat offsprings were subjected to foot shock induced
      aggression test at 8 weeks of age. Two parameters of aggressive behaviour were
      recorded namely, the latency to fight and total number of fighting bouts. The
      results indicate that prenatal exposure to diazepam, phenobarbital, haloperidol
      and fluoxetine caused significantly enhanced aggression in terms of number of
      fighting bouts.

PMID- 10356963
TI  - Effect of cryopreservation on lipid peroxidation in chick cornea.
AB  - A mechanism suggested to cause injury to the preserved organs in vitro is the
      generation of oxygen free radicals either during preservation or after
      transplantation due to reperfusion. Methods to suppress generation of oxygen free
      radicals may lead to improved methods of organ preservation. In this study,
      increase in the levels of lipid peroxidation in chick cornea after
      cryopreservation is reported. Addition of fetal bovine serum (FBS) in
      cryopreservation medium was found to prevent lipid peroxidation. Addition of FBS
      was also found to be protective towards corneal viability during
      cryopreservation.

PMID- 10356964
TI  - Comparative evaluation of antiinflammatory potential of fixed oil of different
      species of Ocimum and its possible mechanism of action.
AB  - Ocimum sanctum fixed oil and linolenic acid found to possess significant
      antiinflammatory activity against PGE2, leukotriene and arachidonic acid-induced
      paw edema. The other species of Ocimum, viz. O. basilicum and O. americanum also
      containing linolenic acid in varying proportions, also showed significant
      inhibition of edema against carrageenan, PGE2, leukotriene and arachidonic acid
      induced paw edema. The fixed oil of O. basiliaum containing maximum percentage of
      linolenic acid showed higher protection. The results suggests that linolenic acid
      percent in the fixed oils of different species of Ocimum has the capacity to
      block both the cyclooxygenase and lipoxygenase pathways of arachidonate
      metabolism and could be responsible for the antiinflammatory activity.

PMID- 10356965
TI  - Hypoglycemic activity of Cajanus cajan (seeds) in mice.
AB  - The effect of roasted and unroasted seeds of C. cajan on serum glucose levels of
      normal and alloxan diabetic mice were studied. Single doses of unroasted seeds
      (60% and 80%) on administration to normal as well as alloxanized mice showed
      significant reduction in the serum glucose levels after 1-2 hr and a significant
      rise at 3 hr. In case of roasted seeds, on other hand there was a significant
      increase in serum glucose levels during 3 hr experimental period. It is therefore
      concluded that roasting of seeds at high temperature for an half hour period
      resulted in the total loss of hypoglycemic principle but not the hyperglycemic
      principle present in the seeds.

PMID- 10356966
TI  - Detection of bluetongue virus genome segment 6 sequences by RT-PCR.
AB  - Reverse transcription-PCR (RT-PCR) technique was adopted to amplify a 101
      basepair nucleotide sequence of bluetongue virus (BTV) genome segment 6. The
      specificity of the amplicon was determined by its approximate size in 3% agarose
      gel electrophoresis, digestion with restriction enzyme MspI, dot-blot
      hybridization and cycle sequencing. The technique was found to be suitable for
      detection of bluetongue virus in infected cell culture and clinical samples.

PMID- 10356967
TI  - Modulation of humoral immune response by ascorbic acid in Oreochromis mossambicus
      (Peters).
AB  - Fish were treated with sublethal doses of ascorbic acid before being immunised
      with different physical forms of bovine serum albumin (BSA). Ascorbic acid
      elevates the antibody response to all the physical forms of BSA tested.
      Generally, there was an inverse relationship between the dose of ascorbic acid
      and antibody response. In fish administered with multiple doses of ascorbic acid,
      no significant enhancement of antibody response was observed.

PMID- 10356968
TI  - In vivo sister chromatid differentiation and base line sister chromatid exchanges
      in Channa punctatus.
AB  - An in vivo system for differentially stained sister chromatids by incorporating
      5' Bromo 2' deoxyuridine at two consecutive round of DNA replication has been
      developed in C. punctatus. The base line developed frequency of sister chromatid
      exchanges (SCEs) was found to be 0.038 SCE/chromosome. This low baseline
      frequency of SCEs could be useful in detecting genotoxicity of pollutants in
      aquatic medium.

PMID- 10356969
TI  - Measuring the perceptual magnet effect in the perception of /i/ by German
      listeners.
AB  - In a study of the internal category structure of the vowel /i/, Kuhl found a
      "perceptual magnet effect": Discrimination sensitivity was poorer for category
      instances that were acoustically similar to the category prototype than it was
      for category instances that were not. The typicality of category exemplars was
      determined by goodness judgments and was found to correlate with the acoustics of
      average production. Analysis and interpretation of discrimination performance
      relied on two important assumptions: that listeners perceived all stimuli
      presented as exemplars of the same vowel category and that, apart from the
      influence of phonetic coding, discrimination sensitivity was the same across the
      investigated part of the vowel space. In the present study, it is shown that
      production and perception estimates of the category prototype may diverge,
      possibly because listeners seem to prefer hyperarticulated variants of vowel
      categories. An approach towards measurement of intra-category discrimination
      minima is put forward and tested that protects against intercategory confounds
      and avoids the isosensitivity assumption.

PMID- 10356970
TI  - Sources of position-perception error for small isolated targets.
AB  - It has often been reported that, in the presence of static reference stimuli,
      briefly presented visual targets are perceived as being closer to the fixation
      point than they actually are. The first purpose of the present study was to
      investigate whether the same phenomenon can be demonstrated in a situation
      without static reference stimuli. Experiment 1, with position naming as the task,
      showed that such a central shift is also observed under these conditions. This
      finding is of importance because it completes an explanation for central near
      location errors in the partial-report bar-probe task. The second purpose of the
      present study was to provide an explanation for these central shifts. For this
      explanation information about the exact size of the central shift is required. In
      Exps. 2, 3, and 4, with cursor setting as the task, it was attempted to assess
      more precisely the size of the central shifts. These experiments revealed that
      two different factors determine the results in cursor setting tasks; a factor
      "target position" and a factor "cursor position." Experiment 5 showed that it is
      the point of fixation, not the fixation point, that serves, at least in part, as
      the reference point in this type of task. All the findings together allow us to
      conclude that the target positions are underestimated by about 10%. From vision
      research it is known that saccadic eye movements, performed for bringing a target
      in the fovea, also show an undershoot of about 10%. It is therefore concluded
      that the system in charge of saccadic eye movements also provides the metric in
      visual space within a single eye fixation.

PMID- 10356971
TI  - Mental rotation, memory scanning, and the central bottleneck.
AB  - Two reaction-time experiments using the psychological refractory period paradigm
      examined whether two prominent tasks, i.e., mental rotation and memory scanning,
      require access to a single-channel mechanism and must therefore be performed
      sequentially with other operations requiring the same mechanism. On each trial,
      subjects made speeded responses to a tone (Exp. 1) or a character (Exp. 2, with
      symbolic SR-compatibility of the character manipulated) as Task 1 and to a letter
      (for blocks with mental rotation) or a digit (for blocks with memory scanning) as
      Task 2. The set-size effect was constant across SOAs, suggesting that memory
      scanning cannot be performed in parallel with response selection of Task 1. The
      effect of orientation, however, decreased with decreasing SOA. The decrease was
      even intensified if Task 1 bottleneck processes were prolonged by symbolic SR
      compatibility. The exact pattern of underadditivity, however, was not predicted
      by current theories of dual-task performance. The results contradict a central
      bottleneck model but are in line with extensions of the model proposed by Meyer
      and Kieras.

PMID- 10356973
TI  - Characterization of a novel cis-benzene dihydrodiol dehydrogenase from
      Pseudomonas putida ML2.
AB  - A second and novel cis-benzene dihydrodiol dehydrogenase which is able to
      dehydrogenate a range of cis-dihydrodiols and other vicinal alcohols has been
      purified from Pseudomonas putida ML2. The enzyme is a tetramer of a polypeptide
      of 39 kDa in molecular mass and has a pH optimum of 9.0. Despite having a primary
      structure that has significant similarity to glycerol dehydrogenases, the kcat/Km
      value of the enzyme for cis-benzene dihydrodiol is 4300-fold higher compared to
      glycerol. The apparent Km values of the enzyme for cis-benzene dihydrodiol and
      glycerol are 0.01 mM and 46 mM, respectively, and 0.22 mM for NAD+.

PMID- 10356972
TI  - Selective peroxisome degradation in Yarrowia lipolytica after a shift of cells
      from acetate/oleate/ethylamine into glucose/ammonium sulfate-containing media.
AB  - We have shown that peroxisomes of the yeast Yarrowia lipolytica are subject to
      specific degradation after exposure of acetate/oleate-grown cells to glucose
      excess conditions. Electron microscopic analysis has revealed that the
      peroxisomes were degraded by uptake in the vacuole. Our results suggest that
      peroxisomes are taken up by macroautophagic processes, because sequestration of
      individual peroxisomes, which occurs typically at the beginning of
      microautophagy, was never observed. The observation that a peroxisomal amine
      oxidase activity is specifically induced by ethylamine was used for the
      development of a plate assay screening procedure to isolate peroxisome
      degradation-defective mutants.

PMID- 10356974
TI  - A downstream splicing enhancer is essential for in vitro pre-mRNA splicing.
AB  - Splicing enhancers have previously been shown to promote processing of introns
      containing weak splicing signals. Here, we extend these studies by showing that
      also 'strong' constitutively active introns are absolutely dependent on a
      downstream splicing enhancer for activity in vitro. SR protein binding to exonic
      enhancer elements or U1 snRNP binding to a downstream 5' splice site serve
      redundant functions as activators of splicing. We further show that a 5' splice
      site is most effective as an enhancer of splicing. Thus, a 5' splice site is
      functional in S100 extracts, under conditions where a SR enhancer is
      nonfunctional. Also, splice site pairing occurs efficiently in the absence of
      exonic SR enhancers, emphasizing the significance of a downstream 5' splice site
      as the enhancer element in vertebrate splicing.

PMID- 10356975
TI  - A 45 amino acid residue domain necessary and sufficient for proteolytic cleavage
      of the MAP1B polyprotein precursor.
AB  - The microtubule-associated proteins 1B and 1A are synthesized as polyprotein
      precursors which are rapidly cleaved to give rise to heavy and light chains
      constituting the respective microtubule-associated protein 1B or microtubule
      associated protein 1A complex. To identify domains necessary for precursor
      processing, we expressed microtubule-associated protein 1B deletion mutants in
      fibroblasts and monitored proteolytic cleavage of the precursor proteins by
      immunoblot analysis. We found that a novel hydrophilic, proline-rich 45 amino
      acid domain containing the cleavage site is necessary and sufficient for
      processing. This domain is conserved in microtubule-associated protein 1A.
      Additional sequences in the N-terminal half of the heavy chain contribute to the
      efficiency of cleavage.

PMID- 10356976
TI  - N-glycans are not the signal for apical sorting of corticosteroid binding
      globulin in MDCK cells.
AB  - It has been suggested that N-glycans act as a general sorting signal for
      secretory proteins in MDCK cells [Scheiffele et al. (1995) Nature 378, 96-98].
      Human corticosteroid binding globulin contains six consensus sites for N
      glycosylation and is known to be secreted to the apical side of MDCK cells. Our
      results show that wild-type corticosteroid binding globulin is N-glycosylated
      when it is recombinantly expressed in MDCK cells. Six mutants, each lacking one
      of the N-glycosylation sites, and a mutant lacking all six N-glycosylation sites
      were also secreted to the apical side of MDCK cells in a polarized manner. Thus,
      the N-glycans on corticosteroid binding globulin do not act as an apical sorting
      signal in MDCK cells.

PMID- 10356977
TI  - Prediction of protein subcellular locations using Markov chain models.
AB  - A novel method was introduced to predict protein subcellular locations from
      sequences. Using sequence data, this method achieved a prediction accuracy higher
      than previous methods based on the amino acid composition. For three subcellular
      locations in a prokaryotic organism, the overall prediction accuracy reached
      89.1%. For eukaryotic proteins, prediction accuracies of 73.0% and 78.7% were
      attained within four and three location categories, respectively. These results
      demonstrate the applicability of this relative simple method and possible
      improvement of prediction for the protein subcellular location.

PMID- 10356978
TI  - Structure of VAT, a CDC48/p97 ATPase homologue from the archaeon Thermoplasma
      acidophilum as studied by electron tomography.
AB  - Valosine-containing protein-like ATPase from Thermoplasma acidophilum is a member
      of the superfamily of ATPases associated with a diversity of cellular activities
      and is closely related to CDC48 from yeast and p97 from higher eukaryotes and
      more distantly to N-ethylmaleimide-sensitive fusion protein. We have used
      electron tomography to obtain low-resolution (2-2.5 nm) three-dimensional maps of
      both the whole 500 kDa complex and the N-terminally truncated valosine-containing
      protein-like ATPase from T. acidophilum complex lacking the putative substrate
      binding domain.

PMID- 10356979
TI  - Beta2 integrin-dependent phosphorylation of protein-tyrosine kinase Pyk2
      stimulated by tumor necrosis factor alpha and fMLP in human neutrophils adherent
      to fibrinogen.
AB  - Tumor necrosis factor alpha and fMLP can activate a broad range of cellular
      functions in neutrophils adherent to biological surfaces. These functions are
      mediated by integrins and involve the activation of tyrosine kinases. Here, we
      report that Pyk2, a member of the focal adhesion kinase family, was present in
      human neutrophils and was rapidly phosphorylated and activated following tumor
      necrosis factor alpha and fMLP stimulation in an adhesion-dependent manner.
      Tyrosine phosphorylation of Pyk2 was attenuated by beta2 integrin blocking with
      specific antibodies. The tyrosine phosphorylation of Pyk2 was downstream of
      protein kinases Lyn, Syk and protein kinase C and cytoskeletal organization. The
      activation of Pyk2 may play a role in adhesion/cytoskeleton-associated
      neutrophils function.

PMID- 10356980
TI  - Assembly of paired helical filaments from mouse tau: implications for the
      neurofibrillary pathology in transgenic mouse models for Alzheimer's disease.
AB  - In Alzheimer's disease and related dementias, human tau protein aggregates into
      paired helical filaments and neurofibrillary tangles. However, such tau
      aggregates have not yet been demonstrated in transgenic mouse models of the
      disease. One of the possible explanations would be that mouse tau has different
      properties which prevents it from aggregating. We have cloned several murine tau
      isoforms, containing three or four repeats and different combinations of inserts,
      expressed them in Escherichia coli and show here that they can all be assembled
      into paired helical filaments similar to those in Alzheimer's disease, using the
      same protocols as with human tau. Therefore, the absence of pathologically
      aggregated tau in transgenic mice cannot be explained by intrinsic differences in
      mouse tau protein and instead must be explained by other as yet unknown factors.

PMID- 10356981
TI  - Gene for a protein capable of enhancing lateral root formation.
AB  - Analysis of genes preferentially expressed in hairy roots caused by infection
      with Agrobacterium rhizogenes has provided insights into the regulation of
      lateral root formation. A hairy root preferential cDNA, HR7, has been cloned from
      hairy roots of Hyoscyamus niger. HR7 encodes a novel protein partially homologous
      to a metallocarboxypeptidase inhibitor and is expressed exclusively in the
      primordium and base of lateral roots in hairy roots. Overexpression of HR7 in
      transgenic roots of H. niger dramatically enhances the frequency of lateral root
      formation. The results of this study indicate that expression of HR7 plays a
      critical role in initiating lateral root formation.

PMID- 10356982
TI  - N-terminal domain, residues 1-91, of ribosomal protein TL5 from Thermus
      thermophilus binds specifically and strongly to the region of 5S rRNA containing
      loop E.
AB  - In this work we show for the first time that the overproduced N-terminal fragment
      (residues 1-91) of ribosomal protein TL5 binds specifically to 5S rRNA and that
      the region of this fragment containing residues 80-91 is a necessity for its RNA
      binding activity. The fragment of Escherichia coli 5S rRNA protected by TL5
      against RNase A hydrolysis was isolated and sequenced. This 39 nucleotides
      fragment contains loop E and helices IV and V of 5S rRNA. The isolated RNA
      fragment forms stable complexes with TL5 and its N-terminal domain. Crystals of
      TL5 in complex with the RNA fragment diffracting to 2.75 A resolution were
      obtained.

PMID- 10356983
TI  - The role of O-linked sugars in determining the very low density lipoprotein
      receptor stability or release from the cell.
AB  - The very low density lipoprotein receptor is a member of the low density
      lipoprotein receptor supergene family for which two isoforms have been reported,
      one lacking and the other containing an O-linked sugar domain. In order to gain
      insight into their functionality, transient and stable transformants separately
      overexpressing previously cloned bovine variants were analyzed. We report
      evidence that the variant lacking the O-linked sugar domain presented a rapid
      cleavage from the cell and that a large amino-terminal very low density
      lipoprotein receptor fragment was released into the culture medium. As only minor
      proteolysis was involved in the other very low density lipoprotein receptor
      variant, the clustered O-linked sugar domain may be responsible for blocking the
      access to the protease-sensitive site(s). To test this hypothesis, a mutant
      Chinese hamster ovary cell line, ldlD, with a reversible defect in the protein O
      glycosylation, was used. The instability of the O-linked sugar-deficient very low
      density lipoprotein receptor on the cell surface was comparable to that induced
      by the proteolysis of the variant lacking the O-linked sugar domain. Moreover,
      our data suggest that the O-linked sugar domain may also protect the very low
      density lipoprotein receptor against unspecific proteolysis. Taken together,
      these results indicate that the presence of the O-linked sugar domain may be
      required for the stable expression of the very low density lipoprotein receptor
      on the cell surface and its absence may be required for release of the receptor
      to the extracellular space. The exclusive expression of the variant lacking the O
      linked sugar domain in the bovine aortic endothelium opens new perspectives in
      the physiological significance of the very low density lipoprotein receptor.

PMID- 10356984
TI  - Resveratrol inhibits MAPK activity and nuclear translocation in coronary artery
      smooth muscle: reversal of endothelin-1 stimulatory effects.
AB  - In porcine coronary arteries, short-term treatment with resveratrol (RSVL)
      substantially inhibited MAPK activity (IC50 = 37 microM); and immunoblot analyses
      revealed consistent reduction in the phosphorylation of ERK-1/-2, JNK-1 and p38,
      at active sites. Endothelin-1 (ET-1), a primary antecedent in coronary heart
      diseases, enhanced MAPK activity, phosphorylation and nuclear translocation in a
      concentration-responsive but RSVL-sensitive manner. RSVL had no effect on basal
      or forskolin-stimulated cAMP levels, a known downregulator of the MAPK cascade.
      Likewise, inhibition of MAPK by RSVL was not reversed by the estrogen receptor
      blockers tamoxifen and ICI-182,780. Conversely, RSVL remarkably attenuated basal
      and ET-1-evoked protein tyrosine phosphorylation. Because MAPKs promote smooth
      muscle proliferation and contraction, their current inhibition may contribute to
      the putative protection by RSVL against coronary heart diseases. These effects
      apparently do not involve interaction with estrogen receptors.

PMID- 10356985
TI  - Characterization of the actin binding properties of the vasodilator-stimulated
      phosphoprotein VASP.
AB  - The vasodilator-stimulated phosphoprotein (VASP) colocalizes with the ends of
      stress fibers in cell-matrix and cell-cell contacts. We report here that
      bacterially expressed murine VASP directly interacts with skeletal muscle actin
      in several test systems including cosedimentation, viscometry and polymerization
      assays. It nucleates actin polymerization and tightly bundles actin filaments.
      The interaction with actin is salt-sensitive, indicating that the complex
      formation is primarily based on electrostatic interactions. Actin binding is
      confined to the C-terminal domain of VASP (EVH2). This domain, when expressed as
      a fusion protein with EGFP, associates with stress fibers in transiently
      transfected cells.

PMID- 10356986
TI  - Differential expression of beta1,3galactosyltransferases in human colon cells
      derived from adenocarcinomas or normal mucosa.
AB  - Two beta1,3galactosyltransferases are detected in human colon cells: one
      corresponds to beta3GalT1, the other (beta3GalTx) is found to be different from
      any cloned beta3GalT since in vitro it utilizes GlcNAc very efficiently under
      specific reaction conditions. Expression of beta3GalT1 transcript is high in
      normal colon mucosa and control neuroectodermal cells, which do not express
      sialyl-Lewis a antigen, and low in colon adenocarcinoma cells, as assessed by
      competitive RT-PCR. beta3GalTx activity is high in adenocarcinoma cells
      expressing sialyl-Lewis a and undetectable in all other cells, suggesting
      differential involvement and opposite regulation of such enzymes during
      carcinogenesis.

PMID- 10356987
TI  - ZIP kinase identified as a novel myosin regulatory light chain kinase in HeLa
      cells.
AB  - A novel myosin light chain kinase (MLCK) cDNA was isolated from a HeLa cell cDNA
      library. The deduced amino acid sequence was identical to that of a zipper
      interacting protein kinase (ZIPK) which mediates apoptosis [Kawai et al. (1998)
      Mol. Cell. Biol. 18, 1642-1651]. Here we found that HeLa ZIPK phosphorylated the
      regulatory light chain of myosin II (MRLC) at both serine 19 and threonine 18 in
      a Ca2+/calmodulin independent manner. Phosphorylation of myosin II by HeLa ZIPK
      resulted in activation of actin-activated MgATPase activity of myosin II. HeLa
      ZIPK is the first non-muscle MLCK that phosphorylates MRLC at two sites.

PMID- 10356988
TI  - Genetic analysis of the role of protein kinase C signaling pathways in behaviors
      by direct gene transfer with HSV-1 vectors.
AB  - A genetic intervention strategy is described to elucidate the specific
      biochemical pathways in identified types of neurons that underlie behavioral
      adaptations. This strategy contains three parts: A Herpes simplex virus (HSV-1)
      vector is used to obtain localized gene transfer, a cell type-specific promoter
      is used to target expression to a particular type of neuron, and a constitutively
      active signal transduction enzyme is expressed to alter neuronal physiology. To
      enable this approach, a constitutively active protein kinase C (PKC) was
      developed which causes a long-lasting, activation-dependent increase in
      neurotransmitter release from cultured sympathetic neurons. This genetic
      intervention strategy was tested using the nigrostriatal system: Microinjection
      of HSV-1 vectors that contain the tyrosine hydroxylase promoter targeted
      expression to dopaminergic nigrostriatal neurons. Expression of the
      constitutively active PKC in a small percentage of nigrostriatal neurons
      (approximately 0.1-2%) produced a long-term (> or = 1 month) change in
      apomorphine-induced rotational behavior, the amount of rotational behavior
      correlated with the number of affected nigrostriatal neurons, and D2-like
      dopamine receptor levels were elevated in the striatal regions innervated by the
      affected nigrostriatal neurons. The strengths and limitations of this genetic
      intervention strategy are discussed.

PMID- 10356989
TI  - Transgenic animals in Alzheimer's disease research.
AB  - Alzheimer's disease (AD) is a neurodegenerative disorder of the brain accounting
      for about 50-70% of the typical late onset cases of dementia. The pathological
      and diagnostic hallmarks of the disease are principally the presence of
      extracellular deposits called neuritic amyloid plaques and the intracellular
      aggregation of neurofibrillary tangles. In addition selective neuronal cell loss
      accompanied by cerebrovascular amyloidosis is detectable. In the case of familial
      AD, defects in at least three different genes (APP, PS1, PS2) leading to
      indistinguishable pathology are now well defined. There is as yet no real
      treatment for AD. Therefore the availability of an easily manipulable animal
      model is crucial for the development of new drugs, which could slow down or, even
      better, stop the progression of the disease. The development and originality of
      such experimental models that could greatly facilitate the investigation of the
      aetiology and pathogenesis of AD are described and discussed in this review. They
      are based mainly on the attempt to reproduce the neurofibrillary tangles or the
      amyloid deposits and plaque formation.

PMID- 10356990
TI  - In vivo neurochemical correlates of cognitive processes: methodological and
      conceptual challenges.
AB  - The advent of the use of in vivo microdialysis and voltammetry techniques in
      behaving animals has ushered in a great deal of research on the neurochemistry of
      cognition. While studies exploring the relationship between neurotransmitter
      release and cognitive processing are quite feasible, a number of methodological
      and conceptual issues pose challenges to the interpretation of experimental
      results. These challenges include: 1) a demonstration that the behavioral task
      highlights the particular cognitive construct under study; 2) a determination of
      the role of non-cognitive variables (i.e. transfer effects, sensory stimulation,
      motivational variables, and motor activity) in affecting transmitter release, and
      3) a recognition of the value of a distributed systems approach to studying the
      neurochemistry of cognition. This review summarizes the data on the validity of
      microdialysis and voltammetry as correlates of neurotransmitter release and then
      illustrates the impact that the above challenges can have on the conclusions
      drawn from various studies.

PMID- 10356991
TI  - The contribution of the anterior cingulate cortex to executive processes in
      cognition.
AB  - The anterior cingulate cortex (ACC), on the medial surface of the frontal lobes,
      has frequently been hypothesized to make critical contributions to the function
      of neural systems involved in the executive control of cognition. Three principal
      theories have been developed to account for this role. The first, 'motivated
      attention', emphasizes the limbic identity of the ACC and the effects of lesions
      to this area of the brain. The second, 'attention allocation', emphasizes the
      fact that during functional neuroimaging studies activation of the ACC is seen
      during tasks that elicit incompatible response tendencies that must be resolved
      for correct performance. The third theory, 'error detection', reflects the
      observation of a negative scalp potential occurring during incorrect responses
      which appears to have a medial frontal generator. The first and last theories
      suggest evaluative functions by the ACC in the service of control, while
      attention allocation suggests a strategic function. We have proposed that the
      data supporting all three theories can be reconciled if the ACC were detecting
      conflicting processes during task performance that might be associated with
      errors. In support of this hypothesis we describe results using event-related
      fMRI which confirm that the ACC does show error related activity but that the
      same region of the brain also shows increased response related activity during
      correct responses associated with response competition. This suggests a re
      conceptualization of the contribution of the ACC to executive processes that
      support an evaluative role, specifically the on-line detection of processing
      conflicts that may be associated with deteriorating performance. Unresolved
      questions related to the contribution of this region to executive processes and
      potential future directions for research on the function of this region of the
      brain are discussed.

PMID- 10356992
TI  - Phencyclidine in the social interaction test: an animal model of schizophrenia
      with face and predictive validity.
AB  - Phencyclidine (PCP) is a hallucinogenic drug that can mimic several aspects of
      the schizophrenic symptomatology in healthy volunteers. In a series of studies
      PCP was administered to rats to determine whether it was possible to develop an
      animal model of the positive and negative symptoms of schizophrenia. The rats
      were tested in the social interaction test and it was found that PCP dose
      dependently induces stereotyped behaviour and social withdrawal, which may
      correspond to certain aspects of the positive and negative symptoms,
      respectively. The effects of PCP could be reduced selectively by antipsychotic
      drug treatment, whereas drugs lacking antipsychotic effects did not alleviate the
      PCP-induced behaviours. Together these findings indicate that PCP effects in the
      rat social interaction test may be a model of the positive and negative symptoms
      of schizophrenia with face and predictive validity and that it may be useful for
      the evaluation of novel antipsychotic compounds.

PMID- 10356993
TI  - Polymer hydrolysis in a cold climate.
AB  - In this review we discuss the activity of an ecologically significant group of
      psychrophilic bacteria, which are involved in the hydrolysis of plant cell wall
      polymers. Until now these organisms have been largely overlooked, despite the key
      role they play in releasing organic carbon fixed by primary producers in
      permanently cold environments such as Antarctica. This review details a specific
      group of plant cell wall polymer-degrading enzymes known as beta-glycanases.
      Studies on "cold" enzymes in general are in their infancy, but it has been shown
      that many exhibit structural and functional modifications that enable them to
      function at low temperature. beta-Glycanases in particular are intriguing because
      their substrates (cellulose and xylan) are very refractile, which may indicate
      that their "cold" modifications are pronounced. In addition, mesophilic beta
      glycanases have been extensively studied and the current state of our knowledge
      is reviewed. This body of information can be exploited to enable meaningful
      comparative studies between mesophilic and psychrophilic beta-glycanases. The aim
      of such investigations is to obtain a deeper insight into those structural and
      functional modifications that enable these enzymes to function at low temperature
      and to examine the evolutionary relationship between mesophilic and psychrophilic
      beta-glycanases.

PMID- 10356994
TI  - NH4+ transport system of a psychrophilic marine bacterium, Vibrio sp. strain ABE
      1.
AB  - NH4(+) transport system of a psychrophilic marine bacterium Vibrio sp. strain ABE
      1 (Vibrio ABE-1) was examined by measuring the uptake of [14C]methylammonium ion
      (14CH3NH3+) into the intact cells. 14CH3NH3+ uptake was detected in cells grown
      in medium containing glutamate as the sole nitrogen source, but not in those
      grown in medium containing NH4Cl instead of glutamate. Vibrio ABE-1 did not
      utilize CH3NH3+ as a carbon or nitrogen source. NH4Cl and nonradiolabeled CH3NH3+
      completely inhibited 14CH3NH3+ uptake. These results indicate that 14CH3NH3+
      uptake in this bacterium is mediated via an NH4+ transport system and not by a
      specific carrier for CH3NH3+. The respiratory substrate succinate was required to
      drive 14CH3NH3+ uptake and the uptake was completely inhibited by KCN, indicating
      that the uptake was energy dependent. The electrochemical potentials of H+ and/or
      Na+ across membranes were suggested to be the driving forces for the transport
      system because the ionophores carbonylcyanide m-chlorophenylhydrazone and
      monensin strongly inhibited uptake activities at pH 6.5 and 8.5, respectively.
      Furthermore, KCl activated 14CH3NH3+ uptake. The 14CH3NH3+ uptake activity of
      Vibrio ABE-1 was markedly high at temperatures between 0 degrees and 15 degrees
      C, and the apparent Km value for CH3NH3+ of the uptake did not change
      significantly over the temperature range from 0 degrees to 25 degrees C. Thus,
      the NH4+ transport system of this bacterium was highly active at low
      temperatures.

PMID- 10356995
TI  - Biodiversity in deep-sea sites located near the south part of Japan.
AB  - We obtained 100 isolates of bacteria from deep-sea mud samples collected at
      various depths (1050-10897m). Various types of bacteria such as alkaliphiles,
      thermophiles, psychrophiles, and halophiles were recovered on agar plates at a
      frequency of 0.8 x 10(2) to 2.3 x 10(4)/ g of dry sea mud. No acidophiles were
      recovered. These extremophilic bacteria were widely distributed, being detected
      at each deep-sea site, and the frequency of isolation of such extremophiles from
      the deep-sea mud was not directly influenced by the depth of the sampling sites.
      Phylogenetic analysis of deep-sea isolates based on 16S rDNA sequences revealed
      that a wide range of taxa were represented in the deep-sea environments. Growth
      patterns under high hydrostatic pressure were determined for the deep-sea
      isolates obtained in this study. No extremophilic strains isolated in this study
      showed growth at 60MPa, although a few of the other isolates grew slightly at
      this hydrostatic pressure.

PMID- 10356996
TI  - Family 10 and 11 xylanase genes from Caldicellulosiruptor sp. strain Rt69B.1.
AB  - Three family 10 xylanase genes (xynA, xynB, and xynC) and a single family 11
      xylanase gene (xynD) were identified from the extreme thermophile
      Caldicellulosiruptor strain Rt69B.1 through the use of consensus PCR in
      conjunction with sequencing and polyacrylamide gel electrophoresis. These genes
      appear to comprise the complete endoxylanase system of Rt69B.1. The xynA gene was
      found to be homologous to the xynA gene of the closely related
      Caldicellulosiruptor strain Rt8B.4, and primers designed previously to amplify
      the Rt8B.4 xynA gene could amplify homologous full-length xynA gene fragments
      from Rt69B.1. The complete nucleotide sequences of the Rt69B.1 xynB, xynC, and
      xynD genes were obtained using genomic walking PCR. The full-length xynB and xynC
      genes are more than 5 kb in length and encode highly modular enzymes that are the
      largest xylanases reported to date. XynB has an architecture similar to the
      family 10 xylanases from Thermoanaerobacterium saccharolyticum (XynA) and
      Clostridium thermocellum (XynX) and may be cell wall associated, while XynC is a
      bifunctional enzyme with an architecture similar to the bifunctional beta
      glycanases from Caldicellulosiroptor saccharolyticus. The xynD gene encodes a two
      domain family 11 xylanase that is identical in architecture to the XynB family 11
      xylanase from the unrelated extreme thermophile Dictyoglomus thermophilum strain
      Rt46B.1. The sequence similarities between the Rt69B.1 xylanases with respect to
      their evolution are discussed.

PMID- 10356998
TI  - Purification and characterization of an ADP-dependent phosphofructokinase from
      Thermococcus zilligii.
AB  - The ADP-dependent phosphofructokinase (PFK) from Thermococcus zilligii has been
      purified 950 fold; it had a specific activity of 190 Umg(-1). The enzyme required
      Mg2+ ions for optimal activity and was specific for ADP. The forward reaction
      kinetics were hyperbolic for both cosubstrates (pH optimum of 6.4), and the
      apparent Km values for ADP and fructose-6-phosphate were 0.6mM (apparent Vmax of
      243Umg(-1)) and 1.47mM (apparent Vmax of 197Umg(-1)), respectively.
      Significantly, the enzyme is indicated to be nonallosteric but was slightly
      activated by some monovalent cations including Na+ and K+. The protein had a
      subunit size of 42.2kDa and an estimated native molecular weight of 66kDa (gel
      filtration). Maximal reaction rates for the reverse reaction were attained at pH
      7.5-8.0, and the apparent Km values for fructose-1,6-bisphosphate and AMP were
      0.56mM (apparent Vmax of 2.9Umg(-1) and 12.5mM, respectively. The biochemical
      characteristics of this unique ADP-dependent enzymatic activity are compared to
      ATP and pyrophosphate-dependent phosphofructokinases.

PMID- 10356997
TI  - Sequence analysis and functional studies of a chromosomal region of alkaliphilic
      Bacillus firmus OF4 encoding an ABC-type transporter with similarity of sequence
      and Na+ exclusion capacity to the Bacillus subtilis NatAB transporter.
AB  - A 14.1-kb DNA fragment was cloned from a lambda library containing inserts of DNA
      from alkaliphilic Bacillus firmus OF4 on the basis of its hybridization to a
      probe from a previously sequenced alkaliphile homolog of the natA gene from
      Bacillus subtilis. Sequence analysis of the entire fragment revealed that, as in
      B. subtilis, the natA gene was part of a putative gene locus encoding an ABC-type
      transporter. In the alkaliphile, the transporter involved three genes, designated
      natCAB, that are part of a larger operon of unknown function. This is in contrast
      to the two-gene natAB operon and to another homolog from B. subtilis, the yhaQP
      genes. Like natAB, however, the alkaliphile natCAB catalyzes Na+ extrusion as
      assessed in a mutant of Escherichia coli that is deficient in Na+ extrusion. The
      full 14.1-kb fragment of alkaliphile DNA sequenced in this study contained
      several probable operons as well as likely monocistronic units. Among the 17
      predicted ORFs apart from natCAB were acsA, a homolog of a halobacterial gene
      encoding acetylCoA synthetase; sspA, a homolog of a small acid-soluble spore
      protein; and malK, an ATP-binding component that was unaccompanied by candidates
      for other mal transport genes but was able to complement a malK-deficient mutant
      of E. coli. No strong candidates for genes encoding a secondary Na+/H+ antiporter
      were found in the fragment, either from the sequence analysis or from analyses of
      complementation of E. coli mutants by subclones of the 14.1-kb piece. There were
      a total of 12 ORFs whose closest and significant homologs were genes from B.
      subtilis; of these, one-third were in apparently different contexts, as assessed
      by the sequence of the neighboring genes, than the B. subtilis homologs.

PMID- 10356999
TI  - Purification and properties of the pyrophosphate-dependent phosphofructokinase
      from Dictyoglomus thermophilum Rt46 B.1.
AB  - The distribution of phosphofructokinase phosphoryl donor subtypes (ATP-, ADP-,
      and pyrophosphate) in the deeply rooted phylogenetic lineages of thermophiles is
      of interest with regard to the evolution of phosphofructokinase activity and of
      the Embden-Meyerhof pathway. In this article we present the first biochemical
      description of a thermostable pyrophosphate-dependent phosphofructokinase from
      the hyperthermophilic bacterium Dictyoglomus thermophilum. The enzyme was not
      allosterically controlled by traditional modulators of phosphofructokinases and
      has significant activity with tripolyphosphate and polyphosphate. Kinetic
      parameters of the enzyme suggest it plays primarily a glycolytic role. The enzyme
      required Mg2+ for optimal activity, was partially activated by some monovalent
      and divalent cations, and was strongly inhibited by Cu2+. The sequence of the 21
      N-terminal residues suggests that the enzyme is most similar to the pyrophosphate
      dependent phosphofructokinases from Amycolatopsis methanolica and the
      hyperthermophilic crenarchaeon Thermoproteus tenax, enzymes which have been
      suggested to represent an ancient lineage of phosphofructokinases (Siebers et al.
      1998). The unexpected finding of a pyrophosphate-dependent phosphofructokinase in
      Dictyoglomus thermophilum, which is phylogenetically related to Thermotoga
      maritima, previously shown to possess an ATP-dependent phosphofructokinase
      activity, is discussed.

PMID- 10357000
TI  - Novel archaeal phylotypes from an East African alkaline saltern.
AB  - DNA has been extracted on site from the brines of the final crystallizing pond of
      an alkaline saltern at Lake Magadi, Kenya. Amplification of 16S rRNA genes
      followed by cloning, sequencing, and phylogenetic analysis has revealed the
      presence of two distinct new archaeal lineages. The majority of cloned sequences
      showed greater than 95% identity to each other, but only 88%-90% similarity to
      any cultivated haloalkaliphilic Archaea, and form a distinct cluster within the
      known Haloarchaea. Two cloned genes showed close similarity to each other but
      only 76% similarity to any known archaeal sequence, and therefore represent a
      distinct phylotype only distantly related to the euryarchaeotal branch of the
      Archaea.

PMID- 10357001
TI  - Heat-stable pullulanase from Bacillus acidopullulyticus: characterization and
      refolding after guanidinium chloride-induced unfolding.
AB  - Heat-stable pullulanase from Bacillus acidopullulyticus was characterized with
      respect to its stability against thermal and chemical denaturation and its
      reactivation after complete chemical unfolding. The enzyme was quite thermostable
      and retained 55% of activity after heating at 60 degrees C for 30 min at pH 5.5.
      At pH 6.0, only 9% residual activity was observed. The addition of sucrose,
      polyols, and Na2SO4 strongly stabilized the enzyme against thermal inactivation.
      The processes of chemical unfolding by guanidinium chloride (GdmCl) and refolding
      were studied by enzymological and spectroscopic criteria. B. acidopullulyticus
      pullulanase was very sensitive to GdmC1 denaturation and had a transition
      midpoint at 1.2M GdmCl. Reactivation after complete unfolding in 5 M GdmCl was
      initiated by dilution of the unfolding mixture: 67% reactivation was observed
      under standard conditions. The influence of some chemical and physical parameters
      (pH, chemical agents, temperature, and unfolding and refolding time) on refolding
      was investigated. Of the additives tested to assist reactivation, only bovine
      serum albumin (BSA) increased the yield of activity to 80%. The full regain of
      structure and activity was proven by comparing the enzymological,
      physicochemical, and spectroscopic properties of the native and refolded
      pullulanase.

PMID- 10357002
TI  - Isolation of a chymotrypsinogen B-like enzyme from the archaeon Natronomonas
      pharaonis and other halobacteria.
AB  - A protease of a molecular mass of approximately 30kDa was isolated and purified
      from the haloalkaliphilic archaeon Natronomonas (formerly Natronobacterium)
      pharaonis. The enzyme hydrolyzed synthetic peptides, preferentially at the
      carboxyl terminus of phenylalanine or leucine, as well as large proteins.
      Hydrolysis occurred over the range of pH from 6 to 12, with an optimum at pH 10.
      The temperature optimum was 61 degrees C. The enzyme was nearly equally active
      over the range of salt concentration from 0.5 to 4M (NaCl or KCl). A strong cross
      reaction with a polyclonal antiserum against human chymotrypsin was observed.
      Enzymatic activity was inhibited by typical serine protease inhibitors. There was
      significant homology between N-terminal and internal sequences from autolytic
      fragments and the sequence of bovine chymotrypsinogen B; the overall amino acid
      composition was similar to that of vertebrate chymotrypsinogens. Evidence for a
      zymogen-like processing of the protease was obtained. Cell extracts from other
      halobacteria exhibited similar proteolytic activity and immunoreactivity. The
      data suggested a widespread distribution of a chymotrypsinogen B-like protease
      among halo- and haloalkaliphilic Archaea.

PMID- 10357004
TI  - Frequent but low titre factor VIII inhibitors in haemophilia A patients treated
      with high purity concentrates.
AB  - The development of inhibitor antibodies is one of the more important
      complications in the management of haemophilia patients. In a previous study, the
      prevalence of inhibitor varies between 5 and 52%, seems to be different for
      different types of concentrates, and is less frequent in multitransfused
      patients. In our prospective study we followed for 3 years 62 multitransfused
      haemophilia patients without inhibitor or past history of inhibitor. Thirty-seven
      haemophilia patients were treated with intermediate purity factor VIII
      concentrates, whereas 25 were given high purity concentrates (from the eighth
      month of the study five of these patients were treated with recombinant
      products). Factor VIII inhibitor antibody developed in seven of 25 haemophilia
      patients treated with high purity concentrates or recombinant products, whereas
      none of the haemophilia patients treated with intermediate purity concentrates
      had inhibitors. The difference was statistically significant (P < 0.001; OR =
      0.06, 95% CI 0.001-0.3). In all patients, the titre of the inhibitor was low and
      no problem occurred in their management. Since inhibitors appeared in
      multitransfused patients when transfused with high purity concentrates and/or
      when the patients were switched to recombinant FVIII product, the development of
      inhibitor seems to be due to the administration of a new concentrate. Therefore
      this potential complication must be considered every time a new concentrate is
      administered.

PMID- 10357003
TI  - Combined effect of the growth temperature and salinity of the medium on the
      accumulation of compatible solutes by Rhodothermus marinus and Rhodothermus
      obamensis.
AB  - In this study we propose revised structures for the two major compatible solutes
      of Rhodothermus marinus. We have also examined the accumulation of compatible
      solutes by the type strains of the slightly halophilic and thermophilic species
      Rhodothermus marinus and Rhodothermus obamensis at several growth temperatures
      and salinities. The major solutes of R. marinus were identified as alpha
      mannosylglycerate (alpha-MG) and alpha-mannosylglyceramide (alpha-MGA), whereas
      R. obamensis accumulated only alpha-mannosylglycerate. The total osmolyte content
      was higher during the early exponential phase and decreased abruptly as growth
      continued into the stationary phase. At low growth temperatures. R. marinus
      responded to water stress by accumulation of alpha-mannosylglycerate and its
      amide, in addition to low levels of trehalose, glutamate, and glucose. At the
      highest growth temperature, alpha-mannosylglycerate was the major compatible
      solute and alpha-mannosylglyceramide was not detected. When both compounds were
      present, an increase in the salinity of the growth medium favored the
      accumulation of alpha-mannosylglyceramide over alpha-mannosylglycerate. The
      absence of alpha-mannosylglyceramide in R. obamensis at all growth temperatures
      and salinities constituted the most pronounced difference in the profiles of
      compatible solute accumulation by the two strains. Trehalose was also a prominent
      solute in this organism. Both organisms accumulated higher levels of alpha
      mannosylglycerate as the temperature was raised. The importance of the two
      compounds in the mechanisms of thermoadaptation and osmoadaptation is discussed.

PMID- 10357005
TI  - Comparison of various D-dimer tests for the diagnosis of deep venous thrombosis.
AB  - Analyses of D-dimers in plasma are frequently used as diagnostic tools for deep
      venous thrombosis (DVT). Enzyme-linked immunosorbent assays (ELISAs) are
      considered to be the method of choice for quantitative assays, but are time
      consuming. Therefore, we have assessed plasma levels of D-dimers in patients with
      clinically suspected DVT using quantitative (Asserachrom D-Di ELISA and
      TintElize), semiquantitative (Minutex latex, D-Di latex, NycoCard D-Dimer) and
      qualitative (INSTANT.I.A) assays. Phlebography was used as the gold standard to
      verify or exclude the suspected diagnosis. We conclude that the fast assays,
      INSTANT.I.A and Minutex, have essentially the same negative predictive value [91%
      and 89%, respectively, using a cut-off value < 0.5 mg/l fibrinogen equivalent
      units (FEU)] for excluding DVT as the Asserachrom D-Di ELISA and TintElize tests
      (92%). The D-Di Latex assay had a negative predictive value of 82% (cut-off < 0.5
      mg/l FEU) and turned out to be less useful in our material. The NycoCard D-dimer
      assay had a negative predictive value of 100% when using the cut-off value < 0.5
      mg/l FEU, but this was substantially lower when the cut-off was changed to < or =
      0.5 mg/l. Thus, we conclude that several fast tests offer a simpler and more
      rapid way of determining plasma levels of D-dimer than conventional ELISA methods
      without loss of clinical usefulness in excluding DVT.

PMID- 10357006
TI  - Can the laboratory assay of protein C activity assist in monitoring the
      hemostatic function in pre-eclampsia?
AB  - Published reports do not agree about whether protein C activity is non
      significantly changed or decreased in a hypercoagulable state induced by pre
      eclampsia without hemolysis-elevated liver enzyme/low platelet (HELLP) syndrome.
      In order to assess the relationship between this anticoagulant and enhanced
      hemostasis, levels of protein C activity, thrombin-antithrombin complexes,
      soluble fibrin, fibrin D-dimers and antithrombin were determined in 30 pre
      eclampsia patients without the HELLP syndrome, in 22 normal pregnant women in
      gestational weeks 30-35, and in 13 non-pregnant controls. Levels of thrombin
      antithrombin complexes, soluble fibrin and D-dimers increased (P < 0.05) whereas
      antithrombin decreased (P < 0.05) in patients with pre-eclampsia, compared with
      normal pregnant women. Levels of protein C did not differ significantly between
      patients with pre-eclampsia, normal pregnant women and controls (P > 0.05). The
      5th and 95th percentiles of protein C levels in normal pregnant women were 0.53
      and 1.30 U/ml, respectively; levels between these two values could be considered
      physiological. When the pre-eclampsia patients were subdivided according to these
      percentiles, none belonged to the subgroup with protein C < or = 5th percentile;
      23% (seven of 30) fell into the subgroup with protein C > or = 95th percentile.
      Elevated levels of hypercoagulation markers were shown in the groups whose
      protein C fell within 5th-95th or > or = 95th percentiles (P < 0.05), compared
      with normal pregnant women. Concentrations of protein C and thrombin-antithrombin
      complex were significantly correlated (r = 0.69, P > 0.05) in patients with pre
      eclampsia. In summary, in subjects with pre-eclampsia without the HELLP syndrome,
      protein C activity may be similar to that in normal pregnant women. However, such
      a 'physiological' anticoagulant level in association with the enhanced thrombin
      generation and fibrin formation does not necessarily reflect a physiological
      capability of coagulation. Thus, assays of protein C activity might not always
      assist in monitoring the hemostatic function during pre-eclamptic pregnancy.

PMID- 10357007
TI  - Increasing plasma fibrinogen, but unchanged levels of intraplatelet cyclic
      nucleotides, plasma endothelin-1, factor VII, and neopterin during cholesterol
      lowering with fluvastatin.
AB  - Lipid-lowering statin treatment reduces cardiovascular morbidity and mortality
      and improves endothelial function in patients with hypercholesterolemia. The aim
      of the present study was to evaluate plasma levels of fibrinogen, factor VII, and
      the macrophage-derived inflammatory mediator neopterin during lipid lowering. In
      addition, the endothelial production of platelet antiaggregatory and vasodilatory
      factors such as nitric oxide and prostacyclin, and vasoconstrictive factors such
      as endothelin-1, was assessed. Plasma fibrinogen, factor VII, endothelin-1, and
      the neopterin and intraplatelet nitric oxide and prostacyclin mediators cyclic 3'
      5'guanosine monophosphate (cGMP) and cyclic 3'-5'adenosine monophosphate (cAMP)
      were measured before and 6 months after the institution of treatment with
      fluvastatin in 17 patients (eight men and nine women, median age 60 years) with
      vascular disease and previously untreated hypercholesterolemia. After 6 months, a
      decrease of 1.62 mmol/l [1.26-2.18 (19%); P < 0.01] was noted in levels of total
      cholesterol, and a decrease of 1.70 mmol/l [1.52-2.30 (28%); P < 0.01] in levels
      of low-density lipoprotein cholesterol. Plasma levels of fibrinogen had increased
      [from 4.81 g/l (4.26-5.27) to 5.17 g/l (4.81-5.67); P < 0.05], whereas no
      significant changes had occurred in intraplatelet levels of cGMP [decrease by
      0.05 pmol/10(9) platelets (-0.17 to 0.24); NS], cAMP [decrease by 0.13 pmol/10(9)
      platelets (-0.37 to 0.86); NS], plasma endothelin-1 [decrease by 0.05 pg/ml (
      0.60 to 0.70); NS], plasma factor VII [from 1.14 IE/ml (0.58-1.38) to 1.22 IE/ml
      (0.96-1.46); NS], or plasma neopterin [from 8.6 nmol/l (7.1-11.5) to 8.7 nmol/l
      (7.9-11.3); NS]. In conclusion, during cholesterol-lowering treatment with
      fluvastatin, plasma levels of fibrinogen increased whereas intraplatelet cyclic
      nucleotide levels and plasma endothelin-1, factor VII and neopterin levels were
      unchanged.

PMID- 10357008
TI  - Lack of association between factor V Leiden and thromboembolism in patients with
      prosthetic heart valves.
AB  - Thromboembolism represents the most serious complication in patients with
      prosthetic heart valves, and causes significant mortality and morbidity. Many
      risk factors for the condition have been identified. However, many patients who
      have a therapeutic level of anticoagulation and no obvious risk factors develop
      thromboembolism. Factor V Leiden, found in 3-7% of the normal population, is the
      most common inherited factor associated with thrombosis. Whether or not this
      factor is associated with thromboembolism in this setting has not been explored.
      This study compares the prevalence of factor V Leiden in patients with prosthetic
      heart valves, with and without thromboembolic complications. A total of 148
      patients were studied. Thirty had documented thromboembolic complications and
      none exhibited the factor V mutation. Of the 118 patients without thromboembolic
      complications, seven (5.9%) were heterozygous for factor V Leiden (P = 0.345, by
      Fisher's two-tailed exact test; odds ratio 0, 95% confidence interval 0.0-4.34).
      We conclude that until future data shows otherwise, routine testing for factor V
      Leiden in patients with prosthetic heart valves is not warranted, except as part
      of ongoing research.

PMID- 10357009
TI  - Abnormalities of von Willebrand factor are also part of the prothrombotic state
      of Cushing's syndrome.
AB  - Glucocorticoids are known to increase plasma concentrations of factor VIII
      (FVIII) and von Willebrand factor (vWF), and their administration is associated
      with an increased incidence of thrombotic complications. Because Cushing's
      syndrome is characterized by an endogenous increase in glucocorticoids, we
      studied levels of FVIII and vWF in 20 patients with Cushing's syndrome. Plasma
      levels of FVIII and vWF were found to be markedly increased. Moreover, the
      molecular organization of plasma vWF appeared to have been altered by the
      presence of unusually large multimers, normally present only in the cellular
      compartments. Spontaneous platelet aggregation and hyperresponsiveness to
      ristocetin were also observed. All patients underwent therapeutic surgery. Within
      1 month of the intervention, regardless of its efficacy as evaluated by the assay
      of plasma and urinary cortisol, an additional significant increase in levels of
      FVIII and vWF was observed, with a concomitant more pronounced representation of
      abnormally large vWF multimers in circulation. In the cured patients, a
      progressive decrease in the levels of FVIII and vWF was observed, beginning in
      the third month after surgery, with complete normalization of the pattern within
      12 months of surgery; a concomitant improvement in the plasma vWF multimer
      pattern was also observed. In contrast, no significant changes in FVIII or vWF
      were found in patients with persistent Cushing's syndrome. Our findings emphasize
      that vWF abnormalities are also part of the prothrombotic state of Cushing's
      syndrome. Moreover, this study also identified a period of additional thrombotic
      risk immediately after surgery, as a result of the worsening of the hemostatic
      pattern.

PMID- 10357010
TI  - Activated protein C ratio as a clue for protein S disorder in Japanese.

PMID- 10357011
TI  - Markers of coagulation and platelet activation during percutaneous mitral
      valvuloplasty.

PMID- 10357012
TI  - Circulating lymphocyte subsets in obsessive compulsive disorder, major depression
      and normal controls.
AB  - BACKGROUND: Obsessive compulsive disorder (OCD) shares several features with
      depressive illness (e.g., comorbidity, early escape from dexamethasone
      suppression, effectiveness of serotonergic pharmacotherapy). It was of interest
      to establish whether OCD, like major depression, was also associated with immune
      alterations, notably elevations of circulating natural killer (NK) cells. METHOD:
      Circulating lymphocytes were determined from morning blood samples taken from OCD
      and major depressive patients, as well as from age- and sex-matched controls.
      Stress perception and coping styles were evaluated in order to assess whether
      such variables accompanied the NK alterations. Finally, in a subset of patients,
      symptoms of the illness, stress/coping, and circulating lymphocytes, were also
      evaluated following 12 weeks of antidepressant medication (serotonergic reuptake
      inhibitor). RESULTS: The major depressive and OCD patients reported increased
      perception of day-to-day stresses, coupled with reliance on emotion focused
      coping styles. Moreover, circulating NK cells were elevated among male OCD and
      major depressive patients, whereas only a modest increase of NK cells was seen in
      female major depressives. Twelve weeks of medication alleviated depressive and
      OCD symptoms, and resulted in normalization of NK cells in the major depressives.
      However, in OCD patients the reduction of symptoms was not accompanied by
      significant variations of circulating NK cells. CONCLUSIONS: Although major
      depression and OCD are both accompanied by elevated circulating NK cells, at
      least in males, normalization of NK cells following treatment was only evident in
      depression. The persistent elevations of NK cells among male OCD patients may
      reflect either a trait characteristic of the illness, or symptom reduction and
      not true remission. LIMITATIONS: Although elevations of lymphocyte subsets in
      major depressive and OCD patients were observed, conclusions concerning immune
      status in OCD ought to be held in abeyance pending assessment of other indices of
      immune and cytokine functioning.

PMID- 10357013
TI  - The influence of anxiety as a risk to early onset major depression.
AB  - OBJECTIVE: we seek to identify and quantify any risk provided by several
      expressions of "anxiety" to major depression overall, and to separate melancholic
      and non-melancholic sub-types. METHOD: a sample of 269 patients with a current
      major depressive episode was assessed for rates of separate formalised anxiety
      disorders, both for lifetime and prior to the initial depressive episode. We also
      sought for evidence of familial anxiety and, early childhood expression of
      anxiety forerunners, measured both state and trait anxiety levels as well as
      anxiety at a "personality" level, and assessed use of anxiolytic medications.
      Depressive sub-typing was undertaken using DSM-IV criteria, while "early onset"
      (EO) depression was defined as an initial onset at 25 years or less, and
      subsequently re-examined with a cut-off age of 20 years or less. RESULTS:
      overall. 42% of our sample were assigned as having EO depression, with there
      being a higher representation of non-melancholic than melancholic EO subjects
      (i.e., 51% vs. 29%), arguing for sub-type status being respected in the analyses.
      For both melancholic and non-melancholic subjects two trait anxiety items
      ("tense"; "keyed up/on edge") were over-represented, suggesting that such a tense
      anxiety style may provide an antecedent risk to depression (of either sub-type)
      or be a consequence of depression. Specificity was most evident in the non
      melancholic sub-sample, where EO depression was associated with a family history
      of anxiety, early childhood expressions of anxiety and with two lifetime anxiety
      disorders (social phobia and obsessive-compulsive disorder). Broadly similar
      results were returned when "EO" definition was reduced to 20 years or less.
      CONCLUSIONS: our study is consistent with previous research in identifying
      anxiety in the form of social inhibition or social avoidance as being
      particularly likely to precede and perhaps be a conduit to early onset non
      melancholic major depression. This conclusion both sharpens risk factor research
      and indicates an important fulcrum that could be used to assist primary
      prevention of the depressive disorders.

PMID- 10357014
TI  - An analysis of the "eveningness-morningness" dimension in "depressive" college
      students.
AB  - BACKGROUND: Circadian variability in depression has not been well characterized
      with respect to the "eveningness-morningness" dimension. METHODS: The
      "eveningness-morningness" dimension, as measured by the Home and Ostberg
      questionnaire, was examined among a student population (n = 1617) that was named
      as "depressive". Three depression scales (BDI, GDS-SF, and CESD) were used to
      determine "depressiveness". The Horne and Ostberg questionnaire was used to
      measure the degree of "eveningness-morningness". It was hypothesized that there
      would be negative and significant correlations between the scores on the Horne
      and Ostberg questionnaire and the depression scales. Consequently, it was
      expected that there would be a significantly higher number of evening types than
      the morning types among the participants identified as "depressives". RESULTS:
      There were significant, negative correlations between the Horne and Ostberg
      questionnaire scores and the responses on the 3 depression scales (for BDI r= 
      .174, GDS-SF r= -.182, CESD r = -.176, all p < .001). Also, a significantly
      higher incidence of evening types than of the morning types among the
      "depressive" students was found (chi2 = 11.18, p < .01). LIMITATIONS: It is
      uncertain to what extent these data generalize to clinical populations.
      CONCLUSIONS: "Depressive" college students are more likely to be evening types.

PMID- 10357015
TI  - Treatment seeking for depression: role of depressive symptoms and comorbid
      psychiatric diagnoses.
AB  - BACKGROUND: General population research has indicated that many persons with
      lifetime major depression report they have never sought medical help for their
      illness. We examined the role played by both depressive symptoms and comorbid
      psychiatric diagnoses in treatment seeking. METHODS: From standardized
      psychiatric interviews of 7214 Edmonton residents, we identified 1348 subjects
      with lifetime depressive illness; 866 subjects (64%) had sought medical
      treatment. RESULTS: Psychomotor retardation (odds ratio, OR = 1.4), suicidal
      ideation (OR = 1.4), comorbid mania (OR = 9.5), comorbid panic disorder (OR =
      3.0), and comorbid drug abuse/dependence (OR = 0.6) were significantly associated
      with treatment seeking in multivariate analysis. CONCLUSION: The finding that
      only a few depressive symptoms were associated with treatment seeking underlines
      the importance of public health education to address the undertreatment of
      depression.

PMID- 10357016
TI  - Self-esteem and depression: ten year follow-up of mothers and offspring.
AB  - OBJECTIVE: The association between maternal bonding style, offspring low self
      esteem and offspring depression status was assessed by maternal depression
      status. SUBJECTS: Sixty mothers and 137 offspring were independently assessed
      over the course of a ten year follow-up study. METHOD: Assessments included the
      Schedule for Affective Disorders and Schizophrenia (SADS-LA), Schedule for
      Affective Disorders and Schizophrenia for School-Aged Children (K-SADS), the
      Coopersmith Self-Esteem Inventory (CSEI) and the Parental Bonding Instrument
      (PBI). RESULTS: Among daughters of mothers with a history of depression, maternal
      affectionless-control was associated with daughter low self-esteem which was
      associated with daughter depression at ten year follow-up. Among daughters of
      mothers without a history of depression, maternal affectionless-control was not
      associated with daughter low self-esteem, which was not associated with daughter
      depression at ten year follow-up but which was associated with a history of
      childhood depression. None of these associations were found to be significant
      among sons. LIMITATIONS: As self-esteem was not measured at ten year follow-up,
      among offspring the stability of self-esteem could not be assessed, nor could the
      association between adult self-esteem and adult depression. CONCLUSION: Clinical
      presentation of low self-esteem in girls should be assessed in the context of
      maternal depression status.

PMID- 10357017
TI  - The revised Anxious Thoughts and Tendencies (AT&T) scale: a general measure of
      anxiety-prone cognitive style.
AB  - BACKGROUND: The AT&T was developed from a perspective which proposes that panic
      disorder with agoraphobia arises from interaction between a specific biological
      predisposition, expressed in spontaneous panic attacks, and a general anxiety
      prone cognitive style. Many items of the original AT&T, a putative measure of the
      cognitive component, were complex and ambiguous; and normative data were not
      available. METHOD: In this research, the items were simplified and clarified. A
      community sample of northern New Mexico Hispanics and geographically matched non
      Hispanic whites was identified from an earlier epidemiological study. The sample
      included 151 Anglos and 168 Hispanics; 98 respondents aged 18-34, 75 aged 35-49,
      69 aged 50-64, and 77 aged 65 or more; and 111 men and 208 women. RESULTS: Factor
      analysis produced one major factor with high loadings from the 15 negatively
      worded items, that accounted for about 41% of the total variation in the 15
      items. The mean major factor score for Anglos was 1.65 with a standard deviation
      of 0.48, and for Hispanics was 1.76+/-0.52. F = 4.17, df = 1/311, P < 0.05, and
      effect size d = 0.22. There were no significant age or gender effects. Item
      analysis of the major factor produced item/total correlations from 0.49 to 0.68
      and a Cronbach's alpha of 0.91. In a separate clinical sample of 30 patients with
      panic disorder, the test-retest correlation of the major factor at baseline and
      after 8 weeks of treatment was 0.75. In the community sample, the correlations of
      the major factor with anxiety-related clusters of the SCL-90 were: Somatization,
      0.36; Anxiety, 0.53: and Phobia, 0.44. CONCLUSIONS AND RECOMMENDATIONS: We
      recommend that the AT&T be reduced to the 15 items of its major factor, and we
      supply quantiles and moments based on the full community sample of 319 as a
      standard of comparison. Further research with the AT&T in clinical samples of
      patients with anxiety disorders is ongoing.

PMID- 10357018
TI  - Perceived parenting pattern and response to antidepressants in patients with
      major depression.
AB  - BACKGROUND: No systematic study has been conducted to explore the relationship of
      dysfunctional parenting early in life, as measured by the Parental Bonding
      Instrument (PBI), to outcomes of depression, although a number of studies have
      related parenting behaviors to the development of depression in adulthood.
      METHODS: The relationship between PBI scores and 4-month outcomes after treatment
      with antidepressants was explored in 60 outpatients with major depression,
      controlling for potentially confounding factors. RESULTS: A multiple logistic
      regression analysis suggested that low levels of paternal care, unmarried
      condition, non-melancholic features, and a high isolation tendency were all
      factors that contributed to poor outcomes for depression. The predictive power of
      low paternal care was not influenced by levels of depression or neuroticism.
      LIMITATION: This study did not attempt to explore whether the effects of
      parenting of father and mother on outcomes for depression may differ between male
      and female subjects. CONCLUSION: The results suggest that low levels of paternal
      care may be an independent predictor of a poor response to treatment with
      adequate antidepressants.

PMID- 10357019
TI  - Depression in Ontario: under-treatment and factors related to antidepressant use.
AB  - Our study examines how depression is treated in Ontario, with particular
      examination of the correlates of antidepressant utilization using a broad model
      of individual (clinical), demographic, and health system determinants of
      treatment. From a community epidemiologic survey, a sample of 333 individuals
      with major depression in the past year was identified. More than half received no
      treatment (untreated n = 170, 51.1%), while 74 (22.2%) received treatment without
      medication, 29 (8.7%) received treatment mainly with anxiolytics, and only 60
      (18.0%) were treated with antidepressants. All four groups had similar rates of
      alcohol and substance abuse. Disability and comorbid anxiety were common, with
      the least in the untreated group and the most in the antidepressant group.
      Increased use of antidepressants was associated with psychiatrist contact, while
      family physicians treated a substantial minority primarily with anxiolytics.
      Under a universal health care system, no differential access to antidepressants
      was found in terms of demographic characteristics. Clinical severity and contact
      with a psychiatrist correlate with antidepressant treatment of depression.

PMID- 10357020
TI  - Teaching front-line health and voluntary workers to assess and manage suicidal
      patients.
AB  - BACKGROUND: To devise and evaluate the retention of a new brief training package
      for non-psychiatrically trained multidisciplinary staff to assess suicide risk
      and manage suicidal patients, including referral of patients at significant risk
      to psychiatric staff. METHOD: 8 h of interview skills training, using role play
      with modelling and video feedback, was taught to 33 health and voluntary workers.
      Evaluation used a controlled before and after training design. Performance of the
      interview skills was assessed blindly by raters using predetermined criteria from
      videotaped role played interviews with actors. Self-rated questionnaires (SIRI-2
      and visual analogue scales) were used to assess the clinical skills and
      confidence respectively of the front-line workers. RESULTS: Suicide risk
      assessment and management skills such as problem solving, future coping and
      provision of immediate support were significantly improved at 1 month after
      training. Training did not significantly improve general interview skills,
      combating hopelessness nor the removal of lethal weapons. Performance on the SIRI
      2 and confidence significantly improved after training. The assessment procedure
      itself did not improve clinical skills nor confidence. LIMITATIONS: Performance
      among individual health disciplines was not assessed. Design was not a randomised
      controlled trial with short follow up and no patient outcome data. CONCLUSIONS: A
      brief training package is available which is effective in teaching suicide risk
      assessment and clinical management skills.

PMID- 10357021
TI  - Early parental separation experiences among patients with bipolar disorder and
      major depression: a case-control study.
AB  - BACKGROUND: Although the association between childhood parental loss and later
      development of mood disorder has received much research interest in the past, the
      results obtained and conclusions drawn have been various, and inconsistent with
      each other. The present study aims to examine this old, yet unresolved, question
      among the Japanese. METHODS: Patients with bipolar disorder (n = 73) and unipolar
      depression (n = 570) and community healthy controls (n = 122) were examined as to
      their psychopathology and childhood parental loss experiences with semi
      structured interviews. RESULTS: Stratified for sex and age, no statistically
      significant difference was observed in the incidence of paternal or maternal
      death or separation before age 16 between bipolar patients and healthy controls.
      Female patients with unipolar depression under the age of 54 experienced
      significantly more maternal loss than the corresponding controls. This excess in
      loss appeared to be largely due to the patients experiencing separation from
      their mothers. CONCLUSION: Our findings concerning bipolar disorder have
      replicated the previous two studies reported in the literature. Those concerning
      unipolar depression appear to be in line with several recent studies on the
      subject but, as stated, many discrepant findings can also be found in the
      literature.

PMID- 10357022
TI  - Diagnostic certainty of a voluntary bipolar disorder case registry.
AB  - BACKGROUND: Strategies for identifying and recruiting persons with bipolar
      disorder are of importance as interest in studying this relatively uncommon, but
      highly disabling illness increases. The development and implementation of a
      bipolar disorder case registry and the assessment of diagnostic certainty of the
      resulting sample are described. METHODS: Eight hundred and four individuals who
      self-reported a history of bipolar disorder were recruited. Telephone
      interviewers gathered demographic information and clinical, medical and treatment
      history information. One hundred randomly-selected registrants completed an in
      person structured diagnostic interview. Self-report of diagnosis was compared to
      the results of the diagnostic interview. RESULTS: Ninety three percent of
      registrants interviewed met criteria for a lifetime bipolar spectrum diagnosis;
      of those, 76.3% were diagnosed with bipolar I disorder. Agreement between self
      reported and SCID diagnoses was 93%, indicating that self-report of a bipolar
      diagnosis is highly reliable. Two-thirds had experienced at least one other
      lifetime Axis I diagnosis, with substance abuse/dependence (55.9%) and panic
      disorder (19.4%) the most common comorbidities. LIMITATIONS: Since nearly all of
      the sample have previously been diagnosed as having bipolar disorder by a
      professional, the sample's representativeness of the population as a whole may be
      somewhat limited. CONCLUSIONS: Persons with bipolar disorder can accurately
      identify themselves as having the disorder via a telephone interview, indicating
      that a case registry method is a useful strategy for recruiting very large
      samples of persons with this disorder. Such large samples will allow for further
      study of treatment variations among patient subgroups, of pathways to treatment,
      and of the effectiveness of new treatments.

PMID- 10357023
TI  - Platelet 5-HT and plasma MHPG levels in patients with bipolar I and bipolar II
      depressions and normal controls.
AB  - BACKGROUND: It has been suggested that platelet serotonin (5-HT) content may
      reflect aspects of the presynaptic reuptake of 5-HT, while plasma 3-methoxy-4
      hydroxy-phenylglycol (MHPG) levels may provide an index of central noradrenergic
      function. METHODS: In order to determine if there is a biological distinction in
      5-HT or noradrenergic function within bipolar I and bipolar II depressions, we
      measured levels of platelet 5-HT and plasma MHPG in 12 patients with bipolar I
      depression, 12 patients with bipolar II depression, and 20 normal healthy
      controls. All subjects were medication free for at least 4 weeks prior to the
      study. RESULTS: There was a trend towards higher platelet 5-HT in bipolar I or II
      depressions when compared to normal controls, whereas there was no difference in
      platelet 5-HT levels between bipolar I and II depressed patients. When bipolar I
      and II patients were pooled, there was a significant increase in platelet 5-HT
      levels in bipolar depressives compared to normal controls, and there was a trend
      towards a weak positive correlation between platelet 5-HT and 21-item HAMD scores
      in the patient group. In contrast, there was no difference in plasma MHPG levels
      between the three groups. LIMITATIONS: This study was limited to a small sample
      size, single point sampling and did not match seasons. CONCLUSIONS: Our findings
      did not provide supportive evidence for a distinctive 5-HT or noradrenergic
      function within bipolar I and bipolar II depressions. However, the finding of
      increased platelet 5-HT levels in bipolar depressed patients compared to normal
      controls is consistent with the results of previous studies, and may suggest an
      increase in presynaptic 5-HT reuptake, presumably resulting from diminished
      synaptic 5-HT availability in this condition.

PMID- 10357024
TI  - SSRI antidepressant use patterns and their relation to clinical global impression
      scores: a naturalistic study.
AB  - BACKGROUND: A cascade of events follows initial antidepressant selection which
      includes the subsequent antidepressant use pattern, resultant clinical outcomes,
      and associated health care expenditures. PURPOSE: The purpose of this study using
      data from a clinical practice setting was to test whether the pattern of
      antidepressant use was correlated with patients' treatment response as measured
      by the score on the Clinical Global Impression-Improvement scale. DATA AND
      METHODS: A retrospective dataset of patients who initiated therapy on fluoxetine,
      fluvoxamine, paroxetine, or sertraline in a primary care setting in Spain was
      used. A Cox proportional hazard analysis was used to predict the likelihood of
      treatment response based upon the pattern of initial antidepressant use, while
      minimizing the influence of other factors. RESULTS: After controlling for other
      observed baseline characteristics including initial disease severity, (a)
      patients who remained on their initial antidepressant therapy for at least 2
      months with no switching, augmentation, or upward dose titration were 1.63 times
      more likely to experience a treatment response than patients who had an
      adjustment to therapy; and (b) patients who initiated therapy on sertraline were
      0.46 times as likely to experience a treatment response as patients who initiated
      therapy on the most common study antidepressant, fluoxetine. CONCLUSION: The
      pattern of antidepressant use is an important determinant of treatment response
      among patients initiating therapy on the newer antidepressants in clinical
      practice.

PMID- 10357025
TI  - A neuroendocrine study of serotonin function in depressed stroke patients
      compared to non depressed stroke patients and healthy controls.
AB  - OBJECTIVES: We employed a neuroendocrine challenge paradigm to study serotonergic
      abnormalities associated with poststroke depression. METHOD: Twelve depressed
      stroke patients (major depression N= 5, minor depression N = 7), 8 nondepressed
      stroke patients and 12 healthy volunteers completed a single-blind, placebo
      controlled, challenge tests. Baseline cortisol (CORT) and prolactin (PRL) values,
      and these hormonal responses to 30 mg of oral d-FEN and placebo over a 4 hour
      period were measured in the three groups. RESULTS: There were intergroup
      differences for baseline adjusted PRL responses (change scores from baseline) to
      d-FEN (group effect F = 4.38, df = 2,29, p = 0.02) while these responses to
      placebo were comparable between groups (group effect F = 1.82, df = 2,29, p =
      0.18). Peak PRL responses (post d-FEN maximal PRL change from baseline scores) in
      depressed stroke patients were significantly greater than in nondepressed
      patients (p = 0.005) but comparable to healthy normals (p = 0.47). However, these
      responses between major and minor depression were not significant (p = 0.34).
      There was a trend suggesting a negative correlation between peak PRL response and
      severity of depression (p = 0.056). Depressed patients were younger than the
      controls (p = 0.054). Also, the depressed group was more functionally impaired (p
      = 0.04) and more likely to have right-sided lesions (p = 0.009) compared with the
      nondepressed group. Differences in baseline adjusted PRL changes between
      depressed and nondepressed groups became non significant when the influence of
      laterality of lesions was covaried, whereas covariation of functional scores and
      age did not alter the significance. CORT responses did not show intergroup
      differences. LIMITATIONS: The study group was small and was heterogenous in
      lesion characteristics, time since stroke and type of depression. A fixed-order
      design was used in the challenge test paradigm. CONCLUSIONS: When laterality of
      stroke lesion was taken into account, depressed and nondepressed stroke patients
      did not differ in PRL responses to d-FEN.

PMID- 10357026
TI  - Is bipolar disorder still underdiagnosed? Are antidepressants overutilized?
AB  - BACKGROUND: Previous studies have suggested that bipolar disorder may be
      underdiagnosed, and that antidepressants may be over-utilized in its treatment.
      METHODS: Consecutively admitted patients (n =48) diagnosed with DSM-IV bipolar
      disorder, type I, (n = 44) or schizoaffective disorder, bipolar type, (n = 4)
      were interviewed systematically and their charts were reviewed to confirm
      diagnosis before admission. They were then treated according to systematic
      structured interview diagnoses. These data reflect the changes in diagnoses and
      treatment. RESULTS: 40% (19/48) were identified with previously undiagnosed
      bipolar disorder, all previously diagnosed with unipolar major depressive
      disorder. A period of 7.5+/-9.8 years elapsed in this group before bipolar
      diagnosis was made. Antidepressant use was high on admission (38%) and was
      reduced with acceptable treatment response rates. The adjunctive use of
      risperidone appeared to be a good treatment alternative. LIMITATIONS: While
      diagnoses were made prospectively, treatment response was assessed
      retrospectively, and was based on non-randomized, naturalistic therapy.
      CONCLUSIONS: Systematic application of DSM-IV criteria identified previously
      undiagnosed bipolar disorder in 40% of a referred population of patients with
      mood disorders, all previously misdiagnosed as unipolar major depressive
      disorder. Antidepressants appeared overutilized and risperidone was an effective
      alternative adjunctive therapy agent.

PMID- 10357027
TI  - Characteristics and psychosocial problems of patients with bipolar disorder at
      high risk for suicide attempt.
AB  - BACKGROUND: Bipolar disorder with a history of substance abuse or suicide attempt
      is a strong predictor of suicide. A high comorbidity of substance use disorders
      may obscure the specificity of findings about suicide behaviors in Western
      patients with bipolar disorder. METHODS: The clinical data of Chinese bipolar
      patients (DSM-III-R) in Taiwan who had been naturalistically followed up for at
      least 15 years were obtained by a combination of chart reviews and interviews
      with patients and family members. The national identity numbers were used to
      search for deceased subjects. RESULTS: There were 158 patients originally
      included for chart review; 4 of them died from suicide. A 9.9% lifetime
      prevalence of alcohol use disorders was found in 101 final subjects who accepting
      interview. Multiple logistic regression showed that subjects with a history of
      suicide attempt (n = 53, 52.5%) were more likely to have interpersonal problems
      with spouse or romantic partner (adjusted odds ratio = 2.85, 95% C.I. = 0.69
      11.51), occupational problems mainly maladjustment and frequently changing job
      (adjusted odds ratio = 3.08, 95% C.I. = 1.12-10.49), and an earlier age (< or =
      22 years) of onset (adjusted odds ratio = 0.96, 95% C.I. = 0.90-1.02).
      LIMITATION: To use an interview schedule for assessing the psychosocial problems
      of clinical population limits the interpretation and generalisability of the
      data. CONCLUSION: Despite low comorbidity of alcohol/drug use disorders in
      Chinese bipolar patients, a consistently high rate of suicide attempts reinforces
      that bipolar disorder is a high-risk group of suicide. An earlier age of onset,
      interpersonal problems with spouse or romantic partner, and occupational
      maladjustment rather than demographic characteristics may collectively identify
      those at high risk of suicide attempt in bipolar disorder.

PMID- 10357028
TI  - Self-criticism, dependency and depressive symptoms in a nationwide sample of
      Norwegian physicians.
AB  - This cross-sectional study examines the associations between dysfunctional
      beliefs concerning self-criticism and dependency and self-reported depressive
      symptoms in a nationwide representative sample of Norwegian physicians (N = 836).
      The dysfunctional beliefs were measured by the Dysfunctional Attitudes Scale
      (DAS), and depressive symptoms by the "severe depression" subscale of the General
      Health Questionnaire. Women reported more depressive symptoms than men, whereas
      men reported more dysfunctional attitudes, especially concerning self-criticism.
      Both self-criticism and dependency were significantly associated with level of
      depressive symptoms in male doctors when age and their medical speciality were
      controlled, whereas no such relationship was demonstrated in female doctors,
      except for a bivariate association between depressive symptoms and two single
      indicators of dependency.

PMID- 10357029
TI  - Bipolar disorder in the latter half of life: symptom presentation, global
      functioning and age of onset.
AB  - BACKGROUND: Little is known about bipolar disorder in late life. Recent research
      has been in acute, in-patient, settings, and has focused on late-onset mania, or
      has produced samples with surprisingly late mean ages of onset. No recent study
      has used a larger out-patient sample to address late-life outcomes of bipolar
      disorder. METHODS: 86 community-residing, middle-aged and older adults who met
      RDC for bipolar I or II were interviewed using the Schedule for Affective
      Disorders and Schizophrenia, three times over 8 months. RESULTS: Participants
      were primarily unmarried and impoverished. Most were living alone or with
      immediate family members. The majority were in depressive episodes. Depressive
      symptoms were more common and more predictive of functioning than manic symptoms.
      Age of onset was related to global functioning. The effect of age of onset was
      mediated by number of depressive episodes. CONCLUSION: Most adults in this sample
      had supports to maintain them in the community in spite of chronic or
      intermittently cycling manifestations of affective disorder and limited
      medication. Consistent with prior research, early age of onset was related to
      poorer functioning, apparently by increasing the number and severity of
      depressive episodes. LIMITATIONS: Limitations stem from possible exclusion of
      those people with the worst and best outcomes. It also is a relatively young
      sample for a gerontological study. CLINICAL RELEVANCE: The study suggests that
      more attention needs to be paid to diagnosing and treating depressive episodes in
      later life.

PMID- 10357030
TI  - The prevalence of depression in Alzheimer's disease and vascular dementia in a
      population sample.
AB  - BACKGROUND: Previous studies have shown that depression is more prevalent in
      vascular dementia than Alzheimer's disease (AD). Subjects for these studies were
      either psychiatry or neurology patients, raising the issue of whether factors
      leading to treatment might have introduced sampling bias. METHODS: Data for the
      present study came from the Canadian Study of Health and Aging (CSHA, 1994), a
      population-based prevalence study of dementia. AD was diagnosed using NINCDS
      ADRDA criteria (McKhann et al., 1984), vascular dementia was diagnosed using
      draft ICD-10 criteria (World Health Organization, 1987) and the Ischemic Scale
      (Hachinski et al., 1975), major depression was diagnosed using an algorithm based
      on DSM-III-R criteria (American Psychiatric Association, 1987). The sample for
      the present study consisted of 481 subjects with AD and 140 with vascular
      dementia. RESULTS: The weighted prevalence rate of major depression was 3.2% for
      AD and 21.2% for vascular dementia, giving a crude odds ratio of 8.2 (95%
      Confidence Interval: 1.7-40.2). This finding was confirmed by a logistic
      regression analysis which adjusted for age, sex, place of residence (community,
      institution), self-reported health, severity of cognitive impairment, and
      antidepressant or beta-blocker use. LIMITATIONS: Data on depressive symptoms were
      more often missing in subjects with dementia resulting in differential loss of
      potential study subjects. Data on depressive symptoms were not sufficiently
      detailed to permit DSM-III-R criteria to be implemented rigorously. The method of
      diagnosing vascular dementia was subject to misclassification. CONCLUSIONS: This
      study confirms in a population sample that depression is more prevalent in
      vascular dementia compared to AD.

PMID- 10357031
TI  - Polysomnography and depressive symptoms in primary alcoholics with and without a
      lifetime diagnosis of secondary depression and in patients with primary major
      depression.
AB  - BACKGROUND: There is evidence suggesting that there is: (1) additive
      polysomnographic effects of alcoholism and depression; and (2) elevated baseline
      REM density in primary alcoholics with (PASD) and without lifetime history of
      secondary depression (NPA). METHODS: 23 PASDs, 59 NPAs, and 23 primary major
      depression patients (PMD) underwent polysomnography. Any drinking within 3 months
      after a 1-month inpatient alcohol rehabilitation defined relapse. RESULTS: PASDs'
      polysomnography was more like NPAs than PMDs. Polysomnography reflected 3-month
      sobriety status more than diagnosis. LIMITATIONS: Not all PASD's met full major
      depression criteria upon admission. CONCLUSIONS: Alcoholism affected
      polysomnography more than depression. Elevated admission REM density predicted 3
      month relapse in PASDs and NPAs.

PMID- 10357032
TI  - Early- versus late-onset dythymic disorder: comparison in out-patients with
      superimposed major depressive episodes.
AB  - BACKGROUND: This study examined the validity of the early-late onset subtyping
      distinction in dysthymic disorder. METHODS: Participants were 340 out-patients
      meeting DSM-III-R criteria for dysthymia and a concurrent major depressive
      episode (MDE). The sample was drawn from a 12-site double-blind randomized
      parallel group trial comparing the efficacy of sertraline and imipramine in the
      treatment of chronic depression. All patients received comprehensive evaluations
      using semi-structured interviews and rating scales. RESULTS: 73% of the sample
      met criteria for the early-onset, and 27% for the late-onset, subtype. The early
      onset patients had a significantly longer index MDE, significantly higher rates
      of personality disorders and lifetime substance use disorders, and a
      significantly greater proportion had a family history of mood disorder. The
      subgroups did not differ in symptom severity or functional impairment at
      baseline, nor in response to a 12-week trial of antidepressants. LIMITATIONS:
      Further work is needed to extend these findings to dysthymic disorder without
      superimposed MDEs. CONCLUSIONS: These results support the distinction between
      early-onset and late-onset dysthymic disorder.

PMID- 10357033
TI  - The effect of stress on salivary cortisol in panic disorder patients.
AB  - BACKGROUND: Various findings suggest the possibility of an abnormal cortisol
      response to CRH in panic disorder patients, which raises the question of whether
      such patients might also produce an abnormal cortisol response to stress. The
      purpose of the present study was to use salivary cortisol measurement in
      assessing differences in response to novelty/mild stress situations between panic
      disorder subjects and controls. METHODS: Subjects were recruited by means of
      posters and subsequently screened for suitability as controls or panic subjects.
      Twenty-four panic disorder (PD) sufferers and 15 panic-free control subjects were
      tested on a range of psychometric and physiological measures, at both the start
      and the end of the experiment. Subjects were tested at the beginning for state
      anxiety, salivary cortisol, heart rate, and blood pressure, and these tests were
      repeated at the end of the session (which had been designed to promote
      reassurance). RESULTS: The state anxiety scores (STAI) showed a reduction in
      anxiety level over the test period, and there was a corresponding fall in both
      blood pressure and heart rate for both groups. Cortisol levels also fell over the
      course of the interview in the control group, but in the PD group cortisol levels
      showed no such reduction. In addition, there was a significant difference in the
      levels of cortisol at the start of the session between the two groups (PD group
      lower). CONCLUSIONS: These data indicate a possible alteration in cortisol
      responsiveness to stress/novelty situations in PD subjects. This was considered
      to be consistent with previous suggestions of HPA axis dysregulation in PD
      patients, although our research indicates unresponsiveness rather than
      responsiveness to be a factor to be considered for future investigation. CLINICAL
      IMPLICATIONS: Our results suggest that not all subjects suffering PD may benefit
      from stress reduction therapies as a first choice of treatment for their panic
      attacks. The existence of nocturnal panic attacks (considering sleep as a
      combination of mental and physical relaxation), in the absence of nightmares, as
      well as the induction of panic attacks during relaxation support this view.
      LIMITATIONS OF THE STUDY: Apart from the difficulty in accessing sufficient
      symptomatic subjects, the induction of higher levels of stress could be useful
      for confirmation of these results. However, this requires specialist support in
      case of subjects developing panic attacks during the experiments, which was not
      available during the present study. SUMMARY: Twenty-four panic disorder (PD)
      sufferers and 15 panic-free control subjects were tested on a range of
      psychometric and physiological measures, at both the start and the end of an
      experimental session. Subjects were tested at the beginning for state anxiety,
      salivary cortisol, heart rate, and blood pressure, and these tests were repeated
      at the end of the session. The state anxiety scores (STAI) showed a reduction in
      anxiety level over the test period for both groups, and there was a corresponding
      fall in both blood pressure and heart rate. Cortisol levels also fell over the
      course of the session in the control group, but in the PD group cortisol levels
      showed no such reduction. In addition, there was a significant difference in the
      levels of cortisol at the start of the session between the two groups (PD group
      lower). These data indicate a possible alteration in cortisol responsiveness to
      stress/novelty situations in PD subjects. This was considered to be consistent
      with previous suggestions of HPA axis dysregulation in PD patients, although our
      research indicates unresponsiveness rather than responsiveness to be a factor to
      be considered for future investigation.

PMID- 10357034
TI  - Temperament and personality features in patients with major depression, panic
      disorder and mixed conditions.
AB  - METHOD: Forty-two patients with Panic Disorder (P), 18 with Major Depression
      (MD), 35 with both conditions (MIX) and 45 healthy subjects (C) were tested with
      the Tridimensional Personality Questionnaire and the Structured Interview for DSM
      III-R Personality Disorders. RESULTS: A different prevalence of Dependent (P =
      16.7%, MD = 5.6%, MIX = 41.4%, C = 2.1%) (P < 0.001), Obsessive-Compulsive (P =
      4.8%, MD = 27.8%, MIX = 3.4%, C = 0%) (P < 0.001) and Histrionic (P =23.8%, MD =
      0%, MIX = 31%, C = 4.2%) (P = 0.001) personality disorders (PD) was found among
      groups. Harm Avoidance (HA) (P < 0.001) and Reward Dependence (RD) (P <0.001)
      were higher in patients than in controls. As expected the patients with comorbid
      conditions (MIX) showed higher HA levels (P < 0.01) and a greater prevalence of
      PDs, particularly of Cluster C compared to patients with pure disorders.
      CONCLUSIONS: This study suggests that high HA and RD scores are associated with
      P, MD and MIX, and the former dimension is even higher in MIX patients.

PMID- 10357035
TI  - Psychosocial predictors of outcome in major depression: a prospective 12-month
      study.
AB  - This study examined the relationship between clinical and psychosocial variables
      and unipolar major depression outcome. Ninety ambulatory patients, with an index
      phase duration of less than 6 months, were followed-up for 12 months. Two
      measures of outcome were used: persistence of severe or partial symptomatology.
      Sixty percent of the patients were asymptomatic (HDRS < 8), 24% improved but not
      totally and 17% persisted with severe symptomatology (HDRS> 18). Personality
      disorder, recurrent depression, low self-esteem and low satisfaction with social
      support were associated to non-full remission. Personality disorder and low
      satisfaction with social support were associated to non-improvement. This work
      underlines the need during treatment to take into account personality and social
      variables.

PMID- 10357036
TI  - Axis I and Axis II disorder comorbidity in unipolar depression with anger
      attacks.
AB  - OBJECTIVE: We evaluated whether anger attacks in patients with major depressive
      disorder (MDD) are associated with higher rates of panic or other Axis I or II
      comorbid disorders. METHODS: 306 out-patients (163 women, mean age 39.5+/-10.5)
      with MDD were administered the Structured Clinical Interviews for Axis I and II
      Disorders, and the Anger Attacks Questionnaire. RESULTS: Patients with anger
      attacks showed only a trend toward a significantly higher rate of current panic
      disorder (P = 0.06) but no other difference in Axis I comorbidity. In addition
      patients with anger attacks had a slightly but significantly greater degree of
      depression severity. Consistent with previous studies, we have also found that
      depressed patients with anger attacks had significantly higher rates of
      dependent, avoidant, narcissistic, borderline, and antisocial personality
      disorders than those without anger attacks. CONCLUSION: Anger attacks do not
      appear to be associated with any specific pattern of Axis I comorbidity, but they
      are certainly linked with certain personality disorders. It is possible that the
      acute depressive state may have confounded the assessment of personality disorder
      rates, as well as the presence of anger attacks. On the other hand, both
      depressed patient groups (with or without anger attacks) were subject to the same
      confounding effect as their depression severity was rather comparable, thereby
      limiting the impact of this potential bias.

PMID- 10357037
TI  - Altered [3H]imipramine and 5-HT2 but not [3H]paroxetine binding sites in
      platelets from depressed patients.
AB  - BACKGROUND: Serotonergic system alterations were studied in 51 depressed patients
      classified according to DSM-III-R criteria for major depression with melancholia
      compared to 31 healthy controls. METHOD: [3H]Imipramine and [3H]paroxetine
      binding sites and the 5HT2 receptor were simultaneously determined in blood
      platelet membranes. RESULTS: A significantly lower maximum binding in
      [3H]imipramine binding was observed in depressed patients compared to controls
      (1134+/-74 vs. 1712+/-106 fmol/mg protein, P<0.0001) without changes in the
      equilibrium dissociation constant (1.10+0.05 vs. 1.25-/+0.09 nM). [3H]Paroxetine
      binding did not differ between the two groups (Bmax, 1441+/-55 vs. 1280+/-81
      fmol/mg protein; Kd, 0.060+/-0.002 vs. 0.062+/-0.002 nM). The K(d) value of 5HT2
      binding was lower in depressed patients than controls (0.95+/-0.04 vs. 1.15+/
      0.09 nM, P<0.039) without changes in maximum binding (140+/-11 vs. 127+/-14
      fmol/mg protein). CONCLUSIONS: Taken together, these results suggest that
      [3H]imipramine and 5HT2 receptors may be good biological markers for serotonergic
      dysfunction in depressive disorders.

PMID- 10357038
TI  - Post-seizure EEG fractal dimension of first ECT predicts antidepressant response
      at two weeks.
AB  - BACKGROUND: Duration of seizure by itself is an insufficient criterion for a
      therapeutically adequate seizure in ECT. Therefore, measures of seizure EEG other
      than its duration need to be explored as indices of seizure adequacy and
      predictors of treatment response. We measured the EEG seizure using a geometrical
      method-fractal dimension (FD) and examined if this measure predicted remission.
      METHODS: Data from an efficacy study on melancholic depressives (n = 40) is used
      for the present exploration. They received thrice or once weekly ECTs, each
      schedule at two energy levels - high or low energy level. FD was computed for
      early-, mid- and post-seizure phases of the ictal EEG. Average of the two
      channels was used for analysis. RESULTS: Two-thirds of the patients (n = 25) were
      remitted at the end of 2 weeks. As expected, a significantly higher proportion of
      patients receiving thrice weekly ECT remitted than in patients receiving once
      weekly ECT. Smaller post-seizure FD at first ECT is the only variable which
      predicted remission status after six ECTs. Within the once weekly ECT group too,
      smaller post-seizure FD was associated with remission status. CONCLUSIONS: Post
      seizure FD is proposed as a novel measure of seizure adequacy and predictor of
      treatment response. CLINICAL IMPLICATIONS: Seizure measures at first ECT may
      guide selection of ECT schedule to optimize ECT. LIMITATIONS: The study examined
      short term antidepressant effects only. The results may not be generalized to
      medication-resistant depressives.

PMID- 10357039
TI  - Prevalence of migraine in bipolar disorder.
AB  - BACKGROUND: This study was undertaken to estimate the prevalence of migraine in
      people suffering from bipolar affective disorder. METHODS: a headache
      questionnaire incorporating the newly introduced International Headache Society
      (IHS) criteria was given to 117 patients on the Dunedin Bipolar Research
      Register. RESULTS: a total of 81 (69%) completed the questionnaire, out of which
      21 (25.9%) reported migraine headaches. 25% of bipolar men and 27% of bipolar
      women suffered from migraine. CONCLUSIONS: these rates are higher than those
      reported in the general population with the rate for bipolar men being almost
      five-times higher than expected. An increased risk of suffering form migraine was
      particularly noted in bipolar patients with an early onset of the disorder. This
      may represent a more severe form of bipolar affective disorder.

PMID- 10357040
TI  - Neuroticism and depression in alcoholics.
AB  - BACKGROUND: To examine neuroticism as a possible determinant of depression in
      alcoholics. METHOD: 24 euthymic depressed alcoholics and 18 never-depressed
      alcoholic controls completed the Eysenck Personality Questionnaire. RESULT:
      Euthymic depressed alcoholics had significantly higher neuroticism scores than
      alcoholic controls. LIMITATION: No women alcoholics were studied. CONCLUSION:
      Neuroticism may be a risk factor for depression in alcoholics.

PMID- 10357041
TI  - CSF 5-HIAA correlates with neuroticism in depressed patients.
AB  - BACKGROUND: To examine for relationships between neurotransmitters and
      personality. METHOD: 27 depressed patients had cerebrospinal fluid (CSF)
      monoamine metabolites measured and completed the Eysenck Personality
      Questionnaire (EPQ). RESULT: CSF concentrations of the serotonin metabolite 5
      hydroxyindoleacetic acid (5-HIAA) correlated significantly with EPQ neuroticism
      scores. CONCLUSION: Central serotonin may play a role in neuroticism, a
      personality dimension predisposing to depression. LIMITATION: The positive
      correlation may partly reflect collinear relationships between both variables and
      anxiety/depression.

PMID- 10357042
TI  - Residual symptoms and social functioning over six-months in recovered outpatients
      with chronic depression.
AB  - BACKGROUND: Scant data exists regarding the global mental health of recovered
      chronically depressed outpatients. The purpose of this study was to compare the
      symptoms and functioning of these patients to those found in a normal control
      group (NCG). METHODS: Social functioning was assessed by the Social Adjustment
      Scale interview. Symptoms were measured with the Symptom Check List-90. RESULTS:
      The overall social functioning of recovered females was more impaired than a NCG.
      Recovered males and females had more psychiatric symptoms than a NCG.
      LIMITATIONS: The two samples were not demographically similar. CONCLUSIONS:
      Though the differences in social functioning and symptoms between the recovered
      patients and NCG's were statistically significant, they were not clinically
      meaningful. In general, recovered females had a relatively robust level of mental
      health.

PMID- 10357043
TI  - Relationship between antidepressant partial and nonresponse and subsequent
      response to antidepressant augmentation.
AB  - OBJECTIVE: To evaluate the relationship between the degree of antidepressant
      nonresponse and subsequent response to lithium and triiodothyronine (T3)
      augmentation. METHOD: This is a retrospective analysis of data combined from two
      previous controlled studies of lithium and triiodothyronine augmentation of
      tricyclic antidepressants. RESULTS: There was no difference in the rate of
      augmentation response between partial and nonresponders to tricyclic
      antidepressant treatment. CONCLUSIONS: Augmentation response does not appear to
      be related to the degree of nonresponse to the preceding antidepressant trial.

PMID- 10357044
TI  - A naturalistic comparison of adverse effects between slow titration and loading
      of divalproex sodium in psychiatric inpatients.
AB  - BACKGROUND: This study compares the incidence, severity and onset of treatment
      emergent adverse effects between slow titration and loading of divalproex sodium
      in psychiatric inpatients. METHOD: Forty-seven patients were prescribed either
      loading or slow titration of divalproex sodium. Under single-blind conditions,
      adverse effects were assessed using a valproate adverse effects rating scale.
      Except for a statistically significant greater incidence of somnolence in the
      slow titration group, no statistically or clinically significant differences in
      incidence, severity or onset of treatment-emergent adverse effects were found
      between groups. RESULTS/CONCLUSION: Overall, adverse effects were well tolerated
      by both groups.

PMID- 10357045
TI  - Perceived family characteristic differences between depressed and anxious
      children and adolescents.
AB  - BACKGROUND: The present study compared anxious vs. depressed children's and
      adolescents' perceptions about their family environment. METHODS: One hundred
      inpatient youngsters were interviewed for the study. Of these participants, 21
      who met criteria for a depressive disorder without an anxiety disorder and 18 who
      met criteria for an anxiety disorder without a depressive disorder were compared
      on several self-report family measures. These measures included the Family
      Adaptability and Cohesion Evaluation Scales-II (FACES-II), Family Strengths, and
      Social Support Questionnaire-Revised (SSQS-R). RESULTS: Youngsters with
      depressive disorders reported having less pride in their families and perceived
      their families as being less adaptable to problems than did anxious children.
      Also, depressed children expressed lower levels of satisfaction with their social
      network than did anxious children. LIMITATIONS: The fact that our study only
      included reports from inpatient youngsters, families of anxious and depressed
      children may differ in the way family members relate to one another and in the
      way they deal with everyday problems. CONCLUSIONS: Based on the evidence obtained
      in this study, anxiety and depression may be two distinct internalizing disorders
      with specific family characteristics.

PMID- 10357046
TI  - Dysthymia: clinical picture, extent of overlap with chronic fatigue syndrome,
      neuropharmacological considerations, and new therapeutic vistas.
AB  - Dysthymia, as defined in the American Psychiatric Association and International
      Classification of Mental Disorders, refers to a prevalent form of subthreshold
      depressive pathology with gloominess, anhedonia, low drive and energy, low self
      esteem and pessimistic outlook. Although comorbidity with panic, social phobic,
      and alcohol use disorders has been described, the most significant association is
      with major depressive episodes. Family history is loaded with affective,
      including bipolar, disorders. The latter finding explains why dysthymia,
      especially when onset is in childhood, can lead to hypomanic switches, both
      spontaneously and upon pharmacologic challenge in as many as 30%. Indeed,
      antidepressants from different classes -tricyclic antidepressants (TCAs),
      monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase
      A (RIMAs), selective serotonin-reuptake inhibitors (SSRIs) and, more recently,
      amisulpride, and spanning noradrenergic, serotonergic as well as dopaminergic
      mechanisms of action - have been shown to be effective against dysthymia in an
      average of 65% of cases. This is a promising development because social and
      characterologic disturbances so pervasive in dysthymia often, though not always,
      recede with continued pharmacotherapy beyond acute treatment. Despite symptomatic
      overlap of dysthymia with chronic fatigue syndrome - especially with respect to
      the cluster of symptoms consisting of low drive, lethargy, lassitude and poor
      concentration - neither the psychopathologic status, nor the pharmacologic
      response profile of the latter syndrome is presently understood. Chronic fatigue
      today is where dysthymia was two decades ago. We submit that the basic science -
      clinical paradigm that has proven so successful in dysthymia could, before too
      long, crack down the conundrum of chronic fatigue as well. At a more practical
      level, we raise the possibility that a subgroup within the chronic fatigue group
      represents a variant of dysthymia.

PMID- 10357048
TI  - High-dose fluconazole therapy in patients with severe fungal infections.

PMID- 10357047
TI  - An open trial of light therapy in hospitalised major depression.

PMID- 10357049
TI  - Prospective, randomized, double-blind trial comparing teicoplanin and cefazolin
      as antibiotic prophylaxis in prosthetic vascular surgery.
AB  - To compare efficacy, tolerability, and cost of antibiotic prophylaxis with
      teicoplanin and cefazolin in clean prosthetic vascular surgery, a randomized,
      prospective, double-blind study was performed at the Vascular Surgery Unit of a
      tertiary-care university hospital. Two-hundred thirty-eight consecutive patients
      undergoing elective, clean, abdominal or lower-limb prosthetic vascular surgery
      were allocated to receive a single intravenous dose of teicoplanin (400 mg) or
      cefazolin (2 g) at the induction of anesthesia. Surgical-site infections occurred
      in 5.9% of teicoplanin recipients (4.2% wound infection, 1.7% graft infection)
      and 1.7% of cefazolin recipients (1.7% wound infection, 0% graft infection)
      (P=0.195). Other postoperative infections occurred in 10% of teicoplanin
      recipients (pneumonia 7%, urinary tract infection 3%) and 12% of cefazolin
      recipients (pneumonia 7%, urinary tract infection 2.5%, bloodstream infections
      2.5%). Overall mortality rate was 3.4% in teicoplanin recipients (4 patients) and
      2.5% in cefazolin recipients (3 patients). Infective deaths occurred in one
      patient for each group. The two prophylactic regimens were well tolerated. Cost
      savings of US $52,510 favoring cefazolin were related to the lower acquisition
      cost (US $1034 vs US $4740) and to the shorter duration of the hospital stay
      (1762 days vs 1928 days). Cefazolin can still be regarded as the drug of choice
      for prophylaxis in clean vascular surgery.

PMID- 10357050
TI  - Distribution of Acinetobacter species on skin of healthy humans.
AB  - The distribution of the 19 currently known genospecies of Acinetobacter on human
      skin, i.e. forehead, forearm and toe webs, was determined. Three selective media
      were compared for their specificity for all genospecies of Acinetobacter. A
      minimal-salts agar supplemented with 1% acetate proved to be more efficient than
      the Leeds medium for the isolation of most genospecies in mixed culture with
      other bacterial species. Acinetobacter isolates were provisionally identified
      using biochemical tests and the DNA transformation assay of Juni. Genospecies
      identification was performed using amplified ribosomal DNA restriction analysis,
      and duplicate isolates of the same genospecies from individuals were ruled out by
      random amplified polymorphic DNA analysis. Over 40% of 192 healthy volunteers
      carried Acinetobacter spp. at one or more body sites, and the frequencies of
      colonisation were as follows: forearm (51%), forehead (47%) and toe web (34%).
      Genospecies 8/9 (Acinetobacter lwoffii) was the most common (61%), followed by
      genospecies 15BJ and 12 (Acinetobacter radioresistens) at 12.5% and 8%,
      respectively. The Acinetobacter baumannii-Acinetobacter calcoaceticus group
      (genospecies 1, 2, 3 and 13TU) that predominates in hospital-acquired infections
      was found in only one individual.

PMID- 10357052
TI  - Evaluation of six commercial tests and the germ-tube test for presumptive
      identification of Candida albicans.
AB  - Six commercial tests (Albicans ID, bioMerieux, France; CandiSelect, Sanofi
      Diagnostics Pasteur, France; CHROMagar Candida, Becton Dickinson, USA;
      Fluoroplate Candida, Merck, Germany; Fongiscreen 4H, Sanofi Diagnostics Pasteur;
      and Murex Candida albicans, Murex Diagnostics, USA) and the germ-tube test for
      presumptive identification of Candida albicans were evaluated using clinical
      isolates of Candida albicans (n = 350) and of non-albicans yeasts (n = 135).
      Sensitivities and specificities of all tests regarding the identification of
      Candida albicans were greater than 97%. The two tests that also allow presumptive
      identification of some non-albicans yeasts (CHROMagar Candida and Fongiscreen 4H)
      did not identify all isolates of Candida glabrata and Candida tropicalis. In
      addition, CHROMagar Candida identified as Candida glabrata some isolates
      belonging to different species of non-albicans yeasts.

PMID- 10357051
TI  - Electrophoretic karyotyping and triazole susceptibility of Candida glabrata
      clinical isolates.
AB  - A series of 35 strains of Candida glabrata isolated from 29 subjects (5 AIDS
      patients and 24 HIV-seronegative individuals) were typed by electrophoretic
      karyotyping and tested for their susceptibilities to both fluconazole and
      itraconazole. Almost every individual harboured his/her own specific isolate (DNA
      type). Neither the source of isolation nor the patient's HIV status was
      associated with a given DNA type. Recurrences were generally due to the
      persistence of the same DNA type over time. Only 9% of the isolates showed
      reduced susceptibility to fluconazole (MIC > or = 8.0 microg/ml), while 43% of
      the isolates showed reduced susceptibility to itraconazole (MIC > or = 0.25
      microg/ml) (P = 0.02). These data show that electrophoretic karyotyping is a
      useful technique for DNA typing of isolates of Candida glabrata. Care must be
      taken prior to initiation of antifungal therapy with either of these drugs.

PMID- 10357053
TI  - Evaluation of a new serologic test for diagnosis of Helicobacter pylori infection
      in children.
AB  - A new semiquantitative enzyme immunoassay (Platelia Helicobacter pylori; Sanofi
      Diagnostics Pasteur, France) was evaluated and compared with two other
      serological assays (Gap-test IgG; Bio-Rad, France; and Cobas Core; Roche,
      Switzerland) for the diagnosis of Helicobacter pylori infection in children. The
      three tests were compared with the examination of biopsy samples obtained from
      160 dyspeptic subjects (mean age, 9 +/- 4.7 years). Discrepant results were
      studied using an immunoblot technique. The response obtained for the Platelia
      assay in children was significantly lower than that obtained in a previously
      described population of 92 adults (Helicobacter pylori-negative mean ratios,
      0.376 vs. 0.504, P<0.000783; Helicobacter pylori-positive mean ratios, 1.95 vs.
      2.67, P<0.000003). Thus, the optimal cut-off for children (0.80) was lower than
      the one recommended for adults (1.10). According to the Receiver Operating
      Characteristic (ROC) curve analysis and to the Wilcoxon value, the Platelia and
      Cobas Core assays showed the highest discriminatory properties (Wilcoxon value,
      0.94 for both) compared with the Gap-test IgG (Wilcoxon value, 0.91). When the
      newly established cut-off value (0.80) was used, the performance of Platelia was
      equivalent to that of Cobas Core (sensitivity: 94.4% for each; respective
      specificities, 86.8% and 90.6%). The Gap-test IgG had a lower sensitivity
      (maximum, 79%) and a higher specificity (maximum, 95.3%), but there were
      difficulties in interpretation because its grey zone encompassed 12% of the sera.
      In conclusion, the results showed good performance of the Platelia Helicobacter
      pylori assay and confirmed the merit of a specific cut-off value for use of this
      test in children.

PMID- 10357055
TI  - Vibrio cholerae O2 sepsis in a patient with AIDS.
AB  - Vibrio cholerae strains other than O1 and 0139 (non-O1 Vibrio cholerae) are
      associated with sporadic diarrheal disorders and limited outbreaks of diarrhea
      and have often been reported in association with extraintestinal infections. The
      following is a presentation of a fatal case of non-O1 Vibrio cholerae septicemia
      with disseminated intravascular coagulation and cutaneous bullous lesions that
      occurred in a patient infected with the acquired immunodeficiency syndrome. In
      order to prevent Vibrio cholerae infection, patients with underlying diseases
      should be warned of the risk factors for acquiring such infection, including
      consumption of raw shellfish and exposure to sea and fresh water where shellfish
      are found.

PMID- 10357054
TI  - Prospective, randomized dose-ranging open phase II pilot study of
      quinupristin/dalfopristin versus vancomycin in the treatment of catheter-related
      staphylococcal bacteremia.
AB  - Two different doses of quinupristin/dalfopristin were compared with intravenous
      vancomycin with regard to the efficacy and safety in the treatment of catheter
      related staphylococcal bacteremia. A total of 39 patients were enrolled from 13
      centers. For all treated patients with a baseline pathogen, outcome was
      comparable for all antibiotic study regimens. Discontinuation of the antibiotic
      for an adverse clinical event occurred in 12% of patients receiving
      quinupristin/dalfopristin and in 15% of those receiving vancomycin.
      Quinupristin/dalfopristin may have the potential to serve as an alternative agent
      in the treatment of catheter-related staphylococcal bacteremia. However, larger
      prospective randomized trials are required.

PMID- 10357056
TI  - Ability of Proteus mirabilis to swarm over urethral catheters.
AB  - The aim of this study was to investigate the ability of Proteus mirabilis to
      swarm over various types of urinary catheters. The test strain was found to swarm
      over catheters for distances of up to 10 cm within 24 h. Migration was
      significantly more rapid over hydrogel-coated latex catheters than over all
      silicone or silicone-coated latex catheters. Scanning electron micrographs
      revealed discrete rafts of typically elongated swarmer cells on catheter
      surfaces. Migration of swarmers along catheters into the bladder could thus
      initiate Proteus mirabilis catheter-associated infections.

PMID- 10357057
TI  - Enteroaggregative and enterotoxigenic Escherichia coli among isolates from
      patients with diarrhea in Austria.
AB  - In a 3-month prospective study among 203 Austrian outpatients with diarrhea, the
      role of pathogenic Escherichia coli and the use of the polymerase chain reaction
      in screening Escherichia coli isolates from clinical stool specimens were
      evaluated. Enteroaggregative Escherichia coli and enterotoxigenic Escherichia
      coli combined were identified as the second most frequent cause of diarrhea. Of a
      total of 85 bacterial pathogens isolated from 80 patients, 15 were pathogenic
      Escherichia coli, 13 enteroaggregative Escherichia coli and two enterotoxigenic
      Escherichia coli. Enteropathogenic, enteroinvasive, and enterohemorrhagic
      Escherichia coli isolates were not detected.

PMID- 10357058
TI  - Increased adherence of fluconazole-resistant isolates of Candida species to
      explanted esophageal mucosa.
AB  - The adherence of fluconazole-resistant and fluconazole-susceptible isolates of
      Candida albicans to explanted rabbit esophageal mucosa was examined in vivo.
      Among six Candida albicans isolates collected from HIV-infected patients, three
      fluconazole-resistant (MIC > 64 microg/ml) isolates attached more avidly than
      three fluconazole-susceptible strains (MIC < or = 0.5 microg/ml) to esophageal
      mucosa (P < or = 0.05). When three strains each of six different Candida spp.
      were compared, the more inherently fluconazole-resistant isolates adhered more
      avidly in the following order: Candida glabrata>Candida krusei>Candida albicans
      fluconazole-sensitive>Candida tropicalis>Candida parapsilosis. Nonetheless,
      fluconazole-resistant Candida albicans demonstrated the greatest degree of
      adherence in comparison to all fluconazole-susceptible Candida albicans (P<0.001)
      and to all Candida spp. tested (P<0.001). Thus, the refractoriness of esophageal
      candidiasis in patients infected with fluconazole-resistant isolates may be
      related to both in vitro drug resistance and increased mucosal adherence.

PMID- 10357059
TI  - Antimicrobial susceptibility of bacterial pathogens in the oropharynx of healthy
      children.
AB  - In a study to determine the prevalence and antimicrobial susceptibility of
      bacterial pathogens in the oropharynx of healthy children, throat swabs obtained
      from 1765 children were cultured and the organisms recovered tested by the disk
      diffusion method and the E test. Six hundred ninety-one children (39.1%) harbored
      Haemophilus influenzae, 112 (6.3%) Streptococcus pyogenes, 73 (4.1%) Moraxella
      catarrhalis, 52 (2.9%) Streptococcus pneumoniae, and 50 (2.8%) Neisseria
      meningitidis in their oropharynx. The rate of penicillin resistance was 2%, 0%,
      and 12%, respectively, for Streptococcus pneumoniae, Streptococcus pyogenes, and
      Neisseria meningitidis. Ampicillin resistance was observed in 8.6% of Haemophilus
      influenzae strains and 78% of Moraxella catarrhalis strains and was associated
      with the presence of beta-lactamase, except in one strain of Haemophilus
      influenzae. Five (4.4%) isolates of Streptococcus pyogenes were resistant to
      macrolides. The low level of resistance observed in this area contrasts with the
      high rates reported in the literature.

PMID- 10357060
TI  - Prevalence of antibodies against the human granulocytic ehrlichiosis agent in
      Lyme borreliosis patients from Germany.
AB  - To contribute to the discussion of whether or not human granulocytic ehrlichiosis
      (HGE) occurs in midwestern Germany, sera from individuals with different risk
      categories for tick exposure were retrospectively examined by means of an
      immunofluorescence assay. The seroreprevalence for the HGE agent accounted for
      5.5% of the 270 patients tested. Specific antibodies were detected more often in
      patients with early Lyme infection than in patients with stage III disease or in
      asymptomatic individuals seropositive for Lyme disease. Investigation of 50
      patients with an active or recent syphilis infection revealed no cross-reactivity
      between Treponema pallidum antibodies and the HGE agent. The prevalence of HGE
      antibodies (13.1%) among 76 Lyme borreliosis patients from this urban area was
      significantly higher (P < 0.05) than that in the control groups (2.6%). The
      findings indicate that concomitant or serial infections with Borrelia burgdorferi
      and the HGE agent or closely related organisms may be a common occurrence in tick
      exposed patients from Germany.

PMID- 10357061
TI  - Susceptibility testing of linezolid by two standard methods.
AB  - To determine to what extent methodological differences affect susceptibility
      testing parameters for linezolid, MICs and disk inhibition zones were compared
      using the methods described by the National Committee for Clinical Laboratory
      Standards and the British Society for Antimicrobial Chemotherapy for 198 strains
      of gram-positive cocci. Zones were 4-5 mm larger by the British Society for
      Antimicrobial Chemotherapy method, but MICs did not differ, except for
      pneumococci, which were more sensitive when the British Society for Antimicrobial
      Chemotherapy method was used. This is because incubation in CO2 depresses the
      activity of linezolid against this species only. Breakpoints for linezolid may
      need adjusting when testing is by other than National Committee for Clinical
      Laboratory Standards methods.

PMID- 10357062
TI  - Aseptic meningitis caused by Mycoplasma pneumoniae in a 19-year-old woman.

PMID- 10357063
TI  - Chronic pulmonary histoplasmosis in a patient with a recent history of
      tuberculosis and persistent round lung lesions.

PMID- 10357064
TI  - Otitis media due to Corynebacterium jeikeium.

PMID- 10357065
TI  - Human rabies despite postexposure vaccination.

PMID- 10357066
TI  - The gospel of the fossil brain: Tilly Edinger and the science of paleoneurology.
AB  - Tilly Edinger (1897-1967) was a vertebrate paleontologist interested in the
      evolution of the central nervous system. By combining methods and insights gained
      from comparative neuroanatomy and paleontology, she almost single-handedly
      founded modern paleoneurology in the 1920s while working at the Senckenberg
      Museum in Frankfurt am Main. Edinger's early research was mostly descriptive and
      conducted within the theoretical framework of brain evolution formulated by O. C.
      Marsh in the late 19th century. Nevertheless, she became immediately known in
      1929 after publishing an extensive review on "fossil brains." Reconstructing
      evolutionary history from the fossil record instead of from the comparative
      analysis of living forms allowed her to identify the sequence of neural
      innovations within several mammalian lineages. Anti-Jewish terrorism forced
      Edinger to leave Nazi Germany in 1939. After finding refuge first in England, she
      continued her career at Harvard's Museum of Comparative Zoology. There she
      documented the occurrence of gross neural correlates of specialized behavior in
      several vertebrate lineages, and identified parallel evolution in mammalian
      sulcation patterns. Her insight that neural innovations need not be "correlated"
      with either nonneural innovations or with evolutionary "success" led her to
      reject Marsh's theory of progressive increase in brain size over time and other
      "anthropocentric" understandings of brain evolution. Edinger's research, her
      insistence on a stratigraphic and evolutionary framework for interpretation, and
      her massive compilations of paleoneurological literature established her as the
      leading definer, practitioner, and chronicler of her field.

PMID- 10357067
TI  - Brain tumor development in rats is associated with changes in central nervous
      system cytokine and neuropeptide systems.
AB  - Cytokines have roles in tumor biology and induce neurological manifestations.
      Cytokines produced in response to a brain tumor may generate neurological
      manifestations via paracrine action. We investigated cytokine modulation in an in
      vivo brain tumor model with behavioral, morphological, and molecular approaches.
      Rat C6 glioma cells were implanted into the third cerebral ventricle of Wistar
      rats, their behavior was monitored, and the development of an intracranial tumor
      of astrocytic origin was confirmed by histology and positive immunostaining for
      vimentin, S-100 protein, and glial fibrillary acidic protein. Sensitive and
      specific RNase protection assays were used to analyze cytokine messenger RNA
      (mRNA) in brain regions from anorexic brain tumor-bearing animals. Brain tumor
      formation was associated with significant increased levels of interleukin (IL)
      1beta, IL-1 receptor antagonist, IL-1 receptor type I, tumor necrosis factor
      (TNF)-alpha, and transforming growth factor (TGF)-beta1 mRNAs in the cerebellum,
      hippocampus, and hypothalamus. IL-1 receptor accessory proteins I and II mRNAs
      were increased in the cerebellum and hypothalamus. We also examined hypothalamic
      feeding-associated components: neuropeptide Y and proopiomelanocortin mRNAs were
      down-regulated, glycoprotein 130 mRNA levels were up-regulated, and leptin
      receptor (OB-R) mRNA levels were unchanged. These dissimilar profiles of mRNA
      expression suggest specificity of brain tumor-induced transcriptional changes.
      The data implicate cytokines as important factors in brain tumor-host
      interactions in vivo. The data also show that the C6 cell-induced glioma can be
      used as a behavioral-molecular model to study cytokine and neuropeptide
      modulation and action during the host biochemical and physiological responses to
      brain tumor development. Paracrine interactions seem pivotal because cytokine
      modulation was observed in various brain regions. These results also suggest that
      cytokine and neuropeptide changes during brain tumor progression are involved in
      brain tumor-associated neurological and neuropsychiatrical manifestations.

PMID- 10357069
TI  - Injection of Xenopus oocytes with mRNA from cultured neurons induces new currents
      and susceptibility to the damaging action of ruthenium red.
AB  - The hexacationic dye ruthenium red produce neuronal death in primary cultures. We
      injected messenger RNA (mRNA) from cultured neurons into Xenopus laevis oocytes
      to test whether this treatment can make oocytes sensitive to the damaging action
      of ruthenium red. Two-microelectrode voltage clamp and resting membrane potential
      were used to evaluate mRNA expression and to assess the effect of the dye on
      oocyte survival, when added to the medium or when injected into the cells, at 20,
      50, or 100 microM concentrations. Injection of mRNA from cultured cortical or
      cerebellar granule neurons produced both new outward currents and membrane
      hyperpolarization. Exposure of mRNA-injected oocytes to extracellular ruthenium
      red for 24 h induced a remarkable depolarization, but no significant damage was
      observed. Injection of the dye into buffer-injected oocytes did not cause any
      change in membrane potential or cell survival, whereas in mRNA-injected oocytes
      an important depolarization was observed at 24 h after ruthenium red
      introduction, and 29% of the cells showed serious damage. The results suggest
      that oocytes become sensitive to intracellular ruthenium red toxicity because
      they express neuronal-specific proteins involved in cell death.

PMID- 10357068
TI  - Neurotrophin-like immunoreactivity in the human hippocampal formation.
AB  - The immunohistochemical occurrence and localisation of the neurotrophins nerve
      growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-4, and
      neurotrophin-3 is described in the human post-mortem hippocampal formation from
      subjects aged 23 weeks of gestation to 68 years. Labeled neuronal cell bodies and
      processes were detectable for each neurotrophin at all examined ages with age
      related changes in their distribution pattern. As a general rule, a higher number
      of immunoreactive perikarya was found in subjects at pre- and perinatal ages than
      in adults. At variance with the other neurotrophins, the BDNF antiserum labelled
      also extensive nerve fibre systems, whose occurrence and distribution widened
      with age. The results obtained provide a morphological ground in support to the
      concept that the neurotrophins play a functional role in the human hippocampal
      circuitry throughout life.

PMID- 10357071
TI  - Effects of metabolic alterations on dopamine release in an in vitro model of
      neostriatal ischaemia.
AB  - Release of neurotransmitters, including dopamine (DA), plays a central role in
      neuronal death during cerebral ischaemia. We investigated the effects of changes
      in energy demand and supply on DA release in cerebral ischaemia in vitro. Rat
      striatal slices were superfused (400 ml/h) with an artificial cerebrospinal fluid
      at 34 degrees C, unless otherwise stated. Ischaemia were mimicked by removal of
      O2 and reduction in glucose concentration from 4 to 2 mM. DA release was
      monitored by voltammetry. The profile of ischaemia-induced DA release was
      temperature-dependent. Hypothermia (to 24 degrees C) delayed, slowed, and reduced
      ischaemia-induced DA release relative to 34 degrees C. Pretreatment of the slices
      for 3 h with creatine (25 mM) delayed and slowed ischaemia-induced DA release.
      Conversely, blockade of Na+/K+ ATPase with ouabain induced an anoxic
      depolarisation and rapid DA release similar to ischaemia. In summary, the onset
      of DA release in this model is controlled by the balance between energy supply
      and utilisation. Strategies that increase availability of energy substrates for
      the membrane sodium pump (i.e., pre-incubation with creatine) or decrease their
      utilisation (hypothermia) slow and delay DA release. Hypothermia may owe part of
      its neuroprotective effect to a delay and slowing of ischaemia-induced release of
      DA and/or other neurotransmitters.

PMID- 10357070
TI  - Involvement of nitric oxide and nitric oxide synthase activity in anticonvulsive
      action.
AB  - The anticonvulsant drug Diazepam (DIA-2 mg/kg b. wt), the nitric oxide (NO) donor
      L-Arginine (L-Arg-2000 mg/kg b. wt) and the putative nitric oxide synthase (NOS)
      inhibitor N(G)-Nitro-L-Arginine methyl ester (L-NAME-50 mg/kg b. wt) were used to
      determine the role of endogenous NO on convulsions induced by picrotoxin (PCT-5
      mg/kg b. wt) in rats. Rats given a convulsant dose of PCT (5 mg/kg b. wt) had
      convulsion and it suppresses the NOS activity and NO concentration in brain
      regions. The anticonvulsant L-Arg alone significantly increases the NO
      concentration and NOS activity in brain regions, but not diazepam. Whereas DIA,
      along with L-Arg, enhances the NO and NOS activity when compared to L-Arg alone.
      The combination of both OIA and L-Arg completely suppressed the convulsions. L
      NAME alone had no effect to produce convulsions but it completely decreased NO
      concentration and NOS activity and potentiated the PCT convulsions. This was
      reverted by pre- and post treatment of DIA plus L-Arg indicating, the increased
      NO concentration and NOS activity in brain regions suppresses convulsions.

PMID- 10357072
TI  - Intracranial self-stimulation in the parafascicular nucleus of the rat.
AB  - A behavioral analysis of intracranial self-stimulation was provided for
      parafascicular nucleus. To evaluate whether intracranial self-stimulation in this
      nucleus could be site-specific and to determine if the positive sites are the
      same parafascicular areas that facilitate learning when stimulated, rats were
      tested via monopolar electrodes situated throughout the parafascicular nucleus.
      Animals were trained to self-stimulate by pressing a lever in a conventional
      Skinner box (1-5 sessions). Twenty-two of the 42 animals included in the study,
      had the electrode at the parafascicular nucleus. Only two of them showed
      intracranial self-stimulation. Histological analyses indicated that the latter
      rats had the electrode implanted at the anterior area of the medial
      parafascicular. Other two animals also showed intracranial self-stimulation but
      they had the electrode in a more posterior brain region, between the Dark
      schewitsch nucleus and the red nucleus. The animals implanted at the
      parafascicular showed higher response rates than the other two rats. These
      results confirm that: (a) the anterior region of the medial parafascicular is a
      positive site for stable and regular intracranial self-stimulation behavior, and
      (b) these positive sites do not coincide with the parafascicular regions related
      to learning improvement.

PMID- 10357073
TI  - Evaluation of the elevated T-maze as an animal model of anxiety in the mouse.
AB  - The elevated T-maze has been developed as an animal model of anxiety to generate
      both conditioned and unconditioned fears in the same rat. This study explores a
      version of the elevated T-maze fit for mice. Inhibitory (passive) avoidance-
      conditioned fear-is measured by recording the latency to leave the enclosed arm
      during three consecutive trials. One-way escape- unconditioned fear-is measured
      by recording the time to withdraw from open arms. The results showed that mice do
      not appear to acquire inhibitory avoidance in the standard T-maze, since their
      latencies to leave enclosed arm did not increase along trials. Nevertheless, the
      open arms seemed to be aversive for mice, because the latency to leave the
      enclosed arm after the first trial was lower in a T-maze with the three enclosed
      arms than in the standard elevated T-maze. In agreement, the exposure of mice to
      an elevated T-maze without shield, that reduces the perception of openness,
      increased significantly the latencies to leave the enclosed arm. However, the
      absence of the shield also increased the time taken to leave the open arms when
      compared to that recorded in standard T-maze. Systematic observation of
      behavioral items in the enclosed arm has shown that risk assessment behavior
      decreases along trials while freezing increases. In the open arms, freezing did
      not appear to influence the high latency to leave this compartment, since mice
      spend only about 8% of their time exhibiting this behavior. These results suggest
      that mice acquire inhibitory avoidance of the open arms by decreasing and
      increasing time in risk assessment and freezing, respectively, along three
      consecutive trials. However, one-way escape could not be characterized.
      Therefore, there are important differences between mice (present results) and
      rats (previously reported results) in the performance of behavioral tasks in the
      elevated T-maze.

PMID- 10357074
TI  - Thrombospondin expression in nerve regeneration I. Comparison of sciatic nerve
      crush, transection, and long-term denervation.
AB  - Patterns of expression of the extracellular matrix molecule thrombospondin (TSP)
      were examined during peripheral nerve regeneration following sciatic nerve crush
      or transection. In noninjured nerve, was present in the axoplasm, Schwann cells,
      endoneurium, and perineurium of the adult mouse sciatic nerve. Following nerve
      crush or nerve transection, levels of TSP rapidly increased distal to the trauma
      site. Elevated levels of TSP were present distal to regenerating axons, while
      expression gradually returned to normal proximal to the regenerating axons. When
      reinnervation was blocked, TSP levels remained high in the endoneurium in excess
      of 30 days, but TSP was absent by 60 days. Following reanastomosis of the
      proximal and distal segments after 60 days of denervation, TSP was re-expressed
      in the distal nerve stump. These results indicate that TSP, which is involved in
      neuronal migrations in the embryo and neurite outgrowth in vitro, appears to play
      a role in axonal regeneration in the adult peripheral nervous system.

PMID- 10357075
TI  - Thrombospondin expression in nerve regeneration II. Comparison of optic nerve
      crush in the mouse and goldfish.
AB  - Expression of the extracellular matrix molecule thrombospondin (TSP) was examined
      following retrobulbar crush injury of the goldfish and mouse optic nerve. TSP was
      present within the glia limitans and surrounding axon fascicles of the control
      normal goldfish optic nerve, but was absent from the normal mouse optic nerve.
      Following crush injury of the goldfish optic nerve, TSP expression increased
      dramatically along the path of regenerating axons and returned to near normal
      levels following axonal outgrowth. In contrast, during the unsuccessful attempt
      at regeneration following crush injury of the mouse optic nerve, TSP expression
      was present only in glial fibrillary acidic protein (GFAP)-negative, macrophage
      rich regions distal to ganglion cell axons. These results indicate that TSP
      expression is increased in a temporal pattern along the path of regenerating
      goldfish optic nerve axons and therefore may be involved in successful central
      nervous system regeneration. The absence of TSP in the environment encountered by
      damaged mouse optic nerve axons may correlate with the lack of regeneration
      observed in the mouse optic nerve.

PMID- 10357076
TI  - Effects of assisted feeding on Wobbler mouse motoneuron disease and on
      serotonergic and peptidergic sprouting in the cervical spinal ventral horn.
AB  - The Wobbler mouse is used as a model of human motoneuron disease (MND). During
      the disease progress, the significant loss of motoneurons in cervical spinal cord
      and cranial motor nuclei leads to the progressive loss of motor function in the
      forelimb, head, and neck regions. The loss of cutting and chewing ability that
      results in the inability to feed properly might lead to a lower mean body weight
      (b. wt.) that is generally one-half that of the normal phenotype littermate
      controls. Nutritional deficit might also influence neuronal processes sprouting
      in the cervical spinal ventral horn. To determine whether nutritional deficits
      contribute to the wt. loss, and influence the progress of MND as well as its
      sprouting phenomenon, Wobbler and normal phenotype control littermates were
      dropper-fed three times daily on a regular laboratory diet of Rat Chow. Weight
      measurements and behavioral tests were taken to monitor the disease.
      Immunocytochemisty of serotonin, substance P, and leucine enkephalin were
      conducted in the cervical spinal cord to investigate if any alteration occurred
      on the previously reported values in ad lib-fed animals. Organ wts. were measured
      to determine where nutritional benefit was incurred. Although mean wt. loss in
      Wobblers was reduced, wt. differed significantly from the control values after
      dropper feeding. However, the progress of the disease or alteration of
      neurotransmitters containing neuronal processes were not affected by nutritional
      factors. Therefore, nutritional intake affects wt. gain, but is not a primary
      consideration in the progress of MND. Behavioral deficits and neurotransmitter
      alterations are probably directly caused by motoneuron losses.

PMID- 10357077
TI  - Sertoli cells decrease microglial response and increase engraftment of human hNT
      neurons in the hemiparkinsonian rat striatum.
AB  - Sertoli cells (SCs) provide immune protection and nutritive support to the
      developing germ cells in the testis. Sertoli cells have also been shown to
      provide immune protection to islets transplanted outside the testes. In this
      study, the ability of these cells to diminish the infiltration/activation of
      microglia into a neural graft implanted in the lesioned striatum of a
      hemiparkinsonian rat was investigated. Human neuron-like cells (hNT neurons) were
      implanted either alone or in combination with rat SCs. Three months later, the
      animals were sacrificed and immunohistochemistry was performed to determine the
      survival of the xenografted neurons as well as microglial
      infiltration/activation. Cotransplantation of the SCs with the hNT neurons
      increased graft survival and was associated with an increase in graft size.
      Furthermore, there were fewer microglia present in the grafted tissue of the
      cotransplantation groups. These results show that SCs retain their
      immunosuppressive ability even within the brain. As immune responses to grafted
      neural tissue within the central nervous system become better understood, this
      ability of the SCs to provide localized immunosuppression to the transplanted
      tissue may become more important. This is particularly true as the search for
      alternative sources of neural tissue to treat neurodegenerative diseases expands
      to encompass other species.

PMID- 10357078
TI  - Amphetamine dose dependently disrupts prepulse inhibition of the acoustic startle
      response in rats within a narrow time window.
AB  - Prepulse inhibition (PPI) of the acoustic startle response refers to the
      reduction in startle amplitude when a weak prepulse precedes a startle-inducing
      pulse. Prepulse inhibition has been shown to be disrupted by amphetamine at doses
      that also stimulate locomotor activity, and it has been suggested that the same
      neuroanatomical substrate, mesolimbic dopamine activation, mediates the effects
      of amphetamine on locomotor activity and PPI. Amphetamine stimulates locomotor
      activity and mesolimbic dopamine release over a 1- to 3-h period, whereas PPI is
      typically measured within the first 30 min following amphetamine treatment. The
      present study therefore determined whether delays in testing would alter the PPI
      disruptive effect of amphetamine in male Wistar rats. Amphetamine dose
      dependently disrupted PPI when the test session occurred 10 min following
      amphetamine treatment and only when the prepulse intensity was 5-10 dB above
      background. Delays of 40 and 60 min post-amphetamine injection, however, resulted
      in a loss of the ability of amphetamine to disrupt PPI although locomotor
      activity was significantly stimulated by amphetamine at these time points. The
      data from the present study therefore do not readily fit with the notion that the
      effects of amphetamine on locomotion and PPI are mediated by the same substrate.

PMID- 10357079
TI  - Muscarinic M1 and M3 receptors are present and increase intracellular calcium in
      adult rat anterior pituitary gland.
AB  - Physiological and biochemical evidence indicates the existence of functional
      muscarinic cholinergic receptors in the anterior pituitary. The selectivity of
      these receptors has been characterised by studying the binding of
      [3H]quinuclidinyl benzilate ([3H]QNB) and [3H]diphenyl-acetoxy-N-methyl
      piperidine ([3H]4-DAMP) in membrane preparation of male rat anterior pituitary at
      25 degrees C. Competition experiments with receptor selective muscarinic
      antagonists were used to characterise specific selective muscarinic receptor
      binding. Both [3H]QNB and [3H]4-DAMP bound to anterior pituitary membranes at low
      concentrations, binding was saturable and was potently displaced by 4-DAMP (M1,
      M3 subtypes selective antagonist) > atropine (general) > pirenzepine (M1).
      Methoctramine (M2) didn't antagonise the [3H]QNB binding efficiently.
      Acetylcholine and carbachol increased the intracellular Ca2+ level in 62% and 65%
      of cultured rat anterior pituitary cells in a dose-dependent manner, and this
      effect was prevented by pirenzepine. Based on these results we suggest that both
      M1 and M3 muscarinic receptors are present and active in the majority of cells in
      the rat anterior pituitary gland, but their physiological role in the adult rat
      remains to be examined.

PMID- 10357080
TI  - Venous thromboembolism as first manifestation of cancer.
AB  - Numerous studies, performed in recent years, have provided the convincing
      demonstration that the incidence of newly diagnosed malignancy is increased among
      patients with unexplained venous thromboembolism during the first 6 to 12 months
      after the thromboembolic event. Among malignancies presenting with venous
      thromboembolism as a first clinical manifestation, prostate and colorectal cancer
      are the most commonly identified. Other common sites are cancer of the lung,
      pancreas, stomach, ovary, brain, and bladder. Extensive screening with computer
      tomography scanning, gastrointestinal endoscopy, and a number of tumor markers
      have the potential to detect occult malignancies. However, whether an extensive
      diagnostic work-up in all patients presenting with unexplained venous
      thromboembolism is cost-effective still remains to be demonstrated.

PMID- 10357081
TI  - The thrombophilic state induced by therapeutic agents in the cancer patient.
AB  - Multiple risk factors contribute to the hypercoagulable state in cancer patients.
      Antineoplastic therapy, including single- or multiagent chemotherapy, hormonal
      therapy, and hematopoietic growth factors, is an unavoidable and a significant
      precipitant of venous and arterial thromboses. The risk of thrombosis following
      cancer treatment also depends on the interaction between treatment agents, type
      and stage of cancer, and the presence of other risk factors for thrombosis such
      as advanced age, surgery, immobilization, and the use of central venous
      catheters. Therefore, although a causal role of cancer treatment in thrombosis is
      widely accepted, the pathogenic mechanisms are poorly understood and are
      difficult to investigate because of the multiple confounding factors that are
      involved. Alterations in coagulation factors, anticoagulant proteins, and
      endothelial damage have all been shown to occur following cytotoxic agents. The
      best-studied drugs with definite hypercoagulable effects are L-asparaginase and
      tamoxifen.

PMID- 10357082
TI  - Thrombotic complications of central venous catheters in cancer patients.
AB  - Central venous catheters are essential to the modern-day management of many
      illnesses especially cancer and hematologic disorders. Catheter malfunction due
      to catheter tip thrombosis and catheter-related central venous thrombosis are two
      common complications seen with the frequent use of long-term central venous
      catheters. These two complications can cause significant problems in patient
      management and can be a source of morbidity and occasional mortality. This review
      focuses on the incidence, risk factors, natural history, diagnostic approaches,
      prophylaxis and treatment of thrombotic complications of central venous catheters
      in cancer patients.

PMID- 10357083
TI  - Thrombophilic state in breast cancer.
AB  - Tumor cell metastasis and thrombosis are the major causes of death in cancer
      patients. Thrombosis in cancer patients may occur when physiologic antithrombotic
      systems are defective or when prothrombotic activities defeat normal physiologic
      antithrombotic mechanisms. Malignancies by themselves may already predispose to a
      hypercoagulable state in cancer patients. Tumor cells can either directly
      activate the blood clotting system or indirectly stimulate mononuclear cells to
      synthesize and express various procoagulants, subsequently leading to prothrombin
      activation, fibrin formation, and generation of a thrombus. In addition, other
      comorbid predisposing factors effecting thrombosis in cancer patients have to be
      considered, including surgery, bed rest, infection, long-term indwelling central
      venous catheters, anticoagulation, and chemotoxic or steroidal anticancer drugs
      used in adjuvant or palliative cancer treatment. Reliable information on the
      incidence of thromboembolism in cancer patients is available for breast cancer;
      less data have been reported for other malignancies. Chemo- and/or hormone
      therapy in patients with primary or metastatic breast cancer is associated with
      an increased thromboembolic risk, although the benefits of treatment far outweigh
      the risks. The current literature discussing the effect of chemo/hormone therapy
      on blood clotting factors and the associated risk of thrombosis is reviewed, with
      emphasis on new developments in the area of tissue-specific SERMs (selective
      estrogen receptor modulators). SERMs are employed as adjuvant therapy in primary
      breast cancer and in the palliation of advanced breast cancer and may be
      clinically useful as potential substitutes for long-term hormone replacement
      therapy, in the treatment of osteoporosis, and for cancer prevention therapy.

PMID- 10357084
TI  - Laboratory diagnosis of the thrombophilic state in cancer patients.
AB  - Perturbations of coagulation in cancer patients have been described for a long
      time. In up to 90% of cancer patients "routine" blood tests are abnormal leading
      to a hypercoagulable state in these patients. Among these tests are an increase
      in clotting factors, fibrinogen, fibrinogen/fibrin degradation products, and
      thrombocytosis. Markers of the activation of coagulation have been developed, and
      levels of FPA, F1+2, TAT, and D-Dimer have been found higher in cancer patients.
      More specific procoagulant activities in cancer (CP and TF) have also been
      described and can be measured but none of them have any predictive value for the
      occurrence of venous thromboembolism in these patients. Consistent with this
      hypercoagulable state in cancer is the finding that most cancer patients have
      reduced plasma levels of inhibitors of coagulation. These complex abnormalities
      are clinically expressed as thrombosis, low-grade or fulminant DIC which can be
      assessed by different laboratory tests, and as hemorrhage when the fibrinolysis
      system is impaired. However, no studies have shown to date a relationship between
      these abnormalities of the coagulation tests and the clinical expression in any
      single individual. Because these patients are at high risk for thrombosis in
      special conditions such as surgery or during chemotherapy, prophylaxis with
      various forms of heparin are recommended.

PMID- 10357085
TI  - Pathophysiology of the thrombophilic state in the cancer patient.
AB  - The "hypercoagulable state" of malignancy is due to a complex interaction of
      tumor cells and their products with host cells, leading to various degrees of
      impairment of the normal defense mechanisms that ordinarily protect the host
      against thrombogenesis. Tumor cells can activate directly the blood clotting
      cascade and cause thrombosis or can induce procoagulant properties and inhibit
      anticoagulant properties of vascular endothelial cells, platelets, and monocytes
      and macrophages. In the setting of the local and systemic effects of cancer
      (e.g., stasis induced by prolonged bed rest and/or vascular invasion by tumor),
      together with iatrogenic complications of the treatment of cancer (e.g., the use
      of central vein catheters and angiopathic chemotherapy), this basic
      pathophysiology conspires to make cancer perhaps the best example of "acquired
      thrombophilia." In this brief review, we have attempted to describe what is
      currently known about the mechanisms for the hypercoagulable state of cancer and
      provide a summary of the evidence that indicates the many levels of defects in
      patients with malignancies that predispose them to thrombosis. A better
      understanding of the pathophysiology of thrombophilia in cancer should provide
      clinicians with an improved rationale for more aggressive and specific
      anticoagulant strategies in selected patients.

PMID- 10357086
TI  - The role of the plasminogen activation system in cancer.
AB  - Hemostatic disorders are frequently observed in patients with malignancy with a
      significant proportion developing thrombotic and/or hemorrhagic complications
      including disseminated intravascular coagulation (DIC), deep venous thrombosis
      (DVT), and thrombocytopenia. Together, these abnormalities are the second most
      common cause of mortality in cancer patients, which has led many investigators to
      try to unravel the pathogenesis of thromboembolic disease, in the eventuality
      that this will lead to novel therapeutic treatments. The plasminogen activation
      system is one pathway that has been consistently implicated in cancer. Its
      relevance to cancer extends from being responsible for many of the hemorrhagic
      episodes that occur in cancer patients to being fundamental to many, if not all
      of the molecular mechanisms that define tumor progression. Recent developments of
      clinical significance shall be reviewed with respect to the role of the
      plasminogen activation system in tumor growth and metastasis dissemination and in
      the thrombophilic state in the cancer patient.

PMID- 10357087
TI  - The hyperviscosity syndromes.
AB  - Impaired blood flow due to abnormal rheologic characteristics results in a
      multiplicity of clinical manifestations, collectively termed the hyperviscosity
      syndrome. A basic knowledge of the principles of rheology is important in the
      understanding of its pathophysiology, especially the relationship between
      viscosity and flow conditions. The flow characteristics in different types of
      blood vessels are also determinants in the location of the clinical
      manifestation. The syndrome can occur in a wide variety of diseases and is best
      grouped according to the causative element or elements in blood. Abnormalities in
      the cellular components of blood can occur in the quantity and the quality of
      erythrocytes, leukocytes, and platelets. Abnormal plasma components can also be
      in both the quantity and quality of the plasma proteins. Clinical manifestations
      are the result of vascular occlusion, especially in the microcirculation. The
      altered rheologic characteristics of either the cellular or the protein component
      may be temperature dependent, being abnormal only at temperatures below 37
      degrees C, so that only the cooler parts of the body are affected. The management
      of these conditions should be primarily directed at the removal of the abnormal
      component. At the same time, it should be accompanied by measures that can
      control the production of the causative element.

PMID- 10357088
TI  - The thrombophilic state in acute promyelocytic leukemia.
AB  - Acute promyelocytic leukemia is characterized by the association with a severe
      coagulopathy resulting in hemorrhagic manifestations. The pathogenesis underlying
      the hemorrhagic syndrome is complex and involves the activation of the
      coagulation cascade and the fibrinolytic system. All-trans-retinoic acid (ATRA)
      appears to correct both procoagulant and fibrinolytic activities in vitro and in
      vivo. Early results of treatment with arsenic trioxide, which acts by inducing
      apoptosis of the leukemic promyelocytes, also show regression in the coagulopathy
      with a decrease in fibrin degradation products and D-Dimer. A clear understanding
      of the relationship between laboratory changes and the effects of ATRA and
      arsenic trioxide requires further studies.

PMID- 10357089
TI  - Thrombotic microangiopathy manifesting as thrombotic thrombocytopenic
      purpura/hemolytic uremic syndrome in the cancer patient.
AB  - The complication of thrombotic thrombocytopenic purpura or hemolytic uremic
      syndrome (TTP/HUS) can occur in cancer patients. It is characterized by a
      microangiopathic hemolytic anemia, severe thrombocytopenia, and renal failure.
      Pulmonary manifestations, especially pulmonary edema, are a common observation.
      Neurologic changes are also frequently seen. The etiology is unknown at this
      time. It has been observed in many different types of cancer and is most commonly
      seen in gastric adenocarcinoma followed by carcinoma of the breast, colon, and
      small cell lung carcinoma. The hemolysis can be massive and is due to red cell
      fragmentation, as schistocytes are present in all the cases. Though immune
      complexes are present in the plasma, the antiglobulin (Coomb's) test is negative.
      Chemotherapeutic agents, especially mitomycin C, have been implicated as
      causative factors. There is a correlation of this complication with the
      cumulative dose. However, chemotherapy cannot account for all the cases as the
      syndrome can occur in untreated patients. It can be differentiated from
      disseminated intravascular coagulation by the absence of a coagulopathy.
      Management should consist of plasma exchange, use of a Staphylococcus aureus
      column (Prosorba), and control of hypertension. Because of the susceptibility to
      pulmonary edema, blood volume overloading should be avoided.

PMID- 10357090
TI  - The multiple organ dysfunction syndrome in cancer patients undergoing
      hematopoietic stem cell transplantation.
AB  - In the past two decades, major improvements in antibiotics and other elements of
      supportive care have decreased the number and severity of complications of
      hematopoietic stem cell transplantation (HSCT). Despite these improvements, many
      subpopulations of transplant patients still have a significant morbidity and
      mortality. It is becoming increasingly clear that medical science does not have a
      good understanding of the pathophysiology of many of the common, potentially
      fatal complications in patients currently undergoing HSCT. As the mechanisms of
      these complications are subjected to increasingly more rigorous scrutiny, it is
      becoming clear that many of these complications are intimately connected one to
      another and are not isolated clinical disorders as previously thought. One
      hypothesis that can explain the close relationship between them is that most of
      the severe complications of HSCT are the result of a systemic inflammatory
      disorder that has escaped biologic control, an inflammatory process begun by the
      preparative regimen and perhaps added to by intercurrent infections, tumor cell
      death and other as yet unidentified stimuli (transfusions, medications?). If this
      is true, this syndrome would have many similarities with the multiple organ
      dysfunction syndrome (MODS) seen in critically ill non-transplant patients. As
      such, this hypothesis has two significant corollaries: (a) That looking for or
      empirically treating for a reversible organ specific cause of single organ
      dysfunction during HSCT (such as infectious pneumonia, intracranial hemorrhage,
      or acute infectious hepatitis) in any given patient is unlikely to be rewarding
      as the defect causing the organ dysfunction is often systemic at the time of its
      presentation, and (b) that MODS is the dose-limiting toxicity of our current
      preparative regimens, suggesting that when we understand its pathophysiology and
      develop therapies for MODS we will be able to escalate their intensity and, by
      doing so, cure more patients of their malignancy. Manipulation of the hemostatic
      system may prove to be one of these therapies, but there is little doubt that
      other interventions designed to modulate the inflammatory process will prove to
      be even more useful in this syndrome. Using the definitions of organ dysfunction
      outlined in this article, we can provide a basis for clinical monitoring of
      patients today and for use in interventional clinical trials in the future.

PMID- 10357091
TI  - Prevention of venous thromboembolism in cancer patients.
AB  - Thrombosis is a common complication in patients with malignancy and its
      occurrence is heightened by therapeutic interventions such as operations or the
      use of chemotherapy. The magnitude of the risk for venous thromboembolism (VTE)
      is well established for cancer surgery where rates twice that for abdominal
      surgery in noncancer subjects are described. The case for routine
      thromboprophylaxis in patients receiving chemotherapy is less clear, and
      prospective studies investigating rates of thrombosis by tumor type, stage of
      disease, and chemotherapeutic regimens are required. For thromboprophylaxis in
      the surgical patient either low-dose heparin or low-molecular-weight (LMW)
      heparin are effective and safe. For patients receiving chemotherapy in advanced
      breast cancer, low-dose warfarin is effective. Interestingly, heparin therapy may
      prolong survival in patients with malignant disease; the mechanism is unclear,
      and observations from retrospective analysis need to be confirmed in prospective
      studies.

PMID- 10357092
TI  - Treatment of venous thromboembolism in cancer patients.
AB  - The occurrence of venous thromboembolism complicates the management of the
      patient with malignant disease because of the need for anticoagulant therapy.
      Cancer patients have an ongoing thrombotic stimulus due to the underlying cancer
      and its associated treatments, but are also considered to be at increased risk
      for anticoagulant-related bleeding. In recent years, the results of clinical
      trials have demonstrated the safety and efficacy of weight-adjusted subcutaneous
      low molecular weight heparin, administered at home, for patients with acute deep
      vein thrombosis. This approach is particularly attractive to patients with cancer
      where quality of life is an important consideration. There are no trials that
      specifically address the question of the duration of oral anticoagulant therapy
      in cancer patients. However, data can be extrapolated from trials evaluating the
      duration of oral anticoagulant therapy in other high-risk patients. Hence, cancer
      patients should continue oral anticoagulant therapy for as long as the cancer
      remains active (usually at least 6 months). There still remain a number of
      unanswered questions about the clinical management of thromboembolism in the
      cancer patient.

PMID- 10357093
TI  - Inhibitory effect of melatonin on GnRH-induced LH release.
AB  - Melatonin inhibits GnRH-induced release of LH and FSH from the neonatal, but not
      the adult, rat anterior pituitary gland. This action of melatonin is mediated by
      the specific high-affinity membrane-bound receptors that are absent in adult
      rats. The intracellular mechanism of melatonin action involves a decrease in
      intracellular calcium [Ca2+]i in the gonadotrophs; melatonin inhibits GnRH
      induced Ca2+ release from endoplasmic reticulum as well as Ca2+ influx through
      voltage-sensitive channels. Melatonin also inhibits GnRH-induced accumulation of
      cAMP, which may result in the decreased influx of Ca2+, because cAMP, acting
      through protein kinase A, stimulates Ca2+ influx into the gonadotrophs. This age
      dependent effect of melatonin on gonadotrophin release from the pituitary may be
      involved in the timing of puberty.

PMID- 10357094
TI  - What knockout mice can tell us about parturition.
AB  - Many molecules, including steroid and peptide hormones, prostaglandins and
      cytokines, regulate the preparation, initiation and progression of parturition in
      mammals. Gene targeting studies show that, in the knockout mice of steroid 5alpha
      reductase type 1 gene, prostaglandin F2alpha receptor gene and cytosolic
      phospholipase A2 gene, parturition was severely disturbed, although live
      offspring were delivered by Caesarean section. Relaxin gene-disrupted mice also
      showed protracted labour. However, most knockout mice in which the steroid
      hormone, prostaglandin, cytokine or peptide hormone (for example, oxytocin,
      corticotrophin releasing hormone and endothelin) endocrine-paracrine systems are
      disrupted are inadequate for analysis of the mechanism of parturition because
      they die before reaching reproductive age or are infertile, or because they
      reproduce normally. A conditional knockout strategy, for example, using the Cre
      LoxP system, should be considered for investigating the biochemical background of
      parturition to overcome these problems.

PMID- 10357095
TI  - Dynamics of immunoglobulins at the feto-maternal interface.
AB  - Transplacental transport of maternal immunoglobulin G (IgG) to the developing
      fetus is extremely important in the protection of the newborn from infection.
      Although the exact mechanisms of the selective and active transfer of IgG across
      the placental barrier are not fully understood, receptors for the Fc part of IgG
      (FcgammaRs) in the placenta are believed to play a key role. Several known Fc
      receptors, FcgammaRI, FcgammaRII, FcgammaRIII and FcRn (neonatal FcR),
      demonstrate heterogeneous expression patterns in placenta. Immunohistochemical
      analysis shows the expression of FcgammaRI on Hofbauer cells in stromal tissue,
      FcbetaRII on Hofbauer cells and fetal blood endothelium, FcgammaRIII on Hofbauer
      cells and trophoblasts, and FcRn on syncytiotrophoblasts and endothelial cells.
      Recent studies provide evidence for important associations among these receptors
      and transcytosis of IgG, as well as scavenger mechanisms for clearing immune
      complexes in the placenta during pregnancy.

PMID- 10357096
TI  - Pathogenesis of testicular germ cell tumours.
AB  - Human germ cell tumours comprise a heterogeneous group of neoplasms. In the
      testis, three entities are distinguished, the teratomas-yolk sac tumours of the
      infantile testis, the seminomas and nonseminomas of adolescents and adults, and
      the spermatocytic seminomas. Studies on epidemiology, histology, clinical
      behaviour, and chromosomal constitution of these tumours support the concept of
      distinct entities derived from germ cells but each with a different pathogenesis.
      Either the teratomas of the infantile testis show no chromosomal aberrations, or
      display a pattern of over- and under-representation of (parts of) chromosomes as
      detected in the yolk sac tumours of the infantile testis. In contrast, the
      seminomas and nonseminomas reveal a consistent pattern of losses and gains, that
      is, chromosomes 11, 13 and 18, and 7, 8 and X, respectively, that is different
      from that found in the infantile testis teratomas and yolk sac tumours. The most
      consistent structural chromosomal abnormality is an isochromosome 12p. Tumours
      lacking i(12p) have other structural abnormalities of 12p, among them
      amplification of 12p11.2-p12.1. The pathogenetically relevant genes on 12p11.2
      p12.1 are probably on a fragment of about 1.7 mb. Gain of 12p sequences may be
      related to invasive growth. Gain of chromosome 9 is the only consistent
      chromosomal anomaly of spermatocytic seminomas. Infantile teratomas and
      spermatocytic seminomas are benign tumours. Infantile yolk sac tumour is a
      malignant germ cell tumour. Seminomas and nonseminomas are malignant, and the
      most common cancer in young Caucasian males. The cure rate of seminomas and non
      seminomas with radio- and chemotherapy is over 90%, which is higher than that of
      any other solid cancer in adults. In addition, the precursor lesions of these
      tumours can be treated readily, justifying efforts to develop means for early
      diagnosis. Finally, the pathogenetic relationship between seminomas and
      nonseminomas, and the available animal models for the three groups of testicular
      germ cell tumours are discussed.

PMID- 10357097
TI  - Mammalian Y chromosome evolution and the male-specific functions of Y chromosome
      borne genes.
AB  - All mammals have an XY chromosomal sex determining system, in which a small Y
      chromosome triggers male development, and contains genes required for
      spermatogenesis. The X and Y chromosomes were originally homologous, but diverged
      during evolution as the Y chromosome was degraded progressively. Comparisons
      among the sex chromosomes of different mammal groups indicate that the X and Y
      chromosomes received additions of material from other chromosomes. Genes on the Y
      chromosome originated from the ancient X-Y pair, or from these additions, or were
      copies of genes on one of the autosomes. Only genes with important male-specific
      functions, such as sex determination and spermatogenesis, are selected for and
      retained on the differential region of the Y chromosome. The mammalian sex
      determining gene, SRY, controls the testis determination pathway, which includes
      at least one related gene. Several candidate spermatogenesis genes have been
      identified, but so far the only one that is conserved on the Y chromosome of all
      therian mammals is RBM (RNA-binding motif gene, Y chromosome).

PMID- 10357098
TI  - Electrophysiological correlates of pulsatile and surge gonadotrophin secretion.
AB  - The hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator governs
      intermittent discharges of GnRH into the pituitary portal circulation and,
      consequently, modulates the pulsatile pattern of gonadotrophin secretion.
      Electrophysiological correlates of pulsatile gonadotrophin secretion have been
      demonstrated in the mediobasal hypothalamus of monkeys, rats and goats by
      recording multiple unit activity. A temporal coincidence between characteristic
      increases in multiple unit activity and gonadotrophin pulses in the circulation
      is seen under a variety of physiological and experimental conditions in all three
      species examined, providing evidence that hypothalamic multiple unit activity
      originates in the GnRH pulse generator. During a preovulatory gonadotrophin surge
      induced by oestrogen in ovariectomized animals or occurring spontaneously in
      intact animals, GnRH pulse generator activity is decelerated, suggesting that it
      is not involved in generating the gonadotrophin surge. The gonadotrophin surge
      may be generated by an oestrogen-responsive neuronal complex intrinsically
      different from the GnRH pulse generator, the electrical operation of which
      remains unknown.

PMID- 10357099
TI  - Transcriptional regulation of pituitary gonadotrophin subunit genes.
AB  - The gonadotrophic hormones, LH and FSH, are synthesized in and secreted from
      gonadotroph cells in the anterior pituitary and comprise a common alpha-subunit
      and a hormone-specific beta-subunit. Gonadotrophic gene expression is activated
      during embryogenesis, independent of GnRH stimulation and increases as GnRH
      output increases, reaching adult levels at puberty. The transcriptional
      regulation of pituitary gonadotrophin subunit gene expression is regulated by two
      types of transcription factor: those that restrict and direct gene expression to
      gonadotrophs and those that modulate GnRH-regulated gene expression. Synergism
      between these two types of factor ensures gonadotroph-specific GnRH-regulated
      gene expression. It is not known whether these two types of transcription factor
      are mutually exclusive or whether they have overlapping functions. GnRH-regulated
      gonadotrophin subunit gene expression is modulated by transcription factors
      controlled by a complex interaction of GnRH, steroids and gonadal peptides, all
      of which bind to receptors that activate disparate intracellular signalling
      pathways. It remains to be established how these signalling pathways interact to
      transduce specific transcriptional activation of common alpha-subunit and LH and
      FSH beta-subunit gene expression.

PMID- 10357100
TI  - Cooking with the polymerase chain reaction.

PMID- 10357102
TI  - Prevalence of feline Chlamydia psittaci and feline herpesvirus 1 in cats with
      upper respiratory tract disease.
AB  - The epidemiology of feline chlamydiosis and feline herpesvirus 1 (FHV1) infection
      in cats was determined using a duplex polymerase chain reaction assay. In cats
      with upper respiratory tract disease (URTD), prevalences of 66 (14.3%) of 462
      cats and 98 (21.2%) of 462 cats were found for Chlamydia psittaci and FHV1,
      respectively. In cats without URTD, prevalences were 1/87 (1.1%) for both
      pathogens. Younger cats, cats sampled in summer, and cats with conjunctivitis
      were more likely to be positive for C psittaci than were cats sampled in other
      seasons and cats without conjunctivitis. Cats with recent contact with cats
      outside the household, cats with acute disease, and sneezing cats were more
      likely to be positive for FHV1 than were cats that had not had recent contact
      with cats outside the household, cats with chronic disease, and cats that were
      not sneezing. Purebred cats were less likely to be positive for FHV1 than were
      mixed breed cats and prevalence varied with year of sampling. Coinfection with
      both pathogens was lower than would be expected from their respective
      prevalences. Vaccinated cats were equally likely to be positive for FHV1 as
      unvaccinated cats. In sneezing cats FHV1 was more likely to be detected than C
      psittaci, particularly in acute cases, and when sneezing was not accompanied by
      conjunctivitis. Cats with reproductive disease concurrent with URTD were more
      likely to be infected with FHV1 than with C psittaci. Thus, the factors that
      should be considered in clinical diagnoses of C psittaci infections are the
      presence of conjunctivitis, age, and season, whereas contact with other cats,
      acute disease, and sneezing should be considered in diagnoses of FHV1 infection.

PMID- 10357101
TI  - Comparison of the polymerase chain reaction and culture for the detection of
      feline Chlamydia psittaci in untreated and doxycycline-treated experimentally
      infected cats.
AB  - The diagnostic sensitivity of the polymerase chain reaction (PCR) was compared
      with that of culture on conjunctival swabs over the course of infection in 4
      doxycycline-treated and 4 untreated cats that were experimentally infected with
      feline Chlamydia psittaci. Treated cats were given 25 mg (5 mg/kg) of doxycycline
      orally twice daily for 3 weeks from day 6 after challenge. Clinical signs
      improved within 3 days of institution of treatment. Culture remained positive for
      1 day and PCR remained positive for up to 5 days after treatment was commenced.
      No recurrence of clinical signs occurred and the organism could not be detected
      by either PCR or culture for 2 weeks after cessation of therapy. In the 4
      untreated cats, conjunctival swabs were taken daily to day 14 and every 2nd
      weekday to day 64 after challenge. PCR was significantly more sensitive than
      culture in untreated cats overall (PCR 85.7%, culture 72.9%, P approximately 0)
      and for cats with clinical signs (PCR 89.2%, culture 79.2%, P = .008). PCR and
      culture had equivalent sensitivity (100%) for cats showing clinical signs in the
      1st month of infection, whereas PCR was considerably more sensitive than culture
      for cats showing clinical signs in the 2nd month (PCR 72.9%, culture 47.9%, P =
      .028). Organisms were not detected by PCR in blood or any tissue collected from
      treated or untreated cats at postmortem. Thus, effective treatment of
      chlamydiosis in cats is possible with much shorter treatment regimens than
      currently recommended, and PCR is the more sensitive diagnostic method in
      chronically infected cats.

PMID- 10357103
TI  - The molecular basis of canine melanoma: pathogenesis and trends in diagnosis and
      therapy.
AB  - Melanoma is a common neoplastic disease of dogs with variable presentation and
      biological behavior. Canine malignant melanoma is a rapidly metastatic disease
      that generally is incurable. The loss of function of cellular safeguards built
      into the genetic program and of immune surveillance systems that cooperate to
      prevent tumor formation and progression appear to be important underlying causes
      of canine malignant melanoma. In effect, many existing cancer treatments restore
      the function of 1 or the other of these mechanisms. For example, chemotherapy and
      radiotherapy often kill tumor cells by initiating a genetic suicide mechanism
      (apoptosis), and immunotherapy initiates or enhances a response by the body's
      immune cells to identify and destroy cancer cells by mechanisms that rely on
      direct cytotoxicity or apoptotic cell death. Nevertheless, standard therapeutic
      approaches have not proved effective in treatment of canine malignant melanoma,
      with only marginal improvement in the outcome of dogs with this disease. The
      advantages of an improved understanding of the molecular basis of canine cancer
      are underscored by recent promising advances in diagnosis and in immunologic and
      genetic therapies that may help reduce the mortality of dogs affected with
      malignant melanoma.

PMID- 10357104
TI  - Twenty-four-hour ambulatory electrocardiography in normal cats.
AB  - Twenty-four-hour ambulatory electrocardiograms were recorded in two age groups of
      10 normal cats each: group 1 (1 to 4 years) and group 2 (8 to 14 years), with
      equal numbers of males and females in each group. Average heart rates over the 24
      hour recording period ranged from 114 to 202 beats/minute (bpm). The mean 24-hour
      average rate did not differ between group 1 and group 2 (157.6 vs. 156.3+/-5.3
      bpm, respectively); however, females (both groups combined) had higher average
      heart rates than males (166.8 vs. 147.1+/-5.3 bpm, respectively). Females also
      had a higher mean minimum heart rate than males (116.9 vs. 96.5+/-4.2 bpm,
      respectively); but there were no gender or age group differences in maximum heart
      rate. Results of hourly analyses of average, minimum, and maximum heart rates
      were similar. Mean heart rates rose from mid-afternoon to about 9:00 PM and were
      lowest just after midnight. Although regular sinus rhythm predominated, periods
      of sinus arrhythmia were evident in most cats, especially in early morning hours.
      Supraventricular extrasystoles were uncommon. Isolated ventricular extrasystoles
      occurred more frequently in group 2 cats; multiform configuration was observed in
      both groups. Repetitive ventricular extrasystoles, which usually consisted of
      occasional couplets, occurred more frequently in group 2 cats. One older cat had
      2 short runs of ventricular tachycardia. Another older cat appeared to have a
      recurrent accelerated idioventricular rhythm.

PMID- 10357105
TI  - Cervical myelopathy associated with extradural synovial cysts in 4 dogs.
AB  - Three Mastiffs and 1 Great Dane were presented to the University of Wisconsin
      Veterinary Medical Teaching Hospital for cervical myelopathy based on history and
      neurologic examination. All dogs were males and had progressive ataxia and
      tetraparesis. Degenerative arthritis of the articular facet joints was noted on
      survey spinal radiographs. Myelography disclosed lateral axial compression of the
      cervical spinal cord medial to the articular facets. Extradural compressive
      cystic structures adjacent to articular facets were identified on magnetic
      resonance imaging (1 dog). High protein concentration was the most important
      finding on cerebrospinal fluid analysis. Dorsal laminectomies were performed in
      all dogs for spinal cord decompression and cyst removal. Findings on cytologic
      examination of the cystic fluid were consistent with synovial fluid, and
      histopathologic results supported the diagnosis of synovial cysts. All dogs are
      ambulatory and 3 are asymptomatic after surgery with a follow-up time ranging
      from 1 to 8 months. This is the 1st report of extradural synovial cysts in dogs,
      and synovial cysts should be a differential diagnosis for young giant breed dogs
      with cervical myelopathy.

PMID- 10357106
TI  - Prognostic value of argyrophilic nucleolar organizer region (AgNOR) staining in
      feline intestinal lymphoma.
AB  - Limited information is available on prognostic factors for cats with lymphoma.
      The quantity of argyrophilic nucleolar organizer region (AgNOR) proteins can be
      used as a measurement of cellular proliferative activity. To determine if AgNORs
      were of prognostic value for feline intestinal lymphoma, the silver staining
      technique was performed on paraffin-embedded sections of 31 cases. Mean number of
      AgNORs per nucleus ranged from 1.02 to 4.32. Twenty-four (78%) cats had small
      AgNORs and 7 (22%) had large AgNORs. All cats were treated identically with a
      combination chemotherapy protocol. Response to chemotherapy was 87%. Median
      remission duration and survival times were 120 days and 201 days, respectively.
      No significant correlation was found between mean number of AgNORs per nucleus or
      AgNOR size and remission rate, remission duration, or survival time. This study
      indicates that AgNOR staining is not a useful prognostic factor for cats with
      intestinal lymphoma.

PMID- 10357107
TI  - Endoscopic aspiration of intestinal contents in dogs and cats: 394 cases.
AB  - Medical records from 394 dogs and cats that had endoscopic aspiration of
      intestinal contents for identification of Giardia sp. trophozoites were
      retrospectively reviewed. The most common indications for endoscopy were chronic
      vomiting (152), chronic diarrhea (108), chronic vomiting and diarrhea (58), and
      acute vomiting (33). Metronidazole had been previously administered to 111
      animals (28.2%), and to 58.6% of those with chronic diarrhea. Six aspirate
      samples (1.5%) were positive for Giardia sp. In 3 of these cases a single fecal
      flotation identified Giardia cysts before endoscopy. The authors conclude that
      intestinal aspiration in animals from a primarily referral population undergoing
      upper gastrointestinal endoscopy rarely identifies Giardia and should not be
      routinely performed. However, animals in which zinc sulfate flotation was not
      performed or those that did not previously receive metronidazole might benefit
      from intestinal aspiration.

PMID- 10357108
TI  - A retrospective study of ehrlichiosis in 62 dogs from North Carolina and
      Virginia.
AB  - The purpose of this retrospective study is to report the clinical signs,
      clinicopathological findings, and response to therapy of 62 dogs from North
      Carolina and Virginia. Ehrlichiosis was diagnosed in all of these dogs, and
      previous retrospective studies of ehrlichiosis in dogs were used as a basis for
      comparison. In this study, the clinical signs commonly associated with
      ehrlichiosis were observed less frequently than in earlier studies, although
      previously reported laboratory abnormalities were similar. Flow cytometry
      revealed an inverted CD4:CD8 ratio in 3 of 4 dogs tested. This finding is
      suggestive of potential immune dysregulation that could predispose infected dogs
      to additional disease processes. Concurrent diseases were frequently reported and
      often contributed to death. Response to therapy was variable, with timely,
      complete recovery reported in only 27% of dogs; a slow, gradual, but complete
      recovery in 18% of dogs; an incomplete treatment response in 25% of dogs; and a
      presumed treatment failure in 16% of dogs.

PMID- 10357109
TI  - Gene defect of dermatan sulfate proteoglycan of cattle affected with a variant
      form of Ehlers-Danlos syndrome.
AB  - A defect of the core protein of dermatan sulfate proteoglycan was suspected in a
      Holstein calf affected with a variant form of Ehlers-Danlos syndrome. The
      mutation was a guanine-to-adenine transition at nucleotide position 254, which
      resulted in a serine-to-asparagine substitution of the bovine proteoglycan core
      protein. This substitution occurred in the serine-glycine dipeptide repeat that
      was suspected to be the binding portion of dermatan sulfate. This point mutation
      in the genome was also detected by the use of restriction fragment length
      polymorphism (RFLP) and polymerase chain reaction (PCR) methods. The results of
      the RFLP and PCR indicated that the calf was a heterozygote of an abnormal gene
      and a normal gene of the core protein. The interpretation of these data revealed
      that the functional abnormality in cutaneous tissues of the calf was caused by an
      abnormal gene of the proteoglycan core protein, which induced a substitution of
      amino acid.

PMID- 10357110
TI  - Peripheral blood lymphocyte subpopulations and immunoglobulin concentrations in
      healthy foals and foals with Rhodococcus equi pneumonia.
AB  - Infectious diseases are common in foals aged 1-5 months. The objectives of this
      investigation were to evaluate immunologic parameters in foals from birth to
      weaning to establish reference values for the proportion of circulating
      lymphocytes that were helper (CD4+) or cytotoxic (CD8+) T cells, or B cells; to
      measure serum immunoglobulin (IgM and IgG) concentrations; and to compare these
      immunologic parameters to values in foals with naturally occurring Rhodococcus
      equi pneumonia and in adult horses. Peripheral blood lymphocyte subpopulations
      were determined by flow cytometric analysis, and serum IgG and IgM concentrations
      were determined by radial immunodiffusion. Flow cytometric analysis of lymphocyte
      subpopulations suggested age-related changes in the cell-mediated immune system
      in horses. Absolute circulating CD4+ and CD8+ T lymphocytes and B cells increased
      linearly up to 3 months of age. Circulating B cell concentrations from birth to 6
      months of age were greater than values in adult horses and the lymphocyte
      differences among the age groups are mainly due to variation in B lymphocytes.
      Both absolute and proportional B cell concentrations were greater in foals with R
      equi pneumonia than in healthy foals at the same age. The increase in absolute
      cell counts of each subpopulation was dependent on the increase of absolute
      peripheral blood lymphocyte count. Serum IgG concentration increased linearly
      from 1 to 3 months of age, and serum IgM concentrations increased from 1 to 6
      months of age. These data suggest age-dependent cell-mediated and humoral
      development in young foals.

PMID- 10357111
TI  - Naturally occurring scrapie in Southdown sheep.
AB  - The purpose of this study was to characterize naturally occurring scrapie in the
      Southdown breed of sheep. Experimental subjects included 4 Southdown ewes
      admitted to the University of Missouri, College of Veterinary Medicine Large
      Animal Clinic. All 4 sheep had signs compatible with clinical scrapie.
      Cerebrospinal fluid (CSF) cell counts ranged from a low of 1 nucleated
      cell/microL to high of 4 cells/microL with a median of 3 cells/microL.
      Cerebrospinal protein concentrations ranged from 26 to 78 mg/dL with a median of
      53 mg/dL. Immunoassay of the CSF for the 14-3-3 protein yielded positive results
      in 3 of the 4 sheep. Sequencing of the prion protein (PrP) gene revealed that all
      4 sheep were homozygous for glutamine at codon 171 and, hence, were of the QQ
      genotype. Histopathologic examination of brain stem tissue sections revealed
      intracytoplasmic neuronal vacuolation and mild spongiform changes in the gray
      matter neuropil in all 4 ewes. The diagnosis of scrapie was confirmed by
      immunohistochemical staining for the abnormal PrP Our results suggest that the
      genetics of scrapie susceptibility are probably similar in Suffolk and Southdown
      sheep. Positive immunoassay results for the 14-3-3 protein were observed in 3 of
      the 4 sheep.

PMID- 10357112
TI  - Sjogren's syndrome and hepatitis C virus.
AB  - Sjogren's Syndrome (SS) is an autoimmune disease that mainly affects exocrine
      glands and usually presents as a persistent dryness of the mouth and eyes. The
      spectrum of the disease extends from an organ-specific autoimmune disease to a
      systemic process. Viral infection has long been suspected as a potential cause of
      SS because several viruses have been incriminated in the aetiology of this
      disease, and a possible relationship between SS and hepatitis C virus (HCV) was
      postulated in 1992. In this paper, we review the literature concerning SS and HCV
      infection and summarise the current knowledge regarding their association and
      their pathogenic, clinical and immunological significances. The main conclusions
      of this review are that the prevalence of antibodies to HCV in patients with
      primary SS ranges between 14 and 19% using third-generation ELISA, chronic HCV
      infection may mimic the main clinical, histological and immunologic features of
      'primary' SS and, finally, testing for HCV infection must be performed in
      patients with SS, especially in those patients with evidence of liver involvement
      or associated cryoglobulinaemia. HCV seems to be a rare cause of 'primary' SS in
      the absence of recognised liver disease or cryoglobulinaemia.

PMID- 10357113
TI  - Application of statistical graphics to facilitate selection of health status
      measures for clinical practice and evaluative research.
AB  - Relatively little attention has been directed towards the study of the ability of
      health status measures to demonstrate clinically meaningful change. We examined
      the use of Tukey's stem and leaf plots and time-path diagrams to assess the
      sensitivity of a health status measure in showing change. We compared the
      evaluative characteristics of the physical ability scales of the Sickness Impact
      Profile (PSIP), and the SF-36 (PSF-36), in 54 consecutive patients undergoing
      elective primary or revision total hip replacement. To validate time-path
      diagrams, we used patients' perception of change in physical function (transition
      question) as an external standard. At baseline there was no clustering at the end
      of the scales. At 3 months, the distribution of the PSIP showed a clustering at
      the upper end of the scale and a strong skewness towards lower scores, whereas
      the PSF-36 showed a wide distribution of the scores. Seven out of 54 patients had
      perfectly normal scores on the PSIP at 3 months, whereas one patient had a
      perfect score on the PSF-36 at 3 months. In time-path diagrams the response
      pattern of the PSIP was similar to that of the PSF-36, with the exception of the
      patient-fifth with the best initial health status. The overall impression of the
      time-path diagram for these patients was that of no change. A closer examination
      revealed that half of these patients had horizontal or downwards sloping lines,
      indicating a worsening in physical function. However, all these patients
      perceived themselves as improved. The PSIP has a ceiling effect for patients with
      relatively good physical health. It was concluded that stem and leaf plots are
      useful in the assessment of health status measures, for discriminative purposes,
      to differentiate patients' health cross-sectionally. Time-path diagrams
      stratified by baseline health status with information on patients' perception or
      valuation of change provide useful information about the ability of an instrument
      to detect change over time.

PMID- 10357114
TI  - N-acetyl-beta-D-glucosaminidase urinary excretion as an early indicator of kidney
      damage in rheumatoid arthritis patients starting on parenteral gold and Depo
      Medrone/placebo injections.
AB  - The purpose of the study was to determine the effect of initiation of gold
      therapy on glomerular and tubular integrity. Urine albumin was used as a marker
      of glomerular damage. N-acetyl-beta-D-glucosaminidase (NAG) urinary excretion
      served as an indicator of proximal tubular damage. This study was an adjunct to a
      clinical trial that investigated the safety and the efficacy of Depo-Medrone
      during the induction phase of gold therapy. The NAG activities and albumin levels
      in the urine of 36 patients with active rheumatoid arthritis treated with sodium
      aurothiomalate weekly up to a total of 1 g were investigated. NAG was assayed in
      565 early morning urine samples of these patients at weekly intervals for 24
      weeks. The mean NAG level rose from 50.2 nmol/mg of creatinine on entry to peak
      NAG excretion of 120.4 nmol/mg of creatinine at week 4 and then fell to 56.3
      nmol/mg of creatinine at week 24. Urinary albumin was assayed in 252 early
      morning urine samples at monthly intervals during gold treatment. Values greater
      than 20 mg/l were observed in 7.5% of urine samples. Microalbuminuria was present
      in 9% of patients at baseline. Two patients who were withdrawn because of
      proteinuria and macroalbuminuria had normoalbuminuria on entry. We conclude that
      raised levels of NAG associated with tubular damage are more frequent than
      glomerular damage on entry to, and during, treatment with gold salts.

PMID- 10357115
TI  - A 5.5 year prospective study of self-reported musculoskeletal pain and of
      fibromyalgia in a female population: significance and natural history.
AB  - In order to investigate the significance and outcome of self-reported pain and
      fibromyalgia (FM) in a female population, 214 women with initially self-reported
      pain were interviewed and examined in 1990 and 1995. In 1990 the sample was
      categorised into four pain status groups: 46 individuals (21%) with nonchronic
      (recurrent) pain, 69 (32%) with chronic regional pain 42 (20%) with chronic
      multifocal pain and 57 with chronic widespread pain (CWP). The last group
      comprised 39 (18%) women with FM, fulfilling the American College of Rheumatology
      1990 criteria. The frequency of tender points, associated symptoms called
      historical variables and individuals with low education increased statistically
      significantly with increasing pain status. In 1995, 48 women had non-chronic pain
      (23%), 46 (21%) chronic regional pain, 39 (18%) chronic multifocal pain and 81
      (38%) CWP; of these, 71 (33%) had FM. Eleven of the 39 women initially with FM no
      longer fulfilled the criteria. The risk of developing CWP among the 157
      individuals with initially a lower pain status was statistically higher in women
      with chronic multifocal pain than in women with less pain extension. Self
      reported pain constitutes a continuum of pain severity and thus of clinical and
      social significance. The overall outcome was poor with an increase of individuals
      with CWP and FM. The prognosis of chronic multifocal pain, CWP and FM was
      especially poor. About half of the women with non-chronic pain or chronic
      regional pain did not deteriorate. However, because the process of developing FM
      started with localised pain in most cases, self-reported pain of any severity
      confers a risk for developing FM. Identifying possible risk factors for FM are at
      present under study and will be presented separately in another report.

PMID- 10357116
TI  - Secondary amyloidosis has decreased in patients with inflammatory joint disease
      in Finland.
AB  - We studied whether the high incidence of secondary amyloidosis (SA) is a
      consistent finding in patients with inflammatory joint disease. A total of 4508
      biopsies of patients with rheumatoid arthritis, psoriatic arthritis or ankylosing
      spondylitis were studied at the Rheumatism Foundation Hospital during 1987-1997.
      The results show that the annual number of findings of SA was reduced from 68 to
      less than 10. We suggest that a change in medication towards more frequent use of
      cytostatic agents is the reason for the reduction in incidence of SA.

PMID- 10357117
TI  - Optic neuropathy in systemic lupus erythematosus and antiphospholipid syndrome
      (APS): clinical features, pathogenesis, review of the literature and proposed
      ophthalmological criteria for APS diagnosis.
AB  - Optic neuropathy is a well-known ocular manifestation occurring in patients with
      systemic lupus erythematosus (SLE), and it remains one of the major causes of
      blindness in these patients. We report data from six SLE patients with optic
      neuropathy, one of whom was considered to have antiphospholipid syndrome (APS).
      This patient had monolateral optic neuropathy, whereas the other five SLE
      patients had bilateral optic nerve disease. We believe that the monolateral
      occurrence of optic neuropathy in our patient can be considered as a 'focal'
      neurological disease due to a thrombotic event involving the ciliary vasculature.
      Conversely, bilateral optic nerve damage in SLE could be considered to be a
      'general' neurological disease due to different immunological mechanisms, such as
      vasculitis. Additionally, the literature on SLE patients affected by optic
      neuropathy is reviewed to evaluate the major clinical features, particularly
      neurological features. In reviewing the literature, it appears that bilateral
      optic neuropathy in SLE occurs more frequently than monolateral optic neuropathy,
      and the main neurological manifestation seen in these patients is transverse
      myelitis, particularly in SLE patients with bilateral optic nerve disease.
      Finally, we propose a clinico-ophthalmological spectrum of APS and outline the
      ocular clinical manifestations that can be considered as diagnostic for the
      syndrome.

PMID- 10357118
TI  - Defective antibody production in patients with rheumatoid arthritis and
      bronchiectasis.
AB  - Bronchiectasis (BR) occurs in about 3% of patients with rheumatoid arthritis
      (RA). Defective antibody production is a rare but well-recognised cause of both
      BR and inflammatory arthritis. We examined the hypothesis that subtle specific
      antibody defects might play a role in the pathogenesis of BR associated with RA.
      Identification of defects in antibody production is important because substantial
      benefits may be gained from immunoglobulin replacement. Specific antibody
      production was assessed in 20 patients with RA and BR, 20 with BR alone, 20 with
      RA alone and 20 healthy controls (all groups matched for age and sex). All had
      normal total IgG. IgA and IgM and IgG subclass levels. Specific antibody
      production was assessed by assay of antibodies to representative polysaccharide
      and protein antigens. Subjects with subprotective titres were challenged with the
      appropriate vaccine. Defective antibody production was defined as a subprotective
      level despite immunisation. Three out of 20 patients with RA and BR had a
      defective IgG2 response to the polysaccharide antigen, but normal responses to
      the protein antigen. All of the subjects in the BR alone or healthy control group
      had normal antibody production. Two out of 20 patients with RA alone had
      defective production of antibodies against both protein and polysaccharide
      antigens; both were receiving gold therapy, a recognised cause of functional
      antibody defects. It was concluded that some patients with RA and BR have
      functional antibody defects and may benefit from antibody replacement. An
      unexpectedly high proportion of patients with RA alone also have functional
      antibody defects, possibly secondary to gold therapy.

PMID- 10357119
TI  - Cardiac involvement in limited systemic sclerosis: non-invasive assessment in
      asymptomatic patients.
AB  - Nineteen patients with limited systemic sclerosis (SSc) and without any cardiac
      symptoms were evaluated non-invasively for silent cardiac involvement using
      electrocardiography; M-mode, two-dimensional and Doppler echocardiography, and
      resting and post exercise radionuclide ventriculography. Left anterior hemiblock
      and mild pericardial effusion were seen in two patients. The interventricular
      septal thickness and left ventricular posterior wall thickness were greater in
      patients compared with controls. Patients with limited SSc also exhibited low
      early diastolic filling velocities and a low early diastolic atrial filling
      ratio. However, these values did not correlate with the age of the patient or
      disease duration. Eight patients (42.1%) were found to have cardiac dysfunction,
      of which four had combined systolic and diastolic dysfunction. Isolated systolic
      and diastolic dysfunction was seen in three patients and one patient,
      respectively. The age and disease duration in patients with cardiac dysfunction
      did not differ from patients without cardiac dysfunction. Functional cardiac
      involvement occurs in a large proportion (42.1%) of patients with limited SSc,
      and can be easily picked up by non-invasive methods such as echocardiography and
      radionuclide ventriculography. The prognostic significance of these findings
      requires further long term studies.

PMID- 10357120
TI  - Clinical equivalence between deflazacort oral drops and tablets in active
      rheumatoid arthritis.
AB  - In order to assess the clinical equivalence between deflazacort oral drops and
      tablets, 18 patients with active rheumatoid arthritis were enrolled in an open,
      controlled, randomised ('tablets --> drops' sequence, or vice versa), two-period
      (21 days each) crossover trial (from tablets to drops, or vice versa). Individual
      dose titration of deflazacort drops or tablets was made weekly on the basis of
      clinical need. Primary outcome measures of efficacy were changes in the joint
      swelling count (JSC), erythrocyte sedimentation rate (ESR), hand-grip strength
      (HGS), joint pain (JP), duration of morning stiffness (MS), physician's global
      evaluation and patient's self-assessment. Sixteen patients were available by the
      end of the study. The formulations were equivalent with respect to HGS and
      improvement in duration of MS, and close to equivalence with respect to JSC and
      ESR decrease; the drops seemed to be more effective than tablets with respect to
      JP reduction. No differences between the two formulations were observed with
      respect to physician's and patient's assessment. The minimum effective dose of
      each preparation and the relative potency ratio were also established. Drops and
      tablets were found to have the same potency.

PMID- 10357121
TI  - Efficacy and safety of a combination therapy of methotrexate, chloroquine and
      cyclophosphamide in patients with refractory rheumatoid arthritis: results of an
      observational study with matched-pair analysis.
AB  - The efficacy and safety of a combination of methotrexate (MTX), chloroquine (CQ)
      and cyclophosphamide (CYC) were studied in patients with refractory rheumatoid
      arthritis. A single-centre, matched-pair observational study with prospectively
      gathered data was performed. Fifty-six patients who had previously failed with
      MTX were treated with 15 mg MTX per week, 50 mg CYC three times a week and 250 mg
      CQ per day (group A). A 50% improvement of the swollen joint count was required
      to continue therapy. Data were compared with the results of the previous MTX
      therapy in the same group and with a matched-patient cohort receiving MTX
      monotherapy for the first time (group B). In group A, the combination therapy
      resulted in a significant decline of the swollen joint count after 1 year, in
      contrast to the previous MTX monotherapy in the same group. Complete remission of
      joint swelling was achieved in 13 patients (23%), compared with 26 patients in
      group B (47%). The median duration of effective combination treatment in group A
      was significantly longer than preceding therapies with MTX alone (19 vs 13
      months, p<0.05). However, patients in group B could be treated for a median of
      57.5 months (p<0.0001 compared with group A). Side-effects were comparable in
      both groups. The applied DMARD combination is safe and beneficial in a
      significant proportion of patients if MTX monotherapy is ineffective.

PMID- 10357122
TI  - Assessment of thoracolumbar rotation in ankylosing spondylitis: a simple tape
      method.
AB  - Results of a 'new' method for thoracolumbar rotation by tape (TRPav), simple
      instrumental rotation (TRi), the modified Schober test and thoracolumbar flexion
      (ThFL) were correlated with radiological changes in patients with ankylosing
      spondylitis (AS). TRPav showed a significant radiological correlation (Ls-r:
      0.38; Th-r: 0.31), while the instrument method (TRi) did not; both the Schober
      test and ThFL, again, correlated fairly highly (Ls-r: 0.71, 0.62; Th-r: 0.49,
      0.42). Both inter- and intratester reliability of the tests was good (Bland and
      Altman plots). Thoracolumbar rotation is one of the three principal levels of
      spinal motion and seems to be less affected by age. TRPav proved a valid and
      reliable method for measuring thoracolumbar rotation and clinically is a non
      invasive, quick and easy complement to AS measurement methodologies.

PMID- 10357123
TI  - Hormonal profiles and immunological studies of male lupus in Taiwan.
AB  - The aims of this study were to describe hormonal profiles, cytokine production
      and Fc-gamma receptor (Fcgamma-R) distribution in male lupus patients in Taiwan,
      and to look for any differences between our patients and normal individuals.
      Sixteen newly diagnosed and untreated male lupus patients were studied. Hormonal
      profiles were determined by radioimmunoassay. Interleukin-1 (IL-1) and IL-1
      receptor antagonist (IL-1ra) production from both monocytes and neutrophils was
      determined by ELISA and murine thymocyte proliferation assay. The FcgammaR
      distribution on both monocytes and neutrophils was detected by flow cytometer.
      There were no significant differences in FSH, LH, testosterone, oestradiol, and
      beta-HCG blood levels in male lupus patients compared with normal individuals;
      however, the prolactin level in lupus patients was significantly higher than in
      normal individuals. Furthermore, there was no difference in IL-1 and IL-1ra
      production from both monocytes and neutrophils among male and female lupus
      patients, and normal individuals. Male lupus patients have a significantly lower
      FcgammaRII distribution on both monocytes and neutrophils when compared with
      female lupus patients and normal individuals. It was concluded that the high
      prolactin level and low FcgammaR distribution may play a role in the pathogenesis
      and prognosis of male lupus.

PMID- 10357124
TI  - Prophylactic antibiotics in recurrent parotitis in a patient with Sjogren's
      syndrome.
AB  - We describe a 41-year-old patient with primary Sjogren's syndrome with a 16-year
      history of recurrent parotitis. The institution of prophylactic antibiotic
      coverage has succeeded, to date, in maintaining her in remission for 4 years.

PMID- 10357125
TI  - Systemic lupus erythematosus, berry aneurysm and subarachnoid haemorrhage.
AB  - A 57-year-old woman with SLE and subarachnoid haemorrhage is described. The
      aetiology of the haemorrhage was a saccular aneurysm. The literature is reviewed.

PMID- 10357126
TI  - Pseudomonas osteomyelitis of the symphysis pubis after inguinal hernia repair.
AB  - Osteitis pubis (OP) is a term used to describe an entity characterised by severe
      pelvic pain, a wide-based gait and bony destruction of the margins of the pubic
      symphysis. It is usually assumed that OP is a non-infectious, self-limiting,
      relatively benign condition. Infectious osteomyelitis of the symphysis pubis
      (IOSP) is very unusual and the clinical presentation can resemble OP. IOSP
      following inguinal hernia repair is extremely rare. A case of IOSP caused by
      Pseudomonas aeruginosa is described. We reiterate the assumption that IOSP can be
      misdiagnosed as OP.

PMID- 10357127
TI  - Successful treatment of systemic lupus erythematosus cerebritis with intravenous
      immunoglobulin.
AB  - Neuropsychiatric lupus includes extremely diverse clinical manifestations,
      ranging from mild cognitive dysfunction to a severe, life-threatening
      presentation. We report a 28-year-old patient with systemic lupus erythematosus
      who had persistent fever for 3 months, and developed within a few hours motor and
      sensory aphasia, rotator nystagmus with deviation of the eyes, and severe nuchal
      rigidity. An extensive series of imaging and laboratory tests were interpreted as
      normal, except for an elevated opening pressure at lumbar puncture, cerebrospinal
      fluid inflammatory findings, and asymmetrical cortical perfusion on single-photon
      emission computed tomography. The patient received one course of high-dose
      intravenous immunoglobulin (IVIg) and within 5 days her condition returned to
      that of 3 months before admission. The mechanisms of injury, along with the
      management of cerebral lupus and the mechanisms of action of IVIg, are discussed.

PMID- 10357128
TI  - Axillary schwannoma masquerading as cervical radiculopathy.
AB  - A 58-year-old woman, suffering from radicular-like pain in the left arm for 3
      years, presented an entirely negative cervical imaging. Careful clinical
      examination disclosed Tinel's sign in the axilla. This clinical finding led to
      further investigation of this region. Computed tomography and magnetic resonance
      imaging disclosed a small tumour highly suggestive of a schwannoma. Surgical
      exploration and microscopic examination confirmed a diagnosis of schwannoma
      located on the radial trunk of the left brachial plexus. After tumour excision,
      the patient had immediate relief of pain without sensitive or motor sequelae. No
      recurrence has been observed after 3 years.

PMID- 10357129
TI  - Pericarditis after therapy with interferon-alpha for chronic hepatitis C.
AB  - We report a patient with pericarditis following therapy with interferon-alpha for
      chronic hepatitis C viral infection. Possible relationships between pericarditis,
      hepatitis C and its treatment with interferon-alpha are briefly discussed.

PMID- 10357130
TI  - Quantification of the fiber architecture and biaxial mechanical behavior of
      porcine intestinal submucosa.
AB  - Porcine small intestinal submucosa (SIS) has been shown to serve as a remodelable
      tissue scaffold in a wide range of applications. Despite the large number of
      experimental studies, there is a lack of fundamental information on SIS
      anisotropic mechanical behavior and how this behavior changes postimplantation.
      As a first step in our study of remodeling biomaterials, we performed biaxial
      mechanical testing to quantify the anisotropic mechanical behavior and used small
      angle light scattering (SALS) to quantify the gross fiber structure of fresh,
      unimplanted SIS. Structural results indicate that SIS displays primarily a
      single, continuous preferred fiber direction oriented parallel to the long axis
      of the intestine. Occasionally, two distinct fiber populations oriented at
      approximately +/-28 degrees with respect to the longitudinal axis could be
      distinguished. Consistent with this structure, SIS exhibited a nonlinear,
      anisotropic mechanical response with higher stresses along the longitudinal axis.
      Further, the circumferential stress-strain response was strongly affected by the
      maximum longitudinal strain level, but the maximum circumferential strain level
      only weakly affected the longitudinal stress-strain response. This asymmetric
      mechanical coupling suggests strong mechanical interactions on a fiber level. SIS
      stress-strain response also was similar to glutaraldehyde-treated bovine
      pericardium, attesting to the substantial strength of SIS in the fresh, untreated
      state. The results of this study will provide a basis for a future analysis of
      the structural and mechanical changes during the remodeling process.

PMID- 10357131
TI  - Alkylsilane-modified surfaces: inhibition of human macrophage adhesion and
      foreign body giant cell formation.
AB  - A homologous set of alkylsilane-modified glass surfaces with chain lengths
      ranging from methyl to octadecyl was prepared in order to examine the influence
      of alkyl surface chemistry on macrophage adhesion and foreign body giant cell
      (FBGC) formation. Contact angle and X-ray photoelectron spectroscopy analysis
      confirmed our silanation technique and indicated a consistent alkyl chain density
      independent of chain length. Human peripheral blood monocytes were isolated and
      cultured on these alkylsilane surfaces for a period of 10 days. The initial
      density of human monocytes was similar on all surfaces. Beyond day 0 the clean
      glass, methyl (DM and C1), propyl (C3), and hexyl (C6) surfaces maintained a high
      cell density and supported macrophage development. In contrast, long-term
      macrophage density was extremely low on the tetradecyl (C14) and octadecyl (C18)
      surfaces. When interleukin-4 was added to induce FBGC formation in vitro, the DM,
      C1, C3, and C6 surfaces supported high levels of macrophage fusion while clean
      glass strongly inhibited fusion. The C14 and C18 surfaces did not contain
      sufficient macrophages to support FBGC formation. Cage implant studies revealed
      that in vivo macrophage density and FBGC formation on clean glass and C6 surfaces
      was similar to in vitro data. In contrast to the monocyte culture results, the
      C18 cage implant samples supported significant FBGC formation, possibly as a
      result of different conditions within each experimental system. Radiotracer
      adsorption studies of eight human serum proteins identified the high
      concentration and tenacious hold of adsorbed von Willebrand factor as being
      possibly involved in the poor long-term macrophage density observed on C14 and
      C18.

PMID- 10357132
TI  - In vitro cytotoxicity and in vivo biocompatibility of poly(propylene fumarate-co
      ethylene glycol) hydrogels.
AB  - The in vitro cytotoxicity and in vivo biocompatibility of poly(propylene fumarate
      co-ethylene glycol) [P(PF-co-EG)] hydrogels were assessed in order to investigate
      the influence of poly(ethylene glycol) molecular weight and copolymer
      composition. These materials have application as injectable cardiovascular
      implants; cytotoxicity due to leachable products, as well as inflammation caused
      by the biomaterial itself, may ultimately affect the biocompatibility of the
      implant. We utilized a 7-day in vitro cytotoxicity assay to quantify cell density
      and cellular proliferation in the presence of copolymer films. The copolymer
      films exhibited slight to moderate cytotoxicity toward cultured endothelial
      cells, showing 20-86% viability relative to controls. Cell viability increased
      with an increasing weight percent of PEG or, to a lesser extent, the molecular
      weight of PEG. In vivo biocompatibility was assessed using a cage implantation
      model over a 21-day time period. This system was used to characterize the local
      cellular and humoral inflammatory response in the surrounding exudate, as well as
      the size and density of macrophages adherent to the material itself. All
      copolymer formulations exhibited excellent biocompatibility relative to controls
      with no significant differences in total leukocyte count among the different
      formulations. The in vivo inflammatory reaction displayed normal wound healing
      over 21 days as shown by a progressive decrease in both leukocyte concentration
      and enzymatic activity. The surface coverage of the copolymer films remained
      relatively constant from 7 to 21 days. There were no cells larger than 0.003 mm2,
      which was previously shown to be the threshold value for foreign-body giant
      cells. These data suggest that P(PF-co-EG) hydrogels have potential for use as
      injectable biomaterials.

PMID- 10357133
TI  - Focal adhesions and assessment of cytotoxicity.
AB  - Focal adhesions are highly ordered assemblies of transmembrane receptors,
      extracellular matrix proteins, and a large number of cytoplasmic proteins,
      including structural proteins, as well as tyrosine kinases, phosphatases, and
      their substrates. They are now accepted as a prime component of signal
      transduction. Because focal adhesions also play an important role in cell
      morphology and migration, it can be argued that their presence is indicative of
      healthy cells. This has been the reason for several research groups to conclude
      that biomaterials sustaining focal adhesion assembly are biocompatible. In this
      study we demonstrate that cells under cytotoxic stress may still be able to
      retain their focal adhesions. Human umbilical vein endothelial cells at passage 2
      were exposed to nickel and zinc ion solutions ranging from 1 to 0.01 mM for 4 and
      24 h. Cells were seeded on fibronectin precoated glass slides or in tissue
      culture quality 96-well plates. MTT conversion with 1 and 0.5 mM nickel and zinc
      was strongly depressed, indicating that these concentrations are cytotoxic.
      Proliferative activity was also affected by these concentrations. Cells exposed
      to zinc typically retracted and detached from the surface, whereas cells exposed
      to nickel remained on the surface without signs of retraction. Nevertheless,
      cells exposed to nickel were impaired to reach confluency, which was determined
      by cadherin-5 expression. All these data indicate that nickel ions at a
      sufficient concentration influence cells in a cytotoxic way. Despite this
      apparent cytotoxicity, focal adhesion distribution as visualized by
      immunofluorescence staining of vinculin was not affected. With zinc the
      morphological changes were accompanied by apparent fusion of focal adhesions
      during retraction and finally dissolution. These data indicate that the mere
      presence of focal adhesions does not allow a reliable statement about the
      functional status of a cell. On the other hand, when focal adhesions are affected
      it is an excellent monitor of disturbed cell function.

PMID- 10357134
TI  - Mechanisms of bioprosthetic heart valve failure: fatigue causes collagen
      denaturation and glycosaminoglycan loss.
AB  - Bioprosthetic heart valve (BPHV) degeneration, characterized by extracellular
      matrix deterioration, remodeling, and calcification, is an important clinical
      problem accounting for thousands of surgeries annually. Here we report for the
      first time, in a series of in vitro accelerated fatigue studies (5-500 million
      cycles) with glutaraldehyde fixed porcine aortic valve bioprostheses, that the
      mechanical function of cardiac valve cusps caused progressive damage to the
      molecular structure of type I collagen as assessed by Fourier transform IR
      spectroscopy (FTIR). The cyclic fatigue caused a progressive loss of helicity of
      the bioprosthetic cuspal collagen, which was evident from FTIR spectral changes
      in the amide I carbonyl stretching region. Furthermore, cardiac valve fatigue in
      these studies also led to loss of glycosaminoglycans (GAGs) from the cuspal
      extracellular matrix. The GAG levels in glutaraldehyde crosslinked porcine aortic
      valve cusps were 65.2 +/- 8.66 microg uronic acid/10 mg of dry weight for control
      and 7.91 +/- 1.1 microg uronic acid/10 mg of dry weight for 10-300 million cycled
      cusps. Together, these molecular changes contribute to a significant gradual
      decrease in cuspal bending strength as documented in a biomechanical bending
      assay measuring three point deformation. We conclude that fatigue-induced damage
      to type I collagen and loss of GAGs are major contributing factors to material
      degeneration in bioprosthetic cardiac valve deterioration.

PMID- 10357135
TI  - Potential of porous poly-D,L-lactide-co-glycolide particles as a carrier for
      recombinant human bone morphogenetic protein-2 during osteoinduction in vivo.
AB  - Several different biodegradable bone graft materials are in clinical or
      preclinical use for the repair of bone defects in orthopedics, maxillofacial
      surgery, and periodontics. This study tested the hypothesis that poly-D,L-lactide
      co-glycolide copolymer (PLG) can be used as an effective carrier of recombinant
      human bone morphogenetic protein-2 (rhBMP-2) and that the composite has
      osteoinductive ability. Porous PLG rods were shredded to a particle size ranging
      from 250 to 850 microm. Active and inactive demineralized freeze-dried bone
      allografts (DFDBA) with a comparable particle size were used as positive and
      negative controls, respectively. PLG particles were treated with vehicle or with
      5 or 20 microg rhBMP-2. DFDBA and PLG particles were placed in gelatin capsules,
      mixed with vehicle or rhBMP-2, and implanted at intramuscular sites in male Nu/Nu
      (nude) mice. Each mouse underwent bilateral implantation with implants of the
      same formulation, resulting in five groups of four mice per group: active DFDBA,
      inactive DFDBA, PLG, PLG + 5 microg rhBMP-2, and PLG + 20 microg rhBMP-2. After
      56 days, the implants were recovered and processed for histology. Bone induction
      was assessed by use of a semiquantitative scoring system based on the amount of
      new bone formed in representative histological sections. Histomorphometry was
      also used to measure the area of new bone formed and the area of residual implant
      material. The results showed that active DFDBA induced the formation of ossicles
      containing new bone with bone marrowlike tissue, whereas inactive DFDBA or PLG
      particles alone did not induce new bone. The addition of rhBMP-2 to PLG particles
      resulted in new bone formation that had a greater bone induction score than
      active DFDBA. Moreover, the histomorphometric analysis showed that the addition
      of rhBMP-2 to PLG particles induced the formation of a greater area of new bone
      and bone marrowlike tissue than active DFDBA. The resorption of the PLG particles
      was markedly increased with the addition of rhBMP-2, suggesting that rhBMP-2 may
      attract and regulate resorptive cells at the implantation site. The results of
      the present study indicate that PLG copolymers are good carriers for BMP and
      promote the induction of new bone formation. Further, the PLG copolymers with
      rhBMP-2 had a greater effect in inducing new bone formation and resorbing the
      implanted material than active DFDBA alone.

PMID- 10357136
TI  - Synthetic nano-scale fibrous extracellular matrix.
AB  - Biodegradable polymers have been widely used as scaffolding materials to
      regenerate new tissues. To mimic natural extracellular matrix architecture, a
      novel highly porous structure, which is a three-dimensional interconnected
      fibrous network with a fiber diameter ranging from 50 to 500 nm, has been created
      from biodegradable aliphatic polyesters in this work. A porosity as high as 98.5%
      has been achieved. These nano-fibrous matrices were prepared from the polymer
      solutions by a procedure involving thermally induced gelation, solvent exchange,
      and freeze-drying. The effects of polymer concentration, thermal annealing,
      solvent exchange, and freezing temperature before freeze-drying on the nano-scale
      structures were studied. In general, at a high gelation temperature, a platelet
      like structure was formed. At a low gelation temperature, the nano-fibrous
      structure was formed. Under the conditions for nano-fibrous matrix formation, the
      average fiber diameter (160-170 nm) did not change statistically with polymer
      concentration or gelation temperature. The porosity decreased with polymer
      concentration. The mechanical properties (Young's modulus and tensile strength)
      increased with polymer concentration. A surface-to-volume ratio of the nano
      fibrous matrices was two to three orders of magnitude higher than those of
      fibrous nonwoven fabrics fabricated with the textile technology or foams
      fabricated with a particulate-leaching technique. This synthetic analogue of
      natural extracellular matrix combined the advantages of synthetic biodegradable
      polymers and the nano-scale architecture of extracellular matrix, and may provide
      a better environment for cell attachment and function.

PMID- 10357137
TI  - Possibilities for strengthening hydroxyapatite ceramics.
AB  - Some physics during heating and sintering of powder pressings of hydroxyapatite
      (HA) under conventional (usual) conditions have been studied. It is revealed that
      heating and firing of the pressings of a middle-dispersity powder are accompanied
      by release of gases. The gas release hinders and can stop the shrinkage
      (sintering). The microhardness is low and has a complicated distribution on the
      surface and in the volume of ceramics. A slight degassing (drying) of the
      pressing before sintering heightens the density and improves the microhardness
      characteristics of the ceramics. The shrinkage stop effect is eliminated in
      pressings of a fine powder. On the basis of the results, a technique and some
      methods for quality improvement of ceramics were proposed and approbated. They
      consisted of the manufacture of samples of a mixture of two powders with
      different dispersity, use of a press technique with two male dies, thermal
      treatment of pressing before sintering, and the choice of moderate sintering
      conditions. The resulting ceramics had a density close to the theoretical, almost
      homogeneous microhardness distribution in the sample and much higher values of
      microhardness and compressive strength.

PMID- 10357138
TI  - Low-temperature crystallization of calcium phosphate coatings synthesized by ion
      beam-assisted deposition.
AB  - Crystallization temperature of the amorphous calcium phosphate coating
      synthesized by ion-beam-assisted deposition successfully was decreased to 400
      degrees C for the making of orthopedic implants with better qualities.
      Transmission electron microscopy (TEM) and X-ray diffraction (XRD) were used to
      investigate the morphological and structural evolution of the crystals in the
      coating during post-heat treatment. The crystallization of calcium phosphate
      coating is a hydroxyl-diffusion-controlled process, which is thought to be the
      mechanism responsible for the decrease of the crystallization temperature. In
      addition, the detailed crystallization process of calcium phosphate coating is
      elaborated in the present paper. The results show that the crystallinity of the
      hydroxyapatite coating can be well controlled by adjusting the post-heat
      treatment time.

PMID- 10357139
TI  - Exploiting glycation to stiffen and strengthen tissue equivalents for tissue
      engineering.
AB  - Glycation, the nonenzymatic crosslinking of proteins by reducing sugars, is known
      to cause stiffening of soft tissues over a lifetime, particularly in diabetics.
      We show here that glycation due to elevated glucose and ribose concentrations in
      cell culture medium can be exploited in a matter of a few weeks of incubation to
      stiffen and strengthen tissue equivalents and to increase their resistance to
      collagenolytic degradation, all without loss of cell viability. Glycated tissue
      equivalents did not elicit inflammation or induce calcification upon subcutaneous
      implantation; rather, they were permissive to host integration and remodeling.
      Thus a pathological process might be used in a targeted way in tissue engineering
      to fabricate tissue equivalents with the required mechanical properties and
      desired resorption rate upon implantation.

PMID- 10357140
TI  - Real time observation of platelet adhesion to opaque biomaterial surfaces under
      shear flow conditions.
AB  - We developed a new system which enables direct observation of platelet adhesion
      on opaque biomaterials under shear flow conditions, by combining a thin quartz
      cone which produces laminar shear flows, with an upright epifluorescence
      microscope which visualizes stained platelets through the rotating cone. This is
      the first report on the observation of platelets adhered to opaque biomaterials
      in real time under shear flow conditions. The direct observation of platelet
      adhesion to expanded polytetrafluoroethylene (ePTFE) as an opaque biomaterial
      revealed that the kinetics of platelet adhesion to ePTFE depended greatly on
      shear stresses, showing that the shear stress of 5.0 dyne/cm2 induced higher
      adhesiveness of platelets to ePTFE than that of either 0.1 or 15 dyne/cm2. The
      observation also showed a difference in platelet adhesiveness among ePTFEs with
      different fibril lengths--0, 3.2, 18, and 35 microm--indicating that ePTFEs with
      shorter fibril length had lower adhesiveness of platelets under a shear stress of
      5.0 dyne/cm2. It is indispensable for analyzing the phenomena of platelet
      adhesion to opaque biomaterials to observe in real-time rolling, adhesion, and
      detachment of platelets under shear stresses without disturbing shear flow
      conditions. The results showed that the mechanical and optical design of the
      system could serve this purpose.

PMID- 10357141
TI  - Influence of biphasic calcium phosphate granulometry on bone ingrowth, ceramic
      resorption, and inflammatory reactions: preliminary in vitro and in vivo study.
AB  - Calcium-phosphate ceramics used in surgery, as bone-bonding materials, are
      currently available in different forms (blocks, granules, etc.). However,
      progress in noninvasive surgery has favored the development of injectable
      composite materials associating a polymeric and a dusty mineral phase. The
      purpose of this study was the in vivo evaluation of biphasic calcium phosphate of
      various grains sizes, to elucidate the role of granulometries in ceramic
      degradation/resorption, bone ingrowth, and inflammatory reactions. Three particle
      sizes were compared: 10-20, 80-100, and 200-400 microm. The 10-20-microm powders
      provided the best bone ingrowth, with a higher resorption/degradation rate in
      conjunction with stronger early inflammatory reactions. The 200-400-microm
      powders showed higher bone ingrowth than 80-100-microm ones, indicating that
      properties of cell recruitment for osseous apposition and mechanical support for
      bone bonding may both play a role in both ingrowth mechanisms. Our results
      suggest that the strong inflammatory reaction in 10-20-microm granulated powders
      was due to a faster reversal of the resorption/apposition sequence in bone. This
      may have resulted from massive release of bone ingrowth factors, which implies
      that the brief inflammatory process observed in the early stages of implantation
      was favorable to the osteoconduction process.

PMID- 10357142
TI  - Evolution of morphology in UHMWPE following accelerated aging: the effect of
      heating rates.
AB  - Accelerated aging methods are used to evaluate the oxidative stability of UHMWPE
      components for total joint replacements. In this study, we traced the evolution
      of the crystalline morphology during accelerated thermal aging of UHMWPE in air
      with the intent of explaining previous, counterintuitive heating rate effects.
      GUR4150HP extruded rod stock material was machined into miniature (0.5 mm thick)
      specimens that were either gamma irradiated in air or in nitrogen (27 +/- 3 kGy)
      or left unirradiated (control). Accelerated aging in an air furnace (at 80
      degrees C, atmospheric pressure) was performed on half of the test samples at a
      heating rate of 0.1 degrees C/min and at 5 degrees C/min for the remaining half.
      Although the initial heating rate, as measured by changes in density, did
      influence the absolute degradation rate by up to 214%, the heating rate effect
      did not appear to influence the relative ranking of UHMWPE in terms of its
      oxidative stability. The heating rate effect is more consistent with a kinetic
      mechanism of the oxidation process than it is with a previously hypothesized
      diffusion mechanism. UHMWPE morphology, as characterized using a transmission
      electron microscope (TEM), demonstrated considerable rearrangement of the
      crystalline regions as a result of the accelerated aging. The stacking of the
      lamellae observed after accelerated aging was not consistent with the morphology
      of naturally aged UHMWPE components. The observed differences in crystalline
      morphology likely result from the enhanced mobility of the polymer chains due to
      thermal aging and may be analogous to an annealing process.

PMID- 10357143
TI  - Differential response of human osteoblast-like cells to commercially pure (cp)
      titanium grades 1 and 4.
AB  - Common dental implants are made of different grades of commercially pure titanium
      (cpTi) that are more than 99% similar in chemical composition. The objective of
      this in vitro study was to determine if human osteoblast-like cells, Saos-2,
      would respond differently when plated on disks of cpTi Grade 1 and Grade 4. Glass
      disks served as controls. In spite of identical preparation, the two grades of
      cpTi acquired different surface topographies, as illustrated by scanning electron
      micrographs and profilometry. Cell responses, such as adhesion, morphology, and
      collagen synthesis also differed on the two grades of cpTi. Between 4 and 24 h,
      the rate of cell attachment to Grade 1 differed significantly compared to cell
      attachment to Grade 4 and to glass. Rhodamine phalloidin fluorescence microscopy
      showed variations in the actin-based cytoskeleton between grades 1 and 4 cpTi in
      cell spreading, shape, and the organization of stress fibers. Immunofluorescent
      staining showed differential expression of vinculin, a focal adhesion protein, on
      the substrates. At 24 h, the percent of collagen synthesized was significantly
      more on Grade 1 than on Grade 4 and on glass. Alkaline phosphatase activity was
      similar on all substrates. The calcium content was significantly higher on Grade
      1 than on Grade 4 and on glass at 24 h and at 4 weeks. Thus, commonly used cpTi
      induced differential morphologic and phenotypic changes in human osteoblast-like
      cells depending on the grade of the material.

PMID- 10357144
TI  - Adjuvancy effect of different types of silicone gel.

PMID- 10357145
TI  - Failure of current strategies in the prevention of thrombosis in patients with
      heparin-induced thrombocytopenia: a clinician's perspective.
AB  - Heparin-induced thrombocytopenia (HIT), and heparin-induced thrombocytopenia with
      thrombosis syndrome (HITTS), are immune-mediated complications of heparin therapy
      associated with significant morbidity and mortality. Although much has been
      learned about the pathophysiology of this syndrome, there are many difficult
      issues remaining for physicians involved in the daily care of the patient about
      the diagnosis, prevention, and treatment. To determine whether the earliest
      detection of HIT and heparin cessation impacted outcome, 116 consecutive patients
      at a single institution, with HIT diagnosed by platelet aggregometry, were
      divided into groups by time to heparin cessation based on daily platelet counts.
      Thrombocytopenia was defined in two ways: as a 50% decline from baseline and an
      absolute platelet count of less than 100x10(9)/L. The overall thrombosis rate was
      39% and was predominantly venous. The mortality rate of 27% was similar in
      patients with both HIT and HITTS. Despite heparin cessation at less than 48 h
      from the onset of thrombocytopenia (mean 0.5 days), there were no differences in
      thrombosis or mortality when compared to patients with later heparin cessation
      (mean 4.3 days). In summary, early detection of HIT with heparin cessation is
      insufficient therapy for the management and treatment of HITTS. An alternative to
      this strategy in the treatment of patients with HIT is indicated.

PMID- 10357146
TI  - Heparin-induced thrombocytopenia in France, 1980-1998.
AB  - Due to the extensive use of unfractionated heparins in France, there is
      considerable experience with heparin-induced thrombocytopenia (HIT). It is
      recommended that platelet counts be performed twice a week for three weeks when
      patients are treated with any form of heparin. A drop in platelet counts can,
      however, occur not only in HIT patients but also for other unrelated reasons. For
      diagnosing HIT, all laboratories in France use platelet aggregometry inspite of
      poor sensitivity. Both false positive and false negative results are obtained.
      The serotonin release test is not used in France. The ELISA test for HIT does not
      always correlate with the platelet aggregation test and many patients with a
      positive ELISA test do not necessarily have other evidence for HIT. This is
      especially true in patients following cardiopulmonary bypass surgery. None of the
      available laboratory tests reliably identify patients with HIT. Patients with HIT
      should not be managed with low-molecular-weight heparins, but danaparoid,
      argatroban and ancrod are viable options. Also, recombinant hirudin has been
      employed. All have advantages and disadvantages. At present, the diagnosis and
      management of patients with HIT remains difficult and properly designed clinical
      studies are needed to obtain answers to several open questions.

PMID- 10357147
TI  - Hematologic complications of heparin-induced thrombocytopenia.
AB  - Heparin-induced thrombocytopenia (HIT) is arguably the most significant of the
      drug-induced thrombocytopenias. Two main types of HIT, types I and II, are
      usually discussed. Type I HIT is characterized by a moderate reduction in
      platelet counts early in heparin therapy, usually within the first 1 to 3 days.
      The platelet count rarely drops below 100x10(9)/L and normalizes in spite of
      continued heparin therapy. Type II HIT is immunologically mediated. The
      definition of Type II HIT varies, but most studies require a platelet count below
      100-150x 10(9)/L for no apparent reason other than heparin administration. Many
      patients with type II HIT suffer no morbidity. Unfortunately, a significant
      number, 30 to 60% or more, do develop serious thrombotic complications resulting
      in morbidity or mortality, including ischemic damage to limbs, central nervous
      system, myocardium, and lungs. Although earlier literature indicated that
      arterial thromboses occurred more frequently than venous, recent reports have
      found that venous thromboses, including deep venous thromboses, pulmonary emboli,
      and clotted venous catheters, have been common occurrences. In some studies,
      venous complications were more frequent than arterial. Most investigators have
      come to believe that these antibodies are largely directed against complexes
      formed between heparin and the tetrameric PF4. Recent studies devoted to
      exploring the mechanism by which these antibodies induce platelet activation and
      thrombosis are discussed.

PMID- 10357148
TI  - Endothelial cell hyperplasia contributes to thrombosis in heparin-induced
      thrombocytopenia.
AB  - Heparin-induced thrombocytopenia (HIT), a well recognized complication of heparin
      administration, is associated with thrombotic complications. An immunologic
      mechanism is believed to be responsible for the thrombocytopenia, but the cause
      of thrombosis is not fully understood. We report a histological and
      immunohistochemical study of thrombosed vessels in surgically removed ischemic
      tissues in patients with HIT complicated by gangrene of the lower limbs. Tissue
      sections were studied by: (1) hematoxylin and eosin staining and immunoperoxidase
      staining using a monoclonal antibody against platelet surface glycoprotein
      Ib(GPIb) for the identification of platelets, and (2) polyclonal antibodies
      against tissue-type plasminogen activator (tPA) and factor VIII for the
      identification of endothelial cells. We observed small arteries occluded by
      multiple small platelet thrombi surrounded by proliferative endothelial cells. In
      addition, depositions of IgG, IgA, and IgM were found in the occluded arteries.
      We postulate that the endothelial cell hyperplasia is caused by immunologic
      injury to endothelial cells as a result of immunoglobulin deposition, and by
      various mitogens derived from the activated platelets in the thrombi. Such
      endothelial cell hyperplasia is a major contributory factor, in addition to the
      microthrombi, of the occlusive vasculature in this disease.

PMID- 10357149
TI  - Current trends in the use of heparins in thromboprophylaxis.
AB  - Unfractionated heparin (UH), administered subcutaneously in low doses of 5000 U
      every 12 h, is safe and effective in preventing thrombosis in most patients.
      However, in persons with neurological disease, surgical replacement of joints, or
      operations for cancer, low-dose UH is often inadequate or unsafe, and dose
      adjusted UH, warfarin, or low molecular weight heparins (LMWH) may be needed. In
      trauma patients, LMWH is significantly more effective than UH in reducing the
      frequency of DVT with a minimal increase in bleeding risk. LMWH also
      significantly decreases thromboembolism in patients with acute spinal cord injury
      and complete motor paralysis, and with less bleeding as compared to UH. In acute
      stroke, a heparinoid was more effective than either placebo or UH (5000 U every
      12 h) in preventing deep-vein thrombosis in acute thrombotic stroke, and the risk
      of bleeding was low. Following total hip or knee replacement, LMWH is more
      efficacious than warfarin but may be associated with perioperative bleeding. The
      duration of thrombo-prophylaxis following arthroplasty is controversial;
      venography demonstrates thrombi in approximately 29% of patients after hospital
      discharge, but only 3% have clinical symptoms. Lastly, perioperative thrombosis
      in cancer patients having abdominal surgery has been decreased by LMWH, and
      experience with outpatient treatment in the long-term management of Trousseau's
      syndrome has been positive.

PMID- 10357150
TI  - Selectins in the HIT syndrome: pathophysiologic role and therapeutic modulation.
AB  - The pathophysiology of heparin-induced thrombocytopenia (HIT) is now known to be
      a complex process which involves platelets, vascular endothelium, and leukocytes.
      The activation products from these sites also contribute to the activation of
      coagulation and to the fibrinolytic deficit. While many of the markers of
      hemostatic activation processes have been found to be at increased levels during
      acute phases of the HIT syndromes, the circulating levels of soluble P-, E-, and
      L- selectins have not been reported. Since the pathophysiology of HIT involves
      the activation of platelets, endothelium, and leukocytes, it is expected that
      activation products related to these hemostatic systems, including soluble
      selectins, will also be increased in circulating blood. These alterations may
      provide an index of the pathophysiologic process. With the availability of highly
      sensitive ELISAs for soluble P-, E-, and L-selectins, it is now possible to
      measure these adhesion molecules in biological fluids. This study reports on the
      circulating levels of P-, E-, and L-selectins in HIT patients and their
      modulation after therapeutic intervention. With the availability of recombinant
      hirudin, it is now possible to provide alternate anticoagulants to HIT patients.
      However, the immunoactivation of platelets and other cells may require additional
      adjunct therapeutic approaches.

PMID- 10357151
TI  - Laboratory tests for the diagnosis of heparin-induced thrombocytopenia.
AB  - Heparin-induced thrombocytopenia (HIT) is associated with high morbidity and
      mortality. Because the pathophysiology of this complex disorder has remained
      unclear, so has the development of supportive diagnostic laboratory assays. The
      currently available laboratory methods for HIT diagnosis include several platelet
      function assays: the platelet aggregation assay, platelet aggregation with
      simultaneous measurement of ATP release (lumi-aggregometry), the serotonin
      release assay, and flow cytometric assays. ELISA assays, which quantitate anti
      heparin/platelet factor 4 antibody titers, have recently become available. Assay
      characteristics for these assays were studied using sera collected from
      clinically diagnosed HIT patients with and without thrombosis, normal
      individuals, various types of hospitalized patients without HIT, heparin or low
      molecular weight heparin-treated patients without HIT, and patients with platelet
      immune disorders other than HIT. The results of our studies suggest that none of
      the assays can be considered a "gold standard" for the laboratory diagnosis of
      HIT as many false-negative and false-positive results were obtained. Furthermore,
      antibodies against the heparin/platelet factor 4 complex, as identified by the
      current ELISA tests, are not the sole cause of HIT since many patients lacking
      clinical symptoms associated with HIT exhibited high antibody titers following
      heparin treatment. An assay using flow cytometry, being developed for HIT
      testing, will be described. At this time, clinical impression remains important
      for the diagnosis of HIT.

PMID- 10357152
TI  - Comparison of two PF4/heparin ELISA assays for the laboratory diagnosis of
      heparin-induced thrombocytopenia.
AB  - Serum samples from 105 patients with suspected heparin-induced thrombocytopenia
      (HIT) were evaluated using the 14C-serotonin release assay (SRA), considered the
      "gold standard" for the diagnosis of HIT, and two enzyme-linked immunosorbent
      assays (ELISA) that measure anti-platelet factor (PF) 4/heparin antibodies to
      determine the performance characteristics of the newly available ELISA assays.
      Relative to the SRA, the sensitivity and specificity of the Asserachrom HPIA
      assay were 73% and 77%, respectively, in this population of patients. The
      sensitivity and specificity of the GTI-HAT assay were 60% and 93%, respectively.
      In serum negative by SRA, GTI-HAT and HPIA detected antibodies in 9% and 25%,
      respectively. Antibodies were detected by HPIA in 18% of the sera negative by
      both SRA and GTI-HAT. In a second study, samples evaluated from patients (n = 10)
      treated for established thrombosis with a low-molecular-weight heparin and who
      had no decrease in platelet counts, showed a weak antibody titer in 50% of the
      patients after 12 days of therapy by GTI-HAT, whereas the HPIA identified a
      strong antibody titer in 75% of the patients after 4 days. These data suggest
      that the currently available ELISA methods for the detection of anti-PF4/heparin
      antibodies offer a limited sensitivity and specificity in comparison to SRA. The
      ELISA assays on their own are thus of limited value for the laboratory diagnosis
      of HIT. SRA-positive sera do not always have positive antibody titers, and
      antibodies can be present in SRA-negative sera. Furthermore, these data show that
      ELISA methods differ in their relative sensitivities and specificities for the
      detection of anti-PF4/heparin antibodies.

PMID- 10357153
TI  - Use of argatroban during percutaneous coronary interventions in patients with
      heparin-induced thrombocytopenia.
AB  - Percutaneous coronary revascularization (PTCR) procedures require intense
      anticoagulation during the procedure to reduce the risk of a thrombotic
      complication. This anticoagulation is almost always performed with unfractionated
      heparin. Heparin, however, is far from the ideal anticoagulant for use in PTCR,
      and its use is contraindicated in patients with known or suspected heparin
      induced thrombocytopenia (HIT) or the heparin-induced thrombocytopenia and
      thrombosis syndrome (HITTS). The incidence of HIT/HITTS in the population
      undergoing PTCR may be increased due to the widespread use of heparin in
      cardiovascular patients. Direct thrombin inhibitors such as argatroban do not
      interact with the antibody that causes HIT/HITTS, and so these agents can be used
      to provide anticoagulation in patients with this dangerous condition. Argatroban
      was used in a trial of 50 patients with known or suspected HIT or HITTS who
      required PTCR. Adequate anticoagulation was achieved in 98% and there was
      procedural success in 98% with only 1 major bleeding event. These preliminary
      data suggest that argatroban can be used safely and effectively as an
      anticoagulant during PTCR in patients with known or suspected HIT or HITTS.

PMID- 10357154
TI  - Coagulation laboratory testing in patients treated with argatroban.
AB  - During clinical trials with the thrombin inhibitor argatroban, appropriate
      methods for drug monitoring were identified. Treated patients presented
      interesting challenges for coagulation laboratory parameter testing in the
      presence of argatroban. These issues are reported here. Regarding the monitoring
      of argatroban, the aPTT and ACT were effectively used clinically for low (0-2.5
      microg/mL) or high (1-15 microg/mL) doses of argatroban. However, system (reagent
      and instrument) differences were noted in the time-to-clot values. A clot-based
      assay using Ecarin as the activator (ECT, Ecarin clotting time) appeared to be
      useful for monitoring both low and high drug levels with less interference from
      other drugs or coagulation defects. Also identified were the chromogenic
      antithrombin assay that could directly quantify argatroban and an HPLC based
      assay that could specifically quantify argatroban and its metabolites. With
      regard to assay interference by argatroban, several important effects were
      observed. The presence of argatroban synergistically interfered with the INR for
      those patients treated with oral anticoagulants. However, a chromogenic based
      method was able to determine factor X levels as a monitor of the oral
      anticoagulation without effect from argatroban. A similar synergistic response on
      the aPTT with heparin and argatroban was observed. Patients receiving argatroban
      evaluated for potential coagulation abnormalities could not be tested with the
      routine functional (clot based) assays for fibrinogen, factor levels or protein
      C. Argatroban acted as an inhibitor in these assays, causing a dose-dependent
      false decrease of fibrinogen and factor levels, and a false increase of protein
      C. Using a chromogenic assay for protein C, values equal to those obtained by an
      immunologic assay were achieved. These issues will most likely hold true for all
      thrombin inhibitors.

PMID- 10357155
TI  - Heparin-induced thrombocytopenia: the role of platelet activation and therapeutic
      implications.
AB  - In the past, heparin has been the sole anticoagulant for interventional
      cardiovascular procedures. Today, several alternate approaches to anticoagulate
      patients with heparin-induced thrombocytopenia (HIT) are under consideration.
      Antiplatelet drugs, such as the ADP receptor antagonists and inhibitors of
      glycoprotein (GP) IIb/IIIa, are currently in development. We investigated the
      effect of two anti-platelet agents on platelet activation induced by HIT serum (n
      = 5 HIT positive sera, n = 5 HIT negative sera and n = 4 donor platelets) and
      heparin, using the traditional platelet aggregation assay, a Lumi-aggregation
      assay to also determine platelet release, and flow cytometry. By all methods, the
      GP IIb/IIIa inhibitor-GPI 562 (Novartis; Nurnberg, Germany)-produced a
      concentration dependent (6.25 to 125 ng/mL) decrease in platelet activation, as
      shown by platelet aggregation, platelet microparticle formation, P-selectin
      expression, and ATP release. Similar results were obtained with the
      thienopyridine ADP receptor antagonist ticlopidine (Sanofi Recherche; Toulouse,
      France) in vitro at high concentrations of 5.0 to 50 microg/mL and ex vivo in a
      patient dosed at 250 mg/day. These studies show that GP IIb/IIIa and ADP receptor
      inhibitors can block platelet activation induced by HIT serum/heparin, providing
      evidence that the mechanism of HIT may be multifactorial involving not only the
      generation of the heparin-PF4 or other antibodies but also involving platelet
      specific processes and, potentially, the generation of proaggregatory substances.
      The new antiplatelet agents may be useful in the clinical management of HIT
      patients.

PMID- 10357156
TI  - Clinical experience with combined treatment of thrombin inhibitors and GPIIb/IIIa
      inhibitors in patients with HIT.
AB  - Despite the use of potent anticoagulants such as r-hirudin and argatroban, the
      morbidity/mortality of heparin-induced thrombocytopenia (HIT) patients remains
      high. In the last several months, we have treated three HIT-positive patients
      with a combined therapy of thrombin inhibitor and GPIIb/IIIa inhibitor when
      treatment with thrombin inhibitor alone failed to alleviate acute thrombosis.
      Combination therapies included r-hirudin (Refludan) with tirofiban (Aggrastat) or
      argatroban (Novastan) with ReoPro. A reduced dose of the thrombin inhibitor with
      the standard dose of the antiplatelet drug was the dosing regimen used. In all
      cases, there was no overt bleeding that required intervention and all patients
      had improved or fully recovered. This first report of the use of GPIIb/IIIa
      inhibitors with thrombin inhibitors in HIT patients with active thrombosis
      suggests that this combined therapy may be more effective than thrombin inhibitor
      treatment alone. The data from these three cases warrant testing of this
      therapeutic regimen in larger studies to determine optimal dosing strategies.

PMID- 10357157
TI  - The abuse of disabled children.

PMID- 10357158
TI  - The assessment and management of risk in adolescents.
AB  - Much of the relevant literature has focused on the assessment of dangerousness in
      adults. Up-to-date thinking and research has now taken on the alternative concept
      of risk and looks not at all-or-nothing long-term predictions, but at short-term
      frequent decisions about risk, which then assist in the management of the
      individual and their situation. For this reason it is essential that those
      presenting evidence for other professionals or for Court should not attempt, or
      be persuaded, to make long-term predictions. Current research is now showing that
      some factors, which can be ascertained clinically, are significantly associated
      with the risk of future violence.

PMID- 10357159
TI  - Social versus biological parenting: family functioning and the socioemotional
      development of children conceived by egg or sperm donation.
AB  - By investigating egg donation families, donor insemination families, adoptive
      families, and families created by in vitro fertilization, the aim of the present
      study was to examine parents' emotional well-being, the quality of parenting, and
      childrens' socioemotional development in families with a child who is genetically
      unrelated to the mother or the father. The differences that were found to exist
      between families according to the presence or absence of genetic ties between
      parents and their children reflected greater psychological well-being among
      mothers and fathers in families where there was no genetic link between the
      mother and the child. The families did not differ with respect to the quality of
      parenting or the psychological adjustment of the child.

PMID- 10357160
TI  - The psychological impact of war and the refugee situation on South Sudanese
      children in refugee camps in Northern Uganda: an exploratory study.
AB  - This paper presents the results of an exploratory study on the psychosocial
      effects of the war situation and subsequent flight on South Sudanese children who
      were compared to a group of Ugandan children who did not have these experiences
      of war and flight. In addition to the independent variables such as
      sociodemographic variables and traumatic events and daily life stress, the
      dependent variable psychological consequences--according to parents and children
      themselves--as well as the influence of the mediating factors of social support
      and coping behaviour are presented. Results showed that Sudanese refugee children
      had experienced significantly more traumatic events and suffered more daily
      hassles than the Ugandese comparison group. They were less satisfied with the
      social support they received. At the same time, they used more coping modes.
      Compared to Ugandan children, the Sudanese reported significantly more PTSD-like
      complaints, behavioural problems, and depressive symptoms.

PMID- 10357161
TI  - Quasi-autistic patterns following severe early global privation. English and
      Romanian Adoptees (ERA) Study Team.
AB  - Six per cent of child in a sample of 111 children who were adopted into U.K.
      families from Romania, and who were systematically assessed at the ages of 4 and
      6 years, showed autistic-like patterns of behaviour. A further 6% showed milder
      (usually isolated) autistic features. Such autistic characteristics were not
      found in a similarly studied sample of 52 children adopted in the first 6 months
      of life within the U.K. The children from Romania with autistic patterns showed
      clinical features closely similar to "ordinary" autism at 4 years but they
      differed with respect to the improvement seen by age 6 years, to an equal sex
      ratio, and to a normal head circumference. The children from Romania with
      autistic features tended to differ from the other Romanian adoptees with respect
      to a greater degree of cognitive impairment and a longer duration of severe
      psychological privation.

PMID- 10357162
TI  - Cognitive and educational attainments at school age of children who failed to
      thrive in infancy: a population-based study.
AB  - A 1-year cohort of children born at term in Newcastle-upon-Tyne in 1987/8 was
      screened for failure to thrive in infancy using a conditional longitudinal
      standard which identified those whose weight gain was in the lowest 5%. A group
      of 136 cases and 136 controls (from the same GP practice and living in a
      neighbourhood with the same deprivation index) was followed up at 7-9 years of
      age, when 79% of cases and 87% of controls were successfully studied. Cases at 7
      9 were significantly shorter (mean 126.0 cm, SD 5.6) than controls (mean 130.7
      cm, SD 5.9); adjusted for parental heights a difference of 4.4 cm (95% CI 2.92 to
      5.90 cm) remained. They had smaller head circumferences (mean 51.9 cm, SD 1.8)
      than controls (mean 52.8 cm, SD 1.7), were significantly lighter (medians 23.8
      kg, IR 21.5 to 26.9 in cases, and 27.9 kg, IR 25.2 to 31.6 in controls) and had a
      lower body mass index (median 14.9, IR 14.1 to 16.0 in cases, and 16.3, IR 15.3
      to 17.8 in controls). Despite these large growth differences, no statistically
      significant differences in cognitive outcomes were found. Mean IQ was 87.6 (SD
      17.4) in cases and 90.6 (SD 17.1) in controls; after adjustment for organic cause
      and mother's IQ the mean difference was 1.7 IQ points (95% CI -5.2 to 1.9). There
      were no statistically significant differences in the reading, spelling, or
      reading comprehension scores; the mean standardised reading score was 93.5 (SD
      16.2) for cases and 94.5 (SD 15.6) for controls. These results show that when
      carefully defined by velocity-based anthropometric criteria, nonorganic failure
      to thrive in infancy is followed by persisting stunting and wasting, and a
      reduced head circumference, but is not associated with cognitive or educational
      disadvantages at school age.

PMID- 10357163
TI  - Psychological disorders and their correlates in an Australian community sample of
      preadolescent children.
AB  - The nature and correlates of psychological disorders of preadolescent children
      from the longitudinal Australian Temperament Project (ATP) are reported. Almost
      half of the children identified via checklists completed by mothers, teachers,
      and the children themselves as being in the at-risk range for disorder received a
      DSM-III-R diagnosis. Nine per cent of comparison, or low-risk, children also
      received a diagnosis. Internalising disorders were the most common, and 44% of
      cases had multiple problems. Children rated as problematic by all three
      informants or by child plus teacher were the most likely to receive a diagnosis.
      The at-risk group had more difficult temperament, poorer family and peer
      relationships, lower levels of social skills, and were of lower SES than the
      comparison group. There were minimal differences on these variables between at
      risk children who did, or did not, receive a DSM-III-R diagnosis. It is argued
      that especially for boys, checklists from multiple informants are effective tools
      for identifying clinically significant disorders.

PMID- 10357164
TI  - Prospective childhood predictors of deviant peer affiliations in adolescence.
AB  - Data gathered over the course of a longitudinal study of a birth cohort of over
      900 New Zealand children were used to examine factors associated with the
      formation of affiliations with delinquent or substance using peers in adolescence
      (15 years). The findings of this study include: (1) Adolescent peer affiliations
      were associated with a wide range of prospectively measured social, family,
      parental, and individual factors. This analysis indicated that those children
      most at risk of forming deviant peer affiliations were those from socially
      disadvantaged backgrounds, dysfunctional families, who showed early onset conduct
      problems and other difficulties. (2) Regression analysis suggested that specific
      factors that were associated with increased risks of later deviant peer
      affiliations included family socioeconomic status, parental conflict,
      mother/child interaction, childhood sexual abuse, parental alcoholism, parental
      criminal offending, parental illicit drug use, parental smoking, early conduct
      problems, early anxiety/withdrawal, and early smoking experimentation. It is
      concluded that peer affiliations in adolescence are shaped by a complex social,
      family, and individual process that includes social stratification, family
      functioning, and individual behavioural predispositions.

PMID- 10357165
TI  - Adolescent reputation enhancement: differentiating delinquent, nondelinquent, and
      at-risk youths.
AB  - This research reports the findings of two studies conducted to measure and then
      investigate differences between delinquent, nondelinquent, and at-risk youths'
      orientations towards reputation enhancement. In the first study, concerning item
      selection and scale development, the factor structure and content validity of a
      potential Reputation Enhancement Scale were tested by examining the item
      responses of the scale completed by 230 high-school students. In the second
      study, the scale was validated by comparing the item responses of 80 delinquent,
      90 at-risk, and 90 nondelinquent adolescents with the responses of the original
      students. The instrument was found to be reliable (alphas from .64 to .92),
      indicating that the factors are dependable across different samples, and the
      coefficients of congruence were sufficiently high to investigate meaningful group
      differences. Three second-order factors (Conforming Reputation, Nonconforming
      Reputation, Self-presentation) were derived from the 15 first-order factors.
      Although multivariate analyses revealed significant differences between the
      reputational orientations of delinquent, at-risk, and nondelinquent participants,
      the self-presentation second-order factor did not differentiate the three groups.

PMID- 10357166
TI  - A typology of parent rated child behavior for a national U.S. sample.
AB  - The purpose of the current study was to build on the emerging effort to produce a
      meaningful typology of child behavior for school-aged children. The Behavior
      Assessment System for Children (BASC) Parent Rating Scales for Children (PRS-C)
      norming data were collected for 2029 6- to 11-year-old children at 116 sites
      representing various regions of the United States. The PRS-C has 130 items that
      are rated by the parent on a 4-point scale of frequency, ranging from "never" to
      "almost always". The Ward method of cluster analysis was used to identify the
      initial centroids or cluster seeds in this norming sample. An iterative
      clustering method, a K-means procedure, was used to refine the Ward cluster
      solution. A nine-cluster solution was selected based on both rational and
      empirical considerations. The resulting clusters were labeled adapted, physical
      complaints/worry, average, well-adapted, minimal problems, attention problems,
      internalizing, general psychopathology-severe, and disruptive behavior problems.
      The nine-cluster solution is similar to those of Achenbach (1991), Thompson,
      Kronenberger, and Curry (1989), and other researchers. At the same time, some
      significant differences exist. The resulting typology points the way toward
      future cluster studies of child psychopathology and normal behavioral development
      by delineating additional research and theoretical directions.

PMID- 10357167
TI  - The assessment of expressed emotion in a standardised family interview.
AB  - This study compared the expressed emotion (EE) scores obtained using individual
      interviews with parents with the scores obtained in whole family interviews.
      Interviews were carried out with 31 parents of 16 adolescents referred because of
      an eating disorder. There was moderate correlation of scores between the two
      interviews regarding critical comments, emotional overinvolvement, and warmth,
      but it was low for positive remarks. The study suggests that the whole family
      interview, which is time saving, is useful in assessing expressed emotion. The
      levels of expressed emotion, particularly the relatively low levels of critical
      comments and emotional overinvolvement, are similar to those of previous studies.

PMID- 10357168
TI  - Behavioural treatment for sleep problems in children with severe learning
      disabilities and challenging daytime behaviour: effect on daytime behaviour.
AB  - The study aimed to investigate a group of children with severe learning
      disabilities, challenging daytime behaviour, and severe sleep problems to see if
      successful behavioural treatment of the children's sleep problems resulted in
      reduced daytime challenging behaviour as reported by mothers and teachers. A
      randomised controlled trial of behavioural interventions for the children's sleep
      problems was conducted (N = 30). The intervention group received an individually
      tailored behavioural programme and were supported by telephone calls from the
      therapist. Baseline assessments of the children's behaviour were made using the
      Aberrant Behavior Checklist and were repeated 1 month and 3 months after the
      start of intervention. There were no behavioural changes that were specific to
      children in the treatment group. However, improvements in some behaviours were
      seen in both the intervention and the control group at the 1-month and 3-month
      assessments and there was agreement between mothers' and teachers' reports for
      many of these changes. The results suggest that nonspecific effects of
      participating in the study (including an increased sleep duration, which was seen
      in both groups), rather than resolution of sleep problem per se, may have a
      beneficial effect on child behaviour and these factors need to be identified for
      therapeutic use.

PMID- 10357169
TI  - Auditory temporal processing in disabled readers with and without oral language
      delay.
AB  - Inferior auditory temporal processing has been postulated as causally linked to
      phonological processing deficits in disabled readers with concomitant oral
      language delay (LDRDs), and absent in specifically disabled readers with normal
      oral language (SRDs). This investigation compared SRDs, LDRDs and normal readers
      aged 7-10 years on measures of auditory temporal processing (temporal order
      judgement) and phonological decoding (nonword reading). LDRDs exhibited deficits
      in temporal order judgement compared with normal readers, from whom SRDs did not
      differ significantly. These findings suggest that auditory temporal processing
      and oral language are related; however, very large within-group variability in
      the auditory temporal processing data further suggests that this relationship
      prevails in only a proportion of disabled readers with concomitant oral language
      weakness. In nonword reading, LDRDs performed worst of all, but SRDs also
      exhibited significant deficits compared with normal readers. Taken together, our
      results preclude the conceptualisation of temporal processing deficits as the
      unitary cause of phonological and language deficits in disabled readers.

PMID- 10357170
TI  - Imitation and identification in autism.
AB  - This study was designed to test the prediction that adolescents with autism would
      have specific limitations in imitating the "style" of another person's actions.
      In a series of original tasks that tested the delayed imitation of novel
      nonsymbolic actions, 16 participants with autism and 16 nonautistic participants
      group-matched for age and verbal ability were proficient in copying goal-directed
      actions, but in 3 out of 4 tasks, strikingly fewer participants with autism
      imitated with style with which the demonstrator executed the actions. An
      additional finding was that on 2 conditions that involved copying self-orientated
      actions, only 5 of the participants with autism but 15 of the 16 nonautistic
      participants spontaneously adopted the orientation-to-self on at least 1
      occasion. The results are discussed with reference to theories concerning
      imitation deficits in autism, and with regard to the proposal that autism
      involves an impairment in intersubjective contact between affected individuals
      and others (Hobson, 1989, 1993; Rogers & Pennington, 1991).

PMID- 10357171
TI  - Sodium channel fragments: contributions to voltage sensitivity and ion
      selectivity.
AB  - The peptide strategy was employed to resolve structure-function relationships in
      the voltage-dependent sodium channel Two families of motifs were studied: the
      four voltage sensors S4 extended with the short cytoplasmic linkers L45 and the
      four P-regions, between S5 and S6, each from the homologous domains of the
      electric eel sodium channel. Macroscopic conductance experiments conducted with
      synthetic S4L45s in neutral lipid planar bilayers pointed to a moderate voltage
      sensitivity for repeat IV which has no proline, whereas S4L45 of repeats I and II
      (Pro 19) and especially of repeat III (Pro 14) were much more voltage-sensitive.
      The influence both of Pro and its position within the sequence was confirmed by
      comparing the human skeletal muscle channel isoform D4/S4 wild-type and the R4P
      analogue. Circular dichroism spectroscopy shows highest and lowest helicities for
      repeats IV and III. The conformational transition (from helix to extended, mainly
      beta forms), which occurs when the solvent dielectric constant increases, was
      broader with repeat III. These structural and functional correlates suggest
      alternative gating mechanisms. The different contributions of each repeat also
      have effects at the level of the main selectivity filter, which suggests self
      recognition between the four P-regions is a key component of intact sodium
      channel selectivity. In addition, the P-region from domain III is significantly
      voltage-sensitive and molecular dynamics simulations show that the C-terminal
      part of P-regions is mainly helical whilst the N-terminus tends to unfold. Such
      specializations of the four domains both in gating and selectivity are
      independently confirmed in recent electrophysiological studies.

PMID- 10357172
TI  - Structure of the ductin channel.
AB  - Gap junctions appear to be essential components of metazoan animals providing a
      means of direct means of communication between neighboring cells. They are sieve
      like structures which allow cell-cell movement of cytosolic solutes below 1000
      MW. The major role of gap junctions would appear to be homeostatic giving rise to
      groups of cells which act as functional units. Ductin is the major core component
      of gap junctions and recent structural data shows it to be a four alpha-helical
      bundle which fits particularly well into a low resolution model of the gap
      junction channel. Ductin is also the main membrane component of the vacuolar H+
      ATPase that is found in all eukaryotes and it seems likely that the gap junction
      channel first evolved as a housing for the rotating spindle of these proton
      pumps. Because ductin protrudes little from the membrane, other proteins are
      required to bring cell surfaces close enough together to form gap junctions. Such
      proteins may include connexins, a large family of proteins found in vertebrates.

PMID- 10357173
TI  - Synthetic peptide fragments as probes for structure determination of potassium
      ion-channel proteins.
AB  - Potassium channels are a diverse class of transmembrane proteins that are
      responsible for diffusion of potassium ion across cell membranes. The lack of
      large quantities of these proteins from natural sources, is a major hindrance in
      their structural characterization using biophysical techniques. Synthetic peptide
      fragments corresponding to functionally important domains of these proteins
      provide an attractive approach towards characterizing the structural organization
      of these ion-channels. Conformational properties of peptides from three different
      potassium channels (Shaker, ROMK1 and minK) have been characterized in aqueous
      media, organic solvents and in phospholipid membranes. Techniques used for these
      studies include FTIR, CD and 2D-NMR spectroscopy. FTIR spectroscopy has been a
      particularly valuable tool for characterizing the folding of the ion-channel
      peptides in phospholipid membranes; the three different types of potassium
      channels all share a common transmembrane folding pattern that is composed of a
      predominantly alpha-helical structure. There is no evidence to suggest the
      presence of any significant beta-sheet structure. These results are in excellent
      agreement with the crystal structure of a bacterial potassium channel (Doyle, D.
      A. et al. (1998) Science 280:69 77), and suggest that all potassium channel
      proteins may share a common folding motif where the ion-channel structure is
      constructed entirely from alpha-helices.

PMID- 10357174
TI  - The behaviour of ions in narrow water-filled pores.
AB  - Today, the equilibrium behavior of ions in solution may be predicted with some
      confidence, essentially because rapid ionic diffusion over small distances
      ensures homogeneity throughout the solution. Equilibrium concepts such as ionic
      strength and pH apply. However, when attempting to understand the behavior of
      ions passing rapidly through narrow pores such as ion channels, no such
      equilibrium state may be assumed. The passing solution may have been in
      equilibrium with conditions at the mouth of the pore but will not be in
      equilibrium with charged molecules on the pore wall. In addition, the water in
      narrow pores will be partially ordered by contact with the pore walls and will
      not behave like bulk water. To illustrate this difference, a simple equilibrium
      calculation of the ion concentrations near a plastic sheet penetrated by narrow
      pores and containing in its surface partially ionized carboxyl groups is shown to
      be in good agreement with experiment. However, to predict the non-equilibrium
      behavior within the narrow pores is much more difficult. To illustrate the
      difficulty, a Monte Carlo computer model is described which attempts to predict
      the rapid switching of ion current observed experimentally with these narrow
      pores.

PMID- 10357175
TI  - Tumor necrosis factor-induced cytotoxicity is not related to rates of
      mitochondrial morphological abnormalities or autophagy-changes that can be
      mediated by TNFR-I or TNFR-II.
AB  - Tumor necrosis factor (TNF) may cause apoptosis or necrosis and induces
      mitochondrial changes that have been proposed to be central to cytotoxicity. We
      report similar patterns of TNF-induced mitochondrial morphological alterations
      and autophagy in cell types with differing sensitivity to TNF-induced
      cytotoxicity. Specific ligation of TNFR-I or TNFR-II induces different rates of
      apoptosis and mitochondrial morphological change, but similar rates of autophagy.
      These changes do not invariably lead to cell death, and survival or progression
      to apoptosis or necrosis following TNF exposure may depend in part on the extent
      of mitochondrial damage and/or the autophagic capacity of the cell.

PMID- 10357176
TI  - Extracellular reduction of Cat1 free radical by transformed human hepatocytes.
AB  - Redox activities associated with plasma membranes of nonphagocytic animal and
      plant cells have been reported by several authors. However, the natural
      substrates, structure and biological role of these putative enzyme systems are
      not known. Data indicating extracellular reduction of a nitroxide free radical
      Cat1 (1-oxy-4-trimethylamine-2,2,6,6,tetramethyl-piperidine) by hepatocytes were
      thought to be artefactual. We report evidence in support of a notion that Cat1 as
      well as a tetrazolium salt, CTC (5-cyano-2,3-ditolyl tetrazolium chloride), are
      reduced extracellularly, probably at the cell surface, by human HepG2 hepatoma
      cells. These data provide evidence confirming the existence of a yet unidentified
      reducing activity associated with outer surface of plasma membranes of
      transformed human hepatocytes.

PMID- 10357177
TI  - Impact of pretransplantation dialysis modality on patient outcome after renal
      transplantation: the role of peritoneal dialysis revisited.

PMID- 10357179
TI  - Pre end-stage renal disease care: opportunities and challenges.

PMID- 10357178
TI  - Relationships between creatinine clearance and Kt/V in peritoneal dialysis: a
      defense of the DOQI document. Dialysis Outcomes Quality Initiative.

PMID- 10357180
TI  - Vaccination for peritoneal dialysis patients.

PMID- 10357181
TI  - Changes in volume of peritoneal mesothelial cells exposed to osmotic stress.
AB  - OBJECTIVE: To evaluate changes in volume of mesothelial cells exposed to
      hypertonic medium and the role of volume regulatory mechanisms in adaptation to
      hyperosmolality. DESIGN: Experiments were performed on primary cultures of human
      peritoneal mesothelial cells. Cell volume was estimated by measuring equilibrated
      (intracellular/extracellular space) 14C-urea in cellular water. Cells in
      monolayers were exposed to hyperosmotic media and changes in cellular water or
      intracellular uptake of 3H-proline were measured. RESULTS: Exposure of
      mesothelial cell monolayers to hyperosmotic media reduced the cell volume; the
      effect was proportional to the osmolality of the medium. Volume of cells exposed
      to medium supplemented with glucose (180 mmol/L) decreased by 26%, p < 0.001,
      after 30 minutes' incubation. Prolonged exposure of mesothelial cells to
      hyperosmotic medium resulted in gradual recovery, after initial decline, of their
      volume. Intracellular uptake of amino acid 3H-proline increased after 240
      minutes' exposure of the mesothelial cells to medium supplemented with glucose
      (90 mmol/L) (+40%, p < 0.05). When cells cultured for 7 days in medium
      supplemented with glucose (45 mmol/L) were exposed to medium with low glucose
      content (5 mmol/L) their volume increased by 17%, p < 0.05. CONCLUSION:
      Mesothelial cells shrink after exposure to hypertonic medium. Increased
      intracellular uptake of amino acids may be one of the regulatory mechanisms that
      ensure subsequent volume increase in these cells. Mesothelial cells chronically
      exposed to hypertonic medium swell after transfer to a medium with physiologic
      osmolality.

PMID- 10357182
TI  - Effect of hypertonic stress on amino acid levels and system A activity in rat
      peritoneal mesothelial cells.
AB  - OBJECTIVE: Peritoneal mesothelial cells (PMC) are exposed to a hypertonic
      environment during peritoneal dialysis. When exposed to a hypertonic medium, many
      types of cells accumulate small osmotically active organic solutes, which are
      called osmolytes, to match the higher external osmolality. However, no
      information has been available concerning the osmolytes in PMC. To investigate
      osmoregulation in rat PMC, the levels of amino acids in the cells and the
      activity of system A, a major neutral amino acid transport, were measured after
      switching to a medium made hypertonic by the addition of NaCl. System A was
      measured by Na+-dependent [14C]-2-methylamino-isobutyric acid (MeAIB) uptake.
      RESULTS: Total amount of 20 amino acids increased from 306 to 757 nmol/mg protein
      after 12 hours of hypertonicity. The amount of neutral amino acids accounted for
      81% of the increase in total amino acids. Glutamine, alanine, glycine, threonine,
      and serine were the major neutral amino acids that accumulated in the hypertonic
      mesothelial cells. The amount of neutral amino acids increased 2.9-fold after 12
      hr of hypertonicity, and decreased thereafter. MeAIB uptake increased 36-fold
      relative to the uptake in isotonic cells after 4-8 hr of hypertonicity. When the
      culture medium was made hypertonic by adding raffinose or glucose, the activity
      of system A was also stimulated (raffinose > glucose > NaCl). System A was
      located on both the apical and basal sides of isotonic PMC, and extracellular
      hypertonicity stimulated the MeAIB uptake on both sides. CONCLUSIONS: These data
      indicate that neutral amino acids and system A transport play an important role
      in early-phase osmoregulation in rat peritoneal mesothelial cells.

PMID- 10357183
TI  - Intraperitoneal hyaluronan production in stable continuous ambulatory peritoneal
      dialysis patients.
AB  - OBJECTIVE: Several cytokines and proteins are excreted intraperitoneally during
      the course of peritonitis and stable states in continuous ambulatory peritoneal
      dialysis (CAPD) patients. Dialysate hyaluronan (HYA) is also regarded as a marker
      of peritoneal healing during bacterial peritonitis. We examined here,
      intraperitoneal HYA production in stable CAPD patients and compared the results
      to those of the peritoneal equilibration test (PET), the length of time on
      dialysis, and other marker proteins. DESIGN: We determined the concentration of
      HYA and other marker proteins in the 4-hour-dwell dialysate at 1-year intervals.
      SETTING: CAPD unit in Hitachi General Hospital. PATIENTS: The subjects were 46
      stable CAPD patients who underwent 104 PETs. RESULTS: A correlation was found
      between the length of time on dialysis and the amount of HYA excretion in the 4
      hr-dwell dialysate (r = 0.403, p < 0.001). A positive but weak correlation was
      found between the dialysate-to-plasma ratio of the creatinine concentration and
      dialysate HYA excretion (r = 0.229, p < 0.05). Seven patients were over the 90th
      percentile in both the concentration of HYA (>349.2 ng/mL) and the amount of HYA
      (>743.6 microg/4-hr dwell). Five patients exceeded 1000 microg of HYA excretion
      in the 4-hr-dwell dialysate, 4 of whom showed an abrupt increase of HYA excretion
      to more than 1000 microg/4-hr dwell, and discontinued CAPD within 6 months due to
      ultrafiltration failure. Two of these 4 patients were diagnosed with sclerosing
      encapsulating peritonitis at autopsy. CONCLUSION: Intraperitoneal HYA production
      increased with both higher permeable membrane and the length of time on CAPD.
      Monitoring of HYA in the peritoneal dialysate may be useful as a marker to assess
      functional and morphological changes in the peritoneum in long-term CAPD
      patients.

PMID- 10357185
TI  - Characterization of subtypes of hypertension in CAPD patients by cyclic guanosine
      monophosphate.
AB  - OBJECTIVE: While most hypertensive patients with end-stage renal disease
      normalize high blood pressure with fluid removal by continuous ambulatory
      peritoneal dialysis (CAPD), there is a significant proportion of CAPD patients
      whose blood pressure can be controlled only by antihypertensive drugs. METHOD AND
      PATIENTS: To study the hypothesis that such patients are still volume overloaded,
      we used plasma cyclic guanosine monophosphate (cGMP) as a marker for hydration
      status. Thirty-two CAPD patients were divided into 3 groups: group 1,
      normotensive patients (n = 12); group 2, hypertensive patients who normalized
      their blood pressure with fluid removal (n = 12); group 3, hypertensive patients
      whose blood pressure was refractory to intensified fluid removal (n = 8).
      RESULTS: Mean cGMP levels were significantly higher in dialysis-sensitive
      hypertension (27 +/- 5 pmol/mL) than in dialysis-refractory hypertension (15 +/-
      2 pmol/mL), or in normotensive patients (13 +/- 4 pmol/mL). Reduction of excess
      fluid in volume overloaded hypertensive CAPD patients resulted in a normalization
      of cGMP levels (14 +/- 8 pmol/mL), but did not affect this volume marker in
      patients with dialysis-resistant hypertension (10 +/- 4 pmol/mL). CONCLUSION:
      Plasma cGMP levels are elevated in volume overload-induced hypertension
      complicating CAPD. Hypertensive CAPD patients whose plasma cGMP levels are within
      normal limits have raised blood pressure refractory to volume removal. Our
      findings are consistent with the hypothesis that inadequate removal of excess
      volume plays a major role in a subset of patients with CAPD hypertension.

PMID- 10357184
TI  - Risk factors influencing the decline of residual renal function in continuous
      ambulatory peritoneal dialysis patients.
AB  - OBJECTIVE: To assess the nature of the decline in residual renal function (RRF)
      after the initiation of peritoneal dialysis, and to identify risk factors
      influencing the preservation of RRF. DESIGN: A retrospective single-center study.
      SETTING: Tertiary medical center. PATIENTS: Eighty patients who were clinically
      stable and had been on continuous ambulatory peritoneal dialysis (CAPD) for a
      minimum of 6 months. MAIN OUTCOME MEASURES: All subjects had at least three
      measurements of RRF, which was calculated as the average of creatinine clearance
      (Ccr) and urea clearance from a 24-hour urine collection. All measurements of RRF
      were plotted on a logarithmic scale and a linear scale against the duration of
      CAPD. Covariables used in the correlation analyses were age, sex, the presence of
      diabetes mellitus, mean blood pressure, mean diastolic blood pressure, hematocrit
      and Ccr at the start of peritoneal dialysis, peritoneal membrane transport
      characteristics by peritoneal equilibration test (PET), and the rate of
      peritonitis. RESULTS: A significant correlation was found between CAPD duration
      and RRF decline represented on a logarithmic scale with a correlation coefficient
      (r) of 0.355 (p < 0.001). In contrast, on a linear scale, the correlation
      coefficient was only 0.273 (p < 0.01). By linear multiple regression analysis,
      the only independent risk factor for the decline of RRF was the rate of
      peritonitis (r = -0.446, p < 0.001). CONCLUSION: These results suggest that RRF
      declines exponentially rather than linearly with time, and that the rate of
      peritonitis is an independent risk factor for the decline of RRF in CAPD
      patients.

PMID- 10357186
TI  - The effect of insulin delivery route on lipoproteins in type I diabetic patients
      on CAPD.
AB  - OBJECTIVE: To evaluate the influence of subcutaneous and intraperitoneal (i.p.)
      insulin on plasma lipoproteins in type I diabetic (IDDM) patients with end-stage
      renal failure (ESRD) treated with continuous ambulatory peritoneal dialysis
      (CAPD). DESIGN: A before-after trial. SETTING: University hospital outpatient
      care. PARTICIPANTS: Eleven IDDM patients with stabilized peritoneal dialysis, age
      42.9 +/- 2.9 (SEM) years and duration of diabetes 31.4 +/- 3.4 years.
      INTERVENTION: Two treatment periods during stabilized CAPD. All patients were
      first treated with subcutaneous and then with i.p. insulin. The studies were
      performed after a median time of 3 months on each treatment. MAIN OUTCOME
      MEASURES: Plasma lipids; apoproteins (Apo) A-I, A-II, and B; high-density
      lipoprotein (HDL) subfractions; glycemic status; and uremic status. RESULTS:
      After changing from subcutaneous insulin to i.p. insulin, plasma HDL cholesterol
      decreased (from 1.29 +/- 0.13 mmol/L to 0.96 +/- 0.06 mmol/L, p < 0.05), and the
      low density to high density lipoprotein (LDL/HDL) cholesterol ratio increased (p
      < 0.05). The HDL cholesterol decreased in both HDL2 and HDL3 fractions, but
      significantly so only in HDL3 (p < 0.01). ApoA-I (p < 0.05) decreased while the
      ApoB/ApoA-I ratio (p < 0.01) and the ApoA-I/HDL-cholesterol ratio (p < 0.01)
      increased during i.p. insulin therapy. Intraperitoneal insulin resulted in
      significantly better glycemic control than subcutaneous insulin (p < 0.01).
      CONCLUSIONS: In diabetic patients on CAPD therapy, i.p. insulin, although
      inducing better glycemic control than subcutaneous insulin, was associated with
      lowered plasma HDL cholesterol and ApoA-I levels. The atherogenic potential is
      probably less than expected as the relative particle size of HDL remained
      unchanged.

PMID- 10357188
TI  - Sclerosing peritonitis and systemic lupus erythematosus: a report of two cases.
AB  - OBJECTIVE: To heighten the awareness of a possible association of sclerosing
      peritonitis in patients with systemic lupus erythematosus (SLE). METHODS AND
      RESULTS: Over the course of 17 years (from January 1981 to December 1997), 371
      patients were treated with continuous ambulatory peritoneal dialysis (CAPD) at
      Rush-Presbyterian-St Lukes Medical Center. The patients were followed on CAPD for
      an average of 25 +/- 21 (SD) months with a median of 19 months (range 0.2-115
      months). During this time only 2 (0.5%) patients were diagnosed with sclerosing
      peritonitis, and both had SLE with ongoing evidence of active disease while on
      CAPD. With a total of 26 SLE patients being treated with CAPD during the
      observation period, the prevalence of sclerosing peritonitis can be said to be as
      high as 8% in this patient population. CONCLUSION: These cases suggest that
      autoimmune diseases, such as SLE, that are well known to cause immune-mediated
      serositis may represent an additional factor predisposing to the development of
      sclerosing peritonitis in patients treated with CAPD.

PMID- 10357187
TI  - Adipose tissue fatty acid composition, serum lipids, and serum alpha-tocopherol
      in continuous ambulatory peritoneal dialysis patients living on the island of
      Crete.
AB  - OBJECTIVE: A pilot study to explore diet-related atherogenic patterns in
      continuous ambulatory peritoneal dialysis (CAPD) patients on the island of Crete.
      Cretans are well known for their high olive consumption and low atherosclerotic
      heart disease mortality, in general. DESIGN: Case-control study. SETTING: This
      was a hospital-based study initiated in 1991. Catchment area was the island of
      Crete, Greece. PARTICIPANTS: Seventeen patients admitted for treatment to the
      General State Hospital of Rethimnon. Controls were selected from the general
      population of the island and consisted of a random sample of 27 subjects from a
      total of 168 healthy subjects who visited the Preventive Medicine Clinic of the
      University Hospital for routine check-up. The control group was age- and sex
      matched with patients. Both CAPD patients and controls had been residents of
      Crete for at least the last 10 years. MAIN OUTCOME MEASURES: Adipose tissue was
      aspirated, and a 12-hour fasting blood sample was collected for determination of
      serum lipid parameters and serum alpha-tocopherol levels; dietary data from a 3
      day recall were recorded. RESULTS: No significant differences between the two
      groups were observed with respect to the mean macronutrient intake. The mean
      levels of serum triglycerides (p = 0.016) and serum alpha-tocopherol (p = 0.001)
      were significantly higher in CAPD patients compared to controls. Mean levels of
      total serum cholesterol, high density lipoprotein (HDL) cholesterol, and low
      density lipoprotein (LDL) cholesterol were not significantly different. In CAPD
      patients the mean total percentage of monounsaturated fatty acids (MUFA) was
      significantly higher (p = 0.006) than in controls. The mean total percentage of
      saturated fatty acids (p = 0.004), along with the mean percentage of omega-6 (p =
      0.002), the mean value of the ratio omega-6/omega-3 (p < 0.0001), and the
      percentage of linoleic acid (p = 0.001) were significantly lower in CAPD patients
      than in the controls. Among subjects with higher levels of MUFA in the adipose
      tissue, the CAPD patients were twice as likely to have high serum alpha
      tocopherol (p < 0.001), and 2.6 times more likely to be in high risk of high
      total cholesterol (TC)/HDL (p = 0.08) compared to the controls. However, CAPD
      patients with high levels of MUFA in the adipose tissue (above the average of
      65%) were unlikely [odds ratio (OR) = 0.001, p < 0.001] to be at risk of high
      TC/HDL (above the average of 4.1), and maybe unlikely (OR = 0.08, but p = 0.1) to
      have low serum alpha-tocopherol, when compared with the CAPD patients with low
      levels of MUFA. CAPD patients with high TC/HDL are 0.15 times less likely (p =
      0.1) to have high levels of serum alpha-tocopherol compared to those with low
      TC/HDL. CONCLUSION: Cretan CAPD patients demonstrate an interesting profile
      consisting of unexpectedly positive aspects when atherogenesis-related factors
      such as those of adipose tissue fatty acid composition, serum lipids, and serum
      antioxidant alpha-tocopherol are considered.

PMID- 10357189
TI  - Gender differences in normalized clearances in CAPD: role of body size and
      normalizing parameters.
AB  - OBJECTIVE: To compare raw (not normalized) and normalized urea and creatinine
      clearances between women and men on continuous ambulatory peritoneal dialysis
      (CAPD). To study whether potential gender differences are due to the
      normalization process. DESIGN: Retrospective analysis of clearance studies.
      SETTING: Dialysis units of four academic medical centers. PARTICIPANTS: The study
      included 302 subjects (135 women and 167 men) on CAPD with four daily exchanges
      and a 2-L exchange volume. INTERVENTION: Measurement of urea and creatinine
      clearances (261 in women, 352 in men) by standard methods. Body water (the volume
      of distribution, V, for both urea and creatinine) was estimated by the Watson
      anthropometric formulas. MAIN OUTCOME MEASURES: Comparison of raw and normalized
      clearances between women and men. Urea clearance was normalized by V (Kt/Vur),
      while creatinine clearances was normalized by both V (Kt/Vcr) and body surface
      area (BSA) (Ccr). RESULTS: Mean values of weekly total (peritoneal plus renal)
      raw clearances were higher in men (urea clearance: women 67.1 L, men 77.4 L; Ccr:
      women 61.7 L, men 78.3 L). Raw renal clearances were higher in men, while raw
      peritoneal clearances were comparable. Mean weekly total Kt/Vur was higher in
      women (2.19 vs 1.94 in men), mean weekly total Kt/Vcr did not differ between the
      genders (women 2.01, men 1.95), while mean weekly Ccr was higher in men (73.0 vs
      64.7 L/1.73 m2 in women). When clearances differed, the differences were
      significant at p < 0.001. Men had greater height and weight, while women had
      greater body mass index. On the average, V in men exceeded V in women by 31%,
      while BSA in men exceeded BSA in women by only 12%. CONCLUSIONS: Normalization of
      clearances by V creates relatively higher clearance values in women, while
      normalization by BSA creates relatively higher clearance values in men. Thus the
      normalization process may create artificial differences in the normalized
      clearances between genders.

PMID- 10357190
TI  - Laparoscopic approach for dysfunctional Tenckhoff catheters.

PMID- 10357191
TI  - Peritoneal dialysis in Poland. Results from the national survey, 1995-1996.

PMID- 10357192
TI  - Fasting plasma amino acids are not normalized by 12-month amino acid-based
      dialysate in CAPD patients.

PMID- 10357193
TI  - Inguinal abscess in a CAPD patient secondary to inguinal hernia and repeated
      episodes of peritonitis: a case report.

PMID- 10357194
TI  - Infusion of dialysis solution using an automatic infusion accelerator.

PMID- 10357195
TI  - Rhabdomyolysis due to bezafibrate in CAPD patients. A role for dihydropyridine
      drugs?

PMID- 10357196
TI  - Fungal peritonitis caused by Candida parapsilosis and subsequently Rhodotorula
      glutinis in a CAPD patient.

PMID- 10357197
TI  - Melioidosis presenting as peritoneal dialysis-related peritonitis. What about the
      flower pot?

PMID- 10357198
TI  - Who is going to benefit from nystatin prophylaxis for fungal peritonitis
      complicating CAPD?

PMID- 10357199
TI  - Literature.

PMID- 10357200
TI  - A novel method for measuring CTL and NK cell-mediated cytotoxicity using annexin
      V and two-color flow cytometry.
AB  - An assay based on two-color flow cytometry has been developed to measure CTL and
      NK cell-mediated cytotoxicity. After effector/target cells are incubated
      together, CTL or NK populations are stained with an effector cell specific PE
      conjugated mAb. Subsequently, annexin V-FITC binds to cells expressing
      phosphatidylserine (an early marker of apoptosis) on the cell surface. Target
      cells are gated upon as PE-negative and quantified with respect to their annexin
      V positivity. The shift from annexin Vneg to annexin Vhi is a discrete event such
      that all target cells fall within discernible populations with respect to annexin
      V. There is a strong correlation between cytotoxicity measured with our assay and
      a standard 51Cr release assay (r2 = 0.989). The PE/annexin V assay shows
      increased sensitivity at early timepoints after target/effector cell mixing. In
      addition, this method allows for analysis of target cells at the single cell
      level. Therefore, we have described a promising new technique to measure in vitro
      cell-mediated cytotoxicity. It avoids the potential difficulties of working with
      radioactive isotopes, and offers increased sensitivity and versatility.

PMID- 10357201
TI  - Immunochemical extraction and detection of LSD in whole blood.
AB  - Polyclonal antibodies raised against the hallucinogenic drug, lysergic acid
      diethylamide (LSD), were used to detect and extract drug from whole blood
      samples. An indirect ELISA was used to detect as little as 1 pg of total drug in
      25 microl blood. The limit of detection of the immunoassay, calculated from the
      mean - 3 SD was 39 pg/ml. The analytical recovery of LSD (2.5-0.2 ng/ml) from
      whole blood was 102-113%. Within-run CVs for LSD spiked in blood at 1.25, 0.16
      and 0.04 ng/ml were 5.6, 3.1, and 8.9%, respectively (n = 4). There was an
      overall decrease in precision when whole blood was used in place of urine, due to
      the increased complexity of the matrix. However, using this technique LSD was
      calibrated in blood in the sub-ng/ml region of forensic interest. Immunoaffinity
      extraction was used to isolate LSD from blood and urine samples. The affinity
      support was prepared by covalently attaching anti-LSD antibodies to Protein A
      coated agarose beads. No pre-treatment of the sample was required other than the
      addition of neutral buffer. Sub-ng/ml concentrations of LSD were routinely
      extracted from blood and urine samples with greater than 80% recovery of drug.
      This technique, which could be used to extract LSD from blood and urine samples
      prior to confirmatory drug analysis, could be completed in about 10 min.

PMID- 10357202
TI  - Production of secreted, soluble human two-domain CD4 protein in Escherichia coli.
AB  - The two-domain form of recombinant soluble human CD4 (rsCD4(183)) has been used
      for structural studies and to probe the interaction of CD4 with its ligands.
      rsCD4(183) has generally been produced in Escherichia coli in the form of
      inclusion bodies. The generation of conformationally native protein from these
      inclusion bodies is a time-consuming and inefficient process, requiring a
      refolding step. Here, we describe a procedure for producing 2-4 mg of secreted,
      conformationally native rsCD4(183) per liter of E. coli, completely bypassing the
      requirement for protein refolding in vitro. Furthermore, the yield of active
      protein is comparable to that reported for expression systems that generate
      inclusion bodies.

PMID- 10357203
TI  - An inducible cell model for studies of V(D)J recombinational control.
AB  - Antigen receptor gene assembly is controlled by enhancer-directed changes in the
      accessibility of chromosomal gene segments to V(D)J recombinase. To dissect
      mechanisms that regulate rearrangement efficiencies, we developed a cell system
      (TDR19) in which recombination activating gene (RAG) expression is repressed by
      tetracycline. Under conditions of RAG repression, recombination substrates were
      consistently integrated into the TDR19 genome in an unrearranged form. Subsequent
      rearrangement of chromosomal substrates containing a transcriptional enhancer
      correlated inversely with tetracycline concentrations. Together, these features
      underscore the utility of TDR19 as a cell model for defining the molecular
      determinants of V(D)J recombinational accessibility.

PMID- 10357204
TI  - Fetal fibronectin as a marker for an imminent (preterm) delivery. A new technique
      using the glycoprotein lectin immunosorbent assay.
AB  - We have developed a new 'glycoprotein lectin immunosorbent assay' (GLIA) which
      permits the obstetrician to identify accurately pregnant women at risk for
      preterm delivery. This GLIA uses two lectins for the quantitative detection of
      glycosylation variants of fibronectins, namely, Maackia amurensis lectin (MAA)
      for the detection of fetal fibronectin (fFN), and Sambucus nigra lectin
      (Elderberry bark lectin; SNA). Fibronectin was quantitated in cervicovaginal
      secretions, amniotic fluid, and plasma of pregnant women. Detection of fFN in
      cervicovaginal secretions was considered to indicate a high risk of imminent
      delivery. The results were as follows: (1) The GLIA could differentiate between
      pregnant women after the onset of labour and/or with rupture of membranes and
      women without any signs of an imminent delivery (sensitivity 94%, specificity
      96%, p < 0.001). (2) Differentiation was possible between asymptomatic pregnant
      women delivering within 10 days of sampling or after more than 10 days
      (sensitivity 93%, specificity 99%; p < 0.001). (3) If fFN was present in the
      cervicovaginal secretions, delivery occurred within 10 days of sampling
      irrespective of preterm delivery or delivery at term (p < 0.001). Thus, this GLIA
      is a useful assay for identifying those asymptomatic pregnant women who will
      deliver within 10 days of sampling.

PMID- 10357205
TI  - Method for the preparation of bispecific F(ab')2mu fragments from mouse
      monoclonal antibodies of the immunoglobulin M class and characterization of the
      fragments.
AB  - Bispecific F(ab')2mu fragments (Bs F(ab')2mu) binding simultaneously both sialyl
      Lewis A antigen (SLA) and human carcinoembryonic antigen (CEA) were prepared by
      disulfide bond exchange between F(ab')2mu fragments derived from IgM monoclonal
      antibodies (mAbs) against SLA and CEA, and were purified to homogeneity in a one
      step procedure of hydrophobic interaction HPLC. The final yield of Bs F(ab')2mu
      from F(ab')2mu fragments was 70-78%, and the purity was higher than 98%. The
      immunoreactivities of the Bs F(ab')2mu fragments against SLA and CEA were almost
      the same as those of the respective parental F(ab')2mu fragments. The
      dissociation constant (0.17 microM) of the Bs F(ab')2mu for CEA was in good
      agreement with that of the parental F(ab')2mu fragments. Although the number of
      applications of IgM mAbs is restricted because of the large molecular mass and
      low solubility, Bs F(ab')2mu might, nevertheless, be a useful tool for
      immunotherapy and immunodiagnosis.

PMID- 10357206
TI  - Efficient generation of monoclonal antibodies against surface-expressed proteins
      by hyperexpression in rodent cells.
AB  - The generation of antibodies is one of the first requirements in the
      characterisation of a newly cloned protein. However, this requires expression and
      purification of the protein in sufficient yield and purity for immunisation of
      animals and screening of fusion wells. Even with the development of highly
      efficient protocols based upon incorporation of specific peptide tags, this can
      be a tedious and time-consuming process. In an effort to improve the speed and
      efficiency of obtaining antibodies reactive with newly cloned proteins we have
      developed an approach based upon the expression of the protein at high level in
      cell lines originating from the species to be used for immunisation. To
      illustrate this approach we describe the generation of antibodies against two
      recently cloned proteins that are normally expressed at the membrane, the rat and
      mouse analogues of human decay accelerating factor (DAF; CD55). However, the
      strategy is applicable not only to membrane proteins but also to other proteins
      which can be expressed on the cell membrane by incorporating at the carboxy
      terminus the signal sequence for glycosyl phosphatidylinositol (GPI) anchor
      addition derived from DAF or another GPI-anchored protein. The strategy also
      permits rapid and efficient screening using flow cytometry on expressing cells.

PMID- 10357207
TI  - Semiquantitation of human chemokine mRNA levels with a newly constructed
      multispecific competitor fragment.
AB  - Chemokines are a group of inducible, locally acting proinflammatory cytokines
      which have been implicated in the pathogenesis of a variety of diseases.
      Important members of the group include monocyte chemoattractant protein (MCP)-1, 
      2, -3, macrophage inhibitory protein (MIP)-1alpha, -1beta and RANTES (regulated
      upon activation, normal T expressed and secreted). To facilitate further
      investigation of the human chemokines, we have constructed a novel multispecific
      competitor fragment containing primer binding sites for the CC-chemokines MCP-1,
      MCP-2, MCP-3, MIP-1alpha, MIP-1beta and RANTES, the CXC-chemokines MIP-2alpha,
      MIP-2beta as well as for the housekeeping gene beta-actin. Using this competitor
      fragment we can demonstrate reliable semiquantitation of reverse transcribed
      chemokine mRNAs. The assay should be useful for further studies, in particular
      for the semiquantitation of chemokine mRNA species from small cell or tissue
      specimens.

PMID- 10357208
TI  - Brefeldin A, but not monensin, completely blocks CD69 expression on mouse
      lymphocytes: efficacy of inhibitors of protein secretion in protocols for
      intracellular cytokine staining by flow cytometry.
AB  - Flow cytometry is increasingly used for cytokine detection where it serves to
      complement ELISA (enzyme-linked immunosorbent assay) and ELISPOT assays. Since it
      is possible to stain both extracellular epitopes and intracellular cytokines on
      the same cells, this is a powerful technique for analysing cytokine expression in
      defined cell populations. However unstimulated cells do not express cytokines.
      Thus, appropriate stimulation is a prerequisite for studying cytokine expression.
      Here phorbol 12-myristate 13-acetate (PMA)/ionomycin in vitro stimulation has
      been applied. In order to accumulate the cytokines within the cells, protein
      secretion needs to be inhibited, by the addition of reagents that inhibit protein
      secretion during the stimulation. The two most widely used reagents are monensin
      and brefeldin A (BFA). These reagents differ somewhat in their mode of action,
      which might explain their different effects. Monensin is an inhibitor of trans
      Golgi function, while BFA inhibits protein transport between the endoplasmic
      reticulum (ER) and the Golgi. CD69, a very early activation marker on lymphocytes
      and neutrophils, was monitored in order to measure the efficacy of the protein
      secretion inhibition. Here we report that: (a) BFA, but not Monensin, is able to
      completely block extracellular CD69 expression on mice splenocytes after in vitro
      stimulation with PMA/ionomycin; (b) Monensin is more toxic than BFA and increases
      the relative amount of CD4+ cells due to a more profound increase in dead cells
      in the CD4- population; (c) CD69 is a useful marker when setting up intracellular
      staining of cytokines for flow cytometry.

PMID- 10357209
TI  - Immunomagnetic concentration of antigens and detection based on a scanning force
      microscopic immunoassay.
AB  - Scanning Force Microscopy has already been shown to be a convenient and rapid
      method for sensitive antigen detection and quantification. Here, we describe
      different improvement steps brought to a TSH Scanning Force Microscopic
      ImmunoAssay (SFMIA), each of them aiming to solve a previous limitation of the
      solid phase test format and leading to a significant sensitivity enhancement.
      First, superparamagnetic nanoparticles conjugated to monoclonal anti alphaTSH
      antibodies were used for the specific TSH capture step. Their magnetic properties
      allowed easy separation of the complexes obtained from relatively large reaction
      volumes by application of a High Gradient Magnetic Field System. As a
      consequence, complex formation could proceed in a stirred solution, which greatly
      enhances binding rates compared to previous 'static' conditions of solid-phase
      reactions. It was established that, despite their small size, magnetic complexes
      could be moved over short distances by a NdFeB magnet magnetic field. This
      property was exploited to overcome diffusion barrier and boundary layer
      constraints and to drive magnetic complexes through the liquid, towards anti
      betaTSH antibodies immobilized on silica wafers. Finally, we significantly
      increased the complex number/surface area by a stepwise reduction of the
      biospecific solid phase area. The proposed steps permitted a 3-fold improvement
      in the TSH SFMIA dynamic range. Moreover, as little as 0.02 pg/ml (0.1 nIU/ml or
      0.8 amol/ml) of TSH could be detected using 1 ml sample volumes. This is over 100
      times more sensitive than the current performance of commercialized automated
      systems.

PMID- 10357210
TI  - Mapping of the minimal domain encoding a conformational epitope by lambda phage
      surface display: factor VIII inhibitor antibodies from haemophilia A patients.
AB  - Haemophilia A patients who receive repeated transfusion of fVIII concentrates
      often develop inhibitor alloantibodies, resulting in reduced efficacy of the
      therapy. Determination of fVIII epitopes for the alloantibodies is essential for
      an understanding of their inhibitory effect on blood coagulation. Random
      fragments of fVIII displayed on lambda phage particles were selected using two
      patient plasmas immobilized onto the surface of a microtiter plate. A set of
      clones defined the minimal domain that consisted of 157 amino acid residues
      including cysteine at both boundaries. The minimal domain absorbed most of the
      binding activities of the plasmas to fVIII, suggesting that the domain contains a
      major determinant for the plasmas. Site-directed mutagenesis and chemical
      denaturation of the domain confirmed that a tertiary structure formed by the
      disulfide bridge was recognized by the antibodies. The epitope domain defined
      overlaps with fVIII binding sites to vWf and phospholipid, and may play an
      important role in blood coagulation. Thus, the bacteriophage lambda surface
      display may be useful for mapping the minimal folding domain of various protein
      antigens that contain a conformational epitope.

PMID- 10357211
TI  - Selection and characterisation of membranes by means of an immunofiltration
      assay. Application to the rapid and sensitive determination of the insecticide
      carbaryl.
AB  - The characterisation and selection of membranes by means of an immunofiltration
      assay is described. The chemical composition of the membranes was: nitro
      cellulose, polyamide, polyvinylidene difluoride, polyethersulfone, cellulose
      acetate, regenerated cellulose, cellulose nitrate, and glass fibre. In order to
      characterise the membranes according to their binding capacity, immobilisation
      stability, sensitivity and hydrodynamic properties, two basic immunofiltration
      formats were performed. In both formats, enzyme label (horseradish peroxidase,
      HRP) and colorimetric detection were used. In the immobilised antibody format,
      three monoclonal antibodies (mAb) against the insecticide carbaryl were
      immobilised on the membranes by passive adsorption. In the immobilised hapten
      format, two haptens conjugated to bovine serum albumin (BSA) were immobilised.
      Immobilon-P was the best membrane with regard to the characterisation criteria
      and permitted the filtration of large volume (5.0 ml) through the membrane
      without release of the receptor. The immobilisation of the receptor (antibody or
      haptenic conjugate) was pH dependent. Good results with regard to mAb-antigen
      recognition, were obtained using 50 mM carbonate/bicarbonate buffer, pH 9.6.
      However, the most sensitive assays were achieved using, 10 mM phosphate buffer,
      137 mM NaCl, 2.7 mM KCI (PBS), pH 7.4 as immobilisation buffer. Furthermore, all
      these results permit the choice of the best membrane for the rapid and sensitive
      determination of carbaryl. This study will assist the development of dipsticks,
      immunoelectrodes, membrane-based immunoreactors or immunoconcentration devices
      that are based on the use of membranes as immunosupports.

PMID- 10357213
TI  - In vivo biotinylated recombinant antibodies: high efficiency of labelling and
      application to the cloning of active anti-human IgG1 Fab fragments.
AB  - In vivo biotinylation of antibody fragments with a gene fusion approach is a
      realistic alternative to conventional in vitro chemical labelling. We have
      previously reported the construction of a vector system suitable for the
      bacterial expression of the binding fragment of antibody (Fab) genetically linked
      to the C-terminal domain of Escherichia Coli biotin carboxy carrier protein
      (BCCP*). A minor fraction of the expressed hybrids was biotinylated in vivo and
      therefore able to interact with streptavidin. We now show that the large majority
      of bacterially-expressed Fab-BCCP* fusions are labelled with biotin when plasmid
      encoded biotin holoenzyme synthetase (BirA) is co-expressed. The yield of
      biotinylated Fab is maximal when overexpression of BirA is driven by a second
      compatible plasmid. We took advantage of this property to develop a novel filter
      assay for the rapid identification of recombinant Fab reacting with
      immunoglobulin. Starting with total RNA of two newly established murine hybridoma
      cell lines producing anti-human IgG1 antibodies, we selected in a single
      experiment the bacterial clones that expressed in vivo biotinylated anti-IgG1
      Fab. Sequence analysis of the isolated Fabs showed that they did not derive from
      a single B clone. In addition, we found that these recombinant Fabs labelled with
      biotin in vivo are useful for the specific detection of human IgG1 by a solid
      phase immunoassay.

PMID- 10357212
TI  - A new isolation method for rat intraepithelial lymphocytes.
AB  - Intraepithelial lymphocytes (IELs) play critical roles in gut immunity. In mice,
      gammadelta T cells are a large component of the IEL population. In the rat,
      gammadelta IELs are reportedly much less common, but technical issues suggest
      that previous analyses should be interpreted cautiously. The study of IELs in
      rats has been impeded by isolation procedures that are lengthy and complex,
      leading to small cell yields. For this reason, it is possible that rat IELs
      analyzed in previous studies have not been representative of the entire IEL
      compartment. We report a new method for the isolation of rat IELs that is based
      on the selective removal of intestinal epithelial cells under conditions that
      leave the basement membrane undisturbed. The method is rapid and requires neither
      enzymatic digestion, nor surgical removal of Peyer's patches, nor vigorous
      mechanical manipulation of the intestine. The yield of rat IELs using this method
      is 5- to 10-fold greater than that reported for other methods. Morphological and
      phenotypic analyses demonstrated that the purified cell population is comprised
      of IELs and is not contaminated with lamina propria or Peyer's patch lymphocytes.
      Phenotypic analysis revealed five major subsets of IELs based on differential
      cell surface expression of CD4, CD8, and alphabeta T cell receptor (TcR). Among
      the alphabetaTcR- cells was a population of gammadelta T cells present at levels
      not previously detected. The isolation of IEL sub-populations using this
      methodology should facilitate studies of the function of these cells in gut
      immunity.

PMID- 10357214
TI  - Fine mapping of the binding sites of monoclonal antibodies raised against the Pk
      tag.
AB  - The monoclonal antibody (mAb) SV5-Pk is used widely in a variety of procedures to
      detect recombinant proteins tagged with the Pk tag, a 14 amino acid sequence
      derived from the P and V proteins of the paramyxovirus Simian Virus 5. Here we
      report on the isolation and characterisation of four additional SV5-Pk mAbs
      (termed SV5-Pk2 to 5) that bind the Pk tag. All the SV5-Pk mAbs can detect Pk
      tagged recombinant proteins in a variety of immunological procedures, including
      ELISA and immunofluorescence. Using SPOT technology, the minimal binding epitope
      of each SV5-Pk mAb was defined by one-sided terminal truncation analysis from
      either the amino- or carboxy-ends of the Pk peptide. Each mAb recognises slightly
      different epitopes within the Pk tag, ranging from 5 to 9 amino acids in length.
      The equilibrium dissociation constants (Kd) of the mAbs, as measured by surface
      plasmon resonance, ranged from approximately 20 to 60 pmol. Cysteine scanner
      mutations throughout the Pk tag revealed that some amino acids within the minimal
      binding epitopes were critical for mAb binding, while others could readily be
      substituted with little or no effect on antibody binding. The development of the
      Pk tag as a spacer arm for site-directed chemical coupling, and the use of the
      mAbs to monitor purification and coupling procedures, is discussed.

PMID- 10357215
TI  - T cell activation by monoclonal antibodies bound to tumor cells by a cell surface
      displayed single-chain antibody.
AB  - Tumor cells often lack the costimulatory molecules necessary for T cell
      activation. However, the transformation of cells with more than one stimulatory
      molecule is a difficult procedure. We therefore developed a retroviral vector for
      the expression of a cell membrane anchored single-chain antibody fragment (scFv)
      directed against the hapten 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one (phOx).
      Proteins and peptides can be readily modified with this hapten, thus, enabling
      them to be bound to cells with the cell surface displayed anti-phOx scFv. To test
      combinations of surface-bound stimulatory molecules on T cell activation, SK
      Mel63 human melanoma cells expressing the membrane anchored anti-phOx scFv were
      incubated with phOx-labeled mAbs against CD3, CD28 and CD5. Cells presenting a
      given mixture of modified anti-CD3 and anti-CD28 molecules stimulated T cell
      activation better than any single antibody and a given mixture of anti-CD3, anti
      CD28 and anti-CD5 provided a stimulatory response higher than the best double
      combination. However, the relative concentrations are very important and must be
      carefully chosen. Concentrations of antibodies giving good T cell responses when
      used alone can block synergistic effects.

PMID- 10357216
TI  - A specific and sensitive ELISA for laminin 5.
AB  - A sandwich ELISA for laminin 5 was developed by using two monoclonal antibodies
      specific for human laminin 5, basement membrane (BM)165 and 6F12, which were
      raised against the laminin alpha3 chain and the laminin beta3 chain,
      respectively. Laminin 5 was purified from squamous carcinoma cell (SCC) 25
      conditioned medium, using 6F12-conjugated Sepharose. This preparation was used as
      the standard for the ELISA. This sandwich ELISA was sensitive enough to detect
      reproducibly as little as 125 pg of laminin 5. This assay could detect laminin 5
      produced by human keratinocytes but not other laminins produced by human
      fibroblasts. A portion of the laminin 5 that was secreted by the keratinocytes
      was deposited around the cells, and the rest was released into the medium. To
      measure total synthesized laminin 5, the intracellular and deposited laminin 5
      was solubilized by treatment with a mixture of several kinds of detergents that
      did not interfere with the sandwich ELISA, and the laminin in both the culture
      medium and the solubilized cell layer was quantified. The amount of laminin 5
      synthesis by keratinocytes depended on the cell number, the duration of culture,
      and the extracellular matrix proteins on which keratinocytes were plated.

PMID- 10357217
TI  - Open sandwich ELISA with V(H)-/V(L)-alkaline phosphatase fusion proteins.
AB  - The Sandwich ELISA is a widely used technique to measure antigen concentration.
      Recently, a novel ELISA based on the interchain interaction of separated V(H) and
      V(L) chains from a single antibody variable region (Fv) was proposed (Open
      Sandwich ELISA). Since it employs a single antibody recognizing one epitope, the
      assay requires, in essence, only one cycle of incubation and washing steps. To
      demonstrate this directly, we have constructed a recombinant gene fusion encoding
      the V(H) chain of an anti-hen egg lysozyme (HEL) antibody HyHEL-10 and
      Escherichia coli alkaline phosphatase (V(H)-PhoA). The same type of gene fusion
      using V(L) chain instead of V(H) chain (V(L)-PhoA) was also constructed and the
      proteins were obtained with an E. coli expression/secretion system. Open Sandwich
      ELISAs were performed using microtiter plates with immobilized V(L) or V(H)
      fragment, and V(H)-PhoA or V(L)-PhoA, respectively, as the detection reagent
      which was simultaneously added to each well with samples. As a result, HEL
      concentrations in the samples were determined after one round of incubation and
      washing steps, with a signal generated in a direct relationship to the
      concentration of HEL added to the reaction mixture. The minimum detectable HEL
      concentration was approximately 10 ng/ml, which was almost equal to the value
      previously obtained with plate-immobilized V(L) and V(H) fragment displayed on
      M13 phage. When the active-site mutant V(H)-PhoA(D101S) was employed instead of
      V(H)-PhoA and reacted at an optimum pH of 10, a significant enhancement in signal
      was attained.

PMID- 10357218
TI  - Lymphoid cell apoptosis induced by trophoblastic cells: a model of active foeto
      placental tolerance.
AB  - To test the hypothesis that CD95-L (Fas-L) present on trophoblastic cells plays a
      part in establishing foeto-placental tolerance by inducing apoptosis of immune
      defence cells, we cocultured trophoblasts with lymphoid cells and scored the
      frequency of cell death in these cultures. We prepared human trophoblastic cells
      from term placentas removed by C-section and placed them in culture for 48 h
      before introducing the lymphoid cells. We added Jurkat cells, a CD3 + lymphoid
      cell line, or purified T cells from human blood to the cultured trophoblasts and
      monitored apoptosis by electron microscopy and flow cytometry after TUNEL or
      annexin V labelling. The frequency of cell death in the CD3 + cell population was
      higher when the lymphoid cells were cocultured with trophoblastic cells than when
      they were cultured alone. This frequency increased with time but was reduced when
      anti-CD95-L antibodies were added to the culture medium. Cell death was less
      frequent in the lymphoid cell population when trophoblasts were replaced with
      human fibroblasts not expressing CD95-L.

PMID- 10357219
TI  - Monoclonal anti-idiotype antibody mimicking the pesticide binding site of
      cutinase: potential for broad specificity organophosphate recognition.
AB  - An anti-idiotype monoclonal antibody (Mab) able to bind the organophosphate
      pesticides, chlorfenvinphos (CFV), ethyl paraoxon, tetrachlorfenvinphos and
      demeton-s-methyl, has been produced using as immunogen a Mab which binds to the
      active site of cutinase. The principle of using an anti-idiotype antibody as the
      mimic of a site on a protein able to bind a group of ligands has, therefore, been
      demonstrated, and may have implications for future research on broad specificity
      immunoanalysis of groups of compounds.

PMID- 10357220
TI  - Frequency of clonally expanded T cells evaluated by PCR from a single cell.
AB  - In analyses of antigen-specific immune responses, it is essential to estimate the
      frequency of individual T cell clonotypes. This frequency has been estimated,
      however, only indirectly by the frequency of T cell receptor (TCR) mRNA. We have
      developed a method to determine T cell frequency directly by cell count using
      reverse transcription polymerase chain reaction (RT-PCR) amplification of TCR
      beta genes from single cell-derived cDNA (single cell PCR). In a study of
      clinical samples, the frequency of clonally expanded T cells estimated by TCR
      frequency analysis was found to be higher than that by single cell PCR. Single
      cell PCR can estimate T cell frequency accurately, as it is not affected by
      skewed PCR amplification or different TCR mRNA expressions in individual T cells.

PMID- 10357221
TI  - On the evolution of ligands: did peptides functionally precede metals and small
      organic molecules?

PMID- 10357222
TI  - Introduction: molecular mechanisms of memory formation--from receptor activation
      to synaptic changes.

PMID- 10357223
TI  - The role of Ca2+/calmodulin-stimulable adenylyl cyclases as molecular coincidence
      detectors in memory formation.
AB  - Evidence from systems as diverse as mollusks, insects and mammals has revealed
      that adenylyl cyclase, cyclic adenosine 3',5'-monophosphate (cAMP) cascade, cAMP
      dependent protein kinases and their substrates are required for the cellular
      events underlying the short-term and long-term forms of memory. In Aplysia and
      Drosophila models, the coincident activation of independent paths converge to
      produce a synergistic activation of Ca2+/calmodulin-stimulable adenylyl cyclase,
      thereby enhancing the cAMP level that appears as the primary mediator of
      downstream events that strengthen enduring memory. In mammals, in which long-term
      memories require hippocampal function, our understanding of the role of adenylyl
      cyclases is still fragmentary. Of the differently regulated isoforms present in
      the hippocampus, the susceptibility of type 1 and type 8 to stimulation by the
      complex Ca2+/calmodulin and their expression in the hippocampus suggest a role
      for these two isoforms as a molecular coincidence device for hippocampus-related
      memory function. Here, we review the key features of Ca2+/calmodulin stimulable
      adenylyl cyclases, as well as the involvement of cAMP-regulated signaling pathway
      in the processes of learning and memory.

PMID- 10357224
TI  - Protein kinases: which one is the memory molecule?
AB  - Encoding of new experiences is likely to induce activity-dependent modifications
      in the brain. Studies in organisms far apart on the phylogenetic scale have shown
      that similar, sometimes identical, signal transduction pathways subserve
      plasticity in neuronal systems, and they may play pivotal roles in the formation
      of long-term memories. It has become evident that
      phosphorylation/dephosphorylation reactions are critical for the initiation of
      cellular mechanisms that embody, retain and modify information in neural
      circuits. Although physiological investigations on synaptic plasticity have had a
      major impact, we have concentrated our review on behavioural studies that provide
      direct or indirect evidence for a role of kinases in mechanisms underlying memory
      formation. From these, it appears that the learning event induces activation of a
      variety of kinases with specific time courses. For instance, the
      calcium/calmodulin-dependent protein kinase II seems to participate in an early
      phase of memory formation. Apparently, activation of both protein tyrosine
      kinases and mitogen-activated protein kinases is required for much longer and may
      thus have a particular function during transformation from short-term into long
      term memory. Quite different time courses appear for protein kinase C (PKC) and
      protein kinase A (PKA), which may function at two different time points, shortly
      after training and again much later. This suggests that PKC and PKA might play a
      role at early and late stages of memory formation. However, we have considered
      some examples showing that these signalling pathways do not function in isolation
      but rather interact in an intricate intracellular network. This is indicative of
      a more complex contribution of each kinase to the fine tuning of encoding and
      information processing. To decipher this complexity, pharmacological, biochemical
      and genetic investigations are more than ever necessary to unravel the role of
      each kinase in the syntax of learning and memory formation.

PMID- 10357225
TI  - If phosphatases go up, memory goes down.
AB  - Previous work has provided conclusive support for a role of various protein
      kinases in processes underlying learning and memory formation. While these
      processes are not yet established in full detail, it is interesting to entertain
      the idea of protein phosphatases being involved in such mechanisms as well.
      Recent advances in this respect have provided preliminary support of this view.
      From the pharmacological as well as the transgenic analysis, it appears that
      especially the calcineurin/inhibitor-1 cascade plays an important role in the
      transition of intermediate-term into long-term memory formation.

PMID- 10357226
TI  - CREB: a message to remember.
AB  - The prevailing hypothesis for the formation of long-term memory (LTM) is that
      introduction of a memory item alters the pattern of existing neuronal
      connectivity to form a neuronal network that will subserve the information for
      long-term storage. Modulation of synaptic efficacy is induced by changes in
      synaptic transmission within selected synapses or alteration in synaptic
      contacts. These changes are in turn supported by molecules that underlie
      transmission or synaptic remodeling. It is suggested that modulation of gene
      expression is needed for LTM formation to overcome the relative short lifetime of
      proteins in neurons (as compared with enduring memory). One of the most salient
      results consonant with this hypothesis is that the transcription factor cAMP
      response element binding (CREB) is involved in the formation of memory in
      organisms with diverse phylogenetic background from mollusks to mammals. CREB
      subserves the formation of memories of various types of tasks that utilize
      different brain structures. Circumstantial evidence is available suggesting that
      CREB regulates the transcription of genes that subserve LTM. The present review
      is focused on the CREB protein, its role in memory formation and considers
      mechanistic models pertaining to CREB action in modulating neuronal networks that
      underlie LTM.

PMID- 10357227
TI  - Activation of immediate early genes and memory formation.
AB  - Long-term plastic changes in the brain, including those supporting memory
      formation, are assumed to depend on permanent functional alterations in neuronal
      cells that require reprogramming of gene expression. Inducible transcription
      factors encoded by immediate early genes such as c-fos, c-jun, jun-B and zif/268
      (also known as krox-24, egr-1, TIS 8, NGFI-A or zenk) are supposed to act as
      messengers in coupling short-term neuronal activity with changes at the level of
      gene transcription. This review will summarize studies on the expression of
      transcription factor-encoding immediate early genes in the vertebrate brain
      during behavioral training. Special emphasis will be given to correlative or
      interventive experimental evidence indicative of a physiological significance of
      inducible transcription factors for processes underlying learning and memory
      formation.

PMID- 10357228
TI  - Memory formation and the regulation of gene expression.
AB  - On a cellular level, formation of memory is based on a selective change in
      synaptic efficacy that is both fast and, in case of important information, long
      lasting. Rapidity of cellular changes is achieved by modifying preexisting
      synaptic molecules (receptors, ion channels), which instantaneously alters the
      efficacy of synaptic transmission. Endurance, that is the formation of long-term
      memory (LTM), is based on transient and perhaps also long-lasting changes in
      protein synthesis. A number of different methods exist to interfere with the
      synthesis of specific proteins or proteins in general. Other methods, in turn,
      help to identify proteins whose synthesis is changed following learning. These
      mostly molecular methods are briefly described in the present review. Their
      successful application in a variety of memory paradigms in invertebrates and
      vertebrates is illustrated. The data support the importance of selective changes
      in gene expression for LTM. Proteins newly synthesized during memory
      consolidation are likely to contribute to restructuring processes at the synapse.
      altering the efficiency of transmission beyond the scope of STM. Increased or,
      less often, decreased synthesis of proteins appears during specific time windows
      following learning. Recent evidence supports older data suggesting that two or
      even more waves of protein synthesis exist during the consolidation period. It is
      expected that the new molecular methods will help to identify and characterize
      molecules whose expression changes during LTM formation even in complex
      vertebrate learning paradigms.

PMID- 10357229
TI  - Making more synapses: a way to store information?
AB  - Although information may be stored in the brain is changes in the strength of
      existing synapses, formation of new synapses has long been thought of as an
      additional substrate for memory storage. The identification of subcellular
      structural changes following learning in mammals poses a serious 'needle-in-the
      haystack' problem. In most attempts to demonstrate structural plasticity during
      learning, animals have been exposed for prolonged periods to complex
      environments, where they are confronted with a variety of sensory, motor- and
      spatial challenges throughout the exposure period. These environments are thought
      to promote several forms of learning. Repeated exposure to such environments has
      been shown to increase the density of spines and dendritic complexity in relevant
      brain structures. The number of neurons has also been reported to increase in
      some areas. It is not clear, however, whether the new synapses emerging from
      these forms of plasticity mediate specific information storage, or whether they
      reflect a more general sophistication of the excited parts of the network.

PMID- 10357230
TI  - Biochemical dysfunction and memory loss: the case of Alzheimer's dementia.
AB  - Among the different types of cognitive impairment that appear with increasing
      age, Alzheimer's disease (AD) is rated as the most frequent. Despite intensive
      research, key questions concerning AD aetiology remain elusive, but it appears
      that many biochemical events crucial for neuronal communication and synaptic
      plasticity fail during the course of the disease. The aim of this review is
      therefore to provide an overview of intracellular cascades involved in AD
      pathology. For almost all factors. it is a matter of controversy whether their
      contribution should be considered to be cause or effect. However, intracellular
      signalling may be crucial as it is in learning and memory mechanisms and
      malfunction of biochemical pathways may be a common denominator in
      neurodegenerative processes, thus providing new venues for treatment and
      therapeutic strategies.

PMID- 10357231
TI  - Glutamate synthase: a complex iron-sulfur flavoprotein.
AB  - Glutamate synthase is a complex iron-sulfur flavoprotein that forms L-glutamate
      from L-glutamine and 2-oxoglutarate. It participates with glutamine synthetase in
      ammonia assimilation processes. The known structural and biochemical properties
      of glutamate synthase from Azospirillum brasilense, a nitrogen-fixing bacterium,
      will be discussed in comparison to those of the ferredoxin-dependent enzyme from
      photosynthetic tissues and of the eukaryotic reduced pyridine nucleotide
      dependent form of glutamate synthase in order to gain insight into the mechanism
      of the glutamate synthase reaction. Sequence analyses also revealed that the
      small subunit of bacterial glutamate synthase may be the prototype of a novel
      class of flavin adenine dinucleotide- and iron-sulfur-containing oxidoreductase
      widely used as an enzyme subunit or domain to transfer reducing equivalents from
      NAD(P)H to an acceptor protein or protein domain.

PMID- 10357232
TI  - Structural properties of matrix metalloproteinases.
AB  - Matrix metalloproteinases (MMPs) are involved in extracellular matrix
      degradation. Their proteolytic activity must be precisely regulated by their
      endogenous protein inhibitors, the tissue inhibitors of metalloproteinases
      (TIMPs). Disruption of this balance results in serious diseases such as
      arthritis, tumour growth and metastasis. Knowledge of the tertiary structures of
      the proteins involved is crucial for understanding their functional properties
      and interference with associated dysfunctions. Within the last few years, several
      three-dimensional MMP and MMP-TIMP structures became available, showing the
      domain organization, polypeptide fold and main specificity determinants.
      Complexes of the catalytic MMP domains with various synthetic inhibitors enabled
      the structure-based design and improvement of high-affinity ligands, which might
      be elaborated into drugs. A multitude of reviews surveying work done on all
      aspects of MMPs have appeared in recent years, but none of them has focused on
      the three-dimensional structures. This review was written to close the gap.

PMID- 10357233
TI  - A molecular recognition hypothesis for nonpeptides: Na+ K+ ATPase and endogenous
      digitalis-like peptides.
AB  - The molecular recognition hypothesis for peptides is that binding sites of
      ligands and their receptors are encoded by short, complementary segments of DNA.
      A corollary hypothesis for nonpeptide ligands posited here is that peptide
      replicas may be encoded by the DNA segment complementary to the receptor binding
      sites for nonpeptides. This corollary was tested for digitalis. a family of
      cardiotonic and natriuretic steroids including ouabain. A hexapeptide (ouabain
      like peptide, OLP) complementary to a ouabain binding site on sodium potassium
      dependent adenosine triphosphatase (Na+ K+ ATPase) exhibited activity in a
      digitalis bioassay. Antisera to the complementary peptide (OLP) stained the
      neurohypophysis in an immunocytochemical procedure. The complementary peptide was
      found to share an identical 4-amino acid region with the 39-amino acid
      glycopeptide moiety of the vasopressin-neurophysin precursor. This glycopeptide
      was isolated from pituitary extracts; it exhibited digitalis-like activity in the
      submicromolar range and cross-reacted with complementary peptide antibodies.
      Another digitalis-like substance with high activity also was detected in the
      extracts. These results demonstrate that the vasopressin-neurophysin glycopeptide
      has digitalis-like activity. Moreover, the findings are consistent with the
      hypothesis that peptide mimetics of nonpeptides are encoded in the genome.

PMID- 10357234
TI  - Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung
      carcinoma and B16 melanoma growth in mice.
AB  - Bone marrow stroma produces positive and negative growth regulators which
      constitute the hematopoietic microenvironment. As many tumors metastasize to the
      bones, these regulators may also influence tumor growth. Hematopoietic cytokines
      may indeed exert both positive and negative effect on tumor growth. We report
      that, when mixed with tumor cells. adherent bone marrow cells inhibit primary
      tumor growth and metastases formation in mice transplanted with Lewis lung
      carcinoma or B16 melanoma. Peritoneal macrophages or lymph node cells did not
      exert any influence. The tumor inhibition was apparently due to soluble factor(s)
      released by marrow stromal cells. In cocultures with B16 melanoma cells, adherent
      bone marrow cells exerted a significant antiproliferative effect which was
      increased by previous culture of the bone marrow cells with granulocyte
      macrophage colony-stimulating factor but not with macrophage colony-stimulating
      factor. Neither neutralizing antibodies against tumor necrosis factor-alpha,
      transforming growth factor-beta or interferon alpha/beta nor addition of
      Escherichia coli lipopolysaccharide to generate inflammatory cytokines could
      affect the antiproliferative effect of bone marrow stromal cells. The bone marrow
      stroma factor(s) which inhibit tumor growth might, therefore, be a novel growth
      regulator.

PMID- 10357235
TI  - Short-range linkage relationships, genomic organisation and sequence comparisons
      of a cluster of five HSP70 genes in Fugu rubripes.
AB  - Twelve cosmids containing sequences resembling genes encoding members of the 70
      kDa heat-shock protein family, HSP70. have been isolated from Fugu rubripes. They
      can be broadly divided into three groups of overlapping cosmids. Restriction
      analysis and sequencing of one set of five cosmids have revealed five intronless
      Fugu HSP70 genes spanning 42 kb, arranged in a combined head-to-head, tail-to
      tail and head-to-tail orientation. The levels of DNA and amino acid identity are
      very high with respect to one another, and are most similar to HSP70 sequences
      linked to the major histocompatibility complex (MHC) region in other species.
      Putative heat-shock consensus elements are identified. Non-HSP70 sequences with
      homology to known genes have been found physically linked to this Fugu HSP70
      cluster: the Drosophila melanogaster SOL gene, the Drosophila melanogaster nemo
      gene, the Caenorhabditis elegans T17E9.1 gene and the sequence encoding the
      serine protease domain. The linkage relationships described here so far bear no
      resemblance to those of HSP70 in other organisms. Convergence of mammalian HSP70
      and MHC class I and II loci probably occurred after fish had diverged.

PMID- 10357236
TI  - Isolation and characterization of biologically active lectin from Korean
      mistletoe, Viscum album var. Coloratum.
AB  - A mistletoe lectin was isolated from water extracts of Korean mistletoe, a
      subspecies of Viscum album, grown on Quercus mongolica using CM-Sepharose
      chromatography followed by an affinity chromatography on a concanavalin A
      Sepharose column. The compound proved to be a mistletoe lectin II with D
      galactose and N-acetyl-D-galactosamine specificity. Matrix-assisted laser
      desorption time-of-flight mass spectroscopy showed it to have an average
      molecular mass of 62.7 kDa and to consist of two subunits of 30.6 kDa and 32.5
      kDa. It was a basic protein with isoelectric points of 9.4 and 9.6 by capillary
      isoelectric focusing and was cytotoxic to Molt4 cell.

PMID- 10357237
TI  - Adequacy in peritoneal dialysis: a true challenge.

PMID- 10357238
TI  - Continuous renal replacement therapy or hemodialysis for acute renal failure?

PMID- 10357239
TI  - Functional iron deficiency and inadequate dialysis: is there a connection?

PMID- 10357240
TI  - Long-term renal allograft recipients from South-east Asia in the pre-cyclosporin
      era.
AB  - The clinical outcome of long-term renal allograft recipients in the Chinese
      population has not been reported previously. We analysed patients from the pre
      cyclosporin era who had grafts that functioned for > 10 years. Forty-five
      patients (31 men, 14 women; mean age 30, follow-up duration 13.3 years),
      representing a 10-year graft survival of 53%, were included. Thirty-six patients
      (80%) received living-related allografts and 9 (20%) received cadaveric or living
      unrelated renal transplantation. The mean serum creatinine at last follow-up was
      1.36 mg/dl (range, 0.83-4.08). Major posttransplantation complications included:
      hypertension in 25 (56%), infection in 16 (36%), acute rejection in 15 (33%),
      lipid disorder in 13 (29%), liver disease in 7 (16%), osteonecrosis in 5 (11%),
      malignancy in 4 (9%), coronary artery disease in 3 (7%), and diabetes mellitus in
      3 (7%). Five grafts were lost: 3 to chronic rejection, and 2 to patients with
      stable function who died of non-renal causes. Proteinuria correlated strongly
      with graft function and survival, and marginally with hypertension. In hepatitis
      B carriers, serum alpha-feto protein is useful in the early detection of
      hepatocellular carcinoma. We conclude that while patients in the pre-cyclosporin
      era can survive with excellent graft function beyond the first decade, the risk
      of complications leading to significant morbidity still remains even when
      patients are receiving minimal doses of immunosuppression in the second decade.

PMID- 10357241
TI  - Oedema, Starling and pulse reverse osmosis: towards a possible biochemical marker
      for oedema.
AB  - Several conflicting theories have been proposed to explain the development of
      oedema. Pulse reverse osmosis (PRO) suggests that oedema occurs when the mean
      pulse capillary pressure exceeds the osmotic gradient between the plasma and the
      interstitial fluid. In order to test this concept mean arterial blood pressures
      and colloid osmotic pressures were taken in a group of healthy volunteers, a
      group of patients with bilateral ankle oedema and a group of treated
      hypertensives. Patients with oedema were found to have colloid osmotic pressures
      (COP's) which were significantly less than those of the healthy volunteers (p
      <0.001) and the treated hypertensives (p <0.001). The results support the oedema
      mechanism proposed by PRO and indicate that the relationship between blood
      pressure and COP may be a useful biochemical marker of oedema and its treatment.
      Further study is required to numerically quantify this relationship.

PMID- 10357242
TI  - Changing acute renal failure treatment from intermittent hemodialysis to
      continuous hemofiltration: impact on azotemic control.
AB  - BACKGROUND: Continuous renal replacement therapy is increasingly used in the
      management of acute renal failure in critically ill patients. The advantages of
      continuous renal replacement therapy (CRRT) over intermittent hemodialysis (IHD),
      however, are not yet fully documented. In particular, it is unknown whether
      continuous veno-venous hemodiafiltration (CVVHDF) provides better control of
      azotemia than IHD. OBJECTIVES: To study the effect on azotemic control of
      changing acute renal failure treatment from IHD to CVVHDF. SETTINGS: Tertiary
      intensive care unit. PATIENTS: Forty seven consecutive critically ill patients
      with multiorgan failure and acute renal failure treated with IHD and 47 similar
      patients treated with CVVHDF. METHODS: Analysis of daily morning urea and
      creatinine concentrations over the period of renal replacement therapy in the
      ICU. Statistical comparison of data. RESULTS: The two groups of patients were
      comparable for mean age (55 years for IHD vs. 60 years for CVVHDF; NS) and number
      of failing organs prior to therapy (mean of 4.2 for IHD vs. 3.7 for CVVHDF; NS).
      Severity of illness at admission as assessed by APACHE II score, however, was
      greater for patients receiving CVVHDF (29.4 vs 25.7; p<0.003). CVVHDF was
      associated with a significantly lower plasma urea (p < 0.0001) and serum
      creatinine (p < 0.01) level at 24 hours of treatment despite similar levels at
      the start of therapy Throughout the duration of therapy, mean urea levels (35.0
      mmol/L for IHD vs 23.4 mmol/L for CVVHDF) and mean serum creatinine levels (513
      micromoles/L for IHD and 263 micromoles/L for CVVHDF) showed significantly (p
      <0.0001) better control of uremia with CRRT. CONCLUSIONS: Changing the form of
      renal replacement therapy from intermittent hemodialysis to continuous
      hemofiltration is associated with improved control of azotemia. The superior
      adequacy of small solute clearance achieved during CVVHDF provides additional
      support for its preferential use in the management of acute renal failure in the
      ICU.

PMID- 10357243
TI  - Bioelectrical impedance analysis before and after Novacor implantation.
AB  - In this study Bioelectrical Impedance Analysis was performed in 5 patients with
      end stage heart failure in whom a left ventricular assist device (Novacor) was
      successfully implanted. Whole body measurements of bioelectrical indices
      resistance and reactance were taken before surgery and 3, 7, 12, and 15 days
      after it. After surgery there was a significant decrease in reactance, indicating
      a shift of body fluids from intra- to extra-cellular space.

PMID- 10357244
TI  - Hemodynamic properties of the hemopump HP14.
AB  - BACKGROUND: The Hemopump HP14 is a catheter-mounted, transvalvular, left
      ventricular assist device intended for femoral percutaneous insertion. The pump
      was developed for patients with postoperative or postinterventional low cardiac
      output and for CABG surgery on the beating heart. Little is known about the
      effect of afterload and hematocrit on the pump performance. METHODS: The
      influence of hematocrit and afterload on the pump flow was tested using an in
      vitro model filled with heparinized bovine blood. Regression analysis of the pump
      flow with respect to three hematocrit values (20%, 30%, 40%) and ten afterload
      levels (30 mmHg-120 mmHg in 10 mmHg increments) was performed for all pump speed
      levels (n = 7). RESULTS: At all pump speed levels reduction of afterload and
      hematocrit were significant predictors for increasing pump flow (p<0.001). For
      hematocrit values between 40% and 20% and highest pump speed, mean pump flow at
      lowest afterload ranged between 2.34 and 2.53 L/min; and at highest afterload
      between 1.31 and 1.53 L/min. For speed level 1, afterload of 120 mmHg and
      hematocrit of 40% there was a maximal retrograde flow of 230+/-35 ml/min.
      CONCLUSIONS: Pump performance is significantly improved by both afterload and
      hematocrit reduction. In the weaning phase and during the removal of the device,
      the pump should run at a speed level of at least three to prevent retrograde flow
      in the pump. Estimates for pump flow in vivo can be extrapolated from our
      diagrams. Our results show that the Hemopump HP14 is a valuable alternative to
      intra-aortic balloon counterpulsation.

PMID- 10357245
TI  - Surface characterization of polymers for medical devices.
AB  - A survey is given on analytical techniques currently applied to the surface
      characterization of biomedical polymers. The techniques include spectroscopies,
      thermodynamic and electrochemical measurements and microscopies, respectively. To
      illustrate the motivation for surface analysis, the hypotheses on the
      correlations between surface parameters and hemocompatibility of polymers are
      briefly examined. The applications of the examined methods are illustrated by a
      number of examples. These examples include the characterization of cellulose
      membranes (low-flux hemodialysis membranes) by streaming potential measurements
      and by inverse contact angle measurements. The use of surface spectroscopies (ATR
      FTIR and XPS) is demonstrated by considering the optimization of surface
      modification procedures of vascular prostheses made from
      poly(tetrafluoroethylene). Furthermore, the characterization of water-swollen
      cellulose membranes by scanning force microscopy is shown. Finally, the extended
      application of physico-chemical surface analysis to the investigation of protein
      adsorption is considered. An example deals with in situ spectroscopic
      ellipsometry used to study the adsorption of fibrinogen onto a plasma-deposited
      hydrophobic fluoropolymer and onto poly(ethyleneoxide)-grafted fluoropolymer,
      respectively.

PMID- 10357246
TI  - Push-pull sorbent-based pheresis treatment in an experimental canine endotoxemia
      model: preliminary report.
AB  - The Biologic-DTPF System (DTPF), an extracorporeal blood treatment device with
      potential to treat sepsis, was tested in a preliminary study using a canine
      endotoxemia model. Six dogs were used and they formed four treatment groups, as
      control group (n=1) and three groups based on the type of sorbent present in the
      plasma filter (PF) system: sham treatment with no sorbent (n=1), charcoal as
      sorbent (n=2), and charcoal/silica as sorbent ("silica" group, n=2).
      Cardiodynamic data were recorded before treatment and every 30 minutes, and blood
      samples were collected to determine blood chemistry and to detect the levels of
      endotoxin and selected plasma cytokines: interleukin-1 (IL-1), interleukin-6 (IL
      6), and tumor necrosis factor (TNF). The dogs were given Escherichia coli
      endotoxin (2 mg/kg) as an intravenous drip (extended over a period of 30
      minutes). Thirty minutes after the end of infusion all animals except the control
      were treated with the DTPF system for four hours. To determine the effect of
      treatment, data collected at one hour from the initiation of treatment until the
      end of treatment were compared between control and treated dogs. The endotoxin
      levels in the control dog were higher (P < 0.05) than other groups. The control
      dog had lower levels of TNF than other groups. The control dog had similar levels
      of IL-1 (P > 0.05) and higher levels (P < 0.05) at 4 hours into treatment
      compared to other groups. The control dog had similar levels of IL-6 as other
      groups (P > 0.05). In the control dog, the mean arterial pressure (MAP) fell and
      then remained low but stable at 1-4 hours. The charcoal group had lower MAP than
      the control dog at 1-4 hours (P < 0.05). The silica group had higher MAP levels
      similar to the control dog. After treatment, the control dog had higher (P <
      0.05) values of hematocrit, hemoglobin, calcium, potassium, and albumin compared
      to the treated groups. As expected for a system removing plasma during sepsis,
      the DTPF System had some adverse effects on the physiologic status of the dogs,
      especially when loaded with charcoal sorbent only. The findings of the present
      study suggest that the filters are capable of eliminating endotoxin and there is
      some evidence of cytokine removal. Although the charcoal dogs did poorly,
      addition of silica to the sorbent offset any negative effects. Further work is
      underway to improve the efficiency of the system, primarily to enhance the
      capacity of the sorbents for cytokines. A more realistic canine sepsis model with
      mortality after several days (the Escherichia coli- infected intraperitoneal
      clot) will also be considered in future studies.

PMID- 10357247
TI  - Differential response of cortical-limbic neuropotentiated compulsive mice to
      dopamine D1 and D2 receptor antagonists.
AB  - We previously created transgenic mice in which dopamine D1 receptor-expressing
      (D1+) neurons in regional subsets of the cortex and amygdala express a
      neuropotentiating cholera toxin (CT) transgene. These 'D1CT' mice engage in
      complex biting, locomotor and behavioral perseverance-repetition abnormalities
      that resemble symptoms of human compulsive disorders associated with cortical
      limbic hyperactivity. Because excessive cortical-limbic stimulation of striatal
      motor pathways may play a critical role in causing compulsive disorders, we
      examined the responsiveness of D1CT mice to dopamine D1 and D2 receptor
      antagonists. D1CT mice were found to be largely resistant to the cataleptic
      action of the D1 receptor antagonist SCH23390. The abnormal repetitive leaping of
      D1CT mice was similarly unaffected by SCH23390. In contrast, the D1CT mice
      displayed supersensitivity to cataleptic induction by the D2 receptor antagonist
      sulpiride. These data are consistent with the hypothesis that complex compulsions
      are mediated by chronic excessive corticostriatal (and/or amygdalostriatal)
      glutamatergic stimulation of the striatal direct and indirect motor pathways.

PMID- 10357249
TI  - Neuroadaptations in the dopaminergic system after active self-administration but
      not after passive administration of methamphetamine.
AB  - Methamphetamine is a strong and long-lasting stimulant that can be easily
      synthesized and is effective when taken either orally, intravenously, or smoked
      as 'ice'. Due to it's escalating abuse, a clear need exists for laboratory
      procedures to evaluate motivational components of methamphetamine abuse and their
      underlying neurobiological mechanisms. In the present experiment, we utilized a
      'yoked' procedure in which rats were run simultaneously in groups of three, with
      two rats serving as yoked controls which received an injection of either 0.1
      mg/kg methamphetamine or saline which was not contingent on responding each time
      a response-contingent injection of 0.1 mg/kg methamphetamine was self
      administered by the third paired rat. Rats that had actively self-administered
      methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h
      showed marked decreases in somatodendritic dopamine D2 autoreceptors levels in
      the ventral tegmental area (34%) and medial (31%) and dorsal (21%) part of the
      substantia nigra zona compacta with a corresponding down-regulation of dopamine
      D1 receptors in the shell of the nucleus accumbens (15%), as measured by in vitro
      quantitative autoradiography. Since the decreases in levels of dopamine D1 and D2
      receptors which occurred in rats self-administering methamphetamine did not occur
      in littermates that received either yoked injections of methamphetamine or
      saline, these changes likely reflect motivational states that were present when
      methamphetamine injection depended on active drug self-administration behavior.

PMID- 10357248
TI  - Effects of antidepressants and benzodiazepine treatments on the dendritic
      structure of CA3 pyramidal neurons after chronic stress.
AB  - Both repeated stress and corticosterone administration induce remodeling of
      apical dendrites of hippocampal CA3 pyramidal neurons. Circulating
      glucocorticoids are involved in the mechanism that produces atrophy, along with
      excitatory amino acids and serotonin (5-hydroxytryptamine, 5-HT). We used 5-HT
      related antidepressants and a benzodiazepine in order to explore indirectly the
      role of serotonin and GABA(A)-benzodiazepine receptors in the stress-induced
      structural changes visualized by the Golgi impregnation of the rat hippocampus.
      The 5-HT reuptake enhancer (+/-)-tianeptine prevented the dendritic atrophy
      caused by repeated restraint stress in a non-stereoselective fashion and two 5-HT
      reuptake antagonists, fluoxetine and fluvoxamine, failed to block dendritic
      atrophy. Tianeptine also functions as a therapeutic tool since it reversed the
      already established hippocampal atrophy caused by treatment with corticosterone
      for 3 weeks. Finally, the benzodiazepine agonist adinazolam was effective in
      preventing the stress-induced dendritic atrophy. These findings suggest that the
      synaptic availability of 5-HT is involved in the mechanism leading to stress
      induced dendritic remodeling and supports the idea that the hippocampal
      inhibitory GABAergic tone may play a regulatory role.

PMID- 10357250
TI  - Effects of adenosine receptor agonists and antagonists on audiogenic seizure
      sensible DBA/2 mice.
AB  - We have studied the effects of selective and non-selective adenosine receptor
      agonists and antagonists in audiogenic-seizure-sensitive DBA/2 mice, an animal
      model of generalized reflex epilepsy. With the exception of the adenosine A3
      receptor agonist, N6-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine (IB-MECA),
      all the agonists studied prevented the development of audiogenic seizures in a
      dose-dependent manner. The ED50 values against the clonic phase of the audiogenic
      seizures were low, that is: 0.06 mg/kg, i.p., for the adenosine A1 receptor
      agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), 0.02 and 0.03 mg/kg, i.p., for
      the adenosine A2A receptor agonists, 2-(4-(2-carboxyethyl)-phenylamino)-5'-N
      ethylcarboxamidoadenosine (CGS 21680) and 2-hexynyl-5'-N-ethyl
      carboxamidoadenosine (2-HE-NECA), and 0.7 mg/kg, i.p., for the adenosine A1/A3
      receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (APNEA). Conversely, the non
      selective agonist, N-ethyl-carboxamidoadenosine (NECA), was highly potent, the
      ED50 being 0.0005 mg/kg, i.p. In the absence of auditory stimulation, the
      adenosine receptor antagonists increased the incidence of both clonic and tonic
      seizures in DBA/2 mice. The ED50 values were: for caffeine, 207.5 mg/kg, i.p.,
      for the adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine
      (DPCPX), 327.8 mg/kg i.p., for the adenosine A2A receptor antagonists, 3,7
      dimethyl-1-propylxanthine (DPMX), 86.7 mg/kg i.p., for the (E,18%-Z,82%)7-methyl
      8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (KF 17837), 69.1 mg/kg i.p., and 5
      amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-(4,3-c)1,2,4-triazolo(1,5 -c)
      pyrimidine (SCH 58261), 321.8 mg/kg i.p. The rank order of convulsant potency in
      our epileptic model, following intracerebroventricular administration, was DPCPX
      > DMPX > 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC) > KF 17837 > Caffeine >
      SCH 58261 > 5-amino-9-chloro-2-(2-furyl)-1,2,4-triazolo(1,5-c)quinazoline (CGS
      15943). Following a subconvulsant audiogenic stimulus of 83 dB, all adenosine
      receptor antagonists induced both tonic and clonic seizures. The ED50 values for
      such proconvulsant effects were: for caffeine 0.04 mg/kg, i.p., for the adenosine
      A receptor antagonist, DPCPX, 5.84 mg/kg, i.p., for the adenosine A2A receptor
      antagonists, DMPX, 0.02 mg/kg, i.p., CGS 15943, 0.29 mg/kg i.p., KF 17837, 0.57
      mg/kg, i.p., CSC 0.12 mg/kg, i.p. and SCH 58261 0.07 mg/kg, i.p., respectively.
      These data suggest that stimulation of adenosine A1 and A2A receptors is involved
      in the suppression of seizures.

PMID- 10357251
TI  - Ifenprodil and arcaine alter amygdala-kindling development.
AB  - The NMDA receptor complex is thought to be altered in kindling, an animal model
      for complex partial epilepsy. This receptor complex has several modulatory sites
      including those for glutamate, glycine and polyamines with activation resulting
      in altered cation channel opening. Two NMDA receptor effectors, ifenprodil and
      arcaine, were evaluated for effects on the acquisition of electrical kindling of
      the amygdala. Rats were administered 0, 3.2, 10, 32 and 100 microg of ifenprodil
      or 0, 32 or 100 microg of arcaine, intracerebroventricularly, 10 min before a
      daily kindling stimulus. Ifenprodil, at low doses, enhanced kindling acquisition,
      while the highest dose, 100 microg, inhibited kindling. Arcaine increased the
      number of trials required to reach fully generalized (stage 5) seizures at the
      100 microg dose. Since these agents had mixed actions on kindling development, it
      is unclear whether these or similar NMDA effectors would be useful in the
      modulation of complex partial seizures.

PMID- 10357252
TI  - Idazoxan preferentially increases dopamine output in the rat medial prefrontal
      cortex at the nerve terminal level.
AB  - The effects of the alpha2-adrenoceptor antagonist idazoxan on extracellular
      concentrations of dopamine in major dopaminergic terminal regions in the brain
      were investigated by means of microdialysis in freely moving rats. Systemic
      administration of idazoxan markedly increased dopamine output in the medial
      prefrontal cortex, whereas it failed to affect dopamine efflux in the striatum or
      in the nucleus accumbens. Local perfusion of idazoxan via reversed dialysis
      markedly enhanced dopamine efflux in cortical but not subcortical areas, in which
      dopamine output was but little affected. Infusion of idazoxan into the ventral
      tegmental area did not alter the dopamine efflux in the medial prefrontal cortex.
      Moreover, the increase in cortical dopamine efflux induced by systemic
      administration of idazoxan was unaffected by tetrodotoxin perfusion of the
      ventral tegmental area. These data show that the alpha2-adrenoceptor antagonist
      idazoxan preferentially increases basal dopamine output in the medial prefrontal
      cortex through a local mechanism, an effect which appears largely independent of
      dopaminergic neuronal activity. An enhanced output of cortical dopamine may
      contribute to the purported augmentation by alpha2-adrenoceptor antagonists of
      the therapeutic effects of both antidepressant and antipsychotic drugs.

PMID- 10357253
TI  - Adrenomedullin attenuates the hypertension in hypertensive pregnant rats induced
      by N(G)-nitro-L-arginine methyl ester.
AB  - We examined the effect of adrenomedullin on the cardiovascular system of an
      animal model for preeclampsia. An inhibitor of nitric oxide synthase, N(G)-nitro
      L-arginine methyl ester (L-NAME), was infused subcutaneously into rats at a
      constant rate from day 14 of pregnancy to make an animal model for preeclampsia.
      Adrenomedullin was continuously infused intravenously at a dose of 3 or 10 pmol/h
      from day 17 of pregnancy. The basal systolic blood pressure was significantly
      higher in the L-NAME treated rats than in the control rats. The adrenomedullin
      administration at day 19 of pregnancy showed a significant decrease in the blood
      pressure in the L-NAME treated rats than in vehicle rats during infusion. The
      blood pressure of normal pregnant rats did not significantly decrease by
      adrenomedullin infusion. The adrenomedullin decreased pup mortality of the L-NAME
      treated rats. Adrenomedullin attenuated the L-NAME induced hypertension and pup
      mortality. On the other hand, adrenomedullin administration in both pregnant rats
      in early gestation (5-11 days of pregnancy) and in non-pregnant rats did not show
      any significant effect on L-NAME-induced hypertension. The adrenomedullin mRNA
      level was predominantly expressed at high levels in the ovary, uterus and
      placenta, but at low levels in other tissues in pregnant rats in late gestation.
      The adrenomedullin mRNA level of the L-NAME treated rats in placenta decreased
      more than in the normal pregnant rats in late gestation (P < 0.05). These
      findings suggest that the adrenomedullin might play an important role in the
      regulation of the cardiovascular system of the mother and fetoplacental unit in
      rats.

PMID- 10357254
TI  - Possible role of Ca2+ channels in the vasodilating effect of 5beta
      dihydrotestosterone in rat aorta.
AB  - It has previously been shown that the androgen, 5beta-dihydrotestosterone (17beta
      hydroxy-5beta-androstan-3-one, 5beta-DHT), is able to produce an endothelium
      independent vasodilating effect in rat aorta. The present study analyzed the
      mechanisms underlying the above vasodilator effect of 5beta-dihydrotestosterone,
      with particular emphasis on verifying a possible interaction with GABA(A)
      receptors, beta-adrenoceptors and Ca2+ channels. Rat aortic rings without
      endothelium were isometrically recorded. 5Beta-dihydrotestosterone produced a
      concentration-dependent relaxation on the contractions induced by noradrenaline
      (NA; 0.3 microM) or K+ (KCl; 60 mM), with the latter being more sensitive to
      5beta-dihydrotestosterone-induced relaxation than the former; the concentration
      response curves showed that 5beta-dihydrotestosterone is significantly more
      potent than 17beta-estradiol(1,3,5(10)-estratrien-3,17beta-diol) to induce
      vasodilatation. The vasodilating effect of 5beta-dihydrotestosterone on
      noradrenaline-induced contraction was resistant to blockade by the GABA(A)
      receptor antagonists, picrotoxin or bicuculline, and the beta-adrenoceptor
      antagonist, propranolol, a finding that excludes an interaction of the steroid
      with GABA(A) receptors and beta-adrenoceptors. Interestingly, the contractions
      evoked by calcium in depolarized tissues were substantially inhibited by 5beta
      dihydrotestosterone, implying that this steroid could be an endogenous calcium
      channel blocker; consistent with this finding, 5beta-dihydrotestosterone was able
      to relax tissues precontracted with the calcium channel opener, Bay K 8644.
      Moreover, although the rings precontracted with noradrenaline and potassium were
      almost equipotently relaxed by 5beta-dihydrotestosterone. Nifedipine was more
      potent than 5beta-dihydrotestosterone to block the potassium-induced contraction,
      but the steroid was more effective than nifedipine to prevent noradrenaline
      induced contraction. The above results suggest that 5beta-dihydrotestosterone
      causes relaxation of rat aorta by acting directly on the membrane of smooth
      muscle cells; this non-genomic action may be explained in terms of a blockade of
      voltage- and receptor-dependent calcium channels, a mechanism that restricts the
      availability of extracellular calcium in the contractile machinery.

PMID- 10357255
TI  - Thiopentone inhibits endothelium-dependent relaxations of rat aortas regulated by
      endothelial Ca2+-dependent K+ channels.
AB  - The present study was designed to examine the mechanisms of inhibitory effect of
      barbiturates on endothelial function by determining whether thiopentone and
      phenobarbitone reduce relaxations to acetylcholine mediated by endothelial Ca2+
      dependent K+ channels in rat aortas. Cumulative applications (10(-9) to 10(-5) M)
      of acetylcholine induced endothelium-dependent relaxations, which are abolished
      by inhibitors of nitric oxide synthase (N(G)-nitro-L-arginine methyl ester, 10(
      4) M) and of soluble guanylate cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline
      1-one; ODQ, 5 x 10(-6) M). Selective inhibitors of large-conductance Ca2+
      dependent K+ channels (iberiotoxin, 5 x 10(-8) M), but not of those with small
      conductance (apamin, 5 x 10(-8) M), significantly reduced the acetylcholine
      induced vasorelaxation. ODQ, but neither iberiotoxin nor apamin, blocked the
      relaxations of arteries without endothelium induced by nitric oxide donors,
      sodium nitroprusside (10(-9) to 10(-5) M) and 1-hydroxy-2-oxo-3-(N-methyl-3
      aminopropyl)-3-methyl-1-triazene (NOC-7; 10(-10) to 10(-5) M). Thiopentone (10(
      4) and 3 x 10(-4) M) but not phenobarbitone (3 x 10(-4) M) significantly impaired
      relaxations to acetylcholine, whereas thiopentone did not alter relaxations to
      sodium nitroprusside. Thiopentone (3 x 10(-4) M) did not affect relaxations to
      acetylcholine in arteries treated with iberiotoxin (5 x 10(-8) M), whereas it
      reduced these relaxations in arteries treated with apamin (5 x 10(-8) M). These
      results suggest that in rat aortas, large-conductance, but not small-conductance,
      Ca2+-dependent K+ channels in endothelial cells, play a role in endothelium
      dependent relaxations to acetylcholine, and that thiopentone, but not
      phenobarbitone, impairs relaxations to acetylcholine mediated by these channels.

PMID- 10357256
TI  - Delta9-tetrahydrocannabinol inhibits gastric motility in the rat through
      cannabinoid CB1 receptors.
AB  - We investigated involvement of the autonomic nervous system in gastric motor and
      cardiovascular responses to delta9-tetrahydrocannabinol (delta9-THC) in
      anesthetized rats. Intravenously administered delta9-THC evoked long-lasting
      decreases in intragastric pressure and pyloric contractility, bradycardia, and
      hypotension. The changes in gastric motor function and bradycardia were abolished
      by vagotomy and ganglionic blockade, whereas spinal cord transection prevented
      the hypotensive response. Administered intravenously alone, N-(piperidin-1-yl)-5
      (4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide, a
      putative cannabinoid CB1 receptor antagonist, evoked transient decrease in
      intragastric pressure, and hypertension that was associated with bradycardia.
      However, this agent completely blocked the gastric motor and cardiovascular
      responses to intravenous delta9-THC. Application of delta9-THC to the dorsal
      surface of the medulla resulted in small and short-lasting decreases in gastric
      motor and cardiovascular function. We conclude that the decrease in gastric motor
      function and bradycardia are partially due to an action of delta9-THC in the
      dorsal medulla and that intact vagal nerves are required. The hypotension was
      mediated through sympathetic pathways. Both gastric motor and cardiovascular
      effects of peripherally administered delta9-THC seem to be mediated through
      cannabinoid CB1 receptors.

PMID- 10357257
TI  - Binding characteristics of [3H]DAA1106, a novel and selective ligand for
      peripheral benzodiazepine receptors.
AB  - Here, we investigated the binding characteristics of [3H]N-(2,5-dimethoxybenzyl)
      N-(5-fluoro-2-phenoxyphenyl)acetamide ([3H]DAA1106), a potent and selective
      ligand for peripheral benzodiazepine receptors, in mitochondrial fractions of the
      rat brain. [3H]DAA1106 bound to the mitochondrial fraction of the rat brain in a
      saturable manner. The dissociation constant (Kd) and maximal number of binding
      sites (Bmax) obtained from Scatchard plot analysis of the saturation curve of
      [3H]DAA1106 binding were 0.12 +/- 0.03 nM and 161.03 +/- 5.80 fmol/mg protein,
      respectively. [3H]DAA1106 binding to mitochondrial preparations of the rat
      cerebral cortex was inhibited by several peripheral benzodiapine receptor
      ligands, and DAA1106 was the most potent inhibitor in inhibiting [3H]DAA1106
      binding among the peripheral benzodiazepine receptor ligands we tested. The
      binding of [3H]DAA1106 was not affected by several neurotransmitter-related
      compounds, including adrenoceptor, gamma-aminobutyric acid (GABA), dopamine, 5
      hydroxytryptamine (5-HT), acetylcholine, histamine, glutamate and central
      benzodiazepine receptor ligands even at a concentration of 10 microM. In the
      cerebral cortex of rhesus monkeys, DAA1106 and 1-(2-chlorophenyl)-N-methyl-(1
      methylpropyl)-3-isoquinoline carboxamide (PK11195) potently inhibited [3H]DAA1106
      binding, while 7-chloro-5-(4-chlorophenyl)-1-methyl-1,3
      dihydrobenzo[e][1,4]diazepin -2-one (Ro5-4864) did not. The highest [3H]DAA1106
      binding was observed in the olfactory bulb, followed by the cerebellum. In
      autoradiographic studies, practically the same results were obtained, in that the
      highest binding of [3H]DAA1106 was in the olfactory bulb. Potent labeling was
      also noted in ventricular structures such as the choroid plexus. Thus,
      [3H]DAA1106 is a potent and selective ligand for peripheral benzodiazepine
      receptors and should prove useful for elucidating the physiological relevance of
      events mediated through peripheral benzodiazepine receptors.

PMID- 10357258
TI  - In vitro pharmacological profile of nonpeptide CRF1 receptor antagonists, CRA1000
      and CRA1001.
AB  - We investigated pharmacological properties of CRA1000 (2-(N-(2-methylthio-4
      isopropylphenyl)-N-ethylamino-4-(4-(3-fluoro phenyl)-1,2,3,6-tetrahydropyridin-1
      yl)-6-methylpyrimidine) and CRA1001 (2-( N-(2-bromo-4-isopropylphenyl)-N
      ethylamino-4-(4-(3-fluorophenyl)-1 ,2,3,6-tetrahydropyridin-1-yl)-6
      methylpyrimidine), novel and selective antagonists for the corticotropin
      releasing factor1 (CRF1) receptor. Both CRA1000 and CRA1001 inhibited [125I]ovine
      CRF binding to membranes of COS-7 cells expressing the rat CRF1 receptor with
      IC50 values of 30 and 38 nM, respectively, without affecting [125I]sauvagine
      binding to membranes of COS-7 cells expressing the rat CRF2alpha receptor. CRF
      elicited intracellular cyclic AMP (cAMP) accumulation in AtT-20 cells which
      express the CRF1 receptor but not the CRF2 receptor, and COS-7 cells expressing
      CRF1 or CRF2alpha receptors. The CRF-induced cAMP accumulation was inhibited by
      both CRA1000 and CRA1001, concentration-dependently, in AtT-20 cells and COS-7
      cells expressing the CRF1 receptor, while these compounds did not attenuate the
      CRF response in COS-7 cells expressing the CRF2alpha receptor. CRF increased
      adrenocorticotropin (ACTH) secretion from AtT-20 cells, and CRA1000 and CRA1001
      inhibited CRF-induced ACTH secretion, concentration-dependently, as did other
      CRF1 receptor antagonists. These results show that both CRA1000 and CRA1001 are
      potent and selective CRF1 receptor antagonists.

PMID- 10357259
TI  - A molecular model for the synergic interaction between gamma-aminobutyric acid
      and general anaesthetics.
AB  - Within the context of the discussion about rational polytherapy, we determined
      the effects of four anaesthetics on the binding of [3H]t
      butylbicycloorthobenzoate ([3H]TBOB) to the GABA(A) receptor complex in the
      presence of several concentrations of GABA (gamma-aminobutyric acid), in order to
      build a molecular model that can describe and quantify the interactions between
      the compounds. The empirical isobole method revealed that GABA and the
      anaesthetics acted synergically in displacing [3H]TBOB. This synergy could be
      described by a simple molecular model in which both GABA and the anaesthetics
      displaced [3H]TBOB allosterically and in which GABA allosterically enhanced the
      binding of the anaesthetics. To get information about the interaction between
      GABA and anaesthetics, we used [3H]TBOB as a tracer ligand. The model indicated
      that GABA enhanced the affinity of thiopental 3.0-fold, propofol 5.0-fold, the
      neuroactive steroids Org 20599 3.5-fold and Org 20549 13-fold. Insight into the
      molecular mechanism and strength of these interactions can help clinicians to
      choose therapeutically optimal drug and dose combinations: a step towards
      rational polytherapy.

PMID- 10357260
TI  - The mechanism of epristeride against benign prostatic hyperplasia.
AB  - Epristeride, a 5alpha-reductase inhibitor, decreases prostate size and improves
      symptoms in men with benign prostatic hyperplasia. However, little is known about
      the histopathology of the prostate after treatment with epristeride. To study the
      relationship between apoptosis and the mechanism of epristeride in the treatment
      of benign prostatic hyperplasia, the induction of apoptosis by epristeride was
      detected and measured in vitro by: (a) observing morphological changes in cells
      by light microscopy; (b) comparing the relative content of dihydrotestosterone in
      the rat prostate epithelial cells untreated and treated with epristeride by
      microspectrophotometry; (c) estimating changes in cell size and DNA integrity by
      flow cytometry; and (d) monitoring nucleosomal DNA fragmentation by agarose gel
      electrophoresis. The cells treated with epristeride showed a reduction in cell
      size, an increase in the cytoplasm/nuclear ratio, which is indicative of the
      condensation of nuclear chromatin, a significant decrease in optical density at
      580 nm (OD580 nm), and an oligonucleosomal ladder and a subdiploid peak of DNA
      characteristic of apoptosis. Therefore, the mechanism of epristeride in the
      treatment of benign prostatic hyperplasia might be apoptosis stimulated by
      decreasing dihydrotestosterone level.

PMID- 10357261
TI  - Differential desensitization of human delta-opioid receptors by peptide and
      alkaloid agonists.
AB  - The efficacy of different opioid agonists to induce acute desensitization of the
      human delta-opioid receptor-mediated inhibition of cAMP accumulation was
      investigated in the neuroblastoma cell line SK-N-BE, which endogenously expresses
      these receptors. While etorphine, a non-selective alkaloid agonist, caused 50%
      desensitization after a 30-min incubation, the same treatment in the presence of
      the selective peptide agonists, DPDPE ([D-Pen2,D-Pen5]enkephalin) and deltorphin
      I (Tyr-D-Ala-Phe-Asp-Val-Val-Gly), almost totally desensitized the delta-opioid
      receptor-mediated inhibition of adenylyl cyclase. When SK-N-BE cells were
      prechallenged either with alkaloid or peptide agonist, we observed a cross
      desensitization that was less marked when cells were pretreated with peptide
      agonists and then challenged with etorphine. Taken together, these results
      demonstrate that human delta-opioid receptors are differentially desensitized by
      alkaloid and peptide agonists.

PMID- 10357263
TI  - Competitive adsorption between phospholipid and plasma protein on a phospholipid
      polymer surface.
AB  - The competitive adsorption of proteins and phospholipids on omega
      methacryloyloxyalkyl phosphorylcholine (MAPC) polymer was evaluated in this
      study. Albumin, fibrinogen, and dimyrstoyl phosphatidylcholine (DMPC) were used
      as model components. The amount of DMPC adsorbed on the MAPC polymers increased
      with an increase in the MAPC unit composition of the polymer. The methylene chain
      length of the MAPC unit was another factor influencing the DMPC adsorption when
      the MAPC unit composition of the MAPC polymer was low. The state of albumin and
      DMPC liposome adsorbed on the 2-methacryloyloxyethyl phosphorylcholine (MPC)
      polymer was determined by dynamic contact angle (DCA) measurement. The adsorption
      strength of albumin on the MPC polymer was weaker than that on the poly[n-butyl
      methacrylate (BMA)], that is, the albumin was detached from the MPC polymer
      during the rinsing process. On the poly(BMA) surface, no difference in the shape
      of the DCA loops before and after contact with the DMPC liposomal suspension was
      observed. Fibrinogen adsorption on the MAPC polymer was detected by gold-colloid
      labeled immunoassay. The amount of fibrinogen adsorbed on every MAPC polymer
      surface was reduced by addition of the DMPC liposome in the fibrinogen solution.
      The number of platelets adhered on the MAPC polymer was also decreased when the
      DMPC liposome was present in the fibrinogen solution during pretreatment. We
      concluded that phospholipids were preferentially adsorbed on the MAPC polymer
      surface compared with plasma protein and that the adsorbed phospholipids played
      an important role in showing an excellent blood compatibility on the MAPC
      polymer.

PMID- 10357262
TI  - Ca2+ and phorbol ester effect on the mast cell phosphoprotein induced by
      cromolyn.
AB  - Several phosphoproteins are involved in stimulus-secretion coupling. The beta and
      gamma subunits of immunoglobulin E binding protein (FC epsilonRI) and three other
      protein bands get phosphorylated during stimulation of mast cell secretion. These
      additional proteins of 42, 59 and 68 kDa are also phosphorylated when secretion
      is stimulated by compound 48/80 (C48/80). A 78 kDa band, however, is
      phosphorylated as secretion wanes after stimulation with C48/80 and by the anti
      allergic drug disodium cromoglycate (cromolyn). Phosphorylation was blocked by
      protein kinase C inhibitors. We investigated the isozyme involved by first
      showing that a cation ionophore prevented the phosphorylation of the 78 kDa
      protein, while a Ca2+ chelator did not affect phosphorylation even though it
      enhanced the inhibitory effect of cromolyn. This protein was identified as moesin
      by immunoprecipitation. Protein kinase C activators had no effect on 78 kDa
      protein phosphorylation either in the presence or absence of Ca2+ ions, but
      prevented its phosphorylation by cromolyn. Protein phosphatase inhibitors
      prolonged the duration, but not the amount of phosphate incorporated in the 78
      kDa protein band while cromolyn had no effect on protein phosphatase action in
      vitro. The insensitivity of the 78 kDa protein phosphorylation to calcium and
      protein kinase C activators suggests that an atypical protein kinase C isozyme
      may be involved. Western blot analysis identified the presence of isozymes alpha,
      beta, delta and zeta, of which only the latter fits the profile suggested by the
      present findings.

PMID- 10357264
TI  - Microcapsules prepared from alginate and a photosensitive poly(L-lysine).
AB  - A photosensitive polymer, alpha-phenylcinnamylideneacetylated poly(L-lysine), was
      synthesized and characterized. This photosensitive poly(L-lysine) had 10% of its
      lysine residues reacted with alpha-phenylcinnamylidene acetyl group and displayed
      an absorption maximum at 329 nm. The photosensitive poly(L-lysine) was used for
      the preparation of microcapsules. The capsules formed from this photosensitive
      poly(L-lysine) and alginate were strengthened significantly by light irradiation.
      The photo cross-linked capsular membrane was permeable to proteins with mass
      transfer rate in the descending order: cytochrome C, myoglobin. and serum
      albumin. GH3 (a rat pituitary tumor cell line) cells were encapsulated and
      cultured with this microencapsulation system. The cells proliferated to a density
      of about 4 x 10(5) cells ml(-1) in the capsules after 6 days cultivation.

PMID- 10357265
TI  - Polyelectroylte complex composed of chitosan and sodium alginate for wound
      dressing application.
AB  - Drug-impregnated polyelectrolyte complex (PEC) sponge composed of chitosan and
      sodium alginate was prepared for wound dressing application. The morphological
      structure of this wound dressing was observed to be composed of a dense skin
      outer layer and a porous cross-section layer by scanning electron microscopy
      (SEM). Equilibrium water content and release of silver sulfadiazine (AgSD) could
      be controlled by the number of repeated in situ PEC reactions between chitosan
      and sodium alginate. The release of AgSD from AgSD-impregnated PEC wound dressing
      in PBS buffer (PH = 7.4) was dependent on the number of repeated in situ complex
      formations for the wound dressing. The antibacterial capacity of AgSD-impregnated
      wound dressing was examined in agar plate against Pseudomonas aeruginosa and
      Staphylococcus aureus. From the behavior of antimicrobial release and the
      suppression of bacterial proliferation, it is thought that the PEC wound dressing
      containing antimicrobial agents could protect the wound surfaces from bacterial
      invasion and effectively suppress bacterial proliferation. In the cytotoxicity
      test, cellular damage was reduced by the controlled released of AgSD from the
      sponge matrix of AgSD-medicated wound dressing. In vivo tests showed that
      granulation tissue formation and wound contraction for the AgSD plus
      dihydroepiandrosterone (DHEA) impregnated PEC wound dressing were faster than any
      other groups.

PMID- 10357266
TI  - Ability of the exopolymer excreted by Pseudoalteromonas antarctica NF3, to coat
      liposomes and to protect these structures against octyl glucoside.
AB  - The ability of an exopolymer of glycoproteic character (GP) excreted by a new
      gram-negative specie Pseudoalteromonas antarctica NF3, to coat
      phosphatidylcholine (PC) liposomes and to protect these bilayers against the
      action of the nonionic surfactant octyl glucoside (OG) has been investigated. TEM
      micrographs of freeze-fractured liposome/GP aggregates reveal that the addition
      of GP to liposomes led to the formation of a covering structure (polymer adsorbed
      onto the bilayers) that tightly coated PC bilayers. The complete coating was
      already achieved when the proportion of GP assembled with liposomes was
      approximately 10% (wt% vs total PC). Higher GP amounts resulted in a growth of
      this coating structure which exhibited at the highest GP proportion in the system
      (31% of assembled GP) a multilayered structure. An increasing resistance of PC
      liposomes to be affected by OG both at sublytic and lytic levels occurred as the
      proportion of GP in the system rose; this protective effect being more effective
      when the proportion of assembled GP was 10-20% in weight. Thus, although a direct
      dependence was found between the growth of the enveloping structure and the
      resistance of the coated liposomes to be affected by OG, the best protection
      occurred when the proportion of assembled GP was about 10 wt%.

PMID- 10357267
TI  - DNA complexes with block and graft copolymers of N-(2
      hydroxypropyl)methacrylamide and 2-(trimethylammonio)ethyl methacrylate.
AB  - Block and graft copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) with 2
      (trimethylammonio)ethyl methacrylate (TMAEM) were synthesized for the preparation
      of polyelectrolyte complexes with calf thymus DNA intended for targeted delivery
      of genes in vivo. In this study, the effects of the poly(HPMA) content of
      copolymers on the parameters of the interpolyelectrolyte complexes is
      investigated. Static and dynamic light scattering methods were used as a main
      tool for characterization. The ability of the copolymers to condense DNA was
      studied by the ethidium bromide displacement method. The stability of the
      complexes against precipitation in 0.15 M NaCl and the resistance of the
      complexed DNA to the action of nucleases was also studied. It was found that the
      presence of poly(HPMA) in the copolymers has not significantly affected the
      ability of poly(TMAEM) parts of the copolymers to form complexes with DNA, but
      has an effect on molecular parameters and aggregation (precipitation) of the
      complexes. The size of the complexes increases with increasing poly(HPMA) content
      while their apparent molecular weight decreases. The complex stability against
      precipitation in 0.15 M NaCl strongly depends on the amount of poly(HPMA) in the
      copolymer structure. The presence of a sufficiently high content of poly(HPMA) is
      a prerequisite for achieving good stability. The structure of the complexes
      changes with increasing poly(HPMA) content from soft balls to the polymer coil.
      The density of the complexes decreases with increasing poly(HPMA) content
      independently of the copolymer structure. The DNA complexes of all copolymers
      showed very good nuclease stability.

PMID- 10357268
TI  - Synthesis and characterization of pH-sensitive dextran hydrogels as a potential
      colon-specific drug delivery system.
AB  - pH-Sensitive dextran hydrogels were prepared by activation of dextran (T-70) with
      4-nitrophenyl chloroformate, followed by conjugation of the activated dextran
      with 4-aminobutyric acid and cross-linking with 1,10-diaminodecane. The cross
      linking efficiencies determined by mechanical measurements were in the range of
      52-63%. Incorporation of carboxylpropyl groups in dextran hydrogels led to a
      higher equilibrium and faster swelling under high pH conditions. The swelling
      reversibility of hydrogels was also observed after repeated changes in buffers
      between pH 2.0 and 7.4. The slow rates of swelling and deswelling in response to
      changes in pH were attributed to the hydrophilic nature of dextran and formation
      of hydrogen bonds between the hydroxyl groups of dextran with water molecules.
      The pronounced effect of carboxylic acid content on degradation of hydrogels was
      observed after 4 h of incubation with dextranase and the influence significantly
      decreased after exposure to the enzyme for 8 h. The mechanism of bulk degradation
      of hydrogels under high swelling extent was substantiated using Coomassie blue
      protein assay. The release rate of bovine serum albumin from hydrogels was
      primarily determined by the swelling extent. The release rate was further
      enhanced by addition of dextranase in buffer solutions.

PMID- 10357269
TI  - Enterococci at the crossroads of food safety?
AB  - Enterococci are gram-positive bacteria and fit within the general definition of
      lactic acid bacteria. Modern classification techniques resulted in the transfer
      of some members of the genus Streptococcus, notably some of the Lancefield's
      group D streptococci, to the new genus Enterococcus. Enterococci can be used as
      indicators of faecal contamination. They have been implicated in outbreaks of
      foodborne illness, and they have been ascribed a beneficial or detrimental role
      in foods. In processed meats, enterococci may survive heat processing and cause
      spoilage, though in certain cheeses the growth of enterococci contributes to
      ripening and development of product flavour. Some enterococci of food origin
      produce bacteriocins that exert anti-Listeria activity. Enterococci are used as
      probiotics to improve the microbial balance of the intestine, or as a treatment
      for gastroenteritis in humans and animals. On the other hand, enterococci have
      become recognised as serious nosocomial pathogens causing bacteraemia,
      endocarditis, urinary tract and other infections. This is in part explained by
      the resistance of some of these bacteria to most antibiotics that are currently
      in use. Resistance is acquired by gene transfer systems, such as conjugative or
      nonconjugative plasmids or transposons. Virulence of enterococci is not well
      understood but adhesins, haemolysin, hyaluronidase, aggregation substance and
      gelatinase are putative virulence factors. It appears that foods could be a
      source of vancomycin-resistant enterococci. This review addresses the issue of
      the health risk of foods containing enterococci.

PMID- 10357270
TI  - Screening and selection of acid and bile resistant bifidobacteria.
AB  - Human fecal samples were used as a source of Bifidobacterium strains which are
      resistant to both acid and bile. The procedure used for screening was as follows:
      enrichment of Bifidobacterium strains with Bifidobacterium-selective transgalacto
      oligosaccharide-propionate (TP) medium followed by acid (pH 2.0) and bile salt
      stressing (1.5% bile salt (w/v)). Two selected Bifidobacterium strains,
      designated HJ 30 and SI 31, showed considerably higher rates of survival when
      incubated in 50 mM phosphate buffer solution adjusted to pH 2.0 or 3.0 or in 50
      mM phosphate buffer (pH 7.0) containing 0.5 or 1.0% (w/v) bile salt. HJ 30 and SI
      31 were the only strains to have significant growth in Man Rogosa Sharpe (MRS)
      medium at 0.15% bile salt. All strains tested had similar growth rates in the
      absence of bile or at an initial pH value of 5.0 or 7.0 as determined by optical
      density measurements. For SI 31 the number of viable cell counts remained high (6
      x 10(7) cfu/ml) for up to 72 h when grown in the skim milk medium, whereas all
      other strains examined declined to below 10(5) cfu/ml. These results demonstrate
      that the screening procedures developed in this study are effective for the
      selection of acid and bile resistant Bifidobacterium strains.

PMID- 10357272
TI  - The use of a fluorescent bacteriophage assay for detection of Escherichia coli
      O157:H7 in inoculated ground beef and raw milk.
AB  - The objective of this study was to develop a fluorescent bacteriophage assay
      (FBA) for the detection of E. coli O157:H7 in ground beef and raw milk. The FBA
      is a two step assay that combines immunomagnetic separation, to separate the
      target organism from mixed culture, with a highly specific fluorescently stained
      bacteriophage to label the E. coli O157:H7 cells. When used in conjunction with
      flow cytometry, the FBA was able to detect 2.2 CFU/g of artificially contaminated
      ground beef following a 6 h enrichment. Between 10(1) and 10(2) CFU/ml of
      artificially contaminated raw milk were detectable after a 10 h enrichment step.
      The results show that the FBA is potentially useful as a rapid technique for the
      preliminary detection of E. coli O157:H7 in food.

PMID- 10357271
TI  - Inhibition of Listeria monocytogenes by Carnobacterium spp. strains in a
      simulated cold smoked fish system stored at 4 degrees C.
AB  - Preservation of smoked salmon from bacterial spoilage, and especially from
      Listeria monocytogenes by bacteriocin producers is a promising challenge. Over a
      hundred lactic acid bacteria, isolated from commercial vacuum packaged cold
      smoked salmon, were screened for their antagonistic activity against L. innocua.
      Twenty-two strains were able to produce bacteriocin-like proteinaceous
      substances. These strains were characterized physiologically and biochemically as
      Carnobacterium strains. Three different groups were determined by pulsed-field
      gel electrophoresis after Sma I and Apa I DNA digestion. Peptidoglycan hydrolases
      patterns completed the characterization of these strains. All were confirmed as
      being Carnobacterium piscicola. Growth and bacteriocin production of three
      strains of each group and two well known bacteriocin producers (C. divergens V41
      and C. piscicola V1) were tested in a simulated cold smoked fish system at 4
      degrees C. These strains were able to reach 10(8) cfu ml(-1) in 21 days and to
      produce as much bacteriocin activities in the cold smoked fish system as in the
      rich media. Carnobacterium divergens V41 and C. piscicola V1 were the most
      effective strains in co-culture experiments, inhibiting L. monocytogenes as early
      as day 4, whereas C. piscicola SF668 inhibiting effect was observed at day 13.
      The potential for using such biopreservation treatments on whole smoked salmon is
      discussed.

PMID- 10357273
TI  - Risk analysis of the thermal sterilization process. Analysis of factors affecting
      the thermal resistance of microorganisms.
AB  - A risk analysis was applied to experimental heat resistance data. This analysis
      is an approach for processing experimental thermobacteriological data in order to
      study the variability of D and z values of target microorganisms depending on the
      deviations range of environmental factors, to determine the critical factors and
      to specify their critical tolerance. This analysis is based on sets of
      sensitivity functions applied to a specific case of experimental data related to
      the thermoresistance of Clostridium sporogenes and Bacillus stearothermophilus
      spores. The effect of the following factors was analyzed: the type of target
      microorganism; nature of the heating substrate; pH, temperature; type of acid
      employed and NaCl concentration. The type of target microorganism to be
      inactivated, the nature of the substrate (reference or real food) and the heating
      temperature were identified as critical factors, determining about 90% of the
      alteration of the microbiological risk. The effect of the type of acid used for
      the acidification of products and the concentration of NaCl can be assumed to be
      negligible factors for the purposes of engineering calculations. The critical non
      uniformity in temperature during thermobacteriological studies was set as 0.5%
      and the critical tolerances of pH value and NaCl concentration were 5%. These
      results are related to a specific case study, for that reason their direct
      generalization is not correct.

PMID- 10357274
TI  - Heat resistance of Yersinia enterocolitica grown at different temperatures and
      heated in different media.
AB  - In the range of 4-20 degrees C, growth temperature did not influence the heat
      resistance at 54-66 degrees C for Yersinia enterocolitica at pH 7 in citrate
      phosphate buffer. However, when cells were grown at 37 degrees C. the D62
      increased from 0.044 to 0.17 min. This increase was constant at all heating
      temperatures tested (z = 5.7-5.8). Growth temperature did not influence the
      proportion of heat-damaged cells after a heat treatment, as measured by their
      response to a 2% of sodium chloride added to the recovery medium. The sensitivity
      of heat treated cells to nisin or lysozyme depended on growth temperature:
      Whereas the number of cells grown at 4 degrees C surviving heat treatment was the
      same regardless of the presence of 100 IU/ml of nisin or 100 microg/ml of
      lysozyme in the recovery medium, that of cells grown at 37 degrees C was, in
      these media, lower. The pH of maximum heat resistance in citrate phosphate buffer
      was pH 7 for cells grown at 37 degrees C, but pH 5 for those grown at 4 degrees
      C. In both suspensions the magnitude of the effect of pH on heat resistance was
      constant at all heating temperatures. For cells grown at 4 degrees C the heat
      resistance at 54-66 degrees C, in skimmed milk or pH 7 buffer, was the same. For
      cells grown at 37 degrees C this also applied for heat treatment at 66 degrees C
      but at 56 degrees C the heat resistance in skimmed milk was higher.

PMID- 10357275
TI  - The antifungal properties of chitosan in laboratory media and apple juice.
AB  - The antimicrobial properties of chitosan glutamate, a derivative of chitin, were
      investigated in laboratory media and apple juice against 15 yeasts and moulds
      associated with food spoilage in order to assess the potential for using chitosan
      as a natural food preservative. Of the seven strains of filamentous fungi
      studied, chitosan reduced the growth rate of Mucor racemosus at 1 g/l whilst
      concentrations of 5 g/l were required to completely prevent growth of three
      strains of Byssochlamys spp. on agar plates incubated at 25 degrees C for 3
      weeks. Three strains of filamentous fungi were resistant to the antifungal
      effects of chitosan at 10 g/l. The presence of chitosan in apple juice (pH 3.4)
      at levels ranging from 0.1 to 5 g/l inhibited growth at 25 degrees C of all eight
      spoilage yeasts examined in this study. The initial effect of chitosan in apple
      juice was biocidal with viable numbers reduced by up to 3 log cycles. Following
      an extended lag phase, some strains recovered and resumed growth to levels
      similar to those observed in unsupplemented apple juice. The most sensitive
      strain was an isolate of Zygosaccharomyces bailii obtained from a spoiled
      carbonated beverage; this yeast was completely inactivated by chitosan at 0.1 and
      0.4 g/l for 32 days of storage at 25 degrees C. The most resistant strain was
      Saccharomycodes ludwigii, an isolate from spoiled cider: a level of addition of 5
      g/l of chitosan was required to inactivate this strain and to maintain yeast-free
      conditions in apple juice for 14 days at 25 degrees C. Growth inhibition and
      inactivation of filamentous moulds and yeasts, respectively, was concentration-,
      pH- and temperature-dependent. It was concluded that chitosan was worthy of
      further study as a natural preservative for foods prone to fungal spoilage.

PMID- 10357276
TI  - Isolation and identification of lactobacilli from novel-type probiotic and mild
      yoghurts and their stability during refrigerated storage.
AB  - A total of 26 Lactobacillus strains were isolated from various mild yoghurts and
      novel-type probiotic dairy products and from a starter culture preparation and
      were identified by using DNA-DNA hybridization technique. The species present in
      those products were found to be Lactobacillus acidophilus, L. johnsonii, L.
      crispatus, L. casei, L. paracasei and L. rhamnosus. DNA homology analysis
      revealed that some strains had been misclassified by their investigators. Three
      strains designated as L. acidophilus (L. acidophilus LA-1, L. acidophilus ATCC
      43121 and the Lactobacillus strain from Biogarde culture) were found to belong to
      L. johnsonii and L. acidophilus L1 to be L. crispatus. Strains designated as L.
      casei were found to be members of three separate species: L. casei, L. paracasei
      and L. rhamnosus. Viable numbers of lactobacilli in mild and probiotic yoghurts
      varied greatly including some products with very low Lactobacillus counts. The
      majority of the probiotic yoghurts, however, contained viable counts above 10(5)
      per g even at the end of the best before use period.

PMID- 10357277
TI  - Analysis of the bacterial surface ripening flora of German and French smeared
      cheeses with respect to their anti-listerial potential.
AB  - The anti-listerial potential of 19 different French smeared cheese bacterial
      consortia was analyzed semi-quantitatively. Comparison of the total viable cell
      count to the direct microscopic count yielded no indication that non-culturable
      bacteria contribute significantly to the undefined, complex ripening floras. From
      2613 isolates, 48 showed clear inhibition of one or more Listeria monocytogenes
      strains on solid medium, while only three isolates excreted an anti-listerial,
      soluble substance when grown in liquid culture. From a total of 299 strains
      isolated from German dairy products, 30 strains inhibited at least one L.
      monocytogenes indicator strain on solid medium. Bacteria with antilisterial
      potential were members of the genera Arthrobacter, Brevibacterium,
      Corynebacterium, Enterococcus, Micrococcus and Microbacterium. Cluster analysis
      of inhibition pattern revealed that similar anti-listerial substances are
      produced by species belonging to different genera. Half of the strains inhibited
      six or more out of 12 Listeria indicator strains and are promising candidates for
      the development of a defined red smear cheese ripening flora. L. monocytogenes
      originating from red-smear cheese had a tendency to be more resistant towards
      anti-listerial activity than those isolated from other sources.

PMID- 10357278
TI  - A model based on absorbance data on the growth rate of Listeria monocytogenes and
      including the effects of pH, NaCl, Na-lactate and Na-acetate.
AB  - A mathematical model was developed for predicting the growth of L. monocytogenes
      at 9 degrees C in the presence of 70 ppm sodium nitrite, and at different levels
      of pH (5.5-6.5), sodium chloride (1.0-4.0%), sodium lactate (0-0.5%) and sodium
      acetate (0-0.6%). Collection of the growth data was done using absorbance
      measurements in broth cultures and the absorbance measurement was evaluated. The
      model was compared to the Food MicroModel, and against the growth of L.
      monocytogenes in a vacuum-packed meat product stored at 9 degrees C. A linear
      relationship was obtained, for the absorbance data on different dilutions of the
      inoculum, in the absorbance interval studied. There was also a linear
      relationship between the values of the maximum specific growth rates derived from
      the absorbance and the ones derived from viable count measurements; and
      corrections were made accordingly. The statistical evaluation showed that all the
      main factors, i.e. pH, sodium chloride, sodium lactate and sodium acetate were
      statistically significant for the growth rate of L. monocytogenes. Comparison to
      the Food MicroModel (FMM) showed a slight underprediction for the developed model
      (bias = 0.84). The predictions were, on average, within 20% of the FMM
      predictions (n = 10). Validation against the observed growth of L. monocytogenes
      inoculated into an emulsion type of sausage (n = 4) also showed a slight
      underprediction by the model. The predictions were, on average, 16% below the
      observed values in the sausage (Bias 0.84, Accuracy 1.26).

PMID- 10357279
TI  - Occurrence and typing of Listeria monocytogenes strains in retail vacuum-packed
      fish products and in a production plant.
AB  - One hundred and ten samples of ready-to-eat, vacuum-packed, smoked and cold
      salted fish products were collected from retail outlets in southern Finland
      during 1996 for examination of the occurrence and level of Listeria
      monocytogenes. The samples originated from 12 producers. Positive samples with
      levels exceeding 100 CFU/g were encountered mainly in one of the producers (no.
      8). Therefore, 200 samples from the plant and the products of this producer were
      studied during August-September 1996 and May-September 1997, as well as 55
      samples from the six fish farms providing raw material fish to this plant, during
      September 1997-January 1998. The isolates were characterised by serotyping and
      pulsed-field gel electrophoresis (PFGE). L. monocytogenes was isolated in 20%
      (22/110) of the samples from the retail market, originating from 6 producers. Ten
      of these positive samples contained L. monocytogenes at > 100 CFU/g (maximum 1.37
      X 10(4) CFU/g). Seventeen percent (5/30) of cold-smoked and 50% (16/32) of cold
      salted rainbow trout samples were contaminated. Only one hot-smoked fish product
      (2%) was found to be positive by enrichment. Nineteen (86%) of the strains
      isolated from the retail samples belonged to serovar 1/2a and three (14%) to
      serovar 4b. In further studies the production line of plant no. 8 was found to be
      contaminated. All of isolates from up until autumn, 1997 both the products and
      the production plant were serovar 1/2a; thereafter one strain of 4b and one of
      1/2 (H-antigen untypeable) were isolated from the plant. The samples from raw
      material fish were all negative for L. monocytogenes. The samples from retail
      market fell into seven PFGE types. Five and nine PFGE types, respectively, were
      found from the products and the plant of producer no. 8. PFGE type A was detected
      from the retail products of four producers and was also dominant among the
      isolates from production plant no. 8. PFGE type A was the only one found
      repeatedly from skinning, salting and slicing units as well as from products
      throughout the whole period. PFGE proved to be a powerful tool for studying
      contamination points and routes in the production plant. The measures based on
      hazard analysis critical control points (HACCP) program resulted in L.
      monocytogenes negative samples at production plant no. 8 from the beginning of
      January 1998.

PMID- 10357280
TI  - Ribotyping as an identification tool for Clostridium botulinum strains causing
      human botulism.
AB  - Ribotyping was used for characterisation of 68 Clostridium botulinum strains and
      five related Clostridium species to determine the applicability of this method
      for identification of species causing human botulism. Thirteen restriction
      enzymes were initially tested for suitability for ribotyping of C. botulinum, of
      which EcoRI and HindIII were selected. Both enzymes clearly differentiated
      between proteolytic (group I) and a nonproteolytic (group II) strains of C.
      botulinum, and can be recommended for Group/species identification. Using a
      commercial software package (GelCompar), a numerical analysis of the
      discriminatory abilities of EcoRI and HindIII ribotyping within and between the
      two C. botulinum groups was performed. EcoRI had the higher discriminatory index
      (0.982), but the ribopatterns generated with group II strains were partly muddled
      and difficult to interpret. All HindIII ribopatterns were easy to analyse and the
      discriminatory index for all strains was almost equally high (0.954), whereas
      this enzyme did not discriminate well between group I isolates. The Clostridium
      strains diverged at 35+/-13% (mean+/-standard deviation) Dice similarity in
      dendrograms based on cluster analysis of the ribotyping results. These findings
      are in good agreement with taxonomical ribotyping studies with other bacterial
      genera, indicating that ribotyping is a highly suitable method for C. botulinum
      species identification.

PMID- 10357282
TI  - Predicting fungal growth: the effect of water activity on Penicillium roqueforti.
AB  - The effect of water activity on the colony growth of Penicillium roqueforti is
      studied by predictive modelling techniques. Measured colony diameter growth
      curves are fitted to estimate the growth rate and lag phase of the curves. The
      colony growth rate was modelled by a quadratic function of transformed water
      activity (a(w)) values, as suggested by Baranyi et al. (Food Microbiol. 10 (1993)
      43-59). The lag time was modelled as a function of water activity, by means of
      the sum of a constant term and a hyperboloid function of a(w) raised to the
      second power. The lag-phase of Penicillium roqueforti was found insensitive to
      the water activity in the range of its higher (a(w) > 0.92) values.

PMID- 10357281
TI  - Saccharomyces cerevisiae cell fatty acid composition and release during
      fermentation without aeration and in absence of exogenous lipids.
AB  - Medium-chain fatty-acids (MCFA) are among the main aroma compounds of fermented
      beverages. High concentrations of MCFA have been found in sluggish and stuck
      fermentations. It has been suggested that they arrest cell growth, as they may be
      toxic, but the causes of sluggish and stuck fermentations are still unclear. The
      aim of this work was to see whether the production of MCFA is related to fatty
      acid synthesis in the absence of exogenous lipids and aeration, and whether their
      increase can be regarded as a consequence, instead of the cause, of sluggish and
      stuck fermentations. Two possibilities were considered: (i) MCFA are produced to
      replace unsaturated fatty acids (UFA) for cell membrane fluidity when the lack of
      oxygen makes desaturation of saturated fatty acids (SFA) impossible; or (ii) MCFA
      are produced following the release of medium-chain acyl-CoA from the fatty acid
      synthetase complex (FAS) due to the accumulation of SFA, and their hydrolysis to
      recycle CoA-SH. In the first hypothesis, MCFA should be active in cell metabolism
      and be found in cell structures; in the second, MCFA should be a discard and
      prevalently found outside the cell. We carried out a Saccharomyces cerevisiae
      fermentation experiment in a synthetic, lipid-free medium without aeration. We
      measured the fatty acid composition of yeast cells and the amounts of MCFA and
      their ethyl esters in the medium throughout the fermentation. Cell growth and the
      oxygen content of the medium were also monitored. We found that MCFA are not
      immobilized in cell structures, but mainly released into the medium. Cell growth
      is arrested because fatty acid biosynthesis is prevented by the lack of oxygen.
      The higher MCFA concentrations found in sluggish and stuck fermentations can be
      thus regarded as an effect, and not the cause, of this arrest. Some suggestions
      for the prevention of these events are proposed.

PMID- 10357283
TI  - Comparison between automatic ribotyping and random amplified polymorphic DNA
      analysis of Bacillus cereus isolates from the dairy industry.
AB  - Discrimination by automatic ribotyping and random amplified polymorphic DNA PCR,
      RAPD, was compared for 40 different B. cereus dairy isolates, 4 different B.
      mycoides isolates and 6 culture collection strains. RAPD-PCR has previously shown
      to be useful for tracing contamination routes of B. cereus to milk. Automatic
      ribotyping using EcoRI and PvuII separated the B. cereus and B. mycoides
      isolates/strains into 36 different ribotypes. RAPD-typing with primers generated
      40 different RAPD-profiles. However, 17 isolates clustered into eight groups,
      irrespective of the primer and restriction enzyme used, and in all but one case,
      the isolates with the same pattern were isolated from the same dairy. Automatic
      ribotyping proved to be a useful, standardized and quick method to discriminate
      between B. cereus strains, only slightly less discriminatory than RAPD-typing.

PMID- 10357284
TI  - Glucosamine content of tempe mould, Rhizopus oligosporus.
AB  - The glucosamine content of Rhizopus oligosporus NRRL 2710 mycelium grown in
      different media was determined. In Sabouraud dextrose broth the glucosamine
      content ranged from 51 g (kg dry biomass)(-1) for mycelial pellets less than 5 mm
      diameter to 107 g kg(-1) for pellets 16-35 mm diameter. Mycelium grown on
      Sabouraud dextrose agar contained 111 g glucosamine (kg dry biomass)(-1) while
      that grown on soymilk agar, used to simulate growth on soybeans in tempe,
      contained 82 g kg(-1). The estimation of glucosamine was reproducible, with a
      mean coefficient of variation of 4% for mycelial pellets and 11% for mycelium
      from agar media. It is suggested that a conversion factor of 12 g dry biomass (g
      glucosamine)(-1) is applicable to determine fungal biomass in tempe fermentation.

PMID- 10357285
TI  - Planning and accountability at AHCPR: applying the quality message at home.
      Agency for Health Care Policy and Research.

PMID- 10357286
TI  - Quality of primary care practice in a large HMO according to physician specialty.
AB  - OBJECTIVE: To determine whether physician specialty was associated with
      differences in the quality of primary care practice and patient satisfaction in a
      large, group model HMO. DATA SOURCES/STUDY SETTING: 10,608 patients ages 35-85
      years, selected using stratified probability sampling from the primary care
      panels of 60 family physicians (FPs), 245 general internists (GIMs), and 55
      subspecialty internists (SIMs) at 13 facilities in the Kaiser Permanente Medical
      Care Program of Northern California. Patients were surveyed in 1995. STUDY
      DESIGN: A cross-sectional patient survey measured patient reports of physician
      performance on primary care measures of coordination, comprehensiveness, and
      accessibility of care, preventive care procedures, and health promotion.
      Additional items measured patient satisfaction and health values and beliefs.
      PRINCIPAL FINDINGS: Patients were remarkably similar across physician specialty
      groups in their health values and beliefs, ratings of the quality of primary
      care, and satisfaction. Patients rated GIMs higher than FPs on coordination
      (adjusted mean scores 68.0 and 58.4 respectively, p<.001) and slightly higher on
      accessibility and prevention; GIMs were rated more highly than SIMs on
      comprehensiveness (adjusted mean scores 76.4 and 73.8, p<.01). There were no
      significant differences between specialty groups on a variety of measures of
      patient satisfaction. CONCLUSIONS: Few differences in the quality of primary care
      were observed by physician specialty in the setting of a large, well-established
      group model HMO. These similarities may result from the direct influence of
      practice setting on physician behavior and organization of care or, indirectly,
      through the types of physicians attracted to a well-established group model HMO.
      In some settings, practice organization may have more influence than physician
      specialty on the delivery of primary care.

PMID- 10357288
TI  - Commentary: practice environment, specialty, and primary care.

PMID- 10357287
TI  - Differences in resource use and costs of primary care in a large HMO according to
      physician specialty.
AB  - OBJECTIVE: To determine if primary care physician specialty is associated with
      differences in use of health services. DATA SOURCES: Automated outpatient
      diagnostic, utilization, and cost data on 15,223 members (35-85 years of age) of
      a large group model HMO. STUDY DESIGN: One-year prospective comparison of primary
      care provided by 245 general internists (GIMs), 60 family physicians (FPs), and
      55 subspecialty internists (SIMs) with case-mix assessed during a nine-month
      baseline period using Ambulatory Diagnostic Groups. PRINCIPAL FINDINGS: Adjusting
      for demographics and case mix, patients of GIMs and FPs had similar
      hospitalization and ambulatory visit rates, and similar laboratory and radiology
      costs. Patients of FPs made fewer visits to dermatology, psychiatry, and
      gynecology (combined visit rate ratio: 0.86, 95% CI: 0.74-0.96). However, they
      made more urgent care visits (rate ratio 1.19, 95% CI: 1.07-1.23). Patients of
      SIMs had higher hospitalization rates than those of GIMs (rate ratio 1.33, 95%
      CI: 1.06-1.68), greater use of urgent care (rate ratio: 1.14, 95% CI: 1.04-1.25),
      and higher costs for pharmacy (cost ratio: 1.17, 95% CI: 0.93-1.18) and
      radiologic services (cost ratio: 1.14, 95% CI: 1.01-1.30). The hospitalization
      difference was due partly to the inclusion of patients with specialty-related
      diagnoses in panels of SIMs. Radiology and pharmacy differences persisted after
      excluding these patients. CONCLUSIONS: In this uniform practice environment,
      specialty differences in primary care practice were small. Subspecialists used
      slightly more resources than generalists. The broader practice style of FPs may
      have created access problems for their patients.

PMID- 10357289
TI  - Prostate cancer treatment and ten-year survival among group/staff HMO and fee-for
      service Medicare patients.
AB  - OBJECTIVE: To compare treatment patterns and the ten-year survival of prostate
      cancer patients in two large, nonprofit, group/staff HMOs to those of patients
      receiving care in the fee-for-service health setting. DATA SOURCES/STUDY DESIGN:
      A cohort of men age 65 and over diagnosed with prostate cancer between 1985 and
      the end of 1992 and followed through 1994. Subjects (n = 21,741) were ascertained
      by two population-based tumor registries covering the greater San Francisco
      Oakland and Seattle-Puget Sound areas. Linkage of registry data with Medicare
      claims data and with HMO inpatient utilization data allowed the determination of
      health plan enrollment and the measurement of comorbid conditions. Multivariate
      regression models were used to examine HMO versus FFS treatment and survival
      differences adjusting for sociodemographic and clinical characteristics.
      PRINCIPAL FINDINGS: Among cases with non-metastatic prostate cancer, HMO patients
      were more likely than FFS patients to receive aggressive therapy (either
      prostatectomy or radiation) in San Francisco-Oakland (odds ratio [OR] = 1.69, 95%
      CI = 1.46-1.96) but not in Seattle (OR = 1.15, 0.93-1.43). Among men receiving
      aggressive therapy, HMO cases were three to five times more likely to receive
      radiation therapy than prostatectomy. Overall mortality was equivalent over ten
      years (HMO versus FFS mortality risk ratio [RR] = 1.01, 0.94-1.08), but prostate
      cancer mortality was higher for HMO cases than for FFS cases (RR = 1.25, 1.13
      1.39). CONCLUSION: Despite marked treatment differences for clinically localized
      prostate cancer, overall ten-year survival for patients enrolled in two nonprofit
      group/staff HMOs was equivalent to survival among patients receiving care in the
      FFS setting, even after adjustment for sociodemographic and clinical
      characteristics. Similar overall but better prostate cancer-specific survival
      among FFS patients is most plausibly explained by differences between the HMO and
      FFS patients in both tumor characteristics and unmeasured patient selection
      factors.

PMID- 10357290
TI  - No exit? The effect of health status on dissatisfaction and disenrollment from
      health plans.
AB  - OBJECTIVE: To examine the implications of serious and chronic health problems on
      the willingness of enrollees to switch health plans if they are dissatisfied with
      their current arrangements. DATA SOURCE: A large (20,283 respondents) survey of
      employees of three national corporations committed to the model of managed
      competition, with substantial enrollment in four types of health plans: fee-for
      service, prepaid group practice, independent practice associations, and point-of
      service plans. STUDY DESIGN: A set of logistic regression models are estimated to
      determine the probability of disenrollment, if dissatisfied, controlling for the
      influence on satisfaction and disenrollment of age, race, education, family
      income and size, gender, marital status, mental health status, pregnancy,
      duration of employment and enrollment in the plan, number of alternative plans,
      and HMO penetration in the local market. Separate coefficients are estimated for
      enrollees with and without significant physical health problems. Additional
      models are estimated to test for the influence of selection effects as well as
      alternative measures of dissatisfaction and health problems. DATA COLLECTION:
      Data were collected through a mailed survey with a response rate of 63.5 percent;
      comparisons to a subsample administered by telephone showed few differences.
      PRINCIPAL FINDINGS: In group/staff model HMOs and point-of-service plans, only 12
      17 percent of the chronically ill enrollees who were so dissatisfied when
      surveyed that they intended to disenroll actually left their plan in the next
      open enrollment period. This compared to 25-29 percent of the healthy enrollees
      in these same plans, who reported this level of dissatisfaction and 58-63 percent
      of the enrollees under fee-for-service insurance. CONCLUSIONS: Switching plans
      appears to be significantly limited for enrollees with serious health problems,
      the very enrollees who will be best informed about the ability of their health
      plan to provide adequate medical care. These effects are most pronounced in plans
      that have exclusive contracts with providers. We conclude that disenrollment
      provides only weak safeguards on quality for the sickest enrollees and that
      reported levels of dissatisfaction and disenrollment represent inaccurate signals
      of plan performance.

PMID- 10357291
TI  - Assertive community treatment for people with severe mental illness: the effect
      on hospital use and costs.
AB  - OBJECTIVE: To determine the effect of the Program for Assertive Community
      Treatment (PACT) model on psychiatric inpatient service use in a population of
      non-emergency psychiatric patients with severe chronic mental illness, and to
      test for variations in this effect with program staffing levels and patient
      characteristics such as race and age. DATA SOURCES/STUDY SETTING: Data are taken
      from a randomized trial of PACT in Charleston, South Carolina for 144 patients
      recruited from August 1989 through July 1991. STUDY DESIGN: Subjects were
      randomly assigned either to one of two PACT programs or to usual care at a local
      mental health center. Effects on hospital use were measured over an 18-month
      follow-up period via multiple regression analysis. DATA COLLECTION METHODS: Data
      were obtained from Medicaid claims, chart reviews, subject, case manager, and
      family interviews; searches of the computerized patient and financial databases
      of the South Carolina Department of Mental Health and relevant hospitals; and
      searches of the hard copy and computerized financial databases of the two major
      local hospitals providing inpatient psychiatric care. PRINCIPAL FINDINGS: PACT
      participants were about 40 percent less likely to be hospitalized during the
      follow-up period. The effect was stronger for older patients. Lower PACT
      client/staff ratios also reduced the risk of hospitalization. No evidence of
      differential race effects was found. Given some hospital use, PACT did not
      influence the number of days of use. CONCLUSIONS: Controlling for other
      covariates, PACT significantly reduces hospitalizations but the size of this
      effect varies with patient and program characteristics. This study shows that
      previous results on PACT can be applied to non-emergency patients even when the
      control condition is an up-to-date CMHC office-based case management program.

PMID- 10357292
TI  - A claims data approach to defining an episode of care.
AB  - OBJECTIVE: To utilize health services research techniques in developing an
      episode of care using an administrative data set. This method is demonstrated for
      an episodic clinical condition, migraine. DATA SOURCES: Medicaid administrative
      data set of 3,372 patients with a diagnosis of migraine (ICD-9-CM 346.0, 346.1)
      in the state of Pennsylvania between May 1990 and March 1992. STUDY DESIGN: The
      duration of a migraine episode was measured by assessing the magnitude of
      resource utilization and the proportion of patients with charges in the period
      after the index migraine as compared to the period before the index migraine. A
      confidence interval (CI) was developed around each measure using bootstrap
      techniques. DATA COLLECTION METHODS: All charge data were extracted daily for a
      113-day observation period surrounding each index migraine in order to observe
      the duration of impact of a migraine diagnosis on resource utilization. PRINCIPAL
      FINDINGS: The lower limits of both the 95% and 99% CIs for the difference in
      charges are greater than 0 for three weeks. The lower limits of both CIs for the
      difference in the proportion of patients with charges are above 0 for six weeks.
      CONCLUSIONS: Our analysis demonstrates that a health services research framework
      can be used to define an episode of care for a chronic disease category such as
      migraine. This method can be used to evaluate episodes of care for clinical
      studies of limited or episodic conditions and to complement clinical expertise in
      developing time horizons for clinical trials.

PMID- 10357294
TI  - The pediatric continuity experience: do academic sites still have a role?

PMID- 10357293
TI  - Patient assessments of hospital maternity care: a useful tool for consumers?
AB  - OBJECTIVE: To examine three issues related to using patient assessments of care
      as a means to select hospitals and foster consumer choice-specifically, whether
      patient assessments (1) vary across hospitals, (2) are reproducible over time,
      and (3) are biased by case-mix differences. DATA SOURCES/STUDY SETTING: Surveys
      that were mailed to 27,674 randomly selected patients admitted to 18 hospitals in
      a large metropolitan region (Northeast Ohio) for labor and delivery in 1992-1994.
      We received completed surveys from 16,051 patients (58 percent response rate).
      STUDY DESIGN: Design was a repeated cross-sectional study. DATA COLLECTION:
      Surveys were mailed approximately 8 to 12 weeks after discharge. We used three
      previously validated scales evaluating patients' global assessments of care
      (three items)as well as assessments of physician (six items) and nursing (five
      items) care. Each scale had a possible range of 0 (poor care) to 100 (excellent
      care). PRINCIPAL FINDINGS: Patient assessments varied (p<.001) across hospitals
      for each scale. Mean hospital scores were higher or lower (p<.01) than the sample
      mean for seven or more hospitals during each year of data collection. However,
      within individual hospitals, mean scores were reproducible over the three years.
      In addition, relative hospital rankings were stable; Spearman correlation
      coefficients ranged from 0.85 to 0.96 when rankings during individual years were
      compared. Patient characteristics (age, race, education, insurance status, health
      status, type of delivery) explained only 2-3 percent of the variance in patient
      assessments, and adjusting scores for these factors had little effect on
      hospitals' scores. CONCLUSIONS: The findings indicate that patient assessments of
      care may be a sensitive measure for discriminating among hospitals. In addition,
      hospital scores are reproducible and not substantially affected by case-mix
      differences. If our findings regarding patient assessments are generalizable to
      other patient populations and delivery settings, these measures may be a useful
      tool for consumers in selecting hospitals or other healthcare providers.

PMID- 10357296
TI  - Suicide attempts among American Indian and Alaska Native youth: risk and
      protective factors.
AB  - CONTEXT: American Indians and Alaska Natives have the highest suicide rates of
      all ethnic groups in the United States, and suicide is the second leading cause
      of death for American Indian and Alaska Native youth. OBJECTIVE: To identify risk
      and protective factors associated with suicide attempts among native male and
      female adolescents. DESIGN: The 1990 National American Indian Adolescent Health
      Survey. SETTING: Schools of reservation communities in 8 Indian Health Service
      areas. PARTICIPANTS: Eleven thousand six hundred sixty-six 7th- through 12th
      grade American Indian and Alaska native youth. MAIN OUTCOME MEASURES: Responses
      were compared among adolescents with and without a self-reported history of
      attempted suicide. Independent variables included measures of community, family,
      and individual characteristics. Separate analyses were conducted for boys and
      girls. RESULTS: Ever attempting suicide was reported by 21.8% of girls and 11.8%
      of boys. By logistic regression done on boys and girls separately, suicide
      attempts were associated with friends or family members attempting or completing
      suicide; somatic symptoms; physical or sexual abuse; health concerns; using
      alcohol, marijuana, or other drugs; a history of being in a special education
      class; treatment for emotional problems; gang involvement; and gun availability.
      For male and female youth, discussing problems with friends or family, emotional
      health, and connectedness to family were protective against suicide attempts. The
      estimated probability of attempting suicide increased dramatically as the number
      of risk factors to which an adolescent was exposed increased; however, increasing
      protective factors was more effective at reducing the probability of a suicide
      attempt than was decreasing risk factors. CONCLUSIONS: A history of attempted
      suicide was associated with several risk and protective factors. In addition to
      targeting youth at increased risk, preventive efforts should include promotion of
      protective factors in the lives of all youth in this population.

PMID- 10357295
TI  - Variables influencing penicillin treatment outcome in streptococcal
      tonsillopharyngitis.
AB  - OBJECTIVE: To examine whether penicillin treatment success for group A beta
      hemolytic streptococcal tonsillopharyngitis is influenced by patient age, number
      of days ill prior to initiation of treatment, number of prior episodes, season,
      total dosage (milligrams per kilogram), and frequency of administration (2 vs 3
      times daily). METHODS: Four hundred seventy-eight children, adolescents, and
      young adults aged 2 to 21 years with acute symptoms compatible with the clinical
      diagnosis of group A beta-hemolytic streptococcal tonsillopharyngitis and a
      positive streptococcus rapid antigen detection test result were enrolled (intent
      to-treat group). Patients were randomly assigned to receive penicillin V
      potassium, 250 mg 3 times daily (n = 239) or 500 mg 2 times daily (n = 239).
      Randomization was independent of patient body weight and treatment was for 10
      days with both regimens. Follow-up examinations occurred, and cultures were
      obtained at 14 to 21 days after the initiation of antibiotic therapy; those with
      group A beta-hemolytic streptococcus isolated from a throat culture and who
      returned for follow-up were assessed for outcome (n = 359). RESULTS: Using a
      logistic regression analysis with a stepwise variable selection, we found the
      major variables associated with penicillin treatment success to be the number of
      days ill prior to initiation of treatment (P = .001; odds ratio, 1.55 [95%
      confidence interval, 1.2-2.1]) and the age of the child when infected (P = .004;
      odds ratio, 1.14 [95% confidence interval, 1.05-1.25]). The number of prior
      episodes within the preceding year, the season, the total daily penicillin dose
      (range, 8-76 mg/kg), and 2 vs 3 times daily dosing did not significantly alter
      treatment outcome. CONCLUSION: Treatment after 2 days of illness and of
      adolescent patients increases penicillin treatment success for group A beta
      hemolytic streptococcal tonsillopharyngitis.

PMID- 10357297
TI  - The effect of patient reassignment on future continuity in a pediatric resident
      continuity practice.
AB  - BACKGROUND: When residents complete their pediatric training, patients from their
      continuity practices in academic settings must be reassigned to either a known
      resident of their selection or an unknown, incoming intern. OBJECTIVES: To
      determine what antecedent factors were associated with patient reassignment to a
      known resident of their selection, whether such reassignment was associated with
      increased health care use, and what factors were associated with continuity with
      the new resident provider. DESIGN: Nonconcurrent cohort study. SETTING: Hospital
      based resident continuity clinic practice. PARTICIPANTS: Patients of residents
      graduating in June 1993. RESULTS: Seven hundred fifty-eight patients of 18
      graduating residents required reassignment: 86 patients (11%) were assigned to a
      resident colleague, defined as the study group. From the remaining 673 patients
      who were assigned to unknown, incoming interns, a control group was randomly
      selected (n = 160), with approximately 2 patients for each study group subject.
      Looking at antecedent factors, study group patients were more likely to have
      chronic medical problems and to have seen their graduating resident more often
      and more recently. Univariate analysis explored the consequent factors of health
      care use and found that study group patients were more likely to return for a
      visit and to make more visits with the new provider. Multiple logistic regression
      analysis demonstrated that being in the study group, younger age at the original
      encounter with the graduating resident, and a shorter interval since the last
      visit with the graduating resident were all associated with increased continuity
      with the new resident. CONCLUSIONS: The method of patient reassignment at a
      continuity clinic was associated with chronic disease of the patient and
      regularity of visits with the graduating resident. Increased continuity with a
      new resident, as determined by multivariate analysis, was associated with the
      method of reassignment, a younger age at first encounter with the graduating
      resident, and a shorter interval since the last visit with the graduating
      resident. This study has implications at ambulatory sites where transitions
      occur.

PMID- 10357298
TI  - Firearm storage practices and children in the home, United States, 1994.
AB  - OBJECTIVES: To estimate the national prevalence of firearm ownership and storage
      practices in the home, to compare storage practices in homes with and without
      children, and to analyze demographic characteristics related to firearm storage
      practices in homes with children. DESIGN: A 1994 random-digit dialing telephone
      survey. We weighted the data to provide national estimates. PARTICIPANTS: English
      and Spanish-speaking adults in households in 50 states and Washington, DC. MAIN
      OUTCOME MEASURES: Ownership of working powder firearm(s) in home and/or vehicle
      and firearm storage practices in the home. RESULTS: Of 5238 households surveyed,
      one third kept at least 1 firearm in the home and/or vehicle. Of 1598 households
      with firearm(s) in the home and known firearm storage practices, 21.5% kept at
      least 1 gun loaded and unlocked in the home, 30.0% stored all firearms unloaded
      and locked, and 48.5% stored firearms in a manners classified between these 2
      practices. Households with children were more likely than households without
      children to store all firearms unloaded and locked (41.5% vs 20.9%); households
      without children were more likely than households with children to store at least
      1 firearm loaded and unlocked (29.8% vs 11.1%). Among households with children
      and firearms, there were regional differences with respect to storage practices.
      CONCLUSIONS: These prevalence data show that children are potentially exposed to
      firearms in many households. This health threat illustrates the need for
      education about the issue of pediatric firearm injuries and for interventions to
      minimize associated risks. Health care providers should take advantage of
      opportunities to counsel patients regarding firearm safety in the home.

PMID- 10357299
TI  - A new brief screen for adolescent substance abuse.
AB  - OBJECTIVE: To develop a brief alcohol and other drug (AOD) screening test for
      adolescents. METHODS: A 9-item test was constructed by combining and modifying
      items from several AOD assessments, and administered concurrently with the
      Personal Involvement With Chemicals Scale (PICS), the criterion standard.
      SETTING: A hospital-based adolescent clinic. SUBJECTS: Fourteen- to 18-year-old
      patients consecutively arriving for routine medical care who were known to have
      used AOD. MEASURES: Internal consistency of the 9 items was calculated using the
      Cronbach alpha. The relationship between the brief screen and PICS raw score was
      determined by stepwise linear regression analysis. The PICS T score has been
      shown to correctly classify substance abuse treatment need as no treatment
      (T<35), brief office intervention (T = 35-40), outpatient or short-term treatment
      (T = 41-54), and inpatient or long-term treatment (T> or =55). Sensitivity and
      specificity rates for predicting a PICS T score of 55 or higher were calculated
      from 2 x 2 tables. RESULTS: Ninety-nine adolescents were tested (70.7% female,
      36.4% black, 32.3% white, 19.2% Hispanic, mean age, 16.3 years). The 9 items had
      good internal consistency (Cronbach alpha = .79). Stepwise linear regression
      analysis identified 6 items whose total combined score was highly correlated with
      PICS (Pearson r = 0.84, P<.01). This model correctly classified 86% of subjects
      according to the PICS criteria. Two or more yes answers had a sensitivity of
      92.3% and specificity of 82.1% for intensive AOD treatment need. The 6 items were
      arranged into a mnemonic (CRAFFT). CONCLUSIONS: Further research must confirm the
      test's psychometric properties in a general clinic population. However, CRAFFT
      seems promising as a brief AOD screening test.

PMID- 10357300
TI  - Improving immunization rates in private pediatric practices through physician
      leadership.
AB  - OBJECTIVE: To determine whether a physician-led quality improvement initiative
      can improve immunization rates in participating private practices. DESIGN:
      Surveys of private pediatric practices at 6-month intervals over an 18-month
      period. SETTING: Ten private pediatric practices in Norfolk and Virginia Beach,
      Va. PATIENTS: Children aged 9 to 30 months attending the private practices.
      INTERVENTIONS: Practice immunization rates were assessed and presented to
      practices on 4 occasions at 6-month intervals. A physician leader convened an
      immunization task force meeting following the first 3 assessments to review
      practice guidelines, examine data, and discuss practice changes. MAIN OUTCOME
      MEASURES: Practice immunization rates for patients at age 24 months, with 3- and
      12-month immunization rates as secondary outcomes. RESULTS: The mean practice
      immunization rate at age 24 months increased significantly (P<.05) from 50.9% at
      baseline to 69.7%. Rates also increased at age 3 months, from 75.5% to 88.9%, and
      at age 12 months, from 72.9% to 84.6%. The median age at administration of the
      fourth dose of diphtheria toxoid, tetanus toxoid, and pertussis vaccine decreased
      (P<.05) from 17.6 to 16.8 months. Physicians also reported making additional
      changes, including improved record keeping and screening for immunizations at
      every visit. CONCLUSION: A quality improvement initiative enabling physician
      leadership can improve preschool immunization practices and coverage levels in
      pediatric practices.

PMID- 10357301
TI  - Introduction of a recorded health information line into a pediatric practice.
AB  - OBJECTIVE: To examine the utilization, satisfaction, and parental health-seeking
      behavior associated with the introduction of the Parent Advice Line (PAL), a
      collection of 278 recorded health-related messages accessible by telephone, into
      a private practice. DESIGN: Booklets listing PAL topics were mailed to eligible
      families, and utilization data were collected for all incoming PAL calls from
      June to August 1996. Satisfaction and effect on health-seeking behavior were
      assessed using a recorded questionnaire appended to each call (n = 561) and a
      randomized telephone questionnaire (n = 821). SETTING: A suburban, 7-pediatrician
      practice in Colorado. PATIENTS: Families with children younger than 12 years seen
      in the practice within 2 years (N = 8365). RESULTS: Of families who reported
      receiving the mailed PAL booklet, 32% used PAL. Sixty percent of PAL calls were
      placed during office hours, 21% from 5 PM to 9 PM, and 8% after midnight; call
      volume was higher on weekdays than on weekend days (25 calls per day vs 10 calls
      per day, respectively; P<.05 by chi2 test). The 5 most commonly requested topic
      categories were toilet training, sexual development, discipline problems, sleep
      problems, and teenage behavior. Preventive care topics predominated in infants,
      behavioral topics in preschool children, and acute illness topics in school-aged
      children. Of users, 88% were satisfied or very satisfied and 98% said that they
      would use PAL again. Respondents to the 2 questionnaires reported that use of PAL
      made a call or visit to their child's physician unnecessary 58% to 69% and 61% to
      70% of the time, respectively. CONCLUSIONS: The PAL was used primarily to access
      information about behavioral and developmental issues during office hours. Its
      use was associated with high rates of satisfaction and, by parental report,
      decreased calls or visits to a physician.

PMID- 10357302
TI  - Bacterial infections in infants 60 days and younger: epidemiology, resistance,
      and implications for treatment.
AB  - OBJECTIVE: To establish what might be more optimal initial antibiotic therapy for
      suspected invasive bacterial infections in infants 60 days or younger who are
      evaluated in the emergency department (ED). SETTING: Urban university-affiliated
      pediatric referral center with an average yearly ED census of 52000 visits during
      the study period. DESIGN AND METHODS: We assembled a retrospective case series of
      all positive blood, urine, and cerebrospinal fluid cultures in children 60 days
      or younger from January 1, 1994, through December 31, 1997, obtained from both
      inpatients and patients initially evaluated in the ED. From this case series we
      determined the frequency of bacterial pathogens responsible for such infections
      in this age group. Pathogens were defined as group B streptococcus, various
      enteric gram-negative rods (GNRs), Listeria monocytogenes, enterococcus,
      Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type B,
      and Staphylococcus aureus. A subgroup analysis was performed to determine
      resistance patterns among the GNRs isolated from patients evaluated in the ED.
      RESULTS: A total of 367 pathogens were isolated: 187 (51.0%) in the neonatal
      intensive care unit, 153 (41.7%) in the ED, 20 (5.4%) in the inpatient wards, and
      7 (1.9%) in the pediatric intensive care unit. Of the 121 pathogens isolated from
      120 ED patients that were eligible for review, 94 (77.7%) were in the urine only,
      16 (13.2%) in blood only, 4 (3.3%) in cerebrospinal fluid only, 3 (2.5%) in blood
      and cerebrospinal fluid, and 4 (3.3%) in blood and urine. Organisms isolated
      included GNRs (n = 96, 79.3%), group B streptococcus (n = 14, 11.6%),
      enterococcus (n = 7, 5.8%), S. pneumoniae (n = 3, 2.5%), and N. meningitidis (n =
      1, 0.8%). No Listeria were isolated. Of the 96 GNRs isolated, 60 (62.5%; 95%
      confidence interval, 52.8%-72.1%) were ampicillin resistant. All were sensitive
      to gentamicin sulfate and cefotaxime sodium. CONCLUSIONS: Our results reveal 2
      important facts: (1) during a 4-year period, no isolates of Listeria were
      identified from any patients 60 days or younger; and (2) of the 96 GNRs isolated
      from patients in the ED, more than 60% were ampicillin resistant. These data
      suggest that in similar centers with a low incidence of infection with Listeria
      and high levels of ampicillin resistance among GNRs, empiric use of ampicillin as
      part of a combination for presumed bacterial infections in patients 60 days or
      younger initially evaluated in the ED may be neither necessary nor beneficial.
      Consideration should be given to empiric initial antibiotic therapy using a third
      generation cephalosporin with or without gentamicin.

PMID- 10357303
TI  - Caregiver knowledge and delivery of a commonly prescribed medication (albuterol)
      for children.
AB  - OBJECTIVE: To evaluate caregiver knowledge and delivery of a prescription
      medication (albuterol) for children. DESIGN: Prospective convenience sample.
      PARTICIPANTS: Caregivers listing albuterol as one of their child's medications.
      SETTING: Two urban, university-affiliated pediatric emergency departments.
      INTERVENTIONS: Caregivers were asked about their knowledge of the medication, the
      child's dose, frequency, duration of use, and where it was prescribed. In a mock
      scenario, they measured and demonstrated medication delivery to their child.
      Common measuring devices and formulations were offered. RESULTS: Forty-one
      caregivers were enrolled. Thirty-six (88%) were high school educated and 39 (95%)
      had a primary care provider. Twenty-six (63%) were out of medication, 7 (17%)
      stated an incorrect dose, 18 (44%) reported an incorrect frequency, and 10 (24%)
      stated an inadequate duration of use. Formulations chosen were liquid (n = 15,
      37%), nebulizers (n= 15, 37%), and inhalers (n = 11, 27%). Metered dosing
      (metered-dosing inhaler or premixed solution) were chosen by 22 caregivers (54%),
      calibrated measuring tools (droppers, syringes) by 15 (37%), and noncalibrated
      delivery devices (teaspoon) by 4 (10%). An improper dose was measured by 9 (22%),
      and the dose intended was inaccurately measured by 7 (17%). All caregivers using
      a teaspoon inaccurately measured their intended dose of the liquid formulation.
      CONCLUSIONS: Metered dosing and calibrated measuring devices aided in the
      accurate delivery of this prescription medication. However, considerable concern
      exists with the use of noncalibrated measuring devices (teaspoons), improper
      frequency, and duration of use. Refilling of medication was also a concern since
      63% were out of albuterol. Caregiver education on use, delivery, and refilling of
      medications must be stressed and assessed at all emergency department and primary
      care visits. In addition, metered dosing and the use of calibrated measuring
      devices should be encouraged.

PMID- 10357304
TI  - Hepatitis B maternal screening, infant vaccination, and infant prophylaxis
      practices in North Carolina.
AB  - OBJECTIVES: To determine if the Advisory Committee on Immunization Practices
      hepatitis B screening, vaccination, and prophylaxis recommendations were being
      followed in North Carolina, and to establish a baseline hepatitis B
      seroprevalence rate. DESIGN: A survey of mother and infant birthing facility
      medical records. SETTING: Four birthing facilities selected from each of the 7
      districts in North Carolina (a total of 28 facilities). PARTICIPANTS: A
      probability proportional to size survey design was used to select 4763 mother
      infant record pairs. All records came from the 1996 birth cohort. MAIN OUTCOME
      MEASURES: Maternal hepatitis B screening status, infant vaccination status,
      infants prophylaxis status, hepatitis B seroprevalence rate, demographic and
      clinical predictors for maternal infection, failure to receive prenatal care or
      for whom status was unknown, failure to screen, and failure to vaccinate.
      RESULTS: Ninety-two percent of pregnant women were screened for hepatitis B
      surface antigen. Eighty-six percent of infants received dose 1 of the hepatitis B
      vaccine. Four of the 9 infants with mothers who were hepatitis B surface antigen
      positive did not receive both vaccine and hepatitis B immune globulin. The
      hepatitis B seroprevalence rate was 0.2%. Mothers who were not screened for
      infection were 3.4 times more likely to have infants who were not vaccinated.
      White mothers were twice as likely not to have their child vaccinated as mothers
      of other races. CONCLUSIONS: Not all infants with hepatitis B-infected mothers
      were receiving vaccine and hepatitis B immune globulin as recommended.
      Seroprevalence of hepatitis B infection may be lower in North Carolina than in
      other states. Hepatitis B laboratory test results should be included in every
      mother's medical record.

PMID- 10357305
TI  - Incidence of streptococcal carriers in private pediatric practice.
AB  - OBJECTIVE: To determine the incidence of group A beta-hemolytic streptococcus
      (GABHS) carriers in children who are well, in children seen with presumed and
      documented viral illnesses with sore throat, and in children after treatment of
      acute GABHS tonsillopharyngitis with 10 days of oral penicillin V potassium, oral
      cephalosporins, or macrolides. METHODS: Prospective collection of clinical and
      microbiologic data from October 1996 to June 1997 in a private pediatric practice
      were obtained from children who were asymptomatic and well, from children with
      both presumed (and documented) viral sore throats, and from children who had
      completed a full antibiotic treatment course for acute GABHS throat infections.
      RESULTS: The incidence of GABHS carriers was 2.5% among well children (n = 227),
      4.4% among children with upper respiratory tract infections including sore throat
      of presumed viral etiology (n= 296), and 6.9% among children with upper
      respiratory tract infections including sore throat from whom viruses were
      isolated (n = 87). Following 10 days' treatment of acute GABHS
      tonsillopharyngitis, 81 (11.3%) of 718 children treated with penicillin, 22
      (4.3%) of 508 children treated with an oral cephalosporin, and 10 (7.1%) of 140
      children treated with a macrolide were GABHS carriers (P<.001). CONCLUSIONS: A
      small percentage of children seen in private pediatric practices who are well or
      who have apparent viral upper respiratory tract infections with sore throat are
      GABHS carriers. Penicillin treatment of acute GABHS tonsillopharyngitis results
      in a higher GABHS carriage rate than occurs following treatment with
      cephalosporins and macrolides.

PMID- 10357306
TI  - Determinants of counseling in primary care pediatric practice: physician
      attitudes about time, money, and health issues.
AB  - OBJECTIVES: To assess pediatrician goals and practice in preventive counseling,
      and to use social learning theory to examine physician attitudes about preventive
      health issues, time, and reimbursement to explain physician counseling behavior.
      DESIGN: Random sample survey of American Academy of Pediatrics fellows.
      PARTICIPANTS: A total of 1620 pediatricians were surveyed with a return rate of
      72%. The 556 pediatricians who had finished training and who currently performed
      child health supervision were included. METHODS: Pediatricians were asked about
      their goals in 6 areas of health supervision: biomedical issues, development,
      behavior, family functioning, safety education, and supportive interpersonal
      interaction. They were also asked about the prevalence of counseling, importance
      of specific topics, their self-efficacy, outcome expectation in these areas, and
      their concerns about time and reimbursement for preventive counseling. RESULTS:
      Assurance of physical health and normal development were the most important goals
      of child health supervision among the pediatricians surveyed. Goals involving
      behavioral, family, and safety issues were less important and less likely to be
      addressed in practice. Most did not regularly discuss family stress, substance
      abuse, gun safety, and television. In these areas, physicians had less confidence
      they could provide guidance and lower expectation that they could prevent
      problems. Only 17% felt that they receive adequate reimbursement for preventive
      counseling. Most have adequate time (53%) and receive adequate respect (57%) for
      their preventive efforts. Physicians who were more concerned about time for
      preventive counseling reported less overall counseling (r = -0.28, P<.001).
      Concern about reimbursement was not associated with reported counseling. Multiple
      regression analysis found that the primary predictors of physician counseling
      were an issue's importance, a physician's perceived self-efficacy, and perceived
      effectiveness of counseling, while concerns about time and reimbursement were
      secondary. CONCLUSIONS: Physician goals in child health supervision were
      primarily biomedical, with psychosocial and safety issues of lesser importance.
      Concern about time for preventive counseling was associated with less reported
      counseling. Physician attitudes regarding the importance of a health issue and
      their confidence and effectiveness in counseling were more predictive of
      physician practice than their attitudes about time and reimbursement for
      preventive care.

PMID- 10357307
TI  - A pediatric clinical skills assessment using children as standardized patients.
AB  - OBJECTIVES: To develop and implement a pediatric clinical skills assessment
      (PCSA) for residents, using children as standardized patients (SPs); to assess
      the psychometric adequacy of the PCSA and use it to evaluate the performance of
      residents; and to evaluate the feasibility of using child SPs and the response of
      the residents and the child SPs to participation in the PCSA. METHODS: Ten 22
      minute complete patient encounters were developed, 7 with child SPs. Fifty-six
      residents (10 second-year pediatric residents, 29 first-year pediatric residents,
      and 17 first-year family practice residents) were evaluated on the following
      clinical skills: history taking, physical examination, interpersonal skills, and
      documentation and interpretation of clinical data/patient note. MAIN OUTCOME
      MEASURES: Patient encounter checklists, focus groups, and questionnaires.
      RESULTS: Average skill scores for the 56 residents were 68% (SD, 12%) for history
      taking, 56% (SD, 26%) for physical examination, 46% (SD, 12%) for patient note,
      and 68% (SD, 16%) for interpersonal skills. Second-year pediatric residents
      scored significantly higher on history taking than first-year pediatric and first
      year family practice residents; first-year pediatric residents scored
      significantly higher on interpersonal skills than second-year pediatric and first
      year family practice residents; and first- and second-year pediatric residents
      scored significantly higher on the patient note component than first-year family
      practice residents. All differences noted were significant at P<.05. There were
      no significant differences on physical examination between the groups.
      Reliabilities were 0.69 for history taking, 0.64 for physical examination, 0.76
      for interpersonal skills, and 0.81 for the patient note component. On a Likert
      scale (5 indicates high; 1, low), residents rated the PCSA 3.9 for realism, 4.1
      for challenge, 3.1 for enjoyment, and 2.9 for fairness. Child SPs found the
      experience positive. No negative effects on the children were identified by their
      real parents or their SP parents. CONCLUSIONS: Our development method gives
      content validity to our PCSA, and resident scores give indication of PCSA
      construct validity. Reliabilities are in the acceptable range. Residents found
      the PCSA challenging and realistic but less than enjoyable and fair. Use of child
      SPs is feasible. Resident performance scores were low relative to the performance
      criteria of the PCSA development group. The adequacy of clinical skills teaching
      and assessment in residency programs needs to be reviewed. Deficits in specific
      skills and overall performance of residents identified by a PCSA could be used to
      guide individual remediation and curricular change.

PMID- 10357308
TI  - Radiological case of the month. Neurenteric cyst.

PMID- 10357309
TI  - Picture of the month. Pili torti.

PMID- 10357310
TI  - Pathological case of the month. Intracranial immature teratoma.

PMID- 10357311
TI  - Oral condylomata in children.

PMID- 10357312
TI  - Relaxation training and levels of secretory IgA in breast milk.

PMID- 10357313
TI  - Supplemental breast milk is the best milk.

PMID- 10357314
TI  - Breast-feeding, jaundice, and formula.

PMID- 10357315
TI  - Formula for jaundiced breast-fed infants.

PMID- 10357316
TI  - Lanolin for sore nipples.

PMID- 10357317
TI  - Systematic transesophageal echocardiographic examination in mitral valve repair:
      the evolution of a discipline into the twenty-first century.

PMID- 10357318
TI  - Has the use of meta-analysis enhanced our understanding of therapies for
      postoperative nausea and vomiting?

PMID- 10357319
TI  - Implantable pain therapies--what training is required?

PMID- 10357320
TI  - Improved evaluation of the location and mechanism of mitral valve regurgitation
      with a systematic transesophageal echocardiography examination.
AB  - Mitral regurgitation (MR) is a major determinant of outcome in cardiac surgery.
      The location and mechanism of mitral lesions determine the approach to various
      repairs and their feasibility. Because of incomplete evaluations or change in
      patient condition, detailed intraoperative transesophageal echocardiography (TEE)
      examination of the mitral valve may be required. We hypothesized that a
      systematic TEE mitral valve examination would allow precise identification of the
      anatomic location and mechanism of MR in patients undergoing mitral surgery. We
      designed a systematic mitral valve examination consisting of six views: five
      chamber, four-chamber, two-chamber anterior, two-chamber mid, two-chamber
      posterior and short-axis. We used this examination prospectively in 13 patients
      undergoing mitral valve surgery for severe MR and compared the results with the
      surgical findings. We then retrospectively interpreted 11 similar patients who
      had undergone intraoperative TEE studies before this examination. TEE correctly
      diagnosed the mechanism and precise location of pathology in 12 of 13 patients in
      the prospective group, but in only 6 of 10 patients in the retrospective group.
      TEE also correctly identified 75 of 78 mitral segments (96%) as being normal or
      abnormal. In the retrospective group, only 42 of 60 segments (70%) were correctly
      identified (P < 0.001). We conclude that this systematic TEE mitral valve
      examination improves identification of mitral segments and precise localization
      of pathologies and may also improve the diagnosis of the mechanism of MR.
      IMPLICATIONS: In this article, we describe how a systematic examination of the
      mitral valve by using transesophageal echocardiography allows identification of
      the different segments of the mitral valve, precise localization of pathology,
      and helps to diagnose the mechanism of mitral regurgitation. This is important in
      determining an approach to mitral valve repair and its feasibility.

PMID- 10357321
TI  - The effect of intravenously administered magnesium on platelet function in
      patients after cardiac surgery.
AB  - After cardiac surgery, magnesium is often administered for prophylaxis and
      treatment of cardiac arrhythmias. Magnesium, however, inhibits platelet function
      in vitro and in healthy volunteers. We performed a randomized, blinded, and
      placebo-controlled study to investigate the effect of magnesium on platelet
      function in patients after cardiac surgery. We studied patients who underwent
      uneventful coronary revascularization with cardiopulmonary bypass on the first
      postoperative day. Before and after an infusion of either 5.4 mmol magnesium (n =
      19) or saline (n = 20), platelet function was investigated by means of in vitro
      bleeding time, platelet aggregation, and flow-cytometric assays. In addition, to
      investigate platelet function in vitro, 1, 5, and 10 mM magnesium were added to
      platelet-rich plasma before and 24 h after surgery in 30 patients. Compared with
      the control group, magnesium prolonged the in vitro bleeding time (22%) and
      inhibited ADP- and collagen-induced platelet aggregation (13% and 17%), platelet
      P-selectin expression (18%), and the binding of fibrinogen to the platelet
      glycoprotein IIb/IIIa receptor (10%). Magnesium also led to significant dose
      dependent inhibition of platelet aggregation (19%), P-selectin expression (14%),
      and fibrinogen binding (11%) before and after surgery in vitro. Although the
      antithrombotic effect of magnesium may be beneficial in patients after coronary
      revascularization, large-dose magnesium therapy should be carefully considered in
      patients with impaired platelet function and co-existing bleeding disorders.
      IMPLICATIONS: In a randomized, blinded, placebo-controlled study of patients 24 h
      after coronary artery bypass grafting, IV administered magnesium inhibited
      platelet function in vitro and in vivo.

PMID- 10357322
TI  - Tissue heat content and distribution during and after cardiopulmonary bypass at
      17 degrees C.
AB  - We measured afterdrop and peripheral tissue temperature distribution in eight
      patients cooled to approximately 17 degrees C during cardiopulmonary bypass and
      subsequently rewarmed to 36.5 degrees C. A nasopharyngeal probe evaluated trunk
      and head temperature and heat content. Peripheral tissue temperature (arm and leg
      temperature) and heat content were estimated using fourth-order regressions and
      integration over volume from 30 tissue and skin temperatures. Peripheral tissue
      temperature decreased to 19.7+/-0.9 degrees C during bypass and subsequently
      increased to 34.3+/-0.7 degrees C during 104+/-18 min of rewarming. The core-to
      peripheral tissue temperature gradient was -5.9+/-0.9 degrees C at the end of
      cooling and 4.7+/-1.5 degrees C at the end of rewarming. The core-temperature
      afterdrop was 2.2+/-0.4 degrees C and lasted 89+/-15 min. It was associated with
      1.1+/-0.7 degrees C peripheral warming. At the end of cooling, temperatures at
      the center of the upper and lower thigh were (respectively) 8.0+/-5.2 degrees C
      and 7.3+/-4.2 degrees C cooler than skin temperature. On completion of rewarming,
      tissue at the center of the upper and lower thigh were (respectively) 7.0+/-2.2
      degrees C and 6.4+/-2.3 degrees C warmer than the skin. When estimated systemic
      heat loss was included in the calculation, redistribution accounted for 73% of
      the afterdrop, which is similar to the contribution observed previously in
      nonsurgical volunteers. IMPLICATIONS: Temperature afterdrop after bypass at 17
      degrees C was 2.2+/-0.4 degrees C, with approximately 73% of the decrease in core
      temperature resulting from core-to-peripheral redistribution of body heat.
      Cooling and rewarming were associated with large radial tissue temperature
      gradients in the thigh.

PMID- 10357323
TI  - D-Dimer formation during cardiac and noncardiac thoracic surgery.
AB  - The ability to make therapeutic decisions regarding excessive fibrinolysis in the
      perioperative period is limited by the lack of availability of a near site
      monitor of fibrinolysis. We investigated the use of a latex agglutination D-dimer
      assay to detect perioperative fibrinolysis in patients undergoing thoracic
      surgery with and without extracorporeal circulation. We studied 27 patients who
      underwent thoracic surgery requiring cardiopulmonary bypass (CPB; coronary artery
      bypass grafting, n = 12; valvular surgery, n = 15) and a cohort of 20 patients
      who underwent noncardiac thoracic surgical procedures not requiring CPB. The
      purpose of this investigation was to determine the relationship among alterations
      in the latex agglutination D-dimer assay, use of extracorporeal circulation, type
      of cardiac surgical procedure, and mediastinal and/or chest tube drainage
      (cardiac surgery only) in patients undergoing thoracic surgery. Perioperative D
      dimer levels, measured by latex agglutination, had significant (P < or = 0.05)
      intragroup changes among patients undergoing cardiac surgery (requiring CPB) and
      the cohort of patients who underwent noncardiac thoracic surgery without CPB.
      Although intraoperative D-dimer levels were not increased in patients undergoing
      noncardiac thoracic surgery, postoperative levels were significantly (P < 0.05)
      increased (compared with preinduction). In cardiac surgery patients requiring
      CPB, intraoperative D-dimer formation was significantly (P < or = 0.05) increased
      but did not demonstrate any intragroup (coronary artery bypass grafting versus
      valvular surgery) differences. Finally, D-dimer levels were not associated with
      postoperative mediastinal and/or chest tube accumulative drainage measured at
      intervals up to 48 h postoperatively in patients undergoing cardiac surgery
      requiring CPB. Our study indicates that the latex agglutination D-dimer assay can
      detect excessive fibrinolysis perioperatively, and that extracorporeal
      circulation can significantly influence the pattern of D-dimer formation in
      patients undergoing thoracic surgery. IMPLICATIONS: We assessed the ability of a
      readily available D-dimer assay to detect excessive fibrinolysis in patients
      undergoing thoracic surgery with and without extracorporeal circulation. The
      findings demonstrate that the assay used in this investigation reflected variable
      amounts of fibrinolysis in patients undergoing both types of thoracic surgery.

PMID- 10357324
TI  - The direct effects of heparin and protamine on canine tracheal smooth muscle
      tone.
AB  - Heparin and protamine are used for cardiopulmonary bypass in cardiac surgery;
      however, the direct effects and mechanisms of these drugs on airway smooth muscle
      tone are still not fully known. We investigated the in vitro effects of these
      drugs on canine tracheal smooth muscle by measuring the muscle tension and
      intracellular Ca2+ concentration ([Ca2+]i) and by measuring inward Ca2+ currents
      (I(Ca)) through voltage-dependent Ca2+ channels. [Ca2+]i was monitored by the 500
      nm light emission ratio of preloaded Ca2+ indicator fura-2. Isometric tension was
      measured simultaneously. Whole-cell patch clamp recording techniques were used to
      investigate the effects of the drugs on I(Ca) in freshly dispersed smooth muscle
      cells. Heparin (0.12-120 U/mL), protamine (0.15-150 U/mL), or heparin-protamine
      complex (4:5 U/U) was introduced into a bath solution. Protamine and heparin
      protamine complex dose-dependently inhibited both carbachol-induced contraction
      of the muscle and increase in [Ca2+]i. These drugs also decreased the I(Ca) of
      the muscle cells and shifted the inactivation curve to a more negative potential.
      Heparin itself had a slight enhancing effect on carbachol-induced muscle
      contraction without changing [Ca2+]i. Protamine and heparin-protamine complex can
      decrease the agonist-induced increase in [Ca2+]i by the inhibition of voltage
      dependent Ca2+ channels both in the activated and inactivated states.
      IMPLICATIONS: Protamine and heparin-protamine complex inhibited carbachol-induced
      canine tracheal smooth muscle contraction by inhibiting the increase in
      intracellular concentration of free Ca2+. These drugs can decrease the agonist
      induced increase in intracellular Ca2+ by the inhibition of voltage-dependent
      Ca2+ channels in both the activated and inactivated states.

PMID- 10357325
TI  - The effects of clonidine on sensitivity to phenylephrine and nitroprusside in
      patients with essential hypertension recovering from surgery.
AB  - Clonidine reduces postoperative circulatory instability in patients with
      essential hypertension. It also increases the sensitivity to vasopressors before
      and during anesthesia. We investigated blood pressure responses to phenylephrine
      and nitroprusside pre- vs postoperatively and the effect of clonidine on these
      responses in patients with essential hypertension. Twenty patients received
      clonidine 6 microg/kg orally 120 min before anesthesia and 3 microg/kg IV over
      the final hour of surgery or an identical placebo. During increasing bolus doses
      of phenylephrine and nitroprusside (30-300 microg), the maximal systolic pressure
      responses were recorded at baseline on the day before surgery, before the
      induction of anesthesia, and 1 and 3 h postoperatively. Sensitivity to
      phenylephrine and nitroprusside was interpolated from linear regression of the
      data. There was no difference between preoperative and postoperative sensitivity
      to phenylephrine or nitroprusside in either group. Clonidine increased
      sensitivity to phenylephrine versus placebo before and after surgery (response to
      dose of 1.5 microg/kg: 42+/-14 vs 27+/-8 mm Hg preinduction, 37+/-10 vs 26+/-8 mm
      Hg 3 h postoperatively; both P < 0.01), but not to nitroprusside (38+/-6 vs 37+/
      10 mm Hg preinduction and 40+/-6 vs 39+/-8 mm Hg postoperatively). Clonidine
      increases the sensitivity to phenylephrine but not nitroprusside at baseline and
      postoperatively in hypertensive patients. IMPLICATIONS: Clonidine increases the
      sensitivity to bolus injections of the vasoconstrictor phenylephrine, but not the
      vasodilator sodium nitroprusside, before and after surgery in patients with
      preexisting hypertension. The doses of vasopressors should be reduced accordingly
      in hypertensive patients receiving perioperative clonidine.

PMID- 10357326
TI  - Cardiopulmonary dysfunction during minimally invasive thoraco-lumboendoscopic
      spine surgery.
AB  - The endoscopic retroperitoneal approach to thoracolumbar anterior spine fusion is
      associated with CO2 insufflation into the thoracic space. We studied the
      cardiopulmonary effects of this CO2 thoraco-retroperitoneal insufflation compared
      with the conventional open surgical procedure using thoraco-phreno-lumbotomy in
      12 pigs under balanced anesthesia, paralysis, and mechanical ventilation. During
      open surgery of the thoracolumbar spine, animals exhibited unchanged systemic and
      pulmonary hemodynamics, as well as ventilation and oxygenation variables. Animals
      retroperitoneally insufflated with CO2 (12 mm Hg) exhibited a significant
      increase of PaCO2 and a moderate decrease of PaO2, SaO2, and pH, with
      insignificant changes of central venous filling pressures and systemic
      hemodynamics. Endoscopic phrenotomy with thoracic CO2 insufflation
      instantaneously and drastically affected hemodynamic status and pulmonary gas
      exchange with marked hypoxia, hypercapnia, systemic hypotension, tachycardia, and
      pulmonary hypertension within minutes. An increase of minute ventilation,
      inspiratory oxygen fraction, and positive end-expiratory pressure promptly
      reversed these cardiopulmonary effects. CO2 evacuation allowed the animals to
      completely recover and regain almost baseline cardiopulmonary status, except for
      a reduced arterial blood pressure. Appropriate monitoring and immediate CO2
      desufflation may be beneficial in cases of therapy-resistant hemodynamic,
      oxygenation, and ventilation difficulties. IMPLICATIONS: For endoscopic thoraco
      lumbar spine fusion, CO2 thoraco-retroperitoneum-induced cardiopulmonary
      dysfunction must be of concern, especially in patients with cardiopulmonary
      compromise. Appropriate monitoring and immediate CO2 desufflation may be
      beneficial in cases of therapy-resistant hemodynamic, oxygenation, and
      ventilation difficulties.

PMID- 10357327
TI  - Bronchial rupture by a double-lumen endobronchial tube during staging
      thoracoscopy.

PMID- 10357328
TI  - Changing temperature management for cardiopulmonary bypass.

PMID- 10357329
TI  - Pulmonary function after cardiac and thoracic surgery.

PMID- 10357330
TI  - Patient preferences for early discharge after laparoscopic cholecystectomy.
AB  - Patients may have concerns about their ability to manage postoperative symptoms
      at home after ambulatory surgery. We assessed patients' attitudes toward
      postoperative care at home or in the hospital after laparoscopic cholecystectomy.
      Thirty-eight patients undergoing elective laparoscopic cholecystectomy were pre-
      and postoperatively (within a week each) presented with scenarios describing
      symptoms of differing severity in either a home or hospital setting and were
      asked to rank and rate the relative desirability of the scenarios using rating
      scale, standard gamble, and willingness-to-pay techniques. Preoperatively, 16
      (42%), 21 (55%), and 30 (79%) patients ranked pain of mild, moderate, and severe
      levels, respectively, as worse than the respective levels of nausea and vomiting.
      Of 24 patients, 19 (79%) preferred home care to hospital care for mild symptoms,
      and 12 of 22 patients (55%) preferred home care to hospital care for moderate
      symptoms. The average ratings were 20, 53, and 90 for mild, moderate, and severe
      symptoms, respectively, where 0 = no symptoms and 100 = the worst symptoms
      possible. Patients who preferred care outside the home indicated that they were
      willing to pay a mean of $142 (maximum $410) as a maximal copayment to have
      postoperative care in the hospital and a mean of $255 to receive care in a
      medical hotel-like facility. Postoperative assessment correlated highly with the
      preoperative assessment (correlation coefficient >0.6 for rating, standard
      gamble, and willingness-to-pay assessments). We conclude that patients vary in
      their attitudes toward where they would like to receive postoperative care.
      Attitudes assessed preoperatively may predict their attitudes postoperatively.
      IMPLICATIONS: Patients preferred to be at home for mild postoperative symptoms
      but in the hospital for worse postoperative symptoms. Preferences did not change
      with different methods of asking and were the same pre- and postoperatively. If
      patients made choices for their care before their procedure, they would still be
      happy with those decisions postoperatively.

PMID- 10357331
TI  - Postoperative analgesia with controlled-release oxycodone for outpatient anterior
      cruciate ligament surgery.
AB  - Reconstruction of the anterior cruciate ligament (ACL) of the knee is associated
      with a considerable degree of postoperative pain. Although immediate-release oral
      opioids are usually effective in relieving moderate to severe pain, they must be
      given every 4-6 h. A controlled-release (CR) formulation of oxycodone maintains
      therapeutic opioid concentrations for a more prolonged period, thus providing
      sustained pain relief. We designed this study to determine whether CR oxycodone
      is more effective and clinically acceptable than immediate-release oxycodone for
      managing pain after ambulatory ACL repair surgery. All patients received a
      standard general anesthetic and postoperative analgesic regimen with one of three
      oxycodone dosing regimens: oxycodone 10 mg every 4 h as needed, oxycodone 10 mg
      every 4 h, and CR oxycodone 20 mg every 12 h. Rescue analgesic consisted of
      oxycodone 5 mg every 6 h as needed. At 24, 36, 48, 60, and 72 h, there was a
      difference in pain scores among the groups (P < 0.0001); there was less pain in
      the CR oxycodone group. At most times, the fixed-dose group had lower pain scores
      than the as-needed group. The sedation scores were significantly different at 12
      h (P < 0.02) and at 24, 36, 48, 60, and 72 h (P < 0.0001); the patients were more
      alert in the CR oxycodone group. The 72-h consumption of oxycodone was less in
      the CR oxycodone group (P < 0.0001). The patients had less sleep disturbance (P <
      0.0001), were more satisfied (P < 0.0001), and experienced less vomiting (P <
      0.02) in the CR oxycodone group compared with the other two groups. In
      conclusion, using CR oxycodone in the immediate 72 h after ambulatory ACL surgery
      provides more effective analgesia with less sedation, sleep disturbance, and
      postoperative vomiting compared with oxycodone prescribed on either a fixed dose
      or as-needed schedule. IMPLICATIONS: A controlled-release formulation of
      oxycodone in patients undergoing anterior cruciate ligament repair on an
      ambulatory basis provides significant analgesic benefit and a lowering of side
      effects compared with either fixed-dose or as-needed oxycodone regimens.

PMID- 10357332
TI  - Patients with malignant osteopetrosis are at high risk of anesthetic morbidity
      and mortality.
AB  - The anesthetic literature contains no focused discussion of the perioperative
      management and risks of children with malignant autosomal recessive osteopetrosis
      (osteopetrosis). We retrospectively analyzed the perioperative morbidity and
      mortality rates encountered in the anesthetic management of children with
      osteopetrosis. We compared the perioperative mortality rate for this patient
      population with that for other pediatric patients in our institution and that
      reported in the literature for children and other high-risk patients. We also
      investigated the inability to intubate the tracheas of children with
      osteopetrosis compared with other pediatric patients in our institution. Using
      Fisher's exact test, patients with osteopetrosis were found to have a higher
      likelihood of perioperative mortality compared with other children or all ASA
      physical status III, but not ASA physical status IV, patients (P < 0.05).
      Finally, we discovered that children with osteopetrosis were more likely to have
      tracheas that could not be intubated than other pediatric patients in our
      institution. We conclude that children with osteopetrosis are at risk of adverse
      respiratory events and mortality associated with these adverse events.
      IMPLICATIONS: Osteopetrosis is a rare disease that increases perioperative
      morbidity and mortality. By performing a retrospective chart review, we found
      that this increased perioperative morbidity and mortality is primarily related to
      airway and respiratory factors. Anesthetic management strategies should consider
      the factors that cause the high frequency of adverse airway events in this
      patient population.

PMID- 10357333
TI  - Preoperative oral antiemetics for reducing postoperative vomiting after
      tonsillectomy in children: granisetron versus perphenazine.
AB  - In a prospective, randomized, double-blinded trial, we evaluated the efficacy of
      two antiemetics given orally, granisetron and perphenazine, for preventing
      postoperative vomiting after tonsillectomy with or without adenoidectomy in
      children. One hundred pediatric patients, ASA physical status I, aged 4-10 yr,
      received either granisetron 40 microg/kg or perphenazine 70 microg/kg (n = 50
      each) orally 1 h before surgery. We used a standard general anesthetic technique.
      The rate of complete response, defined as no emesis and no need for rescue
      antiemetic medication, during 0-3 h after anesthesia was 86% with granisetron and
      60% with perphenazine; the corresponding rate 3-24 h after anesthesia was 86% and
      62%, respectively (P < 0.05). No serious adverse events were observed in any of
      the groups. In conclusion, preoperative oral granisetron is more effective than
      perphenazine for preventing postoperative vomiting in children undergoing
      tonsillectomy with or without adenoidectomy. IMPLICATIONS: We compared the
      efficacy of granisetron and perphenazine given orally for preventing
      postoperative vomiting after tonsillectomy with or without adenoidectomy in
      children. Preoperative oral granisetron was more effective than perphenazine.

PMID- 10357334
TI  - The age-related effects of epidural lidocaine, with and without epinephrine, on
      spinal cord blood flow in anesthetized rabbits.
AB  - The effect of epidural or spinal epinephrine when added to local anesthetics on
      spinal cord blood flow (SCBF)are controversial. We evaluated the effects of
      epidural lidocaine, with or without epinephrine, on spinal cord blood flow in
      young and adult rabbits receiving 2% plain lidocaine, 2% lidocaine with
      epinephrine (1:200,000), or saline epidurally. Colored microspheres were injected
      through the left ventricle 10 min before and 7.5 and 30 min after epidural
      injection. The organs (brain, heart, kidneys, and the L6-7 segment of the spinal
      cord) were analyzed for regional blood flow determination. A significant decrease
      in mean arterial pressure was observed after the administration of lidocaine,
      with or without epinephrine, in both adult and young animals compared with
      saline. SCBF did not change over time in adult rabbits. Conversely, a significant
      decrease in SCBF was observed in the two groups of young rabbits receiving
      lidocaine. This decrease correlated with the decrease in mean arterial pressure
      but did not correlate with the use of epinephrine. We conclude that any reduction
      in blood pressure occurring in pediatric patients receiving a combined epidural
      general anesthetic may result in decreased SCBF. IMPLICATIONS: In young rabbits,
      any decrease in blood pressure was followed by a decrease in spinal cord blood
      flow, a decrease that did not correlate to the use of epinephrine and was not
      observed in adult animals. These data suggest that blood pressure should be
      monitored closely to promptly treat any decrease in blood pressure when combined
      epidural-general anesthesia is used in children.

PMID- 10357335
TI  - Emergence "delirium" after sevoflurane anesthesia: a paranoid delusion?

PMID- 10357336
TI  - The state of implantable pain therapies in the United States: a nationwide survey
      of academic teaching programs.
AB  - The purpose of this questionnaire survey was to provide an overview of
      anesthesiology pain fellowship programs in the United States with regard to
      implantation of spinal cord stimulators (SCS) and opioid infusion devices. Of the
      95 programs solicited, 80% responded to questions pertaining to the prevalence of
      use and technical considerations of implantation. Of the responding programs, 87%
      report implanting SCS, and 84% report implanting neuraxial infusion pumps. All
      programs perform a stimulation or infusion trial before implantation, although
      the duration varied from a trial in the operating room at the time of
      implantation to 25 days. Of the programs, 83% implant cylindrical leads, and 17%
      implant flat leads via laminectomy for their nonrevision SCS implants. Morphine,
      bupivacaine, hydromorphone, and baclofen are the most commonly used drugs and are
      used in implanted pumps by >50% of respondents. The question of industry
      sponsored pain fellow education in implantable techniques is addressed.
      IMPLICATIONS: Of the pain teaching programs in the United States, 80% responded
      to a questionnaire eliciting information about the implantation of spinal cord
      stimulating and opioid infusion devices. The range and diversity of responses
      imply a lack of agreement about implantation techniques, drugs, and protocols.

PMID- 10357337
TI  - Lumbar dura mater biomechanics: experimental characterization and scanning
      electron microscopy observations.
AB  - There is no consensus about the anatomical structure of human dura mater. In
      particular, the orientation of collagen fibers, which are responsible for
      biomechanical behavior, is still controversial. The aim of this work was to
      evaluate the mechanical properties and the microstructure of the lumbar dura
      mater. We performed experimental mechanical characterization in longitudinal and
      circumferential directions and a scanning electron microscopy observation of the
      tissue. Specimens of human dura mater were removed from the dorsal-lumbar region
      (T12-L4/L5) of six subjects at autopsy; specimens of bovine dorsal-lumbar dura
      mater were obtained from two animals at slaughter. Human and bovine tissues both
      exhibited stronger tensile strength and stiffness in the longitudinal than in the
      circumferential direction. Scanning electron microscopy observations of dura
      mater showed that the collagen fibers are mainly oriented in a longitudinal
      direction, which accounts for its stronger tensile strength in this direction. We
      conclude that dura mater has a different mechanical response in the two
      directions investigated because the fiber orientation is predominantly
      longitudinal. IMPLICATIONS: In this experimental work, we studied the structural
      and functional relationship of human lumbar dura mater. We performed mechanical
      tests and microscopic observations on dura mater samples. The results show that
      the dura mater is mainly composed of longitudinally oriented collagen fibers,
      which account for higher tissue resistance in this direction.

PMID- 10357338
TI  - Epidural phenylephrine attenuates hypotension induced by alkalinized lidocaine
      epidural anesthesia.
AB  - In this double-blinded, randomized study, we examined the hemodynamic effects of
      lumbar epidural injection of alkalinized lidocaine with phenylephrine in 81
      patients undergoing inguinal herniorrhaphy. Patients assigned to four equal
      groups received 20 mL of alkalinized lidocaine (17 mL of 2% lidocaine + 3 mL of
      7% sodium bicarbonate) with one of four doses of phenylephrine: 0 (Group 1), 50
      (Group 2), 100 (Group 3), or 200 microg (Group 4) injected via a lumbar epidural
      catheter. Blood pressure, heart rate, and skin temperature on the foot were
      recorded every 5 min for 1 h after injection and were compared among groups.
      Hypotension was defined as mean arterial pressure < 80% of baseline. The
      incidence of hypotension was 45%, 55%, 35%, and 15% in Groups 1-4, respectively.
      Patients in Group 4 showed the smallest reduction in blood pressure compared with
      Groups 1 and 2 (one-sided Fisher's exact test, P < 0.05). We conclude that the
      200-microg dose of epidural phenylephrine (1:100,000 concentration) reduced the
      incidence of hypotension after epidural anesthesia with alkalinized lidocaine.
      IMPLICATIONS: Hypotension after epidural anesthesia is common in general clinical
      practice. Phenylephrine administered epidurally in combination with alkalinized
      lidocaine may reduce the incidence of hypotension.

PMID- 10357339
TI  - Adding clonidine to lidocaine for intravenous regional anesthesia prevents
      tourniquet pain.
AB  - Tourniquet pain often complicates the use of the pneumatic tourniquet during
      surgical procedures performed under IV regional anesthesia. Clonidine-containing
      local anesthetic solutions have better analgesic properties than plain solutions
      when used for spinal, epidural, or peripheral blocks. We tested the hypothesis
      that the addition of clonidine may improve the quality of IV regional anesthesia,
      especially tourniquet tolerance. Forty patients were allocated randomly in a
      double-blinded, randomized study to receive 40 mL of 0.5% lidocaine and either 1
      mL of isotonic saline or clonidine (150 microg). A double-cuffed tourniquet was
      kept inflated until patients complained of pain, leading to release of the distal
      cuff. Pain at the tourniquet site, at the surgical site, and in the distal part
      of the arm was rated on a visual analog scale (VAS) and a verbal rating scale
      (VRS) every 15 min during tourniquet placement and every 15 min for 1 h after
      tourniquet deflation. Motor blockade, sedation, arterial pressure, and heart rate
      were also recorded. VAS and VRS scores were significantly lower in the clonidine
      group 30 and 45 min after tourniquet inflation. The tolerance for the distal
      tourniquet was also significantly longer in the clonidine group (median [range]:
      22 [10-40] vs 10 [5-20] min; P < 0.05); motor blockade was comparable between the
      two groups. Pain was not different in the two groups after tourniquet release.
      The clonidine group experienced a higher degree of sedation. We conclude that
      clonidine improves tourniquet tolerance when added to a local anesthetic
      solution. IMPLICATIONS: A 150-microg dose of clonidine added to lidocaine
      improved tourniquet tolerance during IV regional anesthesia.

PMID- 10357340
TI  - Preincisional dextromethorphan treatment decreases postoperative pain and opioid
      requirement after laparoscopic cholecystectomy.
AB  - In the present study, we examined whether preincisional treatment with
      dextromethorphan (DM) provides preemptive analgesia. Ninety patients scheduled
      for laparoscopic cholecystectomy were included. Patients receiving
      chlorpheniramine maleate (CPM) 20 mg via an IM injection 30 min before skin
      incision were designated as the control group. Patients in Group A received DM 40
      mg (containing CPM 20 mg) IM after removal of the gallbladder, whereas in Group
      B, DM 40 mg (containing CPM 20 mg) was administered IM 30 min before skin
      incision. Meperidine (1 mg/kg IM) was given for postoperative pain relief as
      required. Times to first meperidine injection, total meperidine consumption,
      worst pain score, bed rest time, and side effects were recorded for 48 h after
      surgery. Times to first meperidine injection were 9.3+/-15.9, 17.4+/-3.4, and
      28.6+/-3.9 h for the control group and Groups A and B, respectively. The total
      meperidine consumption was 90.7+/-11.9, 77.5+/-12.7, and 20.0+/-4.4 mg for the
      control group and Groups A and B, respectively. The worst visual analog pain
      scores were 6.0+/-0.2, 6.0+/-0.2, and 4.0+/-0.4 for the control group and Groups
      A and B, respectively. The bed rest times were 21.0+/-0.5, 20.0+/-0.5, and 19.0+/
      0.4 h for the control group and Groups A and B, respectively. The number of
      patients who required meperidine injection was 26, 22, and 12 for the control
      group and Groups A and B, respectively. We conclude that DM is more effective in
      producing postoperative analgesia when it is administered preincision rather than
      after the gallbladder removal treatment, which suggests a preemptive analgesic
      effect. IMPLICATIONS: Preincisional dextromethorphan (40 mg IM) treatment offers
      a preemptive analgesic effect, thus improving the postoperative pain management.

PMID- 10357341
TI  - The costs of intense neuromuscular block for anesthesia during endolaryngeal
      procedures due to waiting time.
AB  - The goal of this double-blinded, prospective study was to compare the costs
      incurred by waiting time of intense neuromuscular block while posttetanic count
      (PTC) was maintained at 0-2 during jet ventilation. Fifty patients were
      randomized into five groups to receive atracurium (ATR), mivacurium (MIV),
      rocuronium (ROC), vecuronium (VEC), and succinylcholine (SUCC). PTC < or =2 was
      maintained until completion of laryngomicroscopy by administering additional
      doses of relaxants or by adjusting the speed of the infusion of SUCC. We compared
      waiting time, i.e., onset time and recovery time, and costs of intense
      neuromuscular block. The expenses due to waiting time were calculated based on
      the average costs in the otorhinolaryngological operating room in Tampere
      University Hospital: FIM 40 (approximately $8) per minute in 1997. MIV and SUCC
      differ favorably from ATR, ROC, and VEC when waiting time and costs are
      concerned. The recovery times with MIV and SUCC were considerably shorter than
      those with ATR, ROC, and VEC (P < 0.001 in all pairwise comparisons). Using the
      muscle relaxant with the longest waiting time instead of that with the shortest
      waiting time (difference 21.8 min) cost more than FIM 800 (approximately $160)
      extra per patient. IMPLICATIONS: In this randomized, double-blinded, prospective
      study, we evaluated the costs of intense neuromuscular block due to waiting time.
      Succinylcholine and mivacurium are the most economical muscle relaxants to use
      when intense neuromuscular block is mandatory. Using intermediate-acting muscle
      relaxants results in unduly prolonged recovery time and extra costs.

PMID- 10357342
TI  - Epidural ropivacaine for the initiation of labor epidural analgesia: a dose
      finding study.
AB  - The purpose of our study was to determine the lowest concentration of ropivacaine
      that offers pain relief for the initiation of labor epidural analgesia. Women in
      active labor were enrolled in this prospective, randomized, double-blinded study
      to receive either ropivacaine 0.20% (Group I), ropivacaine 0.15% (Group II), or
      ropivacaine 0.10% (Group III). After placement of the epidural catheter, 13 mL of
      the study medication was administered. Fifteen minutes later, the adequacy of
      analgesia was assessed. If the woman reported that her degree of analgesia was
      not adequate, an additional 5 mL of the study medication was given, the degree of
      pain relief was reassessed 15 min later, and the study was concluded. A
      sequential study design was used to assess the success rates. We found that 26 of
      28 (93%) women in Group I had adequate analgesia, compared with only 18 of 28
      (64%) in Group II (P = 0.014) and 4 of 12 (33%) in Group III (P = 0.003). We
      conclude that ropivacaine 0.20% offers adequate analgesia significantly more
      often than either ropivacaine 0.15% or ropivacaine 0.10%. If one selects
      ropivacaine as the sole local anesthetic for the initiation of labor epidural
      analgesia, the minimal concentration should be 0.20%. IMPLICATIONS: The lowest
      effective concentration of ropivacaine for the initiation of labor epidural
      analgesia has not been determined. We found that ropivacaine 0.20% offers
      adequate analgesia significantly more often than either ropivacaine 0.15% or
      ropivacaine 0.10%. If one selects ropivacaine as the sole local anesthetic for
      the initiation of labor epidural analgesia, the minimal concentration should be
      0.20%.

PMID- 10357343
TI  - Granisetron/dexamethasone combination for reducing nausea and vomiting during and
      after spinal anesthesia for cesarean section.
AB  - We compared the efficacy of granisetron plus dexamethasone with that of
      granisetron alone for preventing nausea and vomiting in parturients undergoing
      cesarean section under spinal anesthesia. In a randomized, double-blinded manner,
      120 patients received either granisetron 3 mg (Group I, n = 60) or granisetron 3
      mg plus dexamethasone 8 mg (Group II, n = 60) IV immediately after clamping of
      the fetal umbilical cord. A complete response, defined as no emetic symptoms and
      no need for another rescue antiemetic medication in the intraoperative,
      postdelivery period was 83% in Group I and 98% in Group II (P = 0.008); the
      corresponding rates during the first 24 h after surgery was 85% and 98% (P =
      0.016). No clinically serious adverse events were observed in any of the groups.
      In conclusion, the prophylactic use of a granisetron/dexamethasone combination is
      more effective than granisetron alone for reducing nausea and vomiting in
      patients during and after spinal anesthesia for cesarean section. IMPLICATIONS:
      Intraoperative, postdelivery, and postoperative nausea and vomiting are
      distressing to patients undergoing cesarean section under spinal anesthesia. The
      combination of granisetron plus dexamethasone was evaluated and found to be
      effective for preventing these emetic symptoms.

PMID- 10357344
TI  - Paravertebral blockade for modified radical mastectomy in a pregnant patient.

PMID- 10357345
TI  - Efficacy and adverse effects of prophylactic antiemetics during patient
      controlled analgesia therapy: a quantitative systematic review.
AB  - Nausea and vomiting are frequent adverse effects of patient-controlled analgesia
      (PCA) with opioids. To identify the optimal prophylactic antiemetic intervention
      in this setting, we performed a systematic search for randomized trials (MEDLINE,
      EMBASE, Cochrane library, reference lists, hand-searching, no language
      restriction) published up to May 1998 that compared prophylactic antiemetic
      interventions with placebo or no treatment in the postoperative PCA-setting with
      opioids. Fourteen placebo-controlled trials (1117 patients) with different
      regimens of droperidol, ondansetron, hyoscine TTS, tropisetron, metoclopramide,
      propofol, and promethazine were analyzed. One PCA was with tramadol, all others
      were with morphine. At 24 h, the cumulative incidence of nausea and vomiting
      without antiemetics was approximately 50%. Droperidol 0.017-0.17 mg/mg of
      morphine (0.5-11 mg/d droperidol) was statistically significantly more effective
      than placebo without evidence of dose-responsiveness; the number needed to treat
      to prevent nausea compared with placebo was 2.7 (95% confidence interval 1.8
      5.2), and that to prevent vomiting was 3.1 (2.3-4.8). Compared with placebo, the
      incidence of minor adverse effects with droperidol was increased with doses >4
      mg/d. IMPLICATIONS: Of 100 patients treated with droperidol added in a patient
      controlled analgesia pump with morphine, 30 who would have vomited or been
      nauseated had they not received droperidol will not suffer these effects. There
      is no evidence of dose-responsiveness for efficacy with droperidol, but the risk
      of adverse effects is dose-dependent. There is a lack of evidence for other
      antiemetics.

PMID- 10357346
TI  - The use of nonpharmacologic techniques to prevent postoperative nausea and
      vomiting: a meta-analysis.
AB  - We assessed the efficacy of nonpharmacologic techniques to prevent postoperative
      nausea and vomiting (PONV) by systematic review. These studies included
      acupuncture, electroacupuncture, transcutaneous electrical nerve stimulation,
      acupoint stimulation, and acupressure. Of the 24 randomized trials retrieved by a
      search of articles indexed on the MEDLINE and EMBASE databases (1980-1997), 19
      were eligible for meta-analysis. The primary outcomes were the incidence of
      nausea, vomiting, or both 0-6 h (early efficacy) or 0-48 h (late efficacy) after
      surgery. The pooled relative risk (RR) and numbers needed to treat (NNT) were
      calculated. In children, no benefit was found. Some results in adults were
      significant. Nonpharmacologic techniques were similar to antiemetics in
      preventing early vomiting (RR = 0.89 [95% confidence interval 0.47-1.67]; NNT =
      63 [10-infinity]) and late vomiting (RR = 0.80 [0.35-1.81]; NNT = 25 [5
      infinity]) in adults. Nonpharmacologic techniques were better than placebo at
      preventing early nausea (RR = 0.34 [0.20-0.58]; NNT = 4 [3-6]) and early vomiting
      in adults (RR = 0.47 [0.34-0.64]; NNT = 5 [4-8]). Nonpharmacologic techniques
      were similar to placebo in preventing late vomiting in adults (RR = 0.81 [0.46
      1.42]; NNT = 14 [6-infinity]). Using nonpharmacologic techniques, 20%-25% of
      adults will not have early PONV compared with placebo. It may be an alternative
      to receiving no treatment or first-line antiemetics. IMPLICATIONS: This
      systematic review showed that nonpharmacologic techniques were equivalent to
      commonly used antiemetic drugs in preventing vomiting after surgery.
      Nonpharmacologic techniques were more effective than placebo in preventing nausea
      and vomiting within 6 h of surgery in adults, but there was no benefit in
      children.

PMID- 10357347
TI  - Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide
      for preventing postoperative nausea and vomiting: a meta-analysis.
AB  - Postoperative nausea and vomiting are important causes of morbidity after
      anesthesia and surgery. We performed a meta-analysis of published, randomized,
      controlled trials to determine the relative efficacy and safety of ondansetron,
      droperidol, and metoclopramide for the prevention of postoperative nausea and
      vomiting. We performed a literature search of English references using both the
      MEDLINE database and a manual search. Double-blinded, randomized, controlled
      trials comparing the efficiency of the prophylactic administration of
      ondansetron, droperidol, and/or metoclopramide therapy during general anesthesia
      were included. A total of 58 studies were identified, of which 4 were excluded
      for methodological concerns. For each comparison of drugs, a pooled odds ratio
      (OR) with a 95% CI was calculated using a random effects model. Ondansetron
      (pooled OR 0.43, 95% CI 0.31, 0.61; P < 0.001) and droperidol (pooled OR 0.68,
      95% CI 0.54, 0.85; P < 0.001) were more effective than metoclopramide in
      preventing vomiting. Ondansetron was more effective than droperidol in preventing
      vomiting in children (pooled OR 0.49; P = 0.004), but they were equally effective
      in adults (pooled OR 0.87; P = 0.45). The overall risk of adverse effects was not
      different among drug combinations. We conclude that ondansetron and droperidol
      are more effective than metoclopramide in reducing postoperative vomiting.
      IMPLICATIONS: We performed a systematic review of published, randomized,
      controlled trials to determine the relative efficacy and safety of ondansetron,
      droperidol, and metoclopramide for preventing postoperative nausea and vomiting.
      Ondansetron and droperidol were more effective than metoclopramide in reducing
      postoperative vomiting. The overall risk of adverse effects did not differ.

PMID- 10357348
TI  - Does the Murphy eye reduce the reliability of chest auscultation in detecting
      endobronchial intubation?
AB  - Bilateral breath sounds are routinely auscultated after endotracheal intubation
      to verify that the endotracheal tube (ETT) tip is properly positioned. We
      conducted the present study to ascertain whether the eye of the Murphy tube has
      an influence on the reliability of auscultation of breath sounds in detecting
      endobronchial intubation. Twenty patients undergoing scheduled oral and
      maxillofacial surgery participated in this study. After the induction of general
      anesthesia, either the Magill tube or the Murphy tube was inserted through the
      nose into the trachea. The fiberoptic bronchoscope was inserted through the ETT,
      and the distance from the nares to the carina of the trachea was measured. When
      breath sounds from the left side of the chest changed and disappeared while the
      ETT was being advanced, the distance from the nares to the ETT tip was measured.
      Unilateral auscultatory change was not observed until the ETT tip was advanced
      beyond the carina and inserted 1.5+/-0.4 cm into the right mainstem bronchus when
      the Magill tube was used and 2.0+/-0.4 cm when the Murphy tube was used (P <
      0.01). Breath sounds disappeared when the ETT tip was further advanced up to
      3.2+/-0.3 cm from the carina. We demonstrated that the eye of the Murphy tube
      reduces the reliability of chest auscultation in detecting endobronchial
      intubation. IMPLICATIONS: The Murphy eye was designed to allow ventilation of the
      lung when the bevel of the endotracheal tube is occluded. We demonstrated that
      the eye of the Murphy tube reduces the reliability of chest auscultation in
      detecting endobronchial intubation.

PMID- 10357349
TI  - Transient hyperdynamic response associated with controlled hypocapneic
      hyperventilation during sevoflurane-nitrous oxide mask induction in adults.
AB  - We assessed hemodynamic variables during sevoflurane face mask anesthetic
      induction in female ASA physical status I or II patients. Anesthesia was induced
      with a single-breath inhalation method with 8% sevoflurane in 50% nitrous oxide
      in oxygen. Thirty patients were randomized either to breathe spontaneously (SB
      group, n = 15) or to receive controlled ventilation (CV group, n = 15) for 6 min
      after the loss of consciousness. Noninvasive blood pressure and heart rate (HR)
      were recorded at 1-min intervals. Mean +/- SD HR increased from 83+/-18 to 112+/
      24 bpm at 4 min in the CV group (P < 0.001 between groups and within group
      compared with baseline). Mean arterial pressure increased from 97+/-9 to 106+/-26
      mm Hg at 4 min in the CV group, which was significantly higher than that in the
      SB group (P < 0.01). In the SB group, mean arterial pressure decreased
      significantly, from 96+/-8 to 78+/-13 mmHg, at 6 min (P < 0.001), and HR remained
      unchanged. Therefore, hyperventilation should be avoided during the induction of
      sevoflurane anesthesia via a mask. IMPLICATIONS: In this randomized, prospective
      study, we found that controlled hypocapneic hyperventilation delivered manually
      during sevoflurane/ N2O/O2 mask induction was associated with a significant
      transient hyperdynamic response. This kind of hemodynamic arousal can be
      detrimental to many patients and can be avoided by conducting sevoflurane mask
      induction with unassisted spontaneous breathing.

PMID- 10357350
TI  - Hemodynamic and catecholamine stress responses to insertion of the Combitube,
      laryngeal mask airway or tracheal intubation.
AB  - In a prospective, randomized, and controlled trial, we compared the stress
      responses after insertion of the Combitube (CT; Kendall-Sheridan Catheter Corp.,
      Argyle, NY), the laryngeal mask airway (LMA), or endotracheal intubation (ET).
      Seventy-five patients scheduled for routine urological or gynecological surgery
      were randomly allocated to one of three groups and were ventilated via either an
      ET, a LMA, or a CT. All three devices could be inserted easily and rapidly,
      providing adequate ventilation and oxygenation. Insertion of the CT was
      associated with a significant increase in mean maximal systolic arterial pressure
      (160+/-32 mm Hg) and diastolic arterial pressure (91+/-17 mm Hg) compared with ET
      (140+/-24, 78+/-11 mm Hg; P < 0.05, P < 0.01, respectively) or insertion of the
      LMA (115+/-33,63+/-22 mm Hg, both P < 0.001). The mean maximal epinephrine and
      norepinephrine plasma concentrations after insertion of the CT (37.3+/-31.1 and
      279+/-139 pg/mL, respectively) were significantly higher than those after ET
      (35.8+/-89.8 and 195+/-58 pg/mL, respectively) or insertion of a LMA (17.3+/-13.3
      and 158+/-67 pg/mL, respectively). This might be attributed to the pressure of
      the pharyngeal cuff of the CT on the anterior pharyngeal wall. We conclude that
      insertion of the CT causes a pronounced stress response and that precautions
      should be taken when used in patients at risk of hypertensive bleeding.
      IMPLICATIONS: In this study, we showed that the hemodynamic and catecholamine
      stress responses after insertion of the Combitube (Kendall-Sheridan Catheter
      Corp., Argyle, NY) were significantly higher compared with laryngeal mask airway
      or endotracheal intubation. We conclude that the increased stress response to
      insertion of a Combitube may represent a serious hazard to patients with
      cardiovascular disease.

PMID- 10357351
TI  - Hypothesis: volatile anesthetics produce immobility by acting on two sites
      approximately five carbon atoms apart.
AB  - All series of volatile and gaseous compounds contain members that can produce
      anesthesia, as defined by the minimum alveolar anesthetic concentration (MAC)
      required to produce immobility in response to a noxious stimulus. For
      unhalogenated n-alkanes, cycloalkanes, aromatic compounds, and n-alkanols,
      potency (1 MAC) increases by two-to threefold with each carbon addition in the
      series (e.g., ethanol is twice as potent as methanol). Total fluorination
      (perfluorination) of n-alkanes essentially eliminates anesthetic potency: only
      CF4 is anesthetic (MAC = 66.5 atm), which indicates that fluorine atoms do not
      directly influence sites of anesthetic action. Fluorine may enhance the
      anesthetic action of other moieties, such as the hydrogen atom in CHF3 (MAC =
      1.60 atm), but, consistent with the notion that the fluorine atoms do not
      directly influence sites of anesthetic action, adding -(CF2)n moieties does not
      further increase potency (e.g., CHF2-CF3 MAC = 1.51 atm). Similarly, adding 
      (CF2)n moieties to perfluorinated alkanols (CH2OH-[CF2]nF) does not increase
      potency. However, adding a second terminal hydrogen atom (e.g., CHF2-CHF2 or
      CH2OH-CHF2) produces series in which the addition of each -CF2- "spacer" in the
      middle of the molecule increases potency two- to threefold, as in each
      unhalogenated series. This parallel stops at four or five carbon atom chain
      lengths. Further increases in chain length (i.e., to CHF2[CF2]4CHF2 or
      CHF2[CF2]5CH2OH) decrease or abolish potency (i.e., a discontinuity arises). This
      leads to our hypothesis that the anesthetic moieties (-CHF2 and -CH2OH) interact
      with two distinct, spatially separate, sites. Both sites must be influenced
      concurrently to produce a maximal anesthetic (immobility) effect. We propose that
      the maximal potency (i.e., for CHF2[CF2]2CHF2 and CHF2[CF2]3CH2OH) results when
      the spacing between the anesthetic moieties most closely matches the distance
      between the two sites of action. This reasoning suggests that a distance
      equivalent to a four or five carbon atom chain, approximately 5 A, separates the
      two sites. IMPLICATIONS: Volatile anesthetics may produce immobility by a
      concurrent action on two sites five carbon atom lengths apart.

PMID- 10357352
TI  - Clonidine inhibits and phorbol acetate activates glutamate release from rat
      spinal synaptoneurosomes.
AB  - Glutamate is a major neural transmitter of noxious stimulation in the spinal
      cord. We measured glutamate release from rat spinal synaptoneurosomes by using an
      enzyme-linked fluorimetric assay. Glutamate was released from spinal cord
      synaptoneurosomes in response to the addition of 30 mM potassium chloride, 1 mM 4
      aminopyridine, or 1 microM ionomycin in the presence of external calcium. There
      was less release of glutamate in the absence, versus the presence, of external
      calcium. Clonidine significantly reduced the level of glutamate released from the
      spinal cord synaptoneurosomes. Tetradecanoyl phorbol acetate, an activator of
      protein kinase C, enhanced glutamate release. Forskolin, a protein kinase A
      activator, had no effect on the glutamate efflux. Our data indicate that
      glutamate released in the spinal cord is dependent on protein kinase C but is
      independent of the protein kinase A pathway. They also suggest that the
      inhibition of glutamate release may be the underlying mechanism of
      antinociception by clonidine at the spinal cord level. IMPLICATIONS: We
      demonstrated that synaptoneurosomes from rat spinal cord could release glutamate
      in response to depolarization. We showed that an activator of protein kinase C
      increased glutamate released from spinal cord synaptoneurosomes but that
      clonidine decreased it. Glutamate release may be one of the mechanisms of
      antinociception at the spinal cord level.

PMID- 10357353
TI  - Depressant and convulsant barbiturates both inhibit neuronal nicotinic
      acetylcholine receptors.
AB  - Neuronal nicotinic acetylcholine receptors (neuronal nAchRs) are sensitive to
      many anesthetics, including barbiturates, which suggests that these receptors are
      potential sites for anesthetic action. Subtle changes in molecular structures of
      the anesthetic barbiturates can produce compounds with potent convulsant
      activity. Whereas R(-) isomer of 1-methyl-5-phenyl-5-propyl barbituric acid
      (MPPB) exerts anesthetic action, S(+)MPPB exhibits pure excitatory effects,
      including convulsion. 5-(2-cyclohexilidene-ethyl)-5-ethyl barbituric acid is
      another example of a convulsant barbiturate. We compared the effects of
      depressant and convulsant barbiturates on the neuronal nAchR-mediated current to
      determine whether inhibition of neuronal nAchRs contributes to the anesthetic
      action of barbiturates. Whole cell nicotine-induced currents were recorded in
      PC12 derived from rat pheochromocytoma, using the conventional whole cell patch
      clamp technique in the presence and absence of barbiturates. Both depressant and
      convulsant barbiturates inhibited the nicotine-induced inward current reversibly
      and in a dose-dependent manner when co-applied with nicotine. All barbiturates
      accelerated the current decay. There was no significant difference between the
      concentrations for 50% inhibition for MPPB isomers. There was no correlation
      between inhibition of ganglionic nAchRs and anesthetic effects of the
      barbiturates. These results strongly oppose the idea that inhibition of neuronal
      nAchRs contributes to the anesthetic action of barbiturates. IMPLICATIONS: We
      found that both convulsant and depressant barbiturates inhibit the current
      mediated through ganglionic nicotinic acetylcholine receptors in PC12 cells. This
      finding suggests that the inhibition of neuronal nicotinic acetylcholine
      receptors does not contribute to the anesthetic action of barbiturates.

PMID- 10357354
TI  - Middle latency auditory evoked responses and electroencephalographic derived
      variables do not predict movement to noxious stimulation during 1 minimum
      alveolar anesthetic concentration isoflurane/nitrous oxide anesthesia.
AB  - The electroencephalogram (EEG) and middle latency auditory evoked responses
      (MLAER) have been proposed for assessment of the depth of anesthesia. However, a
      reliable monitor of the adequacy of anesthesia has not yet been defined. In a
      multicenter study, we tested whether changes in the EEG and MLAER after a tetanic
      stimulus applied to the wrist could be used to predict subsequent movement in
      response to skin incision in patients anesthetized with 1 minimum alveolar
      anesthetic concentration (MAC) isoflurane in N2O. We also investigated whether
      the absolute values of any of these variables before skin incision was able to
      predict subsequent movement. After the induction of anesthesia with propofol and
      facilitation of tracheal intubation with succinylcholine, 82 patients received 1
      MAC isoflurane (0.6%) in N2O 50% without an opioid or muscle relaxant.
      Spontaneous EEG and MLAER to auditory click-stimulation were recorded from a
      single frontoparietal electrode pair. MLAER were severely depressed at 1 MAC
      isoflurane. At least 20 min before skin incision, a 5-s tetanic stimulus was
      applied at the wrist, and the changes in EEG and MLAER were recorded. EEG and
      MLAER values were evaluated before and after skin incision for patients who did
      not move in response to tetanic stimulation. Twenty patients (24%) moved after
      tetanic stimulation. The changes in the EEG or MLAER variables were unable to
      predict which patients would move in response to skin incision. Preincision
      values were not different between patients who did and did not move in response
      to skin incision for any of the variables. MLAER amplitude increased after skin
      incision. We conclude that it is unlikely that linear EEG measures or MLAER
      variables can be of practical use in titrating isoflurane anesthesia to prevent
      movement in response to noxious stimulation. IMPLICATIONS: Reliable estimation of
      anesthetic adequacy remains a challenge. Changes in spontaneous or auditory
      evoked brain activity after a brief electrical stimulus at the wrist could not be
      used to predict whether anesthetized patients would subsequently move at the time
      of surgical incision.

PMID- 10357355
TI  - Mucosal pressure, mechanism of seal, airway sealing pressure, and anatomic
      position for the disposable versus reusable laryngeal mask airways.

PMID- 10357356
TI  - Visual analog scale scores for labor pain.

PMID- 10357357
TI  - Repeated use of the cuffed oropharyngeal airway in an infant for radiation
      therapy.

PMID- 10357358
TI  - Glottis simulator.

PMID- 10357359
TI  - Massive intraoperative pulmonary embolism: with succinylcholine or not?

PMID- 10357361
TI  - Takes a lickin' and keeps on tickin'.

PMID- 10357360
TI  - Are vasopressors beneficial after cranial trauma?

PMID- 10357362
TI  - Recommended exposure limits for desflurane and isoflurane.

PMID- 10357363
TI  - Arterialization of the dorsum vein on the hand.

PMID- 10357364
TI  - Difficult airway management with balloon inflation.

PMID- 10357365
TI  - Midfemoral block: a new lateral approach to the sciatic nerve.

PMID- 10357366
TI  - Assessment of renal effects of sevoflurane in elderly patients using urinary
      markers.

PMID- 10357367
TI  - Fat embolism and neurological dysfunction.

PMID- 10357368
TI  - Rediscovering the obvious.

PMID- 10357369
TI  - False comfort from a pulse oximeter.

PMID- 10357370
TI  - Use of the laryngeal mask before tracheal intubation in a patient with a
      cancerous nose.

PMID- 10357372
TI  - The HIV/AIDS epidemic in eastern Europe: recent patterns and trends and their
      implications for policy-making.
AB  - OBJECTIVE: To describe recent patterns and trends in the HIV epidemic in eastern
      Europe. METHODS: AIDS programme managers and epidemiologists of 23 countries were
      contacted and requested to provide national HIV surveillance data. Joint United
      Nations Programme on HIV/AIDS/World Health Organisation country fact sheets were
      reviewed and analysed, and this information was supplemented with published HIV
      prevalence and sexually transmitted disease case reporting information,
      unpublished travel reports and expert evaluations. RESULTS: The cumulative number
      of HIV cases reported in the region increased more than fivefold between 1995 and
      1997, from 9111 to 46573; Ukraine, Russia and Belarus accounted for about 90% of
      all new cases. Dramatic increases in the number of HIV-infected injecting drug
      users (IDU) were reported from these countries, and a similar pattern was
      emerging in Moldova, the Baltic States, the Caucasus and Kazakstan. In central
      Europe, the increase in the number of cases was much lower, and (with the
      exception of Poland) homosexual transmission was most common, whereas in the
      Balkan countries, cases due to heterosexual transmission were reported relatively
      more frequently. At the end of 1997, more than 50% of all cases region-wide had
      been reported from IDU. HIV prevalence data were inconclusive. The number of
      reported syphilis cases had risen significantly in the countries of the former
      Soviet Union. CONCLUSION: Our data confirm that HIV must have been rapidly
      spreading among IDU in several countries of the former Soviet Union, whereas
      central and southeast Europe have so far escaped a more extensive spread of HIV.
      Factors that might have fuelled a massive spread among IDU include changes in
      drug demand and supply, migration and specific local drug production and
      consumption patterns. High rates of syphilis reported in the countries of the
      former Soviet Union highlight that subregion's increased vulnerability with
      regards to a further spread of the epidemic, via heterosexual intercourse, into
      the general population.

PMID- 10357371
TI  - Randomized trial comparing saquinavir soft gelatin capsules versus indinavir as
      part of triple therapy (CHEESE study).
AB  - OBJECTIVE: To compare efficacy and tolerability of saquinavir soft gelatin
      capsule (SQV-SGC) formulation and indinavir, both given as part of a triple drug
      regimen containing zidovudine and lamivudine, in HIV-1-infected individuals.
      DESIGN: Randomized, open label, multicentre study. PATIENTS: A total of 70
      patients who were antiretroviral-naive and who had a CD4 cell count < 500 x
      10(6)/I and/or > 10000 HIV RNA copies/ml plasma and/or HIV-related symptoms.
      Subjects were assigned randomly to zidovudine 200 mg three times per day plus
      lamivudine 150 mg twice per day plus either SQV-SGC 1200 mg three times per day
      (SQV-SGC group) or indinavir 800 mg three times per day (indinavir group). Data
      are presented for all patients up to week 24. RESULTS: Mean baseline CD4 cell
      counts (+/- SE) were 301+/-29 x 10(6) cells/l and 310 +/-43 x 10(6) cells/l in
      the SQV-SGC and indinavir groups, respectively. The log10 median baseline HIV RNA
      load was 5.00 copies/ml in the SQV-SGC group and 4.98 copies/ml in the indinavir
      group. No difference in antiretroviral effect between the treatment arms could be
      demonstrated. Intention-to-treat analysis (last observation carried forward
      [LOCF]) at week 24 revealed that RNA levels decreased to < 50 copies/ml in 74.3%
      of patients in the SQV-SGC group and in 71.4% of the patients in the indinavir
      group (P = 0.78). In the on-treatment analysis the proportion of patients < 50
      copies/ml at week 24 was 88.0% in the SQV-SGC group and 84.6% in the indinavir
      group (P = 0.725). Intriguingly, the mean increase of CD4 cells in the first 24
      weeks was 162+/-20 x 10(6) cells/l in the SQV-SGC group and 89+/-21 x 10(6)
      cells/l in the indinavir group (P = 0.01), but preliminary data indicate that
      this difference in CD4 cell count gain may disappear after 24 weeks of treatment.
      Both regimens were generally well tolerated. CONCLUSION: During the first 24
      weeks of the study, we found no difference in antiviral potency between the
      indinavir group and the SQV-SGC group. A significantly higher CD4 response in the
      SQV-SGC group was observed.

PMID- 10357373
TI  - Human astrocytes inhibit HIV-1 expression in monocyte-derived macrophages by
      secreted factors.
AB  - OBJECTIVE: To determine the effects of primary human fetal and adult astrocytes
      on HIV-1 replication in monocyte-derived macrophages (MDM). DESIGN: HIV-1 can
      infect the brain in the early stage of systemic infection. The HIV-1-associated
      cognitive/motor complex develops later in the course of the disease, suggesting
      that brain cells may inhibit the early productive infection and the development
      of neurological disease. In this study, we established an in-vitro coculture
      system to determine whether astrocytes can modulate HIV-1 replication in MDM.
      METHODS: Elutriated human monocytes were differentiated in culture, then infected
      with monocyte tropic HIV-1. One day after infection, MDM were co-cultured with
      primary astrocytes. Reverse transcriptase (RT) activity was used to monitor virus
      replication. RT-polymerase chain reaction (PCR), enzyme-linked immunosorbent
      assay (ELISA) and bioassay were used to assess cytokine production. RESULTS:
      Primary human astrocytes suppressed HIV-1 replication in MDM via the production
      of soluble factors. Cytokine inhibitors of HIV-1, such as IFN-gamma, IL-4, IL-10
      and IL-13, were not detectable, whereas transforming growth factor beta (TGF
      beta) was constitutively produced only in its latent form. Paraformaldehyde-fixed
      astrocytes, unable to secrete cytokines, failed to inhibit HIV-1. These cells
      caused enhanced virus replication, however, which correlated with an increase in
      macrophage colony stimulating factor (M-CSF) production. CONCLUSIONS: Human
      astrocytes can increase and decrease HIV-1 expression in MDM. An imbalance
      between the positive and negative effects of astrocytes may contribute to the
      expression of virus in the brain, and the development of HIV-1-associated
      cognitive/motor complex.

PMID- 10357374
TI  - Depletion in blood CD11c-positive dendritic cells from HIV-infected patients.
AB  - OBJECTIVES: To quantify blood dendritic cells from HIV-positive patients and to
      study the expression of functional molecules, in relation to HIV viral load, CD4
      cell counts and antiretroviral treatment. DESIGN AND METHODS: Three-colour flow
      cytometry analysis was used to quantify blood dendritic cells without previous
      isolation from whole blood and to study the expression of functional molecules
      (MHC class II, CD11c, CD83, CD86) by dendritic cells from 30 HIV-positive
      patients, 15 of whom were treated with combined antiretroviral therapy (viral
      loads from undetectable to 5.4 log copies/ml, CD4 cell counts 1-1895 cells/mm3)
      and 11 non-infected controls. RESULTS: The median proportion of blood dendritic
      cells from HIV-positive patients was significantly decreased when the plasma
      viral load was above 200 copies/ml: 0.2% (0.1-1.1, n = 19) compared with 0.4%
      (0.2-0.8, n = 11) in patients with undetectable viral load whether they were
      treated or not, and to 0.4% (0.2-1.3, n = 11) in controls (P = 0.02). A major
      decrease of the CD11c positive dendritic cells was observed in all HIV-positive
      samples, with only 18% (mean; range: 0.3-80%, median 4.2%) compared with 44% (11
      70%, median 42%) of control dendritic cells (P = 0.0006). In contrast, the
      proportion of dendritic cells expressing CD86, was slightly higher in HIV
      positive patients than in controls (P = 0.03). CONCLUSIONS: The decreased
      proportion of blood dendritic cells correlated with virus replication and the
      lack of dendritic cells expressing CD11c are the first evidence of strong
      dendritic cell alterations in HIV-positive patients. Although the proportion of
      blood dendritic cells are in the normal range in treated HIV-positive patients
      with undetectable viral load, the CD11c alterations persist indicating that
      antiretroviral therapy might only partly correct the alterations of the
      circulating dendritic cells.

PMID- 10357375
TI  - A recombinant vaccinia virus based ELISPOT assay detects high frequencies of Pol
      specific CD8 T cells in HIV-1-positive individuals.
AB  - OBJECTIVES: HIV-1-specific CD8 T cells are considered to be critical in anti-HIV
      responses. It is important to quantify these cells and to determine their
      antigenic targets. Here quantification of interferon (IFN)-gamma secreting, virus
      specific cells was achieved with an enzyme linked immuno spot (ELISPOT) assay.
      METHODS: Peripheral blood mononuclear cells (PBMC) were infected with recombinant
      vaccinia vectors expressing HIV-1 genes (gag, pol, env or nef) and added to wells
      precoated with anti-IFN-gamma monoclonal antibodies. Spot forming cells (SFC),
      i.e. antigen-specific T cells were detected 24 h later by the addition of
      biotinylated anti-IFN-gamma monoclonal antibodies, followed by avidin-bound
      biotinylated horseradish peroxidase. RESULTS: In a cohort of 19 patients, of whom
      15 were on highly active antiretroviral therapy, 18 had primed T cells directed
      against one or more HIV-1 antigens (P < 0.0001). Pol-specific T cells routinely
      dominated the CD8 response with frequencies up to 2000 SFC per 10(6) PBMC. In HLA
      A*0201-positive patients, the vaccinia vectors detected much higher frequencies
      of SFC than haplotype-restricted peptides. Elimination of CD8 T cells resulted in
      > 90% loss of antigen-specific SFC when vaccinia virus was used as a vector. The
      number of CD8 SFC exceeded the number of memory cells detected in limiting
      dilution assays by > 1 log10, whereas a correlation was found between the
      frequency of effector cells detected by both ELISPOT and MHC class I peptide
      tetramer assays. CONCLUSIONS: Vaccinia virus vectors used in ELISPOT assays are
      useful for determining the frequency and specificity of CD8 T cells for
      individual HIV-1 gene products. The dominance of cytolytic T lymphocytes (CTL)
      recognizing pol proteins suggests that this antigen should be considered in
      vaccine strategies.

PMID- 10357376
TI  - Early effects of antiretroviral combination therapy on activation, apoptosis and
      regeneration of T cells in HIV-1-infected children and adolescents.
AB  - OBJECTIVES: To assess the relationship between apoptosis, activation and
      regeneration of T cells, and viral replication in paediatric patients with HIV-1
      infection during antiretroviral therapy (ART). DESIGN: In 15 HIV-1-positive
      children and adolescents sequential blood samples were obtained during 16
      episodes of ART using combinations of nucleosidic HIV-1 reverse transcriptase
      (RT)-inhibitors and HIV-1 protease inhibitors or non-nucleosidic RT-inhibitors.
      METHODS: We assessed sensitivity of freshly isolated peripheral blood T cells
      towards spontaneous, anti-CD95- and anti-CD3-induced apoptosis and activation
      before and after 6-8 weeks of ART. Expression of CD95, CD45RA, CD45RO and CD62L
      on CD4 and CD8 T cells and of CD34 on mononuclear cells was studied by
      multiparameter flow cytometry before and after 10-12 weeks of ART. RESULTS: ART
      caused a significant increase in absolute lymphocyte and CD4 T cell counts (P <
      0.03 and P < 0.02, respectively) and a decrease in both anti-CD95- and anti-CD3
      induced apoptosis of CD4 and CD8 T cells to near normal levels even in patients
      without complete suppression of viral replication. A significant reduction in the
      percentage of CD95 (but not of CD95high) CD4 T cells was observed (P < 0.005).
      Resting/naive cells contributed significantly (P < 0.03) to the rise in CD4 T
      cells especially in infants and young children. CONCLUSIONS: Different mechanisms
      may contribute to early T cell reconstitution in HIV-1-infected children and
      adolescents during ART: decreased activation-induced apoptosis leading to
      increased survival of circulating primed/memory T cells; decreased activation
      induced naive-to-memory shift increasing the frequency of circulating
      resting/naive T cells; increased input of haematopoietic progenitor cells from
      the bone marrow into the thymus and decreased intrathymic T cell death leading to
      an increased thymic output of naive T cells.

PMID- 10357377
TI  - Viral load and burden modification following early antiretroviral therapy of
      primary HIV-1 infection.
AB  - OBJECTIVE: The aim of this study was to monitor the effect on viral DNA and RNA
      of early treatment with highly aggressive antiretroviral therapy (HAART), in
      comparison with zidovudine (ZDV) monotherapy or no treatment in subjects with
      primary HIV-1 infection (PHI). DESIGN AND METHODS: Of the 28 patients selected,
      four were untreated, four received ZDV alone, 10 received a triple combination
      (ZDV, lamivudine (3TC) and saquinavir (SQV)) and 10 received a quadruple
      combination (ZDV, 3TC, SQV and ritonavir (RTV)). Seroconversion was monitored by
      means of Western blot profile analysis. A quantitative polymerase chain reaction
      (PCR) assay in the HIV gag region was used to monitor viral DNA and the nucleic
      acid sequence based amplification (NASBA) system for viraemia (HIV-RNA). RESULTS:
      There was a certain level of heterogeneity in the baseline values of HIV-DNA and
      RNA. Early HAART led to a rapid recovery in the number of CD4 cells and the
      CD4/CD8 cell ratio and a reduction in HIV-RNA to undetectable levels, which was
      significantly greater than in the untreated patients or those treated with ZDV.
      Although a reduction in DNA levels was also observed in the HAART-treated
      subjects, this variation was not significant. CONCLUSIONS: The parameters of
      viral replication and CD4 cell recovery were only slightly better in the patients
      receiving ZDV monotherapy than in the untreated patients, thus confirming that
      the course of the infection is hardly affected by the monotherapy. The early
      introduction of HAART greatly reduces plasma viraemia and restores the number of
      CD4 cells for up to 1 year. HIV-DNA remains detectable, although at low levels,
      thus confirming that the early established reservoir of infected cells is little
      affected. Longer periods of observation and the introduction of complementary
      approaches, such as immunomodulatory therapies, will provide further information
      concerning the possibility of radically interfering with the natural evolution of
      the disease.

PMID- 10357378
TI  - The use of plasma HIV RNA as a study endpoint in efficacy trials of
      antiretroviral drugs.
AB  - OBJECTIVES: To evaluate the utility of HIV RNA as an endpoint in antiretroviral
      efficacy studies. DESIGN: Data collected from antiretroviral efficacy trials were
      analyzed to explore relationships between clinical progression and the magnitude,
      nadir and duration of HIV RNA reductions. The proportion of patients suppressing
      HIV RNA below assay quantification, time to maximal virologic response, and loss
      of virologic response in relation to pretreatment characteristics were also
      analyzed. METHODS: Analyses were conducted using data from individual
      antiretoviral efficacy trials or groups of trials that studied similar types of
      drug regimens and used similar HIV RNA assays. Treatment regimens were pooled for
      most analyses. Clinical progression was defined as the occurrence of an AIDS
      defining event (essentially Centers of Disease Control criteria) or death.
      RESULTS: Treatment-induced reductions in HIV RNA approximating total assay
      variability of about 0.5 log10 copies/ml were associated with decreases in the
      risk of clinical progression. Larger and more sustained reductions in HIV RNA
      were directly associated with lower risks for disease progression. Lower initial
      HIV RNA reductions were associated with more durable HIV RNA suppression.
      CONCLUSIONS: For antiretoviral efficacy studies, plasma HIV RNA is a suitable
      study endpoint that is likely to predict a decreased risk for AIDS progression
      and death. Because greater and more sustained reductions in HIV RNA appear to
      confer greater reductions in clinical risk, maintaining maximal suppression of
      plasma HIV RNA, particularly below the limits of assay quantification, appears to
      be a rigorous benchmark for assessing the efficacy of antiretroviral regimens.

PMID- 10357379
TI  - Reversion of metabolic abnormalities after switching from HIV-1 protease
      inhibitors to nevirapine.
AB  - OBJECTIVES: To assess the effects of switching from HIV-1 protease inhibitors
      (PI) to nevirapine on metabolic abnormalities in patients with fat redistribution
      and on CD4 T lymphocytes and plasma HIV-1 RNA. DESIGN: Longitudinal data analysis
      of 23 consecutive patients treated with two nucleoside reverse transcriptase
      inhibitors and at least one PI who decided to stop PI despite sustained
      virological suppression (< 200 copies/ml) because of psychological repercussions
      caused by body changes. PI were replaced by nevirapine in all patients. METHODS:
      Physical examination [including measurements of body mass index (BMI) and waist:
      hip ratio (WHR)], fasting cholesterol, triglycerides, glucose, insulin, CD4 T
      lymphocytes and plasma HIV-1 RNA were performed at baseline and every 3 months.
      RESULTS: Awareness of body changes occurred after a median of 12 months (range, 6
      26 months) from the commencement of PI. Seventeen patients complained of
      increased abdominal girth (in 15 also of peripheral fat wasting) and six of
      peripheral fat wasting only. Hypertriglyceridemia (> or = 200 mg/dl) was present
      in 23 (100%), hypercholesterolemia (> or = 200 mg/dl) in 18 (78%), and impaired
      fasting glucose (> or = 110 mg/dl) in seven (30%) patients. Baseline CD4 T
      lymphocytes were 514 x 10(6)/l (range, 83-994 x 10(6)/l). HIV-1 RNA had been <
      200 copies/ml a median of 9 months (range, 3-14 months) prior to withdrawal of
      PI. Median follow-up from the replacement of PI by nevirapine was 8 months
      (range, 7-11 months). Six months after PI withdrawal there was a significant
      improvement in cholesterol (decrease of 22%; P = 0.0005), triglycerides (decrease
      of 57%; P = 0.0001), glucose (decrease of 15%; P = 0.008), and fasting insulin
      resistance index (decrease of 45%; P = 0.0001). CD4 T-lymphocyte counts remained
      unchanged (401 x 10(6)/l; range, 57-941 x 10(6)/l; P = 0.13) and in only one
      patient did the viral load become detectable at a low count (546 copies/ml; P =
      0.32). BMI did not vary (23.30 versus 23.56 kg/m2; P = 0.73), but WHR decreased
      significantly from 0.91 to 0.85 (P = 0.048). Twenty-one patients (91%)
      subjectively reported a partial improvement in their body shape (particularly in
      peripheral fat wasting), although none admitted to have their body shaped as
      prior to body changes. CONCLUSIONS: Metabolic abnormalities associated with
      potent antiretroviral regimens including PI may revert at least partially,
      whereas the suppression achieved may be preserved at least at mid-term after
      replacing PI by nevirapine.

PMID- 10357380
TI  - Twice-weekly, directly observed treatment for HIV-infected and uninfected
      tuberculosis patients: cohort study in rural South Africa.
AB  - OBJECTIVE: To determine the effectiveness of twice-weekly directly observed
      therapy (DOT) for tuberculosis (TB) in HIV-infected and uninfected patients,
      irrespective of their previous treatment history. Also to determine the
      predictive value of 2-3 month smears on treatment outcome. METHODS: Four hundred
      and sixteen new and 113 previously treated adults with culture positive pulmonary
      TB (58% HIV infected, 9% combined drug resistance) in Hlabisa, South Africa.
      Daily isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) given in
      hospital (median 17 days), followed by HRZE twice a week to 2 months and HR twice
      a week to 6 months in the community. RESULTS: Outcomes at 6 months among the 416
      new patients were: transferred out 2%; interrupted treatment 17%; completed
      treatment 3%; failure 2%; and cured 71%. Outcomes were similar among HIV-infected
      and uninfected patients except for death (6 versus 2%; P = 0.03). Cure was
      frequent among adherent HIV-infected (97%; 95% CI 94-99%) and uninfected (96%;
      95% CI 92-99%) new patients. Outcomes were similar among previously treated and
      new patients, except for death (11 versus 4%; P = 0.01), and cure among adherent
      previously treated patients 97% (95% CI 92-99%) was high. Smear results at 2
      months did not predict the final outcome. CONCLUSION: A twice-weekly rifampicin
      containing drug regimen given under DOT cures most adherent patients irrespective
      of HIV status and previous treatment history. The 2 month smear may be safely
      omitted. Relapse rates need to be determined, and an improved system of keeping
      treatment interrupters on therapy is needed. Simplified TB treatment may aid
      implementation of the DOTS strategy in settings with high TB caseloads secondary
      to the HIV epidemic.

PMID- 10357381
TI  - Intestinal parasites in patients with diarrhea and human immunodeficiency virus
      infection in Zimbabwe.
AB  - OBJECTIVES: To determine the prevalence of intestinal parasites and risk factors
      for infection associated with diarrhea in HIV-infected patients in Harare,
      Zimbabwe. DESIGN: Prospective observational study. METHODS: Single stool samples
      were collected from 88 HIV-infected individuals presenting with diarrhea of
      greater than 1 week duration. Stools were examined for intestinal parasites using
      modified acid fast stain, fluorescence- labeled monoclonal antibody for
      Cryptosporidium parvum, as well as a modified trichrome stain and a PCR-based
      protocol for Enterocytozoon bieneusi. RESULTS: C. parvum was detected in 9%
      (seven out of 82) of samples evaluated, but no Cyclospora was detected. E.
      bieneusi was detected in 18% (10 out of 55) of stool by trichrome staining and in
      51% (28 out of 55) of stool examined by PCR. Risk factors for E. bieneusi
      infection were: living in rural areas, consumption of nonpiped water, contact
      with cow dung and household contact with an individual with diarrhea. CONCLUSION:
      E. bieneusi infection was common in HIV-infected patients with diarrhea in
      Zimbabwe and may be acquired through person-to-person and fecal-oral
      transmission.

PMID- 10357382
TI  - Detection and quantification of HIV-1 in semen: identification of a subpopulation
      of men at high potential risk of viral sexual transmission.
AB  - BACKGROUND: To assess HIV burden in both acellular and cellular fractions of
      semen in men with different levels of blood plasma HIV RNA by a cross-sectional
      study. PATIENTS: Fifty-two HIV-1-seropositive men (21 receiving antiretroviral
      therapy) with CD4 cell counts ranging from 1 to 1170 x 10(6)/l. METHODS: Semen
      was separated into seminal plasma and fractions enriched in motile spermatozoa or
      non-spermatozoal cells. HIV RNA was quantified by the HIV-Monitor technique
      (Roche) in blood plasma, seminal plasma and spermatozoa fractions. HIV DNA or
      infectious virions in cellular fractions were detected by either PCR or
      qualitative viral culture. RESULTS: HIV RNA was detected in 86.5% of seminal
      plasma specimens and in 14.6% of spermatozoa fractions; HIV DNA was detected in
      57.1% of non-spermatozoal cell fractions. HIV RNA levels in blood plasma and
      seminal plasma were correlated (r5 = 0.56, P < 0.0001, Spearman's rank test). A
      majority of men had lower levels in seminal plasma than in blood plasma: one
      third had HIV-positive seminal cell fractions. However, 20 men (38.5%) with HIV
      RNA levels in seminal plasma (median: 4.65 log10 copies/ml) comparable to or
      higher than those in blood plasma had all HIV-positive non-spermatozoal cells or
      spermatozoa fractions with a high frequency of positive cultures. CONCLUSION: A
      high frequency of men had detectable HIV in semen. We identified a subpopulation
      demonstrating high levels of HIV RNA in seminal plasma, comparable to or higher
      than those in blood plasma, frequently associated with a substantial viral
      shedding in seminal cells, raising the possibility of viral production within the
      genital tract and suggesting heterogeneity in the potential of HIV sexual
      transmission among infected men.

PMID- 10357383
TI  - HIV prevalence and risk behaviour among female injecting drug users in London,
      1990 to 1996.
AB  - OBJECTIVE: To describe trends in HIV prevalence among female injecting drug users
      (IDU) in London between 1990 and 1996. DESIGN: HIV prevalence and risk behaviour
      were measured yearly between 1990 and 1993, and in 1996, in point prevalence HIV
      surveys of IDU recruited from both drug-treatment and community-based settings
      within Greater London. Sample sizes were 173 in 1990, 111 in 1991, 128 in 1992,
      146 in 1993 and 200 in 1996. METHODS: Each survey used structured questionnaires
      and common sampling and interview strategies. Oral fluid specimens were collected
      for testing for antibodies to HIV (anti-HIV). Multiple logistic regression was
      used to assess the trend in HIV prevalence. RESULTS: The percentage of female IDU
      testing positive for antibodies to HIV showed a marked decline over the study
      period, from 15.0% in 1990 to 1.0% in 1996 (P < 0.001). This trend was
      independent of all other variables examined. Each year, higher HIV prevalences
      were found among IDU recruited from community settings compared with treatment
      agencies. CONCLUSIONS: These results concur with those of IDU recruited from
      treatment sites, although the yearly estimates in this study are higher. London
      benefits from low prevalence of HIV infection among IDU, coupled with behaviour
      change facilitated by early intervention. Continued surveillance of injectors
      recruited from both community and treatment settings is necessary in order
      properly to assess HIV prevalence among IDU.

PMID- 10357384
TI  - Risk of cancer in people with AIDS.
AB  - OBJECTIVES: To determine whether the incidence of cancers other than the AIDS
      defining cancers is increased in people with AIDS, and to determine if cancer
      incidence increases with time, a surrogate marker of declining immune function.
      DESIGN: Register-based retrospective cohort study in New South Wales, Australia.
      Age-, sex-, and period-adjusted standardized incidence ratios (SIR) were
      calculated for individual cancers occurring in 1980-1993 in people with AIDS
      registered before 1996. RESULTS: During the study period, 3616 people were
      registered with AIDS; 716 cases of AIDS-defining cancer and 62 cases of non-AIDS
      defining cancer were identified. People with AIDS had a significantly increased
      incidence of Hodgkin's disease [SIR 18.3; 95% confidence interval (CI) 8.39
      34.8], multiple myeloma (SIR 12.1; 95% CI 2.50-35.4), leukaemia (SIR 5.76; 95% CI
      1.57-14.7), lip cancer (SIR 5.94; 95% CI 1.92-13.8) and lung cancer (SIR 3.80;
      95% CI 1.39-8.29). The incidence of Hodgkin's disease increased significantly
      around the time of AIDS diagnosis (P = 0.008 for trend with time), suggesting an
      association with immunodeficiency. CONCLUSIONS: This study provides strong
      support for the hypothesis that Hodgkin's disease is an AIDS-associated
      condition. There was an increased incidence of several other forms of cancer,
      some of which are known to occur at increased rates in transplant recipients who
      have received immunosuppressive therapy. Improved survival in people with HIV
      infection may lead to increases in the number that develop these forms of cancer.

PMID- 10357385
TI  - HIV incidence among repeat HIV testers with sexually transmitted diseases in
      Italy. STD Surveillance Working Group.
AB  - OBJECTIVES: To provide data on the incidence of HIV infection among repeat
      testers with sexually transmitted diseases (STD) in Italy. DESIGN: Retrospective
      longitudinal study. METHODS: Study participants, enrolled by 47 STD centres
      throughout Italy, included individuals with a newly diagnosed STD who were tested
      for HIV at the time of the STD diagnosis and who had a previous documented HIV
      negative test. 'Seroconverters' were defined as those individuals who tested HIV
      positive at the time of the STD diagnosis. The cumulative and the annual
      incidence of HIV in this population were estimated. RESULTS: Of 1950 patients, 47
      were seroconverters, with an incidence rate of 1.7 per 100 person-years (PY) (95%
      confidence interval, 1.2-2.2). HIV incidence was higher among males than among
      females (2.5 versus 0.6 per 100 PY). The highest incidence rate was found among
      homosexual injecting drug users (IDU) (13.8 per 100 PY), whereas the lowest rate
      was observed among heterosexual non-IDU (0.4 per 100 PY). The annual incidence
      decreased from 1.8 per 100 PY in 1989 to 0.9 per 100 PY in 1996. CONCLUSIONS: Our
      results show that new HIV infections have occurred among STD patients in Italy
      since 1988, although a clear decrease in incidence has occurred since 1989.
      However, the rate of seroconversion appears to be alarmingly high in some high
      risk groups. These findings suggest that there is a need for continued monitoring
      of new HIV infections among STD patients, and these individuals may represent a
      useful sentinel population for a better understanding of the HIV epidemic.

PMID- 10357386
TI  - Quality of life outcomes of combination zalcitabine-zidovudine, saquinavir
      zidovudine, and saquinavir-zalcitabine-zidovudine therapy for HIV-infected adults
      with CD4 cell counts between 50 and 350 per cubic millimeter. PISCES (SV14604)
      Study Group.
AB  - BACKGROUND: This double-blind study evaluated treatment with zalcitabine
      zidovudine, saquinavir-zidovudine, or saquinavir-zalcitabine-zidovudine on the
      health-related quality of life of HIV-infected adults with CD4 cell counts
      between 50 and 350 cells/mm3. METHODS: Nine hundred and ninety-three HIV-infected
      male or female quality of life substudy patients aged 18 years or older, with CD4
      cell counts between 50 and 350 cells/mm3 naive to antiretroviral therapy or with
      less than 16 weeks of zidovudine therapy, were randomly assigned to one of three
      daily regimens: zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (ddC/ZDV);
      saquinavir 600 mg and zidovudine 200 mg every 8 h (SQV/ZDV); or saquinavir 600
      mg, zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (SQV/ddC/ZDV). The health
      related quality of life was measured using the Medical Outcome Study HIV (MOS
      HIV) Health Survey subscale and physical and mental health summary scores, and a
      global visual analogue scale (VAS) score. The primary health-related quality of
      life endpoints were the MOS-HIV physical and mental health summary scores.
      RESULTS: After 24 weeks of treatment, no statistically significant differences
      were observed between the three treatment groups on physical health and mental
      health summary scores (global test P = 0.118). After 48 weeks of treatment,
      statistically significant differences among the groups were observed for physical
      health and mental health summary scores (global test P = 0.020); no change in
      physical health summary scores from the baseline were seen in the triple
      combination therapy, whereas the ddC/ZDV combination therapy group showed
      decreases from baseline in physical health summary scores (P = 0.008). Six of the
      10 individual MOS-HIV subscale scores and the VAS scores showed results
      consistent with the physical health summary endpoints after 48 weeks of therapy.
      No statistically significant differences in baseline to 48 week changes in MOS
      HIV subscale or summary scores were seen between the ddC/ZDV and SQV/ZDV groups
      (P > 0.05). CONCLUSIONS: Patients on triple combination therapy maintained their
      quality of life over 48 weeks compared with significant decreases in the quality
      of life for ddC/ZDV combination therapy.

PMID- 10357387
TI  - Poor penetration of the male genital tract by HIV-1 protease inhibitors.

PMID- 10357388
TI  - Cytotoxic T lymphocyte recognition of HLA-B*5101-restricted HIV-1 Rev epitope
      which is naturally processed in HIV-1-infected cells.

PMID- 10357390
TI  - Salvage therapy with ritonavir-saquinavir plus two nucleoside reverse
      transcriptase inhibitors in patients failing with amprenavir-zidovudine
      lamivudine.

PMID- 10357389
TI  - Polymorphism at codon 54 of mannose-binding protein gene influences AIDS
      progression but not HIV infection in exposed children.

PMID- 10357391
TI  - Lipodystrophy associated with nevirapine-containing antiretroviral therapies.

PMID- 10357392
TI  - Cytomegalovirus (re)activation plays no role in the ocular vitritis observed
      after initiation of highly active antiretroviral therapy.

PMID- 10357393
TI  - Gemfibrozil effectively lowers protease inhibitor-associated hypertriglyceridemia
      in HIV-1-positive patients.

PMID- 10357394
TI  - Reply to Gonzalez and Everall: Lest we forget: neuropsychiatry and the new
      generation anti-HIV drugs.

PMID- 10357395
TI  - High plasma levels of nelfinavir and efavirenz in two HIV-positive patients with
      hepatic disease.

PMID- 10357396
TI  - Analysis of the CC chemokine receptor 5 m303 mutation in infants born to HIV-1
      seropositive mothers.

PMID- 10357397
TI  - Pregnancy after breast carcinoma: the ultimate medical challenge.

PMID- 10357398
TI  - Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts.
AB  - BACKGROUND: Extramedullary plasmacytoma (EMP) is a rare entity belonging to the
      category of non-Hodgkin lymphoma. EMPs make up 4% of all plasma cell tumors and
      occur mainly in the upper aerodigestive tract (UAD). Seven patients with EMP
      included in this evaluation were under the authors' care and have been clinically
      followed since 1990. Because there are no general guidelines for the treatment of
      patients with EMP, the authors tried to obtain detailed data about the occurrence
      of this disease and also reviewed the therapies that have been used. To do so,
      they evaluated all EMP cases published in the medical literature until now and
      included their own experience. METHODS: Based on the clinical course and follow
      up of their own EMP patients, the authors evaluated and reinvestigated all EMP
      cases cited in MEDLINE, Index Medicus, DIMDI (Deutsches Institut fur medizinische
      Dokumentation und Information, Cologne, Germany), and the reference lists of the
      publications found through these sources. RESULTS: In a detailed literature
      search, more than 400 publications between 1905 and 1997 were found, and these
      revealed that EMP mainly occurs between the fourth and seventh decades of life.
      Seven hundred fourteen cases (82.2%) were found in the UAD, and 155 cases (17.8%)
      were found in other body regions. The following therapeutic strategies were used
      to treat patients with EMP of the UAD: radiation therapy alone in 44.3%, combined
      therapy (surgery and radiation) in 26.9%, and surgery alone in 21.9%. The median
      overall survival or recurrence free survival was longer than 300 months for
      patients who underwent combined intervention (surgery and radiation). This result
      was statistically highly significant (P = 0.0027, log rank test) compared with
      the results for patients who underwent surgical intervention alone (median
      survival time, 156 months) or radiation therapy alone (median survival time, 144
      months). In most cases of non-UAD EMP, surgery was performed (surgery alone,
      55.6%; surgery and radiation combined, 19.8%; radiation alone, 11.1%), but there
      were no statistical differences in survival (P = 0.62). Overall, after treatment
      for EMP in the UAD, 61.1% of all patients had no recurrence or conversion to
      systemic involvement (i.e., multiple myeloma, MM); however, 22.0% had recurrence
      of EMP, and 16.1% had conversion to MM. After treatment for EMP in non-UAD areas,
      64.7% of all patients had no recurrence or MM, 21.2% had recurrence, and 14.1%
      had conversion to MM. CONCLUSIONS: The current investigation provides evidence
      that surgery alone gives the best results in cases of EMP of the UAD when
      resectability is good. However, if complete surgical tumor resection is doubtful
      or impossible and/or if lymph node areas are affected, then combined therapy
      (surgery and radiation) is recommended. These results, which were obtained from
      retrospective studies, should be confirmed in randomized trials comparing surgery
      with combined radiation therapy and surgery.

PMID- 10357400
TI  - Flow cytometric DNA analysis is useful in detecting multiple genetic alterations
      in squamous cell carcinoma of the esophagus.
AB  - BACKGROUND: Although flow cytometric DNA analysis has been recognized to be a
      useful prognostic indicator for patients with squamous cell carcinoma of the
      esophagus, the biologic significance of DNA aneuploidy remains to be elucidated.
      METHODS: Twenty-five patients with squamous cell carcinoma of the esophagus who
      underwent a curative subtotal esophagectomy were divided into 2 groups according
      to the DNA ploidy pattern. Multiple genetic changes, including the gene
      amplification of bcl-1, epidermal growth factor receptor, and c-myc, and the loss
      of heterozygosity of multiple tumor suppressor genes, including retinoblastoma,
      mutated in colorectal carcinoma, adenomatous polyposis coli, and deleted in
      colorectal carcinoma, in each case were investigated and the frequency of genetic
      alterations compared between both groups. In addition, the clinical outcome of
      these patients was also investigated. RESULTS: Eleven of 15 cases in the
      aneuploid group demonstrated at least 1 genetic change (73.3%) whereas only 2 of
      10 cases in the diploid group did so (20.0%) (P<0.05). Both cases in the diploid
      group with genetic alterations had only 1 genetic change of 7 tested genes
      whereas 9 of 11 cases in the aneuploid group had multiple genetic alterations.
      Patients in the aneuploid group also showed a more unfavorable prognosis than
      patients in the diploid group. CONCLUSIONS: Based on the findings of the current
      study, flow cytometric DNA analysis is considered to be useful for both detecting
      multiple genetic alterations and predicting the prognosis of patients with
      carcinoma of the esophagus.

PMID- 10357399
TI  - Clinocopathologic significance of laminin-5 gamma2 chain expression in squamous
      cell carcinoma of the tongue: immunohistochemical analysis of 67 lesions.
AB  - BACKGROUND: The laminin-5 gamma2 chain plays an important role in cell migration
      during tumor invasion and tissue remodeling. METHODS: Laminin-5 gamma2 chain
      expression in squamous cell carcinomas of the tongue in 67 patients with Stage
      II, III, or IVA,B (excluding the cases with distant metastasis) was examined
      immunohistochemically to determine its associations with the clinicopathologic
      features of each tumor. The predominant staining patterns were categorized as
      follows: A, few or no tumor cells were positive; B, part of the tumor nest
      periphery was positive; C, the tumor nest periphery was circumferentially
      positive; or D, almost all the tumor cells were positive. RESULTS: Laminin-5
      gamma2 chain expression was observed clearly in tumor cell cytoplasm. Of the 67
      tumors examined, 6 (9%), 31 (46%), 19 (28%), and 11 (17%) showed staining
      patterns A, B, C, and D, respectively. With progression from staining pattern A
      to D, the number of immunopositive tumor cells increased significantly
      (P<0.0001), and the tumor histology showed significantly more infiltrative growth
      (P<0.0001) and poorer differentiation (P = 0.0021). Furthermore, both univariate
      (P = 0.0019) and multivariate (P = 0.0003; hazard ratio = 3.132) analysis of the
      patients' survival revealed that the prognosis became significantly poorer with
      progression from staining pattern A to D. CONCLUSIONS: Increased laminin-5 gamma2
      chain immunoreactivity, which may reflect a high invasive potential of cancer
      cells, is a factor indicative of a poor prognosis for patients with squamous cell
      carcinoma of the tongue.

PMID- 10357401
TI  - Clinical significance of spontaneous apoptosis in advanced gastric
      adenocarcinoma.
AB  - BACKGROUND: Spontaneous apoptosis has been detected in gastric carcinoma.
      However, the clinicopathological significance of this remains unclear. The
      objective of this study was to investigate the correlation between spontaneous
      apoptosis and the clinicopathologic and biologic characteristics of advanced
      gastric carcinoma. In addition, the prognostic significance of spontaneous
      apoptosis of tumors was evaluated. METHODS: The occurrence of apoptotic cell
      death (apoptotic index [AI]) in 97 patients with advanced gastric carcinoma was
      analyzed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine
      triphosphate biotin nick end labeling method. The Ki-67 labeling index (LI),
      expression of p53 and p21, DNA ploidy pattern, microvessel density (MVD), density
      of dendritic cells (DCs) in tumors, and degree of lymphocytic infiltration (LI)
      of the tumors were compared with the AI for each patient. In addition, the
      prognostic significance of AI was evaluated in these patients. RESULTS: The mean
      AI of the 97 tumors was 2.05% (range, 0-11.31%). Statistical analyses revealed
      significant correlations between the AIs and the Ki-67 LIs (P = 0.0004) and
      between the AIs and the density of DCs (P = 0.0007), as well as an inverse
      correlation between the AIs and the intratumoral MVD (P = 0.0064). In addition,
      the AI of 47 tumors with high grade LI (2.94+/-2.51%) was significantly higher
      than that of 50 tumors with low grade LI (1.22+/-0.93%) (P<0.0001). However, the
      authors failed to find a significant correlation between the AIs and expression
      of p53 and p21 and the DNA ploidy pattern. In 93 surviving patients, the 5-year
      survival rate of 45 patients who had tumors with high AIs (> or =1.47; 82%) was
      significantly better than that of 48 patients who had tumors with low AIs (<1.47;
      60%) (P = 0.0264). CONCLUSIONS: The findings of the current study suggest that
      the tumors with low neovascularization and high local immunoreactivity may
      regulate their progression by apoptosis. Moreover, less extensive apoptosis in
      gastric adenocarcinoma may contribute to disease progression and could be
      correlated with a poorer prognosis.

PMID- 10357402
TI  - Combination chemotherapy with granulocyte-macrophage-colony stimulating factor in
      patients with locoregional and metastatic gastric adenocarcinoma.
AB  - BACKGROUND: A combination of etoposide, 5-fluorouracil, and folinic acid (ELF)
      remains popular for the treatment of patients with gastric carcinoma and has been
      reported to result in a response rate of up to 40% with good patient tolerance.
      The authors elected to add granulocyte-macrophage-colony stimulating factor (GM
      CSF) to ELF to determine whether the response rate could be increased in patients
      with untreated advanced gastric carcinoma. METHODS: Previously untreated patients
      with measurable metastatic tumor were studied. Outpatient therapy was comprised
      of etoposide, 120 mg/m2 intravenously (i.v.), on Days 1-3; 5-fluorouracil, 500
      mg/m2 i.v., on Days 1-3; and folinic acid, 300 mg/m2 i.v., on Days 1-3. Courses
      were repeated every 21 days. GM-CSF (at a dose of 250 microg/m2/day for 14 days
      from Day 4) was added after the first course of ELF if patients developed Grade 4
      neutropenia in a previous course. RESULTS: Thirty patients were enrolled and 29
      were evaluable for response. Four patients (14%) achieved a partial response
      (median duration of response, 6.5 months). The median duration of survival was
      7.8 months. Grade 4 neutropenia occurred in 16 patients who then received GM-CSF.
      A similar rate of neutropenic fever was observed in courses both with or without
      GM-CSF (15% in courses without GM-CSF and 16% in courses with GM-CSF); however, a
      higher nadir absolute granulocyte count (1300 cells/microL) occurred in courses
      with GM-CSF compared with courses without GM-CSF (300 cells/microL). CONCLUSIONS:
      The ELF regimen resulted in a much lower response rate than reported in the
      literature. The attempt to improve the efficacy of this regimen by the addition
      of GM-CSF did not prove successful. The authors believe this regimen cannot be
      recommended for the treatment of patients with advanced gastric carcinoma outside
      of a protocol setting.

PMID- 10357403
TI  - Intratumoral neovascularization and growth pattern in early gastric carcinoma.
AB  - BACKGROUND: The growth pattern of early gastric carcinoma, based on a volumetric
      analysis, reflects biologic characteristics of the tumor. The authors
      investigated the microvessel density (MVD), expression of vascular endothelial
      growth factor (VEGF), and growth patterns in early gastric carcinoma. METHODS:
      Ninety-four tissue specimens resected from patients with early gastric carcinoma
      invading the submucosal layer were examined. Microvessel quantification was
      performed immunohistochemically using a monoclonal antibody against factor VIII
      related antigen. VEGF expression was studied using an anti-VEGF polyclonal
      antibody. Growth patterns were defined as follows: Pen A type: expansively
      penetrating growth; Pen B type: infiltratively penetrating growth; Super type:
      superficially spreading growth. RESULTS: The mean MVD was 16.9 (range, 5.2-43.0).
      MVD was significantly higher in tumors with venous invasion (P<0.01), lymphatic
      vessel invasion (P<0.05), and lymph node metastases (P<0.05) compared with MVD in
      tumors without venous or lymphatic vessel invasion or lymph node metastases. The
      VEGF-positive rate of Pen A type tumors was 66.7% (18 of 27), that Pen B type was
      10.0% (1 of 10), that of Super type was 19.4% (6 of 31), and that of the
      unclassified type was 15.4% (4 of 26). The VEGF-positive rate in patients with
      Pen A type tumors was significantly higher than that in patients with the other
      three growth patterns(P<0.01). MVD in patients with Pen A type tumors (25.9+/
      9.2) was significantly higher than that in patients with Super type tumors
      (12.6+/-5.4) (P<0.01). Patients with Pen A type tumors had a poorer prognosis
      than patients whose tumors had other growth patterns (P<0.05). According to
      multivariate analysis, VEGF expression and lymphatic vessel invasion were
      significant prognostic factors. CONCLUSIONS: Pen A type gastric carcinoma tends
      to secrete VEGF, thus inducing tumor angiogenesis and resulting in venous
      invasion. Intensive follow-up is necessary for patients with Pen A type tumors,
      because this tumor type has a greater propensity for hematogenous metastasis.

PMID- 10357404
TI  - Combined paclitaxel, cisplatin, and etoposide for patients with previously
      untreated esophageal and gastroesophageal carcinomas.
AB  - BACKGROUND: Paclitaxel (T), etoposide (E), and cisplatin (P) are each active in
      gastric carcinoma, either as single agents or as part of a multidrug regimen. To
      the authors' knowledge, the combination of these three agents in the treatment of
      patients with esophageal or gastroesophageal carcinoma has not been previously
      studied. METHODS: Previously untreated patients with locally advanced carcinoma
      of the stomach, esophagus, or gastroesophageal (GE) junction received at least 2
      cycles of TPE administered twice weekly for 3 weeks, with the cycle repeated
      every 28 days. Drug doses, administered over 3 hours on either Monday and
      Thursday or Tuesday and Friday, consisted of T 50 mg/m2/dose, P 15 mg/m2/dose,
      and E 40 mg/m2/dose. For patients with local disease only, subsequent therapy
      consisted of radiation with or without surgical resection. RESULTS: Twenty-five
      patients with gastric (10) or gastroesophageal or GE junction (15) carcinoma were
      treated. Eighteen had locally advanced disease and 7 had liver metastases at
      presentation. Hematologic toxicity, namely, Grade 3 anemia and neutropenia, was
      experienced by all patients. The median number of treatment cycles was 4 (range,
      2-6). Three patients were not evaluable for response. All 22 evaluable patients
      responded; 3 were complete responders and 19 were partial responders. Eleven
      patients received radiation therapy with (6) or without (5) concomitant 5
      fluorouracil, and 8 patients subsequently underwent surgical resection. Three of
      8 patients had no tumor at surgery, 4 had minimal microscopic tumor at the
      primary site, and 3 had microscopic lymph node involvement. Twenty-three patients
      are alive, of whom 14 are without evidence of disease. Two patients with
      metastatic disease at presentation died at 9 and 29 months, respectively. The
      median survival was 12.5 months (range, 6 to 30+ months). CONCLUSIONS:
      Multifractionated TPE chemotherapy is a highly active regimen in gastric and
      gastroesophageal carcinoma. It could be evaluated in Phase III trials against
      other active regimens for the treatment of patients with this disease. The
      introduction of 5-fluorouracil could also be an interesting direction to explore
      because of its primary role in the treatment of patients with gastric and
      esophageal carcinoma.

PMID- 10357405
TI  - Malignant fibrous histiocytoma of the pancreas: a case report with genetic
      analysis.
AB  - BACKGROUND: Malignant fibrous histiocytoma (MFH) is the most common type of soft
      tissue sarcoma in adults; it occurs frequently in the extremities, the trunk, or
      retroperitoneal tissues. MFH rarely is detected in digestive organs, such as the
      liver or stomach. METHODS: The authors report a patient with MFH of the pancreas
      who was treated with surgery alone. The tumor was studied for genetic alterations
      in the p53, p16ink4a, and DPC4 tumor suppressor genes as well as the K-ras
      oncogene by immunohistochemistry, single strand conformation variant (SSCV)
      analysis, and direct DNA sequencing. RESULTS: The authors believe that this is
      the 13th report of primary pancreatic MFH in the world literature and the first
      genetic analysis of this rare tumor. The patient is alive with no evidence of
      recurrence 34 months after surgery. Immunohistochemistry revealed no abnormal
      accumulation of the p53 protein and normal nuclear p16 expression. Mutation
      analysis of the p53, p16, DPC4, and K-ras genes showed only a polymorphism at
      codon 72 of the p53 gene and no mutations in any of the genes. CONCLUSIONS:
      Genotypically, MFH of the pancreas is clearly different from other malignant
      pancreatic tumors, which further supports the hypothesis that this tumor is a
      rare but distinct entity.

PMID- 10357406
TI  - Lung carcinoma: analysis of T helper type 1 and 2 cells and T cytotoxic type 1
      and 2 cells by intracellular cytokine detection with flow cytometry.
AB  - BACKGROUND: T helper type 1 cells (Th1), Th2, T cytotoxic type 1 cells (Tc1), and
      Tc2 play important immunoregulatory roles. Some recent studies have demonstrated
      that an elevated level of type 2 cytokines, such as interleukin-10, contributes
      to the ability of cancer cells to escape immunosurveillance. However, the impacts
      of Th1, Th2, Tc1, and Tc2 on tumor immunity are unclear. METHODS: The authors
      evaluated the ratio of Th1 to Th2 and that of Tc1 to Tc2 among peripheral blood
      lymphocytes (PBL), regional lymph node lymphocytes (RLNL), and tumor-infiltrating
      lymphocytes (TIL) in 46 nonsmall cell lung carcinoma patients who had just
      undergone surgery; the evaluation involved detecting the intracellular interferon
      gamma and interleukin-4 production with 3-color flow cytometry. They also
      evaluated the same ratios in the peripheral blood lymphocytes of 29 lung
      carcinoma patients with or without recurrence after surgery, and in the
      peripheral blood of normal volunteers. RESULTS: The Th1-to-Th2 and Tc1-to-Tc2
      ratios were significantly elevated in the tumor tissues. These ratios in the TIL
      were significantly elevated in the groups of patients with squamous cell
      carcinoma and a history of smoking. The Th1-to-Th2 and Tc1-to-Tc2 ratios were
      significantly depressed in the PBL of the patients with tumor recurrences.
      CONCLUSIONS: A favorable Th1- and Tc1-dominant pathway is induced in the tumor
      tissues of operable patients, but their pathway can be expected to shift from Th1
      or Tc1 to Th2 or Tc2 with the progression of cancer.

PMID- 10357407
TI  - Pleuropulmonary blastoma in an adult: an initial case report.
AB  - BACKGROUND: Pleuropulmonary blastoma (PPB) is a unique dysontogenetic neoplasm of
      childhood. Its primitive, sarcomatous features are analogous to those of other
      dysembryonic or dysontogenetic tumors, such as Wilms tumor, hepatoblastoma,
      neuroblastoma, and embryonal rhabdomyosarcoma. PPB typically presents in young
      children, most younger than 5 years, as a pulmonary and/or pleural-based tumor
      with cystic, solid, or combined cystic and solid features. These neoplasms are
      characterized histologically by primitive mesenchymal or a mixture of primitive
      and sarcomatous components and generally have an unfavorable clinical outcome:
      death occurs within 1-2 years after diagnosis. METHODS: Clinicopathologic and
      radiographic findings of a man age 36 years with a cystic and solid mass in the
      left hemithorax were reviewed and compared with previously studied cases of PPB.
      RESULTS: Pathologic examination of the mass revealed a cystic and solid neoplasm
      composed of malignant mesenchymal cells that were immunoreactive for vimentin and
      muscle specific actin and focally for desmin. The architectural and cytologic
      appearances as well as the immunohistochemical profile were those of type II PPB.
      CONCLUSIONS: To the authors' knowledge, all previously reported cases of PPB
      occurred in children age 12 years or younger. They believe that this case
      represents the first occurrence of PPB in an adult and documents the finding
      that, although it is uncommon, adults can develop primitive neoplasms that are
      usually associated with the pediatric population. In addition, the
      clinicopathologic features observed in the authors' adult patient were consistent
      with their experience with this tumor type in children. The patient died less
      than 1 year after diagnosis.

PMID- 10357408
TI  - Cisplatin in combination with irinotecan in the treatment of patients with
      malignant pleural mesothelioma: a pilot phase II clinical trial and
      pharmacokinetic profile.
AB  - BACKGROUND: The purpose of this study was to assess the efficacy and toxicity of
      a combination of cisplatin and irinotecan (CPT-11) in the treatment of patients
      with malignant pleural mesothelioma and to characterize the pharmacokinetic
      profiles of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN
      38). METHODS: Fifteen previously untreated patients with malignant pleural
      mesothelioma were treated with cisplatin (60 mg/m2 on Day 1) and CPT-11 (60 mg/m2
      on Days 1, 8, and 15) administered intravenously and followed by a 1-week rest
      period. The course of treatment was repeated every 28 days. After intravenous
      administration, the levels of CPT-11 and SN-38 in the plasma and pleural fluid
      were determined for each histologic subtype of mesothelioma. RESULTS: All
      patients were evaluable for response and toxicity. Four partial responses
      (response rate of 26.7%) with a median response duration of 25.9 weeks and 2
      regressions of evaluable disease (overall response rate of 40%) were observed.
      The median survival time after chemotherapy was 28.3 weeks, and the median time
      to treatment failure was 22.1 weeks. The 1-year survival rate for all patients
      was 38.5%. Toxicity was well tolerated, and there were no treatment-related
      deaths. World Health Organization Grade 3 leukopenia occurred in 3 patients
      (20%), and Grade 1 or 2 diarrhea occurred in 3 patients (20%). There was no
      excess toxicity in patients with large pleural effusions compared with those with
      no pleural effusions. CPT-11 and SN-38 were detected in the pleural fluid 1 hour
      after intravenous administration. The maximum concentrations of CPT-11 and SN-38
      in the pleural fluid were 36.5% and 75.8%, respectively, of the corresponding
      plasma values. CONCLUSIONS: The combination of cisplatin and CPT-11 had definite
      activity against malignant pleural mesothelioma and was well tolerated. The
      intravenous administration of CPT-11 produced adequate distribution of CPT-11 and
      its active metabolite SN-38 into the pleural fluid and allowed a higher
      concentration of the more active SN-38 to make contact with mesothelioma cells in
      the thoracic cavity. These results warrant further clinical evaluation of this
      combination chemotherapy for the treatment of malignant pleural mesothelioma in a
      confirmatory Phase II trial.

PMID- 10357409
TI  - Multiple myeloma and family history of cancer among blacks and whites in the U.S.
AB  - BACKGROUND: In the U.S., the incidence rate of multiple myeloma is more than
      twice as high for blacks as for whites, but the etiology of this malignancy is
      not well understood. METHODS: A population-based case-control interview study of
      565 subjects (361 white, 204 black) with multiple myeloma and 2104 controls (1150
      white, 954 black) living in 3 areas of the U.S. offered the opportunity to
      explore whether family history, of cancer contributes to the risk of multiple
      myeloma and explains the racial disparity in risk. RESULTS: For both races
      combined, the risk of multiple myeloma was significantly elevated for subjects
      who reported that a first-degree relative had multiple myeloma (odds ratio [OR] =
      3.7, 95% confidence interval [CI] = 1.2-12.0). Increased risk was also associated
      with a family history of any hematolymphoproliferative (HLP) cancer (OR = 1.7,
      95% CI = 1.0-2.8), especially in a sibling (OR = 2.3, 95% CI = 1.1-4.5). The risk
      associated with familial occurrence of HLP cancer was higher for blacks than for
      whites, but the difference between the ORs was not statistically significant.
      CONCLUSIONS: These data are consistent with previous studies that indicate a
      familial risk of multiple myeloma, but they explain little of the race-related
      difference in incidence rates.

PMID- 10357410
TI  - Can immunohistochemical markers and mitotic rate improve prognostic precision in
      patients with primary melanoma?
AB  - BACKGROUND: In addition to tumor thickness, several other prognostic parameters
      have been identified in primary human melanomas. Some are available readily
      (localization, gender, age, and ulceration). Others must be evaluated with a
      moderate or even substantial amount of work (mitoses and immunohistochemical
      markers). This study was undertaken to determine whether this extra effort is
      justified because it actually improves the precision of prognostic statements.
      METHODS: Immunohistologic markers were determined on frozen sections from 691
      biopsies of human melanomas with the immunoperoxidase method. Univariate and
      multivariate Cox regression analyses were performed with metastases and with
      death as endpoints. RESULTS: Fifteen parameters were related to disease free
      survival in univariate Cox regression analysis: tumor thickness, ulceration,
      localization, gender, age, mitoses, and the immunohistochemical markers very late
      antigen (VLA)-2, human leukocyte antigen (HLA)-ABC, HLA-DR, NKI-beteb, Mel 14,
      intercellular adhesion molecule (ICAM-1), K-1-2, G-7-E2, and H-2-4-7. Three of
      the easily available parameters exhibited independent significance in
      multivariate Cox regression analysis: tumor thickness, ulceration, and
      localization. If mitotic rate was included in this model, then it had independent
      prognostic significance but ulceration was no longer significant. However, the
      model that included tumor thickness, localization, and ulceration had a slightly
      higher overall chi-square test score, indicating a better performance compared
      with thickness, localization, and mitoses. The model that included tumor
      thickness, localization, and mitoses could not be improved by any of the
      immunohistochemical markers in this study. CONCLUSIONS: Nine immunohistochemical
      markers with established prognostic significance for primary human melanoma were
      not found to improve a prognostic model that included tumor thickness,
      localization, and mitoses. If mitoses was replaced by ulceration, then the model
      performed slightly better, although ulceration was not significant in the
      presence of mitoses.

PMID- 10357411
TI  - Adolescence and breast carcinoma risk.
AB  - BACKGROUND: Breast carcinoma risk may be modified by early life factors,
      including physical growth and development, diet, and life-style factors of
      preadolescence and adolescence, as well as genetic factors. METHODS: The authors
      tested their hypothesis that adolescent growth and development are related to
      breast carcinoma incidence by evaluating 65,140 women who participated in the
      Nurses' Health Study. During 16 years of follow-up, 806 women were diagnosed with
      breast carcinoma prior to menopause, and another 1485 were diagnosed after
      menopause. Because adolescent growth was not directly observed in this cohort,
      the peak height growth velocity for each participant was estimated by using a
      model from another longitudinal study. Finally, Cox proportional hazards
      regression models were used to study associations between breast carcinoma
      incidence and adolescent factors in the Nurses' Health Study. RESULTS: Later
      menarche (relative risk [RR] = 0.52 for > or =15 vs. < or =11 years) and more
      body fatness at age 10 years (RR = 0.60 for fattest vs. leanest) were associated
      with a decreased risk of premenopausal breast carcinoma. The risk of
      postmenopausal breast carcinoma was lower for girls with later menarche (RR =
      0.80), more body fat at age 10 years (RR = 0.72), and shorter adult height (RR =
      1.29 for > or =67 vs. < or =62 inches). Higher peak height growth velocity,
      derived from these 3 variables, was associated with increased risk of both
      premenopausal (RR = 1.31 for highest vs. lowest quintile) and postmenopausal (RR
      = 1.40) breast carcinoma. These analyses controlled for birth cohort, other
      possible risk factors from the adolescent period, and family history. These
      associations persisted after controlling for age at the birth of a first child,
      parity, adult adiposity, and age at menopause. Post-hoc analyses suggested that,
      although childhood body fatness was associated with lower risk, increasing body
      fatness between ages 10 and 20 years was not protective against either
      premenopausal or postmenopausal breast carcinoma. CONCLUSIONS: Earlier menarche,
      extremely lean body mass at age 10 years, and taller adult height were predictive
      of elevated breast carcinoma risk. The same three factors were also predictive of
      higher peak growth velocities during adolescence, lending credence to the
      hypothesis that more rapid adolescent growth may increase the risk of breast
      carcinoma development.

PMID- 10357412
TI  - Monitoring the response of patients with locally advanced breast carcinoma to
      neoadjuvant chemotherapy using [technetium 99m]-sestamibi scintimammography.
AB  - BACKGROUND: Mammographic and physical examination assessments of the response of
      locally advanced breast carcinoma (LABC) to neoadjuvant therapy have been shown
      to be inaccurate. The authors studied the feasibility and accuracy of [technetium
      99m]-sestamibi (MIBI) for monitoring the response of patients with LABC to
      neoadjuvant chemotherapy. METHODS: Patients receiving neoadjuvant chemotherapy
      for LABC underwent prone lateral scintimammography before therapy, after 2 months
      of therapy, and close to the completion of chemotherapy (presurgery) if
      chemotherapy continued for >3 months. Images were analyzed both qualitatively and
      quantitatively using the lesion-to-normal breast MIBI uptake ratio (L:N). Imaging
      results were compared with the clinical response and the pathologic response as
      determined from the posttherapy surgical specimen. RESULTS: A total of 32
      patients (29 who were assessable for primary tumor response and 28 who were
      assessable for lymph node response) were included in the study. The mean change
      in the primary tumor L:N MIBI uptake ratio after 2 months of chemotherapy was 
      35% for clinical responders and +17% for nonresponders (P<0.001). Patients
      achieving a pathologic primary tumor macroscopic complete response (CR) had a
      mean change in uptake on the presurgical scan of -58% versus -18% for patients
      with a partial response (P<0.005). A decrease of > or =40% in the MIBI uptake
      ratio identified CRs with 100% sensitivity and 89% specificity. Pretherapy
      imaging predicted axillary lymph node metastases in 85% of patients ultimately
      found to have > or =1 positive lymph nodes at surgery, but was less accurate in
      identifying residual lymph node disease after therapy (55% sensitivity and 75%
      specificity). CONCLUSIONS: MIBI imaging accurately assessed the response to
      neoadjuvant chemotherapy in patients with LABC. Further studies are needed to
      determine the role of MIBI in this group of patients.

PMID- 10357413
TI  - Pregnancy after breast carcinoma: outcomes and influence on mortality.
AB  - BACKGROUND: To the authors' knowledge, no previous studies have identified an
      adverse effect of pregnancy on patient survival after breast carcinoma. However,
      results are difficult to interpret because of failure to control for stage of
      disease at the time the pregnancy occurred. METHODS: Study participants were
      women diagnosed with invasive breast carcinoma between 1983-1992 who previously
      had participated in a population-based case-control study or, if deceased, proxy
      respondents. Information regarding subsequent pregnancies was obtained by self
      administered questionnaire or telephone interview. Information regarding breast
      carcinoma recurrences was obtained by questionnaire and from cancer registry
      abstracts. Women who became pregnant after a diagnosis of breast carcinoma (n =
      53) were matched with women without subsequent pregnancies based on stage of
      disease at diagnosis and a recurrence free survival time in the comparison women
      greater than or equal to the interval between breast carcinoma diagnosis and
      onset of pregnancy in the women with a subsequent pregnancy. RESULTS: Sixty-eight
      percent of women who became pregnant after being diagnosed with breast carcinoma
      delivered one or more live-born infants. Miscarriages occurred in 24% of the
      patients who became pregnant compared with 18% of the controls (women without
      breast carcinoma) of similar ages from the case-control study. Five of the 53
      women who had been pregnant after breast carcinoma died of the disease. The age
      adjusted relative risk (RR) of death associated with any subsequent pregnancy was
      0.8 (95% confidence interval [95% CI], 0.3-2.3). All five deaths occurred among
      the 36 women who had a live birth (age-adjusted RR = 1.1; 95% CI, 0.4-3.7).
      CONCLUSIONS: The findings of the current study are based on a small number of
      deaths but do not suggest that pregnancy after a diagnosis of breast carcinoma
      has an adverse effect on survival.

PMID- 10357414
TI  - Intraoperative examination of axillary sentinel lymph nodes in breast carcinoma
      patients.
AB  - BACKGROUND: Routine histologic examination of axillary sentinel lymph nodes
      predicts axillary lymph node status and may spare patients with breast carcinoma
      axillary lymph node dissection. To avoid the need for two separate surgical
      sessions, the results of sentinel lymph node examination should be available
      intraoperatively. However, routine frozen-section examination of sentinel lymph
      nodes is liable to yield false-negative results. This study was conducted to
      ascertain whether extensive intraoperative examination of sentinel lymph nodes by
      frozen section examination would attain a sensitivity comparable to that obtained
      by routine histologic examination without intraoperative frozen section
      examination. METHODS: In a consecutive series of 155 clinically lymph node
      negative breast carcinoma patients, the axillary sentinel lymph nodes were
      examined intraoperatively, before complete axillary lymph node dissection. The
      frozen sentinel lymph nodes were sectioned subserially at 50-microm intervals.
      For each level, one section was stained with hematoxylin and eosin and the other
      section immunostained for cytokeratins using a rapid immunocytochemical assay.
      RESULTS: Sentinel lymph node metastases were detected in 70 of the 155 patients
      (45%). In 37 cases the sentinel lymph nodes were the only axillary lymph nodes
      with metastases. Immunocytochemistry did not increase the sensitivity of the
      examination. Five patients had metastases in the nonsentinel axillary lymph nodes
      despite having negative sentinel lymph nodes. The general concordance between
      sentinel and axillary lymph node status was 96.7%; the negative predictive value
      of intraoperative sentinel lymph node examination was 94.1%. CONCLUSIONS: The
      intraoperative examination of axillary sentinel lymph nodes is effective in
      predicting the axillary lymph node status of breast carcinoma patients and may be
      instrumental in deciding whether to spare patients axillary lymph node
      dissection.

PMID- 10357415
TI  - Lymph node metastasis from ductal carcinoma in situ with microinvasion.
AB  - BACKGROUND: Widespread use of mammography has increased the detection of ductal
      carcinoma in situ with microinvasion (DCISM) in pathology specimens. Currently
      there is disagreement regarding the incidence of axillary metastasis from DCISM.
      The controversy centers on whether complete lymphadenectomy is indicated for
      axillary staging, given its morbidity and the reportedly minimal rate of axillary
      involvement in these patients. Intraoperative lymphatic mapping and sentinel
      lymphadenectomy (SLND) may obviate complete axillary lymph node dissection in
      selected breast carcinoma patients. In intraoperative lymphatic mapping,
      isosulfan blue dye is used to demonstrate the course of lymphatic flow from the
      breast tumor to the first draining or sentinel lymph node. This blue-stained
      lymph node is selectively excised for pathologic examination; its tumor status is
      used to predict the tumor status of the other axillary lymph nodes. The authors
      examined whether SLND would be suitable for staging DCISM. METHODS: From February
      1992 to January 1997, 14 patients with DCISM underwent intraoperative lymphatic
      mapping and SLND at the John Wayne Cancer Institute in Santa Monica, California.
      Clinical and pathologic data were prospectively collected. RESULTS: Primary DCISM
      tumors ranged in size from 0.9 to 6.5 cm. Nine patients presented with
      mammographic abnormalities, two patients presented with Paget's disease and a
      palpable lesion, and three patients presented with palpable lesions. Two patients
      (14.3%) had tumor-involved sentinel lymph nodes. One of these patients had two
      sentinel lymph nodes, both of which contained single cancer cells identified by
      immunohistochemistry. The other patient had 1 sentinel lymph node, in which a 0.3
      cm metastasis was revealed by light microscopy. Completion axillary dissection
      was performed on both patients and revealed no further tumor positive lymph node
      metastases. CONCLUSIONS: SLND can detect lymph node micrometastases (tumor
      deposits <2 mm) in patients with DCISM. The clinical relevance of these
      micrometastases is unknown, but their existence shows that DCISM can involve the
      lymph nodes.

PMID- 10357416
TI  - Does a family history of cancer increase the risk for postmenopausal endometrial
      carcinoma? A prospective cohort study and a nested case-control family study of
      older women.
AB  - BACKGROUND: As part of the hereditary nonpolyposis colon carcinoma (HNPCC)
      constellation of neoplasia caused by defects in mismatch repair genes, some
      endometrial carcinomas are known to have a genetic contribution to etiology.
      However, most endometrial carcinomas occur in postmenopausal women, presumably
      without the HNPCC defect. Consequently, the genetic contribution to these cases
      is unclear. The objective of this study was to determine whether family history
      of cancer is a risk factor for endometrial carcinoma in older women. METHODS: The
      authors analyzed incident endometrial carcinoma data, as well as data on family
      history of various cancers in first-degree relatives, from a cohort of 24,848
      postmenopausal Iowa women ages 55-69 years who were cancer free at baseline in
      1986. Because a positive family history is dependent on many factors, including
      the age of the patient, the number of relatives, and the distribution of other
      risk factors in relatives, the authors also conducted a nested case-control study
      on family members of 95 patients with endometrial carcinoma diagnosed during 1988
      1989 and 91 cancer free controls who were chosen randomly from subjects matched
      for age (+/-1 year). RESULTS: During 10 years of follow-up of the cohort, 322
      incident endometrial carcinoma cases occurred. Women who reported a positive
      family history of cancer overall or at any specific site (e.g., the endometrium,
      colon, or breast) were not at increased risk for endometrial carcinoma.
      Adjustment for potential confounders, such as age, obesity, parity, oral
      contraceptive use, and estrogen replacement therapy, did not alter these results.
      Analysis of the family members of the cases and controls produced little evidence
      to suggest that this lack of association between family history and endometrial
      carcinoma could be explained by unequal distribution of known risk factors among
      relatives. Case family members were slightly older than control family members,
      but no significant differences were found in body mass index (kg/m2), age at
      menarche, age at menopause, or number of pregnancies. Relation to a case or
      control was not associated with increased risk of endometrial, ovarian, breast,
      or colon carcinoma for family members. Controlling for a variety of potential
      confounders did not alter the results. CONCLUSIONS: No evidence was found that
      genetics contribute to the risk of postmenopausal endometrial carcinoma for women
      with no personal cancer history.

PMID- 10357417
TI  - Is nuclear expression of Y box-binding protein-1 a new prognostic factor in
      ovarian serous adenocarcinoma?
AB  - BACKGROUND: Nuclear expression of Y box-binding protein (YB-1), a member of the
      DNA binding protein family, has been reported to be much more highly concentrated
      in cisplatin-resistant cell lines than in their parental counterparts, suggesting
      an ability to limit cisplatin sensitivity. Moreover, YB-1 plays a key role in P
      glycoprotein expression. Because ovarian carcinoma traditionally has been treated
      with cisplatin-based chemotherapy, the sensitivity of the tumors to chemotherapy
      could reflect a particular prognosis in patients with ovarian carcinoma. The aim
      of the current study was to determine whether YB-1 expression correlated with
      prognosis in ovarian serous adenocarcinoma patients. METHODS: The expression of
      YB-1 in the nucleus was examined immunohistochemically in 42 paraffin embedded
      primary Stage III (International Federation of Gynecology and Obstetrics) serous
      ovarian carcinoma tumors extirpated by primary surgery at Kyushu University
      Hospital between 1985-1995. RESULTS: Of the 40 primary ovarian tumors examined,
      12 (30%) were positive for YB-1 expression in the nucleus. There was no
      significant difference in intraperitoneal stage, histologic grade, or residual
      tumor size after primary surgery between patients with tumors with positive and
      those with negative nuclear expression of YB-1 protein. The disease free survival
      curve for patients whose tumors were positive for nuclear expression of YB-1
      protein was significantly worse than that for patients whose tumors were negative
      (P = 0.0025). P-glycoprotein was overexpressed in 4 of 12 tumors with nuclear YB
      1 expression (33%) but there was no statistical significance between the
      expression of nuclear YB-1 and P-glycoprotein. CONCLUSIONS: The expression of YB-
      1 protein in the nucleus may be considered a useful prognostic marker and also
      may reflect the sensitivity of ovarian serous adenocarcinoma to chemotherapy.

PMID- 10357418
TI  - p53 alteration in regional lymph node metastases from prostate carcinoma: a
      marker for progression?
AB  - BACKGROUND: Alterations of the p53 tumor suppressor gene are associated with
      advanced stage prostate carcinoma. The biologic significance of p53 nuclear
      accumulation in prostate cancer patients with regional lymph node metastases is
      uncertain. METHODS: The authors investigated p53 alterations by
      immunohistochemistry in 220 lymph node positive patients who were treated with
      radical prostatectomy, bilateral pelvic lymphadenectomy, and androgen deprivation
      therapy between 1987-1992 at the Mayo Clinic. The mean follow-up was 6.3 years.
      Tumor volume of lymph node metastases was measured using the grid method.
      RESULTS: p53 immunoreactivity was detected in 109 of 211 primary tumors (52%) and
      83 of 144 matched regional lymph node metastases (58%); this expression was
      strongly concordant (correlation coefficient 0.53; P = 0.0001). Overexpression of
      p53 protein in lymph node metastases was associated with distant metastasis free
      survival by univariate analysis (P = 0.03), but did not reach statistical
      significance by multivariate analysis (P = 0.07). Regional lymph node cancer
      volume was the single most important predictor of distant metastases after
      adjusting for Gleason score, DNA ploidy, and p53 expression. CONCLUSIONS: The
      findings of the current study suggest that assessment of biologic changes
      (including p53 alterations in regional lymph node metastases) could be of value
      in the assessment of the biologic aggressiveness of prostate carcinoma, whereas
      p53 expression in the primary tumor does not appear to influence patient outcome.

PMID- 10357419
TI  - Long term tolerance of high dose three-dimensional conformal radiotherapy in
      patients with localized prostate carcinoma.
AB  - BACKGROUND: The current study was undertaken to evaluate the incidence and
      predictors of late toxicity in patients with localized prostate carcinoma treated
      with high dose three-dimensional conformal radiotherapy (3D-CRT). METHODS: A
      total of 743 patients with prostate carcinoma classified as T1c-T3 were treated
      with 3D-CRT that targeted the prostate and seminal vesicles. A minimum tumor dose
      of 64.8 gray (Gy) was given to 96 patients (13%), 70.2 Gy to 266 patients (365),
      75.6 Gy to 320 patients (43%), and 81.0 Gy to 61 patients (8%). The median follow
      up time was 42 months (range, 18-109 months). Late toxicity was graded according
      to the Radiation Therapy Oncology Group morbidity scoring scale. RESULTS: Late
      gastrointestinal (GI) and urinary (GU) toxicities were absent or minimal (Grade 0
      or 1) in 90% of patients. The 5-year actuarial likelihood of the development of
      Grade 2 and 3 late GI toxicities was 11% and 0.75%, respectively. A multivariate
      analysis identified doses > or =75.6 Gy (P<0.001), history of diabetes mellitus
      (P = 0.01), and the presence of acute GI symptoms during treatment (P = 0.02) as
      independent predictors of Grade > or =2 late GI toxicity. The 5-year actuarial
      likelihood of the development of Grade 2 and 3 late GU toxicities was 10% and 3%,
      respectively. Doses > or =75.6 Gy (P = 0.008) and acute GU symptoms (P<0.001)
      were independent predictors of Grade > or =2 late GU toxicity. Among 544 patients
      who were potent before treatment (73% of all patients), 211 (39%) became impotent
      after 3D-CRT. The 5-year actuarial risk of potency loss was 60%. Doses > or =75.6
      Gy (P<0.001) and the use of neoadjuvant androgen deprivation (P = 0.01) were
      independent predictors of posttreatment erectile dysfunction. CONCLUSIONS: The
      incidence of severe late complications after high dose 3D-CRT was minimal.
      Radiation doses > or =75.6 Gy and the presence of acute treatment-related
      symptoms during 3D-CRT correlated with a higher incidence of Grade > or =2 late
      GI and GU toxicities. In addition to higher doses, the use of androgen
      deprivation therapy increased the likelihood of permanent impotence in these
      patients. Intensity-modulated radiotherapy, which makes it possible to enhance
      the conformality of the dose distribution, has recently been implemented in an
      attempt to reduce the incidence of moderate grade toxicities in patients
      receiving high dose 3D-CRT.

PMID- 10357420
TI  - Survival of patients with carcinoma in situ of the urinary bladder.
AB  - BACKGROUND: To the authors' knowledge, the long term follow-up of patients with
      carcinoma in situ of the urinary bladder is limited. METHODS: The authors studied
      138 patients diagnosed with urothelial carcinoma in situ of the bladder at the
      Mayo Clinic between 1972-1979. All the histologic slides were reviewed and
      fulfilled the diagnostic criteria for carcinoma in situ according to the newly
      proposed World Health Organization and International Society of Urologic
      Pathology classification system. None of these patients had previous or
      coexisting invasive urothelial carcinoma at the time of diagnosis. Cox
      proportional hazards models were used to determine the prognostic significance of
      numerous clinical and pathologic findings using progression free, cancer
      specific, and all-cause survival as the endpoints for analysis. Progression was
      defined as the development of invasive carcinoma, distant metastases, or death
      from bladder carcinoma. RESULTS: The patients ages at the time of diagnosis
      ranged from 32-90 years (mean, 65.6 years). The male to female ratio was 7:1.
      Carcinoma in situ usually was multifocal (50%) with a predilection for the
      trigone, lateral wall, and dome. The mean follow-up after surgery was 11.0 years
      (range, 0.7-25 years). Actuarial progression free, cancer specific, and all-cause
      survival rates were 63%, 79%, and 55%, respectively, at 10 years, and 59%, 74%,
      and 40%, respectively, at 15 years. The mean interval from the time of diagnosis
      to cancer progression was 5 years. Patient age at diagnosis was significant in
      predicting progression free (P = 0.01) and all-cause survival (P = 0.002).
      Cystectomy performed within 3 months after the initial diagnosis was associated
      with improved all-cause survival (P = 0.03). After controlling for age, there was
      no difference in survival between patients who received immediate cystectomy and
      those did not (P = 0.16). CONCLUSIONS: Patients with carcinoma in situ of the
      bladder are at significant risk of cancer progression and death from bladder
      carcinoma. Cystectomy does not appear to offer a significant survival advantage
      in patients with carcinoma in situ of the bladder after adjusting for age.

PMID- 10357421
TI  - Expression of galectin-3 in fine-needle aspirates as a diagnostic marker
      differentiating benign from malignant thyroid neoplasms.
AB  - BACKGROUND: Galectin-3 is a beta-galactoside-binding protein that has been
      reported to be expressed preferentially in thyroid malignancies. The current
      study was designed to substantiate this finding further and to establish a
      presurgical diagnostic modality of differentiating between benign and malignant
      thyroid neoplasms by analyzing galectin-3 expression in fine-needle aspirates.
      METHODS: The expression of galectin-3 was examined immunohistochemically in total
      of 172 specimens: 45 primary and 20 metastatic papillary carcinomas, 8 primary
      and 2 metastatic follicular carcinomas, 5 primary and 3 metastatic anaplastic
      carcinomas, 3 primary medullary carcinomas, 25 follicular adenomas, 3 goiters,
      and 58 adjacent normal thyroid tissue. Alternatively, epithelial cells were
      isolated from the fine- needle aspirates of 14 thyroid nodules and subjected to
      immunoblotting analysis of galectin-3. RESULTS: Immunohistochemical analysis
      revealed that all thyroid malignancies of follicular cell origin (including
      papillary, follicular, and anaplastic carcinomas) showed high and diffuse
      expression of galectin-3, whereas one of the three medullary carcinomas of
      parafollicular cell origin displayed weaker and focal expression of galectin-3.
      In contrast, neither benign thyroid adenomas, goiters, nor normal thyroid tissues
      expressed galectin-3. Immunoblot analysis of the isolated epithelial cells
      detected galectin-3 in nine thyroid nodules that were proven histologically to be
      malignant ( eight papillary carcinomas and one follicular carcinoma) after
      surgical intervention, whereas galectin-3 was not detected in five nodules proven
      to be benign follicular adenomas. CONCLUSIONS: Galectin-3 serves as a marker of
      thyroid malignancy of follicular cell origin. Analysis of galectin-3 expression
      in fine-needle aspirates enhances the differential diagnostic accuracy between
      benign and malignant thyroid neoplasms.

PMID- 10357422
TI  - The role of high resolution pulsed and color Doppler ultrasound in the
      differential diagnosis of benign and malignant lymphadenopathy: results of
      multivariate analysis.
AB  - BACKGROUND: The role of high resolution pulsed and color Doppler ultrasound in
      the differential diagnosis of benign and malignant lymphadenopathy is still
      unclear. METHODS: High resolution pulsed and color Doppler ultrasound was used
      prospectively to investigate superficial lymph node enlargement in 71 patients
      undergoing surgical biopsy at the onset of lymphadenopathy. The aim of this study
      was to define, in multivariate analysis, the ultrasonographic parameters useful
      in the differential diagnosis of benign and malignant lymphadenopathy. RESULTS:
      Volume, vascularization score, pulsatility index, and resistive index were
      significantly higher in the 53 malignant lymph nodes studied than in the 18
      benign lymph nodes studied. The long-to-short axis ratio was significantly lower
      in neoplastic lymph nodes than in reactive lymph nodes. Stepwise logistic
      regression selected only the long-to-short axis ratio and the vascularization
      score as parameters that independently and significantly contributed to the
      differentiation of neoplastic from reactive lymph nodes. The diagnostic
      efficiency of the combined criteria evaluated by the area under the receiver
      operating characteristic curve was 0.8339. CONCLUSIONS: High resolution pulsed
      and color Doppler ultrasound may provide information that is useful in making
      correct differential diagnoses of malignant or benign lymphadenopathy.

PMID- 10357423
TI  - Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients.

PMID- 10357424
TI  - Outcome and complications of epidural analgesia in patients with chronic cancer
      pain.

PMID- 10357425
TI  - Prenatal exposure to metronidazole and risk of childhood cancer: a retrospective
      cohort study of children younger than 5 years.

PMID- 10357426
TI  - Differential reinforcing and satiating effects of intragastric fat and
      carbohydrate infusions in rats.
AB  - Food intake and preferences are modulated by the postingestive satiating and
      reinforcing actions of nutrients. This experiment compared the feeding effects of
      isocaloric intragastric (i.g.) carbohydrate (maltodextrin) and fat (corn oil)
      infusions in food-restricted rats fed low-fat (12% fat kcal) or high-fat (48% fat
      kcal) diets. In Experiment 1, the rats were given one flavored saccharin solution
      (CS+C) paired with i.g. carbohydrate infusions, a second flavor (CS+F) paired
      with i.g. fat infusions, and a third flavor (CS-) paired with i.g. water
      infusions during 30-min one-bottle training sessions. In subsequent two-bottle
      tests, the rats preferred both CS+s to the CS- (68-83%) and the CS+C to the CS+F
      (68-70%). In Experiment 2, the feeding inhibitory effects of the nutrient
      infusions on an ongoing meal (satiation test) or a subsequent meal (satiety test)
      were compared. The intake of a palatable Polycose+saccharin solution was
      suppressed by a concurrent carbohydrate infusion but not by a fat infusion. Also,
      i.g. carbohydrate preloads suppressed the intake of a subsequent (30-180 min)
      mixed carbohydrate+fat test meal more than did i.g. fat preloads. The satiety
      effects of the fat preloads were more pronounced in rats fed the low-fat diet
      than in rats fed the high-fat maintenance diet. Diet composition did not reliably
      influence the preference conditioning and satiation effects of the nutrient
      infusions. These results confirm prior reports that fat is less satiating than
      carbohydrate, and further demonstrate that i.g. carbohydrate infusions condition
      a stronger flavor preference than fat infusions.

PMID- 10357427
TI  - Flavor preferences conditioned by high-fat versus high-carbohydrate diets vary as
      a function of session length.
AB  - Intragastric (i.g.) infusions of fat and carbohydrate condition flavor
      preferences in rats, but different results have been obtained in studies using
      pure and mixed nutrient infusions. This experiment compared the preference
      conditioning effects of mixed high-carbohydrate (HC) and high-fat (HF) diet
      infusions during short-term and long-term sessions. In Experiment 1 food-deprived
      rats were given one flavored saccharin solution (CS+HC) paired with i.g.
      infusions of an HC liquid diet, a second flavor (CS+HF) paired with HF diet
      infusions, and a third flavor (CS-) paired with i.g. water infusions during 30
      min one-bottle training sessions. In subsequent two-bottle tests (30 min/day),
      the rats preferred both CS+s to the CS- and preferred the CS+HC to the CS+HF. In
      Experiment 2, the same rats were trained and tested with the CSs and paired
      infusions during 22 h/day sessions with chow available ad lib. Both CS+s were
      again preferred to the CS-, but now the CS+HF was preferred to the CS+HC. When
      given additional 30-min choice sessions in Experiment 3 the rats showed no
      reliable preference for the CS+HC versus CS+HF under food-deprived or ad lib
      conditions. In Experiment 4, the rats were given 22-h CS+HC versus CS+HF choice
      sessions every other day. They showed no reliable CS preference during the first
      30 min of each session, but reliably preferred the CS+HF during the remaining
      21.5 h. These findings indicate that previously reported differences in
      preferences conditioned by pure versus mixed nutrient infusions are due to
      training procedures (session length, deprivation state) rather than to the type
      of nutrient infusions per se. The rats displayed different CS+HF versus CS+HC
      preferences as a function of test duration even after being given both short- and
      long-term training. Thus, short-term choice tests do not always predict the long
      term intakes and preferences for high-fat and high-carbohydrate foods.

PMID- 10357428
TI  - Evoked potentials elicited by natural stimuli in the brain of unanesthetized
      crayfish.
AB  - Experiments were conducted to test some characteristics of vision by crayfish
      underwater and in air, and determine possible motion reactions elicited in
      response to naturalistic or quasi-ethological visual stimuli. Chronically
      implanted electrodes on the brain were used to record visually evoked potentials
      in response to moving bars at different speeds or to fish of different sizes.
      Electroretinograms were also recorded to detect when an object or a shadow
      appeared in the crayfish visual field. Ongoing brain activity is mild under basal
      conditions, but increases in RMS by approximately 6% in response to bar passage
      and 12 to 53% in response to fish motionless or swimming in front of the
      crayfish. When crayfish are free to move, fish swimming in front of them elicit
      intense brain activity, together with displacement toward them and an attempt to
      grab them. Visual evoked potentials are elicited by moving objects as small as 1
      degree at a distance of 30 cm in air as well as underwater. None of the stimuli
      used induced evident behavioral responses under our conditions. We conclude that
      vision-action activities can be divided into (a) vision of irrelevant objects
      with short lasting electrical activity and no motion in response to it; (b)
      vision of mildly interesting objects with long-lasting electrical effects, but no
      motion in response to it; and (c) vision of relevant objects with appropriate
      motion reaction.

PMID- 10357429
TI  - The response of crying newborns to sucrose: is it a "sweetness" effect?
AB  - Intraoral sucrose (and other sweet carbohydrates) induce rapid and sustained
      calming in crying newborns and transiently increase mouthing and hand-mouth
      contact ("sucrose effects"). To investigate whether these effects are due to the
      sweetness of sucrose, 60 crying newborns were randomized to receive 250 microL of
      24% sucrose solution, 0.12% of aspartame solution of equivalent sweetness (to
      adults), or 24% polycose, a soluble carbohydrate that is only very slightly sweet
      (to adults), as well as water in a mixed parallel crossover design. Relative to
      water, sucrose persistently reduced crying, and transiently increased mouthing
      and hand-mouth contact, as previously demonstrated. Aspartame also reduced
      crying, and transiently increased mouthing and hand-mouth contact, virtually
      mimicking the time course and the magnitude of the effects obtained in response
      to sucrose. By contrast, polycose solution had no specific effects on crying,
      mouthing, or hand-mouth contact. The results imply that the responses of crying
      newborns to intraoral sucrose are neither specific to sucrose nor to the general
      class of carbohydrates, and that these effects are more appropriately understood
      as "sweetness" effects.

PMID- 10357430
TI  - Effects of bile duct ligation and captopril on salt appetite and renin
      aldosterone axis in rats.
AB  - A ligation of the common bile duct (BDL) produces cholestasis and hypotension and
      increases the daily ingestion of sodium chloride solutions in rats. Low-dose
      captopril (CAP) treatment also modifies the ingestion of water and sodium in
      naive rats, and may do so in cholestatic rats. This study examined whether the
      elevated ingestion of saline by Long-Evans rats after BDL is associated with
      increased plasma renin activity (PRA), and whether treatment with a low dose of
      the angiotensin converting-enzyme inhibitor CAP further exacerbates fluid intake
      and PRA after BDL. In these experiments water and 0.3 M saline intake and PRA and
      plasma aldosterone (PA) were measured in naive and CAP-treated BDL and sham
      ligated rats. We found that BDL elevated rats' daily saline intake 2 weeks after
      the ligation procedure but had no effect on PRA. CAP (0.1 mg/mL) placed in the
      drinking water of some BDL rats further increased saline intake. Both PA and
      hematocrits tended to be reduced in BDL rats, whereas PRA was elevated in both
      BDL and sham-ligated rats receiving CAP in the drinking water or by gavage (0.1
      mg/mL in 10 mL/kg). The data suggest that the ingestion of saline by rats can be
      modified by BDL and CAP administration, but that exaggerated saline intake in BDL
      rats is not associated with excessive renin secretion.

PMID- 10357431
TI  - The mother rat's vomeronasal organ is involved in detection of dodecyl
      propionate, the pup's preputial gland pheromone.
AB  - The aim of the present study was to analyze the respective roles of main and
      accessory olfactory systems in a particular pattern of Wistar rat maternal
      behavior: specific licking of pup's anogenital areas, a behavioral pattern
      crucial to pup survival--nonlicked pups cannot defecate, and die. Dodecyl
      propionate (DP), a chemical agent from rat pup's preputial glands was found to
      direct and regulate pup's anogenital licking. Primiparous dams underwent one of
      the following treatments: surgical removal of the vomeronasal organ (hereafter
      VNX), irrigation of nasal cavities with 5% ZnSO4 solution (ZN), both these
      treatments (VNX + ZN), surgical control (SC), saline irrigation control (SA),
      both these treatments (SC + SA), and normal control (N). Fewer pups (only 75%) of
      VNX dams survived to 15 days of age compared to controls or to females rendered
      anosmic by zinc-sulfate irrigation of the nasal cavity (>95% survival).
      Furthermore, pup growth (mass increase over time) was impaired by VNX and/or ZN
      treatment. Greater than normal amounts of time were spent licking pups'
      anogenital area by VNX females, although these dams did not spend as much time as
      normal females in close contact with either pups heads or filter papers anointed
      with dodecyl propionate. The experiments reported herein suggest that the
      chemosensory receptors in the vomeronasal organ of dams mediate MAGL responses to
      pup pheromone, dodecyl propionate, a pheromone from pups' preputial glands
      secretion, sustaining pups' anogenital licking by dams.

PMID- 10357432
TI  - BXSB mice can learn complex visual pattern discriminations.
AB  - To determine if mice could perceive differences among several complex black/white
      patterns, a water version of a radial-arm maze was modified into a T-maze. BXSB
      mice were able to discriminate between multiple pairs of stimuli.

PMID- 10357433
TI  - GM1 produces attenuation of short-term memory deficits in Hebb-Williams maze
      performance after unilateral entorhinal cortex lesions.
AB  - The Hebb-Williams maze was used to examine spatial abilities of adult male
      Sprague-Dawley rats with unilateral electrolytic entorhinal cortex lesions. The
      injured rats were treated for 14 days with either saline or ganglioside GM1.
      Testing was begun 7 weeks following injury, and involved 12 maze problems with
      independent configurations, with immediate starting replacement used for the six
      trials per problem. Compared to sham-operated counterparts, the rats with lesion
      plus saline treatment were impaired in total number of errors, initial entry
      errors, and repeat errors over 12 consecutive problems. GM1-treated rats showed
      improved performance, making significantly fewer total and repeat errors,
      indicating that this substance may be potentially useful as therapy after
      entorhinal cortex injury.

PMID- 10357434
TI  - Factors influencing metabolic rate in naked mole-rats (Heterocephalus glaber).
AB  - Naked mole-rats (Heterocephalus glaber) are fossorial, eusocial mammals that live
      in colonies averaging about 70 individuals. Metabolic regulation is of particular
      interest in this species because it is one of only two naturally occurring small
      mammals that are hairless. Further, relative to other small mammals, naked mole
      rats exhibit low body temperature (Tb) and weak capacity to maintain Tb above the
      ambient temperature (Ta). The present study examined effects of Ta,
      norepinephrine (NE), and chronic food restriction on O2 consumption (as a measure
      of metabolism) in naked mole-rats. Studies were performed in both awake and
      anesthetized animals. Metabolic rate decreased with increasing T. over the range
      of 23-34 degrees C in awake mole-rats, whereas in anesthetized animals rates of
      O2 consumption were very low over this entire range of Ta and tended to increase
      with increasing Ta. Injections of NE led to rapid increases in metabolic rate at
      all Tas in anesthetized subjects and also at Ta = 34 degrees C in awake mole
      rats. However, at Tas of 29 and 23 degrees C, awake subjects given NE showed
      little stimulation of O2 consumption beyond the already elevated baseline rates
      observed at these Tas. During chronic restriction of food to 60-70% of their
      normal daily consumption mole-rats exhibited decreased rates of metabolism;
      metabolic rate was not altered following several hours of acute food deprivation.
      Food consumption remained somewhat decreased after a period of chronic food
      restriction, even when animals were returned to ad lib conditions. However, body
      weights returned to prerestriction values, despite the continued reduction in ad
      lib food intake. These observations suggest that mole-rats may be capable of long
      lasting metabolic adaptations as a means to cope with restricted food supply.
      These findings are discussed in relation to adaptation of this fossorial species
      to a habitat where food has a patchy distribution. Naked mole-rats, with their
      several unusual thermoregulatory and behavioral features, provide an intriguing
      model for studies of mammalian metabolic regulation.

PMID- 10357435
TI  - Nonphotic entrainment of activity and temperature rhythms in anophthalmic mice.
AB  - Although it is more common to study the effects of light on circadian systems,
      nonphotic stimuli can also influence and entrain circadian clocks. Because
      anophthalmic mice (ZRDCT-AN) have a genetic mutation that prevents the
      development of the eyes, they do not respond to light or entrain to light-dark
      cycles. Thus, entrainment of anophthalmic mice requires a nonphotic zeitgeber
      (entraining stimulus). In the current study we attempted to entrain sighted and
      anophthalmic mice of the same strain, using restricted access to an unlocked
      running wheel as the zeitgeber. First, free-running rhythms were established. The
      running wheels were then locked, and unlocked only from 0930-1130 h each day.
      Finally, a postentrainment free run was measured. In one group of animals, body
      temperature and general activity were measured using a Minimitter telemetry
      system. In another, general activity was measured by a sensitive force plate
      beneath the cage. Running-wheel activity was recorded in both groups. The force
      plate proved satisfactory for observing the behavior of the circadian system
      during wheel locking, and preferable to the temperature transmitters for long
      term studies because the battery life of the mouse temperature transmitters was
      limited. Both sighted and anophthalmic mice were able to entrain to restricted
      wheel access, although not all animals responded. Mice that did not entrain
      showed either no effect of wheel locking or exhibited masking.

PMID- 10357436
TI  - Lipectomy, body weight, and body weight set point in rats.
AB  - Adult, Wistar male rats were lipectomized or sham lipectomized. The food-hoarding
      behavior was measured repeatedly and plotted against the animals' body weights.
      Body weight set point was estimated as the intercept of regression line of
      hoarding with the X axis. Body fat content was measured with a TOBEC body
      composition analyzer. Body weight set point, fat content, and girth were obtained
      initially, after surgery, and after recovery. The hoarding threshold was lowered
      for 2 weeks after surgery, from 561 +/- 20 to 512 +/- 19 g (lipectomized), and
      from 582 +/- 15 to 558 +/- 14 g (sham lipectomized). After a 4-week recovery, all
      rats reached their prelipectomy body weight set point and regained their initial
      body fat. Five weeks after surgery, no significant difference was found between
      the body weight set points of lipectomized and sham-lipectomized rats. This
      indicates that the body weight set point was not mainly modulated by fat depots.
      The transient lowering of the set point is thought to be due to surgical stress.

PMID- 10357437
TI  - Age-related changes in grooming behavior and motor activity in female rats.
AB  - The influence of hormonal status and the age of the rat on the expression of
      grooming behavior and motor activity were studied. Grooming, locomotion, and
      rearing were measured in young (4-months-old), adult (6-8-months-old), and old
      (18-months-old) female rats, during the estrous cycle. These behavioral
      performances were influenced by the hormonal changes that occur in young and
      adult female rats during the estrous cycle. In old rats there were no significant
      differences among the different days of the estrous cycle. A significant age
      related decrease in grooming behavior and motor activity was also found.
      Locomotion and rearing were the parameters most affected by age. These findings
      could be related to: (a) the gonadal hormonal status, which appears to be able to
      modulate behavioral responses; and (b) the age-related changes, which may affect
      the normal display of these behaviors. The possible role of central peptidergic,
      cholinergic, and dopaminergic neural systems is discussed.

PMID- 10357438
TI  - Slow-wave sleep and waking cognitive performance among older adults with and
      without insomnia complaints.
AB  - Previous research has shown that healthy young adults with relatively fast
      reaction times on daytime testing have significantly more nocturnal slow-wave
      sleep than do age-matched subjects with relatively slow reaction times on such
      testing. The current study was conducted to examine the relationship between slow
      wave sleep and cognitive performance among older adults with and without insomnia
      complaints. A sample of 32 noncomplaining older (age > or = 60 years) normal
      sleepers and a like-aged sample of 32 insomniacs, recruited to participate in a
      larger study, served as subjects. All subjects underwent nocturnal sleep
      monitoring immediately prior to undergoing a battery of daytime tests that
      measured simple reaction time, vigilance/signal detection, and complex reaction
      time. Results from the normal sleepers showed no relationship between daytime
      cognitive performance measures and a variety of computer-derived nocturnal slow
      wave sleep measures. In contrast, insomniac subjects with relatively slow
      reaction times showed relative deficits in a spectral analytically derived
      measure of slow-wave power in the 2 to 4 Hz bandwidth. These results suggest that
      relative performance deficits among some older insomniacs may be related to
      specific slow-wave sleep deficiencies. However, among older normal sleepers,
      intersubject differences in performance appear unrelated to slow-wave sleep
      measures. Additional research is needed to further explore the possible
      restorative role slow-wave sleep may serve for cognitive functions other than
      those examined herein.

PMID- 10357439
TI  - Deficit in the water-maze after lesions in the anteromedial extrastriate cortex
      in rats.
AB  - The Morris water-maze task was used to evaluate the role of the anteromedial
      extrastriate visual cortex in the processing of visuospatial information in rats.
      Six gray male rats received bilateral ibotenic acid injections targeted
      stereotactically to the rostral part of the anteromedial extrastriate visual
      cortex. These operated subjects and six other unoperated control rats were tested
      in the maze. Histological analysis confirmed the localization, symmetry, and
      depth of lesions in the rostral part of anteromedial area (AMa) in the operated
      subjects. In these animals, a significantly greater latency to reach the
      submerged platform was found (U = 0, p = 0.004). The Morris water-maze may be
      considered as a reference memory task. It presents a stronger demand on the use
      of allocentric spatial visual cues than on the use of egocentric cues for
      navigation. Therefore, the present data lend support to the participation of area
      AMa in the integration of allocentric visuospatial cues or as a link in the
      memory system involved in the acquisition of this task.

PMID- 10357440
TI  - Behavioral responses to aliphatic aldehydes can be predicted from known
      electrophysiological responses of mitral cells in the olfactory bulb.
AB  - For a better understanding of the encoding of odor quality in the olfactory
      system, it is critical to determine how electrophysiological responses to
      odorants are reflected in the behavioral responses to these odorants. In this
      article, we use a simple behavioral paradigm to show that the behavioral
      responses to similar odorants can be predicted from the electrophysiological
      responses of neurons in the olfactory bulb. Carbon chain length in aliphatic
      aldehydes has been used as a model for graded similarity among odorants. Recent
      electrophysiological experiments have shown that mitral cells in the rabbit
      olfactory bulb respond with similar response patterns to aliphatic aldehydes of
      similar chain length. On average, mitral cells responded with increased spiking
      activity to stimulation with two to three different aldehydes of neighboring
      chain length. We here show that the perception of these odorants can be predicted
      from the electrophysiological responses: rats that are conditioned to a given
      aldehyde generalize to aldehydes with one to two carbon differences in chain
      length from the conditioned aldehyde. When asked to discriminate between
      aldehydes of different chain lengths, rats learned to discriminate between any
      two odorants, but the rate of acquisition depended on the degree of similarity
      between the two odorants.

PMID- 10357441
TI  - Behavioural anxiolytic effects of low-dose anabolic androgenic steroid treatment
      in rats.
AB  - The use of anabolic androgenic steroids (AAS) in supratherapeutic doses has been
      associated with aggressive behaviour as well as with severe affective and
      psychotic symptoms. These symptoms usually follow a chronic exposure for several
      months. However, AAS also may have milder effects with hypomania-like features
      such as an increase in confidence, energy and self-esteem. We have studied the
      short-term effects on male rat behaviour in a modified open-field test of the AAS
      Metenolon administered three times at a low dose (0.01 mg/kg/week x 3). The
      control rats showed indications of increased timidity and aversive learning
      following retesting, a reaction that was absent in the AAS-treated rats. The AAS
      treated rats showed less fear or anticipatory anxiety compared to control
      animals. Furthermore, the suppressed marking behaviour and altered morphological
      allometric relationships were compatible with a modified social and sexual
      competence in the AAS treated rats.

PMID- 10357442
TI  - Perceived effects of stress on food choice.
AB  - Self-reported effects of stress on eating behaviour and food were assessed in a
      brief questionnaire in 212 students. Snacking behaviour was reportedly increased
      by stress in the majority of respondents (73%) regardless of gender or dieting
      status. The overall increase in snacking during stress was reflected by reports
      of increased intake of "snack-type" foods in all respondents, regardless of
      dieting status. In contrast, intake of "meal-type" foods (fruit and vegetables,
      meat and fish) was reported to decrease during stressful periods. The majority of
      the respondents reported an effect of stress on overall amount eaten, but while
      snacking, roughly equal numbers reporting decreased intake (42%) and increased
      intake (38%). The direction of change in intake could be predicted in part by
      dieting status, with dieters being more likely to report stress hyperphagia and
      nondieters being more likely to report stress hypophagia.

PMID- 10357443
TI  - Effect of the H1-histamine receptor agonist betahistine on drinking and eating
      behavior in pygmy goats.
AB  - The effect of different doses of the H1-receptor agonist betahistine (0.9 and 2,
      4 and 8 mg/kg b.wt.(0.75)) on water and food intake was investigated in 12 pygmy
      goats. Intraperitoneal (i.p.) injection of betahistine (2, 4, and 8 mg/kg
      b.wt.(0.75)) stimulated drinking in a dose-dependent manner. Food intake was
      decreased after the injection of 4 or 8 mg/kg b.wt.(0.75) betahistine,
      respectively. The increase in water intake was characterized by an increased
      draft size and decreased latency to drink. The decrease in food intake at the
      highest dose tested was characterized by an increased latency to eat and by a
      decreased meal frequency, and food intake associated to drinking was decreased.
      In line with previous studies, these results support the hypothesis that food
      associated drinking is mediated by stimulation of H1-receptors of histamine in
      pygmy goats.

PMID- 10357444
TI  - Neuroendocrine and behavioral effects of CRH blockade and stress in male rats.
AB  - Our previous data have shown that restraint (RT), a mild nonpainful stressor,
      acutely impairs nonsocial and social behavior in male rats. Corticotropin
      releasing hormone (CRH) is a regulator of these behavioral responses. To evaluate
      whether CRH mediates the neuroendocrine and behavioral alterations present 24 h
      after restraint stress, we administered the CRH antagonist alpha-helical CRH(9
      41) (alpha-hCRH) intracerebroventricularly to male rats and we compared its
      effects with those of saline. Twenty-four hours after treatment, nonsocial
      behaviors were significantly decreased by alpha-hCRH, this effect being
      independent of RT. Among social behaviors, only introductory activity showed
      significant differences as a result of both RT and alpha-hCRH. The concentrations
      of ACTH in the plasma and those of beta-endorphin in the anterior and
      neurointermediate lobes of the pituitary were affected by alpha-hCRH treatment.
      The effect on ACTH was simply related to the administration of the alpha-hCRH,
      while for beta-endorphin, significant interactions between alpha-hCRH and RT were
      found. On the whole, these results point to the role played by CRH in the control
      of neuronal mechanisms involved in the stress-induced effects.

PMID- 10357445
TI  - Modulation of taste reactivity by intestinal distension in rats.
AB  - Discomfort created by intestinal distension may play a role in controlling intake
      behavior. We analyzed these effects in details by the taste reactivity test in
      Long-Evans rats. A balloon inserted into a separated Thiry-Vella intestinal loop
      was distended with different volumes of water (0.05, 0.09, 0.12, and 0.28 mL,
      respectively). Saccharin solution (0.001 M) was infused into the mouth via an
      implanted oral cannula nine times for 30 s, with 5-min intertrial intervals. The
      balloon was distended after the second and released following the seventh trial.
      Taste reactivity (TR) elements were videotaped and later analyzed for appetitive
      and aversive responses. The number of appetitive responses decreased after gut
      distension, whereas aversive elements were infrequent and stable. It is suggested
      that pleasantness of the taste stimulus decreased independently of the
      discomfort, which remained mild but steady; that is, sweet taste gradually lost
      its hedonic value but was not accompanied by an acquired aversion of the same
      taste. This finding may point to the difference of the motivational and
      discriminative effects of the internal stimuli.

PMID- 10357446
TI  - Effects of intracerebroventricularly administered leptin on protein selection in
      the rat.
AB  - The effect of centrally administered rat leptin on selection of 5 and 30% protein
      diets was investigated in male Sprague-Dawley rats with indwelling i.c.v.
      cannulas. Leptin (0 vs 2.5 microg/day) was administered for 4 consecutive days,
      followed by an 8-day withdrawal period. Total intake was reduced to approximately
      50% of that in the vehicle injected group during each day following leptin
      administration. Intake of both the 5 and 30% diets was reduced. Vehicle-treated
      rats selected a 13-15% CP diet. Diet selection in leptin-treated rats was not
      different during the first day, but on Days 2-4, leptin-treated rats selected a
      10% CP diet. Intake began to normalize within 24-48 h after the last treatment,
      and was not different by Day 3 of the withdrawal period. Body weight was reduced
      by leptin treatment, and despite the normalization of food intake, did not
      recover during the withdrawal period. Rats were sacrificed at the end of the 8
      day withdrawal period. Despite the reduction in body and carcass weights, liver,
      kidney, heart, and soleus muscle weights were not different between control and
      leptin-treated groups when expressed on an absolute or relative basis. However,
      epididymal and retroperitoneal fat pad weights were still reduced 56 and 78%,
      respectively, in rats that had been previously treated with leptin for 4 days and
      then not treated for 8 days. In addition, circulating T3 levels remained elevated
      in rats that had been treated with leptin. Centrally administered leptin has
      little effect on muscle mass, but had potent effects on intake of nonobese rats
      and a sustained effect on adipose tissue mass, thyroid hormone status, and body
      weight after withdrawal. Results from rats selecting between diets varying in
      protein content suggest that leptin may cause avoidance of protein.

PMID- 10357447
TI  - A microstructural analysis of the control of water and isotonic saline ingestion
      by postingestional stimulation.
AB  - This study investigated the behavioral expression of the mechanisms of satiation
      from stimulation of the gastrointestinal tract by water and isotonic saline. We
      compared the licking behavior of water-deprived rats ingesting water or isotonic
      saline under real- and sham-drinking conditions. In real-drinking tests the rate
      of ingestion of both types of fluids declined after about 5 min of drinking, and
      had virtually ceased by 20 min, while in the sham-drinking tests the rate of
      drinking remained constant during this period. To assess the impact of
      postingestional stimulation on the microstructure of licking, we compared the
      size of the clusters (SC) of licking and the duration of the pauses between them
      (ICIs), during the 15-min period that began 5 min after the start of drinking in
      the real- and sham-drinking tests. With both fluids postingestional stimulation
      significantly reduced the number of clusters. With water, but not with isotonic
      saline, postingestional stimulation also reduced SC, an effect that was shown to
      be due to differential postingestional not oropharyngeal stimulation.
      Postingestional stimulation had no overall effect on the ICIs, but in tests with
      water, but not saline, it altered the shape of the ICI distribution by increasing
      the duration of the long ICIs. We concluded that the different mechanisms of
      satiation stimulated by the postingestional effects of water and isotonic saline
      are expressed in different patterns of the microstructure of licking.

PMID- 10357448
TI  - Intact learning of artificial grammars and intact category learning by patients
      with Parkinson's disease.
AB  - Patients with Parkinson's disease (PD) have been shown to be impaired on some
      nondeclarative memory tasks that require cognitive skill learning (perceptual
      motor sequence learning, probabilistic classification). To determine what other
      skill-based tasks are impaired, 13 patients with PD were tested on artificial
      grammar learning, artificial grammar learning with transfer to novel lettersets,
      and prototype learning. Patients with PD performed similarly to controls on all 3
      tests. The intact learning exhibited by PD patients on these tests suggests that
      nondeclarative cognitive skill learning is not a single entity supported by the
      neostriatum. If learning the regularities among visual stimuli is the principal
      feature of artificial grammar learning and prototype learning, then these forms
      of skill learning may be examples of perceptual learning, and they may occur in
      early visual cortical processing areas.

PMID- 10357449
TI  - Rhinal cortex lesions produce mild deficits in visual discrimination learning for
      an auditory secondary reinforcer in rhesus monkeys.
AB  - Aspiration, but not neurotoxic, lesions of the amygdala impair performance on a
      visual discrimination learning task in which an auditory secondary reinforcer
      signals which of 2 stimuli will be reinforced with food. Because aspiration
      lesions of the amygdala interrupt projections of the rhinal cortex traveling
      close to the amygdala, it was hypothesized that damage to the rhinal cortex would
      severely impair learning in this task. Rhesus monkeys (Macaca mulatta) were
      trained to solve visual discrimination problems based on an auditory secondary
      reinforcer, were given lesions of the rhinal cortex or the perirhinal cortex
      alone, and were then retested. The monkeys displayed a reliable, albeit mild,
      deficit in postoperative performance. It is concluded that the aspiration lesions
      of the amygdala that produced a severe impairment did so because they interrupted
      connections of temporal cortical fields beyond the rhinal cortex that are also
      involved in learning in this task.

PMID- 10357450
TI  - Distinct roles for striatal subregions in mediating response processing revealed
      by focal excitotoxic lesions.
AB  - This study examined the relative roles of distinct striatal areas in response
      processing. Rats were trained on a reaction time task that enabled performance on
      each side of the rat's body to be assessed independently. Rats then received
      unilateral lesions of the whole dorsal striatum or restricted medial or lateral
      lesions. Both medial and lateral lesions induced a response bias in contralateral
      space, but this bias was less severe in rats with medial lesions. Medial striatal
      lesions led to an increase in premature responses. Lateral striatal lesions
      produced an increase in late responses. It is suggested that the lateral striatum
      mediates the selection of responses, and the medial striatum acts to influence
      inhibitory control over responding. Discrete striatal areas are thus functionally
      dissociable, but both have a crucial role in the organization of responding in
      space.

PMID- 10357451
TI  - Interactions between 192-IgG saporin and intraseptal cholinergic and GABAergic
      drugs: role of cholinergic medial septal neurons in spatial working memory.
AB  - Rats were administered 192-IgG saporin (SAP) or vehicle into the medial septum
      vertical limb of the diagonal band (MS-vDB). Starting 1 week later, the effects
      of intraseptal scopolamine, oxotremorine, and muscimol were tested in a T-maze
      alternation task. Choice accuracy in the absence of infusions did not differ
      between control and SAP-treated rats. Intraseptal scopolamine or muscimol
      impaired the choice accuracy of SAP-treated but not control rats. Oxotremorine
      impaired accuracy similarly in control and SAP-treated rats. The enhanced effects
      of scopolamine and muscimol produced by SAP are consistent with the hypothesis
      that cholinergic MS-vDB neurons are used in spatial working memory. The finding
      that SAP alone did not alter choice accuracy provides further evidence that
      cholinergic MS-vDB neurons are not necessary for spatial working memory. Thus,
      cholinergic MS-vDB neurons are involved in but not necessary for spatial working
      memory.

PMID- 10357453
TI  - Neurotoxic or electrolytic lesions of the ventral subiculum produce deficits in
      the acquisition and expression of Pavlovian fear conditioning in rats.
AB  - The effects of neurotoxic or electrolytic ventral subicular (vSUB) lesions on the
      acquisition and expression of Pavlovian fear conditioning in rats were examined.
      Conditioning consisted of the delivery of tone-footshock trials in a novel
      observation chamber, and freezing served as the measure of conditional fear.
      Pretraining vSUB lesions produced a severe tone freezing deficit and a modest
      context freezing deficit, whereas posttraining lesions produced severe deficits
      in freezing to both a tone and a context conditional stimulus (CS). Similar
      impairments were produced by neurotoxic and electrolytic lesions. Increases in
      motor activity associated with the lesions could not account for freezing
      deficits. These results reveal that neurons in the vSUB have an important role in
      both the acquisition and expression of Pavlovian fear conditioning to contextual
      and acoustic CSs.

PMID- 10357452
TI  - Acquisition of fear conditioning in rats requires the synthesis of mRNA in the
      amygdala.
AB  - In this study, the role of mRNA synthesis in the amygdala was studied during the
      acquisition of conditional fear. Rats with cannulas placed in the basolateral
      region of the amygdala were trained with a series of noise-shock pairings in a
      distinctive observation chamber. One half of the rats were pretreated with the
      mRNA synthesis inhibitor actinomycin-D (act-D). Responding to the training
      context and the auditory stimulus in a novel context measured by defensive
      freezing was assessed. Pretreatment with act-D significantly attenuated fear
      responses to both stimuli. Animals receiving act-D injections exhibited normal
      reactions to the conditioned stimulus-unconditioned stimulus pairings in the
      initial training session and displayed normal learning when retrained 7 days
      after injections. These results indicate that the transcription of new mRNA and
      subsequent protein synthesis in the amygdala may be essential for neural
      plasticity during this form of associative learning.

PMID- 10357454
TI  - Ibotenic acid lesions of the basolateral, but not the central, amygdala interfere
      with conditioned taste aversion: evidence from a combined behavioral and
      anatomical tract-tracing investigation.
AB  - Rats (Rattus norvegicus) with almost complete ibotenic acid lesions (at least
      90%) of the basolateral amygdaloid complex (BLA) failed to learn a conditioned
      taste aversion (CTA; Experiment 1A). In these same BLA rats, the bidirectional
      parabrachial-insular pathway that courses through the central nucleus of the
      amygdala (Ce) was shown to be spared (Experiment 1B), indicating that the BLA per
      se is critical for CTA learning. In contrast to the deleterious effect of BLA
      lesions on CTA, ibotenic acid lesions of the Ce did not block CTA learning
      (Experiment 2). Nonreinforced preexposure to the gustatory stimulus attenuated
      CTA acquisition in normal rats, and, under these conditions, rats with BLA
      lesions were no longer impaired (Experiment 3). Thus, ibotenic acid lesions
      centered over the Ce, sparing a considerable extent of the BLA, together with the
      testing procedure used in previous experiments (e.g., L. T. Dunn & B. J. Everitt,
      1988), led to the belief that the CTA deficits reported after electrolytic
      lesions of the amygdala were the result of incidental damage to fibers of
      passage.

PMID- 10357455
TI  - Different effects on learning ability after injection of the cholinergic
      immunotoxin ME20.4IgG-saporin into the diagonal band of Broca, basal nucleus of
      Meynert, or both in monkeys.
AB  - Immunotoxic lesions of the diagonal band of Broca (VDB) in monkeys disrupted
      cholinergic input to the hippocampus, producing impaired learning of visuospatial
      conditional discriminations but not simple visual discriminations. Immunotoxic
      lesions of the basal nucleus of Meynert (NBM) deprived the cortex of most of its
      cholinergic input, producing impaired learning of simple visual discriminations
      but not visuospatial conditional discriminations. Combined lesions of the NBM +
      VDB resulted in impaired learning of both types of task. The impairment after NBM
      lesions ameliorated with time but could be reinstated by a low dose of the
      glutamate blocking drug MK801, which, at this dose, did not impair simple visual
      discrimination learning in normal monkeys. The cholinergic projections from the
      NBM and VDB may sustain the function of the glutamatergic pyramidal cell pathways
      within the cortex and hippocampus, respectively.

PMID- 10357456
TI  - Isolation reduces contextual but not auditory-cue fear conditioning: a role for
      endogenous opioids.
AB  - Isolation for several hours after fear conditioning reduces contextual but not
      auditory-cue fear conditioning (J. W. Rudy, 1996). This isolation effect is
      reversed by both, centrally and peripherally acting opioid receptor antagonists.
      As in isolation, systemically administered morphine given immediately after
      conditioning also reduces contextual fear conditioning. Morphine's effect is also
      reversed by both centrally and peripherally acting opioid receptor antagonists.
      Exposure to the conditioning context has been shown to eliminate the effect of
      isolation on contextual fear conditioning (J. W. Rudy, 1996). Context preexposure
      also eliminated the effect of morphine on contextual fear conditioning. These
      results imply that opioids released in the periphery play an important role in
      producing the isolation effect and that they do so by disrupting the
      postconditioning memory consolidation processes.

PMID- 10357458
TI  - Recall rendered dependent on an opiate state.
AB  - Remembering may require that the organism be in a state that is similar to that
      in which the event was initially experienced (state dependence [StD]). We
      determined whether morphine induces StD and whether this StD is conceivably
      involved in the analgesic effects that opiates produce. Rats trained while
      treated with morphine recalled the learned response when tested with this opiate
      but not when in their nondrugged state, and vice versa. Furthermore, morphine
      analgesia occurred in a manner that was similar to StD in terms of both dose and
      time. In as much as responses to nociceptive stimulation are learned during the
      course of ontogeny, StD may constitute the psychophysiological mechanism whereby
      opiates produce their characteristic analgesic effects.

PMID- 10357457
TI  - Feeding induced by GABA(A) receptor stimulation within the nucleus accumbens
      shell: regional mapping and characterization of macronutrient and taste
      preference.
AB  - This study investigated the areas of the nucleus accumbens shell involved in the
      modulation of feeding behavior by GABAergic stimulation and characterized this
      response using macronutrient diets as well as saline, sucrose, and saccharin
      solutions. The GABA agonist muscimol induced a pronounced feeding response when
      infused in the medial nucleus accumbens shell but not in the ventral or lateral
      accumbens shell. In the macronutrient preference study, muscimol increased the
      intake of both high fat and high carbohydrate diets when presented separately.
      When both diets were available simultaneously, muscimol stimulated feeding of
      both diets to the same degree. Muscimol elicited a robust increase in the
      consumption of sucrose solution. However, no effect of muscimol was demonstrated
      for water, saline, or saccharin intake. These findings provide evidence for a
      selective role for GABA-sensitive neurons in the medial accumbens shell in the
      regulation of ingestive behavior and further suggest that GABA(A) receptors in
      this region do not modulate palatability, macronutrient selection, or rewarding
      properties of food.

PMID- 10357459
TI  - Lesions centered on the medial amygdala impair scent-marking and sex-odor
      recognition but spare discrimination of individual odors in female golden
      hamsters.
AB  - The medial amygdala (Me) has been implicated in various social behaviors that
      depend on chemosensory cues, but its precise role in discriminating and learning
      social odors is not known. Female golden hamsters (Mesocricetus auratus) received
      electrolytic lesions of the Me or sham surgery and were tested for their ability
      to (a) discriminate between odors of individual males in a habituation
      discrimination task, (b) show preferences for male over female odors in a Y maze,
      and (c) scent-mark in response to male and female odors. All females
      discriminated between scents of individual males. In contrast, Me lesions
      eliminated female preferences for male odors in a Y maze. Females with Me lesions
      also showed a substantial reduction in vaginal marking and virtually no flank
      marking in response to odors. Thus, the Me in female hamsters is critical for
      differential investigation of opposite-sex odors and for scent-marking behavior
      but is not involved in discrimination between odors of individuals.

PMID- 10357460
TI  - Olfactory associative learning in Caenorhabditis elegans is impaired in lrn-1 and
      lrn-2 mutants.
AB  - The C. elegans mutants, lrn-1 and lrn-2, are impaired in associative learning
      using conditioned taste cues. Both mutants are defective in associative learning
      about appetitive and aversive events, indicating that lrn-1 and lrn-2 exert
      effects across motivational boundaries. In a new olfactory associative learning
      paradigm, in which wild type worms learn to avoid a previously attractive
      diacetyl odor after it has been paired with an aversive acetic acid solution, lrn
      1 and lrn-2 are impaired. Although defective in associative learning using a
      conditioned olfactory cue, nonassociative learning (habituation and
      dishabituation) using this same olfactory cue is unaffected. The discovery that
      lrn-1 and lrn-2 are defective in associative learning with both taste and
      olfactory cues may suggest that associative learning in different sensory
      modalities converges on a common genetic pathway in C. elegans that is subserved
      by lrn-1 and lrn-2.

PMID- 10357461
TI  - Conditioning of and contextual sensitization to apomorphine-induced climbing in
      mice: evidence against the habituation hypothesis.
AB  - Several predictions of the habituation hypothesis of conditioned drug effects
      were tested by looking at contextual sensitization to apomorphine-induced
      climbing in mice (Mus musculus). Mice were first sensitized to that effect after
      9 daily injections of 0.4 mg/kg apomorphine in the test context. Other mice
      received the same treatment outside the test context. On Day 10, all mice were
      challenged with either saline (conditioned drug effects test) or apomorphine
      (contextual sensitization test). On both tests, the levels of climbing of mice
      that received apomorphine paired with the test context during the intermittent
      treatment were significantly higher than those of mice that were experiencing the
      test context for the first time (unexposed mice). Also, the rate of extinction in
      conditioned mice did not parallel the rate of habituation in the unexposed mice.
      Results contradict the habituation hypothesis of conditioned drug effects and
      contextual sensitization.

PMID- 10357462
TI  - Microinfusion of cocaine into the medial preoptic area or nucleus accumbens
      transiently impairs maternal behavior in the rat.
AB  - Cocaine was microinfused bilaterally (50 microg/0.5 microl/side) into the medial
      preoptic area (MPOA) or nucleus accumbens (NA), 2 regions within the rat brain
      neural circuit known to mediate maternal behavior (MB). Additionally, 2 sites not
      involved in this neural circuit, the dorsal striatum and dorsal medial
      hippocampus, were used as control sites. Microinfusion of cocaine into the MPOA
      or NA impaired MB, whereas infusion into the control sites did not. MB impairment
      was not temporally coincident with the increased locomotor activity, also
      documented after cocaine infusion into the MPOA or NA, arguing strongly that
      impaired MB is a direct, specific effect of cocaine in these areas, not a
      derivative of increased motor activity. This is the first demonstration that
      cocaine action on single central nervous system (CNS) sites can impair MB to the
      same extent as systemic injections. Thus, cocaine's simultaneous effect on
      multiple CNS sites is not required for MB impairment.

PMID- 10357463
TI  - Intracerebroventricular infusion of the galanin antagonist M40 attenuates
      heterosexual partner preference in ferrets.
AB  - Gonadectomized, estradiol-treated male and female ferrets (Mustela furo) received
      intracerebroventricular (i.c.v.) infusions of 4 doses of the galanin receptor
      antagonist M40 or galanin and were allowed to approach breeding male or female
      ferrets that were placed behind wire mesh barriers in the goal boxes of a T maze.
      After i.c.v. infusion of saline, subjects strongly preferred to approach stimulus
      ferrets of the opposite sex. Male and female subjects approached these preferred
      stimulus animals on significantly fewer trials after i.c.v. infusion of the 2
      highest doses of M40, whereas this drug failed to affect males' coital behavior
      in separate tests with an estrous female. Endogenous galanin may facilitate
      neural reward mechanisms that control heterosexual partner preference in both
      sexes.

PMID- 10357464
TI  - Toward an HIV type 1 vaccine that generates potent, broadly cross-reactive
      neutralizing antibodies.

PMID- 10357465
TI  - High rate of human T lymphotropic virus type IIa infection in HIV type 1-infected
      intravenous drug abusers in Ireland.
AB  - Serological and molecular analyses of a cohort of HIV-1-infected intravenous drug
      abusers (IVDAs) (n = 103) in Dublin, Ireland have demonstrated that 15 of 103
      (14.6%) were infected with HTLV-II, which is the highest infection rate yet
      recorded for any European country. Restriction fragment length polymorphism
      (RFLP) analysis of the env region of the provirus demonstrated that the infection
      involved only the HTLV-IIa subtype; the HTLV-IIb subtype was not detected.
      Phylogenetic analysis of the nucleotide sequences of the long terminal repeat
      (LTR) confirmed infection with the HTLV-IIa subtype, and demonstrated that the
      viruses clustered closely with HTLV-IIa isolates from North American IVDAs.
      Previous observations that IVDAs in southern Europe, specifically Spain and
      Italy, appear to be infected predominantly with the HTLV-IIb subtype, along with
      the present report and evidence that IVDAs in Sweden are infected with the HTLV
      IIa subtype, suggest different origins of HTLV-II infection in Europe.

PMID- 10357466
TI  - Coreceptor requirements of primary HIV type 1 group O isolates from Cameroon.
AB  - HIV-1 group O has its epicenter in Cameroon and neighboring countries and is
      responsible for 3 to 5% of all HIV infections in this region. It is believed that
      HIV-1 group O was introduced into the human population by a separate cross
      species transmission, occurring independently of the HIV-1 (group M and group N)
      and HIV-2 transmissions. We have studied the coreceptor requirements of 12
      primary HIV-1 O-type isolates from individuals with different clinical symptoms.
      Only 2 of these 12 viruses showed a syncytium-inducing phenotype after infection
      of primary peripheral blood mononuclear cells (PBMCs) and were infectious for the
      T cell line C8166. These isolates used CXCR4 as a coreceptor for entry, whereas
      the remaining isolates used only CCR5 efficiently. One isolate was able to use
      BOB and CCR8 as coreceptors in addition to CXCR4. All group O isolates tested
      were efficiently inhibited by SDF-1 or RANTES, the natural ligands of CXCR4 and
      CCR5, respectively. These results indicate that CXCR4 and CCR5 are the principal
      coreceptors for HIV-1 O-type viruses. Most of the HIV-1 group O isolates studied
      were derived from patients at later stages of the disease. Although HIV-1 group O
      and group M infections do not differ in their pathogenesis, the studied isolates
      did not evolve to use a broad range of coreceptors as described for HIV-1 group M
      and HIV-2.

PMID- 10357467
TI  - Treatment of AIDS-related primary central nervous system lymphoma with
      zidovudine, ganciclovir, and interleukin 2.
AB  - AIDS-related primary central nervous system lymphoma (AIDS PCNSL) is a rapidly
      fatal disease. Conventional therapeutic modalities offer little and new
      approaches are needed. Previous work has shown that zidovudine (AZT) in
      combination with other agents is active in retroviral lymphomas. Epstein-Barr
      virus (EBV) is detected in tumor tissue and cerebrospinal fluid of AIDS PCNSL
      patients. In a preliminary in vitro study we found that an Epstein-Barr virus
      positive B cell line underwent apoptosis on coculture with AZT. This effect was
      accentuated by the addition of ganciclovir (GCV). We treated five patients with
      AIDS PCNSL with a regimen consisting of parenteral zidovudine (1.6 g twice
      daily), ganciclovir (5 mg/kg twice daily), and interleukin 2 (2 million units
      twice daily). Four of five had an excellent response. Two patients are alive and
      free of disease 22 and 13 months later; another responded on two separate
      occasions, 5 months apart, and the last patient responded with a 70-80%
      regression of tumor but could not be maintained on therapy owing to
      myelosuppression. We conclude that parenteral zidovudine, ganciclovir, and
      interleukin 2 is an active combination for AIDS-related central nervous system
      lymphoma.

PMID- 10357468
TI  - Sequential analysis of apoptosis induction in peripheral blood mononuclear cells
      and lymph nodes in the early phase of pathogenic and nonpathogenic SIVmac
      infection.
AB  - To investigate the role of apoptosis in the early phase of HIV infection, we used
      macaques infected with simian immunodeficiency virus strain mac (SIVmac) as a
      primate model and examined sequentially the characteristics of apoptosis of
      lymphocytes in peripheral blood mononuclear cells (PBMCs) and lymph nodes in the
      early phase of SIVmac infection. Five macaques infected with a pathogenic strain
      of SIV, SIVmac239, were analyzed during the first 4 weeks after infection.
      Peripheral CD4+ and CD8+ cells transiently decreased at 1 week postinfection. The
      percentage of apoptotic cells in cultured PBMCs increased from about 2 weeks
      postinfection. The number of apoptotic cells in lymph node sections was higher on
      days 13 and 28 postinfection than before infection and on day 5 postinfection.
      Fas antigen expression on peripheral lymphocytes was upregulated from day 8
      postinfection. These results indicate that apoptosis is induced about 2 weeks
      after SIVmac239 infection, following the upregulation of Fas antigen expression
      on lymphocytes. Since apoptosis was induced about 1 week after the decrease in
      peripheral CD4+ and CD8+ cell counts, it appears that the apoptosis induction
      does not play an important role in the transient lymphopenia in the early phase
      of SIVmac infection. In macaques infected with a nonpathogenic derivative of
      SIVmac239, SIVmac delta nef, apoptosis of lymphocytes was induced as it was in
      SIVmac239-infected macaques, but to a lesser degree, suggesting a correlation
      between the extent of apoptosis induction in lymphocytes in the early phase of
      SIVmac infection and the pathogenicity of SIVmac.

PMID- 10357469
TI  - Role of the HIV type 1 glycoprotein 120 V3 loop in determining coreceptor usage.
AB  - Macrophage (M)-tropic HIV-1 isolates use the beta-chemokine receptor CCR5 as a
      coreceptor for entry, while T cell line-adapted (TCLA) strains use CXCR4 and dual
      tropic strains can use either CCR5 or CXCR4. To investigate the viral
      determinants involved in choice of coreceptor, we used a fusion assay based on
      the infection of CD4+ HeLa cells that express one or both coreceptors with
      Semliki Forest virus (SFV) recombinants expressing the native HIV-1 gp160 of a
      primary M-tropic isolate (HIV-1BX08), a TCLA isolate (HIV-1LAI), or a dual-tropic
      strain (HIV-1MN). We examined whether the V3 region of these glycoproteins
      interacts directly with the corresponding coreceptors by assaying coreceptor
      dependent cell-to-cell fusion mediated by the different recombinants in the
      presence of various synthetic linear peptides. Synthetic peptides corresponding
      to different V3 loop sequences blocked syncytium formation in a coreceptor
      specific manner. Synthetic V2 peptides were also inhibitory for syncytium
      formation, but showed no apparent coreceptor specificity. A BX08 V3 peptide with
      a D320 --> R substitution retained no inhibitory capacity for BX08 Env-mediated
      cell-to-cell fusion, but inhibited LAI Env-mediated fusion as efficiently as the
      homologous LAI V3 peptide. The same mutation engineered in the BX08 env gene
      rendered it able to form syncytia on CD4+CXCR4+CCR5-HeLa cells and susceptible to
      inhibition by SDF-1alpha and MIP-1beta. Other substitutions tested (D320 -->
      Q/D324 --> N or S306 --> R) exhibited intermediate effects on coreceptor usage.
      These results underscore the importance of the V3 loop in modulating coreceptor
      choice and show that single amino acid modifications in V3 can dramatically
      modify coreceptor usage. Moreover, they provide evidence that linear V3 loop
      peptides can compete with intact cell surface-expressed gp120/gp41 for CCR5 or
      CXCR4 interaction.

PMID- 10357470
TI  - Molecular analysis of the full-length genome of HIV type 1 subtype I: evidence of
      A/G/I recombination.
AB  - Phylogenetic analysis of partial env sequences of HIV-1 isolates from Cyprus and
      Greece suggested the existence of a distinct subtype of the virus, designated as
      I. We examined whether this subtype represents a distinct group, or a mosaic
      consisting of previously characterized subtypes. The full-length sequences under
      consideration were recovered from serum samples of "subtype I" obtained from two
      nonepidemiologically linked HIV-1-infected subjects in Greece. The first subject
      was an intravenous drug user (IDU), while the second was a vertically infected
      child born in 1984 whose parents were both IDUs. A variety of methods, such as
      diversity plots as well as phylogenetic and informative site analyses, were used
      to classify the DNA sequences. Subsequent detailed analysis revealed a unique
      genomic organization composed of alternating portions of subtypes A, G, and I.
      The two Greek isolates formed a distinct group in most of the pol, gp120, and
      gp41 regions, and in the vif/vpr, vpu, LTR, and 5' terminus of nef. In contrast,
      different parts of env and gag as well as the 3' pol region, and the first exons
      of tat and rev, appeared to have arisen from subtypes A and G. Our results
      indicate that subtype I, which was probably circulating in Greece in the early
      1980s, is a triple mosaic consisting of A, G, and I sequences.

PMID- 10357471
TI  - A sensitive and versatile bioluminescence bioassay for HIV type 1 based on
      adenoviral vectors.
AB  - The construction and characterization of a versatile bioassay for the
      quantification of HIV-1 viral infection and HIV-1 Tat protein activity based on
      recombinant adenoviral vectors carrying an HIV LTR-driven luciferase reporter
      gene is described. The assay system consists of a set of two adeno-reporter
      vectors, one of which is responsive to HIV-1 Tat protein activity, and the second
      of which is not, by virtue of a deletion of the TAR site within the HIV LTR. This
      configuration of the reporter genes allows one to distinguish Tat-specific
      activation from Tat-non-specific HIV LTR-mediated gene expression. The adenoviral
      HIV LTR-mediated luciferase gene expression is highly responsive to Tat and
      increases linearly with increasing levels of HIV-1 infection, reaching levels of
      between 3- and 1000-fold induction. The adeno-reporter viruses can be utilized to
      detect Tat activity and HIV-1 infection in a wide range of cell types, including
      293, CEM, HUT-78, Jurkat, and HeLa-derived cell lines. The resulting bioassay is
      convenient, sensitive, and readily adaptable to automated procedures. These
      characteristics of the adeno-reporter assay make it a valuable reagent for
      studies of HIV infection and for analysis of HIV-inhibitory agents.

PMID- 10357472
TI  - Phylogeny of HIV type 1 group O isolates based on env gene sequences.

PMID- 10357473
TI  - Similar HIV-1 subtype A V3 loop sequences are found in dual HIV-1/HIV-2 and HIV-1
      only seropositives in Ghana.

PMID- 10357474
TI  - Phylogenetic analysis of simian T lymphotropic virus type I from Kenyan olive
      baboons (Papio anubis), lowland Sykes monkeys (Cercopithecus mitis), and vervet
      monkeys (Cercopithecus aethiops pygerythrus).

PMID- 10357475
TI  - Alternative interpretation of lymphocyte depletion studies using monoclonal
      antibodies in animals previously vaccinated with attenuated retroviral vaccines.

PMID- 10357476
TI  - 1999 Gary J. Becker Young Investigator Award. MR-guided transjugular
      portosystemic shunt placement in a swine model.
AB  - PURPOSE: To evaluate the performance of portal venous puncture with use of
      magnetic resonance (MR) guidance, and to place a transjugular intrahepatic
      portosystemic shunt (TIPS) in a swine model. MATERIALS AND METHODS: A study of 12
      swine was performed to evaluate the ability of interventional MR imaging to guide
      portal vein puncture and TIPS placement. Six swine had catheters placed in the
      right hepatic vein under C-arm fluoroscopy. A nitinol guide wire was left in the
      vein and the animals were then moved into an open configuration MR imaging unit.
      A TIPS needle set was used to puncture the portal vein using MR fluoroscopy. The
      animals were transferred to the C-arm, and venography confirmed portal vein
      puncture. A follow-up study was performed in six additional swine to place a TIPS
      using only MR imaging guidance. MR tracking was used to advance a catheter from
      the right atrium into the inferior vena cava. Puncture of the portal vein was
      performed and a nitinol stent was placed, bridging the hepatic parenchyma. MR
      venogram confirmed placement. RESULTS: Successful portal vein puncture was
      achieved in all animals. The number of punctures required decreased from 12 in
      the first animal to a single puncture in the last eight swine. A stent was
      successfully placed across the hepatic tract in all six swine. CONCLUSIONS: Real
      time MR imaging proved to be a feasible method to guide portal vein puncture and
      TIPS placement in pigs.

PMID- 10357477
TI  - Forearm loop, upper arm straight, and brachial-internal jugular vein dialysis
      grafts: a comparison study of graft survival utilizing a combined percutaneous
      endovascular and surgical maintenance approach.
AB  - PURPOSE: To determine rates and duration of patency achievable in forearm loop,
      upper arm straight, and brachial-internal jugular (IJ) vein hemodialysis grafts
      utilizing a combined percutaneous endovascular and surgical maintenance approach.
      MATERIALS AND METHODS: A retrospective analysis of 74 hemodialysis grafts
      (forearm loop, n = 22; upper arm straight, n = 34; and brachial-IJ vein, n = 18)
      in 50 patients with end-stage renal disease was conducted. Operative notes,
      interventional procedural reports, and hospital records were used to construct a
      history for each of these grafts from the time of surgical placement until the
      time the graft was abandoned for an alternative method of dialysis. All
      procedures performed to maintain and/or restore patency during the usable
      lifetime of the grafts were documented. RESULTS: Survival analysis using the
      Kaplan-Meier method demonstrated the following probabilities of primary patency
      at 6, 12, and 16 months, respectively: forearm loop graft = .46, .26, and .26;
      upper arm straight graft = .39, .22, and .16; and brachial-IJ vein graft = .19,
      .06, and .06 (forearm loop vs upper arm straight grafts, P > .05; forearm loop
      and upper arm straight vs brachial-IJ grafts, P < .001, P < .001, respectively).
      The probabilities of secondary patency at 12, 24, and 48 months, respectively,
      were: forearm loop graft = .89, .30, and NA; upper arm straight graft = .52, .35,
      and .17; and brachial-IJ vein graft = .54, .42, and .21 (P < .05 for all three
      comparisons: forearm loop > brachial-IJ > upper arm straight). Six percutaneous
      and two surgical procedures were compared and no significant differences in
      utilization were determined among the three graft types (ANOVA, P range, .38
      .88). CONCLUSION: Kaplan-Meier analysis determined the probability of primary
      patency for forearm loop grafts to be similar to that for upper arm straight
      grafts, and both were significantly greater than for brachial-IJ vein grafts. The
      secondary patency rates for forearm loop grafts are greater than for upper arm
      and brachial-IJ vein grafts, while that for the brachial-IJ vein graft is greater
      than the upper arm straight graft. Utilization of interventional and surgical
      resources required to maintain patency do not significantly differ among the
      three types of upper extremity hemodialysis grafts.

PMID- 10357478
TI  - Endovascular stent placement for angioplasty-induced venous rupture related to
      the treatment of hemodialysis grafts.
AB  - PURPOSE: To assess the use of endovascular stents for treating rupture after
      percutaneous transluminal angioplasty (PTA) in the maintenance of hemodialysis
      grafts. MATERIALS AND METHODS: From February 1, 1994, to August 1, 1997, 683
      hemodialysis-related angioplasty procedures were performed on 277 patients to
      treat thrombosed or poorly functioning polytetrafluoroethylene (PTFE)
      hemodialysis bridge grafts. In each of these procedures, angioplasty of the
      venous anastomosis or the outflow vein was performed. This study is a
      retrospective review to analyze uncovered endovascular stents placed to treat
      ruptures after PTA. RESULTS: Fourteen ruptures were treated with use of an
      uncovered metal stent. Stent placement was technically successful in 11 of 14
      patients, with clinical success in 11 of 14 cases. The primary patencies at 30,
      60, 90, and 120 days were calculated by means of Kaplan-Meier life-table
      analysis; these were 63%, 54%, 46%, and 46%, respectively. The secondary
      patencies at 60, 120, and 180 days were 85%, 75%, and 75%, respectively. No
      complications were attributable to stent placement. The results are comparable to
      those of stents placed for reasons other than rupture, and support the efficacy
      of their use for this indication. CONCLUSION: Endovascular stent placement is a
      safe and effective means of salvaging angioplasty-induced rupture that occurs
      during the treatment of hemodialysis grafts.

PMID- 10357479
TI  - Initial performance of Tesio hemodialysis catheters.
AB  - PURPOSE: This retrospective study was performed to investigate the authors'
      clinical observations that suggest that Tesio hemodialysis catheters may
      initially have suboptimal blood flow rates, which improve spontaneously after
      several hemodialysis treatment sessions. MATERIALS AND METHODS: Sixty Tesio twin
      hemodialysis catheters were placed in 49 patients during a 2-year period. Thirty
      twin catheters were placed by radiologists, and 30 were placed by surgeons. The
      catheter blood flow rates and catheter line pressures, which were recorded during
      each of the first five hemodialysis treatment sessions, were reviewed and
      analyzed to determine the performance of each catheter during the first five
      hemodialysis treatments. In addition, the authors compared the site of catheter
      placement and responsible service (surgery or radiology) using this catheter
      performance data. RESULTS: Twenty-six catheters (43%) provided adequate blood
      flow (250 mL/min) throughout the first five hemodialysis sessions. Twenty-six
      catheters (43%) had inadequate or variable blood flow rates, some of which
      improved without intervention. Eight catheters (13%) required an intervention
      before the first five hemodialysis sessions had been completed. Right-sided
      catheters performed better than left-sided catheters. There was no difference in
      performance between catheters placed by surgeons and those placed by
      radiologists. CONCLUSION: This investigation supports the authors' suspicion that
      some Tesio catheters may have inadequate initial performance but the blood flows
      can improve, without intervention, during the first five hemodialysis sessions/2
      weeks of use.

PMID- 10357480
TI  - Impact of screening MR angiography on referrals for percutaneous intervention in
      renovascular disease.
AB  - PURPOSE: Concern about contrast- and catheter-induced complications inhibits
      liberal use of catheter angiography to screen for renal artery stenosis. The
      authors evaluated the impact on interventional practice growth of offering
      magnetic resonance angiography (MRA) as an alternative screening test for
      renovascular disease. MATERIALS AND METHODS: A retrospective analysis of 339
      patients with renovascular disease identified with MRA from January 1, 1993
      through December 31, 1997, and the subsequent utilization of follow-up catheter
      angiography and/or intervention was performed. The number of patients treated per
      year with percutaneous techniques for renovascular disease was recorded, and was
      correlated with screening MRA. The impact of screening MRA on percutaneous
      management of renovascular disease was evaluated through comparisons of the
      number of percutaneous procedures performed among the individual years during the
      5-year period, and with the number of procedures performed during the 5-year
      period (1988-1992) immediately preceding 1993, prior to the use of screening MRA.
      RESULTS: The number of annual screening MRA examinations increased six-fold
      during the 5-year period, from 17 per year initially to approximately 100 per
      year for each of the last 3 years. One hundred thirty-five (40%) of screening MRA
      examinations were positive for renal artery stenosis or occlusion, and 111 (33%)
      patients had anatomy potentially suitable for percutaneous intervention. Fifty
      two patients with positive screening MR angiograms underwent arteriography: 34
      underwent renal angioplasty or stent placement, seven had surgery, seven with
      stenosis determined with MRA had occlusion on catheter angiography, and four had
      false-positive results of MRA (<50% stenosis). Three additional patients with
      negative screening MR angiograms were also referred for arteriography, which
      confirmed the MRA findings. The percentage of positive catheter angiograms was
      50% greater among patients with a screening MRA, and the number of renal artery
      angioplasties performed annually doubled. Moreover, comparison with the 5-year
      period from 1988 to 1992 (immediately prior to the use of MRA as a screening
      tool), demonstrates that the average number of renal artery percutaneous
      procedures performed per year increased nearly 350% from an average of three per
      year to 15 per year. These findings are entirely attributable to referrals from
      screening MRA. CONCLUSIONS: Marketing of renal artery MRA as a safe, noninvasive
      outpatient screening technique can lead to improved utilization of catheter
      angiography in evaluation of renovascular disease, and can secondarily increase
      the volume of renal artery angioplasty and stent placement procedures for
      treatment of renovascular disease.

PMID- 10357481
TI  - Hyperhomocysteinemia presenting as chronic inferior vena caval thrombosis in an
      adolescent.

PMID- 10357482
TI  - Transjugular intrahepatic portosystemic shunt in patients who have undergone
      liver transplantation.
AB  - PURPOSE: Transjugular intrahepatic portosystemic shunt (TIPS) placement is an
      accepted treatment for refractory variceal bleeding and/or ascites in end-stage
      liver disease and is an effective bridge to liver transplantation. The authors
      present their experience with TIPS in patients with a liver transplant, who
      subsequently developed portal hypertension. MATERIALS AND METHODS: Thirteen TIPS
      were placed in 12 adult patients from 6 months to 13 years after liver
      transplantation for variceal bleeding that failed endoscopic treatment (n = 6)
      and intractable ascites (n = 6). All patients were followed to either time of
      retransplantation or death. RESULTS: No technical difficulties were encountered
      in TIPS placement in any of the patients. Four of six patients treated for
      bleeding stopped bleeding and did not experience re-bleeding, two had functional
      TIPS at 3 and 36 months and two underwent retransplantation at 3 and 7 months.
      Two patients had recurrent bleeding within 1 week and required reintervention. In
      the ascites group, one is 32 months since TIPS placement with control of his
      ascites, two patients underwent retransplantation at 2 and 6 weeks with interval
      improvement in ascites. Two patients died within a week of TIPS of fulminant
      hepatic failure. The last patient died 1 month after TIPS subsequent to a
      splenectomy. CONCLUSION: In conclusion, the placement of a TIPS in a transplanted
      liver, in general, requires no special technical considerations compared to
      placement in native livers. Although this series is small, the authors believe
      that TIPS should be considered a treatment option in liver transplant recipients
      who present with refractory variceal bleeding. TIPS may have a role in the
      management of intractable ascites.

PMID- 10357483
TI  - Transjugular intrahepatic portosystemic shunt after complete obstruction of
      portal vein.

PMID- 10357484
TI  - Brachial plexus neuropathy: a rare complication of patient positioning during
      interventional radiologic procedures.

PMID- 10357485
TI  - Mechanical thromboembolectomy in acute embolic peripheral arterial occlusions
      with use of the AngioJet Rapid Thrombectomy System.

PMID- 10357486
TI  - Transcatheter embolization of internal iliac artery aneurysms.

PMID- 10357487
TI  - Relationship between blood flow, thrombus, and neointima in stents.
AB  - PURPOSE: To establish a relationship between flow, acute thrombus formation, and
      late intimal hyperplasia in arterial stents. MATERIALS AND METHODS: To compare
      short-term stent patency in the canine femoral artery with normal flow to that in
      the opposite femoral artery with restricted flow, 24 dogs were subdivided in four
      groups: groups 1 (no intravenous heparin) and 2 (intravenous heparin) had
      unilateral flow restriction by surgically created stenosis, downstream of a
      Palmaz stent. Group 3 (no intravenous heparin) and 4 (intravenous heparin) had
      sham surgical exposure of the corresponding arterial segment, without flow
      restriction. Thrombocyte activity over the stent segment was evaluated for 3
      hours after stent placement with nuclear scanning, after administration of indium
      111-labeled platelets. To evaluate long-term stent patency in relationship to
      arterial flow, 14 additional dogs were subjected to long-term observation.
      Matched, symmetrically implanted femoral stents with normal and restricted flow,
      were explanted at 1, 12, and 24 weeks for histologic analysis and comparative
      measurement of neointimal thickness. Angiographic studies were performed before
      and after nuclear scanning in the short-term study group and before explant in
      the long-term animal group. RESULTS: In the short-term, groups 2 and 4 showed
      neither increased platelet uptake nor angiographically demonstrable thrombus.
      Group 1 had increased platelet uptake and occlusive or subocclusive angiographic
      thrombus. Group 3 had increased platelet uptake and angiographic thrombus in one
      instance. In the long-term, stents with flow restriction had significantly
      greater neointimal formation in comparison with unrestricted stents. Histologic
      studies suggested that the stent neointima resulted from progressive replacement
      of stent thrombus. CONCLUSION: Regardless of flow condition, intravenous
      heparinization is necessary to prevent thrombus formation in the stent lumen.
      Within the experimental parameters of this study, low flow and absent
      heparinization consistently lead to stent thrombosis. Stent implantation under
      low flow is associated with increased neointima formation. It is not known
      whether this is preventable by antithrombotic medication.

PMID- 10357488
TI  - Polytetrafluoroethylene-encapsulated stent-grafts: use in experimental abdominal
      aortic aneurysm.
AB  - PURPOSE: To evaluate expanded polytetrafluoroethylene (ePTFE) encapsulated stents
      for the treatment of aortic aneurysms with emphasis on the blood and tissue
      material interactions. MATERIALS AND METHODS: Experimental aortic aneurysms were
      created in dogs by enlarging the aortic lumen with an abdominal fascial patch.
      Twenty animals underwent endoluminal repair after allowing the surgically created
      aneurysm to heal for 2 months prior to transluminal aneurysmal exclusion. The
      device used consisted of an 8-cm-long ePTFE encapsulated stent graft. The animals
      were killed in groups at 1 week and at 1, 2.25, 6, and 12 months. Specimens were
      processed for histologic and luminal surface studies. RESULTS: Before the animals
      were killed, aortography demonstrated two thrombosed aortae in the 6-month group
      and two endoleaks in the 12-month group. Endothelialized neointima extended into
      the proximal and distal portions of the prosthetic lumen, with minimal cell
      coverage in the center of the graft. The overall percent surface area covered by
      endothelialized neointima was 22% +/- 6% at 6 months and 18% +/- 10% by 1 year (P
      = .75). Histologic examination demonstrated minimal tissue penetration into the
      ePTFE. CONCLUSION: Transluminal exclusion of abdominal aortic aneurysms by
      encapsulated stent-graft is easily accomplished. With this device, tissue
      coverage and penetration of the stent graft is limited and does not tend to
      increase with time.

PMID- 10357489
TI  - Interventional radiology and the use of metal stents in nonvascular clinical
      practice: a systematic overview.
AB  - PURPOSE: The intent of this systematic overview was to describe the clinical role
      of metal stents in nonvascular health care interventions and the level of
      evidence supporting their use. MATERIALS AND METHODS: Structured searches of
      Medline were conducted and limited to original peer-reviewed articles published
      in English. RESULTS: Clinical practice involving metal stents was reported in
      more than 109 clinical series involving 4,753 patients. Stents were placed mainly
      for palliation of malignant biliary, esophageal, and airway obstruction in
      patients who were untreatable or had surgically unresectable lesions. Assessment
      of these interventions has so far centered on safety and technical success.
      Efficacy, quality of life, and costing factors were not routinely reported.
      Randomized trial evidence was available but limited; six randomized trials
      involving metal stents have been reported. Three trials involved biliary
      malignant obstruction, and all three reported metal stent (132 patients)
      palliation to be superior to plastic stent palliation (136 patients) based on
      longer patency and lower reintervention costs. Safety and complication
      differences between stents, however, were inconsistent across trials. In three
      trials involving esophageal malignant obstruction, metal stent (82 patients)
      palliation was reported to be superior to plastic stent (41 patients), based on
      lower complication and reintervention rates, and superior to laser therapy (18
      patients), based on better dysphagia relief. CONCLUSION: Use of metal stents has
      been reported for obstructed ducts and passageways of most body systems. There
      is, however, limited controlled trial evidence confirming the advantages of their
      use over plastic stents or other forms of treatment.

PMID- 10357490
TI  - Transcervical metallic stents for drainage of uterine collections.

PMID- 10357491
TI  - Carbon dioxide digital subtraction angiography for renal artery stent placement.
AB  - PURPOSE: To determine the efficacy of renal artery stent placement with use of
      carbon dioxide as the primary contrast agent. MATERIALS AND METHODS: Seventeen
      hypertensive patients with renal ostial stenosis were evaluated and underwent
      stent placement with use of CO2 digital subtraction angiography (DSA). Besides
      hypertension, 11 patients had decreased renal function, three had iodinated
      contrast material allergy, one patient had both, and two had neither.
      Supplemental iodinated contrast material (25 mL or less) was used in five
      patients. Preprocedure and postprocedure serum creatinine levels were obtained to
      evaluate the effect of CO2 on renal function. Arteriography was used to evaluate
      stent positioning. RESULTS: Twenty-three Palmaz stents were placed in 17
      patients. Six placements were bilateral, with a total of nine right and 14 left.
      No additional stents were required to correct malposition. One patient had a
      mildly significant, yet transient, rise in the postprocedure creatinine level.
      This patient received 10 mL of iodinated contrast material in addition to CO2.
      There were no allergic reactions. CONCLUSION: The utilization of CO2 DSA
      facilitates the accurate placement of renal artery stents by eliminating the
      concern for contrast material-associated nephropathy and allergy. These
      attributes, coupled with the benefit of low viscosity, permit unrestricted
      imaging, guidance, and precise positioning not afforded by iodinated contrast
      material.

PMID- 10357492
TI  - Long-term follow-up arterial chemoembolization combined with transportal ethanol
      injection used to treat hepatocellular carcinoma.
AB  - PURPOSE: This study was undertaken to evaluate the long-term efficacy of
      transcatheter hepatic arterial chemoembolization (TACE) combined with transportal
      ethanol injection (TPEI) in patients with hepatocellular carcinoma (HCC).
      MATERIALS AND METHODS: Twenty-six patients with unresectable HCC underwent TPEI 2
      6 weeks after TACE. The size of the main tumor ranged from 2.0 to 9.0 cm (mean,
      4.5 cm). Ethanol (10-65 mL) was injected via a percutaneous transhepatic approach
      into the portal vein, perfusing the segment to be treated. TACE was repeated
      after TPEI in 18 patients. RESULTS: The combined therapy was technically
      successfully in all 26 cases; however, irreversible hepatic failure developed in
      two (8%) patients. Recurrent disease occurred either from the treated lesion
      (four patients) or apart from the treated liver segment (five patients) in nine
      of 21 patients (43%) followed up for a mean of 34 months. The survival rates were
      87%, 72%, 72%, 63%, 51, and 51% at 1, 2, 3, 4, 5, and 6 years, respectively.
      Resected and autopsied specimens showed complete necrosis in seven of nine main
      lesions and severe parenchymal damage in the treated liver segment. CONCLUSION:
      In selected patients, combined treatment with TACE and TPEI is safe and
      effective, decreasing recurrence rate in the treated segment, and resulting in a
      51% 6-year survival.

PMID- 10357493
TI  - Embolization of pulmonary pseudoaneurysms secondary to metastatic synovial
      sarcoma of the right atrium.

PMID- 10357494
TI  - Special exhibit for the SCVIR Annual Meeting Film Panel Session: diagnosis and
      discussion of cases 5-8. Society of Cardiovascular & Interventional Radiology.
      Case 5. Traumatic hepatic arterial injury with probable avulsion of the left
      hepatic artery origin. Hematoma within the porta hepatis.

PMID- 10357495
TI  - Data and safety monitoring in the Concorde and Alpha trials.
AB  - Concorde was a randomized trial to compare immediate and deferred zidovudine
      (AZT) treatment for persons with asymptomatic HIV infection. Alpha was a
      randomized trial to compare the efficacy of two doses of didanosine (ddI), in
      persons with symptomatic HIV disease who were intolerant of zidovudine. The two
      trials overlapped in time, and a single Data and Safety Monitoring Committee
      (DSMC) monitored accumulating data from both trials. This paper describes the
      deliberations of the DSMC and its recommendations to the parent steering
      committee during the course of each trial. In the discussion on Concorde, I draw
      attention to the problems of interpreting early survival data and trends in
      surrogate markers. With Alpha, interest focusses on the conflicting
      considerations that arose in discussions about possible termination at an interim
      stage.

PMID- 10357496
TI  - Data and safety monitoring in the Delta trial.
AB  - Delta was a randomized trial designed to test whether combinations of zidovudine
      (AZT) with didanosine (ddI) or zalcitabine (ddC) were more effective than AZT
      alone for HIV-infected persons. A Data and Safety Monitoring Committee (DSMC)
      monitored accumulating data. This paper describes the deliberations and
      recommendations of the DSMC, as clear-cut differences in efficacy gradually
      emerged during the later stages of the trial.

PMID- 10357497
TI  - Sample size and design considerations for phase II clinical trials with
      correlated observations.
AB  - Several methods are available for the design of phase II clinical trials with
      binary endpoints. A primary assumption for most methods is that observations on
      the endpoint of interest are uncorrelated; however, this assumption is violated
      if an individual patient provides more than one observation on the endpoint of
      interest. In such cases, one solution is to use a summary measure for each
      patient; an alternative solution is to perform an observation-specific analysis
      using a technique that properly accounts for the correlation. In this paper, we
      investigate the effect that ignoring correlated observations can have on the
      design properties of the typical phase II clinical trial. In cases in which an
      observation-specific analysis is desirable, we propose a simple method that
      adjusts a standard one- or two-stage phase II design to account for loss of
      information due to correlated observations. Simulations demonstrate that the
      method ensures that type I and type II error rate design requirements are met
      even in the presence of strong correlation. We develop the method in the context
      of phase II oncology trials, but the method applies readily to other clinical
      areas in which multiple responses per patient are of interest.

PMID- 10357498
TI  - Relationship between event rates and treatment effects in clinical site
      differences within multicenter trials: an example from primary Pneumocystis
      carinii prophylaxis.
AB  - The results of multicenter clinical trials may differ across participating
      clinical sites. We present a diagnostic approach for evaluating this diversity
      that emphasizes the relationship between the observed event rates and treatment
      effects. We use as an example a trial of sequential strategies of Pneumocystis
      prophylaxis in human immunodeficiency virus infection with 842 patients randomly
      allocated to start prophylaxis with trimethoprim/sulfamethoxazole, dapsone, or
      pentamidine. Prophylaxis failure rates varied significantly across the 30
      clinical sites (0-30.3%, p = 0.002 by Fisher's exact test) with prominent
      variability in the pentamidine arm (0-63.6%). Starting with oral regimens was
      better than starting with pentamidine in sites with high rates of events, whereas
      the three strategies had more similar efficacy in other sites. Sites enrolling
      fewer patients had lower event rates and had more patients who withdrew
      prematurely or were lost to follow-up. In a hierarchical regression model
      adjusting for random measurement error in the observed event rates, starting with
      trimethoprim/sulfamethoxazole was predicted to be increasingly better than
      starting with aerosolized pentamidine as the risk of prophylaxis failure
      increased (p = 0.01), reducing the risk of failure by 47% when the failure rate
      of pentamidine was 30%, whereas the two regimens were predicted to be equivalent
      when the failure rate was 17%. Differences in event rates could reflect a
      combination of heterogeneity in diagnosis, administration of treatments, and
      disease risk in patients across sites. The evaluation of clinical site
      differences with a systematic approach focusing on event rates may give further
      insight in the interpretation of the results of multicenter trials beyond an
      average treatment effect.

PMID- 10357499
TI  - Survival versus years of healthy life: which is more powerful as a study outcome?
AB  - Studies of interventions that are intended to improve patients' health are often
      evaluated with survival as the primary outcome, even when a measure adjusted for
      quality of survival, such as years of healthy life (YHL), would seem more
      appropriate. The purpose of this article is to determine whether studies based on
      survival are more or less powerful than studies based on YHL in clinical trials
      where either measure might be appropriate. We used data from the Cardiovascular
      Health Study (CHS) to estimate the sample size that would be needed in studies of
      156 different health conditions, for the two outcome measures. The median sample
      size for a 5-year study was 687 if survival was the endpoint and 484 for YHL. YHL
      usually required lower sample sizes than survival, although survival was more
      powerful for some health conditions. We also found that lengthy studies, and
      studies with many follow-up measures per person, did not have appreciably higher
      power than less intensive studies. We conclude that clinical investigations in
      which the goal is to improve health may often be performed more efficiently with
      YHL rather than survival as the primary outcome measure. Such studies can be
      short in duration, with relatively few measures per person of health status.

PMID- 10357500
TI  - A randomized design for repeated binary outcomes used to evaluate continued
      effectiveness of a breast cancer control intervention strategy.
AB  - The literature has not discussed in detail design and evaluation strategies for
      the assessment of continued effectiveness of intervention strategies. In this
      article we present an approach to evaluating continued effectiveness with two
      repeated binary outcomes that are related to the use of preventive services. We
      present a two-stage design with independent randomization procedures for each of
      two successive controlled trials and discuss the implications of the
      randomization plan for the statistical evaluation. Intervention effectiveness for
      each year is determined by an adjusted odds ratio that compares the odds of
      procedure use for those who received the intervention to those who did not.
      Changes in the two adjusted odds ratios between successive years are assessed
      within the context of a regressive logistic model. We demonstrate these methods
      by applying them to the Metropolitan Detroit Project to Reduce Avoidable
      Mortality from Breast Cancer. In this project, computer-generated physician
      mammography reminders placed prominently in medical records were used to promote
      mammography referrals among women visiting primary care clinics during a 2-year
      intervention period. An assessment of the change in intervention effectiveness as
      well as an adjusted estimate of the overall intervention effectiveness for the 2
      years were obtained from a multivariate regressive logistic model. The advantage
      of this approach was its potential for reducing bias and producing a balanced
      comparison between intervention groups during the second year of intervention.
      This issue was important because previous work indicated that having had a
      mammogram had a significant impact on subsequent mammography use. An important
      component in the implementation of this design was an information management
      system that facilitated doing two randomization procedures efficiently. As
      information and computer technology advance, and as more sophisticated
      information systems are used for data management, designs such as these become
      reasonable alternatives to consider.

PMID- 10357502
TI  - Teaching coping skills enhances quality of life more than peer support: results
      of a randomized trial with multiple sclerosis patients.
AB  - This 2-year randomized trial of multiple sclerosis patients compared a coping
      skills group (n = 64) with peer telephone support (n = 68). Growth curve analyses
      that adjusted for neurological deterioration and gender revealed that the coping
      skills intervention yielded gains in psychosocial role performance, coping
      behavior, and numerous aspects of well-being. In contrast, the peer support
      intervention increased external health locus of control but did not influence
      psychosocial role performance or well-being. Subgroup analyses revealed that
      patients with affective problems were more likely to benefit from the peer
      support intervention than the coping skills group in terms of reported
      depression, anxiety, use of avoidant coping, and some aspects of well-being. The
      coping group is discussed as a vehicle for facilitating response shift, helping
      patients to change their internal referents, their conceptualization of quality
      of life, and their priorities.

PMID- 10357501
TI  - Prophylactic coronary artery revascularization for elective vascular surgery:
      study design. Veterans Affairs Cooperative Study Group on Coronary Artery
      Revascularization Prophylaxis for Elective Vascular Surgery.
AB  - This article describes the design of an ongoing randomized trial intended to test
      whether patients who require elective vascular surgery would benefit from
      preoperative coronary artery revascularization prior to the vascular procedure.
      The primary objective is to determine whether coronary artery revascularization
      reduces long-term mortality (mean 3.5 years) in patients undergoing vascular
      surgery. The study design calls for 620 patients to be randomized and followed
      for a mean of 3.5 years following vascular surgery. Secondary endpoints include
      measures of quality of life and cost-effectiveness. Patients with coronary artery
      disease in need of an elective vascular operation are considered candidates for
      the study. Anatomic exclusion criteria include ejection fraction <20%, severe
      aortic stenosis (valve area <1.0 cm2), left main stenosis > or =50%,
      nonobstructive coronary artery disease (stenosis <70%), and coronary arteries
      that are not amenable to revascularization. Prior to the vascular surgery, the
      trial randomizes eligible patients to coronary artery revascularization (either
      bypass surgery or angioplasty) versus medical therapy. The trial stratifies the
      randomization by hospital and type of vascular surgery (intraabdominal versus
      infrainguinal) because of differences in long-term prognosis in those patients. A
      1-year feasibility trial involving five Veterans Affairs (VA) medical centers of
      variable vascular surgical loads has been completed. The results showed that over
      90% of expected patients could be randomized. As a result, a larger VA
      Cooperative Study involving 18 centers will begin recruitment of patients. The
      findings should help determine the best strategy for managing patients with
      coronary artery disease in need of elective vascular surgery.

PMID- 10357503
TI  - Cardiovascular reactivity and central adiposity in older African Americans.
AB  - This study examined central adiposity, as measured by waist circumference (WC),
      in relation to mental-stress induced systolic (SBP) and diastolic blood pressure
      (DBP) and heart rate (HR) responses, body composition, the metabolic syndrome,
      and health practices in 22 older, African American men and women (ages 52-79
      years). The high WC (> 100 cm) group showed significantly greater SBP, DBP, and
      HR reactivity, greater fasting insulin levels, lower high density lipoprotein
      cholesterol levels, greater fat mass in both truncal and peripheral regions, and
      greater body mass index as compared to the low WC (< 100 cm) group. Groups were
      comparable with respect to fat-free mass, peak oxygen consumption (VO2), leisure
      time activity, dietary intake, resting blood pressure, and other metabolic
      variables. The findings support a clustering of metabolic and mental stress risk
      factors that may predispose older African Americans to increased cardiovascular
      and metabolic disease.

PMID- 10357504
TI  - Potassium supplementation induces beneficial cardiovascular changes during rest
      and stress in salt sensitive individuals.
AB  - The typical American diet includes high salt and low potassium, a pattern linked
      to elevated blood pressure (BP) in cross-cultural studies. This study compared
      resting and stress cardiovascular responses on a high salt, low potassium diet to
      those observed during 2 interventions: salt restriction and potassium
      supplementation. Forty-seven percent of the primarily normotensive sample (n = 67
      adults) were salt sensitive, showing a decrease in mean arterial pressure > or =
      5 mmHg during low salt and equivalent reductions during high potassium. The
      equivalent benefits of the interventions were maintained, but not enhanced,
      during exposure to behavioral stress (i.e., no effect on reactivity). Salt
      resistants (SRs) exhibited no change in resting or stress BP across the diets.
      High salt increased cardiac index in both groups, whereas vascular tone was
      decreased only in the SR group. High potassium produced hemodynamic benefits
      similar to low salt, even with continued high salt intake.

PMID- 10357505
TI  - Lipid reactivity to stress: I. Comparison of chronic and acute stress responses
      in middle-aged airline pilots.
AB  - Lipids increase during psychological stress, but no studies have compared the
      effects of acute and chronic stressors on lipid responsivity in the same
      individuals. One hundred middle-aged men (n = 92) and women (n = 8) were examined
      during high chronic occupational stress, low chronic stress, and acute laboratory
      stressors. In addition to measures of perceived stress and affect, an extensive
      battery of lipid and lipoprotein measures was undertaken at each time point. Most
      lipid parameters were significantly increased during the chronic and acute
      stressors, although the responses to the different stressors were not
      consistently associated. For example, significant correlations among the chronic
      and acute stress responses were apparent for the apoproteins, but not for total,
      low density lipoprotein, or high density lipoprotein cholesterol. The factors and
      processes regulating these variables during stress may be different during acute
      and chronic stressors.

PMID- 10357506
TI  - Lipid reactivity to stress: II. Biological and behavioral influences.
AB  - This study examined behavioral and physiological influences on lipid
      concentrations during acute and chronic stressors. One hundred men (n = 92) and
      women (n = 8) were tested during a chronic stressor and during 2 acute stressors.
      During chronic stress, diet, physical activity, exercise, and sleep were
      examined. During the acute stressors, catecholamines, cortisol, plasma volume,
      and cardiovascular responses were examined. None of the behavioral influences
      could explain the lipid response to chronic stress. Responses of the atherogenic
      lipids to acute stressors were not solely reflecting hemoconcentration of the
      plasma but were moderately correlated with cardiovascular, epinephrine, and
      cortisol reactivity. Diastolic blood pressure reactors to the acute stressors had
      larger lipid responses to the chronic stressor than did nonreactors. Elevations
      in blood lipids during stress are not artifacts and may be clinically
      significant.

PMID- 10357507
TI  - Psychosocial predictors of natural killer cell mobilization during marital
      conflict.
AB  - This study examined how specific emotions relate to autonomic nervous and immune
      system parameters and whether cynical hostility moderates this relationship.
      Forty-one married couples participated in a 15-min discussion about a marital
      problem. Observers recorded spouses' emotional expressions during the discussion,
      and cardiovascular, neuroendocrine, and immunologic parameters were assessed
      throughout the laboratory session. Among men high in cynical hostility, anger
      displayed during the conflict was associated with greater elevations in systolic
      and diastolic blood pressure, cortisol, and increases in natural killer cell
      numbers and cytotoxicity. Among men low in cynical hostility, anger was
      associated with smaller increases in heart rate and natural killer cell
      cytotoxicity. These findings suggest that models describing the impact of stress
      on physiology should be refined to reflect the joint contribution of situational
      and dispositional variables.

PMID- 10357508
TI  - Understanding the unprotected sexual behaviors of gay, lesbian, and bisexual
      youths: an empirical test of the cognitive-environmental model.
AB  - The cognitive-environmental model (CEM; M. Fishbein et al., 1991) was used to
      understand the unprotected sexual behaviors of 156 gay, lesbian, and bisexual
      youths. Unprotected anal sex among the males was associated directly with poor
      protection skills (e.g., incorrect use of barrier methods, such as condoms), poor
      intentions to use barrier methods, and poor norms by sexual partners concerning
      barrier methods. Furthermore, the association between low self-efficacy and
      increasing unprotected anal sex was attributed to poor intentions. Direct
      associations of unprotected oral sex with poor intentions and poor partner norms
      also emerged, as did an indirect relation between unprotected oral sex and low
      self-efficacy via poor intentions. These last 3 findings were replicated when
      examining unprotected oral or vaginal-digital sex among the females. Relations
      among the CEM factors supported some CEM-theoretical propositions.

PMID- 10357509
TI  - Self-efficacy and disclosure of HIV-positive serostatus to sex partners.
AB  - HIV-positive persons face significant challenges to disclosing their HIV
      serostatus, and failure to disclose can place their sex partners at risk. The
      current study examined HIV serostatus disclosure in 266 sexually active HIV
      positive persons recruited from the community. Results showed that 41% had not
      disclosed their HIV serostatus to sex partners. Men who had not disclosed to
      partners indicated lower rates of condom use during anal intercourse and scored
      significantly lower on a measure of self-efficacy for condom use compared to
      individuals who had disclosed. Emotional distress was also greatest among persons
      who had not recently disclosed. Having not disclosed to sex partners was closely
      associated with lower self-efficacy for disclosing, with women who had not
      disclosed reporting the lowest disclosure self-efficacy. As people living with
      HIV-AIDS are encouraged to disclose their HIV status, interventions are needed to
      facilitate disclosure decision making.

PMID- 10357510
TI  - Manipulating self-efficacy in the exercise environment in women: influences on
      affective responses.
AB  - Self-efficacy was experimentally manipulated in an exercise context, and its
      effect on affective responses was examined. College women (N = 46) were randomly
      assigned to a high- or low-efficacy condition, and efficacy expectations were
      manipulated by means of bogus feedback and graphs depicting contrived normative
      data. The manipulation successfully influenced affective responses, with
      participants in the high-efficacy group reporting more positive and less negative
      affect than did the low-efficacy group. Efficacy was significantly related to
      feeling-state responses during and after activity but only in the high-efficacy
      condition. The results suggest that self-efficacy can be manipulated and that
      these changes are related to the affective experience associated with exercise.
      Such findings may have important implications for the roles played by self
      efficacy and affect in exercise adherence.

PMID- 10357511
TI  - Role of relationship context in influencing college students' responsiveness to
      HIV prevention videos.
AB  - This research examined the effectiveness of different HIV prevention videos for
      students as a function of whether they were in a dating relationship. Two hundred
      two college students completed pretest measures and were randomly assigned to
      watch one of three 42-min videos (communication skills, technical skills,
      combined skills). Posttest and 3-month follow-up data indicated that receiving
      the technical skills video was associated with greater self-efficacy for condom
      use across several different dimensions. However, students who received the
      combined skills video and were not currently in a dating relationship had the
      greatest proportion of protected acts of intercourse. These findings suggest that
      video-based interventions can be an effective way of decreasing risky sexual
      behavior, and that HIV prevention messages that focus on both technical and
      communication skills are the most successful in leading to behavioral change.

PMID- 10357512
TI  - Perception of cognitive function in older adults following coronary artery bypass
      surgery.
AB  - This study examined the effects of coronary artery bypass grafting (CABG) on
      objective and subjective measures of neurocognitive functioning. Participants
      were 170 older patients (127 men and 43 women; mean age = 61 years) undergoing
      CABG. Measures of neurocognitive function, depression, anxiety, and perceived
      cognitive abilities were administered immediately prior to and 6 weeks following
      surgery. Although objective measures of impaired cognitive performance following
      CABG were not related to perceived cognitive difficulties, the presence of
      anxiety and depression was related to the perception of cognitive functioning.
      Patients who reported high levels of anxiety and depression 6 weeks after surgery
      perceived themselves as having poorer cognitive function. Interventions designed
      to reduce emotional distress could improve patient's perceived cognitive
      abilities following CABG.

PMID- 10357513
TI  - Childhood anxiety: integrating developmental psychopathology and affective
      neuroscience.
AB  - This article reviews progress in research on childhood phobia, generalized
      anxiety, and separation anxiety disorders from the perspectives of developmental
      psychopathology and affective neuroscience. These perspectives represent two
      organizing theoretical schools in the realms of clinical and basic science
      research. Studies in developmental psychopathology suggest the need to identify
      specific subgroups of children with one of these anxiety disorders who are
      particularly at risk for anxiety disorders in adulthood. Studies in affective
      neuroscience suggest potential neurobiological avenues for identifying such
      children who face a particularly high risk for chronic anxiety disorders.

PMID- 10357514
TI  - Persistently increased density of serotonin transporters in the frontal cortex of
      rats treated with fluoxetine during early juvenile life.
AB  - This experimental animal study was performed in order to assess possible long
      term effects of the administration of the selective serotonin reuptake inhibitor
      fluoxetine (Prozac) during early periods of juvenile life on the developing
      central serotonergic and noradrenergic systems. Fluoxetine was administered via
      the drinking water (5 mg/kg/day) for a period of two weeks to very young (day 25)
      and somewhat older (day 50) rats. The effect of this treatment on the density of
      serotonin and noradrenaline transporters was measured by ligand-binding assays in
      various brain regions. The Bmax-values of [3H]-nisoxetine binding were not
      affected by either treatment schedule, but a significant increase of the Bmax
      values of [3H]-paroxetine binding was found in the brains of early fluoxetine
      treated rats. This increase was restricted to the frontal cortex and persisted
      long after the termination of the treatment into adulthood (day 90). The most
      likely explanation of this observation is a stimulatory effect of the fluoxetine
      treatment on the outgrowth of serotonergic projections in the frontal cortex of
      very young rats. This is the first empirical demonstration of long-lasting
      effects of the administration of a selective serotonin reuptake inhibitor during
      juvenile life on the maturation of the central serotonergic system.

PMID- 10357515
TI  - No difference between platelet serotonin--5-HT(2A) receptors from children with
      and without ADHD.
AB  - To further investigate the possible function of the serotonergic system in the
      pathophysiology of attention deficit hyperactivity disorder (ADHD), platelet
      serotonin 5-HT2A receptors were characterized for 19 ADHD children and 17 age
      matched control subjects. Subjects were evaluated using the Diagnostic Interview
      for Children and Adolescents (DICA-R-C)-DSM IV and the Children's Depression
      Inventory. An aggressive subgroup was also determined by the presence of two or
      more positive aggressive symptoms on either subjects' or parents' reports.
      Platelets were isolated from venous blood and 5-HT2A receptor number, and
      affinity was determined using 125I-LSD binding. There was no difference in
      platelet 5-HT2A receptor binding characteristics between the two groups. The
      results from this pilot study suggest a limited function of 5-HT2A receptors in
      the pathophysiology of ADHD and extend the findings of other previous negative
      studies of the peripheral serotonergic system in ADHD.

PMID- 10357516
TI  - A comparison of the pharmacokinetics and tolerability of the novel antimigraine
      compound zolmitriptan in adolescents and adults.
AB  - This open-label, parallel-group study assessed pharmacokinetics and tolerability
      of zolmitriptan, a 5-HT1B/1D agonist for the acute treatment of migraine, and its
      active metabolite, 183C91, in adolescents compared with adults. Twenty-one
      healthy adolescent and 18 healthy adult volunteers (with and without history of
      migraine) received a single 5-mg dose of zolmitriptan. Mean ages were 14.5 years
      (range 12-17) for adolescents (13 girls, 8 boys) and 39.1 years (range 18-65) for
      adults (12 women, 6 men). The area under the curve (AUC) and highest observed
      plasma concentration (Cmax) of zolmitriptan were similar in both age groups; the
      half-life was 3.01 hours in adolescents versus 3.75 hours in adults. The AUC and
      Cmax of 183C91, however, were 36% and 39% higher in adolescents, respectively;
      the half-life was similar in both age groups. Adverse events were similar in both
      groups in terms of nature, intensity, and frequency. Exposure to zolmitriptan was
      not significantly different in adolescents compared with adults, but a shorter
      half-life in adolescents suggests faster elimination in this age group. Exposure
      to 183C91 was higher in adolescents, suggesting that formation of the metabolite
      is at least one of the elimination routes of zolmitriptan that occurs at a faster
      rate in adolescents.

PMID- 10357517
TI  - Risperidone addition in serotonin reuptake inhibitor-resistant trichotillomania:
      three cases.
AB  - Open-label addition of a low-dose typical (pimozide) neuroleptic was shown to be
      beneficial in some patients with serotonin reuptake inhibitor (SRI)-refractory
      trichotillomania (TTM). Risperidone's potentially more benign acute and long-term
      side effect profile makes it a candidate for investigation in the treatment of
      TTM. We report our experience with the systematic addition of open-label
      risperidone 0.5 to 3 mg/day in three patients with SRI-refractory TTM. All three
      patients had a robust decrease in hair pulling as measured by clinician-rated
      instruments. These results suggest that risperidone addition to ongoing treatment
      with SRIs may be an effective treatment strategy for patients with SRI-refractory
      TTM.

PMID- 10357518
TI  - Nimodipine treatment of an adolescent with ultradian cycling bipolar affective
      illness.
AB  - This is a single case report of an open trial of nimodipine, a dihydropyridine
      type calcium antagonist, in the treatment of a 13-year-old boy with refractory,
      ultradian rapid cycling, bipolar disorder type I. Prior clinical trials with
      calcium channel blockers in adults with ultrarapid cycling affective disorder
      supported an empirical trial of nimodipine for treatment of ultradian rapid
      cycling in this adolescent. Severity of mania and depression were rated before
      and after nimodipine therapy. A marked decrease in rapid, repeated, and
      significant mood changes was clinically observed and measured by standardized
      scales after 9 days of nimodipine 180 mg daily. No adverse effects were noticed.
      Remission persisted with continued treatment at 36-month follow-up. Medication
      response was partially attributed to adjunctive therapy with levothyroxine.
      Implications of treatment benefit are discussed in the context of novel
      pharmacotherapies for refractory bipolar disorder. These findings are preliminary
      and do not provide sufficient basis to recommend nimodipine as the treatment of
      choice in adolescents with ultradian cycling bipolar disorder, but suggest that
      controlled studies may be indicated.

PMID- 10357519
TI  - Electroconvulsive treatment of a bipolar adolescent postcraniotomy for brain stem
      astrocytoma.
AB  - This is the first reported use of electroconvulsive treatment (ECT) in an
      adolescent with bipolar mania who had been treated with craniectomy for an
      intracranial neoplasm. The reported case is of a 16-year-old girl with a history
      of brain stem glioma (pontomesencephalic astrocytoma) diagnosed at 13 years of
      age. She presented in a psychiatric emergency room with suicidal ideation,
      depressed mood, irritability, olfactory hallucinations, early insomnia,
      grandiosity, and guilt. Her symptoms failed to respond to a trial of an
      antidepressant, mood stabilizer alone, and mood stabilizer in conjunction with a
      neuroleptic. The decision to use ECT was based on suicidal ideation, extreme
      disinhibition, and danger to self and others. Significant improvement in mood and
      remission in psychosis were noted after the eighth treatment. Comparison of 2
      week pre-ECT and 3-month post-ECT cognitive testing revealed no change in IQ.
      This report highlights rapid response and the ability to tolerate ECT in an
      adolescent diagnosed with bipolar disorder, who had also been treated with
      radiation and craniotomy.

PMID- 10357520
TI  - Therapeutic modalities in hand surgery.
AB  - Therapeutic modalities are useful adjuncts in the rehabilitation of many patients
      commonly seen by hand surgeons. Therapeutic heat, cold, electrical stimulation,
      and laser and magnetic field treatments are evaluated for their respective
      mechanisms of action, indications, contraindications, and clinical results. The
      majority of therapeutic modalities have been extensively investigated and
      relevant basic science and randomized well-controlled clinical studies addressing
      the efficacy of therapeutic modalities are emphasized.

PMID- 10357521
TI  - Anomalous extensor muscles of the hand: a review.
AB  - Anomalous extensor muscles of the hand are not uncommon. Well-recognized
      anomalies anomalous extensor indicis proprius, extensor digitorum brevis manus,
      extensor medii proprius, and extensor indicis et medii communis are reviewed and
      discussed in detail. Anomalous extensor indicis proprius and extensor digitorum
      brevis manus may occasionally give rise to dorsal wrist pain and the diagnosis is
      often confused especially in the presence of other pathologic findings such as a
      ganglion. An analysis of the embryologic development of the extensor muscle mass
      with phylogenetic comparisons between species of the animal kingdom is presented
      to underscore the clinical relevance of these anomalous extensors.

PMID- 10357522
TI  - The dorsal ligaments of the wrist: anatomy, mechanical properties, and function.
AB  - The purpose of this study was to examine the anatomy and mechanical properties of
      the dorsal radiocarpal (DRC) and dorsal intercarpal (DIC) ligaments of the wrist
      and to better understand the functional design of the dorsal ligaments. The DRC
      ligament was consistently found to originate from the dorsal margin of the distal
      radius and extended ulnar obliquely and distally. Its radial fibers attached to
      the lunate and lunotriquetral interosseous ligament. The DRC ligament then
      inserted onto the dorsal tubercle of the triquetrum. The DIC ligament originated
      from the triquetrum and extended radially and attached onto the lunate, inserted
      into the dorsal groove of the scaphoid, and then extended to the trapezium. The
      DRC and DIC ligaments together, in their lateral V configuration, act effectively
      as a dorsal radioscaphoid ligament that has the ability to vary its length by
      changing the angle between the 2 arms of the V. The DRC-DIC ligaments' lateral V
      configuration allows normal carpal kinematics while maintaining its indirect
      dorsal stabilizing effect on the scaphoid throughout the range of motion of the
      wrist.

PMID- 10357523
TI  - Abductor pollicis longus tendon interposition arthroplasty for carpometacarpal
      osteoarthritis of the thumb.
AB  - Thirty-eight thumbs in 35 patients with painful osteoarthritis of the thumb basal
      joint were treated by trapezium excision and abductor pollicis longus tendon
      interposition arthroplasty. Long-term results were obtained from all patients by
      subjective evaluation and 29 patients were re-examined 1 to 11 years after
      surgery (mean, 6 years). The overall result was excellent or good in 79% of the
      cases and 76% of the patients reported good or excellent pain relief. In 6 cases
      (16%) surgery provided no improvement. The range of shortening of the first ray
      was from 2 to 10 mm (mean, 7 mm). Grip and pinch strengths were measured, but the
      results were variable and consequently not informative. On the basis of our
      results we recommend abductor pollicis longus tendon interposition arthroplasty
      for the treatment of osteoarthritis of the thumb basal joint.

PMID- 10357524
TI  - Long-term results and loosening analysis of de la Caffiniere replacements of the
      trapeziometacarpal joint.
AB  - The results of 77 de la Caffiniere arthroplasties for osteoarthritis of the thumb
      carpometacarpal joint were reviewed. The mean follow-up period was 8.5 years
      (range, 2-16 years). The survival rate at 16 years was 72%. Clinical and
      subjective scores were good in primary implants, reasonable in revisions, and
      poor in salvage procedures. The total loosening rate was 44%. Half of the
      loosening cases led to revision; the other half had good results. Loosening
      occurred significantly more often in men and younger women. The use of this
      prosthesis is only advised for women, preferably those older than 60 years.

PMID- 10357525
TI  - Biomechanical analysis of the trapeziometacarpal joint after surface replacement
      arthroplasty.
AB  - A biomechanical analysis of the trapeziometacarpal joint was performed in 7 fresh
      frozen normal human cadaveric hands to compare the kinematics of the
      trapeziometacarpal joint before and after surface total joint replacement. Using
      a 3-space magnetic Isotrak system (Polhemus, Colchester, VT), which provides a 3
      dimensional analysis of motion of joints as well as translation, we found that
      kinematics and stability of the trapeziometacarpal joint could be duplicated by
      joint surface replacement arthroplasty provided that normal ligament tensions
      were present.

PMID- 10357526
TI  - Contact area of the trapeziometacarpal joint.
AB  - Eighteen cadaver hands were studied to determine the contact area of the
      trapeziometacarpal joint by using silicone rubber casts. Casting material was
      introduced into the trapeziometacarpal joint during several motions of the thumb
      and the contact location was observed. The ratios of the contact area to the
      total joint area were calculated. The contact locations in opposition were the
      radial, volar, and ulnar segments of the trapezium and the dorsal, radial, and
      volar segments of the metacarpal. On average, 53% of the trapezium was in contact
      with 53% of the metacarpal in opposition, while 28% of the trapezium was in
      contact with 28% of the metacarpal in palmar abduction and 25% of the trapezium
      was in contact with 25% of the metacarpal in radial abduction. The contact area
      was the largest in opposition. The trapeziometacarpal joint is stable in
      opposition and facilitates a strong pinch.

PMID- 10357527
TI  - Histopathology of the palmar beak ligament in trapeziometacarpal osteoarthritis.
AB  - Eighteen cadaver hands were studied to investigate the relationship between
      degeneration of the palmar beak ligament and articular disease of the
      trapeziometacarpal joint. Eight of 18 joints had chondromalacia alone; 10
      contained areas of eburnation in the palmar aspect of the joint. Beak ligament
      degeneration correlated closely with the presence of articular degeneration; all
      joints with eburnation demonstrated frank detachment of the ligament from its
      metacarpal insertion site. Histologically, the collagen fibers of the beak
      ligament were disorganized at the metacarpal attachment. The normal insertional
      zone of fibrocartilage was often unrecognizable on the metacarpal side and, in
      more degenerative specimens, an intervening synovial recess appeared at the
      palmar beak of the metacarpal. The trapezial insertion of the beak ligament
      showed no degenerative change. Increasingly severe cartilage disease was
      associated with progressive and selective degeneration of the collagen framework
      of the beak ligament at its insertion onto the thumb metacarpal. These localized
      histopathologic findings further support the existence of an anatomically
      distinct intra-articular beak ligament essential to the normal function of the
      trapeziometacarpal joint and suggest an etiologic relationship to osteoarthritic
      disease.

PMID- 10357528
TI  - Palmar oblique ligament reconstruction for carpometacarpal joint dislocation in
      an 11-year-old: a case report.
AB  - Traumatic dislocation of the thumb carpometacarpal joint has been rarely reported
      in children. An 11-year-old boy presented with a traumatic dislocation of the
      trapeziometacarpal joint. He was successfully treated surgically with ligament
      reconstruction as previously described.

PMID- 10357529
TI  - Intraosseous ganglia of the scaphoid and lunate bones: report of 15 cases in 13
      patients.
AB  - Thirteen patients with 15 intraosseous carpal ganglia (6 scaphoid and 9 lunate
      cases) are reported. Eleven cases had cortical defects communicating the bone
      cysts either with the joint space or a coexisting soft tissue ganglion. Nine
      cysts were primary or idiopathic; soft tissue ganglia were found in 6 secondary
      cases and anatomic continuity of the intraosseous and extraosseous components
      through cortical defects was present. Treatment consisted of curettage of the
      cyst wall and cancellous bone grafting. Approaching lunate cysts through a small
      opening in the scapholunate interosseous ligament is described. Results were
      analyzed in 12 cases with at least 1 year of follow-up; the average follow-up
      period in these cases was 47 months (range, 12-119 months). Results were very
      good in all but 1 patient, who suffered a partial lunate collapse, which resulted
      in mild lunocapitate osteoarthritis. No graft reabsorption or recurrence was seen
      in the control radiographs obtained throughout the follow-up period.

PMID- 10357530
TI  - A biomechanical comparison of different wrist external fixators with and without
      K-wire augmentation.
AB  - To compare stability of wrist external fixation, simulated unstable extra
      articular distal radius fractures were created in 7 fresh-frozen cadaveric upper
      extremities and stabilized using 4 different external fixators. Physiologic
      muscle tension across the wrist was simulated by application of 40-N load
      distributed among the wrist tendons. Alternating loads of up to 100 N in flexion
      and extension of the wrist were applied during stability testing and 3
      dimensional kinematics of the proximal and distal fracture fragments were
      determined using attached infrared light-emitting diodes and a 3-dimensional
      motion tracking system. Fracture stability was reassessed for each of the
      constructs after augmentation of the fracture fragments with a single dorsal
      transfixion K-wire. K-wire augmentation demonstrated a significant reduction in
      motion of the distal radial fragment of at least 40% in all 3 rotational planes.
      For flexion/extension, the reduction in motion was from 4.5 degrees to 2.6
      degrees. For radial/ulnar deviation, the range of motion decreased from 3.0
      degrees to 1.5 degrees. Rotational motion declined from an average of 3.2 degrees
      to 1.2 degrees. The addition of the single dorsal transfixion K-wire
      significantly improved stability of each of the 4 fixators in at least 1 of the 3
      planes in which motion was measured. While we compared the most rigid with some
      of the least rigid external fixators, the data do not support an important
      difference in fracture fragment stability among the 4 fixators. The data much
      more strongly support the concept of K-wire augmentation for increasing stability
      of an unstable extra-articular distal radius fracture regardless of the type of
      external fixator that is used.

PMID- 10357531
TI  - Wire-loop fixation of volar displaced osteochondral fractures of the distal
      radius.
AB  - We describe the technique of wire-loop fixation to treat 4 young men with a
      unique variant of Melone's type 4 articular fracture of the volar lunate facet,
      characterized by a displaced rotated articular fragment supported by a limited
      amount of subchondral bone. This is an unusual injury that threatens the
      integrity of both the radiocarpal and distal radioulnar joints. It is the result
      of a compressive force to the wrist and may require trispiral computed tomography
      for delineation. Open reduction and internal fixation is recommended to maintain
      stability and articular congruity. The displaced volar-articular fragment,
      however, may be relatively small; therefore, direct manipulation could lead to
      soft tissue stripping and osteonecrosis. We have found the technique of wire-loop
      fixation to be a simple, reproducible, and effective alternative method of
      internal fixation for these difficult fractures. Malunion, nonunion, loss of
      fixation, tendon rupture, infection, arthrosis, or pain caused by hardware has
      not occurred. Use of this technique is not recommended in patients with
      osteoporotic bone.

PMID- 10357532
TI  - Attritional flexor tendon ruptures due to distal radius fracture and associated
      with volar displacement of the distal ulna: a case report.
AB  - Flexor tendon rupture following distal radius fractures are rare. In this report,
      a volarly displaced distal ulna that perforated the volar wrist capsule caused
      delayed flexor tendon ruptures 25 years after a distal radius fracture. The
      repair with free tendon graft and the excision of the distal ulna produced a
      successful result.

PMID- 10357533
TI  - Forearm interosseous ligament isometry.
AB  - Biomechanical testing was performed to determine isometric interosseous ligament
      graft placement as a preliminary step for reconstruction after an axial forearm
      disruption. Twenty-five combinations of potential ligament graft placement were
      studied on 7 fresh-frozen cadavers. Suture was used to simulate these potential
      ligament reconstructions, and suture excursion was used as an index of isometry.
      Ligament orientation was defined by the angle formed between the ulna and the
      suture (surrogate graft). Ligament position was defined by its insertion on the
      ulna as a percentage of ulna length. Suture-ulna angles from 9 degrees to 38
      degrees produced significantly less suture excursion than angles of > or = 39
      degrees. Minimal suture excursion was noted at angles of < or = 20 degrees, which
      we feel represents the optimal range for reconstruction. The optimal location on
      the ulna for isometric interosseous ligament reconstruction was at 25% to 30% of
      total ulna length, as measured proximally from the distal ulna articular surface.
      The radius isometric location is optimally located by a vector starting from the
      ulna isometric point and directed toward the proximal radius at an angle of < or
      = 20 degrees relative to the long axis of the ulna. Interosseous ligament
      reconstruction may prove beneficial in the long-term outcome of reconstruction
      after axial forearm disruption.

PMID- 10357534
TI  - Resection of elbow ossification and continuous passive motion in postcomatose
      patients.
AB  - Heterotopic periarticular ossifications were surgically excised in 16 elbows of
      14 traumatic brain injury patients an average of 18.9 months (range, 4-67 months)
      after the end of coma. In 11 elbows the ulnohumeral joint was ankylosed in a
      position that ranged from 0 degrees to 100 degrees of flexion (group 1); in 5
      elbows the arc of flexion ranged from 10 degrees to 25 degrees (group 2). Full
      pronation and supination were present in 15 of the elbows; in 1 the
      radiocapitellar joint was fixed at 30 degrees of pronation by a partial
      ossification of the interosseous membrane. The arc of flexion attained after
      surgery averaged 115 degrees (range, 90 degrees to 145 degrees) in the group 1
      elbows and 128 degrees (range, 115 degrees to 140 degrees) in the group 2 elbows.
      In an attempt to prevent postoperative loss of motion and recurrence of
      ossification, continuous passive motion was applied to the affected elbow for 6
      weeks before starting a fully active rehabilitation program. All the patients
      were examined at regular intervals after the surgery. The follow-up period ranged
      from 12 to 60 months (average, 30.7 months). During the follow-up period, all the
      elbows showed improvement in range of motion and the arc of flexion averaged 95
      degrees (range, 30 degrees to 135 degrees) in the group 1 elbows and 116 degrees
      (range, 80 degrees to 145 degrees) in the group 2 elbows. Patients with poor
      neuromuscular control lost part of their postoperative range of motion and
      partial recurrence was observed in 3 elbows. We believe that our improved
      results, compared with those obtained by previous investigators, may have been
      due to the prolonged application of continuous passive motion after surgery.

PMID- 10357535
TI  - Posterior interosseous nerve palsy following placement of the compass elbow hinge
      for acute instability: a case report.
AB  - We describe a case of posterior interosseous nerve palsy that developed after
      application of a hinged elbow external fixation device. Our hypothesis that
      forearm pronation during ulnar half pin insertion may have been causative is
      supported by anatomic findings noted during subsequent cadaveric dissection.
      Based on our observations we recommend that the ulnar half pins required with
      this device be inserted with the forearm in supination.

PMID- 10357536
TI  - Complications of endoscopic and open carpal tunnel release.
AB  - Separate questionnaires regarding surgically treated complications of endoscopic
      and open carpal tunnel release over a 5-year period were sent to members of the
      American Society for Surgery of the Hand to assess and compare major
      complications of the 2 procedures. Four hundred fifty-five major complications
      from endoscopic carpal tunnel release were treated by the 708 respondents. This
      included 100 median nerve lacerations, 88 ulnar nerve lacerations, 77 digital
      nerve lacerations, 121 vessel lacerations, and 69 tendon lacerations. There were
      283 major complications from open carpal tunnel release treated by 616
      respondents, including 147 median nerve lacerations, 29 ulnar nerve lacerations,
      54 digital nerve lacerations, 34 vessel lacerations, and 19 tendon lacerations.
      Although this is a retrospective voluntary study with resultant methodologic
      flaws, the data support the conclusion that carpal tunnel release, be it
      endoscopic or open, is not a safe and simple procedure. Major, if not
      devastating, complications can and do occur with both procedures, of which
      surgeons should be ever cautious.

PMID- 10357537
TI  - Results of surgical treatment for radial tunnel syndrome.
AB  - We reviewed the outcome of radial nerve decompression in 28 patients with an
      average 28-month follow-up period. The outcome was determined by both subjective
      (ie, questionnaire) and objective assessments. Only 11 of the 28 patients (39%)
      had excellent or good results. However, 64% subjectively assessed their results
      as excellent or good. Results were worse in patients receiving workers'
      compensation or who were in litigation. The difference was statistically
      significant. Although previous studies have found a high rate of good results, we
      believe that a high rate of morbidity is associated with both the disease and its
      treatment. Based on our results we suggest that great caution be taken before
      performing radial tunnel release and strict adherence to the indications noted
      during the preoperative examination.

PMID- 10357538
TI  - Restoration of elbow flexion in brachial plexus avulsion injury: comparing spinal
      accessory nerve transfer with intercostal nerve transfer.
AB  - This study was performed to compare the clinical outcome of 2 types of commonly
      used nerve transfers, the spinal accessory nerve transfer and the intercostal
      nerve transfer. This study was a prospective randomized parallel trial involving
      205 patients presenting between 1989 and 1994. All patients were males ranging in
      age from 16 to 43 years. All patients underwent surgery within 6 months of
      injury. Spinal accessory nerve transfer was performed in 130 patients; better
      results were obtained in terms of less operative time, fewer blood transfusions,
      fewer immediate complications, and better motor function (very good and good
      power in 83% of patients). Intercostal nerve transfer was performed in 75
      patients; better results were observed in terms of earlier electromyographic
      evidence of motor reinnervation, improvement in protective sensation, and
      reduction of pain. However, very good and good motor recovery was observed in
      only 64% of patients. There was no significant difference with regard to tidal
      volume, vital capacity, and the FEV1 to FEV ratio before and after surgery in
      either group. Smoking adversely affected the rate of recovery. Spinal accessory
      nerve transfer should be used when motor function of the elbow flexors is the
      major concern. Intercostal nerve transfer should be performed in patients who
      need both motor and sensory reconstruction and in those who have chronic pain
      syndrome after brachial plexus injury.

PMID- 10357539
TI  - The effect of interferon-alpha2b on an in vitro model Dupuytren's contracture.
AB  - The effects of interferon-alpha2b (IFN-alpha2b) on Dupuytren's and control palmar
      fibroblasts were evaluated using the fibroblast-populated collagen lattice model.
      Three paired strains of Dupuytren's and control fibroblasts were exposed to IFN
      alpha2b for 96 hours before incorporation into triplicate collagen lattices.
      Contraction of the lattices was recorded and Northern blot analysis of
      cytoskeletal mRNA was performed. Comparisons of Dupuytren's and control
      fibroblasts revealed significantly increased contractility of the Dupuytren's
      fibroblasts in 2 of the 3 strains. Treatment with IFN-alpha2b significantly
      inhibited contraction in both Dupuytren's and control fibroblasts. In Dupuytren's
      fibroblasts, treatment with IFN-alpha2b significantly down-regulated mRNA
      expression for cytoplasmic beta-actin and gamma-actin.

PMID- 10357540
TI  - Limb allotransplantation in rats: combined immunosuppression by FK-506 and 15
      deoxyspergualin.
AB  - The immunosuppressive effect of combined therapy using FK-506 and 15
      deoxyspergualin was investigated in rat limb allotransplantation. The right
      hindlimb of an inbred Dark Agouti rat (RT1a) was transplanted to a Lewis rat
      (RT1l) and observed for 120 days. Eighty-eight transplantations were performed.
      Rejection of the grafts was evaluated histologically as well as macroscopically.
      A pathologic grading system was used to rate the severity of rejection. Limb
      survival time in Lewis rats receiving FK-506 therapy for days was significantly
      prolonged by combined therapy with 15-deoxyspergualin. Histologic study showed
      practically no rejection in all the graft-composing tissues except the skin and
      bone marrow, in which there was rejection. These results suggest that tissues
      like bone, cartilage, and muscle may survive transplantation with short-term
      combination FK-506 and 15-deoxyspergualin therapy even after withdrawal of both
      agents.

PMID- 10357541
TI  - Osteocutaneous radial forearm flap for hand reconstruction.
AB  - We treated 5 patients (4 men and 1 woman) with bone and soft tissue defects or
      total thumb loss using an osteocutaneous radial forearm flap. Their ages at the
      time of surgery ranged from 27 to 65 years (mean, 53 years). Preoperative
      conditions were traumatic loss of the thumb in 3 cases and severe injuries with
      soft tissue and bone defects in 2. The length of the donated radius ranged from 2
      to 7 cm (mean, 4.7 cm). In 4 patients the radial forearm flap was transposed,
      including the lateral antebrachial cutaneous nerve as a sensory flap.
      Simultaneous iliac bone grafting to the donor site was also performed in 4 of the
      cases. The follow-up period ranged from 44 to 87 months (mean, 64 months). All
      flaps survived over their full extent. Radiographic bone union was attained after
      2 to 3 months (mean, 2.5 months). Two-point discrimination over the 4 sensory
      flaps ranged from 8 to 15 mm (mean, 10.8 mm). No radius fractures occurred. No
      patients showed signs of vascular insufficiency from sacrifice of the radial
      artery. The radial forearm flap provides thin skin of good texture together with
      bone for a 1-stage reconstruction. For patients with skin and bone defects of the
      hand, a radial forearm osteocutaneous flap is recommended. This flap is also
      recommended for patients with traumatic thumb loss, if the dorsalis pedis artery
      is absent, or if the patient declines using tissue from the foot.

PMID- 10357542
TI  - Congenital pseudarthrosis of both forearm bones: long-term results of two cases
      managed by free vascularized fibular graft.
AB  - We analyzed the clinical and radiographic outcome of 2 cases of congenital
      pseudarthrosis of both forearm bones managed by free vascularized fibular grafts.
      The follow-up periods were 17 and 13 years, respectively. The first patient, a 4
      year-old girl, had reconstruction of both the radius and ulna by a vascularized
      fibular graft, restoring pronation/supination to 110 degrees. The second patient,
      a 17-year-old boy, underwent a 1-bone forearm procedure using a vascularized
      fibular graft. After surgery, he had a stable forearm that was shortened by
      approximately 15 cm. In these 2 cases of congenital pseudarthrosis of both
      forearm bones, bone union was obtained by means of vascularized fibular graft.

PMID- 10357543
TI  - Tendon transfers for restoring hand intrinsic muscle function: a biomechanical
      study.
AB  - Four fresh-frozen arms were biomechanically tested to determine the effect of the
      route of tendon transfer (dorsal vs volar) and the site of digital tendon
      insertion (A1 pulley, A2 pulley, proximal phalanx, or lateral band/extensor
      mechanism) on restoring metacarpophalangeal joint flexion and interphalangeal
      joint extension. A volar carpal canal route of tendon transfer appears to be more
      mechanically efficient than a dorsal intermetacarpal route. A lateral band
      insertion provides a small but significant increase in proximal interphalangeal
      and distal interphalangeal joint extension.

PMID- 10357544
TI  - Cadaveric modeling of the pronator teres rerouting tendon transfer.
AB  - The purpose of this study is to report the biomechanics of the supination effect
      of the pronator teres rerouting procedure and to determine the optimum insertion
      point for the transfer using a cadaveric model. Pronator teres rerouting
      procedures were performed on 5 fresh-frozen above-elbow cadaver specimens mounted
      in a forearm rotation mounting frame. The pronator teres was detached from its
      native insertion and tested at 6 insertions on the radius. The amount of rotation
      of the forearm was measured after loading of the pronator teres muscle for each
      insertion site. The experiments were repeated by placing the pronator teres 1 cm
      proximal to the 6 experimental insertion sites for a total testing of 12
      insertions. The results of this study show that placement of the pronator teres
      through the interosseous membrane, around the radius, with reinsertion onto the
      volar surface produced the greatest amount of forearm supination. Rerouting of
      the pronator teres tendon produces supination through a windlass effect when the
      tendon is rerouted through an interosseous window and reinserted onto its
      original insertion or onto the volar surface of the radius. Placement of the
      insertion 1 cm proximal on the radius did not affect the amount of forearm
      supination compared with 6 original insertion sites.

PMID- 10357545
TI  - Distribution of type IV collagen during avian limb bud development.
AB  - Normal limb development is dependent on an epithelial-mesenchymal interaction
      between the overlying apical ectodermal ridge (AER) and the underlying
      mesenchyme. The basement membrane between the epithelium and the mesenchyme has
      been proposed to play an important role in regulating epithelial-mesenchymal
      interactions during development. To explore the role basement membrane type IV
      collagen may play during limb development we investigated the distribution of
      type IV collagen by immunolocalization. Developing avian leg buds were examined
      at 2 developmental stages: stage 23, when the AER is inductively active, and
      stage 28, when the AER is regressing. The proximal basement membrane in stage 23
      limb buds stained much more intensely than the distal basement membrane. This
      proximal-distal immunostaining difference was less in stage 28 limb buds. We used
      the monoclonal antibody IIB12, which recognizes an epitope adjacent to the
      initial collagenase cleavage site on the type IV collagen molecule, to explore
      whether this proximal-distal difference in basement membrane staining could
      result from the loss of type IV collagen. The distal basement membrane of stage
      23 limb buds demonstrated little immunostaining with the IIB12 antibody,
      suggesting enhanced collagenase-associated degradation. The immunostaining was
      increased in stage 28 limb buds. Consistent with a loss of type IV collagen, we
      also found that unfixed stage 23 leg bud cryostat sections stored at 4 degrees C
      lost their immunostaining for type IV collagen, in contrast to stored stage 28
      limb bud cryostat sections. These results demonstrate that type IV collagen is
      distributed in a proximal-distal pattern in the basement membrane of the
      developing chick limb bud and suggest that this pattern may be the result of a
      selective degradation of type IV collagen in the basement membrane underlying the
      active AER. These results are consistent with the hypothesis that the basement
      membrane plays a role in regulating the epithelial-mesenchymal interaction
      responsible for induction of limb outgrowth.

PMID- 10357546
TI  - Extensor tendon lacerations in a preterm neonate.
AB  - A fetus of 30-weeks' gestation sustained 2 extensor tendon lacerations as an
      intraoperative complication of an emergency Cesarean section. This report
      describes treatment of the tendon lacerations in the preterm neonate using 2
      different repair techniques which both yielded an excellent clinical outcome.

PMID- 10357547
TI  - Avascular necrosis of the distal phalangeal epiphysis following physeal fracture:
      a case report.
AB  - Avascular necrosis of the distal phalangeal epiphysis following an unrecognized
      angulated Salter II fracture of the distal phalanx treated by open reduction and
      internal fixation resulted in premature closure of the growth plate and mild
      shortening. The epiphysis itself revascularized and good function of the distal
      interphalangeal joint was maintained.

PMID- 10357548
TI  - Subcutaneous tissue emphysema of the hand secondary to noninfectious etiology: a
      report of two cases.
AB  - Subcutaneous emphysema of the hand can be benign and noninfectious in origin.
      Emphysema from gas-forming organisms is associated with systemic symptoms,
      whereas benign subcutaneous emphysema is not. High-pressure pneumatic tool
      injuries are a well-known cause of subcutaneous emphysema. Minor wounds in the
      web space skin may result in a transport of air across the defect, acting like a
      ball valve mechanism to trap and then force the air into the subcutaneous tissue,
      as illustrated by 1 of our patients. In the second patient, use of a high
      vibration tool without apparent breach of skin was associated with extensive
      subcutaneous emphysema. The benign nature of the emphysema was revealed by a lack
      of local pain and inflammation in the presence of extensive crepitus and a lack
      of systemic symptoms. A noninfectious cause should always be considered. This may
      prevent unnecessary surgical intervention, which occurred in 1 of the 2 cases
      presented here.

PMID- 10357549
TI  - Kienbock's disease and multiple hereditary osteochondromata: a case report.
AB  - A case of bilateral forearm localization of multiple hereditary osteochondromata
      and unilateral Kienbock's disease is reported. Ulnar minus variance is frequent
      in both diseases. Carpal slip is often found in multiple hereditary
      osteochondromata. In this case, the extremity having both multiple hereditary
      osteochondromata and Kienbock's disease had no carpal slip. This might have
      produced an excess load on the lunate, which might have provoked Kienbock's
      disease.

PMID- 10357551
TI  - Persistent or recurrent carpal tunnel surgery following prior endoscopic carpal
      tunnel release.

PMID- 10357550
TI  - Endoscopic cubital tunnel release.

PMID- 10357552
TI  - Critical determinants of cancer metastasis: rationale for therapy.
AB  - The major cause of death from cancer is metastases that are resistant to
      conventional therapies. Several reasons account for treatment failure in patients
      with metastases. First, neoplasms are biologically heterogeneous and contain
      subpopulations of cells with different angiogenic, invasive, and metastatic
      properties. Second, the process of metastasis selects a small subpopulation of
      cells that preexist within a parental neoplasm. Although metastases can have a
      clonal origin, genetic instability results in rapid biological diversification
      and the regeneration of heterogeneous subpopulations of cells. Third, and perhaps
      the most important principle for the design of new cancer therapies, is that the
      outcome of metastasis depends on multiple interactions ("cross-talk") of
      metastatic cells with homeostatic mechanisms which the tumor cells usurp. The
      organ microenvironment can influence the biology of cancer growth, angiogenesis,
      and metastasis in several different ways. For example, the survival and growth of
      tumor cells are dependent on angiogenesis, which is mediated by an imbalance
      between positive and negative regulating molecules released by tumor cells,
      normal cells surrounding a tumor, and infiltrating lymphoid cells. Many cytokines
      that stimulate or inhibit angiogenesis are present in different tissues, and thus
      the organ environment profoundly influences this process. Moreover, the organ
      microenvironment can also influence the response of metastases to chemotherapy by
      regulating the expression of different drug resistance genes, such as mdr-1. The
      finding that the resistance of metastases to some chemotherapeutic agents can be
      mediated by epigenetic mechanisms has obvious implications for therapy. The
      identification of organ-specific cytokines that can upregulate expression of mdr
      1 (or other resistant mechanisms) may suggest an approach to overcome the
      resistance of some metastases to particular chemotherapeutic agents. Therefore
      therapy of metastasis should be targeted not only against metastatic tumor cells,
      but also the homeostatic factors that are favorable to metastasis, growth, and
      survival of the metastatic cells.

PMID- 10357553
TI  - Role of radiosurgery in the management of central nervous system metastases.
AB  - Radiosurgery is being used more routinely to treat patients with inoperable,
      recurrent, or multiple brain metastases from systemic cancer. Results in > 2000
      treated patients have been published during the past 8 years. These results
      indicate that permanent local control can be obtained in > 80% of treated lesions
      with complications in < 10% of patients. Success is independent of the histology,
      ie, melanoma vs adenocarcinoma, of the treated lesion or number of lesions
      treated. The long-term results of radiosurgery compare favorably with those seen
      following surgical resection. The cost-effectiveness of radiosurgery compared to
      surgical resection favors an expanded role for this technology in the treatment
      of selected patients with brain metastases.

PMID- 10357554
TI  - Successful management of microscopic residual disease in large bowel cancer.
AB  - Although cancer surgery has been of great benefit to patients with large bowel
      cancer, a flaw that has caused the death of countless patients has gone
      unrecognized. Although surgeons have dealt successfully with the primary tumor,
      they have neglected to treat microscopic residual disease. Persistent cancer
      cells within the abdomen and pelvis are responsible for the death of 30-50% of
      the patients who die with this disease and for quality of life consequences that
      result from intestinal obstruction caused by cancer recurrence at the resected
      site and on peritoneal surfaces. New surgical techniques for large bowel cancer
      resection minimize the surgery-induced microscopic residual disease that may
      result from surgical trauma. New developments in exposure, hemostasis, adequate
      lymphadenectomy, and qualitatively superior margins of excision have occurred.
      Clinical data show that a 40% improvement in survival with an optimization of
      surgical technique is possible. Not only should the surgical event for primary
      colon and rectal cancer be optimized, but also the successful treatment of
      peritoneal carcinomatosis should be pursued. Resected site disease and peritoneal
      carcinomatosis can be prevented through the use of perioperative intraperitoneal
      chemotherapy in patients at high risk of persistent microscopic residual disease.
      These are patients with perforated cancer, positive peritoneal cytology, ovarian
      involvement, tumor spill during surgery, and adjacent organ involvement. Patients
      with established peritoneal carcinomatosis can be salvaged with an approximate
      50% long-term survival rate if the timely use of peritonectomy procedures,
      intraperitoneal chemotherapy, and knowledgeable patient selection are utilized.
      Peritonectomy procedures allow the removal of all visible peritoneal
      carcinomatosis with acceptable surgical morbidity (25%) and mortality (1.5%)
      rates. Heated intraoperative intraperitoneal chemotherapy using mitomycin C, in
      addition to early postoperative intraperitoneal 5-fluorouracil, can eradicate
      microscopic residual disease in the majority of patients. The peritoneal cancer
      index, which quantitates colon cancer peritoneal carcinomatosis by distribution
      and by lesion size, must be used in the selection of patients who may benefit
      from these advanced oncologic surgical treatment strategies. The completeness of
      the cytoreduction score is the most powerful prognostic indicator in this group
      of patients. The surgeon must be aware that there are no long-term survivors
      unless complete cytoreduction occurs. With a combination of proper techniques for
      the resection of primary disease, peritonectomy procedures for the removal of all
      visible peritoneal implants, intraoperative and early postoperative chemotherapy
      for the eradication of microscopic residual disease, and quantitative tools for
      proper patient selection, one can optimize the surgical treatment of patients
      with large bowel cancer.

PMID- 10357556
TI  - Molecular diagnostic detection of free cancer cells in the peritoneal cavity of
      patients with gastrointestinal and gynecologic malignancies.
AB  - Free cancer cells exfoliated from cancer-invaded serosa contribute to peritoneal
      dissemination, the most frequent pattern of recurrence in patients with gastric
      and ovarian cancers. This study was designed to evaluate the prognostic
      significance of free cancer cells in peritoneal washes detected using the reverse
      transcriptase-polymerase chain reaction (RT-PCR) and cytology. RT-PCR analysis
      with primers specific for the carcinoembryonic antigen (CEA) gene was found to be
      more sensitive than cytology for detection of free tumor cells in the peritoneal
      washes, collected at laparotomy from 199 gastric carcinoma patients, with higher
      detection rates for each of the T-categories in the TNM classification. Six
      patients with synchronous and 5 with recurrent peritoneal dissemination were
      found among 25 advanced cancer patients with positive PCR and negative cytology
      results. Positive PCR results were significantly associated with poor survival of
      curatively resected advanced gastric carcinoma patients (P < 0.001). A rapid
      method for detecting CEA mRNA using the LightCycler and the dsDNA binding dye
      SYBR green I was also developed. The results obtained using this technique were
      essentially the same as those obtained using the conventional RT-PCR method.
      Furthermore, RT-PCR analysis with primers specific for MUC1 epithelial mucin were
      performed on peritoneal washes from patients with ovarian cancer. Peritoneal
      washes from 21 of 25 ovarian carcinoma patients, including all 17 with positive
      cytology results, were positive for MUC1 mRNA, again indicating a higher
      sensitivity using this method than conventional cytology. Highly sensitive and
      rapid detection of free cancer cells in peritoneal washes, most reliably by RT
      PCR, is a powerful technique to predict peritoneal dissemination in patients with
      gastric and ovarian cancers.

PMID- 10357555
TI  - Heterogeneity of multiorgan metastases of human lung cancer cells genetically
      engineered to produce cytokines and reversal using chimeric monoclonal antibodies
      in natural killer cell-depleted severe combined immunodeficient mice.
AB  - Lung cancer is a major cause of cancer deaths, most of which can be attributed to
      distant multiorgan metastases. To examine the cellular and molecular mechanisms
      of lung cancer metastasis to distant organs, we have established novel models of
      human lung cancer (small cell and non-small cell lung cancer) metastasis in
      natural killer cell-depleted severe combined immunodeficient (SCID) mice. We
      investigated whether local production of the cytokines responsible for regulation
      of macrophage function at tumor growth sites affects the pattern of lung cancer
      metastasis in distant organs. Several lung cancer cell lines were genetically
      engineered to produce human macrophage colony-stimulating factor (M-CSF) and
      monocyte chemoattractant protein-1 (MCP-1), and their metastatic potentials were
      assessed. Interestingly, M-CSF gene transduction had an antimetastatic effect for
      the liver and lymph nodes, but not the kidneys. In contrast, MCP-1 gene-modified
      lung cancer cells and their parent cells had identical metastatic potentials.
      These findings indicate a possible role for cytokines and suggest that lung
      cancer has metastatic heterogeneity. Examining ways of controlling human lung
      cancer metastases, we investigated the antimetastatic effect of chimeric
      monoclonal antibodies (MAbs) against P-glycoprotein and ganglioside GM2 (MH162
      and KM966, respectively). Both MAbs, when given on days 2 and 7, inhibited the
      development of distant metastases of lung cancer in a dose-dependent fashion.
      Combined use of anti-P-glycoprotein MAb with M-CSF or MCP-1 gene transduction
      caused complete inhibition of metastasis of H69/VP cells. The antimetastatic
      effect of these MAbs in vivo was mainly due to an antibody-dependent cell
      mediated cytotoxicity reaction mediated by mouse macrophages. These findings
      suggest that the mouse-human chimeric MAb in combination with cytokine gene
      transduction may be useful for the eradication of lung cancer metastases in
      humans.

PMID- 10357557
TI  - SCID-hu mice for the study of human cancer metastasis.
AB  - Cancer metastasis involves dynamic and multistep in vivo processes. While
      generation of metastatic clones requires genetic alterations in cancer cells,
      subsequent selection of the clones is heavily influenced by interactions with the
      surrounding tissue microenvironment. To reproduce the complex cellular
      interactions that occur in human patients is, however, difficult, and has not
      been achieved using currently available in vitro systems or conventional animal
      models. The SCID-hu mouse is generated by surgical implantation of human fetal
      tissues into mutant mice of the severe combined immunodeficient (SCID) phenotype.
      The unique feature of this model is that the implanted human tissues maintain
      their normal architecture and function. Therefore implanted human tissues will
      provide relevant microenvironments for the growth and metastasis of human cancer
      cells. The SCID-hu mouse model, which was specifically designed for the study of
      human cancer biology, enables experimental investigation of cellular events
      involved in cancer metastasis on the basis of interactions between human cancer
      cells and the human tissue microenvironment. It has been demonstrated that
      various types of human cancer cell lines generate tumors in implanted human bone
      marrow and lung, organs frequently involved in metastasis in patients, upon
      intravenous inoculation. Tumorigenic activity in SCID-hu mice faithfully reflects
      the clinical features of the original cancer. Tumor formation and selection of
      high tumorigenic variants occur in a species-specific manner. Furthermore, it was
      shown that metastatic tumor formation is regulated by both cancer cells and
      conditions in the host organs. Conditioning of animals by either whole-body
      irradiation or interleukin 1alpha treatment prior to cancer cell inoculation
      induced metastatic tumor formation by certain small cell lung cancer (SCLC) cell
      lines specifically in human bone marrow. A novel gene has been identified by
      comparing gene expression profiles between high and low tumorigenic SCLC cells in
      human lung. This gene is preferentially expressed in low metastatic lines, and
      transfection of the gene into highly metastatic cells results in suppression of
      metastasis. Recent studies have shown that the gene product is involved in the
      apoptosis induction pathway. Collectively, our results indicate that the SCID-hu
      mouse will serve as a unique platform technology with which to investigate
      cellular events involved in human cancer metastasis, as well as to identify genes
      playing important roles in the growth and metastasis of human cancer, in the
      context of interactions between human cancer cells and human tissue environments.

PMID- 10357558
TI  - Matrix metalloproteinases and metastasis.
AB  - Metastatic disease is responsible for the majority of cancer-related deaths,
      either directly due to tumor involvement of critical organs or indirectly due to
      complications of therapy to control tumor growth and spread. An understanding of
      the mechanisms of tumor cell invasion and metastasis may be important for
      devising therapies aimed at preventing tumor cell spread. Matrix
      metalloproteinases (MMPs) are a family of zinc-dependent endoproteinases whose
      enzymatic activity is directed against components of the extracellular matrix
      (ECM). In humans, 16 members of this family have been identified by cloning and
      sequencing. These proteinases are linked by a core of common domain structures
      and by their relationship to a family of proteinase inhibitors called the tissue
      inhibitors of metalloproteinases (TIMPs). Four members of the TIMP family have
      been cloned and sequenced in humans and they inhibit MMPs by forming tight
      binding, noncovalent associations with the active site of the MMPs. MMPs
      facilitate tumor cell invasion and metastasis by at least three distinct
      mechanisms. First, proteinase action removes physical barriers to invasion
      through degradation of ECM macromolecules such as collagens, laminins, and
      proteoglycans. This has been demonstrated in vitro through the use of
      chemoinvasion assays and in vivo by the presence of active MMPs at the invasive
      front of tumors. Second, MMPs have the ability to modulate cell adhesion. For
      cells to move through the ECM, they must be able to form new cell-matrix and cell
      cell attachments and break existing ones. Using a cell transfection system that
      altered the ratio of MMP-2 to TIMP-2 we have demonstrated significant variation
      in the adhesive phenotype of tumor cells. Finally, MMPs may act on ECM components
      or other proteins to uncover hidden biologic activities. For example, the
      angiogenesis inhibitor angiostatin may be produced from plasminogen by MMP action
      and laminin-5 is specifically degraded by MMP-2 to produce a soluble chemotactic
      fragment. Thus MMPs play multiple key roles in facilitating the metastasis of
      tumor cells. Therapies designed to interfere with specific MMP actions may be
      useful in the control of metastatic disease.

PMID- 10357559
TI  - Matrilysin as a target for chemotherapy for colon cancer: use of antisense
      oligonucleotides as antimetastatic agents.
AB  - Matrilysin (MMP-7) is the smallest member of the matrix metalloproteinase (MMP)
      family. It is frequently expressed in various types of cancer including colon,
      stomach, prostate, and brain cancers. Previous studies have suggested that
      matrilysin plays important roles in the progression and metastasis of colon
      cancer. Recently, we have examined the effects of a matrilysin-specific antisense
      phosphorothioate oligodeoxyribonucleotide on in vitro invasion and liver
      metastasis in nude mice of two human colon carcinoma cell lines (CaR-1 and WiDr).
      In culture, the antisense oligonucleotide effectively inhibited both the
      secretion of matrilysin by CaR-1 cells and their in vitro invasion through a
      reconstituted basement membrane. In a nude mouse model, the antisense
      oligonucleotide potently suppressed the experimental liver metastasis of WiDr
      cells from the spleen. These results suggest that matrilysin has an important
      role in the liver metastasis of human colon cancer and that matrilysin antisense
      oligonucleotides have therapeutic potential for the prevention of metastasis.

PMID- 10357560
TI  - Marimastat (BB2516): current status of development.
AB  - Marimastat (BB-2516) is the first matrix metalloproteinase inhibitor to have
      entered clinical trials in the field of oncology. It has excellent
      bioavailability and has completed phase I and II trials. Phase I studies involved
      healthy volunteers who received short courses of marimastat; these were well
      tolerated. Symptoms experienced by many patients with various malignancies
      included severe joint and muscle pain which were debilitating in >60% of patients
      at doses >50 mg bid. These symptoms were reversible on discontinuation of the
      drug, and their incidence has been decreased by using marimastat 10 mg bid, the
      dose used in current studies. Phase II studies involved the use of serum tumor
      markers as surrogate indicators of antitumor activity. Six studies in colorectal,
      ovarian, and prostate cancer have been completed and pooled analysis has
      demonstrated a dose-dependent biological effect (as defined by the authors); 58%
      of patients respond at doses >50 mg bid. Effects on tumor markers were associated
      with increased survival. Small phase II studies have suggested potential activity
      in pancreatic and gastric cancer and have demonstrated the safety of combining
      cytotoxic chemotherapeutic agents with marimastat. Ongoing phase III studies are
      investigating the effects of marimastat in addition to chemotherapy in the
      treatment of small cell lung cancer and pancreatic and gastric carcinoma.

PMID- 10357561
TI  - Promising new developments in cancer chemotherapy.
AB  - The positive impact on survival of traditional chemotherapeutic agents has
      renewed interest in developing newer cytotoxic agents and orally active compounds
      with improved therapeutic indices. In addition, new insights into the pathways of
      human tumorigenesis have led to novel approaches aimed at specific mechanism
      based targets. The taxane class, of which paclitaxel was the first member, has
      the unique ability to promote and stabilize microtubule function directly,
      thereby inhibiting mitotic progression and inducing apoptotic cell death.
      Paclitaxel provides treatment benefit in a broad range of solid tumors including
      breast, ovarian, and lung cancer. The success with paclitaxel stimulated interest
      in the microtubule as a new therapeutic target. Taxane analogues with improved
      preclinical efficacy have been identified and are entering clinical trials. The
      enthusiasm for oral anticancer agents and the therapeutic importance of platinum
      compounds has led to the development of JM216 (satraplatin), a novel platinum IV
      coordination complex with oral activity in cisplatin-resistant cell lines, which
      is now in phase III trials in prostate cancer. Another compound in late
      development is DPPE, a chemopotentiator that enhances the in vivo antitumor
      effects of cytotoxic agents such as doxorubicin, cyclophosphamide, and cisplatin.
      Agents that inhibit topoisomerase I and II have also been of interest. TAS-103 is
      a dual topoisomerase I and II inhibitor with preclinical efficacy in a broad
      spectrum of tumors and in multidrug-resistant tumor cell lines. Vaccination
      strategies represent a rational therapeutic approach in the minimal residual
      disease or high-risk adjuvant therapy setting. The GMK and MGV vaccines utilizing
      ganglioside antigens overexpressed on human tumors such as melanoma and small
      cell lung cancer appear to induce antibody production reliably at tolerable doses
      and are under further clinical investigation. Inhibition of matrix
      metalloproteinases (MMPs) is another attractive target for intervention in
      several aspects of tumor progression. Local production of MMPs with subsequent
      degradation of the extracellular matrix is implicated in supporting tumor growth,
      invasion, and angiogenesis. The development of orally active, nontoxic MMP
      inhibitors is critical since these compounds will likely require chronic
      administration in conjunction with other therapies. Oncogenes and tumor
      suppressor genes are appealing targets for therapy since they are thought to be
      responsible for a significant number of cancers. Mutations in the Ras oncogene
      occur with great frequency in a number of human cancers including lung, pancreas,
      and colon cancer. Clinical development of potent and selective inhibitors of
      farnesyltransferase, the Ras-processing enzyme, is ongoing. These compounds
      uncouple Ras activity, affect tumor growth, and have demonstrated significant
      antitumor activity against experimental models of human cancer. The exciting
      compounds and novel therapeutic approaches currently under investigation by
      Bristol-Myers Squibb Pharmaceutical Research Institute offer great potential as
      effective cancer chemotherapy agents for the near future.

PMID- 10357562
TI  - Biological implications of macrophage infiltration in human tumor angiogenesis.
AB  - Tumor angiogenesis is believed to be induced by increased production of
      angiogenic factors and decreased production of angiogenic inhibitors by cancer
      cells, vascular endothelial cells, and other stromal cell types. Most solid tumor
      cells are surrounded by stroma comprising interstitial connective tissue, blood
      vessels, fibroblastic cells, etc. Interaction between the stroma and malignant
      cells appears to have a critical role in the development of tumor neovasculature.
      We focused on macrophages, which demonstrate wide heterogeneity in biological
      function and have an essential role in tumor angiogenesis. Macrophages are
      terminally differentiated cells which produce a number of potent angiogenic
      cytokines and growth factors such as vascular endothelial growth factor, tumor
      necrosis factor-alpha, interleukin-8, and basic fibroblast growth factor. They
      also modulate events in the extracellular matrix through the secretion of
      extracellular matrix-degrading enzymes and -modulating enzymes. Thus macrophages
      could influence various stages of angiogenesis either positively or negatively.
      We found a close correlation between increased macrophage index, malignancy, and
      high vascular grade in malignant melanoma, and present a model for the possible
      involvement of activated macrophages in neovascularization in human malignant
      melanoma.

PMID- 10357563
TI  - Involvement of VEGF and its receptors in ascites tumor formation.
AB  - Vascular endothelial growth factor (VEGF) has potent endothelial cell mitotic and
      vascular permeability activity. Several reports have suggested that VEGF may be
      one of the major factors regulating ascites formation, although no quantitative
      and systematic analyses have been carried out. To determine the role of VEGF in
      ascites formation, we examined the expression of VEGF in 13 mouse ascites tumors
      (5 sarcomas, 3 carcinomas, and 5 hematopoietic malignancies). We found that
      significant amounts (6-850 ng/mL) of biologically active VEGF accumulated in the
      ascites fluid of all 13 tumors, particularly in tumors of sarcoma and carcinoma
      origin (430 +/- 234 ng/mL). The microvessel densities in the peritoneal walls of
      tumor-bearing mice, which are significantly higher than those in healthy mice,
      basically correlated with but did not parallel VEGF concentrations, suggesting
      the existence of an additional modulator(s) of the angiogenic process.
      Administration of anti-mouse VEGF-neutralizing antibody to mice bearing the
      carcinoma-derived ascites tumor MM2 suppressed ascites accumulation, tumor
      growth, and tendency to bleed. These results directly demonstrate the crucial
      role of VEGF in carcinoma-derived ascites tumor formation in vivo.

PMID- 10357564
TI  - Thalidomide up-regulates prostate-specific antigen secretion from LNCaP cells.
AB  - Thalidomide has been shown to have species- and metabolic-dependent
      antiangiogenic activity in vitro and in vivo, suggesting its potential in
      treating human angiogenesis-dependent pathologies such as solid tumors. Based on
      promising preclinical studies, thalidomide has entered phase II clinical trials
      for prostate, brain, breast cancer, and Kaposi's sarcoma. However, the
      antiangiogenic mechanism of action is largely unresolved, as are its effects on
      tumor-associated gene expression, cytokine secretion, etc. We have investigated
      the effects of thalidomide on: 1) the secretion of prostate-specific antigen
      (PSA) in a human androgen-dependent prostate cell line; 2) growth and viability
      of human prostate cells; and 3) differential gene expression profiles of
      thalidomide-treated vs untreated human prostate cells. A human androgen-dependent
      prostate carcinoma cell line (LNCaP) and a human androgen-independent prostate
      carcinoma cell line (PC-3) were incubated with thalidomide 0.6, 6, or 60
      microg/mL for 5-6 days. Secreted PSA from LNCaP cells was measured using a
      commercial enzyme-linked immunosorbant assay. Cell viability studies were
      conducted in both LNCaP and PC-3 cells using the same thalidomide concentrations.
      Furthermore, the differential gene expression of thalidomide-treated LNCaP cells
      was compared to that of untreated control cells using a commercially available
      human cancer cDNA expression array system. Thalidomide-treated LNCaP cells
      demonstrated increased PSA/cell levels at all concentrations tested compared to
      untreated control cells. Thalidomide demonstrated a cytostatic effect in LNCaP
      cells but had no appreciable effect on PC-3 cell viability compared to untreated
      control cells. Comparison of cDNA expression arrays hybridized with thalidomide
      treated LNCaP cDNA probes suggests that thalidomide may up- or downregulate
      expression of angiogenesis-related genes, i.e., vitronectin, but these
      differential effects require further verification. Thalidomide over a range of
      doses has demonstrated nontoxic, cytostatic activity in LNCaP cells and
      significant upregulation of LNCaP cell PSA secretion in vitro. Furthermore,
      preliminary data from cDNA nucleic acid arrays of thalidomide-treated LNCaP cells
      suggest that thalidomide upregulates a potential angiogenic modulatory protein,
      the vitronectin precursor, which may eventually link thalidomide's antiangiogenic
      activity with modulation of angiogenic vascular integrin pathways.

PMID- 10357565
TI  - Antitumor effect of the angiogenesis inhibitor TNP-470 on human digestive organ
      malignancy.
AB  - The antitumor and antimetastatic effects of TNP-470, an angiogenesis inhibitor,
      on human gastrointestinal tumors xenotransplanted into nude mice were
      investigated. When two gastric cancer (MT-2 and MT-5) and two colon cancer (TK-4
      and TK-13) xenografts are transplanted orthotopically into nude mice, liver
      metastasis develops 6 weeks after transplantation. TNP-470 30 mg/kg had a
      significant inhibitory effect on primary tumor growth of gastric cancers when
      given on alternate days from 7 days after transplantation. However, when given
      from 10 days or 14 days after transplantation, no inhibitory effect on the growth
      of any tumor xenograft was observed. In contrast, liver metastasis of each
      xenograft type was inhibited significantly by TNP-470. The effect of TNP-470 on
      prognosis was investigated using a hepatic metastatic model of rat hepatoma.
      Although all untreated rats that received AH-130 cell implants died within one
      month of massive hepatic metastasis, >50% of rats treated with TNP-470 survived
      for 4 months. The number of apoptotic cells in hepatic metastatic foci was
      significantly increased by TNP-470 administration. These results suggest that TNP
      470 may provide a new approach to the treatment of digestive organ malignancies.

PMID- 10357566
TI  - In vivo and ex vivo gene therapy strategies to treat tumors using adenovirus gene
      transfer vectors.
AB  - The adaptation of gene therapy strategies to treat tumors has broadened the
      potential armamentarium of anticancer strategies to include approaches for local
      control of tumor growth as well as to enhance systemic antitumor immunity to
      treat metastases. A major focus of the author and colleagues has been to use
      replication-deficient adenovirus vectors, both in vivo and ex vivo, to enhance
      local control of and systemic immunity against cancer. Several examples will be
      used to demonstrate these strategies. Using prodrugs, systemically administered
      drugs converted to toxic metabolites in the local tumor milieu, has proven to be
      a useful strategy for achieving high local concentrations of the toxic product
      while avoiding the systemic toxicity that limits the use of chemotherapy agents.
      Transfer of genes encoding cytosine deaminase (with 5-fluorocytosine) and
      carboxylesterase (CE) (with irinotecan) are two paradigms that have been used in
      our laboratory. The data demonstrate that using adenoviruses to deliver these
      genes to the tumor site leads to production of the active chemotherapeutic agent,
      which diffuses from the cell in which it was produced to suppress tumor growth
      and attain regional control in a single organ. Extensive experimental and
      clinical data now exist to support the concept that tumor growth is critically
      dependent on angiogenesis and that vascular endothelial growth factor (VEGF)
      appears to play a central role in the process of tumor neovascularization. Data
      generated in our laboratory have shown that adenovirus-mediated regional anti
      VEGF therapy using a gene encoding a soluble form of flt-1 (one of the VEGF
      receptors) can be used for regional control of tumor growth. The critical
      dependence of many tumors on VEGF for neovascularization and dissemination
      predicts the general applicability of this strategy for treatment of many solid
      tumors. Another paradigm involves dendritic cells, potent antigen-presenting
      cells that play a critical role in the initiation of antitumor immune responses.
      Immunization of mice with dendritic cells genetically modified using an
      adenovirus vector transferring a gene encoding a tumor antigen confers potent
      protection against a lethal tumor challenge, as well as suppression of
      preestablished tumors, resulting in a significant survival advantage. One
      clinical scenario to which this approach is relevant is treating micrometastases
      present at the time of primary detection of many malignancies. A possible
      clinical strategy would be to modify dendritic cells from such patients using an
      adenovirus vector encoding the relevant tumor antigen, and then administering the
      genetically modified dendritic cells as adjuvant treatment following primary
      therapy.

PMID- 10357567
TI  - Regulatory issues in the evaluation of antimetastatic and other novel anticancer
      therapies.
AB  - This article outlines some of the complexities and challenges confronting
      researchers and the US Food and Drug Administration (FDA) in the area of
      evaluation of antimetastatic and other novel anticancer therapies. The scientific
      regulatory matrix utilized by the FDA is outlined. Subsequently, the
      complications encountered when designing and interpreting studies of
      antimetastatic drugs are described, and finally changes in the regulatory
      landscape both within the USA and internationally are considered.

PMID- 10357568
TI  - Hypertriglyceridemia: changes in the plasma lipoproteins associated with an
      increased risk of cardiovascular disease.
AB  - There is a growing body of evidence from epidemiologic, clinical, and laboratory
      data that indicates that elevated triglyceride levels are an independent risk
      factor for cardiovascular disease. Identification and quantification of
      atherogenic lipoproteins in patients with hypertriglyceridemia are important
      steps in the prevention of cardiovascular disease. Increased levels of apoC-III,
      apoC-I, or apoA-II on the apoB-containing lipoproteins may alter lipoprotein
      metabolism and result in the accumulation of atherogenic remnants.
      Hypertriglyceridemic patients at risk for cardiovascular disease often develop a
      lipoprotein profile characterized by elevated triglyceride, dense LDL, and low
      HDL cholesterol. Understanding that each of these factors contributes separately
      to the patient's risk of cardiovascular disease can help physicians provide
      patients with more effective risk-reduction programs for cardiovascular disease.

PMID- 10357569
TI  - Epidemiology of hypertriglyceridemia and cardiovascular disease.
AB  - Epidemiologic studies provide increasing evidence that hypertriglyceridemia is a
      risk factor for cardiovascular disease. A meta-analysis of 17 population-based
      studies of triglyceride levels and cardiovascular disease identified a 76%
      increase in cardiovascular disease risk in women and a 31% increase in men
      associated with a 1 mmol/L increase in triglyceride levels. Additional
      epidemiologic studies have shown that plasma triglyceride levels and low-density
      lipoprotein particle size predict subsequent coronary artery disease. Taken
      together, the existing epidemiologic data may help identify a group of patients
      who may benefit from interventions aimed at decreasing triglyceride levels
      associated with an increased risk of cardiovascular disease.

PMID- 10357570
TI  - Diabetes, hyperlipidemia, and coronary artery disease.
AB  - Type 2 diabetes is associated with a marked increase in the risk of coronary
      artery disease. Dyslipidemia is believed to be a major source of this increased
      risk. Several studies in diabetic patients have demonstrated a decreased
      incidence of coronary artery disease with the use of drugs that lower the level
      of low-density lipoprotein in diabetic patients, but other forms of dyslipidemia,
      such as hypertriglyceridemia, are believed to play a role in the etiology of
      coronary artery disease in diabetes. Drugs, such as fenofibrate, which improve
      these other forms of dyslipidemia, are being investigated in diabetic patients to
      determine if they decrease mortality and morbidity from coronary artery disease.

PMID- 10357571
TI  - Pathophysiology and management of low high-density lipoprotein cholesterol.
AB  - Low levels of high-density lipoprotein (HDL) cholesterol are associated with an
      increased risk of coronary artery disease events. Data in animals indicate that
      increasing HDL cholesterol levels decreases progression of atherosclerosis. Some
      clinical trials suggest a benefit from increasing HDL cholesterol levels, but
      additional data in humans are needed. Nevertheless, in patients with, or at high
      risk for, coronary artery disease, a decision to institute drug therapy that
      includes an effort to increase HDL cholesterol levels is reasonable based on
      available data. Several clinical trials are underway to determine the most
      effective drug therapy for decreasing the risk of coronary artery disease
      associated with low HDL cholesterol levels.

PMID- 10357572
TI  - Hypertriglyceridemia, insulin resistance, and the metabolic syndrome.
AB  - The metabolic syndrome consists of a cluster of metabolic disorders, many of
      which promote the development of atherosclerosis and increase the risk of
      cardiovascular disease events. Insulin resistance may lie at the heart of the
      metabolic syndrome. Elevated serum triglycerides commonly associate with insulin
      resistance and represent a valuable clinical marker of the metabolic syndrome.
      Abdominal obesity is a clinical marker for insulin resistance. The metabolic
      syndrome manifests 4 categories of abnormality: atherogenic dyslipidemia
      (elevated triglycerides, increased small low-density lipoproteins, and decreased
      high-density lipoproteins), increased blood pressure, elevated plasma glucose,
      and a prothrombotic state. Various therapeutic approaches for the patient with
      the metabolic syndrome should be implemented to decrease the risk of
      cardiovascular disease events. These interventions include decreasing obesity,
      increasing physical activity, and managing dyslipidemia; the latter may require
      the use of pharmacotherapy with cholesterol-lowering and triglyceride-lowering
      drugs.

PMID- 10357573
TI  - Role of fibrates in the management of hypertriglyceridemia.
AB  - Elevated plasma triglyceride levels are increasingly recognized as a risk factor
      for cardiovascular disease. Fibric acid derivatives (fibrates) substantially
      decrease triglyceride levels and have been demonstrated to decrease clinical
      cardiovascular events in some trials. Ongoing research will elucidate the
      molecular mechanisms by which fibrates modify lipoprotein metabolism, clarify
      their use in combination with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
      reductase inhibitors (statins), and determine their role in the prevention of
      cardiovascular events.

PMID- 10357574
TI  - Thrombosis and the role of the platelet.

PMID- 10357575
TI  - Differences among the parenteral platelet glycoprotein IIb/IIIa inhibitors and
      implications for treatment.

PMID- 10357576
TI  - Early clinical results with the new oral glycoprotein IIb/IIIa agents.

PMID- 10357577
TI  - Impact of new pharmacologic agents in the treatment of acute thrombotic
      syndromes.

PMID- 10357578
TI  - [Practice guidelines for the prevention of bacterial endocarditis. Developed by
      the cardiology staff of the Hospital Fernando Fonseca in accord with the American
      Heart Association recommendations].

PMID- 10357580
TI  - Current awareness in NMR in biomedicine.

PMID- 10357579
TI  - Comparing genomes in terms of protein structure: surveys of a finite parts list.
AB  - We give an overview of the emerging field of structural genomics, describing how
      genomes can be compared in terms of protein structure. As the number of genes in
      a genome and the total number of protein folds are both quite limited, these
      comparisons take the form of surveys of a finite parts list, similar in respects
      to demographic censuses. Fold surveys have many similarities with other whole
      genome characterizations, e.g., analyses of motifs or pathways. However,
      structure has a number of aspects that make it particularly suitable for
      comparing genomes, namely the way it allows for the precise definition of a basic
      protein module and the fact that it has a better defined relationship to sequence
      similarity than does protein function. An essential requirement for a structure
      survey is a library of folds, which groups the known structures into 'fold
      families.' This library can be built up automatically using a structure
      comparison program, and we described how important objective statistical measures
      are for assessing similarities within the library and between the library and
      genome sequences. After building the library, one can use it to count the number
      of folds in genomes, expressing the results in the form of Venn diagrams and 'top
      10' statistics for shared and common folds. Depending on the counting methodology
      employed, these statistics can reflect different aspects of the genome, such as
      the amount of internal duplication or gene expression. Previous analyses have
      shown that the common folds shared between very different microorganisms, i.e.,
      in different kingdoms, have a remarkably similar structure, being comprised of
      repeated strand-helix-strand super-secondary structure units. A major difficulty
      with this sort of 'fold-counting' is that only a small subset of the structures
      in a complete genome are currently known and this subset is prone to sampling
      bias. One way of overcoming biases is through structure prediction, which can be
      applied uniformly and comprehensively to a whole genome. Various investigators
      have, in fact, already applied many of the existing techniques for predicting
      secondary structure and transmembrane (TM) helices to the recently sequenced
      genomes. The results have been consistent: microbial genomes have similar
      fractions of strands and helices even though they have significantly different
      amino acid composition. The fraction of membrane proteins with a given number of
      TM helices falls off rapidly with more TM elements, approximately according to a
      Zipf law. This latter finding indicates that there is no preference for the
      highly studied 7-TM proteins in microbial genomes. Continuously updated tables
      and further information pertinent to this review are available over the web at
      http://bioinfo.mbb.yale.edu/genome.

PMID- 10357582
TI  - The Alimentary Disease Week. Manila, Philippines, 25-29 November 1998. Abstracts.

PMID- 10357581
TI  - Proceedings of the International Conference on Acute Respiratory Infections.
      Canberra, Australia, July 1997.

PMID- 10357583
TI  - Histochemistry on the threshold of the third millennium. In memory of Maffo
      Vialli and Giovanni Prenna. Pavia, Italy, June 18-19, 1997.

PMID- 10357584
TI  - GIFT-ICSI for the treatment of male-factor infertility for patients with
      religious objections to in vitro fertilization: a case report.

PMID- 10357585
TI  - Breast cancer in an ovum donor: a case report.

PMID- 10357586
TI  - Time and tide.

PMID- 10357587
TI  - Increased dispersion of ventricular repolarisation during stress test induced
      ischaemia.

PMID- 10357588
TI  - Ten year follow up of patients referred for CABG from a single DGH.

PMID- 10357589
TI  - Brugada syndrome associated with an autonomic disorder.

PMID- 10357590
TI  - Does aspirin treatment influence vascular resistance and fluid filtration in
      patients with congestive heart failure?

PMID- 10357591
TI  - Non-cardiac chest pain: a useful physical sign?

PMID- 10357592
TI  - AV node ablation and implantation of mode switching dual chamber pacemakers:
      effective treatment for drug refractory PAF.

PMID- 10357593
TI  - Management of polycythaemia in adults with cyanotic congenital heart disease.

PMID- 10357594
TI  - Myocardial infarction in young people with normal coronary arteries.

PMID- 10357595
TI  - Value of improved treadmill exercise capacity.

PMID- 10357596
TI  - Heart rate variability and cardiac failure.

PMID- 10357597
TI  - Heart rate variability and cardiac failure.

PMID- 10357598
TI  - Glabal climate change and weakened therapeutic agents against ischaemic heart
      diseases.

PMID- 10357599
TI  - Atrial natriuretic factor and the atrial function.

PMID- 10357600
TI  - Seasonal incidence of acute myocardial infarction in the Chinese population.

PMID- 10357601
TI  - Sumatriptan and sensory neuropeptide activity in subarachnoid haemorrhage: an
      hypothesis.

PMID- 10357602
TI  - Migraine trigger factors in non-clinical Mexican-American population in San Diego
      county: implications for etiology.
AB  - We conducted an investigation of migraine headache in a general population of
      Mexican-Americans living in San Diego county. Specific headache triggers were
      reported and analyzed, the most frequently reported for females with migraine
      being missing meals (58.9%), weather changes (54.4%), menstruation (53.6%), post
      crisis letdown (52.7%), and fatigue (51.8%). The most frequently reported trigger
      factors for migraines reported by males were fatigue (58.8%), sleep (as a
      precipitating factor) (56.3%), post-crisis letdown (41.2%), and weather changes
      (37.5%). Trigger factors were further evaluated using stratification by presence
      or absence of Raynaud's phenomenon (RP), menstrual migraine, family history of
      migraine, and by migraine type. Odds ratios and 95% confidence intervals were
      calculated. These results suggest that subjects with migraine and RP (perhaps
      indicative of a systematic vascular tone disorder) and those with menstrual
      migraine (indicative of sensitivity to hormonal changes) may overall be more
      sensitive to certain environmental stimuli, particularly those involving change
      in the internal environment.

PMID- 10357603
TI  - Airway structure: a role for confocal microscopy?

PMID- 10357604
TI  - Outdoor environmental injury of the airways and development of allergic
      respiratory diseases.

PMID- 10357605
TI  - Combination therapy.

PMID- 10357606
TI  - Interpreting reported health-care benefits.
AB  - When reading published reports on the benefits of different treatments or health
      care programmes, readers are generally interested in judging the applicability of
      the results to their own settings. Thus they need to be able to identify what
      consequences (and costs) were included in the evaluation. This short paper
      describes the different categories of 'benefit' that may arise from health-care
      interventions and explains some of the methodological considerations in their
      measurement. It provides simple advice on avoiding the common pitfalls when
      interpreting the value offered by a particular treatment or configuration of
      health services.

PMID- 10357607
TI  - The macrophage--a cell for all seasons.

PMID- 10357608
TI  - Plant metabolic engineering: are we ready for phase two?

PMID- 10357609
TI  - Genome studies and molecular genetics. Plant biotechnology. Web alert.

PMID- 10357610
TI  - Statistical errors in "A new approach to surgery for Meniere's disease".

PMID- 10357611
TI  - Digital guidance of female urethral catheterization.

PMID- 10357612
TI  - Modified ureterosigmoidostomy (Mainz II): technique and early results.

PMID- 10357613
TI  - Diagnosis and treatment of adrenal tumours: a review of 35 years' experience.

PMID- 10357614
TI  - Proceedings of the World Congresses of Gastroenterology. Vienna, Austria,
      September 6-11, 1998.

PMID- 10357615
TI  - The changing features of celiac disease. Preface.

PMID- 10357617
TI  - Ethics and managed care.

PMID- 10357618
TI  - Perioperative Evaluation and Management. Conference proceedings. Northbrook,
      Illinois, USA. May 16-17, 1998.

PMID- 10357616
TI  - Genetics of IBD: Where do we stand? Introduction.

PMID- 10357619
TI  - A decade of octreotide.

PMID- 10357620
TI  - Octreotide. Outlook.

PMID- 10357621
TI  - Recent publications in hematological oncology.

PMID- 10357622
TI  - Proceedings of the 2nd International Summit Meeting on Immunological Correlates
      of Protection from HIV Infection and Disease. Oxford, United Kingdom, 17-20 April
      1998.

PMID- 10357623
TI  - National Institute of Mental Health 12th International Conference on Mental
      Health Problems in the General Health Care Sector. Baltimore, Maryland, USA. July
      13-14, 1998. Abstracts.

PMID- 10357624
TI  - Insulin resistance: solutions for a common problem.

PMID- 10357625
TI  - HIV-1 Infection, Mucosal Immunity and Pathogenesis. Conference proceedings.
      Bethesda, Maryland, USA. 11-13 September 1997.

PMID- 10357626
TI  - Postoperative pain control after craniotomy.

PMID- 10357627
TI  - Cancer statistics digest. Breast cancer incidence for females in Japan.

PMID- 10357628
TI  - Electronic mailing lists.

PMID- 10357629
TI  - Sceptical medicine.

PMID- 10357630
TI  - Antimicrobial-impregnated central venous catheters.

PMID- 10357631
TI  - Antimicrobial-impregnated central venous catheters.

PMID- 10357632
TI  - Antimicrobial-impregnated central venous catheters.

PMID- 10357633
TI  - Antimicrobial-impregnated central venous catheters.

PMID- 10357634
TI  - Carotid-artery intima and media thickness as a risk factor for myocardial
      infarction and stroke.

PMID- 10357635
TI  - Epinephrine for out-of-hospital cardiac arrest.

PMID- 10357636
TI  - Epinephrine for out-of-hospital cardiac arrest.

PMID- 10357637
TI  - Resolution of chronic hepatitis B after ritonavir treatment in an HIV-infected
      patient.

PMID- 10357638
TI  - Attention-deficit-hyperactivity disorder.

PMID- 10357639
TI  - Attention-deficit-hyperactivity disorder.

PMID- 10357640
TI  - Attention-deficit-hyperactivity disorder.

PMID- 10357641
TI  - Cullen's sign in metastatic thyroid cancer.

PMID- 10357642
TI  - The area under the curve.

PMID- 10357643
TI  - The peritoneal immune system and continuous ambulatory peritoneal dialysis.

PMID- 10357644
TI  - [Hemostasis for the anesthesiologist in surgery and intensive care. Milano,
      Italy, 11-12 February 1999. Proceedings].

PMID- 10357647
TI  - Graded autocatalysis replication domain (GARD): kinetic analysis of self
      replication in mutually catalytic sets.
AB  - A Graded Autocatalysis Replication Domain (GARD) model is proposed, which
      provides a rigorous kinetic analysis of simple chemical sets that manifest mutual
      catalysis. It is shown that catalytic closure can sustain self-replication up to
      a critical dilution rate, lambda c, related to the graded extent of mutual
      catalysis. We explore the behavior of vesicles containing GARD species whose
      mutual catalysis is governed by a previously published statistical distribution.
      In the population thus generated, some GARD vesicles display a significantly
      higher replication efficiency than most others. GARD thus represents a simple
      model for primordial chemical selection of mutually catalytic sets.

PMID- 10357645
TI  - Carbonaceous micrometeorites and the origin of life.
AB  - Giant micrometeorites (sizes ranging from approximately 50 to 500 micrometers),
      such as those that were first recovered from clean pre-industrial Antarctic ices
      in December 1987, represent by far the dominant source of extraterrestrial
      carbonaceous material accreted by the Earth's surface, about 50,000 times the
      amount delivered by meteorites (sizes > or = a few cm). They correspond to large
      interplanetary dust particles that survived unexpectedly well their hypervelocity
      impact with the Earth's atmosphere, contrary to predictions of theoretical models
      of such impacts. They are related to relatively rare groups of carbonaceous
      chondrites (approximately 2% of the meteorite falls) and not to the most abundant
      meteorites (oridinary chondrites and differentiated micrometeorites). About 80%
      of them appear to be highly unequilibrated fine-grained assemblages of mineral
      grains, where an abundant carbonaceous component is closely associated on a scale
      of < or = 0.1 micron to both hydrous and anhydrous minerals, including potential
      catalysts. These observations suggest that micrometeorites could have functioned
      as individual microscopic chemical reactors to contribute to the synthesis of
      prebiotic molecules on the early Earth, about 4 billion years ago. The recent
      identification of some of their complex organics (amino acids and polycyclic
      aromatic hydrocarbons), and the observation that they behave as very efficient
      'cosmochromatographs', further support this 'early carbonaceous micrometeorite'
      scenario. Future prospects include identifying the host phases (probably
      ferrihydrite) of their complex organics, evaluating their catalytic activity, and
      assessing whether synergetic interactions between micrometeorites and favorable
      zones of the early Earth (such as submarine hydrothermal vents) accelerated
      and/or modified such synthesis.

PMID- 10357648
TI  - Internationally adopted children--immunization status.

PMID- 10357649
TI  - Concern about Piracetam treatment for children with Down syndrome.

PMID- 10357650
TI  - Brain hypothermia and QT interval.

PMID- 10357651
TI  - Smoking status as a vital sign in pediatric settings.

PMID- 10357652
TI  - Shining the light on lamp oil.

PMID- 10357653
TI  - The role of the pediatrician in youth violence prevention in clinical practice
      and at the community level.

PMID- 10357654
TI  - [Phylogenetic preservation of genetic study stocks of Saccharomyces cerevisiae].

PMID- 10357655
TI  - [Phylogenetic preservation of genetic study stocks of Schizosaccharomyces pombe].

PMID- 10357656
TI  - [Right-left intra-atrial shunt in the absence of elevated pressures in the right
      cardiac cavities].

PMID- 10357657
TI  - [Proceedings of the 3rd Pneumology Congress of the French Languages. Paris,
      France, 27-30 January 1999].

PMID- 10357658
TI  - [Further specialist titles from the SSO. Societe Suisse d'Odonto-Stomatologie].

PMID- 10357659
TI  - [The current problems of dentistry around the health insurance law. Continuing
      education week, autumn 1998].

PMID- 10357660
TI  - [An open letter to those responsible for developing "quality standards for
      dentistry" and to the organizers of the Interdisciplinary Continuing Education
      Week 1999. 15 March 1999].

PMID- 10357661
TI  - [The prevalence of hepatitis C infection among Swiss dentists. The silent
      epidemic].

PMID- 10357662
TI  - [Quality assurance in dentistry].

PMID- 10357663
TI  - [Hygiene is team work].

PMID- 10357665
TI  - Startling revelations in UC-Genentech battle.

PMID- 10357664
TI  - Gene may promise new route to potent vaccines.

PMID- 10357666
TI  - AIDS windfall.

PMID- 10357667
TI  - New lead found to a possible "insulin pill".

PMID- 10357668
TI  - Scientific misconduct. ORI report tracks gun-shy feds.

PMID- 10357669
TI  - Investing in the World Health Organization.

PMID- 10357670
TI  - Inhumane death?

PMID- 10357671
TI  - Pills or placebos?

PMID- 10357672
TI  - Pills or placebos?

PMID- 10357673
TI  - Pills or placebos?

PMID- 10357674
TI  - Pills or placebos?

PMID- 10357675
TI  - Pills or placebos?

PMID- 10357676
TI  - Pills or placebos?

PMID- 10357677
TI  - The physician-scientist template.

PMID- 10357678
TI  - Uses and abuses of Tuskegee.

PMID- 10357679
TI  - Sensory maps on the move.

PMID- 10357680
TI  - A head for figures.

PMID- 10357682
TI  - A professor, a student and a criminal.

PMID- 10357681
TI  - The mother-to-child HIV transmission debate.

PMID- 10357683
TI  - Proceedings of the 12th International Workshop on Alloantigenic Systems in the
      Rat. Halifax, Nova Scotia, Canada. July 8-10, 1998.

PMID- 10357684
TI  - Guidelines for the Use of Cyclosporine Formulations. Proceedings of a roundtable
      satellite meeting of the Transplantation Society. Montreal, Canada, 13 July 1998.

PMID- 10357686
TI  - Generic Immunosuppressants. Proceedings of a symposium. Montreal, Canada, July
      12, 1998.

PMID- 10357685
TI  - Proceedings of the 5th Basic Sciences Symposium of the Transplantation Society. A
      festschrift honoring Felix Milgrom. Chautauqua, New York, USA. September 6-11,
      1997.

PMID- 10357687
TI  - [15th Annual meeting of the German Association for the Study of the Liver. Kiel,
      29-30 January 1999. Abstracts].

PMID- 10357688
TI  - Proceedings of the Neuroscience Symposium on Molecular and Cellular Mechanisms of
      Neuronal Plasticity. Staten Island, New York, USA. December 4, 1996.

PMID- 10357689
TI  - Cost-effectiveness of diagnostic strategies for patients with chest pain.
AB  - BACKGROUND: Many noninvasive tests exist to determine whether patients should
      undergo coronary angiography. The routine use of coronary angiography without
      previous noninvasive testing is typically not advocated. OBJECTIVE: To determine
      the cost-effectiveness of diagnostic strategies for patients with chest pain.
      DESIGN: Cost-effectiveness analysis. DATA SOURCES: Published data. TARGET
      POPULATION: Patients who present with chest pain, have no history of myocardial
      infarction, and are able to perform an exercise stress test. TIME HORIZON:
      Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: No testing, exercise
      electrocardiography, exercise echocardiography, exercise single-photon emission
      computed tomography (SPECT), and coronary angiography alone. OUTCOME MEASURES:
      Quality-adjusted life expectancy, lifetime cost, and incremental cost
      effectiveness. RESULTS OF BASE-CASE ANALYSIS: The incremental cost-effectiveness
      ratio of routine coronary angiography compared with exercise echocardiography was
      $36,400 per quality-adjusted life-year (QALY) saved for 55-year-old men with
      typical angina. For 55-year-old men with atypical angina, exercise
      echocardiography compared with exercise electrocardiography cost $41,900 per QALY
      saved. If adequate exercise echocardiography was not available, exercise SPECT
      cost $54,800 per QALY saved compared with exercise electrocardiography for these
      patients. For 55-year-old men with nonspecific chest pain, the incremental cost
      effectiveness ratio of exercise electrocardiography compared with no testing was
      $57,700 per QALY saved. RESULTS OF SENSITIVITY ANALYSIS: On the basis of a
      probabilistic sensitivity analysis, there is a 75% chance that exercise
      echocardiography costs less than $50,900 per QALY saved for 55-year-old men with
      atypical angina. CONCLUSIONS: Exercise electrocardiography or exercise
      echocardiography resulted in reasonable cost-effectiveness ratios for patients at
      mild to moderate risk for coronary artery disease in terms of age, sex, and type
      of chest pain. Coronary angiography without previous noninvasive testing resulted
      in reasonable cost-effectiveness ratios for patients with a high pretest
      probability of coronary artery disease.

PMID- 10357690
TI  - Cost-effectiveness of alternative test strategies for the diagnosis of coronary
      artery disease.
AB  - BACKGROUND: The appropriate roles for several diagnostic tests for coronary
      disease are uncertain. OBJECTIVE: To evaluate the cost-effectiveness of
      alternative approaches to diagnosis of coronary disease. DESIGN: Meta-analysis of
      the accuracy of alternative diagnostic tests plus decision analysis to assess the
      health outcomes and costs of alternative diagnostic strategies for patients at
      intermediate pretest risk for coronary disease. DATA SOURCES: Studies of test
      accuracy that met inclusion criteria; published information on treatment
      effectiveness and disease prevalence. TARGET POPULATION: Men and women 45, 55,
      and 65 years of age with a 25% to 75% pretest risk for coronary disease. TIME
      HORIZON: 30 years. PERSPECTIVE: Societal. INTERVENTIONS: Diagnostic strategies
      were initial angiography and initial testing with one of five noninvasive tests-
      exercise treadmill testing, planar thallium imaging, single-photon emission
      computed tomography (SPECT), stress echocardiography, and positron emission
      tomography (PET)--followed by coronary angiography if noninvasive test results
      were positive. Testing was followed by observation, medical treatment, or
      revascularization. OUTCOME MEASURES: Life-years, quality-adjusted life-years
      (QALYs), costs, and costs per QALY. RESULTS OF BASE-CASE ANALYSIS: Life
      expectancy varied little with the initial diagnostic test; for a 55-year-old man,
      the best-performing test increased life expectancy by 7 more days than the worst
      performing test. More sensitive tests increased QALYs more. Echocardiography
      improved health outcomes and reduced costs relative to stress testing and planar
      thallium imaging. The incremental cost-effectiveness ratio was $75,000/QALY for
      SPECT relative to echocardiography and was greater than $640,000 for PET relative
      to SPECT. Compared with SPECT, immediate angiography had an incremental cost
      effectiveness ratio of $94,000/QALY. RESULTS OF SENSITIVITY ANALYSIS: Qualitative
      findings varied little with age, sex, pretest probability of disease, or the test
      indeterminancy rate. Results varied most with sensitivity to severe coronary
      disease. CONCLUSIONS: Echocardiography, SPECT, and immediate angiography are cost
      effective alternatives to PET and other diagnostic approaches. Test selection
      should reflect local variation in test accuracy.

PMID- 10357691
TI  - Use of tunneled femoral catheters to prevent catheter-related infection. A
      randomized, controlled trial.
AB  - BACKGROUND: The risk for catheter-related infection seems higher with femoral
      catheters than with catheters inserted at other sites. OBJECTIVE: To evaluate the
      effect of catheter tunneling on femoral catheter-related infection in critically
      ill patients. DESIGN: Randomized, controlled trial. SETTING: Three intensive care
      units at academic hospitals in Paris, France. PATIENTS: 345 adult patients
      requiring a femoral venous catheter for more than 48 hours. INTERVENTION:
      Tunneled or nontunneled femoral catheters. MEASUREMENTS: Time to occurrence of
      systemic catheter-related sepsis, catheter-related bloodstream infection, and
      quantitative catheter tip culture with a cutoff of 10(3) colony-forming units/mL.
      RESULTS: Of 345 randomly assigned patients, 336 were evaluable. Probable systemic
      catheter-related sepsis occurred in 15 of 168 patients who received a nontunneled
      femoral catheter (controls) and in 5 of 168 patients who received a tunneled
      femoral catheter (estimated absolute risk reduction, 6% [95% CI, 0.9% to 11%]).
      Time to occurrence of catheter-related bloodstream infection was not
      significantly modified (relative risk, 0.28 [CI, 0.03 to 1.92]; P = 0.18); 3
      events occurred in the control group and 1 event occurred in the tunneled
      catheter group. After stratification by treatment center and adjustment for
      variables that were prognostic (use of broad-spectrum antimicrobial agents at
      catheter insertion) or imbalanced between both groups (mechanical ventilation at
      insertion), tunnelized catheterization reduced the proportion of patients who
      developed systemic catheter-related sepsis (relative risk, 0.25 [CI, 0.09 to
      0.72]; P = 0.005) and positive quantitative culture of the catheter tip (relative
      risk, 0.48 [CI, 0.23 to 0.99]; P = 0.045). CONCLUSION: The incidence of femoral
      catheter-related infections in critically ill patients can be reduced by using
      subcutaneous tunneling.

PMID- 10357692
TI  - Increased risk for fetal loss in carriers of the factor V Leiden mutation.
AB  - BACKGROUND: An increased risk for fetal loss caused by placental thrombosis is
      probable in carriers of the factor V Leiden mutation but has not been
      demonstrated consistently in previous studies. OBJECTIVE: To determine the
      overall risk for fetal loss and the separate risks for miscarriage and stillbirth
      in carriers of the factor V Leiden mutation. DESIGN: Retrospective cohort study.
      SETTING: Three university hospitals. PARTICIPANTS: 228 carriers of the factor V
      Leiden mutation (77 propositi, 151 relatives) and 121 noncarrier relatives
      (controls). All participants had been pregnant at least once. MEASUREMENTS: Risks
      for fetal loss, miscarriage (defined as fetal loss within 20 weeks of gestation),
      and stillbirth (defined as fetal loss after >20 weeks of gestation) in women and
      in pregnancies were estimated and compared in carriers and noncarriers. Adjusted
      odds ratios were calculated by using multiple regression analysis. A random
      effects model was used for comparisons of pregnancies. RESULTS: Fetal loss
      occurred in 31.6% of carriers and 22.3% of noncarriers, miscarriage occurred in
      29.4% of carriers and 17.4% of noncarriers, and stillbirth occurred in 5.7% of
      carriers and 5.0% of noncarriers. Fetal loss recurred in 10.1% of carriers and
      4.1% of noncarriers (odds ratio, 2.60 [95% CI, 0.96 to 7.03]). Adjusted odds
      ratios were 2.12 (CI, 1.35 to 3.33) for fetal loss, 2.08 (CI, 1.33 to 3.25) for
      miscarriage, and 1.60 (CI, 0.58 to 4.43) for still-birth when pregnancies in
      carriers and noncarriers were compared. Homozygous carriers had a greater risk
      for fetal loss (odds ratio, 2.01 [CI, 0.94 to 4.32]) and stillbirth (odds ratio,
      4.85 [CI, 0.82 to 25.58]) than heterozygous carriers. CONCLUSIONS: Carriers of
      the factor V Leiden mutation have a greater risk for fetal loss (particularly
      miscarriage) than noncarriers. These data further suggest a greater risk for
      recurrence of fetal loss in carriers than in noncarriers and a greater risk for
      fetal loss and stillbirth in homozygous carriers than in heterozygous carriers.

PMID- 10357693
TI  - Compassionate use of continuous prostacyclin in the management of secondary
      pulmonary hypertension: a case series.
AB  - BACKGROUND: Treatment of patients with secondary pulmonary hypertension has been
      unsatisfactory. OBJECTIVE: To describe exercise capacity, functional class, and
      hemodynamic variables after long-term intravenous infusion of prostacyclin in
      patients with secondary pulmonary hypertension. DESIGN: Case series. SETTING:
      Academic referral center. PATIENTS: 33 patients with secondary, precapillary
      pulmonary hypertension (New York Heart Association class III or IV).
      INTERVENTION: Continuous intravenous prostacyclin administered by portable
      infusion pump on a compassionate-use basis. MEASUREMENTS: Functional class,
      treadmill time, and hemodynamic variables. RESULTS: Patients were followed for an
      average of 12.7 +/- 5.6 months. Exercise tolerance and New York Heart Association
      class improved in each patient. The duration of treadmill exercise increased from
      186 seconds to 491 seconds, an increase of 305 seconds (95% CI, 194 to 417
      seconds; P < 0.001). Mean pulmonary artery pressure decreased from 60 mm Hg to 46
      mm Hg, a decrease of 14 mm Hg (CI, 9 to 19 mm Hg; P < 0.001). Cardiac output
      increased from 3.90 L/min to 6.30 L/min, an increase of 2.40 L/min (CI, 1.56 to
      3.25 L/min; P < 0.001). The pulmonary vascular resistance decreased from 1143
      dynes x s/cm5 to 575 dynes x s/cm5, a decrease of 567 dynes x s/cm5 (CI, 407 to
      727 dynes x s/cm5; P < 0.001). Patients with collagen vascular disease,
      congenital heart disease, and portopulmonary hypertension were analyzed with
      other patients and separately. All groups had a statistically significant
      reduction in mean pulmonary artery pressure and a statistically significant
      increase in cardiac output. CONCLUSION: Intravenous prostacyclin may be effective
      in the treatment of patients with certain types of secondary pulmonary
      hypertension.

PMID- 10357694
TI  - Discussing palliative care with patients. ACP-ASIM End-of-Life Care Consensus
      Panel. American College of Physicians-American Society of Internal Medicine.

PMID- 10357696
TI  - Adrenocortical tumors: recent advances in basic concepts and clinical management.
AB  - Adrenocortical masses are among the most common tumors in humans. However, only a
      small proportion of these tumors cause endocrine diseases (such as primary
      hyperaldosteronism, hypercortisolism, hyperandrogenism, or hyperestrogenism), and
      less than 1% are malignant. In recent years, several of the molecular and
      cellular mechanisms involved in adrenal tumorigenesis have been unraveled. As a
      result, alterations in intercellular communication, local production of growth
      factors and cytokines, and aberrant expression of ectopic receptors on adrenal
      tumor cells have been implicated in adrenal cell growth, hyperplasia, tumor
      formation, and autonomous hormone production. Genetic and chromosomal
      abnormalities, including several chromosomal loci and the genes coding for p53,
      p57, and insulin-like growth factor II, have been reported in adrenal tumors. In
      addition, chromosomal markers have been identified in several familial syndromes
      associated with adrenal tumors; these include menin, which is responsible for
      multiple endocrine neoplasia type I, and the hybrid gene that causes
      glucocorticoid-remediable hyperaldosteronism. Algorithms for endocrine testing
      and imaging procedures are now available to codify screening for, confirmation
      of, and differentiation of causes of primary hyperaldosteronism and the Cushing
      syndrome. Improved radiologic, computerized radiologic, and magnetic resonance
      imaging techniques, as well as selective catheterization studies, are useful in
      localizing adrenal tumors and in distinguishing between benign and malignant
      lesions and between functional and nonfunctional nodules. Finally, recent
      refinements in the field of minimally invasive general surgery have made
      laparoscopic adrenalectomy the method of choice for removing adrenal tumors; this
      type of surgery allows shorter hospital stays, lower morbidity rates, and faster
      recovery.

PMID- 10357695
TI  - The effect of thyroid hormone on skeletal integrity.
AB  - BACKGROUND: Thyroid disease and osteoporosis are common problems often managed by
      primary care physicians. Despite many studies, confusion still exists about the
      effect of thyroid hormone on skeletal health. PURPOSE: To review evidence on the
      effect of thyroid hormone (from hyperthyroidism, exogenous or endogenous
      suppression of thyroid-stimulating hormone [TSH], and thyroid hormone replacement
      therapy) on skeletal integrity. DATA SOURCES: A MEDLINE search of papers
      published between 1966 and 1997. DATA SELECTION: Cross-sectional studies,
      longitudinal studies, and meta-analyses that had appropriate control groups
      (patients matched for age, sex, and menopausal status), made comparisons with
      established databases, or defined thyroid state by TSH level or thyroid hormone
      dose were reviewed. DATA EXTRACTION AND SYNTHESIS: Data synthesis was not
      straightforward because of changes in doses and types of thyroid hormone
      preparations; changes in definitions of thyroid hormone replacement therapy and
      suppressive therapies; problems with study design; differences in skeletal sites
      assessed (hip, spine, forearm, or heel) and techniques used to measure bone
      mineral density; and inclusion of heterogenous and changing thyroid disease
      states. Overall, hyperthyroidism and use of thyroid hormone to suppress TSH
      because of thyroid cancer, goiters, or nodules seem to have an adverse effect on
      bone, especially in postmenopausal women; the largest effect is on cortical bone.
      Thyroid hormone replacement seems to have a minimal clinical effect on bone.
      CONCLUSION: Women with a history of hyperthyroidism or TSH suppression by thyroid
      hormone should have skeletal status assessed by bone mineral densitometry,
      preferably at a site containing cortical bone, such as the hip or forearm.

PMID- 10357697
TI  - Care at the end of life: guiding practice where there are no easy answers.

PMID- 10357698
TI  - The making and unmaking of a journal.

PMID- 10357699
TI  - Saving lives and saving deaths.

PMID- 10357700
TI  - Screening tests for alcohol use disorders.

PMID- 10357701
TI  - Screening tests for alcohol use disorders.

PMID- 10357702
TI  - Genetics of familial Mediterranean fever.

PMID- 10357703
TI  - Genetics of familial Mediterranean fever.

PMID- 10357704
TI  - How physicians communicate about advance directives.

PMID- 10357705
TI  - How physicians communicate about advance directives.

PMID- 10357706
TI  - Textbook geriatrics: not yet of the essence.

PMID- 10357707
TI  - Coexistence of allergic contact dermatitis and granuloma annulare in an HIV-1
      infected patient: A casual association?

PMID- 10357712
TI  - A 10-year retrospective study on benzocaine allergy in the United Kingdom.
AB  - BACKGROUND: Benzocaine has been labeled a notorious sensitizer. It is thought to
      be a common and potent sensitizer. It is suggested that such patients should
      routinely avoid tetracaine and procaine, as cross-reactions between benzocaine
      and such caines occurred commonly. Benzocaine also currently remains the
      screening chemical on the European Standard Battery (ESB) for topical caine
      allergy. OBJECTIVE: To identify the rate of incidence of benzocaine allergy in
      the United Kingdom, and the level of cross reactivity between other caines in the
      ESB. METHODS: The results from a 10-year retrospective study of 5,464 patients,
      subjected to patch testing with a modified ESB, which included caine mix III
      (Chemotechnique Diagnostics, Tygelsjo, Sweden), and the results of caine mix IV
      (Chemotechnique) reactions in 265 of these patients who complained of anogenital
      symptoms, are discussed. RESULTS: Majority of allergic reactions occurred with
      the constituents of caine mix III, with benzocaine reactions being the least
      common allergen in this group. Cross reactivity between benzocaine and other
      caines, occurred infrequently. CONCLUSION: Our data indicate that benzocaine
      allergy is not common in the United Kingdom. As cross-reactivity between
      benzocaine and other caines did not occur commonly, a significant number of
      relevant allergic reactions to other caines may go undetected, as benzocaine
      remains the screening chemical for topical anaesthetic allergy on the ESB. We
      suggest benzocaine be removed from the ESB, and be replaced by caine mix III.

PMID- 10357713
TI  - Individual variation in nickel patch test reactivity.
AB  - BACKGROUND AND OBJECTIVE: Various factors such as hormones, drugs, and
      ultraviolet (UV) radiation may influence patch test reactions. The aim was to
      study the individual variation in nickel reactivity, also in relation to the
      menstrual cycle. METHODS: Thirty women allergic to nickel were studied for 7
      months with patch tests with a serial dilution of nickel sulfate in water on four
      different test occasions. The patients belonged to two different eczema groups,
      one with nickel allergy, atopy, and pompholyx (12 patients); and the other with
      nickel allergy, but without both atopy and hand eczema. RESULTS: None of the
      patients showed the same patch test reactivity on all four occasions, and the
      highest individual difference noticed was 250 times for the four test occasions.
      Furthermore, two of the patients had completely negative test reactions on at
      least one test occasion. CONCLUSION: The variation in nickel reactivity as shown
      in this article is of great importance and should be kept in mind when a patient
      has a positive history of allergic contact dermatitis but negative patch test
      results to nickel.

PMID- 10357714
TI  - Degradation products of monoterpenes are the sensitizing agents in tea tree oil.
AB  - BACKGROUND: Patients using tea tree oil (TTO) topically may become sensitized to
      this natural remedy. More than 30 cases have been documented in the literature
      since 1991. OBJECTIVE: Freshly distilled, as well as oxidized TTO, some
      fractions, and single constituents were used for experimental sensitization in
      guinea pigs. TTO was stored on a window sill to study the influence of light,
      oxygen, and warmth. The oxidized oil and different fractions were devoted to
      experimental sensitization in guinea pigs to determine their sensitizing potency.
      Fifteen constituents were patch tested in TTO-sensitive patients to find how many
      may play a role as contact allergens. METHODS: Guinea pigs were sensitized by a
      modified FCA-method (Freund's complete adjuvant) with freshly distilled TTO,
      oxidized TTO, the monoterpene and sesquiterpene fraction, and 1, 8-cineole. TTO
      sensitive patients were tested with 15 typical constituents and degradation
      products. Gas chromatographic analysis was used to detect degradation products of
      the deteriorated TTO. RESULTS: Fresh TTO was revealed to be a very weak
      sensitizing material whereas oxidized TTO was 3 times stronger. The monoterpene
      fraction showed to be a stronger sensitizer than the sesquiterpene fraction. All
      11 patients reacted mostly with a ++-plus or even a -plus reaction to alpha
      terpinene, terpinolene and ascaridol. alpha-Phellandrene became positive in four
      patients, myrcene in only two. Gas chromatographic analyses showed that the
      formation of peroxides increased within 4 days from less than 50 to more than 500
      ppm. Peroxides, epoxides and endoperoxides were formed. Deterioration products of
      alpha-terpinene were found to be mainly p-cymene, ascaridol, isoascaridol, a
      ketoperoxide, and colorless crystals that likely were 1,2,4-trihydroxy menthane.
      The p-cymene content increased dramatically from 2% to 11.5%. alpha- and gamma
      terpinene, as well as terpinolene, were reduced to one half of their former
      concentration. Ascaridol and isoascaridol have never before been found in TTO.
      CONCLUSION: Tea tree oil kept in open and closed bottles or other containers
      undergoes photooxidation within a few days to several months, leading to the
      creation of degradation products that are moderate to strong sensitizers.
      Peroxides, epoxides and endoperoxides, like ascaridol and 1,2,4-trihydroxy
      menthane, are formed. These must be considered responsible for the development of
      allergic contact dermatitis seen in individuals treating themselves with the oil.
      A test series with 15 characteristic constituents is recommended for patch
      testing.

PMID- 10357715
TI  - Allergic and irritant contact dermatitis to calcipotriol.
AB  - Calcipotriol (Daivonex R; Leo Pharmaceuticals, Zurich, Switzerland) may cause
      irritation of the skin, whereas allergic reactions are less common. In the
      present study we describe two patients with different types of reaction patterns,
      one presenting as an allergic, the other as an irritant contact dermatitis.
      Irritative skin reactions were observed only at higher testings doses, in
      contrast to the allergic type of reaction, which occurred at a lower testing
      dose. The present observation suggests, that a batch of different testing doses,
      including lower testing doses may help to differentiate between an allergic type
      of contact dermatitis and an irritant type of reaction after treatment with
      calcipotriol.

PMID- 10357716
TI  - Contact puzzle: Worsening of a recurrent facial eruption despite treatment.
      Diagnosis: allergic contact dermatitis caused by desonide.

PMID- 10357717
TI  - Occupational protein contact dermatitis to cornstarch in a paper adhesive.
AB  - BACKGROUND: Protein contact dermatitis is better known in food-service and health
      care workers than in industrial workers. Cornstarch has seldom been a problem,
      although it can cause contact urticaria to glove powder. OBJECTIVE: To present
      the case of a paper-bag maker who developed severe occupational (protein) contact
      dermatitis within two-three hours after returning to work. She lacked any
      evidence of urticaria and demonstrated largely negative patch-test results.
      METHODS: Following a history of occupational exposure to a cornstarch-based
      adhesive, the patient was patch-tested to materials with which she had worked,
      which she contacted, and with which she had attempted treatment. Following patch
      testing, she was prick-tested to cornstarch, the principal ingredient in the
      adhesive. RESULTS: Patch testing was negative except for a very mild reaction to
      the adhesive. Prick testing to cornstarch was more severe than the histamine
      control. The test site became eczematous and remained so for more than ten weeks.
      Avoidance of cornstarch and the adhesive was followed by clearing. CONCLUSION:
      Workup for prominent occupational contact dermatitis without urticaria may
      sometimes require testing for type 1 allergy.

PMID- 10357718
TI  - Phytophotodermatitis.
AB  - This article is a concise review of phytophotodermatitis, including the mechanism
      involved, clinical features, and treatment options. The common culprit plant
      families of Umbelliferae, Rutaceae, and Moraceae are discussed along with the
      newly recognized St. John's Wort.

PMID- 10357719
TI  - To patch or not to patch: what is your threshold for patch testing?
AB  - Patch testing is as much art as it is science; we all are influenced by our
      clinical experience as well as by the literature. In an effort to assist those
      new to this often underutilized technique, we have solicited comments from five
      experienced clinicians about when to patch test and when not to patch test. Their
      responses should be a guide for us all.

PMID- 10357720
TI  - Is blockade of pancreatic lipase the answer?

PMID- 10357721
TI  - The war against obesity: attacking a new front.

PMID- 10357722
TI  - Relapse in obesity treatment: biology or behavior?

PMID- 10357723
TI  - Effect of cirrhosis on energy expenditure.

PMID- 10357724
TI  - Iron and folate supplementation: an effective intervention in adolescent females.

PMID- 10357725
TI  - Alcohol, vitamin A, and beta-carotene: adverse interactions, including
      hepatotoxicity and carcinogenicity.
AB  - Isozymes of alcohol and other dehydrogenases convert ethanol and retinol to their
      corresponding aldehydes in vitro. In addition, new pathways of retinol metabolism
      have been described in hepatic microsomes that involve, in part, cytochrome
      P450s, which can also metabolize various drugs. In view of these overlapping
      metabolic pathways, it is not surprising that multiple interactions between
      retinol, ethanol, and other drugs occur. Accordingly, prolonged use of alcohol,
      drugs, or both, results not only in decreased dietary intake of retinoids and
      carotenoids, but also accelerates the breakdown of retinol through cross
      induction of degradative enzymes. There is also competition between ethanol and
      retinoic acid precursors. Depletion ensues, with associated hepatic and
      extrahepatic pathology, including carcinogenesis and contribution to fetal
      defects. Correction of deficiency through vitamin A supplementation has been
      advocated. It is, however, complicated by the intrinsic hepatotoxicity of
      retinol, which is potentiated by concomitant alcohol consumption. By contrast,
      beta-carotene, a precursor of vitamin A, was considered innocuous until recently,
      when it was found to also interact with ethanol, which interferes with its
      conversion to retinol. Furthermore, the combination of beta-carotene with ethanol
      results in hepatotoxicity. Moreover, in smokers who also consume alcohol, beta
      carotene supplementation promotes pulmonary cancer and, possibly, cardiovascular
      complications. Experimentally, beta-carotene toxicity was exacerbated when
      administered as part of beadlets. Thus ethanol, while promoting a deficiency of
      vitamin A also enhances its toxicity as well as that of beta-carotene. This
      narrowing of the therapeutic window for retinol and beta-carotene must be taken
      into account when formulating treatments aimed at correcting vitamin A
      deficiency, especially in drinking populations.

PMID- 10357726
TI  - Toward a new recommended dietary allowance for vitamin C based on antioxidant and
      health effects in humans.
AB  - The current recommended dietary allowance (RDA) for vitamin C for adult
      nonsmoking men and women is 60 mg/d, which is based on a mean requirement of 46
      mg/d to prevent the deficiency disease scurvy. However, recent scientific
      evidence indicates that an increased intake of vitamin C is associated with a
      reduced risk of chronic diseases such as cancer, cardiovascular disease, and
      cataract, probably through antioxidant mechanisms. It is likely that the amount
      of vitamin C required to prevent scurvy is not sufficient to optimally protect
      against these diseases. Because the RDA is defined as "the average daily dietary
      intake level that is sufficient to meet the nutrient requirement of nearly all
      healthy individuals in a group," it is appropriate to reevaluate the RDA for
      vitamin C. Therefore, we reviewed the biochemical, clinical, and epidemiologic
      evidence to date for a role of vitamin C in chronic disease prevention. The
      totality of the reviewed data suggests that an intake of 90-100 mg vitamin C/d is
      required for optimum reduction of chronic disease risk in nonsmoking men and
      women. This amount is about twice the amount on which the current RDA for vitamin
      C is based, suggesting a new RDA of 120 mg vitamin C/d.

PMID- 10357727
TI  - Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting:
      a 1-y study.
AB  - BACKGROUND: Long-term maintenance of weight loss remains a therapeutic challenge
      in obesity treatment. OBJECTIVE: This multicenter, double-blind, placebo
      controlled study was designed to test the hypothesis that orlistat, a
      gastrointestinal lipase inhibitor, is significantly more effective than a placebo
      in preventing weight regain. DESIGN: Obese subjects who lost > or = 8% of their
      initial body weight during a 6-mo lead-in of a prescribed hypoenergetic diet
      (4180-kJ/d deficit) with no adjunctive pharmacotherapy were randomly assigned to
      receive placebo, 30 mg orlistat, 60 mg orlistat, or 120 mg orlistat 3 times daily
      for 1 y in combination with a maintenance diet to help prevent weight regain. Of
      1313 recruited subjects [body mass index (in kg/m2): 28-43], 729 subjects lost >
      or =8% of their initial body weight during the 6-mo weight-loss lead-in period
      and were enrolled in the double-blind phase. RESULTS: After 1 y, subjects treated
      with 120 mg orlistat 3 times daily regained less weight than did placebo-treated
      subjects (32.8 +/- 4.5% compared with 58.7 +/- 5.8% regain of lost weight; P <
      0.001). Moreover, more subjects in the 120-mg orlistat group than in the placebo
      group regained < or = 25% of lost weight (47.5% of subjects compared with 29.9%).
      In addition, orlistat treatment (120 mg 3 times daily) was associated with
      significantly greater reductions in total and LDL-cholesterol concentrations than
      was placebo (P < 0.001). CONCLUSION: The use of orlistat during periods of
      attempted weight maintenance minimizes weight readjustment and facilitates long
      term improvement in obesity-related disease risk factors.

PMID- 10357728
TI  - Meta-analysis of resting metabolic rate in formerly obese subjects.
AB  - BACKGROUND: A low resting metabolic rate (RMR) for a given body size and
      composition is partly genetically determined and has been suggested to be a risk
      factor for weight gain. Moreover, a low relative RMR has been reported in some,
      but not all, studies of formerly obese persons. The inconsistent reports may be
      due to a lack of statistical power to detect small differences in RMR and
      improper adjustment for body size and composition. OBJECTIVE: We conducted a meta
      analysis based on published studies of RMR in formerly obese persons [body mass
      index (in kg/m2) < or = 27] and matched control subjects who had never been
      obese. DESIGN: We performed both an individual subject data meta-analysis and a
      traditional meta-analysis. RESULTS: The individual subject data meta-analysis
      included 124 formerly obese and 121 control subjects. RMR adjusted for
      differences in fat-free mass and fat mass was 2.9% lower in formerly obese
      subjects than in control subjects (P = 0.09). A low relative RMR (> 1 SD below
      the mean of the control group) was found in 3.3% of the control subjects and in
      15.3% of the formerly obese subjects [difference: 12% (95% CI: 4.7%, 19.3%); P <
      0.003]. The traditional meta-analysis was based on 12 studies (including 94
      formerly obese and 99 control subjects) and included 3 studies not represented in
      the individual subject data analysis. In this analysis, relative RMR was lower in
      the formerly obese group than in the control group by 5.1% (95% CI: 1.7%, 8.6%).
      CONCLUSIONS: Formerly obese subjects had a 3-5% lower mean relative RMR than
      control subjects; the difference could be explained by a low RMR being more
      frequent among the formerly obese subjects than among the control subjects.
      Whether the cause of the low RMR is genetic or acquired, the existence of a low
      RMR is likely to contribute to the high rate of weight regain in formerly obese
      persons.

PMID- 10357729
TI  - Seven-year stability of indicators of obesity and adipose tissue distribution in
      the Canadian population.
AB  - BACKGROUND: The prevention of obesity appears to be a better approach than
      treatment; thus, the prediction of future obesity from current status is
      important. OBJECTIVE: The aim of the study was to examine the stability of
      adiposity and adipose tissue distribution (ATD) in the Canadian population.
      DESIGN: The sample included 1048 males and 1063 females aged 7-69 y at baseline
      from the Campbell's Survey, a 7-y follow-up of the Canada Fitness Survey.
      Indicators of adiposity included body mass index (BMI), sum of 5 skinfold
      thicknesses (SF5), and waist circumference (Waist), whereas indicators of ATD
      included the ratio of trunk to extremity skinfold thicknesses adjusted for SF5
      (TER(adj)), and Waist adjusted for BMI (Waist(adj)). RESULTS: Interage
      correlations ranged from 0.53 to 0.91 for BMI, from -0.09 to 0.72 for SF5, from
      0.24 to 0.89 for Waist, from 0.23 to 0.73 for TER(adj), and from 0.18 to 0.77 for
      Waist(adj). Correlations for BMI were higher than for SF5, suggesting that fat
      free mass may contribute to the stability of BMI. Although lower than those for
      BMI, correlations for indicators of ATD were significant, indicating a propensity
      to retain an android or gynoid pattern. Furthermore, the average percentage of
      participants remaining in the lower or upper quintiles for the various indicators
      ranged from 37.8% to 66.7% in males and from 47.0% to 65.3% in females,
      indicating that those in the lower and upper portions of the distribution tend to
      remain there. CONCLUSION: Obesity and ATD showed significant stability over 7 y
      in the Canadian population.

PMID- 10357730
TI  - Effects of physical training and its cessation on the hemostatic system of obese
      children.
AB  - BACKGROUND: Physical training can improve hemostatic function in adults, thereby
      reducing heart disease risk, but no information is available in children on
      whether physical training can enhance hemostatic function. OBJECTIVE: The purpose
      of this investigation was to examine the effects of a physical training program
      on hemostatic variables in a biethnic group of obese children. DESIGN: Children
      were randomly assigned to 2 groups. Group 1 participated in physical training for
      4 mo and then ceased physical training for 4 mo, whereas group 2 did no physical
      training for the first 4 mo and then participated in physical training for 4 mo.
      Plasma hemostatic variables [fibrinogen, plasminogen activator inhibitor 1 (PAI
      1), and D-dimer) were measured at months 0, 4, and 8. RESULTS: Analyses of
      variance revealed no significant group-by-time interactions for the hemostatic
      variables. When data from both groups were combined there was a significant
      decrease in D-dimer after 4 mo of physical training (P < 0.05). Factors
      explaining individual differences in responsiveness to the physical training
      revealed that individuals with greater percentage fat before physical training
      showed greater reductions in fibrinogen and D-dimer, and that blacks showed
      greater reductions in D-dimer than whites (P < 0.05). Stepwise multiple linear
      regression showed that only higher prephysical training concentrations of
      fibrinogen, PAI-1, and D-dimer explained significant proportions of the variation
      in changes in these variables. CONCLUSIONS: In obese children, 4-mo periods of
      physical training did not lead to significant changes in hemostatic variables.
      Children with greater adiposity and concentrations of hemostatic factors before
      physical training showed greater reductions in hemostatic variables after
      physical training than did children with lesser values.

PMID- 10357731
TI  - Differential effects of saturated and monounsaturated fatty acids on postprandial
      lipemia and incretin responses in healthy subjects.
AB  - BACKGROUND: Elevations of postprandial triacylglycerol-rich plasma lipoproteins
      and suppressions of HDL-cholesterol concentrations are considered potentially
      atherogenic. Long-term studies have shown beneficial effects of monounsaturated
      fatty acids (eg, oleic acid) on fasting lipid and lipoprotein concentrations in
      humans. A direct stimulatory effect of oleic acid on the secretion of glucagon
      like peptide 1 (GLP-1) was shown in animal studies. OBJECTIVE: We compared the
      postprandial responses of glucose, insulin, fatty acids, triacylglycerol, gastric
      inhibitory polypeptide (GIP), and GLP-1 to test meals rich in saturated and
      monounsaturated fatty acids. DESIGN: Ten young, lean, healthy persons ingested 3
      meals: an energy-free soup consumed with 50 g carbohydrate (control meal), the
      control meal plus 100 g butter, and the control meal plus 80 g olive oil.
      Triacylglycerol and retinyl palmitate responses were measured in total plasma, in
      a chylomicron-rich fraction, and in a chylomicron-poor fraction. RESULTS: No
      significant differences in glucose, insulin, or fatty acid responses to the 2 fat
      rich meals were seen. Plasma triacylglycerol responses were highest after the
      butter meal, with chylomicron triacylglycerol rising 2.5-5-fold. Retinyl
      palmitate responses were higher and more prolonged after the butter meal than
      after the control and olive oil meals, whereas both postprandial HDL-cholesterol
      concentrations and GLP-1 and GIP responses were higher after the olive oil meal
      than after the butter meal. CONCLUSIONS: Olive oil induced lower triacylglycerol
      concentrations and higher HDL-cholesterol concentrations than butter, without
      eliciting differences in concentrations of glucose, insulin, or fatty acids.
      Furthermore, olive oil induced higher concentrations of GLP-1 and GIP than did
      butter, which may point to a relation between fatty acid composition, incretin
      responses, and triacylglycerol metabolism in the postprandial phase.

PMID- 10357732
TI  - Cholesterol-lowering efficacy of a sitostanol-containing phytosterol mixture with
      a prudent diet in hyperlipidemic men.
AB  - BACKGROUND: Dietary plant sterols (phytosterols) have been shown to lower plasma
      lipid concentrations in animals and humans. However, the effect of phytosterol
      intake from tall oil on cholesterol and phytosterol metabolism has not been
      assessed in subjects fed precisely controlled diets. OBJECTIVE: Our objective was
      to examine the effects of sitostanol-containing phytosterols on plasma lipid and
      phytosterol concentrations and de novo cholesterol synthesis rate in the context
      of a controlled diet. DESIGN: Thirty-two hypercholesterolemic men were fed either
      a diet of prepared foods alone or a diet containing 1.7 g phytosterols/d for 30 d
      in a parallel study design. RESULTS: No overall effects of diet on total
      cholesterol concentrations were observed, although concentrations were lower with
      the phytosterol-enriched than with the control diet on day 30 (P < 0.05). LDL
      cholesterol concentrations on day 30 had decreased by 8.9% (P < 0.01) and 24.4%
      (P < 0.001) with the control and phytosterol-enriched diets, respectively. HDL
      cholesterol and triacylglycerol concentrations did not change significantly.
      Moreover, changes in circulating campesterol and beta-sitosterol concentrations
      were not significantly different between phytosterol-fed and control subjects. In
      addition, there were no significant differences in fractional (0.091 +/- 0.028
      and 0.091 +/- 0.026 pool/d, respectively) or absolute (0.61 +/- 0.24 and 0.65 +/-
      0.23 g/d, respectively) synthesis rates of cholesterol observed between control
      and phytosterol-fed subjects. CONCLUSION: Addition of blended phytosterols to a
      prudent North American diet improved plasma LDL-cholesterol concentrations by
      mechanisms that did not result in significant changes in endogenous cholesterol
      synthesis in hypercholesterolemic men.

PMID- 10357733
TI  - Plasma clearance of chylomicrons from butterfat is not dependent on saturation:
      studies with butterfat fractions and other fats containing triacylglycerols with
      low or high melting points.
AB  - BACKGROUND: Dietary fats influence plasma lipids, and changes in the clearance
      and metabolism of postprandial lipoproteins can affect atherosclerosis. Butterfat
      is considered hypercholesterolemic but contains a multitude of constituent fatty
      acids. OBJECTIVES: We determined triacylglycerol and cholesteryl ester clearances
      of lymph chylomicrons derived from butterfat, fractions of butterfat, and other
      dietary fats. METHODS: Radiolabeled lymph chylomicrons resulting from the
      intestinal absorption of different fats were reinjected into recipient rats to
      measure plasma clearance. Plasma clearance of [14C]triacylglycerol was used as an
      indicator of chylomicron lipolysis whereas clearance of [3H]cholesteryl ester was
      used as an indicator of chylomicron remnant removal. RESULTS: [3H]Cholesteryl
      ester clearance was slower from chylomicrons derived from a solid, high-saturated
      butterfat fraction than from whole butterfat, but clearance of chylomicrons from
      other fractions did not correlate with the fractions' saturated fatty acid
      contents. Clearance of cholesteryl esters in chylomicrons derived from cocoa
      butter, palm oil, and butterfat was slower than clearance of cholesteryl esters
      in chylomicrons derived from safflower oil. Hepatic uptakes of cholesteryl esters
      were generally lower for chylomicrons from all butterfat fractions, cocoa butter,
      and palm oil. CONCLUSIONS: In contrast with minor effects on the lipolysis of
      chylomicron triacylglycerols, chylomicron remnant removal was strongly influenced
      by the type of dietary fat, with slower cholesteryl ester clearances for
      saturated fats with higher melting points. However, remnant removal and hepatic
      uptake of chylomicrons from whole butterfat and fractions of butterfat were not
      correlated with fat saturation. The mechanisms of this apparent paradox remain
      unknown but may be attributable to acyl arrangements in the lipid classes of
      chylomicrons that influence the association with apolipoproteins and receptors
      and hence remnant removal.

PMID- 10357734
TI  - Fat distribution in HIV-infected patients reporting truncal enlargement
      quantified by whole-body magnetic resonance imaging.
AB  - BACKGROUND: Antiretroviral therapy has improved the prospects for people infected
      with HIV, but some develop a syndrome of profound body habitus and metabolic
      alterations that include truncal enlargement. OBJECTIVE: The purpose of this
      study was to define the body-composition changes associated with this syndrome by
      using techniques with the power to estimate regional body composition. DESIGN: We
      compared whole-body and regional skeletal muscle and adipose tissue contents
      measured by magnetic resonance imaging and dual-energy X-ray absorptiometry (DXA)
      in 26 HIV-infected patients and 26 matched control subjects. Twelve of the HIV
      infected patients had evidence of truncal enlargement. RESULTS: HIV-infected men
      and women who noted truncal enlargement had similar amounts of skeletal muscle
      and subcutaneous adipose tissue but greater visceral adipose tissue than HIV
      infected patients without truncal enlargement; these values were larger in men (P
      < 0.001) than in women (P = 0.08). The ratio of visceral to subcutaneous adipose
      tissue was greater in both men (P < 0.02) and women (P = 0.05) with truncal
      enlargement. Two subjects with MRI-confirmed visceral adiposity syndrome (VAS)
      were not taking protease inhibitors. CD4+ lymphocyte counts were higher (P <
      0.001) and plasma viral burdens tended to be lower (P = 0.08) in HIV-infected
      patients with VAS. CONCLUSIONS: There was significantly more visceral adipose
      tissue in the subgroup of HIV-infected patients with truncal enlargement than in
      those without this sign. VAS occurs in both men and women, is associated with
      higher CD4+ lymphocyte counts and lower plasma HIV viral burdens, and is not
      limited to those receiving protease inhibitor therapy.

PMID- 10357735
TI  - Limited effect of refined carbohydrate dietary supplementation on colonization of
      the gastrointestinal tract of healthy subjects by Candida albicans.
AB  - BACKGROUND: Infections due to Candida albicans occur readily in situations in
      which ample glucose is available. In mice, dietary refined carbohydrate
      supplementation leads to higher rates of Candida growth in the gastrointestinal
      tract and favors mucosal invasion. OBJECTIVE: The modulating properties of
      dietary carbohydrate supplementation on colonization of the human
      gastrointestinal tract by C. albicans were evaluated. DESIGN: A 2-step study was
      conducted in 28 healthy volunteers. First, we determined the subjects' habitual
      uptake of refined carbohydrates and correlated these data with the C. albicans
      blastoconidia concentration in the mouth washes and feces of subjects with no
      intervention. Second, we compared C. albicans counts in the specimens before,
      during, and after a high-sugar diet. RESULTS: No correlation between C. albicans
      counts in the specimens and the habitual uptake of refined carbohydrates was
      observed. A high-sugar diet did not increase the frequency of C. albicans
      positive samples, the number of subjects positive for C. albicans in the mouth
      washes, or the concentration of candidal blastoconidia in the samples of the 28
      subjects. However, in selected subjects with elevated counts of oral C. albicans,
      we observed an increase in fecal C. albicans counts in response to the diet.
      CONCLUSIONS: The effect of adding a high amount of refined carbohydrates to the
      diet of healthy human subjects has a limited influence on Candida colonization.
      Follow-up studies should define whether selected patient groups might benefit
      from dietary restriction of refined carbohydrates.

PMID- 10357736
TI  - Euglycemic hyperinsulinemic clamp to assess posthepatic glucose appearance after
      carbohydrate loading. 1. Validation in pigs.
AB  - BACKGROUND: Precise knowledge of the rate of glucose absorption after meal
      feeding requires invasive methods in humans. OBJECTIVE: This study aimed to
      validate in an animal model a technique combining the euglycemic hyperinsulinemic
      clamp and oral carbohydrate loading (OC-Clamp) as a noninvasive procedure to
      quantify the posthepatic appearance of glucose after oral carbohydrate loading.
      DESIGN: Twenty-one pigs were fitted with arterial, jugular, portal, and duodenal
      catheters and a portal blood flow probe. At glucose clamp steady state, duodenal
      glucose (0.9 g/kg; DG-Clamp) and oral carbohydrate (140 g corn or mung bean
      starch as part of a mixed meal; OC-Clamp) were administered while the glucose
      infusion was progressively reduced to compensate for the incremental posthepatic
      appearance of glucose. [3-3H]glucose was used to assess the glucose turnover
      rate. RESULTS: Hepatic glucose production was totally suppressed by insulin
      infusion, and the whole-body glucose turnover rate remained stable during glucose
      absorption. The incremental portal appearance of glucose after the DG load was
      not altered by hyperinsulinemia, and the cumulative posthepatic appearance of
      glucose was 63 +/- 3% (x +/- SEM) of the DG load. The net hepatic portal
      appearance of glucose remained constant during absorption (34 +/- 3% of the
      load). After the OC load, the respective portal appearance rates of glucose were
      significantly different between carbohydrate sources; however, the rates
      paralleled those of the posthepatic appearance of glucose. Again, net hepatic
      glucose uptake expressed as portal appearance was similar for both carbohydrates.
      CONCLUSIONS: The results validate the OC-Clamp method to monitor the posthepatic
      appearance of glucose after carbohydrate ingestion and to discriminate between
      different carbohydrate sources. The results suggest that the technique be used in
      humans.

PMID- 10357737
TI  - Euglycemic hyperinsulinemic clamp to assess posthepatic glucose appearance after
      carbohydrate loading. 2. Evaluation of corn and mung bean starches in healthy
      men.
AB  - BACKGROUND: The rate of absorption of glucose from carbohydrates is important in
      several aspects of health. We recently validated a noninvasive technique in pigs,
      euglycemic hyperinsulinemic clamp plus oral carbohydrate loading (OC-Clamp), to
      quantify the rate of net posthepatic appearance of glucose after ingestion of
      carbohydrates. OBJECTIVE: The OC-Clamp procedure was performed in 8 healthy men
      to compare the net posthepatic appearance of glucose after ingestion of 1 of 3
      carbohydrates. DESIGN: Human volunteers underwent the OC-Clamp procedure at an
      insulin infusion rate of 1.5 mU x kg(-1) x min(-1) (n = 5). The oral carbohydrate
      load (1 g/kg) consisted of glucose, cornstarch, or mung bean starch. During the
      OC-Clamp procedure, the glucose infusion rate decreased during absorption to
      maintain plasma glucose steady state and the decrease reflected the net
      posthepatic appearance of glucose. In addition, carbohydrates were loaded without
      insulin infusion (n = 6) and glycemic indexes were calculated (with glucose as
      the reference). RESULTS: The mean (+/-SEM) glycemic index of cornstarch was
      higher (95 +/- 18) than that of mung bean starch (51 +/- 13). In the OC-Clamp
      experiments, the posthepatic appearance of glucose and cornstarch did not differ
      significantly and represented 79.4 +/- 5.0% and 72.6 +/- 4.0%, respectively, of
      the load after complete absorption (within 3 h). In contrast, the net posthepatic
      appearance of glucose from mung bean starch was significantly lower (35.6 +/-
      4.6% of the load, P < 0.001) than that from glucose and cornstarch, even 4.5 h
      postprandially. CONCLUSIONS: The OC-Clamp technique allows a continuous
      assessment of net posthepatic appearance of glucose after ingestion of
      carbohydrates and significant discrimination between corn and mung bean starches.

PMID- 10357738
TI  - Resting energy expenditure in reduced-obese subjects in the National Weight
      Control Registry.
AB  - BACKGROUND: Weight loss in obese subjects is associated with a reduction in
      resting metabolic rate (RMR). Whether the reduction can be explained solely by a
      reduction in lean body mass remains controversial. OBJECTIVE: Our objective was
      to determine whether the reduction in RMR after weight loss was proportional to
      the decrease in lean mass alone or was greater than could be explained by body
      composition. DESIGN: We measured the RMR, fasting respiratory quotient (RQ), and
      body composition in 40 reduced-obese subjects [ie, 7 men and 33 women who had
      lost > or = 13.6 kg (30 lb) and maintained the loss for > or = 1 y] enrolled in
      the National Weight Control Registry and 46 weight-matched control subjects (9
      men, 37 women). RESULTS: A stepwise multiple regression found lean mass, fat
      mass, age, and sex to be the best predictors of RMR in both groups. After
      adjusting RMR for these variables, we found no significant difference in RMR
      (5926 +/- 106 and 6015 +/- 104 kJ/d) between the 2 groups (P = 0.35). When we
      adjusted fasting RQ for percentage body fat and age, the reduced-obese group had
      a slightly higher (0.807 +/- 0.006) RQ than the control group (0.791 +/- 0.005, P
      = 0.05). This may have been due to the consumption of a diet lower in fat or to a
      reduced capacity for fat oxidation in the reduced-obese group. CONCLUSION: These
      results show that in at least some reduced-obese individuals there does not seem
      to be a permanent obligatory reduction in RMR beyond the expected reduction for a
      reduced lean mass.

PMID- 10357739
TI  - Hypermetabolism in clinically stable patients with liver cirrhosis.
AB  - BACKGROUND: Hypermetabolism has a negative effect on prognosis in patients with
      liver cirrhosis. Its exact prevalence and associations with clinical data, the
      nutritional state, and beta-adrenergic activity are unclear. OBJECTIVE: We
      investigated resting energy expenditure (REE) in 473 patients with biopsy-proven
      liver cirrhosis. DESIGN: This was a cross-sectional study with a controlled
      intervention (beta-blockade) in a subgroup of patients. RESULTS: Mean REE was
      7.12 +/- 1.34 MJ/d and correlated closely with predicted values (r = 0.70, P <
      0.0001). Hypermetabolism was seen in 160 patients with cirrhosis (33.8% of the
      study population). REE was > 30% above the predicted value in 41% of the
      hypermetabolic patients with cirrhosis. Hypermetabolism had no association with
      clinical or biochemical data on liver function. REE correlated with total body
      potassium content (TBP; r = 0.49, P < 0.0001). Hypermetabolic patients had lower
      than normal body weight and TBP (P < 0.05). About 47% of the variance in REE
      could be explained by body composition whereas clinical state could maximally
      explain 3%. Plasma epinephrine and norepinephrine concentrations were elevated in
      hypermetabolic cirrhotic patients (by 56% and 41%, respectively; P < 0.001 and
      0.01). Differences in REE from predicted values were positively correlated with
      epinephrine concentration (r = 0.462, P < 0.001). Propranolol infusion resulted
      in a decrease in energy expenditure (by 5 +/- 3%; P < 0.05), heart rate (by 13 +/
      4%; P < 0.01), and plasma lactate concentrations (by 32 +/- 12%; P < 0.01);
      these effects were more pronounced in hypermetabolic patients (by 50%, 33%, and
      68%, respectively; each P < 0.05). CONCLUSIONS: Hypermetabolism has no
      association with clinical data and thus is an extrahepatic manifestation of liver
      disease. Increased beta-adrenergic activity may explain approximately 25% of
      hypermetabolism.

PMID- 10357740
TI  - Protein pulse feeding improves protein retention in elderly women.
AB  - BACKGROUND: Adequate protein nutrition could be used to limit gradual body
      protein loss and improve protein anabolism in the elderly. OBJECTIVE: We tested
      the hypothesis that an uneven protein feeding pattern was more efficient in
      improving protein anabolism than was an even pattern. DESIGN: After a controlled
      period, 15 elderly women (mean age: 68 y) were fed for 14 d either a pulse diet
      (n = 7), providing 80% of the daily protein intake at 1200, or a spread diet (n =
      8), in which the same daily protein intake was spread over 4 meals. Both diets
      provided 1.7 g protein x kg fat-free mass (FFM)(-1) x d(-1). Protein accretion
      and daily protein turnover were determined by using the nitrogen balance method
      and the end product method (ammonia and urea) after an oral dose of [15N]glycine.
      RESULTS: Nitrogen balance was more positive with the pulse than with the spread
      diet (54 +/- 7 compared with 27 +/- 6 mg N x kg FFM(-1) x d(-1); P < 0.05).
      Protein turnover rates were also higher with the pulse than with the spread diet
      (5.58 +/- 0.22 compared with 4.98 +/- 0.17 g protein x kg FFM(-1) x d(-1); P <
      0.05), mainly because of higher protein synthesis in the pulse group (4.48 +/-
      0.19 g protein x kg FFM(-1) x d(-1)) than in the spread group (3.75 +/- 0.19 g
      protein x kg FFM(-1) x d(-1)) (P < 0.05). CONCLUSION: A protein pulse-feeding
      pattern was more efficient than was a protein spread-feeding pattern in
      improving, after 14 d, whole-body protein retention in elderly women.

PMID- 10357741
TI  - Variations and determinants of energy expenditure as measured by whole-body
      indirect calorimetry during puberty and adolescence.
AB  - BACKGROUND: Adolescence is characterized by rapid anatomic, physiologic, and
      behavioral alterations expected to induce changes in metabolic rate. OBJECTIVE:
      The aim of the present study was to investigate variations in daily energy
      expenditure (DEE) and its main components during adolescence and to quantify
      their significant determinants. DESIGN: Eighty-three children and adolescents (44
      boys and 39 girls aged 10-16 y) participated in this cross-sectional study.
      Tanner stages ranged from 1 to 5. Body composition was assessed by both the
      skinfold-thickness method and bioimpedance analysis. Energy expenditure (EE) was
      determined continuously over 24 h by using 2 whole-body calorimeters. The
      subjects followed a standardized activity program that included four 15-min
      periods of exercise on a cycle ergometer. RESULTS: Body composition, DEE,
      sleeping EE (SEE), resting EE, and EE during meals, miscellaneous activities, and
      physical exercise varied significantly with sex and stage of puberty. The DEE of
      boys and girls averaged 8.22 and 7.60 MJ in prepubertal children, 11.35 and 9.10
      MJ in pubertal children, and 11.73 and 9.68 MJ in postpubertal adolescents,
      respectively. The significant determinants of DEE and SEE, respectively, were fat
      free mass (r2 = 0.842 and 0.826), sex (r2 = 0.017 and 0.022), and season (r2 =
      0.021 and 0.011). Stage of puberty and fat mass were not significant factors. DEE
      and SEE adjusted for fat-free mass were on average 5% higher in boys than in
      girls and 6% higher in spring than in autumn. CONCLUSIONS: The DEE of adolescents
      measured under standardized conditions varied with sex, body composition, and
      season, but not with stage of puberty. These variables could be predicted
      accurately from fat-free mass, sex, and season.

PMID- 10357742
TI  - Molybdenum absorption and utilization in humans from soy and kale intrinsically
      labeled with stable isotopes of molybdenum.
AB  - BACKGROUND: Stable-isotope studies of molybdenum metabolism have been conducted
      in which molybdenum was added to the diet and was assumed to be absorbed and
      utilized similarly to the molybdenum in foods. OBJECTIVE: Our objective was to
      establish whether the molybdenum in foods is metabolized similarly to molybdenum
      added to the diet. DESIGN: We first studied whether sufficient amounts of
      molybdenum stable isotopes could be incorporated into wheat, kale, and soy for
      use in a human study. Enough molybdenum could be incorporated into soy and kale
      to study molybdenum absorption and excretion. Two studies were then conducted,
      one in women and one in men. In the first study, each meal contained
      approximately 100 microg Mo from soy, kale, and extrinsic molybdenum. In the
      second study, soy and extrinsic molybdenum were compared; the meal contained
      approximately 300 microg Mo. RESULTS: In the first study, molybdenum was absorbed
      equally well from kale and an extrinsic source. However, the molybdenum in soy
      was less well absorbed than the molybdenum in kale or that added to the diet. In
      the second study, absorption of molybdenum from soy was less than from the
      extrinsic label. Urinary excretion of soy molybdenum was also lower than urinary
      excretion of the extrinsic label, but excretion as a percentage of the absorbed
      dose was not significantly different between treatments. CONCLUSIONS: The
      molybdenum in soy is less available than molybdenum added to the diet, but the
      molybdenum in kale is as available as molybdenum added to the diet. Once
      absorbed, excretion is not significantly different for soy, kale, and extrinsic
      molybdenum.

PMID- 10357743
TI  - Randomized trial of calcium glycerophosphate-supplemented infant formula to
      prevent lead absorption.
AB  - BACKGROUND: Although additional dietary calcium is recommended frequently to
      reduce the risk of lead poisoning, its role in preventing lead absorption has not
      been evaluated clinically. OBJECTIVE: The objective was to determine the safety
      and to estimate the size of the effect of calcium- and phosphorus-supplemented
      infant formula in preventing lead absorption. DESIGN: One hundred three infants
      aged 3.5-6 mo were randomly assigned to receive iron-fortified infant formula
      (465 mg Ca and 317 mg P/L) or the same formula with added calcium
      glycerophosphate (1800 mg Ca and 1390 mg P/L) for 9 mo. RESULTS: There was no
      significant difference between groups in the mean ratio of urinary calcium to
      creatinine, serum calcium and phosphorus, or change in iron status (serum
      ferritin, total iron binding capacity). At month 4, the median (+/-SD) increase
      from baseline in blood lead concentration for the supplemented group was 57% of
      the increase for the control group (0.04 +/- 0.09 compared with 0.07 +/- 0.10
      micromol/L; P = 0.039). This effect was attenuated during the latter half of the
      trial, with an overall median increase in blood lead concentration from baseline
      to month 9 of 0.12 +/- 0.13 micromol/L for the control group and 0.10 +/- 0.18
      micromol/L for the supplemented group (P = 0.284). CONCLUSIONS: Supplementation
      did not have a measurable effect on urinary calcium excretion, calcium
      homeostasis, or iron status. The significant effect on blood lead concentrations
      during the first 4 mo was in the direction expected; however, because this was
      not sustained throughout the 9-mo period we cannot conclude that the calcium
      glycerophosphate supplement prevented lead absorption in this population.

PMID- 10357744
TI  - Serum ferritin and risk of myocardial infarction in the elderly: the Rotterdam
      Study.
AB  - BACKGROUND: Elevated body iron stores have been suggested to be a risk factor for
      ischemic heart disease. OBJECTIVE: We examined whether elevated serum ferritin
      concentrations, other indicators of iron status, and dietary iron affected the
      incidence of myocardial infarction (MI) in an elderly population. DESIGN: A
      nested, case-control study of 60 patients who had their first MI and 112 age- and
      sex-matched control subjects embedded in the population-based cohort of the
      Rotterdam Study. RESULTS: The age- and sex-adjusted risk of MI for subjects with
      serum ferritin concentrations > or = 200 microg/L was 1.82 (95% CI: 0.90, 3.69; P
      = 0.096). The odds ratio (OR) was 1.26 (95% CI: 0.98, 1.64; P = 0.078) for the
      highest tertile of serum ferritin and was only slightly altered in a multivariate
      model. Risk of MI associated with the highest tertile of ferritin was most
      evident in current or former smokers (OR: 1.68; 95% CI: 1.17, 2.47; P for trend =
      0.008) and in subjects with hypercholesterolemia (OR: 1.43; 95% CI: 0.99, 2.11; P
      for trend = 0.056) or diabetes (OR: 2.41; 95% CI: 1.12, 7.67; P for trend =
      0.027). No association with risk of MI was observed for tertiles of serum iron,
      serum transferrin, or total dietary iron. For dietary heme iron, risk of MI was
      significantly increased in a multivariate model in which dietary energy, fat,
      saturated fat, and cholesterol were adjusted for (OR: 4.01; 95% CI: 1.17, 15.87;
      P for trend = 0.031). CONCLUSION: In the presence of other risk factors, serum
      ferritin may adversely affect ischemic heart disease risk in the elderly.

PMID- 10357745
TI  - Comparison of the effect of medium-chain and long-chain triacylglycerols on
      calcium absorption in healthy subjects.
AB  - BACKGROUND: The absorption efficiency of calcium in humans is low. Some studies
      in infants have shown that calcium absorption can be increased by adding medium
      chain triacylglycerols to the formula diet. OBJECTIVE: The effect of medium- and
      long-chain triacylglycerols on calcium absorption was studied in 18 healthy,
      young men. The results were compared with data obtained from calcium ingestion of
      a protein-carbohydrate formula devoid of triacylglycerols. DESIGN: Calcium
      absorption was measured by using a double-isotope technique and the kinetic
      parameters were obtained by using a deconvolution method. RESULTS: The total
      fractional calcium absorption measured in the presence of medium-chain
      triacylglycerols (0.236 +/- 0.016) or from a protein-carbohydrate formula without
      triacylglycerols (0.235 +/- 0.012) was not significantly different. The same
      result was observed with long-chain triacylglycerols (0.309 +/- 0.026) and the
      protein-carbohydrate formula (0.275 +/- 0.012). No kinetic parameters were
      significantly different regardless of the diet (protein-carbohydrate, medium
      chain triacylglycerol, or long-chain triacylglycerol). This suggests that the
      same mechanism for calcium absorption was operative. CONCLUSIONS:
      Triacylglycerols had no direct effect on calcium absorption from a protein
      carbohydrate formula in healthy subjects. These data do not support the use of
      medium-chain triacylglycerols as adjuvants to increase the absorption of calcium
      in healthy adults.

PMID- 10357746
TI  - Precision, accuracy, and reliability of hemoglobin assessment with use of
      capillary blood.
AB  - BACKGROUND: Previous research has suggested that there may be significant within
      subject variability, both site-to-site and over time, in hemoglobin
      concentrations in capillary blood. OBJECTIVE: This study examined the reliability
      of the portable hemoglobinometer (PHM) system with use of capillary blood and the
      implications of errors of the magnitude found for the classification of anemia
      status in individuals and population groups. The precision and accuracy of the
      method with use of venous blood were also tested. DESIGN: Three empirical data
      sets were used to measure reliability, precision, and accuracy of the PHM system
      [2 from Honduras (n = 87 and 141); 1 from Bangladesh (n = 73)]. Simulation data
      were used to assess the implications of errors for screening individuals for
      anemia and to estimate anemia prevalence. RESULTS: High within-subject
      variability (unreliability) was identified when capillary blood from the left
      hand was compared with that from the right hand (CV: 6.3%) and when measurements
      were taken on 4 consecutive days (CV: 7.0%). Reliability was only 69% and 50%,
      respectively. Precision and accuracy, however, were very high (concordance
      coefficients of 0.99 and 0.98 and CV < 1%). CONCLUSIONS: The simulation data
      showed that errors of the magnitude found due to unreliability can lead to
      misclassification of anemia status in individuals and small biases in anemia
      prevalence estimates. We recommend replicate sampling to reduce the influence of
      unreliability in the use of the PHM system with capillary blood.

PMID- 10357747
TI  - School-administered weekly iron-folate supplements improve hemoglobin and
      ferritin concentrations in Malaysian adolescent girls.
AB  - BACKGROUND: Iron deficiency and its consequent anemia constitute the commonest
      micronutrient deficiency in the world. OBJECTIVE: We investigated whether long
      term, weekly iron-folate supplements administered at school would improve
      hemoglobin and ferritin concentrations in adolescent girls, including those with
      mild-to-moderate anemia and hemoglobin concentrations indicating borderline
      anemia. DESIGN: Subjects were 266 girls with hemoglobin concentrations of 80
      119.9 g/L (group A) and 358 girls with hemoglobin concentrations of 120-130 g/L
      (group B) who were otherwise healthy. Two hundred sixty-six girls in group A and
      268 girls in group B were randomly assigned to receive either 60 or 120 mg Fe
      plus 3.5 mg folic acid weekly for 22 wk. Ninety of the girls in group B were
      randomly assigned to receive only 5 mg folic acid weekly. Capillary hemoglobin
      and plasma ferritin were measured at baseline and after 12 and 22 wk of
      supplementation. RESULTS: By the end of the study, 2% of the girls had dropped
      out and > 96% had taken > or = 20 of the 22 tablets; side effects were minimal.
      Mean plasma ferritin increased significantly in all iron-supplemented groups,
      independently of initial hemoglobin values and iron doses. Ferritin
      concentrations decreased in the girls supplemented with folic acid only. As
      expected, hemoglobin responses to iron were higher in group A than in group B and
      increases were positively correlated with initial plasma ferritin. Hemoglobin
      failed to respond to folate supplementation if initial plasma ferritin
      concentrations were low. Mean hemoglobin increased significantly and consistently
      in relation to the length of treatment. CONCLUSION: Long-term, weekly iron-folate
      supplementation was found to be a practical, safe, effective, and inexpensive
      method for improving iron nutrition in adolescent schoolgirls.

PMID- 10357748
TI  - Adding zinc to prenatal iron and folate supplements improves maternal and
      neonatal zinc status in a Peruvian population.
AB  - BACKGROUND: Maternal zinc deficiency during pregnancy may be widespread among
      women in developing countries, but few data are available on whether prenatal
      zinc supplementation improves maternal and neonatal zinc status. OBJECTIVE: We
      studied whether maternal zinc supplementation improved the zinc status of mothers
      and neonates participating in a supplementation trial in a shantytown in Lima,
      Peru. DESIGN: Beginning at gestation week 10-24, 1295 mothers were randomly
      assigned to receive prenatal supplements containing 60 mg Fe and 250 microg
      folate, with or without 15 mg Zn. Venous blood and urine samples were collected
      at enrollment, at gestation week 28-30, and at gestation week 37-38. At birth, a
      sample of cord vein blood was collected. We measured serum zinc concentrations in
      538 women, urinary zinc concentrations in 521 women, and cord zinc concentrations
      in 252 neonates. RESULTS: At 28-30 and 37-38 wk, mothers receiving zinc
      supplements had higher serum zinc concentrations than mothers who did not receive
      zinc (8.8 +/- 1.9 compared with 8.4 +/- 1.5 micromol/L and 8.6 +/- 1.5 compared
      with 8.3 +/- 1.4 micromol/L, respectively). Urinary zinc concentrations were also
      higher in mothers who received supplemental zinc (P < 0.05). After adjustment for
      covariates and confounding factors, neonates of mothers receiving zinc
      supplements had higher cord zinc concentrations than neonates of mothers who did
      not receive zinc (12.7 +/- 2.3 compared with 12.1 +/- 2.1 micromol/L). Despite
      supplementation, maternal and neonatal zinc concentrations remained lower than
      values reported for well-nourished populations. CONCLUSION: Adding zinc to
      prenatal iron and folate tablets improved maternal and neonatal zinc status, but
      higher doses of zinc are likely needed to further improve maternal and neonatal
      zinc status in this population.

PMID- 10357749
TI  - Restricting access to palatable foods affects children's behavioral response,
      food selection, and intake.
AB  - BACKGROUND: Restricting children's access to palatable foods may appeal to
      parents as a straightforward means of promoting moderate intakes of foods high in
      fat and sugar; however, restricting access to palatable foods may have unintended
      effects on children's eating. The efficacy of restricting children's access to
      palatable foods as a means of promoting patterns of moderate intake of those
      foods is unknown. OBJECTIVE: Two experiments were conducted to test the
      hypothesis that restricting access to a palatable food enhances children's
      subsequent behavioral responses to, selection of, and intake of that restricted
      food. DESIGN: Both experiments used a within-subjects design to examine the
      effects of restricting access to a palatable food on children's subsequent
      behavior, food selection, and food intake. The first experiment examined the
      effects of restriction within and outside the restricted context and the second
      experiment focused on the effects within the restricted context. RESULTS: In both
      experiments, restricting access to a palatable food increased children's
      behavioral response to that food. Experiment 2 showed that restricting access
      increased children's subsequent selection and intake of that food within the
      restricted context. CONCLUSIONS: Restricting access focuses children's attention
      on restricted foods, while increasing their desire to obtain and consume those
      foods. Restricting children's access to palatable foods is not an effective means
      of promoting moderate intake of palatable foods and may encourage the intake of
      foods that should be limited in the diet.

PMID- 10357750
TI  - Effect of 50- and 100-mg vitamin E supplements on cellular immune function in
      noninstitutionalized elderly persons.
AB  - BACKGROUND: It has been suggested that vitamin E can counteract the age
      associated decline in cellular immune responsiveness (CIR). Particularly, T
      helper cell type 1 (Th1) activity, ie, interferon (IFN) gamma-producing Th1
      activity and, hence, delayed-type hypersensitivity (DTH) would be enhanced by
      vitamin E supplementation. OBJECTIVE: Our aim was to study the effects of 6 mo
      supplementation with 50 and 100 mg vitamin E on CIR in the elderly. DESIGN: A
      double-blind, placebo-controlled trial was conducted in 161 healthy elderly
      subjects aged 65-80 y. CIR was measured in vivo by means of DTH skin tests and in
      vitro by assessing the production of interleukin (IL) 2, IFN-gamma (a typical Th1
      cytokine), and IL-4 (a typical Th2 cytokine) by peripheral blood mononuclear
      cells after stimulation with phytohemagglutinin. RESULTS: Both DTH and IL-2
      production showed a trend toward increased responsiveness with increasing dose of
      vitamin E. However, IFN-gamma production decreased whereas IL-4 production
      increased in the groups receiving vitamin E. Only the change in the number of
      positive DTH reactions was borderline significantly larger in the 100-mg vitamin
      E group than in the placebo group (P = 0.06, Bonferroni adjusted). Subjects
      receiving 100 mg vitamin E with low baseline DTH reactivity or who were
      physically less active had a significantly larger increase in the cumulative
      diameter of the skin induration resulting from the DTH test than did the placebo
      group (P = 0.03), although this difference was not significant after Bonferroni
      correction (P = 0.07). CONCLUSION: Possible beneficial effects of 100-mg vitamin
      E supplementation may be more pronounced in particular subgroups of elderly
      subjects.

PMID- 10357751
TI  - Body composition in HIV-infected children: relations with disease progression and
      survival.
AB  - BACKGROUND: Malnutrition is common in HIV-infected children, but the body
      compartment that is most affected has been ill defined. OBJECTIVES: Our
      objectives were to 1) compare the fat-free mass (FFM) of children with HIV
      infection with that of control children, 2) assess the contribution of FFM to
      body weight in HIV-infected children compared with that of control children, and
      3) study the relations between body weight, FFM, and mortality. DESIGN: A cross
      sectional study was performed in 86 HIV-infected and 113 uninfected children
      (mean ages: 6.9 and 7.7 y, respectively). FFM was estimated from single-frequency
      bioelectrical impedance analysis by using 3 different published equations; a
      further estimate was obtained from triceps-skinfold-thickness measurements.
      RESULTS: All 4 estimates of body composition showed that FFM in HIV-infected
      children was significantly less than in control children of similar age. However,
      FFM as a percentage of body weight was not significantly different between
      groups. In the whole group of infected children, an age-specific z score < -2 for
      weight and for FFM was significantly associated with an increased risk of death
      [relative risk (95% CI) = 11.4 (3.1, 41.0) and 5.1 (1.5, 18.2), respectively];
      when only children with more severe disease were considered, only z score for
      weight was significantly associated with an increased risk [4.6 (1.4, 14.9)].
      CONCLUSIONS: These findings suggest that no preferential catabolism of FFM occurs
      in HIV-infected children and that body weight for age is a better prognostic
      indicator than is FFM estimated by bioelectrical impedance analysis.

PMID- 10357752
TI  - Effects of folic acid on homocysteine in persons classified by
      methylenetetrahydrofolate reductase genotype.

PMID- 10357753
TI  - Reports of total-body bone mineral density.

PMID- 10357754
TI  - Study design of an investigation of lactose maldigestion.

PMID- 10357755
TI  - Age-related osteoporosis in Chinese women.

PMID- 10357756
TI  - Antioxidant vitamin supplementation and lipid peroxidation in smokers.

PMID- 10357757
TI  - Food and nutrient exposures: what to consider when evaluating epidemiologic
      evidence.
AB  - Nutritional epidemiology is the science concerned with conducting research into
      the relation between diet and disease risk. The public has a great deal of
      interest in this issue. Much of that interest, however, is fueled by the
      publication of sensationalized, startling, and often contradictory health
      messages. Unfortunately, there is a great deal of confusion in both the
      scientific press and the public or lay press about the nature of nutritional
      epidemiology, its strengths, and its limitations. The purpose of this article is
      to discuss these strengths and limitations. It is hoped that clarification of
      these issues can help lead to a resolution of the research community's and lay
      public's misunderstandings about nutritional epidemiology research.

PMID- 10357768
TI  - p16(INK4a) and the control of cellular proliferative life span.
AB  - Normal somatic cells have a limited proliferative capacity in vitro: after a
      finite number of cell divisions they eventually enter a non-proliferative state
      referred to as senescence. Senescence is thought to be a major tumor suppressor
      mechanism, and many cancers contain cells that have escaped from senescence and
      become immortalized. The role of telomerase activation in immortalization is
      currently attracting considerable attention, but immortalization is often
      associated with other changes including loss of normal function of the tumor
      suppressor locus, INK4a/ARF. Two proteins, p16(INK4a) and p14(ARF), are encoded
      by this locus. Here we focus on p16(INK4a) and review accumulating evidence that
      loss of p16(INK4a) function may be involved in escape from the normal limits on
      cellular proliferative life span.

PMID- 10357769
TI  - Effects of soy or rye supplementation of high-fat diets on colon tumour
      development in azoxymethane-treated rats.
AB  - Evidence is accumulating that a diet high in plant-derived foods may be
      protective against cancer. One class of plant component under increasing
      investigation is the phytoestrogens of which there are two main groups: the
      isoflavones, found mainly in soy products, and the lignans, which are more
      ubiquitous and are found in fruit, vegetables and cereals with high levels being
      found in flaxseed. In this study, we have used carefully balanced high-fat (40%
      energy) diets: a control diet (containing low isoflavone soy protein as the sole
      protein source), a rye diet (the control diet supplemented with rye bran) and a
      soy diet (containing as protein source a high isoflavone soy protein). The effect
      of these diets on the development of colonic cancer was studied in F-344 rats
      treated with the carcinogen, azoxymethane (two doses of 15 mg/kg given 1 week
      apart). Colons from treated animals were examined for aberrant crypt foci (ACF)
      and tumours after 12 and 31 weeks. Results after 12 weeks showed no differences
      in the total number of ACF in the control, soy or rye bran groups. However, the
      soy group had increased numbers of small ACF (less than four crypts/focus) while
      the rye group had decreased numbers of large ACF (greater than six crypts/focus).
      Examination of colons after 31 weeks gave similar low numbers of ACF in each
      group with no differences in multiplicity. There were no differences in the
      number of tumours between the control (1.36 tumours/rat) and soy (1.38
      tumours/rat) groups. However, there was a significant decrease in the number of
      tumours in the rye group (0.17 tumours/rat). These results suggest that soy
      isoflavones have no effect on the frequency of colonic tumours in this model
      while rye bran supplementation decreases the frequency of colon cancer. This
      effect is due not to a decrease in early lesions but in their progression to
      larger multi-crypt ACF. The study also supports the hypothesis that larger ACF
      are more predictive of subsequent tumorigenicity.

PMID- 10357770
TI  - Progression of hepatic neoplasia in medaka (Oryzias latipes) exposed to
      diethylnitrosamine.
AB  - Progression of hepatic neoplasia was assessed in medaka (Oryzias latipes)
      following aqueous exposure to diethylnitrosamine (DEN). Larvae (2 weeks old) were
      exposed to 350 or 500 p.p.m. DEN for 48 h, while adults (3-6 months old) were
      exposed to 50 p.p.m. DEN for 5 weeks. Fish were maintained as long as possible to
      determine malignant potential of resultant neoplasms. A total of 423 medaka with
      106 hepatic neoplasms were examined. There were marked differences in tumor
      prevalence between exposure groups including: (i) higher prevalence of
      hepatocellular carcinomas in medaka exposed as adults (100% of hepatocellular
      tumors in adult-exposed medaka were malignant, while only 51.5% of larval
      hepatocellular tumors were malignant); (ii) higher prevalence of biliary tumors
      in medaka exposed as larvae (46.4% of all tumors in larval-exposed medaka were
      biliary versus 8.1% in adult-exposed fish); (iii) higher prevalence of mixed
      hepato-biliary carcinomas in adult-exposed medaka (24.3%) compared with those
      exposed as larvae (3%). In addition, a unique hepatocellular lesion termed
      'nodular proliferation' was only observed in adult-exposed medaka. The lesion was
      characterized by small size (50-300 microm), complete loss of normal tubular
      architecture and variable megalocytosis. Nodular proliferation was distinct from
      preneoplastic foci of cellular alteration and may represent microcarcinomas.
      There was a step-wise increase in mean diameter with age (days post-exposure)
      from nodular proliferation (174 microm, 17 days) to hepatocellular carcinoma
      (1856 microm, 62 days) and mixed carcinomas (3209 microm, 93 days) in adult
      exposed medaka. Metastasis was observed with 19 neoplasms and tumors with the
      highest metastatic potential were hepatocellular and mixed carcinomas. The most
      common form of metastasis was trans-coelomic, followed by direct invasion and
      distant metastasis, presumably via the vascular route. Differences in tumor
      prevalence between exposure groups were believed to be the result of length of
      DEN exposure rather than age of fish at the time of exposure. In larval medaka
      with brief (48 h) DEN exposure, neoplasms are thought to be the result of
      dedifferentiation of hepatic cells, with slow progression of foci of cellular
      alteration to benign and then malignant tumors. In contrast, with adult medaka
      and prolonged (5 week) DEN exposure, neoplasms are believed to result from
      initiation of committed stem cells and formation of microcarcinomas ('nodular
      proliferation'), before progressing to larger hepatocellular and then mixed
      carcinomas.

PMID- 10357771
TI  - Inverse correlation between p53 protein levels and DNA repair efficiency in human
      fibroblast strains treated with 4-nitroquinoline 1-oxide: evidence that lesions
      other than DNA strand breaks trigger the p53 response.
AB  - Ionizing radiation-induced stabilization and the resultant transient accumulation
      of the p53 tumor suppressor protein is impaired in cells from ataxia
      telangiectasia (AT) patients, indicating a key role for ATM, the gene mutated in
      AT, upstream in the radiation-responsive p53 signaling pathway. Activation of
      this pathway is generally assumed to be triggered by DNA strand breaks produced
      directly following genotoxic stress or indirectly during excision repair of DNA
      lesions. The aim of this study was to identify the triggering signal for
      induction of p53 in diploid human dermal fibroblasts treated with 4
      nitroquinoline 1-oxide (4NQO), a model environmental carcinogen that produces
      both DNA strand breaks (like ionizing radiation) and alkali-stable bulky DNA
      lesions (like UV light). 4NQO treatment of fibroblasts cultured from normal and
      AT donors and those from patients with the UV-hypersensitivity disorder xeroderma
      pigmentosum (XP, complementation groups A, E and G) resulted in up-regulation of
      p53 protein. In normal fibroblasts, there was no temporal relationship between
      the incidence of DNA strand breaks and levels of p53 protein; >90% of strand
      breaks and alkali-labile sites were repaired over 2 h following treatment with 1
      microM 4NQO, whereas approximately 3 h of post-treatment incubation was required
      to demonstrate a significant rise in p53 protein. In contrast, exposure of normal
      fibroblasts to gamma-rays resulted in a rapid up-regulation of p53 and the level
      peaked at 2 h post-irradiation. XP cells with a severe deficiency in the
      nucleotide excision repair pathway showed abnormally high levels of p53 protein
      in response to 4NQO treatment, indicating that lesions other than incision
      associated DNA strand breaks trigger p53 up-regulation. We observed a consistent,
      inverse correlation between the ability of the various fibroblast cultures to
      induce p53 following 4NQO treatment and their DNA repair efficiencies. Treatment
      with 0.12 microM 4NQO, for example, caused a >2-fold up-regulation of p53 in
      excision repair-deficient (AT, XPA and XPG) strains without eliciting any effect
      on p53 levels in repair-proficient (normal and XPE) strains. We conclude that up
      regulation of p53 by 4NQO is mediated solely by an ATM-independent mechanism and
      that the p53 response is primarily triggered by persistent alkali-stable 4NQO-DNA
      adducts.

PMID- 10357772
TI  - Expression of CYP1A1 and CYP1B1 depends on cell-specific factors in human breast
      cancer cell lines: role of estrogen receptor status.
AB  - The impact of estrogen receptor (ER) was examined for expression and activity of
      cytochrome P4501B1 (CYP1B1) and cytochrome P4501A1 (CYP1A1) in two pairs of
      ER+/ER- human breast epithelial cell lines derived from single lineages, and
      representing earlier (T47D) or later (MDA-MB-231) stages of tumorigenesis. Acute
      loss of ER was evaluated using the anti-estrogen ICI 182,780 (ICI). In all lines,
      CYP1B1 was expressed constitutively and was induced by 2,3,7, 8
      tetrachlorodibenzo-p-dioxin (TCDD), whereas CYP1A1 was expressed only following
      induction. Expression of each CYP (with or without TCDD) was greater in T47D
      cells than MDA cells. The ER impacted expression of these genes in opposite
      directions. The ER- phenotype was associated with less TCDD-induced CYP1A1
      expression, but greater basal and induced CYP1B1 expression. A 48 h treatment of
      ER+ cells with ICI did not revert the P450 expression pattern to that of ER-
      cells. Based on activities of recombinant enzyme and expression levels,
      differences in 7,2-dimethylbenz [a]anthracene (DMBA) metabolism between the cell
      lines were consistent with differences in CYP1A1 and CYP1B1 expression. In T47D
      lines, basal microsomal DMBA metabolism was primarily due to CYP1B1, based on
      regioselective metabolite distribution and inhibition by anti-CYP1B1 antibodies
      (>80%). Metabolism in TCDD-induced microsomes was mostly due to CYP1A1 and was
      inhibited by anti-CYP1A1 antibody (>50%). TCDD-induced MDA+ cells demonstrated
      CYP1A1 activity, whereas TCDD-induced MDA- cells displayed CYP1B1 activity. Aryl
      hydrocarbon receptor (AhR) levels, but not AhR nuclear translocator protein
      (ARNT) levels were highly dependent on cell type; AhR was high and ER-independent
      in MDA, and low and ER-linked in T47D. AhR levels were insensitive to ICI. ER
      does not directly modulate the expression of CYP1A1, CYP1B1 or AhR. Indeed,
      factors that have replaced ER in growth regulation during clonal selection
      predominate in this regulation. Characteristics unique to each cell line,
      including ER status, determine CYP1A1 and CYP1B1 expression.

PMID- 10357773
TI  - Hepatocyte growth factor is an invasion/migration factor of rat urothelial
      carcinoma cells in vitro.
AB  - Hepatocyte growth factor (HGF) plays an important role in the growth, progression
      and angiogenesis of various tumors. It is reported that patients with urinary
      bladder cancer have elevated levels of HGF in urine and that bladder cancer
      tissue contains an increased amount of HGF. Thus, the data suggest a functional
      role of HGF in urinary bladder cancer. We evaluated the mechanistic role of HGF
      in urinary bladder carcinoma in vitro using the rat urothelial cell lines MYP3
      (anchorage-dependent and non-tumorigenic in athymic nude mice), LMC19, MYU3L, T6
      and AS-HTB1 (anchorage-independent and tumorigenic). The HGF receptor c-met was
      expressed by all of the cell lines, as determined by northern blot. In MYP3
      cells, HGF strongly stimulated anchorage-dependent growth, but not migration,
      invasion or secretion of matrix metalloproteinases (MMPs). In LMC19, T6 and AS
      HTB1 cells, HGF stimulated migration, invasion and secretion of MMPs. Anchorage
      dependent growth stimulation was limited to AS-HTB1 cells. MYU3L cells were
      refractory to HGF in both growth and invasion assays. However, a neutralizing
      antibody and an anti-sense oligonucleotide to HGF partially inhibited the growth
      only of MYU3L cells, the finding being indicative of an autocrine stimulatory
      mechanism. HGF mRNA expression and protein synthesis were induced in bladder
      stromal cells by the conditioned medium of carcinoma cell lines, and IL-1beta and
      basic fibroblast growth factor were identified as cancer cell-derived HGF
      releasing factors. These results suggest that HGF acts as a mitogen in a non
      tumorigenic cell line, whereas in tumorigenic cell lines it acts as an invasion
      and migration factor by either a paracrine or an autocrine mechanism.

PMID- 10357774
TI  - The p53 tumor suppressor gene of the marsupial Monodelphis domestica: cloning of
      exons 4-11 and mutations in exons 5-8 in ultraviolet radiation-induced corneal
      sarcomas.
AB  - Inactivating p53 mutations are found in many ultraviolet radiation (UVR)-induced
      skin tumors. We examined 12 UVR-induced corneal tumors of the marsupial
      Monodelphis domestica for mutations in exons 5-8 of p53 and compared their
      mutational spectrum with that of UVR-induced skin tumors of other species. First
      we cloned and characterized a cDNA extending from the middle of exon 4 through
      exon 11 of the Monodelphis p53 gene. Based on the sequence information obtained,
      primers were designed to amplify introns 4-9 of the gene; intron primers to
      amplify individually exons 5-8 were subsequently developed. 'Cold' single strand
      conformational polymorphism analysis followed by reamplification of DNA with
      altered mobility and cycle sequencing revealed single p53 mutations in four of 12
      tumors (33%), including one mutation in exon 5, two identical mutations in exon 7
      and one mutation in exon 8. All mutations were at dipyrimidine sites and occurred
      on the non-transcribed strand. Three of the four were hallmark UVR-induced C-->T
      alterations. Three of the mutations were found at sites corresponding to human
      codons 248 and 273, which are mutational hotspots in human and murine UVR-induced
      squamous cell carcinomas. Our findings suggest that UVR-induced corneal sarcomas
      in Monodelphis will be valuable in studying mechanisms of p53 mutation in UVR
      induced tumors.

PMID- 10357775
TI  - Effects of colonic lumenal components on AP-1-dependent gene transcription in
      cultured human colon carcinoma cells.
AB  - We recently suggested that prolonged deregulated expression of AP-1 activity in
      colonic cells by bile acids may contribute to tumour promotion in the colon. In
      the present study, using two human colon carcinoma cell lines, HT-29 and HCT 116,
      transiently transfected with the AP-1-luciferase reporter construct, we showed
      that the bile acids, deoxycholate, chenodeoxycholate, ursodeoxycholate and
      lithocholate, induced AP-1-dependent gene transcription in a dose-dependent
      manner, whereas cholate was without effect. The greatest effect was observed with
      deoxycholate, and the ability of this bile acid to induce reporter gene activity
      was significantly correlated with its ability to induce cell proliferation (r =
      0.91, P = 0.01). Cholesterol and the long chain fatty acids, myristate, palmitate
      and stearate, had no effect on AP-1-dependent gene transcription, whereas the
      short chain fatty acid, butyrate, exhibited a marked effect. Mindful of the fact
      that the concentrations of lumenal components that are actually in or entering
      the epithelial cells in the colon are presumably lower than lumenal values, we
      considered it of interest to determine the effect of dilution on the capacity of
      human faecal water to induce AP-1 activity and also cell proliferation. We
      demonstrated that diluted lipid extracts, from all of the faecal water samples
      examined, significantly induced AP-1-dependent gene transcription in the colonic
      cells, and that this effect differed markedly between the extracts. We confirmed
      that the faecal water lipid extracts, at the same dilution at which they
      increased AP-1 activity, significantly induced proliferation in the same cell
      line. These data suggest that lipid components of human faecal water, which is in
      direct contact with the colon epithelium and may be physiologically more active
      than the solid phase, can activate AP-1, a transcription factor whose activation
      has been associated with the promotion of neoplastic transformation.

PMID- 10357776
TI  - Activation of protein kinase C augments butyrate-induced differentiation and
      turnover in human colonic epithelial cells in vitro.
AB  - As the colonic epithelium is physiologically exposed to butyrate and to
      activators of protein kinase C, we examined the effect of the protein kinase C
      signalling pathway on butyrate-induced expression of markers of differentiation.
      Activators and inhibitors of protein kinase C were used in combination with
      butyrate and effects on the expression of markers of differentiation examined in
      colon cancer cell lines. When the protein kinase C activator phorbol myristate
      acetate (100 nM) was added for 24 h prior to the addition of 2 mM butyrate, there
      was a synergistic increase in alkaline phosphatase activity (154 +/- 11% above
      that for butyrate alone, P = 0.003) in a concentration- and time-dependent
      manner. Butyrate-induced expression of carcinoembryonic antigen and interleukin
      8, dome formation and cell turnover were also markedly augmented by pre-treatment
      with phorbol myristate acetate. A similar effect was observed with propionate or
      acetate (but not other differentiating agents), when phorbol myristate acetate
      and butyrate were added concurrently, or when other protein kinase C activators
      were used. Pharmacological inhibition of protein kinase C activity did not alter
      butyrate-induced alkaline phosphatase activity, but abrogated the augmentation
      induced by phorbol myristate acetate. We conclude that protein kinase C does not
      mediate the differentiating effects of butyrate on colon cancer cells, but its
      activation regulates butyrate-induced cellular differentiation.

PMID- 10357777
TI  - Impairment of peroxisomal biogenesis in human colon carcinoma.
AB  - Peroxisomes and the activities of their enzymes have been reported to be
      significantly reduced in various types of tumors including the colon carcinoma.
      Therefore, the present study was designed to investigate the gene expression of
      several peroxisomal proteins in human colon carcinoma and additionally those of
      the peroxisome proliferator activated receptor alpha (PPARalpha) and PEX5, a
      receptor protein involved in the import of most peroxisomal matrix proteins.
      Samples from adenocarcinomas and adjacent normal colon were analyzed by
      immunohistochemistry and western blotting. The mRNA content was assessed by a
      novel sensitive dot blot RNase protection assay and northern blotting. By
      immunohistochemistry, peroxisomes were distinctly visualized in normal
      colonocytes but were not detected in colon carcinoma cells. The protein levels of
      catalase (CAT), acyl-CoA oxidase as well as the 22 and 70 kDa peroxisomal
      membrane proteins (PMP22 and PMP70) were all significantly decreased in
      carcinomas. The corresponding mRNAs for CAT and PMP70, however, were unchanged.
      In contrast, the mRNA of PEX5 was significantly increased. The expression of
      PPARalpha was not altered in tumors, neither at protein nor mRNA levels. These
      observations show that the reduction of peroxisomes and their proteins in colon
      carcinoma is not due to a generalized reduction of transcription of their genes.
      It seems more likely that this phenomenon is regulated at a post-transcriptional
      or translational level. Alternatively, and more likely, an impairment of the
      biogenesis of the organelle could account for the paucity of peroxisomes in colon
      carcinoma.

PMID- 10357778
TI  - Analyses of bronchial bulky DNA adduct levels and CYP2C9, GSTP1 and NQO1
      genotypes in a Hungarian study population with pulmonary diseases.
AB  - Carcinogen-DNA adducts may represent an intermediate end-point in the
      carcinogenic cascade and may reflect exposure to chemical carcinogens, as well as
      susceptibility and, ultimately, cancer risk. Interindividual variability in
      activity of enzymes involved in the metabolism of polycyclic aromatic
      hydrocarbons to mutagenic diol epoxides may predict adduct levels and,
      indirectly, lung cancer risk. Using 32P-postlabeling methods, the levels of bulky
      DNA adducts were determined in macroscopically normal bronchial tissues obtained
      from resected lobes of 143 Hungarian patients with lung malignancy and other
      pulmonary conditions. DNA from normal tissue was also evaluated for polymorphisms
      in cytochrome P450 2C9 (CYP2C9) at two sites, codons 144 (Arg/Cys) and 359
      (Ile/Leu), for glutathione S-transferase P1 (GSTP1) at codon 105 and for
      NAD(P)H:quinone oxidoreductase (NQO1) at codon 187 (Pro/Ser). Using the Mann
      Whitney U-test and analysis of variance, levels of adducts were evaluated in
      relation to variant genotypes, separately for smokers and non-smokers. As
      previously reported, bulky DNA adduct levels in smokers (n = 104) were estimated
      to be 54% higher than in non-smokers (n = 39) (8.6 +/- 4.2 versus 5.6 +/- 3.3 per
      10(8) nucleotides, respectively, P < 0.01). Adduct levels were 16-29% higher in
      individuals with the homozygous Ile359/Ile359 CYP2C9 allele than in those
      heterozygous for the variant allele (Ile359/Leu359) [8.8 +/- 4.3 (n = 84) versus
      7.6 +/- 3.5 (n = 20) for smokers and 5.8 +/- 3.5 (n = 32) versus 4.5 +/- 1.3 (n =
      7) for non-smokers], although differences were not statistically significant.
      There were no clear differences in adduct levels in relation to genotypes of NQO1
      or GSTP1. Although numbers of patients in this study are large in relation to
      many studies of carcinogen-DNA adducts, it is still possible that significant
      differences were not noted for polymorphisms in xenobiotic metabolizing enzymes
      due to relatively small numbers in stratified data.

PMID- 10357779
TI  - Chemopreventive effect of 4'-demethyl epipodophyllotoxin on DMBA/TPA-induced
      mouse skin carcinogenesis.
AB  - The chemopreventive effect of topical application of 4'-demethyl
      epipodophyllotoxin (DMEP), an antimitotic agent, on a two-stage skin
      carcinogenesis model in Swiss Albino mice induced by 9, 10
      dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) was
      investigated. Two topical applications with 0.24% DMBA over 1 week, followed
      later by 5 nmol of TPA twice weekly produced 100% incidence of tumors in these
      animals by 18 weeks. Treatment of animals with DMEP (until the end of the
      experiment), 30 min before TPA treatment, significantly reduced the tumor
      incidence, tumor volume and the conversion efficiency of papillomas to squamous
      cell carcinomas. The tumor formation and growth was also delayed by DMEP pre
      treatment. Application of DMEP protected against the losses provoked in levels of
      glutathione and activity of catalase and superoxide dismutase in skin and liver
      of animals by the application of DMBA/TPA. Thus, DMEP might possibly be exerting
      its chemopreventive activity by acting as an antioxidant.

PMID- 10357780
TI  - Ingestion of sugar beet fiber enhances irradiation-induced aberrant crypt foci in
      the rat colon under an apoptosis-suppressed condition.
AB  - The induction of aberrant crypt foci (ACF) by irradiation of gamma-rays (60Co),
      and the effect of dietary sugar beet fiber (SBF) on irradiation-induced ACF were
      examined. We found that abdominal irradiation of gamma-rays could induce ACF in
      the rat colon. The irradiation was performed once a week at a dose rate of 2 or 3
      Gy per irradiation. Irradiation-induced ACF were observed in the colon at 10
      weeks after the first irradiation at dose of 2 Gy for six times or 3 Gy for four
      times. Dietary SBF had no effect on the number of ACF, aberrant crypts (AC) or
      AC/focus induced by abdominal gamma-irradiation. However, an ingestion of SBF
      resulted in an increase in the number of these parameters in apoptosis-suppressed
      rats by cycloheximide (CHX). An injection of CHX suppressed irradiation-induced
      apoptosis of the colonic epithelial cells for at least 6 h after the irradiation.
      In CHX-injected rats, an ingestion of SBF significantly increased the number of
      ACF, AC and AC/focus compared with fiber-free fed rats at 9 weeks after the first
      irradiation. On the other hand, in saline-injected rats, no significant
      difference was found between SBF and fiber-free diets in the number of ACF, AC
      and AC/focus through the experimental period. These results suggest that dietary
      SBF may be involved in the elimination of abnormal cells from an irradiated colon
      through the apoptosis of colonic epithelial cells. In this study, we have shown a
      new method for inducing ACF by using gamma-rays which were not influenced by
      luminal contents such as bacterial enzyme, at least in the initiation stage.

PMID- 10357781
TI  - Chemoprevention by curcumin during the promotion stage of tumorigenesis of
      mammary gland in rats irradiated with gamma-rays.
AB  - We have evaluated the chemopreventive effects of curcumin on diethylstilbestrol
      (DES)-induced tumor promotion of rat mammary glands initiated with radiation.
      Sixty-four pregnant rats received whole body irradiation with 2.6 Gy gamma-rays
      from a 60Co source at day 20 of pregnancy and were divided into two groups after
      weaning. In the control group of 39 rats fed a basal diet and then implanted with
      a DES pellet for 1 year, 33 (84.6%) developed mammary tumors. Twenty-five rats
      were fed diet containing 1% curcumin immediately after weaning and received a DES
      pellet, as for the control. The administration of dietary curcumin significantly
      reduced the incidence (28.0%) of mammary tumors. Multiplicity and Iball's index
      of mammary tumors were also decreased by curcumin. Rats fed the curcumin diet
      showed a reduced incidence of the development of both mammary adenocarcinoma and
      ER(+)PgR(+) tumors in comparison with the control group. On long-term treatment
      with curcumin, body weight and ovarian weight were reduced, but liver weight was
      increased. Compared with the control rats, the curcumin-fed rats showed a
      significant reduction in serum prolactin, whereas estradiol-17beta and
      progesterone concentrations were not significantly different between the two
      groups. Curcumin did not have any effect on the concentration of free
      cholesterol, cholesterol ester and triglyceride. Feeding of the curcumin diet
      caused a significant increase in the concentrations of tetrahydrocurcumin,
      arachidonic acid and eicosapentaenoic acid and a significant decrease in
      thiobarbituric acid-reactive substance concentration in serum. Whole mounts of
      the mammary glands showed that curcumin yielded morphologically indistinguishable
      proliferation and differentiation from the glands of the control rats. These
      findings suggest that curcumin has a potent preventive activity during the DES
      dependent promotion stage of radiation-induced mammary tumorigenesis.

PMID- 10357782
TI  - Decrease in linoleic acid metabolites as a potential mechanism in cancer risk
      reduction by conjugated linoleic acid.
AB  - Previous research suggested that conjugated linoleic acid (CLA) feeding during
      the period of pubescent mammary gland development in the rat resulted in
      diminished mammary epithelial branching which might account for the reduction in
      mammary cancer risk. Terminal end buds (TEB) are the primary sites for the
      chemical induction of mammary carcinomas in rodents. One of the objectives of the
      present study was to investigate the modulation of TEB density by increasing
      levels of dietary CLA and to determine how this might affect the risk of
      methylnitrosourea-induced mammary carcinogenesis. The data show a graded and
      parallel reduction in TEB density and mammary tumor yield produced by 0.5 and 1%
      CLA. No further decrease in either parameter was observed when CLA in the diet
      was raised to 1.5 or 2%. Thus, optimal CLA nutrition during pubescence could
      conceivably control the population of cancer-sensitive target sites in the
      mammary gland. Since both CLA and linoleic acid are likely to share the same
      enzyme system for chain desaturation and elongation, it is possible that
      increased CLA intake may interfere with the further metabolism of linoleic acid.
      Fatty acid analysis of total lipid showed that CLA and CLA metabolites continued
      to accumulate in mammary tissue in a dose-dependent manner over the range 0.5-2%
      CLA. There was no perturbation in tissue linoleic acid, however, linoleic acid
      metabolites (including 18:3, 20:3 and 20:4) were consistently depressed by up to
      1% CLA. Of particular interest was the significant drop in 20:4 (arachidonic
      acid), which is the substrate for the cyclooxygenase and lipoxygenase pathways of
      eicosanoid biosynthesis. Thus the CLA dose-response effect on arachidonic acid
      suppression corresponded closely with the CLA dose-response effect on cancer
      protection in the mammary gland. This information is critical in providing new
      insights regarding the biochemical action of CLA.

PMID- 10357783
TI  - Ornithine decarboxylase activity in L929 cells following exposure to 60 Hz
      magnetic fields.
AB  - To determine whether there is a biological basis for epidemiological studies
      which suggest an association between exposure to magnetic fields and cancer, we
      have attempted to replicate earlier findings on cellular enzymes related to cell
      proliferation. Here we report on an effort to replicate the doubling of ornithine
      decarboxylase (ODC) activity in L929 murine fibroblasts following exposure to 60
      Hz magnetic fields reported by Litovitz et al. Efforts were made to reproduce the
      methods and exposure conditions used by the original investigators. Positive
      controls showed that our assay system responded to other known stimuli of ODC
      activity. We extended the previously reported investigations by testing a number
      of exposure conditions and other associated variables. Initial results suggested
      that cells exposed in the original investigators' laboratory demonstrated an
      enhanced enzyme activity, whereas cells exposed in our laboratory did not.
      Experiments in our laboratory using the most important elements of the original
      investigators' exposure system did not demonstrate any enhancement of ODC
      activity. Finally, a series of magnetic field exposure and sham exposure
      experiments conducted in the original investigators' laboratory failed to
      demonstrate an effect of magnetic fields on ODC activity.

PMID- 10357784
TI  - Comparison of the polymorphic regions of the cytochrome P450 CYP2E1 gene of
      humans and patas and cynomolgus monkeys.
AB  - Cytochrome P450 2E1 (CYP2E1) metabolizes low molecular weight toxicants. CYP2E1
      gene polymorphisms have been linked to risk of various cancers and liver disease
      in humans. Since the patas monkey is a promising model for study of cancer
      related alcohol/nitrosamine interactions, we examined CYP2E1 in this monkey for
      characteristics of two regions that are polymorphic in humans, an RsaI site in
      the 5' promoter region and a DraI site in intron 6. Another monkey species often
      used in biomedical research, the cynomolgus monkey, was also examined. Human DNA
      primers used to amplify a 413 bp segment around the RsaI site also amplified a
      segment of similar size (409 bp) from DNA of 25 patas monkeys, whereas a product
      of approximately 800 bp was amplified from DNA of eight cynomolgus monkeys. RsaI
      did not cut the amplified DNA product from either monkey species. Sequencing
      revealed that the patas RsaI site was identical to that in humans with the c2c2
      CYP2E1 genotype, GTAT. The equivalent cynomolgus sequence, CTAC, has not been
      observed in humans. Thus, the patas monkey appears to be a useful model for
      CYP2E1 c2c2 humans, and this genotype, present in 2-25% of humans, may be more
      primitive than c1c1. For the DraI site, the human primers amplified DNA products
      similar in size to those from humans, from all patas and cynomolgus monkey DNA
      samples; none were cut by DraI. Thus, both monkey species appeared to be
      generally similar to humans of CYP2E1 CC DraI genotype, which is the rarer form
      of the gene.

PMID- 10357785
TI  - Effect of vitamin C supplementation on chromosome damage, apoptosis and necrosis
      ex vivo.
AB  - We investigated whether high dose vitamin C influenced the viability of human
      lymphocytes in plasma, in the presence or absence of hydrogen peroxide (512
      microM) by scoring necrotic, apoptotic and micronucleated cells using the
      cytokinesis-block micronucleus assay. The in vitro results showed that vitamin C
      (0.57-2.27 mM) on its own had no effect on the above parameters. However, in the
      presence of hydrogen peroxide vitamin C significantly reduced the number of
      dividing cells and apoptosis, and increased necrosis and micronucleated cells. A
      double-blind placebo controlled intervention, with a cross-over, involving 11
      male subjects, aged 20-40 years, was performed to determine whether high plasma
      vitamin C concentration resulting from vitamin C supplementation promotes or
      protects against genetic damage and cell death ex vivo. Venous blood samples were
      collected before and after an anti-oxidant-poor diet which reduced plasma vitamin
      C concentrations by 15% (P < 0.05), and was followed with a 2 g vitamin C
      supplement, which raised plasma concentrations by 115 and 125% (0.12 mM) after 2
      and 4 h, respectively (P < 0.05). Plasma collected post-vitamin C ingestion did
      not alter micronucleus expression or apoptosis in control or hydrogen peroxide
      treated lymphocytes, but it moderately increased necrosis (P < 0.08). Analysis of
      combined data showed that necrotic cell frequency correlated positively with
      micronucleated cell frequency (r = 0.66, P < 0.0001) and negatively with
      apoptotic cell frequency (r = -0.81, P < 0.0001). Overall, vitamin C
      supplementation did not appear to cause DNA damage under normal physiological
      conditions nor did it protect cells against hydrogen peroxide-induced toxicity.

PMID- 10357786
TI  - Okadaic acid mediates p53 hyperphosphorylation and growth arrest in cells with
      wild-type p53 but increases aberrant mitoses in cells with non-functional p53.
AB  - The protein phosphatase inhibitor and tumor promoting agent okadaic acid (OA),
      has been shown previously to induce hyperphosphorylation of p53 protein, which in
      turn correlated with increased transactivation or apoptotic function. However,
      how the tumor promotion effects of OA relate to p53 tumor supressor function (or
      dysfunction) remain unclear. Rat embryonic fibroblasts harboring a temperature
      sensitive mouse p53 transgene were treated with 50 nM doses of OA. At the wild
      type permissive temperature this treatment resulted in: (i) the
      hyperphosphorylation of sites within tryptic peptides of the transactivation
      domain of p53; (ii) an increase in p53 affinity for a p21(waf1) promotor
      oligonucleotide; (iii) an increase in cellular steady state levels of p21(waf1)
      message; (iv) a G2/M cell cycle blockage in addition to the G1/S arrest
      previously associated with p53; and (v) no increased incidence of apoptosis. On
      the other hand, OA treatment at the mutated p53 permissive temperature resulted
      in a relatively high incidence of aberrant mitosis with no upregulation of
      p21(waf1) message. These results suggest that while wild-type p53 blocks the
      proliferative effects of OA through p21(waf1)-mediated growth arrest, cells with
      non-functional p53 cannot arrest and suffer relatively high levels of OA-mediated
      aberrant mitoses.

PMID- 10357787
TI  - DNA polymerase beta expression differences in selected human tumors and cell
      lines.
AB  - A long-standing question in cancer biology has been the extent to which DNA
      repair may be altered during the process of carcinogenesis. We have shown
      recently that DNA polymerase beta (beta-pol) provides a rate-determining function
      during in vitro repair of abasic sites by one of the mammalian DNA base excision
      repair pathways. Therefore, altered expression of beta-pol during carcinogenesis
      could alter base excision repair and, consequently, be critical to the integrity
      of the mammalian genome. We examined the expression of beta-pol in several cell
      lines and human adenocarcinomas using a quantitative immunoblotting method. In
      cell lines from normal breast or colon, the level of beta-pol was approximately 1
      ng/mg cell extract, whereas in all of the breast and colon adenocarcinoma cell
      lines tested, a higher level of beta-pol was observed. In tissue samples, colon
      adenocarcinomas had a higher level of beta-pol than adjacent normal mucosa.
      Breast adenocarcinomas exhibited a wide range of beta-pol expression: one tumor
      had a much higher level of beta-pol (286 ng/mg cell extract) than adjacent normal
      breast tissue, whereas another tumor had the same level of beta-pol as adjacent
      normal tissue. Differences in beta-pol expression level, from normal to elevated,
      were also observed with prostate adenocarcinomas. All kidney adenocarcinomas
      tested had a slightly lower beta-pol level than adjacent normal tissue. This
      study reveals that the base excision repair enzyme DNA polymerase beta is up
      regulated in some types of adenocarcinomas and cell lines, but not in others.

PMID- 10357788
TI  - Quantitative analysis of 4-aminobiphenyl-C8-deoxyguanosyl DNA adducts produced in
      vitro and in vivo using HPLC-ES-MS.
AB  - Electrospray mass spectrometry (ES-MS) is a powerful tool for analysis of
      carcinogen-adducted DNA. In this study, we developed a quantitative isotope
      dilution method for analysis of N-(deoxyguanosine-8-yl)-4-aminobiphenyl (dG-C8-4
      ABP), the principal nucleoside adduct derived from enzymatic hydrolysis of 4
      aminobiphenyl (4-ABP)-modified DNA. The method used column switching valves to
      perform on-line sample concentration and cleanup, which permitted direct analysis
      of enzymatic DNA hydrolysates using narrow-bore liquid chromatography (LC). ES-MS
      detection was performed using a single quadrupole instrument by monitoring M+H+
      and two fragment ions characteristic for dG-C8-4-ABP, along with M+H+ and a
      fragment ion for the deuterated internal standard. The detection limit for dG-C8
      4-ABP in DNA hydrolysates was approximately 10 pg on-column, equivalent to 0.7 dG
      C8-4-ABP adducts in 10(7) normal nucleotides for a sample containing 100 microg
      DNA. The method was applied to the analysis of calf thymus DNA modified in vitro
      through reaction with N-hydroxy-4-ABP and of hepatic DNA isolated from mice
      treated in vivo with two dose levels of 4-ABP.

PMID- 10357789
TI  - Strain differences of rats in the susceptibility to aberrant crypt foci formation
      by 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine: no implication of Apc and
      Pla2g2a genetic polymorphisms in differential susceptibility.
AB  - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant
      mutagenic heterocyclic amine contained in cooked food, induces colon tumors in
      F344 male rats when administered orally. In the present study, PhIP was
      introduced to various rat strains, and susceptibility to the induction of
      aberrant crypt foci (ACFs) was analyzed as a biomarker for colon carcinogenesis.
      BUF/Nac rats were highly susceptible, giving rise to 12.2 +/- 1.7 ACFs per rat.
      F344 rats were intermediate and ACI/N rats were resistant, giving 3.5 +/- 1.8 and
      0.9 +/- 0.7 ACFs per rat, respectively. In spite of this, the extent of DNA
      damage by PhIP in F344, in terms of the level of PhIP-DNA adducts, was
      significantly lower than that in ACI/N. The differences in formation of ACFs
      could be, in some part, implicated in the differential susceptibility to colon
      carcinogenesis induced by PhIP, especially in a step later than adduct formation.
      In an attempt to determine the genetic factors implicated in the susceptibility
      to formation of ACFs, a possible involvement of the adenomatous polyposis gene
      (Apc) and its modifier secretory phospholipase A2 (Pla2g2a) was analyzed. No
      genetic polymorphisms in either Apc or Pla2g2a showed a significant correlation
      to susceptibility to formation of ACFs among rat strains.

PMID- 10357790
TI  - Induction of high incidence of mammary tumour in female Noble rats with a
      combination of 17beta-oestradiol and testosterone.
AB  - Breast cancer is the most common cancer and the second most frequent cause of
      cancer death in women. Despite extensive research, the precise mechanisms of
      breast carcinogenesis remain unclear. One of the reasons for this is due, at
      least in part, to a lack of a suitable animal model which can closely mimic the
      breast carcinogenesis in normal situations without using chemical carcinogens. We
      have developed an animal model of mammary gland carcinogenesis using a
      combination of oestradiol and testosterone, and succeeded in inducing a high
      percentage of female Noble rats to develop mammary cancer in a relatively short
      time (approximately 6 months). The results showed that androgens might work as a
      promoter to shorten the latency time of mammary gland carcinogenesis.
      Histopathological examination revealed that hyperplasia and dysplasia were first
      observed 2 months after treatment, in situ carcinoma after 3 months, and fully
      developed carcinoma of various forms including cribriform, papillary and camedo
      types were observed from 5 to 6 months after hormone implantation. Animals
      implanted with oestrogen or testosterone alone also developed mammary cancers,
      though with a lower overall incidence than the two hormones combined. They ranged
      from well differentiated to poorly differentiated forms with predominantly
      infiltrating ductal carcinoma. We have also observed a case of secondary cancer
      in the uterus. In addition to the high incidence of carcinoma, there was also a
      peculiar unexplained ipsilateral correlation between the site of hormonal
      implantation and the location of tumours, and the highest incidence of
      carcinogenesis was found to be in thoracic mammary gland. The study showed that
      both oestrogens and androgens are important in mammary cancer development. The
      animal model would prove to be a useful model for analysis of the mechanism(s) of
      hormonal carcinogenesis.

PMID- 10357791
TI  - Role of human N-acetyltransferases, NAT1 or NAT2, in genotoxicity of nitroarenes
      and aromatic amines in Salmonella typhimurium NM6001 and NM6002.
AB  - Human NAT1 and NAT2 genes were subcloned into pACYC184 vector and the plasmids
      thus obtained were introduced into Salmonella typhimurium O-acetyltransferase
      deficient strain NM6000 (TA1538/1, 8-DNP/pSK1002), establishing new strains
      NM6001 and NM6002, respectively. We compared the sensitivities of these two
      strains with those of NM6000 towards carcinogenic nitroarenes and aromatic amines
      in the SOS/umu response. The induction of umuC gene expression by these chemicals
      in the presence and absence of the S9 fraction was assayed by measuring the
      cellular beta-galactosidase activity expressed by the umuC"lacZ fusion gene in
      the tester strains. 2-Nitrofluorene and 2-aminofluorene induced umuC gene
      expression more strongly in the NM6001 strain than in the NM6002 strain. In
      contrast, induction of umuC gene expression by 1, 8-dinitropyrene, 6
      aminochrysene and 2-amino-3,5-dimethylimidazo[4, 5-f]quinoline was weaker in the
      NM6001 strain than in the NM6002 strain. 1-Nitropyrene, 2-amino-6-methyl
      dipyrido[1,2-a:3', 2'-d]imidazole, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 3
      amino-1-methyl-5H-pyrido[4,3-b]indole, 2-amino-1-methyl-6-phenylimidazo[4,5
      b]pyridine and 2-amino-3-methyl-9H-pyrido[2,3-b]indole were found to induce umuC
      gene expression at similar extents in both strains. These results suggest that
      the newly developed strains can be employed for the studies on mechanisms of
      genotoxicity of a variety of nitroarenes and aromatic amines, along with the
      assessment of cancer risk to humans.

PMID- 10357792
TI  - Use of UvrABC nuclease to quantify benzo[a]pyrene diol epoxide-DNA adduct
      formation at methylated versus unmethylated CpG sites in the p53 gene.
AB  - We have used the UvrABC nuclease incision method in combination with ligation
      mediated polymerase chain reaction (LMPCR) techniques to map and quantify (+/
      )anti-7beta, 8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]
      pyrene (BPDE) adduct formation in the p53 gene of human cells. We found that BPDE
      adduct formation, as revealed by UvrABC incision, preferentially occurred at
      methylated CpG sites that correspond to the mutational hotspots observed in human
      lung cancers. Our hypothesis is that it is this methylated CpG sequence-dependent
      preferential adduct formation, rather than selective growth advantage, that is
      the major determinant of the p53 mutation pattern in human cancers. Given the far
      reaching ramifications of such conclusions for cancer etiology, a legitimate
      question is raised regarding the reliability of using the UvrABC incision method
      for quantifying and determining the sequence-dependency of adduct formation. Is
      the higher frequency of UvrABC cutting at methylated versus unmethylated CpG
      sites due to the preference of the nuclease for cutting at those sites or due to
      the preferential formation of BPDE adducts at those sites? In order to
      distinguish between these two possibilities, we have analyzed the kinetics of
      UvrABC incision at BPDE adducts formed at either methylated CpG sites versus
      other sequences, or unmethylated CpG sites versus other sequences in exon 5 of
      the p53 gene. We have found that the UvrABC cutting kinetics are identical for
      both cases. On the basis of these results we conclude that under proper cutting
      conditions, UvrABC nuclease reacts with and incises with equal efficiency, BPDE
      adducts formed at methylated or unmethylated CpG sites as well as other
      sequences, and that the extent of UvrABC incision accurately reflects the extent
      of BPDE-DNA adduct formation. These conclusions were further supported by results
      obtained using a DNA synthesis blockage assay.

PMID- 10357794
TI  - Metabolic proficiency and benzo[a]pyrene DNA adduct formation in APCMin mouse
      adenomas and uninvolved mucosa.
AB  - Tumour formation may involve interactions between genetic factors and
      environmental carcinogens. Adenoma formation in APCMin/+ mice is associated
      homozygous adenomatous polyposis coli (APC) gene mutation, but the effects on
      carcinogen susceptibility are unknown. This study tests the hypothesis that
      APCMin/+ adenoma formation is accompanied by changes in metabolic proficiency and
      carcinogen susceptibility. Cytochrome P450 (CYP)1A1/1A2, glutathione S
      transferase (GST)alpha, mu and pi classes and DNA adduct formation were assayed
      in adenomas and uninvolved mucosa from APCMin/+ mice, before and after
      benzo[a]pyrene (B[a]P) treatment. In untreated adenomas and mucosa, CYP1A1/1A2
      and B[a]P-DNA adducts were undetected but GSTalpha, mu and pi class enzymes were
      constitutively expressed. In adenomas, B[a]P only induced CYP1A1/1A2 to low level
      while GSTalpha and pi class enzymes were unaffected. A GST mu band which was
      absent from mucosa, was induced in adenomas. In mucosa, B[a]P induced CYP1A1/1A2
      and GSTalpha and pi, to high levels. B[a]P-DNA adduct levels were 56 +/- 15/10(8)
      nucleotides (median +/- SE) in adenomas versus 89 +/- 19/10(8) nucleotides in
      mucosa (P < 0.0001). APCMin adenomas show reduced bioactivation capacity and
      sustain less DNA damage from B[a]P exposure, than APCMin uninvolved mucosa. These
      properties could influence mutagenesis and subsequent neoplastic transformation
      of adenomas.

PMID- 10357793
TI  - Hepatic hyperplasia and cancer in rats: alterations in copper metabolism.
AB  - We previously demonstrated that rats exposed to the peroxisome proliferator (PP)
      diethylhexylphthalate (DEHP) had reduced serum ceruloplasmin (CP) oxidase
      activity, which suggests tissue copper deposition. Copper is highly toxic in
      excess, and results in cellular damage and hepatocellular carcinomas (HCC). This
      study addresses changes in expression of copper-related genes and metal
      accumulation in hyperplastic liver and tumors induced by PP. Male rats were fed
      diets containing DEHP or clofibrate (CLF) for 3-60 days (hyperplasia) and 4
      chloro-6-(2,3 xylidino)-2-pyrimidinyl-thio(N-beta-hydroxyethyl) acetamide for 10
      months (HCC). During hyperplasia, an immediate and progressive decrease in serum
      CP activity was observed (P < 0.05), as were reductions in mRNA levels for both
      CP and Wilson's disease gene (WD gene, a P-type ATPase) (P < 0.05). Tumor-bearing
      rats had lower serum CP activity (P < 0.05), and CP and WD gene mRNA levels were
      reduced in tumors (P < 0.05), and in liver surrounding tumors (SL) (P < 0.05).
      Metallothionein mRNA showed no consistent changes during hyperplasia. Tumors
      showed a 2.5-fold induction of metallothionein mRNA (P < 0.05), and a 1.2-fold
      increase in SL. Temporal increases in liver copper content occurred during
      hyperplasia, with increases of 2-fold (DEHP) and 3.3-fold (CLF) at 60 days (P <
      0.05). Copper content was 2.2-fold higher in tumors (P < 0.05) and 1.7-fold
      higher in SL; iron did not increase and zinc decreased temporally. Thus, copper
      accumulation and changes in copper-related gene expression may be contributing
      factors in liver neoplasia in PP-treated rats. Loss of CP results in decreased
      free radical scavenger capacity and thus may enhance oxidative damage induced by
      PPs.

PMID- 10357795
TI  - Mutagenesis induced by benzo[a]pyrene in lacZ mouse mammary and oral tissues:
      comparisons with mutagenesis in other organs and relationships to previous
      carcinogenicity assays.
AB  - Thus far, in vivo mutagenic assays have detected organ-specific effects of
      benzo[a]pyrene (B[a]P) in a number of organs, but not in oral tissues and breast.
      Previous studies have shown that the mouse tongue is a target for tumorigenesis
      induced by B[a]P when incorporated into feed, and polycyclic aromatic
      hydrocarbons are carcinogens in mouse mammary tissue. In order to evaluate the
      capacity of the lacZ mouse in vivo mutagenesis assay to detect mutations in these
      target tissues, we have measured mutagenesis induced by B[a]P in breast and oral
      tissues. The oral tissue consisted of either tongue or a mixture of oral tissues
      from several sites in the oral cavity. B[a]P was more mutagenic in breast tissue
      than in most other organs tested (liver, lung and kidney) when administered at
      relatively high dose by gavage, and more mutagenic than in liver, but not lung,
      at low dose. When administered in an emulsion in drinking water, B[a]P was more
      mutagenic in oral tissues than in liver, and somewhat less mutagenic than in
      lung. Regardless of dose, the mutagenic activity was greatest in colon where it
      was much higher than in other organs. A reasonable correlation was observed
      between mutagenesis observed here and carcinogenesis in previous studies although
      some differences were noted. To our knowledge, this represents the first report
      of in vivo mutagenesis in non-tumor mammary and oral tissue, and the results
      indicate these organs can efficiently metabolize B[a]P to genotoxic products,
      although some transport of active metabolites from the liver cannot be ruled out.
      The lacZ mouse mutagenesis assay may represent a shorter term alternative to
      carcinogenesis assays for investigations of factors affecting initiation of
      carcinogenesis in mammary and oral tissues. However, it is less predictive of
      actual tumor formation.

PMID- 10357796
TI  - Glucuronidation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4, 5-b]pyridine by
      human microsomal UDP-glucuronosyltransferases: identification of specific UGT1A
      family isoforms involved.
AB  - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is a heterocyclic aromatic amine
      found in cooked meats and dietary exposure to PhIP has been implicated in the
      etiology of colon cancer in humans. PhIP, along with other heterocyclic aromatic
      amines, requires metabolic activation to exhibit genotoxic effects. PhIP is
      initially oxidized by the activity of cytochrome P4501A2 to produce 2
      hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP), a reaction
      occurring primarily in the liver. Whereas subsequent biotransformation of N-OH
      PhIP via acetylation or sulfation can produce reactive electrophiles that readily
      bind to DNA, N-glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGTs),
      functions as a detoxification mechanism. Although hepatic glucuronidation of N-OH
      PhIP has been well characterized, the extrahepatic metabolism of this compound is
      poorly understood. Studies in our laboratory now indicate that the intestinal
      tract, and particularly the colon, is a significant site of glucuronidation of N
      OH-PhIP. When assays were performed with microsomes prepared from the mucosa of
      the intestinal tract, it was determined that glucuronidation of N-OH-PhIP occurs
      throughout the intestinal tract, with activity approximately three times higher
      in the colon as that found in the upper intestine. Glucuronidation rates from
      colon microsomes showed considerable interindividual variability and incubation
      with N-OH-PhIP yielded two glucuronides. HPLC analysis showed that the
      predominant product formed is the N-OH-PhIP-N2-glucuronide, while the N3
      glucuronide accounts for <10% of the total glucuronidation product. These rates
      approach the rates found in human liver microsomes, demonstrating the
      significance of extrahepatic metabolism of this food-borne carcinogen. Subsequent
      assays with human recombinant UGTs demonstrated that at least four human UGT
      isoforms, all from the UGT1A subfamily, are capable of catalyzing the
      biotransformation of N-OH-PhIP. Members of the UGT2B family available for this
      study did not conjugate N-OH-PhIP, although immunoinhibition studies in human
      liver microsomes strongly suggest the involvement of a UGT2B isoform(s) in this
      organ.

PMID- 10357797
TI  - Pentachlorophenol (PCP) produces liver oxidative stress and promotes but does not
      initiate hepatocarcinogenesis in B6C3F1 mice.
AB  - To elucidate the mechanism of hepatocarcinogenesis of pentachlorophenol (PCP) in
      mice, critical effects related to carcinogenicity were studied in the livers of
      B6C3F1 male mice administered PCP at concentrations of 600 and 1200 p.p.m. in the
      diet for 8 weeks. Oxidative stress was assessed by measurements of 8
      oxodeoxyguanosine (8-oxodG) in the liver nuclear DNA and hepatocyte cell
      proliferation was quantified by bromodeoxyuridine incorporation. Also, initiation
      and promotion were assessed in a two-stage hepatocarcinogenesis model in which
      one group of mice was given PCP at concentrations of 600 and 1200 p.p.m. as
      initiator for the first 13 weeks with subsequent administration of phenobarbital
      (PB) as promoter at a concentration of 500 p.p.m. in the drinking water for 29
      weeks. A second group was initiated with diethylnitrosamine (DEN) at 20 p.p.m. in
      the drinking water for the first 13 weeks followed after a 4 week recovery
      interval by PCP at concentrations of 300 and 600 p.p.m. in the diet for 25 weeks.
      Significant elevations in 8-oxodG levels and cell proliferation were observed in
      a dose-dependent manner. Incidences and multiplicities of hepatocellular tumors
      in mice treated with PCP after DEN initiation were increased compared with those
      in mice given initiation only. In contrast, in mice given PCP as initiator
      followed by PB no enhancement of neoplastic lesions occurred. These findings are
      interpreted to demonstrate that PCP exerts a promoting action, but not an
      initiating effect on liver carcinogenesis and that the promoting action is
      related to oxidative stress and compensatory hepatocellular proliferation.

PMID- 10357798
TI  - Expression of stably transfected murine glutathione S-transferase A3-3 protects
      against nucleic acid alkylation and cytotoxicity by aflatoxin B1 in hamster V79
      cells expressing rat cytochrome P450-2B1.
AB  - Aflatoxin B1 (AFB1) is activated to AFB1-8,9-oxide (AFBO), a potent mutagenic and
      carcinogenic metabolite of AFB1. In the mouse, AFBO has been shown to be most
      efficiently detoxified by a specific isozyme of alpha-class glutathione S
      transferase (GST), mGSTA3-3 (mGST-Yc). A hamster V79 cell line (V79MZr2B1,
      originally designated V79/SD1) previously transfected with the rat cytochrome
      P450-2B1 was stably transfected with an mGSTA3-3 expression vector, to study the
      chemopreventive role of GST in protecting against cytotoxicity or genotoxicity of
      AFBO. Immunoblotting demonstrated strong expression of an alpha-class GST in the
      mGSTA3-3 transfected cell line, whereas no detectable alpha-class GST protein was
      observed in the control (empty vector-transfected) cells. Previous studies with
      the V79MZr2B1 cell line indicated that it can activate AFB1 to a mutagenic
      metabolite via a transfected rat P450-2B1 stably expressed in the cells. We
      examined the ability of the expressed mGSTA3-3 to protect against AFB1-induced
      cytotoxicity or [3H]-covalent adduct formation in cellular nucleic acids.
      Exposure of empty vector-transfected control cells and mGSTA3-3 expressing cells
      to up to 600 nM [3H]-AFB1 indicated that a 70-80% reduction in DNA and RNA
      adducts was afforded by the expression of mGSTA3-3 in the transfected cells.
      Clonogenic survival assays showed that the mGSTA3-3 cell line was 4.6-fold
      resistant to AFB1 cytotoxicity as compared with the empty vector-transfected
      control SD1 cells, with IC50 values of 69 and 15 microM, respectively. The
      results of these studies demonstrate that mGSTA3-3 confers substantial protection
      against nucleic acid covalent modification and cytotoxicity by AFB1 in this
      transgenic cell model system.

PMID- 10357799
TI  - Familial gastric cancer: clinicopathological characteristics, RER phenotype and
      germline p53 and E-cadherin mutations.
AB  - Gastric cancer frequently occurs in family members with hereditary non-polyposis
      colorectal cancer (HNPCC) and Li-Fraumeni syndrome (LFS) and germline E-cadherin
      mutations were recently identified in a subset of familial gastric cancers. Thus,
      families with an aggregation of gastric cancers were recruited by reviewing the
      genealogical trees of 3632 patients with gastric cancer. The criteria for
      recruiting such families were the following: at least three relatives should have
      gastric cancer and one of them should be a first degree relative of the other
      two; at least two successive generations should be affected; in one of the
      relatives gastric cancer should be diagnosed before age 50. Thirty-one cases
      (0.9%) fitted all three of these criteria. There were only gastric cancer
      patients in 18 of the 31 families and there were no families that fitted clinical
      criteria of HNPCC or LFS. Paraffin-embedded tissues were available in 29 probands
      and DNA was successfully isolated for molecular analyses in 13 probands. RER
      phenotype was detected in three (23%) cases, whereas germline p53 mutations were
      detected in none of 13 cases. A germline E-cadherin mutation was detected in one
      of three diffuse types and none of 10 intestinal types, however, a mutation
      resulting in the replacement of Gly by Val was detected in the precursor
      sequence. Thus, although familial clustering of gastric cancer occurs in
      approximately 1% of gastric cancer patients, germline mutations of the DNA
      mismatch repair, p53 and E-cadherin genes do not significantly contribute to such
      a clustering.

PMID- 10357800
TI  - Retinoic acid and 4-hydroxyphenylretinamide induce growth inhibition and tissue
      transglutaminase through different signal transduction pathways in mouse
      fibroblasts (NIH 3T3 cells).
AB  - 4-Hydroxyphenylretinamide (4-HPR) is a synthetic retinoid with minimal toxicity
      and favorable pharmacokinetics during long-term administration to patients in
      clinical trials. Since 4-HPR binds poorly to the retinoic acid receptors, the
      issue of whether 4-HPR exerts its biological actions via classical retinoid
      receptor pathways remains to be resolved. We have previously reported that stable
      expression of a truncated retinoic acid receptor alpha, RARalpha403, transduced
      in NIH 3T3 cells by a retroviral vector, rendered the cells resistant to retinoic
      acid for growth inhibition and induction of tissue transglutaminase (TGase II).
      Here, we report that stable expression of the dominant negative construct
      RARalpha403 fails to blunt growth inhibition and TGase II induction by 4-HPR, a
      potent chemopreventive retinoid, in the same cells. These data show that retinoic
      acid receptors do not mediate either growth inhibition or induction of TGase II
      activity by 4-HPR in mouse fibroblast cells.

PMID- 10357801
TI  - Comparative tumorigenicity of the cyclopenta-fused polycyclic aromatic
      hydrocarbons aceanthrylene, dihydroaceanthrylene and acephenanthrylene in
      preweanling CD-1 and BLU:Ha mouse bioassays.
AB  - Cyclopenta-fused polycyclic aromatic hydrocarbons are ubiquitous environmental
      pollutants and potential human health biohazards. In this study, the
      tumorigenicity of three single cyclopenta-fused polycyclic aromatic hydrocarbons,
      aceanthrylene, dihydroaceanthrylene and acephenanthrylene, was examined in
      preweanling CD-1 and BLU:Ha mouse bioassays at total doses of 175, 437.5 and 875
      micrograms/mouse. No death or significant toxicity was observed with the
      treatment protocol in the tested animals. In CD-1 mice, a significant increase in
      lung tumor incidence (18-26%, P < 0. 025-0.01) for these three compounds was
      recorded in animals treated with 875 micrograms as compared with the control
      animals (3%). Significant numbers of liver tumors (25-41%, P < 0.01-0.001) were
      induced in all aceanthrylene treatment groups and in animals treated with 875
      micrograms acephenanthrylene (35%) at the termination at 9 months. Most liver
      tumors were induced in male animals. The ED50 values were estimated as 8.5, 10.6
      and 12.8 micromol and the TM1.0 were 15.1, 20.4 and 23.1 micromol for
      aceanthrylene, acephenanthrylene and dihydroaceanthrylene, respectively. In
      BLU:Ha mice, there was a significant dose-dependent increase in lung tumor
      incidence, from 4% for the control group to 33% (P < 0.001) for the animals
      treated with 875 micrograms aceanthrylene and to 24% (P < 0.02) for the animals
      treated with 437.5 micrograms acephenanthrylene. The ED50 values were 6.0 and 4.4
      micromol and the TM1.0 were 9.8 and 6.8 micromol for aceanthrylene and
      acephenanthrylene, respectively. No significant difference in lung tumor
      incidence between male and female mice was found. Based on these data and
      comparisons of tumorigenic potency with other polycyclic aromatic hydrocarbons
      previously tested in these newborn mouse bioassays, aceanthrylene and
      acephenanthrylene were classified as weak tumorigens.

PMID- 10357802
TI  - The effect of 1/3 partial hepatectomy on the growth of glutathione S-transferase
      positive foci.
AB  - Our previous studies indicated that glutathione S-transferase 7-7 (GST 7-7)
      positive foci induced after initiation have a lower threshold towards
      proliferative stimuli compared with surrounding hepatocytes. This observation
      would predict that persistent growth stimuli of low intensity could be very
      effective in promoting the emergence of focal lesions. To test this possibility,
      the present study was designed to determine the effect of 1/3 partial hepatectomy
      (PH) on the incidence and growth of foci in initiated rat liver. The rationale
      for using a 1/3 PH was that it is known to induce a proliferative response which
      is less intense but more prolonged compared with that elicited by 2/3 PH. Male
      Fischer 344 rats (110-120 g) were initiated with diethylnitrosamine (200 mg/kg,
      i.p.). Three weeks later 1/3 PH (median lobe), 2/3 PH (median and left lobes) or
      sham operation (SH) was performed. An additional group of initiated animals had
      the median lobe and the left lobe of the liver removed sequentially (1/3 + 1/3
      PH), 3 weeks apart. All rats were killed 8 weeks after carcinogen administration.
      The results indicated that the number of GST 7-7 positive foci was similar in all
      groups; however, the percent area occupied by foci was increased in rats
      receiving 2/3 PH compared with SH (0.21 +/- 0. 08 versus 0.09 +/- 0.03).
      Interestingly, 1/3 PH was nearly as effective as 2/3 PH in stimulating the growth
      of foci (percent area 0.18 +/- 0.06 versus 0.21 +/- 0.08), although the magnitude
      of the stimulus is only half for the former group compared with the latter; peak
      labeling index was 19 +/- 6 with 1/3 PH compared with 40 +/- 2 with 2/3 PH.
      Moreover, the maximum increase in the size of foci (percent area 0.37 +/- 0.12)
      was achieved when the median and left lobes were removed sequentially, three
      weeks apart. These results indicate that persistent growth stimuli of low
      intensity can be very effective in promoting the growth of focal lesions.

PMID- 10357803
TI  - DNA adduct formation and persistence in rat tissues following exposure to the
      mammary carcinogen dibenzo[a,l]pyrene.
AB  - Dibenzo[a,l]pyrene (DBP), an environmentally significant polycyclic aromatic
      hydrocarbon (PAH), is one of the most potent carcinogens with greater
      carcinogenicity in rodent mammary glands and skin than 7,12
      dimethylbenz[a]anthracene or benzo[a]pyrene, respectively. In this study, we have
      examined the formation and persistence of stable DNA adducts in rats administered
      a carcinogenic intramammillary (i.m.) dose of DBP (0.25 micromol/gland). 32P-post
      labeling analysis of mammary epithelial DNA 6 h, and 2, 5 and 14 days post
      treatment produced one major (approximately 30%) and at least six minor adducts.
      Non-target tissue DNA (lung, heart, bladder and pancreas) also showed essentially
      the same adduct pattern as did mammary DNA, except liver which resulted in four
      additional adduct spots. The mammary DNA was most adducted (2640 +/- 532
      adducts/10(9) nucleotides) on day 5 while the other tissue DNAs had 10- to 65
      fold lower adduct levels (lung > liver > heart > bladder > pancreas). Adduct
      levels continued to increase at all time points examined for all tissues, except
      mammary tissue which showed a decline ( approximately 40%) on day 14.
      Chromatographic comparison with adducts formed in vitro by reaction of syn- and
      anti-DBP-11, 12-diol-13,14-epoxides (DBPDEs) with DNA and individual nucleotides
      indicated that the in vivo adducts were deoxyadenosine- and deoxyguanosine
      derived, formed by interaction with both the anti- and syn-isomers; the adenine
      derived adducts comprised 60-75% of the total adducts. However, the liver
      specific DNA adducts (nos 8-11) were not derived from any of the DBPDE isomers.
      Our data show: (i) significantly higher DBP-DNA adduction in mammary tissue as
      compared with non-target tissues, which is consistent with its mammary
      carcinogenicity; (ii) adenine is highly reactive towards DBP metabolites as has
      been observed for many other PAHs; and (iii) the peak binding of DBP with DNA was
      shifted beyond 14 days for the non-target tissues by i.m. route of exposure.

PMID- 10357804
TI  - Crystal structure of two CD46 domains reveals an extended measles virus-binding
      surface.
AB  - Measles virus is a paramyxovirus which, like other members of the family such as
      respiratory syncytial virus, is a major cause of morbidity and mortality
      worldwide. The cell surface receptor for measles virus in humans is CD46, a
      complement cofactor. We report here the crystal structure at 3.1 A resolution of
      the measles virus-binding fragment of CD46. The structure reveals the
      architecture and spatial arrangement of two glycosylated short consensus repeats
      with a pronounced interdomain bend and some flexibility at the domain interface.
      Amino acids involved in measles virus binding define a large, glycan-free surface
      that extends from the top of the first to the bottom of the second repeat. The
      extended virus-binding surface of CD46 differs strikingly from those reported for
      the human virus receptor proteins CD4 and intercellular cell adhesion molecule-1
      (ICAM-1), suggesting that the CD46 structure utilizes a novel mode of virus
      recognition. A highly hydrophobic and protruding loop at the base of the first
      repeat bears a critical virus-binding residue, thereby defining an important
      recognition epitope. Molecules that mimic the conformation of this loop
      potentially could be effective anti-viral agents by preventing binding of measles
      virus to CD46.

PMID- 10357805
TI  - The crystal structure of the Physarum polycephalum actin-fragmin kinase: an
      atypical protein kinase with a specialized substrate-binding domain.
AB  - Coordinated temporal and spatial regulation of the actin cytoskeleton is
      essential for diverse cellular processes such as cell division, cell motility and
      the formation and maintenance of specialized structures in differentiated cells.
      In plasmodia of Physarum polycephalum, the F-actin capping activity of the actin
      fragmin complex is regulated by the phosphorylation of actin. This is mediated by
      a novel type of protein kinase with no sequence homology to eukaryotic-type
      protein kinases. Here we present the crystal structure of the catalytic domain of
      the first cloned actin kinase in complex with AMP at 2.9 A resolution. The three
      dimensional fold reveals a catalytic module of approximately 160 residues, in
      common with the eukaryotic protein kinase superfamily, which harbours the
      nucleotide binding site and the catalytic apparatus in an inter-lobe cleft.
      Several kinases that share this catalytic module differ in the overall
      architecture of their substrate recognition domain. The actin-fragmin kinase has
      acquired a unique flat substrate recognition domain which is supposed to confer
      stringent substrate specificity.

PMID- 10357806
TI  - Crystal structure of the human protein kinase CK2 regulatory subunit reveals its
      zinc finger-mediated dimerization.
AB  - Protein kinase CK2 is a tetramer composed of two alpha catalytic subunits and two
      beta regulatory subunits. The structure of a C-terminal truncated form of the
      human beta subunit has been determined by X-ray crystallography to 1.7 A
      resolution. One dimer is observed in the asymmetric unit of the crystal. The most
      striking feature of the structure is the presence of a zinc finger mediating the
      dimerization. The monomer structure consists of two domains, one entirely alpha
      helical and one including the zinc finger. The dimer has a crescent shape holding
      a highly acidic region at both ends. We propose that this acidic region is
      involved in the interactions with the polyamines and/or catalytic subunits.
      Interestingly, conserved amino acid residues among beta subunit sequences are
      clustered along one linear ridge that wraps around the entire dimer. This feature
      suggests that protein partners may interact with the dimer through a stretch of
      residues in an extended conformation.

PMID- 10357807
TI  - Functional glycan-free adhesion domain of human cell surface receptor CD58:
      design, production and NMR studies.
AB  - A general strategy is presented here for producing glycan-free forms of
      glycoproteins without loss of function by employing apolar-to-polar mutations of
      surface residues in functionally irrelevant epitopes. The success of this
      structure-based approach was demonstrated through the expression in Escherichia
      coli of a soluble 11 kDa adhesion domain extracted from the heavily glycosylated
      55 kDa human CD58 ectodomain. The solution structure was subsequently determined
      and binding to its counter-receptor CD2 studied by NMR. This mutant adhesion
      domain is functional as determined by several experimental methods, and the size
      of its binding site has been probed by chemical shift perturbations in NMR
      titration experiments. The new structural information supports a 'hand-shake'
      model of CD2-CD58 interaction involving the GFCC'C" faces of both CD2 and CD58
      adhesion domains. The region responsible for binding specificity is most likely
      localized on the C, C' and C" strands and the C-C' and C'-C" loops on CD58.

PMID- 10357808
TI  - Disease states associated with telomerase deficiency appear earlier in mice with
      short telomeres.
AB  - Mice deficient for the mouse telomerase RNA (mTR-/-) and lacking telomerase
      activity can only be bred for approximately six generations due to decreased male
      and female fertility and to an increased embryonic lethality associated with a
      neural tube closure defect. Although late generation mTR-/- mice show defects in
      the hematopoietic system, they are viable to adulthood, only showing a decrease
      in viability in old age. To assess the contribution of genetic background to the
      effect of telomerase deficiency on viability, we generated mTR-/- mutants on a
      C57BL6 background, which showed shorter telomeres than the original mixed genetic
      background C57BL6/129Sv. Interestingly, these mice could be bred for only four
      generations and the survival of late generation mTR-/- mice decreased
      dramatically with age as compared with their wild-type counterparts. Fifty
      percent of the generation 4 mice die at only 5 months of age. This decreased
      viability with age in the late generation mice is coincident with telomere
      shortening, sterility, splenic atrophy, reduced proliferative capacity of B and T
      cells, abnormal hematology and atrophy of the small intestine. These results
      indicate that telomere shortening in mTR-/- mice leads to progressive loss of
      organismal viability.

PMID- 10357809
TI  - The Qo site of cytochrome b6f complexes controls the activation of the LHCII
      kinase.
AB  - We created a Qo pocket mutant by site-directed mutagenesis of the chloroplast
      petD gene in Chlamydomonas reinhardtii. We mutated the conserved PEWY sequence in
      the EF loop of subunit IV into PWYE. The pwye mutant did not grow in phototrophic
      conditions although it assembled wild-type levels of cytochrome b6f complexes. We
      demonstrated a complete block in electron transfer through the cytochrome b6f
      complex and a loss of plastoquinol binding at Qo. The accumulation of cytochrome
      b6f complexes lacking affinity for plastoquinol enabled us to investigate the
      role of plastoquinol binding at Qo in the activation of the light-harvesting
      complex II (LHCII) kinase during state transitions. We detected no fluorescence
      quenching at room temperature in state II conditions relative to that in state I.
      The quantum yield spectrum of photosystem I charge separation in the two state
      conditions displayed a trough in the absorption region of the major chlorophyll
      a/b proteins, demonstrating that the cells remained locked in state I. 33Pi
      labeling of the phosphoproteins in vivo demonstrated that the antenna proteins
      remained poorly phosphorylated in both state conditions. Thus, the absence of
      state transitions in the pwye mutant demonstrates directly that plastoquinol
      binding in the Qo pocket is required for LHCII kinase activation.

PMID- 10357810
TI  - Dislocation of membrane proteins in FtsH-mediated proteolysis.
AB  - Escherichia coli FtsH degrades several integral membrane proteins, including
      YccA, having seven transmembrane segments, a cytosolic N-terminus and a
      periplasmic C-terminus. Evidence indicates that FtsH initiates proteolysis at the
      N-terminal cytosolic domain. SecY, having 10 transmembrane segments, is also a
      substrate of FtsH. We studied whether and how the FtsH-catalyzed proteolysis on
      the cytosolic side continues into the transmembrane and periplasmic regions using
      chimeric proteins, YccA-(P3)-PhoA-His6-Myc and SecY-(P5)-PhoA, with the alkaline
      phosphatase (PhoA) mature sequence in a periplasmic domain. The PhoA domain that
      was present within the fusion protein was rapidly degraded by FtsH when it lacked
      the DsbA-dependent folding. In contrast, both PhoA itself and the TM9-PhoA region
      of SecY-(P5)-PhoA were stable when expressed as independent polypeptides. In the
      presence of DsbA, the FtsH-dependent degradation stopped at a site near to the N
      terminus of the PhoA moiety, leaving the PhoA domain (and its C-terminal region)
      undigested. The efficiency of this degradation stop correlated well with the
      rapidity of the folding of the PhoA domain. Thus, both transmembrane and
      periplasmic domains are degraded by the processive proteolysis by FtsH, provided
      they are not tightly folded. We propose that FtsH dislocates the extracytoplasmic
      domain of a substrate, probably using its ATPase activity.

PMID- 10357811
TI  - Competition between Sec- and TAT-dependent protein translocation in Escherichia
      coli.
AB  - Recently, a new protein translocation pathway, the twin-arginine translocation
      (TAT) pathway, has been identified in both bacteria and chloroplasts. To study
      the possible competition between the TAT- and the well-characterized Sec
      translocon-dependent pathways in Escherichia coli, we have fused the TorA TAT
      targeting signal peptide to the Sec-dependent inner membrane protein leader
      peptidase (Lep). We find that the soluble, periplasmic P2 domain from Lep is re
      routed by the TorA signal peptide into the TAT pathway. In contrast, the full
      length TorA-Lep fusion protein is not re-routed into the TAT pathway, suggesting
      that Sec-targeting signals in Lep can override TAT-targeting information in the
      TorA signal peptide. We also show that the TorA signal peptide can be converted
      into a Sec-targeting signal peptide by increasing the hydrophobicity of its h
      region. Thus, beyond the twin-arginine motif, the overall hydrophobicity of the
      signal peptide plays an important role in TAT versus Sec targeting. This is
      consistent with statistical data showing that TAT-targeting signal peptides in
      general have less hydrophobic h-regions than Sec-targeting signal peptides.

PMID- 10357813
TI  - Enhanced hippocampal long-term potentiation and learning by increased neuronal
      expression of tissue-type plasminogen activator in transgenic mice.
AB  - Adult cortical neurons can produce tissue-type plasminogen activator (tPA), an
      extracellular protease that plays a critical role in fibrinolysis and tissue
      remodelling processes. There is growing evidence that extracellular proteolysis
      may be involved in synaptic plasticity, axonal remodelling and neurotoxicity in
      the adult central nervous system. Here we show that transgenic mice
      overexpressing tPA in post-natal neurons have increased and prolonged hippocampal
      long-term potentiation (LTP), and improved performance in spatial orientation
      learning tasks. Extracellular proteolysis catalysed by tPA may facilitate
      synaptic micro-remodelling, and thereby play a role in activity-dependent
      neuronal plasticity and learning.

PMID- 10357812
TI  - Recruitment of an alternatively spliced form of synaptojanin 2 to mitochondria by
      the interaction with the PDZ domain of a mitochondrial outer membrane protein.
AB  - Synaptojanin 1 is an inositol 5'-phosphatase highly enriched in nerve terminals
      with a putative role in recycling of synaptic vesicles. We have previously
      described synaptojanin 2, which is more broadly expressed as multiple
      alternatively spliced forms. Here we have identified and characterized a novel
      mitochondrial outer membrane protein, OMP25, with a single PDZ domain that
      specifically binds to a unique motif in the C-terminus of synaptojanin 2A. This
      motif is encoded by the exon sequence specific to synaptojanin 2A. OMP25 mRNA is
      widely expressed in rat tissues. OMP25 is localized to the mitochondrial outer
      membrane via the C-terminal transmembrane region, with the PDZ domain facing the
      cytoplasm. Overexpression of OMP25 results in perinuclear clustering of
      mitochondria in transfected cells. This effect is mimicked by enforced expression
      of synaptojanin 2A on the mitochondrial outer membrane, but not by the
      synaptojanin 2A mutants lacking the inositol 5'-phosphatase domain. Our findings
      provide evidence that OMP25 mediates recruitment of synaptojanin 2A to
      mitochondria and that modulation of inositol phospholipids by synaptojanin 2A may
      play a role in maintenance of the intracellular distribution of mitochondria.

PMID- 10357814
TI  - Urokinase receptor-dependent and -independent p56/59(hck) activation state is a
      molecular switch between myelomonocytic cell motility and adherence.
AB  - Anchorage-independent myelomonocytic cells acquire adherence within minutes of
      differentiation stimuli, such as the proteolytically inactive N-terminal fragment
      of urokinase binding to its cognate glycosylphosphatidylinositol (GPI)-anchored
      receptor. Here, we report that urokinase-treated differentiating U937 monocyte
      like cells exhibit a rapid and transient inhibition of p56/59(hck) and p55(fgr)
      whereas no changes in the activity of other Src family kinases, such as
      p53/56(lyn) and p59(fyn) were observed. U937 transfectants expressing a kinase
      defective (Lys267 to Met) p56/59(hck) variant exhibit enhanced adhesiveness and a
      marked F-actin redistribution in thin protruding structures. Conversely,
      urokinase as well as expression of wild-type or constitutively active (Tyr499 to
      Phe) p56/59(hck) stimulates the directional migration of uninduced U937 cells.
      Accordingly, expression of constitutively active or kinase inactive p56/59(hck)
      selectively prevents urokinase receptor-dependent induction of either adhesion or
      motility, indicating that a specific activation state of p56/59(hck) is required
      for each cell response. In conclusion, modulation of the intracellular
      p56/59(hck) tyrosine kinase activity switches cell motility towards adherence,
      providing a mutually exclusive mechanism to regulate these properties during
      monocyte/macrophage differentiation in vivo.

PMID- 10357815
TI  - Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase
      stimulated signaling pathway.
AB  - Serum and glucocorticoid-inducible kinase (SGK) is a novel member of the
      serine/threonine protein kinase family that is transcriptionally regulated. In
      this study, we have investigated the regulatory mechanisms that control SGK
      activity. We have established a peptide kinase assay for SGK and present evidence
      demonstrating that SGK is a component of the phosphoinositide 3 (PI 3)-kinase
      signaling pathway. Treatment of human embryo kidney 293 cells with insulin, IGF-1
      or pervanadate induced a 3- to 12-fold activation of ectopically expressed SGK.
      Activation was completely abolished by pretreatment of cells with the PI 3-kinase
      inhibitor, LY294002. Treatment of activated SGK with protein phosphatase 2A in
      vitro led to kinase inactivation. Consistent with the similarity of SGK to other
      second-messenger regulated kinases, mutation of putative phosphorylation sites at
      Thr256 and Ser422 inhibited SGK activation. Cotransfection of PDK1 with SGK
      caused a 6-fold activation of SGK activity, whereas kinase-dead PDK1 caused no
      activation. GST-pulldown assays revealed a direct interaction between PDK1 and
      the catalytic domain of SGK. Treatment of rat mammary tumor cells with serum
      caused hyperphosphorylation of endogenous SGK, and promoted translocation to the
      nucleus. Both hyperphosphorylation and nuclear translocation could be inhibited
      by wortmannin, but not by rapamycin.

PMID- 10357816
TI  - Induction of cell death by tumour necrosis factor (TNF) receptor 2, CD40 and
      CD30: a role for TNF-R1 activation by endogenous membrane-anchored TNF.
AB  - Several members of the tumour necrosis factor receptor (TNF-R) superfamily can
      induce cell death. For TNF-R1, Fas/APO-1, DR3, DR6, TRAIL-R1 and TRAIL-R2, a
      conserved 'death domain' in the intracellular region couples these receptors to
      activation of caspases. However, it is not yet known how TNF receptor family
      members lacking a death domain, such as TNF-R2, CD40, LT-betaR, CD27 or CD30,
      execute their death-inducing capability. Here we demonstrate in different
      cellular systems that cytotoxic effects induced by TNF-R2, CD40 and CD30 are
      mediated by endogenous production of TNF and autotropic or paratropic activation
      of TNF-R1. In addition, stimulation of TNF-R2 and CD40 synergistically enhances
      TNF-R1-induced cytotoxicity. These findings describe a novel pro-apoptotic
      mechanism induced by some members of the TNF-R family.

PMID- 10357818
TI  - Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates
      STAT proteins.
AB  - Latent membrane protein 1 (LMP1) acts like a permanently activated receptor of
      the tumor necrosis factor (TNF)-receptor superfamily and is absolutely required
      for B cell immortalization by Epstein-Barr virus. Molecular and biochemical
      approaches demonstrated that LMP1 usurps cellular signaling pathways resulting in
      the induction of NF-kappaB and AP-1 via two C-terminal activating regions. We
      demonstrate here that a third region encompassing a proline rich sequence within
      the 33 bp repetitive stretch of LMP1's C-terminus is required for the activation
      of Janus kinase 3 (JAK3). The interaction of LMP1 and JAK3 leads to the enhanced
      tyrosine auto/transphosphorylation of JAK3 within minutes after crosslinking of a
      conditional NGF-R:LMP1 chimera and is a prerequisite for the activation of STAT
      transcription factors. These results reveal a novel activating region in the LMP1
      C-terminus and identify the JAK/STAT pathway as a target of this viral integral
      membrane protein in B cells.

PMID- 10357817
TI  - Excess beta-catenin promotes accumulation of transcriptionally active p53.
AB  - beta-catenin is a multifunctional protein, acting both as a structural component
      of the cell adhesion machinery and as a transducer of extracellular signals.
      Deregulated beta-catenin protein expression, due to mutations in the beta-catenin
      gene itself or in its upstream regulator, the adenomatous polyposis coli (APC)
      gene, is prevalent in colorectal cancer and in several other tumor types, and
      attests to the potential oncogenic activity of this protein. Increased expression
      of beta-catenin is an early event in colorectal carcinogenesis, and is usually
      followed by a later mutational inactivation of the p53 tumor suppressor. To
      examine whether these two key steps in carcinogenesis are interrelated, we
      studied the effect of excess beta-catenin on p53. We report here that
      overexpression of beta-catenin results in accumulation of p53, apparently through
      interference with its proteolytic degradation. This effect involves both Mdm2
      dependent and -independent p53 degradation pathways, and is accompanied by
      augmented transcriptional activity of p53 in the affected cells. Increased p53
      activity may provide a safeguard against oncogenic deregulation of beta-catenin,
      and thus impose a pressure for mutational inactivation of p53 during the later
      stages of tumor progression.

PMID- 10357819
TI  - The role of HMG I(Y) in the assembly and function of the IFN-beta enhanceosome.
AB  - Transcriptional activation of the virus inducible enhancer of the human
      interferon-beta (IFN-beta) gene in response to virus infection requires the
      assembly of an enhanceosome, consisting of the transcriptional activators NF
      kappaB, ATF-2/c-Jun, IRFs and the architectural protein of the mammalian high
      mobility group I(Y) [HMG I(Y)]. Here, we demonstrate that the first step in
      enhanceosome assembly, i.e. HMG I(Y)-dependent recruitment of NF-kappaB and ATF
      2/c-Jun to the enhancer, is facilitated by discrete regions of HMG I and is
      mediated by allosteric changes induced in the DNA by HMG I(Y) and not by protein
      protein interactions between HMG I(Y) and these proteins. However, we show that
      completion of the enhanceosome assembly process requires protein-protein
      interactions between HMG I(Y) and the activators. Finally, we demonstrate that
      once assembled, the IFN-beta enhanceosome is an unusually stable nucleoprotein
      structure that can activate transcription at high levels by promoting multiple
      rounds of reinitiation of transcription.

PMID- 10357820
TI  - Repression by Ikaros and Aiolos is mediated through histone deacetylase
      complexes.
AB  - Here we show that the lymphoid lineage-determining factors Ikaros and Aiolos can
      function as strong transcriptional repressors. This function is mediated through
      two repression domains and is dependent upon the promoter context and cell type.
      Repression by Ikaros proteins correlates with hypo-acetylation of core histones
      at promoter sites and is relieved by histone deacetylase inhibitors. Consistent
      with these findings, Ikaros and its repression domains can interact in vivo and
      in vitro with the mSin3 family of co-repressors which bind to histone
      deacetylases. Based on these and our recent findings of associations between
      Ikaros and Mi-2-HDAC, we propose that Ikaros family members modulate gene
      expression during lymphocyte development by recruiting distinct histone
      deacetylase complexes to specific promoters.

PMID- 10357822
TI  - Novel processing in a mammalian nuclear 28S pre-rRNA: tissue-specific elimination
      of an 'intron' bearing a hidden break site.
AB  - Splitting and apparent splicing of ribosomal RNA, both previously unknown in
      vertebrates, were found in rodents of the genus Ctenomys. Instead of being formed
      by a single molecule of 4.4 kb, 28S rRNA is split in two molecules of 2.6 and 1.8
      kb. A hidden break, mapping within a 106 bp 'intron' located in the D6 divergent
      region, is expressed in mature ribosomes of liver, lung, heart and spleen, as
      well as in primary fibroblast cultures. Testis-specific processing eliminates the
      intron and concomitantly the break site, producing non-split 28S rRNA molecules
      exclusively in this organ. The intron is flanked by two 9 bp direct repeats,
      revealing the acquisition by insertion of a novel rRNA processing strategy in the
      evolution of higher organisms.

PMID- 10357821
TI  - The nucleosome remodeling complex, Snf/Swi, is required for the maintenance of
      transcription in vivo and is partially redundant with the histone
      acetyltransferase, Gcn5.
AB  - Snf/Swi, a nucleosome remodeling complex, is important for overcoming nucleosome
      mediated repression of transcription in Saccharomyces cerevisiae. We have
      addressed the mechanism by which Snf/Swi controls transcription in vivo of an
      Snf/Swi-dependent promoter, that of the SUC2 gene. By single-cell analysis, our
      results show that Snf/Swi is required for activated levels of SUC2 expression in
      every cell of a population. In addition, Snf/Swi is required for maintenance of
      SUC2 transcription, suggesting that continuous chromatin remodeling is necessary
      to maintain an active transcriptional state. Finally, Snf/Swi and Gcn5, a histone
      acetyltransferase, have partially redundant roles in the control of SUC2
      transcription, suggesting a functional overlap between two different mechanisms
      believed to overcome repression by nucleosomes, nucleosome remodeling and histone
      acetylation.

PMID- 10357823
TI  - Mechanism of non-spliceosomal mRNA splicing in the unfolded protein response
      pathway.
AB  - The unfolded protein response is an intracellular signaling pathway that, in
      response to accumulation of misfolded proteins in the lumen of the endoplasmic
      reticulum (ER), upregulates transcription of ER resident chaperones. A key step
      in this pathway is the non-conventional, regulated splicing of the mRNA encoding
      the positive transcriptional regulator Hac1p. In the yeast Saccharomyces
      cerevisiae, the bifunctional transmembrane kinase/endoribonuclease Ire1p cleaves
      HAC1 mRNA at both splice junctions and tRNA ligase joins the two exons together.
      We have reconstituted HAC1 mRNA splicing in an efficient in vitro reaction and
      show that, in many ways, the mechanism of HAC1 mRNA splicing resembles that of
      pre-tRNA splicing. In particular, Ire1p endonucleolytic cleavage leaves 2', 3'
      cyclic phosphates, the excised exons remain associated by base pairing, and exon
      ligation by tRNA ligase follows the same chemical steps as for pre-tRNA splicing.
      To date, this mechanism of RNA processing is unprecedented for a messenger RNA.
      In contrast to the striking similarities to tRNA splicing, the structural
      features of the splice junctions recognized by Ire1p differ from those recognized
      by tRNA endonuclease. We show that small stem-loop structures predicted to form
      at both splice junctions of HAC1 mRNA are required and sufficient for Ire1p
      cleavage.

PMID- 10357824
TI  - Basis for prokaryotic specificity of action of aminoglycoside antibiotics.
AB  - The aminoglycosides, a group of structurally related antibiotics, bind to rRNA in
      the small subunit of the prokaryotic ribosome. Most aminoglycosides are inactive
      or weakly active against eukaryotic ribosomes. A major difference in the binding
      site for these antibiotics between prokaryotic and eukaryotic ribosomes is the
      identity of the nucleotide at position 1408 (Escherichia coli numbering), which
      is an adenosine in prokaryotic ribosomes and a guanosine in eukaryotic ribosomes.
      Expression in E.coli of plasmid-encoded 16S rRNA containing an A1408 to G
      substitution confers resistance to a subclass of the aminoglycoside antibiotics
      that contain a 6' amino group on ring I. Chemical footprinting experiments
      indicate that resistance arises from the lower affinity of the drug for the
      eukaryotic rRNA sequence. The 1408G ribosomes are resistant to the same subclass
      of aminoglycosides as previously observed both for eukaryotic ribosomes and
      bacterial ribosomes containing a methylation at the N1 position of A1408. The
      results indicate that the identity of the nucleotide at position 1408 is a major
      determinant of specificity of aminoglycoside action, and agree with prior
      structural studies of aminoglycoside-rRNA complexes.

PMID- 10357825
TI  - Post-termination ribosome interactions with the 5'UTR modulate yeast mRNA
      stability.
AB  - A novel form of post-transcriptional control is described. The 5' untranslated
      region (5'UTR) of the Saccharomyces cerevisiae gene encoding the AP1-like
      transcription factor Yap2 contains two upstream open reading frames (uORF1 and
      uORF2). The YAP2-type of uORF functions as a cis-acting element that attenuates
      gene expression at the level of mRNA turnover via termination-dependent decay.
      Release of post-termination ribosomes from the YAP2 5'UTR causes accelerated
      decay which is largely independent of the termination modulator gene UPF1. Both
      of the YAP2 uORFs contribute to the destabilization effect. A G/C-rich stop codon
      context, which seems to promote ribosome release, allows an uORF to act as a
      transferable 5'UTR-destabilizing element. Moreover, termination-dependent
      destabilization is potentiated by stable secondary structure 3' of the uORF stop
      codon. The potentiation of uORF-mediated destabilization is eliminated if the
      secondary structure is located further downstream of the uORF, and is also
      influenced by a modulatory mechanism involving eIF2. Destabilization is therefore
      linked to the kinetics of acquisition of reinitiation-competence by post
      termination ribosomes in the 5'UTR. Our data explain the destabilizing properties
      of YAP2-type uORFs and also support a more general model for the mode of action
      of other known uORFs, such as those in the GCN4 mRNA.

PMID- 10357826
TI  - The yeast poly(A)-binding protein Pab1p stimulates in vitro poly(A)-dependent and
      cap-dependent translation by distinct mechanisms.
AB  - Translation initiation in extracts from Saccharomyces cerevisiae involves the
      concerted action of the cap-binding protein eIF4E and the poly(A) tail-binding
      protein Pab1p. These two proteins bind to translation initiation factor eIF4G and
      are needed for the translation of capped or polyadenylated mRNA, respectively.
      Together, these proteins synergistically activate the translation of a capped and
      polyadenylated mRNA. We have discovered that excess Pab1p also stimulates the
      translation of capped mRNA in extracts, a phenomenon that we define as trans
      activation. Each of the above activities of Pab1p requires its second RNA
      recognition motif (RRM2). We have found that RRM2 from human PABP cannot
      substitute functionally for yeast RRM2. Using the differences between human and
      yeast RRM2 sequences as a guide, we have mutagenized yeast RRM2 and discovered
      residues that are required for eIF4G binding and poly(A)-dependent translation
      but not for trans-activation. Similarly, other residues within RRM2 were found to
      be required for trans-activation but not for eIF4G binding or poly(A)-dependent
      translation. These data show that Pab1p has at least two biochemically distinct
      activities in translation extracts.

PMID- 10357827
TI  - Semliki Forest virus mRNA capping enzyme requires association with anionic
      membrane phospholipids for activity.
AB  - The replication complexes of all positive strand RNA viruses of eukaryotes are
      associated with membranes. In the case of Semliki Forest virus (SFV), the main
      determinant of membrane attachment seems to be the virus-encoded non-structural
      protein NSP1, the capping enzyme of the viral mRNAs, which has guanine-7
      methyltransferase and guanylyltransferase activities. We show here that both
      enzymatic activities of SFV NSP1 are inactivated by detergents and reactivated by
      anionic phospholipids, especially phosphatidylserine. The region of NSP1
      responsible for binding to membranes as well as to liposomes was mapped to a
      short segment, which is conserved in the large alphavirus-like superfamily of
      viruses. A synthetic peptide of 20 amino acids from the putative binding site
      competed with in vitro synthesized NSP1 for binding to liposomes containing
      phosphatidylserine. These findings suggest a molecular mechanism by which RNA
      virus replicases attach to intracellular membranes and why they depend on the
      membranous environment.

PMID- 10357829
TI  - Oxidation of LDL in baboons is increased by alcohol and attenuated by
      polyenylphosphatidylcholine.
AB  - Alcohol taken in moderation may prevent atherosclerosis, whereas heavy drinking
      has the opposite effect, in part by promoting oxidation of low density
      lipoproteins (LDL), a pathogenetic factor in atherogenesis. We assess here: 1 )
      whether similar alterations can be reproduced in baboons fed 50% of energy as
      ethanol (the average intake of alcoholics) for 7- 8 years, and 2 ) whether such
      alterations are affected by supplementation with polyenylphosphatidylcholine
      (PPC), a mixture of polyunsaturated phosphatidylcholines, shown to prevent
      alcoholic fatty liver, fibrosis, and cirrhosis. Ten animals were given the
      ethanol-containing diet and ten were pair-fed isocaloric control diets. In half
      of the pairs, the diets were supplemented with 2.8 g of
      polyenylphosphatidylcholine/1000 kcal. Alcohol feeding increased LDL
      lipoperoxides and made LDL-proteins more negatively charged, changes that were
      attenuated or prevented by PPC. The oxidizability of LDL was determined in vitro
      by the formation of conjugated dienes after oxidation with copper. Alcohol
      shortened the lag time (which measures LDL antioxidant capacity); this effect was
      normalized by PPC supplementation. By contrast, PPC produced no changes in the
      controls. Thus polyenylphosphatidylcholine, by markedly attenuating the ethanol
      induced increase in LDL oxidation, opposes one of the effects whereby alcohol
      promotes atherosclerosis.

PMID- 10357830
TI  - Lysophosphatidylcholine stimulates phospholipase D activity in mouse peritoneal
      macrophages.
AB  - Lysophosphatidylcholine (lysoPC) is a bioactive phospholipid that is involved in
      atherogenesis and inflammatory processes. However, the present understanding of
      mechanisms whereby lysophosphatidylcholine exerts its pathophysiological actions
      is incomplete. In the present work, we show that lysoPC stimulates phospholipase
      D (PLD) activity in mouse peritoneal macrophages. PLD activation leads to the
      generation of important second messengers such as phosphatidic acid,
      lysophosphatidic acid, and diacylglycerol, all of which can regulate cellular
      responses involved in atherogenesis and inflammation. The activation of PLD by
      lysoPC was attenuated by down-regulation of protein kinase C activity with
      prolonged incubation with 100 nm of 4beta-phorbol 12-myristate 13-acetate (PMA).
      Preincubation of the macrophages with the tyrosine kinase inhibitor genistein
      also decreased the stimulation of PLD by lysoPC, while pretreatment with
      orthovanadate, which inhibits tyrosine phosphatases, enhanced basal and lysoPC
      stimulated PLD activity. The activation of PLD by lysoPC was attenuated by the
      platelet activating factor (PAF) receptor antagonist WEB-2086, suggesting a role
      for PAF receptor activation in this process. Furthermore, acetylation of lysoPC
      substantially increased its potency in activating PLD, suggesting that a cellular
      metabolite of lysoPC such as 1-acyl 2-acetyl PC might be responsible for at least
      part of the effect of lysoPC on PLD.

PMID- 10357828
TI  - RAD53, DUN1 and PDS1 define two parallel G2/M checkpoint pathways in budding
      yeast.
AB  - Eukaryotic checkpoint genes regulate multiple cellular responses to DNA damage.
      In this report, we examine the roles of budding yeast genes involved in G2/M
      arrest and tolerance to UV exposure. A current model posits three gene classes:
      those encoding proteins acting on damaged DNA (e.g. RAD9 and RAD24), those
      transducing a signal (MEC1, RAD53 and DUN1) or those participating more directly
      in arrest (PDS1). Here, we define important features of the pathways subserved by
      those genes. MEC1, which we find is required for both establishment and
      maintenance of G2/M arrest, mediates this arrest through two parallel pathways.
      One pathway requires RAD53 and DUN1 (the 'RAD53 pathway'); the other pathway
      requires PDS1. Each pathway independently contributes approximately 50% to G2/M
      arrest, effects demonstrable after cdc13-induced damage or a double-stranded
      break inflicted by the HO endonuclease. Similarly, both pathways contribute
      independently to tolerance of UV irradiation. How the parallel pathways might
      interact ultimately to achieve arrest is not yet understood, but we do provide
      evidence that neither the RAD53 nor the PDS1 pathway appears to maintain arrest
      by inhibiting adaptation. Instead, we think it likely that both pathways
      contribute to establishing and maintaining arrest.

PMID- 10357831
TI  - Transgenic mice expressing a human apolipoprotein[a] allele.
AB  - The most important determinant of plasma levels of Lp[a] are sequence differences
      at the highly polymorphic apolipoprotein[a] (apo[a]) locus. To define the
      sequences that mediate the regulation of apo[a] expression, we cloned a 370 kb
      DNA fragment that included a 130 kb apo[a] gene, and 40 kb 5'- and 200 kb 3'
      flanking region from an individual with high plasma levels of Lp[a] using a YAC
      vector. This genomic clone was used to generate transgenic mice. In the YAC
      apo[a] transgenic mouse, apo[a] was only expressed in the liver, as it is in
      humans. The mean serum level of apo[a] in 4-week-old YAC-apo[a] transgenic mice
      was 20 mg/dl. In the female mice the levels of apo[a] varied over a 1.5-fold
      range during the 4-day estrus cycle and the levels correlated directly with serum
      progesterone levels. The serum levels of apo[a] decreased to almost undetectable
      level in male mice after puberty and this decrease was reversed by castration.
      Ingestion of a high-fat diet resulted in a approximately 100-fold fall in hepatic
      apo[a] mRNA levels and >60-fold decrease in serum apo[a] levels. To delimit the
      control elements that mediate tissue-specific and sex hormone-responsive apo[a]
      transcription, we derived a reporter YAC in which 40 kb of 5' flanking sequences
      from the cloned apo[a] allele were linked to a luciferase reporter gene. Analysis
      of four independent transgenic lines revealed no hepatic luciferase expression,
      suggesting that important cis -acting elements located outside the apo[a] 5'
      flanking region are necessary for in vivo expression of apo[a].

PMID- 10357832
TI  - Protein-mediated palmitate uptake and expression of fatty acid transport proteins
      in heart giant vesicles.
AB  - Giant sarcolemmal vesicles were isolated from rat heart and hindlimb muscles for
      a) characterization of long-chain fatty acid transport in the absence of
      metabolism and b) comparison of fatty acid transport protein expression with
      fatty acid transport. Giant vesicles contained cytosolic fatty acid binding
      protein. Palmitate uptake was completely divorced from its metabolism. All
      palmitate taken up was recovered in the intravesicular cytosol as unesterified
      FA. Palmitate uptake by heart vesicles exhibited a K m of 9.7 nm, similar to that
      of muscle (K m = 9.7 nm). Vmax (2.7 pmol/mg protein/s) in heart was 8-fold higher
      than in muscle (0.34 pmol/mg protein/s). Palmitate uptake was inhibited in heart
      (55-80%) and muscle (31-50%) by trypsin, phloretin, sulfo-N-succinimidyloleate
      (SSO), or a polyclonal antiserum against the 40 kDa plasma membrane fatty acid
      binding protein (FABPpm). Palmitate uptake by heart and by red and white muscle
      vesicles correlated well with the expression of fatty acid translocase (FAT/CD36)
      and fatty acid binding protein FABPpm, which may act in concert. The expression
      of fatty acid transport protein (FATP), was 10-fold lower in heart vesicles than
      in white muscle vesicles. It is concluded that long-chain fatty acid uptake by
      heart and muscle vesicles is largely protein-mediated, involving FAT/CD36 and
      FABPpm. The role of FATP in muscle and heart remains uncertain.

PMID- 10357833
TI  - Uptake of type IV hypertriglyceridemic VLDL by cultured macrophages is enhanced
      by interferon-gamma.
AB  - Hypertriglyceridemic (HTG) very low density lipoproteins (VLDL) from subjects
      with type IV hyperlipoproteinemia induce both cholesteryl ester (CE) and
      triglyceride (TG) accumulation in cultured J774 macrophages. We examined whether
      the cytokine interferon-gamma (IFN-gamma), which is expressed by lymphocytes in
      atherosclerotic lesions, would modulate macrophage uptake of HTG -VLDL.
      Incubation of cells with HTG -VLDL alone significantly increased cellular CE and
      TG mass 17- and 4.3-fold, respectively, while cellular free cholesterol (FC) was
      unaffected. Pre-incubation of cells with IFN-gamma (50 U/ml) prior to incubation
      with HTG -VLDL caused a marked enhancement in cellular CE and TG 27- and 6-fold
      over no additions (controls), respectively, and a 1.5-fold increase in FC. IFN
      gamma increased low density lipoprotein (LDL)-induced cellular CE 2-fold compared
      to LDL alone. IFN-gamma did not enhance the uptake of type III (apoE2/E2) HTG 
      VLDL or VLDL from apoE knock-out mice. Incubations in the presence of a
      lipoprotein lipase (LPL) inhibitor or an acylCoA:cholesterol acyltransferase
      (ACAT) inhibitor demonstrated that the IFN-gamma-enhanced HTG -VLDL uptake was
      dependent on LPL and ACAT activities. IFN-gamma significantly increased the
      binding and degradation of 125I-labeled LDL. Binding studies with 125I-labeled
      alpha2-macroglobulin, a known LDL receptor-related protein (LRP) ligand, and
      experiments with copper-oxidized LDL indicated that the IFN-gamma-enhanced uptake
      was not due to increased expression of the LRP or scavenger receptors. Thus, IFN
      gamma may promote foam cell formation by accelerating macrophage uptake of native
      lipoproteins. IFN-gamma-stimulated CE accumulation in the presence of HTG -VLDL
      occurs via a process that requires receptor binding-competent apoE and active
      LPL. IFN-gamma-enhanced uptake of both HTG -VLDL and LDL is mediated by the LDL
      receptor and requires ACAT-mediated cholesterol esterification.

PMID- 10357834
TI  - LDL receptor binds newly synthesized apoE in macrophages. A precursor pool for
      apoe secretion.
AB  - There appear to be multiple post-translational sites for regulation of macrophage
      apolipoprotein (apo)E secretion, including the presence of a distinct cell
      surface pool of apoE. Cell surface proteoglycans have been shown to be involved
      in forming this pool. The current studies were designed to investigate the role
      of an additional cell surface site, i.e., the low density lipoprotein (LDL)
      receptor. Antiserum to the LDL receptor displaced apoE from the macrophage cell
      surface and into the medium during a 4 degrees C incubation from apoE-expressing
      J774 cells, from proteoglycan-depleted apoE-expressing J774 cells, and from human
      monocyte-derived macrophages. Similar results were obtained when purified
      monoclonal antibody to the LDL receptor was added to human monocyte-derived
      macrophages. J774 cells transfected to express an LDL receptor binding-defective
      mutant of apoE did not show a similar response to addition of LDL receptor
      antibody. Studies were conducted in which cells were pulse labeled for 30 min,
      followed by various periods of chase at 4 degrees C or 37 degrees C in the
      presence or absence of LDL receptor antibody. The results of these studies
      indicated that nascent macrophage-derived apoE binds to the LDL receptor, and
      that this apoE served as a precursor pool for apoE released into the medium.
      These studies establish a role for the LDL receptor in forming the cell surface
      pool of apoE and, along with data regarding the importance of proteoglycans,
      indicate that cell surface binding sites for nascent macrophage-derived apoE are
      heterogeneous. The heterogeneity of such sites could have implication for the
      size and turnover of this cell surface pool.

PMID- 10357835
TI  - Association of plasma lipids and apolipoproteins with the insulin response
      element in the apoC-III promoter region in familial combined hyperlipidemia.
AB  - The apoAI-CIII-AIV gene cluster, located on chromosome 11, contributes to the
      phenotype of familial combined hyperlipidemia (FCH), but this contribution is
      genetically complex. Combinations of haplotypes, based on three restriction
      enzyme polymorphisms: XmnI and MspI sites, 5' of the start site of the apoA-I
      gene and SstI polymorphism in the 3' untranslated region of exon 4 of the apoC
      III gene, were analyzed to characterize their effect on the expression of severe
      hyperlipidemia. An epistatic interaction was demonstrated: the S2 allele on one
      haplotype was synergistic in its hyperlipidemic effect to the X2M2 allele on the
      other haplotype (Dallinga-Thie, G. M. et al. J. Clin. Invest. 1997. 99: 953-961).
      In the present study two additional polymorphic sites in the insulin response
      element (IRE) of the apoC-III gene promoter, T-455C: FokI restriction site, C
      482T: MspI restriction site, were studied in 34 FCH pedigrees including 34
      probands, 220 hyperlipidemic relatives, 300 normolipidemic relatives, and 236
      spouses. In contrast to the earlier data for the other polymorphisms in this gene
      cluster (XmnI, MspI/AI, and SstI), there were no differences in frequency
      distributions of the T-455C and the C-482T variants between probands,
      hyperlipidemic and normolipidemic relatives and spouses. No significant
      associations between plasma lipid traits and DNA variants in the IRE were
      observed. Analysis of combinations of haplotypes based on the five polymorphisms
      in the gene cluster provided further evidence for a dominant role of the SstI
      polymorphism as a major susceptibility locus in FCH. The inclusion of the IRE
      markers did not improve genetic informativeness, nor our understanding of the
      observed synergistic relationship associated with the high risk combination of
      haplotypes in FCH families.

PMID- 10357837
TI  - Expression of the monocyte chemoattractant protein-1 receptor CCR2 is increased
      in hypercholesterolemia. Differential effects of plasma lipoproteins on monocyte
      function.
AB  - Monocytes are recruited from the circulation into the subendothelial space where
      they differentiate into mature macrophages and internalize modified lipoproteins
      to become lipid-laden foam cells. The accumulation of monocytes is mediated by
      the interaction of locally produced chemoattractant protein-1 (MCP-1) with its
      receptor CCR2. The objective of the present study is to demonstrate the
      differential effects of plasma lipoproteins on monocyte CCR2 expression. The CCR2
      expression was increased about 2.4-fold in monocytes isolated from
      hypercholesterolemic patients, compared to monocytes from normal controls. There
      was a significant correlation between CCR2 expression and plasma low density
      lipoprotein (LDL). Elevated levels of high density lipoprotein (HDL) blunted and
      even reverted the effects of LDL on CCR2 expression, both in vivo and in vitro.
      The causal relationship between plasma lipoproteins and CCR2 expression was
      further confirmed by modulating the lipoprotein profile. Estrogen supplement
      therapy decreased plasma LDL cholesterol, increased plasma HDL cholesterol, and
      reduced CCR2 expression in hypercholesterolemic postmenopausal women, but had no
      effect on the plasma lipid profile or CCR2 expression in normocholesterolemic
      subjects. The physiological significance of altered CCR2 expression was tested by
      chemotaxis assay, and our results demonstrated that treatment of THP-1 monocytes
      with LDL induced CCR2 expression and substantially enhanced the chemotaxis
      elicited by MCP-1. Our findings suggest that plasma lipoproteins differentially
      control monocyte function and that monocytes from hypercholesterolemic subjects
      are hyperresponsive to chemotactic stimuli. This may increase their accumulation
      in the vessel wall and accelerate the pathogenic events of atherogenesis.

PMID- 10357836
TI  - Arachidonic acid and PGE2 regulation of hepatic lipogenic gene expression.
AB  - N-6 polyunsaturated fatty acids (PUFA) suppress hepatic and adipocyte de novo
      lipogenesis by inhibiting the transcription of genes encoding key lipogenic
      proteins. In cultured 3T3-L1 adipocytes, arachidonic acid (20:4,n-6) suppression
      of lipogenic gene expression requires cyclooxygenase (COX) activity. In this
      study, we found no evidence to support a role for COX-1 or -2 in the 20:4,n-6
      inhibition of hepatocyte lipogenic gene expression. In contrast to L1
      preadipocytes, adipocytes and rat liver, RT-PCR and Western analyses did not
      detect COX-1 or COX-2 expression in cultured primary hepatocytes. Moreover, the
      COX inhibitor, flurbiprofen, did not affect the 20:4,n-6 regulation of lipogenic
      gene expression in primary hepatocytes. Despite the absence of COX-1 and -2
      expression in primary hepatocytes, prostaglandins (PGE2 and PGF2alpha) suppressed
      fatty acid synthase, l-pyruvate kinase, and the S14 protein mRNA, while having no
      effect on acyl-CoA oxidase or CYP4A2 mRNA. Using PGE2 receptor agonist, the PGE2
      effect on lipogenic gene expression was linked to EP3 receptors. PGE2 inhibited
      S14CAT activity in transfected primary hepatocytes and targeted the S14 PUFA
      response region located -220 to -80 bp upstream from the transcription start
      site. Taken together, these studies show that COX-1 and COX-2 do not contribute
      to the n-6 PUFA suppression of hepatocyte lipogenic gene expression. However,
      cyclooxygenase products from non-parenchymal cells can act on parenchymal cells
      through a paracrine process and mimic the effects of n-6 PUFA on lipogenic gene
      expression.

PMID- 10357838
TI  - ApoA-II maintains HDL levels in part by inhibition of hepatic lipase. Studies In
      apoA-II and hepatic lipase double knockout mice.
AB  - High density lipoprotein (HDL) cholesterol levels are inversely related to the
      risk of developing coronary heart disease. Apolipoprotein (apo) A-II is the
      second most abundant HDL apolipoprotein and apoA-II knockout mice show a 70%
      reduction in HDL cholesterol levels. There is also evidence, using human apoA-II
      transgenic mice, that apoA-II can prevent hepatic lipase-mediated HDL
      triglyceride hydrolysis and reduction in HDL size. These observations suggest the
      hypothesis that apoA-II maintains HDL levels, at least in part, by inhibiting
      hepatic lipase. To evaluate this, apoA-II knockout mice were crossbred with
      hepatic lipase knockout mice. Compared to apoA-II-deficient mice, in double
      knockout mice there were increased HDL cholesterol levels (57% in males and 60%
      in females), increased HDL size, and decreased HDL cholesteryl ester fractional
      catabolic rate. In vitro incubation studies of plasma from apoA-II knockout mice,
      which contains largely apoA-I HDL particles, showed active lipolysis of HDL
      triglyceride, whereas similar studies of plasma from apoA-I knockout mice, which
      contains largely apoA-II particles, did not. In summary, these results strongly
      suggest that apoA-II is a physiological inhibitor of hepatic lipase and that this
      is at least part of the mechanism whereby apoA-II maintains HDL cholesterol
      levels.

PMID- 10357839
TI  - Atypical expression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in
      subcutaneous adipose tissue of male rats.
AB  - The mRNAs encoding mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mtHMG
      CoA synthase), the rate limiting enzyme in ketone body production, are highly
      expressed in subcutaneous (SC) and, to a lesser extent, in peri-epididymal (PE)
      rat adipose tissues. This atypical mtHMG-CoA synthase gene expression is
      dependent on the age (from 9 weeks of age) and sex (higher in male than in
      female) of the rats. In contrast, the expression of mtHMG-CoA synthase in SC
      adipose deposit is independent of the nutritional state (fed versus starved) or
      of the thermic environment (24 degrees C versus 4 degrees C). The expression of
      mtHMG-CoA synthase is suppressed in SC fat pads of castrated male rats whereas
      treatment of castrated rats with testosterone restores a normal level of
      expression. Moreover, testosterone injection induces the expression mtHMG-CoA
      synthase in SC adipose tissue of age-matched females. The presence of the mtHMG
      CoA synthase immunoreactive protein confers to mitochondria isolated from SC
      adipose deposits, the capacity to produce ketone bodies at a rate similar to that
      found in liver mitochondria (SC = 13.7 +/- 0.7, liver = 16.4 +/- 1.4 nmol/min/mg
      prot). mtHMG-CoA synthase is expressed in the stromal vascular fraction (SVF)
      whatever the adipose deposit considered. While acetyl-CoA carboxylase (ACC) is
      only expressed in mature adipocytes, the other lipogenic enzymes, fatty acid
      synthase (FAS) and citrate cleavage enzyme (CCE), are expressed both in SVF cells
      and mature adipocytes. The expression of lipogenic enzyme genes is markedly
      reduced in adipocytes but not in SVF cells isolated from 48-h starved male rats.
      When SVF is subfractionated, mtHMG-CoA synthase mRNAs are mainly recovered in two
      fractions containing poorly digested structures such as microcapillaries whereas
      the lowest expression is found in the pre-adipocyte fraction. Interestingly, FAS
      and CCE mRNAs co-segregate with mtHMG-CoA synthase mRNA. The possible
      physiological relevance of such atypical expression of mtHMG-CoA synthase is
      discussed.

PMID- 10357841
TI  - SAA-only HDL formed during the acute phase response in apoA-I+/+ and apoA-I-/-
      mice.
AB  - Serum amyloid A (SAA) is an acute phase protein of unknown function that is
      involved in systemic amyloidosis and may also be involved in atherogenesis. The
      precise role of SAA in these processes has not been established. SAA circulates
      in plasma bound to high density lipoprotein-3 (HDL3). The pathway for the
      production of SAA-containing HDL is not known. To test whether apolipoprotein
      (apo)A-I-HDL is required in the production of SAA-HDL, we analyzed the
      lipopolysaccharide (LPS)-induced changes in apoA-I+/+ and apoA-I-/- mice. In apoA
      I+/+ mice, after injection of LPS, remodeling of HDL occurred: total cholesterol
      increased and apoA-I decreased slightly and shifted to lighter density. Dense
      (density of HDL3) but large (size of HDL2 ) SAA-containing particles were formed.
      Upon fast phase liquid chromatography fractionation of plasma, >90% of SAA eluted
      with HDL that was enriched in cholesterol and phospholipid and shifted "leftward"
      to larger particles. Non-denaturing immunoprecipitation with anti-mouse apoA-I
      precipitated all of the apoA-I but not all of the SAA, confirming the presence of
      SAA-HDL devoid of apoA-I. In the apoA-I-/- mice, which normally have very low
      plasma lipid levels, LPS injection resulted in significantly increased total and
      HDL cholesterol. Greater than 90% of the SAA was lipid associated and was found
      on dense but large, spherical HDL particles essentially devoid of other
      apolipoproteins.We conclude that serum amyloid A (SAA) is able to sequester
      lipid, forming dense but large HDL particles with or without apoA-I or other
      apolipoproteins. The capacity to isolate lipoprotein particles containing SAA as
      the predominant or only apolipoprotein provides an important system to further
      explore the biological function of SAA.

PMID- 10357840
TI  - Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG
      CoA reductase inhibitors, atorvastatin and simvastatin.
AB  - The concept that hepatic cholesterol synthesis regulates hepatocyte assembly and
      secretion of apoB-containing lipoproteins remains controversial. The present
      study was carried out in HepG2 cells to examine the regulation of apoB secretion
      by the HMG-CoA reductase inhibitor atorvastatin. ApoB accumulation in the media
      was decreased by 24% and 36% at 10 microm (P < 0.02) and 20 microm (P < 0.01) of
      atorvastatin, respectively. Atorvastatin inhibited HepG2 cell cholesterol
      synthesis by up to 96% (P < 0.001) and cellular cholesteryl ester (CE) mass by
      54% (P < 0.001). Another HMG-CoA reductase inhibitor, simvastatin, decreased
      cellular cholesterol synthesis and CE mass by up to 96% (P < 0.001) and 52% (P <
      0.001), respectively. However, in contrast to atorvastatin, simvastatin had no
      effect on apoB secretion. To characterize the reduction in apoB secretion by
      atorvastatin (10 microm), pulse-chase experiments were performed and the kinetic
      data were analyzed by multicompartmental modeling using SAAM II. Atorvastatin had
      no affect on the synthesis of apoB, however, apoB secretion into the media was
      decreased by 44% (P = 0.048). Intracellular apoB degradation increased
      proportionately (P = 0.048). Simvastatin (10 microm) treatment did not
      significantly alter either the secretion or intracellular degradation of apoB,
      relative to control. The kinetics of apoB degradation were best described by a
      rapidly and a slowly turning over degradation compartment. The effect of
      atorvastatin on apoB degradation was largely confined to the rapid compartment.
      Neither inhibitor affected apoB mRNA concentrations, however, both significantly
      increased LDL receptor and HMG-CoA reductase mRNA levels. Atorvastatin treatment
      also decreased the mRNA for the microsomal triglyceride transfer protein (MTP) by
      22% (P < 0.02). These results show that atorvastatin decreases apoB secretion, by
      a mechanism that results in an enhanced intracellular degradation in apoB.

PMID- 10357843
TI  - Evidence for a third genetic locus causing familial hypercholesterolemia. A non
      LDLR, non-APOB kindred.
AB  - Monogenically inherited hypercholesterolemia is most commonly caused by mutations
      at the low density lipoprotein receptor (LDLR) locus causing familial
      hypercholesterolemia (FH) or at the apolipoprotein B (APOB) locus causing the
      disorder familial defective apoB (FDB). Probands from 47 kindreds with a strict
      clinical diagnosis of FH were selected from the Cardiovascular Genetics Research
      Lipid Clinic, Utah, for molecular genetic analysis. Using a combination of single
      strand conformation polymorphism (SSCP) and direct sequencing, 12 different LDLR
      gene mutations were found in 16 of the probands. Three of the probands were
      carriers of the APOB R3500Q mutation. In five of the remaining 28 pedigrees where
      no mutation had been detected, samples from enough relatives were available to
      examine co-segregation with the LDLR region using the microsatellite marker
      D19S221, which is within 1 Mb centromeric of the LDLR locus, and D19S394, sited
      within 150 kb telomeric of the LDLR locus. In four of the families there was
      strong evidence for co-segregation between the LDLR locus and the phenotype of
      hypercholesterolemia, but in one large family with 18 living affected members and
      clear-cut bimodal hypercholesterolemia, there were numerous exclusions of co
      segregation. Using length polymorphic markers within and outside the APOB gene,
      linkage of phenotype in this family to the APOB region was similarly excluded. In
      this large family, the degree of hypercholesterolemia, prevalence of tendon
      xanthomata, and occurrence of early coronary disease were indistinguishable from
      the other families studied. In summary, the data provide unequivocal evidence
      that a third locus can be etiological for monogenic familial hypercholesterolemia
      and should be reinvigorating to research in this field.

PMID- 10357842
TI  - Time-dependent changes to lipids and antioxidants in plasma and aortas of
      apolipoprotein E knockout mice.
AB  - Oxidation of lipoproteins is thought to be an early event in atherogenesis. To
      evaluate whether aortic lipoprotein lipid (per)oxidation contributes to
      atherosclerosis, we investigated the time-dependent changes to lipids and
      antioxidants in plasma and aortas of apolipoprotein E gene knockout (apoE-/-)
      mice receiving a high fat diet, and compared these changes with lesion
      development. Circulating buoyant lipoproteins and associated cholesterol (C),
      cholesteryl esters (CE), and alpha-tocopherol (alpha-TOH) increased within 1
      month then remained largely constant up to 6 months. Coenzyme Q (CoQ) remained
      unchanged for the first 3 months and increased marginally after 6 months. With
      increasing duration of the diet, plasma lipids showed an increased propensity to
      undergo peroxyl radical-induced (per)oxidation. Absolute concentrations of aortic
      C, hydroperoxides and hydroxides of CE (CE-O(O)H) and alpha-TOH increased
      gradually while aortic CE increased more markedly with changes to cholesteryl
      linoleate being most pronounced. Aortic CoQ remained largely unchanged. Overall,
      the extent of aortic CE (per)oxidation remained low (</=1%) and the ratio of
      incremental changes of alpha-TOH to oxidizable lipid remained unchanged. Aortic
      biochemistry paralleled lesion formation, particularly that in the descending
      thoracic aorta.Together, our results show that progressing atherosclerosis in
      apoE-/- mice is associated with increased aortic lipid (per)oxidation as assessed
      by the concentrations of CE-O(O)H, measured directly by HPLC. This supports the
      oxidation theory. Measurement of aortic CE-O(O)H may be useful for mechanistic
      studies studying the relationship between inhibition of in vivo lipid
      (per)oxidation and atherosclerosis.

PMID- 10357844
TI  - Structure and phospholipid transfer activity of human PLTP: analysis by molecular
      modeling and site-directed mutagenesis.
AB  - The plasma phospholipid transfer protein (PLTP) is an important regulator of high
      density lipoprotein (HDL) metabolism. We have here, based on sequence alignments
      of the plasma LPS-binding/lipid transfer protein family and the X-ray structure
      of the bactericidal/permeability increasing protein (BPI), modeled the structure
      of PLTP. The model predicts a two-domain architecture with conserved lipid
      binding pockets consisting of apolar residues in each domain. By site-directed
      mutagenesis of selected amino acid residues and transient expression of the
      protein variants in HeLa cells, the pockets are shown to be essential for PLTP
      mediated phospholipid transfer. A solid phase ligand binding assay was used to
      determine the HDL-binding ability of the mutants. The results suggest that the
      observed decreases in phospholipid transfer activity of the N-terminal pocket
      mutants cannot be attributed to altered HDL-binding, but the C-terminal lipid
      binding pocket may be involved in the association of PLTP with HDL. Further, the
      essential structural role of a disulfide bridge between cysteine residues 146 and
      185 is demonstrated. The structural model and the mutants characterized here
      provide powerful tools for the detailed analysis of the mechanisms of PLTP
      function.

PMID- 10357845
TI  - The identification of specific high density lipoprotein3 binding sites on human
      blood monocytes using fluorescence-labeled ligand.
AB  - We previously reported the identity and purification of two HDL3-binding proteins
      in rat liver plasma membranes. As these proteins are candidate high density
      lipoprotein (HDL) receptors and probably multifunctional, including a role in HDL
      metabolism, we have considerable interest in identifying corresponding proteins
      that are present in human tissue. This report describes the identification of
      HDL3-binding sites on human monocytes with the use of fluorescence microscopy and
      flow cytometry assay. After the incubation of mononuclear cells from human blood
      with fluorescein isothiocyanate (FITC)-labeled human HDL3, fluorescence
      micrographs showed dense signals of fluorescent grains on monocytes, but not
      lymphocytes. A significant increase in FITC intensity on monocytes, but not
      lymphocytes, was observed by flow cytometry analysis, and the interaction between
      FITC-HDL3 and human monocytes was concentration-dependent. Although very low
      density (VLDL) and low density lipoprotein (LDL) were ineffective competitors and
      HDL2 only partially competed for binding, a 50-fold concentration of HDL3 did
      compete effectively for binding of FITC-HDL3 to human monocytes. Trypsin
      treatment reduced the FITC intensity of monocytes, showing that a portion of cell
      associated FITC-HDL3 remained bound to the cell surface. Two major HDL-binding
      proteins were identified in CHAPS-solubilized human mononuclear cells by ligand
      blotting, using HDL3 as the ligand. Both showed similar binding parameters,
      specificity, and molecular weight identical to HB1 and HB2 from rat liver plasma
      membrane. We conclude that corresponding candidate HDL receptors or a similar
      receptor complex also exist on human blood monocytes.

PMID- 10357846
TI  - A rapid calcium precipitation method of recovering large amounts of highly pure
      hepatocyte rough endoplasmic reticulum.
AB  - We sought a rapid and non-ultracentrifugal method of recovering large amounts of
      highly pure rough endoplasmic reticulum (RER) membranes from livers. By
      substantially modifying a 20-year-old calcium precipitation technique, we
      obtained a RER fraction from rat liver and established its high degree of purity
      by quantitating classic membrane markers for different subcellular organelles.
      This RER fraction is highly enriched in four known proteins (or enzyme
      activities) required for lipoprotein assembly: apolipoprotein B, microsomal
      triglyceride transfer protein, acyl CoA:diacylglycerol acyltransferase, and acyl
      CoA:cholesterol acyltransferase, when compared to two classical RER markers, RNA
      and glucose-6-phosphatase. From one 10-12 g rat liver, we recover ten to twelve
      RER pellets of 1.5-1.6 cm in diameter containing approximately 110-125 mg of
      total protein, about half of which is sodium carbonate-releasable. By electron
      microscopy, these large RER pellets from rat livers are homogeneously comprised
      largely of non-vesiculated short strips of ribosome-rich membranes. This novel
      technique for isolating RER membranes from liver may provide a useful tool for
      future studies on the assembly of apolipoprotein B-containing lipoproteins as
      well as for research focused on mechanisms of secretory and membrane protein
      translation, translocation, and folding.

PMID- 10357847
TI  - Highly simplified method for gas-liquid chromatographic quantitation of bile
      acids and sterols in human stool.
AB  - A simple method for the gas-liquid chromatographic quantitation of human fecal
      bile acids and sterols is described where bile acids are subjected to n-butyl
      ester derivatization, without prior isolation from the stool, followed by
      trimethylsilylation of the sterols and bile acids. Under these conditions, bile
      acid derivatives are well resolved from each other and from the trimethylsilyl
      ether derivatives of fecal sterols and no overlap occurs. The method was shown to
      be highly reproducible and recoveries were similar to those obtained with other
      methods used for fecal bile acid analysis. Application of the method for bile
      acid and sterol analysis in human stool is described.

PMID- 10357848
TI  - Development and initial evaluation of a novel method for assessing tissue
      specific plasma free fatty acid utilization in vivo using (R)-2-bromopalmitate
      tracer.
AB  - We describe a method for assessing tissue-specific plasma free fatty acid (FFA)
      utilization in vivo using a non-beta-oxidizable FFA analog, [9,10-3H]-(R)-2
      bromopalmitate (3H-R-BrP). Ideally 3H-R-BrP would be transported in plasma, taken
      up by tissues and activated by the enzyme acyl-CoA synthetase (ACS) like native
      FFA, but then 3H-labeled metabolites would be trapped. In vitro we found that 2
      bromopalmitate and palmitate compete equivalently for the same ligand binding
      sites on albumin and intestinal fatty acid binding protein, and activation by ACS
      was stereoselective for the R-isomer. In vivo, oxidative and non-oxidative FFA
      metabolism was assessed in anesthetized Wistar rats by infusing, over 4 min, a
      mixture of 3H-R-BrP and [U-14C] palmitate (14C-palmitate). Indices of total FFA
      utilization (R*f) and incorporation into storage products (Rfs') were defined,
      based on tissue concentrations of 3H and 14C, respectively, 16 min after the
      start of tracer infusion. R*f, but not Rfs', was substantially increased in
      contracting (sciatic nerve stimulated) hindlimb muscles compared with
      contralateral non-contracting muscles. The contraction-induced increases in R*f
      were completely prevented by blockade of beta-oxidation with etomoxir. These
      results verify that 3H-R-BrP traces local total FFA utilization, including
      oxidative and non-oxidative metabolism. Separate estimates of the rates of loss
      of 3H activity indicated effective 3H metabolite retention in most tissues over a
      16-min period, but appeared less effective in liver and heart. In conclusion,
      simultaneous use of 3H-R-BrP and [14C]palmitate tracers provides a new useful
      tool for in vivo studies of tissue-specific FFA transport, utilization and
      metabolic fate, especially in skeletal muscle and adipose tissue.

PMID- 10357849
TI  - A bit of history.
AB  - Reviews of scientific literature began to appear in the 17th century. Journals
      dedicated to them soon followed, leading eventually to this one, which emerged in
      the 1930s as Bacteriological Reviews; it adapted to the many changes in our fluid
      discipline, evolving into the present, much broader Microbiology and Molecular
      Biology Reviews.

PMID- 10357850
TI  - A paean to Microbiology and Molecular Biology Reviews.
AB  - This article celebrates the accomplishments of Microbiology and Molecular Biology
      Reviews from its early days to the present time. The importance of this journal
      in the professional lives of microbiologists is emphasized, and examples of
      outstanding reviews are presented.

PMID- 10357852
TI  - Structural features of the glutamate transporter family.
AB  - Neuronal and glial glutamate transporters remove the excitatory neurotransmitter
      glutamate from the synaptic cleft and thus prevent neurotoxicity. The proteins
      belong to a large and widespread family of secondary transporters, including
      bacterial glutamate, serine, and C4-dicarboxylate transporters; mammalian neutral
      amino-acid transporters; and an increasing number of bacterial, archaeal, and
      eukaryotic proteins that have not yet been functionally characterized. Sixty
      members of the glutamate transporter family were found in the databases on the
      basis of sequence homology. The amino acid sequences of the carriers have
      diverged enormously. Homology between the members of the family is most apparent
      in a stretch of approximately 150 residues in the C-terminal part of the
      proteins. This region contains four reasonably well-conserved sequence motifs,
      all of which have been suggested to be part of the translocation pore or
      substrate binding site. Phylogenetic analysis of the C-terminal stretch revealed
      the presence of five subfamilies with characterized members: (i) the eukaryotic
      glutamate transporters, (ii) the bacterial glutamate transporters, (iii) the
      eukaryotic neutral-amino-acid transporters, (iv) the bacterial C4-dicarboxylate
      transporters, and (v) the bacterial serine transporters. A number of other
      subfamilies that do not contain characterized members have been defined. In
      contrast to their amino acid sequences, the hydropathy profiles of the members of
      the family are extremely well conserved. Analysis of the hydropathy profiles has
      suggested that the glutamate transporters have a global structure that is unique
      among secondary transporters. Experimentally, the unique structure of the
      transporters was recently confirmed by membrane topology studies. Although there
      is still controversy about part of the topology, the most likely model predicts
      the presence of eight membrane-spanning alpha-helices and a loop-pore structure
      which is unique among secondary transporters but may resemble loop-pores found in
      ion channels. A second distinctive structural feature is the presence of a highly
      amphipathic membrane-spanning helix that provides a hydrophilic path through the
      membrane. Recent data from analysis of site-directed mutants and studies on the
      mechanism and pharmacology of the transporters are discussed in relation to the
      structural model.

PMID- 10357851
TI  - Pseudomonas syringae phytotoxins: mode of action, regulation, and biosynthesis by
      peptide and polyketide synthetases.
AB  - Coronatine, syringomycin, syringopeptin, tabtoxin, and phaseolotoxin are the most
      intensively studied phytotoxins of Pseudomonas syringae, and each contributes
      significantly to bacterial virulence in plants. Coronatine functions partly as a
      mimic of methyl jasmonate, a hormone synthesized by plants undergoing biological
      stress. Syringomycin and syringopeptin form pores in plasma membranes, a process
      that leads to electrolyte leakage. Tabtoxin and phaseolotoxin are strongly
      antimicrobial and function by inhibiting glutamine synthetase and ornithine
      carbamoyltransferase, respectively. Genetic analysis has revealed the mechanisms
      responsible for toxin biosynthesis. Coronatine biosynthesis requires the
      cooperation of polyketide and peptide synthetases for the assembly of the
      coronafacic and coronamic acid moieties, respectively. Tabtoxin is derived from
      the lysine biosynthetic pathway, whereas syringomycin, syringopeptin, and
      phaseolotoxin biosynthesis requires peptide synthetases. Activation of phytotoxin
      synthesis is controlled by diverse environmental factors including plant signal
      molecules and temperature. Genes involved in the regulation of phytotoxin
      synthesis have been located within the coronatine and syringomycin gene clusters;
      however, additional regulatory genes are required for the synthesis of these and
      other phytotoxins. Global regulatory genes such as gacS modulate phytotoxin
      production in certain pathovars, indicating the complexity of the regulatory
      circuits controlling phytotoxin synthesis. The coronatine and syringomycin gene
      clusters have been intensively characterized and show potential for constructing
      modified polyketides and peptides. Genetic reprogramming of peptide and
      polyketide synthetases has been successful, and portions of the coronatine and
      syringomycin gene clusters could be valuable resources in developing new
      antimicrobial agents.

PMID- 10357853
TI  - Mechanisms of T-cell activation by human T-cell lymphotropic virus type I.
AB  - The interactions between human T-cell lymphotropic virus type I (HTLV-I) and the
      cellular immune system can be divided into viral interference with functions of
      the infected host T cell and the subsequent interactions between the infected T
      cell and the cellular immune system. HTLV-I-mediated activation of the infected
      host T cell is induced primarily by the viral protein Tax, which influences
      transcriptional activation, signal transduction pathways, cell cycle control, and
      apoptosis. These properties of Tax may well explain the ability of HTLV-I to
      immortalize T cells. It is not clear, though, how HTLV-I induces T-cell
      transformation (interleukin-2 [IL-2] independence). Recent evidence suggests that
      Tax may promote the G1- to S-phase transition, although this may involve
      additional proteins. A role for other viral proteins that may constitutively
      activate the IL-2 receptor pathway has also been suggested. By virtue of their
      activated state, HTLV-I-infected T cells can nonspecifically activate resting,
      uninfected T cells via virus-mediated upregulation of adhesion molecules. This
      may favor viral dissemination. Moreover, the induction of a remarkably high
      frequency of antiviral CD8(+) T cells does not appear to eliminate the infection.
      Indeed, individuals with a high frequency of virus-specific CD8(+) T cells have a
      high viral load, indicating a state of chronic immune system stimulation. Thus,
      while an activated immune system is needed to eradicate the infection, the spread
      of the HTLV-I is also accelerated under these conditions. A detailed knowledge of
      the molecular interactions between virus-specific CD8(+) T cells and
      immunodominant viral epitopes holds promise for the development of specific
      antiviral therapy.

PMID- 10357854
TI  - Bioenergetic aspects of halophilism.
AB  - Examination of microbial diversity in environments of increasing salt
      concentrations indicates that certain types of dissimilatory metabolism do not
      occur at the highest salinities. Examples are methanogenesis for H2 + CO2 or from
      acetate, dissimilatory sulfate reduction with oxidation of acetate, and
      autotrophic nitrification. Occurrence of the different metabolic types is
      correlated with the free-energy change associated with the dissimilatory
      reactions. Life at high salt concentrations is energetically expensive. Most
      bacteria and also the methanogenic Archaea produce high intracellular
      concentrations of organic osmotic solutes at a high energetic cost. All
      halophilic microorganisms expend large amounts of energy to maintain steep
      gradients of NA+ and K+ concentrations across their cytoplasmic membrane. The
      energetic cost of salt adaptation probably dictates what types of metabolism can
      support life at the highest salt concentrations. Use of KCl as an intracellular
      solute, while requiring far-reaching adaptations of the intracellular machinery,
      is energetically more favorable than production of organic-compatible solutes.
      This may explain why the anaerobic halophilic fermentative bacteria (order
      Haloanaerobiales) use this strategy and also why halophilic homoacetogenic
      bacteria that produce acetate from H2 + CO2 exist whereas methanogens that use
      the same substrates in a reaction with a similar free-energy yield do not.

PMID- 10357857
TI  - Cytoplasmic polyadenylation in development and beyond.
AB  - Maternal mRNA translation is regulated in large part by cytoplasmic
      polyadenylation. This process, which occurs in both vertebrates and
      invertebrates, is essential for meiosis and body patterning. In spite of the
      evolutionary conservation of cytoplasmic polyadenylation, many of the cis
      elements and trans-acting factors appear to have some species specificity. With
      the recent isolation and cloning of factors involved in both poly(A) elongation
      and deadenylation, the underlying biochemistry of these reactions is beginning to
      be elucidated. In addition to early development, cytoplasmic polyadenylation is
      now known to occur in the adult brain, and there is circumstantial evidence that
      this process occurs at synapses, where it could mediate the long-lasting phase of
      long-term potentiation, which is probably the basis of learning and memory.
      Finally, there may be multiple mechanisms by which polyadenylation promotes
      translation. Important questions yet to be answered in the field of cytoplasmic
      polyadenylation are addressed.

PMID- 10357860
TI  - Methodological triangulation in public health research - advancement or mirage?

PMID- 10357861
TI  - Field trials of a rapid test for G6PD deficiency in combination with a rapid
      diagnosis of malaria.
AB  - A rapid single-step screening method for detection of glucose-6-phosphate
      dehydrogenase (G6 PD) deficiency was evaluated on Halmahera Island, Maluku
      Province, Indonesia, and in Shan and Mon States, Myanmar, in combination with a
      rapid diagnosis of malaria by an acridine orange staining method. Severe
      deficiency was detected by the rapid test in 45 of 1126 volunteers in Indonesia
      and 54 of 1079 in Myanmar, but it was difficult to distinguish blood samples with
      mild deficiency from those with normal activity. 89 of 99 severely deficient
      cases were later confirmed by formazan ring method in the laboratory, but 5 with
      mild and 5 with no deficiency were misdiagnosed as severe. Of the samples
      diagnosed as mild and no deficiency on-site, none was found to be severely
      deficient by the formazan method. Malaria patients were simultaenously++ detected
      on-site in 273 samples on Halmahera island and 277 samples from Shan and Mon
      States. In Mon State, primaquine was prescribed safely to G6 PD-normal malaria
      patients infected with Plasmodium vivax and/or gametocytes of P. falciparum. The
      new rapid test for G6 PD deficiency may be useful for detecting severe cases
      under field conditions, and both rapid tests combined are can be useful in
      malaria-endemic areas, facilitating early diagnosis, prompt and radical treatment
      of malaria and suppression of malaria transmission.

PMID- 10357858
TI  - DNA bending and wrapping around RNA polymerase: a "revolutionary" model
      describing transcriptional mechanisms.
AB  - A model is proposed in which bending and wrapping of DNA around RNA polymerase
      causes untwisting of the DNA helix at the RNA polymerase catalytic center to
      stimulate strand separation prior to initiation. During elongation, DNA bending
      through the RNA polymerase active site is proposed to lower the energetic barrier
      to the advance of the transcription bubble. Recent experiments with mammalian RNA
      polymerase II along with accumulating evidence from studies of Escherichia coli
      RNA polymerase indicate the importance of DNA bending and wrapping in
      transcriptional mechanisms. The DNA-wrapping model describes specific roles for
      general RNA polymerase II transcription factors (TATA-binding protein [TBP],
      TFIIB, TFIIF, TFIIE, and TFIIH), provides a plausible explanation for
      preinitiation complex isomerization, suggests mechanisms underlying the synergy
      between transcriptional activators, and suggests an unforseen role for TBP
      associating factors in transcription.

PMID- 10357862
TI  - Epidemic of self-poisoning with seeds of the yellow oleander tree (Thevetia
      peruviana) in northern Sri Lanka.
AB  - Deliberate self-harm is an important problem in the developing world. Ingestion
      of yellow oleander seeds (Thevetia peruviana) has recently become a popular
      method of self-harm in northern Sri Lanka -- there are now thousands of cases
      each year. These seeds contain cardiac glycosides that cause vomiting, dizziness,
      and cardiac dysrhythmias such as conduction block affecting the sinus and AV
      nodes. This paper reports a study of the condition's mortality and morbidity
      conducted in 1995 in Anuradhapura General Hospital, a secondary referral centre
      serving 750 000 people in Sri Lanka's north central province. 415 cases were
      admitted to the hospital during 11 months; 61% were women and 46% were less than
      21 years old. A prospective study of 79 patients showed that 6% died soon after
      admission. 43% presented with marked cardiac dysrhythmias which necessitated ther
      transfer to the coronary care unit in Colombo for prophylactic temporary cardiac
      pacing. The reasons for the acts of self-harm were often relatively trivial,
      particularly in children; most denied that they wished to die. Unfortunately, the
      case fatality rate for oleander poisoning in Sri Lanka is at least 10%. This
      epidemic is not only causing many unnecessary deaths, it is also putting immense
      stress on the already stretched Sri Lankan health services. There is an urgent
      need for an intervention which could be used in rural hospitals, thus preventing
      the hazardous and expensive emergency transfer of patients to the capital.

PMID- 10357856
TI  - Formation of mRNA 3' ends in eukaryotes: mechanism, regulation, and
      interrelationships with other steps in mRNA synthesis.
AB  - Formation of mRNA 3' ends in eukaryotes requires the interaction of transacting
      factors with cis-acting signal elements on the RNA precursor by two distinct
      mechanisms, one for the cleavage of most replication-dependent histone
      transcripts and the other for cleavage and polyadenylation of the majority of
      eukaryotic mRNAs. Most of the basic factors have now been identified, as well as
      some of the key protein-protein and RNA-protein interactions. This processing can
      be regulated by changing the levels or activity of basic factors or by using
      activators and repressors, many of which are components of the splicing
      machinery. These regulatory mechanisms act during differentiation, progression
      through the cell cycle, or viral infections. Recent findings suggest that the
      association of cleavage/polyadenylation factors with the transcriptional complex
      via the carboxyl-terminal domain of the RNA polymerase II (Pol II) large subunit
      is the means by which the cell restricts polyadenylation to Pol II transcripts.
      The processing of 3' ends is also important for transcription termination
      downstream of cleavage sites and for assembly of an export-competent mRNA. The
      progress of the last few years points to a remarkable coordination and
      cooperativity in the steps leading to the appearance of translatable mRNA in the
      cytoplasm.

PMID- 10357865
TI  - Community prevalence study of taeniasis and cysticerosis in Bail, Indonesia.
AB  - Taenia solium, a human cestode parasite endemic throughout most of South-east
      Asia, causes a number of public health and economic problems. The parasite is
      endemic in Bali due to a mix of cultural and religious practices.
      Immunoepidemiological investigation of three rural communities revealed a
      taeniasis prevalence of 0.72% (3/415). One of the three cases was due to Taenia
      solium, the other two to Taenia saginata. A further nine cases of Taenia
      infection were identified from patients from villages surrounding the chosen
      communities, suggesting that prevalence levels may be higher in other areas.
      Seroprevalence of human cysticercosis by immunoblot was 1.65% (6/363), though all
      cases were detected within a single community (6/115; prevalence 5.22%). Several
      other cases of subcutaneous cysticercosis were identified from local clinics,
      suggesting continued transmission of Taenia solium in the region. Other
      intestinal helminth parasites identified within the communities were Ascaris
      lumbricoides (29.9%), Trichuris trichiuria (33.9%) and hookworm (8.2%).

PMID- 10357863
TI  - Isolate resistance of Blastocystis hominis to metronidazole.
AB  - Isolates of Blastocystis hominis from infected immigrant workers from Indonesia,
      Bangladesh and infected individuals from Singapore and Malaysia were assessed for
      growth pattern and degree of resistance to different concentrations of
      metronidazole. Viability of the cells was assessed using eosin-brillian cresyl
      blue which stained viable cells green and nonviable cells red. The Bangladeshi
      and Singaporean isolates were nonviable even at the lowest concentration of 0.01
      mg/ml, whereas 40% of the initial inoculum of parasites from the Indonesian
      isolate at day one were still viable in cultures with 1.0 mg/ml metronidazole.
      The study shows that isolates of B. hominis of different geographical origin have
      different levels of resistance to metronidazole. The search for more effective
      drugs to eliminate th parasite appears inevitable, especially since surviving
      parasites from metronidazole cultures show greater ability to multiply in
      subcultures than controls.

PMID- 10357864
TI  - Treatment of toenail onychomycosis with 2% butenafine and 5% Melaleuca
      alternifolia (tea tree) oil in cream.
AB  - The prevalence of onychomycosis, a superficial fungal infection that destroys the
      entire nail unit, is rising, with no satisfactory cure. The objective of this
      randomized, double-blind, placebo-controlled study was to examine the clinical
      efficacy and tolerability of 2% butenafine hydrochloride and 5% Melaleuca
      alternifolia oil incorporated in a cream to manage toenail onychomycosis in a
      cohort. Sixty outpatients (39 M, 21 F) aged 18-80 years (mean 29.6) with 6-36
      months duration of disease were randomized to two groups (40 and 20), active and
      placebo. After 16 weeks, 80% of patients using medicated cream were cured, as
      opposed to none in the placebo group. Four patients in the active treatment group
      experienced subjective mild inflammation without discontinuing treatment. During
      follow-up, no relapse occurred in cured patients and no improvement was seen in
      medication-resistant and placebo participants.

PMID- 10357866
TI  - Prophylactic or therapeutic intervention for varicella zoster in tropical
      countries?

PMID- 10357859
TI  - PAS domains: internal sensors of oxygen, redox potential, and light.
AB  - PAS domains are newly recognized signaling domains that are widely distributed in
      proteins from members of the Archaea and Bacteria and from fungi, plants,
      insects, and vertebrates. They function as input modules in proteins that sense
      oxygen, redox potential, light, and some other stimuli. Specificity in sensing
      arises, in part, from different cofactors that may be associated with the PAS
      fold. Transduction of redox signals may be a common mechanistic theme in many
      different PAS domains. PAS proteins are always located intracellularly but may
      monitor the external as well as the internal environment. One way in which
      prokaryotic PAS proteins sense the environment is by detecting changes in the
      electron transport system. This serves as an early warning system for any
      reduction in cellular energy levels. Human PAS proteins include hypoxia-inducible
      factors and voltage-sensitive ion channels; other PAS proteins are integral
      components of circadian clocks. Although PAS domains were only recently
      identified, the signaling functions with which they are associated have long been
      recognized as fundamental properties of living cells.

PMID- 10357855
TI  - Multiple pathways of recombination induced by double-strand breaks in
      Saccharomyces cerevisiae.
AB  - The budding yeast Saccharomyces cerevisiae has been the principal organism used
      in experiments to examine genetic recombination in eukaryotes. Studies over the
      past decade have shown that meiotic recombination and probably most mitotic
      recombination arise from the repair of double-strand breaks (DSBs). There are
      multiple pathways by which such DSBs can be repaired, including several
      homologous recombination pathways and still other nonhomologous mechanisms. Our
      understanding has also been greatly enriched by the characterization of many
      proteins involved in recombination and by insights that link aspects of DNA
      repair to chromosome replication. New molecular models of DSB-induced gene
      conversion are presented. This review encompasses these different aspects of DSB
      induced recombination in Saccharomyces and attempts to relate genetic, molecular
      biological, and biochemical studies of the processes of DNA repair and
      recombination.

PMID- 10357872
TI  - Phonological and semantic processes influence beginning readers' ability to learn
      to read words.
AB  - Children (4 to 6 years of age) were taught to associate printed 3- or 4-letter
      abbreviations, or cues, with spoken words (e.g., bfr for beaver). All but 1 of
      the letters in the cue corresponded to phonemes in the spoken target word. Two
      types of cues were constructed: phonetic cues, in which the medial letter was
      phonetically similar to the target word, and control cues, in which the central
      phoneme was phonetically dissimilar. In Experiment 1, children learned the
      phonetic cues better than the control cues, and learning correlated with measures
      of phonological skill and knowledge of the meanings of the words taught. In
      Experiment 2, the target words differed on a semantic variable-imageability-and
      learning was influenced by both the phonetic properties of the cue and the
      imageability of the words used.

PMID- 10357873
TI  - Units of analysis in nonword reading: evidence from children and adults.
AB  - Four experiments examined variations in children's (chronological age range: 5
      years 7 months to 9 years 10 months) and adults' reading strategy as a function
      of task demands. Experiment 1 found that less skilled readers (mean reading age:
      8 years 8 months), though able to make use of rime-based spelling-to-sound
      correspondences (reading "by analogy"), predominantly used simple grapheme
      phoneme-level correspondences in reading isolated unfamiliar items. Skilled
      children (mean reading age: 11 years 6 months) were more likely to adopt an
      analogy strategy. Experiments 2 and 3 adopted versions of the "clue word"
      technique used by U. Goswami (1986, Journal of Experimental Child Psychology, 42,
      73-83; 1988, Quarterly Journal of Experimental Psychology, 40A, 239-268) and
      found a much higher incidence of analogical responding by children of all ages,
      suggesting that reading strategy is task-dependent. Experiment 4 showed that
      adults' nonword-reading strategy is determined by list composition, in that
      grapheme-phoneme correspondences are used more when the list context contains
      nonwords. It is concluded that both adults and young children exhibit
      considerable flexibility and task-dependence in the levels of spelling-to-sound
      correspondence (analogies vs decoding) that they use and that grapheme-phoneme
      correspondences are preferred when maximum generalization to unfamiliar items is
      required.

PMID- 10357871
TI  - The effects of misleading and inconsistent postevent information on children's
      recollections of criterion-learned information.
AB  - Similar experimental procedures are used in misinformation studies and in
      retroactive inhibition studies. Despite these similarities, the findings of these
      studies have suggested that misleading postevent information and inconsistent
      postevent information would have different effects on children's recollections.
      To examine this hypothesis, 28 seven-year-olds learned a target game to
      criterion. Two days later, they were administered either type of postevent
      information on either one or three occasions. When the children were tested 3
      weeks later, the results showed that even criterion-learned information could be
      affected detrimentally by exposure to misleading or inconsistent postevent
      information. Notably, children who were administered misinformation on one
      occasion reported more target information than children in all other groups. It
      is suggested that exposure to misinformation had a facilitative effect on these
      children's recollections.

PMID- 10357875
TI  - Human leptin stimulates proliferation and activation of human circulating
      monocytes.
AB  - The Ob gene product, leptin, is an adipocyte-secreted hormone that centrally
      regulates weight control. However, leptin receptor is expressed not only in the
      central nervous system, but also in other systems such as reproductive and
      hematopoietic tissues. Human leptin has previously been shown to enhance cytokine
      production by murine peritoneal macrophages. In this paper we show that human
      leptin stimulates proliferation in a dose-dependent manner and functionally
      activates human circulating monocytes in vitro, by inducing the production of
      cytokines such as TNF-alpha and IL-6. Proliferation was assessed both by
      [3H]thymidine and bromodeoxyuridine incorporation at 48 h. We also checked the
      leptin stimulated monocyte expression of activation markers by flow cytometry:
      CD25, HLA-DR, CD38, CD71, CD11b, and CD11c expression increased after 72 h.
      Moreover, leptin increases the expression of the early activation marker CD69 in
      monocytes but not in lymphocytes. The stimulation produced by leptin is
      comparable to that produced by endotoxin [lipopolysaccharide (LPS)]. In addition,
      leptin can potentiate the stimulatory effect of LPS or PMA. Furthermore, we
      studied cytokine production (TNF-alpha and IL-6) simultaneously by flow
      cytometric detection of intracellular cytokines in the activated monocytes.
      Leptin produced a dose-dependent increase in the number of activated monocytes
      producing cytokines. These data indicate that leptin is a potent stimulatory
      hormone on human peripheral blood monocytes and suggest that it may have a role
      as a proinflammatory cytokine.

PMID- 10357876
TI  - Differential regulation of IFN-gamma, TNF-alpha, and IL-10 production by CD4(+)
      alphabetaTCR+ T cells and vdelta2(+) gammadelta T cells in response to monocytes
      infected with Mycobacterium tuberculosis-H37Ra.
AB  - Mycobacterium tuberculosis bacilli readily activate CD4(+) and gammadelta T
      cells. CD4(+) and gammadelta T cells were compared for their ability to regulate
      IFN-gamma, TNF-alpha, and IL-10 production, cytokines with significant roles in
      the immune response to M. tuberculosis. PBMC from healthy tuberculin positive
      donors were stimulated with live M. tuberculosis-H37Ra. CD4(+) and gammadelta T
      cells were purified by negative selection and tested in response to autologous
      monocytes infected with M. tuberculosis. Both subsets produced equal amounts of
      secreted IFN-gamma. However, the precursor frequency of IFN-gamma secreting
      gammadelta T cells was half that of CD4(+) T cells, indicating that gammadelta T
      cells were more efficient producers of IFN-gamma than CD4(+) T cells. TNF-alpha
      production was markedly enhanced by addition of CD4(+) and gammadelta T cells to
      M. tuberculosis infected monocytes, and TNF-alpha was produced by both T cells
      and monocytes. No differences in TNF-alpha enhancement were noted between CD4(+)
      and gammadelta T cells. IL-10 production by M. tuberculosis infected monocytes
      was not modulated by CD4(+) or gammadelta T cells. Thus CD4(+) and gammadelta T
      cells had similar roles in differential regulation of IFN-gamma, TNF-alpha, and
      IL-10 secretion in response to M. tuberculosis infected monocytes. However, the
      interaction between T cells and infected monocytes differed for each cytokine.
      IFN-gamma production was dependent on antigen presentation and costimulators
      provided by monocytes. TNF-alpha levels were increased by addition of TNF-alpha
      produced by T cells and IL-10 production by monocytes was not modulated by CD4(+)
      or gammadelta T cells.

PMID- 10357874
TI  - Ascorbic acid is a potent inhibitor of various forms of T cell apoptosis.
AB  - This study was designed to examine the effect of ascorbic acid (vitamin C) on
      various death pathways of mouse T cells. Unlike humans, mice produce their own
      ascorbic acid and our study tested the effect of additional ascorbic acid on
      murine T cells. Our data show that three T cell death pathways (growth factor
      withdrawal-, spontaneous-, and steroid-induced death) were inhibited when T cells
      were incubated with ascorbic acid. The data show that both activated and resting
      T cells were responsive to ascorbic acid since both populations were resistant to
      death stimuli when treated with ascorbic acid. Additionally, effector T cells
      were more likely to enter S phase if treated with ascorbic acid. Our data
      implicate ascorbic acid as a potent inhibitor of various forms of T cell death
      and suggest that vitamin C may function as an immune booster through this
      mechanism.

PMID- 10357878
TI  - Administration of glucocorticoids markedly increases the numbers of granulocytes
      and extrathymic T cells in the bone marrow.
AB  - Glucocorticoids, steroid hormones, are widely used as an anti-inflammatory drug.
      However, clinicians have sometimes encountered adverse drug reactions such as
      ulcers and tissue damage. In this study, we investigated how such adverse
      reactions of glucocorticoids are evoked, using an experimental mice model. When
      hydrocortisone (0.5 or 1.0 mg/day/mouse) was administered daily for 2 weeks,
      severe leukocytopenia was induced in all immune system organs. However,
      granulocytes (Gr-1(+)Mac-1(+)) were increased in number in the bone marrow and
      peripheral blood. This seemed to be due to an elevated level of myelopoiesis in
      the bone marrow. As well as increasing in number, granulocytes were functionally
      activated as estimated by the Ca2+ influx and superoxide production. The
      proportion of primordial T cells (CD3(int)IL-2Rbeta+) in the thymus and the
      number of primordial T cells in the bone marrow also increased. Mice administered
      hydrocortisone became susceptible to stress. Thus, these mice showed gastric
      ulcers when they were exposed to restraint stress for 12 h. These results suggest
      that activated granulocytes and primordial T cells might provide a mechanism
      involved in steroid ulcers and tissue damage, possibly through the superoxide
      production of granulocytes and the autoreactivity of primordial T cells.

PMID- 10357877
TI  - Prostaglandin E2 enhancement of interferon-gamma production by antigen-stimulated
      type 1 helper T cells.
AB  - Prostaglandin E2 (PGE2) is a potent mediator generated in immune tissues by
      cyclooxygenation of arachidonic acid. PGE2 affects T cell functions through four
      homologous G protein-coupled receptors termed EP1R, EP2R, EP3R, and EP4R that
      differ in tissue distribution and signaling. Antigen-evoked secretion of
      interferon-gamma (IFN-gamma) by sperm whale myoglobin-specific Th1 cells of DBA/2
      mouse I-Ed-restricted clones, that express EP3Rs and EP4Rs, was enhanced a
      maximum of 3-fold by 10(-10) to 10(-8) M PGE2 and 2.5-fold each for the EP1R/EP3R
      directed agonist sulprostone (10(-8) and 10(-7) M) and for the EP4R/EP3R/EP2R
      agonist misoprostol (10(-9) M). Neither PGE2 nor the synthetic analogs affected
      secretion of IFN-gamma by PMA plus ionomycin-stimulated clones of Th1 cells.
      Antigen-evoked secretion of IFN-gamma by influenza hemagglutinin-specific mouse
      lymph node Th1 cells, that also express EP3Rs and EP4Rs, was increased a maximum
      of 12-fold by 10(-9) to 10(-8) M PGE2, 14-fold by 10(-9) M sulprostone, and 10
      fold by 10(-9) M misoprostol. Production of IFN-gamma by either type of Th1 cell
      was not affected significantly by 10(-6) M PGE2 alone. The generation of IFN
      gamma by antigen-stimulated Th1 cells thus is significantly enhanced by
      physiologically relevant concentrations of PGE2.

PMID- 10357880
TI  - Complement deposition on immune complexes reduces the frequencies of metabolic,
      proteolytic, and superoxide oscillations of migrating neutrophils.
AB  - Neutrophils exhibit intrinsic sinusoidal metabolite concentration oscillations of
      3 min in resting cells and an additional approximately 10- or 20-s oscillation in
      migrating/adhering cells. To better understand immune complex (IC)-mediated
      leukocyte activation, we have studied neutrophil metabolic oscillations in the
      presence of ICs either with or without fixed complement. Using a microscope
      photometer we quantitated NAD(P)H autofluorescence oscillations. Cells exposed to
      ICs exhibited metabolic oscillation periods of approximately 12 s in the absence
      of complement and approximately 22 s in the presence of complement opsonization.
      To determine if the effects could be associated with C3 deposition, we used ICs
      opsonized with only C3 or only C1 and C4. Untreated ICs, heat-inactivated
      complement-treated ICs, and C1,C4-treated ICs trigger rapid metabolic
      oscillations, as do fMLP and yeast; in contrast, ICs treated with full complement
      or C3 alone did not affect NAD(P)H oscillations in comparison to controls. The
      induction of higher frequency (approximately 10 s) NAD(P)H oscillations by ICs
      could be blocked by addition of anti-FcgammaRII, but not FcgammaRIII mAb
      fragments, suggesting the participation of FcgammaRII in cellular metabolic
      responses to ICs. Parallel changes in the frequencies of oxidant release and
      pericellular proteolysis were found for all of these stimuli. Thus, immune
      complex composition affects both intracellular metabolic signals and
      extracellular functional oscillations. We suggest that complement attenuates the
      phlogistic potential of ICs by reducing the frequency of cytoplasmic NAD(P)H
      oscillations.

PMID- 10357879
TI  - Modulation of nitric oxide-induced apoptotic death of HL-60 cells by protein
      kinase C and protein kinase A through mitogen-activated protein kinases and CPP32
      like protease pathways.
AB  - To define the signaling pathways during NO-induced apoptotic events and their
      possible modulation by two protein kinase systems, we explored the involvement of
      three structurally related mitogen-activated protein kinase subfamilies. Exposure
      of HL-60 cells to sodium nitroprusside (SNP) strongly activated p38 kinase, but
      did not activate c-Jun N-terminal kinase (JNK) and extracellular signal-regulated
      kinase (ERK). In addition, SNP-induced apoptosis was markedly blocked by the
      selective p38 kinase inhibitor (SB203580) but not by MEK1 kinase inhibitor
      (PD098059), indicating that p38 kinase serves as a mediator of NO-induced
      apoptosis. In contrast, treatment of cells with phorbol 12-myristate 13-acetate
      (PMA) strongly activated not only JNK but also ERK, while not affecting p38
      kinase. However, although SNP by itself weakly activated CPP32-like protease, SNP
      in combination with PMA markedly increased the extent of CPP32-like protease
      activation. Interestingly, N6,O2-dibutylyl cAMP (DB-cAMP) significantly blocked
      SNP- or SNP plus PMA-induced activation of CPP32-like protease and the resulting
      induction of apoptosis. DB-cAMP also blocked PMA-induced JNK activation.
      Collectively, these findings demonstrate the presence of specific up- or down
      modulatory mechanisms of cell death pathway by NO in which (1) p38 kinase serves
      as a mediator of NO-induced apoptosis, (2) PKC acts at the point and/or upstream
      of JNK and provides signals to potentiate NO-induced CPP32-like protease
      activation, and (3) PKA lies upstream of either JNK or CPP32-like protease to
      protect NO- or NO plus PMA-induced apoptotic cell death in HL-60 cells.

PMID- 10357881
TI  - Regulation of CD44-hyaluronan interactions in Burkitt's lymphoma and Epstein-Barr
      virus-transformed lymphoblastoid B cells by PMA and interleukin-4.
AB  - In this study, we investigated the regulation of CD44-hyaluronan (HA)
      interactions in a panel of EBV+ Burkitt's lymphoma (BL) and lymphoblastoid B cell
      lines (B-LCL) generated by in vitro EBV transformation of normal human B cells.
      The results show that among B cell mitogens, phorbol 12-myristate 13-acetate
      (PMA) alone induced strong HA recognition in EBV+ BL-30/B95-8 cells. Among the
      cytokines that affect B cell growth and differentiation, IL-4 alone induced HA
      recognition in BL-30/B95-8 cells. Attempts to delineate the molecular mechanism
      for this increased HA adhesion in BL-30/B95-8 cells revealed an enhanced
      expression of CD44 H, isoforms containing V3, V6, and V9 exons, alterations in
      the splicing pattern of the V4 exon, and the increased electrophoretic mobility
      of the CD44 H protein. In contrast, the ability to recognize HA was not observed
      in B-LCL cells stimulated with either PMA or IL-4, even though these cells
      respond to IL-4, as observed by upregulation of CD23 expression. The molecular
      pathways that regulate CD44 expression and CD44-mediated HA binding may be
      selectively inactivated in B-LCL cells. These results may have implications with
      respect to the generation and spread of B cell tumors.

PMID- 10357882
TI  - MEK1 activation rescues Jurkat T cells from Fas-induced apoptosis.
AB  - Although the protease cascade initiated by Fas (CD95, Apo-1) is well
      characterized, there remains little known about how kinase pathways may impact on
      Fas-mediated apoptosis. We recently observed that in T lymphocytes Fas strongly
      induced activation of JNK (c-Jun N-terminal kinase) but not of second messengers
      leading to activation of ERK (extracellular regulated kinase). Additionally, Fas
      mediated apoptosis was significantly inhibited with PMA, a potent activator of
      the ERK signaling pathway. This suggested a model whereby activation of the ERK
      pathway might attenuate Fas-mediated apoptosis. This was confirmed in the current
      study by showing that activation of MEK1, the upstream regulator of ERK, reduces
      Fas-mediated apoptosis, whereas inhibition of MEK1 augments apoptosis by Fas.
      Furthermore, Fas-mediated apoptosis of Jurkat T cells is not affected by
      constitutively active or dominant negative variants that modulate the JNK
      pathway. These results demonstrate that Fas-induced JNK activation is not
      required for apoptosis by Jurkat T cells, but rather is more likely secondary to
      cell stress during the early phases of apoptosis. This is supported by the
      ability of the caspase blocker zVAD to inhibit both apoptosis and JNK activation
      by Fas.

PMID- 10357883
TI  - Persistence, immune specificity, and functional ability of murine mutant ras
      epitope-specific CD4(+) and CD8(+) T lymphocytes following in vivo adoptive
      transfer.
AB  - Adoptive T-cell transfer has been shown to be a potentially effective strategy
      for cellular immunotherapy in some murine models of disease. However, several
      issues remain unresolved regarding some of the basic features involved in
      effective adoptive transfer, such as the influence of specific peptide antigen
      (Ag) boost after T-cell transfer, the addition of IL-2 post-T-cell transfer, the
      trafficking of transferred T cells to lymphoid and nonlymphoid tissues, and the
      functional stability of recoverable CD4(+) and CD8(+) T cells. We investigated
      several of these parameters, particularly as they relate to the persistence and
      maintenance of effector functions of murine CD4(+) and/or CD8(+) T lymphocytes
      after adoptive cellular transfer into partially gamma-irradiated syngeneic hosts.
      Our laboratory previously identified murine (H-2(d)) immunogenic CD4(+) and
      CD8(+) T-cell peptide epitopes reflecting codon 12 ras mutations as tumor
      specific Ag. Therefore, the model system chosen here employed epitope-specific
      MHC class II-restricted CD4(+) T cells and MHC class I-restricted CD8(+) T cells
      produced from previously immunized BALB/c mice. Between 2 and 7 days after T-cell
      transfer, recipient mice received various combinations of peptide boosts and/or
      IL-2 treatments. At different times after the T-cell transfer, spleen and lung
      tissues were analyzed phenotypically to monitor the persistence of the immune T
      cells and functionally (via proliferation or cytotoxicity assays) to assess the
      maintenance of peptide specificity. The results showed that immune donor T
      lymphocytes (uncultured immune T cells or cloned T cells) were recoverable from
      the spleens and lungs of recipient mice after transfer. The recovery of Ag
      specific T-cell responses was greatest from recipient mice that received peptide
      boosts and IL-2 treatment. However, mice that received a peptide boost without IL
      2 treatment responded nearly as well, which suggested that including a peptide
      boost after T-cell transfer was more obligatory than exogenous IL-2 treatment to
      sustain adoptively transferred T cells in vivo. Ag-specific T-cell responses were
      weak in mice that either received IL-2 alone or did not receive the cognate
      peptide boost after T-cell transfer. The T-cell clones were also monitored by
      flow cytometry or RT-PCR based on expression of the T-cell receptor Vbeta-chain,
      which was previously characterized. Ag-specific T cells were recovered from both
      spleens and lungs of recipient mice, demonstrating that the T-cell clones could
      localize to both lymphoid and nonlymphoid tissues. This study demonstrates that
      both uncultured and in vitro-cloned T lymphocytes can migrate to lymphoid tissues
      and nonlymphoid (e.g., lung) tissues in recipient hosts and that their functional
      activities can be maintained at these sites after transfer, if they are exposed
      to peptide Ag in vivo.

PMID- 10357884
TI  - A diabetogenic gene prevents T cells from receiving costimulatory signals.
AB  - T cell fate following antigen encounter is determined by several intracellular
      signals generated by the interaction of the T cell with an antigen-presenting
      cell. In the periphery activation requires T cell receptor signaling (signal one)
      in combination with costimulatory signals (signal two), usually provided through
      the cognate interaction of CD28 and B7 molecules. Provision of signal one alone
      to purified murine peripheral T cells in vitro induces apoptosis or anergy rather
      than promoting activation. These T cells can be rescued from apoptosis if they
      are provided with costimulation supplied, for example, by engaging the CD28 co
      receptor with an anti-CD28 monoclonal antibody or by adding an exogenous source
      of interleukin-2. However, a majority of peripheral T cells from autoimmune,
      diabetes-prone Biobreeding (BB) rats exhibited different responses to these
      stimuli. T cells from these rats could not be rescued from apoptosis by
      costimulation. This was not due to the inability of BB-DP T cells to upregulate
      CD28 and the IL-2 receptor in response to TCR crosslinking. The failure of these
      costimulatory interactions to rescue BB-DP T cells segregated with the diabetes
      susceptibility gene iddm1. Iddm1 in the rat causes peripheral T cell lymphopenia,
      which is associated with a dramatically shortened peripheral T cell life span.
      Our results indicate that a diabetogenic gene may contribute to autoimmunity by
      negating costimulatory signals important for the survival of long-lived
      peripheral T cells.

PMID- 10357885
TI  - Lectin-induced nitric oxide production.
AB  - Considering that nitric oxide (NO) may be involved in anti-tumoral and anti
      parasite lectin effects, in this report we investigated whether lectin induces NO
      production. Lectins from Canavalia brasiliensis, Dioclea grandiflora, Pisum
      arvense (PAA), and concanavalin A induced murine peritoneal cells to produce NO
      in vitro. PAA induced similar levels to that obtained with lipopolysaccharide
      plus interferon-gamma. NO production by adherent cells was significantly lower
      than that of unfractionated cells, suggesting a combination of lectin stimuli
      directly on macrophages and via lymphocyte stimulation. Ex vivo experiments
      showed that cells stimulated in vivo could maintain NO production in vitro
      without further stimuli. NO synthesis blockage in vivo can significantly increase
      cell numbers in draining lymph nodes after lectin injection compared to unblocked
      controls, suggesting an in vivo association of lectin stimuli and NO production.
      Taken together these data show that lectins can induce NO production both in
      vitro and in vivo.

PMID- 10357886
TI  - Phenotypic characteristics associated with the acquisition of HSV-specific CD8 T
      lymphocyte-mediated cytolytic function in vitro.
AB  - Class I MHC-restricted, HSV-1-specific CD8(+) cytolytic T lymphocyte (CTL)
      function is rarely detected in lymphocytes isolated directly from the lymph node
      draining the site of infection. However, culture in vitro for 24 to 72 h in the
      absence of exogenous antigen results in the development of easily detectable
      levels of HSV-1-specific CTL effectors. The inability to detect virus-specific
      CTL in HSV-1-infected mice is not well understood. However, since the in vitro
      culture of HSV-1-immune lymphocytes results in the transition to CTL function,
      studies of the changes occurring to the CD8(+) T cell subpopulation may provide
      important insights into the development of virus-specific CTL. Therefore, the
      phenotypic changes taking place in the CD8(+) population of T cells from draining
      popliteal lymph nodes of HSV-1-infected C57BL/6 (B6) mice were investigated,
      focusing on changes in the expression of cell surface markers associated with T
      lymphocyte activation. The results demonstrate an increase in the percentage of
      CD8(+) T cells expressing the activation markers CD44 and CD25 in parallel with
      the acquisition of HSV-specific CTL effector function. Cytolytic function was
      found exclusively within the CD8(+) CD44(hi) CD25(hi) fraction of cells in
      culture, but, surprisingly, was not detectable in CD8(+) CD44(hi) CD25(lo) T
      cells. This suggested that the acquisition of high levels of the high-affinity IL
      2 receptor was closely linked to cytolytic function and may define an important
      developmental stage in the transition from noncytolytic to cytolytic effector
      cell. In support of this, CD8(+) CD25(hi) T cells isolated from the regional
      lymph node exhibited direct ex vivo cytolytic function, indicating that cytolytic
      effector cells were present in the lymph node, but must emigrate rapidly after
      attaining this level of differentiation.

PMID- 10357887
TI  - L11, a unique anti-CD43 monoclonal antibody, inhibits the adoptive transfer of
      diabetes and pancreatic islet, salivary gland, and lacrimal gland inflammation in
      NOD/scid mice.
AB  - L11 is an anti-murine CD43 monoclonal antibody that blocks the migration of T
      cells from blood into lymphoid tissues. We used a T-cell-mediated adoptive
      transfer model to evaluate the ability of L11 to inhibit inflammation and
      destruction in extranodal tissues in the nonobese diabetic (NOD) mouse.
      Splenocytes from diabetic NOD mice were transferred intravenously into NOD/scid
      mice. The host mice were treated with L11, negative control antibody, or saline
      for the first 8 days after transfer. L11 treatment significantly delayed the
      onset of diabetes and inhibited the development of inflammation in pancreatic
      islets, salivary gland, and lacrimal gland. These results suggest that L11 may be
      a useful immunotherapeutic tool for the prevention of T-cell-mediated autoimmune
      diseases.

PMID- 10357888
TI  - Cross-reactivity of Borrelia burgdorferi and myelin basic protein-specific T
      cells is not observed in borrelial encephalomyelitis.
AB  - Borrelial encephalomyelitis, a rare manifestation of Lyme borreliosis, may
      present as a multiple sclerosis (MS)-like disease. It is postulated that in MS,
      inflammation of the white matter is caused by a T-cell response directed to
      myelin antigens. Here, we examined whether a T-cell autoimmune response may play
      a pathogenetic role in Borrelia-associated white matter disease mediated by cross
      reactivity between myelin basic protein (MBP) and B. burgdorferi. We generated a
      total of 1760 short-term T-cell lines against B. burgdorferi or MBP from two
      patients with Borrelial encephalomyelitis and compared these with three patients
      with late Lyme disease, one patient with transverse myelitis, eight patients with
      MS, and four healthy controls. While a few T-cell lines recognized both B.
      burgdorferi and MBP, T-cell clones from these lines responded only to the antigen
      of the original stimulation. Thus, our data do not provide evidence for cross
      reactivity between MBP and B. burgdorferi.

PMID- 10357889
TI  - TGF-beta family signal transduction in Drosophila development: from Mad to Smads.
AB  - The transforming growth factor-beta (TGF-beta) superfamily encompasses a large
      group of soluble extracellular proteins that are potent regulators of development
      in both vertebrates and invertebrates. Drosophila TGF-beta family members include
      three proteins with homology to vertebrate bone morphogenetic proteins (BMPs):
      Decapentaplegic (Dpp), Screw, and Glass bottom boat-60A. Genetic studies of Dpp
      signaling led to the identification of Smad proteins as central mediators of
      signal transduction by TGF-beta family members. Work in mammalian tissue culture
      has elucidated a biochemical model for signal transduction, in which activation
      of receptor serine-threonine kinase activity leads to phosphorylation of specific
      Smad proteins and translocation of heteromeric Smad protein complexes to the
      nucleus. Once in the nucleus Smad proteins interact with other DNA binding
      proteins to regulate transcription of specific target genes. Dissection of Dpp
      response elements from genes expressed during embryonic mesoderm patterning and
      midgut morphogenesis provides important insights into the contributions of Smad
      proteins and tissue-specific transcription factors to spatial regulation of gene
      expression. Genetic studies in Drosophila are now expanding to include multiple
      BMP ligands and receptors and have uncovered activities not explained by the
      current signal transduction model. Identification of more ligand sequences and
      demonstration of a functional Drosophila activin-like signal transduction pathway
      suggest that all TGF-beta signal transduction pathways are present in flies.

PMID- 10357890
TI  - Analyses of oviductal pars recta-induced fertilizability of coelomic eggs in
      Xenopus laevis.
AB  - The acquisition of fertilizability in coelomic eggs of Xenopus laevis has been
      shown to be correlated with the physical, biochemical, and ultrastructural
      alterations of the egg envelope [coelomic envelope (CE)] induced during the
      passage of eggs through the pars recta portion of the oviduct. However, no direct
      evidence that the pars recta renders eggs fertilizable has yet been presented. In
      this study, we show that coelomic eggs are highly fertilizable when they are
      incubated with continuous shaking for 4 h at 15 degrees C in pars recta extract
      (PRE) derived from females prestimulated by pregnant mare serum gonadotropin. The
      PRE from pituitary-stimulated Bufo japonicus was as potent as homologous PRE in
      rendering Xenopus eggs fertilizable. Incubation of coelomic eggs in PRE for 30
      min induced a dramatic increase in the rates of sperm binding to the envelope to
      a level equivalent to that exhibited by the envelope from uterine eggs (VEs). The
      CE-to-VE ultrastructural conversion and a 43k-to-41k hydrolysis of the envelope
      glycoprotein component started 5 min after, and were completed by 15 min after,
      the start of incubation in PRE and were accompanied by an exposure of a new N
      terminal sequence typical to gp41. Thus, the biochemical and ultrastructural
      conversions and the sperm-binding activity of the envelope induced by PREs,
      although being prerequisite, were not sufficient to render coelomic eggs fully
      accessible to fertilizing sperm.

PMID- 10357891
TI  - Regulation of left-right asymmetries in the zebrafish by Shh and BMP4.
AB  - Left-right (LR) asymmetry of the heart in vertebrates is regulated by early
      asymmetric signals in the embryo, including the secreted signal Sonic hedgehog
      (Shh), but less is known about LR asymmetries of visceral organs. Here we show
      that Shh also specifies asymmetries in visceral precursors in the zebrafish and
      that cardiac and visceral sidedness are independent. The transcription factors
      fli-1 and Nkx-2.5 are expressed asymmetrically in the precardiac mesoderm and
      subsequently in the heart; an Eph receptor, rtk2, and an adhesion protein, DM
      GRASP, mark early asymmetries in visceral endoderm. Misexpression of shh mRNA, or
      a dominant negative form of protein kinase A, on the right side reverses the
      expression of these asymmetries in precursors of both the heart and the viscera.
      Reversals in the heart and gut are uncoordinated, suggesting that each organ
      interprets the signal independently. Misexpression of Bone Morphogenetic Protein
      (BMP4) on the right side reverses the heart, but visceral organs are unaffected,
      consistent with a function for BMPs locally in the heart field. Zebrafish mutants
      with midline defects show independent reversals of cardiac and visceral
      laterality. Thus, hh signals influence the development of multiple organ
      asymmetries in zebrafish and different organs appear to respond to a central
      cascade of midline signaling independently, which in the heart involves BMP4.

PMID- 10357892
TI  - Differential distribution of retinoic acid synthesis in the chicken embryo as
      determined by immunolocalization of the retinoic acid synthetic enzyme, RALDH-2.
AB  - Retinaldehyde dehydrogenase type 2 (RALDH-2) is a major retinoic acid generating
      enzyme in the early embryo. Here we report the immunolocalization of this enzyme
      (RALDH-2-IR) in stage 6-29 chicken embryos; we also show that tissues that
      exhibit strong RALDH-2-IR in the embryo contain RALDH-2 and synthesize retinoic
      acid. RALDH-2-IR indicates dynamic and discrete patterns of retinoic acid
      synthesis in the embryo, particularly within the somitic mesoderm, lateral
      mesoderm, kidney, heart, and spinal motor neurons. Prior to somitogenesis, RALDH
      2-IR is present in the paraxial mesoderm with a rostral boundary at the level of
      the presumptive first somite; as the somites form, they exhibit strong RALDH-2
      IR. Cervical presomitic mesoderm exhibits RALDH-2-IR but thoracic presomitic
      mesoderm does not. Neural crest cells do not express detectable levels of RALDH
      2, but migrating crest cells are associated with RALDH-2 expressing mesoderm. The
      developing limb mesoderm expresses little RALDH-2-IR; however, RALDH-2-IR is
      strongly expressed in tissues adjacent to the limb. The most lateral, earliest
      projecting motor neurons at all levels of the spinal cord exhibit RALDH-2-IR.
      Subsequently, many additional motor neurons in the brachial and lumbar cord
      regions express RALDH-2-IR. Motor neuronal expression of RALDH-2-IR is present in
      the growing axons as they extend to the periphery, indicating a potential role of
      retinoic acid in nerve influences on peripheral differentiation. With the
      exception of a transient expression in the facial/vestibulocochlear nucleus,
      cranial motor neurons do not express detectable levels of RALDH-2-IR.

PMID- 10357893
TI  - Expression and genetic interaction of transcription factors GATA-2 and GATA-3
      during development of the mouse central nervous system.
AB  - Here we examine the expression of transcription factors GATA-2 and GATA-3 during
      early stages of embryonic development in the central nervous system (CNS) of the
      mouse. GATA-2 is expressed as early as 9 dpc in the hindbrain, in ventral
      rhombomere 4, and transiently in ventral rhombomere 2 (r2). From 9.5 to 11.5 dpc,
      activation of the gene spreads to many sites of early neuronal differentiation,
      such as the olfactory bulbs, the pretectum, and the oculomotor nucleus in the
      midbrain, a thin stripe of cells lining the floor plate from the mesencephalon to
      the cervical spinal cord and a ventral column of cells spanning the neural tube
      from rostral hindbrain and including motor neuron as well as ventral interneuron
      precursors. GATA-3 is expressed in a pattern very similar to that of GATA-2.
      Distinguishing features are the lack of expression in r2 at 9 dpc and a slight
      delay in its activation. In addition, GATA-2 is activated in both the ventricular
      and the subventricular zones of the neural tube, whereas GATA-3 is restricted
      mainly to the subventricular zone. Expression analyses performed on GATA-2 -/-
      mouse embryos between E9.5 and 10.5 dpc established that: (i) the expression of
      GATA-3 in the developing CNS of the mouse embryo is dependent on the presence of
      GATA-2 and (ii) loss of GATA-2 leads to severe defects in neurogenesis, which
      strongly suggests that GATA-2 is involved, as in hematopoiesis, in the
      maintenance of the pool of ventral neuronal progenitors.

PMID- 10357894
TI  - alyron, an insertional mutation affecting early neural crest development in
      zebrafish.
AB  - alyronz12 (aln) is a recessive lethal mutation that affects early stages of
      neural crest development in the zebrafish. alyron appears to be an insertional
      mutation as the mutation was generated following microinjection of plasmid DNA
      into one-cell embryos and the stably integrated transgenic sequences are closely
      linked to the mutation. The insertion site harbors multiple copies of the plasmid
      sequence that have experienced complex rearrangements. Host-insert junction
      fragments have been molecularly cloned and host sequences adjacent to the
      transgene have been used to map the mutation to the distal arm of linkage group
      15. alyron function is required cell-autonomously in the neural crest lineage.
      alyron mutants have a severe but not complete deficit of premigratory neural
      crest as judged by reduced expression of several markers associated with early
      stages of neural crest development. Lack of premigratory neural crest is likely
      to account for the two most conspicuous characteristics of alyron mutants: the
      absence of body pigmentation and the inability to affect blood circulation. The
      neural crest phenotype of alyron mutants resembles that observed in mouse mutants
      that lack Pax-3 or both Wnt-1 and Wnt-3a function, and expression of the
      zebrafish homologues of these genes is greatly reduced in the dorsal neural keels
      of alyron mutants. In contrast, ventral neural keel identity appears unaffected.
      Given our findings that the mutation is unlinked to pax or wnt genes that have
      been described in the zebrafish, we propose that alyron is a novel gene function
      required for the specification and/or proliferative expansion of neural crest
      progenitors.

PMID- 10357895
TI  - Notch-mediated segmentation and growth control of the Drosophila leg.
AB  - The possession of segmented appendages is a defining characteristic of the
      arthropods. By analyzing both loss-of-function and ectopic expression
      experiments, we show that the Notch signaling pathway plays a fundamental role in
      the segmentation and growth of the Drosophila leg. Local activation of Notch is
      necessary and sufficient to promote the formation of joints between segments.
      This segmentation process requires the participation of the Notch ligands,
      Serrate and Delta, as well as Fringe. These three proteins are each expressed in
      the developing leg and antennal imaginal discs in a segmentally repeated pattern
      that is regulated downstream of the action of Wingless and Decapentaplegic. Our
      studies further show that Notch activation is both necessary and sufficient to
      promote leg growth. We also identify target genes regulated both positively and
      negatively downstream of Notch signaling that are required for normal leg
      development. Together, these observations outline a regulatory hierarchy for the
      segmentation and growth of the leg. The Notch pathway is also deployed for
      segmentation during vertebrate somitogenesis, which raises the possibility of a
      common origin for the segmentation of these distinct tissues.

PMID- 10357896
TI  - Interactions between the foot and the head patterning systems in Hydra vulgaris.
AB  - The Cnidarian, hydra, is an appealing model system for studying the basic
      processes underlying pattern formation. Classical studies have elucidated much
      basic information regarding the role of development gradients, and theoretical
      models have been quite successful at describing experimental results. However,
      most experiments and computer simulations have dealt with isolated patterning
      events such as the dynamics of head regeneration. More global events such as
      interactions among the head, bud, and foot patterning systems have not been
      extensively addressed. The characterization of monoclonal antibodies with
      position-specific labeling patterns and the recent cloning and characterization
      of genes expressed in position-specific manners now provide the tools for
      investigating global interactions between patterning systems. In particular,
      changes in the axial positional value gradient may be monitored in response to
      experimental perturbation. Rather than studying isolated patterning events, this
      approach allows us to study patterning over the entire animal. The studies
      reported here focus on interactions between the foot and the head patterning
      systems in Hydra vulgaris following induction of a foot in close proximity to a
      head, axial grafting of a foot closer to the head, or doubling the amount of
      basal tissue by lateral grafting of an additional peduncle-foot onto host
      animals. Resulting positional value changes as monitored by antigen (TS19) and
      gene (ks1 and CnNK-2) expression were assessed in the foot, head, and intervening
      tissue. The results of the experiments indicate that positional values changed
      rapidly, in a matter of hours, and that there were reciprocal interactions
      between the foot and the head patterning systems. Theoretical interpretations of
      the results in the form of computer simulations based on the reaction-diffusion
      model are presented and predict many, but not all, of the experimental
      observations. Since the lateral grafting experiment cannot, at present, be
      simulated, it is discussed in light of what has been learned from the axial
      grafting experiments and their simulations.

PMID- 10357897
TI  - Dystonin-deficient mice exhibit an intrinsic muscle weakness and an instability
      of skeletal muscle cytoarchitecture.
AB  - Dystonia musculorum (dt) was originally described as a hereditary sensory
      neurodegeneration syndrome of the mouse. The gene defective in dt encodes a
      cytoskeletal linker protein, dystonin, that is essential for maintaining neuronal
      cytoskeletal integrity. In addition to the nervous system, dystonin is expressed
      in a variety of other tissues, including muscle. We now show that dystonin cross
      links actin and desmin filaments and that its levels are increased during
      myogenesis, coinciding with the progressive reorganization of the intermediate
      filament network. A disorganization of cytoarchitecture in skeletal muscle from
      dt/dt mice was observed in ultrastructural studies. Myoblasts from dt/dt mice
      fused to form myotubes in culture; however, terminally differentiated myotubes
      contained incompletely assembled myofibrils. Another feature observed in dt/dt
      myotubes in culture and in skeletal muscle in situ was an accumulation and
      abnormal distribution of mitochondria. The diaphragm muscle from dt/dt mice was
      weak in isometric contractility measurements in vitro and was susceptible to
      contraction-induced sarcolemmal damage. Altogether, our data indicate that
      dystonin is a cross-linker of actin and desmin filaments in muscle and that it is
      essential for establishing and maintaining proper cytoarchitecture in mature
      muscle.

PMID- 10357898
TI  - Developmental morphology of the head mesoderm and reevaluation of segmental
      theories of the vertebrate head: evidence from embryos of an agnathan vertebrate,
      Lampetra japonica.
AB  - Due to the peculiar morphology of its preotic head, lampreys have long been
      treated as an intermediate animal which links amphioxus and gnathostomes. To
      reevaluate the segmental theory of classical comparative embryology, mesodermal
      development was observed in embryos of a lamprey, Lampetra japonica, by scanning
      electron microscopy and immunohistochemistry. Signs of segmentation are visible
      in future postotic somites at an early neurula stage, whereas the rostral
      mesoderm is unsegmented and rostromedially confluent with the prechordal plate.
      The premandibular and mandibular mesoderm develop from the prechordal plate in a
      caudal to rostral direction and can be called the preaxial mesoderm as opposed to
      the caudally developing gastral mesoderm. With the exception of the premandibular
      mesoderm, the head mesodermal sheet is secondarily regionalized by the otocyst
      and pharyngeal pouches into the mandibular mesoderm, hyoid mesoderm, and somite
      0. The head mesodermal components never develop into cephalic myotomes, but the
      latter develop only from postotic somites. These results show that the lamprey
      embryo shows a typical vertebrate phylotype and that the basic mesodermal
      configuration of vertebrates already existed prior to the split of agnatha
      gnathostomata; lamprey does not represent an intermediate state between amphioxus
      and gnathostomes. Unlike interpretations of theories of head segmentation that
      the mesodermal segments are primarily equivalent along the axis, there is no
      evidence in vertebrate embryos for the presence of preotic myotomes. We conclude
      that mesomere-based theories of head metamerism are inappropriate and that the
      formulated vertebrate head should possess the distinction between primarily
      unsegmented head mesoderm which includes preaxial components at least in part and
      somites in the trunk which are shared in all the known vertebrate embryos as the
      vertebrate phylotype.

PMID- 10357899
TI  - Xenopus laevis egg jelly contains small proteins that are essential to
      fertilization.
AB  - The eggs of Xenopus laevis are surrounded by investment layers of egg jelly that
      interact with the sperm immediately prior to fertilization. Components of these
      egg jelly layers are necessary for the fertilization of the egg by incoming
      sperm. Eggs which are stripped of their jelly layers are refractile to
      fertilization by sperm, but the addition of solubilized jelly promotes
      fertilization. We have shown previously that the egg jelly layers are composed of
      a fibrous network of glycoconjugates which loosely hold smaller diffusible
      components. Extracts of these diffusible components were prepared by incubation
      of freshly ovulated eggs in high-salt buffers for 12 h at 4 degrees C. This
      diffusible component extract, when incubated with sperm, promoted the sperm's
      ability to fertilize dejellied eggs in a dose-dependent manner. In contrast, the
      high-molecular-weight "structural" glycoconjugates of jelly that remain after
      extraction of the diffusible components did not increase fertilization efficiency
      of dejellied eggs nor did nonspecific proteins, carbohydrate polymers, or organic
      polymers. The diffusible components, analyzed by SDS-PAGE, consisted of a mixture
      of proteins from 4 to 180 kDa. The protein responsible for fertilization rescue
      appeared to be <50 kDa and appeared to self-aggregate or to bind to larger
      proteins. This protein component was required during sperm binding to the egg,
      its action required an intact egg vitelline envelope, and its action was
      independent of large soluble polymers such as Ficoll.

PMID- 10357900
TI  - NT-3, like NGF, is required for survival of sympathetic neurons, but not their
      precursors.
AB  - Superior cervical ganglia of postnatal mice with a targeted disruption of the
      gene for neurotrophin-3 have 50% fewer neurons than those of wild-type mice. In
      culture, neurotrophin-3 increases the survival of proliferating sympathetic
      precursors. Both precursor death (W. ElShamy et al., 1996, Development 122, 491
      500) and, more recently, neuronal death (S. Wyatt et al., 1997, EMBO J. 16, 3115
      3123) have been described in mice lacking NT-3. Consistent with the second
      report, we found that, in vivo, neurogenesis and precursor survival were
      unaffected by the absence of neurotrophin-3 but neuronal survival was compromised
      so that only 50% of the normal number of neurons survived to birth. At the time
      of neuron loss, neurotrophin-3 expression, assayed with a lacZ reporter, was
      detected in sympathetic target tissues and blood vessels, including those along
      which sympathetic axons grow, suggesting it may act as a retrograde neurotrophic
      factor, similar to nerve growth factor. To explore this possibility, we compared
      neuron loss in neurotrophin-3-deficient mice with that in nerve growth factor
      deficient mice and found that neuronal losses occurred at approximately the same
      time in both mutants, but were less severe in mice lacking neurotrophin-3.
      Eliminating one or both neurotrophin-3 alleles in mice that lack nerve growth
      factor does not further reduce sympathetic neuron number in the superior cervical
      ganglion at E17.5 but does alter axon outgrowth and decrease salivary gland
      innervation. Taken together these results suggest that neurotrophin-3 is required
      for survival of some sympathetic neurons that also require nerve growth factor.

PMID- 10357901
TI  - Distribution of lectin binding sites in Xenopus laevis egg jelly.
AB  - Eggs from the anuran Xenopus laevis are surrounded by a thick jelly coat that is
      required during fertilization. The jelly coat contains three morphologically
      distinct layers, designated J1, J2, and J3. We examined the lectin binding
      properties of the individual jelly coat layers as a step in identifying jelly
      glycoproteins that may be essential in fertilization. The reactivity of 31
      lectins with isolated jelly coat layers was examined with enzyme-linked lectin
      assays (ELLAs). Using ELLA we found that most of the lectins tested showed some
      reactivity to all three jelly layers; however, two lectins showed jelly layer
      selectivity. The lectin Maackia amurensis (MAA) reacted only with J1 and J2,
      while the lectin Trichosanthes kirilowii (TKA) reacted only with J2 and J3. Some
      lectins were localized in the jelly coat using confocal microscopy, which
      revealed substantial heterogeneity in lectin binding site distribution among and
      within jelly coat layers. Wheat germ agglutinin (WGA) bound only to the outermost
      region of J3 and produced a thin, but very intense, band of fluorescence at the
      J1/J2 interface while the remainder of J2 stained lightly. The lectin MAA
      produced an intense fluorescence-staining pattern only at the J1/J2 interface.
      Several lectins were also tested for the ability to inhibit fertilization. WGA,
      MAA, and concanavalin A significantly inhibited fertilization and WGA was found
      to block fertilization by preventing sperm from penetrating the jelly. Using
      Western blotting, we identified high-molecular-weight components in J1 and J2
      that may be important in fertilization.

PMID- 10357903
TI  - The planarian HOM/HOX homeobox genes (Plox) expressed along the anteroposterior
      axis.
AB  - In the freshwater planarian Dugesia japonica, five cDNAs for HOM/HOX homeobox
      genes were cloned and sequenced. Together with sequence data on HOM/HOX homeobox
      genes of platyhelminthes deposited in databases, comparison of the deduced amino
      acid sequences revealed that planarians have at least seven HOM/HOX homeobox
      genes, Plox1 to Plox7 (planarian HOM/HOX homeobox genes). Whole-mount in situ
      hybridization and RT-PCR revealed that Plox4 and Plox5 were increasingly
      expressed along a spatial gradient in the posterior region of intact animals.
      During regeneration, Plox5 was expressed only in the posterior region of
      regenerating body pieces, suggesting that the gene is involved in the
      anteroposterior patterning in planarians. Plox5 was not found to be expressed in
      a blastema-specific manner, which contradicts a previous report (J. R. Bayascas,
      E. Castillo, A. M. Munos-Marmol, and E. Salo. Development 124, 141-148, 1997). X
      ray irradiation experiments showed that Plox5 was expressed at least in some
      cells other than neoblasts, but that the induction of Plox5 expression during
      regeneration might require neoblasts.

PMID- 10357904
TI  - POU domain factor Brn-3b is essential for retinal ganglion cell differentiation
      and survival but not for initial cell fate specification.
AB  - While the mammalian retina is well understood at the anatomical and physiological
      levels, little is known about the mechanisms that give rise to the retina's
      highly ordered pattern or its diverse neuronal cell types. Previous
      investigations have shown that gene disruption of the POU-IV class transcription
      factor Brn-3b (Brn-3.2) resulted in the loss of most retinal ganglion cells in
      retinas of postnatal mice. Here, we used lacZ and human placental alkaline
      phosphatase genes knocked into the brn-3b locus to follow the fate of brn-3b
      mutant cells in the developing retina. We found that Brn-3b was not required for
      the initial commitment of retinal ganglion cell fate or for the migration of
      ganglion cells to the ganglion cell layer. However, Brn-3b was essential for the
      normal differentiation of retinal ganglion cells; without it, the cells underwent
      enhanced apoptosis. Retinal ganglion cells lacking brn-3b extended processes at
      the appropriate time in development, but these processes were disorganized,
      resulting in a thinner optic nerve. Explanted retinas from brn-3b-null embryos
      also extended processes when cultured in vitro, but the processes were shorter
      and less bundled than in wild-type retinas. Ultrastructural and marker analyses
      showed that the processes of mutant ganglion cells had dendritic rather than
      axonal features, suggesting that mutant cells formed dendrites in place of axons.
      These results suggest that Brn-3b regulates the activity of genes whose products
      play essential roles in the formation of retinal ganglion cell axons.

PMID- 10357902
TI  - The transition from proliferation to differentiation is delayed in satellite
      cells from mice lacking MyoD.
AB  - Satellite cells from adult rat muscle coexpress proliferating cell nuclear
      antigen and MyoD upon entry into the cell cycle, suggesting that MyoD plays a
      role during the recruitment of satellite cells. Moreover, the finding that muscle
      regeneration is compromised in MyoD-/- mice, has provided evidence for the role
      of MyoD during myogenesis in adult muscle. In order to gain further insight into
      the role of MyoD during myogenesis in the adult, we compared satellite cells from
      MyoD-/- and wildtype mice as they progress through myogenesis in single-myofiber
      cultures and in tissue-dissociated cell cultures (primary cultures). Satellite
      cells undergoing proliferation and differentiation were traced
      immunohistochemically using antibodies against various regulatory proteins. In
      addition, an antibody against the mitogen-activated protein kinases ERK1 and ERK2
      was used to localize the cytoplasm of the fiber-associated satellite cells
      regardless of their ability to express specific myogenic regulatory factor
      proteins. We show that during the initial days in culture the myofibers isolated
      from both the MyoD-/- and the wildtype mice contain the same number of
      proliferating, ERK+ satellite cells. However, the MyoD-/- satellite cells
      continue to proliferate and only a very small number of cells transit into the
      myogenin+ state, whereas the wildtype cells exit the proliferative compartment
      and enter the myogenin+ stage. Analyzing tissue-dissociated cultures of MyoD-/-
      satellite cells, we identified numerous cells whose nuclei were positive for the
      Myf5 protein. In contrast, quantification of Myf5+ cells in the wildtype cultures
      was difficult due to the low level of Myf5 protein present. The Myf5+ cells in
      the MyoD-/- cultures were often positive for desmin, similar to the MyoD+ cells
      in the wildtype cultures. Myogenin+ cells were identified in the MyoD-/- primary
      cultures, but their appearance was delayed compared to the wildtype cells. These
      "delayed" myogenin+ cells can express other differentiation markers such as MEF2A
      and cyclin D3 and fuse into myotubes. Taken together, our studies suggest that
      the presence of MyoD is critical for the normal progression of satellite cells
      into the myogenin+, differentiative state. It is further proposed that the
      Myf5+/MyoD- phenotype may represent the myogenic stem cell compartment which is
      capable of maintaining the myogenic precursor pool in the adult muscle.

PMID- 10357905
TI  - Forced expression of the homeobox-containing gene Pem blocks differentiation of
      embryonic stem cells.
AB  - Similarities in the differentiation of mouse embryos and ES cell embryoid bodies
      suggest that aspects of early mammalian embryogenesis can be studied in ES cell
      embryoid bodies. In an effort to understand the regulation of cellular
      differentiation during early mouse embryogenesis, we altered the expression of
      the Pem homeobox-containing gene in ES cells. Pem is normally expressed in the
      preimplantation embryo and expressed in a lineage-restricted fashion following
      implantation, suggesting a role for Pem in regulating cellular differentiation in
      the early embryo. Here, we show that the forced expression of Pem from the mouse
      Pgk-1 promoter in ES cells blocks the in vitro and in vivo differentiation of the
      cells. In particular, embryoid bodies produced from these Pgk-Pem ES cells do not
      differentiate into primitive endoderm or embryonic ectoderm, which are prominent
      features of early embryoid bodies from normal ES cells. This Pgk-Pem phenotype is
      also different from the null phenotype, as embryoid bodies derived from ES cells
      in which endogenous Pem gene expression has been blocked show a pattern of
      differentiation similar to that of normal ES cells. When the Pgk-Pem ES cells
      were introduced into subcutaneous sites of nude mice, only undifferentiated EC
      like cells were found in the teratomas derived from the injected cells. The Pem
      dependent block of ES cell differentiation appears to be cell autonomous; Pgk-Pem
      ES cells did not differentiate when mixed with normal, differentiating ES cells.
      A block to ES cell differentiation, resulting from the forced expression of Pem,
      can also be produced by the forced expression of the nonhomeodomain region of
      Pem. These studies are consistent with a role for Pem in regulating the
      transition between undifferentiated and differentiated cells of the early mouse
      embryo.

PMID- 10357906
TI  - alpha6 Integrin is regulated with lens cell differentiation by linkage to the
      cytoskeleton and isoform switching.
AB  - The developing chicken embryo lens provides a unique model for examining the
      relationship between alpha6 integrin expression and cell differentiation, since
      multiple stages of differentiation are expressed concurrently at one stage of
      development. We demonstrate that alpha6 integrin is likely to mediate the
      inductive effects of laminin on lens differentiation as well as to function in a
      matrix-independent manner along the cell-cell interfaces of the differentiating
      cortical lens fiber cells. Both alpha6 isoform expression and its linkage to the
      cytoskeleton were regulated in a differentiation-specific manner. The association
      of alpha6 integrin with the Triton-insoluble cytoskeleton increased as the lens
      cells differentiated, reaching its highest levels in the cortical fiber region
      where the lens fiber cells are formed. In this region of the lens alpha6 integrin
      was uniquely localized along the cell-cell borders of the differentiating fiber
      cells, similar to beta1. alpha6beta4, the primary transmembrane protein of
      hemidesmosomes, is also expressed in the lens, but in the absence of
      hemidesmosomes. Differential expression of alpha6A and alpha6B isoforms with lens
      cell differentiation was seen at both the mRNA and the protein levels. RT-PCR
      studies demonstrated that alpha6B was the predominant isoform expressed both
      early in development, embryonic day 4, and in the epithelial regions of the day
      10 embryonic lens. Isoform switching, with alpha6A now the predominant isoform,
      occurred in the fiber cell zones. Immunoprecipitation studies showed that
      alpha6B, which is characteristic of undifferentiated cells, was expressed by the
      lens epithelial cells but was dramatically reduced in the lens fiber zones.
      Expression of alpha6B began to drop as the cells initiated their differentiation
      and then dropped precipitously in the cortical fiber zone. In contrast,
      expression of the alpha6A isoform remained high until the cells became terminally
      differentiated. alpha6A was the predominant isoform expressed in the cortical
      fiber region. The down-regulation of alpha6B relative to alpha6A provides a
      developmental switch in the process of lens fiber cell differentiation.

PMID- 10357907
TI  - Influence of 5-fluorouracil on colonic healing and expression of transforming
      growth factor-beta 1.
AB  - BACKGROUND: Administration of chemotherapeutic agents in the immediate
      postoperative period may have beneficial effects by decreasing local cancer
      recurrence rates, but this must be weighed against possible impairment of wound
      healing. Since local expression of transforming growth factor-beta1 (TGF-beta1)
      is normally upreglated following creation of experimental colonic anastomoses,
      this study examines the effects of 5-fluorouracil (5-FU) on colonic healing and
      on the local expression of TGF-beta1. MATERIALS AND METHODS: Forty-eight male
      Sprague-Dawley rats underwent transection of the descending colon with primary
      anastomosis and were then randomly assigned to receive either intraperitoneal 5
      FU (20 mg/kg/day) or saline (SAL). On Postoperative Days (PODs) 3, 5, and 7,
      bursting pressure (BP, mm Hg) and bursting energy (BE, mm Hg xs) were determined
      in situ. Anastomotic and nonoperated segments of colon were harvested and
      analyzed using the semiquantitative reverse transcriptase-polymerase chain
      reaction to determine the relative expression of TGF-beta1 normalized to that of
      a constitutive gene. RESULTS: Progressive increases in BP and BE were observed in
      both the 5-FU and the SAL groups, across the time course examined. Overall, these
      measures were decreased in the 5-FU groups compared to SAL, significantly so on
      PODs 5 and 7; BP, 127.8 +/- 7.6 vs 161.1 +/- 7.2 and 139.9 +/- 10.9 vs 186.0 +/-
      8.6; BE, 1093.6 +/- 190.0 vs 2207.9 +/- 308.2, and 1518.5 +/- 326.5 vs 3279.3 +/-
      225.7, respectively. Anastomotic TGF-beta1 expression also increased
      progressively in both groups over the postoperative time course. Expression in
      the 5-FU group, however, was significantly decreased compared to that in the SAL
      group on POD 3; 0.42 +/- 0.05 vs 0.84 +/- 0.04. Interestingly, this preceded the
      reduction in BP and BE in the 5-FU group on PODs 5 and 7. TGF-beta1 expression in
      nonoperated colonic segments did not change during the time points studied or in
      response to 5-FU administration. CONCLUSIONS: Wound healing following a colonic
      anastomosis is associated with local increases in TGF-beta1 expression, which in
      turn is diminished by the administration of 5-FU. If this deleterious effect on
      wound healing could be counteracted, then chemotherapy administration in the
      immediate postoperative period may become safer.

PMID- 10357908
TI  - Fibroblast response to hypoxia: the relationship between angiogenesis and matrix
      regulation.
AB  - A number of studies have demonstrated the critical role of angiogenesis for
      successful wound repair in the surgical patient. Vascular disruption from tissue
      injury due to trauma or surgery leads to a hypoxic zone in the healing wound. In
      this dynamic process, angiogenesis is vital for the delivery of oxygen,
      nutrients, and growth factors necessary to initiate the synthetic processes of
      wound healing. Fibroblasts, invading the wound early in the healing process, are
      involved in extracellular matrix (ECM) deposition as well as wound contraction.
      However, the exact mechanisms by which important genes are regulated remain
      unknown. In order to examine these processes, we studied the effects of hypoxia
      on fibroblasts for the expression of VEGF, type IalphaI collagen, and matrix
      metalloproteinase-3, three genes essential for the regulation of angiogenesis,
      ECM deposition, and ECM degradation in wound healing. Primary cell cultures of
      normal human dermal fibroblasts (NHDFs) were placed in hypoxia for varying
      periods of time. Northern blot hybridization was performed with [alpha32P]dCTP
      labeled cDNA probes for VEGF, type IalphaI collagen, and MMP-3. The results
      demonstrated a time-dependent VEGF mRNA upregulation (470% of baseline) under
      hypoxia. Type IalphaI collagen increased (170% of baseline) at 24 h, but was then
      abruptly downregulated to 3.8% of baseline at 48 h. MMP-3 was incrementally
      downregulated to 2.2% of baseline at 48 h. These experiments focused on the
      effect of hypoxia on genes thought to play a role in wound repair. VEGF
      upregulation in the hypoxic microenvironment of the early wound may serve to
      stimulate angiogenesis. Type IalphaI collagen, though upregulated early on, was
      abruptly downregulated at 48 h. This downregulation may reflect the in vivo
      requirement for angiogenesis to deliver oxygen for successful hydroxylation and
      collagen synthesis in the wound. MMP-3, also downregulated at 48 h, may also
      implicate the need for angiogenesis. These data support the theory that hypoxia
      driven angiogenesis is critical for ECM formation and remodeling in successful
      soft tissue repair. Furthermore, they may represent the role of hypoxia as an
      important regulator to efficiently balance these complex processes in the healing
      wound.

PMID- 10357909
TI  - Serum lysozyme activity can differentiate infection from rejection in organ
      transplant recipients.
AB  - BACKGROUND: The presentation of infection in immunocompromised patients can be
      subtle. Patients often undergo extensive testing and empiric treatment for
      rejection and infection while awaiting the results of the biopsy and culture
      results. Delay in diagnosis of either entity can result in a worse clinical
      outcome. Lysozyme activity has been found to be both a sensitive and a specific
      marker for infection in laboratory animals and trauma patients. Our goal was to
      determine whether lysozyme activity could serve as a reliable marker for
      infection in immunocompromised organ transplant recipients. METHODS: Transplant
      recipients from three clinical categories were enrolled in this study. Group 1 (n
      = 16) were patients hospitalized for sepsis (culture-positive), and Group 2 (n =
      13) for biopsy-proven rejection. Group 3 (n = 51) were recipients who had routine
      blood sampling in the clinic. In Groups 1 and 2, blood was collected within 24 h
      of hospital admission and centrifuged, and serum samples were stored at 80
      degrees C until processing. Lysozyme activity was assayed by turbidimetric
      measurement on a sample of a standard suspension (0.15 mg/ml) of Micrococcus
      lysodeikticus in buffer using a spectrophotometer to read the optical density at
      450 nm. The lysozyme activity level was then determined by the measuring activity
      at 1 min subtracted from activity at 4 min. White blood cell count was determined
      by using a flow cytometer. Statistical comparisons between groups were made using
      paired Student's t test. RESULTS: Serum lysozyme was found to be significantly
      elevated in Group 1; the mean level of activity was 60.1 +/- 13 (P < 0.05)
      compared to the level of activity in Group 2, mean 41.1 +/- 11, and Group 3, mean
      40.8 +/- 13. A level of 45 units of activity/ml of serum or above indicated
      infection and not rejection in the patients admitted to the hospital.
      CONCLUSIONS: These findings indicate that the lysozyme activity assay appears to
      be useful in differentiating infection from rejection in transplant recipients.

PMID- 10357910
TI  - Meta-analysis of sentinel lymph node biopsy in breast cancer.
AB  - BACKGROUND: Sentinel lymph node biopsy (SLNB) is a minimally invasive way to
      diagnose axillary lymph node (ALN) metastases in breast cancer. The most
      important features are ability to identify the SLN (I.D. rate), how often the SLN
      and ALN pathology match (concordance), and how often the SLN is negative for
      cancer when the ALNs are positive (false negative). Technique and patient
      criteria for SLNB vary among studies. This study performed meta-analysis of
      published studies to determine the I.D., concordance, and false negative rate (1)
      overall and for (2) both blue dye and radiocolloid, (3) the injection method, (3)
      palpable and nonpalpable ALNs, and (4) invasive and in situ disease. METHODS:
      Inclusion criteria were patients with breast cancer who had SLNB followed by ALN
      dissection with H&E staining. Meta-analysis was performed using analysis of
      variance with each observation weighted inversely to its variance. P < 0.05 was
      considered significant. RESULTS: Eleven studies (n = 912) met the inclusion
      criteria. Overall, 762 (84%) SLNs were identified, concordance was 747/762 (98%),
      and 15/296 (5%) were falsely negative. Highest I.D. rates (P < 0.05) were
      reported with albumin radiocolloid or dye + radiocolloid (97 and 94%,
      respectively), with injection around an intact tumor (96%), with invasive cancer
      (95%), and in the clinically negative axilla (96%). Concordance and false
      negative rates did not vary. CONCLUSIONS: The SLN can be identified in over 97%
      of patients if certain techniques and inclusion criteria are used. SLNB reflects
      the status of the axilla in 97% of cases and has a 5% false negative rate.

PMID- 10357911
TI  - Sodium salicylate inhibits macrophage TNF-alpha production and alters MAPK
      activation.
AB  - INTRODUCTION: Transcriptional activation of the TNF-alpha gene in LPS-stimulated
      macrophages is dependent upon nuclear factor kappa-B (NF-kappaB) activity.
      Salicylates may interfere with NF-kappaB activity through a MAPK (mitogen
      activated protein kinase)-dependent process. These studies investigate the
      effects of sodium salicylate (NaSal) on TNF-alpha production and MAPK activation
      in macrophages. METHODS: Rat peritoneal macrophages were pretreated or not with
      sodium salicylate or ibuprofen for 1 h and then stimulated with 100 ng/ml LPS.
      Six hours following stimulation, cell viability was assessed by MTT assay. At
      specified time intervals after LPS stimulation, supernatant TNF-alpha was
      measured by ELISA. Western blots of cell lysates were performed for analysis of
      total and activated (phosphorylated) MAPKs. RESULTS: Salicylate and LPS, alone or
      combined, did not significantly alter macrophage viability. Salicylate, but not
      ibuprofen, significantly reduced TNF-alpha production in LPS-stimulated
      macrophages. LPS-stimulated activation of ERK and SAPK/JNK was inhibited by NaSal
      pretreatment. NaSal treatment of macrophages activated p38 MAPK independent of
      LPS stimulation. Pretreatment of samples with the specific p38 MAPK inhibitor,
      SB203580, did not significantly alter TNF-alpha production in either LPS or NaSal
      and LPS-treated samples. CONCLUSIONS: Salicylates alter MAPK signaling and
      suppress TNF-alpha production in LPS-stimulated macrophages. Salicylate-induced
      control of inflammatory mediator production in macrophages may, in part, underlie
      the clinically significant anti-inflammatory effects of these compounds.

PMID- 10357912
TI  - Adenovirus-mediated gene transfer in the midgestation fetal mouse.
AB  - BACKGROUND: The development of strategies for gene transfer in utero will make
      possible the amelioration, and eventually the cure, of genetic diseases
      associated with pre- and postnatal morbidity and mortality. We have developed a
      murine model for in utero, intrahepatic, adenovirus-mediated gene transfer in Day
      15 fetuses and compared the level and distribution of luciferase reporter gene
      expression in newborns with those observed in adult animals injected
      intravenously. MATERIAL AND METHODS: CD-1 fetuses underwent intrahepatic
      injection on Day 15 of gestation with 1 x 10(7) particle-forming units (PFU) of
      an E1- and E3-deleted recombinant adenovirus containing the luciferase reporter
      gene or with normal saline. At birth, pups were euthanized, and the brain, heart,
      intestine, liver, lungs, and spleen harvested and analyzed for luciferase
      activity. RESULTS: Two adenovirus-injected litters proceeded to term and one
      female aborted. Tissues from 10 newborn mice in the experimental group and 5
      newborns in the control group were analyzed; tissues from the remaining newborns
      were reserved for other studies. High-level luciferase expression was detected in
      all adenovirus-injected newborn livers. Lower levels of luciferase activity were
      detected in distant organs. Hepatic toxicity as determined by serum transaminase
      elevations was observed in adult, but not in newborn mice previously injected
      with the adeno-luciferase virus. CONCLUSIONS: In utero intrahepatic gene delivery
      with adenoviral vectors in the developing murine fetus is feasible and produces
      high-level gene expression. These studies suggest that viral and nonviral gene
      delivery vectors may be useful in the development of future approaches to
      prenatal treatment of genetic disorders.

PMID- 10357913
TI  - AsGM1+ NK cells prevent metastasis of invading LD-MCA-38 tumor cells in the nude
      mouse.
AB  - BACKGROUND: Although the liver is a potent tumor cell killing organ it is
      frequently the site of lethal metastases often signifying the endstage for
      patients with colorectal cancers. Enhancing hepatic-associated immunity remains
      elusive until the interactions among hepatic nonparenchymal cells (NPC) are
      deciphered. We sought to modulate the cellular components of the hepatic immune
      system of mice with anti-NK and anti-T-cell-neutralizing antibodies in order to
      determine the cell type most efficacious in preventing liver metastasis.
      MATERIALS AND METHODS: Liver-derived murine colon adenocarcinoma (LD-MCA-38)
      cells were injected into the ileocolic vein (ICV) of immunocompetent and
      immunodeficient C57BL/6 mice. Mice were pretreated 1 day prior to tumor cell
      injection with one of three antibodies: anti-AsGM1, Anti-NK1.1, or Anti-Thy1.2.
      On Day 21 laparotomy was performed to determine the extent of hepatic tumor foci.
      The number of hepatic tumor foci was recorded and compared by the Wilcoxon rank
      sum test. RESULTS: Mice pretreated with anti-AsGM1 or Anti-NK1.1 developed a
      massive increase in the number of hepatic tumor foci and decreased survival
      compared to the control treated mice. Pretreatment with anti-Thy1.2 antibody
      resulted in a significant decrease in the number of hepatic tumor foci. LD-MCA-38
      tumor cells were unable to colonize the liver of C57BL/6 athymic nude mice;
      however, anti-AsGM1 antibody abolished this antimetastatic effect. There was no
      difference in the extent of hepatic metastasis and survival between
      immunodeficient C57BL/6 bg/bg and their conventional littermates bg/+.
      CONCLUSION: AsGM1+ NK cells exhibit a significant antitumor response in the
      absence of T-cells. The concept of stimulating NK cell activity and suppressing T
      cell function may enhance liver-associated immunity and serve as a deterrent for
      blood-borne tumor cells metastasizing to the liver.

PMID- 10357914
TI  - Matrix metalloproteinase inhibition suppresses MMP-2 activity and activation of
      PANC-1 cells in vitro.
AB  - BACKGROUND: We have shown previously that the metalloproteinase inhibitor, BB-94,
      prolongs survival and attenuates MMP-2 activity in a murine model of pancreatic
      cancer. The purpose of this study was to determine the effect of BB-94 on the
      activity and activation of MMP-2 by PANC-1 cells in vitro. MATERIALS AND METHODS:
      The poorly differentiated pancreatic cancer cell line PANC-1 was stimulated in
      vitro with the phorbol ester PMA (20 nM) and grown in the presence of increasing
      doses of BB-94 (0, 40, 200, and 400 ng/ml) for 24 h. Activation of MMP-2 was
      determined by gel zymography. In a separate experiment detailing the effects of
      BB-94 on MMP-2 activity, PANC cells were stimulated for 24 h with PMA and run out
      on four separate zymograms, each incubated in the previously noted concentrations
      of BB-94. Using densitometry, band intensity on all gels was determined and
      compared for each concentration of BB-94. The Matrigel assay was used to
      determine BB-94's effect on the invasive potential of PANC cells at the
      previously studied concentrations. The presence of MT-MMP (a putative component
      of MMP-2 activation) was confirmed using Western blot in each group. RESULTS: BB
      94 inhibited the conversion of latent to active MMP-2 in a dose-dependent
      fashion. BB-94 also inhibited the activity of MMP-2 when run out on gel zymograms
      incubated with increasing concentrations of BB-94. Decreased activity and
      activation of MMP-2 by BB-94 were manifested by a significant reduction in the
      invasive potential of PANC as determined by the Matrigel assay. MT-MMP was
      universally present in each study group. CONCLUSIONS: The previously described
      salutary effects of MMP blockade in mice implanted with pancreatic cancer can be
      explained in vitro by a dose-dependent diminution of MMP-2 activity and
      activation in PANC cells exposed to BB-94.

PMID- 10357915
TI  - Stable gene expression with VSV-G pseudotyped-retrovirus vector in the rat liver.
AB  - BACKGROUND: Pseudotyped-retrovirus-mediated gene transfer to the regenerating rat
      liver was investigated in vivo and the findings were compared with those for
      retrovirus-mediated gene transfer. MATERIALS AND METHODS: Four weeks prior to
      gene transfer, the spleen was transpositioned to the left subcutaneous position
      to develop a port-splenic shunt. Twenty-four hours after a partial hepatectomy
      (68%) was performed, the liver was perfused in situ and kept in contact with
      either a pseudotyped-retrovirus vector encoding LacZ (7 x 10(7) cfu/ml, Group 1)
      or a retrovirus vector encoding LacZ (1 x 10(4) cfu/ml, Group 2) for 30 min. The
      animals were sacrificed at various points after gene transfer, and X-gal
      staining, reversed polymerase chain reaction (RT-PCR), and ONPG assay were
      performed to detect the transferred LacZ cDNA. RESULTS: In X-gal staining, the
      transferred LacZ cDNA started to show a strong beta-galactosidase activity in 30
      to 50% of the hepatocytes at 3 days after gene transfer. Positive staining
      continued to be recognized until 28 days with a slight decrease in its intensity
      thereafter. On the other hand, Group 2 animals showed weak staining, which was
      observed in about 10 to 15% of the hepatocytes from 3 days after gene transfer
      and then decreased thereafter. In RT-PCR, positive mRNA of LacZ was detected
      constitutively until 28 days after gene transfer in Group 1, whereas two-thirds
      of the samples showed a negative band in Groups 2 at 3 days after gene transfer.
      CONCLUSION: In conclusion, the pseudotyped-retrovirus vector was useful in
      establishing a stable and strong expression of the in vivo gene transfer, while
      targeting the regenerating liver.

PMID- 10357916
TI  - Does upregulation of inducible nitric oxide synthase (iNOS) render the stomach
      more susceptible to damage?
AB  - Nitric oxide from constitutive nitric oxide synthase (NOS) augments gastric
      mucosal blood flow and is important in mucosal defense. However, the function of
      the inducible isoform of NOS (iNOS) in the gastric mucosa remains to be fully
      elucidated. This study was done to examine the role of iNOS in gastric mucosal
      blood flow and gastric injury following endotoxemia. Conscious rats were given
      intraperitoneal saline or lipopolysaccharide (LPS, 5 or 20 mg/kg). Five hours
      later, rats were anesthetized, a laparotomy made, gastric fluid aspirated, and 3
      ml of 20% ethanol introduced into the forestomach. Rats were sacrificed 10 min
      later for assessment of macroscopic injury (mm2) to the gastric mucosa. Other
      rats did not receive 20% ethanol, but instead, gastric mucosal blood flow was
      determined with laser Doppler, followed by sacrifice and removal of stomachs for
      determination of gastric mucosal iNOS immunoreactivity (Western immunoblot).
      Lipopolysaccharide dose dependently increased gastric injury, decreased gastric
      mucosal blood flow, and increased gastric mucosal iNOS immunoreactivity compared
      to rats receiving saline. In additional experiments and using a similar protocol,
      intraperitoneal administration of aminoguanidine (45 mg/kg), an iNOS inhibitor,
      reversed lipopolysaccharide-induced gastric injury and restored gastric mucosal
      blood flow to baseline, whereas the nonselective NOS inhibitor, NG-nitro-l
      arginine methyl ester (5 mg/kg) did not. Taken together, these data suggest that
      upregulation of iNOS is in part responsible for the detrimental effects of LPS on
      the gastric mucosa, possibly from a reduction in gastric mucosal blood flow.

PMID- 10357917
TI  - Decreased alpha-adrenergic response in the intestinal microcirculation after "two
      hit" hemorrhage/resuscitation and bacteremia.
AB  - BACKGROUND: The two-hit theory of multiple organ dysfunction syndrome proposes
      that an initial insult primes the host for an altered response to subsequent
      stimuli. We have previously documented enhanced dilator tone in the small
      intestine after a two-hit insult; however, the effects on vasoconstrictor
      function are unknown. We postulated that prior hemorrhage and resuscitation
      followed by bacteremia would alter microvascular responsiveness to alpha
      adrenergic stimulation. METHODS: Male Sprague-Dawley rats underwent fixed-volume
      hemorrhage with resuscitation (H/R) or sham procedure (Sham). At 24 or 72 h, in
      vivo videomicroscopy of the small intestine was performed (inflow A1 and
      premucosal A3 arterioles). Constrictor function was assessed by topical
      application of norepinephrine (NE; 10(-8)-10(-6) M) before and 1 h after
      intravenous Escherichia coli or saline. RESULTS: Sham, 24 or 72 h H/R, and E.
      coli alone produced no significant changes in A1 or A3 response to NE. Sequential
      H/R + E. coli resulted in decreased constrictor response in both A1 (72 h H/R +
      E. coli-38% from baseline vs Sham - 54%, P < 0.05) and A3 arterioles (-8% vs 
      51%, P < 0.05) at high doses of NE (10(-6) M). CONCLUSIONS: Prior H/R primes the
      intestinal microvasculature for an altered response during a subsequent stress
      and these effects persist for up to 72 h following H/R. Sequential insults in
      this two-hit model caused marked hyporesponsiveness to NE. These alterations in
      control of microvascular tone might contribute to the hemodynamic compromise of
      sepsis, impair mucosal blood flow, and contribute to the development of MODS.

PMID- 10357918
TI  - Nonsteroidal anti-inflammatory drugs attenuate epidermal growth factor-induced
      proliferation independent of prostaglandin synthesis inhibition.
AB  - BACKGROUND: The mechanism(s) whereby nonsteroidal anti-inflammatory drugs
      (NSAIDs) attenuate colorectal tumor growth remains poorly understood. This study
      determined if NSAIDs decreased epidermal growth factor (EGF)-induced
      proliferation in human colonic tumor (Caco-2) cells and whether this process
      involved the inhibition of prostaglandin (PG) synthesis. METHODS: Caco-2 cells
      were serum-starved (48 h) and subsequently treated (48 h) with either serum-free
      media or EGF (10 ng/ml) +/- physiologic and noninjurious (as determined by LDH
      release) concentrations of aspirin, indomethacin, and ibuprofen. PG synthesis was
      measured by EIA. Proliferation was quantitated with two assays: cellular protein
      and nucleic acid content. RESULTS: NSAID treatment did not inhibit growth in
      cells treated with only serum-free media. Cells exposed to EGF demonstrated a
      significant increase in PGE2, protein, and nucleic acid. Levels of other
      eicosanoids (PGI2, TXA2) were minimal both before and after EGF treatment.
      Despite varying degrees of PGE2 inhibition, each NSAID group equally attenuated
      EGF-induced protein and nucleic acid synthesis. The correlation between PGE2
      levels and protein (R2 = 0.56) or nucleic acid (R2 = 0.54) was poor. Finally, the
      addition of a physiologically appropriate concentration of exogenous PGE2 failed
      to reverse NSAID-induced growth inhibition. CONCLUSION: These data suggest that
      NSAIDs, independent of PG synthesis inhibition, attenuate EGF-induced
      proliferation in Caco-2 cells. This may provide one explanation for how NSAIDs
      limit colonic neoplasia.

PMID- 10357919
TI  - Lower limb ischemia: phase 1 results of salvage perfusion.
AB  - Revascularization of an ischemic lower extremity is associated with high
      morbidity (20-30%) and perioperative mortality (10-20%) regardless of the mode of
      intervention, surgical or thrombolytic, considered to be due to polymorphonuclear
      (PMN) activation and mediator release. In this study, the safety and feasibility
      of cell-free extracorporeal perfusion of the limb with a solution designed to
      minimize both local and systemic injury was tested. Methods. Patients with severe
      limb ischemia (sensory/motor loss, rest pain/gangrene) were studied prospectively
      by random assignment into the treatment arm (n = 14) or control arm (n = 21).
      Surgical management consisted of restorative procedure, thrombectomy or
      embolectomy (n = 21), or reconstruction (n = 14). Reperfusion of the ischemic
      limb was achieved with hypertonic, hyperoncotic perfusate containing anti
      oxidants delivered via the arterial tree (mean volume 1835 +/- 824 ml) with
      initial venous drainage (mean volume 775 +/- 263 ml) in the restorative group.
      Means were compared by paired t test. Results. No adverse systemic effects were
      detected after limb perfusion (electrolytes, coagulation, platelet function,
      CBC). Rapid lactate wash-out was observed within 30 min of perfusion
      (preperfusion 3.2 +/- 4.1 mM, 30 min postperfusion 0.7 +/- 0.71 mM, P < 0.01).
      Blunting of PMN activation was shown by chemiluminescence (CL) analysis
      (preischemic CL: 0.68 +/- 0.2; 30 min CL: 0.47 +/- 0. 2; P < 0.013). F2
      isoprostanes, a marker of free radical-mediated systemic lipid peroxidation, were
      significantly reduced in patients treated with study perfusion method (70.55 +/-
      39.54 versus control 194.38 +/- 25.24, P < 0.005). Mortality with treatment was
      0/14 versus 5/21 in the control. Complication frequency: MI 0/14 vs 3/21; renal
      0/14 vs 1/21; leg edema 1/14 vs 5/21; amputations 2/14 vs 1/21. Conclusion.
      Modification of limb perfusion in patients with severe limb ischemia, using our
      simple and rapid (15-20 min) method provides beneficial systemic effects.

PMID- 10357920
TI  - Beta cell-specific ablation of target gene using Cre-loxP system in transgenic
      mice.
AB  - Tissue-specific inactivation of a gene using the Cre-loxP system has been used as
      an important tool to define its role in which the inactivation of the gene in
      every cell type results in an embryonic lethality. The expression of Cre
      recombinase (Cre) can be regulated by controlling the timing or spatial
      distribution of Cre expression via tissue-specific promoters, ligand-inducible
      promoters, and ligand-dependent Cre fusion proteins. The rat insulin promoter
      (RIP) has been used in this study to drive the expression of Cre, specifically in
      the beta cells. The Cre coding sequence was ligated with the RIP and the isolated
      RIP-Cre transgene was microinjected into one cell embryo to establish a
      transgenic mouse line. Tissue specificity of the rat insulin promoter was
      demonstrated by reverse transcriptase polymerase chain reaction using total RNA
      from pancreas and other tissues of the RIP-Cre transgenic mice. In addition, the
      efficiency and specificity of RIP was further analyzed by crossbreeding the RIP
      Cre transgenic mice with reporter mice bearing a beta-actin-loxP-CAT-loxP-lacZ
      transgene. In these mice, lacZ is expressed only after excision of the floxed-CAT
      gene by Cre-mediated recombination. Here, we present the data for beta cell
      specific expression of lacZ in the bigenic mice, as proof of concept in a mouse
      model for targeting beta cell-specific gene(s). The RIP-Cre transgenic mice will
      be used as a potential tool for targeting the excision of beta cell-specific
      gene(s) to study their role in islet cell physiology.

PMID- 10357921
TI  - Analysis of the Fas system and Bcl-2 in rat liver allograft rejection.
AB  - BACKGROUND: Apoptosis is involved in the mechanism of cell death observed in
      liver allograft rejection. The liver cells are sensitive to Fas-mediated
      apoptosis; however, little is known about the involvement of the Fas system in
      liver allograft rejection. We used rat models to investigate the expression of
      Fas/Fas ligand and apoptosis-related proteins during liver allograft rejection.
      MATERIALS AND METHODS: DA rats to Lewis, and Lewis to Lewis orthotopic liver
      transplantation were performed; liver samples were collected on days 1, 3, 5, 7,
      and 9 postoperatively (each n = 3). Apoptosis was monitored by TUNEL and electron
      microscopy. The expression of Fas, FasL, bcl-2, and bax was examined at the mRNA
      level and by means of immunohistochemistry. RESULTS: The TUNEL index in the
      allografts and isografts on day 7 was 20.1 +/- 1.5 and 7.7 +/- 2.6/1000 cells,
      respectively. Fas and bax mRNA were constitutively expressed in both of the
      groups. The expression of Fas ligand mRNA in the allografts which rose on day 5
      was 10 times stronger compared to that in the isografts. On the other hand, bcl-2
      mRNA was generally expressed in the isografts while it decreased in the
      allografts. The immunohistochemical analysis also showed an increased reactivity
      of Fas ligand on day 5 in the allograft, which was observed both in parenchymal
      and nonparenchymal cells. CONCLUSIONS: These results strongly suggest that
      Fas/Fas ligand interaction mediates the liver injury during allograft rejection.
      In addition, other regulatory factors of apoptosis, such as bcl-2, might also be
      involved in this pathogenesis.

PMID- 10357922
TI  - The role of mitogen-activated protein kinase and protein kinase C in fibronectin
      production in human vascular smooth muscle cells.
AB  - BACKGROUND: After evaluating various growth factors, cytokines, and extracellular
      matrix (ECM) proteins, we found that the most potent agonists of smooth muscle
      cell (SMC) fibronectin (Fn) production were transforming growth factor-beta (TGF
      beta) and epidermal growth factor (EGF). To determine the possible signaling
      pathways involved in the production of this matrix protein, we investigated the
      role of the intracellular proteins, protein kinase C (PKC) and mitogen-activated
      protein kinase (MAP-K), in TGF-beta- and EGF-induced human vascular SMC Fn
      production. MATERIALS AND METHODS: After stimulation of human SMCs with TGF-beta
      (10 ng/ml) and EGF (100 ng/ml), Fn in the cell medium was assayed by
      immunoblotting using a specific antibody. PKC was activated by brief stimulation
      of SMC with phorbol 12,13-dibutyrate (PDBu) and inhibited by downregulation with
      PDBu or the inhibitor, GF109203X. MAP-K was inhibited with PD098059. RESULTS: PKC
      activation increased basal and synergistically enhanced TGF-beta- and EGF-induced
      Fn production. However, inhibition of PKC by downregulation and GF109203X did not
      diminish Fn production by TGF-beta and EGF. Surprisingly, these two methods of
      inhibition slightly increased basal and agonist-induced Fn production. The MAP-K
      kinase inhibitor, PD098059, produced an almost complete inhibition of EGF and a
      partial inhibition of TGF-beta-induced Fn production. CONCLUSIONS: Activation of
      PKC stimulates Fn production; however, neither TGF-beta nor EGF produce Fn
      through a PKC-dependent pathway. EGF and TGF-beta both stimulate Fn production at
      least in part through the intracellular signaling protein MAP-K. Understanding
      the signaling pathways involved in extracellular matrix protein production will
      allow the design of specific inhibitors of intimal hyperplasia.

PMID- 10357923
TI  - Apoptosis and the pattern of DNase I expression following massive small bowel
      resection.
AB  - INTRODUCTION: Following massive small bowel resection (SBR), histologic evidence
      of increased enterocyte apoptosis has been demonstrated in several animal models.
      Deoxyribonuclease I (DNase I) is requisite for intranuclear cleavage of DNA
      during apoptosis; we therefore hypothesized that the expression of this gene
      would be increased following SBR. METHODS: Male ICR mice underwent either 50%
      proximal SBR or sham surgery (bowel transection/reanastomosis). After 12 h and 1,
      3, and 7 days, rates of enterocyte proliferation and apoptosis were recorded as
      well as DNase I mRNA expression and activity. RESULTS: Adaptation after SBR was
      confirmed at each time point by increased proliferation. Enterocyte proliferation
      was increased by 12 h and apoptosis was increased by 24 h and remained elevated
      through Day 7. When compared with sham-operated mice, SBR resulted in a twofold
      increase in both DNase I expression and activity at 24 h postoperatively, which
      returned to baseline by Postoperative Day 3. CONCLUSIONS: DNase I expression and
      activity are increased early following massive SBR but return to baseline despite
      persistent increased rates of enterocyte apoptosis and proliferation. This enzyme
      may be important in the early induction of apoptosis following massive SBR, but
      not once a new set point has been established in the balance between the rate of
      enterocyte production and enterocyte loss.

PMID- 10357924
TI  - Reduction of lipid peroxidation with intraoperative superoxide dismutase
      treatment decreases intimal hyperplasia in experimental vein grafts.
AB  - BACKGROUND: Vein graft failure is commonly attributed to the development of
      intimal hyperplastic lesions. Oxidative stress has been implicated in the
      initiation and progression of atherosclerosis. In this study we examined the
      effects of local intraoperative treatment with polyethylene glycolated superoxide
      dismutase (PEG-SOD) on lipid peroxidation and on the development of intimal
      hyperplasia in experimental vein grafts. MATERIALS AND METHODS: Forty-one New
      Zealand White male rabbits had a right carotid interposition bypass graft using
      the ipsilateral reversed jugular vein. Sixteen animals received local PEG-SOD
      (4,100 units) treatment; 9 animals received the polyethylene glycol (PEG) vehicle
      without SOD; 16 animals were used as controls. Postoperatively, malondialdehyde
      (MDA, a product of lipid peroxidation) concentration and SOD activity were
      assessed in 3-day vein grafts by colorimetric spectrophotometry. To determine
      wall dimensions and vasomotor function, morphometric and isometric tension
      studies were performed on 28-day vein grafts. RESULTS: MDA concentration was
      increased 5. 7-fold (P < 0.05) in 3-day control vein grafts compared to ungrafted
      jugular veins. Intraoperative PEG-SOD treatment raised SOD activity 5.0-fold (P <
      0.05) and reduced MDA concentration 8-fold (P < 0.05) in 3-day vein grafts
      compared to controls. At 28 days, intimal thickness was reduced by 35% with PEG
      SOD treatment (54 +/- 4 vs 83 +/- 5; P < 0.001) compared to control vein grafts,
      without a change in medial thickness (77 +/- 4 vs 88 +/- 5; P = ns). The
      vasomotor functions of 28-day PEG-SOD-treated vein grafts to norepinephrine,
      serotonin, bradykinin, nitroprusside, and acetylcholine were not significantly
      changed when compared to controls. Treatment with PEG alone did not significantly
      alter lipid peroxidation, wall dimensions, or vasomotor function of vein grafts.
      CONCLUSION: This study demonstrates that intraoperative local treatment of vein
      grafts with PEG-SOD increases SOD activity and decreases lipid peroxidation for
      at least 3 days, resulting in reduced intimal hyperplasia at 28 days. These
      findings further implicate oxidative stress in the hyperplastic response of vein
      grafts and suggest a potential therapeutic role for PEG-SOD in the prevention of
      vein graft failure.

PMID- 10357925
TI  - Secretory event in intestinal grafts during preservation ischemia.
AB  - BACKGROUND: Ischemia triggers secretion of proteins from the intestine, including
      type II secretory phospholipase A2 (sPLA2). This "secretory event" was studied in
      intestinal grafts during the first few hours of preservation by measuring total
      protein, sPLA2, and other enzymes in the UW preservation solution over time. The
      effect of PX-13, a PLA2 inhibitor, was also studied. MATERIALS AND METHODS:
      Twenty-five centimeter intestinal grafts were harvested from Lewis rats, flushed,
      and preserved in UW solution +/- PX-13 at 4 degrees C. UW samples from 0 to 48 h
      (n = 5 each) were analyzed for total protein, sPLA2, lactate dehydrogenase (LDH),
      N-acetylglucosamine (NAGA), and lysozyme. Nonpreserved grafts were homogenized in
      PBS as tissue controls. Standard biochemical methods were used for all assays.
      RESULTS: Total protein increased rapidly by 5 min, continued to rise more slowly
      until 30 min, and then stabilized. The most significant increase in sPLA2
      activity occurred between 90 and 180 min. NAGA increased most markedly between 30
      and 180 min, while LDH increased in the first 30 min, although the level of both
      enzymes was negligible compared to tissue enzyme. Lysozyme levels were minimal at
      all times. PX-13 decreased sPLA2 activity markedly at all time points.
      CONCLUSION: Total protein levels increased before sPLA2, suggesting that sPLA2
      may be secreted in response to other proteins or enzymes released even earlier
      during preservation (e.g., cytokines). These elevations do not appear to be
      caused by cell death. Phospholipase A2 secretion may be blocked, and this may
      greatly improve the outcome of intestinal preservation.

PMID- 10357926
TI  - Cardiotrophin-1 attenuates endotoxin-induced acute lung injury.
AB  - Cardiotrophin-1 (CT-1) is a recently discovered member of the gp130 cytokine
      family, which includes IL-6, IL-11, leukemia inhibitory factor, ciliary
      neurotrophic factor, and oncostatin M. Recent evidence suggests that, like other
      members of this family, CT-1 may possess anti-inflammatory properties. We
      hypothesized that in vivo CT-1 administration would attenuate endotoxin (ETX)
      induced acute lung injury. We studied the effects of CT-1 (100 microgram/kg ip,
      10 min prior to ETX) in a rat model of ETX-induced acute lung injury (Salmonella
      typhimurium lipopolysaccharide, 20 mg/kg ip). Six hours after ETX, lungs were
      harvested for determination of neutrophil accumulation (myeloperoxidase, MPO,
      assay) and lung edema (wet-to-dry weight ratio). Mechanisms of pulmonary
      vasorelaxation were examined in isolated pulmonary artery rings at 6 h by
      interrogating endothelium-dependent (response to acetylcholine) and endothelium
      independent (response to sodium nitroprusside) relaxation following alpha
      adrenergic (phenylephrine)-stimulated preconstriction. CT-1 abrogated the
      endotoxin-induced lung neutrophil accumulation: 2.3 +/- 0.2 units MPO/g wet lung
      (gwl) vs 6. 3 +/- 0.3 units MPO/gwl in the ETX group (P < 0.05 vs ETX, P > 0.05
      vs control). Similarly, CT-1 prevented ETX-induced lung edema: wet-to-dry-weight
      ratio, 4.473 +/- 0.039 vs 4.747 +/- 0.039 in the ETX group (P < 0.05 vs ETX, P >
      0.05 vs control). Endotoxin caused significant impairment of both endothelium
      dependent and -independent pulmonary vasorelaxation, and CT-1 attenuated this
      injury. Thus, cardiotrophin-1 possesses significant anti-inflammatory properties
      in a model of endotoxin-induced acute lung injury.

PMID- 10357927
TI  - Patterning mechanisms in the body trunk and the appendages of Drosophila.
AB  - During evolution, many animal groups have developed specialised outgrowths of the
      body wall, limbs or appendages. The type of appendage depends on the identity of
      the segment where they appear, indicating that the Hox genes contribute to
      appendage specification. Moreover, work carried out principally in Drosophila has
      identified the gene products and the mechanisms involved in pattern formation in
      the appendages. In this essay, we compare the morphogenetic processes in the
      appendages and the body wall; the function of the Hox genes and the response to
      the signalling molecules involved in local patterning. We speculate that,
      although the basic mechanisms are similar, there are significant differences in
      the manner the body trunk and appendages respond to them.

PMID- 10357928
TI  - The centrosomin protein is required for centrosome assembly and function during
      cleavage in Drosophila.
AB  - Centrosomin is a 150 kDa centrosomal protein of Drosophila melanogaster. To study
      the function of Centrosomin in the centrosome, we have recovered mutations that
      are viable but male and female sterile (cnnmfs). We have shown that these alleles
      (1, 2, 3, 7, 8 and hk21) induce a maternal effect on early embryogenesis and
      result in the accumulation of low or undetectable levels of Centrosomin in the
      centrosomes of cleavage stage embryos. Hemizygous cnn females produce embryos
      that show dramatic defects in chromosome segregation and spindle organization
      during the syncytial cleavage divisions. In these embryos the syncytial divisions
      proceed as far as the twelfth cycle, and embryos fail to cellularize. Aberrant
      divisions and nuclear fusions occur in the early cycles of the nuclear divisions,
      and become more prominent at later stages. Giant nuclei are seen in late stage
      embryos. The spindles that form in mutant embryos exhibit multiple anomalies.
      There is a high occurrence of apparently linked spindles that share poles,
      indicating that Centrosomin is required for the proper spacing and separation of
      mitotic spindles within the syncytium. Spindle poles in the mutants contain
      little or no detectable amounts of the centrosomal proteins CP60, CP190 and
      (gamma)-tubulin and late stage embryos often do not have astral microtubules at
      their spindle poles. Spindle morphology and centrosomal composition suggest that
      the primary cause of these division defects in mutant embryos is centrosomal
      malfunction. These results suggest that Centrosomin is required for the assembly
      and function of centrosomes during the syncytial cleavage divisions.

PMID- 10357929
TI  - The N-terminal domain of Sxl protein disrupts Sxl autoregulation in females and
      promotes female-specific splicing of tra in males.
AB  - Sex determination in Drosophila depends upon the post-transcriptional regulatory
      activities of the Sex-lethal (Sxl) gene. Sxl maintains the female determined
      state and activates female differentiation pathways by directing the female
      specific splicing of Sxl and tra pre-mRNAs. While there is compelling evidence
      that Sxl proteins regulate splicing by directly binding to target RNAs, previous
      studies indicate that the two Sxl RNA-binding domains are not in themselves
      sufficient for biological activity and that an intact N-terminal domain is also
      critical for splicing function. To further investigate the functions of the Sxl N
      terminus, we ectopically expressed a chimeric protein consisting of the N
      terminal 99 amino acids fused to ss-galactosidase. The Nss-gal fusion protein
      behaves like a dominant negative, interfering with the Sxl autoregulatory
      feedback loop and killing females. This dominant negative activity can be
      attributed to the recruitment of the fusion protein into the large Sxl:Snf
      splicing complexes that are found in vivo and the consequent disruption of these
      complexes. In addition to the dominant negative activity, the Nss-gal fusion
      protein has a novel gain-of-function activity in males: it promotes the female
      specific processing of tra pre-mRNAs. This novel activity is discussed in light
      of the blockage model for the tra splicing regulation.

PMID- 10357930
TI  - Restriction of developmental potential during divergence of the enteric and
      sympathetic neuronal lineages.
AB  - In the peripheral nervous system, enteric and sympathetic neurons develop from
      multipotent neural crest cells. While local environmental signals in the gut and
      in the region of the sympathetic ganglia play a role in the choice of cell fate,
      little is known about the mechanisms that underlie restriction to specific
      neuronal phenotypes. We investigated the divergence and restriction of the
      enteric and sympathetic neuronal lineages using immuno-isolated neural crest
      derived cells from the gut and sympathetic ganglia. Analysis of neuronal and
      lineage-specific mRNAs and proteins indicated that neural crest-derived cells
      from the gut and sympathetic ganglia had initiated neuronal differentiation and
      phenotypic divergence by E14.5 in the rat. We investigated the developmental
      potential of these cells using expression of tyrosine hydroxylase as a marker for
      a sympathetic phenotype. Tyrosine hydroxylase expression was examined in neurons
      that developed from sympathetic and enteric neuroblasts under the following
      culture conditions: culture alone; coculture with gut monolayers to promote
      enteric differentiation; or coculture with dorsal aorta monolayers to promote
      noradrenergic differentiation. Both enteric and sympathetic neuroblasts displayed
      developmental plasticity at E14.5. Sympathetic neuroblasts downregulated tyrosine
      hydroxylase in response to signals from the gut environment and enteric
      neuroblasts increased expression of tyrosine hydroxylase when grown on dorsal
      aorta or in the absence of other cell types. Tracking of individual sympathetic
      cells displaying a neuronal morphology at the time of plating indicated that
      neuroblasts retained phenotypic plasticity even after initial neuronal
      differentiation had occurred. By E19.5 both enteric and sympathetic neuroblasts
      had undergone a significant loss of their developmental potential, with most
      neuroblasts retaining their lineage-specific phenotype in all environments
      tested. Together our data indicate that the developmental potential of enteric
      and sympathetic neuroblasts becomes restricted over time and that this
      restriction takes place not as a consequence of initial neuronal differentiation
      but during the period of neuronal maturation. Further, we have characterized a
      default pathway of adrenergic differentiation in the enteric nervous system and
      have defined a transient requirement for gut-derived factors in the maintenance
      of the enteric neuronal phenotype.

PMID- 10357932
TI  - Mesonephric cell migration induces testis cord formation and Sertoli cell
      differentiation in the mammalian gonad.
AB  - In mammals a single gene on the Y chromosome, Sry, controls testis formation. One
      of the earliest effects of Sry expression is the induction of somatic cell
      migration from the mesonephros into the XY gonad. Here we show that mesonephric
      cells are required for cord formation and male-specific gene expression in XY
      gonads in a stage-specific manner. Culturing XX gonads with an XY gonad at their
      surface, as a 'sandwich', resulted in cell migration into the XX tissue. Analysis
      of sandwich gonads revealed that in the presence of migrating cells, XX gonads
      organized cord structures and acquired male-specific gene expression patterns.
      From these results, we conclude that mesonephric cell migration plays a critical
      role in the formation of testis cords and the differentiation of XY versus XX
      cell types.

PMID- 10357933
TI  - Patterning of Drosophila leg sensory organs through combinatorial signaling by
      hedgehog, decapentaplegic and wingless.
AB  - During development, global patterning events initiate signal transduction
      cascades which gradually establish an array of individual cell fates. Many of the
      genes which pattern Drosophila are expressed throughout development and specify
      diverse cell types by creating unique local environments which establish the
      expression of locally acting genes. This process is exemplified by the patterning
      of leg microchaete rows. hairy (h) is expressed in a spatially restricted manner
      in the leg imaginal disc and functions to position adult leg bristle rows by
      negatively regulating the proneural gene achaete, which specifies sensory cell
      fates. While much is known about the events that partition the leg imaginal disc
      and about sensory cell differentiation, the mechanisms that refine early
      patterning events to the level of individual cell fate specification are not well
      understood. We have investigated the regulation of h expression along the
      dorsal/ventral (D/V) axis of the leg adjacent to the anterior/posterior (A/P)
      compartment boundary and have found that it requires input from both D/V and A/P
      patterning mechanisms. Expression of the D/V axis h stripe (D/V-h) is controlled
      by dorsal- and ventral-specific enhancer elements which are targets of
      Decapentaplegic (Dpp) and Wingless (Wg) signaling, respectively, but which are
      also dependent on Hedgehog (Hh) signaling for activation. D/V-h expression is
      lost in smoothened mutant clones and is specifically activated by exogenously
      supplied Cubitus interruptus (Ci). D/V-h expression is also lost in clones
      deficient for Dpp and Wg signaling, but ectopic activation of D/V-h by Dpp and Wg
      is limited to the A/P compartment boundary where endogenous levels of full-length
      Ci are high. We propose that D/V-h expression is regulated in a non-linear
      pathway in which Ci plays a dual role. In addition to serving as an upstream
      activator of Dpp and Wg, Ci acts combinatorially with them to activate D/V-h
      expression.

PMID- 10357931
TI  - POU domain factor Brn-3a controls the differentiation and survival of trigeminal
      neurons by regulating Trk receptor expression.
AB  - Mice lacking the POU domain-containing transcription factor Brn-3a have several
      neuronal deficits. In the present paper, we show that Brn-3a plays two distinct
      roles during development of the trigeminal ganglion. In this ganglion, neurons
      expressing the neurotrophin receptors, TrkB and TrkC, are born between E9.5 and
      E11.5. In the absence of Brn-3a, very few neurons ever express TrkC, but TrkB
      expressing neurons are present at E12.5 in elevated numbers, suggesting that Brn
      3a may be a constituent of a regulatory circuit determining which Trk receptor is
      expressed by these early-born neurons. Most neurons expressing the neurotrophin
      receptor TrkA are generated between E11.5 and E13.5 in this ganglion and their
      initial generation is not prevented by absence of Brn-3a. However, after E12. 5,
      absence of Brn-3a results in a progressive loss in neuronal TrkA and TrkB
      expression, which leads to a massive wave of apoptosis that peaks at E15.5.
      Despite complete absence of the Trk receptors at E17. 5 and P0, approximately 30%
      of the normal complement of neurons survive to birth in Brn-3a mutants.
      Approximately 70% of these express the GDNF receptor subunit, c-ret; many can be
      sustained by GDNF, but not by NGF in culture. Thus, the vast majority of
      surviving neurons are probably sustained in vivo by trophic factor(s) whose
      receptors are not regulated by Brn-3a. In conclusion, our data indicate the
      specific functions of Brn-3a in controlling the survival and differentiation of
      trigeminal neurons by regulating expression of each of the three Trk receptors.

PMID- 10357934
TI  - A role for Sonic hedgehog in axon-to-astrocyte signalling in the rodent optic
      nerve.
AB  - Retinal ganglion cell (RGC) axons have been shown to stimulate the proliferation
      of astrocytes in the developing rodent optic nerve, but the signals that mediate
      this effect have not been identified. The following findings suggest that Sonic
      hedgehog (Shh) is one of the signals. (1) RGCs express both Shh mRNA and protein,
      whereas the optic nerve contains the protein but not the mRNA. (2) Astrocytes and
      their precursors in the developing optic nerve express the Hedgehog (Hh) receptor
      gene Patched (Ptc), suggesting that they are being signalled by an Hh protein.
      (3) Ptc expression in the nerve is greatly decreased by either nerve transection
      or by treatment with neutralizing anti-Shh antibodies, suggesting that it depends
      on axon-derived Shh. (4) Astrocyte proliferation in the developing nerve is
      reduced by treatment with anti-Shh antibodies, suggesting that Shh normally helps
      stimulate this proliferation.

PMID- 10357935
TI  - Cbfa1 is required for epithelial-mesenchymal interactions regulating tooth
      development in mice.
AB  - Osteoblasts and odontoblasts, cells that are responsible for the formation of
      bone and dentin matrices respectively, share several molecular characteristics.
      Recently, Cbfa1 was shown to be a critical transcriptional regulator of
      osteoblast differentiation. Mutations in this gene cause cleidocranial dysplasia
      (CCD), an autosomal dominant disorder in humans and mice characterized by
      defective bone formation. CCD also results in dental defects that include
      supernumerary teeth and delayed eruption of permanent dentition. The dental
      abnormalities in CCD suggest an important role for this molecule in the formation
      of dentition. Here we describe results of studies aimed at understanding the
      functions of Cbfa1 in tooth formation. RT-PCR and in situ hybridization analyses
      show that Cbfa1 has a unique expression pattern in dental mesenchyme from the bud
      to early bell stages during active epithelial morphogenesis. Unlike that observed
      in osteoblast differentiation, Cbfa1 is downregulated in fully differentiated
      odontoblasts and is surprisingly expressed in ectodermally derived ameloblasts
      during the maturation phase of enamel formation. The role of Cbfa1 in tooth
      morphogenesis is further illustrated by the misshapen and severely hypoplastic
      tooth organs in Cbfa1-/- mice. These tooth organs lacked overt odontoblast and
      ameloblast differentiation and normal dentin and enamel matrices. Epithelial
      mesenchymal recombinants demonstrate that dental epithelium regulates mesenchymal
      Cbfa1 expression during the bud and cap stages and that these effects are
      mimicked by the FGFs but not by the BMPs as shown by our bead implantation
      assays. We propose that Cbfa1 regulates the expression of molecules in mesenchyme
      that act reciprocally on dental epithelium to control its growth and
      differentiation. Taken together, our data indicate a non-redundant role for Cbfa1
      in tooth development that may be distinct from that in bone formation. In
      odontogenesis, Cbfa1 is not involved in the early signaling networks regulating
      tooth initiation and early morphogenesis but regulates key epithelial-mesenchymal
      interactions that control advancing morphogenesis and histodifferentiation of the
      epithelial enamel organ.

PMID- 10357936
TI  - Axial mesendoderm refines rostrocaudal pattern in the chick nervous system.
AB  - There has long been controversy concerning the role of the axial mesoderm in the
      induction and rostrocaudal patterning of the vertebrate nervous system. Here we
      investigate the neural inducing and regionalising properties of defined
      rostrocaudal regions of head process/prospective notochord in the chick embryo by
      juxtaposing these tissues with extraembryonic epiblast or neural plate explants.
      We localise neural inducing signals to the emerging head process and using a
      large panel of region-specific neural markers, show that different rostrocaudal
      levels of the head process derived from headfold stage embryos can induce
      discrete regions of the central nervous system. However, we also find that
      rostral and caudal head process do not induce expression of any of these
      molecular markers in explants of the neural plate. During normal development the
      head process emerges beneath previously induced neural plate, which we show has
      already acquired some rostrocaudal character. Our findings therefore indicate
      that discrete regions of axial mesendoderm at headfold stages are not normally
      responsible for the establishment of rostrocaudal pattern in the neural plate.
      Strikingly however, we do find that caudal head process inhibits expression of
      rostral genes in neural plate explants. These findings indicate that despite the
      ability to induce specific rostrocaudal regions of the CNS de novo, signals
      provided by the discrete regions of axial mesendoderm do not appear to establish
      regional differences, but rather refine the rostrocaudal character of overlying
      neuroepithelium.

PMID- 10357937
TI  - Analysis of mice carrying targeted mutations of the glucocorticoid receptor gene
      argues against an essential role of glucocorticoid signalling for generating
      adrenal chromaffin cells.
AB  - Molecular mechanisms underlying the generation of distinct cell phenotypes is a
      key issue in developmental biology. A major paradigm of determination of neural
      cell fate concerns the development of sympathetic neurones and neuroendocrine
      chromaffin cells from a common sympathoadrenal (SA) progenitor cell. Two decades
      of in vitro experiments have suggested an essential role of glucocorticoid
      receptor (GR)-mediated signalling in generating chromaffin cells. Targeted
      mutation of the GR should consequently abolish chromaffin cells. The present
      analysis of mice lacking GR gene product demonstrates that animals have normal
      numbers of adrenal chromaffin cells. Moreover, there are no differences in terms
      of apoptosis and proliferation or in expression of several markers (e.g. GAP43,
      acetylcholinesterase, adhesion molecule L1) of chromaffin cells in GR-deficient
      and wild-type mice. However, GR mutant mice lack the adrenaline-synthesizing
      enzyme PNMT and secretogranin II. Chromaffin cells of GR-deficient mice exhibit
      the typical ultrastructural features of this cell phenotype, including the large
      chromaffin granules that distinguish them from sympathetic neurones. Peripherin,
      an intermediate filament of sympathetic neurones, is undetectable in chromaffin
      cells of GR mutants. Finally, when stimulated with nerve growth factor in vitro,
      identical proportions of chromaffin cells from GR-deficient and wild-type mice
      extend neuritic processes. We conclude that important phenotypic features of
      chromaffin cells that distinguish them from sympathetic neurones develop normally
      in the absence of GR-mediated signalling. Most importantly, chromaffin cells in
      GR-deficient mice do not convert to a neuronal phenotype. These data strongly
      suggest that the dogma of an essential role of glucocorticoid signalling for the
      development of chromaffin cells must be abandoned.

PMID- 10357939
TI  - Nuclear beta-catenin and the development of bilateral symmetry in normal and LiCl
      exposed chick embryos.
AB  - Studies in Xenopus laevis and zebrafish suggest a key role for beta-catenin in
      the specification of the axis of bilateral symmetry. In these organisms, nuclear
      beta-catenin demarcates the dorsalizing centers. We have asked whether beta
      catenin plays a comparable role in the chick embryo and how it is adapted to the
      particular developmental constraints of chick development. The first nuclear
      localization of beta-catenin is observed in late intrauterine stages of
      development in the periphery of the blastoderm, the developing area opaca and
      marginal zone. Obviously, this early, radially symmetric domain does not predict
      the future organizing center of the embryo. During further development, cells
      containing nuclear beta-catenin spread under the epiblast and form the secondary
      hypoblast. The onset of hypoblast formation thus demarcates the first bilateral
      symmetry in nuclear beta-catenin distribution. Lithium chloride exposure also
      causes ectopic nuclear localization of beta-catenin in cells of the epiblast in
      the area pellucida. Embryos treated before primitive streak formation become
      completely radialized, as shown by the expression of molecular markers, CMIX and
      GSC. Lithium treatments performed during early or medium streak stages cause
      excessive development of the anterior primitive streak, node and notochord, and
      lead to a degeneration of prospective ventral and posterior structures, as shown
      by the expression of the molecular markers GSC, CNOT1, BMP2 and Ch-Tbx6L. In
      summary, we found that in spite of remarkable spatiotemporal differences, beta
      catenin acts in the chick in a manner similar to that in fish and amphibia.

PMID- 10357938
TI  - The control of cell fate in the embryonic visual system by atonal, tailless and
      EGFR signaling.
AB  - We describe here the role of the transcription factors encoding genes tailless
      (tll), atonal (ato), sine oculis (so), eyeless (ey) and eyes absent (eya), and
      EGFR signaling in establishing the Drosophila embryonic visual system. The
      embryonic visual system consists of the optic lobe primordium, which, during
      later larval life, develops into the prominent optic lobe neuropiles, and the
      larval photoreceptor (Bolwig's organ). Both structures derive from a
      neurectodermal placode in the embryonic head. Expression of tll is normally
      confined to the optic lobe primordium, whereas ato appears in a subset of
      Bolwig's organ cells that we call Bolwig's organ founders. Phenotypic analysis,
      using specific markers for Bolwig's organ and the optic lobe, of tll loss- and
      gain-of-function mutant embryos reveals that tll functions to drive cells to
      optic lobe as opposed to Bolwig's organ fate. Similar experiments indicate that
      ato has the opposite effect, namely driving cells to a Bolwig's organ fate. Since
      we can show that tll and ato do not regulate each other, we propose a model
      wherein tll expression restricts the ability of cells to respond to signaling
      arising from ato-expressing Bolwig's organ pioneers. Our data further suggest
      that the Bolwig's organ founder cells produce Spitz (the Drosophila TGFalpha
      homolog) signal, which is passed to the neighboring secondary Bolwig's organ
      cells where it activates the EGFR signaling cascade and maintains the fate of
      these secondary cells. The regulators of tll expression in the embryonic visual
      system remain elusive, as we were unable to find evidence for regulation by the
      'early eye genes' so, eya and ey, or by EGFR signaling.

PMID- 10357940
TI  - Requirement for the zebrafish mid-hindbrain boundary in midbrain polarisation,
      mapping and confinement of the retinotectal projection.
AB  - The organizer at the midbrain-hindbrain boundary (MHB organizer) has been
      proposed to induce and polarize the midbrain during development. We investigate
      the requirement for the MHB organizer in acerebellar mutants, which lack a MHB
      and cerebellum, but retain a tectum, and are mutant for fgf8, a candidate inducer
      and polarizer. We examine the retinotectal projection in the mutants to assay
      polarity in the tectum. In mutant tecta, retinal ganglion cell (RGC) axons form
      overlapping termination fields, especially in the ventral tectum, and along both
      the anterior-posterior and dorsal-ventral axis of the tectum, consistent with a
      MHB requirement in generating midbrain polarity. However, polarity is not
      completely lost in the mutant tecta, in spite of the absence of the MHB.
      Moreover, graded expression of the ephrin family ligand Ephrin-A5b is eliminated,
      whereas Ephrin-A2 and Ephrin-A5a expression is leveled in acerebellar mutant
      tecta, showing that ephrins are differentially affected by the absence of the
      MHB. Some RGC axons overshoot beyond the mutant tectum, suggesting that the MHB
      also serves a barrier function for axonal growth. By transplanting whole eye
      primordia, we show that mapping defects and overshooting largely, but not
      exclusively, depend on tectal, but not retinal genotype, and thus demonstrate an
      independent function for Fgf8 in retinal development. The MHB organizer, possibly
      via Fgf8 itself, is thus required for midbrain polarisation and for restricting
      axonal growth, but other cell populations may also influence midbrain polarity.

PMID- 10357941
TI  - Responses of plant vascular systems to auxin transport inhibition.
AB  - To assess the role of auxin flows in plant vascular patterning, the development
      of vascular systems under conditions of inhibited auxin transport was analyzed.
      In Arabidopsis, nearly identical responses evoked by three auxin transport
      inhibitor substances revealed an enormous plasticity of the vascular pattern and
      suggest an involvement of auxin flows in determining the sites of vascular
      differentiation and in promoting vascular tissue continuity. Organs formed under
      conditions of reduced auxin transport contained increased numbers of vascular
      strands and cells within those strands were improperly aligned. In leaves,
      vascular tissues became progressively confined towards the leaf margin as the
      concentration of auxin transport inhibitor was increased, suggesting that the
      leaf vascular system depends on inductive signals from the margin of the leaf.
      Staged application of auxin transport inhibitor demonstrated that primary,
      secondary and tertiary veins became unresponsive to further modulations of auxin
      transport at successive stages of early leaf development. Correlation of these
      stages to anatomical features in early leaf primordia indicated that the pattern
      of primary and secondary strands becomes fixed at the onset of lamina expansion.
      Similar alterations in the leaf vascular responses of alyssum, snapdragon and
      tobacco plants suggest common functions of auxin flows in vascular patterning in
      dicots, while two types of vascular pattern alterations in Arabidopsis auxin
      transport mutants suggest that at least two distinct primary defects can result
      in impaired auxin flow. We discuss these observations with regard to the relative
      contributions of auxin transport, auxin sensitivity and the cellular organisation
      of the developing organ on the vascular pattern.

PMID- 10357942
TI  - Composite signalling from Serrate and Delta establishes leg segments in
      Drosophila through Notch.
AB  - The receptor protein NOTCH and its ligands SERRATE and DELTA are involved in many
      developmental processes in invertebrates and vertebrates alike. Here we show that
      the expression of the Serrate and Delta genes patterns the segments of the leg in
      Drosophila by a combination of their signalling activities. Coincident stripes of
      Serrate and Delta expressing cells activate Enhancer of split expression in
      adjacent cells through Notch signalling. These cells form a patterning boundary
      from which a putative secondary signal leads to the development of leg joints.
      Elsewhere in the tarsal segments, signalling by DELTA and NOTCH is necessary for
      the development of non-joint parts of the leg. We propose that these two effects
      result from different thresholds of NOTCH activation, which are translated into
      different downstream gene expression effects. We propose a general mechanism for
      creation of boundaries by Notch signalling.

PMID- 10357943
TI  - her1, a zebrafish pair-rule like gene, acts downstream of notch signalling to
      control somite development.
AB  - During vertebrate embryonic development, the paraxial mesoderm becomes subdivided
      into metameric units known as somites. In the zebrafish embryo, genes encoding
      homologues of the proteins of the Drosophila Notch signalling pathway are
      expressed in the presomitic mesoderm and expression is maintained in a segmental
      pattern during somitogenesis. This expression pattern suggests a role for these
      genes during somite development. We misexpressed various zebrafish genes of this
      group by injecting mRNA into early embryos. RNA encoding a constitutively active
      form of notch1a (notch1a-intra) and a truncated variant of deltaD [deltaD(Pst)],
      as well as transcripts of deltaC and deltaD, the hairy-E(spl) homologues her1 and
      her4, and groucho2 were tested for their effects on somite formation, myogenesis
      and on the pattern of transcription of putative downstream genes. In embryos
      injected with any of these RNAs, with the exception of groucho2 RNA, the paraxial
      mesoderm differentiated normally into somitic tissue, but failed to segment
      correctly. Activation of notch results in ectopic activation of her1 and her4.
      This misregulation of the expression of her genes might be causally related to
      the observed mesodermal defects, as her1 and her4 mRNA injections led to effects
      similar to those seen with notch1a-intra. deltaC and deltaD seem to function
      after subdivision of the presomitic mesoderm, since the her gene transcription
      pattern in the presomitic mesoderm remains essentially normal after misexpression
      of delta genes. Whereas notch signalling alone apparently does not affect
      myogenesis, zebrafish groucho2 is involved in differentiation of mesodermal
      derivatives.

PMID- 10357944
TI  - Increased hemangioblast commitment, not vascular disorganization, is the primary
      defect in flt-1 knock-out mice.
AB  - We previously demonstrated the essential role of the flt-1 gene in regulating the
      development of the cardiovascular system. While the inactivation of the flt-1
      gene leads to a very severe disorganization of the vascular system, the primary
      defect at the cellular level was unknown. Here we report a surprising finding
      that it is an increase in the number of endothelial progenitors that leads to the
      vascular disorganization in flt-1(-/-) mice. At the early primitive streak stage
      (prior to the formation of blood islands), hemangioblasts are formed much more
      abundantly in flt-1(-/-) embryos. This increase is primarily due to an alteration
      in cell fate determination among mesenchymal cells, rather than to increased
      proliferation, migration or reduced apoptosis of flt-1(-/-) hemangioblasts. We
      further show that the increased population density of hemangioblasts is
      responsible for the observed vascular disorganization, based on the following
      observations: (1) both flt-1(-/-) and flt-1(+/+) endothelial cells formed normal
      vascular channels in chimaeric embryos; (2) wild-type endothelial cells formed
      abnormal vascular channels when their population density was significantly
      increased; and (3) in the absence of wild-type endothelial cells, flt-1(-/-)
      endothelial cells alone could form normal vascular channels when sufficiently
      diluted in a developing embryo. These results define the primary defect in flt-1(
      /-) embryos at the cellular level and demonstrate the importance of population
      density of progenitor cells in pattern formation.

PMID- 10357945
TI  - Embryonic mesenchymal cells share the potential for smooth muscle
      differentiation: myogenesis is controlled by the cell's shape.
AB  - Undifferentiated embryonic mesenchymal cells are round/cuboidal in shape. During
      development, visceral myogenesis is shortly preceded by mesenchymal cell
      elongation. To determine the role of the cell's shape on smooth muscle
      development, undifferentiated embryonic mesenchymal cells from intestine
      (abundant visceral muscle), lung (some visceral muscle) or kidney (no visceral
      muscle) were plated under conditions that maintained cell rounding or promoted
      elongation. Regardless of their fate in vivo, all the cells differentiated into
      smooth muscle upon elongation as indicated by the expression of smooth muscle
      specific proteins and the development of membrane potentials of -60 mV and
      voltage-dependent Ca2+ currents, characteristic of excitable cells. Smooth muscle
      differentiation occurred within 24 hours and was independent of cell
      proliferation. Regardless of their fate in vivo, all the round cells remained
      negative for smooth muscle markers, had membrane potentials of -30 mV and showed
      no voltage-activated current. These cells, however, differentiated into smooth
      muscle upon elongation. The role of the cell's shape in controlling smooth muscle
      differentiation was not overcome by treatment with retinoic acid, TGF-beta1, PDGF
      BB or epithelial-conditioned medium (all modulators of smooth muscle
      differentiation). These studies suggest that the mesenchymal cell shape plays a
      main role in visceral myogenesis.

PMID- 10357946
TI  - Blastocyst stage transfer: pitfalls and benefits. The benefits of extended
      culture.

PMID- 10357947
TI  - What are the clinical benefits of recombinant gonadotrophins? Is Puregon a 'good'
      or'super' drug?

PMID- 10357948
TI  - What are the clinical benefits of recombinant gonadotrophins? Clinical efficacy
      of recombinant gonadotrophins.

PMID- 10357949
TI  - What are the clinical benefits of recombinant gonadotrophins? The good,the bad
      and the ugly.

PMID- 10357950
TI  - What are the clinical benefits of recombinant gonadotrophins? Recombinant
      follicle stimulating hormone.

PMID- 10357951
TI  - Early unilateral follicular aspiration compared with coasting for the prevention
      of severe ovarian hyperstimulation syndrome: a prospective randomized study.
AB  - Thirty women undergoing in-vitro fertilization or intracytoplasmic sperm
      injection considered to be at high risk of ovarian hyperstimulation syndrome
      (OHSS) were randomly allocated to have early unilateral follicular aspiration
      (EUFA) (group 1) or coasting (group 2) when the serum oestradiol concentration
      was >6000 pg/ml and there were more than 15 follicles each of >/=18 mm diameter
      in each ovary. EUFA was performed in group 1 at 10-12 h after the human chorionic
      gonadotrophin (HCG) trigger injection and human menopausal gonadotrophin (HMG)
      were withheld for 4.9 +/- 1.6 days until serum oestradiol concentrations fell
      below 3000 pg/ml when HCG was administered. The mean total dose and duration of
      administration of HMG were similar in groups 1 and 2 (48.3 +/- 17.4 and 50.2 +/-
      16.5 ampoules; 13.7 +/- 2.2 and 14.1 +/- 3.2 days respectively). The mean serum
      oestradiol concentrations (9911 pg/ml versus 10 055 pg/ml) and number of
      follicles (43.3 versus 41.4) seen in both ovaries on the day of HCG
      administration in group 1 and on the day coasting was commenced in group 2 were
      also similar. After coasting, the mean serum oestradiol concentration on the day
      of HCG administration in group 2 was lower than in group 1 (1410 pg/ml versus
      9911 pg/ml; P < 0.001). The mean serum progesterone concentrations on the day of
      HCG administration in both groups were similar, and fell in all women in group 2.
      The mean number of oocytes retrieved and percentage of oocytes retrieved per
      follicle punctured was significantly higher in group 1 (15.4 +/- 2.1 versus 9.6
      +/- 3.2, P < 0.001; 91.4 +/- 4.4% versus 28.3 +/- 3.7%, P < 0.001 respectively).
      The fertilization and embryo cleavage rates were similar in both groups. Clinical
      pregnancy was diagnosed in 6/15 (40%) patients in group 1 and in 5/15 (33%)
      patients in group 2, while four women in group 1 and three in group 2 developed
      severe OHSS.

PMID- 10357952
TI  - Luteal phase and clinical outcome after human menopausal
      gonadotrophin/gonadotrophin releasing hormone antagonist treatment for ovarian
      stimulation in in-vitro fertilization/intracytoplasmic sperm injection cycles.
AB  - The luteal phase hormonal profile and the clinical outcome of 69 patients
      undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection
      (ICSI) after ovarian stimulation with human menopausal gonadotrophin (HMG) and
      the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix were analysed.
      Twenty-four patients received Cetrorelix 0.5 mg (group I) while in 45 patients
      Cetrorelix 0.25 mg was administered (group II). Human chorionic gonadotrophin
      (HCG) was used as luteal support. Nine clinical pregnancies were obtained in
      group I (37.5%) and 12 in group II (26. 6%). These results were not significantly
      different. Serum progesterone and oestradiol concentrations did not differ
      between the two groups either in pregnant or non-pregnant patients. An expected
      decrease of the same hormones was observed 8 days after the pre-ovulatory HCG
      injection in non-pregnant women. With regard to serum luteinizing hormone
      concentrations, a decrease was observed 2 days after the pre-ovulatory HCG
      injection and was maintained at almost undetectable levels throughout the entire
      luteal phase in both conception and non-conception cycles of group I and group
      II. This study demonstrates that different doses of GnRH antagonist do not have
      any impact on the luteal phase of IVF/ICSI cycles when hormonal support is given.

PMID- 10357953
TI  - Recombinant follicle stimulating hormone stimulation in poor responders with
      normal basal concentrations of follicle stimulating hormone and oestradiol:
      improved reproductive outcome.
AB  - A total of 30 young infertile patients who exhibited a poor response in two
      previous consecutive cycles, despite having normal basal follicle stimulating
      hormone (FSH) and oestradiol concentrations, were invited to participate in a
      prospective randomized study comparing the clinical efficacy of recombinant
      (rFSH) and urinary (uFSH) follicle stimulating hormone. An evaluation of the
      total dose used (3800 IU versus 4600 IU, P < 0.05) and duration of treatment
      (10.2 days versus 13.2 days, P < 0.05) showed a significantly shorter treatment
      period as well as a significantly lower total dose of FSH required to induce
      ovulation successfully in the group of patients treated with rFSH. Significantly
      more oocytes (7.2 versus 5. 6, P < 0.05) as well as mature oocytes (5.9 versus
      3.2, P < 0.01) were retrieved after rFSH treatment. In addition, significantly
      more good quality embryos were obtained (3.4 versus 1.8, P < 0.05) in the group
      of patients treated with rFSH and, as a result, higher pregnancy (33 versus 7%, P
      < 0.01) and implantation (16 versus 3%, P < 0.01) rates were achieved in these
      patients. It is concluded that rFSH is more effective than uFSH in inducing
      multifollicular development and achieving pregnancy in young low responders.

PMID- 10357954
TI  - Are circulating leptin and luteinizing hormone synchronized in patients with
      polycystic ovary syndrome?
AB  - Animal and human studies suggest that leptin modulates hypothalamic-pituitary
      gonadal axis functions. Leptin may stimulate gonadotrophin-releasing hormone
      (GnRH) release from the hypothalamus and luteinizing hormone (LH) and follicle
      stimulating hormone (FSH) secretion from the pituitary. A synchronicity of LH and
      leptin pulses has been described in healthy women, suggesting that leptin
      probably also regulates the episodic secretion of LH. In some pathological
      conditions, such as polycystic ovarian syndrome (PCOS), LH-leptin interactions
      are not known. The aim of the present investigation was to assess the episodic
      fluctuations of circulating LH and leptin in PCOS patients compared to regularly
      menstruating women. Six PCOS patients and six normal cycling (NC) women of
      similar age and body mass index (BMI) were studied. To assess episodic hormone
      secretion, blood samples were collected at 10-min intervals for 6 h. LH and
      leptin concentrations were measured in all samples. For pulse analysis the
      cluster algorithm was used. To detect an interaction between LH and leptin
      pulses, an analysis of copulsatility was employed. LH concentrations were
      significantly higher in the PCOS group in comparison to NC women, however serum
      leptin concentrations and leptin pulse characteristics for PCOS patients did not
      differ from NC women. A strong synchronicity between LH and leptin pulses was
      observed in NC women; 11 coincident leptin pulses were counted with a phase shift
      of 0 min (P = 0.027), 18 pulses with a phase shift of -1 (P = 0.025) and 24
      pulses with a phase shift of -2 (P = 0.028). PCOS patients also exhibited a
      synchronicity between LH and leptin pulses but weaker (only 20 of 39 pulses) and
      with a phase shift greater than in normal women, leptin pulses preceding LH
      pulses by 20 min (P = 0.0163). These results demonstrate that circulating leptin
      and LH are synchronized in normal women and patients with PCOS. The real
      significance of the apparent copulsatility between LH and leptin must be
      elucidated, as well as the mechanisms that account for the ultradian leptin
      release.

PMID- 10357955
TI  - Effect of prednisolone on serum and follicular fluid androgen concentrations in
      women with polycystic ovary syndrome undergoing in-vitro fertilization.
AB  - Increased androgen concentrations are thought to be detrimental to oocyte quality
      and reproductive potential. Adjuvant treatment with glucocorticoids has been
      tried to suppress androgens in women undergoing infertility treatment. In the
      present study 20 infertile women with polycystic ovary syndrome were
      prospectively randomized in a placebo-controlled study to receive either placebo
      or prednisolone 10 mg at night, during standard in-vitro fertilization (IVF)
      treatment. Serum samples for assays of gonadotrophins, steroids and sex hormone
      binding globulin (SHBG) were collected before treatment, at down-regulation, and
      at oocyte retrieval. Up to five follicles in each ovary were analysed separately
      regarding follicular fluid and oocytes, the rest according to the clinic's
      routines. In the placebo group, serum dehydroepiandrosterone (DHEA) and
      dehydroepiandrosterone-sulphate (DHEA-S) did not change between down-regulation
      and oocyte retrieval, whereas adjuvant prednisolone resulted in a significant
      decrease. In follicular fluid, adjuvant prednisolone resulted in significantly
      lower concentrations of DHEA-S as compared to placebo, no other significant
      differences were found. No significant differences were found in embryo
      characteristics or pregnancy rates between the groups.

PMID- 10357956
TI  - Leptin inhibits gonadotrophin-stimulated granulosa cell progesterone production
      by antagonizing insulin action.
AB  - Recent evidence has demonstrated that expression of leptin and leptin receptors
      is expected in the human ovary, and that leptin alters ovarian steroidogenesis in
      animal models. This study was designed to determine whether leptin modulates
      basal, gonadotrophin-, and insulin-stimulated progesterone production by human
      luteinized granulosa cells (GC). GC were recovered from follicular aspirates
      obtained during transvaginal ultrasound-guided oocyte retrieval for in-vitro
      fertilization-embryo transfer, and cultured in defined medium with various
      combinations of chorionic gonadotrophin (HCG; 0 or 100 ng/ml), insulin (0-30
      microg/ml), and leptin (0-100 ng/ml). Progesterone concentrations in media were
      determined at various time points (2 h to 6 days). Leptin time- and dose
      dependently inhibited (P < 0.05) HCG-stimulated progesterone production by human
      luteinized GC, but did not alter basal steroidogenesis. Moreover, the inhibitory
      effect of leptin on gonadotrophin-stimulated progesterone production was only
      manifested in the presence of insulin. Leptin suppression of insulin-supported
      steroidogenesis was also time- and dose-dependent. We conclude that leptin
      inhibits gonadotrophin-stimulated GC progesterone production apparently by
      antagonizing insulin action. Leptin suppression of progesterone production by
      human luteinized GC is consistent with recent data from animal models, and
      supports the possible role of leptin as a regulator of human ovarian function.

PMID- 10357957
TI  - Purification of a candidate gonadotrophin surge attenuating factor from human
      follicular fluid.
AB  - Gonadotrophin surge attenuating factor (GnSAF) is a new non-steroidal ovarian
      substance, different from inhibin, which attenuates the pre-ovulatory luteinizing
      hormone (LH) surge in superovulated women. Human follicular fluid (FF) was used
      as a source for the isolation of GnSAF, the activity of which was monitored in an
      in-vitro pituitary bioassay. Primary rat pituitary cells were incubated with test
      substances for 48 h and subsequently washed and incubated with 0.1 micromol/l
      gonadotrophin releasing hormone (GnRH) plus test substances for 4 h. GnSAF
      activity was expressed as the reduction of GnRH-induced LH secretion in the 4 h
      incubation. GnSAF was purified from 250 ml of FF which was heat-treated at 80
      degrees C for 5 min. Heparin-sepharose chromatography, Con-A sepharose
      chromatography, reversed-phase high-performance liquid chromatography (HPLC) and
      preparative native gel electrophoresis were used for GnSAF fractionation. Using
      these purification steps, we have obtained an apparently homogeneous preparation
      that stains as a single band on sodium dodecyl sulphate (SDS)-polyacrylamide gel
      electrophoresis. GnSAF has an apparent molecular weight of 12.5 kDa and was
      identified by amino acid sequence (mass spectrometry) to be the C-terminal
      fragment of human serum albumin.

PMID- 10357958
TI  - Elective cryopreservation of all pronucleate embryos in women at risk of ovarian
      hyperstimulation syndrome: efficiency and safety.
AB  - In a prospective randomized study, we analysed 125 patients at risk of ovarian
      hyperstimulation syndrome (OHSS), selected in the period between January 1996 and
      July 1997. All the patients had blood oestradiol concentration >/=1500 pg/ml on
      the day of human chorionic gonadotrophin (HCG) administration and >/=15 oocytes
      were collected. The patients were matched in two groups: group A, control group
      (n = 67), had fresh embryo transfers; group B (n = 58) had cryopreservation of
      all obtained pronucleate embryos. Pregnancy, live birth rates and the incidence
      of OHSS were compared between the two groups. There were no significant
      differences in terms of pregnancies per patient (46.3 versus 48.3%) and live
      birth rates (38. 8 versus 39.6%). No cases of OHSS occurred in group B, while
      four patients developed the syndrome in group A. The implantation rate was
      slightly but not significantly lower in group B (chi2 = 1.03). These results
      suggest that elective cryopreservation of all zygotes might prevent the risk of
      OHSS in patients undergoing IVF treatment. In contrast to what has been reported
      by other authors, our results show that the elective cryopreservation of zygotes
      does not affect pregnancy and live birth rates.

PMID- 10357959
TI  - Cumulative pregnancy and live birth rates in women with antiphospholipid
      antibodies undergoing assisted reproduction.
AB  - The aims of this study were to investigate the influence of antiphospholipid
      antibodies (APA) on cumulative pregnancy and live-birth rates in patients
      undergoing assisted reproductive treatment. Serum samples from 173 patients were
      collected prior to initiation treatment cycle and tested by enzyme-linked
      immunosorbent assay (ELISA) for the presence of immunoglobulin (Ig)G, IgM and IgA
      against cardiolipin, phosphoserine, phosphoethanolamine, phosphoinositol,
      phosphatidic acid, and phosphoglycerol. Fifty-six samples from patients who had
      at least two failed cycles by assisted reproductive treatment were also tested by
      a bioassay for the presence of lupus anticoagulants. Both cumulative pregnancy
      and live birth rates were not affected by the presence of any specific or any
      number of seropositive APA. There was no association between multiple assisted
      reproductive treatment failures and APA seropositivity. Neither the serum
      concentration of any of the 18 APA, nor the number of positive APA was correlated
      with the number of assisted reproductive treatment failed cycles or affected the
      probability of pregnancy. No patient was found to be positive for lupus
      anticoagulants. Using life table analyses, which has been recognized as the most
      appropriate method available to analyse assisted reproductive treatment results,
      we conclude that there is no relationship between circulating APA and assisted
      reproductive treatment outcome. APA do not affect the early process of
      implantation or maintenance of pregnancy among assisted reproductive treatment
      patients.

PMID- 10357960
TI  - A case-control study to compare the variability of operating time in laparoscopic
      and open surgery.
AB  - The purpose of this study was to compare the variability of operating times for
      some of the most common gynaecological procedures performed laparoscopically and
      by open surgery. The case notes of 60 women randomly selected from a cohort of
      600 who had undergone laparoscopic surgery for ectopic pregnancy, ovarian cysts,
      leiomyoma and hysterectomy were reviewed. These patients were matched with an
      equal number of women who had been treated by open surgery for similar
      indications. Additional matching criteria included age (+/-2 years), size of the
      lesion in cases of ovarian cysts and fibroids (+/-3 cm), the period of
      amenorrhoea in ectopic pregnancies, and uterine size and pelvic pathology in
      women undergoing hysterectomy. Comparison of laparoscopy and laparotomy showed
      that the mean procedure times were similar for the two routes of surgery, with
      the exception of hysterectomy which took significantly longer if done
      laparoscopically. The duration of laparoscopic surgery for ectopic pregnancy,
      ovarian cystectomy and hysterectomy was significantly less predictable than at
      laparotomy. These data indicate that with the exception of hysterectomy, the
      average operating time for laparoscopic procedures is comparable to that for
      laparotomy. In contrast, the variability of duration of laparoscopic surgery
      tends to be much greater than with laparotomy for all procedures considered.

PMID- 10357961
TI  - Adhesion preventive effect of hyaluronic acid after intraperitoneal surgery in
      mice.
AB  - Prevention of intraperitoneal adhesion after gynaecological surgery is essential
      for maintaining postoperative fertility. In this study, the adhesion prevention
      effect was examined of a hyaluronic acid (HA) solution obtained from the
      fermentation method and having a molecular weight of 1.9x10(6) with high
      viscosity. Laparotomy was conducted on female mice 7 weeks old, whose menstrual
      periods were synchronized by pregnant mare serum gonadotrophin (PMSG) to injure
      the uterine horn surface. Intraperitoneal adhesions were favourably formed in
      91.7% of cases induced with iodine abrasion, compared with 50% induced by
      electrosurgery. Intraperitoneal administration of HA was evaluated for its effect
      on the prevention of adhesions made by iodine abrasion. Adhesion prevention
      effects of HA were observed at concentrations of 0.3, 0.5, 0.75 and 1.0%, among
      which the most pronounced effect was with the use of a 0.3% solution (92.3% of
      cases). Compared with the control group adhesion score of 2.0 +/- 0. 8,
      significant decreases in adhesion scores were observed at all concentrations. HA
      with a molecular weight of 1.9x10(6) was recognized to have a definitive
      prevention effect on postoperative adhesions in mice after laparotomy and is
      considered to be a prospective material for future clinical use.

PMID- 10357962
TI  - Morphological changes in hysterectomies after endometrial ablation.
AB  - Electrosurgical ablation of the endometrium is a therapeutic choice for those
      patients having abnormal uterine bleeding. When ablation is followed by a
      hysterectomy, tissue damage due to thermal effect can be seen. From a total of
      350 women with endometrial ablation, 12 required subsequent hysterectomy. The
      histological features found in these specimens are described and related to the
      elapsed time between the two surgical procedures. The mean elapsed time between
      ablation and hysterectomy was 19 +/- 17.3 months. Scarring with formation of
      additional endometrial cavities was seen in five cases, and endocervical stenosis
      in two cases. In seven patients, endometrial regrowth was seen at hysterectomy.
      Necrosis, granulomatous and foreign-body giant cell reaction, eosinophilic
      infiltrate and pigment-containing macrophages in the myometrium were seen in the
      long-term post-ablation hysterectomies. Necrosis was seen in short period post
      ablation hysterectomies. Six of the seven patients with endometrial regeneration
      had adenomyosis in the hysterectomy specimen. Endometrial ablation induces
      thermal effects in the endometrium and granulomatous reaction with foreign-body
      giant cell reaction, fibrosis and deposition of pigment within macrophages in the
      myometrium. Adenomyosis is a possible explanation for endometrial regeneration in
      cases of ablation failure.

PMID- 10357963
TI  - Is glycosylated haemoglobin a marker of fertility? A follow-up study of first
      pregnancy planners.
AB  - We performed a follow-up study of time to pregnancy in a population of first-time
      pregnancy planners without previous reproductive experience. The objective of
      this paper is to report and discuss a finding of a strong relationship between
      glycosylated haemoglobin (HbA1C) and fertility. A total of 165 Danish couples
      without previous reproductive experience was followed from termination of birth
      control until pregnancy for a maximum of six menstrual cycles. HbA1C and
      reproductive hormones were measured at entry. Questionnaire data were collected
      at entry and once in each cycle during follow-up. The odds ratio (OR) for
      pregnancy per cycle decreased with increasing concentration of HbA1C (OR per
      percent HbA1C 0.4, 95% CI 0.2-0.9 for all six cycles and 0.2, 95% CI 0.1-0.5 in
      the first three cycles). A high concentration of HbA1C was associated with a high
      concentration of testosterone and a low concentration of inhibin A. No
      association was found between HbA1C and psychosocial distress. The reduced
      fertility among women with high HbA1C may be due to an association with
      subclinical polycystic ovaries as indicated by the hormonal profile.

PMID- 10357964
TI  - Antiphospholipid antibodies in infertile couples with two consecutive
      miscarriages after in-vitro fertilization and embryo transfer.
AB  - Of 682 women who had undergone in-vitro fertilization (IVF) or intracytoplasmic
      sperm injection (ICSI) with embryo transfer, 84 were successful on two occasions,
      with 16 of these resulting in miscarriage before 20 completed weeks.
      Antiphospholipid antibodies (APA) were estimated by enzyme-linked immunosorbent
      assay in these women (group 1) and compared to two control groups: 42 fertile
      women with three or more miscarriages (group 2) and 60 women with primary
      infertility undergoing IVF or ICSI (group 3). An apparently higher prevalence of
      seropositivity was seen in group 1 women (25%) compared to the group 3 women
      (6.6%) and it was similar to that seen in group 2 women (21.4%). Therefore the
      recommendation that women with two consecutive miscarriages after IVF or ICSI
      should have APA estimations performed routinely may be justified.

PMID- 10357965
TI  - Coping with infertility: distress and changes in sperm quality.
AB  - Infertility represents a serious stressor for some patients as well as a risk
      factor for a decrease in sperm quality. The purpose of the present study was to
      identify coping strategies that went along with both better emotional and
      physical adjustment to infertility. The sample consisted of 63 patients who
      contacted an andrological clinic more than one time. Prior to clinical
      examination, patients filled out a questionnaire referring to the way in which
      they coped with their wives' previous menstruation. Participants also completed a
      scale assessing perceived distress due to infertility. Change in sperm
      concentration since baseline semen analysis and the level of distress were used
      to evaluate patient's adjustment. The better-adjusted patients showed less
      prominent overall coping efforts, and a higher proportion of distancing coping
      strategies. An improvement in sperm quality also was associated with a low
      cognitive involvement in infertility. Situational uncontrollability of
      infertility could be a moderator of the effectiveness of coping employed by the
      better-adjusted patients. In addition, the coping behaviour related to better
      adjustment could be due to a dispositional stress resistance factor. For clinical
      implementation of the findings, the attitudes of a patient and the expectations
      of his wife have to be taken into consideration.

PMID- 10357966
TI  - Venous thromboembolic disease and combined oral contraceptives: A re-analysis of
      the MediPlus database.
AB  - In October 1995 the Committee on Safety of Medicines advised UK doctors and
      pharmacists that oral contraceptives containing desogestrel and gestodene were
      associated with double the risk of venous thromboembolic events (VTE) compared to
      pills containing other progestogens. In 1997 data was analysed from the MediPlus
      database of UK general practitioner records, which reported odds ratios for
      desogestrel and gestodene lower than that for levonorgestrel. Here the results of
      a more stringent nested case control analysis on the MediPlus database are
      reported. The study was larger and cases were verified. A crude incidence of
      idiopathic VTE was found amongst users of combined oral contraceptives of 4.6 per
      10 000 exposed women years. Using levonorgestrel 150 microg + ethinyloestradiol
      30 microg as reference, non-significant odds ratios of 1.1 (0.5-2.6) for
      desogestrel 150 microg + ethinyloestradiol 30 microg and 1.1 (0.5-2.4) for
      gestodene 75 microg + ethinyloestradiol 30 microg were found. The results of this
      study show no significant difference in risk between different formulations of
      combined oral contraceptive.

PMID- 10357967
TI  - Ooplasmic injections of rabbit round spermatid nuclei or intact round spermatids
      from fresh, cryopreserved and cryostored samples.
AB  - We compared the outcome of ooplasmic round spermatid nuclear injections (ROSNI)
      versus intact round spermatid injections (ROSI). Rabbit round spermatid nuclei
      and intact round spermatids were recovered and injected into rabbit oocytes
      (groups A and B, respectively). Fertilization, cleavage and embryonic development
      rates were compared. In additional studies, five protocols for cryopreservation
      of round spermatids and two protocols for cryostorage of round spermatids were
      applied. The outcome of ROSNI techniques using frozen-thawed or cryostored-warmed
      round spermatids was evaluated. The cleavage rate and the overall morula plus
      blastocyst development rate were significantly larger in group A than group B.
      ROSNI procedures are superior to ROSI techniques in the rabbit. The largest
      fertilization, cleavage and embryonic development rates after ROSNI techniques
      using cryopreserved or cryostored round spermatids were demonstrated in groups of
      round spermatids in which a mixture of seminal plasma plus test yolk buffer was
      employed as an extender, and dimethyl sulphoxide plus a high concentration of
      glycerol served as cryoprotectants. It appears that the seminal plasma contains
      factors protecting round spermatids during cryopreservation or cryostorage,
      and/or the employment of two cryoprotectants has a beneficial role in the
      maintenance of round spermatid reproductive capacity.

PMID- 10357968
TI  - Effects of hypercholesterolaemia on Leydig and Sertoli cell secretory function
      and the overall sperm fertilizing capacity in the rabbit.
AB  - The effects of hypercholesterolaemia on testicular endocrine and exocrine
      function were evaluated. The influence of hypercholesterolaemia on sperm quality,
      quantity, and fertilizing potential was also determined. Ten mature rabbits
      (group A) were fed chow containing 3% cholesterol for 12 weeks. Ten control
      rabbits (group B) were fed normal chow for the same period. At the end of the
      experimental period testosterone profiles and sperm parameters were evaluated and
      the sperm reproductive potential was assessed by in vitro fertilization (IVF)
      techniques. Peripheral serum testosterone responses to testicular stimulation
      with human chorionic gonadotrophin, androgen-binding protein activity in
      testicular cytosols, sperm concentration, sperm motility, length of sperm
      midpiece, and IVF outcome were all significantly lower in group A than in group
      B. In contrast, serum cholesterol concentrations were significantly higher in
      group A. There were no significant differences in either testicular versus intra
      abdominal temperature differences or cholesterol concentrations in seminal plasma
      or testicular tissue between groups A and B. The results suggest that
      hypercholesterolaemia has a detrimental effect on Leydig and Sertoli cell
      secretory function, spermatogenesis, epididymal sperm maturation process, and the
      overall sperm fertilizing capacity.

PMID- 10357969
TI  - Androgen regulation of glycosidase secretion in epithelial cell cultures from
      human epididymis.
AB  - The human epididymis and its secretions actively promote sperm fertilizing
      capacity and provide protection for spermatozoa against harmful influences. Among
      epididymal secretions, glycosidases have been recently studied and associated
      with molecular changes on the sperm surface. In the present work, we studied the
      influence of different concentrations of testosterone, dihydrotestosterone and
      cyproterone acetate on the secretion of alpha-glucosidase, N-acetyl
      glucosaminidase, beta-glucuronidase and alpha-mannosidase by isolated and
      cultured epithelial cells from human caput, corpus and cauda epididymides. Cell
      cultures were obtained from aggregates of isolated tubule fragments plated on
      extracellular matrix-covered multi-well plates. Activities of the glycosidases
      were measured in conditioned culture media and were higher in the distal regions
      of the epididymis. Testosterone and dihydrotestosterone significantly increase
      the enzyme secretion in a concentration-dependent manner. This increase was
      higher in corpus and/or cauda than in caput epididymis. Cyproterone acetate
      caused a dose-dependent decrease in glycosidase secretion in cultures from all
      epididymal regions. It is concluded that the secretion of epididymal glycosidases
      is regulated by androgen, being stimulated by dihydrotestosterone and
      testosterone and inhibited by the androgen antagonist cyproterone acetate.

PMID- 10357970
TI  - Evaluation of the fertilization potential of freshly isolated, in-vitro cultured
      and cryopreserved human spermatids by injection into hamster oocytes.
AB  - The clinical potential for fertilization was examined by using the human sperm
      hamster oocyte assay system after microinjection of round (RS), elongating (ES)
      or elongated (EtedS) spermatids retrieved from obstructive and non-obstructive
      azoospermic patients. Freshly isolated, in-vitro cultured and cryopreserved
      spermatids were utilized. For each category of microinjected spermatids, we
      demonstrated that the more mature the injected spermatid, the higher the
      incidence of fertilization (for freshly isolated spermatids, P < 0.006 and P <
      0.008, for in-vitro cultured spermatids, P < 0.007 and P < 0.007 and for
      cryopreserved spermatids, P < 0.006 and P < 0.007 for obstructive and non
      obstructive azoospermic patients respectively). Short term in-vitro culture of
      the spermatogenic cells did not improve the incidence of fertilization. However,
      cryopreservation significantly decreased (P < 0.001) the incidence of
      fertilization when each corresponding spermatogenic cell stage was compared. The
      incidence of fertilization was not statistically different when corresponding
      stages of spermatogenic cells were compared from obstructive and non-obstructive
      patients.

PMID- 10357971
TI  - Seminal transforming growth factor-beta in normal and infertile men.
AB  - Transforming growth factor-beta (TGFbeta) is a cytokine with autocrine and
      paracrine action in the testis and potent immunoregulatory and anti-inflammatory
      activities. In the present study, we examined the concentration of latent (acid
      activatable) and free (active) TGFbeta in seminal plasma from normal subjects (n
      = 23) and infertile (n = 40) patients, by using a TGFbeta specific
      immunoenzymological assay, and a bioassay (CCL64 cell line growth inhibition)
      detecting any form of TGFbeta. Free TGFbeta1 was present in normal subjects at a
      concentration (1.82 +/- 1.06 ng/ml) close to that known to give maximal
      stimulation in vitro. In pathological groups, the mean concentrations were not
      significantly different from the normal ones. Latent TGFbeta1 was present in
      normal seminal plasma at a high concentration (92.4 +/- 29.2 ng/ml). In subjects
      with pathologies of both testis and genital apparatus, or with epididymal
      occlusion, mean latent TGFbeta1 concentrations were normal, whereas transferrin
      concentrations were lower. The concentrations found in the epididymal occlusion
      group indicate that TGFbeta1 is, for a large part, secreted by the genital tract.
      In the testicular pathology group, TGFbeta1 concentrations were 130.7 +/- 61.2
      ng/ml, a mean not statistically different from normal, although higher. No
      differences were found between patients with high and normal blood plasma
      follicle stimulating hormone, and this is consistent with the notion that most
      TGFbeta1 in seminal plasma is not of testicular origin. The TGFbeta bioassay
      ensured that immunologically detected TGFbeta was present in a bioactive or
      bioactivatable form. Furthermore, the values found in normal and pathological
      seminal plasmas were usually higher than those detected by the immunoassay,
      suggesting that other forms of TGFbeta might be present. Together, the present
      data show that very large amounts of TGFbeta are present in human seminal plasma.
      The TGFbeta ligand assay in the seminal plasma appears to indicate no differences
      between normal and infertile subjects.

PMID- 10357972
TI  - Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F)
      with urinary human chorionic gonadotrophin for induction of spermatogenesis and
      fertility in gonadotrophin-deficient men.
AB  - In order to evaluate the efficacy and safety of recombinant human follicle
      stimulating hormone (r-hFSH) in combination with urinary human chorionic
      gonadotrophin (HCG) to induce spermatogenesis and fertility in gonadotrophin
      deficient men, we conducted a prospective, open, non-comparative multicentre
      study in two Australian academic medical centres. Ten men with gonadotrophin
      deficiency requiring induction of spermatogenesis and fertility were treated with
      HCG for 3-6 months followed by the s.c. self-administration of injections of r
      hFSH in combination with HCG for 18 months. Among the eight men who commenced r
      hFSH treatment, seven demonstrated sperm output at a median of 6 months and five
      achieved the target sperm output of 1. 5x10(6) per ml at a median of 9 months of
      FSH treatment. Mean testicular volume increased by 4.2 ml during FSH treatment.
      Three men produced pregnancies in their partners, two of which resulted in the
      birth of healthy babies and a third patient's partner had a miscarriage. We
      conclude that r-hFSH is well tolerated and effective in inducing testis growth,
      spermatogenesis and fertility in gonadotrophin-deficient men. The efficacy of r
      hFSH seems comparable with urinary FSH at restoring normal fertility in
      gonadotrophin-deficient men.

PMID- 10357973
TI  - Triplet pregnancy achieved through intracytoplasmic sperm injection with
      spermatozoa obtained by prostatic massage of a paraplegic patient: case report.
AB  - Spinal cord-injured men with ejaculation disorders can have children thanks to
      assisted reproduction techniques. Spermatozoa from these patients are usually
      obtained through vibratory stimulation, electroejaculation or by puncturing the
      seminal duct or the testicle. We present the first published case, as far as we
      are aware, of spermatozoa obtained through prostatic massage of a paraplegic
      patient. Penile vibratory stimulation was unsuccessful in this patient. In-vitro
      fertilization (IVF) with intracytoplasmic sperm injection (ICSI) with spermatozoa
      obtained through electroejaculation was performed at another centre but pregnancy
      was not achieved. Through prostatic massage, we obtained a total semen volume of
      6 ml containing a total count of 12.32x10(6) spermatozoa (6.24x10(6) with tails),
      8% of which had motility (graded + and ++); and 16% of which had normal
      morphology. The spermatozoa obtained were then used to perform IVF with ICSI and
      a triplet pregnancy was achieved. Prostatic massage appears to be an easy, non
      traumatic and risk-free method to obtain spermatozoa from paraplegic patients.

PMID- 10357974
TI  - Morphology and functional characteristics of human ovarian microvascular
      endothelium.
AB  - Corpus luteum formation is characterized by a period of extensive
      vascularization, as capillaries in the thecal layer of the collapsed follicle
      following ovulation invade the previously avascular granulosa layer. In order to
      study these processes in vitro we have developed an endothelial cell preparation
      from the specific microvasculature of the ovarian follicle. Follicular aspirates,
      obtained at oocyte collection for in-vitro fertilization (IVF), were filtered to
      obtain fragments of follicle wall. These were set in Matrigel and then cultured
      allowing the growth of capillary-like structures through the matrix. Upon
      emergence from the Matrigel the growing cells formed monolayers with the
      characteristic cobble-stone morphology of endothelial cells. Immunocytochemistry
      demonstrated the presence of a range of endothelial-specific markers including
      von Willebrand factor (vWF), Ulex europeus agglutinin (UEA)-1, CD31 and E
      selectin, as well as VCAM-1, which is normally associated with stimulated
      endothelial cells. RT-PCR analysis showed the expression of two receptors for
      vascular endothelial growth factor (flt-1 and KDR), and the endothelial nitric
      oxide synthase, adding further evidence of their identity as human ovarian
      microvascular endothelial cells (HOMEC). Thus, the novel preparative procedure
      described now allows the generation of HOMEC cultures from readily available
      material resulting from IVF procedures.

PMID- 10357975
TI  - Effects of follicle-stimulating hormone and serum substitution on the in-vitro
      growth of human ovarian follicles.
AB  - In-vitro maturation (IVM) of human ovarian follicles and oocytes could benefit
      infertile women, and allow the development of in-vitro systems for the study of
      human follicular development. Little is known about the initiation of growth of
      primordial follicles and the regulation of early folliculogenesis. An ovarian
      tissue-slice culture system was used to examine the effects of media composition,
      follicle stimulating hormone (FSH) and serum substitution on the development of
      small human follicles in vitro. Human ovarian cortex biopsies were cut into small
      pieces and cultured for 5, 10 or 15 days. Control (non-cultured) and cultured
      tissue was fixed, serially sectioned, and stained. The follicles contained within
      the tissue pieces were counted, measured, and assessed for stage of development
      and viability. Comparison of the ability of alpha-minimum essential medium (alpha
      MEM), Waymouth's, or Earle's balanced salt solution (EBSS) culture media (all
      with 10% human serum) to support follicle growth demonstrated significantly
      increased initiation and growth of follicles in alpha-MEM during the first 10
      days of culture. The supplementation of alpha-MEM with 300 mIU/ml FSH
      significantly reduced levels of atresia and increased the mean diameter of
      healthy follicles. Follicles in tissue cultured for 10 days with human serum
      albumin and ITS (insulin/transferrin/selenium mix) were significantly larger,
      more developed and showed significantly less atresia than those cultured with
      serum alone. Primordial to small preantral follicles can be grown under serum
      substituted conditions in tissue-slice culture, and are responsive to FSH, which
      is thought to be acting mainly as a survival factor at these early stages.

PMID- 10357976
TI  - Assessment of the follicular cortisol:cortisone ratio.
AB  - Cortisol and cortisone concentrations in serum and follicular fluid (FF) from
      women undergoing in-vitro fertilization (IVF) treatment were monitored. Four
      groups were included: group 1, women in their natural menstrual cycle having an
      endogenous mid-cycle surge of gonadotrophins; group 2, women in their natural
      menstrual cycle receiving human chorionic gonadotrophin (HCG) for ovulation
      induction; group 3, women receiving exogenous gonadotrophins for ovarian
      stimulation and HCG for ovulation induction; and group 4, women receiving
      exogenous gonadotrophins for ovarian stimulation, follicles being aspirated
      immediately before administration of HCG. In this study, 12 follicles contained
      oocytes which resulted in clinical pregnancy after IVF. Cortisone concentrations
      were significantly higher in FF compared with that of matched serum samples,
      while the opposite was observed for cortisol, resulting in cortisol:cortisone
      ratios being significantly lower in FF compared with serum. FF from group 4
      showed significantly higher cortisone concentrations than FF from each of the
      other three groups. FF from group 1 showed significantly higher cortisone
      concentrations and significantly lower cortisol:cortisone ratios in comparison
      with groups 2 and 3. None of the observed parameters pinpointed any of the
      follicles containing oocytes which resulted in a clinical pregnancy. The
      intrafollicular concentrations of cortisol and cortisone suggest that pre
      ovulatory follicles actively convert cortisol to cortisone. Neither FF
      concentrations of cortisol and cortisone nor the cortisol:cortisone ratio seem to
      reflect implantation potential of the derived pre-embryos.

PMID- 10357977
TI  - Assessment of the follicular cortisol:cortisone ratio 
AB  - Cortisol and cortisone concentrations in serum and follicular fluid (FF) from
      women undergoing in-vitro fertilization (IVF) treatment were monitored. Four
      groups were included: group 1, women in their natural menstrual cycle having an
      endogenous mid-cycle surge of gonadotrophins; group 2, women in their natural
      menstrual cycle receiving human chorionic gonadotrophin (HCG) for ovulation
      induction; group 3, women receiving exogenous gonadotrophins for ovarian
      stimulation and HCG for ovulation induction; and group 4, women receiving
      exogenous gonadotrophins for ovarian stimulation, follicles being aspirated
      immediately before administration of HCG. In this study, 12 follicles contained
      oocytes which resulted in clinical pregnancy after IVF. Cortisone concentrations
      were significantly higher in FF compared with that of matched serum samples,
      while the opposite was observed for cortisol, resulting in cortisol:cortisone
      ratios being significantly lower in FF compared with serum. FF from group 4
      showed significantly higher cortisone concentrations than FF from each of the
      other three groups. FF from group 1 showed significantly higher cortisone
      concentrations and significantly lower cortisol:cortisone ratios in comparison
      with groups 2 and 3. None of the observed parameters pinpointed any of the
      follicles containing oocytes which resulted in a clinical pregnancy. The
      intrafollicular concentrations of cortisol and cortisone suggest that pre
      ovulatory follicles actively convert cortisol to cortisone. Neither FF
      concentrations of cortisol and cortisone nor the cortisol:cortisone ratio seem to
      reflect implantation potential of the derived pre-embryos.

PMID- 10357979
TI  - Effect of in-utero diethylstilboestrol exposure on human oocyte quality and
      fertilization in a programme of in-vitro fertilization.
AB  - Genital tract abnormalities and adverse pregnancy outcome are well known in women
      exposed in utero to diethylstilboestrol (DES). Data about adverse reproductive
      performance in women exposed to DES have been published, including controversial
      reports of menstrual dysfunction, poor responses after ovarian stimulation,
      oocyte maturation and fertilization abnormalities. We compared oocyte quality, in
      vitro fertilization results and embryo quality for women exposed in utero to DES
      with a control group. Between 1989 and 1996, 56 DES-exposed women who had 125 in
      vitro fertilization (IVF) attempts were retrospectively compared to a control
      group of 45 women with tubal disease, who underwent 73 IVF attempts. Couples
      suffering from male infertility were excluded. The parameters compared were
      oocyte quality (maturation abnormalities, immature oocyte, mature oocyte),
      fertilization and cleavage rate (per treated and metaphase II oocytes), and
      embryo quality (number and grade). We found no significant difference in oocyte
      maturational status, fertilization rates, cleavage rates, embryo quality and
      development between DES-exposed subjects and control subjects. These results
      suggest that in-utero exposure to DES has no significant influence on oocyte
      quality and fertilization ability as judged during IVF attempts.

PMID- 10357978
TI  - Effects of cryoprotectants and ice-seeding temperature on intracellular freezing
      and survival of human oocytes.
AB  - The accurate determination of the freezing conditions that promote intracellular
      ice formation (IIF) is crucial for designing cryopreservation protocols for
      cells. In this paper, the range of temperatures at which IIF occurs in human
      oocytes was determined. Fresh oocytes with a germinal vesicle, failed-to
      fertilize (metaphase I and metaphase II stages) and polyspermic eggs were used
      for this study. The occurrence of IIF was first visualized at a cooling rate of
      120 degrees C/min using a programmable thermal microscope stage connected to a
      videomicroscope. Then, with a cooling rate of 0.2 degrees C/min, the seeding
      temperature of the extracellular ice was modified to decrease the incidence of
      IIF and increase the survival rate of frozen-thawed human oocytes. After adding
      different cryoprotectants, the median temperature of IIF (TMED) was decreased by
      approximately 23 degrees C in mouse and only by approximately 6.5 degrees C in
      human oocytes. Using 1.5 M propylene glycol and seeding temperatures of -8.0, 
      6.0 and -4.5 degrees C, the incidence of IIF was 22/28 (78%), 8/24 (33%) and 0/33
      (0%) and the 24 h post-thaw survival rate was 10/31(32%), 19/34 (56%) and 52/56
      (93%) respectively. The results show that IIF occurs more readily in human
      oocytes, and that ice seeding between -6 degrees C and -8 degrees C triggers IIF
      in a large number of human oocytes. Undesirable IIF can be prevented and survival
      rates maximized by raising the seeding temperature as close as possible to the
      melting point of the solution, which in our instrument was -4.5 degrees C.

PMID- 10357980
TI  - Checkpoint control of the G2/M phase transition during the first mitotic cycle in
      mammalian eggs.
AB  - The high incidence of chromosomally abnormal human embryos is frequently assumed
      to be due to a lack of checkpoint controls operating during early embryogenesis.
      In our study we have analysed when these mechanisms first become functional.
      Mouse oocytes treated in late metaphase I with either of two different cyclin
      dependent kinase inhibitors [butyrolactone 1 (BL1) or 6-dimethylaminopurine (6
      DMAP)] form nuclei in the cytoplasm. BL1-treated eggs enter S-phase at 16-18 h
      post-treatment and, after completion of DNA synthesis, cleave to 2-cell stage
      embryos. 6-DMAP treatment results in the rapid initiation of DNA synthesis, its
      completion by 12 h and then arrest in the G2 phase. Thus, two different cell
      cycle stages can be obtained at the same time point after the initiation of
      treatment: G1- after BL1 and G2-staged nuclei after 6-DMAP treatment. That this
      approach greatly facilitates cell cycle studies has been shown by analysing
      checkpoint function during the first division. Whilst G2-staged eggs enter M
      phase within 2-3 h when 6-DMAP is washed out, the onset of M phase is delayed
      after their fusion to G1 (BL1) cells. Here M phase occurs only after the less
      advanced nucleus completes DNA replication. Our results indicate that checkpoints
      in mammalian eggs are functional during the first mitotic cycle.

PMID- 10357981
TI  - Evaluation of the effect of interleukin-6 and human extracellullar matrix on
      embryonic development.
AB  - Extracellular matrices and their associated growth factors can modulate the in
      vitro growth of cells. In this study, the effects of culture substrata and the
      cytokine interleukin-6 (IL-6) on embryonic development were investigated. In
      vitro fertilized mouse oocytes were pooled and randomly distributed amongst
      treatment groups. The test treatments were: (i) IL-6, at either 500 or 1000
      pg/ml; (ii) human extracellular matrix (HECM) applied to organ culture dishes at
      either 5.0 or 10.0 microg/ml; and (iii) HECM and IL-6 combined. A total of 1285
      embryos was evaluated. The effect of IL-6 on embryos was dose dependent. Treated
      embryos exhibited higher blastulation and hatching rates than untreated control
      embryos. Culture of embryos on human matrix proteins versus standard culture
      surfaces significantly improved in-vitro hatching. The combination of both of
      these treatments was superior to the medium alone control, and the mean cell
      count per blastocyst was higher (131.7 +/- 29.7 versus 82. 5 +/- 14.3 in control
      embryos; P < 0.0001). In a pilot study with human triploid embryos, the HECM/IL-6
      culture system appeared to support embryonic compaction, blastulation and
      hatching. This work suggests that extracellular matrix components in combination
      with growth factors/cytokines may be another avenue for formulating more
      physiological culture systems.

PMID- 10357982
TI  - Ultrasound evaluation of the uterine zonal anatomy during in-vitro fertilization
      and embryo transfer.
AB  - This study was designed to establish if ultrasound could detect differences in
      uterine zonal anatomy between conception and non-conception in-vitro
      fertilization (IVF)/embryo transfer cycles. A transvaginal ultrasound scan was
      performed on the day of down regulation (D0), on day 8 of ovulation induction
      (D8), on the day of human chorionic gonadotrophin (HCG) injection, at the time of
      oocyte retrieval, and at embryo transfer. Thicknesses of endometrium, junctional
      zone, myometrium and full thickness of the uterus were recorded for every patient
      and comparisons made at all the assessment points. Differences between
      measurements on D0 and all other measurements (temporal changes) and between
      every subsequent measurement (dynamic changes) were also compared. There were no
      statistically significant differences in endometrial thickness between pregnant
      and non-pregnant groups at any time. The diameter of the uterus increased during
      therapy and was significantly greater in the pregnant subset at the time of HCG
      injection, oocyte retrieval and embryo transfer (P < 0.02, 0.03 and 0.02
      respectively). The myometrium was significantly thicker in the pregnant group on
      D0, on D8 and at HCG administration (P < 0.03, 0.004 and 0.02). There was a
      decrease in junctional zone thickness in both groups during the first week of
      ovulation induction, and on D8 the junctional zone in pregnant patients was
      significantly thinner (P < 0.04). The junctional zone became significantly
      thicker at embryo transfer in the pregnant group (P < 0.01). This was confirmed
      by significant temporal and dynamic changes at the time of oocyte retrieval and
      embryo transfer (P < 0.01, 0.0001 and P < 0.05, 0.01 respectively). In the
      patients who did not conceive, changes in the junctional zone were less
      pronounced. In conclusion, it was not possible to predict the likelihood of
      pregnancy from endometrial thickness at any time during the IVF cycle, but
      changes occurred in other uterine layers that were more pronounced in conception
      cycles. The responsiveness of the junctional zone seems to be associated with
      implantation, and its measurements at the time of downregulation and embryo
      transfer can be used to predict treatment outcome.

PMID- 10357983
TI  - Human decidual stromal cells express alpha-smooth muscle actin and show
      ultrastructural similarities with myofibroblasts.
AB  - Previous reports in human and mouse material demonstrated that decidual stromal
      cells expressed antigens associated with haematopoietic cells, exerted immune
      functions, and originated from bone marrow. These findings suggested that these
      cells belonged to the haematopoietic lineage. We purified and expanded in culture
      precursors of human decidual stromal cells, and found in electron microscopic
      images that the ultrastructure of these cells was similar to that of
      myofibroblasts, which are of mesenchymal origin. The relationship between these
      two types of cell was confirmed by the detection (by flow cytometry) in the
      decidual precursors of alpha-smooth muscle actin, a contractile microfilament
      expressed solely by smooth muscle cells, myofibroblasts and related cells. This
      filament was also detected in decidual stromal cells decidualized in vitro by the
      effect of progesterone. We also found vimentin in decidual precursors and
      decidualized cells. This intermediate filament has been previously reported to be
      expressed by all decidual stromal cells and also by myofibroblasts. Desmin,
      another intermediate filament expressed by myofibroblasts, was not detected in
      the decidual precursors; however, this filament was observed in decidualized
      cells. The expression of alpha-smooth muscle actin by decidual stromal cells was
      also found by immunostaining in cryostat sections of early decidua. Our results
      suggest that decidual stromal cells are related to myofibroblasts.

PMID- 10357984
TI  - Association of endometrial blood flow as determined by a modified colour Doppler
      technique with subsequent outcome of in-vitro fertilization.
AB  - An endometrial thickness of 10 mm or more has been reported to be favourable for
      embryo implantation. Nevertheless, many women participating in in-vitro
      fertilization (IVF) programmes have adequate endometrial thickness but do not
      achieve satisfactory implantation. With the aid of power Doppler sonography, we
      examined the association between intra-endometrial vascularity and reproductive
      outcome. For this study, we enrolled only women with endometrial thickness
      >/=ISOdia>/=10 mm and excluded those with apparent endometrial pathologies. Of 95
      women undergoing IVF cycles, there resulted 37 intrauterine pregnancies. The
      women were of similar age, body mass index, peak oestradiol concentration and
      endometrial thickness, and a similar number of embryos were transferred. Those
      women with an intra-endometrial power Doppler area (EPDA) <5 mm2 achieved a
      significantly lower pregnancy rate (23. 5 versus 47.5%, P = 0.021) and
      implantation rate (8.1 versus 20.2%, P = 0.003) than those with an EPDA
      >/=ISOdia>/=5 mm2. We conclude that, in addition to endometrial thickness, EPDA
      may serve as a factor indicative of endometrial receptivity. Women with adequate
      endometrial thickness but a small EPDA tended to have an unfavourable
      reproductive outcome.

PMID- 10357985
TI  - Hepatocyte growth factor concentrations are elevated in peritoneal fluid of women
      with endometriosis.
AB  - The concentrations of hepatocyte growth factor (HGF) in peritoneal fluid (PF)
      from women with endometriosis (n = 36) and without endometriosis (n = 40) were
      measured. All of the PF samples examined contained detectable concentrations of
      HGF. The HGF concentrations in PF from women with stage III/IV endometriosis
      (0.906 ng/ml, 0. 561-1.185; median, interquartile range) were significantly
      higher (P < 0.0001) than those from women without endometriosis (0.315 ng/ml,
      0.251-0.472). The HGF concentrations from women with stage I/II endometriosis
      (0.417 ng/ml, 0.310-1.023) appeared to be intermediate. There were no apparent
      variations detected among the HGF concentrations in women in the follicular or
      luteal phases regardless of the presence of endometriosis. Interestingly, HGF
      concentrations in PF from women on gonadotrophin releasing hormone analogues,
      independent of the presence of endometriosis, were comparable with those from
      untreated women. Given the known mitogenic property of HGF in human endometrial
      cells, these results suggest that HGF might play a role in the progression of
      endometriosis.

PMID- 10357986
TI  - Endothelin concentrations in monochorionic twins with severe twin-twin
      transfusion syndrome.
AB  - The objective of this study was to determine endothelin (ET-1) concentrations in
      monochorionic twin fetuses with and without twin-twin transfusion syndrome
      (TTTS). Fourteen monochorionic twin pregnancies complicated by TTTS and six
      without TTTS were studied. Matched maternal and fetal blood samples were obtained
      both in utero and at birth. Amniotic fluid samples were also collected from twin
      pairs. ET-1 concentrations were measured by radio-immunoassay. ET-1
      concentrations in recipient fetuses were higher than in the donors both in
      utero(P < 0.001) and at birth (P < 0.01). Fetal concentrations of ET-1 in donors
      were similar to non-TTTS twins. Plasma ET-1 concentrations were significantly
      higher (P < 0.01) in recipient fetuses with severe hydrops than those with
      mild/no hydrops. Maternal concentrations of ET-1 were comparable in the two
      groups. Endothelin concentrations in recipient twins were 2(1/2) times higher
      than in their co-twins and this was related to the severity of hydrops.

PMID- 10357987
TI  - Relationship between maternal serum vascular endothelial growth factor
      concentration in early pregnancy and fetal and placental growth.
AB  - Vascular endothelial growth factor (VEGF) has important effects on endothelial
      cells increasing cell proliferation, permeability and nitric oxide production;
      concentrations of VEGF in the maternal serum increase during the first 10 weeks
      of pregnancy. In this study, the relationship of maternal serum VEGF with
      maternal health during pregnancy and with fetal and placental size at mid
      pregnancy and at term was investigated. Serum was obtained from 539 Caucasian
      women with singleton pregnancies between 8 and 20 weeks of pregnancy (mean 14
      weeks). Total serum VEGF concentrations were measured by direct competitive
      radioimmunoassay. Fetal size and placental volume were measured by ultrasound
      between 16 and 20 weeks gestation. Birthweight, placental weight and
      anthropometric measurements of the baby were obtained after delivery. Serum VEGF
      concentrations were found to be higher in women with a lower weight before
      pregnancy (P = 0.01) and in those carrying a female fetus (P = 0.002). VEGF
      concentrations were positively correlated with placental volume (r = 0.17, P =
      0.0001) but not with fetal size between 16 and 20 weeks gestation. Serum VEGF
      concentrations were positively correlated with both birthweight (r = 0.10, P =
      0.02) and placental weight at delivery (r = 0.13, P = 0.003). The data presented
      support the view that VEGF may be one of the factors involved in mediating the
      maternal cardiovascular adaptation to pregnancy.

PMID- 10357988
TI  - A possible role for activated protein C resistance in patients with first and
      second trimester pregnancy failure.
AB  - Thrombophilia was recently suggested as a possible factor in recurrent pregnancy
      losses. We studied prospectively 125 patients (mean age 31.4 +/- 5.6 years) with
      one or more first or second trimester pregnancy losses for the prevalence of
      activated protein C resistance (APCR). Proteins C and S antigens, antithrombin
      III, anticardiolipin, and lupus anti-coagulant were also evaluated. Patients with
      uterine malformations, hormonal abnormalities, chromosomal translocations and
      infectious causes were excluded. A control group of 125 women with no past fetal
      loss were matched with the study group. Whenever the APC-sensitivity ratio (APC
      SR) was </=2.2, polymerase chain reaction for factor V mutation (Leiden) was
      performed. Heterozygosity for the mutation was found in 18 patients (14.4%)
      compared with seven heterozygous among 125 control group (5. 6%; P < 0.05).
      Acquired APCR (APC-SR 1.8 and Leiden negative) was revealed in seven patients
      (5.6%) in the study group and in three of the controls (2.4%; not significant).
      The rate of preclinical pregnancy losses (17/48) and second trimester
      miscarriages (10/48) in mutation carriers was significantly higher than in
      patients with no APCR (25/214) and (14/214) respectively (P < 0.001 and P < 0.01
      respectively). Live birth rate was not different between the two groups.
      Occurrence of APCR with any kind of pregnancy loss calculated per patient, in our
      study group, was approximately 1/7, 1/4 and 1/5 with one, two and three or more
      pregnancy losses respectively. These findings suggest that assessment of APCR
      should be considered in a more extended evaluation of such patients.

PMID- 10357989
TI  - Increased blood vessel density in decidua parietalis is associated with
      spontaneous human first trimester abortion.
AB  - Spontaneous pregnancy loss affects 15-18% of couples, and a number of potential
      causes are being discussed. The purpose of the present study was to assess if
      angiogenic disorders in the decidua of early human pregnancy could be related to
      spontaneous abortions. First trimester human decidua from elective terminations
      of normally progressing pregnancies and from missed abortions were investigated
      immunohistochemically. We quantified vessel density in decidua from normal
      pregnancies and from abortions by von Willebrand factor (vWF), platelet
      endothelial cell adhesion molecule (PECAM-1) and CD34 staining. Decidual blood
      vessel expression of alphavbeta3 integrin was also investigated. Significant
      increase (P < 0.02) in vessel density was observed in decidua parietalis of
      abortions, compared to decidua basalis. This increase was detected on slides
      stained for vWF and CD34, but not for PECAM-1. We observed a 15% increase
      analysing with vWF and a 77% increase with CD34 staining. alphavbeta3 integrin
      expression was not significantly different, neither in decidua parietalis from
      abortion, nor parietalis from normal pregnancies. Our data suggest that the
      increased vascularization in decidua parietalis from abortions could reflect
      complex disorders, such as specific cytokine expressions and hypoxia phenomena
      during the development of the decidua.

PMID- 10357990
TI  - Does an acidic medium enhance the efficacy of vaginal misoprostol for pre
      abortion cervical priming?
AB  - Absorption pharmacokinetics reveal a relationship between plasma concentrations
      of misoprostol and its therapeutic effect. To achieve a constant plasma profile
      and optimal efficacy, it is important to develop a medium that ensures complete
      dissolution of vaginal misoprostol tablets. Vaginal misoprostol is said to
      liquefy better in an acidic medium; thus, the aim of this study was to determine
      whether a 200 microg misoprostol tablet dissolved in acetic acid would be more
      efficacious than 200 microg misoprostol dissolved in water for pre-abortion
      cervical priming. A total of 120 healthy nulliparous women requesting legal
      termination of pregnancy between 6-12 weeks gestation were allocated randomly to
      either of the study groups. Vacuum aspiration was performed 3-4 h after insertion
      of the misoprostol tablet. Using Hegar's dilator, the degree of cervical
      dilatation before operation was measured. Of 60 women, 14 (23%) achieved a
      cervical dilatation of >/=8 mm when the misoprostol dose was dissolved in acetic
      acid; 12 (20%) achieved a similar cervical dilatation when the dose was dissolved
      in water. The mean cervical dilatation for the acid and water media used was 6.3
      mm and 6.2 mm respectively; these differences were not statistically significant,
      neither were pre-operative and intra-operative blood losses statistically
      different between the two groups. Twenty-four (40%) and four (7%) respectively of
      women in whom a water medium was used experienced vaginal bleeding and abdominal
      pain; 20 (33%) and 0 women respectively among those in whom an acetic acid medium
      was used experienced vaginal bleeding and abdominal pain. These differences in
      side effects were not statistically significant. Our study shows that the use of
      acetic acid to dissolve vaginal misoprostol does not improve the efficacy in
      achieving successful cervical dilatation for pre-abortion cervical priming.

PMID- 10357992
TI  - Human chorionic gonadotrophin concentrations in early pregnancy after in-vitro
      fertilization.
AB  - There is increased risk of early pregnancy loss after assisted reproduction. In
      this study the use of serum human chorionic gonadotrophin (HCG) concentrations on
      day 12 after in-vitro fertilization (IVF) and embryo transfer was evaluated to
      predict pregnancy outcome. A total of 417 IVF pregnancies were included. Early
      pregnancy loss was defined as biochemical pregnancies, ectopic pregnancies and
      first trimester abortions. Vital pregnancies were defined as delivered
      singletons, multiple pregnancies and second trimester abortions. On the post
      embryo transfer day 12, the mean HCG concentration of the vital pregnancy group
      was significantly higher than in early pregnancy loss outcomes (P < 0.00001).
      Receiver operating characteristic (ROC) curve analysis was performed to evaluate
      the cut-off value of HCG giving maximal sensitivity and specificity in order to
      discriminate early pregnancy losses from vital pregnancies. A patient with a HCG
      value higher than the calculated cut-off value (55 IU/l) had a 90% chance of
      having a vital pregnancy after IVF and embryo transfer. It can be concluded that
      a discriminatory HCG value on day 12 after IVF and embryo transfer cycles may be
      useful in predicting pregnancy outcome and may guide clinicians in identifying
      those pregnancies at risk for adverse outcomes and instituting more intensive
      surveillance in this population.

PMID- 10357991
TI  - Free amino acids in human fetal liver and fluids at 12-17 weeks of gestation.
AB  - The concentration of 23 free amino acids was measured in homogenates of fetal
      liver and samples of fetal plasma from 20 pregnancies between 12 and 17 weeks
      gestation and compared with those found in matched samples of maternal plasma and
      amniotic fluid. A feto-maternal plasma concentration gradient was observed for 21
      amino acids indicating that the feto-maternal amino acid gradient across the
      placenta is established from very early in pregnancy. The amino acid
      concentration pattern was similar in fetal plasma and amniotic fluid but
      different in fetal liver, supporting the concept that it is essentially placental
      transport and metabolism that provides the fetus with these molecules. The
      highest amino acid concentration was found for glutamine in fetal plasma and
      glutamic acid in fetal liver. Very low concentrations of glutamic acid in fetal
      plasma suggest that this amino acid is actively taken up by the fetal liver.
      Citrulline, alpha-aminobutyric acid, methionine, arginine and tryptophan were not
      measurable in fetal liver tissue, indicating that this organ has a limited role
      in utero in the metabolism of these amino acids. Significant positive
      correlations were found between fetal plasma and amniotic fluid for the
      concentration of most amino acids whereas only the concentration of threonine was
      found to be positively correlated between fetal liver and plasma. These results
      suggest that during the second trimester passive diffusion through the
      unkeratinized fetal skin is the main pathway for amino acids between the fetal
      circulation and the amniotic cavity.

PMID- 10357993
TI  - Successful pregnancy after in-vitro fertilization and transmyometrial embryo
      transfer in a patient with congenital atresia of cervix: case report.
AB  - A case report of a patient with congenital cervical atresia diagnosed at the age
      of 24 years is given. The attempts to create a neocervix were unsuccessful. Since
      no signs of retrograde menstruation or haematometra were observed, in agreement
      with the patient hysterectomy was not performed. At the age of 32 years, a
      successful pregnancy was achieved after an in-vitro fertilization and
      transmyometrial embryo transfer. Due to rapidly progressing pre-eclampsia, an
      elective Caesarean section was performed at 32 weeks gestation. A 1610 g healthy
      male infant in breech presentation was born. The post-partum period was
      uneventful.

PMID- 10357994
TI  - Full term delivery following cryopreservation of human embryos for 7. 5 years.
AB  - Successful pregnancy in a 44 year old woman is described following the transfer
      of embryos which were cryopreserved for 7.5 years. The embryos were obtained
      during a gamete intra-Fallopian transfer (GIFT) procedure in 1989. To our
      knowledge this is one of the longest published periods of cryopreservation of
      embryos which has resulted in a healthy baby. This report illustrates the
      previously presumed viability and normality of human embryos undergoing long-term
      cryopreservation. Additionally, it emphasizes the importance for advanced
      reproductive technique programmes and patients to review and update their embryo
      status.

PMID- 10357995
TI  - Fertility drugs and the risk of breast cancer.
AB  - Several studies have investigated the possible relationship between fertility
      drugs and the risk of breast cancer. To provide further information on this
      issue, we analysed data from a case control study, conducted in Northern Italy
      between 1983 and 1991. Trained interviewers identified and questioned 3415 cases
      (women aged 23-74 years with histologically confirmed breast cancer) and 2916
      controls (women aged 21-74 years admitted to the same hospitals for diseases
      other than malignant, hormonal or gynaecological conditions). Fifty (1.5%) cases
      and 53 (1.8%) controls reported any history of infertility; the corresponding
      multivariate odds ratios (OR) of breast cancer was 0.8 [95% confidence interval
      (CI) 0.5-1.1]. Sixteen (0.5%) cases and 11 (0.4%) controls reported ever using
      fertility drugs; the corresponding OR was 1.2 (95% CI 0.5-2.6). Allowance for
      potential confounding factors did not markedly modify these estimates. In
      conclusion, this study provides reassuring evidence on the absence of an
      association between fertility drug treatment and breast cancer risk.

PMID- 10357996
TI  - Psychosocial stress and treatment outcome following assisted reproductive
      technology.
AB  - This study investigated the association between psychosocial stress and outcome
      of in-vitro fertilization and gamete intra-Fallopian transfer treatment. Ninety
      women, enrolled for treatment at a private infertility clinic, completed two self
      administered psychometric tests (Bi-polar Profile of Mood States, POMS; and State
      Trait Anxiety Inventory, STAI) and a questionnaire to ascertain demographic and
      lifestyle characteristics before the start of treatment. Approximately 12 months
      later an outcome measure was determined for each participant in terms of whether
      she was pregnant or not pregnant and the number of treatment cycles undertaken to
      achieve clinical pregnancy. The women's scores on the psychological tests were
      similar to published normative scores. On univariate analysis, history of a
      previous pregnancy was positively related to the probability of pregnancy and
      full-time employment, a more 'hostile' mood state and higher trait anxiety were
      associated with a lower cumulative pregnancy rate. A Cox multiple regression
      model found previous pregnancy history, trait anxiety, and the POMS agreeable
      hostile and elated-depressed scales to be the most important lifestyle and stress
      variables predictive of pregnancy. The results emphasize the importance of
      psychosocial stress in treatment outcome but indicate that the relationships are
      complex. Further studies are required to validate whether these findings can be
      generalized to other populations.

PMID- 10357997
TI  - A randomized trial of blastocyst culture and transfer in in-vitro fertilization.

PMID- 10357998
TI  - A randomized trial of blastocyst culture and transfer in in-vitro fertilization:
      reply 

PMID- 10357999
TI  - Albumin in the prevention of severe OHSS.

PMID- 10358000
TI  - Albumin in the prevention of severe OHSS: reply 

PMID- 10358001
TI  - Facts of artefacts--epigenetic or episcientific?

PMID- 10358002
TI  - Facilitated target location on DNA by individual Escherichia coli RNA polymerase
      molecules observed with the scanning force microscope operating in liquid.

PMID- 10358003
TI  - Structure of Gialpha1.GppNHp, autoinhibition in a galpha protein-substrate
      complex.
AB  - The structure of the G protein Gialpha1 complexed with the nonhydrolyzable GTP
      analog guanosine-5'-(betagamma-imino)triphosphate (GppNHp) has been determined at
      a resolution of 1.5 A. In the active site of Gialpha1. GppNHp, a water molecule
      is hydrogen bonded to the side chain of Glu43 and to an oxygen atom of the gamma
      phosphate group. The side chain of the essential catalytic residue Gln204 assumes
      a conformation which is distinctly different from that observed in complexes with
      either guanosine 5'-O-3-thiotriphosphate or the transition state analog GDP.AlF4
      . Hydrogen bonding and steric interactions position Gln204 such that it interacts
      with a presumptive nucleophilic water molecule, but cannot interact with the
      pentacoordinate transition state. Gln204 must be released from this auto
      inhibited state to participate in catalysis. RGS proteins may accelerate the rate
      of GTP hydrolysis by G protein alpha subunits, in part, by inserting an amino
      acid side chain into the site occupied by Gln204, thereby destabilizing the auto
      inhibited state of Galpha.

PMID- 10358004
TI  - Precursor of pro-apoptotic cytokine modulates aminoacylation activity of tRNA
      synthetase.
AB  - Endothelial monocyte activating polypeptide II (EMAPII) is a cytokine that is
      specifically induced by apoptosis. Its precursor (pro-EMAPII) has been suggested
      to be identical to p43, which is associated with the multi-tRNA synthetase
      complex. Herein, we have demonstrated that the N-terminal domain of pro-EMAPII
      interacts with the N-terminal extension of human cytoplasmic arginyl-tRNA
      synthetase (RRS) using genetic and immunoprecipitation analyses. Aminoacylation
      activity of RRS was enhanced about 2.5-fold by the interaction with pro-EMAPII
      but not with its N- or C-terminal domains alone. The N-terminal extension of RRS
      was not required for enzyme activity but did mediate activity stimulation by pro
      EMAPII. Pro-EMAPII reduced the apparent Km of RRS to tRNA, whereas the kcat value
      remained unchanged. Therefore, the precursor of EMAPII is a multi-functional
      protein that assists aminoacylation in normal cells and releases the functional
      cytokine upon apoptosis.

PMID- 10358005
TI  - The eukaryotic polypeptide chain releasing factor (eRF3/GSPT) carrying the
      translation termination signal to the 3'-Poly(A) tail of mRNA. Direct association
      of erf3/GSPT with polyadenylate-binding protein.
AB  - The mammalian GTP-binding protein GSPT, whose carboxyl-terminal sequence is
      homologous to the eukaryotic elongation factor EF1alpha, binds to the polypeptide
      chain releasing factor eRF1 to function as eRF3 in the translation termination.
      The amino-terminal domain of GSPT was, however, not required for the binding.
      Search for other GSPT-binding proteins in yeast two-hybrid screening system
      resulted in the identification of a cDNA encoding polyadenylate-binding protein
      (PABP), whose amino terminus is associating with the poly(A) tail of mRNAs
      presumably for their stabilization. The interaction appeared to be mediated
      through the carboxyl-terminal domain of PABP and the amino-terminal region of
      GSPT. Interestingly, multimerization of PABP with poly(A), which is ascribed to
      the action of its carboxyl-terminal domain, was completely inhibited by the
      interaction with the amino-terminal domain of GSPT. These results indicate that
      GSPT/eRF3 may play important roles not only in the termination of protein
      synthesis but also in the regulation of mRNA stability. Thus, the present study
      is the first report showing that GSPT/eRF3 carries the translation termination
      signal to 3'-poly(A) tail ubiquitously present in eukaryotic mRNAs.

PMID- 10358006
TI  - Effects of troponin I phosphorylation on conformational exchange in the
      regulatory domain of cardiac troponin C.
AB  - Conformational exchange has been demonstrated within the regulatory domain of
      calcium-saturated cardiac troponin C when bound to the NH2-terminal domain of
      cardiac troponin I-(1-80), and cardiac troponin I-(1-80)DD, having serine
      residues 23 and 24 mutated to aspartate to mimic the phosphorylated form of the
      protein. Binding of cardiac troponin I-(1-80) decreases conformational exchange
      for residues 29, 32, and 34. Comparison of average transverse cross correlation
      rates show that both the NH2- and COOH-terminal domains of cardiac troponin C
      tumble with similar correlation times when bound to cardiac troponin I-(1-80). In
      contrast, the NH2- and COOH-terminal domains in free cardiac troponin C and
      cardiac troponin C bound cardiac troponin I-(1-80)DD tumble independently. These
      results suggest that the nonphosphorylated cardiac specific NH2 terminus of
      cardiac troponin I interacts with the NH2-terminal domain of cardiac troponin C.

PMID- 10358007
TI  - Processing, activity, and inhibition of recombinant cyprosin, an aspartic
      proteinase from cardoon (Cynara cardunculus).
AB  - The cDNA encoding the precursor of an aspartic proteinase from the flowers of the
      cardoon, Cynara cardunculus, was expressed in Pichia pastoris, and the
      recombinant, mature cyprosin that accumulated in the culture medium was purified
      and characterized. The resultant mixture of microheterogeneous forms was shown to
      consist of glycosylated heavy chains (34 or 32 kDa) plus associated light chains
      with molecular weights in the region of 14,000-18,000, resulting from excision of
      most, but not all, of the 104 residues contributed by the unique region known as
      the plant specific insert. SDS-polyacrylamide gel electrophoresis under non
      reducing conditions indicated that disulfide bonding held the heavy and light
      chains together in the heterodimeric enzyme forms. In contrast, when a construct
      was expressed in which the nucleotides encoding the 104 residues of the plant
      specific insert were deleted, the inactive, unprocessed precursor form
      (procyprosin) accumulated, indicating that the plant-specific insert has a role
      in ensuring that the nascent polypeptide is folded properly and rendered capable
      of being activated to generate mature, active proteinase. Kinetic parameters were
      derived for the hydrolysis of a synthetic peptide substrate by wild-type,
      recombinant cyprosin at a variety of pH and temperature values and the subsite
      requirements of the enzyme were mapped using a systematic series of synthetic
      inhibitors. The significance is discussed of the susceptibility of cyprosin to
      inhibitors of human immunodeficiency virus proteinase and particularly of renin,
      some of which were found to have subnanomolar potencies against the plant enzyme.

PMID- 10358008
TI  - Targeted disruption of the beta2 adrenergic receptor gene.
AB  - beta-Adrenergic receptors (beta-ARs) are members of the superfamily of G-protein
      coupled receptors that mediate the effects of catecholamines in the sympathetic
      nervous system. Three distinct beta-AR subtypes have been identified (beta1-AR,
      beta2-AR, and beta3-AR). In order to define further the role of the different
      beta-AR subtypes, we have used gene targeting to inactivate selectively the beta2
      AR gene in mice. Based on intercrosses of heterozygous knockout (beta2-AR +/-)
      mice, there is no prenatal lethality associated with this mutation. Adult
      knockout mice (beta2-AR -/-) appear grossly normal and are fertile. Their resting
      heart rate and blood pressure are normal, and they have a normal chronotropic
      response to the beta-AR agonist isoproterenol. The hypotensive response to
      isoproterenol, however, is significantly blunted compared with wild type mice.
      Despite this defect in vasodilation, beta2-AR -/- mice can still exercise
      normally and actually have a greater total exercise capacity than wild type mice.
      At comparable workloads, beta2-AR -/- mice had a lower respiratory exchange ratio
      than wild type mice suggesting a difference in energy metabolism. beta2-AR -/-
      mice become hypertensive during exercise and exhibit a greater hypertensive
      response to epinephrine compared with wild type mice. In summary, the primary
      physiologic consequences of the beta2-AR gene disruption are observed only during
      the stress of exercise and are the result of alterations in both vascular tone
      and energy metabolism.

PMID- 10358009
TI  - Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2
      adrenergic receptors.
AB  - The activation state of beta-adrenergic receptors (beta-ARs) in vivo is an
      important determinant of hemodynamic status, cardiac performance, and metabolic
      rate. In order to achieve homeostasis in vivo, the cellular signals generated by
      beta-AR activation are integrated with signals from a number of other distinct
      receptors and signaling pathways. We have utilized genetic knockout models to
      test directly the role of beta1- and/or beta2-AR expression on these homeostatic
      control mechanisms. Despite total absence of beta1- and beta2-ARs, the
      predominant cardiovascular beta-adrenergic subtypes, basal heart rate, blood
      pressure, and metabolic rate do not differ from wild type controls. However,
      stimulation of beta-AR function by beta-AR agonists or exercise reveals
      significant impairments in chronotropic range, vascular reactivity, and metabolic
      rate. Surprisingly, the blunted chronotropic and metabolic response to exercise
      seen in beta1/beta2-AR double knockouts fails to impact maximal exercise
      capacity. Integrating the results from single beta1- and beta2-AR knockouts as
      well as the beta1-/beta2-AR double knock-out suggest that in the mouse, beta-AR
      stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by
      the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by
      all three beta-ARs (beta1-, beta2-, and beta3-AR). Compensatory alterations in
      cardiac muscarinic receptor density and vascular beta3-AR responsiveness are also
      observed in beta1-/beta2-AR double knockouts. In addition to its ability to
      define beta-AR subtype-specific functions, this genetic approach is also useful
      in identifying adaptive alterations that serve to maintain critical physiological
      setpoints such as heart rate, blood pressure, and metabolic rate when cellular
      signaling mechanisms are perturbed.

PMID- 10358010
TI  - Functional characterization of the Betaine/gamma-aminobutyric acid transporter
      BGT-1 expressed in Xenopus oocytes.
AB  - Betaine is an osmolyte accumulated in cells during osmotic cell shrinkage. The
      canine transporter mediating cellular accumulation of the osmolyte betaine and
      the neurotransmitter gamma-aminobutyric acid (BGT-1) was expressed in Xenopus
      oocytes and analyzed by two-electrode voltage clamp and tracer flux studies.
      Exposure of oocytes expressing BGT-1 to betaine or gamma-aminobutyric acid (GABA)
      depolarized the cell membrane in the current clamp mode and induced an inward
      current under voltage clamp conditions. At 1 mM substrate the induced currents
      decreased in the following order: betaine = GABA > diaminobutyric acid = beta
      alanine > proline = quinidine > dimethylglycine > glycine > sarcosine. Both the
      Vmax and Km of GABA- and betaine-induced currents were voltage-dependent, and
      GABA- and betaine-induced currents and radioactive tracer uptake were strictly
      Na+-dependent but only partially dependent on the presence of Cl-. The apparent
      affinity of GABA decreased with decreasing Na+ concentrations. The Km of Na+ also
      depended on the GABA and Cl- concentration. A decrease of the Cl- concentration
      reduced the apparent affinity for Na+ and GABA, and a decrease of the Na+
      concentration reduced the apparent affinity for Cl- and GABA. A comparison of
      22Na+-, 36Cl--, and 14C-labeled GABA and 14C-labeled betaine fluxes and GABA- and
      betaine-induced currents yielded a coupling ratio of Na+/Cl-/organic substrate of
      3:1:1 or 3:2:1. Based on the data, a transport model of ordered binding is
      proposed in which GABA binds first, Na+ second, and Cl- third. In conclusion, BGT
      1 displays significant functional differences from the other members of the GABA
      transporter family.

PMID- 10358011
TI  - Poly-N-acetyllactosamine synthesis in branched N-glycans is controlled by
      complemental branch specificity of I-extension enzyme and beta1,4
      galactosyltransferase I.
AB  - Poly-N-acetyllactosamine is a unique carbohydrate that can carry various
      functional oligosaccharides, such as sialyl Lewis X. It has been shown that the
      amount of poly-N-acetyllactosamine is increased in N-glycans, when they contain
      Galbeta1-->4GlcNAcbeta1-->6(Galbeta1-->4GlcNAcbeta1 -->2)Manalpha1-->6 branched
      structure. To determine how this increased synthesis of poly-N-acetyllactosamines
      takes place, the branched acceptor was incubated with a mixture of i-extension
      enzyme (iGnT) and beta1, 4galactosyltransferase I (beta4Gal-TI). First, N
      acetyllactosamine repeats were more readily added to the branched acceptor than
      the summation of poly-N-acetyllactosamines formed individually on each unbranched
      acceptor. Surprisingly, poly-N-acetyllactosamine was more efficiently formed on
      Galbeta1-->4GlcNAcbeta1-->2Manalpha-->R side chain than in Galbeta1-
      >4GlcNAcbeta1-->6Manalpha-->R, due to preferential action of iGnT on Galbeta1-
      >4GlcNAcbeta1-->2Manalpha-->R side chain. On the other hand, galactosylation was
      much more efficient on beta1,6-linked GlcNAc than beta1,2-linked GlcNAc,
      preferentially forming Galbeta1-->4GlcNAcbeta1-->6(GlcNAcbeta1-->2)Manalph a1-
      >6Manbeta -->R. Starting with this preformed acceptor, N-acetyllactosamine
      repeats were added almost equally to Galbeta1-->4GlcNAcbeta1-->6Manalpha-->R and
      Galbeta1-->4GlcNAcbeta1-->2Manalpha-->R side chains. Taken together, these
      results indicate that the complemental branch specificity of iGnT and beta4Gal-TI
      leads to efficient and equal addition of N-acetyllactosamine repeats on both side
      chains of GlcNAcbeta1-->6(GlcNAcbeta1-->2)Manalpha1-->6Manbet a-->R structure,
      which is consistent with the structures found in nature. The results also suggest
      that the addition of Galbeta1-->4GlcNAcbeta1-->6 side chain on Galbeta1-
      >4GlcNAcbeta1-->2Man-->R side chain converts the acceptor to one that is much
      more favorable for iGnT and beta4Gal-TI.

PMID- 10358012
TI  - Histidine 179 mutants of GTP cyclohydrolase I catalyze the formation of 2-amino-5
      formylamino-6-ribofuranosylamino-4(3H)-pyrimidinone triphosphate.
AB  - GTP cyclohydrolase I catalyzes the conversion of GTP to dihydroneopterin
      triphosphate. The replacement of histidine 179 by other amino acids affords
      mutant enzymes that do not catalyze the formation of dihydroneopterin
      triphosphate. However, some of these mutant proteins catalyze the conversion of
      GTP to 2-amino-5-formylamino-6-ribofuranosylamino-4(3H)-pyrimidinone 5'
      triphosphate as shown by multinuclear NMR analysis. The equilibrium constant for
      the reversible conversion of GTP to the ring-opened derivative is approximately
      0.1. The wild-type enzyme converts the formylamino pyrimidine derivative to
      dihydroneopterin triphosphate; the rate is similar to that observed with GTP as
      substrate. The data support the conclusion that the formylamino pyrimidine
      derivative is an intermediate in the overall reaction catalyzed by GTP
      cyclohydrolase I.

PMID- 10358013
TI  - Identification of critical, conserved vicinal aspartate residues in mammalian and
      bacterial ADP-ribosylarginine hydrolases.
AB  - NAD:arginine ADP-ribosyltransferases and ADP-ribosylarginine hydrolases catalyze
      opposing arms of a putative ADP-ribosylation cycle. ADP-ribosylarginine
      hydrolases from mammalian tissues and Rhodospirillum rubrum exhibit three regions
      of similarity in deduced amino acid sequence. We postulated that amino acids in
      these consensus regions could be critical for hydrolase function. To test this
      hypothesis, hydrolase, cloned from rat brain, was expressed as a glutathione S
      transferase fusion protein in Escherichia coli and purified by glutathione
      Sepharose affinity chromatography. Conserved amino acids in each of these regions
      were altered by site-directed mutagenesis. Replacement of Asp-60 or Asp-61 with
      Ala, Gln, or Asn, but not Glu, significantly reduced enzyme activity. The double
      Asp-60 --> Glu/Asp-61 --> Glu mutant was inactive, as were Asp-60 --> Gln/Asp-61 
      -> Gln or Asp-60 --> Asn/Asp-61 --> Asn. The catalytically inactive single and
      double mutants appeared to retain conformation, since they bound ADP-ribose, a
      substrate analogue and an inhibitor of enzyme activity, with affinity similar to
      that of the wild-type hydrolase and with the expected stoichiometry of one.
      Replacing His-65, Arg-139, Asp-285, which are also located in the conserved
      regions, with alanine did not change specific activity. These data clearly show
      that the conserved vicinal aspartates 60 and 61 in rat ADP-ribosylarginine
      hydrolase are critical for catalytic activity, but not for high affinity binding
      of the substrate analogue, ADP-ribose.

PMID- 10358014
TI  - Negative regulation of the forkhead transcription factor FKHR by Akt.
AB  - The FKHR gene was first identified from its disruption by the t(2;13) chromosomal
      translocation seen in the pediatric tumor alveolar rhabdomyosarcoma. It encodes
      for a member of the forkhead family of transcription factors. Recently, a homolog
      of FKHR in the nematode Caenorhabditis elegans was identified called DAF-16,
      which is a downstream target of two Akt homologs in an insulin-related signaling
      pathway. We have examined the possible role of Akt in the regulation of FKHR. We
      find that FKHR can bind in vitro to the insulin-responsive sequence (IRS) in the
      insulin-like growth factor-binding protein 1 promoter and can activate
      transcription from a reporter plasmid containing multiple copies of the IRS.
      Expression of active but not inactive Akt can suppress FKHR-mediated
      transcriptional activation. Akt can phosphorylate FKHR in vitro on three
      phosphoacceptor sites, at least a subset of which can also be phosphorylated by
      Akt in vivo. Importantly, mutation of these three sites to alanine residues
      enhances the transcriptional activity of FKHR and renders it resistant to
      inhibition by Akt. Expression of an Akt-resistant mutant of FKHR causes apoptosis
      in 293T cells in a manner dependent on DNA binding. These results suggest that
      FKHR may be a direct nuclear regulatory target for Akt in both metabolic and cell
      survival pathways.

PMID- 10358015
TI  - Homo- and heterodimerization of synapsins.
AB  - In vertebrates, synapsins constitute a family of synaptic vesicle proteins
      encoded by three genes. Synapsins contain a central ATP-binding domain, the C
      domain, that is highly homologous between synapsins and evolutionarily conserved
      in invertebrates. The crystal structure of the C-domain from synapsin I revealed
      that it constitutes a large (>300 amino acids), independently folded domain that
      forms a tight dimer with or without bound ATP. We now show that the C-domains of
      all synapsins form homodimers, and that in addition, C-domains from different
      synapsins associate into heterodimers. This conclusion is based on four findings:
      1) in yeast two-hybrid screens with full-length synapsin IIa as a bait, the most
      frequently isolated prey cDNAs encoded the C-domain of synapsins; 2) quantitative
      yeast two-hybrid protein-protein binding assays demonstrated pairwise strong
      interactions between all synapsins; 3) immunoprecipitations from transfected COS
      cells confirmed that synapsin II heteromultimerizes with synapsins I and III in
      intact cells, and similar results were obtained with bacterial expression
      systems; and 4) quantification of the synapsin III level in synapsin I/II double
      knockout mice showed that the level of synapsin III is decreased by 50%,
      indicating that heteromultimerization of synapsin III with synapsins I or II
      occurs in vivo and is required for protein stabilization. These data suggest that
      synapsins coat the surface of synaptic vesicles as homo- and heterodimers in
      which the C-domains of the various subunits have distinct regulatory properties
      and are flanked by variable C-terminal sequences. The data also imply that
      synapsin III does not compensate for the loss of synapsins I and II in the double
      knockout mice.

PMID- 10358016
TI  - cAMP regulates Ca2+-dependent exocytosis of lysosomes and lysosome-mediated cell
      invasion by trypanosomes.
AB  - Ca2+-regulated exocytosis, previously believed to be restricted to specialized
      cells, was recently recognized as a ubiquitous process. In mammalian fibroblasts
      and epithelial cells, exocytic vesicles mobilized by Ca2+ were identified as
      lysosomes. Here we show that elevation in intracellular cAMP potentiates Ca2+
      dependent exocytosis of lysosomes in normal rat kidney fibroblasts. The process
      can be modulated by the heterotrimeric G proteins Gs and Gi, consistent with
      activation or inhibition of adenylyl cyclase. Normal rat kidney cell stimulation
      with isoproterenol, a beta-adrenergic agonist that activates adenylyl cyclase,
      enhances Ca2+-dependent lysosome exocytosis and cell invasion by Trypanosoma
      cruzi, a process that involves parasite-induced [Ca2+]i transients and fusion of
      host cell lysosomes with the plasma membrane. Similarly to what is observed for
      T. cruzi invasion, the actin cytoskeleton acts as a barrier for Ca2+-induced
      lysosomal exocytosis. In addition, infective stages of T. cruzi trigger elevation
      in host cell cAMP levels, whereas no effect is observed with noninfective forms
      of the parasite. These findings demonstrate that cAMP regulates lysosomal
      exocytosis triggered by Ca2+ and a parasite/host cell interaction known to
      involve Ca2+-dependent lysosomal fusion.

PMID- 10358017
TI  - Redox components of cytochrome bc-type enzymes in acidophilic prokaryotes. I.
      Characterization of the cytochrome bc1-type complex of the acidophilic ferrous
      ion-oxidizing bacterium Thiobacillus ferrooxidans.
AB  - The redox components of the cytochrome bc1 complex from the acidophilic
      chemolithotrophic organism Thiobacillus ferrooxidans were investigated by
      potentiometric and spectroscopic techniques. Optical redox titrations
      demonstrated the presence of two b-type hemes with differing redox midpoint
      potentials at pH 7.4 (-169 and + 20 mV for bL and bH, respectively). At pH 3.5,
      by contrast, both hemes appeared to titrate at about +20 mV. Antimycin A, 2
      heptyl-4-hydroxyquinoline N-oxide, and stigmatellin induced distinguishable
      shifts of the b hemes' alpha-bands, providing evidence for the binding of
      antimycin A and 2-heptyl-4-hydroxyquinoline N-oxide near heme bH (located on the
      cytosolic side of the membrane) and of stigmatellin near heme bL (located on the
      periplasmic side of the membrane). The inhibitors stigmatellin, 5-(n-undecyl)-6
      hydroxy-4,7-dioxobenzothiazole, and 2, 5-dibromo-3-methyl-6-isopropyl-p
      benzoquinone affected the EPR spectrum of the Rieske iron-sulfur center in a way
      that differs from what has been observed for cytochrome bc1 or b6f complexes. The
      results obtained demonstrate that the T. ferrooxidans complex, although showing
      most of the features characteristic for bc1 complexes, contains unique properties
      that are most probably related to the chemolithotrophicity and/or acidophilicity
      of its parent organism. A speculative model for reverse electron transfer through
      the T. ferrooxidans complex is proposed.

PMID- 10358018
TI  - Redox components of cytochrome bc-type enzymes in acidophilic prokaryotes. II.
      The Rieske protein of phylogenetically distant acidophilic organisms.
AB  - The Rieske proteins of two phylogenetically distant acidophilic organisms, i.e.
      the proteobacterium Thiobacillus ferrooxidans and the crenarchaeon Sulfolobus
      acidocaldarius, were studied by EPR. Redox titrations at a range of pH values
      showed that the Rieske centers of both organisms are characterized by redox
      midpoint potential-versus-pH curves featuring a common pK value of 6.2. This pK
      value is significantly more acidic (by almost 2 pH units) than that of Rieske
      proteins in neutrophilic species. The orientations of the Rieske center's g
      tensors with respect to the plane of the membrane were studied between pH 4 and 8
      using partially ordered samples. At pH 4, the Sulfolobus Rieske cluster was found
      in the "typical" orientation of chemically reduced Rieske centers, whereas this
      orientation changed significantly on going toward high pH values. The
      Thiobacillus protein, by contrast, appeared to be in the "standard" orientation
      at both low and high pH values. The results are discussed with respect to the
      molecular parameters conveying acid resistance and in light of the recently
      demonstrated long-range conformational movement of the Rieske protein during
      enzyme turnover in cytochrome bc1 complexes.

PMID- 10358019
TI  - EMILIN, a component of the elastic fiber and a new member of the C1q/tumor
      necrosis factor superfamily of proteins.
AB  - EMILIN (elastin microfibril interface located protein) is an extracellular matrix
      glycoprotein abundantly expressed in elastin-rich tissues such as blood vessels,
      skin, heart, and lung. It occurs associated with elastic fibers at the interface
      between amorphous elastin and microfibrils. Avian EMILIN was extracted from 19
      day-old embryonic chick aortas and associated blood vessels and purified by ion
      exchange chromatography and gel filtration. Tryptic peptides were generated from
      EMILIN and sequenced, and degenerate inosine-containing oligonucleotide primers
      were designed from some peptides. A set of primers allowed the amplification of a
      360-base pair reverse transcription polymerase chain reaction product from chick
      aorta mRNA. A probe based on a human homologue selected by comparison of the
      chick sequence with EST data base was used to select overlapping clones from both
      human aorta and kidney cDNA libraries. Here we present the cDNA sequence of the
      entire coding region of human EMILIN encompassing an open reading frame of 1016
      amino acid residues. There was a high degree of homology (76% identity and 88%
      similarity) between the chick C terminus and the human sequence as well as
      between the N terminus of the mature chick protein where 10 of 12 residues, as
      determined by N-terminal sequencing, were identical or similar to the deduced N
      terminus of human EMILIN. The domain organization of human EMILIN includes a C1q
      like globular domain at the C terminus, a collagenous stalk, and a longer segment
      in which at least four heptad repeats and a leucine zipper can be identified with
      a high potential for forming coiled-coil alpha helices. At the N terminus there
      is a cysteine-rich sequence stretch similar to a region of multimerin, a platelet
      and endothelial cell component, containing a partial epidermal growth factor-like
      motif. The native state of the recombinantly expressed EMILIN C1q-like domain to
      be used in cell adhesion was determined by CD spectra analysis, which indicated a
      high value of beta-sheet conformation. The EMILIN C1q-like domain promoted a high
      cell adhesion of the leiomyosarcoma cell line SK-UT-1, whereas the fibrosarcoma
      cell line HT1080 was negative.

PMID- 10358020
TI  - Down-regulation of MARCKS-related protein (MRP) in macrophages infected with
      Leishmania.
AB  - Leishmania, a protozoan parasite of macrophages, has been shown to interfere with
      host cell signal transduction pathways including protein kinase C (PKC)-dependent
      signaling. Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS
      related protein (MRP, MacMARCKS) are PKC substrates in diverse cell types. MARCKS
      and MRP are thought to regulate the actin network and thereby participate in
      cellular responses involving cytoskeletal rearrangement. Because MRP is a major
      PKC substrate in macrophages, we examined its expression in response to infection
      by Leishmania. Activation of murine macrophages by cytokines increased MRP
      expression as determined by Western blot analysis. Infection with Leishmania
      promastigotes at the time of activation or up to 48 h postactivation strongly
      decreased MRP levels. Leishmania-dependent MRP depletion was confirmed by
      [3H]myristate labeling and by immunofluorescence microscopy. All species or
      strains of Leishmania parasites tested, including lipophosphoglycan-deficient
      Leishmania major L119, decreased MRP levels. MRP depletion was not obtained with
      other phagocytic stimuli including zymosan, latex beads, or heat-killed
      Streptococcus mitis, a Gram-positive bacterium. Experiments with [3H]myristate
      labeled proteins revealed the appearance of lower molecular weight fragments in
      Leishmania-infected cells suggesting that MRP depletion may be due to proteolytic
      degradation.

PMID- 10358021
TI  - Differential regulation of Drosophila tyrosine hydroxylase isoforms by dopamine
      binding and cAMP-dependent phosphorylation.
AB  - Tyrosine hydroxylase (TH) catalyzes the first step in dopamine biosynthesis in
      Drosophila as in vertebrates. We have previously reported that tissue-specific
      alternative splicing of the TH primary transcript generates two distinct TH
      isoforms in Drosophila, DTH I and DTH II (Birman, S., Morgan, B., Anzivino, M.,
      and Hirsh, J. (1994) J. Biol. Chem. 269, 26559-26567). Expression of DTH I is
      restricted to the central nervous system, whereas DTH II is expressed in non
      nervous tissues like the epidermis. The two enzymes present a single structural
      difference; DTH II specifically contains a very acidic segment of 71 amino acids
      inserted in the regulatory domain. We show here that the enzymatic and regulatory
      properties of vertebrate TH are generally conserved in insect TH and that the
      isoform DTH II presents unique characteristics. The two DTH isoforms were
      expressed as apoenzymes in Escherichia coli and purified by fast protein liquid
      chromatography. The recombinant DTH isoforms are enzymatically active in the
      presence of ferrous iron and a tetrahydropteridine co-substrate. However, the two
      enzymes differ in many of their properties. DTH II has a lower Km value for the
      co-substrate (6R)-tetrahydrobiopterin and requires a lower level of ferrous ion
      than DTH I to be activated. The two isoforms also have a different pH profile. As
      for mammalian TH, enzymatic activity of the Drosophila enzymes is decreased by
      dopamine binding, and this effect is dependent on ferrous iron levels. However,
      DTH II appears comparatively less sensitive than DTH I to dopamine inhibition.
      The central nervous system isoform DTH I is activated through phosphorylation by
      cAMP-dependent protein kinase (PKA) in the absence of dopamine. In contrast,
      activation of DTH II by PKA is only manifest in the presence of dopamine. Site
      directed mutagenesis of Ser32, a serine residue occurring in a PKA site conserved
      in all known TH proteins, abolishes phosphorylation of both isoforms and
      activation by PKA. We propose that tissue-specific alternative splicing of TH has
      a functional role for differential regulation of dopamine biosynthesis in the
      nervous and non-nervous tissues of insects.

PMID- 10358022
TI  - Metabolic deficiencies in alcohol dehydrogenase Adh1, Adh3, and Adh4 null mutant
      mice. Overlapping roles of Adh1 and Adh4 in ethanol clearance and metabolism of
      retinol to retinoic acid.
AB  - Targeting of mouse alcohol dehydrogenase genes Adh1, Adh3, and Adh4 resulted in
      null mutant mice that all developed and reproduced apparently normally but
      differed markedly in clearance of ethanol and formaldehyde plus metabolism of
      retinol to the signaling molecule retinoic acid. Following administration of an
      intoxicating dose of ethanol, Adh1 -/- mice, and to a lesser extent Adh4 -/-
      mice, but not Adh3 -/- mice, displayed significant reductions in blood ethanol
      clearance. Ethanol-induced sleep was significantly longer only in Adh1 -/- mice.
      The incidence of embryonic resorption following ethanol administration was
      increased 3-fold in Adh1 -/- mice and 1.5-fold in Adh4 -/- mice but was unchanged
      in Adh3 -/- mice. Formaldehyde toxicity studies revealed that only Adh3 -/- mice
      had a significantly reduced LD50 value. Retinoic acid production following
      retinol administration was reduced 4.8-fold in Adh1 -/- mice and 8.5-fold in Adh4
      -/- mice. Thus, Adh1 and Adh4 demonstrate overlapping functions in ethanol and
      retinol metabolism in vivo, whereas Adh3 plays no role with these substrates but
      instead functions in formaldehyde metabolism. Redundant roles for Adh1 and Adh4
      in retinoic acid production may explain the apparent normal development of mutant
      mice.

PMID- 10358023
TI  - A 110-kilodalton subunit of translation initiation factor eIF3 and an associated
      135-kilodalton protein are encoded by the Saccharomyces cerevisiae TIF32 and
      TIF31 genes.
AB  - Translation initiation factor eIF3 is a multisubunit protein complex required for
      initiation of protein biosynthesis in eukaryotic cells. The complex promotes
      ribosome dissociation, the binding of the initiator methionyl-tRNA to the 40 S
      ribosomal subunit, and mRNA recruitment to the ribosome. In the yeast
      Saccharomyces cerevisiae eIF3 comprises up to 8 subunits. Using partial peptide
      sequences generated from proteins in purified eIF3, we cloned the TIF31 and TIF32
      genes encoding 135- (p135) and 110-kDa (p110) proteins. Deletion/disruption of
      TIF31 results in no change in growth rate, whereas deletion of TIF32 is lethal.
      Depletion of p110 causes a severe reduction in cell growth and protein synthesis
      rates as well as runoff of ribosomes from polysomes, indicative of inhibition of
      the initiation phase. In addition, p110 depletion leads to p90 co-depletion,
      whereas other eIF3 subunit levels are not affected. Immunoprecipitation or nickel
      affinity chromatography from strains expressing (His)6-tagged p110 or p33 results
      in the co-purification of the well characterized p39 and p90 subunits of eIF3 as
      well as p110 and p33. This establishes p110 as an authentic subunit of eIF3. In
      similar experiments, p135 and other eIF3 subunits sometimes, but not always, co
      purify, making assignment of p135 as an eIF3 subunit uncertain. Far Western
      blotting and two-hybrid analyses detect a direct interaction of p110 with p90,
      p135 with p33, and p33 with eIF4B. Our results, together with those from other
      laboratories, complete the cloning and characterization of all of the yeast eIF3
      subunits.

PMID- 10358024
TI  - The Doc toxin and Phd antidote proteins of the bacteriophage P1 plasmid addiction
      system form a heterotrimeric complex.
AB  - The toxin (Doc) and antidote (Phd) proteins of the plasmid addiction system of
      bacteriophage P1 were purified as a complex. Cocrystals of the complex contained
      a 2:1 molar ratio of Phd:Doc as assayed by dye binding following SDS
      polyacrylamide gel electrophoresis and as determined by amino acid analysis. Gel
      filtration and analytical ultracentrifugation revealed that the two addiction
      proteins interact in solution to form a P2D trimer composed of one Doc and two
      Phd molecules. These results support a model in which Phd inhibits the toxic
      activity of Doc by direct binding. Circular dichroism experiments showed that
      changes in secondary structure accompany formation of the heterotrimeric complex,
      raising the possibility that Phd may act by an allosteric mechanism. Studies of
      Phd and Doc molecules labeled with fluorescent energy donor and acceptor groups
      gave an equilibrium dissociation constant of about 0.8 microM(2) and a very
      short, sub second half-life of complex dissociation. As a consequence, low
      concentrations of free Doc toxin are likely to be present both transiently and in
      the steady state in cells containing the Phd antidote, making mechanisms of
      single-hit Doc toxicity improbable.

PMID- 10358025
TI  - Structural analysis of the lipopolysaccharide from Chlamydia trachomatis serotype
      L2.
AB  - The lipopolysaccharide (LPS) of Chlamydia trachomatis L2 was isolated from tissue
      culture-grown elementary bodies using a modified phenol/water procedure followed
      by extraction with phenol/chloroform/light petroleum. From a total of 5 x 10(4)
      cm2 of infected monolayers, 22.3 mg of LPS were obtained. Compositional analysis
      indicated the presence of 3-deoxy-D-manno-oct-2-ulopyranosonic acid (Kdo), GlcN,
      phosphorus, and fatty acids in a molar ratio of 2.8:2:2.1:4.5. Matrix-assisted
      laser-desorption ionization mass spectrometry performed on the de-O-acylated LPS
      gave a major molecular ion peak at m/z 1781.1 corresponding to a molecule of 3
      Kdo, 2 GlcN, 2 phosphates, and two 3-hydroxyeicosanoic acid residues. The
      structure of deacylated LPS obtained after successive treatment with hydrazine
      and potassium hydroxide was determined by 600 MHz NMR spectroscopy as Kdoalpha2-
      >8Kdoalpha2-->4Kdoalpha2-->6D-GlcpNbeta1 -->6D-GlcpNalpha 1,4'-bisphosphate.
      These data, together with those published recently on the acylation pattern of
      chlamydial lipid A (Qureshi, N., Kaltashov, I., Walker, K., Doroshenko, V.,
      Cotter, R. J., Takayama, K, Sievert, T. R., Rice, P. A., Lin, J.-S. L., and
      Golenbock, D. T. (1997) J. Biol. Chem. 272, 10594-10600) allow us to present for
      the first time the complete structure of a major molecular species of a
      chlamydial LPS.

PMID- 10358026
TI  - Adipose differentiation related protein (ADRP) expressed in transfected COS-7
      cells selectively stimulates long chain fatty acid uptake.
AB  - Adipose differentiation related protein (ADRP) is a 50-kDa novel protein cloned
      from a mouse 1246 adipocyte cDNA library, rapidly induced during adipocyte
      differentiation. We have examined ADRP function, and we show here that ADRP
      facilitates fatty acid uptake in COS cells transfected with ADRP cDNA. We
      demonstrate that uptake of long chain fatty acids was significantly stimulated in
      a time-dependent fashion in ADRP-expressing COS-7 cells compared with empty
      vector-transfected control cells. Oleic acid uptake velocity increased
      significantly in a dose-dependent manner in ADRP-expressing COS-7 cells compared
      with control cells. The transport Km was 0.051 microM, and Vmax was 57.97
      pmol/10(5) cells/min in ADRP-expressing cells, and Km was 0.093 microM and Vmax
      was 20.13 pmol/10(5) cells/min in control cells. The oleate uptake measured at 4
      degrees C was only 10% that at 37 degrees C. ADRP also stimulated uptake of
      palmitate and arachidonate but had no effect on uptake of medium chain fatty acid
      such as octanoic acid and glucose. These data suggest that ADRP specifically
      enhances uptake of long chain fatty acids by increasing the initial rate of
      uptake and provide novel information about ADRP function as a saturable transport
      component for long chain fatty acids.

PMID- 10358027
TI  - High-affinity binding of basic fibroblast growth factor and platelet-derived
      growth factor-AA to the core protein of the NG2 proteoglycan.
AB  - NG2 is a transmembrane chondroitin sulfate proteoglycan that is expressed by
      immature progenitor cells in several developmental lineages and by some types of
      malignant cells. In vitro studies have suggested that NG2 participates in growth
      factor activation of the platelet-derived growth factor-alpha receptor. In this
      study the ability of recombinant NG2 core protein to interact with several
      different growth factors (epidermal growth factor (EGF), basic fibroblast growth
      factor (bFGF), platelet-derived growth factor (PDGF)-AA, PDGF-BB, vascular
      endothelial growth factor (VEGF)165 and transforming growth factor (TGF)-beta1)
      was investigated using two different assay systems: enzyme-linked immunosorbent
      assay-type solid-phase binding and an optical biosensor (BIAcore) system. High
      affinity binding of bFGF and PDGF-AA to the core protein of NG2 could be
      demonstrated with both types of assays. Using both the BIAcore software analysis
      program and nonlinear regression analysis of the solid phase binding data, KD
      values in the low nanomolar range were obtained for binding of each of these
      growth factors to NG2. The results further indicate that NG2 contains at least
      two binding sites for each of these two growth factors. PDGF-BB, TGF-beta1, VEGF,
      and EGF exhibited little or no binding to NG2 in either type of assay. These data
      suggest that NG2 can have an important role in organizing and presenting some
      types of mitogenic growth factors at the cell surface.

PMID- 10358028
TI  - 20-Epi analogues of 1,25-dihydroxyvitamin D3 are highly potent inducers of DRIP
      coactivator complex binding to the vitamin D3 receptor.
AB  - 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) plays a major role in the stimulation of
      bone growth, mineralization, and intestinal calcium and phosphate absorption; it
      also acts as a general inhibitor of cellular proliferation. Several new,
      clinically relevant compounds dissociate antiproliferative and calcemic
      activities of 1,25(OH)2D3, but the molecular basis for this has not been clearly
      elucidated. Here, we tested whether the potency of one class of compounds, 20-epi
      analogues, to induce myeloid cell differentiation, is because of direct molecular
      effects on vitamin D receptor (VDR). We report that two 20-epi analogues, MC1627
      and MC1288, induced differentiation and transcription of p21(Waf1,Cip1), a key
      VDR target gene involved in growth inhibition, at a concentration 100-fold lower
      than that of 1,25(OH)2D3. We compared this sensitivity to analogue effects on VDR
      interacting proteins: RXR, GRIP-1, and DRIP205, a subunit of the DRIP coactivator
      complex. Compared with the interaction of VDR with RXR or GRIP-1, the
      differentiation dose-response most closely correlated to the ligand-dependent
      recruitment of the DRIP coactivator complex to VDR and to the ability of the
      receptor to activate transcription in a cell-free system. These results provide
      compelling links between the efficiency of the 20-epi analogue in inducing
      VDR/DRIP interactions, transactivation in vitro, and its enhanced ability to
      induce cellular differentiation.

PMID- 10358029
TI  - Interleukin-2 causes an increase in saturated/monounsaturated phosphatidic acid
      derived from 1,2-diacylglycerol and 1-O-alkyl-2-acylglycerol.
AB  - Phosphatidic acid generation through activation of diacylglycerol kinase alpha
      has been implicated in interleukin-2-dependent T-lymphocyte proliferation. To
      investigate this lipid signaling in more detail, we characterized the molecular
      structures of the diradylglycerols and phosphatidic acids in the murine CTLL-2 T
      cell line under both basal and stimulated conditions. In resting cells, 1,2
      diacylglycerol and 1-O-alkyl-2-acylglycerol subtypes represented 44 and 55% of
      total diradylglycerol, respectively, and both showed a highly saturated profile
      containing primarily 16:0 and 18:1 fatty acids. 1-O-Alk-1'-enyl-2-acylglycerol
      represented 1-2% of total diradylglycerol. Interleukin-2 stimulation did not
      alter the molecular species profiles, however, it did selectively reduce total 1
      O-alkyl-2-acylglycerol by over 50% at 15 min while only causing a 10% drop in 1,2
      diacylglycerol. When radiolabeled CTLL-2 cells were challenged with interleukin
      2, no change in the cellular content of phosphatidylcholine nor
      phosphatidylethanolamine was observed thereby ruling out phospholipase C activity
      as the source of diradylglycerol. In addition, interleukin-2 failed to stimulate
      de novo synthesis of diradylglycerol. Structural analysis revealed approximately
      equal amounts of 1,2-diacyl phosphatidic acid and 1-O-alkyl-2-acyl phosphatidic
      acid under resting conditions, both containing only saturated and monounsaturated
      fatty acids. After acute (2 and 15 min) interleukin-2 stimulation the total
      phosphatidic acid mass increased, almost entirely through the formation of 1-O
      alkyl-2-acyl species. In vitro assays revealed that both 1,2-diacylglycerol and 1
      O-alkyl-2-acylglycerol were substrates for 1,2-diacylglycerol kinase alpha, the
      major isoform in CTLL-2 cells, and that the lipid kinase activity was almost
      totally inhibited by R59949. In conclusion, this investigation shows that, in
      CTLL-2 cells, 1,2-diacylglycerol kinase alpha specifically phosphorylates a pre
      existing pool of 1-O-alkyl-2-acylglycerol to form the intracellular messenger 1-O
      alkyl-2-acyl phosphatidic acid.

PMID- 10358030
TI  - Conformation of the core sequence in melanocortin peptides directs selectivity
      for the melanocortin MC3 and MC4 receptors.
AB  - Melanocortin peptides regulate a variety of physiological processes. Five
      melanocortin receptors (MC-R) have been cloned and the MC3R and MC4R are the main
      brain MC receptors. The aim of this study was to identify structural requirements
      in both ligand and receptor that determine gamma-melanocyte-stimulating hormone
      (MSH) selectivity for the MC3R versus the MC4R. Substitution of Asp10 in
      [Nle4]Lys-gamma2-MSH for Gly10 from [Nle4]alpha-MSH, increased both activity and
      affinity for the MC4R while the MC3R remained unaffected. Analysis of chimeric
      MC3R/MC4Rs and mutant MC4Rs showed that Tyr268 of the MC4R mainly determined the
      low affinity for [Nle4]Lys-gamma2-MSH. The data demonstrate that Asp10 determines
      selectivity for the MC3R, however, not through direct side chain interactions,
      but probably by influencing how the melanocortin core sequence is presented to
      the receptor-binding pocket. This is supported by mutagenesis of Tyr268 to Ile in
      the MC4R which increased affinity and activity for [Nle4]Lys-gamma2-MSH, but
      decreased affinity for two peptides with constrained cyclic structure of the
      melanocortin core sequence, MT-II and [D-Tyr4]MT-II, that also displayed lower
      affinity for the MC3R. This study provides a general concept for peptide receptor
      selectivity, in which the major determinant for a selective receptor interaction
      is the conformational presentation of the core sequence in related peptides to
      the receptor-binding pocket.

PMID- 10358031
TI  - The Cdc42p GTPase is involved in a G2/M morphogenetic checkpoint regulating the
      apical-isotropic switch and nuclear division in yeast.
AB  - The Cdc42p GTPase is involved in the signal transduction cascades controlling bud
      emergence and polarized cell growth in S. cerevisiae. Cells expressing the
      cdc42(V44A) effector domain mutant allele displayed morphological defects of
      highly elongated and multielongated budded cells indicative of a defect in the
      apical-isotropic switch in bud growth. In addition, these cells contained one,
      two, or multiple nuclei indicative of a G2/M delay in nuclear division and also a
      defect in cytokinesis and/or cell separation. Actin and chitin were delocalized,
      and septin ring structure was aberrant and partially delocalized to the tips of
      elongated cdc42(V44A) cells; however, Cdc42(V44A)p localization was normal. Two
      hybrid protein analyses showed that the V44A mutation interfered with Cdc42p's
      interactions with Cla4p, a p21(Cdc42/Rac)-activated kinase (PAK)-like kinase, and
      the novel effectors Gic1p and Gic2p, but not with the Ste20p or Skm1p PAK-like
      kinases, the Bni1p formin, or the Iqg1p IQGAP homolog. Furthermore, the
      cdc42(V44A) morphological defects were suppressed by deletion of the Swe1p cyclin
      dependent kinase inhibitory kinase and by overexpression of Cla4p, Ste20p, the
      Cdc12 septin protein, or the guanine nucleotide exchange factor Cdc24p. In sum,
      these results suggest that proper Cdc42p function is essential for timely
      progression through the apical-isotropic switch and G2/M transition and that
      Cdc42(V44A)p differentially interacts with a number of effectors and regulators.

PMID- 10358033
TI  - The anatomy and transcription of a monocistronic expression site for a metacyclic
      variant surface glycoprotein gene in Trypanosoma brucei.
AB  - African trypanosomes evade the immune response of their mammalian hosts by
      switching the expression of their variant surface glycoprotein genes (vsg). The
      bloodstream trypanosome clone MVAT4 of Trypanosoma brucei rhodesiense expresses a
      metacyclic vsg as a monocistronic RNA from a promoter located 2 kilobases (kb)
      upstream of its start codon. Determination of 23 kb of sequence at the metacyclic
      variant antigen type 4 (MVAT) vsg expression site (ES) revealed an ES-associated
      gene (esag) 1 preceded by an ingi retroposon and an inverted region containing an
      unrelated vsg, short stretches of 70-bp repeats and a pseudo esag 3. Nuclear run
      on experiments indicate that the 18-kb region upstream of the MVAT4 vsg promoter
      is transcriptionally silent. However, multiple members of different esag families
      are expressed from elsewhere in the genome. The MVAT4 vsg promoter is highly
      repressed in the procyclic stage, in contrast to the known polycistronic vsg ESs
      which undergo abortive transcription. Activation of the MVAT4 vsg ES occurs in
      situ without nucleotide sequence changes, although this monocistronic ES
      undergoes a pattern of base J modifications similar to that reported for the
      polycistronic ESs. The relative simplicity of the MVAT4 vsg ES and the uncoupled
      expression of the vsg and esags provide a unique opportunity for investigating
      the molecular mechanisms responsible for antigenic variation in African
      trypanosomes.

PMID- 10358032
TI  - RIP3, a novel apoptosis-inducing kinase.
AB  - RIP3 is a novel gene product containing a N-terminal kinase domain that shares
      extensive homology with the corresponding domain in RIP (receptor-interacting
      protein) and RIP2. Unlike RIP, which has a C-terminal death domain, and RIP2,
      which has a C-terminal caspase activation and recruitment domain, RIP3 has a
      unique C terminus. RIP3 binds RIP through its unique C-terminal segment and by
      virtue of this interaction is recruited to the tumor necrosis factor (TNF)
      receptor-1 signaling complex. Previous studies have shown that RIP mediates TNF
      induced activation of the anti-apoptotic NF-kappaB pathway. RIP3, however,
      attenuates both RIP and TNF receptor-1-induced NF-kappaB activation.
      Overexpression studies revealed RIP3 to be a potent inducer of apoptosis, capable
      of selectively binding to large prodomain initiator caspases.

PMID- 10358034
TI  - Leaky transcription of variant surface glycoprotein gene expression sites in
      bloodstream african trypanosomes.
AB  - Trypanosoma brucei undergoes antigenic variation by periodically switching the
      expression of its variant surface glycoprotein (VSG) genes (vsg) among an
      estimated 20-40 telomere-linked expression sites (ES), only one of which is fully
      active at a given time. We found that in bloodstream trypanosomes one ES is
      transcribed at a high level and other ESs are expressed at low levels, resulting
      in organisms containing one abundant VSG mRNA and several rare VSG RNAs. Some of
      the rare VSG mRNAs come from monocistronic ESs in which the promoters are
      situated about 2 kilobases upstream of the vsg, in contrast to the polycistronic
      ESs in which the promoters are located 45-60 kilobases upstream of the vsg. The
      monocistronic ES containing the MVAT4 vsg does not include the ES-associated
      genes (esag) that occur between the promoter and the vsg in polycistronic ESs.
      However, bloodstream MVAT4 trypanosomes contain the mRNAs for many different
      ESAGs 6 and 7 (transferrin receptors), suggesting that polycistronic ESs are
      partially active in this clone. To explain these findings, we propose a model in
      which both mono- and polycistronic ESs are controlled by a similar mechanism
      throughout the parasite's life cycle. Certain VSGs are preferentially expressed
      in metacyclic versus bloodstream stages as a result of differences in ESAG
      expression and the proximity of the promoters to the vsg and telomere.

PMID- 10358035
TI  - Specific binding of human MSH2.MSH6 mismatch-repair protein heterodimers to DNA
      incorporating thymine- or uracil-containing UV light photoproducts opposite
      mismatched bases.
AB  - Previous studies have demonstrated recognition of DNA-containing UV light
      photoproducts by bacterial (Feng, W.-Y., Lee, E., and Hays, J. B. (1991) Genetics
      129, 1007-1020) and human (Mu, D., Tursun, M., Duckett, D. R., Drummond, J. T.,
      Modrich, P., and Sancar, A. (1997) Mol. Cell. Biol. 17, 760-769) long-patch
      mismatch-repair systems. Mismatch repair directed specifically against incorrect
      bases inserted during semi-conservative DNA replication might efficiently
      antagonize UV mutagenesis. To test this hypothesis, DNA 51-mers containing site
      specific T-T cis-syn-cyclobutane pyrimidine-dimers or T-T pyrimidine-(6
      4')pyrimidinone photoproducts, with all four possible bases opposite the
      respective 3'-thymines in the photoproducts, were analyzed for the ability to
      compete with radiolabeled (T/G)-mismatched DNA for binding by highly purified
      human MSH2.MSH6 heterodimer protein (hMutSalpha). Both (cyclobutane-dimer)/AG and
      ((6-4)photoproduct)/AG mismatches competed about as well as non-photoproduct T/T
      mismatches. The two respective pairs of photoproduct/(A(T or C)) mismatches also
      showed higher hMutSalpha affinity than photoproduct/AA "matches"; the apparent
      affinity of hMutSalpha for the ((6-4)photoproduct)/AA-"matched" substrate was
      actually less than that for TT/AA homoduplexes. Surprisingly, although hMutSalpha
      affinities for both non-photoproduct UU/GG double mismatches and for (uracil
      cyclobutane-dimer)/AG single mismatches were high, affinity for the (uracil
      cyclobutane-dimer)/GG mismatch was quite low. Equilibrium binding of hMutSalpha
      to DNA containing (photoproduct/base) mismatches and to (T/G)-mismatched DNA was
      reduced similarly by ATP (in the absence of magnesium).

PMID- 10358036
TI  - Activation of the de novo biosynthesis of sphingolipids mediates angiotensin II
      type 2 receptor-induced apoptosis.
AB  - This study examines the role of sphingolipids in mediating the apoptosis of PC12W
      cells induced by the angiotensin II type 2 (AT2) receptor. PC12W cells express
      abundant AT2 receptor but not angiotensin II type 1 receptor and undergo
      apoptosis when stimulated by angiotensin II. AT2 receptor-induced ceramide
      accumulation preceded the onset of caspase 3 activation and DNA fragmentation.
      AT2 receptor-induced ceramide accumulation did not result from the degradation of
      complex sphingolipids (SL) such as sphingomyelin or glycosphingolipids, as no
      changes in neutral or acidic sphingomyelinase activities, sphingomyelin level,
      nor in cellular glycolipid composition were observed. AT2 receptor activated
      serine palmitoyltransferase with a maximum time of 24 h after angiotensin II
      stimulation. The AT2 receptor-induced accumulation of ceramide was blocked by
      inhibitors of the de novo pathway of SL synthesis, beta-chloro-L-alanine and
      fumonisin B1. Inhibition of the de novo biosynthesis of SLs by fumonisin B1 and
      beta-chloro-L-alanine completely abrogated the AT2 receptor-mediated apoptosis.
      Pertussis toxin and orthovanadate blocked AT2 receptor-mediated ceramide
      production. Taken together our data demonstrate that in PC12W cells the
      stimulation of AT2 receptor induces the activation of de novo pathway, and a
      metabolite of this pathway, possibly ceramide, mediates AT2 receptor-induced
      apoptosis.

PMID- 10358037
TI  - Subtype-specific assembly of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic
      acid receptor subunits is mediated by their n-terminal domains.
AB  - Glutamate receptors (GluR) are oligomeric protein complexes formed by the
      assembly of four or perhaps five subunits. The rules that govern the selectivity
      of this process are not well understood. Here, we expressed combinations of
      subunits from two related GluR subfamilies in COS7 cells, the alpha-amino-3
      hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptors. By co
      immunoprecipitation experiments, we assessed the ability of AMPA receptor
      subunits to assemble into multimeric complexes. Subunits GluR1-4 associated with
      indistinguishable efficiency with each other, whereas the kainate receptor
      subunits GluR6 and 7 showed a much lower degree of association with GluR1. Using
      chimeric receptors and truncation fragments of subunits, we show that this
      assembly specificity is determined by N-terminal regions of these subunits and
      that the most N-terminal domain of GluR2 together with a membrane anchor
      efficiently associates with GluR1.

PMID- 10358038
TI  - Calreticulin is expressed on the cell surface of activated human peripheral blood
      T lymphocytes in association with major histocompatibility complex class I
      molecules.
AB  - Calreticulin is an endoplasmic reticulum resident molecule known to be involved
      in the folding and assembly of major histocompatibility complex (MHC) class I
      molecules. In the present study, expression of calreticulin was analyzed in human
      peripheral blood T lymphocytes. Pulse-chase experiments in [35S]methionine
      labeled T cell blasts showed that calreticulin was associated with several
      proteins in the endoplasmic reticulum and suggested that it was expressed at the
      cell surface. Indeed, the 60-kDa calreticulin was labeled by cell surface
      biotinylation and precipitated from the surface of activated T cells together
      with a protein with an apparent molecular mass of 46 kDa. Cell surface expression
      of calreticulin by activated T lymphocytes was further confirmed by
      immunofluorescence and flow cytometry, studies that showed that both CD8+ and
      CD4+ T cells expressed calreticulin in the plasma membrane. Low amounts of cell
      surface calreticulin were detected in resting T lymphocytes. By sequential
      immunoprecipitation using the conformation independent monoclonal antibody HC-10,
      we provided evidence that the cell surface 46-kDa protein co-precipitated with
      calreticulin is unfolded MHC I. These results show for the first time that after
      T cell activation, significant amounts of calreticulin are expressed on the T
      cell surface, where they are found in physical association with a pool of beta2
      free MHC class I molecules.

PMID- 10358039
TI  - Peptide ligands can bind to distinct sites in integrin alphaIIbbeta3 and elicit
      different functional responses.
AB  - The spatial relationship between the binding sites for two cyclic peptides,
      cyclo(S,S)KYGCRGDWPC (cRGD) and cyclo(S,S)KYGCHarGDWPC (cHarGD), high affinity
      analogs for the RGD and HLGGAKQAGDV peptide ligands, in integrin alphaIIbbeta3
      (GPIIb-IIIa) has been characterized. For this purpose, cRGD and cHarGD were
      labeled with fluorescein isothiocyanate and tetramethylrhodamine 5
      isothiocyanate, respectively. Both cyclic peptides were potent inhibitors of
      fibrinogen binding to alphaIIbbeta3, particularly in the presence of Mn2+; IC50
      values for cRGD and cHarGD were 1 and <0.1 nM in the presence of Mn2+. Direct
      binding experiments and fluorescence resonance energy transfer analysis using the
      purified receptor showed that both peptides interacted simultaneously with
      distinct sites in alphaIIbbeta3. The distance between these sites was estimated
      to be 6.1 +/- 0.5 nm. Although cRGD bound preferentially to one site and cHarGD
      to the other, the sites were not fully specific, and each cyclic peptide or its
      linear counterpart could displace the other to some extent. The binding affinity
      of the cHarGD site was dramatically affected by Mn2+. cRGD, but not cHarGD, bound
      to recombinant beta3-(95-373) in a cation-dependent manner, indicating that the
      cRGD site is located entirely within this fragment. With intact platelets,
      binding of c-RGD and cHarGD to alphaIIbbeta3 resulted in distinct conformational
      alterations in the receptor as indicated by the differential exposure of ligand
      induced binding site epitopes and also induced the opposite on membrane fluidity
      as shown by electron paramagnetic resonance analyses using 5-doxylstearic acid as
      a spin probe. These data support the concept the two peptide ligands bind to
      distinct sites in alphaIIbbeta3 and initiate different functional consequences
      within the receptor itself and within platelets.

PMID- 10358040
TI  - A novel NDP-6-deoxyhexosyl-4-ulose reductase in the pathway for the synthesis of
      thymidine diphosphate-D-fucose.
AB  - The serotype-specific polysaccharide antigen of Actinobacillus
      actinomycetemcomitans Y4 (serotype b) consists of D-fucose and L-rhamnose.
      Thymidine diphosphate (dTDP)-D-fucose is the activated nucleotide sugar form of D
      fucose, which has been identified as a constituent of structural polysaccharides
      in only a few bacteria. In this paper, we show that three dTDP-D-fucose synthetic
      enzymes are encoded by genes in the gene cluster responsible for the synthesis of
      serotype b-specific polysaccharide in A. actinomycetemcomitans. The first and
      second steps of the dTDP-D-fucose synthetic pathway are catalyzed by D-glucose-1
      phosphate thymidylyltransferase and dTDP-D-glucose 4,6-dehydratase, which are
      encoded by rmlA and rmlB in the gene cluster, respectively. These two reactions
      are common to the well studied dTDP-L-rhamnose synthetic pathway. However, the
      enzyme catalyzing the last step of the dTDP-D-fucose synthetic pathway has never
      been reported. We identified the fcd gene encoding a dTDP-4-keto-6-deoxy-D
      glucose reductase. After purifying the three enzymes, their enzymatic activities
      were analyzed by reversed-phase high performance liquid chromatography. In
      addition, nuclear magnetic resonance analysis and gas-liquid chromatography
      analysis proved that the fcd gene product converts dTDP-4-keto-6-deoxy-D-glucose
      to dTDP-D-fucose. Moreover, kinetic analysis of the enzyme indicated that the Km
      values for dTDP-4-keto-6-deoxy-D-glucose and NADPH are 97.3 and 28.7 microM,
      respectively, and that the enzyme follows the sequential mechanism. This paper is
      the first report on the dTDP-D-fucose synthetic pathway and dTDP-4-keto-6-deoxy-D
      glucose reductase.

PMID- 10358041
TI  - The propeptides of the vitamin K-dependent proteins possess different affinities
      for the vitamin K-dependent carboxylase.
AB  - The vitamin K-dependent gamma-glutamyl carboxylase catalyzes the modification of
      specific glutamates in a number of proteins required for blood coagulation and
      associated with bone and calcium homeostasis. All known vitamin K-dependent
      proteins possess a conserved eighteen-amino acid propeptide sequence that is the
      primary binding site for the carboxylase. We compared the relative affinities of
      synthetic propeptides of nine human vitamin K-dependent proteins by determining
      the inhibition constants (Ki) toward a factor IX propeptide/gamma-carboxyglutamic
      acid domain substrate. The Ki values for six of the propeptides (factor X, matrix
      Gla protein, factor VII, factor IX, PRGP1, and protein S) were between 2-35 nM,
      with the factor X propeptide having the tightest affinity. In contrast, the
      inhibition constants for the propeptides of prothrombin and protein C are
      approximately 100-fold weaker than the factor X propeptide. The propeptide of
      bone Gla protein demonstrates severely impaired carboxylase binding with an
      inhibition constant of at least 200,000-fold weaker than the factor X propeptide.
      This study demonstrates that the affinities of the propeptides of the vitamin K
      dependent proteins vary over a considerable range; this may have important
      physiological consequences in the levels of vitamin K-dependent proteins and the
      biochemical mechanism by which these substrates are modified by the carboxylase.

PMID- 10358042
TI  - Crystal structure of allophycocyanin from red algae Porphyra yezoensis at 2.2-A
      resolution.
AB  - The crystal structure of allophycocyanin from red algae Porphyra yezoensis (APC
      PY) at 2.2-A resolution has been determined by the molecular replacement method.
      The crystal belongs to space group R32 with cell parameters a = b = 105.3 A, c =
      189.4 A, alpha = beta = 90 degrees, gamma = 120 degrees. After several cycles of
      refinement using program X-PLOR and model building based on the electron density
      map, the crystallographic R-factor converged to 19.3% (R-free factor is 26.9%) in
      the range of 10.0 to 2.2 A. The r.m.s. deviations of bond length and angles are
      0.015 A and 2.9 degrees, respectively. In the crystal, two APC-PY trimers
      associate face to face into a hexamer. The assembly of two trimers within the
      hexamer is similar to that of C-phycocyanin (C-PC) and R-phycoerythrin (R-PE)
      hexamers, but the assembly tightness of the two trimers to the hexamer is not so
      high as that in C-PC and R-PE hexamers. The chromophore-protein interactions and
      possible pathway of energy transfer were discussed. Phycocyanobilin 1alpha84 of
      APC-PY forms 5 hydrogen bonds with 3 residues in subunit 2beta of another
      monomer. In R-PE and C-PC, chromophore 1alpha84 only forms 1 hydrogen bond with
      2beta77 residue in subunit 2beta. This result may support and explain great
      spectrum difference exists between APC trimer and monomer.

PMID- 10358043
TI  - Biochemical evidence for heme linkage through esters with Asp-93 and Glu-241 in
      human eosinophil peroxidase. The ester with Asp-93 is only partially formed in
      vivo.
AB  - The covalent heme attachment has been extensively studied by spectroscopic
      methods in myeloperoxidase and lactoperoxidase (LPO) but not in eosinophil
      peroxidase (EPO). We show that heme linkage to the heavy chain is invariably
      present, whereas heme linkage to the light chain of EPO is present in less than
      one-third of EPO molecules. Mass analysis of isolated heme bispeptides supports
      the hypothesis of a heme b linked through two esters to the polypeptide. Mass
      analysis of heme monopeptides reveals that >90% have a nonderivatized methyl
      group at the position of the light chain linkage. Apparently, an ester had not
      been formed during biosynthesis. The light chain linkage could be formed by
      incubation with hydrogen peroxide, in accordance with a recent hypothesis of
      autocatalytic heme attachment based on studies with LPO (DePillis, G. D., Ozaki,
      S., Kuo, J. M., Maltby, D. A., and Ortiz de Montellano P. R. (1997) J. Biol.
      Chem. 272, 8857-8860). By sequence analysis of isolated heme peptides after
      aminolysis, we unambiguously identified the acidic residues, Asp-93 of the light
      chain and Glu-241 of the heavy chain, that form esters with the heme group. This
      is the first biochemical support for ester linkage to two specific residues in
      eosinophil peroxidase. From a parallel study with LPO, we show that Asp-125 and
      Glu-275 are engaged in ester linkage. The species with a nonderivatized methyl
      group was not found among LPO peptides.

PMID- 10358044
TI  - Redox factor-1 (Ref-1) mediates the activation of AP-1 in HeLa and NIH 3T3 cells
      in response to heat shock.
AB  - The early response genes, c-Fos and c-Jun, are induced by environmental stress
      and are thought to modulate injury processes via the induction of AP-1-dependent
      target genes. AP-1 activation is thought to be regulated by changes in
      intracellular oxidation/reduction reactions involving the redox factor-1 (Ref-1)
      protein. In this study, NIH 3T3 and HeLa cells were used to determine whether
      heat shock induces the AP-1 transcription factor via signaling pathways involving
      Ref-1. Reverse transcriptase-polymerase chain reaction analysis and
      immunoblotting demonstrated that c-Fos and c-Jun were induced 2-10 h following
      heat shock, and this induction was accompanied by an increase in AP-1 DNA
      binding. Electrophoretic mobility shift assay extracts immunodepleted of Ref-1
      protein demonstrated that the increase in AP-1 DNA-binding activity following
      heating was dependent upon the presence of Ref-1 and that Ref-1 regulates
      inducible, but not basal, AP-1 DNA-binding activity. This was confirmed by the
      restoration of heat-inducible DNA binding upon addition of Ref-1 to
      immunodepleted extracts. The ability of Ref-1 from heated cells to stimulate AP-1
      DNA binding was abolished by chemical oxidation and restored by chemical
      reduction. These results indicate that heat shock activates c-Fos/c-Jun gene
      expression and AP-1 DNA binding and suggests that redox-sensitive signal
      transduction pathways involving Ref-1 may mediate heat-induced alterations in AP
      1 activation.

PMID- 10358045
TI  - STAT protein recruitment and activation in c-Kit deletion mutants.
AB  - Stem cell factor (SCF) and its tyrosine kinase receptor, c-Kit, play a crucial
      role in regulating migration and proliferation of melanoblasts, germ cells, and
      hemopoietic cell progenitors by activating a number of intracellular signaling
      molecules. Here we report that SCF stimulation of myeloid cells or fibroblasts
      ectopically expressing c-Kit induces physical association with and tyrosine
      phosphorylation of three signal transducers and activators of transcription
      (STATs) as follows: STAT1alpha, STAT5A, and STAT5B. Other STAT proteins are not
      recruited upon SCF stimulation. Recruitment of STATs leads to their dimerization,
      nuclear translocation, and binding to specific promoter-responsive elements.
      Whereas STAT1alpha, possibly in the form of homodimers, binds to the sis
      inducible DNA element, STAT5 proteins, either as STAT5A/STAT5B or
      STAT5/STAT1alpha heterodimers, bind to the prolactin-inducible element of the
      beta-casein promoter. The tyrosine kinase activity of Kit appears essential for
      STAT activation since a kinase-defective mutant lacking a kinase insert domain
      was inactive in STAT signaling. However, another mutant that lacked the carboxyl
      terminal region retained STAT1alpha activation and nuclear translocation but was
      unable to fully activate STAT5 proteins, although it mediated their transient
      phosphorylation. These results indicate that different intracellular domains of c
      Kit are involved in activation of the various STAT proteins.

PMID- 10358046
TI  - sgk is an aldosterone-induced kinase in the renal collecting duct. Effects on
      epithelial na+ channels.
AB  - The early phase of the stimulatory effect of aldosterone on sodium reabsorption
      in renal epithelia is thought to involve activation of apical sodium channels.
      However, the genes initiating this effect are unknown. We used a combination of
      polymerase chain reaction-based subtractive hybridization and differential
      display techniques to identify aldosterone-regulated immediate early genes in
      renal mineralocorticoid target cells. We report here that aldosterone rapidly
      increases mRNA levels of a putative Ser/Thr kinase, sgk (or serum- and
      glucocorticoid-regulated kinase), in its native target cells, i.e. in cortical
      collecting duct cells. The effect occurs within 30 min of the addition of
      aldosterone, is mediated through mineralocorticoid receptors, and does not
      require de novo protein synthesis. The full-length sequences of rabbit and mouse
      sgk cDNAs were determined. Both cDNAs show significant homology to rat and human
      sgk (88-94% at the nucleotide level, and 96-99% at the amino acid level).
      Coexpression of the mouse sgk in Xenopus oocytes with the three subunits of the
      epithelial Na+ channel results in a significantly enhanced Na+ current. These
      results suggest that sgk is an immediate early aldosterone-induced gene, and this
      protein kinase plays an important role in the early phase of aldosterone
      stimulated Na+ transport.

PMID- 10358047
TI  - The binding interface between an E2 (UBC9) and a ubiquitin homologue (UBL1).
AB  - Human UBC9 is a member of the E2 (ubiquitin conjugation enzyme) family of
      proteins. Instead of conjugating to ubiquitin, it conjugates with a ubiquitin
      homologue UBL1 (also known as SUMO-1, GMP1, SMTP3, PIC1, and sentrin). UBC9 has
      been shown to be involved in cell cycle regulation, DNA repair, and p53-dependent
      processes. The binding interfaces of the UBC9 and UBL1 complex have been
      determined by chemical shift perturbation using nuclear magnetic resonance
      spectroscopy. The binding site of UBL1 resides on the ubiquitin domain, and the
      binding site of UBC9 is located on a structurally conserved region of E2. Because
      the UBC9-UBL1 system shares many similarities with the ubiquitin system in
      structures and in conjugation with each other and with target proteins, the
      observed binding interfaces may be conserved in E2-ubiquitin interactions in
      general.

PMID- 10358048
TI  - Phosphorylation of MAP kinases by MAP/ERK involves multiple regions of MAP
      kinases.
AB  - Mitogen-activated protein (MAP) kinases are activated with great specificity by
      MAP/ERK kinases (MEKs). The basis for the specific activation is not understood.
      In this study chimeras composed of two MAP kinases, extracellular signal
      regulated protein kinase 2 and p38, were assayed in vitro for phosphorylation and
      activation by different MEK isoforms to probe the requirements for productive
      interaction of MAP kinases with MEKs. Experimental results and modeling support
      the conclusion that the specificity of MEK/MAP kinase phosphorylation results
      from multiple contacts, including surfaces in both the N- and C-terminal domains.

PMID- 10358049
TI  - Crystal structure of human gastric lipase and model of lysosomal acid lipase, two
      lipolytic enzymes of medical interest.
AB  - Fat digestion in humans requires not only the classical pancreatic lipase but
      also gastric lipase, which is stable and active despite the highly acidic stomach
      environment. We report here the structure of recombinant human gastric lipase at
      3.0-A resolution, the first structure to be described within the mammalian acid
      lipase family. This globular enzyme (379 residues) consists of a core domain
      belonging to the alpha/beta hydrolase-fold family and a "cap" domain, which is
      analogous to that present in serine carboxypeptidases. It possesses a classical
      catalytic triad (Ser-153, His-353, Asp-324) and an oxyanion hole (NH groups of
      Gln-154 and Leu-67). Four N-glycosylation sites were identified on the electron
      density maps. The catalytic serine is deeply buried under a segment consisting of
      30 residues, which can be defined as a lid and belonging to the cap domain. The
      displacement of the lid is necessary for the substrates to have access to Ser
      153. A phosphonate inhibitor was positioned in the active site that clearly
      suggests the location of the hydrophobic substrate binding site. The lysosomal
      acid lipase was modeled by homology, and possible explanations for some
      previously reported mutations leading to the cholesterol ester storage disease
      are given based on the present model.

PMID- 10358050
TI  - Physical interaction and functional antagonism between the RNA polymerase II
      elongation factor ELL and p53.
AB  - ELL was originally identified as a gene that undergoes translocation with the
      trithorax-like MLL gene in acute myeloid leukemia. Recent studies have shown that
      the gene product, ELL, functions as an RNA polymerase II elongation factor that
      increases the rate of transcription by RNA polymerase II by suppressing transient
      pausing. Using yeast two-hybrid screening with ELL as bait, we isolated the p53
      tumor suppressor protein as a specific interactor of ELL. The interaction
      involves respectively the transcription elongation activation domain of ELL and
      the C-terminal tail of p53. Through this interaction, ELL inhibits both sequence
      specific transactivation and sequence-independent transrepression by p53. Thus,
      ELL acts as a negative regulator of p53 in transcription. Conversely, p53
      inhibits the transcription elongation activity of ELL, suggesting that p53 is
      capable of regulating general transcription by RNA polymerase II through
      controlling the ELL activity. Elevated levels of ELL in cells resulted in the
      inhibition of p53-dependent induction of endogenous p21 and substantially
      protected cells from p53-mediated apoptosis that is induced by genotoxic stress.
      Our observations indicate the existence of a mutually inhibitory interaction
      between p53 and a general transcription elongation factor ELL and raise the
      possibility that an aberrant interaction between p53 and ELL may play a role in
      the genesis of leukemias carrying MLL-ELL gene translocations.

PMID- 10358051
TI  - Defining the domain of binding of F1 subunit epsilon with the polar loop of F0
      subunit c in the Escherichia coli ATP synthase.
AB  - We have previously shown that the E31C-substituted epsilon subunit of F1 can be
      cross-linked by disulfide bond formation to the Q42C-substituted c subunit of F0
      in the Escherichia coli F1F0-ATP synthase complex (Zhang, Y., and Fillingame, R.
      H. (1995) J. Biol. Chem. 270, 24609-24614). The interactions of subunits epsilon
      and c are thought to be central to the coupling of H+ transport through F0 to ATP
      synthesis in F1. To further define the domains of interaction, we have introduced
      additional Cys into subunit epsilon and subunit c and tested for cross-link
      formation following sulfhydryl oxidation. The results show that Cys, in a
      continuous stretch of residues 26-33 in subunit epsilon, can be cross-linked to
      Cys at positions 40, 42, and 44 in the polar loop region of subunit c. The
      results are interpreted, and the subunit interaction is modeled using the NMR and
      x-ray diffraction structures of the monomeric subunits together with information
      on the packing arrangement of subunit c in a ring of 12 subunits. In the model,
      residues 26-33 form a turn of antiparallel beta-sheet which packs between the
      polar loop regions of adjacent subunit c at the cytoplasmic surface of the c12
      oligomer.

PMID- 10358052
TI  - UV-responsive genes of arabidopsis revealed by similarity to the Gcn4-mediated UV
      response in yeast.
AB  - A UV response that involves the Ras proteins and AP-1 transcription factors has
      recently been described in mammals and yeast. To test whether an equivalent
      response exists in plants, we monitored the expression of Arabidopsis histidinol
      dehydrogenase gene (HDH), a homologue of the yeast HIS4 gene, which is strongly
      induced by UV light and is a target of the transcriptional activator Gcn4. We
      show that HDH mRNA levels increase specifically in response to UV-B light. Only
      small increases were detected upon exposure to other wavelengths. To isolate
      plant genes involved in this UV response, a gcn4 mutant was transfected with an
      Arabidopsis thaliana cDNA library. A new type of nucleotide diphosphate kinase
      (NDPK Ia) with a significant homology to the human tumor suppressor protein Nm23
      rescued the gcn4 phenotype. NDPK Ia specifically binds to the HIS4 promoter in
      vitro and induces HIS4 transcription in yeast. In Arabidopsis, the NDPK Ia
      protein is located in the nucleus and cytosol. Expression studies in seedlings
      revealed that the level of NDPK Ia mRNA, like that of HDH, increases in response
      to UV-B light. It appears that NDPK Ia and HDH are components of a novel UV
      responsive pathway in A. thaliana.

PMID- 10358053
TI  - The Listeria monocytogenes protein InlB is an agonist of mammalian
      phosphoinositide 3-kinase.
AB  - The Gram-positive pathogen Listeria monocytogenes induces its own internalization
      into some non-phagocytic mammalian cells by stimulating host tyrosine
      phosphorylation, phosphoinositide (PI) 3-kinase activity, and rearrangements in
      the actin cytoskeleton. Entry into many cultured cell lines is mediated by the
      bacterial protein InlB. Here we investigate the role of InlB in regulating
      mammalian signal transduction and cytoskeletal structure. Treatment of Vero cells
      with purified InlB caused rapid and transient increases in the lipid products of
      the PI 3-kinase p85-p110, tyrosine phosphorylation of the mammalian adaptor
      proteins Gab1, Cbl, and Shc, and association of these proteins with p85. InlB
      also stimulated large scale changes in the actin cytoskeleton (membrane
      ruffling), which were PI 3-kinase-dependent. These results identify InlB as the
      first reported non-mammalian agonist of PI 3-kinase and demonstrate similarities
      in the signal transduction events elicited by this bacterial protein and known
      agonists such as epidermal growth factor.

PMID- 10358054
TI  - Similar structures and shared switch mechanisms of the beta2-adrenoceptor and the
      parathyroid hormone receptor. Zn(II) bridges between helices III and VI block
      activation.
AB  - The seven transmembrane helices of serpentine receptors comprise a conserved
      switch that relays signals from extracellular stimuli to heterotrimeric G
      proteins on the cytoplasmic face of the membrane. By substituting histidines for
      residues at the cytoplasmic ends of helices III and VI in retinal rhodopsin, we
      engineered a metal-binding site whose occupancy by Zn(II) prevented the receptor
      from activating a retinal G protein, Gt (Sheikh, S. P., Zvyaga, T. A. ,
      Lichtarge, O., Sakmar, T. P., and Bourne, H. R. (1996) Nature 383, 347-350). Now
      we report engineering of metal-binding sites bridging the cytoplasmic ends of
      these two helices in two other serpentine receptors, the beta2-adrenoreceptor and
      the parathyroid hormone receptor; occupancy of the metal-binding site by Zn(II)
      markedly impairs the ability of each receptor to mediate ligand-dependent
      activation of Gs, the stimulatory regulator of adenylyl cyclase. We infer that
      these two receptors share with rhodopsin a common three-dimensional architecture
      and an activation switch that requires movement, relative to one another, of
      helices III and VI; these inferences are surprising in the case of the
      parathyroid hormone receptor, a receptor that contains seven stretches of
      hydrophobic sequence but whose amino acid sequence otherwise shows no apparent
      similarity to those of receptors in the rhodopsin family. These findings
      highlight the evolutionary conservation of the switch mechanism of serpentine
      receptors and help to constrain models of how the switch works.

PMID- 10358055
TI  - Endothelial cell apoptosis induced by the peroxisome proliferator-activated
      receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J2.
AB  - 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) is a bioactive prostanoid
      produced by dehydration and isomerization of PGD2, a cyclooxygenase product. It
      was recently shown to activate the nuclear peroxisome proliferator-activated
      receptor gamma (PPARgamma), a critical transcription factor involved in adipocyte
      and monocyte differentiation. In this report, we show that 15d-PGJ2 is a potent
      inducer of caspase-mediated endothelial cell apoptosis. PPARalpha, -delta, and 
      gamma were expressed by endothelial cells, which, when treated with 15d-PGJ2,
      induced receptor translocation into the nucleus, and an increase in PPAR response
      element-driven reporter gene expression. Ciglitizone, a selective activator of
      PPARgamma, also induced transcriptional activation and endothelial cell
      apoptosis. Endothelial apoptosis induced by 15d-PGJ2 was inhibited by treatment
      of cells with an oligonucleotide decoy to a consensus PPAR response element
      sequence. Furthermore, overexpression of the PPARgamma isotype induced
      endothelial cell apoptosis, which was further potentiated by 15d-PGJ2 treatment.
      We conclude that 15d-PGJ2 induces endothelial cell apoptosis via a PPAR-dependent
      pathway. The PPAR pathway may be a therapeutic target for numerous pathologies in
      which excessive angiogenesis is implicated.

PMID- 10358056
TI  - Identification and characterization of a haploid germ cell-specific nuclear
      protein kinase (Haspin) in spermatid nuclei and its effects on somatic cells.
AB  - We have cloned the entire coding region of a mouse germ cell-specific cDNA
      encoding a unique protein kinase whose catalytic domain contains only three
      consensus subdomains (I-III) instead of the normal 12. The protein possesses
      intrinsic Ser/Thr kinase activity and is exclusively expressed in haploid germ
      cells, localizing only in their nuclei, and was thus named Haspin (for haploid
      germ cell-specific nuclear protein kinase). Western blot analysis showed that
      specific antibodies recognized a protein of Mr 83,000 in the testis. Ectopically
      expressed Haspin was detected exclusively in the nuclei of cultured somatic
      cells. Even in the absence of kinase activity, however, Haspin caused cell cycle
      arrest at G1, resulting in growth arrest of the transfected somatic cells. In a
      DNA binding experiment, approximately one-half of wild-type Haspin was able to
      bind to a DNA-cellulose column, whereas the other half was not. In contrast, all
      of the deletion mutant Haspin that lacked autophosphorylation bound to the DNA
      column. Thus, the DNA-binding activity of Haspin may, in some way, be associated
      with its kinase activity. These observations suggest that Haspin has some
      critical roles in cell cycle cessation and differentiation of haploid germ cells.

PMID- 10358057
TI  - Cloning and characterization of ATRAP, a novel protein that interacts with the
      angiotensin II type 1 receptor.
AB  - The carboxyl-terminal cytoplasmic domain of the angiotensin II type 1 (AT1)
      receptor has recently been shown to interact with several classes of cytoplasmic
      proteins that regulate different aspects of AT1 receptor physiology. Employing
      yeast two-hybrid screening of a mouse kidney cDNA library with the carboxyl
      terminal cytoplasmic domain of the murine AT1a receptor as a bait, we have
      isolated a novel protein with a predicted molecular mass of 18 kDa, which we have
      named ATRAP (for AT1 receptor-associated protein). ATRAP interacts specifically
      with the carboxyl-terminal domain of the AT1a receptor but not with those of
      angiotensin II type 2 (AT2), m3 muscarinic acetylcholine, bradykinin B2,
      endothelin B, and beta2-adrenergic receptors. The mRNA of ATRAP was abundantly
      expressed in kidney, heart, and testis but was poorly expressed in lung, liver,
      spleen, and brain. The ATRAP-AT1a receptor association was confirmed by affinity
      chromatography, by specific co-immunoprecipitation of the two proteins, and by
      fluorescence microscopy, showing co-localization of these proteins in intact
      cells. Overexpression of ATRAP in COS-7 cells caused a marked inhibition of AT1a
      receptor-mediated activation of phospholipase C without affecting m3 receptor
      mediated activation. In conclusion, we have isolated a novel protein that
      interacts specifically with the carboxyl-terminal cytoplasmic domain of the AT1a
      receptor and affects AT1a receptor signaling.

PMID- 10358058
TI  - Molecular characterization of cytosolic phospholipase A2-beta.
AB  - We have isolated a cDNA encoding a 1012-amino acid polypeptide cPLA2-beta, that
      has significant homology with cPLA2-alpha in both the calcium-dependent lipid
      binding domain as well as in the catalytic domain. Transient expression of cPLA2
      beta cDNA in COS cells results in an increase in calcium-dependent phospholipase
      A1 (PLA1) and PLA2 activities compared with vector-transfected cells. cPLA2-beta
      is markedly less selective for cleavage at sn-2 as compared with cPLA2-alpha and
      cPLA2-gamma. Northern analysis reveals a cPLA2-beta transcript of 8 kilobase
      pairs that is expressed in all the human tissues examined. With the
      identification of cPLA2-beta, the newly defined cPLA2 family now comprises three
      members that may have dramatically different mechanisms for regulation of
      expression and enzymatic activation.

PMID- 10358059
TI  - Cytosolic components are required for proteasomal degradation of newly
      synthesized apolipoprotein B in permeabilized HepG2 cells.
AB  - Recent studies have proposed that post-translational degradation of
      apolipoprotein B100 (apoB) involves the cytosolic ubiquitin-proteasome pathway.
      In this study, immunocytochemistry indicated that endoplasmic reticulum (ER)
      associated proteasome molecules were concentrated in perinuclear regions of
      digitonin-permeabilized HepG2 cells. Signals produced by antibodies that
      recognize both alpha- and beta-subunits of the proteasome co-localized in the ER
      with specific domains of apoB. The mechanism of apoB degradation in the ER by the
      ubiquitin-proteasome pathway was studied using pulse-chase labeling and digitonin
      permeabilized cells. ApoB in permeabilized cells incubated at 37 degrees C in
      buffer alone was relatively stable. When permeabilized cells were incubated with
      both exogenous ATP and rabbit reticulocyte lysate (RRL) as a source of ubiquitin
      proteasome factors, >50% of [3H]apoB was degraded in 30 min. The degradation of
      apoB in the intact ER of permeabilized cells was much more rapid than that of
      extracted [3H]apoB incubated with RRL and ATP in vitro. The degradation of apoB
      was reduced by clasto-lactacystin beta-lactone, a potent proteasome inhibitor,
      and by ubiquitin K48R mutant protein, an inhibitor of polyubiquitination. ApoB in
      HepG2 cells was ubiquitinated, and polyubiquitination of apoB was stimulated by
      incubation of permeabilized cells with RRL. These results suggest that newly
      synthesized apoB in the ER is accessible to the cytoplasmic ubiquitin-proteasome
      pathway and that factors in RRL stimulate polyubiquitination of apoB, leading to
      rapid degradation of apoB in permeabilized cells.

PMID- 10358060
TI  - Methionine adenosyltransferase S-nitrosylation is regulated by the basic and
      acidic amino acids surrounding the target thiol.
AB  - S-Adenosylmethionine serves as the methyl donor for many biological methylation
      reactions and provides the propylamine group for the synthesis of polyamines. S
      Adenosylmethionine is synthesized from methionine and ATP by the enzyme
      methionine adenosyltransferase. The cellular factors regulating S
      adenosylmethionine synthesis have not been well defined. Here we show that in rat
      hepatocytes S-nitrosoglutathione monoethyl ester, a cell-permeable nitric oxide
      donor, markedly reduces cellular S-adenosylmethionine content via inactivation of
      methionine adenosyltransferase by S-nitrosylation. Removal of the nitric oxide
      donor from the incubation medium leads to the denitrosylation and reactivation of
      methionine adenosyltransferase and to the rapid recovery of cellular S
      adenosylmethionine levels. Nitric oxide inactivates methionine
      adenosyltransferase via S-nitrosylation of cysteine 121. Replacement of the
      acidic (aspartate 355) or basic (arginine 357 and arginine 363) amino acids
      located in the vicinity of cysteine 121 by serine leads to a marked reduction in
      the ability of nitric oxide to S-nitrosylate and inactivate hepatic methionine
      adenosyltransferase. These results indicate that protein S-nitrosylation is
      regulated by the basic and acidic amino acids surrounding the target cysteine.

PMID- 10358061
TI  - A two-hybrid dual bait system to discriminate specificity of protein
      interactions.
AB  - Biological regulatory systems require the specific organization of proteins into
      multicomponent complexes. Two hybrid systems have been used to identify novel
      components of signaling networks based on interactions with defined partner
      proteins. An important issue in the use of two-hybrid systems has been the degree
      to which interacting proteins distinguish their biological partner from
      evolutionarily conserved related proteins and the degree to which observed
      interactions are specific. We adapted the basic two-hybrid strategy to create a
      novel dual bait system designed to allow single-step screening of libraries for
      proteins that interact with protein 1 of interest, fused to DNA binding domain A
      (LexA), but do not interact with protein 2, fused to DNA binding domain B (lambda
      cI). Using the selective interactions of Ras and Krev-1(Rap1A) with Raf, RalGDS,
      and Krit1 as a model, we systematically compared LexA- and cI-fused baits and
      reporters. The LexA and cI baitr reporter systems are well matched for level of
      bait expression and sensitivity range for interaction detection and allow
      effective isolation of specifically interacting protein pairs against a
      nonspecific background. These reagents should prove useful to refine the
      selectivity of library screens, to reduce the isolation of false positives in
      such screens, and to perform directed analyses of sequence elements governing the
      interaction of a single protein with multiple partners.

PMID- 10358063
TI  - Transient exposure to HIV-1 Tat protein results in cytokine production in
      macrophages and astrocytes. A hit and run phenomenon.
AB  - The pathological correlates of dementia due to human immunodeficiency virus (HIV)
      infection are glial cell activation and cytokine dysregulation. These findings
      occur in the setting of small numbers of productively infected cells within the
      brain. We determined whether exposure of susceptible cells to Tat protein of HIV
      could result in the production of select proinflammatory cytokines. In a dose
      responsive manner, Tat induced interleukin (IL)-1beta production in monocytic
      cells, while astrocytic cells showed an increase in mRNA for IL-1beta, but had a
      translation block for IL-1beta protein production. Conversely, IL-6 protein and
      mRNA productions were strongly induced in astrocytic cells and minimally in
      monocytic cells. IL-1beta and IL-6 production were independent of tumor necrosis
      factor-alpha production. An exposure to Tat for a few minutes was sufficient for
      sustained releases of cytokines for several hours. This prolonged cytokine
      production is likely maintained by a positive feed back loop of Tat-induced
      nuclear factor kappaB activation and cytokine production that is independent of
      extracellular calcium. Thus a transient exposure may be sufficient to initiate a
      cascade of events resulting in cerebral dysfunction and a "hit and run" approach
      may be in effect. Hence cross-sectional measurement of viral load in the brain
      may not be a useful indicator of the role of viral products in the
      neuropathogenesis of HIV dementia.

PMID- 10358062
TI  - Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase
      inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis.
AB  - Molecular mechanisms coupling growth arrest and cell differentiation were
      examined during adipogenesis. Data are presented that document a cascade
      expression of members of two independent families of cyclin-dependent kinase
      inhibitors that define distinct states of growth arrest during 3T3-L1
      preadipocyte differentiation. Exit from the cell cycle into a pre-differentiation
      state of post-mitotic growth arrest was characterized by significant increases in
      p21 and p27. During onset of irreversible growth arrest associated with terminal
      differentiation, the level of p21 declined with a concomitant, dramatic increase
      in p18 and a sustained level of p27. The expression of p18 and p21, regulated at
      the level of protein and mRNA accumulation, was directly coupled to
      differentiation. Stable cell lines were engineered to express adipogenic
      transcription factors to examine the active role of trans-acting elements in
      regulating these cell cycle inhibitors. Ectopic expression of peroxisome
      proliferator-activated receptor (PPAR) gamma in non-precursor fibroblastic cell
      lines resulted in conversion to adipocytes and a coordinated increase in p18 and
      p21 mRNA and protein expression in a PPARgamma ligand-associated manner. These
      data demonstrate a role for PPARgamma in mediating the differentiation-dependent
      cascade expression of cyclin-dependent kinase inhibitors, thereby providing a
      molecular mechanism coupling growth arrest and adipocyte differentiation.

PMID- 10358064
TI  - The human WASP-interacting protein, WIP, activates the cell polarity pathway in
      yeast.
AB  - WIP, the Wiskott-Aldrich syndrome protein-interacting protein, is a human protein
      involved in actin polymerization and redistribution in lymphoid cells. The
      mechanism by which WIP reorganizes actin cytoskeleton is unknown. WIP is similar
      to yeast verprolin, an actin- and myosin-interacting protein required for
      polarized morphogenesis. To determine whether WIP and verprolin are functional
      homologues, we analyzed the function of WIP in yeast. WIP suppresses the growth
      defects of VRP1 missense and null mutations as well as the defects in
      cytoskeletal organization and endocytosis observed in vrp1-1 cells. The ability
      of WIP to replace verprolin is dependent on its WH2 actin binding domain and a
      putative profilin binding domain. Immunofluorescence localization of WIP in yeast
      cells reveals a pattern consistent with its function at the cortical sites of
      growth. Thus, like verprolin, WIP functions in yeast to link the polarity
      development pathway and the actin cytoskeleton to generate cytoskeletal
      asymmetry. A role for WIP in cell polarity provides a framework for unifying,
      under a common paradigm, distinct molecular defects associated with
      immunodeficiencies like Wiskott-Aldrich syndrome.

PMID- 10358065
TI  - The role of arginine 120 of human prostaglandin endoperoxide H synthase-2 in the
      interaction with fatty acid substrates and inhibitors.
AB  - Arg-120 is located near the mouth of the hydrophobic channel that forms the
      cyclooxygenase active site of prostaglandin endoperoxide H synthases (PGHSs)-1
      and -2. Replacement of Arg-120 of ovine PGHS-1 with a glutamine increases the
      apparent Km of PGHS-1 for arachidonate by 1,000-fold (Bhattacharyya, D. K.,
      Lecomte, M., Rieke, C. J., Garavito, R. M., and Smith, W. L. (1996) J. Biol.
      Chem. 271, 2179-2184). This and other evidence indicate that the guanido group of
      Arg-120 forms an ionic bond with the carboxylate group of arachidonate and that
      this interaction is an important contributor to the overall strength of
      arachidonate binding to PGHS-1. In contrast, we report here that R120Q human PGHS
      2 (hPGHS-2) and native hPGHS-2 have very similar kinetic properties, but R120L
      hPGHS-2 catalyzes the oxygenation of arachidonate inefficiently. Our data
      indicate that the guanido group of Arg-120 of hPGHS-2 interacts with arachidonate
      through a hydrogen bond rather than an ionic bond and that this interaction is
      much less important for arachidonate binding to PGHS-2 than to PGHS-1. The Km
      values of PGHS-1 and -2 for arachidonate are the same, and all but one of the
      core residues of the active sites of the two isozymes are identical. Thus, the
      results of our studies of Arg-120 of PGHS-1 and -2 imply that interactions
      involved in the binding of arachidonate to PGHS-1 and -2 are quite different and
      that residues within the hydrophobic cyclooxygenase channel must contribute more
      significantly to arachidonate binding to PGHS-2 than to PGHS-1. As observed
      previously with R120Q PGHS-1, flurbiprofen was an ineffective inhibitor of R120Q
      hPGHS-2. PGHS-2-specific inhibitors including NS398, DuP-697, and SC58125 had
      IC50 values for the R120Q mutant that were up to 1,000-fold less than those
      observed for native hPGHS-2; thus, the positively charged guanido group of Arg
      120 interferes with the binding of these compounds. NS398 did not cause time
      dependent inhibition of R120Q hPGHS-2, whereas DuP-697 and SC58125 were time
      dependent inhibitors. Thus, Arg-120 is important for the time-dependent
      inhibition of hPGHS-2 by NS398 but not by DuP-697 or SC58125.

PMID- 10358066
TI  - Cloning and expression of a novel galactoside beta1, 3-glucuronyltransferase
      involved in the biosynthesis of HNK-1 epitope.
AB  - We isolated a cDNA encoding a novel glucuronyltransferase, designated GlcAT-D,
      involved in the biosynthesis of the HNK-1 carbohydrate epitope from rat embryo
      cDNA by the degenerate polymerase chain reaction method. The new cDNA sequence
      revealed an open reading frame coding for a protein of 324 amino acids with type
      II transmembrane protein topology. The amino acid sequence of GlcAT-D displayed
      50.0% identity to rat GlcAT-P, which is involved in the biosynthesis of the HNK-1
      epitope on glycoproteins. Expression of GlcAT-D in COS-7 cells resulted in the
      formation of the HNK-1 epitope on the cell surface. The enzyme expressed in COS-7
      cells transferred a glucuronic acid (GlcA) not only to asialo-orosomucoid, a
      glycoprotein bearing terminal N-acetyllactosamine structure, but also to
      paragloboside (lacto-N-neotetraosylceramide), a precursor of the HNK-1 epitope on
      glycolipids. Furthermore, substrate specificity analysis using a soluble chimeric
      form of GlcAT-D revealed that GlcAT-D transfers a GlcA not only to Galbeta1
      4GlcNAcbeta1-3Galbeta1-4Glc-pyridylamine++ + but also to Galbeta1-3GlcNAcbeta1
      3Galbeta1-4Glc-pyridylamine++ +. Enzymatic hydrolysis and Smith degradation of
      the reaction product indicated that GlcAT-D transfers a GlcA through a beta1,3
      linkage to a terminal galactose. The GlcAT-D transcripts were detected in
      embryonic, postnatal, and adult rat brain. In situ hybridization analysis
      revealed that the expression pattern of GlcAT-D transcript in embryo is similar
      to that of GlcAT-P, but distinct expression of GlcAT-D was observed in the
      embryonic pallidum and retina. Regions that expressed GlcAT-D and/or GlcAT-P were
      always HNK-1-positive, indicating that both GlcATs are involved in the synthesis
      of the HNK-1 epitope in vivo.

PMID- 10358067
TI  - Identification and cloning of a connective tissue growth factor-like cDNA from
      human osteoblasts encoding a novel regulator of osteoblast functions.
AB  - We have identified and cloned a novel connective tissue growth factor-like (CTGF
      L) cDNA from primary human osteoblast cells encoding a 250-amino acid single
      chain polypeptide. Murine CTGF-L cDNA, encoding a polypeptide of 251 amino acids,
      was obtained from a murine lung cDNA library. CTGF-L protein bears significant
      identity ( approximately 60%) to the CCN (CTGF, Cef10/Cyr61, Nov) family of
      proteins. CTGF-L is composed of three distinct domains, an insulin-like growth
      factor binding domain, a von Willebrand Factor type C motif, and a thrombospondin
      type I repeat. However, unlike CTGF, CTGF-L lacks the C-terminal domain
      implicated in dimerization and heparin binding. CTGF-L mRNA ( approximately 1.3
      kilobases) is expressed in primary human osteoblasts, fibroblasts, ovary, testes,
      and heart, and a approximately 26-kDa protein is secreted from primary human
      osteoblasts and fibroblasts. In situ hybridization indicates high expression in
      osteoblasts forming bone, discrete alkaline phosphatase positive bone marrow
      cells, and chondrocytes. Specific binding of 125I-labeled insulin-like growth
      factors to CTGF-L was demonstrated by ligand Western blotting and cross-linking
      experiments. Recombinant human CTGF-L promotes the adhesion of osteoblast cells
      and inhibits the binding of fibrinogen to integrin receptors. In addition,
      recombinant human CTGF-L inhibits osteocalcin production in rat osteoblast-like
      Ros 17/2.8 cells. Taken together, these results suggest that CTGF-L may play an
      important role in modulating bone turnover.

PMID- 10358068
TI  - Isolation, characterization, and functional analysis of a novel cDNA clone
      encoding a small rubber particle protein from Hevea brasiliensis.
AB  - Biochemical evidence reported so far suggests that rubber synthesis takes place
      on the surface of rubber particles suspended in the latex of Hevea brasiliensis.
      We have isolated and characterized a cDNA clone that encodes a protein tightly
      bound on a small rubber particle. We named this protein small rubber particle
      protein (SRPP). Prior to this study, this protein was known as a latex allergen,
      and only its partial amino acid sequence was reported. Sequence analysis revealed
      that this protein is highly homologous to the rubber elongation factor and the
      Phaseolus vulgaris stress-related protein. Southern and Northern analyses
      indicate that the protein is encoded by a single gene and highly expressed in
      latex. An allergenicity test using the recombinant protein confirmed that the
      cloned cDNA encodes the known 24-kDa latex allergen. Neither ethylene stimulation
      nor wounding changed the transcript level of the SRPP gene in H. brasiliensis. An
      in vitro rubber assay showed that the protein plays a positive role in rubber
      biosynthesis. Therefore, it is likely that SRPP is a part of the rubber
      biosynthesis machinery, if not the rubber polymerase, along with the rubber
      elongation factor.

PMID- 10358069
TI  - DNA-dependent protein kinase-independent activation of p53 in response to DNA
      damage.
AB  - Phosphorylation at serine 15 of the human p53 tumor suppressor protein is induced
      by DNA damage and correlates with accumulation of p53 and its activation as a
      transcription factor. The DNA-dependent protein kinase (DNA-PK) can phosphorylate
      serine 15 of human p53 and the homologous serine 18 of murine p53 in vitro.
      Contradictory reports exist about the requirement for DNA-PK in vivo for p53
      activation and cell cycle arrest in response to ionizing radiation. While primary
      SCID (severe combined immunodeficiency) cells, that have defective DNA-PK, show
      normal p53 activation and cell cycle arrest, a transcriptionally inert form of
      p53 is induced in the SCID cell line SCGR11. In order to unambiguously define the
      role of the DNA-PK catalytic subunit (DNA-PKcs) in p53 activation, we examined
      p53 phosphorylation in mouse embryonic fibroblasts (MEFs) from DNA-PKcs-null
      mice. We found a similar pattern of serine 18 phosphorylation and accumulation of
      p53 in response to irradiation in both control and DNA-PKcs-null MEFs. The
      induced p53 was capable of sequence-specific DNA binding even in the absence of
      DNA-PKcs. Transactivation of the cyclin-dependent-kinase inhibitor p21, a
      downstream target of p53, and the G1 cell cycle checkpoint were also found to be
      normal in the DNA-PKcs -/- MEFs. Our results demonstrate that DNA-PKcs, unlike
      the related ATM protein, is not essential for the activation of p53 and G1 cell
      cycle arrest in response to ionizing radiation.

PMID- 10358070
TI  - Evidence for combinatorial variability of tenascin-C isoforms and developmental
      regulation in the mouse central nervous system.
AB  - The extracellular matrix glycoprotein tenascin-C (TN-C) displays a restricted and
      developmentally regulated distribution in the mouse central nervous system.
      Defined modules of the molecule have been shown to mediate specific functions,
      such as neuron migration, neurite outgrowth, cell adhesion, and cell
      proliferation. The smallest TN-C form contains a stretch of eight fibronectin
      type III (FNIII) domains, which are common to all TN-C isoforms. Unrestricted and
      independent alternative splicing of six consecutive FNIII cassettes between the
      fifth and sixth constitutive FNIII domain bears the potential to generate 64
      different combinations that might code for TN-C proteins with subtly different
      functions. To explore TN-C isoform variability in mouse brain, the alternatively
      spliced region of TN-C mRNAs was examined by the reverse transcription-polymerase
      chain reaction technique. Polymerase chain reaction products of uniform size were
      subcloned and analyzed using domain-specific probes to reveal the expression of
      particular combinations of alternatively spliced FNIII domains. 27 TN-C isoforms
      were identified to be expressed in mouse central nervous system, of which 22 are
      novel. Furthermore, during development, specific TN-C isoforms were found to
      occur in distinct relative frequencies, as demonstrated for isoforms containing
      two alternatively spliced FNIII domains. We conclude that TN-C is expressed in a
      complex and regulated pattern in mouse central nervous system. These findings
      highlight the potential role of TN-C in mediating specific neuron glia
      interactions.

PMID- 10358071
TI  - Characterizing the interactions between the two subunits of the p101/p110gamma
      phosphoinositide 3-kinase and their role in the activation of this enzyme by G
      beta gamma subunits.
AB  - Recently, we have reported the purification and cloning of a novel G protein
      betagamma subunit-activated phosphoinositide 3-kinase from pig neutrophils. The
      enzyme comprises a p110gamma catalytic subunit and a p101 regulatory subunit. Now
      we have cloned the human ortholog of p101 and generated panels of p101 and
      p110gamma truncations and deletions and used these in in vitro and in vivo assays
      to determine the protein domains responsible for subunit interaction and
      activation by betagamma subunits. Our results suggest large areas of p101
      including both N- and C-terminal portions interact with the N-terminal half of
      p110gamma. While modifications of the N terminus of p110gamma could modulate its
      intrinsic catalytic activity, binding to the N-terminal region of p101 was found
      to be indispensable for activation of heterodimers with Gbetagamma.

PMID- 10358072
TI  - Identification of a novel gene family encoding human liver-specific organic anion
      transporter LST-1.
AB  - We have isolated a novel liver-specific organic anion transporter, LST-1, that is
      expressed exclusively in the human, rat, and mouse liver. LST-1 is a new gene
      family located between the organic anion transporter family and prostaglandin
      transporter. LST-1 transports taurocholate (Km = 13.6 microM) in a sodium
      independent manner. LST-1 also shows broad substrate specificity. It transports
      conjugated steroids (dehydroepiandrosterone sulfate, estradiol-17beta
      glucuronide, and estrone-3-sulfate), eicosanoids (prostaglandin E2, thromboxane
      B2, leukotriene C4, leukotriene E4), and thyroid hormones (thyroxine, Km = 3.0
      microM and triiodothyronine, Km = 2.7 microM), reflecting hepatic
      multispecificity. LST-1 is probably the most important transporter in human liver
      for clearance of bile acids and organic anions because hepatic levels of another
      organic anion transporter, OATP, is very low. This is also the first report of
      the human molecule that transports thyroid hormones.

PMID- 10358073
TI  - Four human ras homologs differ in their abilities to activate Raf-1, induce
      transformation, and stimulate cell motility.
AB  - Human cells contain four homologous Ras proteins, but it is unknown whether each
      of these Ras proteins participates in distinct signal transduction cascades or
      has different biological functions. To directly address these issues, we assessed
      the relative ability of constitutively active (G12V) versions of each of the four
      Ras homologs to activate the effector protein Raf-1 in vivo. In addition, we
      compared their relative abilities to induce transformed foci, enable anchorage
      independent growth, and stimulate cell migration. We found a distinct hierarchy
      between the four Ras homologs in each of the parameters studied. The hierarchies
      were as follows: for Raf-1 activation, Ki-Ras 4B > Ki-Ras 4A >>> N-Ras > Ha-Ras;
      for focus formation, Ha-Ras >/= Ki-Ras 4A >>> N-Ras = Ki-Ras 4B; for anchorage
      independent growth, Ki-Ras 4A >/= N-Ras >>> Ki-Ras 4B = Ha-Ras = no growth; and
      for cell migration, Ki-Ras 4B >>> Ha-Ras > N-Ras = Ki-Ras 4A = no migration. Our
      results indicate that the four Ras homologs significantly differ in their
      abilities to activate Raf-1 and induce distinctly different biological responses.
      These studies, in conjunction with our previous report that demonstrated that the
      Ras homologs can be differentially activated by upstream guanine nucleotide
      exchange factors (Jones, M. K., and Jackson, J. H. (1998) J. Biol. Chem. 273,
      1782-1787), indicate that each of the four Ras proteins may qualitatively or
      quantitatively participate in distinct signaling cascades and have significantly
      different biological roles in vivo. Importantly, these studies also suggest for
      the first time that the distinct and likely cooperative biological functions of
      the Ki-ras-encoded Ki-Ras 4A and Ki-Ras 4B proteins may help explain why
      constitutively activating mutations of Ki-ras, but not N-ras or Ha-ras, are
      frequently detected in human carcinomas.

PMID- 10358074
TI  - Oligomerization state influences the degradation rate of 3-hydroxy-3
      methylglutaryl-CoA reductase.
AB  - The steady-state level of the resident endoplasmic reticulum protein, 3-hydroxy-3
      methylglutaryl-coenzyme A reductase (HMGR), is regulated, in part, by accelerated
      degradation in response to excess sterols or mevalonate. Previous studies of a
      chimeric protein (HM-Gal) composed of the membrane domain of HMGR fused to
      Escherichia coli beta-galactosidase, as a replacement of the normal HMGR
      cytosolic domain, have shown that the regulated degradation of this chimeric
      protein, HM-Gal, is identical to that of HMGR (Chun, K. T., Bar-Nun, S., and
      Simoni, R. D. (1990) J. Biol. Chem. 265, 22004-22010; Skalnik, D. G., Narita, H.,
      Kent, C., and Simoni, R. D. (1988) J. Biol. Chem. 263, 6836-6841). Since the
      cytosolic domain can be replaced with beta-galactosidase without effect on
      regulated degradation, it has been assumed that the cytosolic domain was not
      important to this process and also that the membrane domain of HMGR was both
      necessary and sufficient for regulated degradation. In contrast to our previous
      results with HM-Gal, we observed in this study that replacement of the cytosolic
      domain of HMGR with various heterologous proteins can have an effect on the
      regulated degradation, and the effect correlates with the oligomeric state of the
      replacement cytosolic protein. Chimeric proteins that are oligomeric in structure
      are relatively stable, and those that are monomeric are unstable. To test the
      hypothesis that the oligomeric state of the cytosolic domain of HMGR influences
      degradation, we use an "inducible" system for altering the oligomeric state of a
      protein in vivo. Using a chimeric protein that contains the membrane domain of
      HMGR fused to three copies of FK506-binding protein 12, we were able to induce
      oligomerization by addition of a "double-headed" FK506-like "dimerizer" drug
      (AP1510) and to monitor the degradation rate of both the monomeric form and the
      drug-induced oligomeric form of the protein. We show that this chimeric protein,
      HM-3FKBP, is unstable in the monomeric state and is stabilized by AP1510-induced
      oligomerization. We also examined the degradation rate of HMGR as a function of
      concentrations within the cell. HMGR is a functional dimer; therefore, its
      oligomeric state and, we predict, its degradation rate should be concentration
      dependent. We observed that it is degraded more rapidly at lower concentrations.

PMID- 10358076
TI  - Phosphorylation of serine 256 by protein kinase B disrupts transactivation by
      FKHR and mediates effects of insulin on insulin-like growth factor-binding
      protein-1 promoter activity through a conserved insulin response sequence.
AB  - Insulin inhibits the expression of multiple genes in the liver containing an
      insulin response sequence (IRS) (CAAAA(C/T)AA), and we have reported that protein
      kinase B (PKB) mediates this effect of insulin. Genetic studies in Caenorhabditis
      elegans indicate that daf-16, a forkhead/winged-helix transcription factor, is a
      major target of the insulin receptor-PKB signaling pathway. FKHR, a human
      homologue of daf-16, contains three PKB sites and is expressed in the liver.
      Reporter gene studies in HepG2 hepatoma cells show that FKHR stimulates insulin
      like growth factor-binding protein-1 promoter activity through an IRS, and
      introduction of IRSs confers this effect on a heterologous promoter. Insulin
      disrupts IRS-dependent transactivation by FKHR, and phosphorylation of Ser-256 by
      PKB is necessary and sufficient to mediate this effect. Antisense studies
      indicate that FKHR contributes to basal promoter function and is required to
      mediate effects of insulin and PKB on promoter activity via an IRS. To our
      knowledge, these results provide the first report that FKHR stimulates promoter
      activity through an IRS and that phosphorylation of FKHR by PKB mediates effects
      of insulin on gene expression. Signaling to FKHR-related forkhead proteins via
      PKB may provide an evolutionarily conserved mechanism by which insulin and
      related factors regulate gene expression.

PMID- 10358075
TI  - Phosphorylation of the transcription factor forkhead family member FKHR by
      protein kinase B.
AB  - Protein kinase B lies "downstream" of phosphatidylinositide (PtdIns) 3-kinase and
      is thought to mediate many of the intracellular actions of insulin and other
      growth factors. Here we show that FKHR, a human homologue of the DAF16
      transcription factor in Caenorhabditis elegans, is rapidly phosphorylated by
      human protein kinase Balpha (PKBalpha) at Thr-24, Ser-256, and Ser-319 in vitro
      and at a much faster rate than BAD, which is thought to be a physiological
      substrate for PKB. The same three sites, which all lie in the canonical PKB
      consensus sequences (Arg-Xaa-Arg-Xaa-Xaa-(Ser/Thr)), became phosphorylated when
      FKHR was cotransfected with either PKB or PDK1 (an upstream activator of PKB).
      All three residues became phosphorylated when 293 cells were stimulated with
      insulin-like growth factor 1 (IGF-1). The IGF-1-induced phosphorylation was
      abolished by the PtdIns 3-kinase inhibitor wortmannin but not by PD 98059 (an
      inhibitor of the mitogen-activated protein kinase cascade) or by rapamycin. These
      results indicate that FKHR is a physiological substrate of PKB and that it may
      mediate some of the physiological effects of PKB on gene expression. DAF16 is
      known to be a component of a signaling pathway that has been partially dissected
      genetically and includes homologues of the insulin/IGF-1 receptor, PtdIns 3
      kinase and PKB. The conservation of Thr-24, Ser-256, and Ser-319 and the
      sequences surrounding them in DAF16 therefore suggests that DAF16 is also a
      direct substrate for PKB in C. elegans.

PMID- 10358077
TI  - Cytokine-induced apoptosis in epithelial HT-29 cells is independent of nitric
      oxide formation. Evidence for an interleukin-13-driven phosphatidylinositol 3
      kinase-dependent survival mechanism.
AB  - A combination of the pro-inflammatory cytokines interleukin (IL)-1alpha,
      interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha induces nitric
      oxide synthase mRNA expression and nitric oxide (NO) generation in the human
      colon carcinoma cell line HT-29. This can be inhibited by pretreatment with IL-13
      via a phosphatidylinositol (PI) 3-kinase-dependent mechanism (Wright, K., Ward,
      S. G., Kolios, G., and Westwick, J. (1997) J. Biol. Chem. 272, 12626-12633).
      Since NO has been implicated in regulating mechanisms leading to cell death,
      while activation of PI 3-kinase-dependent signaling cascades are thought to be
      involved with promoting cell survival events, we have investigated the outcome of
      these cytokine treatments on apoptosis and cell survival of HT-29 cells.
      Initiation of apoptosis can be achieved by the combinations of IFN-gamma/TNF
      alpha, IFN-gamma/CD95, IL-1alpha/IFN-gamma, and IL-1alpha/IFN-gamma/TNF-alpha to
      varying extents. Induction of apoptotic markers by HT-29 cells in response to
      cytokine treatment is not dependent on NO production. Pretreatment with IL-13
      protects against IL-1alpha/IFN-gamma/TNF-alpha- and IFN-gamma/TNF-alpha- as well
      as IFN-gamma/CD95-induced (but not IL-1alpha/IFN-gamma-induced) cell death. In
      addition, IFN-gamma/TNF-alpha and IL-1alpha/IFN-gamma/TNF-alpha stimulate
      activation of caspase-8 and caspase-3, which IL-13 pretreatment was able to
      partially inhibit and delay. IL-13 also stimulates activation of the major PI 3
      kinase effector, protein kinase B. The PI 3-kinase inhibitors wortmannin and
      LY294002 inhibit IL-13 stimulation of protein kinase B as well as the cell
      survival effects of IL-13. These data demonstrate that cytokine-induced apoptosis
      of HT-29 cells is NO-independent and that the activation of a PI 3-kinase
      dependent signaling cascade by IL-13 is a key signal responsible for the
      inhibition of apoptosis.

PMID- 10358078
TI  - Dexamethasone alters arachidonate release from human epithelial cells by
      induction of p11 protein synthesis and inhibition of phospholipase A2 activity.
AB  - The effect of the glucocorticosteroid, dexamethasone, on arachidonic acid (AA)
      release and on protein levels of p11 and cytosolic phospholipase A2 (cPLA2) was
      studied in two epithelial cell lines, HeLa cells and BEAS-2B cells. Dexamethasone
      treatment of HeLa cells and BEAS-2B cells increased cellular p11 protein and mRNA
      levels in a time- and dose-dependent manner. It had little effect on levels of
      cPLA2 protein. In order to determine if increased p11 protein expression resulted
      in increased interaction between p11 and cPLA2, anti-cPLA2 antibodies were used
      to immunoprecipitate p11.cPLA2 complexes and Western blots of the
      immunoprecipitate were used to detect p11. In cells treated with dexamethasone,
      more p11 was detected in the anti-cPLA2 immunoprecipitate compared with control
      cells. Dexamethasone treatment of HeLa cells prelabeled with [3H]AA decreased the
      release of [3H]AA under basal conditions and after stimulation with the calcium
      ionophore A23187 (10(-6) M). In order to determine if altering the p11 protein
      levels in HeLa cells independent of glucocorticosteroid treatment could also
      produce an effect on [3H]AA release, cells were stably transfected with plasmids
      expressing either p11 antisense mRNA or p11 mRNA. Cloned HeLa cells expressing
      p11 antisense mRNA exhibited less cellular p11 protein compared with control
      cells and greater [3H]AA release compared with cells transfected with a control
      vector. Cloned HeLa cells stably transfected with a p11 expression vector
      exhibited increased p11 cellular protein and diminished [3H]AA release under
      basal conditions and in response to A23187. Therefore, dexamethasone alteration
      of epithelial cell AA release may be due in part to induction of p11 protein
      expression.

PMID- 10358079
TI  - ErbB receptor-induced activation of stat transcription factors is mediated by Src
      tyrosine kinases.
AB  - Epidermal growth factor (EGF) binding to its receptor, ErbB1, triggers various
      signal transduction pathways, one of which leads to the activation of signal
      transducer and activator of transcription (Stat) factors. The mechanism
      underlying ErbB1-induced Stat activation and whether Stats are downstream targets
      of other ErbB receptors have not been explored. In this report we show that
      ErbB2, ErbB3, and ErbB4 do not potentiate Stat5 phosphorylation by EGF. However,
      neu differentiation factor-induced heterodimers of ErbB2 and ErbB4 activated
      Stat5. In A431 cells, Stat1, Stat3, and Stat5, were constitutively complexed with
      ErbB1 and rapidly phosphorylated on tyrosine in response to EGF. Neither mutation
      of the conserved tyrosine residue (Tyr694) nor inactivation of the Stat5a SH2
      domain disrupted this association. However, an intact SH2 domain was necessary
      for EGF-induced Stat5a phosphorylation. In contrast to prolactin, which induced
      only Tyr694 phosphorylation of Stat5a, EGF promoted phosphorylation on Tyr694 and
      additional tyrosine residue(s). Janus kinases (Jaks) were also constitutively
      associated with ErbB receptors and were phosphorylated in response to EGF-related
      ligands. However, we provide evidence that EGF- and neu differentiation factor
      induced Stat activation are dependent on Src but not Jak kinases. Upon EGF
      stimulation, c-Src was rapidly recruited to Stat/ErbB receptor complexes.
      Pharmacological Src kinase inhibitors and a dominant negative c-Src ablated both
      Stat and Jak tyrosine phosphorylation. However, dominant negative Jaks did not
      affect EGF-induced Stat phosphorylation. Taken together, the experiments
      establish two independent roles for Src kinases: (i) key molecules in ErbB
      receptor-mediated Stat signaling and (ii) potential upstream regulators of Jak
      kinases.

PMID- 10358080
TI  - Modulation of human heat shock factor trimerization by the linker domain.
AB  - Heat shock transcription factors (HSFs) are stress-responsive proteins that
      activate the expression of heat shock genes and are highly conserved from bakers'
      yeast to humans. Under basal conditions, the human HSF1 protein is maintained as
      an inactive monomer through intramolecular interactions between two coiled-coil
      domains and interactions with heat shock proteins; upon environmental,
      pharmacological, or physiological stress, HSF1 is converted to a homotrimer that
      binds to its cognate DNA binding site with high affinity. To dissect regions of
      HSF1 that make important contributions to the stability of the monomer under
      unstressed conditions, we have used functional complementation in bakers' yeast
      as a facile assay system. Whereas wild-type human HSF1 is restrained as an
      inactive monomer in yeast that is unable to substitute for the essential yeast
      HSF protein, mutations in the linker region between the DNA binding domain and
      the first coiled-coil allow HSF1 to homotrimerize and rescue the viability defect
      of a hsfDelta strain. Fine mapping by functional analysis of HSF1-HSF2 chimeras
      and point mutagenesis revealed that a small region in the amino-terminal portion
      of the HSF1 linker is required for maintenance of HSF1 in the monomeric state in
      both yeast and in transfected human 293 cells. Although linker regions in
      transcription factors are known to modulate DNA binding specificity, our studies
      suggest that the human HSF1 linker plays no role in determining HSF1 binding
      preferences in vivo but is a critical determinant in regulating the HSF1 monomer
      trimer equilibrium.

PMID- 10358081
TI  - Structural insight into a quinolone-topoisomerase II-DNA complex. Further
      evidence for a 2:2 quinobenzoxazine-mg2+ self-assembly model formed in the
      presence of topoisomerase ii.
AB  - Quinobenzoxazine A-62176, developed from the antibacterial fluoroquinolones, is
      active in vitro and in vivo against murine and human tumors. It has been
      previously claimed that A-62176 is a catalytic inhibitor of mammalian
      topoisomerase II that does not stabilize the cleaved complex. However, at low
      drug concentrations and pH 6-7, we have found that A-62176 can enhance the
      formation of the cleaved complex at certain sites. Using a photocleavage assay,
      mismatched sequences, and competition experiments between psorospermin and A
      62176, we pinpointed the drug binding site on the DNA base pairs between
      positions +1 and +2 relative to the cleaved phosphodiester bonds. A 2:2
      quinobenzoxazine-Mg2+ self-assembly model was previously proposed, in which one
      drug molecule intercalates into the DNA helix and the second drug molecule is
      externally bound, held to the first molecule and DNA by two Mg2+ bridges. The
      results of competition experiments between psorospermin and A-62176, as well as
      between psorospermin and A-62176 and norfloxacin, are consistent with this model
      and provide the first evidence that this 2:2 quinobenzoxazine-Mg2+ complex is
      assembled in the presence of topoisomerase II. These results also have parallel
      implications for the mode of binding of the quinolone antibiotics to the
      bacterial gyrase-DNA complex.

PMID- 10358082
TI  - Suppression of smooth muscle cell proliferation by a c-myc RNA-cleaving
      deoxyribozyme.
AB  - A small catalytic DNA molecule targeting c-myc RNA was found to be a potent
      inhibitor of smooth muscle cell (SMC) proliferation. The catalytic domain of this
      molecule was based on that previously derived by in vitro selection (Santoro, S.
      W., and Joyce, G. F. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 4262-4266) and is
      known as the "10-23" general purpose RNA-cleaving deoxyribozyme. In addition to
      inhibiting SMC proliferation at low concentration, this molecule (targeting the
      translation initiation region of c-myc RNA) was found to efficiently cleave its
      full-length substrate in vitro and down-regulate c-myc gene expression in smooth
      muscle cells. The serum nuclease stability of this molecule was enhanced without
      substantial loss of kinetic efficiency by inclusion of a 3'-3'-internucleotide
      inversion at the 3'-terminal. The extent of SMC suppression was found to be
      influenced by the length of the substrate binding arms. This correlated to some
      extent with catalytic activity in both the short substrate under multiple
      turnover conditions and the full-length substrate under single turnover
      conditions, with the 9 + 9 base arm molecule producing the greatest activity.

PMID- 10358083
TI  - Retinoic acid-regulated expression of fibroblast growth factor 3 requires the
      interaction between a novel transcription factor and GATA-4.
AB  - fgf-3 shows a complex spatial-temporal pattern of transcription during mouse
      development, and the gene product appears to be an important intercellular
      signaling molecule. Here we show that the major enhancer, which is obligatory for
      transcription, is composed of three elements with different properties. Both
      functional analyses in undifferentiated and differentiated F9 cells and
      characterization of DNA-protein complexes in vitro have identified the sequence
      motifs GTGACT(C), ATTGT, and GATA as the key transcription factor binding sites.
      The GTGACT(C) motif, while not essential, is required for full enhancer activity.
      However, binding at ATTGT is crucial for transcriptional activity and is required
      for cooperative binding at the proximal GATA site. The GATA binding site mediates
      the retinoic acid/dibutyryl cyclic AMP stimulation of transcription and
      correlates with the binding of Gata-4 which is induced by retinoic acid in
      differentiating F9 cells. The ATTGT and GATA motifs are inactive when placed
      separately on a minimal thymidine kinase (TK) promoter, but together they act as
      a strong retinoic acid-regulated enhancer. In undifferentiated F9 cells, gata-4
      expression stimulates the fgf-3 promoter, whereas in differentiated F9 cells
      already expressing gata-4, no further increase in promoter activity was observed.

PMID- 10358084
TI  - The oligosaccharyltransferase complex from Saccharomyces cerevisiae. Isolation of
      the OST6 gene, its synthetic interaction with OST3, and analysis of the native
      complex.
AB  - The key step of N-glycosylation of proteins, an essential and highly conserved
      protein modification, is catalyzed by the hetero-oligomeric protein complex
      oligosaccharyltransferase (OST). So far, eight genes have been identified in
      Saccharomyces cerevisiae that are involved in this process. Enzymatically active
      OST preparations from yeast were shown to be composed of four (Ost1p, Wbp1p,
      Ost3p, Swp1p) or six subunits (Ost2p and Ost5p in addition to the four listed).
      Genetic studies have disclosed Stt3p and Ost4p as additional proteins needed for
      N-glycosylation. In this study we report the identification and functional
      characterization of a new OST gene, designated OST6, that has homology to OST3
      and in particular a strikingly similar membrane topology. Neither gene is
      essential for growth of yeast. Disruption of OST6 or OST3 causes only a minor
      defect in N-glycosylation, but an Deltaost3Deltaost6 double mutant displays a
      synthetic phenotype, leading to a severe underglycosylation of soluble and
      membrane-bound glycoproteins in vivo and to a reduced OST activity in vitro.
      Moreover, each of the two genes has also a specific function, since agents
      affecting cell wall biogenesis reveal different growth phenotypes in the
      respective null mutants. By blue native electrophoresis and immunodetection, a
      approximately 240-kDa complex was identified consisting of Ost1p, Stt3p, Wbp1p,
      Ost3p, Ost6p, Swp1p, Ost2p, and Ost5p, indicating that probably all so far
      identified OST proteins are constituents of the OST complex. It is also shown
      that disruption of OST3 and OST6 leads to a defect in the assembly of the
      complex. Hence, the function of these genes seems to be essential for recruiting
      a fully active complex necessary for efficient N-glycosylation.

PMID- 10358085
TI  - Divalent cations differentially regulate integrin alphaIIb cytoplasmic tail
      binding to beta3 and to calcium- and integrin-binding protein.
AB  - We have used recombinant or synthetic alphaIIb and beta3 integrin cytoplasmic
      peptides to study their in vitro complexation and ligand binding capacity by
      surface plasmon resonance. alpha.beta heterodimerization occurred in a 1:1
      stoichiometry with a weak KD in the micromolar range. Divalent cations were not
      required for this association but stabilized the alpha.beta complex by decreasing
      the dissociation rate. alpha.beta complexation was impaired by the R995A
      substitution or the KVGFFKR deletion in alphaIIb but not by the beta3 S752P
      mutation. Recombinant calcium- and integrin-binding protein (CIB), an alphaIIb
      specific ligand, bound to the alphaIIb cytoplasmic peptide in a Ca2+- or Mn2+
      independent, one-to-one reaction with a KD value of 12 microM. In contrast, in
      vitro liquid phase binding of CIB to intact alphaIIbbeta3 occurred preferentially
      with Mn2+-activated alphaIIbbeta3 conformers, as demonstrated by enhanced
      coimmunoprecipitation of CIB with PAC-1-captured Mn2+-activated alphaIIbbeta3,
      suggesting that Mn2+ activation of intact alphaIIbbeta3 induces the exposure of a
      CIB-binding site, spontaneously exposed by the free alphaIIb peptide. Since CIB
      did not stimulate PAC-1 binding to inactive alphaIIbbeta3 nor prevented activated
      alphaIIbbeta3 occupancy by PAC-1, we conclude that CIB does not regulate
      alphaIIbbeta3 inside-out signaling, but rather is involved in an alphaIIbbeta3
      post-receptor occupancy event.

PMID- 10358086
TI  - Characterization of a novel giant scaffolding protein, CG-NAP, that anchors
      multiple signaling enzymes to centrosome and the golgi apparatus.
AB  - A novel 450-kDa coiled-coil protein, CG-NAP (centrosome and Golgi localized PKN
      associated protein), was identified as a protein that interacted with the
      regulatory region of the protein kinase PKN, having a catalytic domain homologous
      to that of protein kinase C. CG-NAP contains two sets of putative RII (regulatory
      subunit of protein kinase A)-binding motif. Indeed, CG-NAP tightly bound to
      RIIalpha in HeLa cells. Furthermore, CG-NAP was coimmunoprecipitated with the
      catalytic subunit of protein phosphatase 2A (PP2A), when one of the B subunit of
      PP2A (PR130) was exogenously expressed in COS7 cells. CG-NAP also interacted with
      the catalytic subunit of protein phosphatase 1 in HeLa cells. Immunofluorescence
      analysis of HeLa cells revealed that CG-NAP was localized to centrosome
      throughout the cell cycle, the midbody at telophase, and the Golgi apparatus at
      interphase, where a certain population of PKN and RIIalpha were found to be
      accumulated. These data indicate that CG-NAP serves as a novel scaffolding
      protein that assembles several protein kinases and phosphatases on centrosome and
      the Golgi apparatus, where physiological events, such as cell cycle progression
      and intracellular membrane traffic, may be regulated by phosphorylation state of
      specific protein substrates.

PMID- 10358087
TI  - Early steps in assembly of the yeast vacuolar H+-ATPase.
AB  - Vacuolar proton-translocating ATPases are composed of a complex of integral
      membrane proteins, the Vo sector, attached to a complex of peripheral membrane
      proteins, the V1 sector. We have examined the early steps in biosynthesis of the
      yeast vacuolar ATPase by biosynthetically labeling wild-type and mutant cells for
      varied pulse and chase times and immunoprecipitating fully and partially
      assembled complexes under nondenaturing conditions. In wild-type cells, several
      V1 subunits and the 100-kDa Vo subunit associate within 3-5 min, followed by
      addition of other Vo subunits with time. Deletion mutants lacking single subunits
      of the enzyme show a variety of partial complexes, including both complexes that
      resemble intermediates in the assembly pathway of wild-type cells and independent
      V1 and Vo sectors that form without any apparent V1Vo subunit interaction. Two
      yeast sec mutants that show a temperature-conditional block in export from the
      endoplasmic reticulum accumulate a complex containing several V1 subunits and the
      100-kDa Vo subunit during incubation at elevated temperature. This complex can
      assemble with the 17-kDa Vo subunit when the temperature block is reversed. We
      propose that assembly of the yeast V-ATPase can occur by two different pathways:
      a concerted assembly pathway involving early interactions between V1 and Vo
      subunits and an independent assembly pathway requiring full assembly of V1 and Vo
      sectors before combination of the two sectors. The data suggest that in wild-type
      cells, assembly occurs predominantly by the concerted assembly pathway, and V
      ATPase complexes acquire the full complement of Vo subunits during or after exit
      from the endoplasmic reticulum.

PMID- 10358088
TI  - A single point mutation in a group I WW domain shifts its specificity to that of
      group II WW domains.
AB  - WW domains can be divided into three groups based on their binding specificity.
      By random mutagenesis, we switched the specificity of the Yes-associated protein
      (YAP) WW1 domain, a Group I WW domain, to that of the FE65 WW domain, which
      belongs to Group II. We showed that a single mutation, leucine 190 (betaB5) to
      tryptophan, is required to switch from Group I to Group II. Although this single
      substitution in YAP WW1 domain is sufficient to precipitate the two protein
      isoforms of Mena, an in vivo ligand of FE65, we showed that an additional
      substitution, histidine 192 (betaB7) to glycine, significantly increased the
      ability of YAP to mimic FE65. This double mutant (L190W/H192G) precipitates eight
      of the nine protein bands that FE65 pulls down from rat brain protein lysates.
      Based on both our data and a sequence comparison between Group I and Group II WW
      domains, we propose that a block of three consecutive aromatic amino acids within
      the second beta-sheet of the domain is required, but not always sufficient, for a
      WW domain to belong to Group II. These data deepen our understanding of WW domain
      binding specificity and provide a basis for the rational design of modified WW
      domains with potential therapeutic applications.

PMID- 10358089
TI  - Topological analysis of the membrane-localized redox-responsive sensor kinase
      PrrB from Rhodobacter sphaeroides 2.4.1.
AB  - Photosynthesis gene expression in Rhodobacter sphaeroides is controlled in part
      by the two-component (Prr) regulatory system composed of a membrane-bound sensor
      kinase (PrrB) and a response regulator (PrrA). Hydropathy profile-based computer
      analysis predicted that the PrrB polypeptide could contain six membrane-spanning
      domains at its amino terminus and a hydrophilic, cytoplasmic carboxyl terminus.
      Both the localization and the topology of the PrrB sensor kinase have been
      studied by generating a series of gene fusions with the Escherichia coli
      periplasmically localized alkaline phosphatase and the cytoplasmic beta
      galactosidase. Eighteen prrB-phoA and five prrB-lacZ fusions were constructed and
      expressed in both E. coli and R. sphaeroides. Enzymatic activity assays and
      immunoblot analyses were performed to identify and to localize the different
      segments of PrrB in the membrane. The data obtained in E. coli generally
      correlated with the data obtained in R. sphaeroides and support the computer
      predictions. On the basis of the theoretical model and the results provided by
      these studies, a topological model for the membrane localization of the PrrB
      polypeptide is proposed.

PMID- 10358090
TI  - Further characterization of the type 3 ryanodine receptor (RyR3) purified from
      rabbit diaphragm.
AB  - We characterized type 3 ryanodine receptor (RyR3) purified from rabbit diaphragm
      by immunoaffinity chromatography using a specific antibody. The purified receptor
      was free from 12-kDa FK506-binding protein, although it retained the ability to
      bind 12-kDa FK506-binding protein. Negatively stained images of RyR3 show a
      characteristic rectangular structure that was indistinguishable from RyR1. The
      location of the D2 segment, which exists uniquely in the RyR1 isoform, was
      determined as the region around domain 9 close to the corner of the square-shaped
      assembly, with use of D2-directed antibody as a probe. The RyR3 homotetramer had
      a single class of high affinity [3H]ryanodine-binding sites with a stoichiometry
      of 1 mol/mol. In planar lipid bilayers, RyR3 displayed cation channel activity
      that was modulated by several ligands including Ca2+, Mg2+, caffeine, and ATP,
      which is consistent with [3H]ryanodine binding activity. RyR3 showed a slightly
      larger unit conductance and a longer mean open time than RyR1. Whereas RyR1
      showed two classes of channel activity with distinct open probabilities (Po),
      RyR3 displayed a homogeneous and steeply Ca2+-dependent activity with Po
      approximately 1. RyR3 was more steeply affected in the channel activity by
      sulfhydryl-oxidizing and -reducing reagents than RyR1, suggesting that the
      channel activity of RyR3 may be transformed more precipitously by the redox
      state. This is also a likely explanation for the difference in the Ca2+
      dependence of RyR3 between [3H]ryanodine binding and channel activity.

PMID- 10358091
TI  - A new nucleoporin-like protein interacts with both HIV-1 Rev nuclear export
      signal and CRM-1.
AB  - The HIV-1 Rev is a shuttling protein required for the nuclear export of unspliced
      and partially spliced viral mRNA. In this study, we have identified a new Rev
      interacting protein, that specifically interacts with the Rev nuclear export
      signal both in yeast and mammalian cells. This protein has features found in
      nucleoporins including many phenylalanine-glycine repeats, a very high serine
      content, a putative zinc finger, and a coiled-coil domain; we thus called it NLP
      1 (nucleoporin-like protein 1). In addition, gene expression analysis and wheat
      germ agglutinin chromatography experiments suggested that NLP-1 is an ubiquitous
      O-glycosylated nuclear protein. Recently, a cellular factor called CRM-1 has been
      shown to be an essential nuclear export factor interacting directly with nuclear
      export signals including the Rev nuclear export signal in a RanGTP-dependent
      manner. We show here that NLP-1, like the previously described Rev-interacting
      protein hRIP/Rab and several nucleoporins, also interacts with CRM-1 both in
      yeast and mammalian cells.

PMID- 10358092
TI  - Mammalian Hsp70 and Hsp110 proteins bind to RNA motifs involved in mRNA
      stability.
AB  - In this study, in vitro RNA binding by members of the mammalian 70-kDa heat shock
      protein (Hsp) family was examined. We show that Hsp/Hsc70 and Hsp110 proteins
      preferentially bound AU-rich RNA in vitro. Inhibition of RNA binding by ATP
      suggested the involvement of the N-terminal ATP-binding domain. By using deletion
      mutants of Hsp110 protein, a diverged Hsp70 family member, RNA binding was
      localized to the N-terminal ATP-binding domain of the molecule. The C-terminal
      peptide-binding domain did not bind RNA, but its engagement by a peptide
      substrate abrogated RNA binding by the N terminus of the protein. Interestingly,
      removal of the C-terminal alpha-helical structure or the alpha-loop domain unique
      to Hsp110 immediately downstream of the peptide-binding domain, but not both,
      resulted in considerably increased RNA binding as compared with the wild type
      protein. Finally, a 70-kDa activity was immunoprecipitated from RNA-protein
      complexes formed in vitro between cytoplasmic proteins of human lymphocytes and
      AU-rich RNA. These findings support the idea that certain heat shock proteins may
      act as RNA-binding entities in vivo to guide the appropriate folding of RNA
      substrates for subsequent regulatory processes such as mRNA degradation and/or
      translation.

PMID- 10358093
TI  - Nitric oxide suppresses apoptosis via interrupting caspase activation and
      mitochondrial dysfunction in cultured hepatocytes.
AB  - Nitric oxide (NO) is a potent inhibitor of apoptosis in many cell types,
      including hepatocytes. We and others have described NO-dependent decreases in
      caspase activity in cells undergoing apoptosis. However, previous work has not
      determined whether NO disrupts the proteolytic processing and thus the activation
      of pro-caspases. Here we report that NO suppresses proteolytic processing and
      activation of multiple pro-caspases in intact cells, including caspase-3 and
      caspase-8. We found that both exogenous NO as well as endogenously produced NO
      via adenoviral inducible NO synthase gene transfer protected hepatocytes from
      tumor necrosid factor (TNF) alpha plus actinomycin D (TNFalpha/ActD)-induced
      apoptosis. Affinity labeling with biotin-VAD-fmk of all active caspase species in
      TNFalpha-mediated apoptosis identified four newly labeled spots (activated
      caspases) present exclusively in TNFalpha/ActD-treated cells. Both NO and the
      caspase inhibitor, Ac-DEVD-CHO, prevented the appearance of the four newly
      labeled spots or active caspases. Immunoanalysis of affinity labeled caspases
      demonstrated that caspase-3 was the major effector caspase. Western blot analysis
      also identified the activation of caspase-8 in the TNFalpha/ActD-treated cells,
      and the activation was suppressed by NO. Furthermore, NO inhibited several other
      events associated with caspase activation in cells, including release of
      cytochrome c from mitochondria, decrease in mitochondrial transmembrane
      potential, and cleavage of poly(ADP-ribose) polymerase in TNFalpha/ActD-treated
      cells. These findings indicate the involvement of multiple caspases in TNFalpha
      mediated apoptosis in hepatocytes and establish the capacity of NO to inhibit not
      only active caspases but also caspase activation.

PMID- 10358094
TI  - Identification of a cytosolic NADP+-dependent isocitrate dehydrogenase that is
      preferentially expressed in bovine corneal epithelium. A corneal epithelial
      crystallin.
AB  - Recently, metabolic enzymes have been observed in both the lens and corneal
      epithelium at levels greatly exceeding what is necessary for normal metabolic
      functions. These proteins have been termed taxon-specific crystallins and are
      thought to play a role in maintaining tissue transparency. We report here that
      cytosolic NADP+-dependent isocitrate dehydrogenase (ICDH) represents a new
      corneal crystallin. Using suppression subtractive hybridization, we identified a
      gene (with a deduced amino acid sequence that showed 94% identity to rat
      cytosolic NADP+-dependent ICDH) that is preferentially expressed in bovine
      corneal epithelium. Northern blots established that its mRNA level in the corneal
      epithelium was 31-, 39-, 133-, 230-, and 929-fold more than in the liver, bladder
      epithelium, stomach epithelium, brain, and heart, respectively. This mRNA was
      detected primarily in corneal epithelial basal cells by in situ hybridization.
      SDS-polyacrylamide gel electrophoresis, two-dimensional gel analysis, and Western
      blotting showed that this protein was overexpressed in the corneal epithelium,
      constituting approximately 13% of the total soluble bovine corneal epithelial
      proteins. Enzyme assays showed a corresponding overabundance of this protein in
      bovine corneal epithelium. Taken together, these data indicate that bovine
      cytosolic ICDH fulfills the criteria for a corneal epithelial crystallin and may
      be involved in maintaining corneal epithelial transparency.

PMID- 10358096
TI  - A novel labeling approach supports the five-transmembrane model of subunit a of
      the Escherichia coli ATP synthase.
AB  - Cysteine mutagenesis and surface labeling has been used to define more precisely
      the transmembrane spans of subunit a of the Escherichia coli ATP synthase.
      Regions of subunit a that are exposed to the periplasmic space have been
      identified by a new procedure, in which cells are incubated with polymyxin B
      nonapeptide (PMBN), an antibiotic derivative that partially permeabilizes the
      outer membrane of E. coli, along with a sulfhydryl reagent, 3-(N
      maleimidylpropionyl) biocytin (MPB). This procedure permits reaction of
      sulfhydryl groups in the periplasmic space with MPB, but residues in the
      cytoplasm are not labeled. Using this procedure, residues 8, 27, 37, 127, 131,
      230, 231, and 232 were labeled and so are thought to be exposed in the periplasm.
      Using inside-out membrane vesicles, residues near the end of transmembrane spans
      1, 64, 67, 68, 69, and 70 and residues near the end of transmembrane spans 5,
      260, 263, and 265 were labeled. Residues 62 and 257 were not labeled. None of
      these residues were labeled in PMBN-permeabilized cells. These results provide a
      more detailed view of the transmembrane spans of subunit a and also provide a
      simple and reliable technique for detection of periplasmic regions of inner
      membrane proteins in E. coli.

PMID- 10358097
TI  - Multiple integrase functions are required to form the native structure of the
      human immunodeficiency virus type I intasome.
AB  - Mu-mediated polymerase chain reaction footprinting was used to investigate the
      protein-DNA structure of human immunodeficiency virus type I (HIV-I)
      preintegration complexes. Preintegration complexes were partially purified from
      cells after using an established coculture infection technique as well as a novel
      technique using cell-free supernatant from transfected cells as the source of
      virus. Footprinting revealed that bound proteins protected the terminal 200-250
      base pairs of each viral end from nuclease attack. Bound proteins also caused
      strong transpositional enhancements near each end of HIV-I. In contrast, regions
      of viral DNA internal to the ends did not show evidence of strong protein
      binding. The end regions of preintegrative HIV-I apparently form a unique
      nucleoprotein structure, which we term the intasome to distinguish it from the
      greater preintegration complex. Our novel system also allowed us to analyze the
      structure and function of preintegration complexes isolated from cells infected
      with integrase mutant viruses. Complexes were derived from viruses defective for
      either integrase catalysis, integrase binding to the viral DNA substrate, or an
      unknown function in the carboxyl-terminal domain of the integrase protein. None
      of these mutant complexes supported detectable integration activity. Despite the
      presence of the mutant integrase proteins in purified samples, none of these
      nucleoprotein complexes displayed the native intasome structure detected in wild
      type preintegration complexes. We conclude that multiple integrase functions are
      required to form the native structure of the HIV-I intasome in infected cells.

PMID- 10358095
TI  - p300/cAMP-responsive element-binding protein interactions with ets-1 and ets-2 in
      the transcriptional activation of the human stromelysin promoter.
AB  - In this paper we show that transcription factors Ets-1 and Ets-2 recruit
      transcription adapter proteins p300 and CBP (cAMP-responsive element-binding
      protein) during the transcriptional activation of the human stromelysin promoter,
      which contains palindromic Ets-binding sites. Ets-2 and p300/CBP exist as a
      complex in vivo. Two regions of p300/CBP between amino acids (a.a.) 328 and 596
      and a. a. 1678 and 2370 independently can interact with Ets-1 and Ets-2 in vitro
      and in vivo. Both these regions of p300/CBP bind to the transactivation domain of
      Ets-2, whereas the C-terminal region binds only to the DNA binding domain of Ets
      2. The N- and the C-terminal regions of CBP (a.a. 1-1097 and 1678-2442,
      respectively) which lack histone acetylation activity independently are capable
      of coactivating Ets-2. Other Ets family transcription factors failed to cooperate
      with p300/CBP in stimulating the stromelysin promoter. The LXXLL sequence,
      reported to be important in receptor-coactivator interactions, does not appear to
      play a role in the interaction of Ets-2 with p300/CBP. Previous studies have
      shown that the stimulation of transcriptional activation activity of Ets-2
      requires phosphorylation of threonine 72 by the Ras/mitogen-activated protein
      kinase signaling pathway. We show that mutation of this site does not affect its
      capacity to bind to and to cooperate with p300/CBP.

PMID- 10358098
TI  - Ribozyme approach identifies a functional association between the G protein
      beta1gamma7 subunits in the beta-adrenergic receptor signaling pathway.
AB  - The complex role that the heterotrimeric G proteins play in signaling pathways
      has become increasingly apparent with the cloning of countless numbers of
      receptors, G proteins, and effectors. However, in most cases, the specific
      combinations of alpha and betagamma subunits comprising the G proteins that
      participate in the most common signaling pathways, such as beta-adrenergic
      regulation of adenylyl cyclase activity, are not known. The extent of this
      problem is evident in the fact that the identities of the betagamma subunits that
      combine with the alpha subunit of Gs are only now being elucidated almost 20
      years after its initial purification. In a previous study, we described the first
      use of a ribozyme strategy to suppress specifically the expression of the gamma7
      subunit of the G proteins, thereby identifying a specific role of this protein in
      coupling the beta-adrenergic receptor to stimulation of adenylyl cyclase activity
      in HEK 293 cells. In the present study, we explored the potential utility of a
      ribozyme approach directed against the gamma7 subunit to identify functional
      associations with a particular beta and alphas subunit of the G protein in this
      signaling pathway. Accordingly, HEK 293 cells were transfected with a ribozyme
      directed against the gamma7 subunit, and the effects of this manipulation on
      levels of the beta and alphas subunits were determined by immunoblot analysis.
      Among the five beta alphas subunits detected in these cells, only the beta1
      subunit was coordinately reduced following treatment with the ribozyme directed
      against the gamma7 subunit, thereby demonstrating a functional association
      between the beta1 and gamma7 subunits. The mechanism for coordinate suppression
      of the beta1 subunit was due to a striking change in the half-life of the beta1
      monomer versus the beta1 heterodimer complexed with the gamma7 subunit. Neither
      the 52- nor 45-kDa subunits were suppressed following treatment with the ribozyme
      directed against the gamma7 subunit, thereby providing insights into the assembly
      of the Gs heterotrimer. Taken together, these data show the utility of a ribozyme
      approach to identify the role of not only the gamma subunits but also the beta
      subunits of the G proteins in signaling pathways.

PMID- 10358099
TI  - A novel insect V-ATPase subunit M9.7 is glycosylated extensively.
AB  - Plasma membrane V-ATPase isolated from midgut and Malpighian tubules of the
      tobacco hornworm, Manduca sexta, contains a novel prominent 20-kDa polypeptide.
      Based on N-terminal protein sequencing, we cloned a corresponding cDNA. The
      deduced hydrophobic protein consisted of 88 amino acids with a molecular mass of
      only 9.7 kDa. Immunoblots of the recombinant 9.7-kDa polypeptide, using a
      monoclonal anti- body to the 20-kDa polypeptide, confirmed that the correct cDNA
      had been cloned. The 20-kDa polypeptide is glycosylated, as deduced from lectin
      staining. Treatment with N-glycosidase A resulted in the appearance of two
      additional protein bands of 16 and 10 kDa which both were immunoreactive to the
      20-kDa polypeptide-specific monoclonal antibody. Thus, extensive N-glycosylation
      of the novel Vo subunit M9.7 accounts for half of its molecular mass observed in
      SDS-polyacrylamide gel electrophoresis. M9.7 exhibits some similarities to the
      yeast protein Vma21p which resides in the endoplasmic reticulum and is required
      for the assembly of the Vo complex. However, as deduced from immunoblots as well
      as from activities of the V-ATPase and endoplasmic reticulum marker enzymes in
      different membrane preparations, M9.7 is, in contrast to the yeast polypeptide, a
      constitutive subunit of the mature plasma membrane V-ATPase of M. sexta.

PMID- 10358100
TI  - DNA tetraplex formation studied with fluorescence resonance energy transfer.
AB  - It is emerging that DNA tetraplexes are pivotal for many major cellular
      processes, and techniques that assess their structure and nature to the point are
      under development. Here we show how the structural conversion of largely
      unstructured single-stranded DNA molecules into compact intrastrand DNA
      tetraplexes can be monitored by fluorescence resonance energy transfer. We
      recently reported that intrastrand tetraplex formation takes place in a nuclease
      hypersensitive element upstream of the human c-myc proto-oncogene. Despite the
      highly repetitive guanine-rich sequence of the hypersensitive element,
      fluorescence resonance energy transfer measurements indicate that only one well
      defined tetraplex structure forms therein. The proposed structure, which is
      specifically stabilized by potassium ions in vitro, has a core of three stacked
      guanine tetrads that is capped by two intrastrand A-T base pairs.

PMID- 10358101
TI  - Complete cDNA cloning, genomic organization, chromosomal assignment, functional
      characterization of the promoter, and expression of the murine Bamacan gene.
AB  - Bamacan is a chondroitin sulfate proteoglycan that abounds in basement membranes.
      To gain insights into the bamacan gene regulation and transcriptional control, we
      examined the genomic organization and identified the promoter region of the mouse
      bamacan gene. Secondary structure analysis of the protein reveals a sequential
      organization of three globular regions interconnected by two alpha-helix coiled
      coils. The N- and the C-terminal ends carry a P-loop and a DA box motif that can
      act cooperatively to bind ATP. These features as well as the high sequence
      homology with members of the SMC (structural maintenance of chromosome) protein
      family led us to conclude that bamacan is a member of this protein family. The
      gene comprises 31 exons and is driven by a promoter that is highly enriched in GC
      sequences and lacks TATA and CAAT boxes. The promoter is highly functional in
      transient cell transfection assays, and step-wise 5' deletions identify a strong
      enhancer element between -659 and -481 base pairs that includes Jun/Fos proto
      oncogene-binding elements. Using backcrossing experiments we mapped the Bam gene
      to distal chromosome 19, a locus syntenic to human chromosome 10q25. Bamacan is
      differentially expressed in mouse tissues with the highest levels in testes and
      brain. Notably, bamacan mRNA levels are low in normal cells and markedly reduced
      during quiescence but are highly increased when cells resume growth upon serum
      stimulation. In contrast, in all transformed cells tested, bamacan is
      constitutively overexpressed, and its levels do not change with cell cycle
      progression. These results suggest that bamacan is involved in the control of
      cell growth and transformation.

PMID- 10358102
TI  - Different mechanisms control the amount and time course of neurotransmitter
      release.

PMID- 10358103
TI  - The mystery of the visual system K pathway.

PMID- 10358104
TI  - Galvanic vestibular stimulation: new uses for an old tool.

PMID- 10358105
TI  - Lactate transport in skeletal muscle - role and regulation of the monocarboxylate
      transporter.
AB  - Skeletal muscle is the major producer of lactic acid in the body, but its
      oxidative fibres also use lactic acid as a respiratory fuel. The stereoselective
      transport of L-lactic acid across the plasma membrane of muscle fibres has been
      shown to involve a proton-linked monocarboxylate transporter (MCT) similar to
      that described in erythrocytes and other cells. This transporter plays an
      important role in the pH regulation of skeletal muscle. A family of eight MCTs
      has now been cloned and sequenced, and the tissue distribution of each isoform
      varies. Skeletal muscle contains both MCT1 (the only isoform found in
      erythrocytes but also present in most other cells) and MCT4. The latter is found
      in all fibre types, although least in more oxidative red muscles such as soleus,
      whereas expression of MCT1 is highest in the more oxidative muscles and very low
      in white muscles that are almost entirely glycolytic. The properties of MCT1 and
      MCT2 have been described in some detail and the latter shown to have a higher
      affinity for substrates. MCT4 has been less well characterized but has a lower
      affinity for L-lactate (i.e. a higher Km of 20 mM) than does MCT1 (Km of 5 mM).
      MCT1 expression is increased in response to chronic stimulation and either
      endurance or explosive exercise training in rats and humans, whereas denervation
      decreases expression of both MCT1 and MCT4. The mechanism of regulation is not
      established, but does not appear to be accompanied by changes in mRNA
      concentrations. However, in other cells MCT1 and MCT4 are intimately associated
      with an ancillary protein OX-47 (also known as CD147). This protein is a member
      of the immunoglobulin superfamily with a single transmembrane helix, whose
      expression is known to be increased in a range of cells when their metabolic
      activity is increased.

PMID- 10358106
TI  - The chromogranins and the counter-regulatory hormones: do they make homeostatic
      sense?
AB  - 1. The chromogranins are ubiquitous proteins which are co-stored and co-secreted
      with many peptide hormones. All appear to be powerful inhibitors of endocrine
      secretions. This poses a problem. 2. When endocrine glands are involved in the
      efferent limbs of homeostatic loops, they are message transmitters. The self
      inhibition caused by the co-secretion of a chromogranin will, on the face of it,
      erase the message. 3. Pairs of counter-regulatory homeostatic hormones also
      present a problem. 4. If both members of the pair have clearly defined set
      points, as suggested by their 'time integral' (or 'growth with time')
      responsiveness to deviations from set point, then, if the two set points are not
      exactly the same, one or other member will always register an error, leading,
      eventually, to an overwhelmingly large and unnecessary response. 5. Our model
      eliminates both paradoxes, and emphasizes the importance of counter-regulation
      and the co-secretion of chromogranins in 'zero steady-state error' (ZSSE)
      homeostasis. 6. If hormone A is secreted into the blood in progressively
      increasing amounts when [Q], the plasma concentration of substance Q, is low, and
      in decreasing amounts when [Q] is high; and hormone B responds in the opposite
      manner, then there will be a [Q], designated [Q]p, at which the secretory rate
      increase, or decrease, of the two hormones is exactly the same. 7. If, in
      addition, the secretion of both hormones is stimulated by low plasma chromogranin
      levels, [Cg], but inhibited by high [Cg] then there will be a different [Q]p for
      every chromogranin concentration in the blood. 8. At one of these points (at a
      unique [Q] and [Cg]) the concentration of neither hormone will increase or
      decrease. This is the equilibrium point to which, according to our model, the
      system always returns regardless of disturbances within physiological limits. 9.
      This is robust ZSSE control.

PMID- 10358107
TI  - Evidence against a major role for Ca2+ in hypoxia-induced gene expression in
      human hepatoma cells (Hep3B).
AB  - 1. The human hepatoma cell line Hep3B is a widely used model for studies of
      hypoxia-related gene expression. Cytosolic free calcium concentration ([Ca2+]i)
      has been implicated in cellular oxygen-sensing processes. We investigated whether
      calcium ions have a significant impact on the production of erythropoietin (EPO)
      and vascular endothelial growth factor (VEGF). 2. We found that the calcium
      ionophore ionomycin induced a rapid and sustained increase of [Ca2+]i while
      thapsigargin, an inhibitor of endoplasmic reticulum calcium ATPase, only caused a
      20 % elevation of [Ca2+]i within 10 min after application. However, the calcium
      content of intracellular stores was considerably reduced by thapsigargin after an
      incubation period of 24 h. 3. Variations in [Ca2+]o did not result in altered EPO
      or VEGF secretion rates. Ionomycin decreased EPO production while the lowering of
      VEGF production was not statistically significant. In the presence of
      extracellular Ca2+ the membrane permeant calcium chelator BAPTA-AM stimulated the
      production of EPO (P < 0.05) but not of VEGF while EGTA-AM, a closely related
      agent, affected neither EPO nor VEGF formation under these conditions. Incubation
      with thapsigargin resulted in decreased EPO synthesis (P < 0.05) but stimulated
      VEGF secretion (P < 0.05). 4. In the absence of extracellular calcium, EGTA-AM
      led to an accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha). This
      treatment significantly stimulated VEGF synthesis but also decreased EPO
      secretion (P < 0.05). 5. Our data suggest that the calcium transient and the
      cytosolic Ca2+ concentration do not play a key role in hypoxia-induced EPO and
      VEGF production in Hep3B cells.

PMID- 10358108
TI  - Auxiliary subunits operate as a molecular switch in determining gating behaviour
      of the unitary N-type Ca2+ channel current in Xenopus oocytes.
AB  - 1. We systematically examined the biophysical properties of omega-conotoxin GVIA
      sensitive neuronal N-type channels composed of various combinations of the
      alpha1B, alpha2/delta and beta1b subunits in Xenopus oocytes. 2. Whole-cell
      recordings demonstrated that coexpression of the beta1b subunit decelerated
      inactivation, whereas the alpha2/delta accelerated both activation and
      inactivation, and cancelled the kinetic effects of the beta1b. The alpha2/delta
      and the beta1b controlled voltage dependence of activation differently: the
      beta1b significantly shifted the current-voltage relationship towards the
      hyperpolarizing direction; however, the alpha2/delta shifted the relationship
      only slightly in the depolarizing direction. The extent of voltage-dependent
      inactivation was modified solely by the beta1b. 3. Unitary currents measured
      using a cell-attached patch showed stable patterns of opening that were markedly
      different among subunit combinations in their kinetic parameters. The
      alpha2/delta and the beta1b subunits also acted antagonistically in regulating
      gating patterns of unitary N-type channels. Open time was shortened by the
      alpha2/delta, while the fraction of long opening was enhanced by the beta1b. The
      alpha2/delta decreased opening probability (Po), while the beta1b increased Po.
      alpha1Balpha2/deltabeta1b produced unitary activity with an open time
      distribution value in between those of alpha1Balpha2/delta and alpha1Bbeta1b.
      However, both the alpha2/delta and the beta1b subunits reduced the number of null
      traces. 4. These results suggest that the auxiliary subunits alone and in
      combination contribute differently in forming gating apparatuses in the N-type
      channel, raising the possibility that subunit interaction contributes to the
      generation of functional diversity of N-type channels in native neuronal
      preparations also.

PMID- 10358110
TI  - Depolarization increases the apparent affinity of the Na+-K+ pump to cytoplasmic
      Na+ in isolated guinea-pig ventricular myocytes.
AB  - 1. In order to investigate the possible effect of membrane potential on
      cytoplasmic Na+ binding to the Na+-K+ pump, we studied Na+-K+ pump current
      voltage relationships in single guinea-pig ventricular myocytes whole-cell
      voltage clamped with pipette solutions containing various concentrations of Na+
      ([Na+]pip) and either tetraethylammonium (TEA+) or N-methyl-D-glucamine (NMDG+)
      as the main cation. The experiments were conducted at 30 C under conditions
      designed to abolish the known voltage dependence of other steps in the pump
      cycle, i.e. in Na+-free external media containing 20 mM Cs+. 2. Na+-K+ pump
      current (Ip) was absent in cells dialysed with Na+-free pipette solutions and was
      almost voltage independent at 50 mM Na+pip (potential range: -100 to +40 mV). By
      contrast, the activation of Ip by 0.5-5 mM Na+pip was clearly voltage sensitive
      and increased with depolarization, independently of the main intracellular cation
      species. 3. The apparent affinity of the Na+-K+ pump for cytoplasmic Na+
      increased monotonically with depolarization. The [Na+]pip required for half
      maximal Ip activation (K0.5 value) amounted to 5.6 mM at -100 mV and to 2.2 mM at
      +40 mV. 4. The results suggest that cytoplasmic Na+ binding and/or a subsequent
      partial reaction in the pump cycle prior to Na+ release is voltage dependent.
      From the voltage dependence of the K0.5 values the dielectric coefficient for
      intracellular Na+ binding/translocation was calculated to be approximately 0.08.
      The voltage-dependent mechanism might add to the activation of the cardiac Na+-K+
      pump during cardiac excitation.

PMID- 10358109
TI  - Voltage dependence of macroscopic and unitary currents of gap junction channels
      formed by mouse connexin50 expressed in rat neuroblastoma cells.
AB  - 1. The macroscopic and single channel gating characteristics of connexin (Cx) 50
      gap junction channels between pairs of N2A neuroblastoma cells transfected with
      mouse Cx50 DNA were investigated using the dual whole-cell voltage clamp
      technique. 2. The macroscopic junctional current (Ij) of Cx50-transfected cells
      decayed exponentially with time in response to transjunctional voltage (Vj) steps
      (time constant (tau) of approximately 4 s at a Vj of 30-40 mV and 100-200 ms at a
      Vj of 80-100 mV). The steady-state junctional conductance (gj) was well described
      by a two-state Boltzmann equation. The half-inactivation voltage (V0), the ratio
      of minimal to maximal gj (gmin/gmax) and the equivalent gating charge were +/- 37
      mV, 0.21 and 4, respectively. 3. The conductance of single Cx50 channels measured
      using patch pipettes containing 130 mM CsCl was 220 +/- 13.1 pS (12 cell pairs).
      A prominent residual or subconductance state corresponding to 43 +/- 4. 2 pS (10
      cell pairs) was also observed at large Vj s. 4. The relationship between channel
      open probability (Po) and Vj was well described by a Boltzmann relationship with
      parameters similar to those obtained for macroscopic gj (V0 = 34 mV, gating
      charge = 4.25, maximum P= 0.98). The ensemble average of single channel currents
      at Vj = 50 mV declined in a monoexponential manner (tau = 905 ms), a value
      similar to the decline of the macroscopic Ij of Cx50 channels at the same
      voltage. 5. Ion substitution experiments indicated that Cx50 channels have a
      lower permeability to anions than to cations (transjunctional conductance of KCl
      vs. potassium glutamate (gammaj, KCl/gammaj,KGlut), 1.2; 6 cell pairs). 6. The
      results have important implications for understanding the role of connexins in
      tissues where Cx50 is a major gap junction component, including the lens.

PMID- 10358111
TI  - Regulation of Na+-K+-2Cl- cotransport by protein phosphorylation in ferret
      erythrocytes.
AB  - 1. Na+-K+-2Cl- cotransport in ferret erythrocytes was measured as the bumetanide
      sensitive uptake of 86Rb. 2. The resting cotransport rate was high but could be
      increased threefold by treating erythrocytes with calyculin A, a potent inhibitor
      of serine/threonine phosphatases. Twenty nanomolar was sufficient to maximally
      and rapidly (within 4 min) stimulate transport. 3. The effects of several kinase
      inhibitors were tested. High concentrations of K-252a, K-252b, calphostin C and
      hypericin caused less than 20 % inhibition. Staurosporine (IC50, 0.06 microM) and
      4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1; IC50, 2.5
      microM) were more potent but still only partially (40-50 %) inhibited transport,
      an effect mimicked by reducing ionized intracellular Mg2+ concentration to
      submicromolar levels. Genistein may inhibit all transport at a sufficiently high
      dose (IC50, 0.36 mM) perhaps by directly inhibiting the transporter. 4.
      Staurosporine, PP1 and the removal of Mg2+ all prevented subsequent stimulation
      by calyculin A, and all inhibited calyculin-stimulated transport by 20-30 %. The
      effects of staurosporine, PP1 and Mg2+ removal were not additive. 5. The
      phosphatase that dephosphorylates the cotransporter is probably Mg2+ (or possibly
      Ca2+ or Mn2+) sensitive and not the target for calyculin A. The data suggest that
      this phosphatase is inhibited by phosphorylation, and that it is the regulation
      of this process which is affected by calyculin A and the kinase inhibitors tested
      here. Phosphorylation of the phosphatase is probably regulated by members of the
      Src family of tyrosine kinases.

PMID- 10358112
TI  - Isozyme-specific inhibitors of protein kinase C translocation: effects on
      contractility of single permeabilized vascular muscle cells of the ferret.
AB  - 1. The effects on contractility of three peptides reported to inhibit protein
      kinase C (PKC) translocation in an isozyme-specific manner were studied: a
      peptide from the C2 domain of conventional PKCs (C2-2), a peptide from the N
      terminal variable domain of epsilonPKC (epsilonV1-2) and a peptide (ABP) from the
      actin-binding domain of epsilonPKC (epsilon(223-228)). 2. Isometric force was
      directly recorded from individual hyperpermeable ferret portal vein or aortic
      smooth muscle cells. 3. Phenylephrine contracted permeabilized portal vein cells
      at pCa 6.7 but not at pCa 7.0. However, phenylephrine did contract aortic cells
      at pCa 7.0. 4. C2-2 inhibited phenylephrine-induced contraction, but did not
      affect resting tension, in portal vein cells at pCa 6.7. In aortic cells at
      either pCa 6.7 or 7.0, C2-2 had no effect on either basal tension or
      phenylephrine-induced contraction. 5. ABP did not evoke any changes in
      phenylephrine-induced contraction or baseline tension in either portal vein or
      aortic cells. 6. epsilonV1-2 inhibited phenylephrine-induced contraction and
      decreased resting tension in aortic cells at pCa 7.0, but not in portal vein
      cells at pCa 6.7. 7. Western blots indicated that portal vein cells contained
      substantially more alphaPKC than aortic cells. Portal vein cells also contained
      small amounts of betaPKC, which was undetectable in aortic cells. In contrast,
      aortic cells contained more epsilonPKC than portal vein cells. Even though
      epsilonPKC was expressed in portal vein and alphaPKC in aorta, imaging studies
      indicated that they were not translocated in these cell types. 8. These results
      suggest that the Ca2+-dependent isozymes of PKC (alpha and/or beta) play a major
      role in contraction of the portal vein but not of the aorta. In contrast, the
      results are consistent with epsilonPKC, but not Ca2+-dependent PKC isozymes,
      regulating contractility of the aorta.

PMID- 10358114
TI  - Laminar distribution of pheromone-receptive neurons in rat vomeronasal
      epithelium.
AB  - 1. Responses of vomeronasal sensory neurons to urine excreted from rats, mice and
      hamsters were studied by the on-cell patch clamp method in slices of sensory
      epithelium from female Wistar rats. 2. The urine excreted from male and female
      Wistar rats, male Donryu rats and male C57BL/6 mice induced relatively large
      responses, while urine from male Sprague-Dawley rats and male Syrian hamsters
      induced small responses. 3. Of the 62 neurons responding to urine, 57 responded
      to only one of the urine preparations. 4. The sensory neurons that responded to
      the male Wistar urine were localized in the apical position of the epithelium
      where one type of GTP-binding protein, Gi2alpha, is selectively expressed. The
      neurons in the basal position of the epithelium, which express Goalpha, responded
      to urine from the other animals. 5. This study demonstrates that sensory neurons
      responsive to different urinary pheromones are localized in a segregated layer in
      the rat vomeronasal sensory epithelium.

PMID- 10358113
TI  - Target-dependent regulation of acetylcholine secretion at developing motoneurons
      in Xenopus cell cultures.
AB  - 1. Myocyte-dependent regulation of acetylcholine (ACh) quantal secretion from
      developing motoneurons was studied in day-3 Xenopus nerve-muscle co-cultures.
      Spontaneous synaptic currents (SSCs) were measured in manipulated synapses by
      using whole-cell voltage-clamped myocytes. Changes in SSC amplitude were assumed
      to reflect changes in the ACh content of secreted quantal packets. Compared with
      natural synapses, motoneurons without any contact with a myocyte (naive neurons)
      released ACh in smaller quantal packets. 2. Bipolar cultured motoneurons, which
      were in contact with a myocyte with one axon branch (contact-end) but remained
      free at another axon branch (free-end), were further used to examine quantal ACh
      secretion. The ACh quantal size recorded at free-end terminals was similar to
      that of naive neurons and was smaller than that at the contact-end, indicating
      that myocyte contact exerts differential regulation on quantal secretion in the
      same neuron. 3. Some of the neurons that formed a natural synapse with a myocyte
      continued to grow forward and ACh quantal secretion from the free growth cone was
      examined. The ACh quantal size recorded at free growth cones was inversely
      proportional to the distance to the natural synapse, implying localized
      regulation of quantal secretion by the myocyte. 4. Chronic treatment of day-1
      cultures with veratridine and d-tubocurarine, respectively, increased and
      decreased the neurotrophic action of myocytes when assayed on day 3. 5. Taken
      together, these findings suggest that the myocyte is an important postsynaptic
      target in the regulation of quantal secretion and that the trophic action is
      spatially restricted to the neighbourhood of the neuromuscular junction.

PMID- 10358116
TI  - Calcium currents during contraction and shortening in enzymatically isolated
      murine skeletal muscle fibres.
AB  - 1. Calcium currents (ICa) were monitored in enzymatically isolated murine toe
      muscle fibres using the two-microelectrode voltage-clamp technique. ICa was
      recorded (i) in hypertonic solution to suppress contraction, and (ii) in actively
      shortening fibres in isotonic solution. 2. In hypertonic solution the threshold
      potential for ICa was about -30 mV for both 2 and 10 mM external Ca2+ solution.
      Maximum peak currents measured -12.6 +/- 2.3 nA (mean +/- s.d.; n = 4) in 2 mM
      Ca2+ and -65 +/- 15 nA (n = 7) in 10 mM Ca2+. The time to peak (TTP) ICa was 96
      +/- 22 ms (n = 4) in 2 mM Ca2+ and 132 +/- 13 ms (n = 7) in 10 mM Ca2+. The
      exponential decay of ICa was similar in 2 and 10 mM Ca2+ with rate constants (tau
      1(V)) of 3.7 s-1 (2 mM) and 3.8 s-1 (10 mM) at +10 mV. 3. ICa in isotonic 10 mM
      Ca2+ solution was recorded by inserting the micropipettes exactly opposite to
      each other close to the centre of mass of the fibre where negligible contraction
      induced movement occurs. 4. In isotonic 10 mM Ca2+ solution ICa had a smaller
      peak amplitude (-45 +/- 5 nA; n = 7) and faster TTP (82.8 +/- 22.1 ms; n = 7)
      than in hypertonic solution. The exponential decay of ICa showed a significantly
      larger tau-1(V) of 6.4 s-1 at +10 mV (P < 0.03). 5. To test for calcium
      depletion, extracellular Ca2+ was buffered by malic acid in isotonic solution to
      9 mM. The decay of ICa had a time constant of 348 +/- 175 ms (n = 14) vs. 107 +/-
      24 ms (n = 12; P < 0.001) at 0 mV in unbuffered 10 mM Ca2+ solution. 6. We
      conclude that calcium depletion from the transverse tubular system contributes
      significantly to the decay of calcium currents in murine toe muscle fibres under
      hypertonic as well as isotonic conditions. In the latter, depletion is even more
      prominent.

PMID- 10358115
TI  - Thrombin and mast cell tryptase regulate guinea-pig myenteric neurons through
      proteinase-activated receptors-1 and -2.
AB  - 1. Proteases regulate cells by cleaving proteinase-activated receptors (PARs).
      Thrombin and trypsin cleave PAR-1 and PAR-2 on neurons and astrocytes of the
      brain to regulate morphology, growth and survival. We hypothesized that thrombin
      and mast cell tryptase, which are generated and released during trauma and
      inflammation, regulate enteric neurons by cleaving PAR-1 and PAR-2. 2. We
      detected immunoreactive PAR-1 and PAR-2 in > 60 % of neurons from the myenteric
      plexus of guinea-pig small intestine in primary culture. A large proportion of
      neurons that expressed substance P, vasoactive intestinal peptide or nitric oxide
      synthase also expressed PAR-1 and PAR-2. We confirmed expression of PAR-1 and PAR
      2 in the myenteric plexus by RT-PCR using primers based on sequences of cloned
      guinea-pig receptors. 3. Thrombin, trypsin, tryptase, a filtrate from
      degranulated mast cells, and peptides corresponding to the tethered ligand
      domains of PAR-1 and PAR-2 increased [Ca2+]i in > 50 % of cultured myenteric
      neurons. Approximately 60 % of neurons that responded to PAR-1 agonists responded
      to PAR-2 agonists, and > 90 % of PAR-1 and PAR-2 responsive neurons responded to
      ATP. 4. These results indicate that a large proportion of myenteric neurons that
      express excitatory and inhibitory neurotransmitters and purinoceptors also
      express PAR-1 and PAR-2. Thrombin and tryptase may excite myenteric neurons
      during trauma and inflammation when prothrombin is activated and mast cells
      degranulate. This novel action of serine proteases probably contributes to
      abnormal neurotransmission and motility in the inflamed intestine.

PMID- 10358117
TI  - V1a- and V2-type vasopressin receptors mediate vasopressin-induced Ca2+ responses
      in isolated rat supraoptic neurones.
AB  - 1. The pharmacological profile of receptors activated by vasopressin (AVP) in
      freshly dissociated supraoptic magnocellular neurones was investigated using
      specific V1a- and V2-type AVP receptor agonists and antagonists. 2. In 97 % of
      AVP-responding neurones (1-3000 nM) V1a or V2 receptor type agonists (F-180 and
      dDAVP, respectively) elicited dose-dependent [Ca2+]i transients that were
      suppressed by removal of external Ca2+. 3. The [Ca2+]i response induced by 1
      microM F-180 or dDAVP was selectively blocked by 10 nM of V1a and V2 antagonists
      (SR 49059 and SR 121463A, respectively). The response to V1a agonist was
      maintained in the presence of the V2 antagonist, and the V2 agonist-induced
      response persisted in the presence of the V1a antagonist. 4. The [Ca2+]i response
      induced by 1 microM AVP was partially (61 %) blocked by 10 nM SR 121463A. This
      blockade was increased by a further 31 % with the addition of 10 nM SR 49059.
      Similarly, the AVP-induced response was partially (47 %) decreased by SR 49059,
      and a further inhibition of 33 % was achieved in the presence of SR 121463A. 5.
      We demonstrate that AVP acts on the magnocellular neurones via two distinct types
      of AVP receptors that exhibit the pharmacological profiles of V1a and V2 types.
      However, since V2 receptor mRNA is not expressed in the supraoptic nucleus (SON),
      and since V1b receptor transcripts are observed in the SON, we propose that the
      V2 receptor agonist and antagonist act on a 'V2-like' receptor or a new type of
      AVP receptor that remains to be elucidated. The possibility that V2 ligands act
      on the V1b receptor cannot be excluded.

PMID- 10358118
TI  - Pharmacological evidence for a KATP channel in renin-secreting cells from rat
      kidney.
AB  - 1. Openers of the ATP-sensitive potassium channel (KATP channel) increase and
      blockers decrease renin secretion. Here we report the effects of levcromakalim
      (LCRK, a channel opener) and glibenclamide (GBC, a blocker) on membrane
      potential, whole-cell current and the cytoplasmic Ca2+ concentration of renin
      secreting cells (RSC). Studies were performed on afferent arterioles from the
      kidney of Na+-depleted rats. 2. As monitored with the fluorescent oxonol dye
      DiBAC4(3), LCRK (0.3 and 1 microM) induced a hyperpolarization of approximately
      15 mV which was abolished by GBC (1 microM). 3. Whole-cell current-clamp
      experiments showed that RSC had a membrane potential of -61 +/- 1 mV (n = 16).
      LCRK (1 microM) induced a hyperpolarization of 9.9 +/- 0.2 mV (n = 16) which, in
      the majority of cells, decreased slowly with time. 4. Capacitance measurements
      showed a strong electrical coupling of the cells in the preparation. 5. At -60
      mV, LCRK induced a hyperpolarizing current in a concentration-dependent manner
      with an EC50 of 152 +/- 31 nM and a maximum current of about 200 pA. 6.
      Application of GBC (1 microM) produced no effect; however, when applied after
      LCRK (300 nM), GBC inhibited the opener-induced hyperpolarizing current with an
      IC50 of 103 +/- 36 nM. 7. LCRK (0.3 and 1 microM) did not significantly affect
      the cytoplasmic Ca2+ concentration either at rest or after stimulation by
      angiotensin II. 8. The data show that LCRK induces a GBC-sensitive
      hyperpolarizing current in rat RSC. This current presumably originates from the
      activation of KATP channels which pharmacologically resemble those in vascular
      smooth muscle cells. The stimulatory effect of KATP channel opening on renin
      secretion is not mediated by a decrease in intracellular Ca2+ concentration.

PMID- 10358119
TI  - Cell-attached measurements of the firing threshold of rat hippocampal neurones.
AB  - 1. The cell-attached configuration of the patch-clamp technique was used to
      assess resting membrane potential and firing threshold of CA1 pyramidal cells and
      interneurones of rat hippocampal slices. 2. Resting potential was inferred from
      the reversal potential of voltage-gated K+ currents with symmetrical
      intracellular and pipette K+ concentrations. Its mean value was -74 +/- 9 mV for
      silent interneurones (mean +/- s.d.; n = 17) and -84 +/- 7 mV for silent
      pyramidal cells (n = 8). Spontaneous action currents occurred in thirteen out of
      thirty-two interneurones and two out of ten pyramidal cells. In active cells,
      membrane potential values fluctuated by up to 20 mV, due in part to the large
      hyperpolarizations that followed an action current. 3. Membrane potential values
      determined from K+ current reversal were 13 +/- 6 mV more hyperpolarized than
      those measured in whole-cell recordings from the same neurones (n = 8), probably
      due to a Donnan equilibrium potential between pipette and cytoplasm. 4. Firing
      threshold of silent cells was determined by elevating external K+ until action
      currents were generated, while membrane potential was monitored from the cell
      attached K+ current reversal. Spike threshold was attained at -49 +/- 8 mV for
      interneurones (n = 17) and at -60 +/- 8 mV for pyramidal cells (n = 8).
      Increasing external Ca2+ from 2 to 4 mM shifted the neuronal voltage threshold by
      +5 mV, without affecting resting potential. 5. For comparison with these values,
      we examined how the rate of membrane polarization influenced firing threshold in
      whole-cell records. Ramp current injections, of duration 15-1500 ms, revealed
      that current threshold followed a classical strength-duration relationship. In
      contrast voltage threshold, determined from current injection or by elevating
      extracellular K+, varied little with the rate of membrane polarization. 6. The
      state of activation and inactivation of Na+ and K+ currents might contribute to
      the stability of the voltage threshold. Cell-attached records showed that 79 +/-
      10 % of Na+ channels and 64 +/- 10 % of K+ channels were available for activation
      at resting potential in silent cells (n = 8). As cells were depolarized to
      threshold, Na+ current availability was reduced to 23 +/- 10 %, and K+ current
      availability to 31 +/- 12 %. 7. The speed of transition into the inactivated
      states also appears to contribute to the invariance of threshold for all but the
      fastest depolarizations. At potentials close to threshold, the rate of
      inactivation of Na+ and K+ followed a double exponential time course, such that
      Na+ currents were 62 % inactivated and K+ currents were 63 % inactivated within
      15 ms.

PMID- 10358120
TI  - All thalamocortical neurones possess a T-type Ca2+ 'window' current that enables
      the expression of bistability-mediated activities.
AB  - 1. The existence of a non-negligible steady-state ('window') component of the low
      threshold, T-type Ca2+current (IT) and an appropriately large ratio of IT to
      ILeak conductance (i.e. gT/gLeak) have been shown to underlie a novel form of
      intrinsic bistability that is present in about 15 % of thalamocortical (TC)
      neurones. 2. In the present experiments, the dynamic clamp technique was used to
      introduce into mammalian TC neurones in vitro either an artificial, i.e. computer
      generated, IT in order to enhance endogenous IT, or an artificial inward ILeak to
      decrease endogenous ILeak. Using this method, we were able to investigate
      directly whether the majority of TC neurones appear non-bistable because their
      intrinsic ionic membrane properties are essentially different (i.e. presence of a
      negligible IT 'window' component), or simply because they possess a gT or gLeak
      conductance that is insufficiently large or small, respectively. 3. The validity
      of the dynamic clamp arrangement and the accuracy of artificial IT were confirmed
      by (i) recreating the low threshold calcium potential (LTCP) with artificial IT
      following its block by Ni2+ (0.5-1 mM), and (ii) blocking endogenous LTCPs with
      an artificial outward IT. 4. Augmentation of endogenous IT by an artificial
      analog or introduction of an artificial inward ILeak transformed all non-bistable
      TC neurones to bistable cells that expressed the full array of bistability
      mediated behaviours, i.e. input signal amplification, slow oscillatory activity
      and membrane potential bistability. 5. These results demonstrate the existence of
      a non-negligible IT 'window' component in all TC neurones and suggest that rather
      than being a novel group of neurones, bistable cells are merely representative of
      an interesting region of dynamical modes in the (gT, gLeak) parameter space that
      may be expressed under certain physiological or pathological conditions by all TC
      neurones and other types of excitable cells that possess an IT 'window' component
      with similar biophysical properties.

PMID- 10358121
TI  - Topographical and electrophysiological characteristics of highly excitable S
      neurones in the myenteric plexus of the guinea-pig ileum.
AB  - 1. Most intracellular electrical recordings from myenteric neurones have been
      made from the centre of large ganglia. In this study, we examined the
      electrophysiological properties of neurones at the corners of large ganglia close
      to internodal strands and in microganglia. 2. Of 150 neurones in these locations:
      111 were tonic S neurones; 9 were phasic S neurones and 30 were AH neurones. 3.
      Tonic S neurones were characterized by: (i) low resting membrane potentials (-50
      +/- 1 mV, mean +/- s.e.m.); (ii) high input impedance (522 +/- 23 MOmega); (iii)
      low threshold for action potential (AP) generation (0.012 +/- 0.004 nA); (iv)
      firing of APs throughout a depolarizing pulse (duration <= 1 s) and one to four
      APs following a hyperpolarizing pulse and (v) spontaneous fast excitatory
      postsynaptic potentials (FEPSPs). A substantial proportion of tonic S neurones
      (43 %) also fired APs spontaneously (7.6 +/- 0.6 Hz; range, 0.3-19 Hz). All APs
      were blocked by tetrodotoxin (1 microM). 4. Tonic S neurones were subclassified,
      according to their post-stimulus responses, as SAH or SAD neurones. Following a
      burst of APs, SAH neurones exhibited a prominent after-hyperpolarization
      (duration, 711 +/- 10 ms) and SAD neurones an after-depolarization (duration, 170
      +/- 10 ms). The after-hyperpolarization was reduced in four of ten neurones by
      apamin (0.3 microM). 5. FEPSPs were evoked in 20 of 38 S neurones by electrical
      stimulation applied both oral and anal to the recording site. Repetitive stimuli
      evoked slow excitatory postsynaptic potentials (SEPSPs) in some tonic S neurones.
      6. Three functional classes of S neurones were identified after injection of
      neurobiotin through the recording microelectrode: (i) longitudinal muscle motor
      neurones, (ii) short circular muscle motor neurones, and (iii) ascending
      interneurones. 7. In conclusion, there appears to be topographical organization
      of highly excitable, tonic S neurones within the myenteric plexus, since, in
      contrast to other S neurones, they can be readily impaled in myenteric ganglia
      close to internodal strands and in microganglia.

PMID- 10358122
TI  - 3-Dimensional configuration of perimysial collagen fibres in rat cardiac muscle
      at resting and extended sarcomere lengths.
AB  - 1. We have used fluorescence confocal laser scanning microscopy to attain the
      three-dimensional (3-D) microstructure of perimysial collagen fibres over the
      range of sarcomere lengths (1.9-2.3 micrometers) in which passive force of
      cardiac muscle increases steeply. 2. A uniaxial muscle preparation (right
      ventricular trabecula of rat) was used so that the 3-D collagen configuration
      could be readily related to sarcomere length. Transmission electron microscopy
      showed that these preparations were structurally homologous to ventricular wall
      muscle. 3. Trabeculae were mounted on the stage of an inverted microscope and
      fixed at various sarcomere lengths. After a trabecula was stained with the
      fluorophore Sirius Red F3BA and embedded in resin, sequential optical sectioning
      enabled 3-D reconstruction of its perimysial collagen fibres. The area fraction
      of these fibres, determined from the cross-sections of seven trabeculae, was 10.5
      +/- 3.9 % (means +/- s.d.). 4. The reconstructed 3-D images show that perimysial
      collagen fibres are wavy (as distinct from coiled) cords which straighten
      considerably as the sarcomere length is increased from 1.85 +/- 0.06 micrometer
      (near-resting length) to 2.3 +/- 0.04 micrometer (means +/- s.d., n = 4). These
      observations are consistent with the notion that the straightening of these
      fibres is responsible for limiting extension of the cardiac sarcomere to a length
      of approximately 2.3 micrometers.

PMID- 10358123
TI  - The efficiency of contraction in rabbit skeletal muscle fibres, determined from
      the rate of release of inorganic phosphate.
AB  - 1. The relationship between mechanical power output and the rate of ATP
      hydrolysis was investigated in segments of permeabilized fibres isolated from
      rabbit psoas muscle. 2. Contractions were elicited at 12 degrees C by photolytic
      release of ATP from the P3 -1-(2-nitrophenyl) ester of ATP (NPE-caged ATP).
      Inorganic phosphate (Pi) release was measured by a fluorescence method using a
      coumarin-labelled phosphate binding protein. Force and sarcomere length were also
      monitored. 3. ATPase activity was determined from the rate of appearance of Pi
      during each phase of contraction. The ATPase rate was 10.3 s-1 immediately
      following release of ATP and 5. 1 s-1 during the isometric phase prior to the
      applied shortening. It rose hyperbolically with shortening velocity, reaching
      18.5 s-1 at a maximal shortening velocity > 1 ML s-1 (muscle lengths s-1). 4.
      Sarcomeres shortened at 0.09 ML s-1 immediately following the photolytic release
      of ATP and at 0.04 ML s-1 prior to the period of applied shortening. The high
      initial ATPase rate may be largely attributed to initial sarcomere shortening. 5.
      During shortening, maximal power output was 28 W l-1. Assuming the free energy of
      hydrolysis is 50 kJ mol-1, the efficiency of contraction was calculated from the
      power output at each shortening velocity. The maximum efficiency was 0.36 at a
      shortening velocity of 0.27 ML s-1, corresponding to a force level 51 % of that
      in the isometric state. 6. At the maximal shortening velocity, only 10 % of the
      myosin heads are attached to the thin filaments at any one time.

PMID- 10358124
TI  - The effect of cyclopiazonic acid on excitation-contraction coupling in guinea-pig
      ureteric smooth muscle: role of the sarcoplasmic reticulum.
AB  - 1. We have investigated the effect of cyclopiazonic acid (CPA), an inhibitor of
      the sarcoplasmic reticulum (SR) Ca2+-ATPase on excitation-contraction (EC)
      coupling in guinea-pig ureter, by measuring membrane currents, action potentials,
      intracellular [Ca2+] and force. 2. CPA (20 micrometers) significantly enhanced
      the amplitude and duration of phasic contractions of ureteric smooth muscle
      associated with action potentials. This was accompanied by an increase in the
      duration of the intracellular Ca2+ transient in intact tissue and single cells
      but not their amplitude. However, CPA also slowed the rate of rise, and fall, of
      the force 1|1|Phiand1Phi Ca2+ transients. 3. Membrane potential recordings showed
      that CPA produced a small depolarization and a large increase in the duration of
      the plateau phase of the action potential. 4. Patch-clamp studies showed marked
      inhibition of outward potassium current in the presence of CPA and an inhibition
      of spontaneous transient outward currents (STOCs). CPA had no effect on inward
      Ca2+ current. 5. These data suggest that the SR plays a major role in modulating
      the excitability of the ureter, particularly via curtailing the action potential
      duration. This in turn will shorten the Ca2+ transient and decrease force. This
      negative action on developed force predominates over any small role it may play
      in initiating force in the guinea-pig ureter.

PMID- 10358125
TI  - Conduction velocities and membrane properties of different classes of rat
      septohippocampal neurons recorded in vitro.
AB  - 1. The membrane properties and conduction velocities of antidromically activated
      medial septum-diagonal band (MS-DB) neurons were examined using whole-cell
      recordings in a longitudinally cut rat brain slice preparation containing the MS
      DB and the dorsal fornix. 2. MS-DB neurons were divided into three groups
      according to their action potential characteristics and firing properties. Slow
      firing neurons displayed a broad action potential followed by a prominent after
      hyperpolarization. Burst firing neurons, when depolarized from hyperpolarized
      holding potentials, exhibited a high-frequency burst of spikes on the crest of a
      slow depolarizing potential. Fast firing neurons did not fire bursts of spikes
      when depolarized from hyperpolarized holding potentials. 3. Eighteen MS-DB
      neurons were identified as septohippocampal by antidromic activation. Of the
      septohippocampal neurons, four were slow firing neurons, five were burst firing
      neurons and nine were fast firing neurons. The mean axon conduction velocities of
      these neurons fell into two significant groups, termed slow conducting and fast
      conducting. Slow firing septohippocampal neurons had significantly slower
      conduction velocities than either fast firing or burst firing neurons (P < 0.05),
      being 0.7 +/- 0.5 ms-1 for slow firing neurons and 2.9 +/- 2.0 and 2.0 +/- 1.4 ms
      1 for burst firing and fast firing neurons, respectively. 4. On the basis of
      previous evidence which has linked firing properties with the neurochemical
      identities of the neurons, we propose that the slow firing septohippocampal
      neurons are cholinergic whereas the burst firing and fast firing septohippocampal
      neurons are GABAergic.

PMID- 10358126
TI  - Noradrenaline synchronizes evoked quantal release at frog neuromuscular
      junctions.
AB  - 1. Noradrenaline (NA) increases synaptic efficacy at the frog neuromuscular
      junction. To test the hypothesis that one of the actions of NA is to shorten the
      period over which evoked quanta are released, we measured the latencies of
      focally recorded uniquantal endplate currents (EPCs). 2. NA shortened the release
      period for evoked quantal release. The interval between the time when responses
      with minimal delay appeared and the point at which 90 % of all latencies had
      occurred was shortened in the presence of 1 x 10-5 M NA by about 35 % at 20 C and
      by about 45 % at 8 C. Inhibitor and agonist experiments showed that NA acts on a
      beta-adrenoreceptor. 3. The better synchronization of release significantly
      increased the size of reconstructed multi- quantal EPCs. This suggests that NA
      facilitates synaptic transmission by making the release of quanta more
      synchronous. 4. The synchronizing action of NA might potentiate neuromuscular
      transmission during nerve regeneration, transmitter exhaustion and other extreme
      physiological states where the quantal content is reduced, such as survival in
      cold and hibernation.

PMID- 10358127
TI  - Does the guinea-pig ileum obey the 'law of the intestine'?
AB  - 1. We report the first simultaneous mechanical reflex responses of the
      longitudinal muscle (LM) and circular muscle (CM) layers of the guinea-pig ileum
      following mucosal stimulation and distension in vitro. 2. Dissection techniques
      were used to prevent mechanical interaction between the LM and CM layers both
      oral and anal to a stimulus site. 3. All graded stimuli produced graded
      contractions of both the LM and CM orally and anally to the stimulus.
      Contractions occurred synchronously in the LM and CM and under no circumstances
      were inhibitory responses recorded in either muscle layer, despite the presence
      of ongoing cholinergic tone in both the LM and CM. Contractions were abolished by
      tetrodotoxin (1.6 microM). 4. Local brush stroking of the mucosa evoked a
      peristaltic wave which readily conducted distally over 13 cm, without the
      presence of fluid in the lumen. No descending relaxation was observed. 5. Apamin
      (300 nM) disrupted evoked peristaltic waves and significantly increased the rate
      of-rise of the LM and CM contractions anal to a stimulus, and the LM oral to a
      stimulus. 6. Nomega-nitro-L-arginine (100 microM), a nitric oxide synthesis
      inhibitor, had no overall significant effect on the characteristics of the LM and
      CM contractions, although on occasion an enhancement in their peak amplitude was
      noted. 7. It is suggested that the guinea-pig ileum does not conform to the 'law
      of the intestine' as postulated by Bayliss & Starling (1899). Rather, local
      physiological stimulation of the ileum elicits a contraction both orally and
      anally to a stimulus, which occurs synchronously in both the CM and LM layers.
      Apamin-sensitive inhibitory neurotransmission modulates the rate-of-rise of the
      anal contraction of the CM, possibly to generate distal propulsion.

PMID- 10358128
TI  - Central CO2 chemoreception: a mechanism involving P2 purinoceptors localized in
      the ventrolateral medulla of the anaesthetized rat.
AB  - 1. The involvement of P2 purinoceptors in chemosensory function in the
      ventrolateral regions of the medulla oblongata was investigated in the
      anaesthetized rat. We have investigated the effect of antagonizing, or
      desensitizing, P2 receptors in the retrofacial area of the ventrolateral medulla
      on factors modifying respiratory activity. 2. Bilateral microinjection of suramin
      (50 nl, 0.02 M), a P2 purinoceptor antagonist, into the retrofacial area in the
      artificially ventilated rat reduced resting phrenic nerve discharge. It also
      markedly affected the response of the phrenic nerve to increases in arterial CO2.
      Under conditions of hyperoxic, hypocapnic apnoea, the mean threshold for inducing
      phrenic nerve activity was raised significantly (from an end-tidal CO2 of 2.5 %
      to 4.5 %, n = 9). 3. In addition, the slope of the respiratory response curve to
      increases in CO2 was reduced after suramin. A similar effect was observed after
      desensitization of certain P2X receptors with alphabeta-methyleneATP. As arterial
      levels of O2 were greater than 100 mmHg, and an equivalent pattern of response
      was observed in sino-aortically denervated and vagotomized animals, we believe
      any contribution of the peripheral chemoreceptors to be minimal. 4. Our data
      suggest that respiratory neurones within the retrofacial area (Botzinger complex)
      represent part of the central site of action of CO2 on respiration. Moreover, our
      observations lead us to suggest that CO2-evoked changes in respiration are
      mediated at least in part by P2X purinoceptors.

PMID- 10358129
TI  - Temporal contrast sensitivity in the lateral geniculate nucleus of a New World
      monkey, the marmoset Callithrix jacchus.
AB  - 1. The temporal contrast sensitivity of koniocellular, parvocellular and
      magnocellular cells in the lateral geniculate nucleus (LGN) of nine adult
      marmosets was measured. The receptive fields of the cells were between 0.3 and 70
      deg from the fovea. The stimulus was a large spatially uniform field which was
      modulated in luminance at temporal frequencies between 0.98 and 64 Hz. 2. For
      each cell group there was a gradual increase in modulation sensitivity,
      especially for temporal frequencies below 8 Hz, with increasing distance from the
      fovea. At any given eccentricity, magnocellular cells had the greatest
      sensitivity. In central visual field, the sensitivity of koniocellular cells lay
      between that of parvocellular and magnocellular cells. In peripheral visual field
      (above 10 deg eccentricity) koniocellular and parvocellular cells had similar
      sensitivity. 3. The contrast sensitivity of each cell class was dependent on the
      anaesthetic used. Cells from animals anaesthetized with isoflurane were less
      sensitive than cells from animals anaesthetized with sufentanil. This effect was
      more marked for temporal frequencies below 4 Hz. 4. These results are
      incompatible with the notion that the koniocellular pathway is functionally
      homologous to a sluggish, W-like pathway in other mammals. At least in terms of
      their temporal transfer properties, many koniocellular cells are more like
      parvocellular cells.

PMID- 10358131
TI  - Effects of galvanic vestibular stimulation during human walking.
AB  - 1. To identify vestibular influences on human walking, galvanic vestibular
      stimulation was applied to normal adult subjects as they walked to a previously
      seen target. A transmastoidal step stimulus commenced as subjects started
      walking. With the eyes shut, the galvanic stimulus caused large turns towards the
      side with the anodal current. 2. Ability to perceive the trajectory of gait
      without visual cues was measured by guiding blindfolded subjects from one
      arbitrary point to another, either walking or seated in a wheelchair. On reaching
      a destination position and removing the blindfold, subjects pointed to indicate
      the starting position. Subjects made considerable errors in estimating the
      trajectory, but were equally accurate whether in the wheelchair or walking. 3. To
      determine the effects of vestibular stimulation on the perception of trajectory,
      the galvanic stimulus was applied to blindfolded subjects as they were guided
      from one point to another in the wheelchair. The vestibular stimulus produced an
      illusory shift in the trajectory travelled. This shift was towards the side with
      the cathode, i.e. in the opposite direction to the turn produced by the stimulus
      during walking. 4. We conclude that galvanic vestibular stimulation during
      walking causes subjects to turn from their planned trajectory. In part, this
      altered course may compensate for an altered perception of trajectory produced by
      the stimulus. However, altered perception of the vertical or the base of support,
      or direct vestibulo-fugal influences on the leg muscles could contribute to the
      changes in gait.

PMID- 10358130
TI  - The effects of exercise and diet manipulation on the capacity to perform
      prolonged exercise in the heat and in the cold in trained humans.
AB  - 1. This study examined the effects of exercise and diet manipulation intended to
      alter initial muscle glycogen levels on the capacity to perform prolonged
      exercise at two ambient temperatures. 2. Six well-trained cyclists participated
      in randomized order in two diet and exercise regimens each lasting 8 days and
      comprising four cycle tests to exhaustion at 70 % of maximum oxygen uptake. On
      days 1 and 5, subjects exercised to exhaustion to deplete muscle glycogen. Three
      days after each depletion trial a diet providing 10 % (low carbohydrate (CHO)) or
      80 % (high CHO) of energy as CHO was consumed, and each diet was followed by a
      performance trial at the same ambient temperature, either 10 or 30 C (days 4 and
      8). This schedule was repeated after a week, but performance trials were carried
      out at the other ambient temperature. 3. In the cold, cycling time increased
      (median (range)) from 89.2 min (78.0-129.5 min) on the low CHO trial to 158.2 min
      (116.9-165.6 min) on the high CHO trial (P < 0.01). In the heat, cycling time
      increased from 44.0 min (31.8-51.4 min) on the low CHO trial to 53.2 min (50.2
      82.2 min) on the high CHO trial (P = 0.02). Total CHO oxidized during exercise in
      the cold after the low CHO diet was higher than in the heat after either diet
      suggesting that exercise in the heat was terminated before all available CHO
      stores had been emptied.

PMID- 10358132
TI  - Cutting edge: anti-CD1 monoclonal antibody treatment reverses the production
      patterns of TGF-beta 2 and Th1 cytokines and ameliorates listeriosis in mice.
AB  - Protection against intracellular bacteria by T cells is regulated by Ag
      presenting molecules, which comprise classical MHC class I molecules, MHC class
      II molecules, and nonclassical MHC class Ib molecules. The role of CD1 molecules,
      which are structurally similar to classical MHC class I gene products, but less
      polymorphic, is not understood so far. We show that CD1 surface expression
      increased on APC in Listeria-infected mice. The in vivo treatment with anti-CD1
      mAb reduced TGF-beta 2 levels and concomitantly increased secretion of the
      proinflammatory cytokine TNF, the Th1 cell promoting cytokine IL-12, and the Th1
      cell cytokine IFN-gamma at the onset of listerial infection. These findings point
      to a regulatory role of CD1-reactive cells in the immune response against
      listeriosis.

PMID- 10358133
TI  - Cutting edge: rapid cloning of tumor-specific CTL suitable for adoptive
      immunotherapy of melanoma.
AB  - Adoptive immunotherapy using CTL has provided some clinical benefit to patients
      with metastatic melanoma. Use of cloned CTL of known specificity might improve
      clinical effect, but technical difficulties have limited exploration of this
      possibility. We have used fluorescence-driven cell sorting to clone tumor
      specific CTL after staining with tetrameric MHC class I/peptide complexes. CTL
      specific for the melanoma Ags melan-A, tyrosinase, and MAGE3 were cloned from the
      peripheral blood, tumor-infiltrated lymph nodes, and skin metastases of five
      patients. Clones were isolated and characterized in as little as 6 weeks, much
      faster than is possible with previous techniques. We show that these CTL clones
      express markers compatible with immunotherapeutic use in melanoma, including the
      cutaneous lymphocyte Ag, which is associated with homing to skin.

PMID- 10358134
TI  - Cutting edge: silencing virus-specific cytotoxic T cell-mediated immune
      recognition by differential splicing: a novel implication of RNA processing for
      antigen presentation.
AB  - Persistent viruses have developed potent strategies to overcome host immune
      defenses. In particular, viral interference with Ag presentation by HLA class I
      molecules can effectively impair the host's CTL function. Here we provide
      evidence for a novel aspect of differential splicing on endogenous processing of
      a latent viral transcript resulting in dominant protein isoforms from which the
      CTL determinant has been deleted. Consequently, virus-infected cells expressing
      these isoforms were poorly recognized by CTLs. Molecular analysis revealed that
      this splicing significantly reduced expression of the viral transcript encoding
      the relevant epitope to levels below the threshold required for CTL recognition.
      The importance of splicing was further reinforced by the observation of efficient
      CTL recognition of target cells expressing a truncated viral transcript that
      abolished differential splicing. Thus, differential splicing, which is a common
      mechanism of gene regulation in many pathogens, may unexpectedly interfere with
      immune recognition.

PMID- 10358135
TI  - Cutting edge: a novel viral TNF receptor superfamily member in virulent strains
      of human cytomegalovirus.
AB  - The UL144 open reading frame found in clinical isolates of human CMV (HCMV)
      encodes a structural homologue of the herpesvirus entry mediator, a member of the
      TNFR superfamily. UL144 is a type I transmembrane glycoprotein that is expressed
      early after infection of fibroblasts; however, it is retained intracellularly. A
      YXXZ motif in the highly conserved cytoplasmic tail contributes to UL144
      subcellular distribution. The finding that no known ligand of the TNF family
      binds UL144 suggests that its mechanism of action is distinct from other known
      viral immune evasion genes. Specific Abs to UL144 can be detected in the serum of
      a subset of HCMV seropositive individuals infected with HIV. This work
      establishes a novel molecular link between the TNF superfamily and herpesvirus
      that may contribute to the ability of HCMV to escape immune clearance.

PMID- 10358136
TI  - Cutting edge: cells that carry A null allele for toll-like receptor 2 are capable
      of responding to endotoxin.
AB  - Toll-like receptor (TLR) 2 and TLR4 have been implicated in the responses of
      cells to LPS (endotoxin). CD14-transfected Chinese hamster ovary (CHO)-K1
      fibroblasts (CHO/CD14) are exquisitely sensitive to endotoxin. Sequence analysis
      of CHO-TLR2, compared with human and mouse TLR2, revealed a single base pair
      deletion. This frameshift mutation resulted in an alternative stop codon,
      encoding a protein devoid of transmembrane and intracellular domains. CHO-TLR2
      cDNA failed to enable LPS signaling upon transient transfection into human
      epithelial kidney 293 cells. Site-directed mutagenesis of CHO-TLR2 enabled
      expression of a presumed full-length hamster TLR2 that conferred LPS
      responsiveness in human epithelial kidney 293 cells. Genomic TLR2 DNA from
      primary hamster macrophages also contained the frameshift mutation found in CHO
      fibroblasts. Nevertheless, hamster peritoneal macrophages were found to respond
      normally to LPS, as evidenced by the induction of cytokines. These results imply
      that expression of TLR2 is sufficient but not essential for mammalian responses
      to endotoxin.

PMID- 10358137
TI  - Cutting edge: expression of functional CD94/NKG2A inhibitory receptors on fetal
      NK1.1+Ly-49- cells: a possible mechanism of tolerance during NK cell development.
AB  - Fetal liver- and thymus-derived NK1.1+ cells do not express known Ly-49
      receptors. Despite the absence of Ly-49 inhibitory receptors, fetal and neonatal
      NK1.1+Ly-49- cells can distinguish between class Ihigh and class Ilow target
      cells, suggesting the existence of other class I-specific inhibitory receptors.
      We demonstrate that fetal NK1. 1+Ly-49- cell lysates contain CD94 protein and
      that a significant proportion of fetal NK cells are bound by Qa1b tetramers.
      Fetal and adult NK cells efficiently lyse lymphoblasts from Kb-/-Db-/- mice. Qa1b
      specific peptides Qdm and HLA-CW4 leader peptide specifically inhibited the lysis
      of these blasts by adult and fetal NK cells. Qdm peptide also inhibited the lysis
      of Qa1b-transfected human 721.221 cells by fetal NK cells. Taken together, these
      results suggest that the CD94/NKG2A receptor complex is the major known
      inhibitory receptor for class I (Qa1b) molecules on developing fetal NK cells.

PMID- 10358139
TI  - Enhancing or suppressive effects of antibodies on processing of a pathogenic T
      cell epitope in thyroglobulin.
AB  - Thyroglobulin (Tg)-specific Abs occur commonly in thyroid disease, but it is not
      clear to what extent they affect Tg processing and presentation to T cells. Here
      we show that generation of the nondominant pathogenic Tg epitope (2549-2560),
      containing thyroxine (T4) at position 2553 (T4(2553)), is augmented by Tg
      specific IgG mAbs that facilitate FcR-mediated internalization of Tg. However,
      other mAbs of the same (IgG1) subclass enhanced Tg uptake by APC but had no
      effect on the generation of this peptide. Treatment of APC with chloroquine or
      glutaraldehyde abrogated enhanced generation of T4(2553). The boosting effect was
      selective, since the enhancing mAbs did not facilitate generation of the
      neighboring cryptic (2495-2511) peptide, which is also pathogenic in mice. When
      Tg was simultaneously complexed to a mAb reactive with T4(2553) and to a mixture
      of boosting mAbs, the presentation of this epitope was totally suppressed. These
      results suggest that Tg-specific Abs alter Tg processing and may boost or
      suppress the presentation of nondominant pathogenic determinants during the
      course of disease.

PMID- 10358138
TI  - Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein
      tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP.
AB  - The genetic defect in X-linked lymphoproliferative syndrome (XLP) is the Src
      homology 2 domain-containing protein SAP. SAP constitutively associates with the
      cell surface molecule, signaling lymphocytic activation molecule (SLAM), and
      competes with SH2-domain containing protein tyrosine phosphatase-2 (SHP-2) for
      recruitment to SLAM. SLAM exhibits homology with the mouse cell surface receptor
      2B4. The human homologue of 2B4 has now been identified. It is recognized by the
      c1.7 mAb, a mAb capable of activating human NK cells. Human 2B4 became tyrosine
      phosphorylated following pervanadate-treatment of transfected cells and recruited
      SHP-2. SAP was also recruited to 2B4 in activated cells. Importantly, the 2B4-SAP
      interaction prevented the association between 2B4 and SHP-2. These results
      suggest that the phenotype of XLP may result from perturbed signaling not only
      through SLAM, but also other cell surface molecules that utilize SAP as a
      signaling adaptor protein.

PMID- 10358140
TI  - Human anti-porcine T cell response: blocking with anti-class I antibody leads to
      hyporesponsiveness and a switch in cytokine production.
AB  - Intervention in the molecular interactions that lead to an immune response is
      possible at various stages of Ag recognition and T cell activation. Perturbation
      of the interaction of the TCR with the MHC/peptide ligand complex is one approach
      that has shown promise for autoimmunity and graft rejection in blocking T cell
      activated responses. In this study, we investigated the effect of altering the
      target MHC class I molecule by blocking with Abs. We established a system that
      analyzed the human T cell response against MHC class I+/class II- porcine
      stimulatory cell targets. The primary human response against porcine smooth
      muscle cells was CD8+ T cell dependent. In the presence of F(ab')2 fragments of
      the MHC class I-reactive Ab, PT-85, the proliferative response was inhibited and
      production of IL-2 and IFN-gamma was blocked. Moreover, in a secondary response,
      proliferation was reduced and type 1 cytokine levels were inhibited. In contrast,
      levels of IL-10 and IL-4 were sustained or slightly increased. These findings
      indicate that Ab against MHC class I blocked the recognition of porcine cells by
      the human CD8+ T cells and altered the cytokine secretion profile. Thus, a single
      treatment with PT-85 F(ab')2 directed against the MHC class I molecule provides
      an attractive approach to the induction of T cell tolerance that may provide long
      term graft survival in porcine-to-human cell transplantation.

PMID- 10358141
TI  - Cytokine-induced protein kinase B activation and Bad phosphorylation do not
      correlate with cell survival of hemopoietic cells.
AB  - Activation of phosphoinositide-3 kinases (PI3Ks), their downstream target protein
      kinase B (PKB), and phosphorylation of Bad have all been implicated in survival
      signaling in many systems. However, it is not known whether these events are
      sufficient or necessary to universally prevent apoptosis. To address this issue,
      we have used three different factor-dependent hemopoietic cell lines, MC/9,
      BaF/3, and factor-dependent (FD)-6, which respond to a range of cytokines, to
      investigate the relationship between PI3K, PKB, and Bad activity with survival.
      The cytokines IL-3, IL-4, stem cell factor (SCF), GM-CSF, and insulin all induced
      the rapid and transient activation of PKB in responsive cell lines. In all cases,
      cytokine-induced PKB activation was sensitive to inhibition by the PI3K
      inhibitor, LY294002. However, dual phosphorylation of the proapoptotic protein
      Bad was found not to correlate with PKB activation. In addition, we observed cell
      type-specific differences in the ability of the same cytokine to induce Bad
      phosphorylation. Whereas IL-4 induced low levels of dual phosphorylation of Bad
      in FD-6, it was unable to in MC/9 or BaF/3. Insulin, which was the most potent
      inducer of PKB in FD-6, induced barely detectable Bad phosphorylation. In
      addition, the ability of a particular cytokine to induce PKB activity did not
      correlate with its ability to promote cell survival and/or proliferation. These
      data demonstrate that, in hemopoietic cells, activation of PKB does not
      automatically confer a survival signal or result in phosphorylation of Bad,
      implying that other survival pathways must be involved.

PMID- 10358142
TI  - The MHC class I molecule H-2Dp inhibits murine NK cells via the inhibitory
      receptor Ly49A.
AB  - MHC class I molecules strongly influence the phenotype and function of mouse NK
      cells. NK cell-mediated lysis is prevented through the interaction of Ly49
      receptors on the effector cell with appropriate MHC class I ligands on the target
      cell. In addition, host MHC class I molecules have been shown to modulate the in
      vivo expression of Ly49 receptors. We have previously reported that H-2Dd and H
      2Dp MHC class I molecules are able to protect (at the target cell level) from NK
      cell-mediated lysis and alter the NK cell specificity (at the host level) in a
      similar manner, although the mechanism behind this was not clear. In this study,
      we demonstrate that the expression of both H-2Dd and H-2Dp class I molecules in
      target cells leads to inhibition of B6 (H-2b)-derived Ly49A+ NK cells. This
      inhibition could in both cases be reversed by anti-Ly49A Abs. Cellular conjugate
      assays showed that Ly49A-expressing cells indeed bind to cells expressing H-2Dp.
      The expression of Ly49A and Ly49G2 receptors on NK cells was down-regulated in H
      2Dp-transgenic (B6DP) mice compared with nontransgenic B6 mice. However, B6DP
      mice expressed significantly higher levels of Ly49A compared with H-2Dd
      transgenic (D8) mice. We propose that both H-2Dd and H-2Dp MHC class I molecules
      can act as ligands for Ly49A.

PMID- 10358143
TI  - Direct effects on antigen-presenting cells and T lymphocytes explain the
      adjuvanticity of a nontoxic cholera toxin mutant.
AB  - The present study has elucidated two distinct mechanisms that may explain how a
      mutant of cholera toxin (mCT), E112K, retains adjuvant effects though it lacks
      ADP-ribosyltransferase activity and associated toxicity. In the first mechanism,
      we show that mCT E112K, like native cholera toxin (nCT), enhances B7-2
      expression, but, to some extent, also enhances B7-1 on Peyer's patch B cells and
      macrophages. Cocultivation of CD4+ T cells with E112K- or nCT-treated B cells and
      macrophages in the presence of anti-CD3 stimulation resulted in the induction of
      T cell-proliferative responses. Further, the responses were blocked by mAbs to B7
      1 and/or B7-2; however, the effect of anti-B7-1 was minimal. In the second
      mechanism, addition of mCT E112K or nCT to anti-CD3 mAb-stimulated Peyer's patch
      CD4+ T cells inhibited proliferative responses, while recombinant CT-B subunit
      (rCT-B) did not. Analysis of cytokine responses showed that both mCT E112K and
      nCT preferentially inhibited IFN-gamma production. Interestingly, however, nCT,
      but not mCT E112K, induced apoptosis in CD4+ T cells activated via the TCR-CD3
      complex. These results indicate that CT uses at least two pathways for inhibition
      of Th1 responses and that, while nCT induces cAMP accumulation that in turn leads
      to apoptosis in Th1-type cells, mCT E112K, which lacks ADP-ribosyltransferase
      activity, inhibits IFN-gamma synthesis by a separate mechanism. Thus, mCT E112K,
      like nCT, induces adjuvant responses via up-regulation of mainly B7-2 on APCs and
      through preferential inhibition of Th1-type CD4+ T cell responses in the absence
      of ADP-ribosyltransferase activity.

PMID- 10358144
TI  - Human vascular endothelial cells favor clonal expansion of unusual alloreactive
      CTL.
AB  - We have shown previously that cultured HUVEC or mixtures of endothelial cells
      (EC) and B lymphoblastoid cells (BLC) induce the differentiation of purified CD8+
      PBL into allospecific, class I MHC-restricted CTL that lyse EC, but not BLC
      autologous to EC. Furthermore, these EC-selective CTL lines secrete little IFN
      gamma after target cell contact. In the present study, we have analyzed these
      polyclonal populations at a single cell level by cloning at limiting dilution and
      propagating the resulting CTL clones in the absence of EC. Phenotypically stable,
      alloreactive EC-selective CTL preferentially emerge from cocultures in which EC
      or EC + BLC are the initial stimulating cell types compared with cocultures
      stimulated by BLC alone (p = 0.005). Compared with BLC-stimulated CTL, EC
      stimulated CTL clones often fail to secrete IFN-gamma after target cell contact
      (p = 0.0006) and constitutively express CD40 ligand (CD40L) at rest (p = 0.0006).
      The absence of IFN-gamma secretion does not result from a switch to IL-4
      secretion. The expression of CD40L inversely correlates with the secretion of IFN
      gamma after target cell contact (p = 0.0001), but correlations of CD40L
      expression and failure to secrete IFN-gamma with EC-selective killing did not
      reach statistical significance. We conclude that in a microenvironment in which
      allogeneic EC are in close contact with infiltrating CD8+ T cells, such as within
      a graft arterial intima, CTL subsets may emerge that display EC selectivity or
      express CD40L and secrete little IFN-gamma after Ag contact.

PMID- 10358145
TI  - CD47 signals T cell death.
AB  - Activation-induced death of T cells regulates immune responses and is considered
      to involve apoptosis induced by ligation of Fas and TNF receptors. The role of
      other receptors in signaling T cell death is less clear. In this study we
      demonstrate that activation of specific epitopes on the Ig variable domain of
      CD47 rapidly induces apoptosis of T cells. A new mAb, Ad22, to this site induces
      apoptosis of Jurkat cells and CD3epsilon-stimulated PBMC, as determined by
      morphological changes, phosphatidylserine exposure on the cell surface, uptake of
      propidium iodide, and true counts by flow cytometry. In contrast, apoptosis was
      not observed following culture with anti-CD47 mAbs 2D3 or B6H12 directed to a
      distant or closely adjacent region, respectively. CD47-mediated cell death was
      independent of CD3, CD4, CD45, or p56lck involvement as demonstrated by studies
      with variant Jurkat cell lines deficient in these signaling pathways. However,
      coligation of CD3epsilon and CD47 enhanced phosphatidylserine externalization on
      Jurkat cells with functional CD3. Furthermore, normal T cells required
      preactivation to respond with CD47-induced apoptosis. CD47-mediated cell death
      appeared to proceed independent of Fas or TNF receptor signaling and did not
      involve characteristic DNA fragmentation or requirement for IL-1beta-converting
      enzyme-like proteases or CPP32. Taken together, our data demonstrate that under
      appropriate conditions, CD47 activation results in very rapid T cell death,
      apparently mediated by a novel apoptotic pathway. Thus, CD47 may be critically
      involved in controlling the fate of activated T cells.

PMID- 10358146
TI  - Reactive oxygen intermediates enhance Fc gamma receptor signaling and amplify
      phagocytic capacity.
AB  - Receptors for the Fc region of IgG (Fc gamma R) mediate internalization of
      opsonized particles by human neutrophils (PMN) and mononuclear phagocytes. Cross
      linking of Fc gamma R leads to activation of protein tyrosine kinases and
      phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) within
      Fc gamma R subunits, both obligatory early signals for phagocytosis. Human PMN
      constitutively express two structurally distinct Fc gamma R, Fc gamma RIIa and Fc
      gamma RIIIb, and can be induced to express Fc gamma RI by IFN-gamma. We have
      previously shown that stimulation of PMN through Fc gamma RIIIb results in
      enhanced Fc gamma RIIa-mediated phagocytic activity that is inhibited by
      catalase. In the present study, we have tested the hypothesis that reactive
      oxygen intermediates (ROI) have the capacity to regulate Fc gamma R responses and
      defined a mechanism for this effect. We show that H2O2 augmented phagocytosis
      mediated by Fc gamma RIIa and Fc gamma RI in PMN and amplified receptor-triggered
      tyrosine phosphorylation of Fc gamma R-associated ITAMs and signaling elements.
      Generation of endogenous oxidants in PMN by cross-linking Fc gamma RIIIb
      similarly enhanced phosphorylation of Fc gamma RIIa and Syk, a tyrosine kinase
      required for phagocytic function, in a catalase-sensitive manner. Our results
      provide a mechanism for priming phagocytes for enhanced responses to receptor
      driven effects. ROI generated in an inflammatory milieu may stimulate quiescent
      cells to rapidly increase the magnitude of their effector function. Indeed, human
      monocytes incubated in the presence of stimulated PMN showed oxidant-induced
      increases in Fc gamma RIIa-mediated phagocytosis. Definition of the role of
      oxidants as amplifiers of Fc gamma R signaling identifies a target for
      therapeutic intervention in immune complex-mediated tissue injury.

PMID- 10358147
TI  - Diverse fine specificity and receptor repertoire of T cells reactive to the major
      VP1 epitope (VP1230-250) of Theiler's virus: V beta restriction correlates with T
      cell recognition of the c-terminal residue.
AB  - Theiler's murine encephalomyelitis virus induces chronic demyelinating disease in
      genetically susceptible mice. The histopathological and immunological
      manifestation of the disease closely resembles human multiple sclerosis, and,
      thus, this system serves as a relevant infectious model for multiple sclerosis.
      The pathogenesis of demyelination appears to be mediated by the inflammatory Th1
      response to viral epitopes. In this study, T cell repertoire reactive to the
      major pathogenic VP1 epitope region (VP1233-250) was analyzed. Diverse minimal T
      cell epitopes were found within this region, and yet close to 50% of the VP1
      reactive T cell hybridomas used V beta 16. The majority (8/11) of the V beta 16+
      T cells required the C-terminal amino acid residue on the epitope, valine at
      position 245, and every T cell hybridoma recognizing this C-terminal residue
      expressed V beta 16. However, the complementarity-determining region 3 sequences
      of the V beta 16+ T cell hybridomas were markedly heterogeneous. In contrast,
      such a restriction was not found in the V alpha usage. Only restricted residues
      at this C-terminal position allowed for T cell activation, suggesting that V beta
      16 may recognize this terminal residue. Further functional competition analysis
      for TCR and MHC class II-contacting residues indicate that many different
      residues can be involved in the class II and/or TCR binding depending on the T
      cell population, even if they recognize the identical minimal epitope region.
      Thus, recognition of the C-terminal residue of a minimal T cell epitope may
      associate with a particular V beta (but not V alpha) subfamily-specific sequence,
      resulting in a highly restricted V beta repertoire of the epitope-specific T
      cells.

PMID- 10358148
TI  - CD28-independent costimulation of T cells by OX40 ligand and CD70 on activated B
      cells.
AB  - OX40 and its ligand (OX40L) have been implicated in T cell-dependent humoral
      immune responses. To further characterize the role of OX40/OX40L in T-B cell
      interaction, we newly generated an anti-mouse OX40L mAb (RM134L) that can inhibit
      the costimulatory activity of OX40L transfectants for anti-CD3-stimulated T cell
      proliferation. Flow cytometric analyses using RM134L and an anti-mouse OX40 mAb
      indicated that OX40 was inducible on splenic T cells by stimulation with
      immobilized anti-CD3 mAb in a CD28-independent manner, while OX40L was not
      expressed on resting or activated T cells. OX40L was inducible on splenic B cells
      by stimulation with anti-IgM Ab plus anti-CD40 mAb, but not by either alone.
      These activated B cells exhibited a potent costimulatory activity for anti-CD3
      stimulated T cell proliferation and IL-2 production. Anti-CD80 and anti-CD86 mAbs
      partially inhibited the costimulatory activity, and further inhibition was
      obtained by their combination with RM134L and/or anti-CD70 mAb. We also found the
      anti-IgM Ab- plus anti-CD40 mAb-stimulated B cells exhibited a potent
      costimulatory activity for proliferation of and IL-2 production by anti-CD3
      stimulated CD28- T cells from CD28-deficient mice, which was substantially
      inhibited by RM134L and/or anti-CD70 mAb. These results indicated that OX40L and
      CD70 expressed on surface Ig- and CD40-stimulated B cells can provide CD28
      independent costimulatory signals to T cells.

PMID- 10358149
TI  - IL-7 up-regulates IL-4 production by splenic NK1.1+ and NK1.1- MHC class I
      like/CD1-dependent CD4+ T cells.
AB  - NK T cells are an unusual subset of T lymphocytes. They express NK1. 1 Ag, are
      CD1 restricted, and highly skewed toward Vbeta8 for their TCR usage. They express
      the unique potential to produce large amounts of IL-4 and IFN-gamma immediately
      upon TCR cross-linking. We previously showed in the thymus that the NK T subset
      requires IL-7 for its functional maturation. In this study, we analyzed whether
      IL-7 was capable of regulating the production of IL-4 and IFN-gamma by the
      discrete NK T subset of CD4+ cells in the periphery. Two hours after injection of
      IL-7 into mice, or after a 4-h exposure to IL-7 in vitro, IL-4 production by CD4+
      cells in response to anti-TCR-alphabeta is markedly increased. In contrast, IFN
      gamma production remains essentially unchanged. In beta2-microglobulin- and CD1
      deficient mice, which lack NK T cells, IL-7 treatment does not reestablish normal
      levels of IL-4 by CD4+ T cells. Moreover, we observe that in wild-type mice, the
      memory phenotype (CD62L-CD44+) CD4+ T cells responsible for IL-4 production are
      not only NK1.1+ cells, but also NK1.1- cells. This NK1.1-IL-4-producing subset
      shares three important characteristics with NK T cells: 1) Vbeta8 skewing; 2) CD1
      restriction as demonstrated by their absence in CD1-deficient mice and relative
      overexpression in MHC II null mice; 3) sensitivity to IL-7 in terms of IL-4
      production. In conclusion, the present study provides evidence that CD4+MHC class
      I-like-dependent T cell populations include not only NK1.1+ cells, but also NK1.1
      cells, and that these two subsets are biased toward IL-4 production by IL-7.

PMID- 10358150
TI  - IFN-gamma exposes a cryptic cytotoxic T lymphocyte epitope in HIV-1 reverse
      transcriptase.
AB  - The proteasome, an essential component of the ATP-dependent proteolytic pathway
      in eukaryotic cells, is responsible for the degradation of most cellular proteins
      and is believed to be the main source of MHC class I-restricted antigenic
      peptides for presentation to CTL. Inhibition of the proteasome by lactacystin or
      various peptide aldehydes can result in defective Ag presentation, and the
      pivotal role of the proteasome in Ag processing has become generally accepted.
      However, recent reports have challenged this observation. Here we examine the
      processing requirements of two HLA A*0201-restricted epitopes from HIV-1 reverse
      transcriptase and find that they are produced by different degradation pathways.
      Presentation of the C-terminal ILKEPVHGV epitope is impaired in ME275 melanoma
      cells by treatment with lactacystin, and is independent of expression of the IFN
      gamma-inducible proteasome beta subunits LMP2 and LMP7. In contrast, both
      lactacystin treatment and expression of LMP7 induce the presentation of the N
      terminal VIYQYMDDL epitope. Consistent with these observations we show that up
      regulation of LMP7 by IFN-gamma enhances presentation of the VIYQYMDDL epitope.
      Hence interplay between constitutive and IFN-gamma-inducible beta-subunits of the
      proteasome can qualitatively influence Ag presentation. These observations may
      have relevance to the patterns of immunodominance during the natural course of
      viral infection.

PMID- 10358151
TI  - Human virus-specific CD8+ CTL clones revert from CD45ROhigh to CD45RAhigh in
      vivo: CD45RAhighCD8+ T cells comprise both naive and memory cells.
AB  - It has been generally believed that human CD8+ memory cells are principally found
      within the CD45ROhigh population. There are high frequencies of CD8+ memory CTL
      specific for the human CMV tegument phosphoprotein pp65 in PBMC of long-term
      virus carriers; the large population of memory CTL specific for a given pp65
      peptide contains individual CTL clones that have greatly expanded. In this study,
      we found high frequencies of pp65 peptide-specific memory CTL precursors in the
      CD45ROhighCD45RA- population, but also appreciable frequencies in the CD45RAhigh
      subpopulation. Because the majority of CD8+ T cells in PBMC are CD45RAhigh, more
      of the total pp65-specific memory CTL pool is within the CD45RAhigh than in the
      CD45ROhigh compartment. Using clonotypic oligonucleotide probes to quantify the
      size of individual pp65-specific CTL clones in vivo, we found the CD45RAhigh
      population contributed 6- to 10-fold more than the CD45ROhigh population to the
      total virus-specific clone size in CD8+ cells. During primary CMV infection, an
      individual virus-specific CTL clone was initially CD45ROhigh, but after
      resolution of infection this clone was detected in both the CD45ROhigh and the
      CD45RAhigh populations. We conclude that CD45RA+ human CD8+ T cells do not solely
      comprise naive cells, but contain a very significant proportion of memory cells,
      which can revert from the CD45ROhigh to CD45RAhigh phenotype in vivo.

PMID- 10358152
TI  - CD19 amplifies B lymphocyte signal transduction by regulating Src-family protein
      tyrosine kinase activation.
AB  - Ligation of the B cell Ag receptor (BCR) induces cellular activation by
      stimulating Src-family protein tyrosine kinases (PTKs) to phosphorylate members
      of the BCR complex. Subsequently, Src-family PTKs, particularly Lyn, are proposed
      to phosphorylate and bind CD19, a cell-surface costimulatory molecule that
      regulates mature B cell activation. Herein, we show that B cells from CD19
      deficient mice have diminished Lyn kinase activity and BCR phosphorylation
      following BCR ligation. Tyrosine phosphorylation of other Src-family PTKs was
      also decreased in CD19-deficient B cells. In wild-type B cells, CD19 was
      constitutively complexed with Vav, Lyn, and other Src-family PTKs, with CD19
      phosphorylation and its associations with Lyn and Vav increased after BCR
      ligation. Constitutive CD19/Lyn/Vav complex signaling may therefore be
      responsible for the establishment of baseline signaling thresholds in B cells
      before Ag receptor ligation, in addition to accelerating signaling following BCR
      engagement or other transmembrane signals. In vitro kinase assays using purified
      CD19 and purified Lyn revealed that the kinase activity of Lyn was significantly
      increased when coincubated with CD19. Thus, constitutive and induced CD19/Lyn
      complexes are likely to regulate basal signaling thresholds and BCR signaling by
      amplifying the kinase activity of Lyn and other Src-family PTKs. These in vivo
      and in vitro findings demonstrate a novel mechanism by which CD19 regulates
      signal transduction in B lymphocytes. The absence of this CD19/Src-family kinase
      amplification loop may account for the hyporesponsive phenotype of CD19-deficient
      B cells.

PMID- 10358153
TI  - Protein kinase C activation inhibits tyrosine phosphorylation of Cbl and its
      recruitment of Src homology 2 domain-containing proteins.
AB  - One of the major proteins that is rapidly tyrosine phosphorylated upon
      stimulation of the TCR/CD3 complex is the 120-kDa product of the c-cbl
      protooncogene (Cbl). Upon activation, tyrosine-phosphorylated Cbl interacts with
      the Src homology 2 (SH2) domains of several signaling proteins, e.g.,
      phosphatidylinositol 3-kinase (PI3-K) and CrkL. In the present study, we report
      that pretreatment of Jurkat T cells with PMA reduced the anti-CD3-induced
      tyrosine phosphorylation of Cbl and, consequently, its activation-dependent
      association with PI3-K and CrkL. A specific protein kinase C (PKC) inhibitor (GF
      109203X) reversed the effect of PMA on tyrosine phosphorylation of Cbl and
      restored the activation-dependent association of Cbl with PI3-K and CrkL. We also
      provide evidence that PKCalpha and PKCtheta can physically associate with Cbl and
      are able to phosphorylate it in vitro and in vivo. Furthermore, a serine-rich
      motif at the C terminus of Cbl, which is critical for PMA-induced 14-3-3 binding,
      is also phosphorylated by PKCalpha and PKCtheta in vitro. These results suggest
      that, by regulating tyrosine and serine phosphorylation of Cbl, PKC is able to
      control the association of Cbl with signaling intermediates, such as SH2 domain
      containing proteins and 14-3-3 proteins, which may consequently result in the
      modulation of its function.

PMID- 10358154
TI  - New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF
      kappa B and AP-1 activation.
AB  - We had previously shown that the drug undecylprodigiosin (UP) blocks human
      lymphocyte proliferation in vitro. We have now investigated the mechanism of
      action of a new analogue of UP, PNU156804, which shows a more favorable activity
      profile than UP in mice. We demonstrate here that the biological effect of
      PNU156804 in vitro is indistinguishable from UP: PNU156804 blocks human T cell
      proliferation in mid-late G1, as determined by cell cycle analysis, expression of
      cyclins, and cyclin-dependent kinases and retinoblastoma phosphorylation. In
      addition, we show that PNU156804 does not block significantly the induction of
      either IL-2 or IL-2R alpha- and gamma-chains but inhibits IL-2-dependent T cell
      proliferation. We have investigated several molecular pathways that are known to
      be activated by IL-2 in T cells. We show that PNU156804 does not inhibit c-myc
      and bcl-2 mRNA induction. On the other hand, PNU156804 efficiently inhibits the
      activation of the NF-kappa B and AP-1 transcription factors. PNU156804 inhibition
      of NF-kappa B activation is due to the inhibition of the degradation of I kappa B
      alpha and I kappa B-beta. PNU156804 action is restricted to some signaling
      pathways; it does not affect NF-kappa B activation by PMA in T cells but blocks
      that induced by CD40 cross-linking in B lymphocytes. We conclude that the
      prodigiosin family of immunosuppressants is a new family of molecules that show a
      novel target specificity clearly distinct from that of other immunosuppressive
      drugs such as cyclosporin A, FK506, and rapamycin.

PMID- 10358155
TI  - p38 alpha mitogen-activated protein kinase is activated by CD28-mediated
      signaling and is required for IL-4 production by human CD4+CD45RO+ T cells and
      Th2 effector cells.
AB  - T cell proliferation and cytokine production usually require stimulation via both
      the TCR/CD3 complex and the CD28 costimulatory receptor. Using purified human
      CD4+ peripheral blood T cells, we show that CD28 stimulation alone activates p38
      alpha mitogen-activated protein kinase (p38 alpha). Cell proliferation induced by
      CD28 stimulation alone, a response attributed to CD4+CD45RO+ memory T cells, was
      blocked by the highly specific p38 inhibitors SB 203580 (IC50 = 10-80 nM) and RWJ
      67657 (IC50 = 0.5-4 nM). In contrast, proliferation induced by anti-CD3 plus anti
      CD28 mAbs was not blocked. Inhibitors of p38 also blocked CD4+ T cell production
      of IL-4 (SB 203580 IC50 = 20-100 nM), but not IL-2, in response to CD3 and CD28
      stimulation. IL-5, TNF-alpha, and IFN-gamma production were also inhibited, but
      to a lesser degree than IL-4. IL-4 production was attributed to CD4+CD45RO+ T
      cells, and its induction was suppressed by p38 inhibitors at the mRNA level. In
      polarized Th1 and Th2 cell lines, SB 203580 strongly inhibited IL-4 production by
      Th2 cells (IC50 = 10-80 nM), but only partially inhibited IFN-gamma and IL-2
      production by Th1 cells (<50% inhibition at 1 microM). In both Th1 and Th2 cells,
      CD28 signaling activated p38 alpha and was required for cytokine production.
      These results show that p38 alpha plays an important role in some, but not all,
      CD28-dependent cellular responses. Its preferential involvement in IL-4
      production by CD4+CD45RO+ T cells and Th2 effector cells suggests that p38 alpha
      may be important in the generation of Th2-type responses in humans.

PMID- 10358157
TI  - Inhibition of tyrosine kinase activation blocks the down-regulation of CXC
      chemokine receptor 4 by HIV-1 gp120 in CD4+ T cells.
AB  - Because the binding of HIV-1 envelope to CD4 initiates a configurational change
      in glycoprotein 120 (gp120), enabling it to interact with fusion coreceptors, we
      investigated how this process interferes with the expression and function of CXC
      chemokine receptor 4 (CXCR4) in CD4+ T lymphocytes. A recombinant gp120 (MN),
      after preincubation with CD4+ T lymphocytes, significantly inhibited the binding
      and chemotaxis of the cells in response to the CXCR4 ligand stromal cell-derived
      factor-1alpha (SDF-1alpha), accompanied by a markedly reduced surface expression
      of CXCR4. gp120, but not SDF-1alpha, induced rapid tyrosine phosphorylation of
      src-like kinase p56lck in CD4+ T cells, whereas both gp120 and SDF-1alpha caused
      phosphorylation of the CXCR4. The tyrosine kinase inhibitor herbimycin A
      abolished the phosphorylation of p56lck and CXCR4 induced by gp120 in association
      with maintenance of normal expression of cell surface CXCR4 and a migratory
      response to SDF-1alpha. Thus, a CD4-associated signaling molecule(s) including
      p56lck is activated by gp120 and is required for the down-regulation of CXCR4.

PMID- 10358156
TI  - Regulation of integrin-mediated T cell adhesion by the transmembrane protein
      tyrosine phosphatase CD45.
AB  - The transmembrane protein tyrosine phosphatase CD45 is required for Ag receptor
      signal transduction in lymphocytes. Recently, a role for CD45 in the regulation
      of macrophage adhesion has been demonstrated as well. To investigate further the
      role of CD45 in the regulation of adhesion, we examined integrin-mediated
      adhesion to fibronectin of two T cell lines and their CD45-deficient variants.
      The absence of CD45 correlated with enhanced adhesion to fibronectin via integrin
      alpha5beta1 (VLA-5), but not alpha4beta1 (VLA-4) in both cell lines. Adhesion
      returned to normal levels upon transfection of wild-type CD45 into the CD45
      deficient lines. Transfection of chimeric or mutant molecules expressing some,
      but not all, CD45 domains and activities demonstrated that both the transmembrane
      domain and the tyrosine phosphatase activity of CD45 were required for regulation
      of integrin-dependent adhesion, but the highly glycosylated extracellular domain
      was dispensable. In contrast, only a catalytically active CD45 cytoplasmic domain
      was required for TCR signaling. Transfectants that restored normal levels of
      adhesion to fibronectin coimmunoprecipitated with the transmembrane protein known
      as CD45-associated protein. These studies demonstrate a novel role for CD45 in
      adhesion regulation and suggest a possible function for its association with CD45
      associated protein.

PMID- 10358158
TI  - Perturbed regulation of ZAP-70 and sustained tyrosine phosphorylation of LAT and
      SLP-76 in c-Cbl-deficient thymocytes.
AB  - Recent studies indicate that c-Cbl and its oncogenic variants can modulate the
      activity of protein tyrosine kinases. This finding is supported by studies
      showing that c-Cbl interacts directly with a negative regulatory tyrosine in ZAP
      70, and that the levels of tyrosine-phosphorylated ZAP-70 and numerous other
      proteins are increased in TCR-stimulated thymocytes from c-Cbl-deficient mice.
      Here, we demonstrate that this enhanced phosphorylation of ZAP-70 and that of two
      substrates, LAT and SLP-76, is not due to altered protein levels but is the
      consequence of two separate events. First, we find increased expression of
      tyrosine-phosphorylated TCRzeta chain in c-Cbl-deficient thymocytes, which
      results in a higher level of zeta-chain-associated ZAP-70 that is initially
      accessible for activation. Thus, more ZAP-70 is activated and more of its
      substrates (LAT and SLP-76) become tyrosine-phosphorylated after TCR stimulation.
      However, an additional mechanism of ZAP-70 regulation is evident at a later time
      poststimulation. At this time, ZAP-70 from both normal and c-Cbl-/- thymocytes
      becomes hyperphosphorylated; however, only in normal thymocytes does this
      correlate with ZAP-70 down-regulation and a diminished ability to phosphorylate
      LAT and SLP-76. In contrast, c-Cbl-deficient thymocytes display altered
      phosphorylation kinetics, for which LAT phosphorylation is increased and SLP-76
      phosphorylation is sustained. Thus, the ability to down-regulate the
      phosphorylation of two ZAP-70 substrates is impaired in c-Cbl-/- thymocytes.
      These findings provide evidence that c-Cbl is involved in the negative regulation
      of the phosphorylation of LAT and SLP-76 by ZAP-70.

PMID- 10358160
TI  - Therapeutic protective effects of IL-12 combined with soluble IL-4 receptor
      against established infections of herpes simplex virus type 1 in thermally
      injured mice.
AB  - The effect of combination therapy between IL-12 and soluble IL-4R (sIL-4R) on the
      established infection of HSV-1 in thermally injured mice (TI mice) was
      investigated. All of the TI mice infected with lethal amounts of HSV-1 died when
      IL-12 was given therapeutically at a dose of 500 U/mouse. However, 80% of these
      mice treated prophylactically with IL-12 survived compared with 0% survival of
      the same mice treated with saline. The therapeutic administration of IL-12 to TI
      mice currently infected with HSV-1 caused an 80% survival of these mice when the
      treatment was combined with sIL-4R. Although IL-12 did not stimulate IFN-gamma
      production in cultures of splenic T cells from TI mice, IFN-gamma was produced by
      stimulation with IL-12 when the producer cells were prepared from TI mice that
      had been treated previously with sIL-4R. After stimulation with anti-CD3 mAb,
      splenic T cells from TI mice with the established infection of HSV-1 produced IL
      4 into their culture fluids. However, IL-4 was not produced by splenic T cells
      that were prepared from the same infected mice treated with IL-12 and sIL-4R in
      combination. The results obtained herein indicate that the efficacies of the
      combination therapy against the established infection of HSV-1 may result from
      the IFN-gamma production stimulated by IL-12 in TI mice that are treated with sIL
      4R for reducing burn-associated type 2 T cell responses.

PMID- 10358159
TI  - Crosstalk between keratinocytes and T lymphocytes via Fas/Fas ligand interaction:
      modulation by cytokines.
AB  - Apoptosis mediated by Fas/FasL interaction plays an important role during many
      inflammatory skin disorders. To estimate whether the expression of FasL, the
      ligand for Fas, might be regulated by cytokines we stimulated primary human
      keratinocytes with several pro- and anti-inflammatory cytokines. Keratinocytes
      cultured to subconfluence expressed FasL constitutively. Cells stimulated with
      the proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and IL-15,
      respectively, increased significantly their intracellular as well as cell surface
      bound FasL expression in a time- and dose-dependent manner. This cytokine-induced
      FasL expression was dependent on new protein synthesis. Despite enhanced
      expression of cell surface-bound FasL, no release of soluble FasL was measured in
      the cell supernatants determined by ELISA. Stimulation of the cells with IL-6, IL
      10, IL-12, TGF-beta1, and GM-CSF did not modulate the constitutive FasL
      expression, but IFN-gamma-mediated FasL up-regulation was significantly
      diminished by IL-10 and TGF-beta1, respectively. Up-regulation of FasL on IFN
      gamma-stimulated keratinocytes led to increased apoptosis within monolayers
      cultured for 48 h. Moreover, coculture experiments performed with Fas+ Jurkat T
      cells revealed that enhanced FasL expression on IFN-gamma-stimulated
      keratinocytes induced apoptosis in cocultured T cells, demonstrating that up
      regulated FasL was functionally active. In summary, our data suggest the
      important regulatory role of cytokine-controlled Fas/FasL interaction in the
      cross-talk between keratinocytes and skin-infiltrating T cells for maintenance of
      homeostasis in inflammatory skin processes.

PMID- 10358161
TI  - Identification of peptide superagonists for a self-K-ras-reactive CD4+ T cell
      clone using combinatorial peptide libraries and mass spectrometry.
AB  - The proliferative responses of a human CD4+ T cell clone 29.15.2, reactive with a
      self-K-ras-derived peptide (3EYKLVVVGAGGVGKSALT20), were tested using a set of X9
      combinatorial peptide libraries containing the flanking residues
      (EYKLVXXXXXXXXXSALT, where X indicates random amino acids). Certain peptide
      libraries, such as EYKLVXXXXXX<cmd UNL>M<cmd /UNL> XXSALT and EYKLVXXXXXXX<cmd
      UNL>H<cmd /UNL> XSALT, stimulated a marked proliferation of 29.15.2. However, no
      combinations of substitutions tested, such as EYKLVXXXXXX<cmd UNL>MH<cmd /UNL>
      XSALT, exhibited additive effects. We subsequently synthesized peptides with
      degenerate sequences (a mixture of 480 species), where each position is composed
      of the wild-type (wt) residue or of amino acids that induced the proliferation of
      29.15.2, in positional scanning. Interestingly, one fraction of degenerate
      peptides, separated by reverse-phase HPLC, stimulated much higher proliferation
      than did the wt; in addition, the retention time of this fraction was distinct
      from that of the wt. Mass spectrometry analysis of this fraction and flanking
      fractions identified five peptide species that exhibit strong signals in a manner
      that parallels the antigenic activity. Finally, 17 candidate peptide sequences
      were deduced from mass spectrometry and hydrophobicity scoring results, of which
      two peptides (EYKLVVVGAGG<cmd UNL>ML<cmd /UNL> KSALT and EYKLVVVGAGG<cmd
      UNL>MI<cmd /UNL> KSALT) did induce 52- and 61-fold stronger proliferation,
      respectively, compared with the wt. These findings indicate that: 1) synthetic
      peptides that carry "the best" residue substitution at each position of
      combinatorial peptide libraries do not always exhibit superagonism, and 2) such a
      drawback can be overcome with the use of mass spectrometry. This approach
      provides new perspectives for the accurate and efficient identification of
      peptide superagonists.

PMID- 10358162
TI  - Protection against CD95-mediated apoptosis by inorganic mercury in Jurkat T
      cells.
AB  - Dysregulation of CD95/Fas-mediated apoptosis has been implicated as a
      contributing factor in autoimmune disorders. Animal studies clearly have
      established a connection between mercury exposure and autoimmune disease in
      rodents, while case reports have suggested a link between accidental mercury
      contamination and autoimmune disease in humans. The mechanism(s) for these
      associations are poorly understood. Using the Jurkat cell model, we have found
      that low levels (</=10 microM) of inorganic mercury (i.e., HgCl2) attenuated anti
      CD95-mediated growth arrest and markedly enhanced cell survival. Several
      biochemical assays for apoptosis, including DNA degradation, poly(ADP-ribose)
      polymerase degradation, and phosphatidylserine externalization, directly verified
      that HgCl2 attenuated anti-CD95-mediated apoptosis. In an attempt to further
      characterize the effect of mercury on CD95-mediated apoptosis, several signaling
      components of the CD95 death pathway were analyzed to determine whether HgCl2
      could modulate them. HgCl2 did not modulate CD95 expression; however, it did
      block CD95-induced caspase-3 activation. HgCl2 was not able to attenuate TNF
      alpha-mediated apoptosis in U-937 cells, or ceramide-C6-mediated apoptosis in
      Jurkat cells, suggesting that mercury acts upstream of, or does not involve,
      these signals. Thus, inorganic mercury specifically attenuates CD95-mediated
      apoptosis likely by targeting a signaling component that is upstream of caspase-3
      activation and downstream of CD95.

PMID- 10358163
TI  - MHC class II antigen processing in B cells: accelerated intracellular targeting
      of antigens.
AB  - Processing and presentation by Ag-specific B cells is initiated by Ag binding to
      the B cell Ag receptor (BCR). Cross-linking of the BCR by Ag results in a rapid
      targeting of the BCR and bound Ag to the MHC class II peptide loading compartment
      (IIPLC). This accelerated delivery of Ag may be essential in vivo during periods
      of rapid Ag-driven B cell expansion and T cell-dependent selection. Here, we use
      both immunoelectron microscopy and a nondisruptive protein chemical
      polymerization method to define the intracellular pathway of the targeting of Ags
      by the BCR. We show that following cross-linking, the BCR is rapidly transported
      through transferrin receptor-containing early endosomes to a LAMP-1+, beta
      hexosaminadase+, multivesicular compartment that is an active site of peptide
      class II complex assembly, containing both class II-invariant chain complexes in
      the process of invariant chain proteolytic removal as well as mature peptide
      class II complexes. The BCR enters the class II-containing compartment as an
      intact mIg/Igalpha/Igbeta complex bound to Ag. The pathway by which the BCR
      targets Ag to the IIPLC appears not to be identical to that by which Ags taken up
      by fluid phase pinocytosis traffick, suggesting that the accelerated BCR pathway
      may be specialized and potentially independently regulated.

PMID- 10358164
TI  - CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular
      regulated kinase activation, leading to cytotoxic function of human NK cells.
AB  - The CD94/NKG2-A complex is the inhibitory receptor for the nonclassical MHC class
      I molecule HLA-E on human NK cells. Here we studied the molecular mechanisms
      underlying the inhibitory activity of CD94/NKG2-A on NK cell functions by
      analyzing its interference on CD16-initiated signaling pathways involved in the
      control of cytolytic activity. Both tyrosine phosphorylation and activation of
      Syk kinase together with tyrosine phosphorylation of CD16 receptor zeta subunit
      are markedly inhibited by the coengagement of CD94/NKG2-A complex. As a
      downstream consequence, CD94/NKG2-A cross-linking impairs the CD16-induced
      activation of extracellular regulated kinases (ERKs), a pathway involved in NK
      cytotoxic function. The block of ERK activation is exerted at an early, PTK
      dependent stage in the events leading to p21ras activation, as the CD16-induced
      tyrosine phosphorylation of Shc adaptor protein and the formation of Shc/Grb-2
      complex are abrogated by CD94/NKG2-A simultaneous engagement. Our observations
      indicate that CD94/NKG2-A inhibits the CD16-triggered activation of two signaling
      pathways involved in the cytotoxic activity of NK cells. They thus provide
      molecular evidence to explain the inhibitory function of CD94/NKG2-A receptor on
      NK effector functions.

PMID- 10358165
TI  - Experimental autoimmune myasthenia gravis may occur in the context of a polarized
      Th1- or Th2-type immune response in rats.
AB  - Experimental autoimmune myasthenia gravis (EAMG) is a T cell-dependent, Ab
      mediated autoimmune disease induced in rats by a single immunization with
      acetylcholine receptor (AChR). Although polarized Th1 responses have been shown
      to be crucial for the development of mouse EAMG, the role of Th cell subsets in
      rat EAMG is not well established. In the present work we show that while the
      incidence and severity of EAMG are similar in Lewis (LEW) and Brown-Norway (BN)
      rats, strong differences are revealed in the immune response generated. Ag
      specific lymph node cells from LEW rats produced higher amounts of IL-2 and IFN
      gamma than BN lymph node cells, but expressed less IL-4 mRNA. IgG1 and IgG2b anti
      AChR isotype predominated in BN and LEW rats, respectively, confirming the
      dichotomy of the immune response observed between the two strains. Furthermore,
      although IL-12 administration or IFN-gamma neutralization strongly influenced the
      Th1/Th2 balance in BN rats, it did not affect the disease outcome. These data
      demonstrate that a Th1-dominated immune response is not necessarily associated
      with disease severity in EAMG, not only in rats with disparate MHC haplotype but
      also in the same rat strain, and suggest that in a situation where complement
      fixing Ab can be generated as a consequence of either Th1- or Th2-mediated T cell
      help, deviation of the immune response will not be an adequate strategy to
      prevent this Ab-mediated autoimmune disease.

PMID- 10358166
TI  - IgMhighCD21high lymphocytes enriched in the splenic marginal zone generate
      effector cells more rapidly than the bulk of follicular B cells.
AB  - Ag encounter will recruit Ag-specific cells from the pool of mature B lymphocytes
      in the spleen and activate them to perform effector functions: generation of Ab
      forming cells (plasma cells) and presentation of Ag to T cells. We have compared
      the ability of mature follicular and marginal zone cells to develop into effector
      B cells. The generation of marginal zone B cells and their localization in the
      marginal sinus area are T cell and CD40 ligand independent, suggesting that they
      do not represent a postgerminal center population. Compared with mature
      recirculating follicular B cells, they express several characteristics of
      previous antigenic experience, including higher levels of B7.1 (CD80) and B7.2
      (CD86) when freshly isolated and following in vitro stimulation. After a brief 6-
      to 8-h in vitro stimulation with LPS or anti-CD40 Abs, marginal zone B cells
      become potent APCs. In addition, their ability to proliferate and differentiate
      into plasma cells in response to low doses of T-independent polyclonal stimuli
      (LPS) is far greater than that of follicular B cells. These findings indicate a
      functional heterogeneity within splenic mature B lymphocytes, with marginal zone
      B cells having the capacity to generate effector cells in early stages of the
      immune response against particulate Ags scavenged efficiently in this special
      anatomical site.

PMID- 10358167
TI  - TCR-mediated involvement of CD4+ transgenic T cells in spontaneous inflammatory
      bowel disease in lymphopenic mice.
AB  - Spontaneous colitis resembling ulcerative colitis developed in 3 of 10
      independent TCR transgenic (Tg) mouse lines maintained under specific pathogen
      free conditions. All three susceptible lines were CD4 lymphopenic, whereas
      resistant lines had normal numbers of CD4+ T cells. Thus, cytochrome c-specific
      5C.C7 TCR Tg mice developed colitis only when crossed onto a SCID- or Rag-1
      deficient background. A second line of lymphopenic cytochrome c-specific Tg mice
      bearing the AND TCR also developed colitis. In both cases, CD4+ T cells
      expressing the Tg-encoded TCR were preferentially activated in inflamed colons
      compared with lymph nodes or spleens. In contrast, Tg+CD4+ T cells remained
      quiescent in both inflamed and unaffected colons in another line of susceptible
      Tg mice carrying a TCR specific for myelin basic protein, suggesting a fortuitous
      cross-reactivity of the IEk-restricted cytochrome c-reactive AND and 5C.C7 TCRs
      with an Ag present in the gut. The percentage of CD4+ T cells expressing only
      endogenous TCR alpha-chains was increased consistently in inflamed colons in AND
      as well as 5C.C7 Rag-1-/- TCR Tg mice, suggesting that polyclonal CD4+ T cells
      were also involved in the pathogenesis of spontaneous colitis. Moreover, our data
      indicate that some alpha-chain rearrangement was still occurring in TCR Tg mice
      on a Rag-1-/- background, since activated CD4+ T cells expressing endogenously
      rearranged alpha-chains paired with the Tg-encoded beta-chain were detected
      consistently in the colons of such mice.

PMID- 10358168
TI  - TNF-alpha-mediated apoptosis is initiated in caveolae-like domains.
AB  - Caveolae-like domains (CLDs) have been hypothesized to mediate apoptosis, since
      they contain sphingomyelin and initiate the conversion of sphingomyelin to
      ceramide. To address whether CLDs are directly involved in apoptosis, CLDs from
      U937 cells were isolated, taking advantage of their detergent insolubility and
      low density. The CLDs contained alkaline phosphatase as well as many signaling
      molecules, including Fyn, protein kinase Calpha, Raf-1, phospholipase Cgamma1,
      and tyrosine phosphoproteins. Immunoblotting and immunofluorescent data showed
      that TNF receptor 1 colocalized with CD36 in CLDs, suggesting that TNF-alpha
      initiated apoptosis occurs in CLDs. When cells were incubated with lipoprotein
      deficient medium, the cholesterol concentration was greatly decreased in CLDs but
      not in other fractions, implying that the CLDs were selectively disrupted. In the
      CLD-disrupted cells, the surface expression of TNF receptor 1 and CD36 was
      significantly reduced. Analysis of cellular morphology, percent DNA
      fragmentation, DNA laddering, and caspase-3 activity showed that TNF-alpha
      mediated apoptosis was blocked in CLD-disrupted cells, whereas anti-Fas-mediated
      apoptosis was not. Since Fas was not found in CLDs of Jurkat cells, apoptosis by
      Fas ligation might not require CLDs. Taken together, these data strongly imply
      that TNF-alpha-mediated apoptosis is initiated in CLDs.

PMID- 10358169
TI  - Fyn membrane localization is necessary to induce the constitutive tyrosine
      phosphorylation of Sam68 in the nucleus of T lymphocytes.
AB  - A close relationship between Sam68, a tyrosine and proline-rich RNA-binding
      protein, and Src protein tyrosine kinases (PTK) has already been established,
      also in T lymphocytes. A constitutive phosphorylation of the molecule has also
      been documented in various transformed T cells, which probably reflects an
      increased expression of PTK of the Src family. Using the hybridoma T cell line,
      T8.1, or Jurkat T cells, we investigated the respective contribution of the two
      Src kinases Fyn and Lck, expressed in T cells, in this phenomenon. By
      overexpressing the two proteins, we show that the constitutive phosphorylation of
      Sam68 in vivo directly correlates with cellular Fyn levels, but not with Lck
      expression, despite the capacity of the PTK to strongly phosphorylate the
      molecule in vitro. Overexpressed Fyn is mainly localized at the cell membrane. We
      find that Sam68 phosphorylation, including in the nuclear fraction in which the
      molecule is predominantly expressed, is lost with a delocalized Fyn mutant
      deleted of its N-terminal membrane-anchoring domain. Finally, we demonstrate,
      using a construct encoding a Sam68 molecule without its nuclear localization
      signal, that nuclear expression of Sam68 is not required for phosphorylation. We
      conclude that the constitutive phosphorylation of Sam68 in T cells is a Fyn
      dependent process occurring in a cell-membrane compartment from which phospho
      Sam68 molecules can thereafter accumulate into the nucleus.

PMID- 10358170
TI  - Extinction of IL-12 signaling promotes Fas-mediated apoptosis of antigen-specific
      T cells.
AB  - In previous studies we have shown that peripheral tolerance achieved by high dose
      feeding of OVA to intact OVA-TCR transgenic mice was enhanced when endogenous IL
      12 was neutralized simultaneously. To generalize this phenomenon, in the present
      study we investigated the tolerogenic mechanisms underlying the blockade of IL-12
      signaling following oral and systemic Ag delivery. We found that the numbers of
      Ag-specific T cells in several lymphoid organs were significantly reduced due to
      T cell apoptosis following oral OVA or systemic OVA administration when combined
      with anti-IL-12 injection, but there was no decrease in T cell numbers for OVA
      fed, OVA-injected, or anti-IL-12 alone-treated mice compared with those in
      untreated control mice. In addition, mostly Fas+ T cells were subject to
      apoptotic deletion in the OVA- plus anti-IL-12-treated groups, and an enhanced
      cell death of T cells upon OVA restimulation in vitro could be partially reversed
      by blockade of the Fas/Fas ligand interaction. Finally, in a murine model of
      superantigen-driven T cell expansion and deletion, we observed no deletional
      effects of anti-IL-12 treatment on CD4+ cells in Fas-deficient (MRL/lpr) mice,
      but did find these effects in MRL wild-type mice. In summary, our data suggest
      that in the course of Ag-induced cell proliferation of Th1 cells, signaling
      through IL-12 is required to prevent an induction of Fas-mediated apoptosis.
      Thus, the use of anti-IL-12 may be potentially useful in modulating peripheral
      immune responses by promotion of Fas-mediated cell death.

PMID- 10358171
TI  - A central role for alpha beta T cells in the pathogenesis of murine lupus.
AB  - We have previously shown that female transgenic mice expressing IFN-gamma in the
      epidermis, under the control of the involucrin promoter, develop inflammatory
      skin disease and a form of murine lupus. To investigate the pathogenesis of this
      syndrome, we generated female IFN-gamma transgenic mice congenitally deficient in
      either alpha beta or gamma delta T cells. TCR delta-/- transgenics continued to
      produce antinuclear autoantibodies and to develop severe kidney lesions. In
      contrast, TCR beta-/- IFN-gamma transgenic mice failed to produce antinucleosome,
      anti-dsDNA, or antihistone autoantibodies, and kidney disease was abolished. Both
      alpha beta- and gamma delta-deficient transgenics continued to develop IFN-gamma
      associated skin disease, lymphadenopathy, and splenomegaly. The data show that
      the autoantibody-mediated pathology of murine lupus in IFN-gamma transgenic mice
      is completely alpha beta T cell dependent and that gamma delta T cells cannot
      drive autoantibody production. These results imply that production of antinuclear
      autoantibodies in IFN-gamma transgenic animals is Ag driven, and we identified
      clusters of apoptotic cells in the epidermis of the mice as a possible source of
      self Ags. Our findings emphasize the relevance of this murine lupus model to the
      human disease.

PMID- 10358172
TI  - The promoter of the C1 inhibitor gene contains a polypurine.polypyrimidine
      segment that enhances transcriptional activity.
AB  - The C1 inhibitor (C1INH) promoter is unusual in two respects: 1) It contains no
      TATA sequence, but instead contains a TdT-like initiator element (Inr) at
      nucleotides -3 to +5; 2) it contains a polypurine.polypyrimidine tract between
      nucleotides -17 and -45. Disruption of the Inr by the introduction of point
      mutations reduced promoter activity by 40%. A TATA element inserted at nucleotide
      -30 in the wild-type promoter and in promoter constructs containing the mutated
      Inr led to a 2-fold increase in basal promoter activity. Previous studies
      suggested that the potential hinged DNA-forming polypurine.polypyrimidine tract
      might be important in the regulation of C1INH promoter activity. The present
      studies indicate that this region is capable of such intramolecular triple helix
      formation. Disruption of the polypurine.polypyrimidine sequence by substitution
      of 5 of the 23 cytosine residues with adenine prevented triple helix formation.
      Site-directed mutagenesis experiments demonstrate that the regulation of promoter
      activity is independent of hinged DNA-forming capacity but requires an intact AC
      box (ACCCTNNNNNACCCT) or the overlapping PuF binding site (GGGTGGG). The C1INH
      gene also contains a number of potential regulatory elements, including an Sp-1
      and an hepatocyte nuclear factor-1 binding site and a CAAT box. The role of these
      elements in regulation of the C1INH promoter was examined. Elimination of the
      hepatocyte nuclear factor-1 site at nucleotides -94 to -81 by truncation reduced
      the activity of the promoter by approximately 50%. Similarly, site-directed
      mutations that disrupt this site reduce promoter activity by 70%.

PMID- 10358173
TI  - IL-12 induces IFN regulating factor-1 (IRF-1) gene expression in human NK and T
      cells.
AB  - IL-12 is a critical immunoregulatory cytokine that promotes cell-mediated immune
      responses and the differentiation of naive CD4+ cells to Th1 cells; however,
      relatively few IL-12 target genes have been identified. To better clarify the
      molecular basis of IL-12 action, we set out to characterize genes up-regulated by
      IL-12, first by contrasting IL-12- and IFN-alpha-inducible genes. We identified
      several genes up-regulated by IL-12, namely, MIP-1alpha, MIP-1beta, IL-1RA, and
      IFN regulatory factor-1 (IRF-1). IRF-1 is a transcription factor regulated by
      IFNs that is also essential for Th1 responses. We demonstrated that IL-12
      directly up-regulates IRF-1 to the same extent as IFN-alpha in normal human T
      cells and in NK cells. We showed that IL-12 had a direct effect on IRF-1, an
      effect not mediated indirectly by the induction of IFN-gamma production.
      Furthermore, IL-2 and IL-12 synergistically induced IRF-1, whereas IFN-alpha and
      IL-12 did not. The participation of STAT4 in the regulation of IRF-1 was
      demonstrated in two ways. First, STAT4 was required for the IL-12-dependent
      transactivation of an IRF-1 reporter construct, and second, STAT4 binding to the
      IRF-1 promoter was shown using EMSA. In contrast to IL-12, no up-regulation of
      IRF-1 was found in IL-4-stimulated cells, and IL-4 did not block IL-12-dependent
      up-regulation of IRF-1. Therefore, IRF-1 may be an important contributor to IL-12
      signaling, and we speculate that the defective IL-12 responses seen in IRF-1-/-
      mice might be attributable, in part, to the absence of this transcription factor.

PMID- 10358175
TI  - Recognition of class I MHC by NK receptor Ly-49C: identification of critical
      residues.
AB  - The Ly-49 family of inhibitory receptors plays a major role in regulating mouse
      NK cell cytotoxicity. Two of its members, Ly-49C and I, are recognized by the mAb
      5E6, which also defines a subset of NK cells involved in the hybrid resistance
      phenomenon. Previous studies have shown that Ly-49C binds to a broad spectrum of
      class I MHC molecules, while Ly-49I apparently does not bind to any class I MHC
      molecules tested. In the present investigation we have defined the amino acid
      residues of Ly-49C that are critical for determining its ligand specificities.
      First, using quantitative COS cell adhesion assays, we demonstrated that Ly-49CB6
      bound to Dd, Db, Kb, or Kk as well as to murine leukemic cell lines GM979 (H-2s)
      and IC-21 (H-2b). In contrast, COS cells expressing Ly-49IB6 did not
      significantly bind to any of the class I MHC tested. To determine which amino
      acid residues of Ly-49C are critical for their specific binding to class I MHC, a
      series of chimeric and mutant Ly-49C and I were generated and tested. Exchanging
      the critical residues between Ly-49C and I significantly affected their binding
      specificities. Finally, we identified the epitopes on Ly-49C recognized by mAbs
      5E6 and 4LO3311 that functionally inhibit Ly-49C recognition of its ligands.
      These results further define the class I specificities of Ly-49C and provide
      insight into the structural basis for how class I MHC is recognized by the Ly-49
      family of NK receptors.

PMID- 10358174
TI  - Single amino acid replacements in an antigenic peptide are sufficient to alter
      the TCR V beta repertoire of the responding CD8+ cytotoxic lymphocyte population.
AB  - Cytotoxic CD8+ T lymphocytes are activated upon the engagement of their Ag
      specific receptors by MHC class I molecules loaded with peptides 8-11 amino acids
      long. T cell responses triggered by certain antigenic peptides are restricted to
      a limited number of TCR V beta elements. The precise role of the peptide in
      causing this restricted TCR V beta expansion in vivo remains unclear. To address
      this issue, we immunized C57BL/6 mice with the immunodominant peptide of the
      vesicular stomatitis virus (VSV) and several peptide variants carrying single
      substitutions at TCR-contact residues. We observed the expansion of a limited set
      of TCR V beta elements responding to each peptide variant. To focus our analysis
      solely on the TCR beta-chain, we created a transgenic mouse expressing
      exclusively the TCR alpha-chain from a VSV peptide-specific CD8+ T cell clone.
      These mice showed an even more restricted TCR V beta usage consequent to peptide
      immunization. However, in both C57BL/6 and TCR alpha transgenic mice, single
      amino acid replacements in TCR-contact residues of the VSV peptide could alter
      the TCR V beta usage of the responding CD8+ T lymphocytes. These results provide
      in vivo evidence for an interaction between the antigenic peptide and the
      germline-encoded complementarity-determining region-beta loops that can influence
      the selection of the responding TCR repertoire. Furthermore, only replacements at
      residues near the C terminus of the peptide were able to alter the TCR V beta
      usage, which is consistent with the notion that the TCR beta-chain interacts in
      vivo preferentially with this region of the MHC/peptide complex.

PMID- 10358176
TI  - HLA-B15 peptide ligands are preferentially anchored at their C termini.
AB  - Therapies to elicit protective CTL require the selection of pathogen- and tumor
      derived peptide ligands for presentation by MHC class I molecules. Edman
      sequencing of class I peptide pools generates "motifs" that indicate that
      nonameric ligands bearing conserved position 2 (P2) and P9 anchors provide the
      optimal search parameters for selecting immunogenic epitopes. To determine how
      well a motif represents its individual constituents, we used a hollow-fiber
      peptide production scheme followed by the mapping of endogenously processed class
      I peptide ligands through reverse-phase HPLC and mass spectrometry.
      Systematically mapping and characterizing ligands from B*1508, B*1501, B*1503,
      and B*1510 demonstrate that the peptides bound by these B15 allotypes i) vary in
      length from 7 to 12 residues, and ii) are more conserved at their C termini than
      their N-proximal P2 anchors. Comparative peptide mapping of these B15 allotypes
      further pinpoints endogenously processed ligands that bind to the allotypes
      B*1508, B*1501, and B*1503, but not B*1510. Overlapping peptide ligands are
      successful in binding to B*1501, B*1503, and B*1508 because these B15 allotypes
      share identical C-terminal anchoring pockets whereas B*1510 is divergent in the C
      terminal pocket. Therefore, endogenous peptide loading into the B15 allotypes
      requires that a conserved C terminus be anchored in the appropriate specificity
      pocket while N-proximal anchors are more flexible in their location and sequence.
      Queries for overlapping and allele-specific peptide ligands may thus be
      contingent on a conserved C-terminal anchor.

PMID- 10358177
TI  - Generation of recombinant fragments of CD11b expressing the functional beta
      glucan-binding lectin site of CR3 (CD11b/CD18).
AB  - CR3 (Mac-1; alphaMbeta2 integrin) functions as both a receptor for the opsonic
      iC3b fragment of C3 triggering phagocytosis or cytotoxicity and an adhesion
      molecule mediating leukocyte diapedesis. Recent reports have suggested that a CR3
      lectin site may be required for both cytotoxic responses and adhesion. Cytotoxic
      responses require dual recognition of iC3b via the I domain of CD11b and specific
      microbial surface polysaccharides (e.g., beta-glucan) via a separate lectin site.
      Likewise, adhesion requires a lectin-dependent membrane complex between CR3 and
      CD87. To characterize the lectin site further, a recombinant baculovirus (rBv)
      system was developed that allowed high level expression of rCD11b on membranes
      and in the cytoplasm of Sf21 insect cells. Six rBv were generated that contained
      truncated cDNA encoding various CD11b domains. Immunoblotting of rBv-infected
      Sf21 cells showed that some native epitopes were expressed by five of six rCD11b
      fragments. Lectin activity of rCD11b proteins was evaluated by both flow
      cytometry with beta-glucan-FITC and radioactive binding assays with [125I]beta
      glucan. Sf21 cells expressing rCD11b that included the C-terminal region, with or
      without the I-domain, exhibited lectin activity that was inhibited by unlabeled
      beta-glucan or anti-CR3 mAbs. The smallest rCD11b fragment exhibiting lectin
      activity included the C-terminus and part of the divalent cation binding region.
      The beta-glucan binding affinities of the three C-terminal region-containing
      rCD11bs expressed on Sf21 cell membranes were not significantly different from
      each other and were similar to that of neutrophil CR3. These data suggest that
      the lectin site may be located entirely within CD11b, although lectin site
      dependent signaling through CD18 probably occurs with the heterodimer.

PMID- 10358178
TI  - Multiple NF-ATc isoforms with individual transcriptional properties are
      synthesized in T lymphocytes.
AB  - The transcription factor NF-ATc that controls gene expression in T lymphocytes
      and embryonic cardiac cells is expressed in three prominent isoforms. This is due
      to alternative splice/polyadenylation events that lead to the predominant
      synthesis of two long isoforms in naive T cells and a shorter NF-ATc isoform in
      effector T cells. Whereas the previously described isoform NF-ATc/A contains a
      relatively short C terminus, the longer isoforms, B and C, span extra C-terminal
      peptides of 128 and 246 aa, respectively. We show here that in addition to the
      strong N-terminal trans-activation domain, TAD-A, which is common to all three NF
      ATc isoforms, NF-ATc/C contains a second trans-activation domain, TAD-B, in its C
      terminal peptide. Various stimuli of T cells that induce the activity of TAD-A
      also enhance the activity of TAD-B, but, unlike TAD-A, TAD-B remains
      unphosphorylated by protein from 12-O-tetradecanoyl 12-phorbol 13-acetate
      stimulated T cells. The shorter C-terminal peptide of isoform NF-ATc/B exerts a
      suppressive transcriptional effect. These properties of NF-ATc/B and -C might be
      of importance for gene regulation in naive T lymphocytes in which NF-ATc/B and -C
      are predominantly synthesized.

PMID- 10358179
TI  - Differences between IL-4- and IL-4 receptor alpha-deficient mice in chronic
      leishmaniasis reveal a protective role for IL-13 receptor signaling.
AB  - IL-4 receptor alpha-chain-deficient (IL-4Ralpha-/-) mice were generated by
      homologous and site-specific recombination, using the Cre/loxP system in BALB/c
      derived embryonic stem cells. In vitro analysis of cells from these mice revealed
      impaired IL-4- and IL-13-mediated functions, demonstrating that the IL-4Ralpha
      chain is an essential component of both the IL-4 and the IL-13 receptor. Whereas
      Leishmania major-infected BALB/c mice developed fatal progressive disease with
      type 2 Ab responses within 3 mo, both IL-4Ralpha-/- and IL-4-/- BALB/c mice
      contained infection with reduced footpad swelling, parasite load, moderate
      histopathology, and type 1 Ab responses during this time period. Conclusively,
      these results demonstrate an IL-4-dependent mechanism of susceptibility in BALB/c
      mice. Nevertheless, in contrast to mutant mice, infected C57BL/6 mice healed
      completely within 3 mo, indicating that additional factors are necessary for
      subsequent healing and elimination of the pathogen. During the further course of
      infection, IL-4Ralpha-/- mice developed progressive disease with massive footpad
      swelling. Lesions became ulcerative and necrotic with subsequent destruction of
      connective tissue and bones, as well as dissemination into organs and consequent
      mortality within the monitored 6 mo of chronic infection. In striking contrast,
      IL-4-/- mice maintained control of infection on a moderate level, but were unable
      to clear the pathogen. The distinct phenotypes of the BALB/c embryonic stem cell
      derived IL-4-/- and IL-4Ralpha-/- mouse strains identify previously unsuspected
      mechanisms for maintaining host immunity to chronic infection with L. major,
      mediated by a functional IL-13 receptor.

PMID- 10358180
TI  - Absolute requirement for an active immune response involving B cells and Th cells
      in immunity to Plasmodium yoelii passively acquired with antibodies to the 19-kDa
      carboxyl-terminal fragment of merozoite surface protein-1.
AB  - Vaccination of mice with the leading malaria vaccine candidate homologue, the 19
      kDa carboxyl terminus of merozoite surface protein-1 (MSP119), results in sterile
      immunity to Plasmodium yoelii, with no parasites detected in blood. Although such
      immunity depends upon high titer Abs at challenge, high doses of immune sera
      transferred into naive mice reduce parasitemia (and protect from death) but do
      not result in a similar degree of protection (with most mice experiencing high
      peak parasitemias); this finding suggests that ongoing parasite-specific immune
      responses postchallenge are essential. We analyzed this postchallenge response by
      transferring Abs into manipulated but malaria-naive mice and observed that Abs
      cannot protect SCID, nude, CD4+ T cell-depleted, or B cell knockout mice, with
      all mice dying. Thus, in addition to the Abs that develop following MSP119
      vaccination, a continuing active immune response postchallenge is required for
      protection. MSP119-specific Abs can adoptively transfer protection to strains of
      mice that are not protected following vaccination with MSP119, suggesting that
      the Ags targeted by the immune response postchallenge include Ags apart from
      MSP119. These data have important implications for the development of a human
      malaria vaccine.

PMID- 10358181
TI  - Poxvirus-encoded serpins do not prevent cytolytic T cell-mediated recovery from
      primary infections.
AB  - Previous observations that the highly conserved poxvirus-encoded serpins inhibit
      cytotoxic activities of alloreactive CTL via granule and/or Fas-mediated pathways
      was taken to indicate their involvement in immune evasion by poxviruses. We now
      show that interference with 51Cr release from target cells by ectromelia and
      cowpoxvirus is limited to alloreactive but not MHC-restricted CTL. The data are
      in support of the paramount importance of CTL and its effector molecule perforin
      in the recovery from primary ectromelia virus infection and question the role of
      serpins in the evasion of poxviruses from killing by CTL. Further analysis of
      poxvirus interference with target cell lysis by alloreactive CTL revealed that
      suppression primarily affects the Fas-mediated, and to a lesser extent, the
      granule exocytosis pathway. Serpin-2 is the main contributor to suppression for
      both killing pathways. In addition, inhibition of lysis was shown to be both
      target cell type- and MHC allotype-dependent. We hypothesize that differences in
      TCR affinities and/or state of activation between alloreactive and MHC-restricted
      CTL as well as the quality (origin) of target cells are responsible for the
      observed phenomenon.

PMID- 10358182
TI  - Virus infection activates IL-1 beta and IL-18 production in human macrophages by
      a caspase-1-dependent pathway.
AB  - Monocytes and macrophages play a significant role in host's defense system, since
      they produce a number of cytokines in response to microbial infections. We have
      studied IL-1 beta, IL-18, IFN-alpha/beta, and TNF-alpha gene expression and
      protein production in human primary monocytes and GM-CSF-differentiated
      macrophages during influenza A and Sendai virus infections. Virus-infected
      monocytes released only small amounts of IL-1 beta or IL-18 protein, whereas 7-
      and 14-day-old GM-CSF-differentiated macrophages readily produced these
      cytokines. Constitutive expression of proIL-18 was seen in monocytes and
      macrophages, and the expression of it was enhanced during monocyte/macrophage
      differentiation. Expression of IL-18 mRNA was clearly induced only by Sendai
      virus, whereas both influenza A and Sendai viruses induced IL-1 beta mRNA
      expression. Since caspase-1 is known to cleave proIL-1 beta and proIL-18 into
      their mature, active forms, we analyzed the effect of a specific caspase-1
      inhibitor on virus-induced IL-1 beta and IL-18 production. The release of IL-1
      beta and IL-18, but not that of IFN-alpha/beta or TNF-alpha, was clearly blocked
      by the inhibitor. Our results suggest that the cellular differentiation is a
      crucial factor that affects the capacity of monocytes/macrophages to produce IL-1
      beta and IL-18 in response to virus infections. Furthermore, the virus-induced
      activation of caspase-1 is required for the efficient production of biologically
      active IL-1 beta and IL-18.

PMID- 10358183
TI  - The Th1/Th2 balance does not account for the difference of susceptibility of
      mouse strains to Theiler's virus persistent infection.
AB  - Theiler's virus causes a persistent infection with demyelination that is studied
      as a model for multiple sclerosis. Inbred strains of mice differ in their
      susceptibility to viral persistence due to both H-2 and non-H-2 genes. A locus
      with a major effect on persistence has been mapped on chromosome 10, close to the
      Ifng locus, using a cross between susceptible SJL/J and resistant B10.S mice. We
      now confirm the existence of this locus using two lines of congenic mice bearing
      the B10.S Ifng locus on an SJL/J background, and we describe a deletion in the
      promoter of the Ifng gene of the SJL/J mouse. We studied the expression of IFN
      gamma, IL-2, IL-10, and IL-12 in the brains of SJL/J mice, B10.S mice, and the
      two lines of congenic mice during the first 2 wk following inoculation. We found
      a greater expression of IFN-gamma and IL-2 mRNA in the brains of B10.S mice
      compared with those of SJL/J mice. Also, the ratio of IL-12 to IL-10 mRNA levels
      was higher in B10.S mice. However, the cytokine profiles were the same for the
      two lines of resistant congenic mice and for susceptible SJL/J mice. Therefore,
      the difference of Th1/Th2 balance between the B10.S and SJL/J mice is not due to
      the Ifng locus and does not account for the difference of susceptibility of these
      mice to persistent infection.

PMID- 10358185
TI  - Tumor cell surface expression of granulocyte-macrophage colony-stimulating factor
      elicits antitumor immunity and protects from tumor challenge in the P815 mouse
      mastocytoma tumor model.
AB  - A novel membrane-bound form of GM-CSF (mbGM-CSF) was expressed on the surface of
      the mouse mastocytoma cell line P815 to target tumor cell-associated Ags to
      epidermal Langerhans cells. Transfected clones stimulated the proliferation of
      syngeneic bone marrow cells, indicating that mbGM-CSF is biologically active. We
      evaluated the in vivo effects of mbGM-CSF by comparing the growth of mbGM-CSF
      cells (termed 1D6.1E5) to that of wild-type P815 cells in DBA/2 mice. The growth
      rates of tumors initiated by P815 and 1D6.1E5 were similar until day 12, after
      which P815 tumors grew to large sizes while 1D6. 1E5 tumors were rejected. In
      contrast, the growth of both tumors was unimpeded when injected into nude mice,
      suggesting that a T cell-dependent antitumor response was induced by 1D6.1E5 in
      normal mice. Lymphocytes from 1D6.1E5-vaccinated mice were able to kill 51Cr
      labeled P815 cells in a dose-dependent fashion that was inhibited by anti-CD8
      Abs, suggesting that the antitumor response involved CD8+ CTL. We then tested
      whether vaccination with these cells would elicit a protective antitumor response
      by injecting mice with either irradiated 1D6.1E5 or P815 cells and challenging
      them with nonirradiated P815 cells. 1D6.1E5-treated mice grew small tumors that
      soon disappeared in all animals. In contrast, the majority of animals receiving
      the irradiated wild-type tumor vaccine grew large tumors, and 50% died. These
      data demonstrate that mbGM-CSF expressed on the surface of tumor cells is
      biologically active and elicits protective antitumor immunity.

PMID- 10358184
TI  - Use of a photoactivatable taxol analogue to identify unique cellular targets in
      murine macrophages: identification of murine CD18 as a major taxol-binding
      protein and a role for Mac-1 in taxol-induced gene expression.
AB  - Taxol, a potent antitumor agent that binds beta-tubulin and promotes microtubule
      assembly, results in mitotic arrest at the G2/M phase of the cell cycle. More
      recently, Taxol was shown to be a potent LPS mimetic in murine, but not in human
      macrophages, stimulating signaling pathways and gene expression indistinguishably
      from LPS. Although structurally unrelated to LPS, Taxol's LPS-mimetic activities
      are blocked by inactive structural analogues of LPS, indicating that despite the
      species-restricted effects of Taxol, LPS and Taxol share a common
      receptor/signaling complex that might be important in LPS-induced human diseases.
      To identify components of the putatively shared Taxol/LPS receptor, a novel,
      photoactivatable Taxol analogue was employed to identify unique Taxol-binding
      proteins in murine macrophage membranes. Seven major Taxol-binding proteins,
      ranging from approximately 50 to 200 kDa, were detected. Although
      photoactivatable Taxol analogue failed to bind to CD14, the prominent Taxol
      binding protein was identified as CD18, the approximately 96-kDa common component
      of the beta2 integrin family. This finding was supported by the concomitant
      failure of macrophage membranes from Mac-1 knockout mice to express
      immunoreactive CD18 and the major Taxol-binding protein. In addition, Taxol
      induced IL-12 p40 mRNA was markedly reduced in Mac-1 knockout macrophages and
      anti-Mac-1 Ab blocked secretion of IL-12 p70 in Taxol- and LPS-stimulated
      macrophages. Since CD18 has been described as a participant in LPS-induced
      binding and signal transduction, these data support the hypothesis that the
      interaction of murine CD18 with Taxol is involved in its proinflammatory
      activity.

PMID- 10358186
TI  - Induction of antitumor immunity with Fas/APO-1 ligand (CD95L)-transfected
      neuroblastoma neuro-2a cells.
AB  - Fas/Apo-1 (CD95)-Fas ligand (FasL) system has been implicated in the suppression
      and stimulation of immune responses. We examined the induction of antitumor
      immunity with neuroblastoma Neuro-2a cells transfected with FasL cDNA (Neuro
      2a+FasL). Neuro-2a+FasL cells expressed FasL on the cell surface and secreted
      soluble FasL. Histologic and flow cytometric analyses revealed that Neuro-2a+FasL
      cells caused neutrophils to infiltrate into the injected site, resulting in
      strong inflammation. Neutrophil infiltration was inhibited by treatment with anti
      FasL mAb and did not occur in Fas-deficient lpr mice. Normal syngeneic mice
      rejected Neuro-2a+FasL cells after the inflammation and acquired tumor-specific
      protective immunity. CD8+ T cells were responsible for the antitumor immunity.
      Neuro-2a+FasL cells formed tumors after far longer latency compared with mock
      transfected Neuro-2a+Neo cells in nude mice, and immune competent mice rejected
      Neuro-2a cells but not sarcoma S713a cells when they were injected with Neuro
      2a+FasL cells in a mixture. These results suggest that neutrophils attracted
      through the Fas-FasL system may impair tumor cells by inflammation at the initial
      step, followed by development of CD8+ T cell-dependent tumor-specific antitumor
      immunity, leading to complete eradication of tumor cells. Importantly, the
      treatment with Neuro-2a+FasL cells exhibited therapeutic efficacy against growing
      tumors.

PMID- 10358187
TI  - Antibody prevents virus reactivation within the central nervous system.
AB  - The neurotropic JHM strain of mouse hepatitis virus (JHMV) produces an acute CNS
      infection characterized by encephalomyelitis and demyelination. The immune
      response cannot completely eliminate virus, resulting in persistence associated
      with chronic ongoing CNS demyelination. The contribution of humoral immunity to
      viral clearance and persistent infection was investigated in mice homozygous for
      disruption of the Ig mu gene (IgM-/-). Acute disease developed with equal
      kinetics and severity in IgM-/- and syngeneic C57BL/6 (wt) mice. However,
      clinical disease progressed in IgM-/- mice, while wt mice recovered. Viral
      clearance during acute infection was similar in both groups, supporting a primary
      role of cell-mediated immunity in viral clearance. In contrast to wt mice, in
      which infectious virus was reduced to below detection following acute infection,
      increasing infectious virus was recovered from the CNS of the IgM-/- mice
      following initial clearance. No evidence was obtained for selection of variant
      viruses nor was there an apparent loss of cell-mediated immunity in the absence
      of Ab. Passive transfer of anti-JHMV Ab following initial clearance prevented
      reactivation of infectious virus within the CNS of IgM-/- mice. These data
      demonstrate the clearance of infectious virus during acute disease by cell
      mediated immunity. However, immunologic control is not maintained in the absence
      of anti-viral Ab, resulting in recrudescence of infectious virus. These data
      suggest that humoral immunity plays no role in controlling virus during acute
      infection, but plays an important role in establishing and maintaining CNS viral
      persistence.

PMID- 10358188
TI  - Human polymorphonuclear leukocytes produce IL-12, TNF-alpha, and the chemokines
      macrophage-inflammatory protein-1 alpha and -1 beta in response to Toxoplasma
      gondii antigens.
AB  - The induction of a type 1 inflammatory cytokine response is a key event in the
      initiation of immunity to Toxoplasma gondii. Because polymorphonuclear leukocytes
      rapidly respond to infection by exiting the peripheral blood and accumulating at
      a site of infection, we sought to determine whether these cells produce cytokines
      in response to T. gondii. When human peripheral blood neutrophils were stimulated
      with parasite Ag, they produced both IL-12 (p70) and TNF-alpha. Similarly, up
      regulated expression of macrophage-inflammatory protein-1 alpha (MIP-1 alpha) and
      MIP-1 beta gene transcripts was induced. Kinetic analysis of IL-12 and TNF-alpha
      production revealed distinct patterns following stimulation by T. gondii or LPS.
      Exogenous TNF-alpha alone also provided a potent stimulus of MIP-1 alpha and MIP
      1 beta expression, and when neutralizing anti-TNF-alpha antiserum was included in
      cultures of parasite-stimulated cells, expression of these CC-family chemokines
      was partially blocked. These results establish that T. gondii possesses the
      ability of driving neutrophil proinflammatory cytokine production, and they
      suggest that parasite-induced MIP-1 alpha and MIP-1 beta partly results from
      autocrine stimulation through TNF-alpha.

PMID- 10358189
TI  - Purine metabolites suppress proliferation of human NK cells through a lineage
      specific purine receptor.
AB  - NK cell proliferation is suppressed in some patients with cancer by unknown
      mechanisms. Because purine metabolites released into the extracellular space
      during cell lysis may affect cell function, we hypothesized that these
      metabolites could serve as feedback regulators of NK cell proliferation. Sorted
      NK (CD56+/CD3-) cells were incubated with IL-2 (1000 U/ml) in a 4-day thymidine
      uptake assay with or without 10-10,000 microM of nucleotides. Adenine nucleotides
      inhibited NK cell proliferation, with ATP = ADP > 5'-adenylylimidodiphosphate >
      AMP = adenosine; ADP-ribose and nicotinamide adenine dinucleotide, but not
      nicotinamide or UTP, caused a dose-dependent suppression of thymidine uptake. A
      total of 100 microM ATP, a concentration that induced a maximal (80%) inhibition
      of thymidine uptake, did not inhibit cytotoxic activity against K562 targets.
      Because NK cells retained the ability to lyse K562 targets 4 days after exposure
      to 500 microM ATP or 1000 microM adenosine, inhibition of thymidine uptake was
      not due to cell death. Incubation of NK cells with dibutyryl cAMP and forskolin
      also suppressed thymidine uptake. Cholera toxin and pertussis toxin suppressed NK
      cell proliferation. Pertussis toxin did not block the adenine nucleotide effects.
      Further, ATP, but not adenosine or other nucleotides, markedly increased
      intracellular cAMP in a dose-dependent manner. The ATP-induced increase in cAMP
      was specific to cytolytic cells, because CD19+ B cells and CD4+ T cells did not
      increase their intracellular cAMP. These studies demonstrate that NK
      proliferation is regulated through purine receptors by adenine nucleotides, which
      may play a role in decreased NK cell activity. The response to adenine
      nucleotides is lineage-specific.

PMID- 10358190
TI  - Plasticity of immune responses suppressing parasitemia during acute Plasmodium
      chabaudi malaria.
AB  - gammadelta T cells have a crucial role in cell-mediated immunity (CMI) against P.
      chabaudi malaria, but delta-chain knockout (KO) (deltao/o) mice and mice depleted
      of gammadelta T cells with mAb cure this infection. To address the question of
      why mice deficient in gammadelta T cells resolve P. chabaudi infections, we
      immunized deltao/o mice by infection with viable blood-stage parasites. Sera from
      infection-immunized mice were tested for their ability to protect JHo/o, deltao/o
      double KO mice passively against P. chabaudi challenge infection. The onset of
      parasitemia was significantly delayed in mice receiving immune sera, compared
      with saline or uninfected serum controls. Immune sera were then fractionated into
      Ig-rich and Ig-depleted fractions by HPLC on a protein G column. Double KO mice
      were passively immunized with either fraction and challenged with P. chabaudi.
      The onset of parasitemia was significantly delayed in recipients of the Ig-rich
      fraction compared with recipients of the Ig-poor fraction of immune sera. We
      conclude that deltao/o mice, which are unable to activate CMI against the
      parasite, suppress P. chabaudi infection by a redundant Ab-mediated process.

PMID- 10358191
TI  - Complex requirements for nascent and memory immunity in pulmonary histoplasmosis.
AB  - The presence of functional T cells is often required for successful resolution of
      infections with intracellular pathogens, yet the mechanisms by which they
      contribute to elimination of the invading pathogen in primary and secondary
      immunity are only partly understood. We report that increased mortality of naive
      alpha/beta TCR+ or CD4+ T cell-depleted mice infected with the fungus Histoplasma
      capsulatum is associated with impairment of IFN-gamma production. Upon secondary
      infection, mice concomitantly depleted of CD4+ and CD8+ cells exhibit decreased
      survival beyond day 25 of rechallenge, whereas elimination of either T cell
      subset or B cell deficiency does not result in accelerated mortality compared
      with controls. Remarkably, despite a decrease of H. capsulatum CFU in lungs of
      CD4+ plus CD8+-deficient mice, a progressive increase in spleen CFU is observed.
      The ability to control fungus growth in lungs is associated with vigorous TNF
      alpha, but not IFN-gamma, production by bronchoalveolar lavage cells. In
      contrast, spleen cells from CD4+ plus CD8+-deficient mice are unable to produce
      TNF-alpha. Thus, the cellular and molecular requirements for protective immunity
      vary between primary and secondary infection. Furthermore, in secondary
      histoplasmosis, a sharp contrast can be drawn between lungs and spleens in their
      reliance upon T cells to control fungal replication. The opposing activities of
      these organs can be ascribed in part to differential production of TNF-alpha.

PMID- 10358192
TI  - Viral infection modulates expression of hypersensitivity pneumonitis.
AB  - Hypersensitivity pneumonitis (HP) is a granulomatous, inflammatory lung disease
      caused by inhalation of organic Ags, most commonly thermophilic actinomycetes
      that cause farmer's lung disease. The early response to Ag is an increase in
      neutrophils in the lung, whereas the late response is a typical Th1-type
      granulomatous disease. Many patients who develop disease report a recent viral
      respiratory infection. These studies were undertaken to determine whether viruses
      can augment the inflammatory responses in HP. C57BL/6 mice were exposed to the
      thermophilic bacteria Saccharopolyspora rectivirgula (SR) for 3 consecutive days
      per wk for 3 wk. Some mice were exposed to SR at 2 wk after infection with
      respiratory syncytial virus (RSV), whereas others were exposed to SR after
      exposure to saline alone or to heat-inactivated RSV. SR-treated mice developed a
      typical, early neutrophil response and a late granulomatous inflammatory
      response. Up-regulation of IFN-gamma and IL-2 gene expression was also found
      during the late response. These responses were augmented by recent RSV infection
      but not by heat-inactivated RSV. Mice with a previous RSV infection also had a
      greater early neutrophil response to SR, with increased macrophage inflammatory
      protein-2 (MIP-2, murine equivalent of IL-8) release in bronchoalveolar lavage
      fluid. These studies suggest that viral infection can augment both the early and
      late inflammatory responses in HP.

PMID- 10358193
TI  - Protection by group II phospholipase A2 against Staphylococcus aureus.
AB  - Group II phospholipase A2 (PLA2) is an enzyme that has marked antibacterial
      properties in vitro. To define the role of group II PLA2 in the defense against
      Staphylococcus aureus, we studied host responses in transgenic mice expressing
      human group II PLA2 and group II PLA2-deficient C57BL/6J mice in experimental S.
      aureus infection. After the administration of S. aureus, the transgenic mice
      showed increased expression of group II PLA2 mRNA in the liver and increased
      concentration of group II PLA2 in serum, whereas the PLA2-deficient mice
      completely lacked the PLA2 response. Expression of human group II PLA2 resulted
      in reduced mortality and improved the resistance of the mice by killing the
      bacteria as indicated by low numbers of live bacteria in their tissues. Human
      group II PLA2 was responsible for the bactericidal activity of transgenic mouse
      serum. These results suggest a possible role for group II PLA2 in the innate
      immunity against S. aureus infection.

PMID- 10358194
TI  - Modulation of C3a activity: internalization of the human C3a receptor and its
      inhibition by C5a.
AB  - The C3a receptor (C3aR) is expressed on most human peripheral blood leukocytes
      with the exception of resting lymphocytes, implying a much higher
      pathophysiological relevance of the anaphylatoxin C3a as a proinflammatory
      mediator than previously thought. The response to this complement split product
      must be tightly regulated in situations with sustained complement activation to
      avoid deleterious effects caused by overactivated inflammatory cells. Receptor
      internalization, an important control mechanism described for G protein-coupled
      receptors, was investigated. Using rabbit polyclonal anti-serum directed against
      the C3aR second extracellular loop, a flow cytometry-based receptor
      internalization assay was developed. Within minutes of C3a addition to human
      granulocytes, C3aR almost completely disappeared from the cell surface. C3aR
      internalization could also be induced by PMA, an activator of protein kinase C.
      Similarly, monocytes, the human mast cell line HMC-1, and differentiated
      monocyte/macrophage-like U937-cells exhibited rapid agonist-dependent receptor
      internalization. Neither C5a nor FMLP stimulated any cross-internalization of the
      C3aR. On the contrary, costimulation of granulocytes with C5a, but not FMLP,
      drastically decreased C3aR internalization. This effect could be blocked by a
      C5aR-neutralizing mAb. HEK293-cells transfected with the C3aR, with or without
      Galpha16, a pertussis toxin-resistant G protein alpha subunit required for C3aR
      signal transduction in these cells, did not exhibit agonist-dependent C3aR
      internalization. Additionally, preincubation with pertussis toxin had no effect
      on C3a-induced internalization on PMNs. C3aR internalization is a rapid negative
      control mechanism and is influenced by the C5aR pathway.

PMID- 10358196
TI  - Alterations in C3 activation and binding caused by phosphorylation by a casein
      kinase released from activated human platelets.
AB  - A casein kinase released from activated human platelets phosphorylates a number
      of plasma proteins extracellularly, and that activation of platelets in systemic
      lupus erythematosus patients parallels an increase in the phosphate content of
      plasma proteins, including C3. The present study was undertaken to characterize
      this platelet protein kinase and to further elucidate the effect(s) on C3
      function of phosphorylation by platelet casein kinase. The phosphate content of
      human plasma C3 was increased from 0.15 to 0.60 mol phosphate/mol of C3 after
      platelet activation in whole blood or platelet-rich plasma. The platelet casein
      kinase was distinct from other casein kinases in terms of its dependence on
      cations, inhibition by specific protein kinase inhibitors, and immunological
      reactivity. C3 that had been phosphorylated with platelet casein kinase was
      tested for its susceptibility to cleavage by trypsin or the classical and
      alternative pathway convertases and its binding to EAC and IgG. Phosphorylation
      did not affect the cleavage of C3 into C3a and C3b, but the binding of fragments
      from phosphorylated C3 to EAC14oxy2 cells and to IgG in purified systems and in
      serum was increased by 1.6-4.5 times over that of unphosphorylated C3. A
      covariation was seen between the enhanced binding of C3 fragments to IgG after
      phosphorylation and an increased ratio of glycerol/glycine binding, from 2.0 for
      unphosphorylated C3 to 4.9 for phosphorylated C3. The present study suggests that
      an overall effect of phosphorylation of C3 by platelet casein kinase is to
      enhance the opsonization of immune complexes.

PMID- 10358195
TI  - Regulation of IFN consensus sequence binding protein expression in murine
      macrophages.
AB  - Recent work has demonstrated that the transcription factor, IFN consensus
      sequence binding protein (ICSBP), plays a critical role in the capacity of mice
      to control infection with Toxoplasma gondii and Leishmania major, agents that
      require highly activated macrophages for their elimination. In this report the
      regulation of ICSBP mRNA and protein were analyzed in murine macrophages
      stimulated with LPS and/or IFN-gamma. Like induction of leishmaniacidal activity,
      LPS and IFN-gamma synergize to induce ICSBP mRNA and protein. Deletion analysis
      of the ICSBP promoter identified regions that were IFN-gamma responsive, regions
      that mediate the ability of LPS and IFN-gamma to activate this promoter
      synergistically, as well as regions that normally repress ICSBP transcription.
      Finally, exogenous expression of ICSBP, found in previous studies to down
      regulate MHC I gene expression, failed to repress basal or IFN-gamma-induced
      ICSBP transcription. This demonstrates that ICSBP can selectively suppress the
      expression of IFN-responsive genes. These findings extend in a significant way
      our understanding of the regulation of ICSBP by LPS and IFN-gamma and provide
      important clues as to its role in macrophage activation.

PMID- 10358197
TI  - Antiproliferative effect of IL-1 is mediated by p38 mitogen-activated protein
      kinase in human melanoma cell A375.
AB  - The role of p38 mitogen-activated protein kinase (MAPK) in IL-1-induced growth
      inhibition was investigated using IL-1-sensitive human melanoma A375-C2-1 cells
      and IL-1-resistant A375-R8 cells. In both cells, p38 MAPK was activated by IL-1.
      A selective inhibitor for p38 MAPK, SB203580, almost completely recovered the IL
      1-induced growth inhibition in A375-C2-1 cells. IL-1-induced IL-6 production was
      also suppressed by SB203580. However, the reversal effect of SB203580 was not due
      to the suppression of IL-6 production because the SB203580 effect was still
      observed in the presence of exogenous IL-6. Down-regulation of ornithine
      decarboxylase (ODC) activity as well as its protein level has been shown to be
      essential for IL-1-induced growth inhibition. SB203580 also reversed the IL-1
      induced down-regulation of ODC activity and intracellular polyamine levels
      without affecting ODC mRNA levels in A375-C2-1 cells. In IL-1-resistant R8 cells,
      however, IL-1 only slightly suppressed ODC activity. In A375-C2-1 cells, the mRNA
      expression level of antizyme (AZ), a regulatory factor of ODC activity, has been
      shown to be up-regulated by IL-1. IL-1-induced up-regulation of AZ mRNA level was
      not affected by SB203580. These findings demonstrate that p38 MAPK plays an
      important role in IL-1-induced growth inhibition in A375 cells through down
      regulating ODC activity without affecting the level of ODC mRNA and AZ mRNA. In
      IL-1-resistant A375-R8 cells, IL-1 signaling pathway is deficient between p38
      MAPK activation and down-regulation of ODC activity.

PMID- 10358198
TI  - Alcohol (ethanol) inhibits IL-8 and TNF: role of the p38 pathway.
AB  - Acute ethanol (EtOH) intoxication has been identified as a risk factor for
      infectious complications in trauma and burn victims. However, the mechanism of
      this immune dysfunction has yet to be elucidated. The monocyte/macrophage
      production of cytokines, in particular IL-8 and TNF-alpha, is critical in the
      regulation of the acute inflammatory response to infectious challenge. IL-8 is a
      potent chemoattractant and activator of neutrophils. TNF-alpha, a proinflammatory
      cytokine, initiates expression of endothelial cell surface adhesion molecules and
      neutrophil migration. p38, a member of the mitogen-activated protein kinases,
      plays an important role in mediating intracellular signal transduction in
      endotoxin-induced inflammatory responses. We examined the effects of LPS and
      ethanol on p38 activation and the corresponding IL-8 and TNF-alpha production in
      human mononuclear cells. LPS-induced IL-8 and TNF-alpha production was inhibited
      in a similar pattern by pretreatment with either EtOH or SB202190 (1 microM), a
      specific inhibitor of p38 kinase. Western blot analysis, using a dual phospho
      specific p38 mitogen-activated protein kinase Ab, demonstrated that EtOH
      pretreatment inhibited LPS-induced p38 activation. These results demonstrate that
      alcohol suppresses the normal host immune inflammatory response to LPS. This
      dysregulation appears to be mediated in part via inhibition of p38 activation.
      Inhibition of IL-8 and TNF-alpha production by acute EtOH intoxication may
      inhibit inflammatory focused neutrophil migration and activation and may be a
      mechanism explaining the increased risk of trauma- and burn-related infections.

PMID- 10358200
TI  - Monoclonal antibodies to murine lipopolysaccharide (LPS)-binding protein (LBP)
      protect mice from lethal endotoxemia by blocking either the binding of LPS to LBP
      or the presentation of LPS/LBP complexes to CD14.
AB  - Cellular responses to LPS, the major lipid component of the outer membrane of
      Gram-negative bacteria, are enhanced markedly by the LPS-binding protein (LBP), a
      plasma protein that transfers LPS to the cell surface CD14 present on cells of
      the myeloid lineage. LBP has been shown previously to potentiate the host
      response to LPS. However, experiments performed in mice with a disruption of the
      LBP gene have yielded discordant results. Whereas one study showed that LBP
      knockout mice were resistant to endotoxemia, another study did not confirm an
      important role for LBP in the response of mice challenged in vivo with low doses
      of LPS. Consequently, we generated rat mAbs to murine LBP to investigate further
      the contribution of LBP in experimental endotoxemia. Three classes of mAbs were
      obtained. Class 1 mAbs blocked the binding of LPS to LBP; class 2 mAbs blocked
      the binding of LPS/LBP complexes to CD14; class 3 mAbs bound LBP but did not
      suppress LBP activity. In vivo, class 1 and class 2 mAbs suppressed LPS-induced
      TNF production and protected mice from lethal endotoxemia. These results show
      that the neutralization of LBP accomplished by blocking either the binding of LPS
      to LBP or the binding of LPS/LBP complexes to CD14 protects the host from LPS
      induced toxicity, confirming that LBP is a critical component of innate immunity.

PMID- 10358199
TI  - POMC gene-derived peptides activate melanocortin type 3 receptor on murine
      macrophages, suppress cytokine release, and inhibit neutrophil migration in acute
      experimental inflammation.
AB  - To investigate the relevance of adrenocorticotrophic hormone (ACTH) therapy in
      human gouty arthritis, we have tested the effect of several ACTH-related peptides
      in a murine model of experimental gout. Systemic treatment of mice with ACTH4-10
      (MEHFRWG) (10-200 microgram s. c.) inhibited neutrophil accumulation without
      altering peripheral blood cell counts or circulating corticosterone levels. A
      similar effect was seen with alpha- and beta-melanocyte stimulating hormones (1
      30 microgram s.c.). In vivo release of the chemokine KC-(detected in the lavage
      fluids before maximal influx of neutrophils) was significantly reduced (-50 to 
      60%) by ACTH4-10. Macrophage activation in vitro, determined as phagocytosis and
      KC release, was inhibited by ACTH and ACTH4-10 with approximate IC50 values of 30
      nM and 100 microM, respectively. The melanocortin receptor type 3/4 antagonist
      SHU9119 prevented the inhibitory actions of ACTH4-10 both in vitro and in vivo.
      However, melanocortin type 3, but not type 4, receptor mRNA was detected in mouse
      peritoneal macrophages by RT-PCR. Therefore, we propose that activation of this
      receptor type by ACTH4-10 and related amino acid sequences attenuates KC release
      (and possibly production of other cytokines) from macrophages with consequent
      inhibition of the host inflammatory response, thus providing a notional anti
      inflammatory mechanism for ACTH that is unrelated to stimulation of
      glucocorticoid release.

PMID- 10358201
TI  - Rhinovirus regulation of IL-1 receptor antagonist in vivo and in vitro: a
      potential mechanism of symptom resolution.
AB  - Rhinovirus (RV) upper respiratory tract infections are prototypic transient
      inflammatory responses. To address the mechanism of disease resolution in these
      infections, we determined if RV stimulated the production of the IL-1 receptor
      antagonist (IL-1ra) in vivo and in vitro. In contrast to IL-1alpha and IL-1beta,
      immunoreactive IL-1ra was readily detected in the nasal washings of normal human
      volunteers. Symptomatic RV infection caused a small increase in IL-1alpha, a
      modest increase in IL-1beta, and an impressive increase in IL-1ra. Maximal
      induction of IL-1alpha and IL-1beta was transiently noted 48 h after RV
      infection. In contrast, maximal induction of IL-1ra was prolonged appearing 48-72
      h after RV infection. These time points corresponded to the periods of peak
      symptomatology and the onset of symptom resolution, respectively. Western
      analysis of nasal washings demonstrated that RV stimulated the accumulation of
      intracellular IL-1ra type I in all and secreted IL-1ra in a subset of volunteers.
      Unstimulated normal respiratory epithelial cells contained intracellular IL-1ra
      type I mRNA and protein. RV infection increased the intracellular levels and
      extracellular transport of this IL-1ra moiety without causing significant changes
      in the levels of IL-1ra mRNA. IL-1ra may play an important role in the resolution
      of RV respiratory infections. RV stimulates epithelial cell IL-1ra elaboration,
      at least in part, via a novel translational and/or posttranslational mechanism.

PMID- 10358202
TI  - Effect of an orally active Th1/Th2 balance modulator, M50367, on IgE production,
      eosinophilia, and airway hyperresponsiveness in mice.
AB  - We have found a novel anti-allergic agent, M50367, which suppresses IgE
      biosynthesis and eosinophil accumulation in vivo. In this study, we evaluated the
      ability of M50367 to modulate Th1/Th2 balance in Th2-background BALB/c mice and
      to inhibit airway hyperresponsiveness in a murine model of atopic asthma. Oral
      M50367 at 3-30 mg/kg/day exhibited 51 to 73% reduction of IL-4/IL-5 production
      and 2- to 5-fold augmentation of IFN-gamma production by Ag-stimulated cultured
      splenocytes of the mice sensitized with DNP-Ascaris. These alterations in Th1/Th2
      cytokine production were accompanied by 55-85% suppression of plasma IgE level.
      Oral M50367 at a dose of 10 mg/kg/day significantly inhibited Ig-independent
      peritoneal eosinophilia by 54%, which was induced by repeated i.p. injections of
      Ascaris suum extract. To develop airway hyperresponsiveness caused by allergic
      airway inflammation, BALB/c mice were sensitized with i.p. OVA injections,
      followed three times by OVA inhalation. Oral M50367 significantly inhibited the
      increase in airway reactivity to acetylcholine, together with the elevation of
      plasma IgE level and pulmonary eosinophilia, which were observed in vehicle
      treated mice 1 day after the last inhalation. Moreover, M50367 treatment reduced
      IL-4 and IL-5 production and tended to enhance IFN-gamma production, not only by
      cultured splenocytes, but also in bronchoalveolar lavage fluid. These results
      suggest that M50367 has a modulating ability of Th1/Th2 balance to down-regulate
      Th2 response in the circulating system as well as at the sites of inflammation,
      and may be beneficial for the treatment of allergic disorders such as atopic
      asthma.

PMID- 10358203
TI  - IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a
      murine psoriasis-like skin disorder.
AB  - The onset of acute psoriasis and the exacerbation of chronic psoriasis are often
      associated with a history of bacterial infection. We demonstrate that while only
      few scid/scid mice develop disease when CD4+CD45Rbhigh T cells are transferred
      alone, coadministration of LPS plus IL-12 or staphylococcal enterotoxin B into
      scid/scid mice 1 day after CD4+CD45Rbhigh T cell transfer greatly enhances
      disease penetrance and severity. Most importantly, the skin lesions induced by
      this method exhibit many of the histologic hallmarks observed in human psoriasis.
      Skin infiltrating CD4+ T cells were predominantly memory/effector cells
      (CD45Rblow) and exhibited a highly polarized Th1 phenotype. To test whether the
      development of pathogenic T cells was dependent on their production of IFN-gamma,
      we transferred IFN-gamma-/- CD4+CD45Rbhigh T cells into scid/scid or into T, B
      and NK cell-deficient scid/beige mice. Surprisingly, the incidence of psoriasis
      was similar to scid/scid animals that received IFN-gamma+/+ T cells, although
      acanthosis of the skin was attenuated. In contrast, the development of psoriasis
      was abolished if anti-IL-12 mAb was administered on day 7 and 35 after T cell
      transfer. Skin-derived IFN-gamma-/- inflammatory cells, but not cells from anti
      IL-12-treated animals, secreted substantial amounts of TNF-alpha, suggesting that
      the inflammatory effect of IFN-gamma-/- T cells may be partly exerted by TNF
      alpha and that the therapeutic effect of anti-IL-12 may depend on its ability to
      down-regulate both TNF-alpha and IFN-gamma. Overall, these results suggest that
      IL-12, independently of IFN-gamma, is able to induce pathogenic, inflammatory T
      cells that are able to induce psoriasiform lesions in mice.

PMID- 10358204
TI  - The role of an epithelial neutrophil-activating peptide-78-like protein in rat
      adjuvant-induced arthritis.
AB  - The chemokine, epithelial neutrophil-activating peptide-78 (ENA-78), is a potent
      neutrophil chemotaxin whose expression is increased in inflamed synovial tissue
      and fluid in human rheumatoid arthritis compared with osteoarthritis. Since ENA
      78 has been implicated in the pathogenesis of RA, we examined the expression of
      an ENA-78-like protein during the development of rat adjuvant-induced arthritis
      (AIA). Using an ELISA assay, we found increased levels of antigenic ENA-78-like
      protein in the sera of AIA animals compared with control normal animals by day 7
      postadjuvant injection. ENA-78-like protein levels continued to increase as AIA
      developed. ENA-78-like protein levels in joint homogenates were increased in AIA
      animals later in the development of the disease, by day 18 during maximal
      arthritis, compared with control animals. Expression of ENA-78-like protein in
      both the AIA serum and joint correlated with the progression of inflammation of
      the joints. Anti-human ENA-78 administered before disease onset modified the
      severity of AIA, while administration of anti-ENA-78 after clinical onset of AIA
      did not modify the disease. These data support a role for an ENA-78-like protein
      as an important chemokine in the progression and maintenance of AIA.

PMID- 10358205
TI  - Oligodendrocyte-specific protein peptides induce experimental autoimmune
      encephalomyelitis in SJL/J mice.
AB  - Oligodendrocyte-specific protein (OSP) is a recently isolated and cloned, 207-aa,
      hydrophobic, four-transmembrane protein found in CNS myelin. It represents
      approximately 7% of total myelin protein. The OSP cDNA sequence has no
      significant homology with previously reported genes, but the predicted protein
      structure suggests that OSP is a CNS homologue of peripheral myelin protein-22.
      We previously reported the presence of anti-OSP Abs in the cerebrospinal fluid of
      relapsing-remitting multiple sclerosis (MS) patients, but not control patient
      groups. In this study, we tested the ability of a panel of 20-mer peptides with
      10-aa overlaps, representing the sequence of murine OSP, to induce experimental
      autoimmune encephalomyelitis (EAE), an animal model for MS. SJL mice challenged
      with murine OSP peptides 52-71, 82-101, 102-121, 142-161, 182-201, and 192-207
      exhibited clinical EAE. OSP:52-71 elicited severe relapsing-remitting EAE in some
      individuals. All other encephalitogenic peptides elicited, at most, a loss of
      tail tonicity from which the mice most often completely recovered. Mononuclear
      cell infiltrates and focal demyelination characteristic of EAE were evident. T
      cell proliferative responses were seen with all encephalitogenic peptides except
      142-161 and 182-201. OSP peptides 72-91 and 132-151 did not cause clinical EAE,
      but did elicit robust proliferative responses. B10.PL and PL/J mice challenged
      with the same OSP peptide doses as SJL mice did not exhibit clinical EAE. These
      results in the SJL EAE model, together with the results from MS patient clinical
      samples, make OSP a promising candidate for autoantigenic involvement in MS.

PMID- 10358206
TI  - Progesterone-induced inhibition of chemokine receptor expression on peripheral
      blood mononuclear cells correlates with reduced HIV-1 infectability in vitro.
AB  - Recent studies have shown that progesterone, a sex steroid hormone, enhances the
      sexual transmission of various pathogens, including SIV. The goal of this study
      was to determine whether progesterone affects mechanisms underlying the sexual
      transmission of HIV-1. We first studied the effects of various physiologic
      concentrations of progesterone on the expression of chemokines and chemokine
      receptors by T cells and macrophages. Chemokines are involved in leukocyte
      recruitment to peripheral sites; in addition, the chemokine receptors CCR5 and
      CXCR4 are HIV-1 coreceptors, and their ligands can block HIV-1 infection.
      Progesterone treatment had no effect on constitutive expression of CCR5 and CXCR4
      by nonactivated T cells and macrophages, but significantly inhibited IL-2-induced
      up-regulation of CCR5 and CXCR4 on activated T cells (p < 0.05). Progesterone
      also inhibited both mitogen-induced proliferation and chemokine secretion
      (macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta,
      RANTES) by CD8+ T lymphocytes. Control and progesterone-treated PBMC cultures
      were also tested for susceptibility to infection by T cell-tropic (HIV-1MN) and
      macrophage-tropic (HIV-1JR-CSF) viral strains in vitro. Infection with low titers
      of HIV-1MN was consistently inhibited in progesterone-treated cultures;
      progesterone effects on infection with the HIV-1JR-CSF strain were more variable,
      but correlated with progesterone-induced reductions in CCR5 levels. These results
      indicate that progesterone treatment can inhibit mechanisms underlying HIV-1
      transmission, including infection of CD4+ target cells via CXCR4/CCR5 coreceptors
      and effects on chemokine-mediated recruitment of lymphocytes and monocytes to
      mucosal epithelia.

PMID- 10358207
TI  - T cell autoimmunity in Ig transgenic mice.
AB  - Autoantibodies directed at a diverse group of proteins of the U1/Sm
      ribonucleoprotein (snRNP) are characteristic of systemic lupus erythematosus and
      are found in the MRL murine model of this disease. This study examines the role
      of transgenic B lymphocytes in the regulation of autoreactive T cells to the
      snRNP autoantigen. Transgenic mice were developed bearing an Ig heavy chain gene
      specific for the D protein component of murine snRNP. B lymphocytes in these mice
      are neither deleted nor anergic and are of an immature (heat-stable Aghigh)
      phenotype. T lymphocytes from anti-snRNP transgenic mice were examined using a
      recombinant form of the D protein of the murine snRNP complex. Our results
      revealed that transgenic anti-snRNP B cell APCs stimulated CD4 T cells from wild
      type C57BL/6 and MRL lpr/lpr mice, while nonspecific APCs failed to stimulate CD4
      T cells. This study demonstrates that autoreactive T cells are not deleted from
      wild-type mice, although their activation is facilitated by autoantigen-specific
      APCs. The snRNP-reactive T cells in C57BL/6 transgenic mice are tolerized, in
      contrast to those T cells from MRL lpr/lpr transgenic mice. These studies
      implicate a role for autoreactive B lymphocytes in the in vivo activation and/or
      diversification of autoreactive T cells.

PMID- 10358208
TI  - Biased TCR repertoire in HIV-1-infected patients due to clonal expansion of HIV-1
      reverse transcriptase-specific CTL clones.
AB  - To study whether an expansion of HIV-1-specific CTL is contributing to the skewed
      TCR repertoire in HIV-1-infection, we characterized the TCR usage of CTL clones
      specific for a conserved epitope in HIV-1 reverse transcriptase (RT/476-484). CTL
      clones from three HIV-1-infected patients displayed highly similar TCR usage and
      used the identical Vbeta6.1 and Valpha2.5 gene segments. CTL clones from two
      patients showed a very high degree of similarity within the TCR complementarity
      determining region-3 (CDR-3). In accordance with the similar molecular structure,
      all three CTL clones also exhibited a similar functional activity with regard to
      recognition of variant peptides and cytokine secretion pattern. In one subject
      clonal expansion of a single CTL specificity could be shown over a 10-mo period.
      TCR spectratyping of PBMC from two patients revealed a marked expansion of CDR-3
      segments of a certain length within the Vbeta6-family. Sequence analysis of these
      CDR-3 yielded sequences identical to the RT/476-484-specific CTL previously
      isolated from the same patients. This analysis demonstrates that clonal expansion
      of HIV-1-specific CTL is contributing to the skewed TCR repertoire in HIV-1
      infected patients.

PMID- 10358209
TI  - IL-13 and IFN-gamma secretion by activated T cells in HIV-1 infection associated
      with viral suppression and a lack of disease progression.
AB  - The immunopathology of HIV-1 infection includes immune defects in T cell cytokine
      secretion, resulting in decreased Ag-specific responses. In this report, IL-13
      and IFN-gamma were analyzed in progressive HIV-1 disease. Both cytokines exert
      positive effects on Ag presentation and inhibit HIV-1 infection of macrophages.
      Anti-CD3/anti-CD28-activated PBMC from HIV-1-infected individuals (n = 74)
      compared with uninfected subjects (n = 30) secreted significantly less IL-13
      (median, 0.64 ng/ml vs 2.07 ng/ml; p < 0. 001) and IFN-gamma (median, 40.96 ng/ml
      vs 129.5 ng/ml; p < 0.005). Decreased IL-13 and IFN-gamma secretion in HIV
      infection was present in sorted CD4+ and CD8+ T cell subsets, and additional
      analysis determined concurrent deficiency at the protein and transcriptional
      level. Longitudinal analysis showed that cytokine secretion levels correlated
      positively with CD4 count and negatively with plasma HIV-1 viral load. Patients
      changing to suppressive antiretroviral therapy during the study showed increases
      in IL-13 and IFN-gamma secretion. Overall, results show a decline in IL-13 and
      IFN-gamma secretion in progressive HIV-1 infection and suggest a role for both
      cytokines as part of T cell adaptive responses associated with a lack of disease
      progression.

PMID- 10358210
TI  - Induction of HIV-1 replication by allogeneic stimulation.
AB  - Allogeneic stimulation presents an immunologic challenge during pregnancy, blood
      transfusions, and transplantations, and has been associated with reactivation of
      latently infected virus such as CMV. Since HIV-1 is transmitted vertically,
      sexually, or via contaminated blood, we have tested the effects of
      allostimulation on HIV-1 infection. 1) We show that allostimulated lymphocytes
      are highly susceptible to acute infection with T cell-tropic or dual-tropic HIV
      1. 2) We show that allostimulation has dichotomous effects on replication of
      macrophage-tropic HIV-1; it activates HIV expression in already infected cells
      but inhibits HIV entry by secreting HIV-suppressive CC chemokines. 3) We show
      that allogeneic stimulation of latently infected, resting CD4+ T cells induced
      replication of HIV-1 in these cells. These observations suggest that allogeneic
      stimulation may play a role in the transmission, replication, and phenotypic
      transition of HIV-1.

PMID- 10358211
TI  - Complement receptor 1 (CD35) on human reticulocytes: normal expression in
      systemic lupus erythematosus and HIV-infected patients.
AB  - The low levels of complement receptor 1 (CR1) on erythrocytes in autoimmune
      diseases and AIDS may be due to accelerated loss in the circulation, or to a
      diminished expression of CR1 on the red cell lineage. Therefore, we analyzed the
      expression of CR1 on reticulocytes (R) vs erythrocytes (E). Healthy subjects had
      a significant higher CR1 number per cell on R (919 +/- 99 CR1/cell) than on E
      (279 +/- 30 CR1/cell, n = 23), which corresponded to a 3. 5- +/- 1.3-fold loss of
      CR1. This intravascular loss was confirmed by FACS analysis, which showed that
      all R expressed CR1, whereas a large fraction of E was negative. The systemic
      lupus erythematosus (SLE), HIV-infected, and cold hemolytic Ab disease (CHAD)
      patients had a CR1 number on R identical to the healthy subjects, contrasting
      with a lower CR1 on their E. The data indicated a significantly higher loss of
      CR1 in the three diseases, i.e., 7.0- +/- 3.8-, 6.1- +/- 2.9-, and 9.6- +/- 5.6
      fold, respectively. The intravascular loss was best exemplified in a patient with
      factor I deficiency whose CR1 dropped from 520 CR1/R to 28 CR1/E, i.e., 18.6-fold
      loss. In one SLE patient and in the factor I-deficient patient, the FACS data
      were consistent with a loss of CR1 already on some R. In conclusion, CR1 is lost
      progressively from normal E during in vivo aging so that old E are almost devoid
      of CR1. The low CR1 of RBC in autoimmune diseases and HIV-infection is due to a
      loss occurring in the circulation by an active process that remains to be
      defined.

PMID- 10358213
TI  - C1.7 antigen expression on CD8+ T cells is activation dependent: increased
      proportion of C1.7+CD8+ T cells in HIV-1-infected patients with progressing
      disease.
AB  - The C1.7 Ag is a surface marker previously shown to be expressed on all NK cells
      and on a subset of CD8+ T cells. We report in this study that C1.7 Ag expression
      on peripheral blood-derived CD8+ T cells overlaps with activation markers
      S6F1high and CD29high and is reciprocally expressed with CD62L. C1.7 Ag
      expression can be induced in vitro on CD8+ T cells by anti-CD3 cross-linking,
      suggesting that C1.7 Ag is activation dependent. In contrast to NK cells, C1.7 Ag
      does not signal on CD8+ T cells, nor does it induce redirected lysis upon
      ligation. The proportion of C1.7 Ag+CD8+ T cells is increased in HIV-infected
      patients compared with healthy donors. In 69 HIV-infected patients, we observed a
      significant inverse correlation between the percentage of C1.7 Ag-expressing CD8+
      T cells and the absolute CD4+ T cell count. Two-year clinical follow-up of
      patients with initial CD4+ T cell count of >400 cells/mm3 and a normal proportion
      of C1.7 Ag+CD8+ T cells revealed that these patients were clinically stable with
      minimal HIV-associated symptoms. In contrast, 10 of 12 patients with CD4+ T cell
      counts of >400 cells/mm3 and an elevated proportion of C1.7 Ag+CD8+ T cells were
      symptomatic. ANOVA analysis of patients indicates that C1.7 Ag is a better
      predictor of disease progression than CD4 count. Overall, our findings indicate
      that C1.7 Ag is the first described marker for activated/memory CD8+ T cells and
      a useful parameter for evaluating the level of CD8+ T cell activation in vivo.

PMID- 10358212
TI  - Induction of MHC class I expression on immature thymocytes in HIV-1-infected SCID
      hu Thy/Liv mice: evidence of indirect mechanisms.
AB  - The SCID-hu Thy/Liv mouse and human fetal thymic organ culture (HF-TOC) models
      have been used to explore the pathophysiologic mechanisms of HIV-1 infection in
      the thymus. We report here that HIV-1 infection of the SCID-hu Thy/Liv mouse
      leads to the induction of MHC class I (MHCI) expression on CD4+CD8+ (DP)
      thymocytes, which normally express low levels of MHCI. Induction of MHCI on DP
      thymocytes in HIV-1-infected Thy/Liv organs precedes their depletion and
      correlates with the pathogenic activity of the HIV-1 isolates. Both MHCI protein
      and mRNA are induced in thymocytes from HIV-1-infected Thy/Liv organs, indicating
      induction of MHCI gene expression. Indirect mechanisms are involved, because only
      a fraction (<10%) of the DP thymocytes were directly infected by HIV-1, although
      the majority of DP thymocytes are induced to express high levels of MHCI. We
      further demonstrate that IL-10 is induced in HIV-1-infected thymus organs.
      Similar HIV-1-mediated induction of MHCI expression was observed in HF-TOC
      assays. Exogenous IL-10 in HF-TOC induces MHCI expression on DP thymocytes.
      Therefore, HIV-1 infection of the thymus organ leads to induction of MHCI
      expression on immature thymocytes via indirect mechanisms involving IL-10.
      Overexpression of MHCI on DP thymocytes can interfere with thymocyte maturation
      and may contribute to HIV-1-induced thymocyte depletion.

PMID- 10358215
TI  - Human CD8+ and CD4+ T lymphocyte memory to influenza A viruses of swine and avian
      species.
AB  - Recently, an avian influenza A virus (A/Hong Kong/156/97, H5N1) was isolated from
      a young child who had a fatal influenza illness. All eight RNA segments were of
      avian origin. The H5 hemagglutinin is not recognized by neutralizing Abs present
      in humans as a result of infection with the human H1, H2, or H3 subtypes of
      influenza A viruses. Subsequently, five other deaths and several more human
      infections in Hong Kong were associated with this avian-derived virus. We
      investigated whether influenza A-specific human CD8+ and CD4+ T lymphocytes would
      recognize epitopes on influenza A virus strains derived from swine or avian
      species, including the 1997 H5N1 Hong Kong virus strains. Our results demonstrate
      that adults living in an urban area of the U.S. possess influenza A cross
      serotype reactive CD8+ and CD4+ CTL that recognize multiple epitopes on influenza
      A viruses of other species. Bulk culture cytotoxicity was demonstrated against
      avian and human influenza A viruses. Enzyme-linked immunospot assays detected
      precursor CTL specific for both human CTL epitopes and the corresponding A/HK/97
      viral sequences. We hypothesize that these cross-reactive CTL might provide
      partial protection to humans against novel influenza A virus strains introduced
      into humans from other species.

PMID- 10358214
TI  - Human CD28-CD8+ T cells contain greatly expanded functional virus-specific memory
      CTL clones.
AB  - At birth, almost all human peripheral blood CD8+ T cells express the
      costimulatory molecule CD28. With increasing age, the proportion of CD8+ T cells
      that lack CD28 increases. Because the Ag specificity of CD28-CD8+ T cells has not
      previously been defined, we studied the contribution of CD28-CD8+ T cells to the
      memory CD8+ CTL response against two human persistent viruses, human CMV (HCMV)
      and HIV. From PBMC of healthy virus carriers we generated multiple independent
      CTL clones specific for defined viral peptides and sequenced their TCR beta
      chains. We designed clonotypic oligonucleotides complementary to each beta-chain
      hypervariable sequence and quantified the size of individual immunodominant CTL
      clones in PBMC. Some individual CTL clones were very large, comprising up to 3.1%
      of all CD8+ T cells in PBMC, and were generally maintained at a stable level for
      months. Individual virus-specific CTL clones were consistently more abundant in
      purified CD28- cells than in the CD8+ population as a whole. Because CD28-CD8+
      cells as a population have been reported to proliferate poorly in response to
      mitogen, we studied the function of these virus-specific CD28- CTL clones by
      quantifying the frequency of peptide-specific CTL precursors using limiting
      dilution analysis. CD28-CD8+ T cells contained high frequencies of functional
      memory CTL precursors specific for peptides of HCMV or HIV, generally higher than
      in the CD8+ T cell population as a whole. We conclude that in asymptomatic HCMV
      and HIV infection, human CD28-CD8+ T cells contain high frequencies of functional
      virus-specific memory CTL clones.

PMID- 10358216
TI  - Method for measuring in vivo oxygen transport rates in a bioartificial organ.
AB  - Oxygen transport is crucial for the proper functioning of a bioartificial organ.
      In many cases, the immunoisolation membrane used to protect the transplanted
      cells from the host's immune system can be a significant barrier to oxygen
      transport. A method is described for measuring the in vitro and in vivo oxygen
      transport characteristics of a planar immunoisolation membrane. The in vitro
      oxygen permeability of the membrane was found to equal 9.22 x 10(-4) cm/sec and
      was essentially the same as the in vivo value of 9.51 x 10(-4) cm/sec. The fact
      that the in vitro and in vivo membrane permeabilities are identical indicates
      that any fibrotic tissue adjacent to the immunoisolation membrane did not present
      a significant resistance to the transport of oxygen. The measured oxygen
      permeability was also found consistent with the solute permeabilities obtained in
      a previous study for larger molecules. Based on the oxygen permeability results,
      theoretical calculations for this particular membrane indicate that about 1,100
      islets of Langerhans/cm2 of membrane area can be sustained at high tissue
      densities and only 660 islets/cm2 can be supported at low tissue densities.

PMID- 10358217
TI  - Development of an in vitro human placenta model by the cultivation of human
      trophoblasts in a fiber-based bioreactor system.
AB  - The in vitro human trophoblast culture system is of significant importance in the
      study of human placenta development and its role as the transport organ between
      maternal and fetal circulations in normal physiology and pathology pregnancy. But
      conventional in vitro model systems fail to reproduce many important features of
      human placenta in vivo. In our study, a perfusion bioreactor system was developed
      with a chemically modified poly(ethylene terephthalate) (PET) fibrous matrix as
      the cell culture scaffold. The dual compartment design of the bioreactor
      simulates maternal and fetal circulation systems in vivo. First trimester human
      trophoblast cells readily attached on a chemically modified PET fiber surface.
      The detection of human fibronectin showed that cells were able to form three
      dimensional structures by aggregation and bridging between fibers. Moreover,
      metabolic and hormone secretion data showed that cells in this perfusion culture
      system maintained their normal functional activities. The results of this study
      demonstrate the feasibility of tissue engineering human trophoblast cells in a
      perfusion bioreactor system for the development of an in vitro drug testing model
      system.

PMID- 10358218
TI  - Cardiac organogenesis in vitro: reestablishment of three-dimensional tissue
      architecture by dissociated neonatal rat ventricular cells.
AB  - The mammalian heart does not regenerate in vivo. The heart is, therefore, an
      excellent candidate for tissue engineering approaches and for the use of
      biosynthetic devices in the replacement or augmentation of defective tissue.
      Unfortunately, little is known about the capacity of isolated heart cells to re
      establish tissue architectures in vitro. In this study, we examined the
      possibility that cardiac cells possess a latent organizational potential that is
      unrealized within the mechanically active tissue but that can be accessed in
      quiescent environments in culture. In the series of experiments presented here,
      total cell populations were isolated from neonatal rat ventricles and recombined
      in rotating bioreactors containing a serum-free medium and surfaces for cell
      attachment. The extent to which tissue-like structure and contractile function
      were established was assessed using a combination of morphological,
      physiological, and biochemical techniques. We found that mixed populations of
      ventricular cells formed extensive three-dimensional aggregates that were
      spontaneously and rhythmically contractile and that large aggregates of
      structurally-organized cells contracted in unison. The cells were differentially
      distributed in these aggregates and formed architectures that were
      indistinguishable from those of intact tissue. These architectures arose in the
      absence of three-dimensional cues from the matrix, and the formation of
      organotypic structures was apparently driven by the cells themselves. Our
      observations suggest that cardiac cells possess an innate capacity to re
      establish complex, three-dimensional, cardiac organization in vitro.
      Understanding the basis of this capacity, and harnessing the organizational
      potential of heart cells, will be critical in the development of tissue
      homologues for use in basic research and in the engineering of biosynthetic
      implants for the treatment of cardiac disease.

PMID- 10358219
TI  - Use of muscle cells to mediate gene transfer to the bone defect.
AB  - Segmental bone defects and nonunions are relatively common problems facing all
      orthopaedic surgeons. Osteogenic proteins, i.e., BMP-2, can promote bone healing
      in segmental bone defects. However, a large quantity of the human recombinant
      protein is needed to enhance the bone healing potential. Cell mediated gene
      therapy in the bone defect can allow a sustained expression of the osteogenic
      proteins and further enhance bone healing. Muscle cells can be easily isolated
      and cultivated, and they are known to be an efficient gene delivery vehicle to
      muscle and nonmuscle tissues. Furthermore, they are capable of transforming into
      osteoblasts when stimulated by BMP-2. Thus, the utilization of muscle cells as
      the gene delivery vehicle to a bone defect would be an important step in
      establishing a less invasive treatment for non-unions and segmental bone defects.
      Muscle cells were transduced when the adenoviral-lacZ vector and injected into
      the bone defect and the muscles surrounding the defect. Expression of the marker
      gene was visualized 7 days after the injection, both macroscopically and
      microscopically, using lacZ histochemistry. The lacZ expressing cells in the
      defect tissue were also stained for desmin, a muscle specific marker, indicating
      the presence of muscle cells that have fused into myofibers in this nonmuscle
      bone defect area. With successful myoblast mediated gene delivery into the
      segmental bone defect, future experiments would focus on delivering viral vectors
      expressing osteogenic proteins to eventually improve bone healing postinjury.

PMID- 10358220
TI  - Biodegradation of hydrogel carrier incorporating fibroblast growth factor.
AB  - In vivo release of basic fibroblast growth factor (bFGF) from a biodegradable
      gelatin hydrogel carrier was compared with the in vivo degradation of hydrogel.
      When gelatin hydrogels incorporating 125I-labeled bFGF were implanted into the
      back subcutis of mice, the bFGF radioactivity remaining decreased with time and
      the retention period was prolonged with a decrease in the water content of the
      hydrogels. The lower the water content of 125I-labeled gelatin hydrogels, the
      faster both the weight of the hydrogels and the gelatin radioactivity remaining
      decreased with time. The decrement profile of bFGF remaining in hydrogels was
      correlated with that of hydrogel weight and gelatin radioactivity, irrespective
      of the water content. Subcutaneous implantation of bFGF-incorporating gelatin
      hydrogels into the mice induced significant neovascularization. The retention
      period of neovascularization became longer as the water content of the hydrogels
      decreased. To study the decrease of activity of bFGF when implanted, bFGF
      incorporating hydrogels were placed in diffusion chamber and implanted in the
      mouse subcutis for certain periods of time. When hydrogels explanted from the
      mice were again implanted, significant neovascularization was still observed,
      indicating that most of the biological activity of bFGF was retained in the
      hydrogels. It was concluded that, in our hydrogel system, biologically active
      bFGF was released as a result of in vivo degradation of the hydrogel. The release
      profile was controllable by changing the water content of hydrogels.

PMID- 10358221
TI  - Preadipocyte seeded PLGA scaffolds for adipose tissue engineering.
AB  - Adipose tissue equivalents have not been addressed as yet despite the clinical
      need in congenital deformities, posttraumatic repair, cancer rehabilitation, and
      other soft tissue defects. Preadipocytes were successfully harvested from rat
      epididymal fat pads of Sprague-Dawley and Lewis rats and expanded ex vivo. In
      vitro cultures demonstrated full differentiation of preadipocytes into mature
      adipocytes with normal lipogenic activity. The onset of differentiation was well
      controlled by regulating preadipocyte confluency. Poly(lactic-co-glycolic) acid
      (PLGA) polymer disks with 90% porosity, 2.5 mm thick, 12 mm diameter, pore size
      range of 135-633 microm were fabricated and seeded with preadipocytes at 10(5)
      cells/mL. Disks in vitro demonstrated fully differentiated mature adipocytes
      within the pores of the disks. Short-term in vivo experiments were conducted by
      implanting preseeded disks subcutaneously on the flanks of rats for 2 and 5
      weeks. Histologic staining of harvested disks with osmium tetroxide (OsO4)
      revealed the formation of adipose tissue throughout the disks. Fluorescence
      labeling of preadipocytes confirmed that formed adipose tissue originated from
      seeded preadipocytes rather than from possible infiltrating perivascular tissue.
      This study demonstrates the potential of using primary preadipocytes as a cell
      source in cell-seeded polymer scaffolds for tissue engineering applications.

PMID- 10358222
TI  - Novel living skin replacement biotherapy approach for wounded skin tissues.
AB  - A novel living skin replacement (LSR) biotherapy concept, addressing the
      challenging problems related to tissue regeneration and wound healing, is
      presented for the treatment of skin burns, traumatic injuries and ulcerations.
      LSR combines elements of cell therapy along with those of tissue engineering to
      allow for the regeneration of wounded skin. It takes advantage of biodegradable
      microspheres onto which donor skin epidermal and dermal cells can be attached and
      expanded in vitro for subsequent direct application down to the deepest recesses
      of the wound bed. The key element of the biotherapy is the ability of the skin
      cells to migrate freely from the microspheres into the wound for regeneration of
      the tissues. The large surface to volume ratio of the microspheres allows for the
      delivery of appropriate cell numbers while minimizing the amount of biomaterial
      to be resorbed. This novel approach presents a number of advantages over existing
      therapies including facilitated cell manipulations, ease of storage and
      transportation, rapid clinical intervention due to the elimination of any
      surgical suturing or stapling, and a more natural three-dimensional tissue
      remodeling and anatomical compliance. Preliminary in vitro and in vivo evidence
      of the LSR functionality and its potential benefits is presented.

PMID- 10358223
TI  - Effects of immunoregulatory cytokines on the immunogenic potential of the
      cellular components of a bilayered living skin equivalent.
AB  - The purpose of this study was to determine if the immunocompatibility of an
      allogeneic living skin equivalent (LSE) would be affected by cytokines that would
      be potentially present at the wound site. Specifically, the ability of
      interleukin-1alpha (IL-1a), interleukin-6 (IL-6), or interleukin-12 (IL-12) to
      induce an allogeneic T cell response to "nonprofessional" antigen presenting
      cells (APC) was investigated in this series of experiments. Since cytokine
      concentrations at the wound site can vary greatly, recombinant IL-1a, IL-6, and
      IL-12 were used over a wide range of concentrations. These cytokines were either
      added directly to a mixed lymphocyte reaction (MLR) culture system or used to
      pretreat APC prior to use in the MLR culture. The addition of IL-12, IL-1alpha,
      or IL-6 into an MLR was examined as a possible means of providing the necessary
      costimulatory signal for functionally deficient APC, such as human keratinocytes
      (HK) and dermal fibroblasts (HF). While the results show that IL-1a and IL-12 can
      significantly augment a primary allogeneic response against appropriately
      equipped antigen presenting cells, the same was not true for HK or HF. Further
      experiments showed that pretreatment of HK, HF, or human umbilical vein
      endothelial cells (HUVEC) with Interferon-gamma (IFNgamma) and either IL-12,
      IL1alpha, or IL-6 had no significant affect on their ability to present
      alloantigen to immune-reactive T lymphocytes over IFNgamma-treatment alone. The
      data suggest that exposure of HK or HF to IL-1alpha, IL-6, or IL-12 in
      combination with IFNgamma does not provide the additional signal(s) required by
      these cells to effectively present alloantigen to unprimed T cells. The data
      suggests that exposure to these immunoregulatory cytokines in the wound bed would
      be unlikely to affect the immunocompatibility of the LSE.

PMID- 10358224
TI  - Hospital infection prevention and control: A global perspective.

PMID- 10358225
TI  - Effect of phenolic and chlorine disinfectants on hepatitis C virus binding and
      infectivity.
AB  - BACKGROUND: The purpose of this study was to evaluate the inhibitory activity of
      2 polyphenolic disinfectants and a chlorine compound (NaDCC) on hepatitis C virus
      (HCV) binding and infectivity. METHODS: VERO cells (a continuous cell line
      derived from cynomolgus kidney cells) suitable for analyzing HCV binding and
      replication, and the competitive reverse transcription (cRT-PCR) technique for
      HCV RNA molecules quantitative evaluation have been chosen as a methodologic
      approach for the antiviral activity testing. RESULTS: At their recommended use
      dilutions, polyphenolic disinfectants inhibited HCV binding and replication. The
      chlorine compound was ineffective, probably a result of its low concentration in
      the presence of protein substances in VERO cell cultures. CONCLUSIONS: Inhibition
      of HCV binding and replication by the tested polyphenolic associations confirm
      their value in instrument decontamination and environmental disinfection against
      this clinically important lipid virus.

PMID- 10358226
TI  - Credentialing, diversity, and professional recognition-foundations for an
      Australian infection control career path.
AB  - BACKGROUND: There are no regulatory, legislative, or professional criteria
      stipulating minimum qualifications or experience that a health care worker must
      meet to be capable of coordinating an Australian infection control (IC) program.
      Measurement of IC competence is important to protect the public and for the
      ongoing credibility and growth of the profession. METHOD: Our study group was all
      1078 nonmedical and nonindustry members of the Australian Infection Control
      Association in 1996. The survey examined perceived level of proficiency, level of
      education, and experience in health care and infection control. Almost three
      quarters (65%) of the members responded, and almost all (85%) of these
      respondents fulfilled the inclusion criterion of coordinating an IC program.
      RESULTS: Experience in IC ranged from less than 2 years (33.6%) to more than 20
      years (10.0%). The majority (65.0%) of infection control professionals (ICPs) had
      between 8 years and 12 years IC experience. The respective proportions of
      respondents' self-ranked levels of proficiency on a 5-point scale were novice
      (3.6%), advanced beginner (21.2%), competent (33.8%), proficient (34.7%), and
      expert (6.8%). Almost half (47%) of the novices agreed that a registered nursing
      (RN) qualification was required, whereas a majority (41%) of advanced beginners
      considered both an RN and a basic IC course (BASIC) were required. Competent ICPs
      agreed less often than the other levels about their requirements. However, 27% of
      competents identified a BASIC and an undergraduate degree (UG) as the minimum
      requirements for a competent ICP. Proficient ICPs agreed that they required an
      RN, UG, BASIC, and a postbasic course in IC. Nearly all experts (80.0%) agreed
      that they required an RN, UG, BASIC, postbasic course, and a course in hospital
      epidemiology (EP). Two thirds of experts expected a master's degree as a
      requirement. CONCLUSION: The Australian IC profession is in an exciting period of
      development; however, the variation in ICP perception of the most appropriate
      qualifications and experience threatens the credibility and viability of the
      profession. This variation indicates the need for a clear-cut pathway that
      includes a system of credentialing, recognition of expertise, adoption of
      divergent roles, and improved networking. This pathway will lead to an
      increasingly credible and viable IC profession in Australia. Developing IC
      communities globally can benefit from the Australian experience.

PMID- 10358227
TI  - Unusual genetic heterogeneity of Acinetobacter baumannii isolates in a university
      hospital in Italy.
AB  - BACKGROUND: Acinetobacter baumannii has become an increasingly important
      nosocomial pathogen, particularly in intensive care units (ICUs). The aim of this
      investigation was to study the molecular epidemiology of A baumanii in a
      university hospital in Italy. METHODS: All A baumanii isolates were collected and
      typed with phenotypic and genotypic methods during a 7-month period. A 1-year
      prospective surveillance of ICU-acquired infections was performed by using the
      National Nosocomial Infections Surveillance methodology. RESULTS: A baumanni
      accounted for 28.4% of all infections and 46.7% of all pneumonia acquired in the
      ICU, with a nosocomial infection rate of 12.4% or 8 infections per 1000 patient
      days. Risk factors for A baumannii acquisition in the ICU were mechanical
      ventilation and previous use of broad-spectrum antibiotics, whereas
      administration of carbapenems showed a significant protective effect. Pulsed
      field gel electrophoresis of genomic Apa I digests identified at least 5
      outbreaks in the ICU caused by 5 different clones, one replacing the other in a
      well-defined temporal order. CONCLUSIONS: Whereas the sequential temporal cluster
      of epidemic clones in the ICU is intriguing and requires further research, the
      clear evidence of cross-contamination of A baumannii isolates involved with
      infections in the ICU demands extensive preventive efforts.

PMID- 10358228
TI  - Prevalence of nonreporting behavior of sharps injuries in Taiwanese health care
      workers.
AB  - BACKGROUND: Health care workers (HCWs) were surveyed to identify factors
      associated with nonreporting behavior of sharps injuries (SIs) in Taiwan.
      METHODS: We surveyed 10,469 full-time medical, nursing, technical, and supporting
      personnel employed at 16 randomly selected hospitals from 132 available
      accredited teaching hospitals in Taiwan. Information about the most recent injury
      and reporting behavior after an SI were collected from July 1996 to June 1997 by
      using a pretested structured questionnaire. Eleven categories, including an open
      ended option, were provided for participants to explain their nonreporting
      behavior. RESULTS: Questionnaires were completed by 82.6% (8645) of our sample,
      of whom 87.3% reported to have experienced a recent SI. A used item was the most
      commonly (P <. 001) involved item in an SI, and SIs with a used item were
      significantly more likely (odds ratio 3.6; CI 95%, 3.03-4.26; P <. 001) to be
      reported compared with an SI that involved unused items. A total of 81.8% of
      injuries were not reported, with job category significantly affecting reporting
      behavior (P <.001). Medical staff had the highest nonreporting rate (85.2%).
      Although attendees of a prevention program were statistically more likely (P
      <.001) to report an injury compared with nonattendees, the level of reporting in
      both groups was not encouraging (21.3% and 17.2%, respectively). All reasons
      given for nonreporting were disconcerting, but none more so than the use of
      subjective assessment of risk by 21.7% of HCWs who did not report their injuries.
      Other reasons for not reporting SIs included that the item was unused (34%) and
      that the HCW was too busy to report the SI (14.9%), unaware of reporting
      requirements (14. 4%), or immune to hepatitis B virus (12.4%). CONCLUSIONS: With
      82% of SIs in Taiwanese HCWs going unreported, the expected national incidence
      will be seriously underestimated and impact the appropriateness of prevention
      programs. The very low rate of reporting suggests that the current reporting
      system requires simplification. Because most injuries involved used items, the
      reporting systems also should include a more responsive management component. The
      results also suggest that the current prevention programs, currently provided by
      the general nursing department, require expert content knowledge in infection
      control if nonreporting and SIs are to be reduced.

PMID- 10358229
TI  - Handwashing with soap or alcoholic solutions? A randomized clinical trial of its
      effectiveness.
AB  - BACKGROUND: The effectiveness of an alcoholic solution compared with the standard
      hygienic handwashing procedure during regular work in clinical wards and
      intensive care units of a large public university hospital in Barcelona was
      assessed. METHODS: A prospective, randomized clinical trial with crossover
      design, paired data, and blind evaluation was done. Eligible health care workers
      (HCWs) included permanent and temporary HCWs of wards and intensive care units.
      From each category, a random sample of persons was selected. HCWs were randomly
      assigned to regular handwashing (liquid soap and water) or handwashing with the
      alcoholic solution by using a crossover design. The number of colony-forming
      units on agar plates from hands printing in 3 different samples was counted.
      RESULTS: A total of 47 HCWs were included. The average reduction in the number of
      colony-forming units from samples before handwashing to samples after handwashing
      was 49.6% for soap and water and 88.2% for the alcoholic solution. When both
      methods were compared, the average number of colony-forming units recovered after
      the procedure showed a statistically significant difference in favor of the
      alcoholic solution (P <.001). The alcoholic solution was well tolerated by HCWs.
      Overall acceptance rate was classified as "good" by 72% of HCWs after 2 weeks
      use. Of all HCWs included, 9.3% stated that the use of the alcoholic solution
      worsened minor pre-existing skin conditions. CONCLUSIONS: Although the regular
      use of hygienic soap and water handwashing procedures is the gold standard, the
      use of alcoholic solutions is effective and safe and deserves more attention,
      especially in situations in which the handwashing compliance rate is hampered by
      architectural problems (lack of sinks) or nursing work overload.

PMID- 10358230
TI  - Infection control in a Brazilian regional multihospital system.
AB  - OBJECTIVE: This study describes the organization of infection control committees
      in a Brazilian multihospital system, identifying their major problems. Our goal
      is to discuss the main deficiencies in infection control and to target some
      interventions that can improve the efficiency of these actions in Brazilian
      hospitals. DESIGN AND SETTING: We used a descriptive epidemiologic design. We
      interviewed the chairs and the nurses of the infection control committees and
      visited the main areas to observe infection control in a multihospital system
      with 3146 beds. For analysis of the results, we performed a standardization
      process, establishing a score for each hospital by using infection control
      organization as a surrogate marker for quality outcome. The mean hospital scores
      for infection control, existence of policies, and infrastructure at each hospital
      were compared by using different stratification and multivariate analysis.
      RESULTS: Statistically significant differences were found among surveyed
      hospitals by using stratification by size, funding status, and presence of
      teaching activities. CONCLUSIONS: Diverse patterns of infection control
      organization were found among surveyed hospitals. Small hospitals represented the
      major problem in providing effective infection control. Chiefly for these
      hospitals, the epidemiologic indicators and the surveillance and control system
      proposed by the Brazilian Ministry of Health and based on the Centers for Disease
      Control and Prevention model showed poor suitability.

PMID- 10358231
TI  - Selected global health care activities of the Hospital Infections Program,
      Centers for Disease Control and Prevention.

PMID- 10358232
TI  - Infectious disease testing related to organ and tissue transplantation: results
      from a national laboratory survey.
AB  - BACKGROUND: The purpose of this national survey in the United States was to
      determine laboratory practices and policies related to infectious disease testing
      of tissue and organ donors. METHODS: Supplementary questions were asked of the
      laboratories that subscribe to the College of American Pathologists' 1996 Donor
      Center (DC-B) and Viral Markers (W1-B and W2-B) surveys. Only the laboratories
      that perform infectious disease testing for the purposes of organ and tissue
      transplantation were asked to respond to the survey. RESULTS: A total of 1563
      laboratories participated in the 1996 DC-B, W1-B, and W2-B surveys. A total of
      203 (13.0%) laboratories indicated that infectious disease testing was performed
      for purposes of tissue and organ transplantation. The majority (81. 1%) of
      respondents were hospital-based laboratories or regional blood centers. Variances
      existed in policies regarding type of testing, turnaround times, maintenance of
      frozen samples, confirmatory testing of positive screening tests, and the
      reporting of results. CONCLUSIONS: Various policies and procedures are practiced
      by laboratories that perform infectious disease testing related to
      transplantation, and standard guidelines do not currently exist. More data is
      needed to assess the variability of infectious disease testing of organ donors,
      as well as the need for standard guidelines.

PMID- 10358233
TI  - Intensive Care Antimicrobial Resistance Epidemiology (ICARE) Surveillance Report,
      data summary from January 1996 through December 1997: A report from the National
      Nosocomial Infections Surveillance (NNIS) System.
AB  - The Intensive Care Antimicrobial Resistance Epidemiology project has established
      laboratory-based surveillance for antimicrobial resistance and antimicrobial use
      at a subset of hospitals participating in the National Nosocomial Infections
      Surveillance system. These data illustrate that, for most antimicrobial resistant
      organisms studied, rates of resistance were highest in the intensive care unit
      areas and lowest in the outpatient areas. For most of the antimicrobial agents,
      the rate of use was highest in the intensive care unit areas in parallel to the
      pattern seen for resistance. These comparative data on antimicrobial use and
      resistance among similar areas (ie, intensive care unit or other inpatient areas)
      can be used as a benchmark by participating hospitals to focus their efforts at
      addressing antimicrobial resistance.

PMID- 10358234
TI  - Parenteral infusions bacterial contamination in a multi-institutional survey in
      Mexico: considerations for nosocomial mortality.
AB  - BACKGROUND: Parenteral infusions can be contaminated during administration
      (extrinsic contamination). A previous survey found that extrinsic contamination
      was not uncommon in a hospital in Mexico with lapses in aseptic techniques. To
      determine whether this problem exists in other similar institutions, we undertook
      a multi-institutional study. METHODS: We surveyed 6 hospitals (A to F) lacking an
      infection control committee to determine the level of extrinsic contamination. We
      visited each hospital and obtained samples of all the parenteral infusions in
      use, drawing 0.5-1 mL from the tubing injection port. Quantitative and
      qualitative bacterial cultures were performed. Chlorine levels of the tap water
      were measured. Visits were repeated until the survey was completed. RESULTS: A
      total of 751 infusions were cultured, of which 16 (2.13%) were contaminated.
      Hospital contamination rates varied from zero to 5.56%. Klebsiella pneumoniae was
      the most common isolate (10 cases). During the first sampling day in hospital C,
      the 7 infusions from the pediatric ward were found to be contaminated with a
      similar K pneumoniae strain. In-service education was started in this hospital.
      Infusion contamination was eliminated followed by a reduction in mortality rate.
      Overall, a higher risk for infusion contamination was noted for pediatric
      patients (P =.01, odds ratio = 3.28, 95% CI, 1.10-9.91) and in wards with
      inadequate water chlorine levels (P =. 02, odds ratio = 3.64, 95% CI, 1.08
      13.51). CONCLUSIONS: If the hospitals surveyed are representative of others in
      developing countries, an endemic level of parenteral infusion contamination could
      exist in many hospitals throughout the world.

PMID- 10358235
TI  - Who coordinates infection control programs in Australia?
AB  - BACKGROUND: Australian infection control practitioners (ICPs) have not been
      previously profiled. Knowledge of their practice is limited, making support and
      evaluation of their programs difficult. To investigate the current role,
      function, and attributes of this group, we undertook a national survey of members
      of the Australian Infection Control Association. METHODS: In 1996 a questionnaire
      was sent to all 1078 nonmedical and nonindustry members of the Australian
      Infection Control Association. More than half (65%) of the membership responded
      to the questionnaire, which measured demographics, experience, infection control
      training and education, staffing levels, perceived deficits, and managerial
      support. RESULTS: Our results indicate that the typical Australian ICP works in a
      public acute-care facility with fewer than 251 beds, has 6 years experience in
      the field, and has completed hospital-based nursing training. Surveillance was
      the activity that consumed most of the ICPs' time. The majority of ICPs had
      responsibilities in addition to infection control, and although they considered
      management to be supportive, additional clerical support was identified as an
      area for program improvement. CONCLUSIONS: We have provided the first
      comprehensive profile of Australian ICPs and their practices. Our findings compel
      professional associations, such as the Australian Infection Control Association,
      to address the following: standardization in practice and surveillance, provision
      of appropriate training and ongoing education, and encouragement of research
      initiatives by infection control staff. These strategies are the key to future
      evidence-based infection control and will ensure survival of this specialty in
      Australia.

PMID- 10358236
TI  - Prescribing practice for antibiotic prophylaxis for 3 commonly performed
      surgeries in a teaching hospital in Brazil.
AB  - BACKGROUND: The contribution of antibiotic prophylaxis to reduce surgical wound
      infection for some procedures is well known. In spite of extensive knowledge
      about the effectiveness of antibiotic prophylaxis, its administrative regimens
      are often inappropriate. METHODS: Antibiotic prophylaxis was evaluated in a
      university-affiliated community teaching hospital. Data were collected from
      medical records of patients undergoing cholecystectomy, hysterectomy, and
      herniorrhaphy during a 9-month observation period. A total of 598 procedures were
      observed. Data were collected about the patient, the surgery, and the antibiotic
      prophylaxis. RESULTS: Based on the existing guidelines, the choice to use the
      prophylactic antibiotic was correct in 75% of the cases. Of these cases, only 3%
      of the patients received the recommended regimen according to the proposed
      procedure. It was verified that antibiotic prophylaxis was performed more
      frequently in patients undergoing open cholecystectomy than laparoscopic
      cholecystectomy (P =.004). In 46% of the cholecystectomies, more than 4 doses
      were administered. In hysterectomy, a single dose was used in 54% of the
      patients, and the antibiotic was administered preoperatively in 80% of the cases.
      Prophylactic antibiotics were used in 47% of herniorrhaphies. CONCLUSION: The
      surgeons infrequently met the hospital guideline for antibiotic prophylaxis, and
      compliance varied by type of procedure.

PMID- 10358237
TI  - Possible role of cross-transmission between neonates and mothers with recurrent
      Clostridium difficile infections.

PMID- 10358238
TI  - Effect of laundering on the barrier properties of reusable surgical gown fabrics.

PMID- 10358239
TI  - Defining the clinical relevance of surgical barrier testing.

PMID- 10358241
TI  - Fine-tuning our terms.

PMID- 10358242
TI  - Temporomandibular joint remodeling in adolescents and young adults during Herbst
      treatment: A prospective longitudinal magnetic resonance imaging and
      cephalometric radiographic investigation.
AB  - The aim of this prospective study was to analyze and compare the
      temporomandibular joint adaptive mechanisms in 25 adolescent and 14 young adult
      Class II malocclusions treated with the Herbst appliance. Temporomandibular joint
      remodeling was analyzed by magnetic resonance imaging. In each subject, 4
      magnetic resonance images of both temporomandibular joints were available: before
      treatment, at the start of treatment (when the Herbst appliance was placed),
      during treatment (6 to 12 weeks after appliance placement), and after treatment
      (when the appliance was removed). Furthermore, effective temporomandibular joint
      changes (the sum of condylar remodeling, fossa remodeling, and condyle-fossa
      relationship changes) were analyzed with the aid of lateral cephalometric
      radiographs from before and after treatment. All subjects were treated to Class I
      or overcorrected Class I dental arch relationships, and their mandibles became
      significantly (P <.001) more prognathic. After 6 to 12 weeks of Herbst treatment,
      signs of condylar remodeling were seen at the posterosuperior border in 48 of the
      50 adolescent condyles and in 26 of the 28 young adult condyles. Bilateral
      remodeling of the mandibular ramus could be detected in 1 adolescent and 2 young
      adult patients. Signs of glenoid fossa remodeling at the anterior surface of the
      postglenoid spine were noted in 36 adolescent and 22 young adult
      temporomandibular joints. Effective temporomandibular joint changes during
      treatment were more horizontally directed and larger in both adolescents and
      young adult patients treated with the Herbst appliance than in an untreated group
      of subjects with ideal occlusion (Bolton standards). The increase in mandibular
      prognathism accomplished by Herbst therapy in both adolescents and young adults
      seems, in particular, to be a result of condylar and glenoid fossa remodeling.
      Because the Herbst appliance is most successful in Class II patients also at the
      end of the growth period, the treatment method could be an alternative to
      orthognathic surgery in borderline skeletal Class II cases. Magnetic resonance
      imaging renders an excellent opportunity to visualize the temporomandibular joint
      remodeling growth processes.

PMID- 10358243
TI  - Friction in perspective.
AB  - In the past, most frictional resistance studies have been conducted in a steady
      state condition that does not simulate the dynamics of the oral environment.
      Various oral functions as chewing, swallowing, speaking, etc, as well as the oral
      tissues contacting any orthodontic appliances, result in periodic, repetitive,
      minute relative motion at the bracket/arch wire interfaces several thousand times
      each day. This in turn affects the normal forces at the interfaces, and because
      frictional resistance is directly proportional to the normal force, a pilot study
      was undertaken to emulate the dynamic environment of the oral cavity and its
      effect on frictional resistance. Tests of a limited sample of stainless steel
      arch wires and brackets typically used in sliding mechanics revealed that
      frictional resistance was effectively reduced to zero each time minute relative
      movements occurred at the bracket/arch wire interfaces. Factors such as the
      degree of dental tipping, relative arch wire/slot clearances, and method of
      tying, did not have a measurable effect on frictional resistance in the simulated
      dynamics of the oral environment.

PMID- 10358244
TI  - Third molars: a dilemma! Or is it?
AB  - The purpose of this article is to review some of the pertinent studies related to
      the management of third molars in an orthodontic context. The clinician should
      base his or her decision to extract or not extract third molars on the most
      current scientific information and what is best for each individual patient.

PMID- 10358245
TI  - Endotoxin affinity for orthodontic brackets.
AB  - Endotoxin, cell envelope lipopolysaccharide produced by gram-negative bacteria
      can activate an immune response through a variety of pathways. In addition, it
      can stimulate bone resorption and reduce the periodontal tissue's healing
      capacity. Previous studies have documented the affinity of lipopolysaccharide for
      restorative materials. This study evaluated the affinity of lipopolysaccharide
      for commercially available orthodontic brackets. Stainless steel, ceramic,
      plastic, and "gold" brackets were exposed to 10 EU/mm2radiolabeled Porphyromonas
      gingivalis or Escherichia coli lipolpoysaccharide in water and incubated for 24
      hours at 37 degrees C. Brackets were then transferred to fresh lipopolysaccharide
      free water and incubated for 24 hours at 37 degrees C to evaluate elution. This
      elution transfer was continued up to 96 hours total incubation.
      Lipopolysaccharide adherence and elution levels were calculated after treatment,
      and elution solutions were evaluated through liquid scintillation spectrometry.
      Mean initial lipopolysaccharide adherence ranged from 2.42 +/- 0.26 EU/mm2(E.
      coli, plastic) to 6.75 +/- 0.34 EU/mm2 (P. gingivalis, stainless steel). P.
      gingivalis lipopolysaccharide adherence was significantly greater than E. coli
      lipopolysaccharide adherence for all bracket types. Moreover, for each
      lipopolysaccharide type, stainless steel brackets exhibited significantly greater
      lipopolysaccharide adherence. Regarding elution, only the P. gingivalis
      lipopolysaccharide-exposed ceramic and plastic brackets at 24 hours and the
      stainless steel and ceramic brackets at 48 hours eluted measurable
      lipopolysaccharide. Results from this study demonstrate that P. gingivalis and E.
      coli LPS exhibit a high affinity for orthodontic brackets. In vivo, this affinity
      could affect the concentration of LPS in the gingival sulcus, thereby
      contributing to inflammation in tissues adjacent to the brackets.

PMID- 10358246
TI  - Palatally ectopic canines: closed eruption versus open eruption.
AB  - This paper reviews the available evidence supporting 2 commonly used methods of
      surgically exposing palatally ectopic canines. The closed eruption method (a
      bonded attachment is placed at operation and the palatal flap is sutured back
      intact) is compared with the open eruption method (a window of palatal mucosa is
      excised and the canine allowed to erupt naturally). The choice of surgical
      technique is reviewed in terms of the long-term periodontal implications, the
      rate of repeat surgery, and treatment time.

PMID- 10358247
TI  - An ultrastructural study of the effects of bisphosphonate administration on
      osteoclastic bone resorption during relapse of experimentally moved rat molars.
AB  - This study was designed to clarify the effects of systemic administration of
      bisphosphonate, pamidronate, on the bone resorbing activity of osteoclasts during
      relapse of rat molars, after experimental movement. An elastic band was inserted
      between the upper first and second molars of 7-week-old rats and removed 21 days
      later. At 1 day before elastic band removal, bisphosphonate was administered via
      a tail vein. After elastic band removal, the rats were further maintained for 0,
      5, or 10 days. The relapse of the first molars was studied by means of light and
      scanning-electron and transmission-electron microscopy. When an elastic band was
      removed, the mean interdental distance between the first and second molars in all
      rats was approximately 435 micrometer. In the control rats, it had decreased to
      108 micrometer by day 5 and 57 micrometer by day 10. In these control rats,
      numerous osteoclasts appeared along the alveolar bone surface in the compressed
      side of the periodontal ligament of first molars. Administration of
      bisphosphonate significantly inhibited the prominent decrease in interdental
      distance. In these rats, it averaged 313 micrometer at day 5 and 115 micrometer
      at day 10. In bisphosphonate-treated rats, osteoclasts aggregated mainly in
      vascular canals of alveolar bone but were occasionally observed along the
      alveolar bone surfaces facing the periodontal ligament. Administration of
      bisphosphonate also induced structural changes, such as disappearance of ruffled
      borders and cytoplasmic polarity, in osteoclasts. A degenerated osteoclast was
      also observed in a bisphosphonate-treated rat. However, bisphosphonate induced no
      structural changes in osteoblasts, osteocytes, or periodontal ligament
      fibroblasts. These results suggest that a single systemic administration of
      bisphosphonate decreases the extent of initial relapse in experimentally moved
      rat molars via a mechanism involving impairment of the structure and resorptive
      functions of osteoclasts.

PMID- 10358248
TI  - Multilingual bracket treatment combined with orthognathic surgery in a skeletal
      class III patient with facial asymmetry.
AB  - A case report is presented on a female adult with a Class III mandibular
      protrusion. Resolution of her dentoskeletal problem required a combination of
      comprehensive multibonded orthodontic mechanotherapy and orthognathic surgery.
      The patient preferred a multilingual bracket appliance because of esthetics. Both
      surgical and orthodontic treatment were quite successful in the correction of the
      facial profile and occlusion. Both psychological and esthetic satisfaction were
      achieved.

PMID- 10358249
TI  - Tongue muscle activity after orthodontic treatment of anterior open bite: a case
      report.
AB  - A case report of a Class I malocclusion with an anterior open bite and
      bimaxillary dental protrusion was presented. The patient had a tongue thrust
      swallow and slight lisping. After the treatment, significant adaptation in
      electromyographic pattern of genioglossus muscle activity during swallowing was
      determined. However, remarkable change in the electromyographic pattern of the
      genioglossus muscle did not occur during chewing.

PMID- 10358250
TI  - Bonded molar tubes: a retrospective evaluation of clinical performance.
AB  - This study investigated time to first failure of stainless steel orthodontic
      first permanent molar tubes (Ormco Corp) bonded with a light-cured resin adhesive
      (Transbond) and assessed whether this was related to patient gender, age of the
      patient at the start of treatment, the presenting malocclusion, or the operator.
      All first molar tubes were bonded to intact buccal enamel, free of any
      restoration. Survival analysis was carried out on data from 483 patients with
      1190 bonded first molar tubes. For each case, a single molar tube, either that
      which was first to fail or had the shortest follow-up time, was chosen for
      analysis. The median time until first bonded tube failure was 699 days with an
      overall failure rate of 21% recorded. There was no significant difference in time
      to first failure of molar tubes with respect to patient gender or presenting
      malocclusion but significant differences were recorded with respect to the
      patients' age at the start of treatment and the operator. Age at the start of
      treatment and operator were identified as independently useful predictors of
      bonded molar tube survival.

PMID- 10358251
TI  - The effectiveness of protraction face mask therapy: a meta-analysis.
AB  - This study examined the effectiveness of maxillary protraction with orthopedic
      appliances in Class III patients. A meta-analysis of relevant literature was
      performed to determine whether a consensus exists regarding controversial issues
      such as the timing of treatment and the use of adjunctive intraoral appliances.
      An initial search identified 440 articles relating to Class III malocclusion.
      Among those articles, 11 studies in English and 3 studies in foreign languages
      met the previously established selection criteria. Data from the selected studies
      were categorized by age and appliance groups for the meta-analysis. The sample
      sizes were comparable between the groups. The statistical synthesis of changes
      before and after treatment in selected cephalometric landmarks showed no distinct
      difference between the palatal expansion group and nonexpansion group except for
      1 variable, upper incisor angulation, which increased to a greater degree in the
      nonexpansion group. This finding implies that more skeletal effect and less
      dental change are produced in the expansion appliance group. Examination of the
      effects of age revealed greater treatment changes in the younger group. Results
      indicate that protraction face mask therapy is effective in patients who are
      growing, but to a lesser degree in patients who are older than 10 years of age,
      and that protraction in combination with an initial period of expansion may
      provide more significant skeletal effects. Overall mean values and corresponding
      standard deviations for the studies selected can also be used to estimate mean
      treatment effects expected from the use of protraction face mask.

PMID- 10358252
TI  - Interleukin-1beta and beta-glucuronidase in gingival crevicular fluid from molars
      during rapid palatal expansion.
AB  - This study examined whether the inflammatory mediators interleukin (IL-1beta) and
      beta-glucuronidase (betaG) are present in the gingival crevicular fluid (GCF) of
      children undergoing rapid palatal expansion and whether their levels vary upon
      activation of the appliance and movement of the maxillary first molars. Nine
      adolescent patients who needed palatal expansion were studied. Each patient
      received a periodontal prophylaxis and instruction in proper home care, including
      rinsing with chlorhexidine. Four weeks later, a modified Hyrax appliance was
      inserted. The jackscrew was activated twice daily until the appropriate expansion
      was achieved. GCF samples were collected at 2 pretreatment observation periods
      and 9 observation periods after placement of the appliance. Samples were
      collected with filter paper strips and analyzed by means of ELISA and time
      dependent fluorometry for IL-1beta and betaG, respectively. The values recorded
      at the observation period 2 weeks after the periodontal prophylaxis were used as
      baseline. Paired t tests were used to compare mediator levels at this baseline to
      the levels obtained at each of the subsequent observations. The results indicate
      that (1) betaG and IL-1beta are present in GCF of young, healthy individuals, (2)
      their levels decrease following a strict regimen of plaque control, (3)
      orthodontic/orthopedic forces evoke changes in the levels of the inflammatory
      mediators IL-1beta and betaG in the periodontal tissues that can be detected in
      GCF. The results of this study support the hypothesis that mechanical stimulus
      causes an inflammatory reaction within the periodontal tissues, which in turn may
      trigger the biological processes associated with bone remodeling.

PMID- 10358253
TI  - Masticatory muscle function in patients with spinal muscular atrophy.
AB  - The purpose of this study was to determine whether spinal muscular atrophy
      affects masticatory muscle strength and mandibular range of motion. A sample of
      15 subjects with spinal muscular atrophy was compared to a sample of age-matched
      and sex-matched controls. Maximum bite force, masticatory muscle electromyography
      activity, mandibular ranges of motion and masticatory muscle endurance were
      evaluated. Results showed that maximum bite forces were one-half as great for the
      sample with spinal muscular atrophy than for the controls, even though their EMG
      activity was not significantly different. Slopes of the relationship between
      electromyography activity and bite force were two to four times steeper for
      patients with spinal muscular atrophy than controls. Maximum opening and
      protrusion were reduced to approximately one-half control values. Fatigue times
      of patients with spinal muscular atrophy were reduced by 30% (17.9 seconds versus
      11.1 seconds). We conclude that the masticatory muscles of patients with spinal
      muscular atrophy are weakened, that their muscles are less efficient, and that
      they fatigue more quickly than controls. In addition, mandibular movements of
      these patients take place over a more limited range than unaffected controls.

PMID- 10358254
TI  - Phase III CCRE option 

PMID- 10358255
TI  - Morphing and warping: Part II.

PMID- 10358256
TI  - Deja vu all over again.

PMID- 10358257
TI  - Assessment of Physical Growth and Pubertal Development.
AB  - Growth is far too complex to be described only in terms of height and weight in
      relation to age. In addition to addressing multiple factors that have clinical
      value in the assessment of growth in adolescence, this chapter discusses the
      interpretation of growth data, growth at puberty, and methods of predicting
      height at maturity.

PMID- 10358259
TI  - Diagnosis and Treatment of Pubertal Disorders.
AB  - This chapter begins with a discussion of normal puberty and goes on to address a
      number of pubertal disorders, including delayed puberty, chromosomally
      incompetent gonadal failure, chromosomally competent gonadal failure, eugonadism,
      central and peripheral precocity, and others. The ages by which various
      milestones should be reached also are described.

PMID- 10358258
TI  - Disorders of Pubertal Development: Too Early, Too Much, Too Late, or Too Little.
AB  - Major disturbances of pubertal development and variations of normal puberty are
      discussed. The authors highlight four kinds of pubertal disorders: "too early"
      (precocious puberty), "too much" (gynecomastia, macroorchidism, and
      hyperandrogenism), "too late" (delayed puberty), and "too little" (hypogonadism).

PMID- 10358260
TI  - Psychosocial Issues Associated with Short Stature.
AB  - Adolescents do not innately conclude that being short is undesirable; they learn
      it through environmental interactions. The authors of this chapter address
      society's expectations and perceptions regarding short stature as well as the
      effects of growth hormone treatment on the psychosocial status of both children
      and adults. They conclude that all short children should have the benefit of the
      evaluation and management of psychosocial problems.

PMID- 10358261
TI  - Adolescent Thyroid Disorders.
AB  - Thyroid disorders are common in adolescents; in fact, they occurred in 3.7% of
      children between the ages of 11 and 18 in one study. Early recognition and
      treatment of these conditions can help to minimize their effects. Here, the
      author details the epidemiology, diagnosis, and clinical management of
      hypothyroidism, hyperthyroidism, thyroid nodules, and cancer.

PMID- 10358262
TI  - Diabetes in Adolescence.
AB  - Recognizing adolescence as a transient developmental phase characterized by rapid
      physical growth, emotional adjustment, and sexual maturation can provide the
      health care team with strategies for dealing with diabetes in adolescents.
      Hormonal adaptations in adolescents, microvascular complications, emotional
      factors, clinical management, and issues such as nutrition and sex and marriage
      are described.

PMID- 10358263
TI  - Contribution of Molecular Biology to Pediatric and Adolescent Gynecology.
AB  - The authors address a few of the contributions that molecular biology has offered
      over the past five years to the fields of reproductive medicine and pediatric and
      adolescent gynecology. They cover a gamut of issues, from subtyping of human
      papillomavirus infection to the analysis of abnormal sexual differentiation.

PMID- 10358264
TI  - Pediatric Adolescent Gynecologic Imaging: Precocious Puberty and Hormone
      producing Neoplasms.
AB  - Evaluating children with precocious puberty or a hormone-producing neoplasm can
      be a challenging and time-consuming clinical task that, if done thoroughly, can
      prove to be well worth the time and effort. A detailed analysis allows the
      physician to prescribe the best diagnostic and cost-efficient work-up. Here, the
      author describes the use of various imaging techniques in precocious puberty and
      neoplasms.

PMID- 10358265
TI  - Breast Disorders in Female Adolescents.
AB  - Although breast malignancies are a rarity in adolescents, all symptoms and
      complaints concerning the breast must be evaluated as they would be in adult
      women. Screening techniques, including the use of fine-needle aspiration, and
      conditions that affect the breast are discussed.

PMID- 10358266
TI  - Hormonally Active Organ Tumors in Children and Adolescents.
AB  - Ovarian tumors are the most frequent genital neoplasms found during childhood and
      adolescence. The authors of this chapter cover feminizing ovarian tumors
      including juvenile granulosa cell tumors, nongestational ovarian choriocarcinoma,
      and others-and masculinizing ovarian tumors such as Sertoli-Leydig cell tumors,
      gynandroblastoma, and steroid cell tumors.

PMID- 10358267
TI  - Hyperandrogenemia: Clinical Perspectives.
AB  - Hirsutism may be the only presenting factor in a number of serious endocrinologic
      or neoplastic diseases. In order to treat hirsutism, the physician must determine
      and eliminate the underlying cause, a process that may require medical, surgical,
      or radiotherapeutic interventions. Physiology, evaluation, and treatment of
      hirsutism are detailed in this chapter.

PMID- 10358268
TI  - Abnormal Uterine Bleeding in the Adolescent.
AB  - Although excessive or unpatterned uterine bleeding is normal in adolescents, and
      most girls with abnormal bleeding will develop normal menstrual cycles, a
      significant number will experience persistently abnormal uterine bleeding.
      Following a discussion of the normal menstrual cycle, the authors detail the
      causes, evaluation, therapy, and prognosis of abnormal bleeding.

PMID- 10358269
TI  - Physiology of Puberty.
AB  - Sequential changes in endocrine activity bring about the remarkable physical and
      psychological changes of puberty. The physical changes of puberty in girls and
      boys are discussed and the onset of both gonadal and adrenal activity at puberty
      is described and illustrated.

PMID- 10358270
TI  - Epidemiology of Chronic Health Conditions in Adolescents.
AB  - Knowledge of the epidemiology of chronic conditions in adolescents is necessary
      to ensure that these patients "do not slip through the cracks in our health care
      infrastructure." This comprehensive chapter reviews the major sources of
      epidemiologic data and the limitations of such data, presents sociodemographic
      characteristics of adolescents with chronic health conditions, and compares and
      contrasts prevalence rates.

PMID- 10358271
TI  - Reciprocal Influences between Chronic Illness and Adolescent Development.
AB  - Chronic illness can affect an adolescent's physical, cognitive, and psychosocial
      development, and, conversely, adolescent development can influence both the
      natural course and medical management of a chronic disease. Providers who are
      aware of this reciprocal relationship and the "feedback loop" to which it can
      lead can intercede and optimize the management of chronic illness in adolescents.

PMID- 10358272
TI  - Educational Issues in Adolescents with Chronic Illness.
AB  - A once overlooked situation, the education of people with disabilities has over
      the past 20 years gained the attention of educators, lawmakers, and health care
      providers. Among the many issues addressed here are legal requirements for public
      education, the role of health care providers in education, eligibility for
      special education services, and the transition to post-secondary education,
      training, and employment.

PMID- 10358273
TI  - Access to Health Care for Adolescents and Young Adults with Disabilities.
AB  - One of every six adolescents lacks health care coverage, and many adolescents
      avoid medical care regardless of whether it is covered. In this chapter, the
      author explores health care financing, programs that guarantee services, access
      to care in a reformed health care system, organization of services, and other
      factors affecting chronically ill adolescents.

PMID- 10358274
TI  - Transition from Pediatric to Adult-Oriented Health Care for the Adolescent with
      Chronic Illness or Disability.
AB  - Adolescents and young adults with chronic conditions are given fewer
      opportunities to be independent health care consumers than their peers, and the
      transition from pediatric to adult-oriented care can be particularly difficult.
      For many chronically ill patients, transition medical services may be
      appropriate. The need for such services and ways to provide them are discussed.

PMID- 10358275
TI  - The Adolescent with Cystic Fibrosis.
AB  - The authors strive to give readers a sense of what it is like to care for
      adolescents with cystic fibrosis. Through case studies, they describe topics that
      are relevant to the care of patients with CF, including fertility and
      reproduction, compliance and independence, psychosocial functioning, terminal
      illness, recreational drug use and suicide, social issues, and other factors.

PMID- 10358277
TI  - Advances in the Treatment of Adolescents with Sickle Hemoglobinopathies.
AB  - This detailed review of sickle hemoglobinopathies covers their incidence and
      epidemiology, pathophysiology, diagnosis, clinical manifestations, complications,
      and organ changes. Issues such as pregnancy and birth control in patients with
      sickle cell disease, surgery and anesthesia, and medical management are also
      discussed.

PMID- 10358276
TI  - Caring for Adolescent Cancer Survivors: Surveillance and Intervention for Delayed
      Sequelae of Malignancy and Its Treatment.
AB  - General practitioners often find themselves caring for adolescents who have
      survived childhood cancer. This chapter reviews the treatment of childhood cancer
      and the medical and behavioral sequelae that may become apparent during
      adolescence. Recommendations for patient care are also described.

PMID- 10358278
TI  - Solid Organ Transplantation in Adolescents: The Blessing and the Curse.
AB  - This chapter addresses the medical dimensions of solid organ transplantation in
      adolescents, with particular emphasis on renal, liver, and heart transplantation.
      It frames the impact of organ transplantation in the context of adolescent
      development and recommends appropriate team strategies to manage these patients.

PMID- 10358279
TI  - The Adolescent with Traumatic Brain Injury: Cognitive, Psychological, and
      Educational Issues.
AB  - Traumatic brain injury kills and disables more adolescents than AIDS or cancer.
      Far from being an isolated event, these injuries shape the evolution of the
      adolescent's self-knowledge and social-emotional interactions. The authors focus
      on the cognitive, psychological, and educational issues facing professionals who
      care for adolescent survivors of brain injuries.

PMID- 10358280
TI  - Adolescent Spinal Cord Injury: Considerations for Post-Acute Management.
AB  - The authors equip clinicians with information useful for the post-acute care of
      adolescents with spinal cord injury. Chapter sections cover the epidemiology of
      spinal cord injury and its costs to society, the common medical problems that
      affect adult and adolescent patients, and special problems that uniquely affect
      the management of these patients.

PMID- 10358281
TI  - Health Care for Deaf Adolescents.
AB  - In an attempt to make up for a dearth of literature on deaf adolescents, the
      author offers a definition of "deafness" and "deaf culture" in the U.S., explains
      the social roles that people take depending on their audiologic and social
      characteristics, discusses controversies surrounding American Sign Language, and
      suggests ways for practitioners to approach and offer services to deaf
      adolescents.

PMID- 10358282
TI  - The National Health Care Reform Debate.
AB  - Because of increasing costs and decreasing access, most policymakers agree with
      the public perception that the health care system in the United States is in need
      of change. This chapter summarizes the various proposals under consideration,
      which ranges from a single-payer model similar to the system in Canada to the
      less radical concept of managed competition.

PMID- 10358283
TI  - Administrative Medicine: A Primer.
AB  - The growing complexity of the health care industry has led to a corresponding
      growth in the time and energy devoted to its administrative growths. The authors
      define the concept of the "physician executive" and discuss major issues related
      to the discipline, including its advantages and disadvantages.

PMID- 10358284
TI  - The Challenges of Change: Conducting an Environmental Opportunity Analysis for
      Medical Practices.
AB  - The current climate of health care reform reinforces the need for physicians to
      consider the various factors that ensure sustained success in their practice. The
      author outlines the steps required for an accurate environmental opportunity
      analysis and discusses the appropriate organizational responses.

PMID- 10358285
TI  - How to Write a Scientific Paper and Get if Published.
AB  - Despite the high expectation for publication of medical articles, many medical
      students do not receive as much guidance in writing papers as was once the case.
      The authors discuss the major priorities in targeting a specific journal and
      preparing a manuscript that requires minimal revision.

PMID- 10358286
TI  - Grant Writing: A Three-Step Process.
AB  - Drawing on seminar presentations and interviews with foundation representatives,
      grant writers, and a federal grant reviewer, the author provides an overview of
      the grant-writing process from conceptualization to submission.

PMID- 10358287
TI  - The Appropriate Use of Computers and Telecommunications in Medicine.
AB  - Although health care financial and administrative functions have been aided by
      computers for some time now, clinical practice has remained relatively
      unaffected. The author examines why clinicians have not made wide use of
      information systems, discusses technologic developments expected in the near
      future, and describes how medical informatics can have a positive effect on
      clinical practice.

PMID- 10358288
TI  - A Consulting Model for Physicians.
AB  - This chapter presents a comprehensive model of medical consultation, including a
      systemic view of the consultant-consultee relationship and the 10-phase content
      of the consultation process.

PMID- 10358290
TI  - Teaching Adolescent Medicine Physicians How to Teach.
AB  - The authors discuss how the faculty member's learning experiences affect his or
      her approach to teaching and working with residents. Also included is a checklist
      to air the faculty member in identifying his or her personal style.

PMID- 10358291
TI  - Lessons from the Past: The Importance of the History of Medicine.
AB  - In addition to its inherent interest, the study of medical history reinforces the
      intellectual and humanistic qualities that make the practice of medicine unique.

PMID- 10358289
TI  - Social Learning Theory as a Basis for Office Counseling: A Tool for the Primary
      Care Physician of the 1990s.
AB  - The increasing dependence of patients on primary care physicians for guidance in
      developing healthy lifestyles and managing psychosocial issues is particularly
      important to practitioners of adolescent medicine. The authors discuss the
      relevance of social learning theory to the special challenges posed by adolescent
      patients.

PMID- 10358293
TI  - Ethical Issues in Research on Adolescents.
AB  - Health threats to adolescents, such as violence, pregnancy, and drug abuse,
      require scientific research to expand the current base of knowledge. The authors
      discuss the ethical issues relevant to studies involving adolescent subjects.

PMID- 10358292
TI  - The ethics of decision making with adolescents: what a physician ought to know.

PMID- 10358294
TI  - Homosexuality in Adolescence.
AB  - Gay and lesbian adolescents are a reality, although they are often invisible
      within a heterosexual culture. Physicians need to be informed of the special
      stresses and problems that affect their transition to healthy adulthood.

PMID- 10358295
TI  - Sports Medicine: An Introduction to Organizational Aspects.
AB  - The authors define the concepts of the sports medicine team and network and
      discuss related ethical and legal issues.

PMID- 10358296
TI  - Youth with Chronic Conditions in Transition to Adult Health Care: An Overview.
AB  - The growing number of young adults with chronic conditions necessitates a careful
      consideration of the issues involved in their transition from a child-focused to
      an adult-oriented health care system.

PMID- 10358297
TI  - Measles.
AB  - Recent outbreaks of measles have reestablished the disease as an important
      pathogen. Various aspects of measles reviewed here include epidemiology, clinical
      presentation, complications, occurrence in pregnancy, prevention, and therapy
      with vitamin A and ribavirin.

PMID- 10358298
TI  - Rubella.
AB  - Despite a 99% reduction in the incidence of rubella in the United States since
      the introduction of rubella vaccine, rubella continues to strike groups such as
      college students, prison inmates, recent immigrants, and populations that lack
      access to health care. The author discusses rubella's clinical manifestations in
      adolescents, cogenital rubella syndrome, diagnostic strategies, and
      immunizations.

PMID- 10358299
TI  - Hepatitis B and Delta in Adolescents.
AB  - Acute and chronic hepatitis B affect a large number of adolescents, and their
      complications are major causes of morbidity and mortality. The authors emphasize
      the importance of targeting adolescents for prevention and discuss the most
      recent diagnostic and therapeutic advances concerning both the hepatitis B and
      hepatitis delta viruses.

PMID- 10358300
TI  - Infectious Hepatitis A and Enteric Hepatitis E.
AB  - Infectious hepatitis A and enteric hepatitis E have a peak incidence in late
      adolescence or young adulthood. Using a 14-year-old boy as an example, the
      authors trace the course of hepatitis A through the preicteric and icteric
      phases, the development of persistent jaundice, relapse, and liver failure. The
      discussion of hepatitis E addresses microbiology and clinical course of the
      condition.

PMID- 10358301
TI  - Varicella-Zoster Virus Infections in Adolescents.
AB  - Adolescents are susceptible to both chickenpox and shingles, and they become more
      ill and more likely to be hospitalized than younger patients infected with
      varicella. Issues such as diagnosis, therapy, infection control, and prevention
      are reviewed as they relate to both varicella and zoster.

PMID- 10358303
TI  - Cytomegalovirus Infection in Adolescents.
AB  - The incidence of cytomeglovirus in adolescents is high, and congenital CMV
      infection is a major problem for infants born to teenaged mothers. The authors
      review the biology, epidemiology, clinical manifestations, diagnosis, treatment,
      and prevention of CMV infection.

PMID- 10358302
TI  - Herpes Simplex Virus Infections in Adolescents.
AB  - The intensity of herpes simplex virus in adolescents can range from trivial to
      life-threatening and, because therapy should begin early, a high index of
      suspicion is required. Various forms of HSV-1 and HSV-2 infections addressed here
      includes gingivostomatitis, anogenital infection, herpetic whitlow, eye
      infections, encephalitis, and infection in the immunocompromised host.

PMID- 10358304
TI  - Epstein-Barr Infections in Adolescents and Young Adults.
AB  - In the United States, Epstein-Barr virus is acquired primarily in late
      adolescence. Acute infectious mononucleosis and other syndromes, complications,
      and atypical infections associated with EBV are described, as are the
      differential diagnosis, management, and treatment.

PMID- 10358305
TI  - Chronic Fatigue Syndrome.
AB  - Despite its new name, chronic fatigue syndrome is not a new disease. This chapter
      reviews current definitions, emphasizing that chronic fatigue syndrome is a
      diagnosis of exclusion. The author also discusses viral infections that are
      associated with CFS, including Epstein-Barr virus, cytomegalovirus, herpesvirus
      type 6, enteroviruses, and retroviruses.

PMID- 10358306
TI  - Human Papillomavirus Infections of the Genital Tract in Adolescents.
AB  - The author describes both the histopathologic and molecular diagnosis of human
      papillomavirus in the lower genital tract. The wide range of other issues that
      are addressed include transmission to adolescent girls, prevalence in sexually
      active adolescents, prognosis of papillomavirus and cervical intraepithelial
      neoplasia, and prevention and treatment.

PMID- 10358307
TI  - Epidemiology and Prevention of Traffic-related Injuries Among Adolescents.
AB  - Traffic-related injuries are the leading cause of mortality and injury morbidity
      among adolescents. This chapter presents a review of the epidemiology of traffic
      related injury during adolescence, summarizes the effectiveness of the major
      interventions that have been implemented, and identifies the gaps in research in
      this area.

PMID- 10358308
TI  - The Changing Risks of Drowning for Adolescents in the U.S. and Effective Control
      Strategies.
AB  - Drowning is the second leading cause of unintentional injury death among
      adolescents. The authors describe the epidemiology of adolescent drowning and
      near-drowning; review the literature with emphasis on what is known about risk
      factors, treatment, and prevention; and identify the gaps in our knowledge on the
      circumstances surrounding submersion injuries in this age group.

PMID- 10358309
TI  - Suicide: Epidemiology, Prevention, and Treatment.
AB  - The number of adolescent and young adult suicides is substantial and is
      increasing. The rate has tripled over the past 30 years, making suicide the third
      leading cause of death in the 15- to 19-year-old age group. The authors discuss
      the demographic characteristics, risk factors, biologic markers, prevention,
      "postvention," and treatment of the suicide among adolescents.

PMID- 10358311
TI  - Family Violence and Development during Adolescence.
AB  - Adolescence is a time of major physical, emotional, social, and personal
      development. This chapter focuses on how these developmental issues are related
      to the types, causes, outcomes, prevention, and treatment of family violence
      involving adolescents. As adolescents are not well represented in the family
      violence literature, the authors conclude the chapter with a section on the need
      for further research in this area.

PMID- 10358310
TI  - "Number One with a Bullet": Epidemiology and Prevention of Homicide among
      Adolescents and Young Adults.
AB  - Homicide has become the leading cause of untimely death among black adolescent
      males in the U.S. and the second leading cause of death for young people overall.
      The authors review adolescent homicide statistics, discuss the epidemiology of
      homicide among young people, examine the crucial role firearms (and handguns in
      particular) play in this process, and suggest potential strategies for prevention
      and intervention.

PMID- 10358312
TI  - Occupational Injuries: Epidemiology, Prevention, and Treatment.
AB  - The authors review the current data on patterns of adolescent employment and
      examine the epidemiology of work-related injuries among adolescents in the U.S.
      They summarize the laws that have been created to protect adolescents against
      exploitation and injury in the workplace and the erosion of those measures that
      has occurred since 1980. Finally, the authors offer recommendations for the
      diagnosis and prevention of occupational injury among adolescents.

PMID- 10358313
TI  - Adolescent Injury Prevention in Primary Care.
AB  - Primary care providers, on the frontline of health care delivery, have an
      opportunity to see adolescents in the office or clinic and to provide counseling
      that can reduce injuries among adolescents. After an initial discussion on the
      barriers to such efforts, the authors offer a framework for the role of primary
      care clinicians in injury prevention, with practical guidelines for implementing
      counseling in practice. The authors also provide extensive information on
      resources available to improve skills in this area and for referring patients who
      need additional counseling or management, and they urge that providers
      participate in community activities related to injury prevention.

PMID- 10358314
TI  - Peer Violence Prevention Programs in Middle and High Schools.
AB  - As the place where adolescents spend a significant portion of their time-and the
      place where an increasing amount of violence is occurring-schools have become a
      primary location for violence-prevention activities. This chapter describes the
      range of school-based interventions currently being employed, comments on the
      availability of data regarding their effectiveness, and offers recommendations
      for improving the research and practice of violence prevention in school
      settings.

PMID- 10358315
TI  - Post-traumatic Stress Disorder in Adolescents: Risk Factors, Diagnosis, and
      Intervention.
AB  - Research on violent trauma and other high-magnitude threats has confirmed that
      exposure to severe traumatic experiences is predictive of later psychopathology
      in young persons, including post-traumatic stress disorder (PTSD). Here the
      authors summarize the literature on child and adolescent PTSD, paying particular
      attention to elements that diverge from the adult disorder and implications
      specific to prevention and treatment in the adolescent.

PMID- 10358316
TI  - The Mass Media: A Role in Injury Causation and Prevention.
AB  - Researchers in recent years have begun to examine the role of the mass media both
      in contributing to adolescent violent behavior and as a valuable means of
      intervention. This chapter examines the role of the mass media in contributing to
      violent behavior, suicide, and alcohol consumption and abuse. For each area of
      discussion, the authors review the literature on the media's contribution to
      these health problems as well as suggestions for prevention strategies that
      involve the mass media as a tool for education.

PMID- 10358317
TI  - Acute Abdomen.
AB  - Abdominal pain is a common complaint in adolescents, and its evaluation is
      challenging. This article provides a method of evaluating the adolescent with
      acute abdominal pain, reviews the more common causes that may lead to surgical
      intervention, and provides algorithms for determining a specific diagnosis and
      mode of treatment.

PMID- 10358318
TI  - Chronic Abdominal Pain.
AB  - Chronic or recurrent abdominal pain is poorly defined, often associated with
      extra-abdominal symptoms, and most likely caused by a multitude of entities. The
      author presents what is know about the causes, treatment, and natural history of
      chronic abdominal pain, stressing the need for a multidisciplinary approach to
      this vexing problem.

PMID- 10358319
TI  - Evaluation and Management of the Adolescent with Infectious Diarrhea.
AB  - Infectious diarrhea continues to be an important cause of morbidity and mortality
      throughout the world and is a common problem in adolescents. It is frequently
      related to travel, ingestion of contaminated water, and food poisoning. This
      article presents an approach to the evaluation and management of the adolescent
      who presents with diarrhea.

PMID- 10358320
TI  - Gastrointestinal Reflux in Adolescents.
AB  - Gastrointestinal reflux disease in otherwise healthy adolescents is relatively
      uncommon. The frequency increases with other chronic medical conditions, such as
      cerebral palsy, asthma, and cystic fibrosis-and GERD should be included in the
      differential diagnosis of a wide range of airway and GI complaints. In this
      article, the authors review the clinical manifestations, pathophysiology,
      diagnosis, and treatment of GERD as it relates to the adolescent.

PMID- 10358321
TI  - Peptic Ulcer Disease in Adolescents.
AB  - This article discusses the pathophysiology, diagnosis, and treatment of peptic
      ulcer disease in adolescents, focusing on the recently recognized pathogen,
      Helicobacter pylori, as an etiologic agent in this disorder.

PMID- 10358322
TI  - Inflammatory Bowel Disease.
AB  - Inflammatory disease comprises at least two forms of chronic intestinal
      inflammation: Crohn's disease and ulcerative colitis. This article reviews the
      epidemiology, cause and pathogenesis, clinical presentation and course, potential
      complications, and treatment of both Crohn's disease and ulcerative colitis.

PMID- 10358323
TI  - Acute and Chronic Pancreatitis.
AB  - Pancreatitis, once thought to be almost exclusively a disease of adults, is
      increasingly being found as the cause of abdominal pain in adolescents. The
      authors review the pathophysiology, diagnosis, managment, and complications of
      acute and chronic pancreatitis, noting that a high index of suspicion is needed
      to properly diagnose and provide optimal care to these patients.

PMID- 10358324
TI  - Gastrointestinal Manifestations of Cystic Fibrosis in Adolescence.
AB  - Because of advances in diagnosis and treatment, cystic fibrosis patients are
      living longer. With increased survival, intestinal, pancreatic, and hepatobiliary
      involvement causes significant disease. In this article, the authors focus on the
      gastrointestinal, nutritional, and hepatobiliary manifestations of cystic
      fibrosis that may be encountered in the older child and adolescent.

PMID- 10358325
TI  - Adolescent Human Immunodeficiency Virus Infection and Gastrointestinal Disease.
AB  - Since 1987 the presence of HIV infection among adolescents has grown
      dramatically. Gastrointestinal complications in HIV infection are a very diverse
      group of problems, all of which can cause significant morbidity and occasional
      mortality. This article discusses these GI disorders and recommends diagnostic
      studies and therapeutic options for this group of patients.

PMID- 10358326
TI  - Adolescent Gallbladder Disease.
AB  - Gallbladder disease in adolescents, although not uncommon, has been neglected in
      the literature, which is unfortunate because adolescents possess a unique set of
      characteristics. Drawing on the relevant available literature, the author
      outlines our current knowledge about gallbladder disease in adolescents.
      Particular attention is devoted to gallstone formation, associated medical
      conditions, and predisposing risk factors.

PMID- 10358327
TI  - Acute Hepatitis.
AB  - The acute onset of hepatitis may occur in adolescents as a result of hepatic
      damage from infectious agents, drugs, or toxins, or it may be the initial
      presentation of a chronic autoimmune or metabolic liver disease. The authors
      characterize the clinical features of each of these disorders emphasizing
      recognition and diagnosis.

PMID- 10358328
TI  - Chronic Hepatitis.
AB  - Advances in the ability to treat primary causes of chronic liver disease in the
      adolescent have highlighted the importance of making a prompt diagnosis. Using a
      case study, this article reviews the clinical findings suggestive of chronic
      liver disease and the causes responsible in the adolescent. As the case evolves,
      an efficient strategy for diagnosing each possibility is presented and
      therapeutic modalities are reviewed.

PMID- 10358329
TI  - PRIMARY GASTRIC LYMPHOMA.

PMID- 10358330
TI  - Genomic imprinting in human biology and pathology.
AB  - Evidence has been recently provided on the relevant role of genomic imprinting in
      the regulation of implantation, embryonic development, placental growth, and also
      in development of proliferative trophoblastic diseases and human carcinogenesis.
      Among the various imprinted genes the cyclin-dependent-kinase inhibitor p57KIP2
      (maternally imprinted) is particularly interesting since it can function as a
      tumor suppressor gene. In this review we describe the different roles of genomic
      imprinting in human diseases, with particular emphasis on the role of p57KIP2 in
      molar pregnancy and in tumorigenesis.

PMID- 10358332
TI  - Clinical assessment of renal vascular involvement and clinical-pathological
      correlations.
AB  - The renal vascular involvement of systemic diseases can be of embolic, thrombotic
      or inflammatory nature. Occlusion of proximal arterial vessels results in a
      dissociation between the rapid progression of renal failure, and the urinary
      abnormalities. Urine examination can be nearly normal and non revealing, except
      for a loss in maximal concentrating ability. In contrast, inflammatory changes of
      distal vessels are variably transmitted to the glomeruli, resulting in
      proteinuria, variable hematuria associated to mixed abnormalities of the urinary
      sediment. In diffuse vascular involvement acute renal failure can supervene,
      difficult to distinguish from that of diffuse glomerulonephritides. Most systemic
      vasculitides, mainly those of SLE, microscopic polyangiitis, Henoch-Schoenlein
      purpura and that of Wegener granulomatosis cause a clinical picture either of
      acute, rapidly progressive glomerulonephritis, or of a nephritic syndrome. The
      vasculitides affecting small arteries, capillaries and venules can result in a
      clinical-histopathologic picture closely mimicking that of acute tubule
      interstitial disease. A thorough evaluation of the clinical picture, of the
      degree and progression of renal failure, of urine analysis, and clinically guided
      biopsies of the appropriate tissues can lead to differentiation of the different
      diseases and precocious diagnosis and effective treatment.

PMID- 10358331
TI  - Cerebrospinal lesions simulating central nervous system neoplasm.
AB  - There is a significant number of inflammatory, vascular or demyelinating diseases
      which may simulate clinically and radiologically primary or metastatic neoplasms
      of CNS. An incorrect diagnosis of CNS tumor may cause a fall of treatment plans
      including radiation therapy and chemotherapy. Not infrequently to define a
      correct diagnosis such cases require surgical procedures. The present report
      reviews the pathologic features of these space-occupying lesions presenting with
      signs and symptoms suggestive of brain neoplasms. Surgical pathologists may
      encounter diagnostic difficulties particularly when dealing with small tissue
      samples. The knowledge of basic histological features of these non-neoplastic
      conditions or the application of immunohistochemical and in situ hybridization
      techniques are essential to their recognition.

PMID- 10358333
TI  - P170 (Pgp) expression in leukemic cells after therapeutic exposure to arabinosyl
      cytosine.
AB  - The expression of the mdr-1 gene coding for a transmembrane 170 KD glycoprotein
      (P170 or PGP) is an important cause of multidrug resistance (MDR). In tumor cells
      the expression of the gene may vary and there is experimental evidence that it
      can be induced by exposure to MDR-unrelated agents. We investigated if the
      therapeutic exposure to Arabinosyl Cytosine (AC) could affect the level of P170
      expression in the blast cells of acute non-lymphocytic leukemia (ANLL). The
      reactivity to the P170-directed MRK 16 monoclonal antibody of the marrow blast
      cells from 27 patients with ANLL prior and after treatment with standard dose AC
      was evaluated by flow cytometry. After treatment with AC the MRK 16 mean
      fluorescence index (MFI) was increased in 5/18 cases of primary and previously
      untreated ANLL and in 7/9 cases of relapsed or secondary leukemia. Overall, the
      mean value of the MFI was 6.8+/-3.6 before and 9.0+/-3.8 after AC (P=0.001,
      Wilkoxon matched pairs test). Therapeutic exposure to AC in vivo may increase
      P170 expression in leukemic cells. This may influence the definition and the
      quantitation of resistance and may have therapeutic implications, concerning the
      association with other cytotoxics and the use of MDR modifiers.

PMID- 10358334
TI  - Novel heart diseases requiring transplantation.
AB  - Cardiac transplantation represents an extraordinary opportunity to study in vivo
      the pathology of native disease in the terminal phase. The experience cumulated
      at the University of Padua in 418 orthotopic cardiac transplant procedures
      allowed to come across previously unrecognized disease: idiopathic left
      ventricular aneurysm, non-compacted (spongy) myocardium, restrictive
      cardiomyopathy. A discrepancy between pre- and post-transplant diagnosis was
      found in 8% of cases. Endomyocardial biopsy and coronary arteriography should be
      carried out in each patient with apparently dilated cardiomyopathy before
      proceeding to heart removal, since alternative therapeutic procedures may be
      available.

PMID- 10358335
TI  - Biochemical markers of perioperative myocardial ischemia in patients with
      coronary artery bypass grafting.
AB  - Aims of the study: The evaluation of significant perioperative ischemic processes
      after coronary artery bypass grafting from postoperative ECG, creatine kinase
      (CK) and CK iso-enzyme MB remains unreliable and, hence, insufficient.
      Additional, early available biochemical markers could improve the diagnostics of
      ischemia. Methods: In 86 patients with multiple vessel disease, activity of serum
      CK and CK-MB as well as mass of CK-MB, myoglobin and troponin-T were analyzed
      before and after surgery. Twelve-lead electrocardiograms were evaluated before
      surgery, 3h postoperatively, and before discharge from hospital. Results: In
      patients with signs of perioperative ischemia in the 3-hour ECG, primary
      postoperative peak values of myoglobin and CK were distinctly higher than in
      patients without signs of ischemia, with median values of 1437 ng/ml vs. 986
      ng/ml for myoglobin and of 632 U/l vs. 481 U/l (n.s.) for CK. Sensitivity and
      specificity of myoglobin were 64 % and 69 %, followed by CK with 61 % and 62 %,
      respectively. Conclusions: Myoglobin, indicating the risk of perioperative
      ischemia approximately 45 minutes after declamping of the aorta, is suggested as
      a candidate for early available routine monitoring.

PMID- 10358336
TI  - Histopathology of vanishing bile duct diseases.
AB  - This manuscript reviews and summarizes the histopathology of the liver in the
      various "vanishing bile duct diseases". These represent conditions associated
      with progressive disappearance of intrahepatic bile duct branches. Congenital
      diseases of this nature comprise so-called extrahepatic bile duct atresia and
      paucity of interlobular bile ducts (syndromic and non-syndromic). In the adult,
      vanishig bile duct diseases are represented amongst others, by primary biliary
      cirrhosis, primary sclerosing cholangitis, idiopathic adulthood ductopenia, liver
      allograft rejection, graft-versus-host disease and drug-induced and toxic
      cholangitis.

PMID- 10358337
TI  - Myxoid tumors of soft tissues: a challenging pathological diagnosis.
AB  - Myxoid tumors (Mts) of soft parts constitute an heterogeneous group of lesions
      characterized by a similar bland, hypocellular morphological appearance,
      reminiscent primitive mesenchyma. In this article the overall diagnostic approach
      is presented with reference to clinical characteristics and distinctive
      histological criteria. In particular for intramuscolar myxoma, superficial
      angiomyxoma, aggressive angiomyxoma low grade fibromyxoid sarcoma, myxoid
      liposarcoma, extraskeletal myxoid chondrosarcoma and myxofibrosarcoma, we discuss
      the diagnostic clues and the differential diagnosis with regard to
      immunohistochemical, ultrastructural and molecular genetic characteristics.

PMID- 10358339
TI  - Real-time diagnoses in telepathology.

PMID- 10358338
TI  - Autologous stem cell transplantation for multiple myeloma: a single centre
      experience.
AB  - Thirty-two patients with multiple myeloma (MM) were autografted in our Centre
      over a 3-year period. Twenty-three patients had a newly diagnosed MM submitted to
      one induction regimen and 9 had a refractory or relapsing disease treated with at
      least two different chemotherapy lines: 15 out of 32 patients were sensitive to
      conventional treatment. In 2 patients BM was harvested while in the majority PBSC
      were collected after administration of 7 g/m2 Cyclophosphamide plus G-CSF (in 25
      patients) or G-CSF alone at the dose of 16 microg/Kg/daily for 5-7 days (in 5
      patients). Conditioning regimen was busulfan 16 mg/Kg plus melphalan 120 mg/m2.
      One patient died of cerebral hemorrhage after reinfusion of PBSC. Out of 31
      evaluable patients, 24 (77%) had a response which was complete in 6 patients
      (19%) and partial in 18 patients (58%), 5 cases (17%) had no response, and 2 (6%)
      showed myeloma progression. There was a statistical difference in the outcome
      between newly diagnosed and pretreated patients (p = 0.003). At a median follow
      up of 9 months (range 5-37), two patients had died for progression and 3 out of
      the 29 alive, relapsed after 17, 18 and 36 months respectively. Although median
      overall survival was not reached, there was a significant survival benefit for
      autografted patients in comparison with a matched control group conventionally
      treated in our Centre before 1994 (p = 0.02).

PMID- 10358341
TI  - Telepathology by the internet.

PMID- 10358340
TI  - Telepathology and Cytology in Kyoto, JAPAN, to Support Regional Medicine, with
      Special References to Their Need, Accuracy and Cost.

PMID- 10358342
TI  - Histkom - evaluation of active telepathology in fieldtests.

PMID- 10358343
TI  - A feasibility study of a static-robotic telepathology system for remote
      diagnosis.

PMID- 10358344
TI  - Validation of realtime telemicroscopy. A preliminary report on 184 cases.

PMID- 10358345
TI  - Remote quantitation in the framework of telepathology.

PMID- 10358347
TI  - Second opinion consultation through the Internet. A three years experience.

PMID- 10358346
TI  - Quality control measures for dna image cytometry in a telepathology network.

PMID- 10358348
TI  - Image quality and acceptance of telepathology.

PMID- 10358349
TI  - A pilot study of low-cost dynamic telepathology using the public telephone
      network.

PMID- 10358351
TI  - Still image consultations via e-mail in surgical pathology. A study of diagnostic
      accuracy.

PMID- 10358350
TI  - Neuropathological consultation by means of telepathology: A clinical tool for
      imposing diagnosis of rare and difficult cases.

PMID- 10358352
TI  - Telepathology-second opinion network in Yugoslavia.

PMID- 10358353
TI  - Telepathology, images, and multimedia archives.

PMID- 10358354
TI  - Benefits of image databank supporting the telepathology system.

PMID- 10358356
TI  - Application of telemedicine technologies for the diabetes care of patients in
      greek rural areas.

PMID- 10358357
TI  - Telecardiology over health care intranet.

PMID- 10358355
TI  - The ph-net project: a feasibility study for isdn based applications of
      telemedicine in the orthopaedic field.

PMID- 10358359
TI  - Interoperability aspects within a telepathology network.

PMID- 10358358
TI  - Image acquisition devices for telepathology.

PMID- 10358360
TI  - MedLink, a telemedicine framework.

PMID- 10358362
TI  - Etiology and primary prevention of cancer.

PMID- 10358361
TI  - Is todays telepathology equipment also appropriate for telecytology? A pilot
      study with pap and blood smears.

PMID- 10358363
TI  - The relevance of genetics and molecular pathology in mesenchymal tumours.
AB  - Genetic and molecular analyses of soft tissue tumours have provided a great
      amount of valuable information over the past ten years. One of the most useful
      diagnostic application is tumour types. Technical advances in techniques such as
      FISH as well as RT-PCR permit, now, the analysis of archival material, expanding
      further the practical usefulness of genetic analysis. Genetics has also proved
      useful as a tool for validating current classification schemes, which still
      represent a source of endless debate. On the basis of cytogenetic data, relevant
      subsets of mesenchymal neoplasms are now categorised more rationally. Molecular
      pathology has greatly contributed to a better understanding of the mechanisms
      involved in both the pathogenesis and the progression of soft tissue sarcomas.
      Furthermore, the analysis of distinct subsets of tumours has shown that
      abberations involving the control of the cell cycle machinery exhibit a certain
      degree of tumour specificity. This wealth of information provides the necessary
      scientific background for both innovative therapeutic approaches and
      epidemiologic strategies for tumour prevention.

PMID- 10358365
TI  - New trends of teleimaging in medicine.
AB  - After a comparison between traditional tele-imaging and traditional PACS
      approaches, the progressive fusion of these two fields of tele-medicine is
      discussed. The need for suitable protocols at different levels and their current
      availability are pointed out. Benefits of the introduction of relational
      databases and of distributed archives are considered. Finally, the integration of
      different types of images, data, signals and reports is presented as the final
      goal of tele-medicine programs.

PMID- 10358364
TI  - DNA content, apoptosis and mitosis in transplanted human hearts.
AB  - Aim of the study: To analyze the changes in DNA content, the percentage of
      apoptosis and the nuclear mitotic frequency of myocytes in transplanted human
      hearts. Methods: Twenty-three transplanted hearts were obtained from 22 patients.
      The mean interval between transplantation and death was 649 days (ranging from 13
      to 2558 days). Ten control hearts were selected from individuals whose death was
      not due to primary heart disease. Tissue samples were obtained from the mid
      section of the lateral wall of left and right ventricles. DNA content was
      evaluated on isolated myocardial cells using image cytometry. In situ detection
      of apoptosis was performed by the terminal deoxynucleotidyl transferase-mediated
      digoxigenin-dUTP nick-end labeling (TUNEL) technique. Mitotic figures were
      examined by staining the nuclear DNA with YOYO-1 iodide. Myocytes were
      distinguished from stromal cells by using antibodies reacting with a-sarcomeric
      actin. Results: Comparing with control hearts, the myocytic changes after cardiac
      transplantation are characterized by: 1) a decrease in mononucleated myocytes and
      an increase in binucleated and multinucleated myocytes; 2) a decrease in diploid
      myocytic nuclei and a distinct augmentation of intermediate ploidies; 3) an
      increase in myocytic nuclei in DNA ploidies higher than 4c; 4) a marked
      augmentation of percentage of apoptotic myocytes and 5) an increased frequency of
      nuclear mitosis of myocytes; this fact appears as a declining phenomenon after
      six months of cardiac transplantation. Conclusion: After cardiac transplantation
      the DNA content of myocytes shows two completely different aspects: 1) a distinct
      increase in subdiploidy and intermediate ploidies related to myocyte injury
      induced by apoptosis and necrosis; 2) an increase in multinucleation,
      polyploidization and mitotic proliferation. Both myocyte growth and myocyte
      injury alter the function of the allograft and contribute to adaptation or
      failure of the graft. Furthermore, a relevant difference of age between the
      recipient and the donor may lead to a more marked myocyte damage and a lower
      myocyte growth. This tendency provides an evidence that age matching could be an
      important aspect in selecting the donor for the recipient.

PMID- 10358366
TI  - Retroperitoneal nodular fasciitis: magnetic resonance imaging (MRI) and
      pathological features.
AB  - A case of pelvic nodular fasciitis, with particular reference to its peculiar
      radiological and pathological features is described. Only a few cases of pelvic
      nodular fasciitis are reported in the English literature and at the best of our
      knowledge, this is the first case of retroperitoneal origin. This report
      discusses the role of MRI in the characterization of soft tissue masses. No
      specific MRI findings of nodular fasciitis were identified and MRI doesn't add
      any contribution to the differential diagnosis between benign and malignant
      lesions. As a consequence, the histopathological examination is necessary for a
      definitive diagnosis.

PMID- 10358367
TI  - 13th International Meeting, Adriatic Society of Pathology Proceedings of a
      symposium. Rijeka, Croatia, June 26-28, 1998.

PMID- 10358368
TI  - Quantitative analysis of AgNOR proteins: a reliable marker of the rapidity of
      cell duplication and a significant prognostic parameter in tumour pathology.
AB  - The rate at which a tumour proliferates represents an important parameter for
      predicting the clinical outcome of patients with neoplastic diseases. Rapidly
      growing tumours are expected to have a worse behaviour than slowly proliferating
      ones, and there is increasing evidence that high growth-rate cancers require
      aggressive treatment for better control of the disease. Cell kinetics data are,
      therefore, useful for pathologists and clinical oncologists in order to obtain
      valuable prognostic information and to define the most appropriate therapeutic
      strategy in single cases. Over the past 20 years, several methods of cell
      proliferation assessment have been developed and employed in routine pathology.
      Among these, the quantitative analysis of AgNOR proteins (namely the argyrophilic
      proteins of the nucleolar organiser regions) has recently been proposed as a
      reliable indicator of the rapidity of cell duplication. In the present review,
      the relationship between AgNOR protein expression and cell proliferation rate is
      discussed, and the principal applications of the AgNOR protein parameter as a
      prognostic marker in tumour pathology are reported.

PMID- 10358369
TI  - Prostatic intraepithelial neoplasia and prostate cancer: analytical evaluation.
AB  - For urologists and pathologists one of the two main issues in prostate pathology
      is the identification of those prognostic factors that could predict the exact
      outcome of individual patients with prostate cancer (PC). Therefore, the goal is
      to tailor the therapeutic approach to the clinical, morphological and biological
      features of each patient. The other issue involves the early detection of PC,
      preferably in the preinvasive phase, in order to treat the patient efficaciously.
      For this reason, understanding the biology of preinvasive or precursors lesions
      has become increasingly important. Prostatic intraepithelial neoplasia is only
      one of these lesions, and the best known to date. The role of others, such as
      atypical adenomatous hyperplasia, is considered as worth exploring. Prostatic
      intraepithelial neoplasia (PIN) represents the putative precancerous end of the
      morphologic continuum of cellular proliferations within prostatic ducts and
      acini. Two grades of PIN are identified (low grade and high grade), and high
      grade PIN is considered the direct precursor of invasive carcinoma. The continuum
      which culminates in high grade PIN and early invasive cancer is characterised by
      basal cell layer disruption, basement membrane disruption, progressive loss of
      markers of secretory differentiation, increasing nuclear and nucleolar
      abnormalities, increasing proliferative potential, and increasing variation in
      DNA content (aneuploidy). Clinical studies suggest that PIN predates carcinoma by
      ten years or more, with low grade PIN first emerging in men in the third decade
      of life. The clinical importance of recognising PIN is based on its strong
      association with carcinoma; its identification in biopsy specimens of the
      prostate warrants further search for concurrent invasive carcinoma. The issue of
      precursors of prostate cancer has several facets which reflect the multiplicity
      of patterns and variants of PC. A big step forward in understanding some basic
      aspects has already been made, especially in relation to PIN. More will be
      available soon. A large contribution to the management of isolated PiN lesions
      found in prostate biopsies is expected from molecular pathology and quantitation
      analysis.

PMID- 10358370
TI  - Anaplastic large cell lymphoma: a concept reviewed.
AB  - The development of the concept of anaplastic large cell lymphoma is reviewed. The
      subtypes of the tumor proposed in the literature, including the so-called
      Hodgkin's-like variant, are discussed both on morphological and clinical grounds.
      The more recent information on the genetic and molecular characteristics of the
      tumor (i.e. 2;5 translocation, formation of the NPM/ALK hybrid gene, and
      production of a specific protein) are presented: their possible implications in
      the future classification and clinical management of the neoplasm are discussed.

PMID- 10358371
TI  - Potential of endocervical lavage for cytogenetic investigation of fetal cells as
      determined by in situ hybridization.
AB  - Aims: Transcervical samples following endocervical lavage from 28 women
      undergoing pregnancy termination were analysed in terms of fetal cells content
      and suitability for in situ hybridization analysis. A non fluorescent protocol of
      hybridization coupled to specific cytological procedures was used for
      simultaneous recognition and investigation on syncitiotrophoblast fragments.
      Methods: A series of endocervical washings was randomised to cytobrushing
      samples. Cervical washings were performed using variable volumes of physiologic
      saline solution (2ml, 5ml, 10ml). Single target in situ hybridization for
      chromosomes 1 and 18 was applied for determining a model of efficiency. Syncitial
      cells were recognized by means of cytoplasmic and nuclear stainings obtained with
      Eosin G (Diff-Quik) and haematoxylin respectively. Results: When 5 - 10ml of
      sterile solution were flushed multiple fragments of syncitio-trophoblast were
      almost constantly recovered. Conversely using 2ml of flushing solution no
      syncitia at all could be retrieved. Fetal cells were collected only in 50% of
      cervical cytobrushing. The per cell hybridization efficiency was on average 50%.
      Following in situ hybridization, a normal number of signal-products (2) was found
      in all nuclei analysed. Conclusion: During endocervical washing the amount of
      volume used is a critical factor to allow successful recovery of fetal cells. By
      using 5 - 10 ml of injecting solution, enough fetal material was generally
      obtained from each individual to guarantee the cytogenetic investigation for two
      chromosomes. The use of Diff-Quik and haematoxylin staining coupled to bright
      field microscope facilitate the recognition of syncitia among a highly
      heterogeneous population of maternal cells. Further studies are ongoing to
      prospectively evaluate safety of the transcervical approach for sampling and
      analysis of fetal cells.

PMID- 10358372
TI  - Image quality and acceptance of Telepathology.
AB  - Aim: To evaluate the quality of components of electronic image, colortruth
      brightness and sharpness, via two capturing systems on acceptance of images,
      diagnostic accuracy and training effect. Methods: Ten histological and 4
      cytological cases of routined breast specimens were capturing by a pathologist in
      Germany via two different capturing systems. The images were digitalized and
      saved on a recordable compact disc with brief clinical informations, and sent to
      a pathologist in Thailand. The test pathologist viewed the images at his own
      station, imitating the environment as daily work and noted the results for the
      analysis. Slides were sent to perform glass-slide diagnosis (GD) and recorded.
      The results were analyzed concerning: overall image quality in each system;
      viewing time; diagnostic accuracy; training effect. Main results: Results of 102
      images are recorded as: number of images; score of the components of image
      quality; viewing Time; telepathology diagnosis (TD); glass-slide diagnosis (GD).
      Conclusions: 1. The capturing part plays an important role performing image
      quality and viewing time, resulting in the acceptance. 2. Electronic images of
      cytological cases are better in quality. 3. Training effect to view electronic
      images helped the acceptance of images used in telepathology, but did not help to
      increase the diagnostic accuracy in this study. 4. The reliability of electronic
      images is as high as viewing microscopic images in this investigation, especially
      in cytological cases via a good capturing machine.

PMID- 10358373
TI  - Discrete T-lymphocytic leptomeningitis of the ventral medullary surface in a case
      of Sudden Unexpected Infant Death.
AB  - The Authors report the case of a 4 month old female infant dying suddenly and
      unexpectedly. At post-mortem examination, nothing significant was found, except a
      focal T-lymphocytic brainstem leptomeningitis, involving the ventral medullary
      surface (VMS) particularly coincidental with the pyramids, with involvement of
      the outer layer of the nucleus arcuatus (NARC). Moreover, the NARC itself
      presented, on serial sections, interdigitated subdivisions. To the present
      authors' best knowledge, no case has been recordered in the literature, as yet,
      exhibiting VMS inflammation, evidently acquired (likely viral) in nature,
      associated to a NARC developmental defect, altogether bespeaking for the etio
      pathogenic importance of such a combined pathology of the central chemosensitive
      field among the long debated mechanisms of SIDS.

PMID- 10358375
TI  - 4th European Congress on Telepathology. Proceedings of a symposium. Udine, Italy,
      June 19-20, 1998.

PMID- 10358374
TI  - NESO meeting revisited.

PMID- 10358376
TI  - Experience based approach to interactive versus "store and forward"
      telepathology.

PMID- 10358377
TI  - Acquisition and transmission of images in anatomic pathology: our experience
      between Internet and ISDN.

PMID- 10358378
TI  - Teaching pathology using interactive image databank.

PMID- 10358379
TI  - The emerging role of MRI in coronary artery disease.

PMID- 10358380
TI  - Cardiac magnetic resonance imaging: technique and anatomy.
AB  - Recent advances achieved in Magnetic Resonance Imaging equipment and procedures
      allow a thorough study of the heart, yielding anatomic, functional and
      angiographic information. Spin-echo sequences are specific for heart morphology
      while gradient-echo sequences are fundamental to the functional study. Fast
      sequences reduce the examination times with the possibility of single breath-hold
      images. Coronary arteries can be directly visualized and cardiac perfusion can be
      assessed. Velocity encoded images allow flow quantification and with myocardial
      tagging, cardiac mechanics is accurately defined.

PMID- 10358381
TI  - Left ventricular function: MRI assessment.
AB  - Biplane left ventricular (LV) angiography has always been considered the standard
      of reference to measure LV volumes and ejection fraction (EF): however,
      angiographic measurements depend on the assumption of geometric models derived
      from two-dimensional information. MRI is the best technique to evaluate cardiac
      volumes and mass providing direct non geometric analysis of the ventricles with a
      high contrast resolution. Standard cine MRI is considered a time-consuming
      technique for acquisition and measurements; breath hold cine MRI and echoplanar
      imaging (EPI) non gated sequences are useful to reduce the acquisition time from
      a few minutes to a few seconds. The evaluation of the heart linear parameters
      (diameters, thickness), areas, volumes and mass is essential in the diagnosis of
      many heart diseases and in the assessment of the ventricular function. The
      modalities to evaluate LV measurements and to obtain functional parameters, the
      acquisition technique and flow analysis were analyzed in this study.

PMID- 10358382
TI  - Magnetic resonance imaging in the study of ischemic heart disease.
AB  - In ischemic heart disease, as compared to other procedures, Magnetic Resonance
      Imaging (MRI) offers the advantage of providing in a single diagnostic session an
      ample and reliable multiparametric analysis. The technological advances of recent
      years have been increasing exponentially and marked qualitative refinements are
      thus predictable in the near future for morphological, functional, perfusional
      and metabolic studies.

PMID- 10358383
TI  - MRI assessment of coronary artery disease.
AB  - With the application of magnetic resonance imaging (MRI) in clinical cardiology,
      important tools have been added to the currently available techniques for the
      evaluation of coronary artery disease (CAD). Technical advantages of MRI in
      comparison to established imaging techniques are the excellent spatial
      resolution, the characterization of myocardial tissue and the potential to
      acquire a three dimensional set of data. This allows the accurate assessment of
      left ventricular mass and volume and the determination of systolic wall
      thickening and wall motion abnormalities. Myocardial perfusion, metabolism and
      inducible myocardial ischemia with the use of pharmacological stress also can be
      assessed by MRI. Future technical improvements in real-time imaging and
      development of non-invasive visualization of the coronary arteries and coronary
      artery bypasses will constitute a considerable progress in clinical cardiology. A
      particular strength of MRI is the potential to encompass cardiac anatomy,
      function, perfusion, metabolism and coronary angiography in a single study. The
      replacement of multiple diagnostic tests with a single MR study allowing to
      assess different aspects of CAD may have a major impact on cardiovascular health
      care economics.

PMID- 10358384
TI  - Echocardiographic imaging in coronary artery disease: new techniques.
AB  - When analyzing left ventricular wall motion and thickening, two-dimensional
      echocardiography (2DE) represents a useful non-invasive tool for diagnosing and
      stratifying ischemic heart disease. New important technical advancements, such as
      harmonic imaging, allow to overcome limitations due to poor echocardiographic
      image quality in a large proportion of patients. Combination of exercise or
      pharmacological stress test with on-line echo images monitoring expands 2DE
      diagnostic and prognostic value in both ischemia or viability assessment. Study
      of contrast agents distribution is very promising for clarifying the complex
      interaction between myocardial perfusion and functional correlates, including
      myocardial stunning, hibernation and no-reflow phenomena. Direct visualization of
      epicardial coronary arteries and assessment of coronary artery blood flow has
      recently been demonstrated to be possible by either transthoracic (TTE) or
      transesophageal echocardiography (TEE). Acoustic quantification (AQ), automatic
      border detection (ABD), tissue Doppler imaging (TDI), and color kinesis are other
      technical modalities which may result to be useful for clinical evaluation of
      patients with either acute or chronic coronary syndromes.

PMID- 10358385
TI  - Myocardial SPECT in the study of ischemic heart disease detection of hibernating
      myocardium and evaluation of cost/benefit ratio.
AB  - From over ten years, the assessment of myocardial viability in akinetic zones
      (stunned or hibernating myocardium) is considered fundamental to the correct
      management of postinfarction patients. The assessment can be performed with
      myocardial scintigraphy (201Thallium rest-redistribution, dobutamine stress
      echocardiography, MRI, 18F-fluorodeoxyglucose PET). A number of experiences have
      shown that scintigraphy is very sensitive but poorly specific in the assessment
      of myocardial akinetic zones with contractile functional recovery after
      revascularization. However, most recent reports have highlighted that the
      recovery of contractile function is not the single purpose of myocardial
      revascularization; in fact, it is able to prevent or attenuate remodeling, the
      contractile reserve is maintained or enhanced, the diastolic function is
      improved, arrhythmias are prevented, symptoms and functional capacity are
      improved. Therefore, the role of very sensitive procedures as myocardial
      scintigraphy or MRI of the heart is still of major diagnostic and prognostic
      significance. The present socioeconomic situation and the most recent advances in
      cardiology tend to shift the clinician's interest from the diagnosis to the
      prognosis of patients with ischemic heart disease and consequently, from maximum
      diagnostic accuracy to the highest prognostic value and maximum cost/effective
      benefit. Therefore, the nuclear cardiologist must become familiar with this novel
      terminology and new diagnostic and prognostic end-points.

PMID- 10358386
TI  - Positron emission tomography for the assessment of myocardial viability: a
      synopsis of methods and indications.
AB  - An improvement of regional and global left ventricle dysfunction can be achieved
      in patients with coronary artery disease either by coronary revascularization
      with percutaneous transluminal coronary angioplasty or coronary artery bypass
      grafting. Several techniques have been developed to identify dysfunctional but
      viable myocardium. In the last decade, positron emission tomography (PET) with
      18F-fluorodeoxyglucose (18F-FDG) has been used for the detection of hibernating
      myocardium. It can accurately predict the recovery of abnormal wall motion in
      hibernating segments prior to surgery. In particular, assessment of viability
      with 18F-FDG is indicated in high-risk surgical candidates being considered for
      revascularization or transplantation. Moreover, patient selection criteria and
      economic consideration are also relevant for cost-effective use of the technique.

PMID- 10358388
TI  - Magnetic resonance blood flow mapping in ischemic heart disease.
AB  - With MR velocity mapping, volume flow can be calculated with high accuracy
      because of the simultaneous acquisition of mean velocity and area of the vessel.
      In addition, MR velocity mapping is the only imaging technique with the potential
      to acquire comprehensive information and is well suited for studying spatial and
      temporal patterns of flow in the human cardiovascular system. Moreover, recently,
      in vivo work in humans has shown good comparison of MRI coronary flow with
      intraarterial Doppler flow wire measurements both with and without navigator echo
      respiratory compensation, the latter being important because of blurring of the
      phase velocity maps caused by respiratory movements and problems with through
      plane flow in small vessels.

PMID- 10358387
TI  - MRI assessment of myocardial viability: comparison with other imaging techniques.
AB  - The identification of dysfunctional but viable myocardium in patients with
      coronary artery disease with or without a history of myocardial infarction is of
      paramount clinical importance since viable myocardial areas are most likely to
      benefit from revascularization, whereas revascularization of scar tissue will not
      lead to improvement of left ventricular function. In some patients cardiac
      catheterization itself already provides important clues to the presence of viable
      myocardium based on the degree of wall motion abnormalities, post-extrasystolic
      improvement of wall motion, the presence of collateral vessels or persisting
      angina in a patient with single vessel disease. However, due to the complexity of
      viability assessment especially in patients with severely depressed left
      ventricular function and multi-vessel disease, viability tests are usually
      requested after the results of coronary angiography are known. Among the
      diagnostic armamentarium to identify viable myocardium the most established
      techniques are single photon emission computed tomography (SPECT), positron
      emission tomography (PET) if available and dobutamine stress-echocardiography.
      With the application of magnetic resonance imaging (MRI) in clinical cardiology
      an important and exciting diagnostic tool has been added for the prospective
      identification of viable myocardium for purposes of guiding therapeutic
      interventions in individual patients. This article reviews comparative studies
      between MRI and established imaging techniques like PET, SPECT and dobutamine
      echocardiography with respect to the assessment of viable myocardium in patients
      with acute myocardial infarction and chronic coronary artery disease.

PMID- 10358390
TI  - Magnetic resonance assessment of coronary artery bypass grafts.
AB  - The increasingly widespread use of myocardial revascularization by aortocoronary
      bypass grafts and the frequent need for their angiographic control require
      noninvasive imaging procedures able to provide reliable information on their
      performance. After an overview of angiography as gold standard and the different
      imaging procedures of aortocoronary bypass grafts alternative to MRI,
      echocardiography, nuclear cardiology, X-ray or electron beam ultrafast CT, main
      MRI procedures for the study of aortocoronary bypass, are illustrated together
      with the results of the personal experience as those of navigator echo technique
      provided with cardiac and respiratory synchronization (91% sensitivity for
      aortocoronary bypass occlusion and 97% specificity for patency). In the near
      future, hardware and software refinements, intravascular contrast media and the
      application to aortocoronary bypass grafts of flowmetric techniques of phase
      velocity mapping will enable the evaluation of bypass stenosis and distal
      coronary arteries as well as a complete functional graft assessment.

PMID- 10358389
TI  - Coronary flow reserve: assessment by magnetic resonance imaging.
AB  - Coronary angiography has been the standard method for quantifying the severity of
      coronary artery stenosis, however its physiological relevance by angiography is
      imperfect. At present velocity-encoded cine phase contrast MRI is a non invasive
      technique that can provide accurate assessment of coronary flow volume and
      coronary flow reserve, validated in animal and human studies by Doppler flow
      measurement. MRI may be recognized as a comprehensive, widely available technique
      independent of any nuclear tracer or contrast media, for evaluation of the
      presence and physiological significance of a variety of heart diseases which
      compromise coronary flow reserve.

PMID- 10358391
TI  - MRI assessment of coronary stents.
AB  - Several types of coronary stents are poorly visualized by fluoroscopy. Until now,
      the only reliable procedure to establish coronary stent patency is to repeat
      coronary angiography. Purpose of this study was to localize previously placed
      coronary artery stents and to verify their patency with MR angiography. 13
      stented coronary arteries (6 RCA, 5 LAD, 2 LCx) were prospectively examined with
      MR angiography one day to 8 months after stent placement. 18 amagnetic stents (6
      Palmatz-Schatz, 6 Multilink, 5 Crossflex, 1 Wiktor) were imaged. Imaging was
      performed on a 1.5 T MR-system (GE Signa Horizon Echo Speed) with a phased array
      multicoil. Segmented k-space fast gradient-echo sequences (TR/TE/FA = 11/4.5/25
      degrees; views per segment = 8; matrix = 256 x 160; thickness = 3 mm; no gap)
      were acquired with and without fat suppression at several phases of the cardiac
      cycle within a single breath-hold. Images of consecutive slice location were
      shown in a cine format. Correlation with coronary angiography (standard of
      reference) was performed in all patients. No MRI-related adverse events were
      observed. All the stents were visualized as areas of signal loss. The length of
      the signal loss corresponded to the length of the stents in all 18 cases. Stents
      were more directly visualized on images without fat suppression. In all cases the
      patent blood flow distal to the stents was observed as a high-signal linear
      structure distal to the signal void, corresponding to stent patency at coronary
      angiography. It was concluded that breath-hold cine coronary MR angiography is a
      safe technique to visualize coronary artery stents. Stent location and patency
      can be noninvasively established with this technique.

PMID- 10358392
TI  - Magnetic resonance spectroscopy of ischemic heart disease.
AB  - An overview of the basic knowledge necessary to understand the procedure of
      Magnetic Resonance Spectroscopy of the myocardium and its most significant
      applications in the study of ischemic heart disease, is presented, with reference
      to the personal experience. The chemical shift phenomenon, the main techniques of
      spectroscopic localization and the general aspects of myocardial 31P and 1H
      Magnetic Resonance Spectroscopy, including proton decoupling and magnetization
      transfer, are illustrated. Postprocessing techniques before and after Fourier
      transform are mentioned. 31P Magnetic Resonance Spectroscopy allows the
      noninvasive assessment of the metabolism of high energy phosphates, PCr/ATP ratio
      in particular, in the in vivo myocardial tissue with significant applications in
      the diagnostic approach to ischemic patients with the support of provocative
      tests (dobutamine). 1H Magnetic Resonance Spectroscopy allows similar evaluations
      based on the peak of total creatinine.

PMID- 10358393
TI  - [Controversies in septic shock].

PMID- 10358394
TI  - [Interferon-alpha in the treatment of chronic myeloid leukemia].

PMID- 10358395
TI  - [Medical education and bedside examination of patients].

PMID- 10358396
TI  - [Mechanisms of essential arterial hypertension].
AB  - Despite a very simple haemodynamic equation of blood pressure (cardiac output
      multiplied by systemic vascular resistances), the precise mechanisms of essential
      hypertension are still unknown. Blood pressure level is determined by many
      physiologic systems which are submitted to complex interactions; the 2 main
      anomalies associated with hypertension are a primitive defect in renal excretion
      of sodium and an excessive rise of vascular tone. Hypertension is probably a
      polygenic disease, with several abnomalies in these systems interacting with a
      particular environment. Genetic data have recently reinforced this concept by
      demonstrating a link between hypertension and particular alleles of candidate
      genes in some population groups.

PMID- 10358398
TI  - [Impact of arterial hypertension on the heart].
AB  - Heart involvement in systemic hypertension more often consists of a concentric
      left ventricular hypertrophy, rather than of an eccentric hypertrophy or of a
      left ventricular remodeling. These morphological abnormalities are seen in 25% of
      the hypertensive patients and can easily be diagnosed by using echocardiography.
      Underlying mechanisms of hypertensive left ventricular hypertrophy are of 2
      types: mechanical, mainly leading to myocyte hypertrophy; neuro-hormonal, mainly
      resulting in a fibroblastic proliferation. Associated with hypertensive left
      ventricular hypertrophy is a poor spontaneous prognosis: arrhythmias, myocardial
      ischaemia (with or without narrowings of epicardial arteries), abnormalities in
      left ventricular diastolic function. Anti-hypertensive drugs result in an
      additional benefit, in terms of cardiovascular morbidity and mortality, when both
      a reduction in blood pressure and a regression of left ventricular hypertrophy
      can be achieved.

PMID- 10358399
TI  - [Impact of essential hypertension on the arteries].
AB  - Arterial remodeling has emerged as a key-concept in the pathophysiology of
      hypertension and its vascular damage. In any given arterial territory,
      hypertension-induced remodeling is characterized by an increased intima-media
      thickness, independently of the lumen and wall cross-sectional areas. Functional
      consequences of hypertension-induced arterial remodeling depend upon the caliber
      of the artery, and thus upon its function. In essential hypertension, the 2 major
      functional consequences of large artery remodeling are the long-term enhancement
      of atherosclerosis and the shorter-term preservation of elastic properties. The
      functional consequences of resistive arteries remodeling can be either
      deleterious (structural increase in peripheral vascular resistances,
      hyperreactivity to vasomotor stimuli, and decrease in perfusion reserve of target
      organs) or rather compensatory (changes in the autoregulation of regional
      perfusions).

PMID- 10358397
TI  - [The measurement of arterial pressure and the diagnosis of hypertension].
AB  - Blood pressure measurement remains the determining factor in defining
      hypertension. In daily practice, measurement in the practitioner's office is the
      reference used for diagnosis and follow-up. According to the classification
      established in the VIth Report of the NIH Joint National Committee in 1997, the
      upper normal value is below 139 mmHg for systolic and 89 mmHg for diastolic
      pressure. Hypertension cannot be confirmed by a single high measurement or at a
      single consultation. In addition, it should be remembered that: self-measurement
      should remain under medical control; its upper normal values (135/85) have the
      advantage of being obtained outside the medical setting; exercise tolerance
      tests, often using an ergometric bicycle, demonstrate the possibility of
      cardiovascular adaptation to physical exercise; ambulatory blood pressure
      measurement affords repeated measurements over 24 h, also with lower reference
      values (135/85 mmHg), and detects "white coat" hypertension and anomalies of the
      nycthemeral cycle.

PMID- 10358400
TI  - [Absolute risk and treatment decisions in hypertensive patients].
AB  - The clinical practice, based on the dichotomy between hypertension or
      normotension, does not correspond to the actual risk due to blood pressure
      increase. Cardiovascular risk being multifactorial, it is necessary to have
      objective tools to assess the absolute risk in each individual. Presently, a 20%
      risk for the occurrence of a coronary event within a period of 10 years is the
      selected threshold. Clinicians must be aware of the numerous limits in the use of
      this risk rate. Risk estimates obtained from the Framingham study cannot be used
      in France without adjustments. Tobacco consumption and diabetes are variables
      expressed simply as present or absent, and age is a very significant and weighty
      factor. Different strategies have been proposed to take into account these
      shortcomings. Evaluation of the absolute risk in the decision to treat or not to
      treat hypertension is, in spite of its limits, an important help in avoiding a
      purely subjective clinical approach.

PMID- 10358401
TI  - [Therapeutic trials in arterial hypertension].
AB  - Therapeutic trials in hypertension taught us that a strategy based on a thiazide
      diuretic, or a beta-blocker as first-line drug, has reduced significantly the
      incidence of stroke (relative risk reduction: -35%), major coronary events (
      14%), cardiovascular death (-18%) and heart failure (-42%). The level of
      cardiovascular risk, taking into account classical risk factors, multiplied by
      relative risk, offers the best estimate of therapeutic absolute benefit. In terms
      of prevention, being treated seems to be more important than the level of blood
      pressure that has been reached.

PMID- 10358402
TI  - [Treatment strategies in essential arterial hypertension].
AB  - Essential hypertension is a very heterogeneous disease. The availability of
      antihypertensive drugs lowering blood pressure by various mechanisms allows most
      often to tailor the treatment, i.e. to find for each patient a drug regimen that
      is both efficient and well tolerated. Frequently medications given as monotherapy
      are not effective enough so that the use of drug combinations is required. When
      combined, low doses of antihypertensive agents are generally sufficient, so that
      tolerability is optimally preserved. Unfortunately many patients do not have
      their blood pressure controlled during antihypertensive therapy. These patients
      therefore do not benefit maximally from the cardiovascular protection afforded by
      blood pressure lowering. It is also imperative to correct all cardiovascular risk
      factors in each hypertensive patient. Such a multifactorial approach is known to
      improve effectively the prevention of cardiovascular diseases.

PMID- 10358403
TI  - [Management of patients with hypertension resistant to treatment].
AB  - A patient with a blood pressure greater than 140/90 mmHg under triple drug
      therapy, including a diuretic, has a resistant hypertension. Management mandates
      the following steps: to identify antihypertensive treatments previously
      prescribed (doses, efficacy, side effects); to evaluate blood pressure levels
      outside the medical office; to inquire about poor compliance; to search for
      secondary hypertension. In most cases, tailoring of treatments improves the care
      of such patients.

PMID- 10358404
TI  - [A little history].

PMID- 10358405
TI  - [Chronic lymphoid leukemia. Diagnosis, course, prognosis, principles of
      treatment].

PMID- 10358406
TI  - [Gastric ulcer and duodenal ulcer (excluding Zollinger-Ellison syndrome).
      Epidemiology, physiopathology, diagnosis, course, treatment].

PMID- 10358407
TI  - [Height-weight growth retardation. Diagnostic trends].

PMID- 10358408
TI  - [Pulmonary embolism. Etiology, physiopathology, diagnosis, treatment, prognosis].

PMID- 10358409
TI  - [Address by the Dean of Charles University Medical School delivered April 1998 on
      the occasion of a commemorative meeting on the 650th anniversary of the founding
      of Charles University].

PMID- 10358410
TI  - [Linear discrimination analysis in blood pressure monitoring].
AB  - The 24-hours blood pressure monitoring (BPM) is a reliable technique largely used
      for hypertension diagnosis in clinical practice. Presence of the lack of a
      nocturnal decrease in blood pressure values is one differentiating criterion
      between essential and secondary hypertension. New useful method of mathematical
      and statistical processing of BPM data using the linear discriminant analysis
      (LDA) was described. This statistical analysis was applied for 123 BPM
      measurements from patients with essential hypertension without and with different
      kidney diseases including hemodialyzed patients. The control group was
      normotensive healthy volunteers. The LDA method successfully separate group of
      patients with essential hypertension from patients with secondary renal
      hypertension but the error of return ranking to these groups was 28.5%. The
      recalculation for groups-controls, hypertensive patients and hypertensive
      hemodialyzed patients leads to decreasing of the error of return ranking to 5.7%.
      This retrospective study of nonhomogeneous groups could not clearly differentiate
      groups of hypertensive patients. The new prospective study on accurately definite
      groups of patients can eliminate these problems.

PMID- 10358411
TI  - [Post-catheterization thrombosis].
AB  - The problems of central venous catheters is discussed, first of all from the
      point of view the risk of postcannulation thrombosis. Thrombosis was found at the
      autopsy in 7 (resp. 13%) patients where pulmonary embolism was the cause of death
      or basic complications. By two of them no other major thrombosis was found. The
      main diagnosis, duration of central cannulation, other disease prevention and
      other problems of the cannulation are discussed.

PMID- 10358412
TI  - [Failure of prevention of hemocoagulation disorders in the postoperative period].
AB  - The author presents analysis of surgical patients decreased in the year 1994.
      Maximal attention is given to pulmonary embolism and the results are compared
      with the method of prophylactic regimes. The failure of prophylactic regimes
      appeared in patients with very bad prognosis, especially with the advanced
      stadium of tumors, severe complications and high age. The author describes a
      small group of patients with the "false" failure of prophylactic method in which
      the method was incorrectly interrupted in the phases of the persistent high grade
      thromboembolic risk.

PMID- 10358413
TI  - [Fatal pulmonary embolisms in surgery patients].
AB  - The authors present results of the study of the fatal pulmonary postoperative
      embolism in the years 1995-1997. The maximum attention is given to the risk
      factors and type of prevention. Among the biggest risks they are malignancy,
      reduction of pulmonary parenchyma, ischaemic coronary disease, high age and
      obesity. Risk factors are described in the relation to basic disease. Further the
      time factors of the pulmonary embolization and the failure or mistakes of
      prevention are studied. The postoperative long-term risk of the thromboembolism
      is confirmed.

PMID- 10358414
TI  - Essential fatty acids, membranes, and obesity.

PMID- 10358415
TI  - [Mitochondrial energy metabolism, uncoupling proteins and adipose tissue
      accumulation].
AB  - New possibilities are explored for supporting classical treatment of obesity.
      There are three main ways for the pharmacotherapy of obesity: (1) inhibition of
      absorption of nutrients in the intestine; (2) modulation of the activity of
      hypothalamic centra controlling satiety and food consumption; and (3) induction
      of energy dissipation in tissues (thermogenesis). The last possibility received
      more attention due to recent discoveries. The goal would be to affect
      mitochondrial energy conversion in a way leading to elevated thermogenesis and
      not to ATP production.

PMID- 10358416
TI  - Microdialysis in investigation of adipose tissue metabolism.
AB  - Microdialysis--a technique available since more than two decades--has been
      recently applied in investigation of metabolism of adipose tissue in humans. The
      technique enables a continuous sampling of metabolites and other small molecules
      in the extracellular space of subcutaneous adipose tissue and it enables a local
      exposure of adipose tissue to metabolically active agents. The method has been
      used to determine the interstitial concentrations of metabolites (glycerol,
      glucose, lactate etc.) in adipose tissue and to investigate the regulation of
      lipolysis and of carbohydrate metabolism in situ in subcutaneous adipose tissue.
      The method has been widely used in clinical research of adipose tissue and it is
      supposed to be used for continuous monitoring of metabolites in clinical
      practice.

PMID- 10358417
TI  - Clinical guidelines for diagnosis and management of obesity in the Czech
      Republic.
AB  - Guidelines for the management of obesity include recommendation about diet,
      exercise, behavioral modification, drug therapy and bariatric surgery in the
      comprehensive management of an obese patient. It is emphasized that the treatment
      of obesity should be individually tailored according to the age of the patient,
      degree and phase of obesity, body fat distribution and an expression of risk
      factors and comorbidities. The new realistic goals in obesity management do not
      focus on the weight loss per se but mainly on the risk factors reduction which
      accompanies even modest weight loss. The system of obesity management introduced
      in the Czech Republic includes obesity management centres attached to major
      teaching hospitals, obesity out-patient clinics (led by an obesity specialist),
      primary care physicians and weight reduction clubs. Postgraduate training in
      obesity management should be recognized by health authorities as a function
      specialty. A time demanding therapeutic strategy in obesity management should be
      taken into account by both health policy makers and health insurance companies.

PMID- 10358419
TI  - [Energy expenditure at rest and obesity].
AB  - Adult human body has to have, because of every day fluctuating energy intake and
      energy needs, very precious adaptive mechanisms for maintenance of heat
      homeostasis in the body and nearly stable body weight and body composition, which
      are optimal for life and reproduction. These short term functioning adaptive
      mechanisms are called "empty biochemical mechanisms", where chemically bound
      energy is transformed to heat without work performance. These mechanisms are
      present on the cellular level (substrates cycles, uncoupling of respiration
      chain), on the interorgan metabolic level (glycolysis and gluconeogenesis between
      liver and adipose tissue-glucose-lactate cycle). Central nervous system controls
      them via many factors; the most important are catecholamines, leptin, insulin,
      thyroid hormones, cortisol, growth and sex hormones. Neurotransmitters and
      neuronal net influence energy intake and other behavior. Obesity seems to be
      associated with the amelioration or overcoming of possibilities of function short
      term effective adaptive mechanisms.

PMID- 10358418
TI  - [Changes in autonomic nervous system activity in obese individuals during weight
      reduction].
AB  - The frequency analysis (fast Fourier transformation) of heart rate variability
      follow-up during modified orthostatic test is the non-invasive method used to the
      evaluation of vegetative nervous system (NS) activity. There are only few data
      about the changes of the parameters in the groups with civilization diseases or
      with the presence of the risk factors of coronary heart disease. In the groups of
      82 volunteers (BMI 24.9 +/- 2.7 kg/m2) and 37 healthy obese people (BMI 36.1 +/-
      4.9 kg/m2) we compare some of the vegetative NS parameters. In 16 volunteers we
      measured the vegetative NS activity changes during the weight reduction regimen
      (10 day's hospitalization, daily energy intake 3300 kJ, weight before 101.5 +/-
      18.1 kg, after 97.5 +/- 17.1 kg, p < 0.0001). Acute reactions to the energy
      restriction were evaluated in 3 groups of 10 volunteers during 3 days of the
      energy intake 3200, 6600 and 13400 kJ. Obese persons show a slight decrease of
      both sympathetic and parasympathetic NS activity. In the supine position only few
      changes in the sympathetic/parasympathetic NS activity ration were observed. In
      the standing position in obese group drop of the most indexes and decrease of
      sympathetic/parasympathetic NS activity ratio were described. Significant
      correlations between sympathetic NS activity and lipid oxidation (r = 0.329, p <
      0.01) as well as saccharide oxidation (r = -0.258, p < 0.05) were observed.
      During the weight reduction slight increase of the parasympathetic NS activity
      and higher one in the sympathetic NS activity were measured. The values after
      weight reduction regime are comparable with the control group of the lean
      persons. Different changes of the parameters were described in standing and in
      supine position. Acute reaction on the low-energy diet was observed in a few
      days. It shows a slight increase of the NS activity parameters. Relative increase
      mainly in the sympathetic nervous system activity doesn't depend on the degree of
      energy deficit only, but some subjective factors may play a role (age,
      psychological and psychosocial factors, agreeability of the diet, behavioral
      factors ...). In the group of obese persons non-specific changes of the
      vegetative NS activity were observed. They are modulated by some behavioral
      factors. The tendency to the higher parasympathetic NS activity confirms the MONA
      LISA theory of the origin of obesity. Important are the informations of the
      return of the indexes after overweight reduction.

PMID- 10358420
TI  - [Importance of monitoring insulinemia in obesity].

PMID- 10358421
TI  - Effect of modified fasting on fibrinolytic capacity.
AB  - Aim of the study was to assess the effect of modified fasting on body weight and
      BMI, and the effect of modified fasting on blood lipids. We aimed also at
      modulation on fibrinolytic components by modified fasting.

PMID- 10358422
TI  - [Non-invasive methods for evaluation of body composition during weight
      reduction].
AB  - As a result of positive energetic balance of organism, there is a cumulation of
      an excessive energy in the adipose tissue. Adipose tissue repletion represents
      the main characteristic of obesity. The objective of our work was to perform the
      comparative study for the evaluation of selected noninvasive methods used for the
      determination of body composition. We analysed the results of 4 methods of the
      body composition measurement: bioelectrical impedance (BIA), physical
      anthropometry (ANTHR), Deurenberg's calculation (FORM) and dual energy X-ray
      absorptiometry (DEN). The most statistically significant correlation was proved
      between the results of BIA and results of DEN method (r = 0.9145), and results of
      BIA and FORM method (r = 0.9014).

PMID- 10358423
TI  - [Anthropologic methods in the evaluation of the weight reduction process in obese
      children].
AB  - Childhood obesity is considered at present one of the most difficult problems in
      paediatrics and it is one of the major health problems of industrialized society.
      Growth and development of obese children is different in several aspects. The
      authors submit the results of an anthropometric survey implemented in 1989 to
      1996 in a group of 1949 Czech obese children (720 boys and 1229 girls) aged 6 to
      18 years. The patients were measured by the standard anthropometric technique
      according to Matrin and Saller at the beginning and end of six-week therapeutic
      weight reduction programme. The skinfold thickness at 14 sites was assessed by
      means of a Best caliper. The body composition was evaluated using Matiegka's
      equations. For evaluation of the weight reduction programme the paired t-test was
      used a criterium of the quality of the evaluated parameters. For the needs of the
      medical profession curves of the empirical percentiles of BMI for both sexes were
      plotted to evaluate the grade of obesity. From the analysis of anthropometric
      data using the paired t-test in 1949 probands ensues that the most valuable
      information as regards circumferential measurements in boys is provided by the
      circumference of the abdomen, the gluteal area followed by the chest
      circumference. In girls the results are partly different--a gluteal circumference
      of thigh highly dominates, gluteal circumference follows, chest circumference
      mesoeternal is the third. As to skinfolds the authors recommended to monitor in
      boys the supraileac, subscapular and abdominal skinfold. In girls the following
      order was assessed: supraileac, thoracic (at the level of the 10th rib) and
      subscapular skinfold. From the accurate assessment of the body composition of
      obese children subjected to weight reduction ensues our recommendation that the
      loss of adipose tissue should be at least seven times greater than the loss of
      musculature. A lower ratio should be an indication for changing the reducing
      treatment. Methods of direct anthropometry, incl. calipering can be unequivocally
      recommended as the method of first choice because of their non-invasive
      character.

PMID- 10358424
TI  - Long-term results of aggressive weight reduction treatment.
AB  - We have checked weight changes in 11 patients eight years after 2-weeks in
      patient weight reduction treatment and weight changes of another group of 11
      patients three years after gastric banding. Using multiple linear regression
      we've looked for factors which could influence the aforementioned weight changes.
      For weight reduction regimens we confirmed only the following connection: BMI
      reduction in 8 years = 12.256 - 2.827 x BMI reduction in 2 weeks. For gastric
      banding it was: BMI reduction in 3 years = -7.880 + 2.383 x BMI reduction in 6
      months. We therefore conclude that the long term effects of reduction regimens is
      not influenced by any hormonal or metabolic characteristics of the patient, but
      can be predicted by the early weight loss of the patient. Patients who lose too
      much during the reduction regimen will find it more difficult to keep the weight
      down, whereas patients who lose weight rapidly after gastric banding have the
      best long term prognosis.

PMID- 10358425
TI  - Long-term treatment of obesity in the obesity unit.
AB  - A group of 318 obese patients followed-up at the Obesity Unit in Prague in 1995
      1997 was included into a study. Their treatment was based on the standard
      combination of a weight reduction diet, physical activity and behavioural
      intervention. In patients with more severe degrees of obesity VLCD in one daily
      portion, pharmacotherapy, in-patient regimen lasting 24 days, including VLCD
      (1,500 kJ/day), exercise and group psychotherapy; or bariatric surgery (mostly
      laparoscopic gastric banding) were used, if necessary. Patients were divided into
      two groups according to their compliance to the weight reducing regimen. Group A
      dropped out before 2 years of follow-up, group B was followed-up 2 years or more.
      The groups did not differ significantly in their mean age, initial body weight,
      initial BMI and fat content and in percentage of males and females. Weight, BMI,
      fat content, essential anthropometric indices (waist circumference, WHR,
      subscapular and triceps skinfolds) and blood pressure are presented in this
      study. The maximum weight loss was significantly higher in group B. We did not
      find any other significant differences between group A and group B. The most
      significant predictor of compliance expressed as duration of follow-up (evaluated
      by multiple regression with stepwise variable selection) was the maximum BMI
      decrease (p < 0.005). The most significant predictors of the weight loss at the
      end of the follow-up were maximum weight loss and maximum decrease of BMI (p <
      0.001). Family history of obesity (obese one or both parents) was significantly
      more often in group B (p < 0.05). This trend was expressed predominantly in
      females (p < 0.01), where also family history of obesity in mother was
      significantly more often in group B (p < 0.05). The frequency of methods used in
      individual patients was estimated. Standard combination of diet, enhanced
      physical activity and behavioural intervention was used in all patients. All
      other methods were used significantly more frequently in group B. In group A in
      patient treatment was significantly more often used in men. The in-patient
      treatment promotes the compliance with the therapeutic regimen in women
      significantly more effectively than in men.

PMID- 10358426
TI  - [Health effects of weight reduction].
AB  - Although weight loss is routinely recommended for obese person, the observational
      literature is controversial in respect of prolongation of life longevity after
      body weight loss. The positive long-term outcome has been found only in
      intentional weight loss in obese people with obesity-related comorbidities. The
      main task in obesity treatment strategy is "primum non nocere". The authors
      analysed the short-term effect and acceptability of low calorie diet (5 MJ) on
      health state of 150 obese people (BMI x = 35.9 kg/m2). The acceptability of this
      diet was 60% only, when the rest of patients has broken this regime mostly after
      second appointment with their physician. The successful patients achieved 10%
      weight loss from initial body weight during in average 5 months (95% CI for BMI
      reduction = (-4.55; -3.01), as well as reduction of percentage of body fat (95%
      CI = -7.7; -3). During this period has been observed in consistency with
      experimental evidence of other authors a decrease of plasma values of
      triacylglycerol, LDL cholesterol in hyperlipidemic patients, but not significant
      increase of HDL cholesterol. During this period obese persons have taken up more
      physical activities and felt themselves more psychologically comfortable.

PMID- 10358427
TI  - Bariatric surgery at First Surgical Department in Prague--Czech Republic--history
      and some technical aspects of the procedures.
AB  - BACKGROUND: There is an increasing number of obese population in the Czech
      Republic in last twenty years. In 1983 we were one of the first surgical
      departments in the country who started with bariatric surgery on regular basis.
      METHODS: In the period from 1983 to 1986 we performed vertical banded
      gastroplasties (VBG) in our department. Because of high rate of various
      complications arising both from the stomach and from the wound we switched in
      1986 to less "aggressive" non-adjustable gastric banding. In 1993 we performed
      the first round the world laparoscopic non-adjustable banding. In 1994 we started
      with laparoscopic placement of adjustable gastric bands. RESULTS: In the group of
      52 patients who underwent VBG and were followed-up, acceptable weight loss
      results (-40.5 kg) were achieved in 24 months following surgery. The
      postoperative complications were high, 17.3% of gastric staple line disruption
      and 15.3% of wound complications--incisional hernias, discharge etc. Since 1986
      we performed non-adjustable gastric banding in 150 patients with the weight loss
      of -38.4 kg in 24 months following surgery. There was no change in the wound
      complications rate, but the complications arising from the stomach and the band
      decreased to 6.3%. Since June 1993 we performed 268 procedures laparoscopically
      either with non-adjustable bands or since 1994 with the adjustable bands. The
      wound complication rate decreased to 0.9% and one complication (6.6%) was
      connected with the adjustable band. CONCLUSIONS: Because of the high rate of
      postoperative complications connected in our experience with VBG we started with
      gastric bandings in 1986. Since than the number of complications arising from the
      stomach decreased substantially. With the laparoscopic technique used in
      bariatric surgery there was another decrease in wound healing problems. With the
      adjustable GB a significant decrease in the stomach related complications
      occurred. Shorter hospital stay is related to the laparoscopic technique. The
      long-term weight loss results are not significantly different among the
      procedures mentioned above.

PMID- 10358428
TI  - The role of exercise in the treatment of obesity in children and adults.

PMID- 10358429
TI  - [Personal experience with unconventional ambulatory therapy of obesity in
      diabetics].

PMID- 10358430
TI  - The relationship between overweight and psychological problems in adult Czech
      population.
AB  - Overweight is often mentioned in causal relationship with various psychological
      problems and a lack of self-control. 438 randomly chosen subjects (selected from
      electoral registers or by random walk method)--men and women from Prague and the
      countryside--were divided according to their body weight into two groups, one
      with BMI equal or lower that 25, the other one with BMI higher than 25. 92.2 per
      cent of the subjects were overweight, 8 per cent had BMI higher than 30.
      Comparison of the two groups with lower and higher body weight based on a self
      report questionnaire (GHQ, CAGE and some other items) showed differences between
      men and women. In men, with growing body weight the self-control in food intake
      decreased and problems related to lack of self-control increased significantly
      (smoking, problems with alcohol). On the contrary, women with overweight reported
      higher self-control in food intake (dieting) and had less problems with alcohol.
      The relationship between psychological problems (depression, anxiety) and
      overweight was not unequivocally proved. Men with higher body weight reported
      significantly less somatic problems in the GHQ. They also suffered comparatively
      less from depression and anxiety. The overweight women showed slightly more
      anxiety and significantly higher social dysfunction than women with normal body
      weight.

PMID- 10358431
TI  - [Experience in group therapy of obese patients].
AB  - The aim of the investigation was to verify in patients repeatedly failing the
      reduction the existence of personality traits which can increase an individual
      predisposition for development and relapse of obesity. In 1995, 65 patients of
      the Geronto-Metabolic Clinic in Hradec Kralove (average age 41.23 +/- 10.9 years,
      BMI 32.4 +/- 1.2 kg/m2) were systematically examined. A psychological examination
      (Freiburg's personality questionnaire SUPOS 7, SCL 90, KSAT) was added to
      standard somatic examination. The results of this investigation demonstrate the
      presence of psychosocial factors in combination with specific configuration of
      personal features that are reflected in the quality of emotional feelings, social
      interactions and in the autoplastic picture of the disease (lower sociability,
      depression, higher score of somatic anxiety, impulsivity, muscle tension,
      increased sensitivity to body image). Knowledge of the patients personal features
      enables a more complex view of the disease. The stimulation of self-healing
      abilities of the patient and forming of her affinities based on partnership are
      the most important. For these reasons, we include person centered approach
      (P.C.A.) in classical cognitive behaviour therapy (CBT) and both these therapies
      are part of the group therapy.

PMID- 10358432
TI  - [Multi-causal etiology of obesity--case report].
AB  - Etiology of obesity is influenced not only by hormonal and metabolic but also
      psychological factors. With increasing number of eating disorders, the number of
      patients without visible psychopathic personal features increases, but some
      personality characteristics which increase vulnerability of human organism and
      probability of disease exist. Therefore, we pay attention to examinations and
      therapy of personal characteristics of the patient and his past history. The
      symptom of the patient is connected not only with special organic changes but
      also with social environment. Multicausal characteristic of obesity can be
      documented by case reports of patients in the group therapy within the Programme
      of Systemic Therapy of Obesity carried out in our Department. In all the case
      long-term or actual incongruence, which does not make possible the change of life
      style and active patient's participation in the therapy, necessary precondition
      for the reduction of weight and its keeping up, is present. The case report of
      R.K., in which the gradual process of change of subjective feeling and self
      exploration of R.K. in the group therapy are documented, is elaborated in more
      detail. The resulting change of Self is the precondition for more effective
      intervention at the level of energetic intake--the energetic expenditure. The
      patient is able to take more responsibility for her food behaviour, smaller
      dependence on the estimation of other people increases the possibility of
      permanent change of life style.

PMID- 10358433
TI  - [Psychological characteristics of obese patients hospitalized at the obesity unit
      of the 4th Internal Medicine Clinic of the Medical School Hospital in Prague].
AB  - This study presents the results of a psychological survey carried out in 1995 and
      1996 in the Obesity Unit of IVth Department of Internal Medicine, General Faculty
      Hospital in Prague. There were 86 patients examined. The patients underwent a
      series of tests and questionnaires--Raven's Progressive Matrices, STAI,
      Miniscripts, Body Image. No significant differences were found between men and
      women. On the basis of this screening the general characteristics of obese
      patients hospitalized in this Unit can be described as follows: average to above
      average level of mental capacity for the general population, a need to "be strong
      and have everything under control", a need for recognition from other people,
      slightly increased level of anxiety. In their perception of their bodies they see
      themselves as overweight, unattractive and in a poor state of health.

PMID- 10358434
TI  - The days of health and physical activity.

PMID- 10358435
TI  - [The work of the dietician in the outpatient obesity unit].
AB  - The dietitian plays an important role in the care of obese patients. The
      dietitian evaluates 7 day food records and according to the individual
      composition of the diet gives dietary advice to the patient. The energy content
      and macronutrient and micronutrient composition is only one aspect of dietary
      counselling. Knowledge of patient's familial and economic status as well as his
      usual eating pattern, his tastes and capabilities of person who does the shopping
      and cooking are necessary before the diet can be recommended. The balanced energy
      restricted diet is used, predominantly with reduction of the fat intake. Energy
      expenditure in individual patients is considered when the diet is planned. The
      regular controls by a dietitian are essential in the long-term treatment of
      obesity.

PMID- 10358436
TI  - [Role of osteoclast differentiation factor, the new member of the TNF ligand
      family, in osteoclast differentiation and function].

PMID- 10358437
TI  - [Replication licensing and S-phase CDK].

PMID- 10358438
TI  - [Synergistic function of TAL1 and LMO in hematopoietic differentiation and T cell
      tumorigenesis].

PMID- 10358439
TI  - [Strategy for analysis of blood group antigen on mucin-type sugar chains].

PMID- 10358440
TI  - [Elongin BC complex as the regulator of multiple cellular functions].

PMID- 10358441
TI  - [Elimination of unwanted cells by phagocytes].

PMID- 10358442
TI  - [Recent progress on the study of methionine adenosyltransferase].

PMID- 10358443
TI  - [Regulatory mechanism of smooth muscle myosin].

PMID- 10358444
TI  - Total pelvic exenteration for advanced rectal cancer.
AB  - Overall recurrence following curative resection for colorectal cancer has been
      variably reported to be between 25% to 50%. Lungs, liver, and locoregional sites
      are most frequently involved, but although isolated hepatic and pulmonary
      metastases have been aggressively targeted, pelvic recurrences have been
      traditionally considered unsalvageable. Loco-regional recurrence is noted in up
      to 19%sd of colonic and 33% of rectal cancers, and may be frequently encountered
      in general surgical practice. In view of the technically demanding nature of
      surgical resection, and the prospect of major morbidity, it is not uncommon to
      withold aggressive intervention and follow a palliative line of management
      notwithstanding the dismal survival outcome. The aim of this article is to
      highlight the diagnostic and therapeutic strategies for locally recurrent
      colorectal cancer which can be of significant survival or palliative value in a
      select group of patients.

PMID- 10358445
TI  - Monitoring digoxin serum concentrations: new thoughts concerning an old drug.

PMID- 10358446
TI  - [Effect of H. pylori eradication regimes on the proliferation index of gastric
      mucosa].
AB  - Eradication regimes with the blocking agent of the proton pump and without it do
      not influence the activity of cell division after treatment of Helicobacter
      pylori (H.p.) when using cytoflowmetric evaluation. The non-significant
      difference in proliferation activity of the gastric mucosa after treatment of
      H.p. can be also a sign of more rapid repair of the gastric mucosa after
      elimination of the inflammatory elements.

PMID- 10358447
TI  - [Erythropoietin in non-specific intestinal inflammation].
AB  - In 39 patients with non-specific intestinal inflammations the authors examined
      the erythropoietin level. They found a significantly higher level of serum
      erythropoietin in patients during relapse, when the organism responds to more
      severe anaemia by increased erythropoietin production. The idea that the
      reactivity of the bone marrow or effectiveness of erythropoietin is influenced by
      mediators of the inflammation is supported by the fact that the group comprised
      patients with high erythropoietin values of 102, 106.6, 109 and 445 ImU/l but
      their anaemia did not improve markedly. The theory on an inadequate
      erythropoietin secretion is supported by the fact that four patients in relapse
      with relatively severe anaemia had low erythropoietin levels and six patients had
      despite a significant drop of haemoglobin normal erythropoietin levels. Contrary
      to other diseases, in non-specific intestinal inflammations the erythropoietin
      secretion depends not only on the severity of the inflammation but probably on
      many other factors, incl. immunological ones.

PMID- 10358448
TI  - [The fatigue syndrome in autoimmune thyroiditis with polyglandular activation of
      autoimmunity].
AB  - The authors compared in a group of 118 patients with autoimmune thyroiditis and a
      positive antibody titre against ovaries the grade of fatigue with the presence of
      organ specific and non-specific autoantibodies in the peripheral blood stream,
      antibodies against EBV and CMV, immunoglobulin concentrations, biochemical
      parameters of the lipid metabolism, glucose tolerance, ion balance and melatonin
      and serotonin levels. Patients with autoimmune thyroiditis were differentiated
      according to the degree of fatigue into three groups: 38 with fatigue typical for
      CFS, 30 with occasional fatigue and 50 without the feeling of fatigue. Fatigue of
      the CSF type was characterized by a significantly higher incidence of
      autoantibodies against the adrenals and a higher cholesterol level. Increased
      fatigue of the patients was associated with a lower melatonin level, a higher
      serotonin level and a lower M/S ratio as compared with patients without fatigue.
      In other indicators no differences were found. Fatigue in CFS could be
      associated, similarly as in autoimmune endocrinopathies, with impaired
      immunoendocrine regulation. In autoimmune thyroiditis, regardless of the
      concomitant presence of fatigue, in addition to antibodies against thyroid
      peroxidase most frequently antibodies against the ovaries were detected.

PMID- 10358449
TI  - [Treatment of Graves' ophthalmopathy with irradiation].
AB  - Orbital radiation therapy appears to be an effective and safe treatment of
      Graves' ophthalmopathy. Five patients with Graves' ophtalmopathy were treated
      with external beam radiotherapy during 1996 and 1997 in St. Ann University
      Hospital. Four of them patients had a past history of hyperthyreoidism, one
      hypothyreoidism. The radiotherapy was performed with high-energy beam of a linear
      accelerator. The technique of irradiation employs 2 opposed beams tilted 5
      degrees posteriorly. The use of the asymetric jaws is necessary to protect
      surrounding normal tissues. A course of radiotherapy 20.0 Gy (2.0 Gy per
      fraction) was given to the patients. The therapy was well tolerated. We have not
      observed any side late effects of radiotherapy. All patients showed good or
      excellent responses. The improvement of symptoms appeared within 3-6 months after
      the irradiation.

PMID- 10358450
TI  - [Effect of Kliogest on bone metabolism, bone mineral density and quality of life
      in postmenopausal patients].
AB  - The author investigated postmenopausal patients (with a natural menopause) (n =
      32) where ammenorrhoea persisted for 1-2.2 years. They found a reduced bone
      mineral density (BMD) (ostoeopenia or osteoporosis) and laboratory tests revealed
      signs of increased bone turnover (so-called "fast losers"). Before administration
      of Kliogest R tablets, Novo Nordisk, Denmark, (1 tablet per day) and after 12
      months the following parameters were evaluated: 1. Laboratory parameters of bone
      turnover: serum osteocalcin (OC) amino-terminal N-telopeptide of collagen I in 24
      hour diuresis (NTx). 2. Bone mineral desnity (BMD) in lumbal vertebrae L1-L4
      assessed by DXA (dual energy X-ray absorptiometry 3. By means of questionnaires
      climacteric symptoms were evaluated (score of climacteric symptoms). For
      statistical analysis of the assessed values the non-paired Wilcoxon-Wilcoxon test
      was used. RESULTS: After treatment the OC levels were significantly lower (alpha
      = 0.05, p < 0.01), the values of NTx were highly significantly lower (alpha =
      0.05, p < 0.001) and the BMD values in the second lumbar vertebra (it is usually
      most affected by osteoporosis), expressed by the T-score, was significantly
      higher (alpha = 0.05, p < 0.001). When evaluating the questionnaire "Score of
      climacteric symptoms" after treatment the number of points characterizing the
      intensity of symptoms was reduced. Most frequently improvement of the following
      symptoms was achieved: hot flushes and noctural perspiration, weakness, fatigue,
      impaired sleep, nervousness, irritability, dry vagina making intercourse
      unpleasant. CONCLUSION: One-year use of Kliogest increased significantly the
      density of the bone mineral in the axial skeleton, reduced the bone turnover and
      improved the quality of life of postmenopausal patients.

PMID- 10358451
TI  - [Gaucher's disease in a 22-year-old female patient].
AB  - Gaucher's disease is a sphingolipidosis with a genetically conditioned deficiency
      of cerebroside-beta-glucosidase which can be encountered in everyday practice and
      not only in paediatrics. The authors submit the case-history of a 22-year-old
      Ukrainian patient with a fully developed type 1 Gaucher disease, and a brief
      review of the diagnostic and therapeutic possibilities. Due to the more extensive
      migration of the population on the territory of the Czech Republic a more
      frequent occurrence of the disease can be envisaged.

PMID- 10358452
TI  - [Sarcoidosis of the liver, a granulomatous process with an unclear prognosis].
AB  - The authors demonstrate on two patients the pitfalls of the diagnosis and
      prognostic uncertainty of systemic sarcoidosis. The typical pulmonary finding was
      in the background due to the very extensive and serious affection of the liver.

PMID- 10358453
TI  - [Malnutrition in a patient with short-bowel syndrome].
AB  - The short bowel syndrome is a relatively frequent complication of extensive
      resection and by reducing the absorption capacity the function of the gut is
      markedly impaired. An important part of postoperative care is therefore to ensure
      nutrition of these patients. The authors demonstrate on the case-history of a 40
      year-old patient after repeated revision of the abdominal cavity on account of
      adhesions the development of severe malnutrition after
      jejunotransversoanastomosis. As the small intestine was not resected (concurrent
      blind loop syndrome), the patient was indicated for surgery. After surgery all
      complaints disappeared and the nutritional status improved.

PMID- 10358454
TI  - [CA 125 in the department of internal medicine--a marker of ovarian tumor,
      thoracic fluid or ascites?].
AB  - The authors describe three cases of falsely elevated values of the tumour marker
      CA 125 which in medical practice is considered above all a sign of ovarian
      tumours. In one case CA 125 was elevated in fibrinopurulent pleuropneumonia and
      refractory ascites and in one instance haemorrhagic fluidothorax was involved
      associated with pleuritis and in one instance an abscess of the subhepatic
      region. From data in the literature ensues that this increase can be associated
      with activation of mesothelioma cells (either in the pleura or peritoneum) in non
      malignant diseases. Therefore in patients with elevated CA 125 and fluidothorax
      or ascites, unless ovarian carcinoma is proved, this fact should be taken into
      account in diagnostic considerations.

PMID- 10358456
TI  - [Ultrasonic tissue characterisation in cardiology].
AB  - Ultrasonic tissue characterization is a relatively new non-invasive examination
      method the application of which in cardiology is steadily increasing. It is
      therefore the objective of the present work to summarize hitherto assembled
      knowledge on the use of this method in clinical practice. Ultrasonic tissue
      characterization uses scattering of ultrasonic waves which penetrate into the
      heart muscle. This scatter is due to particles inside the heart muscle, their
      size being smaller than the wave length of the incident ultrasonic undulation.
      Evaluation of the intensity of the backscatter makes it possible to evaluate
      structural and functional changes of the examined cardiac tissue. Ultrasonic
      tissue characterization is so far used in cardiology for evidence of myocardial
      ischaemia, for evaluation of structural myocardial changes with hypertrophic
      cardiomyopathy, to detect rejection after transplantation of the heart and in the
      diagnosis of myocarditis. Other possibilities for application of this method is
      assessment of the viability of the heart muscle, quantification of the amount of
      fibrous tissue in the heart muscle and differentiation of acute from chronic
      vegetation in patients with infectious endocarditis. Due to some limitations
      ultrasonic tissue characterization is in the majority of the mentioned
      indications rather a subsidiary method which can supplement the diagnosis and
      make it more accurate. Its future position will obviously depend on further
      technical improvement and simplification.

PMID- 10358455
TI  - [Thrombophilic states].
AB  - Thrombophilia is defined as an increased tendency to thrombosis and can be
      inherited or acquired. The thrombotic events in patients with inherited
      thrombophilia tend to occur at a young age, are often idiopathic, recurrent and
      may occur at unusual sites (e.g. mesenteric, portal and cerebral veins and in
      inferior vena cava). The most common of the hereditary defects appear to be
      antithrombin, protein C, protein S deficiency, which account for 10% of
      individuals presenting with venous thromboembolism, resistance to anticoagulant
      effect of activated protein C (APC-R), which is present in 17 to 64% of patients
      with thrombosis and prothrombin 20210 G-->A variant with 6% prevalence in
      patients with thrombosis. APC-R is due in 90% to the presence of factor V Leiden.
      Rarer defects include heparin cofactor II (HC II), plasminogen or tissue
      plasminogen activator deficiency (TPA), elevated plasminogen activator inhibitor
      1 (PAI-1) and dysfibrinogenemia. The most common acquired defects are
      antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies).
      Hyperhemocystinemia is responsible as well for arterial as venous thrombosis. A
      substantial proportion of venous thrombotic events occurs spontaneously, i.e.
      without a precipitating event. Risk factors for thrombosis include surgery,
      trauma, immobility, congestive heart failure, pregnancy including puerperium and
      oral contraceptive usage. The thrombotic risk is increased in patients who are
      homozygous for factor V Leiden and markedly increased in patients with combined
      defects.

PMID- 10358457
TI  - [Electrophysiologic mechanisms of atrial rhythm disorders. I. Atrial
      fibrillation].
AB  - Atrial fibrillation (AF) is a frequent finding in clinical practice. In advanced
      age its incidence is rising and according to the literature the prevalence is as
      high as 3.2-11%. AF doubles the mortality and brings a fivefold risk of the most
      frequent embolic complication--a cerebrovascular attack. The typical
      electrophysiological feature are intra-atrial defects of the conduction and the
      absence of refractory period adaptation with regard to the cycle length. In 1962
      Moe, based on experimental work, postulated the hypothesis on multiple
      independent wavelets which move in a random fashion through the myocardium round
      several islets or strips of refractory tissue. Modern mapping studies confirmed
      the reentry concept as the mechanism of atrial fibrillation. Two forms of reentry
      were observed: the leading circle reentry and the random reentry. The main
      factors which facilitate the development of AF are dilatation of the atria,
      reduced rate of conduction of the impulse and shortening of the refractory. A
      combination of these factors leads to a reduction of the size of the wave which
      is a multiple of the refractory period and rate of the impulse. This leads to the
      formation of smaller waves which may co-exist in greater number in the dilated
      atria. Persistence of AF depends on the number of waves present. A small number
      of waves can disappear at a certain moment or change into one wave and this leads
      to the development of sinus rhythm or atrial flutter.

PMID- 10358458
TI  - [Differential diagnosis of mushroom poisoning].
AB  - Mushroom poisoning is a very urgent problem of internal medicine. Mushroom
      picking is one of the most popular hobbies in the Czech and Slovak Republic. This
      is one of the main reasons of the rising incidence of mushroom poisoning, incl.
      fatal cases. Mushroom poisoning is characterized by a very varied clinical
      picture which is reflected also in recent classification systems. The main
      objective of the present work is to draw attention to cardinal symptoms and signs
      of different types of mushroom poisoning which respect new findings in the
      diagnosis and differential diagnosis of mushroom poisoning.

PMID- 10358459
TI  - [Minocycline in the treatment of rheumatoid arthritis].
AB  - The author presents a review of contemporary knowledge on the treatment of
      rheumatoid arthritis with minocycline. He analyzes the assumed mechanism of
      action, dosage and the most frequently encountered undesirable effects of
      treatment. He informs the reader on the results of the most important studies
      with minocycline.

PMID- 10358460
TI  - [Significance of left ventricular hypertrophy in hypertension].
AB  - Left ventricular hypertrophy (LVH) is supposed to be a useful marker of
      cardiovascular (CV) complications during the course of hypertension (HT). To
      evaluate it, authors compared the clinical findings in hypertensive patients
      (pts) with and without LVH defined by echocardiography (echo). Hospital records
      of hypertensives treated in the 1st Medical Department during the year 1995 were
      analysed. LVH was defined by echo (Penn convention) as left ventricular mass
      index (LVMI) > 125 g/m2 in men and > 115 g/m2 in women. Presence of LVH was found
      in 72 pts (mean age 66 y), absence of LVH in 38 pts (mean age 56 y). There were
      statistically significant more CV complications in LVH-positive pts (incidence of
      myocardial infarction, arrhythmias, heart failure, ischemia (ECG), mitral
      regurgitation) as in LVH-negative. Tendency for other complications in LVH
      positive pts (incidence of renal failure, stroke, LV diastolic dysfunction and
      aortic regurgitation) was also present. LVH-positive pts were about ten years
      older than the LVH-negative. In other risk factors (LVH and age not included) the
      both groups of pts were matched. LVH in pts with HT brings usually a complicated
      course of the disease. Age is an important contributing factor. Authors recommend
      to look after LVH presence in hypertensives as it carries much more complicated
      course of the disease.

PMID- 10358461
TI  - [Haplotypes of the beta-globulin locus in Czechs and Slovaks with beta
      thalassemia and structurally variant hemoglobins].
AB  - In 29 Czech and Slovak families with the most frequent and newly identified beta
      thalassaemic alleles and with some structural haemoglobin variants (Hb E, Hb
      Hana, Hb Santa Ana) haplotypes of the beta-globin locus of alleles with these
      mutations were identified. In most instances haplotypes I and V were involved
      which were found in 57% of the patients. The bond of the most common beta
      thalassaemic mutation: IVS-I-1, IVS-I-110, CD 39 (C-T), IVS-II-745, IVS-I-6 with
      alleles with the same haplotypes as in the mediterranean region suggests a
      mediterranean origin of these mutations. In Hb Santa Ana a hitherto not described
      haplotype was identified (-(+)-(-)-(+3), indicating a de novo origin of the
      mutation. Also in newly identified beta-thalassaemic mutations in CD 7/8 (+G), in
      CD 38/39 (-C) and in HbE and Hb Hana de novo development is probable.

PMID- 10358462
TI  - [Effect of octreotide on the clinical course of acute pancreatitis and levels of
      free oxygen radicals and antioxidants].
AB  - Twenty-one patients with a medium severe form of acute pancreatitis were divided
      into two groups. Eleven were treated with octreotide, 200 micrograms s.c. every 8
      hours, combined with standard conservative treatment, 10 patients had the same
      treatment but without octreotide. In the octreotide-treated group the level of
      free oxygen radicals and important antioxidants--vitamins A, E and C--was
      assessed. In the octreotide-treated group the authors found after five days
      normal levels of originally elevated free oxygen radicals and a significant
      increase of the vitamin C level. As compared with the control group, in the
      octreotide group the period of hospitalization was significantly shorter (9.8 +/-
      3.2 vs. 13.7 +/- 4.7). The number of complications was not affected.

PMID- 10358463
TI  - [Primary hepatosplenic (gamma delta) T-cell lymphoma: clinico-pathologic analysis
      of 3 cases].
AB  - The authors analyze three cases of hepatosplenic (gamma-delta) T-cell lymphoma
      which is a newly defined unit in the spectrum of primary splenic lymphomas. The
      first two were diagnosed in sequential biopsies of bone marrow, splenectomic
      material and the liver of female patients aged 38 and 67 years. In the clinical
      picture dominated symptoms of progressing splenomegaly, hepatomegaly, haemolytic
      anaemia and different manifestations of leuco- and thrombocytopenia with
      expulsion of tumour cells into the peripheral blood. The first patient died after
      complete remission with signs of heart failure, the second one is surviving for
      11 months in partial remission. The third case, a 66-year-old male patient, died
      suddenly during a 16-day hospitalization on account of diagnosis of hepatopathy
      and anaemic syndrome, as a result of cardiorespiratory failure. The diagnosis was
      established only post mortem. In none of the patients signs of affected lymph
      nodes were present. The authors analyze problems of bioptic diagnosis of the
      mentioned lymphoma, in particular biopsy of bone marrow in the stage of its
      initial infiltration. The key to diagnosis is in addition to knowledge of
      clinical manifestations the typical morphology and intrasinusoid propagation of
      tumour cells and immunohistochemical evidence of their T-phenotype. The
      predominance of initial manifestations of haemolytic anaemia calls for
      differential diagnosis of haemolytic conditions and confirmation of their
      secondary character.

PMID- 10358465
TI  - [Adrenal incidentalomas. Clinical experience].
AB  - In the course of two years the authors treated 27 patients with incidentally
      detected adrenal tumours. Detailed morphological and laboratory examination
      revealed four cases of non-classical late type adrenogenital syndrome (AGS) and
      two pheochromocytomas. From the submitted paper ensues that it is essential to
      provide interdisciplinary comprehensive treatment in departments which have
      sufficient experience with this problem.

PMID- 10358464
TI  - [Hepatitis B immunization in hemodialysis patients].
AB  - Infection with the virus of hepatitis B is found in haemodialyzed patients many
      times more frequently than in the normal population and it participates in their
      morbidity and mortality. It is also an important issue in patients after
      transplantation of the kidney. With regard to the alarmingly high prevalence of
      this infection in their haemodialyzation centre the authors analyzed
      retrospectively the effectiveness of the most successful preventive measure-
      active immunization--in 84 patients immunized with Engerix B according to the
      protocol recommended for haemodialyses. They found that: i) active immunization
      started after the onset of haemodialyzation has a low effectiveness and in
      patients who do lack protective antibodies anti-HBs before the onset of
      haemodialysis it is important to look for other preventive measures; ii) a
      certain effectiveness is achieved only by administration of more than three doses
      of vaccine.

PMID- 10358466
TI  - [Assessment of the need for and length of hospitalization at the internal
      medicine department].
AB  - We used the Appropriateness Evaluation Protocol (AEP) to evaluate appropriateness
      of admission and continuing hospitalization (daily till discharge of maximally
      till 15th day of hospitalization) of 260 patients admitted consecutively to
      department of internal medicine of a teaching hospital. Reasons of inappropriate
      admissions and delayed discharges were classified and analyzed. Results of the
      valuation of some patients were subject to control by a committee of fully
      specialized hospital physicians. 63 (24%) of 260 admissions and 1005 (54%) of
      1869 evaluated days of stay failed the AEP criteria. These patients could be well
      served by lower treatment intensity in outpatient clinics, nursery homes or their
      own homes. Such a shift in pattern of provided care requires profound
      organizational changes many of which are out of reach of individual acute
      hospitals. Despite some limitations we find AEP a useful tool for internal
      utilization review. External application of AEP in a representative sample of
      acute care hospitals could provide important data for future development of the
      Czech health care system.

PMID- 10358467
TI  - [Successful treatment of hemothorax with recombinant factor VIIa in a hemophilic
      child with inhibitor].
AB  - rFVIIa is at present the most progressive treatment in different haemorrhages and
      operations in patients with haemophilia A and a high titre of inhibitor. As
      apparent from the presented case of a 4-year-old boy with haemorrhage into the
      pleural cavity, rFVIIa is sufficiently effective to induce haemostasis, while it
      is safe and has no side-effects. It does not induce systemic activation of
      haemostasis. Its application requires, due to the high price, that all criteria
      should be met which were elaborated for the Slovak Republic in the National
      centre of haemostasis and thrombosis.

PMID- 10358468
TI  - [Whipple's disease, early diagnosis, early therapy].
AB  - The authors describe a case of Whipple's disease diagnosed early during
      gastroduodenofibroscopy from a bioptioc specimen of the prepyloric gastric
      mucosa, and treated in time. The disease was complicated by superinfection with
      Salmonella enteritidis. In the clinical picture digestive symptoms predominated,
      loose stools, malabsorption, loss of body weight, anaemia, skin pigmentation.
      After antibiotic and later chemotherapeutic treatment clinical symptoms receded
      and the histological finding in bioptic specimens from the stomach was normal.

PMID- 10358469
TI  - [Determination of cystatin C in serum and its use in prediction of glomerular
      filtration].

PMID- 10358470
TI  - [Beta blockers in the treatment of chronic cardiac failure].
AB  - The authors present contemporary findings on the treatment with beta-blockers in
      patients with chronic heart failure. It is important to differentiate acute and
      chronic administration. The authors discuss theoretical prerequisites for the
      administration of beta-blockers in chronic heart failure. They give an account of
      indications, contraindications and mode of treatment. The dosage pattern for
      different preparations is given. The authors summarize the results of major
      studies with beta-blockers: MDC, CIBIS, ANZ, US Carvedilol Trials and they
      outline the trends of future research and indications for treatment with beta
      blockers.

PMID- 10358471
TI  - [Prevention and treatment of unstable atherosclerotic lesions in
      atherosclerosis].
AB  - Primary, secondary and tertiary prevention and treatment of atherosclerosis and
      unstable atherosclerotic lesions as well as of their sequelae must be
      comprehensively angioprotective (comprehensively antiatherogenic), above all
      antilipidogenic (antihyperlipidaemic), antithrombogenic (antithrombotic) and
      endotheloprotective (cytoprotective). It is important to use an individual
      approach, differentiated with regard to actual results of basic and functional
      physical, instrumental and laboratory angiological examination which must be made
      at frequent, regular intervals. Prevention and treatment must not be alternatives
      substituting each other.

PMID- 10358472
TI  - HCFA appears to shift position.

PMID- 10358473
TI  - Prescribing Zyban for a teen.

PMID- 10358474
TI  - A malpractice primer for NPs.

PMID- 10358475
TI  - Current approaches to depression in children and adolescents.

PMID- 10358476
TI  - Reducing the toll of asthma on children and families.

PMID- 10358477
TI  - Nocturnal enuresis in children.

PMID- 10358478
TI  - The path of least resistance.

PMID- 10358479
TI  - Calling the shots without calling them 'shots'.

PMID- 10358480
TI  - Evaluating for child sexual abuse.

PMID- 10358481
TI  - ADHD in adolescents.

PMID- 10358482
TI  - Maximum mileage. Preventing teen auto deaths.

PMID- 10358483
TI  - Grandparents raising grandchildren.

PMID- 10358484
TI  - More than band-aids and fevers. The changing role of school nurses.

PMID- 10358485
TI  - Internationally adopted children.

PMID- 10358486
TI  - Teaming up for children.

PMID- 10358488
TI  - Are we listening to our patients?

PMID- 10358487
TI  - The power of suggestion.

PMID- 10358489
TI  - Culturally competent care for psychiatric clients who have a history of sexual
      abuse.
AB  - Canadian psychiatric nurses (N = 1,701) participated in a survey in which they
      assessed their ability to nurse clients with a history of sexual abuse when
      cultural differences are present. Thirty-nine percent worked at a facility having
      a significant number of clients from a different culture. Only 4.6% rated
      themselves as "very competent." Four themes emerged from nurses' assessment of
      their ability: culture is not the problem, culture is not an issue, culture
      influences perspective and responses, and culturally specific competence. Only
      one cultural group, First Nations, was identified by sufficient numbers of nurses
      to generate themes concerning the challenge of working with clients from a
      particular culture. These themes (abuse as a cultural norm, concurrent and
      related health and social problems, reluctance to talk about problems, a need to
      learn about First Nations culture, and developing culturally competent
      caregivers), critical areas of concern, and possible solutions suggested by the
      nurses are discussed.

PMID- 10358490
TI  - A typology of consumers of institutional respite care.
AB  - In this descriptive ethnography, a typology of consumers of institutional respite
      care and phases of respite care were formulated from the data collected over a 1
      year period at a 24-bed hospital-based skilled nursing facility in the western
      United States. The sample was drawn from facility billing records, which verified
      the type of care under the term respite care. Using anthropological fieldwork
      methods, data were obtained from 14 caregiving dyads plus two care recipients who
      did not have family caregivers. The identified caregiver categories were
      depletion, maintenance, caregiver surgery or illness, and no available family
      caregiver. Phases of respite care provided information regarding the caregivers'
      experience in the process of decision making, transitioning to time away from the
      care recipient, and postrespite adjustment. This model has implications for the
      structure and process of respite care design and decision making. This may
      provide a promising avenue in the respite care research arena.

PMID- 10358491
TI  - Ventilated patients' self-esteem during intubation and after extubation.
AB  - The primary purpose of this study was to determine if there was a difference in
      patients' self-esteem during intubation and after extubation, when differences in
      acuity were controlled. A secondary purpose was to examine and compare the self
      esteem of subjects intubated for medical or surgical reasons. A descriptive
      longitudinal design compared the self-esteem of 29 subjects during intubation and
      after extubation. A repeated measures analysis of covariance found self-esteem to
      be significantly higher after extubation in subjects as a whole, when acuity at
      extubation was controlled. A repeated measures multivariate analysis of variance
      revealed a significant interaction effect for reason of intubation. Only medical
      patients experienced an increase in self-esteem over time. Their self-esteem was
      also lower when they were intubated. The findings support the dynamic nature of
      self-esteem in hospitalized patients. The implications of the study for research
      and practice are discussed.

PMID- 10358493
TI  - Perceived causes of urinary incontinence and reporting: a study with working
      women.
AB  - The purposes of this study were to describe what working women perceived as the
      cause of their urinary incontinence (UI) and to determine if there was a
      relationship between identifying their UI cause and reporting it.

PMID- 10358492
TI  - Testing a model of the nursing assessment of infant pain.
AB  - The purpose of this study was to test whether elements of an infant pain
      assessment model interacted as postulated by the model. The elements are the
      infant's response to comfort measures and the principle of consolability. Four
      different scenarios for each of 16 videotaped infants were prepared. Each
      scenario represented one of four different combinations of likelihood of pain and
      consolability and consisted of a videotape plus written clinical information.
      Forty-eight volunteer pediatric nurses assessed infant pain of 16 scenarios, each
      depicting one of the 16 infants. Mean level of assessed pain was highest for the
      "high likelihood of pain and difficult to console" group, second highest for the
      "high likelihood of pain and easily consoled" group, third highest for the "low
      likelihood of pain and difficult to console" group and least for the "low
      likelihood of pain and easily consoled" group. Findings supported the infant pain
      assessment model.

PMID- 10358494
TI  - Do nurses make a difference?

PMID- 10358495
TI  - 10 tips for thinking in a new way: getting ready for whatever comes next.

PMID- 10358496
TI  - Tips on overcoming communication breakdown with elderly patients.

PMID- 10358497
TI  - Wake up call.

PMID- 10358498
TI  - How OASIS relates to the Medicare 485.

PMID- 10358499
TI  - Caring for vascular leg ulcers: essential knowledge for the home health nurse.
AB  - Vascular leg ulcers are a significant clinical problem. Home health nurses play a
      critical role in caring for clients with vascular leg ulcers and require an
      understanding of the pathogenesis and treatment of these ulcers. This article
      differentiates the pathogenesis of venous and arterial ulcers and describes the
      critical aspects of their treatment. Interventions include modifying activity,
      promoting blood flow, applying compression therapy, providing local wound and
      skin care, improving nutrition, and treating infection.

PMID- 10358500
TI  - A stepwise guide to cancer pain management in the home.
AB  - Patients experiencing pain from cancer make up a large part of the caseload for
      most home care and hospice nurses. This article presents up-to-date information
      on the medications, strategies, and considerations in managing these patients.
      Helpful tables, reference points, and tips from a pain management expert are also
      presented.

PMID- 10358501
TI  - Preventing drug interactions in the home: a five-step approach for client
      teaching.
AB  - An important area of pharmacologic concern, particularly in the home setting, is
      that of drug interactions. The 1997 action by the Food and Drug Administration
      (FDA) to remove fenfluramine and dexfenfluramine, causing the weight-control phen
      fen scare, is a high-profile example of an issue that occurs every day with
      little fanfare. In drug administration and supervision, there are many factors of
      concern. This article illustrates five basic factors to consider to prevent drug
      interactions in the home setting.

PMID- 10358502
TI  - Using self-efficacy to increase physical activity in patients with heart failure.
AB  - Increasing self-efficacy is not a state that develops quickly. It is unrealistic
      to expect that the factors contributing to illness and disability will be
      modified easily. The home care nurse can positively influence self-efficacy
      expectations in the heart failure population by creating a supportive environment
      to perform physical activities (performance mastery), assisting with
      encouragement and support (verbal persuasion), providing anticipatory guidance
      and sharing how others perform (vicarious experience), and providing a realistic
      assessment of a person's abilities (physiologic state). By enhancing self
      efficacy, the home care nurse can increase physical activity levels in this
      population, leading to decreased symptomatology and improved quality of life.

PMID- 10358503
TI  - Defining homebound status.

PMID- 10358504
TI  - Surviving a downsizing, merger, restructuring ... and any other euphemism.

PMID- 10358505
TI  - Rehabilitation nursing principles and home care theory and practice.

PMID- 10358506
TI  - Medicare & the nurse. 10 DRGs that can affect home care referrals.

PMID- 10358507
TI  - Association promises hope to home care nurses.

PMID- 10358508
TI  - Surfing for life.

PMID- 10358509
TI  - Ambulatory surgical clinical pathway.
AB  - The purpose of this report is to describe the design, implementation, and
      advantages of a clinical pathway for patients undergoing ambulatory surgery. The
      primary purpose of the pathway is to dovetail the preoperative, intraoperative,
      and postoperative care of the ambulatory surgical patient. The pathway provides a
      mechanism to collect data and evaluate patient outcome.

PMID- 10358510
TI  - Clinical care map for the ambulatory laparoscopic cholecystectomy patient.
AB  - Shortened hospital stays, expectations of quick recovery, and rapid turn-around
      times in surgical services challenge perioperative nurses to be creative and
      innovative providers of essential and appropriate patient education. Nurses need
      approaches that enable them to meet these challenges. One such approach is the
      adaptation of a clinical care map to the development of a perioperative patient
      care guide. This article describes the rationale behind the use of this approach
      and its application to the education of the patient undergoing laparoscopic
      cholecystectomy. Steps in the process are described. Nurses can use these steps
      to develop patient care guides suited to their specific practice setting.

PMID- 10358511
TI  - Care of the patient with interstitial cystitis: current theories and management.
AB  - Interstitial cystitis is a disease process that has only come into focus over
      recent years. Researchers are looking for a cause of this painful and frustrating
      disorder of the bladder, but currently, only theories exist. Nurses must
      understand the pathophysiology of the disease and the dysfunction of the bladder
      to educate and assist the patient in the management of this chronic process. This
      report provides the nurse with information and education on the symptoms,
      pathophysiology, nursing diagnoses, and potential treatment modalities.

PMID- 10358512
TI  - Looking to the south.
AB  - The author traveled to Puerto Rico and arranged to visit several hospitals as an
      ambassador for ASPAN. In this article, he describes what he saw and explains the
      similiarities in nursing care between two cultures.

PMID- 10358513
TI  - Vasodepressor syncope: the common faint.
AB  - Perianesthesia patients and families are susceptible to vasodepressor syncope.
      Understanding the physiological mechanisms responsible for syncope, the Bezold
      Jarisch reflex, will allow the perianesthesia nurse to minimize the physical and
      emotional sequele of the common faint.

PMID- 10358514
TI  - How to keep cool in tough times.
AB  - Reengineering is no longer an event that has a beginning and an end. It is an
      ongoing process of change that continues to occur in all types of businesses.
      Because there is no longer the sense of security that doing a job well will
      guarantee continued employment, workers have to approach career planning from a
      different perspective. Moving up the career ladder in a single organization can
      no longer serve as the benchmark of success. The contemporary approach to success
      will be more geared toward the ability to constantly reinvent your unique set of
      job skills that are transferable from one job setting to another, thus ensuring
      employability.

PMID- 10358515
TI  - Anesthesia for cardioversion.
AB  - Elective electrical cardioversions are commonly scheduled to be performed in the
      PACU because of the availability of nursing and anesthesia support. This report
      examines preanesthetic patient preparation as well as a review of the procedural
      aspects of electrical cardioversion. The commonly used anesthetic agents are
      contrasted with regard to their pharmacodynamic considerations. The indications,
      contraindications, and complications associated with the procedure are reviewed.

PMID- 10358516
TI  - Inspiration.

PMID- 10358517
TI  - Evidence-based practice in nursing.

PMID- 10358518
TI  - You make the diagnosis. Case study: diagnoses and interventions with low
      literacy.

PMID- 10358519
TI  - Processes and methodologies for research validation of nursing diagnoses.
AB  - TOPIC: Research validation of nursing diagnoses. PURPOSE: To provide a historical
      review of processes and methodologies for research validation of nursing
      diagnoses and suggested directions for future nursing diagnosis research.
      SOURCES: Nursing diagnosis research methodologies and processes from the
      Invitational Conference on Research Methods for Validating Nursing Diagnoses,
      Nursing Diagnosis: The Journal of Nursing Language and Classification, and the
      North American Nursing Diagnosis Association (NANDA) conference proceedings for
      the first through the 12th conference. CONCLUSIONS: Future nursing diagnosis
      research should include concept analysis, expert validation, clinical validation,
      instrument development, larger studies, powerful statistical analyses,
      replication and comparison of studies, and concerted efforts to support group
      research activities that target priority areas of research.

PMID- 10358521
TI  - Development of bilingual tools to assess functional health patterns.
AB  - TOPIC: The theory and process of developing bilingual assessment tools based on
      Gordon's 11 functional health patterns. PURPOSE: To facilitate assessing the
      individual, family, and community in a student clinical practicum in a Spanish
      speaking country. SOURCES: Multiple family and community health promotion
      theories; translation theories, Gordon's Manual of Nursing Diagnosis (1982);
      translation/back-translation involving Ecuadorian faculty and students; student
      community assessments; faculty and staff workshops in Ecuador. CONCLUSIONS:
      Bilingual, culturally sensitive health assessment tools facilitate history
      taking, establish nursing diagnoses and interventions, and promote mutual
      learning. These outcomes demonstrate potential application to other systems in
      the international nursing community.

PMID- 10358520
TI  - Validation of the defining characteristics of body image disturbance in Japan.
AB  - PURPOSE: To examine the validity of the nursing diagnosis body image disturbance
      and to specify its major and minor defining characteristics in Japanese culture.
      METHODS: A qualified sample of 149 RNs with an average of 10 years of clinical
      experience and knowledge of nursing diagnosis was given a questionnaire
      consisting of 21 defining characteristics from NANDA, 8 additional items from the
      literature, and 2 distracting characteristics. FINDINGS: Four major diagnostic
      content validation (DCV) scores of 0.75 and higher and 15 minor defining
      characteristics with DCV scores from 0.60 to 0.74 were identified. CONCLUSIONS:
      This study provides a foundation for further study of culturally appropriate
      defining characteristics for use in Japan.

PMID- 10358522
TI  - Nursing Diagnosis Extension and Classification (NDEC) report.

PMID- 10358524
TI  - The contemporary debate about 'euthanasia'.

PMID- 10358523
TI  - Nursing diagnosis or patient problem?

PMID- 10358525
TI  - Promoting a good death: an agenda for outcomes research--a review of the
      literature.
AB  - Outcomes research is topical in discussions about health-related research. Its
      emphasis on effectiveness creates an important opportunity for nurse researchers
      to strengthen the linkages between theory, outcomes research and nursing practice
      but, before care can be more effective, it is logical to establish patients'
      desired outcomes. A thorough review of the implications of this requirement for
      the care of hospice patients is needed, but is lacking in the literature.
      Therefore, the literature on a 'good death' is reviewed as a step towards
      assisting hospice patients to achieve what they regard as an acceptable death.
      The starting point is to define more clearly what it means to die a good death.
      The relationship between hospice care and achieving a good death is then
      examined.

PMID- 10358526
TI  - Physician-assisted suicide and voluntary euthanasia: is it time the UK law caught
      up?
AB  - People who wish to end their lives when they consider that they cannot endure
      further pain and suffering cannot legally obtain help to produce a peaceful
      death. The reality of practice seems to be that, covertly, physician-assisted
      suicide and voluntary euthanasia do take place. The value of personal autonomy in
      issues of consent has been clarified in the courts in that a competent adult
      person has the right to refuse or choose alternative treatments even if death
      will be the outcome. This issue needs open discussion and regulation in order to
      protect those vulnerable people in our society.

PMID- 10358527
TI  - Global influence of American nursing: some ethical issues.
AB  - This article raises some questions about the global influence of nursing in the
      USA and describes some problems that may come about because of it. Selected
      American values that are embedded in nursing and ethics are found in American
      nursing education, practice and research. These can then be exported to countries
      with very different cultural definitions and values. One such country is Japan.
      The discrepancy between national cultural norms and imported ideals of nursing
      practices can create ethical problems for nurses in these countries.

PMID- 10358528
TI  - Nondirectiveness in prenatal genetics: patients read between the lines.
AB  - For decades questionnaires have been used to measure the cognitive and
      psychological effects of prenatal genetic testing, but little is known about why
      some women undergo testing and others decline. Research indicates that many
      factors influence decision making, including values and beliefs. What is often
      denied rather than recognized is that the professional and personal values and
      beliefs held by the health care provider influence the patient's decision. It is
      assumed that, if genetic services are delivered in a nondirective manner,
      patients will not be affected by the provider's personal and professional
      standpoint. The qualitative research data reported here challenge this
      assumption. Getting to know patients' moral understanding and patterns of ethical
      reasoning by listening to their personal stories is recommended as a better way
      for nurses to help patients to make informed and autonomous decisions about
      prenatal genetic screening or diagnostic tests.

PMID- 10358529
TI  - When the home becomes a prison: living with a severely disabled child.
AB  - The aim of this study was to generate knowledge about how parents who have been
      part of an ethical decision-making process concerning a son or daughter in a
      neonatal unit experience life with a severely disabled child. A descriptive study
      design was chosen using 30 hours of field observations and seven in-depth
      interviews, carried out over a period of five months with parents who had been
      faced with ethical decisions concerning their own children in a neonatal unit.
      Strauss and Glaser's constant comparative method was used for the analysis. The
      findings seem to indicate that these parents have an extremely tough life. Their
      relationships with their children are somewhat ambivalent. The children are very
      dependent on their parents, who in some ways both love and hate them. Too little
      rest and sleep and feeding the children are the most serious problems. The
      parents require respite facilities. The home can seem like a prison, from which
      it is impossible to escape. It is like having a baby who never grows up.

PMID- 10358530
TI  - Sexuality among institutionalized elderly patients with dementia.
AB  - The subject of sexuality among elderly patients with dementia was examined,
      focusing on two main aspects: the sexual behaviour of institutionalized elderly
      people with dementia; and the reactions of other patients, staff and family
      members to this behaviour. The behaviour was found to be mostly heterosexual and
      ranged from love and caring to romance and outright eroticism. Reactions varied,
      being accepting of love and care but often objecting to erotic behaviour.
      Understanding of the sexual needs of elderly people should become an integral
      part of the training and continued education of health care staff, thus helping
      to resolve conflicts and clarify common misconceptions.

PMID- 10358531
TI  - Getting it right: the teaching of philosophical health care ethics.
AB  - This article seeks to show one way in which moral philosophy, considered by the
      authors to be essential to the nursing and midwifery curricula, can be presented
      to achieve an optimal learning experience for nurses and midwives. It
      demonstrates that what might be considered a standard approach, that is, one that
      begins with ethical principles concerned with rights and duties and then often
      follows a linear pattern of teaching, may be in danger of promoting a focus on
      standardized outcomes. Such use of philosophy could therefore actually detract
      from the process of care. Moral philosophy underpinning health care ethics is
      commonly misperceived as a method of problem solving when there is an obvious
      dilemma regarding appropriate care and/or treatment. However, it is readily
      recognized that key principles within philosophy, for example, deontology and
      utilitarianism, despite their approach to a standard or criterion of right
      action, are both deficient in terms of providing ready-made right decisions. This
      is because their main virtue is to expose the difficulty rather than to solve the
      problem. Given these difficulties, any subsequent principles such as respect,
      beneficence, nonmaleficence and justice, incur the same deficiencies a fortiori.
      It can be argued that the complexity of the environment in which nurses and
      midwives now practice requires them to develop a capability that begins with the
      philosophical construction of an issue. This can subsequently enable a
      recognition of the essential nature of their own involvement as a nurse or
      midwife. By so doing, nurses and midwives can then bring issues into a nursing or
      midwifery paradigm and ensure that this perspective informs debate. Ultimately
      the focus is on the process by which care decisions are made. The intent
      therefore, is not simply for nurses or midwives to learn moral philosophy or to
      copy what is considered by others to be right action, but to recognize that a
      number of right actions are possible and, in so doing, develop their ability
      either to choose or influence a final action through a valid process. This
      article proposes and demonstrates by case example that what is often considered
      as a chance effect for nurses and midwives learning moral philosophy should be
      seen as the main effect and intended outcome.

PMID- 10358533
TI  - The international policy of the Swiss Nurses' Association (SNA).

PMID- 10358532
TI  - Response to the National Council for Hospice and Specialist Palliative Care
      Services--voluntary euthanasia: the council's view, by Ann Marie Begley.

PMID- 10358534
TI  - The Society for Patient's Rights in Israel.

PMID- 10358535
TI  - The use of animals in biomedical research.

PMID- 10358536
TI  - Promoting clinical effectiveness in education and training.

PMID- 10358537
TI  - Oral care in the intensive care setting: a case study.
AB  - Oral care is discussed as an important part of total patient care. The aetiology
      of periodontitis, and the formation and control of plaque, are outlined.
      Principles of mouth care are illustrated through the use of a case study. Results
      of a small pilot study suggest there is a need for evidence-based teaching on
      oral care. Conclusions identify that oral care is an important component of
      promoting comfort.

PMID- 10358538
TI  - The use of senior nurses in administering a standardised protocol for the pre
      operative optimisation of high risk surgical patients.
AB  - The pre-optimisation study is outlined. The pre-operative optimisation of high
      risk elective surgical patients in a District General Hospital is discussed in
      relation to a research study. Issues related to the development of a protocol are
      examined. The use of standardised protocols to guide the pre-optimisation process
      are focused on, emphasising the role of the senior nurse in administering the
      protocol.

PMID- 10358540
TI  - Causes of ICU psychosis: the environmental factors.
AB  - ICU psychosis is common amongst patients admitted to critical care settings. ICU
      psychosis is the result of a complex interaction between physiological and
      psychological factors. Environmental factors will contribute to ICU psychosis
      (including sleep deprivation, excessive noise, separation, poor communication and
      immobilisation). These environmental factors can be manipulated to reduce the
      incidence of ICU psychosis.

PMID- 10358539
TI  - 'Climbing the walls' ICU psychosis: myth or reality?
AB  - The extent of the effect of the ICU environment on the psychological functioning
      on the ICU patient is explored. There is a need to understand all potential
      causes of disruption in psychological functioning in ICU patients. Co-ordination
      of all care carried out by multi-disciplinary team can help re-orientate patients
      and re-establish normal routines.

PMID- 10358541
TI  - How critical care nurses identify and meet the needs of visitors to intensive
      care units.
AB  - This article provides an account of the everyday experience of meeting the needs
      of visitors to intensive care units and how research on the topic assists the
      nurse with this situation. Shortfalls in the available research and the provision
      of appropriate training for the practical experience are considered. A commentary
      on the requirements for further development of knowledge and training is offered.

PMID- 10358542
TI  - Responding within an holistic perspective to relatives on ICU.

PMID- 10358543
TI  - Pulled in all directions: lecturers' accounts of managing critical care courses.
AB  - This paper reports on a recent telephone interview conducted with critical care
      lecturers around the country. Some of the debate is informed by three focus
      groups held with different stakeholders. The advantages and disadvantage of
      telephone interview are outlined, and some practical advice included with regard
      to the use of this research method. The telephone interview was conducted with 84
      course lecturers. Views were gathered from course lecturers/pathway leaders for
      ENB 100, 124, 176/183, 199 and 415. The participants represented a broad
      geographical spread across England. Lecturers described four key sources of
      influence coming from: the higher education sector, curriculum change; the
      purchaser provide commissioning process; and practice demands. All these local
      factors are set in the context of ENB requirements for validation and
      anticipation of the UKCC's deliberations on specialist practice.

PMID- 10358545
TI  - NICE prospects for best practice. National Institute for Clinical Excellence.

PMID- 10358544
TI  - Children in intensive care: physiological considerations.
AB  - The needs of critically ill children have been highlighted on many occasions in
      recent years. The specific physiological and psychosocial needs of critically ill
      children have resulted in the recommendation that they be cared for in specially
      designated units. It is essential that the anatomical and physiological
      differences between adults and children and how these affect them in health and
      illness be considered when providing care for this client group.

PMID- 10358546
TI  - Open to abuse.

PMID- 10358547
TI  - Who's your favourite nurse on TV.

PMID- 10358548
TI  - Steps to valuing diversity.

PMID- 10358549
TI  - Virtual therapy.

PMID- 10358550
TI  - Ignorance and the law.

PMID- 10358551
TI  - Spring is in the air.

PMID- 10358552
TI  - Grim fairy tales.

PMID- 10358553
TI  - The ICN on men's health. International Council of Nurses.

PMID- 10358554
TI  - Occupational stress in the newly qualified staff nurse.
AB  - The transition from student to staff nurse has always been seen as a challenging
      and stressful time in the working life of a nurse, yet it is an area that has
      seen little research. In the light of recent debate on the effectiveness of
      Project 2000 training, this survey looks at the perceived occupational stresses
      experienced by Project 2000 trained staff nurses during their first six months as
      qualified practitioners.

PMID- 10358555
TI  - Harnessing IT systems to support patient care: good practice.
AB  - The incorporation of information management and technology into healthcare
      environments has long been advocated, but resistance from clinicians and
      perceived financial constraints have laboured its successful implementation in
      many trusts. This article looks at the reasons behind these problems and
      highlights the benefits to patients of effective use of information technology in
      the delivery and documentation of patient care.

PMID- 10358556
TI  - Casting: Part two.
AB  - In the second of two articles, Margaret Prior and Susan Miles discuss techniques
      for the adaptation and removal of casts. They also consider common complications,
      the provision of appliances and information to patients, as well as some of the
      problems that may occur when safety is not seen as an inherent part of practice.

PMID- 10358557
TI  - Improving wound care through clinical governance.
AB  - The fundamental role of nurse specialists is to improve and maintain the quality
      of patient care across the organisation. Heather Newton looks at the specialist
      nursing role in the light of the clinical governance arrangements.

PMID- 10358558
TI  - A systematic approach to complex wounds.
AB  - Complex wounds fill most nurses with the feeling of unmanageable dread. This
      article aims to dispel such fears by showing that the nurse, once equipped with
      the correct physiological knowledge and an in-depth awareness of the treatments
      available, can provide effective wound care using the nursing process.

PMID- 10358560
TI  - Nurses with disabilities.

PMID- 10358559
TI  - Nurses' knowledge about pressure sore treatment and healing.
AB  - Although nurses are more knowledgeable about pressure score healing and treatment
      than expected, a small scale study found that there is still room for
      improvement. There appeared to be similar levels of knowledge of pressure sore
      healing among orthopaedic and general surgical nurses, and a strong relationship
      between clinical grade and knowledge, with more senior grade nurses scoring
      higher on a pressure sore healing and treatment score, compared to more junior
      nurses. This has implications for who should be performing pressure sore
      treatment in the clinical setting.

PMID- 10358561
TI  - Primary care groups.

PMID- 10358562
TI  - A brand new NHS for the millennium.

PMID- 10358563
TI  - Starting up the road to recovery.

PMID- 10358565
TI  - Doctors lean on nurses for support.

PMID- 10358564
TI  - Nurses have a crucial role to play in the prevention of child abuse.

PMID- 10358566
TI  - Keeping watch.

PMID- 10358567
TI  - Work makes nurses sick.

PMID- 10358568
TI  - What is a HAZ?

PMID- 10358569
TI  - PREP has the potential to make nurses happier and more effective in their working
      lives.

PMID- 10358570
TI  - It's the soul of the century.

PMID- 10358571
TI  - New dawn for nurse power.

PMID- 10358572
TI  - Bring back the EN. For and against.

PMID- 10358573
TI  - Trouble at sea.

PMID- 10358575
TI  - So you want to be a ... homoeopath.

PMID- 10358574
TI  - User participation. Listen and learn.

PMID- 10358576
TI  - Night on the tiles.

PMID- 10358578
TI  - Join a club.

PMID- 10358577
TI  - ISAs. Individual Savings Accounts.

PMID- 10358579
TI  - Model for integrated mental health care measures up.

PMID- 10358580
TI  - Peritoneal port offers new approach to HIV therapy.
AB  - This article gives a brief overview of HIV care and discusses the nursing aspects
      of implementing a multicentre research project that offers an experimental
      intraperitoneal approach to anti-HIV therapy.

PMID- 10358581
TI  - Management and treatment of patients with acromegaly.
AB  - Untreated acromegaly causes substantial morbidity and mortality, and results in a
      marked reduction in quality of life. For this reason, the treatment goals need to
      be well defined and therapy optimised. This article describes the clinical
      approach to acromegaly, including: Pathophysiology of growth hormone secretion;
      Clinical features; Biochemical and radiological diagnosis; Treatment goals and
      therapeutic options; Prognosis.

PMID- 10358582
TI  - Primary care. Second among equals.

PMID- 10358583
TI  - Primary care. Taken on board.

PMID- 10358584
TI  - Primary care. Trust in the future.

PMID- 10358585
TI  - A social services perspective on primary care groups.

PMID- 10358586
TI  - Primary care. Getting together.

PMID- 10358587
TI  - Random drug testing of staff.

PMID- 10358588
TI  - No regrets. Interview by Mark Gould.

PMID- 10358590
TI  - What is a Healthy Living Centre?

PMID- 10358589
TI  - Outlook brighter. Interview by Rebecca Coombes.

PMID- 10358591
TI  - English regional government. A devolution revolution?

PMID- 10358592
TI  - Will Yorkshire make a stand?

PMID- 10358593
TI  - Wales welcomes self-rule.

PMID- 10358594
TI  - Nurses from the former Yugoslavia.

PMID- 10358595
TI  - Positive attitudes required.

PMID- 10358596
TI  - Hemmed in.

PMID- 10358598
TI  - A fetching little lilac number.

PMID- 10358597
TI  - Beaux parlours and buttons.

PMID- 10358599
TI  - Racism: time to turn words into action.

PMID- 10358600
TI  - NHS trusts are complicating the recruitment crisis through their incompetence.

PMID- 10358601
TI  - Pets and patients. Duty and the beasts.

PMID- 10358602
TI  - Pet therapy.

PMID- 10358604
TI  - So you want to be an acupuncturist.

PMID- 10358603
TI  - Travel insurance.

PMID- 10358605
TI  - A major study on back injury.

PMID- 10358606
TI  - Organ procurement: pitfalls and pathways.
AB  - Current methods of organ procurement are successful but are not adequately
      reducing waiting lists for organs. Alternative methods could result in greater
      organ availability. The small-scale study described here examines attitudes to
      some alternative methods of procurement, emphasies the importance of public
      support in organ donor programmes and makes recommendations for future
      programmes.

PMID- 10358607
TI  - Missing lessons in skills training.

PMID- 10358608
TI  - Learning disabilities: helping women manage menstruation.

PMID- 10358609
TI  - The highs and lows of supermidwifery.

PMID- 10358610
TI  - Midwifery. Fighting for your rights.

PMID- 10358611
TI  - Midwifery. Push! Or is that shove?

PMID- 10358612
TI  - Primary opportunity.

PMID- 10358613
TI  - Myths & facts ... about cystic fibrosis.

PMID- 10358614
TI  - Escherichia coli (E. coli) O157.H7.

PMID- 10358615
TI  - Managing a drug abuser's pain.

PMID- 10358616
TI  - Understanding asthma.

PMID- 10358617
TI  - Solving the puzzle of heart failure.

PMID- 10358618
TI  - When once is enough. Administering aminoglycosides effectively.

PMID- 10358619
TI  - You should be in pictures.... Nurses on picture postcards.

PMID- 10358620
TI  - Crash in the NICU.

PMID- 10358621
TI  - Clarifying advance directives.

PMID- 10358622
TI  - Joe wanted to die alone ... or so he said.

PMID- 10358623
TI  - The art of accessing an implanted port.

PMID- 10358624
TI  - 5 finger sticks.

PMID- 10358625
TI  - Taking a sensitive approach to urinary incontinence.

PMID- 10358626
TI  - Sailing uncharted seas.

PMID- 10358627
TI  - Actionstat. Antifreeze poisoning.

PMID- 10358628
TI  - Caring for a diabetic ulcer.

PMID- 10358629
TI  - Labor and delivery beds.

PMID- 10358630
TI  - Help from an angel.

PMID- 10358631
TI  - The adventures of Muscles Marti and Jumpin' Josh.

PMID- 10358632
TI  - Let's blame education.

PMID- 10358633
TI  - Children's nursing in Europe.

PMID- 10358634
TI  - Comparison of Australian ambulatory paediatrics and community children's nursing
      in the UK.

PMID- 10358636
TI  - The nurse practitioner in children's ambulatory care.
AB  - History-taking, clinical assessment, requesting X-rays and carrying out
      cannulation on children, are just some of the skills which may be undertaken as
      part of developing nursing roles, such as the nurse practitioner. Annette Dearmun
      and Kim Gordon describe the developments of this ground-breaking role in the
      children's ambulatory care unit at Oxford.

PMID- 10358635
TI  - Assessing the need for endotracheal suction.
AB  - Endotracheal suction (ETS) is a common method used to remove broncho-pulmonary
      secretions. This study aimed to investigate whether, and how, nurses in the
      paediatric intensive care environment assess the need for endotracheal suction.
      Overt, non-participant observation and interviews were used to collect data from
      12 nurses on four paediatric intensive care units. The large majority of episodes
      of ETS observed were performed in response to an identified clinical need based
      on changes in a variety of clinical signs and patient behaviour. This study
      highlights the complex nature of nurses' assessment of the need for ETS and has
      implications for training and education of nursing staff.

PMID- 10358637
TI  - Make learning fun.

PMID- 10358638
TI  - Prevalence of cycle helmet use in children.
AB  - A survey was conducted over a five-day period on a cohort of 234 families
      attending a busy regional children's out-patient department in the South West of
      England. A significant result of the survey was that parental use of helmets
      strongly correlated with the use of helmets by children. In addition, income was
      not found to be a major factor in cycle helmet ownership except in the lowest
      income band.

PMID- 10358639
TI  - Preparing tomorrow's children's nursing lecturers.

PMID- 10358640
TI  - Supporting children's nursing and children's services.

PMID- 10358641
TI  - Elective placements in Romania.
AB  - When a group of student nurses embarked on an elective experience to Romania,
      they believed they'd be able to 'make a difference'. However, they quickly became
      disillusioned by a healthcare system still blighted by its past and staff that
      did not welcome their interest. Sylvia Buckingham's advice to others planning
      similar visits, is to go with realistic aims and plenty of time in which to
      achieve them

PMID- 10358642
TI  - Adolescent refusal of treatment--is it an issue?

PMID- 10358643
TI  - Needle phobia.

PMID- 10358644
TI  - 'I've got tummy ache in my head'. Communicating with sick children.
AB  - The traumatic effects of illness and hospitalisation on the child can be
      minimised with appropriate and effective communication, both with and from the
      child. When verbal communication is not possible, alternative means of
      communicating must be set up as soon as feasible, to establish a two-way channel,
      thus reducing the likelihood of misconceptions, misunderstandings, and
      unnecessary fears and frustrations.

PMID- 10358646
TI  - Establishing clinical supervision in NICU.

PMID- 10358647
TI  - Experiences of a degree course in community children's nursing.

PMID- 10358648
TI  - Welcome/Assalaam-u-alaikaam: improving communications with ethnic minority
      families.

PMID- 10358649
TI  - Children and research: ethical and philosophical principles.
AB  - Nurses involved in research must recognise their professional responsibility for
      safeguarding the rights of child research participants. The starting point is an
      understanding of ethical and philosophical principles, argues Tessa Woodfield.

PMID- 10358651
TI  - Maternal death and the medical model.

PMID- 10358650
TI  - Rose's story: understanding events in nursing.

PMID- 10358652
TI  - Active versus expectant management of the third stage of labour.

PMID- 10358653
TI  - Caring for women during the latent phase of labour.

PMID- 10358654
TI  - HIV testing in pregnancy.

PMID- 10358655
TI  - A new approach to antenatal education.

PMID- 10358656
TI  - Project-based learning in midwifery education.

PMID- 10358657
TI  - Women's views of the environment and the facilities in which maternity care takes
      place.

PMID- 10358658
TI  - Sore nipples. A new look at an old problem through the eyes of a dermatologist.

PMID- 10358659
TI  - Alive and kicking. Increasing self-esteem among women living in deprivation.

PMID- 10358660
TI  - The Hinchingbrooke Third Stage trial. What are the implications for practice?

PMID- 10358661
TI  - Ruptured uterus.

PMID- 10358662
TI  - The decision.

PMID- 10358663
TI  - Pleased to meet you.

PMID- 10358664
TI  - Which course? Who's accountable? who's to blame?

PMID- 10358665
TI  - Pictures at a birth.

PMID- 10358667
TI  - Meeting primary oral health care needs of HIV-infected women.

PMID- 10358666
TI  - Prevention of sexually transmitted diseases: the need for social and behavioral
      science expertise in public health departments.

PMID- 10358668
TI  - Breathing freely: the need for asthma research on gene-environment interactions.

PMID- 10358669
TI  - Protecting children from lead poisoning and building healthy communities.

PMID- 10358670
TI  - Sexual mixing patterns in the spread of gonococcal and chlamydial infections.
AB  - OBJECTIVES: This study sought to define, among sexually transmitted disease (STD)
      clinic attendees, (1) patterns of sex partner selection, (2) relative risks for
      gonococcal or chlamydial infection associated with each mixing pattern, and (3)
      selected links and potential and actual bridge populations. METHODS: Mixing
      matrices were computed based on characteristics of the study participants and
      their partners. Risk of infection was determined in study participants with
      various types of partners, and odds ratios were used to estimate relative risk of
      infection for discordant vs concordant partnerships. RESULTS: Partnerships
      discordant in terms of race/ethnicity, age, education, and number of partners
      were associated with significant risk for gonorrhea and chlamydial infection. In
      low-prevalence subpopulations, within-subpopulation mixing was associated with
      chlamydial infection, and direct links with high-prevalence subpopulations were
      associated with gonorrhea. CONCLUSIONS: Mixing patterns influence the risk of
      specific infections, and they should be included in risk assessments for
      individuals and in the design of screening, health education, and partner
      notification strategies for populations.

PMID- 10358671
TI  - Dental care access and use among HIV-infected women.
AB  - OBJECTIVES: This study sought to identify predictors of dental care use in HIV
      infected women. METHODS: In a cross-sectional survey of HIV-infected women
      enrolled in the northern California site of the Women's Interagency HIV Study,
      dental care use and unmet need were assessed in relation to selected variables.
      RESULTS: Among 213 respondents, who were predominantly Black and younger than 45
      years, 43% had not seen a dentist and 53% (among dentate women) reported no
      dental cleaning in more than a year (although 67% had dental insurance coverage,
      mainly state Medicaid). Nine percent were edentulous. Among nonusers of dental
      care, 78% reported that they wanted care but failed to get it. Barriers included
      fear of and discomfort with dentists, not getting around to making an
      appointment, and not knowing which dentist to visit. Multivariate analysis showed
      that lack of past-year dental care was associated mainly with unemployment, a
      perception of poor oral health, and edentulism. CONCLUSIONS: HIV-positive women
      appear to be underusing dental care services. Fear and lack of information
      regarding available resources, in addition to unemployment and perception of poor
      oral health, may be important barriers.

PMID- 10358672
TI  - Building momentum: an ethnographic study of inner-city redevelopment.
AB  - OBJECTIVES: One factor contributing to the decay of inner-city areas, and to
      consequent excess mortality, is the massive loss of housing. This report studied
      the effects of a redevelopment project on social functioning in an inner-city
      community. METHODS: This ethnographic study included the following elements: a
      longitudinal study of 10 families living in renovated housing, repeated
      observations and photographing of the street scene, focus groups, and informal
      interviews with area residents. The project was located in the Bradhurst section
      of Harlem in New York City and was focused on a redevelopment effort sponsored by
      local congregations. RESULTS: Those who were able to move into newly renovated
      housing found that their living conditions were greatly improved. Neighborhood
      revitalization lagged behind the rehabilitation of individual apartment houses.
      This uneven redevelopment was a visual and sensory reminder of "what had been."
      Residents missed the warmth and social support that existed in Harlem before its
      decline. CONCLUSIONS: Rebuilding damaged housing contributes greatly to the well
      being of inner-city residents. The current pace and scope of rebuilding are
      insufficient to restore lost vitality.

PMID- 10358673
TI  - Income inequality and homicide rates in Rio de Janeiro, Brazil.
AB  - OBJECTIVES: This study determined the effect of income inequality on homicide
      rates in the state of Rio de Janeiro, Brazil. METHODS: We conducted an ecological
      study at 2 geographical levels, municipalities in the state of Rio de Janeiro and
      administrative regions in the municipality of Rio de Janeiro. The association
      between homicide and income inequality was tested by multiple regression
      procedures, with adjustment for other socioeconomic indicators. RESULTS: For the
      municipalities of Rio de Janeiro State, no association between homicide and
      income concentration was found an outcome that can be explained by the
      municipalities' different degrees of urbanization. However, for the
      administrative regions in the city of Rio de Janeiro, the 2 income inequality
      indicators were strongly correlated with the outcome variable (P < .01). Higher
      homicide rates were found precisely in the sector of the city that has the
      greatest concentration of slum residents and the highest degree of income
      inequality. CONCLUSIONS: The findings suggest that social policies specifically
      aimed at low-income urban youth, particularly programs to reduce the harmful
      effects of relative deprivation, may have an important impact on the homicide
      rate.

PMID- 10358674
TI  - Unemployment and foster home placements: estimating the net effect of provocation
      and inhibition.
AB  - OBJECTIVES: This study sought, first, to explain and reconcile the provocation
      and inhibition theories of the effect of rising unemployment on the incidence of
      antisocial behavior. Second, it tested the hypothesis, implied by the provocation
      and inhibition theories, that the relationship between unemployment and foster
      home placements forms an inverted "U." METHODS: The hypothesis was tested with
      data from California for 137 months beginning in February 1984. RESULTS: Findings
      showed that the hypothesis was supported. CONCLUSIONS: Rising joblessness
      increases the incidence of foster home placements among families that lose jobs
      or income. Levels of joblessness that threaten workers who remain employed,
      however, inhibit antisocial behavior and reduce the incidence of foster home
      placements. This means that accounting for the social costs of unemployment is
      more complicated than assumed under the provocation theory.

PMID- 10358675
TI  - Linking community-based blood pressure measurement to clinical care: a randomized
      controlled trial of outreach and tracking by community health workers.
AB  - OBJECTIVES: This study assessed the effectiveness of enhanced tracking and follow
      up services provided by community health workers in promoting medical follow-up
      of persons whose elevated blood pressures were detected during blood pressure
      measurement at urban community sites. METHODS: In a randomized controlled trial,
      421 participants received either enhanced or usual referrals to care.
      Participants were 18 years or older, were either Black or White, and had blood
      pressure greater than or equal to 140/90 mm Hg and income equal to or less than
      200% of poverty. The primary outcome measure was completion of a medical follow
      up visit within 90 days of referral. RESULTS: The enhanced intervention increased
      follow-up by 39.4% (95% confidence interval [CI] = 14%, 71%; P = .001) relative
      to usual care. Follow-up visits were completed by 65.1% of participants in the
      intervention group, compared with 46.7% of those in the usual-care group. The
      number needed to treat was 5 clients (95% CI = 3, 13) per additional follow-up
      visit realized. CONCLUSIONS: Enhanced tracking and outreach increased the
      proportion of persons with elevated blood pressure detected during community
      measurement who followed up with medical care.

PMID- 10358676
TI  - Definition and prevalence of sedentarism in an urban population.
AB  - OBJECTIVES: The present study sought to formulate a precise definition of
      sedentarism and to identify activities performed by active people that could
      serve as effective preventive goals. METHODS: A population-based sample of 919
      residents of Geneva, Switzerland, aged 35 to 74 years, completed a 24-hour
      recall. Sedentary people were defined as those expending less than 10% of their
      daily energy in the performance of moderate- and high-intensity activities (at
      least 4 times the basal metabolism rate). RESULTS: The rates of sedentarism were
      79.5% in men and 87.2% in women. Among sedentary and active men, average daily
      energy expenditures were 2600 kcal (95% confidence interval [CI] = 2552, 2648)
      and 3226 kcal (95% CI = 3110, 3346), respectively; the corresponding averages for
      women were 2092 kcal (95% CI = 2064, 2120) and 2356 kcal (95% CI = 2274, 2440).
      The main moderate- and high-intensity activities among active people were sports
      (tennis, gymnastics, skiing), walking, climbing stairs, gardening, and (for men
      only) occupational activities. CONCLUSIONS: The definition of sedentarism
      outlined in this article can be reproduced in other populations, allows
      comparisons across studies, and provides preventive guidelines in that the
      activities most frequently performed by active people are the ones most likely to
      be adopted by their sedentary peers.

PMID- 10358677
TI  - The prevalence of low income among childbearing women in California: implications
      for the private and public sectors.
AB  - OBJECTIVES: This study examined the income distribution of childbearing women in
      California and sought to identify income groups at increased risk of untimely
      prenatal care. METHODS: A 1994/95 cross-sectional statewide survey of 10,132
      postpartum women was used. RESULTS: Sixty-five percent of all childbearing women
      had low income (0%-200% of the federal poverty level), and 46% were poor (0%-100%
      of the federal poverty level). Thirty-five percent of women with private prenatal
      coverage had low income. Most low-income women with Medi-Cal (California's
      Medicaid) or private coverage received their prenatal care at private-sector
      sites. Compared with women with incomes over 400% of the poverty level, both poor
      and near-poor women were at significantly elevated risk of untimely care after
      adjustment for insurance, education, age, parity, marital status, and ethnicity
      (adjusted odds ratios = 5.32 and 3.09, respectively). CONCLUSIONS: This study's
      results indicate that low-income women are the mainstream maternity population,
      not a "special needs" subgroup; even among privately insured childbearing women,
      a substantial proportion have low income. Efforts to increase timely prenatal
      care initiation cannot focus solely on women with Medicaid, the uninsured, women
      in absolute poverty, or those who receive care at public-sector sites.

PMID- 10358678
TI  - High-risk occupations for breast cancer in the Swedish female working population.
AB  - OBJECTIVES: The purpose of this study was to estimate, for the period 1971
      through 1989, occupation-specific risks of breast cancer among Swedish women
      employed in 1970. METHODS: Age-period standardized incidence ratios were
      computed. Log-linear Poisson models were fitted, with geographical area and town
      size taken into account. Risks were further adjusted for major occupational
      group, used as a proxy for socioeconomic status. Risk estimators were also
      calculated for women reporting the same occupation in 1960 and 1970. RESULTS:
      Most elevated risks among professionals, managers, and clerks were reduced when
      intragroup comparisons were carried out, indicating the confounding effect of
      socioeconomic status. Excess risks were found for pharmacists, teachers of
      theoretical subjects, schoolmasters, systems analysts and programmers, telephone
      operators, telegraph and radio operators, metal platers and coaters, and
      hairdressers and beauticians, as well as for women working in 1960 and 1970 as
      physicians, religious workers, social workers, bank tellers, cost accountants,
      and telephonists. CONCLUSIONS: While the high risks observed among professional,
      administrative, and clerical workers might be related to lower birth rates and
      increased case detection, excess risks found for telephone workers and for
      hairdressers and beauticians deserve further attention.

PMID- 10358679
TI  - Health care coverage and use of preventive services among the near elderly in the
      United States.
AB  - OBJECTIVES: It has been proposed that individuals aged 55 to 64 years be allowed
      to buy into Medicare. This group is more likely than younger adults to have
      marginal health status, to be separating from the workforce, to face high
      premiums, and to risk financial hardship from major medical illness. The present
      study examined prevalence of health insurance coverage by demographic
      characteristics and examined how lack of insurance may affect use of preventive
      health services. METHODS: Data were obtained from the Behavioral Risk Factor
      Surveillance System, an ongoing telephone survey of adults conducted by the 50
      states and the District of Columbia. RESULTS: Many near-elderly adults least
      likely to have health care coverage were Black or Hispanic, had less than a high
      school education and incomes less than $15,000 per year, and were unemployed or
      self-employed. Health insurance coverage was associated with increased use of
      clinical preventive services even when sex, race/ethnicity, marital status, and
      educational level were controlled. CONCLUSIONS: Many near-elderly individuals
      without insurance will probably not be able to participate in a Medicare buy-in
      unless it is subsidized in some way.

PMID- 10358680
TI  - The effect of congenital anomalies on mortality risk in white and black infants.
AB  - OBJECTIVES: This population-based study examined the effect of all major
      congenital anomalies on the mortality of White and Black infants by infant sex,
      birthweight, gestational age, and lethality of the anomaly. The study also
      determined the total contribution of anomalies to infant mortality. METHODS:
      California Birth Defects Monitoring Program data were merged with linked birth
      death files for 278,646 singleton non-Hispanic White and Black infants born in
      1983 through 1986. Malformed infants were compared with nonmalformed infants to
      determine the effect of anomalies on mortality. RESULTS: The presence of any
      congenital anomaly increased mortality 9.0-fold (95% CI = 7.3, 11.1) for Black
      infants and 17.8-fold (95% CI = 16.2, 19.6) for White infants. Even "non-lethal"
      anomalies increased mortality up to 8.9-fold. Overall, anomalies contributed to
      33% of White infant deaths, to 19% of Black infant deaths, and to over 60% of
      deaths among Black and White neonates weighing over 1499 g. CONCLUSIONS: The
      contribution of congenital anomalies to mortality of both low- (< 2500 g) and
      normal-birth-weight infants is substantially higher than previously estimated,
      representing a large public health problem for both Black and White infants.

PMID- 10358681
TI  - Premature mortality in the United States: the roles of geographic area,
      socioeconomic status, household type, and availability of medical care.
AB  - OBJECTIVES: This study examined premature mortality by county in the United
      States and assessed its association with metro/urban/rural geographic location,
      socioeconomic status, household type, and availability of medical care. METHODS:
      Age-adjusted years of potential life lost before 75 years of age were calculated
      and mapped by county. Predictors of premature mortality were determined by
      multiple regression analysis. RESULTS: Premature mortality was greatest in rural
      counties in the Southeast and Southwest. In a model predicting 55% of variation
      across counties, community structure factors explained more than availability of
      medical care. The proportions of female-headed households and Black populations
      were the strongest predictors, followed by variables measuring low education,
      American Indian population, and chronic unemployment. Greater availability of
      generalist physicians predicted fewer years of life lost in metropolitan counties
      but more in rural counties. CONCLUSIONS: Community structure factors
      statistically explain much of the variation in premature mortality. The degree to
      which premature mortality is predicted by percentage of female-headed households
      is important for policy-making and delivery of medical care. The relationships
      described argue strongly for broadening the biomedical model.

PMID- 10358682
TI  - Sexual health risk assessment and counseling in primary care: how involved are
      general practitioners and obstetrician-gynecologists?
AB  - OBJECTIVES: This study examined physicians' evaluation of sexual health risks
      during a general medical examination and sexually transmitted disease (STD)
      counseling during consultations for adolescent contraception and treatment of an
      STD. METHODS: An anonymous mail survey was conducted in 1995 with a stratified
      random sample of 1086 general practitioners and all 241 obstetrician
      gynecologists practicing in Quebec, Canada. RESULTS: Fewer than half of the
      respondents reported routinely inquiring about condom use and number of sexual
      partners during a general medical examination. Female general practitioners
      engaged in more sexual health risk assessment and counseling than male general
      practitioners. CONCLUSIONS: This study suggests a low level of involvement in STD
      prevention by generalists and obstetrician-gynecologists.

PMID- 10358683
TI  - Involving men in reproductive health: the Young Men's Clinic.
AB  - OBJECTIVES: This report describes the population of young men who use the Young
      Men's Clinic in New York City, presents a profile of their reproductive
      behaviors, and describes the clinic's model of service delivery. METHODS: Data
      were gathered through a routine clinic visit form administered by clinic staff.
      RESULTS: The clinic sees approximately 1200 predominately Dominican young men
      each year for a wide range of clinical and mental health services. Two thirds of
      clients had ever been sexually active, three quarters had ever used birth
      control, and 69% had used birth control at their last sexual encounter.
      CONCLUSIONS: The Young Men's Clinic may serve as a model for health care delivery
      to adolescent and young adult males.

PMID- 10358684
TI  - Characteristics of nurse-midwife patients and visits, 1991.
AB  - OBJECTIVES: This study describes the patient populations served by and visits
      made to certified nurse-midwives (CNMs) in the United States. METHODS:
      Prospective data on 16,729 visits were collected from 369 CNMs randomly selected
      from a 1991 population survey. Population estimates were derived from a
      multistage survey design with probability sampling. RESULTS: We estimated that
      approximately 5.4 million visits were made to nearly 3000 CNMs nationwide in
      1991. Most visits involved maternity care, although fully 20% were for care
      outside the maternity cycle. Patients considered vulnerable to poor access or
      outcomes made 7 of every 10 visits. CONCLUSIONS: Nurse-midwives substantially
      contribute to the health care of women nationwide, especially for vulnerable
      populations.

PMID- 10358685
TI  - Access to care for the uninsured: is access to a physician enough?
AB  - OBJECTIVES: This study examined a private-sector, statewide program (Kentucky
      Physicians Care) of care for uninsured indigent persons regarding provision of
      preventive services. METHODS: A survey was conducted of a stratified random
      sample of 2509 Kentucky adults (811 with private insurance, 849 Medicaid
      recipients, 849 Kentucky Physicians Care recipients). RESULTS: The Kentucky
      Physicians Care group had significantly lower rates of receipt of preventive
      services. Of the individuals in this group, 52% cited cost as the primary reason
      for not receiving mammography, and 38% had not filled prescribed medicines in the
      previous year. CONCLUSIONS: Providing free access to physicians fills important
      needs but is not sufficient for many uninsured patients to receive necessary
      preventive services.

PMID- 10358686
TI  - The impact of Medicaid managed care on community clinics in Sacramento County,
      California.
AB  - OBJECTIVES: The purpose of this study was to determine the impact of countywide
      Medicaid managed care on service use at community clinics. METHODS: Clinic use
      before and after introduction of Medicaid plans in one county was compared with
      that in a group of comparable counties without such plans. RESULTS: There were
      significant declines of 40% to 45% in the volumes of Medicaid clients,
      encounters, and revenues at clinics with the introduction of Medicaid plans.
      Declines of 23% in uninsured clients and encounters did not differ significantly.
      CONCLUSIONS: The introduction of Medicaid managed care with multiple commercial
      plans can have significant negative effects on nonprofit community clinics.

PMID- 10358687
TI  - Identifying target groups for a potential vaccination program during a hepatitis
      A communitywide outbreak.
AB  - OBJECTIVES: This study sought to identify groups for targeted vaccination during
      a communitywide hepatitis A outbreak in 1996. METHODS: Residents of the Sioux
      City, Iowa, metropolitan area reported with hepatitis A between September 1995
      and August 1996 were sampled and compared with population-based controls.
      RESULTS: In comparison with 51 controls, the 40 case patients were more likely to
      inject methamphetamine, to attend emergency rooms more often than other health
      care facilities, and to have a family member who used the Special Supplemental
      Nutrition Program for Women, Infants, and Children. CONCLUSIONS: Groups at
      increased risk of hepatitis A can be identified that might be [corrected]
      accessed for vaccination during communitywide outbreaks.

PMID- 10358688
TI  - Maternal minimum-stay legislation: cost and policy implications.
AB  - OBJECTIVES: Recently, most state legislatures and Congress have passed laws
      mandating insurance coverage for a minimum period of inpatient care following
      delivery. This study analyzed the likely cost implications of one state's law.
      METHODS: Hospital discharge records for Illinois women who gave birth (n =
      167,769) and infants born (n = 164,905) during a 12-month period predating the
      law were analyzed. RESULTS: As a percentage of total spending on birth-related
      admissions and readmissions, the net effect of the law ranges from a savings of
      0.1% to a cost of 20.2%. CONCLUSIONS: There may be large cost implications to
      this legislation, even with savings from avoided re-admissions.

PMID- 10358689
TI  - A randomized trial of breast cancer risk counseling: the impact on self-reported
      mammography use.
AB  - OBJECTIVES: We evaluated the impact of individualized breast cancer risk
      counseling on mammography use among women at risk for breast cancer. METHODS:
      Participants (n = 508) were randomized to the breast cancer risk counseling
      intervention or a general health education control intervention, and 85%
      completed follow-up. RESULTS: In multivariate modeling, a significant group-by
      education interaction demonstrated that among less-educated participants, breast
      cancer risk counseling led to reduced mammography use. There was no intervention
      effect among the more-educated participants. CONCLUSIONS: These results suggest
      that standard breast cancer risk counseling could have an adverse impact on the
      health behaviors of less-educated women.

PMID- 10358690
TI  - Changes in Canadian women's mammography rates since the implementation of mass
      screening programs.
AB  - OBJECTIVES: This study reports on Canadian mammography rates between 1990, when
      mass screening programs were launched, and 1994/95. METHODS: Mammography rates
      from 2 national surveys were compared according to the presence of a provincial
      screening program. RESULTS: Mammography rates among women aged 50 to 69 years
      (the targeted group) increased significantly, by 16%; increases were twice as
      high in provinces with screening programs. Among women in their 40s (nontargeted
      group), the changes were insignificant and independent of screening program
      status. CONCLUSIONS: Screening programs appear to have influenced the mammography
      rates of targeted women aged 50 to 69 years.

PMID- 10358691
TI  - Lower body osteoarticular pain and dose of analgesic medications in older
      disabled women: the Women's Health and Aging Study.
AB  - OBJECTIVES: This study assessed use and dosage of analgesic medications in
      relation to severity of osteoarticular pain. METHODS: The type and dose of
      analgesic medication and the severity of pain in the lower back, hips, knees, or
      feet of 1002 older disabled women were assessed. RESULTS: Severe pain and the use
      of analgesic medications were reported by 48.5% and 78.8% of women, respectively.
      Among those who had severe pain, 41.2% were using less than 20% of the maximum
      analgesic dose. Overall, 6.6% of women were using more than 100% of the maximum
      dose. CONCLUSIONS: Severe pain is common. Additional, more effective, and safe
      analgesic treatments are needed for controlling pain in older persons.

PMID- 10358692
TI  - Costs and outcomes of hip fracture and stroke, 1984 to 1994.
AB  - OBJECTIVES: This study quantified changes in Medicare payments and outcomes for
      hip fracture and stroke from 1984 to 1994. METHODS: We studied National Long Term
      Care Survey respondents who were hospitalized for hip fracture (n = 887) or
      stroke (n = 878) occurring between 1984 and 1994. Changes in Medicare payment and
      survival were primary outcomes. We also assessed changes in functional and
      cognitive status. RESULTS: Medicare payments within 6 months increased following
      hip fracture (103%) or stroke (51%). Survival improved for stroke (P < .001) and
      to a lesser extent for hip fracture (P = .16). Condition-specific improvements
      were found in functional and cognitive status. CONCLUSIONS: During the period
      1984 to 1994, Medicare payments for hip fracture and stroke rose and there were
      some improvements in survival and other outcomes.

PMID- 10358694
TI  - Hospital volume and survival of breast cancer patients in Connecticut.

PMID- 10358693
TI  - Great expectations: historical perspectives on genetic breast cancer testing.
AB  - Women who test positive for a genetic breast cancer marker may have more than a
      50% chance of developing the disease. Although past screening technologies have
      sought to identify actual breast cancers, as opposed to predisposition, the
      history of screening may help predict the societal response to genetic testing.
      For decades, educational messages have encouraged women to find breast cancers as
      early as possible. Such messages have fostered the popular assumption that
      immediately discovered and treated breast cancers are necessarily more curable.
      Research, however, has shown that screening improves the prognosis of some--but
      not all--breast cancers, and also that it may lead to unnecessary interventions.
      The dichotomy between the advertised value of early detection and its actual
      utility has caused particular controversy in the United States, where the
      cultural climate emphasizes the importance of obtaining all possible medical
      information and acting on it. Early detection has probably helped to lower
      overall breast cancer mortality. But it has proven hard to praise aggressive
      screening without exaggerating its merits. Women considering genetic breast
      cancer testing should weight the benefits and limitations of early knowledge.

PMID- 10358695
TI  - Zidovudine and reduction of vertical transmission of HIV in Africa. ANRS 049
      Trial Group.

PMID- 10358696
TI  - A special niche for MPO.

PMID- 10358697
TI  - On cancer control and the adolescent.

PMID- 10358699
TI  - Serum antibody levels and avidities to Escherichia coli O antigens and poliovirus
      type 1 antigen are increased in children treated for malignant disease.
AB  - BACKGROUND: Treatment of malignant disease in children is often associated with
      low serum immunoglobulin and reduced specific antibody levels. The aim of this
      study was to investigate if the functional affinity of specific antibodies in
      serum and saliva is reduced as well and to evaluate if antigenic exposure or
      treatment duration affects this antibody avidity. PROCEDURE: Serum samples were
      obtained from 45 children and salivary specimens from 30 children with malignant
      disease. The children were tested either prior to, during, or after chemotherapy.
      Levels of antibody to E. coli O and to poliovirus type 1 antigens were determined
      using an ELISA and isotype-specific relative antibody avidity was measured using
      thiocyanate to elute antibodies from solid-phase immobilized antigens. RESULTS:
      Children with malignant disease had higher levels and relative avidity indexes of
      serum antibodies to both antigens as compared to controls. The duration of
      treatment and type of malignant disease were unrelated to these parameters. In
      saliva, the level of antibodies to E. coli O antigens, but not to poliovirus type
      1 antigen, increased during treatment. CONCLUSIONS: Both the amount and avidity
      of serum antibodies to these antigens are increased in children with malignant
      disease. This may be due to a dysregulation of the immune system caused by the
      malignancy and seems not to be dependent on exposure. In contrast, the avidity
      and levels of these antibodies in saliva seem to correlate with the presence of
      antigenic exposure.

PMID- 10358698
TI  - FLAG (fludarabine, high-dose cytarabine, and G-CSF) for refractory and high-risk
      relapsed acute leukemia in children.
AB  - BACKGROUND: The treatment of relapsed and refractory leukemia in children remains
      a challenge. The morbidity of further chemotherapy is considerable, as most
      patients have already been exposed to intensive multiagent chemotherapy. The FLAG
      (fludarabine, high-dose cytarabine, and G-CSF) regimen is as intensive but less
      cardiotoxic because of the avoidance of anthracyclines. PROCEDURE: Nineteen
      children were treated in two U.K. centers with the FLAG regimen for relapsed and
      refractory acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
      There were 13 males and 6 females, with an age range of 1.9 to 14.2 years. AML
      was the diagnosis in 12 children, ALL in 4, biphenotypic leukemia in 3. Eight
      patients had refractory disease, 11 were in relapse (5 in first relapse, 4 in
      second, and 2 in third). RESULTS: Complete remission was obtained in 13 patients,
      partial remission was obtained in 4, and 2 patients were considered
      nonresponders. There were seven patients alive at 12 months (mean) posttherapy;
      one of these is awaiting bone marrow transplantation (BMT). All patients
      experienced grade 4 hematological toxicity; no patient died of infection.
      Thirteen patients received BMT as consolidation (seven unrelated donor; six
      sibling allografts). Six of these have died, four due to pneumonitis.
      CONCLUSIONS: FLAG can be regarded as an effective protocol for inducing remission
      in a group of heavily pretreated children. Its toxicity is acceptable due to the
      avoidance of anthracyclines.

PMID- 10358700
TI  - Safety, efficacy, and acceptability of home intravenous therapy administered by
      parents of pediatric oncology patients.
AB  - BACKGROUND: A prospective study of patients receiving intravenous therapy
      administered at home by parents was conducted over 1 year at a United Kingdom
      regional pediatric oncology center. PROCEDURE: The study defined the patient
      groups for whom this approach was used and evaluated the safety and efficacy of
      home treatment. Parents' evaluation of home therapy was sought to determine the
      acceptability of the scheme from their perspective. Eight-nine courses of
      antibiotics, chemotherapy or antiemetics were given, comprising a total of 469
      days of home treatment. RESULTS: Few clinical problems were encountered. Parents
      felt that home treatment helped them to cope (72%); they felt more in control
      (75%) and learned more about their child's illness and treatment (82%).
      CONCLUSIONS: Home treatment was perceived as less stressful than hospital
      treatment (79%), and all reported benefits to family life. There is a need for
      parents to be taught vigilance in observing for and reporting signs of
      deterioration.

PMID- 10358701
TI  - 131I MIBG therapy in neuroblastoma: mechanisms, rationale, and current status.
AB  - 131I MIBG has been used as palliative treatment of neuroblastoma patients with
      recurrent or persistent disease who failed other modalities of treatment. Since
      the results were promising, the concept arose of using it in conjunction with
      other modalities, either as an up-front treatment or as combination therapy. This
      article reviews the principle of 131I MIBG treatment, in conjunction with other
      modalities currently used for the treatment of neuroblastoma, in an attempt to
      improve the final outcome.

PMID- 10358702
TI  - Nephroblastoma with fibroadenomatous structures revisited.

PMID- 10358703
TI  - Hereditary persistence of alpha-fetoprotein in a child with testicular germ cell
      tumor.

PMID- 10358704
TI  - The eponym "Wilms": a reminder of a surgeon's lifelong contributions to medicine.

PMID- 10358705
TI  - Interparenchymal hemorrhagic neurocytoma: an atypical presentation of a rare CNS
      tumor.

PMID- 10358706
TI  - Successful treatment of monoclonal, aggressive Epstein-Barr virus-associated B
      cell lymphoproliferative disorder in a child with acute lymphoblastic leukemia.

PMID- 10358707
TI  - Biphenotypic lymphoblastic non-Hodgkin lymphoma with a balanced translocation
      t(1;9)(p10;q10): unusual presentation with poor outcome.

PMID- 10358708
TI  - Transient myeloproliferative disorder associated with trisomy 21: is a short
      course of chemotherapy indicated in patients with liver impairment and severe
      clinical problems?

PMID- 10358709
TI  - M-BCR rearrangement in a case of T-cell childhood acute lymphoblastic leukemia.

PMID- 10358710
TI  - Anticoagulation with recombinant hirudin following bone marrow transplantation in
      a patient with activated protein C resistance and heparin-induced antibodies
      showing cross-reactivity to the heparinoid danaparoid.

PMID- 10358711
TI  - Treatment of colorectal carcinoma in adolescents and young adults with surgery, 5
      fluorouracil/leucovorin/interferon-alpha 2a and radiation therapy.

PMID- 10358712
TI  - Near-tetraploid acute lymphoblastic leukaemia with skeletal lesions: a unique
      entity?

PMID- 10358713
TI  - Fatal tumor lysis syndrome and gastric hemorrhage associated with metastatic
      small-cell lung carcinoma.

PMID- 10358714
TI  - Congenital hepatoblastoma: a distinct entity?

PMID- 10358715
TI  - Isolated CNS involvement in Ewing sarcoma.

PMID- 10358717
TI  - Osteonecrosis in children treated for acute leukemia. .

PMID- 10358716
TI  - Atypical extraosseous Ewing sarcoma of the spinal canal with bone marrow
      involvement in a two-month-old boy.

PMID- 10358718
TI  - Meningeal signs as the presenting feature of medulloblastoma.

PMID- 10358719
TI  - Treatment of lymphoid malignancies in patients with ataxia-telangiectasia.

PMID- 10358720
TI  - Unilateral variation of the arterial pattern of the human upper extremity with a
      muscle variation of the hand.
AB  - A unilateral variation in the origin and distribution of the arterial pattern of
      the human upper extremity on the right side is reported on. Apart from its usual
      branches, the third part of the right axillary artery gave origin to a common
      branch, the profunda brachii artery and the superior ulnar collateral artery. The
      right brachial artery, at a point 5.0 cm distal to its origin, bifurcated into
      the radial and ulnar arteries; their origin was in a position opposite the usual
      location. The radial artery continued on the medial side of the arm for 2.5 cm
      and crossed the ulnar artery anteriorly to gain a lateral position in the arm.
      The inferior ulnar collateral artery arose not from the brachial artery, but from
      the ulnar artery. A muscle variation was also observed in the right hand, which
      is compatible with the notion variations within one system of a limb will
      frequently be accompanied by variations in other systems of the same limb.

PMID- 10358721
TI  - Establishment of a drug sensitivity panel using human lung cancer cell lines.
AB  - We established a drug sensitivity panel consisting of 24 human lung cancer cell
      lines. Using this panel, we evaluated 26 anti-cancer agents: three alkylators,
      three platinum compounds, four antimetabolites, one topoisomerase I inhibitor,
      five topoisomerase II inhibitors, seven antimitotic agents and three tyrosine
      kinase inhibitors. This panel showed the following: a) Drug sensitivity patterns
      reflected their clinically-established patterns of action. For example,
      doxorubicin and etoposide were shown to be active against small cell lung cancer
      cell lines and mitomycin-C and 5-fluorouracil were active against non-small cell
      lung cancer cell lines, in agreement with clinical data. b) Correlation analysis
      of the mean graphs derived from the logarithm of IC50 values of the drugs gave
      insight into the mechanism of each drug's action. Thus, two drug combinations
      with reverse or no correlation, such as the combination of cisplatin and
      vinorelbine, might be good candidates for the ideal two drug combination in the
      treatment of lung cancer, as is being confirmed in clinical trials. c) Using
      cluster analysis of the cell lines in the panel with their drug sensitivity
      patterns, we could classify the cell lines into four groups depending on the drug
      sensitivity similarity. This classification will be useful to elucidate the
      cellular mechanism of action and drug resistance. Thus, our drug sensitivity
      panel will be helpful to explore new drugs or to develop a new combination of
      anti-cancer agents for the treatment of lung cancer.

PMID- 10358722
TI  - Delirium in elderly patients admitted to a psychiatric hospital: causative
      factors and treatment.
AB  - We studied the causes and treatments of delirium in 43 patients admitted to the
      geriatric-psychiatric ward of a hospital in Japan. Patients studied were divided
      into three groups according to the type of factor responsible for their delirium.
      We termed these causal factors precipitating, facilitating and predisposing
      factors. Twenty-one patients exhibited precipitating factors, the most common of
      which were overmedication and poisoning. Almost all these cases were treated with
      psychotropic drugs. Facilitating factors were judged responsible in nine cases.
      In six of these, admission to a hospital was thought to be the facilitating
      factor. Thirteen patients who had only predisposing factors were treated with
      psychotropic drugs while 27% of patients without precipitating factors were
      successfully treated for delirium without the use of such drugs.

PMID- 10358723
TI  - Ultrasonographic analysis of shoulder rotator cuff tears.
AB  - Seventy-nine shoulders suspected of rotator cuff tears were examined by
      ultrasonography (US) and forty-three received surgery. Long and short axis scans
      were performed and findings of each were separately classified according to a
      five-grade system, and the results were correlated with the actual extent of tear
      observed during surgery. Internal echogenicity and subacromial impingement were
      analyzed before and after surgery. A accuracy of US in detecting rotator cuff
      tears was analyzed. In addition, the correlation between cuff shape observed by
      US before surgery and actual shape observed during surgery was assessed. It was
      noted that cuff thinning and abnormalities in shape did not recover to normal
      after surgery. However, in the cases of discontinuities observed by US before
      surgery, US findings indicated that the torn cuff was anchored to the greater
      tuberosity and functional during active motion. Although post-operative US
      findings were not normal, clinical results were good in most cases. Sensitivity
      of US for detecting rotator cuff tear was 100% and specificity 94%. US is non
      invasive, cost effective and allows the physician to examine the joint while it
      is in motion. Therefore, at this time, we use US as a screening method for
      detecting rotator cuff tears. Furthermore, US allows us to check for re-tears
      while the joint is in motion, which is essential for accurate diagnosis.

PMID- 10358724
TI  - The results of radiotherapy for T1 glottic cancers; influence of radiation beam
      energy.
AB  - We analyzed the influence of various parameters on the results of radiotherapy
      for T1 glottic cancer by assessing the outcomes of 60 patients with this cancer
      who received definitive radiotherapy between 1985 and 1994. Seven patients were
      treated with a cobalt-60 unit, and the other 53 with a linear accelerator (26
      patients at 3-MV, 10 at 6-MV, and 17 at 10-MV). Of the 17 patients treated at 10
      MV, 4 also received part of their treatment with a cobalt-60 unit. The total
      radiation dose ranged from 56 Gy to 70 Gy (mean, 61 Gy). The total radiation dose
      of 51 patients (85%) was 60 Gy. The factors found to influence local control were
      the strength of the radiation beam energy and whether or not there was gross
      tumor invasion of the anterior commissure. The local control rate was 71% in the
      patients treated with a 10-MV linear accelerator, 56% in those treated with a 6
      MV linear accelerator and, 97% in those treated with a cobalt-60 unit or a 3-MV
      linear accelerator (P = 0.0173). The local control rate was 43% in the patients
      with gross anterior commissure invasion and 88% in those without (P = 0.0075). We
      conclude that low energy photon beams are more suitable for the treatment of
      early glottic cancers, especially if the lesion grossly invades the anterior
      commissure.

PMID- 10358725
TI  - Establishment of a new cell line (MTT-95) showing basophilic differentiation from
      the bone marrow of a patient with acute myelogenous leukemia (M7).
AB  - A new myeloid cell line, MTT-95, was established from the bone marrow of a
      patient with acute myelogenous leukemia (AML, M7). MTT-95 cells differentiate
      into mature basophilic cells in culture medium with no chemical component or
      cytokine. Surface phenotypes were as follows: CD11b 79.3%, CD13 92.4%, CD33
      99.8%, CD34 87.9%, CD41a 77.6% and HLA-DR 0.3%. MTT-95 cells were strongly
      positive for glycoprotein IIb/IIIa by immunohistochemical staining and revealed
      metachromatic granules. MTT-95 cells seem to possess characteristics of both
      megakaryocytes and basophils. These findings suggest that MTT-95 cells are
      basophil progenitors. MTT-95 cells might be useful in the study not only of the
      biological aspects of basophils, but also of the diversities of AML (M7).

PMID- 10358726
TI  - Further comments on Prognostic factors of small-cell lung cancer in Okayama Lung
      Cancer Study Group Trials. How about a more precise laboratory technique?

PMID- 10358727
TI  - Therapy-induced antibodies to interferon-alpha 2a recognise its receptor-binding
      site.
AB  - Fifty-eight patients with chronic hepatitis B (HB) or C (HC) were treated with
      recombinant human interferon (rIFN)-alpha 2 and their sera were assayed for
      antibodies to rIFN-alpha 2c. Twelve of these patients produced low titres and two
      high titres of the antibodies. We localized the region which was recognised by
      the high-titre therapy-induced antibodies on the IFN molecule by testing the
      antibodies with a set of murine monoclonal antibodies (MoAbs) to IFN-alpha 2 in a
      competitive radioimmune assay (RIA). Only MoAbs with epitopes located in the
      amino-terminal portion of IFN-alpha 2 could inhibit the binding of radiolabelled
      IFN-alpha 2 by patients' sera. Our data indicate that the therapy-induced
      antibodies were directed to the receptor-binding domain of IFN-alpha 2 formed by
      amino acids (aa) 30-53. In accordance with this observation, human anti-IFN sera
      inhibited the binding of rIFN-alpha 2 to human cells.

PMID- 10358728
TI  - Effect of rearing at non-permissive temperature on silkworm larvae infected with
      temperature-sensitive lef-8 mutant of bombyx mori nucleopolyhedrovirus.
AB  - A temperature-sensitive (ts) mutant of bombyx mori nucleopolyhedrovirus (BmNPV),
      ts-S1, contains a mutation in a putative RNA polymerase gene, which is involved
      in late viral gene expression. When 4th-instar silkworm larvae were infected with
      1.0 x 10(5) TCID50 of ts-S1 per larva and reared at 33 degrees C, the titre of
      budded virus (BV) and number of occlusion bodies (OBs) in the haemolymph of the
      infected larvae were very low in the early stage but markedly increased in the
      late stage of infection. In contrast, a rapid increase in both BV titre and OB
      number was detected in the haemolymph of infected larvae reared at 25 degrees C.
      LD50 values of ts-S1 and wild type BmNPV (wtBmNPV) for 4th-instar larvae were
      2.41 and 0.96 TCID50 per larva at 25 degrees C, and > 1.0 x 10(6) and 1.70 TCID50
      per larva at 33 degrees C, respectively. These results indicate that the
      virulence of ts-S1 for the larvae reared at 33 degrees C was markedly reduced. To
      examine further the reduction of ts-S1 virulence at the non-permissive
      temperature of 33 degrees C, silkworm larvae were infected with ts-S1 at the
      multiplicity of 1.0 x 10(2) - 1.0 x 10(6) TCID50 per larva, reared for various
      time at 33 degrees C and then shifted to 25 degrees C. Longer rearing periods at
      33 degrees C resulted in better survival rates indicating that the reduction of
      virulence of ts-S1 was proportional to cumulative rearing time at 33 degrees C.
      When large virus inocula were used, a growth alteration of larvae was
      preferentially induced. However, when small virus inocula were used, the
      appearance of abortive infection due to the non-permissive temperature became
      more evident.

PMID- 10358729
TI  - Replication of Spodoptera exigua nucleopolyhedrovirus in permissive and non
      permissive lepidopteran cell lines.
AB  - The Spodoptera exigua multinucleocapsid nucleopolyhedrovirus (SeMNPV) was
      inoculated to eight lepidopteran cell lines derived from Spodoptera exigua
      (Se301), Spodoptera frugiperda (SF21AEII), Spodoptera littoralis (CLS-79),
      Spodoptera litura (SpLi-221), Pseudaletia separata (LeSe-11), Trichoplusia ni (hi
      5), Plutella xylostella (PXL/C) and Bombyx mori (BmN4). The productive infection
      of SeMNPV was observed only in Se301 cells. However, a dot-blot hybridization
      analysis revealed that SeMNPV DNA replicated in five non-permissive cell lines:
      SF21AEII, CLS-79, SpLi-221, hi-5 and BmN4. In addition, the virus-infected hi-5
      and BmN4 cells displayed morphological changes. In contrast, CLS-79 cells
      inoculated with SeMNPV showed membrane blebbing at 20 hrs post inoculation (p.i.)
      and fragmentation of genomic DNA. All that indicated that the infected CLS-79
      cells underwent apoptosis. These findings indicate that the SeMNPV replication
      was restricted at various points in dependence upon each cell line.

PMID- 10358730
TI  - Protection of rabbits against lapinized rinderpest virus with purified envelope
      glycoproteins of peste-des-petits-ruminants and rinderpest viruses.
AB  - Haemagglutinin (HA) and fusion (F) proteins of peste-des-petits-ruminants virus
      (PPRV) and rinderpest virus (RPV) were purified by immunoaffinity chromatography.
      The purified proteins were characterized by polyacrylamide gel electrophoresis in
      the presence of sodium dodecyl sulfate (SDS-PAGE). Rabbit hyperimmune sera were
      raised against the purified HA and F proteins and assayed by enzyme-linked
      immunosorbent assay (ELISA), haemagglutination-inhibition (HAI) and virus
      neutralization (VN) tests. The immunized animals were challenged with a virulent
      lapinized (rabbit-adapted) strain of RPV. Both HA and F proteins of PPRV
      protected rabbits against a lethal challenge with lapinized RPV. As expected, RPV
      HA and F proteins also conferred a similar protection against the homologous
      challenge. The postchallenge antibody responses were of a true anamnestic type.

PMID- 10358731
TI  - Establishment and characterization of Epstein-Barr virus-specific human CD4+ T
      lymphocyte clones.
AB  - We developed a simple method for establishing Epstein-Barr virus (EBV)-specific,
      human CD4+ T cell clones. The method originates from our experience that the
      regression of cell growth in in vitro EBV transformation of B cells occurs when
      round lymphoid cells appear in the culture. Peripheral blood mononuclear cells
      (PBMCs) were cultured with EBV, and IL-2 (20 U/ml) was added to the culture on
      day 17 after the virus addition. The phenotype of the growing cells was CD3+,
      CD4+, and CD8-. The cells were cytotoxic for autologous lymphoblastoid B cell
      line (LCL) and EBV-superinfected autologous LCL. The cytotoxic T lymphocytes
      (CTLs) were confirmed to be CD4+ T cells but not CD8+ T cells in the culture. CTL
      clones were established by a limiting dilution method. All the CTL clones had the
      phenotype of CD3+, CD4+ and CD8-, and proliferated in response to autologous LCL.
      They produced interferon (IFN)-gamma, interleukin 2 (IL-2) and tumour necrosis
      factor (TNF)-beta but not IL-4. All but one clone responded to both autologous,
      EBV-superinfected and non-superinfected LCLs. Proliferative and cytotoxic
      responses to allogenic LCLs were heterogeneous. These results suggest that this
      method induces heterogeneous, EBV-specific CD4+ CTL clones and is useful for
      analysis of CD4+ T cells in EBV infections.

PMID- 10358732
TI  - Association of plasmid integrative J7W-1 prophage with Bacillus thuringiensis
      strains.
AB  - A region homologous to the genome of plasmid integrative phage J7W-1 was detected
      in the largest plasmid in 3 out of 22 type strains of Bacillus thuringiensis,
      dendrolimus (DEN), aizawai (AIZ) and indiana (IND). Phage induction by ethidium
      bromide observed particularly in the J7W-1 lysogen was identified in DEN and IND
      but not AIZ strains. The morphology of the phage induced in DEN and IND strains
      was identical to J7W-1, but the phage production in IND strain was lower as
      compared to the J7W-1 lysogen. Although the restriction analysis indicated that
      the prophage in DEN strain possessed a complete J7W-1 genome, modification and/or
      deletion had presumably occurred in AIZ and IND strains.

PMID- 10358733
TI  - Antibody responses to the herpes simplex virus type 2 glycoprotein G in sera of
      human immunodeficiency virus-infected patients in Slovakia.
AB  - Thirty sera of human immunodeficiency virus-positive (HIV+) and 37 sera of HIV
      negative (HIV-) individuals in Slovakia were tested for the presence of
      antibodies to herpes simplex virus type 2 (HSV-2) glycoprotein G (gG). A notable
      difference between the prevalence of HSV-2-specific antibodies in HIV+ and that
      in HIV- individuals was found (37% vs. 11%) confirming and extending previous
      reports that HSV-2 infection is an important risk factor for HIV transmission.
      Efforts toward the detection of HSV-2 infection and its therapy by anti-HSV drugs
      should be considered an important factor in decreasing the risk of contracting
      and spreading of HIV in Slovakia.

PMID- 10358734
TI  - Isolation of tobacco necrosis virus from strawberry leaves in the Czech Republic.
AB  - Leaves of symptomless Fragaria ananassa Duch cv. Cacanska rana were grafted onto
      Fragaria vesca indicator clones. Thirty-five of 72 grafted indicator plants
      developed leaf mottle symptoms. Isometric virus-like particles were observed in
      purified preparations from symptomatic leaves of F. vesca. The latter were
      mechanically inoculated to herbaceous host plants. A virus was successfully
      purified from Nicotiana occidentalis 37 B symptomatic plants by differential and
      sucrose density gradient centrifugations and a polyclonal antiserum to the virus
      was prepared. On the basis of serological reactions, symptomatology on herbaceous
      hosts and electron microscopy studies the virus was identified as tobacco
      necrosis virus (TNV) D-strain. This is the first isolation of TNV from strawberry
      leaves and its first finding on strawberry in the Czech Republic. The new
      experimental hosts N. aucalis, N. bentamiana, N. occidentalis 37 B (systemic
      hosts), and Ammobium alatum, N. bigelovi, Petunia hybrida (local hosts) for TNV
      are reported. These results may not exclude the presence of strawberry mottle
      virus as a causal agent of mottle symptoms in the tested plant samples. Further
      research is necessary to clarify the aetiology of the strawberry mottle.

PMID- 10358735
TI  - Rapid and sensitive detection of equine arteritis virus in semen and tissue
      samples by reverse transcription-polymerase chain reaction, dot blot
      hybridisation and nested polymerase chain reaction.
AB  - A reverse transcription-polymerase chain reaction (RT-PCR) assay using four
      different primer pairs for the detection of equine arteritis virus (EAV) RNA in
      semen and tissue samples was evaluated. A fragment encoding the leader sequence
      of the EAV genome was most successfully amplified. The specificity and
      sensitivity of RT-PCR was assessed by virus isolation in cell culture,
      restriction analysis, dot blot hybridisation and nested PCR. To this end, 23
      semen samples from seropositive stallions and 11 tissue samples from 4 aborted
      foals were tested. Compared to the virus isolation test in cell culture, the
      sensitivity of the molecular methods proved to be higher. In the RT-PCR, dot blot
      hybridisation and nested PCR tests, semen samples from 11 stallions and tissue
      samples from all 4 foals were found positive, while the virus could be isolated
      in cell culture from only 4 semen samples and tissue samples from 1 aborted foal.
      The sensitivity of the dot blot hybridisation test was superior to that of the RT
      PCR test. The nested PCR test proved to be the most sensitive one, because 3
      semen samples were recognised as positive by this method only. Considering the
      sensitivity, and rapidity and reliability, RT-PCR followed by dot blot
      hybridisation or nested PCR represents the best method for diagnosis of EAV and
      should be included in the official diagnostic regimes.

PMID- 10358736
TI  - Electron microscopic observation of potato virus A using murine monoclonal
      antibodies.
AB  - Six monoclonal antibodies (MoAbs) against potato virus A (PVA) were prepared and
      used in enzyme-linked immunosorbent assay (ELISA), immunoblot analysis and
      electron microscopic study of the virus. Four MoAbs, 151, 290, 328 and 634,
      reacted with purified virus preparation in dot blot test and showed strong
      reaction also with virus coat protein (CP) denatured by sodium dodecyl sulphate
      (SDS), while two MoAbs, 534 and 187, gave significantly weaker reaction with
      denatured CP than with purified virus. On electron micrographs, MoAb 534 effected
      binding only on few separate locations of the virus surface after prolonged
      storage. We presume that this MoAb recognized a conformation-dependent epitope.

PMID- 10358737
TI  - Tomato spotted wilt virus in ornamental plants, vegetables and weeds in the Czech
      Republic.
AB  - The occurrence of tomato spotted wilt virus (TSWV) in horticulture crops and
      weeds in the Czech Republic has been studied in 1992-1997. During this period
      TSWV was established in 91 plant species. Virus identity was based on the host
      range, serology and electron microscopy. Natural TSWV infection was detected in
      glasshouses where the main vector Frankliniella occidentalis was present too. The
      most frequently TSWV-infected plant species were Chrysanthemum morifolium and
      Zantedeschia sp. Among vegetable crops, the TSWV infection was very frequently
      detected in tomatoes and peppers. In all cases these plants were nursed or grown
      in glasshouses together with different species of ornamental plants, many of
      which were TSWV-infected. Among weeds, the TSWV infection occurred very often in
      Stellaria media and Galinsoga parviflora. These two plant species were prevalent
      in glasshouses and were also good hosts of F. occidentalis.

PMID- 10358738
TI  - Were hantaviruses eventually responsible for the lost Anasazi culture?

PMID- 10358739
TI  - Preparation of monoclonal antibodies to N protein of rinderpest virus and their
      use in viral antigen detection.

PMID- 10358740
TI  - Investigation of the relationship between Epstein-Barr virus and ordinary gastric
      carcinoma using the nested polymerase chain reaction.
AB  - To investigate whether Epstein-Barr virus (EBV) is associated with ordinary
      gastric carcinoma and to determine its genotype, samples from ordinary gastric
      carcinoma from 65 patients (40 males, 20 females) and 21 endoscopic biopsies from
      7 individuals with non-neoplastic mucosa were analysed using one-stage and nested
      (two-stage) polymerase chain reaction (PCR) assays. The nested PCR assay yielded
      56.9% (37/65) and 52.3% (11/21) positivity for the ordinary gastric carcinoma and
      control cases, respectively; these results were significantly than those of the
      one-stage PCR assay (13.5% and 0%, respectively). The EBV positivity showed
      similar rate in male and female patients (60% versus 52%, P > 0.05). The dominant
      genotype of EBV was 1 (92%) followed by mixture of 1 + 2 (5.4%) and 2 (2.6%). In
      conclusion, similar positivity rates of EBV in neoplastic and non-neoplastic
      tissues suggest that the relationship of this virus to the ordinary gastric
      carcinoma is not clear.

PMID- 10358741
TI  - Suitability of various Coxiella burnetii antigen preparations for detection of
      serum antibodies by various tests.
AB  - Comparison of four serological tests (complement fixation (CF) test,
      microagglutination (MA) test, microimmunofluorescence (MIF) test, and enzyme
      linked immunosorbent assay (ELISA)) for detection of post-infection antibody
      response in human and animal sera revealed a low sensitivity of the CF test with
      acute Q fever human, goat and sheep sera but not with chronic Q fever human sera
      and sera of aborting cows. The remaining three tests gave similar results with
      human (both acute and chronic) and cow sera, but the ELISA was more sensitive
      than the MA and MIF tests with goat and sheep sera. A treatment of phase I
      Coxiella burnetii (C.b.) cells with chloroform-methanol, potassium periodate and
      trichloroacetic acid (TCA), and mild acidic hydrolysis did not result in increase
      of the sensitivity of the tests when compared with the natural phase I and phase
      II C.b. cells, respectively. The suitability of various C.b. antigen preparations
      for the abovementioned serological tests with various sera is discussed.

PMID- 10358742
TI  - Sequence and characterisation of the Z gene encoding ring finger protein of the
      lymphocytic choriomeningitis virus MX strain.
AB  - We have cloned and characterised a cDNA encoding Z protein of recently identified
      MX strain of lymphocytic choriomeningitis virus (LCMV) persistently infecting
      human MaTu cells. Deduced amino acid sequence of LCMV MX Z protein showed 88.9%
      identity with that of the LCMV Armstrong (ARM) strain and 80.9% identity with
      that of the LCMV Traub (TRA) strain. It contained conserved zinc-binding RING
      finger domain and C-terminal proline-rich region. Northern blot analysis of total
      RNA from MaTu cells revealed presence of abundant truncated forms of L RNA. Z
      protein-specific rabbit antibodies were produced to glutathione S-transferase
      (GST)-Z fusion protein expressed in E. coli and used for the detection of Z
      protein in MaTu cells. Western blot and immunofluorescence analyses detected
      relatively high levels of Z protein indicating its role in maintenance of
      persistent LCMV.

PMID- 10358743
TI  - Detection and genotyping of Epstein-Barr virus by polymerase chain reaction in
      tissues obtained from cases with Hodgkin's disease in Turkey.
AB  - In order to determine the positivity rate and genotype of Epstein-Barr virus
      (EBV) in cases with Hodgkin's disease (HD) in Turkey, 40 tissue specimens from HD
      patients were analysed. Ten non-lymphoid tissue samples from individuals without
      any evidence for lymphoma were used as controls. The cases with HD included 33
      males and 7 females with a mean age of 28 years. Nodular sclerosis was the most
      prevalent histological subtype (16/40) followed by mixed cellularity (10/40),
      lymphocyte predominance (9/40), and lymphocyte depletion (5/40). After
      histopathological evaluation, deparafinisation and lysis of the specimens, one
      stage polymerase chain reaction (PCR) and two-stage (nested) PCR assays were
      performed with the primers common for both EBV genotypes and the primers specific
      for EBV types 1 and 2, respectively. EBV DNA was detected in 22 of 40 (55%) cases
      with HD and in 1 of 10 (10%) control specimens. The distribution of EBV DNA
      positivity according to the histological subtypes was as follows: 10 of 16
      (62.5%) for nodular sclerosis, 3 of 5 (60%) for lymphocyte depletion, 5 of 9
      (55.6%) for lymphocyte predominance, and 4 of 10 (40%) for mixed cellularity.
      Although most of the HD patients were males of 15-34 years of age, there were no
      significant differences between EBV positivities obtained from different sex and
      age groups. The rates of EBV genotypes were 82% for type 1, 9% for type 2, and 9%
      for both types, respectively.

PMID- 10358744
TI  - Inhibition of Mayaro virus replication by cerulenin in Aedes albopictus cells.
AB  - The antibiotic cerulenin, an inhibitor of lipid synthesis, was shown to suppress
      Mayaro virus replication in Aedes albopictus cells at non-cytotoxic doses.
      Cerulenin blocked the incorporation of [3H]glycerol into lipids when present at
      any time post infection (p.i.). Cerulenin added at the beginning of infection
      inhibited the synthesis of virus proteins. However, when this antibiotic was
      added at later stages of infection, it had only a mild effect on the virus
      protein synthesis. The possibility that cerulenin acts by blocking an initial
      step in the Mayaro virus replication after virus entry and before late viral
      translation is discussed.

PMID- 10358745
TI  - Strain analysis and epitope mapping of West Nile virus using monoclonal
      antibodies.
AB  - Monoclonal antibodies (MAbs) against an Indian strain (804994) and an Egyptian
      strain (E 101) of West Nile virus (WNV) were prepared in mice. Nine MAbs against
      the 804994 strain and 5 MAbs against E 101 strain were obtained. All 14 MAbs
      reacted with the envelope (E) protein of WNV in an immunoblot assay. They were
      tested by an enzyme-linked immunosorbent assay (ELISA) for their cross-reactivity
      with WNV, Japanese encephalitis virus (JEV) and Dengue-2 virus (DEN-2), and for
      their reactivity in haemagglutination-inhibition (HAI) test. Based on these
      results MAbs were broadly grouped into three groups, namely WNV-specific HAI
      positive, WNV-JEV cross-reactive HAI-positive, and WNV-JEV cross-reactive HAI
      negative MAbs. The antigenic cross-reactivity between twelve WNV strains isolated
      from different geographical regions and their respective hosts was assessed using
      these MAbs in HAI and complement fixation (CF) tests. The strain analysis by CF
      distinguished Indian from South African strains. However, a similarity between
      some Indian and South African strains in HAI was observed. E 101 strain appeared
      to have antigenic similarity with Indian as well as South African strains.
      Overall it appears that antigenically similar strains of WNV are prevalent in
      India. A single heterogenous domain was apparent on the epitope map of WNV
      deduced by ELISA additivity test.

PMID- 10358746
TI  - Bovine herpesvirus type 1 glycoprotein C expression in MDBK cells and its
      reactivity in enzyme-linked immunosorbent assay.
AB  - Glycoprotein C (gC) of bovine herpesvirus type 1 (BHV-1) is a major viral
      glycoprotein expressed at high level on the surface of infected cells and on the
      virion envelope. This glycoprotein is also a major target of immune response at
      both humoral and cellular levels. The plasmid pRSV-gC having complete coding gene
      for BHV-1 gC was transfected into MDBK cells and the expression of gC in these
      cells was detected by polyacrylamide gel electrophoresis in the presence of
      sodium dodecyl sulfate (SDS-PAGE) and immunoblot analysis. Transcription of the
      gC gene was confirmed by reverse transcription-polymerase chain reaction (RT-PCR)
      of total RNA isolated from transfected cells. MDBK cells expressing BHV-1 gC were
      used as antigen in enzyme-linked immunosorbent assay (ELISA) of antibodies
      against BHV-1 in field sera. The results were found comparable (92.44%) with
      those obtained with BHV-1 purified antigen.

PMID- 10358747
TI  - Analysis of nucleotide sequence variations in herpes simplex virus types 1 and 2,
      and varicella-zoster virus.
AB  - To analyze the difference in the degree of divergence between genes from
      identical herpesvirus species, we examined the nucleotide sequence of genes from
      the herpes simplex virus type 1 (HSV-1) strains VR-3 and 17 encoding thymidine
      kinase (TK), deoxyribonuclease (DNase), protein kinase (PK; UL13) and virion
      associated host shutoff (vhs) protein (UL41). The frequency of nucleotide
      substitutions per 1 kb in TK gene was 2.5 to 4.3 times higher than those in the
      other three genes. To prove that the polymorphism of HSV-1 TK gene is common
      characteristic of herpesvirus TK genes, we compared the diversity of TK genes
      among eight HSV-1, six herpes simplex virus type 2 (HSV-2) and seven varicella
      zoster virus (VZV) strains. The average frequency of nucleotide substitutions per
      1 kb in the TK gene of HSV-1 strains was 4-fold higher than that in the TK gene
      of HSV-2 strains. The VZV TK gene was highly conserved and only two nucleotide
      changes were evident in VZV strains. However, the rate of nonsynonymous
      substitutions in total nucleotide substitutions was similar among the TK genes of
      the three viruses. This result indicated that the mutational rates differed, but
      there were no significant differences in selective pressure. We conclude that HSV
      1 TK gene is highly diverged and analysis of variations in the gene is a useful
      approach for understanding the molecular evolution of HSV-1 in a short period.

PMID- 10358748
TI  - Tumour necrosis factor alfa and glucose levels in sera of mice infected with
      coxsackie B4 and A7 viruses.
AB  - Cytokines have been suggested to play an important role in the pathogenesis of
      type I diabetes mellitus through their direct and indirect effects on the
      pancreatic islet cells. We studied the time course of tumour necrosis factor
      alpha (TNF-alpha) and glucose levels in the sera of mice infected with coxsackie
      B4 and A7 viruses. Two correlating peaks of TNF-alpha and glucose were found.
      These results suggest the involvement of TNF-alpha in the damage of the insulin
      producing cells and thus an immunity-related inflammatory process.

PMID- 10358749
TI  - Mixed respiratory viral infections in Estonia: a long-term laboratory study.
AB  - During the period of 1981-1997, a total of 13,110 patients with acute respiratory
      viral infections were tested simultaneously for influenza virus A and B,
      parainfluenza, adenovirus and respiratory syncytial virus (RSV) infections. Of
      3,800 laboratory-confirmed cases mixed infections were established in average in
      27%. The incidence varied in dependence on the season between 12% and 36%. All
      infections were involved in mixed infections, yet their participation greatly
      varied in different seasons. During a season when the incidence of two
      respiratory viral infections increased, the case number of their mixed infections
      also increased. We assume that respiratory viruses widely co-circulating among
      human population also simultaneously infected the same persons. Therefore a
      proportion of respiratory viral diseases may represent in fact mixed infections
      which, in turn, may lead to the emergence of mixtures of different viruses and
      their spread in humans.

PMID- 10358750
TI  - Oxygen tension and virus replication.
AB  - An evidence is accumulating that the oxygen tension exerts significant effect on
      the virus replication in vitro. When the in vitro oxygen tension is maintained at
      an in vivo physiological level, as a rule higher yields of human viruses are seen
      that at conventional culturing with access of an unphysiologically high oxygen
      concentration in ambient air. Although not fully understood, possible explanation
      for this phenomenon may be provided by a lowered interferon (IFN) output and
      increased cell replication which is often optimal at physiological oxygen
      tension. Furthermore, an indirect evidence suggests that the expression of some
      virus receptors is affected by oxygen tension. Also, the antiviral cell-mediated
      immunity is likely to be found oxygen tension-dependent as both the NK and
      cytotoxic T cell activities towards uninfected target cells are oxygen tension
      sensitive. At present, the in vitro work with viruses at physiological oxygen
      tensions is hampered by the fact that cells adapt in the course of several weeks
      to the new oxygen tension. Whether viruses may adapt to different oxygen tensions
      is not clear. Workbenches combining safety in manipulation with hazardous viruses
      and the convenience of controlled gas atmosphere during both manipulation and
      long-term incubation have been developed. It is suggested that the in vitro
      virology should ensure that the physiological oxygen tension is better mimicked
      in the in vivo processes. Much work is to be done to determine the molecular
      interactions between oxygen tension-sensitive elements of the cell and infecting
      viruses. Of no lesser importance are the questions regarding the role of oxygen
      in virus tissue tropism, the cost-benefit of virus production at different oxygen
      tension levels, and the potential significance of oxygen tension for delivering
      gene effects to the selected target tissues.

PMID- 10358751
TI  - Discovering the origins of immunological competence.
AB  - Work done in the late 1950s and in the 1960s revealed the role of the thymus in
      virus-induced leukemia in mice. Thymectomizing mice at birth to test whether the
      virus first multiplied in thymus tissue and then spread elsewhere ultimately led
      to the conclusion that the thymus was essential to the normal development of the
      immune system. Subsequent testing to try to understand how the thymus contributes
      to the pool of immunocompetent lymphocytes opened a new chapter in immunology and
      required a reappraisal of many immunological phenomena and an understanding of
      the molecular interactions that take place during cell-to-cell interactions.

PMID- 10358752
TI  - The multifaceted regulation of interleukin-15 expression and the role of this
      cytokine in NK cell differentiation and host response to intracellular pathogens.
AB  - Interleukin-15 (IL-15) is a 14- to 15-kDa member of the 4 alpha-helix bundle
      family of cytokines. IL-15 expression is controlled at the levels of
      transcription, translation, and intracellular trafficking. In particular, IL-15
      protein is posttranscriptionally regulated by multiple controlling elements that
      impede translation, including 12 upstream AUGs of the 5' UTR, 2 unusual signal
      peptides, and the C-terminus of the mature protein. IL-15 uses two distinct
      receptor and signaling pathways. In T and NK cells the IL-15 receptor includes IL
      2/15R beta and gamma c subunits, which are shared with IL-2, and an IL-15
      specific receptor subunit, IL-15R alpha. Mast cells respond to IL-15 with a
      receptor system that does not share elements with the IL-2 receptor but uses a
      novel 60- to 65-kDa IL-15RX subunit. In mast cells IL-15 signaling involves
      Jak2/STAT5 activation rather than the Jak1/Jak3 and STAT5/STAT3 system used in
      activated T cells. In addition to its other functional activities in immune and
      nonimmune cells, IL-15 plays a pivotal role in the development, survival, and
      function of NK cells. Abnormalities of IL-15 expression have been described in
      patients with rheumatoid arthritis or inflammatory bowel disease and in diseases
      associated with the retroviruses HIV and HTLV-I. New approaches directed toward
      IL-15, its receptor, or its signaling pathway may be of value in the therapy of
      these disorders.

PMID- 10358753
TI  - Immunodominance in major histocompatibility complex class I-restricted T
      lymphocyte responses.
AB  - Of the many thousands of peptides encoded by a complex foreign antigen that can
      potentially be presented to CD8+ T cells (TCD8+), only a small fraction induce
      measurable responses in association with any given major histocompatibility
      complex class I allele. To design vaccines that elicit optimal TCD8+ responses, a
      thorough understanding of this phenomenon, known as immunodominance, is
      imperative. Here we review recent progress in unraveling the molecular and
      cellular basis for immunodominance. Of foremost importance is peptide binding to
      class I molecules; only approximately 1/200 of potential determinants bind at
      greater than the threshold affinity (Kd > 500 nM) associated with immunogenicity.
      Limitations in the TCD8+ repertoire render approximately half of these peptides
      nonimmunogenic, and inefficient antigen processing further thins the ranks by
      approximately four fifths. As a result, only approximately 1/2000 of the peptides
      in a foreign antigen expressed by an appropriate antigen presenting cell achieve
      immunodominant status with a given class I allele. A roughly equal fraction of
      peptides have subdominant status, i.e. they induce weak-to-nondetectable primary
      TCD8+ responses in the context of their natural antigen. Subdominant determinants
      may be expressed at or above levels of immunodominant determinants, at least on
      antigen presenting cells in vitro. The immunogenicity of subdominant determinants
      is often limited by immunodomination: suppression mediated by TCD8+ specific for
      immunodominant determinants. Immunodomination is a central feature of TCD8+
      responses, as it even occurs among clones responding to the same immunodominant
      determinant. Little is known about how immunodominant and subdominant
      determinants are distinguished by the TCD8+ repertoire, or how (and why)
      immunodomination occurs, but new tools are available to address these questions.

PMID- 10358754
TI  - Integration of T cell receptor-dependent signaling pathways by adapter proteins.
AB  - The initiation of biochemical signal transduction following ligation of surface
      receptors with intrinsic cytoplasmic tyrosine kinase activity is common for many
      cell types. T lymphocytes also require activation of tyrosine kinases following T
      cell receptor (TCR) ligation for maximal stimulation. However, the TCR has no
      intrinsic tyrosine kinase activity. Instead, the TCR must rely on cytoplasmic
      tyrosine kinases that localize to the TCR complex and initiate TCR-mediated
      signaling events. Although much has been learned regarding how these cytosolic
      tyrosine kinases are activated and recruited to the TCR complex, relatively
      little is understood about how these initial events are translated into
      transcriptional activation of genes that regulate cytokine production, cell
      proliferation, and cell death. Recently, it has become clear that the class of
      intracellular molecules known collectively as adapter proteins, molecules with
      modular domains capable of recruiting additional proteins but that exhibit no
      intrinsic enzymatic activity, serve to couple proximal biochemical events
      initiated by TCR ligation with more distal signaling pathways.

PMID- 10358755
TI  - Evolution of antigen binding receptors.
AB  - This review addresses issues related to the evolution of the complex multigene
      families of antigen binding receptors that function in adaptive immunity.
      Advances in molecular genetic technology now permit the study of immunoglobulin
      (Ig) and T cell receptor (TCR) genes in many species that are not commonly
      studied yet represent critical branch points in vertebrate phylogeny. Both Ig and
      TCR genes have been defined in most of the major lineages of jawed vertebrates,
      including the cartilaginous fishes, which represent the most phylogenetically
      divergent jawed vertebrate group relative to the mammals. Ig genes in
      cartilaginous fish are encoded by multiple individual loci that each contain
      rearranging segmental elements and constant regions. In some loci, segmental
      elements are joined in the germline, i.e. they do not undergo genetic
      rearrangement. Other major differences in Ig gene organization and the mechanisms
      of somatic diversification have occurred throughout vertebrate evolution.
      However, relating these changes to adaptive immune function in lower vertebrates
      is challenging. TCR genes exhibit greater sequence diversity in individual
      segmental elements than is found in Ig genes but have undergone fewer changes in
      gene organization, isotype diversity, and mechanisms of diversification. As of
      yet, homologous forms of antigen binding receptors have not been identified in
      jawless vertebrates; however, acquisition of large amounts of structural data for
      the antigen binding receptors that are found in a variety of jawed vertebrates
      has defined shared characteristics that provide unique insight into the distant
      origins of the rearranging gene systems and their relationships to both adaptive
      and innate recognition processes.

PMID- 10358756
TI  - Transcriptional regulation of T lymphocyte development and function.
AB  - The development and function of T lymphocytes are regulated tightly by signal
      transduction pathways that include specific cell-surface receptors, intracellular
      signaling molecules, and nuclear transcription factors. Since 1988, several
      families of functionally important T cell transcription factors have been
      identified. These include the Ikaros, LKLF, and GATA3 zinc-finger proteins; the
      Ets, CREB/ATF, and NF-kappa B/Rel/NFAT transcription factors; the Stat proteins;
      and HMG box transcription factors such as LEF1, TCF1, and Sox4. In this review,
      we summarize our current understanding of the transcriptional regulation of T
      cell development and function with particular emphasis on the results of recent
      gene targeting and transgenic experiments. In addition to increasing our
      understanding of the molecular pathways that regulate T cell development and
      function, these results have suggested novel targets for genetic and
      pharmacological manipulation of T cell immunity.

PMID- 10358757
TI  - Natural killer cells in antiviral defense: function and regulation by innate
      cytokines.
AB  - Natural killer (NK) cells are populations of lymphocytes that can be activated to
      mediate significant levels of cytotoxic activity and produce high levels of
      certain cytokines and chemokines. NK cells respond to and are important in
      defense against a number of different infectious agents. The first indications
      for this function came from the observations that virus-induced interferons
      alpha/beta (IFN-alpha and -beta) are potent inducers of NK cell-mediated
      cytotoxicity, and that NK cells are important contributors to innate defense
      against viral infections. In addition to IFN-alpha/beta, a wide range of other
      innate cytokines can mediate biological functions regulating the NK cell
      responses of cytotoxicity, proliferation, and gamma interferon (IFN-gamma)
      production. Certain, but not all, viral infections induce interleukin 12 (IL-12)
      to elicit NK cell IFN-gamma production and antiviral mechanisms. However, high
      levels of IFN-alpha/beta appear to be unique and/or uniquely dominant in the
      context of viral infections and act to regulate other innate responses, including
      induction of NK cell proliferation in vivo and overall negative regulation of IL
      12 production. A detailed picture is developing of particular innate cytokines
      activating NK cell responses and their consorted effects in providing unique
      endogenous milieus promoting downstream adaptive responses, most beneficial in
      defense against viral infections.

PMID- 10358758
TI  - Mature T lymphocyte apoptosis--immune regulation in a dynamic and unpredictable
      antigenic environment.
AB  - Apoptosis of mature T lymphocytes preserves peripheral homeostasis and tolerance
      by countering the profound changes in the number and types of T cells stimulated
      by diverse antigens. T cell apoptosis occurs in at least two major forms: antigen
      driven and lymphokine withdrawal. These forms of death are controlled in response
      to local levels of IL-2 and antigen in a feedback mechanism termed propriocidal
      regulation. Active antigen-driven death is mediated by the expression of death
      cytokines such as FasL and TNF. These death cytokines engage specific receptors
      that assemble caspase-activating protein complexes. These signaling complexes
      tightly regulate cell death but are vulnerable to inherited defects. Passive
      lymphokine withdrawal death may result from the cytoplasmic activation of
      caspases that is regulated by mitochondria and the Bcl-2 protein. The human
      disease, Autoimmune Lymphoproliferative Syndrome (ALPS) is due to dominant
      interfering mutations in the Fas/APO-1/CD95 receptor and other components of the
      death pathway. The study of ALPS patients reveals the necessity of apoptosis for
      preventing autoimmunity and allows the genetic investigation of apoptosis in
      humans. Immunological, cellular, and molecular evidence indicates that throughout
      the life of a T cell, apoptosis may be evoked in excessive, harmful, or useless
      clonotypes to preserve a healthy and balanced immune system.

PMID- 10358759
TI  - Immunologic basis of antigen-induced airway hyperresponsiveness.
AB  - The incidence, morbidity, and mortality of asthma has increased worldwide over
      the last two decades. Asthma is a complex inflammatory disease of the lung
      characterized by variable airflow obstruction, airway hyperresponsiveness (AHR),
      and airway inflammation. The inflammatory response in the asthmatic lung is
      characterized by infiltration of the airway wall with mast cells, lymphocytes,
      and eosinophils. Although asthma is multifactorial in origin, the inflammatory
      process in the most common form of the disease (extrinsic asthma) is believed to
      be a result of inappropriate immune responses to common aero-allergens in
      genetically susceptible individuals. As such, it has been hypothesized that CD4+
      T cells that produce a Th2 pattern of cytokines play a pivotal role in the
      pathogenesis of this disease. Through the release of cytokines such as IL-4, IL
      13, and IL-5, these cells orchestrate the recruitment and activation of the
      primary effector cells of the allergic response, the mast cell and the
      eosinophil. Activation of these cells results in the release of a plethora of
      inflammatory mediators that individually or in concert induce changes in airway
      wall geometry and produce the symptoms of the disease. The aim of this review is
      to discuss our current understanding of the pathophysiologic mechanisms by which
      Th2 cytokines induce airway disease, and the factors that predispose to the
      generation of these pathogenic cells in response to inhalation of ubiquitous aero
      allergens. Elucidation of the exact immunological basis for allergic asthma may
      yield immunotherapeutic strategies to reverse the development of pathogenic Th2
      mediated immune responses and reduce the morbidity and mortality associated with
      this disease.

PMID- 10358760
TI  - Regulation of T cell fate by Notch.
AB  - The transmembrane receptor Notch participates in diverse cell fate decisions
      throughout embryonic development. Notch receptors and their ligands are expressed
      in the mammalian thymus, raising the possibility that Notch could regulate T cell
      fate decisions. Expression of a constitutively activated form of Notch in
      developing thymocytes causes thymocytes normally destined for the CD4 lineage to
      adopt the CD8 lineage instead. This suggests that Notch activity normally acts to
      direct CD4+CD8+ precursors to the CD8 lineage. The choice between CD4 and CD8 T
      cell fates is also controlled by MHC recognition during positive selection,
      implying that recognition of class I or II MHC might regulate Notch signaling.
      Possible models for the regulation of Notch by MHC recognition during CD4 versus
      CD8 lineage determination are discussed.

PMID- 10358761
TI  - The CD1 system: antigen-presenting molecules for T cell recognition of lipids and
      glycolipids.
AB  - Recent studies have identified the CD1 family of proteins as novel antigen
      presenting molecules encoded by genes located outside of the major
      histocompatibility complex. CD1 proteins are conserved in all mammalian species
      so far examined and are prominently expressed on cells involved in antigen
      presentation, which suggests a role in activation of cell-mediated immunity. This
      has now been confirmed by functional studies demonstrating the ability of CD1
      proteins to restrict the antigen-specific responses of T cells in humans and
      mice. Identification of naturally occurring antigens presented by CD1 has
      revealed the surprising finding that these are predominantly a variety of foreign
      lipids and glycolipids, including several found prominently in the cell walls and
      membranes of pathogenic mycobacteria. Structural, biochemical, and biophysical
      studies support the view that CD1 proteins bind the hydrophobic alkyl portions of
      these antigens directly and position the polar or hydrophilic head groups of
      bound lipids and glycolipids for highly specific interactions with T cell antigen
      receptors. Presentation of antigens by CD1 proteins requires uptake and
      intracellular processing by antigen presenting cells, and evidence exists for
      cellular pathways leading to the presentation of both exogenous and endogenous
      lipid antigens. T cells recognizing antigens presented by CD1 have a range of
      functional activities that suggest they are likely to mediate an important
      component of antimicrobial immunity and may also contribute to autoimmunity and
      host responses against neoplastic cells.

PMID- 10358762
TI  - Tumor necrosis factor receptor and Fas signaling mechanisms.
AB  - Four members of the tumor necrosis factor (TNF) ligand family, TNF-alpha, LT
      alpha, LT-beta, and LIGHT, interact with four receptors of the TNF/nerve growth
      factor family, the p55 TNF receptor (CD120a), the p75 TNF receptor (CD120b), the
      lymphotoxin beta receptor (LT beta R), and herpes virus entry mediator (HVEM) to
      control a wide range of innate and adaptive immune response functions. Of these,
      the most thoroughly studied are cell death induction and regulation of the
      inflammatory process. Fas/Apo1 (CD95), a receptor of the TNF receptor family
      activated by a distinct ligand, induces death in cells through mechanisms shared
      with CD120a. The last four years have seen a proliferation in knowledge of the
      proteins participating in the signaling by the TNF system and CD95. The
      downstream signaling molecules identified so far--caspases, phospholipases, the
      three known mitogen activated protein (MAP) kinase pathways, and the NF-kappa B
      activation cascade--mediate the effects of other inducers as well. However, the
      molecules that initiate these signaling events, including the death domain- and
      TNF receptor associated factor (TRAF) domain-containing adapter proteins and the
      signaling enzymes associated with them, are largely unique to the TNF/nerve
      growth factor receptor family.

PMID- 10358763
TI  - Structural basis of T cell recognition.
AB  - Exciting breakthroughs in the last two years have begun to elucidate the
      structural basis of cellular immune recognition. Crystal structures have been
      determined for full-length and truncated forms of alpha beta T cell receptor
      (TCR) heterodimers, both alone and in complex with their peptide-MHC (pMHC)
      ligands or with anti-TCR antibodies. In addition, a truncated CD8 coreceptor has
      been visualized with a pMHC. Aided in large part by the substantial body of
      knowledge accumulated over the last 25 years on antibody structure, a number of
      general conclusions about TCR structure and its recognition of antigen can
      already be derived from the relatively few TCR structures that have been
      determined. Small, but important, variations between TCR and antibody structures
      bear on their functional differences as well as on their specific antigen
      recognition requirements. As observed in antibodies, canonical CDR loop
      structures are already emerging for some of the TCR CDR loops. Highly similar
      docking orientations of the TCR V alpha domains in the TCR/pMHC complex appear to
      play a primary role in dictating orientation, but the V beta positions diverge
      widely. Similar TCR contact positions, but whose exact amino acid content can
      vary, coupled with relatively poor interface shape complementarity, may explain
      the flexibility and short half-lives of many TCR interactions with pMHC. Here we
      summarize the current state of this field, and suggest that the knowledge gap
      between the three-dimensional structure and the signaling function of the TCR can
      be bridged through a synthesis of molecular biological and biophysical
      techniques.

PMID- 10358764
TI  - Development and maturation of secondary lymphoid tissues.
AB  - The secondary lymphoid tissues are located at strategic sites where foreign
      antigens can be efficiently brought together with immune system regulatory and
      effector cells. The organized structure of the secondary lymphoid tissues is
      thought to enhance the sensitivity of antigen recognition and to support proper
      regulation of the activation and maturation of the antigen-responsive lymphoid
      cells. Although a substantial amount is known about the cellular elements that
      compose the lymphoid and nonlymphoid components of the secondary lymphoid
      tissues, information concerning the signals that control the development of the
      tissues and that maintain the organized tissue microenvironment remain undefined.
      Studies over the past few years have identified lymphotoxin as a critical
      signaling molecule not only for the organogenesis of secondary lymphoid tissues
      but for the maintenance of aspects of their microarchitecture as well. Additional
      signaling molecules that contribute to the formation of normal lymphoid tissue
      structure are being identified at an accelerating pace. Analyses of mouse strains
      with congenital defects in different aspects of secondary lymphoid tissue
      development are beginning to clarify the role of these tissues in immune
      responses and host defense. This review focuses on studies defining recently
      identified crucial signals for the biogenesis of secondary lymphoid organs and
      for the maintenance of their proper microarchitecture. It also discusses new
      insights into how the structure of these tissues supports effective immune
      responses.

PMID- 10358765
TI  - The structural basis of T cell activation by superantigens.
AB  - Superantigens (SAGs) are a class of immunostimulatory and disease-causing
      proteins of bacterial or viral origin with the ability to activate large
      fractions (5-20%) of the T cell population. Activation requires simultaneous
      interaction of the SAG with the V beta domain of the T cell receptor (TCR) and
      with major histocompatibility complex (MHC) class II molecules on the surface of
      an antigen-presenting cell. Recent advances in knowledge of the three-dimensional
      structure of bacterial SAGs, and of their complexes with MHC class II molecules
      and the TCR beta chain, provide a framework for understanding the molecular basis
      of T cell activation by these potent mitogens. These structures along with those
      of TCR-peptide/MHC complexes reveal how SAGs circumvent the normal mechanism for
      T cell activation by peptide/MHC and how they stimulate T cells expressing TCR
      beta chains from a number of different families, resulting in polyclonal T cell
      activation. The crystal structures also provide insights into the basis for the
      specificity of different SAGs for particular TCR beta chains, and for the
      observed influence of the TCR alpha chain on SAG reactivity. These studies open
      the way to the design of SAG variants with altered binding properties for TCR and
      MHC for use as tools in dissecting structure-activity relationships in this
      system.

PMID- 10358766
TI  - The dynamics of T cell receptor signaling: complex orchestration and the key
      roles of tempo and cooperation.
AB  - T cells constantly sample their environment using receptors (TCR) that possess
      both a germline-encoded low affinity for major histocompatibility complex (MHC)
      molecules and a highly diverse set of CDR3 regions contributing to a range of
      affinities for specific peptides bound to these MHC molecules. The decision of a
      T cell "to sense and to respond" with proliferation and effector activity rather
      than "to sense, live on, but not respond" is dependent on TCR interaction with a
      low number of specific foreign peptide:MHC molecule complexes recognized
      simultaneously with abundant self peptide-containing complexes. Interaction with
      self-complexes alone, on the other hand, generates a signal for survival without
      a full activation response. Current models for how this distinction is achieved
      are largely based on translating differences in receptor affinity for foreign
      versus self ligands into intracellular signals that differ in quality, intensity,
      and/or duration. A variety of rate-dependent mechanisms involving assembly of
      molecular oligomers and enzymatic modification of proteins underlie this
      differential signaling. Recent advances have been made in measuring TCR:ligand
      interactions, in understanding the biochemical origin of distinct proximal and
      distal signaling events resulting from TCR binding to various ligands, and in
      appreciating the role of feedback pathways. This new information can be
      synthesized into a model of how self and foreign ligand recognition each evoke
      the proper responses from T cells, how these two classes of signaling events
      interact, and how pathologic responses may arise as a result of the underlying
      properties of the system. The principles of signal spreading and stochastic
      resonance incorporated into this model reveal a striking similarity in mechanisms
      of decision-making among T cells, neurons, and bacteria.

PMID- 10358767
TI  - The regulation of CD4 and CD8 coreceptor gene expression during T cell
      development.
AB  - The two major subsets of T lymphocytes in the peripheral immune system, the
      helper and cytotoxic T cells, are defined by their expression of either the CD4
      or the CD8 glycoproteins, respectively. Expression of these molecules, which
      serve as coreceptors by interacting specifically with either MHC class II or
      class I molecules, also defines discrete stages of T cell development within the
      thymus. Thus, CD4+ and CD8+ single-positive (SP) thymocytes arise from common
      progenitor double positive (DP) cells that express both CD4 and CD8, during a
      process known as positive selection. The molecular mechanisms underlying the
      developmental choice toward the helper or cytotoxic lineage remain poorly
      understood. Because regulation of coreceptor gene expression appears to be
      coupled to the phenotypic choice of the differentiating T cell, it is likely that
      shared signaling pathways direct CD4 and CD8 transcription and the development of
      an uncommited DP thymocyte toward either the helper or cytotoxic lineage.
      Therefore, an understanding of how CD4 and CD8 expression is regulated will not
      only provide insights into transcriptional control mechanisms in T cells, but may
      also result in the identification of molecular factors that are involved in
      lineage choices during T cell development. In this review, we summarize recent
      progress that has been made toward an understanding of how CD4 and CD8 gene
      expression is regulated.

PMID- 10358768
TI  - Genetic analysis of B cell antigen receptor signaling.
AB  - In B lymphocytes, a signaling complex that contributes to cell fate decisions is
      the B cell antigen receptor (BCR). Data from knockout experiments in cell lines
      and mice have revealed distinct functions for the intracellular protein tyrosine
      kinases (Lyn, Syk, Btk) in BCR signaling and B cell development. Combinations of
      intracellular signaling pathways downstream of these PTKs determine the quality
      and quantity of BCR signaling. For example, concerted actions of the PLC-gamma 2
      and PI3-K pathways are required for proper calcium responses. Similarly, the
      regulation of ERK and JNK responses involves both PLC-gamma 2 and GTPases
      pathways. Since the immune response in vivo is regulated by alteration of these
      signaling outcomes, achieving a precise understanding of intracellular molecular
      events leading to B lymphocyte proliferation, deletion, anergy, receptor editing,
      and survival still remains a challenge for the future.

PMID- 10358769
TI  - Mechanisms of phagocytosis in macrophages.
AB  - Phagocytosis of pathogens by macrophages initiates the innate immune response,
      which in turn orchestrates the adaptive response. In order to discriminate
      between infectious agents and self, macrophages have evolved a restricted number
      of phagocytic receptors, like the mannose receptor, that recognize conserved
      motifs on pathogens. Pathogens are also phagocytosed by complement receptors
      after relatively nonspecific opsonization with complement and by Fc receptors
      after specific opsonization with antibodies. All these receptors induce
      rearrangements in the actin cytoskeleton that lead to the internalization of the
      particle. However, important differences in the molecular mechanisms underlying
      phagocytosis by different receptors are now being appreciated. These include
      differences in the cytoskeletal elements that mediate ingestion, differences in
      vacuole maturation, and differences in inflammatory responses. Infectious agents,
      such as M. tuberculosis, Legionella pneumophila, and Salmonella typhimurium,
      enter macrophages via heterogeneous pathways and modify vacuolar maturation in a
      manner that favors their survival. Macrophages also play an important role in the
      recognition and clearance of apoptotic cells; a notable feature of this process
      is the absence of an inflammatory response.

PMID- 10358770
TI  - Population biology of HIV-1 infection: viral and CD4+ T cell demographics and
      dynamics in lymphatic tissues.
AB  - Human immunodeficiency virus-1 (HIV-1) is usually transmitted through sexual
      contact and in the very early stages of infection establishes a persistent
      infection in lymphatic tissues (LT). Virus is produced and stored at this site in
      a dynamic process that slowly depletes the immune system of CD4+ T cells, setting
      the stage for AIDS. In this review, I describe the changes in viral and CD4+ T
      cell populations in LT over the course of infection and after treatment. I
      present recent evidence that productively infected CD4+ T cells play an important
      role in establishing persistent infection from the onset, and that the LT are the
      major reservoir where virus is produced and stored on follicular dendritic cells
      (FDCs). I discuss the methods used to define the size of viral and CD4+ T cell
      populations in LT and the nature of virus-host cell interactions in vivo. These
      experimental approaches have identified populations of latently and chronically
      infected cells in which virus can elude host defenses, perpetuate infection, and
      escape eradication by highly active antiretroviral treatment (HAART). I discuss
      the dramatic impact of HAART on suppressing virus production, reducing the pool
      of stored virus, and restoring CD4+ T cell populations. I discuss the
      contributions of thymopoiesis and other renewal mechanisms, lymphatic homeostasis
      and trafficking to these changes in CD4+ T cell populations in LT, and conclude
      with a model of immune depletion and repopulation based on the limited
      regenerative capacity of the adult and the uncompensated losses of productively
      infected cells that treatment stems. The prediction of this model is that immune
      regeneration will be slow, variable, and partial. It is nonetheless encouraging
      to know that even in late stages of infection, control of active replication of
      HIV-1 provides an opportunity for the immune system to recover from the injuries
      inflicted by infection.

PMID- 10358771
TI  - Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and
      disease.
AB  - In addition to CD4, the human immunodeficiency virus (HIV) requires a coreceptor
      for entry into target cells. The chemokine receptors CXCR4 and CCR5, members of
      the G protein-coupled receptor superfamily, have been identified as the principal
      coreceptors for T cell line-tropic and macrophage-tropic HIV-1 isolates,
      respectively. The updated coreceptor repertoire includes numerous members, mostly
      chemokine receptors and related orphans. These discoveries provide a new
      framework for understanding critical features of the basic biology of HIV-1,
      including the selective tropism of individual viral variants for different CD4+
      target cells and the membrane fusion mechanism governing virus entry. The
      coreceptors also provide molecular perspectives on central puzzles of HIV-1
      disease, including the selective transmission of macrophage-tropic variants, the
      appearance of T cell line-tropic variants in many infected persons during
      progression to AIDS, and differing susceptibilities of individuals to infection
      and disease progression. Genetic findings have yielded major insights into the in
      vivo roles of individual coreceptors and their ligands; of particular importance
      is the discovery of an inactivating mutation in the CCR5 gene which, in
      homozygous form, confers strong resistance to HIV-1 infection. Beyond providing
      new perspectives on fundamental aspects of HIV-1 transmission and pathogenesis,
      the coreceptors suggest new avenues for developing novel therapeutic and
      preventative strategies to combat the AIDS epidemic.

PMID- 10358772
TI  - The IL-4 receptor: signaling mechanisms and biologic functions.
AB  - Interleukin-4 is a multifunctional cytokine that plays a critical role in the
      regulation of immune responses. Its effects depend upon binding to and signaling
      through a receptor complex consisting of the IL-4R alpha chain and the common
      gamma chain (gamma c), resulting in a series of phosphorylation events mediated
      by receptor-associated kinases. In turn, these cause the recruitment of mediators
      of cell growth, of resistance to apoptosis, and of gene activation and
      differentiation. Here we describe our current understanding of the organization
      of the IL-4 receptor, of the signaling pathways that are induced as a result of
      receptor occupancy, and of the various mechanisms through which receptor function
      is modulated. We particularly emphasize the modular nature of the receptor and
      the specialization of different receptor regions for distinct functions, most
      notably the independent regulation of cell growth and gene activation.

PMID- 10358773
TI  - Degradation of cell proteins and the generation of MHC class I-presented
      peptides.
AB  - Major histocompatibility complex (MHC) class I molecules display on the cell
      surface 8- to 10-residue peptides derived from the spectrum of proteins expressed
      in the cells. By screening for non-self MHC-bound peptides, the immune system
      identifies and then can eliminate cells that are producing viral or mutant
      proteins. These antigenic peptides are generated as side products in the
      continual turnover of intracellular proteins, which occurs primarily by the
      ubiquitin-proteasome pathway. Most of the oligopeptides generated by the
      proteasome are further degraded by distinct endopeptidases and aminopeptidases
      into amino acids, which are used for new protein synthesis or energy production.
      However, a fraction of these peptides escape complete destruction and after
      transport into the endoplasmic reticulum are bound by MHC class I molecules and
      delivered to the cell surface. Herein we review recent discoveries about the
      proteolytic systems that degrade cell proteins, how the ubiquitin-proteasome
      pathway generates the peptides presented on MHC-class I molecules, and how this
      process is stimulated by immune modifiers to enhance antigen presentation.

PMID- 10358774
TI  - The central effectors of cell death in the immune system.
AB  - The immune system relies on cell death to maintain lymphoid homeostasis and avoid
      disease. Recent evidence has indicated that the caspase family of cysteine
      proteases is a central effector in apoptotic cell death and is absolutely
      responsible for many of the morphological features of apoptosis. Cell death,
      however, can occur through caspase-independent and caspase-dependent pathways. In
      the case of cells that are irreversibly neglected or damaged, death occurs even
      in the absence of caspase activity. In contrast, healthy cells require caspase
      activation to undergo cell death induced by surface receptors. This review
      summarizes the current understanding of these two pathways of cell death in the
      immune system.

PMID- 10358775
TI  - Selection of the T cell repertoire.
AB  - Advances in gene technology have allowed the manipulation of molecular
      interactions that shape the T cell repertoire. Although recognized as fundamental
      aspects of T lymphocyte development, only recently have the mechanisms governing
      positive and negative selection been examined at a molecular level. Positive
      selection refers to the active process of rescuing MHC-restricted thymocytes from
      programmed cell death. Negative selection refers to the deletion or inactivation
      of potentially autoreactive thymocytes. This review focuses on interactions
      during thymocyte maturation that define the T cell repertoire, with an emphasis
      placed on current literature within this field.

PMID- 10358776
TI  - Regulation of immune responses through inhibitory receptors.
AB  - Major histocompatibility complex class I-specific inhibitory receptors on natural
      killer cells prevent the lysis of healthy autologous cells. The outcome of this
      negative signal is not anergy or apoptosis of natural killer cells but a
      transient abortion of activation signals. The natural killer inhibitory receptors
      fulfill this function by recruiting the tyrosine phosphatase SHP-1 through a
      cytoplasmic immunoreceptor tyrosine-based inhibition motif. This immunoreceptor
      tyrosine-based inhibition motif has become the hallmark of a growing family of
      receptors with inhibitory potential, which are expressed in various cell types
      such as monocytes, macrophages, dendritic cells, leukocytes, and mast cells. Most
      of the natural killer inhibitory receptors and two members of a monocyte
      inhibitory-receptor family bind major histocompatibility complex class I
      molecules. Ligands for many of the other receptors have yet to be identified. The
      inhibitory-receptor superfamily appears to regulate many types of immune
      responses by blocking cellular activation signals.

PMID- 10358777
TI  - The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal
      organization.
AB  - The Wiskott-Aldrich Syndrome (WAS) is a rare X-linked primary immunodeficiency
      that is characterized by recurrent infections, hematopoietic malignancies,
      eczema, and thrombocytopenia. A variety of hematopoietic cells are affected by
      the genetic defect, including lymphocytes, neutrophils, monocytes, and platelets.
      Early studies noted both signaling and cytoskeletal abnormalities in lymphocytes
      from WAS patients. Following the identification of WASP, the gene mutated in
      patients with this syndrome, and the more generally expressed WASP homologue N
      WASP, studies have demonstrated that WASP-family molecules associate with
      numerous signaling molecules known to alter the actin cytoskeleton. WASP/N-WASP
      may depolymerize actin directly and/or serve as an adaptor or scaffold for these
      signaling molecules in a complex cascade that regulates the cytoskeleton.

PMID- 10358778
TI  - The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology.
AB  - The high affinity receptor for immunoglobulin E (designated Fc epsilon RI) is the
      member of the antigen (Ag) receptor superfamily responsible for linking pathogen
      or allergen-specific IgEs with cellular immunologic effector functions. This
      review provides background information on Fc epsilon RI function combined with
      more detailed summaries of recent progress in understanding specific aspects of
      Fc epsilon RI biology and biochemistry. Topics covered include the coordination
      and function of the large multiprotein signaling complexes that are assembled
      when Fc epsilon RI and other Ag receptors are engaged, new information on human
      receptor structures and tissue distribution, and the role of the FcR beta chain
      in signaling and its potential contribution to atopic phenotypes.

PMID- 10358779
TI  - The crystal structure of the human high-affinity IgE receptor (Fc epsilon RI
      alpha).

PMID- 10358780
TI  - Discrimination between viral and nonviral meningitis by visually analyzed and
      quantitative electroencephalography.
AB  - A prospective study was conducted to assess the ability of the visually analyzed
      electroencephalogram (VEEG), the quantitative EEG (QEEG) and the Glasgow Coma
      Scale (GCS) to discriminate between patients with viral and nonviral meningitis.
      The 55 subjects, aged 14-75 years, fell into one of the following categories:
      viral (n = 12), bacterial (n = 19), tuberculous (n = 16) or cryptococcal (n = 8)
      meningitis. EEG recordings and Glasgow Coma Scale (GCS) scores were obtained
      within 48 hours of admission to hospital. The sensitivity of the VEEG and QEEG
      for the prediction of patients with nonviral meningitis (true positives in this
      context) attained reasonably high values of 70% and 80%, respectively. In
      contrast, the sensitivity of the GCS was only 38%. Each of the three tests
      achieved high degrees of consistency in this regard with positive predictive
      values of 94% or better. The specificity for each of the three tests was high,
      100% for the VEEG and the GCS and 82% for the QEEG indicating a high probability
      for the correct prediction of viral meningitis (true negatives). The consistency
      of this prediction was, however, poor due to negative predictive values of only
      53% for the QEEG, 48% for the VEEG and 32% for the GCS. The QEEG results did not
      reveal any obvious advantages over the VEEG. Rather the assessment of the
      occurrence of particular VEEG abnormalities showed that patients with delta
      abnormalities had a very high probability of nonviral meningitis. At the other
      end of the spectrum, all normal VEEGs occurred in viral meningitis. In important
      respects the predictive ability of the EEG was superior to that of the GCS. While
      there was statistically significant agreement between the VEEG and GCS, the
      degree of agreement was poor. This study indicates that the EEG is a valuable and
      probably underestimated test in the acute phase of meningitis and provides
      complementary information to the GCS.

PMID- 10358781
TI  - Development of sleep spindles in young children and adolescents.
AB  - The development of sleep spindles was studied quantitatively in 32 healthy
      subjects between the ages of 4 and 24 years. The peak frequency distribution of
      the spindles showed a bimodal pattern with 11.0 to 12.75 Hz in the frontal area
      and 12.5 to 14.5 Hz in the centroparietal area. The two types of spindle activity
      showed different courses of maturation. The peak frequency of the centroparietal
      spindles gradually increased linearly with age, whereas the frontal spindles
      abruptly increased in frequency during early adolescence. Regarding the power
      spectra, while centroparietal spindles showed little change in power from 4 to 24
      years of age, frontal spindles decreased remarkably in power and became stable at
      about 13 years of age. The two types of spindles and the difference in their
      development may suggest the existence of different generators or a topographical
      difference during maturation in the thalamocortical network. The frontal spindle
      activity could be a good indicator to evaluate CNS maturation in young children
      and adolescents.

PMID- 10358782
TI  - Is there a chronic change of the "Mozart effect" on epileptiform activity? A case
      study.
AB  - This report shows that a patient with the Lennox-Gastaut Syndrome had fewer
      clinical seizures and also fewer generalized bilateral spike and wave complexes
      over a 24-hour period while exposed to Mozart music (K.448) for 10 minutes every
      hour during wakefulness.

PMID- 10358784
TI  - QEEG changes during cardiopulmonary bypass: relationship to postoperative
      neuropsychological function.
AB  - The relationship of changes in intraoperative QEEG and postoperative cognitive
      function was studied in 32 patients undergoing cardiac surgical procedures
      requiring cardiopulmonary bypass (CPB). All patients were anesthetized with a
      high dose narcotic technique in which CPB was carried out using moderate
      hypothermia. EEG recorded continuously throughout each procedure was analyzed
      using the neurometric technique. Neuropsychological (NP) evaluations were
      administered to all patients before, 1 week and 2-3 months postoperatively. A
      decrement in postoperative performance of 2 standard deviations in two or more
      tests from preoperative testing was defined as a new cognitive deficit. Of the
      patients studied, 40.6% demonstrated a new postoperative cognitive deficit at 1
      week. At 2-3 months postoperatively, 28.1% continued to show a cognitive deficit.
      Discriminant analysis of the QEEG as a function of NP performance was calculated
      at select times during the surgical procedure. QEEG prediction of NP performance
      was just above chance at the 1 week comparison but excellent for the 2-3 month
      comparisons. This study suggests that with appropriate monitoring protocols,
      intraoperative QEEG may predict cognitive dysfunction experienced by patients 2-3
      months postoperatively.

PMID- 10358783
TI  - Sources of abnormal EEG activity in the presence of brain lesions.
AB  - In routine clinical EEG, a common origin is assumed for delta and theta rhythms
      produced by brain lesions. In previous papers, we have provided some experimental
      support, based on High Resolution qEEG and dipole fitting in the frequency
      domain, for the hypothesis that delta and theta spectral power have independent
      origins related to lesion and edema respectively. This paper describes the
      results obtained with Frequency Domain VARETA (FD-VARETA) in a group of 13
      patients with cortical space-occupying lesions, in order to: 1) Test the accuracy
      of FD-VARETA for the localization of brain lesions, and 2) To provide further
      support for the independent origin of delta and theta components. FD VARETA is a
      distributed inverse solution, constrained by the Montreal Neurological Institute
      probabilistic atlas that estimates the spectra of EEG sources. In all patients,
      logarithmic transformed source spectra were compared with age-matched normative
      values, defining the Z source spectrum. Maximum Z values were found in 10
      patients within the delta band (1.56 to 3.12 Hz); the spatial extent of these
      sources in the atlas corresponded with the location of the tumors in the CT. In 2
      patients with small metastases and large volumes of edema and in a patient
      showing only edema, maximum Z values were found between 4.29 and 5.12 Hz. The
      spatial extent of the sources at these frequencies was within the volume of the
      edema in the CT. These results provided strong support to the hypothesis that
      both delta and theta abnormal EEG activities are the counterparts of two
      different pathophysiological processes.

PMID- 10358785
TI  - EEG and the passive P300 in dementia of the Alzheimer type.
AB  - Quantitatively analyzed resting electroencephalographic (EEG) activity and P300
      event-related potentials elicited with a passive tone sequence paradigm were
      examined in 30 patients with dementia of the Alzheimer type (DAT) and 15 age
      matched controls. Background electrical rhythms of DAT patients evidenced slowing
      as shown by increased absolute and relative amplitudes in slow frequency bands
      and decreased amplitudes in fast frequency bands (relative to controls).
      Electrical slowing was more evident in patients with higher clinical ratings of
      global intellectual deterioration. Passive P300 amplitude and latency did not
      differentiate patients and controls and were not related to severity of dementia.

PMID- 10358786
TI  - Subjective and objective indices of sleepiness (ESS and MWT) are not equally
      useful in patients with sleep apnea.
AB  - To understand the relationship between subjective and objective indices of
      sleepiness, we studied the relationship of the Epworth Sleepiness Scale (ESS) and
      the Maintenance of Wakefulness Test (MWT) in 41 consecutive patients complaining
      of snoring and excessive day-time sleepiness. The correlation between ESS and MWT
      was significant but small (rho = -0.39). There was considerable discordance
      between the two tests. The Lowess fit line between the ESS and the MWT indicates
      that the ESS falls as the MWT rises to about 4 min. It then stays at a plateau
      until the MWT rises to about 12 min. Thereafter, it resumes its downward slope as
      the MWT rises further. Thus, in patients who are severely sleepy on the MWT, the
      ESS may not be sensitive to different levels of sleepiness. We conclude that the
      ESS and the MWT are not equally useful in assessing sleepiness in patients with
      sleep apnea.

PMID- 10358787
TI  - Frontal lobe atrophy and central motor conduction time in chronic alcoholics.
AB  - The central motor conduction time (CMCT) was investigated in 12 cases of chronic
      alcoholism with frontal lobe atrophy, 12 cases of chronic alcoholism without
      frontal lobe atrophy, and 12 age-matched healthy controls. The CMCT was
      significantly prolonged in the chronic alcoholics with frontal lobe atrophy as
      compared to the chronic alcoholics without frontal lobe atrophy and the healthy
      controls. A significant positive correlation was noted between the CMCT and the
      degree of frontal lobe atrophy. The CMCT may be prolonged in chronic alcoholics
      with frontal lobe atrophy.

PMID- 10358788
TI  - Middle latency auditory evoked potentials during total intravenous anesthesia
      with droperidol, ketamine and fentanyl.
AB  - We investigated whether total intravenous anesthesia with ketamine, fentanyl and
      droperidol would affect middle latency auditory evoked potentials and explicit
      memory, and whether dreams during the anesthesia are related to plasma
      concentrations of fentanyl and the infusion technique. A total number of 40
      patients were the subjects for this study. Twenty patients (group A) were
      maintained with intravenous ketamine 2 mg kg-1 hr-1 and fentanyl 5 micrograms kg
      1 hr-1 for the first 60 min and 3 micrograms kg-1 hr-1 for the next 90 min, and
      droperidol 0.1 mg kg-1. The remaining 20 patients (group B) were maintained with
      intravenous ketamine 2 mg kg-1 hr-1, droperidol 0.1 mg kg-1 and fentanyl 50-100
      micrograms in a bolus intermittently as needed by vital signs such as increases
      in heart rate and arterial blood pressure. Middle latency auditory evoked
      potentials, plasma fentanyl and ketamine levels were measured; explicit memory
      and dreams were also estimated. There were no patients who recollected explicit
      memories of intraoperative events in both groups. The middle latency auditory
      evoked potentials were not significantly changed during the anesthesia in both
      groups. We could find no significant differences in latencies and amplitudes of
      the middle latency auditory evoked potentials between the both groups. Plasma
      fentanyl levels of group B patients were significantly lower than those of group
      A patients and the incidence of the dreams was significantly higher in group B
      patients. We conclude that the anesthesia with ketamine, fentanyl and droperidol
      is not associated with the explicit memories, though the middle latency auditory
      evoked potentials were not significantly changed as compared with those in the
      waking state. In addition, dreams during the anesthesia may correlate with plasma
      fentanyl concentrations or the infusion technique.

PMID- 10358789
TI  - The syndrome of heart failure: emerging concepts in the understanding of its
      pathogenesis and treatment.

PMID- 10358790
TI  - Medical and surgical therapy for cardiac remodeling.
AB  - Ventricular remodeling refers to changes in ventricular geometry, volume, mass,
      and myocellular structure in response to myocardial injury or alteration in
      loading conditions. Although initially adaptive as a consequence of the initial
      damage to the myocardium, progressive ventricular remodeling is ultimately a
      maladaptive process that is associated with significant cardiovascular morbidity
      and mortality. Treatment with an aim to halt or reverse remodeling with mainly
      two classes of medications, angiotensin-converting enzyme inhibitors and beta
      adrenergic blockers, has been shown to improve the long-term outcome. The role of
      pharmacologic and surgical therapy in remodeling is evolving and may have an
      important impact on the development of new directions of therapy for heart
      failure, myocardial infarction, and hypertension.

PMID- 10358791
TI  - An overview of tumor necrosis factor alpha and the failing human heart.
AB  - Recent studies have identified the importance of biologically active molecules
      (e.g., neurohormones) in disease progression in heart failure. In addition to
      neurohormones, another portfolio of biologically active molecules, termed
      cytokines, are also expressed in the setting of heart failure. This article
      reviews recent clinical and experimental material that suggest that the cytokines
      (e.g., tumor necrosis factor alpha), much like the neurohormones, may represent
      another class of biologically active molecules that are responsible for the
      development and progression of heart failure.

PMID- 10358792
TI  - Insights into the pathogenesis of chronic heart failure: immune activation and
      cachexia.
AB  - Body wasting, i.e, cardiac cachexia, is a complication of chronic heart failure
      (CHF). The authors have suggested that cardiac cachexia should be diagnosed when
      nonedematous weight loss of more than 7.5% of the premorbid normal weight occurs
      over a time period of more than 6 months. In an unselected CHF outpatient
      population, 16% of patients were found to be cachectic. The cachectic state is
      predictive of poor survival independently of age, functional class, ejection
      fraction, and exercise capacity. Patients with cardiac cachexia suffer from a
      general loss of fat, lean, and bone tissue. Cachectic CHF patients are weaker and
      fatigue earlier. The pathophysiologic causes of body wasting in patients with CHF
      remain unclear, but initial studies have suggested that humoral neuroendocrine
      and immunologic abnormalities may be of importance. Cachectic CHF patients show
      increased plasma levels of catecholamines, cortisol, and aldosterone. Several
      studies have shown that cardiac cachexia is linked to increased plasma levels of
      tumor necrosis factor alpha. The degree of body wasting is strongly correlated
      with neurohormonal and immune abnormalities. Some investigators have suggested
      that endotoxin may be important in triggering immune activation in CHF patients.
      Available studies suggest that cardiac cachexia is a multifactorial
      neuroendocrine and immunologic disorder that carries a poor prognosis. A complex
      catabolic-anabolic imbalance in different body systems may cause body wasting in
      patients with CHF.

PMID- 10358793
TI  - Noninvasive evaluation of hemodynamics by Doppler echocardiography.
AB  - Doppler echocardiography plays an invaluable role in the diagnosis and management
      of patients with heart disease. Noninvasive measurements of cardiac output,
      pulmonary artery pressures, and left and right ventricular filling pressures can
      be obtained with reasonable accuracy at baseline and at intervals to assess the
      response to therapy. Furthermore, simple measurements of Doppler-acquired mitral
      inflow parameters provide independent and incremental prognostic data in patients
      with restrictive heart disease and in patients with left ventricular systolic
      dysfunction and heart failure.

PMID- 10358794
TI  - Genetic basis of cardiomyopathy.
AB  - The molecular basis of cardiac growth and development is a fundamental question
      that has intrigued many investigators in cardiovascular research. Adult
      cardiomyocytes are terminally differentiated and lose their ability to
      proliferate shortly after birth; however, in response to injury, myocytes have
      the capacity to synthesize new DNA and exhibit plasticity by a compensatory
      growth response, as is shown by re-expression of the fetal isoforms of many
      muscle-specific genes, which is characteristic of the proliferative response. The
      long-term effects of these compensatory responses may lead to the development and
      progression of diseases such as hypertrophic cardiomyopathy and dilated
      cardiomyopathy, because of a single point mutation. This concept has engaged
      scientists to investigate human models to explore the molecular basis of
      hypertrophy or dilation of the myocardium.

PMID- 10358795
TI  - Selection of appropriate patients with heart failure for aortocoronary bypass
      surgery.
AB  - There is a slowly increasing amount of information on surgical revascularization
      of high-risk patients with lower ejection fractions. Many of these patients,
      formerly thought to be best treated by transplantation, can undergo safe and
      effective revascularization with excellent medium-term results. Factors that are
      important in predicting the success of surgical revascularization include left
      ventricular dilitation, elevated left ventricular end-diastolic pressure, redo
      coronary surgery, depressed white ventricular function, the presence of mitral
      regurgitation, and the presence of associated systemic diseases, among others.
      The management of patients with low ejection fraction around the time of coronary
      surgery is of critical importance; a period of pre-operative "tune-up" in the
      hospital on intravenous pressures, intra-aortic balloon, counter pulsation, and
      the use of transesophageal echocardiography, and improved intra-operative
      myocardial protection techniques have all contributed to improved results. The
      improvement in mechanical cardiac systems has also contributed toward improved
      surgical outcomes in this high-risk patient group.

PMID- 10358796
TI  - Ventricular assistance for recovery of cardiac failure.
AB  - Mechanical assist devices have been used increasingly to support patients who
      await heart transplantation. The initial goal was to provide sufficient
      circulatory function to keep these patients alive and to allow them to recover
      from secondary organ dysfunction. A recent observation showed an improvement in
      native heart performance in some transplant candidates who receive support with
      mechanical assist devices. Under these conditions, myocardial recovery has been
      mostly restricted to patients with primary dilated cardiomyopathy and with
      extended periods of ventricular support. Also, the exact mechanisms that lead to
      substantial myocardial recovery remain unknown. Several investigations have
      demonstrated improved myocyte performance, reduced fibrosis, reduced cytokine
      levels, and reduced autoantibodies during long-term mechanical support;
      therefore, the observation of cardiac recovery during mechanical support is in
      accordance with currently discussed models of end-stage heart failure.

PMID- 10358797
TI  - Genetics of neonatal cardiomyopathy.
AB  - Cardiomyopathies, primary disorders of the myocardium, are a leading cause of
      morbidity and mortality in children and adults, and these disorders are
      responsible for a significant percentage of sudden cardiac deaths and cardiac
      transplants. Neonatal cardiomyopathies commonly are associated with poor
      prognosis, and the underlying etiology of this disorder differs considerably from
      cardiomyopathies in older children, adolescents, and adults with similar
      phenotypes. In this review, the major causes of neonatal cardiomyopathy are
      described.

PMID- 10358798
TI  - Developmental and genetic aspects of congenital heart disease.
AB  - Congenital heart defects (CHDs) are the result of abnormal cardiac mesoderm or
      cardiac neural crest development. The molecular cause of most congenital heart
      disease remains unknown, although numerous cardiac regulatory factors have
      recently been described. dHAND and eHAND are basic helix-loop-helix transcription
      factors expressed differentially in the right and left ventricles, respectively,
      and in the cardiac neural crest. Mice lacking dHAND have a hypoplastic right
      ventricle and abnormal development of vessels arising from the heart and cell
      death of craniofacial precursors. By searching for dHAND-dependent genes, a gene
      likely responsible for the cardiac and craniofacial defects associated with
      chromosome 22q11 deletion has been identified. A systematic dissection of
      molecular pathways involved in cardiogenesis should allow for further
      identification of genes responsible for CHD.

PMID- 10358799
TI  - Molecular biology and atrial fibrillation.
AB  - Atrial fibrillation remains one of the most challenging arrhythmias in
      cardiology. Despite the overall advance in the treatment of patients with cardiac
      dysrhythmias with the introduction of radiofrequency ablation, therapeutic
      options in atrial fibrillation have remained largely unchanged and aimed at
      controlling the heart rate and anticoagulation. New surgical and ablation
      compartmentalization techniques are being developed that are promising, but to
      date these techniques are still extremely laborious and available only to a
      handful of patients. Advances in genetics and molecular biology will likely give
      new insights into the development of the disease. Molecular biology research is
      presently focused into two main fields: 1) identification of the genes that cause
      familial forms of the disease, and 2) altered gene expression during the disease
      state. These studies are aimed at identifying not only the triggering factors in
      the acute form but also those that prolong the arrhythmia and convert it into a
      chronic form.

PMID- 10358800
TI  - Ion channels and ventricular arrhythmias: cellular and ionic mechanisms
      underlying the Brugada syndrome.
AB  - Brugada syndrome is characterized by ST segment elevation in the right precordial
      leads, V1-V3 (unrelated to ischemia or structural disease), normal QT intervals,
      apparent right bundle branch block, and sudden cardiac death, particularly in men
      of Asian origin. An autosomal dominant mode of inheritance with variable
      expression has been described. The only gene thus far linked to the Brugada
      syndrome is the cardiac sodium channel gene, SCN5A. The possible cellular and
      ionic basis for these features of the Brugada syndrome are discussed. Strong
      sodium channel block, among other modalities, has been shown to be capable of
      inducing epicardial and transmural dispersion of repolarization, thus providing
      the substrate for the development of phase 2 and circus movement reentry, which
      underlies ventricular tachycardia/ventricular fibrillation.

PMID- 10358801
TI  - Bibliography. Current world literature. Cardiac failure.

PMID- 10358802
TI  - Bibliography. Current world literature. Molecular genetics.

PMID- 10358803
TI  - Academic health centers in turbulent times: strategies for survival.
AB  - Given the increasingly turbulent health care environment, the strategic
      adaptation of academic health centers (AHCs) provides an opportunity to
      investigate the effects of drastic change on a population of organizations. This
      article identifies and categorizes the adaptive behavior using existing strategic
      typologies, while exploring the implications for hospital managers.

PMID- 10358804
TI  - The implementation of business process reengineering in American and Canadian
      hospitals.
AB  - This study of more than 215 U.S. and Canadian hospital executives indicates that
      improved service quality to patients and enhanced financial performance are the
      driving forces for hospitals that undertake business process reengineering (BPR)
      activities. Despite reporting moderate success in achieving organizational
      objectives through BPR, these executives identified lack of staff cooperation,
      buy-in, and skill as important factors that derail BPR implementation efforts.

PMID- 10358805
TI  - Measuring the benefits of clinical decision support: return on investment.
AB  - In an effort to provide high quality care in a more cost-effective manner, health
      care providers have found it necessary to implement a series of decision support
      strategies designed to improve outcomes of care. While each of these strategies
      has measurable benefits, they each come along with additional costs. This article
      will describe a methodology for measuring the costs and direct and indirect
      benefits from decision support activities.

PMID- 10358806
TI  - The impact of managed care on physicians.
AB  - This article investigates physicians' perceptions of how managed care has
      affected them, using data from a 1995 survey of Arizona physicians. Respondents
      report that participation in managed care has had significant and largely
      unpleasant effects on numerous aspects of medical practice: physician-patient
      relationships, clinical decision making, work conditions and settings, and
      overall satisfaction.

PMID- 10358807
TI  - Employee reactions to managed care.
AB  - Employee reactions to managed care get less managerial and research attention
      than organizational reactions to it. This article examines the manner in which
      health services employees react to managed care and finds that their reaction
      affects perceived job insecurity, organizational commitment, and job
      satisfaction. Organization-based self-esteem, role conflict, and supervisory
      support moderate these relationships. The managerial implications of these
      findings are discussed.

PMID- 10358808
TI  - Attitudes of organized labor officials toward health care issues: an exploratory
      survey of Alabama labor officials.
AB  - Delegates to the Alabama AFL-CIO Convention were surveyed concerning their
      attitudes toward their health benefits and various options for health care
      reform. Most are satisfied with their current health care coverage, but
      dissatisfied with its high costs. Participants attribute the high costs to
      providers' pricing policies and insurance companies' overhead.

PMID- 10358809
TI  - Risk-sharing integration efforts in the hospital sector.
AB  - The extent of hospital involvement in integrated delivery systems (IDSs) during
      1996 was assessed by a national sample of 235 short-term private general
      hospitals. Two out of five hospitals were participating in networks with some
      financial risk sharing, and another third reported membership in IDS networks
      without financial obligations. Managed care's presence was the only significant
      factor moving hospitals from a stand-alone status to network membership. The
      decision to share financial risk was influenced not only by managed care
      pressures, but also by the level of local hospital competition and the severity
      of the inpatient case mix.

PMID- 10358810
TI  - Hyphema in a neonate.

PMID- 10358811
TI  - CMV retinitis in two 10-month-old children with AIDS.

PMID- 10358812
TI  - Avulsion of the optic disc after a blow to swimming goggles.

PMID- 10358813
TI  - Adjustable sutures in pediatric ophthalmology and strabismus.

PMID- 10358814
TI  - Surgical technique, visual outcome, and complications of pediatric intraocular
      lens implantation.
AB  - PURPOSE: To evaluate retrospectively the surgical technique, visual outcome, and
      complications of pediatric cataract extraction (CE) and intraocular lens (IOL)
      implantation. METHODS: Forty-three patients ages 2 to 12 underwent CE with IOL
      implantation with a minimum follow up of 1 month. RESULTS: All IOLs were
      implanted in the posterior chamber with 17 (40%) in the bag, 25 (58%) sulcus
      fixated, and one (2%) partially in the bag (one haptic in the bag, one in the
      sulcus). Primary posterior capsulectomy was performed in 12 (28%) cases. A final
      visual acuity of at least 20/40 was achieved in 26 (60%) and at least 20/80 in 32
      (74%). Posterior capsule opacification developed in 18 (42%) and pupillary
      capture in 7 (16%). Seventeen (40%) patients had postoperative visual acuity
      worse than 20/40. Of these, nine (53%) had this visual outcome as a result of
      presumed amblyopia. CONCLUSIONS: Posterior chamber IOL implantation affords a
      safe and effective method of visual rehabilitation for cataractous children 2
      years of age and older. Amblyopia and antecedent posterior segment trauma, rather
      than IOL-related or surgical complications, are the limiting factors in final
      visual outcome.

PMID- 10358815
TI  - Low-dose methotrexate in the treatment of severe juvenile rheumatoid arthritis
      and sarcoid iritis.
AB  - OBJECTIVE: To assess the efficacy of low-dose oral methotrexate (MTX) therapy for
      children with severe iritis. METHODS: MTX in a weekly dose of 7.25 to 12.5 mg/m2
      was administered orally to four patients (two with juvenile rheumatoid arthritis
      [JRA] and two with sarcoidosis) with severe iritis not adequately controlled by
      topical and systemic corticosteroid therapy. The treatment was initiated with
      half of the total dose and increased every 2 weeks until the final dose was
      reached. Iritis was graded from 0 to +4 according to the density of cells in the
      anterior chamber of the eye. RESULTS: There were three girls and one boy with a
      mean age of 10.5 years. Two patients were African American and two were
      Caucasian. The mean age at onset of iritis was 6 years. The mean duration of MTX
      therapy was 28.8 months. Significant improvement was noted in two of the four
      patients in ocular inflammation, demonstrated by reduction of cell density from
      +4 to +1. Two patients had a mild improvement of the iritis. However,
      corticosteroids were significantly reduced in all patients. One patient was
      completely off steroids within 30 months of MTX therapy. In the remaining three
      cases, the steroid dose was successfully tapered from 0.82 mg/kg/d to 0.15
      mg/kg/d (mean doses) within a mean duration of 20 months. No side effects were
      observed with MTX therapy. CONCLUSION: Low-dose MTX therapy was effective and
      safe, and displayed steroid-sparing properties in four children with severe
      iritis.

PMID- 10358816
TI  - Intraocular lens implantation in children and youth.
AB  - PURPOSE: To evaluate the safety and the effectiveness posterior chamber
      intraocular lenses (PCIOLs) in children and youth with cataract. METHODS:
      Retrospective study of operative and postoperative results was based on 146 eyes
      in 125 children ages 6 to 18 years (mean: 11.7 years) who underwent extracapsular
      cataract extraction with IOL implantation in the period from 1986 to 1996. Follow
      up was 1 to 10 years. OUTCOME MEASURE: Best corrected distance and near visual
      acuity, operative complications, and early and late postoperative complications.
      Exclusion criteria were uveitis, retinal detachment, prior glaucoma, and systemic
      diseases. RESULTS: Early postoperative complications were observed in 12.3% of
      cases including iritis in 7.5%, and transient corneal edema in 3.4% of eyes.
      Posterior capsule opacification requiring capsulotomy was needed in 81.5% of eyes
      after 8.5 years. YAG laser capsulotomy was performed in 68.1% and surgical
      intervention in 26.8% of cases. In 5.1% of the cases, both techniques were used.
      In 74.7% of patients, best corrected visual acuity of 0.5 or better was achieved.
      The mean postoperative spherical equivalent was +0.35 diopters (D, SD 1.35).
      Spectacle-corrected near visual acuity of 0.5 on the Snellen chart was obtained
      in 82.8% of eyes. CONCLUSION: IOL implantation in children older than 6 years
      appears to be an efficacious, satisfactory, and safe procedure in the management
      of pediatric cataract.

PMID- 10358817
TI  - Treatment of epibulbar limbal dermoids.

PMID- 10358819
TI  - Neisseria meningitidis endogenous endophthalmitis: case report and literature
      review.

PMID- 10358818
TI  - A case of complicated strabismus in a child with an orbital floor fracture.

PMID- 10358820
TI  - Surgical technique: horizontal muscles recession, variant technique.

PMID- 10358821
TI  - Congenital nystagmus associated with multiple congenital anomalies of the
      extraocular muscles.

PMID- 10358822
TI  - Use of the Pierse procedure to treat congenital upbeat nystagmus with a chin-up
      head position.

PMID- 10358823
TI  - Pediatric meningococcal conjunctivitis.

PMID- 10358824
TI  - Benign paroxysmal tonic upgaze of a child with positive MRI findings.

PMID- 10358825
TI  - [F wave occurrence in patients after stroke].
AB  - F wave parameters are connected with spinal motoneuron excitability. In view of
      this, the authors performed the study of the evolution of that response in 30
      patients after cerebral stroke in three subsequent periods: I--1st or 2nd day, II
      -14th or 15th day, III--5 to 6 weeks after stroke. We found F wave occurrence to
      be reduced in the first period after stroke; subsequently its parameters
      increased greatly. Changes of F wave parameters could be observed earlier than
      changes of clinical status, especially of muscle tonus.

PMID- 10358826
TI  - [Is there true remission in myasthenia gravis? Long-term clinical and
      electrophysiological studies].
AB  - Twenty myasthenic patients were followed up who had in the years 1981-1982 full
      clinical remission (no drugs, no symptoms), lasting at that time at least several
      years. However, in 19 of them neuromuscular transmission defects were then found
      by single fibre electromyography (SFEMG). We then concluded that true remissions
      did not exist in myasthenia (J. Neurol., 1985, 231, 331). Recently, we were able
      to evaluate those patients. One patient, who had full long lasting remission
      after thymomectomy, died at the age of 69 of myocardial infarction in the course
      of a myasthenic relapse. Another patient had a relapse, 20 years after thymoma
      extirpation. Two patients had recurrent fluctuating relapses of myasthenia. One
      patient, who had undergone thymectomy in his childhood, developed immune
      thrombocytopenic syndrome. SFEMG done in 12 patients showed abnormalities in 5
      cases only (mean jitter elongation, increased percentage of potential pairs with
      blocking and jitter elongation more than 55 microseconds). In 7 remaining
      patients the catamnesis covering more than 14 years revealed full clinical and
      electrophysiological remission. Thus, repeated analysis of the group of
      myasthenic patients with remission has lead us to revise our former opinion that
      there are no true remissions, clinical and electrophysiological, in myasthenia.
      They certainly occur but in some patients normalization of the
      electrophysiological pattern appears only several years after they have become
      clinically asymptomatic.

PMID- 10358827
TI  - [The evaluation of central visual fatigue in computer terminal users by visual
      evoked potentials].
AB  - Visual evoked potentials (VEPs) were recorded in a group of 20 operators aged 25
      45 years during two sessions, before and after a 5-hour work at computer
      terminals, in order to assess visual system fatigue. The outcomes were referred
      to the norms established for the age-matched population of 30 subjects not
      exposed to professional contact with computers. Most of the examined operators
      suffered various complaints concerning not only the organ of vision but the
      central nervous system as well. VEPs were elicited by means of monocular
      stimulation using the reversal checkerboard pattern and recorded simultaneously
      from the scalp electrodes placed over the right and the left cerebral hemisphere.
      Only recording acquired after finishing of a working day demonstrated significant
      statistically abnormalities of the VEPs waveforms, which suggests their transient
      character. The changes mentioned above included prolongation of peaks P100 and N2
      latency with concomitant attenuation of their amplitudes and a decrease of the
      correlation coefficient values for the recordings from the hemispheres. The
      preliminary findings presented in this paper seem to justify a conclusion that
      the non-invasive VEPs method can be considered as the objective indicator of the
      central visual fatigue induced by the workload at computer terminals.

PMID- 10358828
TI  - [Concentration of magnesium in serum and cerebrospinal fluid in patients with
      stroke].
AB  - Magnesium concentration in blood serum and cerebrospinal fluid (CSF) was
      determined in 131 patients aged from 21 to 91 years, with RIND, complete stroke,
      cerebral haemorrhage and control group. Magnesium was estimated by the use of
      colorimetry and the method of Mann and Yoe. The results are presented in figures.
      Statistical evaluations revealed significant decrease of magnesium concentrations
      in blood serum and CSF in ischaemic stroke compared with control group. In
      complete stroke significantly lower concentrations of magnesium in blood serum
      and CSF were found compared with RIND. In ischaemic stroke higher MgSER/MgCSF
      index was found compared with control group. Magnesium concentration in blood
      serum was not statistically different within 2 weeks of the disease. No
      relationships were found between blood serum or CSF Mg concentrations and gender
      or age.

PMID- 10358829
TI  - [Effect of hypothermia on lactate acidosis in experimental ischemia of rat
      brain].
AB  - The aim of the work was to evaluate the effect of hypothermia on lactate level in
      the rat cerebral ischaemia. Adult male Wistar rats were subjected to injection of
      0.05 ml of air into the ligation of left common carotid artery. Lactate level
      increased in cerebral hemispheres after 4 hours following air emboli. Mild
      hypothermia (28 degrees-31 degrees C) continued for 4 hours of cerebral
      ischaemia, and its beneficial effect was observed. A statistically significant
      decrease of lactate concentration was noted. The above phenomenon was confirmed
      by the increase of cerebral acidosis after 24 hours when mild hypothermia was
      interrupted from the 4th hour of the experiment on. It seems to be of a great
      importance to adjust proper time of initiation and a duration of hypothermia in
      cerebral ischaemia treatment.

PMID- 10358830
TI  - [The effect of coenzyme Q10 on lactate acidosis at the beginning of experimental
      cerebral ischemia in rats after the use of endothelin 1 (preliminary results)].
AB  - The aim of the work was to evaluate effect of CoQ10 on the lactate level in the
      rat brain after administration of Et-1. Fifty-three male Wistar rats
      (approximately 220-250 g) were used in the experiment. The animals were divided
      into four groups. 1. control; 2-4 under chloride hydrate anaesthesia, the rats
      were subjected to stereotaxic injection into right cerebral lateral ventricle: 2.
      1 microliter Ringer's solution (control) and i.p. 0.5 ml of soybean oil, 3. 10
      pmoles Et-1 diluted in 1 microliter Ringer's solution and i.p. 0.5 ml soybean
      oil, 4. 10 pmoles Et-1 diluted in 1 microliter Ringer's solution and i.p. 10
      mg/kg of the body weight CoQ1O (Sigma). Right and left hemispheres were taken
      after one hour, 4 and 24 hours and the lactate level was assayed by an enzymatic
      method. Et-1 evoked a significant increase of lactate level at all experimental
      time intervals. CoQ10 reduced lactate acidosis after 24 hours from the
      administration of Et-1. The above phenomenon can be explained among other by an
      improvement of the cellular respiratory activity. CoQ10 represents very important
      electron transporter from flavins to cytochromes in the respiratory chain.
      Therefore CoQ10 can be used for prevention and treatment of ischaemic insult in
      human cases.

PMID- 10358831
TI  - [Assessment of blink reflex in hemiparetic patients after stroke].
AB  - Blink reflex (BR) was evaluated in a group of 50 hemiparetic patients after
      stroke with lesions localized in cerebral hemispheres and in a group of 12
      healthy controls. The response was examined and compared, after stimulation of
      the supraorbital nerve, on both paretic and "healthy" side in affected patients.
      Abnormalities of BR were observed in late response only. The damage of one
      hemisphere affects the BR bilaterally. We found prolongation of latency and
      decrease of amplitude of late responses bilaterally when stimulating the
      supraorbital nerve of the paretic side. On the contrary, stimulation of the
      "healthy" side evoked similar abnormalities mainly contralaterally.

PMID- 10358832
TI  - [Selective denervation of neck muscles in the treatment of spasmodic torticollis.
      Preliminary results].
AB  - The authors present a review of the methods of surgical treatment of spasmodic
      torticollis, particularly the selective denervation of cervical muscles. Based on
      the literature and own experience cases treated by means of this method are
      described. Using selective ramisectomy it is possible to attain permanent
      improvement in most patients suffering from spasmodic torticollis, with very low
      complication rate. Our preliminary cases indicates that this method of treatment
      allows to acquire improvement of quality of life in patients with this particular
      type of dystonia.

PMID- 10358833
TI  - [Advances in diagnostic procedures and treatment of spinal neoplasms].
AB  - In the years 1958-1995 in the Department of Neurosurgery in Bydgoszcz we treated
      operatively 160 patients (100 men and 60 women aged 5-81 yrs) with spinal tumours
      causing spinal cord compression. Our material was useful in estimating the
      evolution in diagnostic procedures, treatment and limit of contraindications to
      surgery. We utilized previously analyzed patients' data from the years 1958-1987
      (100 patients) and compared this with results from the years 1988-1995 (60
      patients). In the years 1988-1995 we operated on twice as many patients per year
      than in the period 1958-1987 owing to better diagnostic and operative procedures
      and decrease of contraindications to treatment. In about 60 percent of patients
      the tumours were totally and subtotally removed. In recent period we performed 10
      initial procedures of transpedicular stabilization. In most cases the
      extensiveness of tumours did not reach the level of three spinal segments. We
      confirmed good early results of treatment, particularly in cases with total
      resection of tumours, in about half the patients with spinal neoplasm, although
      the most common histological diagnoses were carcinoma (89 cases). In thirty
      percent of cases with carcinoma only pain was diminished.

PMID- 10358834
TI  - [Influence of coexisting pseudo-radicular syndrome on the results of traction
      treatment in cases of lumbar intervertebral disk hernia].
AB  - 105 patients with lumbar disc disease, confirmed by radiculography, magnetic
      resonance imaging or computed tomography were investigated to evaluate the
      influence of pseudoradicular syndrome on therapeutic effects. On the basis of
      characteristic clinical symptoms of radicular and pseudoradicular syndrome
      patients were divided into two groups: 45 patients with dominant pseudoradicular
      syndrome and 35 persons with dominant radicular syndrome. All patients underwent
      clinical examination before and after traction treatment. Clinical evaluation
      included: the pain syndrome, postural disturbances and nerve root dysfunctions.
      The effects of the traction treatment were significantly worse in patients with
      the pseudoradicular syndrome. These results suggest the necessity of differential
      therapeutic approach in lumbar disc disease patients depending on the
      predominance of the pathomechanism of disease.

PMID- 10358835
TI  - [The usefulness of lumbar infusion test in the evaluation of the intracranial
      volume pressure compensation in hydrocephalus before and after shunt insertion].
AB  - The analysis is presented of selected parameters of the lumbar infusion tests
      performed in hydrocephalic patients before and after shunt. In properly
      functioning shunt (50 cases) the mean values of the variables are on an average
      twice lower than before shunt. In patients with shunt malfunction (surgically
      verified in 7 out of 10 suspected cases) the values of the parameters are similar
      before and after shunt and are statistically significant. Lumbar infusion test is
      proved very useful in the detection of shunt malfunction, particularly when it is
      possible to compare it to the test performed before shunt.

PMID- 10358837
TI  - [The role of cell adhesion molecules in certain neurological diseases].
AB  - Current data on the role of cell adhesion molecules (CAMs) in the pathophysiology
      of laboratory animal and human neurological diseases are presented.
      Classification of CAMs is given in short-Immunoglobulin (Ig) superfamily,
      selectins and integrins. Ig superfamily includes among others ICAM-1, 2, 3; VCAM
      1; PECAM-1. They are glycoproteins located in cellular membrane of different cell
      types, e.g.: endotheliocytes, leucocytes. They facilitate leucocyte passage
      across the blood barrier into inflammatory tissues. We distinguish native forms
      of CAMs (linked with mother cell membrane) and soluble forms found in different
      body fluids. Expression of CAMs is increased in many neurological diseases as
      well as the elevation in the concentration of their soluble forms in blood or
      cerebrospinal fluid. Selections also play a role in creating interactions
      leucocyte-endothelium while integrins serve as a receptor for Ig superfamily
      molecules. In this article we present current views on the role of native forms
      of CAMs as a necessary factor for leucocyte extravasation and the role of soluble
      forms as an agent in negative feedback for leucocyte passage through the blood
      brain barrier to inflammatory brain or peripheral nerves. We consider its
      significance for future treatment of neurological diseases as well.

PMID- 10358836
TI  - [Neurological disorders of vitamin B12 deficiency].
AB  - It is almost two hundred years since the description of the first neurological
      disorders in vitamin B12 deficiency. In spite of that, not all the aspects of the
      biological effect of the vitamin have been explained. It is well known, that the
      vitamin performs an important function in organic metabolism and two types of
      biochemical reactions depend on it. The haematological, gastrological and
      neurological disorders are the result of deficiency of that vitamin. This article
      deals with the neurological disorders--subacute degeneration changes of the
      spinal cord, polyneuropathy and psychical disorders--which accompany vitamin B12
      deficiency. It also presents aetiology, epidemiology, clinical symptoms,
      pathomorphology and it describes the deviations which occur in accessory
      investigations. The authors pay special attention to the abnormalities which can
      occur in neurophysiological and imaging examinations made by neurologists. They
      concentrate on the problems of the differences, especially between multiple
      sclerosis and subacute degeneration. The article presents the treatment of
      neurological disorders with regard to different authors' opinions. The importance
      of the early diagnosis and treatment till regression of pathological symptoms has
      been particularly stressed.

PMID- 10358838
TI  - [Clinimetrics in parkinsonism].
AB  - Clinimetrics, which has been developed beginning from stroke scales, nowadays is
      used in evaluation of many other diseases. It is needed as well for evaluation of
      impairment and functional state as for clinical assessment of new drugs. Lately
      one can observe shifting of attention to psychosocial issues. In this paper the
      most commonly used scales for evaluation of impairment, activities in daily
      living and quality of life in parkinsonism have been critically presented. Those
      scales are reliable and valid in the assessment of treatment, prognosis,
      classification of invalidity and social care decisions.

PMID- 10358839
TI  - [Progressive supranuclear palsy, diagnostic problems in the light of own case].
AB  - A case is reported in which the neurological findings and disease course meet
      fully the criteria of the possible progressive supranuclear palsy. The authors
      discuss the principles of clinical diagnosis of the syndrome, characteristic
      oculomotor disturbances and parkinsonian syndrome especially pronounced in this
      disease in the muscles of the nape, trunk and upper extremities. The main
      features of neuropathological changes are described fibrillary degeneration and
      atrophy of neurons in midbrain and pons, with accumulation of tau protein in the
      neurons and astrocytes in the areas involved by the process.

PMID- 10358840
TI  - [Cortico-basal degeneration. Diagnosis and differentiation and the description of
      the first case in Poland].
AB  - Idiopathic Parkinson Disease accounts for approximately 75% of all cases of
      parkinsonism. The described case of Corticobasal Degeneration (CBD), until now
      not presented in Polish medical literature is a relatively rare example of so
      called "parkinson plus" syndrome. The authors present the case of a 56 years old
      woman with asymmetric onset of rigidity and atypical tremor of upper extremity
      followed by gait disturbances (gait apraxia), dysarthria, bilateral pyramidal
      signs and myoclonus. Complete lack of clinical improvement after treatment with L
      dopa and progressive character were observed from the onset of the disease. The
      presented case seems to be helpful in differential diagnosis of parkinson plus
      syndromes and specially CBD, which seems to be difficult in the first stages of
      the disease. Although the case was not neuropathologically verified (patient is
      still alive) the diagnosis seems to be almost true.

PMID- 10358841
TI  - [Multi-system atrophy or symptomatic orthostatic hypotension].
AB  - The authors describe a case of a 74-year-old patient with orthostatic hypotension
      syndrome. They discuss the possible symptomatic or idiopathic mechanisms of the
      aetiology of this syndrome, taking into account their possible coincident.

PMID- 10358842
TI  - [Intracerebral hemorrhage following amphetamine use].
AB  - We describe a young male who suffered intracerebral hemorrhage (ICH) following
      nasal use of amphetamine. He recovered completely within several weeks of
      hospitalization. Angiography and MRI did not reveal vascular malformation and
      therefore we suspect that the ICH in our patient may be attributed to the effect
      of amphetamine alone.

PMID- 10358843
TI  - [Superior sagittal sinus thrombosis in anti-phospholipid syndrome].
AB  - Authors show the case of the 16 old years patient who was admitted to the
      hospital with symptoms of rise intracranial pressure sign as pseudotumor cerebri.
      The cause of those symptoms was thrombosis of sinus sagitalis superior confirmed
      by MR. Clinical analysis and immunological examination gave a diagnosis of
      secondary antiphospholipid syndrome in the course of Systemic Lupus Erythematosus
      (SLE).

PMID- 10358844
TI  - [Selected problems of neurofibromatosis with presentation of a case of multiple
      intracranial and intramedullary tumors].
AB  - A case of neurofibromatosis type II in a 19-year-old man is described with
      clinical and neuroimaging (MRI) findings. The diagnostic criteria of
      neurofibromatosis type I (NF1) and type II (NF2) and the optimal management
      options are still controversial. The authors suggest that this patient fulfills
      criteria of neurofibromatosis type II as well as partially neurofibromatosis type
      I. At present, without molecular analysis of DNA, this assumption can not be
      verified.

PMID- 10358845
TI  - [Type I Chiari malformation coexisting with syringomyelia: pathogenesis,
      treatment choice and prognostic factors for remote outcome in the light of own
      case].
AB  - The Chiari malformation, condition characterized by herniation of posterior fossa
      contents below the level of foramen magnum coexists very often with solitary or
      multiple syringomyelic cysts in spinal cord. The authors, on the basis of current
      opinions presented in literature and an own case present considerations
      concerning pathogenesis, operative procedures and prognostic factures which are
      of value in prediction of long-term outcome in patients which Chiari type I
      Syringomyelia complex. The presence or absence of three preoperative signs as:
      muscular atrophy, ataxia and scoliosis facilitate, with confidence of 95%,
      prediction of long-term postoperative result. Preoperative incidence of all three
      above signs is much less favourable for outcome. In the presented case all
      unfavourable signs were observed preoperatively and, despite of good MRI-result,
      long-term outcome was only fair.

PMID- 10358846
TI  - [Intraoral surgical approach to tumors destroying the axis. Report of three
      cases].
AB  - Primary and metastatic tumours of the axis vertebra are difficult surgical
      problems. The authors report 3 patients with axis tumours who underwent surgery
      in 1993 and 1994. Clinical symptoms and signs included pain in three, myelopathy
      in two, vertebrobasilar circulatory insufficiency and cranial nerve lesions in
      two patients. Tumours have been resected through transoral and posterior
      pharyngeal wall approach. The purpose of surgery was decompression of nervous and
      vascular structures, and histological verification of the tumour. Tumour
      pathology was diverse and included: multiple myeloma, chordoma and metastatic
      tumour from stomach. There were no postoperative complications and improvement of
      neurological conditions was observed.

PMID- 10358847
TI  - [A case of cerebrospinal rhinorrhea complicated by pneumo-encephalocele 25 years
      after head trauma].
AB  - The authors present a case of a 76 years old man with cerebrospinal rhinorrhoea
      and pneumoencephalocele, 25 years after head trauma. In their opinion all cases
      of cerebro-spinal fluid fistulas must be treated surgically.

PMID- 10358848
TI  - [Report on the Scientific Training Conference on "Rehabilitation of Patients with
      Neurological Complications in Diabetes"].

PMID- 10358849
TI  - [Letter regarding the paper of K Czyzewski, A. Pffefer, M. Barcikowska published
      in N.Nch Pol., vol. 32, No. 1, pg. 125].

PMID- 10358850
TI  - A guest editorial from abroad: meditations on a nightmare of modern midwifery:
      shoulder dystocia.

PMID- 10358851
TI  - Management of cervical cerclage after preterm premature rupture of membranes.
AB  - The optimal management of preterm premature rupture of membranes (PPROM) in a
      patient with a cerclage is controversial. The issues are whether the latency
      period between rupture of membranes and delivery is decreased if the cerclage is
      removed and whether there is an increased rate of maternal or neonatal infection
      if the cerclage is kept in place. The data are sparse in directing management of
      women with prophylactic cerclages placed earlier in their pregnancies who rupture
      membranes. Latency seems to be increased if the cerclage is kept in place, but
      maternal and neonatal infectious morbidity is increased also. In women at early
      gestational ages, keeping the cerclage in place may be warranted until labor
      ensues. In more advanced gestations, it seems preferable to immediately remove
      the cerclage upon diagnosis of PPROM.

PMID- 10358852
TI  - Focus on primary care diagnosis and management of headache in women.
AB  - Women experience unique changes in headache pattern related to changes in their
      reproductive cycles. Changes predictably occur in association with menarche,
      menstrual cycling, the use of oral contraceptives, pregnancy, and menopause.
      These predictable headache changes are linked to changing levels of sex hormones.
      This article describes important relationships between estradiol and
      neurotransmitters involved in the pathogenesis of headache, such as serotonin.
      Treatment of headache in women includes the use of acute care and preventive
      treatments. The effectiveness of both medication and nonmedication treatments is
      reviewed. Also, unique aspects of treating headache with menstruation, pregnancy,
      and menopause are described.

PMID- 10358853
TI  - Polycystic ovary syndrome: clinical perspectives and management.
AB  - The polycystic ovary syndrome (PCOS) is a common hyperandrogenic disorder and is
      characterized by a constellation of signs and symptoms often in association with
      a family history of hyperandrogenism and/or PCOS. It is often associated with
      hyperinsulinism and insulin resistance, which puts patients at risk for possible
      potential complications including type 2 diabetes mellitus and cardiovascular
      disease. Clinical signs may be subtle, and biochemical markers most often include
      an elevation of free testosterone (T) and possibly dehydroepiandrosterone sulfate
      (DHEAS). The diagnosis should be sought in any woman with hyperandrogenic
      features so that appropriate treatment may be used. There is often a good
      therapeutic response of the hirsutism, acne, or oligomenorrhea associated with
      PCOS. The new modalities that increase insulin sensitivity as well as weight
      reduction in the obese woman with PCOS may potentially be useful in modifying the
      potential later complications of this common endocrinopathy of young adult women.

PMID- 10358854
TI  - [Non-invasive instrumental diagnosis of central, peripheral and cerebral
      circulation in essential hypertension].

PMID- 10358855
TI  - [Diagnostic role of lungs electric probing].
AB  - AIM: Basing on the data of spot electric probing (SEP), to derive principles
      underlying changes in conduction characteristics of pulmonary tissue in various
      diseases. MATERIALS AND METHODS: Dynamic SEP of the lungs was made with 4
      electrodes in 72 patients with pulmonary diseases. Two parameters were
      considered: resistivity and frequency variability of resistivity. RESULTS: SEP
      was effective in detection of lung tissue airiness and thickening, accumulation
      of pleural fluid. The use of a novel parameter--frequency variability of
      resistivity--raises diagnostic potential of electric probing. CONCLUSION: SEP is
      an informative method in diagnosis of respiratory diseases. Thus, it holds
      promise for clinical practice.

PMID- 10358856
TI  - [Role of respiratory function tests in differential diagnosis of respiratory and
      cardiac insufficiency].
AB  - AIM: To examine feasibility of using a complex of functional tests for detection
      of chronic respiratory insufficiency (CRI) and its differential diagnosis with
      chronic cardiac failure (CCF). MATERIALS AND METHODS: The study covered 23
      patients with chronic obstructive pulmonary diseases (COPD) and 17 patients
      suffering from ischemic heart disease (IHD) with stable effort angina class II
      III. RESULTS: Different response to the tests of pulmonary gas exchange and
      hemodynamics was noted in COPD and IHD. In hypoxia, oxygen consumption rate
      ranged from 140 to 108% while in IHD this rate reached 106% only in one case.
      COPD patients had increased minute respiratory volume in hyperoxia contrary to
      patients with IHD. In hypoxia, the picture was quite opposite, the differences
      being less obvious. CONCLUSION: Functional respiratory tests provide significant
      differentiation between CRI and CCF.

PMID- 10358857
TI  - [Differential diagnosis of obstructive and central sleep apnea in
      polysomnographic investigation].
AB  - AIM: To try validity of polysomnography in differential diagnosis of obstructive
      and central sleep apnea (SA). MATERIALS AND METHODS: A retrospective analysis was
      made of 138 cases of sleep apnea (SA) subjected to polysomnography. 79 of them
      were treated with continuous positive pressure. RESULTS: In clinical practice it
      is rather difficult to distinguish between central and obstructive SA. In this
      respect, polysomnography was also unreliable as it is predisposed to
      hyperdiagnosis of central SA. CONCLUSION: In SA diagnosis, polysomnography should
      be used in combination with other diagnostic methods. In indeterminate diagnosis,
      a test course of the positive pressure is recommended to exclude obstructive SA.

PMID- 10358858
TI  - [Variants of unstable angina pectoris in the light of current views of
      endothelial damage].

PMID- 10358859
TI  - [Clinical and instrumental diagnosis of cardiac affection in patients with toxic
      diphtheria].
AB  - AIM: To specify myocardial affection in adult patients with toxic diphtheria
      (TD). MATERIALS AND METHODS: Along with routine clinical examination 150 patients
      with toxic diphtheria underwent ECG, echo-CG and biochemical tests. 22, 81, 26,
      14 and 7 patients had subtoxic TD, toxic form of the first degree, second degree,
      third degree and hemorrhagic TD, respectively. RESULTS: Myocardial impairment in
      TD develops very early, but is diagnosed in different time depending on the
      diagnostic technique. Early signs of myocardial involvement are activation of
      cardiospecific enzymes and echo-CG changes. Poor myocardial prognosis in TD is
      predetermined by progressive cardiac failure (primarily right ventricular),
      marked conduction disorders, diminished contractility, hyper- or hypoactivity of
      cardiospecific enzymes. CONCLUSION: The knowledge of myocardial affection
      variants in TD enables the clinician not only to predict the disease course but
      to conduct more adequate therapy resultant in less numerous lethal outcomes of
      toxic TD.

PMID- 10358860
TI  - [Two cases of diagnosis of family hypertrophic cardiomyopathy].

PMID- 10358861
TI  - [Myocardial hypertrophy and coronary insufficiency as a cause of arrhythmia in
      patients with hypertension].
AB  - AIM: To elucidate contribution of left ventricular hypertrophy (LVH) vs
      myocardial ischemia to rhythmic disorders in patients with essential hypertension
      (EH) and LVH. MATERIALS AND METHODS: Echocardiography, coronarography, treadmill
      test, 24-h ECG monitoring were included in examination of 69, 69, 68 and 63
      patients, respectively. All of them had EH stage II and LVH. The comparison was
      made between the groups composed by LVH degree and by the presence or absence of
      coronary artery atherosclerosis (CAA). RESULTS: Subjective arrhythmia was
      recorded in 27% of the examinees, while objective one was registered by 24-h
      monitoring and treadmill test in 85.7 and 42.6% of the patients, respectively.
      Ventricular arrhythmia in EH stage II patients with LVH is associated for the
      most part with coronary insufficiency, often in the presence of atherosclerosis
      of the coronary artery. High-grade ventricular extrasystoles by B. Lown and M.
      Wolf and LVH degree were related. CONCLUSION: An essential role in the onset of
      supraventricular arrhythmia (SVA) in EH stage 2 patients with LVH belongs to the
      size of the left atrium and LVH degree. SVA is related to left ventricular
      myocardial ischemia.

PMID- 10358862
TI  - [Diovan efficacy and tolerance in mild and moderate hypertension].
AB  - AIM: To study clinical effectiveness and tolerance of diovan, a new angiotensin
      II antagonist, in patients with mild and moderate blood hypertension (BH).
      MATERIALS AND METHODS: The trial included 20 patients (13 males and 7 females)
      aged 35-60 years with mild and moderate BH. All the patients received diovan
      (valsartan) for 8 weeks in a dose 80 mg/day. If the hypotensive effect was
      inadequate, the dose was increased to 160 mg/day. RESULTS: 2-week treatment with
      diovan brought a significant fall of both systolic and diastolic blood pressure.
      In 8 weeks the hypotensive effect enhanced. Lowering of diastolic BP to 90 mm Hg
      or at least by 10% was achieved in 90% of the patients. Tolerance was good,
      unfavorable metabolic shifts were absent. CONCLUSION: Diovan proved to be
      effective and safe in therapy of patients with mild and moderate BH.

PMID- 10358863
TI  - [Infectious endocarditis: immune disorders, differentiated therapy].
AB  - AIM: Immunological assessment of variants of infectious endocarditis (IE) and
      design of differentiated approach to the disease therapy. MATERIALS AND METHODS:
      Of 150 patients treated (90 males and 60 females, mean age 41.9 +/- 3.3 years)
      28.7% and 71.3% had primary and secondary endocarditis, respectively. With
      chronization of the process, there was a trend to growing immune unbalance (IU).
      RESULTS: The IU in IE patients manifested with leukocytosis changing for
      leukopenia, reduced absolute and relative number of lymphocytes, complement, T-
      and B-lymphocytes, growing content of CIC, IgM, rheumatoid factor and
      cryoproteins. CONCLUSION: Besides antibacterial therapy, IE patients need
      immunocorrective and efferent therapy.

PMID- 10358864
TI  - [Concentration of heavy elements and their compounds in the cells from BALF and
      pulmonary tumors in radiation-exposed subjects].
AB  - AIM: Measurement of heavy elements in alveolar macrophages (AM) of
      bronchoalveolar lavage (BAL) and pulmonary tumor tissue (PTT); investigation of
      spacial distribution of the heavy particles in the tissues. MATERIALS AND
      METHODS: Laser mass-spectrometry estimated quantitative and qualitative
      characteristics of heavy elements (Mn, Fe, Co, Cu, Zr, etc.) in diagnostic and
      therapeutic BAL of 6 patients exposed to radiation after the Chernobyl accident
      and in pulmonary tumor tissue of patients operated for central small-cell and
      peripheral bronchoalveolar cancer who also had been exposed to radiation after
      the Chernobyl. RESULTS: Heavy elements concentration in the secondary BAL was
      less than in the primary one. This shows effectiveness of the procedures aimed at
      removal of heavy particles from the respiratory organs. Heavy elements content
      was quite different in two histologically different tumors. CONCLUSION: Laser
      mass-spectrometry proved its usefulness in simultaneous study of the quantity and
      quality of heavy elements in AM of BAL and tumors in radiation-exposed subjects,
      in investigation of the elements distribution in the pulmonary tissues and
      changes of elements composition in the tissues in the course of tumors
      development.

PMID- 10358865
TI  - [Lowering of resistance to oxidation of VLDL lipoproteins and some subfractions
      of LDL lipoproteins in patients with non-insulin-dependent diabetes mellitus].
AB  - AIM: To investigate composition of very low density lipoproteins (VLDLP) and some
      subfractions of low density lipoproteins (LDLP), and their resistance to
      oxidation in patients with non-insulin-dependent diabetes mellitus (NIDDM)
      varying in severity compared to healthy subjects. MATERIALS AND METHODS: 26 NIDDM
      patients and 16 healthy controls. VLDLP and subfractions of LDLP were isolated by
      ultracentrifugation. The lipoproteins were assayed for protein, cholesterol,
      initial products of lipid peroxidation (LPO). After autooxidation of
      lipoproteins, fluorimetry examined the degree of the oxidant modification.
      RESULTS: The initial level of LPO products was elevated in VLDLP and light
      subfractions of LDLP in severe and moderate NIDDM patients. Even in mild NIDDM,
      resistance to oxidation of dense LDLP subfractions was low and continued to
      decrease with aggravation of the disease. High ratio cholesterol/ protein
      occurred in VLDLP and subfractions of LDLP from patient with severe NIDDM.
      CONCLUSION: It is shown that subnormal resistance to oxidation of LDLP dense
      subfractions even in mild NIDDM is an informative diagnostic criterion of risk
      factor to develop atherosclerosis.

PMID- 10358866
TI  - [Importance of estimated value of T-cell activation in insulin-dependent diabetes
      mellitus].
AB  - AIM: To determine the role of estimated value HLA-DR+/CD19+ in patients with
      insulin-dependent diabetes mellitus (IDDM) in the course of the disease.
      MATERIALS AND METHODS: The number of CD+ and HLA-DR+ lymphocytes and the ratio
      HLA-DR+/ CD19+ were estimated in the peripheral blood of 70 IDDM patients aged 9
      47 years with the disease duration since the diagnosis 0-10. Indirect
      immunofluorescence with monoclonal antibodies was employed. RESULTS: The index
      HLA-DR+/CD19+ was normal in newly-diagnosed IDDM patients and tended to an
      increase with the disease aggravation. CONCLUSION: The index HLA-DR+/CD19+ can be
      used as an additional marker of T-lymphocyte activation, as a criterium of
      unfavorable IDDM course.

PMID- 10358867
TI  - [Changes in functional activity of blood neutrophils in pollenosis patients:
      effects of specific immunotherapy].
AB  - AIM: The study of effective and regulatory functions of neutrophilic granulocytes
      in patients with pollenosis exacerbation, correction of the impaired neutrophil
      function with standard treatment and specific immunotherapy (SIT). MATERIALS AND
      METHODS: The study included 103 healthy donors (controls) and 122 patients with
      pollenosis aggravation. 69 of the latter received symptomatic treatment. 53
      patients received preseasonal SIT with water-salt extracts of the pollen
      allergens. RESULTS: The untreated pollenosis patients had hyperproduction of
      interleukin-1 (IL-1) by nonstimulated blood neutrophils associated with elevation
      of NBT-reduction and lowering of phagocytic activity in decreasing count of Fc-
      and Ca-receptors. Effective SIT produced recovery of phagocytic activity, the
      number of Fc- and Ca-receptors, IL-1-activity of cell supernatants. CONCLUSION:
      One of the SIT targets in pollenosis patients is neutrophilic granulocytes.

PMID- 10358869
TI  - [Psychogenic factors and psychosomatic role of hyperfibrinogenemia].

PMID- 10358868
TI  - [Purgative drugs in therapy of constipation (lecture)].

PMID- 10358870
TI  - [Acoustic density of tissues: clinical significance in echocardiography].

PMID- 10358871
TI  - [Genetic aspects in pathogenesis and treatment of arterial hypertension].

PMID- 10358872
TI  - Export procedures: MAFF sets out its plans.

PMID- 10358873
TI  - Veterinary medicines: proposed legislation on record-keeping.

PMID- 10358874
TI  - Value of direct smears of synovial fluid in the diagnosis of canine joint
      disease.
AB  - Assessments of direct smears of synovial fluid by four clinicians were compared
      with the results obtained with a Coulter counter. Estimates of total white cell
      counts by the clinicians were inaccurate and generally higher than the Coulter
      counter results. The method had a low sensitivity and specificity for the
      identification of degenerative joint disease and normal joints in comparison with
      the identification of inflammatory joint disease. There were marked variations in
      the results obtained by the four clinicians for all the analyses in the study.

PMID- 10358875
TI  - Infection of gnotobiotic calves with Escherichia coli o157:h7 strain A84.
AB  - Six colostrum-deprived, hysterotomy-derived calves were maintained under sterile
      conditions and fed a milk replacer diet. At five days of age, five of the calves
      were dosed orally with 10(9) cfu of Escherichia coli O157:H7 strain A84. They
      were killed after, one, two, six, 12 and 24 days, and samples were taken for
      bacteriological and pathological examination. The sixth uninfected control calf
      was killed at seven days of age and matched samples were taken for pathological
      comparison. The animals remained normal throughout the observation period.
      Bacteriological data indicated a heavy bacterial load of strain A84 throughout
      the gastrointestinal tract but the bacterium was not found in liver, kidney or
      muscle. No evidence of 'attaching and effacing' lesions in the small or large
      intestine was found although there was a mild inflammatory response in the
      intestinal tract, consisting mainly of infiltrating eosinophils.

PMID- 10358876
TI  - Transfer of sulphamethazine from contaminated dairy feed to cows' milk.
AB  - Four groups of four healthy mid-lactation Friesian cows were fed a compound
      feeding stuff containing either 2, 10 or 250 mg sulphamethazine/kg, corresponding
      to 0, 2, 10 and 250 per cent of the therapeutic inclusion rate in rations for
      pigs, at a flat rate of 3 kg twice daily for 21 days, followed by a seven-day
      withdrawal period. The cows were machine-milked twice daily and pooled milk
      samples from each cow were analysed by a commercially available microbiological
      assay with a sensitivity of 100 micrograms/litre and by a high performance liquid
      chromatography (HPLC) procedure with a limit of detection of 10 micrograms/litre.
      No sulphamethazine was detected by HPLC in the milk samples taken from any of the
      cows fed the concentrate containing 2 or 10 mg/kg. The milk samples from all four
      cows fed the highest concentration of sulphamethazine contained from 21 to 120
      micrograms/litre while they were being fed the contaminated concentrate. The cow
      with the highest concentrations of sulphamethazine was the only one which
      repeatedly tested positive by the microbiological assay. The concentration of
      sulphamethazine declined rapidly during the withdrawal period and the drug was
      not detectable by either method in samples taken from two days after the
      contaminated feed was withdrawn.

PMID- 10358877
TI  - Acquired flexural deformity of the metacarpophalangeal joint in five horses
      associated with tendonous damage in the palmar metacarpus.
AB  - Five cases of acquired flexural deformity of the metacarpophalangeal joint (MCPJ)
      in older horses and ponies were studied. The mean age of affected horses was 14-8
      years. Four deformities developed following desmitis of the accessory ligament of
      the deep digital flexor tendon (ALDDFT) and superficial digital flexor tendon
      (SDFT) and one following tendonitis of the SDFT alone. All cases were markedly
      lame and demonstrated variable degrees of flexural deformity. Ultrasonographic
      examination was performed on all cases which revealed extensive adhesion
      formation between the ALDDFT and SDFT and reduced cross-sectional area of the
      deep digital flexor tendon in each case. A variety of treatments were
      unsuccessfully employed to treat this condition. The prognosis for acquired
      flexural deformity of the MCPJ in old horses following tendonous damage in the
      palmar metacarpus is likely to be poor.

PMID- 10358878
TI  - Actinobacillus seminis as a cause of abortion in a UK sheep flock.

PMID- 10358879
TI  - Rabbit haemorrhagic disease in Saudi Arabia.

PMID- 10358881
TI  - Outbreak of African horse sickness in the Cape Province of South Africa.

PMID- 10358880
TI  - Human exposure to Brucella recovered from a sea mammal.

PMID- 10358882
TI  - Findings in a fox rescued from hounds.

PMID- 10358883
TI  - Findings in a fox rescued from hounds.

PMID- 10358884
TI  - Findings in a fox rescued from hounds.

PMID- 10358886
TI  - Bovine tuberculosis: the Agriculture Committee reports on progress to date.

PMID- 10358885
TI  - Mastitis monitoring.

PMID- 10358887
TI  - Abattoir survey of acquired reproductive abnormalities in ewes.
AB  - Abnormalities of the reproductive tract of female sheep were studied by examining
      9970 reproductive tracts from cull ewes and 23,536 tracts from nulliparous sheep
      (prime lambs) over a period of 12 months in abattoirs in south-west England.
      Overall, 3.37 per cent of the tracts were pregnant (8.11 per cent of cull ewes,
      and 1.36 per cent of nulliparous sheep), with a peak incidence between September
      and December. A total of 655 ewes (6.57 per cent) and 459 nulliparous sheep (1.95
      per cent) had acquired abnormalities of the reproductive tract. Within these
      totals, abnormalities of the ovaries accounted for 3.51 per cent (for the ewes)
      and 10.68 per cent (for the nulliparous sheep) of all the abnormalities, and
      abnormalities of the ovarian bursa and uterine tube accounted for 42.1 per cent
      (for the ewes) and 5.23 per cent (for the nulliparous sheep). In addition,
      uterine lesions (hydrometra and metritis) accounted for 9.92 per cent (for the
      ewes) and 13.51 per cent (for the nulliparous sheep); lesions of the cervix and
      vagina (total of 1.44 per cent) and Cysticercus tenuicollis cysts associated with
      the reproductive tract (total of 3.05 per cent) were less common. Among the ewes
      the most common ovarian lesions were ovulation tags, and follicular cysts were
      the most common in nulliparous animals. Lesions such as bursitis, parametritis
      and abscesses of the reproductive tract were much more common in cull ewes than
      in nulliparous sheep, probably having arisen from peripartum infections.
      Hydrosalpinx and hydrometra, in which the intraluminal fluid was clear, were
      present at relatively high incidence in nulliparous animals, but not in cull
      ewes. The proportion of tracts containing macerated fetal remnants (2.14 per cent
      of all abnormalities in cull ewes) was lower than expected. It was considered
      that the functional significance of many of the lesions, such as ovulation tags
      and C tenuicollis cysts, was likely to be low, although in some cases of the
      latter calcification of the cyst had occluded the uterine tubes. Other lesions,
      notably hydrosalpinx, bursitis and metritis were likely to have made the affected
      animals sterile. The acquired abnormalities were therefore more significant in
      terms of individual animal infertility than as a major cause of infertility in
      flocks.

PMID- 10358888
TI  - Evaluation of a direct ELISA for the serodiagnosis of Oestrus ovis infections in
      sheep.
AB  - Oestrosis is a parasitic disease of sheep and goats caused by the nasal bot fly
      Oestrus ovis. In the United Kingdom the economic losses as a result of
      infestation can be considered negligible, but the differentiation of O ovis cases
      from more serious diseases such as listeriosis, gid and sheep scab is of
      considerable importance. Currently, diagnosis of oestrosis relies on the
      subjective observation of clinical signs or the demonstration of larvae
      postmortem. This paper assesses the effectiveness of a direct enzyme-linked
      immunosorbent assay (ELISA) using a crude somatic antigen from first-stage larvae
      (L1) in the serodiagnosis of oestrosis. The system has been validated with sera
      from both endemic and non-endemic areas and the results correlated with the
      clinical data found postmortem. The sensitivity and specificity of the assay were
      97.4 per cent and 97.6 per cent, respectively, using a cut-off point based on 35
      per cent binding of a reference positive control serum.

PMID- 10358889
TI  - Acute phase protein response of ewes and the release of PGFM in relation to
      uterine involution and the presence of intrauterine bacteria.
AB  - The rate of uterine involution postpartum was monitored in 13 suckling mule ewes
      by using radio-opaque markers and radiography, and each ewe was also monitored
      for intrauterine bacterial contamination during the first week, using a sterile
      guarded swab. Peripheral plasma or serum concentrations of haptoglobin,
      seromucoid, ceruloplasmin and 15-keto-13,14-dihydro-prostaglandin F2 alpha (PGFM)
      were measured up to six weeks postpartum. The maximum reduction in the length of
      the uterine body and in the diameters of the horns occurred by 28 days
      postpartum, except in one ewe in which the size of the uterus continued to
      decrease for 42 days. Four ewes were positive for intrauterine bacterial
      contamination; Escherichia coli, clostridial species, Staphylococcus aureus,
      Streptococcus uberis and Enterococcus species were isolated in pure or mixed
      culture. The presence of intrauterine bacteria did not affect the time for the
      completion of uterine involution. No bacteria were isolated from the ewe in which
      involution was delayed, but it had a different acute phase protein response and
      was therefore excluded from further analyses. In the remaining 12 ewes the mean
      postpartum haptoglobin response increased, with peak concentrations occurring on
      day 1, and decreased slowly as uterine involution progressed, but the four
      contaminated ewes had a significantly greater response. There was no difference
      between the prepartum and postpartum concentrations of seromucoid in the eight
      sterile ewes, but significant increases were observed in the contaminated group;
      the concentrations of ceruloplasmin did not vary in either group. The
      concentrations of PGFM were higher during the early postpartum period in the ewes
      with contaminated uteri.

PMID- 10358890
TI  - Levels of circulating plasma immune complexes after thiacetarsamide treatment in
      dogs naturally infected with Dirofilaria immitis.

PMID- 10358892
TI  - Isolation of Escherichia fergusonii in cases clinically suggestive of
      salmonellosis.

PMID- 10358891
TI  - Pyrrolizidine alkaloid poisoning in yak.

PMID- 10358893
TI  - Welfare of animals in quarantine.

PMID- 10358894
TI  - Displaced abomasum in dairy cattle.

PMID- 10358895
TI  - Generalised green discoloration of a beef carcase.

PMID- 10358896
TI  - [New data on acid-labile alpha-interferon].
AB  - Reviews the information on the new concepts about the composition and properties
      of abnormal alpha-interferon-alpha-acid-labile interferon (alpha-ALI) detected in
      the blood of patients with AIDS, autoimmune, and other diseases. alpha-ALI
      includes alpha- and gamma-interferon which is responsible for acid lability.
      Increased content of serum alpha-ALI and its acid lability are poor prognostic
      signs in AIDS. A decrease in these values, concomitant with clinical improvement
      in some autoimmune diseases, indicates involvement of alpha-ALI in the
      pathogenesis of these diseases. Activating effect of gamma-interferon in vitro is
      demonstrated on different models, including HIV infection of human vascular
      endotheliocytes. The effect of alpha-ALI in patients is apparently determined by
      the ratio of its components alpha- and gamma-interferons.

PMID- 10358897
TI  - [Use of monoclonal antibodies for studying the classical hog cholera virus].
AB  - Numerous monoclonal antibodies (MAb) to hog cholera virus are a highly specific
      and effective instrument for studies of this agent. Panels of MAb for
      differential diagnosis of Pestiviruses are characterized. International reference
      panel of 30 MAbs is a result of cooperation of European scientists; it was
      approved as the official reference for assessing all available and new diagnostic
      agents. MAb permit intraspecies differentiation between hog cholera virus strains
      and, which is particularly important, between vaccine and field strains. Study of
      antigenic structure and functional characteristics of surface proteins of the
      virus with the use of MAb panels helped single out and map the functions of four
      antigenic sites of surface glycoprotein E2 and detect a relationship between
      RNAse activity and structural component of another surface glycoprotein E0.

PMID- 10358898
TI  - [Antigenic specificity of recombinant polypeptides, containing fragments of
      hepatitis E virus proteins].
AB  - Antigenic specificity of recombinant polypeptides HE40 and HE60 containing
      fragments of gene ORF2 and ORF3 protein products of hepatitis E, strain Burma,
      produced in E. coli cells, is analyzed. Blood sera from patients with acute
      hepatitis from an endemic region in Uzbekistan were tested for IgG to recombinant
      antigens by solid-phase enzyme immunoassay with a protein fragment coded by PRF3
      gene, a synthetic peptide previously characterized in a commercial test system,
      as the positive control. 93% sera reacting with recombinant polypeptide HE60 and
      32% reacting with HE40 reacted with the synthetic peptide. No antibodies to the
      studied polypeptides were detected in the sera of Moscow patients with hepatitis
      A, B, or C confirmed by laboratory findings. Antigenic specificity of recombinant
      polypeptide HE60 was confirmed by competitive enzyme immunoassay with the same
      peptide as the competitive antigen. Test system based on recombinant polypeptides
      HE40 and HE60 was used for deciphering the etiological structure of acute viral
      hepatitis which occurred in a hepatitis E endemic region of Uzbekistan in 1993.

PMID- 10358899
TI  - [Formation of two types of a proteolytically cleaved nucleoprotein in cells,
      infected by influenza virus].
AB  - Two types of proteolytically cleaved influenza virus nucleoprotein (NP) are
      formed in cells infected with influenza virus. One, cell membrane-associated
      cleaved NP (C-NP), is heterogeneous in size and during analysis in PAGE is
      localized in the 53 kDa and less zone. Its formation depends on the species
      appurtenance of the infective virus and occurs only in viruses with a low
      efficacy of NP oligomerization. C-NP is incapable of intracellular
      oligomerization. The other type of cleaved NP, extracellular free (F-NP), is most
      likely a secreted product of intracellular proteolysis of 56 kDa NP. Its
      molecular weight is about 53 kDa. Its formation does not depend on the species of
      infective influenza virus and it is capable of intracellular oligomerization.

PMID- 10358900
TI  - [Sensitivity of white mice to influenza virus (A/Aichi/2/68) in aerogenic
      infection].
AB  - Polydispersed aerosols from allantoic fluid of chick embryos induced with
      influenza virus with different median weight aerodynamic diameters of corpuscles
      (0.5, 0.8, 1.1, 2.2, and 6.0 mu are effectively deposited in respiratory organs
      of mice weighing 18-19 g. The sensitivity of mice of different weight to
      aerogenic infection with influenza virus (strain A/Aichi/2/68) was virtually the
      same. The efficacies of aerogenic 50% infective and lethal doses (1.8-2.5 lg) for
      mice of the same weight were different. The sensitivity of mice to aerogenic
      infection and of developing chicken embryos to the virus (ID50 = EID50) is the
      same. Mice weighing 10-19 g can be infected via airways with adapted influenza
      virus in studies of therapeutic and prophylactic effects of drugs.

PMID- 10358901
TI  - [Strain-dependent disruption of the functional activity of bone marrow stromal
      cells from mice infected with influenza A].
AB  - Infection of mice with influenza A virus disturbs the proliferative activity of
      bone marrow stromal fibroblasts involved in regulation of bone marrow
      hemopoiesis. Myelosuppression induced by influenza A virus can be a result of
      dysfunction of bone marrow stromal tissue. Disorders in multiplication of bone
      marrow fibroblasts induced by influenza virus are strain-dependent.

PMID- 10358902
TI  - [Experimental study of residual virulence of viral vaccine strains].
AB  - Residual virulence of three vaccinia strains: Neurovaccine, L-IVP, and its
      recombinant Revacs-B expressing HBs and preS2 antigens of hepatitis B virus is
      compared. Insertion of HBs and preS2 antigens of hepatitis B virus in the genome
      of vaccinia virus strain L-IVP decreases its residual virulence and leads to a
      benign course of vaccinal reaction involving no deaths of rabbits, cotton rats,
      or guinea pigs. We may expect that recombinant vaccine Revacs B based on L-IVP
      strain will cause no postvaccinal complications under conditions of an
      appreciable decrease in population immunity to vaccinia virus.

PMID- 10358904
TI  - [Evaluation of the effectiveness of substance for diagnosing rotaviral infection
      under field conditions].
AB  - A universal mathematical approach (algorithm) to assessment of the efficacy of
      new preparations for the diagnosis of rotavirus infection, analysis and
      processing of the results involves assessment of the detection rate of infection,
      specificity of preparations, probability of positive and negative diagnoses,
      total index of coincidence of results of diagnosis with the reference method, and
      chi 2 and phi2 coefficients indicating the reliability of relation to the
      reference method and the strength of this relation. Diatest software is proposed
      for accelerating statistical processing of the results. Use of the algorithm and
      software permits assessing the efficacy of diagnostic agents for rotavirus and
      other infections.

PMID- 10358903
TI  - [Spread of hepatitis C and separate genotypes of hepatitis C virus in a region
      with a moderately active epidemic process].
AB  - The prevalence of hepatitis C virus (HCV) is studied in different age and risk
      groups in the city of Vladimir and the genotypes of the virus circulating at this
      territory are determined. Anti-HCV are detected in 2.4% donors and 1.4% pregnant
      women. Population immunity to HCV gradually increases with age. AntiHCV are
      detected in 0.9% children aged 3-6 years, in 1.8% in the group aged 20-29 years,
      and in 2.9% in the group aged 30-39 years. Medical workers, mental inpatients,
      hematological patients, patients hospitalized at hemoperfusion departments, and
      imprisoned subjects were referred to groups at risk of HCV infection: antiHCV
      were detected in 3.9, 5.4, 13.8, 53.6, and 24.5% of these groups, respectively.
      Genotype 1b predominates in the structure of HCV genotypes circulating in
      Vladimir: 72.9% in all examined population groups. In addition to this genotype,
      genotypes 2a, 2b, and 3a were detected (2.9, 2.9, and 15.7%, respectively).
      Genotype 3a was the most incident in children aged 0-14 years.

PMID- 10358905
TI  - [Functional status of the interferon system in inapparent and clinical infection
      with hepatitis B and C viruses].
AB  - In vitro production of alpha- and gamma-interferon (IF) by peripheral blood cells
      and the concentrations of serum IF were studied in 47 intravenous drug users
      infected with hepatitides viruses B and C (HBV and HCV) and in 50 inpatients with
      verified diagnosis of hepatitides B or C, 16 of these narcomaniacs. In acute
      disease, the capacity of cells to produce alpha- and gamma-IF was suppressed,
      while the concentration of IF circulating in the blood was increased. Suppression
      of alpha-IF production was more expressed in patients with hepatitides C and B+C
      than in those with hepatitis B. HBV and/or HCV infection without clinical signs
      of disease did not affect the production of IF. In narcomaniacs using opiates and
      ephedrine drugs for up to 5 years IF system did not depend on drug addiction.

PMID- 10358906
TI  - [Diagnosis of the active form of cytomegalovirus infection based on determination
      of IgG antibodies to the immediate-early cytomegalovirus protein by lanthanide
      immunofluorescence analysis].
AB  - A system for time-resolved fluoroimmunoassay (TR-FIA) is developed for detecting
      early IgG during the active stage of cytomegalovirus infection on the basis of
      CMV-control enzyme immunoassay system. The antigen is cloned and expressed in E.
      coli recombinant main immediate early protein of human CMV. The active form of
      CMV infection was detected additionally in 5 out of 25 women who gave birth to
      sick babies by means of the new test system in complex with other laboratory
      diagnostic methods. The test is recommended for prenatal diagnosis of active CMV
      infection in pregnant women and for predicting the risk of neonatal disease.

PMID- 10358907
TI  - [Active aluminum oxide--a new adsorbent for concentrating intestinal viruses from
      water].
AB  - Concentrating properties of a new adsorbent, active aluminum oxide, towards
      poliomyelitis virus type III and simian rotavirus are studied using virus
      contamination of sewage and drinking water. Optimal concentrations of the
      adsorbent for effective adsorption of both rota- and polioviruses are established
      (1.5 and 1 g/liter, respectively) at pH typical of sewage and drinking water (7.0
      8.5), as well as the optimal time of virus contact with the adsorbent (30 min).
      Elution conditions are determined: 3% elution agent beef extract and pH 8.5-9.5
      are optimal for both viruses. Active aluminum oxide is recommended as an
      adsorbent for elimination of enteroviruses from water objects.

PMID- 10358908
TI  - [International conference "Vaccines and Immunization"].

PMID- 10358909
TI  - [Contemporary concept of epilepsy treatment].

PMID- 10358910
TI  - [The alterations of lipid spectrum in patients with migraine].
AB  - The paper presents lipid spectrum in 40 patients aged 19-50 years with migraine.
      Migraine is one of the possible causes of stroke development at young age. There
      were found significant atherogenic changes of blood serum lipid spectrum, which
      didn't depend on clinical peculiarities of the disease, but became more
      pronounced as far as the level of the situational anxiety (according to
      Spilberger's questionnaire) increased. It is suggested that the changes in lipid
      spectrum may be some components in complex alterations of the functions of
      structures of limbic-reticular complex and humoral-endocrine homeostasis which
      are both genetically determined and acquired. These changes are quite important
      in pathogenesis of migraine and may be considered as the risk-factors of the
      development of cerebral stroke at young age.

PMID- 10358911
TI  - [Non-convulsive paroxysmal disorders in exogenous-organic diseases of the brain].
AB  - Examination of 273 patients with exogenous-organic diseases of the brain revealed
      nonconvulsive paroxysmal disorders of traumatic, toxic, infectious, radioactive
      and combined origin in 112 cases (41.0%). Such disorders were characterised by
      pronounced polymorphism and presented with viscero-vegetative (36.6%), affective
      (27.7%), psychosensory (19.6%), sensory (15.2%), ideatoric (11.6%) paroxysms as
      well as with twilight states of consciousness (16.1%), absence seizures (10.7%),
      narcolepsy (2.7%), catalepcy (1.8%) and the states of "deja vu" and "jamais vu"
      (5.4%). In most of the patients such paroxysms were found 5 or more years after
      exogenous influences, i.e. when the severity of the organic brain damage
      increased. A resemblance of nonconvulsive paroxysms was observed in the patients
      with different etiology of the disease. The disorders were seldom detected in
      routine medical practice which may cause in adequate therapy.

PMID- 10358912
TI  - [Investigation of mechanisms of neuro-protective effect of semax in acute period
      of ischemic stroke].
AB  - Semax is the first domestic nootropic drug of an unexhausted type from the group
      of neuropeptides. In experimental studies it showed angioprotective, antihypoxic
      and neurotrophic activity in the doses 100-150 micrograms/kg. A combined clinical
      electrophysiologic study revealed its high efficiency in acute ischemic stroke. A
      clinical trial was performed of immunobiochemical mechanisms of neuroprotective
      properties of Semax in acute period of ischemic stroke. A retrospective
      comparative clinicoimmunobiochemical analysis provided objective data on the
      molecular level on activating influence of Semax on antiinflammatory postischemic
      reactions in the brain. Shifting neuromediatory balance toward a prevalence of
      the antiinflammatory agents (interleukin-10, tumor necrosis factor-alpha) over
      the factors maintaining the inflammation (interleukin-8, C-reactive protein).

PMID- 10358913
TI  - [The influence of phototherapy on psycho-autonomic syndromes].
AB  - Therapy by bright white light was applied to 51 patients. 4 blocks of
      psychoautonomic syndromes of neurotic nature were analysed: 1) pronounced (14
      cases) and mild (12) hypothalamic dysfunction; 2) moderate and pronounced
      depression (21) and the state without depression (9); 3) headache of different
      types--37 patients, including 21 ones with chronic headache of effort, combined
      with migraine--5 cases, or combined with vascular headache--11 patients; 4)
      paroxysmal disorders (43 individuals: 25--with typical panic attacks, 18--with
      atypical panic attacks). More pronounced positive effect was found in the group
      with atypic PA and in the group with slight hypothalamic dysfunction, accompanied
      by solitary neuro-endocrine symptoms with moderate or severe depression, with
      chronic headache of strain including a combination with migraine. Neuroendocrine,
      motivative, psychovegetative, algesic and psychopathologic symptomatology was
      decreased significantly in all the groups with positive effect together with the
      improvement of the objective psychophysiologic indices. Intrahemispheric
      interactions were also improved, exactly: the power of frequency EEG spectrum
      increased, in general, because of both the increase of the slow rhythms from both
      sides and the approach of the coefficient of asymmetry to the control. The least
      effect was observed in the patients with senesto-hypochondric syndrome, with
      prevalence of anxiety over depression, with rude hypothalamic dysfunction, with
      vascular headache, with typic PA.

PMID- 10358914
TI  - [Quantitative evaluation of total electromyography in patients with diphtheria
      polyneuropathy].

PMID- 10358916
TI  - [Risk factors of multiple sclerosis in Moscow population. I. Exogenous risk
      factors].
AB  - Descriptive epidemiologic investigations revealed the necessity of the exogenous
      influence for the development of multiple sclerosis (MS). By means of "case
      control" method the relations of MS with exogenous factors were studied. On the
      first stage there were analysed questionnaire data on 250 "patient-control" pairs
      matched by age, sex, nationality and birth in Moscow or out of it. The
      questionnaire was elaborated on the basis of the epidemiologic one recommended
      for the epidemiologic studies in the countries of South-East Europe. Significant
      correlations were found between MS and exogenous factors, namely: "tonsillitis at
      the age under 15 years" and "predominance of meat in the diet at the age under 15
      years". These associations were confirmed by the data of both stratificative,
      discriminative analysis and logic regression. More detailed questionnaire was
      used on the second stage in 110 "patient-control" pairs. The second study
      confirmed such associations and found the most significant connection between MS
      and both tonsillitis at the age of 7-15 years and consumption of smoked meat. The
      influence of both exogenous factors were probably conditioned by permanent
      antigenic stimulation of the immune system in predisposed individuals.

PMID- 10358915
TI  - [Clinico-immunobiochemical monitoring of factors of focal inflammation in the
      acute period of hemispheric ischemic stroke].
AB  - The changes of cytokinis status and C-reactive protein were evaluated in
      cerebrospinal fluid of 50 patients in the acute period of ischemic hemispheric
      stroke with consideration of influence of the remote consequences of the
      ischemia, established experimentally, on the mechanisms of cerebral infarction
      development as well as on the progression of both atherogenesis and vascular
      encephalopathy in the period after the stroke. Significance both of a surplus
      releasing of the proinflammatory cytokines and deficiency of the protective
      antiinflammatory and trophotropic factors in the development of an inflammatory
      response was established. Immunobiochemical criteria were proposed for grading of
      process for stroke course prediction and for recovery of the altered neurologic
      functions. More favourable prognosis was anticipated in the patients in which a
      the treatment started within of the "therapeutic window".

PMID- 10358917
TI  - [Factors of social workers' training in a medical school for work in psychiatric
      and substance abuse rehabilitation clinics].
AB  - The paper presents experience in training and advanced training of experts for
      the institutions that provide psychiatric and narcological aid on the basis of
      the Arkhangelsk State Medical Academy. The necessity of the interdisciplinary
      methodological approach taking into consideration the international experience of
      the Scandinavian countries is emphasized.

PMID- 10358919
TI  - [Modern approaches to the evaluation of medication effectiveness].

PMID- 10358918
TI  - [Mental disorders in Gorlin-Goltz syndrome].

PMID- 10358920
TI  - [Petr Petrovich and Vsevolod Petrovich Kashchenko].

PMID- 10358921
TI  - [The release of growth hormone in response to injection of trihexiphenidyl in
      patients with Alzheimer's disease, multi infarction dementia and in schizophrenic
      patients with intact cognitive functions (preliminary results)].

PMID- 10358922
TI  - [Mechanisms of brain tissue damage in acute focal ischemia].

PMID- 10358923
TI  - Regulation of phospholipase C isozymes: activation of phospholipase C-gamma in
      the absence of tyrosine-phosphorylation.
AB  - Activation of PLC-gamma isozymes in response to various agonists involves
      tyrosine phosphorylation of the effector enzymes. Recent evidence indicates that
      PLC-gamma isozymes are additionally activated by phosphatidic acid,
      phosphatidylinositol 3,4,5-trisphosphate and arachidonic acid in the absence of
      PLC-gamma tyrosine phosphorylation. These lipid-derived messengers are the
      immediate products of phospholipase D, phosphatidylinositol 3-kinase, and
      phospholipase A2, enzymes which are often stimulated along with PLC-gamma in
      response to an agonist. Furthermore, phosphatidylinositol 4,5-bisphosphate acts
      as a substrate for both PLC-gamma and phosphatidylinositol 3-kinase and as an
      activator for phospholipase D and phospholipase A2. These results reveal an
      elaborate mechanism of cross-talk and mutual regulation between four effector
      enzymes that participate in receptor signaling by acting on phospholipids.

PMID- 10358924
TI  - Regulation of phosphatidylinositol 4,5-bisphosphate levels and its roles in
      cytoskeletal re-organization and malignant transformation.
AB  - It is well known that phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) plays
      important roles not only as a precursor lipid for generating second messengers
      but also as a regulator of cytoskeletal re-organization. The last step of
      PtdIns(4,5)P2 synthesis is catalyzed by PtdIns monophosphate(PIP) kinase. So far,
      three type I PIP kinases(alpha, beta, and gamma), which phosphorylate PtdIns(4)
      to PtdIns(4,5)P2, and three type II PIP kinases(alpha, beta, gamma), which
      phosphorylate PtdIns(5)P to PtdIns(4,5)P2 have been found. On the other hand,
      several inositolpolyphosphate 5-phosphatases which convert PtdIns(4,5)P2 to
      PtdIns(4) are known. Among them, synaptojanin, which associates with tyrosine
      kinase receptors through an adaptor protein, Ash/Grb2, in response to growth
      factors, is capable of hydrolyzing PtdIns(4,5)P2 bound to actin regulatory
      proteins, resulting in actin filament re-organization downstream of tyrosine
      kinases.

PMID- 10358925
TI  - Mammalian phosphatidylinositol transfer proteins: emerging roles in signal
      transduction and vesicular traffic.
AB  - Phosphatidylinositol transfer proteins (PITP) are abundant cytosolic proteins
      found in all mammalian cells. Two cytosolic isoforms of 35 and 36 kDa (PITP alpha
      and PITP beta) have been identified which share 77% identity. These proteins are
      characterized by having a single phospholipid binding site which exhibits dual
      headgroup specificity. The preferred lipid that can occupy the site can be either
      phosphatidylinositol (PI) or phosphatidylcholine (PC). In addition, PITP beta can
      also bind sphingomyelin. A second characteristic of these proteins is the ability
      to transfer PI and PC (or SM) from one membrane compartment to another in vitro.
      The function of PITP in mammalian cells has been examined mainly using
      reconstitution studies utilizing semi-intact cells or cell-free systems. From
      such analyses, a requirement for PITP has been identified in phospholipase C
      mediated phosphatidylinositol bisphosphate (PI(4,5)P2) hydrolysis, in
      phosphoinositide 3-kinase catalyzed PIP3 generation, in regulated exocytosis, in
      the biogenesis of secretory granules and vesicles and in intra-golgi transport.
      Studies aimed at elucidating the mechanism of action of PITP in each of these
      seemingly disparate processes have yielded a singular theme: the activity of PITP
      stems from its ability to transfer PI from its site of synthesis to sites of
      cellular activity. This function was predicted from its in vitro characteristics.
      The second feature of PITP that was not predicted is the ability to stimulate the
      local synthesis of several phosphorylated forms of PI including PI(4)P,
      PI(4,5)P2, PI(3)P, PI(3,4,5)P3 by presenting PI to the lipid kinases involved in
      phosphoinositide synthesis. We conclude that PITP contributes in multiple aspects
      of cell biology ranging from signal transduction to membrane trafficking events
      where a central role for phosphoinositides is recognized either as a substrate or
      as an intact lipid signalling molecule.

PMID- 10358926
TI  - Membrane association of a new inositol 1,4,5-trisphosphate binding protein, p130
      is not dependent on the pleckstrin homology domain.
AB  - The 130-kDa protein was isolated as a novel inositol 1,4,5-trisphosphate
      (Ins(1,4,5)P3) binding protein from rat brain and was molecularly cloned to be
      found similar to phospholipase C-delta 1 (Kanematsu, T., Takeya, H., Watanabe,
      Y., Ozaki, S., Yoshida, M., Koga, T., Iwanaga, S. and Hirata, M., 1992. Putative
      inositol 1,4,5-trisphosphate binding proteins in rat brain cytosol, J. Biol.
      Chem. 267, 6518-6525; Kanematsu, T., Misumi, Y., Watanabe, Y., Ozaki, S., Koga,
      T., Iwanaga, S., Ikehara, Y. and Hirata, M., 1996. A new inositol 1,4,5
      trisphosphate binding protein similar to phospholipase C-delta 1, Biochem. J.
      313, 319-325). The 130-kDa protein and its deleted protein expressed in COS-1
      cells were seen in both the membrane and the cytosol fractions. Truncation of 232
      residues from the N-terminus, the protein molecule lacking the pleckstrin
      homology (PH) domain was also localized in the membrane fraction as much as seen
      with a full-length protein and other deleted proteins, thereby indicating that
      the PH domain is not primarily involved in the membrane localization. The
      addition of Mg2+ to homogenates of COS-1 cells caused the translocation of
      expressed proteins from the cytosol to the membrane fraction, yet further
      addition of AlF4- which induced the activation of GTP binding proteins did not
      cause a further translocation. The protein translocated to the membrane by the
      addition of Mg2+ was hardly extracted with Triton X-100. The inclusion of
      Ins(1,4,5)P3 or phosphatidylinositol 4,5-bisphosphate in cell homogenates caused
      the very small reduction in the amounts of membrane-associated proteins expressed
      by some constructs. These results indicate that (i) the PH domain is not
      primarily involved in the membrane localization of the 130-kDa protein, (ii) the
      activation of GTP binding protein does not appear to cause the translocation of
      the 130-kDa protein, and (iii) intrinsic phosphatidylinositol 4,5-bisphosphate
      present in the membrane appears to be involved in the membrane association of the
      130-kDa protein to a very small extent, probably through the binding site in the
      PH domain.

PMID- 10358927
TI  - Inositol 1,3,4,5-tetrakisphosphate as a second messenger--a special role in
      neurones?
AB  - There has been much controversy over the possibility that inositol 1,3,4,5
      tetrakisphosphate (InsP4) may have a second messenger function. A possible
      resolution to this controversy may stem from the recent cloning of two putative
      receptors for InsP4, GAP1IP4BP and GAP1m. Both these proteins are expressed at
      high levels in neurones, as is inositol 1,4,5-trisphosphate 3-kinase, the enzyme
      that makes InsP4. In this review we discuss the possible relevance of these high
      expression levels to the complex way in which neurones control Ca2+ and use it as
      a second messenger.

PMID- 10358928
TI  - Role of synaptotagmin, a Ca2+ and inositol polyphosphate binding protein, in
      neurotransmitter release and neurite outgrowth.
AB  - Synaptotagmin I (or II), a possible Ca(2+)-sensor of synaptic vesicles, has two
      functionally distinct C2 domains: the C2A domain binds Ca2+ and the C2B domain
      binds inositol high polyphosphates (IP4, IP5, and IP6). Ca(2+)-regulated
      exocytosis of secretory vesicles is proposed to be activated by Ca2+ binding to
      the C2A domain and inhibited by inositol polyphosphate binding to the C2B domain.
      Synaptotagmins now constitute a large family and are thought to be involved in
      both regulated and constitutive vesicular trafficking. They are classified from
      their distribution as neuronal (synaptotagmin I-V, X, and XI) and the ubiquitous
      type (synaptotagmin VI-IX). Among them, synaptotagmins III, V, VI and X are
      deficient in IP4 binding activity due to the amino acid substitutions in the C
      terminal region of the C2B domain, suggesting that these isoforms can work for
      vesicular trafficking even in the presence of inositol high polyphosphates.
      Synaptotagmin I is also known to be present in neuronal growth cone vesicles.
      Antibody against the C2A domain (anti-C2A) that inhibits Ca(2+)-regulated
      exocytosis also blocked neurite outgrowth of the chick dorsal root ganglion (DRG)
      neuron, suggesting that Ca(2+)-dependent synaptotagmin activation is also crucial
      for neurite outgrowth.

PMID- 10358929
TI  - Pathways for phosphoinositide synthesis.
AB  - In eukaryotic cells, phosphatidylinositol can be phosphorylated on the inositol
      ring by a series of kinases to produce at least seven distinct phosphoinositides.
      These lipids have been implicated in a variety of cellular processes, including
      calcium regulation, actin rearrangement, vesicle trafficking, cell survival and
      mitogenesis. The phosphorylated lipids can act as precursors of second messengers
      or act directly to recruit specific signaling proteins to the membrane. A number
      of the kinases responsible for producing these lipids have been purified and
      their cDNA clones have been isolated. The most well characterized of these
      enzymes are the phosphoinositide 3-kinases. However, progress has also been made
      in the characterization of phosphatidylinositol 4-kinases and
      phosphatidylinositol-4-phosphate 5-kinases. In addition, new pathways involving
      phosphatidylinositol-5-phosphate 4-kinases, phosphatidylinositol-3-phosphate 5
      kinases and phosphatidylinositol-3-phosphate 4-kinases have recently been
      described. The various enzymes and pathways involved in the synthesis of cellular
      phosphoinositides will be discussed.

PMID- 10358930
TI  - Synergistic activation of a family of phosphoinositide 3-kinase via G-protein
      coupled and tyrosine kinase-related receptors.
AB  - Phosphoinositide 3-kinase (PI 3-kinase) is a key signaling enzyme implicated in a
      variety of receptor-stimulated cell responses. Stimulation of receptors
      possessing (or coupling to) protein-tyrosine kinase activates heterodimeric PI 3
      kinases, which consist of an 85-kDa regulatory subunit (p85) containing Src
      homology 2 (SH2) domains and a 110-kDa catalytic subunit (p110 alpha or p110
      beta). Thus, this form of PI 3-kinases could be activated in vitro by a
      phosphotyrosyl peptide containing a YMXM motif that binds to the SH2 domains of
      p85. Receptors coupling to alpha beta gamma-trimeric G proteins also stimulate
      the lipid kinase activity of a novel p110 gamma isoform, which is not associated
      with p85, and thereby is not activated by tyrosine kinase receptors. The
      activation of p110 gamma PI 3-kinase appears to be mediated through the beta
      gamma subunits of the G protein (G beta gamma). In addition, rat liver
      heterodimeric PI 3-kinases containing the p110 beta catalytic subunit are
      synergistically activated by the phosphotyrosyl peptide plus G beta gamma. Such
      enzymatic properties were also observed with a recombinant p110 beta/p85 alpha
      expressed in COS-7 cells. In contrast, another heterodimeric PI 3-kinase
      consisting of p110 alpha and p85 in the same rat liver, together with a
      recombinant p110 alpha/p85 alpha, was not activated by G beta gamma, though their
      activities were stimulated by the phosphotyrosyl peptide. Synergistic activation
      of PI 3-kinase by the stimulation of the two major receptor types was indeed
      observed in intact cells, such as chemotactic peptide (N-formyl-Met-Leu-Phe) plus
      insulin (or Fc gamma II) receptors in differentiated THP-1 and CHO cells and
      adenosine (A1) plus insulin receptors in rat adipocytes. Thus, PI 3-kinase
      isoforms consisting of p110 beta catalytic and SH2-containing (p85 or its
      related) regulatory subunits appeared to function as a 'cross-talk' enzyme
      between the two signal transduction pathways mediated through tyrosine kinase and
      G protein-coupled receptors.

PMID- 10358931
TI  - FYVE finger proteins as effectors of phosphatidylinositol 3-phosphate.
AB  - Phosphatidylinositol 3-phosphate (PtdIns(3)P), generated via the phosphorylation
      of phosphatidylinositol by phosphatidylinositol 3-kinase (PI 3-kinase), plays an
      essential role in intracellular membrane traffic. The underlying mechanism is
      still not understood in detail, but the recent identification of the FYVE finger
      as a protein domain that binds specifically to PtdIns(3)P provides a number of
      potential effectors for PtdIns(3)P. The FYVE finger (named after the first letter
      of the four proteins containing it; Fab1p, YOTB, Vac1p and EEA1) is a double-zinc
      binding domain that is conserved in more than 30 proteins from yeast to mammals.
      It is found in several proteins involved in intracellular traffic, and FYVE
      finger mutations that affect zinc binding are associated with the loss of
      function of several of these proteins. The interaction of FYVE fingers with
      PtdIns(3)P may serve three alternative functions: First, to recruit cytosolic
      FYVE finger proteins to PtdIns(3)P-containing membranes (in concert with
      accessory molecules); second, to enrich for membrane bound FYVE finger proteins
      into PtdIns(3)P containing microdomains within the membrane; and third, to
      modulate the activity of membrane bound FYVE finger proteins.

PMID- 10358932
TI  - Diacylglycerol kinases in signal transduction.
AB  - Diacylglycerol kinase (DGK) phosphorylates the second messenger diacylglycerol
      (DAG) to phosphatidic acid. A family of nine mammalian isotypes have been
      identified. Their primary structure shows a diverse array of conserved domains,
      such as a catalytic domain, zinc fingers, pleckstrin homology domains and EF-hand
      structures, known to interact with other proteins, lipids or Ca2+, in signal
      transduction processes. DGK is believed to act in the phosphoinositide cycle in
      which DAG is enriched with arachidonoyl moieties, but the majority of DGK
      isotypes do not show specificity for this DAG species in vitro. This could imply
      that DGKs may also have other functions in the cell. DGK activity is not only
      found in membranes, but also in the nucleus and at the cytoskeleton. Agonist
      induced translocations of DGK to or from these subcellular sites are known to
      occur. Some isotypes are contained in signaling complexes in specific association
      with members of the Rho family of small GTP binding proteins, suggesting that
      they are involved in Rho-mediated processes such as cytoskeletal reorganization.

PMID- 10358933
TI  - Diacylglycerol kinase in the central nervous system--molecular heterogeneity and
      gene expression.
AB  - Diacylglycerol (DAG) is one of the important second messengers, which serves as
      an activator of protein kinase C (PKC). DAG kinase (DGK) phosphorylates DAG to
      generate phosphatidic acid, thus DGK is considered to be a regulator of PKC
      activity through attenuation of DAG. Recent studies have revealed molecular
      structures of several DGK isozymes from mammalian species, and showed that most
      of the isozymes are expressed in the brain in various amounts. We have cloned
      four DGK isozyme cDNAs from rat brain library (DGK alpha, -beta, -gamma, and 
      zeta) (previously also designated DGK-I, -II, -III, and -IV, respectively) and
      examined their mRNA expressions in rat brain by in situ hybridization
      histochemistry. Interestingly, it is revealed that the mRNA for each isozyme is
      expressed in a distinct pattern in the brain; DGK alpha is expressed in
      oligodendrocytes, glial cells that form myelin; DGK beta in neurons of the
      caudate-putamen; DGK gamma predominantly in the cerebellar Purkinje cells; and
      DGK zeta in the cerebellar and cerebral cortices. Molecular diversity and
      distinct expression patterns of DGK isozymes suggest a physiological importance
      for the enzyme in brain function. Furthermore, functional implications of these
      DGK isozymes are briefly discussed.

PMID- 10358934
TI  - Molecular characterization of the type 2 phosphatidic acid phosphatase.
AB  - Phosphatidic acid phosphatase (PAP) converts phosphatidic acid to diacylglycerol,
      thus regulating the de novo synthesis of glycerolipids and also signal
      transduction mediated by phospholipase D. We initially succeeded in the cDNA
      cloning of the mouse 35 kDa PAP bound to plasma membranes (type 2 enzyme). This
      work subsequently led us to the identification of two human PAP isozymes
      designated 2a and 2b. A third human PAP isozyme (2c) has also been described. The
      cloned enzymes are, in common, N-glycosylated and possess six transmembrane
      domains. The transmembrane dispositions of these enzymes are predicted and the
      catalytic sites are tentatively located in the 2nd and 3rd extracellular loops,
      thus suggesting that the type 2 PAPs may act as ecto-enzymes dephosphorylating
      exogenous substrates. Furthermore, the type 2 PAPs have been proposed to belong
      to a novel phosphatase superfamily consisting of a number of soluble and membrane
      bound enzymes. In vitro enzyme assays show that the type 2 PAPs can
      dephosphorylate lyso-phosphatidate, ceramide-1-phosphate, sphingosine-1-phosphate
      and diacylglycerol pyrophosphate. Although the physiological implications of such
      a broad substrate specificity need to be further investigated, the type 2 PAPs
      appear to metabolize a wide range of lipid mediators derived from both glycero-
      and sphingolipids.

PMID- 10358935
TI  - Phospholipase D structure and regulation.
AB  - The recent identification of cDNA clones for phospholipase D has opened the door
      to new types of investigations into its structure and regulation. PLD activity
      has been found to be encoded by at least two different genes that contain
      catalytic domains that relate their mechanism of action to phosphodiesterases. In
      vivo roles for PLD suggest that it may be important for multiples steps in
      regulated secretion and membrane biogenesis.

PMID- 10358936
TI  - Phospholipase D as an effector for ADP-ribosylation factor in the regulation of
      vesicular traffic.
AB  - A mammalian phospholipase D (PLD) activity that is stimulated by ADP-ribosylation
      factor (ARF) has been identified in Golgi-enriched membrane fractions. This
      activity is due to the PLD1 isoform and evidence from several laboratories
      indicates that PLD1 is important for the polymerization of vesicle coat proteins
      on membranes. When expressed in Chinese hamster ovary cells, PLD1 localized to
      dispersed small vesicles that overlapped with the location of the ERGIC53
      protein, a marker for the endoplasmic reticulum (ER)-Golgi intermediate
      compartment. Cells having increased PLD1 expression had accelerated anterograde
      and retrograde transport between the ER and Golgi. Membranes from cells having
      elevated PLD1 activity bound more COPI, ARF, and ARF-GTPase activating protein.
      These membranes also produced more COPI vesicles than did membranes from control
      cells. It is likely that PLD1 participates in both positive and negative feedback
      regulation of the formation of COPI vesicles and is important for controlling the
      rate of this process.

PMID- 10358938
TI  - Interaction of the recombinant herpes simplex virus type 1 thymidine kinase with
      thymidine and aciclovir: a kinetic study.
AB  - Herpes Simplex Virus type 1 thymidine kinase (HSV 1 TK) is a key target for
      antiviral therapy and it phosphorylates a broad spectrum of nucleosides and
      nucleotides. We report the results from kinetic and inhibition experiments with
      HSV 1 TK, and show that there is a preferred, but not exclusive, binding order of
      substrates, i.e. dT binds prior to ATP. Furthermore, the results provide new
      informations on the mechanism of binding suggesting that HSV1 TK undergoes
      conformational changes during the catalytic cycle.

PMID- 10358937
TI  - Possible role of phospholipase D in cellular differentiation and apoptosis.
AB  - Phospholipase D (PLD) is widely distributed in mammalian cells and is implicated
      in a variety of physiological processes that reveal it to be a member of the
      signal transducing phospholipases. Recently, two related PLD isozymes, PLD1 and
      PLD2, were cloned. The former activity is regulated in vitro by protein kinase C
      and small molecular weight GTP-binding proteins (Arf and Rho family). By
      contrast, the basal activity of the latter is high and it is unresponsive in
      vitro to these activators. The cellular PLD activity and mRNA levels of these PLD
      isozymes drastically changed during differentiation and apoptosis in several
      types of cells. The general trend was that the mRNA level of PLD1 increased
      during differentiation, as did the observed GTP gamma S-dependent PLD activity
      which presumably derived from PLD1-specific catalysis. In contrast, the PLD
      activity and mRNA level of PLD1 were down-regulated during apoptosis. In addition
      to these PLD isozymes, there exists another PLD isozyme which is activated by
      unsaturated fatty acids such as oleic acid, although its molecular nature and
      physiological roles are not well defined. We have observed that this type of PLD
      activity is drastically increased during apoptosis of Jurkat T cells, which
      mainly possess this kind of PLD activity. These results suggest the possibility
      that PLD activity is controlled at the transcriptional level in certain
      circumstances, and that PLD plays roles in differentiation, survival and
      apoptosis in mammalian cells.

PMID- 10358939
TI  - An efficient, short synthesis and potent anti-hepatitis B viral activity of a
      novel ring-expanded purine nucleoside analogue containing a 5:7-fused, planar,
      aromatic, imidazo[4,5-e][1,3]diazepine ring system.
AB  - An efficient, short synthesis of a ring-expanded nucleoside analogue containing a
      novel 5:7-fused, planar, and potentially aromatic imidazo[4,5-e][1,3]diazepine
      heterocyclic ring system is reported. The target compound, 6-amino-8-hydroxy-4H-1
      beta-D- ribofuranosylimidazo[4,5-e][1,3]diazepin-4-one (2) was synthesized in a
      single step in > or = 90% yield by condensation of guanidine with either methyl 1
      beta-D-ribofuranosylimidazole-4,5- dicarboxylate(1a) or its 2',3',5'-tri-O
      benzoyl derivative (1b). Compound 2 showed potent anti-hepatitis B virus (anti
      HBV) activity with an EC50 value of 0.17 microM in the transfected hepatoma cell
      line 2.2.15, and a low cellular toxicity with a CC50 value of 2.4 mM (TI >
      14,000).

PMID- 10358940
TI  - Synthesis, lipophilicity and anti-HIV activity of a new brominated analog of
      zidovudine.
AB  - A novel cyclic bromine zidovudine analog, (-)-trans-(5S,6S)-5-bromo-6,5'- epoxy
      5,6-dihydro-3'-azido-3'-deoxythymidine (2), and its diastereoisomer (+)-trans
      (5R,6R)-(3) were synthesized and characterized by spectroscopic methods,
      obtaining 3 in very low yields. The major product 2 presents a selectivity index
      (CCID50/IC50) similar to zidovudine but 55.5 times with higher lipophilicity,
      which should increase the ability of 2 to cross the blood-brain barrier by a non
      facilitated diffusion mechanism.

PMID- 10358941
TI  - Synthesis of a novel C-nucleoside, 2-amino-7-(2-deoxy-beta-D-erythro-
      pentofuranosyl)-3H,5H-pyrrolo-[3,2-d]pyrimidin-4-one (2'-deoxy-9-deazaguanosine).
AB  - A synthesis of the C-nucleoside, 2-amino-7-(2-deoxy-beta-D-erythro-
      pentofuranosyl)-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (9-deaza-2'-deoxyguanosine)
      was achieved starting from 2-amino-6-methyl-3H-pyrimidin-4-one (5) and methyl 2
      deoxy-3,5-di-O-(p-nitrobenzoyl)-D-erythro-pento-furanoside (11). The anomeric
      configuration of the C-nucleoside was established by 1H NMR, NOEDS and ROESY.
      This C-nucleoside did not inhibit the growth of T-cell lymphoma cells.

PMID- 10358942
TI  - Expanding the catalytic repertoire of nucleic acid catalysts: simultaneous
      incorporation of two modified deoxyribonucleoside triphosphates bearing ammonium
      and imidazolyl functionalities.
AB  - Two nucleoside triphosphates, a pyrimidine modified with an ammonium
      functionality and a purine modified with an imidazolyl functionality are
      compatible with all conditions for a combinatorial selection of nucleic-acid
      catalysts. We believe that this work is the first to demonstrate the potential
      for using not one but two modified nucleotides in tandem. The potential for an
      enriched catalytic repertoire is envisioned.

PMID- 10358943
TI  - Novel triazole 2'-deoxy-4'-thionucleosides: stereoselective synthesis and
      biological evaluation.
AB  - A study on the use of protecting groups led to the employment of the para
      methoxybenzoyl (pMB) group as a directing group in the synthesis of novel
      triazole 2'-deoxy-4'-thionucleosides. Use of the pMB group gave alpha:beta ratios
      of 1:6 in the glycosylation step with azidotrimethylsilane. A series of novel
      triazoles were generated for in vitro antiviral evaluation.

PMID- 10358944
TI  - Protective effects of calpain inhibitor for prolonged hypothermic cardiac
      preservation.
AB  - PURPOSE: For successful organ transplantation, it is important to properly
      preserve the donor organ. This study was carried out to investigate tissue damage
      generated by the activation of calpain during prolonged hypothermic cardiac
      preservation using specific antibodies for mu- and m-calpain proenzymes, and to
      ensure the protective effect of calpain inhibitor 1 (N-acetyl-leucyl-leucyl
      norleucinal). METHODS: Excised rat hearts were divided into two groups: in Group
      I, the heart was arrested and immersed in University of Wisconsin solution with
      20 microM of calpain inhibitor 1 (n = 28) and in Group N, the heart was arrested
      and immersed in University of Wisconsin solution without calpain inhibitor (n =
      27). After a 12-hour preservation period at 4 degrees C, the hearts were
      reperfused on an isolated perfusion apparatus. Separation of the myocardial
      calpain isozymes was carried out by DEAE cellulose chromatography and both
      calpain proenzymes were detected by immunoblotting. RESULTS: The cardiac function
      was more satisfactorily maintained in Group I in comparison with Group N.
      Remarkable leakage of creatine kinase, glutamic-oxaloacetic transaminase and
      lactate dehydrogenase was detected in Group N, while it was efficiently
      suppressed in Group I. During ischemia, mu-calpain proenzyme decreased in Group N
      (p < 0.01), but there was no significant change in m-calpain. However, during
      reperfusion, both mu- and m-calpains decreased more in Group N (p < 0.01).
      CONCLUSION: Activation of calpain proenzymes and a decrease in cardiac function
      during preservation and reperfusion were demonstrated. The use of calpain
      inhibitor to protect against tissue damage was suggested as being useful for the
      prolonged preservation of the heart.

PMID- 10358945
TI  - Effect of storage temperature on cell viability in cryopreserved canine aortic,
      pulmonic, mitral, and tricuspid valve homografts.
AB  - We determined how long cryopreserved aortic, pulmonic, mitral, and tricuspid
      valve homografts could be stored in a deep freezer (-80 degrees C) without
      compromising fibroblast viability. Valves harvested from 20 anesthetized mongrel
      dogs were grouped into nonfrozen control, frozen and stored in liquid nitrogen (
      196 degrees C), and frozen and stored in a deep freezer (-80 degrees C). Frozen
      groups were divided into subgroups and stored for 2, 4, 8, or 12 weeks. A leaflet
      of each valve was divided into three fragments, and fibroblast viability was
      analyzed by flow cytometry. Cell viability was defined as staining by fluorescent
      diacetate but not by propidium iodide. The viability of untreated control valves
      from all four sites was about 70%, decreasing to about 50% when treated with low
      doses of antibiotics. The viability of frozen valves stored in liquid nitrogen
      was about 45% without a significant difference among storage periods. The
      viability of valves frozen and stored in a deep freezer was significantly lower
      than for the liquid nitrogen group at 2 weeks for the mitral valve and at 4 weeks
      for other valves. These results suggest that homografts can be stored in a deep
      freezer for up to 2 weeks without deterioration.

PMID- 10358946
TI  - Left antero-axillary thoracotomy as an alternative approach for aortic arch
      reconstruction.
AB  - Antero-axillary thoracotomy--a new approach for the reconstruction of the aortic
      arch--provides a wide view of the arch and makes accessible the superior vena
      cava for retrograde cerebral perfusion as well as the coronary sinus for
      retrograde infusion of cardioplegia. This procedure has been used over 22 months
      for 26 patients with aortic arch aneurysm or aortic dissection, and the surgical
      results were evaluated. The distal arch was replaced in 16 patients, the total
      arch in 9 patients, and the proximal arch in 1 patient, using this technique. The
      mean duration of deep hypothermic circulatory arrest was 38 min, and the hospital
      mortality was 15.4%. Antero-axillary thoracotomy may be an excellent approach for
      the reconstruction of the aortic arch, minimizing the duration of hypothermic
      circulatory arrest.

PMID- 10358947
TI  - Chest size matching in single and double lung transplantation.
AB  - We applied predicted vital capacity to chest size matching between donor and
      recipient in lung transplantation to 15 single-lung transplant recipients with
      pulmonary fibrosis and to 20 double-lung transplant recipients with emphysema or
      non-emphysema. The predicted vital capacity of the donor was significantly
      correlated with the predicted vital capacity of the recipient both in double-lung
      transplantation (r = 0.79, p = 0.001) and single-lung transplantation (r = 0.71,
      p = 0.003). In double-lung transplantation, the post-transplant vital capacity
      was correlated with the predicted vital capacity of the recipient (r = 0.74, p =
      0.002). Emphysema patients and non-emphysema patients contributed equally to this
      correlation. In left single lung transplantation, there was a weak correlation
      between the post-transplant vital capacity and the predicted vital capacity of
      the donor in the allograft (r = 0.57, p = 0.1095). In right single lung
      transplantation, the post-transplant vital capacity of the allograft tended to be
      correlated with the predicted vital capacity of recipient (r = 0.77, p = 0.0735).
      We concluded that donors were actually selected based on the comparison of
      predicted vital capacity between donor and recipient. In double-lung
      transplantation, the post-transplant vital capacity was limited by the
      recipient's normal thoracic volume and was not influenced by underlying pulmonary
      disease. In single-lung transplantation with pulmonary fibrosis, the allograft
      transplanted in the left chest could expand to its own size, and the allograft
      transplanted in the right chest could expand to the recipient's normal thoracic
      volume as in double-lung transplantation.

PMID- 10358948
TI  - Post-parturition infectious endocarditis in a patient with a normal mitral valve.
AB  - A 29-year-old woman with no history of heart disease was admitted for the
      treatment of congestive heart failure. Six months earlier, she had given birth,
      then 20 days later developed a fever and cardiac failure ensued. An
      echocardiogram demonstrated severe mitral valve regurgitation. Her blood cultures
      were positive, and we made a diagnosis of mitral valve regurgitation due to
      infectious endocarditis. Despite treatment for congestive heart failure and
      antibiotic therapy, resulting in negative blood cultures, her congestive heart
      failure did not improve, and vegetation on the mitral valve was observed by
      echocardiography. We successfully removed the infected tissue with mitral valve
      plasty.

PMID- 10358949
TI  - Intrathoracic retroesophageal goiter causing tracheal stenosis.
AB  - A 65-year-old woman presented with stridor revealed a mass on a chest X-ray on
      physical examination. A huge goiter arising in the left lobe of the thyroid had
      extended retroesophageally and across the midline to the right side of the
      posterior mediastinum far caudally down to the level of the carina. The trachea
      was remarkably compressed. Surgery was performed via a combined thoracic and
      cervical approach, and the tumor was completely removed with resultant relief
      from stridor. The patient is presently doing well at 1 year after the operation.

PMID- 10358950
TI  - Stent grafting for aortic dissection.
AB  - We report the successful treatment of a patient with Stanford type B aortic
      dissection, "thrombosed" type with ulcer-like projections, by insertion of a
      stent-graft. The false lumen completely disappeared within 1 year after surgery.
      This maturing procedure is promising in the treatment of thrombosed, aggravated
      aortic dissection.

PMID- 10358951
TI  - Aortic valve replacement in a patient with idiopathic thrombocytopenic purpura.
AB  - A patient with aortic regurgitation and idiopathic thrombocytopenic purpura
      underwent a successful valve replacement. Cardiac surgery requiring a
      cardiopulmonary bypass in idiopathic thrombocytopenic purpura can be safely
      carried out with the preoperative intravenous administration of high-dose
      gammaglobulin, which may thereby reduce the need for either perioperative
      transfusion or prophylactic splenectomy.

PMID- 10358952
TI  - Surgical treatment for metastatic lung tumors with incidentally coexisting lung
      cancer.
AB  - We report four surgically resected cases of a metastatic lung tumors with
      incidentally coexisting lung cancer. Two patients (Cases 1 and 2) were admitted
      for surgical treatment for pulmonary metastases from colon cancer, and the other
      two (Cases 3 and 4) were for pulmonary metastases from renal cell carcinoma. In
      only one patient (Case 3), one lesion among the multiple shadows on the
      preoperative computed tomography examination was rather strongly suspected to be
      primary lung cancer. In three patients (Cases 1, 2 and 3), one of the resected
      lesions in each individual case was diagnosed as lung adenocarcinoma by an
      intraoperative examination using frozen sections, and was later histologically
      confirmed. In Case 4, one of the resected lesions was postoperatively determined
      to be lung adenocarcinoma. All coexisting lung cancers, treated with partial
      resection of the lung, were well-differentiated small-sized adenocarcinoma
      (T1N0), while the other lesions resected in each case were metastases from the
      individual cancer. Problems in preoperative diagnosis and surgical treatment for
      metastatic lung tumors with incidentally coexisting lung cancer are discussed.

PMID- 10358953
TI  - Bronchoscopic removal of bronchial foreign bodies through the laryngeal mask
      airway in pediatric patients.
AB  - The laryngeal mask airway was used to perform fiberoptic removal of bronchial
      foreign bodies (peanuts) in two pediatric patients. Laryngeal mask airway offers
      easy access to the airway, safe respiratory management and direct visualization
      of the airway during bronchoscopic procedures. Laryngeal mask airway allows the
      use of larger bronchoscopes than can usually be used for children when
      bronchoscopy is performed through an endotracheal tube. In each case, the peanuts
      were removed safely and easily using a Fogarty catheter through the fiberoptic
      bronchoscope. These cases suggest that laryngeal mask airway is useful in
      maintaining a secure airway during the removal of bronchial foreign bodies in
      children.

PMID- 10358954
TI  - [Nuclear medicine of the liver--focusing on functional diagnosis].
AB  - For evaluating the hepatic function, intrinsic substances are influenced by the
      physiological activity of homeostasis. Potential reduction of the hepatic reserve
      can be evaluated by the loading of the extrinsic substances. Asialoglycoprotein
      (ASGP) receptor reduces its activity according to the grade of hepatic
      parenchymal injury. The quantitative evaluation was possible with 99mTc
      galactosyl HSA (99mTc-GSA) using an index of GSARmax by a multi-compartment
      analysis. The correlation between GSARmax and the histological activity index
      (HAI) score of the liver in hepatectomized cases was better than that of the
      ICGR15. A safe limit of GSARmax was 0.3 mg/min for 1 segment excision and 0.35
      mg/min for 2 or 3 segment excision. Some cases showed discrepancies between 99mTc
      GSA and ICGR15. ICG mainly reflected hepatic blood flow and GSA was related to
      both the amount of functional hepatocytes and flow. Regional distribution of
      GSARmax presented functional SPECT image of the liver. Since the scale was
      common, the comparison were possible between SPECT images in different studies.
      In reservoir treatment, the injection of 99mTc-MAA in a catheter made it possible
      to estimate the distribution of the anticancer agent. The incorrect perfusion to
      the digestive tracts and shunt flow to the lung were monitored, and it was also
      useful to predict the therapeutic effect.

PMID- 10358955
TI  - [Assessment of cardiac function and myocardial metabolism by nuclear medicine].
AB  - Simultaneous assessment of myocardial perfusion and cardiac function came to be
      possible by 99mTc myocardial perfusion agents. We can use ECG-gated SPECT and
      first pass radionuclide angiocardiography for it. ECG-gated SPECT made it
      possible to assess wall motion using wall thickening and QGS (quantitative gated
      SPECT) analysis, which are useful in various clinical situations. First pass
      radionuclide angiocardiography gives good assessment of cardiac function during
      stress, and supports the diagnosis of myocardial ischemia. On the other hand, the
      assessment of myocardial metabolism is another specific feature of nuclear
      cardiology. 123I-BMIPP SPECT is applicable to various cardiac diseases such as
      ischemic heart disease, and 18F-FDG PET has been considered as the gold standard
      of myocardial viability. Recently, gamma camera for 18F-FDG imaging has been
      developed, which may make FDG imaging more popular.

PMID- 10358956
TI  - [Quantitative assessment of 201Tl-SPECT in tumors of bone and soft tissue].
AB  - 201Tl-SPECT was performed to diagnose the malignancy of bone and soft tissue
      tumors by visual and quantitative assessment in 48 patients (17 malignant lesions
      and 31 benign lesions). SPECT images were obtained in the early phase (15 min
      after injection) and the delayed phase (240 min). By visual assessment a tumor
      was considered malignant if high accumulation was found in the tumor in the early
      phase and the accumulation was confirmed in the delayed phase. Tumors which did
      not meet these criteria were considered benign. For quantitative assessment, the
      ROI (region of interest) accumulation ratios of the tumor to the contralateral
      normal tissue in the early phase (ER) and in the delayed phase (DR), the ROI
      accumulation ratio of the delayed phase to the early phase of the tumor (Td/Te),
      and the ROI accumulation ratio of the delayed phase to the early phase of the
      contralateral normal tissue (Nd/Ne) were obtained. Sixteen patients with
      malignant tumors each had a high accumulation each but 12 of 31 benign lesions
      had no high accumulation on visual assessment. Furthermore, the accuracy was
      85.4%, sensitivity 94.1%, and specificity 80.6%. Quantitative assessment was
      performed for 36 cases of high accumulation. The ER of malignant and benign
      lesions was 5.51 +/- 3.73 and 2.75 +/- 2.17, respectively, and the ER of
      malignant lesions was significantly higher than that of benign lesions. The DR
      did not demonstrate a significant difference. If the tumor having an ER greater
      than 3.9 was assumed to be malignant, the accuracy for differentiating malignant
      lesions from benign lesions was 85.4%. The Td/Te of benign lesions (0.97 +/-
      0.28) was higher than that of malignant lesions (0.77 +/- 0.09). The Nd/Ne of
      normal tissue which contained muscles in both lesions were higher than 1.4. In
      conclusion, 201Tl-SPECT was very useful for the differential diagnosis of benign
      or malignant bone and soft tissue tumors. The ER was important for quantitative
      assessment, but a delayed image was necessary for visual assessment.

PMID- 10358957
TI  - [Correlation of risk area and reverse redistribution of 99mTc-sestamibi SPECT in
      acute myocardial infarction following direct PTCA].
AB  - Redistribution of 99mTc-sestamibi is negligible in usual circumstances, but
      recent reports demonstrated reverse redistribution is detectable in acute
      myocardial patients. Correlation of risk area, observed in 99mTc-sestamibi
      "freezed" SPECT image at onset, and delayed images at 5-25 days after onset (post
      PTCA image) is evaluated in 19 acute myocardial infarction patients treated with
      direct PTCA. Reverse redistribution was observed in 85% of reperfused area.
      Linear relationship of % uptake in each SPECT segment between onset and post-PTCA
      images (taken at 0.5, 4, and 6 hours after injection) is evaluated and the
      relationship improves over time course. The correlation coefficient between onset
      and 6 hours-delayed image is 0.88, and the visual concordance shows 77% of score
      matching. Delayed 99mTc-sestamibi SPECT image on reperfused AMI seems to
      represent risk area with some underestimation. It may be useful to estimate both
      risk and salvaged areas on early and delayed SPECT with a single 99mTc-sestamibi
      injection.

PMID- 10358958
TI  - [99mTc-MIBI uptake in breast abscess: a case report].
AB  - 99mTc-MIBI scintimammography was performed in a 24-year-old female with breast
      abscess. Intense tracer uptake in the breast abscess was noted on both early and
      delayed images. There are few descriptions of 99mTc-MIBI uptake in breast
      abscess, and this case indicated that abscess should be added to the differential
      diagnosis of breast 99mTc-MIBI uptake.

PMID- 10358959
TI  - [Myocardial distribution of iodine-123-iodophenyl-9-methyl-pentadecanoic acid
      (9MPA) in patients with acute myocardial infarction: comparison with regional
      wall motion obtained from technetium-99m-sestamibi gated SPECT].
AB  - 123I-iodophenyl-9-methyl-pentadecanoic acid (9MPA) is a modified long-chain (15
      carbons) fatty acid with a methyl branch on its 9 carbon location. Myocardial
      SPECT images (two sets, 10 min each) were obtained starting 10 min (early phase)
      and 50 min (delay phase) after the injection of 160 MBq 123I-9MPA at rest in 10
      patients with acute myocardial infarction. The segmental myocardial uptake (%
      uptake) and clearance (% washout) from early to delay image were calculated by
      the SPECT data. ECG-gated myocardial SPECT with 99mTc-sestamibi was also
      performed and segmental left ventricular (LV) wall motion was evaluated using QGS
      (quantitative gated SPECT) program. The % uptake of LV segments with hypokinetic
      or akinetic wall motion were significantly lower than those with normokinesis (p
      < 0.01) for both early and delay phases. The % washout of hypokinetic segments
      were significantly lower than those of normokinetic regions (p < 0.01), while the
      % washout of akinetic segments were significantly higher than those of severely
      hypokinetic segments (p < 0.05). Thus, 123I-9MPA myocardial distribution and
      clearance thought to be associated with left ventricular regional wall motion.

PMID- 10358960
TI  - [Adrenal tumors found by chance. Surgical treatment or follow-up?].
AB  - 206 case records of the patients treated from 1985 to 1998 for various diseases
      of the adrenal glands were analyzed. In 39 (18.9%) patients tumors were chance
      finding at ultrasound examination or computer tomography of the abdominal cavity
      and retroabdominal space. 25 patients from this group were operated on, 14
      patients were not operated and were followed up from 1 month to 7 years. All the
      patients underwent complex examination including analysis of the complaints,
      anamnesis and physical examination data, hormonal status examination (ACTH,
      hydrocortisone, 11-oxycorticosteroids, 17-ketosteroids, aldosterone, renin,
      adrenalin, noradrenalin, vanillyl-mandelic acid), device methods of examination
      USE, CT, MRT, superselective phlebography with separate catheterization of
      adrenal veins and blood intake per floor, fine needle aspiration biopsy under
      ultrasound control. Comparison of the results of complex clinical examination
      with morphological data of removed adrenal glands was carried out
      retrospectively. Arteriography and superselective phlebography with separate
      catheterization of adrenal veins and per floor taking of blood samples, performed
      in 36 patients, enabled not only to supplement and define more exactly the other
      methods of topical diagnosis, but also to asses objectively functional actively
      of the affected and contralateral adrenal. Despite the fact that during the study
      of hormonal level in peripheral blood of patients it was normal analysis of the
      data obtained by superselective phlebography of adrenal veins and per floor
      taking of blood samples showed significant increase in hormones level in blood of
      all operated patients. Comparison of the data of superselective phlebography with
      separate catheterization of adrenal veins and per floor taking of blood samples
      and clinical picture of the disease made it possible to suggest the presence of
      preclinical (subclinical) Cushing or Conn syndrome. Operative treatment was not
      indicated in the absence of hormonal activity of the tumor (i.e. preclinical
      syndromes by Icenko-Cushing, Conn, pheochromocytoma, the virilizing and
      feminizing tumors), tumors of small size (less than 3 cm), in absence of
      malignant growth features confirmed by complex instrumental examination (USE, CT,
      MRT, fine-needle aspiration biopsy under US control, superselective phlebography
      with per floor taking of blood samples). Such patients were reexamined in 6
      months. During the follow up period no changes of tumor size, homogeneity,
      hormonal status were revealed.

PMID- 10358962
TI  - [Polarization microscopy of bile for diagnosis of microcholedocholithiasis].
AB  - Comparative analysis of the results of microscopic examination of ductal bile was
      carried out in 2 groups of patients with clinical manifestations of the disease
      of extrahepatic bile ducts (choledocholithiasis, mechanical jaundice,
      cholangitis). In group 1 (17 patients) choledocholithiasis was diagnosed on the
      basis of ultrasound examination (USE) and direct contrast examination of the bile
      ducts at retrograde pancreatocholangiography (RPCG). In group 2 (17 patients) USE
      and RPCG proved to be uninformative and only polarizable microscopy of ductal
      bile taken by the method of direct endoscopical catheterization of the major
      duodenal papillae was able to reveal microcholedocholithiasis. It served an
      indication for endoscopical papillosphincterotomy performance. Thus polarizable
      microscopy of ductal bile is a reliable method of diagnosis of
      microcholedocholithiasis, which makes it possible to establish indications for
      correction of the major duodenal papilla.

PMID- 10358961
TI  - [Optimization of diagnosis and methods of liver resection in alveolar
      echinococcosis].
AB  - 36 resections of the liver were carried out. 66.7% of them were hemihepatectomies
      and extended hemihepatectomies due to sever parasitic lesions of the liver
      parenchyma. During resections of the liver ultrasonic scalpel and high frequency
      electrocoagulation, compression of the hepatoduodenal ligament under the control
      of the intraoperative sonography were performed. In 4 patients (11.1%)
      complications were observed: hepatic insufficiency (2 cases), injury of inferior
      vena cava (1 case) and infrahepatic abscess (1 case). Lethality made up 3.8% (1
      patient died due to development of acute hepatic insufficiency after extended
      right-sided hemihepatectomy.

PMID- 10358963
TI  - [Extended lymphadenectomy in stomach cancer].
AB  - The results of surgical treatment in 120 patients with cancer of the stomach have
      been analyzed. Metastatic involvement in all groups of lymphatic nodes was
      revealed in 68.3% cases, retroperitoneal metastases were detected in 46 patients
      (38.3%). 38 subtotal resections of the stomach and 82 gastrectomies with
      retroperitoneal lymphadenectomy R2 and R3 were performed.
      Esophagojejunoanastomosis end-to-end with a loop excluded by Roux was applied in
      110 patients and esophagoduodenoanastomosis--in 10 patients. Insufficiency of
      esophagointestinal anastomosis was revealed in 3 patients. The rate of
      complications was 29.2%, lethality--8.3%. High rate of postoperative
      complications and lethality were explained by initially severe conditions of the
      patients (61%) and by complicated forms of gastric cancer in 6 patients.
      Improvement of early results of surgical interventions lies in the usage of
      antibacterial prophylaxis, preventive intravenous introductions of 5
      fluorouracil, adequate drainage of the abdominal cavity, careful preparation and
      ligation in the course of the operation.

PMID- 10358964
TI  - [Minimally invasive technologies in surgery of duodenal ulcer].
AB  - The results of surgical treatment of duodenal ulcer are presented. Combined
      miniinvasive method was used in 30 patients with perforated ulcers. The essence
      of the method consisted in laparoscopic sanation of abdominal cavity and
      operative manipulations in the area of perforated ulcer through mini-laparotomy
      approach. Taking into account destructive properties of radiowaves concerning
      nerve cells, the authors have proved in experiments feasibility of vagotomy by
      means of these waves, and used them for 10 patients in laparoscopic vagotomy
      combined with operative manipulations in the area of ulcer through mini
      laparotomy approach. In 4 patients isolated laparoscopic radiofrequency vagotomy
      without gastric drainage in uncomplicated forms of duodenal ulcer was performed
      with good results.

PMID- 10358965
TI  - [Surgical policy in gastrointestinal tract foreign bodies].
AB  - 66 patients (45 males and 21 females) who have swallowed 157 foreign bodies
      (fragments of wire, nails, needles, hafts of spoons, et were treated). If the
      objects were located in the stomach and the duodenum in the absence of
      complications endoscopic method of treatment was preferable, with the help of
      which 31 objects were successfully removed and the terms of treatment were
      significantly decreased. Conservative treatment (diet rich in fiber and
      protective substances, barium sulfate administration) resulted in elimination of
      58 objects by vias naturals, 53 from which were not more that 8 cm long.
      Evacuation of the foreign bodies was carried out only during the first 3 weeks
      after the swallowing. Operative treatment was carried out in 21 patients, in whom
      68 foreign bodies were extracted. An urgent operation in the first 6 hours in
      complications due to foreign bodies (perforation, incarceration, gastrointestinal
      bleeding) was carried out in 13 patients. An urgent operation in terms from 6 to
      24 hours of hospitalization was carried out in 6 patients with large (more that 8
      cm) swallowed objects, conglomerates and bunches of foreign bodies. Early removal
      of these objects prevented development of complications. Elective operation was
      carried out in failure of conservative treatment as was in 2 patients. No
      lethality was registered.

PMID- 10358966
TI  - [Application of suturing devices in gastrointestinal surgery].
AB  - Suturing devices of the firm "Auto Suture" have been widely used for two last
      years in Saratov Medical University clinic of surgery at pediatric faculty. 131
      patients with gastrointestinal diseases (54 had cancer of the stomach, 35--ulcer
      of the stomach and the duodenum and 42--oncoproctologic diseases) were operated
      on with their help. Application of the suturing devices results in improved
      quality of the operations as the devices warrant excellent functional qualities
      of the anastomoses and their reliability. The duration of the operation decreases
      considerably. It works well in rectal surgery to increase significantly the
      number of organ-saving operations.

PMID- 10358967
TI  - [Evolution of operative approach in abdominal surgery].
AB  - The severity of postoperative course after surgery of abdominal organs in the
      majority of cases depends rather on the length of the incision of anterior
      abdominal wall that on the extent of surgical manipulations directly on the
      viscera. Various methods of low invasive surgical procedures possess not only
      undeniable advantages in comparison with routine surgical technique, but also
      some defects. Combination of laparoscopic technique and surgical operation from
      mini-approach permits to avoid disadvantages characteristic to each of them.
      Assisted low-invasive operations could be successfully used on many organs of
      abdominal cavity.

PMID- 10358968
TI  - [Anaerobes in children's acute abdomen].
AB  - Bacterial contamination of the abdominal cavity was studied in 30 children aged
      from 2.5 to 14 years with acute abdominal conditions. Anaerobes were detected in
      63.9% of the children. It was established that on the initial stages of
      development of acute diseases in the abdomen the antagonism between aerobes and
      anaerobes was not present. 3 days and later after surgery the antagonism between
      aerobes and anaerobes arises which results in potentiation of the inflammatory
      process by either aerobes (25% of cases) or anaerobes (75% of cases). The
      complicated course of postoperative period in patients with acute abdomen more
      than in 83% of cases is due to anaerobes and in 50%--to aerobes.

PMID- 10358969
TI  - [Occlusive ileus in colonic cancer].
AB  - The experience of treatment is available for 404 patients with mechanical
      obstruction in cancer of the colon. Clinicoroentgenological and ultrasound
      examinations of the organs of abdominal cavity provided early diagnosis of the
      disease. Radical operations were carried out in 59.7% of the patients, palliative
      ones--in 40.3%. Radical right-sided hemicolectomy was completed by creation of
      ileotransversoanastomosis, in left-sided hemicolectomy it was obligatory to take
      out both ends of the resected colon (if it is possible technically and later
      restoration of its continuity is planned), or the operation of Hartmann type was
      performed. The operation should be completed in bowel decompression by
      nasointestinal intubation. It should be used the term "resolved" or "unresolved"
      bowel obstruction after the performance of conservative measures, and the term
      "partial bowel obstruction" should not be used as it presents formulation of
      treatment policy and may be the cause of undue delay of the operation.

PMID- 10358970
TI  - [Small intestine intubation for treatment of patients with peritonitis and
      intestinal obstruction].
AB  - The analysis of 36 case records of patients with peritonitis (n = 12) and
      intestinal obstruction (n = 24) is presented. Nasogastrointestinal intubation of
      the small bowel was used in combined treatment. The aims, indications and
      contraindications for the intubation are formulated. Bacteriologic and
      biochemical parameters of bowel content were studied. It was established that the
      quantity of enterobacteria and unfermenting gram-negative bacteria was increased
      in intestinal paresis, the alkaline phosphatase, amylase, bilirubin,
      transaminase, a potassium content were increased as well. For the tube to
      function from the first hours after its introduction it should be periodically
      properly washed with sodium hypochlorite in concentration 300 mg/l.

PMID- 10358971
TI  - [Choice of surgical management and methods of detoxication in patients with acute
      intestinal obstruction].
AB  - A comparative analysis of the results of treatment in 892 patients with various
      forms of acute bowel obstruction (ABO) of non-tumor genesis has been performed.
      High informative values of the intraoperative biomicroscopy of bowel wall for
      evaluation of severity of ischemic damage and viability of the intestine in ABO.
      The endotoxicosis (ET) in patients with ABO is proposed to be assessed on the
      basis of integral assessment of clinical and laboratory values of hemostasis.
      Basic principles of the choice of surgical policy and methods of detoxication in
      ABO with regard for the grade of ischemic damage of the bowel wall and the ET
      level are described. The application of the developed methods in patients with
      ABO allows to avoid mistakes in evaluation of bowel viability, to reduce the rate
      of development of toxicoseptic shock from 9.8% to 4.7% and to decrease
      postoperative lethality rate from 12.7% to 6.5%.

PMID- 10358973
TI  - [Surgical treatment of multiple thromboembolism of pulmonary artery segmental
      branches ].
AB  - The experience in the treatment of 32 patients with thromboembolism of the
      pulmonary artery is presented. Thrombolytic therapy has been carried out in 10
      patients, implantation of antiembolism cava-filter REPTELA has been carried out
      in 15 patients. Original method for extraction of multiple emboli from segmental
      branches of pulmonary artery under the conditions of the artificial circulation
      is described.

PMID- 10358972
TI  - [Carcinoids of lungs].
AB  - The analysis of the results of the examination and treatment of 29 patients with
      carcinoids of the lungs has been carried out for 1984-1995. Peripheral carcinoids
      were detected in 59% of cases, of the tumor in the main and lobar bronchi was
      revealed in 41% of cases. The analysis showed that there are no symptoms,
      pathognomonic for carcinoids of the lungs; carcinoid syndrome was not detected in
      any patient. The examination (roentgenography and CT of the lungs, bronchoscopy)
      has not provided any objective, differential diagnostic criteria for carcinoids,
      cancer and benign tumors of the lungs. Morphological examination of the removed
      tumors allowed all the carcinoids to be divided in two types: typical (benign
      neuroendocrine tumor) and atypical (well differentiated neuroendocrine
      carcinoma). The final differentiation is possible only after conduction of
      thorough histological, electron microscopy and immunohistochemical examination.
      The principal method of carcinoids treatment is surgical one. The optimal
      surgical procedure is pneumonectomy or lobectomy with lymphadenectomy. Atypical
      resection of the lung without lymphadenectomy in peripheral location of the tumor
      is justified only in early stages of the disease and in cases of morphological
      verification of benign character of neuroendocrine tumor. Late results were
      followed up in 27 patients. In the group of patients with atypical carcinoids in
      terms of 6 to 12 months 3 patients died from progressing of the main disease.
      There were neither lethal outcomes nor signs of relapse of the disease in the
      group of patients with typical carcinoid. The terms of follow up were from 1 year
      to 12 years.

PMID- 10358974
TI  - [Concealed exclusion of perforant and varicose veins of lower extremities venous
      insufficiency (communication II)].
AB  - The second and the third elements of surgical treatment of a varicose disease and
      chronic venous insufficiency by concealed exclusion of perforant and varicose
      subcutaneous veins are outlined. The exclusion of perforant veins of the shin is
      limited by the zone of Achilles (sub- and retromalleolar) cellular space in
      muscular channel of the lower extremity. Blunt supra- and infrafascial dissection
      of cellular tissue with passing there extramuscular perforant veins is performed
      between two incisions-punctures of the skin of internal surface of the shin at
      the level of 7 and 20 cm from the sole of the foot using firm ligature and
      Jigly's hand-saw. Because of disadvantages of Clapp's method, a modified way of
      putting immersed concealed ligatures on subcutaneous varicose veins is proposed.
      It includes the usage of the second needle with a blunt end as well as returned
      conducting of the ligature's end above the vein in a shape of a double loop.
      After tying a knot with one branch of the loop by pulling another dipping end of
      the ligature the dissection of the tied vein from the skin and its dislocation
      within its own bed is carried out. 58 patients were operated on according to this
      method of treatment for varicose vein disease and recanalized form of the
      postphlebothrombotic syndrome. Unfavorable outcome was detected in 1 patient with
      occlusion form of this syndrome and chronic venous insufficiency of III grade in
      which operative treatment was not strictly indicated.

PMID- 10358976
TI  - [Development of outpatient surgical service in Saint Petersburg].

PMID- 10358978
TI  - [A rare case of generalized neurofibromatosis (Recklinghausen's disease)].

PMID- 10358979
TI  - [Methods of gallbladder intrahepatic bed treatment after cholecystectomy
      (literature review)].

PMID- 10358975
TI  - [Stewart-Treves syndrome--lymphangiosarcoma in sever lymphostasis of arm after
      mastectomy].
AB  - Stewart-Treves Syndrome ('STS) is a rare, extremely malignant and quickly
      progressing tumor. It is angiosarcoma developing in lymphostasis of an arm after
      radical mastectomy for cancer. The patient aged 80 years was followed-up, in whom
      STS had developed 19 years after radical mastectomy. Clinical diagnosis was
      confirmed by pathomorphological examination of dermal biopsy. Advanced age and
      severe associated diseases made it impossible to carry out specific therapy. The
      patient died of intoxication and increasing cardio-vascular insufficiency 9
      months after the onset of the disease.

PMID- 10358977
TI  - [Penetrating injury of abdomen through the perineum].

PMID- 10358980
TI  - Prognostic factors for supratentorial low grade astrocytomas in adults.
AB  - The principal prognostic factors and effect on survival were retrospectively
      evaluated in 56 adult patients with supratentorial low grade astrocytomas treated
      between 1967 and 1993. Fifteen factors were evaluated with uni- and multivariate
      analysis to investigate their importance in predicting the length of survival.
      The median patient age at presentation was 42 years and the median survival was
      5.0 years. The following characteristics were associated with improved patient
      survival by univariate analysis (p < 0.01): Age group, preoperative Karnofsky
      scale, and extent of surgery. Age group and Karnofsky scale were significant by
      multivariate analysis, but not the extent of surgery. Thus the usefulness of
      cytoreductive surgery in the management remains unclear, but the extent of
      surgery is determined by the characteristics of the tumor and the potential of
      the patient. Since 93% of our patients received postoperative radiotherapy, the
      effect of adjuvant irradiation could not be determined.

PMID- 10358981
TI  - Magnetic resonance cisternography using the fast spin echo method for the
      evaluation of vestibular schwannoma.
AB  - Neuroimaging of vestibular schwannoma was performed with the fat-suppression
      spoiled gradient recalled acquisition in the steady state (SPGR) method and
      magnetic resonance (MR) cisternography, which is a fast spin echo method using a
      long echo train length, for the preoperative evaluation of the lateral extension
      of the tumor in the internal auditory canal, and the anatomical identification of
      the posterior semicircular canal and the nerves in the canal distal to the tumor.
      The SPGR method overestimated the lateral extension in eight cases, probably
      because of enhancement of the nerves adjacent to the tumor in the canal. The
      posterior semicircular canal could not be clearly identified, and the cranial
      nerves in the canal were shown only as a nerve bundle. In contrast, MR
      cisternography showed clear images of the lateral extension of the tumor and the
      facial and cochlear nerves adjacent to the tumor in the internal auditory canal.
      The anatomical location of the posterior semicircular canal was also clearly
      shown. These preoperative findings are very useful to plan the extent to which
      the internal auditory canal can be opened, and for intraoperative identification
      of the nerves in the canal. MR cisternography is less invasive since no contrast
      material or radiation is required, as with thin-slice high-resolution computed
      tomography (CT). MR cisternography should replace high-resolution CT for the
      preoperative neuroradiological evaluation of vestibular schwannoma.

PMID- 10358982
TI  - Stereotactic radiosurgery for cavernous sinus cavernous hemangioma--case report.
AB  - A 40-year-old female presented with cavernous sinus cavernous hemangioma
      manifesting as left abducens and trigeminal nerve pareses. Magnetic resonance
      imaging revealed a left cavernous sinus tumor. The tumor was partially removed.
      Histological examination of the specimen confirmed cavernous hemangioma.
      Radiosurgery was performed using the gamma knife. The tumor markedly decreased in
      size after radiosurgery and morbidity was avoided. Cavernous sinus cavernous
      hemangiomas may be difficult to treat surgically due to intraoperative bleeding
      and cranial nerve injury. Stereotactic radiosurgery can be used either as an
      adjunct treatment to craniotomy, or as the primary treatment for small cavernous
      sinus cavernous hemangioma.

PMID- 10358983
TI  - Angiographically occult dural arteriovenous malformation in the anterior cranial
      fossa--case report.
AB  - A 62-year-old male presented with a dural arteriovenous malformation located in
      anterior cranial fossa manifesting as acute right frontal intracerebral and
      subdural hematomas. Cerebral angiography showed only mass sign, but surgical
      exploration disclosed the dural arteriovenous malformation in the anterior
      cranial fossa. Anterior cranial fossa dural arteriovenous malformation should be
      considered if computed tomography reveals intracranial bleeding involving the
      frontal base, even if cerebral angiography does not demonstrate vascular
      anomalies.

PMID- 10358984
TI  - Moyamoya disease showing atypical angiographic findings--two case reports.
AB  - A 7-year-old boy and a 10-year-old girl presented with moyamoya disease showing
      atypical angiographic findings. In these cases, the internal carotid artery (ICA)
      had a tapering occlusion just distal to the origin of the ophthalmic artery,
      whereas the top of the ICA was not occluded and was retrogradely supplied through
      the posterior communicating artery from the posterior circulation. Surgical
      treatment resolved the symptoms in both patients. Moyamoya disease may include a
      number of variant types not showing all the characteristic angiographic findings
      of moyamoya disease.

PMID- 10358985
TI  - Lumbar spinal subdural hematoma following craniotomy--case report.
AB  - A 52-year-old female complained of lumbago and weakness in the lower extremities
      6 days after craniotomy for clipping an aneurysm. Neurological examination
      revealed symptoms consistent with lumbosacral cauda equina compression. The
      symptoms affecting the lower extremities spontaneously disappeared within 3 days.
      Magnetic resonance (MR) imaging 10 days after the operation demonstrated a lumbar
      spinal subdural hematoma (SSH). She had no risk factor for bleeding at this site,
      the symptoms appeared after she began to walk, and MR imaging suggested the SSH
      was subacute. Therefore, the SSH was probably due to downward movement of blood
      from the cranial subdural space under the influence of gravity. SSH as a
      complication of cranial surgery is rare, but should be considered if a patient
      develops symptoms consistent with a lumbar SSH after craniotomy.

PMID- 10358986
TI  - Massive subependymal hemorrhage caused by an occult vascular malformation--two
      case reports.
AB  - Two patients presented with massive subependymal hemorrhage caused by vascular
      anomalies occult to angiography, computed tomography (CT) scanning, and magnetic
      resonance (MR) imaging. A 47-year-old male initially presented with a headache
      and became comatose 3 weeks later. CT and MR imaging demonstrated a massive
      hematoma in the right caudate head projecting into the lateral ventricle. A 60
      year-old male sustained heaviness of his left extremities 8 days prior to
      admission and his condition gradually deteriorated. Neuroimaging revealed a right
      thalamic hematoma adjacent to the lateral ventricle. Cerebral angiography, CT,
      and MR imaging failed to detect any vascular anomaly. The hematomas increased in
      size gradually and were surgically explored. The histological diagnosis was
      arteriovenous malformation for the first case and cavernous angioma for the
      second case that had ruptured repeatedly. These cases were unique in the unusual
      location in the subependyma, and diagnostic neuroimaging modalities could not
      disclose the vascular anomalies, and the hematomas enlarged progressively to
      become critically symptomatic. Surgical intervention is mandatory for mass
      reduction and correct diagnosis of such lesions, with favorable outcome as long
      as the surgery is not delayed until too late.

PMID- 10358987
TI  - Paraganglioma in the frontal skull base--case report.
AB  - A 56-year-old female presented with a paraganglioma in the left anterior cranial
      fossa who manifesting as persistent headache. Computed tomography and magnetic
      resonance imaging showed a solid, enhanced tumor with a cystic component located
      medially. The tumor was attached to the left frontal base and the sphenoid ridge.
      Angiography demonstrated a hypervascular tumor fed mainly by the left middle
      meningeal artery at the left sphenoid ridge. The preoperative diagnosis was
      meningioma of the left frontal base. The tumor was totally resected via a left
      frontotemporal craniotomy. Histological examination revealed the characteristic
      cellular arrangement of paraganglioma generally designated as the "Zellbaren
      pattern" on light microscopy. Only 10 patients with supratentorial paraganglioma
      have been reported, seven located in the parasellar area. The origin of the
      present tumor may have been the paraganglionic cells which strayed along the
      middle meningeal artery at differentiation.

PMID- 10358988
TI  - Migration of the abdominal catheter of a ventriculoperitoneal shunt into the
      scrotum--case report.
AB  - A 3-day-old male neonate presented with migration of the ventriculoperitoneal
      (VP) shunt tip through the patent processus vaginalis resulting in scrotal
      hydrocele. The association of myelomeningocele with hydrocephalus may have been a
      predisposing factor in this rare complication. Development of scrotal swelling or
      hydrocele in a child with VP shunt should be recognized as a possible shunt
      complication.

PMID- 10358989
TI  - Mesh-and-glue technique to prevent leakage of cerebrospinal fluid after
      implantation of expanded polytetrafluoroethylene dura substitute--technical note.
AB  - Expanded polytetrafluoroethylene (ePTFE) can be used as a dura substitute but is
      associated with leakage of cerebrospinal fluid (CSF) through the suture line.
      Fibrin glue alone may not prevent this problem. This new method for sealing the
      suture line in ePTFE membrane uses an absorbable polyglycoic acid mesh soaked
      with fibrinogen fluid placed on the suture line. Thrombin fluid is then slowly
      applied to the wet mesh, forming a large fibrin membrane reinforced by the mesh
      over the suture line. Only one of 33 patients in whom this technique was used had
      CSF leakage, whereas 12 of 59 patients in whom a dural defect was closed with
      ePTFE alone showed postoperative subcutaneous CSF collection (p < 0.05). Our
      clinical experiences clearly show the efficacy of the mesh-and-glue technique to
      prevent CSF leakage after artificial dural substitution. Mesh and glue can
      provide an adequate repair for small dural defect. The mesh-and-glue technique
      may also be used for arachnoid sealing in spinal surgery.

PMID- 10358991
TI  - [The clinical efficacy of a one-time course of infrared laser irradiation in
      stenocardia patients based on 6-month follow-up data].
AB  - As shown by a 6-month follow-up of anginal patients exposed to a single 10-day
      course of infrared laser radiation, the antianginal effect of this laser
      treatment manifested 1 month after the end of the radiation, was registered in 80
      82% of the patients and persisted after 6-month follow-up in 62.5% of the
      patients. The therapeutic effect was the highest in patients with severe coronary
      insufficiency.

PMID- 10358990
TI  - [A validation and trial of the clinical use of tocopherol ultraphonopheresis].

PMID- 10358992
TI  - [The effect of phyto-air ionization on the main homeostatic systems in patients
      with neurocirculatory dystonia and essential hypertension].
AB  - We used phytoaeroionization in patients with neurocirculatory asthenia and
      essential hypertension. We discovered a favourable influence of
      phytoaeroionization on function of the brain and its hemodynamics. It also
      reduced the immunity response tension, activated hormone regulation, promoted
      mobilization of energetic resources of the organism which contribute to
      improvement of adaptation processes.

PMID- 10358993
TI  - [The use of low-frequency ultrasound in the combined therapy of pulmonary
      tuberculosis patients].
AB  - The validity of low-frequency ultrasound (LFU) addition to specific therapy of
      pulmonary tuberculosis (PT) was investigated in 2 groups of PT new cases. The
      study group (n = 25) received specific therapy and ultrasonic treatment (44 KHz,
      amplitude 2 microm to the paravertebral region and PT zones). The control group
      (n = 25) received specific therapy only. The response to treatment was higher in
      the study group. The findings support validity of low-frequency ultrasound use as
      an adjuvant in treatment of PT new cases.

PMID- 10358994
TI  - [The correction of the hormonal response during the treatment of the dumping
      syndrome with potable mineral waters].
AB  - Glucose tolerance test (40 g/lm2 b.s.) in patients with stomach resected for
      gastroduodenal ulcer provoked dumping-syndrome seen 15-30 min after glucose
      introduction. There was also a rise in blood sugar (by 77%), ACTH (by > 400%),
      STH (by > 400%), hydrocortisone (by 56%). Aldosterone levels fell by 68%. There
      was also a marked fall in activity of early insulin pool changed for elevation of
      its secretion by the test minute 60. 65 patients with dumping-syndrome following
      a course of drinking mineral water demonstrated improvement in clinical symptoms
      of the disease and changed hormonal response to glucose which manifested with
      activation of insulin secretion early phase and reduced rise of hydrocortisone
      levels.

PMID- 10358995
TI  - [The effect of electromagnetic radiation in the millimeter range on the
      development of disorders in the liver induced by ether anesthesia (experimental
      research)].
AB  - Rat experiments with ether anaesthesia (EA) indicate that EA induces enlargement
      of hepatic sinusoids, stasis and perivascular edema of the triad vessels and
      other changes in the liver. Right hypochondrium exposure to electromagnetic waves
      (4.76-5.08 mm) up to 20 days in rats given simultaneously ether anaesthesia
      showed that livers from the irradiated rats did not differ from control. Thus,
      millimetric wave radiation may prevent pathological alterations arising in white
      rat liver after ether anaesthesia.

PMID- 10358996
TI  - [Changes in the immune status of peptic ulcer patients after combined treatment
      including deep massage].
AB  - Unsatisfactory results of ulcer drug medication necessitate introduction of new
      approaches to treatment of this disease. We tried massage and therapeutic
      exercise as alternative methods of ulcer treatment as they provide biologically
      validated ways to mobilization of the body defenses. The results of our studies
      showed that deep reflex muscular massage and exercises for extension of the
      skeletal muscles are not inferior in effectiveness in ulcer than routine drug
      therapy. Therefore, the massage and the exercises are advisable adjuvant
      modalities in sparing drug medication improving immune status and treatment
      outcomes in patients with ulcer in exacerbation.

PMID- 10358997
TI  - [The use of puncture physiotherapy for optimizing the mud therapy of spinal
      osteochondrosis patients].
AB  - It is shown that physical puncture effects arouse favourable reactions of human
      organism both in monotherapy and in combined therapy with peloids. This suggests
      a conclusion that indications to physiotherapy of spinal osteochondrosis can be
      extended and cover also acute osteochondrosis, that new complexes of physiopeloid
      therapy may be designed with minimal risk of balneoreactions.

PMID- 10358998
TI  - [The staged medical rehabilitation of patients with secondary chronic
      pyelonephritis in infravesical obstructions].
AB  - The authors believe that chronic pyelonephritis patients operated for
      infravesical obstructions need staged postoperative rehabilitation. In
      antibacterial postoperative treatment, a significant response was seen in 7.9%, a
      partial response in 18.4% and no response in 73.7% of patients. After combined
      physiotherapy--in 38%, 41.7% and 20.3% of patients, respectively.

PMID- 10358999
TI  - [Physical factors in the treatment and rehabilitation of patients with chronic
      prostatitis complicated by impotence].
AB  - 103 patients with chronic prostatitis complicated by erectile impotence were
      given combined treatment including shock-wave massage, mud applications, local
      vacuum magnetotherapy. This combination was found to stimulate copulative
      function, urodynamics of the lower urinary tracts, to produce an antiinflammatory
      effect. These benefits allow to recommend the above physical factors for
      management of chronic prostatitis patients with copulative dysfunction.

PMID- 10359000
TI  - [The clinico-immunological assessment of the efficacy of the intravasal laser
      therapy of bronchial asthma patients].

PMID- 10359001
TI  - [Traction for patients with a pain syndrome in cervical osteochondrosis on an
      outpatient basis].

PMID- 10359002
TI  - [The structural organization and biological activity of artificial and natural
      potable mineral waters].

PMID- 10359003
TI  - [The current demands for the sanitary microbiological evaluation of mineral
      waters].

PMID- 10359004
TI  - [A method for producing humus peloid preparations].

PMID- 10359005
TI  - [The rationalization of the management of the patient rehabilitation process at a
      sanatorium based on computer technology].

PMID- 10359006
TI  - [The concept and methodology of the development of health-improving
      (recuperative) medicine].

PMID- 10359007
TI  - [Autonomic vascular dysfunction and physical therapy methods].

PMID- 10359008
TI  - [Electrotherapy in modern gynecology abroad].

PMID- 10359009
TI  - [The modern concepts of phyto-aromatherapy].

PMID- 10359010
TI  - Nuclear factor kappaB cooperates with c-Myc in promoting murine hepatocyte
      survival in a manner independent of p53 tumor suppressor function.
AB  - The nuclear factor-kappaB (NF-kappaB)/Rel family of transcription factors has
      been implicated in promoting hepatocyte survival during development and liver
      regeneration following partial hepatectomy. Inhibition of NF-kappaB/Rel activity
      by microinjection of the specific inhibitor IkappaB-alpha induces apoptosis in a
      nontransformed normal murine hepatocyte (NMH) cell line. Here, we demonstrate
      that apoptosis resulting from such inhibition requires down-regulation of the c
      Myc proto-oncoprotein and occurs independently of p53 tumor suppressor function.
      NMH cells plated at low density displayed low sensitivity to IkappaB-alpha
      induced apoptosis and high levels of c-Myc protein expression. Comicroinjection
      of IkappaB-alpha with the c-Myc antagonist Mad1-glutathione S-transferase fusion
      protein greatly enhanced cell death. In addition, transient cotransfection of low
      density NMH and AML12 hepatocytes with vectors expressing IkappaB-alpha and
      antisense c-myc transcripts promoted cell death. Conversely, ectopic c-myc
      expression significantly decreased the extent of cell death in NMH cells plated
      at saturating density, which were characterized by very low levels of c-Myc and
      high susceptibility to NF-kappaB inhibition-induced cell death. Finally, IkappaB
      alpha-induced apoptosis was unaffected in NMH cells expressing a dominant
      negative p53 protein. Thus, NF-kappaB cooperates with c-Myc in promoting murine
      hepatocyte survival in a manner independent of p53 tumor suppressor activity.

PMID- 10359011
TI  - p53 is a transcriptional activator of the muscle-specific phosphoglycerate mutase
      gene and contributes in vivo to the control of its cardiac expression.
AB  - The role that the p53 tumor suppressor gene product plays in cellular
      differentiation remains controversial. However, recent evidence indicates that
      p53 is required for proper embryogenesis. We have studied the effect of p53 on
      the expression mediated by the promoter of the rat muscle-specific
      phosphoglycerate mutase gene (M-PGAM), a marker for cardiac and skeletal muscle
      differentiation. Experiments involving transient transfection, mobility shift
      assay, and site-directed mutagenesis demonstrated that p53 specifically binds and
      transactivates the M-PGAM promoter. The p53-related proteins p51A and p73L also
      transactivated M-PGAM. Moreover, stable expression of a p53 dominant mutant in
      C2C12 cells blocked the induction of M-PGAM expression during the myoblast to
      myotube transition and the ability of p53, p51A, and p73L to transactivate the M
      PGAM promoter. In addition, impaired expression of M-PGAM was observed in a
      subset of p53-null animals in heart and muscle tissues of anterior-ventral
      location. These results demonstrate that p53 is a transcriptional activator of M
      PGAM that contributes in vivo to the control of its cardiac expression. These
      data support previous findings indicating a role for p53 in cellular
      differentiation.

PMID- 10359012
TI  - Phorbol ester-induced mononuclear cell differentiation is blocked by the mitogen
      activated protein kinase kinase (MEK) inhibitor PD98059.
AB  - The purpose of this study was to evaluate whether the mitogen-activated protein
      kinase (MAPK) signaling pathway contributes to 12-O-tetradecanoylphorbol-13
      acetate (TPA)-induced mononuclear differentiation in the human myeloblastic
      leukemia ML-1 cells. Upon TPA treatment, the activity of ERK1 and ERK2 rapidly
      increased, with maximal induction between 1 and 3 h, while ERK2 protein levels
      remained constant. The activity of JNK1 was also significantly induced, with JNK1
      protein levels increasing moderately during exposure to TPA. Treatment of cells
      with PD98059, a specific inhibitor of mitogen-activated protein kinase kinase
      (MEK), inhibited TPA-induced ERK2 activity. Furthermore, PD98059 completely
      blocked the TPA-induced differentiation of ML-1 cells, as assessed by a number of
      features associated with mononuclear differentiation including changes in
      morphology, nonspecific esterase activity, phagocytic ability, NADPH oxidase
      activity, mitochondrial respiration, and c-jun mRNA inducibility. We conclude
      that activation of the MEK/ERK signaling pathway is necessary for TPA-induced
      mononuclear cell differentiation.

PMID- 10359013
TI  - Constitutively active mitogen-activated protein kinase kinase MEK1 disrupts
      morphogenesis and induces an invasive phenotype in Madin-Darby canine kidney
      epithelial cells.
AB  - During certain developmental processes, as well as during tumor progression,
      polarized epithelial cells integrated within multicellular structures convert
      into scattered, freely migrating fibroblast-like cells. Despite the biological
      and clinical importance of this phenomenon, the intracellular biochemical
      cascades that control the switch between the epithelial and mesenchymal
      phenotypes have not been elucidated. Using Madin-Darby canine kidney (MDCK) cells
      (clone C7) as a model system, we have assessed the potential role of the mitogen
      activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK)
      cascade in the modulation of epithelial plasticity. When grown in three
      dimensional collagen gels, MDCK-C7 cells form spherical cysts composed of
      polarized epithelial cells circumscribing a central lumen. This morphogenetic
      behavior is profoundly subverted in MDCK-C7 cells expressing a constitutively
      active MAPK/ERK kinase 1 (caMEK1) mutant (C7-caMEK1 cells). When suspended in
      collagen gels, C7-caMEK1 cells assume an elongated fibroblastoid shape and are
      unable to generate multicellular cysts. In addition, when seeded onto the surface
      of a collagen gel, C7-caMEK1 cells penetrate extensively into the underlying
      matrix, unlike wild-type and mock-transfected MDCK-C7 cells, which remain
      confined to the surface of the gel. Similar changes in morphogenetic and invasive
      properties are observed in MDCK-C7F cells, a nontransfected, stably
      dedifferentiated derivative of MDCK-C7 cells that expresses substantially
      increased ERK2 activity. Both C7-caMEK1 and MDCK-C7F cells but not wild-type or
      mock-transfected MDCK-C7 cells express activated M(r) 72,000 gelatinase A [matrix
      metalloproteinase (MMP)-2] as well as elevated levels of membrane type-1 MMP.
      Synthetic MMP inhibitors as well as recombinant tissue inhibitor of
      metalloproteinases 2 and 3 suppress the invasion of collagen gels and restore the
      capacity of C7-caMEK1 cells to form cysts, thereby implicating the membrane type
      1 MMP/MMP-2 proteolytic system in epithelial cell invasiveness and loss of
      multicellular organization. Taken together, our data demonstrate that increased
      activity of the MEK1-ERK2 signaling module in MDCK-C7 cells is associated with
      failure of morphogenesis and expression of a highly invasive phenotype. Sustained
      activation of the MAPK cascade therefore results in the destabilization of the
      three-dimensional architecture and the conversion of polarized epithelial cells
      into migrating mesenchymal-like cells.

PMID- 10359014
TI  - Fra-2-positive autoregulatory loop triggered by mitogen-activated protein kinase
      (MAPK) and Fra-2 phosphorylation sites by MAPK.
AB  - We reported previously that activation of endogenous activator protein 1 (AP-1)
      in chicken embryo fibroblasts is essential for the cellular transformation
      induced by v-src, and we further showed that the activation of AP-1 is
      accompanied by elevation of Fra-2 and c-Jun expression and also high-level
      phosphorylation of Fra-2 by activated endogenous extracellular signal-regulated
      kinase [mitogen-activated protein kinase (MAPK)]. Here, we report that the
      transcriptional activity of Fra-2/c-Jun heterodimer was greatly enhanced by
      cotransfecting a constitutively active mutant of MEK1 gene (MEK-DD) into F9
      cells, indicating that Fra-2 was converted into an active transactivator after
      phosphorylation by MAPK. High-level expression of MEK-DD alone was sufficient to
      induce clear cellular transformation of chicken embryo fibroblasts, which caused
      constitutive activation of endogenous MAPK, hyperphosphorylation of Fra-2, and
      elevation of fra-2 and c-jun gene expression. These results indicate that
      phosphorylation of Fra-2 by MAPK plays an important role in stimulating
      endogenous AP-1 activity in a positive autoregulation mechanism, in which
      phosphorylated Fra-2 induces fra-2 expression through AP-1 binding sites present
      in its promoter. We also localized the Fra-2 phosphorylation sites by MAPK to
      three threonine and three serine residues in the COOH-terminal region by means of
      site-directed mutagenesis and showed that the threonine residues were more
      susceptible to MAPK.

PMID- 10359015
TI  - Overexpression of protein kinase Calpha in MCF-10A human breast cells engenders
      dramatic alterations in morphology, proliferation, and motility.
AB  - A nonmetastatic human mammary epithelial cell line (MCF-10A) was engineered to
      overproduce protein kinase Calpha (PKCalpha) so as to investigate a role for this
      isoform in the metastatic phenotype. PKCalpha transfectants (clone 26alpha)
      expressed an 8-fold higher level of PKCalpha protein without compensatory
      alterations in other isoforms. Clone 26alpha proliferated slowly (accumulating in
      G1 of the cell cycle) but exhibited pronounced increases in motility and
      adhesion. Elevated expression of cell cycle inhibitor p27 and focal adhesion
      proteins was observed, whereas E-cadherin expression decreased to undetectable
      levels. These observations were consistent with the morphology of PKCalpha
      transfectants (large, disaggregated, and flat, with lamellipodia and extensive
      actin fibers) and control cells (small, aggregated, and refractile). Treatment
      with PKC inhibitors or transfection of a dominant negative (dn) mutant of Rac1,
      but neither dn RhoA nor dn cdc42, reduced the motility of clone 26alpha,
      implicating PKCalpha catalytic activity and endogenous Rac1, respectively, in the
      PKCalpha-induced phenotype. Overall, PKCalpha overexpression suppresses
      proliferation while endowing MCF-10A cells with properties consistent with the
      metastatic phenotype.

PMID- 10359016
TI  - Transcriptional up-regulation of matrix metalloproteinase-9 expression during
      spontaneous epithelial to neuroblast phenotype conversion by SK-N-SH
      neuroblastoma cells, involved in enhanced invasivity, depends upon GT-box and
      nuclear factor kappaB elements.
AB  - Spontaneous epithelial (S) to neuroblast (N) conversion enhanced the capacity of
      SK-N-SH neuroblastoma (NB) cells to invade reconstituted basement membrane in
      vitro. This involved a switch to matrix metalloproteinase (MMP) activity, in
      particular MMP-9, and was associated with the induction of MMP-9 expression. N
      type-specific MMP-9 expression was herbimycin A inhibitable tyrosine kinase
      (possibly c-src) dependent and was regulated transcriptionally through GT-box (
      52), and nuclear factor kappaB (NFkappaB; -600) elements within the MMP-9 gene.
      GT-box function was associated with elevated levels of specific nuclear GT-box
      binding complexes in N-type cells. NFkappaB function was associated with specific
      p50- and p65-containing nuclear NFkappaB binding complex(es). No function could
      be attributed to the proximal AP-1 (-79) element, and minimal function was
      attributed to the SP-1 (-560), ets (-540), or distal AP-1 (-533) elements. This
      was despite elevated levels of specific junD/fra-1 containing proximal AP-1
      element binding complex(es) in N-type cells. Our data highlight a pivotal role
      for the GT-box, in concert with the NFkappaB element, in the transcriptional up
      regulation of MMP-9 expression during spontaneous S to N phenotype conversion by
      SK-N-SH cells involved in enhanced basement membrane invasivity.

PMID- 10359017
TI  - New gene targets related to schizophrenia and other psychiatric disorders:
      enzymes, binding proteins and transport proteins involved in phospholipid and
      fatty acid metabolism.
AB  - Phospholipids make up about 60% of the brain's dry weight. In spite of this,
      phospholipid metabolism has received relatively little attention from those
      seeking genetic factors involved in psychiatric and neurological disorders.
      However, there is now increasing evidence from many quarters that abnormal
      phospholipid and related fatty acid metabolism may contribute to illnesses such
      as schizophrenia, bipolar disorder, depression and attention deficit
      hyperactivity disorder. To date the possible specific proteins and genes involved
      have been relatively ill-defined. This paper reviews the main pathways of
      phospholipid metabolism, emphasizing the roles of phospholipases of the A2 and C
      series in signal transduction processes. It identifies some likely protein
      candidates for involvement in psychiatric and neurological disorders. It also
      reviews the chromosomal locations of regions likely to be involved in these
      disorders, and relates these to the known locations of genes directly or
      indirectly involved in phospholipid and fatty acid metabolism.

PMID- 10359018
TI  - The role of prostaglandins in the aetiology and treatment of erectile
      dysfunction.
AB  - Both animal and human penile tissue synthesize prostaglandins (PGs). Furthermore,
      intracavernous injection of certain PGs elicits erection in men with erectile
      dysfunction (ED). It is also well established that PGs are involved in the
      pathophysiology of atherosclerosis and diabetes mellitus (DM). Since
      atherosclerosis and DM are major risk factors for ED, it has been suggested that
      the disruption of PG synthesis in penile tissues and related vasculature may play
      a role in the pathogenesis of ED. In this review, we discuss the role of PGs in
      normal penile erection as well as on the pathophysiology and treatment.

PMID- 10359019
TI  - Generation of thromboxane A2 from highly purified human sinus mast cells after
      immunological stimulation.
AB  - To better understand metabolites of arachidonic acid generated from human mast
      cells, the present study assessed the capacity of human mast cells to synthesize
      thromboxane B2 (TXB2). Anti-IgE challenge of human sinus mast cells resulted in
      the generation of TXB2 in a dose-dependent manner with a maximal generation of
      8.2+/-4.4 ng/10(6) cells (n = 12), which is about 10-fold lower than the maximal
      generation of prostaglandin D2 (PGD2). Pretreatment of the cells with OKY-046, an
      inhibitor of TXA synthase, prevented formation of TXB2 in a dose-dependent manner
      without affecting the generation of PGD2 or leukotriene C4. Experiments using
      indomethacin or MK-591, a potent FLAP inhibitor, showed that shunting of
      arachidonic acid did not occur in a single-cell suspension of mast cells.
      Analysis by RT-PCR revealed that two species of TXA synthase, the full-length TXA
      synthase mRNA (TXAS-1, 570 BP) and a small quantity of the alternate-spliced form
      (400 BP), were present in mast cells. When cellular levels of TXAS-1 mRNA were
      normalized to those of G3PDH mRNA, the relative concentration of TXAS-1 was
      2.06+/-0.60 (n = 7) in highly purified sinus mast cells (92.3+/-3.0% pure) and
      3.66+/-0.98 (n = 5) in eosinophils.

PMID- 10359020
TI  - Ibuprofen attenuates cardiopulmonary dysfunction by modifying vascular tone in
      endotoxemia.
AB  - Ibuprofen, a cyclooxygenase inhibitor, improves pulmonary and cardiovascular
      injury in endotoxemia. We studied the mechanism of the beneficial effects of
      ibuprofen in relation to production of inflammatory mediators which influence
      vascular tone in endotoxemia. Rats were randomly assigned to one of three groups:
      (1) control, (2) endotoxemia alone; and (3) ibuprofen pretreatment and
      endotoxemia. Plasma and lung lavage concentrations of tumor necrosis factor,
      thromboxane B2 (TXB2), leukotriene (LT) C4,D4,E4 and nitric oxide (NO) were
      determined over a 2 h period. Pretreatment with ibuprofen resulted in increased
      survival, and attenuation of pulmonary and cardiovascular dysfunction when
      compared to the rats receiving endotoxin alone. The marked elevation in plasma
      TXB2 concentration in endotoxemic rats was prevented by pretreatment with
      ibuprofen. Similarly, pretreatment with ibuprofen prevented the decrease in lung
      lavage NO levels in endotoxemic rats. The improved survival and cardiopulmonary
      protection in endotoxemic rats pretreated with ibuprofen appears to be related to
      decreased thromboxane production and preservation of endothelial production of
      nitric oxide.

PMID- 10359021
TI  - Arachidonic acid induces mobilization of calcium stores and c-jun gene
      expression: evidence that intracellular calcium release is associated with c-jun
      activation.
AB  - Arachidonic acid (AA) plays a signaling role in the induction of several genes.
      We previously demonstrated that AA induces c-jun gene expression in the stromal
      cell line +/+.1 LDA 11 by a signaling pathway involving activation of the c-jun
      amino-terminal kinase (JNK). This study investigated the role of calcium in AA
      signaling of c-jun activation in +/+.1 LDA 11 cells. AA (10-50 microM) caused a
      rapid dose-dependent rise in cytosolic calcium. AA-induced calcium mobilization
      involved both influx of extracellular calcium and the release of intracellular
      calcium. The importance of calcium was investigated by variation of the
      extracellular calcium concentration, chelation of intracellular calcium and by
      calcium ionophore-induced influx of extracellular calcium. AA-induced c-jun gene
      expression and increased luciferase activity of a construct containing the high
      affinity AP-1 binding site was decreased in cells preincubated with the
      intracellular calcium chelator 1,2-bis(o-aminophenoxy)-eThane-N,N,N',N',
      tetraacetic acid tetra(aceToxymethyl-esTer) (BAPTA-AM, 10 microM) prior to
      stimulation with AA. Similarly, chelation of intracellular calcium decreased AA
      induced JNK activation. On the contrary, changes in the extracellular calcium
      concentration had no effect. Also, ionophore A23187 failed to induce c-jun and
      JNK activation either alone than in combination with AA. These results suggested
      that calcium was required for AA-dependent activation of c-jun, but that calcium
      alone was insufficient to induce activation of c-jun. Thus, release of calcium
      from intracellular stores is implicated in the signaling pathway of AA-induced c
      jun activation in stromal cells.

PMID- 10359022
TI  - Does supplementation of formula with evening primrose and fish oils augment long
      chain polyunsaturated fatty acid status of low birthweight infants to that of
      breast-fed counterparts?
AB  - We investigated whether formulae with evening primrose and fish oils raise long
      chain polyunsaturated fatty acids (LCPUFA) in plasma cholesterol esters (CE),
      erythrocytes (RBC) and platelets (PLT) to levels encountered in breast-fed
      infants. Low birthweight infants (< or =2500 g) received LCP1 formula (n = 16;
      0.31% 18:3 omega6, 0.17% 20:5 omega3 and 0.20% 22:6 omega3) or LCP2 formula (n =
      13; 0.32% 18:3 omega6, 0.34% 20:5 omega3 and 0.43% 22:6 omega3). Fatty acids were
      measured days 10+/-2, 20+/-3 and 42+/-3. The formulae raised CE, RBC and PLT 20:5
      omega3 and 22:6 omega3 dose-dependently (P<0.01), to exceed levels of breast-fed
      babies (n = 18) day 42 (P<0.05). CE, RBC and PLT 20:3 omega6 was comparable with,
      and CE, RBC, PLT 20:4 omega6 were below, that of breast-fed infants (P<0.05).
      Dietary 20:5 omega3 and 22:6 omega3 related with CE, RBC and PLT 20:5 omega3 and
      22:6 omega3 (n = 47; P< or =0.01). Dietary 20:5 omega3 and LCPUFA omega3 related
      inversely with CE, RBC and PLT 20:4 omega6 and LCPUFA omega6 (P< or =0.002). LCP1
      and LCP2 fed infants had similar LCPUFA omega6 status day 42. Added 18:3 omega6
      does not correct 20:4 omega6 to that of breast-fed infants, but improves 20:3
      omega6 status. Fish oil dose-dependently raises 20:5 omega3 and 22:6 omega3, but
      decreases 20:4 omega6 and other LCPUFA omega6.

PMID- 10359023
TI  - Fatty acid desaturation: effect of alphafetoprotein on alpha-linolenic acid
      conversion by fetal rat hepatocytes.
AB  - Freshly isolated fetal hepatocytes transformed 4.3, 8.5 and 19.2 pmol/min/10(6)
      cells of stearic, linoleic and alpha-linolenic acids, respectively, complexed to
      albumin or alpha-fetoprotein (AFP), to more unsaturated derivatives. Thus, fetal
      hepatocytes displayed high elongase and delta9, delta6, delta5-desaturase
      activities, as well as an ability to synthesize hexaene derivatives. Desaturase
      activities decreased when the time of culture of fetal hepatocytes (previous to
      incubation with the substrate) was prolonged, being practically undetectable
      after 24 h of culture. However, the rate of fatty acid uptake remained nearly
      constant. When AFP was used as the carrier the amount of hexaene fatty acid
      derivatives of alpha-linolenic acid recovered in cells was reduced up to 50% by
      albumin. This effect was associated with an increase of radioactivity found in
      the culture medium of hepatocytes incubated with AFP compared to albumin. Both
      observations taken together could be explained by an efflux of hexaene
      derivatives from cells caused by AFP.

PMID- 10359024
TI  - Is endocrinological assessment and follow-up of children after bone marrow
      transplantation necessary? How, and for how long?

PMID- 10359025
TI  - The current status of mycophenolate mofetil in pediatric renal transplantation.

PMID- 10359026
TI  - Current understanding of chemokine involvement in allograft transplantation.
AB  - Multiple studies have demonstrated that chemokines play an essential role in
      regulating and co-ordinating the infiltration of leucocytes into allografts.
      Chemokines are expressed in skin, liver, heart, and kidney allografts following
      initial engraftment, ischemic injury, viral infection, and acute and chronic
      rejection. To date, most of our understanding of chemokine biology has been
      generated from studies of animal models of transplantation and little is known
      about the role of chemokines in human allograft rejection. Chemokines may play
      important mechanistic roles in transplant rejection, in the development of graft
      arteriosclerosis, and in chronic sclerosing cholangiopathy. Furthermore, these
      molecules may serve as sensitive diagnostic indicators for the analysis of
      rejection, including chronic rejection or other forms of graft dysfunction.
      Lastly, it is possible that chemokine-targeted therapy might become a feasible
      option for the treatment of allograft rejection.

PMID- 10359027
TI  - Long-term outcomes in pediatric liver recipients: comparison between cyclosporin
      A and tacrolimus.
AB  - In recent years, tacrolimus (FK506, TAC) has been increasingly utilized in liver
      transplantation. However, long-term risks and benefits as compared with
      conventional cyclosporin A (CsA) have not been fully elucidated. This
      retrospective study examined the potential outcome differences between TAC- and
      CsA-based immunosuppressive therapy in pediatric liver transplant recipients.
      From March 1988 to December 1996, 218 children (aged 0.1-17 yr) underwent 238
      orthotopic liver transplantations; 58.7% (128/218) were under 2 yr of age at time
      of transplant. Initially, the maintenance immunosuppressive regimen consisted of
      CsA and prednisone, with antilymphocytic preparations (MALG, ATGAM, and OKT3) as
      induction therapy. Subsequently, TAC was used first as rescue therapy for steroid
      refractory rejection in CsA patients and then as maintenance immunosuppression.
      Fifty-seven out of the 147 CsA patients were converted to TAC for various reasons
      while 71 patients were placed on TAC as primary maintenance immunosuppression.
      62.6 per cent (92/147) of liver recipients on CsA experienced at least one biopsy
      proven acute rejection episode as compared to 50.7% (36/71) for TAC patients (p =
      0.09); likewise, 34% (50/147) of CsA patients had more than one episode of
      rejection vs. 18.3% (13/71) for patients on TAC (p < 0.02). Rejection was the
      reason for conversion from CsA to TAC in 29 of 57 patients. Conversely, 19.0%
      (28/147) of CsA patients had to be switched to TAC for reasons not related to
      rejection (i.e. side-effects). The overall incidence of histologically proven
      chronic rejection was 7.8% (17/218). 10.9 per cent (16/147) of the children who
      were on CsA initially developed chronic rejection, which was significantly higher
      compared with one of 71 TAC recipients (p < 0.02). Of these 16 CsA patients with
      chronic rejection, 50.0% (8/16) underwent retransplantation for graft failure
      (mean interval from time of diagnosis of chronic rejection to re-transplant, 4.0
      months; range 1-8 months), whereas the TAC patient has remained clinically stable
      with normal liver function tests after 23 months of follow-up. One year after
      liver transplantation, 72.8% (107/147) of CsA patients were still on steroids
      (mean dosage 0.20 mg/kg/d), as compared to 42.3% (30/71) of the TAC patients
      (mean dosage 0.14 mg/kg/d). The incidence of post-transplant lymphoproliferative
      disorder (PTLD) in Epstein-Barr virus (EBV)-infected patients was 2.2% (2/90),
      7.0% (5/71) and 12.3% (7/57) for CsA, primary and TAC-converted groups,
      respectively. The overall incidence of PTLD was 6.9% (15/218). In summary,
      pediatric liver transplant recipients treated with TAC as primary maintenance
      immunosuppressive medication experienced significantly fewer episodes of
      rejection; especially chronic rejection, which lead to graft loss. However, the
      trade-off is a potential increased incidence of EBV-related PTLD in these
      patients.

PMID- 10359028
TI  - Trends in immunosuppressive therapy: a report of the North American Pediatric
      Renal Transplant Cooperative Study (NAPRTCS).
AB  - The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) data
      registry has now compiled data for 11 years, and includes data on 6038 renal
      transplants in 5516 patients. With the availability of new data and
      immunosuppressive medications, trends in their usage continue to change. NAPRTCS
      data have previously demonstrated that increased doses of cyclosporin A (CsA) are
      associated with improved allograft outcomes, and there has been a steady increase
      in the dose of CsA given post-transplantation. Transplants that occurred in 1987,
      1989, 1991, and 1993 received a mean one-year post-transplant dose of 6.5, 7.0,
      7.7, and 8.2 mg/kg/d, respectively. In the 1995 cohort, the dose decreased to 7.4
      mg/kg/d. Since the introduction of Neoral, its use has steadily increased. Of the
      1997 cohort, 81% report Neoral as the formulation of CsA used. The dose of CsA
      given, however, has not changed. At day 30 post-transplant, the dose was 7.0
      mg/kg/d for Sandimmune and 7.4 mg/kg/d for Neoral. Finally, the outcome in black
      transplant patients is inferior to that of nonblack. Evaluation of CsA blood
      levels revealed that at 1 year post-transplant, black patients consistently have
      CsA levels higher than nonblacks, and a lower percentage of black patients have a
      CsA level < 100 ng/mL. The percentage of patients using triple therapy
      (prednisone, azathioprine, and CsA) remained stable from 1987 to 1993 at 80-85%.
      However, in 1996 only 30% of patients were receiving triple therapy. This is
      probably due to the introduction of mycophenolate mofetil (MMF). Comparing the
      1996-97 cohorts, there has been no significant change in the percentage of
      patients receiving prednisone (96.2% vs. 95.4%) or CsA (83.1% vs. 79.6%).
      However, during this time, the use of azathioprine has decreased from 50.0% to
      35.8%, the use of tacrolimus has increased from 2.5% to 10.8%, and the use of MMF
      has increased from 6.5% to 35.8%.

PMID- 10359029
TI  - Mycophenolate mofetil in pediatric renal transplantation.
AB  - The use of mycophenolate mofetil (MMF) in adult renal transplantation has been
      associated with significantly decreased incidence of acute rejection. However,
      limited data are available for children after renal transplantation. A total of
      67 patients undergoing renal transplantation at the University of Alabama at
      Birmingham, AL, USA and Children's Hospital of Boston, MA, USA were enrolled into
      the Cooperative Clinical Trials in Pediatric Transplantation randomized
      controlled trial of induction with OKT3 vs. i.v. cyclosporin A (CsA) at the time
      of transplantation. The first 31 patients entered were begun on azathioprine
      (AZA), 2 mg/kg on the first post-operative day. The subsequent 36 patients were
      begun on MMF, 1000 mg/m2/d. Other maintenance immunosuppression included oral CsA
      and Prednisone. Biopsy confirmation was obtained for all suspected rejection
      episodes. Glomerular filtration rate (GFR) was calculated using the Schwartz
      formula. Data were analyzed using Kaplan Meier survival curves and compared using
      log-rank tests. At the time of analysis, 52 patients (mean age 10.1 +/- 5 yr) had
      completed at least 12 months and 15 others had completed at least 6 months of
      follow-up post-transplantation. Of these, there were 39 male/28 female; 48
      white/15 black/4 other; 49 living donor/18 cadaver donor. There were no
      significant differences in the incidence of rejection episodes, number of
      rejection episodes, the GFR at 6 and 12 months, allograft, or patient survival
      between patients receiving MMF vs. AZA. We could demonstrate no significant
      differences in these outcomes based on sex, race or induction therapy, leading to
      the conclusion that pediatric patients treated under a consistent protocol in two
      institutions have no improvement in short-term allograft outcome with the
      addition of MMF therapy.

PMID- 10359031
TI  - Follow-up experience in pediatric liver transplantation in an academic, non
      transplant-based gastroenterology group.
AB  - As pediatric liver transplantation has become relatively common since the early
      1980s, most long-term follow-up care has shifted from transplant centers to the
      pediatric gastroenterologists at referring institutions. We reviewed our
      experience with 16 patients who have undergone liver transplantation at eight
      institutions from 1987 to 1996. Our initial follow-up visit took place at an
      average 4.1 months after the transplant. The mean duration of follow-up was 41
      months. During this period 11 hospitalizations at the transplant center occured,
      including five that were to rule out lymphoma or post-transplant
      lymphoproliferative disease. At the Schneider Children's Hospital, NY, USA, 158
      outpatient visits were recorded. Forty-two hospitalizations occurred. Twenty of
      the hospital admissions were accounted for by two patients. Forty-nine
      outpatient/inpatient surgical or diagnostic procedures were performed, including
      15 percutaneous liver biopsies. In only one biopsy was there a disagreement in
      the histologic diagnosis between our pathologist and the pathologist at the
      transplant center. In conclusion, comprehensive follow-up care can be provided by
      an academic hospital-based gastroenterology group in conjunction with a
      transplant center.

PMID- 10359030
TI  - Longitudinal gonadal function after bone marrow transplantation for acute
      lymphoblastic leukemia during childhood.
AB  - Total body irradiation and high-dose chemotherapy, applied as a preparatory
      regimen for bone marrow transplantation (BMT) in children with acute
      lymphoblastic leukemia (ALL), are particularly hazardous to the gonads and, in
      addition, can impair hypothalamo pituitary-gonadal control. Longitudinal data on
      pubertal development and gonadal function in these patients are limited. Twenty
      one ALL patients (15 males, 6 females) who had successfully undergone allogeneic
      BMT before puberty (age at BMT: 3.4-12.3 yr) were followed up in University
      Children's Hospital, Tubingen, Germany over 2 (minimum) to 14 (maximum) years.
      Tanner development scores, serum testosterone and estradiol, basal follicle
      stimulating hormone (FSH) and luteinizing hormone (LH) were analyzed. During
      pubertal age, the levels of FSH and LH rose consecutively, resulting in
      noticeably elevated serum concentrations in 100% and 89%, respectively, of boys
      older than 14 years and in 75% and 75%, respectively, of girls older than 13
      years. Nevertheless, pubertal development has been normal in all patients except
      in one boy and two girls who required substitution with sexual steroids, as
      timely puberty (i.e. boys < 14 years, girls < 13 years) did not start. In males
      with normal puberty, testosterone levels, however, were found to be low-normal.
      In conclusion, after BMT preceded by total body irradiation for childhood ALL,
      gonadal function is impaired. Even if normal pubertal development occurs,
      deficiencies in long-term endocrine function cannot be ruled out. In view of the
      high FSH levels, the prognosis for fertility is doubtful.

PMID- 10359032
TI  - Ten-year experience of unrelated bone marrow donor transplants in children with
      malignant and non-malignant conditions.
AB  - Children who require a marrow transplant may receive such hematopoietic cells
      from one of many sources. This study reviews the experience of one center with 58
      children who received marrow from unrelated donors over a 10-year period. These
      children had a variety of malignant and non-malignant diseases. During that time
      period, only three of these children had failed to meet engraftment criteria. All
      donor marrow specimens were T-lymphocyte-depleted using an antibody/complement
      methodology. No difference was demonstrated in outcome between donors who were
      perfectly HLA-DR DNA matched versus those who were only partially matched. The
      increased size of various marrow donor registries has increased the number of
      potential donors available for these patients. The lack of a requirement for
      perfect matching means that there is an ever-increasing number of donors
      available. No graft-versus-host disease (GvHD) or grade III-IV GvHD was
      associated with a poorer outcome. Stable, long-term engraftment with minimal
      morbidity has been demonstrated in these children as evidenced by stability of
      survival curves by two years after marrow transplant.

PMID- 10359033
TI  - Endocrine complications of bone marrow transplantation in children.
AB  - Eighty-seven patients had a bone marrow transplantation (BMT) at our institution
      between 1980 and 1992. We wished to study the endocrine complications that
      accompany this procedure as long-term survival is now much more common. Forty
      three patients were retrospectively available for review and their records were
      examined for evidence of thyroid, pubertal, and growth complications. Fifteen per
      cent of the patients showed evidence of thyroid involvement. Pubertal delay or
      gonadal damage was almost universal in pubertal-aged girls treated with
      busulfan/cyclophosphamide. Gonadal involvement was more frequent in girls than in
      boys (70% vs. 47%). Sixty per cent of children were shorter or grew at a slower
      rate. Sixty-five per cent of the children presented with one or more endocrine
      complications. These are the combined effects of different treatment regimens
      (chemotherapy, radiotherapy, combined therapy). It is essential to know the
      natural history of these patients in order to offer proper guidance and treatment
      as survival rates are increasing.

PMID- 10359034
TI  - Correlation between allograft survival and chimeric state after bone marrow
      infusion in rat small bowel transplantation.
AB  - Methods to enhance natural microchimerism, which occurs after any successful
      organ transplant, are currently explored using unmodified donor bone marrow both
      in experimental and in clinical trials. Because of the potential immunomodulatory
      effects of donor bone marrow cells, we performed this study to evaluate the
      effect of single and multiple donor-specific bone marrow infusions (DSBMI) on
      chimerism and small bowel allograft survival in a fully histoincompatible rat
      model. Forty-five male DA rats and 45 female Lewis rats were used as donors and
      recipients, respectively, for a heterotopic small bowel transplant. Animals were
      separated into 10 groups according to the number of bone marrow infusions and
      immunosuppressive protocol used. Control groups (groups 1 and 2) did not receive
      any bone marrow infusion, groups 3 and 4 received one infusion at day 0 (150 x
      10(6) cells), groups 5 and 6 received two infusions at days 0 and 4 (75 x 10(6)
      cells each), groups 7 and 8 received two infusions at days 4 and 10 (75 x 10(6)
      cells each), and groups 9 and 10 received five infusions at days 4, 10, 15, 20
      and 25 (30 x 10(6) cells each). Animals in groups 1, 3, 5, 7 and 9 were
      immunosuppressed with 0.5 mg/kg FK506 while the remaining groups were
      immunosuppressed with 1 mg/kg FK506, from day 0 to 4 after transplant. Every 15
      days, the chimeric state was determined by flow cytometry in order to detect
      cells expressing DA rat class I antigen, and small bowel biopsies were obtained
      from ileostomies. Animals in all groups showed minimal to moderate acute
      rejection at day 15 after transplant, however, vascular rejection (vasculitis,
      arteritis) was observed in only bone marrow groups (100% in 0.5 mg/kg and 42.1%
      in 1 mg/kg FK506 groups). On day 30, 58.3% of bone-marrow-infused animals and
      66.6% of controls showed severe acute and early chronic rejection. The chimeric
      levels varied from 0 to 12% after transplant and were significantly higher in
      bone-marrow-infused groups compared with controls (p < 0.05). We conclude that
      modulation of immune response with short-course immunosuppression and a single or
      multiple DSBMI did not improve allograft or recipient survival. The inability to
      achieve a stable chimeric state did not allow us to determine the effect of
      chimerism on graft and recipient survival after small bowel transplantation.

PMID- 10359035
TI  - Hepatic artery thrombosis in pediatric liver transplantation: graft salvage after
      thrombectomy.
AB  - Hepatic artery thrombosis (HAT) is a devastating complication that may occur
      after orthotopic liver transplantation (OLT). A higher incidence has been
      reported in children. Salvage of the graft by thrombectomy has been suggested as
      an alternative to re-transplantation. In this study we report the outcome of
      three children who underwent thrombectomy for HAT. Between January 1992 and June
      1998, 14 children (< 17 yrs of age) underwent liver transplantation. Three
      developed HAT (one a whole-liver graft recipient, age 17; two living-related
      graft recipients, ages 4 and 4.5 yr). In the first patient, thrombosis of the
      hepatic artery was associated with scattered areas of parenchymal necrosis on
      computed tomography. In the two living-related patients, HAT was found
      incidentally during re-exploration for bleeding (day 2 and day 10). Thrombectomy
      was performed in all three patients. At 18-24 months after thrombectomy, all
      three children had normal graft function. In the first patient, complete
      regeneration of the liver has been documented by computed tomography and a late
      asymptomatic recurrent thrombosis is suggested by absence of arterial flow on
      Doppler examination. The hepatic artery is patent in the two living-related
      recipients. One of these living-related recipients developed ischemic bile duct
      stricture and underwent successful percutaneous balloon dilatation. We conclude
      that long-term normal graft function can be achieved by thrombectomy in pediatric
      liver recipients with HAT, even in the presence of limited parenchymal damage.

PMID- 10359036
TI  - Mycophenolate mofetil--is it worth the cost? The in-favor opinion.
AB  - Since its introduction, mycophenolate mofetil (MMF) has rapidly gained acceptance
      among renal transplant physicians. Three large multicenter studies have shown
      that MMF decreased the incidence of acute rejection episodes by 50%. While
      clinical data supporting the long-term benefits of MMF are not available, there
      is some experimental evidence which demonstrates that MMF may play a role in the
      prevention of chronic allograft rejection. Furthermore, MM F is a potent
      immunosuppressive agent, which could result in a reduction of the dose of
      cyclosporin A (CsA) required and subsequently reduce its associated toxicity.
      Despite the fact that MMF is six to seven times more expensive than azathioprine
      (AZA), its introduction into maintenance immunosuppressive protocols may not
      increase renal transplant charges during the first year after renal transplant as
      its cost can be offset by the reduced number of acute rejection episodes (ARE).
      The long-term societal impact of MMF will need to be evaluated as the data
      related to graft and patient survival, as well as chronic rejection, become
      available.

PMID- 10359037
TI  - What is the role for mycophenolate mofetil in pediatric renal transplantation?
AB  - Mycophenolate mofetil (MMF) has gained considerable popularity in pediatric renal
      transplantation. This popularity is largely a result of data from three large
      trials of MMF in adult cadaveric transplant patients who demonstrated a decreased
      rate of acute rejection episodes when treated with cyclosporin A (CsA),
      prednisone, and MMF compared with those receiving CsA, prednisone, and
      azathioprine (AZA) or placebo. However, the ability of MMF to reduce acute
      rejection appears to be limited to the first month post-transplant, and its
      effectiveness with microemulsion CsA or tacrolimus-based regimens has not been
      proven. In addition, there are currently no data that convincingly demonstrate
      that this agent improves graft survival, patient survival, graft function or
      protects against chronic rejection. Finally, there may be an increased risk for
      severe cytomegalovirus (CMV) disease and lymphoproliferative disorder with
      central nervous system involvement in patients treated with MMF. These data call
      into question the role of MMF in current immunosuppressive regimens.

PMID- 10359038
TI  - Comparative case-referent study of risk factors among hormone-related female
      cancers in Japan.
AB  - To assess the impact of reproductive and anthropometric factors as a risk
      indicator for female cancers in hormone-related organs, i.e., the breast,
      endometrium and ovary, we conducted a comparative case-referent study using data
      from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center
      (HERPACC), Japan. The case group consisted of 1,465, 133 and 99 women who had
      first been diagnosed as having breast, endometrial and ovarian cancer,
      respectively. The referents were 25,488 female first-visit outpatients who had
      not previously been diagnosed with any type of cancer. The odds ratios (ORs) and
      their 95% confidence intervals (95%CI) were estimated using an unconditional
      logistic regression model. An inverse association with experience of delivery and
      a positive association with body mass index (BMI) and with change of BMI after 20
      years of age, were observed consistently for all three cancer sites. We observed
      similar risk and protective factors for breast and endometrial cancer, but the
      effect of reproduction and overweight condition (BMI> or =25) were more prominent
      in endometrial cancer. Although the present study failed to find site-specific
      risk factors for ovarian cancer, the results provided evidence that being
      overweight and/or weight gain in adult life is a common risk factor for all three
      cancer sites. The results obtained from this study suggested that avoidance of
      weight gain may reduce the risk of female hormone-related cancers.

PMID- 10359039
TI  - Possible chemopreventive effects of bovine lactoferrin on esophagus and lung
      carcinogenesis in the rat.
AB  - A milk component, bovine lactoferrin (bLF), previously shown by us to be a strong
      chemopreventive of colon carcinoma development, was examined for its influence on
      other organs using a rat multi-organ carcinogenesis model. Male F344 rats, aged 6
      weeks, were treated sequentially with diethylnitrosamine (DEN, i.p.), dihydroxy
      di-N-propylnitrosamine (DHPN, in drinking water) and N-nitrosomethylbenzylamine
      (NMBA, s.c.) during the first 8 weeks (DDN treatment), and then bLF was
      administered in the basal diet, at a dose of 2, 0.2, 0.02 or 0.002%. Other groups
      were given DDN treatment or bLF alone as controls. All surviving animals were
      killed at week 41, and major organs were examined histopathologically for
      neoplastic lesions. In the esophagus, a tendency for reduction in development of
      papillomas was evident in the bLF-treated animals, along with a significant
      suppression of relatively large-sized papillomas (more than 50 mm3 volume) at the
      0.2% dose (P<0.05, 11% of the control). The multiplicity of tumors (adenomas and
      carcinomas) in the lung was also decreased in animals fed 0.02% bLF (1.98+/-0.41
      per cm2 lung tissue section, P<0.05) compared to the control group (3.48+/-0.33).
      No enhancing or inhibitory effects of bLF on tumor development in other organs
      were noted. The present results indicate that bLF exerts chemopreventive effects
      in the esophagus and lung in addition to the colon.

PMID- 10359040
TI  - Mechanism of oxidative DNA damage induced by a heterocyclic amine, 2-amino-3,8
      dimethylimidazo[4,5f]quinoxaline.
AB  - Adduct formation has been considered to be a major causal factor of DNA damage by
      carcinogenic heterocyclic amines. By means of experiments with 32P-labeled DNA
      fragments and an electrochemical detector coupled to a high-pressure liquid
      chromatograph, we investigated whether the N-hydroxy metabolite of 2-amino-3,8
      dimethylimidazo[4,5-f]quinoxaline (MeIQx) can cause oxidative DNA damage or not.
      This metabolite [MeIQx(NHOH)] was found to cause Cu(II)-mediated DNA damage,
      including 8-oxo-7,8-dihydro-2'-deoxyguanosine formation. When an endogenous
      reductant, beta-nicotinamide adenine dinucleotide (NADH), was added, the DNA
      damage was greatly enhanced. Catalase and bathocuproine, a Cu(I)-specific
      chelator, inhibited the DNA damage, suggesting the involvement of H2O2 and Cu(I).
      MeIQx(NHOH) frequently induced DNA cleavage at thymine and cytosine residues in
      the presence of NADH and Cu(II). A UV-visible spectroscopic study showed that
      little decomposition of MeIQx(NHOH) occurred in the absence of Cu(II), whilst
      rapid spectral change was observed in the presence of Cu(II), suggesting that
      Cu(II) catalyzes the autoxidation. The addition of NADH reduced the oxidized
      product back to MeIQx(NHOH). These results suggest that a copper-peroxo
      intermediate, derived from the reaction of Cu(I) with H2O2, participates in
      Cu(II)-dependent DNA damage by MeIQx(NHOH), and NADH enhances the DNA damage via
      a redox cycle. We conclude that in addition to DNA adduct formation, oxidative
      DNA damage plays an important role in the carcinogenic process of MeIQx.

PMID- 10359041
TI  - Frequent p53 gene mutations in soft tissue sarcomas arising in burn scar.
AB  - Squamous cell carcinoma (SCC) is the commonest malignancy that arises in burn
      scars, which frequently contain p53 mutations. Soft tissue sarcoma (STS) also
      develops, though less frequently, in burn scars. p53 gene mutations were analyzed
      in paraffin-embedded specimens from 5 patients with STS (4 males and 1 female)
      that had arisen in a burn scar, by means of polymerase chain reaction-single
      strand conformation polymorphism (PCR-SSCP) followed by direct sequencing. Age at
      burn injury ranged from 2 to 10 (median 3) years, and STS developed with a latent
      period ranging from 29 to 79 (median 60) years. Histologically, all were
      malignant fibrous histiocytoma. The PCR-SSCP revealed aberrant bands in 4 (80%)
      of 5 cases. Direct sequencing revealed a total of 11 mutations in these 4 cases:
      1 case had a single mutation, 1 had 2 mutations, and 2 had 4 mutations. Every
      tumor had at least 1 mutation that changed an amino acid, which may have provided
      the selection pressure for expansion. Thus, there is a high frequency of p53 gene
      mutations in STS appearing in burn scars. p53 mutations were also frequent in
      pyothorax-associated lymphoma (PAL), a lymphoma that develops in patients with
      long-standing pyothorax, so p53 mutations might be frequent in malignancies that
      develop in chronic inflammatory sites.

PMID- 10359042
TI  - Polymerase chain reaction-based enzyme immunoassay for quantitation of telomerase
      activity: application to colorectal cancers.
AB  - Telomerase is a specialized reverse transcriptase that synthesizes telomeric
      sequences onto human chromosomal ends. It appears to be present in the majority
      of primary human cancer tissues, and may have potential as a universal tumor
      marker. In this report, we describe a sensitive, non-radioactive, polymerase
      chain reaction (PCR)-based enzyme immunoassay (EIA) for the quantitation of
      telomerase activity in human cells. This PCR-EIA is convenient and can be easily
      completed within 3 h. The correlation coefficient between the results of PCR-EIA
      and the conventional telomeric repeat amplification protocol (TRAP) method, as
      measured on 4 different cell lines, was over 0.98. Evaluation of this method for
      clinical application was conducted with tissues obtained from patients with
      colorectal cancers and the results were compared with those of the conventional
      TRAP method. Our data indicate that telomerase activities measured by
      conventional TRAP and PCR-EIA are highly correlated, and we suggest that the PCR
      EIA method can substitute for conventional TRAP.

PMID- 10359043
TI  - Overexpression of proliferating cell nuclear antigen in mammalian cells negates
      growth arrest by serum starvation and cell contact.
AB  - Proliferating cell nuclear antigen (PCNA) functions as a processivity factor for
      DNA polymerase delta, and is expressed at high levels in growing normal and tumor
      cells. To clarify the relationship between cell proliferation and PCNA
      expression, we generated NIH-3T3 cells that overexpress PCNA and analyzed the
      phenotype of these cells. The resulting 3T3-PCNA cells, which overexpressed PCNA,
      were found to proliferate beyond the saturation density of the parental NIH-3T3
      cells. Although NIH-3T3 cell proliferation is arrested under serum starvation
      conditions, 3T3-PCNA cell proliferation is not arrested by serum starvation. The
      expression levels of cdk2, cdk4 and cdk6 were the same in 3T3-PCNA and NIH-3T3
      cells. The activity of cdk4 was identical for both cell types. However, the
      activity of cdk2 was higher in serum-starved 3T3-PCNA cells than in NIH-3T3
      cells, although the expression of cyclin E decreased in both types of cells,
      suggesting that increases in cdk2 activity are related to negation of growth
      arrest in 3T3-PCNA cells. These results indicate that increases in PCNA
      expression lead to the disruption of growth control and may lead to malignant
      transformation.

PMID- 10359044
TI  - Histological factors associated with initial bone metastasis of invasive ductal
      carcinoma of the breast.
AB  - Bone is one of the most common sites of recurrence of breast cancer. Therefore,
      it would be clinically very useful if breast cancers with a high probability of
      bone metastasis (BM) could be identified by histopathological examination of the
      primary lesions. To elucidate histological characteristics associated with
      predisposition to initial BM, we examined nine histopathological parameters in
      the primary lesions of 110 invasive ductal carcinomas (IDCs) of the breast with 0
      to 3 regional node metastases. These cases had recurrence between 4 months and
      10.1 years after the initial radical surgery. The first metastatic site was bone
      in 24 cases, whereas other sites were involved in 86 cases. IDCs growing in a
      strand growth pattern or with fibrotic focus (FF) had a significantly higher
      frequency of initial BM than those growing in a non-strand growth pattern or
      without FF, respectively. Strand growth pattern was a significant predictor of
      the initial BM in multivariate analysis. In all 54 IDCs that developed BM during
      the follow-up period, osteolytic metastasis was significantly more frequent in
      the group with FF than in that without FF. This study demonstrated that strand
      growth pattern and the presence of FF are significant histopathological factors
      associated with initial BM. The combination of those predictive factors along
      with prognostic factors may provide a useful approach to identify patients at
      high risk for initial BM, enabling early treatment for the recurrent cancer.

PMID- 10359045
TI  - Relation between the serum E-selectin level and the survival rate of patients
      with resected non-small cell lung cancers.
AB  - E-Selectin is an inducible adhesion molecule, which is expressed on cytokine
      activated endothelial cells and is thought to interact with cancer cells to
      initiate metastases. The relationship between serum E-selectin levels and
      prognoses in 101 patients with resected non-small cell lung cancers (NSCLCs) was
      studied, and survival curves were compared in relation to E-selectin levels and
      expression of two carbohydrate antigens, Sialyl Lewisx (SLX) and Sialyl Lewisa
      (CA19-9), which were immunohistochemically detected in resected specimens in 65
      of the 101 cases. The serum E-selectin level on admission was 48.9+/-25.7 ng/ml
      (mean+/-SD, n=101), and the E-selectin-positive rate was 22.7%, being correlated
      with the progression of T-factor. The high E-selectin group showed a
      significantly worse survival rate than the normal E-selectin group. Multivariate
      analysis confirmed the significant prognostic value of E-selectin. The mean
      postoperative E-selectin level in 52 cases (36.93 ng/ml) was significantly lower
      than the preoperative E-selectin level (43.57 ng/ml), indicating that certain
      NSCLCs might induce the expression of E-selectin. In cases expressing
      carbohydrate antigens (SLX, CA19-9), the high E-selectin group showed a
      significantly worse survival curve than the normal E-selectin group. On the other
      hand, there was no significant difference in the survival curve between the high
      and normal E-selectin groups when carbohydrate antigens were negative. These
      results suggest that patients who have high serum E-selectin levels, especially
      with carbohydrate antigen-positive NSCLC, might be expected to have poor
      prognoses.

PMID- 10359046
TI  - High-molecular-weight fibronectin synthesized by adenoid cystic carcinoma cells
      of salivary gland origin.
AB  - To understand the morphogenesis of characteristic cribriform structures and the
      frequent invasion of salivary adenoid cystic carcinomas (ACC) along such basement
      membrane-rich structures as peripheral nerves, we have isolated fibronectin (FN)
      from the culture media of ACC3 cells established from a parotid ACC and
      characterized its glycosylation and alternative splicing status. FN isolated from
      ACC3 cells (ACC-FN) showed a molecular mass of 315 kDa in SDS-PAGE and was less
      heterogeneous and larger than plasma FN (pFN) or FNs from other cell sources.
      Differential enzymatic treatments of immunoprecipitated ACC-FN with
      neuraminidase, peptide-N-glycosidase F and endo-alpha-N-acetylgalactosaminidase
      revealed that ACC-FN was composed of a polypeptide chain of 270 kDa, with 10 kDa
      each of N-linked and O-linked oligosaccharide chains. Reverse transcription
      polymerase chain reaction (RT-PCR), in-situ hybridization, and immunofluorescence
      studies showed that most ACC-FNs contained ED-A, ED-B and IIICS regions in the
      molecules. This alternative splicing status of ACC-FN seemed to contribute to its
      less heterogeneous and larger molecular form. Cell attachment assay demonstrated
      that ACC-FN was more potent than pFN in adhesion of ACC3 cells. The results
      indicated that ACC-FN may function as a substrate for attachment of ACC3 cells,
      or that ACC3 cells trap and retain ACC-FN in their pericellular space. This
      isoform of FN may play an important role in the mode of invasion of ACC and the
      formation of stromal pseudocysts in the characteristic cribriform structure of
      ACC.

PMID- 10359047
TI  - Expression of fibronectin isoforms in human breast tissue: production of extra
      domain A+/extra domain B+ by cancer cells and extra domain A+ by stromal cells.
AB  - The expression of fibronectin (FN) isoforms including extra domain A (EDA) and
      extra domain B (EDB) segments, was investigated in 36 invasive ductal carcinomas
      and 13 benign tumors of human breast tissues by in situ hybridization using
      probes specific to alternative splicing sites. Signals for the constant region of
      FN mRNA in cancer cells were found in 53% of the invasive ductal carcinomas. The
      EDA+ and EDB+ mRNA signals were found in 47% and 33%, respectively. Stromal cells
      expressing FN, EDA+ and EDB+ mRNA signals were present in 100%, 69% and 14% of
      cases, respectively. Expression of FN mRNAs by cancer cells was most frequent in
      intraductal lesions or large cancer nests, and that by stromal cells was
      associated with desmoplastic areas. In representative cases, proportions of FN
      mRNA-positive cancer cells expressing EDA and EDB segments were 45% and 39%,
      respectively, signals for both being frequently found in the same cells. EDA+ and
      EDB+ mRNA were labeled in 25% and 6% of the FN mRNA-positive stromal cells, a
      large proportion thus being EDA-/EDB- FN. In conclusion, the splicing pattern of
      FN pre-mRNA is dependent on the cell type and histology of breast cancer tissues.
      The observed lack of expression in fibroadenomas and other benign conditions
      suggests a link with tumor progression.

PMID- 10359048
TI  - Specific role of T and Tn tumor-associated antigens in adhesion between a human
      breast carcinoma cell line and a normal human breast epithelial cell line.
AB  - The possibility that tumor-associated antigens T and Tn act as adhesion molecules
      between normal and malignant breast epithelial cells at the early stages of
      recognition in the metastatic pathway was examined in vitro. The adhesive
      specificity of the antigens was assessed by means of in vitro adhesion tests
      between a carcinomatous breast cancer cell line (ZR75-30) and a normal epithelial
      breast cell line (HLB100) using both monoclonal antibodies and lectins specific
      as well as nonspecific for each antigen. Adhesion assay was performed using
      monolayers of the normal cell line prepared on plastic culture plates and the
      tumor cell line labeled with a fluorescent dye as a probe. The adhesion between
      the two cell types occurred with significant specificity via T and Tn antigens
      (P<0.001), and was temperature-dependent. The results suggest that at the early
      stages of recognition by tumor cells in the metastatic process, T and Tn antigens
      play a role as adhesion molecules between the tumor cells and adjacent normal
      cells.

PMID- 10359050
TI  - Radioimmunotherapy for liver micrometastases in mice: pharmacokinetics, dose
      estimation, and long-term effect.
AB  - The pharmacokinetics of a therapeutic dose of 131I-labeled antibody and the
      absorbed dose in liver micrometastases of human colon cancer LS174T in female
      BALB/c nu/nu mice were investigated, along with the long-term therapeutic effect.
      Mice with liver micrometastases were given an intravenous injection of 131I
      labeled anti-carcinoembryonic antigen (CEA) antibody F33-104 (8.88 MBq/ 40
      microg). The biodistribution of the antibody was determined 1, 2, 4, 6, and 10
      days later. The absorbed dose was estimated for three hypothetical tumor
      diameters; 1,000, 500, and 300 microm. Autoradiography showed a homogeneous
      distribution of radioactivity in the micrometastases, and a high uptake was
      maintained until day 6 (24.0 % injected dose (ID)/g on day 1 to 17.8 %ID/g on day
      6), but decreased thereafter. The absorbed doses in the 1,000-, 500-, and 300
      microm tumors were calculated to be 19.1, 12.0, and 8.2 Gy, respectively. The
      intravenous injection of the 131I-labeled antibody also showed a dose-dependent
      therapeutic effect (all mice of the nontreated group died, with a mean survival
      period of 4 weeks; 3 of the 8 mice that received 9.25 MBq survived up to 120 days
      with no sign of liver metastasis). These data give further evidence that
      micrometastasis is a good target of radioimmunotherapy, and that an absorbed dose
      of less than 20 Gy can effectively control small metastatic lesions.

PMID- 10359049
TI  - Inhibition of spontaneous rat osteosarcoma lung metastasis by 3S-[4-(N
      hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydroc arbostyril, a
      novel matrix metalloproteinase inhibitor.
AB  - In the present experiment, we examined the effects of OPB-3206, 3S-[4-(N
      hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4- dihydrocarbostyril, a
      novel metalloproteinase inhibitor, on the growth and metastasis of transplantable
      osteosarcomas (spontaneous osteosarcoma, selected lung metastatic lesions; S
      SLM), which were previously established in rats. OPB-3206 inhibited the
      activities of interstitial collagenase, gelatinases A and B, and stromelysin in
      vitro. After oral administration to rats, its serum concentration peaked at 40
      min and the drug was no longer detectable at 8 h. When OPB-3206 was orally
      administered at 0%, 0.1% and 0.4% in the diet for 4 weeks, starting 7 days after
      subcutaneous transplantation of osteosarcomas to male Fischer 344 rats, numbers
      of lung metastatic nodules were significantly reduced by the highest dose, while
      the growth of subcutaneous tumors was not affected. Zymographic analysis showed
      the presence of pro matrix metalloproteinase (proMMP)-2, proMMP-9 and MMP-9
      activities in S-SLM. In animals fed 0.4% OPB-3206, the activity of proMMP-9 was
      increased, but that for MMP-9 had become undetectable. The results thus suggest
      that OPB-3206 selectively inhibits lung metastasis of rat transplantable
      osteosarcomas by inhibiting MMP-9 activation.

PMID- 10359051
TI  - Circumvention of 5-fluorouracil resistance in human stomach cancer cells by
      uracil phosphoribosyltransferase gene transduction.
AB  - A human stomach cancer cell line with acquired resistance to 5-fluorouracil (5
      FU), NUGC-3/5FU/ L, has been found to possess reduced ability to convert 5-FU
      into active metabolites. We attempted in vitro gene therapy for this 5-FU
      resistant cell line. NUGC-3 and NUGC-3/5FU/L cells were infected with recombinant
      adenovirus (Ad) containing Escherichia coli uracil phosphoribosyltransferase
      (UPRT) gene driven by CAG promoter (CA), AdCA-UPRT, and changes in their 5-FU
      metabolism and sensitivity were investigated. Activities of orotate
      phosphoribosyltransferase increased from 10.2 and 1.56 (nmol/mg protein/30 min)
      in the uninfected cells of NUGC-3 and NUGC-3/5FU/L to 216 and 237, respectively,
      after the transfection of UPRT gene. The 5-FU nucleotide level in the acid
      insoluble fraction increased from 7.32 to 15.9 (pmol/mg protein) in NUGC-3 cells
      on infection with AdCA-UPRT, and in NUGC-3/5FU/L cells it increased from 1.91 to
      21.4. The 50% growth-inhibition concentration (IC50) was 12.7 micromol/liter for
      NUGC-3 and much higher than 100 micromol/liter for NUGC-3/5FU/L, indicating over
      8-fold resistance. NUGC-3/ SFU/L transfected with the UPRT gene showed very high
      sensitivity to 5-FU with an IC50 of 3.2 micromol/liter. The high resistance in
      this metabolic activation-deficient cell line was thus completely reversed by
      transduction of an exogenous gene coding for a 5-FU-anabolizing enzyme.

PMID- 10359053
TI  - Factors influencing library penetration of cancer research-associated journals in
      Japanese universities and research institutions.

PMID- 10359052
TI  - Posttreatment M-protein nadir level is a significant prognostic factor associated
      with survival in multiple myeloma. Nagoya Myeloma Cooperative Study Group.
AB  - In the present study 142 patients with myeloma (102 with IgG M-protein and 40
      with IgA) treated with either VMCP (65 patients) or MMCP (77 patients) as
      remission induction therapy were retrospectively analyzed. Response to treatment
      was evaluated in terms of a more-than-50% fall of pretreatment M-protein and the
      posttreatment M-protein nadir. Though significantly more patients treated with
      MMCP achieved partial response (PR) as compared with those treated with VMCP
      (P=0.019) and though patients achieving PR showed a significantly longer survival
      than those with less responsiveness (P=0.0091), the difference in survival curves
      between the two treatment groups was not significant (P=0.1871). The difference
      in response between the treatment groups evaluated in terms of posttreatment
      nadir was not significant (P=0.507). Multivariate analysis identified
      posttreatment M-protein nadir as a significant prognostic factor associated with
      survival, along with 3 other factors: sex, performance status, and hemoglobin.
      The lack of difference between the survival curves for patients treated with the
      2 regimens despite the significantly different response rates evaluated in terms
      of percent fall of pretreatment M-protein levels was considered to be due to the
      lack of a difference in the ability to induce a deep posttreatment nadir between
      the regimens. Posttreatment M-protein nadir is an important prognostic factor
      associated with survival and should be included in the evaluation of the efficacy
      of chemotherapy.

PMID- 10359054
TI  - Regulation of machinery for cancer cell growth, immortality, apoptosis and
      invasion--the Eighteenth International Symposium of Sapporo Cancer Seminar.

PMID- 10359055
TI  - Malaria parasite metabolism in sickle cells.
AB  - Intraerythrocytic malaria parasites meet part of their growth requirements by
      ingesting and digesting haemoglobin (Hb). To see whether this process is affected
      by Hb types, the growth and metabolism of Plasmodium falciparum in normal AA,
      heterozygous AS and homozygous SS erythrocytes were compared in this study.
      Parasites that have been adapted to continuous growth in AA and AS erythrocytes
      in vitro were used, and the cultures were incubated in an environment that
      contained 3% oxygen, 4% carbon dioxide and 93% nitrogen. It was found that
      exposure of the cultures to this gas mixture caused 5-10% of the AS and up to 90%
      of the SS erythrocytes to sickle. Parasite growth was essentially normal in the 3
      cell types, although multiplication was significantly lower in SS than in AS and
      AA erythrocytes. Parasite metabolism was evaluated through measurement of
      haemozoin production. The mean quantity of haemozoin produced by the parasites in
      AA was comparable to that produced in AS, but significantly higher than that
      produced in SS erythrocytes. This finding suggests that P. falciparum metabolism
      is impaired in SS but not in AS erythrocytes. The impairment may be related to
      polymerization of Hb S.

PMID- 10359056
TI  - Evaluation of purine and pyrimidine analogues in human tumor cells from patients
      with low-grade lymphoproliferative disorders using the FMCA.
AB  - The purine analogues fludarabine and cladribine (CdA) have recently become
      established to be effective treatment for low-grade non-Hodgkin's lymphoma (NHL).
      The pyrimidine nucleoside analogue cytarabine (AraC) has an important place in
      the treatment of acute leukemia, and gemcitabine is a new pyrimidin
      antimetabolite which has shown clinical activity against solid tumors. We have
      used the semiautomated fluorometric microculture cytotoxicity assay (FMCA), based
      on the measurement of fluorescence generated from cellular hydrolysis of
      fluorescein diacetate (FDA), to study these drugs. Eighty samples from 60
      patients with low-grade NHL were studied. Fifty samples from patients with acute
      lymphoid leukemia (ALL) and 118 samples from patients with acute myeloid leukemia
      (AML) were included for comparison. The results indicate that the purine- and
      pyrimidine nucleoside analogues tested may be as active against low-grade NHL as
      against acute leukemia. In low-grade NHL, AraC seems to be even more active in
      comparison to CdA (p=<0.0001) and fludarabine (p=0.001). Untreated patients were
      more drug sensitive than previously treated patients. Gemcitabine showed the
      highest correlation with AraC (0.90) whereas CdA showed the highest correlation
      with fludarabine (0.84). Based on these results we propose that AraC and
      gemcitabine may have a role in the treatment of low-grade NHL.

PMID- 10359057
TI  - Evaluation of bone disease in multiple myeloma: a comparison between the
      resorption markers urinary deoxypyridinoline/creatinine (DPD) and serum ICTP, and
      an evaluation of the DPD/osteocalcin and ICTP/osteocalcin ratios.
AB  - Markers of bone metabolism were measured in 73 newly diagnosed myeloma patients
      and in age-matched controls. Correlations to bone disease on X-rays and survival
      were performed. In urine deoxypyridinoline/creatinine (DPD) and in serum
      carboxyterminal pyridinoline cross-linked telopeptide of type I collagen (ICTP),
      procollagen type I carboxy-terminal extension peptide (PICP) and osteocalcin were
      analyzed. The ratios DPD/osteocalcin and ICTP/osteocalcin were calculated.
      Skeletal X-ray findings were divided into no, limited and extensive bone
      involvement. DPD and ICTP levels were significantly elevated in patients compared
      to controls. Levels increased with advancing skeletal involvement. Serum
      osteocalcin was elevated in patients without visible bone disease. The level
      decreased with more advanced bone involvement. The finding of significantly
      elevated osteocalcin and ICTP levels in patients without bone involvement on X
      rays indicates that bone markers might reflect bone disease better than X-rays in
      untreated myeloma patients. Ratios between bone resorption and bone formation
      markers added no further information on bone disease or survival. Only ICTP had
      prognostic value with an inverse correlation between serum levels and survival.

PMID- 10359058
TI  - Bilirubin levels in the acute hemolytic crisis of G6PD deficiency are related to
      Gilbert's syndrome.
AB  - In this study we analyzed the effect of the (TA)7 polymorphism of the UGT1A gene
      associated with Gilbert's syndrome in G6PD-deficient subjects during an acute
      hemolytic crisis (fabic crisis). DNA from 44 subjects originating from the same
      geographic area in Sardinia was analyzed for the UGT1A promoter polymorphism. The
      increase of unconjugated bilirubin level during fabic crisis and its relationship
      with UGT1A polymorphism was evaluated. The UGT1A (TA)7 TATA box variant was found
      in 9/44 (21%) of the G6PD deficient subjects examined. The median value for unit
      of increase of bilirubin (mg/dl)/unit of decrease of hemoglobin (g/dl) was higher
      in variant homozygous than in heterozygous and normal subjects. These findings
      imply a contribution of the UGT1A polymorphism associated to Gilbert's syndrome
      to development of the hyperbilirubinemia in G6PD deficient subjects during acute
      hemolytic anemia.

PMID- 10359059
TI  - Chronic idiopathic neutropenia of adults is associated with decreased bone
      mineral density and alterations in bone turnover biochemical markers.
AB  - The aim of this study was to assess bone mineral density (BMD) and biochemical
      indices of bone metabolism in patients with chronic idiopathic neutropenia of
      adults (CINA) and define the relationships, if any, between these parameters and
      serum levels of interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha
      (TNF-alpha), two cytokines normally involved in bone metabolism. Femoral neck
      BMD, serum osteocalcin (OC), bone-specific alkaline phosphatase (BAP) and type I
      procollagen carboxy-terminal propeptide (PICP), as well as urine-free
      deoxypyridoline (Dpd) cross-links, N-telopeptide (NTx) and C-telopeptide (CTx)
      cross-links of type I of collagen were measured in 45 CINA patients and 36 normal
      subjects. Patients were arbitrarily classified in two groups, A and B, as having
      mild (neutrophils 1700-2500/microl) or 'pronounced' (neutrophils<1700/microl)
      neutropenia, respectively. BMD values were found significantly reduced in both
      groups of patients, compared to controls, and they strongly correlated with the
      number of circulating neutrophils. Serum OC and urinary NTx were significantly
      increased in patients of group B. Both serum OC and urinary NTx correlated
      inversely with the number of circulating neutrophils. Serum BAP and PICP and
      urine Dpd and CTx were within normal range. Serum IL-1beta and TNF-alpha were
      elevated in both groups of patients and correlated inversely with the number of
      circulating neutrophils and the values of BMD. In addition, TNF-alpha, but not IL
      1beta, inversely correlated with OC and NTx. These findings indicate that CINA
      patients have biochemical evidence of increased bone turnover which leads to
      decreased BMD. The elevated serum IL-1beta and TNF-alpha concentrations,
      suggestive of an underlying chronic inflammatory process in these patients, may
      be part of a mechanism accelerating bone turnover which, if prolonged, causes
      lowering of BMD.

PMID- 10359060
TI  - The antiplatelet activity of Escherichia coli lipopolysaccharide is mediated
      through a nitric oxide/cyclic GMP pathway.
AB  - In this study, Escherichia coli LPS dose-dependently (100-500 microg/ml) and time
      dependently (10-60 min) inhibited platelet aggregation in human and rabbit
      platelets stimulated by agonists. LPS also dose-dependently inhibited the
      intracellular Ca2+ mobilization in human platelets stimulated by collagen. In
      addition, LPS (200 and 500 microg/ml) significantly increased the formation of
      cyclic GMP but not cyclic AMP in platelets. LPS (200 microg/ml) significantly
      increased the production of nitrate within a 10-min incubation period.
      Furthermore, LPS also dose-dependently inhibited platelet aggregation induced by
      PDBu (30 nmol/l), a protein kinase C activator. These results indicate that the
      antiplatelet activity of E. coli LPS may be involved in the activation of a
      nitric oxide/cyclic GMP pathway in platelets, resulting in inhibition of platelet
      aggregation. Therefore, LPS-mediated alteration of platelet function may
      contribute to bleeding diathesis in septicemic and endotoxemic patients.

PMID- 10359061
TI  - Clinico-haematological profile of isolated PF3 availability defect: therapeutic
      potential of soya bean--a pilot study.
AB  - Isolated platelet factor 3 (PF3) availability defect has been observed to be a
      common platelet functional disorder (PFD) in the Department of Haematology, All
      India Institute of Medical Sciences, New Delhi, India. One hundred and thirty-two
      patients were diagnosed to have this defect based on the presence of reduced PF3
      availability, normal platelet aggregation with ADP, collagen, adrenaline,
      ristocetin, and arachidonic acid and normal PF3 content. PF3 availability was
      evaluated by measurement of Russel viper venom time (RVVT) on the patient's
      platelet-rich plasma (PRP) after incubation with ADP for 20 min. An RVVT value
      >19.0 s was considered diagnostic of reduced PF3 availability in patients with
      normal prothrombin and activated partial thromboplastin times. Isolated PF3
      availability defect occurred in patients with ages between 2 and 65 yr and had a
      female preponderance (M:F=1:2). One fifth of the patients had a positive family
      history of similar mild bleeding diathesis, indicating an autosomal dominant
      pattern of inheritance. All patients presented with mild bleeding manifestations,
      the commonest symptom being appearance of recurrent ecchymotic spots. In females,
      menorrhagia was the commonest symptom. A pilot study was conducted on 45 patients
      to evaluate the therapeutic role of oral soya bean (50 g/d). The clinical
      response was evaluated after 3 months. Soya therapy resulted in disappearance of
      bleeding problems in 5 patients and reduction in frequency and severity of
      bleeding in 26 patients. A repeat PF3 availability test after 3 months of therapy
      showed complete correction in 4 and partial correction in 12 patients. It is
      evident from McNemer's test that both the clinical and the laboratory parameters
      (PF3 availability) showed a similar response to soya therapy (p>0.05). Pre-soya
      therapy mean PF3 availability values differ significantly from those after soya
      therapy (p<0.01). Thus, soya bean appears to have a therapeutic potential in
      isolated PF3 availability defect.

PMID- 10359062
TI  - Kinetics of indium-111-labelled platelets in HIV-infected patients with and
      without associated thrombocytopaenia.
AB  - Seven to 12% of HIV-infected patients have thrombocytopaenia. The pathophysiology
      of the thrombocytopaenia is not clear. It has been variously suggested that it
      may be caused by an increased peripheral platelet destruction, a defect in
      platelet production, or by a combination of these. The aim of the study was to
      elucidate the pathogenesis of HIV-associated thrombocytopaenia. We determined the
      mean platelet life span (MPLS) and calculated the turnover of autologous indium
      111-labelled platelets in 17 HIV-positive patients, seven with thrombocytopaenia.
      The sites of sequestration of labelled platelets were quantified. The
      thrombocytopaenic patients had a very short MPLS (3.0+/-3.8 h) and a marked
      increase in platelet production (18.2+/-12.6x10(9)/l/h). The majority of these
      patients (5 of 7) had excessive sequestration of platelets in the spleen. Five of
      the patients with a normal blood platelet count had a shortened MPLS (109+/-23 h)
      and increased platelet turnover (3.8+/-1.2x10(9)/l/h), i.e. the increased
      peripheral platelet destruction was compensated for by increased platelet
      production. The other five patients with a normal platelet count had normal MPLS
      (195+/-11 h) and slightly increased platelet production (2.5+/-0.6x10(9)/l/h). We
      conclude that patients with HIV-associated thrombocytopaenia have increased
      peripheral platelet destruction. Platelet production is elevated but is
      insufficient to maintain a normal peripheral platelet count. In these patients
      platelets are predominantly sequestrated in the spleen. Patients with HIV
      infection and a normal blood platelet count may also have increased platelet
      production. This may be an early subclinical phase in the development of full
      blown HIV-associated thrombocytopaenia.

PMID- 10359063
TI  - Megakaryocytic growth in patients with refractory anemia is suppressed by
      treatment with interferon alpha.
AB  - IFN alpha alone or in combination with retinoids or haematopoietic growth factors
      has been used to treat patients with early MDS because of its properties as a
      differentiation inducing agent. We investigated whether treatment of patients
      with refractory anemia (RA) with IFN alpha (1.5x10(6) IU twice a week) and
      intermittent all-trans retinoic acid (ATRA, 25 mg/m2/d) influences in-vitro
      megakaryocytic (MK) proliferation and differentiation stimulated by PEG-rHuMGDF.
      Low-density non-adherent bone marrow (BM) cells from 8 patients with RA were
      assayed prior to any treatment other than supportive and after a period of 6
      months of treatment. MK development was assayed in suspension cultures in the
      presence of PEG-rHuMGDF and SCF for 7 d using morphological criteria and flow
      cytometric analysis of CD42b (GP1b) positive cells. BM-cells from 10 healthy
      individuals served as control. Following stimulation with PEG-rHuMGDF 23+/-7% and
      16+/-4% of control cells were CD42b positive after 5 and 7 d of cultures,
      respectively. In cultures of cells from MDS patients prior to treatment 8+/-2%
      and 7+/-3% of cells were CD42b+ on days 5 and 7. In the course of IFN alpha
      treatment cultures of all BM samples from these MDS patients revealed a
      significant reduction of MK precursor cells (3+/-2%, CD42b+, p=0.03 and 0.04). In
      conclusion, treatment with TFN alpha and ATRA did not result in improved
      megakaryocytopoiesis as assessed by in-vitro cultures. On the contrary, low-dose
      IFN alpha appears to suppress cell proliferation as well as MK development.

PMID- 10359065
TI  - Autoimmune haemolytic anaemia with a paroxysmal nocturnal haemoglobinuria-like
      defect.

PMID- 10359064
TI  - Effects of neopterin and 7,8-dihydroneopterin on hypoxia-induced renal
      erythropoietin production.
AB  - Activation of the human cellular immune system is associated with greatly
      increased formation of the pteridines neopterin and 7,8-dihydroneopterin. It has
      been postulated that pteridines play a role in the pathogenesis of the anaemia of
      inflammation. Herein, we studied effects of pteridines on renal function,
      primarily on the synthesis of erythropoietin (Epo). The experiments were
      performed with isolated rat kidneys which were perfused hypoxically (pO2 26 mmHg)
      at constant pressure (100 mmHg) in a serum-free recirculation system for 3 h. The
      results show that the rate of the production of Epo was significantly lowered
      when neopterin or 7,8-dihydroneopterin were added to the perfusate. Neopterin
      (200 microM) also reduced the renal Epo mRNA level. Both pteridines increased
      renal vascular resistance. 7,8-Dihydroneopterin lowered urine flow and glomerular
      filtration rate more potently than neopterin. Renal O2 consumption and parameters
      of exocrine renal function (fractional reabsorption rates of sodium, glucose and
      water) were not altered by the pteridines, while the glomerular permeability was
      greatly increased. These results suggest that activated macrophages may not only
      inhibit the synthesis of Epo by generating cytokines and reactive O2 species but
      also by the release of pteridines. In vivo, high concentrations of pteridines in
      renal tissue may aggravate the anaemia of inflammation.

PMID- 10359066
TI  - Electron microscopical analysis of myeloperoxidase of leukemic cells in CD7+ stem
      cell leukemia/lymphoma.

PMID- 10359067
TI  - Blood-soluble Fas/APO-1 (CD95) in chronic lymphocytic leukemia.

PMID- 10359068
TI  - Hydroxyurea as a cause of drug fever in essential thrombocythaemia.

PMID- 10359069
TI  - Gender modulates the energy cost of muscle contraction in untrained healthy
      subjects. A 31P magnetic resonance spectroscopy analysis.
AB  - The forearm flexor muscles of 56 untrained volunteers (26 women and 30 men) were
      examined by 31P magnetic resonance spectroscopy, during a rest-exercise-recovery
      protocol, in order to document the impact of gender on muscle energetics.
      Absolute concentrations of high-energy phosphate compounds, intracellular pH and
      rates of aerobic and anaerobic ATP production were calculated. An inverse
      correlation was found between body mass index (BMI) and power output in women but
      not in men. After correcting for power output and BMI, the measured energy cost
      of contraction was twice larger for women than for men. This increase was also
      reflected in larger ATP production from aerobic and anaerobic pathways. This
      higher energy cost might be explained in part by differences in local muscle
      mass, a higher impact of fatness, but also by a reduced metabolic efficiency of
      muscle fibers in untrained women.

PMID- 10359070
TI  - Induction of oxidative DNA damage in anaerobes.
AB  - We compared oxidative DNA damage in strictly anaerobic Prevotella melaninogenica,
      aerotolerant anaerobic Bacteroides fragilis, and facultative anaerobic Salmonella
      typhimurium after exposure to O2 or H2O2. Using HPLC with electrochemical
      detection, we measured 8-hydroxydeoxyguanosine (8OHdG) as a damage marker. O2
      induced 8OHdG in P. melaninogenica but not in B. fragilis, which shows catalase
      activity, or in S. typhimurium. In P. melaninogenica, with catalase, O2 induced
      less 8OHdG; superoxide dismutase had no effect; with glucose and glucose oxidase,
      O2 induced more 8OHdG. H2O2 also markedly increased 8OHdG. O2 was suggested to
      induce 8OHdG through H2O2. O2 or H2O2 decreased survival only in P.
      melaninogenica. Highly sensitive to oxidative stress, P. melaninogenica could
      prove useful for investigating oxidative DNA damage.

PMID- 10359071
TI  - A predominantly hydrophobic recognition of H-antigenic sugars by winged bean
      acidic lectin: a thermodynamic study.
AB  - The thermodynamics of binding of winged bean (Psophocarpus tetragonolobus) acidic
      agglutinin to the H-antigenic oligosaccharide (Fucalpha1-2Galbeta1-4GlcNAc-oMe)
      and its deoxy and methoxy congeners were determined by isothermal titration
      calorimetry. We report a relatively hydrophobically driven binding of winged bean
      acidic agglutinin to the congeners of the above sugar. This conclusion is
      arrived, from the binding parameters of the fucosyl congeners, the nature of the
      enthalpy-entropy compensation plots and the temperature dependence of binding
      enthalpies of some of the congeners. Thus, the binding site of winged bean acidic
      agglutinin must be quite extended to accommodate the trisaccharide, with non
      polar loci that recognize the fucosyl moiety of the H-antigenic determinant.

PMID- 10359072
TI  - Copper-induced LDL peroxidation: interrelated dependencies of the kinetics on the
      concentrations of copper, hydroperoxides and tocopherol.
AB  - Excessive uptake of oxidized low density lipoprotein plays a role in the onset of
      atherosclerosis. Lipid-associated antioxidants, the most abundant of which is
      tocopherol (vitamin E), are therefore believed to have anti-atherogenic
      properties. By contrast, hydroperoxides enhance the peroxidation of low density
      lipoprotein. We demonstrate that none of these compounds markedly affect the
      maximal rate of oxidation of low density lipoprotein, whereas the lag preceding
      rapid oxidation is prolonged by tocopherol but shortened by hydroperoxides. The
      corresponding 'prolongation' and 'shortening' can be compensated by each other in
      low density lipoprotein preparations enriched with both these compounds. The
      dependence of the balance between the effects of tocopherol and hydroperoxides on
      the copper concentration indicates that the antioxidative effect of vitamin E
      increases with the oxidative stress.

PMID- 10359073
TI  - Identification and cloning of TWIK-originated similarity sequence (TOSS): a novel
      human 2-pore K+ channel principal subunit.
AB  - We have identified and cloned a new member of the mammalian tandem pore domain K+
      channel subunit family, TWIK-originated similarity sequence, from a human testis
      cDNA library. The 939 bp open reading frame encodes a 313 amino acid polypeptide
      with a calculated Mr of 33.7 kDa. Despite the same predicted topology, there is a
      relatively low sequence homology between TWIK-originated similarity sequence and
      other members of the mammalian tandem pore domain K+ channel subunit family
      group. TWIK-originated similarity sequence shares a low (< 30%) identity with the
      other mammalian tandem pore domain K+ channel subunit family group members and
      the highest identity (34%) with TWIK-1 at the amino acid level. Similar low
      levels of sequence homology exist between all members of the mammalian tandem
      pore domain K+ channel subunit family. Potential glycosylation and consensus PKC
      sites are present. Northern analysis revealed species and tissue-specific
      expression patterns. Expression of TWIK-originated similarity sequence is
      restricted to human pancreas, placenta and heart, while in the mouse, TWIK
      originated similarity sequence is expressed in the liver. No functional currents
      were observed in Xenopus laevis oocytes or HEK293T cells, suggesting that TWIK
      originated similarity sequence may be targeted to locations other than the plasma
      membrane or that TWIK-originated similarity sequence may represent a novel
      regulatory mammalian tandem pore domain K+ channel subunit family subunit.

PMID- 10359074
TI  - Direct involvement of p53 in the base excision repair pathway of the DNA repair
      machinery.
AB  - The p53 tumor suppressor that plays a central role in the cellular response to
      genotoxic stress was suggested to be associated with the DNA repair machinery
      which mostly involves nucleotide excision repair (NER). In the present study we
      show for the first time that p53 is also directly involved in base excision
      repair (BER). These experiments were performed with p53 temperature-sensitive
      (ts) mutants that were previously studied in in vivo experimental models. We
      report here that p53 ts mutants can also acquire wild-type activity under in
      vitro conditions. Using ts mutants of murine and human origin, it was observed
      that cell extracts overexpressing p53 exhibited an augmented BER activity
      measured in an in vitro assay. Depletion of p53 from the nuclear extracts
      abolished this enhanced activity. Together, this suggests that p53 is involved in
      more than one DNA repair pathway.

PMID- 10359075
TI  - Neurotoxicity of acetylcholinesterase amyloid beta-peptide aggregates is
      dependent on the type of Abeta peptide and the AChE concentration present in the
      complexes.
AB  - Alzheimer's disease (AD) is a neurodegenerative disorder whose hallmark is the
      presence of senile plaques and neurofibrillary tangles. Senile plaques are mainly
      composed of amyloid beta-peptide (Abeta) fibrils and several proteins including
      acetylcholinesterase (AChE). AChE has been previously shown to stimulate the
      aggregation of Abeta1-40 into amyloid fibrils. In the present work, the
      neurotoxicity of different amyloid aggregates formed in the absence or presence
      of AChE was evaluated in rat pheochromocytoma PC12 cells. Stable AChE-Abeta
      complexes were found to be more toxic than those formed without the enzyme, for
      Abeta1-40 and Abeta1-42, but not for amyloid fibrils formed with AbetaVal18-Ala,
      a synthetic variant of the Abeta1-40 peptide. Of all the AChE-Abeta complexes
      tested the one containing the Abeta1-40 peptide was the most toxic. When
      increasing concentrations of AChE were used to aggregate the Abeta1-40 peptide,
      the neurotoxicity of the complexes increased as a function of the amount of
      enzyme bound to each complex. Our results show that AChE-Abeta1-40 aggregates are
      more toxic than those of AChE-Abeta1-42 and that the neurotoxicity depends on the
      amount of AChE bound to the complexes, suggesting that AChE may play a key role
      in the neurodegeneration observed in Alzheimer brain.

PMID- 10359076
TI  - Suppression of the neoplastic phenotype by transfection of phospholipase C beta 3
      to neuroendocrine tumor cells.
AB  - The expression of phospholipase C beta 3 (PLCB3) is low or absent in several
      neuroendocrine neoplasias. To investigate the role of PLCB3 in the neuroendocrine
      tumorigenesis, we transfected a PLCB3 construct to three neuroendocrine tumor
      cell lines with a low PLCB3 expression. The growth rate and tumorigenicity were
      assessed in vitro by [3H]thymidine incorporation and cell counting, in vivo, by
      xenografting to nude mice. In vitro, PLCB3 expressing clones showed a significant
      growth inhibition. The tumor weight was reduced for one of the two xenografted
      PLCB3-transfected cell lines and in both, a reduced number of proliferating (Ki
      67 positive) cells was observed. This study implies an essential role for PLCB3
      in the neuroendocrine tumorigenesis.

PMID- 10359077
TI  - Change to alanine of one out of four selectivity filter glycines in KtrB causes a
      two orders of magnitude decrease in the affinities for both K+ and Na+ of the Na+
      dependent K+ uptake system KtrAB from Vibrio alginolyticus.
AB  - KtrAB from Vibrio alginolyticus is a recently described new type of high affinity
      bacterial K+ uptake system. Its activity assayed in an Escherichia coli K+ uptake
      negative mutant depended on Na+ ions (Km of 40 microM). Subunit KtrB contains
      four putative P-loops. The selectivity filter from each P-loop contains a
      conserved glycine residue. Residue Gly-290 from the third P-loop selectivity
      filter in KtrB was exchanged for Ala, Ser or Asp. KtrB variants Ser-290 and Asp
      290 were without activity. In contrast, KtrB variant Ala-290 was still active.
      This variant transported K+ with a two orders of magnitude decrease in apparent
      affinity for both K+ and Na+ with little effect on Vmax.

PMID- 10359078
TI  - Conversion of an inactive cardiac dihydropyridine receptor II-III loop segment
      into forms that activate skeletal ryanodine receptors.
AB  - A 25 amino acid segment (Glu666-Pro691) of the II-III loop of the alpha1 subunit
      of the skeletal dihydropyridine receptor, but not the corresponding cardiac
      segment (Asp788-Pro814), activates skeletal ryanodine receptors. To identify the
      structural domains responsible for activation of skeletal ryanodine receptors, we
      systematically replaced amino acids of the cardiac II-III loop with their
      skeletal counterparts. A cluster of five basic residues of the skeletal II-III
      loop (681RKRRK685) was indispensable for activation of skeletal ryanodine
      receptors. In the cardiac segment, a negatively charged residue (Glu804) appears
      to diminish the electrostatic potential created by this basic cluster. In
      addition, Glu800 in the group of negatively charged residues 798EEEEE802 of the
      cardiac II-III loop may serve to prevent the binding of the activation domain.

PMID- 10359079
TI  - Mutation of the N-terminal proline 9 of BLMA from Streptomyces verticillus
      abolishes the binding affinity for bleomycin.
AB  - A gene, blmA, from bleomycin (Bm)-producing Streptomyces verticillus, encodes a
      Bm-binding protein, designated BLMA. The expression of BLMA conferred resistance
      to Bm in the Escherichia coli host, whereas a mutant protein, designated Pro
      9/Leu, with the N-terminal proline 9 residue in BLMA replaced by leucine, did
      not. We created a fusion protein between the maltose-binding protein (MBP) and a
      mutant protein Pro-9/Leu/Leu with Met-94 in Pro-9/Leu replaced by leucine. Pro
      9/Leu/Leu from the fusion protein, obtained by digestion with CNBr digestion, did
      not inhibit DNA-cleaving and antibacterial activities of Bm. Native
      polyacrylamide gel electrophoresis (PAGE) and gel filtration column
      chromatographic analysis showed that the molecular size of Pro-9/Leu/Leu is
      roughly half of that of BLMA, suggesting that the mutant protein cannot form
      dimeric structure. Furthermore, Far-UV circular dichroism (CD) spectrum of Pro
      9/Leu/Leu was quite different from that of BLMA and similar to the spectra
      obtained from unordered proteins [Venyaminov, S.Y. and Vassilenko, K.S. (1994)
      Anal. Biochem. 222, 176184], suggesting that the secondary structure of Pro
      9/Leu/Leu is disrupted. These results indicate that the mutation abolishes not
      only dimer formation but also the secondary structure of BLMA, which results in
      the loss of its function as a Bm-resistance determinant.

PMID- 10359080
TI  - A novel plant nuclear gene encoding chloroplast ribosomal protein S9 has a
      transit peptide related to that of rice chloroplast ribosomal protein L12.
AB  - We have cloned a novel nuclear gene for a ribosomal protein of rice and
      Arabidopsis that is like the bacterial ribosomal protein S9. To determine the
      subcellular localization of the gene product, we fused the N-terminal region and
      green fluorescent protein and expressed it transiently in rice seedlings.
      Localized fluorescence was detectable only in chloroplasts, indicating that this
      nuclear gene encodes chloroplast ribosomal protein S9. The N-terminal region of
      rice ribosomal protein S9 was found to have a high sequence similarity to the
      transit peptide region of the rice chloroplast ribosomal protein L12, suggesting
      that these transit peptides have a common lineage.

PMID- 10359081
TI  - The HIV-1 Vpr co-activator induces a conformational change in TFIIB.
AB  - Vpr is a HIV-1 virion-associated protein which plays a role in viral replication
      and in transcription and cell proliferation. We have previously reported that Vpr
      stimulates transcription of genes lacking a common DNA target sequence likely
      through its ability to interact with TFIIB. However, the molecular mechanism of
      the Vpr-mediated transcription remains to be precisely defined. In this in vitro
      study, we show that the binding site of Vpr in TFIIB overlaps the domain of TFIIB
      which is engaged in the intramolecular bridge between the N- and C-terminus of
      TFIIB, highly suggesting that binding of Vpr may induce a change in the
      conformation of TFIIB. Indeed, with a partial proteolysis assay using V8
      protease, we demonstrate that Vpr has the ability to change the conformation of
      TFIIB. We investigated in this partial proteolysis assay a series of Vpr-mutated
      proteins previously defined for their transactivation properties. Our data show a
      correlation between the ability of Vpr-mutated proteins to stimulate
      transcription and their ability to induce a conformational change in TFIIB,
      indicating a functional relevance of the Vpr-TFIIB interaction.

PMID- 10359082
TI  - Differential dissociation kinetics explain the binding preference of insulin-like
      growth factor binding protein-6 for insulin-like growth factor-II over insulin
      like growth factor-I.
AB  - Insulin-like growth factor binding protein-6 binds insulin-like growth factor-II
      with a marked preferential affinity over insulin-like growth factor-I. The
      kinetic basis of this binding preference was studied using surface plasmon
      resonance. Binding of insulin-like growth factor-I and insulin-like growth factor
      II to immobilized insulin-like growth factor binding protein-6 fitted a two-site
      binding kinetic model. Insulin-like growth factor-I and insulin-like growth
      factor-II association rates were similar whereas the dissociation rate was
      approximately 60-fold lower for insulin-like growth factor-II, resulting in a
      higher equilibrium binding affinity for insulin-like growth factor-II. The
      equilibrium binding affinities of a series of insulin-like growth factor-II
      mutants were also explained by differential dissociation kinetics. O
      glycosylation had a small effect on the association kinetics of insulin-like
      growth factor binding protein-6. The insulin-like growth factor binding
      properties of insulin-like growth factor binding protein-6 are explained by
      differential dissociation kinetics.

PMID- 10359083
TI  - The Qo-site inhibitor DBMIB favours the proximal position of the chloroplast
      Rieske protein and induces a pK-shift of the redox-linked proton.
AB  - The interaction of the inhibitor 2,5-dibromo-3-methyl-6-isopropylbenzoquinone
      (DBMIB) with the Rieske protein of the chloroplast b6f complex has been studied
      by EPR. All three redox states of DBMIB were found to interact with the iron
      sulphur cluster. The presence of the oxidised form of DBMIB altered the
      equilibrium distribution of the Rieske protein's conformational substates,
      strongly favouring the proximal position close to heme bL. In addition to this
      conformational effect, DBMIB shifted the pK-value of the redox-linked proton
      involved in the iron-sulphur cluster's redox transition by about 1.5 pH units
      towards more acidic values. The implications of these results with respect to the
      interaction of the native quinone substrate and the Rieske cluster in cytochrome
      bc complexes are discussed.

PMID- 10359084
TI  - Purification of Saccharomyces cerevisiae RNase H(70) and identification of the
      corresponding gene.
AB  - We purified Saccharomyces cerevisiae RNase H(70) to homogeneity, using an
      optimized chromatographic purification procedure. Renaturation gel assay assigned
      RNase H activity to a 70 kDa polypeptide. Sequencing of tryptic peptides
      identified the open reading frame YGR276c on chromosome VII of the S. cerevisiae
      genome as the corresponding gene, which encodes a putative polypeptide of
      molecular mass of 62849. We therefore renamed this gene RNH70. Immunofluorescence
      microscopy using a RNH70-EGFP fusion construct indicates nuclear localization of
      RNase H(70). Deletion of RNH70 from the yeast genome did not result in any
      serious phenotype under the conditions tested. Homology searches revealed
      striking similarity with a number of eukaryotic proteins and open reading frames,
      among them the chimpanzee GOR protein, a homolog of a human autoimmune antigen,
      found to elicit autoimmune response in patients infected with hepatitis C virus.

PMID- 10359085
TI  - Inhibition of virulence factor expression in Staphylococcus aureus by the
      Staphylococcus epidermidis agr pheromone and derivatives.
AB  - The agr quorum-sensing system in Staphylococci controls the production of surface
      proteins and exoproteins. In the pathogenic species Staphylococcus aureus, these
      proteins include many virulence factors. The extracellular signal of the quorum
      sensing system is a thiolactone-containing peptide pheromone, whose sequence
      varies among the different staphylococcal strains. We demonstrate that a
      synthetic Staphylococcus epidermidis pheromone is a competent inhibitor of the
      Staphylococcus aureus agr system. Derivatives of the pheromone, in which the N
      terminus or the cyclic bond structure was changed, were synthesized and their
      biological activity was determined. The presence of a correct N-terminus and a
      thiolactone were absolute prerequisites for an agr-activating effect in S.
      epidermidis, whereas inhibition of the S. aureus agr system was less dependent on
      the original structure. Our results show that effective quorum-sensing blockers
      that suppress the expression of virulence factors in S. aureus can be designed
      based on the S. epidermidis pheromone.

PMID- 10359086
TI  - Defective binding of IRFs to the initiator element of interleukin-1beta
      converting enzyme (ICE) promoter in an interferon-resistant Daudi subline.
AB  - To investigate mechanisms of interferon (IFN) resistance, we have established an
      IFN-resistant Daudi subline (Daudi(res)), which is 1 X 10(4) times more resistant
      to IFN-alpha than parental cells. Among the IFN-inducible genes examined, only
      ICE mRNA expression was deficient in Daudi(res) cells. We then analyzed the
      regulatory mechanisms of ICE transcription, and found that IFN-induced activation
      of the ICE promoter was dependent on the binding of IRFs to its initiator (Inr)
      element. Inr binding of IRFs was markedly diminished in Daudi(res) cells, and
      forced expression of IRF-1 was able to activate the ICE promoter to the level of
      parental cells. These results suggest that IRFs and their target genes, as
      represented by ICE in this study, are involved in IFN resistance.

PMID- 10359087
TI  - Human stromelysin gene promoter activity is modulated by transcription factor ZBP
      89.
AB  - Matrix metalloproteinase expression is under strict regulation in physiological
      conditions. Disruption of the regulatory mechanisms can lead to tissue
      destruction and is associated with tumour invasion and metastasis. Using the one
      hybrid assay technique with a cis-element in the promoter region of the
      stromelysin (matrix metalloproteinase-3) gene, a cDNA encoding a transcription
      factor termed ZBP-89 was obtained. The interaction between ZBP-89 and the
      stromelysin promoter element was confirmed by electrophoretic mobility shift
      assays with a recombinant ZBP-89. Reporter gene expression under the control of
      the stromelysin promoter in transiently transfected cells was significantly
      increased when the cells were cotransfected with a ZBP-89 expression construct.
      These results indicate that ZBP-89 interacts with the stromelysin promoter and
      upregulates its activity. As ZBP-89 expression is known to be increased in
      gastric carcinoma cells, induction of stromelysin expression may be a significant
      factor in tumour metastasis.

PMID- 10359088
TI  - Neuronal nAChR stereoselectivity to non-natural epibatidine derivatives.
AB  - The frog toxin epibatidine is one of the most powerful ligands of the neuronal
      nicotinic receptors and derivatives show promising possibilities for labeling in
      positron emission tomography studies. In an attempt to reduce epibatidine
      toxicity, new methyl derivatives were synthesized, tested in positron emission
      tomography imaging and in electrophysiology. labeling as well as physiological
      experiments highlighted the differences in sensitivity of the neuronal nicotinic
      acetylcholine receptors between two methyl enantiomers and the reduction in
      sensitivity caused by introducing the methyl group. At present, epibatidine
      derivatives seem the most promising compounds for in vivo labeling of neuronal
      nicotinic acetylcholine receptors.

PMID- 10359089
TI  - Identification and characterization of GABA, proline and quaternary ammonium
      compound transporters from Arabidopsis thaliana.
AB  - Arabidopsis thaliana grows efficiently on GABA as the sole nitrogen source,
      thereby providing evidence for the existence of GABA transporters in plants.
      Heterologous complementation of a GABA uptake-deficient yeast mutant identified
      two previously known plant amino acid transporters, AAP3 and ProT2, as GABA
      transporters with Michaelis constants of 12.9 +/- 1.7 and 1.7 +/- 0.3 mM at pH 4,
      respectively. The simultaneous transport of [1-14C]GABA and [2,3-3H]proline by
      ProT2 as a function of pH, provided evidence that the zwitterionic state of GABA
      is an important parameter in substrate recognition. ProT2-mediated [1-14C]GABA
      transport was inhibited by proline and quaternary ammonium compounds.

PMID- 10359090
TI  - Investigation of the interaction of the water oxidising manganese complex of
      photosystem II with the aqueous solvent environment.
AB  - Interaction of the water oxidising manganese complex of photosystem II with the
      aqueous environment has been investigated using electron paramagnetic resonance
      spectroscopy and electron spin echo envelope modulation spectroscopy to detect
      interaction of [2H]methanol with the complex in the S2 state. The experiments
      show that the classical S2 multiline signal is associated with a manganese
      environment which is not exposed to the aqueous medium. An electron paramagnetic
      resonance spectroscopy signal, also induced by 200 K illumination, showing 2H
      modulation by methanol in the medium and a modified multiline electron
      paramagnetic resonance spectroscopy signal formed in parallel to it, are
      suggested to be associated with a second manganese environment exposed to the
      medium.

PMID- 10359091
TI  - Genetic heterogeneity of the immunogenic viral capsid protein region of human
      parvovirus B19 isolates obtained from an outbreak in a pediatric ward.
AB  - Whereas human parvovirus B19 commonly infects children and causes erythema
      infectiosum, it causes more severe diseases when it infects adults. In order to
      examine whether different clinical outcomes of B19 infection can be ascribed to
      the viral genetic heterogeneity, we have determined the nucleotide sequence of
      highly immunogenic portions of the B19 genome obtained from six patients with
      various clinical manifestations in a single outbreak. Our observations
      demonstrated that although the B19 sequences showed a significant heterogeneity,
      it was not correlated with the clinical manifestation. It was thus suggested that
      the host immune response to B19 infection may be a major determinant of clinical
      presentations associated with acute B19 infection.

PMID- 10359092
TI  - Mutation patterns for two flaviviruses: hepatitis C virus and GB virus
      C/hepatitis G virus.
AB  - We studied the mutation patterns of hepatitis C virus (HCV) and GB virus
      C/hepatitis G virus (HGV). Although the mutation patterns of the two viruses were
      similar to each other, they were quite different from that of HIV. In particular,
      the similarity of the patterns between HCV or HGV and human nuclear pseudogenes
      was statistically significant whereas there was no similarity between HIV and
      human nuclear pseudogenes. This finding suggests that the mutation patterns of
      HCV and HGV are similar to the patterns of spontaneous substitution mutations of
      human genes, implying that nucleotide analogues which are effective against HCV
      and HGV may have a side effect on the normal cells of humans.

PMID- 10359093
TI  - Significant enhancement in the binding of p-nitrophenyl-beta-D-xylobioside by the
      E128H mutant F/10 xylanase from Streptomyces olivaceoviridis E-86.
AB  - Mutagenesis studies were carried out to examine the effects of replacement of
      either the nucleophile Glu-236 or the acid/base Glu-128 residue of the F/10
      xylanase by a His residue. To our surprise, the affinity for the p-nitrophenyl
      beta-D-xylobioside substrate was increased by 10(3)-fold in the case of the
      mutant E128H enzyme compared with that of the wild-type F/10 xylanase. The
      catalytic activity of the mutant enzymes was low, despite the fact that the
      distance between the nucleophilic atom (an oxygen in the native xylanase and a
      nitrogen in the mutant) and the alpha-carbon was barely changed. Thus, the
      alteration of the acid/base functionality (Glu-128 to His mutation) provided a
      significantly favorable interaction within the E128H enzyme/substrate complex in
      the ground state, accompanying a reduction in the stabilization effect in the
      transition state.

PMID- 10359094
TI  - Effects of frontotemporal dementia FTDP-17 mutations on heparin-induced assembly
      of tau filaments.
AB  - Missense mutations and intronic mutations in the gene for microtubule-associated
      protein tau cause frontotemporal dementia and Parkinsonism linked to chromosome
      17 (FTDP-17). Most missense mutations have as likely primary effect a reduced
      ability of tau to interact with microtubules. We report here an additional effect
      of several missense mutations, namely the stimulation of heparin-induced filament
      assembly of recombinant tau, despite the absence of any change in structure
      indicated by circular dichroism. These findings indicate that missense mutations
      in tau lead to frontotemporal dementia through potentially multiple mechanisms.

PMID- 10359095
TI  - CIIV, MIIC and other compartments for MHC class II loading.
AB  - Virtually every endocytic compartment has been claimed to be an MIIC, a site
      where class II molecules accumulate. Here, it is argued that the definition of
      MIIC is not accurate and often pointless. MIIC can better be used as a working
      title for a collection of late endocytic compartments that contain the goodies
      necessary for efficient peptide loading of class II molecules.

PMID- 10359097
TI  - Tenascin-C inhibits beta1 integrin-dependent T lymphocyte adhesion to fibronectin
      through the binding of its fnIII 1-5 repeats to fibronectin.
AB  - The extracellular matrix consists of different proteins interacting to form a
      meshwork-like structure. T lymphocyte adhesion to individual matrix proteins is
      mainly regulated at the adhesion receptor level, but it is conceivable that the
      composition of the matrix itself may affect T lymphocyte adhesion to individual
      proteins. We have addressed the latter point by studying the effect of the matrix
      protein tenascin-C (TN-C) on T lymphocyte adhesion to fibronectin. Here we report
      that TN-C inhibits adhesion of T lymphocytes and MOLT-4 lymphoma cells to
      fibronectin. We demonstrate that a TN-C fragment consisting of fibronectin type
      III repeats 1-5 (TNfnIII 1-5) but not TNfnIII A-D and TNfnIII 6-8 inhibited
      alpha5beta1 and alpha4beta1 integrin-mediated T lymphocyte and MOLT-4 adhesion to
      fibronectin. At concentrations that did not inhibit adhesion, TNfnIII 1-5 still
      prevented MOLT-4 cells from spreading on fibronectin. Preincubation and co
      immobilization of TNfnIII 1-5 with fibronectin was more effective in inhibiting
      MOLT-4 adhesion to fibronectin than soluble TNfnIII 1-5 present during the
      adhesion test. Using an enzyme-linked immunosorbent assay we could demonstrate
      binding of TNfnIII 1-5 to fibronectin and fibronectin fragments. Taken together,
      these data demonstrate that the TNfnIII 1-5 domain is implicated in the
      inhibition of T lymphocyte adhesion to fibronectin caused by TN-C, and indicate
      that this effect involves the binding of TN-C repeats TNfnIII 1-5 to fibronectin.

PMID- 10359096
TI  - The engagement of beta1 integrins on promonocytic cells promotes phosphorylation
      of Syk and formation of a protein complex containing Lyn and beta1 integrin.
AB  - The protein-tyrosine kinase Syk participates in signal transduction pathways
      downstream from multiple immune recognition receptors. Recent evidence indicates
      that Syk is also functionally coupled to cell surface integrins, which mediate
      interactions between the actin cytoskeleton and extracellular matrix proteins.
      The interactions of undifferentiated, promonocytic HL60 or U937 cells with
      fibronectin or anti-beta1 integrin antibodies leads to an apparent activation and
      tyrosine phosphorylation of Syk that is independent of tight cellular adhesion
      and spreading. In response to fibronectin or anti-beta1 integrin antibodies,
      beta1 integrins become associated with a complex of proteins that include the Lyn
      protein tyrosine kinase and endogenous kinase substrates of 29 and 75-80 kDa. Lyn
      becomes transiently activated following integrin engagement and co-localizes with
      the actin cytoskeleton. These studies suggest a major role for Lyn in coupling
      beta1 integrins to the activation of Syk.

PMID- 10359098
TI  - Antagonistic activity of HIV-1 T helper peptides flanked by an unrelated carrier
      protein.
AB  - Antagonism is the ability of a modified antigenic peptide (altered peptide
      ligand, APL) to prevent CD4 T cell activation by the original peptide. Here we
      show that antagonistic activity can be conferred to peptides of HIV envelope
      glycoprotein gp120 and reverse transcriptase p66 by adding flanking polypeptide
      sequences at the C or at the N terminus by genetic engineering, rather than by
      introducing substitutions by synthesis. The glutathione S-transferase (GST)
      peptide system has been used to produce molecules that display the peptide at the
      appropriate end of the GST carrier. When the gp120 peptide 191-205 (pep24) was
      expressed at the C terminus of GST (GST-24), antigenicity of specific human CD4 T
      cells was maintained. In contrast, when the peptide was expressed at the N
      terminus of GST (24-GST), antigenicity was abolished and antagonistic activity
      was introduced. Similar results were obtained with a p66-derived peptide at the C
      terminus of the GST carrier. Antagonism was (1) specific; proliferation of a CD4
      T cell line from the same donor responding to the envelope glycoprotein of
      another retrovirus, HTLV-1, was not affected; (2) reversible; proliferative
      response was rescued in T cells exposed to antigen-presenting cells (APC) pulsed
      with the antagonist; (3) dominant; T cells cultured with APC pulsed with the
      agonist and with APC pulsed with the antagonist did not proliferate. The carrier
      could be cleaved by proteolysis while the antagonistic activity was preserved.
      Thus a minimal sequence that confers antagonistic activity can be engineered or
      synthesized with peptides to antagonize undesired CD4 responses as an alternative
      to the use of APL.

PMID- 10359099
TI  - Chronic deletion, escape from deletion and activation of mouse mammary tumor
      virus superantigen-reactive T cells in C57BL/10 mice.
AB  - Though C57BL/10 mice express the mouse mammary tumor virus superantigens (sag)
      encoded by Mtv-8 and Mtv-9, it has been thought that these sag do not bind to the
      MHC class II molecule H2-Ab and consequently do not affect the T cell repertoire.
      However, we show that cells bearing TCR Vbeta chains specific for Mtv-8 and -9
      sag are chronically deleted in C57BL/10 mice. Thymocytes and peripheral T cells
      escaping deletion by Mtv sag display a small reduction in the level of cell
      surface CD4. T cells escaping thymic deletion respond variably to endogenous Mtv
      sag with some, but not all, reactive populations appearing overrepresented in the
      activated/memory subset. The data suggest that in normal mice fine modulation of
      coreceptor expression levels may be a common way by which thymocytes escape
      elimination, that systems utilizing potentially Mtv sag-reactive TCR on a C57BL
      background may be inappropriate for the measurement of the affinity of
      TCR/MHC/peptide interactions required in thymic selection, and that detection of
      the activity of human sag may be aided by analysis of CD4 levels and activation
      markers on T cells in conjunction with studies of the frequency of cells bearing
      specific TCRVbeta chains.

PMID- 10359100
TI  - CD45 modulation of CXCR1 and CXCR2 in human polymorphonuclear leukocytes.
AB  - All leukocytes express the cell surface glycoprotein CD45, which has intrinsic
      intracellular protein tyrosine phosphatase activity. CD45 is known to play a
      regulatory role in activation-induced signaling in lymphocytes; however, little
      is known of its role in non-lymphoid leukocytes. Therefore, we examined the
      potential effect of CD45 on chemokine-induced signaling in human neutrophils
      (polymorphonuclear cells, PMN). Treating isolated PMN for 2 h with an anti-CD45RB
      antibody (Bra11) down-modulated expression of the chemokine receptors CXCR1 and
      CXCR2 to 44 +/- 10% and 47 +/- 9% of their respective controls. The tyrosine
      kinase inhibitors genistein and herbimycin A significantly inhibited the Bra11
      induced down-modulation of CXCR1 and CXCR2. Furthermore, Bra11-treated PMN were
      functionally inhibited in their capacity to exhibit IL-8-induced transient
      intracellular Ca2+ increases. Selected targeting of CXC receptors is indicated by
      the fact that N-formyl-Met-Leu-Phe (fMLP) receptor expression and function were
      not lost following Bra11 treatment. The effect of Bra11 on IL-8-mediated function
      and receptor expression was paralleled by decreased tyrosine phosphorylation of a
      54- to 60-kDa protein. These findings indicate that CD45 can act to modulate PMN
      responses to chemokines; thus agents regulating CD45 can potentially modulate
      leukocyte traffic and may represent a novel therapeutic approach towards the
      treatment of inflammatory diseases.

PMID- 10359101
TI  - Intrathymic deletion of MHC class I-restricted cytotoxic T cell precursors by
      constitutive cross-presentation of exogenous antigen.
AB  - Cross-priming of cytotoxic T lymphocytes by professional antigen-presenting cells
      (APC) is a potential hazard to self tolerance because it exposes naive T cells to
      tissue-specific self antigens in the context of co-stimulatory signals. Here we
      show that cross-presentation of exogenous material occurs constitutively within
      the thymus. Although efficient cross-presentation is a property of relatively few
      APC it results in thymocyte deletion both in vitro and in vivo, suggesting that
      intrathymic cross-presentation can operate as an effective component of tolerance
      to circulating self antigens. The capacity of minor cell populations to mediate
      thymocyte deletion but not positive selection reflects an underlying difference
      in the biology of these two processes.

PMID- 10359103
TI  - Human intestinal mast cells produce IL-5 in vitro upon IgE receptor cross-linking
      and in vivo in the course of intestinal inflammatory disease.
AB  - IL-5, known to be produced by T lymphocytes and eosinophils, is a key regulator
      of intestinal diseases such as parasitosis or eosinophilic gastroenteritis. Here
      we examined if mast cells contribute to the IL-5 production in human intestinal
      mucosa. The number of IL-5-positive lamina propria cells was substantially higher
      in patients with intestinal inflammatory diseases (5.3 +/- 4.6%, n = 17) compared
      to healthy controls (0.5 +/- 0.9%, n = 8, p < 0.01). In patients, the IL-5
      positive cells were eosinophils (70 +/- 13%) and mast cells (29 +/- 14%), whereas
      in controls all IL-5-positive cells were eosinophils. IL-5-positive T cells were
      not detected, likely because they do not store IL-5. In vitro studies with
      isolated human intestinal mast cells and eosinophils showed that mast cells do
      not produce IL-5 constitutively, but release high amounts of IL-5 (315 +/- 115
      pg/10(6) cells) following IgE receptor cross-linking, compared to activated
      eosinophils (24 +/- 5 pg/10(6) cells). Inhibitor studies suggest a regulation of
      IL-5 production at the transcriptional level. In conclusion our data demonstrate
      that activated mast cells are a potent source of IL-5 in the human intestinal
      mucosa.

PMID- 10359102
TI  - Activated T cells enter rat lymph nodes and Peyer's patches via high endothelial
      venules: survival by tissue-specific proliferation and preferential exit of CD8+
      T cell progeny.
AB  - Activated T cells reach the lymph nodes via afferent lymphatics but it is unknown
      to what extent they also enter them directly via high endothelial venules (HEV).
      Little is known about the mechanism mediating the proliferation of activated T
      cells within lymphoid tissues in vivo or the subsequent fate of the progeny.
      Therefore, we stimulated rat T cells via TCR and CD28 in vitro and after
      injection identified them in the blood and the HEV of lymphoid organs at several
      time points. In addition, the proliferation of these cells was studied after
      entering different lymphoid organs. Our results show that, firstly, activated T
      cells continuously enter lymph nodes and Peyer's patches directly via HEV.
      Second, they proliferate within lymphoid organs, the rate significantly depending
      on the microenvironment. Third, mainly CD8+ progeny are able to leave the tissues
      and re-enter the blood. Thus, the distribution of activated T cells circulating
      through the body can be regulated during entry, but also within the tissue by
      influencing their proliferation and subsequent release.

PMID- 10359104
TI  - Molecular cloning of a macrophage-derived, interferon-inducible secreted
      immunoglobulin-binding protein.
AB  - We describe the molecular cloning of a 1803-bp cDNA coding for a product termed
      interferon-induced immunoglobulin-binding protein (IIBP) from a library of IFN
      alpha-induced primary bone marrow macrophages. The open reading frame encodes a
      protein of 26-kDa containing two immunoglobulin-like and one Fc receptor-like
      domain. Due to the constitutive release of low amounts of IFN-beta, the IIBP mRNA
      is already present in macrophage-colony-stimulating factor-cultured macrophages.
      Its expression could be blocked in the presence of either anti-IFN-beta or
      interleukin-4, which down-regulates the endogenous IFN-beta production. Upon
      addition of rIFN-alpha4 a 3-5-fold superinduction of IIBP mRNA was observed. Rat
      monoclonal antibodies detected a protein of the predicted size exclusively in
      cell culture supernatants of primary bone marrow macrophages and a B-cell line.
      In immunoprecipitation experiments an unknown 30-kDa protein co-precipitated. The
      secreted IIBP showed considerable binding to nonspecific rat IgG2a and could be
      precipitated using mouse IgG2a, IgG2b and IgG3 antibodies of irrelevant
      specificities, indicating that this gene product is a novel secreted
      immunoglobulin-binding protein with a new IgG isotype binding pattern that
      differs to that of known Fc receptors.

PMID- 10359105
TI  - The synthesis of platelet-activating factor modulates chemotaxis of monocytes
      induced by HIV-1 Tat.
AB  - HIV-1 Tat protein has been shown to induce chemotaxis and recruitment of
      monocytes. In the present study, we evaluated whether HIV-1 Tat protein was able
      to induce the synthesis of platelet-activating factor (PAF), which is a potent
      mediator of cell motility, and whether the synthesis of PAF was instrumental in
      triggering Tat-induced monocyte chemotaxis. The results obtained indicate that
      Tat, but not gp120 and gp41, induced a time-dependent synthesis of PAF from
      monocytes at concentration as low as 0.1 ng/ml. As inferred by the inhibitory
      effect of anti-Flt-1 antibody and by the desensitization of monocytes following
      preincubation with vascular endothelial growth factor, the synthesis of PAF by
      monocytes stimulated with Tat was induced by activation of vascular endothelial
      growth factor receptor 1. Moreover, the Tat-induced chemotaxis of monocytes was
      abrogated both by WEB 2170 and by CV 3988, two chemically unrelated PAF receptor
      antagonists, suggesting that the synthesized PAF modulates the chemotactic
      response of monocytes to Tat. In conclusion, the results of the present study
      indicate that Tat-induced PAF synthesis plays a critical role in triggering the
      events involved in the migratory response of monocytes.

PMID- 10359106
TI  - The origin of marginal zone B cells in the rat.
AB  - The marginal zone is a unique compartment that is only found in the spleen. Rat
      marginal zone B cells (MZ-B) can be distinguished from other B cells, e.g.
      recirculating follicular B cells (RF-B), by several phenotypic characteristics.
      Typically MZ-B cells are surface (s)IgMhi, sIgDlo and CD45R(B220)lo, whereas RF-B
      cells are sIgMlo, sIgDhi and CD45Rhi. In addition, MZ-B cells stain strongly with
      HIS57, a newly developed monoclonal antibody. The developmental pathway and
      origin of MZ-B cells are not exactly known. However, previous studies indicate
      that recirculating (i. e. thoracic duct) B cells can give rise to MZ-B cells.
      Here the origin of (naive) MZ-B cells was studied using adriamycin (doxorubicin)
      induced B cell depletion. Using three-color flow cytometry and immunohistology we
      show that 2 days after a single i.v. injection of the anti-tumor drug adriamycin
      only RF-B cells can be detected, while all other B cell subpopulations are
      depleted, including all bone marrow precursor B cells. By studying the sequential
      reappearance of various B cell subsets and their precursors after adriamycin
      administration we show that MZ-B cells and the splenic marginal zone can be
      detected at a time point at which newly generated B cells (immature B cells) are
      not yet present. Given the observation that only RF-B cells were present at this
      time, we conclude that RF-B cells are the immediate MZ-B precursor cells.

PMID- 10359107
TI  - Immunogene therapy of murine fibrosarcoma using IL-15 gene with high translation
      efficiency.
AB  - We have recently found that translational efficiency is up-regulated by an
      alternative exon in IL-15 mRNA in mice. In a malignancy model using BALB/c mice
      and syngeneic Meth A fibrosarcoma (Meth A), we successfully applied immunological
      gene therapy with IL-15 protein using alternative IL-15 cDNA with high
      translational efficiency. Two expression vectors carrying the murine IL-15 gene
      were constructed for use in tumor immunotherapy, one utilizing IL-15 cDNA with
      alternative exon 5 and the second utilizing IL-15 cDNA with normal exon 5. The
      first vector induced the production of a large amount of IL-15 protein in Meth A
      cells, whereas tumor cells transfected by the second vector produced only a
      marginal level of IL-15 protein. Although cell growth of both transfectants in
      vitro remained unchanged, inoculation of clones transfected with normal IL-15
      cDNA resulted in progressive tumor growth, while clones transfected with
      alternative IL-15 cDNA led to the rejection of the tumor. The clone producing
      high levels of IL-15 grew progressively in nude mice and mice treated with anti
      CD4 monoclonal antibodies (mAb), whereas the growth of the transfectants was
      retarded in anti-CD8 mAb- or anti-asialo GM1 antibody-treated mice. Cured mice
      were shown to have generated immunity against a subsequent challenge with the
      wild type of Meth A but not against Meth 1 tumor cells, another type of
      fibrosarcoma derived from BALB/c mice. Thus, tumor therapy based on IL-15 gene
      transfection was effective against Meth A tumor cells, suggesting a possible
      application to human neoplasms.

PMID- 10359108
TI  - Antigen presentation by T cells versus professional antigen-presenting cells
      (APC): differential consequences for T cell activation and subsequent T cell-APC
      interactions.
AB  - We compared the effects of antigen (Ag) presentation by T cells and professional
      antigen-presenting cells (APC) on T cell proliferation, cytokine production and
      surface molecule expression. Ag presentation by T cells (T-T presentation)
      induced an initial T cell activation phase as measured by proliferation and IL-2
      production. These activated T cells became anergic upon antigenic restimulation
      by professional APC, as shown by a failure to proliferate or produce IL-2 or IFN
      gamma. Interestingly, such T cells were not intrinsically defective in their
      signal transduction pathways since they did proliferate and produce cytokines
      upon restimulation with mitogenic stimuli. Flow cytometric analysis revealed a
      more profound TCR and CD3 down-regulation during T-T presentation than during APC
      T presentation. However, no up-regulation of CD80, CD86, CD45RC and OX40 (CD134)
      was observed on T cells during T-T presentation or subsequent antigenic
      restimulation of anergic T cells in the presence of professional APC, whereas
      increased expression of these molecules was observed during professional APC-T
      presentation of non-anergic T cells. The impaired expression of co-stimulatory
      and activation molecules on T cells after T-T presentation of Ag might lead to
      altered interactions between T cells and professional APC upon antigenic
      restimulation. We propose that T cell anergy is a functional consequence of these
      altered T cell-APC interactions.

PMID- 10359109
TI  - Characterization of an apparently conserved epitope in E- and P-selectin
      identified by dual-specific monoclonal antibodies.
AB  - E- and P-selectin recognize a wide and overlapping range of oligosaccharide
      ligands including sialyl-Lewis X (sLeX) through their highly homologous C-type
      lectin domains. We report that an epitope apparently conserved between E- and P
      selectin is functionally involved in ligand recognition although distantly
      located from the conventional carbohydrate binding site. We found that a
      previously established anti-E-selectin monoclonal antibody (mAb), 1.2B6, is cross
      reactive with P-selectin, and that the 1.2B6 epitope is in the C-type lectin
      domain and identical to or overlapping with an epitope recognized by other
      independently established anti-E- and P-selectin dual-specific mAb. The epitope
      has been mapped by others to a region distant from the previously identified
      carbohydrate binding site of E-selectin in its three-dimensional structure.
      Nevertheless, it is of note that all dual-specific mAb, including 1.2B6,
      inhibited E- or P-selectin-mediated cell adhesion and also binding to sLeX.
      Engagement of the apparently conserved epitope by the dual-specific mAb may lead
      to inhibition of the ligand binding ability of E- and P-selectin by a previously
      uncharacterized mechanism(s) rather than by direct inhibition of sLeX binding to
      the hitherto identified ligand binding site.

PMID- 10359110
TI  - Cholera toxin increases intracellular pH in B lymphoma cells and decreases their
      antigen-presenting ability.
AB  - Cholera toxin (CT) can function as a potent adjuvant in the mucosal immune
      response. However, we have found that treatment of A20-HL murine B lymphoma cells
      with CT severely inhibits the presentation of ovalbumin (OVA) to cells of the T
      cell clone 42-6A specific for OVA(323-339)/I-Ad, whereas it does not affect the
      presentation of OVA(323-339) peptide. CT treatment did not affect the expression
      of B7-1, B7-2, ICAM-1, LFA-1 or MHC class II on, or the internalization of OVA
      into A20-HL cells. In CT-treated A20-HL cells, degradation of OVA was decreased,
      and intracellular pH was raised to a level approximately equivalent to that in
      CH3NH2-treated cells. Treatment with CH3NH2 is known to raise the pH in endocytic
      structures and thus inhibits antigen processing. Treatment of A20-HL cells with
      dibutyryl-cAMP similarly increased intracellular pH. The increase in
      intracellular pH following CT treatment was inhibited by a cAMP inhibitor, 2',3'
      dideoxyadenosine. These results strongly suggest that CT treatment of A20-HL
      cells inhibits their antigen-presenting cell function by triggering the cAMP
      cascade, increasing intracellular pH, and reducing the degradation of OVA.

PMID- 10359111
TI  - Major histocompatibility class I molecules present Urtica dioica agglutinin, a
      superantigen of vegetal origin, to T lymphocytes.
AB  - The Urtica dioica agglutinin (UDA) shares with the superantigens the property of
      activating T cell subsets bearing particular Vbeta segments of the TCR. However,
      UDA is a lectin capable of binding to many glycoproteins on cell membranes. The
      implication of MHC versus other glycoproteins in UDA presentation was presently
      studied. Using mutant mice lacking MHC class I (MHC-I), MHC class II (MHC-II) or
      both MHC antigens, we provided evidence that MHC-I and MHC-II molecules serve as
      UDA receptors. Presentation by either one of these molecules ensured similar T
      cell responses and co-stimulatory signals were mandatory for optimal T cell
      activation and proliferation both in MHC-I and MHC-II contexts. Remarkably, in
      the absence of MHC molecules, UDA could not be efficiently presented to T cells
      by other glycosylated proteins. Surface plasmon resonance studies were used to
      confirm the binding of UDA to MHC-I molecules using a fusion protein consisting
      of MHC-I domains and beta2-microglobulin. The results indicated that the
      interaction between UDA and MHC-I molecules implicated lectin-binding site(s) of
      UDA. Taken together, our data demonstrate that, in addition to MHC-II antigens,
      MHC-I molecules serve as an alternative ligand for UDA.

PMID- 10359112
TI  - A prototype pathogen bound ex vivo to human erythrocyte complement receptor 1 via
      bispecific monoclonal antibody complexes is cleared to the liver in a mouse
      model.
AB  - Immune complexes (IC) bound to the primate erythrocyte (E) complement receptor
      (CR1) are cleared from the circulation of primates and localized to the liver. IC
      can be bound to E CR1 either via C3b opsonization or with cross-linked mAb
      complexes (heteropolymers, HP) which contain an mAb specific for CR1 and a mAb
      specific for a prototype pathogen. The long-term goal of our work is to apply the
      HP to the treatment of human diseases associated with blood-borne pathogens.
      Therefore we have investigated the feasibility of a non-primate model by studying
      clearance in mice of bacteriophage phiX174 bound via HP to primate E. E-HP
      phiX174 complexes were prepared in vitro and infused into the circulation of mice
      under conditions allowing short term survival of E in the circulation. By
      radioimmunoassays and flow cytometry, we found that phiX174 is removed from E and
      cleared from the circulation coincident with loss of HP and CR1, and that the
      majority of cleared phiX174 is localized to the liver. Through the use of HP
      constructed with Fab' fragments, we verified the requirement for the Fc portion
      of the mAb in clearance; inhibition of C3 activation delayed clearance,
      suggesting a role for complement. The present findings in the mouse confirm
      previous observations in the non-human primate model.

PMID- 10359113
TI  - Cytotoxic T cell recognition of allelic variants of HLA B35 bound to an Epstein
      Barr virus epitope: influence of peptide conformation and TCR-peptide
      interaction.
AB  - Fine specificity analysis of HLA B35-restricted Epstein-Barr virus (EBV)-specific
      cytotoxic T lymphocyte (CTL) clones revealed a unique heterogeneity whereby one
      group of these clones cross-recognized an EBV epitope (YPLHEQHGM) on virus
      infected cells expressing either HLA B*3501 or HLA B*3503, while another group
      cross-recognized this epitope in association with either HLA B*3502 or HLA
      B*3503. Peptide binding and titration studies ruled out the possibility that
      these differences were due to variation in the efficiency of peptide presentation
      by the HLA B35 alleles. Sequence analysis of the TCR genetic elements showed that
      these clonotypes either expressed BV12/AV3 or BV14/ADV17S1 heterodimers.
      Interestingly, CTL analysis with monosubstituted alanine mutants of the YPLHEQHGM
      epitope indicated that the BV12/AV3+ clones preferentially recognized residues
      towards the C terminus of the peptide, while the BV14/ADV17S1+ clones interacted
      with residues towards N terminus of the peptide. Molecular modelling of the MHC
      peptide complexes suggests that the differences in two floor positions (114 and
      116) of the HLA B35 alleles dictate different conformations of the peptide
      residues L3 and/or H7 and directly contribute in the discerning allele-specific
      immune recognition by the CTL clonotypes. These results provide evidence for a
      critical role for the selective interaction of the TCR with specific residues
      within the peptide epitope in the fine specificity of CTL recognition of allelic
      variants of an HLA molecule.

PMID- 10359114
TI  - Functional and phenotypic analysis of thymic B cells: role in the induction of T
      cell negative selection.
AB  - The phenotype of mouse thymic B cells and their capacity to induce T cell
      negative selection in vitro were analyzed. Thymic B cells expressed B cell
      markers such as IgM, Fc gamma receptor, CD44, heat-stable antigen, LFA-1 and
      CD40. In addition, they were positive for the activation molecule CD69 and
      displayed high levels of B7-2. Although thymic B cells expressed CD5 on their
      surface, no CD5-specific mRNA was detected. Moreover, thymic B cells induced a
      stronger deletion of TCR-transgenic (TG) thymocytes than splenic B cells, which
      had low CD69 and B7-2 levels. Interestingly, CD40-activated splenic B cells up
      regulated CD69 and B7-2 and acquired a capacity to induce T cell deletion
      comparable to that of thymic B cells. Moreover, thymic B cells from CD40
      deficient mice displayed lower CD69 and B7-2 levels than control thymic B cells,
      and lower capacity to induce the deletion of TCR TG thymocytes. These results
      support the hypothesis that CD40-mediated activation of thymic B cells determines
      a high efficiency of antigen presentation, suggesting that within the thymus B
      cells may play an important role in the elimination of autoreactive thymocytes.

PMID- 10359115
TI  - CD4 T cell traffic control: in vivo evidence that ligation of OX40 on CD4 T cells
      by OX40-ligand expressed on dendritic cells leads to the accumulation of CD4 T
      cells in B follicles.
AB  - We report here that CD40- but not lipopolysaccharide (LPS)-activated murine
      dendritic cells (DC) express OX40-ligand (OX40L) as has been reported in humans.
      To understand how OX40 ligation affects differentiation of CD4 T cells at the
      time of priming, we constitutively expressed OX40L on DC using the DC-specific
      promoter of CD11c. Transgenic mice showed greatly increased numbers of CD4 but
      not CD8 T cells in their B cell areas. This effect was to a great extent
      immunization dependent, as spleen and lymphoid tissue with no germinal center
      reactions from mice which had not been deliberately immunized did not show marked
      CD4 T cell accumulation. The increased numbers of CD4+ CD62low cells in
      transgenic mice suggest that it is activated CD4 T cells that accumulate within B
      cell follicles. These data are consistent with the notion that physiological
      engagement of OX40 (CD134) on activated CD4 T cells either initiates their
      migration into or causes them to be retained in B follicles. In contrast, LPS
      treated CD did not up-regulate OX40L expression. This dichotomy provides a
      molecular explanation of how DC might integrate environmental and accessory
      signals to control cytokine differentiation and migration in CD4 effector cells.

PMID- 10359116
TI  - Distinct patterns and kinetics of chemokine production regulate dendritic cell
      function.
AB  - Dendritic cells (DC) have been showed to both produce and respond to chemokines.
      To understand how this may impact on DC function, we analyzed the kinetics of
      chemokine production and responsiveness during DC maturation. After stimulation
      with LPS, TNF-alpha or CD40 ligand, the inflammatory chemokines MIP-1alpha, MIP
      1beta and IL-8 were produced rapidly and at high levels, but only for a few
      hours, while RANTES and MCP-1 were produced in a sustained fashion. The
      constitutive chemokines TARC, MDC and PARC were expressed in immature DC and were
      up-regulated following maturation, while ELC was produced only at late time
      points. Activated macrophages produced a similar spectrum of chemokines, but did
      not produce TARC and ELC. In maturing DC chemokine production had different
      impact on chemokine receptor function. While CCR1 and CCR5 were down-regulated by
      endogenous or exogenous chemokines, CCR7 levels gradually increased in maturing
      DC and showed a striking resistance to ligand-induced down-regulation, explaining
      how DC can sustain the response to SLC and ELC throughout the maturation process.
      The time-ordered production of inflammatory and constitutive chemokines provides
      DC with the capacity to self-regulate their migratory behavior as well as to
      recruit other cells for the afferent and efferent limb of the immune response.

PMID- 10359117
TI  - Thyroglobulin monoclonal antibody cross-reacting with thyroperoxidase induces in
      syngeneic mice anti-idiotypic monoclonal antibodies with dual autoantigen binding
      properties. The intertope hypothesis.
AB  - Autoimmune thyroid diseases are characterized by antibodies (Ab) directed to
      thyroglobulin (Tg) and thyroperoxidase (TPO). Some of them, TGPO Ab, are Tg Ab
      with an interspecies idiotype (Id) reacting with TPO. Taking advantage of a
      carefully studied TGPO monoclonal antibody (mAb), we examined the basis of the
      hypothesis that TPO Ab would ultimately derive from TGPO Ab through idiotypic
      induction. We repeatedly immunized naive, syngeneic mice with the TGPO mAb and we
      derived three novel mAb directed to both Tg and TPO. The most reactive of them,
      mAb 4F8, was further purified, radiolabeled and its binding properties studied by
      radioimmunoassay. mAb 4F8 bound to Tg, TPO, the immunogen Ab1 and even to itself,
      being thus considered as a self-binding Ab2. Competitive binding inhibition
      experiments demonstrated that Tg, TPO, Ab1 and Ab2 cross-reacted for Ab2 binding
      to Tg, TPO and Ab1. Fine specificity mapping using panels of specific mAb
      revealed that Ab1 and Ab2 were similar because they were directed against the
      same immunodominant regions on Tg and TPO. We propose that unique Id of TGPO Ab
      resemble dominant epitopes of Tg as well as paratopes of Ab directed against
      dominant TPO epitopes. This category of Id that we called intertopes may induce
      TPO-monospecific Ab from TGPO Ab by idiotypically driven somatic mutations.

PMID- 10359118
TI  - ATP-evoked Ca2+ transients and currents in murine thymocytes: possible role for
      P2X receptors in death by neglect.
AB  - The P2X family of ATP receptors (P2XR) have been implicated in thymocyte death in
      vitro and in vivo. We characterized ATP-evoked Ca2+ transients and membrane
      currents in thymocytes to better understand the role of P2XR during thymocyte
      development. ATP4-, but not UTP or GTP, activated a sustained non-selective
      cation current in voltage-clamped CD4- CD8- and CD4+ CD8+ thymocytes that was
      reversed by apyrase, which hydrolyzes ATP, and by the P2XR antagonists suramin
      and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). The more
      selective P2XR agonist alphabeta-methylene ATP activated a smaller rapidly
      decaying current in both thymocyte populations. Reverse transcription-PCR results
      indicate that P2X1, P2X2, P2X6, and/or P2X7 are expressed in thymocytes. Finally,
      we used PPADS to examine the role of P2XR during thymocyte development in situ.
      PPADS-treated thymi yielded significantly more thymocytes (38%), due to a
      selective increase in CD4+ CD8+ cells. Together these data suggest that one or
      more PPADS-sensitive P2XR (P2X1, P2X2, P2X7) are involved in thymocyte apoptosis,
      and we propose more specifically a role associated with death by neglect.

PMID- 10359119
TI  - NF-kappaB-mediated self defense of macrophages faced with bacteria.
AB  - NF-kappaB is a ubiquitous transcription factor that is extensively exploited by
      immune cells involved in host defense mechanisms. Macrophages participate in the
      first line of defense against microorganisms, but little is known about whether
      and how NF-kappaB is involved in the handling of microbes by macrophages. To
      explore this issue, NF-kappaB-inactive macrophages, NIKMAC(NR), were created by
      overexpression of a super-repressor mutant of IkappaB alpha. When co-cultured
      with Escherichia coli, the NIKMAC(NR) macrophages exhibited impairment of
      bactercidal activity. Microscopic analysis revealed that NIKMAC(NR) cells faced
      with bacteria underwent rapid and fulminant apoptosis. Similary, NIKMAC(NR)
      macrophages cultured in the presence of a bacterial component,
      lipopolysaccharide, showed dramatic apoptosis. Inhibition of RNA synthesis or
      protein synthesis failed to block the apoptosis of NIKMAC(NR) cells, indicating
      that macrophages possess a pre-existing, apoptotic pathway that can be triggered
      by bacteria. Apoptosis was not observed in NIKMAC(NR) macrophages exposed to non
      microbial stimuli including phorbol ester and opsonized zymosan. However,
      NIKMAC(NR) cells were more susceptible to apoptosis triggered by TNF-alpha and
      reactive oxygen intermediates, both of which are produced abundantly by
      macrophages when faced with bacteria. These data suggest a critical role for NF
      kappaB in the survival of macrophages at the site of bacterial infection.

PMID- 10359120
TI  - NKp46 is the major triggering receptor involved in the natural cytotoxicity of
      fresh or cultured human NK cells. Correlation between surface density of NKp46
      and natural cytotoxicity against autologous, allogeneic or xenogeneic target
      cells.
AB  - NKp46 is a novel triggering receptor expressed by all human NK cells that is
      involved in natural cytotoxicity. In this study we show that the surface density
      of NKp46 may vary in different NK cells and that a precise correlation exists
      between the NKp46 phenotype of NK clones and their natural cytotoxicity against
      HLA-class I-unprotected allogeneic or xenogeneic cells. Thus, NKp46bright clones
      efficiently lysed human and murine tumor cells while NKp46dull clones were poorly
      cytolytic against both types of target cells. We also show that the NKp46
      phenotype of NK clones correlates with their ability to lyse HLA-class I
      unprotected autologous cells. Finally, NKp46 was found to be deeply involved in
      the natural cytotoxicity mediated by freshly derived NK cells. This was indicated
      both by the inhibition of cytolysis after monoclonal antibody-mediated masking of
      NKp46 and by the correlation existing between the natural cytotoxicity of fresh
      NK cells derived from different donors and their NKp46 phenotype. In conclusion,
      these studies strongly support the concept that NKp46 plays a central role in the
      physiological triggering of NK cells and, as a consequence (in concert with
      killer inhibitory receptors), in the NK-mediated clearance of abnormal cells
      expressing inadequate amounts of HLA-class I molecules.

PMID- 10359121
TI  - Self glycolipids as T-cell autoantigens.
AB  - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous
      system characterized by discrete areas of demyelination. An autoimmune response
      against components of myelin is thought to contribute to disease pathogenesis.
      Here we identify glycolipids as new targets recognized by T cells in multiple
      sclerosis patients. Circulating T cells reactive with glycolipids are more
      frequent in MS patients than in control donors as shown by enzyme-linked
      immunospot assay. They specifically recognize different types of glycolipids,
      such as gangliosides, sulfatide and galactosylceramide and release IFN-gamma and
      TNF-alpha. T cells specific for gangliosides were found to be CD8+, TCR
      alphabeta+, restricted by the MHC-like CD1b molecule and specific for epitopes
      residing in the carbohydrate moiety of gangliosides. Our findings suggest that in
      addition to self proteins, self glycolipids may represent potential source of
      autoantigens recognized by T cells in autoimmune diseases.

PMID- 10359122
TI  - Activating interactions in human NK cell recognition: the role of 2B4-CD48.
AB  - 2B4 is a cell surface glycoprotein of the immunoglobulin superfamily structurally
      related to CD2-like molecules. It was originally identified in the mouse as a
      receptor that mediates non-MHC-restricted cytotoxicity by NK cells and CD8+ T
      cells. Recently, 2B4 was shown to bind CD48 by molecular binding assays and
      surface plasmon resonance. Here, we have investigated the cell surface
      expression, biochemical characteristics and function of human 2B4. Our results
      show that 2B4 is expressed not only on NK cells and CD8+ T cells, but also on
      monocytes and basophils, indicating a broader role for 2B4 in leukocyte
      activation. In NK cells, engagement of 2B4 with a specific monoclonal antibody or
      with CD48 can trigger NK cell-mediated cytotoxicity. The contribution of 2B4-CD48
      interaction to target cell lysis by different NK cell clones varies, probably
      dependent on the relative contribution of other receptor-ligand interactions. In
      T cells and monocytes, ligation of 2B4 does not lead to T cell or monocyte
      activation. Thus, it appears that the primary function of 2B4 is to modulate
      other receptor-ligand interactions to enhance leukocyte activation.

PMID- 10359123
TI  - Inhibitory effects of the Trypanosoma cruzi membrane glycoprotein AGC10 on the
      expression of IL-2 receptor chains and secretion of cytokines by subpopulations
      of activated human T lymphocytes.
AB  - The Trypanosoma cruzi membrane glycoprotein AGC10 has been shown to alter some
      human macrophage functions (De Diego, J. L. et al., J. Immunol. 1997. 159: 4983
      4989). We show here that, in the presence of AGC10, [3H]thymidine incorporation
      by normal human lymphocytes stimulated with anti-CD3 or phytohemagglutinin (PHA)
      is severely curtailed. This effect was found to involve down-regulation of the
      expression of both CD25 (IL-2R alpha) and CD122 (IL-2R beta) on the lymphocyte
      membrane and a marked decrease in the level of up-regulation of the expression of
      surface CD132 (IL-2R gamma or gamma(c)). These alterations occurred in fairly
      large proportions of CD4+ and CD8+ lymphocytes. AGC10 also inhibited
      proliferation and expression of IL-2 receptor chains by activated T lymphocytes
      virtually depleted of monocytes/macrophages, indicating that these effects do not
      necessarily require prior modification of monocyte/macrophage function by AGC10.
      Human lymphocytes stimulated with anti-CD3 or PHA also displayed a markedly
      decreased capacity to secrete IL-2 and IFN-gamma, suggesting that AGC10 affected
      at least Th1 cell functions. Cell viability in cultures containing or lacking
      AGC10 was comparable over a 72-h period, and neither CD25 expression by, nor the
      viability of, PHA-stimulated Jurkat cells was altered by AGC10, ruling out that
      the effects of AGC10 are due to cell killing. These results highlight down
      regulatory effects on activated T lymphocytes exerted by a membrane molecule from
      a parasite causing a disease whose acute phase is accompanied by
      immunosuppression.

PMID- 10359124
TI  - Impaired apoptotic deletion of myelin basic protein-reactive T cells in patients
      with multiple sclerosis.
AB  - T cell responses to myelin basic protein (MBP) may play an important role in the
      pathogenesis of multiple sclerosis (MS). If MBP-reactive T cells are involved in
      the disease processes and undergo clonal activation and expansion, their
      precursor frequency would be increased in patients with MS. The frequency of MBP
      reactive T cells is also influenced by regulatory mechanisms in vivo, including
      apoptotic deletion. In this study, we examined changes in the frequency of MBP
      reactive T cells in patients with MS as a function of the apoptotic deletional
      mechanism in vivo, using a cell culture-based assay. A significantly increased
      frequency of MBP-reactive T cells was found in patients with MS relative to
      healthy individuals only when Fas-ligand antibody was used to block apoptosis.
      This result indicates that a significant proportion of MBP-reactive T cells are
      sensitive to apoptosis and are not deleted in vivo in patients with MS, as
      opposed to healthy individuals, thus suggesting a functional deficit in apoptotic
      deletional mechanism. Surviving Fas-sensitive MBP-reactive T cell lines represent
      distinct subpopulations preferentially recognizing the 111-139 region of MBP and
      exhibiting a Th2 cytokine profile. The findings are relevant to our understanding
      of regulation of MBP-reactive T cells in vivo in MS.

PMID- 10359125
TI  - Recombinant expression of polymeric IgA: incorporation of J chain and secretory
      component of human origin.
AB  - Mucosal J (joining) chain-expressing IgA immunocytes produce dimeric IgA that is
      actively transported by the epithelial polymeric Ig receptor (pIgR) to exocrine
      secretions. Release of secretory IgA (SIgA) occurs by cleavage of the covalently
      linked pIgR ectodomain, also known as bound secretory component. We have
      identified the human J-chain cDNA sequence through database screening, and
      isolated it from B cells for recombinant expression. Co-expression of this cDNA
      with an alpha heavy chain and a lambda light chain in Chinese hamster ovary (CHO)
      cells resulted in a mixture of recombinant monomeric and dimeric IgA in culture
      supernatants. This dimeric IgA was transported by the pIgR-mediated mechanism in
      vitro. Furthermore, expression of the human pIgR ectodomain together with the
      dimeric IgA, resulted in production of complete SIgA by the CHO cells. These
      results demonstrated that co-expression of the necessary polypeptide components
      allows a single mammalian cell to produce SIgA. Development of production systems
      for human antigen-specific recombinant SIgA may be important for applications in
      passive mucosal vaccination.

PMID- 10359126
TI  - The oncogene product Vav is a crucial regulator of primary cytotoxic T cell
      responses but has no apparent role in CD28-mediated co-stimulation.
AB  - The guanine nucleotide-exchange factor Vav is a regulator of antigen-mediated
      cytoskeletal reorganization required for receptor clustering, proliferation and
      thymic selection. Moreover, Vav has been identified as a major substrate in the
      CD28 signal transduction pathway and overexpression of Vav enhances TCR-mediated
      IL-2 secretion in T cells. Here we show that CD3- plus CD28-mediated
      proliferation and IL-2 production were reduced in vav gene-deficient T cells.
      However, Vav had no apparent role in phorbol 12-myristate 13-acetate-plus CD28
      mediated proliferation and IL-2 production, suggesting that Vav acts downstream
      of the TCR/CD3 complex. In vivo, Vav expression was crucial to generate primary
      vesicular stomatitis virus (VSV)-specific cytotoxic T cell responses. In
      contrast, vav-/- mice exhibited a reduced but significant footpad swelling after
      lymphocytic choriomeningitis virus (LCMV) infections and mounted a measurable
      primary cytotoxic T cell response to LCMV. Upon in vitro restimulation, cytotoxic
      T cell responses of both VSV- and LCMV-infected mice reached near normal levels.
      Our data provide the first genetic evidence that Vav is an important effector
      molecule that relays antigen receptor signaling to IL-2 production and activation
      of cytotoxic T cells.

PMID- 10359127
TI  - TCRzeta is transported to and retained in the Golgi apparatus independently of
      other TCR chains: implications for TCR assembly.
AB  - It is generally assumed that TCR assembly occurs in the endoplasmic reticulum
      (ER), and ER retention/degradation signals have been identified in several of the
      TCR chains. These signals are probably responsible for retention of incompletely
      assembled TCR complexes and free TCR chains in the ER. This study focused on the
      intracellular localization and transport of partially assembled TCR complexes as
      determined by confocal microscopy analyses. We found that none of the TCR chains
      except for TCRzeta were allowed to exit the ER in T cell variants in which the
      hexameric CD3gammaepsilonTi alphabetaCD3 deltaepsilon complex was not formed.
      Interestingly, TCRzeta was exported from the ER independently of other TCR chains
      and was predominantly located in a compartment identified as the Golgi apparatus.
      Furthermore, in the TCRzeta-negative cell line MA5.8, the hexameric
      CD3gammaepsilonTi alphabetaCD3 deltaepsilon complex was allowed to exit the ER
      and was also predominantly located in the Golgi apparatus. However, neither
      hexameric TCR complexes nor TCRzeta chains were efficiently expressed at the cell
      surface without the other. The observations that TCRzeta and hexameric TCR
      complexes are transported from the ER to the Golgi apparatus independently of
      each other and that these partial TCR complexes are unable to be efficiently
      expressed at the cell surface suggest that final TCR assembly occurs in the Golgi
      apparatus.

PMID- 10359128
TI  - Duplication and MHC linkage of the CTX family of genes in Xenopus and in mammals.
AB  - The effects of whole genome duplications that characterize the evolution of
      vertebrates have been studied on the gene of the Xenopus thymocyte molecule CTX
      and its mammalian relatives. CTX, with an extracellular part consisting of one V
      and one C2 external domain, defines a new subset of the immunoglobulin
      superfamily and is conserved from amphibians to mammals. The number of CTX loci,
      their polymorphism, and their genetic linkages have been studied in several
      Xenopus species and in humans. In the genetically simplest species, X. tropicalis
      (2n = 20), the unique CTX locus is linked to the MHC. In the polyploid species,
      all CTX genes, unlike many other immune system genes, have remained in the
      genome; i.e. there are two CTX loci in the tetraploid species X. laevis (2n = 6)
      and six CTX loci in the dodecaploid species X. ruwenzoriensis (2n = 108). In X.
      laevis, one CTX gene is linked to the MHC and the other not, presumably because
      one set of MHC class I and II has been deleted from the corresponding linkage
      group. The various mammalian homologues are less related to each other than are
      the Xenopus CTX genes among each other, and they do not cross-hybridize with each
      other because they stem from the ancient polyploidization. Some human CTX
      homologies are on chromosomes 11 and 21, but others are on chromosomes 1, 6 and
      19, which contain MHC paralogous regions; this suggests that a very ancient
      linkage group has been preserved.

PMID- 10359129
TI  - Truncated or chimeric endogenous protein antigens gain immunogenicity for B cells
      by stress protein-facilitated expression.
AB  - Truncated variants of the SV40 large T antigen (T-Ag) with an intact N terminus
      are as efficiently expressed in eukaryotic transfectants as wild-type (wt) T-Ag.
      Coprecipitation of N-terminal T-Ag fragments with the constitutively expressed,
      cytosolic stress protein hsp73 suggests that this chaperone stabilized expression
      of the truncated T-Ag fragments. In contrast to T-Ag, the 163-residue N-terminal
      preS domain of the hepatitis B surface antigen (HBsAg) is difficult to express.
      When the preS domain is C-terminally fused to a hsp73-binding cytoplasmic T-Ag
      (cT-Ag) fragment its stable expression as a chimeric cT-preS protein is obtained.
      DNA-based vaccination with plasmid DNA encoding either wt or hsp-associated
      mutant T-Ag elicited potent MHC class I-restricted, T-Ag-specific T cell
      responses. In contrast, DNA vaccination with hsp73-binding (mutant or chimeric) T
      Ag variants, but not with wt T-Ag elicited T-Ag-specific antibody responses.
      Furthermore, vaccination with cT-preS-encoding plasmid DNA induced antibodies
      binding to the preS domain of the large HBsAg. Hence, hsp73-bound endogenous
      antigens efficiently stimulate antibody responses. These findings may be relevant
      for tumor immunology and autoimmunity.

PMID- 10359131
TI  - Cardiac troponin T as a marker of myocardial damage caused by antineoplastic
      drugs in rabbits.
AB  - Anthracycline derivatives are among the most effective antineoplastic drugs but
      their therapeutic use is limited by their adverse effects. The cardiac side
      effects of antineoplastic drugs were investigated in rabbits in vivo from the
      viewpoint of release of cardiac troponin T (cTnT) measured by Elecsys Troponin T
      STAT immunoassay (Boehringer Mannheim, Germany). No increase in cTnT was found
      following administration of a single dose of daunorubicin (3 mg/kg i.v., n = 4).
      During development of daunorubicin-induced cardiomyopathy (daunorubicin 3 mg/kg
      i.v., once a week; maximum nine administrations, n = 7), the levels of cTnT were
      within the physiological range (i.e. cTnT <0.1 microg/l) at the beginning of the
      experiment and before and after the 5th administration, but the pathological
      values of cTnT after the 8th administration in 43% animals (0.22+/-0.08 microg/l)
      correlated with their premature death. In the control group, the levels of cTnT
      were always lower than 0.1 microg/l during the experiment. Following
      administration of a new antineoplastic drug - Oracin [6-[2-(2-hydroxyethyl)
      aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno [1,2-c]-isoquinoline hydrochloride,
      10 mg/kg i.v., once weekly, ten administrations, n = 7], there was no increase in
      cTnT levels. These findings correlated with the PEP: LVET index, histological
      examination and no animal succumbing to premature death. It is possible to
      conclude that cTnT is a useful marker for the prediction of experimentally
      induced anthracycline cardiomyopathy and for the evaluation of cardiotoxic (and,
      possibly, cardioprotective) effects of new drugs in rabbits.

PMID- 10359130
TI  - Experimental induction of rhabdomyosarcoma in mice with fractionated doses of
      beta-irradiation.
AB  - Repeated doses of beta-radiation in the mouse skin model have been reported to
      produce carcinomas and sarcomas with equal frequency. Among sarcomas,
      fibrosarcomas and osteosarcomas have been the predominant reported histologies.
      In this report we describe the beta-radiation induction of rhabdomyosarcoma
      (RMS), a histology previously undescribed with tumor induction protocols using
      ionizing radiation in an animal model. Radiation-induced RMS is often seen as a
      secondary tumor following therapeutic irradiation for retinoblastoma in children.
      In our experiment the backs of 50 CD-1 mice were irradiated 3 times weekly for 35
      weeks using a 90Sr source. The initial dose was 5.5 Gy/application, which was
      later reduced to 3 Gy after 15 weeks due to severe skin reactions. In all, 27
      skin and subcutaneous tumors were seen and collected. Of 12 sarcomas seen, 9 had
      a rhabdoid histology; cell lines from 3 such tumors as well as a squamous-cell
      carcinoma (SCC) and a malignant fibrous histiocytoma (MFH) were established.
      Immunohistochemical analysis of their parent tumors showed that the rhabdoid
      tumors expressed desmin, which established the diagnosis of RMS. Two-dimensional
      gel electrophoresis and Western analysis of insoluble protein extracts confirmed
      that the cell lines from RMS tumors expressed desmin. A screen for molecular
      alterations identified a mutant p53 phenotype for RMS and MFH cell lines. These
      radiation-induced RMS cell lines provide a unique opportunity to study the
      molecular biology of this tumor in an animal model and will help provide insight
      into the mechanisms of radiation-induced RMS in humans.

PMID- 10359132
TI  - In vitro influence of lectins and neoglycoconjugates on the growth of three human
      sarcoma cell lines.
AB  - PURPOSE: The aim of our study is to investigate the in vitro effects of plant
      lectins, galectins and neoglycoconjugates on the proliferation of three human
      sarcoma cell lines. METHODS: Proliferation was assessed by means of the
      tetrazolium derivative reduction (MTT) assay. In addition, glycohistochemistry
      was used to make visible the plant-lectin-specific binding sites; the intensity
      of the lectin binding pattern was quantified by means of image analysis. RESULTS:
      Depending on the cell lines, the staining intensity and the percentage of
      labelled cells were different. With respect to growth modulation, the cell lines
      also responded differently to the probes used. Besides a predominant inhibitory
      effect elicited by the probes at 50 microg/ml, dose-dependent effects, including
      growth stimulation, were detectable in several instances. These effects relate to
      the animal galectins tested and several neoglycoconjugates, e.g. the lactose- and
      blood-group-A-trisaccharide-bearing probes. CONCLUSIONS: Endogenous lectins and
      lectin-reactive cellular glycoconjugates can apparently affect the regulation of
      the growth of human sarcoma cells. We suggest that these results are relevant for
      further histopathological monitoring in correlation with prognosis and in vitro
      assays to reveal possible clinical applications.

PMID- 10359133
TI  - Analysis of sensitivity and specificity of cytokeratin 19 reverse
      transcriptase/polymerase chain reaction for detection of occult breast cancer in
      bone marrow and leukapheresis products.
AB  - PURPOSE: The work aimed to evaluate the sensitivity and specificity of the
      cytokeratin (CK) 19 reverse transcriptase/polymerase chain reaction (RT-PCR) for
      the detection of occult breast cancer in bone marrow and leukapheresis products.
      MATERIALS AND METHODS: Peripheral blood and bone marrow samples, obtained from 96
      and 8 healthy donors respectively, served as negative controls. A total of 115
      bone marrow samples and 29 leukapheresis samples from routine patients with
      breast cancer were analysed by CK19 RT-PCR. The PCR results were compared with
      those from routine immunocytology for CK8, 18, 19. RESULTS: The CK19 RT-PCR
      technique with primer pairs from Datta et al. (J Clin Oncol 12: 475-482, 1994),
      using an annealing temperature of 72 degrees C, allowed the detection of one
      tumour cell in 10(7) mononuclear cells. None of the control samples (96
      peripheral blood and 8 bone marrow) that were positive for beta2-microglobulin by
      RT-PCR showed a signal for CK19. However, expression of CK19 mRNA was observed in
      40.87% (70/115) of bone marrow and in 24.13% (7/29) of leukapheresis samples of
      patients with breast cancer. Standard immunocytology and PCR were combined for
      the detection of tumour cells. Five of the 65 bone marrow samples were found to
      be positive by CK19 RT-PCR, but were negative with the immunocytology method.
      CONCLUSION: RT-PCR using CK19-specific primers and optimal experimental
      conditions is a reliable and specific method for the detection of micrometastatic
      breast cancer cells.

PMID- 10359134
TI  - Phase II trial of biochemotherapy with interferon alpha, dacarbazine, cisplatin
      and tamoxifen in metastatic melanoma: a Southwest Oncology Group trial.
AB  - The therapeutic benefit of adding interferon alpha (IFNalpha) to established
      single-agent and combination chemotherapy regimens for the treatment of
      metastatic melanoma has not been proven. We designed the present study to
      estimate the response rate of IFNalpha, dacarbazine, cisplatin and tamoxifen in
      patients who had not been treated with systemic therapy for advanced disease.
      Using a schedule similar to that which had previously been shown to favor
      IFNalpha plus dacarbazine over dacarbazine alone, we treated patients with an
      "induction" regimen of IFNalpha, 15 mU m(-2) day(-1) intravenously 5 days/week
      for 3 weeks. Following induction, schedules of IFNalpha, 5 mU m(-2) day(-1)
      subcutaneously three times a week, and tamoxifen, 10 mg orally twice a day, were
      begun. Dacarbazine, 250 mg m(-2) day(-1) and cisplatin 33 mg m(-2) day(-1) for 3
      consecutive days were repeated every 4 weeks, and subcutaneous IFNalpha and oral
      tamoxifen were continued until the discontinuation of chemotherapy. We treated 25
      patients (18 men and 7 women, median age 52 years) and observed only 1 objective
      response (response rate 4%, 95% confidence interval 0.1%-20%). The toxicities of
      the regimen consisted of moderate myelosuppression and constitutional side
      effects. On the basis of the low antitumor activity of this regimen, we do not
      recommend it for further study or for use as standard therapy of metastatic
      melanoma.

PMID- 10359136
TI  - Primary cutaneous marginal center lymphoma - complete remission induced by
      interferon alpha2a.
AB  - Marginal zone lymphoma (MZL) is a distinct entity among B-cell lymphomas. We
      report on a 53-year-old woman who developed disseminated primary cutaneous MZL
      with secondary lymph node involvement and perinodular spreading. The tumor cell
      phenotype was characterized as CD20/CD79a/kappa/lambda+/ bcl-2-positive,
      CD3/5/15/39/bcl-1-negative. Ki-67 was expressed by 20-35% of tumor cells. There
      was no evidence of systemic (including bone marrow) involvement. The diagnosis of
      MZL with plasmacellular differentiation (Stage IVa) was made. The patient was
      treated with interferon alpha2a injected s.c. at 9x10(6) U 3 days a week for 1
      year. During this time the skin lesions completely disappeared. No evidence of
      lymph node or extracutaneous disease was found. The patient remains in complete
      remission. Side effects were only of grade I (WHO); the Karnovsky index was 90%.
      As shown for other types of primary cutaneous B-cell lymphoma, prolonged
      interferon alpha monotherapy may be effective in controlling the disease and/or
      inducing complete remission in MZL.

PMID- 10359135
TI  - Intracellular distribution of beta-catenin in colorectal adenomas, carcinomas and
      Peutz-Jeghers polyps.
AB  - The interaction of the adenomatous polyposis coli (APC) tumor-suppressor protein
      and the intracellular cell-adhesion protein beta-catenin is crucial for the
      development of colorectal tumors. Since functional nuclear complexes of beta
      catenin with transcription factors have been identified recently, the knowledge
      of level and distribution of beta-catenin in sporadic colorectal tumors will give
      important insights into the intracellular mechanism of sporadic colorectal tumor
      initiation and progression. In contrast to the familiar adenomatous polyposis
      syndrome and to the majority of sporadic colorectal tumors, Peutz-Jeghers (PJ)
      syndrome is not caused by mutations in the APC gene. Since PJ syndrome is an
      inherited disease with an increased risk for gastrointestinal adenocarcinoma,
      whether beta-catenin plays a similarly important role for the development of PJ
      polyps should be further investigated. For these reasons we analyzed the
      distribution of beta-catenin in a total of 60 sporadic colorectal tumors at
      different stages of progression and in 6 PJ polyps. In addition to the
      localization at the cell-to-cell border membranes, fluorescence
      immunohistochemistry revealed a nuclear accumulation of beta-catenin in single
      tumor cells of 10/14 small adenomas with mild dysplasia and in 14/16 adenomas
      with moderate dysplasia. Further tumor progression is accompanied by an expansion
      of cells with increased level of nuclear and cytoplasmic beta-catenin. These
      cells were observed in 5/16 adenomas with moderate dysplasia and in 15/15
      adenomas with severe dysplasia. In all adenocarcinomas investigated, as well as
      in the corresponding lymph node metastases, a sub-population of tumor cells
      exhibited a remarkably increased level of beta-catenin within the entire
      cytoplasm and the nucleus. In contrast to the situation in sporadic colorectal
      tumors, nuclear and cytoplasmic beta-catenin was not increased in PJ polyps.
      These results point to an extensive redistribution of beta-catenin, which starts
      early in colorectal tumorigenesis. The nuclear accumulation in single cells of
      small adenomas can be considered as the first visible sign of the loss of APC
      function. Thus the immunohistochemical detection of beta-catenin distribution
      could serve as a criterion for estimating the malignant potential in the clinico
      pathological evaluation of colon tumors during their early progression.

PMID- 10359138
TI  - Immune functions, clinical parameters and hormone receptor status in breast
      cancer patients.
AB  - We have carried out a detailed analysis of the cellular immune functions of
      breast cancer patients in comparison with healthy controls. A possible
      correlation between immune and clinical parameters was analysed in 50 breast
      cancer patients. Immune parameters, natural killer cell and T lymphocyte
      functions and the numbers of circulating T lymphocytes were analysed against the
      clinical parameters comprising the tumour burden, the stage of the disease and
      the expression of hormone receptors on the tumour. In order to analyse the immune
      function data effectively, low responders were identified with stringent cut-off
      values. Considerably higher proportions of low responders were found among the
      patient population. Elevated numbers of circulating T lymphocytes and CD3
      directed cytolysis correlated with the expression of oestrogen receptors
      independently of the clinical/histological parameters.

PMID- 10359137
TI  - p53 mutations and codon 213 polymorphism of p53 in lung cancers of former uranium
      miners.
AB  - PURPOSE: There is a high prevalence of G-->T transversions of p53 in lung cancers
      of smokers. One study has reported a special "hotspot" mutation at codon 249 of
      p53 in lung cancers of former uranium miners. The aim of our study was to look
      for mutational spectra of p53 in former German uranium miners with lung cancers.
      METHODS: We investigated 16 patients with lung cancer who had worked as uranium
      miners in Germany and 13 lung cancer patients without a mining history of the
      same region. By means of the polymerase chain reaction and sequencing we looked
      for mutations in exons 5 7 of the p53 gene. RESULTS: We could not find any
      suggestion of hotspot mutations. The only G-->T mutation in former uranium miners
      was detected in the only nonsmoker. In 3 patients (19% of the total) we found a
      codon 213/3 polymorphism. CONCLUSIONS: The results indicate that G-->T
      transversions do not seem to be very common mutations in p53 in lung cancers
      probably caused by radiation. Therefore, p53 may be mutated early in lung cancer
      development if radiation exposure is a critical factor in carcinogenesis. In
      accordance with studies of thyroid cancer patients in the Chernobyl region, our
      results may indicate an overrepresentation of codon 213/3 polymorphism in p53 in
      radiation-caused cancers.

PMID- 10359139
TI  - Significance of growth hormone-releasing hormone receptor mRNA in non-neoplastic
      pituitary and pituitary adenomas: a study by RT-PCR and in situ hybridization.
AB  - This study examined the expression of human growth hormone-releasing hormone
      receptor (GHRH-R) mRNA in both non-neoplastic pituitary tissues and pituitary
      adenomas by reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ
      hybridization (ISH). RT-PCR analysis showed that all of the non-neoplastic
      pituitaries and all GH-producing adenomas, one prolactinoma and one third of the
      non-functioning adenomas expressed GHRH-R mRNA. ISH demonstrated that all of GH
      producing adenomas and two prolactinomas expressed GHRH-R mRNA. The expression of
      GHRH-R mRNA in GH-producing adenomas was greater than that in the other adenomas
      by RT-PCR and ISH. GHRH-R mRNA detected by ISH was observed only in GH cells from
      the pituitary gland of a young girl. In pituitary adenomas, a diffuse signal was
      observed in the cytoplasm of all of the GH-producing adenomas and in two
      prolactinomas. Expression of GHRH-R mRNA was not seen in normal prolactin cells,
      or in any adenomas other than GH-producing adenomas and a few prolactinomas.
      These results suggest that GHRH-R mRNA plays a role mainly in the function of GH
      producing adenomas but may also play a role in function of some prolactinomas.

PMID- 10359140
TI  - CDKN2/p16 predicts survival in oligodendrogliomas: comparison with astrocytomas.
AB  - Cyclin-dependent kinase 4 inhibitor (CDKN2/p16) is a cell cycle regulatory
      protein that has been demonstrated to be inactivated by mutations, deletions or
      transcriptional silencing during pathogenesis of a variety of human malignancies.
      We studied the correlation of CDKN2/p16 expression with cell proliferation
      activity and patient survival in 42 oligodendrogliomas and 36 astrocytomas.
      CDKN2/p16 expression was frequently decreased in grade II and anaplastic
      oligodendrogliomas (17/42) where lack of CDKN2/p16 protein predicted poor
      survival (p = 0.0045). In astrocytomas low CDKN2/p16 expression was associated
      with high histologic malignancy grade (p = 0.002): CDKN2/p16 protein level was
      decreased in 9 out of 10 glioblastomas, in 5 out of 9 anaplastic astrocytomas, in
      3 out of 10 grade II astrocytomas and in none of pilocytic astocytomas (0/7). Low
      CDKN2/p16 expression was also associated with high cell proliferation activity
      (MIB-1 immunocytochemistry: p = 0.004; mitotic index: p = 0.007) and poor patient
      survival (p = 0.025) in astrocytomas. Low CDKN2/p16 mRNA expression had the same
      topographic distribution as nuclear CDKN2/p16 immunoreactivity proving for
      reliability of the immunocytochemical findings. Our results are in agreement with
      earlier studies demonstrating CDKN2/p16 inactivation during tumorigenesis of
      astrocytic tumors. Furthermore, our findings suggest that loss of CDKN2/p16
      expression may also play an important role in the progression of
      oligodendrogliomas. According to our findings CDKN2/p16 immunocytochemistry could
      be used as a tool to identify those oligodendrogliomas and low grade astrocytomas
      that are likely to progress and have poor outcome, and thus would need more
      aggressive therapy.

PMID- 10359141
TI  - Effect of dose and infusion time on the delivery of p-boronophenylalanine for
      neutron capture therapy.
AB  - Clinical trials of boron neutron capture therapy (BNCT) for glioblastoma
      multiforme are currently in progress using p-boronophenylalanine (BPA) as the 10B
      delivery agent. Enhancement of tumor boron uptake and/or the tumor-to-blood (T:B)
      boron concentration ratio would have the potential of significantly improving the
      therapeutic gain of BNCT. The effects of total dose, infusion time, and route of
      administration of BPA on tumor and blood boron concentrations were studied in
      rats bearing the 9L gliosarcoma. Increasing the total dose of BPA from 250 to
      1000 mg/kg, administered intravenously over a 2-h infusion period, resulted in an
      increase in tumor boron concentration from approximately 30 to approximately 70
      microg 10B/g, with a constant T:B boron concentration ratio of about 3.7:1.
      Similarly, extension of the infusion time from 2 to 6 h, at a constant dose-rate
      of 125 mg BPA/kg/h, resulted in an increase in tumor boron concentration from
      approximately 30 to approximately 80 microg 10B/g, while, again, maintaining a
      constant T:B ratio of about 3.7:1. In contrast, intracarotid infusion of BPA for
      1 h at a dose rate of 125 mg BPA/kg resulted in an increase in the tumor boron
      concentration from approximately 26 to approximately 38 microg 10B/g with a
      corresponding increase in the T:B ratio from 3.5:1 to 5.0:1. The effects of these
      results on the therapeutic gain potentially achievable with BNCT are discussed.

PMID- 10359142
TI  - Synergistic cytotoxicity, apoptosis and protein-linked DNA breakage by etoposide
      and camptothecin in human U87 glioma cells: dependence on tyrosine
      phosphorylation.
AB  - In this study, simultaneous administration of certain inhibitors of topoisomerase
      I and topoisomerase II produced synergistic cytotoxicity in a series of human
      glioma cell lines. Camptothecin (CPT) and etoposide (VP-16) produced combination
      indices (CI) <1.0 in all glioma cell lines tested, including those that were
      relatively resistant to the two topoisomerase inhibitors individually. In
      contrast, CPT and VP-16 produced additive cytotoxicity in HT-29 and SW-620 colon
      carcinoma cell lines. To explore the molecular basis for synergy in glioma cells,
      we focused on one glioma cell line (U87) in which even sub-cytotoxic doses of CPT
      potentiated the action of VP-16. Except for genistein (a topo II agent with
      tyrosine kinase inhibitory function), all topo II inhibitors tested (doxorubicin,
      ellipticine, and m-AMSA) were synergistic with CPT. While CPT and VP-16 produced
      cytotoxicity and protein-linked DNA breaks (PLDB) that were supra-additive in U87
      glioma cells, CPT and genistein produced additive results. Pretreatment of U87
      cells with the tyrosine kinase inhibitor tyrphostin-A23 or the tyrosine
      phosphatase activator O-phospho-L-tyrosine (OPLT) reduced combination PLDB from
      synergistic to additive levels, but had no effect on the formation of PLDB
      induced by either CPT or VP-16 alone. CPT and VP-16 also produced a synergistic
      accumulation of sub-G0 (apoptotic) cells which was blocked by tyrphostin-A23. No
      significant increase in topoisomerase protein levels could be detected in
      response to combination treatment. Thus, synergistic effects between
      topoisomerase I and topoisomerase II inhibitors in U87 glioma cells may depend
      upon phosphorylation of cellular proteins other than the topoisomerases
      themselves.

PMID- 10359144
TI  - Establishment of two glioma cell lines from two surgical specimens obtained at
      different times from the same individual.
AB  - We established two glioma cell lines from two surgical specimens obtained at
      different times from the same patient. One (No. 9R), which was derived from the
      recurrent tumor (glioblastoma, grade IV), proliferated more rapidly in vitro than
      the other (No. 9) from the primary tumor (slightly anaplastic astrocytoma, grade
      II-III). No. 9R showed heterotransplantability in nude mice, whereas No. 9 did
      not. These findings indicate that No. 9R has a more aggressive or malignant
      nature than No. 9. Both cell lines showed homozygous deletion of the
      representative tumor suppressor p16 and p15 genes, but no p53 gene alteration.
      However, examination of the overall mRNA expression profile using a commercially
      available cDNA-spotted membrane revealed much higher expression levels of several
      mRNAs, at least, in No. 9R than in No. 9, although the relationship between these
      mRNAs and the growth potentials remained unknown. These two cell lines, derived
      from the same individual, with different proliferating potentials may be useful
      for studies on the molecular bases of glioma malignancy and progression.

PMID- 10359143
TI  - Relationship between drug delivery and the intra-arterial infusion rate of SarCNU
      in C6 rat brain tumor model.
AB  - The influences of the flow rate on the concentration and distribution of drug in
      the rat brains and brain tumors after intra-arterial (intra-carotid)
      administration of [3H]SarCNU (sarcosinamide chloroethyl-1-nitrosourea) were
      examined. Results obtained at three flow rates via intra-carotid route were
      compared to those obtained with intravenous administrations. Adult female Wistar
      rats bearing C6 brain tumor were randomized into four-groups. Groups 1 (G.1) to 3
      (G.3) received intra-arterial injection and Group 4 (G.4) received intravenous
      administration of [3H]SarCNU. G.1 (slow infusion rate) was administered 1 ml of
      [3H]SarCNU solution over 60 min (0.017 ml/min), Group 2 (G.2; medium infusion
      rate): 0.2 ml over 5 min (0.04 ml/min), G.3 (fast infusion rate): 1 ml over 5 min
      (0.2 ml/min), and G.4 (intravenous infusion): 1 ml intravenously over 5 min.
      Quantitative autoradiographic method was used to measure the concentration and
      the distribution of [3H]SarCNU in the brain and the brain tumors. The tissue
      uptake constant of SarCNU in both viable (tumor tissue excluding necrosis) and
      peak regions (the area of tumor containing top 20% of the tracer concentration)
      of the intra-arterial injection groups were significantly higher (p < 0.0001)
      than those in the intravenous group. The mean concentrations of the viable tumor
      in the intra-arterial groups were 2.92 (G.1), 16.06 (G.2), and 20.8 (G.3) times
      higher than those of intravenous group. Between the intra-arterial groups, the
      mean concentration in the viable tumors of G.1 (slow flow rate) was significantly
      (p < 0.0001) lower than in G.2 and G.3. However, there was no significant
      difference between G.2 and G.3. In three intra-arterial groups the mean
      concentration delivery ratios of the brain tumors were high and ranged from 3.07
      (G.3) to 3.87 (G.2), but there was no significant difference between them. Only
      G.4, intravenous group, showed significantly (p < 0.005) lower concentration
      delivery ratio, 1.26. These results suggest that higher infusion rate in the
      intra-arterial chemotherapy could have an effect not only on the streaming
      phenomenon which results in the brain toxicities, but also on the increase in the
      concentration and the sufficient distribution of a drug in tumors. By finding
      chemotherapeutic agents to which tumors show high sensitivity and using intra
      arterial administration of these agents at more effective flow rate, better
      clinical results could be achieved in the treatment of patients with malignant
      brain tumors.

PMID- 10359145
TI  - Carboplatin for the treatment of children with newly diagnosed optic chiasm
      gliomas: a phase II study.
AB  - Management of low grade optic glioma in children and adolescents remains
      controversial. Treatment with chemotherapy may delay or eliminate the need for
      radiation therapy. Children with newly diagnosed optic chiasm glioma were
      eligible for enrollment in this phase II trial and received intravenous
      carboplatin (CBDCA) (560 mg/m2) every four weeks. Patients were monitored closely
      for toxicity and tumor status. Twelve children were enrolled. Six patients had
      stable disease, four a partial response and two progressed on therapy. Overall
      progression free survival was 83 +/- 11%. The median duration of follow-up was
      38.6 months (range 18-63 months). No deaths were noted in our series.
      Thrombocytopenia was the major toxicity, and two patients required platelet
      transfusions. One child developed an urticarial reaction requiring
      discontinuation of therapy. Another child developed unilateral high frequency
      hearing loss. No renal toxicity was encountered. We have demonstrated that
      carboplatin can eliminate or delay radiation therapy in children and adolescents
      with low grade optic glioma. CBDCA deserves further investigation in larger
      clinical trials as a treatment for children with optic chiasm glioma.

PMID- 10359146
TI  - Regression of a large solid papillary craniopharyngioma following fractionated
      external radiotherapy.
AB  - We present a patient harboring a large squamous papillary craniopharyngioma. The
      diagnosis was confirmed by a stereotactic biopsy. Because of vegetative symptoms
      indicating hypothalamic derangement, we were reluctant to perform surgical
      resection. Following fractionated megavoltage radiotherapy, MR imaging and CT
      demonstrated complete regression of the craniopharyngioma and the patient
      recovered from endocrine deficiency, chiasmal syndrome and vegetative
      hypothalamic symptoms.

PMID- 10359148
TI  - Recurrent chondrosarcoma of the cranial base: a durable response to ifosfamide
      doxorubicin chemotherapy.
AB  - The case of a 46-year old woman with recurrent chondrosarcoma of the cranial
      base, refractory to neurosurgical intervention and external radiotherapy is
      reported. She received five cycles of systemic chemotherapy utilizing ifosfamide
      and doxorubicin which resulted in a durable clinical and radiographic response
      lasting 52+ months. A review of the management options for recurrent
      chondrosarcoma of the cranial base is also presented.

PMID- 10359147
TI  - Dysembryoplastic neuroepithelial tumors: nonspecific histological forms -- a
      study of 40 cases.
AB  - OBJECTIVE: To demonstrate that DNTs include a large morphological spectrum of
      tumors that cannot be histologically distinguished from conventional categories
      of gliomas. METHODS: All tumors from patients who underwent epilepsy surgery in
      Sainte-Anne hospital (Paris) that histologically resembled gliomas and did not
      conform to current histological criteria for DNTs or gangliogliomas were entered
      in the study. RESULTS: According to the WHO histological classification, the 40
      tumors resembled: pilocytic astrocytomas (4 cases), astrocytomas (16 cases),
      anaplastic astrocytoma (1 case), oligodendrogliomas (10 cases), oligo
      astrocytomas (8 cases) or anaplastic oligo-astrocytomas (1 case). However foci of
      cortical dysplasia could be observed in 47% of the cases. Clinical presentation
      and imaging features were strikingly similar to that observed in typical DNTs.
      Although surgical removal was incomplete in 28% of the cases and none of the
      patients underwent chemo or radiotherapy, none of the tumors recurred (mean
      follow-up: 7 years). Moreover, serial preoperative imaging in 26 patients (mean
      follow-up: 4.5 years) demonstrated that these lesions were perfectly stable.
      CONCLUSIONS: Whatever the histological appearance of a glial tumor, the diagnosis
      of DNT must be considered when all the following criteria are associated: (1)
      partial seizures, with or without secondary generalization, beginning before the
      age 20 years, (2) no neurological deficit or stable congenital deficit, (3)
      cortical topography of the lesion as better demonstrated by MRI and (4) no mass
      effect on imaging.

PMID- 10359149
TI  - Teniposide sometimes effective in brain metastases from non-small cell lung
      cancer.
AB  - In a prospective study we have treated 13 patients with brain metastases from non
      small cell lung cancer with intravenous teniposide, at a dose of 150 mg/m2 on
      days 1, 3 and 5 given every 3 weeks on an out-patient basis. Six of the 13
      patients had previously been treated for brain metastases by surgery and/or
      radiotherapy. Seven patients experienced neurological improvement. Objective
      response was obtained in 3 patients (23%) (2 PR, 1 CR), and stabilization in 5
      patients. Duration of response in the 3 patients with objective response was 16
      weeks, 40 weeks and 80 weeks, respectively. In 2 of these patients extracranial
      disease responded also to teniposide therapy. Although toxicity of teniposide
      therapy was relatively mild, there was one patient who died as a consequence of
      leukopenic sepsis. The results demonstrate that teniposide has some activity in
      de novo as well as recurrent brain metastases from non-small cell lung cancer.

PMID- 10359150
TI  - Variation of post-treatment H-MRSI choline intensity in pediatric gliomas.
AB  - Pediatric brain gliomas are not always amenable for complete surgical excision,
      therefore adjuvant treatment for a large tumor mass is often required. As tumor
      volume shrinkage may not be a reliable method for assessing response to
      treatment, information about the tumor growth potential is desirable for an
      adequate follow-up of the patients. Choline (Cho) signal intensity, determined by
      proton magnetic resonance spectroscopy imaging (H-MRSI), has proved to be a
      reliable indicator of the metabolic activity and of tumor progression in various
      intracranial tumors. In this study we have sought to determine if H-MRSI can be
      of use in monitoring the response of pediatric gliomas to different forms of
      therapy. We performed pretreatment and post-treatment H-MRSI in 10 children with
      biopsed or partially excised brain gliomas. The follow-up period ranged between 6
      and 40 months. A total of 38 H-MRSI were performed. All the patients had
      chemotherapy or radiotherapy. As an indicator of tumor activity we utilized the
      ratio between tumor/brain Cho signal intensity. Treatment response was evaluated
      as a function of tumor volume and clinical outcome. In 6 patients whose tumor
      volume decreased or remained stable we observed that the Cho ratio decreased (p <
      0.01) after treatment and remained low during longitudinal follow-up. In the 4
      patients whose tumors progressed the Cho ratio increased after treatment. These
      observations suggest that serial H-MRSI can provide valuable information
      regarding the response to therapy in pediatric gliomas and therefore be of use in
      the follow-up of these neoplasms of childhood.

PMID- 10359151
TI  - The long-term biological variability of fasting plasma glucose and serum
      fructosamine in healthy Beagle dogs.
AB  - The aim of this study was to estimate the long-term (month-to-month) between-dog,
      within-dog and analytical components of variance for fasting plasma glucose and
      serum fructosamine in healthy dogs to assess the usefulness of a single
      measurement of these analytes in a single dog. Fasting plasma glucose and serum
      fructosamine were measured in blood samples collected every month for 9 months
      from 23 clinically healthy dogs, and the results were subjected to nested
      analysis of variance. The between-dog variation, the within-dog variation, and
      the analytical variation were 3.8%, 9.5% and 3.7%, respectively, for plasma
      glucose and 4.2%, 11.1% and 2.8%, respectively, for serum fructosamine. The
      maximum allowable analytical imprecision, analytical inaccuracy and difference
      between analytical methods were 4.8%, 2.6% and 3.2%, respectively, for plasma
      glucose and 5.6%, 3.0% and 3.7%, respectively, for serum fructosamine. The index
      of individuality, 2.7 for both analytes, indicated that the test results from
      single dogs can be compared usefully to the corresponding population-based
      reference intervals. The number of samples required to estimate the true
      individual mean value +/-5% for a single dog was 16 for fasting plasma glucose
      and 20 for serum fructosamine. The one- and two-sided critical differences
      expressing the difference needed for two serial results from the same dog to be
      significantly different at a 5% level was 24% and 28%, respectively, for plasma
      glucose and 27% and 32%, respectively, for serum fructosamine.

PMID- 10359152
TI  - Adjuvanted outer membrane protein vaccine protects poultry against infection with
      Salmonella enteritidis.
AB  - The immunogenicity of a sonicated extract (SE) and of outer membrane proteins
      (OMP) of Salmonella enteritidis was tested in birds of about 8 weeks of age. The
      dose, route of vaccination and the adjuvant used varied in different groups of
      birds. Two vaccine doses with or without adjuvant were given parenterally or
      orally 3 weeks apart. OMP vaccines gave significantly higher antibody titres than
      SE vaccines, as indicated by ELISA. The vaccines adjuvanted with oil produced
      higher antibody titres than those without any adjuvant. A dose of 1 mg of vaccine
      produced higher antibody titres than 0.5 mg of vaccine. Adjuvanted vaccine given
      subcutaneously elicited higher antibody responses than oral vaccines given
      without adjuvant. The birds were challenged with virulent S. enteritidis
      organisms at the end of the second week after a booster dose. None of the birds
      given 1 mg of OMP vaccine subcutaneously shed the organisms when tested by
      culturing cloacal swabs, although a few birds vaccinated with 0.5 mg of OMP
      vaccine did so. In general, adjuvanted OMP vaccines gave better protection than
      SE vaccines.

PMID- 10359153
TI  - Respiratory epithelium, production performance and behaviour of formaldehyde
      exposed broiler chicks.
AB  - Two experiments were conducted to evaluate the effect of formaldehyde
      vaporization of a hatcher on the tracheal epithelium of chick embryos, and on the
      production performance and behaviour of commercial broiler chicks. In experiment
      1, chick embryos were exposed to 23.5 ppm of formaldehyde vapour during the last
      3 days of incubation. Tracheal samples were taken at 0, 6, 30 and 54 h after
      exposure to formaldehyde and examined by scanning electron microscopy for
      pathological changes. Observable lesions included excessive accumulation of
      mucus, matted cilia, loss of cilia and sloughing of the epithelium. The lesions
      were more severe in chicks exposed for 54 h as compared to those exposed for 6 or
      30 h. In experiment 2, 60 chicks that had been exposed to formaldehyde vapour as
      above and 60 control chicks were used to investigate the effect of formaldehyde
      fumigation on production performance and behaviour. Formaldehyde vaporization
      resulted in higher weekly (days 0-6 and 21-27) and total (days 0-41) feed intake
      and poorer weekly (days 0-6, 7-13, 21-27 and 28-34) and overall (days 0-41) feed
      conversion ratios. Body weight, mortality and behaviour (eating, drinking,
      sitting and standing activities) were not affected by formaldehyde fumigation.

PMID- 10359154
TI  - Effects of the NSAIDs meloxicam and indomethacin on cartilage proteoglycan
      synthesis and joint responses to calcium pyrophosphate crystals in dogs.
AB  - NSAIDs are a major cause for concern for their propensity to cause joint
      deterioration in canine, as in human, patients receiving these drugs for
      treatment of pain in osteoarthritis and other acute and chronic painful
      conditions. To determine the potential effects of the new NSAID meloxicam on
      cartilage integrity, the effects of this drug on proteoglycan biosynthesis in
      vitro and ex vivo were compared with those of indomethacin, a known inhibitor of
      sulphated proteoglycans that accelerates joint injury in human osteoarthritis. In
      vitro cartilage proteoglycan synthesis from a radiosulphate precursor was
      unaffected by 0.5-10.0 micromol/L meloxicam but was significantly inhibited by 50
      micromol/L indomethacin after 6 or 24 h incubation of femoral or tibial cartilage
      explants in organ culture. This is in accord with previous observations in human
      or porcine articular cartilage under the same culture conditions. Studies were
      performed in vivo to establish the effects of the NSAIDs on joint integrity. This
      involved determining cartilage proteoglycan synthesis ex vivo, leukocyte, fluid
      and protein accumulation, as well as pain relief. Thus, meloxicam (0.2 mg/kg i.v.
      x 3 doses) or indomethacin (0.5 mg/kg i.v. x 3 doses) was given for 26 h and the
      effects were compared with a control (1.0 ml saline i.v. x 3 doses) in dogs in
      which acute inflammation had been induced by intra-articular (i.a.) injection of
      calcium pyrophosphate dihydrate (CPPD) crystals into the right stifle joint, an
      equivalent volume of saline being injected into the left stifle joint as a
      control. No effects were observed of the treatment with the NSAIDs on ex vivo
      sulphated proteoglycan synthesis. The lack of the expected inhibitory effects of
      indomethacin may be related to the relatively low plasma concentrations of this
      drug obtained during the 26 h period of treatment. The pain response, which was
      elicited up to 6 h following i.a. injection of CPPD crystals, was totally
      prevented by the treatment with meloxicam and to a lesser extent with
      indomethacin. There were no effects from the drug treatment on synovial
      inflammatory reactions (fluid and cell accumulation), although the protein
      concentration of the exudate was reduced by meloxicam. This indicates that, at
      the doses given, it was possible to discriminate the analgesic action from the
      anti-inflammatory action of the two NSAIDs, this being achieved at relatively low
      plasma concentrations of these drugs. In conclusion, while relatively high
      therapeutic concentrations of indomethacin inhibit cartilage proteoglycan
      synthesis, this is not an effect seen even at high concentrations of meloxicam.
      Furthermore, the lack of effects on proteoglycan synthesis was evident when these
      two drugs were given in vivo to dogs. However, the signs of pain, but not the
      inflammation in the joint, were relieved by low plasma concentrations of the
      drugs. Meloxicam may thus be safely employed for acute analgesia without the
      potential risks of joint cartilage damage that occurs with indomethacin given at
      antiinflammatory doses for long periods of time.

PMID- 10359155
TI  - A preliminary study on the effects of dietary energy and melatonin on the ex vivo
      production of progesterone and prostaglandin F2alpha by the corpora lutea and
      endometrial tissue of ewes.

PMID- 10359156
TI  - The effects of ovine lentivirus infection on some productive aspects in a
      Sardinian sheep flock from Italy.
AB  - The effects of ovine lentivirus infection on the fat, protein and lactose
      concentrations on the somatic cell counts in ewes' milk, on milk production and
      on the birth weight and growth of lambs were studied in a flock of Sardinian
      sheep from central Italy. Data on 61 lactations of ewes positive to both the
      agargel immunodiffusion test and an enzyme-linked immunosorbent assay were
      compared with those on 46 lactations of seronegative ewes. Confounders such as
      parity, age, lactation length, litter size, and the sex of the lambs were
      considered. None of these traits seemed to be negatively influenced by the
      infection.

PMID- 10359157
TI  - Detection of BHV-1 in a naturally infected bovine fetus by a nested PCR assay.
AB  - Bovine herpesvirus 1 (BHV-1) is frequently associated with abortion in naturally
      and experimentally infected cattle. Most of the virus isolation and
      immunofluorescent antibody protocols described in the literature for detecting
      BHV-1 in bovine foetuses are rather laborious, costly and time-consuming. The
      detection is described of BHV-1 in the tissues of a naturally aborted bovine
      foetus by a nested PCR assay with no further hybridization procedures. Optimal
      results were achieved by filtering the foetal tissues on a chromatography column
      before DNA extraction, by using two pairs of primers in a nested PCR and by
      evaluating the amplification products on silver-stained polyacrylamide gels. This
      nested PCR was faster and easier to perform than the virus isolation test. To our
      knowledge, this is the first time that BHV-1 has been detected in the tissues of
      a naturally infected bovine foetus by means of a nested PCR. The test seems to be
      a practical alternative for rapid detection of BHV-1 in bovine foetus.

PMID- 10359158
TI  - Insulinlike growth factor 1 and insulinlike growth factor 3: indices of
      intestinal failure in children.
AB  - BACKGROUND/PURPOSE: A number of pediatric patients with short bowel syndrome
      (SBS) manifest growth failure despite aggressive nutritional support. Exogenous
      growth hormone (GH) therapy in children with SBS has proved disappointing. The
      purpose of this study was to determine if there were characteristic patterns of
      GH, IGF-1, or IGFBP-3 levels in pediatric SBS patients with profound growth
      failure in an effort to elucidate an early strategic approach to management of
      SBS in the subpopulation. METHODS: Forty patients (29 boys, 11 girls; mean age,
      5.3 years; range, 0.5 to 18.6 years) with SBS (<30% total bowel length) who
      received intensive nutrition support and follow-up underwent serological tests
      for GH, IGF-1, IGFBP-3, and thyroid function. Height (HT), weight (WT), and bone
      age were assessed relative to age-appropriate percentiles. Growth failure was
      defined as a HT and WT at less than the fifth percentile and bone age > or = 2
      standard deviations below actual age. Residual small bowel length was determined
      by review of pathological and operative reports. Comparisons between the growth
      factors, bowel length, and anthropometric data were analyzed by chi2. RESULTS:
      Two distinct subgroups of patients emerged from our study. Thirty-eight percent
      of patients (n = 11) had growth failure by anthropometry that was associated
      significantly with low IGF-1 independently and with both IGF-1 and IGFBP-3 levels
      (P< 0.05). There were no significant associations with GH level, thyroid
      function, small bowel length, or the amount of parenteral versus enteral intake
      in either subgroup of these patients. Low IGF-1 and IGFBP-3 but not GH levels may
      be indices of intestinal failure in pediatric SBS. Growth in this subpopulation
      is refractory to aggressive standard approaches to nutritional support and may
      require early interventions. CONCLUSION: Exogenous IGF-1 and IGFBP-3, not GH, may
      be beneficial to treat this subpopulation.

PMID- 10359159
TI  - The expression and activation of EGF and c-NEU receptors are increased in
      enterocytes during intestinal adaptation.
AB  - BACKGROUND/PURPOSE: After massive small bowel resection (SBR), epidermal growth
      factor (EGF) and its intestinal receptor (EGF-R) play major roles during
      adaptation. The expression of a homologous enterocyte receptor termed c-neu (c
      neu-R) is capable of forming heterodimers with EGF-R to facilitate cellular
      signaling. The purpose of this study was to determine the expression and
      activation of EGF-R and c-neu-R during the adaptive intestinal response to SBR.
      METHODS: Male ICR mice underwent either SBR or sham surgery. After 1, 3, and 7
      days, enterocytes were isolated and protein immunoprecipitated with antibody to
      either EGF-R or c-neu-R. Receptor protein expression and activation status were
      determined. RESULTS: When compared with sham operation, the expression and
      activation status of both EGF-R (six- and twofold, respectively) and c-neu-R
      (nine- and twofold, respectively) were increased substantially in enterocytes
      from the adapting ileum after SBR by postoperative day 3. Minimal changes were
      appreciated for either EGF-R or c-neu-R expression or activation in the remnant
      bowel after enterocyte removal, liver, or kidney. CONCLUSIONS: Both the
      expression and activation status of EGF-R and c-neu-R are increased substantially
      in enterocytes from the adapting ileum by postoperative day 3 after massive SBR.
      These changes provide a unique mechanism for the enterocyte to enhance cellular
      signaling in response to EGF during intestinal adaptation.

PMID- 10359160
TI  - What comprises appropriate therapy for children/adolescents with rhabdomyosarcoma
      arising in the abdominal wall? A report from the Intergroup Rhabdomyosarcoma
      Study Group.
AB  - PURPOSE: The aim of this study was to define clinical features and determine the
      best therapy for patients with rhabdomyosarcoma (RMS) of the abdominal wall.
      METHODS: We examined the demographic, clinical features, therapy (especially
      surgical), and outcome of 34 patients. Patients received combination chemotherapy
      after complete surgical resection (group I, n = 14; 41%); resection with
      microscopic residual followed by local irradiation (RT; group II, n = 8; 24%);
      partial resection or biopsy only plus RT with gross locoregional residual tumor
      (group III, n = 4; 12%); or biopsy only plus RT with metastatic disease (group
      IV, n = 8; 24%). Patients with group I or group II tumors had undergone partial
      abdominal wall resection (ie, involved muscle only with preservation of
      peritoneum, n = 11) or complete abdominal wall resection (n = 7). Four additional
      patients had groin lesions. RESULTS: Thirty-four children or adolescents with
      abdominal wall RMS (about 1% of all patients) were treated on Intergroup
      Rhabdomyosarcoma Study I (IRS-I) through IRS-IV. Overall, adolescents comprised
      14 of 34 eligible patients (41%), and 10 of 14 (71%) adolescents had alveolar or
      undifferentiated tumors versus 8 of 20 (40%) younger children (P= .07). Failure
      free survival (FFS) rate and survival rate at 5 years was 65%. Treatment outcome
      was poorer for patients with group III-IV tumors (P = .01), adolescents (P = .09)
      and patients with alveolar or undifferentiated sarcomas (P = .12). CONCLUSION:
      Patients with localized tumors appear to fare better if they undergo complete
      abdominal wall resection (long-term survival rate, 100%) versus partial resection
      (long-term survival rate, 62% [P = .12]).

PMID- 10359161
TI  - The impact of margin of resection on outcome in pediatric nonrhabdomyosarcoma
      soft tissue sarcoma.
AB  - BACKGROUND/PURPOSE: Because the management of pediatric nonrhabdomyosarcoma soft
      tissue sarcomas (NRSTS) is determined by extrapolation from adult studies, the
      effect of margin of tumor resection and postoperative radiation therapy (RT) on
      local tumor recurrence in children has not been assessed. METHODS: Records of
      NRSTS patients from a single institution were reviewed with regard to demographic
      data, TNM staging, grade, histological type and site of primary tumor, RT, and
      local tumor recurrence. The margin of resection was determined by pathological
      review and did not necessarily reflect operative margins. RESULTS: Eighty-eight
      clinical group I patients were treated over a 30-year period. The most common
      histological tumor subtypes were synovial cell sarcoma (n = 26), malignant
      fibrous histiocytoma (n = 17), and fibrosarcoma (n = 7). The mean age was 9.4
      years (range, 0 to 29 years). Thirty-four patients had high-grade tumors. Two of
      ten patients with low-grade tumors and margins less than 1 cm, including one of
      five who had received RT, had a local recurrence. Patients with low-grade tumors
      and margins greater than 1 cm (n = 44) had a lower recurrence rate (2 of 44,
      4.5%). None of these patients had received RT. Fourteen patients with high-grade
      tumors had margins less than 1 cm. Seven of these had RT and had no recurrence.
      Three of the seven patients who received no RT had a recurrence (42.9%). None of
      the 20 patients with high-grade tumors and margins greater than 1 cm received RT;
      four of these patients had recurrences (20%). Seven of the 12 irradiated patients
      (58.3%) had serious radiation-associated complications (wound dehiscence,
      fracture, growth retardation, and joint dysfunction). CONCLUSIONS: Grade alone
      does not determine the rate of local recurrence. In both low- and high-grade
      tumors, a pathological margin of resection greater than 1 cm reduced local
      recurrence. Radiotherapy provided no advantage in low grade tumors but did
      decrease local recurrence rates in high-grade tumors with less than 1 cm
      pathological margins.

PMID- 10359162
TI  - Pathological angiogenesis in a murine model of human Wilms' tumor.
AB  - BACKGROUND/PURPOSE: Pathological vascular architecture is a feature of
      neoangiogenic processes such as diseases of the retina and tumor growth. The
      authors hypothesized that experimental human Wilms' tumors would display a
      vascular architecture similar to retinal diseases that are driven by vascular
      endothelial growth factor (VEGF). METHODS: Human Wilms' tumors were established
      in the right kidneys of nude mice. After 4.5 weeks of tumor growth, fluorescein
      angiograms were performed before death. Representative sections of tumors and
      contralateral, control kidneys were evaluated by fluorescent microscopy. RESULTS:
      Fluorescein angiograms demonstrated a characteristic pathological architecture.
      Vascular tortuosity, capillary tufting, and hemorrhage were noted. These features
      were not present in normal kidneys. CONCLUSIONS: Vascular architecture of Wilms'
      tumor displays the specific features previously described in diseases of the
      retina, which have been shown to be driven by VEGF, suggesting that
      neoangiogenesis in this model is also VEGF driven.

PMID- 10359163
TI  - Effect of unilateral testicular torsion on blood flow and histology of
      contralateral testes.
AB  - BACKGROUND/PURPOSE: Infertility occurs in 25% of patients after unilateral
      testicular torsion; hence, the authors examined hemodynamic and histological
      changes in both testes after acute testicular torsion in neonatal piglets.
      METHODS: The animals were anesthetized, intubated, ventilated, catheterized, and
      assigned randomly to a sham group or one of three experimental groups undergoing
      720 degrees torsion of the left testis for 8 hours after which it was untwisted
      in group I and removed in group II. In group III, both testes were removed. Data
      were collected at baseline (T = 0), 4 hours (T = 4), and 8 hours of torsion (T =
      8) and at the ninth hour of the experiment (T = 9). Testicular blood flow was
      determined by using radiolabeled microspheres. The testes also were examined
      blindly with routine and electron microscopy. RESULTS: In group I, testicular
      blood flow decreased in the affected testis during torsion and increased
      significantly after detorsion, whereas blood flow to the contralateral testis
      increased significantly after detorsion. Sham-operated animals showed no
      histological abnormality in either testis. In all torsion groups, the affected
      testis showed extensive changes caused by hemorrhagic necrosis. The contralateral
      testis only showed changes in group I. CONCLUSION: Unilateral testicular torsion
      resulted in ipsilateral damage caused by a decrease and subsequent increase in
      blood flow while in the contralateral testis; damage was the result of a
      significant increase in blood flow after detorsion.

PMID- 10359164
TI  - Incidence of contralateral inguinal hernia: a prospective analysis.
AB  - BACKGROUND/PURPOSE: Contralateral groin exploration in children with unilateral
      inguinal hernia is still controversial, particularly in infants. The authors have
      attempted to determine the age- and gender-stratified incidence of contralateral
      hernia and the necessity of routine bilateral procedures. METHODS: This is a
      prospective study of 656 patients during a 34-month period at a single
      institution. Patients with unilateral hernia underwent an ipsilateral procedure
      only, regardless of age, gestational age, or gender. Follow-up was 6 to 40 months
      (mean, 25.5 months). Chi-square analysis was used for intergroup comparison (P <
      .05 significant). RESULTS: Of 656 children, 108 (16.5%) presented with
      synchronous bilateral hernias. Bilateral inguinal hernia was significantly more
      common in premature infants (28.0%) and young children (33.8% if <6 months, 27.4%
      if <2 years). Of the remaining 548, a metachronous contralateral hernia developed
      in 48 (8.8%) at a median interval of 6 months (range, 4 days to 7 years). This
      incidence was 13 of 105 (12.4%) in infants less than 6 months of age, 20 of 189
      (10.6%) in children less than 2 years of age, 8 of 54 (14.8%) in premature
      infants, 6 of 81 (7.4%) in girls, and 8 of 29 (27.6%) in children with an
      incarcerated hernia. In the latter group, P < .05, chi2 analysis. CONCLUSION:
      Routine contralateral inguinal exploration, without clinical evidence of a
      hernia, may be advisable in children with incarceration and possibly in premature
      infants. The low incidence of contralateral hernias in all other patients,
      regardless of gender or age, does not justify routine contralateral exploration.

PMID- 10359165
TI  - The ontogeny of TGF-beta1, -beta2, -beta3, and TGF-beta receptor-II expression in
      the pancreas: implications for regulation of growth and differentiation.
AB  - BACKGROUND/PURPOSE: The transforming growth factor-beta (TGF-beta) cytokines are
      important regulators of growth and differentiation in multiple mammalian organ
      systems. Recent studies suggest that they may play a significant role in the
      regulation of pancreatic organogenesis. The authors proposed to examine the
      ontogeny of expression of the TGF-beta cytokine isoforms (TGF-beta1, beta2, and
      beta3), as well as that of the type II TGF-beta receptor (TbetaRII), in the
      pancreas. We hypothesized that their patterns of expression might help to clarify
      the manner in which they influence the development of this organ. METHODS:
      Embryos from pregnant CD-1 mice were harvested on gestational days 12.5, 15.5,
      and 18.5. Microdissection was performed on the embryos to isolate their
      pancreases. The pancreases were fixed, frozen embedded, and sectioned with a
      cryostat. Immunohistochemistrywas performed using polyclonal antibodies to TGF
      beta1, beta2, and beta3, and TbetaRII. RESULTS: The patterns of expression of TGF
      beta1, beta2, and beta3 were similar throughout gestation. They were all present,
      though weakly, early in the development of the pancreas, in the E12.5 epithelial
      cells. Their expression persisted and became localized to the acinar cells later
      in gestation. TbetaRII staining was present in both the E12.5 epithelial cells
      and the surrounding mesenchyme. As the pancreas developed, TbetaRII became
      strongly expressed in the ductal epithelial cells with only minimal staining in
      the acinar and endocrine cells. CONCLUSIONS: TGF-betas may play a role in
      regulating pancreatic organogenesis. Our data suggest that they may be required
      for the normal development of acini. As in other cell systems, TGF-beta1 may act
      as a suppressor of pancreatic cellular growth and differentiation. The
      localization of TbetaRII to the mature ductal epithelium may indicate a need for
      ongoing regulation of growth and differentiation in the pancreatic ducts beyond
      the fetal period.

PMID- 10359166
TI  - TGF-beta1 alters the healing of cutaneous fetal excisional wounds.
AB  - BACKGROUND/PURPOSE: In a number of species, fetal wound healing differs from the
      adult in the absence of inflammation, fibrosis, scar formation, and excisional
      wound contraction. The lack of inflammation also may explain the relative absence
      of any cytokine levels at the wound site, such as transforming growth factor
      (TGF)-beta, and therefore the unique characteristics of fetal wound healing. The
      authors hypothesized that exogenous TGF-beta1 would induce contraction,
      inflammation, fibrosis, and scar formation in cutaneous excisional wounds in the
      fetal rabbit. METHODS: Cellulose discs (3 mm in diameter) were formulated with
      either 1.0 microg TGF-beta1 (n = 6) or bovine serum albumin (BSA; n = 7), as a
      control, for sustained-release over 3 days. Each disc was implanted into the
      subcutaneous tissue on the backs of fetal New Zealand White Rabbits in utero on
      day 24 of gestation (term, 31 days). A full-thickness, 3-mm excisional wound (7.4
      mm2) was then made next to the implanted cellulose disc. All wounds were
      harvested 3 days later. RESULTS: At harvest, the excisional wounds in the TGF
      beta1 group had contracted (5.6 +/- 2.0 mm2), whereas those in the control group
      had expanded (13.5 +/- 1.2 mm2, P< .01). The surrounding dermis in the TGF-beta1
      group had 16.3 inflammatory cells per grid block compared with 12.4 cells in the
      control group (not significant). In addition, a greater amount of fibrosis was
      induced by the TGF-beta1 implant (1.7 +/- 0.3) than the control implant (0.4 +/-
      0.2) on a scale of 0 to 3, P < .01. In situ hybridization analysis showed an
      increase in procollagen type 1alpha1 gene expression in the surrounding dermis of
      the TGF-beta1 group (36.7 +/- 3.6 grains per grid block) compared with the
      control group (7.1 +/- 0.9 grains per grid block, P < .001). CONCLUSIONS: These
      results demonstrate that the cytokine TGF-beta1 can induce fetal excisional
      wounds to contract, stimulate fibrosis, and increase procollagen type 1alpha1
      gene expression. These findings further suggest that the absence of TGF-beta1
      atthe wound site may be responsible in part for the lack of a postnatal healing
      response.

PMID- 10359167
TI  - TGF-beta2 is increased after fetal tracheal occlusion.
AB  - BACKGROUND/PURPOSE: Fetal tracheal occlusion (TO) accelerates lung growth in
      normal and hypoplastic fetal lung. The mechanism of accelerated lung growth
      remains unknown but may be a result of growth factor induction. Previous studies
      of growth factors induced by tracheal ligation have characterized mRNA rather
      than protein expression. Although the transforming growth factor-beta (TGF-beta)
      family participates in normal lung morphogenesis, its role in lung growth after
      TO is unclear. The authors hypothesize that TGF-beta expression is increased with
      TO and may contribute to the accelerated lung growth seen after TO. METHODS:
      Diaphragmatic hernia (DH) was created in 80-day-gestation sheep (n = 6; term,
      145) by excising the left diaphragm. At 110 days, the trachea was occluded (n =
      4) with a clip. DH controls (n = 2) were not occluded. Fetuses were killed at 139
      days, and lung samples were snap frozen for tissue analysis. Non-DH control lungs
      were harvested from full-term animals (n = 2). TGF-beta mRNA was analyzed by
      semiquantitative reverse transcriptionase-polymerase chain reaction (RT-PCR). TGF
      beta protein was assessed by Western blot analysis. RESULTS: TGF-beta1 mRNA and
      protein were not increased with tracheal ligation compared with either non-DH or
      DH controls. TGF-beta2, however, was markedly increased, at both the mRNA and
      protein level, in ligated lungs compared with nonligated controls. CONCLUSIONS:
      TGF-beta2 protein, but not TGF-beta1, is increased in the hypoplastic lungs of
      fetal sheep after tracheal occlusion. Increased TGF-beta2 expression appears to
      result from increased or prolonged expression of mRNA transcripts. This is the
      first study to document a change in growth factor protein levels after TO.
      Increased TGF-beta2 expression may contribute to accelerated lung growth and
      decreased surfactant production observed after tracheal occlusion.

PMID- 10359169
TI  - Diltiazem reduces pulmonary arterial pressures in recurrent pulmonary
      hypertension associated with pulmonary hypoplasia.
AB  - BACKGROUND/PURPOSE: Recurrent pulmonary hypertension in the neonatal population
      is an unusual event with dire consequences. Pulmonary hypertension seen in
      association with pulmonary hypoplasia may be refractory to conventional medical
      management. The effect of the calcium channel antagonist diltiazem was studied in
      five patients with severe pulmonary hypertension. METHODS: A retrospective review
      of the hospital records was performed to determine the efficacy of diltiazem for
      refractory pulmonary hypertension. All five patients experienced and did not
      respond to maximal conventional therapy, which included inhaled nitric oxide,
      intravenous nitrates, and extracorporeal membrane oxygenation (ECMO). Right
      ventricular pressures were determined by transthoracic echocardiograms and were
      used to document improvement in the pressure gradients. Statistical analyses were
      performed using a paired Student's ttest. A P value of less than .05 was
      considered significant. RESULTS: Diltiazem significantly reduced the right
      ventricular systolic pressure (RVSP) from 82 +/- 8.4 mm Hg to 58.4 +/- 7 mm Hg (P
      = .008). Two patients died; one had a large ventricular septal defect, and the
      other suffered multisystem organ failure secondary to sepsis. The surviving
      patients were weaned off diltiazem and did not experience recurrent pulmonary
      hypertension. CONCLUSIONS: In cases of pulmonary hypoplasia with recurrent
      pulmonary hypertension, diltiazem may be considered as a therapy. A multicenter
      prospective trial is advocated.

PMID- 10359168
TI  - Heart hypoplasia in experimental congenital diaphragmatic hernia.
AB  - BACKGROUND/PURPOSE: Heart hypoplasia is associated with congenital diaphragmatic
      hernia (CDH) and decisively influences survival rate. This study examines whether
      nitrofen-exposed fetal rats have heart hypoplasia. METHODS: Pregnant rats
      received either 100 mg nitrofen or vehicle on gestational day 9.5. The hearts
      recovered near full term were either formalin fixed for anatomic studies or snap
      frozen for biochemical studies. Heart weight, ventricular chamber diameters and
      aortic-to-pulmonary root diameter ratios were measured in fixed hearts. Protein
      and DNA were determined in frozen hearts. Analysis of variance (ANOVA) and
      correlation-regression studies were used for statistical assessment. RESULTS: All
      control fetuses were normal, whereas 61% of those exposed to nitrofen had CDH.
      Cardiovascular malformations were found in 73% of CDH and in 50% of non-CDH
      animals. Wet and fixed heart weights in percent of fetal weight, left-to-right
      ventricular diameter ratio, and aortic-to-pulmonary root diameter ratio were
      significantly decreased in fetuses with CDH in comparison with controls. Only wet
      heart was significantly decreased in nitrofen-treated fetuses without CDH,
      although all other variables showed a trend in the same direction. Protein to DNA
      ratios were similar in the three groups. The structure of the myocytes was
      histologically similar in all groups. CONCLUSIONS: The spectrum of lesions in the
      nitrofen model of CDH encompasses heart hypoplasia, further validating its use
      for research on this condition. Heart hypoplasia is related to cardiopulmonary
      compression, but its presence in treated animals without CDH demonstrates that
      the teratogen itself participate directly in its pathogenesis, and this finding
      invites further research on this line.

PMID- 10359170
TI  - Increased tropoelastin and procollagen expression in the lung of nitrofen-induced
      diaphragmatic hernia in rats.
AB  - BACKGROUND/PURPOSE: Collagen and elastin, the predominant components of the lung
      connective tissue network, have been suggested to have an important influence on
      lung compliance and maximal expansion. Decrease in lung compliance and
      distensibility often is seen in human congenital diaphragmatic hernia (CDH) lung
      as well as in experimentally produced CDH lung. The aim of this study was to
      investigate mRNA levels of tropoelastin and alpha1 (I) procollagen, the
      precursors of elastin, and type I collagen, respectively, in CDH lung and to
      determine whether antenatal dexamethasone treatment has any effect on the
      production of these extracellular matrix proteins. METHODS: CDH model was induced
      in pregnant rats after administration of 100 mg nitrofen on day 9.5 of gestation
      (term, 22 days). Dexamethasone (0.25 mg/kg) was given on day 18.5 and 19.5.
      Cesarean section was performed on day 21. The fetuses were divided into three
      groups: group I, normal controls; group II, nitrofen-induced CDH; and group III,
      nitrofen-induced CDH with antenatal dexamethasone treatment. Reverse
      transcription-polymerase chain reaction (RT-PCR) was performed to evaluate
      relative amounts of tropoelastin and alpha1 (I) procollagen mRNA. RESULTS: Levels
      of both tropoelastin and alpha1 (I) procollagen mRNA were significantly increased
      in group II compared with group I (P< .05). Neither tropoelastin nor alpha1 (I)
      procollagen mRNA levels were significantly different between group II and III.
      CONCLUSIONS: The increased local synthesis of tropoelastin and type I procollagen
      in CDH lung may be responsible for the increased rigidity and decreased
      compliance observed in the CDH hypoplastic lung. Glucocorticoids have no effect
      on pulmonary tropoelastin and alpha1 (I) procollagen gene expression in CDH
      lungs.

PMID- 10359171
TI  - Does extracorporeal membrane oxygenation improve survival in neonates with
      congenital diaphragmatic hernia? The Congenital Diaphragmatic Hernia Study Group.
AB  - BACKGROUND/PURPOSE: The benefit of extracorporeal membrane oxygenation (ECMO) in
      improving survival of neonates with congenital diaphragmatic hernia (CDH) has
      never been clearly demonstrated. This may be due to comparisons made between
      treatment groups of unequal illness severity and the low statistical power of
      analyses from previous studies. The authors analyzed the data from the
      multicenter CDH registry to determine if ECMO improves survival in CDH neonates
      with a high risk of mortality. METHODS: A total of 730 neonates were enrolled in
      the CDH Registry from January 1995 to November 1997. Of these, 632 neonates had a
      complete data set and were eligible for ECMO by the weight criterion of greater
      than 2.0 kg. Multivariate logistic regression analysis was used to assess
      mortality risk for each neonate based on previously validated independent
      predictors of survival: birth weight and 5-minute Apgar. Five quintile groups
      were defined based on increasing predictive mortality risk. Multivariate logistic
      regression and chi2 analyses with birth weight, Apgar score at 5 minutes, and
      predictive mortality risk as covariates were then performed to assess survival
      benefit of ECMO compared with conventional therapy alone. Patient survival rate
      was defined as survival to discharge from hospital. RESULTS: When analyzing all
      632 neonates, ECMO neonates (n = 289) had a decidedly lower survival rate (52.9%
      v 77.3%, P< .001) than non-ECMO neonates (n = 343) without standardizing for the
      degree of illness. However, when taking into account the patients' predictive
      mortality risk, ECMO was associated with improved survival in the neonates with
      mortality risk < or = 80% (P < .05). Furthermore, ECMO was shown to be a positive
      independent predictor of survival when accounting for the covariates of birth
      weight, 5-minute Apgar, and mortality risk (P < .05). CONCLUSIONS: ECMO
      significantly improves survival rates for those CDH neonates with a predictive
      mortality risk > or = 80%. Generally, the more critically ill the patient with
      CDH, the more marked the survival benefit obtained.

PMID- 10359172
TI  - In utero bone marrow transplantation induces donor-specific tolerance by a
      combination of clonal deletion and clonal anergy.
AB  - BACKGROUND/PURPOSE: In utero bone marrow transplantation can induce donor
      specific tolerance to postnatal solid organ transplantation, although the
      mechanisms remain poorly defined. In this study, we investigated the role of
      clonal deletion and clonal anergy in the maintenance of tolerance in a murine
      model of in utero bone marrow transplantation. METHODS: DBA/2 mice (MIs(a+)) were
      used as donors of adult bone marrow, and 14-day-gestation fetal Balb/c mice
      (MIs(a-)) were used as recipients. Tolerance was defined by donor-specific skin
      graft survival for more than 8 weeks. Clonal deletion was assessed by flow
      cytometry for Vbeta6 T cell receptor usage. A tolerant animal demonstrating
      partial deletion of CD4+/Vbeta6+ T cells and a nontolerant animal were selected
      for analysis of clonal anergy by a proliferation assay using plate-bound anti
      Vbeta6 antibody for stimulation with or without exogenous interleukin-2 (IL2).
      RESULTS: Vbeta6+ splenocytes constituted 6.32% of CD4+ T cells in the tolerant
      animal compared with 9.19% in the nontolerant animal, demonstrating incomplete
      clonal deletion in the tolerant animal. Stimulation with plate-bound anti-Vbeta6
      induced a good proliferative response in the nontolerant animal but a
      significantly attenuated response in the tolerant animal (P< .001), which was
      abrogated by the addition of IL2. CONCLUSIONS: In this murine model of in utero
      bone marrow transplantation, the tolerant state is characterized by partial
      clonal deletion of donor reactive T cells and clonal anergy of nondeleted donor
      reactive T cells. The anergic state can be abrogated by exogenous IL2, suggesting
      that the mechanism of anergy is a deficiency of IL2 production.

PMID- 10359173
TI  - Progress in the surgical management of vaginal rhabdomyosarcoma: a 25-year review
      from the Intergroup Rhabdomyosarcoma Study Group.
AB  - BACKGROUND/PURPOSE: During its 25 years of experience, the Intergroup
      Rhabdomyosarcoma Study Group (IRSG) has completed four sequential prospective
      clinical trials to improve survival and decrease morbidity rates in childhood
      rhabdomyosarcoma (RMS). Surgical management of vaginal RMS has changed
      dramatically. METHODS: The records of 72 patients with localized vaginal RMS were
      reviewed to assess surgical therapy, chemotherapy, and radiotherapy and their
      relation to outcome. RESULTS: Each successive IRSG trial resulted in decreased
      need for surgical resection (IRS-I, 100%; IRS-II, 70%; IRS-III, 30%; IRS-IV, 13%)
      and excellent disease-free survival using increasingly effective multiagent
      chemotherapy. CONCLUSIONS: Primary chemotherapy after initial biopsy provides
      excellent tumor control. Local resection may be appropriate, but removal of
      organs (ie, complete vaginectomy/hysterectomy) has no role except in persistent
      or recurrent disease. Mature, residual rhabdomyoblasts may be evidence of a
      chemotherapy response, and further surveillance and biopsy without surgical
      resection is adequate treatment.

PMID- 10359174
TI  - Does debulking improve survival rate in advanced-stage retroperitoneal embryonal
      rhabdomyosarcoma?
AB  - BACKGROUND, METHODS, AND PURPOSE: The authors examined demographic and clinical
      features, therapy, and outcome of patients with advanced (group III or IV)
      rhabdomyosarcoma (RMS) of the retroperitoneum and nongenitourinary pelvis treated
      in the Intergroup Rhabdomyosarcoma Study Group (IRSG) III (1984 to 1991, n = 41)
      or IV pilot (1987 to 1991, n = 53) studies to assess the role of initial
      debulking surgery. RESULTS: Ninety-four patients with retroperitoneal primary
      tumors and gross locoregional residual tumor (group III, n = 53) or metastatic
      disease (group IV tumors, n = 41) were treated with combination chemotherapy (ie,
      vincristine, dactinomycin, and cyclophosphamide with or without other agents plus
      radiation therapy, RT) after biopsy only or subtotal resection. These
      retroperitoneal tumors usually were invasive (T2, 76%). Most patients were
      younger than 10 years of age (n = 69, 73%), the male to female ratio was 1.4, and
      tumors usually were embryonal (n = 64, 68%). Overall 4-year failure-free survival
      (FFS) was 50%; survival was 60%. Survival rate was better for girls (4-year
      survival rate, 75% v49% for boys; P = .05) and was not significantly different
      for patients treated in IRS-III (66%) or IRS-IV pilot (52%). However, it was
      better for patients with embryonal versus alveolar or undifferentiated tumors (4
      year survival rate, 70% v 42%; P = .002). In adolescents, RMS is different from
      that seen in children less than 10 years old; most cases are alveolar or
      undifferentiated (16 of 29, 55%). Surgery for most (21 of 24) patients with
      alveolar tumors comprised biopsy only. By contrast, of 64 patients with embryonal
      tumors, 39 (61%) underwent biopsy only, whereas 25 (39%) had debulking surgery.
      Patients whose tumors were debulked fared better than those whose tumors
      underwent biopsy only (4-year FFS rate, 72% v48%; P = 0.03). Patients with group
      IV embryonal tumors fared unexpectedly better than those with group IV alveolar
      or undifferentiated tumors (70% versus 42% 4-year survival rate, P < .05), and
      patients less than 10 years of age with group IV embryonal tumors had 4-year
      survival rate of 77%, indicating the importance of the biology of these tumors.
      CONCLUSIONS: Multimodal therapy, including multiagent chemotherapy plus RT,
      appears to improve survival rate in patients with advanced embryonal RMS arising
      in the retroperitoneum. These data suggest that debulking tumors of embryonal
      histology improves outcome further. This approach will be assessed in IRSG V.

PMID- 10359176
TI  - The impact of intraoperative culture on treatment and outcome in children with
      perforated appendicitis.
AB  - BACKGROUND: Most protocols for the operative treatment of perforated appendicitis
      use a routine culture. Although isolated studies suggest that routine culture may
      not be necessary, these recommendations generally are not based on objective
      outcome data. METHODS: The authors reviewed the records of 308 children who
      underwent operative treatment for perforated appendicitis between 1988 and 1998
      to determine if information gained from routine culture changes the management or
      improves outcome. Inclusion criteria included either gross or microscopic
      evidence of appendiceal perforation. RESULTS: Mean patient age was 7.5 years, 51%
      were boys, and there was no mortality. The majority of children (96%) underwent
      culture that was positive for either aerobes (21%), anaerobes (19%), or both
      (57%). Antibiotics were changed in only 16% of the patients in response to
      culture results. The use of empiric antibiotics, as compared with modified
      antibiotics, was associated with a lower incidence of infectious complication,
      shorter fever duration, and decreased length of hospitalization. We also
      investigated the relationship between culture isolates and antibiotic regimens
      with regard to outcome. The utilization of antibiotics suitable for the
      respective culture isolate or organism sensitivity was associated with an
      increased incidence of infectious complication and longer duration of both fever
      and length of hospitalization. Finally, the initial culture correlated poorly
      with subsequent intraabdominal culture (positive predictive value, 11%).
      CONCLUSION: These outcome data strongly suggest that the practice of obtaining
      routine cultures can be abandoned, and empiric broad spectrum antibiotic coverage
      directed at likely organisms is completely adequate for treatment of perforated
      appendicitis in children.

PMID- 10359175
TI  - Metastasis correlates with production of vascular endothelial growth factor in a
      murine model of human Wilms' tumor.
AB  - BACKGROUND/PURPOSE: The growth and spread of solid tumors are critically
      dependent on the induction of angiogenesis. We hypothesized that vascular
      endothelial growth factor (VEGF) would be detected in Wilms' tumors, and that
      both growth and metastasis would parallel VEGF levels in a murine model. METHODS:
      Primary tumors were established in the right kidneys of nude mice (n = 21). Mice
      were killed at 3, 4.5, or 6 weeks. Tumor-bearing and control kidneys were
      subjected to enzyme-linked immunosorbent assay (ELISA) for VEGF. Representative
      sections were assessed by histology and immunohistochemistry. Lungs were examined
      for metastases. Clinical specimens of Wilms' tumor (n = 12) also were assayed for
      VEGF. RESULTS: The authors detected VEGF by ELISA with increasing frequency, and
      in increasing quantity, as experimental Wilms' tumors were grown over time.
      Immunohistochemistry demonstrated accumulation of VEGF in areas of viable tumor.
      Lung metastases occurred in 8 of 10 animals with VEGF-positive tumors, but in
      only 3 of 11 animals with VEGF-negative tumors, an association that was
      statistically significant. VEGF was found in 10 of 12 clinical Wilms' tumor
      specimens tested. CONCLUSIONS: VEGF is present in both clinical and experimental
      Wilms' tumors. In a murine model, absolute VEGF levels increase as primary tumors
      grow, and VEGF production is significantly associated with tumor metastasis.

PMID- 10359177
TI  - Does early ultrasonography affect management of pediatric appendicitis? A
      prospective analysis.
AB  - BACKGROUND: Appendicitis remains a difficult diagnosis in children.
      Ultrasonography is increasingly used for the diagnosis of appendicitis, although
      the proper clinical role for this test remains unclear. METHODS: To evaluate the
      clinical utility of ultrasonography in appendicitis, the authors analyzed
      prospectively all children evaluated for possible appendicitis from January 1
      through December 31, 1997. Children with a high clinical suspicion of
      appendicitis were referred for surgery (n = 122). Children with equivocal
      findings of appendicitis were referred for early ultrasonography (EUS) and formed
      the study cohort (n = 103). An initial management plan was made to operate or
      observe each patient, and a risk of appendicitis (doubtful, possible, probable)
      was assigned by a pediatric surgery fellow. EUS was then performed, and its
      effect on management was assessed. RESULTS: Using clinical judgment to operate at
      initial presentation, the sensitivity was 38% and specificity was 95%. Using EUS
      alone, the sensitivity was 87% and specificity was 88%. The management of 30 of
      103 patients (30%) was changed after EUS, including a decision to operate in 28
      patients and a decision not to operate in two patients. CONCLUSIONS: EUS appears
      to have substantial clinical utility in children with equivocal findings of
      appendicitis, and its use complements the clinical management. The use of EUS can
      improve patient care and reduce hospital resource utilization.

PMID- 10359178
TI  - The utility of technetium 99m pertechnetate scintigraphy in the evaluation of
      patients with Meckel's diverticulum.
AB  - PURPOSE: The aim of this study was to assess the utility of technetium (Tc) 99m
      pertechnetate scintigraphy in the diagnostic workup of the pediatric patient with
      gastrointestinal (GI) bleeding and a suspected Meckel's diverticulum. METHODS:
      The charts of 235 consecutive patients evaluated with a Meckel's scan (n = 165)
      or with the discharge diagnosis of Meckel's diverticulum (n = 70) between January
      1975 and October 1997 were reviewed for presenting symptoms, bleeding
      characteristics, diagnostic studies and pathological diagnosis. Those patients
      with lower GI bleeding and a serum hemoglobin level less than 11.0 g/dL who
      underwent a 99mTc pertechnetate scan (n = 43) were assessed for utility of the
      scan. RESULTS: In all patients the Meckel's scan had a positive and negative
      predictive value of 0.93. However, in patients with lower GI bleeding and a
      hemoglobin less than 11.0 g/dL the Meckel's scan had a sensitivity of 0.60, a
      positive predictive value of 1.0, a specificity of 0.96, but only a negative
      predictive value of 0.74. As such, the probability that a child who presents with
      GI bleeding and a serum hemoglobin less than 11 g/dL will have a Meckel's
      diverticulum despite a negative Meckel's scan of 0.26. We further evaluated the
      eight patients with a false-negative scan: ectopic gastric mucosa was present on
      pathological examination in all eight patients. Pentagastrin stimulation was
      performed at the time of scintigraphic study in three of eight. Six of these
      eight patients had duplicate scans that also were negative. Patients with a false
      negative (FN) scan had significantly increased hospital charges when compared
      with those with a true positive (TP) scan (TP = $5012 +/- 1992; FN = $8554 +/-
      1506; P = .0001). Clinical suspicion had a major effect on the decision-making
      process in these patients independent of the results of the Meckel's scan, and
      all eight patients ultimately underwent exploratory laparoscopy-laparotomy with
      Meckel's diverticulectomy despite the scan results. CONCLUSIONS: The relatively
      low negative predictive value of the Meckel's scan may result in the need for
      operative evaluation despite the scan data. As such, the contribution of the scan
      to clinical decision making is low. These findings suggest that exploratory
      laparotomy or laparoscopy may be indicated instead of scintigraphic scanning in
      the assessment of the anemic (hemoglobin less than 11 g/dL) pediatric patient
      with lower GI bleeding, especially in patients in whom a high suspicion for a
      bleeding Meckel's diverticulum exists.

PMID- 10359179
TI  - Persistent postnatal transgene expression in both muscle and liver after fetal
      injection of recombinant adenovirus.
AB  - BACKGROUND/PURPOSE: Immune responses to both vector and transgene antigens have
      limited the efficacy of postnatal gene therapy. We hypothesize that the fetal
      period may offer immunologic and developmental advantages for successful gene
      therapy. In this study we examined the efficacy, persistence, and immunologic
      effects of recombinant adenovirus after intramuscular delivery into fetal mice.
      METHODS: E1-deleted adenovirus (AdCMVlacZ) containing the beta-galactosidase
      marker gene was used for injection. Fetal Balb/c mice (14 to 15 days' gestation)
      were injected with AdCMVlacZ in 10-microL volume in either the shoulder or
      hindlimb musculature. Animals were killed at 18 to 20 days' gestation and up to 4
      months postnatally for analysis of transgene expression and adenoviral genome
      persistence. RESULTS: Fetuses were injected with doses of AdCMVlacZ from 1 x
      10(8) to 2 x 10(10) viral particles (n = 80). Optimal survival rate was 83% at 18
      to 20 days' gestation and 55% at 4 weeks of age using a dose of 1 x 10(9)
      particles. Expression of beta-galactosidasae at 18 to 20 days localized to
      multiple muscle groups surrounding the site of injection, as well as bone marrow
      stroma, liver, lung, and dorsal root ganglia. Persistent muscle and liver
      transgene expression was observed for as long as 16 and 8 weeks, respectively,
      after injection. The pattern of liver expression was confined to discrete foci of
      hepatocytes, which appeared to increase in size in older animals. No histological
      evidence of muscle or liver inflammation was observed at any time after
      injection. No neutralizing antibodies were observed postnatally. CONCLUSIONS: Our
      results confirm that gene therapy in the fetus may be advantageous. Distribution
      of vector in the fetus at the site of injection is clearly broader than in the
      adult setting. Furthermore, the absence of immune response and persistence of
      transgene expression suggests that fetal exposure to foreign transgene and vector
      antigens may induce tolerance. Although we have not proven genomic integration,
      the histological appearance of transgene expression in the liver supports this
      conclusion. By understanding the mechanisms that underlie persistent transgene
      expression, fetal gene therapy may become a feasible strategy for the treatment
      of fatal genetic diseases.

PMID- 10359180
TI  - Epithelio-mesenchymal interactions in the developing mouse pancreas:
      morphogenesis of the adult architecture.
AB  - BACKGROUND/PURPOSE: The mammalian pancreas is thought to develop through a
      complex interaction between the budding epithelium and the surrounding
      mesenchyme. The exact nature of this interaction is unclear. Most of what is
      known to date of these interactions comes from a series of organ culture
      experiments done in the late 1960s. Nevertheless, these important experiments may
      have been confounded by less-defined culture media and organ dissection
      techniques, because the results are not reproducible in our hands. The authors
      undertook a study to reexplore these basic epithelio-mesenchymal interactions.
      METHODS: Using previously described organ dissection and culture techniques the
      authors examined the basic interactions between the embryonic pancreatic
      epithelium and its mesenchyme with histological and immunohistological
      techniques. RESULTS: The authors found that, contrary to previous reports, the
      earliest pancreatic anlage did not possess the intrinsic signaling necessary to
      support normal growth and differentiation in vitro. Intimate contact between the
      epithelium and the mesenchyme may be necessary until E11.5 for normal growth and
      differentiation. The age of the mesenchyme seemed to correlate with the degree of
      acinar differentiation, and proximity of mesenchyme was important for acinar
      differentiation. CONCLUSIONS: Previous investigations into the basic epithelio
      mesenchymal interactions in the developing mammalian pancreas may have had
      confounding factors. Extrinsic signals seem necessary for complete pancreatic
      differentiation, and mesenchymal factors appear important for acinar
      differentiation.

PMID- 10359181
TI  - Vascular development in the mouse embryonic pancreas and lung.
AB  - PURPOSE: The purpose of this study was to analyze the formation of blood vessels
      in the developing mouse pancreas and lung by studying two ligands, angiopoietin-1
      (ang1) and angiopoietin-2 (ang2), which are thought to play a role as
      angiogenesis-activating factors in development. Understanding the role of
      vasculogenic peptides in normal embryonic development also may have important
      implications for common clinical problems regarding neonatal pulmonary
      vasculature. METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) as
      well as Southern blotting was used to determine the ontogeny of angiopoietin-1
      and angiopoietin-2 gene expression in the embryonic mouse pancreas and lung.
      Immunohistochemistry was performed for von Willebrand factor, a known marker of
      endothelial cells, to chronicle the development of the vasculature in these
      organs. RESULTS: The authors determined the temporal expression of angiopoietin-1
      and angiopoietin-2 as a function of gestational age. RT-PCR data demonstrated
      expression of ang1 and ang2 in the developing mouse lung between gestational day
      E9.5 and postnatal day 1, and in the developing pancreas between gestational days
      E12.5 and E18.5. Southern blot analysis confirmed PCR data for ang2 expression in
      both the lung and pancreas. The authors also traced the spatial development of
      the vascular system by von Willebrand factor staining. For both lung and pancreas
      specimens, no blood vessels were identifiable by immunohistochemistry until
      embryonic day 12.5. With increased gestational age, the blood vessel networks
      grew larger. CONCLUSION: The authors have demonstrated that ang1 and ang2 may be
      involved in the mechanisms of vascular development in the embryonic mouse lung
      and pancreas.

PMID- 10359182
TI  - Congenital hyperinsulinism and the surgeon: lessons learned over 35 years.
AB  - BACKGROUND/PURPOSE: Congenital hyperinsulinism induces severe and unremitting
      hypoglycemia in newborns and infants. If poorly controlled, seizures and
      irreversible brain damage may result. Subtotal (<95%) or near-total (95% to 98%)
      pancreatectomy have been performed for glycemic control in babies who do not
      respond to aggressive medical therapy. Because hypoglycemia often persists after
      subtotal resection, 95% pancreatectomy has emerged as the procedure of choice. To
      define the effect of more or less extensive pancreatectomy on the management and
      outcome of refractory congenital hyperinsulinism, the authors examined our single
      institutional experience. METHODS: The records of children treated between 1963
      and 1998 for congenital hyperinsulinism, and who required pancreatectomy, were
      reviewed. Outcome parameters included glycemic response to surgery, need for
      reresection, surgical morbidity, surgical and long-term mortality, and
      development of diabetes mellitus (DM). A complete response was defined as
      discharge to home on no glycemic medications, no continuous feedings, and without
      DM. Histological reports were reviewed and categorized as either diffuse or focal
      disease. RESULTS: Of 101 children treated for congenital hyperinsulinism during
      this period, 53 (50%) required pancreatectomy for glucose control. Mean follow-up
      for the study population was 9.8 +/- 1.1 years. Overall, 23 children (43%) showed
      a complete response, occurring in 50% of patients having > or = 95%
      pancreatectomy (n = 34), but in only 19% having less than 95% resection (n = 16).
      The remaining three babies had local excision of a solitary focal lesion, and
      each showed a complete response. Histopathology showed diffuse islet
      abnormalities in 42 specimens (79%) and solitary focal lesions in 11 (21%). A
      complete response was observed for 82% of focal but only 33% of diffuse lesions.
      Eight patients (15%) required reresection for persistent hypoglycemia, seven
      having diffuse lesions and one focal. Surgical morbidity occurred in 13 cases
      (26%), and the 30-day surgical mortality rate was 6%, each death (n = 3)
      occurring before 1975. DM developed in seven children (14%), each having diffuse
      lesions, and was independent of resection type. CONCLUSION: Because euglycemia is
      more readily restored, and because the risks for surgical complications and DM do
      not appear increased, the authors recommend 95% pancreatectomy as the initial
      procedure of choice for newborns and infants with congenital hyperinsulinism.

PMID- 10359183
TI  - Prenatal diagnosis of congenital cystic adenomatoid malformation and its
      postnatal presentation, surgical indications, and natural history.
AB  - BACKGROUND/PURPOSE: Regression of a cystic adenomatoid malformation (CAM) in a
      fetus is well described. Little, however, is known about the postnatal course of
      these infants. This study attempts to correlate the prenatal course of CAMs with
      postnatal symptoms, radiological manifestations, and need for surgery. METHODS:
      The clinical course of patients with a CAM diagnosed prenatally were
      retrospectively reviewed. Inclusion in the study required a prenatal ultrasound
      scan documenting a CAM. RESULTS: Over 10 years, 14 patients with a CAM were
      diagnosed prenatally. Six (43%) showed a partial in utero regression. Four
      patients were symptomatic at birth and underwent a resection as newborns. Ten
      patients were asymptomatic at birth, and eight of these had normal chest x-rays.
      Elective resection has been performed in 3 of these 10, and two additional
      children are scheduled to undergo an excision near 1 year of age. The remaining
      five patients have undergone follow-up nonoperatively for a mean of 36 +/- 15
      months. Of the seven asymptomatic patients not undergoing immediate surgery, only
      one has shown a slight postnatal regression, despite five of these showing
      regression in utero. None have become symptomatic. CONCLUSIONS: The results
      suggest that regression of a CAM on prenatal ultrasound scan is common, but this
      process does not continue after birth. A normal chest x-ray does not indicate
      complete regression of a CAM; a computed tomography (CT) scan is required to
      evaluate such patients, and will generally demonstrate a CAM. Asymptomatic
      patients with a CAM may be followed up nonoperatively with no apparent adverse
      effects. The decision and timing of an excision in an asymptomatic patient
      remains controversial among pediatric surgeons.

PMID- 10359185
TI  - Elevated platelet-derived growth factor-B in congenital cystic adenomatoid
      malformations requiring fetal resection.
AB  - BACKGROUND: During lung development, platelet-derived growth factor-BB (PDGF-BB)
      is maximal during the canalicular stage and decreases by the saccular stage. PDGF
      BB stimulates lung growth by increasing cell proliferation. Fetal CCAMs have been
      shown to have an elevated proliferative index, but it is not known why some CCAMs
      rapidly enlarge in utero and cause fetal hydrops. The authors hypothesized that
      the high proliferative index and rapid enlargement of some fetal CCAMs may be
      caused by persistently elevated PDGF-BB production compared with normal fetal
      lung. METHODS: To test this hypothesis, tissue was obtained at the time of
      resection from two fetal CCAMs (22 weeks), three full-term CCAMs, and three
      normal fetal lungs (21 to 22 weeks). PDGF-BB production by fetal CCAMs was
      compared with normal age-matched fetal lung using immunohistochemistry, reverse
      transcriptionase-polymerase chain reaction (RT-PCR), and Western blot analysis.
      RESULTS: CCAMs resulting in fetal hydrops and requiring fetal resection had
      strong mesenchymal immunostaining for PDGF-BB next to epithelial lined cysts,
      increased PDGF-B gene expression by RT-PCR, and elevated PDGF-BB protein by
      Western blot, compared with normal age-matched fetal lung. Term CCAMs had minimal
      PDGF-BB staining, PDGF-B gene expression, and PDGF-BB protein production.
      CONCLUSIONS: CCAMs that grew rapidly and progressed to hydrops, requiring in
      utero resection, demonstrated increased mesenchymal PDGF-B gene expression and
      PDGF-BB protein production compared with age-matched normal fetal lung, which
      may, in part, be responsible for the autonomous growth and proliferation seen in
      hydropic fetal CCAMs.

PMID- 10359184
TI  - The adaptive intestinal response to massive enterectomy is preserved in c-SRC
      deficient mice.
AB  - BACKGROUND/PURPOSE: The Src family of protein tyrosine kinases has been
      implicated in the downstream mitogenic signaling of several ligands including
      epidermal growth factor (EGF). Because EGF likely plays a role in adaptation
      after massive small bowel resection (SBR), we tested the hypothesis that c-src is
      required for this important response. METHODS: A 50% proximal SBR or sham
      operation (bowel transection or reanastomosis alone) was performed on c-src
      deficient (n = 14) or wild-type (C57bl/6) mice (n = 20). The ileum was harvested
      on postoperative day 3 and adaptive parameters determined as changes in ileal wet
      weight, protein and DNA content, proliferation index, villus height, and crypt
      depth. Comparisons were done using analysis of variance (ANOVA), and a Pvalue
      less than .05 was considered significant. Values are presented as mean +/- SEM.
      RESULTS: The activity of c-src was increased in the ileum of wild-type mice after
      SBR but remained unchanged in c-src-deficient mice. Despite this lack of
      increase, adaptation occurred after SBR in the c-src-deficient mice as
      demonstrated by increased ileal wet weight, protein and DNA content,
      proliferation index, villus height, and crypt depth similar to wild-type mice.
      CONCLUSIONS: The adaptive response of the intestine to massive SBR is preserved
      despite reduced activity of the c-src protein. The mitogenic signaling that
      characterizes intestinal adaptation and is associated with receptor activation by
      EGF or other growth factors probably occurs by mechanisms independent of c-src
      protein tyrosine kinase.

PMID- 10359186
TI  - Management of pediatric liver injuries: a 13-year experience at a pediatric
      trauma center.
AB  - PURPOSE: This study of traumatic liver injuries (LI) in children reviews the
      authors' management and identifies the indications for surgical intervention.
      METHODS: A total of 11,761 admissions over 13 years to a regional pediatric
      trauma center were surveyed. RESULTS: LI were identified in 328 children.
      Mechanisms included 39% pedestrians struck by a vehicle, 34% motor vehicle
      occupants, 13% falls or discrete blows to the abdomen, 5% bicycle injuries, 5%
      child abuse, and 4% penetrating injuries. Eighty-seven of patients with LI were
      treated nonoperatively with a mortality rate of 17%. Six percent of deaths were
      attributed to the LI and massive hemorrhage, all of which presented with
      cardiopulmonary resuscitation (CPR) in progress, with the remainder of deaths
      attributed to massive head, neck, or chest injuries (HNCI, 90%) and sepsis (4%).
      Surgery was performed in 13% of all LI and included major hepatic vascular injury
      (MHVI) repairs (34%), hepatorrhaphies (34%), lobectomies (27%), and biliary
      repairs (4%). Excluding the nonoperative group deaths, the need for blood
      transfusion of more than 25 mL/kg in the first 2 hours as an indicator of
      surgical necessity or a MHVI had, respectively, a sensitivity of 34% and 67%,
      specificity of 98% and 97%, positive predictive value of 79% and 53%, negative
      predictive value of 89% and 98%, and prediction accuracy of 88% and 95%. In the
      surgical management group, the mortality rate was 23% with 40% of deaths
      attributed to MHVI, 30% a combination of MHVI and HNCI, 20% massive HNCI, and 10%
      sepsis. CONCLUSIONS: The majority of pediatric LI are not associated with
      hemodynamic instability and can be successfully managed nonoperatively (72%).
      Hemodynamic instability, as defined by the need for blood transfusion in excess
      of 25 mL/kg within the first 2 hours, was a strong indicator of a MHVI, which was
      often a lethal injury (70%).

PMID- 10359187
TI  - Management of pancreatic injury in pediatric blunt abdominal trauma.
AB  - BACKGROUND/PURPOSE: Nonoperative management of low-grade pancreatic injury is
      widely accepted. Management of major pancreatic parenchymal or ductal injury in
      children remains controversial. This study will review management strategies as
      they relate to site and type of pancreatic injury and their outcomes. METHODS: A
      total of 11,794 consecutive admissions to a regional pediatric trauma center from
      1984 to 1997 were reviewed to identify children with pancreatic injury as
      documented by serum amylase; imaging by computed tomographic (CT) scan,
      ultrasonography (US), and endoscopic retrograde cholangiopancreatography (ERCP);
      and surgical or postmortem reports. RESULTS: Pancreatic injury was documented in
      56 children, age 2 months to 14 years, with blunt mechanisms of injury. Serum
      amylase level was elevated on admission in 40 (71%), and no correlation was found
      between admission amylase values and severity of pancreas injury. An admission CT
      scan was obtained in 44 (79%) patients and was positive for pancreatic injury in
      25 (57%). Twelve children, who had diagnoses of other intraabdominal injury by CT
      scan, had pancreatic injuries discovered on exploratory laparotomy. Seven
      children with normal admission CT scans, and the 12 children who did not undergo
      imaging on admission, had pancreatic injuries that were later documented by
      imaging, exploration, or autopsy. Thirty children were treated with immediate
      exploration, 17 for nonpancreatic indications and 13 with pancreatic injuries on
      admission CT scan. Of 19 minor injuries noted in the operating room, only three
      were treated with external drainage. Seven patients with distal duct injuries
      underwent distal pancreatectomy with splenic preservation. Twenty-six children
      were treated nonoperatively, including 19 with minor pancreas injuries, three
      with proximal pancreatic duct injuries, and four with duct injuries that were
      missed at admission. There were no advantages or complications of external
      drainage versus nondrainage of minor pancreatic injuries. There were seven deaths
      (overall mortality rate, 12.5%), none related to pancreatic injury. Of the seven
      patients in whom pseudocysts developed (two not imaged at admission, two from
      known proximal duct injuries treated nonoperatively, and three from injuries
      missed by initial studies), five were treated by delayed internal drainage and
      recovered promptly, and two resolved spontaneously. Pancreas-related
      complications included one persistent fistula and one prolonged hyperamylasemia,
      both of which resolved. CONCLUSIONS: Pancreatic injuries are uncommon in
      children. Initial serum amylase level does not correlate with the severity of
      pancreatic injury. The majority of pancreatic injuries can be managed
      nonoperatively. Initial nonoperative management of injuries of the proximal
      pancreatic duct allows for the formation and uneventful delayed drainage of a
      pseudocyst, rather than the risks of early radical interventions. Distal duct
      injuries are best managed by prompt spleen-sparing distal pancreatectomy. There
      is no benefit of closed drainage for management of minor pancreatic injuries
      discovered at laparotomy.

PMID- 10359188
TI  - Neurogenic bladder in infants born with anorectal malformations: comparison with
      spinal and urologic status.
AB  - BACKGROUND/PURPOSE: Spinal dysraphism and neurovesical dysfunction (NVD)
      frequently are associated in children with anorectal malformations (ARM). This
      study compares the urodynamic data from a selected group of patients with the
      results of their spinal and urologic imaging studies. METHODS: Twenty-six
      children (20 with isolated imperforate anus and six with persistent cloacal
      malformations) were investigated. All patients were evaluated with leak point
      pressures (LPP), renal ultrasound scan, and voiding cystourethrography. Eight
      children had urodynamics performed before and after posterior sagittal
      anorectoplasty (PSARP). The spinal cord was assessed using ultrasonography or
      magnetic resonance imaging. Current urologic status was obtained to provide long
      term follow-up. RESULTS: Twenty-one of 26 children demonstrated elevated LPPs
      above the established normal value of 40 cm H2O, and 15 of these children had
      normal spinal imaging study findings. Uroradiographic studies findings showed
      that 12 of 21 children with elevated LPPs had hydronephrosis or vesicoureteral
      reflux with seven of these patients having normal spinal cords. LPPs in the eight
      patients with pre- and postoperative studies were 74 +/- 14.7 cm H2O and 68 +/-
      31.8 cm H2O (mean +/- SD), respectively. CONCLUSIONS: These urodynamic and
      radiographic data confirm that NVD (elevated LPP) is common in patients with
      anorectal malformations despite normal spinal cords. Bladder dysfunction does not
      appear to be a sequelae of a properly performed PSARP. Patients with ARM and any
      uroradiographic or clinical urologic abnormality should undergo urodynamic
      testing even though the spinal studies are normal.

PMID- 10359189
TI  - Slow-transit constipation in childhood.
AB  - BACKGROUND/PURPOSE: Intestinal neuronal dysplasia (IND) as a cause for severe
      chronic constipation remains controversial. The authors have identified a
      deficiency of substance P (SP) immunoreactivity in the colonic nerve fibres of
      some children with severe constipation, and aim to correlate this with clinical
      features and transit studies. METHODS: Over 100 children with intractable
      constipation with or without soiling have been assessed by clinical
      questionnaire, nuclear transit study, and laparoscopic seromuscular biopsy of the
      colon labelled with antibodies to SP and vasoactive intestinal peptide (VIP)
      using immunofluorescence. RESULTS: More than 30% of children had delayed passage
      of meconium, and symptoms of constipation appeared by the age of 1 year in 63%.
      More than 80% had significant delay in colonic transit, and of these, about 80%
      had reduced SP immunoreactivity in the axons of the colonic circular muscle. A
      further 6% had heterotopic ganglion cells or hypoplastic ganglia on routine
      histology. CONCLUSIONS: In children with intractable constipation, features of
      early onset and delayed colonic transit correlated with deficiency of SP in
      myenteric axons. The authors propose that deficient SP immunoreactivity may be
      used as a histological marker for severe constipation. Defective excitatory
      neuromuscular transmission may be the cause of slow colonic transit.

PMID- 10359190
TI  - One-stage correction of high imperforate anus in the male neonate.
AB  - PURPOSE: The aim of this study was to examine the feasibility, safety, and short
      term outcome of complete one-stage repair of high imperforate anus in the newborn
      boy. METHODS: A retrospective review was conducted of five full-term male infants
      who underwent posterior sagittal anorectoplasty without a colostomy within the
      first 48 hours of birth. Preoperative imaging was performed to assess associated
      anomalies. All infants underwent cystoscopy before the perineal operation to
      determine the level of the urinary tract fistula, if present. After completion of
      the anoplasty, all were turned supine and the colon irrigated free of meconium.
      Follow-up ranged from 10 to 24 months. RESULTS: Laparotomy was not required for
      any patient. Three patients had a rectoprostatic urethral fistula, one a
      rectovesical fistula, and one no fistula (common wall at level of prostate).
      Tapering rectoplasty was required for only the one patient with a rectovesical
      fistula. There were no intraoperative complications. All patients passed stool
      within 12 hours after operation and took full feeding by 48 hours. The average
      hospital stay was 7 days. Postoperative and stenosis occurred in one patient
      secondary to parental noncompliance with the postoperative dilation regimen.
      There were no perineal wound complications. All patients have a strong urinary
      stream and defecate spontaneously without the aid of oral medication or rectal
      stimulation or enemas. CONCLUSIONS: One-stage repair of high imperforate anus in
      the male neonate is feasible without short-term genitourinary or gastrointestinal
      morbidity. Whether it is preferable compared with a delayed (two or three stage)
      repair depends on ultimate long-term anorectal function, which cannot be assessed
      for several years.

PMID- 10359191
TI  - Restorative proctocolectomy in children with ulcerative colitis utilizing rectal
      mucosectomy with or without diverting ileostomy.
AB  - BACKGROUND: Controversies continue concerning the best way to perform restorative
      proctectomy (RP) for ulcerative colitis (UC). Can rectal mucosectomy and hand
      sewn ileoanal anastomosis (IAA) withstand the challenge posed by extrarectal
      dissection with a double-stapled technique and no mucosectomy? Is a diverting
      ileostomy mandatory after RP? METHODS: The authors describe 30 consecutive
      children with UC who underwent RP with rectal mucosectomy and hand-sewn IAA. The
      authors assess the results and compare the first 14 patients (group 1) treated
      with temporary diverting ileostomies with the next 16 consecutive patients (group
      2) without diverting ileostomies. RESULTS: The average age (13.8 years in group 1
      v 10.4 in group 2), duration of illness before resection (3.2 years in group 1 v
      1.5 in group 2), and gender breakdown (10 of 14 were girls in group 1, 10 of 16
      were girls in group 2) were similar between the two groups. Outcome was not
      significantly different between the two groups. Average bowel movements per 24
      hour period was 5.5 in group 1 and 4.2 in Group 2. Occasional nighttime staining
      occurred in two patients in group 1 and five in group 2. No one suffered daytime
      staining in group 1, and one patient had occasional daytime staining in group 2.
      Average quality of life (on a scale of 0 to 5) as assessed by the patients or
      parents was 4.4 in group 1 and 4.9 in group 2. There were 10 total complications
      in group 1. One child required a permanent stoma for ileoanal separation. Two
      patients required reoperations for complications caused by the diverting
      ileostomy. The single instance of peritonitis was in group 1 caused by
      anastomotic leak after ileostomy closure. There were five total complications in
      group 2, of which, two required temporary stomas for ileoanal separations.
      CONCLUSIONS: RP with rectal mucosectomy and hand-sewn IAA in children with UC
      provides good functional results. Peritonitis did not occur in the absence of
      diversion. Eliminating routine diverting ileostomy avoids the considerable
      complications and morbidity from the stoma and its closure.

PMID- 10359193
TI  - Long-term survival after liver transplantation.
AB  - BACKGROUND: Liver transplantation (LT) remains a high-risk operation, especially
      during the first months after LT when technical complications and preexisting
      illness exert their influence on survival. However, there are late deaths. The
      authors have reviewed their experience to identify factors impacting on long-term
      survival. METHODS: A total of 150 patients who had undergone liver
      transplantation over an 11-year period were reviewed. Thirty-three patients died
      after LT (22%). Of these, 18 of 33 (55%) died in the first 3 postoperative
      months. One hundred thirty-two patients survived beyond 3 months, and 15 patients
      (11%) suffered late deaths. This review concentrates on the latter group.
      RESULTS: The primary cause of death was sepsis in 11 of 15 (73%). In two, sepsis
      complicated retransplantation in chronically debilitated patients. Two additional
      patients had late-presenting postoperative complications (bile leak or abscess,
      intestinal obstruction with perforation). In two cases, pneumocystis carinii
      pneumonia occurred; noncompliance or unplanned discontinuation of prophylaxis was
      directly responsible. Multiple organ system failure from presumed
      immunoincompetence developed in four patients; one had undergone bone marrow
      transplantation for aplastic anemia (AA) after fulminant hepatic failure (FHF).
      Lymphoproliferative disease (LPD) was the cause of death in 3 of 15 cases (20%).
      In only three cases was the cause of death related to the patient's primary
      disease (chronic hepatitis, Alper's syndrome or seizures, and AA with FHF).
      Pretransplant diagnosis, and UNOS status at the time of LT did not influence the
      long-term survival. CONCLUSIONS: Long-term survival in patients who have
      undergone LT was compromised by immunosuppressive complications and sepsis. Early
      mortality factors, such as UNOS status, age at LT, primary diagnosis, and
      technical complications do not predict late deaths. In children who adhere to
      their medical regimen and have good initial allograft function, late
      postoperative infection, especially with Ebstein-Barr virus, accounts for most of
      the late mortality. Improved and decreased immunosuppression may further improve
      these long-term results.

PMID- 10359194
TI  - Living-related liver transplantation in children: the 'Parisian' strategy to
      safely increase organ availability.
AB  - PURPOSE: The aim of the authors was to report their experience with living
      related liver transplantation (LRLT) in children, particularly focusing on the
      safety of the two-center "Parisian" strategy. METHODS: The records of donors and
      recipients of 26 pediatric living-related donor liver transplantations performed
      between November 1994 and March 1998 were reviewed retrospectively. Donors were
      assessed 1 year after transplantation for medical and overall status. RESULTS:
      Indications for LRLT included biliary atresia (n = 18), Byler's disease (n = 5),
      alpha-1-antitrypsin deficiency (n = 1), Alagille syndrome (n = 1), and undefined
      cirrhosis (n = 1). Liver harvesting consisted of either a complete left
      hepatectomy (n = 14) or left lateral hepatectomy (n = 12) without vascular
      clamping. The recipient procedure essentially was the same as in split liver
      transplantation. Mean overall cold ischemia time averaged 140 minutes (range, 90
      to 230 minutes). Twenty-four of 26 patients had end-to-end vascular anastomoses
      without interposition. Biliary reconstruction consisted of a Roux-en-Y
      choledochojejunostomy in all patients. All recipients except one received
      cyclosporine A (CSA). Mean donor hospitalization was 8 days (range, 6 to 13) with
      normalization of all liver function assays by the time of discharge. There were
      no donor deaths and two postoperative complications (perihepatic fluid collection
      and bleeding from the wound). One year after donation, the initial 19 donors had
      resumed their pretransplant status. Two of the children who underwent transplant
      died. Thirteen of the recipients required reoperation for hepatic artery
      thrombosis (n = 2), portal vein thrombosis (n = 2), biliary complications (n =
      6), fluid collection (n = 3), small bowel perforation (n = 1), and plication for
      diaphragmatic eventration (n = 1). With mean follow-up of 2 years, 24 of 26
      patients are alive and well (patient and graft survival rate, 92%). CONCLUSIONS:
      LRLT is still controversial, even with minimal and decreasing donor risk. The
      "Parisian" strategy consists of harvesting the liver in an adult unit by an adult
      hepatic surgery team. The transplantation is then performed in a pediatric
      hospital by the pediatric liver transplantation team. The two steps of the
      procedure allow units specialized in adult surgery, on one hand, and pediatric
      liver transplantation, on the other hand, to dedicate themselves completely to
      their respective procedures, improving the safety of the harvest, and alleviating
      stress for both the medical staff and the families.

PMID- 10359192
TI  - Up-to-date evolution of small bowel transplantation in children with intestinal
      failure.
AB  - PURPOSE: The aim of the authors was to report an up-to-date review of their
      experience with 26 intestinal transplantations in children since 1987. METHODS: A
      retrospective study was conducted of 26 patients with a mean age of 5 years
      (range, 0.3 to 14 years). Three groups were isolated. In group A (1987 to 1990),
      seven patients received nine isolated intestinal transplants for short bowel
      syndrome. Immunosuppression therapy consisted of cyclosporine, aziathioprine, and
      corticosteroids. In group B (1994-current), nine patients received nine isolated
      intestinal transplants for short bowel syndrom (n = 2), intestinal
      pseudoobstruction (n = 2), neonatal intractable diarrhea (n = 3), and
      Hirschsprung' disease (n = 1); hepatic biopsy results showed weak cholestasis or
      fibrosis. In group C (1994-current), 10 patients received 10 combined liver-small
      bowel transplants for short bowel syndrome (n = 3), neonatal intractable diarrhea
      (n = 4), and Hirschsprung' disease (n = 3); hepatic cirrhosis related to total
      parenteral nutrition (TPN) was shown in all cases. Groups B and C received
      immunosupressive treatment consisting of tacrolimus, aziathioprine, and
      corticosteroids. Posttransplant follow-up included intestinal biopsies of the
      small bowel twice a week and more frequently or combined with liver biopsy if
      rejection was suspected. RESULTS: Overall patient survival (PS) and graft
      survival (GS) are 61% (16 of 26) and 50% (13 of 26), respectively. In group A,
      severe intestinal allograft rejection occurred in six patients leading to graft
      removal (GS, 11%). Five patients died of TPN complications after graft removal
      (PS, 28%). One survivor is off TPN, and one currently is waiting for a second
      graft. In group B, six patients survived (PS, 66%). Causes of death include
      hepatic failure (n = 1), renal and liver failure (n = 1), and systemic infection
      (n = 1). Severe intestinal allograft rejection occurred in five patients, which
      neccessitated aggressive immunosuppression (antilymphocyte serum) leading to an
      incomplete functional recovery of the graft. Only two patients currently are off
      TPN. In group C, eight patients survived (PS, 80%) all of which are currently off
      TPN. One patient died during the procedure, and one died of severe systemic
      infection. Intestinal graft rejection occurred in six patients; rejection of the
      liver allograft occurred in five patients, yet all rejections were weak and
      successfully treated by corticosteroids (GS, 80%). CONCLUSIONS: Intestinal
      transplantation is a valid therapeutic option for children with definitive
      intestinal failure and not only for short bowel syndrome. Tacrolimus improves
      graft and patient survival (group A v group B). The lower severity of graft
      rejection in combined liver-small bowel transplantation improves functional
      results of intestinal transplantation in children without additional mortality or
      morbidity (group B vgroup C).

PMID- 10359195
TI  - Cholecystectomy for suspected biliary dyskinesia in children with chronic
      abdominal pain.
AB  - BACKGROUND/PURPOSE: The authors reviewed their experience with a group of
      children with chronic abdominal pain, delayed gallbladder emptying, and no
      cholelithiasis. Clinical presentation, diagnostic evaluation, and effect of
      cholecystectomy on symptoms were investigated. METHODS: Twenty-nine children were
      suspected of having biliary dyskinesia. Diagnosis was based on symptoms of upper
      abdominal pain in conjunction with a lack of sonographically apparent gallstones,
      a cholecystikinin (CCK)-stimulated gallbladder ejection fraction of less that 40%
      at 30 minutes, and a lack of any other clear cause for symptoms. All patients
      underwent cholecystectomy. RESULTS: The duration of symptoms before operation was
      between 3 weeks and 4 years. All patients were evaluated by abdominal
      ultrasonography and CCK cholescintigraphy. Symptoms were relieved completely in
      23 (79%) of the patients who underwent cholecystectomy. Five children had
      persistent pain after cholecystectomy and one had nausea. CONCLUSIONS: Symptoms
      suggestive of biliary colic in children without evidence for cholelithiasis
      frequently may represent biliary dyskinesia. CCK cholescintigraphy should be
      pursued in these patients. Relief of symptoms after cholecystectomy should be
      expected in a majority of those with an ejection fraction of less that 40%.

PMID- 10359196
TI  - Hypokinetic gallbladder disease: a cause of chronic abdominal pain in children
      and adolescents.
AB  - BACKGROUND/PURPOSE: Impaired gallbladder emptying has been identified as a cause
      of chronic abdominal pain in adults. This study aims to define a pediatric
      population with functional abnormalities of gallbladder contractility and to
      assess clinical outcome after cholecystectomy. METHODS: Children and adolescents
      (n = 42) with abdominal complaints underwent gallbladder emptying studies,
      measured by either ultrasonography or scintigraphy with intravenous
      cholecystokinin (CCK). On ultrasound studies, gallbladder volume was measured
      before injection and 15 minutes after injection. Measures of gallbladder emptying
      by scintigraphy were taken at least 30 minutes after CCK injection. A study was
      classified as abnormal for contractility less than 50%. Cholecystectomy was
      performed and outcomes were evaluated during office visits and by telephone
      interview. RESULTS: Abdominal pain and fatty food intolerance were the
      predominant symptoms. Patients were treated by open (n = 2) or laparoscopic (n =
      40) cholecystectomy. In 20 cases the gallbladder showed chronic inflammation on
      pathology. Response to surgical therapy was excellent in 41 patients (mean follow
      up, 20.4 months). CONCLUSIONS: Children and adolescents with persistent abdominal
      pain should undergo functional assessment of gallbladder contractility. Patients
      with abnormal gallbladder contractility benefit from cholecystectomy.

PMID- 10359197
TI  - The role of apoptosis in normal and accelerated lung development in fetal
      rabbits.
AB  - BACKGROUND/PURPOSE: During fetal development, the mammalian lung undergoes
      progressive parenchymal involution. Intrauterine tracheal occlusion induces
      accelerated architectural maturation of the fetal lungs associated with depletion
      of the surfactant-producing type II cells. This study investigates the
      spatiotemporal pattern of apoptosis during normal fetal lung development and its
      modulation in tracheal occlusion-induced accelerated fetal lung growth. METHODS:
      Fetal rabbit lungs were studied at 25 to 31 days' gestational age (DGA; term, 31
      DGA), corresponding to late pseudoglandular through terminal air sac stages of
      fetal lung development. Intrauterine tracheal ligation (TL) was performed at 24
      DGA. TL fetuses were monitored until 29 DGA, a time-point previously shown to
      coincide with significant type II cell depletion. Apoptotic cells were identified
      by light and electron microscopy, as well as terminal deoxynucleotidyl
      transferase-mediated dUTP-FITC nick-end labeling (TUNEL). Epithelial (type I and
      II) cell apoptosis was studied by TUNEL labeling in conjunction with
      antisurfactant protein and anticytokeratin immunohistochemistry. DNA
      fragmentation was analyzed by gel electrophoresis. Sham-operated littermates
      served as controls. RESULTS: The number of apoptotic cells progressively
      increased with advancing lung growth and architectural maturation (apoptotic
      index [Al] 1.2 +/- 0.7 x 10(-3) at 25 DGA v 4.2 +/- 1.4 x 10(-3) at 31 DGA; P<
      .05, analysis of variance). In TL fetuses, the apoptotic rate was significantly
      higher than in non-TL fetuses from the third postligation day on, coinciding with
      the onset of significantly increased airspace distension (Al 4.9 +/- 1.3 x 10(-3)
      in TL v2.6 +/- 0.4 x 10(-3) in controls at 29 DGA; P< .05, Student's ttest).
      Apoptosis occurred in parenchymal cells and in isolated cells within the
      airspaces. The apoptotic activity of type II cells was significantly higher in TL
      fetuses than C fetuses at 29 DGA (type II Al 25.5 +/- 6.3 x 10(-3) in TL v2.3 +/-
      0.8 x 10(-3) in C; P< .001). Electron microscopic studies confirmed the presence
      of apoptotic nuclei in interstitial macrophages and in degenerating intraluminal
      type II cells. DNA analysis showed nucleosomal bands. CONCLUSIONS: Normal fetal
      lung development is associated with a progressive increase of epithelial and
      interstitial apoptotic activity, a process enhanced by TL. Tracheal occlusion
      induces a significant increase of type II cell apoptosis, which likely
      contributes to the observed type II cell depletion after TL. We speculate that
      fetal type II cell apoptosis after TL may be induced by mechanical distension
      (stretch) of the airspaces.

PMID- 10359198
TI  - Apoptosis in tracheoesophageal embryogenesis in rat embryos with or without
      adriamycin treatment.
AB  - PURPOSE: The aim of this study was to determine whether apoptosis participates in
      separation of the foregut into trachea and esophagus and to evaluate the
      potential role of apoptosis in the development of esophageal atresia and
      tracheoesophageal fistula (EA + TEF) induced by Adriamycin. METHODS: Timed
      pregnant rats were injected daily with either saline or Adriamycin (2 mg/kg)
      intraperitoneally on days 6 to 9 of gestation. Paraffin sections were prepared
      from 31 experimental and 31 control embryos at days 12 and 13 of gestation.
      Condensed nuclei were identified on the paraffin sections using the TUNEL method.
      Apoptosis was quantified by counting the positively stained cell nuclei in
      transverse sections of embryos. RESULTS: In day 12 control embryos the number of
      apoptotic nuclei in both lateral ridges of the foregut was high (15.67 +/- 1.38)
      but relatively low (4.17 +/- 0.80) in Adriamycin-treated embryos (P< .0001). In
      day 13 Adriamycin-treated embryos, the number of apoptotic nuclei in the region
      of the upper esophageal pouch was extremely high (23.78.5 +/- 2.20) compared with
      no detectable apoptotic nuclei in the control embryos. CONCLUSIONS: Apoptosis is
      required for normal tracheoesophageal embryogenesis and may be an important
      mechanism to be involved in the embryological development of esophageal atresia
      and tracheoesophageal fistula.

PMID- 10359199
TI  - Septation and differentiation of the embryonic human cloaca.
AB  - BACKGROUND/PURPOSE: Limitations in methodologies have fostered controversy
      regarding the septation of the human embryonic cloaca. The aim of this study was
      to evaluate the septation of the human embryonic cloaca. METHODS: Using the
      Carnegie Embryological Collection and specimens at Johns Hopkins, Baltimore, MD,
      the authors studied 12 embryos and five fetuses. Embryo photomicrographs were
      reconstructed using three-dimensional modeling. RESULTS: In Carnegie stage 13 the
      authors observed a cloaca, distinct primitive urogenital sinus, and anorectum
      separated by the urorectal septum. The primitive urogenital sinus and anorectum
      enter the cloaca separated from the amniotic space by the cloacal membrane. As
      the embryo becomes a fetus it lengthens, grows, expands and rotates through a
      process called transformation. Transformation gives rise to a loss of caudal
      curvature and a decrease in distance between the septum and membrane, but these
      structures do not fuse. Disintegration of the cloacal membrane produces openings
      for the urogenital sinus and anorectum. CONCLUSIONS: The observations suggest
      that the urogenital sinus and anorectum form early and are separated by the
      urorectal septum as a passive structure. There does not appear to be septation or
      differentiation of the cloaca itself.

PMID- 10359200
TI  - Pediatric trauma center criteria: an outcomes analysis.
AB  - BACKGROUND/PURPOSE: Trauma centers (TC) are certified based on widely accepted
      criteria. These specific criteria rarely are scrutinized individually. The
      purpose of this study was to analyze the individual components of a pediatric
      trauma center for their effect on outcome. METHODS: Members of the National
      Pediatric Trauma Registry were queried about the following: (1) separate
      pediatric emergency department (ED), (2) pediatric intensive care unit (PICU),
      (3) pediatric intensivist as PICU director, (4) pediatric surgeon as TC director,
      (5) in-house attending surgeon, (6) in-house pediatric emergency physician, (7)
      24-hour operating room, (8) 24-hour computed tomography (CT) scan. Outcomes
      analyzed included mortality, length of stay, time in ED, days in PICU, and
      disability. Victims were stratified based on age (<7 or > or = 7 years) and
      severity of injury (ISS < or = 16, 17-35, > or = 36). Results were compared using
      Student's t test and chi2 analysis. RESULTS: A total of 59 of 74 centers
      responded, 18 were dropped because of low enrollment (mean, 1.6 patients).
      Questions 3, 4, 6, and 7 were eliminated because of skewed data. An in-house
      surgeon reduced the amount of time a mildly injured patient (ISS < or = 16) spent
      in the ED (210 v434 minutes), as did the separate pediatric ED (333 v592 minutes)
      and pediatric emergency physicians (344 v 507 minutes) in younger patients (> or
      = 7 years). An in-house surgeon reduced the morality rate in older (> or = 7)
      severely injured (ISS > or = 36) patients (46.7% v 56.8%; P < .05 for all). No
      other differences were significant. CONCLUSIONS: In-house personnel improved
      efficiency for the less severely injured, and an in-house attending surgeon
      reduced mortality in the severely injured older patient. None of the other
      variables were found to have a significant impact on outcome.

PMID- 10359201
TI  - Use of the aortic homograft in the reconstruction of complex tracheobronchial
      tree injuries.
AB  - BACKGROUND/PURPOSE: The repair of complex tracheobronchial tree injuries often is
      associated with complications including stenosis and excessive granulation tissue
      formation. Patch reconstruction using pericardium or synthetic material decreases
      the incidence of stenosis. The authors report on the use of the ascending aorta
      cryopreserved homograft in reconstructing the tracheobronchial tree of three
      children. RESULTS: A 10 year old had a through-and-through gun shot wound to the
      left main stem bronchus with cartilaginous loss. A 12 year old double lung
      transplant recipient had a breakdown of one bronchial anastomosis after stent
      placement. A 1 year old had an acquired tracheoesophageal fistula secondary to a
      long standing foreign body. In all three patients, the aortic patches were
      secured with interrupted sutures. All three had uneventful recoveries, and
      postoperative bronchoscopy showed the patches to be completely covered with
      epithelium without stenosis or granulation tissue. CONCLUSIONS: This is the first
      report of the use of the cryopreserved ascending aorta homograft in the
      reconstruction of the tracheobronchial tree. The homograft is strong yet
      malleable. It gets completely covered with epithelium and results in no stenosis
      because of the lack of tension. These characteristics make it an attractive
      alternative for the patch reconstruction of complex tracheobronchial tree
      injuries.

PMID- 10359202
TI  - Transabdominal oxygenation using perfluorocarbons.
AB  - PURPOSE: Evaluation of the intraabdominal (intraperitoneal and intraluminal)
      administration of oxygen-saturated perfluorocarbon on both portal and arterial
      blood oxygenation. METHODS: Eight male rabbits were divided into the test (n = 5)
      and control (n = 3) groups. Each underwent intrajejunal, intraperitoneal, and
      intravascular (artery, portal vein) catheter placements along with ligation of
      the duodenum and the terminal ileum under general anesthesia. The test group
      received oxygen-saturated perfluorotripropylamine (FTPA), and the control group
      received oxygen desaturated FTPA. The oxygen delivery was assessed by serial
      blood gas measurements before and after the administration of FTPA. RESULTS: The
      administration of oxygen-saturated FTPA significantly increased the partial
      pressure of oxygen within both the arterial and the portal venous blood (PaO2,
      PpVO2) without significant changes in PCO2 values. Oxygen desaturated FTPA failed
      to show any effects on blood gas values. Compared with oxygen desaturated FTPA,
      oxygen-saturated FTPA increased PaO2, PpVO2, and oxygen saturation (artery,
      portal vein) significantly at some, but not all of the time-points measured.
      CONCLUSIONS: The intraabdominal administration of saturated FTPA improved both
      the portal venous and the arterial oxygenation. This new mode of oxygenation may
      be helpful as an adjunct to conventional oxygen delivery systems.

PMID- 10359203
TI  - Neuroblastoma regression and immunity induced by transgenic expression of
      interleukin-12.
AB  - PURPOSE: Interleukin-12 (IL-12) is a cytokine with potent antitumor effects. The
      authors sought to assess its capacity to increase tumor immunogenicity when
      expressed by tumor cells in a murine model of neuroblastoma. METHODS: Syngeneic
      A/J mice were inoculated subcutaneously with 2 x 10(6) cells from a murine
      neuroblastoma-derived cell line (neuro-2a). In situ transduction of the
      neuroblastoma cells was achieved by intratumoral injection of an adenoviral
      vector encoding both subunits of the murine IL-12 heterodimer. Growth of the IL
      12 gene-modified tumor cells was compared with untreated neuro-2a cells. Tumor
      immunity was assessed by rechallenging mice that had rejected their tumor with
      unmodified neuroblastoma cells. The contribution of cytotoxic T lymphocytes
      (CTLs) was evaluated through cytotoxicity assays. RESULTS: Eighteen (72%) of 25
      tumor-bearing mice treated with the mlL-12 adenoviral vector exhibited tumor
      regression, with 12 mice (48%) completely rejecting their tumors over 2 to 3
      weeks. None of the mice that had rejected their tumor and were rechallenged with
      unmodified neuro-2a cells subsequently developed new tumors. Pooled splenocytes
      from mice rejecting their tumors showed significant tumor killing (>20%
      cytolysis) in vitro in 51Cr release assays. CONCLUSIONS: Adenoviral-mediated IL
      12 expression by tumor cells in a murine neuroblastoma model produced a
      significant antitumor response. Most treated tumors demonstrated at least
      transient regression, whereas many completely regressed. Cured mice exhibited
      protective immunity and CTL activity against the tumor. These data confirm the
      immunomodulatory efficacy of IL-12 as part of a vaccine-based antineuroblastoma
      strategy.

PMID- 10359204
TI  - Evidence-based practice in pediatric surgery.
AB  - BACKGROUND/PURPOSE: The current medical environment demands the provision of
      quality healthcare at an affordable cost. Both payors and regulators are
      committed to lowering cost through initiation of best practice strategies that
      include practice guidelines, clinical pathways, and standards of care. The only
      practical way to join this debate is through the use of objective, unbiased
      clinical data. This study was undertaken to review the current state of the
      pediatric surgery literature and its value in determining best clinical practice.
      METHODS: The National Library of Medicine Medline database was accessed using the
      Ovid Internet client software. All references, abstracts, and keyword indexes
      from the core pediatric surgery literature, the Journal of Pediatric Surgery, the
      European Journal of Pediatric Surgery, Pediatric Surgery International,
      Zeitschrift fur Kinderchirurgie, and Seminars in Pediatric Surgery were
      downloaded and reviewed. Search criteria were defined to identify prospective,
      randomized, controlled studies. References were then categorized as case reports;
      retrospective case series; prospective case series; randomized, controlled
      studies; laboratory studies; review articles; or miscellaneous studies. RESULTS:
      As of March 1, 1998, there are 9,373 references, excluding citations of letters
      or comments, contained in the core pediatric surgery literature, as provided
      through Medline. Of these, 485 were identified as studies for review, possible
      prospective case series or prospective, randomized, controlled studies. After
      review, 34 studies (0.3%) were classified as prospective, randomized, controlled
      studies, whereas 139 (1.48%) were classified as prospective studies. There were
      3,241 (34.6%) case reports, 5,619 (59.9%) retrospective case series, 1,109
      (11.8%) laboratory studies, 195 (2.1%) review articles, and 36 (0.3%)
      miscellaneous studies that did not fit into other categories. When analyzed by
      decade of publication, prospective studies and prospective, randomized,
      controlled studies (n = 173) numbered 103 in the 1990s, 63 in the 1980s, and
      seven in the 1970s. CONCLUSIONS: There is a paucity of scientifically rigorous
      data on which to base clinical practice in pediatric surgery. The increasing
      numbers of prospective, case-controlled studies or the more sound prospective,
      randomized, controlled trials in the 1990s suggests that pediatric surgeons are
      aware of the need to generate unbiased data to support current clinical practice
      and the development of practice guidelines. Limitations exist in conducting
      prospective, randomized, controlled trials because of the rare nature of many
      pediatric surgical conditions and the lack of clinical "equipoise" over available
      treatment options. The authors encourage the use of multiinstitutional trials and
      the prospective, randomized, controlled study methodology to develop data that
      can be used to guide clinical practice in our evolving healthcare environment.

PMID- 10359205
TI  - Autologous lymphocyte responses to adenovirus-B7-1-transduced human cancer cells.
AB  - Transfection of the costimulatory molecule B7-1 (CD80) into murine tumors can
      increase antitumor immunity and eradicate tumor growth. The purpose of this study
      was to test autologous lymphocyte responses against freshly resected human
      cancers infected in vitro with an adenovirus vector expressing the B7-1 molecule
      (AdB7). Resected tumors (sarcomas, adenocarcinomas, melanomas, and multiple
      myelomas) were disaggregated into single-cell suspensions and divided into three
      groups: (a) native, noninfected tumor cells (TM); (b) AdB7-infected, B7-1(+)
      tumor cells (TMB7); and (c) control Addl70.3-infected, B7-1(-) tumor cells
      (TMAd). B7-1 expression was verified by flow cytometry. Autologous peripheral
      blood lymphocytes from these patients were tested for proliferative and cytotoxic
      activity against the three tumor groups. There was an increased lymphocyte
      proliferative response against B7-1(+) tumor cells, particularly in the presence
      of interleukin-12 (IL-12) or low-dose IL-2. B7-1(+) tumor cells were also killed
      more efficiently than B7-1(-) tumor cells in natural killer cell-mediated
      cytotoxicity assays, and this was most significant when lymphocytes had been
      pretreated with IL-12. Human natural killer cells were found to express CD28, a
      receptor for B7-1. The high efficiency of AdB7-mediated gene transfer and the
      augmented B7-1-mediated lymphocyte responses suggest that AdB7 vectors may be
      effective in human cancer immunotherapy.

PMID- 10359207
TI  - Evaluation of cellular immune responses in rhesus monkeys subjected to adenovirus
      mediated gene transfer into the cervix.
AB  - We reported previously that direct injection of a recombinant adenovirus (rAd),
      Ad5CMV-beta-gal, into the cervix of the rhesus monkey resulted in efficient beta
      galactosidase expression in the cervix within 3 days. In these studies, we also
      observed the induction of anti-adenovirus (Ad)-specific immunoglobulin G
      responses after 22 days. In the continuation of evaluating the anti-Ad-specific
      immune responses resulting from this approach of gene targeting to the cervix, we
      measured the cellular immune responses. The introduction of Ad5CMV-beta-gal into
      the cervix by direct injection, but not by the abrasion technique, resulted in
      the induction of strong proliferative responses against extracts of cells
      infected with Ad5CMV-beta-gal but not against control uninfected cells. These
      responses were initially detected at 22 days postinjection and coincided with the
      abrogation of transgene expression. Significant levels of proliferative responses
      were maintained for < or =83 days. Multiple injections of rAds had no significant
      enhancing effect on either the level or longevity of the proliferative responses.
      At 3 days after the injection of Ad5CMV-beta-gal, when the transgene expression
      in the cervix was clearly evident, proliferative responses against the rAd were
      not detectable. However, the production of low but significant amounts of
      interleukin-10, a cytokine characteristic of T helper type 2 responses that
      promote humoral immune responses, was observed at the 3-day point in these
      animals. These results suggest that significant differences exist between the
      kinetics of transgene expression and the priming of specific host immune
      responses, and that these differences may be important for devising alternate
      strategies to improve techniques for Ad-mediated gene therapy of cervical cancer.

PMID- 10359206
TI  - Specific membrane receptor gene expression targeted with radiolabeled peptide
      employing the erbB-2 and DF3 promoter elements in adenoviral vectors.
AB  - Radioimmunotherapy is limited by a variety of factors, including poor tumor
      penetration of monoclonal antibodies and low levels of intratumoral antigen
      expression. To address these limitations, a gene therapy strategy was devised to
      genetically induce tumor cells to express enhanced levels of membrane receptors
      with high affinity for a radiolabeled peptide. We designated this approach as
      genetic radioisotope targeting strategy. To this end, an adenoviral vector
      (AdCMVGRPr) encoding the murine gastrin-releasing peptide receptor (GRPr) was
      used to achieve a high level of binding of radiolabeled bombesin (BBN). To
      achieve genetic induction of membrane GRPr specifically to tumor cells, we
      constructed two adenoviral vectors encoding the GRPr gene under the control of
      the tumor-specific regulatory elements, DF3 (AdDF3GRPr) or erbB-2 (AderbGRPr). We
      investigated the binding of [125I]BBN to the GRPr following infection with
      AdDF3GRPr and AderbGRPr in a panel of human breast, pancreatic, and
      cholangiocarcinoma tumor cell lines. [125I]BBN binding and GRPr expression
      increased with increasing multiplicities of infection of AdCMVGRPr in all of the
      cell lines tested. Breast cancer cell lines expressing erbB-2 showed significant
      GRPr expression using AderbGRPr. A similar result was observed in breast and
      cholangiocarcinoma cells infected with AdDF3GRPr expressing MUC1 as detected by
      immunohistochemistry but was not seen in the pancreatic cell lines tested. Thus,
      adenoviral vectors with tissue-specific promoter elements can be used to achieve
      a selective expression of membrane receptors that can be targeted with a
      radiolabeled peptide. The use of such a transcriptional targeting approach may
      restrict gene expression to tumors and limit the radiation dose deposited in
      normal tissues in vivo.

PMID- 10359208
TI  - Interleukin-12 requires initial CD80-mediated T-cell activation to support immune
      responses toward human breast and ovarian carcinoma.
AB  - One possible reason for the poor immunogenicity of tumors is the induction of
      peripheral tolerance by tumor cells that fail to deliver costimulatory signals.
      Furthermore, T cells stimulated with wild-type tumor cells often fail to secrete
      cytokines. The present study has been undertaken to identify cytokines that
      cooperate with CD80 in T-cell activation in vitro toward human breast and ovarian
      carcinoma cell lines. Tumor cell-mediated T-lymphocyte activation was analyzed
      directly in allogeneic mixed lymphocyte/tumor cell cultures as proliferation and
      effector functions were assessed in cytotoxic T-cell assays. Interleukin-7 (IL-7)
      amplified the proliferative response toward CD80-transfected breast and ovarian
      carcinomas and stimulated predominantly CD4+ T lymphocytes. IL-12 represses the
      proliferative response of naive T cells but cooperates with CD80-mediated
      activation during secondary stimulations. In long-term T-cell cultures, IL-12
      synergizes with CD80 expression to stimulate cytolytic CD8+ T-cell lines, which
      recognize a breast carcinoma line in a human histocompatibility leukocyte antigen
      restricted manner. These studies illustrate that costimulation is necessary for
      tumor cells to function as alloantigen-presenting cells. Furthermore, when added
      after the priming of T cells with CD80-transfected tumor cells, IL-12 could be
      helpful in propagating sufficient T-cell numbers to be used in adoptive transfers
      during cellular immunotherapy.

PMID- 10359209
TI  - Antigen gene transfer to cultured human dendritic cells using recombinant
      avipoxvirus vectors.
AB  - Advances in understanding the role of dendritic cells (DCs) as the major antigen
      (Ag)-presenting cell type of the immune system combined with the recent
      development of methods for the ex vivo expansion of human DCs have opened the
      possibility for the transfer of tumor Ags to DCs with a view toward tumor
      immunotherapy. In this study, we examined the feasibility of Ag transfer to
      cultured human DCs using the host range-restricted avipoxvirus, fowlpoxvirus
      (FWPV). FWPV was found to infect and express a lacZ marker gene in a number of
      mammalian cell lines of fibroblastic, epithelial, and hemopoietic lineage
      origins. LacZ recombinant FWPV (rFWPV) was found subsequently to infect human DCs
      that had been cultured ex vivo from peripheral blood monocytes. Using rFWPV
      containing lacZ under the control of a vaccinia virus (VV) early/late promoter
      (p7.5K) and a 10 plaque-forming units per cell multiplicity of infection, >80% of
      cells expressed the lacZ marker gene. Quantitative analysis showed that the level
      of expression continued to rise for 5 days postinfection, at which point the
      experiments were terminated. Replication-competent recombinant VV (rVV) was also
      shown to be capable of transferring the marker gene to primary DC cultures.
      However, neither rFWPV nor rVV were able to express transgenes under the control
      of late viral promoters, indicating that both rFWPV and rVV infections are
      arrested at an early stage in human DCs. Infection of CD83 + DCs by rFWPV was
      confirmed by double-staining cytochemistry. We conclude that host range
      restricted FWPV can be used efficiently to transfer Ag genes to human DCs ex vivo
      and may have a role in the development of tumor immunotherapy protocols.

PMID- 10359211
TI  - An effective strategy of human tumor vaccine modification by coupling bispecific
      costimulatory molecules.
AB  - A new, generally applicable procedure is described for the introduction of
      defined costimulatory molecules into human cancer cells to increase their T-cell
      stimulatory capacity. The procedure involves infection with Newcastle disease
      virus to mediate the cell surface binding of costimulatory molecules (e.g.,
      specially designed bispecific antibodies (bsAb)). The modification is independent
      of tumor cell proliferation and laborious recombinant gene technology and can be
      applied directly to freshly isolated and gamma-irradiated patient-derived tumor
      cells as an autologous cancer vaccine. Following the infection of tumor cells
      with a nonvirulent strain of Newcastle disease virus, the cells are washed and
      then further modified by coincubation with bsAbs, which attach with one arm to
      the viral hemagglutinin-neuraminidase (HN) molecule on the infected tumor cells.
      The second specificity of one bsAb (bs HN x CD28) is directed against CD28 to
      augment antitumor T-cell responses by selectively channeling positive
      costimulatory signals via the CD28 pathway. A second bsAb (bs HN x CD3) was
      produced to deliver T-cell receptor-mediated signals either alone (bsCD3 vaccine)
      or in combination with anti-CD28 (bsCD3 vaccine plus bsCD28 vaccine). In human T
      cell stimulation studies in vitro, the bsCD28 vaccine caused an up-regulation of
      early (CD69) and late (CD25) T-cell activation markers on CD4 and CD8 T
      lymphocytes from either normal healthy donors or cancer patients (autologous
      system) and induced tumor cytostasis in nonmodified bystander tumor cells. In
      addition, in combination with the bsCD3 vaccine, augmented antitumor cytotoxicity
      and T-cell proliferative responses were observed. This tumor vaccine modification
      procedure is highly specific, quick, economic, and has a broad range of clinical
      applications.

PMID- 10359210
TI  - Murine interferon-alpha1 gene-transduced ESb tumor cells are rejected by host
      mediated mechanisms despite resistance of the parental tumor to interferon
      alpha/beta therapy.
AB  - The highly metastatic ESb tumor is totally resistant to murine interferon
      alpha/beta (IFN-alpha/beta) therapy, regardless of the number of cells injected
      or the route of inoculation. In contrast, as we show herein, mouse IFN-alpha1
      transduced ESb tumor cells were inhibited markedly when injected subcutaneously
      into immunocompetent mice. IFN-producing ESb tumor rejection was mediated by the
      immune system, because these tumor cells grew normally in immunosuppressed mice.
      Tumor regression was accompanied by extensive necrosis and cellular infiltrates
      in the tumor area. These results further support the use of IFN-alpha in cytokine
      gene therapy of cancer and suggest the advantage of using gene transfer rather
      than cytokine administration to enhance an antitumor immune response.

PMID- 10359212
TI  - Selection of a high activity ribozyme against cytostatic drug resistance
      associated glypican-3 using an in vitro assay containing total tumor RNA.
AB  - We tested 11 hammerhead ribozymes for their ability to bind and cleave RNA
      transcripts of the cytostatic drug resistance-associated glypican-3-encoding gene
      (GPC3, MXR7, OCI-5). To select the optimum target sequence, the activity of each
      hammerhead ribozyme was tested in a short in vitro assay using truncated RNA
      substrates without time-consuming cloning procedures. Glypican-3-derived RNA was
      cleaved effectively by 3 of 11 hammerhead ribozymes. One of these, the hammerhead
      ribozyme Rz967, recognized the GUC sequence at nucleotides +965 to +967 of the
      open reading frame of the glypican-3-encoding mRNA. Rz967 cleaved in vitro
      transcribed fragments derived from glypican-3 mRNA (nucleotides +803 to +1036)
      most efficiently. Cleavage efficiency was confirmed by a rapid in vitro assay
      using full-length total tumor cell RNA. We were able to demonstrate that this new
      in vitro assay is suitable for the selection of hammerhead ribozymes that have
      the capability to cleave glypican-3-encoding mRNA in human tumors.

PMID- 10359213
TI  - Gene therapy study of cytokine-transfected xenogeneic cells (Vero-interleukin-2)
      in patients with metastatic solid tumors.
AB  - On the basis of compelling preclinical data in cats and dogs, we initiated a
      clinical gene therapy study in nine patients with advanced solid tumors using
      xenogeneic fibroblasts secreting human interleukin (IL)-2 (Vero-IL-2 cells).
      Cohorts of three successive patients with tumors accessible to computed
      tomography- or ultrasound-guided injection were treated repeatedly with 5 x
      10(5), 5 x 10(6), or 5 x 10(7) Vero-IL-2 cells. The endpoints of the study were
      feasibility, toxicity, and the clinical and biological effects of this novel
      approach to immunotherapy of cancer. Histopathological, immunological, and
      molecular analyses were performed on biopsy specimens of tumors and blood samples
      before, during, and after treatment. Treatment was well tolerated, and toxicity
      consisted of transient fever in one patient and short-lived, mild itching and
      erythema in two others. One patient with soft-tissue sarcoma showed a reduction
      of >90% and >50% of the volume of two distant, noninjected metastases, lasting
      for 29+ and 26 months, respectively. Four other patients showed stabilization of
      their disease for 3-9 months; of these patients, one with melanoma developed
      marked vitiligo. We conclude that repeated injections of < or =5 x 10(7) Vero-IL
      2 cells are feasible and safe in heavily pretreated patients with advanced solid
      tumors. An additional evaluation of an intratumoral application of Vero-IL-2
      seems warranted.

PMID- 10359215
TI  - Primary socialization theory. Developmental stages, spirituality, government
      institutions, sensation seeking, and theoretical implications. V.
AB  - This fifth and final paper in the series on primary socialization theory includes
      discussion of issues raised by participants in a forum on the theory. The theory
      states that drug use and deviant behaviors occur as an outcome of bonding with
      primary socialization sources and the transmission of norms through those
      sources. Personal traits and secondary socialization sources influence drug use
      and deviance indirectly and through their effects on the primary socialization
      process. Developmentally, the only primary socialization source for the preschool
      child is the family. In early grade school years, the primary socialization
      sources are the family and school. Peer clusters emerge as a primary
      socialization source later, with their greatest effect occurring during
      adolescence. Adults have varied primary socialization patterns. Levels of ego
      development among adults may alter the primary socialization process.
      Spirituality is defined, and its influence on drug use is discussed. Government
      institutions, such as the criminal justice system, welfare, and child protective
      services, are now included among secondary socialization sources. The fact that
      the general theory of primary socialization is not ethnocentric or temporocentric
      is discussed. Implications of the theory for understanding existing or potential
      risk and protective factors for deviance, and for improving the effectiveness of
      prevention and treatment are discussed. [Translations are provided in the
      International Abstracts Section of this issue.]

PMID- 10359214
TI  - Potential of CD80-transfected human breast carcinoma cells to induce peptide
      specific T lymphocytes in an allogeneic human histocompatibility leukocyte
      antigens (HLA)-A2.1+-matched situation.
AB  - Allogeneic human histocompatibility leukocyte antigen (HLA)-matched tumor cell
      lines that have been made immunogenic by the transfer of genes encoding for
      costimulatory molecules such as CD80 are considered to be potential vaccines for
      the induction of systemic immune reactions in cancer patients. We used a human
      HLA-A2.1+ CD80-transfected breast carcinoma cell line (KS-CD80) and investigated
      in vitro the efficiency at which antigen (Ag)-specific responses were induced
      following the stimulation of allogeneic HLA-A2.1-matched T lymphocytes. The
      influenza matrix protein M1 was used as a model Ag. It was either endogenously
      expressed or exogenously loaded as a peptide (matrix protein), and the frequency
      of the generated specific T cells was determined. The expression of CD80 in KS
      cells was required for an effective activation and expansion of Ag-specific T
      cells. This response was augmented following the pretreatment of KS-CD80 cells
      with interferon-gamma and tumor necrosis factor-alpha. Interleukin-4 (IL-4), IL
      7, and IL-12 further increased T-cell expansion. IL-7 was best at supporting the
      generation of T cells with Ag specificity. This investigation demonstrates that
      allogeneic CD80+ tumor cells can induce Ag-specific, HLA-restricted T lymphocytes
      at a high frequency. Our study supports the use of allogeneic cell lines for the
      induction of specific T-cell responses in tumor patients.

PMID- 10359216
TI  - Primary socialization theory and a bio/psycho/social/spiritual practice model for
      substance use.
AB  - This article supports primary socialization theory as a theory for practitioners
      to use in drug-user treatment and prevention interventions. Primary socialization
      theory is compatible with the bio/psycho/social/spiritual practice model and
      targeting the individual within his or her etiological domains/situation to
      initiate specific interventions. Governmental institutions are posited as an
      additional secondary socialization factor for primary socialization theory.
      Gender is stressed as important for primary socialization theory and is
      emphasized for carrying out interventions. [Translations are provided in the
      International Abstracts Section of this issue.]

PMID- 10359217
TI  - A complementary perspective to primary socialization theory.
AB  - Primary socialization theory as formulated by Oetting and his associates
      emphasizes the transmission of societal norms during childhood and adolescence
      within society's three major socializing agencies: family, school, and small,
      intimate peer groups. The norms thus transmitted may be prosocial or deviant,
      with prosocial norms more likely to be transmitted through strong bonds to
      healthy families or schools. Personality traits and other personal
      characteristics influence negative outcomes, such as deviance or drug use, only
      to the extent that they interfere with socialization to family or school. Our own
      research does not address primary socialization theory directly in that we have
      not focused on the transmission of norms per se as central. Nevertheless, we have
      studied social factors, personality factors, and various psychopathologies as
      etiological for deviance and substance use. By and large our research has
      supported the hypotheses of primary socialization theory, even extending them in
      specific areas, such as the importance of family influences as etiological. Our
      work has also emphasized the significance of rebelliousness and impulse control
      in this regard. Like all large-scale theories which necessarily abstract from the
      totality and diversity of human behavior, primary socialization theory leaves
      some gaps requiring further elucidation. Among these is its ethnocentric and
      temporocentric perspective, but even within this perspective it understates the
      difficulties for adolescents in making a successful transition to adult social
      roles (Kingley Davis) and in establishing a unique identity independent of
      parents (Erik H. Erikson). Also, it generally ignores the salience of the youth
      culture as rebellious against the older generation, a particularly important
      characteristic of modern society. And finally, it should cover the process of
      "maturing out" of deviance, which perhaps results in a reaffirmation of the
      legitimacy of norms transmitted earlier, and it should also cover gender
      differences in their transmission and legitimization. Nevertheless, despite these
      caveats and especially because of this theory's insightfulness and path-breaking
      character, its hypotheses should be tested in carefully designed, large-scale
      studies. These studies should allow, among other factors, measurement of the
      effects of genetic factors on the early emergence of deviant personality
      attributes and of their impact on the transmission of prosocial norms.
      [Translations are provided in the International Abstracts Section of this issue.]

PMID- 10359218
TI  - Primary socialization theory: comments on racism, sexism, generational neglect,
      abuse, and abandonment.
AB  - This article asks whether primary socialization theory adequately deals with the
      most distressed and disadvantaged members of society, whether for most of them
      the family, school, and peers are the primary sources of socialization. Children
      who are subjected to the effects of racism, sexism, physical and mental abuse,
      inferior dangerous schools, and abandonment to foster care from birth may find
      other sources of primary socialization which can be either negative and positive.
      "Nihilism" and "anomie" are used to describe such children's position in their
      societies, and the article asks if those without benefit of the three primary
      sources of socialization can find ways to create new and positive norms, or
      whether they are doomed to lives of hopelessness and deviance. [Translations are
      provided in the International Abstracts Section of this issue.]

PMID- 10359219
TI  - Peer networks and sensation seeking: some implications for primary socialization
      theory.
AB  - This article draws on recent work in sensation seeking and peer influences in
      drug use prevention and considers some possible implications for primary
      socialization theory. A particular point of focus is a postulate of the theory
      that an individual's personal characteristics and personality traits do not
      directly relate to drug use and deviance but ordinarily influence those outcomes
      only when they affect interactions between the individual and the primary
      socialization sources. The article suggests a more broadly encompassing
      perspective which holds that socialization learning through the primary
      socialization sources gives people's lives direction; it may be the tugs of
      activation needs which provide impetus for the actions. The authors cite a recent
      study in which they developed a structural equation model of influence of
      individual and peer variables on later alcohol and marijuana use. The model
      indicates an indirect route from individual sensation seeking through peers to
      drug and alcohol use, with adolescents picking persons of similar sensation
      seeking levels, and the sensation-seeking level of these peers tending to
      influence alcohol and marijuana use. Although previous studies have suggested
      causal relationships between sensation seeking and drug use and between peer
      influence and drug use, the findings in this study suggest that the actual
      process involves both. [Translations are provided in the International Abstracts
      Section of this issue.]

PMID- 10359220
TI  - Primary socialization theory: it all begins with the family.
AB  - This commentary is a discussion of primary socialization theory emphasizing the
      centrality of family processes on adolescents' affiliation with deviant peers and
      subsequent deviant behaviors. The focus of the discussion is the persistent
      influence of family processes well into adolescence. An empirical model
      illustrating these processes is presented. The model is based on a sample of 257
      runaway adolescents and indicates that the effects of an abusive family on
      adolescent behaviors are largely transmitted via affiliation with deviant peers.
      The author concludes that primary socialization theory would be strengthened by
      greater emphasis on the persistent influence of family on adolescent behaviors.
      Implications for family-based prevention programs are discussed. [Translations
      are provided in the International Abstracts Section of this issue.]

PMID- 10359221
TI  - Media and primary socialization theory.
AB  - This article discusses the role of media in the socialization process of
      adolescents, and supports the theory of primary socialization which identifies
      media as a secondary factor in the socialization process (as described in other
      articles in this series). Additionally, several models of information processing
      are presented which offer both a cognitive and affective model of processing
      communications. Finally, the article points to the need for future research to
      analyze the cases and implications of media's impact on adolescents when media
      serve as a primary, rather than a secondary, source of socialization.
      [Translations are provided in the International Abstracts Section of this issue.]

PMID- 10359222
TI  - Ethnic and gender differences and similarities in adolescent drug use and
      refusals of drug offers.
AB  - This paper examines the relationship among ethnicity, gender, drug use, and
      resistance to drug offers among a sample of 2,622 African American, Mexican
      American, and White American seventh graders. A number of similarities were
      noted. First, these adolescents did not seem to possess large or sophisticated
      repertoires of offer resistance strategies. Second, most offers came from
      acquaintances in contrast to more intimate offers among older youths. Ethnic and
      gender differences were also noted. Ethnicity had significant effects on use and
      the offer process. Mexican Americans received more offers, used more drugs, and
      were more likely to be offered drugs by peer family members and at parties.
      European Americans were more likely to receive drug offers from acquaintances and
      at friends' homes and on the street. African Americans were more likely to
      receive offers from dating partners and parents, and in the park, and were more
      likely to resist offers of drugs-using explanations. Gender significantly
      affected drug offers and types of offers. Males were more at risk for offers and
      use at a younger age. Offers of drugs to males were more likely to come from
      parents or other males, while offers to females were more likely to come from
      other females or dating partners. Males also were more likely to receive drug
      offers that appeal to their social standing or self-image while females received
      either simple offers or those that minimize effects. Finally, offers of drugs to
      males were more likely to be made in public, while those to females were more
      likely to occur in private. Cultural explanations are offered for these findings.

PMID- 10359223
TI  - Drinking patterns and attitudes toward drinking in the late-middle-aged.
AB  - The main objective of this study was to gain insight into attitudes toward
      drinking, drinking patterns and the relationship between attitudes and drinking
      patterns in the population in the age range 55 to 69. Respondents over 55 years
      of age were compared to those below 55. The former ones were more likely to be
      abstainers and less tolerant toward others' drinking. Being tolerant toward
      others' drinking was negatively associated with abstaining from alcohol. Some
      differences were observed between being tolerant toward drinking patterns of men,
      women, or relatives, and own drinking behavior.

PMID- 10359224
TI  - The subjective experience of craving: an exploratory analysis.
AB  - Craving is a motivational state associated with a variety of addictive behaviors.
      To date no studies have systematically asked substance misusers to describe their
      subjective experience of craving. The aim of the present study was to examine the
      common themes found in descriptions of craving and the situations that give rise
      to the experience of craving in a sample of substance misusers (N = 23). Analyses
      of the interview text revealed that the subjective experience of craving is
      heterogeneous. Eight dimensions were found to be associated with the subjective
      experience of craving: specificity, strength, positive outcomes, behavioral
      intention, thoughts, physical symptoms, affect, and cues. Individual differences
      in the extent to which each of these dimensions is experienced across substance
      misusers was evident in the interview text. Implications of these results for the
      development of a multivariate theory of craving are discussed.

PMID- 10359225
TI  - The heroin/cocaine epidemic in Switzerland 1979-1997: a mathematical analysis of
      law enforcement data.
AB  - The Swiss registry of charges concerning illegal trade and consumption of
      narcotics makes a distinction between first and subsequent charges as well as
      between several types of illegal drugs. It has been previously shown by using a
      mathematical model that changes in incidence of illegal drug use can be inferred
      from the time series of two indicators which are calculated from the numbers of
      first and subsequent charges. This method of data analysis is now refined in
      order to monitor the incidence of heroin/cocaine use. The conclusion is that
      2,500 persons per year may have entered the population of habitual heroin/cocaine
      users in the early 1980s, and about 10,000 each year in 1991-93. After 1993,
      however, the incidence of heroin/cocaine use declined rapidly.

PMID- 10359226
TI  - Gender differences at admission and follow-up in a sample of methadone
      maintenance clients.
AB  - Although one-third of clients enrolled in methadone treatment in the United
      States are female, few studies have looked at gender differences at admission and
      follow-up. Using interview data from 435 clients (31% female) collected at
      admission and approximately 1 year after discharge, females were found to have
      more dysfunctional families of origin and greater prior and current psychological
      and medical problems. Both genders improved following treatment, as evidenced by
      reduced illicit drug, tobacco, and alcohol use, criminal involvement, and
      HIV/AIDS-risky behaviors. Females were more likely to seek further help for both
      drug misuse and psychological problems subsequent to discharge.

PMID- 10359227
TI  - Gambling and risk-taking behavior among university students.
AB  - The present study examines the relationships between risk taking, sensation
      seeking, and level of gambling involvement. The intent of this research was to
      investigate whether risk taking and/or sensation seeking are determinants in
      distinguishing pathological gamblers from problem gamblers and whether risk
      taking and gambling behavior for a university population are positively
      correlated for both males and females. Results indicated that the Risk-Taking
      Questionnaire (RTQ), the Arnett Inventory of Sensation Seeking (AISS), and the
      Sensation Seeking Scale (SSS) distinguished between probable/pathological
      gamblers and nonproblem gamblers with probable/pathological gamblers scoring the
      highest on each measure. However, the RTQ was the only measure able to
      distinguish probable/pathological gamblers from gamblers experiencing some
      problems relating to their gambling behavior. Females encountering some problems
      resulting from their gambling behavior consistently reported higher risk-taking
      and sensation seeking scores than males with no gambling problems. Results
      indicate that excessive gamblers are significantly greater risk takers than
      social gamblers, a finding which could prove useful in advising treatment
      regimens.

PMID- 10359228
TI  - Substance use by Spanish university students.
AB  - The major studies investigating substance use among Spanish university students
      are reviewed, their results and limitations noted, and current and future
      substance use trends are discussed.

PMID- 10359229
TI  - Lemon juice as a solvent for heroin in Spain.
AB  - Preliminary observations and responses to interviews in Valencia, Spain reveal
      that injecting drug users (IDUs) dissolve heroin before injection with two or
      three drops of lemon juice. Solution in lemon juice makes heating of heroin in
      water unnecessary. This pattern apparently developed spontaneously in Spain, but
      is almost unknown elsewhere in the world. Its implications for IDUs' health
      remain speculative, but use of lemon juice to dissolve heroin for injection
      deserves further scientific study.

PMID- 10359230
TI  - The role of epidemiology in developing nutritional recommendations: past,
      present, and future.
AB  - Observations of the relations between food choices and health have been made
      since ancient times, but epidemiology, which can be regarded as the science of
      systematically studying these relations, has played a key role in official
      nutritional guidance only in recent years. In the past 20 y the principal goal of
      nutritional guidance has changed from the prevention of nutritional deficiencies
      to the prevention of chronic diseases. This evolving purpose of nutritional
      guidance has demanded that nutritional epidemiology play an increasingly
      important role. Although no other type of nutritional science can equal
      epidemiology in the relevance of either the dietary exposures or the health
      outcomes, substantial problems limit the ability of nutritional epidemiology to
      convincingly prove causal associations. The classic criteria for causation are
      often not met by nutritional epidemiologic studies, in large part because many
      dietary factors are weak and do not show linear dose-response relations with
      disease risk within the range of exposures common in the population. The most
      important problem in nutritional epidemiology in the past has been the inaccuracy
      of dietary assessment. In the future, an additional problem will be the
      proliferation of hypotheses that can be tested in multiple ways among the many
      subgroups of the population that can be defined by factors such as age, sex, and
      genotype. Future progress in our understanding of the relations between diet and
      health will necessitate improved methods in nutritional epidemiology and a better
      integration of epidemiologic methods with those used in the clinical nutritional
      sciences.

PMID- 10359231
TI  - Causal criteria in nutritional epidemiology.
AB  - Making nutrition recommendations involves complex judgments about the balance
      between benefits and risks associated with a nutrient or food. Causal criteria
      are central features of such judgments but are not sufficient. Other scientific
      considerations include study designs, statistical tests, bias, confounding, and
      measurement issues. At a minimum, the set of criteria includes consistency,
      strength of association, dose response, plausibility, and temporality. The
      current practice, methods, and theory of causal inference permit flexibility in
      the choice of criteria, their relative priority, and the rules of inference
      assigned to them. Our approach is as follows. Consistency across study designs is
      compelling when the studies are of high quality and are not subject to biases. A
      statistically significant risk estimate with a > 20% increase or decrease in risk
      is considered a positive finding. A statistically significant linear or otherwise
      regularly increasing trend reinforces the judgment in favor of a recommendation.
      A plausible hypothesis likewise reinforces a recommendation, although the rules
      of inference for biological evidence are highly variable and depend on the
      situation. Temporality is, for nutrition recommendations, more a consideration of
      the extent to which a dietary factor affects disease onset or progression.
      Evidence supporting these criteria provides a strong basis for making a nutrition
      recommendation, given due consideration of the balance between presumed benefits
      and presumed harms. Recommendations should make clear their breadth of
      application; a narrow recommendation involves a single disease or condition
      whereas a broad recommendation involves all relevant diseases or conditions.

PMID- 10359232
TI  - Study design and hypothesis testing: issues in the evaluation of evidence from
      research in nutritional epidemiology.
AB  - In addressing questions about the relations of dietary factors to disease in
      human populations, epidemiologic studies must account for the complexity of
      dietary habits, the intercorrelations among dietary habits, and the correlations
      of those habits with other behaviors. Furthermore, for studies of chronic
      disease, relevant dietary exposures may occur over decades. The classic
      epidemiologic study designs have been used to examine the associations between
      diet and disease; the strengths and weaknesses of those designs must be
      considered. Concerns have been raised regarding the validity of the measures of
      diet, the differential recall of diet by diseased individuals in case-control
      studies, and confounding by other related factors in both case-control and cohort
      studies. In clinical trials there may be difficulties in effecting the necessary
      dietary changes, especially for macronutrients, and there are also concerns about
      those circumstances in which participants cannot be blinded to their treatment.
      For case-control and cohort studies and for some clinical trials,
      intercorrelations among nutrients are a concern in the identification of factors
      that are important in the etiology of disease. It is important to understand
      these considerations when interpreting nutritional epidemiologic studies for the
      purpose of setting public policy. No one study can be considered definitive in
      the understanding of a diet-disease relation. However, epidemiologic findings
      from multiple studies taken together can contribute significantly to our
      understanding of diet in relation to disease in humans.

PMID- 10359233
TI  - Vitamin E and heart disease: a case study.
AB  - The role of nutritional epidemiology studies in the development of nutritional
      recommendations has been controversial, in part because individual studies
      supporting either side of a given issue can often be identified. Several sets of
      criteria for inference of a causal relation between a dietary factor and a
      disease from epidemiologic studies have been suggested. One such set is that of
      Sir Austin Bradford Hill, which includes criteria such as strength of
      association, dose-response relation, consistency of association, temporally
      correct association, specificity of association, and biological plausibility.
      Another set of criteria, used by the US Preventive Services Task Force, ranks
      evidence according to study design, designating evidence from randomized
      controlled trials as superior to evidence from cohort or case-control studies,
      which are in turn superior to evidence from ecologic studies or opinions of
      respected authorities. The application of these criteria to the question of
      whether vitamin E intake is associated with coronary heart disease is examined
      here. It is suggested that the epidemiologic evidence from prospective cohort
      studies generally supports an inverse association of vitamin E intake and risk of
      coronary heart disease. The information available from randomized trials is
      limited but suggestive of an inverse association with nonfatal, but not with
      fatal, coronary events. It is suggested that the application of criteria for
      causal inference to specific questions in nutritional epidemiology may provide
      clarity to seemingly contradictory information.

PMID- 10359234
TI  - Evaluating epidemiologic evidence of the effects of food and nutrient exposures.
AB  - The objective of this paper is to discuss some of the issues to be considered
      when evaluating and interpreting epidemiologic evidence from observational
      studies that collect data on dietary intake. The assessment of such evidence
      should include consideration of the study design, sample selection, and the
      measurements of exposure and disease. The degree and type of error in nutrient
      data can lead to analytic problems and potentially be a source of bias either
      toward or away from the null value. Because methods of statistical correction and
      adjustment for error, such as energy adjustment, cannot necessarily completely
      compensate for sources of bias in dietary data, additional research should be
      conducted on sources of error in dietary data. Published research using reported
      dietary data should include a discussion of potential sources of error and their
      effect on the results. The most useful studies are likely to be those designed to
      address a clearly defined prior hypothesis about a specific diet-disease
      relation. Because of the potential for bias and confounding, observational
      epidemiologic studies of diet and outcome cannot generally provide decisive
      evidence by themselves either for or against specific hypotheses. Although
      randomized clinical trials of the effects of specific nutrients or dietary
      modifications are not always feasible, they provide more definitive results and
      should generally be considered more valid than observational studies using self
      reported dietary intake. Well-designed observational epidemiologic studies using
      self-reported dietary intake can provide valuable data to support or challenge
      hypotheses derived from clinical or laboratory data and to suggest further
      directions for investigation.

PMID- 10359235
TI  - Beta-carotene and lung cancer: a case study.
AB  - The conflicting evidence of the relation between beta-carotene and lung cancer in
      humans serves as a poignant case study with respect to what types of evidence are
      sufficient to support or change a nutrition recommendation. This article is a
      review of the available evidence of the relation between beta-carotene and lung
      cancer, including data regarding beta-carotene intake (from diet and
      supplements), beta-carotene biochemical status, and vegetable and fruit
      consumption, and a discussion of the role of this evidence in making nutrition
      recommendations. More than 30 case-control and cohort studies were conducted over
      many years in various populations and indicated that people who eat more
      vegetables and fruit, foods rich in carotenoids, and carotenoids (beta-carotene
      in particular), as well as those with higher blood beta-carotene concentrations,
      have a lower risk of lung cancer than those who eat fewer such foods or have
      lower beta-carotene concentrations. In contrast, the intervention results from
      large, controlled trials of beta-carotene supplementation do not support the
      observed beneficial associations or a role for supplemental beta-carotene in lung
      cancer prevention; instead, they provide striking evidence for adverse effects
      (ie, excess lung cancer incidence and overall mortality) in smokers. The findings
      require that caution be exercised in recommending supplemental beta-carotene,
      particularly for smokers, and argue against changing the vegetable-fruit
      recommendations in the direction of greater nutrient specificity. This case study
      of beta-carotene and lung cancer stresses the importance of having results from
      at least one, and preferably more, large, randomized intervention trial before
      public health recommendations concerning micronutrient supplementation are
      considered.

PMID- 10359237
TI  - Health claims and observational human data: relation between dietary fat and
      cancer.
AB  - The US Food and Drug Administration review that provided the basis for
      authorizing a food-label health claim linking the risk of cancer to dietary fat
      intake illustrated several considerations in the use of epidemiologic data, and
      observational data in particular, to support dietary recommendations. The review
      suggested the need for clear and established criteria for judging the quality of
      observational human data as well as the importance of making the evaluation
      process for individual studies transparent and organized. The review, which
      provided for a claim in the absence of controlled human studies, also suggested
      that observational data may play a greater role when the nature of the relation
      to be described by a health-claim statement is broad and general rather than
      targeted and specific. Of particular importance was the relevance of available
      data to the questions inherent in showing a diet-disease relation, the need to
      consider the totality of the evidence, and the key role that existing
      authoritative reports must play in establishing the basis for relation.

PMID- 10359238
TI  - The role of epidemiology in determining when evidence is sufficient to support
      nutrition recommendations. Summary statement.
AB  - This statement summarizes the key points of discussion among a group of
      nutritional epidemiologists who met in Washington, DC, for 2 d in October of 1997
      to reflect on the role of nutritional epidemiology in the development of dietary
      recommendations for the public. Although imprecision in the measurement of diet
      places limits on nutritional epidemiology, no other field of nutritional science
      can provide direct information on relations between nutrition and health in free
      living human populations. Among the nutritional sciences, therefore, epidemiology
      was regarded as being critically important. Nutritional epidemiology can be
      improved in the future by the development of more precise measures of long-term
      dietary exposures, both by improved methods of self-reporting of diet and by the
      development of more useful biomarkers of long-term nutritional status. There is a
      need as well to reconsider the applicability of causal criteria as applied to
      nutritional epidemiology, because many of the important associations between
      dietary behaviors and chronic diseases cannot necessarily be expected to be
      either strong or to manifest linear dose-response relations. In the future,
      scientific evidence from the rapidly growing field of nutritional epidemiology
      will likely play an increasingly important role in developing nutrition policy
      and advice for the public.

PMID- 10359236
TI  - Diet and health risk: risk patterns and disease-specific associations.
AB  - Whether such epidemiologic descriptors as relative risk, dose response, and
      threshold points convey meaningful information is often the subject of debate.
      Thus, using these descriptors to juxtapose the many disease-specific effects of
      nutritional exposures becomes problematic. In this article it is argued that
      epidemiologic patterns of disease-exposure associations must be interpreted in
      light of the profound imprecision of exposure assessment that characterizes
      nutritional epidemiology. In general, this imprecision leads to substantial
      attenuation of disease-exposure associations, such that relative risk, dose
      response, and the extent to which there are thresholds in disease-exposure
      associations can be seriously underestimated. Linking disease-specific relative
      risks, especially when derived from different studies with different methods of
      assessing exposure, is made increasingly difficult. The most critical tasks for
      lessening bias in these epidemiologic descriptors are first, to lessen
      imprecision in measuring exposures, and second, to adjust association estimates
      for attenuation due to measurement imprecision.

PMID- 10359239
TI  - Injectable tissue-engineered cartilage using a fibrin glue polymer.
AB  - The purpose of this study was to demonstrate the feasibility of using a fibrin
      glue polymer to produce injectable tissue-engineered cartilage and to determine
      the optimal fibrinogen and chondrocyte concentrations required to produce solid,
      homogeneous cartilage. The most favorable fibrinogen concentration was determined
      by measuring the rate of degradation of fibrin glue using varying concentrations
      of purified porcine fibrinogen. The fibrinogen was mixed with thrombin (50 U/cc
      in 40 mM calcium chloride) to produce fibrin glue. Swine chondrocytes were then
      suspended in the fibrinogen before the addition of thrombin. The
      chondrocyte/polymer constructs were injected into the subcutaneous tissue of nude
      mice using chondrocyte concentrations of 10, 25, and 40 million chondrocytes/cc
      of polymer (0.4-cc injections). At 6 and 12 weeks, the neocartilage was harvested
      and analyzed by histology, mass, glycosaminoglycan content, DNA content, and
      collagen type II content. Control groups consisted of nude mice injected with
      fibrin glue alone (without chondrocytes) and a separate group injected with
      chondrocytes suspended in saline only (40 million cells/cc in saline; 0.4-cc
      injections). The fibrinogen concentration with the most favorable rate of
      degradation was 80 mg/cc. Histologic analysis of the neocartilage showed solid,
      homogeneous cartilage when using 40 million chondrocytes/cc, both at 6 and 12
      weeks. The 10 and 25 million chondrocytes/cc samples showed areas of cartilage
      separated by areas of remnant fibrin glue. The mass of the samples ranged from
      0.07 to 0.12 g at 6 weeks and decreased only slightly by week 12. The
      glycosaminoglycan content ranged from 2.3 to 9.4 percent for all samples; normal
      cartilage controls had a content of 7.0 percent. DNA content ranged from 0.63 to
      1.4 percent for all samples, with normal pig cartilage having a mean DNA content
      of 0.285 percent. The samples of fibrin glue alone produced no cartilage, and the
      chondrocytes alone produced neocartilage samples with a significantly smaller
      mass (0.47 g at 6 weeks and 0.46 g at 12 weeks) when compared with all samples
      produced from chondrocytes suspended in fibrin glue (p < 0.03). Gel
      electrophoreses demonstrated the presence of type II collagen in all sample
      groups. This study demonstrates that fibrin glue is a suitable polymer for the
      formation of injectable tissue-engineered cartilage in the nude mouse model.
      Forty million chondrocytes per cc yielded the best quality cartilage at 6 and 12
      weeks when analyzed by histology and content of DNA, glycosaminoglycan, and type
      II collagen.

PMID- 10359240
TI  - Digital two-dimensional photogrammetry: a comparison of three techniques of
      obtaining digital photographs.
AB  - Three methods of obtaining digital photographs in a clinical setting were
      compared using direct anthropometry as a reference standard. The methods included
      a digital camera, scanning negatives from a 35-mm single-lens reflex camera, and
      scanning Polaroid photographs taken with a Polaroid camera designed for medical
      documentation. A total of 11 angular and linear anthropometric measurements
      obtained from 30 healthy volunteers were used for the comparison. The data were
      analyzed using a variance covariance approach to repeated measures. The analysis
      revealed that the three cameras were not statistically different from each other.
      Other advantages and disadvantages, such as cost and ease of use, are discussed.

PMID- 10359241
TI  - Three-dimensional computed tomographic analysis of the primary nasal deformity in
      3-month-old infants with complete unilateral cleft lip and palate.
AB  - The purpose of this study was to analyze the geometry of the primary cleft lip
      nasal deformity using three-dimensional computerized tomography in a group of 3
      month-old infants with complete unilateral cleft lip and palate before surgical
      intervention. Coordinates and axes were reconfigured after the three-dimensional
      image was oriented into neutral position (Frankfurt horizontal, true
      anteroposterior, and vertical midline). Display and measurement of skin surface
      and osseous tissues were achieved by adjusting the computed tomographic
      thresholds. S-N, N-ANS, S-N-O, and S-N-ANS were measured from true lateral views.
      Biorbital (LO-LO), interorbital (MO-MO), intercanthal (en-en), and nasal (al-al)
      widths were measured from the anteroposterior view. The bony alveolar cleft width
      was measured from the inferior view. The study group was divided into two groups
      on the basis of skeletal alveolar cleft width: six patients with clefts narrower
      than 10 mm and six patients with clefts wider than 10 mm. Only the S-N-ANS angle
      differed between the two groups, i.e., it was greater in the group with the wider
      clefts (p < 0.05). Coordinates of six landmarks at the base of the nose [sellion
      (se), subnasale (sn), cleft-side and noncleft-side subalare (sbal-cl and sbal
      ncl), and the most posterior point on the lateral piriform margins (PPA-CL and
      PPA-NCL)] were obtained for analysis of the nasal deformity. On average, the
      subnasale point was anterior to sellion and deviated to the noncleft side; the
      cleft-side sbal point was more medial, posterior, and inferior than the noncleft
      side sbal point; and the PPA point on the cleft-side piriform margin was more
      lateral, posterior, and inferior than the PPA point on the noncleft side. These
      discrepancies were not universally observed. However, in all patients, four
      findings were observed without exception (p < 0.01): (1) subnasale (sn) was
      deviated to the noncleft side (mean distance from midline, 5.0 mm; range, 2 to
      9.5 mm), (2) the cleft-side alar base (sbal-cl) was more posterior than the
      noncleft-side alar base (sbal-ncl) (mean difference, 3.6 mm; range, 1 to 5.5 mm),
      (3) the noncleft-side alar base (sbal-ncl) was further from the midline than the
      cleft-side alar base (sbal-cl) (mean difference in lateral distances of sbal-ncl
      and sbal-cl from the midline, 2.8 mm; range, 0.5 to 7 mm), and (4) the cleft-side
      piriform margin (PPA-CL) was more posterior than the noncleft side piriform
      margin (PPA-NCL) (mean difference, 2.1 mm; range, 0.5 to 4 mm). In conclusion,
      the nasal deformity in unilateral cleft lip and palate that has not been operated
      on is characterized by these four features and increased S-N-ANS angle with
      increased alveolar cleft width.

PMID- 10359242
TI  - Asymmetric incision for open rhinoplasty in cleft lip nasal deformity.
AB  - One of the problems in the correction of the unilateral cleft lip nasal deformity
      is the alar web deformity on the mediosuperior side of the nostril. A number of
      methods for the correction of the alar web deformity have been introduced, but no
      single procedure has been identified as the standard. In this report, the
      incision line of the open rhinoplasty was modified and the alar web deformity was
      corrected by using an incision and closure. Open rhinoplasty with the asymmetric
      incision was performed on 18 patients with unilateral cleft lip nasal deformity.
      The incision line used in the normal side was the usual intranasal rim incision
      line and that used for the columella was the transcolumella incision line. For
      the cleft side, an intranasal rim incision line was plotted after the rim was
      lifted upward with forceps to achieve symmetry of the nasal tip. After removal of
      the forceps, the incision line of the cleft side was displaced outside the
      nostril. After such an incision, the alar cartilage mobilization and suspension
      were performed with or without the conchal cartilage graft. All patients used
      nasal retainers for 6 months after the procedures. So far, satisfactory results
      have been obtained with the modification of the incision line for open
      rhinoplasty. This method is unique in designing the incision line, and its
      procedure is rather simple. The postoperative follow-up period has been 12 to 26
      months. A long-term follow-up is still needed, especially in growing children.

PMID- 10359243
TI  - Pure orbital blowout fracture: new concepts and importance of medial orbital
      blowout fracture.
AB  - Pure orbital blowout fracture first occurs at the weakest point of the orbital
      wall. Although the medial orbital wall theoretically should be involved more
      frequently than the orbital floor, the orbital floor has been reported as the
      most common site of pure orbital blowout fractures. A total of 82 orbits in 76
      patients with pure orbital blowout fracture were evaluated with computed
      tomographic scans taken on all patients with any suspicious clinical evidence,
      including nasal fracture. Isolated medial wall fracture was most common (55
      percent), followed by medial and inferior wall fracture (27 percent). The most
      common facial fracture associated with medial wall fracture was nasal fracture
      (51 percent), not inferior wall fracture (33 percent). This finding suggests that
      the force causing nasal fracture is an important causative factor of pure medial
      wall fracture as the buckling force from the medial orbital rim. Of patients with
      medial wall fractures, 25 percent had diplopia and 40 percent had enophthalmos.
      On plain radiographs, diagnostic signs were found in 79 percent of medial wall
      fractures and in 95 percent of inferior wall fractures. On computed tomographic
      scans, late enophthalmos was expected in 76 percent of medial wall fractures.
      Therefore, the medial orbital blowout fracture may be an important cause of late
      enophthalmos, because it has a high incidence of occurrence, a low diagnostic
      rate, and a high severity of defect. Among the causes of limitation of ocular
      motility, muscle traction of the connective septa and direct muscle injury were
      found frequently, but true incarceration of the muscle was extremely rare in all
      fractures. The medial and inferior orbital walls are clearly demarcated by the
      bony buttress, which is an important structure supporting these orbital walls.
      Its buttress was closely correlated with the fracture of these orbital walls.
      Most orbital blowout fractures without collapse of the bony buttress had a
      trapdoor fracture with or without small fragments of punched-out fracture.

PMID- 10359244
TI  - Primary reconstruction of complex midfacial defects with combined lip-switch
      procedures and free flaps.
AB  - Free flaps are generally the preferred method for reconstructing large defects of
      the midface, orbit, and maxilla that include the lip and oral commissure;
      commissuroplasty is traditionally performed at a second stage. Functional results
      of the oral sphincter using this reconstructive approach are, however, limited.
      This article presents a new approach to the reconstruction of massive defects of
      the lip and midface using a free flap in combination with a lip-switch flap. This
      was used in 10 patients. One-third to one-half of the upper lip was excised in
      seven patients, one-third of the lower lip was excised in one patient, and both
      the upper and lower lips were excised (one-third each) in two patients. All
      patients had maxillectomies, with or without mandibulectomies, in addition to
      full-thickness resections of the cheek. A switch flap from the opposite lip was
      used for reconstruction of the oral commissure and oral sphincter, and a rectus
      abdominis myocutaneous flap with two or three skin islands was used for
      reconstruction of the through-and-through defect in the midface. Free flap
      survival was 100 percent. All patients had good-to-excellent oral competence, and
      they were discharged without feeding tubes. A majority (80 percent) of the
      patients had an adequate oral stoma and could eat a soft diet. All patients have
      a satisfactory postoperative result. Immediate reconstruction of defects using a
      lip-switch procedure creates an oral sphincter that has excellent function, with
      good mobility and competence. This is a simple procedure that adds minimal
      operative time to the free-flap reconstruction and provides the patient with a
      functional stoma and acceptable appearance. The free flap can be used to
      reconstruct the soft tissue of the intraoral lining and external skin deficits,
      but it should not be used to reconstruct the lip.

PMID- 10359245
TI  - A prospective evaluation of the prevalence of submucous cleft palate in patients
      with isolated cleft lip versus controls.
AB  - Although there is an established relationship between cleft lip and overt cleft
      palate, the relationship between isolated cleft lip and submucous cleft palate
      has not been investigated. To test the hypothesis that patients with isolated
      cleft lip have a greater association with submucous cleft palate, a double-armed
      prospective trial was designed. A study group of 25 consecutive children
      presenting with an isolated cleft lip, with or without extension through the
      alveolus but not involving the secondary palate, was compared with a control
      group of 25 children with no known facial clefts. Eligible patients were examined
      for the presence of physical criteria associated with classic submucous cleft
      palate, namely, (1) bifid uvula, (2) absence of the posterior nasal spine, and
      (3) zona pellucida. Nasoendoscopy was subsequently performed just after induction
      of general anesthesia, and the findings were correlated with digital palpation of
      the palatal muscles. Patients who did not satisfy all three physical criteria and
      in whom nasoendoscopy was distinctly abnormal relative to the control group were
      classified as having occult submucous cleft palate. Classic submucous cleft
      palate was found in three study group patients (12 percent), all of whom had
      flattening or a midline depression of the posterior palate and musculus uvulae on
      nasoendoscopy and palpable diastasis of the palatal muscles under general
      anesthesia. An additional six study group patients (24 percent) had similar
      nasoendoscopic criteria and palpable diastasis of the palatal muscles; they were
      classified as having occult submucous cleft palate. No submucous cleft palate was
      identified in the control group. Seventeen patients in the study group had an
      alveolar cleft with a 53 percent (9 of 17) prevalence of submucous cleft palate.
      In the present study, classic submucous cleft palate in association with isolated
      cleft lip was 150 to 600 times the reported prevalence in the general population.
      All children with an isolated cleft lip should undergo peroral examination and
      speech/resonance assessment no later than the age of 3 years. Any child with an
      isolated cleft lip with velopharyngeal inadequacy or before an adenoidectomy
      should be assessed by flexible nasal endoscopy to avoid missing an occult
      submucous cleft palate.

PMID- 10359246
TI  - Another indication for liposuction: small facial lipomas.
AB  - The treatment of facial lipomas at times requires the use of incisions that are
      less than satisfactory in either size or location. In an effort to minimize
      scarring, the authors have been removing these lesions with liposuction. The
      purpose of this study was to review the authors' experience in treating small
      facial lipomas using liposuction. Over the last 10 years, the authors treated
      five patients with forehead lipomas by removal with liposuction through hair
      bearing scalp incisions. All patients were evaluated after the procedure for
      bleeding, paresthesias, recurrence, scarring, and overall satisfaction with the
      procedure. All of these patients had lipomas that measured 4 cm or less at the
      time of surgery. No patient experienced hematoma, nerve injury, or recurrence.
      All patients were completely satisfied with their result and scar. The literature
      describes an advantage to using liposuction for the treatment of medium (4 to 10
      cm) and large (>10 cm) lipomas. Because small lipomas (<4 cm) can be extracted
      through small incisions, the literature reports no advantage to removal with
      liposuction. However, favorable aesthetic results can be obtained by removing
      small facial lipomas with liposuction through strategically placed incisions.

PMID- 10359247
TI  - Liposuction technique and lymphatic lesions in lower legs: anatomic study to
      reduce risks.
AB  - Liposuction is a standard procedure in plastic surgery. Especially, lipectomy
      with suction of the lower extremities has been of greater interest in recent
      years. Until now, however, there was no definite information about the integrity
      of epifascial lymph collectors during this procedure. To study the effect of
      liposuction devices on lymph vessel injury, postmortem lymphatic preparations
      were done in five human cadavers (10 lower extremities). Conventional liposuction
      with a blunt 4-mm cannula and a dry technique was used. Adiposuction was
      performed either in parallel to the extremity axis and, therefore, in parallel to
      the superfascial lymph vessels or transversally in an 80- to 90-degree angle to
      the extremity. Careful surgical preparation of the regions followed. A specific
      macroscopic lymph vessel injury score was applied to differentiate 3 degrees of
      lymph vessel lesions according to the extravasation of patent blue. In all lower
      extremities, postmortem lymph flow occurred as indicated by patent blue staining
      of the lymph vessels. Lymph vessel injury was more severe in areas where
      liposuction was performed transversally, vertical to the extremity's axis, than
      in those after a longitudinal procedure. The difference was statistically
      significant (p < 0.01). The volumes of adipoaspirate and of the compared regions
      were comparable between both groups, verified by circumference measurements.
      Longitudinal liposuction of the lower extremities is unlikely to cause major
      lesions of epifascial lymph vessels and, therefore, should be preferred in
      comparison to liposuction vertical to the extremity.

PMID- 10359248
TI  - Breast reconstruction with latissimus dorsi flap: improved aesthetic results
      after transection of its humeral insertion.
AB  - Does transecting the tendinous insertion of the latissimus dorsi on the humerus
      improve aesthetic results and avoid the displeasing bulge in the armpit that
      sometimes occurs when the latissimus dorsi is used for breast reconstruction? In
      a prospective study, 60 patients who were having breast cancer surgery and
      simultaneous breast reconstruction using the latissimus dorsi flap were
      randomized for cutting (n = 29) or leaving intact (n = 31) the tendinous muscle
      insertion on the humerus. The cosmetic outcome was evaluated by patients and
      surgeons 6 to 12 months postoperatively. Patients reported good cosmetic results
      in 29 of 31 cases with the humeral insertion left intact and in 26 of 29 cases
      when the tendon was cut (p = 0.59), as compared with 21 of 31 cases versus 25 of
      29 cases (p = 0.091), according to the surgeon's evaluation. A lateral bulge was
      more frequently observed by the surgeons in the group with intact insertion (10
      of 31 patients), as compared with the group with a transected humeral insertion
      (2 of 29 patients). Discomfort caused by this bulge was reported by 19 of 31
      patients with intact insertion, but only 3 of 29 patients with the tendon cut (p
      < 0.0001). The additional transection of the tendon was not associated with any
      complications. The additional transection of the tendinous humeral insertion of
      the latissimus dorsi muscle improves aesthetic results and avoids a displeasing
      bulge in the axilla when the latissimus dorsi flap is used for breast
      reconstruction.

PMID- 10359249
TI  - Reduction mammaplasty in postburn breasts.
AB  - Thermal injury to the anterior chest in the adolescent girl can lead to severe
      disfigurement of the breasts. Just as in certain non-burn female patients,
      mammary hyperplasia can occur in patients with previous full-thickness burns of
      their breasts. Most plastic surgeons have been reluctant to perform reduction
      mammaplasty in these patients for fear of devascularizing the skin graft or the
      nipple-areola complex. A series of six patients with full-thickness burns of the
      breasts and subsequent skin graft coverage before reduction mammaplasty is
      reported. Four patients had bilaterally burned breasts requiring reduction. Two
      patients had one burned breast reduced, and one required a balancing procedure on
      the unburned side. Reduction mammaplasty was performed using the inferior-pedicle
      technique. The mean amount of tissue removed for the left and right breasts was
      454 and 395 g, respectively. There was no nipple loss, hematoma, infection, or
      major loss of skin flaps. Reduction mammaplasty in this group of patients is safe
      and carries minimal risk if certain key concepts are followed carefully.

PMID- 10359250
TI  - The effect of unilateral partial facial paralysis on nasofrontal sutural growth:
      an experimental study in the rabbit.
AB  - In a previous study in the rabbit, it was demonstrated that paralysis of the
      midfacial musculature results in decreased anteroposterior growth of the snout.
      At the end of growth, these animals showed macroscopically striking similarities
      to animals with unilateral fusion of the nasofrontal suture. In this study,
      whether nasofrontal sutural growth is unilaterally restricted in animals with
      unilateral partial facial paralysis was investigated. A left-sided partial facial
      paralysis was induced in sixteen 12-day-old New Zealand White rabbits. At the
      ages of 5, 9, 12, and 17 weeks, four animals were randomly assigned to be killed
      for analysis of nasofrontal sutural growth. In each animal, the left experimental
      side was compared with the right control side. By means of histomorphometric
      measurements, it was shown that diminished sutural growth activity was present on
      the left paralyzed side in periods of rapid growth. On the other hand, no
      significant alterations in sutural width were found. These findings seem to
      explain some of the macroscopic growth alterations (i.e., diminished anterior
      maxillary length) observed in rabbits with unilateral partial facial paralysis.

PMID- 10359251
TI  - The timing and nature of neovascularization of jejunal free flaps: an
      experimental study in a large animal model.
AB  - The present study was designed (1) to determine whether a free jejunal transfer
      in a large animal model can develop collateral circulation that is adequate to
      maintain viability after division of the pedicle and (2) to determine the
      earliest time pedicle ligation is safe after transplantation. A 15-cm jejunal
      segment was transferred to the necks of 18 dogs weighing 25 to 35 kg. The bowel
      segment was inset longitudinally under the skin on one side of the neck,
      partially covered by the neck muscles, and the mesenteric vessels were
      anastomosed to recipient vessels in the neck. The proximal and distal bowel
      stomas were exteriorized through skin openings 12 cm apart and matured. The dogs
      were subjected to ligation of the vascular pedicle at different intervals:
      postoperative day 7 (group I, n = 3), day 14 (group II, n = 5), day 21 (group
      III, n = 5), and day 28 (group IV, n = 5). Blood perfusion was measured in the
      proximal and distal bowel stomas before pedicle division (control) and 24 hours
      later using hydrogen gas clearance and fluorescein dye. Bowel necrosis was
      analyzed using planimetry. The bowel was also stained with hematoxylin and eosin
      and factor VIII, and new blood vessels were counted. Mean values (+/- standard
      deviation) were compared with control values for each test and with normal values
      in the intact bowel using analysis of variance with Neumann-Keuls post-hoc test
      for multiple comparisons. No jejunal free flaps survived when the vascular
      pedicle was divided 1 week postoperatively. Bowel survival was 60 percent at 2
      weeks, 83 percent at 3 weeks, and 100 percent at 4 weeks. Hydrogen gas clearance
      values (ml/min/100 g) were 49.6 +/- 8.7 in the mucosa of the intraabdominal
      jejunum and 37.9 +/- 9.4 in the jejunum that was transferred to the neck before
      division of the pedicle. Twenty-four hours after pedicle division, hydrogen gas
      clearance values were 2.8 +/- 6.4 in group I (p < 0.05), 22.4 +/- 12.4 in group
      II, 23.9 +/- 9.3 in group III, and 34.2 +/- 7.5 in group IV. FluoroScan readings
      in the transferred jejunum were 201 +/- 7.2 in the control group, 9.3 +/- 2.8 in
      group I (p < 0.05), 79.1 +/- 10.6 in group II, 66.2 +/- 7.3 in group III, and 164
      +/- 11.9 in group IV. New vessel formation as identified by factor VIII staining
      correlated with increasing bowel perfusion and flap survival rate. Bowel
      neovascularization, perfusion, and survival increased progressively 1 week after
      transfer. Significant portions of the transferred bowel will neovascularize and
      survive as early as 2 weeks postoperatively. However, a minimum of 4 weeks before
      ligation of the pedicle is necessary to maximize flap perfusion and guarantee
      survival.

PMID- 10359252
TI  - Skin graft survival after external beam irradiation.
AB  - Difficulties with skin graft ulceration after radiation therapy for cancer have
      led many to question the suitability of this method of soft-tissue coverage and
      its cost-effectiveness. The objective of this study was, therefore, to assess
      skin-graft integrity subjected to postoperative external beam irradiation in a
      rat model. The model consisted of a rectangular full-thickness skin graft raised
      and reapplied to its original bed on the dorsum of each rat. Five groups of adult
      male Sprague-Dawley rats (n = 8 per group) were established. Group A was the
      control group and was not given postoperative irradiation. Groups B, C, D, and E
      received postoperative unfractionated cobalt60 irradiation 4 weeks after grafting
      for a total dose of 15, 20, 25, or 30 Gy, respectively. Weekly skin-graft
      evaluation was performed for the 4 weeks after irradiation (8 weeks after
      surgery) by measuring areas of graft loss using computerized planimetry. After
      the animals were killed, histologic samples were obtained from normal
      unirradiated skin and from both intact and ulcerated skin-graft sites. Graft loss
      after irradiation of < or = 20 Gy was similar to that of the unirradiated
      controls. Occurring as early as 1 week after treatment, a two-fold increase in
      graft ulceration was observed with doses of > or = 25 Gy (p = 0.0007). Only
      partial healing of ulcerations was noted by the fourth week after treatment.
      Histologic changes associated with the irradiation of skin grafts using doses of
      25 Gy or higher included hyaline degeneration, fibrinoid necrosis,
      telangiectasia, and edema. Granulation tissue predominated as a mechanism of
      healing in areas of graft ulceration. The intensity of inflammatory cell
      infiltrate did not correlate with radiation dose. The authors concluded that
      postoperative, unfractionated irradiation can induce skin-graft loss at doses of
      25 Gy or higher. Fractionated irradiation or longer intervals between grafting
      and irradiation may increase skin-graft tolerance; however, further studies are
      warranted.

PMID- 10359253
TI  - Effects of rhBMP-2 and osteopromotive membranes on experimental bone grafting.
AB  - A problem with using autogeneic bone for onlay grafting is its degree of
      incorporation and volumetric persistence. This study explored whether improved
      graft volumetric maintenance can be achieved by recombinant human bone
      morphogenetic protein-2 (rhBMP-2) and whether a combination of rhBMP-2 and
      osteopromotive membranes is advantageous in this respect. Unicortico-cancellous
      bone grafts were positioned below the temporal muscle bilaterally in 48 adult
      Lewis rats. The recipient bone was ground, and the grafted area was randomly
      treated according to one of eight different alternatives. Two doses of rhBMP-2 (4
      microg/80 microl or 32 microg/80 microl buffer) in a collagenous carrier were
      tested, with or without coverage with expanded polytetrafluoroethylene membranes.
      As controls, membrane and carrier, alone or in combination, and onlay grafts only
      were used. The results were evaluated after 4 and 20 weeks by routine histologic
      examination and immunohistochemical labeling for various bone and cartilage
      matrix proteins. After 4 weeks, rhBMP-2-treated grafts showed complete
      integration, whereas for controls, only the membrane-alone group attained
      incorporation after 20 weeks. The combined treatment with high-dose rhBMP-2 and
      membrane demonstrated, as compared with the remaining rhBMP-2 groups, pronounced
      bone formation and less graft resorption, resulting in maintained or increased
      graft size. This was observed after 4 weeks, and the result remained at 20 weeks.
      Treatment with high-dose rhBMP-2 without membrane placement, in contrast,
      resulted in extensive resorption and graft size reduction at 20 weeks. Control
      groups showed less success in graft size persistence. It was concluded that a
      combination of high-dose rhBMP-2 and osteopromotive membranes had a synergistic
      effect, leading to rapid, complete graft integration and size maintenance. In the
      absence of a membrane, the protein seemed to accelerate the remodeling of the
      graft.

PMID- 10359254
TI  - Mechanical function of muscle reinnervated by end-to-side neurorrhaphy.
AB  - End-to-side neurorrhaphy is a surgical technique for peripheral nerve
      reconstruction when end-to-end neurorrhaphy is not an option. To define the
      effectiveness of end-to-side neurorrhaphy as a method of nerve repair, the
      authors tested the null hypothesis: there is no difference in the mechanical
      function of skeletal muscle denervated and reinnervated by end-to-side versus end
      to-end neurorrhaphy. Adult Lewis rats underwent either transection and end-to-end
      epineurial repair of the left peroneal nerve (n = 9) or end-to-side repair of the
      distal stump of the peroneal nerve to the side of the tibial nerve (n = 8). After
      a 6-month recovery period, isometric force (Fo) was measured, and specific force
      (sFo) was calculated for the extensor digitorum longus muscle of each animal.
      Immunohistochemical staining for neural cell adhesion molecule (NCAM) was
      performed to identify populations of denervated muscle fibers. The mean extensor
      digitorum longus muscle mass in the end-to-end group (195 +/- 32 g) was
      significantly greater than that of the end-to-side group (146 +/- 55 g) (p <
      0.05). A significantly greater percentage of denervated fibers was identified in
      the extensor digitorum longus muscles of animals in the end-to-side group (9.4 +/
      3.2 percent) than in those in the end-to-end group (3.8 +/- 1.0 percent) (p <
      0.05). Despite a lower muscle mass and a higher percentage of denervated fibers,
      neither Fo nor sFo was significantly different in the two groups. These data
      support the null hypothesis that, under appropriate circumstances, there is no
      difference in the recovery of whole muscle force and specific force production in
      muscles reinnervated by end-to-side versus end-to-end neurorrhaphy.

PMID- 10359255
TI  - FK506 accelerates functional recovery following nerve grafting in a rat model.
AB  - The sometimes dramatic and permanent functional deficits that result from severe
      peripheral nerve injuries provide compelling incentives to identify exogenous
      agents that may expedite axonal regrowth and avoid prolonged denervation of end
      organs. The purpose of this study was to identify, whether the regular systemic
      administration of tacrolimus (FK506) or cyclosporin A (CsA) would influence the
      speed and efficiency of nerve regeneration through short nerve grafts. A total of
      35 Buffalo rats each received a 2-cm posterior tibial nerve graft and were
      randomized to one of three experimental groups. Group I animals were left
      untreated, group II received daily CsA (5 mg/kg intraperitoneally), and group III
      received daily FK506 (1 mg/kg intraperitoneally). Walking tracks were obtained
      starting 3 weeks after graft placement and continuing biweekly for the next 7
      weeks. FK506-treated animals fully recovered hindlimb function 7 days earlier
      than CsA-treated animals or untreated control animals. Regenerated nerves from
      one-half of each treatment group were harvested for histomorphometric analysis at
      7 weeks, shortly after recovery was complete in the FK506-treatment group but not
      in the other two groups, and once again at 10.5 weeks when recovery of function
      had stabilized in all groups. At 7 weeks, FK506-treated animals had significantly
      greater fiber density and percentage of neural tissue per nerve and a
      significantly larger population of mature, myelinated fibers in comparison with
      either CsA-treated or untreated animals. The authors concluded that the daily,
      systemic administration of low-dose FK506 facilitates peripheral nerve recovery
      and regeneration after nerve grafting.

PMID- 10359256
TI  - Algorithm for recipient vessel selection in free tissue transfer to the lower
      extremity.
AB  - The proper selection of a recipient vessel is essential for the success of free
      tissue transfer, especially when the transfer is to the lower extremity. However,
      a general agreement on which vessel to use has not been reached yet. Conflicting
      data have been reported on the survival and outcome of the transferred flaps,
      depending on the vessel used or the location of anastomosis. The aim of this
      study was to identify the patterns and problems in the selection of recipient
      vessels for free tissue transfer to the lower extremity and to establish a
      general guideline for proper selection. From September of 1990 to December of
      1997, 50 consecutive, microvascular, free tissue transfers were performed on the
      lower extremity. The causes requiring soft-tissue coverage included trauma (25),
      unstable scar (11), chronic osteomyelitis (7), and tumors (7). The mean follow-up
      period was 22.4 months (range, 2 to 41 months). In 25 cases, the posterior tibial
      vessel was used as the recipient vessel. The microvascular anastomosis was done
      proximal to the zone of injury in 45 cases. The two most important factors in the
      selection of a recipient vessel are the site of injury and the vascular status of
      the lower extremity. Less important factors include the flap to be used, method,
      and site of microvascular anastomosis. All the currently feasible options for
      recipient vessels are included, and the opinions of other surgeons are reviewed.
      A general guideline is established, and an algorithm for the proper selection of
      a recipient vessel is proposed. This algorithm is a fast and convenient guide for
      evaluating the wound and planning the free flap to the lower extremity.

PMID- 10359257
TI  - In vivo microscopic assessment of cremasteric microcirculation during hindlimb
      allograft rejection in rats.
AB  - Experimental and clinical studies of vascular allogenic extremity transplantation
      have yielded disappointing results and have not been clinically useful. With
      recent advances in transplantation immunology, considerable interest has focused
      on the understanding of leukocyte-endothelial interaction at the microcirculatory
      level. The objective of this study was to characterize the alterations in
      leukocyte-endothelial interaction in the early stages of rat hindlimb allograft
      rejection. To study the changes at the microcirculatory level, a new
      microsurgical model was developed; the cremaster muscle was incorporated into the
      transplanted hindlimb. The purpose of this study was to report on the
      microcirculatory changes during rat hindlimb allograft rejection. A total of 24
      transplantations were performed among the four experimental groups. In a control
      group, 12 rat hindlimb-cremaster grafts were transplanted between genetically
      identical animals, Lewis to Lewis. Microcirculatory measurements of graft
      survival were taken at 24 hours (group 1A, n = 6) and at 72 hours (group 1B, n =
      6). In the rejection control group, 12 transplantations were performed across a
      major histocompatibility barrier between Lewis-Brown Norway and Lewis rats.
      Microcirculatory measurements were taken at 24 (group 2A, n = 6) and 72 hours
      (group 2A, n = 6) as above. The following parameters were evaluated to discover
      the leukocyte-endothelial interaction: endothelial edema index and the number of
      rolling, adherent, and transmigrating leukocytes and lymphocytes in the
      postcapillary venule. Physical signs of limb rejection, such as edema, erythema,
      scaling, plaque formation on the skin, hair loss, and skin surface temperature,
      were monitored. Microcirculatory signs of rejection included the following. There
      was a significant increase in the number of adherent leukocytes in allograft
      transplants at both 24 hours (205 percent; 2.05 +/- 0.38) and 72 hours (431
      percent; 9.11 +/- 3.41) when compared with isograft controls (1.00 +/- 0.89 at 24
      hours; 2.11 +/- 0.34 at 72 hours) (p < 0.05). The activation of leukocyte
      transmigration increased more than 7-fold in muscle allografts at 24 hours (0.55
      +/- 0.25 versus 4.16 +/- 1.89) and more than 6-fold at 72 hours (0.72 +/- 0.38
      versus 4.38 +/- 1.28) after transplantation (p < 0.05). Endothelial edema index,
      a measure of endothelial swelling and cellular deposit accumulation, increased
      more than 119 percent in the allograft group 72 hours after transplantation (1.23
      +/- 0.07 versus 1.46 +/- 0.09) (p < 0.05). The first clinical signs of limb
      rejection were scaling of the skin or hair loss; they were observed between the
      seventh and ninth postoperative days. The composite rat hindlimb-cremaster model
      presented in this study introduces a new in vivo approach to monitor acute graft
      rejection using the intravital microscopy system. This is a valuable model for
      defining the timing, sequence, and correlation between immunologic events and
      clinical signs during the acute phase of allograft rejection.

PMID- 10359258
TI  - Secondary expansion of a replanted scalp salvaged by an intrinsic arteriovenous
      shunt.
AB  - 1. Although scalping injuries reported in most large series rarely involve young
      children, partial scalp replantation, even in a 2-year-old boy after a dog-bite
      avulsion, should also be warranted. However, technical difficulties because of
      the diminutive vasculature can be expected. 2. Unconventional methods for
      reestablishing inflow or outflow for the replanted scalp may become the only
      practical alternative and must not be overlooked. In this case, an arteriovenous
      shunt between the frontal branch of the superficial temporal artery within the
      amputated part itself to a more distal scalp vein at the superior edge of the
      fragment allowed high-output flow to maintain patency after recurrent thromboses
      of the conventional superficial temporal arterial anastomosis. This fistula was
      assumed to be the major contributor to nutrient flow of the remaining scalp, as
      the parietal branch was truncated along the margin of the avulsion. 3. Delayed
      tissue expansion is also an option. In this case, delayed expansion of the
      replanted scalp that survived allowed elimination of the skin grafts needed to
      cover areas where necrosis ensued, restoration of the anterior hairline, and
      resulted in a more normal appearance.

PMID- 10359259
TI  - Subtotal maxillectomy for melanotic neuroectodermal tumor of infancy.
AB  - Melanotic neuroectodermal tumor of infancy is a rare pigmented neoplasm occurring
      in infants before 1 year of age. It is a rapidly growing tumor that most
      frequently affects the craniofacial skeleton. Although melanotic neuroectodermal
      tumor of infancy is benign in the vast majority of cases, inadequate excision,
      occasional multicentricity, and a small malignant potential result in a fairly
      high recurrence rate. On the basis of data obtained from the literature and our
      clinical experience, we advocate an aggressive surgical approach consisting of
      complete surgical excision when vital structures are not involved.
      Histopathologic confirmation of complete excision is mandatory to minimize the
      risk of recurrence and provide the patient with curative treatment and minimal
      morbidity.

PMID- 10359260
TI  - Desmoplastic fibroma of the zygoma.
AB  - Desmoplastic fibroma is an exceedingly rare primary bone tumor. Previous reports
      have not included the presentation of this tumor associated with the zygoma. This
      report describes the unusual presentation and surgical management of a
      desmoplastic fibroma of the zygoma.

PMID- 10359261
TI  - The clinical, histologic, and ultrastructural presentation of polyvinyl sponge
      (Ivalon) breast prostheses removed for massive fluid accumulation.
AB  - The current study describes what we believe is the first report of bilateral
      massive seromas associated with open-cell Ivalon sponges. Additionally, the
      gross, histologic, and ultrastructural features consistent with previous reports
      of polyvinyl alcohol prostheses are presented. Despite the reported chemical
      inertness of polyvinyl alcohol, this material may incite a biologic response in
      some patients, leading to dense fibrosis and occasional foreign-body giant-cell
      reaction. It is postulated that the molecular breakdown products of the polyvinyl
      alcohol polymer may create an osmotic gradient across the periprosthetic capsule,
      which may lead to intracapsular fluid accumulation, as presented in this case.

PMID- 10359263
TI  - Preventing postoperative noise in saline breast implants.
AB  - The occurrence of postoperative noise in saline breast implants is caused by
      inadvertent retention or injection of air during filling at the time of
      implantation. A volume of air as small as 2 cc in most breast implant sizes can
      result in this phenomenon. A simple method of prefilling and aspiration of saline
      before implantation can completely eliminate the possibility of its postoperative
      occurrence.

PMID- 10359262
TI  - The use of iliac bone flap as a penile stiffener in a diabetic patient with
      erectile dysfunction.
AB  - A diabetic man with erectile dysfunction in whom two previous attempts at penile
      prosthesis implantation had failed was treated by using an iliac bone flap as a
      penile stiffener. The patient had satisfactory sexual function with his penis; it
      retained its size and stiffness during the 1-year follow-up period. We recommend
      this method for use in patients in whom multiple earlier attempts at penile
      prosthesis implantation were unsuccessful.

PMID- 10359264
TI  - A novel method of securing the nail following nail bed repair.

PMID- 10359265
TI  - Reverse flow instep island flap.
AB  - The retrogradely perfused medial plantar artery flap was used in a leprosy
      patient with a plantar ulcer over the heads of the second and third metatarsals.
      The flap is based on the anastomosis of the medial plantar artery with the branch
      of the first plantar metatarsal artery, which supplies the medial side of the
      great toe. This design provides reconstruction with like local tissues while not
      distorting the weight-bearing pattern of the foot.

PMID- 10359266
TI  - Vilray P. Blair, his surgical descendants, and their roles in plastic surgical
      development.
AB  - Perhaps one of the most historically well-known plastic surgeons is Vilray P.
      Blair. As commander of the U.S. Army corps of head and neck surgeons during World
      War I, he became well known for his work in posttraumatic reconstruction. Blair's
      efforts in the early part of this century helped to develop plastic surgery as a
      distinct surgical subspecialty in the United States. His prowess as a surgeon
      allowed him to build one of the largest plastic surgery centers in the country
      and to train many of the top young American surgeons. Blair excelled as a
      teacher. He produced academic surgeons such as James Barrett Brown and Bradford
      Cannon, who took the lead in the care of wartime injuries during World War II. At
      Valley Forge General Hospital, Blair's trainees dedicated themselves to the
      reconstruction of injured patients and trained other young plastic surgeons in
      the care of postwar trauma. This exceptional level of patient care resulted in
      the U.S. government recognizing plastic surgery as a subspecialty following World
      War II. Since that time, Blair's surgical descendants at Washington University
      have led the country in the development of new training concepts and ideals and
      have gone on to become leaders in plastic surgery worldwide.

PMID- 10359267
TI  - Simplifying cosmetic surgery: improving safety or refinement?

PMID- 10359268
TI  - Changes in compliance predict pulmonary morbidity in patients undergoing
      abdominal plication.
AB  - The incidence and severity of the effects of pulmonary compliance changes were
      investigated in patients undergoing abdominal plication surgery. A total of 20
      healthy adults scheduled for abdominal plication surgery who had no significant
      history of pulmonary disease and 20 adults scheduled for nonabdominal,
      nonthoracic surgery (control group) underwent general endotracheal anesthesia;
      neuromuscular blockade was confirmed with electrical twitch monitoring. Before
      abdominal plication, the mean airway compliance was measured under total
      neuromuscular blockade at 33.4 +/- 2.1 ml/cm water, which was not significant
      when compared with control patient values. After abdominal plication was
      performed, the mean airway compliance was remeasured under total neuromuscular
      blockade; it was significantly decreased at 24.0 +/- 1.8 ml/cm water when
      compared with values for control patients (32.6 +/- 1.6 ml/cm) and with
      preplication values. Patients with airway compliance changes of less than 4 ml/cm
      water (when compared with preplication pulmonary mechanics) had far less
      incidence of atelectasis, requirements for supplemental oxygen at 24 hours or
      longer, or hypoxia when compared with patients with compliance changes of greater
      than 4 ml/cm water. Patients with compliance changes greater than 9 ml/cm water
      had the highest incidence of pulmonary morbidity. These data suggest that
      significant changes in pulmonary compliance occur after abdominal plication and
      that these airway compliance changes are associated with a clinically increased
      incidence of pulmonary morbidity in the postoperative period.

PMID- 10359269
TI  - Sensory changes after traditional and ultrasound-assisted liposuction using
      computer-assisted analysis.
AB  - Postoperative sensory changes (i.e., hypesthesias) that occur after suction
      assisted lipoplasty (SAL) are expected clinical sequelae. These disturbances
      usually return to normal within several weeks to months postoperatively. The
      presumed mechanism of injury is direct trauma to the peripheral nerves from the
      suction cannula. In addition, the potential for demyelination of peripheral
      nerves secondary to cavitation during ultrasound-assisted liposuction (UAL) is
      well known. Quantitative data describing hypesthesia after both procedures are
      limited. The purpose of this study was to objectively evaluate the severity and
      duration of postoperative hypesthesia after liposuction to better educate
      patients preoperatively. Furthermore, the authors use the three-stage UAL
      technique and wanted to determine whether a clinical difference in sensory return
      existed between suction- and ultrasound-treated areas. A total of 21 patients
      underwent liposuction performed by the senior author (RJ.R.). The abdomen,
      flanks, thighs, and medial knees were tested for objective sensation with the
      Pressure Specified Sensory Device preoperatively and at 2, 6, and 10 weeks
      postoperatively. A total of 102 sites were tested. On average, the SAL-treated
      areas improved to normal sensation by 6 weeks, whereas the UAL-treated areas
      took, on average, 10 weeks to recover. The severity of the hypesthesia was not
      correlated with larger aspiration volumes or longer UAL exposure time per site.
      At 10 weeks, 90 percent of UAL-treated patients and 89 percent of liposuction
      patients overall had recovered normal sensation. This study provides the body
      contouring surgeon with good, objective data with which to educate patients
      regarding sensory return after liposuction.

PMID- 10359270
TI  - A simplified transblepharoplasty subperiosteal cheek lift.
AB  - Surgical treatment of the aging face is continuing to evolve. Recent emphasis has
      focused on managing the malar region, specifically ptosis of the cheek pad.
      Several authors have described techniques for correcting facial aging changes in
      the midface through an endoscopic approach or transblepharoplasty approach. The
      latter procedure requires a lateral canthoplasty, which adds technical difficulty
      and potential complications to the procedure. We have modified these procedures
      and now perform a simplified transblepharoplasty subperiosteal cheek lift without
      routine canthoplasty or canthopexy. Sixty patients who had this procedure were
      evaluated. Analysis of these patients revealed that our simplified approach to
      transblepharoplasty subperiosteal cheek lift provides excellent correction of
      midfacial aging changes with a low incidence of postoperative complications. This
      article describes this technique and reviews our results.

PMID- 10359271
TI  - Algorithm for canthoplasty: the lateral retinacular suspension: a simplified
      suture canthopexy.
AB  - Results of aesthetic lower eyelid surgery have improved through a better
      understanding of the anatomy, indications for surgery, and more effective,
      individualized solutions for the varied problems. Most treatment options have the
      potential risk of inducing lower eyelid malposition if support is not applied
      through either canthoplasty or canthopexy. An algorithm for selecting the most
      appropriate method of canthal support in lower eyelid and midfacial rejuvenation
      is presented. A new, simplified, effective, and aesthetic suture canthopexy, the
      transpalpebral lateral retinacular suspension, is introduced; it can be
      universally applied.

PMID- 10359272
TI  - Anatomy of the buccal fat pad and its clinical significance.

PMID- 10359273
TI  - The Gordian knot of multiple authorship.

PMID- 10359274
TI  - Man's best friend revisited: who's watching the children?

PMID- 10359276
TI  - Tangentially split gluteus maximus myocutaneous island flap based on perforator
      arteries for the reconstruction of pressure sores.
AB  - From 1995 to 1997, the authors used tangentially split gluteus maximus
      myocutaneous island flaps based on the musculocutaneous perforator arteries for
      the reconstruction of pressure sores located in the trochanteric, sacral, and
      ischial regions of 30 ambulatory and paraplegic patients. The postoperative
      follow-up period was 18 months. Postoperative electromyograms were performed on
      the ambulatory patients to compare the function of the gluteus maximus muscles on
      each side. There were one major and two minor postoperative complications. There
      was no total flap loss. The major advantage of this technique is the preservation
      of most of the gluteus maximus for stair climbing and single-limb support in the
      ambulatory patient. The tangentially split gluteus maximus myocutaneous island
      flap is recommended as the procedure of choice for closure of sacral, ischial,
      and trochanteric ulcers in both the ambulatory and nonambulatory patient.

PMID- 10359277
TI  - Melanoma of the eyelid.

PMID- 10359278
TI  - MacGyver Midface.

PMID- 10359279
TI  - Be careful: it might be a nasal dermoid cyst.

PMID- 10359280
TI  - Endoscopic excision and repair of simulated bilateral cleft lips in fetal lambs.

PMID- 10359281
TI  - Hypertrophic mental tubercle of the mandible.

PMID- 10359282
TI  - Thermal injuries as a result of CO2 laser resurfacing.

PMID- 10359283
TI  - Squamous cell carcinoma arising from a hydrochloric acid burn.

PMID- 10359284
TI  - A bone distraction for the face.

PMID- 10359285
TI  - Umbilicated or retractile nipples?

PMID- 10359286
TI  - A simple device for marking the areola in vertical mammaplasty.

PMID- 10359287
TI  - Preoperative infiltration with lidocaine and epinephrine for breast reduction.

PMID- 10359288
TI  - Reevaluating the need for routine drainage in reduction mammaplasty.

PMID- 10359289
TI  - Reevaluating the need for routine drainage in reduction mammaplasty.

PMID- 10359290
TI  - A tribute to Dr. Carl Hartrampf.

PMID- 10359291
TI  - Brown pigmentation with double lumen breast implants.

PMID- 10359292
TI  - Breast implants: are we following the norms of plastic surgery?

PMID- 10359293
TI  - An inexpensive infusion cannula for injection of tumescent mixtures for
      liposuction.

PMID- 10359294
TI  - Combined median and ulnar entrapment neuropathies.

PMID- 10359295
TI  - Tie-over dressing using a buckle.

PMID- 10359296
TI  - Lipoma induced by pigmented villonodular synovitis of the ankle.

PMID- 10359297
TI  - Primary correction of unilateral cleft nose: a more accurate diagram.

PMID- 10359298
TI  - Mycobacterium ulcerans--a mini-review.

PMID- 10359299
TI  - Occurrence of methicillin-resistant and -susceptible Staphylococcus aureus within
      a single colony contributing to MRSA mis-identification.
AB  - Many methods have been described for the detection of methicillin-resistant
      Staphylococcus aureus (MRSA), but the homogeneous or heterogeneous expression of
      methicillin resistance affects the reliability of those methods. This study
      demonstrates that close association between methicillin-susceptible S. aureus
      (MSSA) and MRSA strains in the host colonisation site can present additional
      problems for the detection of MRSA in clinical laboratories, which may contribute
      to failure in the control of MRSA infection in hospital. Worse, this association
      may also account for the emergence of MRSA during antibiotic therapy.

PMID- 10359300
TI  - Significance of Cryptosporidium in acute diarrhoea in North-Eastern India.
AB  - In a hospital-based study, stool samples from 2095 patients of all ages were
      examined for different fungal, protozoal and bacterial enteropathogens over a
      period of 2 years (July 1994-June 1996). Cryptosporidium was detected in 151
      specimens (7.2%) and was the third commonest pathogen found. The highest
      prevalence of this organism was in the group aged 16-45 years and during the
      rainy months (July-Oct.). Diarrhoea caused by the protozoon was of mild to
      moderate severity and features of dysentery were absent. Amongst other
      enteropathogens, Candida albicans was the most frequently isolated, followed by
      enteropathogenic and enterotoxigenic Escherichia coli, Salmonella spp.,
      Campylobacter jejuni, Entamoeba histolytica, Giardia duodenalis (lamblia),
      Shigella spp., Vibrio cholerae and Aeromonas spp.

PMID- 10359301
TI  - Growth, cellular differentiation and virulence factor expression by Proteus
      mirabilis in vitro and in vivo.
AB  - A uropathogenic strain of Proteus mirabilis was grown in vitro in human and mouse
      urine and brain-heart infusion broth (BHIB) and in vivo in subcutaneous open
      chambers (SOC) in mice, intraperitoneal diffusion chambers (IPC) in rats and by
      ascending urinary tract infection in mice in order to compare growth pattern,
      cellular differentiation and expression of virulence factors. Although the growth
      rate was slower in vivo than in vitro, the extent of growth was similar after 24
      h. PR mirabilis differentiated into filamentous swarmer cells in all in-vitro
      culture conditions, but no filamentous cells were observed in either of the in
      vivo chamber models. Transurethrally infected mice showed a rapid release or loss
      of filamentous cells and these could not be seen in kidney or bladder homogenates
      7 days after infection. Bacteria showed increasing haemagglutination titres for
      fresh and tanned red blood cells after subculturing in BHIB, but bacteria grown
      in vivo did not show haemagglutination. An increasing resistance to normal serum
      was found when bacteria were grown in vivo. Significant haemolytic activity was
      detected with bacteria grown in BHIB and IPC, but almost no activity was found
      when bacteria had grown in urine. These findings improve the understanding of the
      role of P. mirabilis uropathogenic virulence factors in vivo.

PMID- 10359302
TI  - Effect of glucose and pH on uropathogenic and non-uropathogenic Escherichia coli:
      studies with urine from diabetic and non-diabetic individuals.
AB  - It is generally assumed that one of the reasons why diabetics are more
      susceptible to urinary tract infections than non-diabetics is their 'sweet
      urine'. However, very little information is available on this subject. Therefore,
      the growth rates of different Escherichia coli strains were studied in human
      urine with and without added glucose and with and without a constant pH, and
      compared with their growth rates in Mueller-Hinton broth (MHB). Eight isolates
      were used (three from blood cultures from urosepsis patients, two urinary
      isolates, two faecal isolates and one laboratory strain K12). All isolates grew
      better in MHB than in urine, but with the exception of the laboratory strain,
      they had the same growth rate in urine. No significant difference was found
      between the growth rate in urine from diabetics without glucosuria and that in
      urine from non-diabetics. The addition of glucose (up to a concentration of 1000
      mg/dl) to urine and MHB enhanced the growth rate of all isolates. However, very
      high concentrations of glucose (up to 10000 mg/dl) in urine and MHB caused a
      decrease in bacterial growth rate when the urinary pH was not kept constant. The
      stationary phase was reached later and the final bacterial yield was greater when
      the urine was made less acidic. As the uropathogenic strains did not grow better
      in urine than the other isolates, it may be concluded that better growth in urine
      is not one of the causes of the greater virulence of these strains.

PMID- 10359303
TI  - Ability of lactoferrin to promote the growth of Bifidobacterium spp. in vitro is
      independent of receptor binding capacity and iron saturation level.
AB  - Lactoferrin (Lf) is an iron-binding protein which has been shown to inhibit the
      growth of various bacterial pathogens and promote the growth of anaerobic
      bacteria of the genus Bifidobacterium in vitro. The present study was designed to
      investigate whether the bifidobacteria growth promotion activity of Lf is
      correlated with either the binding of Lf to bifidobacterial cells or the iron
      saturation of Lf. Bovine Lf (bLf) from mature milk increased the growth of B.
      infantis and B. breve in vitro in a dose-dependent fashion, while much less
      growth promotion activity was found for B. bifidum. In contrast, human Lf (huLf)
      from mature milk promoted the growth of B. bifidum and was inactive for B.
      infantis and B. breve, while bLf from colostrum was devoid of bifidobacteria
      growth promotion activity. Changes in the iron content of Lf did not alter the
      bifidobacteria growth promotion activity of either bLf or huLf preparations.
      Competitive binding studies with biotinylated milk bLf showed that binding of bLf
      was inhibited by unlabelled bLf and huLf but not by beta-lactoglobulin, alpha
      lactalbumin or transferrin. Binding of bLf to B. bifidum and B. breve was c. 40
      fold higher than binding to Escherichia coli. Colostrum bLf was also found to
      bind to B. bifidum and B. breve, despite a lack of in-vitro growth promotion
      activity. Collectively, these results demonstrate that the ability of Lf to
      promote the growth of Bifidobacterium spp. in vitro is independent of the iron
      saturation level for Lf and suggest that binding of Lf to bifidobacteria cells
      may be involved but is not sufficient for stimulation of bifidobacterial growth.

PMID- 10359305
TI  - Phenotypic and genotypic typing of food and clinical isolates of Enterobacter
      sakazakii.
AB  - Enterobacter sakazakii, designated a unique species in 1980, has been implicated
      as the causative organism in a rare but severe form of neonatal meningitis. Dried
      infant formula milk has been identified as a potential source of the organism. E.
      sakazakii isolates from dried infant formula available in Canada and clinical
      isolates obtained from Canadian hospital culture collections were characterised
      by phenotypic (biotype and antibiograms) and genotypic (ribotyping, random
      amplification of polymorphic DNA and pulsed-field gel electrophoresis) methods.
      Three biotypes and four antibiogram patterns were observed in the 18 isolates
      examined. Ribotyping with the Dupont Riboprinter microbial identification system
      divided the 18 isolates into 10 ribotypes. Three isolates from the same hospital
      had indistinguishable ribotyping patterns although each was isolated in a
      different year, as did three food isolates from one company. Pulsed-field gel
      electrophoresis (PFGE) and random amplification of polymorphic DNA (RAPD)
      profiles indicated minor differences between the isolates that were
      indistinguishable by ribotyping. PFGE (with the restriction endonucleases Xba1
      and Spe1) and RAPD gave discrete patterns that enabled easy comparison of E.
      sakazakii isolates, with a high degree of discrimination. The discriminatory
      index showed RAPD and PFGE were shown to be the most discriminatory typing
      schemes for E. sakazakii, followed by ribotyping, biotyping and antibiograms.

PMID- 10359304
TI  - A novel mucin-sulphatase activity found in Burkholderia cepacia and Pseudomonas
      aeruginosa.
AB  - Lung infections due to Burkholderia cepacia and Pseudomonas aeruginosa in
      patients with cystic fibrosis (CF) are common, are associated with respiratory
      morbidity and are a cause of mortality. Respiratory mucin in CF patients is
      highly sulphated, which increases its resistance to bacterial degradation.
      Desulphation increases the susceptibility of mucin to degradation by bacterial
      glycosidases and proteinases, and subsequent deglycosylation may facilitate
      bacterial colonisation by increasing available substrates and binding sites. This
      study determined whether clinical and environmental strains of B. cepacia and P.
      aeruginosa had the ability to desulphate mucin. Mucin-sulphatase activity was
      tested by incubating bacterial cell suspensions with 35S-sulphated mucins
      purified from LS174T and HT29-MTX human colon carcinoma cell lines. These mucins
      were also used to test for differences in substrate specificities. Mucin
      sulphatase activity was detected in all nine B. cepacia strains and in four of
      six P. aeruginosa strains. There was strain variability in the level of mucin
      sulphatase activity. Aryl-sulphatase activities of Pseudomonas isolates
      (determined with methylumbelliferyl sulphate) were c. 20-fold higher than those
      of B. cepacia strains, and were independent of mucin-sulphatase activity. This is
      the first report to demonstrate desulphation of mucin by B. cepacia and P.
      aeruginosa. It is concluded that B. cepacia and P. aeruginosa produce one or more
      cell-bound glycosulphatase(s), in addition to aryl-sulphatase activity. Mucin
      sulphatase activity of B. cepacia and P. aeruginosa may contribute to their
      association with airway infections in patients with cystic fibrosis.

PMID- 10359306
TI  - Molecular epidemiology of poliovirus infection in Tunisia.
AB  - This report is an overview of poliomyelitis surveillance in Tunisia from 1991 to
      1996. In all, 2088 stool specimens, collected from 152 acute flaccid paralysis
      (AFP) cases and from 1747 of their healthy contacts were investigated. Virus
      isolation was done systematically in RD and HEp-2C cell lines and isolated
      viruses were typed by sero-neutralisation as polioviruses or non-polio
      enteroviruses. Poliovirus isolates were analysed systematically for their wild or
      vaccine-related origin by two methods--one based on antigenic differences and one
      on genetic differences between strains. All type 2 polioviruses were vaccine
      related and most wild viruses belonged to polio serotype 3. Wild polio type 3
      viruses were detected in 1991 and 1992 in six cases of paralytic polio. A silent
      circulation of wild polio 1 and wild polio 3 was detected in 1994. No wild virus
      was detected in Tunisia from 1995 onwards. Wild polioviruses were sequenced and
      compared with Tunisian wild strains isolated during the 1980s, as well as other
      genotypes from the international database. These investigations revealed a single
      Tunisian polio 3 genotype that has been circulating from 1985 to 1994 and two
      different polio 1 genotypes. These results reflect effective control strategies
      within the country and contribute to the improvement of the polio eradication
      programme effectiveness at national and global levels.

PMID- 10359307
TI  - Mycobacterium avium infection in BALB/c and SCID mice.
AB  - BALB/c and severe combined immunodeficient (SCID) mice were inoculated
      intraperitoneally with Mycobacterium avium and the numbers of cfu were monitored
      for 70 days in spleen, liver, lung, kidney, brain and peritoneum. While BALB/c
      mice formed typical granulomas and controlled bacterial growth in organs, a delay
      in development of lesions and a modest containment of infection were observed in
      SCID mice. In the spleen of BALB/c mice, in which bacterial growth was contained,
      macrophages (Mo) and natural killer (NK) cell numbers increased > or = 4.2 times
      and T- and B-cell numbers increased > or = 1.8 times after 42 days of infection;
      conversely, a low recruitment of mononuclear cells was observed in the spleen of
      SCID mice, where M. avium proliferated efficiently. Unlike visceral organs, a
      pronounced decrease in the number of cfu was observed in the peritoneum of BALB/c
      mice, concomitantly with a > or = 31.7-fold increase in Mo and NK cells and a >
      or = 9.1-fold increase in T and B cells. In the peritoneum of SCID mice only a
      bacteriostatic effect was observed despite a > or = 56.7-fold increase in Mo and
      NK cells and a > or = 22.3-fold increase in T and B cells. These results suggest
      that while an intact immune response can efficiently control M. avium infection
      in the spleen and peritoneum of BALB/c mice, cells of the innate immune system
      such as Mo and NK cells play a role in the containment of bacterial growth in the
      peritoneum, but not spleen, of SCID mice.

PMID- 10359308
TI  - Isolation and partial characterisation of the Triton X-100 solubilised protein
      antigen from Mycobacterium tuberculosis.
AB  - This report describes extraction of a new native antigen fraction from
      Mycobacterium tuberculosis without massive degradation of proteins by Triton X
      100. The Triton X-100 solubilised protein (TSP) antigen showed a characteristic
      antigen profile and reproducible extraction pattern. To characterise the nature
      of their composition, the TSP antigen was fractionated by Triton X-114 phase
      partitioning. The TSP antigen contained a variety of lipids and glycoconjugates
      as well as diverse proteins. Most proteins were partitioned into the aqueous
      phase during phase fractionation, whereas non-protein molecules and lipoproteins
      were recovered in the detergent phase. The lymphoproliferative responses to the
      TSP aqueous fraction in healthy tuberculin reactors were significantly higher
      than those to the purified protein derivative (PPD) and unfractionated TSP. In
      contrast, the antibody responses to TSP aqueous fraction in tuberculosis patients
      showed weak reactivity. This study suggests that the TSP aqueous fraction can be
      used as a T-cell antigen associated with protective immunity against
      tuberculosis.

PMID- 10359309
TI  - Absorption of IgG does not enhance toxoplasma IgM and IgA immunoblotting.
AB  - Total IgG, IgM and IgA levels and toxoplasma IgG, IgM and IgA immunoblotting
      patterns were assayed in 10 sera before and after IgG absorption with Protein G
      Sepharose 4. Removal of IgG (mean reduction 96%) was accompanied by a significant
      reduction in the level of IgM (mean reduction 56%) and IgA (mean reduction 53%)
      in nine of the 10 sera. The absorbed supernates showed fewer and weaker IgM bands
      in five sera, but IgA immunoblotting patterns were unaffected by absorption.
      There was no benefit in removing IgG in toxoplasma IgM and IgA immunoblotting.

PMID- 10359310
TI  - Distribution of aggA and aafA gene sequences among Escherichia coli isolates with
      genotypic or phenotypic characteristics, or both, of enteroaggregative E. coli.
AB  - Two types of fimbriae, designated aggregative adherence fimbria I and II (AAF/I
      and AAF/II) have been described in enteroaggregative Escherichia coli (EAEC)
      strains. These fimbriae mediate the aggregative pattern of adherence (AA) to
      epithelial cells. The genes encoding the structural subunit of each fimbria have
      been designated aggA and aafA, respectively. The prevalence of these genes was
      investigated in 155 faecal EAEC isolates that displayed AA to HeLa cells and were
      isolated from children in Sao Paulo, Brazil. Hybridisation assays with aggA and
      aafA sequences showed that 9.7% of these isolates carried aggA, 3.9% aafA, and
      none hybridised with both sequences. Of the 78 isolates displaying AA that
      reacted with the previously described EAEC probe (CVD432), 19.2% and 7.7%
      hybridised with the aggA and aafA probes, respectively. None of the 77 isolates
      displaying AA but lacking the EAEC probe sequence hybridised with either probe.
      These results clearly indicate that additional factors are involved in the AA
      phenotype in these EAEC strains.

PMID- 10359311
TI  - Fatal Campylobacter jejuni bacteraemia in patients with AIDS.
AB  - Two fatal cases of Campylobacter jejuni septicaemia in patients with AIDS were
      characterised by severe HIV-related immunodeficiency, negative stool cultures and
      presentation during hospitalisation, developing a clinical picture of fulminant
      septic shock despite therapy with appropriate antibiotics. Campylobacter spp. are
      important opportunist pathogens in HIV disease and may cause a septicaemic
      illness in the absence of enteric disease.

PMID- 10359312
TI  - Parallel processing in the mammalian retina: the Proctor Lecture.

PMID- 10359313
TI  - Bacterial conjunctivitis in Muc1 null mice.
AB  - PURPOSE: In contrast to wild-type mice, genetically engineered Mucin1 (Muc1) null
      animals display a marked propensity for development of blepharitis and
      conjunctivitis. Molecular approaches confirmed the presence of Muc1 mRNA and
      protein in the conjunctival tissue of wild-type mice and identified the bacterial
      species in Muc1 null symptomatic mice. METHODS: Muc1 null animals housed in a
      conventional facility were examined for visually apparent inflammation of the eye
      and surrounding tissue. Blood taken from overtly affected animals was assayed for
      antibodies to common murine viral agents. Swabs of infected eyes and whole eye
      preparations were used to detect and speciate bacterial pathogens. Frozen
      sections of whole eye, lid margin, and Harderian gland were immunostained with
      antibodies to Muc1 and cytokeratin 14, both epithelial cell markers. Northern
      blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) were
      performed on RNA isolated from conjunctiva and Harderian gland of wild-type mice
      to compare relative levels of transcript. RESULTS: Student's unpaired t-test
      performed on the eye inflammation frequency of Muc1 null mice confirmed a
      statistical significance (P < 0.01) when compared to wild-type background animals
      housed in the same room. Analysis of blood samples from affected Muc1 null
      animals detected no common murine viral pathogens. Bacterial analysis of
      conjunctival swabs and whole eye preparations demonstrated the presence of
      coagulase-negative Staphylococcus, Streptococcus type alpha, and Corynebacterium
      group G2. Muc1 antibody staining of wild-type sections revealed the presence of
      Muc1 on conjunctival goblet and non-goblet cells and on the epithelium of the
      Harderian gland. Serial sections stained with cytokeratin 14 antibody confirmed
      the epithelial nature of cells expressing the Muc1 protein. RNA from conjunctiva
      and Harderian gland subjected to RT-PCR and northern blot analysis showed an
      abundance of Muc1 transcript in these tissues. CONCLUSIONS: Muc1 mRNA and protein
      are present in murine conjunctival and Harderian gland epithelia. Animals lacking
      Muc1 mRNA and protein are predisposed to developing eye inflammation when
      compared to wild-type animals with an intact Muc1 gene. Muc1 appears to play a
      critical protective role at the ocular surface, presumably by acting as a barrier
      to infection by certain bacterial strains.

PMID- 10359314
TI  - Soluble P-selectin glycoprotein ligand 1 inhibits ocular inflammation in a murine
      model of allergy.
AB  - PURPOSE: To assess the anti-inflammatory modality of a soluble extracellular form
      of P-selectin glycoprotein ligand 1 (sPSGL-1) in a mouse model of ocular allergic
      response. METHODS: Potential anti-inflammatory effects of sPSGL-1 were
      investigated in SWR/J mice sensitized by topical application of short ragweed
      pollen to the nasal mucosa followed by a challenge of the ocular mucosa with the
      same allergen. Five experimental groups were included in these studies: A, mice
      neither sensitized nor challenged with pollen (control group 1); B, animals
      sensitized but not challenged (control group 2); C, animals not sensitized but
      challenged (control group 3); D, animals sensitized and challenged; and E,
      sensitized animals treated with sPSGL-1 before pollen challenge. All experimental
      groups were evaluated for gross morphologic ocular changes, and histologic
      assessments were made to determine the onset/progression of inflammatory
      reactions and to look for evidence of eosinophil infiltration. RESULTS: Mice
      sensitized and challenged with pollen developed clinical signs consistent with
      human allergic conjunctivitis. These signs correlate with histologic changes in
      the conjunctival epithelium and stroma (e.g., edema and extensive eosinophil
      infiltration). Moreover, the ocular changes also correlated with evidence of
      eosinophil degranulation. However, sensitized and challenged mice concurrently
      treated with sPSGL-1 displayed no inflammatory ocular changes associated with a
      ragweed-induced type-1 hypersensitivity reaction. The lack of ocular changes
      included the absence of histologic late-phase inflammatory changes of the
      conjunctiva and a 97% reduction in the induced eosinophil infiltrate.
      CONCLUSIONS: The antagonistic intervention of cell- cell interactions through the
      blockade of selectin-dependent leukocyte adhesion may offer novel therapeutic
      strategies to modulate inflammatory responses. The potent inhibitory effects on
      eosinophil recruitment and late-phase inflammation suggest a role for sPSGL-1 in
      the treatment of ocular allergic diseases.

PMID- 10359315
TI  - Pax-6 interactions with TATA-box-binding protein and retinoblastoma protein.
AB  - PURPOSE: To identify proteins that physically interact with Pax-6, a paired
      domain- and homeodomain (HD)-containing transcription factor that is a key
      regulator of eye development. METHODS: Protein-protein interactions involving Pax
      6, TATA-box-binding protein (TPB), and retinoblastoma protein were studied using
      affinity chromatography with Pax-6 as ligand, glutathione-S-transferase (GST)
      pull-down assays, and immunoprecipitations. RESULTS: The authors have shown that
      Pax-6 is a sequence-specific activator of many crystallin genes, all containing a
      TATA box, in the lens. Others have shown that lens fiber cell differentiation,
      characterized by temporally and spatially regulated crystallin gene expression,
      depends on retinoblastoma protein. In the present study it was shown that Pax-6
      interacted with the TBP, the DNA-binding subunit of general transcription complex
      TFIID. GST pull-down assays indicated that this interaction was mediated by the
      Pax-6 HD, with a substantial role for its N-terminal arm and first two alpha
      helices. The experiments also indicated a binding role for the C-terminal
      activation domain of the protein. In addition, the present study showed that the
      HD of Pax-6 interacted with retinoblastoma protein. Immunoprecipitation
      experiments confirmed retinoblastoma protein/Pax-6 complexes in lens nuclear
      extracts. CONCLUSIONS: Blending the present results with those in the literature
      suggests that Pax-6 and retinoblastoma protein participate in overlapping
      regulatory pathways controlling epithelial cell division, fiber cell elongation,
      and crystallin gene expression during lens development.

PMID- 10359316
TI  - Changes in corneal wavefront aberrations with aging.
AB  - PURPOSE: To investigate whether corneal wavefront aberrations vary with aging.
      METHODS: One hundred two eyes of 102 normal subjects were evaluated with
      videokeratography. The data were decomposed using Taylor and Zernike polynomials
      to calculate the monochromatic aberrations of the cornea for both small (3-mm)
      and large (7-mm) pupils. RESULTS: For a 3-mm pupil, the amount of total
      aberrations (Spearman rank correlation coefficient r(s) = 0.145; P = 0.103) and
      spherical-like aberrations (r(s) = -0.068; P = 0.448) did not change with aging,
      whereas comalike aberrations exhibited a weak but statistically significant
      correlation with age (r(s) = 0.256; P = 0.004). For a 7-mm pupil, total
      aberrations (r(s) = 0.552; P < 0.001) and comalike aberrations (r(s) = 0.561; P <
      0.001) significantly increased with aging, but spherical-like aberrations showed
      no age-related changes (r(s) = 0.124; P = 0.166). Simulated pupillary dilation
      from 3 mm to 7 mm caused a 38.0+/-28.5-fold increase in the total aberrations,
      and the extent of increases significantly correlated with age (r(s) = 0.354; P <
      0.001). Pupillary dilation influenced the comalike aberrations more in the older
      subjects than in the younger subjects (r(s) = 0.243; P = 0.006), but such age
      dependence was not found for spherical-like aberrations (r(s) = 0.141; P =
      0.115). CONCLUSIONS: Comalike aberrations of the cornea correlate with age,
      implying that the corneas become less symmetrical along with aging. Spherical
      like aberrations do not vary significantly with aging. Pupillary dilation
      markedly increases wavefront aberrations, and those effects are more prominent in
      older subjects than in younger subjects.

PMID- 10359317
TI  - Loss of fenamate-activated K+ current from epithelial cells during corneal wound
      healing.
AB  - PURPOSE: The corneal epithelium provides a barrier between the external
      environment and the cornea. It also serves as an ion transporting epithelium.
      Because of its proximity with the external environment, the corneal epithelium is
      frequently injured through physical or chemical insult. The purpose of this study
      was to determine whether corneal epithelial cell whole-cell currents change
      during corneal wound healing as the author of the present study has previously
      reported for corneal keratocytes and endothelial cells. METHODS: Rabbit corneal
      epithelial cells were injured by scraping, heptanol exposure, or freezing. The
      epithelium was allowed to heal for 12 to 74 hours. Cells were dissociated from
      corneas, and whole-cell currents were examined using the amphotericin-perforated
      patch technique. RESULTS: Cells from the wounded corneal groups had significantly
      increased capacitance values, indicating increased surface area compared with
      that of control cells. As previously reported, the primary control whole-cell
      current was a fenamate-activated K+ current. An inwardly rectifying K+ current
      and a Cl- current were also observed. In epithelial cells from heptanol-wounded
      corneas, these conductances were generally unchanged. In cells from scrape- and
      freeze-wounded corneas, however, the fenamate-activated current was absent or
      significantly attenuated. CONCLUSIONS: As they do in corneal keratocytes and
      endothelial cells, K+ channels disappear during some models of corneal epithelial
      wound healing. In addition, cell capacitance, a measurement of cell surface area,
      increases. These results suggest that substantial K+ channel activity is not
      required for in vivo epithelial cell proliferation during corneal wound healing.

PMID- 10359318
TI  - Effect of PDGF, IL-1alpha, and BMP2/4 on corneal fibroblast chemotaxis:
      expression of the platelet-derived growth factor system in the cornea.
AB  - PURPOSE: The purpose of this study was to examine expression of platelet-derived
      growth factor (PDGF) and PDGF receptors in the human cornea and to study the
      effects of the PDGF isotypes on proliferation and chemotaxis of human corneal
      fibroblasts. The effects of interleukin (IL)-1alpha, bone morphogenic protein
      (BMP)2, and BMP4 on chemotaxis of human corneal fibroblasts were also studied.
      METHODS: mRNA expression was monitored with reverse transcription-polymerase
      chain reaction (RT-PCR) in primary cultured cells. Protein expression in fresh
      frozen human corneal sections was studied with immunocytology. Chemotaxis was
      measured using a modified Boyden chamber, and proliferation was quantitated by
      cell counting. RESULTS: PDGF A, PDGF B, PDGF receptor alpha, and PDGF receptor
      beta mRNAs were detected in corneal epithelial cells, fibroblasts, and
      endothelial cells in culture. The proteins were expressed in each major cell type
      in human corneal sections, with PDGF A and PDGF B detected at high levels in the
      epithelial basement membrane. PDGF, BMP2, and BMP4 had attractive chemotactic
      effects on corneal fibroblasts, with the PDGF BB dimer having a significantly
      greater positive chemotactic effect than the other PDGF isotypes. Interleukin
      1alpha had a repulsive chemotactic effect on corneal fibroblasts. PDGF AA, AB,
      and BB stimulated proliferation of human corneal fibroblasts. CONCLUSIONS: The
      PDGF growth factor receptor system is expressed in the human cornea. PDGF, BMP2,
      BMP4, and IL-1alpha may modulate keratocyte chemotaxis and proliferation during
      homeostasis and wound healing.

PMID- 10359319
TI  - High-resolution ultrasonic imaging of blood flow in the anterior segment of the
      eye.
AB  - PURPOSE: To develop a noninvasive technique to visualize and measure blood flow
      in the iris and ciliary body. METHODS: Echo data from 50-MHz ultrasound scans of
      the iris and ciliary body of rabbits were digitized using a new "swept scan"
      modality. The method makes use of spatial oversampling to identify regions with
      scatterers whose range changes with time. The data allowed construction of high
      resolution B-mode images with embedded flow information. Pulsatility over the
      cardiac cycle was evaluated by sending a series of pulses along a single line of
      sight containing a vessel of interest. Local blood flow and changes over the
      cardiac cycle before and after application of atropine were quantified. RESULTS:
      Flow was identified in the radial vessels and major arterial circle of the iris.
      Vessels with lumens as small as 40 microm in diameter and flow velocities as low
      as 0.6 mm/sec were measured. Change in blood velocity over the cardiac cycle was
      determined to be approximately 27%. Peak systolic velocity after administration
      of topical atropine increased by 72%. CONCLUSIONS: This technique allowed
      visualization of flow using the same type of very-high-frequency transducer now
      widely used for imaging the anterior segment. The technique can also be used at
      lower frequencies for more posterior tissues with similar improvement of
      resolution over Doppler. The ability to examine flow in the anterior segment of
      the eye offers a new tool for study of glaucoma, hypotony, tumors, and other
      disorders.

PMID- 10359320
TI  - Enthacrynic and acid effects on inner wall pores in living monkeys.
AB  - PURPOSE: The influence of the inner wall of Schlemm's canal on aqueous outflow
      facility remains poorly understood. We examined the relationship between inner
      wall pore characteristics and outflow facility in living primate eyes in which
      facility had been pharmacologically increased by ethacrynic acid (ECA) infusion
      and in contralateral control eyes. METHODS: Outflow facility (two-level constant
      pressure perfusion) was measured in eight pairs of living monkey eyes before and
      after administration of a bolus dose of either 0.125 mM ECA or vehicle. After
      exsanguination, eyes were fixed in situ under constant-pressure conditions (mean
      fixation pressure approximately 19 mm Hg). The density and diameter of inner wall
      pores and the number and area of platelet aggregates on the inner wall of
      Schlemm's canal were measured by scanning electron microscopy. RESULTS: In ECA
      treated eyes, outflow facility increased 63% (P < 0.0001), intracellular pore
      density decreased 46% (P = 0.0094), intracellular pore size increased 27% (P =
      0.049), platelet aggregate density increased 158% (P < 0.0001), and area covered
      by platelets increased 210% (P = 0.012) relative to contralateral controls.
      Although the average density and size of intercellular pores were essentially
      unaffected by ECA, an increased density of large (> or = 1.90 microm)
      intercellular pores was seen in ECA-treated eyes. The density of intracellular
      pores increased with the duration of fixative perfusion. Other than a weak
      negative correlation between outflow facility and intracellular pore density in
      ECA-treated eyes (P = 0.052), facility was not correlated with inner wall pore
      features. CONCLUSIONS: Our data are most consistent with a scenario in which ECA
      promotes formation of large intercellular pores in the inner wall of Schlemm's
      canal, which are then masked by platelet aggregates. Masking of intercellular
      pores, combined with fixation-induced alteration of inner wall pore density,
      greatly complicates attempts to relate facility to inner wall structure and
      suggests that in vivo pore density is smaller than in fixed tissue. Additionally,
      facility-influencing effects of ECA on the juxtacanalicular tissue cannot be
      excluded.

PMID- 10359321
TI  - Development of characterization of a immortal and differentiated murine
      trabecular meshwork cell line.
AB  - PURPOSE: To study mouse trabecular meshwork (TM) and to develop a murine TM cell
      line. METHODS: Mouse TM in situ was studied by light and electron microscopy
      (EM). In addition, TM was isolated from the H-2K(b)-tsA58 transgenic mouse strain
      in which promoter sequences of the major histocompatibility complex H-2Kb class 1
      gene are fused to sequences of the SV40 mutant temperature-sensitive (ts) strain
      tsA58. The promoter is inducible by interferon (IFN)-gamma, and the tsA58 gene
      product is active at 33 degrees C (permissive conditions), but not at 37 degrees
      C (nonpermissive conditions). The TM explant was cultured in permissive
      conditions. Outgrowing cells were passaged through two rounds of single-cell
      cloning. One clonal cell line (MUTM-NEI/1) was characterized in nonpermissive
      conditions by EM, immunohistochemistry, reverse transcription-polymerase chain
      reaction (RT-PCR), and northern blot hybridization. In addition, MUTM-NEI/1 cells
      were transfected with plasmid DNA. RESULTS: The mouse eye has a circumferentially
      oriented outflow vessel and a TM that is subdivided in an outer juxtacanalicular
      or cribriform part and an inner lamellated or trabecular part. From the TM of the
      H-2Kb-tsA58 mouse, a clonal cell line (MUTM-NEI/1) was established. In permissive
      conditions, MUTM-NEI/1 cells remained proliferative through at least 80
      generations without change in phenotype. In nonpermissive conditions,
      proliferation was slower, and MUTM-NEI/1 cells differentiated and synthesized
      collagen types I, III, IV, and VI; laminin; and fibronectin. MUTM-NEI/1 cells
      were immunoreactive for vimentin, alphaB-crystallin, and neural cell adhesion
      molecule (NCAM), but not for desmin or cytokeratin. Less than 10% of MUTM-NEI/1
      cells stained for alpha-smooth muscle actin, whereas after 3 days of treatment
      with transforming growth factor-beta1 almost all cells were positive. MUTM-NEI/1
      cells expressed mRNA for NCAM, aquaporin 1, myocilin/trabecular meshwork
      glucocorticoid-inducible protein, and alphaB-crystallin, which was increased
      after oxidative stress. MUTM-NEI/1 cells could be successfully transfected with
      plasmid DNA. CONCLUSIONS: The architecture of the murine outflow system is
      comparable to that in primates. The MUTM-NEI/1 cell line is a clonal, immortal,
      and differentiated TM cell line that will be an important tool for study of the
      expression of TM genes.

PMID- 10359322
TI  - Stimulation of maxi-K channels in trabecular meshwork by tyrosine kinase
      inhibitors.
AB  - PURPOSE: Muscarinic agonists contract and tyrosine kinase inhibitors relax
      precontracted trabecular meshwork, a smooth muscle-like tissue involved in the
      regulation of aqueous humor outflow. The effect of tyrosine kinase inhibitors on
      membrane currents of cells stimulated by acetylcholine was examined. METHODS:
      Cells from bovine trabecular meshwork were studied using both the perforated
      patch-clamp technique with nystatin and the single-channel technique. RESULTS:
      Application of the tyrosine kinase inhibitor genistein (5 x 10(-5) M) on
      trabecular meshwork cells stimulated with acetylcholine resulted in a reversible
      increase in outward current to 578%+/-154% (n = 16) of the initial current level.
      The effect of genistein was dose dependent. Reversal potential was hyperpolarized
      by 15+/-3 mV (n = 9). Tyrphostin 51, a synthetic inhibitor of tyrosine kinases,
      had the same effect (433%+/-46%; n = 7). Daidzein, a nonactive structural
      analogue of genistein, had no effect (n = 4). The stimulation of outward current
      by tyrosine kinase inhibitors was blocked by substitution of tetraethylammonium
      (TEA+) for potassium, whereas the potassium channel blockers glibenclamide (K
      ATP) and apamin (low-conductance calcium-activated potassium channel) had no
      effect. Blockage of the high-conductance calcium-activated potassium channel
      (maxi-K) by charybdotoxin or iberiotoxin (10(7) M) suppressed 86%+/-18% (n = 4)
      of the response. Depleting the cells of calcium did not have an effect on the
      current stimulated by genistein. In the excised inside-out configuration, open
      probability increased to 417%+/-39% (n = 3) after exposure to genistein.
      CONCLUSIONS: In trabecular meshwork, tyrosine kinase inhibitors activate maxi-K
      (K(Ca)) channels. Hyperpolarization caused by efflux of potassium could lead to
      the relaxation of trabecular meshwork by tyrosine kinase inhibitors.

PMID- 10359323
TI  - Effect of aqueous humor on apoptosis of inflammatory cell types.
AB  - PURPOSE: To determine whether aqueous humor promotes cell death in cells involved
      in inflammatory responses. METHODS: Multiple immune cell types, most
      characteristically involved in inflammatory responses, were incubated for 24, 48,
      and 72 hours in the presence or absence of 50% aqueous humor. Promotion of cell
      death was assayed by staining for an early indicator of apoptosis. The percentage
      of cells undergoing apoptosis was measured by flow cytometry. To identify
      partially the apoptosis inducing factor, aqueous humor was pretreated with
      proteinase K to degrade protein. In other experiments, aqueous humor was
      fractionated by centrifugation on filters capable of separating molecules above
      and below 10 kDa or 30 kDa kilodaltons in size. RESULTS: Rabbit aqueous humor
      promoted apoptosis in a wide variety of immune cells, including lymphokine
      activated natural killer cells, resting T cells, an activated T-cell line, RAW
      264.7 and J774A0.1 monocyte-macrophage cell lines, and neutrophils. As previously
      shown, aqueous humor did not promote apoptosis of murine corneal endothelial
      cells. Apoptosis was also not induced in human corneal endothelium, mouse corneal
      epithelium, or iris/ciliary body cell lines. Instead, aqueous humor partially
      protected these ocular tissues from starvation-induced cell death. Pretreatment
      with proteinase K inhibited the apoptosis-inducing activity. Moreover, the
      apoptosis-inducing activity segregated with the aqueous humor fraction containing
      molecules less than than 10 kDa in size. CONCLUSIONS: These data show that
      aqueous humor contains a factor or factors that promote death of cells that
      participate in inflammatory processes. By contrast, ocular tissues, such as the
      corneal endothelium and iris/ciliary body, are impervious to aqueous humor
      induced cell death. The aqueous humor- borne factor(s) may contribute to the
      immune privilege of the anterior chamber by purging potential inflammatory cells.

PMID- 10359324
TI  - Expression of cell adhesion molecules on limbal and neovascular endothelium in
      corneal inflammatory neovascularization.
AB  - PURPOSE: To investigate the expression of cell-adhesion molecules on corneolimbal
      and neovascular endothelium and the associated leukocyte infiltration in an
      experimental model of inflammatory corneal neovascularization (NV). METHODS:
      Corneal NV was induced in BALB/c mice by placement of nylon sutures. Interleukin
      1 receptor antagonist (IL-1ra) was used topically to determine whether
      suppression of IL-1 could affect adhesion molecule expression and leukocytic
      infiltration. At set time points, corneal samples were analyzed
      immunohistochemically for expression of P-selectin, E-selectin, intercellular
      adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, and platelet-
      endothelial adhesion molecule (PECAM)-1. Leukocytic infiltration at different
      time points was quantified histologically. In companion experiments mice
      deficient in ICAM-1 were investigated to determine the functional relevance of
      this molecule in corneal leukocyte infiltration. RESULTS: Significant enhanced
      expression of ICAM-1 was detected on the corneolimbal vascular endothelium as
      early as 8 hours and on the newly formed corneal NV by day 3, and treatment with
      IL-1ra led to significant suppression of this expression. IL-1ra-induced
      suppression of ICAM-1 expression was accompanied by a profound decrease in
      corneal leukocytic infiltration by 44.6% at day 1 (P < 0.003), 71.8% at day 3 (P
      < 0.001), 60.1% at day 7 (P < 0.001), and 63.8% at day 14 (P < 0.001), compared
      with control corneas. Similarly, in ICAM-1 knockout mice, the corneal leukocytic
      infiltration was 50.3%, 52.9%, and 36.4%, compared with wild-type control animals
      on day 1 (P < 0.001), day 7 (P < 0.005), and day 14 (P < 0.001), respectively.
      Expression of PECAM-1 was constitutively present on perilimbal vascular
      endothelium and had no response to IL-1ra treatment. No significant expression of
      P-selectin, E-selectin, or VCAM-1 was detected in this experimental model.
      CONCLUSIONS: These results suggest that leukocytic infiltration in this model of
      inflammatory corneal NV is closely associated with ICAM-1 expression, and that
      topical IL-1ra displays corneal anti-inflammatory effects, largely by suppressing
      ICAM-1 expression on vascular endothelial cells.

PMID- 10359325
TI  - Exogenous gene expression and protein targeting in lens fiber cells.
AB  - PURPOSE: To test the ability of lens fiber cells at various stages of
      differentiation to transcribe and translate microinjected DNA templates. METHODS:
      Expression plasmids encoding green fluorescent protein (GFP) or a GFP-tagged
      membrane protein (human CD46) were microinjected into organ-cultured embryonic
      chicken lenses. Protein expression was visualized by confocal microscopy.
      RESULTS: GFP expression was detected within 12 hours of microinjection, evenly
      distributed throughout the cytoplasm of the injected cell. All nucleated fiber
      cells were competent to express GFP, whereas the anucleated central fiber cells
      were not. When GFP was fused to the C-terminal of CD46, the fusion protein was
      synthesized intact and properly inserted in the fiber cell plasma membrane. In
      contrast, N-terminal fusions were cleaved during synthesis, resulting in
      retention of the GFP tag in the endoplasmic reticulum. CONCLUSIONS:
      Microinjection of expression plasmids is an effective technique for introducing
      exogenous genes into individual fiber cells. With this approach, the results show
      that fiber cells are transcriptionally and translationally competent until the
      time of organelle loss, and that fiber cells deep within the lens are capable of
      synthesizing new plasma membrane proteins. The techniques described here should
      have broad application in studies of fiber cell differentiation and provide a
      useful complement to conventional transgenic approaches.

PMID- 10359326
TI  - Lens epithelium-derived growth factor: increased resistance to thermal and
      oxidative stresses.
AB  - PURPOSE: To investigate the role of lens epithelium- derived growth factor
      (LEDGF) in lens epithelial cells subjected to heat or oxidative stress and to
      determine the localization of LEDGF in lens epithelial cells at different
      temperatures. METHODS: Mouse lens epithelial cells overexpressing a fusion
      protein between a green fluorescent protein (GFP) and LEDGF (GFP-LEDGF) were
      cultured for up to 7 days at various temperatures or for 24 hours in the presence
      of hydrogen peroxide. Translocation of GFP-LEDGF in the lens epithelial cells was
      monitored with a fluorescence microscope. Cell survival was determined with the
      trypan blue dye exclusion test. Expression of heat shock proteins (Hsps) was
      studied with protein blot analyses using antibody probes. RESULTS: LEDGF was
      found in the cytosol of lens epithelial cells at 4 degrees C, 15 degrees C, and
      28 degrees C, and in the nucleus and nucleolus at 37 degrees C. At 41 C, it was
      apparent at higher levels in the cytosol, nucleus, and nucleolus. Lens epithelial
      cells overexpressing LEDGF manifested resistance to thermal and oxidative stress.
      Levels of Hsp 27, and alphaB-crystallin were elevated in these cells. Depriving
      lens epithelial cells of LEDGF with anti-LEDGF antibodies reduced nuclear
      localization of LEDGF and induced cell death. CONCLUSIONS: The overexpression of
      LEDGF in lens epithelial cells conferred resistance to thermal and oxidative
      stress. The mechanism of this resistance appears to involve the increased
      expression of Hsp 27 and alphaB-crystallin.

PMID- 10359327
TI  - Lens epithelia contain a high-affinity, membrane steroid hormone-binding protein.
AB  - PURPOSE: To describe the serendipitous discovery of a high-affinity, membrane
      steroid-binding protein (MSBP) in lens epithelial cells and to examine the
      binding of progesterone to epithelial cell membranes. METHODS: Bovine lens
      epithelial cells (BLECs) were cultured in media containing 3H-mevalonolactone to
      examine protein prenylation by mevalonate-derived isoprenes. Cell proteins were
      divided into insoluble and soluble fractions, separated by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE) and label detected by fluorography.
      Insoluble proteins were then fractionated on a C18 reversed-phase column. A high
      performance liquid chromatography fraction containing a 28kDa 3H-labeled
      hydrophobic protein was collected, lyophilized, and subjected to SDS-PAGE and the
      separated proteins transferred to membrane. Protein in the recovered 28-kDa band
      was submitted for identification by N-terminal sequence analysis. Microsomal
      membranes prepared from fresh epithelia of intact bovine, rat, and human lens and
      cultured BLECs were tested for the presence of MSBP by western blot analysis
      using an antiserum to porcine liver microsomal MSBP. Radiolabeling of MSBP from
      3H-mevalonate was confirmed by immunoprecipitation using the same antiserum. 3H
      Progesterone was incubated with microsomal membrane from bovine lens epithelia to
      measure high-affinity binding. Radiolabeled progesterone-protein complexes were
      trapped on glass filters and radioactivity measured and the binding data
      subjected to Scatchard analysis. RESULTS: Membrane recovered from BLECs incubated
      with 3H-mevalonolactone contained a 3H-labeled 28-kDa protein fraction. The N
      terminal sequence of the principal protein in this fraction was very similar to
      that of the recently discovered MSBP. Western blot analysis with antiserum to
      MSBP indicated the presence of the 28-kDa protein in the microsomal fraction from
      BLECs and epithelia of bovine, rat, and young human lenses but not in lens fiber
      cell membrane. Microsomal membrane from intact bovine lens epithelium bound
      progesterone with high affinity, with disso ciation constant (Kd) at
      approximately 75 nM and a receptor concentration of approximately 3 picomoles/mg
      protein. CONCLUSIONS: The lens epithelium contains a 28-kDa membrane protein that
      can bind progesterone and perhaps other steroid hormones with high affinity. The
      protein appears to be microsomal and prenylated. The MBSP may mediate rapid
      nongenomic steroid effects that contribute to steroid-induced cataracts.

PMID- 10359329
TI  - Chronic hypoxemia: effects on developing nitrergic and dopaminergic amacrine
      cells.
AB  - PURPOSE: Very low birth weight and growth-restricted children have visual
      impairments including reduced contrast sensitivity, a parameter mediated in part
      by dopaminergic amacrine cells. The origin of these deficits is uncertain. In
      experimental fetal growth restriction, induced by placental insufficiency, the
      morphology and number of dopaminergic amacrine cells as identified by tyrosine
      hydroxylase staining were examined. In addition, the subclass of nitrergic
      amacrine cells was examined because nitric oxide released from nitric oxide
      synthase- containing neurons is proposed as a mediator of neurotoxicity and might
      contribute to the injury of dopaminergic amacrine cells in this situation.
      METHODS: Fetal sheep were subjected to 20 or 30 days of placental embolization
      leading to fetal hypoxemia, hypoglycemia, and growth restriction during the last
      third of gestation (term, approximately 147 days). Retinal tissue was prepared as
      wholemounts or cryostat sections and analyzed for retinal area, total number,
      density, somal size and cell process length of amacrine cells immunoreactive for
      tyrosine hydroxylase or nitric oxide synthase, and widths of retinal layers.
      Retinas from fetal sheep at 72, 96, 113, and 140 days' gestation and adults were
      collected for an ontogenetic study of tyrosine hydroxylase-immunoreactive
      neurons. RESULTS: In growth-restricted fetuses, the number of tyrosine
      hydroxylase-immunoreactive neurons and the total length of stained processes per
      cell were significantly reduced compared to control fetuses. The total number of
      neuronal nitric oxide synthase- containing neurons was not different between
      growth-restricted and control fetuses. The thickness of the inner retinal layers
      was reduced in hypoxemia. CONCLUSIONS: There is damage to tyrosine hydroxylase
      immunoreactive amacrine cells during fetal chronic placental insufficiency. This
      damage might be involved in the altered retinal dopaminergic system observed in
      very low birth weight infants, some of whom are growth-restricted. Furthermore, a
      differential susceptibility of tyrosine hydroxylase-immunoreactive and neuronal
      nitric oxide synthase-containing amacrine cells to hypoxemic injury has been
      demonstrated. These observations add to the current hypothesis that neuronal
      nitric oxide synthase- containing neurons are resistant to hypoxemic injury and
      may be involved in mediating some of the neuronal damage that results from
      hypoxemic insults.

PMID- 10359328
TI  - Genistein inhibits the regulation of active sodium-potassium transport by
      dopaminergic agonists in nonpigmented ciliary epithelium.
AB  - PURPOSE: To determine whether dopamine receptor stimulation regulates Na,K-ATPase
      mediated ion transport in cultured nonpigmented ciliary epithelium (NPE).
      METHODS: Using a rabbit NPE cell line, active Na-K transport activity was
      determined by measuring ouabain-sensitive potassium (86Rb) uptake in cell
      monolayers. Western blot analysis of membrane material obtained from cell
      homogenates was conducted to examine tyrosine phosphorylation of membrane
      proteins. RESULTS: Ouabain-sensitive potassium (86Rb) uptake was inhibited in the
      presence of either dopamine or the D1-selective agonist SKF82958. The response
      was suppressed by SCH23390, a D1 antagonist, but not by sulpiride, a D2-selective
      antagonist. Quinpirole, a D2-selective agonist, did not cause inhibition of
      ouabain-sensitive potassium (86Rb) uptake. Cyclic adenosine monophosphate (cAMP)
      was detectably increased in SKF82958-treated cells, although the concentration of
      SKF required to elevate cell cAMP was higher than the concentration needed to
      inhibit ouabain-sensitive potassium (86Rb) uptake. The protein kinase A inhibitor
      H89 prevented the 86Rb uptake response to SKF82958. Genistein, an inhibitor of
      tyrosine kinases, also prevented the 86Rb uptake response to SKF82958. Membrane
      material isolated from cells exposed to SKF82958 showed an increase in the
      density of several phosphotyrosine bands. These changes in phosphotyrosine
      immunoblot density were not observed in material isolated from cells that
      received either genistein or SCH23390 before SKF82958 treatment. CONCLUSIONS: The
      results of this study suggest D1 agonists cause a reduction of Na,K-ATPase
      mediated ion transport by a mechanism that could involve a tyrosine kinase step.

PMID- 10359330
TI  - Inhibition of choriocapillaris regeneration with genistein.
AB  - PURPOSE: To test the effects of genistein on choriocapillaris regeneration and
      retinal pigment epithelial (RPE) wound healing in a surgical model in the rabbit.
      METHODS: Intravitreal injections of either 0.1 ml of a 90-microM concentration of
      genistein, dimethyl sulfoxide (DMSO; negative control), or 2 microg cycloheximide
      (positive control) were given 24 hours before surgical debridement of RPE in
      rabbits. Scanning electron microscopy (EM) of choroidal vascular casts and the
      RPE wounds and histologic evaluation by light microscopy and EM of the disturbed
      areas were performed at days 1, 7, and 30 after surgery. Quantitative analysis of
      the area of the choriocapillaris bed and RPE was performed by automated image
      analysis, and the results were analyzed by paired Student's t-test. RESULTS: Loss
      of RPE caused a rapid initial atrophy followed by slower subsequent
      revascularization of the choriocapillaris, which paralleled the RPE wound
      healing. Choriocapillaris regeneration appeared nearly normal by day 30 in the
      DMSO group. Inhibition of choriocapillaris revascularization by genistein was
      significant at day 30 when compared with the DMSO-treated negative control (P =
      0.013). There was a strong trend toward inhibition in the cycloheximide-treated
      positive control group (P = 0.062), which reached significance at day 7 compared
      with the DMSO group (P = 0.02). RPE covered the wound area by day 7 in all
      groups. CONCLUSIONS: Intravitreal injection of genistein was found to cause
      significant inhibition of choriocapillaris regeneration without apparent effect
      on RPE wound healing. Tyrosine kinase inhibitors such as genistein may be useful
      as a pharmacologic approach in the treatment of choroidal neovascularization.

PMID- 10359331
TI  - Intravitreal toxicology in rabbits of two preparations of 1-O-octadecyl-sn
      glycerol-3-phosphonoformate, a sustained-delivery anti-CMV drug.
AB  - PURPOSE: To determine intraocular toxicity and efficacy of the lipid prodrug of
      foscarnet, 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA), as a long
      acting, nontoxic intravitreous injectable drug delivery system for
      cytomegalovirus (CMV) retinitis. METHODS: ODG-PFA was synthesized by coupling the
      phosphonate residue of PFA to the 3 hydroxyl of 1-O-octadecyl-sn-glycerol and
      formulated as micelles and liposomes at concentrations so that, after injection
      into the rabbit vitreous, the resultant intravitreal concentrations were 0.2 mM,
      0.63 mM, and 2 mM in micellar formulation and 0.02 mM, 0.063 mM, 0.2 mM, and 0.63
      mM for liposomal formulation. The compounds were injected, and toxicology
      evaluations were performed. RESULTS: Intravitreal injections of micellar ODG-PFA
      resulted in aggregation of the material in vitreous and variable local retinal
      damage. Intravitreal injections of the liposomal ODG-PFA revealed even dispersion
      of the compounds and a clear vitreous, using final concentration in the vitreous
      of 0.2 mM. No intraocular toxicity was found with the 0.632 mM final
      concentration. The 50% inhibitory concentration (IC50) for CMV of ODG-PFA was
      0.43+/-0.27 microM, and the therapeutic index of ODG-PFA after intravitreal
      injection was estimated to be 1470:1. CONCLUSIONS: Lipid-derivatized foscarnet
      liposome formulations may be a useful long-acting delivery system for the therapy
      of CMV retinitis.

PMID- 10359332
TI  - Effect of focal X-ray irradiation on experimental choroidal neovascularization.
AB  - PURPOSE: Radiation therapy has been used to treat choroidal neovascularization
      (CNV) in patients with age-related macular degeneration. The in vivo effect of
      applying focal x-ray irradiation to the eye of rabbits with experimental CNV was
      investigated. METHODS: CNV was induced in the rabbit eyes by subretinal
      implantation of gelatin hydrogel microspheres impregnated with basic fibroblast
      growth factor. Three weeks after implantation, 17 of 34 eyes with CNV lesions
      accompanied by fluorescein leakage were irradiated with a single dose of 20 Gy;
      the other 17 eyes were not irradiated and served as the controls. The eyes were
      examined before irradiation and 1, 2, and 4 weeks after irradiation, by indirect
      ophthalmoscopy and fluorescein angiography. The degree of a decreasing amount of
      fluorescein leakage from the CNV lesions after irradiation was graded using a
      computerized image analysis system and was compared in the irradiated and
      nonirradiated eyes. These eyes were also examined histologically and
      immunohistochemically. RESULTS: Fluorescein leakage from the CNV lesions had
      significantly decreased in the eyes irradiated with 20 Gy compared with the
      control eyes, throughout the study period (P < 0.05). Histologic and
      immunohistochemical studies at 4 weeks after irradiation demonstrated that the
      degree of vascular formation and the number of vascular endothelial cells in the
      subretinal membrane of the irradiated eyes were less than those of the control
      eyes. CONCLUSIONS: Focal x-ray irradiation at the ocular region effectively
      reduced experimental CNV activity. These results support the possibility that
      radiation therapy may be beneficial in treating CNV.

PMID- 10359333
TI  - Human fetal retinal pigment epithelial cells induce apoptosis in the T-cell line
      Jurkat.
AB  - PURPOSE: To investigate the mechanism(s) involved in human fetal retinal pigment
      epithelium (HFRPE)-mediated T-cell death. METHODS: Pure HFRPE cells were isolated
      and cultured. Normal and interferon (IFN)-gamma-activated HFRPE from early and
      late in vitro passages were incubated with cells from the human T-cell leukemia
      line Jurkat (Jkt). Cultures were pulsed with [3H]-thymidine to measure Jkt cell
      proliferation. Jkt cells were evaluated for apoptosis either by staining with an
      ethidium bromide/acridine orange mixture (AO/EB) or with Annexin V-phycoerythrin.
      The role of Fas ligand (FasL) molecule in HFRPE-mediated apoptosis was assessed
      by using a mutant Jkt cell line (DD3), which is deficient in Fas-mediated
      signaling. The involvement of the antiapoptotic human gene bcl-xL was determined
      by using Jkt cells that were stably transfected with bcl-x(L). The role of cell-
      cell contact in the induction of apoptosis was evaluated in a transwell system in
      the presence or absence of neutralizing antibodies against IFN-gamma and tumor
      necrosis factor (TNF)-alpha. RESULTS: HFRPE cells inhibited the proliferation of
      Jkt cells by inducing apoptosis through a FasL-independent pathway. Passaging and
      IFN-gamma activation strengthened the inhibitory effect of HFRPE cells on the
      proliferation of Jkt cells. At lower HFRPE passages (P2), bcl-alphaL,
      overexpression rescued the HFRPE cell-mediated apoptosis. The separation of the
      cells by the transwell system did not affect the HFRPE cell-mediated suppression.
      This suppressive effect was not mediated by the secretion of IFN-gamma or TNF
      alpha molecules. CONCLUSIONS: HFRPE cells suppressed the proliferation of Jkt
      cells by inducing apoptosis. HFRPE cells induced a stronger inhibitory effect on
      Jkt cells at higher in vitro passages. The HFRPE-induced apoptosis was not
      mediated through the FasL/Fas pathway or through the secretion of the apoptosis
      inducing cytokines IFN-gamma and TNF-alpha. The bcl-xL gene may play a role in
      preventing HFRPE cell-induced apoptosis in Jkt cells. These combined results
      suggest that the HFRPE-mediated suppression of primary T cells may also be
      mediated by the induction of apoptosis. Therefore, the retinal pigment epithelium
      may play a role in the induction of immune privilege in the subretinal space.

PMID- 10359334
TI  - Inhibitory effect of TNP-470 on experimental choroidal neovascularization in a
      rat model.
AB  - PURPOSE: To determine whether an angiogenic inhibitor, TNP- 470 (TNP), an
      analogue of fumagillin, inhibits choroidal neovascularization (CNV) induced by
      diode laser photocoagulation in a rat experimental model. METHODS: Fundus laser
      photocoagulation was performed on Brown Norway rats to induce CNV. In the
      treatment group, TNP was administered intraperitoneally at the time of laser
      photocoagulation and on day 7 (50 mg/kg at each time). The incidence of CNV
      formation was evaluated by fluorescein angiography. The retina was collected from
      the rats on days 1, 3, 7, and 14 after laser photocoagulation, and
      semiquantitative polymerase chain reaction (PCR) analyses for the expression of
      mRNA of basic fibroblast growth factor (bFGF) and vascular endothelial growth
      factor (VEGF) were carried out. Localization of bFGF mRNA was studied by in situ
      reverse transcription-PCR (RT-PCR). The numbers of positively labeled cells for
      bFGF mRNA were compared between the TNP treatment and control groups. RESULTS:
      The incidence of CNV formation was 22.7% in the TNP-treated rats and that in the
      control rats was 61.4% (P < 0.001). The semiquantitative PCR analyses showed that
      bFGF mRNA was upregulated on days 3 and 7 in the control rats, but no significant
      changes were found in TNP-treated rats. There was no detectable difference in
      VEGF gene expression between the control and TNP-treated rats. bFGF mRNA was
      detected by in situ RT-PCR in the regenerated retinal pigment epithelial cells
      and cells of the outer and inner nuclear layers of the control rats. The number
      of positive cells for bFGF mRNA in the TNP treatment group was significantly
      smaller than that of the control group (P < 0.05) on days 3 and 14. CONCLUSIONS:
      TNP- 470 treatment reduced the incidence of laser-induced CNV formation in this
      experimental model. The expression of bFGF associated with CNV formation was also
      significantly reduced by the TNP treatment.

PMID- 10359335
TI  - Differential distribution of dystrophins in rat retina.
AB  - PURPOSE: Duchenne muscular dystrophy is frequently associated with a reduced
      amplitude of b-wave under scotopic conditions in the electroretinogram. This
      suggests that the dystrophin gene-encoded proteins play a role in retinal
      neurotransmission. The abnormal neurotransmission has been attributed to altered
      expressions of C-terminal products of the dystrophin gene in the outer plexiform
      layer, where photoreceptor cells form synapses with secondary neurons. The
      present study was undertaken to determine the cellular distribution of each
      member of the dystrophin superfamily in rat retina. METHODS: Examined in the
      study were the developmental pattern of dystrophins in rat retinae that exhibit
      inherited progressive photoreceptor degeneration; dystrophins messengers
      expression in the outer and the inner retina of normal rats, prepared by
      mechanical fractionation through the outer plexiform layer; and
      immunolocalization of dystrophin proteins and utrophin in normal and degenerated
      adult rat retinae, with several antibodies prepared against specific regions of
      the dystrophin superfamily. RESULTS: The results showed that Dp260 is exclusively
      localized in photoreceptor cells; Dp140 seems to be present in perivascular
      astrocytes; the exon 78 spliced isoform of Dp71 and the unspliced form are
      located in Muller glial cells and in perivascular astrocytes, respectively.
      Muller glial cells also contain utrophin. CONCLUSIONS: Although the role of these
      membrane cytoskeletal proteins remains to be elucidated in retina, the results
      support the hypothesis that b-wave reduction may be caused by molecular anomalies
      of C-terminal products of the dystrophin gene expressed in both neuron and glial
      cells.

PMID- 10359336
TI  - Effects of the neurotrophin brain-derived neurotrophic factor in an experimental
      model of retinal detachment.
AB  - PURPOSE: To examine the effects of brain-derived neurotrophic factor (BDNF) in an
      animal model of retinal detachment. METHODS: Cat retinas were detached from the
      retinal pigment epithelium for either 7 or 28 days. Animals received either an
      intravitreal injection of BDNF (100 ILg) or phosphate-buffered saline (PBS), the
      vehicle for BDNF. Retinas were evaluated using morphology and
      immunocytochemistry. The width of the outer segment zone was measured, and the
      retinas were evaluated for changes in protein expression by labeling with
      antibodies to rod opsin, phosducin, synaptophysin, calbindin D, and glial
      fibrillary acidic protein (GFAP). The effect of BDNF on both proliferation and
      apoptotic cell death was examined. RESULTS: Although there was variability in the
      treated retinas, most of the animals receiving BDNF had well-organized outer
      segments that were longer than those in vehicle-treated controls.
      Immunocytochemistry revealed that treated retinas had consistently less opsin
      redistribution to the plasma membrane, less phosducin upregulation, and fewer
      calbindin D-labeled horizontal cell processes. BDNF did not reduce overall cell
      death in the detachments or death of photoreceptors by apoptosis. However, it
      significantly reduced the proliferative response of Miller cells and the extent
      of upregulation of GFAP. CONCLUSIONS. The results suggest that BDNF may aid in
      the recovery of the retina after reattachment by maintaining the surviving
      photoreceptor cells, by reducing the gliotic effects in Muller cells, and perhaps
      by promoting outer segment regeneration.

PMID- 10359337
TI  - Rescue effects of IPE transplants in RCS rats: short-term results.
AB  - PURPOSE: The aim of this study was to investigate the possible rescue effect of
      subretinal iris pigment epithelial (IPE) cell transplantation in Royal College of
      Surgeons (RCS) rats by light and electron microscopic histology. METHODS: IPE
      cells were harvested from 20- to 26-day-old Long-Evans rats and were directly
      trans planted transsclerally into the subretinal space of 32 16- to 20-day-old
      RCS rats using a 32-gauge Hamilton syringe. Specimens of transplanted eyes were
      embedded for electron microscopy after 8 weeks. Specimens from the iris and
      retinal pigment epithelium (RPE) of Long-Evans rats and RPE from RCS rats without
      surgical treatment were also embedded. Sham surgery was also performed in 8 eyes.
      RESULTS: The IPE cells transplanted into the subretinal space were localized
      between host RPE and retina, had round cell shapes without polar organization,
      and contained phagosomes resulting from rod outer segment (ROS) uptake. The
      underlying host RPE cells were heavily pigmented. RPE cells from RCS rats
      revealed fragmentation of endoplasmic reticulum, which distinguishes them
      ultrastructurally from pigment epithelial cells of Long-Evans rats.
      Ultrastructural alterations were observed in the cytoplasm of transplanted cells.
      Melanin granules in the IPE cells were found in large vacuoles, which also
      contained phagosomes originating from ROS uptake. In 13 eyes, 1 to 4 rows and 5
      to 8 rows of saved photoreceptors were detected facing transplanted IPE cells in
      6 (46%) and 4 (31%) eyes, respectively, 2 months after surgery. However, in 10
      (53%) and 7 (37%) of 19 eyes, 1 to 4 rows and 5 to 8 rows, respectively, were
      also found at sites without IPE cells in the plane of section. ROS directed
      toward transplanted IPE cells were seen in one case, but these rods were
      shortened and disorganized. At most sites between transplanted cells and inner
      segments of photoreceptors, outer segments and cellular debris were absent. In
      eyes without transplanted cells no photoreceptor cells were alive at the age of 2
      months. After sham surgery 6 (75%) eyes had 1 to 4 rows and 2 (25%) 5 to 8 rows
      of photoreceptors. CONCLUSIONS: Transplanted IPE cells can take up and degrade
      ROS in vivo in RCS rats. Uptake of ROS alters the morphology of pigment granules
      in transplanted IPE cells. Pigmentation is an uncertain marker for identifying
      transplanted pigment cells. IPE transplants are not as good as RPE transplants in
      rescuing photoreceptors. However, there is a significant difference between
      transplanted eyes and nontreated eyes. The rescue effect of IPE cells was not
      significantly different from that of sham surgery.

PMID- 10359338
TI  - Successful cotransplantation of intact sheets of fetal retina with retinal
      pigment epithelium.
AB  - PURPOSE: Many retinal diseases, such as macular degeneration, affect both retinal
      pigment epithelium (RPE) and photoreceptors. Therefore, retinal repair may
      require transplantation of both tissues together as a cograft. METHODS: As
      recipients of retina-RPE cografts, 7- to 10-week-old albino Royal College of
      Surgeons rats that lose their photoreceptors because of a pigment epithelium
      defect were used. Freshly harvested intact sheets of RPE with neural retina from
      pigmented normal rat fetuses were gel embedded for protection and transplanted
      into the subretinal space. RESULTS: After 6 to 7 weeks, with the support of the
      cografted RPE sheet, transplanted photoreceptors developed fully in organized
      parallel layers in the subretinal space. Immunohistochemistry for rhodopsin, rod
      alpha-transducin, and S-antigen and peanut agglutinin labeling for cone
      interphotoreceptor matrix domains suggested that the photoreceptors in the graft
      were capable of normal function. CONCLUSIONS: Freshly harvested intact sheets of
      fetal RPE and retina, transplanted together into the subretinal space, can
      develop a normal morphology. Such transplants have the potential to benefit
      retinal diseases with dysfunctional RPE and photoreceptors.

PMID- 10359339
TI  - Interobserver agreement for grating acuity and letter acuity assessment in 1- to
      5.5-year-olds with severe retinopathy of prematurity.
AB  - PURPOSE: To evaluate interobserver test-retest reliability of the Teller Acuity
      Card procedure for assessment of grating acuity at ages 1, 2, 3.5, 4.5, and 5.5
      years, for HOTV letter acuity at 3.5 and 4.5 years, and for Early-Treatment
      Diabetic Retinopathy Study (ETDRS) letter acuity at 5.5 years in the multicenter
      study of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP). METHODS: Subjects
      were the 73 participants in the CRYO-ROP study who had acuity assessed at one or
      more ages by two of the seven study visual acuity testers as part of a quality
      control procedure. All subjects had birth weights of less than 1251 g, and all
      had severe (threshold) ROP in one or both eyes. RESULTS: For sighted eyes,
      interobserver agreement for grating acuity (across all five test ages) was 0.5
      octave or better in 57% of eyes and 1.0 octave or better in 85% of eyes.
      Interobserver agreement for letter acuity (3.5-, 4.5-, and 5.5-year test ages)
      was 0.5 octave or better in 71% of eyes and 1.0 octave or better in 93% of eyes.
      For all eyes (sighted and blind), Kendall rank correlation coefficients (Tau)
      were 0.86, 0.83, and 0.94 for grating, HOTV, and ETDRS acuity, respectively.
      Kappa statistics on data from all eyes indicated excellent interobserver
      agreement for grating, HOTV, and ETDRS acuity (0.73, 0.80, and 0.84,
      respectively). Interobserver agreement was not related to age or to severity of
      retinal residua of ROP. CONCLUSIONS: Excellent interobserver agreement for
      grating acuity measurements and for letter acuity measurements was obtained.
      Results suggest that with careful training and implementation of quality control
      procedures, high reliability of visual acuity results is possible in clinical
      populations of young children.

PMID- 10359340
TI  - Naturally occurring vitreous chamber-based myopia in the Labrador retriever.
AB  - PURPOSE: To investigate whether myopia is present in a breed of domestic dog, the
      Labrador retriever, and how the ocular components are related to refractive error
      in this breed. METHODS: Cycloplegic refractive error was measured in 75 Labrador
      retrievers by retinoscopy. Corneal and crystalline lens radii of curvature were
      measured in the right eyes of 57 of these dogs using a video-based
      keratophakometer, with axial ocular dimensions measured using A-scan
      ultrasonography. RESULTS: Of the 75 dogs tested, 11 (14.7%) were myopic by at
      least -0.50 D in one eye, and 6 (8.0%) were myopic in both eyes (full range of
      refractive errors, +3.50 D to -5.00 D). Of the 57 dogs with ocular component
      measurements, seven (12.3%) were myopic by at least -0.50 D in the right eye.
      There was a significant negative correlation between refractive error and
      vitreous chamber depth (Spearman r = -0.42; P < 0.001). Myopic eyes had an
      elongated vitreous chamber depth (10.87+/-0.34 mm for myopic dogs, 10.02+/-0.40
      mm for nonmyopic dogs; P < 0.0001, Kruskal-Wallis test). There was also a
      significant quadratic association between lens thickness and vitreous chamber
      depth (P < 0.005; R2 = 0. 11), indicating that thinner lenses occurred at both
      shorter and longer vitreous chamber depths. CONCLUSIONS: Myopia in the Labrador
      retriever is analogous to human myopia in that it is caused by an elongated
      vitreous chamber. Thinner crystalline lenses found at longer vitreous chamber
      depths may be analogous to lens thinning documented in human ocular development.
      The Labrador retriever warrants investigation as a potential model of myopia that
      is naturally occurring rather than experimentally induced.

PMID- 10359341
TI  - Direct visual resolution of gene copy number in the human photopigment gene
      array.
AB  - PURPOSE: To visualize by direct fluorescent in situ hybridization the entire
      human visual pigment gene array on single X-chromosome fibers and to compare the
      results with values obtained by other molecular techniques. METHODS: The size of
      the opsin gene array on the X-chromosome in eight male subjects was investigated
      by (i) direct visual in situ hybridization (DIRVISH) on elongated DNA fibers:
      (ii) quantitation of genomic restriction fragments after Southern blot
      hybridization; (iii) quantitation of restriction fragment length polymorphism
      after PCR amplification (PCR/RFLP), and (iv) sizing of NotI fragments by pulsed
      field gel electrophoresis and Southern blot detection. Each male subject's color
      vision was assessed by Rayleigh matches on a Nagel Type 1 anomaloscope. RESULTS:
      The number of genes resolved by the DIRVISH protocol, which ranges from 1 to 6,
      agrees exactly with the gene array sizes obtained in the same male subjects from
      pulsed field gel electrophoresis, but differs from the estimates derived from the
      commonly used indirect Southern blot hybridization and PCR/RFLP quantitation
      methods. In particular, the PCR/RFLP method overestimates the copy number in all
      but the smallest arrays. CONCLUSIONS: Visualization of the X-chromosome opsin
      gene array by DIRVISH provides a new, direct method for obtaining exact copy
      numbers and helps to resolve the controversy about the range and the average
      visual pigment gene number in the human population in favor of smaller average
      array sizes.

PMID- 10359342
TI  - Senescence-associated beta-galactosidase histochemistry for the primate eye.
AB  - PURPOSE: To develop a senescence-associated beta-galactosidase histochemistry and
      bleaching protocol for the primate posterior pole. METHODS: Rhesus monkey eyes of
      different ages were enucleated after death, fixed in 4% paraformaldehyde for up
      to 16 hours, and cryoprotected using a graded sucrose infiltration technique. Ten
      micrometer tissue sections were treated with beta-galactosidase, pH 4 (lysosomal)
      or pH 6 (senescence-associated) activity, for various times. Bleaching of retinal
      pigment epithelial (RPE) cell and choroidal melanocyte pigment was performed
      after beta-galactosidase histochemistry using 0.1% to 1% potassium permanganate
      incubation for 1 minute to 2 hours followed by 0.5% oxalic acid immersion.
      RESULTS: A 6-hour incubation with beta-galactosidase, pH 4 or 6, demonstrated
      optimal staining of the RPE. Uniform staining of the RPE for pH 4 beta
      galactosidase was seen in both young and old eyes. In contrast, senescence
      associated beta-galactosidase (pH 6) staining was seen in the RPE of 16 and 29
      year-old, but not 1- and 2-year-old eyes. Senescence-associated beta
      galactosidase staining was evident in RPE cells adjacent to cuticular drusen.
      Optimal bleaching without loss of beta-galactosidase staining was obtained using
      a 25-minute incubation with 0.05% permanganate. CONCLUSIONS: The senescence
      associated beta-galactosidase histochemistry assay, adapted for use in the
      primate posterior pole, showed staining of RPE cells in older eyes. Visualization
      of beta-galactosidase activity in the RPE was enhanced by permanganate bleaching
      of melanin pigment. This technique could be valuable for identifying senescent
      RPE cells in human eyes.

PMID- 10359343
TI  - A new video pachometer.
AB  - PURPOSE: Many studies of the cornea would benefit from a simple, objective method
      to measure corneal thickness. In this study, a new optical pachometer based on
      video and computer technology was designed and tested. METHODS: The slit beam of
      a photographic slit lamp was monitored with a video camera through one half of
      the biomicroscope. When the slit was properly aligned with the cornea, the
      operator triggered a flash, and one video frame that included the flash was
      captured. A custom software package detected epithelial and endothelial edges.
      Corneal thickness was calculated from the median corneal image width and image
      widths from similar measurements of contact lenses with known thicknesses.
      Corneal thickness was measured in 25 subjects by using this new instrument and
      was compared to thickness measured by using a conventional Haag-Streit
      pachometer. RESULTS: Corneal thickness in the 25 subjects measured on the new
      instrument was 512+/-20 microm and 515-/+21 microm in the right and left eyes,
      respectively (mean+/-SD). Thickness of the same corneas measured on the Haag
      Streit pachometer was 530+/-22 microm and 534+/-20 microm in right and left eyes,
      respectively. The average SD of 10 consecutive measurements was 6.6 microm and
      6.7 microm on the video and Haag-Streit pachometers, respectively (n = 50
      corneas). CONCLUSIONS: The video pachometer provides a fast, objective means of
      measuring corneal thickness. It is simple to use and provides precision equal to
      that of the Haag-Streit pachometer.

PMID- 10359344
TI  - Effects of ethacrynic acid on Schlemm's canal inner wall and outflow facility in
      human eyes.
AB  - PURPOSE: The role of the inner wall of Schlemm's canal in determining aqueous
      outflow facility is poorly understood. To quantify the relationship between inner
      wall pore characteristics and aqueous outflow facility in human eyes, both
      control eyes and eyes in which facility had been pharmacologically increased by
      ethacrynic acid (ECA) infusion were studied. METHODS: Outflow facility was
      measured in enucleated human eyes before and after delivery of 0.25 mM ECA (one
      eye of each of 6 pairs) or 2.5 mM ECA (one eye of each of 13 pairs). ECA, and
      vehicle in contralateral eyes, was delivered into Schlemm's canal by
      retroperfusion, thereby largely avoiding drug exposure to the trabecular
      meshwork. After facility measurement, eyes were fixed under conditions of either
      constant pressure (physiological intraocular pressure, 13 pairs) or "equal flow"
      (6 pairs) and were microdissected to expose the inner wall of Schlemm's canal.
      The density and diameter of intercellular and intracellular inner wall pores were
      measured using scanning electron microscopy. RESULTS: Retroperfusion with 2.5 mM
      ECA increased facility by 73% (P < 0.001), whereas 0.25 mM ECA increased facility
      by 19% (not statistically significant). The density of intercellular pores in the
      inner wall of Schlemm's canal was increased by 520% in 2.5 mM ECA-retroperfused
      eyes (P < 0.00004), whereas intracellular pore density remained approximately
      constant. Large pores (size > or = 1.1 microm) were particularly enhanced in ECA
      retroperfused eyes. The net change in facility due to ECA was not correlated with
      changes in pore density or other inner wall pore statistics. CONCLUSIONS: Our
      data are most consistent with a model in which pores in the inner wall of
      Schlemm's canal indirectly influence facility. However, measured changes in
      facility due to changes in inner wall properties did not agree with quantitative
      predictions of the pore funneling theory, suggesting that changes in facility may
      instead be due to gel leakage from the extracellular spaces of the
      juxtacanalicular tissue. More definitive experiments are required to confirm this
      hypothesis.

PMID- 10359345
TI  - Contact lens-induced infection--a new model of Candida albicans keratitis.
AB  - PURPOSE: A model of experimental keratomycosis was established that mimics human
      disease in which the only fungi present are those that are actively growing
      within the cornea. METHODS: Dutch-belted rabbits received a subconjunctival
      injection of triamcinolone acetonide to one eye. One day later the epithelium was
      removed from the central cornea and a standardized inoculum of Candida albicans
      blastoconidia was placed on the corneal surface and covered with a contact lens.
      The lids were closed with a lateral tarsorrhaphy. After 24 hours, the lid sutures
      and contact lens were removed. Five days later the animals were killed, and their
      corneas were subjected to separate isolate recovery and histology studies. A
      group of similarly infected rabbits without corticosteroid injection served as
      controls. RESULTS: Both groups developed invasive corneal disease. Although
      isolate recovery was not significantly different from corticosteroid-treated
      rabbits compared with controls, fungal biomass was increased. Hyphal invasion was
      limited to the anterior cornea in control eyes, but penetrated deep stroma in
      most of the corticosteroid-treated rabbits. CONCLUSIONS: Invasive corneal disease
      can be established with a surface inoculum. Corticosteroid administration
      increased corneal penetration of hyphae. Quantitative isolate recovery is not a
      reliable measure of the fungal load within the cornea.

PMID- 10359346
TI  - Immunopathology of pineal glands from horses with uveitis.
AB  - PURPOSE: Pinealitis accompanying uveitis is well established in laboratory models
      of experimental autoimmune uveoretinitis. In naturally occurring uveitis,
      pinealitis has been demonstrated in the pineal gland from a mare with active
      uveitis and is suspected in some human uveitides. We have evaluated pineal glands
      from horses with various stages of uveitis for signs of immunopathology
      accompanying spontaneous uveitis. METHODS: Pineal glands from 10 horses with
      uveitis and from 13 horses without uveitis were evaluated for histochemical (H&E,
      collagen) and immunohistochemical (MHC class II antigen expression, infiltration
      of T and B lymphocytes, and glial fibrillary acidic protein (GFAP) and vimentin
      upregulation) evidence of inflammation. RESULTS: Septal areas of pineal glands
      from horses with uveitis had clusters of MHC class II antigen-expressing cells, T
      lymphocytes, and enhanced collagen deposition. These changes were not as readily
      observed in pineal glands from horses without uveitis. B lymphocytes were
      detected only in the pineal gland from the one mare with active uveitis in which
      T and B lymphocytes were organized into follicles. No differences in GFAP or
      vimentin immunoreactivity were noted in pineal glands from horses with or without
      uveitis. CONCLUSIONS: These pineal gland changes suggest that the pinealitis
      associated with equine uveitis is transient just as the uveitis of these horses
      is recurrent. Study of pineal glands from horses with clinically documented
      uveitis allows demonstration of subtle pineal changes associated with natural
      uveitis. Similar changes would be difficult to document in human patient
      populations.

PMID- 10359347
TI  - Effects of UV-A radiation on lens epithelial NaK-ATPase in organ culture.
AB  - PURPOSE: To investigate the mechanisms involved in the damage caused by UV-A
      irradiation at 365 nm on the eye lens. METHODS: Bovine lenses obtained from
      animals 1 to 5 years of age were placed in specially designed organ culture
      chambers for preincubation. Twenty-four hours later, the lenses were irradiated
      by 33 J/cm2 UV-A at 365 nm. During irradiation, the lenses were oriented in the
      culture so that the anterior surface faced the incident UV-A radiation source.
      After irradiation, lens optical quality was monitored throughout the 8 days of
      the culture period, and lens samples were taken for analysis of NaK-ATPase
      activity. RESULTS: Lens optics and NaK-ATPase activity were affected by
      irradiation of 33 J/cm2. The effects on lens epithelial NaK-ATPase activity were
      stronger at the equators than at the center. The damage to the activity at the
      center was reversible, as the lens optically recovered from the LW-A damage.
      CONCLUSIONS: Lens NaK-ATPase activity can recover from damage caused by UV-A at
      365 nm. When the lenses received irradiation of 33 J/cm2, NaK-ATPase activity
      recovered from the damage during the culture period only at the center and not at
      the equators of the epithelium.

PMID- 10359348
TI  - Population pharmacokinetics of 2% topical dorzolamide in the aqueous humor of
      humans.
AB  - PURPOSE: To evaluate the concentration and kinetics of dorzolamide in the aqueous
      humor after its topical application. METHODS: Samples of aqueous humor were
      collected at the beginning of routine cataract surgery at defined intervals after
      topical application of a 2% solution of dorzolamide. After deep-frozen storage of
      the samples, drug extraction was achieved with a mixture of solvents.
      Quantification was carried out by high-performance liquid chromatography on a
      reversed-phase column. RESULTS: Peak concentrations of dorzolamide in aqueous
      humor were reached approximately 2 hours after application with 1000 ng/ml.
      Average values were approximately 1000 to 700 ng/ml after 4 to 6 hours and
      approximately 200 ng/ml after 12 hours. Mean half-life of absorption was 1.2
      hours and for elimination 3.0 hours. CONCLUSIONS: Pharmacokinetics of dorzolamide
      in the aqueous humor of humans are in comparable dimensions as previously
      reported in experimental trials in pigmented rabbits. There is a clear linear
      absorption and elimination kinetic, which is demonstrated using the Bateman
      function. A better knowledge of the distribution and kinetics of dorzolamide will
      help to explain its reported effects on intraocular hemodynamics, distinct from
      its intraocular pressure lowering effect.

PMID- 10359349
TI  - Suppression of retinal neovascularization by the NF-kappaB inhibitor pyrrolidine
      dithiocarbamate in mice.
AB  - PURPOSE: To evaluate the effect of pyrrolidine dithiocarbamate (PDTC), an
      inhibitor of nuclear factor kappaB (NF-kappaB), on retinal neovascularization in
      a murine model of ischemic retinopathy. METHODS: One-week-old C57BL/6N mice were
      exposed to 75%+/-2% oxygen for 5 days and then were returned to room air to
      induce retinal neovascularization. After the return to room air, the left and
      right eyes were injected intravitreally with PDTC or a vehicle, respectively.
      Retinal neovascularization was examined by injecting fluorescein dextran and
      angiography after 5 days in room air and was quantitated histologically with a
      masked protocol. The effects of PDTC on NF-kappaB activation were evaluated by
      immunohistochemistry. To examine the toxicity of PDTC, the histologic change in
      the retina was examined by light and electron microscopy. RESULTS: Retinal
      neovascularization in the eye injected with PDTC by intravitreal methods was
      reduced in 100% of animals compared with that apparent in the vehicle-treated
      eye. The inhibitory effect was dose-dependent, with a maximal inhibition of 39%
      (P < 0.01) at a dose of 1 nmole. The immunostaining intensity for NF-KB in the
      retina was reduced by PDTC injections. No side effects by PDTC in the retina were
      observed by light and electron microscopy. CONCLUSIONS: NF-kappaB activation
      appears to be required for retinal angiogenesis, given that the administration of
      PDTC suppressed retinal neovascularization. PDTC may prove beneficial in the
      treatment of ischemic neovascular diseases such as diabetic retinopathy and
      retinal vein occlusion.

PMID- 10359350
TI  - The longitudinal study of surgical residents, 1994 to 1996.
AB  - BACKGROUND: The American College of Surgeons (ACS) has conducted a detailed
      annual survey of residents enrolled in surgical graduate medical education (GME)
      programs since 1982 and has regularly published the resulting data as the
      Longitudinal Study of Surgical Residents. This report documents surgical resident
      enrollment and graduation for the academic years 1994-95 and 1995-96. STUDY
      DESIGN: The Medical Education Research and Information Database of the American
      Medical Association was supplemented by the existing ACS Resident Masterfile and
      by personal contact with program directors and their staffs to verify accuracy
      and completeness of reporting. Each resident was tracked individually through
      surgical GME. RESULTS: The total number of surgical residents graduating from
      surgical GME in 1995 and 1996 has not changed since 1982. Most graduates of
      surgical residency programs are in obstetrics and gynecology, followed by general
      surgery; demographic analysis of the graduating cohort shows that most are
      Caucasian male graduates of US or Canadian medical schools, and that their age at
      graduation is 33 to 35 years. International medical graduates (IMG) make up 8.9%
      of entering surgical residents and 6% of graduates. Osteopathic medical school
      graduates account for 1.2% to 1.3% of entering and graduating surgical residents.
      Women represent 27% of entering and 23% to 24% of graduates of surgical GME. The
      largest number and proportion of women in surgical GME are enrolled in obstetrics
      and gynecology residency programs, where they make up the majority of entering
      and graduating classes. When all other surgical residency program enrollments are
      considered together, women make up 17% and 16% of entering residents in 1994 and
      1995, respectively, and 13% and 14% of graduates in those years. CONCLUSIONS:
      Surgical GME enrollment and graduation is stable. Few women and ethnic minorities
      are enrolled in surgical residency programs. IMG enrollment and graduation in
      surgical GME is low.

PMID- 10359351
TI  - Axillary dissection in breast-conserving surgery for stage I and II breast
      cancer: a National Cancer Data Base study of patterns of omission and
      implications for survival.
AB  - BACKGROUND: Breast conservation (partial mastectomy, axillary node dissection or
      sampling, and radiotherapy) is the current standard of care for eligible patients
      with Stages I and II breast cancer. Because axillary node dissection (AND) has a
      low yield, some have argued for its omission. The present study was undertaken to
      determine factors that correlated with omission of AND, and the impact of the
      decision to omit AND on 10-year relative survival. STUDY DESIGN: A retrospective
      review of National Cancer Data Base (NCDB) data for 547,847 women with Stage I
      and Stage II breast cancer treated in US hospitals from 1985 to 1995 was
      undertaken. A subset of 47,944 Stage I and 23,283 Stage II women treated with
      breast-conserving surgery (BCS) was identified. Cross-tab analysis was used to
      compare patterns of surgical care within this subset. Relative survival was
      calculated as the ratio of observed survival to the expected survival for women
      of the same age and racial/ethnic background. RESULTS: The rate of BCS with and
      without AND increased steadily from 17.6% and 6.4% of patients from 1985-1989, to
      36.6% and 10.6% of patients from 1993-1995 respectively. AND was more likely to
      be omitted in women with Stage I than women with Stage II disease (14.5% versus
      5.5%). Similarly, AND was omitted more frequently in women with Grade 1 than
      women with higher grades (Grade 1, 14.9%; Grade 2, 10.1%; Grade 3, 7.1%; Grade 4,
      7%). Although the rate of BCS with AND varied considerably according to location
      in the breast, the overall rate of BCS without AND appeared independent of site
      of lesion. Women over the age of 70 years were more than twice as likely to have
      AND omitted from BCS than their younger counterparts. Women with lower incomes,
      women treated in the Northeast, or at hospitals with annual caseloads <150 were
      all less likely to undergo AND than their corresponding counterparts. Ten-year
      relative survival for Stage I women treated with partial mastectomy and AND was
      85% (n = 1242) versus 66% (n = 1684) for comparable women in whom AND was
      omitted. BCS with AND followed by radiation therapy for Stage I disease resulted
      in 94% (n = 5469) 10-year relative survival, compared with 85% (n = 1284) without
      AND. Addition of both radiation and chemotherapy to BCS with AND for Stage I
      disease resulted in 86% (n = 2800) versus 58% (n = 512) without AND. In contrast,
      Stage II women treated with BCS with AND followed by radiation and chemotherapy
      experienced a 72% 10-year relative survival. CONCLUSIONS: A significant number of
      women with Stage I breast cancer do not undergo AND as part of BCS. The trend is
      most pronounced for the elderly, but significant fractions of women of all ages
      are also being undertreated by current standards. Ten-year survival is
      significantly worse when AND is omitted. This adverse survival effect is not
      solely from understaging.

PMID- 10359352
TI  - Sentinel lymphadenectomy for breast cancer: experience with 180 consecutive
      patients: efficacy of filtered technetium 99m sulphur colloid with overnight
      migration time.
AB  - BACKGROUND: Axillary node status remains the most important prognostic indicator
      of survival in breast cancer patients. Only 25% to 35% of patients having
      standard level I/II axillary dissection have involved nodes, yet all accept the
      potential for morbidity after the operation. This study was conducted to assess
      whether status of the sentinel node(s) was an accurate predictor of the presence
      of metastatic disease in axillary or internal mammary nodes. STUDY DESIGN: In 180
      patients, technetium 99m sulphur colloid was injected in a 4-quadrant peritumoral
      distribution. During the first phase of the study, 72 patients had sentinel node
      excision followed by a level I/II axillary dissection. During the second phase of
      the study, 108 patients had sentinel node excision and only those with positive
      nodes had completion axillary dissection. Nodes were examined after formalin
      fixation by taking 10 sections at 20-microm intervals and staining with
      hematoxylin-eosin. RESULTS: Sentinel nodes were found in 162 (90%) of 180
      patients. The mean number of sentinel nodes examined was 3.1. Of the 162 patients
      with successful lymphatic mapping, positive sentinel nodes were found in 44
      (27%). In 23 (66%) of 35 patients with positive sentinel nodes who had a
      completion level I/II axillary dissection, the sentinel nodes were the only
      positive nodes. The concurrent negative predictive value was 4% in the first 72
      patients who had completion axillary dissection after sentinel node excision, and
      2% for the entire series. With evolution of technique, identification of sentinel
      nodes with radiolabeled colloid was successful in 97% of the last 100 patients.
      CONCLUSIONS: Because the concurrent negative predictive value was low, sentinel
      node excision appeared to accurately identify node status, potentially avoiding
      the need for standard level I/II axillary dissection in sentinel node-negative
      patients.

PMID- 10359353
TI  - Racial variation in the use of laparoscopic cholecystectomy in the Department of
      Veterans Affairs medical system.
AB  - BACKGROUND: While studies have found racial differences in the rates of use of
      established invasive cardiac and cerebrovascular procedures, no study has
      evaluated racial variation in the rates of adoption of new surgical procedures.
      For patients undergoing laparoscopic cholecystectomy, the procedure represents a
      new and safe option that shortens the duration of postoperative hospitalization
      by almost one week. In this study, we evaluated whether, in the equal access
      Veterans Affairs (VA) medical system, the rate of adoption of this procedure and
      improvements in the duration of postoperative hospitalization differed between
      African-American and Caucasian patients. STUDY DESIGN: Data were obtained from
      two sources-administrative claims files and prospectively compiled dinical data
      from medical records and patient interviews. In both data sets, frequency of use,
      length of stay, and outcomes for African-American and Caucasian patients
      undergoing minimally invasive and open gallbladder surgery were analyzed for the
      first four years of use of the procedure in the VA system (1992 to 1995).
      RESULTS: Analyses based on claims files indicated that, after adjustment for
      potentially confounding variables, African-American patients who underwent
      cholecystectomy in VA medical centers were 25% less likely to undergo a minimally
      invasive cholecystectomy during the first 4 years of use of the new procedure
      (adjusted odds ratio, 0.74; 95% confidence interval, 0.66-0.83). Shortening of
      the average postoperative length of stay from 9 days or more in the
      prelaparoscopic era to less than 4.5 days for patients undergoing the
      laparoscopic procedure occurred in the first year for Caucasian patients, but did
      not occur until the fourth year for African-American patients (p<0.001). The
      overall difference in postoperative length of stay between African-American and
      Caucasian patients more than doubled from 1.7 days before introduction of
      laparoscopic cholecystectomy to 3.8 days in the fourth year. In comparison,
      analyses based on nurse-compiled clinical data indicated that, after adjustment
      for relevant clinical factors, racial variations in the rate of laparoscopic
      surgery were even larger (adjusted odds ratio for laparoscopic versus open
      cholecystectomy for African-American versus Caucasian veterans, 0.68; 95%
      confidence interval, 0.55-0.84). CONCLUSIONS: Compared to Caucasian patients,
      African-American patients who underwent cholecystectomy in VA medical centers had
      an approximately 25% to 32% lower likelihood of undergoing minimally invasive
      cholecystectomy procedures. The differences in rates of adoption of laparoscopic
      surgery did not appear to be from more comorbid illnesses among African-American
      patients. African-American and Caucasian veterans may differ in their preference
      for new surgical procedures like laparoscopic cholecystectomy. Conversely, VA
      physicians may have been less likely to recommend laparoscopic cholecystectomies
      to African-American patients.

PMID- 10359354
TI  - Anterior lesser curve seromyotomy using a stapling device and posterior truncal
      vagotomy for the treatment of chronic duodenal ulcer: longterm results.
AB  - BACKGROUND: Recently, gastric stapling with posterior truncal vagotomy has been
      performed, either by conventional or laparoscopic surgery, as an alternative to
      highly selective vagotomy and the Taylor procedure for the treatment of chronic
      duodenal ulcer. Our aim was to investigate the longterm effects after a stapling
      modified Taylor procedure, conventional and laparoscopic, on gastric secretion
      and emptying and on clinical indices and recurrence rates in patients treated for
      duodenal ulcer before 1994. STUDY DESIGN: Thirty-one patients, aged 40 to 76
      years (mean 53 years), were treated between 1986 and 1993, 21 by conventional and
      10 by a laparoscopic stapling-modified Taylor procedure. Outcomes were studied
      for gastric acid secretion, solid and liquid gastric emptying, euterogastric
      reflux, endoscopic findings, and clinical indices using the Visick grading.
      RESULTS: Endoscopy revealed a healing ulcer in 29 patients. Two patients showed
      signs of chronic ulcerative disease with mild symptoms, without gastritis or
      pyloric stenosis indicative of progressive ulcerative diathesis, and were
      classified as Visick III. Twenty-four patients were classified as Visick I and 5
      as Visick II. The enterogastric reflux index ranged from 0% to 27%, and basal and
      peak acid output were 1.5+/-0.6 mmol H+/h and 12.2+/-6.4 mmol H+/h, respectively.
      The half-emptying time of solid and liquid meals was 78+/-9 minutes and 18+/-6
      minutes, respectively. These results are likely to be similar to those obtained
      from the series of patients who underwent highly selective vagotomy or Taylor
      procedure and are close to those achieved in healthy controls. CONCLUSIONS: This
      modification of the original Taylor operation (conventional and laparoscopic)
      allows a more rapid, technically easier, and radical performance of the operation
      with excellent longterm results and should be considered an effective alternative
      for the treatment of duodenal ulcer.

PMID- 10359355
TI  - Surgical approach to cecal diverticulitis.
AB  - BACKGROUND: Cecal diverticulitis is a rare condition in the Western world, with a
      higher incidence in people of Asian descent. The treatment for cecal
      diverticulitis has ranged from expectant medical management, which is similar to
      uncomplicated left-sided diverticulitis, to right hemicolectomy. STUDY DESIGN: A
      retrospective chart review was conducted of the 49 patients treated for cecal
      diverticulitis at Olive View-UCLA Medical Center from 1976 to 1998. This was the
      largest-ever single-institution review of cecal diverticulitis reported in the
      mainland US. RESULTS: The clinical presentation was similar to that of acute
      appendicitis, with abdominal pain, low-grade fever, nausea/vomiting, abdominal
      tenderness, and leukocytosis. Operations performed included right hemicolectomy
      in 39 patients (80%), diverticulectomy in 7 patients (14%), and appendectomy with
      drainage of intraabdominal abscess in 3 patients (6%). Of the 7 patients who had
      diverticulectomy, 1 required right hemicolectomy at 6 months followup for
      continued symptoms. Of the three patients who underwent appendectomy with
      drainage, all required subsequent hemicolectomy for continued inflammation. Of
      the 39 patients who received immediate hemicolectomies, there were complications
      in 7 (18%), with no mortality. CONCLUSIONS: We endorse an aggressive operative
      approach to the management of cecal diverticulitis, with the resection of all
      clinically apparent disease at the time of the initial operation. In cases of a
      solitary diverticulum, we recommend the use of diverticulectomy when it is
      technically feasible. When confronted with multiple diverticuli and cecal
      phlegmon, or when neoplastic disease cannot be excluded, we advocate immediate
      right hemicolectomy. This procedure can be safely performed in the unprepared
      colon with few complications. Excisional treatment for cecal diverticulitis
      prevents the recurrence of symptoms, which may be more common in the Western
      population.

PMID- 10359356
TI  - Systemic effects and side effects of interstitial techniques used in liver
      tissue.
AB  - BACKGROUND: Percutaneous ethanol injection (PEI) and cryosurgery are increasingly
      used for the treatment of liver malignancies. To create a safety margin and to
      destroy completely diffusely growing tumors, the precise destruction of healthy
      liver tissue is necessary. Little is known about the effects of operating on this
      type of tissue. This study evaluated the effects and side effects of PEI and
      cryosurgery when applied to normal parenchyma of the liver. STUDY DESIGN: Two
      groups of six minipigs each were treated with either PEI or cryosurgery to create
      necrosis in the liver. During and after the procedures, vital signs were
      monitored and necrotic areas were observed by ultrasonography. Standard and
      immunohistochemistry stains were made from samples of the necrosis, the liver,
      and the lung. RESULTS: In the PEI group, thromboembolic complications occurred in
      all animals (fatality rate 50%). Hematogenous spread of hepatocytes was
      demonstrated by immunohistochemistry and was a cause of pulmonary embolism. In
      the cryosurgery group, neither specific complications nor signs of cell spillage
      occurred. Because of an isolating effect of blood perfusion, hepatocytes close to
      the portal triads were less damaged, vital cells were present in the periphery,
      and the necroses were smaller than the induced lesions. CONCLUSIONS: The effect
      of PEI in healthy liver tissue is unpredictable. This makes the creation of a
      safety margin or the treatment of a diffusely infiltrating tumor impossible. PEI
      always introduces the risk of hematogenous cell spread. Effects of cryosurgery
      are less dependent on tissue qualities. In both techniques, the real extent of
      complete tissue destruction cannot be visualized by ultrasonography.

PMID- 10359357
TI  - Extrapancreatic necrotizing pancreatitis with viable pancreas: a previously under
      appreciated entity.
AB  - BACKGROUND: Necrotizing pancreatitis is generally considered to involve the
      pancreatic parenchyma in all patients, and, as an extension of the necrotic
      process, the peripancreatic tissues as well. We identified a subgroup of patients
      in whom the necrotic process involves apparently extrapancreatic tissues alone
      (EXPN), as opposed to the usual combined parenchymal and peripancreatic necrosis
      (PN). STUDY DESIGN: The objective of this study was to compare clinical courses
      of EXPN and PN. Data were reviewed on 82 consecutive patients with necrotizing
      pancreatitis treated operatively between 1983 and 1997. The extent of pancreatic
      parenchymal necrosis (expressed as percent of pancreas based on contrast-enhanced
      CT and operative findings) was estimated in 62 patients. Diagnosis of EXPN
      required normal enhancement of entire pancreas on dynamic CT and operative
      documentation of viability of the gland. RESULTS: Twelve patients (19%) had EXPN
      and 50 (81%) had PN. Gender, age, body mass index, etiology of pancreatitis,
      prevalence, and type of infection were similar between groups, but APACHE-II
      scores on admission were less in EXPN (6+/-2 versus 10+/-1, p = 0.02). Patients
      with EXPN required fewer reoperative necrosectomies (0.7 versus 3.2, p = 0.009)
      and did not develop pancreatic or gastrointestinal fistulas (0 versus 19
      patients) or hemorrhage (0 versus 8 patients). ICU stays were similar, but
      hospital stays in EXPN were shorter (29+/-6 versus 54+/-5 days, p = 0.01) and
      mortality was less (8% and 20%, p<0.001). CONCLUSIONS: Necrotizing pancreatitis
      manifesting as EXPN is not rare. EXPN is a less aggressive form of necrotizing
      pancreatitis, locally and systemically, and signifies a better prognosis.

PMID- 10359358
TI  - Patients with laparoscopically staged unresectable pancreatic adenocarcinoma do
      not require subsequent surgical biliary or gastric bypass.
AB  - BACKGROUND: Laparoscopic staging is an effective and accurate means of staging
      pancreatic cancer. But, the frequency of subsequent surgical bypass to treat
      biliary or gastric obstruction in laparoscopically staged patients with
      unresectable adenocarcinoma is unknown. The development of biliary and gastric
      obstruction in patients with unresectable pancreatic adenocarcinoma has been
      reported to occur in as many as 70% and 25% of patients, respectively.
      Previously, staging for patients with pancreatic cancer was achieved by
      laparotomy and the anticipated high rate for these patients to develop
      obstruction led to prophylactic bypass procedures. As laparoscopic staging for
      pancreatic cancer becomes a standard modality, the need for prophylactic bypass
      procedures in these patients needs to be examined. STUDY DESIGN: Analyses of
      laparoscopically staged patients (n = 155) with unresectable, histologically
      proved pancreatic adenocarcinoma, from a single institution treated between 1993
      1997 were performed. The frequency of surgical bypass in a prospective cohort of
      patients with unresectable pancreatic adenocarcinoma who did not undergo open
      enteric or biliary bypass at the time of laparoscopic staging was determined.
      RESULTS: Laparoscopic staging revealed that 40 patients had locally advanced
      disease and 115 had metastatic disease. Median survival for patients with locally
      advanced and metastatic disease was 6.2 and 7.8 months, respectively.
      Postlaparoscopy followup revealed that 98% (152 of 155) of these patients did not
      require a subsequent open surgical procedure to treat biliary or gastric
      obstruction. CONCLUSIONS: These results do not support the practice of routine
      prophylactic bypass procedures. As such, we propose that surgical biliary bypass
      can be advocated only for those patients with obstructive jaundice who fail
      endoscopic stent placement, and gastroenterostomy should be reserved for patients
      with confirmed gastric outlet obstruction.

PMID- 10359359
TI  - Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s.
AB  - BACKGROUND: Advances in the nonoperative staging and palliation of periampullary
      carcinoma have dramatically changed the management of this disease. Currently,
      surgical palliation is used primarily for patients found to be unresectable at
      the time of laparotomy performed for the purpose of determining resectability.
      STUDY DESIGN: A review of all patients undergoing operative management for
      periampullary adenocarcinoma at a single, high-volume institution was performed.
      The review focused on patients found to be unresectable who, therefore, underwent
      surgical palliation. RESULTS: Between December 1991 and December 1997, 256
      patients with unresectable periampullary adenocarcinoma were operatively
      palliated. During the same time period, 512 patients underwent
      pancreaticoduodenectomy (PD) for periampullary carcinoma. Sixty-eight percent of
      patients were unresectable secondary to liver metastases or peritoneal
      metastases, and 32% were deemed unresectable because of local vascular invasion.
      Of the 256 patients, 51% underwent double bypass (hepaticojejunostomy [HJ] and
      gastrojejunostomy [GJ]), 11% underwent HJ alone, 19% underwent GJ alone, and 19%
      did not undergo any form of bypass. Celiac block was performed in 75% of
      patients. Palliated patients were significantly younger, with a mean age of 64.0
      years compared with 65.8 years in the resected group (p = 0.04). Gender and race
      distributions were similar in the 2 groups, with 57% of palliated patients and
      55% of resected patients being men (p = NS) and 91% of patients in each group
      being Caucasian (p = NS). Palliative procedures were performed with a mortality
      rate of 3.1%, compared to 1.9% in those successfully resected (p = NS). Those
      undergoing operative palliation had a significantly lower incidence of
      postoperative complications when compared with those undergoing
      pancreaticoduodenectomy (22% versus 35%, p<0.0001) and had significantly shorter
      lengths of stay (10.3 days versus 14.8 days, p<0.0001). As expected, palliated
      patients had a significantly poorer prognosis, with 1-, 2- and 4-year survivals
      of 25%, 9%, and 6% (median 6.5 months), respectively, compared with 75%, 47%, and
      24% in their resectable counterparts (median 21 months, p<0.0001). CONCLUSIONS:
      Surgical palliation continues to play an important role in the management of
      periampullary carcinoma. In this high-volume center, 33% of patients undergoing
      operative management of this disease were unresectable. Surgical palliation can
      be accomplished with acceptable perioperative mortality (3.1%) and morbidity
      (22%), with excellent longterm results.

PMID- 10359360
TI  - A survey of hospital management practices for vulvar melanoma.
AB  - BACKGROUND: Vulvar melanoma is a very rare form of cancer. The purpose of this
      study was to describe practice patterns for the management of vulvar melanoma.
      STUDY DESIGN: The National Cancer Data Base was reviewed from 1985 through 1994
      for patient reports submitted with a diagnosis of vulvar melanoma. RESULTS: Five
      hundred sixty-nine patients with vulvar melanoma were identified. A substantial
      number of patients were older; during the latter period of this study (1990 to
      1994), 50% were 70 years old or older. Surgery was used in more than 90% of
      patients with stages 0 to III. Local excision was used mainly in early-stage (0
      and I) disease. Adjuvant therapy was used infrequently. Lymph node evaluation was
      performed in more than half of the patients, with greater frequency for patients
      who had advanced disease. The overall 5-year relative survival rate was 62%. If
      the lymph nodes contained metastases, survival was poor. Patients with recurrent
      disease also had poor survival. CONCLUSIONS: Surgery remains the mainstay of
      therapy for vulvar melanoma. The use of excision and radical operations remained
      constant during the 10 years of the study.

PMID- 10359361
TI  - The longitudinal study of surgical residents 1994-1996.

PMID- 10359362
TI  - Tamoxifen and contralateral breast cancer.

PMID- 10359363
TI  - Breast cancer prevention (termed risk-reduction): a new era?

PMID- 10359364
TI  - Hypothermia in trauma patients.
AB  - Hypothermia occurs commonly in severely injured patients and is associated with a
      high mortality rate. It perturbs the normal homeostatic response to injury and
      affects multiple organ systems and physiologic processes. In trauma patients,
      hypothermia-induced coagulopathy often leads to marked bleeding diathesis and
      frequently provides a challenge for the surgeon. Once hypothermia occurs, it is
      often difficult to correct. Efforts to prevent and treat hypothermia in trauma
      patients should be instituted in the field and continued as an integral part of
      the resuscitation process. Hospital personnel and physicians at various levels
      caring for trauma patients from the initial injury and thereafter should bear in
      mind that a patient's temperature is as important as any other vital sign.
      Appropriate measures for preventing and treating hypothermia should be instituted
      promptly and tended to with utmost vigilance.

PMID- 10359366
TI  - Primary percutaneous endoscopic button gastrostomy: a modification of the "push"
      technique.

PMID- 10359365
TI  - Video-assisted neck surgery: endoscopic resection of thyroid tumors with a very
      minimal neck wound.

PMID- 10359367
TI  - Ureteroneocystostomy for renal transplantation.

PMID- 10359368
TI  - Pediatricians alerted to five new vaccines.

PMID- 10359369
TI  - Billions in compensation for toxic oil poisoning victims.

PMID- 10359370
TI  - New report rejects accrediting of those who provide ethics consultation services.

PMID- 10359371
TI  - Association for patient-oriented research.

PMID- 10359372
TI  - From the Food and Drug Administration.

PMID- 10359373
TI  - From the Centers for Disease Control and Prevention. Aldicarb as a cause of food
      poisoning--Louisiana, 1998.

PMID- 10359374
TI  - From the Centers for Disease Control and Prevention. Impact of multiple births on
      low birthweight--Massachusetts, 1989-1996.

PMID- 10359375
TI  - From the Centers for Disease Control and Prevention. Frequency of vaccine-related
      and therapeutic injections--Romania, 1998.

PMID- 10359376
TI  - Adding behavioral therapy to medication for smoking cessation.

PMID- 10359377
TI  - Adding behavioral therapy to medication for smoking cessation.

PMID- 10359378
TI  - Adding behavioral therapy to medication for smoking cessation.

PMID- 10359379
TI  - Adding behavioral therapy to medication for smoking cessation.

PMID- 10359380
TI  - Glycemic control and quality of life in patients with type 2 diabetes.

PMID- 10359381
TI  - Glycemic control and quality of life in patients with type 2 diabetes.

PMID- 10359382
TI  - Screening for type 2 diabetes.

PMID- 10359383
TI  - Screening for type 2 diabetes.

PMID- 10359384
TI  - Should beta-blockers be used to treat hypertension in elderly patients?

PMID- 10359385
TI  - Diagnosing abdominal aortic aneurysm.

PMID- 10359386
TI  - Diagnosing abdominal aortic aneurysm.

PMID- 10359387
TI  - Differences in preferences for neonatal outcomes among health care professionals,
      parents, and adolescents.
AB  - CONTEXT: In neonatal intensive care, parents make important clinical management
      decisions in conjunction with health care professionals. Yet little information
      is available on whether preferences of health care professionals and parents for
      the resulting health outcomes differ. OBJECTIVE: To measure and compare
      preferences for selected health states from the perspectives of health care
      professionals (ie, neonatologists and neonatal nurses), parents of extremely low
      birth-weight (ELBW) or normal birth-weight infants, and adolescents who were
      either ELBW or normal birth-weight infants. DESIGN: Cross-sectional cohort study.
      SETTING AND PARTICIPANTS: A total of 742 participants were recruited and
      interviewed between 1993 and 1995, including 100 neonatologists from hospitals
      throughout Canada; 103 neonatal nurses from 3 regional neonatal intensive care
      units; 264 adolescents (aged 12-16 years), including 140 who were ELBW infants
      and 124 sociodemographically matched term controls; and 275 parents of the
      recruited adolescents. MAIN OUTCOME MEASURE: Preferences (utilities) for 4 to 5
      hypothetical health states of children were obtained by direct interviews using
      the standard gamble method. RESULTS: Overall, neonatologists and nurses had
      similar preferences for the 5 health states, and a similar proportion rated some
      health states as worse than death (59% of neonatologists and 68% of nurses;
      P=.20). Health care professionals rated the health states lower than did parents
      of ELBW and term infants (P<.001). Overall, 64% of health care professionals and
      45% of parents rated 1 or more health states to be worse than death (P<.001).
      Differences in mean utility scores between health care professionals and parents
      and adolescent respondents were most pronounced for the 2 most severely disabled
      health states (P<.001). CONCLUSIONS: When asked to rate the health-related
      quality of life for the hypothetical conditions of children, health care
      professionals tend to provide lower utility scores than do adolescents and their
      parents. These findings have implications for decision making in the neonatal
      intensive care unit.

PMID- 10359388
TI  - Long-term intake of dietary fiber and decreased risk of coronary heart disease
      among women.
AB  - CONTEXT: Epidemiological studies of men suggest that dietary fiber intake
      protects against coronary heart disease (CHD), but data on this association in
      women are sparse. OBJECTIVE: To examine the association between long-term intake
      of total dietary fiber as well as fiber from different sources and risk of CHD in
      women. DESIGN AND SETTING: The Nurses' Health Study, a large, prospective cohort
      study of US women followed up for 10 years from 1984. Dietary data were collected
      in 1984, 1986, and 1990, using a validated semiquantitative food frequency
      questionnaire. PARTICIPANTS: A total of 68782 women aged 37 to 64 years without
      previously diagnosed angina, myocardial infarction (MI), stroke, cancer,
      hypercholesterolemia, or diabetes at baseline. MAIN OUTCOME MEASURE: Incidence of
      acute MI or death due to CHD by amount of fiber intake. RESULTS: Response rate
      averaged 80% to 90% during the 10-year follow-up. We documented 591 major CHD
      events (429 nonfatal MIs and 162 CHD deaths). The age-adjusted relative risk (RR)
      for major CHD events was 0.53 (95% confidence interval [CI], 0.40-0.69) for women
      in the highest quintile of total dietary fiber intake (median, 22.9 g/d) compared
      with women in the lowest quintile (median, 11.5 g/d). After controlling for age,
      cardiovascular risk factors, dietary factors, and multivitamin supplement use,
      the RR was 0.77 (95% CI, 0.57-1.04). For a 10-g/d increase in total fiber intake
      (the difference between the lowest and highest quintiles), the multivariate RR of
      total CHD events was 0.81 (95% CI, 0.66-0.99). Among different sources of dietary
      fiber (eg, cereal, vegetables, fruit), only cereal fiber was strongly associated
      with a reduced risk of CHD (multivariate RR, 0.63; 95% CI, 0.49-0.81 for each 5
      g/d increase in cereal fiber). CONCLUSIONS: Our findings in women support the
      hypothesis that higher fiber intake, particularly from cereal sources, reduces
      the risk of CHD.

PMID- 10359389
TI  - Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with
      type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS
      49). UK Prospective Diabetes Study (UKPDS) Group.
AB  - CONTEXT: Treatment with diet alone, insulin, sulfonylurea, or metformin is known
      to improve glycemia in patients with type 2 diabetes mellitus, but which
      treatment most frequently attains target fasting plasma glucose (FPG)
      concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c
      (HbA1c) below 7% is unknown. OBJECTIVE: To assess how often each therapy can
      achieve the glycemic control target levels set by the American Diabetes
      Association. DESIGN: Randomized controlled trial conducted between 1977 and 1997.
      Patients were recruited between 1977 and 1991 and were followed up every 3 months
      for 3, 6, and 9 years after enrollment. SETTING: Outpatient diabetes clinics in
      15 UK hospitals. PATIENTS: A total of 4075 patients newly diagnosed as having
      type 2 diabetes ranged in age between 25 and 65 years and had a median
      (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259)
      mg/dL], HbA1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29
      (6) kg/m2. INTERVENTIONS: After 3 months on a low-fat, high-carbohydrate, high
      fiber diet, patients were randomized to therapy with diet alone, insulin,
      sulfonylurea, or metformin. MAIN OUTCOME MEASURES: Fasting plasma glucose and
      HbA1c levels, and the proportion of patients who achieved target levels below 7%
      HbA1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following
      diagnosis. RESULTS: The proportion of patients who maintained target glycemic
      levels declined markedly over 9 years of follow-up. After 9 years of monotherapy
      with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG
      levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c
      levels below 7%. In obese patients randomized to metformin, 18% attained FPG
      levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below
      7%. Patients less likely to achieve target levels were younger, more obese, or
      more hyperglycemic than other patients. CONCLUSIONS: Each therapeutic agent, as
      monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c
      below 7% compared with diet alone. However, the progressive deterioration of
      diabetes control was such that after 3 years approximately 50% of patients could
      attain this goal with monotherapy, and by 9 years this declined to approximately
      25%. The majority of patients need multiple therapies to attain these glycemic
      target levels in the longer term.

PMID- 10359390
TI  - Protein-energy undernutrition among elderly hospitalized patients: a prospective
      study.
AB  - CONTEXT: Numerous studies have identified strong correlations between the
      severity of nutritional deficits and an increased risk of subsequent morbid
      events among the hospitalized elderly, but whether inadequate nutrient intake
      during hospitalization contributes to such nutritional deficits or the risk of
      adverse outcomes is not known. OBJECTIVES: To identify the distribution of
      average daily nutrient intake among the nonterminally ill hospitalized elderly,
      ascertain what factors contribute to persistently low intakes, and determine
      whether the adequacy of nutrient intake correlates with the risk of mortality.
      DESIGN: Prospective cohort study conducted from 1994 to 1997. SETTING: University
      affiliated Department of Veterans Affairs hospital. PATIENTS: A total of 497
      patients 65 years or older (mean [SD] age, 74 [6] years; 97% male; 86% white)
      with a length of stay of 4 days or more. MAIN OUTCOME MEASURES: Daily in-hospital
      nutrient intake, in-hospital mortality, and 90-day mortality. RESULTS: A total of
      102 patients (21%) had an average daily in-hospital nutrient intake of less than
      50% of their calculated maintenance energy requirements. Admission illness
      severity, average length of stay, and admission albumin and prealbumin levels for
      this low nutrient group did not differ significantly from those of the remaining
      patients. However, the low nutrient group had lower mean (SD) discharge serum
      total cholesterol (154 [44] mg/dL [4 [1.1] mmol/L] vs 173 [42] mg/dL [4.5 [1.1]
      mmol/L]; P=.001), albumin (29.1 [6.7] vs 33.2 [6.1] g/L, P=.001), and prealbumin
      (162 [69] vs 205 [68] mg/L; P=.001) concentrations and a higher rate of in
      hospital mortality (relative risk, 8.0; 95% confidence interval, 2.8-22.6) and 90
      day mortality (relative risk, 2.9; 95% confidence interval, 1.4-6.1).
      Contributing to the problem of inadequate nutrient intake, patients were
      frequently ordered to have nothing by mouth and were not fed by another route.
      Neither canned supplements nor nutritional support were used effectively.
      CONCLUSIONS: Throughout their hospitalization, many elderly patients were
      maintained on nutrient intakes far less than their estimated maintenance energy
      requirements, which may contribute to an increased risk of mortality. Given the
      difficulties reversing established nutritional deficits in the elderly, greater
      efforts should be made to prevent the development of such deficits during
      hospitalization.

PMID- 10359391
TI  - Effect of oral androstenedione on serum testosterone and adaptations to
      resistance training in young men: a randomized controlled trial.
AB  - CONTEXT: Androstenedione, a precursor to testosterone, is marketed to increase
      blood testosterone concentrations as a natural alternative to anabolic steroid
      use. However, whether androstenedione actually increases blood testosterone
      levels or produces anabolic androgenic effects is not known. OBJECTIVES: To
      determine if short- and long-term oral androstenedione supplementation in men
      increases serum testosterone levels and skeletal muscle fiber size and strength
      and to examine its effect on blood lipids and markers of liver function. DESIGN
      AND SETTING: Eight-week randomized controlled trial conducted between February
      and June 1998. PARTICIPANTS: Thirty healthy, normotestosterogenic men (aged 19-29
      years) not taking any nutritional supplements or androgenic-anabolic steroids or
      engaged in resistance training. INTERVENTIONS: Twenty subjects performed 8 weeks
      of whole-body resistance training. During weeks 1, 2, 4, 5, 7, and 8, the men
      were randomized to either androstenedione, 300 mg/d (n = 10), or placebo (n =
      10). The effect of a single 100-mg androstenedione dose on serum testosterone and
      estrogen concentrations was determined in 10 men. MAIN OUTCOME MEASURES: Changes
      in serum testosterone and estrogen concentrations, muscle strength, muscle fiber
      cross-sectional area, body composition, blood lipids, and liver transaminase
      activities based on assessments before and after short- and long-term
      androstenedione administration. RESULTS: Serum free and total testosterone
      concentrations were not affected by short- or long-term androstenedione
      administration. Serum estradiol concentration (mean [SEM]) was higher (P<.05) in
      the androstenedione group after 2 (310 [20] pmol/L), 5 (300 [30] pmol/L), and 8
      (280 [20] pmol/L) weeks compared with presupplementation values (220 [20]
      pmol/L). The serum estrone concentration was significantly higher (P<.05) after 2
      (153 [12] pmol/L) and 5 (142 [15] pmol/L) weeks of androstenedione
      supplementation compared with baseline (106 [11] pmol/L). Knee extension strength
      increased significantly (P<.05) and similarly in the placebo (770 [55] N vs 1095
      [52] N) and androstenedione (717 [46] N vs 1024 [57] N) groups. The increase of
      the mean cross-sectional area of type 2 muscle fibers was also similar in
      androstenedione (4703 [471] vs 5307 [604] mm2; P<.05) and placebo (5271 [485] vs
      5728 [451] mm2; P<.05) groups. The significant (P<.05) increases in lean body
      mass and decreases in fat mass were also not different in the androstenedione and
      placebo groups. In the androstenedione group, the serum high-density lipoprotein
      cholesterol concentration was reduced after 2 weeks (1.09 [0.08] mmol/L [42 (3)
      mg/dL] vs 0.96 [0.08] mmol/L [37 (3) mg/dL]; P<.05) and remained low after 5 and
      8 weeks of training and supplementation. CONCLUSIONS: Androstenedione
      supplementation does not increase serum testosterone concentrations or enhance
      skeletal muscle adaptations to resistance training in normotestosterogenic young
      men and may result in adverse health consequences.

PMID- 10359392
TI  - Users' guides to the medical literature: XVII. How to use guidelines and
      recommendations about screening. Evidence-Based Medicine Working Group.

PMID- 10359393
TI  - Geographic variation in physician visits for uninsured children: the role of the
      safety net.
AB  - CONTEXT: Although an extensive literature exists comparing national access to
      health care for uninsured vs insured children, few data exist regarding
      differences in access across states. OBJECTIVE: To examine variation in access to
      physician services for uninsured children in 10 states, the safety net's role in
      explaining this variation, and the potential effects of the State Children's
      Health Insurance Program (CHIP) on insurance coverage and access. DESIGN AND
      SETTING: The population-based Robert Wood Johnson Foundation Family Health
      Insurance Survey, conducted between summer 1993 and spring 1994 in 10 states
      (Colorado, Florida, Minnesota, New Mexico, New York, North Dakota, Oklahoma,
      Oregon, Vermont, and Washington), with a response rate of families by state
      ranging from 61% to 83%. PARTICIPANTS: A total of 8565 children who were
      uninsured (1586), covered by Medicaid (2723), or covered by employer-sponsored
      private insurance (4256) for 1 full year prior to the survey. MAIN OUTCOME
      MEASURES: Percentage of low-income children who are uninsured and predicted
      annual physician visits by state if insurance was provided to uninsured children
      in families with incomes of less than 200% of poverty level. RESULTS: In the 10
      study states, low-income children ranged from 61% to 86% of all uninsured
      children and the uninsured rate for low-income children varied from 9% to 31%. On
      average, providing public coverage would increase annual physician visits from
      2.3 to 4.6 (a 105% increase), but the increase would range from 41% to 189%
      across states. The annual physician visit rate in the 3 states with the highest
      access for the uninsured was 160% of that in the 3 lowest-access states. Safety
      net capacity in the high-access states ranged from 120% to 220% of that in the
      low-access states. CONCLUSIONS: Our data suggest that the potential effects of
      CHIP vary substantially across states. Notably, improvements in access to health
      care by uninsured low-income children should be greater in states with the fewest
      safety net resources.

PMID- 10359394
TI  - Decisions regarding treatment of seriously ill newborns.

PMID- 10359395
TI  - Medical, legal, and societal implications of androstenedione use.

PMID- 10359396
TI  - Primary care physicians should be coordinators, not gatekeepers.
AB  - Primary care gatekeeping, in which the goal of the primary care physician (PCP)
      is to reduce patient referrals to specialists and thereby reduce costs, is not an
      adequate system in which to practice medicine. However, returning to the pre
      managed care model of uncoordinated open access to specialists is a poor
      solution. The primary care model should be retained, but PCPs should be
      transformed from gatekeepers into coordinators of care, in which the goal of the
      PCP is to integrate both primary and specialty care to improve quality. Changes
      in the PCP's daily work process, as well as the referral and payment processes,
      need to be implemented to reach this goal. This model would eliminate the
      requirement that referrals to specialists be authorized by the primary care
      physician or managed care organization. Financial incentives would be needed, eg,
      to encourage PCPs to provide management of complex cases and discourage both over
      referral and underreferral to specialists. Budgeting specialists should control
      excess costs that might be created by the elimination of the primary care
      gatekeeper. Pilot projects are needed to test and refine this model of PCP as
      coordinator of care.

PMID- 10359397
TI  - JAMA Patient Page: fiber.

PMID- 10359398
TI  - Health risks of genetically modified foods.

PMID- 10359400
TI  - Metabolic complications of urinary diversion.

PMID- 10359399
TI  - Inflammatory mediators in heart failure: homogeneity through heterogeneity.

PMID- 10359401
TI  - New approach to prevention of kernicterus.

PMID- 10359402
TI  - "Doctor, is wine good for my heart?".

PMID- 10359403
TI  - Exposure assessment in community-based epidemiological studies.

PMID- 10359404
TI  - Towards a coherent public-health analysis for epilepsy.

PMID- 10359405
TI  - Long-term effect of inhaled budesonide in mild and moderate chronic obstructive
      pulmonary disease: a randomised controlled trial.
AB  - BACKGROUND: Little is known about the long-term efficacy of inhaled
      corticosteroids in chronic obstructive pulmonary disease (COPD). We investigated
      the efficacy of inhaled budesonide on decline in lung function and respiratory
      symptoms in a 3-year placebo-controlled study of patients with COPD. METHODS: We
      used a parallel-group, randomised, double-blind, placebo-controlled design in a
      singlecentre study, nested in a continuing epidemiological survey (the Copenhagen
      City Heart Study). Inclusion criteria were as follows: no asthma; a ratio of
      forced expiratory volume in 1 s (FEV1) and vital capacity of 0.7 or less; FEV1
      which showed no response (<15% change) to 1 mg inhaled terbutaline or
      prednisolone 37.5 mg orally once daily for 10 days. 290 patients were randomly
      assigned budesonide, 800 microg plus 400 microg daily for 6 months followed by
      400 microg twice daily for 30 months, or placebo for 36 months. The mean age of
      the participants was 59 years and the mean FEV1 2.37 L or 86% of predicted. The
      main outcome measure was rate of FEV1 decline. Analyses were by intention to
      treat. FINDINGS: The crude rates of FEV1 decline were slightly smaller than
      expected (placebo group 41.8 mL per year, budesonide group 45.1 mL per year). The
      estimated rates of decline from the regression model did not differ significantly
      (49.1 mL vs 46.0 mL per year; difference 3.1 mL per year [95% CI -12.8 to 19.0];
      p=0.7). Before the study, the minimum relevant difference was defined as 20 mL
      per year; this difference was outside the 95% CI. No effect of inhaled budesonide
      was seen on respiratory symptoms. 316 exacerbations occurred during the study
      period, 155 in the budesonide group and 161 in the placebo group. Treatment was
      well tolerated. INTERPRETATION: Inhaled budesonide was of no clinical benefit in
      COPD patients recruited from the general population by screening. We question the
      role of long-term inhaled corticosteroids in the treatment of mild to moderate
      COPD.

PMID- 10359406
TI  - Low-potency oestrogen and risk of endometrial cancer: a case-control study.
AB  - BACKGROUND: Urogenital symptoms are common among postmenopausal women. Such
      symptoms may be alleviated by low-potency oestrogen formulations administered
      orally or vaginally. Although low-potency oestrogen formulations are assumed to
      have few, if any, adverse effects on the endometrium, risk of endometrial
      neoplasia has not been quantified. METHODS: In a nationwide population-based case
      control study in Sweden of endometrial cancer among postmenopausal women, we
      obtained detailed information on hormone replacement from 789 cases of
      endometrial cancer and 3368 population controls. In a histopathological review,
      80 cases were reclassified as having endometrial atypical hyperplasia. Odds
      ratios and 95% CI were calculated with unconditional logistic regression.
      FINDINGS: After multivariate adjustment, oral use of oestriol 1-2 mg daily
      increased the relative risk of endometrial cancer and endometrial atypical
      hyperplasia: the odds ratios for at least 5 years of use compared with never use
      were 3.0 (95% CI 2.0-4.4) and 8.3 (4.0-17.4), respectively. The association was
      stronger for well-differentiated cancers and those with limited invasion. The
      excess relative risk was lost rapidly after cessation of treatment. Only weak
      associations were observed between vaginal application of low-potency oestrogen
      formulations and relative risk of endometrial neoplasia. INTERPRETATION: Oral,
      but not vaginal, treatment with low-potency oestrogen formulations increases the
      relative risk of endometrial neoplasia. Thus close surveillance of patients is
      needed, and addition of a progestagen should be considered.

PMID- 10359407
TI  - Mother-to-child transmission of toxoplasmosis: risk estimates for clinical
      counselling.
AB  - BACKGROUND: Women who acquire toxoplasmosis infection during pregnancy (in most
      cases detected through serological screening) require counselling about the risk
      of congenital infection and its clinical sequelae. Reliable estimates of risk are
      not currently available. We undertook an analysis of data from women referred to
      the toxoplasmosis reference laboratory, Lyon, France, between 1987 and 1995.
      METHODS: Information was collected from clinical notes kept at the laboratory
      and, where necessary, from the relevant obstetrician or paediatrician via
      telephone. Methods were developed to derive estimates of the risk of congenital
      toxoplasmosis by exact duration of gestation at maternal seroconversion.
      FINDINGS: We analysed obstetric and paediatric data on 603 confirmed maternal
      toxoplasmosis infections. At least 564 women received antiparasitic drugs
      according to a standard protocol. Congenital infection status was ascertained in
      554 cases, and infected children were followed-up for a median of 54 months. The
      overall maternal-fetal transmission rate was 29% (95% CI 25-33), which masked a
      sharp increase in risk with duration of gestation from 6% at 13 weeks to 72% at
      36 weeks. However, fetuses infected in early pregnancy were much more likely to
      show clinical signs of infection. These effects counterbalance, and women who
      seroconverted at 24-30 weeks of gestation carried the highest risk (10%) of
      having a congenitally infected child with early clinical signs who was thus at
      risk of long-term complications. INTERPRETATION: This information will assist the
      clinical counselling of pregnant women diagnosed with acute toxoplasmosis and may
      guide individual decisions on investigative and therapeutic options. Further
      studies are required to determine the long-term risks of clinical symptoms and
      disability due to congenital toxoplasmosis.

PMID- 10359408
TI  - Feasibility of neonatal screening for toxoplasma infection in the absence of
      prenatal treatment. Danish Congenital Toxoplasmosis Study Group .
AB  - BACKGROUND: The best method for prevention and control of congenital toxoplasma
      infection is uncertain. Prenatal screening is done in Austria and France, but the
      effect of treatment during pregnancy is not well documented. The aim of our study
      was to find out the maternofetal transmission rate and outcome in infants born to
      mothers who were not treated during pregnancy. METHODS: We analysed 89873 eluates
      from phenylketonuria (PKU) cards from neonates and paired first-trimester serum
      samples from the mothers for specific IgG antibodies to Toxoplasma gondii.
      Children born to mothers who seroconverted during pregnancy were followed-up
      clinically and serologically to 12 months of age. In addition, 21144 PKU cards
      were analysed for toxoplasma-specific IgM antibodies during the last 12 months of
      the study. FINDINGS: In 24989 (27.8%) cases both the PKU eluate and the first
      trimester samples were IgG positive, which indicates previous maternal infection.
      139 of the 64884 seronegative women acquired toxoplasma infection during
      pregnancy and gave birth to 141 infants (two sets of twins). 27 of these children
      were diagnosed with congenital toxoplasma infection. The transmission rate was
      19.4% (95% CI 13.2-27.0). Clinical signs and symptoms were found in four (15%) of
      the 27 children. The additional analysis for toxoplasma-specific IgM antibodies
      from the PKU card identified seven of nine children with congenital toxoplasma
      infection. The false-positive rate for the IgM test was 0.19 per 1000, and no
      false-negatives were found. INTERPRETATION: The risks of transmission of
      infection and of disease in the infant are low in an area with a low risk of
      toxoplasma infection. A neonatal screening programme based on detection of
      toxoplasma-specific IgM antibodies alone will identify between 70% and 80% of
      cases of congenital toxoplasmosis.

PMID- 10359409
TI  - Endotoxin and immune activation in chronic heart failure: a prospective cohort
      study.
AB  - BACKGROUND: Immune activation in patients with chronic heart failure may be
      secondary to endotoxin (lipopolysaccharide) action. We investigated the
      hypothesis that altered gut permeability with bacterial translocation and
      endotoxaemia would be increased in patients with oedema secondary to congestive
      heart failure. METHODS: We compared 20 patients who had chronic heart failure
      with recent-onset peripheral oedema (mean age 64 years [SD 10], New York Heart
      Association [NYHA] class 3.3 [0.7]), 20 stable non-oedematous patients with
      chronic heart failure (mean age 63 years [19], NYHA class 2.6 [0.7]), and 14
      healthy volunteers (mean age 55 years [16]). Biochemical markers of endotoxaemia,
      inflammation, and immune activation were measured. Ten patients were studied
      within 1 week of complete resolution of oedema. Five patients survived longer
      than 6 months and were restudied again after remaining free of oedema for more
      than 3 months. FINDINGS: Mean endotoxin concentrations were higher in oedematous
      patients with chronic heart failure than in stable patients with chronic heart
      failure (0.74 [SD 0.45] vs 0.37 EU/mL [0.23], p=0.0009) and controls (0.46 EU/mL
      [0.21], p=0.02). Oedematous patients had the highest concentrations of several
      cytokines. After short-term diuretic treatment, endotoxin concentrations
      decreased from 0.84 EU/mL [0.49] to 0.45 EU/mL [0.21], p<0.05) but cytokines
      remained raised. After freedom of oedema for more than 3 months after oedema
      resolved, endotoxin concentrations remained unchanged from the previous visit
      (0.49 EU/mL [0.06], p=0.45). INTERPRETATION: Raised concentrations of endotoxin
      and cytokines are found in patients with chronic heart failure during acute
      oedematous exacerbation. Intensified diuretic treatment can normalise endotoxin
      concentrations. Our preliminary findings suggest that endotoxin may trigger
      immune activation in patients with chronic heart failure during oedematous
      episodes.

PMID- 10359411
TI  - Disorientation and vertebral fractures.

PMID- 10359410
TI  - Acquired rifamycin monoresistance in patients with HIV-related tuberculosis
      treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials
      Consortium.
AB  - BACKGROUND: Rifapentine is a cyclopentyl-substituted rifamycin whose serum half
      life is five times that of rifampin. The US Public Health Service Study 22
      compared a once-weekly regimen of isoniazid and rifapentine with twice weekly
      isoniazid and rifampin in the continuation phase (the last 4 months) of treatment
      for pulmonary tuberculosis in HIV-seropositive and HIV-seronegative patients.
      This report concerns only the HIV-seropositive part of the trial, which has
      ended. The HIV-seronegative part will stop follow-up in 2001. METHODS: Adults
      with culture-positive, drug-susceptible pulmonary tuberculosis who completed 2
      months of four-drug (isoniazid, rifampin, pyrazinamide, ethambutol) treatment
      (induction phase) were randomly assigned 900 mg isoniazid and 600 mg rifapentine
      once weekly, or 900 mg isoniazid and 600 mg rifampin twice weekly. All therapy
      was directly observed. Statistical analysis used univariate, Kaplan-Meier, and
      logistic and proportional hazards regression methods. FINDINGS: 71 HIV
      seropositive patients were enrolled: 61 completed therapy and were assessed for
      relapse. Five of 30 patients in the once-weekly isoniazid/rifapentine group
      relapsed, compared with three of 31 patients in the twice-weekly
      isoniazid/rifampin group (log rank chi2=0.69, p=0.41). However, four of five
      relapses in the once-weekly isoniazid/rifapentine group had monoresistance to
      rifamycin, compared with none of three in the rifampin group (p=0.05). Patients
      who relapsed with rifamycin monoresistance were younger (median age 29 vs 41
      years), had lower baseline CD4 cell counts (median 16 vs 144 microL), and were
      more likely to have extrapulmonary involvement (75% vs 18%, p=0.03) and
      concomitant therapy with antifungal agents (75% vs 9%, p=0.006). No rifamycin
      monoresistant relapse has occurred among 1004 HIV-seronegative patients enrolled
      to date. INTERPRETATION: Relapse with rifamycin monoresistant tuberculosis
      occurred among HIV-seropositive tuberculosis patients treated with a once-weekly
      isoniazid/rifapentine continuation-phase regimen. Until more effective regimens
      have been identified and assessed in clinical trials, HIV-seropositive people
      with tuberculosis should not be treated with a once-weekly isoniazid/rifapentine
      regimen.

PMID- 10359412
TI  - Erythropoietin, given enterally, stimulates erythropoiesis in premature infants.

PMID- 10359413
TI  - Children with type-1 diabetes and their unaffected siblings have fewer symptoms
      of asthma.

PMID- 10359415
TI  - Are live saccharomyces yeasts harmful to patients?

PMID- 10359414
TI  - L-dopa slows the progression of familial parkinsonism.

PMID- 10359416
TI  - Laveran remembered: malaria haemozoin in leucocytes.

PMID- 10359417
TI  - Is needle diathermy excision of the transformation zone a better treatment for
      cervical intraepithelial neoplasia than large loop excision?

PMID- 10359418
TI  - Increased concentrations of follicle-stimulating hormone in mothers of children
      with Down's syndrome.

PMID- 10359419
TI  - Vancomycin-resistant enterococci in imported chickens in Japan.

PMID- 10359420
TI  - Screening mammography for women starting hormone replacement therapy.

PMID- 10359421
TI  - HIV-1 infected patients with toxic epidermal necrolysis: an occupational risk for
      healthcare workers.

PMID- 10359422
TI  - Geography of biomedical publications in the European Union, 1990-98.

PMID- 10359423
TI  - Better salvage therapy for HIV-1 infection still needed.

PMID- 10359424
TI  - US prevalence of Helicobacter pylori may plummet in next century.

PMID- 10359425
TI  - Ruth Bishop: rotaviruses and vaccines. Interview by Amanda Tattam.

PMID- 10359426
TI  - Medical services continue to decline in Iraq.

PMID- 10359427
TI  - Management of chronic pain.
AB  - Chronic pain is a common condition for which patients seek care from various
      health-care providers. This type of pain causes much suffering and disability and
      is frequently mistreated or undertreated. Patients who present for evaluation for
      chronic pain should undergo a careful assessment before therapy. Patients with
      chronic pain commonly experience depression, sleep disturbance, fatigue, and
      decreased overall physical and mental functioning. They frequently require an
      interdisciplinary model of care to allow care givers to address the multiple
      components of the patient's pain experience. After a careful evaluation, therapy
      may include medication, nerve blocks, active physical therapy, behavioural
      interventions, and assistance with vocational evaluation and training. Less
      frequently therapy may include placement of implantable devices to alter the pain
      experience. These patients suffer from a chronic condition and often require long
      term care, with frequent reassessment and adjustment of therapy. Although cure is
      possible, it is also infrequent. Therefore, therapy is provided with the aim of
      decreasing pain and suffering while improving physical and mental functioning.

PMID- 10359429
TI  - Human germline gene modification: a dissent.

PMID- 10359428
TI  - Paul Martini: the first clinical pharmacologist?

PMID- 10359430
TI  - Gut rot.

PMID- 10359431
TI  - Science, ethics, and future of research into maternal-infant transmission of HIV
      1.

PMID- 10359432
TI  - Science, ethics, and future of research into maternal-infant transmission of HIV
      1.

PMID- 10359433
TI  - Science, ethics, and future of research into maternal-infant transmission of HIV
      1.

PMID- 10359434
TI  - Science, ethics, and future of research into maternal-infant transmission of HIV
      1.

PMID- 10359435
TI  - Science, ethics, and future of research into maternal-infant transmission of HIV
      1.

PMID- 10359436
TI  - Perianal ulcer.

PMID- 10359437
TI  - Acquired activated protein-C resistance.

PMID- 10359438
TI  - The UKPDS: what was the question?

PMID- 10359439
TI  - Leflunomide for active rheumatoid arthritis.

PMID- 10359440
TI  - Leflunomide for active rheumatoid arthritis.

PMID- 10359441
TI  - In defence of the Milquetoast phenotype.

PMID- 10359442
TI  - Haemopoietic stem-cell transplantation for juvenile chronic arthritis.

PMID- 10359443
TI  - Haemopoietic stem-cell transplantation for juvenile chronic arthritis.

PMID- 10359444
TI  - Stroke prevention.

PMID- 10359445
TI  - Oral corticosteroids and bone pain after pamidronate in adults with cystic
      fibrosis.

PMID- 10359446
TI  - A NICE programme.

PMID- 10359447
TI  - A NICE programme.

PMID- 10359448
TI  - Health hijack.

PMID- 10359449
TI  - More lessons from unfortunate events in Toronto.

PMID- 10359450
TI  - Declaration of Helsinki.

PMID- 10359451
TI  - Change of HAART. Highly active antiretroviral therapy.

PMID- 10359453
TI  - The Nobel chronicles. 1956: Werner Forssmann (1904-79); Andre Frederic Cournand
      (1895-1988); and Dickinson Woodruff Richards, Jr (1895-1973).

PMID- 10359454
TI  - 32P-Postlabeling analysis of lipophilic DNA adducts resulting from interaction
      with (+/-)-3-hydroxy-trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo
      [a]pyrene.
AB  - Bay-region diol epoxides are considered the putative ultimate carcinogens of
      polynuclear aromatic hydrocarbons. However, the results of studies on
      tumorigenesis and DNA binding of benzo[a]pyrene (BP) and its bay-region diol
      epoxide, (+)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyren
      e [(+)-anti-BPDE] suggest that, in addition to anti-BPDE, other reactive
      metabolite(s) of BP may also be involved in BP-induced carcinogenesis. Recent
      studies have demonstrated that 3-hydroxy-trans-7,8-dihydroxy-anti-9,10-epoxy
      7,8,9,10-tetrahydrobenzo[a ]pyrene (anti-BPTE) is another highly reactive
      metabolite of BP. In order to identify syn- and anti-BPTE-derived DNA adducts and
      their base selectivity, we synthesized both compounds by two different methods
      and reacted in vitro with calf thymus DNA and individual nucleotides. The
      resultant adducts were analyzed by nuclease P1-enhanced 32P-postlabeling. Anti
      BPTE produced three major and several minor adducts with DNA; dAp and dGp were
      the preferred substrates, while dCp and dTp were the least reactive. In contrast,
      syn-BPTE produced two major adducts each with DNA and dGp; dAp generated only one
      adduct. Co-chromatography of anti-BPTE-derived DNA adducts with those of
      mononucleotide adducts revealed that the major adducts in DNA were guanine
      derived. Further, co-chromatographic results revealed that the anti-BPTE-DNA
      adducts were distinctly different from that of anti-BPDE-DNA adducts. These
      observations indicate that both syn- and anti-BPTE can react with DNA bases and
      these DNA adducts may also contribute to BP-induced carcinogenesis.

PMID- 10359455
TI  - Influence of nitroreductase and O-acetyltransferase on the mutagenicity of
      substituted nitrobenzothiophenamines in Salmonella typhimurium.
AB  - The mutagenic activity of 17 substituted (aryl)(2-nitrobenzo[b]thiophen
      3yl)amines has been evaluated in the Ames test with different isogenic strains of
      Salmonella typhimurium, that varied in their expression of nitroreductase and O
      acetyltransferase. Active derivatives induced frameshift mutations in TA98
      strain, and differences in the chemical structure resulted in up to 15-fold
      changes in mutagenic activity. The non-mutagenic compounds are the unsubstituted
      parent compound and derivatives with para-chloro, para-fluoro, para-diethylamino,
      meta-bromo and para-dimethylamino groups. They do not show any activity even in
      strains with higher level of nitroreductase or O-acetyltransferase. The addition
      of S9 fraction decreases the mutagenic potential or gives comparable results to
      those obtained without metabolic activation. For electron-donating substituents,
      the meta-isomers display the greatest mutagenic potency, whereas the transfer of
      the group to the para-position leads to less active or unactive molecules. All
      active nitrobenzothiophenes are substrates for bacterial nitroreductase and O
      acetyltransferase, as shown by the reduced mutagenicity in the deficient strains
      and increased mutagenicity in the corresponding overproducing bacteria. Previous
      reports have pointed out interest in nitrothiophene analogues with para-chloro
      and para-fluoro substituents as promising anti-inflammatory drugs. The present
      study further enhances the putative interest in these derivatives, based on
      absence of mutagenicity.

PMID- 10359456
TI  - Induction of inducible nitric oxide synthase gene expression by Pokeweed mitogen.
AB  - The present study has characterized the expression of iNOS gene in Pokeweed
      mitogen (PWM)-driven murine macrophage RAW 264.7 cells. PWM significantly induced
      nitric oxide production in a dose-dependent manner. Quantitative reverse
      transcription-polymerase chain reaction analysis demonstrated that the inducible
      nitric oxide synthase gene expression is increased by PWM treatment. Since iNOS
      transcription has recently been shown to be under the control of the nuclear
      factor (NF)-kappaB/Rel family of transcription factors, the effects of PWM on NF
      kappaB/Rel activation were examined using a transient transfection assay and an
      electrophoretic mobility shift assay (EMSA). Transient expression assays with NF
      kappaB/Rel binding sites linked to the chloramphenicol acetyltransferase gene
      suggest that the PWM-induced increase in transcription is mediated by the NF
      kappaB/Rel transcription factor complex. Using DNA fragments containing the NF
      kappaB/Rel binding sequence, PWM was shown to activate the protein/DNA binding of
      NF-KB/Rel to its cognate site as measured by EMSA. Supershift EMSA showed the
      presence of p50 and c-Rel protein in the complex at the kappaB site. Western blot
      analysis of isolated nuclear fractions, using p65 and c-Rel-specific antibodies,
      provided further evidence that c-Rel is increased by PWM treatment. N-Tosyl-1
      phenylalanine chloromethyl ketone, a potent inhibitor of NF-kappaB/Rel
      activation, inhibited PWM-induced nitrite generation in a dose-dependent manner.
      Collectively, the results of these experiments indicate that c-Rel is positively
      regulated by PWM to assist in the initiation of iNOS gene expression.

PMID- 10359457
TI  - UV-induced CYP1A1 gene expression in human cells is mediated by tryptophan.
AB  - Induction of cytochrome P-4501A1 (CYP1A1) activity by UV has been observed
      earlier in animal studies via a mechanism that has not yet been resolved. Our
      previous data have indicated that formylated indolocarbazoles which are formed by
      UV irradiation of tryptophan solutions are very potent Ah-receptor agonists. To
      evaluate the effect of UV light on cytochrome P4501A1 gene expression, we studied
      the induction of CYP1A1 mRNA by UV irradiation of cultured human keratinocytes
      (HaCaT cell line), primary human blood lymphocytes and mouse Hepa-1 cells. The
      cells were exposed to UV light delivered by a bank of 6 Philips TL20/12RS sun
      lamps emitting primarily in the UVB range in the absence and presence of
      tryptophan. A semiquantitative reverse transcriptase-linked polymerase chain
      reaction (RT-PCR) was used for analysis of gene expression in the treated cells.
      The results show that the CYP1A1 mRNA level induced by UV in the presence of
      tryptophan was higher than that induced by UV alone in both HaCaT cells and
      lymphocytes after 3 h of incubation post-UV irradiation. To find out if the
      induction by UV light is caused by the formation of an Ah receptor ligand, Hepa-1
      wild-type and Ah receptor deficient c12 cell lines were applied. Wild-type (wt)
      cells were inducible either by the tryptophan photoproduct 6-formylindolo[3,2
      b]carbazole (FICZ) or by UV-irradiation but very low or undetectable levels were
      observed in the c12 cells. This shows that the induction of gene expression by
      FICZ and UV is Ah receptor dependent. Together, these results indicate that UV
      induced CYP1A1 gene expression in mammalian cells is mediated by an Ah receptor
      ligand formed from tryptophan. Thus, the photoproducts of tryptophan are
      suggested to be mediators of light via binding to the Ah receptor and as such
      also could have a role in light-regulated biological rhythms.

PMID- 10359458
TI  - DNA methylation by tert-butyl hydroperoxide-iron (II): a role for the transition
      metal ion in the production of DNA base adducts.
AB  - Metabolic degradation of both endogenous and exogenous peroxides is associated
      with the etiology of several diseases including cancer. Tert-butyl hydroperoxide
      (TBHP) has been widely employed as a model compound to study the cytotoxicity and
      promoting effects of organic peroxides. Recently, we reported that incubations of
      TBHP with iron (II) and calf thymus DNA led to generation of high yields of
      methyl radicals and to DNA methylation. Interestingly, DNA was methylated to
      products expected from both free radical and ionic mechanisms such as 8
      methylguanine (C8-MeGua) and 7-methylguanine (N7-MeGua), respectively. To
      elucidate the mechanisms by which methyl radicals can produce different types of
      DNA adducts, we examined the effects of transition metal ions (iron (II), iron
      (III) and copper (I)) and metal ion chelators (ethylenediamine-N,N,N",N"
      tetraacetate (EDTA) and desferal) on the nature and the yields of the DNA adducts
      produced during TBHP decomposition. The results led us to propose that a direct
      methyl radical attack on DNA guanine residues produces C8-MeGua whereas N7-MeGua
      and 3-methyladenine (N3-MeAde) are likely to be produced by attack of
      nucleophilic DNA centers on methyl radical generated in situ by the assistance of
      transition metal ions bound to DNA.

PMID- 10359459
TI  - Characterization of Phase I and Phase II hepatic drug metabolism activities in a
      panel of human liver preparations.
AB  - The role of drug metabolism in drug discovery (lead compound selection) and the
      traditional role of identifying the enzymes involved in biotransformation
      pathways (reaction phenotyping) have both relied heavily on the availability and
      use of a human liver bank. The assessment of drug metabolizing enzyme activity
      and variability in a series of individual human livers is essential when
      characterizing the enzymes involved in metabolic pathways (i.e. correlation
      analysis). In this regard, a human liver bank of 21 samples (14 males, six
      females, and one unknown) was characterized with respect to the activity of
      several important drug metabolizing enzymes. The total CYP450 content of the
      livers ranged from 0.06 to 0.46 nmol/mg microsomal protein. The fold variations
      found in specific enzyme contents were as follows: CYP1A2 (3x), CYP2A6 (21x),
      CYP2C9 (8x), CYP2C19 (175x), CYP2D6 (18x), CYP2E1 (5x), CYP3A4 (18x), FMO (2.5x),
      UDPGT (4x), NAT (7x), COMT (5x), ST (5x), TPMT (3x), and GST (2.5x). In general,
      the fold variation of the Phase II enzymes was lower compared with the Phase I
      enzymes, with the exceptions of CYP1A2, CYP2E1, and FMO. Similar data were
      reviewed from other established liver banks and compared with regard to the
      relative variability observed in drug metabolizing capacities found in this
      study.

PMID- 10359460
TI  - Characterization of the human hepatic cytochromes P450 involved in the in vitro
      oxidation of clozapine.
AB  - It was aimed to identify the cytochrome(s) P450 (CYPs) involved in the N
      demethylation and N-oxidation of clozapine (CLZ) by various approaches using
      human liver microsomes or microsomes from human B-lymphoblastoid cell lines. The
      maximum rates of formation were measured in the microsomal fraction of human
      livers and the Michaelis-Menten kinetics one enzyme model was found to best fit
      the data with mean K(M) for CLZ N-oxide and N-desmethyl-CLZ of 336 and 120
      microM, respectively. Significant correlations were observed between the maximum
      rates of formation (Vmax) for CLZ N-oxide and N-desmethyl-CLZ with the microsomal
      immunoreactive contents of CYP1A2 (r = 0.92, P < 0.009 and r = 0.77, P < 0.077;
      respectively) and CYP3A (r = 0.89, P < 0.02 and r = 0.82, P < 0.05;
      respectively). Antibodies directed against CYP1A2 and CYP3A inhibited formation
      of CLZ N-oxide in human liver microsomes by 10.7+/-6.1%) and 37.2+/-6.9% of
      control, respectively, whereas CLZ N-demethylation was inhibited by 32.2+/-15.4%
      and 33.6+/-7.4%, respectively. Troleandomycin (CYP3A inhibitor) and furafylline
      (CYP1A2 inhibitor) inhibited CLZ N-oxidation in human liver microsomes by 23.2+/
      12.1% and 7.8+4.3%, respectively, whereas CLZ N-demethylation was inhibited by
      17.5+/-13.9% and 25.6+/-16.5%, respectively. While ketoconazole did not inhibit N
      oxidation of CLZ, the N-demethylation pathway was inhibited by 34.1+/-10.0%.
      Formation in stable expressed enzymes indicated involvement of CYP3A and CYP1A2
      in CLZ N-oxide formation and CYP2D6, CYP1A2 and CYP3A4 in CLZ N-demethylation.
      This apparent involvement of CYP2D6 in the N-demethylation of CLZ did not
      corroborate with the findings of other experiments. In conclusion, these data
      indicate that while both CYP isoforms readily catalyze both metabolic routes in
      vitro, CYP1A2 and CYP3A4 are more important in N-demethylation and N-oxidation,
      respectively.

PMID- 10359461
TI  - Psychosocial treatments for cocaine dependence: National Institute on Drug Abuse
      Collaborative Cocaine Treatment Study.
AB  - BACKGROUND: This was a multicenter investigation examining the efficacy of 4
      psychosocial treatments for cocaine-dependent patients. METHODS: Four hundred
      eighty-seven patients were randomly assigned to 1 of 4 manual-guided treatments:
      individual drug counseling plus group drug counseling (GDC), cognitive therapy
      plus GDC, supportive-expressive therapy plus GDC, or GDC alone. Treatment was
      intensive, including 36 possible individual sessions and 24 group sessions for 6
      months. Patients were assessed monthly during active treatment and at 9 and 12
      months after baseline. Primary outcome measures were the Addiction Severity Index
      Drug Use Composite score and the number of days of cocaine use in the past month.
      RESULTS: Compared with the 2 psychotherapies and with GDC alone, individual drug
      counseling plus GDC showed the greatest improvement on the Addiction Severity
      Index-Drug Use Composite score. Individual group counseling plus GDC was also
      superior to the 2 psychotherapies on the number of days of cocaine use in the
      past month. Hypotheses regarding the superiority of psychotherapy to GDC for
      patients with greater psychiatric severity and the superiority of cognitive
      therapy plus GDC compared with supportive-expressive therapy plus GDC for
      patients with antisocial personality traits or external coping style were not
      confirmed. CONCLUSION: Compared with professional psychotherapy, a manual-guided
      combination of intensive individual drug counseling and GDC has promise for the
      treatment of cocaine dependence.

PMID- 10359462
TI  - Psychosocial treatments for cocaine dependence: rethinking lessons learned.

PMID- 10359463
TI  - Old psychotherapies for cocaine dependence revisited.

PMID- 10359464
TI  - A national evaluation of treatment outcomes for cocaine dependence.
AB  - BACKGROUND: This national study focused on posttreatment outcomes of community
      treatments of cocaine dependence. Relapse to weekly (or more frequent) cocaine
      use in the first year after discharge from 3 major treatment modalities was
      examined in relation to patient problem severity at admission to the treatment
      program and length of stay. METHODS: We studied 1605 cocaine-dependent patients
      from 11 cities located throughout the United States using a naturalistic,
      nonexperimental evaluation design. They were sequentially admitted from November
      1991 to December 1993 to 55 community-based treatment programs in the national
      Drug Abuse Treatment Outcome Studies. Included were 542 patients admitted to 19
      long-term residential programs, 458 patients admitted to 24 outpatient drug-free
      programs, and 605 patients admitted to 12 short-term inpatient programs. RESULTS:
      Of 1605 patients, 377 (23.5%) reported weekly cocaine use in the year following
      treatment (dropping from 73.1% in the year before admission). An additional 18.0%
      had returned to another drug treatment program. Higher severity of patient
      problems at program intake and shorter stays in treatment (<90 days) were related
      to higher cocaine relapse rates. CONCLUSIONS: Patients with the most severe
      problems were more likely to enter long-term residential programs, and better
      outcomes were reported by those treated 90 days or longer. Dimensions of
      psychosocial problem severity and length of stay are, therefore, important
      considerations in the treatment of cocaine dependence. Cocaine relapse rates for
      patients with few problems at program intake were most favorable across all
      treatment conditions, but better outcomes for patients with medium- to high-level
      problems were dependent on longer treatment stays.

PMID- 10359465
TI  - We've come a long way: comments on cocaine treatment outcome research.

PMID- 10359466
TI  - Cost-effectiveness of brief psychodynamic-interpersonal therapy in high utilizers
      of psychiatric services.
AB  - BACKGROUND: It is known that a small number of patients with mental health
      problems have chronic disorders and account for a disproportionate amount of
      mental health costs. This randomized controlled trial evaluated the cost
      effectiveness of psychodynamic-interpersonal therapy vs treatment as usual in
      patients with mental health problems who were unresponsive to usual treatment.
      METHOD: Subjects (N = 110) with nonpsychotic disorders unresponsive to 6 months
      of routine specialist mental health treatment were enrolled in a randomized
      controlled trial. Sixty-three percent were women, the mean age was 41.4 years,
      the median duration of illness was 5 years, 68% were unemployed or receiving
      state benefits because of illness, and 75.5% had a depressive illness.
      Intervention patients received 8 weekly sessions of psychodynamic-interpersonal
      psychotherapy. Control patients received usual care from their psychiatrist.
      Outcome measures included ratings of psychological distress and health status and
      a detailed economic evaluation. Analysis was conducted on an intent-to-treat
      basis. RESULTS: Subjects randomized to psychotherapy had a significantly greater
      improvement than controls in psychological distress and social functioning 6
      months after the trial. Baseline treatment costs were similar for both groups.
      Subjects who received psychotherapy showed significant reductions in the cost of
      health care utilization in the 6 months after treatment compared with controls.
      The extra cost of psychotherapy was recouped within 6 months through reductions
      in health care use. CONCLUSION: These preliminary findings suggest that brief
      psychodynamic-interpersonal therapy may be cost-effective relative to usual care
      for patients with enduring nonpsychotic symptoms who are not helped by
      conventional psychiatric treatment.

PMID- 10359467
TI  - Decreased memory performance in healthy humans induced by stress-level cortisol
      treatment.
AB  - BACKGROUND: Glucocorticoids (GCs) can regulate hippocampal metabolism,
      physiologic functions, and memory. Despite evidence of memory decreases during
      pharmacological GC treatment, and correlations between memory and cortisol levels
      in certain disease conditions, it remains unclear whether exposure to the
      endogenous GC cortisol at levels seen during physical and psychological stress in
      humans can inhibit memory performance in otherwise healthy individuals. METHODS:
      Randomized, double-blind, placebo-controlled comparison of 2 fixed oral doses of
      cortisol (40 mg/d and 160 mg/d using split doses to approximate circadian rhythm)
      given for 4 days to matched groups of healthy subjects (n = 51). Lower-dose
      treatment approximated cortisol exposure during mild stress, whereas the higher
      dose approximated cortisol exposure during major stress. Cognitive testing and
      plasma sampling were done at baseline, after 1 and 4 days of treatment, and after
      a 6-day washout period, hypothesizing dose-dependent decreases in verbal
      declarative memory. RESULTS: Cortisol treatment at the higher dose produced
      reversible decreases in verbal declarative memory without effects on nonverbal
      memory, sustained or selective attention, or executive function. A significant
      interaction between time and treatment condition for paragraph recall was
      explained by treatment-induced differences in performance after 4 treatment days,
      with lower immediate and delayed recall performance during higher-dose cortisol
      treatment compared with lower-dose treatment and placebo. CONCLUSIONS: Several
      days of exposure to cortisol at doses and plasma concentrations associated with
      physical and psychological stress in humans can-similar to pharmacological GC
      treatment-reversibly decrease specific elements of memory performance in
      otherwise healthy individuals.

PMID- 10359468
TI  - Cortical abnormalities in schizophrenia identified by structural magnetic
      resonance imaging.
AB  - BACKGROUND: Relatively few magnetic resonance imaging studies of schizophrenia
      have investigated the entire cerebral cortex. Most focus on only a few areas
      within a lobe or an entire lobe. To assess expected regional alterations in
      cortical volumes, we used a new method to segment the entire neocortex into 48
      topographically defined brain regions. We hypothesized, based on previous
      empirical and theoretical work, that dorsolateral prefrontal and paralimbic
      cortices would be significantly volumetrically reduced in patients with
      schizophrenia compared with normal controls. METHODS: Twenty-nine patients with
      DSM-III-R schizophrenia were systematically sampled from 3 public outpatient
      service networks in the Boston, Mass, area. Healthy subjects, recruited from
      catchment areas from which the patients were drawn, were screened for
      psychopathologic disorders and proportionately matched to patients by age, sex,
      ethnicity, parental socioeconomic status, reading ability, and handedness.
      Analyses of covariance of the volumes of brain regions, adjusted for age- and sex
      corrected head size, were used to compare patients and controls. RESULTS: The
      greatest volumetric reductions and largest effect sizes were in the middle
      frontal gyrus and paralimbic brain regions, such as the frontomedial and
      frontoorbital cortices, anterior cingulate and paracingulate gyri, and the
      insula. In addition, the supramarginal gyrus, which is densely connected to
      prefrontal and cingulate cortices, was also significantly reduced in patients.
      Patients also had subtle volumetric increases in other cortical areas with strong
      reciprocal connections to the paralimbic areas that were volumetrically reduced.
      CONCLUSION: Findings using our methods have implications for understanding brain
      abnormalities in schizophrenia and suggest the importance of the paralimbic areas
      and their connections with prefrontal brain regions.

PMID- 10359469
TI  - An agenda for psychiatric genetics.
AB  - Although it has long been known that people inherit vulnerabilities to particular
      forms of mental illness, ongoing advances in psychiatric genetics and DNA
      technology are only now making it possible to actually find the specific genes
      and gene variants that play critical roles in complex disorders, such as
      schizophrenia and bipolar disorder. For this reason, the National Institute of
      Mental Health convened a work group "to facilitate the search for the genes that
      influence mental disorders"--genes whose identification will affect diagnosis,
      prevention, and treatment. This article briefly summarizes the problems addressed
      by the work group and its main recommendations.

PMID- 10359470
TI  - Big mountain.

PMID- 10359471
TI  - Preparing for gene discovery: a further agenda for psychiatry.

PMID- 10359472
TI  - Miles to go before we sleep.

PMID- 10359473
TI  - Major depressive disorder in a community-based twin sample: are there different
      genetic and environmental contributions for men and women?
AB  - BACKGROUND: Depression affects more women than men and often aggregates in
      families. Using a community-based sample of twins, we examined the contributions
      of genetic and environmental factors to the risk of developing major depressive
      disorder and the effect of sex and different definitions of depression on the
      relative contributions of genetic and environmental effects. Sex differences in
      genetic effects were also studied. METHODS: A volunteer sample of Australian
      twins (2662 pairs) was interviewed using an abbreviated version of the Semi
      Structured Assessment for the Genetics of Alcoholism, a semi-structured lay
      interview designed to assess psychiatric disorders. Depression was defined using
      3 different criteria sets: DSM-III-R major depressive disorder, DSM-IV major
      depressive disorder, and severe DSM-IV major depressive disorder. Genetic and
      environmental contributions to the liability to develop depression were estimated
      using genetic model fitting. RESULTS: Lifetime prevalences were 31% in women and
      24% in men for DSM-III-R major depressive disorder, 22% in women and 16% in men
      for DSM-IV major depressive disorder, and 9% in women and 3% in men for severe
      DSM-IV major depressive disorder. In women, the simplest model to fit the data
      implicated genetic factors and environmental factors unique to the individual in
      the development of depression, with heritability estimates ranging from 36% to
      44%. In men, depression was only modestly familial, and thus individual
      environmental factors played a larger role in the development of depression. For
      DSM-III-R major depressive disorder, there were statistically different estimates
      for heritability for men vs. women. For both sexes, the relative contributions of
      genetic and environmental factors were stable using different definitions of
      depression. CONCLUSIONS: There was moderate familial aggregation of depression in
      women and this primarily was attributable to genetic factors. In men, there was
      only modest familial aggregation of depression. For both men and women,
      individual environmental experiences played a large role in the development of
      depression. Major depressive disorder as defined by DSM-III-R was more heritable
      in women as compared with men. The relative contributions of genetic and
      environmental factors in the development of depression were similar for varying
      definitions of depression, from a broad definition to a narrow definition.

PMID- 10359474
TI  - Cost-effectiveness of clozapine in patients with high and low levels of hospital
      use. Department of Veterans Affairs Cooperative Study Group on Clozapine in
      Refractory Schizophrenia.
AB  - BACKGROUND: This study examined the relationship between pretreatment hospital
      use and the cost-effectiveness of clozapine in the treatment of refractory
      schizophrenia. METHODS: Data from a 15-site randomized clinical trial were used
      to compare clozapine with haloperidol in hospitalized Veterans Affairs patients
      with refractory schizophrenia (n = 423). Outcomes were compared among those with
      many days in the hospital use (hereafter, high hospital users) (n = 141; mean =
      215 psychiatric hospital days in the year prior to study entry) and those with
      few days in the hospital use (hereafter, low hospital users) (n = 282; mean = 58
      hospital days). Analyses were conducted with the full intention-to-treat sample
      (n = 423) and with crossovers excluded (n = 291). RESULTS: Clozapine treatment
      resulted in greater reduction in hospital use among high hospital users (35 days
      less than controls, P = .02) than among low users (21 days less than controls, P
      = .05). Patients taking clozapine also had lower health care costs; after
      including the costs of both medications and other health services, costs were
      $7134 less than for controls among high hospital users (P = .14) but only $759
      less than for controls among low hospital users (P = .82). Clinical improvement
      in the domains of symptoms, quality of life, extrapyramidal symptoms, and a
      synthetic measure of multiple outcomes favored clozapine in both high and low
      hospital user groups. CONCLUSIONS: Substantial 1-year cost savings with clozapine
      are observed only among patients with very high hospital use prior to initiation
      of treatment while clinical benefits are more similar across groups. Cost
      effectiveness evaluations, and particularly studies of expensive treatments,
      cannot be generalized across type of use groups.

PMID- 10359475
TI  - Efficacy of interpersonal psychotherapy for depressed adolescents.
AB  - BACKGROUND: Psychotherapy is widely used for depressed adolescents, but evidence
      supporting its efficacy is sparse. METHODS: In a controlled, 12-week, clinical
      trial of Interpersonal Psychotherapy for Depressed Adolescents (IPT-A), 48 clinic
      referred adolescents (aged 12-18 years) who met the criteria for DSM-III-R major
      depressive disorder were randomly assigned to either weekly IPT-A or clinical
      monitoring. Patients were seen biweekly by a "blind" independent evaluator to
      assess their symptoms, social functioning, and social problem-solving skills.
      Thirty-two of the 48 patients completed the protocol (21 IPT-A-assigned patients
      and 11 patients in the control group). RESULTS: Patients who received IPT-A
      reported a notably greater decrease in depressive symptoms and greater
      improvement in overall social functioning, functioning with friends, and specific
      problem-solving skills. In the intent-to-treat sample, 18 (75%) of 24 patients
      who received IPT-A compared with 11 patients (46%) in the control condition met
      recovery criterion (Hamilton Rating Scale for Depression score < or =6) at week
      12. CONCLUSIONS: These preliminary findings support the feasibility,
      acceptability, and efficacy of 12 weeks of IPT-A in acutely depressed adolescents
      in reducing depressive symptoms and improving social functioning and
      interpersonal problem-solving skills. Because it is a small sample consisting
      largely of Latino, low socioeconomic status adolescents, further studies must be
      conducted with other adolescent populations to confirm the generalizability of
      the findings.

PMID- 10359476
TI  - Substance abuse as a risk factor for violence in major mental disorders.

PMID- 10359477
TI  - Candidate genes and behavioral traits--candidly!

PMID- 10359478
TI  - Relationship between social rhythms and mood in patients with rapid cycling
      bipolar disorder.
AB  - Disruptions in the sleep-wake cycle frequently characterize affective illness and
      have led to a number of theories linking sleep-wake and/or circadian rhythm
      disturbance to affective illness. Recently, researchers have expanded these
      chronobiological theories to include the role of lifestyle regularity, or daily
      social rhythms. In this study, the Social Rhythm Metric (SRM) was used to explore
      the relationship between social rhythms and mood in patients with rapid cycling
      bipolar disorder and to compare the social rhythms of patients with those of
      healthy control subjects. Patients' SRM scores and activity level indices were
      significantly lower than those of control subjects. In addition, the timing of
      five, mostly morning, activities was phase delayed in patients compared to
      control subjects. Patients also demonstrated a phase delay in the timing of
      morning activities during depression compared to hypomania or euthymia. The phase
      changes in the timing of morning activities are consistent with other data
      implicating morning zeitgebers in the pathophysiology of rapid cycling bipolar
      disorder.

PMID- 10359479
TI  - Serotonin hypothesis of winter depression: behavioral and neuroendocrine effects
      of the 5-HT(1A) receptor partial agonist ipsapirone in patients with seasonal
      affective disorder and healthy control subjects.
AB  - Winter depressions in seasonal affective disorder (SAD) are associated with
      central serotonergic (5-HT) dysfunction. SAD patients demonstrate rather
      specific, state-dependent, abnormal increases in 'activation-euphoria' ratings
      following intravenous infusion of the 5-HT receptor agonist meta
      chlorophenylpiperazine (m-CPP). Several studies are also consistent with abnormal
      serotonergic regulation of the hypothalamic-pituitary-adrenal (HPA) axis in SAD.
      Here, we investigated the effects of the 5-HT1A receptor partial agonist
      ipsapirone, which produces behavioral effects and HPA-axis activation, to further
      characterize the 5-HT receptor subtype-specificity of these disturbances in SAD.
      Eighteen SAD patients and 18 control subjects completed two drug challenges
      (ipsapirone 0.3 mg/kg and placebo) separated by 3-5 days in randomized order. We
      measured behavioral responses with the NIMH self-rating scale, and plasma ACTH,
      cortisol, and prolactin concentrations. Compared with placebo, ipsapirone was
      associated with significant increases in self-rated 'functional deficit' and
      'altered self-reality', and in each of the hormones. There were no differences
      between groups on any measures. The level of depression in SAD patients was
      inversely correlated with their ipsapirone-induced cortisol responses. There were
      significant drug x order effects on baseline 'anxiety' scores, ACTH and cortisol
      concentrations, such that subjects were significantly more stressed (higher
      'anxiety', ACTH and cortisol) prior to their first challenge compared with their
      second. In conclusion, post-synaptic 5-HT1A receptors appear to function normally
      in SAD. The previously observed m-CPP-induced behavioral abnormality may be
      mediated by either 5-HT2C or 5-HT7 receptors.

PMID- 10359480
TI  - Serotonin and externalizing behavior in young children.
AB  - Considerable evidence suggests that there is a relationship between pathologic
      aggressive behavior and low cerebrospinal fluid (CSF) concentrations of the
      serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in both humans and non
      human primates. The purpose of this investigation is to examine the relationship
      between CSF concentrations of human newborn 5-HIAA and subsequent aggressive
      behavior observed at 30 months of age. Leftover portions of culture negative CSF
      drawn from febrile infants (age, birth to 3 months) were assayed for 5-HIAA.
      Family environment and child behavior were assessed at 30 months by parent
      report. Subjects with 5-HIAA levels below the median of the distribution had
      higher externalizing behavior scores at 30 months than did subjects whose 5-HIAA
      levels fell above the median (P = 0.02). While it is likely that serotonin
      mediates one component of genetic liability to antisocial outcome, the magnitude
      of that component may be less than what has been inferred from previously
      published reports.

PMID- 10359481
TI  - Etiology of the impulsivity/aggression relationship: genes or environment?
AB  - Genetic and environmental influences on the phenotypic relationship between the
      Barratt Impulsiveness Scale and the aggression scales from the Buss-Durkee
      Hostility Inventory in adult males were examined. This study used 182 pairs of
      male MZ twins and 118 pairs of male DZ twins from the Vietnam Era Twin Registry.
      Phenotypic relationships between the measure of impulsivity and subscales of the
      measure of aggression (direct assault, verbal assault, indirect assault, and
      irritability) ranged from 0.22 to 0.51. Genetic and environmental mediation of
      the phenotypic relationship between impulsivity and aggression were approximately
      the same for all four models. Multivariate model-fitting analysis indicated that
      irritability and impulsivity had a larger phenotypic relationship, as well as a
      greater portion of shared genes and environment than the other three subscales of
      aggression. This suggests, for example, that there are more overlapping genetic
      and environmental influences accounting for the relationship between irritability
      and impulsivity than between direct assault and impulsivity. The effects of such
      findings on our understanding of impulsive aggression are discussed.

PMID- 10359482
TI  - Serotonin transporter gene not associated with psychotic symptomatology of mood
      disorders.
AB  - A functional polymorphism in the upstream regulatory region of the serotonin
      transporter gene (5-HTTLPR) has been recently reported to be associated with mood
      disorders. In the present study we investigated the possible influence of 5
      HTTLPR on the symptomatology of mood disorders. Two hundred and thirty inpatients
      affected by mood disorders (160 bipolar and 70 major depressive disorder) were
      assessed by the Operational Criteria checklist for psychotic illness (OPCRIT) and
      were also typed for the 5-HTTLPR variants using PCR techniques. Mania,
      Depression, Delusion and Disorganization were the four symptomatologic factors
      used as phenotype definition. 5-HTTLPR variants were not associated with these
      symptomatologic factors, and consideration of possible stratification effects,
      such as sex, age of onset and polarity, did not reveal any association either.
      The serotonin transporter gene does not, therefore, appear to be associated with
      the symptomatology of mood disorders.

PMID- 10359483
TI  - Association of a regulatory polymorphism in the promoter region of the monoamine
      oxidase A gene with antisocial alcoholism.
AB  - We analyzed a novel functional 30-bp repeat polymorphism in the promoter region
      of the X-chromosomal monoamine oxidase A gene (MAOA) to test whether length
      variation of the repeat polymorphism contributes to variation in the individual
      vulnerability to antisocial behavior and liability to alcohol dependence. The
      repeat number (3-5) of the MAOA polymorphism was assessed in 488 male subjects of
      German descent, a sample comprising 185 psychiatrically screened control subjects
      and 303 alcohol-dependent subjects including 59 alcoholics with antisocial
      personality disorder. The frequency of the low-activity 3-repeat allele was
      significantly increased in 59 antisocial alcoholics compared to 185 control
      subjects (51 vs. 35%; P = 0.031) and to 244 alcoholics without antisocial
      personality disorder (51 vs. 32%; P = 0.008), respectively. We found no
      significant difference in the frequency of the 3-repeat allele between 244
      alcoholics without an antisocial personality disorder and the control subjects.
      Our findings suggest that the low-activity 3-repeat allele of the MAOA promoter
      polymorphism confers increased susceptibility to antisocial behavior rather than
      alcohol dependence per se in alcohol-dependent males.

PMID- 10359484
TI  - Intellectual and neuropsychological features of patients with psychogenic
      pseudoseizures.
AB  - Psychogenic pseudoseizures typically are thought to reflect emotional
      disturbances. Studies have suggested that patients with psychogenic
      pseudoseizures may also have impaired neuropsychological function. We examined
      intellectual and neuropsychological performance in a large sample of patients
      with well-documented psychogenic pseudoseizures. Patients with pseudoseizures
      only (Pure group) and patients with both pseudoseizures and epilepsy (Mixed
      group) were included. For the total sample, the WAIS-R IQ scores were quite
      variable. Full Scale and Performance IQ ranged from deficient to very superior.
      The Full Scale IQ was in the low average or borderline range in 41.5% of
      patients. A striking finding was the high incidence of impaired performance on
      the Halstead-Reitan Neuropsychological Battery in both the Pure and Mixed groups.
      Considering the neuropsychological variables for which published cut-off scores
      are available, more than 50% of the total sample (as well as the Pure and Mixed
      groups) scored in the impaired range on more than half the measures. The Halstead
      Impairment Index, which reflects the overall level of neuropsychological
      performance, was in the impaired range (0.5-1.0) in 63% of the sample. Given the
      high incidence of accidents and physical trauma reported by our patients, we
      postulate that head trauma might be responsible for neuropsychological impairment
      in an appreciable number of the patients in this sample.

PMID- 10359485
TI  - Hypokalemia and agitation in acute psychotic patients.
AB  - Hypokalemia is caused partly by intensive exercise. Some evidence suggests that
      psychological distress may cause hypokalemia. The relationship between the
      decline of serum potassium concentration and the level of symptoms of acute
      agitation, which was defined as a total score on a subset of six categories on
      the 18-item Brief Psychiatric Rating Scale (anxiety, tension, mannerism and
      posturing, hostility, uncooperativeness, psychomotor excitement), was examined in
      313 schizophrenic men, admitted on an emergency basis during a 24-month period.
      In addition, change in serum potassium concentration after sedation was
      investigated. Serum potassium concentration in the severely agitated group was
      lower than that in the mild group. There was a significant correlation between
      serum potassium concentration and the level of symptoms of acute agitation (r = 
      0.30, P < 0.0001). Although the decline of serum potassium concentration in the
      patients who were sufficiently sedated improved within 8 h, that in the patients
      showing high scores on the acute agitation subset even 8 h after emergency
      admission was prolonged. Results indicate that sedation improves acute agitation
      induced hypokalemia. rights

PMID- 10359486
TI  - Predicted and observed growth and toxigenesis by Clostridium botulinum type E in
      vacuum-packaged fishery product challenge tests.
AB  - The observed growth and toxigenesis by Clostridium botulinum type E in vacuum
      packaged unprocessed, raw pickled and cold-smoked rainbow trout stored at
      slightly abusive temperatures were compared to predictions generated by two
      currently available predictive microbiological programs, Food MicroModel and
      Pathogen Modelling Program. In unprocessed fish there was only a 2 log increase
      in type E cell count at the time the toxicity first occurred after 2 weeks
      storage at 8 degrees C. Neither growth or toxin production was observed in raw
      pickled fish with a NaCl concentration of 6.7% (w/v) during 6 weeks storage at 6
      degrees C. In cold-smoked fish with a NaCl level of 3.2% (w/v) toxic samples were
      detected after 3 and 4 weeks storage at 8 degrees C and 4 degrees C,
      respectively, without any increase in type E count. Both models were hampered by
      limitations to controlling environmental factors set by the programs which also
      had an adverse effect on the reliability of predictions. Most predictions
      generated by the models were inconsistent with the results observed in the
      challenge studies. In certain situations, the models seemed to be 'fail-safe', in
      that, the growth rate predicted from the model was faster or a predicted time to
      toxicity shorter than that which actually occurred in the food. In other
      situations, the predictions showed the product to be safe when it was not. The
      results demonstrate the need for further development and rigorous validation of
      the models before they are accepted for wider use by inspecting officials and the
      food industry.

PMID- 10359487
TI  - Aroma improving in microvinification processes by the use of a recombinant wine
      yeast strain expressing the Aspergillus nidulans xlnA gene.
AB  - A recombinant wine yeast strain has been constructed expressing the gene coding
      for beta-(1,4)-endoxylanase from Aspergillus nidulans under the control of the
      yeast actin gene promoter. The resulting recombinant strain is able to secrete
      active xylanase enzyme into the culture medium. Wines obtained by
      microvinification with the control and the recombinant wine yeast strain did not
      differ in their physicochemical characteristics although an increase in fruity
      aroma was organoleptically detected in the wine produced by the recombinant
      yeast. Also, an increase in the concentration of some esters, higher alcohols and
      terpenes was observed in the case of the recombinant strain.

PMID- 10359488
TI  - Influence of temperature shifts on survival, growth, and toxin production by
      psychrotrophic and mesophilic strains of Bacillus cereus in potatoes and chicken
      gravy.
AB  - A study was done to determine the influence of temperature on growth and toxin
      production characteristics of psychrotrophic and mesophilic strains of Bacillus
      cereus when inoculated into mashed potatoes and chicken gravy containing various
      concentrations of sodium chloride and held at temperatures different from those
      at which cells had been cultured. Logarithmic growth phase cells (10 h, 30
      degrees C) of psychrotrophic (F3802A/84) and mesophilic (B4ac-1) strains of
      Bacillus cereus were inoculated into rehydrated commercially processed instant
      mashed potatoes and chicken gravy supplemented with 0, 2, or 4% sodium chloride.
      Growth, survival, and diarrheal toxin production in potatoes and gravy held at
      30, 37, and 10 degrees C (strain F3802A/84) or 30, 40, and 10 degrees C (strain
      B4ac-1) were monitored. Both strains grew in both foods containing no added
      sodium chloride or 2% sodium chloride when held at 30, 37, or 40 degrees C for 2
      days. Strain B4ac-1 grew better than strain F3802A/84 in foods containing 4%
      sodium chloride. Maximum amounts of enterotoxin (1024 ng/g) were produced by
      strain B4ac-1 in chicken gravy held at 30 and 40 degrees C. Strain F3802A/84 grew
      to populations of 7 log10 CFU/g in foods containing no added sodium chloride or
      2% sodium chloride at 10 degrees C. Strain F3802A/84 produced the highest amount
      of enterotoxin (1024 ng/g) at 30 degrees C in chicken gravy containing 0.7 or 2%
      sodium chloride; however, little or low amounts of toxin (4-16 ng/g) were
      produced in chicken gravy at 10 degrees C. Compared to strain B4ac-1, cells of
      strain F3802A/84 subjected to a downward shift in incubation temperature (10
      degrees C) grew more rapidly in chicken gravy. Strain B4ac-1 produced the highest
      amount of toxin (1024 ng/g) at 30 degrees C in gravy containing 4% sodium
      chloride and at 40 degrees C in gravy containing 0.7% sodium chloride. Toxin was
      not detected in inoculated mashed potatoes. Results of this study indicate that
      shifts in incubation temperature influence growth and toxin production by
      psychrotrophic and mesophilic strains of B. cereux differently. It is important
      to store pasteurized, ready-to-eat foods at a temperature low enough to prevent
      the growth of B. cereus.

PMID- 10359489
TI  - Modeling the inhibitory effects of organic acids on bacteria.
AB  - The inhibitory effect of acids on microbial growth has long been used to preserve
      foods from spoilage. While much of the effect can be accounted for by pH, it is
      well known that different organic acids vary considerably in their inhibitory
      effects. Because organic acids are not members of a homologous series, but vary
      in the numbers of carboxy groups, hydroxy groups and carbon-carbon double bonds
      in the molecule, it has typically not been possible to predict the magnitude, or
      in some cases even the direction, of the change in inhibitory effect upon
      substituting one acid for another or to predict the net result in food systems
      containing more than one acid. The objective of this investigation was to attempt
      to construct a mathematical model that would enable such prediction as a function
      of the physical and chemical properties of organic acids. Principal Components
      Analysis (PCA) was applied to 11 properties for each of 17 acids commonly found
      in food systems; this resulted in four significant principal components (PCs),
      presumably representing fundamental properties of the acids and indicating each
      acid's location along each of these four scales. These properties correspond to
      polar groups, the number of double bonds, molecular size, and solubility in non
      polar solvents. Minimum inhibitory concentrations (MICs) for each of eight acids
      for six test microorganisms were determined at pH 5.25. The MICs for each
      organism were modeled as a function of the four PCs using partial least squares
      (PLS) regression. This produced models with high correlations for five of the
      bacteria (R2 = 0.856, 0.941, 0.968, 0.968 and 0.970) and one with a slightly
      lower value (R2 = 0.785). Acid susceptible organisms (Bacillus cereus, Bacillus
      subtilis, and Alicyclobacillus) exhibited a similar response pattern. There
      appeared to be two separate response patterns for acid resistant organisms; one
      was exhibited by the two lactobacilli studied and the other by E. coli.
      Predicting the inhibitory effects of the organic acids as a function of their
      chemical and physical properties is clearly possible.

PMID- 10359491
TI  - Contamination of meat with Campylobacter jejuni in Saitama, Japan.
AB  - To determine the source of food contamination with Campylobacter jejuni, we
      investigated retail meat, a chicken processing plant and a broiler farm. C.
      jejuni was found in domestic retailed poultry (45.8%) and imported poultry
      (3.7%), but not in beef or pork. In the poultry processing plant, there is
      significant contamination with C. jejuni in chicken carcasses, equipment and
      workers' hands. This contamination increases during the defeathering and
      evisceration processes. RAPD analysis shows that contamination with C. jejuni is
      of intestinal origin. In a broiler farm, C. jejuni was first isolated from a
      faecal sample of broiler chicken after the 20th day of age. Two weeks later, all
      birds in this farm became C. jejuni positive. RAPD analysis indicated that C.
      jejuni spread rapidly from one broiler flock to the other flocks on the farm.

PMID- 10359490
TI  - Arginine dihydrolase pathway in Lactobacillus plantarum from orange.
AB  - Lactobacillus plantarum N8 and N4 strains isolated from orange degraded L
      arginine to citrulline, ornithine and ammonia. Citrulline and ornithine were
      consumed. Lactobacillus plantarum N4 utilized arginine and ornithine to a higher
      extent than Lactobacillus plantarum N8. Urea was not detected during arginine
      degradation, indicating that the amino acid degradation was carried out only by
      the arginine dihydrolase pathway. Citrulline increased the growth of the two
      strains, arginine only increased the growth of Lactobacillus plantarum N4.
      Ornithine did not modify the growth of the strains studied. With different
      behavior, Lactobacillus plantarum N8 and N4 strains were able to derive energy
      and ammonia from arginine or citrulline catabolism. This is interesting for
      microorganisms developing in a stressful environment.

PMID- 10359492
TI  - Incidence of coagulase positive Staphylococcus on beef carcasses in three
      Australian abattoirs.
AB  - The contamination of beef carcasses with coagulase-positive staphylococci (CPS)
      was studied at three beef abattoirs (A, B and C). The incidence and the number of
      CPS were determined on cattle hides immediately after slaughter and on three
      carcass sites (brisket, flank and round) at different points during processing
      along the slaughter line. The incidence of CPS on cattle hides ranged from 20 to
      68.6%. At abattoir A, 6.5% of the carcasses sampled before evisceration were
      contaminated with CPS, compared to 40% of the carcasses after evisceration. The
      incidence on carcasses changed little during further processing; however, after
      chilling for 72 h, the incidence increased to 83%. After evisceration, the
      brisket and flank areas were more often contaminated than the round. A similar
      pattern of contamination was observed at abattoir B. At abattoir C, 26.7% of the
      samples collected before evisceration were contaminated and this fell to 16.7%
      after evisceration. After chilling for 72 h, the incidence of carcass
      contamination with CPS increased to 46.7%. The average number of CPS on
      contaminated carcasses prior to and after overnight chilling was less than 50
      colony-forming units (cfu)/cm2 and, after weekend chilling, increased to 64 and
      112 cfu/cm2 in abattoirs A and B, respectively. Of the isolates tested, 71.4%
      produced staphylococcal enterotoxin and 21% could not be classified
      phenotypically. The hands of workers and environmental sites associated with the
      evisceration process were examined for CPS at abattoir A. Hands were heavily
      contaminated and were the likely source of CPS contamination at this abattoir.

PMID- 10359493
TI  - Bibliography of food microbiology.

PMID- 10359494
TI  - Long-term inpatient audiovisual scalp EEG monitoring.
AB  - Long-term audiovisual scalp EEG monitoring is an essential diagnostic tool for
      the evaluation of paroxysmal disorders. The definitive classification of both
      nonepileptic and epileptic events is often possible only with the use of this
      technique. Assessment of response to treatment and the noninvasive presurgical
      localization of seizure foci are other important uses. The optimization of both
      clinical semiology and electrophysiologic data obtained from such studies is the
      subject of significant research efforts. Outcomes studies and advanced EEG
      analysis research should ultimately serve to minimize the cost of this valuable
      technique as well as maximizing its utility.

PMID- 10359495
TI  - Pediatric electroencephalographic video monitoring.
AB  - Pediatric EEG video monitoring is based on methodology that is similar to that
      used for monitoring of adults, although there are important differences. In
      addition, the range of clinical events suspected of being seizures in the
      pediatric population is quite different from those in adults and, within
      childhood, is age-specific. Thus, the clinical utility of monitoring in neonates,
      infants, and children is based on an understanding of the full range of normal
      and abnormal epileptic and nonepileptic events that may occur in this age group.
      Similarly, the findings of the EEG are age-dependent and must be considered when
      they are interpreted as part of the monitoring study and when they are correlated
      with clinical events captured on video. Monitoring can be utilized in the
      detection, characterization, and quantification of various types of seizure
      disorders in children. The most effective application of monitoring, which can
      ensure the greatest chance for clinically useful information, occurs when
      monitoring is well-planned; utilizes appropriate EEG and polygraphic-physiologic
      parameters; incorporates optimal video recording techniques; maintains age
      appropriate recording environments within the context of medical necessity; and
      is conducted in a laboratory with adequate support staff. Pediatric monitoring
      has been effective in the clinical management of neonatal seizures, infantile
      spasms, other seizure types in infancy, epilepsy in late childhood, and in the
      evaluation of pediatric patients of all ages for epilepsy surgery.

PMID- 10359497
TI  - The role of ambulatory EEG in the evaluation of patients for epilepsy surgery.

PMID- 10359496
TI  - Ambulatory EEG monitoring.
AB  - Advances in computer technology offer increased capabilities for ambulatory EEG
      monitoring. The technical specifications of currently available ambulatory EEG
      machines reasonably approximate inpatient EEG equipment. However, the evolution
      of ambulatory EEG from 3-channel analog cassette recordings to reformatable 32
      channel digital devices with computer-assisted spike and seizure detection raises
      several unresolved issues. Should patients with nondiagnostic routine EEG receive
      ambulatory EEG? Is ambulatory EEG as accurate for patients with unclear clinical
      diagnoses as inpatient video-EEG monitoring? If the diagnostic yield of
      ambulatory EEG is less than inpatient monitoring, do outpatient savings still
      make the technique cost-effective? This article reviews the development of
      ambulatory EEG and the investigations of its clinical utility. An evidence-based
      analysis explores the benefits and limitations of ambulatory EEG, and offers
      aspects of its use which require additional clinical research.

PMID- 10359498
TI  - Automatic detection of seizures and spikes.
AB  - The recording of seizures and spikes is of primary importance in the evaluation
      of epileptic patients. This is not always an easy process because these events
      can be rare and are usually unpredictable. Since the earliest days of computer
      analysis of the EEG, researchers have developed methods for the automatic
      detection of spikes and, more recently, of seizures. The problems are complex
      because spikes and seizures are not clearly defined and have extremely varied
      morphologies. Nevertheless, it has been possible to develop automatic detection
      methods that can be of great assistance during long-term monitoring of epileptic
      patients. No method is absolutely fail-safe and all require human validation, but
      they save a considerable amount of time in the interpretation of long recordings.
      Recent developments include detection of the patterns specific to newborns, and
      the possibility of warning a patient or observer that a seizure is starting.

PMID- 10359499
TI  - Can patients perform volitional motor acts at the start of a seizure?
AB  - A seizure warning device might allow some individuals with partial seizures to
      protect themselves against consequences of seizures, but a prerequisite is the
      ability to take volitional action in response to a warning. The authors reviewed
      consecutive seizures in their epilepsy monitoring unit to determine whether
      patients could squeeze an event bulb, as instructed, at the start of their
      seizure. Only complex partial seizures with EEG changes and with the patient on
      camera were analyzed. Data were obtained from 77 patients, 42 with scalp
      monitoring and 35 with depth electrodes. Forty-seven percent had a left
      hemisphere focus, 42% a right-hemisphere focus, and 11% multifocal seizures. The
      seizure focus was temporal in 68%. A magnetic resonance imaging consistent with
      mesial temporal sclerosis was seen in 29% of patients. Overall, 44% of the
      patients made at least one attempt to reach for the event bulb at the start of
      their seizures. Among the 72% of patients who gave a history of auras, 53% were
      able to press the event bulb compared to 20% with no history of auras (P =
      0.016). EEG changes occurred a mean of 2.9+/-30.5 seconds after reaching for the
      bulb for scalp-recorded seizures (n = 20), and 16.2+/-13.7 seconds before
      behavior for depth-recorded seizures (n = 14, difference significant at P =
      0.02). Neither seizure focus nor seizure laterality influenced the ability to
      press the event bulb. The authors conclude that nearly half of individuals with
      complex partial seizures can take volitional motor action at the start of their
      seizure. A method to enhance the intensity and timeliness of a seizure warning
      would not be wasted.

PMID- 10359500
TI  - Periodicity of a noninvasive measure of cardiac vagal tone during non-rapid eye
      movement sleep in non-sleep deprived and sleep-deprived normal subjects.
AB  - Cyclic alternating pattern (CAP) of microarousals reported in EEG studies is now
      regarded as an integrating mechanism for the different parts of the central
      nervous system including the autonomic system. A recently developed continuous
      index of cardiac parasympathetic activity (CIPA) can be time locked to the EEG
      allowing the relationship between EEG and autonomic changes to be studied in
      sleep. Eleven normal subjects were studied for evidence of periodicity in CIPA in
      non-REM sleep, five of whom had been sleep deprived. Fast Fourier's
      transformation of the CIPA data confirmed its periodicity with four frequency
      peaks in the range of 0.015 to 0.3 Hz. The frequency peaks previously reported as
      caused by respiration, Mayer waves and vasomotor thermoregulatory activity, were
      within what we called the alpha and beta rhythms of CIPA. There was an additional
      very slow peak not previously described and we called it the gamma rhythm. It
      covered the frequency range below 0.03 Hz. The gamma rhythm was the largest of
      all peaks in CIPA rhythms and its magnitude increased further in sleep-deprived
      subjects, but it invariably decreased during stage 4 sleep in both groups. Bursts
      of alpha waves in the EEG recorded concomitantly with CIPA in stage 1 sleep were
      associated with both peaks and troughs of the gamma rhythm. These results support
      previous proposals that cyclic alternating pattern in the EEG may be an
      integrating mechanism associated with functions of the central nervous system,
      and we have shown here its relationship with CIPA. Because cyclic alternating
      pattern can also be measured in CIPA, clinical exploitation of this phenomenon
      could include monitoring of epilepsy, studies of the effects of drug therapy, and
      assessment of other sleep disorders. All these are known to affect cyclic
      patterns of sleep EEG.

PMID- 10359501
TI  - Actigraphy and leg movements during sleep: a validation study.
AB  - A study comparing actigraphy and polysomnography in the detection of leg
      movements was performed in a group of 35 patients with sleep disorders. Visual
      scoring used epochs of 5-second duration, and in each epoch, electromyographic
      activity of tibialis anterior muscle was classified in eight types on the basis
      of its duration and amplitude. Activity levels of the actigraphic data were
      logged in 5-second intervals and stored in memory for computer retrieval. To
      assess the reproducibility of actigraphic detection scoring, in 10 patients
      actigraphic and polysomnographic data were compared during two consecutive
      nights. Despite a high correlation between polysomnography and actigraphy in the
      detection of muscular activity (r = 0.78; P = 0.001), no agreement was obtained
      between the two analyses according to the Bland and Altman method of concordance
      (mean bias: -117.5). The greater agreement was found for electromyographic
      activity lasting more than 3 seconds and with an amplitude of more than 50
      microV. In the group of patients examined during two consecutive nights the
      scoring error did not differ significantly. The results demonstrated that (1)
      despite a significant correlation between actigraphic and polysomnographic data,
      actigraphy substantially underestimated leg electromyographic activity and
      therefore could not be used routinely for diagnostic purposes; and (2) because
      error scoring did not undergo significant changes across the two nights,
      actigraphy may be used for follow-up evaluation.

PMID- 10359502
TI  - The lateral femoral cutaneous nerve: nerve conduction technique.
AB  - In 58 subjects without signs or symptoms of peripheral nerve disorders, an
      antidromic sensory nerve conduction study was performed on the lateral femoral
      cutaneous nerve. Anatomic dissections were performed on two cadavers to reveal
      the course of the nerve and to localize the optimal stimulation and recording
      sites. Mean sensory nerve action potential latency was measured at 1.7 msec (SD =
      0.23) with a mean amplitude of 10.5 microV (SD = 4.0). The optimal localization
      of recording and stimulating surface electrodes and nerve conduction technique
      procedures are discussed. Reliable electrophysiologic criteria, according to age
      and body mass index, are obtained.

PMID- 10359503
TI  - Peripheral neuropathy in systemic lupus erythematosus.
AB  - The prevalence of clinically apparent peripheral neuropathy in systemic lupus
      erythematosus is reported to be between 2% to 18%. The purpose of this
      prospective case-control study was to determine the prevalence of peripheral
      neuropathy (PN) using electrodiagnostic criteria. Subgroup analysis was performed
      to determine whether PN correlated with disease activity, renal involvement, or
      serum immune markers. Fifty-four systemic lupus erythematosus patients and 30
      controls were recruited in the study. The right median, ulnar, peroneal, tibial,
      and sural sensory and motor nerve conduction studies were obtained. PN in our
      study was defined as any abnormal values in motor and sensory distal latency,
      sensory action potential, motor action potential, or conduction velocity
      affecting 2 or more nerves. Of the 54 patients studied, PN was present in 15
      patients (27.8%) of which 4 were symptomatic. There was a significant correlation
      between PN and anti-SM antibody, and there was a trend showing decreased motor
      and sensory action potential amplitudes in our systemic lupus erythematosus group
      compared to the controls. This observation was also seen in an active disease
      group when compared to those with inactive disease. The amplitude of the action
      potential was more often affected than the distal latency, and sensory nerves
      were more susceptible than motor nerves. The sural sensory action potential
      amplitude appears to be the most sensitive indicator of PN which may be used as
      an index to monitor disease activity.

PMID- 10359504
TI  - A case of central carcinoma of the mandible arising from a recurrent odontogenic
      keratocyst: delineation of surgical margins and reconstruction with bilateral
      rectus abdominis myocutaneous free flaps.
AB  - A case of central carcinoma of the mandible arising from a recurrent odontogenic
      keratocyst is reported. A 38-year-old man was admitted to the Tokai University
      Hospital due to postoperative infection of a recurrent odontogenic keratocyst of
      the left mandible. He had had a cystectomy for an odontogenic keratocyst 4 years
      ago. The lesion revealed bony destruction of the mandible with worm-eating shaped
      margins with extension to the facial skin. A biopsy specimen revealed squamous
      cell carcinoma. The mandible was resected with facial skin and the sublingual
      space was dissected to preserve the lingual nerve. The oral and the facial
      resections were reconstructed with a titanium plate and bilateral rectus
      abdominis myocutaneous free flaps. The plate was removed due to infection around
      the margins and readjustment of the flaps was conducted 5 months after the
      surgery. He has not had a local relapse, metastasis, or incisional hernia for 8
      months following surgery. Good occlusion has been attained by the residual
      mandible, and he is able to eat without any problems.

PMID- 10359505
TI  - Colorectal cancer recurrence in the liver: detection by PET.
AB  - Positron emission tomography (PET) has been successfully used in the imaging of
      various cancers. In this retrospective study, we examined clinical utility of PET
      in the imaging of liver metastasis from colorectal cancer. Results of PET were
      compared with those of ultrasonography (US) and contrast-enhanced computer
      tomography (CT) in 11 liver metastases seen in eight patients with recurrent
      colorectal cancer. The detection rates were 73% (8 of 11 metastases) by US, 73%
      (8 of 11 metastases) by CT, and 82% (9 of 11 metastases) by PET. PET correctly
      identified US-negative and CT-negative liver metastases. However, PET was
      negative in one patient with minute metastases. The findings in our preliminary
      study were in agreement with those of previous reports. A prospective study is
      warranted to determine the optimum role of PET in the management of patients with
      colorectal liver metastasis.

PMID- 10359506
TI  - Detection of fowl mites inside two hospital rooms.
AB  - Many mites were found on bookshelves near the windows in 2 rooms of the
      Department of Pediatrics on the 4th floor in the Tokai University Hospital.
      Fortunately, nobody reported being bitten by, or experiencing itching due to, the
      mites. The arthropods were tentatively identified as adults of the northern fowl
      mite, Ornithonyssus sylviarum (Canestrini et Frazago, 1877), commonly called
      "Torisashi-dani" in Japanese. It appears the mites came from an empty wagtail
      nest which was outside the windows. Since migrating birds like the wagtail may
      carry O. sylviarum and other pests and pathogens, and their possible transfer to
      domestic birds, more attention should be paid to the danger posed by bird mites.

PMID- 10359507
TI  - Factors affecting depth of gastric ulcers.
AB  - PURPOSE: We investigated the differences in background factors, clinical
      features, and gastric function tests among gastric ulcers of various depths.
      PATIENTS AND METHODS: The subjects were 68 patients (male 64, female 4) who were
      diagnosed as having a gastric ulcer at the angulus. The ulcers were classified
      according to depth based on the following: UL2 (shallow) ulceration to the
      submucosa; UL3 (intermediate), to the muscularis propria; and UL4 (deep
      excavation), beyond the muscularis propria. The depth of each ulcer was
      determined by endoscopic ultrasonography and/or ordinary endoscopic findings. We
      assessed clinical features, age, gender, smoking habit, alcohol consumption,
      ulcer history, presence of H. pylori, gastric acid secretion, gastric emptying,
      serum gastrin level, healing rate, and recurrence rate. RESULTS: Patients with
      UL4-type ulcers had a higher rate of recurrence and a significantly higher
      incidence of H. pylori infection. Patients with hyperacidity and currently
      smoking or consuming alcohol were significantly more likely to have UL4-type
      ulcers than of UL2 or 3 ulcers. Furthermore, a close relationship was recognized
      between recurrence, intractability and deeply excavated ulcers. Ulcer depth was
      not correlated significantly with any of the following factors: 1) patient's
      profile; including gender and hemorrhagic symptoms; 2) gastric function;
      including gastric emptying and serum gastrin levels. CONCLUSIONS: Smoking,
      alcohol consumption, recurrence of ulcers, hyperacidity and H. pylori infections
      are important factors associated with deep ulcers.

PMID- 10359508
TI  - Episcleritis associated with pigmentary retinal degeneration in an HTLV-I
      carrier.
AB  - Human T-cell lymphotropic virus type I (HTLV-I) has been reported as the cause of
      a kind of endogenous uveitis (HTLV-I associated uveitis; HAU). We observed a case
      of episcleritis in a HTLV-I carrier with pigmentary retinal degeneration. HTLV-I
      infection might be associated with the development of episcleritis and pigmentary
      retinal degeneration. Patients with episcleritis or pigmentary retinal
      degeneration should be examined for HTLV-I infection.

PMID- 10359509
TI  - How to use cerebral vasodilators and metabolic activators.
AB  - Cerebral vasodilators and metabolic activators (enhancers) for the treatment of
      cerebrovascular disorders (CVD) have been categorized and introduced into
      clinical practice according to their pharmacological actions and clinical
      indications. The main therapeutic goal of these drugs is to relieve residual
      subjective symptoms and neuropsychological dysfunction, which reduce the quality
      of life of patients in the chronic stage of stroke. Selection of the most
      suitable drug for the individual symptoms of each patient is an important
      therapeutic principle.

PMID- 10359510
TI  - Effect of chronic furosemide administration on acid-base balance in patients with
      chronic hypercapnic respiratory failure.
AB  - We quantitatively analyzed the effect of long-term administration of oral
      furosemide on the PaCO2 - H+ relationship in patients with chronic hypercapnic
      respiratory failure. In this study we measured arterial blood gases of eighteen
      outpatients (mean duration of visits, 7.6 years; mean rise of PaCO2, 15.4 mmHg).
      We obtained linear regression lines for PaCO2 - H+, and determined their Y-axis
      intercepts and slopes. The results indicated that an increase in the administered
      dose of furosemide decreased linearly the Y-axis intercept of the regression line
      [(Y-intercept) = - 6.9(dose of furosemide) + 30.9, r = 0.81], and increased
      linearly the slope of the regression line [(slope) = 0.094(dose of furosemide) +
      0.22, r = 0.74]. Thus, the regression line of the PaCO2 - H+ relationship moved
      downward and became steeper at higher doses of furosemide. The regression lines
      for each dose of furosemide crossed at a PaCO2 of 75 mmHg. We concluded that
      there is a mutual interaction between the renal and respiratory mechanisms for
      acid-base balance in chronic hypercapnia and the effect of furosemide on the
      PaCO2 - H+ relationship is negligible in severe hypercapnia.

PMID- 10359511
TI  - Purification and characterization of alkaline phosphatase from human seminomas.
AB  - Despite the apparent link between the presence of alkaline phosphatase (ALP) and
      various cancers, it has so far been difficult to determine distinct differences
      between seminoma-derived ALP and placental ALP (PLAP). In order to determine
      specificity, we purified ALP from a seminoma type of human testicular cancer
      tissue and compared its biochemical and immunological properties with those of
      PLAP. The purified ALP had a specific activity of 66 units per mg of protein, and
      it was possible to obtain 169 microg of purified preparation from 60 g of tissue.
      The molecular weight of the purified seminoma enzyme was approximately 500 kDa.
      We found that a novel type of ALP from human testicular cancer tissue exists,
      with a high molecular weight and differing in degree, from the seminoma ALP
      previously reported.

PMID- 10359512
TI  - Ultrastructure of the parotid gland in two species of naked-backed bats.
AB  - Naked-backed bats of the genus Pteronotus (family Mormoopidae) occur in the
      Neotropics from Mexico through northern South America. These are relatively small
      sized insectivorous species that frequently roost in caves. Eight specimens of
      naked-backed bats (Pteronotus parnellii) were live-trapped in Suriname and one in
      Cuba (P. quadridens). Their parotid glands were fixed in an aldehyde mixture
      designed for field work and postfixed in the laboratory with osmium tetroxide.
      Tissues were further prepared for electron microscopy by conventional means. The
      parotid glands of the two species of Pteronotus closely resemble each other
      except for the substructure of their serous secretory granules. Serous granules
      in P. parnellii are bizonal, with a moderately dense inner matrix and an outer,
      denser corona or crescent. The matrix is occupied by laminae, flakes, and
      filaments in random array. In contrast, serous granules in P. quadridens consist
      of a uniform matrix that contains dense, usually stacked toroids or tubules
      either in random array or packed in bundles. A parotid gland from one specimen of
      P. parnellii contained an endpiece that consisted of cells that contained giant
      (up to 9 pm in diameter) serous granules. Serous cells in both species contain
      aggregates of small, uniformly dense, rod-like, membrane-delimited organelles as
      well as occasional bundles of cytofilaments. The endpieces are separated from
      intercalated ducts by a ring of granulated cells that contain secretory granules
      that often have a bull's-eye configuration. Intercalated and striated ducts are
      typical in appearance, except that many of the cells in the latter contain small,
      dense secretory granules in their apical cytoplasm. The parotid glands in the two
      species of naked-baked bats differ slightly in terms of acinar secretory granule
      ultrastructure, but otherwise are fairly conservative. It is thought that the
      glands in these particular bats might represent the "basal" condition of the
      salivary glands of insectivorous bats and thus can serve as a reference point for
      making comparisons to the highly diversified (in terms of diet) phyllostomid
      bats.

PMID- 10359513
TI  - Shape of large bound polysomes in cultured fibroblasts and thyroid epithelial
      cells.
AB  - Large bound polysomes were observed by conventional electron microscopy in
      surface or en face views of the rough endoplasmic reticulum (RER) in two cultured
      cell types. Cultured thyroid follicular epithelial cells and dermal fibroblasts,
      both from rats, were prepared for electron microscopy. Ultrathin sections were
      cut in the plane of the flattened cells to maximize the incidence of RER surface
      views. Some observations were also made on tissue sections of rat thyroid. Most
      of the large, RER-bound polysomes in both cell types appeared as two parallel
      rows of ribosome, thus resembling the shape of long hairpins, although probably
      closed at both ends. The two parallel rows of ribosomes were about 14 nm apart,
      and the center-to-center distance between ribosomes in the strands averaged 25
      nm. Most of the large bound polysomes in thyroid epithelial cells were presumably
      making thyroglobulin subunits (330 kDa), while a majority of those in the
      fibroblasts were probably making prepro-alpha chains of collagen I (150 kDa). It
      was not possible in this material to see complete large polysomes, because their
      size usually caused them to extend out of the plane of section. In addition to
      the hairpin polysomes, there were smaller numbers of other forms. A
      characteristic large spiral polysome was seen occasionally in both cell types and
      contained as many as 31 ribosomes. One or two dense particles were sometimes seen
      in the center of spiral or circular polysomes. The consistent hairpin shape of
      most large bound polysomes observed in this study suggests that their shape is
      quite stable.

PMID- 10359514
TI  - Sex difference in target seeking behavior of developing cremaster muscles and the
      resulting first visible sign of somatic sexual differentiation in marsupial
      mammals.
AB  - Cremaster muscles are present in both male and female developing and adult
      marsupial mammals. They are complex structures and composed of several distinct
      bundles of striated muscle fibers provided with: (1) a distinct and extensive
      innervation; (2) a distinct blood vascular supply; (3) a distinct tendineous
      origin on the anterosuperior iliac spine; and (4) distinct target structures. The
      muscles thus seem to be separate anatomical entities and not a part of one or
      more of the layers of the ventral abdominal wall musculature. Cremaster muscles
      in males are elongated, are larger than in females, and for the most part are a
      component of the funiculus spermaticus. They insert on the distal part of the
      tunica vaginalis. The distal parts of the muscles in females are flattened ("fan
      shaped") and insert over a broad area on the dorsal borders of the mammary
      glands. Muscles in males have no relation whatsoever to the male mammary
      glandular rudiments. Muscles in females are attached at the base of the uterine
      round ligament. The remarkable sex difference in target structures of marsupial
      cremaster muscles becomes noticeable during perinatal life when outgrowing
      muscles take a different path in males and females. The initial appearance of
      this sexually dimorphic trait precedes the sexual differentiation of the genital
      ducts and external genitalia. In fetal males, the cremaster muscles grow in the
      direction of the site where scrotal bulges initially appear in the subcutaneous
      layers and later on the inguinal skin surface. They also take the gubernacular
      core of the ventral abdominal wall and the attached peritoneal epithelium with
      them during this outgrowth process. Consequently, this results in the development
      of a slitlike evagination of the abdominal lumen as the primary step to
      development of the processus vaginalis, while the testis and adjacent mesonephros
      and its duct are still attached to the posterior abdominal wall. In fetal
      females, the outgrowing cremaster muscles pass along the gubernacular core and,
      subsequently, this structure develops further as the tip (attached to the tubo
      uterine junction) of the intra-abdominally protruding and further developing
      uterine round ligament. The female cremaster muscles grow further into caudal
      direction to shape a dorsal border of the developing mammary glands. The early
      onset of this sexually dimorphic outgrowth of cremaster muscles indicates that
      the "classical hormones" of sexual differentiation (anti-Mullerian hormone [AMH]
      and steroidal androgens) are not involved in this process. It could thus depend
      on primary genetic control with male development associated with the male-limited
      activity of genes on the Y-chromosomes and female development as the default
      process. Alternatively, the process in males could be under the control of an as
      yet unidentified third fetal testicular hormone involved in sexual
      differentiation processes which must then show an unexpectely early (i.e.,
      perinatal) onset of its secretion.

PMID- 10359515
TI  - 13-cis-Retinoic acid alters neural crest cells expressing Krox-20 and Pax-2 in
      macaque embryos.
AB  - This study investigates hindbrain and associated neural crest (NCC), otocyst, and
      pharyngeal arch development in monkey embryos following teratogenic exposure to
      13-cis-retinoic acid (cRA). cRA was orally administered (5 mg/kg) to pregnant
      long-tailed macaques (Macaca fascicularis) between gestational days (GD) 12 and
      27. Embryos were surgically collected at desired stages during treatment,
      analyzed for external morphological changes, and processed for
      immunohistochemistry. Two transiently expressed nuclear proteins, Krox-20 and Pax
      2, were used as markers for the target cellular and anatomical structures.
      Rhombomere (r) expression patterns of Pax-2 (r4/r6) and Krox-20 (r3/r5) were
      maintained after cRA treatment, but r4 and r5 were substantially reduced in size.
      In untreated embryos, Krox-20 immunoreactive NCC derived from r5 migrated
      caudally around the developing otocyst to contribute to the third pharyngeal arch
      mesenchyme. In cRA-treated embryos, a subpopulation of NCC rostral to the otocyst
      also showed Krox-20 immunoreactivity, but there was a substantial reduction in
      Krox-20 post-otic NCC. Pax-2 immunoreactive NCC migrating from r4 to the second
      pharyngeal arch were substantially reduced in numbers in treated embryos.
      Alteration in the otic anlage included delayed invagination, abnormal
      relationship with the adjacent hindbrain epithelium, and altered expression
      boundaries for Pax-2. cRA-associated changes in the pharyngeal arch region due to
      cRA included truncation of the distal portion of the first arch and reduction in
      the size of the second arch. These alterations in hindbrain, neural crest, otic
      anlage, and pharyngeal arch morphogenesis could contribute to some of the
      craniofacial malformations in the macaque fetus associated with exposure to cRA.

PMID- 10359516
TI  - Developmental changes of sugar residues and secretory protein in mucous cells of
      the early postnatal rat parotid gland.
AB  - Mucous cells have been identified in the terminal portions of the early postnatal
      parotid gland in human and rat, although mature parotid gland acini are composed
      of serous cells or seromucous cells. Previously, Ikeda et al. demonstrated that
      mucous cells are present in the rat parotid gland on days 1 to 8 after birth and
      that the secretory granules within these mucous cells share some histochemical
      characteristics with mature serous cells. However, it is still not clear whether
      the mucous cells change into serous cells as the gland develops. The purpose of
      this study was to determine whether the mucous cells that appear in the early
      postnatal rat parotid gland change into serous cells. Parotid glands were
      obtained from male or female Wistar rats (aged 0-14 days and adults). Fixed
      tissue sections were reacted with soybean agglutinin (SBA) and wheat germ
      agglutinin (WGA) to detect glycoconjugates, or were stained using an anti
      neonatal submandibular gland protein B1 (SMG-B1) antibody to identify serous
      acinar cells. The sections were observed by transmission electron microscopy.
      Electron microscopy revealed that cells with characteristics intermediate between
      those of mucous and serous cells (transitional cells) appeared around day 8 and
      that the nuclei of these cells did not show chromatin condensation, a
      characteristic of apoptotic cells. Lectin histochemistry showed that the mucous
      cells had the same sugar residues as the serous cells, which appeared after day
      10. Immunohistochemistry with an anti-SMG-B1 antibody gave a positive reaction
      not only in the cells with highly electron-dense granules but also in the
      electron-dense cores of bipartite or tripartite granules in the transitional
      cells. Cells with morphological characteristics intermediate between those of
      mucous and serous cells (transitional cells) appearing in the early postnatal rat
      parotid gland begin to produce B1-immunoreactive protein common to serous acinar
      cells during development of the gland.

PMID- 10359517
TI  - Joint anatomy, design, and arthroses: insights of the Utah paradigm.
AB  - This model of joint design argues 1) that excessive fatigue damage (MDx) in
      articular cartilage collagen can be the "final cause" of an arthrosis; 2) that
      known responses of a growing joint's anatomy and geometry, and modeling and
      maintenance activities, to mechanical loads minimize that cause and thus
      arthroses; 3) and many biomechanical, biochemical, cell-biologic, genetic and
      traumatic "first causes" of arthroses could lead to that final cause. The model
      depends partly on the following facts (marked by a single asterisk) and ideas
      (marked by a double asterisk). A) During growth a joint's total loads can
      increase over 20 times without causing an arthrosis, yet in adults an equal
      loading increase would cause one. B) Fatigue damage (MDx) occurs in joint
      tissues, larger strains increase it, and minimizing strains reduces it. C) Bone
      can repair amounts of MDx below an "MDx threshold," but larger amounts can escape
      repair and accumulate. The model assumes articular cartilage has similar
      features. D) Bone modeling makes bones strong enough to keep their strains below
      bone's MDx threshold and minimize MDx. Chondral modeling shapes and sizes joints
      during growth; that would keep articular cartilage strains below the chondral MDx
      threshold to minimize chondral MDx and arthroses. Normal chondral modeling nearly
      stops in adults, which might explain point A above. E) Throughout life
      maintenance activities preserve optimal physical, chemical and biologic
      properties of a joint's tissues. To past emphases on the biochemical, genetic,
      cellular and molecular biologic features of adult joint physiology, this model
      adds organ-level, tissue-level and vital-biomechanical features of growing joints
      that invite study and understanding at lower levels of biologic organization.

PMID- 10359518
TI  - Morphologic characteristics of initial lymphatics of the healthy and diseased
      human gingiva.
AB  - Investigation was performed on healthy and inflamed human gingivae. In the
      healthy mucosa lymphatic vessels generally appeared as flattened channels with a
      reduced lumen. Only in very inflamed tissue were some more evident vessels with a
      distended wall detectable. Ultrastructurally, most of the vessels had the
      characteristics of capillaries and they were delimited by a thin and irregular
      endothelial wall with large intercellular spaces. These observations indicate
      that in the gingival tissues, which are continuously exposed to inflammatory
      agents and need a really efficient draining system, the pathway of interstitial
      exudation and cell migration may include both the lymphatic vessel system and the
      intercellular spaces of the permeable junctional epithelium.

PMID- 10359519
TI  - Intercellular bridges between granulosa cells and the oocyte in the elasmobranch
      Raya asterias.
AB  - In the present ultrastructural study intercellular bridges, connecting somatic
      granulosa cells to oocyte, have been detected for the first time and their
      modifications have been followed during Raja oogenesis. Intercellular bridges
      make their first appearance in small previtellogenic follicles as connecting
      devices between small cells and the oocyte. Later on, when the follicular
      epithelium becomes polymorphic and multilayered, for the presence of small,
      large, and pyriform-like cells, intercellular bridges link the oocyte and the
      different granulosa cells. Intercellular bridges contain ribosomes, whorl of
      membranes, mitochondria and vacuoles. Such cytoplasmic components are present
      also in the cell apex of large and pyriform-like cells thus suggesting, in
      agreement with other species (Motta et al. J. Exp. Zool., 1996;276:223-241) they
      may flow toward the oocyte. In this regard the presence of intercellular bridges
      during the oogenesis of cartilagineous fish may represent a crucial event of the
      active cooperation between granulosa cells and the oocyte.

PMID- 10359520
TI  - Persistence of hybrid fibers in rat soleus after spinal cord transection.
AB  - The effects of a chronic (up to 360 days) reduction in neuromuscular activity
      (defined as electrical activation and loading) on myosin heavy chain (MHC)
      isoform expression in the rat soleus muscle were studied. A complete mid-thoracic
      (T7-T8) spinal cord transection (ST) was used to induce a reduction in soleus
      muscle neuromuscular activity. Electrophoretic analyses revealed that MHC-I was
      progressively decreased after ST, accounting for approx. 90% of the total soleus
      MHC in controls and only approx. 12% 1 year after ST. The reductions in the
      proportion of MHC-I were countered by increases in MHC-IIa and MHC-IIx with the
      increase in MHC-IIx preceding the increase in MHC-IIa. Curiously, MHC-IIb was
      expressed only at very low levels. Thus, a complete transformation from
      predominantly MHC-I to MHC-IIb did not occur. Many fibers (up to approx. 80%)
      contained multiple MHCs (hybrid fibers) after ST. The proportion of hybrid fibers
      was maintained at a high level (approx. 50%) 1 year after ST. These data suggest
      that: 1) a prolonged reduction in neuromuscular activity was not sufficient to
      induce high level MHC-IIb expression by the soleus muscle; and 2) hybrid fibers
      were not simply transitional fibers. Thus, it appears that under appropriate
      conditions hybrid fibers may represent a "stable" fiber phenotype.

PMID- 10359521
TI  - Age-related hypermineralization in the female proximal human femur.
AB  - Hip fracture incidence increases exponentially with age in virtually every human
      population that has been studied. In spite of this, relatively few studies have
      examined age-related changes in the metaphyseal cortex of the proximal femur. The
      present study investigates cortical aging changes in the female proximal femur,
      with particular reference to regions of hypermineralization. Thirty-three femora
      from Caucasian females were obtained at autopsy and analyzed using backscattered
      electron imaging. Variations in hypermineralized tissue area, cortical bone area,
      and porosity were quantified with standard stereological methods. Cortical width
      was quantified with digital calipers. Gender differences were examined by
      statistical comparison with previously published results. Hypermineralized tissue
      volume was significantly (P < 0.001) greater in elderly individuals.
      Hypermineralized tissue preferentially appeared near ligamentous or tendinous
      insertion sites, suggesting the hypermineralized tissue may be a calcified
      fibrocartilage. Cortical width significantly (P < 0.001) decreased with age and
      porosity significantly (P < 0.001) increased with age, however the changes were
      site-specific. The femoral neck and intertrochanteric cortices had a smaller
      change in cortical width and porosity with age than the diaphysis, but the
      femoral neck and intertrochanteric cortices had a larger increase in
      hypermineralized tissue. Comparison with previous data suggests that cortical
      aging in the proximal femur is similar between males and females and is unlikely
      to explain the higher incidence of fracture in females. However, the data
      strongly indicates that age-related changes in the femoral diaphysis cannot be
      directly extrapolated to either the femoral neck or intertrochanteric cortices.

PMID- 10359522
TI  - Does the subepicardial mesenchyme contribute myocardioblasts to the myocardium of
      the chick embryo heart? A quail-chick chimera study tracing the fate of the
      epicardial primordium.
AB  - Morris (J. Anat., 1976;121:47-64) proposed that the subepicardial mesenchyme
      might represent a continuing source of myocardioblasts during embryonic and fetal
      development. Recent studies have shown that the epicardium and subepicardial
      mesenchyme, and the coronary vasculature are all derived from a region of the
      pericardial wall, called the proepicardial serosa. In avian embryos, the cells
      from the proepicardial serosa colonize the heart via a secondary tissue bridge
      formed by attachment of proepicardial villi to the heart. In the present study,
      Morris's hypothesis was tested by tracing the fate of the proepicardial serosa.
      This was achieved by constructing quail-chick chimeras. The proepicardial serosa
      was transplanted from HH16/17 quail embryos to HH16/17 chick embryos (ED3). A new
      transplantation technique facilitated an orthotopic attachment of the quail
      proepicardial villi to the chicken heart, and prevented the attachment of the
      chicken proepicardial villi to the heart. The fate of the grafted quail cells was
      traced in chimeras from ED4 to ED18 with immunohistochemistry, using quail
      specific antibodies (QCPN, QH-1). From ED4 onward, the transplant was connected
      to the dorsal heart wall via its proepicardial villi. Starting from the point of
      attachment of the quail proepicardial villi to the heart, the originally naked
      myocardium became almost completely covered by quail-derived epicardium, and
      quail mesenchymal cells populated the subepicardial, myocardial, and
      subendocardial layers including the av-endocardial cushions. Quail cells formed
      the endothelial and smooth muscles cells of the coronary vessels, and the
      perivascular and intramyocardial fibroblasts. Quail myocardial cells were never
      found in the subepicardial, myocardial, and subendocardial layers. This suggests
      that the subepicardial mesenchyme normally does not contribute a substantial
      number of myocardioblasts to the developing avian heart. The new transplantation
      technique presented facilitates the production of chimeric hearts in which the
      derivatives of the proepicardial serosa are almost completely of donor origin.
      This technique might be useful for future studies analyzing the role of certain
      genes in cardiac development by the creation of somatic transgenics.

PMID- 10359523
TI  - Ultrastructural and ultracytochemical features of secretory granules in the
      ampullary epithelium of the hamster oviduct.
AB  - The epithelium of mammalian oviducts consists mainly of ciliated and non-ciliated
      secretory cells. In some mammals, secretory products originating from oviductal
      secretory cells have been shown to bind to the surface of, or accumulate within,
      ovulated eggs and/or developing embryos. These findings suggest that the
      secretions of the oviductal epithelial cells may play an important role in
      reproductive and developmental events that occur in the oviduct. In the present
      study, ultrastructural and cytochemical features of secretory cells in the
      hamster ampullary epithelium were shown by routine electron microscopy, lectin
      gold cytochemistry and both conventional freeze-fracture and rapid-freezing
      techniques with special reference to the organizational aspects of their
      secretory granules. The use of ferrocyanide-reduced osmium tetroxide as a post
      fixative in the Epon embedment of ampullary tissue samples also proved to be
      advantageous especially in revealing the carbohydrate contents of certain
      cellular compartments. The most conspicuous characteristic of the secretory
      cells, based on their staining property, was the presence of two types of
      secretory granules: those with a homogeneous electron-dense matrix and those with
      an electron-lucent matrix. Under favorable conditions, distinct features of the
      organizational arrangement of a crystalline lattice inside the secretory granules
      were also revealed. This well organized crystalline lattice shown in sections of
      Epon-embedded oviductal tissue was confirmed by examination of replicas of freeze
      fractured oviducts prepared by the rapid-freezing technique. We also demonstrated
      with high resolution lectin-gold cytochemistry the intracellular distribution of
      lectin-binding glycoconjugates in the secretory cells of the hamster oviductal
      ampulla often in a linear array following the crystalline lattice. The results
      obtained in this study, taken together, provide insight into a possible link of
      the internal topographical features of oviductal secretory granules along with
      the cytochemical properties of their contents to the anticipated regulatory
      mechanism underlying their process of secretions.

PMID- 10359524
TI  - Conversion of HPV 18 positive non-tumorigenic HeLa-fibroblast hybrids to invasive
      growth involves loss of TNF-alpha mediated repression of viral transcription and
      modification of the AP-1 transcription complex.
AB  - AP-1 represents a transcription factor, which plays a pivotal role in initiating
      and maintaining the expression of human papillomavirus (HPV) oncoproteins E6 and
      E7 during HPV-linked carcinogenesis of the uterine cervix. AP-1 stands as a
      synonym for different proteins such as c-Jun, JunB, JunD, c-Fos, FosB as well as
      the Fos-related antigens Fra-1 and Fra-2, which can either homo- or
      heterodimerize to build up a functional transcription complex. AP-1 is mainly
      considered as a positive regulator, which binds to cognate DNA sequences within
      the viral upstream regulatory region. By using non-tumorigenic HeLa-fibroblast
      hybrids ('444'), their tumorigenic segregants ('CGL3') as well as HPV 18 positive
      HeLa cells as a experimental model system, evidence is provided that AP-1
      composition differs considerably between these cell lines. In nuclear extracts
      obtained from non-tumorigenic cells, Jun-family members (in the order c
      Jun>JunD>JunB) were mainly heterodimerized with Fra-1, a protein, known to be
      involved in the abrogation of AP-1 activity under certain experimental
      conditions. In contrast, Fra-1 concentration is low in extracts from tumorigenic
      cells. Conversely, c-Fos, the canonical dimerization partner of Jun proteins is
      expressed in substantial quantity in HeLa- and 'CGL3' cells, but it is completely
      absent in AP-1 complexes from non-tumorigenic '444' cells. Ectopical expression
      of c-fos under a heterologous promoter in '444'-cells induces tumorigenicity and
      a change of the Jun/Fra-1 ratio towards a constellation initially detected in
      'CGL3'-and HeLa cells. Furthermore, conversion to tumorigenicity is accompanied
      with a resistance against TNF-alpha, a cytokine, capable to selectively suppress
      HPV 18 transcription in formerly non-malignant cells. These data propose a novel
      role for AP-1 as an essential component of an inter- and intracellular
      surveillance mechanism negatively controlling HPV transcription in non
      tumorigenic cells.

PMID- 10359525
TI  - An acidic environment leads to p53 dependent induction of apoptosis in human
      adenoma and carcinoma cell lines: implications for clonal selection during
      colorectal carcinogenesis.
AB  - As tumours are known to acidify their microenvironment and fluctuations in
      lumenal pH have been reported in a number of colonic disease conditions, we
      investigated whether loss of p53 function, commonly associated with the adenoma
      to carcinoma transition in human colorectal epithelium, was implicated in the
      cellular response to changes in extracellular pH. Human colonic adenoma and
      carcinoma derived cell lines were incubated at an initial pH range of 5.5-8.0 and
      the attached cell yield and apoptotic cell yield determined after 4 days.
      Exposure of all cell lines to an acidic growth environment was associated with a
      G1 arrest, down regulation of the retinoblastoma protein (pRb) protein and switch
      to the hypophosphorylated form of the protein, and increased expression of the
      p21 protein. However, induction of apoptosis, associated with increased p53
      protein expression but not with changes in Bcl-2 expression, was only detected in
      the adenoma derived BH/C1 and AA/C1 cell lines which express wild type p53
      activity. Furthermore, this induction of apoptosis was inhibited in the
      transfected cell line AA/273p53/B, in which the wild type p53 function has been
      abrogated. These results suggest that acidification of the microenvironment would
      provide a selective growth advantage for cells that have lost wild type p53
      function, leading to clonal expansion of aberrant cell populations.

PMID- 10359526
TI  - Mutations in serines 15 and 20 of human p53 impair its apoptotic activity.
AB  - Phosphorylation of the p53 tumor suppressor protein is likely to play an
      important role in regulating its activity. To study the regulatory role of
      potential phosphorylation sites within the N-terminal transactivation domain of
      human p53 (hp53), a series of p53 serine mutants were evaluated for
      transcriptional transactivation and sequence specific DNA binding. The role of
      these mutations in regulating p53-mediated growth suppression and programmed cell
      death was examined. This mutational analysis comprised serine residues located at
      positions 6, 9, 15, 20, 33 and 37 of human p53. Substitution of serine for
      alanine, either at individual residues or at all six residues together, did not
      affect the suppression of cell growth and cell transformation, or the ability to
      bind DNA specifically and to transactivate different promoters, nor did it alter
      p53 expression. However, the ability of p53 to induce apoptosis was impaired by
      specific serine substitutions. Mutations in all six N-terminal serines together
      reduced the apoptotic activity of p53 in H1299 cells by 50%. Analysis of
      individual mutants revealed that mutations in serine 15 and 20 are primarily
      responsible for this impairment. Our results suggest that these serines play a
      role in the regulation of p53-mediated apoptosis.

PMID- 10359527
TI  - Repression of NF-kappaB impairs HeLa cell proliferation by functional
      interference with cell cycle checkpoint regulators.
AB  - NF-kappaB is an inducible transcription factor, which is regulated by interaction
      with inhibitory IkappaB proteins. Previous studies linked the activity of NF
      kappaB to the proliferative state of the cell. Here we have analysed the function
      of NF-kappaB in the cell cycle. Inhibition of NF-kappaB in HeLa cells by stable
      overexpression of a transdominant negative IkappaB-alpha protein reduced cell
      growth. A kinetic analysis of the cell cycle revealed a retarded G1/S transition.
      The IkappaB-alpha overexpressing cell clones showed a decreased percentage of
      cells in the S phase and an impaired incorporation of bromodeoxyuridine (BrdU).
      The amounts of cyclins A, B1, D1, D3, and E were unchanged, but the G1-specific
      proteins cyclin D2 and cdk2 were strongly elevated in the IkappaB-alpha
      overexpressing cell clones. These cell clones also displayed an increase in
      cyclin D1-dependent kinase activity, pointing to a cell cycle arrest at the late
      G1 phase. IkappaB-alpha overexpression crosstalked to cell cycle checkpoints via
      a reduction of transcription factor p53 and elevation of p21WAF. Surprisingly,
      the IkappaB-alpha overexpressing cells showed an enrichment of c-Myc in the
      nucleoli, although the total amount of c-Myc protein was unchanged. These
      experiments identify an important contribution of the NF-kappaB/IkappaB system
      for the growth of HeLa cells.

PMID- 10359528
TI  - Amplification and overexpression of the hepatocyte growth factor receptor
      (HGFR/MET) in rat DMBA sarcomas.
AB  - In the present study subcutaneous fibrosarcomas were induced by the carcinogen
      7,12-dimethylbenz(a)anthracene (DMBA) in rats from F1 generation cross breedings
      of two different inbred strains. Comparative genomic hybridization (CGH)
      analysis, which allows detection of DNA sequence copy changes, was applied to one
      of the tumors and it was found that there were increased copy numbers of
      sequences at chromosome 4q12-q21 in this tumor. We have previously determined
      that the loci for the hepatocyte growth factor (Hgf) and hepatocyte growth factor
      receptor (Hgfr/Met), a protooncogene, are situated in this particular chromosome
      region. Using probes for the two genes in FISH (fluorescence in situ
      hybridization) and in Southern blots we found that the Hgfr/Met gene was
      amplified in five of the 19 sarcomas studied, and that the Hgf gene was
      coamplified in two of them. Northern and Western blots and tyrosine
      phosphorylation analysis showed that the HGF receptor was overexpressed and
      functional in all five tumors, as well as in two additional tumors. In summary,
      both amplification and overexpression of the Hgfr/Met gene was found in about 25%
      of DMBA-induced experimental rat sarcomas, and HGF receptor overexpression alone
      was seen in two additional tumors. Possibly this reflects an involvement in
      paracrine or autocrine stimulation of growth and invasiveness by HGF. Our finding
      could provide a rodent model system to increased knowledge about causality and
      therapy, which may be applicable to the sizeable fraction of human
      musculoskeletal tumors displaying MET overexpression.

PMID- 10359529
TI  - A function of p21 during promyelocytic leukemia cell differentiation independent
      of CDK inhibition and cell cycle arrest.
AB  - Retinoic Acid (RA) treatment induces disease remission of Acute Promyelocytic
      Leukemias (APL) by triggering differentiation of neoplastic cells.
      Differentiation is mediated by the APL-specific transforming protein PML/RAR
      alpha and involves its activity as ligand-dependent enhancer factor on RA-target
      genes. We report here the identification of p21 as a transcriptional target of
      PML/RAR alpha during RA-induced differentiation of APL cells. We found that RA
      treated APL cells undergo two rounds of cell division before entering post
      mitotic G1, that progression through the G1-S is indispensable for
      differentiation and coincides with the duration of commitment. RA-treatment
      induced two peaks of p21 synthesis: early (from the 2nd to the 6th hour),
      dependent on PML/RAR alpha expression and associated with G1-S transition and
      high CDK activity; late (from 3rd to the 4th day), independent from PML/RAR alpha
      and associated with G1 block and low CDK activity. Increased p21 in PML/RAR alpha
      cells during G1-S had no effect on the cell cycle while an antisense p21
      prevented RA-induced differentiation without altering G1-S transition and the
      late G1 block. These results demonstrate that p21 is an effector of the activity
      of PML/RAR alpha on differentiation and suggest that p21 exerts a function in G1
      S connected to differentiation-commitment and uncoupled from cell cycle and CDK
      inhibition.

PMID- 10359530
TI  - BAG-1 accelerates cell motility of human gastric cancer cells.
AB  - BAG-1 is a Hsp70/Hsc70-binding protein that interacts with Bcl-2, Raf-1, steroid
      hormone receptors, Siah-1, and hepatocyte growth factor (HGF) receptors, implying
      multiple functions for the BAG-1 protein. Here, we provide evidence that gene
      transfer-mediated overexpression of BAG-1 markedly enhances the motility of human
      gastric cancer cells. Two independent in vitro migration assays showed that the
      BAG-1-expressing MKN74 cells exhibited more active migration compared with
      control transfectants or parent MKN74 cells. In MKN74 cells, the overexpression
      of BAG-1 affected neither cell adhesion capability nor migration responses to
      HGF. The promotive effect of BAG-1 on cell migration was similarly observed in
      transfectants of another human gastric cancer MKN45 cell line. In BAG-1
      transfected gastric cancer MKN74 cells, BAG-1 colocalized with cytokeratin as
      well as actin filaments, and was concentrated at membrane ruffles induced by
      lysophosphatidic acid (LPA). Taken together, these studies demonstrate that BAG-1
      has a novel function as promoter of cell migration in human gastric cancer cells,
      possibly through cooperation with cytoskeletal proteins.

PMID- 10359531
TI  - Expression and androgen regulation of C-CAM cell adhesion molecule isoforms in
      rat dorsal and ventral prostate.
AB  - C-CAM is an epithelial cell adhesion molecule with two major splice variants that
      differ in the length of the cytoplasmic domain. C-CAM1 (long (L)-form) strongly
      suppresses the tumorigenicity of human prostate carcinoma cells. In contrast, C
      CAM2 (short (S)-form) does not exhibit tumor-suppressive activity. In the present
      study we have investigated the functional significance of L-form and S-form C-CAM
      in rat prostate by examining their expression and distribution in different
      prostate lobes and their response to androgen deprivation. RNase protection
      assays with a probe for both C-CAM isoforms detected high levels of C-CAM
      messages in the rat dorso-lateral prostate (DLP). L- and S-form proteins,
      localized by indirect immunofluorescence using isoform-specific antipeptide
      antibodies, were co-expressed on the apical surface of prostate epithelial cells
      in normal DLP. Androgen depletion did not significantly change the steady state
      levels of C-CAM message and protein expression in the DLP, although there was a
      change in the pattern of protein expression in these lobes. In contrast, C-CAM
      isoform messages and proteins were undetectable in normal ventral prostate (VP)
      but increased markedly in this lobe in response to castration, producing isoform
      ratios similar to those in DLP. These results demonstrate that coordinate
      expression of C-CAM isoforms is maintained in the VP following androgen depletion
      and suggest that androgen suppresses C-CAM expression in VP but not in DLP. These
      results suggest that balanced expression of L- and S-form C-CAM is important for
      normal prostate growth and differentiation.

PMID- 10359532
TI  - C-CAM1 expression: differential effects on morphology, differentiation state and
      suppression of human PC-3 prostate carcinoma cells.
AB  - Studies in rat prostate and liver have suggested that C-CAM1 is involved in the
      formation and maintenance of histotypic associations in tissues and possibly
      tumors. Most recently, C-CAM1 has been shown to suppress tumorigenicity of
      prostate and colon carcinoma cells. However, the mechanisms whereby C-CAM1
      suppresses growth and the relationship of this activity to its proposed role in
      histotypic interactions remain largely unknown. In the present study, we have
      analysed the growth, phenotypic, morphological and ultrastructural
      characteristics of four human PC-3 prostate carcinoma cell lines transduced with
      C-CAM1 retrovirus. We report that three of four lines regained their tumorigenic
      phenotype in vivo while maintaining high levels of C-CAM1 expression and a growth
      retarded phenotype in vitro. These findings suggested that high levels of C-CAM1
      expression were negatively influencing recovery during reconstitution after
      freezing or during the latency period after subcutaneous injection and that loss
      of suppression resulted from changes in expression of other molecules required
      for full disclosure of C-CAM1 mediated growth inhibition. Results from Northern
      blot and immunofluorescence analyses of tumor nodules demonstrated that C-CAM1
      decreased rather than enhanced phenotypic differentiation and induced
      ultrastructural and morphological changes that occurred independently of tumor
      suppression.

PMID- 10359533
TI  - Chromosomal deletions occur in restricted regions of 5q in testicular germ cell
      cancer.
AB  - Since the biologic behavior and molecular genetic changes observed in testicular
      germ cell cancer differ from those seen in more common epithelial tumors, it is
      likely that hitherto uncharacterized genes play a role in the development of germ
      cell tumors. Our previous work on testicular germ cell cancer suggested that
      chromosome 5q might contain one or more novel tumor suppressor genes that play a
      role in this malignancy. In this study, we performed a high resolution loss of
      heterozygosity (LOH) study of testicular cancer using 37 informative markers on
      chromosome 5. We detected allelic losses in 20/48 (42%) specimens and identified
      three common sites of loss on chromosome 5q14, 5q21 and 5q34-qter, defined
      respectively by minimal regions of deletion of < or = 1 cM, 10 cM and
      approximately 20 (cM). Using an overlapping series of YACs and radiation hybrid
      mapping, we have constructed a physical map of the 5q14 deletion that should aid
      in the isolation and characterization of the putative tumor suppressor gene
      located therein.

PMID- 10359534
TI  - Methylation and silencing of the Thrombospondin-1 promoter in human cancer.
AB  - Neovascularization is a common feature of many human cancers, but relatively few
      molecular defects have been demonstrated in genes regulating angiogenesis.
      Decreased expression of Thrombospondin-1 (THBS1), a P53 and Rb regulated
      angiogenesis inhibitor, has been observed in some human tumors, including
      glioblastoma multiforme (GBM). To study whether methylation-associated
      inactivation is involved in down-regulating THBS1 expression in cancer, we
      analysed the methylation status of THBS1 in several cell lines and primary
      tumors. Three cell lines (RKO, CEM and RAJI) were completely methylated at
      several CpG sites within the THBS1 5' CpG island, and had no detectable
      expression by RT-PCR. THBS1 expression was readily reactivated using the
      methylation-inhibitor 5-deoxy-azacytidine in all three lines. Furthermore, THBS1
      methylation was present in 33% (14/42) of primary GBMs. Thus, de novo methylation
      may serve as a potential way to inactivate THBS1 expression in human neoplasms.

PMID- 10359536
TI  - The EWS/TEC fusion protein encoded by the t(9;22) chromosomal translocation in
      human chondrosarcomas is a highly potent transcriptional activator.
AB  - The EWS/TEC gene fusion generated by the t(9;22) chromosomal translocation found
      in extraskeletal myxoid chondrosarcomas encodes a fusion protein containing the
      amino-terminal domain of the EWS protein fused to the whole coding sequence of
      the orphan nuclear receptor TEC. We have compared the DNA-binding and
      transcriptional activation properties of various TEC isoforms and the
      corresponding EWS/TEC fusion proteins. Band-shift experiments show that the full
      length TEC receptor can efficiently bind the NGFI-B Response Element (NBRE),
      whereas an isoform lacking the entire carboxyl-terminal domain of the receptor
      binds much less efficiently the NBRE. Addition of the amino-terminal domain of
      EWS to either isoforms does not alter significantly their DNA-binding properties
      to the NBRE. Co-transfection experiments of COS cells and human chondrocytes
      indicate that whereas TEC moderately activates transcription from a NBRE
      containing promoter, the corresponding EWS/TEC fusion protein is a highly potent
      transcriptional activator of the same promoter, being approximately 270-fold more
      active than the native receptor. EWS/TEC may thus exert its oncogenic potential
      in chrondrosarcomas by activating the transcription of target genes involved in
      cell proliferation.

PMID- 10359535
TI  - Growth inhibition by CDK-cyclin and PCNA binding domains of p21 occurs by
      distinct mechanisms and is regulated by ubiquitin-proteasome pathway.
AB  - The CDK inhibitor, p21(WAF1/Cip1) blocks cell cycle progression. In vitro, the N
      terminus of p21 binds and inhibits CDK-cyclin kinase activity, whereas the C
      terminus binds and inhibits PCNA (proliferating cell nuclear antigen) function.
      PCNA is essential for processivity of both DNA polymerase delta and epsilon. We
      have performed a detailed analysis of growth inhibition by the N- and C-terminal
      regions of p21, and determined whether the N- and C-terminal regions mediate this
      effect by different mechanisms. Expression of either the N- or the C-terminal
      region of p21 inhibits DNA synthesis and cell growth, but not as efficiently as
      full length p21. The effectiveness of the two p21 domains is dependent on their
      stability which is determined by the ubiquitin-proteasome pathway. The
      stabilization of the N- and C-terminal region of p21 increases their
      effectiveness as inhibitors of DNA synthesis to levels comparable to full length
      p21. Inhibition of DNA synthesis by the N-terminal region of p21 involves
      suppression of E2F activity. In contrast, inhibition by the C-terminal region of
      p21 is not accompanied by suppression of E2F activity, but is mediated via PCNA
      binding. The C-terminal region of p21 therefore inhibits cell growth by a
      mechanism distinct from that of the N-terminal region containing the CDK-cyclin
      inhibitory domain.

PMID- 10359537
TI  - Taxing the cellular capacity for repair: human T-cell leukemia virus type 1, DNA
      damage, and adult T-cell leukemia.

PMID- 10359538
TI  - BRCA1 and BRCA2: a small part of the puzzle.

PMID- 10359539
TI  - Hepatitis C vaccine hampered by viral complexity, many technical restraints.

PMID- 10359540
TI  - "Look back" program initiated for hepatitis C infection.

PMID- 10359541
TI  - Researchers use radiofrequency ablation to "cook" and destroy human tumors.

PMID- 10359542
TI  - Hormonal manipulations may also reduce breast cancer risk.

PMID- 10359543
TI  - Can skin cancers be minimized or prevented in organ transplant patients?

PMID- 10359544
TI  - Colorectal cancer: molecules and populations.
AB  - The epidemiology and molecular biology of colorectal cancer are reviewed with a
      view to understanding their interrelationship. Risk factors for colorectal
      neoplasia include a positive family history, meat consumption, smoking, and
      alcohol consumption. Important inverse associations exist with vegetables,
      nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and
      physical activity. There are several molecular pathways to colorectal cancer,
      especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor;
      a transcriptional activator) pathway and the pathway involving abnormalities of
      DNA mismatch repair. These are important, both in inherited syndromes (familial
      adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer
      [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways
      exist. Expression of key genes in any of these pathways may be lost by inherited
      or acquired mutation or by hypermethylation. The roles of several of the
      environmental exposures in the molecular pathways either are established (e.g.,
      inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and
      tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a
      source of folate, antioxidants, and inducers of detoxifying enzymes). The roles
      of other factors (e.g., physical activity) remain obscure even when the
      epidemiology is quite consistent. There is also evidence that some metabolic
      pathways, e.g., those involving folate and heterocyclic amines, may be modified
      by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate
      reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some
      evidence that the general host metabolic state can provide a milieu that enhances
      or reduces the likelihood of cancer progression. Understanding the roles of
      environmental exposures and host susceptibilities in molecular pathways has
      implications for screening, treatment, surveillance, and prevention.

PMID- 10359545
TI  - Defective DNA repair in cells with human T-cell leukemia/bovine leukemia viruses:
      role of tax gene.
AB  - BACKGROUND: Human T-cell leukemia virus (HTLV)/bovine leukemia virus (BLV) group
      retroviruses, which cause hematopoietic cancers, encode a unique protein, Tax,
      involved in the transformation of infected cells. Our purpose was to determine
      whether the mechanism by which Tax protein induces transformation in HTLV- or BLV
      infected cells involves DNA damage. METHODS: We used a micronucleus assay to
      measure chromosomal damage and alkali denaturation analysis to test host-cell DNA
      integrity in cells infected with HTLV, BLV, or simian T-lymphotropic virus or in
      cells transfected with the tax gene of HTLV or BLV. Controls included uninfected
      cells and cells infected with other oncogenic retroviruses or oncogenic DNA
      viruses. We used a plasmid reactivation assay to examine whether the damage might
      be due to the inhibition of DNA repair. To ascertain which of several repair
      pathways might be inhibited, chemical methods were used to selectively introduce
      lesions repaired by specific pathways into the reporter plasmid. RESULTS: The
      presence of Tax was associated with DNA damage. HTLV- or BLV-infected or tax
      transfected cells showed normal ability to repair damage induced by
      deoxyribonuclease I or psoralen but markedly decreased ability to repair damage
      induced by UV light, quercetin, or hydrogen peroxide. CONCLUSIONS: These data
      suggest that the DNA repair pathway most inhibited by Tax is base-excision repair
      of oxidative damage. To our knowledge, this is the first report demonstrating
      inhibition of DNA repair by any retrovirus and suggests that this inhibition of
      DNA repair may contribute to the mechanism of cell transformation by the HTLV/BLV
      group of viruses.

PMID- 10359546
TI  - Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast
      cancer.
AB  - BACKGROUND: Mutations in the BRCA1 and BRCA2 genes are found in most families
      with cases of both breast and ovarian cancer or with many cases of early-onset
      breast cancer. However, in an outbred population, the prevalence of BRCA1 and
      BRCA2 mutations in patients with breast cancer who were unselected for a family
      history of this disease has not been determined. METHODS: Mutations in the BRCA1
      and BRCA2 genes were detected in blood samples from two population-based series
      of young patients with breast cancer from Britain. RESULTS: Mutations were
      detected in 15 (5.9%) of 254 women diagnosed with breast cancer before age 36
      years (nine [3.5%] in BRCA1 and six [2.4%] in BRCA2) and in 15 (4.1%) of 363
      women diagnosed from ages 36 through 45 years (seven [1.9%] in BRCA1 and eight
      [2.2%] in BRCA2). Eleven percent (six of 55) of patients with a first-degree
      relative who developed ovarian cancer or breast cancer by age 60 years were
      mutation carriers, compared with 45% (five of 11) of patients with two or more
      affected first- or second-degree relatives. The standardized incidence ratio for
      breast cancer in mothers and sisters was 365 (five observed and 1.37 expected)
      for 30 mutation carriers and 199 (64 observed and 32.13 expected) for 587
      noncarriers. If we assume recent penetrance estimates, the respective proportions
      of BRCA1 and BRCA2 mutation carriers are 3.1% and 3.0%, respectively, of patients
      with breast cancer who are younger than age 50 years, 0.49% and 0.84% of patients
      with breast cancer who are age 50 years or older, and 0.11% and 0.12% of women in
      the general population. CONCLUSIONS: Mutations in the BRCA1 and BRCA2 genes make
      approximately equal contributions to early-onset breast cancer in Britain and
      account for a small proportion of the familial risk of breast cancer.

PMID- 10359547
TI  - Physical activity, body mass index, and prostaglandin E2 levels in rectal mucosa.
AB  - BACKGROUND: Evidence suggests a relationship between prostaglandin levels in
      colonic mucosa and risk of colon cancer. Physical inactivity and a higher body
      mass index (BMI; weight in kilograms divided by [height in meters]2) have been
      consistently shown to increase risk of this cancer. We investigated whether
      higher levels of leisure-time physical activity or a lower BMI was associated
      with lower concentrations of prostaglandin E2 (PGE2) in rectal mucosa. METHODS:
      This study was conducted in 41 men and 22 women, 42-78 years of age, with a
      history of polyps, who participated in a randomized clinical trial testing the
      effects of piroxicam on rectal mucosal PGE2 levels. An [125I]PGE2
      radioimmunoassay kit was used to determine PGE2 levels in samples of extracted
      rectal mucosa collected before randomization. Leisure-time physical activity was
      assessed through a self-administered questionnaire collected at baseline. The
      reported time spent at each activity per week was multiplied by its typical
      energy expenditure, expressed in metabolic equivalents (METs), to yield a MET
      hours per week score. A repeated measures model was used to assess the effect of
      BMI and physical activity as predictors of PGE2 concentration. All statistical
      tests were two-sided. RESULTS: After adjustment for age, a higher BMI was
      associated with higher PGE2 levels (P = .001). A higher level of leisure-time
      physical activity was inversely associated with PGE2 concentration (P<.03). An
      increase in BMI from 24.2 to 28.8 kg/m2 was associated with a 27% increase in
      PGE2. An increase in activity level from 5.2 to 27.7 MET-hours per week was
      associated with a 28% decrease in PGE2. CONCLUSIONS: Physical activity and
      obesity may alter the risk of colon cancer through their effects on PGE2
      synthesis.

PMID- 10359548
TI  - Detection of human papillomavirus DNA in cytologically normal women and
      subsequent cervical squamous intraepithelial lesions.
AB  - BACKGROUND: Human papillomavirus (HPV) infection has been strongly associated
      with cervical carcinoma and its cytologic precursors, squamous intraepithelial
      lesions (SIL). We investigated the risk of SIL prospectively following polymerase
      chain reaction (PCR)-based DNA testing for a wide range of genital HPV types in a
      cohort of initially cytologically normal women, to clarify the role of HPV in the
      etiology of SIL. METHODS: Starting in April 1989, 17,654 women who were receiving
      routine cytologic screening at Kaiser Permanente (Portland, OR) were followed for
      the development of incident SIL. During follow-up, 380 incident case patients and
      1037 matched control subjects were eligible for this nested case-control study.
      Cervical lavages collected at enrollment and, later, at the time of case
      diagnosis (or the corresponding time for selection of control subjects) were
      tested for HPV DNA using a PCR-based method. The data were analyzed as
      contingency tables with two-sided P values or, for multivariable analyses, using
      odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: In comparison
      with initially HPV-negative women, women who tested positive for HPV DNA at
      enrollment were 3.8 times (95% CI = 2.6-5.5) more likely to have low-grade SIL
      subsequently diagnosed for the first time during follow-up and 12.7 times more
      likely (95% CI = 6.2-25.9) to develop high-grade SIL. At the time of diagnosis,
      the cross-sectional association of HPV DNA and SIL was extremely strong (OR =
      44.4 and 95% CI = 24.2-81.5 for low-grade SIL and OR = 67.1 and 95% CI = 19.3
      233.7 for high-grade SIL). HPV16 was the virus type most predictive of SIL, even
      low-grade SIL. CONCLUSIONS: These findings are consistent with the hypothesis
      that HPV infection is the primary cause of cervical neoplasia. Furthermore, they
      support HPV vaccine research to prevent cervical cancer and efforts to develop
      HPV DNA diagnostic tests.

PMID- 10359549
TI  - Androgen receptor exon 1 CAG repeat length and breast cancer in women before age
      forty years.
AB  - BACKGROUND: We conducted a population-based, case-control-family study to
      determine whether androgen receptor (AR) exon 1 polymorphic CAG repeat length
      (CAGn) was a risk factor for early-onset breast cancer in the Australian
      population. METHODS: Case subjects under 40 years of age at diagnosis of a first
      primary breast cancer and age-matched control subjects were interviewed to assess
      family history and other risk factors. AR CAGn length was determined for 368 case
      subjects and 284 control subjects. Distributions in the two groups were compared
      by linear and logistic regression, allowing adjustment for measured risk factors.
      All statistical tests were two-tailed. RESULTS: When analyzed as either a
      continuous or a dichotomous variable, there was no association between CAG,
      length and breast cancer risk, before or after adjustment for risk factors. Mean
      (95% confidence interval [CI]) CAGn lengths were 22.0 (21.8-22.2) for case
      subjects and 22.0 (21.7-22.3) for control subjects (P = .9). The frequency (95%
      CI) of alleles with 22 or more CAGn repeats was 0.531 (0.494-0.568) for case
      subjects and 0.507 (0.465-0.549) for control subjects (P = .4). After adjustment,
      the average effect on log OR (odds ratio) per allele was 0.16 (95% CI = -0.03 to
      0.40; P = .2), and the effect of any allele was equivalent to an OR of 1.40 (95%
      CI = 0.94-2.09; P = .1). Stratification by family history also failed to reveal
      any association. Similar results were obtained when alleles were defined by other
      cutoff points. CONCLUSION: We found no evidence for an association between AR
      exon 1 CAGn length and breast cancer risk in women under the age of 40, despite
      having 80% power to detect modest effects.

PMID- 10359550
TI  - Chemical carcinogen-induced tumorigenesis in parous, involuted mouse mammary
      glands.

PMID- 10359551
TI  - Re: Effects of the antiestrogens tamoxifen, toremifene, and ICI 182,780 on
      endometrial cancer growth.

PMID- 10359552
TI  - Re: Trends in reported incidence of primary malignant brain tumors in children in
      the United States.

PMID- 10359553
TI  - A novel fusion gene, SYT-SSX4, in synovial sarcoma.

PMID- 10359554
TI  - The differential risk of oral contraceptives: the impact of full exposure
      history.
AB  - Previous discussions have indicated that the small increases of risk of venous
      thromboembolism (VTE) associated with newer combined oral contraceptives (third
      generation, containing desogestrel and gestodene) may be attributed to bias due
      to cohort effects. In a case-control analysis, this may produce an overestimate
      of risk of newer preparations. In 10 centres in Germany and the UK, the
      Transnational Study analysed data from 502 women aged 16-44 years with VTE, and
      from 1864 controls matched for 5-year age group and region. Information on
      lifetime exposure history from all subjects was added to the dataset used in
      previous analyses and entered into a Cox regression model with time-dependent
      covariates. Based on 17 622 continuous exposure episodes comprising 47 914 person
      years of observation, the adjusted hazard ratio (equivalent to odds ratio, OR) of
      VTE for the comparison of current users of third-generation versus current users
      of second-generation (primarily levonorgestrel compounds) combined oral
      contraceptives was 0.8 (0.5 to 1.3). The OR obtained in standard case-control
      analysis had been 1.5 (1.1 to 2.1). Adjustment for past exposures includes more
      information and appears more valid than the standard cross-sectional analysis.
      Using this approach, the Transnational Study data show no evidence for an
      increased risk of VTE with third- compared with second-generation combined oral
      contraceptives.

PMID- 10359556
TI  - Complexity in simplicity: monogenic disorders and complex cardiomyopathies.

PMID- 10359555
TI  - Not a mouse stirring: deletion of the EP2 and love's labor's lost.

PMID- 10359557
TI  - At last, direct evidence that lipoxygenases play a role in atherogenesis.

PMID- 10359559
TI  - A novel role for cardiac neural crest in heart development.
AB  - Ablation of premigratory cardiac neural crest results in defective development of
      the cardiac outflow tract. The purpose of the present study was to correlate the
      earliest functional and morphological changes in heart development after cardiac
      neural crest ablation. Within 24 hours after neural crest ablation, the external
      morphology of the hearts showed straight outflow limbs, tighter heart loops, and
      variable dilations. Incorporation of bromodeoxyuridine in myocytes, an indication
      of proliferation, was doubled after cardiac neural crest ablation. The myocardial
      calcium transients, which are a measure of excitation-contraction coupling, were
      depressed by 50% in both the inflow and outflow portions of the looped heart
      tube. The myocardial transients could be rescued by replacing the cardiac neural
      crest. The cardiac jelly produced by the myocardium was distributed in an uneven,
      rather than uniform, pattern. An extreme variability in external morphology could
      be attributed to the uneven distribution of cardiac jelly. In the absence of
      cardiac neural crest, the myocardium was characterized by somewhat disorganized
      myofibrils that may be a result of abnormally elevated proliferation. In
      contrast, endocardial development appeared normal, as evidenced by normal
      expression of fibrillin-2 protein (JB3 antigen) and normal formation of cushion
      mesenchyme and trabeculae. The signs of abnormal myocardial development
      coincident with normal endocardium suggest that the presence of cardiac neural
      crest cells is necessary for normal differentiation and function of the
      myocardium during early heart development. These results indicate a novel role
      for neural crest cells in myocardial maturation.

PMID- 10359558
TI  - Peroxisome proliferator-activated receptor alpha mediates the adaptive response
      to fasting.
AB  - Prolonged deprivation of food induces dramatic changes in mammalian metabolism,
      including the release of large amounts of fatty acids from the adipose tissue,
      followed by their oxidation in the liver. The nuclear receptor known as
      peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a
      role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting
      that PPARalpha may be involved in the transcriptional response to fasting. To
      investigate this possibility, PPARalpha-null mice were subjected to a high fat
      diet or to fasting, and their responses were compared with those of wild-type
      mice. PPARalpha-null mice chronically fed a high fat diet showed a massive
      accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha
      null mice fasted for 24 hours, who also displayed severe hypoglycemia,
      hypoketonemia, hypothermia, and elevated plasma free fatty acid levels,
      indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown
      that to accommodate the increased requirement for hepatic fatty acid oxidation,
      PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate
      that PPARalpha plays a pivotal role in the management of energy stores during
      fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid
      oxidation to supply substrates that can be metabolized by other tissues.

PMID- 10359560
TI  - Pulmonary prostacyclin synthase overexpression in transgenic mice protects
      against development of hypoxic pulmonary hypertension.
AB  - Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic
      pathway leading to prostacyclin (PGI2) production. Patients with severe pulmonary
      hypertension have a PGIS deficiency of their precapillary vessels, but the
      importance of this deficiency for lung vascular remodeling remains unclear. We
      hypothesized that selective pulmonary overexpression of PGIS may prevent the
      development of pulmonary hypertension. To study this hypothesis, transgenic mice
      were created with selective pulmonary PGIS overexpression using a construct of
      the 3.7-kb human surfactant protein-C (SP-C) promoter and the rat PGIS cDNA.
      Transgenic mice (Tg+) and nontransgenic littermates (Tg-) were subjected to a
      simulated altitude of 17,000 ft for 5 weeks, and right ventricular systolic
      pressure (RVSP) was measured. Histology was performed on the lungs. The Tg+ mice
      produced 2-fold more pulmonary 6-keto prostaglandin F1alpha (PGF1alpha) levels
      than did Tg- mice. After exposure to chronic hypobaric hypoxia, Tg+ mice have
      lower RVSP than do Tg- mice. Histologic examination of the lungs revealed nearly
      normal arteriolar vessels in the Tg+ mice in comparison with vessel wall
      hypertrophy in the Tg- mice. These studies demonstrate that Tg+ mice were
      protected from the development of pulmonary hypertension after exposure to
      chronic hypobaric hypoxia. We conclude that PGIS plays a major role in modifying
      the pulmonary vascular response to chronic hypoxia. This has important
      implications for the pathogenesis and treatment of severe pulmonary hypertension.

PMID- 10359561
TI  - Oligospermic infertility associated with an androgen receptor mutation that
      disrupts interdomain and coactivator (TIF2) interactions.
AB  - Structural changes in the androgen receptor (AR) are one of the causes of
      defective spermatogenesis. We screened the AR gene of 173 infertile men with
      impaired spermatogenesis and identified 3 of them, unrelated, who each had a
      single adenine-->guanine transition that changed codon 886 in exon 8 from
      methionine to valine. This mutation was significantly associated with the
      severely oligospermic phenotype and was not detected in 400 control AR alleles.
      Despite the location of this substitution in the ligand-binding domain (LBD) of
      the AR, neither the genital skin fibroblasts of the subjects nor transfected cell
      types expressing the mutant receptor had any androgen-binding abnormality.
      However, the mutant receptor had a consistently (approximately 50%) reduced
      capacity to transactivate each of 2 different androgen-inducible reporter genes
      in 3 different cell lines. Deficient transactivation correlated with reduced
      binding of mutant AR complexes to androgen response elements. Coexpression of AR
      domain fragments in mammalian and yeast two-hybrid studies suggests that the
      mutation disrupts interactions of the LBD with another LBD, with the NH2-terminal
      transactivation domain, and with the transcriptional intermediary factor TIF2.
      These data suggest that a functional element centered around M886 has a role, not
      for ligand binding, but for interdomain and coactivator interactions culminating
      in the formation of a normal transcription complex.

PMID- 10359562
TI  - Mild spherocytosis and altered red cell ion transport in protein 4. 2-null mice.
AB  - Protein 4.2 is a major component of the red blood cell (RBC) membrane skeleton.
      We used targeted mutagenesis in embryonic stem (ES) cells to elucidate protein
      4.2 functions in vivo. Protein 4. 2-null (4.2(-/-)) mice have mild hereditary
      spherocytosis (HS). Scanning electron microscopy and ektacytometry confirm loss
      of membrane surface in 4.2(-/-) RBCs. The membrane skeleton architecture is
      intact, and the spectrin and ankyrin content of 4. 2(-/-) RBCs are normal. Band 3
      and band 3-mediated anion transport are decreased. Protein 4.2(-/-) RBCs show
      altered cation content (increased K+/decreased Na+)resulting in dehydration. The
      passive Na+ permeability and the activities of the Na-K-2Cl and K-Cl
      cotransporters, the Na/H exchanger, and the Gardos channel in 4. 2(-/-) RBCs are
      significantly increased. Protein 4.2(-/-) RBCs demonstrate an abnormal regulation
      of cation transport by cell volume. Cell shrinkage induces a greater activation
      of Na/H exchange and Na-K-2Cl cotransport in 4.2(-/-) RBCs compared with
      controls. The increased passive Na+ permeability of 4.2(-/-) RBCs is also
      dependent on cell shrinkage. We conclude that protein 4.2 is important in the
      maintenance of normal surface area in RBCs and for normal RBC cation transport.

PMID- 10359563
TI  - Reproductive failure and reduced blood pressure in mice lacking the EP2
      prostaglandin E2 receptor.
AB  - Prostaglandins (PGs) are bioactive lipids that modulate a broad spectrum of
      biologic processes including reproduction and circulatory homeostasis. Although
      reproductive functions of mammals are influenced by PGs at numerous levels,
      including ovulation, fertilization, implantation, and decidualization, it is not
      clear which PGs are involved and whether a single mechanism affects all
      reproductive functions. Using mice deficient in 1 of 4 prostaglandin E2 (PGE2)
      receptors -- specifically, the EP2 receptor -- we show that Ep2(-/-) females are
      infertile secondary to failure of the released ovum to become fertilized in vivo.
      Ep2(-/-) ova could be fertilized in vitro, suggesting that in addition to
      previously defined roles, PGs may contribute to the microenvironment in which
      fertilization takes place. In addition to its effects on reproduction, PGE2
      regulates regional blood flow in various vascular beds. However, its role in
      systemic blood pressure homeostasis is not clear. Mice deficient in the EP2 PGE2
      receptor displayed resting systolic blood pressure that was significantly lower
      than in wild-type controls. Blood pressure increased in these animals when they
      were placed on a high-salt diet, suggesting that the EP2 receptor may be involved
      in sodium handling by the kidney. These studies demonstrate that PGE2, acting
      through the EP2 receptor, exerts potent regulatory effects on two major
      physiologic processes: blood pressure homeostasis and in vivo fertilization of
      the ovum.

PMID- 10359564
TI  - Myeloperoxidase-generated reactive nitrogen species convert LDL into an
      atherogenic form in vitro.
AB  - Oxidized LDL is implicated in atherosclerosis; however, the pathways that convert
      LDL into an atherogenic form in vivo are not established. Production of reactive
      nitrogen species may be one important pathway, since LDL recovered from human
      atherosclerotic aorta is enriched in nitrotyrosine. We now report that reactive
      nitrogen species generated by the MPO-H2O2-NO2- system of monocytes convert LDL
      into a form (NO2-LDL) that is avidly taken up and degraded by macrophages,
      leading to massive cholesterol deposition and foam cell formation, essential
      steps in lesion development. Incubation of LDL with isolated MPO, an H2O2
      generating system, and nitrite (NO2-)-- a major end-product of NO metabolism-
      resulted in nitration of apolipoprotein B 100 tyrosyl residues and initiation of
      LDL lipid peroxidation. The time course of LDL protein nitration and lipid
      peroxidation paralleled the acquisition of high-affinity, concentration
      dependent, and saturable binding of NO2-LDL to human monocyte-derived macrophages
      and mouse peritoneal macrophages. LDL modification and conversion into a high
      uptake form occurred in the absence of free metal ions, required NO2-, occurred
      at physiological levels of Cl-, and was inhibited by heme poisons, catalase, and
      BHT. Macrophage binding of NO2-LDL was specific and mediated by neither the LDL
      receptor nor the scavenger receptor class A type I. Exposure of macrophages to
      NO2-LDL promoted cholesteryl ester synthesis, intracellular cholesterol and
      cholesteryl ester accumulation, and foam cell formation. Collectively, these
      results identify MPO-generated reactive nitrogen species as a physiologically
      plausible pathway for converting LDL into an atherogenic form.

PMID- 10359565
TI  - The IL-1 receptor and Rho directly associate to drive cell activation in
      inflammation.
AB  - IL-1-stimulated mesenchymal cells model molecular mechanisms of inflammation.
      Binding of IL-1 to the type I IL-1 receptor (IL-1R) clusters a multi-subunit
      signaling complex at focal adhesion complexes. Since Rho family GTPases
      coordinately organize actin cytoskeleton and signaling to regulate cell
      phenotype, we hypothesized that the IL-1R signaling complex contained these G
      proteins. IL-1 stimulated actin stress fiber formation in serum-starved HeLa
      cells in a Rho-dependent manner and rapidly activated nucleotide exchange on
      RhoA. Glutathione S-transferase (GST) fusion proteins, containing either the full
      length IL-1R cytosolic domain (GST-IL-1Rcd) or the terminal 68 amino acids of IL
      1R required for IL-1-dependent signal transduction, specifically coprecipitated
      both RhoA and Rac-1, but not p21(ras), from Triton-soluble HeLa cell extracts. In
      whole cells, a small-molecular-weight G protein coimmunoprecipitated by anti-IL
      1R antibody was a substrate for C3 transferase, which specifically ADP
      ribosylates Rho GTPases. Constitutively activated RhoA, loaded with [gamma
      32P]GTP, directly interacted with GST-IL-1Rcd in a filter-binding assay. The IL
      1Rcd-RhoA interaction was functionally important, since a dominant inhibitory
      mutant of RhoA prevented IL-1Rcd-directed transcriptional activation of the IL-6
      gene. Consistent with our previous data demonstrating that IL-1R-associated
      myelin basic protein (MBP) kinases are necessary for IL-1-directed gene
      expression, cellular incorporation of C3 transferase inhibited IL-1R-associated
      MBP kinase activity both in solution and in gel kinase assays. In summary, IL-1
      activated RhoA, which was physically associated with IL-1Rcd and necessary for
      activation of cytosolic nuclear signaling pathways. These findings suggest that
      IL-1-stimulated, Rho-dependent cytoskeletal reorganization may cluster signaling
      molecules in specific architectures that are necessary for persistent cell
      activation in chronic inflammatory disease.

PMID- 10359566
TI  - The immunoglobulin-like modules Cepsilon3 and alpha2 are the minimal units
      necessary for human IgE-FcepsilonRI interaction.
AB  - Atopic allergy is a genetically determined immunodisorder that affects almost 20%
      of the population worldwide. Immediate symptoms of type I allergy are caused by
      the release of biologic mediators from effector cells induced by IgE-allergen
      complexes that cross-link the high-affinity receptor for IgE (FcepsilonRI).
      Chronic disease manifestations result from allergen-specific T-cell activation, a
      process that is enhanced when allergens are presented via FcepsilonRI-bound IgE.
      We report the baculovirus expression, as soluble recombinant proteins, of the
      minimal units required for human IgE and FcepsilonRI interaction: Cepsilon3
      represents the third constant domain of the IgE heavy chain, and alpha2 is the
      membrane-proximal Ig-like module from FcepsilonRIalpha. Native overlay
      experiments showed binding of human FcepsilonRIalpha to recombinant Cepsilon3 and
      of natural or recombinant human IgE to recombinant alpha2. Moreover, recombinant
      Cepsilon3 inhibited binding of natural IgE antibodies to alpha2, and
      preincubation of human IgE with alpha2 inhibited anti-IgE-triggered histamine
      release from human basophils. Isolated Cepsilon3 and alpha2 can now be used for
      the molecular and structural analysis of the IgE-FcepsilonRI interaction, as well
      as for diagnostic and therapeutic applications.

PMID- 10359567
TI  - Apo E structure determines VLDL clearance and atherosclerosis risk in mice.
AB  - We have generated mice expressing the human apo E4 isoform in place of the
      endogenous murine apo E protein and have compared them with mice expressing the
      human apo E3 isoform. Plasma lipid and apolipoprotein levels in the mice
      expressing only the apo E4 isoform (4/4) did not differ significantly from those
      in mice with the apo E3 isoform (3/3) on chow and were equally elevated in
      response to increased lipid and cholesterol in their diet. However, on all diets
      tested, the 4/4 mice had approximately twice the amount of cholesterol, apo E,
      and apo B-48 in their VLDL as did 3/3 mice. The 4/4 VLDL competed with human LDL
      for binding to the human LDL receptor slightly better than 3/3 VLDL, but the VLDL
      clearance rate in 4/4 mice was half that in 3/3 mice. On an atherogenic diet,
      there was a trend toward greater atherosclerotic plaque size in 4/4 mice compared
      with 3/3 mice. These data, together with our earlier observations in wild-type
      and human APOE*2-replacement mice, demonstrate a direct and highly significant
      correlation between VLDL clearance rate and mean atherosclerotic plaque size.
      Therefore, differences solely in apo E protein structure are sufficient to cause
      alterations in VLDL residence time and atherosclerosis risk in mice.

PMID- 10359568
TI  - Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8.
AB  - Keratins K8 and K18 are the major components of the intermediate-filament
      cytoskeleton of simple epithelia. Increased levels of these keratins have been
      correlated with various tumor cell characteristics, including progression to
      malignancy, invasive behavior, and drug sensitivity, although a role for K8/K18
      in tumorigenesis has not yet been demonstrated. To examine the function of these
      keratins, we generated mice expressing the human K8 (hk8) gene, which leads to a
      moderate keratin-content increase in their simple epithelia. These mice displayed
      progressive exocrine pancreas alterations, including dysplasia and loss of acinar
      architecture, redifferentiation of acinar to ductal cells, inflammation,
      fibrosis, and substitution of exocrine by adipose tissue, as well as increased
      cell proliferation and apoptosis. Histological changes were not observed in other
      simple epithelia, such as the liver. Electron microscopy showed that transgenic
      acinar cells have keratins organized in abundant filament bundles dispersed
      throughout the cytoplasm, in contrast to control acinar cells, which have scarce
      and apically concentrated filaments. The phenotype found was very similar to that
      reported for transgenic mice expressing a dominant-negative mutant TGF-beta type
      II receptor (TGFbetaRII mice). We show that these TGFbetaRII mutant mice also
      have elevated K8/K18 levels. These results indicate that simple epithelial
      keratins play a relevant role in the regulation of exocrine pancreas homeostasis
      and support the idea that disruption of mechanisms that normally regulate keratin
      expression in vivo could be related to inflammatory and neoplastic pancreatic
      disorders.

PMID- 10359569
TI  - Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E
      deficient mice.
AB  - Atherosclerosis may be viewed as an inflammatory disease process that includes
      early oxidative modification of LDLs, leading to foam cell formation. This
      "oxidation hypothesis" has gained general acceptance in recent years, and
      evidence for the role of lipoxygenases in initiation of, or participation in, the
      oxidative process is accumulating. However, the relative contribution of
      macrophage-expressed lipoxygenases to atherogenesis in vivo remains unknown.
      Here, we provide in vivo evidence for the role of 12/15-lipoxygenase in
      atherogenesis and demonstrate diminished plasma IgG autoantibodies to oxidized
      LDL epitopes in 12/15-lipoxygenase knockout mice crossbred with atherosclerosis
      prone apo E-deficient mice (apo E-/-/L-12LO-/-). In chow-fed 15-week-old apo E-/
      /L-12LO-/- mice, the extent of lesions in whole-aorta en face preparations (198
      +/- 60 microm2) was strongly reduced (P < 0.001, n = 12) when compared with 12/15
      lipoxygenase-expressing controls (apo E-/-/L-12LO+/+), which showed areas of
      lipid deposition (15,700 +/- 2,688 microm2) in the lesser curvature of the aortic
      arch, branch points, and in the abdominal aorta. These results were observed
      despite cholesterol, triglyceride, and lipoprotein levels that were similar to
      those in apo E-deficient mice. Evidence for reduced lesion development was
      observed even at 1 year of age in apo E-/-/L-12LO-/- mice. The combined data
      indicate a role for 12/15-lipoxygenase in the pathogenesis of atherosclerosis and
      suggest that inhibition of this enzyme may decrease disease progression.

PMID- 10359570
TI  - Annexin II increases osteoclast formation by stimulating the proliferation of
      osteoclast precursors in human marrow cultures.
AB  - Annexin II (AXII), a calcium-dependent phospholipid-binding protein, has been
      recently found to be an osteoclast (OCL) stimulatory factor that is also secreted
      by OCLs. In vitro studies showed that AXII induced OCL formation and bone
      resorption. However, the mechanism of action by which AXII acts as a soluble
      extracellular protein to induce OCL formation is unknown. In this paper, we
      demonstrate that AXII gene expression is upregulated by 1,25-dihydroxyvitamin D3
      [1, 25-(OH)2D3] and that addition of AXII significantly increased OCL-like
      multinucleated cell formation. Time-course studies suggested that AXII acted on
      the proliferative stage of OCL precursors and that AXII increased thymidine
      incorporation in OCL precursors. Moreover, AXII enhanced the growth of CFU-GM,
      the earliest identifiable OCL precursor, when bone marrow cultures were treated
      with low concentrations of GM-CSF. This capacity of AXII to induce OCL precursor
      proliferation was due to induction of GM-CSF expression, because the addition of
      neutralizing antibodies to GM-CSF blocked the stimulatory effect of AXII on OCL
      formation. RT-PCR analysis using RNA from highly purified subpopulations of
      marrow cells demonstrated that T cells, especially CD4(+) T cells, produced GM
      CSF in response to AXII. Furthermore, FACS(R) analysis of T-cell subpopulations
      treated with fluorescein-labeled AXII suggested that the CD4(+), but not CD8(+),
      subpopulation of T cells express an AXII receptor. Taken together, these data
      suggest that AXII stimulates OCL formation by activating T cells through a
      putative receptor to secrete GM-CSF. GM-CSF then expands the OCL precursor pool
      to enhance OCL formation.

PMID- 10359571
TI  - Early induction of cyclin D2 expression in phorbol ester-responsive B-1
      lymphocytes.
AB  - B-1 lymphocytes represent a distinct B cell subset with characteristic features
      that include self-renewing capacity and unusual mitogenic responses. B-1 cells
      differ from conventional B cells in terms of the consequences of phorbol ester
      treatment: B-1 cells rapidly enter S phase in response to phorbol ester alone,
      whereas B-2 cells require a calcium ionophore in addition to phorbol ester to
      trigger cell cycle progression. To address the mechanism underlying the varied
      proliferative responses of B-1 and B-2 cells, we evaluated the expression and
      activity of the G1 cell cycle regulator, cyclin D2, and its associated cyclin
      dependent kinases (Cdks). Cyclin D2 expression was upregulated rapidly, within 2
      4 h, in phorbol ester-stimulated B-1 cells, in a manner dependent on intact
      transcription/translation, but was not increased in phorbol ester- stimulated B-2
      cells. Phorbol ester-stimulated cyclin D2 expression was accompanied by the
      formation of cyclin D2-Cdk4, and, to a lesser extent, cyclin D2-Cdk6, complexes;
      cyclin D2- containing complexes were found to be catalytically functional, in
      terms of their ability to phosphorylate exogenous Rb in vitro and to specifically
      phosphorylate endogenous Rb on serine780 in vivo. These results strongly suggest
      that the rapid induction of cyclin D2 by a normally nonmitogenic phorbol ester
      stimulus is responsible for B-1 cell progression through G1 phase. The ease and
      rapidity with which cyclin D2 responds in B-1 cells may contribute to the
      proliferative features of this subset.

PMID- 10359572
TI  - bcl-x prevents apoptotic cell death of both primitive and definitive erythrocytes
      at the end of maturation.
AB  - bcl-x is a member of the bcl-2 gene family, which regulates apoptotic cell death
      in various cell lineages. There is circumstantial evidence suggesting that bcl-x
      might play a role in the apoptosis of erythroid lineage cells, although there is
      no direct evidence. In this study, we used Bcl-X null mouse embryonic stem (ES)
      cells, and showed that Bcl-X is indispensable for the production of both
      embryonic primitive erythrocytes (EryP) and adult definitive erythrocytes (EryD)
      at the end of their maturation. In vivo, bcl-x-/- ES cells did not contribute to
      circulating EryD in adult chimeric mice that were produced by blastocyst
      microinjection of the bcl-x-/- ES cells. bcl-x-/- EryP and EryD were produced by
      in vitro differentiation induction of ES cells on macrophage colony-stimulating
      factor-deficient stromal cell line OP9, and further analysis was carried out. The
      emergence of immature EryP and EryD from bcl-x-/- ES cells was similar to that
      from bcl-x+/+ ES cells. However, prominent cell death of bcl-x-/- EryP and EryD
      occurred when the cells matured. The data show that the antiapoptotic function of
      bcl-x acts at the very end of erythroid maturation.

PMID- 10359573
TI  - Exercise provides direct biphasic cardioprotection via manganese superoxide
      dismutase activation.
AB  - Epidemiologic investigations have shown that exercise reduces morbidity and
      mortality from coronary artery disease. In this study, using a rat model, we
      attempted to determine whether exercise can reduce ischemic injury to the heart
      and elucidate a mechanism for the cardioprotective effect of exercise. Results
      showed that exercise significantly reduced the magnitude of a myocardial
      infarction in biphasic manner. The time course for cardioprotection resembled
      that of the change in manganese superoxide dismutase (Mn-SOD) activity. The
      administration of the antisense oligodeoxyribonucleotide to Mn-SOD abolished the
      expected decrease in infarct size. We showed that the level of tumor necrosis
      factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) increased after
      exercise. The simultaneous administration of the neutralizing antibodies to the
      cytokines abolished the exercise-induced cardioprotection and the activation of
      Mn-SOD. Furthermore, TNF-alpha can mimic the biphasic pattern of cardioprotection
      and activation of Mn-SOD. An antioxidant completely abolished cardioprotection
      and the activation of Mn-SOD by exercise or the injection of TNF-alpha as well as
      exercise-induced increase in TNF-alpha and IL-1beta. The production of reactive
      oxygen species and endogenous TNF-alpha and IL-1beta induced by exercise leads to
      the activation of Mn-SOD, which plays major roles in the acquisition of biphasic
      cardioprotection against ischemia/reperfusion injury in rats.

PMID- 10359574
TI  - Identification of Grb2 as a novel binding partner of tumor necrosis factor (TNF)
      receptor I.
AB  - Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine. Its
      pleiotropic biological properties are signaled through two distinct cell surface
      receptors: the TNF receptor type I (TNFR-I) and the TNF receptor type II. Neither
      of the two receptors possesses tyrosine kinase activity. A large majority of TNF
      alpha-dependent activities can be mediated by TNFR-I. Recently, c-Raf-1 kinase
      was identified as an intracellular target of a signal transduction cascade
      initiated by binding of TNF-alpha to TNFR-I. However, the mechanism engaged in
      TNF-alpha-dependent activation of c-Raf-1 kinase is still enigmatic. Here we
      report that the cytosolic adapter protein Grb2 is a novel binding partner of TNFR
      I. Grb2 binds with its COOH-terminal SH3 domain to a PLAP motif within TNFR-I and
      with its NH2-terminal SH3 domain to SOS (son of sevenless). A PLAP deletion
      mutant of TNFR-I fails to bind Grb2. The TNFR-I/Grb2 interaction is essential for
      the TNF-alpha-dependent activation of c-Raf-1 kinase; activation of c-Raf-1
      kinase by TNF-alpha can be blocked by coexpression of Grb2 mutants harboring
      inactivating point mutations in the NH2- or COOH-terminal SH3 domain, cell
      permeable peptides that disrupt the Grb2/TNFR-I interaction or transdominant
      negative Ras. Functionality of the TNFR-I/Grb2/SOS/Ras interaction is a
      prerequisite but not sufficient for TNF-alpha-dependent activation of c-Raf-1
      kinase. Inhibition of the TNFR-I/FAN (factor associated with neutral
      sphingomyelinase) interaction, which is essential for TNF-alpha-dependent
      activation of the neutral sphingomyelinase, either by cell-permeable peptides or
      by deletion of the FAN binding domain, prevents activation of c-Raf-1 kinase. In
      conclusion, binding of the Grb2 adapter protein via its COOH-terminal SH3 domain
      to the nontyrosine kinase receptor TNFR-I results in activation of a signaling
      cascade known so far to be initiated, in the case of the tyrosine kinase
      receptors, by binding of the SH2 domain of Grb2 to phosphotyrosine.

PMID- 10359575
TI  - Immunoglobulin-binding sites of human FcalphaRI (CD89) and bovine Fcgamma2R are
      located in their membrane-distal extracellular domains.
AB  - To localize the immunoglobulin (Ig)-binding regions of the human Fcalpha receptor
      (FcalphaRI, CD89) and the bovine Fcgamma2 receptor (bFcgamma2R), chimeric
      receptors were generated by exchanging comparable regions between these two
      proteins. FcalphaRI and bFcgamma2R are highly homologous and are more closely
      related to each other than to other human and bovine FcRs. Nevertheless, they are
      functionally distinct in that FcalphaRI binds human IgA (hIgA) but not bovine
      IgG2 (bIgG2), whereas bFcgamma2R binds bIgG2 but not hIgA. FcalphaRI and
      bFcgamma2R possess extracellular regions consisting of two Ig-like domains, a
      membrane-distal extracellular domain (EC1), a membrane-proximal EC domain (EC2),
      a transmembrane region, and a short cytoplasmic tail. Chimeras constructed by
      exchanging complete domains between these two receptors were transfected to COS-1
      cells and assayed for their ability to bind hIgA- or bIgG2-coated beads. The
      results showed that the Ig-binding site of both FcalphaRI and bFcgamma2R is
      located within EC1. Supporting this observation, monoclonal antibodies that
      blocked IgA binding to FcalphaRI were found to recognize epitopes located in this
      domain. In terms of FcR-Ig interactions characterized thus far, this location is
      unique and surprising because it has been shown previously that leukocyte
      FcgammaRs and FcepsilonRI bind Ig via sites principally located in their EC2
      domains.

PMID- 10359576
TI  - pH-dependent peptide binding properties of the type I diabetes-associated I-Ag7
      molecule: rapid release of CLIP at an endosomal pH.
AB  - MHC class II molecules and invariant chain assemble at a neutral pH in the
      endoplasmic reticulum and are transported to a low pH compartment where the
      invariant chain is trimmed to the class II-associated invariant chain peptide
      (CLIP). For many major histocompatibility complex class II molecules, DM is
      required for rapid removal of CLIP, which allows binding of antigenic peptides.
      Since I-Ag7 confers susceptibility to type I diabetes in NOD mice, the
      biochemical requirements for peptide loading were examined using soluble I-Ag7
      expressed in insect cells. I-Ag7 formed long-lived complexes with naturally
      processed peptides from transferrin and albumin, whereas several peptides that
      represent T cell epitopes of islet autoantigens were poor binders. I-Ag7-peptide
      complexes were not sodium dodecyl sulfate (SDS) resistant, indicating that SDS
      sensitivity may be an intrinsic property of I-Ag7. Complexes of I-Ag7 and CLIP
      formed at a neutral pH, but rapidly dissociated at pH 5. This rapid dissociation
      was due to a poor fit of M98 of CLIP in the P9 pocket of I-Ag7, since
      substitution of M98 by a negatively charged residue greatly enhanced the
      stability of the complex. These biochemical properties of I-Ag7 result in the
      rapid generation of empty molecules at an endosomal pH and have a global effect
      on peptide binding by I-Ag7.

PMID- 10359577
TI  - Cytokine signals are sufficient for HIV-1 infection of resting human T
      lymphocytes.
AB  - Lentiviral vectors have been advocated to be effective vehicles for the delivery
      and stable expression of genes in nondividing primary cells. However, certain
      cell types, such as resting T lymphocytes, are resistant to infection with HIV-1.
      Establishing parameters for stable gene delivery into primary human lymphocytes
      and approaches to overcome the resistance of resting T cells to HIV infection may
      permit potential gene therapy applications, genetic studies of primary cells in
      vitro, and a better understanding of the stages of the lentiviral life cycle.
      Here we demonstrate that an HIV-1-derived vector can be used for stable delivery
      of genes into activated human T cells as well as natural killer and dendritic
      cells. Remarkably, a sizeable fraction of resting T cells was stably transduced
      with the HIV-1 vector when cultured with the cytokine interleukin (IL)-2, IL-4,
      IL-7, or IL-15, or, at a lower level, with IL-6, in the absence of any other
      stimuli. Resting T cells stimulated with these cytokines could also be infected
      with replication-competent HIV-1. To test the utility of this system for
      performing structure-function analysis in primary T cells, we introduced wild
      type as well as a mutant form of murine CD28 into human T cells and showed a
      requirement for the CD28 cytoplasmic domain in costimulatory signaling. The
      ability to stably express genes of interest in primary T cells will be a valuable
      tool for genetic and structure-function studies that previously have been limited
      to transformed cell lines. In addition, the finding that cytokine signals are
      sufficient to permit transduction of resting T cells with HIV may be relevant for
      understanding mechanism of HIV-1 transmission and pathogenesis.

PMID- 10359579
TI  - Modification of cysteine residues in vitro and in vivo affects the immunogenicity
      and antigenicity of major histocompatibility complex class I-restricted viral
      determinants.
AB  - In studying the subdominant status of two cysteine-containing influenza virus
      nuclear protein (NP) determinants (NP39-47 and NP218-226) restricted by H-2Kd, we
      found that the antigenicity of synthetic peptides was enhanced 10-100-fold by
      treatment with reducing agents, despite the fact that the affinity for Kd was not
      enhanced. Reducing agents also markedly enhanced the immunogenicity of cysteine
      containing peptides, as measured by propagation of long-term T cell lines in
      vitro. Similar enhancing effects were obtained by substituting cysteine with
      alanine or serine in the synthetic peptides, demonstrating that sulfhydryl
      modification of cysteine is responsible for the impaired antigenicity and
      immunogenicity of NP39-47 and NP218-226. We found similar effects for two widely
      studied, cysteine-containing peptides from lymphocytic choriomeningitis virus.
      The major modifications of cysteine-containing synthetic peptides are
      cysteinylation and dimerization occurring through cysteine residues. We
      demonstrate that both of these modifications occur in cells synthesizing a
      cytosolic NP218-226 minigene product and, further, that T cells specific for
      cysteinylated NP218-226 are induced by influenza virus infection in mice,
      demonstrating that this modification occurs in vivo. These findings demonstrate
      that posttranslational modifications affect the immunogenicity and antigenicity
      of cysteine-containing viral peptides and that this must be considered in
      studying the status of such peptides in immunodominance hierarchies.

PMID- 10359578
TI  - BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell
      growth.
AB  - Members of the tumor necrosis factor (TNF) family induce pleiotropic biological
      responses, including cell growth, differentiation, and even death. Here we
      describe a novel member of the TNF family, designated BAFF (for B cell activating
      factor belonging to the TNF family), which is expressed by T cells and dendritic
      cells. Human BAFF was mapped to chromosome 13q32-34. Membrane-bound BAFF was
      processed and secreted through the action of a protease whose specificity matches
      that of the furin family of proprotein convertases. The expression of BAFF
      receptor appeared to be restricted to B cells. Both membrane-bound and soluble
      BAFF induced proliferation of anti-immunoglobulin M-stimulated peripheral blood B
      lymphocytes. Moreover, increased amounts of immunoglobulins were found in
      supernatants of germinal center-like B cells costimulated with BAFF. These
      results suggest that BAFF plays an important role as costimulator of B cell
      proliferation and function.

PMID- 10359580
TI  - Acquisition of selectin binding and peripheral homing properties by CD4(+) and
      CD8(+) T cells.
AB  - Different T cell subsets exhibit distinct capacities to migrate into peripheral
      sites of inflammation, and this may in part reflect differential expression of
      homing receptors and chemokine receptors. Using an adoptive transfer approach, we
      examined the ability of functionally distinct subsets of T cells to home to a
      peripheral inflammatory site. The data directly demonstrate the inability of
      naive T cells and the ability of effector cells to home to inflamed peritoneum.
      Furthermore, interleukin (IL)-12 directs the differentiation of either CD4(+) or
      CD8(+) T cells into effector populations that expresses functional E- and P
      selectin ligand and that are preferentially recruited into the inflamed
      peritoneum compared with T cells differentiated in the presence of IL-4.
      Recruitment can be blocked by anti-E- and -P-selectin antibodies. The presence of
      antigen in the peritoneum promotes local proliferation of recruited T cells, and
      significantly amplifies the Th1 polarization of the lymphocytic infiltrate.
      Preferential recruitment of Th1 cells into the peritoneum is also seen when
      cytokine response gene 2 (CRG-2)/interferon gamma-inducible protein 10 (IP-10) is
      used as the sole inflammatory stimulus. We have also found that P-selectin binds
      only to antigen-specific T cells in draining lymph nodes after immunization,
      implying that both antigen- and cytokine-mediated signals are required for
      expression of functional selectin-ligand.

PMID- 10359581
TI  - MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like
      receptor 4.
AB  - Toll-like receptor 4 (TLR4) is a mammalian homologue of Drosophila Toll, a
      leucine-rich repeat molecule that can trigger innate responses against pathogens.
      The TLR4 gene has recently been shown to be mutated in C3H/HeJ and C57BL/10ScCr
      mice, both of which are low responders to lipopolysaccharide (LPS). TLR4 may be a
      long-sought receptor for LPS. However, transfection of TLR4 does not confer LPS
      responsiveness on a recipient cell line, suggesting a requirement for an
      additional molecule. Here, we report that a novel molecule, MD-2, is requisite
      for LPS signaling of TLR4. MD-2 is physically associated with TLR4 on the cell
      surface and confers responsiveness to LPS. MD-2 is thus a link between TLR4 and
      LPS signaling. Identification of this new receptor complex has potential
      implications for understanding host defense, as well as pathophysiologic,
      mechanisms.

PMID- 10359582
TI  - Thioredoxin, a redox enzyme released in infection and inflammation, is a unique
      chemoattractant for neutrophils, monocytes, and T cells.
AB  - Thioredoxin (Trx) is a ubiquitous intracellular protein disulfide oxidoreductase
      with a CXXC active site that can be released by various cell types upon
      activation. We show here that Trx is chemotactic for monocytes, polymorphonuclear
      leukocytes, and T lymphocytes, both in vitro in the standard micro Boyden chamber
      migration assay and in vivo in the mouse air pouch model. The potency of the
      chemotactic action of Trx for all leukocyte populations is in the nanomolar
      range, comparable with that of known chemokines. However, Trx does not increase
      intracellular Ca2+ and its activity is not inhibited by pertussis toxin. Thus,
      the chemotactic action of Trx differs from that of known chemokines in that it is
      G protein independent. Mutation of the active site cysteines resulted in loss of
      chemotactic activity, suggesting that the latter is mediated by the enzyme
      activity of Trx. Trx also accounted for part of the chemotactic activity released
      by human T lymphotropic virus (HTLV)-1-infected cells, which was inhibited by
      incubation with anti-Trx antibody. Since Trx production is induced by oxidants,
      it represents a link between oxidative stress and inflammation that is of
      particular interest because circulating Trx levels are elevated in inflammatory
      diseases and HIV infection.

PMID- 10359583
TI  - Secondary rearrangements and hypermutation generate sufficient B cell diversity
      to mount protective antiviral immunoglobulin responses.
AB  - Variable (V) region gene replacement was recently implicated in B cell repertoire
      diversification, but the contribution of this mechanism to antibody responses is
      still unknown. To investigate the role of V gene replacements in the generation
      of antigen-specific antibodies, we analyzed antiviral immunoglobulin responses of
      "quasimonoclonal" (QM) mice. The B cells of QM mice are genetically committed to
      exclusively express the anti-(4-hydroxy-3-nitrophenyl) acetyl specificity.
      However, approximately 20% of the peripheral B cells of QM mice undergo secondary
      rearrangements and thereby potentially acquire new specificities. QM mice
      infected with vesicular stomatitis virus (VSV), lymphocytic choriomeningitis
      virus, or poliovirus mounted virus-specific neutralizing antibody responses. In
      general, kinetics of the antiviral immunoglobulin responses were delayed in QM
      mice; however, titers similar to control animals were eventually produced that
      were sufficient to protect against VSV-induced lethal disease. VSV neutralizing
      single-chain Fv fragments isolated from phage display libraries constructed from
      QM mice showed VH gene replacements and extensive hypermutation. Thus, our data
      demonstrate that secondary rearrangements and hypermutation can generate
      sufficient B cell diversity in QM mice to mount protective antiviral antibody
      responses, suggesting that these mechanisms might also contribute to the
      diversification of the B cell repertoire of normal mice.

PMID- 10359585
TI  - Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation: a link
      between the apoptosome and the proteasome pathway.
AB  - Injury of the endothelial cells by the induction of apoptotic cell death may play
      an important role in the pathophysiology of atherosclerosis and the progression
      of inflammatory diseases. Here, we demonstrate an essential role for the
      ubiquitin-dependent proteasome complex in stimulus-induced degradation of the
      antiapoptotic protein Bcl-2. Bcl-2 is specifically degraded after stimulation of
      human endothelial cells with tumor necrosis factor (TNF)-alpha in a process that
      is inhibited by specific proteasome inhibitors. In addition, the mutation of the
      potential ubiquitin-acceptor amino acids of Bcl-2 provides protection against TNF
      alpha- and staurosporine-induced degradation in vitro and in vivo. Moreover,
      mimicking phosphorylation of the putative mitogen-activated protein (MAP) kinase
      sites of the Bcl-2 protein (Thr 56, Thr 74, and Ser 87) abolishes its
      degradation, suggesting a link between the MAP kinase pathway to the proteasome
      pathway. Finally, inhibition of Bcl-2 degradation either by suppressing ubiquitin
      dependent proteasomal degradation or by mimicking continuous phosphorylation of
      the putative MAP kinase sites in the Bcl-2 protein confers resistance against
      induction of apoptosis. Thus, the degradation of Bcl-2 may unleash the inhibitory
      function of Bcl-2 over the apoptosome and may thereby amplify the activation of
      the caspase cascade.

PMID- 10359584
TI  - MRL-lpr/lpr mice exhibit a defect in maintaining developmental arrest and
      follicular exclusion of anti-double-stranded DNA B cells.
AB  - A hallmark of systemic lupus erythematosus and the MRL murine model for lupus is
      the presence of anti-double-stranded (ds)DNA antibodies (Abs). To identify the
      steps leading to the production of these Abs in autoimmune mice, we have compared
      the phenotype and localization of anti-dsDNA B cells in autoimmune (MRL+/+ and
      lpr/lpr) mice with that in nonautoimmune (BALB/c) mice. Anti-dsDNA B cells are
      actively regulated in BALB/c mice as indicated by their developmental arrest and
      accumulation at the T-B interface of the splenic follicle. In the MRL genetic
      background, anti-dsDNA B cells are no longer developmentally arrested, suggesting
      an intrinsic B cell defect conferred by MRL background genes. With intact Fas,
      they continue to exhibit follicular exclusion; however, in the presence of the
      lpr/lpr mutation, anti-dsDNA B cells are now present in the follicle. Coincident
      with the altered localization of anti-dsDNA B cells is a follicular infiltration
      of CD4 T cells. Together, these data suggest that MRL mice are defective in
      maintaining the developmental arrest of autoreactive B cells and indicate a role
      for Fas in restricting entry into the follicle.

PMID- 10359586
TI  - Evolution of antigen-specific T cell receptors in vivo: preimmune and antigen
      driven selection of preferred complementarity-determining region 3 (CDR3) motifs.
AB  - Antigen (Ag)-driven selection of helper T cells (Th) in normal animals has been
      difficult to study and remains poorly understood. Using the major
      histocompatibility complex class II- restricted murine response to pigeon
      cytochrome c (PCC), we provide evidence for both preimmune and Ag-driven
      selection in the evolution of Ag-specific immunity in vivo. Before antigenic
      challenge, most Valpha11(+)Vbeta3(+) Th (70%) express a critical complementarity
      determining region 3 (CDR3) residue (glutamic acid at TCR-alpha93) associated
      with PCC peptide contact. Over the first 5 d of the primary response, PCC
      responsive Valpha11(+)Vbeta3(+) Th expressing eight preferred CDR3 features are
      rapidly selected in vivo. Clonal dominance is further propagated through
      selective expansion of the PCC-specific cells with T cell receptor (TCR) of the
      "best fit." Ag-driven selection is complete before significant emergence of the
      germinal center reaction. These data argue that thymic selection shapes TCR-alpha
      V region bias in the preimmune repertoire; however, Ag itself and the nongerminal
      center microenvironment drive the selective expansion of clones with preferred
      TCR that dominate the response to Ag in vivo.

PMID- 10359587
TI  - The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor
      kappaB activation and prevention of apoptosis.
AB  - The IkappaB kinase (IKK) complex is composed of three subunits, IKKalpha,
      IKKbeta, and IKKgamma (NEMO). While IKKalpha and IKKbeta are highly similar
      catalytic subunits, both capable of IkappaB phosphorylation in vitro, IKKgamma is
      a regulatory subunit. Previous biochemical and genetic analyses have indicated
      that despite their similar structures and in vitro kinase activities, IKKalpha
      and IKKbeta have distinct functions. Surprisingly, disruption of the Ikkalpha
      locus did not abolish activation of IKK by proinflammatory stimuli and resulted
      in only a small decrease in nuclear factor (NF)-kappaB activation. Now we
      describe the pathophysiological consequence of disruption of the Ikkbeta locus.
      IKKbeta-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a
      phenotype that is remarkably similar to that of mice deficient in both the RelA
      (p65) and NF-kappaB1 (p50/p105) subunits of NF-kappaB. Accordingly, IKKbeta
      deficient cells are defective in activation of IKK and NF-kappaB in response to
      either tumor necrosis factor alpha or interleukin 1. Thus IKKbeta, but not
      IKKalpha, plays the major role in IKK activation and induction of NF-kappaB
      activity. In the absence of IKKbeta, IKKalpha is unresponsive to IKK activators.

PMID- 10359588
TI  - Neutrophil-specific granule deficiency results from a novel mutation with loss of
      function of the transcription factor CCAAT/enhancer binding protein epsilon.
AB  - Neutrophil-specific granule deficiency (SGD) is a rare disorder characterized by
      recurrent pyogenic infections, defective neutrophil chemotaxis and bactericidal
      activity, and lack of neutrophil secondary granule proteins. CCAAT/enhancer
      binding protein (C/EBP)epsilon, a member of the leucine zipper family of
      transcription factors, is expressed primarily in myeloid cells, and its knockout
      mouse model possesses distinctive defects, including a lack of neutrophil
      secondary granule proteins. Sequence analysis of the genomic DNA of a patient
      with SGD revealed a five-basepair deletion in the second exon of the C/EBPepsilon
      locus. The predicted frame shift results in a truncation of the 32-kD major
      C/EBPepsilon isoform, with loss of the dimerization domain, DNA binding region,
      and transcriptional activity. The multiple functional defects observed in these
      early neutrophil progenitor cells, a consequence of C/EBPepsilon deficiency,
      define SGD as a defect in myelopoiesis and establish the requirement for
      C/EBPepsilon for the promyelocyte-myelocyte transition in myeloid
      differentiation.

PMID- 10359589
TI  - E.B. Wilson Lecture, 1998. Eukaryotic RNAs: once more from the beginning.

PMID- 10359590
TI  - Transformation by v-Src: Ras-MAPK and PI3K-mTOR mediate parallel pathways.
AB  - An increase in the level of active, GTP-bound Ras is not necessary for
      transformation of chicken embryo fibroblasts (CEF) by v-Src. This suggests that
      other Ras-independent pathways contribute to transformation by v-Src. To address
      the possibility that activation of phosphatidylinositol-3-kinase (PI3K) and the
      mammalian target of rapamycin (mTOR/FRAP), represents one of these pathways, we
      have examined the effect of simultaneous inhibition of the Ras-MAPK and PI3K-mTOR
      pathways on transformation of CEF by v-Src. Transformation was assessed by the
      standard parameters of morphological alteration, increased hexose uptake, loss of
      density inhibition, and anchorage-independent growth. Inhibition of the Ras-MAPK
      pathway by expression of the dominant-negative Ras mutant HRasN17 or by addition
      of the MAPK kinase (MEK) inhibitor PD98059 reduced several of these parameters
      but failed to block transformation. Similarly, inhibition of the PI3K-mTOR
      pathway by addition of the PI3K inhibitor 2-[4-morpholinyl]-8-phenyl-4H-1
      benzopyran-4-one (LY294002) or the mTOR inhibitor rapamycin, although reducing
      several parameters of transformation, also failed to block transformation.
      However, simultaneous inhibition of signaling by the Ras-MAPK pathway and the
      PI3K-mTOR pathway essentially blocked transformation. These data indicate that
      transformation of CEF by v-Src is mediated by two parallel pathways, the Ras-MAPK
      pathway and the PI-3K-mTOR pathway, which both contribute to transformation. The
      possibility that simultaneous activation of other pathways is also required is
      not excluded.

PMID- 10359591
TI  - Somatic cell mutants resistant to retrovirus replication: intracellular blocks
      during the early stages of infection.
AB  - To identify cellular functions involved in the early phase of the retroviral life
      cycle, somatic cell mutants were isolated after selection for resistance to
      infection. Rat2 fibroblasts were treated with chemical mutagens, and individual
      virus-resistant clones were recovered after selection for resistance to
      infection. Two clones were characterized in detail. Both mutant lines were
      resistant to infection by both ecotropic and amphotropic murine viruses, as well
      as by human immunodeficiency virus type 1 pseudotypes. One clone showed a strong
      block to reverse transcription of the retroviral RNA, including formation of the
      earliest DNA products. The second clone showed normal levels of viral DNA
      synthesis but did not allow formation of the circular DNAs normally found in the
      nucleus. Cell fractionation showed that the viral preintegration complex was
      present in a form that could not be extracted under conditions that readily
      extracted the complex from wild-type cells. The results suggest that the DNA was
      trapped in a nonproductive state and excluded from the nucleus of the infected
      cell. The properties of these two mutant lines suggest that host gene products
      play important roles both before and after reverse transcription.

PMID- 10359592
TI  - The Saccharomyces cerevisiae v-SNARE Vti1p is required for multiple membrane
      transport pathways to the vacuole.
AB  - The interaction between v-SNAREs on transport vesicles and t-SNAREs on target
      membranes is required for membrane traffic in eukaryotic cells. Here we identify
      Vti1p as the first v-SNARE protein found to be required for biosynthetic traffic
      into the yeast vacuole, the equivalent of the mammalian lysosome. Certain vti1-ts
      yeast mutants are defective in alkaline phosphatase transport from the Golgi to
      the vacuole and in targeting of aminopeptidase I from the cytosol to the vacuole.
      VTI1 interacts genetically with the vacuolar t-SNARE VAM3, which is required for
      transport of both alkaline phosphatase and aminopeptidase I to the vacuole. The v
      SNARE Nyv1p forms a SNARE complex with Vam3p in homotypic vacuolar fusion;
      however, we find that Nyv1p is not required for any of the three biosynthetic
      pathways to the vacuole. v-SNAREs were thought to ensure specificity in membrane
      traffic. However, Vti1p also functions in two additional membrane traffic
      pathways: Vti1p interacts with the t-SNAREs Pep12p in traffic from the TGN to the
      prevacuolar compartment and with Sed5p in retrograde traffic to the cis-Golgi.
      The ability of Vti1p to mediate multiple fusion steps requires additional
      proteins to ensure specificity in membrane traffic.

PMID- 10359593
TI  - Cloning and characterization of peter pan, a novel Drosophila gene required for
      larval growth.
AB  - We identified a new Drosophila gene, peter pan (ppan), in a screen for larval
      growth-defective mutants. ppan mutant larvae do not grow and show minimal DNA
      replication but can survive until well after their heterozygotic siblings have
      pupariated. We cloned the ppan gene by P-element plasmid rescue. ppan belongs to
      a highly conserved gene family that includes Saccharomyces cerevisiae SSF1 and
      SSF2, as well as Schizosaccharomyces pombe, Arabidopsis, Caenorhabditis elegans,
      mouse, and human homologues. Deletion of both SSF1 and SSF2 in yeast is lethal,
      and depletion of the gene products causes cell division arrest. Mosaic analysis
      of ppan mutant clones in Drosophila imaginal disks and ovaries demonstrates that
      ppan is cell autonomous and required for normal mitotic growth but is not
      absolutely required for general biosynthesis or DNA replication. Overexpression
      of the wild-type gene causes cell death and disrupts the normal development of
      adult structures. The ppan gene family appears to have an essential and
      evolutionarily conserved role in cell growth.

PMID- 10359594
TI  - Pex19p interacts with Pex3p and Pex10p and is essential for peroxisome biogenesis
      in Pichia pastoris.
AB  - We report the cloning and characterization of Pichia pastoris PEX19 by
      complementation of a peroxisome-deficient mutant strain. Import of peroxisomal
      targeting signal 1- and 2-containing peroxisomal matrix proteins is defective in
      pex19 mutants. PEX19 encodes a hydrophilic 299-amino acid protein with sequence
      similarity to Saccharomyces cerevisiae Pex19p and human and Chinese hamster PxF,
      all farnesylated proteins, as well as hypothetical proteins from Caenorhabditis
      elegans and Schizosaccharomyces pombe. The farnesylation consensus is conserved
      in PpPex19p but dispensable for function and appears unmodified under the
      conditions tested. Pex19p localizes predominantly to the cytosolic fraction.
      Biochemical and two-hybrid analyses confirmed that Pex19p interacts with Pex3p,
      as seen in S. cerevisiae, but unexpectedly also with Pex10p. Two-hybrid analysis
      demonstrated that the amino-terminal 42 amino acids of Pex19p interact with the
      carboxyl-terminal 335 amino acids of Pex3p. In addition, the extreme carboxyl
      terminus of Pex19p (67 amino acids) is required for interaction with the amino
      terminal 380 amino acids of Pex10p. Biochemical and immunofluorescence microscopy
      analyses of pex19Delta cells identified the membrane protein Pex3p in peroxisome
      remnants that were not previously observed in S. cerevisiae. These small
      vesicular and tubular (early) remnants are morphologically distinct from other
      Pppex mutant (late) remnants, suggesting that Pex19p functions at an early stage
      of peroxisome biogenesis.

PMID- 10359595
TI  - Membrane tubule-mediated reassembly and maintenance of the Golgi complex is
      disrupted by phospholipase A2 antagonists.
AB  - Although membrane tubules can be found extending from, and associated with, the
      Golgi complex of eukaryotic cells, their physiological function has remained
      unclear. To gain insight into the biological significance of membrane tubules, we
      have developed methods for selectively preventing their formation. We show here
      that a broad range of phospholipase A2 (PLA2) antagonists not only arrest
      membrane tubule-mediated events that occur late in the assembly of the Golgi
      complex but also perturb its normal steady-state tubulovesicular architecture by
      inducing a reversible fragmentation into separate "mini-stacks." In addition, we
      show that these same compounds prevent the formation of membrane tubules from
      Golgi stacks in an in vitro reconstitution system. This in vitro assay was
      further used to demonstrate that the relevant PLA2 activity originates from the
      cytoplasm. Taken together, these results demonstrate that Golgi membrane tubules,
      sensitive to potent and selective PLA2 antagonists, mediate both late events in
      the reassembly of the Golgi complex and the dynamic maintenance of its steady
      state architecture. In addition, they implicate a role for cytoplasmic PLA2
      enzymes in mediating these membrane trafficking events.

PMID- 10359597
TI  - The small GTP-binding protein R-Ras can influence integrin activation by
      antagonizing a Ras/Raf-initiated integrin suppression pathway.
AB  - The rapid modulation of ligand-binding affinity ("activation") is a central
      property of the integrin family of cell adhesion receptors. The small GTP-binding
      protein Ras and its downstream effector kinase Raf-1 suppress integrin
      activation. In this study we explored the relationship between Ras and the
      closely related small GTP-binding protein R-Ras in modulating the integrin
      affinity state. We found that R-Ras does not seem to be a direct activator of
      integrins in Chinese hamster ovary cells. However, we observed that GTP-bound R
      Ras strongly antagonizes the Ras/Raf-initiated integrin suppression pathway.
      Furthermore, this reversal of the Ras/Raf suppressor pathway does not seem to be
      via a competition between Ras and R-Ras for common downstream effectors or via an
      inhibition of Ras/Raf-induced MAP kinase activation. Thus, R-Ras and Ras may act
      in concert to regulate integrin affinity via the activation of distinct
      downstream effectors.

PMID- 10359596
TI  - Deciphering the nuclear import pathway for the cytoskeletal red cell protein
      4.1R.
AB  - The erythroid membrane cytoskeletal protein 4.1 is the prototypical member of a
      genetically and topologically complex family that is generated by combinatorial
      alternative splicing pathways and is localized at diverse intracellular sites
      including the nucleus. To explore the molecular determinants for nuclear
      localization, we transfected COS-7 cells with epitope-tagged versions of natural
      red cell protein 4.1 (4.1R) isoforms as well as mutagenized and truncated
      derivatives. Two distant topological sorting signals were required for efficient
      nuclear import of the 4.1R80 isoform: a basic peptide, KKKRER, encoded by
      alternative exon 16 and acting as a weak core nuclear localization signal (4.1R
      NLS), and an acidic peptide, EED, encoded by alternative exon 5. 4.1R80 isoforms
      lacking either of these two exons showed decreased nuclear import. Fusion of
      various 4.1R80 constructs to the cytoplasmic reporter protein pyruvate kinase
      confirmed a requirement for both motifs for full NLS function. 4.1R80 was
      efficiently imported in the nuclei of digitonin-permeabilized COS-7 cells in the
      presence of recombinant Rch1 (human importin alpha2), importin beta, and GTPase
      Ran. Quantitative analysis of protein-protein interactions using a resonant
      mirror detection technique showed that 4.1R80 bound to Rch1 in vitro with high
      affinity (KD = 30 nM). The affinity decreased at least 7- and 20-fold,
      respectively, if the EED motif in exon 5 or if 4.1R NLS in exon 16 was lacking or
      mutated, confirming that both motifs were required for efficient importin
      mediated nuclear import of 4.1R80.

PMID- 10359598
TI  - A constitutively "phosphorylated" guanylyl cyclase-linked atrial natriuretic
      peptide receptor mutant is resistant to desensitization.
AB  - Dephosphorylation of the natriuretic peptide receptor-A (NPR-A) is hypothesized
      to mediate its desensitization in response to atrial natriuretic peptide (ANP)
      binding. Recently, we identified six phosphorylation sites within the kinase
      homology domain of NPR-A and determined that the conversion of these residues to
      alanine abolished the ability of the receptor to be phosphorylated or to be
      activated by ANP and ATP. In an attempt to generate a form of NPR-A that mimics a
      fully phosphorylated receptor but that is resistant to dephosphorylation, we
      engineered a receptor variant (NPR-A-6E) containing glutamate substitutions at
      all six phosphorylation sites. Consistent with the known ability of negatively
      charged glutamate residues to substitute functionally, in some cases, for
      phosphorylated residues, we found that NPR-A-6E was activated 10-fold by ANP and
      ATP. As determined by guanylyl cyclase assays, the hormone-stimulated activity of
      the wild-type receptor declined over time in membrane preparations in vitro, and
      this loss was blocked by the serine/threonine protein phosphatase inhibitor
      microcystin. In contrast, the activity of NPR-A-6E was more linear with time and
      was unaffected by microcystin. The nonhydrolyzable ATP analogue adenosine 5'
      (beta,gamma-imino)-triphosphate was half as effective as ATP in stimulating the
      wild-type receptor but was equally as potent in stimulating NPR-A-6E, suggesting
      that ATP is required to keep the wild-type but not 6E variant phosphorylated.
      Finally, the desensitization of NPR-A-6E in whole cells was markedly blunted
      compared with that of the wild-type receptor, consistent with its inability to
      shed the negative charge from its kinase homology domain via dephosphorylation.
      These data provide the first direct test of the requirement for dephosphorylation
      in guanylyl cyclase desensitization and they indicate that it is an essential
      component of this process.

PMID- 10359599
TI  - Amino acid sequence requirements of the transmembrane and cytoplasmic domains of
      influenza virus hemagglutinin for viable membrane fusion.
AB  - The amino acid sequence requirements of the transmembrane (TM) domain and
      cytoplasmic tail (CT) of the hemagglutinin (HA) of influenza virus in membrane
      fusion have been investigated. Fusion properties of wild-type HA were compared
      with those of chimeras consisting of the ectodomain of HA and the TM domain
      and/or CT of polyimmunoglobulin receptor, a nonviral integral membrane protein.
      The presence of a CT was not required for fusion. But when a TM domain and CT
      were present, fusion activity was greater when they were derived from the same
      protein than derived from different proteins. In fact, the chimera with a TM
      domain of HA and truncated CT of polyimmunoglobulin receptor did not support full
      fusion, indicating that the two regions are not functionally independent. Despite
      the fact that there is wide latitude in the sequence of the TM domain that
      supports fusion, a point mutation of a semiconserved residue within the TM domain
      of HA inhibited fusion. The ability of a foreign TM domain to support fusion
      contradicts the hypothesis that a pore is composed solely of fusion proteins and
      supports the theory that the TM domain creates fusion pores after a stage of
      hemifusion has been achieved.

PMID- 10359600
TI  - A Rab2 mutant with impaired GTPase activity stimulates vesicle formation from pre
      Golgi intermediates.
AB  - Rab2 immunolocalizes to pre-Golgi intermediates (vesicular-tubular clusters
      [VTCs]) that are the first site of segregation of anterograde- and retrograde
      transported proteins and a major peripheral site for COPI recruitment. Our
      previous work showed that Rab2 Q65L (equivalent to Ras Q61L) inhibited
      endoplasmic reticulum (ER)-to-Golgi transport in vivo. In this study, the
      biochemical properties of Rab2 Q65L were analyzed. The mutant protein binds GDP
      and GTP and has a low GTP hydrolysis rate that suggests that Rab2 Q65L is
      predominantly in the GTP-bound-activated form. The purified protein arrests
      vesicular stomatitis virus glycoprotein transport from VTCs in an assay that
      reconstitutes ER-to-Golgi traffic. A quantitative binding assay was used to
      measure membrane binding of beta-COP when incubated with the mutant. Unlike Rab2
      that stimulates recruitment, Rab2 Q65L showed a dose-dependent decrease in
      membrane-associated beta-COP when incubated with rapidly sedimenting membranes
      (ER, pre-Golgi, and Golgi). The mutant protein does not interfere with beta-COP
      binding but stimulates the release of slowly sedimenting vesicles containing
      Rab2, beta-COP, and p53/gp58 but lacking anterograde grade-directed cargo. To
      complement the biochemical results, we observed in a morphological assay that
      Rab2 Q65L caused vesiculation of VTCs that accumulated at 15 degrees C. These
      data suggest that the Rab2 protein plays a role in the low-temperature-sensitive
      step that regulates membrane flow from VTCs to the Golgi complex and back to the
      ER.

PMID- 10359601
TI  - Activation of RhoA by lysophosphatidic acid and Galpha12/13 subunits in neuronal
      cells: induction of neurite retraction.
AB  - Neuronal cells undergo rapid growth cone collapse, neurite retraction, and cell
      rounding in response to certain G protein-coupled receptor agonists such as
      lysophosphatidic acid (LPA). These shape changes are driven by Rho-mediated
      contraction of the actomyosin-based cytoskeleton. To date, however, detection of
      Rho activation has been hampered by the lack of a suitable assay. Furthermore,
      the nature of the G protein(s) mediating LPA-induced neurite retraction remains
      unknown. We have developed a Rho activation assay that is based on the specific
      binding of active RhoA to its downstream effector Rho-kinase (ROK). A fusion
      protein of GST and the Rho-binding domain of ROK pulls down activated but not
      inactive RhoA from cell lysates. Using GST-ROK, we show that in N1E-115 neuronal
      cells LPA activates endogenous RhoA within 30 s, concomitant with growth cone
      collapse. Maximal activation occurs after 3 min when neurite retraction is
      complete and the actin cytoskeleton is fully contracted. LPA-induced RhoA
      activation is completely inhibited by tyrosine kinase inhibitors (tyrphostin 47
      and genistein). Activated Galpha12 and Galpha13 subunits mimic LPA both in
      activating RhoA and in inducing RhoA-mediated cytoskeletal contraction, thereby
      preventing neurite outgrowth. We conclude that in neuronal cells, LPA activates
      RhoA to induce growth cone collapse and neurite retraction through a G12/13
      initiated pathway that involves protein-tyrosine kinase activity.

PMID- 10359602
TI  - Dynamics of gene expression revealed by comparison of serial analysis of gene
      expression transcript profiles from yeast grown on two different carbon sources.
AB  - We describe a genome-wide characterization of mRNA transcript levels in yeast
      grown on the fatty acid oleate, determined using Serial Analysis of Gene
      Expression (SAGE). Comparison of this SAGE library with that reported for glucose
      grown cells revealed the dramatic adaptive response of yeast to a change in
      carbon source. A major fraction (>20%) of the 15,000 mRNA molecules in a yeast
      cell comprised differentially expressed transcripts, which were derived from only
      2% of the total number of approximately 6300 yeast genes. Most of the mRNAs that
      were differentially expressed code for enzymes or for other proteins
      participating in metabolism (e.g., metabolite transporters). In oleate-grown
      cells, this was exemplified by the huge increase of mRNAs encoding the
      peroxisomal beta-oxidation enzymes required for degradation of fatty acids. The
      data provide evidence for the existence of redox shuttles across organellar
      membranes that involve peroxisomal, cytoplasmic, and mitochondrial enzymes. We
      also analyzed the mRNA profile of a mutant strain with deletions of the PIP2 and
      OAF1 genes, encoding transcription factors required for induction of genes
      encoding peroxisomal proteins. Induction of genes under the immediate control of
      these factors was abolished; other genes were up-regulated, indicating an
      adaptive response to the changed metabolism imposed by the genetic impairment. We
      describe a statistical method for analysis of data obtained by SAGE.

PMID- 10359603
TI  - The phosphatidylinositol 3-phosphate binding protein Vac1p interacts with a Rab
      GTPase and a Sec1p homologue to facilitate vesicle-mediated vacuolar protein
      sorting.
AB  - Activated GTP-bound Rab proteins are thought to interact with effectors to elicit
      vesicle targeting and fusion events. Vesicle-associated v-SNARE and target
      membrane t-SNARE proteins are also involved in vesicular transport. Little is
      known about the functional relationship between Rabs and SNARE protein complexes.
      We have constructed an activated allele of VPS21, a yeast Rab protein involved in
      vacuolar protein sorting, and demonstrated an allele-specific interaction between
      Vps21p and Vac1p. Vac1p was found to bind the Sec1p homologue Vps45p. Although no
      association between Vps21p and Vps45p was seen, a genetic interaction between
      VPS21 and VPS45 was observed. Vac1p contains a zinc-binding FYVE finger that may
      bind phosphatidylinositol 3-phosphate [PtdIns(3)P]. In other FYVE domain
      proteins, this motif and PtdIns(3)P are necessary for membrane association. Vac1
      proteins with mutant FYVE fingers still associated with membranes but showed
      vacuolar protein sorting defects and reduced interactions with Vps45p and
      activated Vps21p. Vac1p membrane association was not dependent on PtdIns(3)P,
      Pep12p, Vps21p, Vps45p, or the PtdIns 3-kinase, Vps34p. Vac1p FYVE finger mutant
      missorting phenotypes were suppressed by a defective allele of VPS34. These data
      indicate that PtdIns(3)P may perform a regulatory role, possibly involved in
      mediating Vac1p protein-protein interactions. We propose that activated-Vps21p
      interacts with its effector, Vac1p, which interacts with Vps45p to regulate the
      Golgi to endosome SNARE complex.

PMID- 10359604
TI  - The interaction of activated integrin lymphocyte function-associated antigen 1
      with ligand intercellular adhesion molecule 1 induces activation and
      redistribution of focal adhesion kinase and proline-rich tyrosine kinase 2 in T
      lymphocytes.
AB  - Integrin receptors play a central role in the biology of lymphocytes, mediating
      crucial functional aspects of these cells, including adhesion, activation,
      polarization, migration, and signaling. Here we report that induction of
      activation of the beta2-integrin lymphocyte function-associated antigen 1 (LFA-1)
      in T lymphocytes with divalent cations, phorbol esters, or stimulatory antibodies
      is followed by a dramatic polarization, resulting in a characteristic elongated
      morphology of the cells and the arrest of migrating lymphoblasts. This cellular
      polarization was prevented by treatment of cells with the specific tyrosine
      kinase inhibitor genistein. Furthermore, the interaction of the activated
      integrin LFA-1 with its ligand intercellular adhesion molecule 1 induced the
      activation of the cytoplasmic tyrosine kinases focal adhesion kinase (FAK) and
      proline-rich tyrosine kinase 2 (PYK-2). FAK activation reached a maximum after 45
      min of stimulation; in contrast, PYK-2 activation peaked at 30 min, declining
      after 60 min. Upon polarization of lymphoblasts, FAK and PYK-2 redistributed from
      a diffuse localization in the cytoplasm to a region close to the microtubule
      organizing center in these cells. FAK and PYK-2 activation was blocked when
      lymphoblasts were pretreated with actin and tubulin cytoskeleton-interfering
      agents, indicating its cytoskeletal dependence. Our results demonstrate that
      interaction of the beta2-integrin LFA-1 with its ligand intercellular adhesion
      molecule 1 induces remodeling of T lymphocyte morphology and activation and
      redistribution of the cytoplasmic tyrosine kinases FAK and PYK-2.

PMID- 10359605
TI  - Microtubule-based endoplasmic reticulum motility in Xenopus laevis: activation of
      membrane-associated kinesin during development.
AB  - The endoplasmic reticulum (ER) in animal cells uses microtubule motor proteins to
      adopt and maintain its extended, reticular organization. Although the orientation
      of microtubules in many somatic cell types predicts that the ER should move
      toward microtubule plus ends, motor-dependent ER motility reconstituted in
      extracts of Xenopus laevis eggs is exclusively a minus end-directed, cytoplasmic
      dynein-driven process. We have used Xenopus egg, embryo, and somatic Xenopus
      tissue culture cell (XTC) extracts to study ER motility during embryonic
      development in Xenopus by video-enhanced differential interference contrast
      microscopy. Our results demonstrate that cytoplasmic dynein is the sole motor for
      microtubule-based ER motility throughout the early stages of development (up to
      at least the fifth embryonic interphase). When egg-derived ER membranes were
      incubated in somatic XTC cytosol, however, ER tubules moved in both directions
      along microtubules. Data from directionality assays suggest that plus end
      directed ER tubule extensions contribute approximately 19% of the total
      microtubule-based ER motility under these conditions. In XTC extracts, the rate
      of ER tubule extensions toward microtubule plus ends is lower ( approximately 0.4
      microm/s) than minus end-directed motility ( approximately 1.3 microm/s), and
      plus end-directed motility is eliminated by a function-blocking anti-conventional
      kinesin heavy chain antibody (SUK4). In addition, we provide evidence that the
      initiation of plus end-directed ER motility in somatic cytosol is likely to occur
      via activation of membrane-associated kinesin.

PMID- 10359606
TI  - Erp1p and Erp2p, partners for Emp24p and Erv25p in a yeast p24 complex.
AB  - Six new members of the yeast p24 family have been identified and characterized.
      These six genes, named ERP1-ERP6 (for Emp24p- and Erv25p-related proteins) are
      not essential, but deletion of ERP1 or ERP2 causes defects in the transport of
      Gas1p, in the retention of BiP, and deletion of ERP1 results in the suppression
      of a temperature-sensitive mutation in SEC13 encoding a COPII vesicle coat
      protein. These phenotypes are similar to those caused by deletion of EMP24 or
      ERV25, two previously identified genes that encode related p24 proteins. Genetic
      and biochemical studies demonstrate that Erp1p and Erp2p function in a
      heteromeric complex with Emp24p and Erv25p.

PMID- 10359607
TI  - Localization and recycling of gp27 (hp24gamma3): complex formation with other p24
      family members.
AB  - We report here the characterization of gp27 (hp24gamma3), a glycoprotein of the
      p24 family of small and abundant transmembrane proteins of the secretory pathway.
      Immunoelectron and confocal scanning microscopy show that at steady state, gp27
      localizes to the cis side of the Golgi apparatus. In addition, some gp27 was
      detected in COPI- and COPII-coated structures throughout the cytoplasm. This
      indicated cycling that was confirmed in three ways. First, 15 degrees C
      temperature treatment resulted in accumulation of gp27 in pre-Golgi structures
      colocalizing with anterograde cargo. Second, treatment with brefeldin A caused
      gp27 to relocate into peripheral structures positive for both KDEL receptor and
      COPII. Third, microinjection of a dominant negative mutant of Sar1p trapped gp27
      in the endoplasmic reticulum (ER) by blocking ER export. Together, this shows
      that gp27 cycles extensively in the early secretory pathway. Immunoprecipitation
      and coexpression studies further revealed that a significant fraction of gp27
      existed in a hetero-oligomeric complex. Three members of the p24 family, GMP25
      (hp24alpha2), p24 (hp24beta1), and p23 (hp24delta1), coprecipitated in what
      appeared to be stochiometric amounts. This heterocomplex was specific.
      Immunoprecipitation of p26 (hp24gamma4) failed to coprecipitate GMP25, p24, or
      p23. Also, very little p26 was found coprecipitating with gp27. A functional
      requirement for complex formation was suggested at the level of ER export.
      Transiently expressed gp27 failed to leave the ER unless other p24 family
      proteins were coexpressed. Comparison of attached oligosaccharides showed that
      gp27 and GMP25 recycled differentially. Only a very minor portion of GMP25
      displayed complex oligosaccharides. In contrast, all of gp27 showed modifications
      by medial and trans enzymes at steady state. We conclude from these data that a
      portion of gp27 exists as hetero-oligomeric complexes with GMP25, p24, and p23
      and that these complexes are in dynamic equilibrium with individual p24 proteins
      to allow for differential recycling and distributions.

PMID- 10359608
TI  - Vesicle-associated membrane protein 4 is implicated in trans-Golgi network
      vesicle trafficking.
AB  - The trans-Golgi network (TGN) plays a pivotal role in directing proteins in the
      secretory pathway to the appropriate cellular destination. VAMP4, a recently
      discovered member of the vesicle-associated membrane protein (VAMP) family of
      trafficking proteins, has been suggested to play a role in mediating TGN
      trafficking. To better understand the function of VAMP4, we examined its precise
      subcellular distribution. Indirect immunofluorescence and electron microscopy
      revealed that the majority of VAMP4 localized to tubular and vesicular membranes
      of the TGN, which were in part coated with clathrin. In these compartments, VAMP4
      was found to colocalize with the putative TGN-trafficking protein syntaxin 6.
      Additional labeling was also present on clathrin-coated and noncoated vesicles,
      on endosomes and the medial and trans side of the Golgi complex, as well as on
      immature secretory granules in PC12 cells. Immunoprecipitation of VAMP4 from rat
      brain detergent extracts revealed that VAMP4 exists in a complex containing
      syntaxin 6. Converging lines of evidence implicate a role for VAMP4 in TGN-to
      endosome transport.

PMID- 10359609
TI  - The PDZ domain of the LIM protein enigma binds to beta-tropomyosin.
AB  - PDZ and LIM domains are modular protein interaction motifs present in proteins
      with diverse functions. Enigma is representative of a family of proteins composed
      of a series of conserved PDZ and LIM domains. The LIM domains of Enigma and its
      most related family member, Enigma homology protein, bind to protein kinases,
      whereas the PDZ domains of Enigma and family member actin-associated LIM protein
      bind to actin filaments. Enigma localizes to actin filaments in fibroblasts via
      its PDZ domain, and actin-associated LIM protein binds to and colocalizes with
      the actin-binding protein alpha-actinin-2 at Z lines in skeletal muscle. We show
      that Enigma is present at the Z line in skeletal muscle and that the PDZ domain
      of Enigma binds to a skeletal muscle target, the actin-binding protein
      tropomyosin (skeletal beta-TM). The interaction between Enigma and skeletal beta
      TM was specific for the PDZ domain of Enigma, was abolished by mutations in the
      PDZ domain, and required the PDZ-binding consensus sequence (Thr-Ser-Leu) at the
      extreme carboxyl terminus of skeletal beta-TM. Enigma interacted with isoforms of
      tropomyosin expressed in C2C12 myotubes and formed an immunoprecipitable complex
      with skeletal beta-TM in transfected cells. The association of Enigma with
      skeletal beta-TM suggests a role for Enigma as an adapter protein that directs
      LIM-binding proteins to actin filaments of muscle cells.

PMID- 10359610
TI  - The human G2 checkpoint control protein hRAD9 is a nuclear phosphoprotein that
      forms complexes with hRAD1 and hHUS1.
AB  - Eukaryotic cells actively block entry into mitosis in the presence of DNA damage
      or incompletely replicated DNA. This response is mediated by signal transduction
      cascades called cell cycle checkpoints. We show here that the human checkpoint
      control protein hRAD9 physically associates with two other checkpoint control
      proteins, hRAD1 and hHUS1. Furthermore, hRAD1 and hHUS1 themselves interact,
      analogously to their fission yeast homologues Rad1 and Hus1. We also show that
      hRAD9 is present in multiple phosphorylation forms in vivo. These phosphorylated
      forms are present in tissue culture cells that have not been exposed to exogenous
      sources of DNA damage, but it remains possible that endogenous damage or
      naturally occurring replication intermediates cause the observed phosphorylation.
      Finally, we show that hRAD9 is a nuclear protein, indicating that in this signal
      transduction pathway, hRAD9 is physically proximal to the upstream (DNA damage)
      signal rather than to the downstream, cytoplasmic, cell cycle machinery.

PMID- 10359611
TI  - Vimentin dephosphorylation by protein phosphatase 2A is modulated by the
      targeting subunit B55.
AB  - The intermediate filament protein vimentin is a major phosphoprotein in mammalian
      fibroblasts, and reversible phosphorylation plays a key role in its dynamic
      rearrangement. Selective inhibition of type 2A but not type 1 protein
      phosphatases led to hyperphosphorylation and concomitant disassembly of vimentin,
      characterized by a collapse into bundles around the nucleus. We have analyzed the
      potential role of one of the major protein phosphatase 2A (PP2A) regulatory
      subunits, B55, in vimentin dephosphorylation. In mammalian fibroblasts, B55
      protein was distributed ubiquitously throughout the cytoplasm with a fraction
      associated to vimentin. Specific depletion of B55 in living cells by antisense
      B55 RNA was accompanied by disassembly and increased phosphorylation of vimentin,
      as when type 2A phosphatases were inhibited using okadaic acid. The presence of
      B55 was a prerequisite for PP2A to efficiently dephosphorylate vimentin in vitro
      or to induce filament reassembly in situ. Both biochemical fractionation and
      immunofluorescence analysis of detergent-extracted cells revealed that fractions
      of PP2Ac, PR65, and B55 were tightly associated with vimentin. Furthermore,
      vimentin-associated PP2A catalytic subunit was displaced in B55-depleted cells.
      Taken together these data show that, in mammalian fibroblasts, the intermediate
      filament protein vimentin is dephosphorylated by PP2A, an event targeted by B55.

PMID- 10359612
TI  - High-voltage electron tomography of spindle pole bodies and early mitotic
      spindles in the yeast Saccharomyces cerevisiae.
AB  - The spindle pole body (SPB) is the major microtubule-organizing center of budding
      yeast and is the functional equivalent of the centrosome in higher eukaryotic
      cells. We used fast-frozen, freeze-substituted cells in conjunction with high
      voltage electron tomography to study the fine structure of the SPB and the events
      of early spindle formation. Individual structures were imaged at 5-10 nm
      resolution in three dimensions, significantly better than can be achieved by
      serial section electron microscopy. The SPB is organized in distinct but coupled
      layers, two of which show ordered two-dimensional packing. The SPB central plaque
      is anchored in the nuclear envelope with hook-like structures. The minus ends of
      nuclear microtubules (MTs) are capped and are tethered to the SPB inner plaque,
      whereas the majority of MT plus ends show a distinct flaring. Unbudded cells
      containing a single SPB retain 16 MTs, enough to attach to each of the expected
      16 chromosomes. Their median length is approximately 150 nm. MTs growing from
      duplicated but not separated SPBs have a median length of approximately 130 nm
      and interdigitate over the bridge that connects the SPBs. As a bipolar spindle is
      formed, the median MT length increases to approximately 300 nm and then decreases
      to approximately 30 nm in late anaphase. Three-dimensional models confirm that
      there is no conventional metaphase and that anaphase A occurs. These studies
      complement and extend what is known about the three-dimensional structure of the
      yeast mitotic spindle and further our understanding of the organization of the
      SPB in intact cells.

PMID- 10359613
TI  - Trafficking, assembly, and function of a connexin43-green fluorescent protein
      chimera in live mammalian cells.
AB  - To examine the trafficking, assembly, and turnover of connexin43 (Cx43) in living
      cells, we used an enhanced red-shifted mutant of green fluorescent protein (GFP)
      to construct a Cx43-GFP chimera. When cDNA encoding Cx43-GFP was transfected into
      communication-competent normal rat kidney cells, Cx43-negative Madin-Darby canine
      kidney (MDCK) cells, or communication-deficient Neuro2A or HeLa cells, the fusion
      protein of predicted length was expressed, transported, and assembled into gap
      junctions that exhibited the classical pentalaminar profile. Dye transfer studies
      showed that Cx43-GFP formed functional gap junction channels when transfected
      into otherwise communication-deficient HeLa or Neuro2A cells. Live imaging of
      Cx43-GFP in MDCK cells revealed that many gap junction plaques remained
      relatively immobile, whereas others coalesced laterally within the plasma
      membrane. Time-lapse imaging of live MDCK cells also revealed that Cx43-GFP was
      transported via highly mobile transport intermediates that could be divided into
      two size classes of <0.5 microm and 0.5-1.5 microm. In some cases, the larger
      intracellular Cx43-GFP transport intermediates were observed to form from the
      internalization of gap junctions, whereas the smaller transport intermediates may
      represent other routes of trafficking to or from the plasma membrane. The
      localization of Cx43-GFP in two transport compartments suggests that the dynamic
      formation and turnover of connexins may involve at least two distinct pathways.

PMID- 10359614
TI  - Direct visualization of a protein nuclear architecture.
AB  - Whether the cell nucleus is organized by an underlying architecture analagous to
      the cytoskeleton has been a highly contentious issue since the original isolation
      of a nuclease and salt-resistant nuclear matrix. Despite electron microscopy
      studies that show that a nuclear architecture can be visualized after
      fractionation, the necessity to elute chromatin to visualize this structure has
      hindered general acceptance of a karyoskeleton. Using an analytical electron
      microscopy method capable of quantitative elemental analysis, electron
      spectroscopic imaging, we show that the majority of the fine structure within
      interchromatin regions of the cell nucleus in fixed whole cells is not
      nucleoprotein. Rather, this fine structure is compositionally similar to known
      protein-based cellular structures of the cytoplasm. This study is the first
      demonstration of a protein network in unfractionated and uninfected cells and
      provides a method for the ultrastructural characterization of the interaction of
      this protein architecture with chromatin and ribonucleoprotein elements of the
      cell nucleus.

PMID- 10359615
TI  - Congruent docking of dimeric kinesin and ncd into three-dimensional electron
      cryomicroscopy maps of microtubule-motor ADP complexes.
AB  - We present a new map showing dimeric kinesin bound to microtubules in the
      presence of ADP that was obtained by electron cryomicroscopy and image
      reconstruction. The directly bound monomer (first head) shows a different
      conformation from one in the more tightly bound empty state. This change in the
      first head is amplified as a movement of the second (tethered) head, which tilts
      upward. The atomic coordinates of kinesin.ADP dock into our map so that the
      tethered head associates with the bound head as in the kinesin dimer structure
      seen by x-ray crystallography. The new docking orientation avoids problems
      associated with previous predictions; it puts residues implicated by proteolysis
      protection and mutagenesis studies near the microtubule but does not lead to
      steric interference between the coiled-coil tail and the microtubule surface. The
      observed conformational changes in the tightly bound states would probably bring
      some important residues closer to tubulin. As expected from the homology with
      kinesin, the atomic coordinates of nonclaret disjunctional protein (ncd).ADP dock
      in the same orientation into the attached head in a map of microtubules decorated
      with dimeric ncd.ADP. Our results support the idea that the observed direct
      interaction between the two heads is important at some stages of the mechanism by
      which kinesin moves processively along microtubules.

PMID- 10359616
TI  - Activation of utrophin promoter by heregulin via the ets-related transcription
      factor complex GA-binding protein alpha/beta.
AB  - Utrophin/dystrophin-related protein is the autosomal homologue of the chromosome
      X-encoded dystrophin protein. In adult skeletal muscle, utrophin is highly
      enriched at the neuromuscular junction. However, the molecular mechanisms
      underlying regulation of utrophin gene expression are yet to be defined. Here we
      demonstrate that the growth factor heregulin increases de novo utrophin
      transcription in muscle cell cultures. Using mutant reporter constructs of the
      utrophin promoter, we define the N-box region of the promoter as critical for
      heregulin-mediated activation. Using this region of the utrophin promoter for DNA
      affinity purification, immunoblots, in vitro kinase assays, electrophoretic
      mobility shift assays, and in vitro expression in cultured muscle cells, we
      demonstrate that ets-related GA-binding protein alpha/beta transcription factors
      are activators of the utrophin promoter. Taken together, these results suggest
      that the GA-binding protein alpha/beta complex of transcription factors binds and
      activates the utrophin promoter in response to heregulin-activated extracellular
      signal-regulated kinase in muscle cell cultures. These findings suggest methods
      for achieving utrophin up-regulation in Duchenne's muscular dystrophy as well as
      mechanisms by which neurite-derived growth factors such as heregulin may
      influence the regulation of utrophin gene expression and subsequent enrichment at
      the neuromuscular junction of skeletal muscle.

PMID- 10359617
TI  - Basolateral localization of the Caenorhabditis elegans epidermal growth factor
      receptor in epithelial cells by the PDZ protein LIN-10.
AB  - In Caenorhabditis elegans, the EGF receptor (encoded by let-23) is localized to
      the basolateral membrane domain of the epithelial vulval precursor cells, where
      it acts through a conserved Ras/MAP kinase signaling pathway to induce vulval
      differentiation. lin-10 acts in LET-23 receptor tyrosine kinase basolateral
      localization, because lin-10 mutations result in mislocalization of LET-23 to the
      apical membrane domain and cause a signaling defective (vulvaless) phenotype. We
      demonstrate that the previous molecular identification of lin-10 was incorrect,
      and we identify a new gene corresponding to the lin-10 genetic locus. lin-10
      encodes a protein with regions of similarity to mammalian X11/mint proteins,
      containing a phosphotyrosine-binding and two PDZ domains. A nonsense lin-10
      allele that truncates both PDZ domains only partially reduces lin-10 gene
      activity, suggesting that these protein interaction domains are not essential for
      LIN-10 function in vulval induction. Immunocytochemical experiments show that LIN
      10 is expressed in vulval epithelial cells and in neurons. LIN-10 is present at
      low levels in the cytoplasm and at the plasma membrane and at high levels at or
      near the Golgi. LIN-10 may function in secretion of LET-23 to the basolateral
      membrane domain, or it may be involved in tethering LET-23 at the basolateral
      plasma membrane once it is secreted.

PMID- 10359618
TI  - Teledermascopy: a preliminary study.

PMID- 10359619
TI  - Remedial physical activities program geared to aid handicapped or underdeveloped
      youths.

PMID- 10359620
TI  - Results of four antismoking therapy methods.

PMID- 10359621
TI  - Chronic pulmonary disease in a morphine addict. A clinicopathologic conference.

PMID- 10359622
TI  - Cystoangiography for determining the extent of bladder tumors.

PMID- 10359623
TI  - Tiger by the tail.

PMID- 10359624
TI  - Many physicians are 'at home' in the world of the arts.

PMID- 10359625
TI  - Poison control centers in Pennsylvania.

PMID- 10359626
TI  - Determining community health service needs.

PMID- 10359640
TI  - Oxidation of indole-3-acetic acid by dioxygen catalysed by plant peroxidases:
      specificity for the enzyme structure.
AB  - Indole-3-acetic acid (IAA) can be oxidized via two mechanisms: a conventional
      hydrogen-peroxide-dependent pathway, and one that is hydrogen-peroxide
      independent and requires oxygen. It has been shown here for the first time that
      only plant peroxidases are able to catalyse the reaction of IAA oxidation with
      molecular oxygen. Cytochrome c peroxidase (CcP), fungal peroxidases (manganese
      dependent peroxidase, lignin peroxidase and Arthromyces ramosus peroxidase) and
      microperoxidase were essentially inactive towards IAA in the absence of added
      H2O2. An analysis of amino acid sequences allowed five structurally similar
      fragments to be identified in auxin-binding proteins and plant peroxidases. The
      corresponding fragments in CcP and fungal peroxidases showed no similarity with
      auxin-binding proteins. Five structurally similar fragments form a subdomain
      including the catalytic centre and two residues highly conserved among
      'classical' plant peroxidases only, namely His-40 and Trp-117. The subdomain
      identified above with the two residues might be responsible for the oxidation of
      the physiological substrate of classical plant peroxidases, IAA.

PMID- 10359639
TI  - The trappin gene family: proteins defined by an N-terminal transglutaminase
      substrate domain and a C-terminal four-disulphide core.
AB  - Recently, several new genes have been discovered in various species which are
      homologous to the well-characterized human epithelial proteinase inhibitor
      elafin/SKALP (skin-derived anti-leukoproteinase). Because of the high degree of
      conservation and the similarities in genomic organization, we propose that these
      genes belong to a novel gene family. At the protein level, the family members are
      defined by: (1) an N-terminal domain consisting of a variable number of repeats
      with the consensus sequence Gly-Gln-Asp-Pro-Val-Lys that can act as an anchoring
      motif by transglutaminase cross-linking, and (2) a C-terminal four-disulphide
      core or whey acidic protein (WAP) domain, which harbours a functional motif
      involved in binding of proteinases and possibly other proteins. We have proposed
      the name trappin gene family as a unifying nomenclature for this group of
      proteins (trappin is an acronym for TRansglutaminase substrate and wAP domain
      containing ProteIN, and refers to its functional property of 'getting trapped' in
      tissues by covalent cross-linking). Analysis of the trappin family members shows
      extensive diversification in bovidae and suidae, whereas the number of primate
      trappins is probably limited. Recent biochemical and cell biological data on the
      human trappin family member elafin/SKALP suggest that this molecule is induced in
      epidermis by cellular stress. We hypothesize that trappins play an important role
      in the regulation of inflammation and in protection against tissue damage in
      stratified epithelia.

PMID- 10359641
TI  - Dexamethasone- and osmolarity-dependent expression of the multidrug-resistance
      protein 2 in cultured rat hepatocytes.
AB  - Expression of the conjugate export pump multidrug-resistance protein 2 (MRP2) in
      liver is regulated by endotoxin and anti-tumour agents. This paper reports on the
      effects of dexamethasone and osmolarity on MRP2 expression. MRP2 expression was
      studied at the protein, mRNA, immunocytochemical and functional levels in
      cultured rat hepatocytes. Protein and mRNA expression of MRP2 in rat hepatocytes
      24 and 48 h after isolation were largely dependent on the presence of
      dexamethasone (100 nmol/l) in the culture medium. MRP2 was localized at the
      pseudocanalicular membrane and increased expression of MRP2 was accompanied by a
      widening of the pseudocanaliculi. In presence of dexamethasone, hypo-osmolarity
      (205 mosmol/l) led to a strong induction of MRP2 mRNA and protein, whereas
      expression was decreased by hyperosmolarity (405 mosmol/l). Also, a decay of MRP2
      protein and mRNA following dexamethasone withdrawal was osmosensitive. Expression
      of dipeptidylpeptidase IV, another canalicular protein, was unaffected by
      dexamethasone and osmolarity. It is concluded that glucocorticoids are strong
      inducers of MRP2 in liver. Besides short-term carrier insertion/retrieval,
      osmoregulation of MRP2 also involves a long-term effect on MRP2 expression.

PMID- 10359642
TI  - Molecular cloning and immunolocalization of a novel vertebrate trp homologue from
      Xenopus.
AB  - We report the sequence, structure and distribution of a novel transient receptor
      potential (trp) homologue from Xenopus, Xtrp, determined by screening an oocyte
      cDNA library. On the basis of sequence similarity and predicted structure, Xtrp
      appears to be a homologue of mammalian trp1 proteins. Two polyclonal antibodies
      raised against distinct regions of the Xtrp sequence revealed Xtrp expression in
      various Xenopus tissues, and the localization of Xtrp at the plasma membrane of
      Xenopus oocytes and HeLa cells. Since capacitative calcium entry into Xenopus
      oocytes has been shown previously to be substantially inhibited by trp1 antisense
      oligonucleotides [Tomita, Kaneko, Funayama, Kondo, Satoh and Akaike (1998)
      Neurosci. Lett. 248, 195-198] we suggest that Xtrp may underlie capacitative
      calcium entry in Xenopus tissues.

PMID- 10359643
TI  - H,K-ATPase alpha subunit C-terminal membrane topology: epitope tags in the insect
      cell expression system.
AB  - The H,K-ATPase responsible for gastric acidification is a heterodimeric (alpha
      and beta subunit) P-type ATPase, an integral protein of parietal cell apical
      membranes, which promotes the electroneutral exchange of K+ for protons, is
      stimulated by K+ and is inhibited by 2-methyl-8-(phenylmethoxy)imidazo[1, 2
      alpha]pyridine-3-acetonitrile (SCH 28080). Hydropathy analysis of the catalytic
      alpha subunit has been interpreted in terms of four N-terminal transmembrane
      domains, a cytoplasmically oriented segment containing ATP binding and
      phosphorylation sites, and a C-terminal region with four or six putative
      transmembrane domains. Several lines of evidence implicate the C-terminal region
      of P-type ATPases in cation-binding and occlusion, conformational changes, and
      interactions with the beta subunit (HKbeta), making the definition of topology a
      prerequisite for understanding the structural basis of these functions. Influenza
      haemagglutinin epitopes (YPYDVPDYA; flu tag) were inserted in predicted
      hydrophilic segments of the alpha subunit (HKalpha) to establish the membrane
      orientation of two amino acids with different predicted topologies in the C
      terminal four- and six-transmembrane models. Wild-type and mutated HKalpha and
      HKbeta cDNA species were expressed in insect cells (Sf9) via recombinant
      baculovirus infection, and expression of H,K-ATPase was verified by
      immunoblotting with HKalpha- and HKbeta-specific and flu-tag-specific antibodies.
      Functional assays showed K+-stimulated, SCH 28080-sensitive ATPase activity,
      confirming neo-native topology in H,K-ATPase heterodimers expressed in Sf9 cells.
      The topology of flu tags was determined by microsomal protease protection assays
      in Sf9 cells and immunolabelling of HKalpha and HKbeta in intact and
      permeabilized Sf9 cells. In addition, MS of native H,K-ATPase tryptic peptides
      identified cytoplasmically oriented HKalpha residues. The results indicated
      cytoplasmic exposure of Leu844 and Phe996, and luminal exposure of Pro898,
      leading to a revised secondary structure model of the C-terminal third of
      HKalpha.

PMID- 10359644
TI  - Isolation and characterization of proteoglycans from human follicular fluid.
AB  - Two proteoglycans differing in size and composition were isolated from human
      follicular fluid. The larger one of high density had a molecular mass of
      3.0x10(6) Da, as determined by laser light-scattering, and was substituted with
      15-20 chondroitin sulphate (CS) chains (Mr 60000-65000). Half of the CS
      disaccharides were 6-sulphated, whereas the remaining ones were non-sulphated.
      Digestion of the CS proteoglycan with chondroitinase ABC lyase, followed by
      SDS/PAGE, yielded a protein core of 600 to 700 kDa including substituted
      oligosaccharides, and a band of 70 kDa that was identified as the heavy-chain
      component of the inter-alpha-trypsin inhibitor (ITI). Western blotting of the CS
      proteoglycan showed that this had reactivity with antibodies raised against human
      versican. Electron microscopy (EM) of the CS proteoglycan also revealed a
      versican-like structure, with one globular domain at each end of a long extended
      segment substituted with CS side chains, as well as a structure interpreted as
      being the heavy chain of ITI attached to CS chains. Laser light-scattering
      revealed that the smaller proteoglycan had a molecular mass of 1. 1x10(6) Da, and
      EM demonstrated that it had a globular-protein core structure. The core protein,
      which showed immunological reactivity with perlecan antibodies, was substituted
      with approximately seven heparan sulphate (HS) and CS chains of similar size (50
      55 kDa), the CS disaccharides being mainly 6-sulphated (68%), with a small
      proportion being 4-sulphated. The protein core was shown to be heterogeneous,
      with bands occurring at 215, 330 and 400 kDa after enzymic degradation of the
      glycosaminoglycan chains followed by SDS/PAGE analysis. The demonstration of
      intact molecules and fragments obtained after stepwise degradations, as shown by
      gel chromatography, supported a 'composite' structure of this proteoglycan.

PMID- 10359645
TI  - How aneuploidy affects metabolic control and causes cancer.
AB  - The complexity and diversity of cancer-specific phenotypes, including de
      differentiation, invasiveness, metastasis, abnormal morphology and metabolism,
      genetic instability and progression to malignancy, have so far eluded explanation
      by a simple, coherent hypothesis. However, an adaptation of Metabolic Control
      Analysis supports the 100-year-old hypothesis that aneuploidy, an abnormal number
      of chromosomes, is the cause of cancer. The results demonstrate the currently
      counter-intuitive principle that it is the fraction of the genome undergoing
      differential expression, not the magnitude of the differential expression, that
      controls phenotypic transformation. Transforming the robust normal phenotype into
      cancer requires a twofold increase in the expression of thousands of normal gene
      products. The massive change in gene dose produces highly non-linear (i.e.
      qualitative) changes in the physiology and metabolism of cells and tissues. Since
      aneuploidy disrupts the natural balance of mitosis proteins, it also explains the
      notorious genetic instability of cancer cells as a consequence of the perpetual
      regrouping of chromosomes. In view of this and the existence of non-cancerous
      aneuploidy, we propose that cancer is the phenotype of cells above a certain
      threshold of aneuploidy. This threshold is reached either by the gradual,
      stepwise increase in the level of aneuploidy as a consequence of the
      autocatalysed genetic instability of aneuploid cells or by tetraploidization
      followed by a gradual loss of chromosomes. Thus the initiation step of
      carcinogenesis produces aneuploidy below the threshold for cancer, and the
      promotion step increases the level of aneuploidy above this threshold. We
      conclude that aneuploidy offers a simple and coherent explanation for all the
      cancer-specific phenotypes. Accordingly, the gross biochemical abnormalities,
      abnormal cellular size and morphology, the appearance of tumour-associated
      antigens, the high levels of secreted proteins responsible for invasiveness and
      loss of contact inhibition, and even the daunting genetic instability that
      enables cancer cells to evade chemotherapy, are all the natural consequence of
      the massive over- and under-expression of proteins.

PMID- 10359646
TI  - Colicin E1 forms a dimer after urea-induced unfolding.
AB  - Unfolding of the soluble colicin E1 channel peptide was examined with the use of
      urea as a denaturant; it was shown that it unfolds to an intermediate state in
      8.5 M urea, equivalent to a dimeric species previously observed in 4 M
      guanidinium chloride. Single tryptophan residues, substituted into the peptide at
      various positions by site-directed mutagenesis, were employed as fluorescent
      probes of local unfolding. Unfolding profiles for specific sites within the
      peptide were obtained by quantifying the shifts in the fluorescence emission
      maxima of single tryptophan residues on unfolding and plotting them against urea
      concentration. Unfolding reported by tryptophan residues in the C-terminal region
      was not characteristic of complete peptide denaturation, as evidenced by the
      relatively blue-shifted values of the fluorescence emission maxima. Unfolding was
      also monitored by using CD spectroscopy and the fluorescent probe 2-(p
      toluidinyl)-naphthalene 6-sulphonic acid; the results indicated that unfolding of
      helices is concomitant with the exposure of protein non-polar surface. Unfolding
      profiles were evaluated by non-linear least-squares curve fitting and calculation
      of the unfolding transition midpoint. The unfolding profiles of residues located
      in the N-terminal region of the peptide had lower transition midpoints than
      residues in the C-terminal portion. The results of unfolding analysis
      demonstrated that urea unfolds the peptide only partly to an intermediate state,
      because the C-terminal portion of the channel peptide retained significant
      structure in 8.5 M urea. Characterization of the peptide's global unfolding by
      size-exclusion HPLC revealed that the partly denatured structure that persists in
      8.5 M urea is a dimer of two channel peptides, tightly associated by hydrophobic
      interactions. The presence of the dimerized species was confirmed by SDS/PAGE and
      intermolecular fluorescence resonance energy transfer.

PMID- 10359647
TI  - Characterization of the membrane quinoprotein glucose dehydrogenase from
      Escherichia coli and characterization of a site-directed mutant in which
      histidine-262 has been changed to tyrosine.
AB  - The requirements for substrate binding in the quinoprotein glucose dehydrogenase
      (GDH) in the membranes of Escherichia coli are described, together with the
      changes in activity in a site-directed mutant in which His262 has been altered to
      a tyrosine residue (H262Y-GDH). The differences in catalytic efficiency between
      substrates are mainly related to differences in their affinity for the enzyme.
      Remarkably, it appears that, if a hexose is able to bind in the active site, then
      it is also oxidized, whereas some pentoses are able to bind (and act as
      competitive inhibitors), but are not substrates. The activation energies for the
      oxidation of hexoses and pentoses are almost identical. In a previously published
      model of the enzyme, His262 is at the entrance to the active site and appears to
      be important in holding the prosthetic group pyrroloquinoline quinone (PQQ) in
      place, and it has been suggested that it might play a role in electron transfer
      from the reduced PQQ to the ubiquinone in the membrane. The H262Y-GDH has a
      greatly diminished catalytic efficiency for all substrates, which is mainly due
      to a marked decrease in their affinities for the enzyme, but the rate of electron
      transfer to oxygen is unaffected. During the processing of the PQQ into the
      apoenzyme to give active enzyme, its affinity is markedly dependent on the pH,
      four groups with pK values between pH7 and pH8 being involved. Identical results
      were obtained with H262Y-GDH, showing that His262 it is not directly involved in
      this process.

PMID- 10359648
TI  - Palmitoylation of the three isoforms of human endothelin-converting enzyme-1.
AB  - Endothelin-converting enzyme-1 (ECE-1) is a membrane-bound metalloprotease that
      catalyses the conversion of inactive big endothelins into active endothelins.
      Here we have examined whether the three isoforms of human ECE-1 (ECE-1a, ECE-1b
      and ECE-1c) are modified by the covalent attachment of the fatty acid palmitate
      and have evaluated a potential functional role of this modification. To do this,
      wild-type and mutant enzymes were expressed and analysed by metabolic labelling
      with [3H]palmitate, immunoprecipitation and SDS/PAGE. All three ECE-1 isoforms
      were found to be palmitoylated via hydroxylamine-sensitive thioester bonds. In
      addition, the isoforms showed similar levels of acylation. Cys46 in ECE-1a, Cys58
      in ECE-1b and Cys42 in ECE-1c were identified as sites of palmitoylation and each
      of these cysteines accounted for all the palmitoylation that occured in the
      corresponding isoform. Immunofluorescence analysis demonstrated further that
      palmitoylated and non-palmitoylated ECE-1 isoforms had the same subcellular
      localizations. Moreover, complete solubility of the three isoforms in Triton X
      100 revealed that palmitoylation does not target ECE-1 to cholesterol and
      sphingolipid-rich membrane domains or caveolae. The enzymic activities of ECE-1a,
      ECE-1b and ECE-1c were also not significantly affected by the absence of
      palmitoylation.

PMID- 10359649
TI  - Protein modification during biological aging: selective tyrosine nitration of the
      SERCA2a isoform of the sarcoplasmic reticulum Ca2+-ATPase in skeletal muscle.
AB  - The accumulation of covalently modified proteins is an important hallmark of
      biological aging, but relatively few studies have addressed the detailed
      molecular-chemical changes and processes responsible for the modification of
      specific protein targets. Recently, Narayanan et al. [Narayanan, Jones, Xu and Yu
      (1996) Am. J. Physiol. 271, C1032-C1040] reported that the effects of aging on
      skeletal-muscle function are muscle-specific, with a significant age-dependent
      change in ATP-supported Ca2+-uptake activity for slow-twitch but not for fast
      twitch muscle. Here we have characterized in detail the age-dependent functional
      and chemical modifications of the rat skeletal-muscle sarcoplasmic-reticulum (SR)
      Ca2+-ATPase isoforms SERCA1 and SERCA2a from fast-twitch and slow-twitch muscle
      respectively. We find a significant age-dependent loss in the Ca2+-ATPase
      activity (26% relative to Ca2+-ATPase content) and Ca2+-uptake rate specifically
      in SR isolated from predominantly slow-twitch, but not from fast-twitch, muscles.
      Western immunoblotting and amino acid analysis demonstrate that, selectively, the
      SERCA2a isoform progressively accumulates a significant amount of nitrotyrosine
      with age (approximately 3.5+/-0. 7 mol/mol of SR Ca2+-ATPase). Both Ca2+-ATPase
      isoforms suffer an age-dependent loss of reduced cysteine which is, however,
      functionally insignificant. In vitro, the incubation of fast- and slow-twitch
      muscle SR with peroxynitrite (ONOO-) (but not NO/O2) results in the selective
      nitration only of the SERCA2a, suggesting that ONOO- may be the source of the
      nitrating agent in vivo. A correlation of the SR Ca2+-ATPase activity and
      covalent protein modifications in vitro and in vivo suggests that tyrosine
      nitration may affect the Ca2+-ATPase activity. By means of partial and complete
      proteolytic digestion of purified SERCA2a with trypsin or Staphylococcus aureus
      V8 protease, followed by Western-blot, amino acid and HPLC-electrospray-MS (ESI
      MS) analysis, we localized a large part of the age-dependent tyrosine nitration
      to the sequence Tyr294-Tyr295 in the M4-M8 transmembrane domain of the SERCA2a,
      close to sites essential for Ca2+ translocation.

PMID- 10359650
TI  - Arginine kinase evolved twice: evidence that echinoderm arginine kinase
      originated from creatine kinase.
AB  - Arginine kinase (AK) was isolated from the longitudinal muscle of the sea
      cucumber Stichopus japonicus. Unlike the monomeric 40 kDa AKs from molluscs and
      arthropods, but like the cytoplasmic isoenzymes of vertebrate creatine kinase
      (CK), the Stichopus enzyme was dimeric. To explore the evolutionary origin of the
      dimeric AK, we determined its cDNA-derived amino acid sequence of 370 residues. A
      comparison of the sequence with those of other enzymes belonging to the
      phosphagen kinase family indicated that the entire amino acid sequence of
      Stichopus AK is apparently much more similar to vertebrate CKs than to all other
      AKs. A phylogenetic tree also strongly suggests that the Stichopus AK has evolved
      from CK. These results support the conclusion that AK evolved at least twice
      during the evolution of phosphagen kinases: first at an early stage of phosphagen
      kinase evolution (its descendants are molluscan and arthropod AKs) and secondly
      from CK later in metazoan evolution. A comparison of the amino acid sequence
      around the guanidino specificity (GS) region (which is a possible candidate for
      the guanidine substrate recognition site in the phosphagen kinase family) of the
      Stichopus enzyme with those of other phosphagen kinases showed that the GS region
      of the Stichopus enzyme was of the AK type: five amino acid deletions in the
      flexible loop region that might help to accommodate larger guanidine substrates
      in the active site. The presence of the AK-type deletions in the Stichopus AK,
      even though it seems that the enzyme's most immediate ancestor was probably CK,
      strongly suggests that the GS region has a role in substrate specificity.
      Stichopus AK and presumably other echinoderm AKs seem to have evolved from the CK
      gene; the sequence of GS region might have been replaced by the AK type via exon
      shuffling. The presence of an intron near the GS region in the Stichopus AK gene
      supports this hypothesis.

PMID- 10359651
TI  - Lipid phosphate phosphohydrolase-1 degrades exogenous glycerolipid and
      sphingolipid phosphate esters.
AB  - Lipid phosphate phosphohydrolase (LPP)-1 cDNA was cloned from a rat liver cDNA
      library. It codes for a 32-kDa protein that shares 87 and 82% amino acid sequence
      identities with putative products of murine and human LPP-1 cDNAs, respectively.
      Membrane fractions of rat2 fibroblasts that stably expressed mouse or rat LPP-1
      exhibited 3.1-3. 6-fold higher specific activities for phosphatidate
      dephosphorylation compared with vector controls. Increases in the
      dephosphorylation of lysophosphatidate, ceramide 1-phosphate, sphingosine 1
      phosphate and diacylglycerol pyrophosphate were similar to those for
      phosphatidate. Rat2 fibroblasts expressing mouse LPP-1 cDNA showed 1.6-2.3-fold
      increases in the hydrolysis of exogenous lysophosphatidate, phosphatidate and
      ceramide 1-phosphate compared with vector control cells. Recombinant LPP-1 was
      located partially in plasma membranes with its C-terminus on the cytosolic
      surface. Lysophosphatidate dephosphorylation was inhibited by extracellular Ca2+
      and this inhibition was diminished by extracellular Mg2+. Changing intracellular
      Ca2+ concentrations did not alter exogenous lysophosphatidate dephosphorylation
      significantly. Permeabilized fibroblasts showed relatively little latency for the
      dephosphorylation of exogenous lysophosphatidate. LPP-1 expression decreased the
      activation of mitogen-activated protein kinase and DNA synthesis by exogenous
      lysophosphatidate. The product of LPP-1 cDNA is concluded to act partly to
      degrade exogenous lysophosphatidate and thereby regulate its effects on cell
      signalling.

PMID- 10359652
TI  - Expression and characterization of a glycine-binding fragment of the N-methyl-D
      aspartate receptor subunit NR1.
AB  - N-Methyl-D-aspartate receptor channels are composed of an NR1 subunit and at
      least one of the NR2 subunits (NR2A-D). Activation of the N-methyl-d-aspartate
      receptor requires the co-agonists glycine and glutamate. It has been proposed
      that the NR1 subunit possesses a glycine-binding site. We have expressed a
      soluble form of the NR1 subunit, which was produced by connecting the N-terminal
      extracellular region with the extracellular loop between the third and fourth
      membrane segments, by a baculovirus system along with full-length and truncated
      membrane-bound forms. The soluble NR1 receptor was efficiently secreted into the
      culture medium and showed a high affinity for ligands. The Kd of a glycine-site
      antagonist, [3H]MDL 105,519 [(E)-3-(2-phenyl-2-carboxyethenyl)-4, 6-dichloro-1H
      indole-2-carboxylic acid], for the soluble receptor was 3.89+/-0.97 nM, which was
      comparable to the Kd of 4.47+/-1.39 nM for the membrane-bound full-length form.
      These values were close to the values reported previously with the use of rat
      brain membranes and Chinese hamster ovary cells expressing the full-length form
      of the NR1 subunit. The Ki values of other glycine-site antagonists, L-689,560
      (trans-2-carboxy-5,7-dichloro - 4 - phenylaminocarbonylamino - 1,2,3,4 -
      tetrahydroquinoline), 5, 7-dichlorokynurenate and 5,7-dinitroquinoxaline-2,3
      dione, for the soluble receptor were also similar to those for the full-length
      form of NR1. [3H]MDL 105,519 binding was also inhibited by the agonists glycine
      and d-serine. Thus the affinity and selectivity of ligand-binding characteristics
      of the NR1 subunit is conferred on the soluble form of the NR1 subunit. This
      soluble receptor provides a good experimental tool for initiating a biophysical
      analysis of the N-methyl-d-aspartate receptor channel protein.

PMID- 10359653
TI  - N-terminal domains of fibrillin 1 and fibrillin 2 direct the formation of
      homodimers: a possible first step in microfibril assembly.
AB  - Aggregation of fibrillin molecules via disulphide bonds is postulated to be an
      early step in microfibril assembly. By expressing fragments of fibrillin 1 and
      fibrillin 2 in a mammalian expression system, we found that the N-terminal region
      of each protein directs the formation of homodimers and that disulphide bonds
      stabilize this interaction. A large fragment of fibrillin 1 containing much of
      the region downstream from the N-terminus remained as a monomer when expressed in
      the same cell system, indicating that this region of the protein lacks
      dimerization domains. This finding also confirms that the overexpression of
      fibrillin fragments does not in itself lead to spurious dimer formation. Pulse
      chase analysis demonstrated that dimer formation occurred intracellularly,
      suggesting that the process of fibrillin aggregation is initiated early after
      biosynthesis of the molecules. These findings also implicate the N-terminal
      region of fibrillin 1 and fibrillin 2 in directing the formation of a dimer
      intermediate that aggregates to form the functional microfibril.

PMID- 10359654
TI  - Effects of the amyloid precursor protein Glu693-->Gln 'Dutch' mutation on the
      production and stability of amyloid beta-protein.
AB  - Hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D), is a
      cerebral amyloidosis characterized by prominent vascular deposits and fatal
      haemorrhages. The disorder is caused by a point mutation in codon 693 of the gene
      encoding the amyloid precursor protein (APP), resulting in a Glu-->Gln amino acid
      substitution at position 22 of the amyloid beta-protein (Abeta) region. The
      pathogenetic mechanisms of HCHWA-D are unknown but could involve alterations in
      the proteolytic processing of APP and in amyloid fibril formation. We examined
      Abeta production and stability by using cultured human embryonic kidney 293 cells
      stably expressing wild-type or 'Dutch' APP. Radiosequencing and quantitative
      immunoprecipitation experiments showed that cells expressing Dutch APP secreted
      increased quantities of Abeta peptides beginning at Asp1, and of truncated
      peptides beginning at Val18 and Phe19. The ratio of levels of 4 kDa (Abeta) to 3
      kDa (p3) peptides remained constant due to co-ordinate decreases in other peptide
      species. Novel truncated or elongated peptides were not observed. Pulse-chase
      experiments showed that the Dutch mutation did not affect the stability of the
      Abeta or p3 populations. These results are consistent with a disease process in
      which the Dutch mutation results in the production of Abeta peptides with
      enhanced propensities for fibrillogenesis, leading to accelerated vascular
      deposition and disease.

PMID- 10359655
TI  - Evidence that cysteine-166 is the active-site nucleophile of Pseudomonas
      aeruginosa amidase: crystallization and preliminary X-ray diffraction analysis of
      the enzyme.
AB  - Wild-type and site-specific mutants C166S and C166A (Cys-166-->Ser and Cys-166-
      >Ala respectively) of the amidase (acylamide amidohydrolase, EC 3.5.1.4) from
      Pseudomonas aeruginosa were expressed in Escherichia coli by using the vector
      pKK223-3. Both mutant proteins were catalytically inactive but showed complete
      cross-reactivity with polyclonal antiserum raised against the wild-type enzyme,
      as well as CD spectra identical with that of the wild-type enzyme, which were
      indicative of correct folding. Cys-166 is therefore implicated as the active-site
      nucleophile. Titration of free thiol groups with 5,5'-dithiobis-(2-nitrobenzoic
      acid) indicated that Cys-166 is not a rapidly reacting residue. Crystals of both
      wild-type and C166S amidase grew with identical, rhombohedral morphology; X-ray
      diffraction analysis established the unit cell dimensions (a=b=c=84 A;
      alpha=beta=gamma=75 degrees) and space group (R3 or R32). These results imply a
      quaternary structure of six subunits, with most probably 32 symmetry; the
      existence of a hexameric structure was supported by molecular mass determinations
      based on gel filtration and electrophoretic mobility.

PMID- 10359656
TI  - Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon
      receptor that affect CYP1A1 transcription differentially.
AB  - Transcriptional activation of the human CYP1A1 gene (coding for cytochrome P450
      1A1) is mediated by the aryl hydrocarbon receptor (AhR). In the present study we
      have examined the effect of the common dietary polyphenolic compounds quercetin
      and kaempferol on the transcription of CYP1A1 and the function of the AhR in MCF
      7 human breast cancer cells. Quercetin caused a time- and concentration-dependent
      increase in the amount of CYP1A1 mRNA and CYP1A1 enzyme activity in MCF-7 cells.
      The increase in CYP1A1 mRNA caused by quercetin was prevented by the
      transcription inhibitor actinomycin D. Quercetin also caused an increase in the
      transcription of a chloramphenicol reporter vector containing the CYP1A1
      promoter. Quercetin failed to induce CYP1A1 enzyme activity in AhR-deficient MCF
      7 cells. Gel retardation studies demonstrated that quercetin activated the
      ability of the AhR to bind to an oligonucleotide containing the xenobiotic
      responsive element (XRE) of the CYP1A1 promoter. These results indicate that
      quercetin's effect is mediated by the AhR. Kaempferol did not affect CYP1A1
      expression by itself but it inhibited the transcription of CYP1A1 induced by the
      prototypical AhR ligand 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), as measured
      by a decrease in TCDD-induced CYP1A1 promoter-driven reporter vector activity,
      and CYP1A1 mRNA in cells. Kaempferol also abolished TCDD-induced XRE binding in a
      gel-shift assay. Both compounds were able to compete with TCDD for binding to a
      cytosolic extract of MCF-7 cells. Known ligands of the AhR are, for the most
      part, man-made compounds such as halogenated and polycyclic aromatic
      hydrocarbons. These results demonstrate that the dietary flavonols quercetin and
      kaempferol are natural, dietary ligands of the AhR that exert different effects
      on CYP1A1 transcription.

PMID- 10359657
TI  - NO synthase II in mouse skeletal muscle is associated with caveolin 3.
AB  - The inducible-type NO synthase (NOS II; iNOS) is constitutively expressed in slow
      twitch skeletal muscle fibres of guinea-pigs [Gath, Closs, Godtel-Armbrust,
      Schmitt, Nakane, Wessler and Forstermann (1996) FASEB J. 10, 1614-1620]. Here we
      studied the expression of NOS II in skeletal muscle of wild-type and NOS II
      deficient mice and investigated the molecular basis for the membrane association
      of this NOS in muscle. A basal expression of NOS II mRNA and protein was detected
      in skeletal muscle from untreated wild-type mice; expression increased when mice
      were treated with bacterial lipopolysaccharide (LPS). No NOS II was found in any
      tissue of untreated or LPS-treated NOS II-deficient mice. Immunoprecipitation
      experiments were performed with homogenates of gastrocnemius muscle from
      untreated or LPS-treated wild-type mice. A NOS II-specific antibody precipitated
      caveolin 3 in all homogenates investigated, the effect being most pronounced in
      skeletal muscle from LPS-treated animals. Conversely, an antibody against
      caveolin 3 co-precipitated NOS II in muscle homogenates. Similarly, a weak co
      precipitation of NOS II and caveolin 3 was seen in homogenates of untreated
      murine C2C12 myotubes; co-precipitation was markedly enhanced in cells stimulated
      with LPS/interferon gamma. The association of NOS II with caveolin 3 might have
      implications for the regulation of contraction of, and/or glucose uptake by, slow
      twitch muscle fibres.

PMID- 10359658
TI  - Phosphorylation of arylsulphatase A occurs through multiple interactions with the
      UDP-N-acetylglucosamine-1-phosphotransferase proximal and distal to its retrieval
      site by the KDEL receptor.
AB  - Phosphorylation of oligosaccharides of the lysosomal enzyme arylsulphatase A
      (ASA), which accumulate in the secretions of cells that mis-sort most of the
      newly synthesized lysosomal enzymes due to a deficiency of mannose 6-phosphate
      receptors, was found to be site specific. ASA residing within the secretory route
      of these cells contains about one third of the incorporated [2-3H]mannose in
      phosphorylated oligosaccharides. Oligosaccharides carrying two phosphate groups
      are almost 2-fold less frequent than those with one phosphate group and only a
      few of the phosphate groups are uncovered. Addition of a KDEL (Lys-Asp-Glu-Leu)
      retention signal prolongs the residence time of ASA within the secretory route 6
      fold, but does not result in more efficient phosphorylation. In contrast, more
      than 90% of the [2-3H]mannose incorporated into secreted ASA (with or without a
      KDEL retention signal) is present in phosphorylated oligosaccharides. Those with
      two phosphate groups are almost twice as frequent as those with one phosphate
      group and most of the phosphate groups are uncovered. Thus, ASA receives N
      acetylglucosamine 1-phosphate groups in a sequential manner at two or more sites
      located within the secretory route proximal and distal to the site where ASA is
      retrieved by the KDEL receptor, i.e. proximal to the trans-Golgi. At each of
      these sites up to two N-acetylglucosamine 1-phosphate groups can be added to a
      single oligosaccharide. Of several drugs known to inhibit transit of ASA through
      the secretory route only the ionophore monensin had a major inhibitory effect on
      phosphorylation, uncovering and sialylation.

PMID- 10359659
TI  - Expression and targeting to the plasma membrane of xClC-K, a chloride channel
      specifically expressed in distinct tubule segments of Xenopus laevis kidney.
AB  - ClC-K channels are Cl- channels specifically expressed in vertebrate kidneys.
      Although their heterologous functional expression is still controversial,
      indirect evidence points to them as major factors involved in Cl- reabsorption in
      the nephron. We cloned xClC-K, an amphibian (Xenopus) homologue of mammalian ClC
      K. The cDNA encodes a 77 kDa protein presenting 62% similarity with human ClC-Kb.
      The protein is monoglycosylated and is expressed primarily in the Xenopus kidney.
      It is localized in the basolateral membranes of proximal convoluted tubules of
      the nephron and in the apical region of the diluting segments. Heterologous
      expression of xClC-K in HEK-293 cells showed that the full-length protein is
      glycosylated and targeted to the cell membrane, but no associated Cl- current
      could be observed with the patch-clamp recording technique. N-glycosylation of
      both the native kidney channel and the recombinant protein expressed in HEK-293
      conferred on them anomalous behaviour in denaturing PAGE, which is indicative of
      strong interactions at the extracellular side of the plasma membrane. The
      expression of ClC-K channels in both mesonephric and metanephric kidneys will
      permit further comparative physiological studies of Cl- permeabilities at the
      molecular level.

PMID- 10359660
TI  - Autoinhibition of neuronal nitric oxide synthase: distinct effects of reactive
      nitrogen and oxygen species on enzyme activity.
AB  - Nitric oxide (NO) synthases (NOSs), which catalyse the oxidation of L-arginine to
      L-citrulline and an oxide of nitrogen, possibly NO or nitroxyl (NO-), are subject
      to autoinhibition by a mechanism that has yet to be fully elucidated. In the
      present study we investigated the actions of NO and other NOS-derived products as
      possible autoregulators of enzyme activity. With the use of purified NOS-I, L
      arginine turnover was found to operate initially at Vmax (0-15 min, phase I)
      although, despite the presence of excess substrate and cofactors, prolonged
      catalysis (15-90 min, phase II) was associated with a rapid decline in L-arginine
      turnover. Taken together, these observations suggested that one or more NOS
      products inactivate NOS. Indeed, exogenously applied reactive nitrogen oxide
      species (RNSs) decreased Vmax during phase I, although with different potencies
      (NO->NO> ONOO-) and efficacies (NO>NO-=ONOO-). The NO scavengers oxyhaemoglobin
      (HbO2; 100 microM) and 1H-imidazol-1 - yloxy - 2 - (4-carboxyphenyl) - 4,5 -
      dihydro - 4,4,5,5 - tetramethyl - 3 -oxide (CPTIO; 10 microM) and the ONOO-
      scavenger GSH (7 mM) had no effect on NOS activity during phase I, except for an
      endogenous autoinhibitory influence of NO and ONOO-. However, superoxide
      dismutase (SOD; 300 units/ml), which is thought either to increase the half-life
      of NO or to convert NO- to NO, lowered Vmax in an NO-dependent manner because
      this effect was selectively antagonized by HbO2 (100 microM). This latter
      observation demonstrated the requirement of SOD to reveal endogenous NO-mediated
      autoinhibition. Importantly, during phase II of catalysis, NOS became uncoupled
      and began to form H2O2 because catalase, which metabolizes H2O2, increased enzyme
      activity. Consistent with this, exogenous H2O2 also inhibited NOS activity during
      phase I. Thus during catalysis NOS is subject to complex autoinhibition by both
      enzyme-derived RNS and H2O2, differentially affecting enzyme activity.

PMID- 10359661
TI  - Characterization of a novel spermidine/spermine acetyltransferase, BltD, from
      Bacillus subtilis.
AB  - Overexpression of the BltD gene in Bacillus subtilis causes acetylation of the
      polyamines spermidine and spermine. BltD is co-regulated with another gene, Blt,
      which encodes a multidrug export protein whose overexpression facilitates
      spermidine export [Woolridge, Vazquez-Laslop, Markham, Chevalier, Gerner and
      Neyfakh (1997) J. Biol. Chem. 272, 8864-8866]. Here we show that BltD acetylates
      both spermidine and spermine at primary propyl amine moieties, with spermine
      being the preferred substrate. In the presence of saturating concentrations of
      acetyl CoA, BltD rapidly acetylates spermine at both the N1 and N12 positions.
      The Km (app) values for spermine, spermidine and N1-acetylspermine are </=67, 200
      and 1200 microM, respectively. Diamines ranging from 1, 3-diaminopropane to 1,12
      diaminododecane, monoacetylputrescine and N8-acetylspermidine were not substrates
      for BltD. Putrescine (1, 4-diaminobutane) and N8-acetylspermidine were
      competitive inhibitors of spermidine acetylation by BltD, with Ki values of 0.25
      and 5.76 mM, respectively. CoA competitively inhibited both spermidine and acetyl
      CoA interactions with BltD. These data and other results indicate that the
      mechanism of spermidine and spermine acetylation by BltD is a random-order
      mechanism of bi-molecular kinetics.

PMID- 10359663
TI  - Identification of a functional transcriptional factor AP-1 site in the sheep
      interferon tau gene that mediates a response to PMA in JEG3 cells.
AB  - To examine regulatory mechanisms of sheep interferon tau (oIFNtau) gene
      expression, potential enhancer/silencer elements of the oIFNtau gene were
      examined using a transient transfection system with oIFNtau gene-chloramphenicol
      acetyltransferase (oIFNtau-CAT) reporter constructs in human choriocarcinoma
      cells, JEG3. Experiments with 5'-deletion constructs revealed that the upstream
      regions from bases -654 to -607 and from bases -606 to -555 were essential for
      oIFNtau gene expression. In a heterologous transcriptional system in which the
      upstream regions of oIFNtau were inserted in front of simian virus 40 (SV40)
      promoter, the regions between bases -654 and -555 were determined as being the
      enhancer region required for oIFNtau-SV40-CAT transactivation. A subsequent study
      with the oIFNtau-CAT constructs lacking the upstream region between bases -542
      and -124 revealed that, in addition to the further upstream region between bases 
      1000 and -654, the sequences from bases -543 to -452 seemed to act as silencer
      regions. The oIFNtau-CAT constructs with site-specific mutagenesis revealed that
      multiple enhancer elements existed between bases -654 and -555 of the oIFNtau
      gene. On the basis of nucleotide sequence analysis, there are numerous sites
      between bases -654 and -555 to which potential transcriptional factors, AP-1,
      GATA and GATA-related proteins, could bind. Furthermore, gel mobility-shift
      assays revealed that AP-1 or other nuclear factors could bind to these elements.
      In co-transfection studies, the expression of c-Jun plus c-Fos enhanced the
      transactivation of oIFNtau-CAT but the expression of GATA-1, GATA-2 or GATA-3 did
      not. Taken together, these results suggest that the upstream region between bases
      -654 and -555 could be considered as the enhancer region for oIFNtau gene
      transactivation.

PMID- 10359662
TI  - Presence of a vacuolar H+-pyrophosphatase in promastigotes of Leishmania donovani
      and its localization to a different compartment from the vacuolar H+-ATPase.
AB  - Inorganic pyrophosphate promoted the acidification of an intracellular
      compartment in permeabilized promastigotes of Leishmania donovani, as measured by
      Acridine Orange uptake. The proton gradient generated by pyrophosphate was
      collapsed by addition of nigericin or NH4Cl. Pyrophosphate-driven proton
      translocation was stimulated by potassium ions, and inhibited by NaF, the
      pyrophosphate analogues imidodiphosphate and aminomethylenediphosphonate (AMDP),
      dicyclohexylcarbodiimide, and the thiol reagents p-hydroxymercuribenzoate and N
      ethylmaleimide, all at concentrations similar to those that inhibit the plant
      vacuolar proton-pumping pyrophosphatase (H+-PPase). The proton translocation
      activity had a pH optimum in the range 7.0-7.5, and was unaffected by bafilomycin
      A1 (40 nM), concanamycin A (5 nM), sodium o-vanadate (500 microM) and KNO3 (200
      mM). AMDP-sensitive pyrophosphate hydrolysis was also detected in promastigotes,
      and potassium ions also stimulated this activity. Sodium ions disrupted pH
      gradients established in the presence of ATP but not in the presence of
      pyrophosphate, and sequential addition of ATP and pyrophosphate resulted in
      partially additive Acridine Orange accumulation, suggesting that the vacuolar H+
      PPase is in a different intracellular compartment from the vacuolar H+-ATPase and
      Na+/H+ exchanger of L. donovani promastigotes. Separation of promastigote
      extracts on Percoll gradients yielded a dense fraction that contained H+-PPase
      activity but lacked ATPase activity and markers for mitochondria, glycosomes and
      lysosomes. The organelles in this fraction appeared by electron microscopy to
      consist of electron-dense vacuoles. In summary, these results indicate that, in
      contrast to plant vacuoles, vacuolar H+-PPase and vacuolar ATPase activities are
      present in different compartments in L. donovani promastigotes.

PMID- 10359664
TI  - Phosphorylation of the myristoylated protein kinase C substrate MARCKS by the
      cyclin E-cyclin-dependent kinase 2 complex in vitro.
AB  - The myristoylated alanine-rich C-kinase substrate (MARCKS) purified from brain
      was recently characterized as a proline-directed kinase(s) substrate in vivo
      [Taniguchi, Manenti, Suzuki and Titani (1994) J. Biol. Chem. 269, 18299-18302].
      Here we have investigated the phosphorylation of MARCKS by various cyclin
      dependent kinases (Cdks) in vitro. We established that Cdk2, Cdk4 and, to a
      smaller extent, Cdk1 that have been immunoprecipitated from cellular extracts
      phosphorylate MARCKS. Comparison of MARCKS phosphorylation by protein kinase C
      (PKC) and by the purified cyclin E-Cdk2 complex suggested that two residues were
      phosphorylated by Cdk2 under these conditions. To identify these sites, Cdk2
      phosphorylated MARCKS was digested with lysyl endoprotease and analysed by
      electrospray MS. Comparison with the digests obtained from the unphosphorylated
      protein demonstrated that two peptides, Gly12-Lys30 and Ala138-Lys152, were
      phosphorylated by cyclin E-Cdk2. The identity of these peptides was confirmed by
      automatic Edman degradation. On the basis of the consensus phosphorylation
      sequence described for Cdk2, and on MS/MS analysis of the Ala138-Lys152 peptide,
      we concluded that Ser27, one of the phosphorylation sites identified in vivo, and
      Thr150 were the Cdk2 targets in vitro. None of the other sites described in vivo
      were phosphorylated in these conditions. Interestingly, a preliminary
      phosphorylation of MARCKS by PKC improved the initial rate of phosphorylation by
      Cdk2 without modifying the number of sites concerned. In contrast,
      phosphorylation of MARCKS by Cdk2 did not significantly affect further
      phosphorylation by PKC.

PMID- 10359665
TI  - Targeted delivery of oligodeoxynucleotides to parenchymal liver cells in vivo.
AB  - Anti-sense oligodeoxynucleotides (ODNs) hold great promise for correcting the
      biosynthesis of clinically relevant proteins. The potential of ODNs for
      modulating liver-specific genes might be increased by preventing untimely
      elimination and by improving the local bioavailability of ODNs in the target
      tissue. In the present study we have assessed whether the local ODN concentration
      can be enhanced by the targeted delivery of ODNs through conjugation to a ligand
      for the parenchymal liver cell-specific asialoglycoprotein receptor. A capped ODN
      (miscellaneous 20-mer sequence) was derivatized with a ligand with high affinity
      for this receptor, N2-[N2-(N2,N6-bis{N-[p-(beta-d-galactopyranosyloxy) anilino]
      thiocarbamyl}-L-lysyl)-N6-(N-{p-[beta-D -galactopyranosyloxy] anilino}
      thiocarbamyl)-L-lysyl]-N6-[N- (p-{beta-D
      galactopyranosyloxy}anilino)thiocarbamyl]-L-lysine (L3G4) (Kd 6.5+/-0.2 nM,
      mean+/-S.D.). Both the uptake studies in vitro and the confocal laser scan
      microscopy studies demonstrated that L3G4-ODN was far more efficiently bound to
      and taken up by parenchymal liver cells than underivatized ODN. Studies in vivo
      in rats showed that hepatic uptake could be greatly enhanced from 19+/-1% to 77+/
      6% of the injected dose after glycoconjugation. Importantly, specific ODN
      accumulation of ODN into parenchymal liver cells was improved almost 60-fold
      after derivatization with L3G4, and could be attributed to the asialoglycoprotein
      receptor. In conclusion, the scavenger receptor-mediated elimination pathway for
      miscellaneous ODN sequences can be circumvented by direct conjugation to a
      synthetic tag for the asialoglycoprotein receptor. In this manner a crucial
      requisite is met towards the application of ODNs in vivo to modulate the
      biosynthesis of parenchymal liver cell-specific genes such as those for
      apolipoprotein (a), cholesterol ester transfer protein and viral proteins.

PMID- 10359666
TI  - Purification, characterization, DNA sequence and cloning of a pimeloyl-CoA
      synthetase from Pseudomonas mendocina 35.
AB  - A pimeloyl-CoA synthetase from Pseudomonas mendocina 35 was purified and
      characterized, the DNA sequence determined, and the gene cloned into Escherichia
      coli to yield an active enzyme. The purified enzyme had a pH optimum of
      approximately 8.0, Km values of 0.49 mM for pimelic acid, 0.18 mM for CoA and
      0.72 mM for ATP, a subunit Mr of approximately 80000 as determined by SDS/PAGE,
      and was found to be a tetramer by gel-filtration chromatography. The specific
      activity of the purified enzyme was 77.3 units/mg of protein. The enzyme was not
      absolutely specific for pimelic acid. The relative activity for adipic acid (C6)
      was 72% and for azaleic acid (C9) was 18% of that for pimelic acid (C7). The N
      terminal amino acid was blocked to amino acid sequencing, but controlled
      proteolysis resulted in three peptide fragments for which amino acid sequences
      were obtained. An oligonucleotide gene probe corresponding to one of the amino
      acid sequences was synthesized and used to isolate the gene (pauA, pimelic acid
      utilizing A) coding for pimeloyl-CoA synthetase. The pauA gene, which codes for a
      protein with a theoretical Mr of 74643, was then sequenced. The deduced amino
      acid sequence of the enzyme showed similarity to hypothetical proteins from
      Archaeoglobus fulgidus, Methanococcus jannaschii, Pyrococcus horikoshii, E. coli
      and Streptomyces coelicolor, and some limited similarity to microbial succinyl
      CoA synthetases. The similarity with the protein from A. fulgidus was especially
      strong, thus indicating a function for this unidentified protein. The pauA gene
      was cloned into E. coli, where it was expressed and resulted in an active enzyme.

PMID- 10359667
TI  - Identification of oligopeptide sequences which inhibit migration induced by a
      wide range of chemokines.
AB  - We have identified an amino acid sequence, termed peptide 3, corresponding to
      amino acids 51-62 of the mature human monocyte chemoattractant protein-1 (MCP-1),
      which inhibits human mononuclear-cell and THP-1-cell migration induced by a wide
      range of chemokines. For example, peptide 3 inhibited MCP-1-induced THP-1
      migration in a transwell assay with an ED50 of approx. 8 microM. Peptide 3 binds
      directly to THP-1 cells with an association constant of approx. 10 microM, and is
      therefore likely to be a direct receptor antagonist for CC and CXC chemokine
      receptors. By performing a structure-function analysis of this peptide, we have
      identified a sequence variant that shows an approx. 3-4-fold greater potency as
      an inhibitor of chemokine-induced migration [Leu4Ile11 peptide 3 (1-12)].
      Furthermore, unlike peptide 3, which binds to the Duffy antigen receptor for
      chemokines on human erythrocytes with a similar affinity to the specific
      chemokine receptors on THP-1 cells, the Leu4Ile11 peptide 3 (1-12) sequence
      variant shows at least 20-fold greater selectivity for the specific receptors.
      Derivatives of Leu4Ile11 peptide 3 (1-12) are therefore the best candidates among
      the molecules we have investigated for use as a chemokine inhibitor in vivo.

PMID- 10359668
TI  - Interaction of mammalian neprilysin with binding protein and calnexin in
      Schizosaccharomyces pombe.
AB  - Neutral endopeptidase (neprilysin or NEP, EC 3.4.24.11) is a zinc metallo
      endopeptidase expressed in many eukaryotic cell types and displaying several
      important physiological roles. In the brain (and central nervous system), this
      enzyme is involved in the molecular mechanism of pain by its action in the
      degradation of enkephalin molecules. In the kidney, NEP is implicated in the
      degradation of regulatory factors involved in the control of arterial pressure,
      including atrial natriuretic peptide and bradykinin. In this study we assessed
      the potential of the fission yeast Schizosaccharomyces pombe to overproduce
      rabbit NEP and secreted NEP (sNEP, a soluble derivative of this integral membrane
      protein). Both recombinant NEP and sNEP were produced at high levels (5 mg/l) in
      this system. Enzymic studies revealed that these recombinant proteins were fully
      active and exhibit kinetic parameters similar to those of the bona fide enzyme.
      Immunofluorescence microscopy and enzymic assays demonstrated that recombinant
      NEP is correctly targeted to the cell membrane. Furthermore, co
      immunoprecipitation studies showed that folding intermediates of NEP and sNEP,
      produced in S. pombe, interact in the endoplasmic reticulum (ER) with binding
      protein (BiP) and calnexin (Cnx1p). The amount of sNEP coprecipitated with both
      BiP and Cnx1p augmented when cells were subjected to various stresses causing the
      accumulation of unfolded proteins in the ER. The interactions of NEP with BiP and
      Cnx1p were, however, more refractive to the same stresses.

PMID- 10359669
TI  - Copper(II)-induced self-oligomerization of alpha-synuclein.
AB  - alpha-Synuclein is a component of the abnormal protein depositions in senile
      plaques and Lewy bodies of Alzheimer's disease (AD) and Parkinson's disease
      respectively. The protein was suggested to provide a possible nucleation centre
      for plaque formation in AD via selective interaction with amyloid beta/A4 protein
      (Abeta). We have shown previously that alpha-synuclein has experienced self
      oligomerization when Abeta25-35 was present in an orientation-specific manner in
      the sequence. Here we examine this biochemically specific self-oligomerization
      with the use of various metals. Strikingly, copper(II) was the most effective
      metal ion affecting alpha-synuclein to form self-oligomers in the presence of
      coupling reagents such as dicyclohexylcarbodi-imide or N-(ethoxycarbonyl)-2
      ethoxy-1,2-dihydroquinoline. The size distribution of the oligomers indicated
      that monomeric alpha-synuclein was oligomerized sequentially. The copper-induced
      oligomerization was shown to be suppressed as the acidic C-terminus of alpha
      synuclein was truncated by treatment with endoproteinase Asp-N. In contrast, the
      Abeta25-35-induced oligomerizations of the intact and truncated forms of alpha
      synuclein were not affected. This clearly indicated that the copper-induced
      oligomerization was dependent on the acidic C-terminal region and that its
      underlying biochemical mechanism was distinct from that of the Abeta25-35-induced
      oligomerization. Although the physiological or pathological relevance of the
      oligomerization remains currently elusive, the common outcome of alpha-synuclein
      on treatment with copper or Abeta25-35 might be useful in understanding
      neurodegenerative disorders in molecular terms. In addition, abnormal copper
      homoeostasis could be considered as one of the risk factors for the development
      of disorders such as AD or Parkinson's disease.

PMID- 10359670
TI  - Digestion of crystalline cellulose substrates by the clostridium thermocellum
      cellulosome: structural and morphological aspects.
AB  - The action of cellulosomes from Clostridium thermocellum on model cellulose
      microfibrils from Acetobacter xylinum and cellulose microcrystals from Valonia
      ventricosa was investigated. The biodegradation of these substrates was followed
      by transmission electron microscopy, Fourier-transform IR spectroscopy and X-ray
      diffraction analysis, as a function of the extent of degradation. The
      cellulosomes were very effective in catalysing the complete digestion of
      bacterial cellulose, but the total degradation of Valonia microcrystals was
      achieved more slowly. Ultrastructural observations during the digestion process
      suggested that the rapid degradation of bacterial cellulose was the result of a
      very efficient synergistic action of the various enzymic components that are
      attached to the scaffolding protein of the cellulosomes. The degraded Valonia
      sample assumed various shapes, ranging from thinned-down microcrystals to
      crystals where one end was pointed and the other intact. This complexity may be
      correlated with the multi-enzyme content of the cellulosomes and possibly to a
      diversity of the cellulosome composition within a given batch. Another aspect of
      the digestion of model celluloses by cellulosomes is the relative invariability
      of their crystallinity, together with their Ialpha/Ibeta composition throughout
      the degradation process. Comparison of the action of cellulosomes with that of
      fungal enzymes indicated that the degradation of cellulose crystals by
      cellulosomes occurred with only limited levels of processivity, in contrast with
      the observations reported for fungal enzymes. The findings were consistent with a
      mechanism whereby initial attack by a cellulosome of an individual cellulose
      crystal results in its 'commitment' towards complete degradation.

PMID- 10359671
TI  - Cloning and characterization of a novel human olfactory UDP
      glucuronosyltransferase.
AB  - Xenobiotic metabolizing enzymes in the olfactory epithelium have been suggested
      to catalyse inactivation and facilitate elimination of odorants. We report here
      the molecular cloning and functional characterization of a human olfactory UDP
      glucuronosyltransferase (UGT). The cloned protein is composed of 527 amino acids
      with an identity of 87% with a rat olfactory UGT and of 43-62% with other human
      UGT isoforms. Based on the sequence homology, it has been designated hUGT2A1. The
      gene was mapped to chromosome 4q13 by fluorescence in situ hybridization. The
      expression appeared to be specific for the olfactory tissue. The substrate
      specificity of this isoform was assessed using Chinese hamster V79 cells stably
      transfected with the isolated cDNA. The expressed enzyme showed a broad substrate
      spectrum including a range of phenolic compounds as well as aliphatic and
      monoterpenoid alcohols, among them many odorants. Furthermore, some steroids,
      especially androgens, some drugs and carcinogens were conjugated. The results
      support a role of the enzyme in olfactory perception and in protection of the
      neural system against airborne hazardous chemicals.

PMID- 10359672
TI  - Sigmoidal kinetic model for two co-operative substrate-binding sites in a
      cytochrome P450 3A4 active site: an example of the metabolism of diazepam and its
      derivatives.
AB  - Cytochrome P450 3A4 (CYP3A4) plays a prominent role in the metabolism of a vast
      array of drugs and xenobiotics and exhibits broad substrate specificities. Most
      cytochrome P450-mediated reactions follow simple Michaelis-Menten kinetics. These
      parameters are widely accepted to predict pharmacokinetic and pharmacodynamic
      consequences in vivo caused by exposure to one or multiple drugs. However, CYP3A4
      in many cases exhibits allosteric (sigmoidal) characteristics that make the
      Michaelis constants difficult to estimate. In the present study, diazepam,
      temazepam and nordiazepam were employed as substrates of CYP3A4 to propose a
      kinetic model. The model hypothesized that CYP3A4 contains two substrate-binding
      sites in a single active site that are both distinct and co-operative, and the
      resulting velocity equation had a good fit with the sigmoidal kinetic
      observations. Therefore, four pairs of the kinetic estimates (KS1, kalpha, KS2,
      kbeta, KS3, kdelta, KS4 and kgamma) were resolved to interpret the features of
      binding affinity and catalytic ability of CYP3A4. Dissociation constants KS1 and
      KS2 for two single-substrate-bound enzyme molecules (SE and ES) were 3-50-fold
      greater than KS3 and KS4 for a two-substrate-bound enzyme (SES), while respective
      rate constants kdelta and kgamma were 3-218-fold greater than kalpha and kbeta,
      implying that access and binding of the first molecule to either site in an
      active pocket of CYP3A4 can enhance the binding affinity and reaction rate of the
      vacant site for the second substrate. Thus our results provide some new insights
      into the co-operative binding of two substrates in the inner portions of an
      allosteric CYP3A4 active site.

PMID- 10359673
TI  - Transcription factor GCN4 for control of amino acid biosynthesis also regulates
      the expression of the gene for lipoamide dehydrogenase.
AB  - The yeast LPD1 gene encoding lipoamide dehydrogenase is subject to the general
      control of amino acid biosynthesis mediated by the GCN4 transcription factor.
      This is striking in that it demonstrates that GCN4-mediated regulation extends
      much farther upstream than simply to the direct pathways for amino acid and
      purine biosynthesis. In yeast, lipoamide dehydrogenase functions in at least
      three multienzyme complexes: pyruvate dehydrogenase and 2-oxoglutarate
      dehydrogenase (which function in the entry of pyruvate into, and metabolism via,
      the citric acid cycle) and glycine decarboxylase. When wild-type cells were
      shifted from growth on amino acid-rich to amino acid-deficient medium, the
      expression of lipoamide dehydrogenase was induced approx. 2-fold. In a similar
      experiment no such induction was observed in isogenic gcn4 mutant cells. Northern
      analysis indicated that amino acid starvation affected levels of the LPD1
      transcript. In the upstream region of LPD1 are three matches to the consensus for
      control mediated by GCN4. Directed mutagenesis of each site, and of all
      combinations of sites, suggests that only one site might be important for the
      general control response under the conditions tested. Gel-retardation analysis
      with GCN4 protein synthesized in vitro has indicated that GCN4 can bind in vitro
      to at least two of the consensus motifs.

PMID- 10359675
TI  - 'Un chant d'appel amoureux': acoustic communication in moths 
AB  - Tympanal sound receptors in moths evolved in response to selective pressures
      provided by echolocating insectivorous bats. The presence of these ultrasound
      detectors also set the stage for the later evolution of ultrasonic courtship
      signals in the tympanate moth families. Male moths have repeatedly exploited the
      bat-detection mechanisms in females for the purpose of finding, identifying and
      obtaining mates. Ultrasonic courtship has been described in several members of
      the moth families Arctiidae, Noctuidae and Pyralidae, and ultrasound is predicted
      to play a significant role in the courtship of other tympanate moths including
      the Sphingidae, Lymantriidae, Notodontidae and Geometridae. Ultrasonic signals
      are involved in species recognition, in male-male competition for mates and in
      female mate-choice systems. Pre-existing motor systems, including those involved
      in bat defence, have also been exploited for the purpose of generating high
      frequency courtship signals. Sound production mechanisms in moths include
      thoracic tymbals, tegular tymbals, alar castanets and genital stridulatory
      organs. Thus, in both their sensory and motor aspects, the weapons of bat/moth
      warfare have frequently evolved into components of courtship systems.

PMID- 10359676
TI  - Kinematics of flap-bounding flight in the zebra finch over a wide range of speeds
AB  - It has been proposed elsewhere that flap-bounding, an intermittent flight style
      consisting of flapping phases interspersed with flexed-wing bounds, should offer
      no savings in average mechanical power relative to continuous flapping unless a
      bird flies 1.2 times faster than its maximum range speed (Vmr). Why do some
      species use intermittent bounds at speeds slower than 1.2Vmr? The 'fixed-gear
      hypothesis' suggests that flap-bounding is used to vary mean power output in
      small birds that are otherwise constrained by muscle physiology and wing anatomy
      to use a fixed muscle shortening velocity and pattern of wing motion at all
      flight speeds; the 'body-lift hypothesis' suggests that some weight support
      during bounds could make flap-bounding flight aerodynamically advantageous in
      comparison with continuous flapping over most forward flight speeds. To test
      these predictions, we studied high-speed film recordings (300 Hz) of wing and
      body motion in zebra finches (Taenopygia guttata, mean mass 13.2 g, N=4) taken as
      the birds flew in a variable-speed wind tunnel (0-14 m s-1). The zebra finches
      used flap-bounding flight at all speeds, so their flight style was unique
      compared with that of birds that facultatively shift from continuous flapping or
      flap-gliding at slow speeds to flap-bounding at fast speeds. There was a
      significant effect of flight speed on all measured aspects of wing motion except
      percentage of the wingbeat spent in downstroke. Changes in angular velocity of
      the wing indicated that contractile velocity in the pectoralis muscle changed
      with flight speed, which is not consistent with the fixed-gear hypothesis.
      Although variation in stroke-plane angle relative to the body, pronation angle of
      the wing and wing span at mid-upstroke showed that the zebra finch changed within
      wingbeat geometries according to speed, a vortex-ring gait with a feathered
      upstroke appeared to be the only gait used during flapping. In contrast, two
      small species that use continuous flapping during slow flight (0-4 m s-1) either
      change wingbeat gait according to flight speed or exhibit more variation in
      stroke-plane and pronation angles relative to the body. Differences in kinematics
      among species appear to be related to wing design (aspect ratio, skeletal
      proportions) rather than to pectoralis muscle fiber composition, indicating that
      the fixed-gear hypothesis should perhaps be modified to exclude muscle physiology
      and to emphasize constraints due to wing anatomy. Body lift was produced during
      bounds at speeds from 4 to 14 m s-1. Maximum body lift was 0.0206 N (15.9 % of
      body weight) at 10 m s-1; body lift:drag ratio declined with increasing air
      speed. The aerodynamic function of bounds differed with increasing speed from an
      emphasis on lift production (4-10 m s-1) to an emphasis on drag reduction with a
      slight loss in lift (12 and 14 m s-1). From a mathematical model of aerodynamic
      costs, it appeared that flap-bounding offered the zebra finch an aerodynamic
      advantage relative to continuous flapping at moderate and fast flight speeds (6
      14 m s-1), with body lift augmenting any savings offered solely by flap-bounding
      at speeds faster than 7.1 m s-1. The percentage of time spent flapping during an
      intermittent flight cycle decreased with increasing speed, so the mechanical cost
      of transport was likely to be lowest at faster flight speeds (10-14 m s-1).

PMID- 10359674
TI  - Regulation of photoreceptor phosphodiesterase catalysis by its non-catalytic cGMP
      binding sites.
AB  - The photoreceptor 3':5'-cyclic nucleotide phosphodiesterase (PDE) is the central
      enzyme of visual excitation in rod photoreceptors. The hydrolytic activity of PDE
      is precisely regulated by its inhibitory gamma subunit (Pgamma), which binds
      directly to the catalytic site. We examined the inhibition of frog rod outer
      segment PDE by endogenous Pgamma, as well as by synthetic peptides corresponding
      to its central and C-terminal domains, to determine whether the non-catalytic
      cGMP-binding sites on the catalytic alphabeta dimer of PDE allosterically
      regulate PDE activity. We found that the apparent binding affinity of Pgamma for
      PDE was 28 pM when cGMP occupied the non-catalytic sites, whereas Pgamma had an
      apparent affinity only 1/16 of this when the sites were empty. The elevated basal
      activity of PDE with empty non-catalytic sites can be decreased by the addition
      of nanomolar levels of cGMP, demonstrating that the high-affinity non-catalytic
      sites on the PDE catalytic dimer mediate this effect. No evidence for a direct
      allosteric effect of the non-catalytic sites on catalysis could be detected for
      the activated enzyme lacking bound Pgamma. The intrinsic affinity of a synthetic
      C-terminal (residues 63-87) Pgamma peptide to bind and to inhibit the hydrolytic
      activity of activated PDE was enhanced 300-fold in the presence of cGMP compared
      with cAMP. We conclude that the binding of cGMP to the non-catalytic sites of PDE
      induces an allosteric change in the structure of the catalytic domain that
      greatly enhances the interaction of the C-terminus of Pgamma with the catalytic
      domain.

PMID- 10359677
TI  - Mechanical versus physiological determinants of swimming speeds in diving
      Brunnich's guillemots.
AB  - For fast flapping flight of birds in air, the maximum power and efficiency of the
      muscles occur over a limited range of contraction speeds and loads. Thus,
      contraction frequency and work per stroke tend to stay constant for a given
      species. In birds such as auks (Alcidae) that fly both in air and under water,
      wingbeat frequencies in water are far lower than in air, and it is unclear to
      what extent contraction frequency and work per stroke are conserved. During
      descent, compression of air spaces dramatically lowers buoyant resistance, so
      that maintaining a constant contraction frequency and work per stroke should
      result in an increased swimming speed. However, increasing speed causes
      exponential increases in drag, thereby reducing mechanical versus muscle
      efficiency. To investigate these competing factors, we have developed a
      biomechanical model of diving by guillemots (Uria spp.). The model predicted
      swimming speeds if stroke rate and work per stroke stay constant despite changing
      buoyancy. We compared predicted speeds with those of a free-ranging Brunnich's
      guillemot (U. lomvia) fitted with a time/depth recorder. For descent, the model
      predicted that speed should gradually increase to an asymptote of 1.5-1.6 m s-1
      at approximately 40 m depth. In contrast, the instrumented guillemot typically
      reached 1.5 m s-1 within 10 m of the water surface and maintained that speed
      throughout descent to 80 m. During ascent, the model predicted that guillemots
      should stroke steadily at 1.8 m s-1 below their depth of neutral buoyancy (62 m),
      should alternate stroking and gliding at low buoyancies from 62 to 15 m, and
      should ascend passively by buoyancy alone above 15 m depth. However, the
      instrumented guillemot typically ascended at 1.25 m s-1 when negatively buoyant,
      at approximately 1.5 m s-1 from 62 m to 25 m, and supplemented buoyancy with
      stroking above 25 m. Throughout direct descent, and during ascent at negative and
      low positive buoyancies (82-25 m), the guillemot maintained its speed within a
      narrow range that minimized the drag coefficient. In films, guillemots descending
      against high buoyancy at shallow depths increased their stroke frequency over
      that of horizontal swimming, which had a substantial glide phase. Model
      simulations also indicated that stroke duration, relative thrust on the
      downstroke versus the upstroke, and the duration of gliding can be varied to
      regulate swimming speed with little change in contraction speed or work per
      stroke. These results, and the potential use of heat from inefficient muscles for
      thermoregulation, suggest that diving guillemots can optimize their mechanical
      efficiency (drag) with little change in net physiological efficiency.

PMID- 10359678
TI  - Arterial blood gas levels and cardiovascular function during varying
      environmental conditions in a mudskipper, periophthalmodon schlosseri 
AB  - Changes in blood gas levels, blood pressure and heart rate were studied in
      chronically cannulated mudskippers, Periophthalmodon schlosseri, subjected to air
      exposure (6 h), aquatic hypoxia with access to air (water PO2 <0.9 kPa, 6 h) and
      forced submersion in normoxic water (12 h) at 30 degrees C. Air exposure did not
      affect either blood O2 and had little effect on blood CO2 levels, but blood pH
      increased slightly, but significantly. Blood ammonia concentration was elevated
      sixfold during air exposure. Aquatic hypoxia caused no significant changes in
      blood gas levels. When the fish was forcibly submerged, blood O2 saturation
      decreased rapidly to approximately 30 %. Blood PCO2 and total CO2 also decreased,
      but blood pH was unaffected by forcible submersion. Air exposure did not affect
      blood pressure or heart rate. Aquatic hypoxia did not affect blood pressure but
      transiently increased heart rate. In contrast, forced submersion significantly
      depressed heart rate throughout the period of submersion, while blood pressure
      decreased only transiently. Upon emersion, the heart rate immediately increased
      to above the control level when the fish took its first air breath.

PMID- 10359679
TI  - Na+/Ca2+ exchange current in ventricular myocytes of fish heart: contribution to
      sarcolemmal Ca2+ influx 
AB  - Influx of extracellular Ca2+ plays a major role in the activation of contraction
      in fish cardiac cells. The relative contributions of Na+/Ca2+ exchange and L-type
      Ca2+ channels to Ca2+ influx are, however, unknown. Using a physiological action
      potential as the command pulse in voltage-clamped heart cells, we examined
      sarcolemmal Ca2+ influx through Na+/Ca2+ exchange and L-type Ca2+ channels in
      crucian carp (Carassius carassius L.) ventricular myocytes. When other cation
      conductances were blocked, a Ni2+-sensitive current with the characteristic
      voltage- and time-dependent properties of the Na+/Ca2+ exchange current could be
      distinguished. At the maximum overshoot voltage of the ventricular action
      potential (+40 mV; [Na+]i=10 mmol l-1), the density of the Na+/Ca2+ exchange
      current was 2.99+/-0.27 pA pF-1 for warm-acclimated fish (23 degrees C) and
      2.38+/-0.42 pA pF-1 for cold-acclimated fish (4 degrees C) (means +/- s.e.m., N=5
      6; not significantly different, P=0.26). The relative contributions of the
      Na+/Ca2+ exchanger and L-type Ca2+ channels to Ca2+ influx were estimated using
      two partly different methods. Integration of the Ni2+-sensitive Na+/Ca2+ exchange
      current and the verapamil- and Cd2+-sensitive L-type Ca2+ current suggests that,
      during the action potential, approximately one-third of the activating Ca2+ comes
      through Na+/Ca2+ exchange and approximately two-thirds through L-type Ca2+
      channels. An alternative method of analysis, using the inward tail current as a
      measure of the total sarcolemmal Ca2+ flux from which the Ni2+-sensitive Na+/Ca2+
      exchange current was subtracted to obtain the Ca2+ influx through the channels,
      suggests that L-type Ca2+ channels and Na+/Ca2+ exchange are almost equally
      important in the activation of contraction. Furthermore, the time course of cell
      shortening is not adequately explained by sarcolemmal Ca2+ influx through the
      channels alone, but is well approximated by the sum of Ca2+ influx through the
      channels and the exchanger. The present results indicate that reverse Na+/Ca2+
      exchange in crucian carp ventricular myocytes has sufficient capacity to trigger
      contraction and suggest that the exchange current makes a significant
      contribution to contractile Ca2+ during the physiological action potential. The
      relative significance of channels and exchanger molecules in sarcolemmal Ca2+
      entry into crucian carp ventricular myocytes was unaffected by thermal
      acclimation when determined at 22 degrees C.

PMID- 10359680
TI  - A high-resolution in vitro bioassay to identify neurons containing red pigment
      concentrating hormone 
AB  - The release of red pigment concentrating hormone (RPCH) by single peptidergic
      neurons of the crayfish X organ/sinus gland system (XO-SG) was demonstrated using
      a novel in vitro bioassay in which XO neurons were co-cultured with tegumentary
      erythrophores. Local retraction of the pigmentary matrix within filipodia from
      erythrophores plated next to presumptive RPCH-containing neurons suggest
      spontaneous hormone release. Topical application of synthetic RPCH onto long
      filipodia also produced a local response. The time course of pigmentary matrix
      aggregation depended on the dose of synthetic RPCH. The effect of peptide on the
      cultured target cells was blocked by a polyclonal antiserum against RPCH. In co
      culture conditions, the time course of pigmentary matrix aggregation was
      accelerated when presumptive RPCH-containing neurons were depolarized by
      intracellular current injection or by voltage-clamping to activate the Ca2+
      current. The aggregation response evoked by these maneuvers was similar to that
      obtained with synthetic RPCH at a concentration of 1 fmol l-1. The immune serum
      was also used to identify a subset of 3-7 immunoreactive neurons localized in the
      external rim of the XO close to the medulla interna. Under culture conditions,
      this subset of neurons corresponded to the cells that induced the erythrophore
      response.

PMID- 10359681
TI  - Modulatory effects of some amino acids and neuropeptides on luminescence in the
      brittlestar amphipholis squamata 
AB  - Amphipholis squamata is a polychromatic luminescent ophiuroid. The effects of
      amino acids ( &ggr; -aminobutyric acid, GABA, taurine, glycine and glutamate), N
      methyl-d-aspartate (NMDA) and the invertebrate neuropeptides Antho-RFamide,
      FMRFamide and SALMFamides S1 and S2 were tested on acetylcholine-induced
      luminescence from isolated arms of clear and black specimens of Amphipholis
      squamata. The results showed that GABA, glycine and Antho-RFamide inhibited ACh
      induced luminescence of clear specimens and had no significant effect on black
      specimens. Glutamic acid had no significant effect on ACh-induced luminescence,
      but triggered luminescence in the absence of ACh in both types of specimen.
      Taurine, NMDA and FMRFamide showed no significant effects on either clear or
      black specimens. S1 potentiated ACh-induced luminescence of clear and black
      specimens, while S2 had no clear modulatory effect on luminescence. These results
      suggest that, in addition to the previously described cholinergic system in
      Amphipholis squamata, there is also a modulatory component to luminescence
      control. Moreover, we observed a difference in modulation of luminescence between
      clear and black specimens.

PMID- 10359682
TI  - Echolocation behaviour and prey-capture success in foraging bats: laboratory and
      field experiments on Myotis daubentonii.
AB  - During prey-capture attempts, many echolocating bats emit a 'terminal buzz', when
      pulse repetition rate is increased and pulse duration and interpulse interval are
      shortened. The buzz is followed by a silent interval (the post-buzz pause). We
      investigated whether variation in the structure of the terminal buzz, and the
      calls and silent periods following it, may provide information about whether the
      capture attempt was successful and about the size of prey detected - detail that
      is valuable in studies of habitat use and energetics. We studied the trawling bat
      Myotis daubentonii. The time between the first call of the approach phase and the
      end of the terminal phase was not related to prey size in the laboratory. The
      last portion of the terminal buzz (buzz II) was shortened or omitted during
      aborted capture attempts. Both in the laboratory and in the field, the mean
      interpulse interval immediately after the terminal buzz (post-buzz interpulse
      interval) was longer in successful captures than in unsuccessful attempts. In the
      laboratory, the post-buzz pause was longer after successful captures than for
      unsuccessful attempts, and the minimum frequency of the first search-phase call
      emitted after the buzz (Fmin) was higher than that of the last such call prior to
      the buzz. These effects were not apparent in field data. Both in the laboratory
      (85%) and in the field (74%), significant discrimination between successful and
      unsuccessful capture attempts was possible when the duration of the post-buzz
      pause, post-buzz interpulse interval and Fmin were entered into a discriminant
      analysis. Thus, variation in the echolocation calls of bats during prey-capture
      attempts can reveal substantial information about capture success and prey size.

PMID- 10359683
TI  - Transduction of mechanical energy into sound energy in the cicada cyclochila
      australasiae 
AB  - The anatomy of the paired tymbal muscles of Cyclochila australasiae was
      described. Force-distance relationships of the sound-producing in-out cycle of
      tymbal movement were measured. The largest forces were measured when the push
      occurred at the apodeme pit on the tymbal plate at angles similar to the angles
      of internal pull of the tymbal muscle. Initially, inward movement was opposed by
      the elasticity of the tymbal, which stored energy. At a mean force of 0. 38 N
      after a mean inward strain of 368 microm, the tymbal ribs buckled, the mean
      energy release being 45.1 microJ. The energy release occurred over 2-10 ms in
      three or four sound-producing steps as successive tymbal ribs buckled inwards.
      After the ribs had buckled, the force decreased to a mean value of 0.17 N. The
      force returned to zero during the outward movement, during which the tymbal ribs
      buckled outwards. The mean energy dissipated in the outward movement was 32.8
      microJ. During contraction, the tymbal muscle produced mean values for the peak
      active force of 0.31 N over 295 microm, which gave mean values for the area of
      the work loops of 47.0 microJ. The calling song of C. australasiae had a mean
      pulse rate of 234 Hz (117 Hz for each side of the insect). The peak power to mean
      power ratio for the songs was 8.51:1 (+9.30 dB). Measurements of the sound field
      around tethered insects and of the peak power to mean power ratio of the songs
      gave values for the mean power of the song of 3.15-7 mW; these correspond to an
      energy per song pulse of 13.5-30 microJ. Previously reported mean values are 3.
      15 mW for protest song and 5.1 mW for calling song. The efficiency of
      transduction of mechanical energy into sound energy is between 18 and 46 %.

PMID- 10359684
TI  - Lipid accumulation in the ovaries of a marine shrimp penaeus semisulcatus (de
      haan) 
AB  - By the end of oocyte development, the ovaries of Penaeus semisulcatus have
      accumulated almost equal amounts (approximately 16 mg lipid g-1 protein) of
      phospholipids and triacylglycerols. The phospholipids consist mainly of
      phosphatidylcholine (75-80 %) and phosphatidylethanolamine (20-25 %).
      Approximately 30 % of the total fatty acid content of both phospholipids and
      triacylglycerols is made up of polyunsaturated fatty acids. In fractions obtained
      by centrifugation of ovarian homogenates, most of the increase in levels of
      ovarian lipids during ovarian maturation was associated with an increase in
      triacylglycerol levels in the floating fat fraction and of phospholipids in the
      infranatant fraction. The presence of polyunsaturated fatty acids in the ovaries
      indicates the occurrence of lipid transport to the ovary during oocyte
      maturation. The gradual decrease in the relative abundance of polyunsaturated
      fatty acids as the ovaries matured supports previously published results
      suggesting intra-ovarian synthesis of saturated and mono-unsaturated fatty acids.
      Most of the lipids found in the female haemolymph (64.8 %) were recovered in the
      high-density lipoprotein fraction after density ultracentrifugation. The
      haemocyanin fraction recovered from this stage of fractionation contained
      substantial amounts of lipid (16.8 %) that could be removed by further sequential
      centrifugation at a higher NaBr density, leaving less than 0.9 % of the total
      haemolymph lipids associated with this fraction. While 16.2 % of the lipids were
      recovered from the very high-density lipoprotein fractions, these lipoproteins
      carried only 64-89 microg lipid mg-1 protein compared with 538.9 microg lipid mg
      1 protein in the high-density lipoprotein fraction, indicating that the high
      density lipoproteins are more likely to be the main transporters of lipids to the
      ovary. However, the contribution of very high-density lipoproteins to lipid
      transport cannot be ruled out at this stage. In this study, we present two models
      for lipid transport to the ovary based on the abundance of phospholipids and
      triacylglycerols in the haemolymph and on the amounts of polyunsaturated fatty
      acids accumulated within the ovary during vitellogenesis.

PMID- 10359685
TI  - Learning walks and landmark guidance in wood ants (Formica rufa) 
AB  - We have examined a behaviour pattern in wood ants which in some respects
      resembles and in other respects differs from the learning flights of bees and
      wasps. Wood ants returning to their nest from a newly discovered food source turn
      back and look at landmarks near to the feeder, but the feeder itself does not
      attract sustained fixations. The frequency of landmark inspections is highest
      when the ant is close to the feeder and falls as the ant moves away. In common
      with learning flights, inspections of landmarks on departure become less frequent
      as ants become familiar with their surroundings and reappear after a long
      interval without foraging. A principal difference between the learning flights of
      wasps and bees and this putative learning behaviour in ants is the emphasis that
      ants place on landmark fixation. Ants and honeybees move differently when
      searching for a goal within an array of transformed landmarks. We have explored,
      using computer simulation, whether this difference can be explained by the
      prominence ants give to the matching of landmarks viewed in the frontal visual
      field.

PMID- 10359686
TI  - No evidence for olfactory blocking in honeybee classical conditioning 
AB  - We use binary odorant compounds to investigate 'blocking' in honeybees which
      learn to associate an odorant (A-D) with a sucrose reward as the reinforcer (+).
      'Blocking' means that learning about a stimulus B is reduced when trained in
      compound with a stimulus A that has previously been trained alone. Thus,
      reinforcement of B in these circumstances is not sufficient to induce learning.
      Such blocking is a frequently observed phenomenon in vertebrate learning and has
      also recently been reported in honeybee olfactory learning. To explain blocking,
      current models of conditioning include cognition-like concepts of attention or
      expectation which, consequently, seem also to apply to honeybees. Here, we first
      reproduce a blocking-like effect in an experimental design taken from the
      literature. We identify two confounding variables in that design and
      experimentally demonstrate their potential to support a blocking-like effect.
      After eliminating these confounding variables using a series of different
      training procedures, the blocking-like effect disappeared. Thus, convincing
      evidence for blocking in honeybee classical conditioning is at present lacking.
      This casts doubt on the applicability of cognition-like concepts to honeybees.

PMID- 10359687
TI  - Biological sensors: More than one way to sense oxygen.
AB  - Recently determined structures of the oxygen-sensing heme domain of the bacterial
      protein FixL have revealed a new binding environment and signal transduction
      mechanism for heme; they have also provided new insights into the diverse 'PAS'
      domain superfamily.

PMID- 10359688
TI  - Leukocyte adhesion: High-speed cells with ABS.
AB  - In order to decide where to exit blood vessels and enter tissues, leukocytes roll
      along endothelial surfaces. Recent studies suggest that an 'automatic braking
      system' (ABS), involving selectin cell-adhesion molecules, enables leukocytes to
      roll at a fairly constant velocity despite large variations in blood flow rate.

PMID- 10359689
TI  - Oxidative stress: Protein folding with a novel redox switch.
AB  - A novel cellular response to oxidative stress has been discovered, in which the
      activity of a molecular chaperone, Hsp33, is modulated by the environmental redox
      potential. This provides a rapid first defence mechanism against the potentially
      very harmful toxic effects of oxidative stress.

PMID- 10359690
TI  - Pre-mRNP particles: From gene to nuclear pore.
AB  - It has been difficult to establish whether pre-messenger ribonucleoprotein (pre
      mRNP) particles move from the gene towards the periphery of the nucleus in a
      directed or random manner. Two recent in vivo studies indicate that most pre-mRNP
      particles move randomly in the nucleus, apparently by free diffusion.

PMID- 10359691
TI  - Chromatin replication: Finding the right connection.
AB  - Nucleosomes are preferentially assembled on replicating DNA by chromatin assembly
      factor 1; recent studies have shown that replicated DNA is marked for assembly
      into chromatin by the replication-fork-associated protein PCNA.

PMID- 10359692
TI  - CNS development: The obscure origins of adult stem cells.
AB  - Stem cells of the adult central nervous system are the focus of a great deal of
      attention because of their potential for making new neural cells. A recent study
      has claimed to identify their in vivo location, but this important issue remains
      controversial.

PMID- 10359693
TI  - Multidrug resistance: Versatile drug sensors of bacterial cells.
AB  - One way that bacteria resist antimicrobial agents involves 'drug sensors',
      proteins that bind a range of structurally unrelated antimicrobial drugs and
      induce expression of multidrug resistance pumps. The basis for drug recognition
      is now becoming clear from the recently determined crystal structure of a drug
      sensor.

PMID- 10359694
TI  - Intracellular signaling: Fleshing out the TGFbeta pathway.
AB  - Recent studies of the intracellular signaling pathway initiated by ligands of the
      transforming growth factor beta (TGFbeta) family have provided new insights into
      how the receptors for such ligands phosphorylate their substrates - the Smads -
      and how signaling specificity is achieved.

PMID- 10359695
TI  - Localization and anchoring of mRNA in budding yeast.
AB  - BACKGROUND: Eukaryotic cells localize selected mRNAs to a region of the cell as a
      means to sequester proteins. Signals within the 3' untranslated region (3' UTR)
      facilitate mRNA localization by both actin and microtubule cytoskeletal systems.
      Recently, an mRNA in the yeast Saccharomyces cerevisiae, ASH1, was shown to
      coalesce into a discrete particle that is maintained at the bud tip. Mutations in
      five genes, SHE1-SHE5, cause defects in particle formation and/or localization of
      the ASH1 transcript. Factors at the destination of the mRNA transport remain to
      be identified. RESULTS: We have developed a system to label mRNA in living yeast
      with green fluorescent protein (GFP) and follow the dynamics of mRNA movement and
      localization. Constitutively expressing an ASH1 mRNA containing the bacteriophage
      MS2 coat-protein binding site adjacent to the ASH1 3' UTR allowed us to visualize
      ASH1 mRNA with an MS2-coat-protein-GFP fusion protein (together denoted
      'gRNAASH1'). The gRNAASH1 was restricted to the bud tip in small to large budded
      cells, migrated to the bud neck prior to cell separation and then rapidly
      relocalized to the incipient site of bud growth. It also localized to regions of
      polarized growth during mating. In cells lacking Bud6p/Aip3p or Bnilp/She5p,
      which are involved in polarity establishment and actin organization, gRNAASH1
      migrated to the bud but failed to remain at the bud tip. These studies reveal
      discrete transport and anchoring steps in mRNA localization. CONCLUSIONS: The
      ASH1 mRNA was maintained at sites of polarized growth throughout the vegetative
      and mating cell cycles. Bud6p/Aip3p and Bni1p/She5p are required to maintain the
      transcript at the cortical bud cap.

PMID- 10359696
TI  - Wound-induced assembly and closure of an actomyosin purse string in Xenopus
      oocytes.
AB  - BACKGROUND: Both single cells and multicellular systems rapidly heal physical
      insults but are thought to do so by distinctly different mechanisms. Wounds in
      single cells heal by calcium-dependent membrane fusion, whereas multicellular
      wounds heal by a variety of different mechanisms, including circumferential
      contraction of an actomyosin 'purse string' that assembles around wound borders
      and is dependent upon the small GTPase Rho. RESULTS: We investigated healing of
      puncture wounds made in Xenopus oocytes, a single-cell system. Oocyte wounds
      rapidly assumed a circular morphology and constricted circumferentially,
      coincident with the recruitment of filamentous actin (F-actin) and myosin-II to
      the wound borders. Surprisingly, recruitment of myosin-II to wound borders
      occurred before that of F-actin. Further, experimental disruption of F-actin
      prevented healing but did not prevent myosin-II recruitment. Actomyosin purse
      string assembly and closure was dependent on Rho GTPases and extracellular
      calcium. Wounding resulted in reorganization of microtubules into an array
      similar to that which forms during cytokinesis in Xenopus embryos. Experimental
      perturbation of oocyte microtubules before wounding inhibited actomyosin
      recruitment and wound closure, whereas depolymerization of microtubules after
      wounding accelerated wound closure. CONCLUSIONS: We conclude the following:
      actomyosin purse strings can close single-cell wounds; myosin-II is recruited to
      wound borders independently of F-actin; purse-string assembly is dependent on a
      Rho GTPase; and purse-string assembly and closure are controlled by microtubules.
      More generally, the results indicate that actomyosin purse strings have been co
      opted through evolution to dispatch a broad variety of single-cell and
      multicellular processes, including wound healing, cytokinesis and morphogenesis.

PMID- 10359697
TI  - Threshold of pre-T-cell-receptor surface expression is associated with alphabeta
      T-cell lineage commitment.
AB  - BACKGROUND: The development of immature thymocytes is regulated by the pre-T-cell
      receptor (pre-TCR). The pre-TCR is involved in several developmental processes
      including rescuing cells from programmed cell death, allelic exclusion and
      alphabeta versus gammadelta T-cell lineage commitment. A major issue is how the
      pre-TCR functions to integrate these processes in developing thymocytes. RESULTS:
      We have used a sensitive immunofluorescence technique to reveal the surface
      expression profile of the pre-TCR on immature thymocyte subsets. We show that
      early pre-T cells (CD25(+)CD44(-)) can be subdivided on the basis of the level of
      surface pre-TCR expression. Detectable surface pre-TCR expression identified a
      rapidly cycling population of early pre-T cells which had successfully undergone
      beta-selection and been rescued from programmed cell death. Late pre-T cells
      (CD25(-)CD44(-)), which had traversed the beta-selection checkpoint, expressed
      surprisingly heterogeneous surface levels of the pre-TCR: high levels of surface
      pre-TCR expression were associated with commitment to the alphabeta T-cell
      lineage, whereas late pre-T cells with lower levels of surface pre-TCR could
      develop along both the alphabeta or gammadelta T-cell lineages. CONCLUSIONS:
      These data demonstrate that the surface expression of the pre-TCR can be used to
      reveal newly identified stages of T-cell development and to provide insights into
      alphabeta T-cell lineage commitment. They show that, although pre-TCR expression
      does not act as a developmental switch per se, its level of surface expression on
      late pre-T cells predicts their developmental potential.

PMID- 10359698
TI  - Nodal signalling and the roles of the transcription factors SnR and Pitx2 in
      vertebrate left-right asymmetry.
AB  - Left-specific mesodermal expression of the homeobox gene Pitx2 links a gastrula
      stage intercellular signalling cascade to the later development of vertebrate
      left-right organ asymmetry through the Nodal signalling pathway [1] [2][3] [4][5]
      [6]. SnR (Drosophila snail-related), a gene conserved in vertebrates and encoding
      a zinc-finger protein, appears to function in a similar manner to Pitx2, but
      through right-specific mesodermal expression [7] [8]. Here, we present direct
      evidence for an earlier proposal [7] that Nodal signalling specifically represses
      expression of SnR in left lateral mesoderm, and thus ensures its normal
      confinement to the right, while activating Pitx2 on the left. We addressed the
      relationship between Pitx2 and SnR using antisense disruption of SnR. Relatively
      severe antisense-SnR treatment led to massive ectopic expression of Pitx2 on the
      right, accompanied by randomisation of situs with embryos showing aspects of left
      cardiac isomerism. This indicates a gene cascade relationship in the propagation
      of left-right information, whereby nodal activates Pitx2 on the left through a
      double-negative mechanism involving the repression of SnR's repressor role on
      Pitx2. Milder antisense-SnR treatment reversed heart-loop direction and embryo
      torsion at significant incidence, although Pitx2 expression remained normally
      left-confined throughout. This reversed morphology following SnR disruption alone
      appeared different from that in which additional ectopic right-hand Pitx2
      expression was seen. Therefore, in addition to their regulatory gene cascade
      relationship, these two transcription factors appear to have further, parallel
      but non-redundant, roles in directly controlling normally right- and left
      specific morphogenetic processes.

PMID- 10359699
TI  - Muscle founder cells regulate defasciculation and targeting of motor axons in the
      Drosophila embryo.
AB  - During Drosophila embryogenesis, motor axons leave the central nervous system
      (CNS) as two separate bundles, the segmental nerve (SN) and intersegmental nerve
      (ISN). From these, axons separate (defasciculate) progressively in a
      characteristic pattern, initially as nerve branches and then as individual axons,
      to innervate target muscles [1] [2]. This pattern of branching resembles the
      outgrowth and defasciculation of motor axons from the neural tube of vertebrate
      embryos. The factors that trigger nerve branching are unknown. In vertebrate
      limbs, the branched innervation may depend on mesodermal cues, in particular on
      the connective tissues that organise the muscle pattern [3]. In Drosophila, the
      muscle pattern is organised by specific mesodermal cells, the founder myoblasts,
      which initiate the development of individual muscles [4][5][6]. Founder myoblasts
      fuse with neighbouring non-founder myoblasts and entrain these to a specific
      muscle programme, which also determines their innervation [4] [7]. In the absence
      of mesoderm, ISN and SN can form, but motor axons fail to defasciculate from
      these bundles [7]. The cue(s) for nerve branching therefore lie within the
      mesoderm, most likely in the muscles and/or in the precursor cells of the adult
      musculature [8]. Here, we show that founder myoblasts are the source of the
      cue(s) that are required to trigger defasciculation and targeted growth of motor
      axons. Moreover, we found that a single founder myoblast can trigger the
      defasciculation of an entire nerve branch. This suggests that the muscle field is
      structured into sets of muscles, each expressing a common defasciculation cue for
      a particular nerve branch.

PMID- 10359700
TI  - Oligomeric ring structure of the Bloom's syndrome helicase.
AB  - Bloom's syndrome is a recessive human genetic disorder associated with an
      elevated incidence of many types of cancer. The Bloom's syndrome gene product,
      BLM, belongs to the RecQ subfamily of DNA helicases and is required for the
      maintenance of genomic stability in human cells - in particular, the suppression
      of reciprocal exchanges between sister chromatids. We have investigated the
      quaternary structure of BLM using a combination of size-exclusion chromatography
      and electron microscopy with reference-free image processing. We found that BLM
      forms hexameric ring structures with an overall diameter of approximately 13 nm
      surrounding a central hole of approximately 3.5 nm diameter. A fourfold symmetric
      square form with approximately 11 nm sides and a hole of approximately 4 nm
      diameter was also detected, which might represent a distinct oligomeric species
      or a side view of the hexameric form. Chromatography studies indicated that the
      majority of enzymatically active BLM has an apparent molecular mass of > 700 kDa,
      which is consistent with an oligomeric structure for BLM. This provides the first
      structural analysis of an oligomeric ring helicase of eukaryotic cellular origin.
      These results have implications for the mechanism of action of BLM and suggest
      that other RecQ family helicases, including the WRN protein associated with
      Werner's syndrome, might also adopt ring structures.

PMID- 10359702
TI  - Induction of NF-kappaB by the Akt/PKB kinase.
AB  - The serine/threonine kinase Akt (also known as protein kinase B, PKB) is
      activated by numerous growth-factor and immune receptors through lipid products
      of phosphatidylinositol (PI) 3-kinase. Akt can couple to pathways that regulate
      glucose metabolism or cell survival [1]. Akt can also regulate several
      transcription factors, including E2F, CREB, and the Forkhead family member Daf-16
      [2] [3] [4]. Here, we show that Akt can regulate signaling pathways that lead to
      induction of the NF-kappaB family of transcription factors in the Jurkat T-cell
      line. This induction occurs, at least in part, at the level of degradation of the
      NF-kappaB inhibitor IkappaB, and is specific for NF-kappaB, as other inducible
      transcription factors are not affected by Akt overexpression. Furthermore, the
      effect requires the kinase activity and pleckstrin homology (PH) domain of Akt.
      Also, Akt does not act alone to induce cytokine promoters and NF-kappaB
      reporters, because signals from other pathways are required to observe the
      effect. These studies uncover a previously unappreciated connection between Akt
      and NF-kappaB induction that could have implications for the control of T-cell
      growth and survival.

PMID- 10359701
TI  - Suckling defect in mice lacking the soluble haemopoietin receptor NR6.
AB  - Cytokines control a variety of cellular responses including proliferation,
      differentiation, survival and functional activation, via binding to specific
      receptors expressed on the surface of target cells [1]. The cytokine receptors of
      the haemopoietin family are defined by the presence of a conserved 200 amino acid
      extracellular domain known as the haemopoietin domain [2]. We report here the
      isolation of NR6, a haemopoietin receptor that, like the p40 subunit of
      interleukin-12 (IL-12) [3] and the EBI3 gene induced by Epstein-Barr virus
      infection in lymphocytes [4], contains a typical haemopoietin domain but lacks
      transmembrane and cytoplasmic domains. Although in situ hybridisation revealed
      NR6 expression at multiple sites in the developing embryo, mice lacking NR6 did
      not display obvious abnormalities and were born in the expected numbers. Neonatal
      NR6(-/-) mice failed to suckle, however, and died within 24 hours of birth,
      suggesting that NR6 is necessary for the recognition or processing of pheromonal
      signals or for the mechanics of suckling itself. In addition, NR6(-/-) mice had
      reduced numbers of haemopoietic progenitor cells, suggesting a potential role in
      the regulation of primitive haemopoiesis.

PMID- 10359704
TI  - The art of grant writing.

PMID- 10359703
TI  - O-linked glycans mediate apical sorting of human intestinal sucrase-isomaltase
      through association with lipid rafts.
AB  - The plasma membrane of polarised epithelial cells is characterised by two
      structurally and functionally different domains, the apical and basolateral
      domains. These domains contain distinct protein and lipid constituents that are
      sorted by specific signals to the correct surface domain [1]. The best
      characterised apical sorting signal is that of glycophosphatidylinositol (GPI)
      membrane anchors [2], although N-linked glycans on some secreted proteins [3] and
      O-linked glycans [4] also function as apical sorting signals. In the latter
      cases, however, the underlying sorting mechanisms remain obscure. Here, we have
      analysed the role of O-glycosylation in the apical sorting of sucrase-isomaltase
      (SI), a highly polarised N- and O-glycosylated intestinal enzyme, and the
      mechanisms underlying this process. Inhibition of O-glycosylation by benzyl-N
      acetyl-alpha-D-galactosaminide (benzyl-GalNAc) was accompanied by a dramatic
      shift in the sorting of SI from the apical membrane to both membranes. The
      sorting mechanism of SI involves its association with sphingolipid- and
      cholesterol-rich membrane rafts because this association was eliminated when O
      glycosylation was inhibited by benzyl-GaINAc. The results demonstrate for the
      first time that O-linked glycans mediate apical sorting through association with
      lipid rafts.

PMID- 10359705
TI  - Biology in pictures: From one cell to many.

PMID- 10359707
TI  - Early man, late journalists.

PMID- 10359706
TI  - Red GFP and endogenous porphyrins.

PMID- 10359708
TI  - The eye captures...

PMID- 10359709
TI  - Nucleic acid enzymes.
AB  - Last year provided new structural data, particularly for the group I intron and
      the Hepatitis delta ribozymes, that were essential for a better understanding of
      the RNA structure/function relationship. The role of metal ions in catalysis of
      ribozyme action still remains elusive, however. In vitro selection has continued
      to be a rich source for obtaining data on new nucleic acid enzyme activities.

PMID- 10359710
TI  - Combinatorial synthetic design.
AB  - The range and diversity of solid-phase synthetic methodology continues to develop
      very rapidly, allowing the generation of previously inaccessible compound
      libraries. The design of such libraries requires consideration of linkage
      strategies, newly developed solid-phase reactions and emerging solution-phase
      processes.

PMID- 10359711
TI  - Protein evolution by molecular breeding.
AB  - Natural evolution has guided the development of 'molecular breeding' processes
      used in the laboratory for the rapid modification of subgenomic sequences
      including single genes. The most significant recent development has been the in
      vitro permutation of natural diversity. Homologous recombination of multiple
      related sequences produced high-quality libraries of chimeric sequences encoding
      proteins with functions that differ dramatically from any of the parents.
      Increasingly powerful screening methods are also being developed, allowing these
      libraries to be screened for novel biocatalysts.

PMID- 10359712
TI  - Host-guest chemistry: combinatorial receptors.
AB  - A combinatorial approach to receptor design provides an expedient method to
      discover the most effective host-guest complexes from within a library. Recent
      advances focus on generation of larger libraries, facile detection, combinatorial
      catalysis and the formation of dynamic receptor libraries.

PMID- 10359713
TI  - Totally in vitro protein selection using mRNA-protein fusions and ribosome
      display.
AB  - Both chemists and biochemists have great interest in creating peptides and
      proteins with desired structure, recognition and catalytic properties. Recently,
      two techniques have been developed that afford functional selection of proteins
      entirely in vitro: mRNA-protein fusions, and ribosome display. Improvements in
      both methods have allowed peptide and protein libraries of unprecedented size
      (10(11)-10(13) different members) to be generated and screened for function.

PMID- 10359714
TI  - Diversity assessment.
AB  - Several themes have been highlighted recently in both conferences and
      publications: the availability of product-focused and pharmacophore-based methods
      for the analysis and design of combinatorial libraries; the power of cell-based
      methods for molecular similarity, diversity and library design applications;
      methods for 'rational' diverse subset selection (with applicability to library
      design); the need for specialized optimization programs for the design of
      combinatorial libraries that maximize the use of common reagents; and the concept
      of 'drug-likeness' and its importance in the design of combinatorial libraries.

PMID- 10359715
TI  - Solution-phase chemical library synthesis using polymer-assisted purification
      techniques.
AB  - During the past few years, polymer-assisted solution-phase synthesis has become a
      prevalent method for the parallel synthesis of chemical libraries. This
      methodology allows for intermediate and final product purification by various
      resin-based sequestration techniques, which allow for the removal of excess
      reactants, by-products or side products from solution-phase reactions. The
      methodology has continued to expand, providing the practitioner with a broad
      range of ingenious purification methods, allowing single-step transformations as
      well as multistep syntheses to be performed in solution. The polymer-assisted
      solution-phase technology is currently being utilized for both the synthesis of
      lead generation and lead optimization libraries in the pharmaceutical arena and
      has also expanded into other disciplines.

PMID- 10359716
TI  - Combinatorial catalyst discovery.
AB  - There have been recent attempts to use the principles of combinatorial chemistry
      and high-throughput screening strategies for catalyst identification. With the
      technology available that allows the synthesis of large libraries, scientists of
      varied backgrounds have implemented screening efforts to identify active and
      selective catalysts. Within this context, several techniques have come to light
      in the past year: infrared thermography is used to identify optimal catalysts by
      monitoring the change in temperature for exothermic reactions; fluorescence and
      colored-dye assays, a familiar tool to biologists, is being applied to the
      identification of catalysts that exhibit the highest activity. Whereas none of
      these screening methods provide a general solution to the problem of screening
      large combinatorial libraries (there is likely to be no general solution), each
      advance represents an important intellectual and technological step forward.

PMID- 10359717
TI  - Mass spectrometric analysis in combinatorial chemistry.
AB  - The continuing success of the combinatorial approach is heavily reliant on
      analytical methodologies, which allow for the rapid and accurate characterisation
      of medicinally relevant molecules from compound libraries. Mass spectrometry has
      recently been touted as the most suitable tool for a range of combinatorial
      applications such as structural elucidation and screening. The refinement of
      conventional methods, developments of techniques such as Fourier transform ion
      cyclotron resonance and new screening methodologies have allowed the medicinal
      chemist to tackle the growing analytical challenges posed by combinatorial
      chemistry.

PMID- 10359718
TI  - Combinatorial synthesis of carbohydrates.
AB  - Combinatorial chemistry principles have been applied to the generation of
      oligosaccharide libraries, both in solution and on the solid phase, with a view
      to producing inhibitors of carbohydrate-protein binding. The rich stereochemistry
      and high degree of functionalization of sugars has also resulted in their
      increasing use in the synthesis of glycomimetics and as scaffolds for the
      presentation of pharmacophore groupings to receptors that are noncarbohydrate
      recognizing proteins.

PMID- 10359719
TI  - Microreactors for chemical synthesis.
AB  - The advances of the past few years in microreactors have demonstrated that the
      miniaturization of chemistry has significant advantages with respect to cost,
      safety, throughput, kinetics and scale-up. The use of chemical microreactors for
      catalytic oxidations, heterocyclic syntheses and photochemical reactions has
      illustrated the utility and benefits for both chemical discovery and chemical
      development applications.

PMID- 10359720
TI  - Boundaries for an RNA world.
AB  - Before large, specific peptides could be made, in an RNA world our ancestors may
      have used an RNA-like molecule for both catalysis and information storage. Taken
      together, RNA activities suggest RNA could have performed most of the essential
      informational functions of an ancient organism (i.e. those functions most similar
      to RNA's role today). In contrast, though compellingly reasoned optimism about
      RNA-catalyzed small-molecule metabolism is plentiful, fundamental problems remain
      to be solved.

PMID- 10359721
TI  - Thinking combinatorially.
AB  - Biopolymers and chemical compounds with novel functions can be selected or
      screened from randomized libraries. Recently, it has become possible to augment
      the functions of biopolymers via the conjugation or incorporation of unnatural
      chemical moieties. In the future, it should prove possible to engineer systems
      that can self-evolve and thereby reveal unexpected emergent properties.

PMID- 10359723
TI  - False aortic aneurysm secondary to chest trauma : june 8, 1999 

PMID- 10359722
TI  - Combinatorial chemistry: the search continues 

PMID- 10359724
TI  - Challenging conventional and unconventional wisdom.

PMID- 10359725
TI  - Triglyceride-rich lipoprotein remnant particles and risk of atherosclerosis.

PMID- 10359726
TI  - Is it all in the genes...? Nitric oxide synthase and coronary vasospasm.

PMID- 10359727
TI  - Remnant lipoprotein levels in fasting serum predict coronary events in patients
      with coronary artery disease.
AB  - BACKGROUND: Remnant lipoproteins are atherogenic, but assays of remnants have not
      been available in routine clinical laboratories because of the lack of practical
      and validated methods. A simple and reliable method for such an assay, using an
      immunochemical approach, has recently been developed. This study prospectively
      examined whether remnant lipoprotein levels in fasting serum, measured by our
      method, may have prognostic value in patients with coronary artery disease (CAD).
      METHODS AND RESULTS: Remnant lipoprotein levels in fasting serum were measured in
      135 patients with CAD by an immunoaffinity mixed gel containing anti
      apolipoprotein (apo) A-1 and anti-apoB-100 monoclonal antibodies. Patients were
      followed up for </=36 months until occurrence of 1 of the following clinical
      coronary events: recurrent or refractory angina pectoris requiring coronary
      revascularization, nonfatal myocardial infarction, or cardiac death. Kaplan-Meier
      analysis demonstrated a significantly higher probability of developing coronary
      events in patients with the highest tertile of remnant levels (>5.1 mg
      cholesterol/dL; 75th percentile of distribution of remnant levels) than in those
      with the lowest tertile of remnant levels (</=3.3 mg cholesterol/dL; 50th
      percentile of the distribution). Higher levels of remnants were a significant and
      independent predictor of developing coronary events in multivariate Cox hazard
      analysis including the following covariates: extent of coronary artery stenosis,
      age, sex, smoking, hypertension, diabetes mellitus, hypercholesterolemia, low HDL
      cholesterol, and hypertriglyceridemia. CONCLUSIONS: Higher levels of remnant
      lipoproteins in fasting serum predict future coronary events in patients with CAD
      independently of other risk factors. Thus, measurement of fasting remnant levels,
      assessed by the current immunoseparation method, may be helpful in assessment of
      CAD risk.

PMID- 10359728
TI  - High-dose heparin impairs nitric oxide pathway and vasomotion in rats.
AB  - BACKGROUND: Platelet-activating effects have been reported with high-dose heparin
      in acute thrombotic disorders. Recent studies have shown that increased platelet
      aggregation is due to reduced nitric oxide (NO) production in endothelial cells
      cultured in the presence of high-dose heparin. The aim of this study was to
      determine whether heparin can affect the NO pathway and the regulation of the
      vascular tone in vivo. METHODS AND RESULTS: Anesthetized and mechanically
      ventilated Sprague-Dawley rats were treated with high-dose heparin. After 4
      hours, the endothelial constitutive NO synthase (ecNOS) protein content in the
      aorta decreased (36% reduction, P<0.05), as detected by immunoblotting, and NO
      dependent vascular reactivity was impaired. In fact, the increase in mean
      arterial blood pressure after inhibition of ecNOS with NG-nitro-L-arginine methyl
      ester (30 mg/kg) was smaller in heparin-treated animals than in controls (+26.
      9+/-4.8 versus +48.3+/-9.1 mm Hg, P<0.05), and further infusion of the biological
      ecNOS substrate L-arginine (0.5 g/kg) was ineffective in reversing systemic
      vasoconstriction (-1% versus 28% vasodilatation, P<0.001). CONCLUSIONS: High-dose
      heparin can significantly affect vascular reactivity in vivo by downregulation of
      ecNOS protein expression.

PMID- 10359729
TI  - T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide
      synthase gene is associated with coronary spasm.
AB  - BACKGROUND: Coronary spasm plays an important role in the pathogenesis of
      ischemic heart diseases in general. However, the precise mechanism(s) responsible
      for coronary spasm remains to be elucidated, and we examined the molecular
      genetics of coronary spasm. METHODS AND RESULTS: We searched for the possible
      mutations in the endothelial nitric oxide synthase (eNOS) gene in patients with
      coronary spasm. In this study, we demonstrate the existence of 3 linked mutations
      in the 5'-flanking region of the eNOS gene (T-786-->C, A-922-->G, and T-1468-
      >A). The incidence of the mutations was significantly greater in patients with
      coronary spasm than in the control group (P<0.0001). Multiple logistic regression
      analysis with forward stepwise selection using the environmental risk factors and
      the eNOS gene variant revealed that the most predictive independent risk factor
      for coronary spasm was the mutant allele (P<0.0001). As assessed by luciferase
      reporter gene assays, the T-786-->C mutation resulted in a significant reduction
      in eNOS gene promoter activity (P<0.05), whereas neither the A-922-->G nor the T
      1468-->A mutation had any affect. CONCLUSIONS: Taken together, these findings
      strongly suggest that the T-786-->C mutation in the eNOS gene reduces the
      endothelial NO synthesis and predisposes the patients with the mutation to
      coronary spasm.

PMID- 10359730
TI  - Improvement in coronary flow reserve determined by positron emission tomography
      after 6 months of cholesterol-lowering therapy in patients with early stages of
      coronary atherosclerosis.
AB  - BACKGROUND: Early stages of coronary atherosclerosis are characterized by a
      mainly functional impairment of coronary vasodilator capacity under the impact of
      such risk factors as hypercholesterolemia. The goal of this study was to
      determine whether 6-month cholesterol-lowering therapy improves coronary flow
      reserve in patients with angina, reduced flow reserve despite minimally diseased
      coronary vessels or even normal angiogram, and mild to moderately elevated LDL
      levels on average. METHODS AND RESULTS: We noninvasively investigated 23
      consecutive patients (18 men, 5 women; mean age, 56+/-7.6 years) with a mean LDL
      level of 165+/-34 mg/dL at baseline by PET for myocardial blood flow measurement
      with [13N]ammonia at rest and under dipyridamole stress (0.56 mg/kg) before and
      after lipid-lowering therapy with simvastatin for 6 months. Between baseline and
      the 6-month follow-up, total cholesterol concentration fell from 241+/-44 to
      168+/-34 mg/dL, and the LDL level decreased from 165+/-34 to 95+/-26 mg/dL
      (P<0.001). Overall, coronary flow reserve increased from 2.2+/-0.6 to 2.64+/-0.6
      (P<0.01). Maximal coronary flow increased significantly from 182+/-36 to 238+/-58
      mL/minx100 g (P<0.001) at follow-up. Minimum coronary resistance declined
      significantly from 0. 51+/-0.12 to 0.40+/-0.14 mm Hg. mL-1. minx100 g (P<0.001).
      Concomitantly, a regression of anginal symptoms was observed in most patients.
      CONCLUSIONS: Our results suggest that cholesterol-lowering therapy with
      simvastatin may improve overall coronary vasodilator capacity assessed
      noninvasively by PET in patients with mild to moderate hypercholesterolemia.
      Consequently, intensive lipid-lowering therapy is considered a vasoprotective
      treatment for selected patients in very early stages of coronary atherosclerosis
      with the potential of preventing further disease progression.

PMID- 10359731
TI  - Glycosylphosphatidylinositol-specific phospholipase D is expressed by macrophages
      in human atherosclerosis and colocalizes with oxidation epitopes.
AB  - BACKGROUND: Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) may
      play an important role in inflammation, because it can hydrolyze the GPI anchors
      of several inflammatory membrane proteins (eg, CD106, CD55, and CD59) and its
      hydrolytic products upregulate macrophage cytokine expression (eg, interleukin-1
      and tumor necrosis factor-alpha). Because of its potential regulatory role in
      inflammatory reactions, we hypothesized that GPI-PLD might be expressed in
      atherosclerosis. METHODS AND RESULTS: Immunohistochemistry using human GPI-PLD
      specific rabbit polyclonal antiserum was performed on a total of 83
      nonatherosclerotic and atherosclerotic human coronary arteries from 23 patients.
      Macrophages, smooth muscle cells, apoA-I, and oxidation epitopes also were
      identified immunohistochemically. Cell-associated GPI-PLD was detected in 95% of
      atherosclerotic segments, primarily on a subset of macrophages. Extracellular GPI
      PLD was present in only 30% of atherosclerotic segments and localized to regions
      with extracellular apoA-I. In contrast, GPI-PLD was not detected in
      nonatherosclerotic segments. Expression of GPI-PLD mRNA by human macrophages was
      confirmed in vitro by reverse transcription/polymerase chain reaction. Further
      studies demonstrated that GPI-PLD-positive plaque macrophages contained oxidation
      epitopes, suggesting a link between oxidant stress and GPI-PLD expression. This
      possibility was supported by studies in which exposure of a macrophage cell line
      to H2O2 led to a 50+/-3% increase in steady-state GPI-PLD mRNA levels.
      CONCLUSIONS: Collectively, these results suggest that oxidative processes may
      regulate GPI-PLD expression and suggest a role for GPI-PLD in inflammation and in
      the pathogenesis of atherosclerosis.

PMID- 10359732
TI  - Distinct patterns of transforming growth factor-beta isoform and receptor
      expression in human atherosclerotic lesions. Colocalization implicates TGF-beta
      in fibrofatty lesion development.
AB  - BACKGROUND: Some animal studies suggest that transforming growth factor-beta (TGF
      beta) protects vessels from atherosclerosis by preventing intima formation, but
      others indicate a role in vessel proteoglycan accumulation and lipoprotein
      retention. To distinguish between these possibilities in humans,
      immunohistochemical studies were performed examining the coexpression of TGF-beta
      isoforms and the TGF-beta receptors ALK-5 and TbetaR-II in aorta during the
      various stages of atherosclerotic lesion development. METHODS AND RESULTS: The
      spatial relationships between TGF-beta1, TGF-beta3, ALK-5, and TbetaR-II
      expression were compared in aortic segments from 21 subjects. Nonatherosclerotic
      intima contained predominantly TGF-beta1, low concentrations of TbetaR-II, and
      barely detectable amounts of ALK-5. In contrast, fatty streaks/fibrofatty lesions
      contained high concentrations of both TGF-beta isoforms. Smooth muscle cells
      (SMCs), macrophages, and foam cells of macrophage and SMC origin contributed to
      these high levels. These lesions also contained high, colocalized concentrations
      of ALK-5 and TbetaR-II. Despite fibrous plaques containing TGF-beta1, its
      receptors were at detection limits. We found no evidence for truncated TbetaR-II
      expression in either normal intima or the various atherosclerotic lesions.
      CONCLUSIONS: TGF-beta appears to be most active in lipid-rich aortic intimal
      lesions. The findings support the hypothesis that TGF-beta contributes primarily
      to the pathogenesis of lipid-rich atherosclerotic lesions by stimulating the
      production of lipoprotein-trapping proteoglycans, inhibiting smooth muscle
      proliferation, and activating proteolytic mechanisms in macrophages.

PMID- 10359733
TI  - Clinical significance of thrombocytopenia during a non-ST-elevation acute
      coronary syndrome. The platelet glycoprotein IIb/IIIa in unstable angina:
      receptor suppression using integrilin therapy (PURSUIT) trial experience.
AB  - BACKGROUND: The significance of thrombocytopenia in patients experiencing an
      acute coronary syndrome (ACS) has not been examined systematically. We evaluated
      this condition in a large non-ST-elevation ACS clinical trial, with particular
      interest paid to its correlation with clinical outcomes. METHODS AND RESULTS:
      Patients presenting without persistent ST elevation during an ACS were randomized
      to receive a double-blind infusion of the platelet glycoprotein (GP) IIb/IIIa
      inhibitor eptifibatide or placebo in addition to other standard therapies
      including heparin and aspirin. The primary end point was death/nonfatal
      myocardial infarction (MI) at 30 days, whereas bleeding and stroke were the main
      safety outcomes. Thrombocytopenia (nadir platelet count <100x10(9)/L or <50% of
      baseline) occurred in 7.0% of enrolled patients. The time to onset was a median
      of 4 days in both treatment arms. Patients with thrombocytopenia were older,
      weighed less, were more likely nonwhite, and had more cardiac risk factors. These
      patients experienced significantly more bleeding events: they were more than
      twice as likely to experience moderate/severe bleeding after adjustment for
      confounders. Univariably, ischemic events (stroke, MI, and death) occurred
      significantly (P<0.001) more frequently in patients with thrombocytopenia;
      multivariable regression modeling preserved this association with death/nonfatal
      MI at 30 days. Neither the use of heparin or eptifibatide was found to
      independently increase thrombocytopenic risk. CONCLUSIONS: Although causality
      between thrombocytopenia and adverse clinical events could not be established
      definitively, thrombocytopenia was highly correlated with both bleeding and
      ischemic events, and the presence of this condition identified a more-at-risk
      patient population.

PMID- 10359734
TI  - Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of
      ischemic heart disease. A meta-analysis.
AB  - BACKGROUND: We assessed in meta-analyses the effect of the Gly188Glu, Asp9Asn,
      Asn291Ser, and Ser447Ter substitutions in lipoprotein lipase in the heterozygous
      state on lipid metabolism and risk of ischemic heart disease (same order used
      below). METHODS AND RESULTS: In 29 separate studies, 20 903 white subjects were
      screened for >/=1 of these substitutions; each meta-analysis included only some
      of these individuals. In population-based studies, heterozygote frequencies
      ranged from 0.04% to 0.2%, 2% to 4%, 1% to 7%, and 17% to 22% for the respective
      substitutions. Postheparin plasma lipoprotein lipase activity decreased 53% (95%
      CI, 31% to 75%) (only 1 study), 30% (22% to 37%), and 22% (8% to 35%) and was
      unchanged at 4% (-10% to 19%), respectively. Plasma triglycerides increased 78%
      (95% CI, 64% to 92%), 20% (9% to 33%), and 31% (20% to 43%) and decreased 8% (4%
      to 11%), respectively. HDL cholesterol decreased 0. 25 mmol/L (0.18 to 0.32),
      0.08 mmol/L (0.04 to 0.12), and 0.12 mmol/L (0.10 to 0.15) and increased 0.04
      mmol/L (0.02 to 0.06), respectively. Odds ratios for ischemic heart disease were
      4.9 (95% CI, 1.2 to 20) (only 1 study), 1.4 (0.8 to 2.4), 1.2 (0.9 to 1.5), and
      0.8 (0.7 to 1.0), respectively. Subgroup analysis indicated that women with the
      Asn291Ser substitution may have an increased risk of ischemic heart disease.
      CONCLUSIONS: These meta-analyses suggest that compared with noncarriers, carriers
      of the Gly188Glu, Asp9Asn, and Asn291Ser substitutions have an atherogenic
      lipoprotein profile, whereas carriers of the Ser447Ter substitution have a
      protective lipoprotein profile. Accordingly, risk of ischemic heart disease in
      heterozygous carriers is increased for Gly188Glu carriers; at most, the increase
      is borderline for Asp9Asn and Asn291Ser carriers; and risk is possibly decreased
      for Ser447Ter carriers.

PMID- 10359735
TI  - Heightened tissue factor associated with tissue factor pathway inhibitor and
      prognosis in patients with unstable angina.
AB  - BACKGROUND: This study was designed to evaluate the plasma levels of tissue
      factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with unstable
      angina and investigate whether there is a relationship between these levels and
      unfavorable outcome. METHODS AND RESULTS: The plasma TF and free TFPI antigen
      levels were determined in plasma samples taken from 51 patients with unstable
      angina, 56 with stable exertional angina, and 55 with chest pain syndrome. The
      plasma TF and free TFPI antigen levels were higher in the unstable angina group
      than in the stable exertional angina and chest pain syndrome group. There was a
      good correlation between TF and TFPI. We established borderline as maximum level
      in the patients with chest pain syndrome. Seven patients (of the 22 in the high
      TF group) required revascularization to control their unstable angina during in
      hospital stay. On the other hand, only 1 of the 29 patients in the low TF group
      required myocardial revascularization. Four patients of the 14 patients in the
      high free TFPI group required myocardial revascularization during in-hospital
      stay, and 4 of the 37 patients in the low free TFPI group required myocardial
      revascularization. We compared the TF and free TFPI levels between the cardiac
      event (+) group and cardiac event (-) group. TF levels were significantly higher
      in the cardiac event (+) group than in the cardiac event (-) group. CONCLUSIONS:
      We have demonstrated that not only the plasma TF levels but also the plasma-free
      TFPI levels are elevated in patients with unstable angina. Patients with unstable
      angina and heightened TF and free TFPI are at increased risk for unfavorable
      outcomes. The heightened TF level was a more important predictor in patients with
      unstable angina.

PMID- 10359736
TI  - Angiotensin-converting enzyme-independent contraction to angiotensin I in human
      resistance arteries.
AB  - BACKGROUND: In vitro studies of myocardial tissue suggest that angiotensin II
      (Ang II) may be generated by both ACE and chymase. A similar dual pathway may
      exist in the vasculature. We studied the effects of ACE and chymase inhibitors on
      the contractile response to angiotensin I (Ang I) in human resistance arteries to
      investigate ACE-independent generation of Ang II. METHODS AND RESULTS:
      Subcutaneous resistance arteries (250 to 350 microm) were obtained from gluteal
      biopsies from volunteers and New Zealand White rabbits and mounted on a wire
      myograph. Contractile ability was tested with high-potassium depolarization and
      norepinephrine 10 micromol/L and endothelial integrity by relaxation to
      acetylcholine 3 micromol/L. Cumulative concentration-response curves were
      constructed for Ang I in the presence of enalaprilat 1 micromol/L, chymostatin 10
      micromol/L, or both inhibitors together. In the rabbit, enalaprilat completely
      inhibited the Ang I response. In human vessels, enalaprilat or chymostatin alone
      had no effect, but the combination of enalaprilat and chymostatin almost
      completely inhibited the response to Ang I. CONCLUSIONS: A dual pathway for Ang
      II generation exists in human resistance arteries, mediated by ACE and a
      chymostatin-sensitive enzyme, probably chymase. We confirm that a marked species
      difference exists in the mechanism of Ang II generation between the human and the
      rabbit. More efficacious suppression of the renin-angiotensin system may require
      development of novel enzyme inhibitors or combinations of currently available
      drugs.

PMID- 10359737
TI  - Prevalence of myocardial viability as detected by positron emission tomography in
      patients with ischemic cardiomyopathy.
AB  - BACKGROUND: Detection of myocardial viability is important in patients with
      ischemic cardiomyopathy. Restoration of blood flow to viable myocardium is
      associated with improved left ventricular function and improved patient
      prognosis. However, the prevalence of viable myocardium in patients with ischemic
      cardiomyopathy is unknown. METHODS AND RESULTS: To determine the prevalence of
      myocardial viability, clinical [13N]ammonia/18F-deoxyglucose PET studies
      performed in 283 patients (age, 63+/-10 years) with ischemic heart disease (mean
      ejection fraction, 26+/-8%) were visually analyzed for the presence and extent of
      viable and nonviable myocardium. The myocardium was divided into 19 segments. The
      extent of viable myocardium was considered "functionally" significant if >/=5
      segments ( approximately 25% of the left ventricular myocardium) exhibited a
      blood flow/metabolism mismatch and "prognostically" significant if 1 to 4 left
      ventricular segments did so. Of all patients, 41% had no evidence of viable
      myocardium, 55% had viable myocardium, and 4% had normal blood flow and
      metabolism within an enlarged left ventricle. Functionally significant viability
      was found in 27% and prognostically significant viability in 28% of the patients.
      Multivariate analysis revealed the presence of angina to be the only clinical
      parameter associated with the presence of functionally significant viability.
      CONCLUSIONS: Revascularization might improve patient prognosis in 55% and result
      in improved left ventricular function in 27% of all patients with ischemic
      cardiomyopathy.

PMID- 10359738
TI  - Assessment of permanent dual-chamber pacing as a treatment for drug-refractory
      symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized,
      double-blind, crossover study (M-PATHY).
AB  - BACKGROUND: Dual-chamber pacing (DDD) has been proposed as a treatment
      alternative to surgery for severely symptomatic patients with obstructive
      hypertrophic cardiomyopathy (HCM), based largely on uncontrolled studies. METHODS
      AND RESULTS: This prospective, multicenter trial assessed pacing in 48
      symptomatic HCM patients with >/=50 mm Hg basal gradient, refractory to drug
      therapy. Patients were randomized to 3 months each of DDD pacing and pacing
      backup (AAI-30) in a double-blind, crossover study design, followed by an
      uncontrolled and unblinded 6-month pacing trial. With randomization, no
      significant differences were evident between pacing and no pacing for subjective
      or objective measures of symptoms or exercise capacity, including NYHA functional
      class, quality of life score, treadmill exercise time or peak oxygen consumption.
      After 6 additional months of unblinded pacing, functional class and quality of
      life score were improved compared with baseline (P<0.01), but peak oxygen
      consumption was unchanged. Outflow gradient decreased 40%, 82+/-32 mm Hg to 48+/
      32 mm Hg (P<0. 001), and was reduced in 57% of patients but showed no change or
      an increase in 43%. At 12 months, 6 individual patients (12%) showed improved
      functional capacity; each was 65 to 75 years of age. Left ventricular wall
      thicknesses in the overall study group showed no remodeling between baseline
      (22+/-5 mm) and 12 months (21+/-5 mm; P=NS). CONCLUSIONS: (1) Pacing cannot be
      regarded as a primary treatment for obstructive HCM; (2) with randomization,
      perceived symptomatic improvement was most consistent with a substantial placebo
      effect; (3) longer, uncontrolled pacing periods were associated with some
      subjective benefit but unaccompanied by objective improvement in cardiovascular
      performance and should be interpreted cautiously; (4) modest reduction in outflow
      gradient was achieved in most patients; and (5) a small subset (12%) >/= 65 years
      of age showed a clinical response, suggesting that DDD pacing could be a
      therapeutic option for some elderly patients.

PMID- 10359739
TI  - Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis.
AB  - BACKGROUND: The importance of free radical homeostasis and apoptosis in normal
      and diseased hearts and their interrelationships are poorly defined. We tested
      whether reactive oxygen species can trigger apoptosis in cardiomyocytes, and we
      explored the underlying pathways. METHODS AND RESULTS: A cell culture model of
      isolated cardiac cells and different reactive oxygen species (ROS)-generating
      systems were used. Apoptosis became evident when cardiomyocytes were exposed to
      either H2O2 or superoxide anion (O2-). Both H2O2- and O2--induced apoptosis of
      cardiomyocytes were associated with an increase in p53 protein content, whereas
      protein levels of Bax and Bcl-2 were unaltered. H2O2, but not O2-, induced an
      increase in the protein content of Bad. Furthermore, H2O2 elicited translocation
      of Bax and Bad from cytosol to mitochondria, where these factors formed
      heterodimers with Bcl-2, which was followed by the release of cytochrome c,
      activation of CPP32, and cleavage of poly(ADP-ribose) polymerase. Interestingly,
      this pathway was not activated by O2-. Instead, O2- used Mch2alpha to promote the
      apoptotic pathway, as revealed by the activation of Mch2alpha and the cleavage of
      its substrate, lamin A. CONCLUSIONS: Taken together, these results indicate that
      ROS may play an important pathophysiological role in cardiac diseases
      characterized by apoptotic cell death and suggest that different ROS-induced
      activations of the apoptotic cell death program in cardiomyocytes involve
      distinct signaling pathways.

PMID- 10359740
TI  - Troglitazone inhibits voltage-dependent calcium currents in guinea pig cardiac
      myocytes.
AB  - BACKGROUND: It has been suggested that intracellular Ca2+ overload in cardiac
      myocytes leads to the development of diabetic cardiomyopathy. Troglitazone, an
      insulin-sensitizing agent, is a promising therapeutic agent for diabetes and has
      been shown to prevent diabetes-induced myocardial changes. To elucidate the
      underlying mechanism of troglitazone action on cardiac myocytes, the effects of
      troglitazone on voltage-dependent Ca2+ currents were examined and compared with
      classic Ca2+ antagonists (verapamil and nifedipine). METHODS AND RESULTS: Whole
      cell voltage-clamp techniques were applied in single guinea pig atrial myocytes.
      Under control conditions with CsCl internal solution, the voltage-dependent Ca2+
      currents consisted of both T-type (ICa,T) and L-type (ICa,L) Ca2+ currents.
      Troglitazone effectively reduced the amplitude of ICa,L in a concentration
      dependent manner. Troglitazone also suppressed ICa,T, but the effect of
      troglitazone on ICa,T was less potent than that on ICa,L. The current-voltage
      relationships for ICa,L and the reversal potential for ICa,L were not altered by
      troglitazone. The half-maximal inhibitory concentration of troglitazone on ICa,L
      measured at a holding potential of -40 mV was 6.3 micromol/L, and 30 micromol/L
      troglitazone almost completely inhibited ICa,L. Troglitazone 10 micromol/L did
      not affect the time courses for inactivation of ICa,L and inhibited ICa,L mainly
      in a use-independent fashion, without shifting the voltage-dependency of
      inactivation. This effect was different from those of verapamil and nifedipine.
      Troglitazone also reduced isoproterenol- or cAMP-enhanced ICa,L. CONCLUSIONS:
      These results demonstrate that troglitazone inhibits voltage-dependent Ca2+
      currents (T-type and L-type) and then antagonizes the effects of isoproterenol in
      cardiac myocytes, thus possibly playing a role in preventing diabetes-induced
      intracellular Ca2+ overload and subsequent myocardial changes.

PMID- 10359741
TI  - Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in
      rats with chronic heart failure. Role of nitric oxide, prostanoids, and oxidant
      stress.
AB  - BACKGROUND: Flow-mediated dilatation (FMD) of the peripheral arteries may be
      impaired in chronic heart failure (CHF), and this could contribute to the
      increased peripheral resistance and exercise intolerance that occur with this
      disease. Physical exercise improves the FMD of large conduit arteries in CHF, but
      whether a similar impairment also occurs in smaller arteries is unknown. The
      mechanisms of the changes in FMD after CHF or exercise are also unknown. METHODS
      AND RESULTS: FMD was assessed in isolated, perfused, and preconstricted gracilis
      muscle arteries from sham-operated rats or CHF rats (coronary artery ligation)
      who were either sedentary or exercised (30-minute swimming period twice a day for
      10 weeks, starting 7 days after ligation). In animals with hemodynamic and
      echographic signs of CHF, FMD was abolished and converted into vasoconstriction
      (percent change in diameter after 370 microL/min flow: sham, 42+/-5%; CHF, -4+/
      3%; P<0.05). Exercise partially restored FMD (18+/-3%; P<0.05 versus CHF). In
      sham rats, FMD was abolished by the nitric oxide-synthase inhibitor Nomega-nitro
      L-arginine (L-NA) but unaffected by the cyclooxygenase inhibitor diclofenac or
      the free radical scavenger N-(2-mercaptopropionyl)-glycine (MPG). In arteries
      from sedentary CHF rats, FMD was not modified by L-NA, but it was partially
      restored by diclofenac or MPG. In exercised CHF rats, FMD was abolished by L-NA
      and only moderately improved by diclofenac or MPG. Likewise, endothelial nitric
      oxide synthase mRNA expression (determined by reverse transcription polymerase
      chain reaction at the level of the gracilis muscle) was reduced by CHF, and this
      was prevented by exercise. CONCLUSIONS: CHF abolishes the FMD of small arteries
      by impairing the nitric oxide pathway, increasing oxidant stress, and releasing a
      prostanoid-contracting factor. Exercise partially restores FMD by increasing
      expression of endothelial nitric oxide synthase and preventing the production of
      vasoconstrictor prostanoids and free radicals. Such restoration of FMD might
      contribute to the increase in exercise capacity after physical exercise in CHF.

PMID- 10359743
TI  - The cardiology lesson 

PMID- 10359742
TI  - Ganglionic mechanisms contribute to diminished vagal control in heart failure.
AB  - BACKGROUND: Previous work has shown that spontaneous and stimulated vagal
      activity is diminished in heart failure (HF) despite upregulation of functional
      postsynaptic cholinergic mechanisms. We therefore examined function of the
      postganglionic neuron in the paced canine model of HF as a possible site for
      diminished control. METHODS AND RESULTS: We measured sinus cycle length changes
      in response to electrical stimulation of preganglionic and postganglionic
      parasympathetic neurons innervating the sinoatrial node in control and HF dogs
      (both, n=8). Cervical vagus stimulation (preganglionic) demonstrated attenuated
      responses in the HF group at all levels of stimulation (P<0.05). Stimulation of
      the right atrial fat pad, containing both postganglionic nerves and terminals of
      preganglionic neurons, showed no such difference between control and HF (200+/-25
      versus 192+/-18 ms). To ensure that preganglionic input and different levels of
      baseline sympathetic activity did not contribute to the group difference, similar
      stimulations were done in the presence of ganglionic and beta-adrenergic
      blockade. Under these conditions, postganglionic stimulation showed smaller
      changes in sinus cycle length, but the HF group response remained significantly
      higher than in controls (76+/-10 versus 20+/-2 ms; P<0. 01), indicating that the
      difference was independent of preganglionic input and sympathetic activity.
      CONCLUSIONS: A component of attenuated parasympathetic control in HF is located
      within the peripheral efferent limb. This defect is located within the
      parasympathetic ganglion. Future work should be focused on determining mechanisms
      of attenuated ganglionic transmission so that means targeted at restoring vagal
      activity can be developed.

PMID- 10359744
TI  - Images in cardiovascular medicine. Rapid dissolution of massive intracoronary
      thrombosis with platelet glycoprotein IIb/IIIa receptor inhibitor.

PMID- 10359745
TI  - Assessment of atrioventricular junction ablation and VVIR pacemaker versus
      pharmacological treatment in patients with heart failure and chronic atrial
      fibrillation.

PMID- 10359746
TI  - Minimally invasive coronary bypass surgery: an example for optimal teamwork
      between cardiologists and cardiac surgeons?

PMID- 10359747
TI  - Minimally invasive heart surgery.

PMID- 10359748
TI  - Constitutive expression of phVEGF165 after intramuscular gene transfer promotes
      collateral vessel development in patients with critical limb ischemia.

PMID- 10359749
TI  - Long-term oral anticoagulant therapy in patients with unstable angina or
      suspected non-Q-wave myocardial infarction.

PMID- 10359751
TI  - Abscisic acid 

PMID- 10359752
TI  - Models of treatment effects when responses are heterogeneous.

PMID- 10359750
TI  - False aortic aneurysm secondary to chest trauma.

PMID- 10359753
TI  - Self-assembly of chlorophenols in water.
AB  - In saturated solutions of some di- and trichlorophenols, structures with complex
      morphologies, consisting of thin, transparent sheets often coiling into helices
      and ultimately twisting into filaments, were observed under the optical
      microscope. Freeze-fracture electron microscopy, x-ray diffraction, phase
      diagrams, and molecular modeling were performed to elucidate the observed
      phenomena. Here, we present evidence that the chlorophenols studied, when
      interacting with water, self-assemble into bilayers. The fact that some
      chlorophenols form the same supramolecular structures as those described
      previously for structurally nonrelated surfactants sheds light on the mechanisms
      of self-assembly.

PMID- 10359754
TI  - Catalysis of peptide dissociation from class II MHC-peptide complexes.
AB  - Certain peptides such as dynorphin A [dynA-(1-13)] enhance the release of
      antigenic peptides bound to class II MHC molecules at neutral pH. This enhanced
      release has been termed push off. Previous work has shown that the antigenic
      pigeon cytochrome c peptide PCC-(89-104) has at least two conformational isomers
      when bound to the class II MHC protein I-Ek. We have accordingly studied the push
      off of PCC-(89-104) from the complex PCC-(89-104)/I-Ek to see whether these
      isomeric conformations are distinguished by the push-off effect. A comparison of
      the association and dissociation kinetics of PCC-(89-104)/I-Ek in the presence of
      dynA-(1-13) shows that dynA-(1-13) does not simply replace PCC-(89-104) but
      rather acts catalytically. The major product is peptide-free I-Ek, which is
      receptive to further peptide binding. Evidence is presented that a two peptide
      one MHC complex is formed in solution. This ternary complex represents the first
      step of the mechanism of push off. 19F NMR data are presented that indicate that
      dynA-(1-13) interacts specifically with only one of the two isomeric complexes of
      PCC-(89-104) and I-Ek. A push-off mechanism is proposed in which dynA-(1-13)
      binds outside the peptide binding groove. In a second step, the dissociation of
      one of the two isomers is specifically enhanced. Thus the push-off effect may be
      useful for identifying conformational isomers and for separating them.

PMID- 10359755
TI  - Cytochrome b562 folding triggered by electron transfer: approaching the speed
      limit for formation of a four-helix-bundle protein.
AB  - Ferrocytochrome b562 [Fe(II)cyt b562] folding can be triggered by photoinduced
      electron transfer to unfolded Fe(III)cyt b562 in 2-3 M guanidine hydrochloride
      solutions. The folding rates increase with decreasing guanidine hydrochloride;
      the extrapolated time constant for this folding process in the absence of
      denaturant (5 micros) is near the predicted value for intrachain diffusion. The
      relatively smooth energy landscape indicated for Fe(II)cyt b562 folding accords
      with the helical, highly symmetrical structure of the protein.

PMID- 10359756
TI  - Accurate quantitation of protein expression and site-specific phosphorylation.
AB  - A mass spectrometry-based method is described for simultaneous identification and
      quantitation of individual proteins and for determining changes in the levels of
      modifications at specific sites on individual proteins. Accurate quantitation is
      achieved through the use of whole-cell stable isotope labeling. This approach was
      applied to the detection of abundance differences of proteins present in wild
      type versus mutant cell populations and to the identification of in vivo
      phosphorylation sites in the PAK-related yeast Ste20 protein kinase that depend
      specifically on the G1 cyclin Cln2. The present method is general and affords a
      quantitative description of cellular differences at the level of protein
      expression and modification, thus providing information that is critical to the
      understanding of complex biological phenomena.

PMID- 10359757
TI  - The force exerted by a molecular motor.
AB  - The stochastic driving force exerted by a single molecular motor (e. g., a
      kinesin, or myosin) moving on a periodic molecular track (microtubule, actin
      filament, etc.) is discussed from a general viewpoint open to experimental test.
      An elementary "barometric" relation for the driving force is introduced that (i)
      applies to a range of kinetic and stochastic models, (ii) is consistent with more
      elaborate expressions entailing explicit representations of externally applied
      loads, and (iii) sufficiently close to thermal equlibrium, satisfies an Einstein
      type relation in terms of the velocity and diffusion coefficient of the (load
      free) motor. Even in the simplest two-state models, the velocity-vs.-load plots
      exhibit a variety of contrasting shapes (including nonmonotonic behavior).
      Previously suggested bounds on the driving force are shown to be inapplicable in
      general by analyzing discrete jump models with waiting time distributions.

PMID- 10359758
TI  - Vibro-acoustography: an imaging modality based on ultrasound-stimulated acoustic
      emission.
AB  - We describe theoretical principles of an imaging modality that uses the acoustic
      response of an object to a highly localized dynamic radiation force of an
      ultrasound field. In this method, named ultrasound-stimulated vibro-acoustography
      (USVA), ultrasound is used to exert a low-frequency (in kHz range) force on the
      object. In response, a portion of the object vibrates sinusoidally in a pattern
      determined by its viscoelastic properties. The acoustic emission field resulting
      from object vibration is detected and used to form an image that represents both
      the ultrasonic and low-frequency (kHz range) mechanical characteristics of the
      object. We report the relation between the emitted acoustic field and the
      incident ultrasonic pressure field in terms of object parameters. Also, we
      present the point-spread function of the imaging system. The experimental images
      in this report have a resolution of about 700 microm, high contrast, and high
      signal-to-noise ratio. USVA is sensitive enough to detect object motions on the
      order of nanometers. Possible applications include medical imaging and material
      evaluation.

PMID- 10359759
TI  - A small nucleolar RNA:ribozyme hybrid cleaves a nucleolar RNA target in vivo with
      near-perfect efficiency.
AB  - A hammerhead ribozyme has been localized to the yeast nucleolus by using the U3
      small nucleolar RNA as a carrier. The hybrid small nucleolar RNA:ribozyme,
      designated a "snorbozyme," is metabolically stable and cleaves a target U3 RNA
      with nearly 100% efficiency in vivo. This is the most efficient in vivo cleavage
      reported for a trans-acting ribozyme. A key advantage of the model substrate
      featured is that a stable, trimmed cleavage product accumulates. This property
      allows accurate kinetic measurements of authentic cleavage in vivo. The system
      offers new avenues for developing effective ribozymes for research and
      therapeutic applications.

PMID- 10359760
TI  - Duplex DNA catalyzes the chemical rearrangement of a malondialdehyde
      deoxyguanosine adduct.
AB  - The primary DNA lesion induced by malondialdehyde, a byproduct of lipid
      peroxidation and prostaglandin synthesis, is 3-(2'-deoxy-beta-D-erythro
      pentofuranosyl)-pyrimido[1, 2-a]purin-10(3H)-one (M1G). When placed opposite
      cytosine (underlined) at neutral pH in either the d(GGTMTCCG).d(CGGACACC) or
      d(ATCGCMCGGCATG). d(CATGCCGCGCGAT) duplexes, M1G spontaneously and quantitatively
      converts to the ring-opened derivative N2-(3-oxo-1-propenyl)-dG. Ring-opening is
      reversible on thermal denaturation. Ring-opening does not occur at neutral pH in
      single-stranded oligodeoxynucleotides or when T is placed opposite to M1G in a
      duplex. The presence of a complementary cytosine is not required to stabilize N2
      (3-oxo-1-propenyl)-dG in duplex DNA at neutral pH. When N2-(3-oxo-1-propenyl)-dG
      is placed opposite to thymine in a duplex, it does not revert to M1G. A mechanism
      for the conversion of M1G to N2-(3-oxo-1-propenyl)-dG is proposed in which the
      exocyclic amino group of the complementary cytosine attacks the C8 position of
      the M1G exocyclic ring and facilitates ring opening via formation of a transient
      Schiff base. Addition of water to the Schiff base regenerates the catalytic
      cytosine and generates N2-(3-oxo-1-propenyl)-dG. These results document the
      ability of duplex DNA to catalyze the transformation of one adduct into another,
      which may have important consequences for mutagenesis and repair.

PMID- 10359761
TI  - The telomerase RNA pseudoknot is critical for the stable assembly of a
      catalytically active ribonucleoprotein.
AB  - Telomerase is a ribonucleoprotein reverse transcriptase that synthesizes
      telomeric DNA. A pseudoknot structure is phylogenetically conserved within the
      RNA component of telomerase in all ciliated protozoans examined. Here, we report
      that disruptions of the pseudoknot base pairing within the telomerase RNA from
      Tetrahymena thermophila prevent the stable assembly in vivo of an active
      telomerase. Restoring the base-pairing potential of the pseudoknot by
      compensatory changes restores telomerase activity to essentially wild-type
      levels. Therefore, the pseudoknot topology rather than sequence is critical for
      an active telomerase. Furthermore, we show that disruption of the pseudoknot
      prevents the association of the RNA with the reverse transcriptase protein
      subunit of telomerase. Thus, we provide an example of a structural motif within
      the telomerase RNA that is required for telomerase function and identify the
      domain that is required for telomerase complex formation. Hence, we identify a
      biological role for a pseudoknot: promoting the stable assembly of a
      catalytically active ribonucleoprotein.

PMID- 10359762
TI  - Collaborative role of E2F transcriptional activity and G1 cyclindependent kinase
      activity in the induction of S phase.
AB  - A considerable body of evidence points to a role for both cyclin E/cyclin
      dependent kinase (cdk)2 activity and E2F transcription activity in the induction
      of S phase. We show that overexpression of cyclin E/cdk2 in quiescent cells
      induces S phase, that this coincides with an induction of E2F activity, and that
      coexpression of E2F enhances the cyclin E/cdk2-mediated induction of S phase.
      Likewise, E2F overexpression can induce S phase and does so in the apparent
      absence of cyclin E/cdk2 activity. In addition, although the inhibition of cyclin
      E/cdk2 activity blocks the induction of S phase after growth stimulation of
      normal mouse embryo fibroblasts, inhibition of cyclin E/cdk2 does not block S
      phase induction in Rb-/- cells where E2F activity is deregulated. These results
      point to the important roles for E2F and cyclin E/cdk2 in the induction of S
      phase. Moreover, the nature of the E2F targets and the suspected targets for
      cyclin E/cdk2 suggests a potential molecular mechanism for the collaborative
      action of cyclin E/cdk2 and E2F in the induction of S phase.

PMID- 10359763
TI  - Solution structure of a DNA decamer duplex containing the stable 3' T.G base pair
      of the pyrimidine(6-4)pyrimidone photoproduct [(6-4) adduct]: implications for
      the highly specific 3' T --> C transition of the (6-4) adduct.
AB  - The pyrimidine(6-4)pyrimidone photoproduct [(6-4) adduct] is one of the major
      photoproducts induced by UV irradiation of DNA and occurs at TpT sites. The (6-4)
      adduct is highly mutagenic and leads most often to a 3' T --> C transition with
      85% replicating error frequency [LeClerc, J. E., Borden, A. & Lawrence, C. W.
      (1991) Proc. Natl. Acad. Sci. USA 88, 9685-9689]. To determine the origin of the
      specific 3' T --> C transition of the (6-4) adduct, we have used experimental NMR
      restraints and molecular dynamics to determine the solution structure of a (6-4)
      lesion DNA decamer duplex that contains a mismatched base pair between the 3' T
      residue and an opposed G residue. Normal Watson-Crick-type hydrogen bonding is
      retained at the 5' T of the lesion site. The O2 carbonyl of the 3' T residue
      forms hydrogen bonds with the imino and amino protons of the opposed G residue.
      This potential hydrogen bonding stabilizes the overall helix and restores the
      highly distorted conformation of the (6-4) adduct to the typical B-form-like DNA
      structure. This structural feature can explain the marked preference for the
      insertion of an A residue opposite the 5' T and a G residue opposite the 3' T of
      the (6-4) lesion during trans-lesion synthesis. Thus these insertions yield the
      predominant 3' T --> C transition.

PMID- 10359764
TI  - Interfacial membrane docking of cytosolic phospholipase A2 C2 domain using
      electrostatic potential-modulated spin relaxation magnetic resonance.
AB  - The C2 domain of cytosolic phospholipase A2 (C2cPLA2) plays an important role in
      calcium-dependent transfer of the protein from the cytosol to internal cellular
      membranes as a prelude for arachidonate release from membrane phospholipids. By
      using a recently developed electron paramagnetic resonance approach together with
      13 site-specifically nitroxide spin labeled C2cPLA2s and membrane-permeant and 
      impermeant spin relaxants, we have determined the orientation of C2cPLA2 with
      respect to the surface of vesicles of the phospholipid 1,2-dioleoyl-sn-glycero-3
      phosphomethanol. The structure reveals that the two calcium-binding regions on
      C2cPLA2 that display hydrophobic residues, CBR1 and CBR3, are partially inserted
      into the core of the membrane. CBR2 that contains predominantly hydrophilic
      residues is close to the membrane but not inserted. The long axis of the
      cylindrical C2cPLA2 molecule is tilted with respect to the bilayer normal, which
      brings a cluster of basic protein residues close to the phospholipid headgroups.
      Such an orientation places the two bound calcium ions close to the membrane
      surface. All together, the results provide structural support for previous
      proposals that binding of C2cPLA2 to the membrane interface is driven in part by
      insertion of hydrophobic surface loops into the membrane core. The results are
      contrasted with previous studies of the interfacial binding of the first C2
      domain of synaptotagmin I, which has shorter surface loops that display basic
      residues for electrostatic interaction with the bilayer surface.

PMID- 10359765
TI  - Hemoglobin induction in mouse macrophages.
AB  - The common perception that hemoglobin is involved solely in the transport of
      oxygen and carbon dioxide has been challenged by recent studies with nitric oxide
      (NO). These studies have shown that the primordial bacterial flavohemoglobin
      functions to consume NO enzymatically (to protect from nitrosative stress),
      whereas mammalian hemoglobin functions to deliver NO (thus maximizing oxygen
      delivery in the respiratory cycle). Here we report that murine macrophages
      stimulated to produce NO with lipopolysaccharide and interferon-gamma express the
      betaminor hemoglobin subunit. Consumption of NO, however, was not increased by
      cytokines or by hemoglobin expression. These data suggest alternative functions
      for globins in mammalian cells, and they challenge the prevailing view that the
      expression of alpha- and beta-globin genes is always balanced and coordinated.

PMID- 10359766
TI  - Feedback control of a master bacterial cell-cycle regulator.
AB  - The transcriptional regulator CtrA controls several key cell-cycle events in
      Caulobacter crescentus, including the initiation of DNA replication, DNA
      methylation, cell division, and flagellar biogenesis. CtrA is a member of the
      response regulator family of two component signal transduction systems.
      Caulobacter goes to great lengths to control the time and place of the activity
      of this critical regulatory factor during the cell cycle. These controls include
      temporally regulated transcription and phosphorylation and spatially restricted
      proteolysis. We report here that ctrA expression is under the control of two
      promoters: a promoter (P1) that is active only in the early predivisional cell
      and a stronger promoter (P2) that is active in the late predivisional cell. Both
      promoters exhibit CtrA-mediated feedback regulation: the early P1 promoter is
      negatively controlled by CtrA, and the late P2 promoter is under positive
      feedback control. The CtrA protein footprints conserved binding sites within the
      P1 and P2 promoters. We propose that the P1 promoter is activated after the
      initiation of DNA replication in the early predivisional cell. The ensuing
      accumulation of CtrA results in the activation of the P2 promoter and the
      repression of the P1 promoter late in the cell cycle. Thus, two transcriptional
      feedback loops coupled to cell cycle-regulated proteolysis and phosphorylation of
      the CtrA protein result in the pattern of CtrA activity required for the temporal
      and spatial control of multiple cell-cycle events.

PMID- 10359767
TI  - On the structure of endogenous ouabain.
AB  - The ouabain-like sodium pump inhibitor in mammals (so-called "endogenous
      ouabain") has been considered a subtle structural isomer of ouabain. Its
      structural investigation, however, has long been hindered by the paucity of
      sample material. Our recent purification of endogenous ouabain (3 micrograms)
      from bovine hypothalamus allowed the measurement of its 1H-NMR. The obtained
      spectrum as well as reexamination of past microscale structural studies on
      endogenous ouabain led us to identify the purified material as ouabain in an
      unusual manner. It turned out that the structural analysis had been complicated
      by a facile ouabain-borate complexation in borosilicate glassware. In retrospect,
      it is not surprising that the polyhydroxylated ouabain molecule serves as a
      polydentate ligand to inorganic species. In its physiological environment,
      ouabain may exist as some unknown complex. The chemical species giving rise to
      the reported biological activities of hypothalamic inhibitory factor preparations
      remain to be clarified.

PMID- 10359768
TI  - CPF: an orphan nuclear receptor that regulates liver-specific expression of the
      human cholesterol 7alpha-hydroxylase gene.
AB  - Cholesterol 7alpha-hydroxylase is the first and rate-limiting enzyme in a pathway
      through which cholesterol is metabolized to bile acids. The gene encoding
      cholesterol 7alpha-hydroxylase, CYP7A, is expressed exclusively in the liver.
      Overexpression of CYP7A in hamsters results in a reduction of serum cholesterol
      levels, suggesting that the enzyme plays a central role in cholesterol
      homeostasis. Here, we report the identification of a hepatic-specific
      transcription factor that binds to the promoter of the human CYP7A gene. We
      designate this factor CPF, for CYP7A promoter binding factor. Mutation of the CPF
      binding site within the CYP7A promoter abolished hepatic-specific expression of
      the gene in transient transfection assays. A cDNA encoding CPF was cloned and
      identified as a human homolog of the Drosophila orphan nuclear receptor fushi
      tarazu F1 (Ftz-F1). Cotransfection of a CPF expression plasmid and a CYP7A
      reporter gene resulted in specific induction of CYP7A-directed transcription.
      These observations suggest that CPF is a key regulator of human CYP7A gene
      expression in the liver.

PMID- 10359769
TI  - Myosin light-chain kinase of smooth muscle stimulates myosin ATPase activity
      without phosphorylating myosin light chain.
AB  - Myosin light-chain kinase (MLCK) of smooth muscle is multifunctional, being
      composed of N-terminal actin-binding domain, central kinase domain, and C
      terminal myosin-binding domain. The kinase domain is the best characterized; this
      domain activates the interaction of smooth-muscle myosin with actin by
      phosphorylating the myosin light chain. We have recently shown that the Met-1-Pro
      41 sequence of MLCK binds to actin to inhibit this interaction. However, it is
      not known whether the myosin-binding domain modifies the actin-myosin
      interaction. We designed MLCK.cDNA to overexpress the Asp-777-Glu-972 sequence in
      Escherichia coli. The purified Asp-777-Glu-972 fragment, although devoid of the
      kinase activity, exerted a stimulatory effect on the ATPase activity of
      dephosphorylated myosin (Vmax = 7.36 +/- 0.44-fold, Km = 1.06 +/- 0. 20 microM, n
      = 4). When the N-terminal 39 residues of the fragment were deleted from the
      fragment, the resultant fragment, Met-816-Glu-972, lost the stimulatory activity.
      We synthesized the Ala-777-Ser-815 peptide that was deleted from the fragment and
      confirmed its stimulatory effect of the peptide (Vmax = 3.03 +/- 0. 22-fold, Km =
      6.93 +/- 1.61 microM, n = 3). When this peptide was further divided into Asp-777
      Met-795 and Ala-796-Ser-815 peptides, the stimulatory activity was found in the
      latter. We confirmed that the myosin phosphorylation did not occur during the
      experiments with the above fragments and peptides. Therefore, we suggest that
      phosphorylation is not obligatory for smooth-muscle myosin not to be active.

PMID- 10359770
TI  - Substrate binding and catalysis by ribonuclease P from cyanobacteria and
      Escherichia coli are affected differently by the 3' terminal CCA in tRNA
      precursors.
AB  - We have studied the effect of the 3' terminal CCA sequence in precursors of tRNAs
      on catalysis by the RNase P RNA or the holoenzyme from the cyanobacterium
      Synechocystis sp. PCC 6803 in a completely homologous system. We have found that
      the absence of the 3' terminal CCA is not detrimental to activity, which is in
      sharp contrast to what is known in other bacterial systems. We have found that
      this is also true in other cyanobacteria. This situation correlates with the
      anomalous structure of the J15/16 loop in cyanobacteria, which is an important
      loop in the CCA interaction in Escherichia coli RNase P, and with the fact that
      cyanobacteria do not code the CCA sequence in the genome but add it
      posttranscriptionally. Modification of nucleotides 330-332 in the J15/16 loop of
      Synechocystis RNase P RNA from GGU to CCA has a modest effect on kcat for CCA
      containing substrates and has no effect on cleavage-site selection. We have
      developed a direct physical assay of the interaction between RNase P RNA and its
      substrate, which was immobilized on a filter, and we have determined that
      Synechocystis RNase P RNA binds with better affinity the substrate lacking CCA
      than the substrate containing it. Our results indicate a mode of substrate
      binding in RNase P from cyanobacteria that is different from binding in other
      eubacteria and in which the 3' terminal CCA is not involved.

PMID- 10359771
TI  - Lon and Clp family proteases and chaperones share homologous substrate
      recognition domains.
AB  - Lon protease and members of the Clp family of molecular chaperones and protease
      regulatory subunits contain homologous regions with properties expected for
      substrate-binding domains. Fragments corresponding to these sequences are stably
      and independently folded for Lon, ClpA, and ClpY. The corresponding regions from
      ClpB and ClpX are unstable. All five fragments exhibit distinct patterns of
      binding to three proteins that are protease substrates in vivo: the heat shock
      transcription factor sigma32, the SOS mutagenesis protein UmuD, and Arc repressor
      bearing the SsrA degradation tag. Recognition of UmuD is mediated through peptide
      sequences within a 24-residue N-terminal region whereas recognition of both
      sigma32 and SsrA-tagged Arc requires sequences at the C terminus. These results
      indicate that the Lon and Clp proteases use the same mechanism of substrate
      discrimination and suggest that these related ATP-dependent bacterial proteases
      scrutinize accessible or disordered regions of potential substrates for the
      presence of specific targeting sequences.

PMID- 10359772
TI  - ZEB represses transcription through interaction with the corepressor CtBP.
AB  - ZEB is an active transcriptional repressor that regulates lymphocyte and muscle
      differentiation in vertebrates. Its homologue in Drosophila (zfh-1) is also
      essential for differentiation of somatic and cardiac muscle. Here, we demonstrate
      that ZEB and zfh-1 interact with the corepressor CtBP to repress transcription.
      ZEB and zfh-1, both contain the sequence PLDLS in the same region of the
      repressor domain, and we demonstrate that this sequence binds CtBP-1 and -2. In
      vertebrate species, ZEB contains two additional CtBP-like binding sites
      (variations of the PLDLS sequence) that also bind CtBP proteins and are required
      for full repressor activity. The three sites have an additive effect, and
      mutation of all three sites is necessary to abolish both binding to CtBP and
      repressor activity. Finally, we demonstrate that the interaction of CtBP with ZEB
      at the promoter is necessary for repressor activity.

PMID- 10359773
TI  - Declines in mitochondrial respiration during cardiac reperfusion: age-dependent
      inactivation of alpha-ketoglutarate dehydrogenase.
AB  - We previously reported that cardiac reperfusion results in declines in
      mitochondrial NADH-linked respiration. The degree of inactivation increased with
      age and was paralleled by modification of protein by the lipid peroxidation
      product 4-hydroxy-2-nonenal. To gain insight into potential sites of oxidative
      damage, the present study was undertaken to identify specific mitochondrial
      protein(s) inactivated during ischemia and reperfusion and to determine which of
      these losses in activity are responsible for observed declines in mitochondrial
      respiration. Using a Langendorff rat heart perfusion protocol, we observed age
      dependent inactivation of complex I during ischemia and complex IV and alpha
      ketoglutarate dehydrogenase during reperfusion. Although losses in complex I and
      IV activities were found not to be of sufficient magnitude to cause declines in
      mitochondrial respiration, an age-related decrease in complex I activity during
      ischemia may predispose old animals to more severe oxidative damage during
      reperfusion. It was determined that inactivation of alpha-ketoglutarate
      dehydrogenase is responsible, in large part, for observed reperfusion-induced
      declines in NADH-linked respiration. alpha-Ketoglutarate dehydrogenase is highly
      susceptible to 4-hydroxy-2-nonenal inactivation in vitro. Thus, our results
      suggest a plausible mechanism for age-dependent, reperfusion-induced declines in
      mitochondrial function and identify alpha-ketoglutarate dehydrogenase as a likely
      site of free radical-mediated damage.

PMID- 10359774
TI  - Regulation of eukaryotic protein synthesis: selective influenza viral mRNA
      translation is mediated by the cellular RNA-binding protein GRSF-1.
AB  - To better understand regulation of eukaryotic protein synthesis, we studied
      cellular and viral mRNA translation in influenza virus-infected cells. Influenza
      virus infection results in a dramatic shut-off of cellular protein synthesis that
      is concomitant with selective viral mRNA translation. Earlier work showed that
      these events are mediated by viral and/or cellular factors binding to the 5'
      untranslated region (5' UTR) of viral mRNAs. To identify trans-acting cellular
      proteins responsible for selective viral protein synthesis, we employed the yeast
      three-hybrid system. Using the 5' UTR of the influenza virus nucleocapsid protein
      (NP) mRNA as bait, we identified the cellular RNA-recognition motif containing
      RNA-binding protein G-rich sequence factor 1 (GRSF-1) as a positive-acting
      translational regulatory factor. The in vivo yeast assay revealed GRSF-1
      specifically bound to the NP 5' UTR but not select NP 5' UTR mutants or cellular
      RNA 5' UTRs. These data were confirmed by gel shift assays using recombinant GRSF
      1. Importantly, recombinant GRSF-1 specifically stimulated translation of a NP 5'
      UTR-driven template in cell-free translation systems. Furthermore, translation
      efficiency of NP 5' UTR-driven templates was reduced markedly in GRSF-1-depleted
      HeLa cell extracts, but restored in GRSF-1-reconstituted extracts. GRSF-1 also
      stimulated translation of an NP 5' UTR-driven template in HeLa cell extracts that
      were depleted of essential factors by addition of RNA oligonucleotides
      representing the viral 5' UTR RNA. Taken together, these data document the
      functional demonstration of a cellular protein binding to influenza virus RNAs
      and, importantly, suggest that influenza virus may recruit GRSF-1 to the 5' UTR
      to ensure preferential translation of viral mRNAs in infected cells.

PMID- 10359775
TI  - Nonlinear optical measurement of membrane potential around single molecules at
      selected cellular sites.
AB  - Membrane potential around single molecules has been measured by using the
      nonlinear optical phenomenon of second harmonic generation. This advance results
      from the interaction between a highly dipolar molecule with a selectively
      directed highly polarizable 1-nm gold particle. With this approach, a second
      harmonic signal, which is enhanced by the nanoparticle, is detected from a volume
      of nanometric dimensions. This present work clearly shows that functional
      cellular imaging around single molecules is possible by selectively directing an
      antibody with a 1-nm gold label to a specific membrane protein. The results of
      this work open the way for three-dimensional, high resolution functional imaging
      of membrane electrophysiology in cells and cellular networks.

PMID- 10359776
TI  - Direct observation of the anchoring process during the adsorption of fibrinogen
      on a solid surface by force-spectroscopy mode atomic force microscopy.
AB  - Atomic force microscopy in a force-spectroscopy mode has been used to investigate
      the kinetics of the adsorption process of fibrinogen molecules on a silica
      surface. An original "approach/retraction" cycle of the tip/surface was used for
      this purpose. Fibrinogen molecules were adsorbed on the atomic force microscopy
      tip and were brought into contact with the silica surface for different
      interaction times varying from 5 to 2,000 ms. Multiple consecutive ruptures were
      observed. The mean number of ruptures nr per cycle increases steadily with the
      interaction time as well as the mean strength fr which varies from 300 pN for 5
      ms to 1,400 pN for 2,000 ms. The minimal interaction time for a fibrinogen
      molecule to bind strongly to a silica surface during an adsorption process
      appears to lie between 50 and 200 ms. The histograms of the distances between two
      consecutive ruptures in one cycle exhibit maxima around 20-25 nm. This length is
      comparable to the characteristic distance between D and E globules of one
      fibrinogen molecule and suggests that fibrinogen molecules mainly adsorb through
      their D and E globules.

PMID- 10359777
TI  - Osmotic pressure contribution of albumin to colloidal interactions.
AB  - Two surfaces that come in close contact in a solution with macromolecules present
      experience an attractive force caused by the osmotic pressure. We present a
      measurement of this effect by using a micrometer-sized sphere bound to a flat
      plate through a single molecular attachment in an albumin-containing solution. We
      obtain the osmotic part of the interaction potential with a resolution of <1 nm
      and a fraction of kTroom. This attractive interaction is seen to have a range
      comparable to the size of the albumin molecule. The results are broadly in
      agreement with a geometric model first proposed by Asakura and Oosawa.

PMID- 10359778
TI  - Intermediates can accelerate protein folding.
AB  - The effect of intermediates on the rate of protein folding is explored by
      applying Kramers' theory of diffusive barrier crossing in the high friction
      limit. Intermediates are represented as local minima in the transition barrier.
      We observe that very large or very small additional barriers created by the
      intermediates slow down the folding process. The rate of folding markedly
      increases, however, when the additional barriers become >1 kBT but leave the
      overall barrier height unchanged. This rate-enhancing effect is caused by a
      favorable entropic contribution to the free energy of activation, and it
      increases with the number of intermediates up to a limiting value. From these
      calculations, we conclude that optimized transition barriers should contain
      partially folded high energy intermediates.

PMID- 10359779
TI  - Clathrin-coated vesicles bearing GAIP possess GTPase-activating protein activity
      in vitro.
AB  - Galpha-interacting protein (GAIP) is a member of the RGS (regulators of G protein
      signaling) family, which serve as GAPs (GTPase-activating proteins) for Galpha
      subunits. Previously, we demonstrated that GAIP is localized on clathrin-coated
      vesicles (CCVs). Here, we tested whether GAIP-enriched vesicles could accelerate
      the GTPase activity of Galphai proteins. A rat liver fraction containing
      vesicular carriers (CV2) was enriched (4.5x) for GAIP by quantitative
      immunoblotting, and GAIP was detected on some of the vesicles in the CV2 fraction
      by immunoelectron microscopy. When liver fractions were added to recombinant
      Galphai3 and tested for GAP activity, only the CV2 fraction contained GAP
      activity. Increasing amounts of CV2 increased the activity, whereas
      immunodepletion of the CV2 fraction with an antibody against the C terminus of
      GAIP decreased GAP activity. CCV fractions were prepared from rat liver by using
      a protocol that maintains the clathrin coats. GAIP was enriched in these
      fractions and was detected on CCVs by immunogold labeling. Addition of increasing
      amounts of CCV to recombinant Galphai3 protein increased the GTPase activity. We
      conclude that CCVs possess GAP activity for Galphai3 and that membrane-associated
      GAIP is capable of interacting with Galphai3. The reconstitution of the
      interaction between a heterotrimeric G protein and GAIP on CCVs provides
      biochemical evidence for a model whereby the G protein and its GAP are
      compartmentalized on different membranes and come into contact at the time of
      vesicle fusion. Alternatively, they may be located on the same membrane and
      segregate at the time of vesicle budding.

PMID- 10359780
TI  - Signaling via beta1 integrins and mitogen-activated protein kinase determines
      human epidermal stem cell fate in vitro.
AB  - Human epidermal stem cells express higher levels of beta1 integrins and are more
      adhesive than keratinocytes that are destined to differentiate. To investigate
      whether high beta1 integrin expression and adhesiveness are essential for
      maintaining keratinocytes in the stem cell compartment, we introduced a dominant
      negative beta1 integrin mutant, CD8beta1, into cultured human keratinocytes,
      thereby interfering with beta1 integrin function. Surface beta1 integrin levels,
      adhesiveness, and mitogen-activated protein (MAP) kinase activation on
      fibronectin were reduced, and exit from the stem cell compartment was stimulated.
      Adhesiveness and proliferative potential were restored by overexpressing wild
      type beta1 integrin or by constitutive MAP kinase activation. Conversely, a
      dominant-negative MAP kinase kinase 1 mutant decreased adhesiveness and stem cell
      number in the absence of CD8beta1. MAP kinase activation by alpha6beta4-mediated
      adhesion and mitogens was normal in CD8beta1 cells, and constitutive MAP kinase
      activation did not affect adhesion and proliferation of control keratinocytes. We
      conclude that beta1 integrins and MAP kinase cooperate to maintain the epidermal
      stem cell compartment in vitro.

PMID- 10359781
TI  - A dominant-negative pleiotrophin mutant introduced by homologous recombination
      leads to germ-cell apoptosis in male mice.
AB  - Pleiotrophin (PTN) is an 18-kDa heparin-binding secretory growth/differentiation
      factor for different cell types. Its gene is differentially expressed in both
      mesenchyme and central nervous system during development and highly expressed in
      a number of different human tumors. Recently, a PTN mutant was found to act as a
      dominant-negative effector of PTN signaling. We have now used homologous
      recombination to introduce the dominant-negative PTN mutant into embryonic stem
      cells to generate chimeric mice. All highly chimeric male mice with germinal
      epithelium exclusively derived from embryonic stem cells with the heterologous
      PTN mutation were sterile. Their testes were uniformly atrophic, and the
      spermatocytes were strikingly apoptotic at all stages of development. The results
      support a central role of PTN signaling in normal spermatogenesis and suggest
      that interruption of PTN signaling may lead to sterility in males.

PMID- 10359782
TI  - A Crm1p-independent nuclear export path for the mRNA-associated protein,
      Npl3p/Mtr13p.
AB  - mRNA export involves association of mRNAs with nucleoplasmic proteins, delivery
      to the nuclear pore complex, translocation to the cytoplasm, and reimport of
      recycling components. Many yeast mutants inhibit mRNA export, but there is little
      information concerning the RNA carriers and steps of transport that they affect.
      The hnRNP/serine-arginine-rich-like protein, Npl3p/Mtr13p, binds poly(A)+ RNA and
      shuttles between the nucleus and cytoplasm. Its export accelerates on inhibition
      of RNA synthesis. In vivo tests show that its export requires two proteins with
      putative leucine-rich nuclear export signals: Gle1p, Mex67p, and several
      additional nuclear and nuclear pore complex-associated proteins. Surprisingly, a
      nonnuclear pool of an import factor (the importin alpha homologue, Srp1p) is also
      required. Changes in the methylation status of Npl3p do not correlate with its
      nucleocytoplasmic distribution. A crm1 mutant that inhibits export of proteins
      with leucine-rich nuclear export signals and mRNAs does not inhibit Npl3p export.
      Moreover, several proteins needed for Npl3p export are not needed for export of a
      typical Crm1p cargo. Thus, Npl3p export requires only a subset of proteins
      implicated in mRNA export, suggesting that more than one mRNA export path exists.
      A distinct group of mutants, including a mutation of a member of the importin
      beta superfamily, inhibits Npl3p reimport from the cytoplasm.

PMID- 10359783
TI  - Broad patterns of gene expression revealed by clustering analysis of tumor and
      normal colon tissues probed by oligonucleotide arrays.
AB  - Oligonucleotide arrays can provide a broad picture of the state of the cell, by
      monitoring the expression level of thousands of genes at the same time. It is of
      interest to develop techniques for extracting useful information from the
      resulting data sets. Here we report the application of a two-way clustering
      method for analyzing a data set consisting of the expression patterns of
      different cell types. Gene expression in 40 tumor and 22 normal colon tissue
      samples was analyzed with an Affymetrix oligonucleotide array complementary to
      more than 6,500 human genes. An efficient two-way clustering algorithm was
      applied to both the genes and the tissues, revealing broad coherent patterns that
      suggest a high degree of organization underlying gene expression in these
      tissues. Coregulated families of genes clustered together, as demonstrated for
      the ribosomal proteins. Clustering also separated cancerous from noncancerous
      tissue and cell lines from in vivo tissues on the basis of subtle distributed
      patterns of genes even when expression of individual genes varied only slightly
      between the tissues. Two-way clustering thus may be of use both in classifying
      genes into functional groups and in classifying tissues based on gene expression.

PMID- 10359784
TI  - Ultraviolet A radiation induces immediate release of iron in human primary skin
      fibroblasts: the role of ferritin.
AB  - In mammalian cells, the level of the iron-storage protein ferritin (Ft) is
      tightly controlled by the iron-regulatory protein-1 (IRP-1) at the
      posttranscriptional level. This regulation prevents iron acting as a catalyst in
      reactions between reactive oxygen species and biomolecules. The ultraviolet A
      (UVA) radiation component of sunlight (320-400 nm) has been shown to be a source
      of oxidative stress to skin via generation of reactive oxygen species. We report
      here that the exposure of human primary skin fibroblasts, FEK4, to UVA radiation
      causes an immediate release of "free" iron in the cells via proteolysis of Ft.
      Within minutes of exposure to a range of doses of UVA at natural exposure levels,
      the binding activity of IRP-1, as well as Ft levels, decreases in a dose
      dependent manner. This decrease coincides with a significant leakage of the
      lysosomal components into the cytosol. Stabilization of Ft molecules occurs only
      when cells are pretreated with lysosomal protease inhibitors after UVA treatment.
      We propose that the oxidative damage to lysosomes that leads to Ft degradation
      and the consequent rapid release of potentially harmful "free" iron to the
      cytosol might be a major factor in UVA-induced damage to the skin.

PMID- 10359785
TI  - Control of the low voltage-activated calcium channel of mouse sperm by egg ZP3
      and by membrane hyperpolarization during capacitation.
AB  - Sperm adhesion to egg zonae pellucidae initiates sperm acrosome reactions, an
      exocytotic event that is an early step during fertilization. Previously, it was
      suggested that zona pellucida-evoked Ca2+ entry into sperm through low voltage
      activated Ca2+ channels is an essential step in acrosome reactions, based on the
      inhibitory effects of Ca2+ channel antagonists. However, analysis of this channel
      is limited by the inability to apply electrophysiological methods directly to
      sperm. In this report, optical methods of determining membrane potential and
      internal Ca2+ levels were used to demonstrate that (i) contact with zonae
      pellucidae activates a transient Ca2+ response in sperm that has a time course
      and antagonist sensitivity anticipated of low voltage-activated Ca2+ channels;
      (ii) these channels are unavailable for opening in uncapacitated sperm because of
      voltage-dependent, steady state inactivation; (iii) membrane hyperpolarization
      during sperm capacitation is sufficient to recruit channels into a closed state,
      from which they are available for opening during fertilization; and (iv) channel
      conductance state may be a factor in determines the efficacy with which channel
      antagonists inhibit fertilization. This study provides evidence for the
      activation of sperm Ca2+ channels during gamete adhesion and offers a mechanism
      that may account for aspects of the regulation of sperm fertility during
      capacitation through the control of channel availability. Finally, these results
      suggest that channel conductance state may be a central feature in the design of
      channel antagonists that inhibit sperm function.

PMID- 10359786
TI  - Two distinct forms of the 64,000 Mr protein of the cleavage stimulation factor
      are expressed in mouse male germ cells.
AB  - Polyadenylation in male germ cells differs from that in somatic cells. Many germ
      cell mRNAs do not contain the canonical AAUAAA in their 3' ends but are
      efficiently polyadenylated. To determine whether the 64,000 Mr protein of the
      cleavage stimulation factor (CstF-64) is altered in male germ cells, we examined
      its expression in mouse testis. In addition to the 64,000 Mr form, we found a
      related approximately 70,000 Mr protein that is abundant in testis, at low levels
      in brain, and undetectable in all other tissues examined. Expression of the
      approximately 70,000 Mr CstF-64 was limited to meiotic spermatocytes and
      postmeiotic spermatids in testis. In contrast, the 64,000 Mr form was absent from
      spermatocytes, suggesting that the testis-specific CstF-64 might control
      expression of meiosis-specific genes. To determine why the 64,000 Mr CstF-64 is
      not expressed in spermatocytes, we mapped its chromosomal location to the X
      chromosome in both mouse and human. CstF-64 may, therefore, be absent in
      spermatocytes because the X chromosome is inactivated during male meiosis. By
      extension, the testis-specific CstF-64 may be expressed from an autosomal homolog
      of the X chromosomal gene.

PMID- 10359787
TI  - Rapid and reversible relocalization of heat shock factor 1 within seconds to
      nuclear stress granules.
AB  - Heat shock factor 1 (HSF1) is essential for the stress-induced expression of heat
      shock genes. On exposure to heat shock, HSF1 localizes within seconds to discrete
      nuclear granules. On recovery from heat shock, HSF1 rapidly dissipates from these
      stress granules to a diffuse nucleoplasmic distribution, typical of unstressed
      cells. Subsequent reexposure to heat shock results in the rapid relocalization of
      HSF1 to the same stress granules with identical kinetics. Although the appearance
      of HSF1 stress granules corresponds to the hyperphosphorylated, trimeric DNA
      binding state of HSF1 and correlates temporally with the inducible transcription
      of heat shock genes, they are also present in heat-shocked mitotic cells that are
      devoid of transcription. This finding suggests a role for HSF1 stress granules as
      a nuclear compartment for the temporal regulation and spatial organization of
      HSF1 activity and reveals new features of the dynamics of nuclear organization.

PMID- 10359788
TI  - Acute cholesterol depletion inhibits clathrin-coated pit budding.
AB  - Many biologically important macromolecules are internalized into cells by
      clathrin-coated pit endocytosis. The mechanism of clathrin-coated pit budding has
      been investigated intensively, and considerable progress has been made in
      characterizing the proteins involved in internalization. Membrane lipid
      composition and the lateral organization of lipids and proteins within membranes
      are believed to play an important role in the regulation of membrane-trafficking
      processes. Here we report that membrane cholesterol plays a critical role in
      clathrin-coated pit internalization. We show that acute cholesterol depletion,
      using beta-methyl-cyclodextrin, specifically reduces the rate of internalization
      of transferrin receptor by more than 85%, without affecting intracellular
      receptor trafficking back to the cell surface. The effect on endocytosis is
      attributable to a failure of coated pits to detach from the plasma membrane, as
      visualized by using a green fluorescent protein-clathrin conjugate in living
      cells. Ultrastructural studies indicate that acute cholesterol depletion causes
      accumulation of flat-coated membranes and a corresponding decrease in deep-coated
      pits, consistent with the possibility that flat clathrin lattices are direct
      precursors of indented pits and endocytic vesicles in intact cells. We conclude
      that clathrin is unable to induce curvature in the membrane depleted of
      cholesterol.

PMID- 10359789
TI  - Chromosome healing in mouse embryonic stem cells.
AB  - The addition of new telomeres to the ends of broken chromosomes, termed
      chromosome healing, has been extensively studied in unicellular organisms;
      however, its role in the mammalian cell response to double-strand breaks is
      unknown. A system for analysis of chromosome healing, which involves the
      integration of plasmid sequences immediately adjacent to a telomere, has been
      established in mouse embryonic stem cells. This "marked" telomere contains a neo
      gene for positive selection in G418, an I-SceI endonuclease recognition sequence
      for introducing double-strand breaks, and a herpes simplex virus thymidine kinase
      gene for negative selection with ganciclovir for cells that have lost the
      telomere. Transient expression of the I-SceI endonuclease results in terminal
      deletions involving telomeric repeat sequences added directly onto the end of the
      broken chromosome. The sites of addition of the new telomeres contain short
      regions of complementarity to telomeric repeat sequences. The most common site of
      addition is the last A of the ATAA 3' overhang generated by the I-SceI
      endonuclease, without the loss of a single nucleotide from the end of the
      chromosome. The next most frequent site involved 5 bp of complementarity, which
      occurred after the loss of four nucleotides from the end of the chromosome. The
      new telomeres are generally much shorter than in the parental cell line, and most
      increase in size with time in culture. These results demonstrate that chromosome
      healing is a mechanism for repair of chromosome breaks in mammalian cells.

PMID- 10359790
TI  - Mitochondrial Lon of Saccharomyces cerevisiae is a ring-shaped protease with
      seven flexible subunits.
AB  - Lon (or La) is a soluble, homooligomeric ATP-dependent protease. Mass
      determination and cryoelectron microscopy of pure mitochondrial Lon from
      Saccharomyces cerevisiae identify Lon as a flexible ring-shaped heptamer. In the
      presence of ATP or 5'-adenylylimidodiphosphate, most of the rings are symmetric
      and resemble other ATP-driven machines that mediate folding and degradation of
      proteins. In the absence of nucleotides, most of the rings are distorted, with
      two adjacent subunits forming leg-like protrusions. These results suggest that
      asymmetric conformational changes serve to power processive unfolding and
      translocation of substrates to the active site of the Lon protease.

PMID- 10359791
TI  - A quantitative analysis of signal transduction from activin receptor to nucleus
      and its relevance to morphogen gradient interpretation.
AB  - Previous work has shown that Xenopus blastula cells sense activin concentration
      by assessing the absolute number of occupied receptors per cell (100 and 300
      molecules of bound activin activate Xbra and Xgsc transcription, respectively; a
      difference of only 3-fold). We now ask how quantitative differences in the
      absolute number of occupied receptors lead to the qualitatively distinct gene
      responses in the nucleus through SMAD2, a transducer of concentration-dependent
      gene responses to activin. We show that the injection of 0.2 or 0.6 ng of Smad2
      mRNA activates Xbra or Xgsc transcription, respectively, involving, again, only a
      3-fold difference. Furthermore, Xbra transcription is down-regulated by
      overexpression of SMAD2 as it is after activin signaling. We have developed a
      method to isolate nuclei from animal cap cells and subsequently have quantified
      the amount of nuclear SMAD2 protein. We find that the injection of 0.2 or 0.6 ng
      of Smad2 mRNA into an egg leads to only a 3-fold difference in the amount of
      SMAD2 protein in the nuclei of the blastula cells that express Xbra or Xgsc. We
      conclude that a 3-fold difference in the absolute number of occupied activin
      receptors can be maintained only as a 3-fold difference in the level of nuclear
      SMAD2 protein. Therefore, in this example of morphogen action, there appears to
      be no amplification of a key cytoplasmic transduction response, and a small but
      developmentally important change in extracellular signal concentration is relayed
      directly to the nucleus.

PMID- 10359792
TI  - The Rpd3 histone deacetylase is required for segmentation of the Drosophila
      embryo.
AB  - Previous studies have implicated histone deacetylation and chromatin condensation
      as critical mechanisms of transcription repression in yeast and mammals. A
      specific histone deacetylase, Rpd3, interacts with a variety of sequence-specific
      transcriptional repressors, including Mad-Max heterodimers and members of the
      nuclear receptor superfamily. Here, we present evidence that a strong hypomorphic
      mutation in the Drosophila Rpd3 gene causes embryonic lethality and a specific
      pair-rule segmentation phenotype. The analysis of a number of segmentation genes
      suggests that the repressor function of Even-skipped (Eve) may be diminished,
      causing an indirect loss of Ftz-mediated activation of engrailed. The relatively
      mild defects observed in Rpd3 mutants suggest that the recently identified
      Groucho and dCtBP corepressor proteins do not function solely through the
      recruitment of histone deacetylases. We discuss the possibility that Eve mediates
      multiple mechanisms of repression, so that Rpd3 mutants disrupt the regulation of
      just a subset of Eve target genes.

PMID- 10359793
TI  - Activity regulation of Hox proteins, a mechanism for altering functional
      specificity in development and evolution.
AB  - The closely related Hox transcription factors Ultrabithorax (Ubx) and
      Antennapedia (Antp) respectively direct first abdominal (A1) and second thoracic
      (T2) segment identities in Drosophila. It has been proposed that their functional
      differences derive from their differential occupancy of DNA target sites. Here we
      show that a hybrid version of Ubx (Ubx-VP16), which possesses an enhanced
      transcriptional activation function, no longer directs A1 denticle pattern in
      embryonic epidermal cells. Instead, it mimics Antp in directing T2 denticle
      pattern, and it can rescue the cuticular loss-of-function phenotype of Antp
      mutants. In cells that do not produce denticles, Ubx-VP16 appears to have largely
      retained its normal repressive regulatory functions. These results suggest that
      the modulation of Hox activation and repression functions can account for segment
      specific morphological differences that are controlled by different members of
      the Hox family. Our results also are consistent with the idea that activity
      regulation underlies the phenotypic suppression phenomenon in which a more
      posterior Hox protein suppresses the function of a more anterior member of the
      Hox cluster. The acquisition of novel activation and repression potentials in Hox
      proteins may be an important mechanism underlying the generation of subtle
      morphological differences during evolution.

PMID- 10359794
TI  - Phytoremediation of methylmercury pollution: merB expression in Arabidopsis
      thaliana confers resistance to organomercurials.
AB  - Methylmercury is an environmental toxicant that biomagnifies and causes severe
      neurological degeneration in animals. It is produced by bacteria in soils and
      sediments that have been contaminated with mercury. To explore the potential of
      plants to extract and detoxify this chemical, we engineered a model plant,
      Arabidopsis thaliana, to express a modified bacterial gene, merBpe, encoding
      organomercurial lyase (MerB) under control of a plant promoter. MerB catalyzes
      the protonolysis of the carbon---mercury bond, removing the organic ligand and
      releasing Hg(II), a less mobile mercury species. Transgenic plants expressing
      merBpe grew vigorously on a wide range of concentrations of monomethylmercuric
      chloride and phenylmercuric acetate. Plants lacking the merBpe gene were severely
      inhibited or died at the same organomercurial concentrations. Six independently
      isolated transgenic lines produced merBpe mRNA and MerB protein at levels that
      varied over a 10- to 15-fold range, and even the lowest levels of merBpe
      expression conferred resistance to organomercurials. Our work suggests that
      native macrophytes (e.g., trees, shrubs, grasses) engineered to express merBpe
      may be used to degrade methylmercury at polluted sites and sequester Hg(II) for
      later removal.

PMID- 10359795
TI  - Four intracellular genomes direct weevil biology: nuclear, mitochondrial,
      principal endosymbiont, and Wolbachia.
AB  - Cell physiology in the weevil Sitophilus oryzae is coordinated by three
      integrated genomes: nuclear, mitochondrial, and the "S. oryzae principal
      endosymbiont" (SOPE). SOPE, a cytoplasmic bacterium (2 x 10(3) bacteria per
      specialized bacteriocyte cell and 3 x 10(6) bacteria per weevil) that belongs to
      the proteobacteria gamma3-subgroup, is present in all weevils studied. We
      discovered a fourth prokaryotic genome in somatic and germ tissues of 57% of
      weevil strains of three species, S. oryzae, Sitophilus zeamais, and Sitophilus
      granarius, distributed worldwide. We assigned this Gram-negative prokaryote to
      the Wolbachia group (alpha-proteobacteria), on the basis of 16S rDNA sequence and
      fluorescence in situ DNA-RNA hybridization (FISH). Both bacteria, SOPE and
      Wolbachia, were selectively eliminated by combined heat and antibiotic
      treatments. Study of bacteria involvement in this insect's genetics and
      physiology revealed that SOPE, which induces the specific differentiation of the
      bacteriocytes, increases mitochondrial oxidative phosphorylation through the
      supply of pantothenic acid and riboflavin. Elimination of this gamma3
      proteobacterium impairs many physiological traits. By contrast, neither the
      presence nor the absence of Wolbachia significantly affects the weevil's
      physiology. Wolbachia, disseminated throughout the body cells, is in particularly
      high density in the germ cells, where it causes nucleocytoplasmic
      incompatibility. The coexistence of two distinct types of intracellular
      proteobacteria at different levels of symbiont integration in insects illustrates
      the genetic complexity of animal tissue. Furthermore, evolutionary timing can be
      inferred: first nucleocytoplasm, then mitochondria, then SOPE, and finally
      Wolbachia. Symbiogenesis, the genetic integration of long-term associated members
      of different species, in the weevil appears to be a mechanism of speciation (with
      Wolbachia) and provides a means for animals to acquire new genes that permit
      better adaptation to the environment (with SOPE).

PMID- 10359796
TI  - Molecular genetics of ecological diversification: duplication and rapid evolution
      of toxin genes of the venomous gastropod Conus.
AB  - Predatory snails in the marine gastropod genus Conus stun prey by injecting a
      complex mixture of peptide neurotoxins. These conotoxins are associated with
      trophic diversification and block a diverse array of ion channels and neuronal
      receptors in prey species, but the evolutionary genesis of this functional
      diversity is unknown. Here we show that conotoxins with little amino acid
      similarity are in fact products of recently diverged loci that are rapidly
      evolving by strong positive selection in the vermivorous cone, Conus abbreviatus,
      and that the rate of conotoxin evolution is higher than that of most other known
      proteins. Gene duplication and diversifying selection result in the formation of
      functionally variable conotoxins that are linked to ecological diversification
      and evolutionary success of this genus.

PMID- 10359797
TI  - The distribution and copy number of copia-like retrotransposons in rice (Oryza
      sativa L.) and their implications in the organization and evolution of the rice
      genome.
AB  - We used 22 fragments corresponding to the reverse transcriptase domain of copia
      like retrotransposons as representatives to study the organization and
      distribution of these elements in the rice genome. The loci detected by these 22
      fragments were assigned to 47 locations in the molecular-linkage map involving
      all 12 chromosomes. The distributional features of copia-like retrotransposons
      found in the rice genome indicated that (i) the loci detected were located mainly
      in one arm of each chromosome; (ii) one fragment usually detected several loci
      that were mapped to similar locations of different chromosomes; (iii)
      retrotransposons sharing high identity in nucleotide sequences were usually
      assigned to similar locations of the chromosomes; and (iv) concurrences of
      multiple loci, detected by different fragments, in similar locations or stretches
      of different chromosomes were common in the rice genome. We also determined that
      the copy number of copia-like retrotransposons in rice genome may be as low as
      approximately 100 per haploid genome. The restricted distribution, along with low
      copy number, suggested that copia-like retrotransposons in rice were relatively
      inactive during evolution compared with those in other plants. The distributional
      features of the copia-like retrotransposons suggested the existence of possible
      lineages among the rice chromosomes, which in turn suggested that chromosome
      duplication and diversification may be a mechanism for the origin and evolution
      of the rice chromosomes. The information provided by fine mapping of the
      retroelements in the genetic linkage map may also be useful for gene tagging and
      molecular cloning.

PMID- 10359798
TI  - A new structure for the murine Xist gene and its relationship to chromosome
      choice/counting during X-chromosome inactivation.
AB  - In this report, we present structural data for the murine Xist gene. The data
      presented in this paper demonstrate that the murine Xist transcript is at least
      17.4 kb, not 14.3 kb as previously reported. The new structure of the murine Xist
      gene described herein has seven exons, not six. Exon VII encodes an additional
      3.1 kb of information at the 3' end. Exon VII contains seven possible sites for
      polyadenylation; four of these sites are located in the newly discovered 3' end.
      Consequently, it is possible that several distinct transcripts may be produced
      through differential polyadenylation of a primary transcript. Alternative use of
      polyadenylation signals could result in size changes for exon VII. Two major
      species of Xist are detectable by Northern analysis, consistent with differential
      polyadenylation. In this paper, we propose a model for the role of the Xist 3'
      end in the process of X-chromosome counting and choice during embryonic
      development.

PMID- 10359799
TI  - GCN5-dependent histone H3 acetylation and RPD3-dependent histone H4 deacetylation
      have distinct, opposing effects on IME2 transcription, during meiosis and during
      vegetative growth, in budding yeast.
AB  - Diploid yeast undergo meiosis under certain conditions of nutrient limitation,
      which trigger a transcriptional cascade involving two key regulatory genes. IME1
      is a positive activator of IME2, which activates downstream genes. We report that
      Gcn5, a histone H3 acetylase, plays a central role in initiation of meiosis via
      effects on IME2 expression. An allele, gcn5-21, was isolated as a mutant
      defective in spore formation. gcn5-21 fails to carry out meiotic DNA replication,
      recombination, or meiotic divisions. This mutant also fails to induce IME2
      transcription; IME1 transcription, however, is essentially normal. Further
      investigation shows that during wild-type meiosis the IME2 promoter undergoes an
      increase in the level of bound acetylated histone H3. This increase is
      contemporaneous with meiotic induction of IME2 transcription and is absent in
      gcn5-21. In contrast, the RPD3 gene, which encodes a histone H4 deacetylase and
      is known to be required for repression of basal IME2 transcription in growing
      yeast cells, is not involved in induction of IME2 transcription or IME2 histone
      acetlyation during meiosis. These and other results suggest that Gcn5 and Rpd3
      play distinct roles, modulating transcription initiation in opposite directions
      under two different cellular conditions. These roles are implemented via opposing
      effects of the two gene products on acetylation of two different histones.
      Finally, we find that gcn5 and rpd3 single mutants are not defective in meiosis
      if acetate is absent and respiration is promoted by a metabolically unrelated
      carbon source. Perhaps intracellular acetate levels regulate meiosis by
      controlling histone acetylation patterns.

PMID- 10359800
TI  - Human XIST yeast artificial chromosome transgenes show partial X inactivation
      center function in mouse embryonic stem cells.
AB  - Initiation of X chromosome inactivation requires the presence, in cis, of the X
      inactivation center (XIC). The Xist gene, which lies within the XIC region in
      both human and mouse and has the unique property of being expressed only from the
      inactive X chromosome in female somatic cells, is known to be essential for X
      inactivation based on targeted deletions in the mouse. Although our understanding
      of the developmental regulation and function of the mouse Xist gene has
      progressed rapidly, less is known about its human homolog. To address this and to
      assess the cross-species conservation of X inactivation, a 480-kb yeast
      artificial chromosome containing the human XIST gene was introduced into mouse
      embryonic stem (ES) cells. The human XIST transcript was expressed and could coat
      the mouse autosome from which it was transcribed, indicating that the factors
      required for cis association are conserved in mouse ES cells. Cis inactivation as
      a result of human XIST expression was found in only a proportion of
      differentiated cells, suggesting that the events downstream of XIST RNA coating
      that culminate in stable inactivation may require species-specific factors. Human
      XIST RNA appears to coat mouse autosomes in ES cells before in vitro
      differentiation, in contrast to the behavior of the mouse Xist gene in
      undifferentiated ES cells, where an unstable transcript and no chromosome coating
      are found. This may not only reflect important species differences in Xist
      regulation but also provides evidence that factors implicated in Xist RNA
      chromosome coating may already be present in undifferentiated ES cells.

PMID- 10359801
TI  - An experimental solution for the Luria-Delbruck fluctuation problem in measuring
      hypermutation rates.
AB  - A cell line harboring all trans-acting elements necessary for hypermutation was
      transfected with a plasmid harboring the major cis-acting elements plus a green
      fluorescent protein gene containing a premature chain-termination codon.
      Transfected cells do not fluoresce unless the stop codon reverts. When a sizable
      cell population is purged of revertants by sorting, the frequency of mutants
      increases linearly with time, and there is no Luria-Delbruck fluctuation effect.
      Moreover, as mutant frequencies seemed to vary less than cell numbers in
      replicate cultures, it is suggested that hypermutation might not be coupled
      closely to cell division.

PMID- 10359802
TI  - Different mutator phenotypes in Mlh1- versus Pms2-deficient mice.
AB  - Deficiencies in DNA mismatch repair (MMR) result in increased mutation rates and
      cancer risk in both humans and mice. Mouse strains homozygous for knockouts of
      either the Pms2 or Mlh1 MMR gene develop cancer but exhibit very different tumor
      spectra; only Mlh1(-/-) animals develop intestinal tumors. We carried out a
      detailed study of the microsatellite mutation spectra in each knockout strain.
      Five mononucleotide repeat tracts at four different chromosomal locations were
      studied by using single-molecule PCR or an in vivo forward mutation assay. Three
      dinucleotide repeat loci also were examined. Surprisingly, the mononucleotide
      repeat mutation frequency in Mlh1(-/-) mice was 2- to 3-fold higher than in Pms2(
      /-) animals. The higher mutation frequency in Mlh1(-/-) mice may be a consequence
      of some residual DNA repair capacity in the Pms2(-/-) animals. Relevant to this
      idea, we observed that Pms2(-/-) mice exhibit almost normal levels of Mlh1p,
      whereas Mlh1(-/-) animals lack both Mlh1p and Pms2p. Comparison between Mlh1(-/-)
      animals and Mlh1(-/-) and Pms2(-/-) double knockout mice revealed little
      difference in mutator phenotype, suggesting that Mlh1 nullizygosity is sufficient
      to inactivate MMR completely. The findings may provide a basis for understanding
      the greater predisposition to intestinal cancer of Mlh1(-/-) mice. Small
      differences (2- to 3-fold) in mononucleotide repeat mutation rates may have
      dramatic effects on tumor development, requiring multiple genetic alterations in
      coding regions. Alternatively, this strain difference in tumor spectra also may
      be related to the consequences of the absence of Pms2p compared with the absence
      of both Pms2p and Mlh1p on as yet little understood cellular processes.

PMID- 10359803
TI  - A novel mechanism for P element homing in Drosophila.
AB  - P element insertion is essentially random at the scale of the genome. However, P
      elements containing regulatory sequences from Drosophila engrailed and
      polyhomeotic genes and from the Bithorax and Antennapedia complexes show some
      insertional specificity by frequently inserting near the parent gene (homing)
      and/or near genes containing Polycomb group response elements (preferential
      insertion). This phenomenon is thought to be mediated by Polycomb group proteins.
      In this report, we describe a case of homing of P elements containing regulatory
      sequences of the linotte gene. This homing occurs with high frequency (up to 20%
      of the lines) and high precision (inserted into a region of <1 kilobase). We
      present evidence showing that it is not mediated by Polycomb group proteins but
      by a new, as yet unknown, mechanism. We also suggest that P element homing could
      be a more frequent phenomenon than generally assumed and that it could become a
      powerful tool of Drosophila reverse genetics, for which there is no other
      described gene targeting technique.

PMID- 10359804
TI  - The role of transient hypermutators in adaptive mutation in Escherichia coli.
AB  - Microbial populations under nonlethal selection can give rise to mutations that
      relieve the selective pressure, a phenomenon that has come to be called "adaptive
      mutation." One explanation for adaptive mutation is that a small proportion of
      the cells experience a period of transient hypermutation, and that these
      hypermutators account for the mutations that appear. The experiments reported
      here investigated the contribution that hypermutators make to the mutations
      occurring in a Lac- strain of Escherichia coli during selection for lactose
      utilization. A broad mutational screen, loss of motility, was used to compare the
      frequency of nonselected mutations in starved Lac- cells, in Lac+ revertants, and
      in Lac+ revertants carrying yet another nonselected mutation. These frequencies
      allowed us to calculate that the hypermutating subpopulation makes up
      approximately 0.06% of the population and that its mutation rate is elevated
      approximately 200-fold. From these numbers we conclude that the hypermutators are
      responsible for nearly all multiple mutations but produce only approximately 10%
      of the adaptive Lac+ mutations.

PMID- 10359805
TI  - Paternal monoallelic expression of the paired immunoglobulin-like receptors PIR-A
      and PIR-B.
AB  - A diverse pattern of polymorphism is defined for the paired Ig-like receptors
      (PIRs) that serve as activating (PIR-A) and inhibitory (PIR-B) receptors on B
      lymphocytes, dendritic cells, and myeloid-lineage cells in mice. The monoclonal
      anti-PIR antibody 10.4 is shown to recognize an allelic PIR-A/PIR-B determinant
      on cells from BALB/c but not C57BL/6 mice. Other strains of inbred mice also can
      be typed on the basis of their expression of this PIR allelic determinant.
      Analysis of (BALB/c x C57BL/6) F1 hybrid offspring indicates that PIR molecules
      bearing the paternal PIR allotype are expressed whereas PIR-A and PIR-B molecules
      bearing the maternal allotype are not. The monoallelic expression of the
      polymorphic PIR-A and PIR-B molecules, and possibly of their human Ig-like
      transcript/leukocyte Ig-like receptor/monocyte/macrophage Ig-like receptor and
      killer cell inhibitory receptor relatives, may influence innate and specific
      immune responses in outbred populations.

PMID- 10359806
TI  - CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their
      ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions.
AB  - Multiple sclerosis (MS) is a T cell-dependent chronic inflammatory disease of the
      central nervous system. The role of chemokines in MS and its different stages is
      uncertain. Recent data suggest a bias in expression of chemokine receptors by Th1
      vs. Th2 cells; human Th1 clones express CXCR3 and CCR5 and Th2 clones express
      CCR3 and CCR4. Chemokine receptors expressed by Th1 cells may be important in MS,
      as increased interferon-gamma (IFN-gamma) precedes clinical attacks, and IFN
      gamma injection induces disease exacerbations. We found CXCR3(+) T cells
      increased in blood of relapsing-remitting MS, and both CCR5(+) and CXCR3(+) T
      cells increased in progressive MS compared with controls. Furthermore, peripheral
      blood CCR5(+) T cells secreted high levels of IFN-gamma. In the brain, the CCR5
      ligand, MIP-1alpha, was strongly associated with microglia/macrophages, and the
      CXCR3 ligand, IP-10, was expressed by astrocytes in MS lesions but not unaffected
      white matter of control or MS subjects. Areas of plaque formation were
      infiltrated by CCR5-expressing and, to a lesser extent, CXCR3-expressing cells;
      Interleukin (IL)-18 and IFN-gamma were expressed in demyelinating lesions. No
      leukocyte expression of CCR3, CCR4, or six other chemokines, or anti-inflammatory
      cytokines IL-5, IL-10, IL-13, and transforming growth factor-beta was observed.
      Thus, chemokine receptor expression may be used for immunologic staging of MS and
      potentially for other chronic autoimmune/inflammatory processes such as
      rheumatoid arthritis, autoimmune diabetes, or chronic transplant rejection.
      Furthermore, these results provide a rationale for the use of agents that block
      CCR5 and/or CXCR3 as a therapeutic approach in the treatment of MS.

PMID- 10359807
TI  - Broad tumor-associated expression and recognition by tumor-derived gamma delta T
      cells of MICA and MICB.
AB  - Human MHC class I-related molecules, MICA and MICB, are stress-induced antigens
      that are recognized by a subset of gamma delta T cells expressing the variable
      region Vdelta1. This functional association has been found to be limited to
      intestinal epithelium, where these T cells are prevalent and where MICA and,
      presumably, MICB are mainly expressed. However, increased frequencies of Vdelta1
      gamma delta T cells have been observed in various epithelial tumors; moreover,
      MICA/B are expressed on diverse cultured epithelial tumor cells. With freshly
      isolated tumor specimens, expression of MICA/B was documented in many, but not
      all, carcinomas of the lung, breast, kidney, ovary, prostate, and colon. In
      tumors that were positive for MICA/B, the frequencies of Vdelta1 gamma delta T
      cells were significantly higher than in those that were negative. Vdelta1 gamma
      delta T cell lines and clones derived from different tumors recognized MICA/B on
      autologous and heterologous tumor cells. In accord with previous evidence, no
      constraints were observed in these interactions, such as those imposed by
      specific peptide ligands. Thus, MICA/B are tumor-associated antigens that can be
      recognized, in an apparently unconditional manner, by a subset of tumor
      infiltrating gamma delta T cells. These results raise the possibility that an
      induced expression of MICA/B, by conditions that may be related to tumor
      homeostasis and growth, could play a role in immune responses against tumors.

PMID- 10359808
TI  - Matrix metalloproteinase deficiencies affect contact hypersensitivity:
      stromelysin-1 deficiency prevents the response and gelatinase B deficiency
      prolongs the response.
AB  - Matrix metalloproteinases (MMPs) are expressed by T cells and macrophages, but
      there is a paucity of evidence for their role in immune responses. We have
      studied mice with deficiencies of stromelysin-1 (MMP-3) or gelatinase B (MMP-9)
      in a dinitrofluorobenzene (DNFB)-induced model of contact hypersensitivity (CHS).
      Stromelysin-1-deficient mice showed a markedly impaired CHS response to topical
      DNFB, although they responded normally to cutaneously applied phenol, an acute
      irritant. Lymphocytes from lymph nodes of DNFB-sensitized stromelysin-1-deficient
      mice did not proliferate in response to specific soluble antigen
      dinitrobenzenesulfonic acid, but did proliferate identically to lymph node
      lymphocytes from wild-type mice when presented with the mitogen Con A. An
      intradermal injection of stromelysin-1 immediately before DNFB sensitization
      rescued the impaired CHS response to DNFB in stromelysin-1-deficient mice. Unlike
      stromelysin-1-deficient mice, gelatinase B-deficient mice exhibited a CHS
      response comparable to wild-type controls at 1 day postchallenge, but the
      response persisted beyond 7 days in contrast to the complete resolution observed
      in wild-type mice by 7 days. However, gelatinase B-deficient mice had a normal
      rate of resolution of acute inflammation elicited by cutaneous phenol. Gelatinase
      B-deficient mice failed to show IL-10 production at the site of CHS, an essential
      feature of resolution in control mice. These results indicate that stromelysin-1
      and gelatinase B serve important functions in CHS. Stromelysin-1 is required for
      initiation of the response, whereas gelatinase B plays a critical role in its
      resolution.

PMID- 10359809
TI  - The tyrosine kinases Syk and Lyn exert opposing effects on the activation of
      protein kinase Akt/PKB in B lymphocytes.
AB  - The protein kinase Akt/PKB is a crucial regulator of cell survival in response to
      mitogenic signals. The increased kinase activity of v-akt, an oncogenic form of
      Akt/PKB, causes mouse T cell lymphoma, and overexpression of Akt/PKB is
      associated with progression of several tumor types in human. In this study, we
      demonstrate that ligation of B cell antigen receptor (BCR) leads to activation of
      Akt/PKB in B lymphocytes. BCR-induced activation of Akt/PKB required the tyrosine
      kinase Syk, which was not previously known to regulate Akt/PKB. In contrast, BCR
      crosslinking of Lyn-deficient B cells resulted in markedly enhanced
      hyperphosphorylation and activation of Akt/PKB compared with wild-type B cells,
      indicating that this Src-family kinase acts as an endogenous antagonist of BCR
      induced Akt/PKB activation. Lyn inhibited Akt/PKB additively with an okadaic acid
      sensitive endogenous phosphatase(s). Expression of exogenous Lyn in mutant cells
      restored normal BCR-induced phosphorylation of Akt/PKB. Negative regulation of
      Akt/PKB by Lyn was not dependent on the protein phosphatases SHP-1, SHP-2, or
      SHIP. Our results show that Lyn provides a mechanism for negative regulation and
      opposes the effect of Syk on BCR-mediated activation of Akt/PKB. Deregulation of
      Akt/PKB correlates with the hyperresponsiveness of B cells from Lyn-deficient
      mice stimulated by BCR crosslinking and may contribute to the autoimmune syndrome
      that develops in Lyn-deficient animals.

PMID- 10359811
TI  - Tumor necrosis factor alpha is a key component in the obesity-linked elevation of
      plasminogen activator inhibitor 1.
AB  - Obesity is associated with a cluster of abnormalities, including hypertension,
      insulin resistance, hyperinsulinemia, and elevated levels of both plasminogen
      activator inhibitor 1 (PAI-1) and transforming growth factor beta (TGF-beta).
      Although these changes may increase the risk for accelerated atherosclerosis and
      fatal myocardial infarction, the underlying molecular mechanisms remain to be
      defined. Although tumor necrosis factor alpha (TNF-alpha) has been implicated in
      the insulin resistance associated with obesity, its role in other disorders of
      obesity is largely unknown. In this report, we show that in obese (ob/ob) mice,
      neutralization of TNF-alpha or deletion of both TNF receptors (TNFRs) results in
      significantly reduced levels of plasma PAI-1 antigen, plasma insulin, and adipose
      tissue PAI-1 and TGF-beta mRNAs. Studies in which exogenous TNF-alpha was infused
      into lean mice lacking individual TNFRs indicate that TNF-alpha signaling of PAI
      1 in adipose tissue can be mediated by either the p55 or the p75 TNFR. However,
      TNF-alpha signaling of TGF-beta mRNA expression in adipose tissue is mediated
      exclusively via the p55 TNFR. Our results suggest that TNF-alpha is a common link
      between the insulin resistance and elevated PAI-1 and TGF-beta in obesity. The
      chronic elevation of TNF-alpha in obesity thus may directly promote the
      development of the complex cardiovascular risk profile associated with this
      condition.

PMID- 10359810
TI  - Antibodies to CD44 and integrin alpha4, but not L-selectin, prevent central
      nervous system inflammation and experimental encephalomyelitis by blocking
      secondary leukocyte recruitment.
AB  - The role of various adhesion molecules in lymphocyte homing to the brain and in
      inflammatory autoimmune disease of the central nervous system (CNS) was examined
      in mice. Activated T cell lines and clones expressed CD44 and integrin alpha4,
      but not L-selectin, and entered the CNS independent of their antigen specificity.
      mAbs directed against CD44 and integrin alpha4 prevented the transfer of
      experimental autoimmune encephalomyelitis (EAE) by myelin basic protein-specific
      T cells. T cells preincubated with anti-CD44 or antiintegrin alpha4 were blocked
      only partially from entering the brain parenchyma. However, both antibodies
      efficiently prevented CNS inflammation and clinical expression of EAE when
      injected in vivo. This effect lasted as long as antibodies were administered.
      Antibodies specific for L-selectin had no effect on homing of encephalitogenic T
      cells to the brain or development of EAE. Antiintegrin alpha4 and anti-CD44 did
      not impair the activation and function of encephalitogenic T cells in vitro and
      did not deplete integrin alpha4- or CD44-positive cells in vivo. These data
      suggest that, in the absence of leukocyte recruitment, the entry of a reduced
      number of activated myelin basic protein-reactive T cells in the CNS is not
      sufficient for the development and expression of EAE. We propose that antibodies
      to integrin alpha4 and CD44 prevent clinical disease by partially targeting the
      primary influx of encephalitogenic T cells and by preventing the secondary influx
      of leukocytes to lesions initiated by the transferred T cells.

PMID- 10359812
TI  - Vancomycin-resistant enterococci in intensive-care hospital settings:
      transmission dynamics, persistence, and the impact of infection control programs.
AB  - Vancomycin-resistant enterococci (VRE) recently have emerged as a nosocomial
      pathogen especially in intensive-care units (ICUs) worldwide. Transmission via
      the hands of health-care workers is an important determinant of spread and
      persistence in a VRE-endemic ICU. We describe the transmission of nosocomial
      pathogens by using a micro-epidemiological framework based on the transmission
      dynamics of vector-borne diseases. By using the concept of a basic reproductive
      number, R0, defined as the average number of secondary cases generated by one
      primary case, we show quantitatively how infection control measures such as hand
      washing, cohorting, and antibiotic restriction affect nosocomial cross
      transmission. By using detailed molecular epidemiological surveillance and
      compliance monitoring, we found that the estimated basic reproductive number for
      VRE during a study at the Cook County Hospital, Chicago, was approximately 3-4
      without infection control and 0.7 when infection control measures were included.
      The impact of infection control was to reduce the prevalence from a predicted 79%
      to an observed 36%. Hand washing and staff cohorting are the most powerful
      control measures although their efficacy depends on the magnitude of R0. Under
      the circumstances tested, endemicity of VRE was stabilized despite infection
      control measures, by the constant introduction of colonized patients. Multiple
      stochastic simulations of the model revealed excellent agreement with observed
      pattern. In conjunction with detailed microbiological surveillance, a
      mathematical framework provides a precise template to describe the colonization
      dynamics of VRE in ICUs and impact of infection control measures. Our analyses
      suggest that compliance for hand washing significantly in excess of reported
      levels, or the cohorting of nursing staff, are needed to prevent nosocomial
      transmission of VRE in endemic settings.

PMID- 10359814
TI  - Myocardial infarction mediated by endothelin receptor signaling in
      hypercholesterolemic mice.
AB  - Myocardial infarction is linked to atherosclerosis, yet the sequence leading from
      silent coronary atherosclerosis to acute myocardial infarction has remained
      unclear. Here we show that hypercholesterolemic apolipoprotein E-/- low density
      lipoprotein receptor-/- mice develop not only coronary atherosclerosis but also
      myocardial infarction. Exposure of mice to mental stress or hypoxia led to acute
      ischemia, which, in a large proportion of the mice, was followed by
      electrocardiographic changes, leakage of troponin T, and loss of dehydrogenase
      from the myocardium, all indicative of acute myocardial infarction. Apoptotic
      death of cardiomyocytes was followed by inflammation and fibrosis in the heart.
      All these pathological changes could be prevented by a blocker of the endothelin
      type A receptor. Thus, stress elicits myocardial infarction through endothelin
      receptor signaling in coronary atherosclerosis caused by hypercholesterolemia.

PMID- 10359813
TI  - MRP3, an organic anion transporter able to transport anti-cancer drugs.
AB  - The human multidrug-resistance protein (MRP) gene family contains at least six
      members: MRP1, encoding the multidrug-resistance protein; MRP2 or cMOAT, encoding
      the canalicular multispecific organic anion transporter; and four homologs,
      called MRP3, MRP4, MRP5, and MRP6. In this report, we characterize MRP3, the
      closest homolog of MRP1. Cell lines were retrovirally transduced with MRP3 cDNA,
      and new monoclonal antibodies specific for MRP3 were generated. We show that MRP3
      is an organic anion and multidrug transporter, like the GS-X pumps MRP1 and MRP2.
      In Madin-Darby canine kidney II cells, MRP3 routes to the basolateral membrane
      and mediates transport of the organic anion S-(2,4-dinitrophenyl-)glutathione
      toward the basolateral side of the monolayer. In ovarian carcinoma cells (2008),
      expression of MRP3 results in low-level resistance to the epipodophyllotoxins
      etoposide and teniposide. In short-term drug exposure experiments, MRP3 also
      confers high-level resistance to methotrexate. Neither 2008 cells nor Madin-Darby
      canine kidney II cells overexpressing MRP3 showed an increase in glutathione
      export or a decrease in the level of intracellular glutathione, in contrast to
      cells overexpressing MRP1 or MRP2. We discuss the possible function of MRP3 in
      (hepatic) physiology and its potential contribution to drug resistance of cancer
      cells.

PMID- 10359815
TI  - Multiple event activation of a generic prodrug trigger by antibody catalysis.
AB  - Chemotherapeutic regimes are typically limited by nonspecific toxicity. To
      address this problem we have developed a broadly applicable drug-masking
      chemistry that operates in conjunction with a unique broad-scope catalytic
      antibody. This masking chemistry is applicable to a wide range of drugs because
      it is compatible with virtually any heteroatom. We demonstrate that generic drug
      masking groups may be selectively removed by sequential retro-aldol-retro-Michael
      reactions catalyzed by antibody 38C2. This reaction cascade is not catalyzed by
      any known natural enzyme. Application of this masking chemistry to the anticancer
      drugs doxorubicin and camptothecin produced prodrugs with substantially reduced
      toxicity. These prodrugs are selectively unmasked by the catalytic antibody when
      it is applied at therapeutically relevant concentrations. We have demonstrated
      the efficacy of this approach by using human colon and prostate cancer cell
      lines. The antibody demonstrated a long in vivo half-life after administration to
      mice. Based on these findings, we believe that the system described here has the
      potential to become a key tool in selective chemotherapeutic strategies.

PMID- 10359816
TI  - Lysophosphatidic acid mediates the rapid activation of platelets and endothelial
      cells by mildly oxidized low density lipoprotein and accumulates in human
      atherosclerotic lesions.
AB  - Oxidized low density lipoprotein (LDL) is a key factor in the pathogenesis of
      atherosclerosis and its thrombotic complications, such as stroke and myocardial
      infarction. It activates endothelial cells and platelets through mechanisms that
      are largely unknown. Here, we show that lysophosphatidic acid (LPA) was formed
      during mild oxidation of LDL and was the active compound in mildly oxidized LDL
      and minimally modified LDL, initiating platelet activation and stimulating
      endothelial cell stress-fiber and gap formation. Antagonists of the LPA receptor
      prevented platelet and endothelial cell activation by mildly oxidized LDL. We
      also found that LPA accumulated in and was the primary platelet-activating lipid
      of atherosclerotic plaques. Notably, the amount of LPA within the human carotid
      atherosclerotic lesion was highest in the lipid-rich core, the region most
      thrombogenic and most prone to rupture. Given the potent biological activity of
      LPA on platelets and on cells of the vessel wall, our study identifies LPA as an
      atherothrombogenic molecule and suggests a possible strategy to prevent and treat
      atherosclerosis and cardiocerebrovascular diseases.

PMID- 10359817
TI  - P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2.
AB  - The INK4a-ARF locus encodes two distinct tumor suppressors, p16(INK4a) and
      p19(ARF). Whereas p16(INK4a) restrains cell growth through preventing
      phosphorylation of the retinoblastoma protein, p19(ARF) acts by attenuating Mdm2
      mediated degradation of p53, thereby stabilizing p53. Recent data indicate that
      Mdm2 shuttles between the nucleus and the cytoplasm and that nucleo-cytoplasmic
      shuttling of Mdm2 is essential for Mdm2's ability to promote p53 degradation.
      Therefore, Mdm2 must export p53 from the nucleus to the cytoplasm where it
      targets p53 for degradation. We show here that coexpression of p19(ARF) blocks
      the nucleo-cytoplasmic shuttling of Mdm2. Moreover, subnuclear localization of
      Mdm2 changes from the nucleoplasm to the nucleolus in a shuttling time-dependent
      manner, whereas p19(ARF) is exclusively located in the nucleolus. In
      heterokaryons containing Mdm2 and p19(ARF), the longer the Mdm2 shuttling is
      allowed, the more Mdm2 protein colocalizes with p19(ARF) in the nucleolus,
      implying that Mdm2 moves from the nucleoplasm to the nucleolus and then
      associates with p19(ARF) there. Furthermore, whether or not Mdm2 colocalizes with
      p19(ARF) in the nucleolus, p19(ARF) prevents Mdm2 shuttling. This observation
      suggests that Mdm2 might be exported through the nucleolus and p19(ARF) could
      inhibit the nuclear export of Mdm2 by tethering Mdm2 in the nucleolus. Taken
      together, p19(ARF) could stabilize p53 by inhibiting the nuclear export of Mdm2.

PMID- 10359818
TI  - p53 gene mutations are not required for early dissemination of cancer cells.
AB  - The p53 protein is involved in several central cellular processes, including gene
      transcription, DNA repair, cell cycling, genomic stability, chromosomal
      segregation, senescence, and apoptosis. p53 mutations frequently result in an
      immunocytochemically detectable accumulation of the p53 protein in tumor cells.
      To evaluate whether p53 gene mutations are required for the onset of
      hematogeneous tumor cell dissemination, we compared the p53 status of primary and
      micrometastatic tumor cells. Disseminated carcinoma cells could be detected in
      bone marrow aspirates obtained from 46 (40%) of 114 patients with various types
      of epithelial tumors without overt skeleton metastases. There was no correlation
      between the detection of p53 protein in primary lung carcinomas and the presence
      of tumor cells in bone marrow. Further analyses revealed that the disseminated
      carcinoma cells rarely accumulate mutated p53 protein and that 10 cell lines
      derived thereof did not harbor p53 mutations even in the presence of such
      mutations in the autologous primary tumors. These observations indicate that
      tumor cells can leave the primary tumor before mutations of the p53 gene occur
      and that these mutations are not essential for such early hematogeneous
      dissemination of cancer cells. Thus, the value of mutated p53 as a target for
      diagnosis and treatment of micrometastatic disease in cancer patients is
      questionable.

PMID- 10359819
TI  - An estrogen receptor-selective coregulator that potentiates the effectiveness of
      antiestrogens and represses the activity of estrogens.
AB  - The action of nuclear hormone receptors is tripartite, involving the receptor,
      its ligands, and its coregulator proteins. The estrogen receptor (ER), a member
      of this superfamily, is a hormone-activated transcription factor that mediates
      the stimulatory effects of estrogens and the inhibitory effects of antiestrogens
      such as tamoxifen in breast cancer and other estrogen target cells. To understand
      how antiestrogens and dominant negative ERs suppress ER activity, we used a
      dominant negative ER as bait in two-hybrid screening assays from which we
      isolated a clone from breast cancer cells that potentiates the inhibitory
      activities of dominant negative ERs and antiestrogen-liganded ER. At higher
      concentrations, it also represses the transcriptional activity of the estradiol
      liganded ER, while having no effect on other nuclear hormone receptors. This
      clone, denoted REA for "repressor of estrogen receptor activity," encodes a 37
      kDa protein that is an ER-selective coregulator. Its competitive reversal of
      steroid receptor coactivator 1 enhancement of ER activity and its direct
      interaction with liganded ER suggest that it may play an important role in
      determining the sensitivity of estrogen target cells, including breast cancer
      cells, to antiestrogens and estrogens.

PMID- 10359820
TI  - Phage-display library selection of high-affinity human single-chain antibodies to
      tumor-associated carbohydrate antigens sialyl Lewisx and Lewisx.
AB  - mAbs against tumor-associated carbohydrate antigens have the potential to play a
      prominent role in cancer immunotherapy. However, it has not been possible to
      fully exploit the clinical utility of such antibodies primarily, because those of
      adequate affinity could be derived only from murine sources. To address this
      problem, we prepared a single-chain Fv (scFv) antibody library from the
      peripheral blood lymphocytes of 20 patients with various cancer diseases.
      Completely human high-affinity scFv antibodies were then selected by using
      synthetic sialyl Lewisx and Lewisx BSA conjugates. These human scFv antibodies
      were specific for sialyl Lewisx and Lewisx, as demonstrated by ELISA, BIAcore,
      and flow cytometry binding to the cell surface of pancreatic adenocarcinoma
      cells. Nucleotide sequencing revealed that at least four unique scFv genes were
      obtained. The Kd values ranged from 1.1 to 6.2 x 10(-7) M that were comparable to
      the affinities of mAbs derived from the secondary immune response. These
      antibodies could be valuable reagents for probing the structure and function of
      carbohydrate antigens and in the treatment of human tumor diseases.

PMID- 10359821
TI  - Proteolytic release and nuclear translocation of Notch-1 are induced by
      presenilin-1 and impaired by pathogenic presenilin-1 mutations.
AB  - The Notch family of proteins consists of transmembrane receptors that play a
      critical role in the determination of cell fate. Genetic studies in
      Caenorhabditis elegans suggest that the presenilin proteins, which are associated
      with familial Alzheimer's disease, regulate Notch signaling. Here we show that
      proteolytic release of the Notch-1 intracellular domain (NICD), an essential step
      in the activation of Notch signaling, is markedly reduced in presenilin-1 (PS1)
      deficient cells and is restored by PS1 expression. Nuclear translocation of the
      NICD is also markedly reduced in PS1-deficient cells, resulting in reduced
      transcriptional activation. Mutations in PS1 that are associated with familial
      Alzheimer's disease impair the ability of PS1 to induce proteolytic release of
      the NICD and nuclear translocation of the cleaved protein. These results suggest
      that PS1 plays a central role in the proteolytic activation of the Notch-1
      signaling pathway and that this function is impaired by pathogenic PS1 mutations.
      Thus, dysregulation of proteolytic function may underlie the mechanism by which
      presenilin mutations cause Alzheimer's disease.

PMID- 10359822
TI  - Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of
      the murine SOCS-3 promoter.
AB  - Pituitary corticotroph SOCS-3 is a novel intracellular regulator of leukemia
      inhibitory factor (LIF)-mediated proopiomelanocortin gene expression and
      adrenocorticotropic hormone (ACTH) secretion, inhibiting LIF-activated Janus
      kinase-signal transducers and activators of transcription (STAT) signaling in a
      negative autoregulatory loop. We now demonstrate in corticotroph AtT-20 cells
      that LIF-stimulated endogenous SOCS-3 mRNA expression is blocked in stable
      transfectants of SOCS-3 wild type or in dominant negative STAT-3 mutants,
      respectively. We characterized approximately 3.8-kb genomic 5' sequence of murine
      SOCS-3, including approximately 2.9-kb sequence upstream of the transcription
      start site (+1), which was determined by 5' rapid amplification of cDNA ends and
      RNase protection assay. Different 5' constructs were cloned into the pGL3Basic
      vector, and luciferase activity was assayed in transiently transfected ACTH
      secreting corticotroph AtT-20 cells. A STAT-1/STAT-3 binding element, located at
      nucleotides -72 to -64, was essential for LIF stimulation of SOCS-3 promoter
      activity. LIF induced 10-fold increased luciferase activity in a wild-type
      construct spanning -2757 to +929 bases. However, deletion or point mutation of
      the STAT-1/STAT-3 binding element abrogated LIF action (2- to 3-fold).
      Electrophoretic mobility-shift assay analysis confirmed specific binding of STAT
      1 and STAT-3 to this region. These results characterize the genomic 5' region of
      murine SOCS-3 and identify an important STAT-1/STAT-3 binding element therein.
      Thus, LIF-stimulated SOCS-3 gene expression is at least in part mediated by STAT
      3 and STAT-1. The cytokine inhibitor SOCS-3 acts in a negative loop to
      autoregulate its own gene expression, thus limiting its accumulation in the
      corticotroph cell. These results demonstrate a mechanism for corticotroph
      plasticity with rapid "on" and "off" ACTH induction in response to neuro-immuno
      endocrine stimuli, such as LIF.

PMID- 10359824
TI  - Clonal dynamics of progressive neoplastic transformation.
AB  - In a recent study, we found that newly isolated clones of NIH 3T3 mouse cells
      undergo neoplastic transformation more readily than uncloned cultures from which
      they were derived. After eleven low-density passages (LDPs), most of the 29
      clones produced lightly stained early-stage transformed foci when grown to
      confluence in a primary assay for transformation, and one of them consistently
      produced a few tiny dense foci. In the present work, six of the clones were kept
      in LDPs for 56 passages and assayed for focus formation at confluence at six
      passage levels. The clone that produced tiny dense foci switched to light foci
      during the LDPs, four others produced light foci at different passage levels, and
      one progressed from light to dense foci after the last passage. By contrast, all
      the clones progressed to dense focus formation in five or fewer serial
      repetitions of the assay at confluence. Because all but one of the clones
      underwent about half as many total divisions at each LDP as they did when grown
      to the stationary state at confluence, the latter is more efficient in eliciting
      progression than the exponential growth of the LDPs. Extension of the period at
      confluence of uncloned cultures results in the appearance of dense foci within
      light foci. Because the latter are localized clonal populations, the intrafocal
      progression reinforces the conclusion that clonal expansion favors
      transformation. We discuss the significance of these results for the clonal
      origin of human cancer and the increased incidence of cancer with age.

PMID- 10359823
TI  - Immunostimulatory oligodeoxynucleotides promote protective immunity and provide
      systemic therapy for leishmaniasis via IL-12- and IFN-gamma-dependent mechanisms.
AB  - Resistance to murine leishmaniasis correlates with development of a CD4(+) T
      helper 1 (Th1)-predominant immune response. To determine whether
      immunostimulatory CpG-containing oligodeoxynucleotides (CpG-ODN), known to
      promote a Th1 immune response, could provide protection from Leishmania
      infection, CpG-ODN and freeze-thawed (F/T) Leishmania major were coinjected
      intradermally into susceptible BALB/c mice. A Leishmania-specific Th1-predominant
      immune response was induced, and 40% of animals were protected from subsequent
      challenge with infectious organisms, with 0% protection of animals injected with
      F/T Leishmania organisms and PBS, F/T organisms and control ODN, or F/T organisms
      alone. More striking protection (65-95%) was seen in mice first infected with
      intact Leishmania organisms and then injected with CpG-ODN, either at the site of
      infection or at a remote site. To determine whether the therapeutic protection
      provided by CpG-ODN depended on IL-12 and IFN-gamma production, both IFN-gamma
      deficient BALB/c mice and BALB/c mice treated with neutralizing anti-IL-12 mAb
      were first inoculated with Leishmania and then treated with either CpG-ODN, ODN,
      or PBS. None of these IFN-gamma-deficient mice survived (0/20, 0/20, and 0/20
      respectively). Furthermore, neutralization of IL-12 completely abolished the
      therapeutic protection provided by CpG-ODN (0/20 mice surviving). We conclude
      that immunostimulatory DNA sequences likely exert systemic effects via IL-12 and
      IFN-gamma-dependent mechanisms and hold considerable promise as both vaccine
      adjuvants and potential therapeutic agents in the prevention and treatment of
      leishmaniasis.

PMID- 10359825
TI  - A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes
      carbohydrate-deficient glycoprotein syndrome type-Ic.
AB  - Carbohydrate-deficient glycoprotein syndrome (CDGS) represents a class of genetic
      diseases characterized by abnormal N-linked glycosylation. CDGS patients show a
      large number of glycoprotein abnormalities resulting in dysmorphy,
      encephalopathy, and other organ disorders. The majority of CDGSs described to
      date are related to an impaired biosynthesis of dolichyl pyrophosphate-linked
      Glc3Man9GlcNAc2 in the endoplasmic reticulum. Recently, we identified in four
      related patients a novel type of CDGS characterized by an accumulation of
      dolichyl pyrophosphate-linked Man9GlcNAc2. Elaborating on the analogy of this
      finding with the phenotype of alg5 and alg6 Saccharomyces cerevisiae strains, we
      have cloned and analyzed the human orthologs to the ALG5 dolichyl phosphate
      glucosyltransferase and ALG6 dolichyl pyrophosphate Man9GlcNAc2 alpha1,3
      glucosyltransferase in four novel CDGS patients. Although ALG5 was not altered in
      the patients, a C-->T transition was detected in ALG6 cDNA of all four CDGS
      patients. The mutation cosegregated with the disease in a Mendelian recessive
      manner. Expression of the human ALG5 and ALG6 cDNA could partially complement the
      respective S. cerevisiae alg5 and alg6 deficiency. By contrast, the mutant ALG6
      cDNA of CDGS patients failed to revert the hypoglycosylation observed in alg6
      yeasts, thereby proving a functional relationship between the alanine to valine
      substitution introduced by the C-->T transition and the CDGS phenotype. The
      mutation in the ALG6 alpha1,3-glucosyltransferase gene defines an additional type
      of CDGS, which we propose to refer to as CDGS type-Ic.

PMID- 10359826
TI  - Molecular cloning, characterization, and promoter analysis of the human 25
      hydroxyvitamin D3-1alpha-hydroxylase gene.
AB  - The human 25-hydroxyvitamin D3-1alpha-hydroxylase (1alpha-OHase) gene has been
      cloned. It contained nine exons and eight introns spanning approximately 6.5 kb
      and a 1.4-kb 5'-flanking region. The 5'-flanking region contains consensus or
      highly conserved sequences for TATA, Pu, and CCAAT boxes, four cAMP response
      elements, two activator protein-1 (AP-1) response elements, two AP-2 response
      elements, three specific protein-1 (Sp1) response elements, and four NF-kappaB
      binding sites, but no vitamin D response element. By using luciferase reporter
      gene constructs of truncated forms of the 1alpha-OHase promoter transfected into
      a modified pig kidney cell line, AOK-B50, we identified regulatory regions of the
      1.4-kb 1alpha-OHase promoter for parathyroid hormone 1-34 [PTH(1-34)], forskolin,
      and 1,25-hydroxyvitamin D3 [1,25(OH)2D3]. The 1.4-kb 1alpha-OHase promoter (AN1)
      modestly (1.7-fold) induced luciferase activity, whereas 1,100- (AN2), 827-
      (AN3), 672- (AN4), 463-(AN5), and 363-bp (AN6)-truncated promoters greatly
      stimulated luciferase activity by 494-fold, 18.4-fold, 55.3-fold, 643-fold, and
      56.4-fold, respectively. PTH(1-34) and forskolin stimulated the activity of all
      constructs to varying degrees with significantly greater responsiveness for both
      compounds on AN2 and AN5. 1,25(OH)2D3 suppressed PTH(1-34)-induced activity on
      AN2 and AN5 constructs by 58% and 52%, respectively, but had no effect on the
      other constructs. These studies characterize the regulatory regions of the human
      1alpha-OHase gene and provide insight into the physiologic basis for regulation
      of the expression of this gene by PTH and 1,25(OH)2D3.

PMID- 10359827
TI  - Immunization against genital herpes with a vaccine virus that has defects in
      productive and latent infection.
AB  - An effective vaccine for genital herpes has been difficult to achieve because of
      the limited efficacy of subunit vaccines and the safety concerns about live
      viruses. As an alternative approach, mutant herpes simplex virus strains that are
      replication-defective can induce protective immunity. To increase the level of
      safety and to prove that replication was not needed for immunization, we
      constructed a mutant herpes simplex virus 2 strain containing two deletion
      mutations, each of which eliminated viral replication. The double-mutant virus
      induces protective immunity that can reduce acute viral shedding and latent
      infection in a mouse genital model, but importantly, the double-mutant virus
      shows a phenotypic defect in latent infection. This herpes vaccine strain, which
      is immunogenic but has defects in both productive and latent infection, provides
      a paradigm for the design of vaccines and vaccine vectors for other sexually
      transmitted diseases, such as AIDS.

PMID- 10359828
TI  - Intranuclear localization of human papillomavirus 16 E7 during transformation and
      preferential binding of E7 to the Rb family member p130.
AB  - To study intracellular pathways by which the human papillomavirus 16 oncogene E7
      participates in carcinogenesis, we expressed an inducible chimera of E7 by fusion
      to the hormone-binding domain of the estrogen receptor. The chimeric protein
      (E7ER) transformed rodent fibroblast cell lines and induced DNA synthesis on
      addition of estradiol. In coimmunoprecipitation experiments, E7ER preferentially
      bound p130 when compared to p107 and pRb. After estradiol addition, E7ER
      localization changed to a more intense intranuclear staining. Induction of E7
      function was not correlated with binding to p130 or pRb but rather with
      intranuclear localization and modest induction of binding to p107.

PMID- 10359829
TI  - Unexpected abundance of self-splicing introns in the genome of bacteriophage
      Twort: introns in multiple genes, a single gene with three introns, and exon
      skipping by group I ribozymes.
AB  - Analysis of RNA that can be labeled with GTP indicates the existence of group I
      introns in genes of at least three transcriptional classes in the genome of
      Staphylococcus aureus bacteriophage Twort. A single ORF of 142 amino acids
      (Orf142) is interrupted by three self-splicing group I introns, providing the
      first example of a phage gene with multiple intron insertions. Twort Orf142 is
      encoded in a message that is abundant 15-20 min after infection and is highly
      similar to a late gene product (Orf8) of the morphologically related Listeria
      phage A511. The introns in orf142 are spliced in vivo and contain all the
      conserved features of primary sequence and secondary structure of group I introns
      in subgroup IA2, which includes the introns in Escherichia coli phage T4 and the
      Bacillus phages beta22 and SPO1. Introns I2 and I3 in orf142 are highly similar,
      and their intron insertion sites are closely spaced. The presence of transcripts
      with a skipped exon between these introns indicates that they may fold into a
      single active ribozyme resulting in alternative splicing. Alternatively, the
      cleaved 5' exon preceding I2 may undergo trans splicing to the 3' exon that
      follows I3. Regardless of the detailed mechanism, these results demonstrate a new
      means whereby a single gene can give rise to multiple messenger RNAs.

PMID- 10359831
TI  - A practical method for simultaneously determining the effective burst sizes and
      cycle times of viruses.
AB  - We describe combined analytic and experimental methods for determining
      reproductive statistics from time-series data. Our computational methods derive
      four fundamental measures from laboratory experiments: (i) average number of
      viral daughters; (ii) mean viral cycle time; (iii) standard deviation of the
      viral cycling time; and (iv) viral doubling time. Taken together, these four
      reproductive statistics characterize "age-specific fertility," a quantity that
      provides complete information on the reproduction of the average viral particle.
      In this paper, we emphasize applications relating to HIV and experiments for
      assessing cellular tropism, viral phenotypes, antiviral drugs, humoral immunity,
      and cytotoxic cellular immunity. Nevertheless, our method is quite flexible and
      applicable to the evaluation of drugs against bacterial, fungal, and parasitic
      infections, antineoplastic agents against cancer cells, and perturbations
      involving pest and wildlife releases in ecosystems.

PMID- 10359830
TI  - Sequence anomalies in the Cag7 gene of the Helicobacter pylori pathogenicity
      island.
AB  - The severity of Helicobacter pylori-related disease is correlated with a
      pathogenicity island (the Cag region of about 26 genes) whose presence is
      associated with the up-regulation of an IL-8 cytokine inflammatory response in
      gastric epithelial cells. Statistical analysis of the Cag gene sequences
      calculated from the complete genome of strain 26695 revealed several unusual
      features. The Cag7 sequence (1,927 aa) has two repeat regions. Repeat region I
      runs 317 aa in a form of AAA proximal to the protein N terminal; repeat region II
      extends 907 aa in the middle of the protein sequence consisting of 74 contiguous
      segments composed from selections among six consensus sequences and includes 58
      regularly distributed cysteine residues with consecutive cysteines mostly 12, 18,
      or 24 aa apart. This "regular" cysteine arrangement may provide a scaffolding of
      linker elements stabilized by disulfide bridges. When Cag7 homologues from
      different strains are compared, differences were found almost exclusively in the
      repeat regions, resulting from deletion and/or insertion of repeating units.
      These observations suggest that the anomalous repetitive structure of the
      sequence plays an important role in the conformation of Cag7 gene product and
      potentially in the function of the pathogenicity island. Other facets of the Cag7
      sequence show significant charge clusters, high multiplet count, and extremes of
      amino acid usage.

PMID- 10359832
TI  - Calexcitin transformation of GABAergic synapses: from excitation filter to
      amplifier.
AB  - Encoding an experience into a lasting memory is thought to involve an altered
      operation of relevant synapses and a variety of other subcellular processes,
      including changed activity of specific proteins. Here, we report direct evidence
      that co-applying (associating) membrane depolarization of rat hippocampal CA1
      pyramidal cells with intracellular microinjections of calexcitin (CE), a memory
      related signaling protein, induces a long-term transformation of inhibitory
      postsynaptic potentials from basket interneurons (BAS) into excitatory
      postsynaptic potentials. This synaptic transformation changes the function of the
      synaptic inputs from excitation filter to amplifier, is accompanied by a shift of
      the reversal potential of BAS-CA1 postsynaptic potentials, and is blocked by
      inhibiting carbonic anhydrase or antagonizing ryanodine receptors. Effects in the
      opposite direction are produced when anti-CE antibody is introduced into the
      cells, whereas heat-inactivated CE and antibodies are ineffective. These data
      suggest that CE is actively involved in shaping BAS-CA1 synaptic plasticity and
      controlling information processing through the hippocampal networks.

PMID- 10359833
TI  - "Global" cell replacement is feasible via neural stem cell transplantation:
      evidence from the dysmyelinated shiverer mouse brain.
AB  - Many diseases of the central nervous system (CNS), particularly those of genetic,
      metabolic, or infectious/inflammatory etiology, are characterized by "global"
      neural degeneration or dysfunction. Therapy might require widespread neural cell
      replacement, a challenge not regarded conventionally as amenable to neural
      transplantation. Mouse mutants characterized by CNS-wide white matter disease
      provide ideal models for testing the hypothesis that neural stem cell
      transplantation might compensate for defective neural cell types in
      neuropathologies requiring cell replacement throughout the brain. The
      oligodendrocytes of the dysmyelinated shiverer (shi) mouse are "globally"
      dysfunctional because they lack myelin basic protein (MBP) essential for
      effective myelination. Therapy, therefore, requires widespread replacement with
      MBP-expressing oligodendrocytes. Clonal neural stem cells transplanted at birth
      using a simple intracerebroventricular implantation technique-resulted in
      widespread engraftment throughout the shi brain with repletion of MBP.
      Accordingly, of the many donor cells that differentiated into oligodendroglia
      there appeared to be a shift in the fate of these multipotent cells toward an
      oligodendroglial fate-a subgroup myelinated up to 52% (mean = approximately 40%)
      of host neuronal processes with better compacted myelin of a thickness and
      periodicity more closely approximating normal. A number of recipient animals
      evinced decrement in their symptomatic tremor. Therefore, "global" neural cell
      replacement seems feasible for some CNS pathologies if cells with stem-like
      features are used.

PMID- 10359834
TI  - Optical recording of light-evoked calcium signals in the functionally intact
      retina.
AB  - Using two-photon excitation of fluorescent indicator dyes, we measured calcium
      concentration transients in retinal ganglion and amacrine cells without
      destroying the light sensitivity of the retina by maximally activating or
      bleaching the photoreceptors. This allowed an immediate assessment of the
      cellular morphology and study of the calcium signals evoked by visual stimuli.
      Calcium dynamics in individual dendritic processes could be examined for
      extensive periods without deterioration and with little apparent phototoxicity at
      excitation wavelengths of from 930 to 990 nm. Light-evoked increases in calcium
      were resolved in ganglion- and amacrine-cell neurites, making it possible to use
      optical recording to study the relationship between calcium signaling and retinal
      function.

PMID- 10359835
TI  - Recombinant Semliki Forest virus and Sindbis virus efficiently infect neurons in
      hippocampal slice cultures.
AB  - Gene transfer into nervous tissue is a powerful tool for the analysis of gene
      function. By using a rat hippocampal slice culture preparation, we show here that
      Semliki Forest virus (SFV) and Sindbis virus (SIN) vectors are useful for the
      effective infection of neurons. The stratum pyramidale and/or the granular cell
      layer were injected with recombinant virus encoding beta-galactosidase (LacZ) or
      green fluorescent protein (GFP). By using low concentrations of injected SFV-LacZ
      or SIN-LacZ, we detected LacZ staining of pyramidal cells, interneurons, and
      granule cells. About 60% of the infected cells showed clear neuronal morphology;
      thus, relatively few glial cells expressed the transgene. Expression of GFP from
      SFV and SIN vectors gave similar results, with an even higher percentage (>90%)
      of the GFP-positive cells identified as neurons. Infected pyramidal cells were
      readily recognized in living slices, displaying GFP fluorescence in dendrites of
      up to fourth order and in dendritic spines. They appeared morphologically normal
      and viable at 1-5 days postinfection. We conclude that both SFV and SIN vectors
      efficiently transfer genes into neurons in hippocampal slice cultures. In
      combination with the GFP reporter, SFV and SIN vectors will allow the
      physiological examination of identified neurons that have been modified by
      overexpression or suppression of a specific gene product.

PMID- 10359836
TI  - Leptin actions on food intake and body temperature are mediated by IL-1.
AB  - Leptin regulates energy balance through its actions in the brain on appetite and
      energy expenditure and also shares properties with cytokines such as IL-1. We
      report here that leptin, injected into rats intracerebroventricularly or
      peripherally, induces significant dose-dependent increases in core body
      temperature as well as suppression of appetite. Leptin failed to affect food
      intake or body temperature in obese (fa/fa) Zucker rats, which posses a defective
      leptin receptor. Furthermore, injection of leptin increased levels of the
      proinflammatory cytokine IL-1beta in the hypothalamus of normal Sprague-Dawley
      rats. Central injection of IL-1 receptor antagonist (IL-1ra) inhibited the
      suppression of food intake caused by central or peripheral injection of leptin
      (60 and 84%, respectively) and abolished the leptin-induced increase in body
      temperature in both cases. Mice lacking (gene knockout) the main IL-1 receptor
      (80 kDa, R1) responsible for IL-1 actions showed no reduction in food intake in
      response to leptin. These data indicate that leptin actions in the brain depend
      on IL-1, and we show further that the effect of leptin on fever, but not food
      intake, is abolished by a cyclooxygenase inhibitor. Thus, we propose that in
      addition to its role in body weight regulation, leptin may mediate neuroimmune
      responses via actions in the brain dependent on release of IL-1 and
      prostaglandins.

PMID- 10359837
TI  - Peptide nucleic acids targeted to the neurotensin receptor and administered i.p.
      cross the blood-brain barrier and specifically reduce gene expression.
AB  - Intraperitoneal injection of an unmodified antisense peptide nucleic acid (PNA)
      complementary to mRNA of the rat neurotensin (NT) receptor (NTR1) was
      demonstrated by a gel shift assay to be present in brain, thus indicating that
      the PNA had in fact crossed the blood-brain barrier. An i.p. injection of this
      antisense PNA specifically inhibited the hypothermic and antinociceptive
      activities of NT microinjected into brain. These results were associated with a
      reduction in binding sites for NT both in brain and the small intestine.
      Additionally, the sense-NTR1 PNA, targeted to DNA, microinjected directly into
      the brain specifically reduced mRNA levels by 50% and caused a loss of response
      to NT. To demonstrate the specificity of changes in behavioral, binding, and mRNA
      studies, animals treated with NTR1 PNA were tested for behavioral responses to
      morphine and their mu receptor levels were determined. Both were found to be
      unaffected in these NTR1 PNA-treated animals. The effects of both the antisense
      and sense PNAs were completely reversible. This work provides evidence that any
      antisense strategy targeted to brain proteins can work through i. p. delivery by
      crossing the normal blood-brain barrier. Equally important was that an antigene
      strategy, the sense PNA, was shown in vivo to be a potentially effective
      therapeutic treatment.

PMID- 10359838
TI  - Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic
      mice.
AB  - Stimulation of cardiac beta1-adrenergic receptors is the main mechanism that
      increases heart rate and contractility. Consequently, several pharmacological and
      gene transfer strategies for the prevention of heart failure aim at improving the
      function of the cardiac beta-adrenergic receptor system, whereas current clinical
      treatment favors a reduction of cardiac stimulation. To address this controversy,
      we have generated mice with heart-specific overexpression of beta1-adrenergic
      receptors. Their cardiac function was investigated in organ bath experiments as
      well as in vivo by cardiac catheterization and by time-resolved NMR imaging. The
      transgenic mice had increased cardiac contractility at a young age but also
      developed marked myocyte hypertrophy (3.5-fold increase in myocyte area). This
      increase was followed by progressive heart failure with functional and
      histological deficits typical for humans with heart failure. Contractility was
      reduced by approximately 50% in 35-week-old mice, and ejection fraction was
      reduced down to a minimum of approximately 20%. We conclude that overexpression
      of beta1-adrenergic receptors in the heart may lead to a short-lived improvement
      of cardiac function, but that increased beta1-adrenergic receptor signalling is
      ultimately detrimental.

PMID- 10359839
TI  - Guanosine triphosphatase stimulation of oncogenic Ras mutants.
AB  - Interest in the guanosine triphosphatase (GTPase) reaction of Ras as a molecular
      drug target stems from the observation that, in a large number of human tumors,
      Ras is characteristically mutated at codons 12 or 61, more rarely 13. Impaired
      GTPase activity, even in the presence of GTPase activating proteins, has been
      found to be the biochemical reason behind the oncogenicity of most Gly12/Gln61
      mutations, thus preventing Ras from being switched off. Therefore, these
      oncogenic Ras mutants remain constitutively activated and contribute to the
      neoplastic phenotype of tumor cells. Here, we show that the guanosine 5'
      triphosphate (GTP) analogue diaminobenzophenone-phosphoroamidate-GTP (DABP-GTP)
      is hydrolyzed by wild-type Ras but more efficiently by frequently occurring
      oncogenic Ras mutants, to yield guanosine 5'-diphosphate-bound inactive Ras and
      DABP-Pi. The reaction is independent of the presence of Gln61 and is most
      dramatically enhanced with Gly12 mutants. Thus, the defective GTPase reaction of
      the oncogenic Ras mutants can be rescued by using DABP-GTP instead of GTP,
      arguing that the GTPase switch of Ras is not irreversibly damaged. An exocyclic
      aromatic amino group of DABP-GTP is critical for the reaction and bypasses the
      putative rate-limiting step of the intrinsic Ras GTPase reaction. The crystal
      structures of Ras-bound DABP-beta,gamma-imido-GTP show a disordered switch I and
      identify the Gly12/Gly13 region as the hydrophobic patch to accommodate the DABP
      moiety. The biochemical and structural studies help to define the requirements
      for the design of anti-Ras drugs aimed at the blocked GTPase reaction.

PMID- 10359840
TI  - Isolation and characterization of a dual-substrate phosphodiesterase gene family:
      PDE10A.
AB  - We report here the cloning, expression, and characterization of a dual-substrate,
      cAMP and cGMP, cyclic nucleotide phosphodiesterase (PDE) from mouse. This PDE
      contains the consensus sequence for a PDE catalytic domain, but shares <50%
      sequence identity with the catalytic domains of all other known PDEs and,
      therefore, represents a new PDE gene family, designated PDE10A. The cDNA for
      PDE10A is 3, 370 nt in length. It includes a full ORF, contains three in-frame
      stop codons upstream of the first methionine, and is predicted to encode a 779-aa
      enzyme. At the N terminus PDE10A has two GAF domains homologous to many signaling
      molecules, including PDE2, PDE5, and PDE6, which likely constitute a low-affinity
      binding site for cGMP. PDE10A hydrolyzes cAMP with a Km of 0.05 microM and cGMP
      with a Km of 3 microM. Although PDE10A has a lower Km for cAMP, the Vmax ratio
      (cGMP/cAMP) is 4.7. RNA distribution studies indicate that PDE10A is expressed at
      highest levels in testis and brain.

PMID- 10359842
TI  - Identification of the gregarization-associated dark-pigmentotropin in locusts
      through an albino mutant.
AB  - In response to crowding, locusts develop characteristic black patterns that are
      well discernible in the gregarious phase at outbreaks. We report here a dark
      color-inducing neuropeptide (dark-pigmentotropin) from the corpora cardiaca of
      two plague locusts, Schistocerca gregaria and Locusta migratoria. The
      chromatographic isolation of this neuropeptide was monitored by using a bioassay
      with an albino mutant of L. migratoria. The neurohormone, consisting of 11 amino
      acids, is identical to [His7] corazonin, previously isolated from corpora
      cardiaca of another acridid without known function. The present results show that
      even in isolated (solitary) nymphs, [His7] corazonin induces gregarious black
      patterns. Its primary structure shows some similarity with the vertebrate
      melanophore stimulating hormone.

PMID- 10359841
TI  - Differentiation between vasculoprotective and uterotrophic effects of ligands
      with different binding affinities to estrogen receptors alpha and beta.
AB  - Estrogen-based drug therapy in cardiovascular diseases has been difficult because
      it has not been possible to separate the wanted vasculoprotective effect from the
      unwanted effects of the hormone to the reproductive system. Here, we demonstrate
      that, after endothelial denudation of rat carotid artery, the mRNA of the
      classical estrogen receptor (ERalpha) is constitutively expressed at a low level
      whereas the expression of the novel ERbeta mRNA increases >40-fold. Under in situ
      hybridization and immunohistochemistry, ERbeta mRNA and protein colocalize with
      the smooth muscle cells in the media and neointima. Treatment of ovariectomized
      female rats with the isoflavone phytoestrogen genistein, which shows 20-fold
      higher binding affinity to ERbeta than to ERalpha, or with 17beta-estradiol,
      which does not differentiate between the two receptors, provides similar dose
      dependent vasculoprotective effect in rat carotid injury model. In addition in
      concentrations <10 microM, both ligands are equally inhibitory to the replication
      and migration of smooth muscle cells in vitro. However, only treatment with
      17beta-estradiol, but not with genistein, is accompanied with a dose-dependent
      uterotrophic effect. The results suggest that preferential targeting to ERbeta
      will provide vasculoprotective estrogen analogs devoid of effects to the
      reproductive system.

PMID- 10359843
TI  - Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF
      I in blood but is not required for postnatal body growth in mice.
AB  - The body growth of animals is regulated by growth hormone and IGF-I. The
      classical theory of this regulation is that most IGF-I in the blood originates in
      the liver and that body growth is controlled by the concentration of IGF-I in the
      blood. We have abolished IGF-I production in the livers of mice by using the
      Cre/loxP recombination system. These mice demonstrated complete inactivation of
      the IGF-I gene in the hepatocytes. Although the liver accounts for less than 5%
      of body mass, the concentration of IGF-I in the serum was reduced by 75%. This
      finding confirms that the liver is the principal source of IGF-I in the blood.
      However, the reduction in serum IGF-I concentration had no discernible effect on
      postnatal body growth. We conclude that postnatal body growth is preserved
      despite complete absence of IGF-I production by the hepatocytes.

PMID- 10359844
TI  - Corticotropin-releasing hormone deficiency unmasks the proinflammatory effect of
      epinephrine.
AB  - Traditionally, the adrenal gland has been considered an important endocrine
      component of the pathway to inhibit acute inflammation via hypothalamic
      corticotropin-releasing hormone (CRH)-mediated secretion of glucocorticoid.
      Immunoreactive CRH found in inflamed tissues is a potent proinflammatory factor.
      Using genetic and pharmacological models of CRH deficiency, we now show that CRH
      deficiency unmasks a major proinflammatory effect of epinephrine secreted from
      the adrenal medulla. Together, epinephrine and peripheral CRH stimulate
      inflammation, and glucocorticoid acts as a counterbalancing force in this regard.
      Our findings suggest that stimulation of the acute inflammatory response should
      be included with the other "fight-or-flight" actions of epinephrine.

PMID- 10359845
TI  - Map-based cloning of chloronerva, a gene involved in iron uptake of higher plants
      encoding nicotianamine synthase.
AB  - The uptake of iron in plants is a highly regulated process that is induced on
      iron starvation. In tomato, the mutant chloronerva exhibits constitutive
      expression of iron uptake responses and intercostal chlorosis. Biochemically,
      chloronerva is an auxotroph for nicotianamine, a key polyamine in plant iron
      uptake metabolism. The chloronerva gene has been fine-mapped onto the long arm of
      chromosome 1 in a large segregating tomato population and yeast artificial
      chromosome clones encompassing the region were isolated by using flanking
      markers. A cosmid contig containing the chloronerva gene was established, and
      complementing cosmids were identified by transformation into the mutant. The
      chloronerva transcript was identified by cDNA isolation using the complementing
      cosmids. The gene encodes a unique protein of 35 kDa. The mutant harbors a single
      base change compared with the wild type. Based on enzyme activity and sequence
      similarity to the coding DNA sequence of the purified barley enzyme the
      chloronerva gene encodes the enzyme nicotianamine synthase.

PMID- 10359846
TI  - beta-Phaseolin gene activation is a two-step process: PvALF- facilitated
      chromatin modification followed by abscisic acid-mediated gene activation.
AB  - We have shown previously that a rotationally and translationally positioned
      nucleosome is responsible for the absence of transcriptional expression from the
      phaseolin (phas) gene promoter in leaf tissue and that the repressive chromatin
      structure is disrupted on transcriptional activation during embryogenesis. To
      investigate how the chromatin structure is modified, we ectopically expressed
      PvALF, a putative seed-specific phas activator, in leaf tissue of a tobacco line
      transgenic for a chimeric phas/uidA construct. DNase I footprinting in vivo
      revealed that the ectopic expression of PvALF resulted in remodeling of the
      chromatin architecture over the TATA region of the phas promoter but did not lead
      to transcriptional activation in the absence of abscisic acid (ABA). Treatment of
      the transgenic tobacco leaves with ABA in the absence of PvALF neither alleviated
      the repressive chromatin architecture nor activated transcription. However, in
      the presence of PvALF, high levels of beta-glucuronidase expression were obtained
      on exposure of leaves to ABA. These results reveal that expression from the phas
      promoter involves at least two discrete steps: chromatin potentiation by PvALF
      followed by ABA-mediated transcriptional activation.

PMID- 10359847
TI  - AtPCS1, a phytochelatin synthase from Arabidopsis: isolation and in vitro
      reconstitution.
AB  - Phytochelatins, a class of posttranslationally synthesized peptides, play a
      pivotal role in heavy metal, primarily Cd2+, tolerance in plants and fungi by
      chelating these substances and decreasing their free concentrations. Derived from
      glutathione and related thiols by the action of gamma-glutamylcysteine dipeptidyl
      transpeptidases (phytochelatin synthases; EC 2.3.2.15), phytochelatins consist of
      repeating units of gamma-glutamylcysteine followed by a C-terminal Gly, Ser, or
      beta-Ala residue [poly-(gamma-Glu-Cys)n-Xaa]. Here we report the suppression
      cloning of a cDNA (AtPCS1) from Arabidopsis thaliana encoding a 55-kDa soluble
      protein that enhances heavy-metal tolerance and elicits Cd2+-activated
      phytochelatin accumulation when expressed in Saccharomyces cerevisiae. On the
      basis of these properties and the sufficiency of immunoaffinity-purified epitope
      tagged AtPCS1 polypeptide for high rates of Cd2+-activated phytochelatin
      synthesis from glutathione in vitro, AtPCS1 is concluded to encode the enzyme
      phytochelatin synthase.

PMID- 10359849
TI  - Intrasellar adenoid cystic carcinoma and papillary mucinous adenocarcinoma: two
      previously undescribed primary neoplasms at this site.
AB  - Most carcinomas involving the sella turcica are metastases. We report two
      previously undescribed carcinomas that appear to be primary at this site. The
      first occurred in a 44-year-old woman who presented with hemianopsia. A mass was
      noted by computed tomography to occupy the sella turcica, from which it appeared
      to originate. Transphenoidal biopsy showed the tumor to be an adenoid cystic
      carcinoma with a typical cribriform pattern. The patient died shortly after a
      subsequent attempt at tumor resection. The second tumor arose in a 55-year-old
      man who presented with diplopia. Computed tomography showed a mass in the sella
      turcica that was presumed to be a pituitary adenoma. However, transphenoidal
      resection revealed a mucinous adenocarcinoma composed of small papillae and
      glands lined by columnar epithelium. The tumor cells exhibited varying degrees of
      stratification with prominent interspersed mucin vacuoles. Focal solid areas
      showed a component of signet ring-type cells. In contrast to the apparent
      aggressive behavior of the adenoid cystic carcinoma, the papillary mucinous
      adenocarcinoma appeared much less aggressive, as the second patient was alive and
      without evidence of disease 5 years later. Both tumors may be derived from
      epithelial rests within the pituitary gland, either minor salivary gland rests or
      Rathke's cleft remnants.

PMID- 10359848
TI  - Identification of a novel Sry-related gene and its germ cell-specific expression.
AB  - Sox family proteins are characterized by a unique DNA-binding domain, a HMG box
      which shows at least 50% sequence similarity with mouse Sry, the sex-determining
      factor. At present almost 30 Sox genes have been identified. Members of this
      family have been shown to be conserved during evolution and to play key roles
      during animal development. Some are involved in human diseases, including sex
      reversal. Here we report the isolation of a novel member of the Sox gene family,
      Sox30, which may constitute a distinct subgroup of this family. Using a
      bacterially expressed DNA-binding domain of Sox30, we show that it is able to
      specifically recognize the ACAAT motif. Furthermore, Sox30 is capable of
      activating transcription from a synthetic promoter containing the ACAAT motif.
      The specific expression of Sox30 in normal testes, but not in maturing germ cell
      deficient testes, suggests the involvement of Sox30 in differentiation of male
      germ cells. Mapping analyses revealed that the Sox30 gene is located on human
      chromosome 5 (5q33) and on mouse chromosome 11.

PMID- 10359850
TI  - Pseudomesotheliomatous carcinoma involving pleura and peritoneum: A
      clinicopathologic and immunohistochemical study of three cases.
AB  - Pseudomesotheliomatous carcinoma is a rare variant of peripheral adenocarcinoma
      of the lung that can manifest clinical, radiologic, and pathologic features
      similar to malignant mesothelioma. We present three patients with
      pseudomesotheliomatous carcinoma of the lung. In one patient the carcinoma
      extended beyond the thorax and extensively involved the peritoneum, mesentery,
      omentum, and intestines. All patients experienced weight loss and chest pain. All
      were white men aged 63, 65, and 67 years. Two were smokers and had shortness of
      breath, cough, and pleural effusion. One had a history of asbestos exposure. No
      patient developed dyspnea or hemoptysis. One was successfully treated for
      prostatic carcinoma 18 months earlier. Radiographically, all tumors were pleura
      based. Grossly, the tumors spread extensively over pleural (and in one case
      peritoneal) surfaces and mimicked malignant mesothelioma. Histologically, all
      tumors were poorly differentiated and necrotic; two tumors exhibited spindle-cell
      components and desmoplasia. Mucin production was detectable in none, 10%, and 50%
      of tumor cells. The percentages of tumor cells immunoreactive for Ber-EP4 were
      70%, 100%, and 80%; for Leu MI 0%, 90%, and 50%; for epithelial membrane antigen
      80%, 80%, and 100%; for B 72.3%, 0%, 90%, and 20%; for polyclonal
      carcinoembryonic antigen 0%, 10%, and 10%; and for monoclonal 5%, 0%, and 0%. Of
      these, Ber-EP4 and B 72.3 rendered the most reliable diagnostic results. The
      clinical, radiologic, and gross and routine histologic findings were similar to
      those of a malignant mesothelioma; the final diagnosis could be made based mainly
      on immunocytochemical results. We have reviewed the English and German literature
      regarding 65 such tumors and present our experience with three additional cases.
      We emphasize the application of immunocytochemical studies on pleura-based poorly
      or undifferentiated malignant tumors of unknown origin.

PMID- 10359851
TI  - The histogenesis of mucinous adenocarcinoma of the stomach from observations in
      early gastric cancer.
AB  - Eighteen cases of primary mucinous early gastric cancer (EGC) were studied with
      regard to histogenetic implications. This type of carcinoma was found in 10.7% of
      168 cases of EGC and was removed surgically. In 11 patients, mucinous tumor was
      mainly found in the submucosal layer of the stomach. These findings are in
      keeping with the hypothesis that mucinous adenocarcinoma develops during
      progression of an ordinary adenocarcinoma. In two cases of well-differentiated
      mucinous intramucosal EGC, mucinous tumor was associated with a villous adenoma,
      as is the case in intestinal-type adenocarcinoma. In five cases of poorly
      differentiated mucinous carcinoma, tumor was seen at the middle level of the
      mucosa, with normal foveolae in the upper mucosa and normal specialized antral
      and body type glands in the lower part. There were no associated areas of
      dysplasia or intestinal metaplasia. These histologic findings suggest that a
      subset of mucinous EGC develops from the proliferative zone (the neck region) of
      nonmetaplastic glands, as reported in diffuse carcinoma of the stomach. These
      results suggest a histogenetic heterogeneity in the entity of the mucinous
      carcinoma. Well- and poorly differentiated mucinous intramucosal EGCs show a
      histogenesis similar to that of gastric carcinoma of the intestinal and diffuse
      types, respectively.

PMID- 10359852
TI  - Immunoreactivity of ductal cells with putative myoepithelial markers: A potential
      pitfall in breast carcinoma.
AB  - The identification of an intact layer of myoepithelial cells (MECs) located
      between epithelial cells and the basal lamina is useful in differentiating benign
      breast lesions and carcinoma in situ from invasive breast carcinoma. In the
      present study we used three antibodies considered to be putative markers of MECs
      (S100 protein, muscle-specific actin [HHF-35], and smooth muscle actin [SMA]) in
      100 formalin-fixed, paraffin-embedded histologic sections of breast in an attempt
      to compare their value in demonstrating MECs in benign breast tissue and breast
      carcinomas. We concluded that for identifying MECs in benign breast tissue, SMA
      appears to be the most reliable, followed closely by HHF-35, but S100 is very
      unreliable for this purpose. In breast carcinoma, all three stains showed
      variable cross-reactivity with myofibroblasts, being greatest with SMA. A
      significant number of tumor cells in ductal carcinoma, both intraductal and
      invasive, stain with these markers and this "cross-reactivity" is extremely high
      with HHF-35. Thus, immunohistochemistry should be interpreted cautiously in
      differentiating benign, in situ, and invasive breast neoplasms. The "cross
      reactivity" also suggests the possibility of myoepithelial differentiation and/or
      high actin content of breast tumor cells.

PMID- 10359853
TI  - Adenomyomatous hyperplasia of the papilla of Vater: A sequela of chronic
      papillitis?
AB  - A case of adenomyomatous hyperplasia of the papilla of Vater is described. The
      lesion presented as a small polypoid tumor projecting into the duodenal lumen,
      causing obstruction and dilatation of the common bile duct. Serial cross-section
      of the ampulla showed diffuse thickening of the muscular layer corresponding to
      Oddi's sphincter, with resulting narrowing of the lumen. Many ductal or glandular
      components were dispersed within the mucosa and the muscular layer and were
      admixed with lymphocytes, a few lymphoid aggregates, and fibrosis. Based both on
      the absence of cellular atypia and the presence of inflammation, fibrosis, and
      preservation of the normal architecture of the ampulla, we favor the
      interpretation that this hyperplastic lesion represents a sequela of chronic
      papillitis. The different diagnoses for this lesion are presented along with a
      review of the literature.

PMID- 10359854
TI  - Simultaneous strumal ovarii and lymphoma with emphasis on the diagnostic
      usefulness of immunohistochemical stains.
AB  - Strumal ovarii has been rarely associated with other tumors, such as carcinoid
      tumor, carcinoma, and primary ovarian malignant lymphoma. We report the
      coexistence of a strumal ovarii and ovarian involvement by malignant lymphoma in
      a 70-year-old woman. The tumors were detected 10 years following exposure to
      ionizing radiation during the Chernobyl nuclear tragedy.

PMID- 10359855
TI  - Intracranial extracerebral neuroglial heterotopia: A case report and review of
      the literature.
AB  - Heterotopic masses of neuroglial tissue are uncommon and most frequently involve
      extracranial midline structures. We report an unusual case of an intracranial,
      extracerebral neuroglial heterotopia involving the middle and anterior cranial
      fossae of a 5-year-old girl who presented with facial asymmetry. The lesion was
      composed of mature but disorganized gray and white matter admixed with
      surrounding soft tissues and exhibited histologic features reminiscent of
      cortical dysplasia. These rare lesions have been postulated to arise from a
      protrusion of tissue from the neuraxis through a pial defect, from abnormalities
      in the migration of embryonic neuroepithelial tissue, or from an accessory
      evagination of the neural tube inferior to the telencephalic vesicles. Regardless
      of the underlying pathogenic mechanism, these lesions must be histologically
      distinguished from both teratomas and primary central nervous system neoplasms.

PMID- 10359856
TI  - Clarity on the diagnosis line (the devil is in the details)
AB  - The diagnosis line of a surgical pathology report obviously influences therapy
      and is often critical for proper initiation of same. If the word choice,
      phrasing, or terminology in the diagnosis is potentially ambiguous or subject to
      misinterpretation, this could have adverse or sometimes even disastrous
      consequences. Usually the potential for misinterpretation is a subtle facet of
      the wording and is not apparent to the pathologist. This discussion aims to help
      the pathologist become more aware of the types of subtle wording nuances that can
      be important and we hope to foster the habit of searching for and correcting such
      potentially troublesome nuances.

PMID- 10359857
TI  - An autopsy: A historical vignette.
AB  - This paper recounts a case report from 1853 that describes the circumstances
      surrounding the death of a young woman, the request for and granting of
      permission for an autopsy, and exposition of how the autopsy findings were used
      from the point of view of education, quality control of practice, and vital
      statistics. There is, in addition, a description of the evolution of the use of
      the word autopsy.

PMID- 10359858
TI  - Rockefeller, Florey, and the penicillin connection.

PMID- 10359859
TI  - [Study on telomerase inhibition by ribozyme targeted to telomerase RNA
      component].
AB  - OBJECTIVE: To evaluate the possibility of using ribozyme technology for
      telomerase inhibition and cancer therapy. METHODS: A hammer head ribozyme
      (telomerase ribozyme, teloRZ) directed against the RNA component of human
      telomerase (hTR) was designed and synthesized to serve as a telomerase inhibitor.
      An in vitro transcription plasmid and a eukaryotic expression plasmid containing
      teloRZ gene were constructed. In vitro cleavage reaction was carried out by
      mixing the ribozyme RNA with DIG-labeled-hTR in different reaction conditions.
      Cleavage bands were detected by digoxin chemilumines- cent assay. The eukaryotic
      expression plasmid was inducted into HeLa cells by lipofectamine; the telomerase
      activities and bio-characteristics of HeLa cells were detected continuously.
      RESULTS: teloRZ showed a specific cleavage activity against the telomerase RNA
      component used as template. The in vitro cleavage ratio reached about 60%. The
      telomerase activities of cells expressing teloRZ dropped to eight times; the
      doubling times became longer and apoptosis ratios became higher with increasing
      population doublings (PDS); at 19-20 PDS 95% cells showed apoptosis. CONCLUSION:
      These findings support the potential use of this ribozyme against immortalized
      cancer cells.

PMID- 10359860
TI  - [The relation between mitochondrial DNA mutation and aminogly- coside antibiotics
      induced deafness].
AB  - OBJECTIVE: To nvestigate the relation between mitochondrial DNA mutation and
      aminoglycoside antibiotics-induced deafness. METHODS: Mitochondrial DNA (mtDNA)
      of peripheral blood from 48 sporadic cases was analysed using PCR-BsmAI digestion
      and PCR-direct DNA silver sequencing. RESULTS: Six of 48 sporadic patients had A
      to G mutation in 12S rRNA gene of mtDNA at nucleotide 1555. CONCLUSION: The
      results suggest that mtDNA 1555(G) mutation is related to the occurring of
      aminoglycoside antibiotics-induced deafness which can cause genetic
      susceptibility to aminoglycoside antibotics ototoxicity.

PMID- 10359861
TI  - [Screening for mitochondrial 1555(G) mutation in patients with aminoglycoside
      antibiotic-induced deafness].
AB  - OBJECTIVE: To identify the incidence of the 1555(G) mutation in pedigrees and
      sporadic patients with aminoglycoside antibiotic- induced deafness so as, to
      privide the theoretical evidence for establishing the method of diagnosis of this
      disease. METHODS: Blood samples were obtained from two pedigrees and seven
      sporadic patients with aminoglycoside antibiotic-induced deafness, and five
      mothers of the sporadic patients. DNA was extracted from the isolated leukocytes.
      The mitochondrial DNA fragments were amplified by PCR; 1555(G) mutation was
      detected by Alw26 I restriction endonuclease digestion. RESULTS: Fourteen
      individuals from two pedigrees carried homoplasmic 1555(G) mutation. Seven
      sporadic patients and the five mothers did not have 1555(G) mutation. CONCLUSION:
      The incidence of the 1555(G) mutation in pedigrees with aminoglycoside antibiotic
      induced deafness is fairly high, while in sporadic patients is low. Screening for
      mitochondrial 1555(G) mutation is of potential value to clinical use.

PMID- 10359862
TI  - [Angiotensin 1-converting enzyme gene insertion/deletion polymorphism in patients
      with coronary artery disease and essential hypertension and its nucleotide
      sequence].
AB  - OBJECTIVE: To determine angiotensin 1-coverting enzyme(ACE) gene
      insertion/deletion(I/D) polymorphism distributions in patients with coronary
      artery disease(CAD) and essential hypertension(EH),and to detect its nucleotide
      sequence. METHODS: ACE genotypes of 137 patients with CDA, 42 patients with EH
      and 63 healthy people were detected by PCR methods. At the same time, nucleotide
      sequences of D and I allele were determined by fluorescein labeling automatic
      sequencing method. RESULTS: the frequency of DD genotype in CAD group was
      significantly higher than that in control group (0.45 and 0.21,P < 0.01), but
      there was no significant difference of ACE geneI/D polymorphism distribution
      between EH and control group. The lengths of D and I alleles are 191bp and 479bp
      separately and their nucleotide sequences are somewhat different with the results
      of foreign countries. CONCLUSION: ACE gene I/D polymorphism is an independent
      risk factor of CAD, but it has no relationship with EH. A 288bp insertion segment
      results in the I/D polymorphism of ACE gene.

PMID- 10359863
TI  - [Molecular characterization of glucose-6-phosphate dehydrogenase variants in four
      ethnic groups in Yunnan province of China].
AB  - OBJECTIVE: In order to understand the molecular evolution, race origin and the
      relationship between the G6PD gene structure and clinical symptoms, the authors
      identified the molecular characterization of glucose-6-phosphate dehydrogenase
      and determined the G6PD gene frequency in four ethnic groups in Yunnan province
      of China. METHODS: The point mutations of G6PD were detected by Mismatch-PCR/RE,
      SSCP,ARMS,DNA sequence and so on. G6PD gene frequency was determined by Hardy
      Weinberg Law. RESULTS: G6PD G1388A, G1376T,A95G mutations were determined in Bai
      and Dai people for the first time and G1388A also in Harni people by DNA
      sequence. G6PD C1024T were detected in Dai population by Mismatch-PCR/RE. The
      gene frequency of G6PD in Bai population in Dali city is 0.0113, and the
      incidence is 1.19% which are different from those in Dai population. CONCLUSION:
      G6PD G1388A,G1376T, A95G and C1024T are the mutations in national minorities as
      well as in the Han people. The results suggest that different national minorities
      of China may have the same ancestor. The incidence of G6PD deficiency and the
      G6PD gene frequency in Bai population are different from those in Dai population.
      The distribution of G6PD deficiency in Yunnan is associated with the distribution
      of malaria epidemic in that province.

PMID- 10359864
TI  - [Computerized ribosomal RNA secondary structure modeling of mutants found in Rett
      syndrome patients and their mothers].
AB  - OBJECTIVE: To identify the secondary structure of rRNA mutants, mtDNA2835(C-->T)
      and mtDNA2706(A-->G) found in Rett syndrome patients and their mothers. METHODS:
      Both wild type mtDNA sequence of rRNA gene and mutated sequence were input into
      computer (converted into RNA sequences) and analyzed by the sofware DNASIS v6.
      14. The unique prediction size is set 300 bases and the maximum bulge and
      interior loop size,30 bases. RESULTS: Similar to the positive controls, the
      mtDNA2835(C-->T) made the 16S rRNA secondary structure totally different,and the
      energy changes a lot. On the contrary, the mtDNA2706(A-->G) altered little of
      secondary structure with a small energy shift. CONCLUSION: Computerized folding
      programs have provided us with a quick prediction of rRNA structure changes
      induced by these two mutations. Of them, the mtDNA2835(C-->T) might relate to the
      pathogenesis of Rett syndrome, but the mtDNA2706(A--> G) might be less
      meaningful.

PMID- 10359866
TI  - [Distribution of six STR loci in Bai ethnic group in Yunnan province of China].
AB  - OBJECTIVE: This study was conducted to make known the distribution of six STR
      loci in Bai ethnic group in Yunnan province. METHODS: DAN extraction from blood
      samples (126 in number ) and multiplex amplification of CSF1PO,TPOX, TH01,F13A01,
      FESFPS and vWA were carried out. Using denaturing polyacrylamide gel
      electrophoresis and silver stain, the authors investigated the distribution of
      allele frequencies of CSF1PO, TPOX,TH01,F13A01,FESFPS and vWA loci in Bai ethnic
      group living in Yunnan province. RESULTS: 7 alleles and 19 genotypes of CSF1PO
      locus, 5 alleles and 11 genotypes of TPOX locus, 6 alleles and 16 genotypes of
      TH01 locus 6 alleles and 16 genotypes of F13A01 locus, 7 alleles and 15 genotypes
      of FESFPS locus,and 7 alleles and 21 genotypes of vWA locus were observed.
      CONCLUSION: The allele distribution of the loci was in good agreement with the
      Hardy-Weinberg equilibrium.

PMID- 10359865
TI  - [Mutation in the promoter region of 21-hydroxylase gene of patients with
      congenital adrenal hyperplasia].
AB  - OBJECTIVE: To investigate the mutations in the 21-hydroxylase gene promoter
      region of patients with congenital adrenal hyperplasia (CAH). METHODS: The
      authors amplified a 1.6 kb fragment of the CYP21 gene which was confirmed by
      endonuclease digestion. The PCR product was re-amplified with promoter-region
      specific primers. The amplified fragments were analyzed using SSCP and
      endonuclease digestion methods. RESULTS: Among 12 patients, 6 patients presented
      an abnormal band on SSCP analysis. By endonuclease digestion test, the authors
      found a patient who presented one mutation in KpnI recognition site located in
      the CK-2 (-101) binding region and one in Taq I recognition site located -201.
      These mutations were confirmed by sequencing. CONCLUSION: Novel mutations were
      found in the promoter of 21-hydroxylase gene in CAH patients and the findings
      spurred on further expression studies.

PMID- 10359867
TI  - [The correlation between t(14;18) chromosomal translocation and hepatocarcinoma].
AB  - OBJECTIVE: To study the correlation between t(14;18) chromosomal translocation
      and the occurrence of hepatocarcinoma. METHODS: bcl-2/JH fusion gene in 54 cases
      of hepatocarcinoma including 40 cases of hepatocellular carcinoma(HCC) and 14
      cases of cholangicellular carcinoma (CCC) were investigated using seminested in
      situ PCR. RESULTS: Bcl-2/JH fusion gene was present in 25% (10/40) HCC and
      negative in CCC. CONCLUSION: These findings indicated that t(14;18) chromosomal
      translocation might play a role in the pathogenesis of HCC but seemed to bear no
      relation with CCC. mbr and mcr are the two important breakpoints of bcl-2 gene in
      HCC.

PMID- 10359868
TI  - [Genetic polymorphism at FES locus in Chinese and German populations].
AB  - OBJECTIVE: The aim of this study on the genetic polymorphism at FES locus was to
      know whether there is genetic relationship between Chinese and German
      populations. METHODS: EDTA-blood specimens were collected from 311 healthy
      unrelated Han individuals in Jilin, Chengdu and Guangzhou in China and from 123
      healthy unrelated individuals in Germany. The DNA samples were extracted using
      Chelex method and amplified by PCR technique. The PAGE horizontal electrophoresis
      was used for typing the PCR product.DNA sequences were analyzed by ALF. RESULTS:
      There were nine alleles at FES locus in the Chinese population. The allele
      frequencies were FES*6,0-0. 0051; FES *8,0-0.0042; FES*9,0.0083-0.0202;
      FES*10,0.0202-0.0604; FES*11,0.4066-0.5101; FES*12,0.2424-0.3099;FES*13, 0.1860
      0.2198; FES*14,0.0041-0.0165; and FES*15,0-0.0050, respectively. In the German
      population, a variation in 5 flanking region and nine alleles at FES locus were
      noted. The allele frequencies were FES*8,0.0120; FES*10a,0.02317; FES*10,0.0407;
      FES*11a,0.0122; FES*11,0.4146; FES*12a, 0.0041; FES*12, 0.2357; FES*13, 0.0447;
      and FES*14, 0.0041, respectively. The results of test for Hardy-Weinberg
      equilibrium showed that the genotype distributions observed in the populations
      were correspondent with the expected. CONCLUSION: There is a remarkable
      difference in the distribution of allele frequencies at FES locus between Chinese
      and German populations.

PMID- 10359869
TI  - [The mutation of deletion for glutathione S-transferase M1 gene in the tissue of
      hepatocellular carcinoma].
AB  - OBJECTIVE: To Study whether the mutation of deletion for glutathione S
      transferase M1 (GSTM1) gene occurred during the development of hepatocellular
      carcinoma (HCC). METHODS: The genotypes of GSTM1 of 46 pairs of HCC tissue and
      the noncancerous liver tissue were detected by polymerase chain reaction (PCR).
      RESULTS: The frequency of GSTM1 null genotype for HCC tissue was 78.26%, but
      65.22% for the noncancerous liver tissue (P<0.05). The GSTM1 null genotypes of 6
      HCC tissue were transformed from the non- null genotypes of the noncancerous
      liver tissue. According to Hardy-Weinberg law., the rate of deletion mutation for
      GSTM1 gene was inferred to be 38.89%. CONCLUSION: The results suggested that the
      mutation of deletion for GSTM1 gene had occurred during the development of HCC.

PMID- 10359870
TI  - [Cloning the 5 ' end fragment of ST13 cDNA by nested PCR].
AB  - OBJECTIVE: To clone and sequence the 5' -end fragment of ST13 cDNA. METHODS: The
      5' -end fragment of the ST13cDNA was amplified directly from cDNA library by
      nested PCR method, and cloned into pGEM-T. easy vector, then the sequencing of
      the inserted PCR product was performed. RESULTS: After primary and secondary PCR,
      two PCR products obtained with the size of about 550bp and 480bp, respectively,
      were both proved to be the 5' -end of ST13 cDNA by sequencing. CONCLUSION: the
      method presented is very simple and effective for cloning and sequencing the 5'
      end of a target gene.

PMID- 10359871
TI  - [Preparation and amplification of cDNAs from a single cell].
AB  - OBJECTIVE: To set up the technique by which gene expression analysis could be
      done from a few cells so as to resolve the challenging problem between
      increasingly needs of cellular gene expression pattern analysis and the
      difficulty of obtaining homogeneous cell materials in some cases. METHODS: Pick
      up a single cell to do reverse transcription directly, and then amplify cDNA in
      sequence-independent manner by using a single primer containing oligo (dT) and
      test the representation of cDNA. RESULTS: Representatively amplified cDNAs from a
      single HL-60 cell. CONCLUSION: Producing whole cellular cDNAs probe from samples
      as small as a single cell could provide an ideal way to analyze differential gene
      expression in heterogeneous highly differentiating system and to establish cell
      type/tissue type specific gene expression profiles.

PMID- 10359872
TI  - [Capillary free zone electrophoresis of globin chains].
AB  - OBJECTIVE: To introduce a new technique for rapid separation of globin chains
      from clinical samples. METHODS: The authors used the uncoated capillary and the
      electrophoresis buffer which contained 100mmol/L NaH2PO4 +7mmol/L urea +1% Triton
      X-100 +1% 2-mercaptoethanol +0.25% PEG-600. Capillary free zone electrophoresis
      was employed in analyzing the hemoglobin-water solutions which were made from HbA
      control and 74 clinical blood samples. The globin chains were separated from the
      samples. RESULTS: IN 40 minutes, five globin chains: alpha, beta, Ggamma, delta,
      Agamma were separated clearly by capillary free zone electrophoresis using
      nanolitres of sample. In electrophoresis figure the baselines were stable and the
      peaks were clear. The time coefficient of variation (CV) was under 3%, and the
      area CV below 4%. Also, The authors measured the relative concentration of globin
      chains from 60 normal cases and 14 thalassemia patients. CONCLUSION: The
      capillary free zone electrophoresis for the separation of globin chains from
      clinical samples has been successfully achieved. It is a rapid, simple and
      sensitive technique suitable for rapid diagnosis of hemoglobinopathies.

PMID- 10359873
TI  - [Isolating candidate inserted fragment from positive fused phage clones using
      quantitative PCR].
AB  - OBJECTIVE: To isolate quickly and exactly the specific inserted fragment from
      fused phage clones which were obtained from cDNA library by hybridization.
      METHODS: According to the amplification principle of quantitative polymerase
      chain reaction (PCR) and based on the difference of original template
      quantity,target cDNA fragment was isolated and identified by two PCRs. RESULTS: A
      positive clone with specific cDNA fragment of HumGT-H1 gene was obtained from a
      two-phage fused clone by using this method,and the inserted fragment was verified
      to be the 5' cDNA sequence of HumGT-H1,1.9kb in length. So another hybridization
      screening is not necessary. CONCLUSION: The method presented is effective and
      rapid in gene cloning and can greatly save time and materials.

PMID- 10359874
TI  - Food allergy. Part 2: diagnosis and management.
AB  - Patients with food-induced allergic disorders may be first seen with a variety of
      symptoms affecting the skin, respiratory tract, gastrointestinal tract, and/or
      cardiovascular system. The skin and respiratory tract are most often affected by
      IgE-mediated food-induced allergic reactions, whereas isolated gastrointestinal
      disorders are most often caused by non-IgE-mediated reactions. When evaluating
      possible food-induced allergic disorders, it is often useful to categorize
      disorders into IgE- and non-IgE-mediated syndromes. The initial history and
      physical examination are essentially identical for IgE- and non-IgE-mediated
      disorders, but the subsequent evaluation differs substantially. Proper diagnoses
      often require screening tests for evidence of food-specific IgE and proof of
      reactivity through elimination diets and oral food challenges. Once properly
      diagnosed, strict avoidance of the implicated food or foods is the only proven
      form of treatment. Clinical tolerance to food allergens will develop in many
      patients over time, and therefore follow-up food challenges are often indicated.
      However, a number of novel immunomodulatory strategies are in the developmental
      stage and should provide more definitive treatment for some of these food-induced
      allergic disorders in the next several years.

PMID- 10359875
TI  - Chromatin-based regulatory mechanisms governing cytokine gene transcription.
AB  - On initial contact with antigen, naive T cells differentiate and acquire effector
      characteristics, including the ability to transcribe specific cytokine genes
      rapidly and at high levels on subsequent exposure to antigen. Several effector T
      cell subsets showing distinct patterns of cytokine gene transcription have been
      described. The patterns of cytokine expression in response to pathogenic
      challenges have a significant impact on the outcome of immune and inflammatory
      reactions. Here we review recent studies suggesting that the ability of naive T
      cells to differentiate into specific cytokine-expressing cells is regulated by
      epigenetic changes in the accessibility and chromatin structure of cytokine
      genetic loci. Antigen and cytokine stimulation of naive T cells activates diverse
      intracellular signaling pathways, which result in chromatin remodeling and
      demethylation of cytokine genes. These changes are likely to increase, in a
      stable and heritable fashion, the accessibility of these genes to the basal
      transcriptional machinery. Chromatin-based regulatory mechanisms may explain
      several features of cytokine gene expression in effector versus naive T cells,
      including their monoallelic expression, coordinate regulation, and stable
      maintenance in memory T cells. The hypothesis of epigenetic changes occurring
      during T-cell differentiation provides a framework for a comprehensive
      understanding of cytokine expression by T cells.

PMID- 10359876
TI  - Specific IgE without clinical allergy.

PMID- 10359877
TI  - Animal allergens: looking beyond the tip of the iceberg.

PMID- 10359878
TI  - Specific IgE to cross-reactive carbohydrate determinants strongly affect the in
      vitro diagnosis of allergic diseases.
AB  - BACKGROUND: Cross-reacting carbohydrate determinants (CCDs) are antigenic
      structures shared by allergenic components from taxonomically distant sources.
      The case history of a patient with a great discrepancy between skin test and
      specific IgE results led us to investigate the role of these determinants in his
      specific case and in an allergic population. OBJECTIVE: We sought to determine
      the role of CCDs in causing false-positive and clinically irrelevant results in
      in vitro tests. METHODS: The involvement of CCDs was studied by specific IgE
      inhibition by using glycoproteins with a known carbohydrate structure. Direct and
      inhibition assays were performed by commercially available systems, in-house
      ELISA, and the immunoblotting technique. The binding to the periodate-oxidated
      carbohydrate structure of glycoproteins and allergenic extracts was also
      evaluated. A comparative study between skin test and specific IgE responses to
      the antigens studied was carried out in 428 consecutive allergic subjects.
      RESULTS: All the tests performed suggested that cross-reacting carbohydrate
      epitopes were the cause of false-positive specific IgE results in one of the
      commercial systems and the high reactivity in all the solid-phase in vitro tests.
      None of the cross-reacting carbohydrate allergens yielded a positive skin test
      response. Periodate treatment caused variable degrees of reduction of IgE binding
      to the different antigens studied, indicating that CCDs played a different role
      in each of them. About 41% of patients allergic to pollen had specific IgE for a
      glycoprotein, without a positive skin test response to the same molecule.
      CONCLUSIONS: CCDs must be taken into account when evaluating the clinical
      relevance of positive results in in vitro specific IgE assays, at least in the
      diagnosis of patients with pollen allergy. Commercial systems should be carefully
      assessed for the ability to detect specific IgE for carbohydrate determinants to
      avoid false-positive or clinically irrelevant results.

PMID- 10359879
TI  - School as a risk environment for children allergic to cats and a site for
      transfer of cat allergen to homes.
AB  - BACKGROUND: Many children are allergic to furred pets and avoid direct pet
      contact. The school may be a site of indirect exposure to pet allergens, which
      may induce or maintain symptoms of allergic diseases. OBJECTIVE: We sought to
      investigate airborne levels of cat allergen (Fel d 1) at schools and in homes
      with or without cats and to study clothes as a route for dissemination of
      allergens between homes and school. METHODS: Airborne cat allergen was collected
      with personal samplers from (1) children attending classes with many (>25%) or
      few (<10%) cat owners and (2) homes with or without cats. A recently developed
      amplified ELISA assay, which detects low levels of airborne cat allergen in pet
      free environments, was used. Dust samples were collected from clothes and
      mattresses. RESULTS: There was a 5-fold difference in the median levels of
      airborne cat allergen between classes with many and few cat owners (2.94 vs 0.59
      ng/m3; P <.001). The median airborne cat allergen concentration in classes with
      many cat owners was significantly higher than that found in the homes of non-cat
      owners (P <.001) but lower than that found in homes with cats (P <.001). Allergen
      levels in non-cat owners' clothes increased after a school day (P <.001). Non-cat
      owners in classes with many cat owners had higher levels of mattress-bound cat
      allergen (P =.01). CONCLUSION: The results indicate significant exposure to cat
      allergen at school. Allergen is spread through clothing from homes with cats to
      classrooms. There the allergen is dispersed in air and contaminates the clothes
      of children without cats. The allergen levels in non-cat owners' homes correlate
      with exposure to cat allergen at school.

PMID- 10359881
TI  - Comparison of the effects of terfenadine with fexofenadine on nasal provocation
      tests with allergen.
AB  - BACKGROUND: Fexofenadine, the hydrochloride salt of terfenadine active
      metabolite, is a nonsedative, noncardiotoxic antihistamine derivative for the
      treatment of allergic rhinitis. OBJECTIVE: We sought to compare the effects of
      terfenadine and fexofenadine on nasal provocation tests with allergen. METHODS: A
      preliminary provocation test (screening phase) was performed in 25 patients with
      a history of seasonal allergic rhinitis to grass pollen to determine the combined
      nasal reaction threshold, which was defined as 2 of the 3 following criteria: (1)
      at least a 40% decrease in peak nasal inspiratory flow and/or a 30% decrease in
      minimal cross-sectional area as measured by acoustic rhinometry, nasal secretions
      of 0.5 g, and 5 to 10 sneezes per minute. Patients were then included into a
      double-blind, randomized, 2-way crossover study to receive terfenadine or
      fexofenadine 120 mg 2 hours before provocation. Rhinorrhea, sneezing, peak nasal
      flow, and minimal nasal cross-sectional area, as well as symptom scores for nasal
      congestion and itchiness, were recorded at each allergen concentration up to the
      reaction threshold. The whole study was performed out of allergy season. RESULTS:
      Fexofenadine was as potent as terfenadine in limiting pruritus and nasal
      congestion. Rhinorrhea and sneezing were better controlled by fexofenadine than
      by terfenadine. Overall, the allergen concentration necessary to reach the
      combined reaction threshold was increased after treatment with both drugs.
      Comparison between screening and each treatment phase indicated that the shift in
      allergen concentration to reach the reaction threshold was significantly greater
      after fexofenadine than after terfenadine (P =. 033). CONCLUSION: After oral
      administration, fexofenadine provided better protection than terfenadine against
      the immediate allergic reaction.

PMID- 10359880
TI  - Relevance of allergens from cats and dogs to asthma in the northernmost province
      of Sweden: schools as a major site of exposure.
AB  - BACKGROUND: The prevalence of asthma in the northernmost region of Sweden has
      been estimated at 6% to 8% in spite of the very dry climate. The causes of the
      increase in asthma are not clear, but conditions are unfavorable for dust mite
      growth, and domestic animals are thought to be the primary source of indoor
      allergens. OBJECTIVES: We sought to investigate the relationship between asthma,
      exposure, and sensitization in Northern Sweden, with a focus on the role of
      schools. METHODS: Serum was collected from 110 asthmatic children, 55 children
      with symptoms of asthma but no established diagnosis, and 63 control children
      (age, 7 and 8 years). Total IgE and specific IgE to 7 allergens were measured.
      Dust samples were collected from the classrooms of 7- and 8-year-old children in
      22 schools from Kiruna and Lulea, Sweden. For comparison, dust was also collected
      from 24 homes in Kiruna and 2 schools in Virginia in the United States. RESULTS:
      Serum IgE antibody assays on 165 children with respiratory symptoms confirmed
      that there was a high degree of sensitization to cat, dog, and birch in Northern
      Sweden. Cat and dog allergens were present in almost all of the school samples in
      Sweden. By contrast, dust mite and cockroach allergens were generally
      unmeasurable. The highest levels of cat and dog allergens were found in samples
      from desks and chairs. Cat and dog allergen levels in the schools were comparable
      with but higher than those in the homes without pets. The schools in Virginia had
      similar allergen levels, except that samples from this humid region also had
      significant mite allergen. CONCLUSIONS: In this climate the primary sensitization
      associated with asthma is to cat dander and dog dander but also to birch pollen.
      Mite and cockroach allergens were not present in the dust samples, and
      sensitization to these allergens was not significant. The schools appear to be a
      major site of exposure to cat and dog allergens. These results are relevant both
      to an understanding of the reasons for the increase in asthma in this region and
      to any proposal to reduce exposure to allergens.

PMID- 10359882
TI  - Inhibition of methylprednisolone elimination in the presence of clarithromycin
      therapy.
AB  - BACKGROUND: Macrolide antibiotics have long been used as steroid-sparing agents
      in patients with severe steroid-dependent asthma. Their efficacy and their
      propensity to potentiate glucocorticoid adverse effects have been attributed in
      part to their ability to delay glucocorticoid clearance. OBJECTIVE: We sought to
      determine whether clarithromycin, a newer macrolide antibiotic, can alter the
      pharmacokinetic profile of oral glucocorticoids and thereby increase the risk of
      steroid-induced adverse effects. METHODS: An open-label study in a paired design
      (before and after treatment) was conducted in a hospital-based outpatient clinic.
      Participants were 6 adult patients (mean age, 30 years) with mild-to-moderate
      asthma. Prednisone (40 mg/1.73 m2) and methylprednisolone (40 mg/1.73 m2) were
      given as single randomized doses on consecutive study days before and on days 8
      and 9 of a clarithromycin (500 mg twice daily) course. Twelve-hour
      pharmacokinetic profiles with measurement of plasma methylprednisolone and
      prednisolone levels were taken before and after clarithromycin therapy. RESULTS:
      Clarithromycin therapy resulted in a 65% reduction of methylprednisolone
      clearance and significantly higher mean plasma methylprednisolone concentrations
      compared with preclarithromycin concentrations but had no significant effect on
      prednisolone clearance or mean prednisolone plasma concentrations. CONCLUSIONS:
      Clinicians must be aware of potential drug interactions that could place patients
      at increased risk for steroid-induced adverse effects. Such an effect has been
      demonstrated between clarithromycin and methylprednisolone, two drugs that may be
      administered concomitantly in asthma. To avoid potential steroid-enhancing
      effects, prednisone should be substituted for methylprednisolone during prolonged
      courses of clarithromycin therapy.

PMID- 10359884
TI  - Diminished IL-10 production in subjects with allergy after infection with
      influenza A virus.
AB  - BACKGROUND: Recent studies have documented a link between respiratory viral
      infections and the expression of asthma and other allergic disorders. Results
      from other studies have suggested that diminished production of IL-10, an anti
      inflammatory cytokine, may contribute to the pathophysiologic features of these
      diseases. OBJECTIVE: The objective of this study was to determine whether
      diminished IL-10 production and TH2 cytokine skewing occur in allergic, as
      compared with nonallergic, subjects after experimental infection with the
      influenza A virus. METHODS: PBMCs were isolated from 11 subjects with allergy and
      14 subjects with no allergy before and after influenza A infection and stimulated
      with either mitogen (PHA) or antigen (influenza A). Supernatants were assayed for
      IL-10, IL-4, and IFN-gamma by ELISA. RESULTS: PBMC IL-10 production was
      significantly diminished in subjects with allergy, as compared with subjects with
      no allergy, after experimental infection with influenza A virus. However,
      significant TH2 skewing and enhanced airway symptoms were not observed in these
      same subjects. CONCLUSIONS: These data provide further support that subjects with
      allergy have an intrinsic inability to upregulate IL-10 production in response to
      inflammatory stimuli and extend this observation to include respiratory viral
      infections. Future studies in this area could lead to a better understanding of
      the pathogenesis of asthma and other allergic disorders

PMID- 10359883
TI  - Monocyte chemotactic proteins in allergen-induced inflammation in the nasal
      mucosa: effect of topical corticosteroids.
AB  - BACKGROUND: Human allergen-induced rhinitis is associated with the recruitment
      and activation of inflammatory cells, particularly eosinophils and CD4(+) T
      cells, in the nasal mucosa. Chemokines are inflammatory mediators capable of
      attracting specific inflammatory cell populations. Monocyte chemotactic proteins
      (MCPs), a subfamily of CC chemokines, have been shown to induce chemotactic
      activity particularly in eosinophils, T cells, and monocytes under in vitro assay
      conditions. OBJECTIVE: To assess the contribution of MCPs in the recruitment of
      inflammatory cells in vivo, we investigated the allergen-induced late response in
      subjects with allergic rhinitis. METHODS: Patients were randomized to receive a 6
      week treatment with either topical corticosteroid (n = 6) or a matched placebo (n
      = 6). Nasal inferior turbinate biopsy specimens were obtained from all subjects
      before and during allergen-induced late responses. By using immunocytochemistry,
      tissue sections were examined for the presence of MCP-1, MCP-3, and MCP-4 and for
      the phenotype of infiltrating cells within the nasal mucosa. In addition, double
      sequential immunocytochemistry was used to confirm the phenotype of MCP
      immunoreactive positive cells. Furthermore, the effect of topical corticosteroids
      on the expression of MCPs and on the cellular infiltrate was also examined.
      RESULTS: MCP-1, MCP-3, and MCP-4 were expressed in all the baseline samples, with
      prominent staining observed within the nasal epithelium. Biopsy specimens taken
      after challenge exhibited significant upregulation in the expression of MCP-3 and
      MCP-4 (P <.001). On the other hand, this increase in response to allergen was
      reduced in patients pretreated with topical corticosteroids. Colocalization
      experiments revealed that the majority of MCP+ cells in the subepithelium were
      macrophages, followed by T cells and eosinophils. CONCLUSION: Our results
      demonstrate that allergen-induced rhinitis is associated with an increased
      expression of MCP-3 and MCP-4, which may be closely related to the influx of
      inflammatory cells and may thus contribute to the pathogenesis of allergic
      rhinitis.

PMID- 10359885
TI  - Tolerance to the bronchoprotective effect of beta2-agonists: comparison of the
      enantiomers of salbutamol with racemic salbutamol and placebo.
AB  - BACKGROUND: Regular use of racemic salbutamol results in the partial loss of its
      bronchoprotective effect. The 2 enantiomers of salbutamol, the bronchodilator R
      salbutamol and nonbronchodilator S-salbutamol, are now available. OBJECTIVE: We
      sought to compare the effect of regular use of S-salbutamol, R-salbutamol,
      racemic salbutamol, and placebo on the bronchoprotective effect of a single dose
      of racemic salbutamol against methacholine-induced bronchoconstriction. METHODS:
      Eleven of 13 well-controlled beta2 -agonist-free asthmatic subjects completed a
      double-blind, randomized study comparing racemic salbutamol 2.5 mg, S-salbutamol
      1. 25 mg, R-salbutamol 1.25 mg, and diluent placebo nebulized and inhaled 3 times
      daily for 6 days (>/=6-day washout period). Ten to 12 hours after the last dose,
      the subjects performed measurement of FEV1, methacholine PC20, and a repeat
      methacholine PC20 done 1 hour after the first methacholine test and 10 minutes
      after 2 puffs (200 microgram) of racemic salbutamol administered from a metered
      dose inhaler. The primary endpoint was the methacholine PC20 dose shift (Deltalog
      PC20/log 2) from before to after administration of 200 microgram of racemic
      salbutamol. RESULTS: The methacholine dose shift was 3.2 doubling doses (9-fold
      increase in methacholine PC20 after 200 microgram of racemic salbutamol) during
      the placebo treatment and was unaltered (3.2) after administration of S
      salbutamol. The dose shift was significantly lower after both the R-salbutamol
      and racemic salbutamol treatments (2.2 and 2.6 doubling doses, respectively);
      there was no significant difference between R-salbutamol and racemic salbutamol.
      There was no treatment effect on baseline FEV1, baseline methacholine PC20, or
      bronchodilation. CONCLUSION: Regular treatment with racemic salbutamol or R
      salbutamol, but not S-salbutamol, results in a partial loss of bronchoprotection,
      without loss of bronchodilation, compared with placebo.

PMID- 10359886
TI  - Effect of AA-2414, a thromboxane A2 receptor antagonist, on airway inflammation
      in subjects with asthma.
AB  - BACKGROUND: Asthma is a chronic inflammatory disease of the airways. The
      chemokines are potent chemoattractants for eosinophils and other types of cells
      associated with allergic inflammation. AA-2414, a new thromboxane A2 receptor
      antagonist, reduces bronchial hyperresponsiveness in asthmatic subjects, but its
      mechanism of action is unclear. OBJECTIVE: We tested the hypothesis that the
      beneficial effects of AA-2414 in asthma result from reduction in the number of
      inflammatory cells infiltrating the airway associated with inhibition of
      chemokine release. METHODS: We studied bronchial biopsy specimens from 31
      asthmatic subjects before and after oral treatment with AA-2414 (80 mg/day) or
      matched placebo for 4 months in a double-blind manner. Biopsy specimens were
      examined by immunohistochemistry. Each subject recorded symptom score and peak
      expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine
      were measured before and after treatment. RESULTS: After treatment, significant
      improvements in symptom score (P <.05), PEF (P <.01), diurnal variation of PEF (P
      <.01), and bronchial responsiveness (P <.01) were observed in the AA-2414 group
      compared with the placebo group. These improvements were accompanied by a
      significant decrease in the number of submucosal EG2(+) eosinophils (P <.05).
      There was also a reduction in the number of cells expressing RANTES (P <.05) and
      macrophage inflammatory protein (MIP)-1alpha (P <.05) in the epithelium and of
      cells expressing monocyte chemotactic protein-3 (P <.01), RANTES (P <.05), MIP
      1alpha (P <.01), and eotaxin (P <.01) in the submucosa in the AA-2414 treatment
      group. A significant correlation was found between the number of EG2(+)
      eosinophils and numbers of monocyte chemotactic protein-3(+) (rs = 0.52, P
      <.005), MIP-1alpha+ (rs = 0.34, P <.05), and eotaxin+ cells (r s = 0.47, P <.01)
      in the submucosa. There was a significant negative correlation between the
      increase in bronchial responsiveness and the change in number of submucosal
      EG2(+) cells (rs = -0.65, P <.001). CONCLUSIONS: These findings suggest that AA
      2414 treatment of patients with asthma may inhibit activated eosinophil
      infiltration in part by modulating the expression of chemokines in bronchial
      tissues.

PMID- 10359887
TI  - Fluticasone propionate powder and lack of clinically significant effects on
      hypothalamic-pituitary-adrenal axis and bone mineral density over 2 years in
      adults with mild asthma.
AB  - BACKGROUND: Although inhaled corticosteroids are widely used for the treatment of
      inflammation in asthma, prospective, long-term, placebo-controlled trials
      characterizing their systemic safety with chronic use are lacking. OBJECTIVE:
      This study was designed to prospectively evaluate the long-term safety of inhaled
      fluticasone propionate therapy. METHODS: Fluticasone propionate powder, 500
      microgram, or placebo was administered twice daily by means of the Diskhaler for
      104 weeks to 64 adults with mild persistent asthma in a randomized, double-blind,
      parallel-group study. Primary safety variables were measured at baseline and
      every 6 months thereafter. Although evaluation of efficacy was not an objective
      of this study, pulmonary function testing was performed at monthly intervals.
      RESULTS: Two years of treatment with fluticasone propionate had no significant
      effects on the skeletal system. No clinically significant changes were observed
      in ophthalmic parameters (glaucoma and posterior subcapsular cataracts). Mean
      change from baseline in lumbar spine (L1 to L4 ) bone density at week 104 was not
      significantly different between fluticasone propionate (-0.006 +/- 0.008 g/cm2)
      and placebo (-0.007 +/- 0.010 g/cm2). Markers of bone formation (serum
      osteocalcin) and resorption (urinary N-telopeptide) did not differ significantly
      between treatment groups. The effects of fluticasone propionate treatment on the
      hypothalamic-pituitary-adrenal axis were minimal, with no alterations in morning
      plasma cortisol concentrations and minor but statistically significant decreases
      in poststimulation mean peak plasma cortisol concentrations (P =.021) and 8-hour
      plasma cortisol area under the curve values (P =.020) at week 104. Drug-related
      adverse events were primarily topical effects of inhaled corticosteroids.
      Pulmonary function improved significantly during 2 years of fluticasone
      propionate treatment. CONCLUSION: Fluticasone propionate powder, 500 microgram
      twice daily for up to 2 years, was efficacious and well tolerated, with no
      clinically relevant effects on the hypothalamic-pituitary-adrenal axis, bone
      density, or ophthalmic parameters in adults with mild asthma.

PMID- 10359888
TI  - House dust mite avoidance for children with asthma in homes of low-income
      families.
AB  - BACKGROUND: Home exposure to high levels of house dust mite allergen has been
      shown to aggravate airways reactivity and asthma. OBJECTIVE: The purpose of this
      study was to determine whether specific house dust mite control measures could
      reduce exposure levels and asthma severity. METHODS: This double-blinded,
      randomized trial compared asthma progression over 1 year in children whose homes
      received standard environmental control intervention with those whose homes
      received aggressive intervention for dust mite elimination. The primary end point
      was doubling in PD20 methacholine. RESULTS: Symptom scores and quality-of-life
      scores were similar for the standard and aggressive intervention groups. PD20
      methacholine doubling occurred in 9 members of the aggressive intervention group
      vs 4 control patients (P <.05). Dust mite levels decreased in the aggressive
      intervention homes compared with the standard intervention homes (P <.05).
      CONCLUSION: Aggressive dust mite intervention decreased dust mite levels and
      improved bronchial hyperresponsiveness.

PMID- 10359889
TI  - Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma.
AB  - BACKGROUND: Salmeterol, a long-acting beta2 -agonist, and zafirlukast, a
      leukotriene receptor antagonist, are both indicated for the treatment of asthma
      in adolescent and adult patients. OBJECTIVE: We sought to compare the effect of 4
      weeks of treatment with inhaled salmeterol xinafoate versus oral zafirlukast in
      the treatment of persistent asthma. METHODS: This was a randomized, double-blind,
      double-dummy, parallel-group, multicenter clinical trial. Patients, over 80% of
      whom were on a concurrent inhaled corticosteroid regimen, were treated for 4
      weeks with either inhaled salmeterol xinafoate 42 microgram twice daily
      administered by means of a metered-dose inhaler or oral zafirlukast 20 mg twice
      daily. The primary efficacy measure was morning peak expiratory flow (PEF);
      secondary efficacy measures included evening PEF, asthma symptom scores,
      supplemental albuterol use, nighttime awakenings, sleep symptoms, asthma
      exacerbations, and FEV1. RESULTS: Both inhaled salmeterol and oral zafirlukast
      resulted in within-group improvements from baseline in measures of pulmonary
      function, asthma symptoms, and supplemental albuterol use. Salmeterol treatment
      resulted in significantly greater improvements from baseline compared with
      zafirlukast for most efficacy measurements, including morning PEF (29.6 vs 13.0
      L/min; P </= .001), percentage of symptom-free days (22.4% vs 8.8%; P </= .001),
      and percentage of days and nights with no supplemental albuterol use (30.5% vs
      11.3%; P </= .001). There were no differences in safety profiles as assessed by
      adverse event monitoring. CONCLUSION: In patients with persistent asthma, most of
      whom were concurrently using inhaled corticosteroids, treatment with inhaled
      salmeterol provided significantly greater improvement than oral zafirlukast in
      overall asthma control over the 4-week treatment period.

PMID- 10359890
TI  - Effects of topical corticosteroids on inflammatory mediator-induced eicosanoid
      release by human airway epithelial cells.
AB  - BACKGROUND: Airway epithelial cells are among the first cells to come in contact
      with aerosolized corticosteroids. However, the relative potencies and time course
      of action of the several commonly used aerosolized corticosteroids on eicosanoid
      production by airway epithelial cells are unknown. OBJECTIVES: This study
      compared the effects of fluticasone, budesonide, and triamcinolone on eicosanoid
      output by human airway epithelial cells in vitro. We also determined the spectrum
      of eicosanoids affected and the mechanism for corticosteroid action. METHODS:
      Cultured BEAS-2B airway epithelial cells (a transformed cell line) were exposed
      to corticosteroids (1 nmol/L to 1 micromol/L) for 2 to 48 hours and then assayed
      for basal- and bradykinin (BK)-stimulated eicosanoid output. The eicosanoid
      profile was identified by HPLC in tritiated arachidonic acid prelabelled cells,
      and PGE2, the major eicosanoid product, was quantitated by RIA. The effect of
      corticosteroids on the immunoreactivity of key proteins involved in eicosanoid
      metabolism (ie, cyclooxygenase [COX], phospholipase A2 [PLA2], and Clara cell
      protein, a PLA2 inhibitor) was determined by Western blotting. RESULTS:
      Eicosanoid output was largely confined to prostaglandins with values of 5 +/- 2
      and 82 +/- 35 ng PGE2/10(6) cells for basal- and BK stimulation, respectively (n
      = 8). All 3 corticosteroids inhibited basal- and BK-induced PGE2 output in a dose
      and time-dependent manner. Fluticasone and budesonide completely eliminated PGE2
      output in nanomolar concentrations in contrast to triamcinolone, which required
      micromolar concentration. The rank order of potency was: fluticasone = budesonide
      > triamcinolone. The time course of action for PGE2 inhibition also differed,
      with budesonide acting more slowly than the other 2 corticosteroids (P = .04).
      All 3 corticosteroids markedly reduced COX2 with little effect on COX1, cPLA2
      (Type IV), or iPLA2 (Type VI) immunoreactivity or their relative distribution in
      cytosol versus membrane fractions. Clara cell protein immunoreactivity was
      undetectable in control and corticosteroid-treated cell lysates. CONCLUSION:
      These results show that in a human airway epithelial cell line, the 3 inhaled
      corticosteroids commonly used to treat asthma differ in onsets of action as
      inhibitors of prostaglandin synthesis and vary considerably in potency. All 3
      corticosteroids act mechanistically in similar fashion by inhibiting COX2
      synthesis.

PMID- 10359891
TI  - The potential clinical utility of serum alpha-protryptase levels.
AB  - BACKGROUND: Because biopsy criteria for diagnosing systemic mastocytosis are not
      precise, the value of serum alpha-protryptase levels in the work-up of suspected
      systemic mastocytosis should be considered. OBJECTIVE: A retrospective analysis
      was performed on subjects with total tryptase serum levels that were high (>/=20
      ng/mL), while beta-tryptase serum levels were normal (<1 ng/mL) or modestly
      elevated (1 to 5 ng/mL). METHODS: Over a 3.5-year period, 52 qualifying specimens
      were identified from 1369 consecutive samples. The corresponding subjects were
      divided into those with suspected mastocytosis and those with suspected
      anaphylaxis. Subjects with suspected mastocytosis were subdivided into 3
      subgroups on the basis of biopsy results (positive, negative, or not available).
      Subjects with suspected anaphylaxis were subdivided into living and deceased
      subgroups. RESULTS: Among the 15 subjects who underwent biopsy, alpha-protryptase
      serum levels (the difference between directly-measured levels of serum total
      tryptase and beta-tryptase), when greater than 75 ng/mL (n = 9), were always
      associated with a positive biopsy result for systemic mastocytosis; levels from
      20 to 75 ng/mL (n = 6) were associated with a positive biopsy result in 50% of
      subjects. alpha-Protryptase serum levels may be a more sensitive screening test
      than a bone marrow biopsy for this disorder. Also, elevated alpha-protryptase
      serum levels in some adult patients return to normal over time, suggesting that
      mast cell hyperplasia resolved in these patients. Finally, a high alpha
      protryptase level may reveal anaphylaxis to be a presenting manifestation of
      systemic mastocytosis or mast cell hyperplasia. CONCLUSION: Levels of serum alpha
      protryptase, relative to those of beta-tryptase, appear to be useful in the
      diagnostic work-up and follow-up of subjects with suspected systemic
      mastocytosis.

PMID- 10359892
TI  - IL-1 receptor-type expression in relation to atopy.
AB  - BACKGROUND: IL-1 has 2 receptors, type I (IL-1RI) and type II (IL-1RII), which
      have 2 forms each, membrane (m) and soluble (s). When IL-1 binds to mIL-1RI, the
      active receptor, an inflammatory response is initiated, which does not occur when
      IL-1 binds to mIL-1RII, the decoy receptor. Both sIL-1RI and sIL-1RII function as
      IL-1-mopping mechanisms. We hypothesized that the ratio of active (mIL-1RI) to
      inactive (mIL-1RII, sIL-1RI, and sIL-1RII) receptors is important in determining
      the amount of inflammation produced in allergic reactions. OBJECTIVE: Our aim was
      to compare the concentrations of mIL-1RI and mIL-1RII on cultured PBLs and sIL
      1RI, sIL-1RII, and IL-1beta in sera and supernatants of cultured PBMCs from
      atopic and nonatopic subjects. METHODS: The membrane receptors, soluble
      receptors, and IL-1beta concentrations were measured by ELISA with specific mAbs.
      RESULTS: Although there was no difference in the level of serum IL-1beta between
      the 2 groups, PBMCs from atopic persons spontaneously secreted higher levels of
      IL-1beta than those from nonatopic donors (P < .05). PBLs from atopic subjects
      compared with those from nonatopic individuals expressed higher mIL-1RI (P <
      .0001) and mIL-1RII (P < .05). Levels of both the soluble receptors from both
      serum (P < .0001) and PBMCs (P < .05) of nonatopic donors were higher than those
      found in atopic donors. CONCLUSION: This augmentation of mIL-1RI concomitant with
      a reduction in soluble receptors may be an important contributory factor to the
      inflammation that occurs with allergen exposure.

PMID- 10359893
TI  - Murine mast cells exposed to mercuric chloride release granule-associated N
      acetyl-beta-D-hexosaminidase and secrete IL-4 and TNF-alpha.
AB  - BACKGROUND: Mast cells, by virtue of their location within the skin, respiratory
      tract, and gastrointestinal system, are considered as potential targets for
      environmental agents with immunotoxic effects. Mercuric chloride (HgCl2), is a
      xenobiotic, which induces autoimmune glomerulonephritis and stimulates polyclonal
      IgE production. OBJECTIVE: We sought to determine the ability of HgCl2 to
      degranulate murine mast cells and promote cytokine secretion and whether this was
      an active biologic process. METHODS: Bone marrow-derived murine mast cells were
      exposed to HgCl2, and the release of N-acetyl-beta-D-hexosaminidase and secretion
      of IL-4 and TNF-alpha were measured. RESULTS: HgCl2 was found to directly
      activate murine mast cells to release the granule-associated enzyme N-acetyl-beta
      D-hexosaminidase and to secrete the proinflammatory cytokines IL-4 and TNF-alpha.
      Cytokine secretion occurred hours after exposure to HgCl2 and required
      transcription and protein synthesis. The secretion of cytokines mediated by HgCl2
      was additive to that which followed FcepsilonRI-induced mast cell activation. The
      IL-4 secretion by mast cells occurred at concentrations of HgCl2 (10(-6) mol/L to
      10(-5) mol/L) comparable with those required to induce upregulation of IgE
      production in experimental animals. CONCLUSION: These findings demonstrate that
      HgCl2 will directly activate mast cells, which is followed by degranulation and
      IL-4 and TNF-alpha synthesis and secretion. These findings are consistent with
      recognition of HgCl2 as a biologically important environmentally derived
      immunotoxic agent for mast cells.

PMID- 10359894
TI  - Effects of diesel organic extracts on chemokine production by peripheral blood
      mononuclear cells.
AB  - BACKGROUND: Polyaromatic hydrocarbons (PAHs) associated with diesel exhaust
      particles (DEPs) are found in the atmospheric urban pollution. Such compounds
      have been shown to favor IgE production, bronchial hyperresponsiveness, and
      airway inflammation. Chemokines are a group of chemotactic cytokines involved in
      the recruitment of inflammatory cells. OBJECTIVE: We investigated the effect of
      DEP-PAHs on the release and mRNA expression of IL-8, MCP-1, and RANTES by PBMCs
      obtained from healthy subjects. METHODS: Protein production in supernatants was
      assessed by ELISA, and mRNA expression was evaluated by semiquantitative RT-PCR.
      RESULTS: Secretion of IL-8 and RANTES increased in a dose-dependent manner with
      increasing concentrations of DEP-PAHs (range, 0.5 ng to 50 ng/mL). On the
      contrary, the release of MCP-1 was significantly inhibited, also in a dose
      dependent manner. Messenger RNA production coding for IL-8, RANTES, and MCP-1
      showed parallel variations to the production of the correspondent proteins.
      Effects of DEP-PAHs became significant at 7 hours and up to 48 hours time culture
      for MCP-1, and up to 24 hours time culture for IL-8 and RANTES. Moreover,
      supernatants from DEP-PAH-activated cells, compared with those of controls,
      exhibited a significantly enhanced chemotactic activity for neutrophils and
      eosinophils, which was significantly inhibited by pretreatment with anti-IL-8 and
      anti-RANTES neutralizing antibodies, respectively. CONCLUSION: These findings
      suggest that the chemokine pathways are modulated by DEP-PAHs at the
      transcriptional level, reinforcing the idea that the development of inflammatory
      reactions might be affected by diesel exhaust emission.

PMID- 10359895
TI  - Binding of YY1 and Oct1 to a novel element that downregulates expression of IL-5
      in human T cells.
AB  - BACKGROUND: IL-5 controls development of eosinophilia and has been shown to be
      involved in the pathogenesis of allergic diseases. In both atopic and nonatopic
      asthma, elevated IL-5 has been detected in peripheral blood and the airways. IL-5
      is produced mainly by activated T cells, and its expression is regulated at the
      transcriptional level. OBJECTIVE: This study focuses on the functional analysis
      of the human IL-5 (hIL-5) promoter and characterization of cis -regulatory
      elements and transcription factors involved in the suppression of IL-5
      transcription in T cells. METHODS: Methods used in this study include DNase I
      footprint assays, electrophoretic mobility shift assays, and functional analysis
      by mammalian cell transfection involving deletion analysis and site-directed
      mutagenesis. RESULTS: We identified 5 protein binding regions (BRs) located
      within the proximal hIL-5 promoter. Functional analysis indicates that the BRs
      are involved in control of hIL-5 promoter activity. Two of these regions, BR3 and
      BR4 located at positions -102 to -73, have not previously been described as
      regulators of IL-5 expression in T cells. We show that the BR3 sequence contains
      a novel negative regulatory element located at positions -90 to -79 of the hIL-5
      promoter, which binds Oct1, octamer-like, and YY1 nuclear factors. Substitution
      mutations, which abolished binding of these proteins to the BR3 sequence,
      significantly increased hIL-5 promoter activity in activated T cells. CONCLUSION:
      We suggest that Oct1, YY1, and octamer-like factors binding to the -90/-79
      sequence within the proximal IL-5 promoter are involved in suppression of IL-5
      transcription in T cells.

PMID- 10359896
TI  - Increased expression of the CD80 accessory molecule by alveolar macrophages in
      asthmatic subjects and its functional involvement in allergen presentation to
      autologous TH2 lymphocytes.
AB  - BACKGROUND: Alveolar macrophages (AMs) are more efficient antigen-presenting
      cells in allergic individuals than in nonatopic subjects. OBJECTIVE: We studied
      whether this difference may be correlated to increased expression of membrane
      costimulatory molecules, such as the B7 molecules (CD80 and CD86). METHODS:
      Eleven subjects with allergic asthma sensitized to Dermatophagoides pteronyssinus
      and 5 healthy nonatopic volunteers underwent bronchoalveolar lavage, and the
      costimulatory molecule expression on AMs was evaluated. Peripheral blood T cells,
      either freshly isolated or as established D pteronyssinus -specific cell lines,
      were cultured with autologous monocytes or AMs as antigen-presenting cells. In
      vitro allergen-induced proliferation and cytokine production were evaluated in
      the presence of B7-blocking reagents. RESULTS: Allergic individuals had a
      significantly higher proportion of AMs expressing the CD80 molecule than control
      subjects (28.5% +/- 14.8% vs 1.4% +/- 1.2%; P <.001), whereas no difference was
      observed in CD86 expression (2.0% +/- 2.3% vs 1.1% +/- 0.6; P >.1). In a large
      proportion of the asthmatic subjects we studied, AMs were presenting soluble
      antigens (tetanus toxoid and streptolysin-O) to freshly isolated T cells more
      efficiently than AMs from nonatopic control subjects. Finally, both T-cell
      proliferation and cytokine production of D pteronyssinus- specific established T
      cell lines were inhibited by a CD80-blocking antibody in a dose-dependent manner.
      CONCLUSION: Costimulation by means of CD80 expressed by AMs is probably involved
      in the amplification of the allergen-specific T-lymphocyte response in the
      airways of asthmatic subjects.

PMID- 10359897
TI  - Inhibitory effect of heparin on skin reactivity to autologous serum in chronic
      idiopathic urticaria.
AB  - BACKGROUND: Most patients with chronic idiopathic urticaria (CIU) show cutaneous
      reactivity to intradermal injection of autologous serum. In some cases this
      reactivity is associated with the presence of autoantibodies directed against IgE
      or IgE receptors expressed on mast cells, whereas in others no autoimmune
      mechanisms can be documented. OBJECTIVES: The aims of this study were to compare
      the cutaneous reactivity to serum and plasma samples in a series of patients with
      active CIU and to address the mechanisms of the inhibitory effect exerted by
      heparin on the cutaneous responsiveness to the histamine-releasing factors (HRFs)
      present in CIU serum. METHODS: Fourteen patients with CIU were injected
      intradermally with autologous serum, plasma (anticoagulated by either heparin or
      EDTA), or serum samples to which heparin had been added. The effects of heparin
      injection on cutaneous responsiveness to allergens was tested in 5 atopic
      patients. Moreover, in a set of experiments sera were also adsorbed with
      Sepharose-conjugated heparin. RESULTS: All the patients had positive cutaneous
      reactions to autologous serum injection. When heparinized plasma was injected,
      negative reactions were observed in 12 of 14 patients, and a sizable reduction in
      the wheal-and-flare reactions was recorded in the remaining 2. Compared with
      results obtained with serum, no substantial change was observed in 6 of 8
      patients injected with EDTA-anticoagulated plasma. When heparin was added to
      serum, abrogation of skin reactivity was seen; nonetheless, no change in the
      cutaneous response to allergens was associated with locally administered heparin
      in 5 atopic patients with no history of CIU. Finally, adsorption of CIU sera with
      solid-phase heparin abrogated the ability to induce cutaneous reactions in 5 of 7
      patients, whereas in the remaining 2 a sizable reduction was observed.
      CONCLUSIONS: These data indicate that heparin is able to profoundly inhibit the
      cutaneous response to HRFs present in the sera of patients with CIU. Although the
      precise level of action of this heparin-mediated effect is unclear from present
      data, preliminary evidence seems to indicate that heparin could directly
      interfere with HRFs present in CIU sera.

PMID- 10359898
TI  - Month of birth and prevalence of atopic dermatitis in schoolchildren: dry skin in
      early infancy as a possible etiologic factor.
AB  - BACKGROUND: Month of birth has been shown to affect later development of allergic
      diseases. OBJECTIVE: We sought to evaluate the relationship between month of
      birth and the prevalence of atopic dermatitis (AD) in a large-scale general
      population of schoolchildren and to elucidate the possible mechanism for this
      relationship. METHODS: Questionnaire data on the prevalence of allergic diseases
      were obtained for 33,725 schoolchildren aged 7 to 15 years. In a separate study
      the water-holding capacity of "uninvolved" skin was compared for children with
      and without AD. RESULTS: We found striking differences in the prevalence of AD
      according to the month of birth (chi2 = 34.9, P <.0001). Overall, those born in
      autumn showed the highest (7.5%), and those born in spring showed the lowest
      (5.5%), prevalence of AD. There was little or no such tendency for the prevalence
      of bronchial asthma (chi2 = 17.2, P =.103) and allergic rhinitis (chi2 = 24, P
      =.01). We found no statistical variation across birth month in the ratio of AD
      with no other allergic disease/total AD, indicating that this deviation was
      observed whatever the allergic predisposition of the subjects. In a separate
      study a significantly lower water-holding capacity of uninvolved skin was
      observed in children with AD even from early infancy. CONCLUSION: These findings
      lead us to speculate that the climate in early infancy affects the skin condition
      and that those born in autumn have dry skin in early infancy, which may
      ultimately result in a higher prevalence of AD among young schoolchildren. This
      might be at least one of the "nonallergic" etiologic factors of this complex
      disease.

PMID- 10359899
TI  - A cross-sectional survey of sensitization to Aspergillus oryzae-derived lactase
      in pharmaceutical workers.
AB  - BACKGROUND: The presence of IgE-mediated occupational respiratory sensitization
      to microbial enzymes has been well documented in a variety of industries.
      Aspergillus oryzae -derived lactase is used as a dietary aid for patients with
      lactose intolerance. OBJECTIVE: In 1993, a cross-sectional survey of 94
      pharmaceutical workers exposed to lactase for a mean duration of 23 months and 24
      nonexposed recently hired employees was initiated to identify lactase-sensitized
      workers and potential risk factors that could be used in making recommendations
      for preventing future cases of lactase sensitization. METHODS: The survey
      included a physician-administered questionnaire, skin prick testing to lactase
      enzyme and a panel of common aeroallergens, and spirometry. RESULTS: Twenty-seven
      of 94 lactase-exposed workers (29%) had positive skin test responses to lactase.
      These workers were 9 times more likely to have upper or lower respiratory
      symptoms compared with workers with negative skin test responses. Atopic workers
      were 4 times more likely to have lactase skin sensitivity than nonatopic workers.
      However, atopy was not a risk factor for the development of upper and/or lower
      respiratory symptoms. Lactase skin reactivity was not observed in the 24
      nonexposed employees. CONCLUSION: This cross-sectional survey revealed that
      atopic workers were more likely to have lactase sensitization and that lactase
      sensitized workers were more likely to have upper and/or lower respiratory
      symptoms, but atopy was not a risk factor for upper or lower respiratory
      symptoms. In spite of these findings, the company allowed only nonatopic,
      nonlactase-sensitized workers to continue working in high lactase-exposure areas
      with careful symptom monitoring and use of protective clothing. Although this
      strategy was successful in total prevention of new cases of occupational
      respiratory disease after 5 years, the results of this cross-sectional survey do
      not support exclusion of atopic workers from working with industrial enzymes.

PMID- 10359900
TI  - Purification of the antigenic components of pigeon dropping extract, the
      responsible agent for cellular immunity in pigeon breeder's disease.
AB  - BACKGROUND: Pigeon breeder's disease (PBD) is a lung disease caused by inhalation
      of antigens derived from pigeons. OBJECTIVE: This study was undertaken to
      characterize the responsible component of pigeon dropping extract (PDE) for PBD.
      METHODS: First, crude PDE was applied to SDS-PAGE followed by immunoblotting by
      using antibodies in bronchoalveolar lavage (BAL) fluid. Second, 9 bands of PDE
      were separated by SDS-PAGE and used for antigen-induced PBMCs. Finally, amino
      terminal sequencing was conducted on an isolated 21-kd protein by 2-dimensional
      electrophoresis. RESULTS: Immunoblots with BAL fluid from patients with PBD
      identified 9 bands. Similar patterns were observed by using BAL fluid from 10
      control patients (9 with summer-type hypersensitivity pneumonitis or idiopathic
      pulmonary fibrosis and 1 asymptomatic breeder), except for the 21-kd protein,
      which was detected in 10 patients with PBD and 1 asymptomatic breeder. The
      stimulation indices of PBMCs determined by using proteins electroeluted from the
      9 bands were higher in patients with PBD than in the 10 control patients. The 21
      kd protein was separated into 5 spots by 2-dimensional electrophoresis; these
      spots were all reactive with BAL fluid from patients with PBD as determined by
      immunoblotting. The sequence of the 21-kd protein had 57% identity to a
      Saccharomyces cerevisiae chromosome X reading frame. A synthetic peptide, derived
      from the amino acid sequence of the N-terminal of the native protein, induced
      significant proliferation of PBMCs obtained from 5 patients with PBD, but not
      with PBMCs obtained from control patients. CONCLUSION: The 21-kd protein is the
      only protein that identified individuals exposed to pigeons by immunoblotting.
      Only PBMCs from patients with PBD showed significant proliferation to the 21-kd
      protein and to the synthetic peptide on the basis of the N-terminal sequence of
      the native peptide. The 21-kd protein will be an important antigen for studies on
      the epidemiology, diagnosis, and pathogenesis of PBD.

PMID- 10359901
TI  - Human IgE-binding epitopes of the latex allergen Hev b 5.
AB  - BACKGROUND: Hev b 5 is an acidic protein (isoelectric point, 3.5) rich in
      glutamic acid with 9 repeated amino acid (AA) sequences of XEEX or XEEEX.
      Although its function in Hevea brasiliensis is unknown, Hev b 5 has been
      identified as a major latex allergen. Immunoblot inhibition studies suggest Hev b
      5 exists as multiple isoforms or contains a common epitope found in several other
      proteins. OBJECTIVE: The purpose of this study was to further characterize Hev b
      5 and to identify linear IgE-binding epitopes. METHODS: Octapeptides spanning the
      entire Hev b 5 protein were synthesized on a derivatized cellulose membrane. The
      membrane was reacted with sera pooled from health care workers allergic to latex
      or rabbits immunized with latex proteins. B-cell epitopes were identified by
      subsequent incubations with the appropriate secondary antibodies and detected by
      using chemifluorescence. RESULTS: Sera from patients allergic to latex recognized
      6 IgE-binding regions located throughout the molecule. Two epitopes (2 and 4) had
      the common AA sequence of KTEEP. Epitopes 3 and 5 had a similar AA sequence of
      EEXXA, where X was P, T, or K. Epitopes 1 and 6 appeared to be unrelated to the
      other epitopes. Database analysis could not identify other proteins with similar
      sequences. Neither of the XEEEX sequences bound IgE. Control sera failed to react
      to any peptides. CONCLUSIONS: Hev b 5 exists as multiple isoforms, but only small
      amounts are present in the nonammoniated latex preparations, such as those used
      for diagnostic tests, and this may help to explain the relatively poor
      sensitivity of some in vitro tests.

PMID- 10359902
TI  - Natural course of sensitization to food and inhalant allergens during the first 6
      years of life.
AB  - BACKGROUND: Specific IgE antibody responses to alimentary and environmental
      allergens are one of the hallmarks of atopic diseases. The knowledge of the time
      course of allergic sensitization during early life may facilitate measures for
      preventive interventions. OBJECTIVE: In a prospective birth cohort study (the
      Multicenter Allergy Study [MAS]) we investigated annual incidence and prevalence
      rates of sensitization to food and inhalant allergens during the first 6 years of
      life. METHODS: For 216 children of a prospective birth cohort (MAS), a complete
      follow-up of specific IgE measurements to 9 food and inhalant allergens was
      available at 1, 2, 3, 5, and 6 years of age. On the basis of these measurements,
      sensitization rates were estimated for the reference population of 4082 children
      by weighted analysis. RESULTS: Annual incidence rates of sensitization to food
      allergens decreased from 10% at 1 year of age to 3% at the 6 years of age.
      Incidences of sensitization to inhalant allergen, however, increased with age
      (from 1.5% at 1 year to 8% at 6 years). Point prevalences of allergic
      sensitization to at least 1 of the 9 tested allergens increased from 11% at 1
      year up to 30% at 6 years. This increase was due to markedly increasing
      sensitization rates to inhalant allergens (1.5% to at least 1 inhalant allergen
      at 1 year and 26% at 6 years of age), whereas sensitization rates to food
      allergens remained stable during the first 6 years of life (10%). CONCLUSION: The
      earliest serologic marker for atopic immunoreactivity in infancy is the presence
      of IgE antibodies to egg, followed by milk. The development of sensitization to
      inhalant allergens occurs mostly after infancy. Beyond the third birthday annual
      incidence and prevalence increase markedly with age. Rates for outdoor allergens
      are twice those for indoor allergens.

PMID- 10359903
TI  - Systemic allergic reaction to coconut (Cocos nucifera) in 2 subjects with
      hypersensitivity to tree nut and demonstration of cross-reactivity to legumin
      like seed storage proteins: new coconut and walnut food allergens.
AB  - BACKGROUND: Two patients with tree nut allergy manifested by life-threatening
      systemic reactions reported the subsequent onset of systemic reactions after the
      consumption of coconut. OBJECTIVE: Herein, the IgE-binding proteins from coconut
      are described, and in vitro cross-reactivity with other nuts is investigated.
      METHODS: The IgE-binding profile of coconut endosperm tissue extract was analyzed
      by SDS-PAGE followed by immunoblotting. Immunoblot inhibition studies with
      walnut, almond, peanut, and coconut were performed. RESULTS: Sera IgE from both
      patients recognized reduced coconut allergens with molecular weights of 35 and
      36.5 kd. IgE from 1 patient also bound a 55-kd antigen. Preabsorption of sera
      with nut extracts suppressed IgE binding to coconut proteins. Preabsorption of
      sera with coconut caused the disappearance of IgE binding to protein bands at 35
      and 36 kd on a reduced immunoblot of walnut protein extract in 1 patient and
      suppression of IgE binding to a protein at 36 kd in the other patient.
      CONCLUSION: The reduced coconut protein at 35 kd was previously shown to be
      immunologically similar to soy glycinin (legumin group of seed storage proteins).
      The clinical reactivity in these 2 patients is likely due to cross-reacting IgE
      antibodies primarily directed against walnut, the original clinical allergy
      reported, and most likely to a walnut legumin-like protein. Coconut allergy in
      patients with tree nut allergy is rare; these are the first 2 patients ever
      reported, and therefore there is no general indication to advise patients with
      tree nut allergy to avoid coconut.

PMID- 10359904
TI  - A diagnostic protocol for evaluating nonimmediate reactions to aminopenicillins.
AB  - BACKGROUND: Maculopapular and urticarial rashes are nonimmediate manifestations
      common during aminopenicillin (AP) treatment, and the former often represent cell
      mediated hypersensitivity. OBJECTIVES: We sought to determine the significance
      and incidence of skin test reactions to APs in adults reporting adverse reactions
      during therapy with these beta-lactams and, particularly, to evaluate the
      potential of patch tests, delayed-reading skin tests, and challenges in the
      diagnosis of nonimmediate reactions. METHODS: We used skin tests with
      penicilloylpolylysine, minor determinant mixture, benzylpenicillin, ampicillin,
      and amoxicillin, as well as patch tests with the last 3 drugs. We also performed
      in vitro assays for specific IgE and challenges with the suspect penicillin in
      subjects with nonimmediate reactions. RESULTS: Among the 144 patients reporting
      nonimmediate manifestations (mostly maculopapular rashes), delayed
      hypersensitivity was diagnosed in 62 on the basis of positive patch test and/or
      delayed intradermal test results and responses to challenges; negative reactions
      to challenges allowed us to reasonably exclude the possibility of allergy in 66
      subjects, and the challenge confirmed that 1 patient had linear IgA bullous
      dermatosis. Definitive diagnoses could not be provided for the remaining 15
      subjects, who had negative allergologic test results, because they did not
      consent to challenges. In 40 of 49 immediate reactors, a diagnosis of IgE
      mediated hypersensitivity was made. CONCLUSIONS: Both patch and intradermal tests
      are useful in evaluating nonimmediate reactions to APs. Positive patch test and
      delayed intradermal responses together indicate delayed hypersensitivity.
      Intradermal testing appears to be more sensitive than patch testing, but the
      pattern of positive delayed intradermal test responses and negative patch test
      responses needs further investigation because of false-positive cases.

PMID- 10359905
TI  - Allergenicity of goat's milk in children with cow's milk allergy.
AB  - BACKGROUND: Cow's milk allergy (CMA) is a common disease of infancy and
      childhood. An appropriate cow's milk (CM) substitute is necessary for feeding
      babies with CMA. CM substitutes are soy formulas and casein- or whey-based
      extensively hydrolyzed formulas. In several countries, including Italy, goat's
      milk (GM) formulas are available, and some physicians recommend them for feeding
      babies with CMA. OBJECTIVE: We sought to investigate, in vitro and in vivo, the
      allergenicity of GM in 26 children with proven IgE-mediated CMA. METHODS: All the
      children underwent skin tests with CM and GM; detection of specific serum IgE to
      CM and GM; and double-blind, placebo-controlled, oral food challenges (DBPCOFCs)
      with fresh CM, GM, and, as placebo, a soy formula (Isomil, Abbott, Italy). CAP
      inhibition and immunoblotting inhibition assays were also carried out in 1 of 26
      and 4 of 26 children with positive RAST results to both CM and GM, respectively.
      RESULTS: All the children had positive skin test responses and CAP results to
      both CM and GM, all had positive DBPCOFC results to CM, and 24 of 26 had positive
      DBPCOFCs to GM. In CAP inhibition tests, preincubation of serum with CM or GM
      strongly inhibited IgE either to CM or to GM. In immunoblotting inhibition
      assays, preincubation with CM completely extinguished reactivity to GM, whereas
      GM partially inhibited reactivity to CM. CONCLUSIONS: These data strongly
      indicate that GM is not an appropriate CM substitute for children with IgE
      mediated CMA. A warning on the lack of safety of GM for children with CMA should
      be on the label of GM formulas to prevent severe allergic reactions in babies
      with CMA.

PMID- 10359906
TI  - Deposition of eosinophil-granule major basic protein and expression of
      intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the
      mucosa of the small intestine in infants with cow's milk-sensitive enteropathy.
AB  - BACKGROUND: Cow's milk-sensitive enteropathy (CMSE) is an important cause of
      chronic diarrhea and failure to thrive in infancy. The immunopathology of the
      mucosal lesion associated with CMSE has not yet been described. OBJECTIVES: This
      study investigated the eosinophil activation and the role of adhesion molecules
      in the pathogenesis of intestinal mucosal damage associated with CMSE. METHODS:
      Twenty-one patients with chronic diarrhea and abnormal mucosa on duodenal biopsy
      specimens were included. The patients had negative responses to skin prick tests
      and RASTs with milk. Fourteen patients were diagnosed with CMSE by milk challenge
      test and were designated as the CMSE group. Seven patients with no milk
      intolerance were defined as the non-CMSE group. Four infants with frequent
      vomiting and no mucosal abnormalities were also studied as the control group.
      Immunohistochemical stains for eosinophil major basic protein (MBP), vascular
      cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 on
      endoscopic duodenal biopsy specimens were performed. RESULTS: The degree of
      eosinophil degranulation, as evidenced by localization of extracellular MBP, was
      significantly greater in the CMSE group compared with the non-CMSE and control
      groups (P <.05). Expression of VCAM-1 on mononuclear cells was higher in the CMSE
      group compared with the non-CMSE and control groups (P <.05). The severity of
      villous atrophy was positively correlated with the deposition of MBP (r = 0.79, P
      <.001). CONCLUSION: These results strongly suggest eosinophils and VCAM-1 are
      implicated in the pathogenesis of mucosal damage associated with CMSE.

PMID- 10359908
TI  - Palladium allergy exacerbating bronchial asthma.

PMID- 10359907
TI  - Suppression of antigen-specific T- and B-cell responses by intranasal or oral
      administration of recombinant bet v 1, the major birch pollen allergen, in a
      murine model of type I allergy.
AB  - BACKGROUND: Mucosal (nasal or oral) administration of soluble protein antigens
      induces a state of antigen-specific immunologic hyporesponsiveness. Several
      studies have shown that induction of mucosal tolerance can prevent the onset or
      reduce the severity of certain TH1 -mediated experimental autoimmune diseases.
      Only a few studies describe similar results for type I allergies, which are
      caused by excessive TH2 cell activities. OBJECTIVE: We sought to investigate
      whether mucosal tolerance induction would also be efficient in preventing an
      allergic type I immune response. METHODS: A murine model of inhalative type I
      allergy, leading to sensitization to birch pollen and its major allergen Bet v 1
      in BALB/c mice, was used. Recombinant Bet v 1 was nasally or orally applied in
      low doses before sensitization. At the time of death, immediate-type skin tests
      were performed. Blood was taken, and serum was used for measurement of allergen
      specific antibodies. Spleen cell cultures were performed to determine cytokine
      production (IL-4, IL-5, IL-10, and IFN-gamma), as well as levels of TGF-beta
      mRNA. RESULTS: Both nasal and oral administration of minimal doses of recombinant
      Bet v 1 before aerosol sensitization with birch pollen suppressed the allergen
      specific antibody production of all isotypes. Consequently, the in vivo type I
      skin test responses to the allergen were negative in the tolerized, in contrast
      to the sensitized, group. Moreover, allergen-specific lymphoproliferative
      responses and cytokine production in vitro (ie, IFN-gamma, IL-4, IL-5, and IL-10)
      were markedly reduced. In contrast, expression of TGF-beta mRNA was markedly
      increased in spleen cells from nasally tolerized animals, indicating regulatory
      mechanisms for tolerance induction. CONCLUSION: We conclude from the present
      study that nasal, as well as oral, administration of recombinant allergen is an
      effective way to prevent allergen-specific T- and B-cell responses in a TH2
      model.

PMID- 10359909
TI  - Serum-soluble Fas levels as a marker to distinguish allergic and nonallergic
      rhinitis.

PMID- 10359910
TI  - Lupin allergy in a child.

PMID- 10359911
TI  - IgE antithyroid microsomal antibodies in a patient with chronic urticaria.

PMID- 10359912
TI  - Expansion of gammadelta T cells in an infant with severe combined
      immunodeficiency syndrome after disseminated BCG infection and bone marrow
      transplantation.

PMID- 10359913
TI  - Presence of eotaxin in tears of patients with atopic keratoconjunctivitis with
      severe corneal damage.

PMID- 10359914
TI  - Severe combined immunodeficiency in an infant with multiple congenital
      abnormalities.

PMID- 10359915
TI  - Systemic effects of inhaled fluticasone propionate.

PMID- 10359916
TI  - Effectiveness and safety of inhaled corticosteroids.

PMID- 10359918
TI  - Value of negative dobutamine stress echocardiography in predicting long-term
      cardiac events.
AB  - To determine the value of negative dobutamine stress echocardiography (DSE)
      results in predicting subsequent long-term cardiac event rates, we
      retrospectively reviewed all dobutamine stress echocardiograms performed at our
      institution over a 3-year period (1992-1994). Follow-up was accomplished through
      the completion of a detailed questionnaire compiled from data obtained through
      chart review and direct telephone contact. Information regarding death also was
      determined by referencing patient data with mortality data available on the World
      Wide Web. Event rates were determined for hard (myocardial infarction [MI] or
      cardiac death) and soft (hospitalization for angina and/or congestive heart
      failure, coronary angioplasty, or coronary bypass surgery) cardiac events
      occurring after the negative DSE results for up to 7 years after the test.
      Negative test results were defined as those showing no new or worsening wall
      motion abnormalities after either a normal resting echocardiogram (normal
      negative [NN]) or an abnormal segmental resting echocardiogram (fixed-negative
      [FN]). RESULTS: Of the 346 interpretable tests, 224 were negative for inducible
      wall motion abnormalities, with 171 NN and 53 FN. In the NN group, the MI rate
      was 1.5% per patient/year, and the mortality rate was 0.13% per patient/year. In
      the FN group, the MI rate was 0.7% per patient/year, and the mortality rate was
      0% per patient/year. CONCLUSIONS: DSE results in both NN and FN groups predict a
      very low subsequent hard event rate and mortality for up to 5 years after the
      test.

PMID- 10359919
TI  - Effect of an acute increase in afterload on left ventricular regional wall motion
      velocity in healthy subjects.
AB  - We recorded left ventricular (LV) wall motion velocities before and after
      angiotensin II infusion by pulsed tissue Doppler imaging in 20 healthy subjects,
      and evaluated the responses of systolic and diastolic LV function along the long
      and short axes during an acute increase in afterload. Angiotensin II was
      administered intravenously to obtain a 30% increase in mean blood pressure. After
      angiotensin II infusion, LV end-systolic dimension and end-systolic
      circumferential wall stress increased significantly, and the percentage of LV
      fractional shortening decreased significantly. Peak first systolic LV wall motion
      velocity (Sw1 ) along the long axis decreased markedly compared with that along
      the short axis, and peak second systolic LV wall motion velocity (Sw2 ) along the
      short axis decreased significantly compared with that along the long axis. Early
      diastolic LV wall motion velocities along both the long and short axes decreased
      significantly, whereas atrial systolic LV wall motion velocity did not change. In
      conclusion, an acute increase in afterload caused a significant decrease in
      longitudinal fiber shortening during the isovolumic contraction phase (Sw1 along
      the long axis), circumferential fiber shortening during the ejection phase (Sw2
      along the short axis), and LV relaxation during early diastole (early diastolic
      LV wall motion velocities along both axes) in healthy subjects. Pulsed tissue
      Doppler imaging may be useful for detecting the effect of various loading
      conditions on LV wall motion velocities along the long and short axes.

PMID- 10359920
TI  - Temporal variability of exercise Doppler echocardiography in patients with
      nonstented aortic bioprostheses.
AB  - Temporal variability and reproducibility of Doppler-derived variables obtained
      during supine symptom-limited exercise was investigated in 26 patients who were
      in clinically and hemodynamically stable condition with normally functioning
      nonstented aortic bioprostheses (stentless porcine, n = 13; cryopreserved
      homografts, n = 13). All patients had normal systolic left ventricular function
      and underwent 2 similar exercise tests within 12 months (mean time interval 7.2
      +/- 1.9 months). The coefficient of variation was 8% to 9% for primary Doppler
      derived variables (ie, velocities and velocity time integrals) at rest and during
      exercise. The coefficient of variation for calculated maximal pressure difference
      was 16% at rest and 15% at peak exercise. Measurement variability assessed from
      repeated measurements from the same videotaped recording was approximately 2%.
      High reproducibility was shown for most variables with intraclass correlation
      coefficients of 0.85 or more. We conclude that Doppler echocardiography can be
      used in patients with nonstented aortic bioprostheses with the same high
      reproducibility during exercise as at rest. The results provide clinically useful
      information regarding temporal variability for Doppler-derived variables.

PMID- 10359921
TI  - Reproducibility of pulsed wave tissue Doppler echocardiography.
AB  - Four hundred and eighty paired recordings obtained from 16 patients (55 +/- 10
      yrs; 10 men, 6 women) were analyzed to determine the reproducibility of both
      acquiring and measuring myocardial velocities recorded by tissue Doppler
      echocardiography. To assess intraobserver variability, 1 observer recorded and
      measured the data twice, from the same patients, and to assess interobserver
      variability, patients were examined by 2 independent observers. For the left
      ventricle, intraobserver reproducibility was higher when assessing long-axis
      velocities (+/- 10% to 16%) than short-axis velocities (+/- 14% to 24%). For the
      right ventricle, intraobserver reproducibility was high for the tricuspid annulus
      (+/- 9% to 15%), but unsatisfactory for the right ventricular anterior wall (+/-
      21% to 25%). The highest interobserver reproducibilities were obtained for
      systolic and diastolic velocities of the lateral mitral annulus (+/- 9% to 17%)
      and systolic velocity of the tricuspid annulus (+/-13%). Interobserver
      reproducibility of the ratio of early-to-late peak diastolic velocities was very
      low for all investigated sites (+/- 20% to 52%). With the use of current
      techniques and software, reproducibility of acquiring and measuring tissue
      Doppler echocardiography is suboptimal for both systolic and diastolic myocardial
      velocities.

PMID- 10359922
TI  - Diastolic flow pattern in the normal left ventricle.
AB  - OBJECTIVES: This study sought to clarify the diastolic flow pattern in the normal
      left ventricle. BACKGROUND: During left ventricular filling, basally directed
      (retrograde) velocities are seen in the outflow compartment. These velocities may
      represent blood returned from the apical region or a shortcut at a more basal
      level. METHODS: Left ventricular flow patterns were identified in 18 healthy
      individuals (age 47 +/- 12 years) with the use of high frame-rate two-dimensional
      color Doppler and color M-mode Doppler echocardiography techniques.
      Intraventricular velocities were measured with single pulsed Doppler at 3 levels
      in both inflow and outflow compartments (posterolateral and anteroseptal parts of
      the left ventricle). RESULTS: During early transmitral flow acceleration, all
      intraventricular velocities were directed towards the apex. However, after peak
      early and late inflow velocities and during diastasis, retrograde velocities were
      identified in the outflow compartment. These retrograde velocities occurred
      earlier, and were higher, at the level of the deflected anterior mitral leaflet
      tip compared with more apical levels (P <.001). A velocity pattern was
      established, consistent with early intraventricular vortex formation behind both
      mitral leaflets. The vortex adjacent to the anterior leaflet subsequently
      enlarged to include a major part of the left ventricle. CONCLUSION: Uniform
      diastolic flow patterns were identified in the normal left ventricles. The
      findings suggest that both early and late diastolic filling start with an initial
      motion of a fluid column, succeeded by vortex formation, which explains
      retrograde flow in the outflow compartment.

PMID- 10359923
TI  - Cardioversion in patients with atrial fibrillation and left atrial thrombi on
      initial transesophageal echocardiography: should transesophageal echocardiography
      be repeated before elective cardioversion? A cost-effectiveness analysis.
AB  - BACKGROUND: Transesophageal echocardiography (TEE) is used to expedite early
      cardioversion for patients with atrial fibrillation in whom TEE excludes the
      presence of atrial thrombi. However, the management of patients with atrial
      thrombi on initial TEE is controversial. Some advocate cardioversion after 3 to 4
      weeks of anticoagulant therapy, whereas others perform a follow-up TEE to
      document thrombus resolution. We performed a cost-effectiveness analysis to
      compare the two strategies. METHODS AND RESULTS: A computer-based decision
      analysis model was used to compared 2 strategies: No Follow-up TEE-patients with
      thrombi on initial TEE complete 4 weeks of anticoagulation and undergo elective
      cardioversion. Follow-up TEE-patients undergo a follow-up TEE after 4 weeks of
      anticoagulant therapy. If a thrombus is detected, cardioversion is not performed
      and patients remain in atrial fibrillation; patients without a thrombus undergo
      cardioversion. Under our baseline estimates, the Follow-up TEE strategy is less
      costly and slightly more effective than the No Follow-up TEE strategy. The
      results are most sensitive to changes in the risk of postcardioversion stroke for
      patients with atrial thrombi on initial TEE who have completed 4 weeks of
      anticoagulation and to the probability of residual thrombi on follow-up TEE.
      CONCLUSIONS: In this cost-effectiveness analysis for patients with atrial
      fibrillation and left atrial thrombi detected on initial TEE, a Follow-up TEE
      strategy may be more cost-effective than the No Follow-up TEE strategy. However,
      the decision is particularly dependent on the risk of postcardioversion stroke in
      patients with undetected residual left atrial thrombi.

PMID- 10359924
TI  - Evaluation of descending aortic flow volumes and effective orifice area through
      aortic coarctation by spatiotemporal integration of color Doppler data: An in
      vitro study.
AB  - Flow volumes in an in vitro model of the aorta with 3 different degrees of
      stiffness (stiff, moderately stiff, and compliant) proximal to a coarctation were
      calculated by using a digital color Doppler echocardiography flow calculation
      method that semiautomatically integrates spatial and temporal color flow velocity
      data. These flow volumes were compared with those obtained by the conventional
      pulsed Doppler method with reference to ultrasonic flowmeter. Flow volumes
      determined by the automated method agreed well with those obtained by ultrasonic
      flowmeter, even in this compliant aorta model with vessel size changing with
      pulsation, whereas the pulsed Doppler method overestimated the reference data,
      especially for more compliant descending aortic segments. The combination of flow
      data with continuous wave Doppler allows definition of effective orifice area for
      coarctation.

PMID- 10359925
TI  - Incidence of complications in pediatric transesophageal echocardiography:
      experience in 1650 cases.
AB  - The purpose of this study was to tabulate the complications encountered in 1650
      patients who underwent pediatric transesophageal echocardiography. The occurrence
      of complications and their type and severity were prospectively recorded. The
      patients had a mean age of 3.6 years (range 1 day to 21 years) and a mean weight
      of 17.2 kg (range 1.6 to 118 kg). Of the 1650 cases, 1534 were intraoperative.
      Most patients studied (97%) had congenital heart disease. Complications occurred
      in 52 (3.2%) of the 1650 patients. Failure to insert the probe occurred in 13
      (0.8%) patients; if those cases are not counted as complications, the incidence
      of overall complications falls to 2.4%. Airway obstruction occurred in 14 (1%)
      patients, right mainstem advancement of the endotracheal tube in 3 (0.2%),
      inadvertent tracheal extubation in 8 (0.5%), vascular compression in 10 (0.6%),
      and single additional complications in 4 (0.2%). No significant bleeding,
      arrhythmias, esophageal injuries, or deaths occurred. Failure to insert the probe
      and airway complications occurred predominantly and significantly in smaller
      subjects. It is concluded that the incidence of complications during pediatric
      transesophageal echocardiography is low.

PMID- 10359926
TI  - Atrial thrombosis in cardiac amyloidosis: diagnostic contribution of
      transesophageal echocardiography.
AB  - Few cases of atrial thrombosis detected by transesophageal echocardiography (TEE)
      in cardiac amyloidosis have been reported recently. We present the cases of 3
      consecutive patients affected by AL-type cardiac amyloidosis, symptomatic for
      heart failure and in sinus rhythm. All patients had a cardiac restrictive pattern
      at Doppler examination. TEE showed left atrial thrombus in 2 patients and
      biatrial thrombi in 1 patient; conventional transthoracic echocardiography
      detected only 1 left atrial thrombus. Our experience confirms the association
      between cardiac amyloidosis and atrial thrombosis, even in sinus rhythm. TEE
      should be considered to assess thromboembolic risk in all cases of cardiac
      amyloidosis with severe diastolic dysfunction.

PMID- 10359927
TI  - Prosthetic valve obstruction with normal disk motion: usefulness of
      transesophageal echocardiography to define cause.
AB  - We describe a rare case of Bjork-Shiley prosthetic valve obstruction with normal
      motion of the tilting disk. The cause of obstruction was the annular pannus
      ingrowth and was well defined by transesophageal echocardiography, but not by
      cardiac catheterization nor cineradiography.

PMID- 10359928
TI  - Airway obstruction caused by transesophageal echocardiography in a patient with
      double aortic arch and truncus arteriosus.

PMID- 10359929
TI  - The New England Society for Vascular Surgery: 25 years and counting.

PMID- 10359930
TI  - The cost-effectiveness of endovascular repair versus open surgical repair of
      abdominal aortic aneurysms: A decision analysis model.
AB  - PURPOSE: Endovascular repair (EVR) is a less-invasive method for the treatment of
      abdominal aortic aneurysms (AAAs) as compared with open surgical repair (OSR).
      The potential benefits of EVR include increased patient acceptance, less resource
      utilization, and cost savings. This study was designed to determine whether the
      EVR of AAAs is a cost-effective alternative to OSR. METHODS: A cost-effectiveness
      analysis was performed using a Markov decision analysis model to compute long
      term survival rates in quality-adjusted life years and lifetime costs for a
      hypothetical cohort of patients who underwent either OSR or EVR. Probability
      estimates of the different outcomes of the two alternative strategies were made
      on the basis of a review of the literature. The average costs of (1) the
      immediate hospitalization ($16,016 for OSR, $20,083 for EVR), (2) the
      complications that resulted from each procedure, (3) the subsequent
      interventions, and (4) the surveillance protocol were determined on the basis of
      average resource utilization as reported in the literature and from our
      hospital's cost accounting system. Our measure of outcome was the cost
      effectiveness ratio. RESULTS: For our base-case analysis (70-year-old men with 5
      cm AAAs), EVR was cost-effective with a cost-effectiveness ratio of $22,826
      society usually is willing to pay for interventions with cost-effectiveness
      ratios of less than $60,000 (eg, cost-effectiveness ratios for coronary artery
      bypass grafting and dialysis are $9500 and $54,400, respectively). This
      conclusion did not vary significantly with increases in procedural costs for EVR
      (ie, if the cost of the endograft increased from $8000 to $12,000, EVR remained
      cost-effective with a cost-effectiveness ratio of $32,881). The cost
      effectiveness of EVR was critically dependent on EVR producing a large reduction
      in the combined mortality and long-term morbidity rate (stroke, dialysis
      dependent renal failure, major amputation, myocardial infarction) as compared
      with OSR (ie, a reduction in the combined mortality and long-term morbidity rate
      of OSR from 9.1% to 4.7% made EVR no longer cost-effective). CONCLUSION: Despite
      the high cost of new technology and the need for close postoperative
      surveillance, EVR is a cost-effective alternative for the repair of AAAs.
      However, the cost-effectiveness of this new technology is critically dependent on
      its potential to reduce morbidity and mortality rates as compared with OSR. EVR
      may not be cost-effective in medical centers where OSR can be performed with low
      risk.

PMID- 10359931
TI  - Should endovascular surgery lower the threshold for repair of abdominal aortic
      aneurysms?
AB  - PURPOSE: Because endovascular repair of abdominal aortic aneurysms (AAAs) is less
      invasive, some investigators have suggested that this increasingly popular
      technique should broaden the indications for elective AAA repair. The purpose of
      this study was to calculate quality-adjusted life expectancy rates after
      endovascular and open AAA repair and to estimate the optimal diameter for
      elective AAA repair in hypothetical cohorts of patients at average risk and at
      high risk. METHODS: A Markov decision analysis model was used in this study.
      Assumptions were made on the basis of published reports and included the
      following: (1) the annual rupture rate is a continuous function of the AAA
      diameter (0% for <4 cm, 1% for 4.5 cm, 11% for 5.5 cm, and 26% for 6.5 cm); (2)
      the operative mortality rate is 1% for endovascular repair (excluding the risk of
      conversion to open repair) and 3.5% for open repair at age 70 years; and (3)
      immediate endovascular-to-open conversion risk is 5%, and late conversion rate is
      1% per year. The main outcome measure in this study was the benefit of AAA repair
      in quality-adjusted life years (QALYs). The optimal threshold size (the AAA
      diameter at which elective repair maximizes benefit) was measured in centimeters.
      RESULTS: The benefit of endovascular repair is consistently greater than that of
      open repair, but the additional benefit is small-0.1 to 0.4 QALYs. For men in
      average health with gradually enlarging AAAs with initial diameters of 4 cm,
      endovascular surgery reduces the optimal threshold diameter by very little: from
      4.6 to 4.6 cm (no change) at age 60 years, from 4.8 to 4.7 cm at age 70 years,
      and from 5.1 to 4.9 cm at age 80 years. For older men in poor health,
      endovascular surgery reduces the optimal threshold diameter substantially (8.1 to
      5.7 cm at age 80 years), but the benefit of repair in this population is small
      (0.2 QALYs). CONCLUSION: For most patients, the indications for AAA repair are
      changed very little by the introduction of endovascular surgery. Only for older
      patients in poor health does endovascular surgery substantially lower the optimal
      threshold diameter for elective AAA repair.

PMID- 10359932
TI  - New duplex ultrasound scan criteria for managing symptomatic 50% or greater
      carotid stenosis.
AB  - PURPOSE: The North American Symptomatic Carotid Endarterectomy Trial (NASCET)
      showed that selected patients benefited from surgery when their carotid artery
      was 50% or more stenosed. This study assessed the accuracy of color-flow duplex
      ultrasound scanning (DUS) parameters to detect 50% or greater carotid artery
      stenosis and to determine the situations in which carotid endarterectomy (CEA)
      without angiography could be justified. METHODS: From March 1, 1995, to December
      1, 1995, all patients considered for CEA were studied with DUS and carotid
      angiography. Results of the two tests were blindly compared. DUS measurements of
      internal carotid artery (ICA) peak systolic velocity (PSV), end diastolic
      velocity, and ratio of the ICA to common carotid artery PSV (ICA/CCA) were
      subjected to receiver operator characteristic curve analysis to determine the
      most accurate criterion predicting 50% or greater angiographic stenosis. The
      criterion for identifying patients for CEA without angiography was selected from
      criteria with a high positive predictive value (PPV) and sensitivity. RESULTS: A
      total of 188 carotid bifurcations were available for comparison. A PSV (ICA/CCA)
      of 2 or higher was the most accurate criterion for detection of 50% or greater
      stenosis, with an accuracy rate of 93% (sensitivity, 96%; specificity, 89%; PPV,
      92%). A PSV (ICA/CCA) of 3.6 or higher was the best criterion for identifying
      candidates for CEA who had not undergone earlier angiography, with PPV,
      sensitivity, specificity, and accuracy rates of 98%, 77%, 98%, and 86%,
      respectively. CONCLUSION: These redefined criteria detect the NASCET-defined
      threshold level of 50% or greater ICA stenosis, above which CEA results in stroke
      reduction. A management algorithm based on these criteria should help to minimize
      both angiography and unnecessary intervention.

PMID- 10359933
TI  - Cerebral tomographic findings in patients undergoing carotid endarterectomy for
      asymptomatic carotid stenosis: short-term and long-term implications.
AB  - PURPOSE: Preoperative cerebral imaging has been considered not to be cost
      effective in carotid endarterectomy (CEA) for asymptomatic carotid stenosis. Yet,
      silent brain infarction (SBI) has been associated with the embolization potential
      of a severe carotid stenosis. Thus the presence of SBI may represent an
      additional indication for CEA in asymptomatic patients. We examined the
      predictive value of preoperatively detected silent cerebral lesions on early and
      late outcomes in patients undergoing CEA for asymptomatic carotid stenosis.
      METHODS: Preoperative cerebral tomographic (CT) scans performed on 301
      asymptomatic patients undergoing 346 CEAs from 1986 to 1995 were reviewed by a
      single neuroradiologist blinded to patients' records. Mean follow-up was 67. 3
      months (range, 24-130 months). The degree of internal carotid lumen reduction was
      measured bilaterally in all patients (602 carotid arteries); carotid stenosis of
      60% or more was found in 399 carotid arteries. RESULTS: Of the 103 (34%) CT scans
      positive for cerebral lesions, 58% were lacunar. No significant association was
      observed between the side of the cerebral lesion on CT scan and the severity of
      the corresponding carotid stenosis; 38 silent lesions were detected in the 203
      hemispheres ipsilateral to carotid stenoses that were less than 60% versus 95
      SBIs in the 399 hemispheres ipsilateral to carotid stenoses that were 60% or more
      (19% vs 24%; P =.2). There were no significant differences in the perioperative
      stroke/death rate in patients with or without cerebral CT lesions (2% vs 1%; odds
      ratio, 1.94; P =.6). Mortality rate during follow-up was 22% in patients with
      preoperative SBI and 15% in patients without SBI (P =.1). However, actuarial
      survival at 10 years was shorter (P =.02) in patients with SBI. Late stroke
      occurred in 11% of patients with preoperative SBI and in 3% of patients without
      preoperative SBI (P =.006). Cox regression analysis showed that both preoperative
      lacunar and nonlacunar infarctions were independent predictors of late stroke
      (hazard ratio, 3.6; P =.04; and hazard ratio, 7.1; P =.001; respectively).
      CONCLUSION: In our experience, preoperative SBI did not occur more frequently in
      the hemisphere ipsilateral to asymptomatic severe carotid stenosis. Although our
      study lacks a medically treated control group, our data show that SBI is
      predictive of poor neurologic outcome in asymptomatic patients undergoing CEA. We
      conclude that CT before CEA, selectively applied, provides information on long
      term neurologic prognosis and that a less aggressive attitude towards CEA in
      asymptomatic patients with SBI may be justified.

PMID- 10359934
TI  - Renal insufficiency and altered postoperative risk in carotid endarterectomy.
AB  - PURPOSE: Higher complication rates have been reported in patients with renal
      insufficiency (RI) undergoing peripheral vascular surgery. Little attention has
      been paid specifically to carotid endarterectomy (CEA) in patients with RI where
      the risk/benefit considerations are very sensitive to small increases in
      postoperative complications. METHODS: One thousand one consecutive CEAs performed
      since 1990 were reviewed from our vascular registry, and 73 CEAs on patients with
      RI were identified. For comparison, two groups were established: group I (n =
      928), normal renal function (creatinine level, <1.5 mg/dL); and group II (n =
      73), RI (creatinine level, >/=1.5 mg/dL). RESULTS: Differences in the nonfatal
      stroke rates and combined stroke and death rates were statistically significant
      (P <.02) between the groups: group I (1. 08% and 1.18%) and group II (5.56% and
      6.94%) respectively. Both groups were similar in regard to operative indications.
      In addition with the comparison of group I to group II, there was a statistically
      significant increase in hematoma rate, 1.61% versus 12. 5% ( P <.001), total
      cardiac morbidity, 1.72% versus 6.94% (P =.003), and total complications, 6.24%
      versus 36.1% (P =.001). Multivariate analysis demonstrated pre-existing RI to be
      the only significant predictor for perioperative stroke and hematoma. CONCLUSION:
      Patients with preoperative RI are at a higher, but not prohibitive, risk for
      stroke and death after CEA than patients with normal renal function. They are
      also at risk for hematoma formation, cardiac morbidity, and overall
      complications. Care in selection of these patients for CEA must be emphasized.

PMID- 10359935
TI  - Surgical renal artery reconstruction without contrast arteriography: the role of
      clinical profiling and magnetic resonance angiography.
AB  - PURPOSE: Contrast arteriography is the accepted gold standard for diagnosis and
      treatment planning in patients with atherosclerotic renovascular disease (RVD).
      In this study, the results of a selective policy of surgical renal artery
      reconstruction (RAR) with magnetic resonance angiography (MRA) as the sole
      preoperative imaging modality are reviewed. METHODS: From May 1993 to May 1998,
      25 patients underwent RAR after clinical evaluation, and aortic/renal MRA
      performed with a gadolinium-enhanced and 3-dimensional phase contrast technique.
      Clinical presentations suggested severe RVD in all patients and included poorly
      controlled hypertension (16 patients), hospitalization for hypertensive crises
      and/or acute pulmonary edema (13), and deterioration of renal function within one
      year of operation (15). Thirteen patients had associated aortic pathologic
      conditions (12 aneurysms, 1 aortoiliac occlusive disease), and eight of these
      patients also underwent noncontrast computed tomography scans. Significant renal
      dysfunction (serum creatinine level, >/=2.0 mg/dL) was present in all but 4
      patients with 14 of 25 patients having extreme (creatinine level, >/=3.0 mg/dL)
      dysfunction. RESULTS: Hemodynamically significant RVD in the main renal artery
      was verified at operation in 37 of 38 reconstructed main renal arteries (24/25
      patients). A single accessory renal artery was missed by MRA. RAR was
      comprehensive (bilateral or unilateral to a single-functioning kidney) in 21 of
      25 patients and consisted of hepatorenal bypass graft (3 patients), combined
      aortic and RAR (13 patients), isolated transaortic endarterectomy (8 patients),
      and aortorenal bypass graft (1 patient). Early improvement in both hypertension
      control and/or renal function was noted in 21 of 25 patients without operative
      deaths or postoperative renal failure. Sustained favorable functional results at
      follow-up, ranging from 5 months to 4 years, were noted in 19 of 25 patients.
      CONCLUSION: MRA is an adequate preoperative imaging modality in selected patients
      before RAR. This strategy is best applied in circumstances where the clinical
      presentation suggests hemodynamically significant bilateral RVD and/or in
      patients at substantial risk of complications from contrast angiography.

PMID- 10359936
TI  - Improved graft patency and altered remodeling in infrainguinal vein graft
      reconstruction for aneurysmal versus occlusive disease.
AB  - PURPOSE: This study attempted to determine whether autogenous vein used for
      infrainguinal reconstruction in patients with aneurysmal disease might
      demonstrate an altered adaptive response compared with those patients who
      underwent reconstructive surgery for occlusive disease, potentially altering
      graft patency. METHODS: From 1974 to 1997, 43 patients underwent vein grafting
      for 60 popliteal artery aneurysms (PAA). RESULTS: In an attempt to monitor early
      vein graft adaptation, serial graft surveillance by Duplex ultrasound scan was
      performed in a statistically valid subset of age-, sex-, and distal anastomotic
      site-matched patients with PAA and patients with occlusive disease (OD; n = 8
      PAA; n = 8 OD). Compared with an age-matched and sex-matched cohort of patients
      (n = 60 grafts in each group) with occlusive disease and who had femoral below
      knee bypass grafts (FBP) only, patients undergoing infrainguinal reconstruction
      for PAA had a higher 5-year primary graft patency (92% +/- 4% for PAA vs 66% +/-
      7% for FBP; P <.01). Duplex surveillance demonstrated a progressive increase in
      arterialized vein graft diameter in the PAA group versus the OD group. In
      univariant analysis, aneurysmal disease was a significant predictor of final
      follow-up diameter (P =.002). In a linear regression model, controlling for
      diameter at first follow-up after bypass grafting, first follow-up diameter was
      also predictive of final follow-up diameter. CONCLUSION: These data suggested
      altered remodeling of vein grafts in patients with popliteal artery aneurysm,
      which may have a beneficial effect on patency.

PMID- 10359937
TI  - Thrombospondin-1 induces activation of focal adhesion kinase in vascular smooth
      muscle cells.
AB  - PURPOSE: Vascular smooth muscle cell (VSMC) proliferation and migration are
      important events in the development of intimal hyperplasia. Thrombospondin-1 (TSP
      1), an extracellular matrix protein present in intimal hyperplastic lesions, has
      been shown to stimulate VSMC proliferation and migration. We hypothesized that
      the focal adhesion plaque, specifically the focal adhesion kinase (FAK) protein,
      may be important in the signal transduction pathway for TSP-1-induced VSMC
      migration. METHODS: Growth-arrested bovine aortic VSMCs were treated with TSP-1
      (20 microg/mL) for set intervals (15, 30, and 120 minutes) and compared with
      VSMCs grown in serum-free medium (negative control) or in the presence of a known
      mitogen and chemotactic factor, platelet-derived growth factor (10 ng/mL;
      positive control). Crude cell lysates and anti-FAK immunoprecipitates were
      assayed for phosphotyrosine activity by means of antiphosphotyrosine
      immunoblotting. The blots were quantified by means of densitometric analysis.
      RESULTS: TSP-1 increased tyrosine phosphorylation of three protein bands of
      molecular weights 68, 125 (consistent with FAK), and 180 kDa. Immunoprecipitation
      with FAK antibody, followed by antiphosphotyrosine immunoblotting, indicated that
      there was an increase in tyrosine phosphorylation of FAK at 15, 30, and 120
      minutes in the TSP-1-treated groups (P <.05). CONCLUSION: Tyrosine
      phosphorylation of FAK is induced by TSP-1 stimulated VSMCs. This suggests an
      outside-inside signaling pathway by which TSP-1 stimulates VSMC migration.

PMID- 10359938
TI  - Long-term outcome of surgical revascularization in ischemic nephropathy:
      normalization of average decline in renal function.
AB  - OBJECTIVE: Renovascular disease may lead to ischemia of the nephrons and to
      fibrosis, which is generally considered to be irreversible and progressive. We
      investigated the potential of revascularization to recover and stabilize renal
      function in patients with ischemic nephropathy. METHODS: In a retrospective
      analysis of all our 61 patients with ischemic nephropathy who underwent treatment
      with surgical revascularization, we determined the long-term course of renal
      function decline with an estimated glomerular filtration rate (EGFR; Cockcroft
      and Gault formula). With the assumption of normal renal function at age 25 years,
      the preoperative slope of EGFR and the postoperative slope of EGFR were
      determined from the EGFR before surgery, at the short-term follow-up examination
      (on average, 8 months after surgery), and at the long-term follow-up examination
      (on average, at 47 months after surgery). These declines in renal function were
      compared with EGFR values in age-matched and sex-matched samples from a large
      cross-sectional population study. RESULTS: The overall surgical mortality rate
      amounted to 13.1%. Five patients became dialysis dependent-two with preexisting
      end-stage renal disease and three at later follow-up examination-and two
      patients, who before surgery were dialysis dependent, could be withdrawn from
      dialysis treatment. Shortly after the operation, the mean EGFR level had
      increased from 28.3 to 43.1 mL/min/1.73 m2 ( P <. 01). The rate of decline in
      renal function had decreased from an estimated -2.57 mL/min/1.73 m2/year before
      surgery (weighted mean: interquartile range, -2.71 to -1.98) to -0.66 mL/min/1.73
      m2/year (weighted mean: interquartile range, -2.00 to -0.18) in the short-term
      interval to the long-term interval, which was even slightly better than the slope
      of -0.84 mL/min/1.73 m 2/year in the age-matched and sex-matched control
      population. CONCLUSION: Surgical revascularization in selected patients with
      renovascular disease and ischemic nephropathy restores renal function and makes
      the average long-term rate of decline in renal function equal to that of the
      general population. This indicates that in most patients a "point-of-no-return"
      has not yet been passed even though their renal function is already markedly
      impaired before surgery. Therefore, in well-selected patients with ischemic
      nephropathy, considerable improvement of renal function can be realized.

PMID- 10359939
TI  - Axillary vein transfer in trabeculated postthrombotic veins.
AB  - PURPOSE: This study assessed whether axillary vein transfer can be successfully
      performed in trabeculated veins and whether patients with this severe form of
      postthrombotic syndrome can be helped by an aggressive approach. METHODS: A total
      of 102 axillary vein transfer procedures were carried out in 83 limbs with
      trabeculated veins. More than one venous segment was repaired in 38 limbs with a
      second axillary valve in 19, and a different technique was used in the remainder.
      The superficial and deep femoral veins were the most common target sites. "Bench
      repair" of leaky axillary valves was performed before the transfer in 32 cases.
      Venous stasis dermatitis or ulceration was present in 90% of the limbs. The
      operability rate and chance of successful valve reconstruction was high, even in
      the presence of severe venographic appearance. RESULTS: The actuarial transplant
      patency rate was 83% at 10 years. The actuarial freedom from recurrent ulceration
      rate was more than 60% at 10 years, similar to the results obtained in a matched
      group of axillary vein transfers to nontrabeculated veins. Severe preoperative
      ambulatory venous hypertension (venous filling time [VFT] of less than 5
      seconds), which was present in 67% of patients, did not adversely affect outcome,
      but short VFTs that persisted after surgery did. VFT and VFI90 (venous filling
      index, air plethysmography) improved after valve transfer. Swelling disappeared
      or was significantly reduced in 55% of patients (11 of 20 patients) who had
      moderate or severe preoperative swelling. In 82% of patients (31 of 37 patients)
      who had mild or no preoperative swelling, the swelling remained stable after
      surgery, and in 18% of patients (6 of 37 patients), it became worse. Pain was
      significantly diminished in 70% of patients; 23% of patients with severe pain had
      complete resolution. CONCLUSION: Axillary vein transfer, in combination with
      other antirefluxive procedures when indicated, is safe, effective, and durable in
      patients with trabeculated veins and severe forms of postthrombotic syndrome. It
      may be considered as an option when conservative therapy or other types of
      surgery fail.

PMID- 10359940
TI  - Lower limb deep venous flow in patients with peripheral vascular disease.
AB  - PURPOSE: A prospective controlled study was undertaken to determine how
      peripheral vascular disease (PVD) influences flow in the deep veins of the leg.
      METHODS: Eighty-nine patients with peripheral vascular disease and 35 age-matched
      control subjects were studied. The popliteal vein diameter and flow velocity were
      measured at rest by means of color duplex ultrasound scanning, and these
      measurements were compared with the ankle-brachial pressure index. For 23
      subjects, measurements were also performed during reactive hyperemia and then
      repeated after venous return from the foot was prevented by an ankle cuff.
      RESULTS: There was a significant correlation between the ankle-brachial pressure
      index and the popliteal vein diameter (r = 0.35, P <.001) but a negative
      correlation between the ankle-brachial pressure index and venous flow velocity
      among patients with PVD (r = -0.24, P =.002). In PVD patients the diameter
      decreased further in reactive hyperemia, whereas it increased in control subjects
      ( P <.001). Preventing venous return from the foot in PVD patients led to
      diameter increase at rest and abolished the reduction in diameter caused by
      reactive hyperemia. Despite the reduction in diameter during reactive hyperemia,
      flow velocity increased less in patients with PVD than it did in control subjects
      (P =.01). CONCLUSION: Chronic tissue ischemia results in constriction of the
      popliteal vein. This appears to be an active process related to the washout of
      humoral factors from ischemic tissues distally, which leads to an increase in
      flow velocity. The latter may confer some protection against the deep vein
      thrombosis that would otherwise tend to occur with low venous flow rates.

PMID- 10359941
TI  - The postthrombotic syndrome in relation to venous hemodynamics, as measured by
      means of duplex scanning and strain-gauge plethysmography.
AB  - PURPOSE: Venous hemodynamics were evaluated in relation to the postthrombotic
      syndrome (PTS) 7 to 13 years after deep venous thrombosis (DVT). METHODS: The
      presence of flow, reflux, and compressibility of 1394 vein segments in 82
      patients was assessed by means of duplex scanning. The venous outflow resistance
      was measured by means of strain-gauge plethysmography. The venous hemodynamics
      were related to the clinical severity of the PTS, characterized by the CEAP
      (clinical, etiologic, anatomic, pathophysiologic) classification. RESULTS: In
      patients with severe clinical symptoms of PTS, the prevalence of reflux was
      significantly higher. There was no relationship between the severity of the PTS
      and the noncompressibility or the combination of reflux and noncompressibility or
      an increased venous resistance. By means of multiple regression analysis with the
      variables of age, gender, reflux, and venous resistance, age and reflux were
      shown to be the main contributors to the severity of PTS. Significantly more
      patients (64%) with severe signs of PTS had a combination of deep and superficial
      reflux. In each of the traceable vein segments, the mean of the CEAP
      classification was calculated for the vein segments with and without reflux. In
      the proximal superficial femoral vein (P <.001), distal superficial femoral vein
      (P <.05), and popliteal vein (P <.05), a significantly higher mean CEAP
      classification was found in the veins with reflux, whereas in the distal, long,
      and short saphenous veins, no such relationship was found. CONCLUSION: Most
      patients with severe PTS had a combination of deep and superficial reflux. Reflux
      in the deep proximal veins contributes significantly to the PTS.

PMID- 10359942
TI  - Effect of exercise on hemodynamic conditions in the abdominal aorta.
AB  - PURPOSE: The beneficial effect of exercise in the retardation of the progression
      of cardiovascular disease is hypothesized to be caused, at least in part, by the
      elimination of adverse hemodynamic conditions, including flow recirculation and
      low wall shear stress. In vitro and in vivo investigations have provided
      qualitative and limited quantitative information on flow patterns in the
      abdominal aorta and on the effect of exercise on the elimination of adverse
      hemodynamic conditions. We used computational fluid mechanics methods to examine
      the effects of simulated exercise on hemodynamic conditions in an idealized model
      of the human abdominal aorta. METHODS: A three-dimensional computer model of a
      healthy human abdominal aorta was created to simulate pulsatile aortic blood flow
      under conditions of rest and graded exercise. Flow velocity patterns and wall
      shear stress were computed in the lesion-prone infrarenal aorta, and the effects
      of exercise were determined. RESULTS: A recirculation zone was observed to form
      along the posterior wall of the aorta immediately distal to the renal vessels
      under resting conditions. Low time-averaged wall shear stress was present in this
      location, along the posterior wall opposite the superior mesenteric artery and
      along the anterior wall between the superior and inferior mesenteric arteries.
      Shear stress temporal oscillations, as measured with an oscillatory shear index,
      were elevated in these regions. Under simulated light exercise conditions, a
      region of low wall shear stress and high oscillatory shear index remained along
      the posterior wall immediately distal to the renal arteries. Under simulated
      moderate exercise conditions, all the regions of low wall shear stress and high
      oscillatory shear index were eliminated. CONCLUSION: This numeric investigation
      provided detailed quantitative data on the effect of exercise on hemodynamic
      conditions in the abdominal aorta. Our results indicated that moderate levels of
      lower limb exercise are necessary to eliminate the flow reversal and regions of
      low wall shear stress in the abdominal aorta that exist under resting conditions.
      The lack of flow reversal and increased wall shear stress during exercise suggest
      a mechanism by which exercise may promote arterial health, namely with the
      elimination of adverse hemodynamic conditions.

PMID- 10359943
TI  - Bacterial resistance of refrigerated and cryopreserved aortic allografts in an
      experimental virulent infection model.
AB  - PURPOSE: The bacterial resistance of refrigerated and cryopreserved aortic
      allografts in a highly virulent infection in a dog model was studied. METHODS:
      The infrarenal aorta of 12 dogs was replaced with either a cryopreserved aortic
      allograft (group I, n = 6) or a refrigerated aortic allograft (group II, n = 6)
      in infected sites. Allografts were harvested from dogs and stored for 1 week,
      either by cryopreservation (-140 degrees C) or refrigerated method (4 degrees C),
      in a preservation medium. At the time of implantation, induction of infection was
      achieved with an infected piece of knitted Dacron placed just beneath the
      allograft. The Dacron was contaminated in vitro by soaking it in a solution with
      Staphylococcus aureus PR209. All 12 dogs received no adjunct antibiotic or
      antithrombotic therapy. Four weeks after implantation, the animals were killed to
      recover the grafts for bacteriological and histological analyses. Bacterial
      results were expressed as colony-forming units (CFU)/cm2 of graft material.
      RESULTS: In group I, only one allograft grew bacteria at 2. 16 x 10(6 )CFU/cm2,
      with a blood culture positive for S aureus. In group II, one dog died at 3 weeks
      from a false septic aneurysm rupture, all the allografts were infected (P <.05)
      with a mean bacterial count of 9.41 +/- 6.8 x 10(4) CFU/cm2, and three blood
      cultures were positive for S aureus. The patency of the grafts was analyzed at
      the time of recovery. Three laminar thrombi without occlusion were present in
      group I; none were present in group II. A better preserved endothelium in group I
      was revealed by means of histologic analysis staining with factor VIII antibody
      before implantation. After 4 weeks of implantation in the infected site, infected
      allografts presented polynuclear infiltrates in the media with a high degree of
      inflammatory reaction, and endothelial recovery was more significant in group I,
      with numerous young plump cells. CONCLUSION: This study demonstrates that
      cryopreserved allografts implanted in infected sites in a dog model can produce
      greater bacterial resistance.

PMID- 10359944
TI  - Propionyl-L-carnitine dilates human subcutaneous arteries through an endothelium
      dependent mechanism.
AB  - PURPOSE: The vasoactive effects of propionyl-L-carnitine (PLC) on human arteries,
      including endothelial and smooth muscle cell influences, were studied. METHODS:
      Small (less than 200 microm) subcutaneous fat arteries (n = 19), obtained from
      human patients undergoing vascular surgery, were dissected and mounted in an
      arteriograph system that allowed measurement of lumen diameter and control of
      transmural pressure. To investigate the role of the endothelium, arteries were
      compared intact, intact and in the presence of either 0.3 mmol/L nitro-L-arginine
      (an inhibitor of nitric oxide synthesis) or 10 micromol/L indomethacin (an
      inhibitor of prostaglandin synthesis), or denuded of endothelium. After a 1-hour
      equilibration at a pressure of 50 mm Hg, arteries were precontracted 50% with an
      intermediate concentration of norepinephrine, and clinically relevant
      concentrations of PLC (0.1 to 100 micromol/L) were cumulatively added to the bath
      while the lumen diameter was continually measured. RESULTS: Intact arteries dose
      dependently dilated to PLC, with the half maximal dilation occurring at 2.9 +/-
      1.2 micromol/L, increasing diameter 91% +/- 5% at 100 micromol/L. In contrast,
      PLC had significantly less effect on deendothelialized arteries, increasing
      diameter only 24% +/- 11% at 100 micromol/L (P <.01 vs. intact). This indicates
      the endothelial dependency of this compound. Blockade of nitric oxide did not
      inhibit this vasodilation, with the half-maximal response occurring at 8.6 +/- 7
      micromol/L, increasing diameter 85% +/- 8% at 100 micromol/L ( P >.05 vs.
      intact). However, this vasodilation was significantly diminished in the presence
      of indomethacin, which dilated arteries only 53% +/- 18% at 100 micromol/L (P
      <.01 vs. intact; P >.05 vs. denuded). CONCLUSION: PLC is an endothelium-dependent
      vasodilator, the mechanism of which is partially mediated by prostaglandin
      synthesis, not nitric oxide. The beneficial effects of this compound may, in
      part, be related to vasodilation and enhanced blood flow.

PMID- 10359945
TI  - Special communicationthe critical role of mechanical forces in blood vessel
      development, physiology and pathology
AB  - The following extended abstracts were presented at the Research Initiatives in
      Vascular Disease Conference, Movers and Shakers in the Vascular Tree-Hemodynamic
      and Biomechanical Factors in Blood Vessel Pathology, sponsored by The Lifeline
      Foundation and the Cardiovascular & Interventional Radiology Research and
      Educational Foundation; jointly sponsored by the International Society for
      Cardiovascular Surgery, North American Chapter, The Society for Vascular Surgery,
      and The Society of Cardiovascular and Interventional Radiology; in cooperation
      with the National Institutes of Health-National Heart, Lung &Blood Institute on
      Mar 11-12, 1999, in Bethesda, Md.

PMID- 10359946
TI  - Periprosthetic leak and rupture after endovascular repair of abdominal aortic
      aneurysm: the significance of device design for long-term results.
AB  - We present a case of abdominal aortic aneurysm treated with an endovascular
      bifurcated aortic graft in which a periprosthetic leak caused by a tear in the
      polyester prosthesis appeared between 9 and 12 months after surgery. The tear
      appeared adjacent to a suture breakage that caused separation of two struts of
      the nitinol wire framework in the body of the stent graft. The leak was sealed
      with insertion of a new endovascular tube graft into the body of the bifurcation.
      Eight months later, the patient had a nonfatal rupture of the abdominal aortic
      aneurysm because detachment of the second limb from the bifurcation caused a new
      major periprosthetic leak. According to the manufacturer of this device, suture
      breakage with separation of metal components is commonly seen, but perforation of
      the polyester prosthesis caused by movement of the metal stent against the fabric
      has not been reported. It is likely that this occurred in our patient. Detachment
      of the second limb from the bifurcated stent, causing a rupture, has been
      described before. Increasing angulation and tortuosity of the stent graft, as a
      result of either remodeling of the sac or elongation of the stent, and reduced
      compliance to angulation after the stent-in-stent procedure might have
      contributed to the detachment in this case.

PMID- 10359947
TI  - Vascular reconstruction utilizing artery from an amputated extremity: A case
      report.
AB  - Although infrainguinal arterial reconstruction is best performed with autologous
      tissue, reconstruction with vein in an infected field has been associated with
      vein graft disruption and hemorrhage. H.P., a 61-year-old man with peripheral
      vascular disease, was initially seen with an infected prosthetic right femoral
      tibioperoneal artery bypass graft. Because of the presence of purulent drainage
      from the proximal and distal anastomotic regions and his comorbidities, a right
      through-knee guillotine amputation was performed, followed by graft excision and
      groin debridement. Right hip and thigh perfusion was preserved via arterial
      reconstruction by using a segment of endarterectomized popliteal artery,
      harvested from the amputated extremity. Arterial reconstruction with autologous
      tissue from an amputated extremity allowed us to balance our patient's overall
      risks with life and tissue preservation. This technique may be applied in the
      settings of lower extremity ischemia, trauma, or malignancy requiring concomitant
      arterial or venous reconstruction.

PMID- 10359948
TI  - Superior mesenteric artery syndrome as a result of enlarged abdominal aortic
      aneurysm.

PMID- 10359950
TI  - Problems with the dissemination of up-to-date information on the results of
      endograft repair for abdominal aortic aneurysm.

PMID- 10359951
TI  - William J. von liebig 1923-1999

PMID- 10359949
TI  - The limits of endovascular aortic aneurysm repair.

PMID- 10359952
TI  - Management of Urinary Tract Infections in the Adolescent Male.
AB  - Although urinary tract infections are uncommon in adolescent boys, they are
      easily treated. The author chronicles the management of UTIs with concise
      descriptions of their history, pathophysiology, epidemiology, symptoms and signs,
      laboratory tests, diagnostic problems, treatment, and prognosis. Costs of
      antibiotics for UTIs are compared.

PMID- 10359953
TI  - Sexual Dysfunction and the Primary Care Physician.
AB  - In addition to discussing the epidemiology and pathophysiology of sexual
      dysfunction, this comprehensive review addresses a host of chronic illnesses,
      including spinal cord injuries and endocrine, cardiopulmonary, hemato-oncologic,
      neurologic, nephrologic, rheumatologic, and orthopedic disorders. Subjects the
      physician should cover when taking the medical history and physical examination
      are detailed.

PMID- 10359954
TI  - Experiences with a Clinic for Young Men.
AB  - The authors argue the case for every college campus having a men's clinic that
      can address concerns of the late adolescent and function as more than "a sexually
      transmitted disease clinic by some other name." Case examples describe situations
      that physicians in such clinics can expect to encounter.

PMID- 10359955
TI  - Bladder Dysfunction Syndromes.
AB  - A discussion of normal voiding and urodynamic testing for bladder dysfunction is
      followed by a description of the causes, clinical features, and treatment of
      voiding disorders including unstable bladder, enuresis, Hinman's syndrome,
      bladder neck dysfunction, low pressure and low flow, and prostatodynia.

PMID- 10359956
TI  - Ectoparasitic Infestation.
AB  - The author considers the two primary ectoparasitic infections of the genital
      region in young men: scabies and pediculosis pubis. In view of the widely held
      perception that poor hygiene is associated with these parasites, the need for
      attention to the patient's emotional state is stressed.

PMID- 10359957
TI  - Molluscum Contagiosum.
AB  - Molluscum contagiosum is described as an easily treated benign viral disease of
      the skin. Treatments detailed include cryosurgery and curettage-the treatments of
      choice-and podophyllotoxin and tretinoin. History and virology also are outlined.

PMID- 10359958
TI  - Nongonococcal Urethritis: Diagnosis, Management, and Complications.
AB  - Topics covered here include the role of noninfectious and common and uncommon
      infectious agents in the development of nongonococcal urethritis; the relative
      usefulness of a variety of laboratory tests for organisms such as Chlamydia
      trachomatis and Neisseria gonorrhoeae; and complications including acute
      epididymitis, prostatitis, and Reiter's syndrome.

PMID- 10359959
TI  - Gonococcal Infection in the Adolescent Male.
AB  - Although the incidence of gonorrhea steadily declined in the United States for
      two decades, a reversal in the trend has begun. Clinical presentation, diagnosis,
      treatment, and prevention are outlined in an attempt to reacquaint physicians
      with this centuries-old infection.

PMID- 10359961
TI  - Human Papillomavirus Infection.
AB  - Condyloma acuminata, the anogenital expression of human papillomavirus commonly
      called genital warts, is the focus here. Of particular emphasis is HPV's
      association with genital cancer. The use of androscopy for the examination and
      treatment with cryotherapy, podophyllin, trichloroacetic acid, and 5-fluorouracil
      also are assessed.

PMID- 10359960
TI  - Herpes, Syphilis, and Other Ulcerogenital Conditions.
AB  - This well-illustrated overview of herpes simplex virus infection, syphilis, and
      chancroid focuses on history, biology, pathophysiology, epidemiology, natural
      history, signs and symptoms, laboratory tests, and diagnostic problems.
      Clinicians are reminded of the high correlation between genital ulcer disease and
      infection with the human immunodeficiency virus.

PMID- 10359962
TI  - Benign Scrotal Masses in the Adolescent Male: Varicoceles, Spermatoceles, and
      Hydroceles.
AB  - Because scrotal masses may be a source of embarrassment for adolescents concerned
      about fertility and sexual prowess, supportive counseling should be included in
      treatment. The authors summarize the history, pathophysiology, epidemiology,
      natural history, signs and symptoms, laboratory tests, diagnostic problems,
      treatment, and prognosis of these masses.

PMID- 10359963
TI  - Testicular Trauma.
AB  - This chapter stresses the importance of prompt diagnostic staging and management
      of testicular trauma to preserve testicular function. Types of injuries are
      described, as well as the role of the physical examination, radiographic studies,
      and operative and conservative treatment.

PMID- 10359964
TI  - Testicular Tumors.
AB  - The prognosis for testicular tumors has greatly improved along with advances in
      imaging, chemotherapy, and surgical techniques. Factors examined include
      epidemiology, causes of tumors, histologic classification, diagnosis, staging,
      and management.

PMID- 10359965
TI  - School-Based Services and Adolescent Health: Past, Present, and Future.
AB  - Health programs were introduced into schools approximately 100 years ago. Since
      that time, changes in school health programs and philosophies have been
      influenced by trends in the fields of both education and health care. This
      article describes the beginnings of school health in the United States, suggests
      the varying roles health and education have played in the evolution of its
      character, outlines the philosophical and political underpinnings of the system,
      and identifies three perspectives on school health as it is conceptualized and
      practiced in the 1990s.

PMID- 10359966
TI  - Comprehensive School-Based Health Centers: Implementing the Model.
AB  - Increasing numbers of school health centers are being established nationwide as a
      means of easing access to and increasing utilization of primary health care
      services for high-risk youth. The multiple issues involved in establishing and
      maintaining a school-based health center are presented. The authors discuss the
      steps necessary to assess student needs and build community support, develop the
      plan for delivery of school-based primary care, implement the school-based health
      center model, and evaluate the health center program.

PMID- 10359967
TI  - School-Based Primary Care in a Managed Care Environment: Options and Issues.
AB  - As school-based health centers have established a track record in providing
      access to primary care services for underserved school-age populations, financial
      viability of these programs has become increasingly dependent upon revenues
      generated from Medicaid and other third-party payers. The introduction of managed
      care concepts into this situation has created great uncertainty for the future.
      The authors discuss the various types of managed care models that school-based
      health centers are being called upon to work with and summarize the key issues
      (communications, confidentiality, linkages, reimbursement, and quality
      improvement) around which those relationships are being developed.

PMID- 10359968
TI  - Research and Evaluation in School-Based Health Care.
AB  - With the rapid growth of school-based health centers has come a challenge to
      produce evidence that they are having an effect on the health and lives of the
      students they serve. The authors discuss the sources of data that are currently
      in place to assess the effects of school-based programs, present findings from
      these sources, address the problems of conducting research and evaluation in
      school settings, and present ideas about future data collection and research
      studies.

PMID- 10359969
TI  - Issues and Opportunities in the Middle School Years: Implementation of the
      Turning Points Recommendations.
AB  - Educational reforms intended to improve the learning and social environment for
      middle school students are now under way. These are aimed at making junior high
      schools student-centered, interdisciplinary, and flexible. The author reviews
      what has been learned from several major projects undertaken to accomplish middle
      school reform, presents examples from communities that are successfully
      implementing these reforms, and concludes with a series of guidelines that can be
      used by those interested in enhancing the experience of middle school students.

PMID- 10359970
TI  - Health Care in College.
AB  - Where college health services were once medical offices focused solely on
      treating disease, these services now are integrated into the mission of the
      academic village as accountable, responsible, and authoritative partners in the
      educational enterprise. In this article, the author discusses up-to-date issues
      in the management of college health services, the medical and mental health care
      provided, the special care offered to international students, the research and
      training performed at these health services, and the interdepartmental and
      coordination issues involved in providing college health care.

PMID- 10359972
TI  - Can School-Based Health Services Reduce Absenteeism and Dropping Out of School?
AB  - Studies have shown that a high school diploma, and preferably some post-high
      school education, is essential to economic success for most individuals in
      American society today. With large numbers of adolescents having excessive
      absenteeism or dropping out of school, programs are being developed to address
      these issues. The author examines what is known about the impact of health on
      absenteeism and dropping out, and the effects of programs that have tried to
      address these problems.

PMID- 10359971
TI  - Evaluation and Management of Learning Difficulties.
AB  - The "adolescent with learning difficulties" is a descriptive label that can refer
      to many different problems and causes for these problems. These can include
      specific learning disorders, attention-deficit hyperactivity disorders, other
      types of psychiatric disorders, reactions to stressful experiences, the result of
      temporary crises in development, or any combination of these. This article
      addresses causal factors, definitions, assessment, and treatment of learning
      difficulties in adolescents.

PMID- 10359974
TI  - Roles and Responsibilities of School Nurses and Physicians in Adolescent School
      Health Programs.
AB  - Studies indicate that more than 60% of all junior and senior high schools have at
      least one nurse providing school health services, whereas more than 30% include
      physicians in their health care programs. The diverse roles played by nurses and
      physicians in school health care are reviewed, with an emphasis on guidelines
      developed by the National Association of School Nurses and positions promulgated
      by the American Academy of Pediatrics.

PMID- 10359973
TI  - Comprehensive School Health.
AB  - The Division of Adolescent and School Health of the Centers for Disease Control
      and Prevention has developed a model for comprehensive school health programs
      which consists of eight components that allow for collaboration among health care
      providers, educators, community groups, and other professionals concerned about
      the well-being of adolescents. This article presents the overall comprehensive
      school health program and offers strategies for health care practitioners who are
      interested in collaborating with school personnel and community members
      responsible for the eight components of the program.

PMID- 10359975
TI  - School-Based Nutrition Education Programs and Services for Adolescents.
AB  - School-based nutrition education programs and services can offer a systematic and
      efficient venue for promoting health-enhancing eating behaviors among youth. This
      article reviews priority nutrition concerns of adolescents; guidelines for
      healthful eating; and plans of action schools can take to improve nutritional
      health of students, including an integrated model for comprehensive school-based
      nutrition education consisting of eight interrelated components.

PMID- 10359976
TI  - Mental Health in the Schools: Promising Directions for Practice.
AB  - Discontent with the state-of-the-art of mental health services being provided in
      schools has led to fundamental shifts in thinking about these services. This
      article reviews existing programs and highlights emerging trends in school mental
      health services. The authors demonstrate how mental health programs are changing
      from narrowly focused to comprehensive, from fragmented to coordinated, from
      problem-specific to cross-disciplinary, and from being supplementary services in
      the school to essential components that enable learning.

PMID- 10359978
TI  - A Change in Diagnosis of Abdominal Pain.
AB  - A 17-year-old female was admitted to the hospital with symptoms of right-sided
      abdominal and flank pain, slight dysuria, and tactile temperature. Her
      presumptive diagnosis was pyelonephritis. She weighed 73.5 kg and had had a
      previous normal pregnancy. Pathology revealed multiple yellow calculi with
      thickened wall of the gallbladder, consistent with chronic pyelonephritis. She
      continued to have intermittent symptoms and underwent laparoscopic
      cholecystectomy 2 months after admission.

PMID- 10359977
TI  - Searching for Clues to Fever of Unknown Origin.
AB  - A 13-year-old adolescent girl of Greek descent presented with fever of unknown
      origin and arthralgias of wrists and ankles 3 weeks following vacationing in
      Greece. On the initial physical examination there were no signs of arthritis and
      the neurologic signs were normal. On the outpatient follow-up, fever and
      arthralgia persisted and pedal pulses were absent. Magnetic resonance angiography
      (MRA) showed irregular narrowing of the iliac arteries. The diagnosis of
      Takayasu's arteritis was made and the symptoms improved rapidly with prednisone.

PMID- 10359979
TI  - Chest Pain, Cough, and Hemoptysis.
AB  - An 18-year-old male presented with a 2-day history of left-side anterior chest
      pain. The pain was intermittent, crampy, and worsened with exertion. Associated
      symptoms were cough with sputum, night sweats, fever, decreased appetite, and 4.5
      kg weight loss; cavitary lesions were seen on chest radiograph. The patient also
      had significant dental caries. Nasal biopsy revealed findings consistent with
      Wegener's granulomatosis. Combined treatment with cyclophosphamide and prednisone
      significantly improved his symptoms over the long term.

PMID- 10359980
TI  - Distortions of Space and Time.
AB  - A 15-year-old male was referred for evaluation of dizziness for the past 2
      months. He complained of visual distortion and feeling of disorientation, was a
      poor student, and denied recreational drug use. His symptoms were consistent with
      the so-called "Alice in Wonderland" syndrome associated with Epstein-Barr virus
      infection. This case is an illustration of neurologic symptoms appearing without
      the features of infectious mononucleosis.

PMID- 10359981
TI  - Acute Muscle Pain in an Adolescent Athlete.
AB  - An 18-year-old female athlete presented with severe, incapacitating pain in both
      thighs, inability to walk, loss of bladder control, and brown urine following a
      strenuous soccer practice 3 days earlier. Physical examination revealed exquisite
      tenderness in each quadriceps, and her urine was positive for blood, protein, and
      myoglobin. Upon hospital admission, extracorporeal hemodyalisis was carried out
      every other day for 3 weeks and her renal function gradually returned to normal.
      Enzyme assays of a muscle biopsy eventually revealed a type 2 carnitine
      palmitoyltransferase deficiency (CPTD 2).

PMID- 10359982
TI  - Periodic Abdominal Pain: Response to NSAIDs Hides the Diagnosis.
AB  - A 17-year-old African-American patient presented to the emergency department with
      acute onset of severe, constant, lower abdominal pain that radiated to the lower
      back. The only associated symptom was nausea. She has been taking ibuprofen for a
      previously diagnosed chronic dysmenorrhea and had had good response to therapy.
      Rectovaginal examination revealed a tender mass in the cul de sac. Pelvic
      ultrasound led to the presumptive diagnosis of endometriomas, but could not
      exclude ovarian neoplasms. Urgent surgery revealed both left and right 3 x 6 cm
      ovarian cysts containing red to brown fluid, consistent with endometriomas.
      Postoperative course was uncomplicated.

PMID- 10359983
TI  - Generalized Weakness.
AB  - A 16-year-old female presented with weakness that began about 2 weeks earlier and
      has become progressively worse. It was accompanied by occasional dizziness and
      two brief episodes of syncope. Her history was remarkable for self-induced
      vomiting in order to lose weight. Her obvious diagnosis was bulimia nervosa, but
      it was further complicated by abnormal unexplained weakness. Upon careful
      questioning, she admitted using ipecac to induce vomiting for the past several
      weeks. She was placed on a strict eating disorder protocol combined with careful
      cardiac monitoring and her weakness eventually resolved.

PMID- 10359984
TI  - Another Positive Pregnancy Test.
AB  - A 16-year-old female presented to an emergency department with complaints of
      nausea and vomiting, dehydration, increasing weakness, and resting tremor. The
      past history included mild exercise-induced asthma. She denied sexual activity,
      but a urine test for beta-human chorionic gonadotropin was positive and she was
      transferred to a gynecology service for management of pregnancy. She also had
      primary amenorrhea and delayed growth for age. Further complaints included
      headaches accompanied with worsening of visual activity. Pelvic ultrasound
      revealed no intrauterine or ectopic pregnancy. Head CT scan showed a suprasellar
      tumor, better defined on an MRI as a hypothalamic tumor. Pathology following
      partial tumor resection revealed a mixed germ cell tumor with negative metastatic
      work-up.

PMID- 10359985
TI  - A Sleepy, Hungry Teenager.
AB  - A 16-year-old male was admitted for repeated episodes of hypersomnia,
      hyperphagia, and abnormal behavior, the first of which was preceded by alcohol
      and marijuana use. He was started on lithium therapy and lethargy and hyperphagia
      gradually improved, although he remained oppositional and irritable. After
      careful evaluation, his symptoms were concluded to meet Critchley's criteria for
      the diagnosis of Klein-Levin syndrome, which was supported by his response to
      prophylactic use of lithium.

PMID- 10359986
TI  - Lateral Neck Mass in an Adolescent Athlete.
AB  - A 17-year-old African-American athlete presented with complaints of allergies. He
      had a history of seasonal allergic rhinitis and otorrhea for many years, but this
      time it was accompanied by right-sided neck swelling. His right
      sternocleidomastoid was slightly enlarged, soft, nontender, and no discrete
      masses were palpable. He was active in shot-put and was right-handed. Following
      discharge with antihistamine therapy, he returned a month later with a visible
      enlargement of the right lateral neck and bilateral cervical adenopathy. The
      biopsy of the nasopharyngeal mass revealed an undifferentiated squamous
      nasopharyngeal carcinoma, staged at T2N3MX. Chemotherapy followed by radiation
      was recommended.

PMID- 10359987
TI  - Postprandial Vomiting and Abdominal Pain.
AB  - A 14-year-old Asian female presented with complaints of abdominal pain that was
      intermittent, crampy, periumbilical, without radiation, and aggravated by eating.
      She had been vomiting "green-colored" material 4 days earlier, after meals,
      associated with abdominal pain. On hospital day 3, after no improvement was
      noted, an upper GI series demonstrated an obstruction at the third portion of the
      duodenum. She was evaluated for an eating disorder, but further history failed to
      elicit diagnostic criteria. She responded favorably to total parenteral nutrition
      and symptoms were relieved with changes in position. Her symptoms and diagnostic
      studies were consistent with the diagnosis of superior mesenteric artery (SMA)
      syndrome.

PMID- 10359988
TI  - Who Is the Customer?
AB  - A 14-year-old girl was diagnosed at age 6 with type 1 diabetes mellitus. Both of
      her parents have been actively involved in her diabetic management. She recently
      gained 5.8 kg. At the time of presentation she was 174.2 cm tall and weighed 73.9
      kg. While she was only moderately concerned about her recent weight gain, both
      her parents showed much more concern about her weight than about her blood sugar
      and vehemently objected to their daughter being interviewed separately, so that
      it became important to establish who the primary requester of treatment was. A
      very careful and delicate approach was chosen in which the adolescent was
      recommended to develop a regular exercise and eating regimen with participation
      and support of her parents.

PMID- 10359989
TI  - Fever, Adenopathy, Thrush, and a Negative HIV Antibody Test.
AB  - A 21-year-old male presented with a 1-month history of fever, diarrhea, fatigue,
      sore throat, mouth lesions, lymphadenopathy, and a 9-kg weight loss. His medical
      history was remarkable for peptic ulcer disease, urinary tract infections, recent
      5-month history of asthma, and pericarditis 4 months earlier. He had two suicide
      attempts, one of which was prompted by turmoils about his homosexuality, a
      history of polysubstance abuse, including intravenous drugs, and unsafe sex
      practices. Initial HIV-1 antibody by ELISA, HIV-1 antigen test, and HIV-1 culture
      were all negative, as were the urinalysis and serologies for hepatitis B and C.
      Four months later HIV-1 antigen test was still negative, but ELISA and Western
      blot test were positive, and his CD4 count was dropping. This case was consistent
      with severe primary HIV disease, with negative HIV antibody test due to the
      recent exposure to the virus; seroconversion took approximately 5 months.

PMID- 10359990
TI  - Beware of Cloudy Serum.
AB  - An 11 1/2-year-old African-American male presented with a 3-day history of
      abdominal pain that was constant, dull, and localized to the right lower
      quadrant. It was associated with anorexia, bile-stained vomiting, and enema
      relieved constipation. His white blood cell count was elevated and the serum was
      lipemic. He had an immediate appendectomy, which revealed purosanguinous fluid in
      the peritoneal cavity. Postoperatively his triglycerides and total cholesterol
      were markedly elevated, and his pancreas was enlarged and poorly delineated, with
      no pseudocysts. He was diagnosed with type V primary hyperlipidemia and placed on
      gemfibrozil regimen. He was compliant with medication and made dietary changes,
      which all contributed to lower cholesterol and triglyceride levels.

PMID- 10359991
TI  - Poorly Controlled Diabetes?
AB  - A 17-year-old male with insulin-dependent diabetes mellitus was referred because
      of difficulties with diabetic control. Since his diagnosis at age 10, he has been
      hospitalized more than 60 times for diabetes or its complications, mostly
      ketoacidosis. He also has short stature, pubertal delay, and hepatomegaly, and on
      exam was uncooperative and hostile. The long-standing practice of binging and
      purging followed by vomiting was revealed. His condition was consistent with
      Mauriac syndrome. Addressing an associated eating disorder may improve diabetes
      control, but this combination significantly increases the risk of diabetic
      complications.

PMID- 10359992
TI  - PID or Not PID? That Is the Question.
AB  - A 14-year-old female was seen for acute abdominal, back, and flank pain,
      accompanied with dysuria, increased frequency of urination, nausea, and decreased
      appetite. After an initial diagnosis of pyelonephritis, a presumptive diagnosis
      of pelvic inflammatory disease (PID) was made. The cervical culture was positive
      for Chlamydia trachomatis and a pelvic sonogram demonstrated abnormal right
      adnexal structures and a possible mass. Exploratory laparotomy was performed,
      which demonstrated right-sided inflammation in the fimbria and fallopian tube as
      well as an ovarian cyst on the right. Her postoperative course was uncomplicated
      and was continued on oral doxycycline.

PMID- 10359993
TI  - An Old Disease Makes a Comeback.
AB  - A 15-year-old African-American female was hospitalized following 7 days of fever,
      pharyngitis, and neck pain. Physical exam revealed enlarged tonsils. A rapid
      group A streptococcus antigen test was negative, and the throat culture showed no
      streptococci. The blood culture grew Fusobacterium necrophorum. Lumbar puncture
      results were negative. Chest CT scan showed apical cavitary lesions of the lungs.
      Doppler and CT scan of the neck showed narrowing of the right internal jugular
      vein, compatible with thrombophlebitis. The diagnosis of Lemierre's disease was
      made and patient improved rapidly following intravenous therapy of clindamycin,
      ceftriaxone, and heparin.

PMID- 10359994
TI  - Multiple Health Issues in a Homeless Adolescent.
AB  - A 19-year-old homeless youth presented to the emergency department with right arm
      pain at the site of previous intravenous line and abdominal pain following a
      fight. Several days previously he had been treated for an unwitnessed grand mal
      seizure. The patient stated his history of seizure disorder, cardiac arrhythmia,
      reactive airway disease, and HIV infection (he reported CD4 count of 350
      cells/mm(3)), and physical and sexual abuse. Upon admission, his CD4 count and
      percent were normal and HIV antibody test was negative. He refused to accept
      those results and kept none of his follow-up appointments. The case was
      consistent with factitious HIV disorder in adolescents.

PMID- 10359995
TI  - A Routine CBC Leads to a Nonroutine Diagnosis.
AB  - A 20-year-old Hispanic female had 3 episodes of blood in her bowel movements,
      anal itching, burning, and constipation, and a history of hemorrhoids,
      hypothyroidism secondary to thyroiditis, depression, and an attempted suicide 3
      months earlier. Family history was remarkable for iron deficiency anemia and
      hypothyroidism. Complete blood chemistry results indicated that she had vitamin
      B12 deficiency, but, except depression, did not exhibit other neuropsychiatric
      symptoms of cobalamin deficiency. A two-part Schiling test indicated that she was
      not producing adequate or active intrinsic factor, thus she was diagnosed with
      pernicious anemia and requires 1 mg of vitamin B12 intramuscularly for the rest
      of her life.

PMID- 10359996
TI  - Biopsychosocial Aspects of Chronic Illness.
AB  - A 17-year-old female was brought in complaining of severe chest pain and
      difficulty breathing after being raped in the subway. During the assault, she
      developed palpitations, followed by dizziness, and ultimately loss of
      consciousness. Her medical history is significant for multiple surgeries for
      congenital heart disease. At the time of admission she was on furosemide and
      digoxin therapy but her compliance was doubtful. Both her parents were afflicted
      with AIDS. She had expressed suicidal thoughts, was sexually active, rarely used
      condoms and no other methods of birth control, and was regularly using marijuana.
      Her cardiac condition was promptly stabilized with cardioversion, but this case
      illustrates the important aspects of the interaction of biopsychosocial factors
      and chronic illness in adolescence. Serious sequelae, such as noncompliance with
      medical regimens, unintended pregnancies, sexually transmitted disease, substance
      abuse, sexual victimization, and suicide attempts, can result from failure to
      address such concerns in a timely fashion.

PMID- 10359997
TI  - Winging of the Scapula in a Young Athlete.
AB  - A 15-year-old high school football player noticed asymmetry of his right shoulder
      and thought that he was losing muscle mass around his right shoulder over the
      previous 2-3 weeks. There was no history of pain, recent or past direct trauma or
      surgery of the neck or thorax. He was diagnosed with serologically confirmed
      infectious mononucleosis about 2 months earlier, and was recovering clinically.
      Physical examination was normal, except for significant asymmetry and winging of
      the right scapula, and electromyographic and nerve conduction studies revealed
      demyealination and axonal damage to the right long thoracic nerve and paralysis
      of serratus anterior, most likely caused by Epstein-Barr virus infection.
      Conservative treatment approach allowing continued activity and strengthening
      exercises resulted in full functional recovery over the next 6-8 months.

PMID- 10359998
TI  - How Prepared is Prepared Enough?
AB  - A 17-year-old female was in the final stage in treatment of right unilateral
      cleft lip and palate. She had undergone a number of previous surgeries. Hearing
      and speech were good on evaluation, and her social and family situation were
      deemed excellent. After preparatory orthodontics she underwent a Lefort I
      maxillary advancement. Surgery was successful and she was admitted into
      postoperative recovery. However, the lack of adequate preoperative preparation
      caused traumatic reaction from the patient and her parents: anxiety over
      appearance, crying, refusal of oral fluids and oral care, refusal of analgesia,
      and refusal to mobilize. The patience and persistence of hospital staff slowly
      overcame all adversities and the patient moved on to full and successful
      recovery, but this case prompted changes in preoperative procedures and
      involvement of patients and their families in postoperative meal selection,
      planing, and preparation.

PMID- 10359999
TI  - Comorbidity of STDs.
AB  - A 16-year-old African-American female presented with a 4-week history of
      intermittent fever, night sweats, and bilateral upper quadrant abdominal pain,
      bifrontal headache, left eye pain, pruritic rash on arms and chest, 7-kg weight
      loss, and 2-week history of pain with defecation and urination coincident with
      the development of perineal ulcers. Her past medical history is unremarkable.
      Chest x-ray showed bilateral interstitial nodular densities. The laboratory tests
      that returned positive were herpes simplex culture of the genital ulcer, rapid
      plasma reagin (1:32), microhemagglutination-Treponema pallidum test, and HIV
      ELISA and Western blot tests. Open lung biopsy was positive for Histoplasma
      capsulatum. Syphilis, herpes simplex type II, and HIV infection were all
      transmitted sexually from a single (and first) sexual encounter a year before
      admission.

PMID- 10360000
TI  - Severe Menorrhagia.
AB  - A 15-year-old African-American female presented with prolonged menstrual bleeding
      accompanied by a 1-week history of weakness, fatigue, dizziness, and bifrontal
      headaches. Her previous period was 5 weeks earlier, lasted 3 weeks, with heavy
      passage of clots. Family history is significant for bleeding disorders. Her
      platelet count was in the 60,000-80,000 range, platelet aggregometry was low, and
      antiplatelet antibodies positive; she received platelet transfusion that
      increased and stabilized her platelet count. She was diagnosed with reactive
      thrombocytosis due to severe iron deficiency anemia. She was placed on ethynil
      estradiol plus norethindrone therapy until her platelet count rose to 2,275,000.

PMID- 10360001
TI  - Lower Abdominal Pain in a Perimenarchal Adolescent.
AB  - A 13-year-old girl presented to the emergency department with a 5-day history of
      lower abdominal pain and dysuria that coincided with the onset of her last
      menstrual period. Menarche occurred 4 months previously and previous cycles were
      normal. The CAT scan of the abdomen and pelvis revealed a uterus didelphis with
      obstruction. Abdominal pain was due to hematocolpos and hematometra. The left
      hemivagina was distended with hematocolpos, and left renal agenesis was also
      noted. The vaginal septum was removed surgically without complications and she
      continued to be monitored closely.

PMID- 10360002
TI  - Failure to Diagnose Failure to Grow.
AB  - A 14-year-old female presented with a 3-week history of sore throat, hoarseness,
      croupy nonproductive cough, fever, diarrhea, and 5.5-kg weight loss. She was a
      poor student and "picky eater," and both her current weight and height (18.5 kg
      and 128 cm) were far below the fifth percentile. Her apparent failure to thrive
      was a source of concern, and although her diarrhea appeared to be acute, she
      began to have guaiac-positive stools, and admitted to chronic episodes of
      diarrhea and recurrent abdominal pains. A colonoscopy revealed chronic aphthous
      ulcers consistent with Crohn's disease of the large bowel. She was discharged on
      nutritional supplements, high-dose prednisone therapy, and mesalimine delayed
      release tablets.

PMID- 10360003
TI  - Primary Amenorrhea with Pubertal Development.
AB  - A 16-year-old Guatemalan adolescent presented for routine immunizations. She was
      still amenorrheic and appeared significantly younger than her stated age. Her
      evaluation revealed pubertal development and primary amenorrhea due to primary
      ovarian failure of unknown etiology, characterized by hypergonadotrophic
      hypogonadism with an infantile uterus and no visible adnexa. At the time of
      evaluation, her diagnosis was thought to be 46XX gonadal dysgenesis. Due to the
      problems related to the patient's lack of medical insurance, uncompliance with
      medications and follow-ups, and family objections and attitudes, her evaluation
      was still incomplete 26 months later on high school graduation.

PMID- 10360004
TI  - "Fever in the Hand"
AB  - A 14-year-old female adolescent was being treated for malnutrition secondary to
      anorexia nervosa. She complained of severe "shooting" pain, swelling, and color
      and temperature changes in her left (dominant) hand. She had recently suffered a
      fall during a hockey game and pounded on the table during a "temper tantrum." On
      exam, the left hand was cyanotic, edematous, and cold, with severe hyperesthesia.
      A bone scan showed marked reduction in flow to the left hand. She underwent eight
      sympathetic ganglion blocks resulting in transitory Horner's syndrome. Favorable
      plethysmographic changes occurred and her recovery was complete. Her eventual
      diagnosis was reflex sympathetic dystrophy syndrome.

PMID- 10360005
TI  - Office-based Adolescent Health Care: Issues and Solutions.
AB  - Because the field of adolescent medicine is relatively young, guidelines for care
      are still in need of definition. This chapter provides an overview of the issues
      related to the provision of health care to adolescents, including training of
      physicians, considerations in establishing an office-based practice, consent and
      confidentiality, and health care reimbursement.

PMID- 10360007
TI  - A Primer on Adolescent Psychopharmacology.
AB  - Because new applications for known medications are emerging, focusing on
      medications rather than syndromes enables the primary care physician to apply
      known medications to new indications. The article is accordingly organized around
      classes of medications rather than diagnostic entities. To be truly effective,
      adolescent psychopharmacology must be practiced in the context of a broader
      knowledge of adolescent development and psychodynamics.

PMID- 10360006
TI  - Chronic Complaints in Adolescence: Chest Pain, Chronic Fatigue, Headaches,
      Abdominal Pain.
AB  - Most patients and their parents tend to favor a physical explanation of symptoms;
      to counter this trend, the author emphasizes the need for health care providers
      to maintain a more psychosocial approach in treating adolescents. The necessity
      and wisdom of extensive lab testing in the absence of definitive symptoms are
      questioned. Physical and psychological etiologies for the most common complaints
      are detailed.

PMID- 10360008
TI  - Assessing and Managing Adolescents with School Problems.
AB  - Although school performance is highly influenced by socioeconomic and cultural
      forces, neurodevelopmental and psychological factors are major determinants of
      educational success. Clinicians should approach school problems as a health
      issue, with the specific objectives of determining whether a primary disease
      process or neurodevelopmental disorder is interfering with learning; providing
      medical evidence to support further evaluation of the patient; and offering
      medical treatment for conditions responsive to medication. The author also
      recognizes the value of effective collaboration with school staff and mental
      health professionals and primary care clinicians in assisting the adolescent
      patient to address his or her school difficulties.

PMID- 10360009
TI  - Acne Vulgaris.
AB  - Adolescent acne appears with the onset of puberty and occurs in at least 85% of
      adolescents. Although many patients have only mild forms, acne that is left
      untreated can leave emotional and physical scars that last a lifetime. An
      understanding of the adolescent patient's psychological vulnerability and patient
      education maximize the effectiveness of any treatment program. The author reviews
      the causes and treatments of acne vulgaris, and evaluates the efficacy and
      appropriateness of the most widely used topical and oral medications.

PMID- 10360010
TI  - Common Menstrual Problems of Adolescence.
AB  - Menstrual symptoms and patterns of menstrual bleeding are common complaints of
      adolescent patients. All presenting menstrual concerns must be clearly defined
      and should not be minimized, including both the patient's and parent's or
      guardian's perceptions of the problem and possible consequences to health. The
      author outlines the initiation and control of menstrual cycles and the spectrum
      of menstrual problems, including evaluation and treatment strategies. Symptoms
      associated with dysmenorrhea and premenstrual strategies are reviewed, along with
      other diagnoses that should be considered.

PMID- 10360011
TI  - Adolescent Syncope: Faint or Feigned?
AB  - Adolescent syncope may have cardiac causes (vasodepressor syncope) or stem from a
      neuropsychogenic condition (such as epilepsy or drug abuse). This article reviews
      the various causes of syncope in adolescents, with emphasis on pathophysiology,
      diagnostic considerations, and treatment options for the most common cause of
      fainting, vasodepressor syncope. The authors suggest that history and physical
      examination are usually more useful and cost-effective in determining the cause
      of syncope than more expensive and invasive diagnostic tools.

PMID- 10360012
TI  - Asthma, Allergies, and Sinusitis in Adolescence.
AB  - The two most common chronic diseases in adolescence are asthma and allergic
      rhinitis. Along with acute and chronic sinusitis, they account for significant
      morbidity and, therefore, require effective management. This article discusses
      the pathophysiology of each condition and offers a practical approach to therapy,
      which first establishes the severity and then outlines both pharmacologic and
      nonpharmacologic means to control each disorder and provide symptomatic relief.

PMID- 10360013
TI  - Update: Immunizations for Adolescents.
AB  - Vaccinations against hepatitis B, varicella, tetanus, and diphtheria are
      especially important during the adolescent years. Recommendations for some of
      these vaccines have recently changed, and other seemingly rare infections are
      reemerging, making this topic highly relevant to adolescent care. In this
      article, the author reviews the composition of these illnesses and outlines
      guidelines for prevention and treatment.

PMID- 10360014
TI  - Preparticipation Physical Examinations: Critical Controversies.
AB  - The area of sports medicine has developed into a complex and ever-changing field
      over the past few decades. For example, physicians who wish to effectively treat
      young athletes must remain informed of the newest information and not rely solely
      on their knowledge of general practice. The author illustrates how this need for
      specialized knowledge, as well as the dramatic changes in the major causes of
      morbidity and mortality among adolescents, has contributed to the controversies
      related to the preparticipation physical examination (PPE) of junior and senior
      high school athletes.

PMID- 10360015
TI  - Proteinuria, Hematuria, and Urinary Tract Infections in Adolescence.
AB  - Urinary tract infection (UTI) is one of the most common bacterial infections in
      adolescents and young adults. It is also not unusual to encounter occult blood or
      protein in the urine of an otherwise healthy adolescent, although neither finding
      is as common as UTI. This chapter assists the adolescent medicine practitioner in
      the diagnosis and treatment of UTI, in any subsequent urinary tract evaluation
      that may be indicated, and in the identification of patients in whom proteinuria
      or hematuria is more likely to reflect the presence of underlying renal disease
      and for whom further evaluation or referral may be indicated.

PMID- 10360016
TI  - Treating Adolescent Obesity.
AB  - Obesity's genetic, metabolic, behavioral, and environmental influences make the
      disorder difficult, but not impossible, to manage. Treatment at an early age is
      crucial, as 80% of obese adolescents will become obese adults, and are unlikely
      to "outgrow" obesity on their own. The author describes some of the current
      notions about the etiology of obesity, associated medical risks, and behavioral
      and medical treatments available for obese adolescents.

PMID- 10360017
TI  - Lesbian and Gay Youth: Care and Counseling.
AB  - Adolescents face many barriers in accessing appropriate primary care. Among the
      most underserved are lesbian, gay, and bisexual youth who are often neglected by
      traditional systems of care. This is a reference guide that provides background
      knowledge, substantive references, and detailed information on the stressors,
      health needs, experiences, and developmental challenges facing lesbian and gay
      youth. The first part focuses on experiences and needs of lesbian and gay
      adolescents-health challenges, identity development, their experiences,
      vulnerabilities, and risks, and confidentiality and legal issues that are of
      concern. The second part deals with primary care and disease prevention
      objectives in this group of adolescents-most frequent health concerns, issues of
      transgendered youth, special populations, primary interventions and anticipatory
      guidance, medical assessment, treatment, and prevention, and mental health
      concerns, assessment, and treatment. The third part presents an overview of HIV
      infection in all adolescents, with a focus on issues of concern for lesbians and
      gay males. It covers issues of HIV counseling, testing, and prevention as well as
      clinical care and prevention. Several appendices offer additional resources for
      primary care needs of lesbian and gay adolescents, resources for parents and
      youth, recommended reading for providers, adolescent HIV counseling and testing
      protocols and clinical care protocols.

PMID- 10360018
TI  - Changing Health Care Environments and Adolescent Health Care: Legal and Policy
      Challenges.
AB  - The changes in the health care system and shifts toward managed care affect
      adolescents like all other age groups. This chapter deals with the key issues
      that concern adolescent health care providers while creating the health care
      models of the future. Questions such as adequate health insurance for
      adolescents, health care delivery to uninsured and underinsured adolescents, and
      protection of confidentiality all need to be addressed for adolescents to receive
      the health care they need.

PMID- 10360019
TI  - Discrimination in Minority Health Care.
AB  - Racial/ethnic minority adolescents are reported to have lower general health
      status, including higher prevalence of many infectious diseases, than white, non
      Hispanic youth. Factors such as lower socioeconomic position, neighborhoods they
      live in, different cultural views on health, and different role of the family in
      health care providing are all thought to contribute to this situation. This
      chapter comprehensively reviews the existing data on the health status of
      minority adolescents, social, demographic, educational and cultural determinants
      of racial/ethnic minority populations and how they might interfere with health
      care delivery to the adolescents, and discusses the need for initiatives to
      improve the existing conditions.

PMID- 10360020
TI  - Acculturation Issues in Adolescent Immigrants: How Are They Related to Health?
AB  - Following immigration to a new country, adolescents must deal with many
      challenges in addition to the normal intergenerational conflicts that
      characterize this age. The need to learn a new language and adapt to a different
      educational system combined with the struggle to make new friends can have
      visible consequences on the health status of immigrant youth, many of whom
      suffered severe deprivations prior to immigration. This chapter reviews physical
      and mental health-related problems, such as posttraumatic stress disorder,
      depression, anxiety, and psychosomatic problems, that concern adolescent
      immigrants and their families.

PMID- 10360021
TI  - "Sex, Drugs, Rock 'n' Roll," and the Media-Are the Media Responsible for
      Adolescent Behavior?
AB  - The old controversy about the role of the media in violent behaviors of
      adolescents can be combined with another unsettled question-Does the media simply
      reflect the violent, aggressive, and sexually oriented society, or does it
      actually cause some of the behaviors it depicts? This chapter reviews existing
      studies on the exposure of adolescents to media-derived violence, sexual
      behaviors, and use of tobacco, alcohol, and drugs, and the influences that such
      images have on this population.

PMID- 10360022
TI  - The Health Care Provider's Role in Adolescent Medical Decision-Making.
AB  - In caring for adolescent patients, health care providers often face problems
      other than their medical conditions. This chapter presents three case studies
      that illustrate a diversity of ethical questions that arise in the context of
      adolescent health care. The investigators present and define the basic ethical
      principles that should govern a health care provider's approach to treating an
      adolescent. Even though this study was primarily directed toward adolescents who
      live without proper adult supervision, the principles and guidelines derived from
      this study can apply to the health care of all adolescents.

PMID- 10360023
TI  - Confidentiality in an Age of Managed Care: Can It Exist?
AB  - Adolescents in need of medical care can be greatly influenced by concerns about
      privacy; therefore confidentiality remains one of the foundations of adolescent
      health care. This article discusses confidentiality and quality adolescent care
      in different settings of managed care. With consent laws that vary from state to
      state and different administrative restrictions of managed care, confidentiality
      of adolescent health care often may be compromised, causing adolescents to look
      outside the health care insurer for the medical help they need. The author
      discusses the benefits of HMO models able to provide easily accessible, quality
      confidential care to adolescents, including preventive adolescent medicine.

PMID- 10360024
TI  - School-based Health Centers.
AB  - Over the past decade there has been a rapid increase in the number of school
      based health centers (SBHCs). This chapter discusses the expanding role of SBHCs
      in adolescent health care, the controversies that surround the provision and
      utilization of such services, and different relationships between SBHCs and
      managed care organizations.

PMID- 10360025
TI  - Should Adolescents Have Over-the-Counter Access to Oral Contraceptive Pills and
      Antibiotics?
AB  - The rate of teenage pregnancy and abortion in the U.S. is the highest in the
      developed world. Oral contraceptive pills (OCPs) are an effective method of
      contraception that has very few contraindications in healthy adolescents. This
      article discusses the issue of whether adolescents should be allowed access to
      OCPs and antibiotics for treatment of sexually transmitted diseases without prior
      consultation with a health care provider. The author argues that patient
      education and counseling that result from an interaction with a clinician are
      necessary for sexually active adolescents and could be greatly diminished if OCPs
      become available over-the-counter.

PMID- 10360026
TI  - Condom Availability in High Schools.
AB  - Increased incidence of sexually transmitted diseases, especially HIV/AIDS, and
      unintended pregnancies among adolescents call for immediate measures that should
      educate adolescents and reduce risk from such outcomes. This article discusses
      school-based condom availability programs as one means to facilitate access to
      condoms and provide additional counseling for prevention of undesired
      consequences of adolescent sexual behaviors.

PMID- 10360027
TI  - Emergency Contraception.
AB  - Emergency contraception uses oral contraceptives or postcoital insertion of an
      intrauterine device (IUD) to prevent pregnancy after an episode of unprotected
      intercourse. This chapter reviews the available data on the efficacy of emergency
      contraceptive pills (ECPs), indications and contraindications, availability,
      safety, and potential side effects. It also addresses the controversial issues
      that arise from equating ECPs with abortion, as well as the effects of ECPs on
      contraceptive practices of adolescents.

PMID- 10360028
TI  - Adolescents and HIV: Controversies Old and New.
AB  - Increased incidence of HIV infection among adolescents has put more emphasis on
      trying to improve HIV screening of the adolescent population. This chapter
      presents some of the controversies surrounding HIV testing and counseling, the
      options of adolescent consent to such testing, and the confidentiality of the
      test results. It also discusses recent advances achieved with HIV combination
      therapy and availability of new therapeutic approaches to infected adolescents.

PMID- 10360029
TI  - Medical Abortions in Adolescents: Should Pediatricians Perform Them?
AB  - This chapter discusses medical abortion as an alternative to surgical abortion,
      as well as its safety, efficacy, and availability to adolescent patients. Medical
      abortion is viewed by many patients as a less traumatic and more private way to
      achieve pregnancy termination, and the issues of privacy and confidentiality are
      even more emphasized with adolescents. The author presents medical abortion
      methods currently approved in the U.S., discusses the attitudes and preferences
      of adolescent vs. adult patients, and argues that, assuming proper training and
      patient selection, this method of abortion can be safely and effectively
      administered by pediatricians caring for their adolescent patients.

PMID- 10360030
TI  - One Test Too Many: Toward an Integrated Approach to Psychosomatic Disorders.
AB  - Conditions such as chronic fatigue syndrome (CFS), fibromyalgia, and several
      others belong to the group of disorders in which both physiologic and psychologic
      factors are substantially involved, and in some cases there may be no real
      distinction between the two. However, primary patient assessment usually employs
      an array of clinical tools, and only after known physiologic factors are excluded
      is the patient referred for psychologic or psychiatric evaluation. This chapter
      suggests that clinical evaluation should initially include both physiologic and
      psychosocial assessment, which would minimize the division and greatly improve
      the efficacy of the treatment.

PMID- 10360031
TI  - Controversies in the Diagnosis and Treatment of Attention Deficit/Hyperactivity
      Disorder in Adolescents.
AB  - Attention deficit/hyperactivity disorder (AD/HD) is one of the most common
      behavioral problems in childhood, and for about 80% of diagnosed cases remains a
      problem through adolescence. This article discusses general controversies that
      surround recognition, correct diagnosis, and treatment of AD/HD in children, and
      its relationship to conduct disorder in adolescents and adults.

PMID- 10360032
TI  - Rebellious Adolescents: Is Toughlove the Answer?
AB  - Grassroots, mutual-help groups exist as an alternative or an addition to
      professional help for families who are experiencing aggressive and antisocial
      behaviors by their rebellious adolescents. The Toughlove approach is one example
      of a mutual-help program created to help parents deal with serious behavioral
      problems of their children. This chapter discusses the concepts, limitations, and
      benefits of such a family-based program and its effectiveness in children vs.
      adolescents.

PMID- 10360033
TI  - The Medical Clinician's Roles in Preventing Adolescent Involvement in Violence.
AB  - This chapter discusses the role of health care providers in preventing adolescent
      exposure to violence and involvement in violent and criminal behaviors. The
      author reviews the existing primary, secondary, and tertiary violence prevention
      programs. The chapter also offers practical suggestions for clinicians to
      identify adolescents exposed to and involved in violence and provide clinical
      interventions to help youth suffering from substance abuse, AD/HD, anxiety,
      depression, and other mental health problems associated with exposure to
      violence.

PMID- 10360034
TI  - How Should Pediatricians Approach the Depressed Adolescent?
AB  - Mood disorders, such as depression, dysthymia, and bipolar disorder, affect a
      large number of adolescents and impair their normal development. This chapter
      discusses the pediatrician's approaches to treatment of such disorders in
      adolescents and specifically addresses the role of pharmacotherapy in achieving
      the best therapeutic results.

PMID- 10360035
TI  - Growth Hormone Treatment for Children without Growth Hormone Deficiency: Does It
      Work and Will It Produce Adolescents Who Are Better Adjusted?
AB  - The development of recombinant DNA technology offered a breakthrough for
      treatment of children with growth hormone (GH) deficiency. However, children who
      are not GH-deficient but have idiopathic short stature (ISS) represent another
      group of frequent candidates for GH treatment. This chapter reviews the results
      of existing studies of GH treatment of such children and discusses the
      necessities, benefits, and limitations of this approach.

PMID- 10360036
TI  - Cosmetic Plastic Surgery in Adolescents.
AB  - Perceived or real physical defects may be important for an adolescent trying to
      establish self-image and adjust socially. Port-wine stains, breasts too small or
      too large, ethnic nose, prominent ears or chin, excess of adipose tissue-all
      these "defects" can lead to loss of self-esteem and have severe consequences with
      regard to an adolescent's development. This chapter discusses surgical procedures
      that can help adolescents change their physical appearance and consequently
      improve their self-confidence and social integration.

PMID- 10360037
TI  - Pressurized metered-dose inhalers and holding chambers for inhaled glucocorticoid
      therapy in childhood asthma.

PMID- 10360038
TI  - [Low-dose estrogens in the treatment of the climacteric syndrome].
AB  - The present prospective study is aimed to estimate the effect of a low-dose
      combined oestrogen drug Cyclo-Menorette on climacteric syndrome in women with
      early menopause. MATERIAL AND METHODS: The criteria for inclusion in the study
      were ac follows: 9-12 months of menopause, increased FSH levels, moderately
      expressed climacteric syndrome confirmed by the menopausal index of Kupperman and
      Hamilton-Anxiety-Scale /HAMA/. According to acceptance of hormone replacement
      therapy /HRT/ the women were divided into 2 groups--control T /n = 31/ and Cunder
      treatment T /n = 35/. The degree of climacteric syndrome expression after
      Kupperman and HAMA was estimated in all patients at the beginning as well as on
      the 3-d, 6-th 12-d months. The presence and dynamics of side effects were
      followed in the patients treated with HRT. RESULTS: Spontaneous improvement of
      complaints was found out in the control group with an increase of intragroup
      differences during the follow-up period. Most expressed improvement in the group
      under treatment was established during the first 3-6 months, the beneficial
      effect being preserved until the end of the study. CONCLUSION: The use of 1 mg
      oestradiol valerat in combination with 2 mg oestriol results in a significant
      decrease of climacteric syndrome manifestation with slightly expressed and
      transient side effects.

PMID- 10360039
TI  - [Cesarean section frequency and its indications at the State University Hospital
      Maternity Home over a 12-year period].
AB  - The aim of this retrospective study is to analyse the tendency of change of the
      rate of CS and the indications for them. The data are taken from the hospital
      medical documentation. For each year is determine the rate of CS and the
      indications. Only the first two leading indications are taken because next are
      most often consequence or subgroup of them. The incidence of each indications is
      calculate on the sum of this indications from different cases to the sum of
      indications from all CS. From 1986 to 1997 year there were 49,855 deliveries and
      9384 CS. CS rate at 1986 was 13.9 and increased to 24.0 at 1997 year. The mean CS
      rate for the period is 18.75. The leading indications are: dystocia (39.2%),
      previous CS (20.9%), fetal distress (16.9%), breech presentation (14.6%). In more
      than half of CS in the leading indication there are relative indications. For the
      period there is significant tendency of decrease of the indications: previous CS,
      hearth diseases, myoma, elderly patients. We found increase in the indications
      like: unfavorable pelvic score, atypical or pathological cephalic presentations,
      ophthalmic diseases, prolonged period of ruptured membranes. The increase of CS
      rate is mainly due to the relative indication and to the indications based on the
      subjective assessment of the fetal well-being and of the obstetric status.

PMID- 10360040
TI  - [Delivery with epidural analgesia (a preliminary report)].
AB  - In the last decade delivery by continuous epidural analgesia (CEA) has become a
      golden standard in most modem perinatal centers. The aim of this study is to find
      the effect of CEA on the quality of labor, mode of delivery and the condition of
      mother and fetus after delivery. The study is prospective and includes 15
      parturients. CEA was delivered with 0.25% solution of Marcaine. RESULTS: The
      average age of the parthers was 23 +/- 5.05 years and their body weights 63 +/-
      9.82 kg. 13 of the women were nulliparous and 2 multiparous. All were delivered
      vaginally normally. The average length of the first period of labor was 4 Hours
      (+/- 3.18 h) and of the second period 20 minutes (+/- 11.06) q which is different
      from data from current literature. Labor was estimated in the cases with i.v.
      infusion of oxytocin. Apgar scores of the newborns was 8-10 points. We can
      conclude that deliveries with CEA are eutocic, shorter and promote and excellent
      psychoemotional state of the parturients.

PMID- 10360041
TI  - [The characteristics of the perinatal period in women whose death is related to
      pregnancy, labor and puerperal pathologies].
AB  - Mortality rate of the hospitalized for delivery women depends on their condition
      before entrance into hospital. This indicator is also related to the
      possibilities of Ob./Gyn. clinics to provide highly qualified assistance as well
      as to the prophylactics, dispensary and partronage work and activity of the
      women's consultation cabinets. Table N1 is of interest as it presents the
      prevention of death/complication that caused death/of dead pregnant women, women
      in delivery and young mothers. We accept that unpreventation of death is owed
      mainly to some medical and biological causes and to the advent of severe
      irreversible damages of organs of vital importance. An issue of interest to the
      clinician and to the maternal health care are the periods, in which pregnant
      women and young mothers--before delivery, during delivery, after delivery and in
      the first month after month after delivery most frequently die (tab. N 2).

PMID- 10360042
TI  - [The course of pregnancy and labor in patients with epilepsy].
AB  - For a 10-year period we studied the effects of epilepsy on the course of
      pregnancy, delivery, and perinatal complications among 27 women with epilepsy;
      70.37% had epilepsy for 10 years. Before pregnancy, 74.08% of the patients had
      grand mal seizure. During pregnancy, grand mal characteristics were observed in
      14.18% of patients, which mandated better titration of AED therapy. Two thirds of
      the pregnant women received therapy with carmabazepins and valproate. Delivery
      was normal in 81.48%, by forceps in 7.41% due to fetal distress, and by cesarean
      section in 11.11%. In only 1 patient was epilepsy the primary indication for
      cesarean section. In all cases, perinatal outcome was good and no fetal
      malformations were noted. We conclude that epilepsy does not lead to any
      significant complications during pregnancy and delivery except in those with
      tonic-clonic characteristics, which are difficult to control conservatively.

PMID- 10360043
TI  - [Sarcoidosis and pregnancy].

PMID- 10360044
TI  - [The zinc concentration of the blood serum in women with ovarian tumors
      (preliminary report)].
AB  - The aim of the study is to determine the concentration of blood serum zinc of
      women with ovarian tumors. The patients included in the study are as follows: 15
      women with benign ovarian cysts, 5 with endometrial cysts and 5 with ovarian
      carcinoma. The control group consists of 157 healthy women whose serum zinc
      concentration was 13.50 +/- 2.60 mmol/L. We could not demonstrate a significant
      difference in serum zinc concentration of different groups: benign cysts,
      endometrial cysts and ovarian carcinoma in comparison control group.

PMID- 10360045
TI  - [The protein profile of the cervical mucus: cyclic and ovulatory values].
AB  - Immunological and biochemical analysis on cervical mucus requested application of
      micromethods on sindle small specimens. The following micro-methods in agar gel
      are applied: immunoelectrophoresis--the normal cervical mucus developed by
      antiserum against total human serum is presented with 5 precipitin lines:
      prealbumin, albumin, a1-antitrypsin, transferrin and IgG. The single
      immunodiffusion technique in agar gel (Mancini et al., 1964) is suitable method
      to assess these proteins. The same diffusion method is applied for enzyme
      assessment with special importance like a-amilase and muraminidase (lysozyme).
      The assessment of these proteins shows pre-ovulatory decrease and post-ovulatory
      remarkable increase. These changes are not simply due to the increased water
      content of the cervical mucus during the fertile period but reflects estrogen
      effect on cervical secretions.

PMID- 10360046
TI  - [A clinico-genetic study of male infertility with globozoospermia].
AB  - Eight patient with male infertility due to isolated or combined with other
      defects anomaly--round-headed spermatozoa, have been studied. Five of them have
      been studied. Five of the patients have been sporadic cases, whereas three cases
      have been familial ones. 100% of the spermatozoa in ejaculates from the patients
      with familial infertility had morphology of round-headed spermatozoa with lack of
      any proteolytic activity. In the patients with sporadic infertility the round
      headed spermatozoa represented between 60 and 95% of the ejaculated cells. All of
      the patients were studied by chromosomal analyses (G-banding) and revealed normal
      male karyotypes 46, XY. The ratio affected: unaffected males in the 8 families
      studied implicates a monogenetic mode of inheritance (Coefficient of heredity
      0.57) of the sperm anomaly. The distribution of the affected males in the three
      pedigrees with familial character of globozoospermia supports X-linked, sex
      restricted dominant, or autosomal recessive modes of inheritance.

PMID- 10360047
TI  - [The evaluation of the transvaginal ultrasonography of endometrial thickness in
      women with postmenopausal bleeding and suspected endometrial carcinoma].
AB  - The aim of our research work was to assess the transvaginal ultrasonography for
      measurement of endometrial thickness in women with postmenopausal bleeding, and
      in this way to determine the less invasive treatment. We wanted to make a grading
      of endometrial cancer, in order to choose patients who need pelvic and para
      aortal lymph dissection. We examined 84 patients by ultrasonography and
      histological examination of the endometrium. Under 8 mm thickness were not found
      precancer and cancer lesions. The mean endometrial thickness was 8.25c1.63 mm,
      while in non pathological lesions was 1.36c1.10 mm. In order to diagnose
      endometrial pathology we determined border of 5 mm. Over 5 mm the ultrasonography
      has a 88.6% sensitivity, 90.6% specificity, 4.6% false negatives results--3
      polyps, 1 glandular hyperplasia. Nevertheless that we determined border of 5 mm
      under which with great possibility there is no endometrial cancer, we don't
      support authors who advise not make a D&C. Future examinations in this field will
      give more light on this problem.

PMID- 10360049
TI  - [Carcinoma of the cervix uteri--the morphological changes after preoperative
      radiotherapy].
AB  - A retrospective morphological research is made on 11 patients with squamous cell
      carcinoma of the cervix for a three-years period of time (1995-1997).
      Preoperative radiotherapy (intracavitary radiotherapy with Cs and/or external
      radiation) is carried out. A control group of 10 patients with cancer of uterine
      cervix without preoperative radiotherapy is also studied. All of the women
      undergo a wider hysterectomy by the method of Piver class IV. The radiation
      alterations in the tumor and the surrounding normal uterine tissues are also
      researched. A full regression of the tumor Ts size. There are demonstrative
      changes in the tumor and surrounding normal tissues, which are the prove the
      answer to the ionizing irradiation.

PMID- 10360048
TI  - [The use of Ovestin to overcome the side effects of treatment with GnRH agonists
      (Zoladex)].
AB  - The LHRH analogues are used very much in gynecological practice, mostly for a
      long treatment periods. The menopausal side effects occur often and causes the
      patients to withdraw from treatment. The GnRh analogues are used for the
      treatment of endometriosis, uterine fibroids, for breast cancer, and pre and post
      operatively as hormonal therapy for endometrial cancer. 12 patients were given
      combined vaginal Ovestin and GnRh analogues (Zoladex). Another 12 patients were
      taking GnRh analogues alone without Ovestin creme, and this group searched as a
      control group. The group with the Ovestin had less side effects than the control
      group. This difference was statistically significant about the cervicovaginal
      symptoms (p less than 0.01). The treatment with vaginal estrogenes can better and
      improve the tolerance to therapy with GnRh analogues.

PMID- 10360050
TI  - [Combined gynecological operations].
AB  - During the objective examination of patients admitted for operation, changes in
      the gynaecological status, corresponding to primary disease and demanding also
      operation, were determined. The authors studied clinical status of 33 women with
      the following primary diseases: myoma uteri, static anomalies of female genitalia
      and accompanying diseases like urinary stress incontinence, uterine cervical
      laceration and the accompanying static anomalies. Authors applied combined
      operative techniques, abdominal and vaginal (hysterectomy with
      colpouretherosuspension by Burch, vaginal hysterectomy with
      colpouretherosuspension by Ratz, myomectomy with colpouretherosuspension and
      ligamentopexy by McColl, etc.), in order to treat definitively the primary
      disease and the accompanying ones as well. The results showed that in
      appropriately selected cases and operative techniques, a good therapeutic outcome
      was achieved. In conclusion we may say that the operative approach should include
      simultaneously all pathological deviations of women genitalia.

PMID- 10360051
TI  - [Prognostic factors and the risk of axillary metastases in early breast cancer].
AB  - The authors analyzed the clinical and pathomorphological of T tumors for their
      association with the likelihood of axillary metastases. Two hundred forty three
      patients with early breast cancer (T1N0M0 T1N1M0) were studied. All underwent
      complete lymph node dissection. The parameters of the primary tumor evaluated
      included size, histologic subtype, hystological grade, hormone receptor status,
      lymphatic/vascular invasion (LVI). Clinical parameters were age, menopausal
      status and clinical lymph node status. Sixty two (25.5%) on 243 axillary
      dissection contained metastases. Univariate analysis showed that nodal
      involvement were associated with tumors larger than 1 cm and presence of LVI.
      Decision for complete axillary dissection should be individualized based on
      prognostic factors for lymph node involvement.

PMID- 10360052
TI  - [The triple diagnosis of breast diseases].
AB  - The aim of the study is to assess the data of clinical, mammographic, cytological
      and triple diagnosis of breast diseases. 188 patients are included in the study.
      The hystological findings are as follow: 58 patients with carcinoma and 130 with
      benign diseases. The coincidence of the exams are: 1. clinical examination--109
      benign and 46 with carcinoma 2. mammography--114 for the benign group and 51 with
      carcinoma 3. cytology of FNB--104 to 40 4. triple diagnosis--118 to 40 The best
      method of diagnosis, according to our study, is the triple method.

PMID- 10360053
TI  - [Fetal pulse oximetry--a method for monitoring fetal status during labor].

PMID- 10360054
TI  - [A surgical technic for cesarean section and gynecological laparotomy without
      suturing of the parietal and visceral peritoneum and the single-layer suturing of
      the uterus during the section (a review of the literature and initial
      experience)].

PMID- 10360055
TI  - [The current potentials for optimal whole-blood transfusion and component therapy
      with blood products--erythrocytes in obstetrics and gynecology--the indications,
      means and methods].

PMID- 10360056
TI  - [The potentials of current transfusion hematology for component therapy with
      thrombocytes, granulocytes, plasma and plasma factors in obstetrics and
      gynecology].

PMID- 10360057
TI  - [Dysgerminoma into gonadoblastoma--a clinico-morphological interpretation of 2
      cases in female patients with gonadal dysgenesis].

PMID- 10360058
TI  - [The late dimensions and complications following paraffin injection into the
      breast].

PMID- 10360059
TI  - [The course of pregnancy, labor and the postpartum period in a woman with a
      myomatous node of the uterus who gave birth to twins].

PMID- 10360060
TI  - [Cervical screening--its essence and quality-control methodology in cytology
      laboratories].
AB  - The essence and importance of the quality control in the activity of the
      cytological laboratories, fulfilling the 1st step of the cervical screening are
      discussed. The methodology is presented, as well as the possibilities of the
      different kinds of internal and external control and the place of the introduced
      in the practice of the developed countries automated analyzing systems are under
      consideration.

PMID- 10360061
TI  - [Several problems in organization of anesthesiological and intensive care in
      emergency situations].

PMID- 10360062
TI  - [Approaches to decreasing polypragmasy in intensive care of patients with severe
      injuries].
AB  - A total of 277 patients with grave combined injuries were treated. Polypragmasy
      involved all the trends of intensive care and was most often observed in infusion
      transfusion and drug therapy. Three main approaches to decreasing polypragmasy in
      intensive care of victims with grave combined injuries consist in decreasing the
      volume of infusion-transfusion therapy, use of a limited number of antihypoxants,
      and early short courses of antibiotics.

PMID- 10360063
TI  - [Diagnosis and treatment of thermochemical injuries of the airways in patients
      with severe burns].
AB  - Chromobronchoscopy allows objective assessment of the size and depth of injury to
      tracheobronchial mucosa. The type of inhalation injury to the tracheobronchial
      tree is an important parameter determining the preventive use of high-frequency
      assisted and artificial ventilation of the lungs (HFAVL and AVL, respectively).
      In patients with slight injuries to the airways, inflicted by burning products,
      the criteria of transfer to HFAVL or AVL should be traditional. In medium severe
      involvement HFAVL should be started immediately through a microtracheostoma.
      Severe and extremely severe inhalation injuries require urgent transfer to AVL
      even if there are no signs of acute respiratory failure.

PMID- 10360064
TI  - [Diagnosis, outcome prognosis and treatment strategy in inhalation trauma in
      patients with thermal injuries].
AB  - Sixty-seven therapeutic fibrobronchoscopies (FBS) were carried out in burnt
      patients with suspected inhalation injuries at Center for Burns at the Janelidze
      Institute of Emergency Care in 1996-1998. The severity of inhalation injury was
      assessed from the extent and severity of mucosal edema, spot hematomas and their
      type, erosions and ulcers, discharge, and ventilation obstruction. An original
      score is developed for evaluating the severity of inhalation injuries in burnt
      patients. Inhalation injuries were diagnosed in 63 patients. FBS was performed
      with tracheobronchial lavage with antibiotics, proteolysis enzymes, and repair
      stimulants. Mortality among burnt patients with inhalation injuries was decreased
      to 38%.

PMID- 10360066
TI  - [Intact consciousness during surgical intervention under general anesthesia: a
      present-day viewpoint].

PMID- 10360065
TI  - [Prolonged regional intra-arterial therapy in multimodal treatment of patients
      with severe skeletal trauma].
AB  - A total of 108 victims with open fractures of long tubular bones of different
      localization are examined. Regional intraarterial therapy was added to their
      treatment protocols. Stable functional disorders in local hemodynamics in these
      patients impede the repair processes and can lead to development of infectious
      complications. Regional intraarterial therapy allows early elimination of
      hemodynamic disorders, selective antibiotic therapy, and improves the adaptation
      potential of the immune system.

PMID- 10360067
TI  - [Ways of improving postoperative analgesia].
AB  - Analysis of many-year experience gained in the use of a variety of methods and
      means for treating the painful syndrome in victims and patients after planned and
      urgent surgery allowed the authors to determine the optimal approaches to
      postoperative analgesia. Special attention is paid to introduction of new drugs
      and methods of analgesia with differentiated approach to prevention and treatment
      of the painful syndrome. A conclusion on the necessity of pathogenetically based
      and strictly individual postoperative analgesia is made; such analgesia is often
      to be multilevel and multicomponent, with consideration for the complex origin of
      painful reaction (including the components of the painful syndrome) and the
      armory of available means.

PMID- 10360068
TI  - [Experience in the use of midazolam in esthetic surgery].
AB  - Anesthesias with midazolam are described. The drug has a favorable effect on the
      course of anesthesia and consciousness recovery. The authors claim that midazolam
      can virtually supersede other benzodiazepines in anesthesia for esthetic surgery.

PMID- 10360069
TI  - [Postoperative oxadol analgesia in oncologic patients].
AB  - Oxadol (nefopam hydrochloride), a central analgesic, was used for postoperative
      pain relief in patients operated on the abdominal and pelvic organs for cancer.
      The analgesic effect of oxadol was sufficient for arresting moderate
      postoperative pain. Although the drug exerts rather many side effects, none of
      them notably deteriorated the clinical status of patients.

PMID- 10360070
TI  - [Clofelin-fentanyl analgesia in adrenalectomy].
AB  - Anesthesia for adrenalectomy as exemplified in 60 patients is discussed.
      Anesthesia was based on a combination of fentanyl with a central adrenoagonist
      clofelin. This method supplemented by accurate hemodynamic monitoring ensures
      adequate analgesia without side effects on the hemodynamics.

PMID- 10360071
TI  - [Bronchoscopic monitoring: an element of intensive care during the operative
      period in lung resections].

PMID- 10360072
TI  - [Visceral mycoses in intensive care].
AB  - Mycotic involvement of viscera and nervous system develops in patients with
      immunodeficiency, during antibiotic treatment, and application of invasive
      methods of diagnosis and treatment, promoting penetration of the agent into the
      blood, which often results in development of mycotic foci in the visceral
      parenchyma and nervous system. The involvement is diagnosed from resistance to
      common therapy and is verified by laboratory investigations: microscopic
      examination of biological substrates, inoculation in nutrient media, serological
      tests, and histological analysis of biopsy specimens. Etiotropic therapy is
      carried out by antimycotic drugs with due regard for the agent sensitivity, drug
      pharmacokinetics, and drug tolerance. Antimycotic therapy should be carried out
      by a physician with at least the minimal knowledge of mycology.

PMID- 10360073
TI  - [Empirical antimicrobial chemoprophylaxis and chemotherapy of infections in
      surgical patients].
AB  - Philosophy of antibacterial chemotherapy (ACT) in threatened and developing
      infection in surgical patients is formulated, based on clinical experience and
      analysis of published reports. Indications for ACT and choice of drugs during and
      after various surgical interventions are discussed. A variant of a protocol of
      antibiotic therapy is presented. Errors and inaccuracies in ACT are discussed.

PMID- 10360074
TI  - [Mycotic infections in the practice of an intensive care specialist].
AB  - The authors report their experience gained in intensive care of patients with a
      grave complication of the underlying diseases: disseminated mycotic infection.
      Factors of risk of the complication are enumerated, diagnosis and treatment of
      mycotic involvement in patients of intensive care wards are described.

PMID- 10360075
TI  - [Acute intermittent porphyria in the practice of an intensive care specialist].
AB  - Acute intermittent porphyria (AIP) is a hereditary disease caused by disordered
      haem biosynthesis and characterized by paroxysmal exacerbations. It usually
      manifests in adult women. Provoking factors are pregnancy, alcohol, and
      "porphyrogenic" drugs. Grave attacks of AIP require urgent hospitalization in
      intensive care wards, rapid purposeful diagnosis and adequate therapy,
      determining the prognosis. The number of drugs should be minimized and drugs with
      a known porphyrogenic effect absolutely ruled out. A 35-year-old patient with the
      first episode of AIP is described; the disease eventuated in death after 2
      months.

PMID- 10360076
TI  - [Changes in the oxidant-antioxidant system activity in patients with hepatic
      failure treated with hyperbaric oxygenation and actoprotectors].
AB  - Effects of hyperbaric oxygenation, bemitil, and solcoseryl used in preoperative
      treatment of patients with hepatic failure on the oxidant-antioxidant system are
      studied. Lipid peroxidation (LPO) was assessed from changes in the levels of
      malonic dialdehyde and diene conjugate and the antioxidant system from the number
      of SH-groups. Hyperbaric oxygenation led to activation of LPO processes. Bemitil
      decreased the intensity of LPO by extending the potentialities of the antioxidant
      system. Antioxidant properties of solcoseryl were not realized through the thiol
      buffer of the antioxidant system. Only a course of treatment with this drug
      brings about a stable effect.

PMID- 10360077
TI  - [Prognostication and prevention of acute postoperative pancreatitis].
AB  - Equations for accurate prediction of the course of postoperative pancreatitis are
      developed by multifactorial regression analysis for purposeful prevention of this
      condition. An injury to the pancreas and the "readiness" of hepatoduodenal organs
      to a degenerative destructive process are significant for the development of
      pancreatitis. A differentiated strategy is developed for preventing this
      complication during the post- and intraoperative period by protease inhibitors,
      cytostatics, and other nonspecific methods.

PMID- 10360078
TI  - [Our experience in the use of a Russian preparation of pulmonary surfactant in
      the treatment of acute respiratory distress syndrome and severe pneumonia in
      children].
AB  - Six critical patients aged 2 months to 13 years with lung diseases were treated
      by pulmonary surfactant preparation. Three of these children developed the acute
      respiratory distress syndrome in the presence of grave pneumonia (1 case),
      asphyxial drowing (1 case), and small-small intestinal invagination (1 case),
      three others developed acute bilateral large focal pneumonia with or without
      repeated atelectases. The drug Surfactant-BL was administered in a dose of 400
      micrograms/m2 by instillations (2 cases) or by inhalation aerosols. The drug
      improved blood gases, lung compliance, x-ray picture, and clinical status of all
      patients, permitting a decrease in IMV/SIMV parameters within 12-48 h after the
      last administration and discontinuation of IMV/SIMV in 3 patients within 24 h
      after 1 or two administrations. Five children survived, 1 (with asphyxial
      drowning) died with brain edema and wedging syndrome. Surfactant-BL is a safe and
      effective drug; administration through alveolar nebulisers should be preferred.

PMID- 10360079
TI  - [Perioperative use of ultra-fast acting beta blockers].

PMID- 10360080
TI  - Occupational health education in Poland: new needs, new requirements, new
      programmes.
AB  - The conditions of modern work environment in Poland generate new problems, new
      needs and new expectations in the area of occupational health. They are
      associated not only with the rapidly changing technologies and new professions
      but also with the psychosocial factors pertaining to extensive transformations of
      the political and economic systems. New needs and expectations determine a new
      approach: firstly, to the responsibilities of the occupational health
      specialists; secondly, to the organisation and management of the workers health
      care; and thirdly, to the general principles of the occupational health,
      including in particular relevant legislation. The new requirements concerning the
      operation of the occupational health system in all the three dimensions must be
      addressed in the design of the new training programmes in occupational health
      whether under- or postgraduate. Subjects to updating and modification should be
      not only the content of the training but also its forms and methodology.
      Competence-based learning should be accompanied by the modern methods of problem
      solving, distant learning, organised self-education and self-assessment. The
      growing interest in the quality of the training should be expressed, first of
      all, in the activities aiming at the development of procedures to assess the
      effectiveness of the training. It seems also necessary to adopt the active
      learning approach intensifying acquisition and verification of the knowledge and
      skills. This approach would also lead to deeper changes in the students'
      mentality and behaviour, e.g. to make them able to estimate their own and others'
      level of professional competence or shape the personal system of professional
      values under the conditions of the free-market economy in the health care which
      entails quality requirements for the services and the competition among its
      providers.

PMID- 10360081
TI  - Self-assessment of competence in public health management as a measure of
      effectiveness of postgraduate training.
AB  - The main goal of the postgraduate training in public health is to make already
      experienced students develop appropriate competence to deal with health problems
      existing and emerging within different spheres of social reality. The task
      involves the checking on and evaluation of the students' learning process and the
      didactic qualifications of teaching personnel. A serious problem is posed here by
      the specificity of the postgraduate training in the course of which new
      competences have to be transmitted in the context of competence already
      possessed, which should be also improved refreshed, revised etc. Moreover, the
      influence of the experience and attitude components is here stronger than in the
      case of undergraduate studies. All these need to be reflected in the curricula,
      teaching methods, and assessment procedures. In the introductory part of the
      paper the authors discuss briefly an approach to and the adopted definition of
      professional competence. The body is devoted to the assessment of competence
      acquired and the methods applied after a 2-year postgraduate studies for public
      health managers. Seventeen types of competence transmitted to the students were
      made the points of reference in a special self-assessment questionnaire. The
      respondents were asked to assess the contribution of particular courses to the
      acquisition or improvement of each type of competence. The results obtained in a
      group of students suggest that some modifications and improvements in the
      educational objectives and programmes should be introduced.

PMID- 10360082
TI  - Psychosocial factors at work and back pain: a prospective study in office
      workers.
AB  - A prospective one-year follow-up study was carried out among 189 civil servants
      of a municipal social service department. Its aim was to investigate whether
      psychosocial factors at work predict back pain prevalence at follow-up. The
      workers were questioned twice about personal characteristics, psychosocial
      factors at work, physical workload, back pain experience, and general health and
      well-being. Back pain was assessed as twelve month prevalence and pain intensity
      on a visual analogue scale (VAS). In a univariate analysis the variables: high
      job demands, confinement to the workplace, depression, psychological complaints,
      and general health complaints, were positively related to back pain prevalence at
      follow-up. In a multivariate analysis, however, none of the odds ratios for
      psychosocial stressors differed significantly from one another. Among the back
      pain variables, pain intensity on the VAS was the best predictor of back pain at
      follow-up. In a final multivariate logistic regression model none of the above
      mentioned variables contributed significantly, except for initial back pain.
      Initial back pain with low intensity and high intensity significantly predicted
      the prevalence of back pain at follow-up with odds ratios of 3.0 (90% CI: 1.5
      6.0) and 10.3 (90% CI: 4.1-25.5), respectively. In conclusion, the present study
      does not provide clear evidence that psychosocial factors at work predict back
      pain.

PMID- 10360083
TI  - A comparison of noise induced disability assessments in the UK and Poland.
AB  - The difference between the legal assessment of the disability associated with
      noise induced hearing loss and that experienced by the worker has not as yet been
      successfully resolved. Legal assessment is driven by financial consideration
      rather than the rehabilitation needs of the subject. The aim of this paper is to
      present this problem and consider the formulae currently used in the UK and
      Poland in the assessment of noise induced hearing disability.

PMID- 10360084
TI  - Electromagnetic field pattern in the environment of GSM base stations.
AB  - Three mobile phone systems are used in Poland: analog, operated at the 450 MHz
      frequency range, and two digital systems operated at 900 MHz and 1800 MHz. The
      GSM--Global System for Mobile Communication meets all relevant requirements, and
      it is most widely used throughout the world. According to the mobile phone
      concept, the whole communication area is divided into sub-areas (cells) where
      base stations are located. The base stations are provided with the transmitter
      units mounted on free-standing masts, high chimneys and building roofs, including
      those of the residential buildings. The transmitter antennas of the base stations
      constitute a source of 935-960 EMF radiation. This work analyses the essential
      characteristics of the base station antennas from the point of view of radiation
      intensity. The analysis is based on the results of EMF measurements performed by
      experts of two relevant research institutes. For inaccessible antennas, the
      measurements were performed at the accredited laboratory.

PMID- 10360085
TI  - Occupational exposure to ethylene oxide of hospital staff.
AB  - Occupational exposure to ethylene oxide was assessed among the workers remaining
      in direct contact with ethylene oxide or with ethylene oxide-sterilized
      instruments in 13 hospitals located in the city of Lodz and its suburbs.
      Individual dosimetry and stationary sampling methods were employed. The samples
      collected from the occupational environment were analysed by gas chromatography
      with mass detection. The analytical method enabled determination of low ethylene
      oxide concentrations in the presence of the accompanying chemicals, such as ethyl
      alcohol, isopropyl alcohol, ethyl ether and isoflurene. In total, 227
      determinations were made, and ethylene oxide at concentrations above 0.01 mg/m3
      (which was the detection limit of the method) was found to be present in 164
      samples. The ethylene oxide levels were found to vary widely, from lower than
      0.01 TLV to several hundred times the TLV value.

PMID- 10360087
TI  - Neurotoxicity assessment of selected organic solvents based on spontaneous and
      evoked cortical and hippocampal activity in rats.
AB  - In a series of acute experiments on rats the potential of toluene, mesitylene,
      hemimellitene and pseudocumene to affect the CNS function was assessed following
      an analysis of spontaneous and evoked hippocampal and cortical activity. The
      electrophysiological examinations were performed on rats with recording
      electrodes chronically implanted into selected brain structures. Solvent
      concentration in peripheral blood was determined by gas chromatography combined
      with the head space technique in rats with no surgical treatment. The experiments
      revealed significant quantitative differences between hippocampal and cortical
      EEG after i.p. injections of equimolar doses of the solvents. A relationship was
      found between the changes in spontaneous EEG and blood concentration of the
      solvents. Hemimellitene, with the lowest recorded blood level was found to have
      the highest potential for inducing the CNS effects.

PMID- 10360086
TI  - Mutagenic activity of 3,6-diamino-10-methyl-9,10-dihydroacridine in Salmonella
      typhimurium cells.
AB  - Mutagenic evaluation of 3,6-diamino-10-methyl-9,10-dihydroacridine (AcrH), a new
      synthesized acridine derivative was undertaken using short-term in vitro test.
      The mutagenic potential of AcrH was evident from the reverse mutation induced in
      the presence and absence of S9-mix of Salmonella typhimurium TA97a, TA98, TA100
      and TA102 cells. The levels of the mutagenic activity of AcrH in TA97a are
      comparable with that of acriflavine.

PMID- 10360088
TI  - Is it safe to apply the additivity rule to evaluating health effects of exposure
      to Farbasol?
AB  - Neurotoxic and sensory respiratory irritation effects of Farbasol in male rats
      and male Balb/C mice were investigated in condition of acute inhalation exposure.
      Rotarod performance and pain sensitivity behaviour were tested in rats exposed to
      Farbasol at concentrations of 4665-9622 mg/m3 immediately after termination of a
      four-hour exposure. The respiratory rate was measured in mice by the whole body
      plethysmographic method in 6 min duration exposure to various concentrations of
      Farbasol. Exposure to Farbasol resulted in concentration-dependent disturbances
      in rotarod performance and decrease in pain sensitivity in rats, and depression
      of respiratory rate in mice. The EC50 value for rotarod performance behaviour
      disturbances was 5497 mg/m3 and for pain sensitivity EC50 was 6589 mg/m3. The
      concentration depressing the respiratory rate to 50% (RD50) was 3139 mg/m3. The
      comparison of Farbasol EC50 and RD50 values and its individual constituents such
      as trimethylbenzene isomers and 4-ethyl toluene established in similar
      experimental conditions indicate their similar toxic effects potency. Application
      of additivity rule for establishing the MAC value for Farbasol seems to be safe.

PMID- 10360089
TI  - Protection against noise: a European Commission concerted action.

PMID- 10360090
TI  - Europaeds.

PMID- 10360091
TI  - The medical management of chronic stable angina.

PMID- 10360092
TI  - Alpha 1-antitrypsin deficiency.

PMID- 10360093
TI  - The reality of torture.

PMID- 10360094
TI  - Audit in health care--the process of reviewing quality. Research Committee of the
      Faculty of Public Health Medicine.

PMID- 10360095
TI  - Neonatal abstinence syndrome.
AB  - A 12 month review of infants admitted with neonatal abstinence syndrome to a
      neonatal intensive care unit was undertaken. The relationship of maternal drug
      abuse to symptoms, the effectiveness of pharmacologic agents in controlling
      symptoms and the length of inpatient stay were investigated. A retrospective
      review of maternal and infant records was performed. Those infants with a serial
      Finnegan score greater than 8 were treated. Pharmacologic treatment was oral
      morphine sulphate (0.2 mg 4-6 hourly), phenobarbitone (3-7 mgs/kg/day), or
      combination of the above. 43 infants were admitted to the hospital during the
      year. The average maternal age was 24.6 years, (18-34 years). Drug use
      volunteered by the mothers was methadone alone in 6 cases, methadone and
      benzodiazepines in 14, methadone and heroin and benzodiazepines in 7, methadone
      and heroin in 10, heroin alone in 2, and other multiple drug use including oral
      morphine sulphate, dothiepin and cannabis in 4. Average gestational age was 40.3
      (35-42 weeks). The average birthweight was 2.81 kgs (1.89-3.91 kgs). Time to
      onset of withdrawal symptoms was 2.8 (1-13) days. The duration of pharmacologic
      treatment (oral morphine sulphate and/or phenobarbitone) was 21.8 (1-62) days.
      The total hospital stay for the 43 infants was 1,011 days. This study confirms
      that polydrug abuse is the commonest type of drug abuse in Dublin. The duration
      of withdrawal symptoms is loosely related to drug type, but increasing duration
      of symptoms is noted for infants exposed to benzodiazepines. Our experience would
      favour the use of morphine sulphate to treat pure opiate withdrawal symptoms.
      Over the 12-month period, there was an average occupancy of 3 beds per day in the
      paediatric department.

PMID- 10360096
TI  - Potential for treatment with thrombolysis in an Irish stroke unit.
AB  - Since the publication of the NINDS rt-PA trial in 1995, tissue plasminogen
      activator has been licensed for the treatment of acute cerebral infarction in the
      U.S. The demonstrated benefit was confirmed to patients presenting within three
      hours of symptom onset on adhering to study guidelines, which subsequently have
      formed the basis for a protocol for thrombolysis in acute stroke. The
      implementation of a thrombolysis programme in Ireland would require a
      restructuring of hospital facilities to manage acute stroke. We conducted a
      prospective study of 100 patients admitted to an acute stroke unit to assess the
      potential for intervention with t-PA under NINDS guidelines. Data was collected
      on stroke type. CT appearances, time of onset of stroke and laboratory
      parameters. Only 6% of all strokes assessed were eligible for thrombolysis and
      time to presentation was the major excluding factor. When time was removed as an
      exclusion criteria only 1/5 of all strokes were potential candidates in this best
      case scenario. Thrombolysis does improve outcome in cerebral infarction in a a
      strictly controlled setting but only 6% of our patients would currently be
      eligible for treatment. While this may improve with better public education
      regarding stroke and it's treatment, only a 1/5 of our patients would still be
      eligible were they all to present within 2 hours of symptoms onset.

PMID- 10360097
TI  - An outbreak of multidrug-resistant Salmonella typhimurium food poisoning at a
      wedding reception.
AB  - An outbreak of gastrointestinal illness among 127 persons attending a wedding
      reception in Dublin was investigated. One hundred and fifteen wedding guests were
      interviewed and information obtained about demographic and clinical
      characteristics, and food consumed at the reception. Faecal samples from ill
      guests were submitted for microbiological examination and environmental
      investigations conducted at the catering facilities. Fifty-eight cases (diarrhoea
      within three days after having eaten at the reception) were identified. Forty-six
      cases submitted stool samples, of which 39 were culture positive for Salmonella
      typhimurium. Two isolates were phage-typed and found to be DT 104. Turkey was
      identified as a potential vehicle for this outbreak. A sample of litter from
      young birds at the poultry farm which had supplied the turkeys also tested
      positive for Salmonella Typhimurium DT104. In the Republic of Ireland
      S.typhimurium accounts for almost 50% of all human salmonella isolates.
      Epidemiological and microbiological studies which relate the human and animal
      spectrum of this disease need to be undertaken as a priority.

PMID- 10360098
TI  - Mobility screening in the elderly and resulting referral.
AB  - The aims of this study were to test the usefulness of the Royal College of
      General Practitioners' (RCGP) mobility screening questionnaire in Irish general
      practice and to use it to assess the level of mobility problems in the over-75
      year old population. Questionnaire screening survey in six faculty areas of the
      Irish College of General Practitioners(ICGP) well-spread geographically to be
      representative of the Irish population. Participants were a random sample of 627
      people aged 75 years or over, from the General Medical Services list of 92
      volunteer general practitioners. The Royal College of General Practitioners'
      screening questionnaire for mobility was administered by each person's doctor.
      Suggested interventions were also noted. 92% felt able to get around the house
      independently, with 78% able to manage stairs independently. The commonest aid to
      mobility was a stick, used by 27%. Mental impairment was closely associated with
      inability to get around the house (86% of those not independent around the house
      scored less than 8 on the Abbreviated Mental Test Score). Analysis of referral
      patterns indicated possible deficiencies in the availability of physiotherapy in
      certain areas. The RCGP mobility screening questionnaire was easy to use, and
      helpful in detecting problems which might require attention.

PMID- 10360099
TI  - Unusual ureteric strictures: diagnosis and management.

PMID- 10360100
TI  - The issue of consent in medical law: exceptions to the informed consent rule.

PMID- 10360102
TI  - Rare foreign body in uterus.

PMID- 10360101
TI  - Influenza vaccine: are those at risk taking it?

PMID- 10360103
TI  - Temporomandibular joint (TMJ) dislocation in association with stroke.

PMID- 10360104
TI  - Specialist registrar grade.

PMID- 10360105
TI  - Specialist registrar grade--the Irish perspective.

PMID- 10360107
TI  - Has the media influenced public attitudes to schizophrenia?

PMID- 10360106
TI  - Design and minimum standards for modern general practice.

PMID- 10360108
TI  - Current thinking on the management of schizophrenia.

PMID- 10360109
TI  - Reduce the risk of cot death guidelines. The effect of a revised intervention
      programme. National Sudden Infant Death Register, Dublin.
AB  - In March 1992 the 'Reduce the Risk of Cot Death' guidelines were launched in the
      Republic of Ireland. In response to epidemiological surveys conducted in 1993 and
      1994 these guidelines were revised in November 1995 and a new leaflet was
      distributed. The study set out to compare parents interviewed in 1994 (n = 153)
      and 1996 (n = 132) to determine their source of information on the guidelines and
      the extent of parental change in infant care practice as recommended in these
      guidelines. In both time periods the media was the most frequent source of
      information with 63% (n = 97) of respondents having received advice from the
      media in 1994 compared to 55% (n = 72) in 1996. However a significant number of
      parents especially young (64%) and new (58%) mothers were uninterested or unable
      to access the relevant health care literature indicating a group needing a
      tailored educational package in the future. Medical sources especially Public
      Health Nurses ranked second in delivering information at 47% (n = 72) in 1994 vs
      46% (n = 60) in 1996 while other sources such as family and friends were the
      least frequent sources of information. In 1996 more respondents (59%; n = 78) put
      their children to sleep on their back than in 1994 (35%; n = 54) but they used
      heat more frequently at night [73% (n = 96) in 1996 vs 57% (n = 87) in 1994].
      There was no significant difference in the percentage of parents smoking [29% (n
      = 45) vs 33% (n = 43)], the uptake of breast feeding [40% (n = 61) vs 49% (n =
      64)] and the way parents clothed their children [60% (n = 92) vs 58% (n = 77)
      used more than ten tog] between 1994 and 1996. Although in 1996 the message to
      reduce the risks of cot death was more specific and direct, it seems to have had
      less effect on further changing parents' practices. However, the overall effect
      of the two education programmes has been successful in yielding a low percentage
      (2%; n = 2) of babies sleeping prone in 1996). Smoking remains the major
      modifiable risk factor for SIDS in Ireland.

PMID- 10360110
TI  - Extradural haematoma--a preventable cause of death.
AB  - Traumatic extradural haematoma (EDH) complicates 1-4% of all head injuries and is
      a major factor contributing to morbidity and mortality. Clinical awareness and
      early diagnosis are the keys to successful management. With the advent of
      computerised tomographic (CT) scanning a trend towards 'zero mortality' has been
      reported. We report four adolescent cases presenting with mild head injury
      (Glascow Coma Score 13-15) who subsequently died as a result of EDH. We suggest
      that excessive delay both in recognising the condition and the subsequent
      referral and transfer are factors contributing to the mortality of these
      patients.

PMID- 10360111
TI  - Prenatal diagnosis of lethal fetal malformation in Irish obstetric practice.
AB  - The diagnosis of lethal fetal malformation prenatally has profound implications
      for the pregnancy, the expectant couple and the medical care provided. The aim of
      this study was to investigate these implications and the medical factors
      pertaining to prenatal diagnosis of lethal fetal abnormality in current obstetric
      practice in Ireland. Data was collected prospectively from all cases of lethal
      fetal malformation diagnosed at the Fetal Medicine Unit, University College
      Hospital Galway from December 1997 to June 1998 inclusive. Diagnosis was made on
      the basis of ultrasound findings and invasive procedures (amniocentesis and
      chorionic villus sampling). Thirteen cases of lethal fetal abnormality were
      diagnosed: Edward's syndrome, Patau's syndrome, bilateral multicystic renal
      dysplasia, Potters sequence, hypoplastic left heart, anencephaly with
      craniorrhachischisis, lethal osteogenesis imperfecta and non-immune hydrops.
      Intrauterine death occurred in four cases. Four women had preterm complications
      e.g. preterm premature rupture of membranes, preterm labour, placental abruption,
      coagulopathy and severe pre-eclampsia. Three pregnancies progressed to term, two
      of which had a vaginal delivery and one had an elective caesarean section for
      malpresentation, all of which were early neonatal deaths. Three women chose to
      travel abroad in order to obtain a termination of pregnancy. Obstetric and
      neonatal dilemmas in management of lethal fetal malformation are discussed.

PMID- 10360112
TI  - A one year prospective census of workload and process at a community hospital
      casualty room.
AB  - A prospective census of patients attending the casualty room of Wicklow District
      Hospital (a general practitioner operated service) for one year was performed. A
      total of 1564 attendances were recorded, of which 904 (58%) were male and 953
      (61%) were eligible for free medical care. Almost half, 735 (47%) attended
      outside daytime hours. Concerning type of presentation, 637 (41%) attended with
      acute trauma, 450 (29%) attended with acute medical and 477 (30%) attended with
      elective problems. Repeat visits accounted for 5% of the total. Concerning
      outcome of consultation, 409 (26%) were given a prescription, 307 (20%) had blood
      tests, 263 (17%) received dressings, 183 (12%) were referred to secondary care,
      168 (11%) were followed up by their GP, 146 (9%) had minor surgery, and 86 (5%)
      had no intervention. This study indicates that the hospital is responsible for a
      considerable workload, with a significant out of hours component.

PMID- 10360113
TI  - Peritonsillar abscess and infectious mononucleosis: an association or a different
      presentation of the same condition.
AB  - Few reports document the coexistence of Peritonsillar Abscess (PTA) and
      Infectious Mononucleosis (IM). In this paper, we are reporting on two cases that
      presented to our department with the two conditions simultaneously. We also
      review the literature and discuss the current theories behind what was
      considered, for sometime, an unusual presentation of a common problem.

PMID- 10360114
TI  - Unlicensed and off label drug use for children with child psychiatric problems.

PMID- 10360115
TI  - Bioethics body needed.

PMID- 10360116
TI  - Gender: what's the difference?

PMID- 10360117
TI  - Images in neuroscience. Cognition. Perception 2.

PMID- 10360118
TI  - Childhood sexual abuse as a risk factor for depression in women: psychosocial and
      neurobiological correlates.
AB  - OBJECTIVE: Depression is twice as common in women as in men, but the reason for
      this sexual dimorphism is unknown. This article reviews recent studies of the
      role of childhood sexual abuse in the subsequent development of major depressive
      disorder, and the biological and psychosocial mechanisms by which early stressors
      may contribute to adult-onset depression in women. Particular attention is paid
      to investigations of the long-term effects of early stress on hypothalamic
      pituitary-adrenal (HPA) axis function. METHOD: Studies were identified by means
      of computerized and manual searches; further references were obtained from the
      bibliographies of reviewed articles. RESULTS: Childhood sexual abuse is
      associated with adult-onset depression in both men and women, and occurrence of
      such abuse is more common in girls than in boys. There is evidence from both
      animal and human studies that early stressors produce long-term dysregulation of
      the HPA axis similar to that seen in depressed patients and that such
      dysregulation results in a differential response to stressors in adulthood. In
      addition, it appears that the HPA axis in females may be more susceptible to
      stress-induced dysregulation, which might contribute to an increased
      vulnerability to depression in adulthood. CONCLUSIONS: Childhood sexual abuse is
      an important early stressor that may predispose individuals to adult-onset
      depression by means of dysregulation of the HPA axis. Investigation of the
      mechanisms mediating the relationship between childhood sexual abuse and adult
      onset depression, and the study of gender differences in exposure to this and
      other stressors, may improve our understanding of the etiology of depressive
      illness in general.

PMID- 10360120
TI  - Causal relationship between stressful life events and the onset of major
      depression.
AB  - OBJECTIVE: Stressful life events are associated with the onset of episodes of
      major depression. However, exposure to stressful life events is influenced by
      genetic factors, and these factors are correlated with those that predispose to
      major depression. The aim of this study was to clarify the degree to which
      stressful life events cause major depression. METHOD: The authors assessed the
      occurrence of 15 classes of stressful life events and the onset of DSM-III-R
      major depression over a 1-year period in female twins ascertained from a
      population-based registry. The sample contained 24,648 person-months and 316
      onsets of major depression. Stressful life events were individually rated on
      contextual threat and dependence (the degree to which the stressful life event
      could have resulted from the respondent's behavior). The nature of the
      relationship between stressful life events and major depression was tested by 1)
      discrete-time survival analysis examining the relationship between dependence and
      the depressogenic effect of stressful life events and 2) a co-twin control
      analysis. RESULTS: While independent stressful life events were significantly
      associated with onsets of depression, when level of threat was controlled, the
      association was significantly stronger for dependent events. The odds ratio for
      onset of major depression in the month of a stressful life event was 5.64 in all
      subjects, 4.52 within dizygotic pairs, and 3.58 within monozygotic pairs.
      CONCLUSIONS: Stressful life events have a substantial causal relationship with
      the onset of episodes of major depression. However, about one-third of the
      association between stressful life events and onsets of depression is noncausal,
      since individuals predisposed to major depression select themselves into high
      risk environments.

PMID- 10360119
TI  - Placebos, drug effects, and study design: a clinician's guide.
AB  - OBJECTIVE: This article examines the role of placebos in evaluating the efficacy
      of psychiatric drugs. Also addressed are the identification of placebo effects on
      drugs, the relevance of active placebo, the need for placebo groups in
      psychotherapy studies, and ethical issues concerning the use of placebo. METHOD:
      Psychiatric drug treatment trials were reviewed. Emphasis was placed on studies
      with ambiguous outcomes, studies using an active placebo, and studies attempting
      to understand the role of placebo effects on patients receiving a drug. The
      concept of pattern analysis for identifying true drug effect is reviewed.
      RESULTS: Evidence that placebos are required to prevent a false conclusion about
      drug efficacy is presented. The public health implications of concluding that an
      ineffective drug is beneficial are examined. Active placebos do not appear
      necessary, and there is some evidence that the odds of identifying a patient who
      has improved as a result of true drug effect (as opposed to placebo effect)
      exceed chance with pattern analysis. CONCLUSIONS: Psychiatric disorders have a
      fluctuating course, psychiatry's phenomenologically based nosological system is
      inexact, and the interaction between these two leads to a large proportion of
      patients experiencing a placebo effect. It may be possible to identify patients
      receiving an antidepressant who improved as a result of a placebo effect. This is
      an educated guess that may be helpful in planning the treatment of patients who
      have a contraindication to continuing a psychopharmacological regimen.

PMID- 10360121
TI  - Gender and age influences on human brain mu-opioid receptor binding measured by
      PET.
AB  - OBJECTIVE: Both age and gender are being increasingly recognized as important
      factors influencing CNS structure and function. However, there are relatively few
      data on actual neurochemical differences between the sexes in human subjects or
      on their interaction with age. One of the central neurotransmitter systems for
      which sex differences have been suggested by animal models and clinical human
      data is the opioid. In this study the authors examined age- and gender-associated
      variations in mu-opioid receptor binding with positron emission tomography (PET).
      METHOD: Healthy human subjects were studied with PET and the radiotracer
      [11C]carfentanil, a selective mu-opioid agonist. Two separate subject groups were
      examined: one group of 24 men and 12 women was studied in a retrospective
      analysis of data, and a second group of 12 men and 18 women was recruited
      prospectively and studied with a higher-resolution scanner. RESULTS: Mu-opioid
      receptor binding potential (Bmax/Kd) was found to increase with age in
      neocortical areas and the putamen. Sex differences, with higher mu-opioid binding
      in women, were observed in a number of cortical and subcortical areas. Gender-by
      age interactions were observed in the thalamus and the amygdala; in vivo mu
      opioid binding declined in postmenopausal women to levels below those of men.
      CONCLUSIONS: These data imply that both age and gender are important variables to
      consider in the interpretation of investigations of human function in which the
      opioid system plays a role. Also, women's reproductive status (reproductive age
      versus postmenopausal) may influence the function of CNS opioid systems.

PMID- 10360122
TI  - Antisocial personality disorder and psychopathy in cocaine-dependent women.
AB  - OBJECTIVE: The goal of this study was to examine the lifetime prevalence of
      antisocial personality disorder according to five diagnostic systems and the
      prevalence of psychopathy in a study group of women. The relationship between
      antisocial personality disorder and psychopathy was also examined. Finally,
      differences in treatment admission variables based on the presence or absence of
      antisocial personality disorder and/or psychopathy were evaluated. METHOD:
      Antisocial personality disorder was diagnosed in 137 treatment-seeking, cocaine
      dependent women according to the Feighner criteria, Research Diagnostic Criteria
      (RDC), and DSM-III, DSM-III-R, and DSM-IV criteria. Psychopathy was assessed by
      the Revised Psychopathy Checklist. RESULTS: Rates of antisocial personality
      disorder varied from 76% according to the Feighner criteria to 11% for the RDC.
      Nineteen percent (N = 26) of the women scored in the moderate to high range on
      the Revised Psychopathy Checklist. All of these women were diagnosed with
      antisocial personality disorder according to DSM-III and Feighner criteria, but
      only 15 of the 26 were diagnosed according to DSM-III-R, 12 according to DSM-IV,
      and six with the RDC. Moderate levels of psychopathy were associated with a
      history of illegal activity at treatment admission, whereas antisocial
      personality disorder was not. CONCLUSIONS: There was relatively little diagnostic
      agreement between classification systems. This study indicates that antisocial
      personality disorder and psychopathy are not synonymous terms for the same
      disorder. Findings support a need to redefine antisocial personality disorder
      diagnostic criteria to make them gender neutral by including behaviors associated
      specifically with antisociality in women.

PMID- 10360123
TI  - Maternal smoking during pregnancy and risk of criminal behavior among adult male
      offspring in the Northern Finland 1966 Birth Cohort.
AB  - OBJECTIVE: The goal of this study was to test the hypothesis that maternal
      smoking during pregnancy is associated with greater risk for criminal behavior of
      the offspring in adulthood. METHOD: An unselected, general population cohort
      composed of 11,017 subjects (5,636 men, 5,381 women) was followed up
      prospectively from the sixth month of pregnancy to age 28 years. Interviews with
      the mother during the pregnancy, health records, and an assessment of the
      offspring at age 1 year provided information on risk factors. The Ministry of
      Justice provided information on criminal offenses for all subjects. RESULTS:
      Because of the low rate of criminal offenses among women, the present analyses
      are restricted to men (N = 5,636). Compared to the sons of mothers who did not
      smoke, the sons of mothers who smoked during pregnancy had more than a twofold
      risk of having committed a violent crime or having repeatedly committed crimes,
      even when other biopsychosocial risk factors were controlled. While maternal
      smoking during pregnancy alone explained 4% of the variance associated with
      violent offenses among male offspring, it was not significantly associated with
      nonviolent offenses among male offspring. When maternal smoking during pregnancy
      was combined with a maternal age of less than 20 years, a single-parent family,
      an unwanted pregnancy, and a developmental lag in walking or talking, the odds
      ratios for violent offenses increased up to ninefold and for persistent offenses
      up to 14-fold. CONCLUSIONS: Maternal smoking during pregnancy is associated with
      violent offenses and persistent offenses, but not with nonviolent offenses, among
      male offspring in adulthood.

PMID- 10360125
TI  - Suggested minimal effective dose of risperidone based on PET-measured D2 and 5
      HT2A receptor occupancy in schizophrenic patients.
AB  - OBJECTIVE: Multicenter trials with the novel antipsychotic risperidone have
      suggested a standard dose of 6 mg/day. However, a dose producing the highest
      response rate in fixed-dose studies is likely to exceed the minimal effective
      dose in most patients. The aim of this positron emission tomography (PET) study
      was to suggest a minimal effective dose of risperidone based on measurements of
      dopamine D2 and serotonin 5-HT2A receptor occupancy. METHOD: Eight first-episode
      or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for
      4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks,
      with [11C]raclopride to measure D2 receptor occupancy and [11C]N-methylspiperone
      to measure 5-HT2A receptor occupancy. RESULTS: Seven patients completed the study
      and responded to treatment with risperidone. No patient had extrapyramidal side
      effects at the time of inclusion in the study. At the 6-mg/day dose, mean D2
      receptor occupancy was 82% (range = 79%-85%), 5-HT2A receptor occupancy was 95%
      (range = 86%-109%), and six patients had developed extrapyramidal side effects.
      After dose reduction to 3 mg/day, D2 receptor occupancy was 72% (range = 53%
      78%), and 5-HT2A receptor occupancy was 83% (range = 65%-112%). Three patients
      had extrapyramidal side effects at this time. CONCLUSIONS: Treatment with
      risperidone, 6 mg/day, is likely to induce unnecessarily high D2 receptor
      occupancy, with a consequent risk of extrapyramidal side effects. High 5-HT2A
      receptor occupancy did not prevent extrapyramidal side effects completely. The
      authors previously suggested an optimal interval for D2 receptor occupancy of 70%
      80%. To achieve this, resperidone, 4 mg/day, should be a suitable initial dose
      for antipsychotic effect with a minimal risk of extrapyramidal side effects in
      most patients.

PMID- 10360124
TI  - Rehospitalization rates of patients recently discharged on a regimen of
      risperidone or clozapine.
AB  - OBJECTIVE: The purpose of this study was to examine rehospitalization rates of
      people receiving risperidone or clozapine who had been discharged from state
      psychiatric hospitals in Maryland. METHOD: Rehospitalization status was monitored
      for all patients discharged from state psychiatric facilities on a regimen of
      either risperidone or clozapine between March 14, 1994, and Dec. 31, 1995.
      Patients were followed up with respect to readmission until Dec. 31, 1996. Time
      to readmission was measured by the product-limit (Kaplan-Meier) formula. Risk
      factors associated with rehospitalization were examined. RESULTS: One hundred
      sixty patients were discharged on risperidone, 75 having the diagnosis of
      schizophrenia. The patients with schizophrenia were more likely to be readmitted
      than the 85 patients with other mental disorders. Recidivism rates for
      schizophrenic patients discharged on risperidone versus those discharged on
      clozapine were not significantly different over the 24-month study period.
      However, no patient who received clozapine and remained discharged for more than
      10 months (N = 49) was readmitted, while the readmission rate for risperidone
      treated patients appeared to be steady up to 24 months. At 24 months 87% of the
      clozapine-treated patients and 66% of the risperidone-treated patients remained
      in the community. No clinical or demographic variables were found to predict
      rehospitalization. CONCLUSIONS: This study demonstrates that the
      rehospitalization rates of patients taking the second-generation antipsychotics
      risperidone and clozapine are lower than those in previously published reports of
      conventional antipsychotic treatment.

PMID- 10360126
TI  - Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation
      for low receptor occupancy and early clinical relapse upon withdrawal of
      clozapine or quetiapine.
AB  - OBJECTIVE: In an attempt to understand the basis of early relapse after
      antipsychotic withdrawal, the objective of this study was to determine whether
      the low occupancy of dopamine D2 receptors by clozapine and by quetiapine, as
      seen by brain imaging, could arise from a rapid release of some of the D2-bound
      clozapine or quetiapine by the brain imaging compounds and by the action of a
      physiological concentration of dopamine. METHOD: Human cloned D2 receptors were
      first pre-equilibrated with the [3H]antipsychotic drug, after which raclopride,
      iodobenzamide, or dopamine (at the physiological concentration in the synapse)
      was added, and the time course of release of the [3H]antipsychotic from the D2
      receptor was measured. RESULTS: Within 5 minutes, low concentrations of
      raclopride and iodobenzamide displaced appreciable amounts of [3H]clozapine and
      [3H]quetiapine from the D2 receptors but, during the course of 1 hour, did not
      displace any of the other antipsychotic [[3H]ligands. [3H]Clozapine and
      [3H]quetiapine, moreover, were displaced by dopamine (100 nM) at least 100 times
      faster than the other antipsychotic [3H]ligands. CONCLUSIONS: Clozapine and
      quetiapine are loosely bound to the D2 receptor, and the injected radioactive
      ligand at its peak concentration may displace some of the D2-bound antipsychotic
      drug, resulting in apparently low D2 occupancies. Therefore, under clinical brain
      imaging conditions with [11C]raclopride, D2 occupancies by clozapine and by
      quetiapine may be higher than currently estimated. These considerations may
      result in high levels of the D2 receptors being occupied by therapeutic doses of
      clozapine or quetiapine. The rapid release of clozapine and quetiapine from D2
      receptors by endogenous dopamine may contribute to low D2 receptor occupancy and
      to early clinical relapse upon withdrawal of these medications.

PMID- 10360127
TI  - Persistence of haloperidol in human brain tissue.
AB  - OBJECTIVE: After discontinuation of neuroleptic drugs, their antipsychotic and
      antiparkinsonian effects are still present for a prolonged period. It is not
      known whether the extended effects of neuroleptic drugs in humans are due to the
      continued presence of drug in brain tissue or to long-lasting drug-induced
      physiologic changes. The aim of this study was to directly examine haloperidol
      concentrations in human brain tissue in relation to drug-free time. METHOD:
      Haloperidol concentrations were measured in five regions (temporal cortex,
      cingulate gyrus, caudate nucleus, dentate nucleus, corpus callosum) of the
      postmortem brains of 11 patients previously treated with haloperidol. Haloperidol
      was analyzed by means of high-performance liquid chromatography with ultraviolet
      detection. The half-life in brain tissue was estimated by a population kinetic
      analysis. RESULTS: Haloperidol concentrations in the human brain tissue were 10
      30 times higher than optimal serum concentrations used in the treatment of
      schizophrenia. Haloperidol concentrations appeared to be homogeneously
      distributed across different brain areas within a single patient. There was no
      apparent relation between duration of treatment and mean haloperidol
      concentration. Higher doses of haloperidol seemed to be related to higher
      concentrations in brain tissue. The elimination half-life from brain tissue was
      calculated to be 6.8 days. CONCLUSIONS: The results may have implications for
      clinical treatment decisions and the design of clinical research protocols.
      Patients exposed to haloperidol cannot be considered to be free of residual
      effects of the drug for a number of weeks after withdrawal.

PMID- 10360128
TI  - Hypofrontality in attention deficit hyperactivity disorder during higher-order
      motor control: a study with functional MRI.
AB  - OBJECTIVE: Functional magnetic resonance imaging (MRI) was used to investigate
      the hypothesis that attention deficit hyperactivity disorder (ADHD) is associated
      with a dysfunction of prefrontal brain regions during motor response inhibition
      and motor timing. METHOD: Generic brain activation of seven adolescent boys with
      ADHD was compared to that of nine comparison subjects equivalent in sex, age, and
      IQ while they were performing a stop task, requiring inhibition of a planned
      motor response, and a motor timing task, requiring timing of a motor response to
      a sensory cue. RESULTS: The hyperactive adolescents showed lower power of
      response in the right mesial prefrontal cortex during both tasks and in the right
      inferior prefrontal cortex and left caudate during the stop task. CONCLUSIONS:
      ADHD is associated with subnormal activation of the prefrontal systems
      responsible for higher-order motor control. Functional MRI is a feasible
      technique for investigation of neural correlates of ADHD.

PMID- 10360129
TI  - Diagnostic orphans: adolescents with alcohol symptom who do not qualify for DSM
      IV abuse or dependence diagnoses.
AB  - OBJECTIVE: Little is known about the validity of the DSM-IV criteria for alcohol
      use disorders when applied to adolescents. This report describes a group of
      "diagnostic orphans," adolescents with one or two DSM-IV alcohol dependence
      symptoms who do not meet the DSM-IV criteria for alcohol abuse or alcohol
      dependence. METHOD: The study included 199 male and 173 female subjects aged 13
      19 years. All subjects were regular drinkers, recruited from community sources
      and alcohol treatment programs. At baseline and at 1-year follow-up, DSM-IV
      alcohol use disorders were assessed with a version of the Structured Clinical
      Interview for DSM-III-R, modified for DSM-IV criteria. RESULTS: Diagnostic
      orphans represented 31% of the drinkers without an alcohol use disorder. The
      orphans were similar to the alcohol abusers and dissimilar to the other drinkers
      in alcohol and substance use patterns and in the course of alcohol problems over
      1 year. CONCLUSIONS: The results indicate limitations of the DSM-IV criteria for
      alcohol use disorders when applied to adolescents. Diagnostic orphans should be
      considered separately from other drinkers in research and treatment efforts.

PMID- 10360130
TI  - Previous exposure to trauma and PTSD effects of subsequent trauma: results from
      the Detroit Area Survey of Trauma.
AB  - OBJECTIVE: With the exception of a few reports of higher rates of childhood
      trauma in Vietnam veterans with posttraumatic stress disorder (PTSD), little is
      known about the influence of previous exposure to trauma on the PTSD effects of
      subsequent trauma. The authors examine interrelated questions about the effects
      of previous exposure to trauma. METHOD: A representative sample of 2,181
      individuals in southeast Michigan were interviewed by telephone to record
      lifetime history of traumatic events specified in DSM-IV as potentially leading
      to PTSD. PTSD was assessed with respect to a randomly selected index trauma from
      the list of events reported by each respondent. RESULTS: History of any previous
      exposure to traumatic events was associated with a greater risk of PTSD from the
      index trauma. Multiple previous events had a stronger effect than a single
      previous event. The effect of previous assaultive violence persisted over time
      with little change. When they examined several features of the previous exposure
      to trauma, the authors found that subjects who experienced multiple events
      involving assaultive violence in childhood were more likely to experience PTSD
      from trauma in adulthood. Furthermore, previous events involving assaultive
      violence--single or multiple, in childhood or later on--were associated with a
      higher risk of PTSD in adulthood. CONCLUSIONS: Previous exposure to trauma
      signals a greater risk of PTSD from subsequent trauma. Although these results are
      consistent with a sensitization hypothesis, like the results from previous
      research on PTSD, they do not address the mechanism of increased responsivity to
      trauma. Long-term observational studies can further elucidate these observations.

PMID- 10360131
TI  - Short screening scale for DSM-IV posttraumatic stress disorder.
AB  - OBJECTIVE: The authors' goal was to construct a short screening scale for DSM-IV
      posttraumatic stress disorder (PTSD). METHOD: They used data from the Detroit
      Area Survey of Trauma, which is a representative population sample of 2,181
      subjects 18-45 years of age. Random digit dialing was used to select the sample,
      and a computer-assisted telephone interview was used to collect data on traumatic
      experiences and PTSD. Presence or absence of PTSD was assessed with a telephone
      administered structured interview that closely followed the National Institute of
      Mental Health Diagnostic Interview Schedule for DSM-IV and the World Health
      Organization Composite International Diagnostic Interview, version 2.1. Best
      subset regression analysis and receiver operating characteristic analysis were
      used to select a subset of items from the structured interview that most
      efficiently predicted PTSD as diagnosed in the full-length interview. RESULTS: A
      seven-symptom screening scale for PTSD was selected; five of the symptoms were
      from the avoidance and numbing group, and two were from the hyperarousal group. A
      score of 4 or greater on this scale defined positive cases of PTSD with a
      sensitivity of 80%, specificity of 97%, positive predictive value of 71%, and
      negative predictive value of 98%. CONCLUSIONS: The short screening scale is an
      efficient method to screen for PTSD in epidemiologic and clinical studies, given
      limitations on resources and burden on respondents.

PMID- 10360132
TI  - Long-acting psychotraumatic properties of a cardiac arrest experience.
AB  - OBJECTIVE: Progress in resuscitation medicine allows an increasing proportion of
      patients to survive an out-of-hospital cardiac arrest. However, little is known
      about long-term adaptation to the vital breakdown. The present study assessed the
      long-term prevalence and severity of emotional disability of cardiac arrest
      survivors and ascertained whether survivors suffer from recurrent and intrusive
      recollections of the cardiac arrest. METHOD: Follow-up analysis was performed on
      all cardiac arrest survivors discharged from the hospital over a 5-year interval
      (1990-1994) in a defined inner city and suburban area. From 118 initially
      hospitalized cardiac arrest survivors, 45 patients were discharged alive from the
      hospital. After a mean follow-up period of 39 months (range = 22-64), 25 patients
      exhibited sufficient cerebral performance for psychodiagnostic assessment; 21
      patients were assessed. RESULTS: Despite an impaired ability to concentrate,
      cardiac arrest survivors had levels of psychological adjustment at follow-up that
      were similar to those of 35 cardiac patients whose clinical course was not
      complicated by cardiac arrest. However, the diagnosis of psychotraumatic symptoms
      in cardiac arrest survivors led to a sharp separation between favorable and
      nonfavorable outcome in affective regulation and level of functioning. Of the
      cardiac arrest patients, those with high scores of intrusion and avoidance (N =
      8) reported an enduring sense of demoralization with significantly more somatic
      complaints, depression, anxiety, lack of confidence in the future, and narrowing
      of social activities than those with low scores (N = 11). Long-acting sedation at
      illness onset significantly predicted a favorable outcome. CONCLUSIONS: This
      study provides the first empirical evidence that the application of the
      posttraumatic stress disorder paradigm in the long-term evaluation of cardiac
      arrest survivors significantly contributes to defining a patient population at
      high risk for serious emotional disability.

PMID- 10360134
TI  - Gaps in service utilization by Mexican Americans with mental health problems.
AB  - OBJECTIVE: The purpose of this study was to ascertain the degree of
      underutilization of services for mental health problems among urban and rural
      Mexican American adults. METHOD: A probability sample (N = 3,012) was used to
      represent the Mexican American population of Fresno County, California, and face
      to-face interviews were conducted with the use of the Composite International
      Diagnostic Interview. Bivariate and multivariate analyses were used to analyze
      the data on diagnosis and service utilization. RESULTS: Among the respondents
      with DSM-III-R-defined disorders, only about one-fourth had used a single service
      or a combination of services in the past 12 months, and Mexican immigrants had a
      utilization rate which was only two-fifths of that of Mexican Americans born in
      the United States. Overall use of mental health care providers by persons with
      diagnosed mental disorders was 8.8%, use of providers in the general medical
      sector was 18.4%, use of other professionals was 12.7%, and use of informal
      providers was only 3.1%. According to logistic regression analyses, factors
      associated with utilization of mental health services included female sex, higher
      educational attainment, unemployment, and comorbidity. CONCLUSIONS: Immigrants
      are unlikely to use mental health services, even when they have a recent
      disorder, but may use general practitioners, which raises questions about the
      appropriateness, accessibility, and cost-effectiveness of mental health care for
      this population. Several competing hypotheses about the reasons for low
      utilization of services need to be examined in future research.

PMID- 10360133
TI  - Service utilization and cost of community care for discharged state hospital
      patients: a 3-year follow-up study.
AB  - OBJECTIVE: This study examined the mental health service utilization and costs of
      321 discharged state hospital patients during a 3-year follow-up period compared
      with costs if the patients had remained in the hospital. METHOD: The study
      subjects were long-stay patients discharged from Philadelphia State Hospital
      after 1988. A longitudinal integrated database on all mental health and medical
      services reimbursed by Medicaid and Medicare as well as state- and county-funded
      services was used to construct service utilization and unit cost measures.
      RESULTS: During the 3-year period after discharge, 20%-30% of the patients
      required rehospitalization an average of 76-91 days per year. The percentage of
      rehospitalized patients decreased over time, but the number of hospital days
      increased. All of the discharged patients received case management services, and
      a majority also received outpatient mental health care (66%-70%) and residential
      services (75%) throughout the follow-up period. The total treatment cost per
      person was approximately $60,000 a year after controlling for inflation, with
      costs rising slightly over the 3-year period. The estimated cost of state
      hospitalization, with the use of 1992 estimates, would have been $130,000 per
      year if the patients had remained institutionalized. CONCLUSIONS: This analysis
      suggests that most former long-stay patients are able to live in residential
      settings while receiving community outpatient treatment and intensive case
      management services at a reduced cost. There is no indication of cost shifting
      from the psychiatric to the health care sector; however, some cost shifting from
      the state mental health agency to the Medicaid program has occurred, since most
      psychiatric hospital care now takes place in community hospitals.

PMID- 10360135
TI  - Late-onset psychosis: clinical, research, and ethical considerations.

PMID- 10360137
TI  - Recurrence of first-episode geriatric depression after discontinuation of
      maintenance antidepressants.
AB  - OBJECTIVE: Later age at onset of depression appears to be a risk factor for early
      recurrence. Therefore, the authors examined the 2-year outcomes of elderly
      patients with first-episode major depression following discontinuation of their
      maintenance antidepressant medication. METHOD: The study group consisted of 21
      elderly patients who had recovered from a first lifetime episode of major
      depression. They had taken maintenance antidepressant medication for 2 years and
      had not had a relapse or recurrence during that time. The antidepressant was then
      withdrawn, and patients were followed for another 2 years or until recurrence,
      whichever occurred first. RESULTS: The cumulative probability of suffering a
      recurrence of major depression was 61%. Eleven of the 12 patients who suffered a
      recurrence restarted the antidepressant, and 10 responded. CONCLUSIONS: Elderly
      patients with first-episode major depression were at high risk of recurrence
      following discontinuation of maintenance antidepressant medication. However, the
      vast majority of patients who experienced a recurrence responded to reinstated
      treatment.

PMID- 10360138
TI  - Double-blind controlled investigation of transcranial magnetic stimulation for
      the treatment of resistant major depression.
AB  - OBJECTIVE: The efficacy and safety of left prefrontal repetitive transcranial
      magnetic stimulation (rTMS) for treating resistant major depression were examined
      in a double-blind, controlled study. METHOD: Eighteen medication-resistant
      depressed subjects were randomly assigned to 2 weeks of real or sham rTMS, then
      permitted up to 4 weeks of real rTMS. Effects on mood, neuropsychological
      function, EEG, and hearing were assessed. RESULTS: The groups receiving real and
      sham rTMS improved in mood significantly over the 2-week double-blind period, but
      there was no significant difference between groups. CONCLUSIONS: Repetitive
      transcranial magnetic stimulation did not provide significantly greater
      improvement than did sham treatment. A 4-week course of rTMS, as administered in
      this study, was safe.

PMID- 10360139
TI  - Prediction of medium-term outcome by cortisol response to the combined
      dexamethasone-CRH test in patients with remitted depression.
AB  - OBJECTIVE: Current hypotheses hold that mechanisms underlying abnormal
      hypothalamic-pituitary-adrenocortical (HPA) function are causal factors in the
      precipitation of depression. If this is the case, then normalization of initially
      disturbed HPA regulation should indicate a good prognosis and persistent HPA
      dysregulation should be associated with a greater likelihood of relapse or
      chronicity. METHOD: The combined dexamethasone/corticotropin-releasing hormone
      test was administered twice to inpatients with major depression (N = 40), once
      after initiation of treatment and once after remission, shortly before discharge.
      RESULTS: Patients with a high cortisol response on both occasions or with a
      substantially increased cortisol response at discharge were at much higher risk
      for relapse within the next 6 months than those with low cortisol responses.
      CONCLUSIONS: An easy-to-administer neuroendocrine test allows the prediction of
      medium-term outcome in patients with remitted depression.

PMID- 10360140
TI  - Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of
      alcohol-dependent and hepatic encephalopathy patients.
AB  - OBJECTIVE: The aim of the study was to compare levels of neuroactive amino acids
      in the cerebral cortex of healthy subjects, recently detoxified alcohol-dependent
      patients, and patients with hepatic encephalopathy. METHOD: Metabolite levels
      were measured in the occipital cortex by using spatially localized 1H-MRS. Five
      recently detoxified alcohol-dependent and five hepatic encephalopathy patients
      with alcohol and non-alcohol-related disease were compared with 10 healthy
      subjects. RESULTS: The combined level of gamma-aminobutyric acid (GABA) plus
      homocarnosine was lower in the alcohol-dependent and hepatic encephalopathy
      patients than in the healthy subjects. CONCLUSIONS: The findings suggest that
      GABA-ergic systems are altered in both alcohol-dependent and hepatic
      encephalopathy patients.

PMID- 10360141
TI  - Chart-recorded psychiatric diagnoses in women giving birth in California in 1992.
AB  - OBJECTIVE: Although major advances have been made in the diagnosis and treatment
      of mental disorders in primary care, few population-based investigations have
      focused on the obstetrical sector. This study examines the occurrence of chart
      recorded psychiatric discharge diagnoses among all women delivering in California
      hospitals in 1992. METHOD: The authors undertook an archival analysis of the
      California Health Information for Policy Project data set, which consists of
      linked hospital discharge and birth certificate data for 580,282 deliveries.
      Frequencies of ICD-9 psychiatric diagnoses were ascertained. RESULTS: Among all
      women delivering, 1.5% received psychiatric or substance use diagnoses. Of
      diagnoses recorded, 75% were substance use disorders, 21% were classified
      generically as "mental disorder of pregnancy," and other psychiatric disorders
      accounted for 4%. CONCLUSIONS: The occurrence of psychiatric diagnoses in these
      women is markedly lower than expected, suggesting an underreporting of
      psychiatric disorders at delivery. Further investigations into the detection of
      mental disorders in the obstetrical sector are needed.

PMID- 10360143
TI  - Treatment of corticosteroid-induced mood changes with olanzapine.

PMID- 10360142
TI  - MRI changes during water loading in patients with polydipsia and intermittent
      hyponatremia.
AB  - OBJECTIVE: Patients with polydipsia and intermittent hyponatremia have greater
      ventricle-brain ratios (VBRs) than matched patients without polydipsia and
      intermittent hyponatremia and normal subjects. Unlike previous studies, this
      study controlled for the impact of water loading when examining the volume of
      intracranial structures. METHOD: Under controlled conditions, eight male
      schizophrenic patients with polydipsia and intermittent hyponatremia were first
      assigned to either normal fluid intake or oral water loading and then the
      alternative condition the following day. Magnetic resonance imaging (MRI)
      volumetric measurements were made with the use of a standardized protocol.
      RESULTS: During water loading, total VBR and lateral ventricle volume
      significantly decreased by 13.1% and 12.6%, respectively. A strong association
      between change in serum sodium concentration and change in VBR was noted across
      conditions. CONCLUSIONS: These findings indicate that 1) water loading does not
      account for the diminished brain volume observed in patients with polydipsia and
      intermittent hyponatremia in previous studies, and 2) hyponatremia can
      significantly alter brain morphology on MRI.

PMID- 10360144
TI  - Mood stabilization and weight loss with topiramate.

PMID- 10360145
TI  - Testosterone-patch-induced psychotic mania.

PMID- 10360146
TI  - Prolonged QT interval after trazodone overdose.

PMID- 10360148
TI  - Mania onset while using dehydroepiandrosterone.

PMID- 10360147
TI  - Hyperglycemia and olanzapine.

PMID- 10360149
TI  - Schizophreniform disorder: exception proves the rule.

PMID- 10360150
TI  - Gabapentin-induced ejaculatory failure and anorgasmia.

PMID- 10360152
TI  - Allergic reactions from injectable methadone.

PMID- 10360151
TI  - Severe vasculitis after therapy with diazepam.

PMID- 10360153
TI  - Clozapine and paroxetine in the treatment of schizophrenia with obsessive
      compulsive features.

PMID- 10360154
TI  - Distinguishing change in primary and secondary negative symptoms.

PMID- 10360156
TI  - Psychotherapy with a borderline patient.

PMID- 10360155
TI  - Progress in ECT research.

PMID- 10360157
TI  - Multiples: no amnesia for child abuse.

PMID- 10360158
TI  - Multiples: no amnesia for child abuse.

PMID- 10360159
TI  - Selective serotonin reuptake inhibitors and delusional depression.

PMID- 10360160
TI  - Freud's practice of psychoanalysis.

PMID- 10360161
TI  - Freud's practice of psychoanalysis.

PMID- 10360162
TI  - Freud's practice of psychoanalysis.

PMID- 10360163
TI  - Mood stabilizer combinations for bipolar disorder.

PMID- 10360164
TI  - Eating attitudes among black South Africans.

PMID- 10360165
TI  - Obsessive-compulsive disorder with eating disorders.

PMID- 10360166
TI  - Integration, not discrimination.

PMID- 10360167
TI  - "Monk" requesting castration.

PMID- 10360168
TI  - "Monk" requesting castration.

PMID- 10360169
TI  - Alteration of personality by serotonergic intervention.

PMID- 10360170
TI  - Premorbid social functioning with schizophrenia and bipolar disorder.

PMID- 10360171
TI  - Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.
AB  - The major metabolic pathway for elimination of cholesterol is via conversion to
      bile acids. In addition to this metabolic function, bile acids also act as
      signaling molecules that negatively regulate their own biosynthesis. However, the
      precise nature of this signaling pathway has been elusive. We have isolated an
      endogenous biliary component (chenodeoxycholic acid) that selectively activates
      the orphan nuclear receptor, FXR. Structure-activity analysis defined a subset of
      related bile acid ligands that activate FXR and promote coactivator recruitment.
      Finally, we show that ligand-occupied FXR inhibits transactivation from the
      oxysterol receptor LXR alpha, a positive regulator of cholesterol degradation. We
      suggest that FXR (BAR) is the endogenous bile acid sensor and thus an important
      regulator of cholesterol homeostasis.

PMID- 10360172
TI  - Identification of a specific role for the Na,K-ATPase alpha 2 isoform as a
      regulator of calcium in the heart.
AB  - It is well accepted that inhibition of the Na,K-ATPase in the heart, through
      effects on the Na/Ca exchanger, raises the intracellular Ca2+ concentration and
      strengthens cardiac contraction. However, the contribution that individual
      isoforms make to this calcium regulatory role is unknown. Assessing the
      phenotypes of mouse hearts with genetically reduced levels of Na,K-ATPase alpha 1
      or alpha 2 isoforms clearly demonstrates different functional roles for these
      isoforms in vivo. Heterozygous alpha 2 hearts are hypercontractile as a result of
      increased calcium transients during the contractile cycle. In contrast,
      heterozygous alpha 1 hearts are hypocontractile. The different functional roles
      of these two isoforms are further demonstrated since inhibition of the alpha 2
      isoform with ouabain increases the contractility of heterozygous alpha 1 hearts.
      These results definitively illustrate a specific role for the alpha 2 Na,K-ATPase
      isoform in Ca2+ signaling during cardiac contraction.

PMID- 10360173
TI  - Reversible activation of c-Myc in skin: induction of a complex neoplastic
      phenotype by a single oncogenic lesion.
AB  - The protooncogene c-myc regulates cell growth, differentiation, and apoptosis,
      and its aberrant expression is frequently observed in human cancer. However, the
      consequences of activating c-Myc in an adult tissue, in which these cellular
      processes are part of normal homeostasis, remain unknown. In order to achieve
      this, we have targeted expression of a switchable form of the c-Myc protein to
      the skin epidermis, a well characterized homeostatic tissue. We show that
      activation of c-MycER in adult suprabasal epidermis rapidly triggers
      proliferation and disrupts differentiation of postmitotic keratinocytes.
      Sustained activation of c-Myc is sufficient to induce papillomatosis together
      with angiogenesis--changes that resemble hyperplastic actinic keratosis, a
      commonly observed human precancerous epithelial lesion. All these premalignant
      changes spontaneously regress upon deactivation of c-MycER.

PMID- 10360174
TI  - Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its
      ability to block nuclear export of MDM2 and p53.
AB  - The mammalian ARF-INK4a locus uniquely encodes two cell cycle inhibitors by using
      separate promoters and alternative reading frames. p16INK4a maintains the
      retinoblastoma protein in its growth suppressive state while ARF stabilizes p53.
      We report that human ARF protein predominantly localizes to the nucleolus via a
      sequence within the exon 2-encoded C-terminal domain and is induced to leave the
      nucleolus by MDM2. ARF forms nuclear bodies with MDM2 and p53 and blocks p53 and
      MDM2 nuclear export. Tumor-associated mutations in ARF exon 2 disrupt ARF's
      nucleolus localization and reduce ARF's ability to block p53 nuclear export and
      to stabilize p53. Our results suggest an ARF-regulated MDM2-dependent p53
      stabilization and link the human tumor-associated mutations in ARF with a
      functional alteration.

PMID- 10360175
TI  - Specific transcriptional pausing activates polyadenylation in a coupled in vitro
      system.
AB  - We have developed a coupled in vitro transcription-polyadenylation system to
      investigate RNA polymerase II (Pol II) termination, which depends on active
      polyadenylation of the nascent RNA. Specific G-rich sequences originally
      identified as binding sites for the transcription factor MAZ both pause Pol II
      and activate polyadenylation of an upstream poly(A) signal. They do not affect
      polyadenylation efficiency in an uncoupled cleavage assay. In contrast, pausing
      of Pol II elongation induced by a high-affinity DNA-binding protein does not
      activate polyadenylation, indicating that G-rich MAZ sequences have a specific
      effect on polyadenylation. They also promote intrinsic pausing of purified Pol
      II, indicating a general role in the modulation of cotranscriptional RNA
      processing events.

PMID- 10360176
TI  - Novel roles for classical factors at the interface between translation
      termination and initiation.
AB  - The pathway of bacterial ribosome recycling following translation termination has
      remained obscure. Here, we elucidate two essential steps and describe the roles
      played by the three translation factors EF-G, RRF, and IF3. Release factor RF3 is
      known to catalyze the dissociation of RF1 or RF2 from ribosomes after polypeptide
      release. We show that the next step is dissociation of 50S subunits from the 70S
      posttermination complex and that it is catalyzed by RRF and EF-G and requires GTP
      hydrolysis. Removal of deacylated tRNA from the resulting 30S:mRNA:tRNA
      posttermination complex is then necessary to permit rapid 30S subunit recycling.
      We show that this step requires initiation factor IF3, whose role was previously
      thought to be restricted to promoting specific 30S initiation complex formation
      from free 30S subunits.

PMID- 10360177
TI  - RecQ helicase and topoisomerase III comprise a novel DNA strand passage function:
      a conserved mechanism for control of DNA recombination.
AB  - E. coli RecQ protein is a multifunctional helicase with homologs that include the
      S. cerevisiae Sgs1 helicase and the H. sapiens Wrn and Blm helicases. Here we
      show that RecQ helicase unwinds a covalently closed double-stranded DNA (dsDNA)
      substrate and that this activity specifically stimulates E. coli topoisomerase
      III (Topo III) to fully catenate dsDNA molecules. We propose that these proteins
      functionally interact and that their shared activity is responsible for control
      of DNA recombination. RecQ helicase has a comparable effect on the Topo III
      homolog of S. cerevisiae, consistent with other RecQ and Topo III homologs acting
      together in a similar capacity. These findings highlight a novel, conserved
      activity that offers insight into the function of the other RecQ-like helicases.

PMID- 10360178
TI  - Crystallographic and functional studies of very short patch repair endonuclease.
AB  - Vsr endonuclease plays a crucial role in the repair of TG mismatched base pairs,
      which are generated by the spontaneous degradation of methylated cytidines; Vsr
      recognizes the mismatched base pair and cleaves the phosphate backbone 5' to the
      thymidine. We have determined the crystal structure of a truncated form of this
      endonuclease at 1.8 A resolution. The protein contains one structural zinc
      binding module. Unexpectedly, its overall topology resembles members of the type
      II restriction endonuclease family. Subsequent mutational and biochemical
      analyses showed that certain elements in the catalytic site are also conserved.
      However, the identification of a critical histidine and evidence of an active
      site metal-binding coordination that is novel to endonucleases indicate a
      distinct catalytic mechanism.

PMID- 10360179
TI  - Crystal structures of c-Src reveal features of its autoinhibitory mechanism.
AB  - Src family kinases are maintained in an assembled, inactive conformation by
      intramolecular interactions of their SH2 and SH3 domains. Full catalytic activity
      requires release of these restraints as well as phosphorylation of Tyr-416 in the
      activation loop. In previous structures of inactive Src kinases, Tyr-416 and
      flanking residues are disordered. We report here four additional c-Src structures
      in which this segment adopts an ordered but inhibitory conformation. The ordered
      activation loop forms an alpha helix that stabilizes the inactive conformation of
      the kinase domain, blocks the peptide substrate-binding site, and prevents Tyr
      416 phosphorylation. Disassembly of the regulatory domains, induced by SH2 or SH3
      ligands, or by dephosphorylation of Tyr-527, could lead to exposure and
      phosphorylation of Tyr-416.

PMID- 10360180
TI  - Crystal structure of Hck in complex with a Src family-selective tyrosine kinase
      inhibitor.
AB  - The crystal structure of the autoinhibited form of Hck has been determined at 2.0
      A resolution, in complex with a specific pyrazolo pyrimidine-type inhibitor, PP1.
      The activation segment, a key regulatory component of the catalytic domain, is
      unphosphorylated and is visualized in its entirety. Tyr-416, the site of
      activating autophosphorylation in the Src family kinases, is positioned such that
      access to the catalytic machinery is blocked. PP1 is bound at the ATP-binding
      site of the kinase, and a methylphenyl group on PP1 is inserted into an adjacent
      hydrophobic pocket. The enlargement of this pocket in autoinhibited Src kinases
      suggests a route toward the development of inhibitors that are specific for the
      inactive forms of these proteins.

PMID- 10360181
TI  - A molecular mechanism for the phosphorylation-dependent regulation of
      heterotrimeric G proteins by phosducin.
AB  - Visual signal transduction is a nearly noise-free process that is exquisitely
      well regulated over a wide dynamic range of light intensity. A key component in
      dark/light adaptation is phosducin, a phosphorylatable protein that modulates the
      amount of transducin heterotrimer (Gt alpha beta gamma) available through
      sequestration of the beta gamma subunits (Gt beta gamma). The structure of the
      phosphophosducin/Gt beta gamma complex combined with mutational and biophysical
      analysis provides a stereochemical mechanism for the regulation of the phosducin
      Gt beta gamma interaction. Phosphorylation of serine 73 causes an order-to
      disorder transition of a 20-residue stretch, including the phosphorylation site,
      by disrupting a helix-capping motif. This transition disrupts phosducin's
      interface with Gt beta gamma, leading to the release of unencumbered Gt beta
      gamma, which reassociates with the membrane and Gt alpha to form a signaling
      competent Gt alpha beta gamma heterotrimer.

PMID- 10360182
TI  - Tick histamine-binding proteins: isolation, cloning, and three-dimensional
      structure.
AB  - High-affinity histamine-binding proteins (HBPs) were discovered in the saliva of
      Rhipicephalus appendiculatus ticks. Their ability to outcompete histamine
      receptors indicates that they suppress inflammation during blood feeding. The
      crystal structure of a histamine-bound HBP, determined at 1.25 A resolution,
      reveals a lipocalin fold novel in containing two binding sites for the same
      ligand. The sites are orthogonally arranged and highly rigid and form an internal
      surface of unusual polar character that complements the physicochemical
      properties of histamine. As soluble receptors of histamine, HBPs offer a new
      strategy for controlling histamine-based diseases.

PMID- 10360183
TI  - GAL4 is regulated by the RNA polymerase II holoenzyme-associated cyclin-dependent
      protein kinase SRB10/CDK8.
AB  - Phosphorylation of the yeast transcription factor GAL4 at S699 is required for
      efficient galactose-inducible transcription. We demonstrate that this site is a
      substrate for the RNA polymerase holoenzyme-associated CDK SRB10. S699
      phosphorylation requires SRB10 in vivo, and this site is phosphorylated by
      purified SRB10/ SRB11 CDK/cyclin in vitro. RNA Pol II holoenzymes purified from
      WT yeast phosphorylate GAL4 at sites observed in vivo whereas holoenzymes from
      srb10 yeast are incapable of phosphorylating GAL4 at S699. Mutations at GAL4 S699
      and srb10 are epistatic for GAL induction, demonstrating that SRB10 regulates
      GAL4 activity through this phosphorylation in vivo. These results demonstrate a
      function for the SRB10/ CDK8 holoenzyme-associated CDK that involves regulation
      of transactivators by phosphorylation during transcriptional activation.

PMID- 10360184
TI  - DNA polymerase epsilon catalytic domains are dispensable for DNA replication, DNA
      repair, and cell viability.
AB  - DNA polymerase epsilon (Pol epsilon) is believed to play an essential catalytic
      role during eukaryotic DNA replication and is thought to participate in
      recombination and DNA repair. That Pol epsilon is essential for progression
      through S phase and for viability in budding and fission yeasts is a central
      element of support for that view. We show that the amino-terminal portion of
      budding yeast Pol epsilon (Pol2) containing all known DNA polymerase and
      exonuclease motifs is dispensable for DNA replication, DNA repair, and viability.
      However, the carboxy-terminal portion of Pol2 is both necessary and sufficient
      for viability. Finally, the viability of cells lacking Pol2 catalytic function
      does not require intact DNA replication or damage checkpoints.

PMID- 10360185
TI  - [Therapeutic attitude to HIV infection: uncertain and variable scientific
      attitudes. 1998 national survey of physicians prescribing antiretroviral drugs].
AB  - OBJECTIVES: Analyze the attitudes of French practitioners managing HIV infected
      patients towards multidrug antiretroviral therapies with protease inhibitors,
      open issues, and the official guidelines (Dormont report). METHODS: A telephone
      survey was conducted in February-March 1998 on a random sample of the nation file
      of hospital physicians prescribing antiretroviral drugs (response rate 87%, n =
      483). RESULTS: The responding clinicians were in general agreement on defining
      virological efficacy at three months treatment as an undetectable viral load
      (86.5%). There was a general concensus on multidrug therapy with a protease
      inhibitor in case of primary infection (83.2%) or sexual exposure with risk of
      HIV transmission (83.2%). Inversely, only 43.7% abandoned PCP and toxoplasmosis
      prophylaxis in patients with CD4 counts above 350/mm3 taking tritherapy
      antiretroviral regimens. When asked to state their approach to a hypothetical
      case of an asymptomatic patient with a CD4 count of 450, 35.6% would not propose
      multidrug therapy with an antiprotease, 29.8% would only envisage such a regimen
      if the viral load was above 10,000 copies/ml, and finally 34.6% would prescribe a
      multidrug regimen with a protease inhibitor whatever the viral load. CONCLUSION:
      The variability observed in routine clinical practices would appear to be
      justified in light of the uncertainty about the long-term effects of the new
      antiretroviral drugs for HIV/AIDS.

PMID- 10360186
TI  - [Laryngeal cancer in a young adult].
AB  - BACKGROUND: Carcinoma of the larynx is uncommon in young adults. Persistent
      dysphonia despite medical treatment is generally the primary manifestation. CASE
      REPORT: A 21-year-old woman with no known risk factors developed squamous cell
      carcinoma of the left vocal cord. Clinical cure was considered to be achieved 40
      months after external radiotherapy. DISCUSSION: Clinicians should be aware of the
      possibility of carcinoma of the larnyx in young patients with no risk factors.
      Treatment should take into consideration not only the aggressive nature of these
      tumors but also the long-term side effects and the major functional and
      psychological sequelae.

PMID- 10360188
TI  - [Isolated chronic cough during interferon therapy].

PMID- 10360187
TI  - [Polymyositis induced by tiopronine].
AB  - BACKGROUND: D-penicillamine-induced muscle disorders are well-known, tiopronine
      induced disorders are less often reported. CASE REPORT: A 62-year-old patient,
      given tiopronine for rheumatoid arthritis, developed severe polymyositis with
      characteristic clinical and pathology features. The course was favorable after
      tiopronine withdrawal and substitution with methotrexate. DISCUSSION: Clinicians
      should be aware of the side-effects of tiopronine, particularly muscle disorders,
      and implement careful surveillance to achieve early diagnosis and appropriate
      therapy.

PMID- 10360189
TI  - [Diagnosis of malaria: beware of false-negative diagnosis with dip-stick].

PMID- 10360190
TI  - [Muscular aspergillosis in an AIDS patient: a new case].

PMID- 10360191
TI  - [Duality of angiotensin II receptors and risk for stroke and cancer: what is the
      connection?].
AB  - Angiotensin II (AII) acts by 2 types of receptors: the ATI receptor which
      mediates its actions on vasoconstriction, renin (inhibition) and aldosterone
      (stimulation) secretions, cellular proliferation and angiogenesis and the non-AT1
      (often called AT2) receptors. Mainly expressed in the embryon these latter may
      favor cellular differentiation and recruitment of collateral circulation.
      Angiotensin converting enzyme inhibitors (ACEI) decrease the synthesis of All and
      therefore the stimulation of both receptor types whereas AT1-receptor antagonists
      (AT1RA) block only the stimulation of these latter and increase the stimulation
      of AT2 receptor since they increase the production of All secondarily to the
      inhibition of the feedback of renin secretion by All. Experimentally ACEI and
      AT1RA decrease angiogenesis and cellular proliferation and favor cellular
      differentiation which could explain the protective effect of ACEI against cancer
      suggested recently in a Scotish study. Despite of their common suppressive effect
      on angiogenesis AT1RA may better than ACEI protect against ischemic events
      specially the cerebral ones because they favor the rapid recruitment of
      collateral circulation. This has been demonstrated for losartan in case of abrupt
      ligation of the carotid in the gerbil since its previous administration protects
      against fatal cerebral ischemia whereas its previous administration with
      enalapril abolishes this protection. These data may explain why, in the CAPP
      trial, captopril which has prevented more effectively diabetes occurrence could
      not be proved superior to diuretics and/or betablocker in the prevention of
      myocardial infarction and specially of strokes for which exist on the contrary a
      suspicion of a lower protection. Therefore a comparative trial between AT1RA and
      ACEI in the prevention of stroke recurrence should appear as a priority for
      Public Health and Pharmaceutical Industry Authorities.

PMID- 10360192
TI  - [Vascular filling in relative or absolute hypovolemia].

PMID- 10360193
TI  - [Apropos of vascular filling. Interview with Prof. J.F. Baron].

PMID- 10360194
TI  - [Biologic rhythms. Circadian, ultradian and seasonal rhythms].
AB  - CIRCADIAN RHYTHMS: Our knowledge of the genetic and molecular mechanisms
      regulating the principal circadian clock located in the suprachiasmatic nuclei is
      progressing. The clock's intrinsic period varies from one species to another and
      to a lesser degree from one individual to another. In humans, the intrinsic
      period is slightly over 24 hours. The clock is capable of synchronizing itself to
      the surrounding environment by reacting to outside factors or zeitgebers (time
      givers). Light-dark cycles are the main zeitgebers; meals, the social
      environment, and locomotor activity also affect the circadian clock. In addition,
      the circadian clock acts as an internal timer, providing the organism with a
      means of synchronizing the function of multiple biochemical and physiological
      systems. ULTRADIAN RHYTHMS: The frequency of ultradian rhythms varies
      considerably form one species to another and from one parameter to another. In
      humans, several functions oscillate at 60-120 minute intervals, rhythms which are
      sometimes superimposed on other functions oscillating at 3 to 5 minute intervals.
      SEASONAL RHYTHMS: Several mechanisms allow living organisms to adapt to seasonal
      variations in the environment. In certain species, reproduction functions are
      stimulated at appropriate moments in the yearly cycle, optimizing the newborn's
      chances of survival. Such seasonal variations are much less marked in humans.

PMID- 10360195
TI  - [Biologic rhythms. Nyctemeral variation in man].
AB  - CORTICOTROPIC AXIS: The nycthemeral pattern of cortisol is a good marker of the
      circadian clock. Cortisol levels fluctuate between a peak level, observed in the
      early hours of the morning, and a minimal level around midnight. This variability
      is considerably reduced or even abolished in Cushing s syndrome. THYREOTROPIC
      AXIS: The nycthemeral pattern of TSH secretion is dependent on both the circadian
      clock and sleep (which inhibits hormone secretion). The moment of the evening
      rise is a reliable marker of the circadian rhythmicity. SOMATOTROPIC AXIS: Growth
      hormone is essentially pulsatile. GH levels are often undetectable between
      pulses. The circadian rhythmicity plays only a minor role in the regulation of
      growth hormone secretion. LACTOTROPIC AXIS: Nycthemeral variations in prolactin
      secretion are mainly regulated by wake-sleep cycles; peak levels occur in the
      middle of the night. Prolactin secretion is also modulated by the circadian
      rhythmicity. GONADOTROPIC AXIS: Gonadotropins are secreted in pulses, following
      the pulses of GnRH secretion. In adult women, nycthemeral variations in LH are
      strongly modulated by the menstrual cycle. MELATONIN: The nychtemeral pattern of
      melatonin is an excellent marker of the circadian clock. Diurnal concentrations
      are low and vary little whereas peak levels are observed in the middle of the
      night. Melatonin rhythmicity is not influenced by sleep, but is dependent on
      exposure to light and darkness.

PMID- 10360196
TI  - [Biologic rhythms. Effect of aging on the desynchronization of endogenous
      rhythmicity and environmental conditions].
AB  - CIRCADIAN AND PULSATILE RHYTHMICITY IN THE AGING PROCESS: The aging process
      produces morphological and neurochemical alterations in the suprachiasmatic
      nuclei as well as major alterations in the quality of sleep. In addition, aging
      is frequently accompanied by changes in life style due to different, often less
      demanding, social and occupational activities, leading to an attenuation of the
      synchronizing effects of the light-dark and activity-rest cycles. Together, these
      different elements contribute to a decline in temporal organization in the
      elderly, a phenomenon which starts in the third decade for some variables. There
      is a characteristic phase shift with age: in an 80-year-old individual, the
      circadian cortisol peak occurs about 3 hours earlier than in a 20 year-old
      individual. JET LAG AND NIGHT SHIFT WORK: The circadian rhythm and environmental
      conditions can become desynchronized after transmeridian flights, a phenomenon
      commonly called jet lag. In night shift workers, such desynchronization creates
      an important public health problem. The impact may be underestimated since 15 to
      20% of the work force in industrialized countries work permanently or
      occasionally on night shifts. The resulting dissociation between environmental
      signals and the wake-sleep cycle leads to various health problems. No truly
      effective therapeutic strategy has been developed although ongoing research,
      particularly on the use of light and/or melatonin, provides some promising
      perspectives.

PMID- 10360197
TI  - [Antibiotic therapy of secondary nosocomial peritonitis].

PMID- 10360198
TI  - Peer conflict.

PMID- 10360199
TI  - Behavioral indicators of child maltreatment.
AB  - While dentists as a group may be sufficiently knowledgeable of the physical signs
      of child abuse and neglect, many are unaware of the associated behavioral
      indicators presented by the maltreated child. The beliefs, feelings, and
      attitudes, as well as the specific behavior of such children, are discussed,
      along with behavioral peculiarities of the abusive adult. The longer a child is
      abused or neglected, the greater the impact is on his physical, emotional, and
      intellectual development. Integrating observations of the physical and behavioral
      indicators exhibited by the child, the behavior of the parent, and the
      interaction of parent and child will enable dentists to diagnose properly and
      report suspected cases of child maltreatment.

PMID- 10360201
TI  - Stomatognathic function in juvenile rheumatoid arthritis and in developmental
      open-bite subjects.
AB  - Patients affected with juvenile rheumatoid arthritis present clear radiological
      alterations of the condyles of the temporomandibular joint (TMJ) due to the
      inflammatory process, with a prevalence ranging from 17 percent to 63 percent.
      This work is a comparison between a group of subjects with juvenile rheumatoid
      arthritis presenting signs and symptoms of TMT dysfunction and a group of the
      same age not suffering from any rheumatic morbidity, but presenting an open bite
      > 3 mm. The aim is to verify whether the open bite can induce an alteration in
      mandibular function comparable to that observed in juvenile rheumatoid arthritis.
      Statistically significant difference is found in the juvenile rheumatoid
      arthritis group only regarding spontaneous and provoked muscle pain and the
      lateral opening deviations of the mouth, but mostly the two groups seem alike and
      present the same stomatognathic pattern.

PMID- 10360200
TI  - Conservative interproximal box-only polyacid modified composite restorations in
      primary molars, twelve-month clinical results.
AB  - The treatment of proximal caries has changed during the last decade. The present
      study evaluates a recently developed material, applied in box-only preparations
      in primary molars. At the twelve-month evaluation of this clinical study, it
      became obvious that Dyract can be an alternative for Tytin in the primary
      dentition, though there is some change in color of the Dyract material. In time,
      the marginal adaptation of Dyract seems to improve. The preparation time for both
      materials is comparable. The total treatment time of box-only Dyract restorations
      (including an occlusal sealant), however, is longer compared to conventional
      class II Tytin restorations. Although in both groups radiolucencies were found at
      the baseline radiograph evaluation, no sign was found of secondary caries. One
      recurrent caries lesion was found adjacent to a Dyract restoration. It should be
      emphasized that one-year data do not indicate the longterm success of
      restorations.

PMID- 10360202
TI  - Dentists' behavior in response to child dental fear.
AB  - Dental fear is a multifactorial problem frequently encountered during dental
      treatment of children. Studies have indicated that, among others, the behavior of
      the dentist may play a part in the development of this dental fear. The present
      study was undertaken to examine the behavioral aspects of the dentist-patient
      relationship, and specific dentists' behavior that can reduce dental fear. The
      behavior of forty children referred to a center for special dental care and of
      two dentists was assessed during treatment. T-test results showed that the
      children's level of fear decreased after treatment (mean 3.2 vs. 2.1, t = -5.6, p
      = .000). In addition, it was found that the dentists behaved more directly and
      authoritatively during the treatment of highly fearful children than during the
      treatment of relatively less fearful children (p < or = .034). It seems that this
      direct approach had a positive, long-term effect on these children's fearful
      behavior during treatment.

PMID- 10360203
TI  - A study of psychological stress created in dentists by children during pediatric
      dental treatment.
AB  - Stresses on dental practitioners arising from pediatric examination and treatment
      can be broadly divided into those produced by the child and those produced by the
      child's guardian (usually the mother). The present study examined the
      psychological influence of the child. A series of questions regarding
      psychological stress caused by child patients was administered to a group of
      dentists and, by factor analysis, reduced to a 21-item scale. The effectiveness
      of this instrument was examined for reliability and validity. The following
      results were obtained: 1. The 21 items in the scale were selected for their
      association with three primary factors: stress from mild resistance behavior,
      stress from moderate resistance behavior, and stress from determined resistance
      behavior. 2. The scale demonstrated high internal consistency and, by test
      retest, high stability over time. 3. High scores on a standardized scale for
      psychological stress in everyday life were found to correlate positively to
      scores on the scale created in the present study. The correlation was significant
      beyond the 5 percent level. Confirmatory factor analysis found factor loading for
      all items of 0.50 or greater, with no duplication of factors within items. Both
      tests confirmed the validity of the scale. The above results indicate that the
      scale created in the present study is an effective instrument for measuring
      psychological stress in dental practitioners created by children during pediatric
      dental treatment and examination.

PMID- 10360204
TI  - The effect of metoclopramide and hydroxyzine in sedation of infants undergoing
      dental treatment.
AB  - The purpose of the present study was to determine whether the administration of 5
      mg of the anti-emetic drug metoclopramide (MTP) would improve the effectiveness
      of 3.7 mg/kg of hydroxyzine (HYZ) in dental treatment of young patients. Thirty
      uncooperative children, with a mean age of twenty-nine months, and needing at
      least two restorative visits, participated in this study. The patients were
      assigned randomly to receive either 3.7 mg/kg HYZ or the same drug in conjunction
      with MTP; alternate regimens were administered at the two appointments. All the
      children received 50 percent nitrous oxide, and were restrained in a Papoose
      Board with a head holder. The following parameters were evaluated at baseline
      (before initiation of treatment), and at five-minute intervals throughout the
      procedure: degree of alertness, crying and movement. Evaluation of the overall
      behavior at each session was performed by one investigator, who was blind to the
      drug regimen the child had received, utilizing a separate rating scale. The
      results were submitted to statistical analysis. No differences were observed in
      the behavior of the children receiving both regimens. Successful sedation, as
      assessed by lack or minimal crying and/or movement was observed in all the
      treatment visits, with both regimens (mean score 4.4 for HYZ + MTP and 4.6 for
      HYZ). In the few occasions, however, where the restorative sessions were longer
      (45 to 60 minutes), more children fell asleep after receiving protocol A (pramin
      + hydroxyzine), suggesting a possible trend to improve effectiveness in these
      situations. No adverse effects were observed, and all the treatments were
      successfully completed. Although no significant differences could be observed in
      treatments lasting up to a half hour, the addition of MTP could help in sedations
      lasting longer than a half hour.

PMID- 10360205
TI  - The prevalence of nursing caries in one-to-four-year-old children in Jordan.

PMID- 10360206
TI  - Managed (not to) care: Medicaid and children with disabilities.
AB  - The emphasis that managed care programs place on cost containment complicates
      further the already complex setting for Medicaid health services for children
      with disabilities by adding an additional barrier to access care to those that
      already exist. A review considers the attitudes toward and working of Medicaid
      managed care arrangements for children in general and children with disabilities
      in particular.

PMID- 10360207
TI  - Elective mutism: effect of dental treatment with N2/O2-inhalation sedation:
      review and report of case.
AB  - Elective mutism in children is characterized by a marked, emotionally determined
      selectivity in speaking, such that the child demonstrates his or her language
      competence in some situations but fails to speak in other situations. An eight
      year-old boy with elective mutism had to undergo restorative dental treatment. It
      was chosen to use relative analgesia to perform this treatment. The sedation with
      oxygen and nitrous oxide resulted in complete symptom remission as long as the
      sedation lasted.

PMID- 10360208
TI  - Premature dental eruption: report of case.
AB  - This case report reviews the variability of dental eruption and the possible
      sequelae. Dental eruption of the permanent teeth in cleft palate children may be
      variable, with delayed eruption the most common phenomenon. A case of premature
      dental eruption of a maxillary left first premolar is demonstrated, however, in a
      five-year-old male. This localized premature dental eruption anomaly was
      attributed to early extraction of the primary dentition, due to caries.

PMID- 10360209
TI  - Clinical engineering and information systems: bridging the gap. Interview by
      Brian Porras.

PMID- 10360210
TI  - Beyond Y2K: status of key health care information systems projects.

PMID- 10360211
TI  - Implantable defibrillator recipients' responses to device implantation and
      design.
AB  - The implantable cardioverter defibrillator (ICD) is a surgically inserted device
      that follows a well-established pattern of technology innovation and rapid
      adoption without extensive clinical trials. Few devices are as obviously life
      saving in potentially fatal situations and deliver such sudden and sometimes
      painful therapy. Although patients' quality of life and adjustment to the device
      both physically and psychologically are relatively well-documented, few studies
      have explored recipients' responses to the device itself or elicited their
      thoughts on the technological design. The findings presented here are from a
      prospective Australian study that surveyed 110 ICD recipients pre-insertion and
      at 3, 12, and 18 months post-insertion. Recipients' responses to the device and
      their thoughts on design were sought. Respondents were overwhelmingly willing to:
      1) accept the ICD, 2) recommend it to others, and 3) welcome such innovations as
      warning tones, device-controlled drug delivery, and telephone interrogation of
      the device.

PMID- 10360212
TI  - How to diagnose ultrasound transducer problems.

PMID- 10360214
TI  - Liquid ventilation state-of-the-art, Part I.

PMID- 10360215
TI  - Liquid ventilation: clinical experiences.
AB  - Liquid breathing has been in the medical literature for nearly 80 years and has
      been proposed as a means of improving gas exchange in patients with acute
      respiratory failure since the 1970s. There are many potential clinical
      applications of perfluorochemical (PFC) liquids that span many specialties in
      medicine. The ability to lower surface tension directed the initial clinical
      focus on neonatal therapy in the treatment of respiratory distress syndrome. The
      first clinical trial of PFC ventilation was performed in neonates in 1989.
      Additional trials using LiquiVent, a medical-grade PFC liquid, were initiated in
      1993 in infants, children, and adults with severe respiratory distress. Based on
      the results of several studies during this time, it was concluded that the
      technique of liquid ventilation seemed to be safe, improve lung function, and
      recruit lung volume in patients from these various populations. More than 100
      patients from preterm neonates to elderly patients with respiratory distress have
      been studied. In general, patients experience improvement in lung function and
      oxygenation, without adverse events. The results of such trials are encouraging
      and suggest the feasibility of this technique in the neonate with severe
      respiratory failure requiring respiratory support. Limitations of the technique
      include a limited understanding of how it works and its effectiveness in
      different patient populations. It has also become evident that there is a need
      for additional diagnostic and therapeutic instrumentation to expedite its
      implementation in the intensive care environment. This article discusses clinical
      experiences with liquid ventilation and highlights the technical needs to
      facilitate its implementation in respiratory care management.

PMID- 10360216
TI  - Multifactorial analysis of exchanger efficiency and liquid conservation during
      perfluorochemical liquid-assisted ventilation.
AB  - Liquid-assisted ventilation (LAV) of the lung with perfluorochemical (PFC)
      requires a method of oxygenating and removing CO2 from the liquid. Current PFC
      LAV techniques consist of total liquid ventilation, PFC lavage, and partial
      liquid ventilation. Because PFC liquid is volatile, it may be lost from the lung
      or ventilator circuit in the expired gas. This study evaluated the efficiencies
      of two types of exchangers (spray bubbler and membrane oxygenator) with respect
      to CO2 elimination from the PFC liquid and prevention of the loss of PFC liquid.
      A multifactorial analysis of exchanger efficiency was performed with respect to
      liquid conservation and CO2 removal. PFC losses and relative efficiencies of two
      types of exchangers to eliminate CO2 from expired PFC liquid were evaluated,
      along with two types of PFC liquids. Gas (100% O2 at 4 and 8 L/min) and PFC
      liquid were circulated countercurrently through the exchangers (oxygenator and
      bubbler) through a temperature-controlled (25 degrees or 37 degrees C) open
      circuit. To evaluate effectiveness of CO2 elimination, an exchanger efficiency
      index (EEI) for CO2 was calculated applying mass-transfer theory to characterize
      gas transport down a concentration gradient where EEI equals: [PPFCCO2 out-
      PPFCCO2 in]/PgasCO2 in--PPFCCO2 in]. Rate of PFC loss from the circuit was
      calculated from mixed expired gas samples using a thermal detector analyzer. EEI
      and PFC loss rate were analyzed with respect to gas: PFC liquid flow ratios
      (analogous to the V/Q ratio). The results showed that 1) PFC loss rate and
      exchanger efficiency to remove CO2 increased with increasing gas: PFC liquid flow
      rates independent of the type of exchanger or PFC liquid; 2) PFC loss rate at any
      gas or liquid flow rate was greater for the bubbler than for the oxygenator; 3)
      the oxygenator was more efficient than the bubbler with respect to CO2
      elimination; 4) although PFC loss rate increased with temperature and vapor
      pressure, there was little difference in the EEIs for the temperatures studied.
      These results 1) identify exchanger requirements necessary to maintain effective
      CO2 elimination up to four times normal CO2 loading conditions during LAV; 2)
      suggest that using a membrane oxygenator as the gas exchanger, in concert with
      stringent fluid temperature control, improves PFC liquid conservation and CO2
      elimination relative to bubbler exchanger configurations; 3) highlight the
      importance of matching the exchanger type to the physiocochemical properties of
      the specific PFC liquid to optimize CO2 elimination while reducing PFC liquid
      loss by minimizing gas relative to PFC liquid flow rates. Because PFC liquid loss
      occurs with all current means of oxygenating and removing CO2, this study raises
      the importance of developing alternative, bulk-gas-flow-independent, means to
      recondition PFC liquids.

PMID- 10360217
TI  - Software for real-time control of a tidal liquid ventilator.
AB  - The purpose of this project was to develop and test computer software and control
      algorithms designed to operate a tidal liquid ventilator. The tests were executed
      on a 90-MHz Pentium PC with 16 MB RAM and a prototype liquid ventilator. The
      software was designed using Microsoft Visual C++ (Ver. 5.0) and the Microsoft
      Foundation Classes. It uses a graphic user interface, is multithreaded, runs in
      real time, and has a built-in simulator that facilitates user education in liquid
      ventilation principles. The operator can use the software to specify ventilation
      parameters such as the frequency of ventilation, the tidal volume, and the
      inspiratory-expiratory time ratio. Commands are implemented via control of the
      pump speed and by setting the position of two two-way solenoid-controlled valves.
      Data for use in monitoring and control are gathered by analog-to-digital
      conversion. Control strategies are implemented to maintain lung volumes and
      airway pressures within desired ranges, according to limits set by the operator.
      Also, the software allows the operator to define the shape of the flow pulse
      during inspiration and expiration, and to optimize perfluorochemical liquid
      transfer while minimizing airway pressures and maintaining the desired tidal
      volume. The operator can stop flow during inspiration and expiration to measure
      alveolar pressures. At the end of expiration, the software stores all user
      commands and 30 ventilation parameters into an Excel spreadsheet for later review
      and analysis. Use of these software and control algorithms affords user-friendly
      operation of a tidal liquid ventilator while providing precise control of
      ventilation parameters.

PMID- 10360218
TI  - Recent innovations in total liquid ventilation system and component design.
AB  - In addition to partial liquid ventilation (PLV), total liquid ventilation (TLV)
      is being explored as a potential therapy to mitigate ventilator-associated lung
      injury and acute lung failure. TLV is ventilation of the completely liquid-filled
      lung using tidal flow of oxygenated perfluorochemical (PFC) liquid delivered by a
      "liquid ventilator." Most TLV research to date has focused on "small" lung
      (animals < 20 kg; vast majority < 5 kg), with primary relevance to its use in
      children. Recent investigations regarding TLV in larger lungs have helped define
      new design challenges for liquid ventilator systems to succeed as clinical
      products. Adult TLV requires the delivery of significantly higher liquid tidal
      volumes, with proportionately greater O2 and CO2 exchange. Although a simple
      scale-up of liquid ventilator components such as pumps, tubing, fittings, and gas
      and heat exchangers might be considered the most straightforward way to
      compensate for the increased demand, there are a number of practical problems
      with this approach. These include requirements to: 1) minimize priming volume, 2)
      minimize PFC evaporative loss, 3) suppress flow-induced cavitation in fittings
      and components, 4) monitor and control ventilation based on pressure signals
      exhibiting noise, 5) maintain ability and accuracy of delivered breaths in a
      fluid mechanical environment having higher inertial forces and pressure losses
      than for small lung systems, 6) use disposable or sterilizable fluid-contacting
      components, and 7) maintain PFC materials compatibility. TLV system and component
      innovations implemented on a new large-animal liquid ventilator prototype are
      presented. The advantages of new pumps, gas exchangers, and temperature-control
      components are discussed.

PMID- 10360219
TI  - The link between exocrine pancreatic cancer and the endocrine pancreas.
AB  - CONCLUSION: Experimental and human studies during 20 years of research in our
      laboratories point to the importance of pancreatic islets in the development of
      ductal-type adenocarcinomas. We believe that pancreatic cancer that develops
      within ducts, but more frequently within islets, derives from pancreatic stem
      cells that are distributed within the ductal trees and within the islets.
      BACKGROUND: The histogenesis of pancreatic cancer is still debatable. Ductal,
      ductular, and acinar cells all have been declared the tumor progenitor cells. Our
      long-term human and experimental studies indicate that pancreatic ductal
      adenocarcinomas arise within ductal cells and islets. Supporting studies are
      presented in this article. METHODS: Several human studies and experimental
      studies on Syrian hamsters conducted within the last 20 years were used in this
      article. Hamster and human islets were established, and their growth and
      morphologic changes were examined electron microscopically,
      immunohistochemically, cytogenetically, and molecular biologically. RESULTS:
      Studies using the hamster pancreatic cancer model showed that most pancreatic
      adenocarcinomas develop within islets, most probably from stem cells, which are
      also believed to be the progenitor cells for tumors that develop within ducts.
      Studies in newly established human and hamster islets culture validated the
      immense potential of islet cells to differentiate and become malignant. The
      higher susceptibility of islet cells to become malignant could be related to
      their high drug-metabolizing enzymes and their high proliferation rate. Dietary
      studies indicate that the promoting effect of a high-fat diet on pancreatic
      carcinogenesis is unrelated to the energy intake, but rather is related to its
      effect on islet cell replication.

PMID- 10360220
TI  - Serum and correspondent tissue measurements of epidermal growth factor (EGF) and
      epidermal growth factor receptor (EGF-R). Clinical relevance in pancreatic cancer
      and chronic pancreatitis.
AB  - CONCLUSION: The results of this study show that routine measurements of epidermal
      growth factor (EGF) and epidermal growth factor receptor (EGF-R) cannot improve
      screening for pancreatic cancer despite the frequently present tissue
      overexpression. Both values fail to reveal this malignancy in a serum test.
      Patients with chronic pancreatitis exhibit no or very low concentrations of EGF.
      In cases where preoperative diagnosis is difficult the noninvasive EGF and EGF-R
      serum measurements may be helpful in discriminating between pancreatic cancer and
      chronic pancreatitis. BACKGROUND: EGF and EGF-R are frequently overexpressed in
      the tissue of patients suffering from ductal pancreatic cancer and to lesser
      degree in patients with chronic pancreatitis. The aim of this study was to
      determine the value of serum measurements in these patients to detect malignant
      pancreatic disease. In cases of pancreatic cancer, the tissue expression of EGF
      and EGF-R was evaluated by immunohistochemistry. METHOD: Thirty-five patients
      with chronic pancreatitis and 31 patients with pancreatic cancer were evaluated;
      71 patients admitted for routine surgery (hernia repair, cholecystectomy, goiter
      surgery) served as controls. RESULTS: EGF and EGF-R values were not significantly
      different in pancreatic cancer as compared to controls and did not correlate with
      other tumor markers (CA 19-9, carcinoembryonic antigen [CEA], tumor polypeptide
      antigen [TPA]) or with the stage of the disease. Fourteen patients (67%) with
      pancreatic cancer displayed tissue overexpression for EGF and 11 patients for EGF
      R (52%). These patients, however, also failed to exhibit any significant
      pathological changes in serum concentration. In chronic pancreatitis, EGF and EGF
      R were significantly decreased as compared to pancreatic cancer and controls.
      This was an unexpected finding. There was a positive correlation to clinical
      exocrine insufficiency.

PMID- 10360221
TI  - Genomic analysis of the thymine-DNA glycosylase (TDG) gene on 12q22-q24.1 in
      human pancreatic ductal adenocarcinoma.
AB  - CONCLUSION: Abnormality of the thymine-DNA glycosylase (TDG) gene on 12q22-q24.1
      appears to play a limited role in pancreatic ductal carcinogenesis. BACKGROUND:
      Recently, a human G/T-specific TDG gene was identified. This protein acts in a
      system correcting G/T mispairs to G/C pairs. TDG was mapped to chromosome bands
      12q22-q24.1, one of the regions frequently lost in pancreatic cancer. Therefore,
      there is the possibility that the TDG gene on 12q is one of the genes responsible
      for pancreatic ductal carcinogenesis. METHODS: Nucleotide sequences of the entire
      coding region of the TDG gene were analyzed in 21 human pancreatic cancer cell
      lines. mRNA expression of the TDG gene was also analyzed by Northern
      hybridization in several human tissues and 21 human pancreatic cancer cell lines.
      RESULTS: Decreased levels of mRNA expression were detected in the pancreatic
      cancer cell lines, but no somatic mutations were observed.

PMID- 10360222
TI  - Mortality from acute pancreatitis. Late septic deaths can be avoided but some
      early deaths still occur.
AB  - CONCLUSION: In patients with acute pancreatitis, late "septic" deaths resulting
      from infection of pancreatic tissue can be avoided, but some early deaths are
      unavoidable owing to serious multiorgan dysfunction often combined with age or
      other comorbid conditions. METHODS: A retrospective review was conducted of 105
      patients admitted to the Royal Lancaster Infirmary with the diagnosis of acute
      pancreatitis over a 2-yr period (January 1, 1996 to December 31, 1997). RESULTS:
      Six patients admitted during the study period died with a mortality rate of 5.7%.
      All patients died within 6 d of admission and received care in the intensive care
      unit. All presented with serious comorbid medical problems and/or developed early
      multiorgan dysfunction syndrome (MODS). Ten patients underwent pancreatic
      necrosectomy with no mortality.

PMID- 10360223
TI  - Usefulness of alanine and aspartate aminotransferases in the diagnosis of
      microlithiasis in idiopathic acute pancreatitis.
AB  - CONCLUSION: Serum increases of aminotransferases, especially alanine
      aminotransferase (ALT), were suggestive of microlithiasis in idiopathic acute
      pancreatitis, particularly when assessed early after the onset of abdominal pain.
      BACKGROUND: It has been shown that biochemical laboratory values only are useful
      parameters in distinguishing gallstone from nongallstone acute pancreatitis. We
      assessed the diagnostic usefulness of alanine aminotransferase (ALT) and
      aspartate aminotransferase (AST) for identification of occult microlithiasis in
      idiopathic acute pancreatitis. METHODS: Ninety-one patients with idiopathic acute
      pancreatitis who underwent microscopic examination of stimulated duodenal bile
      sediments were retrospectively studied. According to earliness of ALT and AST
      assay after the onset of abdominal pain, patients were divided into two groups:
      group A, within the first 24 h (n = 56) and group B, between 24 and 72 h (n =
      35). RESULTS: ALT and AST values expressed as number of elevations of the upper
      limits of normal were higher in group A patients with positive biliary drainage
      than in group B. Median (range) ALT and AST values were 2.5 (0.1-18.1) vs 0.4
      (0.1-8.6) and 3 (0.3-17.4) vs 0.5 (0.3-11.9), respectively. In the univariate
      analysis and receiver operating characteristic (ROC) curves, ALT within the first
      24 h showed a sensitivity of 73%, specificity of 86%, and positive predictive
      value of 92% for a cutoff of 1.2 elevations of the upper limit of normal. These
      values were slightly higher, although without statistically significant
      differences, than those of AST (73, 80, and 89%, respectively).

PMID- 10360224
TI  - Proteases and protease inhibitors in taurocholate-induced acute pancreatitis in
      rats.
AB  - CONCLUSION: Taurocholate-induced acute pancreatitis (AP) in the rat mimics early
      necrotizing human pancreatitis. Protease activation and protease inhibitor
      consumption occur consistent with a two-stage development, and contact-phase
      activation is a possible primary event in this model. BACKGROUND: Proteases and
      protease inhibitors have been indicated to play an important role in both human
      and experimental acute pancreatitis, although little is known about them in rats.
      METHODS: Three percent sodium taurocholate was infused into the bilio-pancreatic
      duct to induce AP, and over 0-72 h we measured lipase, amylase, albumin,
      prekallikrein, factor X, alpha-1-macroglobulin, alpha-2-antiplasmin, antithrombin
      III, alpha-1-protease inhibitor, and C1-esterase inhibitor (all in plasma) and
      histologic and macroscopic findings. RESULTS: A severe necrotizing, nonlethal, AP
      was induced with an early increase in plasma lipase and alpha-amylase activity
      levels and peritoneal exudate followed by a return to near control levels after
      72 h. Histologic score and pancreatic wet weight ratio increased initially and
      remained high during the observation period. The protease inhibitors C1-esterase
      inhibitor, alpha-2-antiplasmin, and antithrombin III decreased early, within 0-6
      h, whereafter levels normalized. The protease inhibitors alpha-1-macroglobulin
      and alpha-1-protease inhibitor later gradually decreased over the 72 h.

PMID- 10360225
TI  - Nonoperative management of pancreatic pseudocysts. Problems in differential
      diagnosis.
AB  - CONCLUSION: The evaluation of pancreatic cystic lesions entails a misdiagnosis
      risk. Awareness of the problem, knowledge of the natural history of these
      lesions, and meticulous posttreatment follow-up can reduce the consequences of
      diagnostic errors. If all these precautions are adopted, pancreatic pseudocysts
      can be safely treated nonoperatively. BACKGROUND: The accurate diagnosis of
      pancreatic cystic lesions remains a problem. The aim of this study was to
      ascertain the incidence of and the reasons the diagnostic errors occurred in a
      series of pseudocysts drained percutaneously and to compare these data to those
      reported in the literature. METHODS: Data from 70 patients bearing one or more
      pseudocysts who underwent a percutaneous drainage were reviewed. The pretreatment
      workup included medical history, physical examination, ultrasound (US) and
      computed tomography (CT) scans, amylase assay in both the serum and the cystic
      fluid, culture and cytology of the cystic fluid. After removal of the drainage,
      the minimum follow-up period was 12 mo. RESULTS: Four patients died, and two
      cancer-associated pseudocysts were identified before removal of the drainage.
      Sixty-four patients were followed up for a mean of 51.9 mo (range 12-154 mo). A
      third cancer and a mucinous cystic tumor, fully communicating with the main duct,
      were further detected during this period.

PMID- 10360227
TI  - Chronic unilateral lymphoedema caused by a pancreatic pseudocyst.

PMID- 10360226
TI  - Pancreas divisum.
AB  - Endoscopic retrograde cholangiopancreatography (ERCP) is diagnostic. Similarly,
      secretin stimulated ultrasonography may positively predict the outcome of minor
      papilla therapy. Computed tomography is only helpful for the detection of
      complications. Magnetic resonance cholangiopancreatography (MRCP) is a new
      noninvasive diagnostic tool in development. It is accurate and might replace ERCP
      for diagnosis. Clinically, symptomatic patients with PD may be divided into five
      groups: group 1, those with minimal symptoms; group 2, those with recurrent acute
      pancreatitis or upper abdominal pain with no other cause; group 3, those with
      chronic pancreatitis; group 4, those with chronic pancreatic pain; and group 5,
      those with other complications. Group 1 should be treated with medical therapy
      alone. The response to surgical or endoscopic therapy of the minor papilla is
      good in group 2 (75-90%), moderate in group 3 (40-60%), and poor in group 4 (20
      40%). A few patients require other forms of pancreatic surgery, such as Puestow's
      operation, Beger's operation, or distal pancreatectomy. With careful selection of
      patient and therapy, good response to the therapy can be achieved. Pancreas
      divisum (PD) is the most common congenital anomaly of the pancreas, with an
      incidence of up to 10%. Symptoms or complications developing in individuals with
      PD are uncommon (5% of individuals with PD). It seems unlikely that PD alone
      could cause obstructive pancreatitis and the presence of another factor, such as
      minor papilla insufficiency, is probably required for this relatively common
      anomaly to develop complications.

PMID- 10360228
TI  - Experience with duodenal necrosis. A rare complication of acute necrotizing
      pancreatitis.
AB  - Duodenal necrosis is a rare, but very serious complication of acute necrotizing
      pancreatitis that most likely is the result of vascular compromise and ischemia
      of the peri-Vaterian aspect of the duodenal wall. In this article, we present
      three patients with duodenal necrosis complicating acute necrotizing
      pancreatitis. The diagnosis was made at the time of necrosectomy. Management
      options of this challenging complication of necrotizing pancreatitis are
      discussed.

PMID- 10360229
TI  - Alpha-actinin in different invertebrate muscle cell types of Drosophila
      melanogaster, the earthworm Eisenia foetida, and the snail Helix aspersa.
AB  - The presence and distribution of alpha-actinin has been studied in several
      invertebrate muscle cell types. These comprised transversely striated muscle
      (flight muscle) from the fruit fly Drosophila melanogaster, transversely striated
      muscle (heart muscle) from the snail Helix aspersa, obliquely striated muscle
      (body wall muscle) from the earthworm Eisenia foetida, smooth muscle (retractor
      muscle) from H. aspersa, and smooth muscle (outer muscular layer of the
      pseudoheart) from E. foetida. The study was carried by means of Western blot
      analysis, ELISA, and immunohistochemical electron microscopy, using anti alpha
      actinin antibody. Immunoreaction for a protein with the same molecular weight as
      that of mammalian alpha-actinin was detected in all muscle types studied,
      although the amount and intensity of immunoreaction varied among them. In the
      insect muscle, immunolabelling was found along the whole Z-line. In both the
      transversely striated muscle from the snail and the obliquely striated muscle
      from the earthworm, immunolabelling did not occupy the whole Z-line but showed
      discontinuous, orderly arranged patches along the Z-line course. In the two
      smooth muscles studied (snail and earthworm), immunolabelling was limited to
      small patches which did not show an apparently ordered distribution. Since it is
      assumed that alpha-actinin is located at the anchorage sites for actin filaments,
      present observations suggest that, only in the Drosophila muscle, actin filaments
      are parallelly arranged in all their course, whereas in the other invertebrate
      muscles studied these filaments converge on discontinuously distributed anchorage
      sites.

PMID- 10360230
TI  - The effect of length on the sensitivity to phenylephrine and calcium in intact
      and skinned vascular smooth muscle.
AB  - The length dependency of the sensitivity to activators of the smooth muscle of
      different blood vessels is not yet fully understood. Muscle preparations of the
      aorta, the femoral artery and the portal vein of the rabbit were investigated for
      the length dependency of the sensitivity to phenylephrine and calcium in both
      intact and triton X-100 skinned preparations. For intact smooth muscles we found
      that at increased preparation length, the sensitivity of contraction was
      increased. The femoral artery showed the largest effect and the portal vein the
      smallest. In the skinned preparations of the three preparations the calcium
      sensitivity was not dependent on the preparation length. We conclude that the
      changes of the sensitivity in intact preparations are not caused by changes of
      the calcium sensitivity of the contractile proteins.

PMID- 10360231
TI  - Vacuole formation in fatigued single muscle fibres from frog and mouse.
AB  - Force recovery from fatigue in skeletal muscle may be very slow. Gross
      morphological changes with vacuole formation in muscle cells during the recovery
      period have been reported and it has been suggested that this is the cause of the
      delayed force recovery. To study this we have used confocal microscopy of
      isolated, living muscle fibres from Xenopus and mouse to visualise transverse
      tubules (t-tubules) and mitochondria and to relate possible fatigue-induced
      morphological changes in these to force depression. T-tubules were stained with
      either RH414 or sulforhodamine B and mitochondrial staining was with either
      rhodamine 123 or DiOC6(3). Fatigue was produced by repeated, short tetanic
      contractions. Xenopus fibres displayed a marked vacuolation which started to
      develop about 2 min after fatiguing stimulation, reached a maximum after about 30
      min, and then receded in about 2 h. Vacuoles were never seen during fatiguing
      stimulation. The vacuoles developed from localised swellings of t-tubules and
      were mostly located in rows of mitochondria. Mitochondrial staining, however,
      showed no obvious alterations of mitochondrial structure. There was no clear
      correlation between the presence of vacuoles and force depression; for instance,
      some fibres showed massive vacuole formation at a time when force had recovered
      almost fully. Vacuole formation was not reduced by cyclosporin A, which inhibits
      opening of the non-specific pore in the mitochondrial inner membrane. In mouse
      fibres there was no vacuole formation or obvious changes in mitochondrial
      structure after fatigue, but still these fibres showed a marked force depression
      at low stimulation frequencies ('low-frequency fatigue'). Vacuoles could be
      produced in mouse fibres by glycerol treatment and these vacuoles were not
      associated with any force decline. In conclusion, vacuoles originating from the t
      tubular system develop after fatigue in Xenopus but not in mouse fibres. These
      vacuoles are not the cause of the delayed force recovery after fatigue.

PMID- 10360232
TI  - Effect of stretching on undamped elasticity in muscle fibres from Rana
      temporaria.
AB  - Muscle stiffness was measured from the undamped elastic recoil taking place when
      the force attained during ramp stretches of muscle fibres, tetanized on the
      plateau of the tension-length relation, was suddenly reduced to the isometric
      value developed before the stretch, T0. Sarcomere elastic recoil was measured on
      a tendon-free segment of the fibre by means of a striation follower. After small
      ramp stretches, stiffness increases to a value 1.33x greater than that measured
      during release from a state of isometric contraction to 0.9 T0. While the
      relative increase in stiffness is equal to that reported for fibres of Rana
      esculenta (Piazzesi et al., 1992), the absolute value of stiffness measured
      during release from isometric contraction is just over half. As stretch amplitude
      is increased, on the plateau of the force-length relation, stiffness decreases
      toward the isometric value. This finding shows that the decrease in stiffness
      with large stretches cannot be due to a decrease in myofilament overlap (as may
      be the case when stretching occurs on the descending limb of the tension-length
      relation, Sugi & Tsuchiya, 1988), but must be due to an effect of the ramp
      stretch per se. For a given stretch amplitude, the after-stretch transient
      shortening against T0 taking place after the elastic recoil (which is expression
      of the work enhancement induced by stretching, Cavagna et al., 1986, 1994) is
      similar in fibres with very different stiffness of their undamped elastic
      elements. This suggests that this work enhancement is not due to the recoil of
      damped elastic structures recruited during stretching because of sarcomere length
      inhomogenity, a condition which would result in a decrease in stiffness (Morgan
      et al., 1996).

PMID- 10360235
TI  - The XXVII European Muscle Conference. Lund, Sweden, 11-16 September 1998. Report
      and abstracts.

PMID- 10360233
TI  - Cardiac glycosides inhibit detubulation in amphibian skeletal muscle fibres
      exposed to osmotic shock.
AB  - It has recently been suggested that the 'vacuolation' of the transverse tubular
      system that follows the imposition of an osmotic shock is a component process in
      the eventual 'detubulation' of amphibian skeletal muscle. However, such a
      hypothesis requires net fluid transfers from the intracellular space into the
      lumina of the transverse tubules against the prevailing transmembrane osmotic
      gradients. The present experiments tested the effects of cardiac glycosides on
      the consequences of established osmotic protocols known reliably to achieve high
      levels of both detubulation and vacuolation in Rana temporaria sartorius muscle.
      Tubular isolation (detubulation) was assessed through electrophysiological
      observations of the abolition or otherwise of the after-depolarisation components
      of muscle action potentials. Vacuolation was assessed by stereological estimation
      of the volume fraction of muscle that was occupied by fluorescence-labelled
      vacuoles observed using confocal microscopy. Introduction of ouabain in the
      osmotic shock solutions sharply reduced such measures of vacuolation from 48.5 +/
      3.6% (mean +/- SEM; n = 70) to 12.1 +/- 2.7% (n = 190) of the total fibre
      volume. This was accompanied by sharp reductions in the incidence of detubulation
      (detubulation index reduced from 96.3 +/- 2.6% to 0.0 +/- 0.0%). The presence of
      ouabain was critical at the osmotic shock stage in the procedures at which the
      hypertonic glycerol-containing solutions were replaced by isotonic Ca(2+)-Mg(2+)
      Ringer solutions. Finally, the alternative cardiac glycosides, strophanthidine
      and digoxin, exerted similar effects. These findings support a scheme in which
      the osmotic shock initiates a metabolically dependent fluid expulsion. This
      distends the transverse tubules into vacuoles that in turn lead to fibre
      detubulation.

PMID- 10360234
TI  - The beta enolase subunit displays three different patterns of microheterogeneity
      in human striated muscle.
AB  - In higher vertebrates, the glycolytic enzyme enolase (2-phospho-D-glycerate
      hydrolyase; EC 4.2.1.11) is active as a dimeric protein formed from three
      subunits--alpha: ubiquitous, beta: muscle specific, and gamma: neuron specific-
      encoded by different genes. In the present study, we have shown that an antiserum
      previously produced against the mouse beta beta enolase is also a specific
      reagent for the muscle specific human enolase. Using this antiserum to study
      human muscles, we demonstrated novel patterns of the beta subunit
      microheterogeneity which are distinctive from those observed previously in
      rodents and which appear to be independent of age, gender and muscular activity.
      Two variants of the beta subunit differing by their size have been detected: one
      heavy form of 46 kDa (beta H) and one light form of 45 kDa (beta L). Muscle
      biopsies expressed either beta H or beta L or beta H + beta L, and all muscles of
      an individual expressed the same variants. The products of in vitro translation
      of RNA prepared from human muscle displayed beta subunit variants identical to
      those of the protein present in the biopsy. Therefore the differences observed
      between individuals reveal a difference already present at the level of the RNA
      transcripts. These observations suggest the existence of an yet undescribed
      polymorphism of the human beta enolase gene which could affect the coding
      sequence. Comparative immunocytochemical and histochemical analyses of biopsies
      demonstrated that the beta subunit was expressed in all fast fibres (type II),
      but not in slow fibres (type I). No difference was observed in the intensity of
      beta enolase immunolabelling between the various types (IIA, IIAB, IIB) of fast
      fibres. No significant difference in fibre type composition and histological
      appearance was visible between muscles presenting either one of the three
      patterns of microheterogeneity.

PMID- 10360236
TI  - Is vitamin D redundant in an aquatic habitat?
AB  - Certain fish are very rich sources of vitamin D as compared to most of the higher
      vertebrates which have insignificant amounts of this vitamin. Not only the
      teleosts, which possess a calcified skeleton, but also the elasmobranchs, which
      lack calcified skeleton, contain extremely high concentrations of this vitamin,
      leading to the speculation that the function of vitamin D in fish may be
      different from its known classical functions in terrestrial animals.
      Interestingly, the two most common calcemic hormones associated with Ca and P
      homeostasis in higher vertebrates are either missing [parathyroid hormone (PTH)]
      or inactive [calcitonin (CT)] in fish. In fact, these hormones appear to have
      developed after transition of life from water (Ca-P rich environment) to land
      (environment poor in Ca and P). Thus, living in an aquatic environment with a
      continuous rich supply of Ca and P, do fish need vitamin D? If so, does it need
      to be converted to its polar forms? Additionally what are the functions of
      vitamin D and its metabolites in fish? Since fish stand between the invertebrates
      and higher vertebrates in evolution, they serve as a unique model for the study
      of the evolutionary and physiological significance of vitamin D. Investigations
      have demonstrated that the source of a high amount of vitamin D in them is
      primarily through their food-chain (plankton). In addition, it appears from the
      studies in fish that vitamin D perhaps had no physiological function in the
      calcium-rich aquatic environment, and its metabolism was essentially for
      catabolic purposes. During the course of evolution, when life started on calcium
      poor terrestrial environment, vitamin D became functional and its metabolism, an
      anabolic one, was concerned with calcium homeostasis.

PMID- 10360237
TI  - Vitamin D3 and its metabolites have no role in calcium and phosphorus metabolism
      in Tilapia mossambica.
AB  - The physiological function of vitamin D in fishes still remains uncertain.
      Earlier we observed no relationship between vitamin D3 content of several
      freshwater fishes and their calcemic/phosphatemic status and bone mineral
      content. In the present study the effects of vitamin D3 and its metabolites, 25
      hydroxy vitamin D3 (25-OH-D3) and 1,25-dihydroxy vitamin D3 [1,25-(OH)2D3],
      administration on serum calcium-phosphorus levels, intestinal calcium absorption,
      whole-body calcium-phosphorus uptake, and gill calcium binding protein (CaBP)
      activity in the freshwater fish, Tilapia mossambica (Tilapia) was examined. It
      was observed that vitamin D3 and its metabolites could alter neither serum
      calcium-phosphorus levels nor intestinal calcium absorption and gill CaBP
      activity in fish at various doses. Further, the whole-body uptake of labelled
      calcium and phosphorus was also unaffected by vitamin D3/1,25-(OH)2D3 at
      different levels and/or at various lengths of time. Thus these studies indicate
      that unlike in terrestrial vertebrates, vitamin D3 or its metabolites are not
      needed for calcium-phosphorus homeostasis in fish.

PMID- 10360238
TI  - Vitamin D2 is not biologically active for Rora (Labeo rohita) as vitamin D3.
AB  - The present investigation was directed towards finding the relative biopotency of
      vitamin D3 and D2 in fish. The freshwater column feeder fish Labeo rohita (Rora)
      was used for the study. The feeding of Rora with graded levels of vitamin D2
      (550, 1,100 and 1,650 i.u./kg diet) and vitamin D3 (1,100 and 1,650 i.u./kg diet)
      resulted in no behavioural or morphological changes in comparison with the group
      fed a vitamin D-deficient diet. Also, the growth rate, feed efficiency, mortality
      rate, carcass protein, total lipids, calcium and phosphorus were found to remain
      unaltered in the vitamin D-deficient fish and fish fed any form of the vitamin.
      Further, there is no difference in any of the above parameters between the
      different doses of vitamin D3 or vitamin D2. Thus, the results of this study
      indicate that both of the forms of vitamin D (D2 or D3) are not biologically
      active for Rora (Labeo rohita) as a representative of freshwater fish.

PMID- 10360239
TI  - Therapeutic values of different routes of administration of vitamin A with
      ferrous sulfate in treating deferoxamin-induced iron-deficiency anemia.
AB  - About half the pregnant women in developing countries suffer from iron-deficiency
      anemia. The treatment of choice for these patients includes iron compounds such
      as ferrous sulfate. It was recently shown that a concomitant administration of
      vitamin A with ferrous sulfate increases iron-induced hematopoietic effect. In
      the current study, the efficacy of various routes of administration of vitamin A
      with ferrous sulfate in deferoxamin-treated anemic rats were compared. The work
      reveals no difference among various routes of administration, including several
      alternates of oral and intramuscular injection of vitamin A and ferrous sulfate
      for 28 d. It was therefore concluded that the therapeutic effect of vitamin A in
      iron-deficiency anemia is probably not via its influence on iron absorption from
      the gastrointestinal tract.

PMID- 10360240
TI  - Variability in alpha-tocopherol antioxidant activity in the core and surface
      layers of low- and high-density lipoproteins.
AB  - The effect of alpha-tocopherol enrichment of low- and high-density lipoproteins
      on Cu(2+)-catalyzed lipid peroxidation in the hydrophobic core and in the
      hydrophilic envelope of lipoproteins was investigated by using two pyrene
      derivatives, namely, cholesteryl pyrenyl hexanoate (P6Chol) and pyrene dodecanoyl
      sulfatide (P12CS). The progressive decrease in fluorescence of P6Chol was used to
      monitor lipid peroxidation in the core of LDL and HDL, whereas that of P12CS was
      used to follow lipid peroxidation in the envelope of both lipoproteins. alpha
      Tocopherol enrichment of LDL and HDL was obtained by incubating blood plasma at
      37 degrees C with different concentrations of the vitamin (25-500 microM) before
      lipoprotein separation. The incorporation of alpha-tocopherol in LDL and HDL
      presents a progressive, time-dependent increase up to 200 microM alpha
      tocopherol, then a plateau up to 500 microM. In the envelopes, the added
      tocopherol causes a great decrease in the rate of peroxidation and a dramatic
      increase in the latency phase in both lipoproteins. In the cores the lengthening
      of latency phase resulting from alpha-tocopherol enrichment was by far greater in
      LDL than in HDL, and the decrease in the rate of peroxidation in both
      lipoproteins was less than in the envelopes.

PMID- 10360241
TI  - Isolation of 9Z beta-carotene from Dunaliella bardawil and its stereoselective
      synthesis.
AB  - An isolation of 9Z beta-carotene from Dunaliella bardawil was accomplished by low
      pressure column chromatography with Ca(OH)2 column. Furthermore, it was
      stereoselectively synthesized by Wittig reaction between the C10-phosphonium salt
      2 and 9Z beta-apo-8'-carotenal 1, which was prepared by Emmons-Horner reaction of
      9Z beta-ionylideneacetaldehyde 3 with phosphonates 6 and 7 or 8a and 9.

PMID- 10360242
TI  - Regulation of plasma and liver total cholesterol levels by dietary oleic acid in
      rats fed a high-cholesterol diet.
AB  - The effects of diets containing fats and oils or fatty acids on the lipid
      metabolism were investigated in male rats of the Wistar strain fed
      hypercholesterolemic diets, especially focusing our attention on the correlation
      between dietary oleic acid (OLE) contents and the levels of plasma and liver
      total cholesterol (T-CHOL) or the fatty acid profiles in plasma and liver CHOL
      ester. In the rats fed the free (FR)-type fatty acids, the concentrations of
      plasma and liver T-CHOL were high and the amounts of neutral steroids excreted
      into the feces were low when compared with those of rats given the
      triacylglycerol (TG)-type fatty acids, showing that TG-type fatty acids suppress
      the intestinal CHOL absorption more than the FR-type fatty acids do. The
      concentrations of plasma T-CHOL were highest in rats fed the oleic acid (OLE)
      rich diets, followed in order by rats supplied with the palmitic acid (PAL)-rich
      diets, the hydrogenated coconut oil (HCO) diet, and the linoleic acid (LIN)-rich
      diets; the lowest was in rats given tristearin (TSTE) and linseed oil (LIS)
      diets. A positive correlation was obtained between the dietary OLE contents and
      the levels of plasma and liver T-CHOL or OLE in the plasma and liver CHOL-ester,
      and an inverse correlation between dietary OLE contents and the amounts of
      excreted neutral steroids. These results suggest that the dietary OLE contents
      regulate the levels of plasma and liver T-CHOL in CHOL-loaded rats.

PMID- 10360243
TI  - Heart rate monitoring as a field method for estimating energy expenditure as
      evaluated by the doubly labeled water method.
AB  - Energy expenditure (TEE) determined by the doubly labeled water technique (DLW)
      in 10 adult subjects (5 males and 5 females) was used to evaluate the energy
      expenditure estimated from 24 h heart rate monitoring records (HR method) for 2 d
      randomly sampled during 2 weeks of DLW study. Individual data on HR and oxygen
      consumption, obtained during a step test (resting conditions, and up and down at
      3 or 4 stepping rates) and postabsorptive conditions (resting metabolic rate:
      RMR), were used to calculate three types of calibration regression line, i.e.,
      straight-linear regression (EE-HR: A for TEEhr-A), log-linear regression (lnEE
      HR: B for TEEhr-B), and two-linear regression (flex-HR method: C for TEEhr-C).
      When the 24 h HR records were applied, these calibration regressions provided
      three estimates of TEE (mean +/- SD kcal/24 h): TEEhr-A (3,059 +/- 1,246 in all
      subjects), TEEhr-B (2,472 +/- 843), and TEEhr-C (2,759 +/- 1,228). Mean TEE
      determined by the DLW method (TEEdlw) was 2,544 +/- 378 kcal/24 h. Although no
      mean values estimated by HR methods were significantly different statistically
      from the mean value of TEEdlw, the variances of the estimates (e.g., SD) by the
      HR method were much greater than that of TEEdlw (between twofold and threefold).
      TEEhr-B estimated by lnEE-HR regression provided the smallest differences from
      that of TEEdlw (mean difference of -3.1% with a range of -35.1(-)+36.6%). From
      these observations, the following conclusions were made: 1) The estimates of TEE
      by HR are useful as a group mean, but interpretation of the individual TEE
      estimates requires caution because of great deviations from the reference values.
      2) Among the calibration methods tested, the log-linear calibration regression
      (lnEE on HR) gives the best estimates of TEE by the HR method and is recommended
      for use in future studies.

PMID- 10360244
TI  - Extract of wine phenolics improves aortic biomechanical properties in stroke
      prone spontaneously hypertensive rats (SHRSP).
AB  - We studied the effect of the extract of wine phenolics (EWP) on blood pressure,
      vasorelaxing activity and aortic biomechanical properties in stroke-prone
      hypertensive rats (SHRSP). Thirty-six 4-week-old male SHRSP/Izm rats were divided
      into 6 equal groups fed one of the following 6 diets: A control diet (plain
      laboratory diet), the control diet substituted with 0.5 or 1.0% polyphenolic
      compounds derived from the extract of apple phenolics (EAP), the control diet
      substituted with 0.5 or 1.0% polyphenolic compounds derived from the extract of
      tea phenolics (ETP), or the control diet along with drinking water containing
      1.0% polyphenolic compounds derived from EWP. Systolic blood pressure (SBP) and
      body weight (BW) were checked once a week. At the end of the 8th week of feeding,
      all of the rats were sacrificed and the heart weight and aortic biomechanical
      properties were measured. The relaxation effect of the addition of EWP on
      endothelium-intact aortic rings precontracted with prostaglandin (PG) F2 alpha
      was also measured. Only EWP, not EAP or ETP, significantly lowered the SBP values
      a compared with the control group at the 4th, 7th and 8th weeks of feeding (p <
      0.05). The heart weight and ventricular weight, expressed as the percentage of
      BW, were significantly lower in the EWP group than in the control group (p <
      0.05). The aortic maximum stress was significantly increased (p < 0.05), and the
      aortic incremental elastic modulus was significantly reduced (meaning higher
      elasticity) (p < 0.001) in the EWP group as compared with the control group. The
      aortic rings showed concentration-dependent relaxation induced by EWP, and the
      relaxation was significantly greater than that induced by a commercial red wine
      preparation. In conclusion, EWP attenuated the elevation of blood pressure in
      SHRSP possibly by increasing the vasorelaxation activity. The aortic fragility
      and elasticity were also improved in EWP-fed SHRSP.

PMID- 10360245
TI  - In vitro and in vivo effects of exogenous nucleotides on the proliferation and
      maturation of intestinal epithelial cells.
AB  - To determine the nutritional role of nucleotides, the in vitro and in vivo
      effects of exogenous nucleotides on the development of intestine were
      investigated. First, the in vitro effects of nucleotides on the proliferation and
      maturation of enterocytes were studied by using a human colon tumor cell line
      (Caco-2) and a rat normal small intestinal crypt cell line (IEC-6). Second, the
      in vivo effects of nucleotides were also studied in early weaned rats fed
      nucleotide-unsupplemented or high-nucleotide-supplemented diet. Nucleotide
      composition resembled that of human milk (CMP:UMP:AMP:IMP:GMP = 10:1:1:1:1, in
      weight). Nucleotide supplement did not enhance Caco-2 cells proliferation;
      however, it significantly enhanced maltase and sucrase activities. In contrast,
      nucleotides supplement enhanced ICE-6 cells proliferation and maltase activity.
      CMP, predominantly contained in the mixture, enhanced most effectively the
      proliferation and maturation of cells. In the in vivo experiment, nucleotides
      significantly enhanced sucrase activity in the intestinal mucosa of early weaned
      rats. The results presented here suggest that a nucleotide supplement may enhance
      enterocyte proliferation and/or maturation in vivo and in vitro. Therefore
      exogenous nucleotides may play an important role in the development of the
      intestine.

PMID- 10360246
TI  - An evaluation of the bioavailability of selenium in high-selenium yeast.
AB  - The bioavailability of selenium (Se) in high-Se yeast (SeY) was evaluated by
      measuring tissue Se accumulation and glutathione peroxidase (GSHPx) activity. For
      4 weeks, 4-week-old male Wistar rats were fed a Torula yeast-based Se-deficient
      diet (basal diet) or a diet supplemented with a graded level (0.04, 0.08, 0.16,
      and 0.32 microgram/g) of Se as either sodium selenite or SeY, which was obtained
      from two different sources. Se supplementation did not influence growth,
      hematological values, or serum biochemical tests. Se contents and GSHPx
      activities in the liver, serum, and erythrocytes increased gradually with
      increases of the supplemented Se. At lower Se levels (0.04 and 0.08 microgram/g),
      selenite produced higher Se deposition and higher GSHPx activities than SeY did,
      but at a higher Se level (0.32 microgram/g), SeY showed higher measures. Strong
      correlations were detected between the supplementary Se levels and the tissue Se
      contents or GSHPX activities when the regression was fitted to this equation: R
      Rb = m log X + k, where R represented tissue Se content or GSHPx activity in rats
      fed the diet supplemented with Se at X level, Rb corresponding mean value in rats
      fed the basal diet, m slope, and k constant. The bioavailability of Se in SeY, as
      assessed by slope ratio analysis using selenite as a reference Se, was 135% to
      165% in the tissue Se content and 105% to 197% in the GSHPx activities. These
      results indicate that Se in SeY is more bioavailable than selenite Se, and
      therefore it is the preferred form for supplementation.

PMID- 10360247
TI  - Absorption and distribution of lycopene in rat colon.
AB  - Colonic absorption and distribution of lycopene, which inhibited rat colon
      carcinogenesis in our previous studies, were investigated in Sprague-Dawley rats.
      Three groups of six rats each with or without a single-barreled colostomy at the
      mid colon were given a single intragastric or intracolonic dose of 0.2 mL of corn
      oil containing 12 mg of lycopene. Twenty-four hours later, all rats were
      sacrificed and the blood and some tissues were collected. The contents of
      lycopene in the samples were assayed by HPLC. Lycopene was detected in an
      appreciable amount in the liver, but only in trace amount in the serum of all
      rats treated with an intracolonic dose of lycopene and in rats with an
      intragastric dose. After an intragastric lycopene treatment, lycopene was
      detected in the mucosa of the proximal colon and of the distal colon of the
      colostomized rats, whose distal colon had been excluded from the fecal stream. A
      large amount of lycopene was recovered in the feces. None was detected in any
      sample from the control rats treated with an intragastric or intracolonic dose of
      plain corn oil. The results suggest that lycopene is absorbed from the colon and
      also from the small intestine. It might be concluded that both ways of absorption
      contribute to a comparative amount of lycopene accumulation in the colon mucosa
      after ingestion of this carotenoid.

PMID- 10360248
TI  - The effects of tea catechins on fecal conditions of elderly residents in a long
      term care facility.
AB  - This study was carried out to evaluate the effects of tea catechins on fecal
      contents and metabolites of elderly people who were on a diet of solid food. The
      subjects were 35 residents in a long-term care facility who were all on the same
      diet, consisting of rice gruel and minced food. Tea catechins (300 mg), which
      were divided into 3 doses a day, were a meal supplement every day for 6 weeks.
      Fecal specimens were collected by the nursing staff, and their moisture content,
      pH, ammonia, sulfide, and oxidation-reduction potential (ORP) were determined
      before, during, and after the administration of tea catechins. In a comparison of
      values before the administration, all these fecal parameters decreased
      significantly during the tea catechin administration. After termination of the
      administration, these data tended to return toward the levels before
      administration. The reduction of such fecal parameters as moisture, pH, ammonia,
      sulfide, and ORP by tea catechin administration indicated very favorable
      improvements of the subjects' bowel conditions.

PMID- 10360249
TI  - Amelioratory effect of dietary ingestion with red bell pepper on learning
      impairment in senescence-accelerated mice (SAMP8).
AB  - The effect of dietary red bell pepper (Capsicum annuum L.) on learning
      performance was studied in the senescence-accelerated mouse (SAM). An
      experimental diet, which contained 20% (w/w) lyophilized powder of red bell
      pepper, was fed to SAMP8 mice. The mice that received the experimental diet
      showed much better acquisition in passive avoidance tasks as compared with a
      control group given a common diet. This indicated that the dietary ingestion of
      red bell pepper ameliorated the learning impairment in SAMP8.

PMID- 10360250
TI  - Outpatient minilaparotomy for ovarian cysts.
AB  - OBJECTIVE: To design an operative procedure for the ambulatory management of
      ovarian cysts using classical surgical techniques. STUDY DESIGN: One hundred
      consecutive patients 55 years old or younger with 115 persistent or complex
      ovarian cysts less than 10 cm in diameter were managed as outpatients by
      minilaparotomy. Minilaparotomy is defined as a transverse or vertical incision 3
      5 cm in length. The procedure and anesthetic were dictated by each clinical
      situation. Bupivacaine HCl with epinephrine was injected in the wound
      preemptively, and ketorolac was administered systemically perioperatively.
      Operative times, complications and pathology were determined for each case.
      RESULTS: The procedures (unilateral cystectomy, 65; bilateral cystectomy, 9;
      unilateral salpingo-oophorectomy, 20; and bilateral salpingo-oophorectomy, 6)
      were performed under general endotracheal anesthesia in 89, laryngeal mask
      anesthesia in 5 and spinal block in 6. Mean operative time was 46 minutes.
      Estimated blood loss in 96% of cases was < 50 mL, and none was > 100 mL.
      Pathology in two cases revealed adenocarcinoma of borderline malignancy.
      Remaining histology included endometrioma, 40; dermoid, 25; serous cystadenomas,
      14; hemorrhagic corpus luteum, 9; mucinous cystadenoma, 8; cystadenofibroma, 7;
      follicular cyst, 3; fibrothecoma, 2; and peritoneal inclusion cyst, 1. Ninety-six
      of 100 patients were discharged on the day of surgery. Two were admitted for
      urinary retention, one for severe nausea and vomiting, and one for diabetes
      control. CONCLUSION: Minilaparotomy is a safe, rapid procedure for the management
      of ovarian cysts on an ambulatory basis. It can be performed under regional
      anesthesia, avoids intraperitoneal spill and requires only basic operative
      techniques and instrumentation. Minilaparotomy is also a cost-effective technique
      for outpatient management of ovarian cysts.

PMID- 10360251
TI  - Perforin-positive cytotoxic lymphocytes in pregnancy.
AB  - OBJECTIVE: To investigate whether perforin-positive, cytotoxic lymphocytes are
      present in the first and second trimester as well as at term during normal
      gestation. STUDY DESIGN: A monoclonal antibody raised against human perforin was
      used to detect perforin expression in mononuclear cells in first-trimester
      abortion, second-trimester preterm labor due to cervical incompetence and term
      placentas obtained after normal delivery. Fresh frozen tissue sections containing
      first- and second-trimester decidua and placental tissues as well as decidua of
      maternal and fetal surfaces of term placenta were stained using an
      immunoperoxidase method. RESULTS: Occasional perforin-positive lymphocytes were
      present in stroma of chorionic villi of term placenta, while most were found in
      decidua and coagulated blood in maternal vessels and intervillous spaces. The
      majority of these lymphocytes were CD3-, CD2+ and CD56+. Quantitative comparison
      of decidual perforin-positive lymphocytes demonstrated a relative increase in
      these lymphocytes in decidua of second-trimester and term placentas. CONCLUSION:
      The presence of perforin-positive cytotoxic lymphocytes in maternal blood and
      decidua during gestation suggests their roles in pregnancy.

PMID- 10360252
TI  - Psychosomatic aspects of vulvodynia. Comparison with the chronic pelvic pain
      syndrome.
AB  - OBJECTIVE: To examine psychosomatic aspects of vulvodynia (VD) in comparison with
      the chronic pelvic pain syndrome (CPPS). STUDY DESIGN: Sixty-seven VD patients
      and 97 CPPS patients were examined with psychological tests (Freiburg Personality
      Inventory, Giessen Test) and compared with a control group of 34 healthy women.
      Sociodemographic data and psychoanalytic diagnoses were collected for 36 VD
      patients and 106 CPPS patients (inpatients). Descriptive statistics, chi 2 test
      and multivariant analyses were used. RESULTS: CPPS patients had significantly
      higher somatization than VD patients (P < .004). Both CPPS and VD patients, as
      inpatients, were significantly more depressive than the control group. In milder
      forms of VD, the patients (outpatients) exhibited no depression. The incidences
      of sexual abuse and severe psychological disturbances were significantly higher
      in the CPPS group (P < .01). CONCLUSION: VD and CPPS are two, distinct
      psychosomatic gynecologic syndromes and indicate psychosomatically oriented
      therapy.

PMID- 10360253
TI  - Carter-Thomason uterine suspension and positioning by ligament investment,
      fixation and truncation.
AB  - OBJECTIVE: To describe a technique and results of uterine suspension and
      positioning by extraperitoneal ligament investment, fixation and truncation
      (UPLIFT). STUDY DESIGN: Seventy-five women aged 19-48 years in a private referral
      center with chronic pelvic pain, dyspareunia and dysmenorrhea seeking treatment
      were evaluated and treated over a two-year period. Laparoscopic uterine
      suspension was performed using the Carter-Thomason 2-mm needle point suture
      passer. The instrument was passed within and along the round ligament. Thus, a
      pledget of round ligament and bridge of fascial tissue were created. Performing
      the uterine suspension procedure in this manner created shortened, thickened and
      strengthened ligaments that suspended the uterine fundus securely in a mildly
      anteverted position at the level of the exit point of the round ligaments through
      the inguinal canal. RESULTS: The procedure was performed without complications in
      75 patients over a two-year span. Each patient was evaluated for degree of
      retroversion and was assessed by ultrasound to identify any uterine or ovarian
      abnormalities. Pelvic pain and dyspareunia were reproduced by palpation of the
      retroverted uterus. The procedure took an average of 12 minutes to perform. All
      procedures were performed as outpatient procedures with same-day discharge, and
      there were no intraoperative complications. Delayed postoperative pain at the
      suspension site significant enough to require oral analgesia or injection with
      local anesthesia occurred in five patients (7%), four for one week and one for
      one month. For all 75 patients the pain with menses decreased from 8.4 to 1.7,
      with 0 being no pain and 10 being the worst pain the patient had ever experienced
      (P < .01, Wilcoxon's Signed Rank Test). Pain with intercourse decreased from 8.1
      to 1.5 (P < .01, Wilcoxon's Signed Rank Test). Sixty-three patients (84%)
      reported essentially no pain (0-2), while 5 (7%) reported mild pain (2-5), 3 (4%)
      reported moderate pain (5-7), and 4 (5%) continued to have the pain that they had
      had before the surgery (8-10). For the 20 patients for whom a retroverted uterus
      was the only significant pathologic finding, 18 of these (90%) had immediate and
      sustained relief from their symptoms. CONCLUSION: When dyspareunia, dysmenorrhea
      and pelvic pain are associated with a retroverted uterus, the uterus can be
      repositioned to a slightly anteverted position by UPLIFT with the Carter-Thomason
      needle point suture passer. Results with this anatomically correct technique are
      consistent with those previously given for other uterine suspension procedures.
      The advantages of this procedure are ease of performance, strengthening of the
      ligaments by shortening and the investment procedure, and a repair that maintains
      normal anatomic relationships.

PMID- 10360254
TI  - Chaperone use by obstetrician/gynecologists.
AB  - OBJECTIVE: To describe current practices of chaperone use during pelvic
      examinations among obstetrician/gynecologists affiliated with a large tertiary
      care teaching hospital. STUDY DESIGN: Questionnaires were distributed at
      department of obstetrics and gynecology grand rounds to all practicing attending
      physicians to obtain physician demographic data, including age, years in
      practice, practice type (solo or group) and whether chaperones were currently
      used when performing pelvic examinations at the first obstetric or gynecologic
      office visit. Physicians were also asked whether they were taught to use
      chaperones for pelvic examinations during medical school or residency. RESULTS:
      Of the 59 attending physicians, 100% responded to the questionnaire. As compared
      to female physicians, male physicians used chaperones more at the first obstetric
      examination (76.9% vs. 27.8%, P < .002), at gynecologic office visits (70.0% vs.
      22.2%, P < .002) and for breast examinations (51.2% vs. 11.1%, P < .01).
      Physicians greater than 40 years old, in practice longer than 10 years and taught
      as medical students or residents to use chaperones were statistically more likely
      to use chaperones. No attendings, male or female, reported losing a patient to
      another provider or being sued or threatened with legal action because of not
      using a chaperone. CONCLUSION: Chaperones were used more frequently during pelvic
      examinations by male physicians, age greater than 40, solo practice, and
      physicians in practice longer than 10 years. Education affected current practices
      as specific medical student or residency training influenced the use of
      chaperones in private practice.

PMID- 10360255
TI  - Induced abortion. Physician training and practice patterns.
AB  - OBJECTIVE: To examine the relationship between training in induced abortion
      during residency and subsequent practice patterns in providing abortion services.
      STUDY DESIGN: An anonymous survey of all obstetrician-gynecologists with
      admitting privileges at a tertiary care hospital in New England was conducted.
      Physicians were asked about their residency training experience in performing
      abortions, current practices and attitudes toward abortion. RESULTS: Ninety-two
      of 110 physicians (84%) completed the questionnaire. Six physicians who received
      training after residency and two with incomplete information were excluded from
      the analysis. Forty-four respondents received training specifically in first
      trimester abortion, and 42 did not. Physicians who received training were more
      likely to provide abortion services (49% vs. 21%, P = .01), to ask patients about
      their plans for continuing pregnancy (65% vs. 41%, P = .007) and to support
      medical assistance funding for abortion (84% vs. 45%, P = .001) than were
      physicians who did not receive training during residency. Beliefs were
      significantly associated with current practice, even after controlling for
      differences in residency training in abortion. CONCLUSION: Differences in
      practice patterns exist between physicians who receive abortion training and
      those who do not. Practice patterns are associated with beliefs even after
      controlling for variations in training.

PMID- 10360256
TI  - Risk factors associated with blood transfusion in ectopic pregnancy.
AB  - OBJECTIVE: To determine the risk factors associated with blood transfusion in
      ectopic pregnancy. STUDY DESIGN: A retrospective chart review of the presentation
      and hospital course of ectopic pregnancies managed over five years at two
      hospitals was undertaken. Thirty-two variables, including demographics,
      presenting signs and symptoms, and intraoperative findings, were examined with
      univariate and multivariate logistic modeling. RESULTS: Among 185 patients with
      histologically confirmed ectopics who were managed surgically, 8.6% (16 women)
      required transfusion. Multivariate analysis of risk factors for blood transfusion
      demonstrated a statistically significant association with (1) initial hemoglobin
      < 10 g/dL (odds ratio [OR] 38.8, 95% confidence interval [CI] 6.0-356.8); (2)
      human chorionic gonadotropin levels > or = 6,500 mIU (OR 18.1, 95% CI 3.6-158.1);
      and (3) abnormal bleeding on presentation (OR 0.08, 95% CI 0.007-0.42). The
      presence of two of these factors had a sensitivity of 82% (95% CI 48-98%) and a
      positive predictive value of 33% (95% CI 16-54%). No case had all three factors.
      CONCLUSION: This study was, to our knowledge, the first regression analysis of
      risk factors for transfusion associated with ectopic pregnancy. It demonstrated
      that initial hemoglobin and human chorionic gonadotropin levels as well as
      abnormal bleeding on presentation are independent risk factors for blood
      transfusion in ectopic pregnancy.

PMID- 10360258
TI  - Quantitative evaluation of biopty gun testis needle biopsy. Correlation between
      biopsy score of varicocele-bearing testis and sperm count.
AB  - OBJECTIVE: To investigate the applicability of quantitative evaluation of needle
      biopsy of the testis and any correlation between biopsy score and sperm
      parameters in infertile or subfertile men with varicocele. STUDY DESIGN: A total
      of 45 infertile men with clinical left varicocele were included in the study. All
      patients underwent left varicocelectomy and bilateral biopty gun needle biopsy of
      both testes. Spermiograms were obtained before and three months after the
      operation. The biopsy specimens were evaluated for Johnsen and Agger score,
      Leydig cell score, germ cell/Sertoli cell ratio, mean tubular diameter,
      peritubular fibrosis, and tubular and basement membrane hyalinization. RESULTS:
      Mean sperm count, motility and normally configured motile sperm counts increased
      20%, 25% and 60% by month 3, respectively (P < .05). We did not observe any
      significant change in normally configured sperm counts. A mean of 14 tubuli per
      testis were obtained with single-pass needle biopsy. Johnsen and Agger scores,
      Leydig cell scores, mean tubular diameter and germ cell/Sertoli cell ratios of
      both testes were comparable. However, there was significantly less peritubular
      fibrosis, tubular hyalinization and basal membrane hyalinization in the right
      testis when compared to the varicocele-bearing left testis (P < .05). We found
      positive correlations between Johnsen and Agger score of varicocele-bearing left
      testis and preoperative normally configured motile sperm counts (Pearson's r =
      .34 and P < .05 and Pearson's r = .41 and P < .05, respectively). The Leydig cell
      score of varicocele-bearing testis correlated inversely with sperm counts
      (Pearson's r = -0.37, P < .05). CONCLUSION: These observations may prove of
      prognostic value in infertile or subfertile men with varicocele.

PMID- 10360257
TI  - Electronic fetal monitoring. Are we meeting documentation standards?
AB  - OBJECTIVE: To test whether fetal heart rate documentation requirements for high
      risk pregnancies are too stringent to achieve compliance, especially during the
      second stage of labor. STUDY DESIGN: Random retrospective chart and monitor strip
      review of deliveries occurring one year earlier were reviewed. Thirty-four low
      risk and 34 high-risk pregnancies were selected and assessed for compliance with
      nationally accepted documentation guidelines. RESULTS: All monitor strips and
      charts were successfully retrieved from medical records. Charted documentation of
      the strips met national requirements in the active phase of the first stage of
      labor in 97% of cases, as did documentation during the second stage. For high
      risk pregnancies, compliance during the active phase of the first stage of labor
      was 65% as compared to 35% in the second stage. All infants had normal five
      minute Apgar scores, and none had umbilical arterial acidemia. CONCLUSION: Given
      current resources, we cannot reliably meet established documentation standards
      for high-risk pregnancies. Such overly stringent documentation standards pose a
      significant risk in cases going to litigation. A standard should be developed
      that is based on outcome data.

PMID- 10360259
TI  - Serum and peritoneal fluid levels of IGF I and II and insulinlike growth binding
      protein-3 in endometriosis.
AB  - OBJECTIVE: To examine whether insulinlike growth factor I (IGF I), IGF II and IGF
      binding protein 3 (IGFBP 3) in serum and peritoneal fluid (PF) correlate with the
      presence and severity of endometriosis. STUDY DESIGN: Case-control study
      including 29 patients with endometriosis and 15 controls. The revised American
      Fertility Society classification stages of I and II were pooled as early-stage (n
      = 15), and stages III and IV were taken as late stage (n = 14). Simultaneous
      sampling of blood and PF was performed during laparoscopy, and IGF I, IGF II and
      IGFBP 3 levels were determined by immunoradiometric assay. RESULTS: The serum
      levels of all three proteins were higher than PF levels except for a reversed IGF
      I PF: serum ratio in the early stage. There were no significant differences in
      IGF II and IGFBP 3 levels among the groups. The mean serum IGF I levels of
      controls and early-stage patients were significantly lower than those in the late
      stage. Also, mean PF IGF I levels in controls were significantly lower than in
      the late stage. CONCLUSION: IGF I may be an important mediator in the development
      and/or maintenance of endometriosis or progression to late-stage disease.

PMID- 10360260
TI  - Screening for hypothyroidism in infertile women.
AB  - OBJECTIVE: To determine the frequency of an elevated thyroid-stimulating hormone
      (TSH) level in 704 patients seeking treatment for infertility. STUDY DESIGN: Sera
      from 704 women evaluated for infertility were assayed for TSH levels using
      radioimmunoassay (normal, 0.45-4.09 mIU/mL). All women had at least one year of
      infertility. Women with a known history of thyroid disease were excluded from the
      review. RESULTS: Sixteen of 704 patients (2.3%) had elevated TSH levels and were
      treated with levothyroxine to normalize TSH. None of these women had overt
      clinical signs or symptoms of hypothyroidism. Of these women, 11 of 16, or 69%,
      had ovulatory dysfunction, and 7 (64%) later became pregnant while on thyroid
      replacement. Five of 704 (0.7%) women with infertility who presented without a
      history of ovulatory dysfunction had elevated TSH levels, and none became
      pregnant with treatment. CONCLUSION: The prevalence of elevated TSH in 704 women
      with at least one year of infertility was 2.3%. The majority of women diagnosed
      with hypothyroidism (11 of 16, or 69%) had ovulatory dysfunction. With treatment
      for hypothyroidism, successful pregnancies resulted in 7 of 11 (64%) of patients.
      Women with infertility and ovulatory dysfunction should be screened for
      hypothyroidism. Screening for hypothyroidism as part of a routine infertility
      workup in women with normal ovulatory function will yield few abnormal tests.

PMID- 10360261
TI  - Immune abnormalities in endometriosis compromising fertility in IVF-ET patients.
AB  - OBJECTIVE: To evaluate the incidence of immune abnormalities in patients with
      endometriosis and primary or secondary infertility. STUDY DESIGN: This study
      analyzed the incidence of alloantibodies and autoantibodies in 100 women with
      endometriosis and 62 patients with unexplained infertility without endometriosis
      who enrolled in an assisted reproduction program at the Colombian Fertility and
      Sterility Center from January 1, 1996, to May 30, 1997. The alloimmune status of
      the women was determined by testing for the presence or absence of antileukocyte
      antibodies. The autoimmune studies included antinuclear antibodies,
      antiphospholipid antibodies and lupus anticoagulant antibody. RESULTS: Negative
      titers of IgG antipaternal antibodies were identified in 34% of patients with
      primary infertility and in 34% of women with secondary infertility and a history
      of pregnancy losses. Positive titers of antinuclear antibodies were found in 27%
      (27/100) of the group of patients with endometriosis; of them, 30% (15/50) had
      primary infertility and 24% (12/50), secondary infertility. The average titer was
      1/80. Forty-eight percent of the infertile patients (48/100) showed titers of
      antiphospholipid antibodies for IgG and IgM; 46% of these patients had primary
      infertility (23/50) and 50% (25/50), secondary infertility. This was
      significantly higher than in controls (P < .05). Two patients were positive for
      lupus anticoagulant antibody. In the group of patients with unexplained
      infertility without endometriosis, the incidence of antinuclear antibodies was
      17.7% and of antiphospholipid antibodies, 30.6%. CONCLUSION: For women with
      endometriosis, alloimmune and autoimmune evaluation is recommended prior to their
      undergoing assisted reproduction in order to provide appropriate therapy for each
      case.

PMID- 10360262
TI  - Telomerase activity in complete hydatidiform mole.
AB  - OBJECTIVE: To investigate whether telomerase is activated in complete
      hydatidiform mole and whether it could predict the development of persistent
      gestational trophoblastic tumors (GTTs). STUDY DESIGN: For this prospective
      study, 21 patients with complete hydatidiform mole were recruited. Molar tissue
      was obtained for telomerase activity measurement using the telomeric repeat
      amplification protocol assay. Patients' clinical characteristics, telomerase
      activity and subsequent clinical outcome were analyzed. RESULTS: Telomerase
      activity was detected in 12 cases (57.1%) with varied intensity. Two of four
      patients who had telomerase activity, uterine size larger than expected and
      preevacuation serum beta-human chorionic gonadotropin (beta-hCG) levels > 10(6)
      mIU/mL developed persistent GTT. CONCLUSION: Telomerase activity is detectable in
      some complete hydatidiform moles and might be useful for predicting persistent
      GTT when combined with uterine size and preevacuation serum beta-hCG level.

PMID- 10360263
TI  - Postpartum hemolytic-uremic syndrome associated with lupus anticoagulant. A case
      report.
AB  - BACKGROUND: Hemolytic uremic syndrome is a rare thrombotic microangiopathy
      characterized by acute renal failure, thrombocytopenia and hemolysis. The
      underlying abnormality is currently thought to involve enothelial injury within
      the microcirculation. CASE: A 30-year-old woman, gravida 2, para 1, underwent
      emergency cesarean delivery at 36 +/- 2 weeks' estimated gestational age for
      repetitive late decelerations and presumed severe preeclampsia. Postoperatively,
      the blood pressure remained persistently elevated despite multigent hypertensive
      therapy. By postpartum day 4 the patient continued to display acute oliguric
      renal failure, persistent severe thrombocytopenia and worsening hemolysis.
      Percutaneous renal biopsy was consistent with the clinical diagnosis of hemolytic
      uremic syndrome. Lupus anticoagulant was present, corroborated by markedly
      abnormal tissue thromboplastin inhibition and platelet neutralization procedures.
      With supportive therapy and daily plasmapheresis, the patient was discharged 22
      days after delivery, with full recovery of renal function and resolution of the
      hemolytic process. CONCLUSION: Hemolytic uremic syndrome can be associated with
      lupus anticoagulant. This autoantibody may promote localized platelet
      aggregation, causing endothelial damage.

PMID- 10360264
TI  - Successful pregnancy in a woman with secondary biliary cirrhosis with portal
      hypertension from recurrent pyogenic cholangitis. A case report.
AB  - BACKGROUND: Pregnancy in women with secondary biliary cirrhosis due to recurrent
      pyogenic cholangitis is extremely rare. Little information is available on the
      effect of pregnancy on the disease and vice versa. CASE: A patient who had
      secondary biliary cirrhosis due to recurrent pyogenic cholangitis complicated by
      splenomegaly and portal hypertension had a successful pregnancy. Although she had
      a history of esophageal variceal bleeding before this pregnancy, there was no
      such bleeding during pregnancy. She had an uneventful antenatal course except
      that her liver enzyme level fluctuated slightly. The serum bilirubin level
      increased during the third trimester of pregnancy but returned to the prepregnant
      level after delivery. CONCLUSION: Termination of pregnancy may not be the only
      option for management. The management protocol for patients with primary biliary
      cirrhosis complicating pregnancy, which includes regular fetal surveillance and
      monitoring of maternal liver function, should be considered for pregnant women
      with secondary biliary cirrhosis.

PMID- 10360265
TI  - Analyzing contraceptive failure.

PMID- 10360266
TI  - Analyzing contraceptive failure.

PMID- 10360267
TI  - Ethical guidelines on human reproduction and women's health. FIGO Committee for
      the Ethical Aspects of Human Reproduction and Women's Health.

PMID- 10360268
TI  - The use of monoclonal antibodies in human prion disease.
AB  - Detection of PrP and its pathological isoform(s) is the key to understanding the
      etiology and pathogenesis of transmissible spongiform encephalopathy. There is
      ample evidence that PrP isoforms constitute a major component of an unknown and
      perhaps unconventional infectious agent. An etiological relationship between
      human and zoonotic transmissible spongiform encephalopathies may be revealed with
      monoclonal antibodies. Knowledge of the conformational transition rendering a non
      pathogenic, almost ubiquitous cellular protein into a pathogenic one is crucial
      to defining pathomechanisms. The stepwise or even continuous formation of
      pathogenic molecules can be monitored. Any improvement in the early diagnosis
      could help to conceive new therapeutic measures which are not currently
      available. Determination of PrP isoforms in tissue, cells, or body fluids may be
      of prognostic value. Many experimental approaches in molecular medicine and
      molecular biology of the prion protein already rely on monoclonal antibodies.
      Recombinant antibodies such as the single-chain Fv may soon replace traditional
      hybridoma techniques. Binding affinity can easily be manipulated by a number of
      techniques, including in vitro mutagenesis--a step which could never be carried
      out using the traditional hybridoma technology. Monoclonal antibodies are and
      will remain an essential support for ongoing research on the prion protein in
      general and on the unconventional infectious prions.

PMID- 10360269
TI  - A model system for organ engineering: transplantation of in vitro induced
      embryonic kidney.

PMID- 10360270
TI  - Selection for activity level alters the properties of the circadian pacemaker in
      Drosophila jambulina.

PMID- 10360271
TI  - Closing the condom gap.
AB  - The need for condoms is growing as HIV/AIDS and other sexually transmitted
      infections (STIs) spread. Making condoms more accessible, lowering their cost,
      promoting them more, and helping to overcome social and personal obstacles to
      their use would save many lives and reduce the enormous consequences and costs of
      STIs and unintended pregnancies.

PMID- 10360272
TI  - [The hematologic analyzer Vet ABC: evaluation of its use for dogs and cats].
AB  - The blood analyser Vet ABC was evaluated using the blood of dogs and cats. The
      correlation of results with those obtained with standard reference methods,
      reproducibility, and ease of operation were investigated. Good accuracy
      reproducibility were found in both species for leucocyte and erythrocyte counts,
      haematocrit, haemoglobin level, MCV, MCH, and MCHC. However, for some parameters
      new reference values will have to be established. The Vet ABC is not reliable for
      the measurement of platelets in the cat, and in the dog it does not give
      reproducible measurements of low numbers of platelets. In general, the Vet ABC is
      easy to use and does not need much maintenance.

PMID- 10360273
TI  - [Giardia, a potential cause of diarrhea].
AB  - Diarrhoea is a common problem in young animals living in densely populated
      surroundings, such as kennels and catteries. One possible causative agent is
      Giardia. The aim of this article is to increase awareness of this parasite.

PMID- 10360274
TI  - [Veterinary drug profile. Clomipramine (Clomicalm)].

PMID- 10360275
TI  - [Predecessors: veterinarians from earlier times. 33. Andreas Christian Gerlach
      (1811-1877)].

PMID- 10360276
TI  - [Beginning of the practice test for animal safety index].

PMID- 10360277
TI  - [Afternoon study of living meat chickens].

PMID- 10360278
TI  - [Fight against infectious bovine rhinotracheitis postponed].

PMID- 10360280
TI  - [Four times first course day Recognizing Cattle Veterinarians].

PMID- 10360281
TI  - [Group for swine medicine].

PMID- 10360282
TI  - Macular vasculopathy and its evolution in incontinentia pigmenti.
AB  - PURPOSE: To describe macular vasculopathy in incontinentia pigmenti. METHODS:
      Twelve baby girls with incontinentia pigmenti were examined under general
      anesthesia by fluorescein angiography of the macula. Nine eyes of 9 patients had
      sufficient detail to allow evaluation of capillary changes. Angiography was
      initiated as early as 3 months of age and was repeated in 7 eyes at 3- to 12
      month intervals. Changes in capillary patterns were identified. RESULTS:
      Irregularly enlarged or distorted foveal avascular zones were noted in all 9
      maculas. Sparseness of the perifoveolar capillary bed was a characteristic
      finding. Sequential macular angiography demonstrated non-progressive (stable)
      capillary closure in 2 eyes; progressive closure in another macula; progressive
      closure plus addition or reopening of macular capillaries in 3 eyes; and central
      retinal artery occlusion, with cherry-red spot formation, in 1 eye at 12 days of
      age. In addition, progressive tractional detachment of the macula occurred in 2
      of these eyes, and progressive macular neovascularization occurred in 1 eye.
      CONCLUSIONS: Macular ischemia is characteristic of incontinentia pigmenti and is
      often progressive. It is the initiating event of a typical vasculopathy,
      characterized by capillary remodelling and, occasionally, by neovascularization
      and tractional detachment of the retina.

PMID- 10360283
TI  - The etiology and treatment of macular detachment associated with optic nerve pits
      and related anomalies.
AB  - PURPOSE: Up to two thirds of patients with optic disc pits develop a sight
      limiting maculopathy. There is confusion regarding the etiology and nature of the
      maculopathy in these cases. We present 7 cases of serous macular detachment
      occurring in association with optic pits or related cavitary anomalies and
      identify a rhegmatogenous etiology. METHODS: We reviewed the records of 7
      patients with optic nerve anomalies and macular detachment. Patients were treated
      with observation, barricade laser, vitrectomy, and/or gas tamponade. RESULTS:
      Seven patients were noted to have serous macular detachment associated with an
      optic nerve pit or other cavitary anomaly. A hole or tear in the diaphanous
      tissue overlying the optic pit was identified in all cases. None of the patients
      had a posterior vitreous detachment. Two were treated with photocoagulation only,
      and 5 underwent pars plana vitrectomy with fluid-gas exchange with or without
      photocoagulation. Pretreatment visual acuity ranged from 20/30 to 6/200.
      Posttreatment acuity ranged from 20/25 to 20/100. Five of 7 eyes had final
      acuities of 20/30 or better, and all treated eyes improved. CONCLUSIONS: A tear
      in the diaphanous tissue overlying the optic nerve pit is responsible for the
      development of serous macular detachment and is consistent with findings in
      similar conditions, such as retinal detachment in association with chorioretinal
      coloboma. These tears may be quite subtle, and careful biomicroscopic examination
      is required to appreciate them. The treatment of this condition remains
      controversial. However, because of the relatively poor prognosis, we believe
      treatment should include the formation of a barricade to fluid movement as well
      as sealing and relief of traction from the hole. The value of laser treatment may
      be increased by the early identification of a defect in the diaphanous membrane
      prior to the development of macular detachment. Consideration of prophylactic
      laser might then reduce the need for later, more invasive measures, and improve
      the prognosis.

PMID- 10360284
TI  - Demonstration of exclusive cilioretinal vascular system supplying the retina in
      man: vacant discs.
AB  - PURPOSE: To report the fluorescein angiographic and Doppler ultrasonographic
      findings in a patient with apparent exclusive ciliary vascular supply of the
      retina of both eyes. METHODS: Case report. RESULTS: The ophthalmoscopic
      appearance of all arterial vessels emanating from both discs was consistent with
      a cilioretinal origin. Retinal veins also entered each disc peripherally near the
      margin, leaving the central part of each disc vacant. Fluorescein angiography
      showed filling of all arterial vessels simultaneous with the early-phase
      choroidal background flush bilaterally. Color and power Doppler ultrasonographic
      imaging demonstrated unequivocally the absence of central retinal vessels within
      the optic nerves. Both discs were normal in size and excavated with central glial
      tissue present. The clinical history of monocular, alternating episodes of
      failing vision with partial resolution and the retinal pigmentation patterns
      bilaterally were consistent with, though not conclusive for, previous episodes of
      serous retinal detachments. Coincident systemic anomalies consisted of small
      kidneys with reduced renal parenchyma discovered on ultrasonography, along with
      chronic interstitial nephritis. CONCLUSIONS: The ophthalmoscopic appearance of
      optic discs with apparent all-cilioretinal vascular supply has been reported
      previously, but proof of the absence of central retinal vessels requires Doppler
      ultrasonographic evidence corroborated by angiographic findings, as exemplified
      in our case report. We describe the association of this disc anomaly with renal
      parenchymal disease and its distinction from colobomatous defects.

PMID- 10360285
TI  - Role of retinal vascular endothelial cells in development of CMV retinitis.
AB  - PURPOSE: Although cytomegalovirus (CMV) retinitis is known to occur in
      association with retinal microangiopathy in individuals with marked
      immunodeficiency, glial cells are believed to be the initial target cells in the
      development of retinitis. Moreover, it has been hypothesized that CMV gains
      access to the retinal glia because of altered vascular permeability. In an
      attempt to address the hypothesis, we studied 30 autopsy eyes of AIDS patients
      with systemic CMV infection, with or without clinically apparent CMV retinitis.
      METHODS: The autopsy eyes were processed in three ways. First, dual
      immunohistochemical studies were done by using anti-CMV antibodies for immediate
      early, early, and late antigens. The retinal cell types infected with the virus
      were then determined by using anti-GFAP, anti-VonWillebrand's factor, neuronal
      specific enolase, and leukocyte marker CD68. Second, selected eyes were processed
      for in situ hybridization with DNA probe specific to CMV. Third, an eye with
      clinically apparent CMV retinitis was submitted for electron microscopic
      examination. RESULTS: At the site of retinal necrosis in those eyes with a
      clinical diagnosis of CMV retinitis, the immunohistochemical, in situ
      hybridization, and ultrastructural examinations revealed that CMV was present
      primarily in the Muller cells and in perivascular glial cells. Adjacent to these
      infected cells, focal areas of positive staining for CMV antigen were seen in the
      glial cells, neuronal cells, and retinal pigment epithelial cells. At these sites
      most of the retinal capillaries were devoid of endothelial cells. Few vessels
      located at the advancing margin of retinal necrosis showed the presence of viral
      proteins in the endothelial cells. CONCLUSIONS: The present results indicate that
      retinal vascular endothelial cells could be the initial target in the development
      of viral retinitis, with subsequent spread of the infection to perivascular glia,
      Muller cells, and other retinal cells, including the retinal pigment epithelium.

PMID- 10360286
TI  - Results of peripheral laser photocoagulation in pars planitis.
AB  - PURPOSE: To determine the effect of peripheral retinal laser photocoagulation
      (PLP) on visual acuity, intraocular inflammation, and other ocular findings,
      including retinal neovascularization in eyes with pars planitis. METHODS: A
      retrospective chart review of eyes with pars planitis that had undergone PLP.
      RESULTS: Twenty-two eyes in 17 patients with pars planitis had undergone
      treatment with PLP at 2 centers. The mean age at the time of treatment was 19.3
      years. Following treatment, mean follow-up was 16.3 months (range, 6 to 37
      months). Mean visual acuity was 20/60 preoperatively and 20/50 postoperatively.
      This level of improvement was not statistically significant (P > .10), but there
      was a statistically significant decrease in the use of corticosteroids between
      the preoperative examination and the last postoperative examination (86% versus
      27%, P < .05). There was also a statistically significant decrease in vitritis at
      the last follow-up (P = .0008) and a decrease in neovascularization of the
      vitreous base (P = .03) and in clinically apparent cystoid macular edema (P =
      .02). Epiretinal membranes were noted in 23% of eyes preoperatively and in 45% of
      eyes postoperatively. Only one of these epiretinal membranes was considered to be
      visually significant. One eye developed a tonic dilated pupil, which slowly
      improved. CONCLUSIONS: Although the long-term natural history of clinical
      findings in pars planitis is not well documented, PLP appears to decrease the
      need for corticosteroids while stabilizing visual acuity. It also appears to
      decrease vitreous inflammation. PLP has few complications and should be
      considered in patients with pars planitis who are unresponsive or have adverse
      reactions to corticosteroids.

PMID- 10360287
TI  - The use of topical aqueous suppressants in the prevention of postoperative
      intraocular pressure elevation following pars plana vitrectomy with long-acting
      gas tamponade.
AB  - PURPOSE: To determine if topical aqueous suppressant therapy applied after pars
      plana vitrectomy (PPV) with gas tamponade successfully prevents postoperative
      elevation of intraocular pressure (IOP). METHODS: A prospective, controlled study
      was performed on patients who met inclusion criteria and underwent PPV with gas
      tamponade (SF6 18%-20% or C3F8 12%-16%) over a 1-year period. Treatment eyes
      received topical aqueous suppressants at the end of surgery. Postoperative IOP
      checks were performed at 4 to 6 hours, 1 day, and 1 week. RESULTS: Twenty-one
      control (C) and 20 treatment (T) eyes met the inclusion criteria. The IOP (in mm
      Hg) measured at 4 to 6 hours (23.05 [C], 14.73 [T] and 1 day (23.24 [C], 17.28
      [T]) postoperatively showed a statistically significant difference between the
      groups (P = .0038) at 4 to 6 hours, and a trend toward significance (P = .057) at
      1 day. Eleven control and 3 treatment eyes had an IOP spike above 25 mm Hg at 4
      to 6 hours or 1 day postoperatively (P = .02), and 6 control and 1 treatment eye
      had a postoperative IOP above 30 mm Hg. A pressure rise above 40 mm Hg was seen
      in 2 control eyes and no treatment eyes. CONCLUSIONS: Use of topical aqueous
      suppressants following PPV with long-acting gas tamponade is effective in
      preventing significant postoperative IOP elevation in a majority of cases.

PMID- 10360288
TI  - Goniosurgery for prevention of aniridic glaucoma.
AB  - PURPOSE: We conducted a retrospective study to report the long-term success and
      complications of modified goniosurgery to prevent aniridic glaucoma, an entity
      that typically is difficult to control medically or surgically. METHODS: Fifty
      five eyes in 33 patients who had aniridia without glaucoma and who had
      goniosurgery were identified. Ninety-one procedures were performed on 55 eyes by
      1 surgeon (D.S.W.). Each eye had an average of 1.65 procedures and an average of
      200 degrees of goniosurgery. Average patient age at time of initial goniosurgery
      was 37 months. There were no operative complications. RESULTS: No eye had a
      decrease in visual acuity at last follow-up. All eyes had a preoperative
      intraocular pressure (IOP) of less than 21 mm Hg. At last follow-up (average, 9
      years 6 months; range, 8 months to 24 years), 49 eyes (89%) had IOP of less than
      22 mm Hg without medications. The remaining 6 eyes (11%) had IOP of less than or
      equal to 22 mm Hg with up to 2 eye drops. Of 224 aniridic eyes of 112 patients
      that were seen for eye care by 1 of the authors (D.S.W.), 119 eyes (53%)
      demonstrated glaucoma, as defined by IOP of greater than 21 mm Hg. CONCLUSIONS:
      Without prophylactic goniotomy, aniridic glaucoma may be expected in half of
      patients, and when it occurs, it is extremely difficult to control. Prophylactic
      goniosurgery in selected eyes of young patients with aniridia is effective in
      preventing aniridic glaucoma.

PMID- 10360289
TI  - Acute and chronic structural effects of pilocarpine on monkey outflow tissues.
AB  - PURPOSE: Determine the effects of supraclinical topical doses of pilocarpine on
      the structure of the trabecular meshwork (TM), ciliary muscle (CM), and ciliary
      processes in monkeys. METHODS: Cynomolgus monkeys received topical pilocarpine
      hydrochloride doses of 1 to 2 mg unilaterally once or twice daily for 1 to 211
      days. Both eyes were examined by light and electron microscopy. RESULTS: After 1
      dose, the TM was expanded and the flow pathways open. Some elastic anterior CM
      tendons were disconnected from the muscle tips and/or the tips themselves were
      disrupted; macrophage-like cells accumulated in these regions. In eyes that had
      long-term treatment, scar tissue at the muscle tips and disruption of myofibrils
      within muscle cells indicated regions of previous disconnection. Most collagen
      tendons inserting into the peripheral cornea were unaffected. With increasing
      treatment duration in younger monkeys, there was anteroposterior shortening of
      Schlemm's canal, TM densification due to collapse, and increased cellularity in
      the subendothelial region of Schlemm's canal. TM densification and Schlemm's
      canal shortening were not found in older monkeys, implicating posterior movement
      of the elastic young limbal region induced by strong CM contraction, rather than
      pilocarpine toxicity. In the ciliary body we found vasodilation, Greeff's
      vesicles, and blood-aqueous barrier breakdown in the anterior ciliary processes
      and vasodilation, edema, and round-cell infiltration in the posterior pars plana.
      CONCLUSIONS: Large pilocarpine doses induce morphologic changes in the monkey
      anterior segment, likely consequent to intense CM contraction. Changes in the TM
      and Schlemm's canal are seen only in young monkeys, apparently owing to
      mechanical deformation of the elastic limbal region.

PMID- 10360290
TI  - Spherical and aspherical photorefractive keratectomy and laser in-situ
      keratomileusis for moderate to high myopia: two prospective, randomized clinical
      trials. Summit technology PRK-LASIK study group.
AB  - OBJECTIVE: Determine the outcomes of single-zone photorefractive keratectomy
      (SZPRK), aspherical photorefractive keratectomy (ASPRK), and laser in-situ
      keratomileusis (LASIK) for the correction of myopia between -6 and -12 diopters.
      DESIGN: Two simultaneous prospective, randomized, multi-center clinical trials.
      PARTICIPANTS: 286 first-treated eyes of 286 patients enrolled in one of two
      studies. In Study I, 134 eyes were randomized to SZPRK (58 eyes) or ASPRK (76
      eyes). In Study II, 152 eyes were randomized to ASPRK (76 eyes) or to LASIK (76
      eyes). INTERVENTION: All eyes received spherical one-pass excimer laser ablation
      as part of PRK or LASIK performed with the Summit Technologies Apex laser under
      an investigational device exemption, with attempted corrections between -6 and 
      12 diopters. MAIN OUTCOME MEASURES: Data on uncorrected and best spectacle
      corrected visual acuity, predictability and stability of refraction, and
      complications were analyzed. Follow-up was 12 months. RESULTS: At 1 month
      postoperatively, more eyes in the LASIK group achieved 20/20 and 20/25 or better
      uncorrected visual acuity than PRK-treated eyes; at the 20/25 or better level,
      the difference was significant for LASIK (29/76 eyes, 38%) over SZPRK (10/58
      eyes, 17%) (P = .0064). At all subsequent postoperative intervals, no difference
      was seen between treatment groups. Similarly, best corrected visual acuities were
      better for LASIK than all PRK eyes at 1 month postoperatively, and LASIK was
      better than SZPRK at 3 months follow-up (e.g., for 20/20 or better at 1 month,
      LASIK 50/76 eyes (66%) versus SZPRK 24/57 eyes (42%), P = .0066). PRK eyes had a
      mean loss of BCVA through 6 months, while LASIK eyes had a slight gain of mean
      BCVA through month 6; at 12 months, both ASPRK groups but not SZPRK continued to
      have a small mean loss of BCVA (e.g., compared to preoperative, mean BCVA at 12
      months for SZPRK was + 0.3, LASIK was +.21, ASPRK I was -0.11, and ASPRK II -0.31
      (SZPRK versus ASPRK II, P = .0116). Predictability was better for PRK than LASIK
      at all follow-up intervals (e.g., for manifest refraction spherical equivalent +/
      1.0 diopters at 6 months, ASPRK I 42/62 eyes (68%) versus LASIK 29/72 eyes
      (40%), P = .0014%). Stability was slightly but insignificantly less in the LASIK
      eyes compared to PRK eyes. All visual outcome measures were better for eyes with
      preoperative myopia between -6 and -8.9 D compared with eyes with myopia between 
      9 and -12 D. No consistent differences in refractive outcomes or postoperative
      corneal haze were seen between aspherical and single-zone ablations; haze
      diminished over 12 months and was judged to be vision-impairing in only one ASPRK
      eye. Microkeratome and flap complications occurred in 4 eyes, resulting in delay
      of completion of the procedure in 3 eyes but not causing long-term impairment.
      CONCLUSIONS: Improvement in uncorrected visual acuity and return of best
      corrected visual acuity was more rapid for LASIK than PRK, but efficacy outcomes
      in the longer term through 12 months were similar for all treatment groups. LASIK
      eyes tended toward undercorrection with the nomogram employed in this study
      compared to PRK, but the scatter was similar, suggesting little difference
      between these procedures for most patients by 6 months and thereafter. No
      consistent advantage was demonstrated between aspherical and single-zone ablation
      patterns. Predictability was much better for all procedures for corrections of -6
      to -8.9 D compared with -9 to -12 D. Sporadic loss of best corrected vision in
      the PRK eyes not found in the LASIK eyes and other measures of visual function
      require further study.

PMID- 10360291
TI  - Clinical estimation of corneal endothelial pump function.
AB  - PURPOSE: To develop a technique to estimate the corneal endothelial pump rate in
      human subjects. METHODS: Corneal hydration control is thought to be maintained by
      a pump-leak mechanism whereby the leak of solutes and fluid across the
      endothelial barrier into the stroma is, in the steady state, exactly balanced by
      the pumping of solutes and passive fluid transfer across the endothelium to the
      aqueous humor. Overall corneal hydration control can be measured from the rate at
      which the swollen cornea thins (deswells), and a measure of the leak can be
      obtained simultaneously from the endothelial permeability to fluorescein. From
      the pump-leak hypothesis, the deswelling rate is directly proportional to the
      pump rate and inversely proportional to the leak rate. The relative endothelial
      pump rate can be estimated as the product of the normalized deswelling rate and
      the normalized endothelial permeability. This procedure was used to obtain the
      relative endothelial pump rate in 41 patients with diabetes mellitus, 12 patients
      with long-term corneal transplants, 20 long-term wearers of contact lenses, and
      19 normal volunteer subjects after the short-term administration of topical
      dorzolamide. RESULTS: The relative endothelial pump rate did not differ
      significantly from that of control subjects in diabetics, in contact lens
      wearers, and after dorzolamide administration, but was markedly decreased in the
      patients with corneal transplants, despite a reduction in permeability (reduced
      leak). CONCLUSIONS: This method allows the estimation of both the barrier and
      pump arms of corneal endothelial function and should be useful in the
      investigation of causes and mechanisms of functional endothelial insufficiency.

PMID- 10360292
TI  - Ocular explosion during cataract surgery: a clinical, histopathological,
      experimental, and biophysical study.
AB  - INTRODUCTION: An increasing number of cases are being recognized in which a
      peribulbar anesthetic for cataract surgery has been inadvertently injected
      directly into the globe under high pressure until the globe ruptures or explodes.
      We reviewed the records of 6 such cases (one of which was reported previously by
      us), and one additional case has been reported in the literature. Surprisingly, 2
      of these 7 cases went unrecognized at the time, and the surgeons proceeded with
      the cataract operation; all of the patients ultimately developed severe visual
      loss and/or loss of the eye. OBJECTIVES: To reproduce this eye explosion in a
      live anesthetized rabbit model and to perform a clinical, histopathological,
      experimental, biophysical, and mathematical analysis of this injury. METHODS:
      Eyes of live anesthetized rabbits were ruptured by means of the injection of
      saline directly into the globe under high pressure. The clinical and pathological
      findings of the ruptured human and animal eyes were documented photographically
      and/or histopathologically. An experimental, biophysical, and mathematical
      analysis of the pressures and forces required to rupture the globe via direct
      injection using human cadavers, human eye-bank eyes, and classic physics and
      ophthalmic formulas was performed. The laws of Bernoulli, LaPlace, Friedenwald,
      and Pascal were applied to the theoretical and experimental models of this
      phenomenon. RESULTS: The clinical and pathological findings of scleral rupture,
      retinal detachment, vitreous hemorrhage, and lens extrusion were observed. In the
      exploded human and rabbit eyes, the scleral ruptures appeared at the equator, the
      limbal area, or the posterior pole. In 2 of the 7 human eyes, the anterior
      segments appeared entirely normal despite the rupture, and cataract surgery was
      completed; surgery was canceled in the other 4 cases. In 4 of the 5 injected and
      ruptured rabbit eyes, the anterior segments appeared essentially normal. The
      experiments with human eye-bank eyes and the theoretical analyses of this entity
      show that the pressure required to produce such an injury is much more easily
      obtained with a 3- or 5-mL syringe than with a syringe 10 mL or larger.
      CONCLUSIONS: Explosion of an eyeball during the injection of anesthesia for
      ocular surgery is a devastating injury that may go unrecognized. The probability
      of an ocular explosion can be minimized by careful use of a syringe 10 mL or
      larger with a blunt needle, by discontinuing the injection if resistance is met,
      and by inspecting the globe prior to ocular massage or placement of a Honan
      balloon. When ocular explosion occurs, immediate referral to and intervention by
      a vitreoretinal surgeon is optimal. Practicing ophthalmologists should be aware
      of this blinding but preventable complication of ocular surgery.

PMID- 10360294
TI  - Computer-assisted photographic image enhancement and modification in
      ophthalmology.

PMID- 10360293
TI  - The effect of propranolol versus placebo on resident surgical performance.
AB  - PURPOSE: To determine whether propranolol can decrease surgical tremor and
      anxiety in residents performing ocular microsurgery without impairing patient or
      physician safety. METHODS: In this randomized, double-masked, crossover study, 5
      third-year ophthalmology residents ingested a capsule containing either
      propranolol, 40 mg, or placebo 1 hour prior to performing ophthalmic
      microsurgery. All residents were healthy men under age 30 years. Prior to
      commencement of the study, all participants had successfully been administered a
      test dose of propranolol without side effects. The study took place over a 10
      week period. At the conclusion of each case, both the resident and attending
      surgeon observer independently completed a form grading, on a sliding scale: (1)
      amount of overall tremor; (2) amount of tremor during placement of the first 3
      sutures after lens or nucleus extraction; (3) anticipated difficulty of the case;
      (4) actual difficulty with the case; and (5) anxiety (surgeon only). In addition,
      the type of procedure performed, complications encountered, and surgeon side
      effects were recorded. The data were analyzed with a 2-way analysis of variance
      for unbalanced data. RESULTS: A total of 73 surgical cases were performed; the
      surgeons were administered propranolol for 40 cases and placebo for 33. As judged
      by the resident surgeon, there was a highly significant effect of propranolol in
      decreasing anxiety (P = .0058), reducing surgical tremor overall (P < .0001), and
      reducing tremor while placing the first 3 sutures following lens extraction (P <
      .0001). There was no treatment-by-surgeon interaction for any of the measures.
      Complications and difficulty of the case, as judged by both the resident and
      attending surgeons, were not significantly different in the propranolol versus
      placebo groups (P > .05). There were no side effects reported or observed in any
      of the surgeons. CONCLUSIONS: Propranolol, 40 mg, administered 1 hour prior to
      surgery, significantly decreases tremor and anxiety in the surgeon without
      untoward effects to the surgeon and the patient. However, it is unknown whether
      decreased tremor and anxiety improved surgical outcome.

PMID- 10360295
TI  - Ophthalmic abnormalities in patients with cutaneous T-cell lymphoma.
AB  - PURPOSE: To determine the frequency of ophthalmic abnormalities in patients with
      cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome) and T-cell
      lymphoma involving the skin and to describe the clinical course of the disease
      with selected examples. METHODS: A computerized diagnostic retrieval system was
      used to identify all patients with T-cell lymphoma involving the skin who were
      examined at the Mayo Clinic (Rochester, Minnesota) between January 1, 1976 and
      December 31, 1990. The medical records of affected patients were reviewed.
      RESULTS: During the 15-year interval from 1976 through 1990, cutaneous T-cell
      lymphoma was diagnosed in 2,155 patients. Of these 2,155 patients, 42 (1.95%; 26
      male and 16 female) had at least 1 ophthalmic abnormality attributable to the
      disease. The diagnoses in these 42 patients were mycosis fungoides in 19,
      clinical variants of T-cell lymphoma of the skin (most commonly, peripheral T
      cell lymphoma) in 11, and Sezary syndrome in 12. Cicatricial eyelid ectropion was
      the most common finding, affecting 17 (40.4%) of the 42 patients. Thirty-seven
      patients had findings that, although probably not a direct consequence of
      cutaneous T-cell lymphoma, have been cataloged in previous studies. CONCLUSION:
      Although ophthalmic abnormalities in patients with cutaneous T-cell lymphoma are
      relatively uncommon, the manifestations of the disease are diverse and frequently
      difficult to treat.

PMID- 10360296
TI  - Orbital blow-out fractures: correlation of preoperative computed tomography and
      postoperative ocular motility.
AB  - BACKGROUND/PURPOSE: Although the management of orbital blow-out fractures was
      controversial for many years, refined imaging with computed tomography (CT)
      helped to narrow the poles of the debate. Many orbital surgeons currently
      recommend repair if fracture size portends late enophthalmos, or if diplopia has
      not substantially resolved within 2 weeks of the injury. While volumetric
      considerations have been generally well-served by this approach, ocular motility
      outcomes have been less than ideal. In one series, almost 50% of patients had
      residual diplopia 6 months after surgery. A fine network of fibrous septa that
      functionally unites the periosteum of the orbital floor, the inferior fibrofatty
      tissues, and the sheaths of the inferior rectus and oblique muscles was
      demonstrated by Koornneef. Entrapment between bone fragments of any of the
      components of this anatomic unit can limit ocular motility. Based on the
      pathogenesis of blow-out fractures, in which the fibrofatty-muscular complex is
      driven to varying degrees between bone fragments, some measure of soft tissue
      damage might be anticipated. Subsequent intrinsic fibrosis and contraction can
      tether globe movement, despite complete reduction of herniated orbital tissue
      from the fracture site. We postulated that the extent of this soft tissue damage
      might be estimated from preoperative imaging studies. METHODS: Study criteria
      included: retrievable coronal CT scans; fractures of the orbital floor without
      rim involvement, with or without extension into the medial wall; preoperative
      diplopia; surgical repair by a single surgeon; complete release of entrapped
      tissues; and postoperative ocular motility outcomes documented with binocular
      visual fields (BVFs). Thirty patients met all criteria. The CT scans and BVFs
      were assessed by different examiners among the authors. Fractures were classified
      into 3 general categories and 2 subtypes to reflect the severity of soft tissue
      damage within each category. "Trap-door" injuries, in which bone fragments
      appeared to have almost perfectly realigned, were classified as type I fractures.
      In the I-A subtype, no orbital tissue was visible on the sinus side of the
      fracture line. In the I-B subtype, soft tissue with the radiodensity of orbital
      fat was visible within the maxillary sinus. In type II fractures, bone fragments
      were distracted and soft tissue was displaced between them. In the II-A subtype,
      soft tissue displacement was less than, or proportional to, bone fragment
      distraction. In the II-B subtype, soft tissue displacement was greater than bone
      fragment distraction. In type III fractures, displaced bone fragments surrounded
      displaced soft tissue in all areas. In the III-A subtype, soft tissue and bone
      were moderately displaced. In the III-B subtype, both were markedly displaced.
      Motility outcomes were quantified by measuring the vertical excursion in BVFs.
      The interval between trauma and surgical repair was also determined. RESULTS:
      Among the 15 patients with a motility outcome in BVFs which was poorer than the
      median (86 degrees or less of single binocular vertical excursion), 4 patients
      (27%) had type A fractures; 11 patients (73%) had type B fractures. Among the 15
      patients with a better outcome than the median (88 degrees or more), 10 patients
      (67%) had type A fractures; 5 patients (33%) had type B fractures. These
      differences became more defined as analysis moved away from the median. Among 5
      patients with type B fractures and better than the median result in BVFs, 3
      patients (60%) had surgical repair during the first week after injury. Among the
      11 patients with type B fractures and less than the median result, 1 patient (9%)
      had repair during the first week. CONCLUSIONS: When the CT-depicted relationship
      between bone fragments and soft tissues is considered, a wide spectrum of
      injuries is subsumed under the rubric of blow-out fractures. In general, greater
      degrees of soft tissue incarceration or displacement, with presumably greater
      intrinsic damage and subsequent fibrosis, appear to result in poorer motility
      outcomes. Although this retrospective study does not conclusively prove its
      benefit, an urgent surgical approach to selected injuries should be considered.

PMID- 10360297
TI  - The role of ultrasound biomicroscopy in ocular trauma.
AB  - PURPOSE: To demonstrate the usefulness of ultrasound biomicroscopy (UBM) in
      detecting and localizing small ocular foreign bodies. METHODS: This is a
      retrospective study of the records of 555 consecutive patients evaluated by UBM
      by the Visual Physiology Unit of the Wills Eye Hospital from August 1994 to
      November 1997. RESULTS: In 9 patients, a foreign body was identified. In 6
      patients, the history suggested the presence of a foreign body, but one could not
      be detected by clinical examination. In 2 patients, the referring physicians
      requested UBM to determine whether or how deep a known foreign body had
      penetrated the globe. In 1 patient, the foreign body was not suspected
      clinically. In regard to other diagnostic techniques, CT failed to identify the
      foreign body in 1 patient. In another, contact B-scan ultrasonography failed. In
      a third, both CT and contact B-scan ultrasonography failed. The foreign body was
      intracorneal in 2 eyes, subconjunctival in 2, intrascleral in 3, and intraocular
      in 2. Six were nonmetallic. Two were metallic. In one case, the foreign body was
      lost and its composition is unknown. In 5 cases, the UBM findings altered the
      patient's management. CONCLUSIONS: UBM is a valuable adjunct in the evaluation of
      small, anteriorly located foreign body that may not be detectable by other
      methods. UBM may be especially useful for finding nonmetallic foreign bodies.

PMID- 10360298
TI  - The puzzle of autism: an ophthalmologic contribution.
AB  - PURPOSE: A previous study of 86 thalidomide-affected subjects with ophthalmic
      manifestations revealed the unexpected finding of autism in 4 of the 5 severely
      retarded individuals. The subjects had anomalies associated with an early
      gestational effect of thalidomide, including facial nerve palsy and incomitant
      strabismus. Because autism has been observed in a few cases of Mobius sequence
      (Mobius syndrome), a condition characterized by involvement of the sixth and
      seventh cranial nerves, the similarity to early thalidomide embryopathy suggested
      a relation between cranial nerve involvement and autism. The present study was
      undertaken to further evaluate the association of autism with patients
      manifesting findings of Mobius syndrome. METHODS: A prospective study of 25
      Swedish patients with Mobius sequence was conducted. The patients had a complete
      multidisciplinary evaluation, including ophthalmologic and psychiatric
      examinations and standard testing for autism. Findings associated with autism
      were compared with the ocular and systemic anomalies of the 4 thalidomide
      affected subjects. RESULTS: In the Mobius group 6 patients had autism, achieving
      the criteria for autism according to all the diagnostic manuals that were used.
      One patient showed autistic-like conditions meeting fewer numbers of the
      criteria. A few were too young to be meeting evaluated. Incomitant strabismus
      ranging from primary abduction defects alone to a horizontal gaze paresis pattern
      was noted in these patients, in addition to characteristic findings of seventh
      nerve paresis. Aberrant lacrimation was observed in many cases, especially often
      associated with autism. CONCLUSION: The common group of anomalies noted in both
      cases of thalidomide embryopathy and Mobius sequence suggests that brain-stem
      damage probably early in embryogenesis can sometimes be associated with autism.

PMID- 10360299
TI  - Dissociated vertical deviation: an exaggerated normal eye movement used to damp
      cyclovertical latent nystagmus.
AB  - PURPOSE: Dissociated vertical deviation (DVD) has eluded explanation for more
      than a century. The purpose of this study has been to elucidate the etiology and
      mechanism of DVD. METHODS: Eye movement recordings of six young adults with DVD
      were made with dual-coil scleral search coils under various conditions of
      fixation, illumination, and head tilt. Horizontal, vertical, and torsional eye
      movements were recorded for both eyes simultaneously. Analyses of the
      simultaneous vertical and torsional movements occurring during the DVD response
      were used to separate and identify the component vergence and version eye
      movements involved. RESULTS: Typically, both horizontal and cyclovertical latent
      nystagmus developed upon occlusion of either eye. A cycloversion then occurred,
      with the fixing eye intorting and tending to depress, the covered eye extorting
      and elevating. Simultaneously, upward versions occurred for the maintenance of
      fixation, consisting variously of saccades and smooth eye movements, leading to
      further elevation of the eye behind the cover. The cyclovertical component of the
      latent nystagmus became partially damped as the DVD developed. CONCLUSIONS: In
      patients with an early-onset defect of binocular function, the occlusion of one
      eye, or even concentration on fixing with one eye, produces unbalanced input to
      the vestibular system. This results in latent nystagmus, sometimes seen only with
      magnification. The cyclovertical component of the latent nystagmus, when present,
      is similar to normal vestibular nystagmus induced by dynamic head tilting about
      an oblique axis. Such vestibular nystagmus characteristically produces a
      hyperdeviation of the eyes. In the case of cyclovertical latent nystagmus, the
      analogous hyperdeviation will persist unless corrected by a vertical vergence. A
      normal, oblique-muscle-mediated, cycloversion/vertical vergence is called into
      play. This occurs in the proper direction to correct the hyperdeviation, but it
      occurs in an exaggerated form in the absence of binocular vision, probably as a
      learned response. The cycloversion/vertical vergence helps damp the cyclovertical
      nystagmus (a cyclovertical "nystagmus block-age" phenomenon), aiding vision in
      the fixing eye. But this mechanism also produces unavoidable and undesirable
      elevation and extortion of the fellow eye, which we call DVD.

PMID- 10360300
TI  - The therapy of amblyopia: an analysis of the results of amblyopia therapy
      utilizing the pooled data of published studies.
AB  - CONTEXT: Although the treatment of amblyopia with occlusion has changed little
      over the past 3 centuries, there is little agreement about which regimes are most
      effective and for what reasons. OBJECTIVE: To determine the outcome of occlusion
      therapy in patients with anisometropic, strabismic, and strabismic-anisometropic
      amblyopia employing the raw data from 961 patients reported in 23 studies
      published between 1965 and 1994. DESIGN: Analysis of the published literature on
      amblyopia therapy results during the above interval, utilizing primary data
      obtained from the authors of these articles or tables published in the articles
      detailing individual patient outcomes. PARTICIPANTS: 961 amblyopic patients,
      participants in 23 studies, undergoing patching therapy for amblyopia from 1965
      to 1994 with anisometropia, strabismus, or anisometropia-strabismus. MAIN
      OUTCOMES: In the pooled data set, success of occlusion therapy was defined as
      visual acuity of 20/40 at the end of treatment. RESULTS: Success by the 20/40
      criteria was achieved in 512 of 689 (74.3%) patients. By category, 312 of 402
      (77.6%) were successful in strabismic amblyopia, 44 of 75 (58.7%) in strabismic
      anisometropic amblyopia, and 72 of 108 (66.7%) in anisometropic amblyopia.
      Success was not related to the duration of occlusion therapy, type of occlusion
      used, accompanying refractive error, patient's sex, or eye. Univariate analyses
      showed that success was related to the age at which therapy was initiated; the
      type of amblyopia; the depth of visual loss before treatment for the
      anisometropic patients and the strabismic patients, but not for the anisometropic
      strabismic patients; and the difference in spherical equivalents between eyes,
      for the anisometropic patients. Logistic/linear regression revealed that 3 were
      independent predictors of a successful outcome of amblyopia therapy. CONCLUSIONS:
      Factors that appear most closely related to a successful outcome are age, type of
      amblyopia, and depth of visual loss before treatment. These may be related to
      factors, as yet undetermined in the pathogenesis of amblyopia. With present
      emphasis on the value of screening and prevention and the development of new
      screening tools, such a look at the results of amblyopia therapy in a large
      population seems indicated.

PMID- 10360301
TI  - Results following treatment of third cranial nerve palsy in children.
AB  - PURPOSE: To investigate the etiology, sensory, motor, and cosmetic results of
      treatment for oculomotor (CNIII) palsy in children. METHODS: We conducted a
      retrospective review of the clinical records of children with a diagnosis of
      CNIII palsy who were followed up in our practice between 1981 and 1996. RESULTS:
      During the 15-year period, 49 children with 53 affected eyes were followed for a
      mean of 5.5 years. CNIII palsy was congenital in one third of cases and secondary
      to postnatal trauma in another third. Thirty-three of the eyes were affected
      before visual maturation (age 8 years) and 27 eyes developed amblyopia. None of
      the 6 eyes with amblyopia in which visual acuity could be quantitated had
      measurable improvement of Snellen acuity after treatment. Overall, visual acuity
      was between 6/5 and 6/12 at the last follow-up visit in 56% of affected eyes.
      Ocular alignment was greatly improved after recess-resect procedures on the
      horizontal rectus muscles, but binocular function was difficult to preserve or
      restore. Blepharoptosis improved after levator palpebrae muscle resection or
      eyelid suspension procedures. CONCLUSIONS: CNIII palsy may undergo partial
      resolution in children, but surgical treatment is frequently necessary. Although
      surgery can result in cosmetically acceptable alignment of the eyes, it rarely
      results in restoration or achievement of binocular function. Multiple procedures
      are often necessary to maintain good ocular alignment. Several surgical
      procedures may be needed to correct related blepharoptosis and maintain an
      acceptable eyelid position. Treatment of amblyopia is only effective in
      maintaining the level of visual acuity present at the onset of the CNIII palsy,
      and improvement in acuity is difficult to achieve.

PMID- 10360302
TI  - Rehabilitation of children with cataracts.
AB  - Over a period of 10 years, 160 children with cataracts underwent operation at the
      University of Tennessee Medical Center, Memphis. The surgical, optical, and
      psychosocial rehabilitation of these patients was analyzed and studied. The
      optical rehabilitation included patients with glasses, intraocular lens implants,
      epikeratophakia, and contact lenses. Seventy three of these patients were chosen
      at random and reevaluated as to visual outcome, and 46 were subjected to a
      psychosocial test to evaluate their quality of life and their rehabilitation.
      Eighteen of these were also given a psychosocial test to evaluate the quality of
      life enjoyed by these children at an older age following treatment for the
      cataract. Surgical, optical, and psychosocial rehabilitation of such children is
      also discussed. This is the first report of the psychological evaluation of such
      children. The further needs of these children as they approach adulthood are
      discussed in detail.

PMID- 10360303
TI  - Cataract extraction and lens implantation with and without trabeculectomy: an
      intrapatient comparison.
AB  - OBJECTIVE: To determine whether cataract extraction and lens implantation
      combined with trabeculectomy provides better long-term results than cataract
      extraction and lens implantation alone in a group of patients with primary open
      angle glaucoma and cataract randomly selected to receive surgery with
      trabeculectomy in one eye and without in the other. METHODS: A prospective,
      randomized clinical trial involving 35 patients with bilateral symmetric primary
      open-angle glaucoma and visually disabling cataracts with procedures performed by
      a single surgeon in a private practice setting with follow-up for more than 5
      years in all cases. RESULTS: After an average of 87 months of follow-up, cataract
      extraction and lens implantation reduced intraocular pressure 4.4 mm Hg, reduced
      number of medications by 1.28, increased diopter vector of astigmatism by 1.49,
      and was associated with visual field loss in 6 of 35 eyes. After an average of 80
      months of follow-up, cataract extraction, lens implantation, and trabeculectomy
      reduced intraocular pressure 8.2 mm Hg, reduced number of medications by 1.76,
      increased diopter vector of astigmatism by 1.14, and was associated with visual
      field loss in 1 eye. Both groups had similar improvement in visual acuity and
      perioperative complications. CONCLUSIONS: Extracapsular cataract extraction, lens
      implantation, and trabeculectomy is a complex procedure that was beneficial in
      the long-term control of intraocular pressure and in prevention of visual field
      loss. This procedure should be considered in patients who may not be able to
      comply with a complex medical regimen, in whom pressure elevation in the
      immediate postoperative period would be undesirable, or in whom long-term
      pressure control at a lower level would be beneficial in preventing further optic
      nerve damage.

PMID- 10360305
TI  - "Oxidative protector" enzymes in the macular retinal pigment epithelium of aging
      eyes and eyes with age-related macular degeneration.

PMID- 10360306
TI  - A randomized, controlled trial of varying radiation doses in the treatment of
      choroidal melanoma.

PMID- 10360307
TI  - Tumor vascularity and hematogenous metastasis in experimental murine intraocular
      melanoma.
AB  - PURPOSE: The purpose of this study is to test the hypothesis that primary tumor
      vascularity in a murine model of intraocular melanoma positively correlates with
      the development and hematogenous spread of metastasis. METHODS: Forty 12-week-old
      C57BL6 mice were inoculated in either the anterior chamber (AC) or posterior
      compartment (PC) of 1 eye with 5 x 10(5) cells/microL of Queens tissue culture
      melanoma cells. The inoculated eye was enucleated at 2 weeks; the mice were
      sacrificed at 4 weeks postinoculation, and necropsies were performed. The
      enucleated eyes were examined for histologic and ultrastructural features,
      including relationship of tumor cells to tumor vascular channels, vascular
      pattern, and mean vascular density. RESULTS: Melanoma grew and was confined to
      the eye in 12 of 20 AC eyes and 10 of 20 PC eyes. Histologic and electron
      microscopic examination showed tumor invasion into vascular channels. Five of 12
      AC tumors (42%) and 8 of 10 PC tumors (80%) metastasized. All of the AC tumors,
      but none of the PC tumors, that distantly metastasized also metastasized to
      ipsilateral cervical lymph nodes (P = .00535). There was no statistically
      significant difference of vascular pattern between the melanomas that did and did
      not metastasize to lungs in the PC group (P = .24), although there was a
      significant difference in the AC group (P = .02). Tumors with high-grade vascular
      patterns were more likely to metastasize than tumors with low-grade vascular
      patterns in the AC group. The mean vascular density positively correlated with
      the presence and number of metastases in both groups (P = .0000 and P < .001,
      respectively). There was no statistically significant difference of vascular
      pattern and mean vascular density for AC versus PC melanoma (P = .97).
      CONCLUSIONS: The rate of metastasis in this murine intraocular melanoma model
      positively correlates with primary tumor vascularity. The melanoma metastasizes
      via invasion of tumor vascular channels. AC melanoma also metastasizes through
      regional lymphatics.

PMID- 10360304
TI  - The incidence, pathogenesis and treatment of cystoid macular edema following
      cataract surgery.

PMID- 10360309
TI  - The ocular manifestations of congenital infection: a study of the early effect
      and long-term outcome of maternally transmitted rubella and toxoplasmosis.
AB  - PURPOSE: To study the spectrum of adverse ocular effects which result from
      maternally transmitted rubella and toxoplasma infection; further, to record the
      long-term visual and neurodevelopmental outcomes of these 2 major causes of fetal
      infection. STUDY DESIGN AND PATIENTS: A series of 55 patients with congenital
      infection have been studied prospectively on a long-term basis. The study group
      included a cohort of 34 cases with congenital rubella syndrome demonstrated by
      virus isolation, and 21 cases with a clinical diagnosis of congenital
      toxoplasmosis and serologic confirmation. All patients had specific disease
      related ocular defects. Rubella patients were first identified during or
      following the last major rubella epidemic in 1963-1964, and some have been
      followed serially since that time. A separate study group of representative
      toxoplasmosis patients presented for examination and diagnosis at varying time
      periods between 1967 and 1991. OBSERVATIONS AND RESULTS: This study confirms that
      a broad spectrum of fetal injury may result from intrauterine infection and that
      both persistent and delayed-onset effects may continue or occur as late as 30
      years after original infection. Many factors contribute to the varied outcome of
      prenatal infection, the 2 most important being the presence of maternal immunity
      during early gestation and the stage of gestation during which fetal exposure
      occurs in a nonimmune mother. RUBELLA: As a criteria of inclusion, all 34 rubella
      patients in this study exhibited one or more ocular defects at the time of birth
      or in the immediate neonatal period. Cataracts were present in 29 (85%) of the
      34, of which 21 (63%) were bilateral. Microphthalmia, the next most frequent
      defect, was present in 28 (82%) of the 34 infants and was bilateral in 22 (65%).
      Glaucoma was recorded in 11 cases (29%) and presented either as a transient
      occurrence with early cloudy cornea in microphthalmic eyes (4 patients), as the
      infantile type with progressive buphthalmos (1 patient), or as a later-onset,
      aphakic glaucoma many months or years following cataract aspiration in 11 eyes of
      6 patients. Rubella retinopathy was present in the majority of patients, although
      an accurate estimate of its incidence or laterality was not possible because of
      the frequency of cataracts and nystagmus and the difficulty in obtaining adequate
      fundus examination. TOXOPLASMOSIS: Twenty-one patients with congenital
      toxoplasmosis have been examined and followed for varying time periods, 7 for 20
      years or more. The major reason for initial examination was parental awareness of
      an ocular deviation. Twelve children (57%) presented between the ages of 3 months
      and 4 years with an initial diagnosis of strabismus, 9 of whom had minor
      complaints or were diagnosed as part of routine examinations. All cases in this
      study have had evidence of retinochoroiditis, the primary ocular pathology of
      congenital toxoplasmosis. Two patients had chronic and recurrent inflammation
      with progressive vitreal traction bands, retinal detachments, and bilateral
      blindness. Macular lesions were always associated with central vision loss;
      however, over a period of years visual acuity gradually improved in several
      patients. Individuals with more severe ocular involvement were also afflicted
      with the most extensive central nervous system deficits, which occurred following
      exposure during the earliest weeks of gestation. CONCLUSIONS: Although congenital
      infection due to rubella virus has been almost completely eradicated in the
      United States, the long-term survivors from the prevaccination period continue to
      experience major complications from their early ocular and cerebral defects. They
      may be afflicted by the persistence of virus in their affected organs and the
      development of late manifestations of their congenital infection. Congenital
      toxoplasmosis continues to be the source of major defects for 3,000 to 4,100
      infants in the United States each year; the spectrum of defects is wide and may
      vary from blindness and severe mental retardation to minor retinochoroidal
      lesions of little consequence. Effective solutions for either the prevention or
      treatment of congenital toxoplasmosis have not been developed in this country but
      are under intensive and continuing investigation.

PMID- 10360308
TI  - Correlation of quality of life with clinical symptoms and signs at the time of
      glaucoma diagnosis.
AB  - PURPOSE: To examine the relationship between clinical measures of visual function
      and patient-reported measures of symptoms and health status in a large cohort of
      glaucoma patients at the time of diagnosis. SUBJECTS AND METHODS: The 607
      patients in the Collaborative Initial Glaucoma Treatment Study (CIGTS) received
      standardized examinations of visual acuity and visual field at enrollment. In
      addition, they completed a health-related quality-of-life instrument, which
      included the Visual Activities Questionnaire (VAQ), Sickness Impact Profile
      (SIP), a symptom and a comorbidity chart, a question about their degree of worry
      about becoming blind, and many other items. RESULTS: The SIP total and dimension
      scores correlated only weakly, and not significantly, with visual acuity and
      visual field measures. The VAQ total and subscale scores, particularly the
      peripheral vision subscale, correlated weakly and significantly with visual
      acuity and visual field scores, especially those from the better eye. Worry about
      blindness and symptoms attributed to glaucoma correlated weakly but significantly
      to visual field scores from the worse eye. Attempts to improve correlations by
      scoring the visual fields differently, including only paracentral and pericentral
      test locations in the scores, and simulating binocular visual field scores were
      largely unsuccessful. CONCLUSIONS: At diagnosis, most patients were relatively
      free of glaucoma-induced impairments, so clinical measures were poor predictors
      of a patient's perception of health-related quality of life. The vision-specific
      VAQ and glaucoma-related symptom score correlated better than the generic SIP
      with clinical measures at the time of enrollment into CIGTS.

PMID- 10360311
TI  - North Carolina macular dystrophy: clinical features, genealogy, and genetic
      linkage analysis.
AB  - PURPOSE: To study the North Carolina macular dystrophy phenotype (MCDR1) in
      multiple families of different ethnic backgrounds, to determine the genetic
      relationships of these families, and to determine the minimal candidate region of
      the MCDR1 gene. METHODS: Thirteen families with the North Carolina MCDR1 were
      ascertained. These families were of various ethnic and geographic origins, such
      as Caucasian, Mayan Indian, African American, French, British, German, and
      American. Extensive genealogical investigations were performed for all families.
      A total of 232 members of these families underwent comprehensive ophthalmic
      examinations, including blood collection for genotyping. Of these, 117 were found
      to be affected with the disorder. Genetic linkage simulation studies were
      performed using the computer program SIMLINK. Two-point linkage analysis,
      haplotype analysis, and multipoint linkage analyses were performed using the
      computer programs M-LINK, VITESSE, and FASTLINK. RESULTS: The clinical features
      were consistent with the diagnosis of North Carolina macular dystrophy in all
      families studied. Multipoint linkage analysis and haplotype analysis indicate
      that the MCDR1 gene is in the 1.1-centimorgan (cM) interval between the genetic
      markers D6D249 and D6S1671, with a maximum LOD score of 40.03. There was no
      evidence of genetic heterogeneity. Families 765, 768, 772, 1193, and 1292 shared
      the same chromosomal haplotype in this region, suggesting they are the result of
      the same ancestral mutation. The remaining families each likely represent
      independent origins of the mutation in the MCDR1 gene. North Carolina macular
      dystrophy is present worldwide and does not emanate from a single founder from
      North Carolina.

PMID- 10360312
TI  - Phospholipid analogue distribution in Capnocytophaga.
AB  - Polar lipids of nineteen previously characterised culture collection strains of
      Capnocytophaga were analysed using fast atom bombardment mass spectrometry (FAB
      MS) in negative mode. All strains examined had a major peak at m/z 241,
      consistent with the expected presence of the pentadecanoate anion. The most
      intense higher mass anions, consistent with expected presence of phospholipid
      molecular species, were as follows: m/z 574, 588, 618 and 662 which are
      consistent with presence of PE(24:2), PE(25:2), PE(27:1) and PE(30:0)
      respectively. Other anions putatively identified as phospholipid anions were: m/z
      572, 578, 592, 602, 604, 616 and 720 consistent with presence of PE(24:3),
      PE(24:0), PE(25:0), PE(26:2), PE(26:1), PE(27:2) and OH-PE(33:0). Capnocytophaga
      isolates share a distinctive phospholipid fingerprint which appears to lack the
      somewhat higher mass phospholipid analogues observed in related oral bacteria.
      Within the genus, the profiles obtained showed only quantitative differences
      which did not correlate with previous studies.

PMID- 10360313
TI  - IgG western blot as a confirmatory test in early syphilis.
AB  - Sensitivity and specificity of IgG detection by Western blotting performed with a
      lysate of Treponema pallidum whole cells were compared with those of the most
      common assays used in the laboratory diagnosis of syphilis, i.e. fluorescent
      treponemal antibody absorption test (FTA-ABS) and treponemal haemagglutination
      assay (TPHA). Thirty-five serum samples obtained from twenty-one patients with a
      clinical diagnosis of early syphilis, based on the presence of typical chancre or
      skin or mucous membrane lesions, were studied. In addition, thirty blood samples
      from donors, ten sera positive for Borrelia burgdorferi and five positive for
      Leptospira interrogans were tested as controls. The clinical diagnosis was the
      reference method used to compare the performance of the serological tests.
      Western blotting performed with a sensitivity and specificity of 100%, whereas
      the corresponding sensitivity and specificity for FTA-ABS were 88.5% and 98%,
      respectively. The performance of TPHA showed a sensitivity of 86% and a
      specificity of 100%.

PMID- 10360310
TI  - Acquired mitochondrial impairment as a cause of optic nerve disease.
AB  - BACKGROUND: Blindness from an optic neuropathy recently occurred as an epidemic
      affecting 50,000 patients in Cuba (CEON) and had clinical features reminiscent of
      both tobacco-alcohol amblyopia (TAA) and Leber's hereditary optic neuropathy
      (Leber's; LHON). Selective damage to the papillomacular bundle was
      characteristic, and many patients also developed a peripheral neuropathy.
      Identified risk factors included vitamin deficiencies as well as exposure to
      methanol and cyanide. In all 3 syndromes, there is evidence that singular or
      combined insults to mitochondrial oxidative phosphorylation are associated with a
      clinically characteristic optic neuropathy. PURPOSE: First, to test the
      hypothesis that a common pathophysiologic mechanism involving impairment of
      mitochondria function and, consequently, axonal transport underlies both genetic
      optic nerve diseases such as Leber's and acquired toxic and nutritional
      deficiency optic neuropathies. According to this hypothesis, ATP depletion below
      a certain threshold leads to a blockage of orthograde axonal transport of
      mitochondria, which, in turn, leads to total ATP depletion and subsequent cell
      death. Second, to address several related questions, including (1) How does
      impaired energy production lead to optic neuropathy, particularly since it seems
      to relatively spare other metabolically active tissues, such as liver and heart?
      (2) Within the nervous system, why is the optic nerve, and most particularly the
      papillomacular bundle, so highly sensitive? Although there have been previous
      publications on the clinical features of the Cuban epidemic of blindness, the
      present hypothesis and the subsequent questions have not been previously
      addressed. METHODS: Patients in Cuba with epidemic optic neuropathy were
      personally evaluated through a comprehensive neuro-ophthalmologic examination. In
      addition, serum, lymphocytes for DNA analysis, cerebrospinal fluid (CSF), sural
      nerves, and eyes with attached optic nerves were obtained from Cuban patients, as
      well as from Leber's patients, for study. Finally, we developed an animal model
      to match the low serum folic acid and high serum formate levels found in the CEON
      patients, by administering to rats low doses of methanol after several months of
      a folic acid-deficient diet. Optic nerves and other tissues obtained from these
      rats were analyzed and compared with those from the Cuban patients. RESULTS:
      Patients from the Cuban epidemic of optic neuropathy with clinical evidence of a
      selective loss of the papillomacular bundle did much better once their
      nutritional status was corrected and exposure to toxins ceased. Patients with
      CEON often demonstrated low levels of folic acid and high levels of formate in
      their blood. Histopathologic studies demonstrated losses of the longest fibers
      (in the sural nerve) and those of smallest caliber (papillomacular bundle) in the
      optic nerve, with intra-axonal accumulations just anterior to the lamina
      cribrosa. Our animal model duplicated the serologic changes (low folic acid, high
      formate) as well as these histopathologic changes. Furthermore, ultrastructural
      examination of rat tissues demonstrated mitochondrial changes that further
      matched those seen on ultrastructural examination of tissues from patients with
      Leber's. CONCLUSION: Mitochondria can be impaired either genetically (as in
      Leber's) or through acquired insults (such as nutritional or toxic factors).
      Either may challenge energy production in all cells of the body. While this
      challenge may be met through certain compensatory mechanisms (such as in the
      size, shape, or number of the mitochondria), there exists in neurons a threshold
      which, once passed, leads to catastrophic changes. This threshold may be that
      point at which mitochondrial derangement leads to such ATP depletion that axonal
      transport is compromised, and decreased mitochondrial transport results in even
      further ATP depletion. Neurons are singularly dependent on the axonal transport
      of mitochondria. (

PMID- 10360314
TI  - The fate of Yersinia pseudotuberculosis lipopolysaccharide (LPS) in
      intraperitoneally and intraarticularly infected rats.
AB  - Persistence and in vivo effects of Yersinia pseudotuberculosis serotype III LPS
      (prepared from bacteria grown at 25 degrees and 37 degrees C) in rats were
      investigated after intraperitoneal and intraarticular injection during the 30 day
      period of examination. Localization and persistence of LPS in the peritoneal and
      synovial cavities were demonstrated by using the immunofluorescence technique.
      Peritoneal and synovial exudative cell infiltration as well as changes in some
      parameters (glycolytic and acid phosphatase activities, killing ability of
      peritoneal cells, lactate-dehydrogenase concentration in synovial fluid) were
      studied. The results indicated that LPS expressed at 37 degrees C induced
      stronger peritoneal cell response (increased "killing" ability and elevation of
      glycolytic and acid phosphatase activities) in comparison to that synthesized at
      25 degrees C. It was also found, that LPS persisted longer in the synovial rather
      than in the peritoneal cavity of rats and induced long-lasting synovial
      inflammation.

PMID- 10360315
TI  - Cold-induced augmentation of I blood group antigen interactions with
      galactophilic lectins.
AB  - The I antigen appears on human cells in the postnatal period, by addition of N
      acetyllactosamine (beta 1-6) branching to the fetal i antigen structure, which is
      specified by linear oligo N-acetyllactosamine (beta 1-3) chain. Concurrently with
      the I antigen appearance on adult human erythrocytes most human sera exhibit low
      levels of anti-I agglutinins. These antibodies induce hemagglutination mainly at
      low temperatures (4 degrees C) and scantly at body temperature. Therefore they
      were named "cold agglutinins". We have used these antibodies and several
      hemagglutinating galactophilic animal, plant, and microbial lectins that also
      react with the I antigen, to study whether the cold-favored agglutination of the
      I antigen-bearing cells is a peculiar property of the anti-I antibodies or a
      special trait of that antigen. It has been found that the interactions of all of
      the examined lectins, irrespective of their source, with the adult human
      erythrocytes significantly increased at 4 degrees C, in contrast to those of the
      same cells with diverse I-insensitive antibodies and lectins, which were
      significantly higher at room temperature.

PMID- 10360316
TI  - The ketolide antibiotic HMR 3647, a candidate substance for the treatment of
      systemic and intracerebral infections with Listeria monocytogenes.
AB  - HMR 3647 is a novel macrolide derivative with a broad spectrum of activity
      against grampositive bacteria and some fastiduous gramnegative bacteria,
      anaerobes and Toxoplasma gondii. In this work, its activity against the
      facultatively intracellular bacterium, Listeria monocytogenes, was examined in
      vitro, in tissue culture and in animal models of systemic and intracerebral
      infection and compared with that of erythromycin. All strains of L. monocytogenes
      were susceptible to the substance, with minimal inhibitory concentrations (MICs)
      that were consistently lower than the MICs of erythromycin. HMR 3647 was
      bacteriostatic against L. monocytogenes since concentrations of up to 64 times
      the MIC did not kill the bacteria within 24 hours. HMR 3647 produced a pronounced
      postantibiotic effect (PAE) and was bacteriostatic in tissue culture cells
      infected with L. monocytogenes. In animal models of systemic and intracerebral
      infection, HMR 3647 was slightly more effective than erythromycin in the livers
      and spleens and comparably effective in the brains when given in the same dosage.
      In conclusion, HMR 3647 is a candidate substance for the treatment of infections
      with L. monocytogenes in immunocompetent subjects.

PMID- 10360317
TI  - Antimicrobial substances and effects on sessile bacteria.
AB  - Biofilms occur in natural aquatic ecosystems and on surfaces of biomaterials.
      They are generally associated with clinical infections predominantly of
      prosthetic hip joints, heart valves and catheters. Sessile microorganisms may be
      intimately associated with each other and to solid substratum through binding to
      and inclusion into exopolymer matrices on biofilms. The establishment of
      functional colonies within the exopolymeric matrices generate physico-chemical
      gradients within biofilms, that modify the metabolism and cell-wall properties of
      the microorganism. A consequence of biofilm growth is an enhanced microbial
      resistance to chemical antimicrobial agents and antibiotics. Investigations on
      the antimicrobial efficacy of antibiotics, antiseptics and antimicrobial heavy
      ions, however, gave controversial results. No single antimicrobial substance has
      been developed for the efficient eradication of adherent bacteria. This review
      elucidates the mechanisms of microbial resistance in biofilms and strategies for
      the prevention of biofilm development. Pharmacokinetical and pharmacodynamical
      issues for the screening of biofilm-active drugs are presented. Combinations of
      antistaphylococcal antibiotics with rifampin may be advantageous for preventing
      and curing biomaterial infections.

PMID- 10360318
TI  - High-frequency transduction (HFT) of resistance to ceftazidime and other
      antibiotics by a wild-type Pseudomonas aeruginosa phage.

PMID- 10360319
TI  - Leukocidal toxins of staphylococci.
AB  - Leukocidal toxins (synergohymenotropic toxin) are cytotoxins produced by
      staphylococci (S. aureus and S. intermedius) and consist of two separate
      components. The toxic effect depends on the synergistic action of two proteins.
      One of them belongs to class F (e.g. LukF-PV, LukF-R, LukF-I, LukM, HlgB) and the
      other, to class S (e.g. LukS-PV, LukS-R, LukS-I, HlgA, HlgC). Best known are the
      toxins produced by S. aureus: gamma-haemolysins, HlgA/HlgB and HlgC/HlgB and
      leukocidin Panton-Valentine, LukS-PV/LukF-PV (Luk-PV, PVL). Very few data are
      available concerning the relationship between the production of these toxins and
      the pathology of staphylococcal infections, because little is known about local
      and general effects of these leukocidal products in vivo. Frequent isolations of
      staphylococcal strains producing leukocidal toxins from necrotic skin lesions and
      furuncles suggest a role of these toxins in the virulence of staphylococci, at
      least in cutaneous infections. Recent data on mechanisms of cytotoxic effects of
      staphylococcal leukocidal toxins in vitro as well as effects of leukocidal toxins
      in vitro are discussed. Cell membranes appear to be a primary target for
      triggering the lysis of phagocytic cells caused by staphylococcal leukocidal
      toxins.

PMID- 10360320
TI  - Synergistic anti-varicella-zoster virus activity of interferon-alpha 2a and
      acyclovir in corneal cells.
AB  - Human corneal stromal (HCS) cells in cultures established from donor corneas can
      serve as host cells for replication of varicella-zoster virus (VZV). Comparative
      infectious centers assays suggest that HCS cells are more restrictive hosts than
      MRC-5 cells, a line of human embryonic lung fibroblasts, commonly used for VZV
      isolation. VZV propagated in MRC-5 cells was infectious for both MRC-5 and HCS
      cells, but titers in HCS were one fifth of those in MRC-5 cells. Inhibition of
      VZV replication in HCS cells by acyclovir (ACV), recombinant human interferon
      alpha 2a (IFN-alpha 2a), or the combination of these two antivirals was detected
      by both an infectious centers-plaque-reduction assay and an ELISA method using
      monoclonal anti-VZV antibody. In the infectious centers-plaque-reduction assay
      combinations of ACV with IFN-alpha 2a showed synergistic anti-VZV activity. VZV
      protein synthesis, as detected by the ELISA, was a less sensitive measure of the
      antiviral effects producing an ED50 value of 50 microM for ACV, five to ten times
      the ED50 determined in the plaque reduction assay. In the ELISA, high titers of
      IFN-alpha 2a (2000 IU/ml) decreased virus antigen expression only slightly, while
      combinations of ACV and IFN-alpha 2a were synergistic in their detected anti-VZV
      activity. These data document the replication of VZV in HCS cells and demonstrate
      that VZV is sensitive to the synergistic antiviral action of combinations of IFN
      alpha 2a and ACV.

PMID- 10360321
TI  - Histopathological evolution of experimental paracoccidioidomycosis in Wistar
      rats.
AB  - Twenty Wistar rats were inoculated, by the intracardiac route, with 0.5 ml each
      of a yeast phase suspension of Paracoccidioides brasiliensis Utero strain. The
      rats were sacrificed at regular intervals post-infection, at which time their
      lungs, heart, liver, spleen and kidneys were removed, fixed and stained for
      study. The parameters of interest for the lung specimens were: (a) extent of the
      lesions; (b) number of fungi; (c) presence of a lymphomononuclear halo.
      Extrapulmonary lesions were also sought. Until the fourth month post-infection,
      the lesions were progressive in nature, contained great numbers of viable fungi,
      and were surrounded by an important lymphomononuclear halo which tended to be
      confluent. At four and a half months p.i., the extent of the pulmonary lesions
      was reduced, the granulomas were less compact with fewer viable fungi,
      macrophages showed microvacuolation, and the lymphomononuclear halo was less
      pronounced. Extrapulmonary lesions, which were frequently identified in the first
      months post-infection, diminished from the seventh month onwards. The
      histological characteristics of extrapulmonary lesions were always the same as
      those found in the lungs. Infection tended to be controlled by the animals from
      the fourth month, but without complete resolution of the lesions.

PMID- 10360322
TI  - Identification of a 21 kDa laminin-binding component of Candida albicans.
AB  - Binding of Candida albicans strain JCM0239 to radiolabelled laminin was studied
      to identify possible receptors. When two forms of the organism were examined,
      laminin was found to bind to germinating blastoconidia. There was only weak
      binding to blastoconidia without germ tubes. Laminin-binding to germinating
      blastoconidia was inhibited by non-labelled laminin or fibrinogen but not by
      fibronectin, a fibronectin peptide (Gly-Arg-Gly-Asp-Ser), or a laminin peptide
      (Tyr-Ile-Gly-Ser-Arg). A cell extract from germinating blastoconidia was analyzed
      by using SDS-PAGE and Western blotting, and 125I-labelled laminin was shown to
      bind to a 21 kDa component.

PMID- 10360323
TI  - Evaluation of the effectiveness of vaccination against diphtheria among medical
      staff of the chair and the Jagiellonian University Hospital of Infectious
      Diseases in Cracow, Poland. Some epidemiological observations.
AB  - In Poland, twenty-five cases of diphtheria, mostly among adults (including five
      foreigners) in the region adjacent to the eastern border were registered in the
      years 1992-1996. In 1993-1994, because of the threat of diphtheria infection, 41
      healthy members of the medical staff of the University Hospital of Infectious
      Diseases in Krakow, mainly women aged 25-57 years were immunized with Td and d
      vaccines with a 6-month interval between courses. Prior to vaccination, 17(41%)
      individuals showed a lack of diphtheria antibodies as determined with a passive
      haemagglutination test. 14 of them were aged 30-49 years. Six months after the
      2nd dose of vaccine, all seronegative persons had developed a protective level of
      antibodies. Moreover, all vaccinated subjects showed a statistically significant
      increase of the antibody titre between the first and last serological
      examinations.

PMID- 10360325
TI  - Direct methods in protein electron crystallography--beef liver catalase in its
      fully hydrated form at room temperature.
AB  - The crystal structure of beef liver catalase was determined ab initio in
      projection to 9 A resolution using electron diffraction data at room temperature
      from hydrated specimens maintained in an environmental chamber in the electron
      microscope. A conservative combination of symbolic addition with maximum entropy
      and likelihood led to a model with a Patterson correlation coefficient C = 0.89
      to the observed data. This independent solution could then be compared favorably
      to a previous 23 A analysis of electron micrographs from frozen hydrated
      preparations. Prediction of the higher-resolution structure by extension of the
      lower-resolution image-based phase basis set also gave a good match to the direct
      methods solution, particularly for the most intense reflections.

PMID- 10360326
TI  - Prediction of peptide retention times in normal-phase liquid chromatography with
      only a single gradient run.
AB  - Previous studies of peptide separation by normal-phase liquid chromatography have
      shown a linear relationship between the logarithm of the capacity factor and the
      logarithm of the volume fraction of modifier in the mobile phase. This permitted
      the use of a model to predict isocratic and gradient retention times based on
      data obtained by two initial gradient runs. In the present study, chromatographic
      behavior of 25 peptides in normal-phase liquid chromatography with isocratic
      elution have been studied and a linear relationship between the slope (S) and
      intercept [log k(0)] was obtained. This relationship was combined with the
      algorithm of prediction reported in the previous paper. The prediction of peptide
      retention times with only a single experimental gradient retention data was
      investigated.

PMID- 10360327
TI  - On-line solid-phase extraction-short-column liquid chromatography combined with
      various tandem mass spectrometric scanning strategies for the rapid study of
      transformation of pesticides in surface water.
AB  - The applicability of solid-phase extraction-short-column liquid chromatography
      using two short columns (i.e., 10 and 20 mm long) coupled on-line with tandem
      mass spectrometric detection is demonstrated for the rapid degradation study of
      pesticides and their transformation products in water at the low-microgram/l
      level. Photolysis was used as a means to transform the parent compounds into
      their degradation products and the experiments were carried out at
      environmentally relevant concentrations. The use of on-line sample
      enrichment/separation in photodegradation studies allows the rapid analysis of
      aqueous samples directly after irradiation without further transformation of the
      compounds of interest. The versatility of MS allows various selective screening
      strategies to be employed, i.e., full-scan mode, neutral loss, precursor-ion and
      product-ion scan modes. This allows the identification of possible degradation
      products and the calculation of the rates of disappearance of the parent compound
      and appearance of transformation products.

PMID- 10360328
TI  - Utility of isotachophoresis-capillary zone electrophoresis, mass spectrometry and
      high-performance size-exclusion chromatography for monitoring of interleukin-6
      dimer formation.
AB  - The utility of isotachophoresis-capillary zone electrophoresis (ITP-CZE) and high
      performance size-exclusion chromatography (HPSEC) was investigated for
      determination of dimeric and monomeric recombinant human interleukin-6 (rhIL-6).
      Using ITP-CZE heterogeneity of dimeric rhIL-6 could be revealed resolving two
      peaks in the electropherograms, while with HPSEC dimeric rhIL-6 eluted as one
      homogeneous fraction. Both protein forms were monitored during incubation of
      monomeric rhIL-6 at different pH and temperature. The selectivity of counterflow
      ITP-CZE in conjunction with the low concentration determination limits enabled
      reanalysis of HPSEC fractions for identification of the dimer in the
      electropherograms. Both ITP-CZE and HPSEC were shown to be suitable to monitor
      the dimerization of rhIL-6, similar monomer-to-dimer peak area ratios were
      obtained throughout the incubation. Dimer formation kinetics increased with
      decreasing pH and with increasing temperature, it was entirely suppressed at
      neutral pH and room temperature. In contrast to HPSEC, ITP-CZE enabled separation
      of further still unidentified artifacts apparently formed during incubation of
      rhIL-6. CZE analysis in conjunction with electrospray ionization mass
      spectrometry revealed the non-covalent binding character of the dimeric rhIL-6
      complex and facilitated interpretation of the electropherograms.

PMID- 10360329
TI  - Effects of gel material on fluorescence lifetime detection of dyes and dye
      labeled DNA primers in capillary electrophoresis.
AB  - Investigations of fluorescence lifetimes of the dye 6-[N-(7-nitrobenz-2-oxa-1,3
      diazol-4-yl)amino]hexanoic acid (NBD-HA) and of DNA M13 primers labeled with NBD
      HA, Cy3, rhodamine green and 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s
      indacene++ +-3-propionic acid (BODIPY-FL) dyes in polyacrylamide gels of various
      degrees of crosslinking and different crosslinkers, and in a cellulose sieving
      buffer with different organic modifiers, are described. The dependence of
      fluorescence lifetime on gel matrix and on experimental conditions was studied in
      order to identify which factors may be important for optimization of multiplex
      fluorescence lifetime detection. Lifetimes were determined in both batch solution
      and on-the-fly, on-column in CE. Results show that lifetimes of the primer
      attached dyes remain constant in gels of different composition. Additionally,
      multiexponential fluorescence decays are observed for primer-attached dyes in
      batch solutions of the cellulose sieving buffers but are reduced to
      monoexponential decays when measured on-the-fly, on-column in CE. Lifetime
      detectability can be improved by addition of an organic modifier to the gel
      matrix.

PMID- 10360330
TI  - Detection of bovine whey proteins by on-column derivatization capillary
      electrophoresis with laser-induced fluorescence monitoring.
AB  - 1-Anilinonaphthalene-8-sulfonic acid (1,8-ANS), 4,4'-dianilino-1,1'-binaphthyl
      5,5'-disulfonic acid (bis-ANS) and 2-(p-toluidino)naphthalene-6-sulfonic acid
      (2,6-TNS) were evaluated as additives in different buffers for the detection of
      bovine whey proteins using laser-induced fluorescence (LIF) monitoring in
      capillary electrophoresis (CE). These N-arylaminonaphthalene sulfonates furnish a
      large fluorescence emission when associated to some proteins whereas their
      emission in aqueous buffers, such as those used in CE separations, is very small.
      To select the best detection conditions, the fluorescence of these probes was
      first compared using experiments carried out in a fluorescence spectrophotometer.
      Using bovine serum albumin (BSA) as a model protein, it was demonstrated that 2
      (N-cyclohexylamino)ethanesulfonic acid (CHES) buffer (pH 8 and pH 10.2) and the
      fluorescent probe 2,6-TNS gave rise to the highest increase in fluorescence for
      BSA. When the composition of these separation buffers was optimized for the
      electrophoretic separations, CHES buffer, pH 10.2 was chosen as the most suitable
      buffer to detect bovine whey proteins. The limit of detection obtained for some
      whey proteins in CE separations was about 6.10(-8) M for BSA, 3.10(-7) M for beta
      lactoglobulin A (beta-LGA), 3.10(-7) M for beta-lactoglobulin B (beta-LGB), and
      3.10(-6) M for alpha-lactalbumin (alpha-LA). These detection limits were compared
      to those achieved using UV detection under the same separation conditions. The
      results showed that the detection limits of BSA, beta-LGA and beta-LGB were twice
      as good using LIF than with UV detection. However, the limit of detection for
      alpha-LA was better when UV was used. The applicability of LIF detection to CE
      separation of whey proteins in bovine milk samples was also demonstrated.

PMID- 10360331
TI  - Ion/ion chemistry of high-mass multiply charged ions.
AB  - Electrospray ionization has enabled the establishment of a new area of ion
      chemistry research based on the study of the reactions of high-mass multiply
      charged ions with ions of opposite polarity. The multiple-charging phenomenon
      associated with electrospray makes possible the generation of multiply charged
      reactant ions that yield charged products as a result of partial neutralization
      due to ion/ion chemistry. The charged products can be readily studied with mass
      spectrometric methods, providing useful insights into reaction mechanisms. This
      review presents the research done in this area, all of which has been performed
      within the past decade. Ion/ion chemistry has been studied at near-atmospheric
      pressure in a reaction region that leads to the atmospheric/vacuum interface of a
      mass spectrometer, and within a quadrupole ion trap operated with a bath gas at a
      pressure of 1 mtorr. Proton transfer has been the most common reaction type for
      high-mass ions, but other forms of "charge transfer," such as electron transfer
      and fluoride transfer, have also been observed. For some ion/ion reactions,
      attachment of the two reactants has been observed. Multiply charged ion/ion
      reactions are fast, due to the long-range Coulombic attraction, and they are
      universal in that any pair of oppositely charged ions is expected to react due to
      the high exothermicity associated with mutual neutralization. The kinetics of
      reaction for multiply charged ions, derived from the same molecule with a given
      singly charged reactant ion, follow a charge-squared dependence, at least under
      normal quadrupole ion trap conditions. This dependence suggests that reaction
      rates are determined by the long-range Coulomb attraction, and that the ions
      react with constant efficiency as a function of charge state. In the case of
      proton transfer reactions from polypeptides to even-electron perfluorocarbon
      anions, no fragmentation of the polypeptide product ions has, as yet, been
      observed. Electron transfer from small oligonucleotide anions to rare gas
      cations, on the other hand, results in extensive fragmentation of the nucleic
      acid product ions. The extent of fragmentation decreases as the size of the
      oligonucleotide anions increases, reflecting a decrease in fragmentation rates
      associated with an increase in the number of internal degrees of freedom of the
      oligonucleotide. When ion-cooling rates become competitive with dissociation
      rates, the initially formed product ions are stabilized and fragmentation is
      avoided. Collisional cooling, therefore, likely plays an important role in the
      relative lack of dissociation observed thus far as a result of ion/ion reactions
      for most high-mass ions. The observed dependence of ion/ion reaction rates on the
      square of the ion charge, the universal nature of mutual neutralization, and the
      relative lack of fragmentation that arises from ion/ion reactions, makes ion/ion
      chemistry a particularly useful means for manipulating charge states. This review
      emphasizes applications that take advantage of the unique characteristics of
      ion/ion proton transfer chemistry for manipulating charge states. These
      applications include mixture analysis by electrospray, precursor ion charge state
      manipulation for tandem mass spectrometry studies, and simplified interpretation
      of product ion spectra.

PMID- 10360332
TI  - Evaluation of a multidimensional measure of dyspepsia-related health for use in a
      randomized clinical trial.
AB  - In previous work, we developed a multidimensional measure of dyspepsia-related
      health. To evaluate the adequacy of this instrument as an outcome measure for a
      large-scale, multicenter, randomized clinical trial, we used Rasch analysis to
      address three questions: (1) Are the scales interval-level? (2) Do the scales
      measure precisely across the entire range of dyspepsia outcomes? (3) Do the
      scales' items have an optimal number of response categories? We found that the
      scales were not interval-level and that they did not measure effectively at low
      or high levels of the dyspepsia-related outcomes. Our results also suggest that
      patients were capable of discriminating among only four- to seven-item response
      categories. Further studies are needed to identify items that effectively measure
      high and low levels of dyspepsia-related outcomes and to validate that decreasing
      the number of response categories improves the psychometric properties of these
      scales.

PMID- 10360333
TI  - Problems in using age-stratum-specific reference rates for indirect
      standardization.
AB  - Disease risk in a study cohort can be compared with that in a reference
      population using the method of indirect standardization, adjusting for a
      difference in age distribution between the cohort and reference population. The
      common epidemiological practice is to use categorical age, typically in the form
      of 5-year age strata, in the standardization. This article discusses problems
      that arise owing to the categorization of age, including biased estimation and
      incorrect statistical inference on relative risk parameters. The same problems
      further extend to more general analyses using Poisson regression. We illustrate
      the problems using a hypothetical example and propose a simple remedy using
      linear splines. A slightly more elaborate method and its computer program are
      given in the appendix.

PMID- 10360334
TI  - Estimation and sample design in prevalence surveys of dementia.
AB  - Population prevalence rates of dementia using stratified sampling have previously
      been estimated using two methods: standard weighted estimates and a logistic
      model-based approach. An earlier study described this application of the model
      based approach and reported a small computer simulation comparing the performance
      of this estimator to the standard weighted estimator. In this article we use
      large-scale computer simulations based on data from the recently completed Kame
      survey of prevalent dementia in the Japanese-American residents of King County,
      Washington, to describe the performance of these estimators. We found that the
      standard weighted estimator was unbiased. This estimator performed well for a
      sample design with proportional allocation, but performed poorly for a sample
      design that included large strata that were lightly sampled. The logistic model
      based estimator performed consistently well for all sample designs considered in
      terms of the extent of variability in estimation, although some modest bias was
      observed.

PMID- 10360335
TI  - Statistical issues encountered in the comparison of health-related quality of
      life in diseased patients to published general population norms: problems and
      solutions.
AB  - The objectives of this study were (1) to illustrate the statistical problems
      encountered when comparing health-related quality of life (HRQL) measured by the
      Medical Outcome Study Short Form-36 (SF-36) in a diseased group to general
      population norms, and (2) to define age- and gender-standardized dichotomous
      indicator variables for each health concept and show that these indicator
      variables facilitate comparisons between the diseased sample and the general
      population. Our "diseased" group consisted of 136 sequentially consenting
      patients referred to the syncope clinic for assessment and treatment.
      Participants completed the SF-36 questionnaire before undergoing diagnostic
      testing. General population norms for the SF-36 are available from the responses
      of 2474 participants in the National Survey of Functional Health Status,
      conducted in 1990 in the United States. Comparison of the SF-36 in a diseased
      sample with general population norms is difficult, owing to skewed and unusual
      distributions in both groups. In addition, making comparisons within age and
      gender strata is difficult if the within strata sample size is small. We propose
      a dichotomous indicator variable for each health concept that classifies an
      individual as having impaired health if he or she scored lower than the 25th
      percentile for the appropriate age and gender general population strata. By
      definition, the prevalence of impaired health in the general population is 25%
      for all eight health concepts. Comparison between the eight health-concept
      variables is easy because the population norm is the same for each of them. These
      indicator variables are age and gender adjusted, so that even if the sample did
      not have the age and gender distribution as the general population, comparisons
      can still be made with the value of 25.

PMID- 10360336
TI  - Cardiovascular risk profile of type 2 diabetic patients cared for by general
      practitioners or at a diabetes clinic: a population-based study.
AB  - The aims of this study were to compare the cardiovascular risk profiles of
      patients with type 2 diabetes mellitus cared for by general practitioners and
      those regularly attending a diabetes center. Out of an Italian population-based
      cohort of 1967 diabetic patients, 1574 (80%) were investigated. Patients
      exclusively cared for by general practitioners (23.8%) were older and showed
      lower prevalence of hypertension (79.0% vs 85.9%, P < 0.001), poor blood glucose
      control (HbA1c >8.0, 33.4% vs 47.9%, P < 0.001) and coronary heart disease (18.1%
      vs 22.3%, P = 0.003), and lower plasma fibrinogen (3.5 +/- 0.8 vs 3.7 +/- 0.9
      g/L, P < 0.001). In logistic regression analysis, they had significantly lower
      ORs for HbA1c >8.8% (OR 0.67, 95% CI 0.45-0.99), hypertension (OR 0.53, 95% CI
      0.36-0.78), fibrinogen >4.1 g/L (OR 0.50, 95% CI 0.32-0.77), smoking (OR 0.60,
      95% Cl 0.36-1.00), and coronary heart disease (OR 0.65, 95% CI 0.45-0.93), after
      adjustment for age, sex, duration of diabetes, BMI, and antidiabetic treatment.
      Patients regularly cared for at a diabetes clinic had a higher cardiovascular
      risk profile, suggesting selective referral to the clinics of patients with more
      difficult management and/or severity of the disease. These findings have
      implications in the interpretation of morbidity and mortality clinic-based
      studies.

PMID- 10360337
TI  - Capturing health care utilization after occupational low-back pain: development
      of an interviewer-administered questionnaire.
AB  - The aim of this study was to develop and test the feasibility and validity of a
      patient questionnaire to assess health care utilization after occupational low
      back pain (LBP). Items generated after a literature search were revised and
      refined on the basis of their face and content validity (judged by a group of
      practitioners) and pretested with six lay subjects who had LBP. The 73-item
      questionnaire was then tested in interviews with subjects with acute, subacute,
      or chronic LBP. Its validity was judged by comparison with a prospective patient
      diary and with care-provider reports. Chance-corrected agreement was estimated
      using the kappa statistic. Response rates were 78%, 70%, and 59% for interview,
      diary, and provider reports, respectively. Eighty of 102 eligible workers
      completed the interview in an average of 45 minutes (SD = 17.7). Most LBP
      subjects (90.1%) found it easy to answer. In the opinion of the interviewer,
      94.7% of subjects showed adequate comprehension and ability to recall. With a few
      exceptions, there was moderate to substantial agreement between the interview and
      the patient diary (most K values between 0.38 and 0.78). Overall, subjects
      reported more health care services to the interviewer than they recorded in the
      diary. Owing to the low response rate from providers, comparison with provider
      reports had to be restricted to 48 subjects and to physicians' reports only.
      Agreement between interviews and physicians' reports was substantial in use of
      plain X-rays (kappa = 0.79) and computed tomography scans (kappa = 0.85), but
      physicians often reported referrals not volunteered by the subjects. Agreement on
      prescription medications was fair (kappa = 0.29-0.46) with no systematic over
      reporting or under reporting. Our interviewer-administered questionnaire had
      better return rate than the patient diary and provider reports. It was easy to
      administer and understand. On the basis of our comparison with patient diaries
      and physicians' reports, we conclude that this questionnaire is a sufficiently
      valid source of health care utilization data in subjects with LBP.

PMID- 10360338
TI  - Diet and the risk of breast cancer in a case-control study: does the threat of
      disease have an influence on recall bias?
AB  - It has been suggested that recall bias may explain the discrepant results between
      case-control and cohort studies on diet and the risk of breast cancer. Two
      control groups were used for this case-control study of 25 to 75-year-old breast
      cancer cases (n = 310). The first group consisted of population controls drawn
      from the Finnish National Population Register (n = 454). The second group
      consisted of women who were referred to the same examinations as were the cases
      because of clinical suspicion of breast disease but who were later diagnosed as
      healthy (referral controls; n = 506). Because the diagnosis was unknown at the
      time of interview, it was possible to assess by comparing the two control groups
      whether the self-reporting of diet changed under the threat of disease. Dietary
      habits were examined using a validated, self-administered food-frequency
      questionnaire. Premenopausal women misreported their consumption of liquid milk
      products, tea, and sugar. Reporting bias was also associated with the intake of
      fat and vitamins. Postmenopausal women misreported consumption of milk products.
      When recall bias was taken into consideration, milk was associated with increased
      risk of premenopausal breast cancer, whereas high consumption of poultry or high
      intake of monounsaturated fatty acids, n-3 fatty acids, n-6 fatty acids, and
      vitamin E were related to lower risk. The study suggested that oil, milk, cheese,
      coffee and beta-carotene may act as protective factors in postmenopausal women,
      whereas butter and cream may be risk factors for breast cancer. In summary, it is
      possible that some food items may be overreported or underreported under the
      threat of disease in health-conscious population. However, most of the results in
      this study were not modified by recall bias.

PMID- 10360340
TI  - Colorectal cancer deaths as determined by expert committee and from death
      certificate: a comparison. The Minnesota Study.
AB  - For deaths during the first 13 years of follow-up of the Minnesota Colon Cancer
      Control Study, an expert committee using numerous medical documents, and a
      nosologist using only the death certificate independently determined whether
      colorectal cancer caused the death and, if not, whether the disease was present
      at death. Deaths due to colorectal cancer numbered 318 according to the
      nosologist and 323 according to the committee, a discrepancy of 1.5%, which is
      similar in magnitude to that in three previous studies. The nosologist and
      committee agreed that colorectal cancer caused the death in each of 290
      individual cases; they disagreed widely on the number of deaths from other causes
      but with colorectal cancer. If it is important to know only the gross number of
      deaths from colorectal cancer, then the death certificate alone appears to be
      sufficiently accurate; if it is important to know the cause of death of
      individual subjects or the number dying from other causes but with colorectal
      cancer, then the expert committee method provides more accurate information.

PMID- 10360339
TI  - Symptoms of Raynaud's phenomenon in an inner-city African-American community:
      prevalence and self-reported cardiovascular comorbidity.
AB  - The objective of this study was to determine the prevalence of symptoms and the
      morbidity associated with Raynaud's phenomenon (RP) among African Americans. A
      total of 2196 randomly selected residents of an inner-city community, in
      Baltimore, completed a health-assessment survey. Symptoms of RP consisted of cold
      sensitivity plus cold-induced white or blue digital color change. One third (n =
      703) reported cold sensitivity and 14% (n = 308) reported digital color change;
      84 residents with symptoms of RP were identified, yielding an overall prevalence
      rate of 3.8% (95% confidence interval [CI] 3.0-4.6). RP was associated with poor
      or fair health status (odds ratio [OR] = 1.82, CI 1.18-2.81), heart disease (OR =
      2.32, CI 1.39-3.87), and stroke (OR = 2.20, CI 1.17-4.15), after adjustment for
      age, gender, and physician-diagnosed arthritis. The prevalence of symptoms of RP
      in this African-American community is comparable to published reports from other
      populations. These community-based data suggest that identification of RP among
      African Americans should raise consideration of possible comorbidity,
      particularly cardiovascular disease.

PMID- 10360341
TI  - Risk factor profiles of placental abruption in first and second pregnancies:
      heterogeneous etiologies.
AB  - The objective of this study was to identify risk factors for placental abruption
      in first and second pregnancies and to compare the risk-factor profiles for
      evidence of etiologic heterogeneity. A prospective cohort design was used. The
      study took place at university-based medical centers that participated in the
      U.S. Collaborative Perinatal Project (1959-1965). A total of 10,774 first
      pregnancies only and 6529 first and second pregnancies of women were enrolled in
      the study. Participation rate was 96%. All pregnancies were selected at some
      centers, whereas other centers used either random or systematic sampling. The
      main outcome measure was placental abruptions in first and second pregnancies.
      The placental abruption rate was 1.7% (n = 182) for first and 2.2% (n = 143) for
      second pregnancies. Prior abruption increased risk in second pregnancies
      significantly (odds ratio [OR] = 3.2, 95% confidence interval [CI]: 1.7-5.8)
      after adjusting for other risk factors. Placental infarcts and smoking duration
      were associated with an increased risk for abruption in second but not first
      pregnancies. Effect of placental infarcts was modified by gestational age with
      strongest risk for abruption at shortest gestations. For each year of smoking
      prior to pregnancy, risk of abruption increased 40% (OR = 1.4, 95% CI 1.0-1.8).
      Etiologies of placental abruption for first and second pregnancies were
      different, indicating heterogeneity in their risk-factor profiles. Future
      research would best consider abruption as a heterogeneous complication to further
      knowledge of its etiology.

PMID- 10360342
TI  - Information on radiation treatment in patients with breast cancer: the advantages
      of the linked medicare and SEER data. Surveillance, Epidemiology and End Results.
AB  - Several studies have found underutilization of radiotherapy in patients with
      breast cancer; but there are concerns about the completeness of various databases
      on radiotherapy. We used the linked Medicare-SEER (Surveillance, Epidemiology and
      End Results) database to compare information on receipt of radiotherapy after
      diagnosis of breast cancer. More than 18% of women identified by Medicare data as
      receiving radiotherapy were not so identified by SEER, and 7% of those identified
      as receiving radiotherapy by SEER were not identified by Medicare. Risk of
      discordance on radiotherapy information between the two data sets was especially
      high in women receiving breast-conserving surgery. The combined SEER-Medicare
      database gives a more complete picture on the use of radiotherapy. The previously
      reported geographic variations in the use of radiotherapy for breast cancer may
      be due in part to underreporting of radiotherapy in some areas.

PMID- 10360343
TI  - Drug consumption in workers in France: a comparative study at a 10-year interval
      (1996 versus 1986).
AB  - This study compared drug consumption and associated social factors in workers in
      France between 1986 and 1996. The same transversal survey was performed in 1986
      and 1996 using the same methodology by means of an anonymous questionnaire given
      to the subject and answered in the presence of an occupational physician. The
      1996 population (2674 subjects) was found to be older (37.0 +/- 9.8 versus 35.7
      +/-10.2 years) and to take more drugs (+5.1%) than the population of 1986 (2221
      subjects). There were fewer manual workers in the 1996 population. In both
      periods, women used significantly more drugs in general and more psychoactive
      (mainly anxiolytic), cardiovascular, endocrine metabolic, and homeopathic drugs
      than men. The mean value of estimated difficulty of work was higher in subjects
      taking drugs in general, and especially those taking hypnotic, anxiolytic,
      psychoactive, antiinflammatory, and digestive drugs in 1986 as well in 1996. In
      1986 as well as in 1996, manual workers took no more drugs than did nonmanual
      workers in general, except for analgesic and antiinflammatory drugs. Nonmanual
      workers used homeopathic drugs more than manual workers. The presence of
      extraprofessional problems was associated with an increase in consumption of
      drugs in general and psychoactive, hypnotic, anxiolytic, antiinflammatory,
      cardiovascular, digestive, and endocrine metabolic drugs in particular, in 1986
      as well as in 1996. After adjustment for variables linked to drug use, there was
      no significant change in total drug consumption in general but a significant
      decrease in psychoactive (-49%) (mainly hypnotic [-71%]), and digestive (-39%)
      drug consumption in this population between 1986 and 1996. In contrast, analgesic
      use significantly increased (+36%). This study underscores the high level of drug
      consumption in workers (more than 40% of the subjects were taking drugs).
      Although there were no quantitative changes, marked qualitative modifications
      were found with a decrease in consumption of psychoactive (and mainly hypnotic)
      and digestive drugs and an increase in analgesic drug use between 1986 and 1996.
      Thus, specific drug information programs designed to reduce psychoactive drug
      consumption and to favor analgesic drugs for better pain management seem to have
      been (at least partly) followed. The study also underscores the importance of
      some social factors associated to general and specific drug use (mainly
      difficulty of work and presence of extraprofessional problems, and to a lesser
      extent, kind of work). Their weight remained similar in 1986 and 1996.

PMID- 10360344
TI  - Unraveling the mysteries of transcription.

PMID- 10360345
TI  - Two domains and one RNA: a molecular threesome.

PMID- 10360346
TI  - Forming and inhibiting PRT active sites.

PMID- 10360347
TI  - Picture story. Rules for protein-DNA interactions.

PMID- 10360348
TI  - RNA phylogeny.

PMID- 10360349
TI  - David C. Phillips.

PMID- 10360350
TI  - The CuA domain of Thermus thermophilus ba3-type cytochrome c oxidase at 1.6 A
      resolution.
AB  - The structure of the CuA-containing, extracellular domain of Thermus thermophilus
      ba3-type cytochrome c oxidase has been determined to 1.6 A resolution using
      multiple X-ray wavelength anomalous dispersion (MAD). The Cu2S2 cluster forms a
      planar rhombus with a copper-copper distance of 2.51 +/- 0.03 A. X-ray absorption
      fine-structure (EXAFS) studies show that this distance is unchanged by
      crystallization. The CuA center is asymmetrical; one copper is tetrahedrally
      coordinated to two bridging cysteine thiolates, one histidine nitrogen and one
      methionine sulfur, while the other is trigonally coordinated by the two cysteine
      thiolates and a histidine nitrogen. Combined sequence-structure alignment of
      amino acid sequences reveals conserved interactions between cytochrome c oxidase
      subunits I and II.

PMID- 10360351
TI  - The crystal structure of HasA, a hemophore secreted by Serratia marcescens.
AB  - Free iron availability is strongly limited in vertebrate hosts, making the iron
      acquisition by siderophores inappropriate. Pathogenic bacteria have developed
      various ways to use the host's iron from iron-containing proteins. Serratia
      marcescens can use the iron from hemoglobin through the secretion of a hemophore
      called HasA, which takes up the heme from hemoglobin and shuttles it to the
      receptor HasR, which in turn, releases heme into the bacterium. We report here
      the first crystal structure of such a hemophore, bound to a heme group at two
      different pH values and at a resolution of 1.9 A. The structure reveals a new
      original fold and suggests a hypothetical mechanism for both heme uptake and
      release.

PMID- 10360352
TI  - The two types of 3-dehydroquinase have distinct structures but catalyze the same
      overall reaction.
AB  - The structures of enzymes catalyzing the reactions in central metabolic pathways
      are generally well conserved as are their catalytic mechanisms. The two types of
      3-dehydroquinate dehydratase (DHQase) are therefore most unusual since they are
      unrelated at the sequence level and they utilize completely different mechanisms
      to catalyze the same overall reaction. The type I enzymes catalyze a cis
      dehydration of 3-dehydroquinate via a covalent imine intermediate, while the type
      II enzymes catalyze a trans-dehydration via an enolate intermediate. Here we
      report the three-dimensional structures of a representative member of each type
      of biosynthetic DHQase. Both enzymes function as part of the shikimate pathway,
      which is essential in microorganisms and plants for the biosynthesis of aromatic
      compounds including folate, ubiquinone and the aromatic amino acids. An
      explanation for the presence of two different enzymes catalyzing the same
      reaction is presented. The absence of the shikimate pathway in animals makes it
      an attractive target for antimicrobial agents. The availability of these two
      structures opens the way for the design of highly specific enzyme inhibitors with
      potential importance as selective therapeutic agents.

PMID- 10360354
TI  - A complex of influenza hemagglutinin with a neutralizing antibody that binds
      outside the virus receptor binding site.
AB  - The structure of a complex of influenza hemagglutinin (HA) with a neutralizing
      antibody shows that the antibody binds to HA at a distance from the virus
      receptor binding site. Comparison of the properties of this antibody and its Fab
      with those of an antibody that recognizes an epitope overlapping the receptor
      binding site leads to two main conclusions. First, inhibition of receptor binding
      is an important component of neutralization. Second, the efficiency of
      neutralization by the antibodies ranks in the same order as their avidities for
      HA, and their large size makes these antibodies highly efficient at
      neutralization, regardless of the location of their epitope in relation to the
      virus receptor binding site. These observations provide rationales for the range
      of antibody specificities that are detected in immune sera and for the
      distribution of sequence changes on the membrane-distal surface of influenza HAs
      that occur during 'antigenic drift.'

PMID- 10360353
TI  - A novel two-chain proteinase inhibitor generated by circularization of a
      multidomain precursor protein.
AB  - Female reproductive tissues of the ornamental tobacco amass high levels of serine
      proteinase inhibitors (PIs) for protection against pests and pathogens. These PIs
      are produced from a precursor protein composed of six repeats each with a
      protease reactive site. Here we show that proteolytic processing of the precursor
      generates five single-chain PIs and a remarkable two-chain inhibitor formed by
      disulfide-bond linkage of N- and C-terminal peptide fragments. Surprisingly, PI
      precursors adopt this circular structure regardless of the number of inhibitor
      domains, suggesting this bracelet-like conformation is characteristic of the
      widespread potato inhibitor II (Pot II) protein family.

PMID- 10360355
TI  - Crystal structure and improved antisense properties of 2'-O-(2-methoxyethyl)-RNA.
AB  - 2'-O-(2-Methoxyethyl)-RNA (MOE-RNA) is a nucleic acid analog with promising
      features for antisense applications. Compared with phosphorothioate DNA (PS-DNA),
      the MOE modification offers improved nuclease resistance, enhanced RNA affinity,
      improved cellular uptake and intestinal absorption, reduced toxicity and immune
      stimulation. The crystal structure of a fully modified MOE-RNA dodecamer duplex
      (CGCGAAUUCGCG) was determined at 1.7 A resolution. In the majority of the MOE
      substituents, the torsion angle around the ethylene alkyl chain assumes a gauche
      conformation. The conformational preorganization of the MOE groups is consistent
      with the improved RNA affinity and the extensive hydration of the substituents
      could play a role in the improved cellular uptake of MOE-RNA. A specific
      hydration pattern that bridges substituent and phosphate oxygen atoms in the
      minor groove of MOE-RNA may explain its high nuclease resistance.

PMID- 10360356
TI  - Simulations of the dynamics at an RNA-protein interface.
AB  - Molecular dynamics simulations of the RNA-binding domain of the U1A spliceosomal
      protein in complex with its cognate RNA hairpin, performed at low and high ionic
      strength in aqueous solution, suggest a pathway for complex dissociation. First,
      cations condense around the RNA and compete with the protein for binding sites.
      Then solvated ions specifically destabilize residues at the RNA-protein
      interface. For a discrete cluster of residues at the complex interface, the
      simulations reveal an increased deviation from the crystal structure at high salt
      concentrations while the remaining protein scaffold is stabilized under these
      conditions. The microscopic picture of salt influence on the complex suggests
      guidelines for rational design of interface inhibitors targeted at RNA-protein
      complexes.

PMID- 10360357
TI  - Stability of hairpin ribozyme tertiary structure is governed by the interdomain
      junction.
AB  - The equilibrium distributions of hairpin ribozyme conformational isomers have
      been examined by time-resolved fluorescence resonance energy transfer. Ribozymes
      partition between active (docked) and inactive (extended) conformers,
      characterized by unique interdomain distance distributions, which define
      differences in folding free energy. The active tertiary structure is stabilized
      both by specific interactions between the catalytic and the substrate-binding
      domains and by the structure of the intervening helical junction. Under
      physiological conditions, the docking equilibrium of the natural four-way
      junction dramatically favors the active conformer, while those of a three-way and
      the two-way junction used in gene therapy applications favor the inactive
      conformer.

PMID- 10360358
TI  - Extremely rapid folding of the C-terminal domain of the prion protein without
      kinetic intermediates.
AB  - The kinetics of folding of mPrP(121-231), the structured 111-residue domain of
      the murine cellular prion protein PrP(C), were investigated by stopped-flow
      fluorescence using the variant F175W, which has the same overall structure and
      stability as wild-type mPrP(121-231) but shows a strong fluorescence change upon
      unfolding. At 22 degrees C and pH 7.0, folding of mPrP(121-231)-F175W is too fast
      to be observable by stopped-flow techniques. Folding at 4 degrees C occurs with a
      deduced half-life of approximately 170 micros without detectable intermediates,
      possibly the fastest protein-folding reaction known so far. Thus, propagation of
      the abnormal, oligomeric prion protein PrP(Sc), which is supposed to be the
      causative agent of transmissible spongiform encephalopathies, is unlikely to
      follow a mechanism where kinetic folding intermediates of PrP(C) are a source of
      PrP(Sc) subunits.

PMID- 10360359
TI  - Chain collapse can occur concomitantly with the rate-limiting step in protein
      folding.
AB  - We have directly characterized the extent of chain collapse early in the folding
      of protein L using time-resolved small angle X-ray scattering. We find that,
      immediately after the initiation of refolding, the protein exhibits dimensions
      indistinguishable from those observed under highly denaturing, equilibrium
      conditions and that this expanded initial state collapses with the same rate as
      that of the overall folding reaction. The observation that chain compaction need
      not significantly precede the rate-limiting step of folding demonstrates that
      rapid chain collapse is not an obligatory feature of protein folding reactions.

PMID- 10360360
TI  - Three photoconvertible forms of green fluorescent protein identified by spectral
      hole-burning.
AB  - Several studies have led to the conclusion that, in the green fluorescent protein
      (GFP) of the jellyfish Aequorea victoria, a photoconversion involving excited
      state proton transfer occurs from an A- to a B-form, while an intermediate I-form
      was held responsible for the green fluorescence. Here we have identified the I
      form of wild-type GFP in absorption, located the 0-0 transitions of all three
      forms A, B and I, and determined vibrational frequencies of the ground and
      excited states. The intrinsically narrow 0-0 transitions are revealed by the
      wavelengths at which holes can be burnt. The pathways of photointerconversion are
      unraveled by excitation, emission and hole-burning spectroscopy. We present an
      energy-level scheme that has significant implications for GFP-mutants, which
      likewise can occur in the three photo-interconvertible forms.

PMID- 10360361
TI  - Revealing the structure of the oxygen-evolving core dimer of photosystem II by
      cryoelectron crystallography.
AB  - Here we present cryoelectron crystallographic analysis of an isolated dimeric
      oxygen-evolving complex of photosystem II (at a resolution of approximately 0.9
      nm), revealing that the D1-D2 reaction center (RC) proteins are centrally located
      between the chlorophyll-binding proteins, CP43 and CP47. This conclusion supports
      the hypothesis that photosystems I and II have similar structural features and
      share a common evolutionary origin. Additional density connecting the two halves
      of the dimer, which was not observed in a recently described CP47-RC complex that
      did not include CP43, may be attributed to the small subunits that are involved
      in regulating secondary electron transfer, such as PsbH. These subunits are
      possibly also required for stabilization of the dimeric photosystem II complex.
      This complex, containing at least 29 transmembrane helices in its asymmetric
      unit, represents one of the largest membrane protein complexes studied at this
      resolution.

PMID- 10360362
TI  - The structure of a cypovirus and the functional organization of dsRNA viruses.
AB  - Cytoplasmic polyhedrosis virus (CPV) is unique among the double-stranded RNA
      viruses of the family Reoviridae in having a single capsid layer. Analysis by
      cryo-electron microscopy allows comparison of the single shelled CPV and
      orthoreovirus with the high resolution crystal structure of the inner shell of
      the bluetongue virus (BTV) core. This suggests that the novel arrangement
      identified in BTV, of 120 protein subunits in a so-called 'T=2' organization, is
      a characteristic of the Reoviridae and allows us to delineate structural
      similarities and differences between two subgroups of the family--the turreted
      and the smooth-core viruses. This in turn suggests a coherent picture of the
      structural organization of many dsRNA viruses.

PMID- 10360363
TI  - Acceleration of the refolding of Arc repressor by nucleic acids and other
      polyanions.
AB  - The refolding rate of the Arc repressor dimer can be accelerated 30-fold or more
      by negatively charged polymers including single-stranded and double-stranded DNA,
      RNA, and polyvinylsulfate but not by neutral or positively charged polymers. The
      salt-dependence of the polyanion-mediated process and mutant studies indicate
      that electrostatic interactions are important in the rate acceleration. Urea
      dependence studies suggest that Arc is relatively unstructured in the transition
      state for polyanion-stimulated refolding. At low ionic strength, the observed
      kinetics of refolding are consistent with a model in which denatured Arc monomers
      bind rapidly and nonspecifically to the polyanion and complete folding in the
      bound state.

PMID- 10360364
TI  - Structure, specificity and CDR mobility of a class II restricted single-chain T
      cell receptor.
AB  - Using NMR spectroscopy, we determined the solution structure of a single-chain T
      cell receptor (scTCR) derived from the major histocompatibility complex (MHC)
      class II-restricted D10 TCR. The conformations of complementarity-determining
      regions (CDRs) 3beta and 1alpha and surface properties of 2alpha are different
      from those of related class I-restricted TCRs. We infer a conserved orientation
      for TCR V(alpha) domains in complexes with both class I and II MHC-peptide
      ligands, which implies that small structural variations in V(alpha) confer MHC
      class preference. High mobility of CDR3 residues relative to other CDR or
      framework residues (picosecond time scale) provides insight into immune
      recognition and selection mechanisms.

PMID- 10360365
TI  - Transition-state analogs as inhibitors of human and malarial hypoxanthine-guanine
      phosphoribosyltransferases.
AB  - The proposed transition state for hypoxanthine-guanine phosphoribosyltransferases
      (HGPRTs) has been used to design and synthesize powerful inhibitors that contain
      features of the transition state. The iminoribitols (1S)-1-(9-deazahypoxanthin-9
      yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate (immucillinHP) and (1S)-1-(9
      deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate (immucillinGP) are
      the most powerful inhibitors yet reported for both human and malarial HGPRTs.
      Equilibrium binding constants are >1,000-fold tighter than the binding of the
      nucleotide substrate. The NMR spectrum of malaria HGXPRT in the Michaelis complex
      reveals downfield hydrogen-bonded protons. The chemical shifts move farther
      downfield with bound inhibitor. The inhibitors are lead compounds for species
      specific antibiotics against parasitic protozoa. The high-resolution crystal
      structure of human HGPRT with immucillinGP is reported in the companion paper.

PMID- 10360366
TI  - The 2.0 A structure of human hypoxanthine-guanine phosphoribosyltransferase in
      complex with a transition-state analog inhibitor.
AB  - The structure of human HGPRT bound to the transition-state analog immucillinGP
      and Mg2+-pyrophosphate has been determined to 2.0 A resolution. ImmucillinGP was
      designed as a stable analog with the stereoelectronic features of the transition
      state. Bound inhibitor at the catalytic site indicates that the oxocarbenium ion
      of the transition state is stabilized by neighboring-group participation from
      MgPPi and O5'. A short hydrogen bond forms between Asp 137 and the purine ring
      analog. Two Mg2+ ions sandwich the pyrophosphate and contact both hydroxyls of
      the ribosyl analog. The transition-state analog is shielded from bulk solvent by
      a catalytic loop that moves approximately 25 A to cover the active site and
      becomes an ordered antiparallel beta-sheet.

PMID- 10360367
TI  - The formation of a native-like structure containing eight conserved hydrophobic
      residues is rate limiting in two-state protein folding of ACBP.
AB  - The acyl-coenzyme A-binding proteins (ACBPs) contain 26 highly conserved sequence
      positions. The majority of these have been mutated in the bovine protein, and
      their influence on the rate of two-state folding and unfolding has been measured.
      The results identify eight sequence positions, out of 24 probed, that are
      critical for fast productive folding. The residues are all hydrophobic and
      located in the interface between the N- and C-terminal helices. The results
      suggest that one specific site dominated by conserved hydrophobic residues forms
      the structure of the productive rate-determining folding step and that a
      sequential framework model can describe the protein folding reaction.

PMID- 10360368
TI  - The biological basis for the attenuation of mucositis: the example of interleukin
      11.
AB  - Oral mucositis is common, painful, dose-limiting toxicity of drug and radiation
      therapy for cancer. In granulocytopenic patients, the ulcerations which accompany
      mucositis are frequent portals of entry for indigenous oral bacteria often
      leading to bacteremias or sepsis. The complexity of mucositis as a biological
      process has only recently been appreciated. The condition appears to represent a
      sequential interaction of the oral mucosal cells and tissues, pro-inflammatory
      cytokines, and local environmental factors in the mouth such as microorganisms
      and saliva. The recognition that the pathophysiology of mucositis is a
      multifactorial process has presented opportunities for intervention based on
      biological attenuation. Interleukin-11, a pleotropic cytokine, has a range of
      activities which is potentially relevant to mucositis. Consequently, it has been
      used successfully to modify the development, severity and course of mucositis in
      an animal model which closely mimics the equivalent human condition.

PMID- 10360369
TI  - Guidelines for the characterization and publication of human malignant
      hematopoietic cell lines.
AB  - Continuous human malignant hematopoietic (MH) cell lines have become invaluable
      tools for hematological diagnosis and research. Over the last 35 years several
      hundred cell lines spanning almost the whole spectrum of hematopoietic cell
      lineages have been described. The cardinal features of MH cell lines are their
      monoclonal origin, arrest of differentiation, genetic alterations, and unlimited
      proliferation; the major advantages of cell lines are the unlimited supply of
      cell material and the infinite storability and recoverability at will of the
      cells. Categorization of cell lines usually follows the physiological stages of
      hematopoietic differentiation in the various cell lineages. For an adequate
      classification, a detailed and comparative characterization of both primary and
      cultured cells is absolutely necessary. New cell lines, in particular, must be
      adequately characterized. While clinical and cell culture data and immunological
      and cytogenetic features are the most important data, cell lines should be
      described in as much additional detail as possible allowing any singular features
      to be pointed out. In addition to detailed characterization, immortality of the
      culture, proof of neoplasticity, authentication of the true origin of the cells,
      scientific significance and availability of the cell line for other investigators
      are of paramount importance. In summary, MH cell lines have the potential to
      greatly facilitate diverse studies of normal and malignant hematopoiesis; to that
      end, these cell lines must be extensively characterized and adequately described.

PMID- 10360370
TI  - Multicenter randomized phase II trial of idarubicin vs mitoxantrone, combined
      with VP-16 and cytarabine for induction/consolidation therapy, followed by a
      feasibility study of autologous peripheral blood stem cell transplantation in
      elderly patients with acute myeloid leukemia.
AB  - To compare the antileukemic efficacy of idarubicin and mitoxantrone in elderly
      patients with acute myeloid leukemia (AML) and to evaluate the feasibility of
      autologous transplantation using PBSC after consolidation in those with a good
      performance status, 160 patients (median age 69 years), with AML at diagnosis,
      118 of them with de novo AML and 42 with AML secondary to myelodysplastic
      syndrome or toxic exposure (sAML), received induction treatment with idarubicin,
      8 mg/m2/day or mitoxantrone, 7 mg/m2/day, on days 1, 3, and 5, both combined with
      VP-16, 100 mg/m2/day on days 1 to 3 and cytarabine (araC), 100 mg/m2/day, on days
      1 to 7. G-CSF, 5 microg/kg/day, was administered after chemotherapy in patients
      aged more than 70 years. Patients in complete remission (CR) received one course
      of consolidation using the same schedule as for induction except the araC
      administration was shortened to 5 days. Some patients younger than 70 years were
      then scheduled for autologous stem cell harvest on days 5 to 7 of G-CSF, 5
      microg/kg/day, initiated after hematopoietic recovery from consolidation.
      Autologous transplantation was performed following an additional chemotherapy
      conditioning. Ninety-five patients (59%) achieved CR, without significant
      difference between the idarubicin (56% CR) and mitoxantrone (63% CR) group. There
      was also no significant difference in CR rate between de novo AML (63%) and
      secondary AML (55%) (P = 0.12). Patients aged < 70 years had 67% CR, while
      patients aged > or = 70 years had 49% (P = 0.02). There was no significant
      difference in the duration of aplasia between the two arms. Median time to
      neutrophil recovery was 22 days in patients who received G-CSF following
      induction and 27 days in patients who did not (P = 0.006). Severe
      extrahematologic toxicities of induction did not differ between the two arms and
      included sepsis (39%), diarrhea (13%), hyperbilirubinemia (8%), hemorrhage (6%)
      and vomiting (6%). Overall, 14 patients (9%), died from toxicity of induction.
      First consolidation was administered in 74 patients of whom seven (9%) died from
      toxicity. Nineteen patients have received transplantation. Median time to
      recovery of neutrophils > 0.5 x 10(9)/l was 13 days and of platelets > 50 x
      10(9)/l 43 days following consolidation. There were two toxic deaths. Median
      disease-free survival and survival from time of achieving CR of non transplanted
      patients are 6 and 7 months respectively without difference between the two arms.
      Fourteen transplanted patients relapsed at a median of 5 months post-transplant.
      We conclude that this regimen is well tolerated and has a good efficacy to induce
      CR, without a significant difference in efficacy and toxicity between idarubicin
      and mitoxantrone. Intensive postinduction, including transplantation, is
      feasible; however, this procedure did not seem to prevent early relapse in the
      majority of patients. Neither the high rate of CR nor consolidation nor
      transplant procedure in a selected group of patients did translate into improved
      DFS and/or survival.

PMID- 10360371
TI  - Treatment of newly diagnosed AML, RAEB-t or RAEB with lisofylline or placebo in
      addition to chemotherapy.
AB  - To determine whether the addition of lisofylline (LSF) to idarubicin (12 mg/m2
      daily x 3) + ara-C (1.5 g/m2 daily x 4) affects the rates of infection, serious
      infection, CR or mortality during remission induction of newly diagnosed AML,
      RAEB-t or RAEB, we randomized 70 patients to 3 mg/kg lisofylline or placebo every
      6 h i.v., to begin 6 h before the first dose of idarubicin and to continue until
      recovery of neutrophil and platelet counts or for 28 days, whichever came first.
      Eligibility required that patients be below age 71 years, have no history of
      abnormal counts, or chemotherapy for a prior malignancy, and have a creatinine
      <1.6 mg/dl and bilirubin <3.0 mg/dl. The study was double-blinded and infections
      were tabulated separately and independently at MD Anderson and by a three-member
      outside panel of experts. Logistic regression was used to assess the relative
      effects of treatment arm (LSF or placebo), age, performance status, treatment
      site (laminar air flow room or not), and cytogenetics on rates of infection and
      serious infection following the first course of chemotherapy, and on CR rate.
      There were 84% and 87% concordance between the expert panel and MD Anderson
      enumerations of infection and serious infections, respectively. Both analyses
      found no significant (P < 0.05) differences between the rates of infection, or
      serious infection, in the placebo and LSF groups. CR, 60-day, and overall
      mortality rates were similar in the two groups, as were time to neutrophil and
      blood count recovery and outcome once in CR. Logistic regression analyses
      supported the above conclusions. Severe nausea/vomiting and mucositis were more
      frequent in the LSF group. Our results suggest that larger studies of LSF in
      newly diagnosed AML, RAEB-t, or RAEB are not warranted.

PMID- 10360372
TI  - Therapeutic targeting of Src-kinase Lyn in myeloid leukemic cell growth.
AB  - Protein tyrosine kinases play a major role in promoting cell growth, and their
      activity in solid tumors is well established. Inhibitors of protein tyrosine
      kinases are now in advanced clinical trials for the treatment of breast and brain
      cancers. Because Src-related PTK have been shown to be activated in leukemic cell
      lines, we studied their activation in human myeloid leukemia. Blasts from the
      majority of patients with acute leukemia showed constitutive activity of the Src
      kinase Lyn. In contrast, no patient samples showed constitutive activation of
      Jak2. Genetic and pharmacologic targeting of Lyn was used to determine its
      contribution to leukemic cell growth. Antisense Lyn oligonucleotide treatment
      resulted in the inhibition of tritiated thymidine incorporation following GM-CSF
      stimulation of the factor-dependent line MO7e. The Src kinase inhibitor PD166285
      inhibited the growth of human leukemic cell lines and leukemic blasts. When
      combined with doxorubicin, an additive effect on the inhibition of leukemic cell
      growth occurred. These studies demonstrate the importance of Src kinases in
      promoting leukemic cell growth and suggests that further development of agents
      which target Src kinases and their inclusion in multidrug regimens are warranted
      for novel therapies of myeloid leukemia.

PMID- 10360373
TI  - Atypical response to all-trans retinoic acid in a der(5)t(5;17) acute
      promyelocytic leukemia.
AB  - Typical acute promyelocytic leukemia (APL) is associated with the t(15;17)
      translocation, expression of a PML/RARA fusion transcript, and responsiveness to
      all-trans retinoic acid (ATRA). Rare APL cases implicating the RARA but not the
      PML gene have been reported. Cases with t(11;17)(q23;q21) which fuses the PLZF
      and RARA genes do not respond to ATRA. In contrast, cases with t(11;17)(q13;q21)
      and t(5;17)(q35;q21) which fuse RARA with NuMA and NPM, respectively, were
      reported to be sensitive to ATRA. We described previously an APL case with an
      unbalanced t(5;17) implicating RARA but neither PML nor PLZF. Here, we show that
      in this case: (1) the NPM gene is not involved, as demonstrated by RT-PCR and
      Southern blot; (2) response to ATRA in vitro is atypical, as demonstrated by
      morphological and functional maturation assays; and (3) PML nuclear bodies are
      not disrupted, as evidenced by immunofluorescence staining.

PMID- 10360374
TI  - Deletions and losses in chromosomes 5 or 7 in adult acute lymphocytic leukemia:
      incidence, associations and implications.
AB  - Deletions or losses in chromosomes 5 or 7 are recurrent non-random abnormalities
      in acute myeloid leukemia (AML), and are associated with prior exposure to
      carcinogens or leukemogenic agents, and with poor prognosis. Their occurrence and
      significance in adult acute lymphocytic leukemia (ALL) is not well described. The
      aim of the study was to evaluate the incidence, associations and implications of
      chromosome 5 or 7 abnormalities in adult ALL. Patients with newly diagnosed ALL
      referred to MD Anderson Cancer Center between 1980 and 1996 were analyzed.
      Characteristics and outcome of patients with or without chromosome 5 or 7
      abnormalities were compared by standard statistical methods. Thirty-one of 468
      patients (6.6%) had chromosome 5 or 7 abnormalities. Loss of chromosome 5
      occurred in six cases, three of them had both chromosome 5 and 7 abnormalities.
      Deletion or loss of chromosome 7 occurred as a single abnormality in three
      patients; in 28 patients it was associated with other abnormalities. The most
      significant cytogenetic association was with the Philadelphia chromosome (Ph)
      abnormality occurring in nine patients (29%). Compared with patients without the
      abnormalities, patients with chromosome 5 or 7 abnormalities tended to express
      CD34 more frequently (74% vs 54% P = 0.07), to be older (age >60 years 29% vs 18%
      P = 0.14), and to be associated with Ph (29% vs 11% P = 0.004). With therapy, the
      complete response (CR) rate with chromosome 5 or 7 abnormalities was lower (64%
      vs 79% P = 0.038) but the survival rate was similar (3-year survival rate 32% vs
      36% P = 0.14). When the 22 patients without Ph were considered separately, the CR
      and survival rates were similar among patients with or without chromosome 5 or 7
      abnormalities. Abnormalities in chromosome 5 or 7 are not specific for AML, and
      may occur in ALL. Unlike in AML, chromosome 5 or 7 abnormalities in ALL were not
      predictive of worse prognosis, which is accounted for mostly by the association
      with Ph.

PMID- 10360375
TI  - B cell prolymphocytic leukaemia (B-PLL) with complex karyotype and concurrent
      abnormalities of the p53 and c-MYC gene.
AB  - We report the cytogenetic, molecular and biological characterization of a case of
      B-PLL with a complex karyotype and concurrent abnormalities on the p53 and c-MYC
      genes. Conventional cytogenetics suggested that both 17q arms were translocated
      to chromosomes 1q and 14p, respectively, whereas both 17p arms were not
      identified. In addition, a Burkitt's-like variant translocation t(2;8) was found.
      Study of loss of heterozygosity at 17p13 and p53 direct sequencing demonstrated
      the presence of only one copy of the p53 gene. A 27 bp deletion in exon 8 that
      resulted in the expression of a p53 protein lacking nine amino acids from the DNA
      binding region was also found. To confirm the presence of one copy of the p53
      gene and localize it, fluorescent in situ hybridization (FISH) studies using a
      p53 gene probe was performed. Only one signal of p53 was visualized. Moreover,
      the DAPI profile of the chromosome containing the hybridization spot for the p53
      probe did correspond to the cytogenetic marker identified as der(14)t(14;17).
      Whole chromosome 14 paint, centromere-specific for chromosome 17 and p53 gene
      probes were cohybridized to the preparations. This demonstrated that the der(14)
      contained the 17 centromere and distally the p53 gene suggesting that the der(14)
      contained the short arm of chromosome 17 with the breakpoint occurring in the
      long arm. FISH studies confirmed the involvement of c-MYC and KAPPA in the t(2;8)
      translocation. To our knowledge, this is the first case of B-PLL with
      inactivation of the p53 gene by mutation together with a Burkitt's-like t(2;8)
      translocation involving the c-MYC gene. The cooperation of these genes may have
      conferred a growth advantage which was critical in the development of this
      aggressive form of B-PLL.

PMID- 10360376
TI  - Cancer-specific region of hypermethylation identified within the HIC1 putative
      tumour suppressor gene in acute myeloid leukaemia.
AB  - Abnormal DNA methylation has been found to be a common feature in cancer cells,
      although the mechanism of this alteration remains poorly understood. HIC1 is a
      putative tumour suppressor gene on chromosome 17p13.3 and is hypermethylated in a
      number of cancers including leukaemia. In this study, using bisulphite genomic
      sequencing, we have identified a 'boundary' sequence within the HIC1 CpG island
      that shows a marked junction between methylated and unmethylated DNA in normal
      haematopoietic cells. Surprisingly, this boundary of differential methylation
      lies exactly between the intron 2 and exon 3 junction. In contrast to normal
      haematopoietic cells, hypermethylation extends past this boundary at a high
      frequency (83%) in newly diagnosed acute myeloid leukaemias (AML). Identification
      of the hypermethylated boundary sequence not only provides the first step in
      understanding the mechanisms that normally protect CpG islands from de novo
      methylation but also may prove to be a useful cancer-specific marker.

PMID- 10360377
TI  - p16/MTS1/INK4A gene is frequently inactivated by hypermethylation in childhood
      acute lymphoblastic leukemia with 11q23 translocation.
AB  - The p16 gene encoding a specific inhibitor of cyclin-dependent kinases 4 and 6
      has been reported to be inactivated at a variety of rates in malignant tumors. We
      studied frequency and mechanism of inactivation of the p16 gene in various types
      of childhood acute lymphoblastic leukemia (ALL) using 36 leukemic cell lines
      established from children (B precursor-ALL, 28; B-ALL/Burkitt's lymphoma, 3; and
      T-ALL, 5). On Southern blot, homozygous deletions or hemizygous deletions with
      rearrangement were detected in 14 cell lines. The expression of p16 protein was
      not observed on Western blot in 18 of 22 cell lines with intact p16 gene, but
      induced in 16 cell lines after treatment with the demethylating agent, indicating
      the silencing of the p16 gene by hypermethylation. Of note, the p16 gene was
      inactivated by hypermethylation of the 5' CpG island in nine of nine cell lines
      with 11q23 translocation, but was restored with the treatment of the
      demethylating agent. Partial methylation of the p16 gene was also demonstrated in
      three of eight primary leukemia samples with this translocation, suggesting that
      the p16 gene inactivation by hypermethylation might play a role in the
      leukemogenesis and disease progression of ALL with 11q23 translocation.

PMID- 10360378
TI  - WT1 and GATA1 expression in myelodysplastic syndrome and acute leukemia.
AB  - The Wilms' tumor protein, WT1, represses transcription from several growth factor
      genes. WT1 transcription is regulated in erythroid and myeloid lineages by the
      transcription factor GATA-1. Using a sensitive, isotopic duplex RT-PCR procedure
      amplifying WT1 or GATA-1 together with beta-actin as the internal control in a
      single reaction mix, we quantitated the expression of WT1 and GATA-1 mRNA of 16
      patients with myelodysplastic syndrome (MDS), 56 with acute myeloid leukemia
      (AML) and 22 with acute lymphoblastic leukemia (ALL). K562 was used as reference
      positive control for this cell line expresses both WT1 and GATA-1. Among MDS
      patients, increased WT1 expression was found in refractory anemia with excess
      blast (RAEB) and RAEB in transformation (RAEB-T) subtypes compared to the normal
      controls, whereas WT1 expression in refractory anemia (RA) was not different from
      the normal control level. All of AML cases of subtypes M0, M1, M2 and M3
      expressed WT1 more than three times the normal WT1 level. Subtypes M4 to M7
      showed significantly lower WT1 levels than M1 to M3 and AML cases with CD14+
      expressed less WT1 than CD14-. Higher than normal WT1 levels were also expressed
      in cases of ALL.

PMID- 10360379
TI  - Treatment with temozolomide and poly(ADP-ribose) polymerase inhibitors induces
      early apoptosis and increases base excision repair gene transcripts in leukemic
      cells resistant to triazene compounds.
AB  - Methylating triazenes have shown marked antileukemic effects, possibly through
      generation of a variety of DNA adducts. Cells tolerant to O6-methylguanine due to
      a defect in the mismatch repair system (MRS), might become sensitive to other
      methyl adducts, by inhibiting the N-methylpurine repair, which requires base
      excision repair (BER) and poly(ADP-ribose) polymerase (PADPRP). Therefore, MRS
      deficient Jurkat leukemic cells resistant to methylating triazenes, have been
      treated with temozolomide (TZM) and PADPRP inhibitors. Expression of PADPRP or
      molecules involved in the BER system [3-methylpurine-DNA glycosylase (MPG) and X
      ray repair cross-complementing 1 (XRCC1)], have been explored. Cytotoxic effects
      of TZM associated with PADPRP inhibitors are evident shortly after treatment,
      suggesting that completion of cell division is not required for the lethal effect
      of the drug combination. Increase of PADPRP or MPG transcripts was found after
      treatment with TZM alone or combined with PADPRP inhibitor. XRCC1 transcript was
      positively modulated only in the case of drug combination. This could suggest
      that in the presence of PADPRP inhibitor, persistence of DNA damage triggers
      XRCC1 transcription. Our results suggest that association of TZM and PADPRP
      inhibitors might be of benefit for MRS-deficient malignancies unresponsive to the
      methylating agent.

PMID- 10360380
TI  - Methylation analysis of the human multidrug resistance 1 gene in normal and
      leukemic hematopoietic cells.
AB  - Expression of the human multidrug resistance 1 gene (MDR1), which encodes the P
      glycoprotein transmembrane efflux pump, has been associated with treatment
      failure of some leukemias, primarily acute myeloid leukemia (AML). To elucidate
      the epigenetic events associated with overexpression of MDR1 in AML, we analyzed
      the methylation status of a 2000 bp region within the MDR1 locus using a
      bisulphite genomic sequencing technique. A CpG-rich domain, approximately 1 kb in
      size, encompasses the promoter region, exon I, and intron I. This domain was
      found to be relatively unmethylated in five out of six primary and cultured human
      hematopoietic cells, as well as five out of six AML patient samples, independent
      of the MDR1 phenotype. The data suggest that the methylation status of the CpG
      rich domain does not act as a 'switch' to regulate expression of the MDR1 gene.
      In addition, we found an upstream Alu repeat sequence to be unmethylated in three
      out of five cultured hematopoietic cell lines, both MDR1 expressing and non
      expressing. However, analysis of primary CD8-positive T cells and AML patient
      samples revealed dense methylation of this region which is consistent with
      methylation of Alu repeat sequences observed in somatic tissues.

PMID- 10360381
TI  - Potentiation of antitumor effects of cyclophosphamide derivatives in B-chronic
      lymphocytic leukemia cells by 2-chloro-2'-deoxyadenosine.
AB  - Because 2-chloro-2'-deoxyadenosine (CdA) is active in B-chronic lymphocytic
      leukemia (B-CLL), and may interfere with DNA repair, we investigated the
      potentiating effect of CdA on the cytotoxicity induced in vitro in B-CLL
      lymphocytes by cyclophosphamide (CP) derivatives, which induce DNA damage by DNA
      cross-linking. Exposure to CdA at clinically achievable concentrations for 2 h,
      followed by mafosfamide (MAF) or 4-hydroxycyclophosphamide (4HC) for 22 h,
      resulted in synergistic cytotoxicity in the majority of B-CLL samples tested.
      Synergy between CdA and MAF was observed in cell samples of sensitive/untreated
      patients, as well as in cells of resistant/pretreated patients, particularly at
      the highest concentrations of MAF. In the cells treated with CdA and MAF, we
      observed loss in ATP and hallmarks of apoptosis, as evidenced by cellular
      morphology and high molecular weight DNA fragmentation. The synergy could be
      explained neither by an influence of MAF on the phosphorylation of CdA, nor by an
      increase in the incorporation of CdA into DNA in the presence of MAF. The in
      vitro synergy between CdA and CP derivatives provides a rationale for the use of
      this association in B-CLL patients.

PMID- 10360382
TI  - Aberrant hematopoiesis in mice with inactivation of the gene encoding SOCS-1.
AB  - Mice with homozygous inactivation of the gene encoding the suppressor of cytokine
      signaling-1 (SOCS-1) protein die within 21 days of birth with low body weight,
      fatty degeneration and necrosis of the liver, infiltration of the lung, pancreas,
      heart and skin by macrophages and granulocytes and a profound depletion of T- and
      B-lymphocytes. In the present study, SOCS-1 -/- mice were found to have a
      moderate neutrophilia, and reduced platelet and hematocrit levels. Replacement of
      the SOCS-1 gene by a lac-Z reporter gene allowed documentation by FACS sorting
      that at least a proportion of granulocyte-macrophage progenitor cells transcribe
      SOCS-1. Most hematopoietic progenitor cell frequencies were normal in -/- marrow
      as were the size and cellular content of colonies formed by -/- progenitor cells
      in response to various stimulating factors. However, there was an increased
      frequency of macrophage progenitor cells in -/- mice and, abnormally, one quarter
      of all progenitor cells were located in the liver. Progenitor cells from -/- mice
      were hyper-responsive to stimulation by GM-CSF but not by M-CSF or Multi-CSF (IL
      3). Progenitor cells from -/- mice were also hypersensitive to inhibition by
      interferon-gamma (IFN-gamma), the degree of inhibition varying markedly with the
      stimulating factor used. The suppressive effects of IFN-gamma therefore appear to
      involve interactions with particular growth factor-initiated signals in -/- cells
      -interactions that are strongly modulated by the action of the SOCS-1 protein.

PMID- 10360383
TI  - Megakaryocytic differentiation of human progenitor cells is negatively influenced
      by direct contact with stroma.
AB  - The recently defined ligand for the Mpl receptor, thrombopoietin (TPO), has been
      found to be the principal regulatory cytokine of megakaryocytopoiesis.
      Furthermore, it has been hypothesized that direct interaction between stroma or
      stroma-derived extracellular matrix (ECM) and human progenitor cells (HPC) may
      modulate megakaryocytopoiesis. For that purpose, we studied megakaryocytic
      development of HPC, obtained from patients with hematological malignancies in
      complete remission or solid tumors without bone marrow involvement, under the
      influence of megakaryocyte growth and development factor (MGDF, a pegylated,
      truncated molecule related to the endogenous Mpl ligand). The megakaryocytic
      development of HPC cultured in contact with a stromal layer (contact cultures)
      was compared with cultures in which HPC were grown separated from a stromal layer
      by a microporous membrane (non-contact cultures). A significantly lower number of
      megakaryocytes (CD41- and CD61-positive cells) was obtained from contact cultures
      compared to non-contact cultures. Furthermore, the expression of CD42b was higher
      in non-contact cultures, as compared to contact cultures, indicating an increase
      in megakaryocyte maturation in non-contact cultures. In contrast, no difference
      in clonogenic capacity was observed (CFU-GM, BFU-E, CFU-Mk). The possibility that
      direct contact between HPC and stroma induces the production of a soluble
      inhibitory cytokine as an explanation for the diminished megakaryocytic
      development in contact cultures, was excluded by performing transwell experiments
      in which HPC were cultured in direct contact and in a transwell simultaneously.
      The percentage of megakaryocytes raised from HPC present in the transwell did not
      decrease, irrespective of the presence of HPC simultaneous below the transwell in
      direct contact with stroma. It is concluded that both megakaryocytic development
      out of HPC and megakaryocytic differentiation is reduced in contact cultures, as
      compared to non-contact cultures. This is due to modulation by adhesive
      interactions with stroma, stroma-derived ECM or cytokines bound to the membrane
      of stromal cells, rather than resulting from the production of diffusible
      cytokines by stromal cells.

PMID- 10360384
TI  - Analysis of CD34 populations in mobilised peripheral blood stem cell harvests and
      in bone marrow by fluorescent in situ hybridisation for the bcr/abl gene fusion
      in patients with chronic granulocytic leukaemia.
AB  - For those patients ineligible for allogeneic bone marrow transplant and who are
      non-responsive to interferon, autotransplant with peripheral blood stem cells
      (PBSC) mobilised after intensive chemotherapy, may provide a novel approach to
      improve prognosis in patients with chronic granulocytic leukaemia. PBSC harvests
      are assessed for CD34-positive cell numbers, which serve as an indicator of
      engraftment potential, and are also analysed cytogenetically to ascertain tumour
      cell contamination. However, a more accurate assessment of PBSC harvest
      contamination requires investigation of the Philadelphia (Ph) status of the
      CD34pos population, in which the cells that provide long-term engraftment are
      contained. In this study, we have analysed these levels in mobilised PBSC and
      also in bone marrow (BM) harvests, taken several weeks prior to mobilising
      chemotherapy. Using fluorescent in situ hybridisation for the bcr/abl gene
      fusion, we have shown that the median number of Ph negative cells in CD34pos
      isolated populations was 14.95% in BM compared to 79.05% in PBSC harvests and
      that in all PBSC samples tested, Ph positivity in CD34pos populations was always
      detectable either by FISH or one round PCR methods. In paired assessments of both
      PBSC and BM harvests, higher levels of Ph negative CD34pos cells (> or = 14%)
      isolated from BM harvests, taken prior to intensive chemotherapy, correlated with
      higher levels of Ph negative CD34pos cells (> or = 78.5%) in PBSC harvests. These
      data may aid in the selection of patients for whom PBSC harvesting, after
      mobilisation, is more likely to achieve an autograft product containing
      predominantly Ph negative CD34pos cells and may exclude those patients for whom
      the risk, morbidity and expense of stem cell harvesting may have no apparent
      benefit over a chronic phase BM harvest.

PMID- 10360385
TI  - Intensive sequential chemotherapy (ISC 95) with growth factors and blood stem
      cell support in high-intermediate and high-risk (IPI 2 and IPI 3) aggressive non
      Hodgkin's lymphoma: an oligocentric report on 42 patients.
AB  - We previously reported feasibility and efficacy of a monocentric pilot study of
      intensive sequential chemotherapy (ISC) in poor-risk aggressive non-Hodgkin's
      lymphoma (NHL) in patients < 60 years. To validate these results on a large
      cohort of patients, we designed a new and oligocentric study. After a COP
      (cyclophosphamide (Cy), vincristine (Vcr), prednisone (Pred) debulking, patients
      received four courses of high-dose CHOP (Cy, doxorubicin (Doxo), Ver, Pred), with
      the addition of etoposide and cisplatin during the two last courses. G-CSF was
      delivered after each cycle, and peripheral blood stem cells (PBSC) were used to
      support the two last cycles. Total duration of chemotherapy was 13 weeks, with a
      planned dose-intensity (DI) of 1420 mg/m2/week and 23 mg/m2/week for Cy and Doxo,
      respectively. Radiotherapy (involved fields) was then delivered for patients with
      node size > or = 5 cm at diagnosis. Forty-two patients were enrolled in this
      study; 36 completed the treatment and received 75% or more of the planned DI for
      both Cy and Doxo. Median duration of grade 4 neutropenia was 14 days (range, 2 to
      28) for the regimen as a whole, and median duration of rehospitalization for
      febrile neutropenia was 18 days (range, 4 to 41). Overall response rate was 83%,
      with 29 patients (69%) in complete response (CR). Six patients failed to respond
      and one died of toxicity. With a median follow-up of 22.5 months (range, 10 to
      42), the 3-year event-free survival (EFS) is 55% (95% CI, 39-71), while disease
      free survival (DFS) is 79% (95% CI, 63-95). Ambulatory ISC is accessible and
      feasible in an oligocentric study. PBSC allow repeated delivery of high-dose
      chemotherapy cycles, and result in encouraging CR, EFS, and DFS rates for poor
      risk aggressive NHL's patients.

PMID- 10360386
TI  - Detection of BCR-ABL transcripts in chronic myeloid leukemia (CML) using a 'real
      time' quantitative RT-PCR assay.
AB  - Quantitative competitive RT-PCR techniques have been developed to detect BCR-ABL
      fusion transcripts in CML but they are hardly reproducible. In this work, we have
      developed BCR-ABL quantification by real time RT-PCR using the ABI PRISM 7700
      (Perkin Elmer), a new technique which allows simple and rapid quantification of a
      target sequence during the extension phase of PCR amplifications. A fluorogenic
      probe labeled with both a reporter dye at the 5' end and a quencher-dye at the 3'
      end hybridizes to the target sequence on the third exon of the ABL gene. The
      exonuclease activity of the Taq DNA polymerase cleaves the probe and releases the
      reporter dye, resulting in an increase in the fluorescence signal. The absolute
      copy number of the target sequence (BCR-ABL) or a control gene (ABL) in an
      unknown sample can then be calculated using a calibration curve prepared from a
      set of BCR-ABL RNA standards, and results are expressed as a BCR-ABL/ABL ratio.
      In our hands, the sensitivity of a serial dilution of total RNA from a positive
      cell line (K562) in a negative cell line (HL60) was 10(-4). Fifteen CML patients
      in cytogenetic CR, including 11 allografted patients, two autografted patients
      and two patients treated by IFN were studied sequentially by this new real time
      quantitative RT-PCR technique in parallel with conventional qualitative two round
      nested RT-PCR. The two autografted patients showed high BCR-ABL/ABL ratio in all
      samples. The two patients treated by IFN showed a progressive decrease in the
      ratio. In the 11 allografted patients, four were sequentially studied 2 years or
      more after allo-BMT, and all ratios were below 10(-4). The four patients remained
      in clinical and cytogenetic CR. The seven other allografted patients were studied
      immediately after the procedure. Three of them showed a progressive decrease in
      the BCR-ABL/ABL ratio which reached 10(-4) 7 months after allo-BMT. The three
      patients remained in hematologic and cytogenetic CR. The remaining four
      allografted patients had progressive increase of BCR-ABL ratio; three developed
      cytogenetic relapse 9, 11, 28 months after allo-BMT, and the last patient
      remained in cytogenetic CR in the bone marrow but developed granulocytic sarcoma.
      Results of real-time quantitative RT-PCR were in agreement with those of
      qualitative two round nested PCR. However, evolution changes in the results of
      real-time quantitative RT-PCR often preceded those of the conventional technique:
      a decrease of the BCR-ABL/ABL ratio preceded progression from first round to
      second round positivity and then negativity with the classical technique;
      conversely, an increase in the ratio preceded evolution with the classical
      technique. Thus, real-time quantitative RT-PCR may show better correlation with
      clinical and cytogenetic evolution than conventional qualitative techniques and
      may help in making early therapeutic decisions in CML, especially after molecular
      relapse.

PMID- 10360387
TI  - Detection of T cell receptor beta (TCRB) gene rearrangement patterns in T cell
      malignancies by Southern blot analysis.
AB  - Reliable detection of clonal T cell receptor beta (TCRB) gene rearrangements is
      essential for clonality assessment of suspect T cell proliferations. Since no
      appropriate Southern blot probes were available, we developed a new set of
      optimized TCRB gene probes. The TCRBJ1 and TCRBJ2 probes are positioned just
      downstream of the Jbeta1 and Jbeta2 gene segments, respectively, and can be used
      for detection of both incomplete Dbeta-Jbeta and complete Vbeta-Jbeta
      rearrangements, whereas the TCRBD1U and TCRBD2U probes upstream of the Dbeta
      segments can be used to confirm incomplete Dbeta-Jbeta rearrangements. Less
      frequently occurring Vbeta-Dbeta rearrangements can easily be detected via the
      downstream TCRBD1 and TCRBD2 probes. Although both EcoRI and HindIII are
      appropriate restriction enzymes to be used in combination with all these probes,
      false-positivity due to partial digestion of the EcoRI site in the Jbeta2-Cbeta
      intron has to be excluded via the TCRBC probe. Application of the TCRB probes in
      a large series of nearly 200 T cell malignancies revealed clonal rearrangements
      in all immature and mature TCR alphabeta+ T cell malignancies, in the vast
      majority of TCR gammadelta+ T cell acute lymphoblastic leukemias (T-ALL)
      (approximately 95%) and even in most CD3- T-ALL (approximately 80%). TCRB gene
      rearrangement patterns differed between the various categories of T cell
      malignancies. An increased frequency of complete Vbeta-Jbeta1 rearrangements was
      observed in TCR alphabeta+ T-ALL as compared to CD3- and TCR gammadelta+ T-ALL
      (33% vs 16% and 11%, respectively), and also incompletely rearranged V-D, D-D, or
      D-J alleles in the beta2 region occurred more frequently in TCR alphabeta+ cases
      than in CD3- and TCR gammadelta+ T-ALL (27% vs 15% and 18%, respectively).
      Furthermore, in comparison to TCR alphabeta+ T-ALL, less Vbeta-Jbeta1 and more
      Vbeta-Jbeta2 rearrangements were detected in mature TCR alphabeta+ T cell
      malignancies. The occurrence of the different types of TCRB rearrangement
      patterns has implications for PCR-based clonality assessment and for PCR-based
      detection of minimal residual disease via TCRB gene analysis. For instance,
      focussing on the beta2 region of T-ALL will allow detection of rearrangements in
      70%, 75%, and 90% of CD3-, TCR gammadelta+, and TCR alphabeta+ cases,
      respectively. Therefore the here-described results will facilitate the design of
      the most appropriate primer sets for PCR analysis of TCRB gene rearrangements at
      the DNA level.

PMID- 10360388
TI  - Molecular characterization of a complex chromosomal translocation breakpoint
      t(10;14) including the HOX11 oncogene locus.
AB  - Based on cytogenetic studies, non-random chromosomal translocations which involve
      the HOX11 gene at locus 10q24 and the TCR genes at loci 7q35 or 14q11 have been
      reported to occur in 5% of T-ALL. HOX11, a member of the homeobox family of
      genes, has been shown to play a role in T-ALL. The activation of the HOX11 gene
      by translocations to the TCR locus results in the inappropriate expression of a
      2.3 kb transcript. In this paper we describe a t(10;14)(q24;q11) breakpoint from
      a T-ALL patient specimen. The breakpoint appears to be mediated by errors in the
      TCR/V(D)J recombination system, but is more complex than commonly described
      reciprocal translocations between the HOX11 and TCR genes, since it involves an
      inversion event of the TCRdelta genes. In addition, the breakpoint was
      characterised to a previously unsequenced area of the 10q24 locus, 3.4 kb
      upstream of the HOX11 gene. This breakpoint is more centromeric than the
      breakpoint cluster region previously shown to be involved in the majority of
      reported t(10;14)(q24;q11) translocations. Hence, our investigations of the
      translocation breakpoint in this patient identify another breakpoint region in
      the 10q24 locus and may define a novel recombination 'hot spot'. Surprisingly,
      our studies provide a mechanism for a previously unexplained complex
      translocation described by another group which involves the same region of the
      HOX11 promoter.

PMID- 10360389
TI  - Low-dose cytarabine (LD-AraC) plus recombinant human granulocyte colony
      stimulating factor (rhG-CSF) for myelodysplastic syndromes (MDS)

PMID- 10360390
TI  - Are we ready to curtail testing for TEL/AML1 fusion? Pediatric Hematology Working
      Group in the Czech Republic.

PMID- 10360391
TI  - Proteus syndrome: diagnostic criteria, differential diagnosis, and patient
      evaluation.
AB  - Proteus syndrome is a complex disorder comprising malformations and overgrowth of
      multiple tissues. The disorder is highly variable and appears to affect patients
      in a mosaic manner. This intrinsic variability has led to diagnostic confusion
      associated with a dearth of longitudinal data on the natural history of Proteus
      syndrome. To clarify some of these issues, a workshop on Proteus syndrome was
      held in March 1998 at the National Institutes of Health, and participants
      developed recommendations for diagnostic criteria, differential diagnosis, and
      guidelines for the evaluation of patients. This is a review of those
      recommendations.

PMID- 10360392
TI  - Achondroplasia-hypochondroplasia complex in a newborn infant.
AB  - We describe the case of an 8-month-old girl with achondroplasia-hypochondroplasia
      complex. The diagnosis was suggested antenatally when obstetrical ultrasonography
      at 27 weeks of gestation showed short limbs, small chest, and macrocephaly. The
      father has achondroplasia due to the common G1138A (G380R) mutation in the
      fibroblast growth factor receptor 3 (FGFR3) gene, while the mother has
      hypochondroplasia due to the C1620G (N450K) mutation in the FGFR3 gene. Neither
      had had genetic counseling or molecular testing prior to the pregnancy. Antenatal
      ultrasound study at 29 weeks of gestation showed a large head, very short limbs,
      and a small chest; the findings were more severe than in achondroplasia or
      hypochondroplasia alone. The patient was born by cesarean section at 37 weeks of
      gestation and had rhizomelic shortness of limbs with excess skin creases, large
      head, and small chest, diagnostic of achondroplasia. Radiographs showed shortness
      of the long bones and flaring of the metaphyses. She had mild hypoplasia of
      lungs. Molecular testing showed both the G1138A and the C1620G mutations in
      FGFR3, confirming the diagnosis of achondroplasia-hypochondroplasia complex. At 8
      months, she has disproportionate shortness of the long bones and a large head
      with frontal bossing and a depressed nasal bridge. Her chest remains small, and
      she is on home oxygen at times of respiratory stress. She has a large gibbus. She
      is delayed in her motor development and has significant head lag. To our
      knowledge, there is only one previously published report of achondroplasia
      hypochondroplasia complex.

PMID- 10360393
TI  - Compound heterozygosity for the Achondroplasia-hypochondroplasia FGFR3 mutations:
      prenatal diagnosis and postnatal outcome.
AB  - We report on a male newborn infant, a compound carrier of heterozygous mutations
      in the FGFR3 gene causing achondroplasia and hypochondroplasia. The mother has
      achondroplasia and carries the common G1138 (G380R) mutation in the FGFR3 gene;
      the father has hypochondroplasia due to the C1620A (N540K) mutation in the same
      gene. The fetus was found to carry both mutations diagnosed prenatally by
      amniocentesis at 17.6 weeks of gestation, following maternal serum screening
      which showed an increased risk for Down syndrome (1:337). Detailed fetal
      ultrasound studies showed a large head, short limbs, and a small chest at 22
      weeks of gestation. The changes were more severe than those of either
      achondroplasia or hypochondroplasia. The patient was born by cesarean section at
      38 weeks of gestation and had rhizomelic shortness of the upper and lower limbs
      with excess skin folds, large head, enlarged fontanelles, frontal bossing, lumbar
      gibbus, trident position of the fingers, and a narrow chest with a horizontal
      line of demarcation at the narrowest area of the chest. Skeletal radiographs
      showed shortness of the long bones and flare of metaphyses. He had respiratory
      difficulties and was treated with nasal prongs. Seizures developed on day 2 of
      life and recurred on day 9 and responded to treatment with phenobarbital. Brain
      computed tomographic scan showed possible grey matter heterotopia, partial
      agenesis of the corpus callosum, and cortical dysplasia. To our knowledge, there
      are only two previously published cases of compound heterozygous achondroplasia
      hypochondroplasia patients. The diagnosis was confirmed by DNA mutation analysis
      of the FGFR3 gene in both cases.

PMID- 10360394
TI  - Presenility of granulocytes in Down syndrome individuals.
AB  - Neutrophil function defects occur in individuals with Down syndrome (DS). We
      examined apoptosis of granulocytes (neutrophils and eosinophils) in DS
      individuals and control healthy subjects. Granulocyte survival was shortened in
      DS individuals, and the percentage of apoptotic granulocytes from DS during
      incubation was significantly higher than that from healthy subjects. The
      difference was time-dependent, and that between DS and healthy subjects was
      nearly 30% after longer periods of incubation. In control granulocytes, both
      granulocyte-macrophage colony-stimulating factor (10 ng/ml) and interleukin-5 (5
      ng/ml) counteracted the programmed cell death and delayed the apoptosis caused by
      anti-Fas antibodies, whereas those inflammatory cytokines were not able to
      completely prevent cellular apoptosis in DS patients. Apoptosis and functional
      impairment of granulocytes may contribute to the risk of infections underlying
      pathological conditions of DS, and accelerated apoptosis of granulocytes may be a
      factor to prevent chronic airway inflammation and bronchial asthma in DS
      individuals.

PMID- 10360395
TI  - Descriptive analysis of tibial pseudarthrosis in patients with neurofibromatosis
      1.
AB  - Five percent of individuals with neurofibromatosis type 1 (NF1) present with
      congenital long bone pseudarthrosis (PA). In large series, 50-80% of patients
      with congenital long bone PA also have NF1. Very little information exists on the
      natural history and pathogenesis of PA in NF1. This report is a descriptive
      analysis of a large series of patients with NF1 and tibial bowing or PA. Study A
      is a case-control study using the National Neurofibromatosis Foundation
      International Database (NNFFID). Eighty-five patients with PA were compared to a
      control group from the same database. There was a statistically significant male
      predominance of NF1 cases with PA (54 males to 31 females), compared to controls
      (85 males to 87 females) (chi2 = 4.0, P = 0.046, using a two-tailed test with
      Yates' correction). There was no significant difference in the clinical
      presentation of NF1 manifestations in NF1 patients with PA than in NF1 patients
      without PA. Of the affected individuals with PA, there were 24 de novo cases and
      21 familial cases (9 through maternal and 12 through paternal inheritance).
      Questions that could not be answered by Study A were addressed by a partially
      overlapping case-series report, Study B, in which data on 75 cases ascertained
      through questionnaires completed by NF center directors were collected. From
      Study B we determined that half of the patients who had a fracture sustained it
      before age 2, and approximately 16% of the pseudarthrosis patients had an
      amputation. Our data indicate a male predominance and no parent-of-origin effect.
      Male gender may be a susceptibility factor for pseudarthrosis in NF1.

PMID- 10360396
TI  - Fabry disease: comparison of enzymatic, linkage, and mutation analysis for
      carrier detection in a family with a novel mutation (30delG).
AB  - Fabry disease (FD) is an X-linked recessive disorder caused by the deficient
      activity of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). Affected
      males are reliably diagnosed by demonstration of deficient alpha-Gal A activity
      in plasma or leukocytes. However, identification of female carriers is
      problematic due to Lyonization, requiring mutation identification and/or linkage
      studies for accurate carrier detection. Here, we describe a large Brazilian
      kindred with Fabry disease that permitted comparison of biochemical and molecular
      diagnostic techniques. Initially, the plasma alpha-Gal A activities were
      determined in at-risk affected males and potential female carriers; affected
      males were readily diagnosed, while the females had variable results. To detect
      carrier females, haplotype analysis using 10 polymorphic markers adjacent to the
      gene was performed. Subsequently, solid-phase direct sequencing of the alpha-Gal
      A gene demonstrated a novel single base deletion in exon 1 (30delG).
      Discrepancies were observed between the enzymatic and molecular diagnoses in two
      at-risk females. These findings emphasize the need for precise heterozygote
      diagnosis by mutation and/or haplotype analyses in all families with Fabry
      disease.

PMID- 10360397
TI  - Notochordal remnants in human iniencephaly suggest disturbed dorsoventral axis
      signaling.
AB  - Iniencephaly is a central nervous system malformation in which brain and spinal
      cord are not normally separated at the level of the foramen magnum. The occipital
      region is fastened to the back of the body at different levels. The purpose of
      this study of a 16-week human fetus with iniencephaly and holoprosencephaly was
      to examine the body axis for notochordal remnants in order to determine if an
      abnormality of dorsoventral axis signaling may be responsible for the development
      of the iniencephaly abnormality. This aspect of iniencephaly has not been
      described previously. Radiographic and histochemical investigations were
      performed. The fetus described here appeared to exhibit an abnormal notochordal
      course in the upper lumbar, thoracic, and cervical regions. This finding leads us
      to the hypothesis that iniencephaly might arise because of deviant gene
      expression in the embryonic period affecting the dorsoventral orientation of the
      body axis, anatomically indicated by the notochordal malpositions.

PMID- 10360398
TI  - An efficient, robust and unified method for mapping complex traits (III):
      combined linkage/linkage-disequilibrium analysis.
AB  - Extending the method for linkage analysis [Zhao et al., 1998a: Am. J. Med. Genet.
      77:366-383; 1998b: Am. J. Med. Genet. 79:49-61], this article describes a method
      for the linkage-disequilibrium analysis, and for combining linkage and linkage
      disequilibrium analyses. As highly dense markers are increasingly used in genome
      scans, one or more markers are not only linked with the disease genes if they
      exist, but also likely in linkage-disequilibrium with those putative genes.
      Hence, linkage-disequilibrium analysis potentially offers additional information
      about positions of putative disease genes. Combining both linkage and linkage
      disequilibrium signals, this approach is able to improve positional signals. As
      before, the proposed method is a model-based approach, but semiparametric via the
      estimating equation technique. Under the assumptions of penetrance and allele
      frequency, this method efficiently estimates recombination fractions for linkage
      analysis and odds ratios for linkage-disequilibrium analysis. As described in two
      previous papers, this method is relatively more robust than the lod score
      methods, since it requires weaker assumption than conditional independence. While
      the estimated recombination fractions are used for inference as part of linkage
      analysis, the estimated odds ratios are used for linkage-disequilibrium inference
      and combined linkage, and linkage-disequilibrium parameters can be used to test
      combined linkage/linkage-disequilibrium analysis. This approach has been
      implemented, named gSCAN, and its compiled version is available for trial on
      request via the web site (http:/lynx.fhcrc.org/qge). We applied this new approach
      to affected sib-pair data collected for the genome scan to localize type 1
      diabetes genes. Under an assumed autosomal dominant gene model, the linkage
      analysis confirms an earlier suggestion of one major gene around D6S281.
      Interestingly, the linkage-disequilibrium analysis suggests several additional
      signals around D6S250, GATA30, D6S311, D6S441, D6S442, D6S415, D6S411, D6S305,
      and a290xh9. The linkage analysis, on the other hand, suggests a signal around
      D6S281, while providing supporting evidence for several other marker loci.
      However, the combined analysis did not provide strong support for any of the
      findings, implying that linkage and linkage-disequilibrium findings are not
      consistent.

PMID- 10360400
TI  - Microdeletion of chromosome sub-band 2q37.3 in two patients with abnormal situs
      viscerum.
AB  - We report on two cases of microdeletion of chromosome sub-band 2q37.3 with
      abnormal situs viscerum. The first patient had dextrocardia, duodenal and jejunal
      atresia, and an abdominal hernia. The liver was in the left upper quadrant,
      stomach in the right upper quadrant. In contrast anema the ascending colon was in
      the left, and descending colon on the right, with an area of atresia in the mid
      jejunum. The second patient had malrotation and malposition of large and small
      bowel, with most of the bowels positioned above the liver and spleen. There was
      incomplete rotation of the cecum. The right kidney was malrotated and mal
      positioned. The finding of 2q37.3 deletion in both patients implies that a locus
      or loci involved in the development of normal body situs lies within this
      chromosome region. Molecular cytogenetic evaluation for a possible 2q37.3
      deletion should be considered in patients with abnormal situs viscerum.

PMID- 10360399
TI  - Genetic homogeneity, high-resolution mapping, and mutation analysis of the
      urofacial (Ochoa) syndrome and exclusion of the glutamate oxaloacetate
      transaminase gene (GOT1) in the critical region as the disease gene.
AB  - The urofacial (Ochoa) syndrome (UFS) is a rare autosomal recessive disorder
      characterized by abnormal facial expression and urinary abnormalities.
      Previously, we mapped the gene to a genomic interval of approximately 1 cM on
      chromosome region 10q23-24, using families from Columbia. Here we demonstrate
      genetic homogeneity of the syndrome through homozygosity mapping in American
      patients with Irish heritage. We established a physical map and identified novel
      polymorphic markers in the UFS critical region. Haplotype analysis using the new
      markers mapped the UFS gene within one YAC clone of 1,410 kb. We also determined
      the precise location of the gene encoding for glutamate oxaloacetate transaminase
      (GOT1) within the new UFS critical region and determined its genomic structure.
      However, mutation analysis excluded GOT1 as a candidate for the UFS gene.

PMID- 10360401
TI  - Skeletal malformations in fetuses with Meckel syndrome.
AB  - In six fetuses with Meckel syndrome (gestational age 16-23 weeks, crown-rump
      length 130-170 mm) the skeleton was examined as part of the autopsy procedure
      using whole body radiography and special radiographic techniques. In the upper
      and lower limbs we found similar types of polydactyly. We noted four types, based
      on the number and morphology of metacarpals and metatarsals. In the individual
      fetus there was more often similarity in the pattern of malformation in the two
      hands or in the two feet than there was between the pattern of malformation seen
      in the hands and that seen in the feet. Only one foot was normal. Malformations
      of the cranial base (the basilar part of the occipital bone or the postsphenoid
      bone) occurred in five cases, and the vertebral bodies in the lumbar region of
      the spine were malformed (cleft) in three cases. It is proposed that a skeletal
      analysis be included in the future evaluation of phenotypes in Meckel syndrome.

PMID- 10360402
TI  - Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3
      mutations.
AB  - The platyspondylic lethal skeletal dysplasias (PLSDs) are a heterogeneous group
      of short-limb dwarfing conditions. The most common form of PLSD is thanatophoric
      dysplasia (TD), which has been divided into two types (TD1 and TD2). Three other
      types of PLSD, or TD variants (San Diego, Torrance, and Luton), have been
      distinguished from TD. The most notable difference between TD and the variants is
      the presence of large rough endoplasmic reticulum (rER) inclusion bodies within
      chondrocytes of the variants. We examined 22 cases of TD variants for the
      presence of missense mutations in the fibroblast growth factor receptor 3 (FGFR3)
      gene. All 17 cases of the San Diego type (PLSD-SD) were heterozygous for the same
      FGFR3 mutations found in TD1. No mutations were identified in the Torrance and
      Luton types. Large inclusion bodies were found in all 14 cases of PLSD-SD.
      Similar inclusion bodies were present in two of 72 TD1 cases, but not in 39
      controls. The material retained within the rER stained only with antibody to the
      FGFR3 protein. The radiographic and morphologic differences between TD and PLSD
      SD may be a consequence of other genetic factors, perhaps in the processing of
      mutant FGFR3 molecules within the rER. The presence of rER inclusion bodies
      cannot reliably discriminate between closely related skeletal dysplasias.

PMID- 10360403
TI  - Carbohydrate-deficient glycoprotein syndrome due to phosphomannomutase
      deficiency: the first reported cases from Latin America.

PMID- 10360404
TI  - Glucocerebrosidase mutations among Chinese neuronopathic and non-neuronopathic
      Gaucher disease patients.

PMID- 10360405
TI  - Hemispheric asymmetry in depression and mania. A longitudinal QEEG study in
      bipolar disorder.
AB  - BACKGROUND: previous research has been inconclusive about the nature of
      hemispheric asymmetry in emotional processing. METHOD: 13 patients with DSM-IV
      bipolar disorder received repeated QEEGs over 2 years in different mood states. Z
      score measures of asymmetry were assessed. RESULTS: asymmetry in frontotemporal
      slow-wave activity appeared to be in opposite directions in depression compared
      to mania/hypomania. CONCLUSIONS: mood change in bipolar disorder is associated
      with change in QEEG asymmetry. LIMITATIONS: study of larger numbers of more
      homogenous patients under similar conditions is needed. CLINICAL RELEVANCE: study
      of mood state-dependent asymmetry changes in bipolar disorder may lead to better
      understanding of hemispheric processing of emotion.

PMID- 10360406
TI  - Exogenous corticosteroid exposures are associated with increased recollection of
      traumatic life events.
AB  - BACKGROUND: Exogenous corticosteroid exposures are associated with depression in
      clinical samples, however, the mechanisms underlying this association are
      unknown. Recent animal studies have shown that corticosteroids enhance
      conditioning in stressful learning paradigms. It has been hypothesized that
      corticosteroids may enhance the recollection of stressful experiences in humans,
      potentially contributing to the etiology of corticosteroid induced depression.
      This hypothesis has not been evaluated in human subjects. METHODS: The first
      phase of the Canadian National Population Health Survey collected data from a
      probability sample of 17626 members of the general Canadian population over the
      age of 12. The data set included measures of drug exposure (including
      corticosteroid exposures) and childhood and adult psychosocial stressors,
      including traumatic life events. In this study, self-reported traumatic life
      events were cross-tabulated against corticosteroid exposures in order to evaluate
      whether these variables were associated. RESULTS: 52% of subjects treated with
      corticosteroids in the month prior to the interview, as compared to 41% of non
      exposed subjects reported one or more of the following stressors: parental
      divorce, long term parental unemployment, a "frightening" event that was "thought
      about for years after", being sent away from home for doing something wrong,
      parental drug or alcohol abuse, or physical abuse. This difference was
      statistically significant at the 5% level of confidence. LIMITATIONS: The use of
      cross-sectional survey data in this study precluded confirmation that changes in
      the pattern of trauma recollection followed exposure to corticosteroids. Also,
      the study relied on unconfirmed self reported medication exposure data, and
      ratings from brief survey instruments concerned with life events, stress levels
      and traumatic experiences. CONCLUSIONS: What we report is consistent with, but
      not confirmatory of, the hypothesis that increased recollection of stressful
      events may be a mechanism underlying associations between corticosteroids and
      depression. Additional research is needed in order to determine whether the basis
      for this association is an altered recollection of life events, or in a differing
      pattern of life experiences.

PMID- 10360407
TI  - Neurological correlates of depressive symptoms in Alzheimer's disease and
      vascular dementia.
AB  - BACKGROUND: Organic brain disease such as dementia or stroke is associated with
      depression. In dementia, depressive symptoms are common where there is evidence
      of vascular disease and in Alzheimer's disease they often coexist with
      extrapyramidal signs. METHOD: In a study of 60 patients with Alzheimer's disease
      and 39 patients with vascular dementia, depressive symptoms were rated using the
      Cornell Scale for Depression in Dementia. Neurological signs were assessed and
      severity of cognitive impairment was measured with the Mini-Mental State
      Examination. RESULTS: Depressive symptoms were more severe in vascular dementia.
      Pyramidal tract signs had no relationship to depression in either type of
      dementia. In vascular dementia, extrapyramidal and grasp reflexes were strongly
      related to the severity of depression, and were associated with neurovegetative
      features. In Alzheimer's disease, extrapyramidal signs were the strongest
      independent predictor of the severity of depression. CONCLUSION: Depressive
      symptoms are more severe in vascular dementia compared to Alzheimer's disease and
      were related to neurological abnormalities.

PMID- 10360408
TI  - The Edinburgh Postnatal Depression Scale: validation for an Italian sample.
AB  - A sample of 113 women has been recruited for the Italian validation of Edinburgh
      Post Natal Depression Scale (EPDS). These women, between the eighth and the
      twelfth week after delivery, were admnistered the EPDS and diagnosed according
      the DSM-III-R criteria using the MINI Interview. At the 8/9 cut-off score the
      sensitivity is 94.4%, specificity 87.4% and PPV 58.6%. The internal consistency
      of the EPDS Italian version was tested using Chronbach's alpha coefficient
      (0.7894) and Guttman split-half coefficient (0.8191). Finally a receiver
      operating characteristic (ROC) analysis was carried out to evaluate the global
      functioning of the scale: the area under ROC curve AUC is 0.7470 and the logistic
      estimate for the threshold score of 11/12 fitted the model sensitivity at 75% and
      model specificity at 67%. Our data confirm the validity of EPDS in identifying
      postnatal depression also in its Italian version and the scale could be used as
      an useful instrument in the clinical practice.

PMID- 10360409
TI  - When the cradle falls: the treatment of postnatal depression in a psychiatric day
      hospital compared with routine primary care.
AB  - BACKGROUND: Postnatal depression affects one in ten women within 6 months of
      childbirth. The most effective treatment strategy for postnatal depression is not
      clear. METHODS: This prospective, naturalistic study of the treatment of
      postnatal depression compared 30 women treated at a specialised psychiatric day
      hospital with 30 women treated using routine primary care (RPC). Clinical,
      marital and social adjustment were assessed on three occasions over 6 months
      using: the Edinburgh Postnatal Depression Questionnaire (EPDS); the Clinical
      Interview schedule (CIS); the Anxiety Subscale of the Hospital Anxiety and
      Depression Scale; the Dyadic Adjustment Scale (DAS); and the Work Leisure and
      Family Life Questionnaire-Modified (WLFLQ-M). RESULTS: There were no significant
      differences between the two groups at baseline. However, there were significant
      differences in outcome at 3 and 6 months follow-up for all outcome measures
      except the DAS. At 6 month follow-up 21 of the PBDU group were no longer
      depressed compared with 7 of the RPC group. CONCLUSIONS: A specialised day
      hospital is a more effective treatment setting for postnatal depression than
      routine primary care. LIMITATIONS OF THE STUDY: The study is not an RCT, so
      systematic bias is possible. The sample size is relatively small and the duration
      of follow-up relatively short.

PMID- 10360410
TI  - Sociodemographic, clinical, and attitudinal characteristics of the untreated
      depressed in Ontario.
AB  - BACKGROUND: Epidemiologic surveys consistently document high rates of untreated
      depression, yet why this unmet need exists is only partially understood. METHODS:
      We compared untreated depressed, treated depressed and "healthy" subjects on
      sociodemographic characteristics, need for treatment, and help-seeking attitudes
      using household survey data from Ontario, Canada (n = 9953). DSM-III R Major
      Depression was assessed by structured interview (UM-CIDI), and treatment was
      defined as seeking formal mental health care. Need for treatment was assessed
      using a broad array of clinical, disability, and risk measures. RESULTS:
      Depressed (treated and untreated) and "healthy" respondents differed
      significantly on nearly all comparative measures. However, the two depressed
      groups showed few sociodemographic or "need for treatment" differences. Notably,
      there were no significant clinical differences although the untreated did report
      less physical comorbidity (33.9% vs 60.0% treated depressed). There were,
      however, several attitudinal differences. Compared to the treated depressed,
      untreated respondents were less likely to feel they had a mental health problem
      (51.6% vs. 78.8%), to say they would seek help for a serious problem (36.6% vs
      64.7%) or to feel comfortable consulting a professional (19.0% vs. 43.2%).
      LIMITATIONS: Because the data are cross-sectional, temporal relationships cannot
      be directly addressed. CONCLUSIONS: Despite appreciable morbidity, access to care
      by the untreated depressed may be hindered by their self-perceptions and greater
      discomfort with help-seeking. Lower physical comorbidity may also contribute
      through decreased health care contact and thus fewer opportunities for disclosing
      or detecting their illness.

PMID- 10360411
TI  - Treatment of major depression in the context of panic disorder.
AB  - BACKGROUND: Individuals with major depression frequently have panic attacks, and
      often panic disorder, but rarely have researchers studied the impact of
      comorbidity of panic on the outcome of psychological treatment of depression.
      METHODS: In this study, patients with comorbid panic and depression were first
      treated with cognitive-behavioral therapy (CBT) for panic. Depression symptoms in
      this treated group were compared to a group of patients with major depression who
      were on a minimal therapist contact waitlist. In the second phase of the study,
      patients in both groups (comorbid and depression-only) were treated with CBT for
      depression. RESULTS: CBT for panic had little effect on co-existing depression,
      suggesting a specificity of action for CBT directed at different disorders. In
      addition, the presence of current or recently remitted panic attacks or
      agoraphobic avoidance did not interfere with the outcome of CBT for depression.
      CONCLUSION: These findings stand in contrast to previous studies showing greater
      linkage between depression and panic in treatment outcome. LIMITATIONS: While
      there are implications for treatment planning, these conclusions may be limited
      by the exclusion criteria and the highly structured treatment approach of
      separating treatment for panic from treatment for depression.

PMID- 10360412
TI  - The incidence of akathisia in bipolar affective disorder treated with
      neuroleptics--a preliminary report.
AB  - BACKGROUND: Akathisia is a common side effect of neuroleptic therapy. Prevalence
      and incidence studies of akathisia have been predominantly undertaken in patients
      with schizophrenia and schizoaffective disorder. Investigations of akathisia in
      neuroleptic treated patients suffering from bipolar disorder are lacking. METHOD:
      In the present study, 23 patients with bipolar affective disorder who were
      treated with neuroleptics were assessed for akathisia and parkinsonism, using the
      Barnes Akathisia Rating Scale and DSM-IV criteria, respectively. RESULTS: 15
      patients (65.2%) developed akathisia. Eighteen patients (78.3%) had parkinsonism,
      including all of the akathisia-group. In six patients (40%) of the akathisia
      group the onset of akathisia was after neuroleptic dose reduction or after
      additional administration of mood stabilizers. CONCLUSIONS: Neuroleptic-induced
      side effects may occur frequently in patients with bipolar affective disorder and
      should therefore be monitored thoroughly. Demasking effects due to diminishing
      parkinsonian symptoms may contribute to akathisia-onset after neuroleptic dose
      reduction. Early application of alternative treatment regimens, e.g. monotherapy
      with mood stabilizers in combination with benzodiazepines should be considered.
      FUTURE DIRECTIONS: The preliminary findings require further investigation
      regarding dose dependency, incidence of akathisia in untreated patients with
      bipolar affective disorder, akathisia in patients with depressed episodes on
      SSRI, and possible differences between various mood stabilizers in their
      propensity to enhance akathisia, as well as possible sex differences.

PMID- 10360413
TI  - Is depression associated with immune activation?
AB  - BACKGROUND: Some research immunologists have suggested that major depression amd
      chronic fatigue syndrome (CFS) are characterized by immune activation. To test
      this hypothesis, we compared immunological function in patients with major
      depression and in patients with CFS who developed major depression after the
      onset of CFS to that of sedentary healthy controls. METHODS: Subjects completed
      the Centers for Epidemiological Study-Depression (CES-D) questionnaire and
      allowed venisection. We performed flow cytometric analysis on 13 groups of white
      blood cells and used a reverse transcriptase PCR method to assay m-RNA of eight
      cytokines. RESULTS: CES-D scores were high in both patient groups and did not
      differ significantly. We found no evidence for immune activation in either
      patient group. Instead the data suggested immunological downregulation in
      depression. LIMITATIONS: Not all the subjects in the two patient groups were off
      antidepressants. CONCLUSIONS: The data indicate that immune activation is not
      necessary in depression--either alone or with CFS.

PMID- 10360414
TI  - Effectiveness of treatments for major depression in primary medical care
      practice: a post hoc analysis of outcomes for African American and white
      patients.
AB  - OBJECTIVE: To retrospectively determine whether race differentially influences
      treatment adherence and clinical outcomes among 68 African Americans and 92
      whites treated for major depression in four urban, primary care settings. METHOD:
      Study participants were randomly assigned to standardized interpersonal
      psychotherapy or pharmacotherapy with nortriptyline, and were assessed at
      baseline, and successive time points up to 8 months for severity of depression,
      and mental and physical health-related functioning. RESULTS: Intent-to-treat
      analyses revealed no treatment or race-specific differences in symptomatic
      recovery when both groups were provided standardized psychotherapy or
      pharmacotherapy. However, African Americans had poorer functional outcomes than
      whites. CONCLUSIONS: African American and white primary medical care patients are
      effectively treated with standardized psychotherapy and pharmacotherapy. Future
      research should assess the impact of cultural context on symptom presentation,
      psychosocial functioning, and treatment adherence and response.

PMID- 10360416
TI  - Determination of homocysteine and its related compounds by solid-phase
      microextraction-gas chromatography-mass spectrometry.
AB  - The purpose of this study was to develop a simple and accurate analytical method
      to determine homocysteine (Hcy), cysteine (Cys), and methionine (Met) in aqueous
      samples. Until now, the most frequently used method for the assay of Hcy, Cys,
      and Met has been high-performance liquid chromatography with fluorescence
      detection after fluorescent tagging. The newly developed method involves the
      employment of the SPME (solid-phase microextraction) technique together with GC
      MS. For application to a gas chromatographic system, alkyl formate derivatives
      were prepared in the form of N(O,S)-alkoxycarbonyl alkyl ester with the analytes
      in the aqueous samples. The optimum derivatizing regent for N(O,S)-alkoxycarbonyl
      alkyl ester was chosen by comparing the efficiency of the derivatized analytes in
      a GC through the SPME method and liquid-liquid extraction. The optimum conditions
      of the SPME system for the analytes derivatized with N(O,S)-ethoxycarbonyl propyl
      ester in the aqueous matrix were pH 3.0 and no salt, and 30 min equilibration
      time using an 85 microm PA (polyacrylate) fiber. The developed method is
      inexpensive, easy and rapid.

PMID- 10360415
TI  - Sad, glad, or mad hearts? Epidemiological evidence for a causal relationship
      between mood disorders and coronary artery disease.
AB  - OBJECTIVE: To examine the epidemiological evidence to determine if there is
      sufficient support for the hypothesis that mood disorders convey a risk factor in
      the pathogenesis of coronary artery disease (CAD). METHOD: Based on a review of
      the related research on Type A behavioral pattern (TABP) and other variables such
      as anger and hostility and their relationship to coronary artery disease (CAD),
      the findings were analyzed to ascertain any clinical patterns or similarities
      between behaviors of Type A and those in mood disorders. Using the given
      epidemiological criteria for a causal relationship, the association between the
      mood and coronary artery disease was explored. RESULTS: There are similar
      symptoms and behaviors noted among Type A, manic, cyclothymic and hyperthymic
      individuals. There is sufficient historical and contemporaneous epidemiological
      evidence to support the notion that mood disorders confer risk for CAD, but it is
      premature to describe it as a causative factor. Depressive symptoms and general
      mood disorders emerged as toxic risk factors for CAD. LIMITATION: This article
      presents only a selective literature review, and it is limited by an
      epidemiological analyses of secondary sources. The impact of this limitation on
      the interpretation of the analyses is discussed. CLINICAL RELEVANCE: Patients
      require scrupulous clinical assessment for the presence of mood disorders
      including subtype; the stakes are high, since their cardiac health status may
      depend upon it. Pathophysiological pathways may play a covariate role in both
      mood and coronary disease, and some tentative hypotheses regarding the role of
      catchecholamines and cortisol are explored. CONCLUSIONS: There is evidence to
      justify studying the role of mood as a covariate risk factor in the pathogenesis
      of CAD. Implications for mental health, public health, primary care practice, and
      psychometric measurement are discussed. The hypothesis that mood disorders are a
      cause of CAD requires further research.

PMID- 10360417
TI  - Serial lectin affinity chromatography demonstrates altered asparagine-linked
      sugar-chain structures of prostate-specific antigen in human prostate carcinoma.
AB  - Differences between prostate carcinoma (PCA) and benign prostatic hyperplasia
      (BPH) in asparagine (N)-linked sugar-chain structures of prostate-specific
      antigen (PSA) were investigated using serial lectin affinity chromatography. The
      amounts of PSA passing through columns of concanavalin A (Con A),
      phytohaemagglutinin E4 (PHA-E4) and PHA-L4 were significantly greater for PCA
      derived PSA than BPH. We propose that the sugar moiety structure of PSA which is
      increased in PCA is a multiantennary complex type with branched N
      acetylglucosamine beta(1->4) mannose. We suggest that N-linked sugar chains in
      PSA are altered during oncogenesis in the human prostate and may serve as
      diagnostic tools for PCA.

PMID- 10360419
TI  - High-performance liquid chromatographic assay of (+/-)-lactic acid and its
      enantiomers in calf serum.
AB  - Two high-performance liquid chromatographic methods are described for the
      determination of lactic acid and its enantiomers in calf serum. A 300x8.0 mm I.D.
      column packed with sulfonated styrene-divinylbenzene copolymer and a 50x4.6 mm
      ODS column with N,N-dioctyl-L-alanine were used. UV detection was at 205 and 236
      nm for the non-chiral and chiral assays, respectively. Both assays demonstrated
      excellent linear relationships between peak area ratios and serum concentrations
      over a range of 0.5 to 20 mM, based on 100 microl bovine serum. Recovery was
      complete. Inter- and within-batch bias and relative standard deviation were <15%.

PMID- 10360418
TI  - Application of high-performance liquid chromatography of plasma fatty acids as
      their phenacyl esters to evaluate splanchnic and renal fatty acid balance in
      vivo.
AB  - Plasma fatty acids from renal and hepatic veins, and arterialized hand vein
      obtained in 20 subjects before and after insulin infusion were separated by
      reversed-phase high-performance liquid chromatography following phenacyl
      esterification. Separation and quantification over the range 1.0-100 nmol per
      injection of nine fatty acids was achieved within 60 min using [2H31]palmitic
      acid as internal standard. Analytical recoveries were greater than 90% and the
      intra- and inter-assay coefficients of variation were less than 2.5 and 4.0%,
      respectively. Following insulin infusion, net splanchnic uptake of total fatty
      acids decreased from 3.0+/-0.3 to 1.0+/-0.1 micromol/kg min (p<0.01), whereas net
      renal balance remained neutral (-0.04+/-0.04 vs. -0.06+/-0.03 micromol/kg min,
      p=N.S.). Individual fatty acid balance varied from a low of 0.012+/-0.005
      (myristic acid) to a high of 0.95+/-0.08 (oleic acid) micromol/kg min across the
      splanchnic tissues and from 0.005+/-0.002 (stearic acid) to 0.21+/-0.1 (oleic
      acid) micromol/kg min across the kidney. There is a substantial diversity in
      changes in plasma concentration and regional balance of individual fatty acid
      during short-term fasting and hyperinsulinemia. This method is simple, accurate,
      and can be applied to assess individual fatty acid metabolism in vivo.

PMID- 10360421
TI  - Analysis of diagnostic metabolites by capillary electrophoresis-mass
      spectrometry.
AB  - We describe here a procedure by capillary electrophoresis-mass spectrometry (CE
      MS) for the direct analysis of urine samples on diagnostic metabolites, which are
      present in patient urine with metabolic disorders. The method was demonstrated
      using urine samples spiked with diagnostic metabolites, including glutathione for
      gamma-glutamyl transpeptidase deficiency, pyroglutamate for generalized
      glutathione deficiency, adenylosuccinate for adenylosuccinase deficiency,
      omithine for gyrate atrophy, histidine for histidinemia, and homogentisic acid
      for alcaptonuria, at concentrations similar to those found in patients' urine. A
      coaxial sheath liquid flow was used for coupling CE and MS in electrospray
      ionization mode. Identification of the metabolites is based on their molecular
      weights and fragmentation patterns. The CE-MS method is highly specific and
      sensitive comparing to the previously reported method using migration time and UV
      absorption for identification. It should find broad application in clinical and
      pharmaceutical research and development.

PMID- 10360420
TI  - Determination of 5-S-cysteinyldopa in plasma and urine using a fully automated
      solid-phase extraction--high-performance liquid chromatographic method for an
      improvement of specificity and sensitivity of this prognostic marker of malignant
      melanoma.
AB  - 5-S-Cysteinyldopa (5-SCD) in plasma and urine was determined by means of a newly
      developed method. This method incorporates optimized conditions for blood
      collection and storage, as well as a new extraction and separation technique,
      required for the strong oxidation and light sensitive 5-SCD. The new aspects of
      the method are the following: immediate centrifugation and freezing of the
      samples after blood collection, fully automatical solid-phase extraction (SPE)
      with phenylboronic acid (PBA) cartridges and immediate HPLC injection of the
      eluate, nearly complete exclusion of light and air-oxygen during extraction,
      constant sample cooling, use of the more suitable internal standard 5-S-D
      cysteinyldopa and easy, sensitive and selective HPLC conditions (RP18-column with
      isocratic separation and electrochemical detection). The method has a linear
      range from 0.25 to 50 microg l(-1) and 25 to 5000 microg l(-1) for plasma and
      urine samples, respectively, a limit of detection of 0.17 microg l(-1), intra
      assay variabilities from 1.7 to 3.6%, inter-assay variabilities from 4.0 to 18.3%
      and an average relative recovery of 103.5% for plasma and 105.4% for urine
      samples. In our study the measured 5-SCD concentrations of patients with
      melanomas at various stages correlated better with their clinical pictures than
      described in literature up to date. The results were obtained in comparison to
      patients with other skin tumors and in comparison to healthy control persons.

PMID- 10360422
TI  - Separation and identification of neuropeptide Y, two of its fragments and their
      degradation products using capillary electrophoresis-mass spectrometry.
AB  - This paper describes the development of an analytical method for the separation
      and identification of neuropeptide Y (NPY) and two important NPY fragments by
      capillary electrophoresis (CE) and mass spectrometry (MS). A satisfactory
      separation and the highest sensitivity were obtained with formic acid at high
      concentrations (250 mM, pH 2.75). The addition of 25 or 50 mM triethylamine (TEA)
      improved the separation. When applying full scan CE-MS, the separated peptides
      could be detected and identified using the spectra of each peak. The use of TEA
      as an additive to the formic acid slightly decreased the sensitivity but was
      compensated by the improved efficiency. The best compromise for optimal
      separation and MS detection was found to be 50 mM formic acid to which 50 mM TEA
      was added. CE-MS could be used for identification of the decomposition products
      of NPY. Decomposition products with one amino acid difference, which could not be
      distinguished with CE-UV, could be distinguished with CE-MS.

PMID- 10360423
TI  - Use of capillary electrophoresis-based competitive immunoassay for a large
      molecule.
AB  - A systematic study on the optimization of capillary electrophoresis-based
      immunoassay (CEIA) was performed using bovine serum albumin (BSA) and monoclonal
      anti-BSA. The immunocomplex could not be resolved from free BSA or anti-BSA with
      UV detection. When fluorescein isothiocyanate-labeled BSA (FITC-BSA) was used as
      tracer, the free and bound FITC-BSA were well separated giving definite peaks
      with laser induced fluorescence detection. The factors affecting the separation
      of the free and bound FITC-BSA, including voltage, pH and ionic strength of the
      running buffer, were systematically analyzed. Competitive CEIAs were demonstrated
      in uncoated and coated capillaries with whole or Fab fragment of the antibody.
      The coefficient of variation for the quantification of BSA in coated capillary
      was less than that in uncoated capillary. This study demonstrated that
      competitive CEIA could be applied to quantify high-molecular-mass protein in
      biological fluids.

PMID- 10360424
TI  - Simple and rapid method for the measurement of nitrite and nitrate in human
      plasma and cerebrospinal fluid by capillary electrophoresis.
AB  - Nitrite and nitrate levels in physiological fluids are commonly used as an index
      of nitric oxide production. We developed simple and rapid method for the
      determination of these anions by capillary zone electrophoresis employing borate
      buffer (pH 10, 100 mmol/l) as running electrolyte. The anions were analyzed in
      plasma and cerebrospinal fluid (CSF) without deproteinization of the samples.
      Electrophoresis was carried out in a capillary (36.5 cm x 75 microm) at a
      potential of 15 kV, with on-column UV detection at 214 nm. Mean retention times
      for nitrite and nitrates were 4.631 and 5.152 min, respectively. The method was
      linear (r=0.999) within a 1-500 micromol/l concentration range. Physiological
      levels of nitrate in plasma (40.2 micromol/l) and CSF (15.3 micromol/l) could be
      determined with good precision (coefficients of variation <6%) and accuracy
      (recoveries of added nitrate to plasma and CSF were 97.4 and 104.5%,
      respectively). Measurements of the physiological levels of nitrite in plasma (6.1
      micromol/l) and CSF (0.9 micromol/l) were less precise and accurate.

PMID- 10360425
TI  - Highly sensitive gas chromatographic-tandem mass spectrometric method for the
      determination of morphine and codeine in serum and urine in the femtomolar range.
AB  - A sensitive and specific method was developed for the determination of codeine
      and morphine in human serum and for the determination of trace amounts of
      endogenous morphine in human urine. The analytes were recovered from serum by a
      simple liquid-liquid extraction method. Urine samples were hydrolyzed, and
      purified by two liquid-liquid extraction steps and a solid-phase extraction.
      Samples were derivatized to the pentafluoropropionic esters and measured by gas
      chromatography tandem mass spectrometry. Using the deuterated analogues as
      internal standards a limit of quantification of 20 fmol/ml (5.7 pg/ml) morphine
      and 500 fmol/ml (150 pg/ml) codeine in human serum and of 2.5 fmol/ml (0.71
      pg/ml) morphine in urine was achieved. The method was suitable for the
      determination of morphine and codeine in pharmacokinetic studies and for the
      determination of the urinary excretion of endogenous morphine.

PMID- 10360426
TI  - Ultra-sensitive method for determination of ethanol in whole blood by headspace
      capillary gas chromatography with cryogenic oven trapping.
AB  - We have established an ultra-sensitive method for determination of ethanol in
      whole blood by headspace capillary gas chromatography (GC) with cryogenic oven
      trapping. After heating a blood sample containing ethanol and isobutyl alcohol
      (internal standard, IS) in a 7.0-ml vial at 55 degrees C for 15 min, 5 ml of the
      headspace vapor was drawn into a glass syringe and injected into a GC port. All
      vapor was introduced into an Rtx-BAC2 wide-bore capillary column in the splitless
      mode at -60 degrees C oven temperature to trap entire analytes, and then the oven
      temperature was programmed up to 240 degrees C for GC measurements with flame
      ionization detection. The present method gave sharp peaks of ethanol and IS, and
      low background noise for whole blood samples. The mean partition into the gaseous
      phase for ethanol and IS was 3.06+/-0.733 and 8.33+/-2.19%, respectively. The
      calibration curves showed linearity in the range 0.02-5.0 microg/ml whole blood.
      The detection limit was estimated to be 0.01 microg/ml. The coefficients of intra
      day and inter-day variation for spiked ethanol were 8.72 and 9.47%, respectively.
      Because of the extremely high sensitivity, we could measure low levels of
      endogenous ethanol in whole blood of subjects without drinking. The concentration
      of endogenous ethanol measured for 10 subjects under uncontrolled conditions
      varied from 0 to 0.377 microg/ml (mean, 0.180 microg/ml). Data on the diurnal
      changes of endogenous ethanol in whole blood of five subjects under strict food
      control are also presented; they are in accordance with the idea that endogenous
      blood ethanol is of enteric bacterial origin.

PMID- 10360427
TI  - Screening urine for exogenous testosterone by isotope ratio mass spectrometric
      analysis of one pregnanediol and two androstanediols.
AB  - We propose a new screening method for testosterone (T) doping in sport. The
      current method for detecting T administration is based on finding a T to
      epitestosterone ratio (T/E) in urine that exceeds six. The difficulties with T/E
      are that T administration does not always result in a T/E>6 and that a rare
      individual will have T/E>6 in the absence of T administration. Our previous
      studies reveal that carbon isotope ratio helps to determine the origin of the
      urinary T because the values for T and its metabolites decrease after the
      administration of exogenous T. In this study, we present a rapid and efficient
      screening sample preparation method based on three successive liquid-solid
      extractions, deconjugation with E. coli beta-glucuronidase after the first
      extraction, acetylation after the second extraction, and a final extraction of
      the acetates. The 13C/12C of two T metabolites (5beta-androstane-3alpha,17beta
      diol and 5alpha-androstane-3alpha,17beta-diol) and one pregnanediol as endogenous
      reference (5beta-pregnane-3alpha,20alpha-diol) was measured by gas chromatography
      combustion-isotope ratio mass spectrometry (GC-C-IRMS) on 10 ml of urine
      collected from 10 healthy men before and after T administration. Following T
      administration, the 13 C/12C of 5beta-androstane-3alpha,17beta-diol diacetate and
      5alpha-androstane-3alpha,17beta-diol diacetate declined significantly from -26.2
      per thousand to -30.8 per thousand and from -25.2 per thousand to -29.9 per
      thousand, respectively and the 13C/12C of 5beta-pregnane-3alpha,20alpha-diol
      diacetate was unchanged. In addition, the ratio of androstanediols to
      pregnanediol increased in the post-T urines.

PMID- 10360428
TI  - Stereoselective determination of fenfluramine enantiomers in rat liver microsomal
      incubates.
AB  - An enantioselective assay for l- and d-fenfluramine in rat liver microsomal
      incubates was developed. The method involves extraction of fenfluramine from the
      microsomal incubates, and formation of fenfluramine diastereomeric derivatives
      with the chiral reagent S-(-)-N-trifluoroacetyl prolyl chloride. Separation and
      quantitation of the diastereomeric fenfluramine derivatives are carried out by a
      capillary gas chromatographic system with flame ionization detection. The assay
      is linear from 1 to 50 microg/ml for each enantiomer. The analytical method
      affords average recoveries of 92.28 and 96.44% for l- and d-fenfluramine,
      respectively. The limits of detection and quantitation for the method are 0.1 and
      1.0 microg/ml for the l- and d-fenfluramine isomers, respectively. The
      reproducibility of the assay was <10% (RSD). The method allowed study of the
      depletion of l- and d-fenfluramine in rat liver microsomal incubates. The
      stereoselectivity of fenfluramine phase I metabolism was observed.

PMID- 10360429
TI  - Determination of lamotrigine in human plasma by high-performance liquid
      chromatography.
AB  - The method involves precipitation of plasma proteins with acetonitrile and
      analysis of the supernatant by high-performance liquid chromatography using a 5
      microm Zorbax C8 column. Quantitation was performed by measurement of the UV
      absorbance at a wavelength of 306 nm. The method was linear in the range of 1-20
      microg/ml, with a mean coefficient of determination (r2=0.998). The limit of
      detection was 0.6 microg/ml and the lower limit of quantitation was 1 microg/ml
      using 200 microl of plasma. Within- and between-day accuracy and precision were
      below 6% at all analysed concentrations except at the limit of quantitation. No
      interfering peaks were found by commonly monitored antiepileptic drugs. Recovery
      was found to be > or =99%. Satisfactory performance was obtained in the
      evaluation of epileptic patient samples, whose results of plasma concentration
      measurements are briefly discussed. We conclude that this is a reliable method
      for the routine monitoring of lamotrigine concentration in plasma in the clinical
      setting.

PMID- 10360430
TI  - Rapid high-performance liquid chromatographic determination of serum gabapentin.
AB  - Gabapentin (GBP) is a new antiepileptic drug approved for clinical treatment of
      partial seizures in the USA. Serum GBP concentrations in 283 patients were
      studied using high-performance liquid chromatography with fluorescence detection.
      The standard curves were linear over a range of 60 ng to 15 microg/ml. The
      coefficient of variations were 3.4 to 8.8% and 1.4 to 9.8% for intra- and inter
      assay studies, respectively. The lower limit of quantitation was 10 ng/ml. Of the
      283 patients studied, 72.5% had GBP levels between 2 and 10 microg/ml, 14.8% were
      below 2 microg/ml and 12.7% above 10 microg/ml. The mean+/-S.E. of GBP in 283
      patients was 5.38+/-0.23 microg/ml. Peak concentrations of more than 15 microg/ml
      and trough levels as low as 0.1 microg/ml were not uncommon. The method described
      was rapid, simple, highly sensitive and reproducible. Other antiepileptic drugs
      and endogenous compounds did not interfere with the assay.

PMID- 10360431
TI  - Automated microanalysis of gabapentin in human serum by high-performance liquid
      chromatography with fluorometric detection.
AB  - An automated high-performance liquid chromatographic method for the determination
      of gabapentin, 1-(amino-methyl)cyclohexaneacetic acid, in serum is described. The
      procedure involves protein precipitation with methanol followed by using a
      robotized derivatization with o-phthaldialdehyde reagent and automated high
      performance liquid chromatography. The analog of gabapentin, 1
      (aminomethyl)cycloheptaneacetic acid, was used as the internal standard. Blank
      serum was fortified with gabapentin (0.1-10.0 microg/ml) and internal standard.
      Separation was achieved on a Waters 5-microm reversed-phase column (10 cmx4.6 mm)
      with mobile phase consisting of 0.02 M phosphate buffer (pH 4.5)-acetonitrile
      (50:50, v/v). Eluents were monitored by fluorescence spectroscopy with excitation
      and emission wavelengths of 230 and 420 nm, respectively. The calibration curve
      for gabapentin in serum was linear (r=0.999) over the concentration range 0.1
      10.0 microg/ml. The inter- and intraassay variations for three different
      gabapentin concentrations were < or =10% throughout. The lower limit of
      quantitation was found to be 0.1 microg/ml. Chromatography was unaffected by a
      range of commonly employed antiepileptic drugs or selected amino acids.

PMID- 10360432
TI  - Semi-automated solid-phase extraction procedure for the high-performance liquid
      chromatographic determination of alinastine in biological fluids.
AB  - A solid-phase extraction (SPE) method for sample clean-up followed by a reversed
      phase HPLC procedure for the assay of alinastina (pINN) in biological fluids is
      reported. The effects of the sample pH, composition of the washing and elution
      solvents and the nature of the SPE cartridge on recovery were evaluated. The
      selectivity of SPE was examined using spiked rat urine and plasma samples and the
      CH and PH cartridges gave rise to the cleanest extracts. The recoveries obtained
      in spiked rat urine and plasma samples were 91.2+/-2.7 and 99.9+/-2.8%,
      respectively. The proposed SPE method coupled off-line with a reserved-phase HPLC
      system with fluorimetric detection was applied to the quantitation of alinastine
      in real rat urine samples. The analytical method was also applied and validated
      for the determination of alinastine in dog plasma. The recovery from spiked dog
      plasma samples using the PH cartridge was around 65%. The within-day and between
      day precisions were 7 and 12%, respectively. The detection and quantitation
      limits in dog plasma were 0.024 and 0.078 microg/ml, respectively.

PMID- 10360433
TI  - Simultaneous determination of the HIV-protease inhibitors indinavir, nelfinavir,
      saquinavir and ritonavir in human plasma by reversed-phase high-performance
      liquid chromatography.
AB  - A sensitive high-performance liquid chromatographic method has been developed for
      the simultaneous determination of the four licensed HIV-protease inhibitors
      indinavir, nelfinavir, saquinavir and ritonavir. An aliquot of 500 microl plasma,
      spiked with internal standard, was extracted with 0.5 ml 0.1 M NH4OH and 5 ml
      methyl tert.-butyl ether. After evaporating, the residue was dissolved in eluent
      consisting of acetonitrile-50 mM phosphate buffer, pH 5.63 (40:60, v/v).
      Subsequently, the eluent was washed with hexane. Chromatography was performed
      using a C18 reversed-phase column and gradient elution with a linear increase of
      acetonitrile from 36 to 66%. Ultraviolet detection at 215 nm was used. Linearity
      of the method was obtained in the concentration range of 45-30 000 ng/ml for all
      four analytes. The method was validated extensively and stability tests under
      various conditions were performed. The assay is now in use to analyse plasma
      samples from patients treated with (combinations of) HIV-protease inhibitors.

PMID- 10360434
TI  - Rapid quantification of delavirdine, a novel non-nucleoside reverse transcriptase
      inhibitor, in human plasma using isocratic reversed-phase high-performance liquid
      chromatography with fluorescence detection.
AB  - Delavirdine is a novel non-nucleoside reverse transcriptase inhibitor for the
      treatment of HIV-1-infected patients. A simple and rapid high-performance liquid
      chromatographic method for the quantification of delavirdine in human plasma
      suitable for drug monitoring in patients is described. Sample pretreatment
      consists of protein precipitation with acetonitrile and subsequent evaporation of
      the extract to concentrate the analyte. The drug is separated from endogenous
      compounds by isocratic reversed-phase, high-performance liquid chromatography
      coupled with fluorescence detection. The optimal excitation and emission
      wavelengths are 300 and 425 nm, respectively. The method has been validated over
      the range of 50-50 000 ng/ml using only 200 microl of plasma samples. The assay
      is linear over this concentration range as indicated by the F-test for lack of
      fit. Within- and between-day precisions are less than 4.4% for all quality
      control samples. The lower limit of quanititation is 50 ng/ml. Recovery of
      delavirdine from human plasma is 93.8%. Delavirdine is stable under various
      conditions, for example 1 h at 60 degrees C and one week at 4 degrees C. This
      validated assay is suited for use in pharmacokinetic studies with delavirdine and
      can readily be implemented in the setting of a hospital laboratory for the
      monitoring of delavirdine concentrations.

PMID- 10360435
TI  - Improved validated assay for the determination of mefloquine and its carboxy
      metabolite in plasma, serum and whole blood using solid-phase extraction and high
      performance liquid chromatography.
AB  - An improved high-performance liquid chromatography method using a low silanol
      activity octadecylsilica column and a solid-phase extraction technique is
      validated for the simultaneous analysis of mefloquine and its carboxy metabolite
      in whole blood, plasma and serum. An octadecylsilica column with high silanol
      activity is compared to a column of low activity in terms of pH dependent
      variability of chromatographic retention times for mefloquine and its carboxy
      metabolite. The low silanol activity column showed a relatively large mobile
      phase pH range where retention times for both components are consistent. The
      solid-phase extraction procedure consists of a simple protein precipitation step
      followed by sample concentration and extraction using a C18 membrane disk. The
      inter- and intra-assay variability for a therapeutic concentration of mefloquine
      (1000 ng/ml) is less than 2% in whole blood, plasma and serum while
      carboxymefloquine (1000 ng/ml) is 2.3% or less. At concentrations as low as 100
      ng/ml the inter-assay variability is 6.2% or less for both analytes. This method
      shows a robust analytical procedure for the simultaneous analysis of mefloquine
      and its carboxy metabolite where precise measurements are useful in
      pharmacokinetic studies and in estimating drug compliance.

PMID- 10360436
TI  - Determination of benzimidazole residues using liquid chromatography and tandem
      mass spectrometry.
AB  - The determination of residues of benzimidazole using liquid chromatography and
      tandem mass spectrometry (LC-MS-MS) with ion spray ionization is described. Swine
      muscle tissue was spiked with a mixture of fifteen benzimidazoles, including
      metabolites of fenbendazole and albendazole. As clean-up procedure, an ethyl
      acetate extraction followed by solid-phase extraction on styrol-divinyl-benzene
      cartridge was used. The evaluation was performed by selecting the characteristic
      product ions for the benzimidazoles and using multiple reaction mode. 2-n
      Butylmercaptobenzimidazole was used as internal standard. Blank muscle samples
      were fortified in the concentration range of 1-22 microg/kg. The limits of
      detection were below 6 microg/kg and the limits of quantification for most
      benzimidazoles were below 10 microg/kg. The matrix effect was checked using
      spiked muscle tissues of cattle and sheep as well as liver of cattle. Practical
      application will be shown by incurred egg material from laying hens treated with
      flubendazole. The recovery of the clean-up was mostly above 50% in muscle tissue
      and 70% in egg yolk.

PMID- 10360437
TI  - Validated method for the quantitation of quercetin from human plasma using high
      performance liquid chromatography with electrochemical detection.
AB  - A validated method for the quantitation of trace levels of quercetin from human
      plasma to be used in pharmacokinetic and biomarker studies is presented.
      Quercetin conjugates were hydrolysed enzymatically, plasma proteins were removed
      using a Bond Elut C18 extraction column and additional interferences were removed
      by extracting them into a toluene-dichloromethane mixture. The HPLC system
      consisted of an Inertsil ODS-3 column (250 x 4.0 mm) and a mobile phase with 59%
      methanol in phosphate buffer (pH 2.4). High selectivity and a low quantitation
      limit (0.63 microg/l) were achieved by using electrochemical detection at a low
      potential. The method has excellent reproducibility: R.S.D. values of peak
      heights were 2% and 7.9%, respectively, for within-day and between-day precision.
      The method was applied to a small scale study of quercetin pharmacokinetics and
      quercetin was shown to be absorbed from a 20 mg dose. No free quercetin was
      detected in plasma and no evidence of significant amounts of quercetin glycosides
      in plasma was found.

PMID- 10360438
TI  - Quantification of topotecan and its metabolite N-desmethyltopotecan in human
      plasma, urine and faeces by high-performance liquid chromatographic methods.
AB  - Sensitive high-performance liquid chromatographic (HPLC) methods have been
      developed and validated for the simultaneous determination of the antitumor drug
      topotecan and its metabolite N-desmethyltopotecan in human plasma, urine and
      faeces. Both compounds are reversibly hydrolysed to their hydroxycarboxylate
      forms at physiologic pH. Separate HPLC systems have been developed for the
      determination of lactone and total (lactone plus hydroxycarboxylate forms)
      concentrations in plasma. The instability of the analytes in plasma requires
      immediate protein precipitation with ice-cold methanol. The lactone forms of the
      analytes were stable in the methanol extracts for at least 15 months when stored
      at -70 degrees C. For the determination of the total levels, the plasma extracts
      were acidified with 25 mM phosphoric acid to convert the compounds into their
      lactone forms quantitatively. The sample pretreatment procedure for urine
      included dilution in methanol while the faecal samples were homogenized in
      distilled water and then extracted twice with an acetonitrile-ammonium acetate
      mixture. Separation was achieved on reversed-phase columns (Zorbax SB-C18) and
      detection was performed fluorimetrically at 380/527 nm. Within-run and between
      run precisions were less than 10% and average accuracies were between 90 and
      110%. The methods were used in a mass balance study in patients with malignant
      solid tumors to determine the disposition and routes of elimination of topotecan
      and N-desmethyltopotecan.

PMID- 10360439
TI  - Quantitative high-performance liquid chromatographic method for pharmacokinetic
      studies of the potent mast cell inhibitor 4-(4'-hydroxyphenyl)amino-6,7
      dimethoxyquinazoline (WHI-P131).
AB  - The novel quinazoline derivative 4-(4'-hydroxyphenyl)amino-6,7
      dimethoxyquinazoline (WHI-P131) has recently been identified as a potent mast
      cell inhibitor capable of preventing IgE/antigen induced cutaneous as well as
      systemic fatal anaphylaxis in mice. Here we describe a sensitive high-performance
      liquid chromatography (HPLC)-based quantitative detection method for measurement
      of WHI-P131 levels in plasma as well as in target mast cells. The average
      extraction recovery for WHI-P131 was 88.4% for plasma and 75.7% for RBL-2H3 mast
      cell lysates. Good linearity (r>0.999) was observed throughout the concentration
      range of 0.1-20 microM in plasma and 0.01-5 nmol in 5 x 10(6) cells (0.5-238
      microM per cell) for WHI-P131. Intra- and inter-assay variabilities were <7% and
      the lowest detection limit of WHI-P131 was 0.05 microM in plasma and 0.005 nmol
      in 5 million cells, respectively, at a signal-to-noise ratio of approximately 2.
      The practical utility of this new HPLC method was confirmed in a pilot
      pharmacokinetic study in BALB/c mice as well as in a cellular drug uptake and
      disposition study in RBL-2H3 mast cells. After intraperitoneal administration of
      a non-toxic 40 mg/kg bolus dose of WHI-P131, the estimated maximum plasma
      concentration was 92.7 microM, which is approximately 1-log higher than the
      effective in vitro mast cell inhibitory concentrations of WHI-P131. The drug
      absorption was rapid with an absorption half-life of only 2.9 min and the
      estimated time to reach the maximum plasma concentration was 8.3 min. WHI-P131
      was cleared with an apparent systemic clearance rate of 2586 ml/h/kg and an
      elimination half-life of 1.8 h. An intracellular exposure level (AUC) of 55
      microM x h was obtained after in vitro treatment of RBL-2H3 mast cells with WHI
      P131 at a 33.6 microM final concentration in culture medium. The availability of
      the described quantitative HPLC detection method for WHI-P131 provides the basis
      for further development of WHI-P131 as an anti-allergic drug through detailed
      pharmacodynamic studies in preclinical animal models.

PMID- 10360440
TI  - Microbore high-performance liquid chromatographic determination of cisapride in
      rat serum samples using column switching.
AB  - For the determination of cisapride from serum samples, an automated microbore
      high-performance liquid chromatographic method with column switching has been
      developed. After serum samples (100 microl) were directly injected onto a Capcell
      Pak MF Ph-1 pre-column (10 x 4 mm I.D.), the deproteinization and concentration
      were carried out by acetonitrile-phosphate buffer (20 mM, pH 7.0) (2:8, v/v) at
      valve position A. At 2.6 min, the valve was switched to position B and the
      concentrated analytes were transferred from MF Ph-1 pre-column to a C18
      intermediate column (35x2 mm I.D.) using washing solvent. By valve switching to
      position A at 4.3 min, the analytes were separated on a Capcell Pak C18 UG 120
      column (250 x 1.5 mm I.D.) with acetonitrile-phosphate buffer (20 mM, pH 7.0)
      (5:5, v/v) at a flow-rate of 0.1 ml/min. Total analysis time per sample was 18
      min. The linearity of response was good (r=0.999) over the concentration range of
      5-200 ng/ml. The within-day and day-to-day precision (CV) and inaccuracy were
      less than 3.7% and 3.8%, respectively. The mean recovery was 96.5+/-2.4% with the
      detection limit of 2 ng/ml.

PMID- 10360441
TI  - Simple and rapid analytical method for carbapenems using capillary zone
      electrophoresis.
AB  - A simple and rapid analytical method for carbapenems using high-performance
      capillary electrophoresis is described. All therapeutic carbapenem injections in
      Japan (imipenem, panipenem and meropenem) and four other beta-lactams
      (piperacillin, cefotiam, cefotaxime, latamoxef) were separated and determined
      with good repeatability in about 10 min using simple free zone capillary
      electrophoresis. The electrophoresis buffer was 100 mM phosphate buffer of pH
      8.0, and a fused-silica capillary of 25 microm I.D. and 47 cm length was adopted.
      The present method was successfully applied to monitor the degradation of
      carbapenems under various conditions (at various temperatures or in coexistence
      with other drugs prescribed in the case of methicillin-resistant Staphylococcus
      aureus).

PMID- 10360442
TI  - Quantitative analysis of human serum corticosterone by high-performance liquid
      chromatography coupled to electrospray ionization mass spectrometry.
AB  - An original method based upon high-performance liquid chromatography coupled to
      electrospray ionization mass spectrometry has been developed for corticosterone
      (B) quantification in human serum. After extraction by diethyl ether using
      triamcinolone (T) as an internal standard, solutes are separated on a C18
      microbore column (250 X 1.0 mm, I.D.), using acetonitrile-water-formic acid
      (40:59.9:0.1, v/v/v) as the mobile phase (flow-rate 40 microl/min). Detection is
      performed on an API 1 single quadrupole mass spectrometer equipped with a ESI
      interface and operated in positive ionization mode. Corticosterone
      quantifications were realized by computing peak area ratios (B/T) of the serum
      extracts analyzed in SIM mode (m/z 347 and m/z 395 for B and T. respectively),
      and comparing them with the calibration curve (r=0.998).

PMID- 10360443
TI  - Thiopurine methyl transferase activity: new extraction conditions for high
      performance liquid chromatographic assay.
AB  - A new liquid-liquid extraction is described for thiopurine methyl transferase
      (TPMT, EC 2.1.1.67) activity determination: the use of a pH 9.5 NH4Cl buffer
      solution, before adding the solvent mixture, allows more rapid extraction,
      avoiding a centrifugation step, and reduces the global cost of analysis. After
      the extraction step, 6-methylmercaptopurine, synthesised during the enzymatic
      reaction, is determined by a liquid chromatographic assay. Analytical performance
      of the assay was tested on spiked erythrocyte lysates. The linear concentration
      range was 5-250 ng ml(-1) (r> or =0.997, slope=1.497, intercept=-0.367). The
      recoveries were 82.8, 89.9 and 82.2% for 75, 125 and 225 ng ml(-1), respectively.
      The coefficients of variation were < or =6.1% for within-day assay (n=6) and < or
      =9.5% for between-day assay precision (n=6; 14 days). TPMT activity was
      determined in a French adult Caucasian population (7 =70). The results ranged
      from 7.8 to 27.8 nmol h(-1) ml(-1) packed red blood cells and the frequency
      distribution histogram is similar to that previously published.

PMID- 10360444
TI  - Rapid and sensitive method for determination of nimesulide in human plasma by
      high-performance liquid chromatography.
AB  - A rapid and sensitive high-performance liquid chromatographic method for
      determination of nimesulide in human plasma has been developed. The
      chromatographic system uses a reversed-phase C18 column with UV-Vis detection at
      230 nm. Mobile-phase consisted of phosphate buffer (pH 5.5)-methanol-acetonitrile
      (50:20:30, v/v) at a flow-rate of 1.4 ml/min. Nimesulide was extracted in a
      single step into dichloromethane. The overall mean extraction recoveries were
      above 98% for both inter- and intra-assay reproducibility, with CVs from 0.3 to
      1%. The calibration curve was linear in the concentration range of 0.05-5
      microg/ml, and the lower limit of detection was 30 ng/ml. This simple and
      sensitive method allows for determination of the range of plasma concentrations
      that is observed after administration of clinically relevant doses of nimesulide.

PMID- 10360445
TI  - Simple high-performance liquid chromatography determination of ampicillin in
      human serum using solid-phase extraction disk cartridges.
AB  - A simple and reproducible method for the analysis of ampicillin in human serum
      was developed. Serum samples were extracted using solid-phase extraction disk
      cartridges containing a sorbent of styrene divinyl/benzene. Extracts were
      separated by reversed-phase C18 high-performance liquid chromatography with UV
      detection at 220 nm. The mobile phase consisted of acetonitrile-10 mM NaH2PO4
      (6.5:93.5, v/v). Using this extraction procedure, recovery from serum was 98.4+/
      5.6%. The quantitation limit was 0.19 microg/ml using 0.5 ml of serum. The
      calibration curves from 0.19 to 9.41 microg/ml were linear with correlation
      coefficients of 0.999. This method is suitable for therapeutic drug monitoring of
      ampicillin (ABPC) after oral administration of lenampicillin hydrochloride.

PMID- 10360446
TI  - Hemodialysis membrane biocompatibility--does it matter?

PMID- 10360447
TI  - Predictive value of prostate-specific antigen, tumour stage and tumour grade for
      the outcome of bone scintigraphy in patients with newly diagnosed prostate
      cancer.
AB  - OBJECTIVE: In order to evaluate the negative predictive value of a low prostate
      specific antigen (PSA) for a positive bone scan, we performed a retrospective
      study in a patient material from the Umea region in Northern Sweden. We also
      evaluated whether different tumour grades could influence this predictive value.
      MATERIAL AND METHODS: Four-hundred-and-forty-six patients of newly diagnosed
      prostate cancer were reviewed. We analysed different levels of PSA, tumour grade,
      tumour stage and combinations of these parameters for their use in making a
      positive bone scintigraphy (BS) prediction. RESULTS: Among 214 patients with PSA
      <20 ng/ml, 9 showed a positive BS. When tumours of grades 2 and 3 were excluded,
      the number of positive BS predictions decreased to 6. For 350 of these 446
      patients, a classification according to TNM was available; 162 of these 350 had a
      PSA value <20 ng/ml, and when this group comprised only small and well
      differentiated tumours (T1-2, G1), only one of the remaining 81 patients had a
      positive BS result. CONCLUSIONS: We conclude that in most patients with small and
      well-differentiated tumours (T1-2, G1) and PSA <20, BS staging need not be
      carried out.

PMID- 10360448
TI  - Lower urinary tract symptoms--a population survey using the Danish Prostatic
      Symptom Score (DAN-PSS) questionnaire.
AB  - OBJECTIVE: To describe voiding problems and the trouble they cause in a Danish
      population. Furthermore, to find symptoms specific for the ageing man, and
      thereby symptoms that might relate to an enlarged prostate. MATERIAL AND METHODS:
      The DAN-PSS questionnaire was mailed to a gender- and age-stratified random
      sample of 500 inhabitants in Herlev municipality. Prevalence of the symptoms and
      the trouble they cause were calculated and related to age and gender by the x2
      test for trend and the chi2 test, respectively. RESULTS: The response rate was
      73.6%. In total, 84.5% of the subjects had experienced at least one symptom
      within the previous fortnight. The various symptom prevalences ranged from 3.8
      67.1%. Although many subjects experienced symptoms, they were not always bothered
      by them, and women were generally more bothered than men. Weak stream, hesitancy
      and dribbling occurred more often among men, whereas incontinence (stress, mixed)
      occurred more often among women. Nocturia and mixed incontinence increased in
      prevalence with increasing age among both men and women. Weak stream, incomplete
      emptying, stress and urge incontinence showed an age-related increase in
      prevalence among men, but not among women. These might therefore be symptoms of
      an enlarged prostate. CONCLUSION: Lower urinary tract symptoms occur with high
      prevalence in the background population, but they do not always cause trouble.
      Weak stream, incomplete emptying, stress and urge incontinence seem to be
      symptoms of an enlarged prostate.

PMID- 10360449
TI  - Surgical repair of vesicovaginal fistulae--a ten-year retrospective study.
AB  - OBJECTIVE: Vesicovaginal fistulae in the western world generally occur as
      complications to pelvic surgery or radiation therapy of pelvic cancers. We have
      reviewed our results of vesicovaginal fistula closure procedures over a 10-year
      period. PATIENTS AND METHODS: From 1985 to 1996, 55 patients were referred to our
      department due to vesicovaginal fistulae. Five patients had fistulae due to
      malignant recurrence and one patient was considered inoperable. Thus, 49 patients
      were operated on. Thirty patients had fistulae resulting from pelvic surgery.
      Nineteen of the 25 patients admitted with fistulae secondary to radiation therapy
      of pelvic cancers were operated on. RESULTS: Of the 30 patients with
      postoperative fistulae, 23 had an abdominal repair and 7 a vaginal repair. A
      success rate of 90% was achieved after a first closure procedure, as 3 patients
      within a month experienced a recurrence. These three recurrences were all
      successfully closed in a second operation, augmenting the success rate to 100% in
      this group of patients. In the group of patients with fistulae caused by
      irradiation, a urinary diversion was performed in 12 patients, and in 7 patients
      a primary attempt to close the fistula was made, either by an abdominal approach
      (2 patients) or by a vaginal approach (5 patients). The fistula recurred in 6 of
      these 7 patients. Despite several additional attempts to close the recurrent
      fistulae, only one patient was successfully operated on. CONCLUSION: It seems
      that vesicovaginal fistulae resulting from pelvic surgery, in our hands, can be
      managed successfully either by an abdominal or vaginal approach. For patients
      with vesicovaginal fistulae resulting from radiation therapy, a urinary diversion
      appears to be the method of choice.

PMID- 10360450
TI  - Intravesical capsaicin in patients with detrusor hyper-reflexia--a placebo
      controlled cross-over study.
AB  - The aim of this study was to determine whether intravesical treatment with
      capsaicin could block detrusor hyper-reflexia (DH) and alter the substance P
      content, nerve fibres and mucosa of the bladder. Twelve patients with spinal cord
      disease with DH and urinary incontinence resistant to anticholinergic treatment
      underwent intravesical administration of 50 ml 2% lignocaine. followed by either
      100 ml 1 mmol/l capsaicin or 100 ml physiological saline for 30 min. Cross-over
      to the alternative treatment took place after 4 weeks. Varying degrees of burning
      sensation were experienced by all but one patient during the capsaicin treatment
      and precluded the possibility of conducting studies of this type in a blind
      manner. No preference for capsaicin treatment was found, and micturition and VAS
      scores were unchanged after treatment with capsaicin. The mean volume of the
      contents of the bladder at which DH first appeared was 175 ml after saline and
      195 ml after capsaicin (mean difference 20 ml with a 5% confidence interval from 
      25 to 65). Bladder biopsies taken 2 weeks after treatment with capsaicin showed
      more pronounced inflammation, superficial haemorrhage, squamous epithelial
      metaplasia and a more condensed bladder stroma. Immunohistochemical staining for
      substance P and neuronal cell adhesive molecule revealed the presence of small
      terminal axons and small nerve bundles in all of the biopsies. Intravesical
      treatment with capsaicin did not have a beneficial effect on DH or a destructive
      effect on nerve fibres. It did, however, produce significant reactive changes in
      the mucosa of the bladder.

PMID- 10360451
TI  - Nocturnal enuresis can be caused by absorptive hypercalciuria.
AB  - OBJECTIVE: The aim of this study was to determine whether nocturnal enuresis (NE)
      can be caused by absorptive hypercalciuria. MATERIALS AND METHODS: From 1981 to
      1995, 406 patients with primary monosymptomatic nocturnal enuresis were studied.
      Up to 1989 (Group 1), urinary electrolytes and urinary creatinine were not
      evaluated, but since 1990 (Group 2) these tests have been performed routinely. In
      doing so, we noticed that in 8 patients in Group 2 and in 13 patients in Group 1
      with persistent NE the urinary calcium and the urinary calcium/creatinine ratios
      were significantly high (p < 0.001). These patients were submitted to Pak's test
      and parathyroid hormone (PTH) and antidiuretic hormone (ADH) measurements.
      RESULTS: In all 21 patients, PTH and ADH levels were normal, while the Pak's test
      showed absorptive hypercalciuria. They were given an appropriate diet. After 3
      months, NE had ceased completely in 4 patients (19%); bedwetting episodes
      diminished and calciuria levels were found to be borderline in the remaining 17.
      A new urodynamic evaluation showed normal patterns in 12 and detrusor instability
      (DI) in 5. Patients with DI received oxybutinine: enuresis disappeared in all.
      The remaining 12 children with persistent NE and normal urodynamic findings and
      the child with DI and persistent NE empirically received DDAVP; enuresis ceased
      in all of them within 1 month and calciuria stabilized at normal levels.
      CONCLUSIONS: This study revealed that absorptive hypercalciuria can be
      responsible for NE and can be treated with the combination of diet and DDAVP.

PMID- 10360452
TI  - Effectiveness of oxybutynin hydrochloride in the treatment of enuresis nocturna-
      a clinical and urodynamic study.
AB  - OBJECTIVE: To find the efficacy and optimal dosage of oxybutynin HC1 in a group
      of enuretic children, who were non-responsive to imipramine. MATERIAL AND
      METHODS: Thirty-six patients with enuresis who were non-responsive to imipramine
      were urodynamically assessed and subsequently treated with oxybutynin
      hydrochloride (HCl). Patients with inadequate bladder storage function (IBSF)
      were started on 10-mg daily oxybutynin HCl for one month. If the initial
      treatment was found to be inadequate, the dose was increased to 15 mg daily. The
      dose in patients who were non-responsive to 15-mg daily dose was increased to 20
      mg daily dose. Patients who were normal urodynamically were treated with a dose
      of 15 mg daily for one month. RESULTS: Before the treatment, 17 patients had IBSF
      (47.2%). The majority of the patients (88.2%) with IBSF were responsive to the 15
      mg daily oxybutynin HCl. The treatment in patients with normal bladder function
      was generally unsuccessful. CONCLUSIONS: Oxybutynin HCl in sufficient dosages
      seems to be effective in the treatment of enuretic patients with IBSF.

PMID- 10360453
TI  - A variation and ureterovascular hydronephrosis.

PMID- 10360454
TI  - Effects of pentoxifylline on the haematologic status in anaemic patients with
      advanced renal failure.
AB  - OBJECTIVE: Erythropoietin (EPO) deficiency is the main cause of renal anaemia.
      However, inhibition of erythropoiesis by cytokines such as tumour necrosis factor
      alpha (TNF-a) may play an important role. The aim of this work was to study the
      effects of pentoxifylline, an agent with anti-TNF-a properties, on the
      haematologic status in anaemic patients with advanced renal failure. MATERIAL AND
      METHODS: In a prospective study, 7 anaemic patients with advanced renal disease
      (creatinine clearance <30 ml/min) were treated with pentoxifylline (400 mg orally
      daily) for 6 months. The evolution of haemoglobin, haematocrit, creatinine
      clearance and serum EPO and TNF-a a concentrations were compared with those
      obtained from an untreated control group. RESULTS: Haemoglobin and haematocrit
      significantly increased in the pentoxifylline-treated patients (9.9+/-0.5 g/dl
      and 27.9+/-1.6% at baseline; 10.6+/-0.6 g/dl and 31.3+/-1.9% at the 6th month,
      respectively, p < 0.01), whereas no variation was seen in the control group.
      Serum EPO levels remained stable in all patients. However, the serum TNF-a
      concentration decreased significantly in patients receiving pentoxifylline (basal
      623+/-366 pg/ml; 6th month 562+/-358 pg/ml, p < 0.01), but not in the control
      group. CONCLUSIONS: Our findings suggest that the inhibition of erythropoiesis by
      cytokines may play a significant role in renal anaemia. The administration of
      agents with anti-cytokine properties, such as pentoxifylline, can improve the
      haematologic status in anaemic patients with advanced renal failure.

PMID- 10360455
TI  - Ureteric obstruction due to kinking of the reservoir inlet in a continent urinary
      reservoir.
AB  - We report a case of symptomatic intermittent upper tract obstruction in a
      continent urinary reservoir. The ureters were of great intraperitoneal length and
      were positioned in front of the mesenterium, resulting in a mobile reservoir.
      Only the retroperitoneal part of the ureters was dilated due to kinking in the
      peritoneal passage. After the ureters were shortened and reanastomosed
      retroperitoneally, the repeated episodes of abdominal pain and discomfort
      disappeared..

PMID- 10360456
TI  - Renal lymphoma in an azotemic patient--usefulness of magnetic resonance imaging.
AB  - An azotemic patient benefited from diagnostic magnetic resonance imaging (MRI) in
      the evaluation of his renal mass. This led to suspicion of lymphoma, and provided
      guidance for percutaneous biopsy. Chemotherapy was then initiated, and an
      unnecessary nephrectomy was avoided. After a year of follow-up, evolution was
      stable and renal function significantly improved.

PMID- 10360457
TI  - Unilateral traumatic hematocele--an unusual presentation of bilateral testicular
      rupture.
AB  - The case of a young male patient with penile laceration and right hematocele
      following blunt trauma to the genitalia is presented. Both testes were found
      ruptured at exploration and were repaired. The value of early surgical
      intervention in scrotal trauma is reiterated and indications for bilateral
      testicular exploration in cases of unilateral traumatic hematocele are suggested.

PMID- 10360458
TI  - Extra-adrenal phechromocytoma and renal cell carcinoma--an unusual case of tumour
      synchronism.
AB  - We report an unusual case of tumour synchronism combining an extra-adrenal
      pheochromocytoma and a renal cell carcinoma in a 48-year-old male. The most usual
      forms of presentation are described in accordance with their clinical
      significance. We emphasize the diagnostic importance of specific biochemical
      studies and the accurate anatomical localization of extra-adrenal chromaffin
      tissue by magnetic resonance imaging (MRI) and scintigraphy with 131 Iodine
      methyliodobenzylguanidine (131I-MIBG). Surgical excision was the treatment of
      choice after the institution of adequate preoperative cardiovascular management.
      Pertinent features of the natural history of these tumours are described in
      accordance with their different embryological origin.

PMID- 10360459
TI  - Simultaneous contralateral testicular metastasis from a renal clear cell
      carcinoma.
AB  - The case of a 66-year-old male with a right renal cell carcinoma and a left
      testicular mass is reported. Radical nephrectomy and contralateral orchidectomy
      were performed. Histology revealed a metastasis of the renal cell carcinoma of
      clear cell type into the left testis. The patient died seven months post
      operatively of disseminated lung metastases. The case demonstrates the multi
      ocular metastatic potential of renal cell carcinoma.

PMID- 10360460
TI  - Multiple leiomyoma of the renal capsule.
AB  - Multiple renal capsular leiomyoma is an extremely rare tumour. We describe one
      such case which was managed by renal sparing surgery.

PMID- 10360461
TI  - Metastatic renal cell carcinoma mimicking pleural mesothelioma.
AB  - Although it is well known that renal cell carcinoma metastasizes to the thorax,
      sole pleural metastasis is rare. We report a case of mesothelioma-like metastasis
      of renal cell carcinoma.

PMID- 10360462
TI  - In musculoskeletal epidemiology are we asking the unanswerable in questionnaires
      on physical load?

PMID- 10360463
TI  - Shift work, risk factors and cardiovascular disease.
AB  - The literature on shift work, morbidity and mortality from cardiovascular
      disease, and changes in traditional risk factors is reviewed. Seventeen studies
      have dealt with shift work and cardiovascular disease risk. On balance, shift
      workers were found to have a 40% increase in risk. Causal mechanisms of this risk
      via known cardiovascular risk factors, in relation to circadian rhythms,
      disturbed sociotemporal patterns, social support, stress, behavior (smoking,
      diet, alcohol, exercise), and biochemical changes (cholesterol, triglycerides,
      etc) are discussed. The risk is probably multifactorial, but the literature has
      focused on the behavior of shift workers and has neglected other possible causal
      connections. In most studies methodological problems are present; these problems
      are related to selection bias, exposure classification, outcome classification,
      and the appropriateness of comparison groups. Suggestions for the direction of
      future research on this topic are proposed.

PMID- 10360464
TI  - Relationship between shift work and onset of hypertension in a cohort of manual
      workers.
AB  - OBJECTIVES: This study investigated the possibility of a relationship between
      blood pressure level and rotating 3-shift work in a prospective follow-up of
      workers in a zipper and aluminum sash factory in Japan. METHODS: Altogether 1551
      men aged 18-49 years were followed prospectively for 5 years, and the cumulative
      incidence of hypertension among 3-shift workers was compared with that of day
      workers. A multiple logistic analysis was used for adjusting for base-line
      characteristics such as age, body mass index, blood pressure, and drinking habit.
      RESULTS: In the younger age group, the relative risk of the rotating 3-shift
      workers during the observational period was increased compared with that of day
      workers after adjustment for the confounding factors. In the older group, the
      cumulative incidence of hypertension was not higher for workers who had continued
      shift work. However, a relatively high risk of hypertension was found for workers
      who converted from 3-shift work to day work when compared with those who remained
      on shift work and day work. CONCLUSIONS: It is suggested that there is an
      association between 3-shift work and blood pressure.

PMID- 10360465
TI  - Validation of a questionnaire for assessing physical work load.
AB  - OBJECTIVES: Reliable, valid, and compatible methods are required for exploring
      the complex interactive effects of psychosocial and physical stressors on
      complaints and disorders. An instrument for assessing physical work load that
      integrates information from a biomechanical model of lumbar load is presented and
      validated. METHODS: Four hundred and fifty-five people working in nursing homes
      for elderly people in Germany filled out the developed questionnaire 3 times
      within 1 year. Test-retest reliability was calculated, and validity was checked
      several times. Relationships with other, theoretically related and unrelated
      variables were examined. RESULTS: The test-retest reliability of the
      questionnaire measures was about 0.65. The convergent and discriminant validity
      was satisfactory, and the questionnaire was able to separate professional
      subgroups with different physical work loads. The Spearman rank-order
      correlations between physical load and musculoskeletal complaints were about
      0.30. CONCLUSIONS: The method developed in this study is a reliable and valid
      instrument for assessing physical work load. The integration of statistical
      methods from psychological testing and theory in the development of methods
      exploring the effects of physical work load is advocated.

PMID- 10360466
TI  - Agreement between symptom surveys, physical examination procedures and
      electrodiagnostic findings for the carpal tunnel syndrome.
AB  - OBJECTIVES: The goal of this study was to evaluate the concordance between
      various clinical screening procedures for carpal tunnel syndrome. METHODS: The
      subject population consisted of 824 workers from 6 facilities. The evaluated
      procedures included bilateral sensory nerve conduction testing, physical
      examinations, and symptom surveys, including hand diagrams. The agreement between
      the outcomes of various combinations of these procedures was assessed by
      determining the kappa coefficient. RESULTS: There was relatively poor overlap
      between the reported symptoms, the physical examination findings, and the
      electrodiagnostic results consistent with carpal tunnel syndrome. Overall, only
      23 out of 449 subjects (5%) with at least 1 positive finding met all 3 criteria
      (symptoms, physical examination findings, and electrophysiological results
      consistent with carpal tunnel syndrome) for the dominant hand. The screening
      procedures showed poor or no agreement with kappa values ranging between 0.00 and
      0.18 for all the case definitions evaluated for carpal tunnel syndrome.
      CONCLUSIONS: The poor overlap between the various screening procedures warns
      against the use of electrodiagnostic findings alone without the symptom
      presentation being considered. The results of this study also point to a need for
      the further development and evaluation of methods for detecting carpal tunnel
      syndrome.

PMID- 10360467
TI  - Etiologic clues to lip cancer from epidemiologic studies on farmers.
AB  - OBJECTIVES: This study examined the risk factors for lip cancer among farmers.
      METHODS: A series of meta-analyses of peer-reviewed studies of lip cancer and
      farming were performed using 21 studies published between 1981 and 1997. Prior to
      the meta-analyses, all the studies were reviewed and evaluated for heterogeneity
      and publication bias. Combined relative risks (RR) were calculated using the
      random effect model. RESULTS: The combined RR for lip cancer was 2.0 [95%
      confidence interval (95% CI) 1.74-2.30] for all the studies and 1.28 (95% CI 0.79
      2.08) for studies involving female farmers. Additional meta-analyses were
      undertaken on a subset of studies reporting on skin cancer among farmers. The
      combined RR for nonmelanotic skin cancer was 1.0 (95% CI 0.89-1.14), and for
      malignant melanoma it was 0.88 (95% CI 0.74-1.05). CONCLUSIONS: The findings
      suggest that male farmers have a significantly elevated risk for lip cancer. Lip
      cancer and skin cancer do not share a common etiologic factor. Besides sunlight
      exposure, other factors such as viral infection or reduced immunity may play a
      role in the etiology of lip cancer.

PMID- 10360468
TI  - Exposure to polycyclic aromatic hydrocarbons and genotoxic effects on nonsmoking
      Swedish road pavement workers.
AB  - OBJECTIVES: The objective of this study was to investigate exposure to polycyclic
      aromatic hydrocarbons (PAH) from asphalt fumes among Swedish road pavement
      workers and determine whether any effects could be detected with genotoxic tests.
      METHODS: The study included 28 nonsmoking road pavers and 30 nonsmoking
      referents. The concentration of PAH was determined in the breathing zone of the
      road pavers. 1-Hydroxypyrene was analyzed before and after shifts of asphalt work
      and during the afternoon for referents. Sister chromatid exchanges (SCE) and
      micronuclei (MN) were determined in peripheral lymphocytes. RESULTS: Several 3-
      or 4-ring PAH were found, and the analysis indicated that they occurred in
      bitumen fumes rather than in traffic fumes. The average total concentration of
      PAH was 2.3 (range 0.2-23.8) microg/m3. The concentration of 1-hydroxypyrene in
      urine was higher for the road pavers than for the referents, but there was no
      significant difference between the pre- and postshift values of the road pavers.
      The road pavers had no significant increase in SCE or MN. CONCLUSIONS: The study
      showed that Swedish road pavers have an increased exposure to PAH from bitumen
      fumes, but no genotoxic effects could be detected by SCE or MN tests.

PMID- 10360469
TI  - Nasal patency and lavage biomarkers in relation to settled dust and cleaning
      routines in schools.
AB  - OBJECTIVES: This study determined the relations between settled dust and cleaning
      routines in classrooms on one hand, and nasal symptoms, nasal cavity dimensions,
      and the concentration of selected biomarkers of inflammation in nasal lavage on
      the other. METHODS: Measurements of settled dust via standardized vacuum cleaning
      and an investigation of the cleaning routines were performed in 12 randomly
      selected primary schools in the municipality of Uppsala. Clinical examinations
      including acoustic rhinometry and nasal lavage were performed in the school
      environment among 279 school personnel working in the main buildings of the
      schools. Eosinophil cationic protein (ECP), myeloperoxidase (MPO), lysozyme, and
      albumin were analyzed in the lavage fluid. The relationships between the medical
      and hygienic data were analyzed both bivariately and with a multiple regression
      model controlling for age, gender, smoking, atopy, room temperature, and urban
      vicinity of the school. RESULTS: The amount of settled dust was positively
      related to subjective nasal obstruction and smaller nasal cavity dimensions
      measured with acoustic rhinometry. The noses were less patent, and the levels of
      ECP or lysozyme in the lavage were increased for the subjects in schools with a
      lower frequency of floor mopping, a lower frequency of desk cleaning, and where
      wet mopping was used. CONCLUSIONS: Our results indicate that the actual dust
      levels in Swedish classrooms can affect the occurrence of nasal obstruction among
      school personnel. A beneficial effect on the clinical signs of the nasal mucosa
      was observed for a higher frequency of both floor mopping and desk cleaning,
      whereas the use of wet mopping seemed disadvantageous in comparison with dry
      mopping. These findings illustrate the need for adequate cleaning procedures to
      minimize the environmental effects on the airway mucosa.

PMID- 10360470
TI  - Work stress and menstrual patterns among American and Italian nurses.
AB  - OBJECTIVES: This study assessed whether job stress alters menstrual patterns
      among nurses working in 2 different settings: a tertiary care hospital in New
      York (99 nurses) and a university hospital in Rome (25 nurses). METHODS: Data on
      menstrual patterns were collected by a daily diary in which the nurses recorded
      their basal body temperature (BBT) and their menstrual bleeding status for a 3
      month period. The BBT curves were used to classify cycles as biphasic or
      monophasic, and as adequate or inadequate with respect to the luteal phase. Job
      stress was evaluated by both objective (environmental and work characteristics)
      and subjective (perceived stress) criteria. RESULTS: The American nurses,
      especially those assigned to high stress units, had an increased risk for long
      and monophasic cycles [relative risk (RR) 4.3, 95% confidence interval (95% CI)
      1.1-16.2 and RR 5.5, 95% CI 1.2-25.5, respectively]. Among those who perceived
      their stress at work to be high or reported strenuous work activity, the risk for
      longer cycles was also raised (RR 2.3, 95% CI 0.6-8.0 and RR 1.6, 95% CI 0.7-4.2,
      respectively). Luteal phase inadequacy followed the same pattern. Similar trends
      were observed in the Italian data. In addition, the rotating shiftwork pattern
      prevalent in the Italian group was possibly associated with higher rates of short
      cycles and inadequate luteal phases when compared with those of nurses working
      fixed shifts either day or night. CONCLUSIONS: Menstrual function may be affected
      by stressful work conditions.

PMID- 10360472
TI  - Total quality strategy in the formative process of the occupational physician.
AB  - Interest in applying the concepts of total quality management to the fields of
      health care and medical education is growing. This paper analyzes the field of
      education in occupational medicine to explore the relationships between teaching
      and the deliverance of a product or a service. Issues such as defining teaching
      customers, addressing customer needs, teaching processes, and assessing and
      improving quality teaching are described. The occupational physician is requested
      to act according to particular competencies. This demand implies the need to meet
      specific requirements. To assure the achievement of these goals, the
      implementation of a teaching process must include (i) targeting the learning
      objectives (the knowledge, skills, and attitudes the specialist should have),
      (ii) planning the evaluation system (ability of the course to assure the
      achievement of the objective), (iii) evaluating the curriculum (compliance of the
      acquired competencies to the needs).

PMID- 10360471
TI  - Repeated hand urticaria due to contact with fishfood.
AB  - BACKGROUND: The etiology of urticaria is often difficult to determine. However,
      in case of repeated circumstance-connected urticaria, the reason may be easily
      clarifyable. CASE: A 51-year-old healthy woman repeatedly experienced
      occupational hand urticaria when handling fish food. An unexpected reason for the
      urticaria was found in that the fishfood contained histamine as a "contaminant".
      CONCLUSIONS: In fishfood batches, biological degradation can produce histamine
      and possibly other toxic substances that can lead to occupational health
      problems.

PMID- 10360473
TI  - International workshop on biomarkers for isocyanates.

PMID- 10360474
TI  - Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro.
AB  - Medulloblastoma is a malignant paediatric central nervous system tumor with a
      poor prognosis, stimulating the evaluation of improved treatment strategies.
      Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A
      reductase, is currently used to treat patients with hypercholesterolemia. This
      compound also inhibits the production of non-steroidal mevalonate derivatives
      that are implicated in the control of cellular proliferation, and can induce cell
      cycle arrest in vitro. We recently showed that lovastatin inhibited growth and
      promoted apoptosis of neuroblastoma, the peripheral nervous system 'cousin' of
      medulloblastoma. Therefore the potential of lovastatin as a possible anticancer
      drug against medulloblastoma was evaluated in vitro. Four medulloblastoma cell
      lines, Daoy, UW228, D341 Med and D283 Med, were treated with 1-40 microM of
      lovastatin in vitro. Analysis of cell morphologic changes, cell viability, DNA
      fragmentation and flow cytometry in all four cell lines showed growth inhibition
      and induction of apoptosis with lovastatin treatment. As little as 10 microM of
      lovastatin was sufficient to cause a marked reduction in cell numbers, and more
      than 20 microM of lovastatin induced >90% cells to undergo apoptosis, after
      intervals ranging between 36 and 96 h, depending on the cell line. Lovastatin
      induced apoptosis in these cell lines was concomitant with cell cycle arrest in
      G1. The attached cell lines UW228 and Daoy were more sensitive to lovastatin than
      D283 Med and D341 Med. Daoy cells which survived several cycles of lovastatin
      treatment could still be induced to undergo apoptosis after longer treatment
      times. The efficient induction of apoptosis by lovastatin favours this drug as a
      potential new avenue of therapeutic intervention for medulloablastoma.

PMID- 10360475
TI  - Effects of amifostine on cisplatin induced DNA adduct formation and toxicity in
      malignant glioma and normal tissues in rat.
AB  - The chemoprotective effect of amifostine (WR2721) was studied in a BDIX rat model
      with intracerebral BT4C glioma implants. Twenty-one rats were given cisplatin 5
      mg/kg i.p., 21 were given amifostine 200 mg/kg i.p. + cisplatin 5 mg/kg i.p. Ten
      rats served as untreated controls. An immunohistochemical method for analysis of
      cisplatin-DNA adducts was used to elucidate the adduct formation in tumor, normal
      brain and kidney. Tumor volume and serum creatinine level were analysed 10 days
      after treatment. In animals pretreated with amifostine there was a delayed adduct
      formation rate in the normal brain, and in the kidney cortex the number of
      tubular cells with extremely high adduct level was reduced. No difference in
      adduct formation was seen in tumors. Tumor volume was significantly larger
      following amifostine + cisplatin (66% of controls) compared to cisplatin alone
      (38% of controls). Weight loss was, however, severe in rats given cisplatin
      alone. In the tumor growth study only 3 out of 11 rats treated with cisplatin 5
      mg/kg alone survived until time of sacrifice at 10 days, whereas all those
      pretreated with amifostine survived. Mean serum creatinine was 48 micromol/l
      (controls), 146 micromol/l (cisplatin) and 59 micromol/l (amifostine +
      cisplatin). A marked reduction of histopathological renal changes was found when
      amifostine was added. Amifostine thus significantly reduced general and renal
      toxicity of cisplatin. The tumor growth retardation was stronger when cisplatin
      was given alone but this is probably related to general toxicity and malnutrition
      indirectly supported by the fact that amifostine did not significantly reduce
      cisplatin-DNA adduct formation in tumors. The results of the present study
      suggest that amifostine may have a role in increasing the therapeutic ratio of
      cisplatin, also in the treatment of malignant glioma.

PMID- 10360476
TI  - Differentiation and growth inhibition of glioma cells induced by transfer of trk
      A proto-oncogene.
AB  - The induction of growth inhibition and differentiation of a glioma cell line by
      transfection of trk A cDNA was examined, and production of endogenous nerve
      growth factor (NGF) also was studied in these cells. When human trk A cDNA was
      transfected into a human glioma cell line, U-251MG, which lacks expression of
      both endogenous trk A and low-affinity NGF receptor, the transfectant expressed
      the exogenous trk A mRNA and a functional high-affinity NGF receptor.
      Transfection of trk A cDNA caused a partial induction of cell differentiation, G1
      arrest, growth inhibition, tyrosine phosphorylation of the trk A proto-oncogene
      product, and activation of MAP kinase. Exogenous NGF treatment induced further
      terminal differentiation and growth inhibition. In summary, our data suggest that
      endogenous NGF secreted by glioma cells has an important role in the induction of
      glioma-cell differentiation occuring with transfer of exogenous trk A cDNA.

PMID- 10360477
TI  - Growth inhibition and radiosensitization of cultured glioma cells by nitric oxide
      generating agents.
AB  - The authors examined the effect of nitric oxide (NO) generating agents on the
      growth and radiosensitivity of cultured glioma cells. Three glioma, rat C6, and
      human T98G and U87 cell lines were treated with the NO generating agents, S
      nitroso-N-acetyl-penicillamine (SNAP) or sodium nitroprusside (SNP). These agents
      released NO in the cell culture media and inhibited the growth of the glioma
      cells. Growth-inhibition was attenuated by hemoglobin, a known inhibitor of NO,
      suggesting it is mediated by NO. When C6 and T98G cells were irradiated in the
      presence of SNAP or SNP at 100 microM, radiosensitization was observed. SNAP at
      100 microM exhibited a sensitizer enhancement ratio (SER) of 1.4 for C6 cells and
      1.8 for T98G cells. SNP at 100 microM only radiosensitized T98G cells with a SER
      of 1.9. The effect of SNP on radiosensitization of C6 cells was unclear. We
      conclude that NO generating agents are potential growth inhibitors and
      radiosensitizers for malignant glioma cells. NO mediated radiosensitization of
      glioma cells by NO generating agents may offer a new therapeutic approach for
      malignant glioma.

PMID- 10360478
TI  - Exogenous expression of p16INK4a is associated with decrease in telomerase
      activity.
AB  - In this study, gene transfection was used to determine whether the exogenous
      expression of p16INK4a modulated the biological characteristics of glioblastoma
      cells. The human glioblastoma cell line U87MG was doubly transfected with the
      plasmids pVgRXR and pIND harboring the wild-type p16 gene. The expression of
      p16INK4a in the resulting transfectants was regulated by the addition of the
      ecdysone homologue, muristerone A. When the cells expressed p16INK4a, their
      growth capacity was reduced and morphological changes such as an increase in cell
      size and cellular flattening were observed. The analysis of cell cycle regulation
      provided evidence that cells expressing p16INK4a were inhibited from entry into
      the cell cycle, as assessed by Ki-67 antigen expression. In addition, it was
      observed that the exogenous expression of p16INK4a was associated with decrease
      in telomerase activity.

PMID- 10360479
TI  - Morphometrical characterization of two glioma models in the brain of
      immunocompetent and immunodeficient rats.
AB  - Although several glioma models exist, systematic morphometrical studies on such
      experimental tumors are lacking. The purpose of this study was the quantitative
      assessment of how rat strains, cell lines, injection techniques and location
      affect tumors reproducibility and histopathological features. Glioma cells were
      implanted in 3 brain locations, with different injection techniques (free hand,
      stereotactic, water-tight device), variable volumes, cell concentrations and
      infusion rates. Tumors were developed from 2 rat glioma cell lines (9L and C6) in
      immunocompetent (Wistar and Fischer 344) and immunodeficient rats (New Zealand).
      Animals underwent daily neurological examination. At the scheduled time the
      tumors were macro and microscopically evaluated and a quantitative morphometrical
      analysis was performed. C6 gliomas appeared very infiltrative and irregularly
      shaped; 9L gliomas showed, by using the same injection technique, a grossly
      regular shape. Margins at the tumor-brain interface were macroscopically
      demarcated in the immunocompetent rats. In the nude rats, 9L tumors appeared
      microscopically more infiltrative, although regularly shaped, with a closer
      morphological resemblance to human gliomas. The implantation in the frontal area,
      anterior to the nucleus caudatus (3 mm anterior the coronal suture) gave
      reproducible tumor shape and size, no hydrocephalus and no early neurological
      deterioration. The use of a stereotactic technique or of a water-tight device,
      small volume (< 10 microl) of cell suspension, low infusion rate were useful to
      reduce morbidity and to improve data reproducibility. No difference in morbidity
      and mortality were observed in immunocompetent and immunodeficient rats. The 9L
      glioma model with stereotactic implantation constitutes a good option for
      reliable morphometrical evaluation of tumor growth. We propose a location for
      tumor implantation anterior to the nucleus caudatus. This produced the longest
      symptom-free survival.

PMID- 10360480
TI  - Hypophyseal non-Hodgkin's lymphoma presenting with diabetes insipidus: a case
      report.
AB  - We report the case of a 64 year old male patient with a history of ischemic heart
      disease who underwent surgery for an abdominal mass. The histological diagnosis
      was highly malignant non-Hodgkin's lymphoma. After surgery the patient was
      admitted to our Department and received 6 courses of chemotherapy according to
      the COP schedule, followed by radiotherapy to the left upper abdominal region and
      ipsilateral lung base. The patient achieved partial remission. One month later he
      began to complain of left axillary lymphadenomegaly, polydipsia and polyuria. A
      NMR brain scan showed a hypophyseal mass. The patient was treated with DDAVP and
      chemotherapy with the PRO-MACE protocol; the polyuria and lymphadenomegaly
      disappeared and the size of the hypophyseal mass reduced markedly. The clinical
      picture was, therefore, attributed to a hypophyseal localization of the non
      Hodgkin's lymphoma, which is a very rare manifestation of lymphomatous spread to
      the central nervous system. Our case is also interesting because it shows that a
      favorable outcome can be obtained with chemotherapy, provided that the latter is
      sufficiently aggressive. This is not necessarily the case with radiotherapy which
      may also be followed by late and severe neurologic sequelae.

PMID- 10360481
TI  - Toxicities related to intraarterial infusion of cisplatin and etoposide in
      patients with brain tumors.
AB  - Chemotherapy for malignant brain tumors has a limited efficacy largely due to
      restricted blood-brain barrier permeability for chemotherapeutic drugs.
      Intraarterial chemotherapy (IAC) has the advantage of increased uptake during the
      first passage of the drugs through tumor capillaries. Initial IAC trials had less
      than satisfactory results due to unacceptable toxicities. Between 1987 and 1996,
      173 patients with primary and metastatic brain tumors were treated with
      intraarterial (intracarotid and/or intravertebral) cisplatin and etoposide (VP
      16). Out of these, 168 patients, who received a total of 438 cycles, were
      evaluated for the incidence of toxicities. Patients received either cisplatin at
      40 mg/m2 and VP-16 at 20 mg/m2 or cisplatin at 60 mg/m2 and VP-16 at 40 mg/m2.
      Nausea and vomiting were the most common toxicities (42 patients, 14% of cycles).
      Arterial puncture was associated with a 1.6% incidence of groin hematomas (6
      patients), and a 0.7% incidence of failure to canulate the carotid or vertebral
      arteries (3 patients). Neurologic toxicities included headache (1.4% of cycles, 5
      patients), focal seizures (1.4% of cycles, 5 patients), transient confusion and
      urinary retention/incontinence (1.9% of cycles, 8 patients), and blurred vision
      (0.9% of cycles, 4 patients). We have not seen visual loss, strokes, major vessel
      dissection or thrombosis, or myelosuppression. Toxicity incidence was higher in
      patients with metastatic brain tumors than in those with primary brain tumors
      (34% versus 17%, p < 0.001). It was also higher in patients who had brain
      radiation therapy (RT) prior to IAC than in those who had RT concomitant with IAC
      (31% versus 19%, p = 0.05). No significant difference in toxicity incidence was
      noticed between patients who received RT concomitant with IAC and those who
      received RT after IAC (19% and 23% respectively, p = 0.08). Intracarotid
      chemotherapy given prior to RT resulted in 23 months of median survival for
      patients with glioblastoma multiforme. Intraarterial chemotherapy with cisplatin
      and VP-16 is a relatively safe treatment modality, especially in patients with
      primary brain tumors who have not received brain radiotherapy.

PMID- 10360482
TI  - Primary meningeal fibrosarcoma: a particular neuroradiological presentation.
AB  - Primary meningeal fibrosarcoma is a rare malignant tumor of the central nervous
      system. About seventeen cases have been reported in the literature since 1980. We
      present the case of a patient whose initial neuroradiological manifestation of
      primary meningeal fibrosarcoma was an en plaque meningioma. Fifteen months later,
      he developed a dramatic clinical deterioration and coma. CT scan revealed a large
      frontal lesion. The mass was completely removed and histological examination was
      characteristic of meningeal fibrosarcoma.

PMID- 10360484
TI  - History of the Section on Surgery, the American Academy of Pediatrics: the first
      25 years (1948-1973).

PMID- 10360483
TI  - Radiation therapy of metastatic spinal cord compression. Multidisciplinary team
      diagnosis and treatment.
AB  - PURPOSE: To evaluate the effectiveness of a multidisciplinary approach to spinal
      cord compression (SCC) in accordance with prospective protocol, providing a
      uniform approach to diagnosis, decision making concerning optimal treatment
      modality in any particular case of SCC, treatment performance and evaluation of
      treatment results. The SCC patients treated by radiation therapy are described.
      MATERIALS AND METHODS: Patients with SCC were examined and treated by a
      multidisciplinary team consisting of a neurologist, radiologist, oncologist,
      orthopedic surgeon, and neurosurgeon. Seventy-nine patients for whom radiation
      was recommended received a 30 Gy radiation dose to a compression-causing mass and
      course of high dose dexamethasone. Three fractions of 5 Gy and 5 fractions 3 Gy
      each were delivered by Co60 or 8 MV photon beam in 12 days. Treatment outcome was
      essentially evaluated by ambulation capabilities which were considered to be the
      main problem of SCC. Changes in other neurologic motor, sensory and autonomic
      disturbances were also evaluated. RESULTS: Seventy-two percent of the patients
      were already non-ambulatory at diagnosis. The first symptom was motor deficiency
      in only 33% of them while in all other cases it was pain. Ambulation capability
      was the main prognosticator of treatment outcome; 90% of patients who were
      ambulatory before treatment remained so while 33% of the non-ambulatory patients
      regained their ability to walk. The grade of motor disturbance was also an
      important variable: among the non-ambulatory patients, 50% of the paretic but
      only 14% of the plegic ones became ambulatory. Overall, 51% of the study patients
      were ambulatory after undergoing radiation. The ambulatory state after treatment
      was the main predictor for survival. CONCLUSION: Close cooperation of a
      multidisciplinary team in diagnosis and treatment according to the above protocol
      enabled the achievement of good results of radiation treatment in SCC. Early
      diagnosis and early treatment should further enhance therapeutic outcome.

PMID- 10360485
TI  - History of the Section on Surgery, the American Academy of Pediatrics: the second
      25 years (1973-1998).

PMID- 10360486
TI  - Ladd's vision.

PMID- 10360487
TI  - A perspective on the early days of pediatric surgery.

PMID- 10360488
TI  - From an acorn to an oak.

PMID- 10360489
TI  - Coding and reimbursement for endourologists. Endourologic Society.

PMID- 10360490
TI  - Secure transmission of urologic images and records over the Internet.
AB  - PURPOSE: Telemedicine has become a common method for the transmission of images
      and patient data across long distances. Our goal was to assess the efficiency and
      accuracy of Photomailer MD software, a store-and-forward telemedicine system, in
      the urologic setting. METHODS: Photomailer MD software was loaded on two
      computers in the host institution, one with a T1 connection to the Internet and
      the other with a dial-up modem connection (24,000 bits/second), and computers at
      three remote sites. A total of 14 clinical cases, comprised of digitized
      histories and radiographic images, were sent to the remote institutions four
      separate times using the four transmission modes available: nonencrypted, 56-bit
      encryption, 128-bit encryption, and 128-bit encryption with password. The
      following data points were recorded: file size before and after encryption, file
      transmission times, and diagnostic accuracy of the remote urologists. One-way
      ANOVA was used to compare mean values statistically, while the z-test was used to
      compare diagnostic accuracies. RESULTS: Encryption increased the file size by a
      mean of 37.8%, with the three encryption modes increasing file sizes by the same
      number of kilobytes. When a dial-up modem was used, encrypted files required a
      significantly longer transmission time (P < 0.05) than the unencrypted files. The
      same trend was seen with the T1 connection, although the differences often were
      not significant. When T1 transmission times were compared with modem times with
      other variables held constant, modem times were significantly longer (P < 0.05).
      Diagnostic accuracies for each of the three remote centers ranged from 85.7% to
      100%. Differences in accuracy rates between attending physicians and residents
      were not significant. CONCLUSIONS: Photomailer MD provides a secure, convenient,
      and affordable method of transmitting patient images and records via the
      Internet. Transmission speed was significantly greater when using a T1 line and
      also tended to be faster when files were not encrypted. There was no significant
      difference in transmission time among the three encryption modes; therefore, 128
      bit encryption with a password should be used to maximize security. Diagnostic
      accuracies were comparable to those in the literature. In general, 640 x 480
      pixel resolution was adequate for urologic diagnoses, although higher-resolution
      images may improve accuracy.

PMID- 10360491
TI  - Extracorporeal shockwave lithotripsy in the pediatric population.
AB  - BACKGROUND: Shockwave lithotripsy (SWL) is being used increasingly as a
      therapeutic modality for childhood urolithiasis. We reported our experience and
      results of SWL in the pediatric population. METHODS: The 59 renal units (RU) of
      54 patients were retrospectively reviewed. The mean patient age was 10+/-3.5
      years. All patients were treated with the Lithostar lithotripter in outpatient
      settings. Those with positive culture results were treated under appropriate
      antibiotic coverage. Seven patients were treated under general anesthesia and the
      rest under sedoanalgesia. Shielding of the lung fields or gonads was not used.
      For the upper pole stones, protection of the lungs was accomplished by elevating
      the upper half of the body with supportive pillows, thus moving the kidney away
      from the lung fields. Six RUs were catheterized via double-pigtail ureteral
      catheters or by percutaneous nephrostomy tube prior to treatment. The average
      stone load was 1.8+/-2.5 cm2. RESULTS: Patients were treated with an average of
      2.5 sessions. A total of 1000 to 2500 shockwaves were delivered between 14.5 and
      17.8 kV. Routine spasmolytic treatment was not initiated. The stone-free rate was
      64%, and clinically insignificant residual fragments (CIRF) were present in 29%
      of RUs; thus, the success rate was 93%. Fever that necessitated hospitalization
      occurred in one patient. No other complications were seen except skin bruising
      and early hematuria. CONCLUSION: Shockwave lithotripsy is a safe and effective
      treatment modality for childhood stones of appropriate size and radiologic
      characteristics.

PMID- 10360492
TI  - The role of ureteral stent placement in the prevention of Steinstrasse.
AB  - BACKGROUND AND OBJECTIVE: Steinstrasse constitutes a potentially serious
      complication of extracorporeal shock-wave lithotripsy (SWL). Ureteral stent
      placement has been used to prevent Steinstrasse after fragmentation of larger
      stones. However, particularly more recently, its preventive efficacy has been
      questioned. The aim of this study therefore was to analyze the role of ureteral
      stent placement in the prevention of Steinstrasse. METHODS: We analyzed data of
      1087 patients who had been treated with a Wolf Piezolith 2300 in the General
      Infirmary in Leeds/UK for stones ranging from 10 to 95 mm in diameter. RESULTS:
      The incidence of Steinstrasse was 6.3%. The likelihood was significantly
      correlated with the stone size and was significantly less in patients with stones
      >20 mm if a stent had been inserted prior to SWL. Moreover, in these patients,
      the risk of acute clinical symptoms in the event of Steinstrasse was greatly
      reduced, and the treatment could be continued safely in the majority of cases
      (86%). Treatments of the Steinstrasse itself with SWL resulted in its clearance
      in most of the cases (78%). It was always possible to clear even extended
      persistent Steinstrasse by laser lithotripsy. CONCLUSION: These results provide a
      clear indication for the pre-SWL insertion of a ureteral stent in patients with
      stones >20 mm in diameter. In the event of Steinstrasse, SWL of the collection
      should be tried before more invasive endourologic procedures are considered.

PMID- 10360494
TI  - Endoscopy vs. extracorporeal shockwave lithotripsy in the treatment of distal
      ureteral stones: ten years' experience.
AB  - BACKGROUND: The lower third is the location of the great majority of ureteral
      stones. Treatment of these stones remains controversial: in situ extracorporeal
      shockwave lithotripsy (SWL) vs. ureteroscopy (URS). METHODS: During the last
      decade, 633 distal ureteral calculi were treated at our institution using in situ
      SWL (Siemens Lithostar electromagnetic lithotripter) in 395 patients and URS
      (with 11.5F instrument and ultrasonic lithotripsy) in 228 patients. The patients'
      age and stone size were similar in the two groups. All SWL therapies were
      performed on an outpatient basis. RESULTS: The overall success rate was 99% for
      SWL, and the efficiency quotient (EQ) was 92.4%. The treatment was more effective
      for <10 mm calculi. In the URS group, there was a 92% overall success rate with
      an EQ at 91.2%. Compared with SWL, URS was more time consuming, at least for the
      initial cases; often required intravenous sedation; entailed routine placement of
      a ureteral stent; and more often led to hospitalization. On the other hand, stone
      clearance was rapid after URS, although most of the SWL patients were stone free
      at the end of 6 weeks. The cost was similar in the two groups. CONCLUSION: We
      believe that multiple factors should be considered when deciding the most
      appropriate approach to distal ureteral calculi. In situ SWL provides optimal
      first-line treatment for calculi < 10 mm, whereas URS is better reserved for
      stones >10 mm.

PMID- 10360493
TI  - Piezoelectric lithotripsy of ureteral stones: influence of shockwave frequency on
      sedation and therapeutic efficiency.
AB  - OBJECTIVE: The aim of this randomized study was to assess the relation between
      shockwave frequency, sedation, and efficiency in piezoelectric extracorporeal
      shockwave lithotripsy (SWL) for ureteral calculi. METHODS: A random sample of 114
      patients aged between 15 and 74 (mean 45) years were treated at the shockwave
      frequencies of 1 (N = 57) or 4 (N = 57) per second using the EDAP LT 02
      lithotripter at maximum energy. The stones' largest diameter ranged from 5 to 18
      mm (mean 7.6 mm). Lower ureteral stones were treated with the patient in the
      prone position and upper ureteral stones in supine position. The duration of SWL
      sessions and stone measurements were statistically similar for patients treated
      at low and high frequencies. The levels of required sedation (none, intramuscular
      analgesia, intravenous sedation-analgesia) and stone-free rates after one session
      were analyzed by Student's t-test or Fisher's exact test. RESULTS: Sedation did
      not differ statistically with SWL frequency for mid and lower ureteral calculi.
      However, the use of intravenous sedation-analgesia was less common for patients
      with upper ureteral stones treated at low rather than high frequency (19% and
      100%, respectively; P < 0.0001). The success rate was significantly lower (P =
      0.04) for lower ureteral calculi treated at low v high frequency (65 % and 89%,
      respectively) but was not statistically affected by frequency for upper ureteral
      stones. CONCLUSION: We recommend high frequency for piezoelectric SWL of lower
      ureteral calculi, especially for stones with a maximum diameter > or =8 mm. On
      the other hand, low-frequency SWL appears to be suitable for the treatment of
      upper ureteral stones.

PMID- 10360495
TI  - Effect of pressure distribution of shockwave on renal hemorrhage after
      extracorporeal shockwave lithotripsy: comparison of EDAP LT-01 and Siemens
      Lithostar.
AB  - BACKGROUND: Renal hemorrhage is the most common adverse effect of SWL, and it has
      been speculated to be related to the type of lithotripter used. METHODS: We
      investigated the incidence of renal hemorrhage in patients with urinary stones
      who underwent lithotripsy using either the EDAP LT-01 or the Siemens Lithostar.
      In addition, we performed in vitro experiments using pressure-sensitive paper in
      conjunction with gelatin, agar, or porcine tissue models of renal lithotripsy.
      RESULTS: Thirty-one (16.6%) of 187 kidneys treated with the EDAP LT-01 and 44
      (19.6%) of 225 kidneys treated with the Siemens Lithostar showed intrarenal or
      subcapsular hemorrhage or perinephric hematoma. In particular, the incidence of
      subcapsular hematoma was significantly higher in the Lithostar-treated patients
      (P < 0.0001). We discuss our results in light of the patterns of pressure
      distribution obtained from the two lithotripter units using in vitro models with
      colorometric, pressure-sensitive paper. CONCLUSION: It appears that the Siemens
      Lithostar exerts a greater pressure on the renal capsule, which may account for
      the higher incidence of subcapsular hematoma.

PMID- 10360496
TI  - Percutaneous suprapubic cystolithotripsy for vesical calculi in children.
AB  - BACKGROUND: The majority of vesical calculi in adults can now be treated per
      urethrally with the use of ultrasonic or pneumatic lithotripsy. However, the use
      of these devices is restricted in pediatric patients by the narrow caliber of the
      urethra. A percutaneous suprapubic approach to the bladder circumvents the
      problem of urethral caliber in these situations. PATIENTS AND METHODS: Thirty
      eight children presenting with bladder stones underwent percutaneous suprapubic
      cystolithotripsy (PCCL) between November 1989 and April 1996. The age ranged from
      1.5 to 7 years. The stone size ranged from 0.8 to 2.4 cm. Seven of these were
      recurrent stones, and five of the patients were female. The procedure was done
      under general anesthesia, and the equipment was the same as for upper tract
      endourology. The bladder was distended with saline and a suprapubic puncture
      made. The nephroscope was introduced after tract dilation and the stone removed,
      intact if small or after fragmentation if >1 cm. The procedure was done without
      fluoroscopy. A suprapubic catheter was left in for 48 hours. RESULTS: All
      patients had an uneventful recovery following stone removal. The average hospital
      stage was 3 days. Here, the access provided by percutaneous suprapubic cystostomy
      has been combined with the experience gained in upper-tract endourology to
      perform procedures that would otherwise require open operation because of
      nonavailability of urethral access. CONCLUSION: Extension of endourologic
      procedures to the lower tract reduces morbidity and hospital stay and thus the
      cost of treatment. Percutaneous suprapubic cystolithotripsy, in our experience,
      is a safe and cost-effective alternative to open surgery in children.

PMID- 10360497
TI  - Almost totally tubeless percutaneous nephrolithotomy: further evolution of the
      technique.
AB  - BACKGROUND AND OBJECTIVES: There is renewed interest in the concept of foregoing
      placement of the postoperative nephrostomy tube (PNT) after percutaneous
      nephrolithotomy (PCNL) with the intent of reducing postoperative discomfort and
      hospital stay. We have omitted the PNT and placed an internal ureteral stent or
      externalized ureteral catheter after PCNL in selected patients. We reviewed our
      experience in order to assess the efficacy and safety of this practice. PATIENTS
      AND METHODS: Primary PCNL was performed in 26 renal units in 21 patients (5
      bilateral PCNL, 4 of which were simultaneous) by one surgeon at the University of
      Michigan and the Ann Arbor Veterans Affairs Medical Center. A postoperative
      nephrostomy tube was placed if the stone burden was >3 cm, more than one access
      site was used, the renal anatomy was obstructive, significant bleeding or
      perforation was noted, or a second look was required. RESULTS: No PNT was placed
      in 10 renal units in 8 patients (no-PNT group). In six no-PNT kidneys, internal
      ureteral stents were used, and in four, externalized ureteral stents were placed
      for 1 to 2 days. The mean stone size in the PNT and no-PNT patients was 3.0 and
      1.8 cm, respectively. Of the 16 kidneys in the PNT group, 4 were initially
      eligible for omission of PNT, but a PNT was placed because of bleeding or other
      access-related problem. All patients were rendered stone free except for three
      (one PNT and two no-PNT) patients, who each had a fragment < or =4 mm. Omission
      of PNT placement resulted in decreased mean length of stay (2.3 days in the no
      PNT group v 3.6 days in the PNT group). There were four complications, all
      managed with delayed stenting (one in a no-PNT patient and the remaining three in
      the PNT group). CONCLUSION: Omission of PNT placement in selected patients may
      reduce morbidity without compromising efficacy and safety, but further study is
      needed.

PMID- 10360498
TI  - Holmium: YAG lithotripsy: photothermal mechanism.
AB  - OBJECTIVE: A series of experiments were conducted to test the hypothesis that the
      mechanism of holmium:YAG lithotripsy is photothermal. METHODS AND RESULTS: To
      show that holmium:YAG lithotripsy requires direct absorption of optical energy,
      stone loss was compared for 150 J Ho:YAG lithotripsy of calcium oxalate
      monohydrate (COM) stones for hydrated stones irradiated in water (17+/-3 mg) and
      hydrated stones irradiated in air (25+/-9 mg) v dehydrated stones irradiated in
      air (40+/-12 mg) (P < 0.001). To show that Ho:YAG lithotripsy occurs prior to
      vapor bubble collapse, the dynamics of lithotripsy in water and vapor bubble
      formation were documented with video flash photography. Holmium:YAG lithotripsy
      began at 60 microsec, prior to vapor bubble collapse. To show that Ho:YAG
      lithotripsy is fundamentally related to stone temperature, cystine, and COM mass
      loss was compared for stones initially at room temperature (approximately 23
      degrees C) v frozen stones ablated within 2 minutes after removal from the
      freezer. Cystine and COM mass losses were greater for stones starting at room
      temperature than cold (P < or = 0.05). To show that Ho:YAG lithotripsy involves a
      thermochemical reaction, composition analysis was done before and after
      lithotripsy. Postlithotripsy, COM yielded calcium carbonate; cystine yielded
      cysteine and free sulfur; calcium hydrogen phosphate dihydrate yielded calcium
      pyrophosphate; magnesium ammonium phosphate yielded ammonium carbonate and
      magnesium carbonate; and uric acid yielded cyanide. To show that Ho:YAG
      lithotripsy does not create significant shockwaves, pressure transients were
      measured during lithotripsy using needle hydrophones. Peak pressures were <2
      bars. CONCLUSION: The primary mechanism of Ho:YAG lithotripsy is photothermal.
      There are no significant photoacoustic effects.

PMID- 10360499
TI  - Geometry of laparoscopic suturing and knotting techniques.
AB  - BACKGROUND: Spatial limitation, together with a fixed trocar position, restricted
      handling, and movement of the instruments, is inevitably associated with
      reconstructive laparoscopy and retroperitoneoscopy. This problem includes not
      only suturing technique and instruments but also geometric factors of endoscopic
      reconstruction, such as optimal distances between the working trocars, length of
      instruments, and angles between the instruments and the object. We present an
      experimental access to determine the specific impact of these factors on
      reconstructive laparoscopy. MATERIALS AND METHODS: In an in vitro model, end-to
      end anastomoses of porcine intestine were performed using a standardized
      intracorporeal suturing technique. Suturing was performed without and after
      training in reconstructive surgery with variation of the following geometric
      factors: (1) the distance between the working trocars (between 6 and 12 cm); (2)
      the position of the object (lateral right, medially, lateral left); (3) the
      camera position (medially, lateral right, lateral left); (4) the angle between
      the instruments and a horizontal line (15 degrees , 55 degrees, 90 degrees); (5)
      the intracorporeal length of instruments (between 10 and 25 cm); and (6) narrowed
      space available for the instruments (between 4 and 25 cm). RESULTS: Continual
      training decreased the time required for suturing between 30% to 50%. Training
      decreased the time required for nonsuturing activities between 50% and 70% but
      the time required for suturing activities only between 20% and 45%. If the space
      between instruments and camera was limited, shifting the camera into a lateral
      position simplified the procedure of intracorporeal suturing. Angles of <55
      degrees between instruments and the horizontal line simplified laparoscopic
      suturing, as did angles of <45 degrees between the instruments. In cases of
      maximally narrowed space (diameter of 4 cm), a suture filament length of <10 cm
      decreased the time required by 30%. CONCLUSION: We suggest an isosceles triangle
      between the instruments with an angle between 25 degrees and 45 degrees and an
      angle of <55 degrees between the instruments and the horizontal line as the
      optimal geometry for intracorporeal suturing. These data should be considered
      when planning a reconstructive laparoscopic procedure (i.e., alignment of
      trocars, table position). However, further studies are required to confirm these
      preliminary results.

PMID- 10360500
TI  - Role of color-coded Doppler sonography in the assessment of internal ureteral
      stent patency.
AB  - OBJECTIVE: To evaluate the role of color-coded Doppler sonography (CCDS) in the
      assessment of internal ureteral stent patency. PATIENTS AND METHODS: We compared
      micturating cystography (MC) and CCDS in 48 patients with internal ureteral
      stents. Forty-five of these patients had pyelocaliectasis on renal sonography.
      RESULTS: In all of the 48 patients, the distal end of the internal ureteral stent
      could be seen sonographically in the bladder. The color images of 30 patients
      showed typical flow from the distal holes of the stent. Micturating cystography
      demonstrated patency of the stents in 36 patients. The two procedures showed the
      same results in 42 of 48 patients. Six patients had no detectable flow by CCDS,
      but the MCs showed patency of the stents. CONCLUSION: The CCDS is a valid
      noninvasive method for the assessment of internal ureteral stent patency with a
      sensitivity of 100%, a specificity of 83%, a positive predictive value of 67%,
      and a negative predictive value of 100%.

PMID- 10360501
TI  - Nephroscopy sheath characteristics and intrarenal pelvic pressure: human kidney
      model.
AB  - We developed an in vitro human kidney model to study the intrarenal pelvic
      pressures generated during percutaneous nephroscopy. Higher intrapelvic pressures
      were associated with nephroscopy sheaths of smaller caliber and greater length.
      In addition, the position of the sheath within the kidney markedly influenced
      intrapelvic pressure. The results of this study have influenced our practice and
      are especially important during cases involving percutaneous removal of infected
      urinary calculi and transitional-cell carcinoma.

PMID- 10360502
TI  - Heightened suspicion and rapid evaluation with CT for early diagnosis of partial
      renal infarction.
AB  - BACKGROUND AND OBJECTIVE: Although renal infarction has been well studied and
      clearly defined, it remains greatly underdiagnosed, resulting in significant
      morbidity. Acute segmental renal infarction is a diagnosis even more problematic,
      as the problem can appear insidiously and masquerade as other entities including
      stone, infection, and even tumor. The clinical manifestations and evaluation of
      partial renal infarction in our patients were reviewed. PATIENTS AND METHODS:
      Seven patients presenting to the emergency department who were subsequently found
      to have partial renal infarction were identified from the 5-year records of a
      single institution. Patients were evaluated for presenting complaints, physical
      findings, temperature, and blood pressure. Laboratory analysis consisted of a
      complete blood count (CBC); measurements of creatinine, lactate dehydrogenase
      (LDH), aspartate transaminase/alanine transaminase (AST/ALT), and alkaline
      phosphatase; and urinalysis. The sequence of the work-up was recorded, as well as
      time to diagnosis. The etiology of infarction was identified for all patients.
      RESULTS: All seven patients were eventually discovered to have partial renal
      infarction as a result of dysrhythmia (N = 4), mural thrombus (N = 2), or septic
      emboli (N = 1). The average time to diagnosis was 65.2 hours with a range of 9.5
      to 168 hours. The chief complaint was flank pain (N = 3), nonspecific abdominal
      pain (N = 2), left lower-quadrant pain (N = 1), and mental status change (N = 1).
      The presenting signs and symptoms included abdominal tenderness (N = 4), nausea
      and vomiting (N = 4), temperature >100.5 degrees F (N = 3), and hypertension (N =
      3). Laboratory studies revealed a white cell count >11,000/microL in six,
      microhematuria in four, proteinuria in four, elevated LDH in all patients,
      elevated AST/ALT in two, and elevated alkaline phosphatase in one. The work-up
      varied by presentation, but definitive diagnosis was made by CT in all five
      patients scanned and by angiography in two. Angiography confirmed the CT findings
      in four of the five patients. CONCLUSION: In evaluating partial renal infarction,
      a strong clinical suspicion is necessary. We found a history of dysrhythmia or
      other cardiac disease, the presence of abdominal or flank pain, fever with an
      elevated white cell count, and an elevated LDH to be clinically significant, and
      their presence should alert the clinician to the possibility of renal infarction.
      Once a degree of suspicion exists, early evaluation with CT should speed the
      diagnosis and effect decreased morbidity.

PMID- 10360503
TI  - Holmium: YAG laser resection of the prostate.
AB  - The holmium laser is a relatively new multipurpose medical laser that recently
      became available for use in urology. There has been considerable interest in this
      device, as it seems to combine the cutting properties of the carbon dioxide laser
      with the coagulating properties of the neodymium:YAG laser, making it
      particularly appealing for many surgical applications. The last decade has seen
      enthusiasm for the use of laser energy for the treatment of benign prostatic
      hyperplasia. In this article, we review the technique of Ho:YAG laser resection
      of the prostate, including the essential equipment and perioperative patient
      care.

PMID- 10360504
TI  - Metal mesh stents for ureteral obstruction caused by hormone-resistant carcinoma
      of prostate.
AB  - BACKGROUND: Long-segment ureteral obstruction by hormone-refractory carcinoma of
      the prostate is a difficult problem to manage. J-Stents often obstruct by
      compression. Metal mesh stents have been used successfully in the management of
      extrinsic ureteral obstruction caused by malignant disease. In this paper, we
      review our results in three patients in terms of the defined objective of
      palliation. PATIENTS AND METHODS: All three patients presented with painful
      obstructed kidneys and renal failure from long (7-10-cm) distal ureteral
      strictures responding to nephrostomy drainage. Endoluminal metal mesh stents of 7
      to 8-mm diameter of various lengths (depending on the size of the stricture) were
      implanted after antegrade balloon dilatation of the stricture by a standard
      technique. The case notes were reviewed for technical success, preservation of
      the renal units, complications, and the impact on the overall quality of life.
      RESULTS: All three stents were placed without any complication and showed patency
      on contrast study. In one patient, the stent obstructed after 5 months,
      necessitating placement of a nephrostomy tube. In the remaining two patients, the
      stents obstructed within 3 months. During these 3 months, both patients had
      multiple admissions for stent-related complications and other symptoms of their
      disease. Overall quality of life was poor for these patients. CONCLUSION: Metal
      mesh ureteral stents give poor palliation in distal strictures caused by hormone
      refractory carcinoma of the prostate. Permanent nephrostomy may be a more
      acceptable alternative in these patients with short life expectancies.

PMID- 10360505
TI  - Combined transurethal resection and vaporization of the prostate using newly
      designed electrode: a promising treatment alternative for benign prostatic
      hyperplasia.
AB  - BACKGROUND AND OBJECTIVE: Postoperative irritative symptoms and lack of tissue
      samples for histologic examination are the two main disadvantages of
      transurethral electrovaporization of the prostate. To decrease the postoperative
      irritative symptoms while minimizing intraoperative and postoperative bleeding
      and also to obtain tissue samples, we have combined the techniques of
      transurethral resection and vaporization, a procedure we have termed Vapor-cut,
      by using the Wolf Wing gold-plated electrode. PATIENTS AND METHODS: Forty-eight
      patients with symptomatic benign prostatic hyperplasia (BPH) were enrolled in the
      study. Adverse events during the procedure, including serial changes in both
      serum hematocrit and sodium, and postoperative irritative symptoms were recorded
      after removal of the urethral catheter. Preoperative and postoperative symptom
      scores and maximum flow rates (Qmax) were obtained in each patient. The volume of
      the prostate was measured preoperatively and postoperatively using transrectal
      ultrasonography. RESULTS: During the procedure, there was minimal bleeding, and
      serum sodium and hematocrit levels were not changed significantly. The mean
      operative time was 49.3 minutes. The catheterization time and hospital stay were
      48 and 60 hours, respectively. Only five patients (10%) reported transient and
      intermittent postoperative hematuria lasting for 1 week. After removal of the
      urethral catheter, four patients (8%) had irritative voiding symptoms. No
      patients experienced postoperative urinary retention or required subsequent
      catheterization. At 3-month follow-up, the improvement in the mean Qmax was 114%,
      and the decrease in the symptom score was 72%. The average reduction in the
      weight of the prostate was 55%. CONCLUSION: Vapor-cut of the prostate appears to
      be a safe, effective alternative to the standard loop resection and vaporization.
      It has the advantages of minimal blood loss, excellent operative visibility,
      decreased postoperative irritative symptoms, and availability of tissue samples
      with short catheterization and hospitalization times.

PMID- 10360507
TI  - A role for maternal serum screening in detecting chromosomal abnormalities in
      fetuses with isolated choroid plexus cysts: a prospective multicentre study.
AB  - A prospective multicentre study was performed to identify patients with fetal
      choroid plexus cysts and examine the association between choroid plexus cysts and
      chromosome abnormalities in the context of variables such as maternal age, serum
      triple-screen results, race, other prenatally-identified fetal anomalies and cyst
      characteristics. A total of 18 437 scans were performed in 5 centres and 257
      fetuses were identified with choroid plexus cysts. Outcome was available on 250
      patients, and of these, chromosomal abnormalities were detected in a total of 13
      (5.2 per cent) fetuses. 26 patients in the group had additional ultrasound
      abnormalities, and 8 of these had fetal chromosome abnormalities. Among the 224
      patients with isolated choroid plexus cysts, 5 (2.2 per cent) were found to have
      chromosomal abnormalities. All cases with identified chromosomal abnormalities
      were associated with an additional risk factor, such as other ultrasound
      findings, advanced maternal age or abnormal maternal serum triple-screen results.

PMID- 10360506
TI  - Low levels of natural killer cells in pregnant women transmitting Toxoplasma
      gondii.
AB  - The role of cell-mediated immunity in the maternal-fetal transmission of
      Toxoplasma gondii was investigated in 17 pregnant women with primary T. gondii
      infection, in 7 of whom fetal infection occurred. 18 healthy pregnant women were
      followed-up as controls. Fetal outcome was uneventful in six women who were
      treated early in pregnancy with spiramycin, while stillbirth due to T. gondii
      encephalitis occurred in the offspring of one patient who started with therapy at
      34 weeks' gestation. All patients who transmitted T. gondii showed significant
      changes in the mean levels of immune cells. The most prominent finding was a
      significantly lower level of natural killer (NK) cells in the mothers
      transmitting T. gondii to the fetus compared with non-transmitters and controls
      both in the number (99.7 (71.8-107.5)/microl versus 320.9 (307.9-356.4)/microl
      and 172.1 (122.4-213.3)/microl: median (25 degrees-75 degrees). p<0.001) and the
      percentage of NK cells (4.0+/-1.5 per cent versus 13.2+/-2.3 per cent and 10.2+/
      3.4 per cent; mean+/-SD, p<0.001). Although limited by the small number of
      patients, our data suggest that the assessment of NK cells may be considered as a
      prognostic marker of primary T. gondii infection in pregnancy.

PMID- 10360508
TI  - Long-term psychological effects of carrier testing and prenatal diagnosis of
      haemophilia: comparison with a control group.
AB  - The long-term psychological effects resulting from carrier testing and prenatal
      diagnosis (PD) of haemophilia were evaluated by comparing mental symptomatology
      scores (Symptom Check List, SCL-90) for 50 carriers of haemophilia who had
      undergone PD about five years earlier, 55 carriers who had not undergone PD and
      262 control women who were not carriers. All of the women had children. Carrier
      testing for haemophilia per se and in combination with PD does not appear to have
      negative long-term psychological effects. A low tendency for somatization seems
      to be a factor characteristic of carriers considering PD for haemophilia and it
      was particularly salient when carriers had to consider the more invasive late PD
      procedures (amniocentesis and fetal blood sampling). Women who performed late PD
      appeared to represent a positive selection of carriers for whom a good sense of
      coherence and social support protected them from negative long-term psychological
      effects. It is reassuring that early PD by CVS, which is the current method of
      choice for PD for haemophilia, did not appear to have negative long-term
      psychological effects, even for women who had had an early abortion following PD.

PMID- 10360509
TI  - Insights into the pathogenesis and natural history of fetuses with multicystic
      dysplastic kidney disease.
AB  - To better delineate the natural history of multicystic displastic kidney disease
      (MCDKD) and provide insights into the pathogenesis of this condition, we report
      our experience in 102 prenatally detected cases. MCDKD is most commonly an
      incidental finding on prenatal ultrasound examination. The abnormality may be
      unilateral (76 per cent) or bilateral (24 per cent). In unilateral cases,
      abnormality of the contralateral kidney is common (33 per cent). Associated non
      renal abnormalities occur frequently with both unilateral (26 per cent) and
      bilateral (67 per cent) MCDKD, and increase the risk for an abnormal chromosome
      study. Males are more likely to be affected than females with a ratio of 2.4:1,
      but females are twice as likely to have bilateral MCDKD and associated non-renal
      abnormalities, and four times more likely to have an abnormal chromosome study.
      We suggest that the option of chromosomal analysis should be discussed with all
      patients diagnosed with MCDKD in their fetus, if there is bilateral renal
      involvement or if an associated non-renal abnormality is present. Unilateral
      MCDKD without associated renal or non-renal abnormalities was not associated with
      an abnormal chromosome study, and resulted in favourable outcomes. While
      unilateral MCDKD, lack of associated anomalies, normal chromosome study and
      adequate amniotic fluid are all reassuring findings, a complete neonatal urologic
      work-up should be performed in all newborns. We believe the evaluation should
      include voiding cystourethrography to rule out vesicoureteral reflux. Our
      findings allow more precise counselling of patients regarding prognosis, and
      subsequent management of the fetus found to have MCDKD.

PMID- 10360510
TI  - RhD status of a fetus at risk for haemolytic disease with a discrepant maternal
      DNA-based RhD genotype.
AB  - The cloning of the RHD gene has made it possible to determine the RhD status of
      fetuses at risk for haemolytic disease due to RhD iso-immunization using amniotic
      fluid or chorionic villi-derived DNA and the polymerase chain reaction. However,
      some Rh haplotypes are associated with false-positive or negative DNA-based
      results with the potential for an adverse outcome. We determined the RhD status
      of a fetus using amniotic fluid-derived DNA for an anti-D iso-immunized woman.
      Initially, we obtained the ethnic background and the complete RhD and RhCcEe
      phenotypes of both parents. The mother was RhD negative (Cde/cde) but her DNA was
      positive for exon 10 of the RHD gene. The fetus was positive for both exons 4 5
      and exon 10. Southern analysis confirmed that the maternal DNA contained a
      portion of the RHD gene with a restriction pattern that was similar to RhD
      positive individuals. This report illustrates that, in addition to fetal DNA
      genotyping, the same PCR assays, complete with RhD and RhCcEe phenotypes, and
      ethnic background of the parents should be obtained to alert the molecular
      diagnostic laboratory to the presence of rare Rh haplotypes that are associated
      with DNA genotyping errors.

PMID- 10360511
TI  - Prenatal diagnosis of beta-thalassaemia by reverse dot-blot hybridization.
AB  - Thalassaemia is the most common genetic disease and is a public health problem of
      Thailand. Prevention and control of beta-thalassaemia diseases need accurate
      diagnosis of carriers and proper genetic counselling. Prenatal diagnosis is
      needed to prevent birth of the thalassaemic offspring in the couple at risk. This
      can be performed in the first trimester of pregnancy by DNA analysis using the
      polymerase chain reaction (PCR). Since there are more than 20 mutations causing
      beta-thalassaemia in Thailand, the point mutation detection by reverse dot-blot
      allele-specific oligonucleotide (ASO) hybridization was developed using two sets
      of ASO probes. The first battery of ASO probes has been designed to detect 10
      common beta-globin gene mutations including codon 26, G->A (Hb E): codons 41/42, 
      TCTT; codon 17, A->T; IVS 2 nt 654, C->T; IVS 1 nt 1, G->T; IVS 1 nt 5. G->C;
      codon 19, A->G (Hb Malay); codon 35, C->A; codons 71/72, +A and -28 ATA, A->G.
      The second set of ASO probes detect 14 uncommon beta-thalassaemia mutations. We
      applied this reverse dot-blot hybridization technique to perform prenatal
      diagnosis in 105 pregnancies at risk of having severe beta-thalassaemia diseases.
      36 fetuses (34 per cent) were found to be affected with homozygous beta
      thalassaemia or beta-thalassaemia/Hb E disease in which one was twin pregnancy.
      The others included 31 fetuses with heterozygous beta-thalassaemia, 22
      heterozygous Hb E, 1 homozygous Hb E and 16 normal fetuses. The common set of ASO
      probes detected about 95 per cent of cases which suggests that prenatal diagnosis
      for beta-thalassaemia disease can be easily carried out by this approach.

PMID- 10360512
TI  - Prenatal detection of extra structurally abnormal chromosomes (ESACs): new cases
      and a review of the literature.
AB  - We present 16 cases, 10 de novo and 6 familial, in which extra structurally
      abnormal chromosomes (ESACs) were diagnosed prenatally and identified by
      fluorescence in situ hybridization (FISH) studies with follow up from birth. We
      review the literature on prenatally diagnosed ESACs arising de novo and suggest a
      management protocol for these cases.

PMID- 10360513
TI  - Prenatal diagnosis of Charcot-Marie-Tooth disease type 1A by interphase
      fluorescence in situ hybridization.
AB  - Charcot-Marie-Tooth Disease (CMT) is the most common cause of peripheral
      neuropathy, with an incidence of 1:2500 persons affected. Previously, we reported
      the use of fluorescence in situ hybridization (FISH) to detect the common
      submicroscopic duplication of 17p12 found in more than 98 per cent of individuals
      with CMT1A. We found that FISH is a reliable means for the diagnosis of the
      duplication of 17p12 in peripheral blood and reported the validation of the FISH
      assay for amniotic fluid specimens. Herein, we report the validation of the FISH
      assay for use on chorionic villus samples (CVS) to prenatally diagnose CMT1A
      duplications and the testing of 17 prenatal specimens. Seven fetuses were found
      to carry the duplication and are predicted to be affected. FISH is a rapid assay
      in prenatal specimens, with a 9.3 day average turn-around time. Limited follow-up
      on pregnancies indicates that the duplication found in CMT1A is reliably
      diagnosed in the fetus, using FISH on either amniotic fluid specimens or CVS.

PMID- 10360514
TI  - Experience in prenatal testing for Huntington's disease in The Netherlands:
      procedures, results and guidelines (1987-1997).
AB  - We have performed 31 exclusion tests (43 per cent) and 41 direct tests (57 per
      cent) in 43 couples at risk, in the period 1987 to 1997 in Leiden, The
      Netherlands. This resulted in termination of 28 pregnancies (39 per cent), with
      an increased risk. In 28 couples (65 per cent), the woman was at risk. Prenatal
      testing in consecutive pregnancies (mean number: 3) was performed in 15 couples
      (35 per cent), with a mean time interval of 15 months. Parents should make an
      independent choice for (every) pregnancy, although most (86 per cent) did not
      change their initial choice. It is important that the position of children in the
      same family, of whom some know their status as a result of prenatal testing,
      whereas others remain at risk, is taken into consideration in counselling. The
      relative number of exclusion tests when compared with direct tests has diminished
      since the mutation was identified. The prenatal exclusion-definitive test (Fig.
      1) was rarely used (2/72, 3 per cent). Nowadays, direct mutation testing of the
      fetus only is simpler and faster and the risk of disclosure of the genetic status
      of the at-risk parent is only 25 per cent. This test should therefore be offered
      as another option and included in the international guidelines. The uptake for
      prenatal testing is low: for 2 per cent of the at-risk persons, 11 per cent of
      the tested carriers and a small group of at-risk persons wishing not to be tested
      themselves, prenatal testing seems an acceptable choice regarding reproduction.

PMID- 10360515
TI  - Early pregnancy screening for fetal aneuploidy with serum markers and nuchal
      translucency.
AB  - We determined the aneuploidy detection rate achievable by early pregnancy
      screening with pregnancy associated plasma protein (PAPP)-A, free beta human
      chorionic gonadotrophin (hCG) and ultrasound nuchal translucency (NT)
      measurement. Women having prenatal diagnosis were scanned, and a blood sample was
      taken and stored. Stored samples were tested and a total of 37 were found to have
      Down syndrome, 8 to have Edwards syndrome and 255 were controls. Results were
      expressed in multiples of the gestation-specific median (MOM) value in the
      controls after regression and, for the serum markers, maternal weight adjustment.
      In Down syndrome the medians were for PAPP-A 0.63 MOM (95 per cent confidence
      interval (CI) 0.45-0.87); free beta-hCG 1.88 MOM (1.33-2.66); and NT 2.34 MOM
      (1.70-3.22). Using these parameters the expected detection rate for a 5 per cent
      false-positive rate for different marker combinations were: 55.3 per cent for
      PAPP-A and free beta-hCG; 68.4 per cent for NT alone; and 84.6 per cent for PAPP
      A, free beta-hCG and NT. The median values for Edwards syndrome were: 0.17 MOM
      for PAPP-A; 0.18 MOM for free beta-hCG; and 2.64 MOM for NT. Early pregnancy
      screening with the combined measurement of maternal serum PAPP-A and free beta
      hCG and fetal nuchal translucency could achieve a high Down syndrome detection
      rate.

PMID- 10360516
TI  - Second-trimester maternal serum inhibin-A screening for fetal Down syndrome in
      Asian women.
AB  - Case control studies in the Caucasian population showed that maternal serum
      inhibin-A is elevated in Down syndrome pregnancies and may be a useful second
      trimester marker in addition to human chorionic gonadotrophin (hCG) and alpha
      fetoprotein (AFP). Data in the Asian population are lacking. We measured inhibin
      A levels in the stored maternal sera of 49 Down syndrome pregnancies and 341
      controls with a commercially available assay and expressed them as the multiples
      of the median of the gestational week. The log means and standard deviations for
      case and control inhibin-A MOMs were 0.209, 0.226, and 0.002 and 0.177,
      respectively. Median inhibin-A MOM in Down syndrome cases was elevated to 1.62
      (95 per cent confidence interval, 1.29-1.82). 36 per cent of Down syndrome cases
      were expected to be detected at a 5 per cent false-positive rate. However,
      inhibin-A MOMs were strongly correlated with hCG MOMs in the cases (r=0.73,
      p<0.001) and the controls (r=0.56, p<0.001). This will diminish the value of
      adding inhibin-A to the existing hCG and AFP screening protocol.

PMID- 10360517
TI  - Transplacental passage of anti-thyroid auto-antibodies in a pregnant woman with
      auto-immune thyroid disease.
AB  - We report the intra-uterine and postnatal thyroid status of a newborn, whose
      mother, affected with Hashimoto's thyroiditis superimposed on a previous Graves'
      disease, again became hyperthyroid during the third trimester of pregnancy. The
      mother had very high levels of anti-thyroid auto-antibodies, including TSH
      receptor auto-antibodies (TRAb) measured as TSH-binding inhibiting auto
      antibodies (TBIAb). In order to exclude fetal thyroid dysfunction due to passive
      transplacental transfer of TRAb, fetal blood samples were obtained by
      cordocentesis at 21, 27 and 32 weeks of gestation. A transplacental transfer of
      TRAb was already seen at 21 weeks, but no alteration of fetal thyroid function
      was present at that time. In the following weeks, a rise in TRAb and circulating
      thyroid hormones was observed both in the fetus and mother, accompanied by overt
      hyperthyroidism in the mother and by growth retardation in the fetus. At birth,
      TRAb were shown to have stimulating activity both in the newborn and mother. This
      report documents the early transplacental passage of thyroid auto-antibodies and
      underlines the importance of close follow-up of pregnant women with auto-immune
      thyroid disorders.

PMID- 10360518
TI  - Prenatal findings in trisomy 16q of paternal origin.
AB  - A 34-year-old pregnant woman was referred at 30 weeks of gestation with suspected
      fetal congenital heart disease. On prenatal ultrasound the following anomalies
      were detected: intra-uterine growth retardation, micrognathia, coarctation of the
      aorta with ventricular and atrial septal defects, ambiguous external genitalia,
      and clinodactyly of one hand with adducted thumb. Prenatal karyotyping was
      offered but refused by the patient. The fetus was delivered by Caesarean section
      due to fetal distress at 36 weeks of gestation. The neonate, weighing 2150 g was
      transferred to the neonatal intensive care unit, where he died 10 days later. The
      karyotype from peripheral blood lymphocytes was
      46,XY+der(20)t(16;20)(q12.1;p13)pat. The maternal karyotype was unremarkable,
      whereas the father had the translocation t(16;20)(q12.1;p13). Necropsy confirmed
      all the prenatal findings. These are discussed together with the implications of
      the chromosomal diagnosis and the pertinent literature is reviewed.

PMID- 10360519
TI  - Second-trimester maternal serum progesterone levels in Turner syndrome with and
      without hydrops and in trisomy 18.
AB  - Placental proteins, such as inhibin A and hCG and its subunits, as well as the
      placental steroid progesterone, are elevated in second-trimester maternal serum
      from cases of fetal Down syndrome. Since different cellular mechanisms are
      required for protein versus steroid synthesis and secretion, these data suggest
      that a generalized placental hypersecretory phenomenon is associated with Down
      syndrome. Inhibin A and hCG are also elevated in cases of Turner syndrome with
      hydrops, and are reduced in cases of Turner syndrome without hydrops and in
      trisomy 18. The objective of the present study was to determine maternal serum
      levels of the placental steroid progesterone in cases of Turner syndrome and
      trisomy 18. Twenty-one cases of trisomy 18, 10 cases of Turner syndrome without
      hydrops and 12 cases of Turner syndrome with hydrops were identified and each
      matched to five control samples. Maternal serum progesterone levels were
      significantly elevated in Turner syndrome with hydrops (2.11 MoM), slightly
      reduced in Turner syndrome without hydrops (0.90 MoM) and modestly, though
      significantly, reduced in trisomy 18 (0.73 MoM). These data are similar to the
      patterns seen for inhibin A and hCG, suggesting that the overall synthetic and/or
      secretory activity of the placenta is increased in Turner syndrome with hydrops
      and decreased in Turner syndrome without hydrops and in trisomy 18. These data
      may be helpful in understanding the pathophysiological basis of serum marker
      patterns in these aneuploidies.

PMID- 10360520
TI  - Prenatal diagnosis of a mosaic extra structurally abnormal chromosome by spectral
      karyotyping.
AB  - A de novo mosaic extra structurally abnormal chromosome (ESAC) was detected in 33
      per cent of cultured amniotic fluid cells from a pregnant woman. Neither Q
      banding nor fluorescence in situ hybridization (FISH) employing a DNA probe for
      nucleolar organizer region demonstrated the presence of satellites on the ESAC.
      Spectral karyotyping (SKY) was performed in this prenatal case and led to a quick
      and accurate determination of the ESAC as chromosome 14 in origin. The SKY
      finding was confirmed by conventional FISH analysis using a chromosome 14
      specific painting probe. Subsequent hybridizations with a centromeric probe and a
      14q subtelomeric probe were also performed to further characterize the ESAC.
      Absence of (TTAGGG)n sequence on the ESAC, determined postnatally, suggested it
      is a ring chromosome 14. Genetic counselling concerning these findings was
      provided to the parents who chose to continue the pregnancy. The male infant had
      no apparent abnormal phenotype at birth.

PMID- 10360521
TI  - Prenatal diagnosis in a family with severe type I plasminogen deficiency,
      ligneous conjunctivitis and congenital hydrocephalus.
AB  - Severe type I plasminogen deficiency may cause severe ligneous conjunctivitis, a
      rare and unusual form of chronic pseudo-membranous conjunctivitis that usually
      starts in early infancy, but also pseudo-membranous lesions of other mucous
      membranes in the mouth, nasopharynx, trachea and female genital tract, and in
      rare cases congenital occlusive hydrocephalus. The index patient, the daughter of
      a consanguineous marriage, had suffered from severe ligneous conjunctivitis and
      had died from decompensated congenital hydrocephalus despite numerous shunt
      revisions. She was found to be homozygous for a non-sense mutation in exon 15 of
      the plasminogen gene (Trp597->Stop). In her next pregnancy, the mother asked for
      prenatal diagnosis of the plasminogen deficiency. Chorionic villus biopsy was
      performed at 12 weeks of gestation. DNA analysis of the plasminogen gene by PCR
      and single-strand conformation polymorphism (SSCP) revealed that the fetus
      exhibited an identical heterozygous band pattern as observed in the healthy
      mother. Therefore, the fetus was heterozygous for the Trp597->Stop mutation in
      plasminogen exon 15. In addition, the fetus was found to be male by cytogenetic
      analysis and by multiplex PCR analysis using two polymorphic X-chromosomal
      markers (DXS424, HPRT). These findings excluded the possibility of contamination
      by maternal DNA. It was concluded that the fetus was not at risk for ligneous
      conjunctivitis and its associated complications. After the birth of a healthy
      boy, plasminogen functional activity was shown to be 38 per cent. DNA analysis
      confirmed prenatal molecular genetic results.

PMID- 10360523
TI  - Maternal serum alpha-fetoprotein levels in congenital nephrotic syndrome carrier
      pregnancies.

PMID- 10360524
TI  - Current awareness in prenatal diagnosis.

PMID- 10360522
TI  - Serum hyperglycosylated hCG: a potential screening test for fetal Down syndrome.

PMID- 10360525
TI  - For diagnostic imaging film will eventually be of historical interest only.

PMID- 10360526
TI  - Digital radiology using active matrix readout: amplified pixel detector array for
      fluoroscopy.
AB  - Active matrix array technology has made possible the concept of flat panel
      imaging systems for radiography. In the conventional approach a thin-film circuit
      built on glass contains the necessary switching components (thin-film transistors
      or TFTs) to readout an image formed in either a phosphor or photoconductor layer.
      Extension of this concept to real time imaging--fluoroscopy--has had problems due
      to the very low noise required. A new design strategy for fluoroscopic active
      matrix flat panel detectors has therefore been investigated theoretically. In
      this approach, the active matrix has integrated thin-film amplifiers and readout
      electronics at each pixel and is called the amplified pixel detector array
      (APDA). Each amplified pixel consists of three thin-film transistors: an
      amplifier, a readout, and a reset TFT. The performance of the APDA approach
      compared to the conventional active matrix was investigated for two
      semiconductors commonly used to construct active matrix arrays--hydrogenated
      amorphous silicon and polycrystalline silicon. The results showed that with
      amplification close to the pixel, the noise from the external charge
      preamplifiers becomes insignificant. The thermal and flicker noise of the readout
      and the amplifying TFTs at the pixel become the dominant sources of noise. The
      magnitude of these noise sources is strongly dependent on the TFT geometry and
      its fabrication process. Both of these could be optimized to make the APDA active
      matrix operate at lower noise levels than is possible with the conventional
      approach. However, the APDA cannot be made to operate ideally (i.e., have noise
      limited only by the amount of radiation used) at the lowest exposure rate
      required in medical fluoroscopy.

PMID- 10360527
TI  - Characterization of the reciprocity law failure in three mammography screen-film
      systems.
AB  - The purpose of this project was to quantify reciprocity law failure (RLF) for
      mammography screen-film systems. Three widely used screen-film systems were
      evaluated: the Kodak MinR 2000 system. Fuji UM Mammo Fine screen and Fuji UM MA
      HC film, and Agfa MR Detail screen and Agfa Mammoray MR5 film. The logit
      algorithm that linearizes logistic curve shapes was utilized to characterize film
      sensitometric response. Different values of mammographic phantom thickness, tube
      current, and kVp were used to vary screen-film exposure rates. RLF was quantified
      by examining the dependence of logit parameters (maximum and minimum film
      density, curve shift, and slope) on exposure rate. The shift of the logit curve
      was found to be a good indicator of the screen-film system speed, while the slope
      of the logit curve is affected by the RLF. RLF leads to changes in film contrast
      as well as speed. For the range of exposure rates measured (50-fold), screen-film
      contrast and speed varied by factors of 2 and 3.5, respectively. Film contrast
      decreased as exposure rate increased. The greatest changes were observed with the
      Kodak MinR 2000 screen-film system.

PMID- 10360528
TI  - Optimal noise control in and fast reconstruction of fan-beam computed tomography
      image.
AB  - We proposed a linear approach that exploits statistically complementary
      information inherent in the projection data of fan-beam computed tomography (CT)
      for achieving a bias-free image-variance reduction in fan-beam CT. This linear
      approach leads to the development of infinite classes of hybrid algorithms for
      image reconstruction in fan-beam CT. These hybrid algorithms are computationally
      more efficient and numerically less susceptible to data noise and to the effect
      of finite sampling than the conventional fan-beam filtered back-projection (FFBP)
      algorithm. We also developed infinite classes of generalized fan-beam filtered
      back-projection (GFFBP) algorithms, which include the conventional FFBP algorithm
      as a special member. We demonstrated theoretically and quantitatively that the
      hybrid and GFFBP algorithms are identical (or different) in the absence (or
      presence) of data noise and of the effect of finite sampling. More importantly,
      we identified the statistically optimal hybrid algorithm that may have
      potentially significant implication to image reconstruction in fan-beam CT.
      Extensive numerical results of computer-simulation studies validated our
      theoretical results.

PMID- 10360529
TI  - Quantitative evaluation of vessel tracking techniques on coronary angiograms.
AB  - Accurate, automated determination of vessel center lines is essential for two-
      and three-dimensional analysis of the coronary vascular tree. Therefore, we have
      been developing techniques for vessel tracking and for evaluating their accuracy
      and precision in clinical images. After points in vessels are manually indicated,
      the vessels are tracked automatically by means of a modified sector-search
      approach. The perimeters of sectors centered on previous tracking points are
      searched for the pixels with the maximum contrast. The sector size and radius are
      automatically adjusted based on local vessel tortuosity. The performance of the
      tracking technique in regions of high-intensity background is improved by
      application of a nonlinear adaptive filtering technique in which the vessel
      signal is effectively removed prior to background estimation. The tracking
      results were evaluated visually and by calculation of distances between the
      tracked and user-indicated centerlines, which were used as the "truth." Two
      hundred and fifty-six coronary vessels were tracked in 32 angiograms. Vessels as
      small as 0.6 mm in diameter were tracked accurately. This technique correctly
      tracked 255/256 (>99%) vessels based on an average of 2-3 indicated points per
      vessel. The one incorrect tracking result was due to a low signal-to-noise ratio
      (SNR<2). The distance between the tracked and the "true" centerlines ranged from
      0.4 to 1.8 pixels, with an average of 0.8 pixels. These results indicate that
      this technique can provide a reliable basis for 2D and 3D vascular analysis.

PMID- 10360530
TI  - Linear motion correction in three dimensions applied to dynamic gadolinium
      enhanced breast imaging.
AB  - Quantitative analysis of dynamic gadolinium-DTPA (diethylenetriamine pentaacetic
      acid) enhanced magnetic resonance imaging (MRI) is emerging as a highly sensitive
      tool for detecting malignant breast tissue. Three-dimensional rapid imaging
      techniques, such as keyhole MRI, yield high temporal sampling rates to accurately
      track contrast enhancement and washout in lesions over the course of multiple
      volume acquisitions. Patient motion during the dynamic acquisitions is a limiting
      factor that degrades the image quality, particularly of subsequent subtraction
      images used to identify and quantitatively evaluate regions suggestive of
      malignancy. Keyhole imaging is particularly sensitive to motion since datasets
      acquired over an extended period are combined in k-space. In this study, motion
      is modeled as set of translations in each of the three orthogonal dimensions. The
      specific objective of the study is to develop and implement an algorithm to
      correct the consequent phase shifts in k-space data prior to offline keyhole
      reconstruction three-dimensional (3D) volume breast MR acquisitions.

PMID- 10360531
TI  - A method for incorporating organ motion due to breathing into 3D dose
      calculations.
AB  - A method is proposed that incorporates the effects of intratreatment organ motion
      due to breathing on the dose calculations for the treatment of liver disease. Our
      method is based on the convolution of a static dose distribution with a
      probability distribution function (PDF) which describes the nature of the motion.
      The organ motion due to breathing is assumed here to be one-dimensional (in the
      superior-inferior direction), and is modeled using a periodic but asymmetric
      function (more time spent at exhale versus inhale). The dose distribution
      calculated using convolution-based methods is compared to the static dose
      distribution using dose difference displays and the effective volume (Veff) of
      the uninvolved liver, as per a liver dose escalation protocol in use at our
      institution. The convolution-based calculation is also compared to direct
      simulations that model individual fractions of a treatment. Analysis shows that
      incorporation of the organ motion could lead to changes in the dose prescribed
      for a treatment based on the Veff of the uninvolved liver. Comparison of
      convolution-based calculations and direct simulation of various worst-case
      scenarios indicates that a single convolution-based calculation is sufficient to
      predict the dose distribution for the example treatment plan given.

PMID- 10360532
TI  - Accuracy of a photogrammetry-based patient positioning and monitoring system for
      radiation therapy.
AB  - A photogrammetry system designed to reduce simulator-to-treatment and treatment
      to-treatment patient positioning errors has been developed. Two complete systems
      have been installed in our department: one in the simulator room and one in a
      treatment room. Each system consists of three charge-coupled device (CCD)
      cameras; a ring of infrared LEDs around the lens of each camera; and several
      small, circular, retroreflective markers that are applied to the patient. The
      markers reflect infrared light directly back to the cameras, producing a binary
      image of oval hot spots when the image is thresholded. The three-dimensional
      position of each marker is calculated by conventional photogrammetry methods. At
      simulation, marker positions are measured, then transferred to the treatment room
      system. The system may be used to actively position patients, and to passively
      monitor a patient's position and motion during treatment. Studies have focused on
      measuring the system's temporal stability, precision, and accuracy; on optimal
      positioning of markers and cameras; and on assessing the system's capability to
      reduce the positioning error. The repeatability of measuring a marker's position
      is <0.1 mm in each orthogonal direction. The accuracy is approximately 0.5 mm
      over a 40 X 40 X 40 cm3 field of view. The system drift over four hours is
      approximately +/-0.2 mm. The photogrammetry system has been used to actively
      position a lead BB, embedded within a head phantom, at the isocenter;
      repeatability was +/-0.3 mm, as determined radiographically. The system has also
      been used to passively monitor the positioning of several head and neck patients
      that were set up by a therapist; setup errors of up to 10 mm in each orthogonal
      direction were measured, as well as the motion of the patient during treatment.

PMID- 10360534
TI  - Performance and beam characteristics of the Siemens Primus linear accelerator.
AB  - Siemens Primus is a small footprint, klystron driven medical linear accelerator
      incorporating a compact solid state modulator. A double focused multileaf
      collimator (MLC) replaces the lower jaw. The first Primus in the world was
      installed at St. Jude Children's Research Hospital in early 1997 with x-ray
      energies of 6 and 15 MV and electron energies of 8, 10, 12, 15, 18, and 21 MeV.
      The 10 cm depth dose for a 100 cm SSD 10 X 10 cm2 beam is 68% and 77% for 6 and
      15 MV x rays, respectively. For both x-ray energies, beam flatness is slightly
      better than the manufacturers specification of 3% and beam symmetry is
      considerably better than 1%. The double focus design of the MLC produces a sharp
      penumbra (5-7 mm at 6 MV and 6-8 mm at 15 MV), increasing modestly with beam
      size. MLC leaf leakage is less than 1.25%. The depths of the 80% depth dose for
      the six electron energies of 8, 10, 12, 15, 18, and 21 MeV are 2.6, 3.2, 4.0,
      4.9, 6.0, and 7.4 cm, respectively. Beam flatness is typically 2%-3% for all
      electron energies except 21 MeV, where it reaches 4% for a 25 X 25 cm2 cone.
      Electron beam symmetry is better than 1% for all energies except 21 MeV, where it
      is equal to 1%. The results are stored electronically and may be retrieved using
      anonymous ftp from the American Institute of Physics, Physics Auxiliary
      Publication Service.

PMID- 10360533
TI  - Dosimetric characteristics of a double-focused miniature multileaf collimator.
AB  - The dosimetric characteristics of a double-focused miniature multileaf collimator
      (mMLC) attached to a Philips SL75/5 linear accelerator (linac) have been
      investigated. Output factors, percentage depth-dose, penumbra, leaf transmission,
      and leakage between the leaves were measured for the 6 MV x-ray beam on this
      accelerator. Because leakage both through and between the leaves is minimal, the
      linac jaws can be kept fixed while the mMLC leaf configuration is modified for
      different aperture shapes. This allows for accurate output prediction using the
      equivalent square formalism. Percent depth-dose measured for fields defined by
      the mMLC show little deviation from the percent depth-dose measured for fields
      defined by the machine jaws or Lipowitz metal blocks. Because the mMLC matches
      beam divergence in both directions, allows minimal beam transmission, and has a
      large source-to-collimator distance, the penumbra is sharper for fields defined
      by the mMLC than for fields defined by the linac jaws or Lipowitz metal blocks.
      Based on these data, dose calculations for mMLC-defined fields can be applied
      with no change in procedures from those used for fields defined using
      conventional methods.

PMID- 10360535
TI  - Verification of segmented beam delivery using a commercial electronic portal
      imaging device.
AB  - In modern radiotherapy, three-dimensional conformal dose distributions are
      achieved through the delivery of beam ports having precalculated planar
      distributions of photon beam intensity. Although sophisticated means to calculate
      and deliver these spatially modulated beams have been developed, means to verify
      their actual delivery are relatively cumbersome, making equipment and treatment
      quality assurance difficult to enforce. An electronic portal imaging device of
      the scanning liquid ionization chamber type yields images which, once calibrated
      from a previously determined calibration curve, provide highly precise planar
      maps of the incident dose rate. For verification of an intensity-modulated beam
      delivered in the segmented approach with a multileaf collimator, a portal image
      is acquired for each subfield of the leaf sequence. Subsequent to their
      calibration, the images are multiplied by their respective associated monitor
      unit settings, and summed to produce a planar dose distribution at the
      measurement depth in phantom. The excellent agreement of our portal imager
      measurements with calculations of our treatment planning system and measurements
      with a one-dimensional beam profiler attests to the usefulness of this method for
      the planar verification of intensity-modulated fields produced in the segmented
      approach on a computerized linear accelerator equipped with a multileaf
      collimator.

PMID- 10360536
TI  - Monte Carlo investigation of electron beam output factors versus size of square
      cutout.
AB  - A major task in commissioning an electron accelerator is to measure relative
      output factors versus cutout size (i.e., cutout factors) for various electron
      beam energies and applicator sizes. We use the BEAM Monte Carlo code [Med Phys.
      22, 503-524 (1995)] to stimulate clinical electron beams and to calculate the
      relative output factors for square cutouts. Calculations are performed for a
      Siemens MD2 linear accelerator with beam energies, 6, 9, 11, and 13 MeV. The
      calculated cutout factors for square cutouts in 10 X 10 cm2, 15 X 15 cm2, and 20
      X 20 cm2 applicators at SSDs of 100 and 115 cm agree with the measurements made
      using a silicon diode within about 1% except for the smallest cutouts at SSD= 115
      cm where they agree within 0.015. The details of each component of the dose, such
      as the dose from particles scattered off the jaws and the applicator, the dose
      from contaminant photons, the dose from direct electrons, etc., are also
      analyzed. The calculations show that inphantom side-scatter equilibrium is a
      major factor for the contribution from the direct component which usually
      dominates the output of a beam. It takes about 6 h of CPU time on a Pentium Pro
      200 MHz computer to simulate an accelerator and additional 2 h to calculate the
      relative output factor for each cutout with a statistical uncertainty of 1%.

PMID- 10360537
TI  - A comparison of Monte Carlo and analytic first scatter dose spread arrays.
AB  - We compare first scattered point dose spread arrays generated by Monte Carlo and
      an analytic method. The analytic method models energy deposition using Klein
      Nishina cross sections for Compton scatter and approximations for electron
      transport. Assumptions in the analytic method are shown to be valid within a
      region of the point dose spread kernel in which meaningful comparisons can be
      made. Differences between the models are less than 10% for the forward scatter
      directions for radii greater than the electron range associated with the first
      scattered Compton photon. Differences in the backscatter region are discussed and
      indicate that the analytic model is useful for identifying large errors that
      might be present in numerically generated first scatter point dose spread arrays.
      The analytic method is simple and useful for validating first scatter kernels.

PMID- 10360538
TI  - XINPUT: a program to edit "DOSRZ" input files.
AB  - The DOSRZ user code, which is part of the EGS4 standard distribution, is widely
      used in medical physics for the calculation of dose deposition in cylindrical
      geometries. The code provides the use of advanced Monte-Carlo techniques (PRESTA)
      and variance reduction methods. In the case of complex cylinder geometries the
      input of coordinates and radii is not only tedious but also prone to a high error
      rate. Coordinates are to be stated in absolute numbers. A change of one number,
      e.g., the slab thickness, requires the change of all subsequent numbers.
      Furthermore, parameters are only stated as numbers with no indication of their
      meaning. Obviously, there is a need for a user interface to facilitate the input
      for DOSRZ and to largely reduce the possibility for errors. We, therefore, wrote
      a graphical user interface (GUI) consisting of an input mask, a coordinate input
      interpreter, and a two-dimensional and/or pseudo-three-dimensional display
      section. The GUI is based on the scripting language Tcl/Tk, which runs under
      various platforms such as UNIX (LINUX), w95, and WIN NT. It consists of a main
      window which provides common-style menus and buttons to navigate through the edit
      dialog boxes. The most important tools are the region input, which enables the
      user to create the simulation geometry, and the graphics section where the scaled
      output can be displayed. Different media are shown in different colors which are
      user defined. Furthermore, the program contains some tools to reduce the
      probability of an erroneous input in the EGS4 input file. Since Tcl/Tk is a
      modern scripting language, it offers advanced tools to create the GUI and to
      "glue" different applications to it. XINPUT may also be considered as a model
      program for the development of a more general interface to other input areas of
      the EGS4 simulation code.

PMID- 10360539
TI  - The impact of edema on planning 125I and 103Pd prostate implants.
AB  - Permanent transperineal interstitial 125I and 103Pd prostate implants are
      generally planned to deliver a specific dose to a clinically defined target
      volume; however, the post-implant evaluation usually reveals that the implant
      delivered a lower or higher dose than planned. This difference is generally
      attributed to such factors as source placement errors, overestimation of the
      prostate volume on CT, and post-implant edema. In the present work we investigate
      the impact of edema alone. In routine prostate implant planning, it is customary
      to assume that both the prostate and seeds are static throughout the entire
      treatment time, and post-implant edema is not taken into consideration in the
      dosimetry calculation. However, prostate becomes edematous after seed
      implantation, typically by 50% in volume [Int. J. Radiat. Oncol., Biol., Phys.
      41, 1069-1077 (1998)]. The edema resolves itself exponentially with a typical
      half-life of 10 days. In this work, the impact of the edema-induced dynamic
      change in prostate volume and seed location on the dose coverage of the prostate
      is investigated. The total dose delivered to the prostate was calculated by use
      of a dynamic model, which takes edema into account. In the model, the edema
      resolves exponentially with time, as reported in a separate study based on serial
      CT scans [Int. J. Radiat. Oncol., Biol., Phys. 41, 1069-1077 (1998)]. The model
      assumes that the seeds were implanted exactly as planned, thus eliminating the
      effect of source placement errors. Implants based on the same transrectal
      ultrasound (TRUS) images were planned using both 125I and 103Pd sources
      separately. The preimplant volume and planned seed locations were expanded to
      different degrees of edema to simulate the postimplant edematous prostate on day
      0. The model calculated the dose in increments of 24 h, appropriately adjusting
      the prostate volume, seed locations, and source strength prior to each time
      interval and compiled dose-volume histograms (DVH) of the total dose delivered. A
      total of 30 such DVHs were generated for each implant using different
      combinations of edema half-life and magnitude. In addition, a DVH of the plan was
      compiled in the conventional manner, assuming that the prostate volume and seeds
      were static during treatment. A comparison of the DVH of the static model to the
      30 edema corrected DVHs revealed that the plan overestimated the total dose by an
      amount that increased with the magnitude of the edema and the edema half-life.
      The maximum overestimation was 15% for 125I and 32% for 103Pd. For more typical
      edema parameters (a 50% increase in volume and a 10 day half-life) the static
      plan for 125I overestimated the total dose by about 5%, whereas that for 103Pd
      overestimated it by about 12%.

PMID- 10360540
TI  - In-vivo rectal dose measurements with diodes to avoid misadministrations during
      intracavitary high dose rate brachytherapy for carcinoma of the cervix.
AB  - Our purpose in this paper is to present an in vivo dosimetry program designed
      both for measuring the rectal dose and for avoiding misadministrations in
      gynecological intracavitary implants. A device containing an energy compensated
      diode was specially designed for these measurements. Our calibration procedure as
      well as the clinical protocol is described. Measurements have been performed for
      50 treatments delivered with a Fletcher Suit Delclos applicator. The calculated
      and in vivo measured values for the "20% reading," i.e., the dose delivered to
      the diode by the initial 20% of the total dwell time, agreed to within 15%.

PMID- 10360541
TI  - The effect of contrast medium and balloon shape on dosimetry for arterial
      irradiation with 188Re.
AB  - The radiation dosimetry associated with the use of the beta particle emitter
      188Re in an angioplasty balloon is investigated for the case when the balloon has
      an elliptical rather than circular cross section and when iodinated x-ray
      contrast medium is included inside the balloon. It is found that the elliptical
      cross section introduces significant dose corrections when the eccentricity of
      the ellipse is equal to or greater than 0.7. However, for cases where the artery
      is nearly circular in cross section, the corrections are likely to be small. As
      expected, the dose is reduced along the major axis of the ellipse and increased
      along the minor axis. The corrections are greatest at larger distances from the
      surface of the balloon. The effect on dose of contrast in the balloon is
      significant for 33% Omnipaque in saline. Since this is a typical concentration of
      contrast that is used for imaging the radiation-filled balloon, correction for
      the effects of contrast medium in the balloon should in general be applied. To
      enable corrections to be readily applied for other types and concentrations of
      contrast media, formulas have been derived that allow the dose correction to be
      calculated for a range of balloon diameters and at various distances from the
      surface of the balloon. To undertake this calculation, the elemental composition
      and density of the material in the balloon needs to be known.

PMID- 10360542
TI  - Treatment of macular degeneration with proton beams.
AB  - Subfoveal neovascular membranes (SNVMs) are a leading cause of severe visual loss
      in the elderly in the United States. Previously, the only treatment that could
      halt progression of this disease was laser photocoagulation, which was, however,
      accompanied by immediate reduction in visual acuity. A single narrow proton beam
      was used to irradiate 45 patients to either 8 or 14 Cobalt Gray Equivalent. The
      alignment technique and dosimetry of these treatments are described. The proton
      beam direction, range, and modulation were planned with the assistance of an eye
      specific planning program. A single anterior beam was used, with patients looking
      nasally toward a blinking fixation light at an angle of 30 degrees. Patients were
      aligned using a light field projected through a slit collimator. Patients'
      positions were monitored during treatment with a short-focal-length camera. Depth
      dose in a flat phantom was measured with a small-diameter parallel plate
      ionization chamber. Lateral profiles were measured at several depths with silver
      halide film. Each treatment session lasted 15 min, of which 1 min consisted of
      beam delivery. The proton beam stopped in the orbital cavity, delivering no
      primary proton dose to the brain. Dose to the center of the lens of the involved
      eye was less than 0.5% of the dose delivered to the macula. Treatments of SNVMs
      with proton beams require only a short visit to the hospital, little
      immobilization effort, and a minimal amount of treatment room and beam time.
      Compared to previous treatment trials using x-ray beams, the dose to nonocular
      tissues is reduced significantly.

PMID- 10360543
TI  - Monte Carlo calculations to characterize the source for neutron therapy
      facilities.
AB  - Modern radiation treatment planning for photons includes full 3D modeling of the
      adsorbed dose distribution, accurate inclusion of the patient anatomy, and
      consideration of significant changes in material density and composition. Such
      efforts are founded in an accurate description of the radiation source and the
      beam delivery system. Modern fast neutron therapy facilities employ highly
      penetrating beams and isocentric beam delivery. Treatment planning is largely
      based on analytic models adapted from photon codes and interaction cross sections
      normalized to macroscopic attenuation. However, the recent PEREGRINE initiative
      at Lawrence Livermore Laboratory offers the possibility of fully stochastic
      modeling if the neutron source can be adequately described. In this article we
      report neutron source modeling of three high energy facilities. Neutron
      production is based on the intra-nuclear cascade model of the LAHET code while
      neutron transport through the beam delivery system is managed by MCNP using cross
      section libraries extended to 100 MeV neutron energy. PEREGRINE is then used to
      transport the neutron beam through typical phantoms. The resulting neutron
      sources are in excellent agreement with the limited experimental information and
      the measured phantom data are well described by the PEREGRINE transport using the
      LAHET/MCNP determined neutron sources.

PMID- 10360544
TI  - Measurements of low-energy (d,n) reactions for BNCT. Boron Neutron Capture
      Therapy.
AB  - Neutron yields and energy spectra have been measured for various deuteron-induced
      reactions at low energy. Neutrons of energy > 100 keV emitted in the 9Be(d,n)10B,
      12C(d,n)13N, and 13C(d,n)14N reactions at Ed= 1.5 MeV were detected at five
      angles by means of liquid scintillator detectors. While low-energy neutrons were
      observed in all studied reactions, only 13C(d,n)14N is characterized by a
      relatively large yield with spectral features potentially interesting for an
      accelerator-based neutron source for BNCT.

PMID- 10360545
TI  - Intrapatient consistency of imaging biodistributions and their application to
      predicting therapeutic doses in a phase I clinical study of 90Y-based
      radioimmunotherapy.
AB  - Intrapatient variation in the biodistribution of the chimeric monoclonal antibody
      cT84.66 was assessed in 19 patients having a variety of carcinoembryonic antigen
      (CEA) positive tumors. The two studies, including whole-body imaging and blood
      and urine specimen collections, were conducted within 14 days of each other using
      (111)In-cT84.66 at a fixed total protein dose of 5 mg per patient per study. An
      initial pretherapy infusion of (111)In-cT84.66 was administered followed by a
      therapy coinfusion of (111)In-ct84.66 and 90Y-cT84.66 A closed five-compartment
      model was used to integrate source organ activity curves as residence time inputs
      into the MIRDOSE3 program. Normal organ absorbed doses were estimated for 90Y
      cT84.66, the corresponding radiotherapeutic agent. For the two (111)In-cT84.66
      biodistributions, all data were modeled with a R2 value of between 0.72 and 1.00
      with the exception of the urine data taken during therapy. This was due to the
      need of diethylenetriaminepentaacetic acid during the therapy phase because of
      the possibility that yttrium might escape from the chelator attached to the
      antibody. With the assurance that the biodistributions were reproducible, we were
      able to estimate the 90Y-cT84.66 absorbed doses on a per-patient basis.
      Concordance coefficients showing the agreement between the imaging and therapy
      phase dose estimates were between the 0.60 and 0.99 levels for liver, spleen, red
      marrow, total body, and other organ systems. Median results were: 27, 17, and 2.7
      rad/mCi of 90Y-cT84.66 for liver, spleen, and red marrow, respectively. Because
      of decreases in platelets and white cells as the amount of 90Y was increased,
      dose-limiting toxicity was found at 22 mCi/m2. We conclude that patient
      biodistributions were consistent over time to 14 days so as to allow absorbed
      dose estimation in a radioimmunotherapy trial involving the cT84.66 anti-CEA
      antibody.

PMID- 10360546
TI  - Experimental assessment of power and temperature penetration depth control with a
      dual frequency ultrasonic system.
AB  - A novel ultrasound applicator for superficial simultaneous thermoradiotherapy
      consisting of two parallel-opposed linear arrays and a double-sided scanning
      reflector was constructed and tested for penetration depth control. In this
      design the arrays operate at different frequencies (1 and 5 MHz, in this study)
      and the input power to each array element (five 2 X 2 cm2 elements per array) is
      computer adjustable. The ultrasonic beams from the arrays are aimed at the
      scanning reflector which in turn deflects them simultaneously and in parallel
      toward the treatment volume. Relative intensity distributions generated by the
      prototype were measured in a degassed water phantom using a thermal technique for
      a selected reflector position; these showed that the ultrasonic intensity
      distribution can be controlled in the lateral dimensions by varying the input
      power level to individual array elements. A fixed-perfused canine kidney phantom
      was employed to demonstrate experimentally that real time penetration depth
      control is possible by varying the excitation magnitude of one array (frequency)
      relative to that of the other. It is concluded that the dual-frequency scanned
      reflected ultrasound applicator offers a degree of dynamic three-dimensional
      control of the power deposition pattern of clinical significance.

PMID- 10360547
TI  - Relationship between acoustic aperture size and tumor conditions for external
      ultrasound hyperthermia.
AB  - External ultrasound hyperthermia is a very flexible modality for heating deep
      seated tumors due to its deep penetration and focusing ability. However, under
      the constraints of the available acoustic aperture size for the ultrasonic beam,
      ultrasonic attenuation, as well as other anatomic properties, it may not be able
      to deliver sufficient ultrasonic energy to heat a large tumor located in a deep
      region without overheating the normal tissue between the tumor and the aperture.
      In this work, we employ a simulation program based on the steady-state bioheat
      transfer equation and an ideal ultrasound power deposition (a cone with
      convergent/divergent shape) to examine the relationship between the minimal
      diameter of the acoustic aperture and the tumor conditions. Tissue temperatures
      are used to determine the appropriate aperture diameter and the input power level
      for a given set of tumor conditions. Due to the assumed central axis symmetry of
      the power intensity deposition and anatomic properties, a two-dimensional (r-z)
      simulation program is utilized. Factors determining the acoustic aperture
      diameter and the input power level considered here are the tumor size, tumor
      depth, ultrasonic attenuation in tissue, blood perfusion, and temperature of the
      surface cooling water. Simulation results demonstrate that tumor size, tumor
      depth, and ultrasonic attenuation are major factors affecting the aperture
      diameter of the ultrasonic beam to obtain an appropriate temperature
      distribution, while blood perfusion and the temperature of the surface cooling
      water are the minor factors. Plots of the effects of these factors can be used as
      the guideline for designing an optimal ultrasound heating system, arranging the
      transducers, and planning further treatments.

PMID- 10360549
TI  - A novel 675.2 nm diode laser densitometer for use with GafChromic films.
AB  - In this article we compare the accuracy of a diode laser densitometer emitting
      675.2 nm to that of a commercial He-Ne laser densitometer emitting 632.8 nm for
      GafChromic MD-55 film readout. A Leksell gamma unit (AB Elekta Stockholm, Sweden)
      Model B with a 14 and 8 mm collimator at the same isocenter (combined 11 mm
      collimator) was used to irradiate GafChromic MD-55 films. Dose response curves,
      dose cross profile and FWHM were measured with a custom-designed diode laser
      scanning device, emitting light at 675.2 nm. The same data were recorded with a
      commercial He-Ne laser densitometer (PTW FIPS Plus, Freiburg, Germany), emitting
      light at 632.8 nm. Both measurements were compared to dose cross profiles of a
      radiosurgery dose planning program (GammaPlan 5.12, Elekta, Sweden). Compared to
      the commercial He-Ne laser densitometer, the custom-designed diode laser scanning
      device showed better agreement with the calculated dose cross profile. For two
      axes, the full width half maxima (FWHM) of the diode laser scanning device was
      within 0.1 mm deviation compared to the data calculated by the dose planning
      program. The FWHM of the commercial He-Ne laser densitometer was less accurate
      (1.6 and 2.1 mm deviation). Our data show that a diode laser scanning device
      using a light source emitting 675.2 nm increases the accuracy of a GafChromic MD
      55 film readout. This greater accuracy may be related to the diode laser
      measuring the optical density close to maximum absorption of the GafChromic film
      MD-55 (671-675 nm).

PMID- 10360548
TI  - Self-tuning fuzzy logic control for ultrasound hyperthermia with reference
      temperature based on objective functions.
AB  - The purpose of this paper is to develop and evaluate a self-tuning fuzzy logic
      controller for a scanned focused ultrasound hyperthermia system with the
      reference temperature (Tr) determined from objective functions. This work employs
      simulation programs to develop the power deposition for the scanned focused
      ultrasound system and to solve the responses of temperature profiles based on the
      transient bioheat transfer equation. A fuzzy logic control algorithm is employed
      to determine the output power level for the heating system and an observer for
      blood perfusion variation is used to enhance the capability of the controller to
      adjust the required output power level for the treatment due to the drastic
      change of the blood perfusion. The reference temperature (Tr) for the controller
      is based on objective functions to tune its value during the heating process,
      while a control temperature (Tc) from the thermosensors located in the tumor
      region is used as the input for the controller. The objective function based on
      the entire temperature profile is used to evaluate the appropriateness of the
      heating temperature distribution for a time-variational blood perfusion.
      Simulation results demonstrate that the tumor region can be rapidly heated to the
      desired temperature level and maintained at that level despite blood perfusion
      variation. The resulting temperature profile, the objective function, and the
      output power level are related to the magnitude of blood perfusion, but are
      almost independent of the Tc location and the initial setting value of Tr. The
      fuzzy logic control algorithm with Tr determined from objective functions can be
      used for controlling the entire temperature distribution through a single control
      temperature, and the combination of control and optimization allows appropriate
      temperature fields to be created during the entire heating process. The control
      algorithm does not require the accurate prior knowledge of the locations of the
      thermosensors and the appropriate setting value for Tr.

PMID- 10360550
TI  - An EGS4 Monte Carlo examination of the response of a PTW-diamond radiation
      detector in megavoltage electron beams.
AB  - The EGS4 Monte Carlo code has been used to investigate the response of a
      PTW/diamond detector irradiated in both clinical and monoenergetic megavoltage
      electron beams ranging in energy from 5 to 20 MeV. The sensitive volume of the
      PTW/diamond detector simulated has a thickness of 0.4 mm and a diameter of 4.4
      mm. Irradiation was simulated at various depths in a water phantom. The results
      show that the PTW/diamond detector has a constant response (within 1.0%) in
      electron beams if irradiated at depths closed to dmax, and its response is almost
      independent of irradiation depth or incident electron energy (within 3%). A
      detailed examination of the average detector dose shows that the sensitive volume
      of the PTW/diamond detector acts as a Spencer-Attix cavity within 1%. The
      encapsulation of the bare diamond detector with low-Z epoxy and polystyrene wall
      material does not affect its response in electron beams. The difference in
      response between the unencapsulated (TLD) and the encapsulated form of the
      detector is less than 0.5% for all depths over electron energy range
      investigated.

PMID- 10360551
TI  - Comparison of superheated drop detector with phosphorous pentoxide powder for the
      detection of neutrons in 18 MV x rays.
AB  - Neutron dose equivalent measurements were performed in and around an 18 MV x-ray
      beam using superheated drop detectors (SDD) and phosphorous pentoxide (P2O5)
      powder. The neutron dose equivalent profiles for various field sizes of 10 X 10
      cm2, 20 X 20 cm2, and 30 X 30 cm2 were measured. The results measured with the
      P2O5 were checked for any gross systematic errors by comparing with the published
      results computed by using Monte Carlo calculations. A comparison was then made
      between the neutron dose equivalent profiles measured with the P2O5 and the SDD.
      The results of this comparison show that the neutron dose equivalents measured
      with the two types of detectors agree with each other for measurements about 20
      cm away from the beam edges. However, in and near the beam edges the SDD
      measurements are upto 50% less than the neutron dose equivalents measured using
      P2O5 for the 18 MV x-ray beam.

PMID- 10360554
TI  - A sorry affair.

PMID- 10360553
TI  - The wages of spin.

PMID- 10360552
TI  - Response to the Letter to the Editor "Estimating RBEs at clinical doses from
      microdosimetric spectra" [Med. Phys. 25, 1055 (1998)].

PMID- 10360555
TI  - Britain opens biotech regulation to greater public involvement.

PMID- 10360557
TI  - South Africa reveals plans to make AIDS a notifiable disease.

PMID- 10360556
TI  - Trade concerns dominate GM debate in US.

PMID- 10360558
TI  - Charges fly in $1bn hormone patent battle.

PMID- 10360560
TI  - Ethicists urge funding for extraction of embryo cells.

PMID- 10360559
TI  - NIH strives to keep resource sharing alive.

PMID- 10360561
TI  - Europe's molecular biologists could join global e-journal plan.

PMID- 10360562
TI  - NASA beefs up life science involvement.

PMID- 10360563
TI  - Guidelines point the way on genetics ethics.

PMID- 10360564
TI  - Genentech stands by original data.

PMID- 10360565
TI  - Statement from Peter Seeburg.

PMID- 10360566
TI  - Innocents suffer as rogue regime rapped.

PMID- 10360567
TI  - Will biomedicine outgrow support?

PMID- 10360568
TI  - Ageing. A message from the gonads.

PMID- 10360569
TI  - Virus on virus infects bacterium.

PMID- 10360570
TI  - Analysis of telomere lengths in cloned sheep.

PMID- 10360571
TI  - Evidence for lateral gene transfer between Archaea and bacteria from genome
      sequence of Thermotoga maritima.
AB  - The 1,860,725-base-pair genome of Thermotoga maritima MSB8 contains 1,877
      predicted coding regions, 1,014 (54%) of which have functional assignments and
      863 (46%) of which are of unknown function. Genome analysis reveals numerous
      pathways involved in degradation of sugars and plant polysaccharides, and 108
      genes that have orthologues only in the genomes of other thermophilic Eubacteria
      and Archaea. Of the Eubacteria sequenced to date, T. maritima has the highest
      percentage (24%) of genes that are most similar to archaeal genes. Eighty-one
      archaeal-like genes are clustered in 15 regions of the T. maritima genome that
      range in size from 4 to 20 kilobases. Conservation of gene order between T.
      maritima and Archaea in many of the clustered regions suggests that lateral gene
      transfer may have occurred between thermophilic Eubacteria and Archaea.

PMID- 10360572
TI  - Complex dynamics and phase synchronization in spatially extended ecological
      systems.
AB  - Population cycles that persist in time and are synchronized over space pervade
      ecological systems, but their underlying causes remain a long-standing enigma.
      Here we examine the synchronization of complex population oscillations in
      networks of model communities and in natural systems, where phenomena such as
      unusual '4- and 10-year cycle' of wildlife are often found. In the proposed
      spatial model, each local patch sustains a three-level trophic system composed of
      interacting predators, consumers and vegetation. Populations oscillate regularly
      and periodically in phase, but with irregular and chaotic peaks together in
      abundance-twin realistic features that are not found in standard ecological
      models. In a spatial lattice of patches, only small amounts of local migration
      are required to induce broad-scale 'phase synchronization, with all populations
      in the lattice phase-locking to the same collective rhythm. Peak population
      abundances, however, remain chaotic and largely uncorrelated. Although
      synchronization is often perceived as being detrimental to spatially structured
      populations, phase synchronization leads to the emergence of complex chaotic
      travelling-wave structures which may be crucial for species persistence.

PMID- 10360573
TI  - Auditory collusion and a coupled couple of outer hair cells.
AB  - The discrepancies between measured frequency responses of the basilar membrane in
      the inner ear and the frequency tuning found in psychophysical experiments led to
      Bekesy's idea of lateral inhibition in the auditory nervous system. We now know
      that basilar membrane tuning can account for neural tuning, and that sharpening
      of the passive travelling wave depends on the mechanical activity of outer hair
      cells (OHCs)3, but the mechanism by which OHCs enhance tuning remains unclear.
      OHCs generate voltage-dependent length changes at acoustic rates, which deform
      the cochlear partition. Here we use an electrical correlate of OHC mechanical
      activity, the motility-related gating current, to investigate mechano-electrical
      interactions among adjacent OHCs. We show that the motility caused by voltage
      stimulation of one cell in a group evokes gating currents in adjacent OHCs. The
      resulting polarization in adjacent cells is opposite to that within the
      stimulated cell, which may be indicative of lateral inhibition. Also such
      interactions promote distortion and suppression in the electrical and,
      consequently, the mechanical activity of OHCs. Lateral interactions may provide a
      basis for enhanced frequency selectivity in the basilar membrane of mammals.

PMID- 10360574
TI  - Signals from the reproductive system regulate the lifespan of C. elegans.
AB  - Understanding how the ageing process is regulated is a fascinating and
      fundamental problem in biology. Here we demonstrate that signals from the
      reproductive system influence the lifespan of the nematode Caenorhabditis
      elegans. If the cells that give rise to the germ line are killed with a laser
      microbeam, the lifespan of the animal is extended. Our findings suggest that
      germline signals act by modulating the activity of an insulin/IGF-1 (insulin-like
      growth factor) pathway that is known to regulate the ageing of this organism.
      Mutants with reduced activity of the insulin/IGF-1-receptor homologue DAF-2 have
      been shown to live twice as long as normal, and their longevity requires the
      activity of DAF- 16, a member of the forkhead/winged-helix family of
      transcriptional regulators. We find that, in order for germline ablation to
      extend lifespan, DAF-16 is required, as well as a putative nuclear hormone
      receptor, DAF-12. In addition, our findings suggest that signals from the somatic
      gonad also influence ageing, and that this effect requires DAF-2 activity.
      Together, our findings imply that the C. elegans insulin/IGF-1 system integrates
      multiple signals to define the animal's rate of ageing. This study demonstrates
      an inherent relationship between the reproductive state of this animal and its
      lifespan, and may have implications for the co-evolution of reproductive
      capability and longevity.

PMID- 10360575
TI  - The homeobox gene Phox2b is essential for the development of autonomic neural
      crest derivatives.
AB  - The sympathetic, parasympathetic and enteric ganglia are the main components of
      the peripheral autonomic nervous system, and are all derived from the neural
      crest. The factors needed for these structures to develop include the
      transcription factor Mash1, the glial-derived neurotrophic factor GNDF and its
      receptor subunits, and the neuregulin signalling system, each of which is
      essential for the differentiation and survival of subsets of autonomic neurons.
      Here we show that all autonomic ganglia fail to form properly and degenerate in
      mice lacking the homeodomain transcription factor Phox2b, as do the three cranial
      sensory ganglia that are part of the autonomic reflex circuits. In the anlagen of
      the enteric nervous system and the sympathetic ganglia, Phox2b is needed for the
      expression of the GDNF-receptor subunit Ret and for maintaining Mash1 expression.
      Mutant ganglionic anlagen also fail to switch on the genes that encode two
      enzymes needed for the biosynthesis of the neurotransmitter noradrenaline,
      dopamine-beta-hydroxylase and tyrosine hydroxylase, demonstrating that Phox2b
      regulates the noradrenergic phenotype in vertebrates.

PMID- 10360576
TI  - Clathrin self-assembly is mediated by a tandemly repeated superhelix.
AB  - Clathrin is a triskelion-shaped cytoplasmic protein that polymerizes into a
      polyhedral lattice on intracellular membranes to form protein-coated membrane
      vesicles. Lattice formation induces the sorting of membrane proteins during
      endocytosis and organelle biogenesis by interacting with membrane-associated
      adaptor molecules. The clathrin triskelion is a trimer of heavy-chain subunits
      (1,675 residues), each binding a single light-chain subunit, in the hub domain
      (residues 1,074-1,675). Light chains negatively modulate polymerization so that
      intracellular clathrin assembly is adaptor-dependent. Here we report the atomic
      structure, to 2.6 A resolution, of hub residues 1,210-1,516 involved in mediating
      spontaneous clathrin heavy-chain polymerization and light-chain association. The
      hub fragment folds into an elongated coil of alpha-helices, and alignment
      analyses reveal a 145-residue motif that is repeated seven times along the
      filamentous leg and appears in other proteins involved in vacuolar protein
      sorting. The resulting model provides a three-dimensional framework for
      understanding clathrin heavy-chain self-assembly, light-chain binding and
      trimerization.

PMID- 10360577
TI  - A bacteriophage encoding a pathogenicity island, a type-IV pilus and a phage
      receptor in cholera bacteria.
AB  - The virulence properties of many pathogenic bacteria are due to proteins encoded
      by large gene clusters called pathogenicity islands, which are found in a variety
      of human pathogens including Escherichia coli, Salmonella, Shigella, Yersinia,
      Helicobacter pylori, Vibrio cholerae, and animal and plant pathogens such as
      Dichelobacter nodosus and Pseudomonas syringae. Although the presence of
      pathogenicity islands is a prerequisite for many bacterial diseases, little is
      known about their origins or mechanism of transfer into the bacterium. The
      bacterial agent of epidemic cholera, Vibrio cholerae, contains a bacteriophage
      known as cholera-toxin phage (CTXphi), which encodes the cholera toxin, and a
      large pathogenicity island called the VPI (for V. cholerae pathogenicity island)
      which itself encodes a toxin-coregulated pilus that functions as a colonization
      factor and as a CTXphi receptor. We have now identified the VPI pathogenicity
      island as the genome of another filamentous bacteriophage, VPIphi. We show that
      VPIphi is transferred between V. cholerae strains and provide evidence that the
      TcpA subunit of the toxin-coregulated type IV pilus is in fact a coat protein of
      VPIphi. Our results are the first description of a phage that encodes a receptor
      for another phage and of a virus-virus interaction that is necessary for
      bacterial pathogenicity.

PMID- 10360578
TI  - Structure of Cdc42 in complex with the GTPase-binding domain of the 'Wiskott
      Aldrich syndrome' protein.
AB  - The Rho-family GTP-hydrolysing proteins (GTPases), Cdc42, Rac and Rho, act as
      molecular switches in signalling pathways that regulate cytoskeletal
      architecture, gene expression and progression of the cell cycle. Cdc42 and Rac
      transmit many signals through GTP-dependent binding to effector proteins
      containing a Cdc42/Rac-interactive-binding (CRIB) motif. One such effector, the
      Wiskott-Aldrich syndrome protein (WASP), is postulated to link activation of
      Cdc42 directly to the rearrangement of actin. Human mutations in WASP cause
      severe defects in haematopoletic cell function, leading to clinical symptoms of
      thrombocytopenia, immunodeficiency and eczema. Here we report the solution
      structure of a complex between activated Cdc42 and a minimal GTPase-binding
      domain (GBD) from WASP. An extended amino-terminal GBD peptide that includes the
      CRIB motif contacts the switch I, beta2 and alpha5 regions of Cdc42. A carboxy
      terminal beta-hairpin and alpha-helix pack against switch II. The Phe-X-His-X2
      His portion of the CRIB motif and the alpha-helix appear to mediate sensitivity
      to the nucleotide switch through contacts to residues 36-40 of Cdc42.
      Discrimination between the Rho-family members is likely to be governed by GBD
      contacts to the switch I and alpha5 regions of the GTPases. Structural and
      biochemical data suggest that GBD-sequence divergence outside the CRIB motif may
      reflect additional regulatory interactions with functional domains that are
      specific to individual effectors.

PMID- 10360579
TI  - Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK.
AB  - The proteins Cdc42 and Rac are members of the Rho family of small GTPases (G
      proteins), which control signal-transduction pathways that lead to rearrangements
      of the cell cytoskeleton, cell differentiation and cell proliferation. They do so
      by binding to downstream effector proteins. Some of these, known as CRIB (for
      Cdc42/Rac interactive-binding) proteins, bind to both Cdc42 and Rac, such as the
      PAK1-3 serine/threonine kinases, whereas others are specific for Cdc42, such as
      the ACK tyrosine kinases and the Wiscott-Aldrich-syndrome proteins (WASPs). The
      effector loop of Cdc42 and Rac (comprising residues 30-40, also called switch I),
      is one of two regions which change conformation on exchange of GDP for GTP. This
      region is almost identical in Cdc42 and Racs, indicating that it does not
      determine the specificity of these G proteins. Here we report the solution
      structure of the complex of Cdc42 with the GTPase-binding domain ofACK. Both
      proteins undergo significant conformational changes on binding, to form a new
      type of G-protein/effector complex. The interaction extends the beta-sheet in
      Cdc42 by binding an extended strand from ACK, as seen in Ras/effector
      interactions, but it also involves other regions of the G protein that are
      important for determining the specificity of effector binding.

PMID- 10360581
TI  - Graft survival is improved by hepatic denervation before organ harvesting.
AB  - BACKGROUND: In a recent study, disturbances of hepatic microcirculation at
      harvesting caused by in situ organ manipulation dramatically reduced survival
      after a liver transplant. Because hepatic innervation is involved in the
      regulation of liver hemodynamics, the effect of denervation before harvesting was
      assessed here. METHODS: The livers were harvested from female Lewis rats (200-230
      g) within 25 min. Briefly, after minimal dissection during the first 12 min, the
      livers were either manipulated gently or left alone for 13 min. Subsequently, an
      orthotopic liver transplant was performed after 1 hr of storage in cold UW
      solution. Some donors livers underwent microsurgical denervation before
      harvesting or rats were given hexamethonium (10 mg/kg, i.v.), a ganglionic
      blocking agent. RESULTS: In the nonmanipulated group, survival was 100% after the
      transplant; however, gentle manipulation decreased survival by about 50%.
      Furthermore, manipulation elevated serum transaminases and bilirubin 6- to 8-fold
      8 hr after the transplant and caused necrosis of about 25% of hepatocytes. After
      organ harvesting, the rate of entry and exit of fluorescein dextran, a dye
      confined to the vascular space, was decreased 2- to 4-fold, and the maximal
      increase of surface fluorescence was blunted about 2-fold. Pimonidazole binding,
      which reflects tissue hypoxia, was increased 2-fold by manipulation. Denervation
      of the liver before organ harvesting or treatment with hexamethonium prevented
      the effects of organ manipulation on all parameters studied. CONCLUSION: These
      data indicate for the first time that hepatic denervation before organ harvesting
      prevents detrimental effects of brief, gentle manipulation of the liver during
      harvesting on survival after the transplant. This is consistent with the
      hypothesis that organ manipulation disturbs the hepatic microcirculation and
      causes hypoxia at harvesting using mechanisms dependent on innervation.

PMID- 10360580
TI  - Marked mitigation of transplant vascular sclerosis in FasLgld (CD95L) mutant
      recipients. The role of alloantibodies in the development of chronic rejection.
AB  - BACKGROUND: In the acute rejection of allografts, the interaction between Fas
      (CD95) and its ligand (FasL; CD95L) has been shown to be involved in mediating
      apoptotic cell death. The role, however, of these molecules in the pathogenesis
      of transplant vascular sclerosis is as yet undetermined. The present study was
      therefore designed to address this issue. MATERIAL: C3H/HEJ FasLgld (FasL-; H2k)
      spontaneously mutant mice were used either as donors or recipients of aortic
      allografts; wild-type C57B1/6 (B6; H2b) were used as corresponding recipients or
      donors (n=6/group), respectively. Controls included aortas transplanted across
      appropriate allogeneic and syngeneic strain combinations. For histopathological
      evaluations, the grafts were harvested at day 40 after transplantation, at which
      time, splenocytes and sera were also obtained for mixed leukocyte reaction and
      complement-mediated microcytotoxicity assays, respectively. RESULTS: Similar to
      aortas obtained from allogeneic controls, allografts harvested from FasL- -->B6
      recipients had morphological evidence of chronic rejection characterized by
      circumferential intimal thickening with partial disruption of the elastic
      membranes. Correspondingly, heightened antidonor cellular reactivity was also
      witnessed in these recipients. On the contrary, B6 allografts harvested from the
      majority of C3H-->FasL- recipients exhibited marked preservation of aortic
      morphology. Although these recipients had diminished antidonor cellular
      proliferation, the titers of alloantibodies were markedly elevated. CONCLUSION:
      The presence of FasL-expressing functional cytotoxic T cells is required for the
      pathogenesis of transplant vascular sclerosis. The significant reduction and/or
      absence of chronic rejection with the concomitant retention of antidonor humoral
      response in C3H FasL- recipients of B6 aortas prompt us to suggest that perhaps
      posttransplantation vasculopathy is initiated by cell-mediated cytotoxicity with
      its perpetuation facilitated by alloantibodies.

PMID- 10360583
TI  - Auxiliary partial orthotopic living donor liver transplantation as an aid for
      small-for-size grafts in larger recipients.
AB  - BACKGROUND: In countries where living donors are the only source of liver grafts,
      restrictions on graft size are a serious obstacle for the expansion of
      indications for adult recipients. To overcome this problem, auxiliary partial
      orthotopic liver transplants (APOLT*) was performed on the basis of the concept
      that the residual native liver would support the graft function until the graft
      had grown enough to function by itself. METHODS: APOLT as an aid for small-for
      size (SFS) grafts was reviewed retrospectively to evaluate its feasibility.
      Between April 1995 and March 1998, 20 recipients underwent APOLT, which was
      indicated because of a SFS graft in 15 of them. The indication was based on the
      estimated graft/recipient's body weight ratio (GRWR). If the ratio was <0.8%,
      APOLT was performed. The other 5 patients had a graft with a GRWR >0.8% and
      underwent APOLT on the basis of the residual native liver supporting the graft
      function temporarily, 4 for supplementation of the defective enzyme in metabolic
      liver diseases and one for leaving the potential of the regeneration of the
      native liver in fulminant hepatic failure. The recipients who underwent APOLT
      because of a SFS graft were categorized as the SFS group, and the others were the
      second group. RESULTS: In the SFS group, the age of the recipients ranged from 13
      to 48 (median 23). The original indications of this group were fulminant hepatic
      failure in 2 recipients, acute deterioration of chronic liver diseases in 3,
      Wilson's disease in 2, biliary atresia in 4, primary biliary cirrhosis in 3, and
      primary sclerosing cholangitis (PSC) in one. The actual GRWR ranged from 0.45 to
      0.72 (median 0.55). The graft was implanted after resection of the left lateral
      segment of the native liver. Except in the first two patients, the portal vein to
      the residual native liver was completely transected so that all of the portal
      blood drained into the graft liver. This procedure was successful in 9 patients.
      The cause of death in the other 6 was mainly infection. The mortality rate among
      the recipients with signs of advanced liver failure, such as massive ascites or
      hepatic coma, was higher, even though APOLT was used to support the SFS graft. In
      the second group, in the other five recipients who underwent APOLT for other
      indications, one recipient with fulminant hepatic failure died of sepsis caused
      by the dehiscence of bilio-enteric anastomosis. CONCLUSIONS: APOLT as an aid for
      a SFS graft is technically viable. This procedure can thus expand the indication
      of living donor liver transplants for adult recipients when the native liver
      retains some functional capability to support the grafted liver during the
      immediate postoperative period.

PMID- 10360582
TI  - A pilot study on the safety and effectiveness of immunosuppression without
      prednisone after liver transplantation.
AB  - BACKGROUND: Corticosteroids are commonly used in the immunosuppression therapy
      after liver transplantation, yet are associated with considerable side effects.
      Retrospective studies have shown that corticosteroids can be safely withdrawn
      from months to years after transplant. We prospectively investigated the effects
      of early immunosuppression without the use of corticosteroids on graft outcome
      and transplant complications. METHODS: Forty-five patients undergoing liver
      transplantation were randomized to receive immunosuppression composed of
      cyclosporine microemulsion and azathioprine with (n=22) or without prednisone
      (n=23), in conventional doses. In those patients who received prednisone, this
      was withdrawn within 3 months after transplant. The median follow-up of survivors
      was 14 months (range: 6-24). The study end points were to determine graft
      survival and function, infectious complications, including hepatitis C virus
      (HCV)-RNA levels in HCV-infected recipients, acute rejection, kidney function,
      and metabolic complications. RESULTS: Eleven deaths occurred, 6 of which were in
      the prednisone group. Two-year survival did not differ between patients treated
      with or without prednisone (70.2% vs. 78.3%, P=0.83), nor did the causes of
      death. No differences were observed with regard to graft function, renal
      function, and infectious complications. In the subset of patients who received
      transplants for HCV-related cirrhosis, the dynamics of virus replication HCV-RNA
      was faster among those treated with prednisone. The incidence and severity of
      acute rejection was similar in the two groups. More than 80% of acute rejections
      in both groups were classified as mild or moderate and underwent spontaneous
      resolution. Only two patients in each group had severe acute rejection requiring
      additional treatment with high-dose steroids. Patients receiving prednisone
      tended to have greater biochemical signs of cholestasis, higher serum cholesterol
      and glucose levels, and more frequent insulin requirement than those treated
      without corticosteroids. CONCLUSIONS: Liver transplantation can be performed
      safely without using corticosteroids in the early postoperative course, and there
      is no need for routine aggressive steroid treatment of established acute
      rejections.

PMID- 10360584
TI  - Renal transplantation across the ABO barrier using A2 kidneys.
AB  - BACKGROUND: The waiting list for cadaveric kidney transplantation has continued
      to grow, and with the relative scarcity of cadaver donors, the median waiting
      time for patients in the United States increased to 824 days in 1994. The median
      waiting times for patients with blood groups B or O were 1329 and 1007 days,
      respectively. Allocation of blood group A2 kidneys (20% of group A) to blood
      group O and B patients expands their potential donor pool and shortens their
      waiting time for a kidney transplantation. METHODS: Between May 1991 and June
      1998, we transplanted 15 A2 kidneys into 6 blood group O and 9 blood group B
      patients. Anti-A isoagglutinins were measured before transplantation, and
      patients with anti-A1 titers > or = 1:8 underwent plasmapheresis (PP). RESULTS:
      One patient with high titer anti-A antibodies, who did not receive PP, lost her
      allograft because of hyperacute rejection. Allograft function was excellent in
      the remaining 14 patients, with a mean serum creatinine level of 1.7 (+/-0.89)
      mg/dl at 1 month and 1.3 (+/-0.34) mg/dl at 1 year. The actuarial 1-year graft
      survival rate was 93.3+/-6.4% and the patient survival rate was 100%. CONCLUSION:
      We conclude that the allocation of blood group A2 kidneys for blood group O and B
      recipients is a practical way to expand the donor pool for these transplant
      candidates. PP may be important for reducing the levels of anti-A1 and anti-A2
      antibodies and for reducing the risk of hyperacute rejection. Splenectomy seems
      to be unnecessary.

PMID- 10360585
TI  - Racial differences between solid organ transplant donors and recipients in
      British Columbia: a five-year retrospective analysis.
AB  - BACKGROUND: We attempted to determine whether significant racial differences
      exist between organ donors and transplant recipients in British Columbia, and
      whether differences exist between individual organ transplant programs (lung,
      heart, kidney, liver, and pancreas). The design of the study was a retrospective
      review. METHODS: We used the database of the British Columbia Transplant Society,
      a provincial agency, for the years 1992 to 1997 inclusive. The outcome measures
      were a comparison of racial characteristics of organ donors and transplant
      recipients collectively and by individual organ transplant program. RESULTS:
      There were 236 organ donors and 766 transplant recipients. Comparing racial
      groups between donors and recipients, Caucasians contributed the most donors
      (93.2%) but received proportionately fewer organs (73.4%, P<0.000001). Orientals
      donated 3.4% of all organs but constituted 14.4% of all recipients (P<0.00001).
      Non-Oriental, non-Caucasians (predominantly Asian Indians and Native Aboriginals)
      constituted 3.4% of all donors and 12.2% of all recipients (P=0.0001). Among the
      individual organ transplant programs, lung, heart, and pancreas recipients were
      predominantly Caucasian (148 of 156 recipients). Oriental recipients were more
      likely to be kidney recipients (19.8% of all kidney recipients) compared with all
      Oriental recipients (P<0.000001). Likewise, Asian Indians were more likely to be
      kidney recipients (7.2% of all kidney recipients) compared with all Asian Indian
      recipients (P<0.0001). Native Aboriginals, however, were more likely to be liver
      allograft recipients (8.3% of all liver transplants) than nonliver allograft
      recipients (P=0.017). CONCLUSIONS: In British Columbia, disparity exists between
      Oriental and non-Oriental, non-Caucasian donors and recipients. Orientals and
      Asian Indians were more likely to be kidney graft recipients than nonkidney graft
      recipients, whereas Native Aboriginal recipients seemed more likely to have
      undergone liver transplantation.

PMID- 10360586
TI  - The use of an anti-TCRalphabeta monoclonal antibody to control host-versus-graft
      reactions in canine marrow allograft recipients conditioned with low dose total
      body irradiation.
AB  - BACKGROUND: A limitation in the application of marrow transplantation has been
      complications related to the conditioning regimens that have been intensified to
      the point where organ toxicities have been common, resulting in morbidity and
      mortality. METHODS: A conditioning regimen consisting of low-dose total body
      irradiation (TBI*) was used to test whether postgrafting therapy with a
      monoclonal antibody (mAb) against the T cell receptor (TCR)alphabeta facilitated
      sustained engraftment of marrow from dog leukocyte antigen (DLA)-identical canine
      littermates. The anti-TCRalphabeta mAb 15.9D5 was selected for in vivo studies
      because it induced hyporesponsiveness to allogeneic stimulator cells in mixed
      leukocyte culture and was not mitogenic in vitro. RESULTS: When recipients of
      genotypically DLA-identical marrow were conditioned by the barely "lethal" dose
      of 450 cGy TBI alone, almost 60% of grafts failed (n=39). The remainder
      engrafted, either in the form of stable mixed donor/host or all donor
      hematopoietic chimerism. In contrast to results in controls, 5 of 6 dogs that
      were given, in addition, a loading dose of mAb 15.9D5 of 1 mg/kg on day -1, 450
      cGy TBI on day 0, followed by mAb at 0.3 mg/kg/day until day +7, showed sustained
      engraftment (P=.058). To accomplish a comparable rate of engraftment in the
      absence of anti-TCRalphabeta antibody, 920 cGy TBI were needed for pretransplant
      conditioning. CONCLUSIONS: Results strongly suggested that in vivo administration
      of a mAb against TCRalphabeta prevented rejection of allogeneic marrow grafts in
      the setting of conditioning with a relatively nontoxic but otherwise suboptimal
      dose of 450 cGy TBI. In vivo administration of m Ab 15.9D5 was well tolerated
      without any noticeable side effects. The exact mechanism by which the mAb works
      in vivo is as yet poorly understood, but it does not involve CD3/TCR complex
      modulation or elimination of T cells from the circulation.

PMID- 10360587
TI  - Sequencing of two HLA-A blank alleles: implications in unrelated bone marrow
      donor matching.
AB  - BACKGROUND: DNA-based methods can type for HLA antigens with no or very low cell
      surface expression. The role of such serological blank antigens in bone marrow
      donor selection is unknown. METHODS: HLA-A serological blank antigens detected in
      two leukemic patients were cloned and sequenced from genomic DNA. mRNA expression
      and exon 3 splicing were determined by reverse transcriptase-polymerase chain
      reaction (PCR). RESULTS: Two patients typed A2/x and A3/x by serology were
      revealed to be A*01/A*0201 and A*03/A*24 by DNA typing. The HLA-A*O1 blank
      antigen was identified as the A*0104N allele with a C insertion in exon 4, which
      results in a stop codon. The HLA-A*24 blank antigen was identified as the
      A*2402102L allele characterized by a mutation in intron 2 leading to impaired
      splicing of mainly exon 3. As a consequence, functional A24 mRNA was reduced to
      less than 5% compared with the other HLA-A allele. For both patients, a search
      for an unrelated donor was initiated on the basis of the functional absence of
      the serologically blank allele. The second patient with the A*24 blank antigen
      could undergo transplantation with marrow from a "fully A/B/C/DRB1/DRB5/DQB1
      compatible" donor, homozygous for the A antigen. Donor T cells did not react
      against the patient in a pretransplantation cytotoxic T lymphocyte precursor
      frequency test known to detect all class I incompatibilities. However, despite
      this functional pretransplantation compatibility, the patient died 44 days after
      bone marrow transplantation, suffering from graft-versus-host disease grade IV.
      The presence of potentially functional A*2402 mRNA could be demonstrated by
      reverse transcriptase-PCR and sequencing: 50% of the A24 mRNA molecules were
      estimated to contain exon 3 with a correct splice site. CONCLUSIONS: These
      findings show that serological blank antigens with low mRNA expression might
      still be recognized after bone marrow transplantation. The determination of such
      alleles by molecular methods and the assessment of mRNA expression should
      therefore be included in the unrelated bone marrow donor search protocol.

PMID- 10360588
TI  - Inhibition of human dendritic cell functions by methylprednisolone.
AB  - BACKGROUND: The aim of this study was to better define how glucocorticoids
      influence primary human T cell responses. Dendritic cells (DC*) are the most
      effective antigen presenting cells able to activate naive T cells. Previous
      studies have shown that dexamethasone impaired the function of murine DC. Here,
      we analyzed how methylprednisolone (MP) might affect the function and maturation
      of human DC. METHODS: Human DC were generated from peripheral blood mononuclear
      cells cultured in granulocyte macrophage-colony stimulating factor and
      interleukin (IL)4. DC maturation was induced either by lipopolysaccharide (LPS)
      or by fibroblast transfected with the CD40-ligand gene (3T6-CD40L). DC phenotype
      was characterized by flow cytometric analysis, their cytokine production by
      ELISA. The ability of DC to activate naive T cells was evaluated in mixed
      leukocyte reactivity. RESULTS: Although MP did not affect viability of DC, it
      enhanced their antigen uptake and down-regulated their basal expression of CD86.
      The expression of CD80 and CD54 by DC was slightly decreased and HLA-DR
      expression was not modified. MP prevented LPS-induced DC maturation as assessed
      by the inhibition of CD86, CD80 and CD54 up-regulation, CD83 induction and
      production of TNF-alpha, IL-6, and IL-12. In contrast, when DC were stimulated by
      3T6-CD40L, MP prevented only the synthesis of IL-12. Moreover, MP-treated DC were
      deficient in their ability to elicit proliferative responses of CD4+CD45RA+
      allogeneic T cells as well as their synthesis of interferon (IFN)-gamma, IL-5,
      and IL-13. CONCLUSION. Glucocorticoids exert potent suppressive effects on human
      DC and thereby inhibit the induction of primary T cell responses.

PMID- 10360589
TI  - Preserved long-term repopulation and differentiation properties of hematopoietic
      grafts subjected to ex vivo expansion with stem cell factor and interleukin 11.
AB  - BACKGROUND: The ex vivo expansion of hematopoietic grafts has been proposed as an
      efficient procedure for improving the hematological recovery of recipients. The
      fate of the long-term repopulating cells during the ex vivo manipulation of the
      graft is, however, a critical issue in ex vivo expansion protocols and ultimately
      will define the applicability of this new technology in hematopoietic
      transplants. METHODS: The repopulating ability of mouse hematopoietic samples was
      determined by means of bone marrow (BM*) competition assays, using congenic
      strains that express the pan-leukocyte Ly-5.1 and Ly-5.2 antigens. The generation
      of potential changes in the repopulating properties of human hematopoietic
      samples subjected to ex vivo expansion was determined by comparing the
      engraftment of fresh and ex vivo-manipulated CD34+ cord blood cells in irradiated
      nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. RESULTS: Under
      our optimized conditions of mouse BM incubation (stem cell factor plus
      interleukin-11, either with or without macrophage inflammatory protein-1alpha or
      Flt3 ligand), both the short-term and the mid-term repopulating ability of the ex
      vivo-expanded samples were significantly improved when compared with fresh
      samples. In the long-term, no changes in the repopulation and differentiation
      properties of the graft were observed as a result of the ex vivo expansion
      process. As deduced from the analysis of NOD/SCID mice transplanted with fresh
      and ex vivo expanded human CD34+ cord blood cells, the in vitro stimulation
      mediated by SCF/IL-11/FLT3L was capable of preserving the ability of the grafts
      to repopulate the lympho-hematopoiesis of recipients for at least 3 months.
      CONCLUSION: These results indicate that under our optimized conditions of ex vivo
      expansion, the amplification of the hematopoietic progenitors responsible for the
      short- and mid-term repopulating properties of the graft can take place without
      compromising the long-term lympho-hematopoietic repopulating properties.

PMID- 10360590
TI  - Role of donor leukocyte chimerism in establishing the etiology of neutropenia
      after liver transplantation.
AB  - BACKGROUND: The quantitation of donor leukocyte chimerism may aid in establishing
      the etiology of neutropenia after liver transplantation. METHODS: The incidence
      and clinical and laboratory characteristics of severe neutropenia were studied in
      adults who have undergone liver transplantation at our institution over the last
      4 years. RESULTS: Severe neutropenia developed in 5 of 156 patients (3%). The
      clinical and pathological features were nonspecific. In two patients with a
      delayed diagnosis of graft-versus-host disease (GVHD), donor leukocytes comprised
      > or = 50% of the circulating peripheral blood mononuclear cells. In a third
      patient, an earlier diagnosis of GVHD was suspected on the basis of a donor
      leukocyte count of 3-10% in the peripheral blood. In contrast, donor leukocyte
      chimerism was < or = 0.01% in two patients with probable drug-induced neutropenia
      CONCLUSIONS: The determination of donor leukocyte chimerism has an important role
      in the investigation of neutropenia after liver transplantation, allowing early
      diagnosis and treatment of GVHD.

PMID- 10360591
TI  - Interferon-gamma is necessary for initiating the acute rejection of major
      histocompatibility complex class II-disparate skin allografts.
AB  - BACKGROUND: Although interferon (IFN)gamma has immunostimulatory functions, it is
      not essential for the acute rejection of fully allogeneic grafts in mice. It is
      not known whether IFNgamma plays a critical role in the acute rejection of MHC
      class I- or MHC class II-disparate allografts. METHODS: We studied the survival
      of skin allografts transplanted from fully allogeneic (BALB/c), MHC class I
      disparate (bml), or MHC class II-disparate (bm12) donors to C57BL/6 wild-type
      (IFNgamma+/+) and IFNgamma gene-knockout (IFNgamma-/-) recipients. We also
      investigated the in vitro responses of IFNgamma+/+ and IFNgamma-/- T cells to MHC
      class II-disparate splenocytes. RESULTS: We found that IFNgamma-/- recipients
      reject BALB/c and bml skin grafts at the same rate as IFNgamma+/+ mice but are
      not capable of rejecting bm12 skin. Despite the inability of IFNgamma-/- mice to
      reject bm12 skin grafts, IFNgamma-/- T cells displayed vigorous proliferation and
      cytotoxic responses when stimulated with bm12 splenocytes in vitro. Furthermore,
      priming IFNgamma-/- recipients with bm12 splenocytes enabled these mice to reject
      bm12 skin grafts at a normal rate and to mount a cutaneous delayed-type
      hypersensitivity response to the bm12 antigen. CONCLUSION: The data demonstrate
      that IFNgamma is not necessary for generating effector mechanisms associated with
      acute transplant rejection but that it is required for initiating alloimmune
      responses to MHC class II-disparate skin grafts.

PMID- 10360592
TI  - Acquired protein S deficiency with multiple thrombotic complications after
      orthotopic liver transplant.
AB  - BACKGROUND: Orthotopic liver transplantation (OLT) is frequently complicated by
      thrombotic events that may threaten the viability of the allograft and severely
      compromise the overall outcome in these patients. Although multiple prothrombotic
      pathogenic mechanisms may be involved, a role for inadequate natural
      anticoagulant levels in the early postoperative period has been postulated.
      METHODS: We describe a case of a woman who suffered multiple thrombotic
      complications after a second OLT. Prospective assays of procoagulant and natural
      anticoagulant factor levels, in addition to screening tests for a variety of
      inherited and acquired hypercoagulable states, were carried out. RESULTS: Serial
      studies confirmed an acquired, isolated deficiency of Protein S associated with
      the second transplanted liver. Protein S levels were normal after the patient's
      first and third OLTs. There was no laboratory evidence of other underlying
      prothrombotic conditions. CONCLUSIONS: This unusual case of acquired Protein S
      deficiency demonstrates that the hypercoagulable phenotype may develop in the
      recipient of a liver from a heterozygous deficient donor. Furthermore, isolated
      low Protein S may be causally associated with hepatic artery thrombosis after
      OLT.

PMID- 10360594
TI  - Epstein-Barr virus (EBV) associated B-cell lymphoproliferative disease following
      HLA identical sibling marrow transplantation for aplastic anaemia in a patient
      with an EBV seronegative donor.
AB  - BACKGROUND: B-cell lymphoproliferative disorders (BLPD*) caused by Epstein-Barr
      virus (EBV) occurring after allogeneic bone marrow transplantation (BMT) are
      usually of donor origin. Treatment such as discontinuation of immunosuppression
      may be successful in some cases, but infusion of donor T cells results in
      successful eradication of EBV BLPD in most cases. METHODS AND RESULTS: We report
      a case of EBV positive aggressive BLPD after HLA matched sibling BMT for aplastic
      anaemia. The tumour completely regressed after withdrawal of cyclosporin and
      donor lymphocyte infusion. However, although the tumor was of donor origin, the
      donor serum was negative for antibodies to EBV antigens and no EBV-specific
      cytotoxicity was detected in donor peripheral blood mononuclear cells. The
      recipient was seropositive for EBV before BMT. CONCLUSIONS: We speculate that a
      'second primary' EBV infection occurred involving donor cells in the recipient
      during BMT immunosuppression, with subsequent outgrowth of donor-derived BLPD.
      EBV infection may have been by an endogenous EBV isolate, from external sources,
      or from third party transfusions.

PMID- 10360595
TI  - Foscarnet-induced crystalline glomerulonephritis with nephrotic syndrome and
      acute renal failure after kidney transplantation.
AB  - Foscarnet nephrotoxicity has been reported to be associated with acute
      tubulointerstitial nephritis. Crystals in glomerular capillary lumens have also
      been observed in patients with acquired immunodeficiency syndrome who were
      treated with foscarnet for cytomegalovirus disease. We describe a kidney
      transplant recipient who developed a nephrotic syndrome with microscopic
      hematuria and nonoliguric acute renal failure within 15 days after starting
      foscarnet therapy for cytomegalovirus infection. A kidney biopsy specimen showed
      the presence of crystals in all glomeruli and in proximal tubules. Fourier
      transform infrared microscopy analysis demonstrated that crystals were made from
      several forms of foscarnet salts: mixed calcium and sodium salts, and unchanged
      trisodium foscarnet salts. Renal function and proteinuria spontaneously improved,
      and a second transplant biopsy performed 8 months after the first one revealed
      fibrotic organization of half of the glomeruli and of interstitial tissue, and
      crystal vanishing. We were thus able to provide proof of the possible
      precipitation of foscarnet in a transplanted kidney.

PMID- 10360593
TI  - Successful liver transplantation after induction chemotherapy in children with
      inoperable, multifocal primary hepatic malignancy.
AB  - BACKGROUND: The prognosis for primary epithelial liver tumor in children in whom
      radical surgery cannot be performed after chemotherapy is poor. Orthotopic liver
      transplantation has resulted in mortality up to 50%, largely as a result of
      problems in determining the criteria for transplantation. METHODS: We report
      results on liver transplantation for primary epithelial liver malignancy in five
      children (mean age at transplantation: 6.0 years). Only patients with inoperable
      residual tumor in the liver after four cycles of multidrug chemotherapy, but
      without extrahepatic infiltration or metastases, were considered eligible for
      transplantation. RESULTS: Mean follow-up was 4.6 years. Patient and graft
      survival was 100%, with no signs of residual or de novo malignancy. CONCLUSION:
      In children with inoperable primary liver malignancy with no extrahepatic tumor
      growth, orthotopic liver transplantation has an excellent outcome.

PMID- 10360596
TI  - Posttransplantation B lymphoblastic leukemia with Burkitt-like features.
AB  - BACKGROUND: Posttransplantation Epstein-Barr virus-associated lymphoproliferative
      disease (PTLPD) occurs as a spectrum of disease ranging from benign, polyclonal,
      localized lymphoid hyperplasia to malignant, monoclonal, disseminated lymphoma,
      sometimes involving the bone marrow. To our knowledge, PTLPD has not been
      previously reported to present as acute lymphoblastic leukemia. METHODS: We
      report the case of a boy who developed PTLPD in the form of acute lymphoblastic
      leukemia 6 years after cardiac transplantation. He had greater than 90% bone
      marrow invasion by Epstein-Barr virus-positive B lymphoblasts with Burkitt-like
      features and a t(8;14) translocation. RESULTS: He was successfully treated with
      combination chemotherapy but unfortunately died, 6 months after completing
      treatment, from ischemic heart disease. CONCLUSIONS: B lymphoblastic leukemia may
      occur as a manifestation of PTLPD and should be included in the classification of
      these diseases. Bone marrow examination should be an essential part of the
      investigation of patients suspected of having PTLPD.

PMID- 10360597
TI  - Microchimerism in sensitized renal patients.
AB  - BACKGROUND: Patients exposed to allogeneic human tissue sometimes produce anti
      HLA antibody for many years in the absence of further obvious antigen exposure.
      To investigate the mechanism of sustained sensitization, we identified females
      awaiting renal transplantation with high panel-reactive antibody but no exposure
      to allogeneic tissue for at least 1 month. METHODS: We analyzed peripheral blood
      microchimerism using nested polymerase chain reaction amplification specific for
      the SRY region of the Y chromosome. RESULTS: Microchimerism was detected in 3 of
      10 patients but in none of 8 normal female subjects. In two cases, the amplified
      DNA polymerase chain reaction product was sequenced and was confirmed to be
      identical to the SRY gene. The estimated level of chimerism as compared with
      serial dilutions of DNA from male peripheral blood leukocytes was about 1/50000.
      CONCLUSION: These results do not establish causality but support the possibility
      that antigens from microchimeric donor cells may sustain the HLA antibody
      response in certain patients.

PMID- 10360598
TI  - HaNDL syndrome after "benign" OKT3-induced meningitis.

PMID- 10360599
TI  - Cryptophycin 1 cellular levels and effects in vitro using L1210 cells.
AB  - Cryptophycin 1 is a natural product that was initially isolated from blue-green
      algae which has shown potent broad spectrum antitumor activity in preclinical in
      vitro and in vivo models. The drug strongly binds to tubulin and disrupts
      microtubule assembly for more than 24 hours after its removal. We evaluated cell
      survival, intracellular levels and inhibition of macromolecular synthesis in
      L1210 cells following exposure to cryptophycin 1 in vitro. Cell survival was
      strongly inhibited following drug exposure for either 1 or 4 hours. Intracellular
      drug levels were minimally affected by temperature (4 degrees C versus 37 degrees
      C) or exposure times up to 1 hour. However, extracellular drug concentration in
      culture media and increasing cell numbers did affect the concentration of
      intracellular drug levels in a nearly proportional manner. The synthesis of DNA
      and RNA was inhibited less than 5%, while protein synthesis inhibition was near
      30%. Thus, none of the macromolecules were inhibited enough to explain the
      inhibition of tumor cell growth.

PMID- 10360601
TI  - Effects of SW 33377, SW 68210 and SW 71425 thioxanthones on in vitro colony
      formation of freshly explanted human tumor cells.
AB  - Thioxanthones are aromatic hydrocarbons with cytotoxic activity against several
      tumor models. Potential mechanisms of action may include DNA intercalation,
      inhibition of nucleic acid biosynthesis, and topoisomerase inhibition, as well as
      formation of intracellular DNA single strand breaks. Such a broad spectrum of
      expected antitumor activity makes this class of compounds particularly
      interesting and worth pursuing in clinical studies. SW 33377 (Win 33377, SR
      233377) was so promising in vitro that it was taken into Phase I clinical trials
      for further evaluation. The compound had undesirable cardiac effects, so new
      analogs were sought that would have similar antitumor effects without the
      undesirable side effects. In the present study, two new analogs SW 68210 (WIN
      68210), and SW 71425 (WIN 71425) are compared to the antiproliferative action of
      SW 33377 against a variety of freshly explanted human tumor specimens using an in
      vitro soft agar cloning system. All compounds were more effective with continuous
      exposure than 1 hour exposure and a concentration-response effect was evident
      with all compounds. SW 68210 with continuous exposure showed similar activity to
      SW 33377 at all concentrations. SW 71425 with continuous exposure was less
      effective at the lower concentrations but was nearly as effective at 10 microg/ml
      as the other two compounds and was highly effective at 50 microg/ml. At the 10
      microg/ml concentration all compounds were similarly effective against breast,
      colon, non-small cell lung, and ovarian tumors. The two new analogs, SW 68210 and
      SW 71425 have activity similar to SW 33377 and are both likely candidates for
      further development.

PMID- 10360600
TI  - The folate receptor as a potential therapeutic anticancer target.

PMID- 10360602
TI  - Compatibility and stability of bryostatin 1 in infusion devices.
AB  - Bryostatin 1 is currently in phase II clinical trial sponsored by the National
      Cancer Institute as an anticancer chemotherapeutic agent. Bryostatin 1 for
      injection was supplied in a dual pack containing a drug vial and a diluent vial
      and was manufactured by Ben Venue Laboratories, Inc (Bedford, OH). The stability
      and compatibility of the bryostatin 1-PET formulation, diluted to 1 and 10 ug/mL
      in saline and benzyl alcohol preserved saline, with polypropylene (PP) and
      polyvinyl chloride (PVC) bags at room temperature (27 degrees C) were studied.
      All experiments were conducted in triplicate and analyses were performed using a
      validated, stability-indicating, high performance liquid chromatography (HPLC)
      assay. Bryostatin 1 solutions were compatible with PP bags. At both
      concentrations and with both salines, the bryostatin content remained unchanged
      during the 28-day storage period, benzyl alcohol concentration in the preserved
      saline solutions also remained relatively constant. In PVC bags, however, a
      decrease in bryostatin 1 concentrations without generation of decomposition
      products was observed at both dilutions and with both salines during the 28-day
      storage. A decrease in benzyl alcohol concentration in the preserved saline was
      also observed. While no diethylhexylphthalate (DEHP) leakage into the solution
      was observed in PP bags, DEHP leakage in PVC infusion bags was observed on day 2
      of storage which increased with storage time and leveled off on day 6. The amount
      of DEHP leached into drug solution is dependent on the drug concentration. This
      study suggests bryostatin-PET formulation diluted with preserved saline can be
      used for long-term (4 week) intravenous administration using PP infusion bags,
      but not with PVC bags.

PMID- 10360603
TI  - Phase I study of paclitaxel administered by ten-day continuous infusion.
AB  - PURPOSE: Pre-clinical data have suggested that prolonged exposure to paclitaxel
      enhances its cytotoxicity, but various clinical trials utilizing long-term
      infusions of paclitaxel have been limited by unacceptable hematologic toxicity,
      most notably significant neutropenia. A phase I study of paclitaxel administered
      over 10 days, was performed to evaluate the hematologic and non-hematologic
      toxicities as well as to determine the maximum-tolerated dose for the 10-day
      infusion duration. PATIENTS AND METHODS: Twenty-nine solid tumor patients
      (predominantly non-small cell lung cancer and head and neck cancer) were treated
      with paclitaxel at doses ranging from 5 mg/m2/day to 25 mg/m2/day administered as
      a 10-day continuous infusion via a pump every 21 days. Dose escalation was
      permitted within individual patients. Dose-limiting toxicity (DLT) was defined as
      grade 3 or 4 non-hematologic toxicity, ANC < or = 500 or platelet count < or =
      25,000 for > or = 7 days or febrile neutropenia. The maximum tolerated dose (MTD)
      was defined as the highest dose level at which less than two out of six patients
      developed DLT. All of the patients had received prior chemotherapy; approximately
      two-thirds had received prior radiation as well. All patients received standard
      pre-medications for paclitaxel, including anti-histamines and corticosteroids.
      Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used. RESULTS:
      A total of 110 courses of paclitaxel were administered to 29 patients. The
      incidence of hematologic and non-hematologic toxicity was quite low among the
      patients treated at dose levels below 17 mg/m2/day. At higher doses, non
      hematologic toxicities including arthralgias, myalgias, fatigue, nausea,
      stomatitis, and peripheral neuropathy were seen, although nearly all of the
      toxicities were less than grade 3 (NCI toxicity criteria). Hematologic toxicity
      mostly consisted of neutropenia and was more common at dose levels of 17
      mg/m2/day or higher. Nevertheless, even at the highest dose levels (21 mg/m2/day
      and 25 mg/m2/day) grade 3 or 4 neutropenia occurred in only 50% of patients. Dose
      limiting hematologic toxicity occurred in 2 of 4 patients treated at the 25
      mg/m2/day dose level. CONCLUSION: Paclitaxel can be safely administered as a 10
      day infusion. The MTD for this schedule is 210 mg/m2. Unlike the 96-hour
      paclitaxel infusions, dose-reduction for myelosuppression may not be necessary
      because the MTD of paclitaxel when administered over a 10-day infusion is similar
      to the MTD of paclitaxel when infused over 3 or 24 hours.

PMID- 10360604
TI  - Phase I and pharmacologic study of oral (E)-2'-deoxy-2'-(fluoromethylene)
      cytidine: on a daily x 5-day schedule.
AB  - (E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), one of the most potent
      inhibitors of ribonucleoside diphosphate reductase, was selected for clinical
      development because of its novel mechanisms of action, and strong antitumor
      activity against experimental tumor models. This study was designed to determine
      the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of
      FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients
      with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic
      studies were carried out on days 1 through 5 of the first cycle. Ten patients
      with non-small cell lung cancer received 15 courses of FMdC at doses which were
      de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe
      toxicities at the starting dose level. Neutropenia was the dose-limiting
      toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were
      the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six
      patients developed grade 3-4 neutropenia. At the 4 mg/m2/day dose level, the mean
      terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and
      mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h,
      respectively. The recommended dose for phase II studies with this schedule is
      also 4 mg/m2/day for 5 days. Further investigations are necessary to establish
      optimal dosing schedules and routes for the administration of FMdC.

PMID- 10360605
TI  - Phase II trial of circadian infusion floxuridine (FUDR) in hormone refractory
      metastatic prostate cancer.
AB  - Circadian administration of chemotherapy has been reported to decrease toxicity
      and possibly enhance efficacy. Between March 1991 and December 1993, 18 evaluable
      patients with progressive, hormone-refractory metastatic prostate cancer were
      treated in this phase II trial of circadian infusion floxuridine (FUDR). The drug
      was delivered through a central venous catheter using a CADD-Plus computerized
      pump such that approximately 70% of the drug was administered between 3 and 9
      p.m. and the rest (30%) was administered between 9 p.m. and 3 p.m. The dose of
      FUDR was 0.15 mg/kg/day x 14 days every 4 weeks. A total of 79 complete cycles
      was administered. Two of 18 evaluable patients (11.1%) had decreases in PSA
      lasting five and eight months. No objective responses or improvement in bone
      scans was noted. The major toxicity observed was diarrhea. Although circadian
      infusion FUDR is feasible and tolerable, it has limited activity in hormone
      refractory prostate cancer.

PMID- 10360606
TI  - A phase II study of Didemnin B (NSC 325319) in advanced malignant melanoma: an
      Eastern Cooperative Oncology Group study (PB687).
AB  - PURPOSE: Didemnin B is a novel marine natural product cyclic depsipeptide
      containing unusual amino acid moieties. This agent demonstrates promising
      preclinical antitumor activity, including activity against B16 melanoma and
      against melanoma isolates in the human tumor stem cell assay. METHODS: We
      conducted a phase II study of Didemnin B, given in Cremophor, at a starting dose
      of 4.2 mg/m2/IV q 28 days. Patients with measurable metastatic or advanced
      malignant melanoma were eligible. All patients were previously untreated with
      chemotherapy and had performance status 0 or 1. Doses were escalated to 4.9 and
      5.6 mg/m2 in cycles 2 and 3, respectively. RESULTS: Nineteen patients were
      entered and treated with a median of one cycle per patient. Eight of these
      patients went off study for toxicity including 7 with anaphylactoid reactions in
      the first or second cycle. One patient went off study after 3 cycles with severe
      myopathy, a newly described toxicity. Two were not evaluable for response and
      five were considered stable, including one patient with a transient PR of soft
      tissue disease in the first cycle. Another patient had stable disease for twelve
      cycles before progressing and one went off study electively after 3 cycles, for a
      total of 7 patients with stable disease. One patient with a measurable partial
      remission (PR) and went off study after three cycles due to severe myopathy, a
      then newly-described toxicity. No hematologic toxicity was seen. Nausea and
      vomiting were controlled with anti-emetics. CONCLUSIONS: This study was
      indeterminate with respect to the activity of Didemnin B in melanoma. Signs of
      activity were seen, particularly in soft tissue masses, though a large number of
      patients could not be evaluated fully for activity due to the occurrence of
      anaphylactoid reactions. This study does not preclude a clinically important
      level of activity for Didemnin B.

PMID- 10360607
TI  - Phase II trial of docetaxel with dexamethasone premedication in patients with
      advanced non-small cell lung cancer: the Canadian experience.
AB  - We performed a Phase II trial to evaluate the activity and tolerability of
      docetaxel as a single agent in the treatment of advanced non-small cell lung
      cancer (NSCLC). Forty-four patients with metastatic and/or locally advanced NSCLC
      received i.v. docetaxel 100 mg/m2 every 3 weeks for a median of 4 (range 1-11)
      cycles. All patients received premedication with oral dexamethasone 8 mg twice
      daily for 5 days starting the day before chemotherapy. Seven partial responses
      were observed among 35 evaluable patients, and the overall response rate was 20%
      (95% CI 8-37). The median response duration was 5 months, median survival time
      was 10 months and the estimated 1-year survival rate was 42%. Treatment was
      generally well tolerated. Febrile neutropenia occurred in 10 patients (23%);
      neutropenic infection occurred in 4 patients, and led to 2 toxic deaths (both
      patients had borderline exclusion criteria). The corticosteroid premedication
      effectively reduced the overall incidence (34%) and severity (4% severe) of fluid
      retention, and delayed the median time to onset from cycle 4 to cycle 7. This
      study shows the promising efficacy of docetaxel as monotherapy in advanced NSCLC,
      and combination chemotherapy regimens incorporating docetaxel are now being
      evaluated in this clinical setting.

PMID- 10360608
TI  - Evaluation of Tomudex in patients with recurrent or metastatic squamous cell
      carcinoma of the head and neck: a Southwest Oncology Group study.
AB  - A phase II trial of Tomudex (raltitrexed, ZD 1694), a new thymidylate synthase
      inhibitor, was performed in patients with recurrent or metastatic squamous cell
      carcinoma of the head and neck. This trial demonstrated that Tomudex was well
      tolerated in this patient population. Nausea and vomiting were minimal, and
      hematologic toxicities were relatively infrequent. Only one patient was withdrawn
      from the study due to toxicity (grade 4 diarrhea). One patient exsanguinated from
      a rent in the carotid artery in an area of tumor involvement, and was categorized
      as a grade 5 toxicity. Thus 25/27 patients were able to complete at least 2
      cycles of treatment. Tomudex demonstrated a 3.7% response rate (95% CI 0.1-19%),
      with a median survival of 6 months in this highly resistant disease population.
      Tomudex is not considered active enough as monotherapy for further evaluation in
      this disease population.

PMID- 10360609
TI  - Phase II trial of 150-minute weekly infusion of gemcitabine in advanced
      colorectal cancer: minimal activity in colorectal cancer.
AB  - Metastatic colorectal cancer is very common in the Western hemisphere and current
      treatment modalities are not effective. In this study a prolonged (150-minute)
      infusion of gemcitabine at a constant dose rate of 10 mg/m2/min administered
      weekly for 3 consecutive weeks repeated every 4 weeks revealed a response rate of
      4% (90% CI < 1%-18%). There were no complete responses. Treatment with
      gemcitabine produced moderate to severe toxicity as grade 3-4 neutropenia
      requiring dose modification was seen in 40% of patients treated. When used in
      this dose and schedule, gemcitabine does not appear to be effective for patients
      with metastatic colorectal cancer.

PMID- 10360610
TI  - Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced
      hepatocellular carcinoma.
AB  - Although UFT 300 mg/m2/day and leucovorin 90 mg/day administered orally in
      divided doses administered every 8 hours for 28 days repeated every 35 days could
      be administered safely to patients with advanced hepatomas and good performance
      status, this combination and schedule has limited activity in treating advanced
      hepatoma. BACKGROUND/PURPOSE: Biochemical modulation of 5-fluorouracil has
      yielded higher response rates in hepatoma when compared to treatment with 5
      fluorouracil as a single agent, although the impact on survival has been
      negligible. This study was conducted to determine the activity and evaluate the
      toxicity of uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol
      Myers Squibb, Wallingford, CT) plus oral calcium leucovorin in the treatment of
      patients with advanced hepatocellular carcinoma (hepatoma). PATIENTS AND METHODS:
      Sixteen patients with advanced measurable hepatocellular carcinoma were enrolled
      onto the trial. All patients had a Karnofski performance status > or = 60%,
      platelet count > or = 75,000/micro L, total bilirubin < or = 2.0 x institutional
      upper limit of normal but otherwise normal liver and kidney function profile and
      bidimensionally measurable disease by CT or ultrasound examination. None of these
      patients received prior cytotoxic chemotherapy or radiation therapy for advanced
      disease. Fourteen patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin
      administered orally in divided daily doses every 8 hours for 28 days repeated
      every 35 days. Two patients registered for the trial but did not receive study
      medication. Objective tumor response, the primary purpose of this trial, was
      evaluated after two courses of therapy. Other end-points included toxicity, time
      to progression, and overall survival. RESULTS: Fourteen patients were evaluable
      for response and toxicity, respectively. No complete or partial responders were
      observed in this trial. Three patients had stable disease lasting 17 to 22 weeks.
      Toxicity was mild with severe (grade 3 or 4) liver pain, diarrhea,
      anorexia/nausea, fatigue, dyspnea, hyperbilirubinemia, anemia, and edema seen in
      3 (21%), 2 (14%), 3 (21%), 2 (14%), 1 (7%), 1 (7%), 1 (7%) and 1 (7%) patients,
      respectively. The most frequent grade I and 2 toxic effects included fever of
      unknown origin, dyspnea, nausea, vomiting and diarrhea. CONCLUSION: UFT 300
      mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate
      antitumor activity against advanced hepatomas. Further treatment using this
      regimen is not recommended for this disease.

PMID- 10360611
TI  - The history of electroconvulsive therapy in the United States and its place in
      American psychiatry: a personal memoir.
AB  - The history of electroconvulsive therapy (ECT) in the United States is traced
      from its crude beginnings in 1940 to its emergence as a highly sophisticated and
      effective treatment for many severe psychiatric disorders. The general distrust
      of all somatic therapies in the 1930s and 1940s expressed by many prominent
      psychiatrists (both analysts and nonanalysts) contributed to an ambivalent
      relationship between ECT and the rest of American psychiatry. The media coverage
      of ECT is reviewed, and suggestions for dealing with the antipsychiatry movement
      and anti-ECT prejudice are discussed.

PMID- 10360612
TI  - Psychiatric diagnosis in clinical practice: is comorbidity being missed?
AB  - The recognition of comorbidity has important clinical significance. Comorbidity
      predicts a poorer outcome for patients with depressive and anxiety disorders, and
      the presence of multiple psychiatric disorders is associated with greater
      psychosocial impairment. In routine clinical settings, an unstructured interview
      is typically used to assess patients. However, unstructured interviews may result
      in missed diagnoses, with potential negative clinical consequences. The goal of
      the present study was to examine whether diagnostic comorbidity is less
      frequently identified during a routine clinical evaluation versus a
      semistructured diagnostic interview. Axis I diagnoses derived from structured and
      unstructured clinical interviews were compared in two groups of psychiatric
      outpatients in the same practice setting. Five hundred individuals presenting for
      an intake appointment to a general adult psychiatric practice underwent a routine
      unstructured clinical interview. Subsequent to completion of the first study, the
      method of conducting diagnostic evaluations was changed and 500 individuals were
      interviewed with the Structural Clinical Interview for DSM-IV Axis I Disorders
      (SCID). The two groups had similar demographic characteristics and scored
      similarly on symptom questionnaires. Individuals interviewed with the SCID were
      assigned significantly more axis I diagnoses than individuals assessed with an
      unstructured interview. More than one third of the patients interviewed with the
      SCID were diagnosed with three or more disorders, in contrast to fewer than 10%
      of the patients assessed with an unstructured interview. Fifteen disorders were
      more frequently diagnosed in the SCID sample, and these differences occurred
      across mood, anxiety, eating, somatoform, and impulse-control disorder
      categories. The results suggest that in routine clinical practice, clinicians
      underrecognize diagnostic comorbidity. Anxiety, somatoform, and not otherwise
      specified (NOS) disorders were the most frequently underdetected disorders. The
      implications of underdiagnosis for the treatment outcome are discussed.

PMID- 10360613
TI  - Predicting service utilization after psychiatric hospitalization.
AB  - The purposes of this study were to determine (1) the extent of service
      utilization in the posthospitalization period and (2) the probability of
      specified service utilization outcomes for patients with given characteristics,
      using ordered logit models. The sample consisted of former inpatients who were
      evaluated for 6 months and responded to a mailed questionnaire or telephone
      interview at both the 3- and 6-month follow-up points. Significant independent
      predictors of service utilization at 6 months were the diagnosis, length of
      hospital stay, history of suicide attempts, perceived stress, and medication
      compliance at 3 months. High service utilization was evident in a sizable
      proportion of the sample and could be predicted using this model.

PMID- 10360614
TI  - Health resource utilization and clinical outcomes with risperidone therapy in
      patients with serious mental illness.
AB  - This report is an analysis of our experience with risperidone therapy in a
      veteran population with severe, suboptimally responsive psychosis from a
      perspective of clinical response and health resource utilization. We conducted a
      computer search for all patients who received risperidone therapy at our facility
      from February 1994 until July 1, 1996. Risperidone at our facility is prescribed
      when psychiatric symptoms appear to be refractory or suboptimally responsive to
      conventional antipsychotic therapy. A control group of patients on conventional
      antipsychotic therapy were also selected via the electronic data base. One
      hundred twenty-nine patients received risperidone therapy at a mean dosage of
      5.05+/-2.4 mg/d, for a mean duration of 247.4+/-223.5 days. The largest
      proportion of patients (48.1%) had marked improvement on risperidone therapy.
      There were 35 patients who received at least 1 year of risperidone therapy. These
      patients had a significant decrease in hospital length of stay (LOS) from 80.7 to
      28.7 days (P = .003) on risperidone with no compensatory increase in outpatient
      visits. The group of patients who received conventional antipsychotic therapy
      during the study time period had a more modest mean reduction in LOS over a 2
      year time period from 78.9 days during the initial identified year of
      conventional antipsychotic therapy to 56.4 days during the second identified year
      of conventional antipsychotic therapy (P = .2). However, when change in LOS for
      the entire group was compared, the difference in change in LOS between
      risperidone and conventional antipsychotic treated patients did not reach
      statistical significance (P = .2). This preliminary study concurs with other
      reports that risperidone therapy may be effective in severely mentally ill
      patients and may be associated with significant reductions in health resource
      utilization. Comparison of resource utilization between patients receiving
      risperidone and conventional antipsychotic therapy is still unclear and should be
      explored in larger and prospective studies.

PMID- 10360615
TI  - Effect of comorbid anxiety, depressive, and personality disorders on treatment
      outcome of somatoform disorders.
AB  - Comorbid mental disorders of DSM-IV axis I and axis II have repeatedly been found
      to be a negative predictor for the treatment of axis I disorders, although recent
      contrary findings exist. Little is known about the effect of comorbidity on the
      therapy outcome of somatoform disorders. We compared three types of comorbidity,
      (1) personality disorders (PDs), (2) major depression (MDD) and anxiety (ANX)
      disorders, and (3) PDS and MDD and ANX, with regard to their relevance for the
      treatment outcome of somatoform disorders. One hundred twenty-six inpatients were
      assessed at least 4 weeks before admission to treatment, upon admission, and
      again at discharge. Somatoform, hypochondriacal, and depressive symptomatology,
      dysfunctional cognitions about body and health, dysfunctional social
      relationships, and other clinical characteristics were measured. Diagnostic
      assessments were based on the DSM-IV. Our findings suggest that none of the three
      types of comorbidity influence the therapy outcome of somatoform disorders or
      have a modifying effect on the level of psychopathology.

PMID- 10360616
TI  - Symptomatology and comorbidity of generalized anxiety disorder in children and
      adolescents.
AB  - This study investigated the symptomatology and comorbidity of generalized anxiety
      disorder (GAD) in a clinically referred sample of Italian children and
      adolescents as a function of age and gender. The sample consisted of 58 subjects
      (19 children and 39 adolescents), 23 males and 35 females screened from
      consecutively referred children and adolescents. This sample was divided into two
      groups of younger children (19 subjects, eight males and 11 females aged 7 to 12
      years; mean age, 9.6) and adolescents (39 subjects, 15 males and 24 females aged
      12 to 18 years; mean age, 14.9). Feelings of tension, apprehension, the need for
      reassurance, irritability, negative self-image, and physical complaints were
      reported in more than 70% of the subjects. Differences in the symptomatic profile
      between males and females were not significant. Children and adolescents did not
      show significant differences in the number of symptoms. The need for reassurance
      was significantly more frequent in children, and brooding was more frequent in
      adolescents. Other anxiety disorders were commonly comorbid with GAD. More than
      half of the patients with GAD showed a concurrent depressive disorder; no
      differences were found for comorbidity between children and adolescents, except
      for higher rates of separation anxiety disorder in children.

PMID- 10360617
TI  - Multidimensional assessment of anger in Vietnam veterans with posttraumatic
      stress disorder.
AB  - This study examined the effects of combat exposure and posttraumatic stress
      disorder (PTSD) on dimensions of anger in Vietnam veterans. Vietnam combat
      veterans were compared with Vietnam era veterans without war zone duty on the
      Multidimensional Anger Inventory (MAI). Combat veterans were not significantly
      more angry than their veteran peers who did not serve in Southeast Asia.
      Additionally, various parameters of war zone duty were not highly associated with
      anger scores. However, combat veterans with PTSD scored significantly higher than
      veterans without PTSD on measures of anger arousal, range of anger-eliciting
      situations, hostile attitudinal outlook, and tendency to hold anger in. These
      results suggest that PTSD, rather than war zone duty, is associated with various
      dimensions of angry affect.

PMID- 10360618
TI  - Electroencephalogram, bilateral ear temperature, and affect changes induced by
      lateral visual field stimulation.
AB  - Fifteen subjects evaluated while wearing, in random order, four pairs of glasses,
      two limiting vision to either the left or right lateral visual field (LVF) and
      two monocular glasses (MGs) limiting vision to either eye, manifested significant
      differences in laterality indices in the predicted direction for the theta
      electroencephalogram (EEG) (P < .003) and ear canal temperature (P < .02) between
      the LVF glasses, but not the MGs. There was a significant correlation between
      lateral shifts in the theta EEG and ear canal temperature (r2 = .47, F(1,10) =
      8.72, P < .015). The LVF glasses induced an absolute difference in anxiety
      greater (P < .05) than that induced by the MGs. LVF glasses appear to induce a
      shift in affect and hemispheric dominance.

PMID- 10360619
TI  - Sleep quality and pain threshold in patients with fibromyalgia.
AB  - The purpose of the study was to examine the association between the subjective
      sleep quality and pain threshold in fibromyalgia. Sixteen patients with
      fibromyalgia were included in the study. The pain threshold was determined using
      a manual algometer. The Pittsburgh Sleep Quality Index (PSQI) was used to assess
      sleep quality. The pain threshold was negatively correlated with the scores for
      subjective sleep quality, habitual sleep efficiency, and sleep disturbance and
      the PSQI global score. We conclude that there is a negative correlation between
      pain and sleep disturbance: increased pain sensitivity is associated with greater
      sleep disturbance.

PMID- 10360620
TI  - A preliminary report on pain thresholds in bulimia nervosa during a bulimic
      episode.
AB  - Subjects with bulimia nervosa (BN) have been shown to exhibit abnormal satiety
      responses. Short-term satiety is largely mediated by afferent vagal activity.
      Activation of afferent vagal fibers has also been found to stimulate a descending
      pain inhibitory pathway that leads to elevation in somatosensory pain thresholds.
      Therefore, the study of pain thresholds in BN subjects may lead to a better
      understanding of afferent vagal function in this disorder. In this preliminary
      study, pressure pain thresholds were assessed in nine subjects with BN on 3
      consecutive days during a binge-eating and vomiting (B/V) episode, during a
      normal meal, and after an overnight fast. A significant time versus condition
      effect was found with a significant change in the pain threshold in BN subjects
      under the B/V condition only. These data are consistent with the hypothesis that
      vagal afferent activation by a B/V episode also activates the descending pain
      inhibitory pathway.

PMID- 10360622
TI  - Chaos theories and therapeutic commonalities among depression, Parkinson's
      disease, and cardiac arrhythmias.
AB  - This report reviews and compares all therapies that have shown efficacy in
      depression and Parkinson's disease, although some are not in current use and
      others are at the experimental stage. They include pharmacological modification
      of neurotransmitter pathways, electroconvulsive therapy (ECT), sleep deprivation,
      psychosurgery, electrical stimulation through cerebral electrodes, and
      transcranial magnetic stimulation. Stemming from a pathophysiological model that
      stresses the brain as an open, complex, and nonlinear system, all therapies have
      been attributed a common mechanism of action. This report suggests that the
      therapeutic isomorphism is related to their ability to help the CNS deactivate
      cortical-subcortical circuits that are dysfunctionally coupled. These circuits
      are self-organized among neurons of their informational subsystem (rapid
      conduction) and modulating subsystem (slow conduction). Finally, this report
      extends the analysis and comparison of these therapies to some cardiac
      arrhythmias.

PMID- 10360621
TI  - Gender differences in glycosylated hemoglobin levels in seasonal affective
      disorder patients and controls.
AB  - Seasonal affective disorder (SAD) has been shown to manifest different symptoms
      in female and male patients. Specifically, women with SAD have been shown to have
      greater increases in overeating, weight gain, and increased sleep as compared
      with their male counterparts. Given these dietary changes, we predicted that
      female SAD patients would exhibit increased glycosylated hemoglobin (HbA1)
      levels, indicative of chronically elevated glucose levels. Twenty-two patients
      (15 women and seven men) and matched controls were enrolled during the winter
      season and tested for HbA1 levels. A three-way analysis of variance (ANOVA;
      gender x group x season) was insignificant and the result was a negative study.
      After the initial hypothesis was rejected, we undertook a post-hoc analysis of
      the data, from which emerged that in winter, women patients had higher HbA1
      levels as compared with matched controls. As our original hypothesis was
      rejected, we cannot accept the results of the post-hoc study. However, numerous
      other studies have demonstrated that female and male SAD patients differ in their
      pathophysiology, and are suggestive that in future analyses ought to consider
      analyzing subjects separately across gender.

PMID- 10360623
TI  - Consensus conference on combination oral contraceptives and cardiovascular
      disease.

PMID- 10360625
TI  - Immune-mediated enteric neuron dysfunction in scleroderma.

PMID- 10360624
TI  - C1q receptors and endothelial cell activation.

PMID- 10360626
TI  - Carriage of Staphylococcus aureus: epidemiology and clinical relevance.

PMID- 10360627
TI  - Alveolar macrophage interactions with Pneumocystis carinii.

PMID- 10360629
TI  - Myenteric neuronal antibodies in scleroderma: passive transfer evokes alterations
      in intestinal myoelectric activity in a rat model.
AB  - Although the mechanism for neuropathic gastrointestinal motility disturbances in
      scleroderma is unknown, we have previously described anti-myenteric antibodies in
      some patients with scleroderma. The aim of this study was to screen patients with
      scleroderma who had gastrointestinal symptoms for the presence of anti-myenteric
      neuronal antibodies and then purify the immunoglobulin G (IgG) fraction from
      serum samples for passive immunization into a rat model and observe for
      intestinal motility effects. Patients with scleroderma were screened, a serum
      sample from a patient with high titer anti-myenteric neuronal antibodies was
      obtained, and IgG was purified. Using a rat model with chronic indwelling
      intestinal electrodes to measure intestinal myoelectric activity, we passively
      transferred the IgG from either control subjects or this patient with
      scleroderma. We immunosuppressed the rats and intraperitoneally injected IgG from
      control subjects and this patient with scleroderma daily for 7 days. Recordings
      of myoelectric activity in control injected rats revealed no difference from
      baseline, but a prolongation in the activity front duration and interval and a
      disruption were seen after scleroderma IgG injections. IgG from a patient with
      scleroderma with antimyenteric neuronal antibodies, when passively immunized into
      a rat model, evokes intestinal myoelectric activity alterations. We hypothesize
      that these antibodies could account for the gastrointestinal neuropathic motility
      disturbances seen in scleroderma.

PMID- 10360628
TI  - Up-regulation of endothelial cell binding proteins/receptors for complement
      component C1q by inflammatory cytokines.
AB  - Endothelial cells express a variety of receptor systems involved in humoral
      defense, including receptors for the collagen-like and globular domains of the
      complement component C1q, designated cC1qR and gC1qR, respectively. In the
      present study a microvascular endothelial cell line was used to test the
      hypothesis that expression of these C1q-binding proteins may be affected by
      vascular inflammatory reactions. The results demonstrate that the expression of
      both cC1qR and gC1qR by bone marrow vascular endothelial cells is up-regulated by
      inflammatory mediators, interferon-gamma, tumor necrosis factor-alpha, and
      lipopolysaccharide (Escherichia coli, 055:B5) in a dose- and time-dependent
      manner, as detected by enzyme-linked immunosorbent assay. cC1qR and gC1qR
      expression increased significantly (P < .05) within 4 to 7 hours and doubled
      after 22 hours of stimulation. 3H-thymidine incorporation studies and direct cell
      counts confirmed that increased C1qR expression was not due to increased cell
      proliferation. Northern blot analysis revealed that the up-regulation of cC1qR
      and gC1qR protein expression was preceded by increases in corresponding mRNA
      levels, suggesting increased gene transcription. Indeed C1qR mRNA up-regulation
      was prevented by actinomycin D, and C1qR protein synthesis was inhibited by
      cycloheximide. Bone marrow vascular endothelial cell exposure to C1q, however,
      did not alter cC1qR or gC1qR expression, but up-regulation of the leukocyte
      adhesion molecule ICAM-1 was noted in the presence of aggregated C1q. The up
      regulation of C1qR by inflammatory mediators and the ability of C1q itself to
      increase ICAM-1 expression suggest a potential role for these binding sites in
      vascular inflammation and immune injury.

PMID- 10360630
TI  - Antithrombin prevents stress-induced gastric mucosal injury by increasing the
      gastric prostacyclin level in rats.
AB  - The interaction of antithrombin (AT) with cell surface glycosaminoglycans has
      been shown to promote the endothelial release of prostacyclin (PGI2). Because
      PGI2 plays an important role in gastric cytoprotection, we examined whether AT
      prevents water-immersion restraint stress (WIR)-induced gastric mucosal injury in
      rats by promoting the endothelial release of PGI2. Intravenous administration of
      AT (250 U/kg) prevented WIR-induced gastric mucosal injury in rats. Gastric
      levels of 6-keto-prostaglandin F1alpha, a stable metabolite of PGI2, were
      significantly increased 0.5 and 1 hour after WIR in animals administered AT
      compared with control animals. The effects induced by AT in animals subjected to
      WIR were not observed in animals that were administered DEGR-Xa, a selective
      inhibitor of thrombin generation, or Trp49-modified AT, which lacks affinity for
      heparin. In animals subjected to WIR gastric mucosal blood flow was significantly
      reduced with a simultaneous increase in gastric mucosal microvascular
      permeability. Activated neutrophils have been implicated in the WIR-induced
      reduction of gastric mucosal blood flow by increasing microvascular permeability.
      Although AT prevented the reduction of gastric mucosal blood flow and the
      increase in gastric mucosal microvascular permeability in animals subjected to
      WIR, neither DEGR-Xa nor Trp49-modified AT had any effect. Pretreatment of
      animals with indomethacin completely inhibited the protective effects of AT
      against WIR-induced gastric mucosal injury and the AT-induced increase in post
      WIR gastric 6-keto-prostaglandin F1alpha levels. These results strongly suggest
      that AT prevents stress-induced gastric mucosal injury by increasing the gastric
      levels of PGI2 through the interaction of AT with cell-surface
      glycosaminoglycans, thus increasing gastric mucosal blood flow both by
      vasodilation and by inhibiting neutrophil activation.

PMID- 10360632
TI  - Genetic and nongenetic factors influencing plasma homocysteine levels in patients
      with ischemic cerebrovascular disease and in healthy control subjects.
AB  - Moderately elevated plasma homocysteine levels have been established as an
      independent risk factor for atherosclerosis and its complications, including
      cerebrovascular disease. A common mutation (C677T) in the gene encoding for the
      enzyme methylenetetrahydrofolate reductase (MTHFR) has been linked to increased
      plasma homocysteine levels in homozygous carriers, particularly in the presence
      of low folate levels. However, the results of most of the previous studies
      suggest that the C677T MTHFR mutation is not a significant risk factor for
      arterial disease. This discrepancy might, at least partly, be due to the fact
      that plasma homocysteine levels are influenced by several other factors,
      including age, gender, renal function, and vitamin status. We investigated the
      relation between plasma homocysteine levels, the C677T MTHFR mutation, and these
      other factors in a population of 96 patients with transient ischemic attacks or
      minor strokes and in 96 age- and sex-matched healthy control subjects. We further
      tested the value of a multivariate model for the prediction of plasma
      homocysteine levels under particular consideration of the MTHFR mutation status.
      In the patients, plasma homocysteine levels were significantly higher than in the
      healthy control subjects. With regard to the MTHFR mutation, the distribution of
      the C/C, C/T, and T/T genotypes was not significantly different between patients
      and healthy control subjects. Univariate (linear regression) analysis revealed
      significant (positive) correlations between plasma homocysteine levels on the one
      hand and age and creatinine on the other, the latter particularly in subjects
      with creatinine levels in the upper quartile. Significant (negative) correlations
      were found between plasma homocysteine levels, vitamin B12, and folate levels.
      However, these relations could much better be expressed by means of a
      multiplicative regression model. T/T subjects exhibited slightly higher
      homocysteine levels than C/C and C/T subjects; however, the differences between
      the 3 genotypes were not significant. Multivariate (stepwise regression) analysis
      revealed age, vitamin B12 levels, folate levels, and creatinine levels as
      significant independent variables influencing plasma homocysteine levels, whereas
      the MTHFR mutation status and gender were removed from the model. Considering all
      192 subjects, only 28.8% of the variance of plasma homocysteine levels could be
      accounted for by the model. However, in homozygous carriers of the MTHFR
      mutation, the predictive power of the model is very high, explaining 76.1% of the
      variance of plasma homocysteine levels. According to our results, the C677T
      mutation does not constitute a major risk factor for transient ischemic attack or
      minor stroke, even under consideration of other possibly confounding factors that
      are known to affect plasma homocysteine levels. However, it is possible to
      predict plasma homocysteine levels in homozygous carriers of the mutation with
      high accuracy. The knowledge of the MTHFR mutation status may therefore help to
      identify subjects at high risk for hyperhomocysteinemia.

PMID- 10360631
TI  - Inhibitory effect of a new anti-rheumatic drug T-614 on costimulatory molecule
      expression, cytokine production, and antigen presentation by synovial cells.
AB  - The present study was undertaken to investigate the immunoregulatory effects of T
      614 (3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-o ne) on
      synovial cells in vitro. Synovial cells were cultured with T-614 in the presence
      or absence of various cytokines. After incubation, the costimulatory molecule
      expression on synovial cells and cytokine production in culture supernatants were
      analyzed by an indirect immunofluorescence method and enzyme-linked immunosorbent
      assay, respectively. We also examined the effect of T-614 on the function of
      synovial cells as antigen-presenting cells (APCs). The costimulatory molecules
      including CD54, CD58, and CD106 were constitutionally expressed on the surface of
      synovial cells. However, neither CD80 nor CD86 nor CD102 was found on the
      surface, and these costimulatory molecules could not be induced by any cytokines.
      T-614 itself did not affect the costimulatory molecule expression and cytokine
      production of unstimulated synovial cells. The stimulation of synovial cells with
      interferon-gamma (IFN-gamma), interleukin-1beta, or 12-O-tetradecanoyl phorbol 13
      acetate enhanced the expression of costimulatory molecules and the
      proinflammatory cytokine production of these cells. Both the up-regulated
      expression of these costimulatory molecules and the enhanced production of
      proinflammatory cytokines were significantly inhibited by T-614. Autologous T
      cell proliferation in response to purified protein derivative by IFN-gamma
      treated synovial cells was significantly suppressed by T-614. T-614 has
      considerable immunosuppressive effects on synovial cells by inhibiting the
      costimulatory molecule expression and cytokine production of these cells and the
      antigen-specific T cell proliferation mediated by the synovial cells. These
      results suggest that T-614 plays an important immunoregulatory role in rheumatoid
      synovial tissues.

PMID- 10360633
TI  - Tumor necrosis factor-alpha alters glucose metabolism in suckling rats.
AB  - Tumor necrosis factor-alpha (TNF-alpha), an important mediator of endotoxic
      shock, induces hypoglycemia and shock in adult animals. Indomethacin ameliorates
      TNF-alpha-induced hypoglycemia in the adult. However, effects of TNF-alpha on
      glucose metabolism in the newborn have not been well documented. The present
      study showed that in 10-day-old rats injected with TNF-alpha (4.5 x 10(7) U/kg,
      intraperitoneally) the plasma glucose concentration increased from 4.1 +/- 0.3
      mmol/L to 6.9 +/- 0.5 mmol/L (P < .05) at 2 hours and subsequently decreased to
      1.4 +/- 0.5 mmol/L (P < .05) at 6 hours, although plasma lactate concentration
      increased from 1.1 +/- 0.1 mmol/L to 5.5 +/- 0.3 mmol/L (P < .05) at 6 hours.
      Plasma insulin concentration remained unchanged throughout the experiment. TNF
      alpha increased GLUT 1 messenger RNA (mRNA) abundance in the brain, liver,
      muscle, and fatty tissue (P < .05). Glucose uptake increased in association with
      the increase of GLUT1 mRNA abundance. TNF-alpha decreased mRNA abundance of GLUT
      2 and phosphoenolpyruvate carboxykinase (PEPCK) in liver, suggesting decreased
      gluconeogenesis. Indomethacin (1.5 mg/kg 20 minutes before TNF-alpha,
      intraperitoneally) attenuated the hypoglycemia, the lactacidemia, and the
      increase of GLUT1 mRNA abundance and glucose uptake. Indomethacin attenuated the
      decrease of PEPCK mRNA abundance. We concluded that TNF-alpha induced
      hypoglycemia, increasing GLUT1 mRNA abundance and glucose uptake and decreasing
      PEPCK mRNA abundance in 10-day-old rats. Indomethacin attenuated the TNF-alpha
      induced glucose dyshomeostasis.

PMID- 10360634
TI  - Role of gender in the toxicity of norcocaine.
AB  - Gender differences may significantly influence the toxicity of cocaine in
      mammals. In this study, the influence of gender on the toxicity of norcocaine, a
      pharmacologically active metabolite of cocaine, was compared with its parent
      compound in adult male and female rats. In addition, the plasma and tissue
      norcocaine concentrations were evaluated after the administration of norcocaine
      and cocaine. Norcocaine or cocaine was administered intravenously at a rate of 2
      mg/kg/min until circulatory collapse. Arterial blood samples as well as heart,
      liver, and brain tissues were obtained at circulatory collapse for the
      measurement of concentrations of norcocaine as well as cocaine and its major
      metabolites. There were no gender-related differences in the doses of norcocaine
      required to produce circulatory collapse; however, there were significant gender
      related differences in the norcocaine tissue-to-plasma concentration ratios (T:P
      ratios). After the administration of norcocaine, T:P ratios for heart, liver, and
      brain tissue were significantly greater in males. Furthermore, after cocaine
      administration, the hepatic norcocaine T:P ratio was approximately 3-fold greater
      in the male rats than in the female rats. In contrast, female rats had a greater
      percentage of norcocaine in the plasma at circulatory collapse after acute
      cocaine administration. Although no gender differences in the lethality of
      norcocaine were observed, it remains to be seen whether the gender differences in
      the distribution and uptake of norcocaine play a role in the hepatotoxicity of
      the drug, particularly after chronic exposure.

PMID- 10360635
TI  - Urine electrolytes and the urine anion and osmolar gaps.
AB  - Urine ammonia concentration is crucial to understanding and quantifying the
      kidney's response to metabolic acidosis. This test is generally not performed by
      clinical laboratories. The urine anion gap and osmolar gaps have been proposed as
      surrogate measures of urine ammonia in patients with hyperchloremic acidosis. We
      measured ammonium and other electrolytes in the urine of patients attending our
      renal disease clinic who did not have severe metabolic acidosis and compared the
      results with those calculated by standard formulae for the anion and osmolar
      gaps. We found no correlation between measured ammonium values and the anion gap
      and attributed this lack of agreement to the presence in urine of substantial
      amounts of unmeasured inorganic anions, which the formula fails to consider.
      There was significant correlation between measured ammonium and the osmolar gap
      but not good agreement between the absolute values provided by the 2 methods.
      Solutes including sulfate and phosphate were quantified in 24-hour urine
      collections and showed great variability with respect to measured chloride and
      estimated protein catabolism. We conclude from these studies that there is no
      substitute for the direct determination of urine ammonium when an accurate
      concentration is desired.

PMID- 10360636
TI  - Low-density lipoprotein susceptibility to oxidation and cytotoxicity to
      endothelium in sickle cell anemia.
AB  - Patients with sickle-cell anemia exhibit pro-oxidative metabolic perturbations.
      We hypothesize that because of chronic oxidative stress, plasma low-density
      lipoprotein (LDL) from patients with sickle-cell anemia is more susceptible to
      oxidation. To test this hypothesis, LDL susceptibility to copper-mediated
      oxidation was measured in 24 patients with sickle-cell anemia and 48 control
      subjects. Sickle-cell LDL was more susceptible to oxidation than control LDL,
      measured by a 22% shorter mean lag time between LDL exposure to CuSO4 and
      conjugated diene formation (97 vs 124 minutes; P = .023). LDL vitamin E, iron,
      heme, and cholesterol ester hydroperoxide (CEOOH) levels were also measured. LDL
      vitamin E levels were significantly lower in patients with sickle-cell anemia
      compared with control subjects (1.8 vs 2.9 mol/mol LDL; P = .025), but there was
      no correlation with lag time. Pro-oxidant heme and iron levels were the same in
      sickle-cell and control LDL. LDL CEOOHs were not significantly different in
      sickle and control LDL (3.1 vs 1.2 mmol/mol of LDL unesterified cholesterol, P =
      .15), but LDL CEOOH levels were inversely correlated with lag times in patients
      with sickle-cell anemia (r2 = 0.38; P = .018). The cytotoxicity of partially
      oxidized LDL to porcine aortic endothelial cells was inversely correlated with
      lag times (r2 = 0.48; P = .001). These preliminary data suggest that increased
      LDL susceptibility to oxidation could be a marker of oxidant stress and
      vasculopathy in patients with sickle-cell anemia.

PMID- 10360638
TI  - The sulfhydryl containing compounds WR-2721 and glutathione as radio- and
      chemoprotective agents. A review, indications for use and prospects.
AB  - Radio- and chemotherapy for the treatment of malignancies are often associated
      with significant toxicity. One approach to reduce the toxicity is the concomitant
      treatment with chemoprotective agents. This article reviews two sulfhydryl
      compounds, namely the agent WR-2721 (amifostine), a compound recently registered
      for use in human in many countries, and the natural occurring compound
      glutathione (GSH). GSH is not registered as a chemoprotective agent. WR-2721 is
      an aminothiol prodrug and has to be converted to the active compound WR-1065 by
      membrane-bound alkaline phosphatase. WR-1065 and GSH both act as naturally
      occurring thiols. No protective effect on the tumour has been found when these
      compounds are administered intravenously. There is even in vitro evidence for an
      increased anti-tumour effect with mafosfamide after pretreatment with WR-2721,
      and in vivo after treatment with carboplatin and paclitaxel. Randomized clinical
      studies have shown that WR-2721 and GSH decrease cisplatin-induced nephrotoxicity
      and that WR-2721 reduces radiation radiotherapy-induced toxicity. Side-effects
      associated with WR-2721 are nausea, vomiting and hypotension, GSH has no side
      effects. An exact role of WR-2721 and GSH as chemoprotectors is not yet
      completely clear. Future studies should examine the protective effect of these
      drugs on mucositis, cardiac toxicity, neuro- and ototoxicity, the development of
      secondary neoplasms and their effect on quality of life.

PMID- 10360639
TI  - Biosynthesis of HLA-C heavy chains in melanoma cells with multiple defects in the
      expression of HLA-A, -B, -C molecules.
AB  - Recent investigations have shown that malignant transformation may down-regulate
      the expression of class I HLA molecules, beta2-microglobulin (beta2m) and members
      of the antigen-processing machinery. In the present study, we HLA-genotyped and
      identified at a biochemical level the three (HLA-A25, -B8, -Cw7) class I alleles
      expressed by the previously described [D'Urso CM et al (1992) J Clin Invest 87:
      284-292] beta2m-defective human melanoma FO-1 cell line and tested their ability
      to interact with calnexin, calreticulin and the TAP (transporter associated with
      antigen processing) complex. All these alleles were found to bind calnexin, but
      not calreticulin or the poorly expressed TAP complex, both in parental and beta2m
      transfected FO-1 cells, demonstrating a complex defect of class I expression in
      FO-1 cells. In these conditions, Cw7 heavy chains interacted with calnexin more
      strongly than A25 and B8, and preferentially accumulated in the endoplasmic
      reticulum, in both a calnexin-associated and a calnexin-free form. In addition,
      they could be transported to the cell surface at low levels even in the absence
      of beta2m, without undergoing terminal glycosylation. These results establish a
      parallel between HLA-C and the murine Db and Ld molecules which have been found
      to be surface expressed and functional in beta2m-defective cells. They also
      demonstrate distinctive features of HLA-C molecules. We propose that the
      accumulation of several assembly intermediates of HLA-C might favour the binding
      of peptide antigens not readily bound by HLA-A and -B molecules in neoplastic
      cells with suboptimal class I expression.

PMID- 10360640
TI  - Non-autocrine, constitutive activation of Met in human anaplastic thyroid
      carcinoma cells in culture.
AB  - Activation of Met by its ligand HGF has been shown to elicit both mitogenic and
      motogenic responses in thyrocytes in vitro. In the present study we have
      investigated the expression of Met in human anaplastic thyroid carcinoma cells in
      culture. There was a variation in expression level and size of Met in the
      different cell lines; high Met expression was found in four cell lines, compared
      to non-neoplastic human thyrocytes. Treatment with glucoproteinase F showed that
      the size differences observed were due to variances in the degree of
      glycosylation. Interestingly, in cell lines with high expression of Met, the
      receptor proteins were found to be constitutively tyrosine phosphorylated. None
      of these cell lines expressed HGF mRNA, and addition of suramin did not affect
      the level of tyrosine phosphorylation of Met in unstimulated cells, suggesting
      the absence of autocrine stimulatory pathways. Furthermore, we did not observe
      MET gene amplification, activating mutations or phosphatase defects. The tyrosine
      phosphorylated receptors appeared functionally active since the receptors
      associated with the adaptor molecule Shc. In summary, we have found ligand
      independent constitutively activated Met in four out of six anaplastic thyroid
      carcinoma cell lines.

PMID- 10360641
TI  - Complex post-transcriptional regulation of EGF-receptor expression by EGF and TGF
      alpha in human prostate cancer cells.
AB  - The epidermal growth factor receptor (EGFR) plays an important role in the
      development and progression of prostate cancer and its overexpression is
      associated with decreased survival. With progression, prostate cancer cells
      switch from epidermal growth factor (EGF) to transforming growth factor alpha
      (TGF-alpha) synthesis, which contributes to autocrine growth and unrestrained
      proliferation. To define the molecular mechanisms involved in the regulation of
      EGFR expression by EGF and TGF-alpha we studied three human prostate cancer cell
      lines, androgen-responsive (LNCaP) and -unresponsive (DU145 and PC3). Here we
      show that TGF-alpha stabilized EGFR mRNA two- to threefold in all three cell
      lines, whilst EGF stabilized EGFR mRNA approximately twofold in LNCaP and DU145
      cells, but not in PC3 cells. Both ligands increased EGFR transcription in LNCaP
      and DU145 cells, with less effect in PC3 cells. In all three cell lines EGF
      reduced total EGFR protein levels more than TGF-alpha, but this was associated
      with a greater increase in de novo protein synthesis with EGF compared to TGF
      alpha. Only EGF, however, shortened EGFR protein stability (half-life decreased
      from 5 h to 120 min), resulting in rapid disappearance of newly synthesized EGFR
      protein. Both ligands increased total LNCaP and DU145 cell numbers. These studies
      demonstrate that the EGF- and TGF-alpha-induced upregulation of EGFR mRNA and
      protein in human prostate cancer cell lines is complex and occurs at multiple,
      transcriptional and post-transcriptional levels. Taken together, these data
      provide novel insight into the molecular mechanisms by which TGF-alpha would
      preferentially maintain an autocrine loop in human prostate cancer cells.
      Furthermore, this work suggests that in human prostate cancer cells ligand
      specific differential intracellular trafficking of the EGFR plays a major role in
      regulating its expression.

PMID- 10360642
TI  - Loss of functional pRB is not a ubiquitous feature of B-cell malignancies.
AB  - Human cancers frequently sustain genetic mutations that alter the function of
      their G1 cell cycle control check point. These include changes to the
      retinoblastoma gene and to the genes that regulate its phosphorylation, such as
      the cyclin-dependent kinase inhibitor p16INK4a. Altered expression of
      retinoblastoma protein (pRb) is associated with non-Hodgkin's lymphoma,
      particularly centroblastic and Burkitt's lymphomas. pRb is expressed in normal B
      cells and its regulatory phosphorylation pathway is activated in response to a
      variety of stimuli. Since human B-lymphoma-derived cell lines are often used as
      in vitro model systems to analyse the downstream effects of signal transduction,
      we examined the functional status of pRb in a panel of human B-cell lines. We
      identified eleven cell lines which express the hyperphosphorylated forms of pRb.
      Furthermore, we suggest that the pRb protein appears to be functional in these
      cell lines.

PMID- 10360643
TI  - Rodent fibroblast model for studies of response of malignant cells to exogenous 5
      aminolevulinic acid.
AB  - All nucleated mammalian cells synthesize protoporphyrin IX (PpIX) when exposed to
      exogenous 5-aminolevulinic acid (ALA). The response to exogenous ALA under
      standard conditions (the ALA phenotype) is characteristic for each cell type.
      Significantly more PpIX accumulates in malignant and premalignant cells than in
      the normal cells from which they were derived. A rodent fibroblast model was
      developed to study the mechanisms responsible for this phenomenon. Exogenous ALA
      induced the accumulation of substantial concentrations of PpIX in fibrosarcoma
      cells, and in immortalized fibroblasts transfected with the oncogene c-myc, IGF-1
      receptor, IGF-1 and its receptor, v-fos, v-raf, v-Ki-ras, v-abl, or polyomavirus
      middle T antigen with G418 resistance selection. Much lower concentrations of
      PpIX accumulated in primary fibroblast cultures, in immortalized fibroblast cell
      lines, and in immortalized fibroblasts transfected with the G418-resistance gene
      only. The mechanisms responsible for the increased accumulation of ALA-induced
      PpIX by transformed cells (the malignant ALA phenotype) therefore appear to be
      closely linked to the mechanisms responsible for malignant transformation.
      Identification of the nature of that linkage may lead to new approaches to cancer
      therapy.

PMID- 10360644
TI  - Regulation and function of the extracellular matrix protein tenascin-C in ovarian
      cancer cell lines.
AB  - The extracellular matrix glycoprotein tenascin-C (TN) is overexpressed in the
      stroma of malignant ovarian tumours particularly at the interface between
      epithelia and stroma leading to suggestions that it may be involved in the
      process of invasion (Wilson et al (1996) Br J Cancer 74: 999-1004). To define
      regulation of TN further and investigate its function in ovarian cancer, a range
      of cell line models were studied. Concentrations of secreted TN in media from
      cultures of ovarian fibroblast cell lines were at least 100-fold greater than
      from carcinoma cell lines. Evidence for paracrine regulation of TN secretion was
      obtained by co-culture of carcinoma cells with fibroblast cells wherein secretion
      into the media was greater than from fibroblasts alone. Transforming growth
      factor (TGF)-beta1, insulin-like growth factor (IGF)-II and progesterone all
      stimulated TN secretion while human choriogonadotropin (hCG), follicle
      stimulating hormone (FSH) and gamma-interferon inhibited secretion. TGF-beta1
      produced the greatest stimulation of TN in cultured fibroblasts and its co
      expression with TN was examined in primary ovarian tumours. There was a
      significant association between the presence of moderate-strong expression of TN
      and TGF-beta1. Evidence for TN having a functional role in ovarian carcinoma was
      obtained from adhesion and migration assays. The PE01, PE04, SKOV-3 and 59M cell
      lines all demonstrated marked adhesion to plastic coated with TN relative to the
      control protein bovine serum albumin (BSA) and expressed alpha2beta1 and
      alpha3beta1 integrins. The SKOV-3 cell line migrated more rapidly through TN than
      through BSA indicating that TN can facilitate migration of ovarian carcinoma
      cells.

PMID- 10360645
TI  - Ceramide triggers p53-dependent apoptosis in genetically defined fibrosarcoma
      tumour cells.
AB  - p53 mutations are among the most common genetic alterations in human cancer and
      are frequently described in intrinsic or acquired radio- and chemotherapy
      resistance. Radiation-induced cell kill is not only mediated by DNA damage but
      also by the activation of signal transduction cascades generated at the plasma
      membrane like the sphingomyelin pathway. We used genetically defined wild-type
      p53 or p53-deficient mouse fibrosarcoma cells to investigate the p53-dependence
      of tumour response upon activation of the sphingomyelin pathway. Treatment of the
      tumour cells with neutral sphingomyelinase drastically reduced the amount of wild
      type p53 fibrosarcoma cell proliferation over 72 h in a clear dose-response (0.2
      1.0 U ml(-1) nSMase). Sphingomyelinase had no effect on cell proliferation in
      tumour cells lacking p53. Similarly, cell proliferation was abolished by C2
      ceramide (5-20 microM) only in wild-type p53 cells. FACS-analysis revealed that
      C2-ceramide induced massive p53-dependent apoptosis (40-50% after 12-24 h) and
      cell cycle analysis showed a transient G1 arrest in p53-deficient tumour cells 12
      24 h after C2-ceramide exposure. These results suggest that ceramide-induced
      apoptosis in tumour cells can be dependent on the status of p53 and imply that
      p53 is also important for stress-induced apoptotic signal transduction cascades
      generated at the plasma membrane.

PMID- 10360646
TI  - Loss of DNA mismatch repair facilitates reactivation of a reporter plasmid
      damaged by cisplatin.
AB  - In addition to recognizing and repairing mismatched bases in DNA, the mismatch
      repair (MMR) system also detects cisplatin DNA adducts and loss of MMR results in
      resistance to cisplatin. A comparison was made of the ability of MMR-proficient
      and -deficient cells to remove cisplatin adducts from their genome and to
      reactivate a transiently transfected plasmid that had previously been inactivated
      by cisplatin to express the firefly luciferase enzyme. MMR deficiency due to loss
      of hMLH1 function did not change the extent of platinum (Pt) accumulation or
      kinetics of removal from total cellular DNA. However, MMR-deficient cells,
      lacking either hMLH1 or hMSH2, generated twofold more luciferase activity from a
      cisplatin-damaged reporter plasmid than their MMR-proficient counterparts. Thus,
      detection of the cisplatin adducts by the MMR system reduced the efficiency of
      reactivation of the damaged luciferase gene compared to cells lacking this
      detector. The twofold reduction in reactivation efficiency was of the same order
      of magnitude as the difference in cisplatin sensitivity between the MMR
      proficient and -deficient cells. We conclude that although MMR-proficient and 
      deficient cells remove Pt from their genome at equal rates, the loss of a
      functional MMR system facilitates the reactivation of a cisplatin-damaged
      reporter gene.

PMID- 10360647
TI  - Sodium butyrate enhances STAT 1 expression in PLC/PRF/5 hepatoma cells and
      augments their responsiveness to interferon-alpha.
AB  - Although interferon-alpha (IFN-alpha) has shown great promise in the treatment of
      chronic viral hepatitis, the anti-tumour effect of this agent in the therapy of
      liver cancer is unclear. Recent studies have demonstrated that differentiation
      inducing agents could modulate the responsiveness of cancer cells to IFN-alpha by
      regulating the expression of signal transducers and activators of transcription
      (STAT) proteins, a group of transcription factors which play important roles in
      the IFN signalling pathway. We have reported that sodium butyrate is a potent
      differentiation inducer for human hepatoma cells. In this study, we investigated
      whether this drug could regulate the expression of STAT proteins and enhance the
      anti-tumour effect of IFN-alpha in hepatoma cells. We found that sodium butyrate
      specifically activated STAT1 gene expression and enhanced IFN-alpha-induced
      phosphorylation and activation of STAT1 proteins. Co-treatment with these two
      drugs led to G1 growth arrest, accompanied by down-regulation of cyclin D1 and up
      regulation of p21WAF-1, and accumulation of hypophosphorylated retinoblastoma
      protein in hepatoma cells. Additionally, internucleosomal DNA fragmentation, a
      biological hallmark of apoptosis, was detected in hepatoma cells after continuous
      incubation with a combination of these two drugs for 72 h. Our results show that
      sodium butyrate potently enhances the anti-tumour effect of IFN-alpha in vitro
      and suggest that a rational combination of these two drugs may be useful for the
      treatment of liver cancer.

PMID- 10360648
TI  - Caspase-3 activation during apoptosis caused by glutathione-doxorubicin
      conjugate.
AB  - Glutathione-doxorubicin (GSH-DXR) effectively induced apoptosis in rat hepatoma
      cells (AH66) at a lower concentration than DXR. After 24 h of drug treatment, DNA
      fragmentation of the cells was observed at the concentration of 1.0 microM DXR or
      0.01 microM GSH-DXR. Increase in caspase-3 activity and DNA fragmentation were
      observed within 12 h and 15 h after treatment with either drug. Intracellular
      caspase-3 activity was increased in a dose-dependent manner after treatment with
      DXR or GSH-DXR, and caspase-3 activity correlated well with the ability to induce
      DNA fragmentation. When the cells were treated with either DXR or GSH-DXR for
      only 6 h, apoptotic DNA degradation and caspase-3 activation occurred 24 h after
      treatment. DNA fragmentation caused by these drugs was prevented completely by
      simultaneous treatment with the caspase-3 inhibitor, acetyl-Asp-Glu-Val-Asp
      aldehyde (DEVD-CHO), at 10 microM. By contrast, DNA fragmentation was not
      prevented by the caspase-1 inhibitor, acetyl-Tyr-Val-Ala-Asp-aldehyde (YVAD-CHO),
      at the same concentration as DEVD-CHO, and caspase-1 was not activated at all by
      the treatment of AH66 cells with both DXR and GSH-DXR. These results demonstrate
      that DXR and GSH-DXR induce apoptotic DNA fragmentation via caspase-3 activation,
      but not via caspase-1 activation, and that GSH-DXR enhances the activation of
      caspase-3 approximately 100-fold more than DXR. Moreover, the findings suggested
      that an upstream apoptotic signal that can activate caspase-3 is induced within 6
      h by treating AH66 cells with the drug.

PMID- 10360649
TI  - Thalidomide increases both intra-tumoural tumour necrosis factor-alpha production
      and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid.
AB  - 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), synthesized in this laboratory and
      currently in phase I clinical trial, is a low molecular weight inducer of tumour
      necrosis factor-alpha (TNF-alpha). Administration of DMXAA to mice with
      established transplantable tumours elicits rapid vascular collapse selectively in
      the tumour, followed by extensive haemorrhagic necrosis mediated primarily
      through the production of TNF-alpha. In this report we have investigated the
      synthesis of TNF-alpha mRNA in hepatic, splenic and tumour tissue. Co
      administration of thalidomide with DMXAA increased anti-tumour activity and
      increased intra-tumoural TNF-alpha production approximately tenfold over that
      obtained with DMXAA alone. Thalidomide increased splenic TNF-alpha production
      slightly but significantly decreased serum and hepatic levels of TNF-alpha
      induced with DMXAA. Lipopolysaccharide (LPS) induced 300-fold higher serum TNF
      alpha than did DMXAA at the maximum tolerated dose, but induced similar amounts
      of TNF-alpha in spleen, liver and tumour. Splenic TNF-alpha activity induced with
      LPS was slightly increased with thalidomide, but serum and liver TNF-alpha levels
      were suppressed. Thalidomide did not increase intra-tumoural TNF-alpha production
      induced with LPS, in sharp contrast to that obtained with DMXAA. While
      thalidomide improved the anti-tumour response to DMXAA, it had no effect on the
      anti-tumour action of LPS that did not induce a significant growth delay or cures
      against the Colon 38 tumour. The increase in the anti-tumour action by
      thalidomide in combination with DMXAA corresponded to an increase in intra
      tumoural TNF-alpha production. Co-administration of thalidomide may represent a
      novel approach to improving selective intra-tumoural TNF-alpha production and
      anti-tumour efficacy of DMXAA.

PMID- 10360650
TI  - Evidence for characteristic vascular patterns in solid tumours: quantitative
      studies using corrosion casts.
AB  - The vascular architecture of four different tumour cell lines (CaX, CaNT, SaS,
      HEC-1B) transplanted subcutaneously in mice was examined by means of
      microvascular corrosion casting in order to determine whether there is a
      characteristic vascular pattern for different tumour types and whether it differs
      significantly from two normal tissues, muscle and gut. Three-dimensional
      reconstructed scanning electron microscope images were used for quantitative
      measurements. Vessel diameters, intervessel and interbranch distances showed
      large differences between tumour types, whereas the branching angles were
      similar. In all tumours, the variability of the vessel diameters was
      significantly higher than in normal tissue. The quantitative data provide strong
      evidence for a characteristic vascular network determined by the tumour cells
      themselves.

PMID- 10360651
TI  - Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates
      with the level of invasion in malignant melanomas.
AB  - Since proteolysis of the dermal collagenous matrix and basement membranes is
      required for local invasive growth and early metastasis formation of cutaneous
      melanomas, we have analysed the activities/expression levels of certain
      metalloproteinases in melanomas and cultured melanoma cells by in situ
      hybridization and Northern analysis. In addition to collagenases-1 and -3 that
      have been implicated in invasive growth behaviour of various malignant tumours,
      we analysed the levels of 72-kDa gelatinase and its activators MT1-MMP and TIMP-2
      in cultured melanoma cells. The lesions examined included three cases of lentigo
      maligna and 28 cases of Clark grade I-V melanomas. The premalignant as well as
      the grade I tumours were consistently negative for collagenase-1 and -3 and TIMP
      1 and -3. The collagenases were predominantly expressed in the cancer cells of
      Clark grade III and IV tumours. TIMP-1 and -3 were abundantly expressed in the
      cancer and/or stromal cells of grade III and IV melanomas, while TIMP-2 protein
      was detected also in melanomas representing lower invasive potential. Northern
      analysis of seven melanoma cell lines showed that the expression of collagenase-1
      and TIMPs-1 and -3 was associated with 72-kDa gelatinase positivity. All melanoma
      cell lines were positive for MT1-MMP and TIMP-2 mRNAs. Our results suggest that
      overexpression of collagenases-1 and -3 and TIMPs-1 and -3 is induced during
      melanoma progression. Expression of TIMPs may reflect host response to tumour
      invasion in an effort to control MMP activity and preserve extracellular matrix
      integrity.

PMID- 10360652
TI  - Short- and long-term normal tissue damage with photodynamic therapy in pig
      trachea: a fluence-response pilot study comparing Photofrin and mTHPC.
AB  - The damage to normal pig bronchial mucosa caused by photodynamic therapy (PDT)
      using mTHPC and Photofrin as photosensitizers was evaluated. An endobronchial
      applicator was used to deliver the light with a linear diffuser and to measure
      the light fluence in situ. The applied fluences were varied, based on existing
      clinical protocols. A fluence finding experiment with short-term (1-2 days)
      response as an end point showed considerable damage to the mucosa with the use of
      Photofrin (fluences 50-275 J cm(-2), drug dose 2 mg kg(-1)) with oedema and blood
      vessel damage as most important features. In the short-term mTHPC experiment the
      damage found was slight (fluences 12.5-50 J cm(-2), drug dose 0.15 mg kg(-1)).
      For both sensitizers, atrophy and acute inflammation of the epithelium and the
      submucosal glands was observed. The damage was confined to the mucosa and
      submucosa leaving the cartilage intact. A long-term response experiment showed
      that fluences of 50 J cm(-2) for mTHPC and 65 J cm(-2) for Photofrin-treated
      animals caused damage that recovered within 14 days, with sporadic slight
      fibrosis and occasional inflammation of the submucosal glands. Limited data on
      the pharmacokinetics of mTHPC show that drug levels in the trachea are similar at
      6 and 20 days post injection, indicating a broad time window for treatment. The
      importance of in situ light dosimetry was stressed by the inter-animal variations
      in fluence rate for comparable illumination conditions.

PMID- 10360654
TI  - A prospective multicentre study in Sweden and Norway of mental distress and
      psychiatric morbidity in head and neck cancer patients.
AB  - A Swedish/Norwegian head and neck cancer study was designed to assess
      prospectively the levels of mental distress and psychiatric morbidity in a
      heterogeneous sample of newly diagnosed head and neck cancer patients. A total of
      357 patients were included. The mean age was 63 years, and 72% were males. The
      patients were asked to answer the HAD scale (the Hospital Anxiety and Depression
      scale) six times during 1 year. The number of possible or probable cases of
      anxiety or depression disorder was calculated according to standardized cut-offs.
      Approximately one-third of the patients scored as a possible or probable case of
      a major mood disorder at each measurement point during the study year. There were
      new cases of anxiety or depression at each time point. The anxiety level was
      highest at diagnosis, while depression was most common during treatment. Females
      were more anxious than males at diagnosis, and patients under 65 years of age
      scored higher than those over 65. Patients with lower performance status and more
      advanced disease reported higher levels of mental distress and more often scored
      as a probable or possible cases of psychiatric disorder. Our psychometric
      analyses supported the two-dimensional structure and stability of the HAD scale.
      The HAD scale seems to be the method of choice for getting valid information
      about the probability of mood disorder in head and neck cancer populations. The
      prevalence of psychiatric morbidity found in this study emphasizes the importance
      of improved diagnosis and treatment.

PMID- 10360653
TI  - Boswellic acids and malignant glioma: induction of apoptosis but no modulation of
      drug sensitivity.
AB  - Steroids are essential for the control of oedema in human malignant glioma
      patients but may interfere with the efficacy of chemotherapy. Boswellic acids are
      phytotherapeutic anti-inflammatory agents that may be alternative drugs to
      corticosteroids in the treatment of cerebral oedema. Here, we report that
      boswellic acids are cytotoxic to malignant glioma cells at low micromolar
      concentrations. In-situ DNA end labelling and electron microscopy reveal that
      boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires
      protein, but not RNA synthesis, and is neither associated with free radical
      formation nor blocked by free radical scavengers. The levels of BAX and BCL-2
      proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression
      is induced by boswellic acids via a p53-independent pathway. Ectopic expression
      of wild-type p53 also induces p21, and facilitates boswellic acid-induced
      apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells
      enhances rather than decreases boswellic acid toxicity. Ectopic expression of
      neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to
      steroids, subtoxic concentrations of boswellic acids do not interfere with cancer
      drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death
      assays. Also, in contrast to steroids, boswellic acids synergize with the
      cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect
      is probably mediated by inhibition of RNA synthesis and is not associated with
      changes of CD95 expression at the cell surface. Further studies in laboratory
      animals and in human patients are required to determine whether boswellic acids
      may be a useful adjunct to the medical management of human malignant glioma.

PMID- 10360657
TI  - The development of a structured rating schedule (the BAS) to assess skills in
      breaking bad news.
AB  - There has been considerable interest in how doctors break bad news, with calls
      from within the profession and from patients for doctors to improve their
      communication skills. In order to aid clinical training and assessment of the
      skills used in breaking bad news there is a need for a reliable, practical and
      valid, structured rating schedule. Such a rating schedule was compiled from
      agreed criteria in the literature. Video-taped recordings of simulated
      consultations breaking bad news were independently assessed by three raters using
      the schedule and compared to three experts who gave global ratings. The primary
      outcome measures were internal consistency of the schedule and level of agreement
      between raters. The internal consistency was high with a Cronbach's alpha of
      0.93. Agreement between raters using the schedule was moderate to good. The
      majority of the variation in scores was due to the differences in skills
      demonstrated in the interviews. The agreement between raters not using the
      schedule was poor. The BAS provides a simple to use, reliable, and consistent
      rating schedule for assessing skills used in breaking bad news. It could be a
      valuable aid to teaching this difficult task.

PMID- 10360656
TI  - A randomized phase II trial of 5-fluorouracil, with or without human interferon
      beta, for advanced colorectal cancer.
AB  - This study compared the efficacy and safety of 5-fluorouracil (5-FU) monotherapy
      to that of 5-FU combined with natural human interferon-beta (IFN-beta) in
      patients with unresectable, advanced colorectal carcinoma. Forty-nine
      chemotherapy-naive patients were randomized to 5-FU alone or to the combination.
      All patients received 750 mg m(-2) day(-1) 5-FU for 5 days by continuous
      intravenous (i.v.) infusion, followed after day 15 by a weekly i.v. bolus of 750
      mg m(-2). IFN-beta was injected intramuscularly three times weekly at 9 M IU.
      Treatment continued for 52 weeks, or until disease progression or intolerable
      toxicity. Clinical endpoints were tumor response, time to progression, survival
      and toxicity. The addition of IFN-3 to 5-FU significantly improved response rate
      (33.3% vs 4.5% for evaluable patients; P = 0.021), time to progression (median
      7.2 vs 4.2 months; P = 0.0435), and survival time (median 15.9 vs 7.2 months; P =
      0.038) without significantly increasing toxicity compared to 5-FU alone.
      Cumulative 5-FU dose was higher with combined therapy (P < 0.001): more patients
      receiving monotherapy discontinued treatment because of disease progression.
      Fever was more frequent with combined therapy (P = 0.008); there were no other
      differences in toxicity. The only grade IV toxicity observed was neutropenia (two
      patients per group). A randomized phase III trial has been initiated to confirm
      the synergy between 5-FU and IFN-beta.

PMID- 10360655
TI  - Multi-institutional randomized clinical study on the comparative effects of
      intracavital chemotherapy alone versus immunotherapy alone versus
      immunochemotherapy for malignant effusion.
AB  - The current prospective randomized study was designed to compare the effects of
      intracavitary (i.c.) chemotherapy vs immunotherapy vs immunochemotherapy for
      malignant effusion. Between 1992 and 1995, a total of 42 patients with malignant
      effusion were registered, and 41 patients were eligible for statistical analysis.
      The primary diseases of the eligible patients included 27 gastric, four
      colorectal, four pancreatic, three lung, two liver and one oesophageal cancers.
      The patients with malignant effusion were randomly assigned into one of three
      i.c. therapeutic regimens: chemotherapy alone with weekly injection of anticancer
      agents (ACAs: cisplatin, mitomycin-C, adriamycin, etc.) (Group A, n = 13);
      immunotherapy alone with weekly injection of streptococcal preparation OK-432
      (Group B, n = 14); or immunochemotherapy with ACAs and OK-432 (Group C, n = 14).
      The response of the effusion, patient survival and the kinetics of cytokines in
      the effusion were compared. There were no differences in the patients'
      backgrounds. The side-effects of the regimens included pain, anorexia, fever,
      leucopenia and anaemia and there were no differences in their incidence among the
      three groups. One patient died after cisplatin (CDDP) administration in Group A.
      Cytologic examination revealed that tumour cells in the effusion disappeared in
      23% of Group A cases, 36% of Group B cases and 36% of Group C cases. The
      malignant effusion did not disappear in any of the Group A cases; however, the
      effusion disappeared in 29% of Group B cases and 43% of Group C cases (P = 0.03,
      Group A vs Group C). Furthermore, the 50% survival period was 1.6 months for
      Group A, 2.4 months for Group B and 3.5 months for Group C. The 6-month survival
      rate was 7% for Group A, 6% for Group B and 34% for Group C, and the 1-year
      survival rate was 0%, 0% and 17% respectively (P = 0.048, Group A vs Group C by
      the log-rank test). The analysis of the cytokine kinetics revealed a prominent
      increase in the level of interleukin-6 in the effusion in Group C. These results
      suggest that i.c. immunochemotherapy with OK-432 and ACAs may be more beneficial
      than i.c. chemotherapy alone or immunotherapy alone.

PMID- 10360658
TI  - Long-term effects on sexual function and fertility after treatment of testicular
      cancer.
AB  - This retrospective study evaluates the types and incidences of sexual
      disturbances and fertility distress in patients cured from testicular cancer and
      examines whether there is an effect resulting from different treatment
      modalities. A self-reported questionnaire was sent to 124 randomly selected
      patients who were treated at Hanover University Medical School between 1970 and
      1993. Ninety-eight patients were included in the study, representing a response
      rate of 78%. All patients had been in complete remission (CR) for at least 24
      months. The median age at diagnosis was 28 years (range 17-44). The median follow
      up at the time of study was 12.0 years (range 2.8-25.6). Twenty patients (20%)
      had been treated for seminomatous and 78 patients (80%) for non-seminomatous germ
      cell tumours. Treatment included surveillance (7%), primary retroperitoneal lymph
      node dissection (RPLND) (13%), chemotherapy (CT) (33%), CT + secondary resection
      of residual retroperitoneal tumour mass (SRRTM) (43%) and infradiaphragmatic
      radiotherapy (4%). Patients receiving two treatment modalities (CT+SRRTM)
      reported more frequent an unfulfilled wish for children. Inability of ejaculation
      was clearly associated with RPLND and SRRTM. Subjective aspects of sexuality,
      like loss of sexual drive and reduced erectile potential, occurred only in a
      minority of patients after treatment. No abnormalities were observed concerning
      the course of pregnancies of partners. In conclusion, sexual dysfunction and
      infertility are common long-lasting sequelae in testicular cancer survivors
      affecting approximately 20% of patients. The relative risk for infertility
      appeared to be elevated for patients treated with the combination of CT+SRRTM.
      Twenty-one of 40 patients were able to fulfil their wish for children, and no
      congenital abnormalities were observed in these children.

PMID- 10360659
TI  - Thyroid nodular disease after radiotherapy to the neck for childhood Hodgkin's
      disease.
AB  - Patients who receive radiotherapy to the neck are at risk of developing thyroid
      dysfunction. This prospective study of patients whose treatment for Hodgkin's
      disease in childhood included radiotherapy to the neck aimed to investigate the
      incidence and natural history of thyroid dysfunction and the morphological
      changes of the gland demonstrated on ultrasound. Forty-seven patients were
      investigated by clinical examination, thyroid function tests and thyroid
      ultrasound. Only six patients had a clinically detectable abnormality, but 64%
      had abnormal thyroid function tests. All patients had an abnormal thyroid
      ultrasound scan and 42% had at least one focal abnormality. A significant
      association was found between the presence of a focal lesion on ultrasound and
      young age at radiotherapy, longer follow-up and the length of time that the
      thyroid-stimulating hormone (TSH) level had been elevated. During follow-up, 65%
      of patients not on thyroxine developed new focal abnormalities. The longest time
      interval between radiotherapy and an increase in TSH level was 94 months, and
      from radiotherapy to the appearance of a focal abnormality on thyroid ultrasound
      was over 18 years. Three patients were found to have a thyroid carcinoma. These
      findings indicate the importance of long-term follow-up for patients treated by
      neck irradiation for Hodgkin's disease in childhood.

PMID- 10360660
TI  - Cost-effectivenes of paclitaxel plus cisplatin in advanced non-small-cell lung
      cancer.
AB  - The aim of this study was to assess the cost-effectiveness of combination
      chemotherapy with paclitaxel/cisplatin, compared with standard
      etoposide/cisplatin in patients with advanced non-small cell lung cancer (NSCLC).
      We obtained the primary survival and resource utilization data from a large three
      arm randomized trial comparing: paclitaxel 135 mg m(-2) by 24-h intravenous
      (i.v.) infusion + cisplatin; paclitaxel 250 mg m(-2) by 24-h i.v. infusion +
      cisplatin + granulocyte colony-stimulating factor (G-CSF); and standard
      etoposide/cisplatin in patients with stage IIIb or IV NSCLC. We also modelled the
      regimens with paclitaxel 135 mg m(-2) + cisplatin administered as an outpatient
      by 3-h infusion, as clinical data suggest that this is equivalent to 24-h
      infusion. We collected costing data from the Ottawa Regional Cancer Centre and
      applied it to the resources consumed in the randomized trial. We integrated these
      data into the Statistics Canada POpulation HEalth Model (POHEM), which generated
      hypothetical cohorts of patients treated with each regimen. The POHEM model
      assigned diagnostic work-up, treatment, disease progression and survival
      characteristics to each individual in these cohorts and tabulated the costs
      associated with each. We did sensitivity analyses around the costs of
      chemotherapy and its administration, and the survival differences between the two
      regimens. All costs are in 1997 Canadian dollars ($1.00 Canadian approximately
      Pound 0.39 sterling). The perspective is that of the Canadian health care system.
      In the trial, the two paclitaxel-containing arms had almost identical survival
      curves with a median survival of 9.7 months compared with 7.4 months for
      etoposide/cisplatin. As administered in the trial, paclitaxel/cisplatin cost
      $76,370 per life-year gained (LYG) and paclitaxel/cisplatin/G-CSF $138,578 per
      LYG relative to etoposide/cisplatin. However, when modelled as an outpatient 3-h
      infusion, paclitaxel/cisplatin was moderately cost-effective at $30,619 per LYG.
      When compared with historical controls treated with best supportive care, this
      regimen of paclitaxel/cisplatin cost $4539 per LYG. Assuming a 3-h paclitaxel
      infusion yields the same survival advantage as the 24-h infusion did in the
      randomized trial, paclitaxel/cisplatin is a cost-effective improvement over
      standard etoposide/cisplatin for patients with advanced non-small cell lung
      cancer.

PMID- 10360661
TI  - Prognostic significance of loss of heterozygosity at loci on chromosome 17p13.3
      ter in sporadic breast cancer is evidence for a putative tumour suppressor gene.
AB  - Several studies indicate that the short arm of chromosome 17 is one of the most
      frequently altered regions in sporadic breast carcinomas (45-60%). In the present
      report the 17p13.3-ter locus in tumour DNA of breast cancer patients, along with
      their matching normal lymphocyte DNA, have been mapped with four markers (D17S5,
      D17S379, ABR and D17S34), spanning nearly 3 cM of the telomer. Sixty-five of 143
      heterozygous tumours had lost at least one of the markers at the minimum region
      of loss (45%). High levels of loss of these distal markers on 17p13.3 are
      independent of TP53 mutations and are associated with tumour cell proliferation.
      A follow-up period of over 7 years demonstrates that loss of these markers
      correlates both with disease-free (P = 0.004) and overall survival (P = 0.007).
      In addition we show that for disease-free survival the prognostic power of this
      genetic alteration is second only to axillary lymph node involvement (3.1 vs 6.3
      relative risk), and is a better predictor than the mutational status of TP53 (1.6
      relative risk). Our results are further evidence of the presence, within the
      region, of at least a second tumour suppressor gene distal to TP53, that might be
      targeted by deletions.

PMID- 10360662
TI  - Expression of vascular endothelial growth factor (VEGF) and its mRNA in uterine
      cervical cancers.
AB  - To know the potential of growth, invasion and metastasis of uterine cervical
      cancer associated with neovascularization, localization of vascular endothelial
      growth factor (VEGF) and microvessel density in tumours were determined by
      immunohistochemical staining, the levels of VEGF subtypes were determined by
      Western blot analysis and by a sandwich enzyme immunoassay, and the levels of
      VEGF subtype mRNAs were determined by reverse transcription polymerase chain
      reaction (RT-PCR)-Southern blot analysis in uterine cervical cancers. The
      relation between VEGF subtype expressions and microvessel density, histological
      types and clinical stages of uterine cervical cancers was analysed. The
      expression of VEGF was seen dominantly in the cancer cells, and correlated with
      microvessel density in uterine cervical cancers. Among the four subtypes of VEGF,
      the populations of VEGF165 and VEGF121 were dominant in normal uterine cervices
      and uterine cervical cancers. The levels of VEGF and VEGF165 and VEGF121 mRNAs
      were remarkably higher in some stage II and III/IV adenocarcinomas of the cervix
      than in other cases, including normal cervices. Therefore, the elevation of
      VEGF165 and VEGF121 might contribute to the relatively late advancing via
      angiogenic activity in some adenocarcinomas of the cervix.

PMID- 10360663
TI  - New classification of oesophageal and gastric carcinomas derived from changing
      patterns in epidemiology.
AB  - The current ICD-O classification of carcinomas of the oesophagus and stomach
      causes epidemiological and clinical confusion. This study compares the
      epidemiological and clinical features of each subtype and subsite of
      adenocarcinomas of the oesophagus and stomach, to assess requirements for a new
      classification of these carcinomas. Data were extracted with appropriate validity
      checks on all cases of oesophageal and gastric carcinomas identified throughout
      the period 1974-1993 by the Merseyside and Cheshire Cancer Registry, which covers
      a population of 2.5 million. The incidence of adenocarcinomas of the lower
      oesophagus and cardia trebled in males, and doubled in females, whereas
      adenocarcinoma of the subcardia region of the stomach declined in both sexes.
      Adenocarcinomas of the lower oesophagus and of the cardia were similar for median
      age at diagnosis, male to female ratio, percentage of patients who smoked and
      survival; both were significantly different from carcinomas of the subcardia in
      these respects. These data imply that adenocarcinomas of the lower oesophagus and
      cardia are the same disease. A new subsite classification of oesophageal and
      gastric carcinomas is proposed that includes the gastro-oesophageal junction as a
      distinct subsite, to facilitate surveillance, management and research.

PMID- 10360665
TI  - Deletion mapping of chromosome 16q in hepatocellular carcinoma.
AB  - Hepatocellular carcinoma (HCC) frequently shows an allelic imbalance (AI) on
      chromosome 16q. In order to define the commonly affected regions on chromosome
      16q, we assessed AI studies in 41 HCCs using a panel of 37 microsatellite
      markers. Thirty-five cases (85%) showed AI at one or more loci. Among the 35
      cases with AI, 21 cases showed multiple AI, suggesting the wide scope of deletion
      on the long arm of chromosome 16, and the remaining 14 cases showed partial AI.
      Detailed deletion mapping identified two independent commonly deleted regions on
      this chromosome arm. These included the D16S3106 locus and D16S498 locus. In
      conclusion, we have demonstrated frequent AI on 16q in HCCs and identified two
      loci with frequent AI, which may harbour new tumour suppressor genes.

PMID- 10360664
TI  - Frequent allelic losses at 11q24.1-q25 in young women with breast cancer:
      association with poor survival.
AB  - Previous studies have demonstrated that the pathological features of breast
      cancer are more aggressive in younger women than in their older counterparts, and
      that young age may be an independent marker for adverse prognosis. These findings
      have raised the question whether these differences are also present at the
      molecular level. In order to characterize the genetic alterations associated with
      early-onset breast cancer, 102 cases selected for age under 37 at diagnosis were
      examined for loss of heterozygosity (LOH) at nine different loci on chromosomes
      11, 13 and 17. Ninety cases (88%), exhibited LOH for at least one marker. The
      D17S855 marker, intragenic in the BRCA1 gene, showed a high proportion of LOH
      (63%), whereas the intragenic marker for the TP53 gene, HP53, exhibited LOH in
      43% of the cases. On chromosome 11, frequencies of LOH peaked at the D11S969 and
      D11S387 markers, which expressed LOH in 53% and 48% of the informative cases,
      whereas D11S1818, which is proximate to the ATM gene, exhibited an LOH frequency
      of 24%. A statistically significant correlation was found between LOH at the
      D11S387 marker and poor survival (P = 0.028). No such correlation was found for
      the adjacent D11S969 marker, located approximately 500 kb centromeric to D11S387.
      We conclude that one or more as yet unidentified genes, situated in chromosome
      bands 11q24.1-q25, could be involved in the initiation and/or progression of
      breast cancer in younger women.

PMID- 10360666
TI  - Propylnitrosourea-induced T-lymphomas in LEXF RI strains of rats: genetic
      analysis.
AB  - Oral administration of propylnitrosourea (PNU) in drinking water induces high
      incidence of lympho-haemopoietic malignancies in rats. Previously we reported
      that F344 strain rats were highly susceptible to T-lymphomas, and LE/Stm rats, to
      erythro- or myeloid leukaemias. For analysis of the genetic factors determining
      types of diseases, we have established LEXF recombinant inbred strains of rats
      comprising 23 substrains, each derived from intercross between F344 and LE/Stm
      rats. Rats of 23 LEXF substrains were given PNU, and the development of tumours
      was observed. The overall incidence of haemopoietic tumours ranged from 100% to
      66.7%, and the fractions of T-lymphomas, from 100% to 4%, showing a continuous
      spectrum. Based on the genetic profile published as a strain distribution pattern
      table for the LEXF, we screened the potential quantitative trait loci involved in
      determination of the types of disease and length of the latency period.
      Statistical calculation was performed using the Map Manager QT software developed
      by Manly. Four loci, on chromosome 4, 7, 10 and 18, were suggested to associate
      with the T-lymphoma susceptibility and three loci, on chromosome 1, 5 and 16,
      with the length of the latency period. These putative loci were further examined
      in backcross (F344 x LE)F1 x LE. Among seven loci suggested by the recombinant
      inbred study, three loci, on chromosome 5, 7 and 10, were significantly
      associated with T-lymphomas and another locus on chromosome 1, just weakly. These
      observations indicate that PNU-induced lymphomagenesis is a multifactorial
      genetic process involving a number of loci linked with susceptibility and
      resistance.

PMID- 10360667
TI  - Comparative genomic hybridization and chromosomal instability in solid tumours.

PMID- 10360668
TI  - Identification of women with early breast cancer by analysis of p43-positive
      lymphocytes.
AB  - Regular screening mammographies and increasing knowledge of high-risk groups have
      resulted in an improvement in the rate of detection of smaller malignant lesions.
      However, uncertain minimal mammographic features frequently require further
      costly and often uncomfortable investigation, including repeat radiological
      controls or surgical procedures, before cancerous lesions can be identified.
      Placental isoferritin (p43), a protein with immunosuppressive effects, has been
      detected on the surface of lymphocytes taken from peripheral blood in patients
      with breast cancer. In this study we evaluated the sensitivity and specificity of
      the expression of p43-positive lymphocytes as a marker in early stage breast
      cancer and also investigated its expression on T-cell subpopulations. The
      presence of p43-positive lymphocytes was investigated using the monoclonal
      antibody CM-H-9 and flow cytometry in 76 women with controversial, non-palpable
      mammographic findings who were undergoing surgical biopsy. Patients with early
      breast cancer (n = 48) had significantly higher p43-positive cell values (median
      3.83%, range 0.98-19.4) than patients with benign lumps (n = 28, median 1.43%,
      range 0.17-3.7) or controls (n = 22, median 1.3%, range 0.4-1.87) (P < 0.0001).
      At a cut-off level of 2% p43-positive cells a sensitivity of 91.7% and a
      specificity of 89.3% for detection of breast cancer could be reached. While the
      median ratio of total CD4+/CD8+ cells was 2.6, a ratio of 1.3 was found for the
      p43-positive subpopulation (P < 0.001), thus indicating a significant link
      between p43 and CD8+ cells. The determination of p43-positive lymphocytes in
      peripheral blood could serve as an additional diagnostic tool in patients with
      controversial mammographic findings and could also reduce the need for cost
      intensive and often uncomfortable management of these patients.

PMID- 10360669
TI  - European multicenter study on LOH of APOC3 at 11q23 in 766 breast cancer
      patients: relation to clinical variables. Breast Cancer Somatic Genetics
      Consortium.
AB  - High frequencies of loss of heterozygosity (LOH) in chromosome 11q22-qter have
      been observed in various malignancies, including breast cancer. Previous studies
      on breast carcinomas by Winqvist et al (Cancer Res 55: 2660-2664) have indicated
      that a survival factor gene is located in band 11q23, and that the highly
      informative microsatellite polymorphism at the APOC3 locus would be a suitable
      tool to perform more extensive LOH studies. In this European multicentre study,
      we have examined the occurrence of APOC3 LOH and evaluated the effect of LOH of
      this chromosomal subregion on the clinical behaviour of the disease in a cohort
      of 766 breast cancer patients in more detail. LOH for APOC3 was found in 42% of
      the studied tumours, but it was not found to be significantly associated with any
      of the studied clinical variables, including cancer-specific survival time or
      survival time after recurrent/metastatic disease. According to the present
      findings, the putative survival factor gene on 11q23 is not located close enough
      to the APOC3 gene, but apparently at a more proximal location.

PMID- 10360670
TI  - Reproducibility of detection of tyrosinase and MART-1 transcripts in the
      peripheral blood of melanoma patients: a quality control study using real-time
      quantitative RT-PCR.
AB  - In recent years, large discrepancies were described in the success rate of the
      tyrosinase reverse transcription polymerase chain reaction (RT-PCR) for detecting
      melanoma cells in the peripheral blood of melanoma patients. We present a quality
      control study in which we analysed the reproducibility of detection of tyrosinase
      and MART-1 transcripts in 106 blood samples from 68 melanoma patients (mainly
      stages III and IV). With this study, we aimed to improve insight in the
      reproducibility of a RT-PCR for the detection of (minimal) amounts of circulating
      melanoma cells. We performed two reverse transcriptions on each mRNA sample and
      performed tyrosinase and MART-1 nested PCRs in duplicate per cDNA sample. Thus,
      four tyrosinase and four MART-1 measurements were performed per blood sample. In
      our study, the majority of blood samples was negative for tyrosinase (80%) or
      MART-1 (66%). Only four samples were positive in all four determinations for
      tyrosinase and seven for MART-1. Variable results (1-3 times positive results)
      were obtained for tyrosinase and MART-1 in 16% and 27% respectively. MART-1 PCR
      had a better performance than tyrosinase PCR. Sensitivity increased when both
      markers were used. We reasoned that the low number of melanoma marker PCR
      positive blood samples can be explained by differences in mRNA quality. By using
      real-time quantitative PCR, we found that this was not the case: amplification of
      porphobilinogen deaminase (PBGD), a low copy household gene, was not different in
      blood samples in which a melanoma marker was not detected from groups in which
      this marker was detected more or less consistently (1-4 times). When applying
      real-time quantitative PCR for tyrosinase and MART-1, we found that a low amount
      of SK-MEL-28 cell equivalents was present in the blood of melanoma patients, with
      a higher number of equivalents in the group with a consistently positive result.
      We conclude that low reproducibility of a repeated assay for the detection of
      circulating melanoma cells is not caused by differences in mRNA quality between
      the samples, but due to low numbers of amplifiable target mRNA molecules in the
      mRNA sample. Use of more than one marker and repetition of the assay will
      increase the probability of finding positive PCR results.

PMID- 10360671
TI  - Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum
      levels of advanced cancer patients.
AB  - We have compared the platelet number and the serum concentration of vascular
      endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and
      interleukin-6 (IL-6) in 80 blood samples of 50 patients with advanced cancer. We
      have also measured the mitogenic effect of patient sera on endothelial cells in
      vitro in order to estimate the biological activity of serum VEGF. Serum VEGF
      concentration correlated with platelet number (r = 0.61; P < 10(-4)). Serum IL-6
      levels correlated with platelet count (r = 0.36; P < 10(-3)), with serum VEGF
      levels (r = 0.55; P < 10(-4)) and with the calculated load of VEGF per platelet
      (r = 0.4; P = 3 x 10(-4)). Patients with thrombocytosis had a median VEGF serum
      concentration which was 3.2 times higher (P < 10(-4)) and a median IL-6 serum
      level which was 5.8 times higher (P = 0.03) than in other patients. Serum bFGF
      did not show an association with any of the other parameters. Patient sera with
      high VEGF and bFGF content stimulated endothelial cell proliferation
      significantly more than other sera (P = 4 x 10(-3)). These results support the
      role of platelets in the storage of biologically active VEGF. Platelets seem to
      prevent circulating VEGF from inducing the development of new blood vessels
      except at sites where coagulation takes place. IL-6, besides its thrombopoietic
      effect, also seems to affect the amount of VEGF stored in the platelets. This is
      in accordance with the indirect angiogenic action of IL-6 reported previously.
      The interaction of IL-6 with the angiogenic pathways in cancer might explain the
      stimulation of tumour growth occasionally observed during IL-6 administration. It
      also conforms to the worse outcome associated with high IL-6 levels and with
      thrombocytosis in several tumour types and benign angiogenic diseases.

PMID- 10360672
TI  - Production of VEGF and expression of the VEGF receptors Flt-1 and KDR in primary
      cultures of epithelial and stromal cells derived from breast tumours.
AB  - Production of vascular endothelial growth factor (VEGF) and expression of its
      receptors Flt-1 and KDR was determined in primary cultures of separated
      epithelial and stromal-enriched cultures derived from ten primary human breast
      carcinomas. By enzyme-linked immunosorbent assay, epithelial cells produced a
      mean VEGF of 33 +/- 7 pg ml(-1) microg(-1) RNA (range 11-70). Stromal cells
      produced similar levels, with a mean of 48 +/- 11 pg ml(-1) microg(-1) RNA (range
      7-92). This was significantly greater than the amount produced by similar
      cultures derived from normal breast tissue (epithelial mean 19 +/- 5 pg ml(-1)
      microg(-1) RNA, range 9-34, P < 0.05 vs tumour epithelial culture; stromal mean
      26 +/- 8 pg ml(-1) microg(-1) RNA, range 3-56). Flt-1 and KDR receptors were
      analysed by semi-quantitative reverse transcription polymerase chain reaction.
      Flt-1 was expressed by four of six epithelial and five of six stromal cultures.
      When expressed by both cell types, Flt-1 appeared to be significantly more
      abundant on stromal cells compared with epithelial cultures. Only a single
      tumour, a lobular carcinoma, failed to express Flt-1 on either cell type. With
      KDR, the reverse was true with constitutive expression of this receptor by
      epithelial cultures and zero or reduced (3/6) expression by stromal cultures.
      Differences in the expression pattern of VEGF receptors may reflect a
      differential response to VEGF by specific cell types. Thus, production of VEGF
      and expression of VEGF receptors Flt-1 and KDR by breast cancer epithelial and
      stromal cells suggests that VEGF may fulfil not only an angiogenic role, but also
      play a fundamental role as an autocrine/paracrine regulator in breast cancer,
      thereby facilitating tumour proliferation and subsequent invasion.

PMID- 10360673
TI  - Somatic mutation of PTEN in bladder carcinoma.
AB  - The tumour suppressor gene PTEN/MMAC1, which is mutated or homozygously deleted
      in glioma, breast and prostate cancer, is mapped to a region of 10q which shows
      loss of heterozygosity (LOH) in bladder cancer. We screened 123 bladder tumours
      for LOH in the region of PTEN. In 53 informative muscle invasive tumours (> or =
      pT2), allele loss was detected in 13 (24.5%) and allelic imbalance in four
      tumours (overall frequency 32%). LOH was found in four of 60 (6.6%) informative,
      non-invasive tumours (pTa/pT1). We screened 63 muscle invasive tumours for PTEN
      mutations by single-strand conformation polymorphism (SSCP) analysis and for
      homozygous deletion by duplex quantitative polymerase chain reaction (PCR). Two
      homozygous deletions were identified but no mutations. Of 15 bladder tumour cell
      lines analysed, three showed homozygous deletion of all or part of the PTEN gene,
      but none had mutations detectable by SSCP analysis. Our results indicate that
      PTEN is involved in the development of some bladder tumours. The low frequency of
      mutation of the retained allele in tumours with 10q23 LOH suggests that there may
      be another predominant mechanism of inactivation of the second allele, for
      example small intragenic deletions, that hemizygosity may be sufficient for
      phenotypic effect, or that there is another target gene at 10q23.

PMID- 10360674
TI  - Clonality analysis suggests that early-onset acute lymphoblastic leukaemia is of
      single-cell origin and implies no major role for germ cell mutations in parents.
AB  - Childhood leukaemia presenting at a young age has been suspected of resulting
      from a leukaemogenic mutation in parental germ cells, either spontaneously or due
      to the exposure of a parent to leukaemogenic environmental hazards, particularly
      ionizing radiation. Mathematical modelling of leukaemogenesis suggests that any
      such patient would be especially prone to multiple independent leukaemogenic
      events leading to multiclonality in terms of cell of origin (analogous to
      bilaterality in familial retinoblastoma). To test this hypothesis we have carried
      out a search for multiclonal leukaemogenesis in infant and childhood acute
      lymphoblastic leukaemia (ALL). We used a polymerase chain reaction-based analysis
      of the X-linked monoamine oxidase A (MAOA) gene locus to study the clonality of
      marrow samples obtained from female paediatric ALL patients at the time of
      disease presentation. We obtained presentation samples from 102 patients of whom
      72 were found to be informative at the MAOA locus. These included 20 infant
      leukaemias (< 1 year at diagnosis). Sixty-six samples were found to be
      unequivocally monoclonal while the remaining six could not, with certainty, be
      assigned a clonal origin. We also obtained bone marrow aspirates at first relapse
      as well as at presentation from eight patients. In each case the same pattern of
      X-linked allelic inactivation was observed at both time points of the course of
      the disease. No evidence was found for leukaemic multiclonality in any age group
      at presentation or for leukaemic 'clone-switching' in relapse. These findings
      suggest that both infant and childhood ALL is of single-cell origin and implies
      that leukaemic predisposition resulting from germ cell mutation is unlikely to
      have a major role in their pathogenesis.

PMID- 10360675
TI  - Overexpression of rck/p54, a DEAD box protein, in human colorectal tumours.
AB  - The RCK gene is a target of the t(11;14)(q23;q32) chromosomal translocation
      observed in human B-cell lymphoma, and the overexpression of its protein
      (rck/p54) by the translocation was shown to cause malignant transformation. The
      rck/p54 protein belongs to the DEAD box protein/RNA helicase family, which has a
      variety of functions such as translation initiation, pre-mRNA splicing and
      ribosome assembly. The expression of rck p54 in colorectal adenocarcinoma cells
      was examined by immunohistochemistry and Western blot analysis. The rck/p54
      protein was found to be overexpressed in tumour tissues resected from 13 (50%)
      out of 26 cases of colorectal adenocarcinomas and two out of two (100%) cases of
      colonic severe dysplastic adenomas. In view of activities of rck/p54 determined
      in other tissue types, we suggest that rck/p54 may contribute to the cell
      proliferation and carcinogenesis at the translational level in the development of
      colorectal tumours.

PMID- 10360676
TI  - Expression of CD44 by rhabdomyosarcoma: a new prognostic marker?
AB  - The expression pattern of CD44 standard and variant isoforms are prognostically
      significant in a number of malignancies. The aim of this study was to evaluate
      the role of the standard isoform of CD44 in predicting the clinical behaviour of
      rhabdomyosarcoma. Immunohistochemical analysis of CD44 was undertaken using a
      panel of antibodies recognizing the three core domains of the CD44 molecule.
      Labelling was repeated in triplicate and reported blind with respect to
      histological type and outcome. Tumours were characterized as positive in more
      than 60% of tumour cells labelled and negative if less than 40% of tumour cells
      labelled. Tumours with 40-60% of tumour cells labelling were considered
      indeterminate. Eleven of 20 favourable histology tumours were positive for CD44
      compared with one of seven unfavourable tumours (P = 0.07). Eleven of 12 patients
      with CD44-positive tumours are alive in first remission compared with five of 15
      CD44-negative tumours (P = 0.001). Expression of CD44 correlates directly with
      prognosis; however, larger studies are required so that multivariate analysis can
      be undertaken.

PMID- 10360677
TI  - Radioimmunoluminography: a tool for relating tissue antigen concentration to
      clinical outcome.
AB  - Proteins control cell function and measurement of their concentration is crucial
      for understanding their roles in health and disease. However, current methods for
      their detection in tissue sections are not quantitative. Radioimmunoluminography
      (RILG) is a system for direct measurement of quantity and distribution of protein
      in histological sections. Histological carcinomas were reacted with antigen
      saturating concentrations of 125I-antibody to carcinoembryonic antigen (CEA).
      Antibody distribution and concentration was mapped by phosphor imaging.
      Radioactivity in each pixel of the digital image was proportional to antigen
      concentration, calculated from a standard line generated from a nitrocellulose
      CEA dot-blot assay. RILG gave a linear correlation with standards of known CEA
      concentration (r = 0.999). Six tumour xenografts with differing CEA
      concentrations by radioimmunoassay (RIA) were studied by RILG and
      immunohistochemistry (IHC). RILG gave a linear correlation with CEA by RIA (r =
      0.994) but IHC failed to do so (r = 0.42). CEA levels measured by RILG, in
      cryostat (n = 15) and paraffin (n = 19) sections from colorectal cancer patients
      showed a range of CEA concentration (38.9-594 ng g(-1) and 22.5-212.5 ng g(-1)
      respectively). Tumour CEA concentration by RILG was significantly correlated with
      dose of antibody (% injected radioactivity kg(-1)) localized in tumour (P = 0.04
      and P < 0.02 respectively), in patients receiving radioimmunoguided surgery.
      Clinical relevance of RILG is illustrated by identifying patients with high
      tumour CEA, most likely to benefit from antibody targeted therapy. Knowledge of
      the pathophysiology of many diseases may be enhanced by quantitative estimation
      of antigen concentration related to tissue morphology.

PMID- 10360679
TI  - Apolipoprotein E4 isoform-specific actions on neuronal cells in culture.
AB  - Apolipoprotein E (apoE) allele epsilon4 is a major risk factor for Alzheimer's
      disease (AD); however, the molecular mechanism underlying the acceleration of the
      development of AD in patients possessing epsilon4 remains to be determined. To
      investigate the isoform-specific effects of apoE on neurons, primary neuron
      cultures were prepared from fetal rat cerebral cortices. Inhibition of de novo
      cholesterol synthesis by compactin, a 3-hydroxyl-3-methylglutaryl CoA reductase
      inhibitor, induced neuronal cell death in a dose dependent manner. In the
      presence of a sublethal dose of compactin, apoE4 with beta-migrating very low
      density lipoproteins (beta-VLDL) caused apoptotic cell death in neuronal
      cultures. The same results were obtained with inhibition of de novo cholesterol
      synthesis by sublethal doses of squalestatin, an inhibitor of squalene synthase.
      The de novo cholesterol synthesis was suppressed to a higher degree by apoE4 than
      by apoE3, administered with beta-VLDL in the presence or absence of compactin.
      Mevalonate and squalene, which are metabolites of the cholesterol synthesis
      pathway, protected neuronal cells from apoE4-induced cell death. These results
      may suggest that apoE4 may exhibit neurotoxic action when de novo cholesterol
      synthesis is suppressed to a certain level, and that apoE4 induces neuronal cell
      death through the suppression of de novo cholesterol synthesis via an
      undetermined isoform-specific mechanism.

PMID- 10360678
TI  - Age-related chemical modification of the skeletal muscle sarcoplasmic reticulum
      Ca-ATPase of the rat.
AB  - Much emphasis has been placed on the description of age-related changes in
      skeletal muscle physiology. The present paper summarizes the chemical
      characterization of age-related post-translational modifications of the rat
      skeletal muscle sarcoplasmic reticulum (SR) Ca-ATPase isoforms SERCA1 and SERCA2a
      obtained from 5- and 28-month-old male Fischer 344 rats. Whereas the SERCA1
      isoform shows an age-dependent loss of Cys and Arg, the SERCA2a isoform displays
      a loss of Cys but also a significant accumulation of 3-nitrotyrosine. The in
      vitro exposure of SR vesicles particularly rich in SERCA1 (>90%) from 5-month-old
      rats to low levels of peroxyl radicals yielded SR vesicles with physical
      properties of the SR Ca-ATPase identical to those observed for the SR Ca-ATPase
      obtained from 28-month-old rats. The peroxyl radical-modified SR Ca-ATPase showed
      a loss of Cys and Arg but also of Ser and Met, indicating that peroxyl radicals,
      though a good model oxidant to generate 'aged' SR vesicles, may not be the only
      oxidant responsible for the chemical modification of the SR Ca-ATPase in vivo. In
      fact, efficient thiol modification of the SERCA1 was also observed after the
      exposure to peroxynitrite. Peroxynitrite selectively nitrated the tyrosine
      residues of the SERCA2a isoform even in the presence of an excess of SERCA1.
      Thus, peroxynitrite may be responsible for the age-dependent modification of the
      SR Ca-ATPase in vivo.

PMID- 10360680
TI  - Carbonylated proteins in aging and exercise: immunoblot approaches.
AB  - Protein carbonyls were studied in aging and exercise by immunoblot followed by
      one- or two-dimensional polyacrylamide gel electrophoresis using antibodies
      against 2,4-dinitrophenylhydrazones. Proteins of rat kidneys exhibited
      significant age-related increase in the amount of carbonyl while those of the
      brain and liver did not. Major carbonylated proteins in the kidney included serum
      albumin. In nematodes in which protein carbonyls increased with age, one of the
      carbonylated proteins was identified as vitellogenin, an egg-yolk protein. A
      possible biological significance of this protein present in abundance even after
      egg-laying stages is discussed in terms of protection against oxidative stress.
      Exhaustive exercise induced significant increase in the carbonylation of selected
      but unidentified proteins in the lung. This oxidative stress might be caused by
      xanthine oxidase in this tissue and hypoxanthine derived from ATP-depleted
      muscles. Exercise at high altitude caused higher carbonylation of the skeletal
      muscle proteins, most notably a protein likely to be actin, than that at sea
      level but no significant difference was observed in lipid peroxidation. These
      studies emphasize the value of immunoblot analysis of tissue protein carbonyls in
      a variety of situations where oxidative stress is likely involved.

PMID- 10360681
TI  - Expression of heat shock protein 70 decreases with age in hepatocytes and
      splenocytes from female rats.
AB  - A decline in the induction of heat shock protein 70 (hsp70) expression with age
      has been shown to occur in a variety of tissues from male rodents. Because the
      age-related change in the expression of many genes often differ in male and
      female rodents, we have measured the induction of hsp70 expression in hepatocytes
      and splenocytes from young/adult (4-8 months) and old (20-22 months) female
      Fischer 344 rats. Hepatocytes and splenocytes isolated from old female rats
      showed a marked decrease in the induction of hsp70 mRNA and protein levels by
      heat shock when compared to hepatocytes and splenocytes isolated from young/adult
      female rats. Because the heat shock transcription factor HSF1 mediates the heat
      induced transcription of hsp70, the effect of age on HSF1 was also studied. The
      ability of extracts from heat-shocked splenocytes to bind to the heat shock
      element (HSE) decreased with age. Interestingly, the levels of HSF1 protein were
      similar in splenocytes and hepatocytes from old female rats compared to
      young/adult female rats, even though the levels of HSE-binding were lower for
      splenocytes isolated from old rats. In this study, we show an age-related decline
      in the expression of hsp70, and this decline was similar to what we had
      previously observed in male Fischer 344 rats.

PMID- 10360682
TI  - Expression and structure of senescence marker protein-30 (SMP30) and its
      biological significance.
AB  - We previously identified a novel protein, the amounts of which are down-regulated
      in an androgen-independent manner with aging in the rat liver. We designated this
      protein as senescence marker protein-30 (SMP30). SMP30 is preferentially
      expressed in cytosol of hepatocytes and renal tubular epithelia, and its
      expression is maintained at high level throughout the tissue maturing stage as
      well as young and adult stages, but decreases during senescent stages in both
      sexes. Subsequently, we cloned cDNAs encoding SMP30 from rat, human and mouse and
      found that the amino acid sequence of SMP30 is well conserved with remarkable
      homology among these species. We also determined the genome organization and 5'
      flanking region of SMP30 in mouse genome. In the meantime, SMP30 turned out to be
      identical to a Ca2+-binding protein called regucaltin. In order to elucidate the
      functional significance of SMP30, we have generated Hep G2 cells that stably
      express large amounts of SMP30 by transfecting human SMP30 cDNA. Cell biological
      analyses on these SMP30 transfectants suggest that SMP30 regulates Ca2+
      homeostasis by enhancing plasma membrane Ca2+-pumping activity in Hep G2 cells.
      This result implies that the down-regulation of SMP30 may contribute to hepatic
      deterioration of cellular functions during aging. In this review, we present a
      overview of SMP30 in its structure, expression and possible physiological roles.
      We also discuss hypothetical role(s) of SMP30 in aging and Ca2+ homeostasis.

PMID- 10360683
TI  - Implications of presenilin 1 mutations in Alzheimer's disease.
AB  - Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are the most common
      genetic factors underlying the development of early-onset familial Alzheimer's
      disease (FAD). To investigate the pathogenic mechanism of PS1 mutations linked to
      FAD, we established inducible mouse neuroblastoma (Neuro 2a) cell lines
      expressing the human wild-type (wt) or mutated PS1(M146L or deltaexon 10) under
      the control of the Lac repressor. Using this inducible PS1 system, the influence
      of PS1 mutations on the generation of endogenous murine Abeta species was
      assessed using a highly sensitive immunoblotting technique. The induction of
      mutated PS1 resulted in an increase in the extra- and intracellular levels of two
      distinct Abeta species ending at residue 42, Abeta1-42 and its N-terminally
      truncated variant(s), Abetax-42. In addition, the intracellular generation of
      these Abeta42 species was completely blocked by brefeldin A. In contrast, it
      exhibited differential sensitivities to monensin such that there was an increased
      accumulation of intracellular Abetax-42 but an inhibition of intracellular Abeta1
      42 generation. These data strongly suggest that Abetax-42 is generated in a
      proximal Golgi compartment, whereas Abeta1-42 is generated in a distal Golgi
      and/or a post-Golgi compartment. Thus, it appears that PS1 mutations enhance the
      degree of 42-specific gamma-secretase cleavage which occurs (i) in the ER or the
      early Golgi apparatus prior to gamma-secretase cleavage, or (ii) in the distinct
      sites where Abetax-42 and Abeta1-42 are generated. To date, the site of Abeta42
      generation has not been firmly established. Our data provide new information
      regarding the site of Abeta42 generation mediated by the FAD-linked mutant PS1.

PMID- 10360684
TI  - Lateral mobility of proteins and lipids of cell surface membranes during aging:
      do the data support 'The Membrane Hypothesis of Aging'?
AB  - Many previous studies regarding the change with age in surface membrane fluidity
      of different cell types, including hepatocytes, as determined by the fluorescence
      anisotropy method, are in conflict, demonstrating decreased, unchanged or even
      increased fluidity with age. In contrast, the results of our series of works
      using the fluorescence recovery after photobleaching (FRAP) technique, which
      measures protein lateral diffusion coefficients of hepatocyte surface membranes
      (Dp), have demonstrated that Dp generally declines in a linear fashion with age
      in hepatocytes of all animal strains and species examined. The major coworker (I.
      Zs.-Nagy) of these studies insists that our observations support his original
      hypothesis, 'The Membrane Hypothesis of Aging' (MHA), the primary assumption of
      which is that changes in cell surface membranes with age cause a general decline
      in intracellular enzyme activities. However, while it seems clear that cell
      surface membrane changes do occur with age, a number of past observations
      including those from the laboratory of this author, provide strong evidence that
      intracellular enzyme activities do not generally decline with age. This paper
      presents the data in detail, along with the author's view that the results do not
      support the main assumption of the MHA, but are more likely related to
      alterations in membrane functions with age.

PMID- 10360685
TI  - Methionine residues may protect proteins from critical oxidative damage.
AB  - Cysteine and methionine are the two sulfur-containing residues normally found in
      proteins. Cysteine residues function in the catalytic cycle of many enzymes, and
      they form disulfide bonds which contribute to protein structure. In contrast, the
      key functions of methionine residues are not known. We propose that methionine
      residues constitute an important antioxidant defense mechanism. A variety of
      oxidants react readily with methionine to form methionine sulfoxide, and surface
      exposed methionine residues create an extremely high concentration of reactant,
      providing for efficient scavenging of oxidants. The effect of hydrogen peroxide
      exposure upon glutamine synthetase from Escherichia coli was studied as an in
      vitro model system. Eight of the sixteen methionine residues could be oxidized
      with little effect on activity. The oxidizable methionine residues were found to
      be relatively surface exposed while the intact residues were generally buried
      within the core of the protein. Further, the susceptible residues were physically
      arranged in an array which guarded the entrance to the active site. Methionine
      sulfoxide can be reduced back to methionine by the enzyme methionine sulfoxide
      reductase, providing a catalytic amplification of the antioxidant potential of
      each methionine residue. Given the importance of oxidative stress during aging,
      the potential function of methionine residues as antioxidants during aging should
      be investigated experimentally.

PMID- 10360686
TI  - Receptors for proteins modified by advanced glycation endproducts (AGE)--their
      functional role in atherosclerosis.
AB  - Long-term incubation of proteins with glucose leads, through the formation of
      early stage products such as Schiff base and Amadori rearrangement products, to
      the formation of advanced glycation end products (AGE). Recent studies of AGE
      structures as well as the receptor for AGE-proteins (AGE-receptors) have
      emphasized the involvement of protein modification by AGE in aging and age
      enhanced disease processes. Immunohistochemical analyses of human atherosclerotic
      lesions using a monoclonal anti-AGE antibody have demonstrated diffuse
      extracellular AGE-deposition as well as dense intracellular AGE-deposition in
      macrophage- and vascular smooth muscle cell (SMC)-derived foam cells. In vitro
      experiments using both CHO cells overexpressing macrophage scavenger receptor-A
      (MSR-A) and peritoneal macrophages from MSR-A-knockout mice have shown that the
      MSR-A plays a major role in endocytic uptake of AGE-proteins by macrophages.
      Furthermore, in vitro experiments with rabbit arterial SMCs demonstrated a novel
      AGE-receptor mediating endocytosis of AGE-proteins. These in vivo and in vitro
      experiments suggest that AGE-proteins formed extracellularly in atherosclerotic
      lesions are endocytosed by macrophages through MSR-A in the early stage, and by
      SMCs through the novel AGE-receptor in the advanced stage, implicating functional
      contribution of the AGE-receptor-mediated interaction of AGE-proteins with these
      cells to atherosclerotic processes in arterial walls.

PMID- 10360687
TI  - The mechanisms of simultaneous stereoinversion, racemization, and isomerization
      at specific aspartyl residues of aged lens proteins.
AB  - Proteins have been considered to consist exclusively of L-amino acids in living
      tissues. However, we found biologically uncommon D-aspartyl (Asp) residues at
      specific sites in alphaA- and alphaB-crystallin from the aged human lens (mean
      age: 80 years). In alphaB-crystallin, the Asp-36 and Asp-62 residues are highly
      racemized (D/L ratios: 0.92 for Asp-36; 0.54 for Asp-62). More interestingly, the
      configuration of the Asp-58 and Asp-151 residues in alphaA-crystallin is inverted
      to the D-isomer (D/L ratio: 3.1 for Asp-58, 5.7 for Asp-151). A D/L ratio > 1.0
      is not considered to be due to racemization, but rather is thought to result from
      stereoconfiguration inversion. Our report was the first observation that
      inversion occurred in the configuration of amino acids in vivo during the natural
      aging process. We also found that these enantiomers were simultaneously
      isomerized to form beta-Asp residues. We propose that the mechanism of D- and
      beta-Asp formation in the protein depends on the primary structure and the
      presence of a chiral reaction field, which induces formation of D-Asp.

PMID- 10360688
TI  - New horizons in orthopaedic research: elucidation of cellular signal transduction
      pathways.

PMID- 10360689
TI  - Signaling pathways for tumor necrosis factor-alpha and interleukin-6 expression
      in human macrophages exposed to titanium-alloy particulate debris in vitro.
AB  - BACKGROUND: Loosening of the implant after total joint arthroplasty remains a
      serious problem. The activation of macrophages by wear debris from implants,
      mediated by the release of cytokines that elicit bone resorption, may lead to
      loosening. The purpose of the present study was to elucidate the mechanisms of
      macrophage activation by titanium particles from the components of implants and
      to identify the signaling pathways involved in particle-mediated release of
      cytokines. METHODS: Macrophages were isolated from mononuclear leukocytes
      obtained from healthy human donors and were exposed to titanium-alloy particles
      that had been obtained from periprosthetic membranes collected at revision total
      joint arthroplasties and then enzymatically prepared. The experimental protocols
      included examination of the effects of the inhibition of phagocytosis and the
      binding of antibodies to macrophage complement receptors on particle-induced
      macrophage activation. The release of the proinflammatory cytokines TNF-alpha
      (tumor necrosis factor-alpha) and IL-6 (interleukin-6) was used to assess
      macrophage activation. The signaling pathways involved in the induction of
      cytokine release were analyzed by identification of phosphorylated proteins with
      use of the Western blot technique and by translocation of the transcription
      factors nuclear factor-kappa B (NF-kappaB) and nuclear factor-interleukin-6 (NF
      IL-6) into the nuclear protein fraction with use of electrophoretic mobility
      shift assays. The role of serine/threonine and tyrosine kinase pathways in the
      activation of nuclear factors and the release of cytokines was examined with use
      of selective pharmacological agents. RESULTS: Exposure of macrophages to titanium
      alloy particles in vitro for forty-eight hours resulted in a fortyfold increase
      in the release of TNF-alpha and a sevenfold increase in the release of IL-6
      (p<0.01). Phagocytosis of particles occurred in approximately 73 percent of the
      macrophages within one hour of exposure. Pretreatment of the macrophages with
      cytochalasin B reduced phagocytosis by 95 percent but did not reduce the release
      of TNF-alpha or IL-6. Thus, phagocytosis of particles was not necessary for
      induction of the release of TNF-alpha or IL-6 in the cultured macrophages.
      Ligation of the macrophage CD11b/CD18 receptors by integrin-specific antibodies
      also increased the release of TNF-alpha and IL-6. Antibodies to CD11b/ CD18
      receptors (macrophage Mac-1 receptors) reduced phagocytosis of particles by 50
      percent (p<0.05). (The CD11b/CD18 macrophage receptor is the macrophage receptor
      for the complement component CR3bi. The CD11b/CD18 macrophage receptor can also
      bind to ICAM-1 and ICAM-2. CD is the abbreviation for cluster of differentiation,
      and ICAM is the abbreviation for intercellular adhesion molecule.) Inhibition of
      phagocytosis was not accompanied by a decrease in the release of TNF-alpha and IL
      6. Blocking RNA synthesis with actinomycin D or preventing protein synthesis with
      cycloheximide abolished or decreased particle-induced release of TNF-alpha and IL
      6 from the macrophages. Macrophage release of TNF-alpha and IL-6 in response to
      particles coincided with increased tyrosine phosphorylation and mitogen-activated
      protein kinase activation. Inhibition of tyrosine and serine/threonine kinase
      activity decreased the particle-induced release of cytokines. Exposure of
      macrophages to either titanium-alloy particles or to antibodies to the receptor
      proteins CD11b and CD18 for thirty minutes activated the transcription factors NF
      kappaB and NF-IL-6. Inhibition of particle phagocytosis did not block activation
      of the transcription factors. However, inhibition of tyrosine and
      serine/threonine kinase activity decreased the activation of NF-kappaB and NF-IL
      6. CONCLUSIONS: These data suggest that particle induced macrophage release of
      TNF-alpha and IL-6 does not require phagocytosis but is dependent on tyrosine and
      serine/threonine kinase activity culminating in activation of

PMID- 10360690
TI  - Proteins bound to polyethylene components in patients who have aseptic loosening
      after total joint arthroplasty. A preliminary report.
AB  - BACKGROUND: Immunological responses to proteins that adhere to ultra-high
      molecular weight polyethylene have not, to our knowledge, been examined
      previously in patients who have aseptic loosening. In the current study,
      polyethylene components from forty-nine failed prostheses recovered during
      revision procedures were examined for the presence of antibodies that were bound
      to the polyethylene surface or that were reactive with other proteins that were
      bound to the polyethylene surface. METHODS: The polyethylene components consisted
      of thirty acetabular cups recovered during revision total hip arthroplasties and
      nineteen tibial components recovered during revision total knee arthroplasties.
      After extensive washing, bound proteins were extracted from the polyethylene
      components with use of 0.1-molar glycine-hydrogen chloride solution followed by
      four-molar guanidine hydrochloride solution. RESULTS: Sufficient protein for
      analysis was recovered from forty-two polyethylene components. Polyacrylamide gel
      electrophoresis demonstrated a minimum of one and a maximum of twelve protein
      bands, with molecular weights ranging from thirteen to 231 kilodaltons.
      Immunoblotting revealed the presence of type-I collagen in most (thirty-four) of
      the forty-two explants, whereas aggrecan proteoglycans were detected in eight
      samples. Immunoglobulin also was detected in most (thirty-three) extracts,
      whereas type-II collagen was consistently absent. The presence of autologous
      antibodies directed against polyethylene-bound proteins in sera drawn at the time
      of the revision was investigated. Antibodies that were reactive against the ultra
      high molecular weight polyethylene-bound proteins were detected in twenty-six of
      the forty-two patients with use of the Western blot technique. The number of
      reactive bands ranged from one to six, and the strongest binding was directed
      against a 103-kilodalton protein. Assays for specificity revealed that these sera
      autologous antibodies were reactive against the type-I collagen that was present
      in the explant solutions. CONCLUSIONS: We hypothesize that immunoglobulin
      complexed with polyethylene may fix complement and that the complement cascade
      may in turn attract inflammatory cells to the polyethylene surface. Our data
      support the hypothesis that an immunological response to antigens bound to the
      polyethylene surface may contribute to aseptic loosening. CLINICAL RELEVANCE:
      Despite improvements in materials and designs of prostheses, aseptic loosening is
      the most common complication of total joint replacement, frequently leading to
      revision operations. We examined the immunological response to proteins that bind
      to ultra-high molecular weight polyethylene in patients who had aseptic loosening
      and discovered a high prevalence of antibodies to polyethylene-bound proteins.
      This immunological response may contribute to an inflammatory reaction in the
      periprosthetic tissue, ultimately leading to increased bone resorption around the
      prosthesis.

PMID- 10360691
TI  - Distraction osteogenesis for lengthening of the tibia in patients who have limb
      length discrepancy or short stature.
AB  - BACKGROUND: This study was performed to determine the safety and effectiveness of
      lengthening of the tibia, in patients who have a limb-length discrepancy or a
      short stature, with use of distraction osteogenesis, a technique based on the
      principle of distracting the callus that is formed after a subperiosteal
      osteotomy of the proximal portion of the diaphysis of a long bone. METHODS: A
      total of 230 tibial lengthening procedures were done in 150 patients. Seventy
      procedures were performed because of a limb-length discrepancy, which was
      secondary to trauma (thirty limbs), congenital fibular hemimelia (twenty-six),
      poliomyelitis (ten), or infection (four). The remaining 160 procedures were
      performed because of a short stature, which was secondary to achondroplasia
      (fifty-eight limbs), Turner syndrome (thirty-four), an idiopathic etiology
      (twenty-two), hypochondroplasia (twenty), achondroplasia (ten), Ellis-van Creveld
      syndrome (six), rickets (four), or adrenogenital syndrome, Laron syndrome, or
      pseudoachondroplasia (two limbs each). The age of the patients at the time of the
      operation was 18.4+/-6.2 years (average and standard deviation), with a range of
      six to forty-one years. The procedures were performed according to one of three
      protocols. In Group A (ninety procedures), an Orthofix telescopic fixator and a
      variable number of screws were used and the tibiofibular syndesmosis was not
      stabilized; in Group B (ninety-six procedures), an Orthofix reconstruction system
      was used, the syndesmosis was stabilized, and a tenotomy of the Achilles tendon
      was performed; and in Group C (forty-four procedures), an Orthofix Garches
      lengthening device was used, the syndesmosis was stabilized, and a tenotomy of
      the Achilles tendon was performed. RESULTS: At the time of the latest follow-up
      (average, five years; range, two to seven years), the average gain in length
      after the seventy procedures performed because of a limb-length discrepancy was
      4.0+/-1.98 centimeters (range, 2.5 to 9.5 centimeters), or 14 percent (range, 7
      to 45 percent). The average gain in length after the 160 procedures that were
      performed because of a short stature was 7.8+/-2.28 centimeters (range, 2.5 to
      fifteen centimeters), or 33 percent (range, 10 to 78 percent). Ten (14 percent)
      of the seventy procedures performed because of a limb-length discrepancy and
      forty-six (29 percent) of the 160 performed because of a short stature were
      associated with a complication. There was only one permanent sequela in the
      entire series. CONCLUSIONS: Although the three operative protocols resulted in
      similar healing indices, the rates of complications differed significantly among
      the groups (p<0.0001). Group C (the Garches device) had the lowest rate of
      complications (7 percent). It is important to be aware of potential complications
      as well as the need for additional procedures in order to avoid predictable
      problems. These procedures include percutaneous tenotomy of the Achilles tendon
      and fixation of the distal segment of the fibula to the tibia to maintain the
      integrity of the tibiotalar articulation and the alignment of the foot.

PMID- 10360692
TI  - Long-term follow-up of pyrolytic carbon metacarpophalangeal implants.
AB  - BACKGROUND: The metacarpophalangeal joint is the most commonly involved joint
      when rheumatoid arthritis affects the hand. Many prosthetic implants have been
      designed for the replacement of this joint. Although studies of these implants
      have shown relief of pain, they have generally demonstrated a poor range of
      motion, progression of ulnar drift, and bone loss, as well as failure, fracture,
      and dislocation of the implant. METHODS: From December 1979 to February 1987, 151
      pyrolytic carbon metacarpophalangeal implants were inserted in fifty-three
      patients. The implants had an articulating, unconstrained design with a
      hemispherical head and grooved, offset stems. Forty-four patients had rheumatoid
      arthritis; five, posttraumatic arthritis; three, osteoarthritis; and one,
      systemic lupus erythematosus. Three patients (eleven implants) were lost to long
      term follow-up, and twenty patients (fifty-one functioning implants) died after
      the implant had been in situ for an average of 7.2 years. Eighteen implants (12
      percent) in eleven patients were revised. Fourteen of the eighteen implants were
      replaced with a silicone-elastomer or another type of implant, and the remaining
      four were removed and a pyrolytic carbon implant was reinserted with the addition
      of bone cement or bone graft, or both. Twenty-six patients (seventy-one implants)
      were available for long-term review at an average of 11.7 years (range, 10.1 to
      16.0 years) after implantation. RESULTS: The implants improved the arc of motion
      of the fingers by an average of 13 degrees and elevated the arc by an average of
      16 degrees. As a result, fingers were in a more functional, extended position. A
      complete set of preoperative, postoperative, and follow-up radiographs was
      available for fifty-three of the seventy-one implants that were followed long
      term. There was a high prevalence of joint stability: fifty (94 percent) of the
      fifty-three implants were in a reduced position postoperatively, and forty-one
      (82 percent) of those fifty implants were still in the postoperative reduced
      position at the time of long-term follow-up. Ulnar deviation averaged 20 degrees
      preoperatively and 19 degrees at the time of follow-up, with only the long finger
      having an increase in deviation. No adverse remodeling or resorption of bone was
      seen. Fifty (94 percent) of the fifty-three implants had evidence of
      osseointegration, with sclerosis around the end and shaft of the prosthetic
      stems. Radiolucent changes were seen adjacent to twelve implants. There was
      minimum-to-moderate subsidence (four millimeters or less) of thirty-four
      implants; most of the subsidence occurred immediately postoperatively.
      Survivorship analysis demonstrated an average annual failure rate of 2.1 percent
      and a sixteen-year survival rate of 70.3 percent. The five and ten-year survival
      rates were 82.3 percent (95 percent confidence interval, 74.6 to 88.2 percent)
      and 81.4 percent (95 percent confidence interval, 73.0 to 87.8 percent),
      respectively. None of the revised implants had any visible changes of wear or
      deformity of the surfaces or stems. Four instances of chronic inflammatory tissue
      and three instances of proliferative synovitis were noted histologically. Focal
      pigment deposits were seen in three fingers, one of which had removal of the
      implant two months after a fracture. No evidence of intracellular particles or
      particulate synovitis was found. CONCLUSIONS: The results of this study
      demonstrate that pyrolytic carbon is a biologically and biomechanically
      compatible, wear-resistant, and durable material for arthroplasty of the
      metacarpophalangeal joint.

PMID- 10360693
TI  - Comparison of the natural history, the outcome of microsurgical repair, and the
      outcome of operative reconstruction in brachial plexus birth palsy.
AB  - BACKGROUND: The purposes of this study were to document the natural history of
      brachial plexus birth palsy, in relation to the recovery of biceps function, in
      the first six months of life; to assess the outcome after microsurgical repair of
      the brachial plexus in patients who had no recovery of biceps function at six
      months; and to compare the results of transfer of the latissimus dorsi and teres
      major tendons with the results of derotation osteotomy of the humerus and to
      compare the results of the tendon transfers and the osteotomy with the natural
      history of the disorder. METHODS: Sixty-six patients (sixty-seven lesions) who
      had brachial plexus birth palsy were seen for an initial evaluation when they
      were less than three months old. The time of recovery of biceps function was
      recorded for each month of life for six months from the date of birth. The
      patients were divided into groups according to the month of life during which
      recovery of biceps strength was noted. A physical examination and an assessment
      with use of the functional criteria of Mallet were performed each month.
      Microsurgical repair of the brachial plexus was performed in six infants who had
      no evidence of biceps function within the first six months of life. Another group
      of twenty-seven patients were referred for evaluation of chronic neuropathy after
      they were six months old. A transfer of the latissimus dorsi and teres major
      tendons to the rotator cuff was performed in nine of these patients and a
      derotation osteotomy of the humerus was performed in seven because of an internal
      rotation contracture or functional weakness of the external rotators of the
      shoulder. RESULTS: Twenty-two infants had recovery of biceps function within the
      first three months of life and had normal function at the time of the latest
      evaluation. Infants who had recovery of biceps function during the fourth, fifth,
      or sixth month of life later had significantly worse function, according to the
      criteria described by Mallet, than those who had had recovery in the first three
      months (p<0.005). The clinical results for the six patients who had had
      microsurgical repair six months after birth were significantly better (p<0.04)
      than those for the fifteen patients who had had recovery of biceps function in
      the fifth month of life. However, the results for the patients who had had repair
      of the brachial plexus were not found to be better than those for the eleven
      patients who had had recovery of biceps function in the fourth month of life. The
      improvement in function, as assessed with use of the Mallet criteria, after
      tendon transfer (p<0.001) and humeral osteotomy (p<0.0001) was significant.
      CONCLUSIONS: The present study confirms the observation of Gilbert and Tassin
      that it is rare for infants who have recovery of biceps function after the age of
      three months to have complete neurological recovery. Microsurgical repair was
      effective in improving function in the small subgroup of patients who had no
      evidence of recovery of biceps function within the first six months of life.

PMID- 10360694
TI  - Geometric analysis of commonly used prosthetic systems for proximal humeral
      replacement.
AB  - BACKGROUND: The anatomy of the proximal part of the humerus is extremely
      variable. The extent to which existing prosthetic systems and operative technique
      allow replication of this variability has not been established. METHODS: Four
      commonly used press-fit prosthetic systems for shoulder arthroplasty were
      compared with respect to their ability to match the superior-inferior and medial
      lateral dimensions of the articular surface in twenty-one cadaveric humeri. The
      comparisons were accomplished with a computer optimization algorithm that
      searched a database of prosthetic geometry and selected the best match to the
      original anatomy. The algorithm assumed an osteotomy of the humeral head at an
      angle equivalent to the stem-head angle of the prosthesis, without violation of
      the greater tuberosity or the metaphyseal bone. The best match was defined as the
      prosthetic combination (stem and head) that least displaced the center of
      rotation and the articular surface, with both factors weighted equally. RESULTS:
      None of the prosthetic systems that were evaluated allowed identical replication
      of the articular surface. Rather, they displaced the center of rotation a mean of
      14.7 millimeters (range, 3.3 to 31.4 millimeters) from its original position. To
      reach this minimized displacement, the prosthetic combinations that were selected
      by the algorithm also resulted in a mean diminution of the arc of the articular
      surface (a smaller head size) of 26 degrees (range, 11 to 41 degrees). In every
      instance, the selected prosthesis imposed a superior and lateral shift of the
      center of rotation that in effect shifted a smaller prosthetic humeral head up
      the slope of the humeral osteotomy. CONCLUSIONS: Press-fit prosthetic systems for
      shoulder arthroplasty that are commonly used necessitate marked alterations of
      the original anatomy. To the extent that a shoulder arthroplasty is an attempt to
      reproduce the normal anatomy, these findings have profound implications for
      operative technique and future prosthetic design. CLINICAL RELEVANCE: We believe
      that the superior position of the prosthetic head predicted by the present study
      plays a role in late complications of shoulder arthroplasty, such as rotator cuff
      tendinopathy, superior humeral migration, and loosening of the glenoid component.

PMID- 10360695
TI  - Prospective analysis of preoperative and intraoperative investigations for the
      diagnosis of infection at the sites of two hundred and two revision total hip
      arthroplasties.
AB  - BACKGROUND: Total hip arthroplasty is a commonly performed procedure in the
      United States and Canada that is associated with a definite risk of postoperative
      infection. Moreover, diagnosing an infection after total hip arthroplasty can
      present a challenge as there are no preoperative tests that are consistently
      sensitive and specific for infection in patients who need a revision
      arthroplasty. The present prospective study was performed to evaluate a variety
      of investigations for the diagnosis of infection at the site of a previous
      arthroplasty in order to determine if any combination of diagnostic studies could
      be used to determine which patients are at risk for a postoperative wound
      infection. METHODS: We prospectively analyzed the preoperative and intraoperative
      investigations used for the diagnosis of infection in 178 patients who had a
      total of 202 revision hip replacements. Clinical data were collected
      preoperatively. Investigations to determine the presence or absence of infection
      included a white blood-cell count, measurement of the erythrocyte sedimentation
      rate, measurement of the level of C-reactive protein, preoperative aspiration of
      the joint, intraoperative gram-staining and culture of periprosthetic tissue, a
      white blood-cell count in synovial fluid, and examination of intraoperative
      frozen sections. Frozen sections were analyzed in a blinded fashion without
      knowledge of clinical or laboratory data. Patients receiving antibiotics at the
      time of aspiration or collection of specimens for intraoperative culture were
      excluded from the analysis of those investigations, regardless of the results of
      the cultures. A positive result (suggestive of infection) was clearly defined for
      each of the investigations. RESULTS: Thirty-five hips (17 percent) were
      determined to be infected on the basis of clinical findings and positive results,
      according to the defined criteria, of investigations. With inflammatory
      conditions excluded, the sensitivity, specificity, positive predictive value, and
      negative predictive value were 0.82, 0.85, 0.58, and 0.95, respectively, for the
      erythrocyte sedimentation rate and 0.96, 0.92, 0.74, and 0.99, respectively, for
      the level of C-reactive protein. All patients who had a periprosthetic infection
      had an elevated erythrocyte sedimentation rate or level of C-reactive protein,
      but not always both. When patients who were receiving antibiotics were excluded,
      the results of aspiration of the joint were 0.86 for sensitivity, 0.94 for
      specificity, 0.67 for the positive predictive value, and 0.98 for the negative
      predictive value. Intraoperative studies revealed sensitivities, specificities,
      positive predictive values, and negative predictive values of 0.19, 0.98, 0.63,
      and 0.89, respectively, for gram-staining of specimens of the most inflamed
      appearing tissue; 0.36, 0.99, 0.91, and 0.90, respectively, for the white
      bloodcell count in synovial fluid; and 0.89, 0.85, 0.52, and 0.98, respectively,
      for a neutrophil count in synovial fluid of more than 80 percent. The
      sensitivity, specificity, positive predictive value, and negative predictive
      value were 0.80, 0.94, 0.74, and 0.96, respectively, for the frozen sections and
      0.94, 0.97, 0.77, and 0.99, respectively, for the intraoperative cultures.
      CONCLUSIONS: The combination of a normal erythrocyte sedimentation rate and C
      reactive protein level is reliable for predicting the absence of infection.
      Aspiration should be used when the erythrocyte sedimentation rate or the C
      reactive protein level is elevated or when a clinical suspicion of infection
      remains. We found the gram stain to be unreliable. Examination of intraoperative
      frozen sections is useful in equivocal cases or when hematological markers may be
      falsely elevated because of an inflammatory or other condition.

PMID- 10360696
TI  - Analysis of frozen sections of intraoperative specimens obtained at the time of
      reoperation after hip or knee resection arthroplasty for the treatment of
      infection.
AB  - BACKGROUND: Despite the effectiveness of a two-stage exchange protocol for the
      treatment of deep periprosthetic infection, infection can persist after resection
      arthroplasty and treatment with antibiotics, leading to a failed second-stage
      reconstruction. Intraoperative analysis of frozen sections has been shown to have
      a high sensitivity and specificity for the identification of infection at the
      time of revision arthroplasty; however, the usefulness of this test at the time
      of reoperation after resection arthroplasty and treatment with antibiotics is, to
      our knowledge, unknown. METHODS: The medical records of sixty-four consecutive
      patients who had had a resection arthroplasty of either the knee (thirty-three
      patients) or the hip (thirty-one patients) and had had intraoperative analysis of
      frozen sections of periprosthetic tissue obtained at the time of a second-stage
      operation were reviewed. The mean interval between the resection arthroplasty and
      the attempted reimplantation was nineteen weeks. The results of the
      intraoperative analysis of the frozen sections were compared with those of
      analysis of permanent histological sections of the same tissues and with those of
      intraoperative cultures of specimens obtained from within the joint. The findings
      of the analyses of the frozen sections and the permanent histological sections
      were considered to be consistent with acute inflammation and infection if a mean
      of ten polymorphonuclear leukocytes or more per high-power field (forty times
      magnification) were seen in the five most cellular areas. RESULTS: The
      intraoperative frozen sections of the specimens from two patients (one of whom
      was considered to have a persistent infection) met the criteria for acute
      inflammation. Four patients were considered to have a persistent infection on the
      basis of positive intraoperative cultures or permanent histological sections.
      Overall, intraoperative analysis of frozen sections at the time of reimplantation
      after resection arthroplasty had a sensitivity of 25 percent (detection of one of
      four persistent infections), a specificity of 98 percent, a positive predictive
      value of 50 percent (one of two), a negative predictive value of 95 percent, and
      an accuracy of 94 percent. CONCLUSIONS: A negative finding on intraoperative
      analysis of frozen sections has a high predictive value with regard to ruling out
      the presence of infection; however, the sensitivity of the test for the detection
      of persistent infection is poor.

PMID- 10360697
TI  - Efficacy of prophylaxis against thromboembolism with intermittent pneumatic
      compression after primary and revision total hip arthroplasty.
AB  - BACKGROUND: Thromboembolism is a common and important complication after total
      hip arthroplasty. A variety of pharmacological and mechanical measures have been
      proposed for prophylaxis. The purpose of the present study was to evaluate the
      efficacy of intermittent pneumatic compression as prophylaxis against
      thromboembolism following total hip arthroplasty. METHODS: The prospective study
      involved a consecutive series of 425 patients in whom a total of 502 (324 primary
      and 178 revision) total hip arthroplasties had been performed by two surgeons.
      The patients were managed intraoperatively and postoperatively with use of thigh
      high elastic compression stockings and thigh-high intermittent pneumatic
      compression sleeves. Experienced vascular technologists performed venous duplex
      ultrasonography on both lower extremities of all patients at a mean of six days
      (range, two to fifteen days) postoperatively. All patients were followed for at
      least one year in order to detect late thromboembolism. RESULTS: An asymptomatic
      deep-vein thrombosis was noted on the scans made after twenty-three (4.6 percent)
      of the 502 procedures. Nineteen (3.8 percent) of the arthroplasties were followed
      by the development of a proximal thrombosis and four (0.8 percent), a distal
      thrombosis. Nineteen of the thromboses were ipsilateral (eighteen were proximal
      and one, distal), and four were contralateral (one was proximal and three,
      distal). No symptomatic deep-vein thrombosis developed in the hospital. In
      addition, three (two proximal and one distal) symptomatic ipsilateral deep-vein
      thromboses (a prevalence of 0.6 percent) developed three to twenty-three weeks
      after postoperative scans revealed negative findings and the patients were
      discharged from the hospital. Three symptomatic pulmonary embolisms (a prevalence
      of 0.6 percent) were confirmed by ventilation-perfusion scanning while the
      patients were in the hospital. There were no symptomatic pulmonary embolisms
      after discharge, and there were no fatal pulmonary embolisms. With the numbers
      available, we were unable to detect an association between deep-vein thrombosis
      and age (p = 0.76), gender (p = 0.13), body-mass index (p = 0.12), type of
      arthroplasty (primary or revision) (p = 0.12), operative approach (p = 0.37),
      duration of the operation (p = 0.21), type of anesthesia (general or regional) (p
      = 0.51), units of blood transfused (autologous, p = 0.79; homologous, p = 0.57),
      blood type (p = 0.18), or the presence of a so-called classic risk factor for the
      development of thrombosis (p = 0.22). Five arthroplasties (1.0 percent) were
      followed by the development of a wound hematoma, but only one hematoma
      necessitated operative drainage. CONCLUSIONS: The use of intraoperative and
      postoperative thigh-high intermittent pneumatic compression, combined with duplex
      ultrasonography performed by experienced vascular technologists, is effective for
      prophylaxis against thromboembolism after both primary and revision total hip
      arthroplasties. The low prevalence of deep-vein thrombosis (4.6 percent) and
      symptomatic pulmonary embolism (0.6 percent) is comparable with that associated
      with pharmacological prophylaxis.

PMID- 10360698
TI  - Total knee arthroplasty with retention of both cruciate ligaments. A nine to
      eleven-year follow-up study.
AB  - BACKGROUND: Although many early designs of total knee arthroplasty allowed the
      retention of both cruciate ligaments, in most current designs of knee replacement
      systems, either both cruciate ligaments are removed or the posterior cruciate
      ligament alone is retained. This report is a review of a series of total knee
      arthroplasties in which both cruciate ligaments were retained. METHODS: The
      results of 163 total knee arthroplasties (130 patients) in which both cruciate
      ligaments were retained were assessed prospectively. One hundred and seven knees
      (eighty-nine patients) were followed for an average of ten years. There were
      thirty-four men and ninety-six women, and the average age at the time of the
      index arthroplasty was sixty-seven years (range, forty-two to eighty-four years).
      The diagnosis was osteoarthritis in 122 (75 percent) of the knees and rheumatoid
      arthritis in forty-one (25 percent). Twenty-six knees had a valgus deformity, 109
      had a varus deformity, and twenty-eight had a normal alignment of 5 to 10 degrees
      of valgus. The anterior cruciate ligament was relatively normal in ninety-six
      knees and was partly degenerated in sixty-seven knees. With use of the rating
      system of the Knee Society, all 163 knees were prospectively evaluated at yearly
      intervals; fifty-six of these knees (in forty-one patients) were followed in this
      manner until the patient died or was lost to follow-up. RESULTS: One hundred and
      four (97 percent) of the 107 knees available for study at an average of ten years
      had an excellent or good result. At the time of the latest follow-up, pain was
      adequately relieved in ninety-seven knees (91 percent) and the average range of
      flexion was 107+/-12.6 degrees (range, 65 to 135 degrees). Ninety-five knees (89
      percent) had normal anteroposterior stability (less than five millimeters of
      movement in this plane), and twelve knees (11 percent) had five to ten
      millimeters of movement as demonstrated by the drawer sign. Ninety-six knees (90
      percent) had normal mediolateral stability, and eleven (10 percent) had 5 to 10
      degrees of laxity. Ninety-four knees (88 percent) had valgus alignment of 5 to 10
      degrees. The average knee score was 91+/-8.4 points (range, 54 to 100 points),
      and the average functional score was 82+/-21 (range, 10 to 100 points). The
      survival rate at ten years, with revision as the end point, was 95+/-2.0 percent.
      Seven (4 percent) of the 163 knees in this series were revised. There were no
      revisions for patellar problems or aseptic loosening of the tibial component.
      CONCLUSIONS: The good anteroposterior stability in this series after an average
      follow-up period of ten years indicates that both the anterior and the posterior
      cruciate ligaments, even when partly degenerated, remain functional when they are
      preserved in a total knee arthroplasty.

PMID- 10360699
TI  - Recurrent giant-cell tumor presenting as a soft-tissue mass. A report of four
      cases.

PMID- 10360700
TI  - Missed posterior fracture-dislocation of the humeral head. A case report with a
      fifteen-year follow-up after delayed open reduction and internal fixation.

PMID- 10360701
TI  - Valgus deformity after reconstruction of the anterior cruciate ligament in a
      skeletally immature patient. A case report.

PMID- 10360702
TI  - Lumbar arthrodesis for the treatment of back pain.

PMID- 10360703
TI  - The outcomes movement in orthopaedic surgery: where we are and where we should
      go.

PMID- 10360704
TI  - Metal mania: fact or fiction?

PMID- 10360705
TI  - The value of the system of King et al. for the classification of idiopathic
      thoracic scoliosis.

PMID- 10360706
TI  - Good news, bad news for diabetic versus nondiabetic end-stage renal disease:
      incidence and mortality.

PMID- 10360707
TI  - Physiology of nonpulsatile circulation: acute versus chronic support.
AB  - Mammals seem to be able to adapt to nonpulsatile circulation. For chronic
      support, pressure and flow, not the presence of a pulse, are the major
      requirements to sustain normal organ function. Pulsatile flow, however, seems to
      offer advantages over nonpulsatile flow for acute support in maintaining
      lymphatic flow, decreasing systemic vascular resistance, improving peripheral and
      pulmonary capillary perfusion, and reversing shock. These advantages may not be
      seen with chronic support with adaptation to nonpulsatile flow.

PMID- 10360708
TI  - In vivo evaluation of an intrathoracic ventricular assist device.
AB  - In this series of experiments, the Unified System components of the HeartSaver
      Ventricular Assist Device (VAD) version 5.0 were isolated from the controller and
      power supply for independent assessment. Five systems with external
      controller/power supply via a percutaneous lead configuration were tested in 13
      male calves (101.8+/-4.3 kg). Two studies were ended acutely because of improper
      filling and air embolism, respectively. Duration of support was from 2.2 hours to
      30 days (mean, 99+/-62 hours). The 30 day survivor was euthanized electively.
      Study termination was related to postoperative complications in five calves: two
      with bleeding/tamponade, one with thromboembolism caused by inadequate
      anticoagulation, and two with respiratory insufficiency. Other causes of
      termination were: one caused by main building power failure, two from errors in
      communication between the device and controller, and two caused by hydraulic
      fluid loss related to housing defects. From these experiments, an intrathoracic
      position for the calf has been defined, the procedure for implantation without
      cardiopulmonary bypass has been developed, refinements to the controller have
      been made, and inflow and outflow cannulae have been reinforced. Hydraulic fluid
      losses will be solved by proceeding with use of a titanium housing instead of
      polyurethane. In conclusion, the development of the HeartSaver VAD is
      progressing, in part because of these experimental and informative animal
      studies. Further in vivo evaluation of the final version will be conducted before
      clinical trials.

PMID- 10360709
TI  - Rapid cell isolation by magnetic flow sorting for applications in tissue
      engineering.
AB  - Rapid and efficient cell sorting methods are important for tissue progenitor cell
      isolation. We built and evaluated a laboratory prototype of a continuous flow,
      quadrupole magnetic cell sorter. The sorter was tested on a model cell system of
      human peripheral lymphocytes. The helper T cell subpopulation was targeted by
      primary, mouse anti-CD4 monoclonal antibody conjugated to a fluorochrome (FITC),
      and magnetized by secondary, anti-FITC antibody magnetic colloid. The purities
      and recoveries of the cell fractions were measured by flow cytometry and an
      automated cell counter. Cells were spread across the flow according to their
      magnetophoretic mobilities. The purity of the CD4 cell enriched fraction was
      99.6%, and the purity of the CD4 cell depleted fraction was 2% for an initial CD4
      cell purity of 36%; the corresponding recovery of the enriched CD4 cell fraction
      was 59% at a sorting speed of 4,200 cells/s (four experiments). The recovery
      could be increased to 90% with a concomitant decrease in the purity of CD4 cell
      enriched fraction to 66%. This type of sorting should be applicable to any cells
      in suspension for which a suitable antibody exists, in particular, to large,
      fragile cells.

PMID- 10360710
TI  - Replacement of the tracheobronchial bifurcation by a newly developed Y-shaped
      artificial trachea.
AB  - We have previously reported on a straight artificial trachea developed by our
      group that can be applied to the cervical and thoracic trachea. In this study, a
      new Y-shaped artificial trachea was designed and adapted for experimental
      replacement of defective tracheal bifurcations in 20 dogs. The Y-shaped Marlex
      mesh tube was reinforced with a polypropylene spiral and coated with collagen
      made from porcine skin. This coating process makes the prosthesis biocompatible
      and airtight. Replacement of the tracheobronchial bifurcation was performed
      through a right thorachotomy, and omentopexy was added in all 20 dogs. Six of the
      20 dogs have survived. The causes of death of the other 14 dogs were obstruction
      of the main bronchus (one dog), omental necrosis (three dogs), and air leakage
      from the prostheses and suture points (10 dogs). In all six surviving dogs, the
      artificial tracheas are covered with regenerated tissue and there is no evidence
      of stenosis or dehiscence. These results indicate that the prosthesis can be
      effective and safe in the long-term; however, air leakage from the prosthesis is
      a serious complication. Therefore, a better method is needed to make the
      prosthesis airtight to improve the postoperative result.

PMID- 10360711
TI  - The relationship between cardiac output and access flow during hemodialysis.
AB  - Satisfactory hemodialysis access flow (Qa) is necessary for dialysis adequacy.
      However, high access flows are postulated to increase cardiac output (CO). The
      relationship between Qa and CO is not well defined. The purpose of this study was
      to observe the relationship between Qa and CO and to evaluate the effect of blood
      volume change (BVdelta) on Qa and CO during hemodialysis (HD). Measurements of Qa
      and CO (ultrasound dilution; Transonics Monitor, Ithaca, NY) were performed
      sequentially at baseline in 18 patients (13 forearm arteriovenous fistulae, 5
      Gore-Tex grafts) and after an intervention involving either HD with attempted
      zero BVdelta (mean: -0.4%; range: -2.6 to 1.6%) or a significant BVdelta (mean: 
      7.3%; range: -3.1 to -11.9%). Measurement of BVdelta was done by hematocrit
      dilution (Crit-Line Monitor, In-Line Diagnostics, Riverdale, UT). The volume
      ultrafiltered (V(UF)) and the mean arterial pressure (MAP) were recorded at
      baseline and after intervention. In five patients with fistulae, CO was measured
      after manual occlusion of the fistula for 1 min. At baseline, mean (+/-SD) Qa was
      1455+/-600 ml/min, and CO was 6.8+/-1.8 L/min. The relationship between Qa and CO
      was strong, Qa = 0.20 CO + 0.06 (r = 0.62; p = 0.01); this was not significantly
      altered with either intervention. Access flow was not changed with either zero
      BVdelta or significant BVdelta. Cardiac output was not altered when there was no
      BVdelta; however, CO did decrease by 1.2+/-0.6 L/min (p<0.001) after BVdelta
      reduction. The Qa/CO ratio was unchanged after zero BVdelta but was increased
      after BVdelta (p = 0.004). There were no correlations with MAP change or V(UF).
      There were no differences in Qa, CO, or Qa/CO by access type. The mean Qa/CO was
      21+/-6%. Three patients had Qa/CO <15%, and they all had access stenoses. Cardiac
      output did not decrease after transient (1 min) occlusion of the fistula. In
      conclusion, there is a strong relationship between Qa and CO. With BVdelta, the
      Qa is maintained while the CO falls and the Qa/CO increases, perhaps by reflex
      vasoconstriction of the systemic circulation. Longitudinal studies are required
      to determine which is the dependent variable. A low Qa/CO may indicate access
      dysfunction.

PMID- 10360712
TI  - Measurement of blood access flow rate during hemodialysis from conductivity
      dialysance.
AB  - An on line clearance monitor automated for measurements of conductivity
      dialysance (Dcn) was used to measure blood access flow rate (cnQac) during
      hemodialysis. From mathematical analysis of transport, it was shown that cnQacc =
      [(Dcn*Decn)/(Dcn - Decn)] [1/bwf], where Dcn is measured with standard cocurrent
      flow of dialyzer blood (Qb) and Qac; Decn is measured with countercurrent Qb/Qac;
      and bwf is fractional blood water content. An identical equation was derived to
      measure Qac from urea dialysance (uQac, Du, Deu). In vitro studies showed
      excellent correlation between volumetric measurement of Qac (vQac) and cnQac, r =
      0.98, n = 29, and between uQac and cnQac, r = 0.97, n = 28. In vivo studies
      showed comparable agreement between uQac and cnQacc, r = 0.97, n = 14. In two of
      the patients studied, there was unsuspected severe midgraft stenosis (no
      recirculation in cocurrent flow) with a Qac of 89 and 202 ml/min disclosed by
      both cnQac and uQac measurements. Mathematical analysis also showed that when Qb
      is greater than Qac and there is recirculation in cocurrent flow, the above
      equations always return the value Qac = Qb. An equation was derived to calculate
      cnQac without reversal of blood lines in this case, using Dcn calculated from the
      dialyzer transport coefficient and flow rates.

PMID- 10360713
TI  - Intervention based on monthly monitoring decreases hemodialysis access
      thrombosis.
AB  - We randomized 103 patients (68 arteriovenous [AV] fistulas, 35
      polytetrafluoroethylene [PTFE] grafts; mean follow-up 197 days) to monthly
      measurement of access flow (QAT), monthly measurement of static venous pressure
      (VPS), or no monthly monitoring (control patients) to determine whether access
      thrombosis would decrease. Patients with access flow <750 cc/min or with static
      venous pressure > or =0.5 were referred for angiography and angioplasty of
      stenotic lesions > or =50%. Six of sixty-two (9.7%) of monthly monitored patients
      (MM) developed access thrombosis vs. 9 of 41 (22%) of control patients (p<0.05).
      Fewer MM patients developed thrombosis in AV fistulas (2.4% [2 of 42] vs. 15.4%
      [4 of 26] control patients; p<0.05). Monthly monitored patients had fewer
      thrombotic episodes than control patients (19 vs. 125 per 100 patient-years;
      p<0.01). Thrombosis rates were lowest in patients receiving monthly access flow
      measurement (5.9 [QAT] vs. 30.3 per 100 patient-years [VPS]; p<0.05). In
      conclusion, intervention based on monthly access flow measurement or static
      venous pressure decreased hemodialysis access thrombosis. Measurement of access
      flow tended to result in lower thrombosis rates than after static venous
      pressure. We believe that monthly access flow measurement will ensure the lowest
      incidence of thrombosis and decrease the cost of access maintenance.

PMID- 10360714
TI  - Duocart biofiltration: a new method of hemodialysis.
AB  - DuoCart biofiltration (DCB) is a new hemodialysis method using a dialysate with
      only sodium chloride and bicarbonate obtained from two separate powder cartridges
      (BiCart and SelectCart, Gambro, Sweden). The ionic complement is directly
      reinfused in postdilution mode, using one 2 L bag of a specially designed sterile
      solution. The adaptation of the quantity of these infused substances to their
      removal through the dialysis membrane is made possible by repeated measurements
      of ionic dialysance (D), which are automatically performed every 30 min by the
      Diascan module, systematically available on the Integra dialysis monitor (Hospal,
      Italy), and by subsequent modification of the infusion rate (Q(R)). An
      appropriate kinetic model was used to determine the composition of the reinfusion
      solution (mM: 57 K, 47 Ca, 14.5 Mg, 180 Cl), the conductivity dialysate (set at
      14.8 mS/cm) and the ratio Q(R)/D (set at 1/28). This ratio is kept constant by
      updating Q(R) after each measurement of D. The implementation of this technique
      requires an Integra dialysis monitor equipped with a two-powder-cartridge
      dialysate generation system. Fifteen dialysis sessions were performed (duration:
      213+/-38 min; blood flow: 238+/-26 ml/min; ultrafiltration rate: 16+/-6 ml/min).
      The per-dialytic changes of ion plasma concentrations were monitored and found to
      be within the predicted range. The results substantiate the feasibility of this
      new hemodialysis method that presents several advantages: dialysate concentrates
      are in powder form, an alkaline and acetate-free dialysate is used with superior
      dialysate biocompatibility, no precipitation of Ca and Mg carbonate occurs in the
      dialysate circuit, the supply of calcium and potassium is easily adapted to
      individual patients' needs by change in the composition of the reinfusion
      solution, and a calcium-free dialysate that facilitates citrate anticoagulation
      is used.

PMID- 10360716
TI  - Ventricular radius reduction without resection: a computational analysis.
AB  - Reducing a dilated left ventricle's radius by wedge resection lowers wall stress,
      improving performance. However, compliance falls, stroke volume improvement is
      limited, and, later, both functional deterioration and serious dysrhythmias are
      frequent. These all may result from loss of circumference, loss of contractile
      mass, and myocardial trauma, none of which would occur in geometric remodeling.
      One specific technique is bimeridianal restraint, which uses two indenting bars
      to remodel the left ventricle (LV) as two widely communicating "lobes" of reduced
      radius. Computational analysis of this technique, applied to the dilated
      ventricular dimensions of four pretransplant patients, showed that 20% radius
      reduction would be accomplished by two < or =18 mm wide bars, indenting the
      epicardium < or =8.3 mm with < or =6.4 mm greatest outward displacement.
      Projected stroke volume (SV) for the subject ventricles was then modeled and
      compared with projections for resected ventricles. Assuming that equally improved
      contractile fraction will follow equal radius reduction, however that reduction
      is accomplished, improvement is dramatic: if postresection remodeling SV were
      1.0, 1.2, or 1.5 times baseline, then postgeometric remodeling SV would be 1.36+/
      0.06, 1.66+/-0.05, or 2.14+/-0.04 times baseline, respectively. These results,
      preservation of contractile mass and circumferential length, complete
      reversibility, and minimal operative trauma, warrant study of implementing
      mechanical designs.

PMID- 10360715
TI  - A new sterile bicarbonate dialysis solution for use during cardiopulmonary
      bypass.
AB  - Adding a dialysis filter to the perfusion circuit at the end of cardiopulmonary
      bypass (CPB) has become an accepted means of reducing potassium rapidly and
      safely. Rapid removal of solute requires a dialysate for diffusion, and
      peritoneal dialysis solutions have been the standard because of availability,
      although occasionally normal saline or bicarb/ saline mixtures are used.
      Cardioplegia solution is high in glucose as well as potassium and, with many
      diabetic patients undergoing CPB, it is desirable to minimize glucose loads. In
      this prospective cohort study, six patients received a commercially available
      sterile bicarbonate dialysate prepared in a point of care fashion. From the
      cardiovascular data base, four control patients (receiving lactate based dialysis
      solution during CPB) were matched for age, surgery type, body surface area (BSA),
      and pump duration for each of the six patients receiving bicarbonate dialysate.
      All of the control patients were dialysed against lactate buffered peritoneal
      dialysis solution. Plasma levels of potassium, glucose, and bicarb were measured
      before and after dialysis for each dialysate. Plasma potassium, glucose, and
      bicarb were not significantly different at start of dialysis. The lactate
      dialysate (LD) group received a mean of 17.4+/-7.7 L of lactate containing
      dialysate versus 14.6+/-4.7 L of bicarbonate dialysate (BD) (p = 0.41). After
      dialysis, potassium had been reduced to a similar degree in both groups, but
      plasma glucose levels had increased during LD while they fell during BD, and
      bicarbonate levels fell during LD while they rose during BD. Use of a
      commercially available sterile bicarbonate dialysate can safely help to lower
      plasma potassium during CPB and preserve more physiologic levels of glucose and
      bicarbonate.

PMID- 10360717
TI  - Estimation of timing errors for the intraaortic balloon pump use in pediatric
      patients.
AB  - The use of the intraaortic balloon pump (IABP) for managing acute left
      ventricular failure in pediatric patients is less successful than in adults. It
      is often reported that rapid pediatric heart rates make accurate timing difficult
      to achieve. Traditional IABP theory requires that the balloon inflate during
      diastole (after aortic valve closure), for optimum coronary pressure and flow
      augmentation, and deflate just before the next systole for optimal ventricular
      afterload reduction. Errors in timing balloon inflation and deflation may result
      in the reduced IABP efficacy seen in children. To investigate timing errors when
      using the traditional IABP inflation and deflation markers in pediatric patients,
      six patients (age, 2.2+/-1.4 years; weight, 11.5+/-3.9 kg) were studied
      intraoperatively. Radial artery pressure (RAP) waveforms from a standard, fluid
      filled pressure monitoring system were recorded on an FM data tape recorder
      simultaneously with high-fidelity, aortic root pressure waveforms, aortic root
      flow waveforms, and M-mode echocardiography. For each patient, a sequence of five
      recorded waveforms was analyzed. The mean +/- standard deviation of the time
      delay between aortic root and RAP markers and percentage delay of the
      corresponding part of the cardiac cycle were determined. When compared with
      aortic root waveforms, the RAP waveform consistently showed a delay in the IABP
      timing markers. A 107+/-23 msec (53+/-11%) delay in diastolic inflation and a
      92+/-11 msec (40+/-4%) delay in presystolic deflation was found. If IABP timing
      to the RAP markers were to be used, the delay in IABP inflation would result in
      reduced diastolic augmentation, and the delay in IABP deflation into the systolic
      period would increase afterload. M-mode echocardiography provided timing markers
      that were identical to those provided by high-fidelity aortic root pressure
      waveforms. The combined effect of these delays on IABP function could
      substantially reduce the efficacy of the IABP in pediatric patients, indicating
      the need for more accurate indices for IABP timing in this patient group.

PMID- 10360719
TI  - Muscle powered blood pump: design and initial test results.
AB  - A pneumatic ventricular assist device (Sarns/3M) has been redesigned for low
      volume hydraulic actuation to accommodate muscle powered drive systems. Design
      modifications include adding a bellows/piston mechanism (to compress the blood
      sac) and a compliance chamber for volume compensation. A simple prototype device
      was constructed to measure the efficacy of piston pump actuation and to validate
      pusher plate design. Device manufacture was affected by removing the drive line
      housing from the pneumatic pump and replacing it with a piston/bushing mechanism.
      A convex piston profile was chosen to maximize ejection fraction and minimize
      device size. Stroke volume was found to be a linear function of piston
      displacement (approximately 3 ml/mm) and reached a maximum value of 45 ml. Mean
      compression forces of 46-56 N acting during a 12 mm stroke (2.1 L/min at 60
      cycles/min) were sufficient to generate mean afterload pressures of 70-110 mm Hg
      in a mock circulatory loop. Peak compression forces ranged from 72 to 86 N and
      work input was calculated to be 552-672 mJ/stroke. These data indicate that this
      method for delivering muscle power to the bloodstream is both mechanically viable
      and compatible with the functional capacity of conditioned latissimus dorsi
      muscle.

PMID- 10360718
TI  - A genetically engineered, nonthrombogenic cellular lining for LVADs: in vitro
      preconditioning before in vivo implantation.
AB  - Because of the clinical success of left ventricular assist devices (LVADs) used
      for short-term "bridge to transplant" and the limited availability of donor
      organs, heart assist devices are being considered for long-term implantation as
      an alternative to heart transplantation. In an effort to improve
      biocompatibility, our laboratory has developed a nonthrombogenic cellular lining
      from genetically engineered smooth muscle cells (GE-SMC) for the
      Thermocardiosystems Heartmate LVAD. Smooth muscle cells have been transduced with
      the gene for endothelial nitric oxide synthase (NOS III) and produce NO at
      concentrations that reduce platelet deposition and smooth muscle cell
      proliferation when tested in vitro. In this investigation, the adhesive
      capabilities of GE-SMC linings were examined. An in vitro circulatory loop was
      designed to expose cell lined LVADs to in vivo operating conditions. Cumulative
      cell loss from cell lined LVADs was less than 10% after 24 hours of flow. Using a
      protocol for "preconditioning" the cell lining within the mock circulatory loop,
      the first implantation of an LVAD containing a genetically engineered SMC lining
      was successfully implemented in a bovine model. Results from this 24 hour study
      indicate that the flow-conditioned cellular lining remained intact with no
      evidence of thromboembolization and only minimal changes in coagulation studies.

PMID- 10360720
TI  - Chronic animal health assessment during axial ventricular assistance: importance
      of hemorheologic parameters.
AB  - Chronic testing of the Nimbus/UOP Axial Flow Pump was performed on 22 calves for
      periods of implantation ranging from 27 to 226 days (average, 74 days). The
      following parameters were measured: plasma free hemoglobin, blood and plasma
      viscosity, erythrocyte deformability and mechanical fragility, oxygen delivery
      index (ODI), blood cell counts, hematocrit, hemoglobin, blood urea nitrogen,
      creatinine, bilirubin, total protein, fibrinogen, and plasma osmolality. Most of
      the above parameters were stable during the full course of support. Compared with
      baseline, statistically significant differences during the entire period of
      implantation were only found in: hematocrit (p<0.001), hemoglobin (p<0.005), red
      blood cell (RBC) count (p<0.001), and whole blood viscosity (p<0.01). Plasma
      viscosity and ODI were mostly stable during the period of implantation. In some
      animals, an acute increase in fibrinogen concentration, plasma and blood
      viscosity, and a decrease in ODI were found to be early signs of the onset of
      infection. A small (10%) decrease in deformability of RBCs was found during the
      first 2 weeks after implantation. This alteration in RBC deformability was highly
      correlated (r = 0.793) with changes in total plasma protein concentration that
      fell more than 15% (p<0.001) during the same period. Mechanical fragility of RBCs
      was found to be slightly increased after implantation. Plasma free hemoglobin
      remained close to baseline level (p>0.2). After the first 2 weeks of the
      postoperative period, pump performing parameters for all animals were consistent
      and stable. In general, the Nimbus/UOP Axial Flow Pump demonstrated basic
      reliability and biocompatibility and did not produce significant alterations in
      the mechanical properties of blood or animal health status. The pump provided
      adequate hemodynamics and was well tolerated by the experimental animal for
      periods as long as 7.5 months. Monitoring rheologic parameters of blood is very
      helpful for evaluation of health during heart-assist device application.

PMID- 10360721
TI  - Steady state hemodynamic and energetic characterization of the Penn State/3M
      Health Care Total Artificial Heart.
AB  - Total Artificial Heart (TAH) development at Penn State University and 3M Health
      Care has progressed from design improvements and manufacturing documentation to
      in vitro and in vivo testing to characterize the system's hemodynamic response
      and energetic performance. The TAH system is completely implantable and intended
      for use as an alternative to transplantation. It includes a dual pusher plate
      pump and rollerscrew actuator, welded electronics and battery assembly,
      transcutaneous energy transmission system, telemetry, and a compliance chamber.
      In vitro testing was conducted on a Penn State mock circulatory loop with
      glycerol/water solution at body temperature. Tests were performed to characterize
      the preload and afterload response, left atrial pressure control, and power
      consumption. A sensitive preload response was demonstrated with left atrial
      pressure safely maintained at less than 15 mm Hg for flow rates up to 7.5 L/min.
      Variations in aortic pressure and pulmonary vascular resistance were found to
      have minimal effects on the preload sensitivity and left atrial pressure control.
      In vivo testing of the completely implanted system in its final configuration was
      carried out in two acute studies using implanted temperature sensors mounted on
      the electronics, motor, and energy transmission coil in contact with adjacent
      tissue. The mean temperature at the device-tissue interface was less than 4
      degrees C above core temperature.

PMID- 10360722
TI  - A remote monitoring system for patients with implantable ventricular assist
      devices with a personal handy phone system.
AB  - The usefulness of a remote monitoring system that uses a personal handy phone for
      artificial heart implanted patients was investigated. The type of handy phone
      used in this study was a personal handy phone system (PHS), which is a system
      developed in Japan that uses the NTT (Nippon Telephone and Telegraph, Inc.)
      telephone network service. The PHS has several advantages: high-speed data
      transmission, low power output, little electromagnetic interference with medical
      devices, and easy locating of patients. In our system, patients have a mobile
      computer (Toshiba, Libretto 50, Kawasaki, Japan) for data transmission control
      between an implanted controller and a host computer (NEC, PC-9821V16) in the
      hospital. Information on the motor rotational angle (8 bits) and motor current (8
      bits) of the implanted motor driven heart is fed into the mobile computer from
      the implanted controller (Hitachi, H8/532, Yokohama, Japan) according to 32-bit
      command codes from the host computer. Motor current and motor rotational angle
      data from inside the body are framed together by a control code (frame number and
      parity) for data error checking and correcting at the receiving site, and the
      data are sent through the PHS connection to the mobile computer. The host
      computer calculates pump outflow and arterial pressure from the motor rotational
      angle and motor current values and displays the data in real-time waveforms. The
      results of this study showed that accurate data on motor rotational angle and
      current could be transmitted from the subjects while they were walking or driving
      a car to the host computer at a data transmission rate of 9600 bps. This system
      is useful for remote monitoring of patients with an implanted artificial heart.

PMID- 10360723
TI  - Recent progress in the development of Terumo implantable left ventricular assist
      system.
AB  - The research group of the Terumo Corporation, the NTN Corporation, and Setsunan
      University (T. Akamatsu) has been developing an implantable left ventricular
      assist system (ILVAS) featuring a centrifugal blood pump with a magnetically
      suspended impeller (MSCP). The impeller of the MSCP is suspended by a magnetic
      bearing, providing contact-free rotation of the impeller inside the pump housing.
      Thus the MSCP is expected to provide years of long-term durability. Ex vivo
      chronic sheep experiments using the extracorporeal model (Model I) demonstrated
      long-term durability, nonthrombogenicity, and a low hemolysis rate (plasma free
      Hb <6 mg/dl) for more than 2 years. The prototype implantable model (Model II;
      196 ml, 400 g) was evaluated ex vivo in 2 sheep and intrathoracically implanted
      in a small sheep (45 kg). These experiments were terminated at 70, 79, and 17
      days, respectively, because of blood leakage through the connector system within
      the housing of Model II. There was no thrombus formation on the retrieved pump
      surfaces. A new connector system was introduced to the Model II pump (modified
      Model II), and the pump was intrathoracically implanted in a sheep. Pump flow
      rate was maintained at 3-7 L/min at 1700-1800 rpm. The temperature elevation on
      the surfaces of the motor and the electromagnet inside the pump casing was kept
      less than 6 degrees C. The temperature of the tissue adjacent to the pump casing
      became normal 10 days postoperatively. The sheep survived for more than 5 months
      without any sign of mechanical failure or thromboembolic complication. In vitro
      real-time endurance tests of motor bearings made of stainless steel and silicone
      nitride have been conducted for more than 1 year without any sign of bearing
      wear. The next prototype system (Model III), with an implantable controller and a
      new MSCP with reduced input power, has been developed with a view toward a
      totally implantable LVAS.

PMID- 10360724
TI  - Electric analog model of the aortic valve for calculation of continuous beat-to
      beat aortic flow using a pressure gradient.
AB  - The objective was to develop a technique for calculating continuous, beat-to-beat
      aortic flow (AoF) using only left ventricular pressure (LVP) and aortic pressure
      (AoP). An electric analog model of the aortic valve was developed that includes
      resistance (R), inertance (L), and compliance (C) parameters, and resulting
      second order differential equations were derived. Aortic flow, AoP, and LVP
      recorded in eight subjects during a 5 day period and during lower body negative
      pressure (LBNP) were used to validate the model. Resistance, L, and C were
      estimated using a least-squares fit to the measured AoF on day 0 and during 0 mm
      Hg LBNP. For days 1-4, AoF was calculated using measured values of AoP and LVP
      and the R, L, and C values from day 0. Similarly, for LBNP, AoF was calculated
      using measured values of AoP and LVP, and the R, L, and C values from 0 mm Hg
      LBNP. The calculated and measured AoF were compared. Differences in cardiac
      output between the calculated and measured flows were less than 13.1+/-17% across
      days and under minor altered physiologic conditions (LBNP). Waveform morphology
      for the calculated AoF also agreed well with the measured AoF. Spectral analysis
      showed differences in magnitude and phase between measured and calculated aortic
      flow for the first five harmonics across days, less than 20+/-6% and 25+/-14
      degrees, respectively. Preliminary evaluation indicates that our model works well
      for calculating flow through a biologic valve using LVP and AoP. We speculate
      that it may perform better for a mechanical valve, and if so it may be possible
      to develop an instrumented mechanical valve capable of continuous LVP, AOP, and
      AoF measurements.

PMID- 10360725
TI  - Biomembrane mimicry provides improved thromboresistance for total artificial
      hearts.
AB  - Thromboembolic events remain a significant issue in mechanical circulatory
      support. The aim of this study was to evaluate the potential benefit of surface
      modification in total artificial hearts (TAHs) using polymeric phospholipids
      (biomembrane mimicry). For this purpose, pneumatic TAHs (vacuum formed pellethane
      housing, hard double flap hinged inflow valves, soft trileaflet polyurethane
      outflow valves) had their blood-exposed surfaces either modified with polymeric
      phospholipids or unmodified before evaluation in bovine experiments. Orthotopic
      implantation of the TAHs was performed with cardiopulmonary bypass (CPB) using
      tip-to-tip heparin surface coated perfusion equipment and very low systemic
      heparinization (50 IU/kg bodyweight). After weaning from CPB and stabilizing
      hemodynamics, circulating heparin was neutralized with protamine (1:1). All
      animals were totally supported for 24 hours before elective sacrifice. No heparin
      was added at any time during support. Mean activated coagulation time (ACT) was
      167+/-24 s at baseline before heparinization for CPB, 330+/-45 s at the end of
      CPB, 181+/-25 s after 1 hour of support, 180+/-31 s after 6 hours, and 185+/-28 s
      after 18 hours. After explantation, the TAHs perfused without anticoagulation
      were carefully analyzed. Atrial cuff coverage with red clot was 30+/-21% for
      artificial surfaces modified by biomembrane mimicry versus 100+/-0% for standard
      control surfaces (p<0.01). The number of macroscopic deposits found on the inflow
      valves was 1.33+/-0.47 for surfaces modified by biomembrane mimicry versus 3.83+/
      1.86 for standard control surfaces (p<0.05). Likewise, on the outflow valves the
      number of macroscopic deposits was 0.00+/-0.00 for surfaces modified by
      biomembrane mimicry versus 1.00+/-0.81 for standard control surfaces (p<0.05). We
      conclude that presence and distribution of red clots and other macroscopic
      deposits are significantly different for artificial surfaces with biomembrane
      mimicry versus standard control surfaces. Application of the biomembrane mimicry
      concept has the potential to provide improved TAHs.

PMID- 10360726
TI  - In vivo experiment leading to clinical application of an electrohydraulic
      ventricular assist device with magnetic coupling.
AB  - We developed an electrohydraulic ventricular assist device with magnetic
      coupling. The integrated system consists of a blood pump, a water conduit for
      pressure transmission, a bellows type pumping sac, an actuator for transforming
      the circular motion of a motor to the linear motion of a pusher plate attached to
      the pumping sac with magnetic coupling, and a controller. The purpose of the
      coupling was to prevent excessive sucking against the atrial wall. Number 21
      Medtronic Hall (Irvine, CA) mechanical valves were used in the inflow and outflow
      ports of the blood pump. Maximum dynamic stroke volume was 48 ml, and against a
      mean afterload of 100 mm Hg, maximum pump output was 7 L/min. Chronic in vivo
      experiments were performed in three sheep, and during these evaluations the
      system showed no noticeable problems related to mechanical or electronic devices.
      When left atrial pressure decreased below 0 mm Hg, the magnetic coupling system
      decoupled the pumping sac and pusher plate with satisfactory reliability. The
      device was clinically applied in a postoperative patient with chronic dilating
      cardiomyopathy, and no significant device related problems ensued. These results
      prove that the electrohydraulic ventricular assist system with magnetic coupling
      is a suitable ventricular assist device.

PMID- 10360727
TI  - Quality of life outcomes in left ventricular assist system inpatients and
      outpatients.
AB  - This study empirically evaluates the quality of life (QOL) effects associated
      with hospital discharge among heart transplant candidates whose lives are
      maintained by left ventricular support systems (LVAS). Thirty-five LVAS
      inpatients (18 Novacor, 17 Thoratec) received structured QOL assessments
      approximately 1 month after device implant. Ten of the patients (8 Novacor, 2
      Thoratec) were subsequently discharged to either home or a home-like outpatient
      facility where their QOL was reassessed. The QOL of LVAS patients, before and
      after discharge, was compared with that of demographically similar
      nonhospitalized heart transplant candidates (n = 55) and recipients (n = 97).
      Their caregivers' QOL was also assessed. The QOL of LVAS outpatients showed
      statistically significant (p<0.05) advantages over remaining LVAS inpatients and
      nonhospitalized heart candidates. Advantages appeared in physical, emotional, and
      social functioning domains. The QOL of LVAS outpatients also improved (p<0.05)
      over their own QOL before discharge, with the greatest change in physical
      functional and emotional status. The QOL of LVAS outpatients most closely
      resembled QOL in the transplant recipients. Family caregivers to LVAS outpatients
      reported some increases in caregiving burden after patient discharge, but their
      overall well being was not adversely affected. These data provide an empiric
      basis for the provision of outpatient programs as appropriate care for eligible
      LVAS patients.

PMID- 10360728
TI  - Observations: Risk, reason, and regulation in contemporary medical devices.

PMID- 10360730
TI  - Evaluation of microparticles released from an adsorber used for low density
      lipoprotein apheresis.

PMID- 10360729
TI  - Intensive tandem cryofiltration apheresis and hemodialysis to treat a patient
      with severe calciphylaxis, cryoglobulinemia, and end-stage renal disease.
AB  - This is the first report on tandem cryofiltration apheresis (CFA) and
      hemodialysis (HD). A 44 year old white man with Type II mixed cryoglobulinemia,
      hepatitis C virus (HCV), severe skin lesions, and end-stage renal disease (ESRD)
      on maintenance hemodialysis was air-transferred for CFA, which is only available
      at our medical center. The patient failed to respond to high dose steroids,
      immunosuppression, intravenous immunoglobulin (IVIG), and plasma exchange for the
      treatment of his cryoglobulinemia, and he failed alpha-interferon therapy for his
      HCV. On arrival, he was also found to have severe calciphylaxis secondary to ESRD
      with generalized, painful skin ulceration, necrosis, and penile gangrene. To
      treat both conditions, intensive, tandem CFA/HD was initiated. He received
      extensive wound care and surgical debridement. To prevent pressure ulcers and
      worsening of skin lesions, he was placed on the FluidAir (Kinetic Concepts Inc.,
      San Antonio, TX) controlled air bed. The patient received 18 tandem CFA/HD
      treatments, and four extra HD treatments in one month. Sodium citrate was used as
      an anticoagulant for the CFA procedure. His plasma cryoglobulin (CG) level
      dropped from 6,157 to 420 microg/ml, and his calciphylaxis also improved. The CFA
      effectively removed 93% of CG, without significant removal of IgG, IgM, IgA,
      albumin, and fibrinogen. No albumin or fresh frozen plasma (FFP) was required as
      replacement fluid for CFA. No citrate toxicity or evidence of complement
      activation with the cryofilter was observed. The entire CFA procedure time
      (3(1/2) hours) was considered. Intensive, tandem CFA/HD was performed in a
      critically ill patient with no apparent adverse consequences.

PMID- 10360731
TI  - Evaluation of microparticles released from an adsorber used for low density
      lipoprotein apheresis.

PMID- 10360732
TI  - trans-2,6-,3,6- and 4,6-diaza-5,6,6a,7,8,12b-hexahydro-benzo[c]phenanthrene-10,11
      diols as dopamine agonists.
AB  - The title compounds were synthesized by replacing the thiophene moiety of A
      86929(2a) with variously substituted pyridines. Dopamine D-1 and D-2 binding and
      adenylate cyclase assays indicate that 4,6-diaza compounds 15 are potent and
      selective full D1 agonists when R1 is H or a small substituent and R2 = H, with
      D1 binding affinity and adenylate cyclase functional potency equivalent to that
      of A-86929(2a).

PMID- 10360733
TI  - A highly stereoselective synthesis of plaunotol and its thiourea derivatives as
      potent antibacterial agents against Helicobacter pylori.
AB  - Practical and highly stereoselective synthesis of diterpene alcohol, plaunotol
      (1) and its thiourea derivatives 2a, 3a and 4a, via Z-selective Wittig reaction
      between alpha-acetal ketone 5 and phosphonium salt 6 and their antibacterial
      activity against Helicobacter pylori are described.

PMID- 10360734
TI  - A novel molecular design of thrombin receptor antagonist.
AB  - In a computer modeling of transmembrane domains of human thrombin receptor, Lys
      158 was found near the ligand binding site. To capture this basic residue,
      analogs of peptide ligand containing a series of acidic amino acids were
      synthesized and assayed for human platelet aggregation, and Ser-(p-F)Phe-Aad(=
      alphaaminoadipic acid)-Leu-Arg-Asn-Pro-NH2 was found to be a potent antagonist.

PMID- 10360735
TI  - Low-molecular-weight anti-HIV-1 peptides from the amino-terminal sequence of
      RANTES: possible lead compounds for coreceptor-directed anti-HIV-1 agents.
AB  - A series of small peptides corresponding to the amino-terminal sequence of RANTES
      were synthesized, and their anti-HIV-1 activity was evaluated. Pentapeptides, H
      (10Ala-RANTES 6-10)-OH and Ac-(10Ala-RANTES 6-10)-NH2, were the smallest anti-HIV
      1 peptides so far developed, and would be potentially important lead compounds
      for coreceptor-directed anti-HIV-1 drugs.

PMID- 10360736
TI  - S1319: a novel beta2-andrenoceptor agonist from a marine sponge Dysidea sp.
AB  - In the course of screening of potential leads for beta2-receptor agonists, we
      found a novel beta2-adrenoceptor selective agonist, S1319, from a marine sponge
      Dysidea sp. The active compound was isolated and structurally characterized as 4
      hydroxy-7-[1-(1-hydroxy-2-methylamino)ethyl]-1,3-benzothiazole-2(3H)-o ne, a new
      member of the beta2-adrenoceptor agonist. This is the first example of a sponge
      derived beta2-adrenoceptor agonist.

PMID- 10360737
TI  - Methionyl adenylate analogues as inhibitors of methionyl-tRNA synthetase.
AB  - Four stable analogues of methionyl adenylate (3-6) were designed as inhibitors of
      methionyl-tRNA synthetase and synthesized from 2',3'-isopropylideneadenosine.
      They strongly inhibited aminoacylation activity of methionyl-tRNA synthetases
      isolated from Escherichia coli, Mycobacterium tuberculosis, Saccharomyces
      cerevisiae and human. Among the microorganisms tested, however, these chemicals
      showed the growth inhibition effect only on E. coli.

PMID- 10360738
TI  - Synthesis and protein kinase C binding activity of benzolactam-V7.
AB  - Benzolactam-V7 (3a), a simplified analogues of (-)-indolactam-V with twist-form
      conformation, was synthesized and evaluated as a new protein kinase C modulator.
      Both 3a and its-7-substituted analogue 3c showed weak binding activity to
      displace PDBU binding from recombinant PKCalpha.

PMID- 10360739
TI  - Acyl-CoA: cholesterol acyltransferase inhibitory activity of ginseng sapogenins,
      produced from the ginseng saponins.
AB  - Ginseng sapogenins were produced from ginseng saponins, isolated from Korean
      ginseng roots. Ginseng saponins very mildly inhibited acyl-CoA:cholesterol
      acyltransferase (ACAT) in vitro, however, the sapogenins showed strong inhibitory
      activity on microsomal ACAT. Therefore, the sapogenins will be one of key
      ingredients of ginseng affected a lowering of the serum total cholesterol level.

PMID- 10360740
TI  - N-substituted-3-arylpyrrolidines: potent and selective ligands at serotonin 1A
      receptor.
AB  - 3-Arylpyrrolidines are synthesized through the coupling of N-benzyl-3
      (methanesulfonyloxy)pyrrolidine with diarylcuprates. Pharmacological evaluation
      of a series of N-substituted-3-arylpyrrolidines toward several neurotransmitter
      receptors indicated that some of them are good ligands for serotonin 1A receptor.
      Particularly, N-[(N-saccharino)butyl]pyrrolidines were found to be potent and
      selective ligands. A preliminary biological evaluation for several selected
      compounds indicated that they are potentially effective antianxiety and
      antidepressant agents.

PMID- 10360741
TI  - Efficient inhibition of muscle and liver glycogen phosphorylases by a new
      glucopyranosylidene-spiro-thiohydantoin.
AB  - Reaction of C-(1-bromo-1-deoxy-beta-glucopyranosyl)formamide 2 with thiocyanate
      ions was the key step of a short synthesis of D-glucopyanosylidene-spiro
      thiohydantoin 7 which proved to be a potent inhibitor of muscle and liver
      glycogen phosphorylases.

PMID- 10360742
TI  - Short synthesis and anti-rhinoviral activity of imidazo[1,2-a]pyridines: the
      effect of acyl groups at 3-position.
AB  - Various 2-amino-3-acyl-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]-imidazo[1 ,2
      a]pyridines, structurally related to Enviroxime were prepared to determine the
      effect of acyl groups on the anti-rhinoviral activity. A short and efficient
      means for the construction of the imidazo nucleus as well as biological
      evaluation of the final compounds are disclosed.

PMID- 10360743
TI  - Novel fluorogenic substrates for acid phosphatase.
AB  - Fluorinated versions of fluorescein diphosphate (FDP) can provide significantly
      enhanced fluorescence upon hydrolysis by acid phosphatase, as compared with FDP,
      when measured at the reaction pH.

PMID- 10360745
TI  - Piperidine-renin inhibitors compounds with improved physicochemical properties.
AB  - Piperidine renin inhibitors with heterocyclic core modifications or hydrophilic
      attachments show improved physical properties (lower lipophilicity, improved
      solubility). Tetrahydroquinoline derivative rac-30 with a molecular weight of 517
      and a log D(pH 7.4) of 1.9 displays potent and long lasting blood pressure
      lowering effects after oral administration to sodium depleted conscious
      marmosets.

PMID- 10360744
TI  - Substituted piperidines--highly potent renin inhibitors due to induced fit
      adaptation of the active site.
AB  - The identification, synthesis and activity of a novel class of piperidine renin
      inhibitors is presented. The most active compounds show activities in the
      picomolar range and are among the most potent renin inhibitors ever identified.

PMID- 10360746
TI  - Design, synthesis and structure-activity relationships of novel strychnine
      insensitive glycine receptor ligands.
AB  - The in vitro activities of 3-hydroxy-imidazolidin-4-one derivatives demonstrated
      very restricted structure-activity relationships at the strychnine-insensitive
      glycine site of the NMDA receptor. The most active compound (3a) was completely
      unsubstituted and exhibited affinity and efficacy similar to that of D
      cycloserine, the prototypical partial agonist at this site.

PMID- 10360747
TI  - Competitive inhibition of a glutamate carboxypeptidase by phosphonamidothionate
      derivatives of glutamic acid.
AB  - Several N-thiophosphonyl-glutamates were found to be potent competitive
      inhibitors of a zinc-dependent glutamyl hydrolase, carboxypeptidase G (CPG). Weak
      inhibition exhibited by an analogous N-phosphonyl-glutamate suggests that the
      enhanced potency of the phosphonamidothioates is due to the presence of their
      sulfur ligand and its favorable interactions with active site features,
      presumably zinc(II).

PMID- 10360748
TI  - Enhancing solid phase synthesis by a noncovalent protection strategy-efficient
      coupling of rhodamine to resin-bound peptide nucleic acids.
AB  - Resins for solid-phase synthesis can affect coupling efficiencies by interacting
      with reactants. We have observed that polyethylene glycol-polystyrene (PEG-PS)
      solid support absorbs added activated fluorophores, preventing efficient labeling
      of peptide nucleic acids (PNAs). We now report that addition of an inexpensive
      unactivated fluorophore blocks the resin and allows efficient labeling. This
      protection strategy may have general benefits for peptide and combinatorial
      synthesis.

PMID- 10360749
TI  - Heterocycle-peptide hybrid compounds. Aminotriazole-containing agonists of the
      thrombin receptor (PAR-1).
AB  - The thrombin receptor PAR-1 is activated by alpha-thrombin to stimulate cells,
      including platelets, through the tethered-ligand sequence SFLLRN. We have
      discovered a novel series of heterocycle-peptide hybrids comprised of a
      tripeptide segment, such as Cha-Arg-Phe, and an N-terminal heterocyclic group,
      many of which behave as full PAR-1 agonists. Certain compounds with an
      aminotriazole group, such as 4 and 16, are nearly as potent as SFLLRN-NH2 in
      inducing platelet aggregation. Also, some arylethenoyl "N-capped" compounds, such
      as 52 and 57, exhibit mixed PAR-1 agonist-antagonist activity.

PMID- 10360750
TI  - Uncarinic acids: phospholipase Cgamma1 inhibitors from hooks of Uncaria
      rhynchophylla.
AB  - Bioactivity-guided fractionation of the CHCl3 extract from hooks of Uncaria
      rhynchophylla led to the isolation of two triterpene esters, namely uncarinic
      acids A (1) and B (2). Their structures were established by spectroscopic and
      chemical methods. These compounds inhibited phospholipase Cgamma1 with IC50
      values of 35.66 and 44.55 microM, respectively.

PMID- 10360751
TI  - Syntheses of (+/-)-shinflavanone and its structural analogues as potent
      inhibitors of bone resorption pits formation.
AB  - The first total syntheses of (+/-)-shinflavanone and its structural analogues
      were achieved. (+/-)-Shinflavanone, appears to be a strong inhibitor of bone
      resorption pits formation by osteoclast-like cell induced by 1alpha, 25-dihydroxy
      vitamine D3 (IC50 = 0.70 microg/mL).

PMID- 10360752
TI  - Asymmetric synthesis of L-azetidine-2-carboxylic acid and 3-substituted congeners
      -conformationally constrained analogs of phenylalanine, naphthylalanine, and
      leucine.
AB  - Enantiopure L-azetidine-2-carboxylic acid, the (3R)-phenyl, (3R)-naphthyl and
      (3S)-isopropyl analogs were prepared based on a zinc-mediated asymmetric addition
      of allylic halides to the camphor sultam derivative of glyoxylic acid O-benzyl
      oxime.

PMID- 10360753
TI  - Phosphofurylalanine, a stable analog of phosphohistidine.
AB  - Phosphorylated histidine residues occur in a number of signal-transduction
      pathways in bacteria as well as in eukaryotes. Phosphohistidine is hydrolytically
      labile and therefore difficult to study, this by contrast to stable
      phosphoserine, phosphothreonine or phosphotyrosine. Here we report the design and
      enantioselective synthesis of (4'-phospho-2'-furyl)alanine 1, a non-hydrolyzable
      analog of 1-phosphohistidine. This novel amino-acid should be useful to
      synthesize peptides incorporating a stable analog phosphohistidine.

PMID- 10360754
TI  - Adenosine-5'-carboxylic acid peptidyl derivatives as inhibitors of protein
      kinases.
AB  - A new class of protein kinase bisubstrate-analog inhibitors was designed on the
      basis of adenosine-5'-carboxylic acid derivatives, where a short peptide was
      attached to the 5'-carbon atom of the adenosine sugar moiety via a linker chain.
      The potency and selectivity of these inhibitors were adjusted by relevant
      combination of these structural fragments, resembling the structure of the
      bisubstrate complex of the peptide phosphorylation reaction.

PMID- 10360755
TI  - P1, P2'-linked macrocyclic amine derivatives as matrix metalloproteinase
      inhibitors.
AB  - A novel series of 13- and 14-membered macrocyclic amines was developed by linking
      the P1 and P2' groups. The synthesis entails stereoselective Frater alkylation to
      install the anti-succinate configuration and macrocyclic amination via
      nucleophilic displacement. This strategy resulted in a new class of
      conformationally constrained inhibitors that are potent and selective for MMP-8
      and 9 over MMP-1 and 3.

PMID- 10360756
TI  - Synthesis and structure-activity relationship of novel glycylcycline derivatives
      leading to the discovery of GAR-936.
AB  - A number of new glycylcyclines were synthesized for structure-activity
      relationship study. Many of the derivatives exhibit potent, broad spectrum
      antibacterial activity against both tetracycline susceptible and resistant
      organisms. GAR-936 (TBG-MINO) shows better activity than the previously reported
      DMG-MINO and DMG-DMDOT.

PMID- 10360757
TI  - The structure-based design and synthesis of selective inhibitors of Trypanosoma
      cruzi dihydrofolate reductase.
AB  - This paper describes the design and synthesis of potential inhibitors of
      Trypanosoma cruzi dihydrofolate reductase using a structure-based approach. A
      model of the structure of the T. cruzi enzyme was compared with the structure of
      the human enzyme. The differences were used to design modifications of
      methotrexate to produce compounds which should be selective for the parasite
      enzyme. The derivatives of methotrexate were synthesised and tested against the
      enzyme and intact parasites.

PMID- 10360758
TI  - Metallopeptide approach to the design of biologically active ligands: design of
      specific human neutrophil elastase inhibitors.
AB  - A series of compounds was designed to inhibit human neutrophil elastase utilizing
      a modified metallopeptide scheme developed in our laboratory termed metal-ion
      induced distinctive array of structures (MIDAS). These metallopeptides,
      synthesized by solution and solid-phase methods, exhibited excellent structural
      diversity and specificity in inhibiting human neutrophil elastase.

PMID- 10360759
TI  - Interleukin-12: amiss in MS.

PMID- 10360760
TI  - Mitochondrial encephalomyopathies: back to Mendelian genetics.

PMID- 10360761
TI  - Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with
      disease activity and characterize different disease stages in multiple sclerosis.
AB  - It has been shown that proinflammatory and antiinflammatory cytokines correlate
      with disease activity in multiple sclerosis (MS). To establish whether such
      correlations depend on the disease stage, we assessed in a longitudinal fashion
      the expression of interleukin (IL)-12 (p40 and p35), tumor necrosis factor-alpha,
      interferon-gamma, and IL-10 mRNA by competitive polymerase chain reaction in
      unstimulated peripheral blood mononuclear cells of relapsing-remitting (RR) and
      secondary progressive (SP) MS patients, in relation to monthly clinical and
      magnetic resonance imaging monitoring. MS patients had increased levels of IL
      12p40 and decreased levels of IL-10 mRNA compared with controls; this difference
      was most pronounced in SP patients. Both RR and SP patients had increased levels
      of IL-12p40 mRNA compared with controls during the development of active lesions.
      Moreover, in RR MS an increase was found before relapse. IL-12p35 mRNA was
      decreased in both groups, and in relation to disease activity it showed a pattern
      different from IL-12p40 mRNA. In RR MS, IL-10 mRNA was low 4 weeks before
      magnetic resonance imaging activity and 6 weeks before relapse; a significant
      increase to normal levels was noted when active lesions became apparent. In
      contrast, SP patients showed low IL-10 mRNA levels constitutively, suggesting
      that IL-10 plays an important role in the control of disease progression.

PMID- 10360762
TI  - From genotype to phenotype: a clinical pathological, and biochemical
      investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the
      P301L tau mutation.
AB  - Frontotemporal dementia is a heterogeneous, often inherited disorder that
      typically presents with the insidious onset of behavioral and personality
      changes. Two genetic loci have been identified and mutations in tau have been
      causally implicated in a subset of families linked to one of these loci on
      chromosome 17q21-22. In this study, linkage analysis was performed in a large
      pedigree, the MN family, suggesting chromosome 17q21-22 linkage. Mutational
      analysis of the tau coding region identified a C-to-T change in exon 10 that
      resulted in the conversion of proline to a leucine (P301L) that segregated with
      frontotemporal dementia in this family. The clinical and pathological findings in
      the MN family emphasize the significant overlap between Pick's disease,
      corticobasal degeneration, and frontotemporal dementia and challenge some of the
      current dogma surrounding this condition. Pathological studies of two brains from
      affected members of Family MN obtained at autopsy demonstrate numerous tau
      positive inclusions that were most prominent in the frontal lobes, anterior
      temporal lobes, and brainstem structures, as well as Pick-like bodies and
      associated granulovacuolar degeneration. These Pick-like bodies were observed in
      1 patient with motor neuron disease. Because exon 10 is present only in tau mRNA
      coding for a protein with four microtubule binding repeats (4R), this mutation
      should selectively affect 4Rtau isoforms. Indeed, immunoblotting demonstrated
      that insoluble 4Rtau is selectively aggregated in both gray and white matter of
      affected individuals. Although there was significant pathological similarity
      between the 2 cases, the pattern of degenerative changes and tau-positive
      inclusions was not identical, suggesting that other genetic or epigenetic factors
      can significantly modify the regional topology of neurodegeneration in this
      condition.

PMID- 10360764
TI  - Apoptotic neurodegeneration following trauma is markedly enhanced in the immature
      brain.
AB  - Age dependency of apoptotic neurodegeneration was studied in the developing rat
      brain after percussion head trauma. In 7-day-old rats, mechanical trauma, applied
      by means of a weight drop device, was shown to trigger widespread cell death in
      the hemisphere ipsilateral to the trauma site, which first appeared at 6 hours,
      peaked at 24 hours, and subsided by 5 days after trauma. Ultrastructurally,
      degenerating neurons displayed features consistent with apoptosis. A decrease of
      bcl-2 in conjunction with an increase of c-jun mRNA levels, which were evident at
      1 hour after trauma and were accompanied by elevation of CPP 32-like proteolytic
      activity and oligonucleosomes in vulnerable brain regions, confirmed the
      apoptotic nature of this process. Severity of trauma-triggered apoptosis in the
      brains of 3- to 30-day-old rats was age dependent, was highest in 3- and 7-day
      old animals, and demonstrated a subsequent rapid decline. Adjusting the
      mechanical force in accordance with age-specific brain weights revealed a similar
      vulnerability profile. Thus, apoptotic neurodegeneration contributes in an age
      dependent fashion to neuropathological outcome after head trauma, with the
      immature brain being exceedingly vulnerable. These results help explain
      unfavorable outcomes of very young pediatric head trauma patients and imply that,
      in this group, an antiapoptotic regimen may constitute a successful
      neuroprotective approach.

PMID- 10360763
TI  - Brainstem mechanisms of autonomic dysfunction in encephalopathy-associated Shiga
      toxin 2 intoxication.
AB  - Acute encephalopathy is the major determinant of death in an early stage of Shiga
      toxin (Stx)-producing Escherichia coli infection. Rapid progress toward
      refractory hypotension and dysfunction of breathing implies autonomic center
      dysfunction of patients. To clarify whether autonomic dysfunction becomes an
      ultimate cause of death in Shiga toxemia, we injected purified Stx2 (20
      microg/kg) intravenously into rabbits, and monitored changes in cardiovascular
      and respiratory function together with renal sympathetic nerve activity (RSNA) in
      the conscious state. After an approximately 24-hour silent (lag) period, all
      rabbits given Stx2 developed hemorrhagic diarrhea (25.7 +/- 1.1 hours) and limb
      paralysis (31.2 +/- 1.3 hours). This limb paralysis was observed initially in the
      hind legs, and then it gradually extended to the forelegs. After 23.2 +/- 2.3
      hours, RSNA increased gradually, and arterial blood pressure was maintained
      within normal limits together with an increase in the maximum gain of baroreflex
      response. Severe hypotension developed within 34.8 +/- 2.2 hours, without any
      increase in heart rate; RSNA significantly increased by 39.5 +/- 0.9 hours. In
      the final stage, RSNA decreased concurrently with decreases in arterial blood
      pressure, heart rate, and baroreflex response, suggesting dysfunction of the
      baroreflex control system. Thereafter, all rabbits died within 47.8 +/- 1.2 hours
      after the intravenous Stx2 injection. Magnetic resonance imagings of the central
      nervous system (T2-weighted images) showed high-intensity areas in the dorsal two
      thirds of the cervical spinal cord and brainstem 48 hours after Stx2
      administration. These results show that the cause of death is circulatory failure
      caused by impairment of the cardiovascular center in the medulla. We believe that
      this animal model helps to clarify the mechanism of rapid progress to death of
      patients with Shiga toxin-producing E. coli infection.

PMID- 10360765
TI  - ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson's disease.
AB  - Studies in animal models show a selective D1 receptor agonist with full
      functional efficacy compared with dopamine to have antiparkinsonian efficacy of
      similar magnitude to levodopa, without the same propensity for inducing
      dyskinesia. To date, no such agent has been tested in humans. ABT-431 is the
      prodrug of A-86929, a full, selective D1 receptor agonist. Subjects (n = 14) with
      levodopa-responsive Parkinson's disease received five doses of ABT-431 (5, 10,
      20, 30, and 40 mg) and one of placebo after a 12-hour levodopa holiday. Response
      was assessed by using the Unified Parkinson's Disease Rating Scale motor
      subsection. Dyskinesia was separately graded. ABT-431 showed efficacy
      significantly superior to placebo at doses of 10 mg and more, and of similar
      magnitude to that seen with levodopa. Dyskinesia was reduced in several patients
      after receiving ABT-431. There were no serious adverse events, the most common
      minor events being nausea and emesis, dizziness, and hypotension. Assuming that
      ABT-431 is not transformed in humans into an unknown active D2 metabolite, and
      remains selective for D1 receptors, it is the first dopamine D1 receptor agonist
      to demonstrate a full antiparkinsonian effect in patients with Parkinson's
      disease. These preliminary findings also suggest that it may exhibit a reduced
      tendency to provoke dyskinesia. The emergence of a well-tolerated D1 agonist
      should allow for the development of a better understanding of the relation
      between motor efficacy and dyskinesia in Parkinson's disease.

PMID- 10360766
TI  - Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex
      genetic disease in Balkan Gypsies: clinical and electrophysiological
      observations.
AB  - During a study of hereditary motor and sensory neuropathy-Lom in Bulgaria, a
      previously unrecognized neurological disorder was encountered, mainly in
      Wallachian Gypsies, who represent a relatively recent genetic isolate. The
      disorder has been termed the congenital cataracts facial dysmorphism neuropathy
      (CCFDN) syndrome to emphasize its salient features. Fifty individuals from 19
      extended pedigrees were identified and examined clinically and
      electrophysiologically. At least 1 patient from each family was admitted to the
      hospital in Sofia for full investigation. Pedigree analysis indicates autosomal
      recessive inheritance. The disorder is recognized in infancy by the presence of
      congenital cataracts and microcorneas. A predominantly motor neuropathy beginning
      in the lower limbs and later affecting the upper limbs develops during childhood
      and leads to severe disability by the third decade. Associated neurological
      features are a moderate nonprogressive cognitive deficit in most affected
      individuals together with pyramidal signs and mild chorea in some. Accompanying
      nonneurological features include short stature, characteristic facial
      dysmorphism, and hypogonadotrophic hypogonadism. Nerve conduction studies suggest
      a hypomyelinating/demyelinating neuropathy, confirmed by nerve biopsy. The CCFDN
      syndrome is thus a pleomorphic autosomal recessive disorder displaying a
      combination of neurological and nonneurological features.

PMID- 10360767
TI  - Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and
      correlation between the number of KpnI repeats at the 4q35 locus and clinical
      phenotype.
AB  - Genotype analysis by using the p13E-11 probe and other 4q35 polymorphic markers
      was performed in 122 Italian facioscapulohumeral muscular dystrophy families and
      230 normal controls. EcoRI-BlnI double digestion was routinely used to avoid the
      interference of small EcoRI fragments of 10qter origin that were found in 15% of
      the controls. An EcoRI fragment ranging between 10 and 28 kb that was resistant
      to BlnI digestion was detected in 114 of 122 families (93%) comprising 76
      familial and 38 isolated cases. Among the unaffected individuals, 3 were somatic
      mosaics and 7, carrying an EcoRI fragment larger than 20 kb, could be rated as
      nonpenetrant gene carriers. In a cohort of 165 patients with facioscapulohumeral
      muscular dystrophy we found an inverse correlation between fragment size and
      clinical severity. A severe lower limb involvement was observed in 100% of
      patients with an EcoRI fragment size of 10 to 13 kb (1-2 KpnI repeats left), in
      53% of patients with a fragment size of 16 to 20 kb (3-4 KpnI repeats left), and
      in 19% of patients with a fragment size larger than 21 kb (>4 KpnI repeats left).
      Our results confirm that the size of the fragment is a major factor in
      determining the facioscapulohumeral muscular dystrophy phenotype and that it has
      an impact on clinical prognosis and genetic counseling of the disease.

PMID- 10360768
TI  - Anti-GalNAc-GD1a antibody-associated Guillain-Barre syndrome with a predominantly
      distal weakness without cranial nerve impairment and sensory disturbance.
AB  - The serum antibodies to N-acetylgalactosaminyl GD1a (GalNAc-GD1a) and other
      gangliosides as well as to Campylobacter jejuni were determined in 147 patients
      with Guillain-Barre syndrome (GBS). We found a distinctive clinical pattern in
      patients with anti-GalNAc-GD1a antibodies compared with those without the
      antibodies, that is, lack of cranial nerve involvement (87% versus 38%), distal
      dominant weakness (80% versus 25%), and no sensory disturbance (73% versus 22%).
      The frequency of distal-dominant weakness was significantly higher in patients
      with both C. jejuni infection and anti-GalNAc-GD1a positivity (100%) than in C.
      jejuni-negative/anti-GalNAc-GD1a-positive (25%), C. jejuni-positive/anti-GalNAc
      GD1a-negative (32%) and C. jejuni-negative/anti-GalNAc-GD1a-negative patients
      (20%). Lack of cranial nerve involvement and sensory disturbance were found in
      most C. jejuni-positive/anti-GalNAc-GD1a-positive and C. jejuni-negative/anti
      GalNAc-GD1a-positive patients, but not in C. jejuni-positive/anti-GalNAc-GD1a
      negative and C. jejuni-negative/anti-GalNAc-GD1a-negative patients. Although the
      anti-GM1-positive/anti-GalNAc-GD1a-negative patients mostly (75%) lacked cranial
      nerve involvement, distal-dominant weakness (38%) and lack of sensory disturbance
      (13%) were infrequent. These results may indicate that (1) the combination of C.
      jejuni infection and anti-GalNAc-GD1a antibodies, but not anti-GalNAc-GD1a, anti
      GM1, or C. jejuni infection alone, is associated with a predominantly distal
      weakness, (2) the presence of anti-GalNAc-GD1a, rather than C. jejuni infection
      or anti-GM1 antibody, is associated with a lack of sensory disturbance, (3) both
      anti-GalNAc-GD1a and anti-GM1 antibodies are independently associated with a lack
      of cranial nerve impairment.

PMID- 10360769
TI  - Decreased striatal monoaminergic terminals in multiple system atrophy detected
      with positron emission tomography.
AB  - We examined the density of striatal presynaptic monoaminergic terminals, using a
      ligand for the type 2 vesicular monoamine transporter, (+)
      [11C]dihydrotetrabenazine, with positron emission tomography in 7 normal control
      subjects, 8 multiple system atrophy (MSA) patients with predominantly
      parkinsonian features (MSA-P), 8 MSA patients with principally cerebellar
      dysfunction (MSA-C), and 6 sporadic olivopontocerebellar atrophy (sOPCA)
      patients. The findings were correlated with the results of neurological
      evaluations and magnetic resonance imaging studies. Specific binding was
      significantly reduced in the putamen of all patient groups in the order MSA-P <
      MSA-C < sOPCA, compared with controls. Mean blood-to-brain ligand transport (K1)
      was significantly decreased in the putamen of all patient groups and in the
      cerebellar hemispheres of MSA-C and sOPCA but not MSA-P groups, compared with
      controls. Significant negative correlations were found between striatal binding
      and the intensity of parkinsonian features and between cerebellar K1 and the
      intensity of cerebellar dysfunction. The results suggest fundamental differences
      between MSA-P and MSA-C groups reflecting differential severity of degeneration
      of nigrostriatal and cerebellar systems in these two forms of MSA. The findings
      also show that some sOPCA patients have subclinical nigrostriatal dysfunction and
      are at risk of developing MSA with disease progression.

PMID- 10360770
TI  - Corticostriatal plasticity is restricted by myelin-associated neurite growth
      inhibitors in the adult rat.
AB  - After unilateral cortical lesions in neonatal rats, the spared unablated
      hemisphere is known to demonstrate remarkable neuroanatomical plasticity in
      corticofugal connectivity. This same type of structural plasticity is not seen
      after similar lesions in adult rats. One possibility for the lack of such a
      plastic response in the adult central nervous system may be the presence of
      myelin-associated neurite growth inhibitory proteins NI-35/NI-250. These proteins
      have previously been found to play a crucial role in preventing axotomized fibers
      from regenerating after adult rat spinal cord lesions. The aim of this study was
      to determine if blocking these inhibitory proteins by the application of the
      specific monoclonal antibody IN-1 would enhance corticostriatal plasticity from
      the spared hemisphere after unilateral cortical lesions in adult rats. Six- to 8
      week-old Lewis rats underwent unilateral aspiration lesion of the sensorimotor
      cortex. Animals were immediately treated with either monoclonal antibody IN-1 or
      a control antibody released from hybridoma cells in Millipore filter capsules.
      After a survival period of 12 weeks, the opposite sensorimotor cortex was
      stereotaxically injected with the anterograde tracer biotinylated dextran amine,
      and biotinylated dextran amine-positive corticostriatal fibers were analyzed. The
      monoclonal antibody IN-1-treated animals showed an increase in corticostriatal
      fibers in the dorsolateral striatum contralateral to the injection site compared
      with control antibody-treated animals or normal controls, indicating a specific
      sprouting response in the deafferented zone. These results support the idea that
      through blockade of myelin-associated neurite inhibitory proteins, lesion-induced
      corticofugal plasticity is possible even in the adult central nervous system.

PMID- 10360771
TI  - Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded
      subunit of complex I.
AB  - Leigh syndrome is the phenotypical expression of a genetically heterogeneous
      cluster of disorders, with pyruvate dehydrogenase complex deficiency and
      respiratory chain disorders as the main biochemical causes. We report the first
      missense mutation within the nuclear encoded complex I subunit, NDUFS7, in 2
      siblings with neuropathologically proven complex I-deficient Leigh syndrome.

PMID- 10360772
TI  - Chromatic sensitive epilepsy: a variant of photosensitive epilepsy.
AB  - We herein report 4 Japanese children who suffered epileptic seizures while
      watching a popular animated TV program. They showed a photoparoxysmal response
      that is more frequently observed in response to rapid color (blue/red) frame
      changes than monochromatic ones. These patients were all considered to have
      photosensitive epilepsy; however, chromatic sensitivity also plays an important
      role in the generation of such seizures.

PMID- 10360773
TI  - Diffusion-weighted magnetic resonance imaging: detection of ischemic injury 39
      minutes after onset in a stroke patient.
AB  - A neurologist witnessed the in-hospital onset of an ischemic stroke in a 71-year
      old right-handed male who suddenly developed global aphasia and right hemiplegia.
      Diffusion-weighted magnetic resonance imaging (DWI) 39 minutes after the ictus
      demonstrated high signals in the left internal carotid artery territory. T1- and
      T2-weighted images failed to detect this change. Magnetic resonance angiography
      showed occlusions in branches of the left anterior and middle cerebral arteries
      and an atheromatous stenotic lesion in the ipsilateral proximal internal carotid
      artery. The patient was treated with intravenous heparin and low molecular
      dextran solution. Repeated magnetic resonance imagings identified an infarction
      slightly smaller than the abnormality demonstrated by the initial DWI. DWI
      detects hyperacute ischemic injury within 1 hour of symptom onset in human
      ischemic stroke.

PMID- 10360774
TI  - The postmigrational development of polymicrogyria documented by magnetic
      resonance imaging from 31 weeks' postconceptional age.
AB  - We report the case of a 27-week premature infant in whom magnetic resonance
      imaging (MRI) at 4 postnatal weeks (postconceptional age, 31 weeks), term, and 6
      months of age documented the postnatal postmigrational evolution of bilateral
      perisylvian polymicrogyria. The polymicrogyria was readily detected by ultrafine
      1.5-mm coronal slices on three-dimensional, Fourier-transformed, spoiled gradient
      recalled and T2-weighted MRI sequences. These MRI sequences provide the first in
      vivo documentation of the postmigrational evolution of polymicrogyria. The
      likelihood that the polymicrogyria was related to an ischemic encephaloclastic
      mechanism is supported by the simultaneous occurrence of periventricular
      leukomalacia.

PMID- 10360775
TI  - Extensive cerebral white matter abnormality without clinical symptoms: a new
      hereditary condition?
AB  - A 30-year-old father and his 2 sons with slight hyperkinesia and mildly
      dysmorphic features and their close relatives were examined clinically and with
      computed tomography (CT) and magnetic resonance imaging (MRI). Neurophysiological
      and biochemical examinations were normal; however, brain MRI of the father and
      sons revealed extensive cerebral white matter changes. No radiological
      progression could be detected at a 13-year follow-up examination of the father,
      and proton magnetic resonance spectroscopy (MRS) of the father at the age of 30
      years was normal. MRI findings in the relatives were normal, suggesting an
      autosomal dominant syndrome due to a new mutation in the father.

PMID- 10360776
TI  - Association of anti-Yo (type I) antibody with paraneoplastic cerebellar
      degeneration in the setting of transitional cell carcinoma of the bladder:
      detection of Yo antigen in tumor tissue and fall in antibody titers following
      tumor removal.
AB  - Anti-Yo (type I) autoantibodies reactive with Purkinje cell cytoplasmic antigens
      of 34 and 62 kd are found in the serum and cerebrospinal fluid of patients with
      paraneoplastic cerebellar degeneration associated with cancer of the ovary,
      uterus, adnexa, or breast. Anti-Yo antibody response is rarely associated with
      other tumors. Here, we present a patient who developed paraneoplastic cerebellar
      degeneration and anti-Yo antibody response in association with transitional cell
      carcinoma of the bladder. The presence of anti-Yo antibodies was confirmed by
      immunofluorescence assay and by Western blot analysis against both Purkinje cell
      lysates and the CDR62 fusion protein. Yo antigen was demonstrated in sections of
      the patient's tumor. Antibody titers fell after tumor removal. Transitional cell
      carcinoma should be considered in patients presenting with subacute cerebellar
      degeneration and anti-Yo antibody response in whom ovarian, adnexal, uterine, or
      breast cancer cannot be detected.

PMID- 10360777
TI  - Ataxia with isolated vitamin E deficiency: a Japanese family carrying a novel
      mutation in the alpha-tocopherol transfer protein gene.
AB  - We report a Japanese family with ataxia with isolated vitamin E deficiency
      (AVED). Gene analysis revealed a single nucleotide substitution of T to C at
      nucleotide position 2 in the alpha-tocopherol transfer protein gene (TTPA). This
      substitution abolishes the start codon. The proband and his affected sister were
      homozygous for this mutation, and their serum alpha-tocopherol concentrations
      were remarkably reduced. Relations between the mutations and clinical features
      are discussed.

PMID- 10360778
TI  - A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K
      mutation coupled with valine at codon 129 and type 2 protease-resistant prion
      protein.
AB  - A novel phenotype of familial Creutzfeldt-Jakob disease (CJD) with mutated codon
      200 of the prion protein gene (PRNP) coupled with the valine codon 129 (E200K
      129V haplotype) has two features never observed in subjects carrying the
      pathogenic mutation coupled with the methionine codon 129 (E200K-129M haplotype):
      (1) plaque-like prion protein (PrP) deposits in the cerebellum and (2) type 2
      protease-resistant prion protein (PrP(res)). This observation further underlines
      the role of codon 129 on the mutated PRNP allele in modulating the phenotype of
      familial prion diseases.

PMID- 10360779
TI  - Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired
      immunodeficiency syndrome patients with biopsy-proven progressive multifocal
      leukoencephalopathy.
AB  - The detection and semiquantitation of JC virus (JCV) DNA in cerebrospinal fluid
      (CSF) is prognostic of survival and is a marker of the course of progressive
      multifocal leukoencephalopathy (PML). CSF samples from 15 acquired
      immunodeficiency syndrome (AIDS) patients with biopsy-proven PML were analyzed by
      semiquantitative polymerase chain reaction (PCR). A low JCV burden was predictive
      of longer survival compared with a high JCV burden (median survival from entry,
      24 [2-63] vs 7.6 [4-17] weeks). Further analyses indicated a possible threshold
      of 50 to 100 copies/microl separating high- and moderate-risk cases. Patients
      with a JCV load below this level survived longer than those with a JCV load above
      it.

PMID- 10360781
TI  - Malignant glioma: who benefits from adjuvant chemotherapy?

PMID- 10360780
TI  - Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene.
AB  - We report the first molecular defect in an NADH-dehydrogenase gene presenting as
      isolated myopathy. The proband had lifelong exercise intolerance but no weakness.
      A muscle biopsy showed cytochrome c oxidase (COX)-positive ragged-red fibers
      (RRFs), and analysis of the mitochondrial enzymes revealed complex I deficiency.
      Sequence analysis of the mitochondrial genes encoding the seven NADH
      dehydrogenase subunits showed a G-to-A transition at nucleotide 11832 in the
      subunit 4 (ND4) gene, which changed an encoded tryptophan to a stop codon. The
      mutation was heteroplasmic (54%) in muscle DNA. Defects in mitochondrially
      encoded complex I subunits should be added to the differential diagnosis of
      mitochondrial myopathies.

PMID- 10360782
TI  - Further evidence for double-strand breaks originating from a paired radical
      precursor from studies of oxygen fixation processes.
AB  - By using a fast reaction technique which employs H2S gas as a fast-reacting
      chemical repair agent, it is possible to measure the competition kinetics between
      chemical repair reactions and oxygen fixation reactions in model DNA and cellular
      systems. In plasmid pBR322 DNA irradiated with electrons, we have compared the
      oxygen fixation reactions of the free radical precursors that lead to the
      production of single-strand (SSBs) and double-strand breaks (DSBs). For the
      oxygen-dependent fixation of radical damage leading to SSBs, a second-order rate
      constant of 2.3 x 10(8) dm3 mol(-1) s(-1) was obtained compared to 8.9 x 10(7)
      dm3 mol(-1) s(-1) for DSBs. The difference is in general agreement with
      predictions from a multiple-radical model where the precursor of a DSB originates
      from two radicals. The fixation of this precursor by oxygen will require both
      radicals to be fixed for the DSB to be formed, which will have slower kinetics
      than that of single free-radical precursors of SSBs.

PMID- 10360783
TI  - Induction and rejoining of large DNA fragments after ion irradiation.
AB  - Radiation-induced DNA double-strand breaks (DSBs) were analyzed by separating
      large DNA fragments by pulsed-field gel electrophoresis. Human U-343MG glioma and
      K562 erythroleukemia cells were irradiated with 60Co gamma rays or nitrogen ions
      with high linear energy transfer (125 keV/microm). By comparing the fraction of
      DNA released into the gel below different size thresholds, corresponding to
      megabase-pair-sized DNA fragments, the relative effectiveness of the nitrogen
      ions was found to be dependent on both dose and the threshold size used in the
      evaluation. This dose dependence was most evident for the smallest threshold (6
      Mbp) and was due to a linear dose response for release of the fragments for the
      ions compared to the curvilinear response for the gamma rays. The two curves
      intersected, and the relative yield of fragments (nitrogen ions/gamma rays)
      decreased from more than 3 below 1.5 Gy to 0.8 at 30 Gy. For the larger sizes (6
      10.5 Mbp), the relative yield was constant at around 0.7. Thus the ion-induced
      fragments were shifted to smaller sizes compared to the 60Co gamma rays, and the
      data for nitrogen ions could not be fitted to random fragment distributions at
      doses < or =20 Gy. From these results, we conclude that a substantial fraction of
      the DSBs induced by heavy ions were nonrandomly distributed, correlated with DSBs
      within a region of < or =2 Mbp. After a dose of 20 Gy, the rejoining curves for
      ion-induced DSBs were different for each fragment size, resulting in different
      levels of unrejoined breaks after 6 h.

PMID- 10360784
TI  - Lethal effect of carbon K-shell photoionizations in Chinese hamster V79 cell
      nuclei: experimental method and theoretical analysis.
AB  - To test a possible specific effect of carbon K-shell ionizations in DNA, survival
      curves for Chinese hamster V79 cells were measured for X irradiations at energies
      below and above the carbon K-shell ionization threshold. Specific values of the X
      ray energies (250 and 340 eV) were chosen to ensure isoattenuation of the two
      kinds of radiation within the cell. An enhancement of lethality by a factor of
      about 2 was found for X rays at 340 eV compared to below the threshold at 250 eV.
      This may be attributed to the production of highly efficient carbon K-shell
      ionizations located on DNA. A model of X-ray lethality (Goodhead et al., Radiat.
      Prot. Dosim. 52, 217-223, 1994) was extended to allow for a possible lethal
      effect from clusters of reactive species induced by K-shell photoionizations (K
      shell clusters). Within this model, the increase in lethality above the carbon K
      shell threshold may be explained by a value of 2% for the lethal efficiency of K
      shell clusters overlapping the DNA. An extrapolation to the lethal effect of more
      complex ion-induced K-shell ionizations indicates that K-shell ionization may be
      a major process in the biological effectiveness of heavy ions.

PMID- 10360785
TI  - G2/M-phase arrest and death by apoptosis of HL60 cells irradiated with
      exponentially decreasing low-dose-rate gamma radiation.
AB  - Cells of the TP53-deficient human leukemia cell line HL60 continue to progress
      throughout the cell cycle and arrest in the G2/M phase during protracted exposure
      to exponentially decreasing low-dose-rate radiation. We have hypothesized that
      G2/M-phase arrest contributes to the extent of radiation-induced cell death by
      apoptosis as well as to overall cell killing. To test this hypothesis, we used
      caffeine and nocodazole to alter the duration of G2/M-phase arrest of HL60 cells
      exposed to exponentially decreasing low-dose-rate irradiation and measured the
      activity of G2/M-phase checkpoint proteins, redistribution of cells in the phases
      of the cell cycle, cell death by apoptosis, and overall survival after
      irradiation. The results from these experiments demonstrate that concomitant
      exposure of HL60 cells to caffeine (2 mM) during irradiation inhibited radiation
      induced tyrosine 15 phosphorylation of the G2/M-phase transition checkpoint
      protein CDC2/p34 kinase and reduced G2/M-phase arrest by 40-46% compared to cells
      irradiated without caffeine. Radiation-induced apoptosis also decreased by 36-50%
      in cells treated with caffeine and radiation compared to cells treated with
      radiation alone. Radiation survival was significantly increased by exposure to
      caffeine. In contrast, prolongation of G2/M-phase arrest by pre-incubation with
      nocodazole enhanced radiation-induced apoptosis and overall radiation-induced
      cell killing. To further study the role of cell death by apoptosis in the
      response to exponentially decreasing low-dose-rate irradiation, HL60 cells were
      transfected with the BCL2 proto-oncogene. The extent of G2/M-phase arrest was
      similar for parental, neomycin-transfected control and BCL2-transfected cells
      during and after exponentially decreasing low-dose-rate irradiation. However,
      there were significant differences (P < 0.01) in the extent of radiation-induced
      apoptosis of parental and neomycin- and BCL2-transfected cells after irradiation,
      with significantly less radiation-induced apoptosis and higher overall survival
      in BCL2-transfected cells than similarly irradiated control cells. These data
      demonstrate that radiation-induced G2/M-phase arrest and subsequent induction of
      apoptosis play an important role in the response of HL60 cells to low-dose-rate
      irradiation and suggest that it may be possible to increase radiation-induced
      apoptosis by altering the extent of G2/M-phase arrest. These findings are
      clinically relevant and suggest a novel therapeutic strategy for increasing the
      efficacy of brachytherapy and radioimmunotherapy.

PMID- 10360786
TI  - Association between G2-phase block and repair of radiation-induced chromosome
      fragments in human lymphocytes.
AB  - We have studied the induction of chromosomal aberrations in human lymphocytes
      exposed in G0 to X rays or carbon ions. Aberrations were analyzed in G0, G1, G2
      or M phase. Analysis during the interphase was performed by chemically induced
      premature chromosome condensation, which allows scoring of aberrations in G1, G2
      and M phase; fusion-induced premature chromosome condensation was used to analyze
      the damage in G0 cells after incubation for repair; M-phase cells were obtained
      by conventional Colcemid block. Aberrations were scored by Giemsa staining or
      fluorescence in situ hybridization (chromosomes 2 and 4). Similar yields of
      fragments were observed in G1 and G2 phase, but lower yields were scored in
      metaphase. The frequency of chromosomal exchanges was similar in G0 (after
      repair), G2 and M phase for cells exposed to X rays, while a lower frequency of
      exchanges was observed in M phase when lymphocytes were irradiated with high-LET
      carbon ions. The results suggest that radiation-induced G2-phase block is
      associated with unrejoined chromosome fragments induced by radiation exposure
      during G0.

PMID- 10360788
TI  - Correlation between unirradiated cell TP53 protein levels and radiosensitivity in
      MOLT-4 cells.
AB  - MOLT-4 cells undergo apoptosis after X irradiation. A radiosensitive variant,
      MOLT-4N1, and a radioresistant variant, MOLT-4N2, have been studied with respect
      to their radiosensitivity and its relationship to the levels of TP53 protein
      (formerly known as p53). X irradiation induces apoptosis in both cell lines with
      the following difference: The induction of apoptosis in MOLT-4N2 cells occurred
      later than in MOLT-4N1 cells as determined by the morphological changes and DNA
      fragmentation. The levels of cell death measured by the dye exclusion test
      coincided with the levels of apoptosis in both cell lines, suggesting that
      radiation-induced cell killing is determined by the induction of apoptosis.
      Unirradiated MOLT-4N1 cells contained a significantly higher intracellular level
      of TP53 protein and a much higher level of TP53 mRNA compared to MOLT-4N2 cells.
      X irradiation led to an accumulation of TP53 protein in both cell lines that was
      greater in MOLT-4N1 cells. This accumulation of TP53 protein preceded changes in
      DNA degradation and ladder formation and in nuclear morphology. These results
      strongly suggest that the radiosensitivity of MOLT-4 cells correlates well with
      the unirradiated control levels of TP53 mRNA and TP53 protein, and that the
      quantitative levels of TP53 protein must reach a threshold for the cells to
      undergo apoptosis.

PMID- 10360787
TI  - Critical target and dose and dose-rate responses for the induction of chromosomal
      instability by ionizing radiation.
AB  - To investigate the critical target, dose response and dose-rate response for the
      induction of chromosomal instability by ionizing radiation, bromodeoxyuridine
      (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of
      doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status
      of chromosomal stability was determined by fluorescence in situ hybridization
      approximately 20 generations after irradiation in clonal populations derived from
      single progenitor cells surviving acute exposure. Overall, nearly 700 individual
      clones representing over 140,000 metaphases were analyzed. In cells unsubstituted
      with BrdU, a dose response was found, where the probability of observing delayed
      chromosomal instability in any given clone was 3% per gray of X rays. For cells
      substituted with 25-66% BrdU, however, a dose response was observed only at low
      doses (<1.0 Gy); at higher doses (>1.0 Gy), the incidence of chromosomal
      instability leveled off. There was an increase in the frequency and complexity of
      chromosomal instability per unit dose compared to cells unsubstituted with BrdU.
      The frequency of chromosomal instability appeared to saturate around
      approximately 30%, an effect which occurred at much lower doses in the presence
      of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy
      min(-1)) produced no significant differences in the frequency of chromosomal
      instability. The enhancement of chromosomal instability promoted by the presence
      of the BrdU argues that DNA comprises at least one of the critical targets
      important for the induction of this end point of genomic instability.

PMID- 10360789
TI  - Sensitization to the cytotoxicity of adriamycin by verapamil and heat in
      multidrug-resistant Chinese hamster ovary cells.
AB  - Development of multidrug resistance to anticancer agents is a major limitation
      for the success of cancer chemotherapy. The chemosensitizer verapamil increases
      intracellular accumulation of drugs such as adriamycin in certain multidrug
      resistant cell lines. When combined with verapamil, hyperthermia should be able
      to alter membrane permeability to adriamycin and to enhance the cytotoxicity of
      the drug. Verapamil increased the cytotoxicity of adriamycin in multidrug
      resistant Chinese hamster ovary cells (CH(R)C5) but not in drug-sensitive cells
      (AuxB1). Hyperthermia (42 degrees C) alone clearly increased the cytotoxicity of
      adriamycin in AuxB1 cells. There was also a small increase in CH(R)C5 cells at 42
      and 43 degrees C. In drug-resistant cells, the cytotoxicity of adriamycin
      increased considerably when verapamil was combined with heat. This effect was
      dependent on temperature and increased with time of incubation. At 37 degrees C,
      verapamil increased the uptake of adriamycin in CH(R)C5 cells, while drug efflux
      decreased. When verapamil was combined with hyperthermia, drug efflux decreased
      even further. These results led to an overall increase in intracellular
      accumulation of the drug. In drug-sensitive cells, hyperthermia increased both
      the uptake and efflux of adriamycin, but verapamil had no effect. Verapamil plus
      heat increased the cytotoxicity of adriamycin in drug-resistant cells, and this
      was accompanied by altered permeability of the membrane to the drug. Hyperthermia
      combined with verapamil could be beneficial by increasing the effectiveness of
      adriamycin in the elimination of multidrug-resistant cells in a localized target
      region.

PMID- 10360790
TI  - A high dose of ionizing radiation induces tissue-specific activation of nuclear
      factor-kappaB in vivo.
AB  - Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) is one
      of the important responses of cells to an external stress such as ionizing
      radiation. We studied radiation-induced NF-kappaB activation in vivo in male
      BALB/c mice. After the mice were exposed to 8.5 Gy total-body gamma irradiation,
      the spleen, mesenteric lymph nodes, thymus, liver, lung, colon, brain and bone
      marrow were harvested 1, 2.5, 5, 10 and 20 h postirradiation. NF-kappaB DNA
      binding activity was analyzed in the nuclear protein extracts by a gel shift
      assay. When compared to the levels in untreated control mice, radiation induced
      activation of NF-kappaB in spleen, mesenteric lymph nodes and bone marrow but not
      in the other tissues examined. In contrast, an i.p. injection of a lethal dose (3
      mg/kg) of lipopolysaccharide also increased activity of NF-kappaB in the liver
      and lung. The gel supershift assay with Nfkb1, Rela and/or Rel antibodies
      revealed that the specific molecular forms of NF-kappaB activated by radiation in
      the spleen were Nfkb1 homodimers and Nfkb1/Rela heterodimers. In mesenteric lymph
      nodes, the heterodimerized Rel/Rela NF-kappaB was also activated. In bone marrow,
      an NF-kappaB-like binding factor was induced that may be Nfkb1/Rela- and Rel/Rela
      like heterodimers, but it exhibited a higher mobility than Nfkb1 homodimers.
      These results indicate that in vivo, ionizing radiation induces NF-kappaB
      activation that varies in both tissue distribution and moleoular composition.

PMID- 10360791
TI  - TP53 tumor suppressor protein in normal human fibroblasts does not respond to 837
      MHz microwave exposure.
AB  - The TP53 tumor suppressor protein (formerly known as p53) responds to a wide
      variety of environmental insults. To evaluate the safety of cellular telephones,
      TP53 responses in human fibroblast cells were studied after exposure to 837 MHz
      microwaves. Cells were exposed in a temperature-controlled transverse
      electromagnetic (TEM) chamber to a specific absorption rate (SAR) of 0.9 or 9.0
      W/kg at 837 MHz continuous-wave (CW) microwave irradiation for 2 h. The TP53
      protein levels were measured by Western blot at 2, 8, 24 and 48 h after
      treatment. The TP53 protein levels in microwave-treated cells, sham-treated
      cells, and untreated cells remained unchanged relative to each other at all times
      tested (Fisher test and Student-Newman-Keuls test, P > 0.05). No morphological
      alterations were observed in microwave-treated cells compared to sham-treated
      cells. We conclude that TP53 protein expression levels in cultured human
      fibroblast cells do not change significantly during a 48-h period after exposure
      to 837 MHz continuous microwaves for 2 h at SAR levels of 0.9 or 9.0 W/kg.

PMID- 10360792
TI  - The suppression of metastases and the change in host immune response after low
      dose total-body irradiation in tumor-bearing rats.
AB  - We have shown that metastasis is suppressed by low-dose total-body irradiation
      (TBI) in tumor-bearing rats. We have evaluated the immunological effects of low
      dose TBI. Total-body irradiation with 0.2 Gy was given 14 days after the
      implantation of 5 x 10(5) allogenic hepatoma cells (KDH-8) which produce
      transforming growth factor beta (TGF-beta). On day 21, the splenocytes and tumor
      tissue infiltrating lymphocytes were analyzed by FACScan and RT-PCR for the mRNA
      of the genes that encode tumor necrosis factor alpha (TNF-alpha), interferon
      gamma (IFN-gamma), TGF-beta, interleukin (IL)-4, IL-10 and IL-6. The same
      procedure was conducted with untreated rats and with rats that underwent local
      irradiation with 0.2 Gy. The low-dose TBI significantly decreased the incidence
      of lung and lymph node metastasis (P < 0.01), whereas the same dose of local
      irradiation had no effect on the incidence of metastasis. The proportion of CD8+
      cells in splenocytes increased in the low-dose TBI group (P < 0.01) compared to
      the locally irradiated and the untreated groups. The tumor-tissue infiltrating
      lymphocytes were also significantly increased after low-dose TBI (P < 0.01). The
      FACScan analysis revealed that 72% of the tumor-tissue infiltrating lymphocytes
      were CD8+. In both spleen and tumor tissue after low-dose TBI, mRNA expression of
      the genes that encode IFN-gamma and TNF-alpha increased, while that of the Tgfb
      gene decreased. There was no expression of the mRNAs of the Il4, Il6 and Il10
      genes. CD8+ cells and the cytokine network may play an important role in the
      antitumor effect of low-dose TBI.

PMID- 10360793
TI  - Angiotensin II-induced modulation of rat mesangial cell phenotype.
AB  - Inhibition of angiotensin II (AII) can ameliorate the severity of experimental
      radiation nephropathy. To determine the ability of AII to modulate mesangial cell
      phenotype, primary cultures of rat mesangial cells (passage number 6-11) were
      placed in serum-free medium 24 h prior to addition of AII (10(-9)-10(-5) M);
      control cells received serum-free medium alone. Cells were maintained in serum
      free medium for a further 48 h. Addition of AII to quiescent mesangial cells
      resulted in significant (P < 0.05) time- and/or dose-dependent increases in Fn
      and Pail mRNA and/or immunoreactive protein. No significant change was observed
      in terms of Tgfb1 mRNA. A significant increase in total Tgfb1 protein (P < 0.01)
      secreted by AII-treated mesangial cells was noted; however, this increase was
      primarily in terms of latent TGF-beta; the relative proportion of active TGF-beta
      secreted decreased after AII incubation. AII had no effect on the activity of
      Mmp2 or Mmp9. However, AII-treated mesangial cells did show an increase in the
      amount of tissue inhibitor of metalloproteinase-2 (Timp2) immunoreactive protein
      secreted into the medium. The AII-mediated increase in Pail mRNA levels appeared
      due in part to activation of the AT1 receptor and was independent of TGF-beta; co
      incubation with TGF-beta-neutralizing antibody failed to inhibit the AII-mediated
      increase in Pail mRNA. Thus mesangial cells treated with AII exhibit a pro
      fibrosis phenotype.

PMID- 10360794
TI  - Effects of radiation on the longitudinal trends of total serum cholesterol levels
      in the atomic bomb survivors.
AB  - The effects of radiation on the long-term trends of the total serum cholesterol
      levels of the Hiroshima and Nagasaki atomic bomb survivors were examined using
      data collected in the Adult Health Study over a 28-year period (1958-1986). The
      growth-curve method was used to model the longitudinal age-dependent changes in
      cholesterol levels. For each sex, temporal trends of cholesterol levels were
      characterized with respect to age, body mass index, city and birth year. We then
      examined whether the temporal trends differed by radiation dose. We showed that
      the mean growth curve of cholesterol levels for the irradiated subjects were
      significantly higher than that for the unirradiated subjects, and that the
      increase was greater for women than for men. No difference in dose response was
      detected between Hiroshima and Nagasaki. An increased mean level of cholesterol
      was evident for irradiated women in general, but a notable increase was apparent
      in males only for the youngest birth cohort of 1935-1945. The difference in the
      mean cholesterol levels between the irradiated and unirradiated subjects
      diminished past 70 years of age. It is not known whether this is due to natural
      progression or is an artifact of nonrandom variation in the rate of participation
      in the examinations. The maximum predicted increase at 1 Gy for women occurred at
      age 52 years for the 1930 cohort: 2.5 mg/dl (95% CI 1.6-3.3 mg/dl) for Hiroshima
      and 2.3 mg/dl (95% CI 1.5-3.1 mg/dl) for Nagasaki. The corresponding increase for
      men occurred at age 29 years for the 1940 cohort: 1.6 mg/dl (95% CI 0.4-2.8) for
      Hiroshima and 1.4 mg/dl (95% CI 0.3-2.6) for Nagasaki. Controlling for cigarette
      smoking did not alter the dose-response relationship. Although the difference in
      the mean growth curves of the irradiated and unirradiated groups was
      statistically significant, there was a considerable overlap in the individual
      growth curves of the two groups. The significant sex difference and the greater
      magnitude of radiation effects in women suggest that hormonal changes resulting
      from radiation exposure, such as accelerated menopause, is an area worth
      investigating to delineate the mechanisms underlying the increased cholesterol
      levels of the irradiated female subjects. This increase may also partially
      explain the increased rate of coronary heart disease seen in the atomic bomb
      survivors.

PMID- 10360795
TI  - Effect of gemcitabine on the tolerance of the lung to single-dose irradiation in
      C3H mice.
AB  - In an early phase II trial combining gemcitabine (dFdC) and radiotherapy for lung
      carcinomas, severe pulmonary toxicity was observed. In this framework, the
      objective of this study was to investigate the effect of dFdC on the tolerance of
      the lungs of C3H mice to single-dose irradiation. The thoraxes of C3H mice were
      irradiated with a graded single dose of 8 MV photons; dFdC (150 mg/kg) or saline
      (control animals) was administered i.p. 3 or 48 h prior to irradiation. Lung
      tolerance was assessed by the LD50 at 7-180 days after irradiation. For
      irradiation alone, the LD50 reached 14.45 Gy (95% CI 13.33-15.66 Gy). With a 3-h
      interval between administration of dFdC and irradiation, the LD50 reached 13.29
      (95% CI 12.26-14.44 Gy); the corresponding value with a 48-h interval reached
      13.01 Gy (95% CI 11.92-14.20 Gy). Our data also suggested a possible effect of
      dFdC on radiation-induced esophageal toxicity. dFdC has a minimal effect on lung
      tolerance after single-dose irradiation. However, a proper phase I-II trial
      should be designed before any routine use of combined dFdC and radiotherapy in
      the thoracic region.

PMID- 10360796
TI  - The survival of monolayers of cells growing in clusters irradiated by 211At
      appended to the cell surfaces.
AB  - A model of cell survival is described for the case of closely packed clusters of
      cells growing in monolayers. For alpha-particle decays on the cell surfaces, it
      is shown that cross-firing between cells produces nonuniform dose distributions
      within the cluster and that cells in larger clusters are exposed on average to
      greater doses. The model is used to simulate the survival of SK-MEL-28 human
      melanoma cells labeled with different radiolabeled monoclonal antibodies. The
      survival data suggest that this cell line is more sensitive to high-LET radiation
      than previously thought.

PMID- 10360797
TI  - Salivary sIgA response in HIV-1 infection.
AB  - Local and systemic production of total and HIV-1 specific IgA was determined in
      whole saliva and serum from 45 HIV-1-infected individuals and 15 healthy
      controls. The antigenic domains important for sIgA and IgG binding, respectively,
      was investigated with epitope mapping using synthetic peptides of HIV-1 proteins.
      Decreased levels of total sIgA in saliva were found among patients with low CD4+
      cell counts in advanced stages of acquired immunodeficiency. HIV-1 specific IgA
      response, predominantly directed to the envelope proteins, was found in saliva
      and serum also at later stages of disease. Analyses using peptide enzyme-linked
      immunosorbent assays (ELISA) showed that the sIgA antibody response in saliva was
      mainly directed to the V4 region (aa 385-409) and a more C-terminal part of the
      V3-region (aa 325-344) compared with the IgG response, which predominantly was
      directed to a more central part of the V3 loop (aa 308-325). A similar picture
      was seen for immunoglobulins of the two isotypes derived from serum. We have in
      this study shown IgA epitope-specific immune response within HIV-1 gp160,
      indicating that antibodies of IgA isotype may recognize somewhat different
      antigenic domains compared to IgG antibodies.

PMID- 10360798
TI  - Role of macrophage protection in the development of murine AIDS.
AB  - Macrophages play a key role in AIDS pathogenesis and thus controlling infectivity
      and viral replication in these cells is a key issue in any antiretroviral
      therapy. In the present study, using a murine model of AIDS, we evaluated new
      therapeutic approaches specifically designed for the protection of macrophages.
      Based on previous observations, we took advantage of the unique ability of
      autologous erythrocytes to deliver drugs selectively to macrophages. The
      antiviral drugs selected were a new homodimer of AZT (AZTp2AZT) and reduced
      glutathione (GSH). The addition of an oral drug for the protection of lymphocytes
      (i.e., AZT) was also investigated. C57BL/6 mice infected with the retroviral
      complex LP-BM5 were treated with GSH-loaded erythrocytes, GSH-loaded erythrocytes
      plus oral AZT, or GSH/AZTp2AZT-loaded erythrocytes plus oral AZT. The treatments
      including AZT and erythrocytes loaded with GSH alone or with GSH plus AZTp2AZT
      provided similar results and were most effective in inhibiting the progression of
      MAIDS; they reduced splenomegaly, lymphadenopathy, and hypergammaglobulinemia by
      about 70%, 90% and 83%, respectively, when compared with infected animals at 10
      weeks postinfection. Evaluation of BM5d proviral DNA content in infected organs
      revealed that both treatments were able to almost completely protect most
      infected animals. They were also able to normalize the blood lymphocyte phenotype
      and to restore the responses of T and B cells to mitogens significantly.
      Treatment with GSH-loaded erythrocytes alone did not provide significant results
      for most parameters investigated, but a marked reduction in proviral DNA content
      was obtained in infected organs, including the brain. The results reported in
      this paper confirm the important role of macrophages in retroviral infection and
      moreover prove that erythrocytes, by selectively protecting these cells, strongly
      affect MAIDS progression. Furthermore, the combination of GSH- or GSH/AZTp2AZT
      loaded erythrocytes with an oral nucleoside analogue (AZT) for the protection of
      lymphocytes provides additive responses in all the parameters investigated.

PMID- 10360799
TI  - Herpes simplex virus chronically infected human T lymphocytes are susceptible to
      HIV-1 superinfection and support HIV-1 pseudotyping.
AB  - Peripheral blood lymphocytes (PBL) and CEM CD4+ T-cell line can be infected by
      herpes simplex virus-1 (HSV-1). CEM cells were characterized as a cellular model
      to study interactions occurring between HSV-1 and HIV-1. Virtually all cells were
      persistently infected by HSV-1 (CEM(HSV)) and expressed the latency associated
      transcripts, whereas only a fraction tested positive for HSV-antigens. CD4 and
      CXCR-4 expression and function were not affected in CEM(HSV) cells and no
      significant increase of deoxyribonucleotide pools was noticed. Superinfection of
      CEM(HSV) cells with HIV-1 led to a cell line chronically infected by both viruses
      (CEM(HSV/HSV)). Evidence was also obtained that this cell line can produce HIV-1
      pseudotyped by HSV-1 envelope. These results may have important implications for
      a better understanding of AIDS pathogenesis.

PMID- 10360800
TI  - Comprehensive classification of symptoms and signs reported among 218 patients
      with acute HIV-1 infection.
AB  - Acute HIV-1 illness presents a wide range of clinical manifestations. We assessed
      a classification and data reduction of clinical features among 218 patients with
      acute HIV-1 infection enrolled in four prospective seroincidence studies. Factor
      analysis allows the definition of eight factors based on groups of symptoms and
      signs: gastrointestinal transit disturbances, weight loss/abdominal pain,
      lymphadenopathy, myalgia/arthralgia, neurologic features, constitutional and
      mucocutaneous features, oral candidiasis, and anorexia/pharyngitis. These groups
      reflected the main target systems involved at the time of acute HIV-1 disease.
      Grouping of symptoms and signs based on groups of patients is potentially more
      informative than observations made on individual patients. It might facilitate
      diagnosis, suggest pathogenic mechanisms and reduce the number of variables for
      characterizing acute HIV-1 illness.

PMID- 10360801
TI  - Changes in body habitus and serum lipid abnormalities in HIV-positive women on
      highly active antiretroviral therapy (HAART).
AB  - Twenty-one women (propositi) who expressed serious concerns about changes in body
      habitus during highly active antiretroviral therapy (HAART) were evaluated by
      thorough physical examination, anthropometric measurements, and serum lipid and
      endocrine assays. The same evaluations were carried out in a comparison group of
      21 women who received HAART but did not complain of changes in habitus. No
      significant demographic differences were found between the propositi and the
      comparison group, nor were there significant differences in CD4 count or plasma
      viral load (PVL) between the two groups. Lipid analyses were also performed on
      plasma obtained prior to HAART from 12 of the women. The frequency of changes
      reported by the 21 propositi were increase in abdominal size (90%), increase in
      breast size (71%), weight gain of >5 kg (43%), peripheral fat wasting (43%),
      buttock fat wasting (38%) and development of cervicodorsal fat pad (19%). A
      subset of patients in the comparison group experienced increase in abdominal size
      (29%) and weight gain >5 kg (19%), but none experienced clinically detectable
      peripheral or buttock fat wasting, increased breast size, or development of
      cervicodorsal fat pads. Mean waist circumference, waist-to-hip ratios (WHR), body
      fat, and body mass index (BMI) were above the desirable range for women in both
      propositi and the comparison group. Levels of total cholesterol, triglycerides,
      low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL)
      cholesterol associated with increased cardiovascular risk were found in 48%, 62%,
      45%, and 33%. respectively, of the propositi, with similar findings in the
      comparison group. Fasting insulin levels were elevated in 4 propositi and 6 of
      the comparison group; mean insulin levels were within the normal range for both
      groups. In the comparison of lipids for the subset of patients before and after
      HAART therapy, HAART was associated with significant increases in total
      cholesterol, apolipoprotein B, and HDL cholesterol. Changes in body habitus
      caused by redistribution of fat occur commonly in women receiving HAART. Serum
      lipid abnormalities also are common during HAART and appear to be as frequent in
      women who do not experience clinically apparent body fat redistribution as in
      those who do. The observed changes in body fat distribution and in serum lipid
      levels are alterations that have been strongly correlated with increased risk for
      cardiovascular disease. Therefore, an understanding of the basis of these
      phenomena, and the risks with which they may be associated in this population,
      will be important for therapeutic decision making in women with HIV disease.

PMID- 10360802
TI  - Why is highly active antiretroviral therapy (HAART) not prescribed or
      discontinued? Swiss HIV Cohort Study.
AB  - In this cross-sectional survey conducted at the end of 1997 among the physicians
      of participants of the Swiss HIV Cohort Study (SHCS), 1487 of 2154 patients
      (69.0%) were treated with highly active antiretroviral treatment (HAART) defined
      as triple therapy with a combination of one or two reverse transcriptase
      inhibitors, and one or two protease inhibitors; 541 patients (25.1%) had never
      received such treatment. The physician's perception that the patient would not
      comply with treatment was one reason for not prescribing HAART to 20% of these
      patients (110). Physicians indicated that the most common reasons for the patient
      to refuse HAART were the fear of side effects (18%) and the patient's perception
      that treatment was too complicated (18%). Among 126 patients (5.8%) no longer
      receiving HAART, the most common reasons for discontinuing treatment were actual
      side effects (61%) or the fear of side effects (25%). Overall, 16% of patients
      did not receive therapy in accord with official Swiss guidelines. Multivariate
      logistic regression analysis indicated that patients with lower education, active
      intravenous drug users outside of a drug substitution program, and those who
      acquired HIV infection through intravenous drug use had a significantly higher
      risk of inadequate treatment. The physician's judgment of patient adherence and
      the physician's perception of the patient's fear of side effects are critical for
      the prescription of HAART. Physicians should address these issues to prevent
      unilateral withholding of treatment and increase the proportion of patients who
      may benefit from current antiretroviral therapy.

PMID- 10360803
TI  - Heterosexual transmission of HIV-1 is associated with high plasma viral load
      levels and a positive viral isolation in the infected partner.
AB  - Risk factors for heterosexual HIV transmission are not fully understood. In fact,
      a proportion of people with sexual exposure to HIV remain uninfected despite
      multiple and continuous intercourse with HIV-infected partners. In this work, we
      have analyzed those virologic parameters potentially involved in the transmission
      of HIV through heterosexual contact. Thirty-eight couples with continuous
      unprotected sexual intercourse were included. HIV transmission occurred in 10 of
      38 couples. No differences in clinical characteristics, exposure time, sexual
      practices, CD4 counts, or polymorphism in CCR5 were found between transmitter and
      nontransmitter groups. In contrast, virologic data were different between both
      groups; median values of viral load were 21.139 and 5.484 RNA copies/ml of plasma
      in the transmitter and nontransmitter groups, respectively, and a significant
      difference was found in mean viral load values (p = .03, Mann-Whitney test).
      Viral isolation was obtained in 90% of transmitters, but in only 44% of
      nontransmitter subjects (p = .02, Fisher's exact test). These data show that
      viral load levels and a positive viral isolation in culture must be considered as
      risk factors for heterosexual transmission of HIV-1.

PMID- 10360804
TI  - Sensitivity, specificity, reliability, and clinical validity of provider-reported
      symptoms: a comparison with self-reported symptoms. Outcomes Committee of the
      AIDS Clinical Trials Group.
AB  - BACKGROUND: If symptoms are to be recognized and effectively addressed in
      clinical research, they must be collected using sensitive, specific, reliable,
      and clinically meaningful methods. OBJECTIVE: To perform a comparison of self
      administered symptom survey data with data from conventional provider-reports.
      DESIGN/METHODS: Secondary data analysis of AIDS Clinical Trials Group Study 081
      (ACTG 081), a randomized trial taking place in 33 sites comparing three
      approaches to prophylaxis for Pneumocystis carinii-related pneumonia that found
      no difference among treatment arms. The study was performed on 842 subjects with
      advanced HIV infection. No intervention was undertaken as a result of this study.
      ACTG 081 included data on functional status, global quality of life and survival,
      and two methods of symptom measurement: an open-ended, provider-reported symptom
      assessment (provider-report) and a self-administered symptom survey (self
      report). Agreement was measured using kappa scores. Sensitivity and specificity
      were calculated using self-report as the standard. Reliability was measured by
      intersite variation and test-retest reliability (8 weeks later). Clinical
      validity was evaluated by testing expected associations with functional status,
      global quality of life, and survival. RESULTS: Symptom data were available for
      808 patients (96%). Patient and provider agreement was poor (mean kappa, 0.14;
      range, 0.07-0.25). Compared with self-report, providers underreported the
      presence and severity of symptoms (mean symptom count, 5.2 versus 1.3; mean
      severity score, 1.3 versus 0.74). provider-report demonstrated greater
      variability by site (R2 associated with site, 0.02 versus 0.16) and poorer test
      retest reliability (mean kappa, 0.34 versus 0.25). Provider-report severity
      scores were less strongly associated than were self-report with functional status
      (chi2, 252 versus 80), global quality of life (R2 for model, 0.57 versus 0.15),
      and survival (chi2, 38 versus 24). Self-reported symptom severity was strongly
      correlated to patient-reported global quality of life (p, 0.75; p < .0001).
      CONCLUSIONS: Provider-reported symptoms as currently collected within the ACTG
      are less sensitive and reproducible than a self-administered symptom survey.
      Provider-reported severity scores are also more weakly associated with functional
      status, global quality of life, and survival. A self-reported symptom survey may
      provide a better method of symptom measurement for HIV research.

PMID- 10360805
TI  - Validity of two scales in identifying HIV-associated dementia.
AB  - OBJECTIVES: To examine and compare the validity of the HIV Dementia Scale (HDS)
      and Executive Interview (EXIT) in detecting HIV/AIDS dementia. METHODS: The
      sample included hospitalized or skilled nursing/assisted-living facility (SNF)
      HIV/AIDS patients (N = 103). Participants completed the HDS, EXIT, and the
      Structured Clinical Interview from the Diagnostic and Statistical Manual of
      Mental Disorders, 4th edition (DSM-IV). A chart review also was performed.
      RESULTS: Sample was predominantly male (93%) and white (79%), with a mean age of
      38 years (standard deviation [SD] = 8 years). Twelve patients had a clinical
      diagnosis of HIV dementia. Cutoff scores of 10 or less for the HDS and 11 or more
      for the EXIT optimized sensitivity and specificity. Education level was related
      to performance for both tests. Using separate logistic regression analyses, the
      HDS and the EXIT were significant individual predictors of dementia. When entered
      together, the EXIT was the only significant predictor of dementia. Selected items
      of the HDS and EXIT also performed well in identifying patients with dementia.
      CONCLUSIONS: The HDS and the EXIT show promise as brief, well-tolerated screening
      tools for HIV dementia in ill patients. The HDS was more sensitive, but the EXIT
      added additional predictive power over the HDS in identifying dementia.

PMID- 10360806
TI  - Prevalence of and risk factors for tuberculin positivity and skin test anergy in
      HIV-1-infected and uninfected at-risk women. Women's Interagency HIV Study
      (WIHS).
AB  - OBJECTIVES: To determine differences in rates of reactivity to purified protein
      derivative (PPD) tuberculin and of skin test anergy in relationship to
      serostatus, immune status, demographic characteristics, and other risk factors in
      women infected with or at high risk for infection with HIV-1; and to compare the
      usefulness of three different antigens in assessing delayed type
      hypersensitivity. DESIGN/METHODS: Cross-sectional analysis of baseline data in a
      multicenter prospective cohort study of 1343 HIV-1-seropositive and 390
      seronegative but at-risk women recruited from sites of HIV primary care and
      through community-based outreach for a longitudinal cohort study. RESULTS: 4.7%
      of the 1343 HIV-1-seropositive women and 15.4% of the 390 HIV-seronegative women
      were tuberculin-positive (p < .001). A lower threshold in millimeters of
      induration for tuberculin reactivity among HIV-seropositive women resulted in a
      smaller difference between the seropositive and the seronegative groups. Even
      when a 2-mm threshold was used in HIV-seropositive respondents, with a 10-mm
      threshold among seronegative participants, the difference between the
      seropositive (6.9% reactive) and the seronegative (15.4% reactive) groups
      remained statistically significant (p < .001). Limiting analysis to women who
      responded to the non-PPD antigens did not eliminate the differences in PPD
      reactivity between the HIV-seropositive and HIV-seronegative women. In
      multivariate analysis, tuberculin reactivity was associated with HIV-negative
      serostatus, a history of tuberculosis infection or disease, geographic site, and
      CD4 count >200 cells/mm3 in the HIV-seropositive women. In all, 41% of HIV
      seropositive women and 12% of seronegative women were anergic (p < .001). Candida
      antigen had the lowest response rates. In multivariate analyses, only HIV
      serostatus and CD4 cell counts in HIV-seropositive women were significantly
      associated with anergy. CONCLUSIONS: In this community-based cohort of HIV
      seropositive and HIV-seronegative women, we found significant differences between
      the seronegative and seropositive women even with a lower threshold of induration
      defining PPD reactivity among seropositive women and among women not anergic to
      the non-PPD antigens. Prevalence of PPD reactivity was higher than in previously
      described in cohorts of homosexual men, but lower than in cohorts of
      predominantly male injection drug users. Rates of anergy were similar to those in
      most previously described cohorts.

PMID- 10360807
TI  - Prevalence of sexual and drug-related HIV risk behaviors in the U.S. adult
      population: results of the 1996 National Household Survey on Drug Abuse.
AB  - CONTEXT: Data on the prevalence of HIV risk behavior that are representative of
      the general population are needed to help evaluate the effectiveness of
      prevention programs. OBJECTIVE: To use data from a large national interview
      survey to make estimates of the prevalence of sexual and drug-related HIV risk
      behaviors in the adult population of the United States. DESIGN: Nationally
      representative cross-sectional survey with in-person interviews collecting
      information on drug use and sexual behavior. SETTING AND PARTICIPANTS: 12,381
      U.S. adults aged between 18 and 59 who were respondents to the 1996 National
      Household Survey on Drug Abuse, as part of sample of the noninstitutionalized
      population. Interviews took place in respondents homes using face-to-face
      interviewer-administered and self-administered questionnaires. RESULTS: In total,
      2.8% of respondents were classified as having increased risk for HIV through
      sexual behavior; this represents 3.9 million persons. 1.7% reported some degree
      of risk through drug-related behaviors, representing 1.2 million persons. 3.5% of
      adults (5 million persons) were found to have some degree of HIV risk from sexual
      or drug-related behavior. Persons who were at risk through drug behavior were
      much more likely than others to be at risk through sexual behavior. Condom use
      was not related to HIV risk, although having a recent HIV test was found to be.
      Among those who reported some behaviors that placed them at increased risk for
      HIV infection, only 22% used a condom the last time they had sex with a regular
      partner. CONCLUSIONS: The high rate of sexual risk behavior on the part of drug
      users suggests increasing condom use for this group should be a priority goal for
      programs, especially condom use with main partners. Survey work needs to be
      continued and improved to make it possible to assess the impact of successful
      local prevention efforts on national rates of HIV risk behavior.

PMID- 10360808
TI  - Infection by different HIV-1 subtypes (B and C) results in a similar immune
      activation profile despite distinct immune backgrounds.
AB  - We compared the immune activation profile of 46 HIV-negative and 75 HIV-positive
      Israelis infected with HIV-1 subtype B, with 85 HIV-negative and 102 HIV-positive
      Ethiopian immigrants to Israel, who were infected with HIV subtype C. The HIV
      negative Ethiopians had exceedingly high blood levels of eosinophils,
      immunoglobulin E (IgE), and p75s tumor-necrosis factor receptors (p75sTNFR);
      secretion of interleukin-4 (IL-4) and IL-10 by peripheral blood mononuclear cells
      (PBMC); proportion of human leukocyte antigen (HLA)-DR+ cells within CD3+, CD4+,
      and CD8+ T-cell subsets; and proportion of CD45RO+ CD4+ cells; while having
      significantly lower secretion of interferon-gamma (IFN-gamma) by PBMC and
      percentage of CD45RA+ CD4+ and CD28+ CD8+ cells. HIV infection in both
      populations was associated with reduced IL-2, IL-4, IL-10, and IL-12 secretion,
      number of CD28+ and CD45RA+ CD8+ cells, and increased number of HLA-DR+-CD3+,
      CD4+, and CD8+ cells, and CD45RO+ CD8+ cells. Thus, infection with HIV-1 subtypes
      B and C of studied Israelis and Ethiopians, respectively, results in a similar
      immune activation profile at all stages of the infection when living in the same
      environment, despite the striking different immune profile observed in the HIV
      negative Israeli and Ethiopian populations. Together with our previous
      observations, this indicates that HIV subtype is not a major determinant in the
      natural course of HIV infection.

PMID- 10360809
TI  - Increase of HIV-1 subtype A in Central African Republic.
AB  - The concomitant presence of five distinct HIV-1 subtypes and of unclassified HIV
      1 was reported in Bangui, Central African Republic (C.A.R.) between 1990 and
      1991. This previous study was conducted in individuals belonging to the C.A.R.
      Armed Forces (FACA) Cohort and in patients from the University Hospital of
      Baugui. To follow the HIV-1 subtype distribution in Bangui over time, we
      conducted a cross-sectional surveillance of HIV-1 subtypes between 1987 and 1997
      in three groups of individuals in Bangui: 47 men belonging to the FACA Cohort, 38
      patients from the CNHUB hospital, and 51 individuals consulting the sexually
      transmitted diseases (STD) clinic. One hundred and ten HIV-1 were subtyped by
      heteroduplex mobility assay (HMA) and/or sequencing of env regions encompassing
      the V3 domain. By comparing the HIV-1 distribution in two time periods (1987-1991
      and 1991-1996) in the FACA cohort, we observed a significant increase of subtype
      A from 43.7% to 83.9%. This subtype distribution does not seem specific to the
      FACA cohort, in that subtype A accounted for 46.7% of the HIV-1 infections in
      CNHUB patients in the first time period studied and for 69.6% in the second time
      period. In STD patients, subtype A infections were predominant in 1995 (72.7%)
      and 1997 (89.7%). Subtype E viruses could be identified in the second time
      period, but represented only between 6.5% and 21.8% of the infections in the
      three groups of individuals studied. Other subtypes (B, C, H) and non-classified
      HIV-1 in C2-V3 were detected with only a 3.2% to 9.1% frequency for each in the
      second time period. Phylogenetic analysis excluded infection by a single source
      for the individuals included in the study. Our data demonstrate an increase in
      the proportion of HIV-1 subtype A infections in Bangui that raises the question
      of a preferential transmissibility of specific HIV-1 variants.

PMID- 10360810
TI  - Prevalence of HIV-1 among recent arrestees in Los Angeles County, California:
      serial cross-sectional study, 1991-1995.
AB  - Injection drug users (IDU), crack smokers, and commercial sex workers engage in
      illegal activities that place them at risk for HIV infection. The marginalized
      nature of these groups often limits use of customary sampling methods to assess
      HIV prevalence. We tested urine samples of recent arrestees to evaluate HIV
      prevalence of at-risk populations that are difficult to access using standard
      surveillance methods. We tested for HIV-1 antibodies in urine specimens of recent
      Los Angeles County (California, U.S.A.) arrestees as part of the Drug Use
      Forecasting (DUF) Program funded by the U. S. National Institute of Justice. Data
      are presented for 5 years of a serial cross-sectional study of arrestees. Results
      from 1991 through 1995 indicate a slight HIV prevalence increase among crack
      smokers (from 4% to 6%). Prevalence estimates were relatively stable for IDU
      (6%), male (3%) and female arrestees (3%), arrestees who share needles (9%), and
      commercial sex workers (6%). HIV status was independently associated with
      injection drug use, crack smoking, and ever having exchanged sex for money or
      drugs. Prevalence of HIV among arrestee subgroups may reflect prevalence in the
      community. However the benefit of using the DUF sample must be weighed against
      bias introduced from using nonrandom samples to estimate prevalence.

PMID- 10360811
TI  - Epstein-Barr virus and cytomegalovirus in relation to testicular-cancer risk: a
      nested case-control study.
AB  - An infectious etiology of testicular cancer has been suggested. We have evaluated
      seroreactivity against cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in
      relation to testicular-cancer risk in a case-control study, nested within a
      cohort of prospectively collected serum specimens from 293,692 individuals. For
      each of 81 cases of testicular cancer identified, 3 controls were randomly
      selected from the cohort. Serum IgG antibody titers against CMV and EBV were
      determined using enzyme-linked immunosorbent assays (ELISAs) and
      immunofluorescence methods. Odds ratios (OR) were obtained from conditional
      logistic-regression models. No association was found between CMV positivity and
      testicular cancer overall (OR = 1.08; 95% confidence interval 0.60-1.94); risk
      for testicular seminoma was increased among CMV seropositive [OR = 1.70 (0.80
      3.59)], whereas seropositivity was associated with decreased risk for testicular
      non-seminoma [OR = 0.54 (0.19-1.56)] (p for heterogeneity, 0.09). For EBV, the
      risk for testicular cancer was increased among individuals seropositive for viral
      capsid antigen (VCA) [OR = 2.74 (0.62-12.12)]. The results lend some support to
      the hypothesis of an infectious etiology, and we propose that future studies
      should take into account age at infection.

PMID- 10360812
TI  - Monocyte-chemo-attractant-protein-1 (MCP-1)-gene expression in cervical intra
      epithelial neoplasias and cervical carcinomas.
AB  - Chemokines play a central role in the chemotactic activation of immunological
      effector cells. One of the currently best characterized chemokines is the
      monocyte-chemo-attractant protein-1 (MCP-1), which is involved in the cross-talk
      with cells of the monocyte-macrophage lineage. Since macrophages and macrophage
      derived cytokines appear to be important in the transcriptional regulation of
      "high-risk" types of human papillomaviruses (HPV), we monitored MCP-1 expression
      by in situ hybridization (ISH) in histologically distinct stages of cervical
      intra-epithelial neoplasms (CIN), cervical cancer and non-HPV-associated cases of
      erosive endocervicitis. Here, we demonstrate that high-grade dysplasia (CIN III,
      n = 9) completely lacks both MCP-1 expression and CD68+-macrophage infiltration,
      while MCP-1-specific signals were occasionally detectable in one out of 5 CIN-II
      and in one out of 3 CIN-I lesions. Inspection of hyperplastic squamous epithelium
      adjacent to cervical carcinomas reveals high MCP-1 expression and accumulation of
      infiltrating macrophages. In contrast, no macrophages could be detected in
      corresponding hyperplastic tissue areas surrounding CIN-II and CIN-III lesions,
      although MCP-1 was found to be highly expressed. Finally, in agreement with our
      earlier in vitro data, invasive carcinomas of the cervix uteri showed MCP-1
      specific hybridization signals and macrophage infiltration only in the stroma
      surrounding the carcinoma cells and in endothelial cells of capillaries,
      especially at the invasion front of the tumor, while the inner mass of the
      carcinomas was completely negative. On the other hand, ISH and histochemical
      evaluation of inflammatory, non-HPV-associated cases of erosive endocervicitis
      indicate strong MCP-1 expression, which is regularly accompanied by chemotactic
      appearance of macrophages. These observations indicate that dysregulation of MCP
      1-gene expression may represent an important step during HPV-linked
      carcinogenesis, allowing the escape of virus-positive cells from local immune
      response.

PMID- 10360813
TI  - Microglial/macrophage expression of interleukin 10 in human glioblastomas.
AB  - Interleukin 10 (IL-10) expression has been found to be correlated with the extent
      of malignancy in gliomas. In vitro, IL-10 increases proliferation and migratory
      capacity in human glioma cell lines. In this study, we localized the site of IL
      10 synthesis in gliomas to cells of microglial origin. Biopsy specimens from 11
      patients with malignant glioma were processed on native tissues and at early cell
      culture passages (0-4). IL-10 mRNA was analyzed by RT-PCR and in situ
      hybridization. Protein was quantitatively assessed by ELISA in cell culture
      supernatants, and cells expressing IL-10 were determined by a combination of
      immunohistochemistry for CD68 (specific for microglia/macrophage lineage) and IL
      10 in situ hybridization. IL-10 mRNA decreased from passage 0 to 4 in all samples
      and was undetectable beyond passage 5. Such downregulation of mRNA leads to a
      steep decrease of IL-10 protein in culture supernatants (below detection level,
      0.05 ng/ml, beyond passage 1). The combination of in situ hybridization for IL-10
      and CD68 immunostaining revealed that only cells of the microglia/macrophage
      lineage produced IL-10 mRNA. Our results identify microglia/macrophage cells as
      the major source of IL-10 expression in gliomas which decreases markedly during
      early passages of primary cultures of human gliomas due to a progressive
      reduction of microglia/macrophages present.

PMID- 10360814
TI  - Functional analyses of a unique p53 germline mutant (Y236delta) associated with a
      familial brain tumor syndrome.
AB  - We have evaluated the functional properties of the unique p53 mutant Y236delta
      (deletion of codon 236) that gave rise to apparent cell-type specific tumor
      development. Four family members carrying this mutation in the germline developed
      early onset brain tumors, as previously reported. Deletion of residue Y236, which
      is tightly packed in an evolutionary conserved hydrophobic pocket, results in a
      protein with a mutant conformation according to immunoprecipitation with the
      conformation-sensitive antibodies PAb240 and PAb1620. The Y236delta mutant lacks
      specific DNA binding to the p53-responsive element in the WAF1-promoter, and
      functional analysis in Saos-2 cells revealed inability to transactivate the p53
      responsive elements in the WAF1-promoter and the RGC sequence. The mutant has
      retained a functional oligomerization domain, a key element mediating the
      dominant negative effect, and inhibits DNA binding of wild-type p53. In addition,
      transactivation of endogenous wild-type p53 in LoVo cells was inhibited upon
      transfection of the mutant in a dose-dependent manner. Thus, in vitro and in vivo
      data suggest the loss of important tumor-suppressing functions and demonstrate a
      dominant negative effect of this unique p53 mutant that is associated with an
      unusual clustering of familial brain tumors.

PMID- 10360815
TI  - Stage of breast cancer in relation to body mass index and bra cup size.
AB  - Most studies on women with breast cancer indicate that obesity is positively
      associated with late-stage disease. Some results have shown a similar
      relationship between breast size and stage. A recent study found that the
      association between body mass index (BMI) and stage was limited to cancers that
      were self-detected, suggesting that the BMI-stage relation may be due to delayed
      symptom recognition. We examined the relationships between stage and both BMI and
      breast (bra cup) size, stratified by method of detection, using data from a
      population-based case-control study of 1,361 women (ages 20-44 years) diagnosed
      with breast cancer during 1990-1992. Height and weight measurements and
      information on bra cup size, method of cancer detection and other factors
      predictive of stage at diagnosis were collected during in-person interviews. A
      case-case comparison was conducted using logistic regression to estimate odds of
      regional or distant stage rather than local stage in relation to BMI and bra
      size. Odds of late-stage disease were increased with higher BMI [adjusted odds
      ratio (OR) for highest to lowest tertile = 1.46, 95% confidence interval (CI)
      1.10-1.93] and larger bra cup size (OR for cup D vs. cup A = 1.61, 95% CI 1.04
      2.48). These relationships were not modified by the method of detection.
      Differences in etiologic effects, rather than differences in detection methods,
      may explain the relations observed between stage and both BMI and breast size.

PMID- 10360816
TI  - Study of diet, biomarkers and cancer risk in the United States, China and Costa
      Rica.
AB  - One striking paradox in epidemiologic research is the strong association between
      diet and cancer in ecologic studies compared with the weaker associations
      reported in many within-country case-control and cohort studies. However, most
      ecologic studies have relied on indirect measures of dietary intake, such as food
      disappearance data. The objectives of our study were to assess the feasibility of
      collecting dietary and biomarker data from individuals living in countries having
      markedly different dietary patterns and cultures and to examine the magnitude of
      the between-country variation in their measurement. Adults surveyed in Shanghai
      (China), Costa Rica and King County (Washington, USA) completed a 24-hr dietary
      recall, a cancer risk factor survey, and provided a blood sample. We analyzed a
      subset of the blood specimens for vitamins C, E, carotenoids and phospholipid
      fatty acids. We observed substantial differences in nutrient intakes and in mean
      plasma concentrations of dietary biomarkers across the study populations. For
      example, King County participants had the highest daily intake of vitamin C (mean
      78.3 +/- 12.2 mg compared with 42.6 +/- 38.3 mg in Shanghai and 34.8 +/- 43.8 mg
      in Costa Rica). The mean plasma vitamin C level in King County was also the
      highest of the 3 study sites: 927.9 +/- 43.9 microg/dl in King County, 585.7 +/-
      35.9 microg/dl in Shanghai and 461.1 +/- 33.1 microg/dl in Costa Rica. Plasma
      trans fatty acids (a biomarker of a diet high in hydrogenated fats) were highest
      in King County and lowest in Shanghai.

PMID- 10360817
TI  - Meat intake and risk of squamous cell esophageal cancer: a case-control study in
      Uruguay.
AB  - In order to examine the relationship between different types of meat and squamous
      cell cancer of the esophagus, a case-control study was carried out in Uruguay.
      Eighty-two cases and 248 hospitalized controls were frequency-matched on age,
      sex, residence and urban/rural status. All patients responded to a detailed
      questionnaire, which included a food-frequency form for 64 food items
      representative of the usual Uruguayan diet. Whereas increases in risk were
      observed for high intake of salted meat [odds ratio (OR) 2.5, 95% confidence
      interval (CI) 1.1-5.4] and lamb (OR 2.1, 95% CI 1.1-4.2), beef from cow was
      inversely associated with the risk of esophageal cancer (OR 0.4, 95% CI 0.2-0.9).
      Also, polyunsaturated fat from meat was associated with an increased risk (OR
      3.2, 95% CI 1.0-9.8). Finally, total meat intake was not associated with squamous
      cell cancer of the esophagus.

PMID- 10360818
TI  - Lifestyle and endometrial cancer risk: a cohort study from the Swedish Twin
      Registry.
AB  - Case-control studies of lifestyle factors have been inconclusive in the study of
      endometrial cancer, and prospective data are scarce. Our aim was to examine the
      associations of physical activity, weight and weight change, fruit, vegetable,
      and alcohol consumption, socio-economic status, parity and presence of diabetes
      mellitus with the risk of endometrial cancer in a cohort study. In 1967, 11,659
      women in the Swedish Twin Registry, born 1886-1925, answered a 107-item
      questionnaire, including questions about diet, physical activity and other
      lifestyle factors. Complete follow-up through 1992 was attained through record
      linkage to the Swedish Cancer and Death Registers. The relative risks for
      endometrial cancer were estimated in proportional hazards models that adjusted
      confidence limits for correlated outcomes. We observed 133 incident cases of
      endometrial cancer in the cohort. There was no clear pattern of risk over strata
      of alcohol or fruit and vegetable intake, although the data suggest an increased
      risk with very low fruit and vegetable intake. Increasing physical activity
      markedly decreased the risk of endometrial cancer (p for trend < 0.01),
      independently of weight and parity; the risk in the highest quartile, relative to
      the sedentary category, was 0.2 (95% CI 0.3-0.8). As expected, higher weight in
      middle age increased the risk (p for trend < 0.01), as did higher weight in early
      adulthood. Contrary to previous findings, weight gain did not have an effect
      independent of weight at enrollment. We did not find a genetic component to
      endometrial cancer. Our results confirm that environmental factors are the most
      important, especially physical activity, parity, and weight in young and middle
      age.

PMID- 10360819
TI  - Structural alterations of transforming growth factor-beta receptor genes in human
      cervical carcinoma.
AB  - The development and progression of invasive uterine cervical carcinomas appear to
      be associated with the progressive loss of sensitivity to transforming growth
      factor-beta (TGFbeta)-mediated cell cycle arrest. In order to identify possible
      molecular mechanisms responsible for TGFbeta resistance, we screened the 7 exons
      of the type II (TbetaR-II) TGFbeta receptor and the 9 exons of the type I (TbetaR
      I) TGFbeta receptor genes for mutations in 16 paraffin-embedded primary invasive
      cervical carcinoma specimens. In one of these carcinomas, we found a novel G-->T
      transversion in exon 3 of TbetaR-II that introduces a premature stop codon
      (E142Stop) and presumably results in the synthesis of a truncated soluble
      exoreceptor. In one tumor, a silent A-->C transversion mutation that may affect
      mRNA splicing was present in exon 6 of TbetaR-I. In addition, 7 of 16 cases were
      heterozygous for a G-->A polymorphism in intron 7 of TbetaR-I. Finally, we
      identified a 9 base pair in-frame germline deletion in exon 1 of TbetaR-I
      resulting in loss of 3 of 9 sequential alanine residues at the N-terminus in 6 of
      16 cases. Analysis of specimens from case-control studies indicated that carriers
      of this del(GGC)3 TbetaR-I variant allele may be at a increased risk for the
      development of cervical carcinoma (p=0.22). Furthermore, the response of cells
      expressing the variant receptor to TGFbeta was diminished. Our results support
      the notion that diverse alterations in the TGFbeta signaling pathway may play a
      role in the development of cervical cancer.

PMID- 10360820
TI  - Detection of CD43 (leukosialin) in colon adenoma and adenocarcinoma by novel
      monoclonal antibodies against its intracellular domain.
AB  - CD43 is a leukocyte-associated sialoglycoprotein which is also expressed in human
      colon adenoma and carcinoma. To obtain monoclonal antibodies (MAbs) that would
      react with CD43 in a glycosylation-independent way, antibodies were raised
      against a peptide corresponding to a portion of the CD43 cytoplasmic domain.
      Hybridomas were screened on paraffin sections from CD43-positive colon tumours.
      The reactivity of the antibodies with CD43 was verified by Western blot analysis
      of lysate of CHO cells transfected with human CD43 cDNA and by
      immunoprecipitation of lysates from CD43+ cell lines. Epitope mapping of
      antibodies was done using overlapping heptameric peptides. A detailed
      characterisation of one of the novel antibodies (CD43-3A1) is presented. This
      antibody reacts with the CD43 protein regardless of its glycosylation in Western
      blot analysis, immunoprecipitation and immuno-histochemistry of paraffin
      sections. Immuno-histochemical analysis of paraffin sections from colon adenoma
      and carcinoma tissues as well as colon cancer cell lines revealed that CD43 was
      predominantly localised intracellularly, in contrast to leukocyte-type cells. The
      MAb reacted more efficiently with paraffin-embedded colon adenoma and carcinoma
      cells than previously characterised CD43-specific antibodies. This should
      facilitate the evaluation of a potential role of CD43 during cancer development.

PMID- 10360821
TI  - Microsatellite instability and/or loss of heterozygosity in young gastric cancer
      patients in Italy.
AB  - Gastric cancers are rarely diagnosed before the age of 40 years and the incidence
      reaches a peak during the 7th decade in the general population. A molecular
      mechanism of early tumor onset may be determined by comparing microsatellite
      instability (MSI), indicative of error-prone mismatch repair, and loss of
      heterozygosity (LOH) between gastric cancers in patients < or = 40 years of age
      and those of older ages. Three to 5 chromosomal loci, where MSI and/or LOH are
      commonly found in gastric cancers in the general population, were examined in
      formalin-fixed, paraffin-embedded samples from 102 patients < or = 40 years of
      age using a polymerase chain reaction-based non-radioactive screening method. MSI
      and/or LOH at a minimum of 1 locus were detected in 11/102 patients. The
      frequency of MSI and/or LOH at the D11S904 locus was significantly higher than
      that at the D2S119, D2S123, D5S409 and IFNA regions. No preferential genetic
      changes at the D11S904 locus were observed in elderly patients. Among several
      clinicopathological variables, a statistically significant association with MSI
      and/or LOH was observed only for tumors located at the cardia, compared with
      tumors at the antrum and the corpus. Our findings suggest that a unique mechanism
      may be involved in increasing the susceptibility of the D11S904 locus for either
      MSI or LOH, especially for cardia tumors in young patients. Early onset of
      gastric cancers in patients < or = 40 years of age is associated with genetic
      changes at preferential chromosomal loci, including D11S904.

PMID- 10360823
TI  - Changes in cadherin-catenin complexes in the progression of human bladder
      carcinoma.
AB  - We are investigating the hypothesis that cancer progression involves the
      formation of abnormal cadherin-catenin complexes. The detailed analysis of
      cadherins and catenins expressed in a panel of 17 human bladder-cancer cell lines
      revealed that E-cadherin was down-regulated at the mRNA level in 5 cell lines.
      Interestingly, plakoglobin was also down-regulated at the mRNA level in these 5
      cell lines only. Furthermore, a slower migrating form of pp120 was detected in
      these cell lines and in 2 cell lines with heterogeneous E-cadherin expression.
      Cloning of the cadherins expressed in the bladder lines revealed that P-cadherin
      is expressed in the lines expressing E-cadherin and down-regulated at the mRNA
      level in lines devoid of E-cadherin. N-cadherin was expressed in the 5 lines with
      reduced E-cadherin expression, in the 2 lines with heterogeneous E-cadherin
      expression and in 2 other cell lines. Thus, we showed that catenin changes occur
      in correlation with lack of E-cadherin expression and that N-cadherin becomes
      predominantly expressed in cells that have lost E-cadherin expression. Our data
      suggest that co-regulation of the expression of genes encoding different members
      of the classical cadherins occurs during tumor progression and that expression of
      some catenins is also coordinated with cadherin expression.

PMID- 10360822
TI  - Microsatellite instability and clonal heterogeneity of MDR1 messenger RNA
      expression in trimetrexate-resistant human leukemia MOLT-3 cells developed in
      thymidine.
AB  - Various gene alterations are involved in the drug resistance of leukemia cells.
      To understand the mechanism that underlies the emergence of cells with such gene
      alterations in human leukemia, we performed clonal analysis of the gene
      expression of mutant dihydrofolate reductase (DHFR) and mdr1 in trimetrexate
      resistant human leukemia MOLT-3 cells. Trimetrexate-resistant (70- and 60-fold)
      sublines were developed in the presence or absence of an exogenous supply of
      thymidine (MOLT-3/TMQ70/Th+, MOLT-3/TMQ60/Th-, respectively). Ten clonal lines
      were isolated by methyl cellulose cloning from each of the 2 trimetrexate
      resistant MOLT-3 sublines. All the clonal lines from the 2 sublines expressed
      mutated DHFR mRNA, with a base change (T --> C) at the second position of codon
      31, as well as the wild-type mRNA, in accordance with cross-resistance to
      methotrexate. On the other hand, mdr1 mRNA expression was demonstrated by reverse
      transcription polymerase chain reaction only in clonal lines from MOLT
      3/TMQ70/Th+ cells. mdr1 mRNA expression in clonal lines from MOLT-3/TMQ70/Th+
      cells and subclonal lines subsequently obtained from the 3 clonal lines with
      different mdr1 mRNA expression levels was heterogeneous, and its high expression
      levels were correlated with acquisition of the multidrug resistance (MDR)
      phenotype. Polymerase chain reaction-based assay for separate microsatellites,
      mfd27 and mfd41, demonstrated genomic instability among clonal and subclonal
      lines of MOLT-3. The clonal analysis of polymorphic microsatellites also
      suggested that emergence of MDR in trimetrexate-resistant MOLT-3 cells in
      thymidine was not only heterogeneous but also progressively expanding among
      clones. Genomic instability may play a role in the establishment and clonal
      evolution of drug resistance in leukemia cells.

PMID- 10360824
TI  - Human breast-cancer metastasis formation in a nude-mouse model: studies of
      hyaluronidase, hyaluronan and hyaluronan-binding sites in metastatic cells.
AB  - Few animal models are available to study metastasis formation. The purpose of the
      present study was to obtain a useful model of metastasis formation in nude mice
      in an attempt to analyze the stroma reaction and in particular the production and
      the expression of hyaluronan (HA), hyaluronidase, and HA-binding sites by
      cultivated cells, and HA and hyaluronectin (HN) in the invasive areas of tumors.
      Nude mice were subjected to i.p. injections of several human cancer cell lines
      (PLC/PRF/5, HepG2, CB 191, CB 193, PC3, CAL 51, SA 87 and SA 98), and formation
      of metastases was analyzed in different organs (lung, liver, kidney, spleen and
      axillary nodes) by immunohistochemical techniques. CAL 51, a breast-cancer
      metastasis-derived cell line with a normal karyotype, produced i.p. tumors in 75%
      animals and metastases in 90% animals (detected in the liver and axillary nodes).
      Two modes of invasion by CAL 51 cells were observed in the liver: one, direct,
      from the surface of the liver and the other, indirect, via the bloodstream. HA
      and HN were strongly expressed at the invasion areas. A cell line derived from
      hepatic metastasis of CAL 51 (HMD CAL 51) presented an abnormal karyotype. HMD
      CAL 51 produced more hyaluronidase (12-fold) and HA (10-fold) and expressed more
      CD44 (1.6-fold) and other HA-binding sites (9.5-fold) than the established cell
      line CAL 51. Our results show that i.p. injection of the CAL 51 cell line into
      nude mice provides a useful model of metastasis formation. The passage of the CAL
      51 cells from the primary state to the metastatic state was characterized by a
      dramatic increase of HA and hyaluronidase production, and expression of HA, HN
      and HA-binding sites.

PMID- 10360825
TI  - Synergistic interaction of ultrasonic shock waves and hyperthermia in the Dunning
      prostate tumor R3327-AT1.
AB  - Pulsed high-energy ultrasound shock waves (PHEUS), similar to those used for
      clinical lithotripsy, can deposit energy deep in tissue and thereby destroy the
      microvasculature of solid tumors. We investigated the potential of PHEUS,
      generated by an electromagnetic shockwave source (19 kV capacitor voltage, 1 Hz
      pulse frequency), as a local cancer-therapy modality alone and in combination
      with local tumor hyperthermia (43.5 +/- 0.1 degrees C, 30 min). Copenhagen rats
      transplanted with the anaplastic Dunning-prostate-tumor sub-line R3327-AT1
      received 1000 PHEUS pulses, which delayed tumor growth by one tumor-doubling time
      (5 days). Histopathology revealed hemorrhage, disruption of tumor vasculature,
      and necrosis in the focus of the sound field. Bromodeoxyuridine (BUdR)
      incorporation was significantly lower in PHEUS-treated tumors than in controls.
      Dynamic magnetic resonance imaging (MRI) studies using gadolinium-DTPA as
      contrast agent showed a strong reduction of tumor perfusion after PHEUS
      treatment, although this effect was partly reversible within 3 days after PHEUS.
      While hyperthermia alone produced no significant delay in tumor growth, the
      combination of PHEUS and hyperthermia produced tumor-growth delay by 2 tumor
      volume-doubling times. The maximum growth delay was achieved when PHEUS and
      hyperthermia were separated by 24 hr at the time of maximum perfusion reduction
      indicated by MRI. Thus, the cytotoxic effect of PHEUS was enhanced by
      hyperthermia in the anaplastic prostate tumor R3327-AT1 grown on Copenhagen rats
      in a synergistic manner, due to blood-flow reduction. In conjunction with other
      agents, such as hyperthermia, PHEUS might become a local cancer-therapy modality
      in solid tumors accessible to ultrasound.

PMID- 10360826
TI  - Leukemia-induced bone marrow depression: effects of gangliosides on erythroid
      cell production.
AB  - Bone marrow depression is a common feature in hematological malignancies or other
      bone marrow-involving cancers. The mechanism of this hemopoietic suppression
      resulting in pancytopenia and especially anemia has not been elucidated.
      Gangliosides can be shed by cancer cells. Therefore, we investigated the effects
      of exogenously added gangliosides on erythropoiesis in a human and murine in
      vitro system. A dose-dependent inhibition of murine colony-forming-unit-erythroid
      (CFU-E) and burst-forming-unit-erythroid (BFU-E) colony growth was observed.
      Furthermore the maturation of BFU-Es into CFU-Es was inhibited. The inhibition by
      gangliosides was not abolished by increasing the dose of erythropoietin (10
      U/ml). FACS-analysis studies with human CD34+ cells cultured with gangliosides
      (GM3), erythropoietin (EPO) and stem cell factor (SCF) demonstrated a strong
      inhibition on cell growth. This resulted in a significantly higher percentage of
      immature cells (CD34+/GpA-, 24% vs. 3%), and a lower percentage of mature
      erythroid cells (CD34-/GpA+, 36% vs. 89%). Under these circumstances the effects
      on erythroid cell growth were much higher than on other cell lineages. The
      inhibitory effect of gangliosides isolated from acute lymphoblastic leukemic
      patients on in vitro erythropoiesis suggests that in vivo hemopoietic suppression
      might have its origin in the gangliosides present and probably shed by the
      malignant cells in the microenvironment and plasma. Our results show that
      gangliosides inhibit erythropoiesis in vitro at several stages of development, by
      a mechanism involving modulation of the maturation of erythroid cells.

PMID- 10360827
TI  - ckshs expression is linked to cell proliferation in normal and malignant human
      lymphoid cells.
AB  - Cyclin kinase sub-units (CKS) are known to interact with cyclin-dependent kinases
      (CDKs), but their functions are not completely understood and their expression in
      human tissues is not documented. For analyzing relationships of CKS with cell
      proliferation and/or with differentiation, we investigated the expression of
      ckshs1 and ckshs2 in normal and malignant human lymphoid cells. ckshs1 and ckshs2
      expression appeared to be related to cell proliferation: (i) mRNAs increased with
      stimulation of normal peripheral-blood lymphocytes, and from the G1 to the SG2M
      phase in elutriated cells; (ii) P9 proteins were also induced by lymphocyte
      stimulation and were localized in nucleus where phosphorylated forms of CDK1 were
      also found; (iii) in vitro, the phosphorylated forms of CDK1 and CDK2 were
      preferentially linked to CKS. Among 45 patients presenting acute or chronic
      lymphoid malignancy, ckshs1 and ckshs2 mRNAs varied in a similar way and were
      significantly correlated to cell proliferation (p < 0.0001). When analysis was
      restricted solely to acute lymphoblastic leukemia (ALL) this correlation was
      still found and ckshs1 and ckshs2 were significantly more expressed in T-cell ALL
      than in B-cell-lineage ALL. These results confirm relationships between ckshs
      expression and cell proliferation, and pose the question of a link with cell
      differentiation.

PMID- 10360828
TI  - Combined therapy with anti-P-glycoprotein antibody and macrophage colony
      stimulating factor gene transduction for multiorgan metastases of multidrug
      resistant human small cell lung cancer in NK cell-depleted SCID mice.
AB  - Our aim was to determine the antimetastatic potential of anti-P-glycoprotein (P
      gp) antibodies (Abs) against multidrug-resistant (MDR) human small cell lung
      cancer (SCLC) cells expressing P-gp. Human SCLC cells H69 (P-gp negative) and its
      etoposide-resistant variant H69/YP (P-gp positive) were used. H69 and H69/VP
      cells injected i.v. metastasized to the liver, kidneys and systemic lymph nodes
      of NK cell-depleted severe combined immunodeficient (SCID) mice. H69/VP cells,
      but not H69 cells, were resistant to treatments with vindesine. Treatment with
      mouse-human chimeric anti-P-gp Ab (MH162) and its mouse counterpart (MRK-16)
      reduced metastasis of H69/VP cells in various organs and prolonged the survival
      of tumor-bearing mice, although they were less effective if injected at late
      times (after 28 days). Treatment with another mouse anti-Pgp Ab, MRK-17, was
      effective only against liver metastasis. MH162 and MRK-16 efficiently induced Ab
      dependent cellular cytotoxicity (ADCC) by peritoneal macrophages against H69/VP
      cells in vitro, but MRK-17 was less effective, in accordance with their in vivo
      antimetastatic potential. Gene transfection of macrophage colony-stimulating
      factor (M-CSF) into H69/VP cells to augment macrophage-mediated ADCC resulted in
      inhibition of metastasis to the liver and lymph nodes, but not kidneys. Combined
      treatment with a low dose of MRK-16 completely cured metastasis of M-CSF
      transfectant, but not of the mock transfectant. Our findings suggest that while
      anti-P-gp Abs had antimetastatic potential against SCLC cells expressing P-gp,
      combined treatment with M-CSF gene transduction to augment the therapeutic
      efficacy of anti-P-gp Abs may be beneficial for eradicating metastatic MDR SCLC
      in humans.

PMID- 10360829
TI  - Correlation of overexpression of the low-affinity p75 neurotrophin receptor with
      augmented invasion and heparanase production in human malignant melanoma cells.
AB  - The role of growth factor receptors in regulating the progression of human
      melanocytes toward tumorigenicity and ultimately a malignant phenotype is poorly
      understood. In particular, the autocrine and paracrine influences that modulate
      cellular invasion and extracellular matrix (ECM)-degradative enzymes in melanoma
      cells remain undefined at the molecular level. The low-affinity p75 neurotrophin
      receptor (p75NTR), a cysteine-rich transmembrane glycoprotein, is frequently
      expressed in advanced stages of human melanoma, but the biological consequences
      of this expression are unknown. p75NTR can enhance the invasive potential of
      brain-metastatic melanoma cells in vitro. We have extended here these results and
      related the level of p75NTR in human metastatic melanoma cells to their invasive
      potential to target organs other than brain. Fluorescence activated cell sorting
      (FACS) analysis showed that 3 melanoma cell lines (SK-MEL-146, SK-MEL-119, 70W)
      had differential p75NTR contents, whereas SK-MEL-147 cells had elevated amounts
      of p75NTR. Two other melanoma cell lines (SK-MEL-94, SK-MEL-110) with point
      mutations in the p75NTR transmembrane domain had reduced (SK-MEL-94) or absent
      (SK-MEL-110) p75NTR. We also examined these cell lines for presence of TrkA
      receptor, the high-affinity receptor for nerve growth factor (NGF), the
      prototypic neurotrophin. No TrkA receptor expression was detected in any of the
      cell lines. The extent of p75NTR expression correlated with the capability of NGF
      to promote cellular invasion and with production of heparanase, an important ECM
      degradative enzyme. Melanoma cells sorted for high p75NTR expression (p75NTR-H
      cells) had markedly greater (9- to 13-fold increase) invasive capabilities in
      response to NGF exposure than those sorted for low p75NTR expression (p75NTR-L
      cells). Additionally, NGF induced a 8- to 10-fold increase of heparanase activity
      in p75NTR-H cells. Thus, we propose that p75NTR-mediated trophic support
      profoundly affects melanoma cell invasion to neurotrophin-rich organs.

PMID- 10360830
TI  - Induction of carcinoembryonic antigen (CEA)-specific cytotoxic T-lymphocyte
      responses in vitro using autologous dendritic cells loaded with CEA peptide or
      CEA RNA in patients with metastatic malignancies expressing CEA.
AB  - The application of dendritic cells (DC) to the active immunotherapy of cancer
      currently relies on the generation of potent DC capable of presenting tumor
      antigens such as carcinoembryonic antigen (CEA). It is unknown whether the T
      cells of patients with advanced malignancies can be reliably stimulated against
      tumor antigens by their autologous DC. In this study, starting with the
      peripheral blood mononuclear cells (PBMC) of patients with metastatic
      malignancies expressing CEA, autologous DCs were generated in vitro in serum-free
      media supplemented with GM-CSF and IL-4. The DCs from HLA A2 positive patients
      were loaded with the CEA peptide CAP-1 and the DCs from HLA A2 negative patients
      were depleted of bystander lymphocytes and loaded with mRNA encoding CEA. The DC
      preparations were tested to determine their phenotype and were used to stimulate
      autologous PBMC twice, separated by 10-14 days. The stimulated cells were then
      tested for their ability to lyse CEA-expressing target cells. We successfully
      generated an adequate number of DC for a clinical trial from all patients. The
      harvested DC preparations contained 49% DC and 87% DC if depleted of bystander
      lymphocytes. Phenotypic analysis showed the typical pattern of CD11c+ CD40+ CD86+
      HLA-DR+ CD80(low) CD83(low) CD14(low). All preparations but one were able to
      stimulate CEA-specific cytotoxic T-lymphocyte (CTL) activity, suggesting that the
      majority of patients are not anergic to CEA and possess functional DC. The CTL
      activity was similar for the CEA peptide and CEA RNA-loaded DC.

PMID- 10360831
TI  - bcl-2 inhibits mitochondrial metabolism and lonidamine-induced apoptosis in
      adriamycin-resistant MCF7 cells.
AB  - Lonidamine (LND), a selective inhibitor of the energy metabolism of tumor cells,
      induces apoptosis, independently of the p53 gene, in the adriamycin(ADR)
      resistant MCF7 breast-cancer cell line (MCF7 ADR). On the contrary, LND fails to
      activate the apoptotic program in the parental MCF7-sensitive cell line (MCF7
      WT). The extent of bcl-2 expression might account for the different effect of LND
      on these cell lines. In fact, the MCF7 ADR line shows a low level of bcl-2
      protein, whereas MCF7 WT expresses a high level of bcl-2. We therefore
      investigated the relationship between the amount of bcl-2 and the ability of LND
      to induce apoptosis, using 4 clones over-expressing bcl-2. The effect of bcl-2 on
      the energy metabolism was also evaluated. We demonstrated that over-expression of
      bcl-2 inhibited LND-induced apoptosis, while reducing 14CO2 production, oxygen
      uptake and ATP content, whereas aerobic lactate production was essentially
      unaffected. In addition, LND decreased the oxidative metabolism of the MCF7 ADR
      cells to a greater extent than it did in the bcl-2 transfectants.

PMID- 10360833
TI  - Tight junction protein ZO-2 is differentially expressed in normal pancreatic
      ducts compared to human pancreatic adenocarcinoma.
AB  - Differential display of hamster mRNA identified a fragment present in normal
      pancreatic duct cells that is not expressed in pancreatic duct carcinoma cells.
      Sequence analysis showed an 88% and 82% identity, respectively, to the cDNA of
      the canine and human tight junction zo-2 gene. Semi-quantitative RT-PCR analysis
      of human ZO-2 revealed a striking difference in the expression of various regions
      of the ZO-2 transcript in normal and neoplastic cells and the presence of an
      abnormality at the 5'-end of mRNA. RACE analysis identified 2 human ZO-2 mRNAs
      that encode proteins of different lengths, designated as ZO-2A and ZO-2C. The
      difference between the 2 forms of ZO-2 is the absence of 23 amino acid residues
      at the N terminus of ZO-2C compared with ZO-2A. Although ZO-2C was expressed in
      normal pancreatic cells and a majority of neoplastic tissues analyzed, ZO-2A was
      undetectable except in one case in all of the pancreatic adenocarcinomas
      analyzed. This suggests the presence of a yet to be identified motif important
      for cell-growth regulation within the 23-amino acid residue N-terminal peptide of
      ZO-2A, MPVRGDRGFPPRRELSGWLRAPG.

PMID- 10360832
TI  - Inhibition of angiogenesis and breast cancer xenograft tumor growth by VEGI, a
      novel cytokine of the TNF superfamily.
AB  - Recently, we reported a novel protein of the tumor necrosis factor (TNF)
      superfamily, named vascular endothelial cell growth inhibitor (VEGI), which is
      expressed predominantly in endothelial cells. When a secreted form of this new
      protein was overexpressed in mouse colon cancer cells, the growth of tumors
      formed by these cells in black mice was inhibited. We now report that recombinant
      VEGI inhibits the proliferation of endothelial cells but not that of other types
      of cells examined. The protein also inhibits formation of capillary-like
      structures by endothelial cells in collagen gels, and the growth of capillaries
      into collagen gels placed on the chick chorioallantoic membrane. The anticancer
      potential of VEGI was examined in a breast cancer xenograft tumor model in which
      the cancer cells were co-injected with Chinese hamster ovary cells overexpressing
      a secreted form of the protein. The co-injection resulted in potent inhibition of
      xenograft tumor growth. Our findings are consistent with the view that VEGI is an
      endothelial cell-specific negative regulator of angiogenesis.

PMID- 10360834
TI  - Increased growth capacity of cervical-carcinoma cells over-expressing manganous
      superoxide dismutase.
AB  - Increases in the expression of manganese-dependent superoxide dismutase (MnSOD)
      have been detected in several classes of human and experimental tumors and appear
      to correlate with poorer prognosis in human neuro-epithelial, ovarian and
      cervical tumors. To delineate the relevance of MnSOD expression to tumor-cell
      growth and survival, a human MnSOD cDNA was over-expressed in the HeLa cervical
      carcinoma cell line. MnSOD over-expression had marginal effects on the growth of
      HeLa cells in standard medium, but markedly protected the cells from growth
      suppression and cell death in conditions of serum deprivation. Serum starvation
      did not affect expression of endogenous MnSOD in wild-type HeLa cells, but was
      associated with increases in cell death and in the generation of intracellular
      oxygen radicals. By contrast, in HT29 colon-carcinoma cells, which are relatively
      resistant to growth-factor withdrawal, serum deprivation was associated with
      increases in MnSOD expression and activity. Together these observations suggest
      that MnSOD provides a mechanism for counteracting the intracellular oxidative
      processes that impair cell growth and viability in the context of growth-factor
      withdrawal and, in this context, may promote tumor-cell survival in vivo in
      conditions normally unfavorable to cell growth.

PMID- 10360835
TI  - Vegetables and fruit and human cancer: update of an Italian study.

PMID- 10360836
TI  - EVI2B, a gene lying in an intron of the neurofibromatosis type 1 (NF1) gene, is
      as the NF1 gene involved in differentiation of melanocytes and keratinocytes and
      is overexpressed in cells derived from NF1 neurofibromas.
AB  - The EVI2B gene is one of three genes embedded in intron 27b of the
      neurofibromatosis type 1 (NF1; M. Recklinghausen) gene, which are transcribed in
      the direction opposite that of the NF1 gene. The function of EVI2B and its
      relation to NF1 symptoms is unknown. Here, the amounts of NF1 and EVI2B mRNA were
      investigated in detail in cells involved in NF1 manifestations as cafe-au-lait
      macules and neurofibromas. These investigations showed that aside from the NF1
      gene, EVI2B is involved in melanocyte and keratinocyte differentiation. Whereas
      in NF1 melanocytes from cafe-au-lait macules, EVI2B expression was not altered,
      in fibroblast-like cells derived from neurofibromas, an increased level of EVI2B
      mRNA was found. We investigated whether this increase was attributable to an
      influence of NF1 gene expression on the expression of the EVI2B gene, as
      suggested by the fact that the EVI2B primary transcript is antisense to the NF1
      primary transcript. Investigations of cells derived from patients with different
      amounts of NF1 pre-mRNA showed no correlation between the amount of NF1 pre-mRNA
      and the increased level of EVI2B mRNA.

PMID- 10360837
TI  - Growth arrest of melanoma cells is differentially regulated by contact inhibition
      and serum deprivation.
AB  - Both growth-factor deprivation and contact inhibition suppress cell growth;
      however, the mechanisms by which they inhibit cell proliferation may not be
      identical. The function of antiproliferative genes and the induction of
      programmed cell death are among the potential differences between these growth
      arrest mechanisms. Specifically, an inverse relation between the expression of
      cyclin-dependent kinase inhibitors (CDKIs) and the susceptibility to apoptosis
      has been reported. To test this relation, we examined the features of growth
      arrest in a canine melanoma cell line, TLM1. Both contact inhibition and serum
      deprivation halted cell-cycle progression of TLM1 cells in the G1 phase.
      Prolonged growth arrest of the cells without restimulation resulted in apoptosis;
      conversely, the cells reentered the cell cycle after release from contact
      inhibition or on restimulation with serum. Cell-to-cell contact, but not serum
      deprivation, led to the expression of p53 and p21/Waf-1. The expression of
      p21/Waf-1 did not prevent apoptosis. Moreover, the ectopic overexpression of
      CDKIs increased apoptosis. These results support the premise that growth arrest
      induced by contact inhibition and serum deprivation are mediated through distinct
      mechanisms. Furthermore, CDKIs are not universal inhibitors of apoptosis, and in
      some cases, they may initiate or enhance the apoptotic program.

PMID- 10360838
TI  - Cloning, expression, and characterization of human metalloprotease 1: a novel
      member of the pitrilysin family of metalloendoproteases.
AB  - A novel cDNA, designated human metalloendoprotease 1 (hMP1), was identified on
      the basis of homology to known metalloendoproteases of the pitrilysin family. The
      full-length MP1 codes for a protein with an open reading frame of 1038 amino
      acids. The N-terminal region contains the HXXEH(X)76E catalytic domain that is
      conserved in the members of pitrilysin family, namely insulin-degrading enzyme
      and NRD convertase. The hMP1 mRNA is expressed in a number of cell lines and
      tissues as a single species of about 3.4 kb. The expression of hMP1 mRNA is
      higher in muscle and heart than in brain, pancreas, liver, lung, and placenta.
      The full-length hMP1 was expressed in the baculovirus system and purified to
      homogeneity using isoelectrofocusing and ion-exchange chromatography. The enzyme
      exhibited a neutral pH optimum and high sensitivity to thiol reagents. HMP1 was
      inactivated by 1,10-phenanthroline, a specific inhibitor of Zn(+2)-dependent
      metalloproteases. The enzyme was not inhibited by agents that inhibit neutral
      metalloendoproteases of the thermolysin family such as thimet endo
      oligopeptidase, enkephalinase, or angiotensin-converting enzyme. HMP1 cleaved a
      prodynorphin-derived peptide, leumorphin, N-terminal to Arg in the monobasic
      processing site, as evidenced by MALDI-TOF mass spectrometry. However, the enzyme
      did not exhibit strict monobasic cleavage specificity, as peptide substrates with
      amino acid substitutions around the monobasic site was cleaved efficiently by
      hMP1. Taken together, these results suggest that hMP1 is a novel member of the
      metalloendoprotease superfamily with ubiquitous distribution that could play a
      broad role in general cellular regulation.

PMID- 10360839
TI  - Comparative analysis of KRAB zinc finger proteins in rodents and man: evidence
      for several evolutionarily distinct subfamilies of KRAB zinc finger genes.
AB  - Although the KRAB zinc finger proteins probably constitute the single largest
      class of transcription factors within the human genome, almost nothing is known
      about their biological function. To increase our knowledge about this interesting
      and relatively unexplored family of potent transcriptional repressors, we here
      present the cloning, structural analysis, and expression study of three novel
      mouse KRAB zinc finger proteins. In addition, we present an extensive comparative
      analysis of various members of this gene family based on the structure of the
      common KRAB A motif. At least three larger subfamilies of KRAB zinc finger
      proteins are identified: one carrying the classical KRAB A motif only, another
      holding both a classical KRAB A and a classical KRAB B motif, and a third holding
      a classical KRAB A and a highly divergent KRAB B domain, named b. A large
      variation both in size and in primary amino acid sequence was observed in the
      linker region between the KRAB domain and the C-terminally located zinc finger
      repeats. This variability indicates that this region is of minor importance for
      the biological function of KRAB-containing zinc finger proteins. The fact that in
      many zinc finger genes, the entire or almost the entire linker region is composed
      of degenerate finger motifs substantiates this conclusion. The absence of
      identifiable KRAB A and B motifs in the genome of yeast, Saccharomyces
      cerevisiae, indicates a relatively late appearance of the KRAB domain in
      evolution and may suggest that the biological functions are restricted to
      multicellular organisms. In addition, we show that the expression of individual
      members of one subfamily of KRAB zinc finger genes is restricted to specific
      hematopoietic cell lineages. This finding suggests that KRAB zinc finger proteins
      may play a role in lineage commitment, possibly silencing leakage transcription
      from nonlineage-expressed genes.

PMID- 10360840
TI  - Chimeric forms of neuronal nitric oxide synthase identify different regions of
      the reductase domain that are essential for dimerization and activity.
AB  - Nitric oxide synthase (NOS) is the enzyme responsible for the conversion of L
      arginine to L-citrulline and nitric oxide. Dimerization of the enzyme is an
      absolute requirement for catalytic activity. Each NOS monomer contains an N
      terminal heme-binding domain and a C-terminal reductase domain. It is unclear how
      the reductase domain is involved in controlling dimerization and whether dimer
      formation alone controls enzyme activity. Our initial studies demonstrated that
      no dimerization or activity could be detected when the reductase domain of rat
      neuronal NOS (nNOS) was expressed either separately or in combination with the
      heme domain. To further evaluate the reductase domain, a set of expression
      plasmids was created by replacing the reductase domain of nNOS with other
      electron-transport proteins, thereby creating nNOS chimeric fusion proteins. The
      rat nNOS heme domain was linked with either cytochrome P450 reductase,
      adrenodoxin reductase, or the reductase domain from Bacillus megaterium
      cytochrome P450, BM-3. All the chimeric enzymes retained the ability to dimerize
      but were unable to metabolize L-arginine (<8% of wildtype activity levels),
      indicating that dimerization alone is insufficient to produce an active enzyme.
      Because the greatest regions of homology between electron-transport proteins are
      in the flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), and
      nicotinamide adenine dinucleotide phosphate (NADPH) binding regions, we produced
      truncation mutants within the nNOS reductase domain to investigate the role of
      these sequences in the ability of nNOS to dimerize and to metabolize L-arginine.
      The results demonstrated that the deletion of the final 56 amino acids or the
      NADPH-binding region had no effect on dimerization but produced an inactive
      enzyme. However, when the FAD-binding site (located between amino acids 920 and
      1161) was deleted, both activity and dimerization were abolished. These results
      implicate sequences within the FAD-binding site as essential for nNOS
      dimerization but sequences within amino acids 1373 to 1429 as essential for
      activity.

PMID- 10360841
TI  - Expression of human prohormone convertase PC2 in a baculovirus-insect cell
      system.
AB  - PC2 is a member of the eukaryotic family of subtilisin-related proprotein
      convertases which are thought to be involved in the intracellular proteolytic
      processing of prohormones and proneuropeptides. The presence of only small
      amounts of PC2 in the secretory granules of certain mammalian neuroendocrine cell
      types has made the characterization and further study of this enzyme difficult.
      We report here the expression of proteolytically active human PC2 protein in the
      insect cell-baculovirus system. Human PC2 expressed in insect cells is a calcium
      dependent intracellular protein active at neutral pH. In insect cells, human PC2
      was found intracellularly as 75-kDa and 71-kDa proteins. Both 73-kDa and 68-kDa
      forms were found in the conditioned medium, but no PC2 proteolytic activity was
      detected. We demonstrated the presence of a soluble inhibitor in infected-cell
      medium which may block PC2 activity.

PMID- 10360842
TI  - Genomic organization of mouse gene zfp162.
AB  - We report the cloning and characterization of the alternatively spliced mouse
      gene zfp162, formerly termed mzfm, the homolog of the human ZFM1 gene encoding
      the splicing factor SF1 and a putative signal transduction and activation of RNA
      (STAR) protein. The zfp162 gene is about 14 kb long and consists of 14 exons and
      13 introns. Comparison of zfp162 with the genomic sequences of ZFM1/SF1 revealed
      that the exon-intron structure and exon sequences are well conserved between the
      genes, whereas the introns differ in length and sequence composition. Using
      fluorescent in situ hybridization, the zfp162 gene was assigned to chromosome 19,
      region B. Screening of a genomic library integrated in lambda DASH II resulted in
      the identification of the 5'-flanking region of zfp162. Sequence analysis of this
      region showed that zfp162 is a TATA-less gene containing an initiator control
      element and two CCAAT boxes. The promoter exhibits the following motifs: AP-2,
      CRE, Ets, GRE, HNF5, MRE, SP-1, TRE, TCF1, and PU.1. The core promoter, from
      position -331 to -157, contains the motifs CRE, SP-1, MRE, and AP-2, as
      determined in transfected CHO-K1 cells and IC-21 cells by reporter gene assay
      using a secreted form of human placental alkaline phosphatase. The occurrence of
      PU.1/GRE supports the view that the zfp162 gene encodes a protein involved not
      only in nuclear RNA metabolism, as the human ZFM1/SF1, but also in as yet unknown
      macrophage-inherent functions.

PMID- 10360843
TI  - Frizzled-suc2 fusion gene studies in Saccharomyces cerevisiae.
AB  - The frizzled (fz) gene is required for development of planar tissue polarity in
      the epidermis of Drosophila melanogaster; it likely encodes an integral membrane
      protein that functions as a receptor for a tissue polarity-signaling molecule. On
      the basis of hydropathy analyses, it has been postulated that Fz protein contains
      seven transmembrane domains. Consistent with that model, the amino terminus of Fz
      was found to be extracellular, whereas the carboxyl terminus was intracellular.
      In the present study, the membrane topology of Fz was further examined in vivo by
      constructing various fz-suc2 fusion genes and analyzing their invertase activity
      in transformed yeast. We observed that plating efficiency and growth rate on
      sucrose media, as well as invertase secretion, were consistent with the proposed
      seven-pass model of Fz. This study provides the first experimental assessment of
      overall Fz topology.

PMID- 10360844
TI  - Informed consent for research: the achievements of the past and the challenges of
      the future.

PMID- 10360845
TI  - The influence of age on propofol pharmacodynamics.
AB  - BACKGROUND: The authors studied the influence of age on the pharmacodynamics of
      propofol, including characterization of the relation between plasma concentration
      and the time course of drug effect. METHODS: The authors evaluated healthy
      volunteers aged 25-81 yr. A bolus dose (2 mg/kg or 1 mg/kg in persons older than
      65 yr) and an infusion (25, 50, 100, or 200 microg x kg(-1) x min(-1)) of the
      older or the new (containing EDTA) formulation of propofol were given on each of
      two different study days. The propofol concentration was determined in frequent
      arterial samples. The electroencephalogram (EEG) was used to measure drug effect.
      A statistical technique called semilinear canonical correlation was used to
      select components of the EEG power spectrum that correlated optimally with the
      effect-site concentration. The effect-site concentration was related to drug
      effect with a biphasic pharmacodynamic model. The plasma effect-site
      equilibration rate constant was estimated parametrically. Estimates of this rate
      constant were validated by comparing the predicted time of peak effect with the
      time of peak EEG effect. The probability of being asleep, as a function of age,
      was determined from steady state concentrations after 60 min of propofol
      infusion. RESULTS: Twenty-four volunteers completed the study. Three parameters
      of the biphasic pharmacodynamic model were correlated linearly with age. The
      plasma effect-site equilibration rate constant was 0.456 min(-1). The predicted
      time to peak effect after bolus injection ranging was 1.7 min. The time to peak
      effect assessed visually was 1.6 min (range, 1-2.4 min). The steady state
      observations showed increasing sensitivity to propofol in elderly patients, with
      C50 values for loss of consciousness of 2.35, 1.8, and 1.25 microg/ml in
      volunteers who were 25, 50, and 75 yr old, respectively. CONCLUSIONS: Semilinear
      canonical correlation defined a new measure of propofol effect on the EEG, the
      canonical univariate parameter for propofol. Using this parameter, propofol
      plasma effect-site equilibration is faster than previously reported. This fast
      onset was confirmed by inspection of the EEG data. Elderly patients are more
      sensitive to the hypnotic and EEG effects of propofol than are younger persons.

PMID- 10360846
TI  - Comparison of the effect-site k(eO)s of propofol for blood pressure and EEG
      bispectral index in elderly and younger patients.
AB  - BACKGROUND: Drug effect lags behind the blood concentration. The goal of this
      investigation was to determine the time course of plasma concentration and the
      effects of propofol demonstrated by electroencephalogram or blood pressure
      changes and to compare them between elderly and young or middle-aged patients.
      METHODS: A target-controlled infusion was used to rapidly attain and maintain
      four sequentially increasing, randomly selected plasma propofol concentrations
      from 1 to 12 microg/ml in 41 patients aged 20-85 yr. The target concentration was
      maintained for about 30 min. Bispectral index (BIS), spectral edge frequency, and
      systolic blood pressure (SBP) were used as measures of propofol effect. Because
      the time courses of these measures following the started drug infusion showed an
      exponential pattern, the first-order rate constant for equilibration of the
      effect site with the plasma concentration (k(eO)) was estimated by fitting a
      monoexponential model to the effect versus time data resulting from the pseudo
      steady-state propofol plasma concentration profile. RESULTS: The half-times for
      the plasma-effect-site equilibration for BIS were 2.31, 2.30, 2.29, and 2.37 min
      in patients aged 20-39, 40-59, 60-69, and 70-85 yr, respectively (n = 10 or 11
      each). The half-times for SBP were 5.68, 5.92, 8.87, and 10.22 min in the
      respective age groups. All were significantly longer than for BIS (P < 0.05). The
      propofol concentration at half of the maximal decrease of SBP was significantly
      greater (P < 0.05) in the elderly than in the younger patients. CONCLUSIONS: The
      effect of propofol on BIS occurs more rapidly than its effect on SBP. Age has no
      effect on the rate of BIS reduction with increasing propofol concentration,
      whereas with increasing age, SBP decreases to a greater degree but more slowly.

PMID- 10360847
TI  - Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral
      morphine therapy for cancer pain management.
AB  - BACKGROUND: Guidelines for cancer pain management include nonsteroidal
      antiinflammatory drugs with opioids administered in a time-contingent manner.
      This study was designed to evaluate the role of oral ketamine or transdermal
      nitroglycerin polymer, a nitric oxide donor, as coadjuvants to oral morphine in
      cancer pain therapy. METHODS: After institutional approval and informed patient
      consent were obtained, 60 patients with cancer pain were randomized to one of
      four groups (n = 15) and studied prospectively to evaluate analgesia and any
      adverse effects. A visual analog scale that consisted of a 10-cm line with 0
      representing "no pain at all" and 10 representing "the worst possible pain" was
      introduced. All patients were regularly taking oral amitriptyline 50 mg at
      bedtime. The morphine regimen was adjusted individually to a maximal oral dose of
      80-90 mg/day to keep the visual analog scale score less than 4. When patients
      reported pain (visual analog scale of 4 or more), despite taking 80-90 mg oral
      morphine daily, the test drug was added as follows: the control group (CG)
      received an additional 20 mg oral morphine (10 mg at 12-h intervals); the
      nitroglycerin group (NG) received a 5-mg nitroglycerin patch daily; the ketamine
      group (KG) received 0.5 mg/kg oral ketamine at 12-h intervals; and the dipyrone
      group (DG) received 500 mg oral dipyrone at 6-h intervals. Patients were free to
      manipulate their daily morphine consumption when the test drug was introduced to
      keep their visual analog scale score less than 4. RESULTS: The groups were
      similar with respect to demographic data and visual analog scale pain scores
      before treatment. The visual analog scale scores after the test drug was
      introduced were similar among the groups. The daily consumption of oral morphine
      was as follows: on day 15: CG = DG = NG (P > 0.05), CG > KG (P = 0.036); on day
      20: CG > NG = KG (P < 0.02) (CG > KG, P < 0.005; CG > NG, P < 0.02), DG > KG (P <
      0.05); on day 30: CG = DG > KG = NG (P < 0.05). Patients in the CG and DG groups
      reported somnolence, but patients in the NG and KG groups did not. CONCLUSIONS:
      Low-dose ketamine and transdermal nitroglycerin were effective coadjuvant
      analgesics. In conjunction with their opioid tolerance-sparing function, joint
      delivery of ketamine or nitric oxide donors with opiates may be of significant
      benefit in cancer pain management.

PMID- 10360848
TI  - Study of three different doses of epidural neostigmine coadministered with
      lidocaine for postoperative analgesia.
AB  - BACKGROUND: Intrathecal neostigmine produces analgesia in volunteers and
      patients. However, the use of epidural neostigmine has not been investigated. The
      purpose of the current study was to define the analgesic effectiveness of
      epidural neostigmine coadministered with lidocaine and side effects in patients
      after minor orthopedic procedures. METHODS: After Institutional Review Board
      approval and informed consent, 48 patients (n = 12) undergoing knee surgery were
      randomly allocated to one of four groups and studied in a prospective way. After
      0.05-0.1 mg/kg intravenous midazolam premedication, patients were randomized to
      receive 20 mg intrathecal bupivacaine plus epidural lidocaine (85 mg) with saline
      (control group); 1 microg/kg epidural neostigmine (1 microg group); 2 microg/kg
      epidural neostigmine (2 microg group); or 4 microg/kg epidural neostigmine (4
      microg group). The concept of the visual analog scale, which consisted of a 10-cm
      line with 0 equaling "no pain at all" and 10 equaling "the worst possible pain"
      was introduced. Postoperatively, pain was assessed using the visual analog scale,
      and intramuscular 75 mg diclofenac was available at patient request. RESULTS:
      Groups were demographically the same and did not differ in intraoperative
      characteristics (blood pressure, heart rate, ephedrine consumption, oxyhemoglobin
      saturation, sensory loss before start of surgery, or duration of sensory motor
      block). The visual analog scale score at first rescue analgesic and the incidence
      of adverse effects were similar among groups (P > 0.05). The time (min +/- SD) to
      first rescue analgesic was as follows: control group: 205+/-48; 1-microg group:
      529+/-314; 2-microg group: 504+/-284; 4-microg group: 547+/-263 (P < 0.05). The
      analgesic consumption (number of intramuscular diclofenac injections [mean, 25th
      75th percentile]) in 24 h was as follows: control group: 3 [3 or 4]; 1-microg
      group: 1 [1 or 2]; 2-microg group: 2 [1 or 2]; 4-microg group: 2 [1-3] (P <
      0.05). The 24-h-pain visual analog scale score (cm +/- SD) that represents the
      overall impression for the last 24 h was as follows: control group: 5+/-1.6; 1
      microg group: 1.6+/-1.8; 2-microg group: 1.4+/-1.6; 4-microg group: 2.2+/-1.9 (P
      < 0.005). The incidence of adverse effects was similar among groups (P > 0.05).
      CONCLUSION: Epidural neostigmine (1, 2, or 4 microg/kg) in lidocaine produced a
      dose-independent analgesic effect (approximately 8 h) compared to the control
      group (approximately 3.5 h), and a reduction in postoperative rescue analgesic
      consumption without increasing the incidence of adverse effects.

PMID- 10360849
TI  - The effect of naloxone on ketamine-induced effects on hyperalgesia and ketamine
      induced side effects in humans.
AB  - BACKGROUND: The (NMDA) receptor plays a significant role in wind-up and spinal
      hypersensitivity and is involved in the occurrence of secondary hyperalgesia.
      Ketamine is an NMDA-receptor antagonist and has proven effective in alleviating
      secondary hyperalgesia in humans. Although it is disputed, the actions of
      ketamine have been ascribed not only to NMDA receptor antagonism, but also to
      opioid receptor agonism. A study therefore was designed in which the abolishment
      of a previously demonstrated effect of ketamine on secondary hyperalgesia was
      sought by pretreatment with naloxone. METHODS: Twenty-five volunteers were
      subjected to three treatment regimens. A standardized first-degree burn injury
      was induced. On appearance of primary and secondary hyperalgesia, one of the
      following infusion schemes was applied in a randomized, double-blind, cross-over
      fashion: (1) infusion of naloxone (0.8 mg/15 min followed by 0.4 mg/h), succeeded
      by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1)
      x h(-1)); (2) infusion of placebo, succeeded by infusion of ketamine (0.3 mg x
      kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); and (3) infusion of
      placebo, succeeded by infusion of placebo. Heat-pain detection thresholds,
      magnitude of secondary hyperalgesia around the burn injury, and side effects were
      determined. RESULTS: Ketamine reduced secondary hyperalgesia. Naloxone did not
      affect the action of ketamine. The magnitudes of side effects were equal if the
      subjects received ketamine, regardless of preceding infusion of naloxone.
      CONCLUSIONS: In this experimental setting, opioid receptor blockade does not
      inhibit ketamine-induced reductions of secondary hyperalgesia.

PMID- 10360850
TI  - Phase-contrast MRI measurement of systolic cerebrospinal fluid peak velocity
      (CSFV(peak)) in the aqueduct of Sylvius: a noninvasive tool for measurement of
      cerebral capacity.
AB  - BACKGROUND: Cerebrospinal fluid (CSF) outflow to intra- and extracranial
      subarachnoid spaces caused by arterial inflow to the brain predominantly
      compensates systolic increases in cerebral blood volume. Phase-contrast magnetic
      resonance imaging is a new tool for noninvasive assessment of CSF displacement by
      measuring CSF peak velocity (CSFV(Peak)). The authors tested this new tool in an
      experimental human model of increased intracranial pressure and reduced cerebral
      capacity by means of continuous positive airway pressure (CPAP) breathing.
      METHODS: The authors investigated systolic CSFV(Peak) in the aqueduct of Sylvius
      in 11 awake, normocapnic (end-tidal carbon dioxide [ET(CO2)] = 40 mmHg)
      volunteers without CPAP and at two different CPAP levels (6 and 12 cm H2O) by
      means of electroencephalography-gated phase-contrast magnetic resonance imaging.
      RESULTS: Administration of 6 cm H2O CPAP did not change systolic CSFV(Peak) (
      4.9+/-2.8 cm/s vs. control: -5.1+/-2.7 cm/s), whereas 12 cm H2O CPAP
      significantly reduced systolic CSFV(Peak) (-4.0+/-1.8 cm/s vs. control: -5.1+/
      2.7 cm/s; P < 0.05). CONCLUSIONS: These findings in awake volunteers show that
      monitoring CSFV(Peak) in the aqueduct of Sylvius is a sensitive method for
      detecting even minor impairment of cerebral capacity caused by experimentally
      induced increases in intracranial pressure.

PMID- 10360851
TI  - Augmentation of the rocuronium-induced neuromuscular block by the acutely
      administered phenytoin.
AB  - BACKGROUND: The effects of an acute administration of phenytoin on the magnitude
      of the rocuronium-induced neuromuscular block were evaluated. METHODS: Twenty
      patients (classified as American Society of Anesthesiologists physical status I
      or II) scheduled for craniotomy were studied: 15 received phenytoin during
      operation (10 mg/kg), and the others served as controls. Anesthesia was induced
      with thiopental and fentanyl and maintained with nitrous oxide (65%) in oxygen
      and end-tidal isoflurane (1%). The ulnar nerve was stimulated supramaximally and
      the evoked electromyography was recorded using a neuromuscular transmission
      monitor. Continuous infusion of rocuronium maintained the neuromuscular block
      with first twitch (T1) between 10 and 15% for 45 min before the start of an
      infusion of either phenytoin or NaCl 0.9%. Twitch recordings continued for 60 min
      thereafter. Arterial blood samples were collected at the predefined time points
      (four measurements before and four after the start of the infusion) to determine
      the concentrations of phenytoin and rocuronium and the percentage of rocuronium
      bound to plasma proteins. RESULTS: The first twitch produced by an infusion of
      rocuronium remained constant during the 15 min before and the 60 min after the
      start of the saline infusion. After the phenytoin infusion, the twitch decreased
      progressively, but the plasma concentrations and the protein-bound fraction of
      rocuronium did not change. CONCLUSION: Phenytoin acutely augments the
      neuromuscular block produced by rocuronium without altering its plasma
      concentration or its binding to plasma proteins.

PMID- 10360852
TI  - Determination of the potency of remifentanil compared with alfentanil using
      ventilatory depression as the measure of opioid effect.
AB  - BACKGROUND: Remifentanil is a new opioid with properties similar to other mu
      specific agonists. To establish its pharmacologic profile relative to other known
      opioids, it is important to determine its potency. This study investigated the
      relative potency of remifentanil compared with alfentanil. METHODS: Thirty young
      healthy males were administered double-blind remifentanil or alfentanil
      intravenously for 180 min using a computer-assisted continuous infusion device.
      Depression of ventilation was assessed by the minute ventilatory response to 7.5%
      CO2 administered via a "bag in the box" system. The target concentration of the
      study drug was adjusted to obtain 40-70% depression of baseline minute
      ventilation. Multiple blood samples were obtained during and following the
      infusion. The concentration-effect relationship of each drug was modeled, and the
      concentration needed to provide a 50% depression of ventilation (EC50) was
      determined. RESULTS: Only 11 subjects in each drug group completed the study;
      however, there were sufficient data in 28 volunteers to model their EC50 values.
      The EC50 (mean and 95% confidence interval) for depression of minute ventilation
      with remifentanil was 1.17 (0.85-1.49) ng/ml and the EC50 for alfentanil was 49.4
      (32.4-66.5) ng/ml. CONCLUSION: Based on depression of the minute ventilatory
      response to 7.5% CO2, remifentanil is approximately 40 (26-65) times more potent
      than alfentanil when remifentanil and alfentanil whole-blood concentrations are
      compared. As alfentanil is usually measured as a plasma concentration,
      remifentanil is approximately 70 (41-104) times more potent than alfentanil when
      remifentanil whole-blood concentration is compared with alfentanil plasma
      concentration. This information should be used when performing comparative
      studies between remifentanil and other opioids.

PMID- 10360853
TI  - Patient-controlled antiemesis: a randomized, double-blind comparison of two doses
      of propofol versus placebo.
AB  - BACKGROUND: The role of propofol for the management of postoperative nausea and
      vomiting (PONV) is not well established. This study determines the efficacy of
      small doses of propofol administered by patient-controlled device for the
      treatment of PONV. METHODS: Patients presenting for ambulatory surgery received a
      standardized general anesthetic. Those who experienced significant nausea or
      emesis within 1 h of arrival in the recovery room were randomized to receive
      repeated doses of propofol 20 mg (P-20), propofol 40 mg (P-40), or intralipid
      (placebo) on demand. Study medications (in equal volumes) were administered with
      a patient-controlled delivery device for 2 h. A lockout interval of 5 min between
      doses was used. The following parameters were assessed: nausea, vomiting, rescue
      antiemetic use, recovery profile, study drug administration history, and
      satisfaction with treatment. RESULTS: Sixty-nine patients participated in the
      study. Patient demographics were similar. The average nausea score for a patient
      in the P-20 and P-40 groups was 25% and 29% less, respectively, compared with
      placebo during the study period (P < 0.05). This difference was apparent 15 min
      after initiation of therapy. More placebo patients vomited (P-20, 12%; P-40, 23%;
      placebo, 56%; P = 0.003) and needed rescue antiemetics (P-20, 17%; P-40, 23%;
      placebo, 70%; P = 0.001) compared with treatment groups. Sedation scores were
      similar between groups. Propofol-treated patients had shorter stays in the post
      anesthesia care unit (PACU; P-20, 131+/-35 min [mean +/- SD]; P-40, 141+/-34 min;
      placebo, 191+/-92 min; P = 0.005) and higher satisfaction with their control of
      PONV than placebo (P < 0.01). CONCLUSIONS: Propofol is effective in managing PONV
      with shorter PACU stay and great degree of patient satisfaction. There were two
      episodes of oversedation in the P-40 group. Hence, propofol at a demand dose of
      20 mg seems more appropriate.

PMID- 10360854
TI  - Propofol requirement is decreased in patients with large supratentorial brain
      tumor.
AB  - BACKGROUND: The anesthetic requirement is decreased in animals with head injury,
      but there are no data regarding the effect of intracranial tumor on the potency
      for intravenous anesthetics. The authors compared the quantal dose-response
      curves for propofol in patients having large (> or = 30 mm, mass effect) brain
      tumor with those having smaller (< 30 mm) lesions and with control patients
      undergoing noncranial surgery. METHODS: Sixty patients in each group were
      randomly assigned to receive one of the six doses of propofol (0.5, 0.7, 1.0,
      1.3, 1.8, or 2.5 mg/kg) over 10 s. Two minutes after drug administration,
      patients were asked to open their eyes as a test for response to verbal command.
      Patients who failed to respond were given a 10-s, 50-Hz, 80-mA transcutaneous
      tetanic electrical current to the ulnar nerve as a test for response to painful
      stimulus. Purposeful movement indicated positive response. Log dose-response
      curves for loss of response to verbal command and tetanic stimulus were
      calculated after logit transformation. RESULTS: The median effective doses
      (ED50s; 95% confidence interval) for suppressing response to verbal command and
      tetanic stimulus were 0.75 (0.65-0.86) mg/kg and 1.28 (1.11-1.49) mg/kg,
      respectively, in patients with large brain tumor. These values were significantly
      less than the corresponding ED50s in patients with small tumor, 1.01 (0.88-1.15)
      mg/kg and 1.76 (1.51-2.07) mg/kg, or healthy control subjects, 0.98 (0.86-1.12)
      mg/kg and 1.89 (1.62-2.23) mg/kg. CONCLUSIONS: The doses of propofol required to
      suppress response to verbal command and tetanic stimulus were 23% less and 32%
      less in patients with large brain tumor compared with control subjects. Small
      tumor did not affect potency of propofol.

PMID- 10360855
TI  - L-arginine infusion dilates coronary vasculature in patients undergoing coronary
      bypass surgery.
AB  - BACKGROUND: Nitric oxide-dependent factors (serotonin, activated platelets,
      acetylcholine) cause vasodilation in normal coronary arteries but vasoconstrict
      atherosclerotic vessels. This experiment tested the hypothesis that intravenous
      systemic infusions of L-arginine, a precursor for nitric oxide production, dilate
      the coronary vascular bed of patients undergoing coronary artery bypass graft
      surgery. METHODS: Twenty patients scheduled for coronary artery bypass graft
      surgery surgery were studied in a prospective, blinded, randomized clinical
      trial. Saphenous vein graft blood flow was measured with a transit time flow
      probe, and coronary vascular resistance was calculated. After weaning from
      bypass, patients were given a venous infusion (placebo or 10% arginine
      hydrochloride [30 g]) over 15 min. Arterial blood samples for the determination
      of L-arginine and L-citrulline levels were drawn before, 10 min after starting
      infusion, and 10 min after end of infusion. RESULTS: The placebo group
      experienced an increase in mean arterial pressure and coronary vascular
      resistance and a decrease in graft blood flow. Patients in the L-arginine group
      maintained their baseline values. Mean arterial pressure (L-arginine, 88+/-17 to
      92+/-13 mmHg vs. placebo, 80+/-12 to 92+/-9 mmHg, P = 0.021), coronary vascular
      resistance (L-arginine, 97,000+/-60,000 to 99,600+/-51,000 dynes x s x cm(-5) vs.
      placebo, 81,000+/-69,000 to 117,000+/-64,000 dynes x s x cm(-5), P = 0.05), and
      graft blood flow (L-arginine, 55+/-25 to 50+/-19 ml/min vs. placebo, 60+/-34 to
      46+/-18, P = 0.05) remained more stable in the L-arginine-treated patients.
      CONCLUSIONS: Systemic L-arginine infusion reduced postbypass coronary
      vasoconstriction. There were no adverse events associated with the drug infusion.

PMID- 10360856
TI  - The effect of pyrogen administration on sweating and vasoconstriction thresholds
      during desflurane anesthesia.
AB  - BACKGROUND: General anesthetics increase the sweating-to-vasoconstriction
      interthreshold range (temperatures not triggering thermoregulatory defenses),
      whereas fever is believed to only increase the setpoint (target core
      temperature). However, no data characterize thresholds (temperatures triggering
      thermoregulatory defenses) during combined anesthesia and fever. Most likely, the
      combination produces an expanded interthreshold range around an elevated
      setpoint. The authors therefore tested the hypothesis that thermoregulatory
      response thresholds during the combination of fever and anesthesia are simply the
      linear combination of the thresholds resulting from each intervention alone.
      METHODS: The authors studied eight healthy male volunteers. Fever was induced on
      the appropriate days by intravenous injection of 30 IU/g human recombinant
      interleukin 2 (IL-2), followed 2 h later by an additional 70 IU/g. General
      anesthesia consisted of desflurane 0.6 minimum alveolar concentration (MAC). The
      volunteers were randomly assigned to the following groups: (1) control (no
      desflurane, no IL-2); (2) IL-2 alone; (3) desflurane alone; and (4) desflurane
      plus IL-2. During the fever plateau, volunteers were warmed until sweating was
      observed and then cooled to vasoconstriction. Sweating was evaluated from a
      ventilated capsule and vasoconstriction was quantified by volume plethysmography.
      The tympanic membrane temperatures triggering significant sweating and
      vasoconstriction identified the respective response thresholds. Data are
      presented as the mean +/- SD; P < 0.05 was considered significant. RESULTS: The
      interthreshold range was near 0.40 degrees C on both the control day and during
      IL-2 administration alone. On the IL-2 alone day, however, the interthreshold
      range was shifted to higher temperatures. The interthreshold range increased
      significantly during desflurane anesthesia to 1.9+/-0.6 degrees C. The
      interthreshold range during the combination of desflurane and IL-2 was 1.2+/-0.6
      degrees C, which was significantly greater than on the control and IL-2 alone
      days. However, it was also significantly less than during desflurane alone.
      CONCLUSION: The combination of desflurane and IL-2 caused less thermoregulatory
      inhibition than would be expected based on the effects of either treatment alone.
      Fever-induced activation of the sympathetic nervous system may contribute by
      compensating for a fraction of the anesthetic-induced thermoregulatory
      impairment.

PMID- 10360857
TI  - Clinical effects and maternal and fetal plasma concentrations of 0.5% epidural
      levobupivacaine versus bupivacaine for cesarean delivery.
AB  - BACKGROUND: Bupivacaine exists as a mixture of two enantiomers, levobupivacaine
      and dexbupivacaine. Data suggest that levobupivacaine has equal local anesthetic
      potency, with reduced potential for central nervous system and cardiovascular
      toxicity. The present study compares the efficacy of 0.5% levobupivacaine with
      0.5% bupivacaine for epidural anesthesia in parturients undergoing elective
      cesarean delivery. METHODS: Sixty healthy obstetric patients undergoing elective
      cesarean delivery with epidural anesthesia completed the study. Patients were
      randomized to receive 30 ml of either 0.5% levobupivacaine or 0.5% bupivacaine in
      a double-blind fashion. The efficacy endpoint measures included onset, offset,
      and quality of anesthesia. Neonatal blood gas analyses, Apgar score
      determinations, and neurobehavioral examinations were performed. Venous samples
      for pharmacokinetic studies and serial electrocardiograms were obtained in 10
      patients in each group. RESULTS: Levels of sensory block, motor block, muscle
      relaxation, and overall quality of anesthesia did not differ between groups. The
      frequency of hypotension was 84.4% in the levobupivacaine group and 100% for the
      bupivacaine group (P < or = 0.053). No significant difference in observed maximum
      concentration of drug after dosing or area under the plasma drug concentration
      versus time curve were seen. The maximum concentrations were 1.017 and 1.053
      microg/ml, and the areas were 4.082 and 3.765 h(microg/ml) for the
      levobupivacaine and bupivacaine groups, respectively. Umbilical vein-to-maternal
      vein ratios were 0.303 for the levobupivacaine group and 0.254 for the
      bupivacaine group. CONCLUSIONS: The use of epidural 0.5% levobupivacaine for
      cesarean delivery results in equally efficacious anesthesia compared with 0.5%
      bupivacaine. Pharmacokinetic parameters were similar in the two groups.

PMID- 10360858
TI  - Comparison of ropivacaine and lidocaine for intravenous regional anesthesia in
      volunteers: a preliminary study on anesthetic efficacy and blood level.
AB  - BACKGROUND: Ropivacaine may be useful for intravenous regional anesthesia, but
      its anesthetic effectiveness and toxicity have not been evaluated. METHODS: Two
      doses of ropivacaine (1.2 and 1.8 mg/kg) and one dose of lidocaine (3 mg/kg) were
      compared for intravenous regional anesthesia in 15 volunteers. An arm tourniquet
      was inflated for 30 min after injection and then deflated in two cycles. Sensory
      block was measured by response to touch, cold, pinprick, and transcutaneous
      electric stimulation, and motor function was measured by hand grip strength and
      muscle power. Median, ulnar, radial, and musculocutaneous nerve functions were
      tested before local anesthetic injection and then at 5-min intervals until blocks
      resolved. The plasma ropivacaine and lidocaine concentrations were determined
      from arterial and venous blood samples drawn from the unanesthetized arm.
      RESULTS: Sensory and motor blocks were complete within 25 min and 30 min,
      respectively, in all three treatment groups. However, recovery of sensory and
      motor block after tourniquet release was slowest in the high-dose ropivacaine
      group. Anesthesia to pinprick and transcutaneous electric stimulation was
      sustained in all the volunteers in the high-dose ropivacaine group for 55 min and
      85 min, respectively, whereas complete recovery was observed in the lidocaine
      group (P = 0.008) and partial recovery in the low-dose ropivacaine group (P <
      0.05) during the same period. Motor block also was sustained in the high-dose
      ropivacaine group for 70 min, which was significantly longer than in the
      lidocaine group (P < 0.05). All volunteers (five of five) given lidocaine and one
      volunteer given high-dose ropivacaine reported light-headedness and hearing
      disturbance during tourniquet release when the arterial plasma lidocaine and
      ropivacaine concentrations were 4.7+/-2.1 microg/ml (mean) and 2.7 micro/ml,
      respectively. CONCLUSION: Compared with lidocaine, intravenous regional
      anesthesia with ropivacaine appears to be comparable but has longer-lasting
      residual anesthesia.

PMID- 10360860
TI  - Effect of combined mouth closure and chin lift on upper airway dimensions during
      routine magnetic resonance imaging in pediatric patients sedated with propofol.
AB  - BACKGROUND: In pediatric patients, obstruction of the upper airway is a common
      problem during general anesthesia. Chin lift is a commonly used technique to
      improve upper airway patency. However, little is known about the mechanism
      underlying this technique. METHODS: The authors studied the effect of the chin
      lift maneuver on airway dimensions in 10 spontaneously breathing children (aged 2
      11 yr) sedated with propofol during routine magnetic resonance imaging. The
      minimal anteroposterior and corresponding transverse diameters of the pharynx
      were determined at the levels of the soft palate, dorsum of the tongue, and tip
      of the epiglottis before and during the chin lift maneuver. Additionally, cross
      sectional areas were calculated at these sites, including tracheal areas 2 cm
      below the glottic level. RESULTS: Minimal anteroposterior diameter of the pharynx
      increased significantly during chin lift at all three levels in all patients. The
      diameters of the soft palate, tongue, and epiglottis increased from 6.7+/-2.8 mm
      (SD) to 9.9+/-3.6 mm, from 9.6+/-3.6 mm to 16.5+/-3.1 mm, and from 4.6+/-2.5 mm
      to 13.1+/-2.8 mm, respectively. The corresponding transverse diameter of the
      pharynx also increased significantly at all three levels in all patients but
      without significant predominance. The diameters at the levels of the soft palate,
      tongue, and epiglottis increased from 15.8+/-5.1 mm to 22.8+/-4.5 mm, from 13.5+/
      4.9 mm to 18.7+/-5.3 mm, and from 17.2+/-3.9 mm to 21.2+/-3.7 mm, respectively.
      Cross-sectional pharyngeal areas increased significantly at all levels (soft
      palate, from 0.88+/-0.58 cm2 to 1.79+/-0.82 cm2; tongue, from 1.15+/-0.45 cm2 to
      2.99+/-1.30 cm2; epiglottis, from 1.17+/-0.70 cm2 to 3.04+/-0.99 cm2), including
      the subglottic level (from 0.44+/-0.15 cm2 to 0.50+/-0.14 cm2). CONCLUSIONS: This
      study shows that all children had a preserved upper airway at all measured sites
      during propofol sedation. Chin lift caused a widening of the entire pharyngeal
      airway that was most pronounced between the tip of the epiglottis and the
      posterior pharyngeal wall. In pediatric patients, chin lift may be used as a
      standard procedure during propofol sedation.

PMID- 10360859
TI  - Shivering and shivering-like tremor during labor with and without epidural
      analgesia.
AB  - BACKGROUND: Effective treatment and prevention of hyperthermia and shivering-like
      tremor during labor is hindered by a poor understanding of their causes. The
      authors sought to identify the incidence of nonthermoregulatory shivering-like
      tremor and the factors associated with this activity. METHODS: The authors
      studied women in spontaneous full-term labor who chose epidural analgesia (n =
      21) or opioid sedation (n = 31). Shivering-like tremor and sweating were
      evaluated by observation. Core temperature was recorded in the external auditory
      canal using a compensated infrared thermometer. Arteriovenous shunt tone was
      evaluated with forearm minus fingertip skin temperature gradients; gradients less
      than 0 were considered evidence of vasodilation. Tremor was considered
      nonthermoregulatory when core temperature exceeded 37 degrees C and the arms were
      vasodilated. Pain was evaluated using a visual analog scale. RESULTS: Shivering
      like tremor was observed in 18% of 290, 30-min data-acquisition epochs before
      delivery. The patients were both normothermic and vasodilated during 15% of these
      epochs. Shivering was observed in 16% of 116 postdelivery epochs and was
      nonthermoregulatory in 28%. Sweating was observed in 30% of predelivery epochs,
      and the patients were both hypothermic and vasoconstricted during 12%. The mean
      core temperature in patients given epidural analgesia was approximately 0.2
      degrees C greater than in those given sedation. Hyperthermia was observed during
      10 epochs (38.4+/-0.3 degrees C) during epidural analgesia and during 10 epochs
      (38.4+/-0.3 degrees C) with sedation. The patients were vasoconstricted in more
      than 50% of these epochs in each group. Multivariate mixed-effects modeling
      identified high pain scores and vasoconstriction as significant predictors of
      shivering. There were no predictors for shivering epochs in patients who were
      simultaneously normothermic and vasodilated. Significant predictors of sweating
      were time before delivery, high pain scores, hypothermia with vasoconstriction,
      high thermal comfort, and low mean skin temperature. There were no predictors for
      sweating epochs in patients who were simultaneously hypothermic and
      vasoconstricted. CONCLUSIONS: This study confirms the clinical impression that
      some peripartum shivering-like tremor is nonthermoregulatory. The authors also
      identified nonthermoregulatory sweating. These data indicate that shivering-like
      tremor and sweating in the peripartum period is multifactorial.

PMID- 10360861
TI  - Pharmacokinetics of epsilon-aminocaproic acid in patients undergoing
      aortocoronary bypass surgery.
AB  - BACKGROUND: Epsilon-aminocaproic acid (EACA) is commonly infused during cardiac
      surgery using empiric dosing schemes. The authors developed a pharmacokinetic
      model for EACA elimination in surgical patients, tested whether adjustments for
      cardiopulmonary bypass (CPB) would improve the model, and then used the model to
      develop an EACA dosing schedule that would yield nearly constant EACA blood
      concentrations. METHODS: Consenting patients undergoing elective coronary artery
      surgery received one of two loading doses of EACA, 30 mg/kg (group I, n = 7) or
      100 mg/kg (group II, n = 6) after CPB, or (group III) a 100 mg/kg loading dose
      before CPB and a 10 mg x kg(-1) x h(-1) maintenance infusion continued for 4 h
      during and after CPB (n = 7). Two patients with renal failure received EACA in
      the manner of group III. Blood concentrations of EACA, measured by high
      performance liquid chromatography, were subjected to mixed-effects
      pharmacokinetic modeling. RESULTS: The EACA concentration data were best fit by a
      model with two compartments and corrections for CPB. The elimination rate
      constant k10 fell from 0.011 before CPB to 0.0006 during CPB, returning to 0.011
      after CPB. V1 increased 3.8 l with CPB and remained at that value thereafter. Cl1
      varied from 0.08 l/min before CPB to 0.007 l/min during CPB and 0.13 l/min after
      CPB. Cl2 increased from 0.09 l/min before CPB to 0.14 l/min during and after CPB.
      Two patients with renal failure demonstrated markedly reduced clearance. Using
      their model, the authors predict that an EACA loading infusion of 50 mg/kg given
      over 20 min and a maintenance infusion of 25 mg x kg(-1) x h(-1) would maintain a
      nearly constant target concentration of 260 microg/ml. CONCLUSIONS: EACA
      clearance declines and volume of distribution increases during CPB. The authors'
      model predicts that more stable perioperative EACA concentrations would be
      obtained with a smaller loading dose (50 mg/kg given over 20 min) and a more
      rapid maintenance infusion (25 mg x kg(-1) x h(-1)) than are typically employed.

PMID- 10360862
TI  - The independent effect of propofol anesthesia on whole body protein metabolism in
      humans.
AB  - BACKGROUND: The purpose of this study was to examine the effect of general
      anesthesia with propofol in the absence of surgical stimulation on whole body
      protein metabolism. METHODS: Six unpremedicated patients were studied. General
      anesthesia included propofol (120 microg x kg(-1) x min(-1)), vecuronium bromide,
      and oxygen-enriched air. Changes in protein breakdown, protein oxidation, and
      synthesis were measured by an isotope dilution technique using a constant
      infusion of the stable isotope tracer L-[1-13C]leucine (0.008 mg x kg(-1) x min(
      1)) before and during 100 min of propofol anesthesia. The plasma concentrations
      of glucose, lactate, non-esterified fatty acids, and cortisol were measured
      before and during anesthesia. RESULTS: An isotopic steady state of plasma [1
      13C]alpha-ketoisocaproate (taken to represent the intracellular leucine precursor
      pool enrichment for protein synthesis) and expired 13C-carbon dioxide were
      obtained before and during propofol infusion. Whole body protein breakdown
      decreased during propofol anesthesia by 6% (P < 0.05), whereas protein synthesis
      and oxidation did not change significantly. Plasma concentration of cortisol
      decreased after 90 min of propofol anesthesia (P < 0.05). No significant changes
      of plasma concentrations of glucose, lactate, and non-esterified fatty acids
      occurred during propofol administration. CONCLUSIONS: Propofol anesthesia did not
      significantly affect whole body protein synthesis and oxidation but caused a
      small, although significant, decrease in whole body protein breakdown, possibly
      mediated through the suppression of plasma cortisol concentration.

PMID- 10360863
TI  - Neurokinin-1 receptors are involved in behavioral responses to high-intensity
      heat stimuli and capsaicin-induced hyperalgesia in mice.
AB  - BACKGROUND: The neurokinin-1 (NK-1) receptor and its ligand, substance P, are
      thought to play important roles in nociception and hyperalgesia. This study
      evaluated the role of the NK-1 receptor in processing noxious stimuli in normal
      and inflammatory states. METHODS: Behavioral responses to heat and mechanical and
      chemical stimuli were studied in NK-1 receptor knockout mice and wild-type
      control mice. Thermal nociception was evaluated by measuring paw lick or jump
      latencies to hot plate (52, 55, and 58 degrees C) and paw withdrawal latencies to
      radiant heat applied to the hind paws. Mechanical nociception was measured by von
      Frey monofilament applications to the hind paws. Intraplantar capsaicin-induced
      (10 microg/20 microl) paw licking and mechanical and heat hyperalgesia were
      compared in NK-1 knockout and wild-type mice. RESULTS: Withdrawal responses to
      radiant heat (4.3+/-0.18 s for knockout and 4.4+/-0.8 s for wild-type mice) and
      von Frey monofilaments were similar in knockout and wild-type mice. In the hot
      plate test, increasing the hot plate temperature from 52 degrees C to 58 degrees
      C resulted in a decrease in the response latency in the wild-type mice (30.4+/
      17.5 s to 15.2+/-6.8 s, P < 0.05), whereas in the knockout mice the response
      latencies remained constant (28.2+/-19.8 s to 29+/-15.1 s, not significant).
      Capsaicin-induced paw licking (14.5+/-12.8 s for knockout and 41.3+/-37.3 s for
      wild-type mice, P < 0.05) and mechanical and heat hyperalgesia were attenuated in
      the knockout mice. CONCLUSION: NK-1 receptors contribute to the withdrawal
      responses to high-intensity heat stimuli and to capsaicin-induced mechanical and
      heat hyperalgesia.

PMID- 10360864
TI  - The effects of two antiinflammatory pretreatments on bacterial-induced lung
      injury.
AB  - BACKGROUND: Two antiinflammatory therapies that have been effective in preventing
      acid-induced lung injury were evaluated. Specifically, their effects on a
      subsequent bacterial-airspace challenge were compared. Bacteria were instilled 24
      h after acid-induced lung injury. Pseudomonas aeruginosa PAO-1 was used as the
      bacteria, because its effects in healthy lungs was documented previously.
      METHODS: New Zealand white rabbits were anesthetized and three pretreatments were
      administered: (1) pentoxifylline pretreatment (a 20-mg/kg bolus dose and then 6
      mg x kg(-1) x h(-1) given intravenously), (2) 1 ml anti-tumor necrosis factor
      alpha antiserum given intravenously, or (3) normal saline given intravenously.
      The pretreatment doses were shown previously to prevent acid-induced lung injury.
      Then 1.2 ml/kg hydrochloric acid (HCl), pH 1.25, was instilled into the rabbits'
      right lungs. All the animals underwent mechanical ventilation for 8 h. Twenty
      four hours after the acid instillation, the rabbits were anesthetized again and 2
      ml/kg (10(9) colony forming units/ml) PAO-1 was instilled into their left lungs.
      The rabbits' breathing was aided by mechanical ventilation for another 8 h, and
      then they were killed and exsanguinated. RESULTS: Both pretreatments attenuated
      the acid-induced lung injury of the noninstilled left lungs. Arterial oxygen
      tension and the lung edema of pretreated, acid-exposed animals were significantly
      and almost equally improved (compared with no pretreatments) by either of the
      pretreatments. However, when the bacteria were instilled into the left lungs 24 h
      after the acid injury, the pentoxifylline pretreatment but not the anti-tumor
      necrosis factor alpha pretreatment prevented much of the bacteria-induced lung
      injury. Pentoxifylline pretreatment significantly improved the measurements of
      left lung edema and epithelial and endothelial permeability. There was also a
      trend for improved oxygenation in the pentoxifylline-pretreated and infected
      animals. In contrast, the anti-tumor necrosis factor alpha pretreatment did not
      prevent the bacteria-induced lung injury and increased some of the measurements
      of lung injury. CONCLUSIONS: Two antiinflammatory therapies that prevented acid
      induced lung injury to the noninstilled left lungs had significantly different
      effects on a subsequent bacteria-induced lung injury to the left lungs. The
      therapies differed in their mechanism of tumor necrosis factor alpha blockade,
      and this may have affected the bacteria-induced injury to the lungs.

PMID- 10360865
TI  - Interaction of halogenated anesthetics with dobutamine in rat myocardium.
AB  - BACKGROUND: Halogenated anesthetics potentiate the positive inotropic effects of
      alpha- and beta-adrenoceptor stimulations, but their interactions with dobutamine
      remain unknown. METHODS: The effects of halothane, isoflurane, sevoflurane, and
      desflurane (1 and 2 minimum alveolar concentration) on the inotropic responses
      induced by dobutamine (10(-8)-10(-4) M) were studied in rat left ventricular
      papillary muscles in vitro. Inotropic effects were studied under low (isotony)
      and high (isometry) loads. The authors also studied the lusitropic effects in
      isotonic (R1) and isometric (R2) conditions. Data are the mean percentage of
      baseline +/- SD. RESULTS: Dobutamine induced a positive inotropic effect (active
      isometric force: 185+/-36%, P < 0.001) and a positive lusitropic effect under low
      load (R1: 78+/-9%, P < 0.001), but not under high load (R2: 95+/-21%, not
      significant). Halothane, isoflurane, and sevoflurane did not modify the positive
      inotropic effect of dobutamine. Even in the presence of alpha-adrenoceptor
      blockade, isoflurane did not potentiate the positive inotropic effect of
      dobutamine. Desflurane significantly enhanced the positive inotropic effect of
      dobutamine (active isometric force: 239+/-35%, P < 0.001), but this potentiation
      was abolished by pretreatment with reserpine. In contrast to halothane,
      isoflurane, sevoflurane, and desflurane did not significantly modify the
      lusitropic effects of dobutamine. CONCLUSIONS: Halogenated anesthetics, except
      desflurane, did not modify the positive inotropic effects of dobutamine.
      Desflurane enhanced the positive inotropic effect of dobutamine, but this effect
      was related to the desflurane-induced release in intramyocardial catecholamine
      stores.

PMID- 10360866
TI  - Effects of halothane and isoflurane on fast and slow inactivation of human heart
      hH1a sodium channels.
AB  - BACKGROUND: Cloning and heterologous expression of ion channels allow biophysical
      and molecular studies of the mechanisms of volatile anesthetic interactions with
      human heart sodium channels. Volatile anesthetics may influence the development
      of arrhythmias arising from cardiac sodium channel dysfunction. For that reason,
      understanding the mechanisms of interactions between these anesthetics and
      cardiac sodium channels is important. This study evaluated the mechanisms of
      volatile anesthetic actions on the cloned human cardiac sodium channel (hH1a)
      alpha subunit. METHODS: Inward sodium currents were recorded from human embryonic
      kidney (HEK293) cells stably expressing hH1a channels. The effects of halothane
      and isoflurane on current and channel properties were evaluated using the whole
      cell voltage-clamp technique. RESULTS: Halothane at 0.47 and 1.1 mM and
      isoflurane at 0.54 and 1.13 mM suppressed the sodium current in a dose- and
      voltage-dependent manner. Steady state activation was not affected, but current
      decay was accelerated. The voltage dependence of steady state fast and slow
      inactivations was shifted toward more hyperpolarized potentials. The slope factor
      of slow but not fast inactivation curves was reduced significantly. Halothane
      increased the time constant of recovery from fast inactivation. The recovery from
      slow inactivation was not affected significantly by either anesthetic.
      CONCLUSIONS: In a heterologous expression system, halothane and isoflurane
      interact with the hH1a channels and suppress the sodium current. The mechanisms
      involve acceleration of the transition from the open to the inactivated state,
      stabilization of the fast and slow inactivated states, and prolongation of the
      inactivated state by delayed recovery from the fast inactivated to the resting
      state.

PMID- 10360867
TI  - The comparative toxicity of cocaine and its metabolites in conscious rats.
AB  - BACKGROUND: The metabolites of cocaine, benzoylecgonine and ecgonine methyl
      ester, have been considered pharmacologically inactive when administered
      systemically. However, recent in vitro studies suggest that this may not be true.
      The current study was designed to evaluate the systemic toxicity of cocaine and
      its metabolites when administered systemically to awake rats fitted with
      catheters for long-term monitoring. METHODS: Cocaine, norcocaine, cocaethylene,
      benzoylecgonine, and ecgonine methyl ester were infused intravenously to produce
      sequential behavioral alterations and central nervous system and cardiovascular
      toxic effects. Arterial blood pressure and heart rate were monitored
      continuously. Plasma and tissue samples were analyzed for all compounds by
      capillary gas chromatography-mass spectrometry. RESULTS: The dose of norcocaine
      necessary to produce toxic effects was smaller than that of cocaine and
      cocaethylene. Benzoylecgonine and ecgonine methyl ester did not produce toxic
      manifestations at infusion rates that produced toxicity in the cocaine,
      norcocaine, and cocaethylene groups. Furthermore, 30- and 60-fold higher doses of
      benzoylecgonine and ecgonine methyl ester, respectively, were necessary to
      produce only mild neurobehavioral changes. Benzoylecgonine was not lethal even at
      doses 100 times greater than cocaine. CONCLUSIONS: These results indicate that
      benzoylecgonine and ecgonine methyl ester are not as toxic as cocaine,
      norcocaine, or cocaethylene when administered intravenously to pharmacologically
      naive rats.

PMID- 10360868
TI  - Halothane presynaptically depresses synaptic transmission in wild-type Drosophila
      larvae but not in halothane-resistant (har) mutants.
AB  - BACKGROUND: General anesthetics produce important changes in neural function, but
      the relation between the many individual changes produced by anesthetics in
      neural components and the responsiveness of the whole organism is uncertain. An
      analysis of genetically altered animals that have modified responses to volatile
      anesthetics may help to allay this uncertainty. METHODS: The authors evaluated
      the effect of halothane on synaptic transmission at the larval neuromuscular
      junction in wild-type (Ore-R) and halothane-resistant (har) mutants of Drosophila
      melanogaster. The body wall muscles, which are innervated by glutamatergic
      nerves, were voltage clamped at -60 mV using the patch-clamp technique in the
      whole cell configuration. Nerve-evoked excitatory junctional currents and
      miniature excitatory junctional currents were recorded. The effects of halothane
      on the amplitude of these currents were compared in Ore-R and two bar mutants
      derived from the Ore-R strain. The time course and frequency of miniature
      excitatory junctional currents also were analyzed in the presence of halothane.
      RESULTS: In Ore-R, halothane (1.8%; 1.01 mM) significantly reduced the amplitude
      of nerve-evoked excitatory junctional currents (61.9+/-17% of control, mean +/-
      SD; n = 7), but not that of miniature excitatory junctional currents. Conversely,
      in two har mutants, halothane had no effect on the amplitude of either nerve
      evoked excitatory junctional currents or miniature excitatory junctional
      currents. In Ore-R, the frequency of miniature excitatory junctional currents was
      decreased significantly in the presence of halothane (0.9-2.7%; 0.52-1.46 mM),
      whereas halothane did not change the frequency in two har mutants. The miniature
      excitatory junctional current decay time constant, thought to reflect the kinetic
      properties of junctional glutamate receptor channels, was not changed by
      halothane in either the Ore-R strain or the har mutants. CONCLUSIONS: Halothane
      depresses synaptic transmission at the wild-type Drosophila neuromuscular
      junction, most likely by affecting presynaptic properties. The absence of an
      effect by halothane in the har mutants provides evidence that the depression of
      presynaptic function at the glutamate-mediated synapses is an important
      contributor to the way halothane alters the responsiveness of the whole animal.

PMID- 10360869
TI  - The placental transfer and fetal effects of levobupivacaine, racemic bupivacaine,
      and ropivacaine.
AB  - BACKGROUND: The purposes of this study were to assess the effects of
      levobupivacaine on uterine blood flow and fetal well-being and to compare its
      placental transfer with that of bupivacaine and ropivacaine. METHODS: After a
      control period, pregnant ewes that were fitted with instruments for long-term
      monitoring were randomized to receive a two-step intravenous infusion of
      levobupivacaine, bupivacaine, or ropivacaine, in a blinded manner, for 1 h.
      Maternal and fetal hemodynamics were monitored during the study. Arterial blood
      samples were drawn at 30 and 60 min of infusion from the mother and fetus to
      determine the acid-base status (60 min only) and serum drug concentrations. The
      fetal brain, heart, liver, lungs, adrenal glands, and kidneys were obtained to
      measure tissue drug levels. RESULTS: Maternal blood pressure, central venous and
      intraamniotic pressures, acid-base status and uterine blood flow were unaffected
      by any drug infusion. In contrast to the other two local anesthetics, the
      infusion of bupivacaine was associated with a small but significant decrease in
      the ewe's heart rate. At the end of the study, the heart rate in the bupivacaine
      treated animals was significantly less than in the animals treated with the other
      two drugs. All fetuses were in good condition at the start of study, and none of
      the local anesthetics affected fetal well-being. No significant differences were
      found among the three drugs in the maternal serum, fetal serum, fetal tissue
      concentrations, and tissue:serum concentration ratios. CONCLUSIONS:
      Levobupivacaine was similar to bupivacaine and ropivacaine in causing no
      important hemodynamic changes in the pregnant ewe and fetus. There were no
      significant differences in the fetal serum and tissue levels of the drugs.

PMID- 10360870
TI  - Comparison of the effects of convulsant and depressant barbiturate stereoisomers
      on AMPA-type glutamate receptors.
AB  - BACKGROUND: Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type
      glutamate receptors mediate fast excitatory synaptic transmission in the central
      nervous system. Although barbiturates have been shown to suppress the AMPA
      receptor-mediated responses, it is unclear whether this effect contributes to the
      anesthetic action of barbiturates. The authors compared the effects of depressant
      [R(-)] and convulsant [S(+)] stereoisomers of 1-methyl-5-phenyl-5-propyl
      barbituric acid (MPPB) on the AMPA and gamma-aminobutyric acid type A (GABA(A))
      receptor-mediated currents to determine if the inhibitory effects on AMPA
      receptors correlate to the in vivo effects of the isomers. METHOD: The authors
      measured whole-cell currents in the rat cultured cortical neuron at holding
      potential of -60 mV. Kainate 500 microM was applied as the agonist for AMPA
      receptors. Thiopental (3-300 microM), R(-)-MPPB or S(+)-MPPB (100-1,000 microM)
      was coapplied with kainate under the condition in which the GABA(A) receptor
      mediated current was blocked. Effects of MPPB isomers on the current elicited by
      GABA 1 microM were studied in the separate experiments. RESULTS: Thiopental
      inhibited the kainate-induced current reversibly and in a dose-dependent manner,
      with a concentration for 50% inhibition of 49.3 microM. Both R(-)-MPPB and S(+)
      MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)
      MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)
      MPPB enhanced but S(+)-MPPB reduced the GABA-induced current. CONCLUSIONS: Both
      convulsant and depressant stereoisomers of the barbiturate inhibited the AMPA
      receptor-mediated current despite of their opposite effects on the central
      nervous system in vivo. Although thiopental exhibited a considerable inhibition
      of AMPA receptors, the results suggest that the inhibition of AMPA receptors
      contributes little to the hypnotic action of the barbiturates.

PMID- 10360871
TI  - Preparation of barbiturate optical isomers and their effects on GABA(A)
      receptors.
AB  - BACKGROUND: Barbiturate anesthetics are optically active and usually exist in two
      mirror-image enantiomeric forms. Their stereoselective effects in mammals are
      well known, but remarkably few data are available concerning their effects on
      anesthetic targets in vitro. This is in part because of the lack of availability
      of pure barbiturate enantiomers. Such in vitro data could be used to test the
      relevance of putative molecular targets. METHODS: A high-performance liquid
      chromatography technique using a permethylated beta-cyclodextrin column was used
      to separate the optical isomers of three barbiturates in preparative quantities.
      The effects of the isomers on GABA-induced currents in stably transfected mouse
      fibroblast cells were investigated using the whole-cell patch-clamp technique.
      RESULTS: Highly purified optical isomers of hexobarbital, pentobarbital, and
      thiopental were prepared, and their effects were studied on a gamma-aminobutyric
      acid type A receptor of defined subunit composition. For each of the three
      barbiturates, both enantiomers potentiated gamma-aminobutyric acid-induced
      currents at pharmacologically relevant concentrations, with the S-enantiomer
      being more potent than the R-enantiomer by a factor of between 1.7 and 3.5. The
      degree of stereoselectivity did not vary greatly with anesthetic concentration.
      CONCLUSIONS: The rank order and degree of stereoselectivity that we have observed
      for the enantiomers of hexobarbital, pentobarbital, and thiopental acting on the
      gamma-aminobutyric acid type A receptor are entirely consistent with this
      receptor playing a central role in the anesthetic actions of barbiturates.

PMID- 10360872
TI  - 4-chloro-m-cresol triggers malignant hyperthermia in susceptible swine at doses
      greatly exceeding those found in drug preparations.
AB  - BACKGROUND: Chlorocresols are used as preservatives in numerous commercial drugs
      that have been shown to induce myoplasmic Ca2+ release; the most potent isoform
      is 4-chloro-m-cresol. The aims of this study were to (1) examine the in vivo
      effects of 4-chloro-m-cresol on swine susceptible to malignant hyperthermia and
      (2) contrast in vivo versus in vitro dose-response curves. METHODS: Susceptible
      swine (weight: 38.5 kg+/-3.55 kg) were anesthetized and monitored for variations
      in physiological responses, including end-tidal CO2, heart rate, blood pressure,
      blood chemistry, and temperatures. In the first animals studied, 4-chloro-m
      cresol, at equivalent cumulative doses of 0.14, 0.28, 0.57, 1.14, 2.27, 4.54, and
      9.08 mg/kg (n = 3; 12.5, 25, 50, 100, 200, 400, and 800 micromol) were
      administered, and in a second group, larger doses were used: 1.14, 3.41, 7.95,
      17.04 (n = 4), and/or 35.22 (n = 1) mg/kg (100, 300, 700, 1,500, and/or 3,100
      micromol). For comparison, in vitro rectus abdominis muscle preparations obtained
      from normal and susceptible swine were exposed to 4-chloro-m-cresol, at
      cumulative concentrations of 6.25, 12.5, 25, 50, 100, 200, 400, 800, and 1,600
      micromol; standard caffeine and halothane contracture testing was also performed.
      RESULTS: Episodes of malignant hyperthermia were not triggered in response to
      administration of low doses of 4-chloro-m-cresol, but transient cardiovascular
      reactions (e.g., tachycardia, arrhythmias, and hypotension) were observed.
      Subsequently, episodes in these animals were triggered when halothane (0.87; 1
      MAC) and succinylcholine (2 mg/kg) were given. Animals administered the higher
      doses of 4-chloro-m-cresol all had fulminant episodes of malignant hyperthermia
      that were fatal, when equivalent cumulative concentrations were greater than
      1,500 micromol. The levels of 4-chloro-m-cresol in the plasma rapidly decreased:
      e.g., 5 min postadministration of the 1,500-micromol dose, the mean plasma level
      was only 52+/-18 micromol (n = 4). Hemolysis was detected following 4-chloro-m
      cresol administration at concentrations > 200 micromol. In vitro, muscle from
      susceptible animals elicited contractures > 200 mg at 50-micromol bath
      concentrations of 4-chloro-m-cresol (n = 29), whereas normal muscle did not
      elicit such contractures until bath concentrations were > 800 micromol (n = 10).
      CONCLUSIONS: 4-chloro-m-cresol is a trigger of malignant hyperthermia in
      susceptible swine, but only when serum concentrations are far above those likely
      to be encountered in humans. A relatively low concentration of 4-chloro-m-cresol,
      50 micromol, is sufficient to activate sarcoplasmic [Ca+2] release in vitro
      (e.g., contractures); this same bolus dose administered in vivo (0.57 mg/kg) has
      minimal effects due to the rapid decrease in its plasma levels.

PMID- 10360873
TI  - 4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine.
AB  - BACKGROUND: 4-Chloro-m-cresol (4-CmC) induces marked contractures in skeletal
      muscle specimens from individuals susceptible to malignant hyperthermia (MHS). In
      contrast, 4-CmC induces only small contractures in specimens from normal (MHN)
      patients. 4-CmC is a preservative within a large number of commercially available
      drug-preparations (e.g., insulin, heparin, succinylcholine), and it has been
      suggested that 4-CmC might trigger malignant hyperthermia. This study was
      designed to investigate the effects of 4-CmC in vivo and in vitro in the same
      animals. METHODS: After approval of the animal care committee, six Pietrain MHS
      and six control (MHN) swine were anesthetized with azaperone 4 mg/kg
      intramuscularly and metomidate 10 mg/kg intraperitoneally. After endotracheal
      intubation, lungs were mechanically ventilated (inspired oxygen fraction 0.3) and
      anesthesia was maintained with etomidate 2.5 mg x kg(-1) x h(-1) and fentanyl 50
      microg x kg(-1) x h(-1). Animals were surgically prepared with arterial and
      central venous catheters for measurement of hemodynamic parameters and to obtain
      blood samples. Before exposure to 4-CmC in vivo, muscle specimens were excised
      for in vitro contracture tests with 4-CmC in concentrations of 75 and 200 microM.
      Subsequently, pigs were exposed to cumulative administration of 3, 6, 12, 24, and
      48 mg/kg 4-CmC intravenously. If an unequivocal episode of malignant hyperthermia
      occurred, as indicated by venous carbon dioxide concentration > or = 70 mmHg, pH
      < or = 7.25, and an increase of temperature > or = 2 degrees C, the animals were
      treated with dantrolene, 3.5 mg/kg. RESULTS: All MHS swine developed malignant
      hyperthermia after administration of 4-CmC in doses of 12 or 24 mg/kg. Venous
      carbon dioxide concentration significantly increased and pH significantly
      decreased. Temperature increased in all MHS animals more than 2 degrees C. Blood
      lactate concentrations and creatine kinase levels were significantly elevated.
      All MHS swine were treated successfully with dantrolene. In contrast, no MHN
      swine developed signs of malignant hyperthermia. After receiving 4-CmC in a
      concentration of 48 mg/kg, however, all MHN animals died by ventricular
      fibrillation. The in vitro experiments showed that both concentrations of 4-CmC
      produced significantly greater contractures in MHS than in MHN specimens.
      CONCLUSIONS: 4-CmC is in vivo a trigger of malignant hyperthermia in swine.
      However, the 4-CmC doses required for induction of malignant hyperthermia were
      between 12 and 24 mg/kg, which is about 150-fold higher than the 4-CmC
      concentrations within clinically used preparations.

PMID- 10360874
TI  - Deep sedation and mechanical ventilation without paralysis for 3 weeks in normal
      beagles: exaggerated resistance to metocurine in gastrocnemius muscle.
AB  - BACKGROUND: Patients in the intensive care unit may have muscle weakness in the
      recovery phase, and disuse atrophy may play a role in this weakness. To assess
      this problem, the authors measured changes in the potency of the nondepolarizing
      neuromuscular blocking agent metocurine in a canine model that involved 3 weeks
      of intensive care, nonparalyzing anesthesia with pentobarbital, and positive
      pressure ventilation. METHODS: Six dogs were anesthetized with pentobarbital to a
      sufficient depth that spontaneous and reflex muscle movements were absent. Their
      tracheas were intubated, their lungs were mechanically ventilated, and they
      received round-the-clock intensive medical and nursing care for 3 weeks.
      Transduced gastrocnemius muscle responses to metocurine were determined weekly. A
      4- to 15-min infusion of 148-4,300 microg/min (longer durations and greater
      concentrations on progressive weeks) yielded more than 80% paralysis. Serial
      metocurine plasma concentrations during the onset of the block and recovery
      provided data to determine pharmacokinetics using NONMEM. Metocurine plasma
      concentrations and the degree of paralysis were used to model the effect
      compartment equilibration constant, and the Hill equation was used to yield the
      slope factor and potency within the effect compartment. RESULTS: The metocurine
      effect compartment concentration associated with a 50% diminution of twitch
      height after 3 weeks was 1,716+/-1,208 ng/ml (mean +/- SD), which was
      significantly different from 257+/-34 ng/ml, the value on day 0. There were no
      pharmacokinetic differences. CONCLUSION: The absence of muscle tone and reflex
      responsiveness for 3 weeks was associated with exaggerated resistance to the
      neuromuscular blocker metocurine.

PMID- 10360875
TI  - Is outpatient laparoscopic cholecystectomy safe and cost-effective? A model to
      study transition of care.
AB  - BACKGROUND: There is increasing pressure to perform traditional inpatient
      surgical procedures in an outpatient setting. The aim of the current trial was to
      determine the safety and cost savings of performing laparoscopic cholecystectomy
      in an outpatient setting using a "mock" outpatient setting. METHODS: Patients who
      were scheduled for laparoscopic cholecystectomy by four attending surgeons and
      for whom operating time was available in the outpatient center were studied. All
      patients received a standardized anesthetic, including ondansetron, and were
      discharged from the outpatient postanesthesia care unit if appropriate. At
      discharge, all patients were admitted to a clinical research center where they
      were observed in a "mock home" setting and monitored for complications that would
      have necessitated readmission. A decision analysis was created assuming all
      patients underwent outpatient surgery with either direct admission or discharge
      to home and readmission if complications developed. RESULTS: Of 99 patients who
      were enrolled in this study, 96 patients would have met the discharge criteria
      for home. No major complications were observed in these 96 patients. Eleven
      patients experienced postoperative nausea and vomiting, 3 of whom required an
      additional 24 h of hospital observation. In the decision model, the optimal
      strategy would be to perform the procedure on an outpatient basis and readmit
      patients only for complications, with an average baseline cost savings of
      $742/patient. CONCLUSIONS: The results show that outpatient laparoscopic
      cholecystectomy is safe and cost-effective in selected patients, and that the
      mock home setting provides a means of studying the safety of transition of care.

PMID- 10360877
TI  - Rovenstine Lecture: who will lead us?

PMID- 10360876
TI  - Henry Knowles Beecher and the development of informed consent in anesthesia
      research.

PMID- 10360879
TI  - Bilateral fixed mydriasis reversible during orthopedic surgery in the prone
      position.

PMID- 10360878
TI  - The efficacy of intrathecal baclofen in severe tetanus.

PMID- 10360880
TI  - A case of normalization of Wolff-Parkinson-White syndrome conduction during
      propofol anesthesia.

PMID- 10360881
TI  - Accidental middle turbinectomy: a complication of nasal intubation.

PMID- 10360882
TI  - Ropivacaine-induced convulsions and severe cardiac dysrhythmia after sciatic
      block.

PMID- 10360883
TI  - Informed consent and "reform" Jehovah's Witness patients.

PMID- 10360884
TI  - Up-down sequential allocation technique to investigate the influence of opioids
      on the efficacy of epidural local anesthetics in labor pain.

PMID- 10360885
TI  - Patient selection and presentation of antiemetic outcome variables.

PMID- 10360886
TI  - Applied anatomy of cervical plexus blockade.

PMID- 10360887
TI  - How to measure plasma vasopressin in pig.

PMID- 10360888
TI  - More on the legacy of Atropos, with special reference to Datura stramonium.

PMID- 10360889
TI  - Anesthetic uses of hyoscine and atropine alkaloids in surgical Arabic book.

PMID- 10360890
TI  - The media and the BIS monitor.

PMID- 10360891
TI  - Acute severe hemodilution to a hemoglobin of 1.3 g/dl tolerated in the presence
      of mild hypothermia.

PMID- 10360892
TI  - Airway management in an infant with Tessier type 3 cleft.

PMID- 10360893
TI  - Intracuff saline infusion for the short-term repair of an endotracheal tube cuff
      leak.

PMID- 10360894
TI  - Transient neurologic symptoms: a diagnosis of exclusion?

PMID- 10360895
TI  - Report of 15th Annual Fall Meeting of the Society for Education in Anesthesia.
      Orlando, Florida. October 16, 1998.

PMID- 10360896
TI  - Society of Neurosurgical Anesthesia and Critical Care. Orlando, Florida, October
      16, 1998.

PMID- 10360897
TI  - Chemokines and human reproduction.
AB  - OBJECTIVE: To review the available information regarding chemotactic cytokines
      and their possible implications in human reproduction. DESIGN: A thorough
      literature and MEDLINE search was conducted to identify studies relating to the
      role of chemokines in ovulation, menstruation, implantation, cervical ripening
      and preterm labor, and endometriosis. RESULT(S): Chemokines mediate leukocyte
      traffic through their specific receptors in various tissues. Although four
      families have been described to date, two remain the major subfamilies: alpha
      chemokines (with interleukin-8 as representative for this group), and beta
      chemokines (with monocyte chemotactic protein-1 as representative). Interleukin
      8, monocyte chemotactic protein-1, and growth-regulated oncogene-alpha are
      involved in follicular development and atresia, ovulation, steroidogenesis, and
      corpus luteum function. Interleukin-8 showed cycle-dependent expression in human
      endometrium, and at the same time, stimulated endometrial stromal cell growth,
      acting as an autocrine growth factor. Interleukin-8 has been identified in human
      amnion, chorion, decidua, and villous placenta, and its level increases during
      labor. Levels of interleukin-8 correlate with the release of collagenases, a
      crucial step that regulates the process of cervical extracellular matrix
      remodeling. The levels of monocyte chemotactic protein-1; regulated on
      activation, normal T-expressed and secreted (RANTES); interleukin-8; and growth
      regulated oncogene-alpha are elevated in the peritoneal fluid of women with
      endometriosis, and they correlate with the stage of the disease. CONCLUSION(S):
      Chemokines play a relevant role in many physiologic and pathologic situations,
      such as ovulation, menstruation, implantation, cervical ripening and preterm
      labor, and endometriosis. Their regulation soon may provide new therapeutic
      strategies.

PMID- 10360898
TI  - Comment on ABA's proposed frozen embryo disposition policy. American Bar
      Association.

PMID- 10360899
TI  - Disposition of frozen embryos by divorcing couples without prior agreement.

PMID- 10360900
TI  - Impact of "non-physician factors" on the "physician factor" of in vitro
      fertilization success: is it the broth, the cooks, or the statistics?

PMID- 10360901
TI  - Impact of the "physician factor" on pregnancy rates in a large assisted
      reproductive technology program: do too many cooks spoil the broth?
AB  - OBJECTIVE: To determine whether in one program with unified treatment protocols,
      patients can expect varying treatment outcomes with different physicians. DESIGN:
      Retrospective data analysis. SETTING: University-affiliated infertility center
      with 14 physicians. PATIENT(S): One thousand eight hundred fifty IVF cycles
      performed consecutively between August 1995 and June 1997. INTERVENTION(S): The
      pregnancy rate and implantation rate per ET were evaluated for individual
      physicians between August 1995 and June 1996 (phase I). Physicians with lower
      success rates underwent strict supervision from July 1996 to June 1997 (phase
      II). MAIN OUTCOME MEASURE(S): Variations in success rates between physicians.
      RESULT(S): The pregnancy rate varied among the physicians from 13.2%-37.4%, and
      the implantation rate varied from 4.4%-14%. Some physicians' outcomes improved
      between phase I and phase II of the study, whereas others' did not. The pregnancy
      and implantation rates varied significantly for some physicians, depending on
      whether they were responsible for the choice of stimulation protocol, supervision
      of cycle monitoring, or ET in their own or other physicians' patients.
      CONCLUSION(S): Outcomes of IVF vary depending on the treating physician. Lower
      than expected pregnancy and implantation rates usually are not caused by poor ET
      techniques alone, but appear to be disproportionately the consequences of poor
      cycle stimulation.

PMID- 10360902
TI  - Single high dose of local methotrexate for the management of relatively advanced
      ectopic pregnancies.
AB  - OBJECTIVE: To evaluate the limits of the conservative management of relatively
      advanced ectopic pregnancies (EPs) with local methotrexate given at a higher than
      standard dose. DESIGN: Nonrandomized prospective study. SETTING: A tertiary
      teaching hospital and an affiliated infertility center. PATIENT(S): We treated
      118 EPs of up to 56 days' gestation (8 weeks) regardless of the presence of fetal
      heart activity, the size of the gestational mass, and the initial beta-hCG
      levels. INTERVENTION(S): Transvaginal intraamniotic or laparoscopic intratubal
      injection of 100 mg of methotrexate as a single dose. MAIN OUTCOME MEASURE(S):
      beta-hCG levels, red and white blood cell count, and liver function tests before
      and after methotrexate injection, followed by repeat transvaginal color Doppler
      assessments. RESULT(S): Treatment was successful in 105 (88.98%) of the 118
      patients included in the study. In 7 of them with persistent fetal cardiac
      activity after the methotrexate injection, treatment was concluded with a
      complementary intracardiac injection of 10% KCl. No grade 3 or important
      clinical, hematologic, or biochemical toxicities occurred. CONCLUSION(S): Local
      administration of a single high dose of methotrexate (100 mg) proved safe and
      effective in the medical management of relatively advanced and unselected EPs,
      including cases with fetal heart activity, with high initial beta-hCG levels, and
      with a gestational mass beyond the standard maximum of 3.5 cm. Complementary
      hypertonic KCl proved to be effective in cases with persistent cardiac activity.

PMID- 10360903
TI  - Clinical application of a new assisted hatching method using a piezo
      micromanipulator for morphologically low-quality embryos in poor-prognosis
      infertile patients.
AB  - OBJECTIVE: To assess the effect of a assisted hatching technique using a piezo
      micromanipulator on pregnancy rates in poor-prognosis infertile patients. DESIGN:
      A prospective randomized study. SETTING: The Infertility and IVF unit of the
      Kyoto University Hospital. PATIENT(S): Infertile patients who had been treated
      for >4 years and failed in previous IVF trials at least twice. INTERVENTION(S):
      Two hundred forty-eight IVF cycles from 173 patients were divided into two
      groups: cycles with the transfer of embryos treated by assisted hatching and
      cycles with the transfer of nontreated embryos. Each group was subdivided into
      two groups according to embryo morphology: cycles in which three or two
      morphologically good-quality embryos were transferred and cycles in which one or
      no morphologically good-quality embryos were transferred. Assisted hatching was
      performed by a piezo-micromanipulator. MAIN OUTCOME MEASURE(S): The clinical
      pregnancy rates and implantation rates. RESULT(S): The clinical pregnancy and
      implantation rates were significantly higher in the assisted hatching group of
      patients with three or two good-quality embryos than in the other three groups.
      CONCLUSION(S): The assisted hatching using a piezo-micromanipulator improved the
      pregnancy and implantation rates in poor-prognosis infertile patients with good
      quality embryo transfer but had no effect in patients with low-quality embryo
      transfer.

PMID- 10360904
TI  - Numerical dose-compensated in vitro fertilization inseminations yield high
      fertilization and pregnancy rates.
AB  - OBJECTIVE: To evaluate in cases with morphologically abnormal sperm whether
      fertilization and pregnancy rates are increased by normalizing the number of
      sperm inseminated and whether biomarkers can identify cases of reduced or failed
      fertilization. DESIGN: Prospective studies of sperm morphology and function.
      SETTING: University hospital assisted human reproduction program. PATIENT(S):
      Partners of 308 women undergoing IVF. INTERVENTION(S): Motile sperm populations
      were assessed for sperm head morphology, for surface receptors for mannose and
      progesterone binding, and the ability to undergo a free mannose-induced acrosome
      reaction. Zinc in seminal plasma was determined by atomic absorption
      spectroscopy. MAIN OUTCOME MEASURE(S): Sperm morphology was associated with
      fertilization and clinical pregnancy rates. Biomarker analyses were correlated
      with fertilization rates using Kruskal-Wallis tests, chi2 tests, and Spearman
      rank order correlations. RESULT(S): Fertilization and pregnancy rates after
      numerical dose compensation inseminations were indistinguishable between men with
      differing percentages of normal sperm. Biomarker deficits were identified
      irrespective of sperm head morphology in 96% of cases of reduced or failed
      fertilization. CONCLUSION(S): Fertilization and pregnancy rates in cases of
      abnormal morphology are optimized by inseminating at least 25,000 sperm/mL with
      normal acrosomes. Reduced or failed fertilization can be predicted by testing for
      molecular deficits in mannose receptor expression and mannose-stimulated acrosome
      loss.

PMID- 10360905
TI  - Transmission of de novo mutations of the deleted in azoospermia genes from a
      severely oligozoospermic male to a son via intracytoplasmic sperm injection.
AB  - OBJECTIVE: To investigate the transmission of microdeletions in the deleted in
      azoospermia (DAZ) genes to a male offspring via intracytoplasmic sperm injection
      (ICSI). DESIGN: Case report. SETTING: Reproductive unit of a university teaching
      hospital. PATIENT(S): A 29-year-old, severely oligozoospermic male with
      microdeletions of the DAZ genes in Yq interval 6 and his son, who was conceived
      via ICSI. INTERVENTION(S): DNA screening for the microdeletions in Yq interval 6
      with 24 sequence tagged sites with the use of polymerase chain reaction
      amplification for the patient, the patient's father, and the patient's son.
      Paternity identification was performed using nine hypervariable short tandem
      repeats. MAIN OUTCOME MEASURE(S): Deletion mapping of Yq interval 6 from sequence
      tagged sites and electropherogram of short tandem repeats for DNA fingerprinting.
      RESULT(S): The son had the same microdeletions of the DAZ genes as the patient,
      and the patient's father had normal DAZ genes. The paternity of the patient, the
      patient's father, and the patient's son was verified. CONCLUSION(S): De novo DAZ
      microdeletions in an infertile male can be transmitted to a male offspring via
      ICSI. DNA screening tests for DAZ genes before ICSI may help in the genetic
      counseling of patients with idiopathic azoospermia or severe oligozoospermia.

PMID- 10360906
TI  - In vitro fertilization plus preimplantation genetic diagnosis in patients with
      recurrent miscarriage: an analysis of chromosome abnormalities in human
      preimplantation embryos.
AB  - OBJECTIVE: To analyze the incidence of numeric chromosomal abnormalities in
      preimplantation embryos from women with unexplained recurrent miscarriage (RM) so
      as to seek an etiology and to determine whether the use of IVF may be indicated
      to treat these cases. DESIGN: Prospective controlled study. SETTING: University
      laboratory of reproductive genetics and a tertiary referral center for
      infertility. PATIENT(S): Nine women with a mean (+/-SD) of 3.9 +/- 0.6 RMs who
      were undergoing IVF and preimplantation genetic diagnosis, and a control group of
      young (n = 10) and older (n = 6) patients who were undergoing preimplantation
      genetic diagnosis because of sex-linked diseases. INTERVENTION(S): In vitro
      fertilization, embryo culture for 72 hours, blastomere biopsy, and analysis of
      chromosomes 13, 16, 18, 21, 22, X, and Y with the use of fluorescent in situ
      hybridization. Transfer of chromosomally normal embryos into the uterus. MAIN
      OUTCOME MEASURE(S): Numeric chromosomal abnormalities in human embryos.
      RESULT(S): Sixty-six embryos from patients with RM were compared with 62 embryos
      from young patients and 41 embryos from older patients. There was a significant
      increase in the rate of abnormal embryos in the patients with RM and the older
      patients compared with the controls. Abnormalities in most of the chromosomes
      studied were higher in the RM group than in the control group, especially those
      affecting chromosome 13. CONCLUSION(S): There was an increase in numeric
      chromosomal abnormalities in preimplantation embryos from women with RM that
      could be the cause of infertility in many couples with unexplained RM. The use of
      IVF in such circumstances may be indicated if successful preimplantation genetic
      diagnosis is added to the procedure.

PMID- 10360907
TI  - Endometrial estrogen and progesterone receptor and pinopode expression in
      stimulated cycles of oocyte donors.
AB  - OBJECTIVE: To study the effect of controlled ovarian hyperstimulation and the
      ovarian response on several features of endometrial morphology simultaneously.
      DESIGN: Prospective controlled study. SETTING: Academic infertility center.
      PATIENT(S): Twenty-five oocyte donors undergoing COH and 10 ovulatory controls.
      INTERVENTION(S): Endometrial biopsies during the luteal phase and measurement of
      serum E2 and progesterone levels on days 12, 13, and 18-20. MAIN OUTCOME
      MEASURE(S): Endometrial morphology as judged by histologic dating, pinopode
      expression, and estrogen and progesterone receptor content. RESULT(S): Controlled
      ovarian hyperstimulation caused the early expression of endometrial features as
      judged by histologic dating criteria, estrogen and progesterone receptor
      expression, and the timing of pinopode expression in many of the subjects. A
      significant correlation within subjects with regard to their particular result on
      any one measure (e.g., histologic examination) and the others (e.g., estrogen and
      progesterone receptors, pinopodes) was observed. Those with higher levels of
      progesterone the day after hCG administration exhibited the most prematurity of
      morphologic features. CONCLUSION(S): Many controlled ovarian hyperstimulation
      cycles are associated with synchronous early expression of the expected pattern
      of histologic features, estrogen and progesterone receptors, and pinopodes. The
      most predictive feature of this premature expression was the level of
      progesterone the day after hCG administration.

PMID- 10360909
TI  - Spontaneous abortion: a randomized, controlled trial comparing surgical
      evacuation with conservative management using misoprostol.
AB  - OBJECTIVE: To compare the efficacy of surgical evacuation of the uterus with
      medical evacuation using misoprostol in cases of spontaneous abortion. DESIGN: A
      prospective, randomized, controlled trial. SETTING: A university teaching
      hospital. PATIENT(S): Six hundred thirty-five women who aborted spontaneously and
      who consented to pretreatment randomization. INTERVENTION(S): Routine surgical
      evacuation or medical evacuation of the uterus using misoprostol. MAIN OUTCOME
      MEASURE(S): Immediate, short-term (2-3 weeks), and medium-term (6 months) medical
      complications. RESULT(S): There was a significantly lower incidence of immediate
      and short-term complications in the group treated with misoprostol compared with
      the surgically treated group. There were also fewer major complications in the 6
      months after treatment in the medically treated group. Approximately 50% of the
      medically treated group subsequently required surgical evacuation, and these
      subjects required significantly more analgesia. CONCLUSION(S): Treatment with
      misoprostol can reduce the demand for surgical evacuation in cases of spontaneous
      abortion, and its use is associated with fewer medical complications.

PMID- 10360908
TI  - Hypercoagulable state mutation analysis in white patients with early first
      trimester recurrent pregnancy loss.
AB  - OBJECTIVE: Antiphospholipid antibodies (APA) and other coagulation abnormalities
      have been associated with an increased risk of venous, arterial, and placental
      thrombosis and recurrent pregnancy loss (RPL). Factor V Leiden (a point mutation
      [1691G-->A] in the factor V gene), the prothrombin 20210G-->A mutation, and
      homozygosity for a common polymorphism in the methylene tetrahydrofolate
      reductase (MTHFR) gene (677C-->T) have been associated with arterial and venous
      thrombosis and arterial occlusive disease. We explored an association between
      these markers of thrombophilic states and RPL. DESIGN: Prospective case-control
      evaluation. SETTING: University-associated private practice. PATIENT(S): Fifty
      nonpregnant women with three or more pregnancy losses and 50 healthy, nonpregnant
      controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Anticardiolipin and
      antiphosphatidylserine antibodies were detected in serum by ELISA. Polymerase
      chain reaction was performed to identify the factor V Leiden (1691G-->A)
      mutation, the thermobile MTHFR (677C-->T) mutation, and the prothrombin 20210G-
      >A mutation. RESULT(S): The following were identified by restriction fragment
      linked polymorphism analyses: 1 (2%) factor V Leiden heterozygosity; 1 (2%)
      prothrombin 20210G-->A heterozygosity; and 4 (8%) thermolabile MTHFR
      homozygosity. None of these mutation frequencies in women with RPL were
      statistically significantly different from controls. CONCLUSION(S): These data
      suggest that factor V Leiden, thermolabile MTHFR (677C-->T), and prothrombin
      20210G-->A are not found at an increased frequency in women with a history of
      early RPL.

PMID- 10360910
TI  - Prevalence and heterogeneity of antiphosphatidylethanolamine antibodies in
      patients with recurrent early pregnancy losses.
AB  - OBJECTIVE: To describe the prevalence of antiphospholipid antibodies to both
      anionic and zwitterionic phospholipids in women with early recurrent pregnancy
      losses (RPLs). DESIGN: Retrospective data analysis. SETTING: Tokai University
      Hospital, Kanagawa, Japan. PATIENT(S): One hundred thirty-nine patients with
      unexplained early RPLs. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Enzyme
      linked immunosorbent assays were used to measure autoantibodies to
      phosphatidylethanolamine, cardiolipin, and phosphatidylserine. RESULT(S): Twenty
      eight (20.1%), 17 (12.2%), and 2 (1.4%) patients of the 139 total patients were
      positive for immunoglobulin (Ig) G, IgM, and IgA antiphosphatidylethanolamine
      antibodies, respectively. Because 3 patients had two isotypes, 44 (31.7%) of the
      patients were positive for antiphosphatidylethanolamine antibodies. Six patients
      (4.3%) and 1 patient (0.7%) were positive for IgG and IgM antiphosphatidylserine
      antibodies, respectively. Seven patients (5%) were positive for beta2
      glycoprotein I-independent anticardiolipin IgG, and 1 patient was positive for
      beta2-glycoprotein I-dependent anticardiolipin IgG. Two patients (1.4%) had lupus
      anticoagulant. CONCLUSION(S): Our data show a statistically stronger association
      between RPLs and antiphosphatidylethanolamine antibodies than between RPLs and
      antibodies to anionic phospholipids for early gestational losses. Our data
      suggest that antiphosphatidylethanolamine antibodies may be a risk factor in
      patients with early RPLs.

PMID- 10360911
TI  - Human fertility does not decline: evidence from Sweden.
AB  - OBJECTIVE: To assess changes in human fertility over time. DESIGN: Time-trend
      analyses and age-period-cohort modeling. SETTING: Sweden, 1983-1993. PATIENT(S):
      All primiparous women aged > or =20 years during the study period. There were
      401,653 women who were identified through the nationwide Medical Birth Register.
      INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Risk of subfertility, defined as
      > or =1 year of involuntary childlessness. RESULT(S): Subfertility problems
      decreased dramatically over successive maternal birth cohorts. Further, the risk
      of subfertility increased with age and decreased with increasing formal
      education. CONCLUSION(S): A decrease in male fertility cannot be ruled out on the
      basis of these results, but if present, it is minor and totally outweighed by
      other favorable developments. As the main explanation for our findings, we
      propose a decrease in the prevalence of secondary subfertility as a result of the
      eradication of gonorrhea.

PMID- 10360912
TI  - Prospective, randomized, crossover study to evaluate the benefit of human
      chorionic gonadotropin-timed versus urinary luteinizing hormone-timed
      intrauterine inseminations in clomiphene citrate-stimulated treatment cycles.
AB  - OBJECTIVE: To compare two methods of timing IUI, urinary LH monitoring and
      transvaginal ultrasonography/ hCG timing of ovulation, in patients receiving
      clomiphene citrate. DESIGN: Prospective, randomized, crossover study. SETTING:
      Yale University Reproductive Medicine Center. PATIENT(S): Infertile couples
      undergoing IUI because of unexplained infertility, anovulation, or male factor
      infertility. INTERVENTION(S): Patients received clomiphene citrate on days 3-7 of
      the menstrual cycle and were randomized initially to one of two monitoring
      protocols. In protocol A, urinary LH monitoring was used to time IUI. Urinary LH
      levels were determined daily with the use of commercial kits, starting on day 10
      of the cycle. When urinary LH was detected, IUIs were performed daily for the
      next 2 days. In protocol B, ultrasound monitoring of folliculogenesis was
      performed until a leading follicle of > or = 18 mm was noted, at which time hCG
      (10,000 IU) was given intramuscularly and IUIs were performed daily for the next
      2 days. If no pregnancy occurred, the couple crossed over to the alternate
      protocol for the next cycle and continued this alternating therapy for a total of
      four cycles. MAIN OUTCOME MEASURE(S): Pregnancy rate per cycle. RESULT(S): One
      hundred forty-one cycles were completed. In these cycles, six pregnancies
      occurred, for an overall pregnancy rate of 4.26% per cycle. The pregnancy rate
      with LH-timed IUI was 4.29% (3/70) and that with hCG-induced ovulation was 4.23%
      (3/71); the difference was not statistically significant. CONCLUSION(S): Timing
      IUI with the use of a relatively expensive and time-consuming method such as
      ultrasound monitoring of folliculogenesis and hCG induction of ovulation does not
      appear to produce an increased pregnancy rate over urinary LH monitoring of
      ovulation.

PMID- 10360913
TI  - Alternate pathway 17,20-lyase enzyme activity in the adrenals is enhanced in
      patients with polycystic ovary syndrome.
AB  - OBJECTIVE: To assess the activity of the enzyme cytochrome P450c17alpha in
      patients with polycystic ovary syndrome (PCOS). DESIGN: Prospective clinical
      study. SETTING: Outpatients at Erciyes University Medical School, Kayseri,
      Turkey. PATIENT(S): Twenty-eight women with PCOS aged 25.44 +/- 4.37 years (mean
      +/- SD) and 18 normal women aged 26.94 +/- 3.17 years. MAIN OUTCOME MEASURE(S):
      Serum levels of 11-deoxycortisol, androstenedione (A), and 17alpha-hydroxy
      progesterone were measured before and 30 and 60 minutes after ACTH (0.25 mg i.v.)
      injection. RESULT(S): There was a statistically significant correlation between
      basal levels of 11-deoxycortisol (4.05 +/-1.16 ng/mL) and A (3.36 +/- 0.97 ng/mL)
      (r = 0.539). The peak level of 11-deoxycortisol (7.82 +/- 2.36 ng/mL) was also
      significantly correlated with the peak level of A (6.66 +/- 1.32 ng/mL) (r =
      0.570) in women with PCOS. There was no statistically significant correlation
      between basal A (2.33 +/- 0.50 ng/mL) and basal 11-deoxycortisol (2.71 +/- 0.59
      ng/mL) or between peak A (3.38 +/- 0.50 ng/mL) and peak 11 -deoxycortisol (3.68
      +/- 0.48 ng/mL) levels in control subjects. CONCLUSION(S): We believe that PCOS
      is characterized by enhanced activity of 17,20-lyase enzyme in an alternate
      pathway between 11-deoxycortisol and A in the adrenal glands.

PMID- 10360914
TI  - Effect of age on the response of the hypothalamo-pituitary-ovarian axis to a
      combined oral contraceptive.
AB  - OBJECTIVE: To examine the effect of age on the response to treatment with a
      combined oral contraceptive. DESIGN: Prospective, controlled clinical study.
      SETTING: Reproductive medicine unit in a tertiary care university medical center.
      PATIENT(S): Twenty-six healthy female volunteers aged 21-45 years.
      INTERVENTION(S): After a control cycle, all the women were given a combined oral
      contraceptive containing 20 microg of ethinylestradiol with 75 microg of
      gestodene for three cycles. The women were examined through the posttreatment
      cycle. MAIN OUTCOME MEASURE(S): Pituitary and ovarian activity was assessed with
      ultrasound and measurement of ovarian steroids. RESULT(S): Follicular activity
      was observed in all treatment cycles, although ovulation was inhibited. Ovarian
      suppression was maximal in cycle 1. Mean endogenous E2 levels were lower during
      cycles 2 and 3 in the older group. Serum FSH levels were higher in the control
      cycle and on day 28 of the treatment cycles in the older group. Most women
      ovulated during the posttreatment cycle. CONCLUSION(S): Combined oral
      contraceptives did not inhibit all ovarian activity; maximal suppression was seen
      in cycle 1. Less follicular activity was observed in cycles 2 and 3 in the older
      group. Raised FSH levels with age reflect increasing ovarian resistance to
      follicular development.

PMID- 10360915
TI  - Effect of sex steroids on beta-endorphin levels at rest and during submaximal
      treadmill exercise in anovulatory and ovulatory runners.
AB  - OBJECTIVE: To examine the interaction between circulating beta-endorphin levels
      and sex steroids during sustained submaximal exercise in runners who are either
      anovulatory and oligomenorrheic (AO) or ovulatory and eumenorrheic (EO). DESIGN:
      Controlled clinical study. SETTING: General clinical research center at an
      academic medical center. PATIENT(S): Three AO and four EO runners.
      INTERVENTION(S): The athletes underwent 60 minutes of submaximal treadmill
      exercise on three separate occasions. Anovulatory and oligomenorrheic runners
      underwent exercise at baseline and after physiologic estrogen and combined
      estrogen and progesterone replacement. Ovulatory and eumenorrheic runners
      underwent exercise in the follicular and luteal phases and after GnRH agonist
      desensitization. MAIN OUTCOME MEASURE(S): Serum cortisol, beta-endorphin,
      progesterone, estrogen, and gonadotropin levels at rest and during exercise.
      RESULT(S): Serum levels of E2 increased in response to exercise in both EO and AO
      runners during sex steroid replacement. Baseline peripheral beta-endorphin and
      cortisol levels were not different between the EO and AO groups. A significant
      increase in beta-endorphin levels in response to exercise occurred only in the EO
      group after GnRH agonist desensitization. CONCLUSION(S): Alterations in menstrual
      cyclicity and ovulation in conditioned runners probably are not due to an
      increase in opioid tone. The hypothalamic-gonadotropic axis appears to be intact
      in AO runners, as measured by the gonadotropic response to exogenous exposure to
      estrogen and progesterone. Sex steroid administration had no effect on basal beta
      endorphin levels, but this probably was not due to preexisting increased opioid
      tone.

PMID- 10360916
TI  - Reproductive effects of in utero exposure to estrogen and progestin drugs.
AB  - OBJECTIVE: To determine whether in utero exposure to estrogens and progestins
      other than diethylstilbestrol reduces fertility in offspring. DESIGN:
      Retrospective cohort study. SETTING: Helsinki, Finland. PATIENT(S): One thousand
      eight hundred eighty-eight women and men exposed to female hormone drugs in utero
      from 1954-1963 and 2,044 age-matched controls. INTERVENTION(S): None. MAIN
      OUTCOME MEASURE(S): The numbers and timing of live births and marriages for men
      and women and of unsuccessful pregnancies for women. RESULT(S): There were no
      differences between the exposed and control men in most outcome indicators.
      However, fewer exposed men than control men had their first liveborn child within
      a short time after getting married, and the mean time from the first to the
      second live birth was shorter. The former also was found for the women. The
      overall cumulative proportions of liveborn children and pregnancies were similar
      in the exposed and control groups, but younger exposed men and women had liveborn
      children and pregnancies somewhat later. CONCLUSION(S): Estrogen- and progestin
      containing drugs as used in the study population did not have much impact on the
      fertility of offspring.

PMID- 10360917
TI  - Estrogen receptor alpha and beta expression in the vaginal walls and uterosacral
      ligaments of premenopausal and postmenopausal women.
AB  - OBJECTIVE: To assess the expression of messenger RNA (mRNA) for estrogen
      receptors alpha and beta in the vaginal walls and uterosacral ligaments of
      premenopausal and postmenopausal women. DESIGN: In vitro experiment. SETTING:
      Academic research environment. PATIENT(S): Sixteen consecutively seen women who
      underwent hysterectomy. INTERVENTION(S): Samples of anterior vaginal walls and
      uterosacral ligaments were obtained during hysterectomy. MAIN OUTCOME MEASURE(S):
      Reverse transcriptase-polymerase chain reaction analysis for estrogen receptor
      mRNA. RESULT(S): Messenger RNA transcripts for estrogen receptor alpha were
      present in all samples of vaginal walls (16/16) and uterosacral ligaments
      (16/16). Estrogen receptor beta mRNA was detected in all samples of vaginal walls
      from premenopausal women (12/12) but in none of those from postmenopausal women
      (0/4). Estrogen receptor beta mRNA was found in most samples of uterosacral
      ligaments from premenopausal women (10/12) and in some of those from
      postmenopausal women (2/4). CONCLUSION(S): Estrogen receptors alpha and beta were
      expressed in the vaginal walls and uterosacral ligaments of premenopausal and
      postmenopausal women. Estrogen receptor beta was absent from the vaginal walls of
      postmenopausal women.

PMID- 10360918
TI  - Suppressive effect of anticardiolipin antibody on the proliferation of human
      umbilical vein endothelial cells.
AB  - OBJECTIVE: To determine whether sera that show a positive anticardiolipin test
      result have a suppressive effect on the proliferation of endothelial cells
      collected from human umbilical veins. DESIGN: Retrospective in vitro study.
      SETTING: University hospital outpatient clinic for the treatment of infertility.
      PATIENT(S): Thirteen patients with recurrent fetal miscarriages who were positive
      for anticardiolipin antibody and 14 patients with recurrent miscarriages who were
      negative for anticardiolipin antibody. INTERVENTION(S): Serum was obtained from
      each patient. MAIN OUTCOME MEASURE(S): Suppressive effect of the sera on the
      culture of human umbilical vein endothelial cells. RESULT(S): The proliferation
      of human umbilical vein endothelial cells decreased significantly in cultures
      that contained sera showing positive anticardiolipin antibody activity that had
      been collected from patients with recurrent fetal miscarriages. CONCLUSION(S):
      The results strongly suggest that anticardiolipin antibody has a suppressive
      effect on the proliferation of human umbilical vein endothelial cells.

PMID- 10360919
TI  - Binding of human secretory leukocyte protease inhibitor in uterine cervical mucus
      to immunoglobulins: pathophysiology in immunologic infertility and local immune
      defense.
AB  - OBJECTIVE: To identify an Fc receptor-like molecule in human cervical mucus.
      DESIGN: Controlled experimental laboratory study. SETTING: Department of
      Obstetrics and Gynecology, School of Medicine, University of Tokushima.
      PATIENT(S): Women undergoing treatment for infertility. INTERVENTION(S): Sodium
      dodecyl sulfate-polyacrylimide gel electrophoresis and Western blot were used for
      analysis. MAIN OUTCOME MEASURE(S): A water-insoluble protein with immunoglobulin
      binding activity was purified from human cervical mucus by ammonium sulfate
      fractionation. The initial 21 amino acids of the N-terminus of the immunoglobulin
      binding protein were determined and analyzed in a computer search for homology.
      RESULT(S): The purified fraction contained a 15-kd protein that binds
      immunoglobulin A, immunoglobulin M, and all subclasses of human immunoglobulin G
      as determined by Western blot analysis. The amino acid sequence of the N-terminus
      is identical to that of secretory leukocyte protease inhibitor. The capacity of
      secretory leukocyte protease inhibitor to bind immunoglobulins was confirmed by
      Western blot analysis. CONCLUSION(S): A component in human cervical mucus capable
      of binding immunoglobulins was identified as secretory leukocyte protease
      inhibitor. The capacity to bind immunoglobulins is a unique property of the
      protein, providing additional support for the contention that it plays an
      important physiologic role in local tissue defense mechanisms. It also is
      involved in the pathogenesis of immunologic infertility by trapping sperm in the
      cervical mucus.

PMID- 10360920
TI  - Autoantibodies to markers of oxidative stress are elevated in women with
      endometriosis.
AB  - OBJECTIVE: To measure autoantibodies that recognize oxidatively modified proteins
      in the sera of women with surgically proven endometriosis. DESIGN: Prospective
      study. SETTING: Tertiary care academic medical center. PATIENT(S): Women
      undergoing surgery for endometriosis or tubal ligation. INTERVENTION(S): None.
      MAIN OUTCOME MEASURE(S): Serum and peritoneal fluid autoantibody titers to
      malondialdehyde-modified low-density lipoprotein, oxidized low-density
      lipoprotein, and lipid peroxide-modified rabbit serum albumin determined by
      ELISA. Correlation of autoantibody titers with revised American Fertility Society
      staging classification, symptoms, and morphologic type of endometriosis.
      RESULT(S): Mean (+/-SEM) serum autoantibody titers (in optical density units) to
      the three antigens were as follows: [1] lipid peroxide-modified rabbit serum
      albumin, 0.49 +/- 0.12 units in the patients with endometriosis and 0.2 +/- 0.02
      units in the controls; [2] oxidized low-density lipoprotein, 0.22 +/- 0.005 units
      in the patients with endometriosis and 0.18 +/- 0.006 units in the controls; and
      [3] malondialdehyde-modified low-density lipoprotein, 0.21 +/- 0.005 units in the
      patients with endometriosis and 0.16 +/- 0.003 units in the controls. There was
      no correlation between autoantibody titers and revised American Fertility Society
      stage, symptoms, or morphologic type of endometriosis. Peritoneal fluid did not
      contain autoantibodies to any of the three antigens. CONCLUSION(S):
      Autoantibodies to markers of oxidative stress were significantly increased in
      women with endometriosis. These findings strongly support our data demonstrating
      that women with endometriosis have enhanced oxidative stress.

PMID- 10360921
TI  - Adhesion of human endometrial fragments to peritoneum in vitro.
AB  - OBJECTIVE: To evaluate the adhesion of endometrial fragments obtained during the
      proliferative phase of the menstrual cycle to fresh human peritoneum obtained
      during abdominal surgery. DESIGN: A prospective, descriptive, morphologic and
      cell biologic study. SETTING: Tertiary care university medical center.
      PATIENT(S): Six female volunteers. INTERVENTION(S): After endometrial biopsies
      performed during diagnostic laparoscopy, endometrial fragments were generated by
      enzymatic digestion and mechanical separation. Peritoneum was obtained during
      abdominal operations for benign indications. MAIN OUTCOME MEASURE(S): Adhesion of
      endometrial fragments was studied by histologic examination and scanning and
      transmission electron microscopy. RESULT(S): After incubation, the mesothelium
      was intact in some areas, whereas in other areas mesothelial cells were damaged
      or absent. Adhesion of endometrial fragments was observed only at locations where
      the basement membrane was exposed. In areas largely denuded of mesothelial cells,
      endometrial fragments spread over the basement membrane to form monolayers.
      CONCLUSION(S): Human peritoneum is suitable for studying the adhesion of
      endometrial fragments. Intact mesothelium prevents the adhesion of endometrial
      fragments, suggesting that trauma to the mesothelial lining is a prerequisite for
      endometrial cell adhesion.

PMID- 10360922
TI  - Progestin modulation of c-fos and prolactin gene expression in the human
      endometrium.
AB  - OBJECTIVE: To evaluate the influence of the menstrual cycle and the effects of
      medroxyprogesterone acetate (MPA) on the expression of the protooncogene c-fos
      and of prolactin (PRL) in the human endometrium in vivo. DESIGN: Double-blind,
      placebo-controlled trial. SETTING: Healthy volunteers in an academic research
      environment. PATIENT(S): Regularly cycling women who were not taking hormonal
      medication. INTERVENTION(S): Medroxyprogesterone acetate (10 mg/d) or placebo was
      given for 10 days. Endometrial and blood samples were collected 8-12 hours after
      the last dose. MAIN OUTCOME MEASURE(S): Immunohistochemical localization of PRL
      and c-fos in the endometrium, PRL and c-fos messenger RNA levels in the
      endometrium, and E2 and progesterone levels in the serum. RESULT(S):
      Immunoreactive c-fos was concentrated in the nucleus of stromal cells and was
      observed in a higher proportion of proliferative endometrial specimens compared
      with secretory specimens from placebo or MPA-treated patients. The levels of c
      fos messenger RNA were greatly reduced in the secretory endometrium regardless of
      treatment with placebo or MPA, compared with the proliferative endometrium. The c
      fos gene expression correlated positively with the serum E2 levels (r = 0.56) and
      inversely with the progesterone/E2 ratio (r = -0.56). The endometrial PRL gene
      expression (messenger RNA and protein) was rare in the proliferative samples,
      increased from the early to the mid and late secretory samples, and was increased
      markedly after treatment with MPA compared with placebo. CONCLUSION(S): The
      differentiation of secretory endometrium is accompanied by decreased c-fos and
      increased PRL gene expression. The inhibition of c-fos gene expression may
      contribute to the antiproliferative effect of progestins on the endometrium.

PMID- 10360923
TI  - The use of Matrigel at low concentration enhances in vitro blastocyst formation
      and hatching in a mouse embryo model.
AB  - OBJECTIVE: To determine the effect of Matrigel at a low concentration on the
      growth of mouse embryos in culture. DESIGN: Randomized case-control study of
      mouse embryos. SETTING: An academic research environment. ANIMALS: Mouse embryos.
      INTERVENTION(S): Embryos were cultured in Quinn's or Celbio's human tubal fluid
      (HTF) enriched with 1.5% bovine serum albumin and 0.8% liquid Matrigel. Each HTF
      was compared with the same medium devoid of Matrigel. Afterward, Quinn's and
      Celbio's HTF, both containing Matrigel, were compared directly. Embryos were
      cultured in four-well dishes, and their morphology and viability were assessed at
      96 hours. MAIN OUTCOME MEASURE(S): Level of interleukin-1alpha in media collected
      at the end of culture. RESULT(S): In both types of HTF, the presence of Matrigel
      allowed a larger number of embryos to reach the blastocyst stage and to hatch;
      blastocyst morphology also was improved. These positive effects were enhanced in
      Quinn's HTF: embryos cultured in its Matrigel-enriched version secreted a higher
      level of interleukin-1alpha than those in Celbio's HTF plus Matrigel and also
      showed a better morphology. CONCLUSION(S): In the mouse embryo model, Matrigel
      improves culture conditions in terms of both embryo viability and morphology, and
      these effects are enhanced in Quinn's HTF.

PMID- 10360925
TI  - Influence of advanced age on the blastocyst development rate and pregnancy rate
      in assisted reproductive technology.
AB  - OBJECTIVE: To evaluate the percentage of blastocysts developing, the pregnancy
      rate, the implantation rate, and the abortion rate in women >40 years of age
      using a cell-free culture system for the development of viable human blastocysts.
      DESIGN: Retrospective clinical study. SETTING: Private IVF units. PATIENT(S): Two
      hundred ninety-three cycles in patients undergoing IVF treatment for infertility.
      Sixty-two cycles were in patients > or =40 years of age, and 231 cycles were in
      patients <40 years of age. INTERVENTION(S): Pronucleate oocytes obtained from IVF
      were cultured in vitro for 5-6 days. One to four embryos were transferred. MAIN
      OUTCOME MEASURE(S): Blastocyst development rate, pregnancy rate, implantation
      rate, and abortion rate. RESULT(S): From 293 cycles, 3,115 pronucleate oocytes
      were cultured, producing 1,175 blastocysts. In the women >40 years of age, the
      blastocyst development rate was 22.2%, and in the younger group, the rate was
      40.5%. The pregnancy rate and implantation rate in the > or =40-year age group
      were 21.1% and 8.9%, respectively; corresponding rates in the younger group were
      44.6% and 19.9%. The abortion rate was increased for the > or =40-year age group
      (25% versus 13.3%). CONCLUSION(S): Success rates for the development of viable
      human blastocysts, pregnancy, and implantation decline significantly in women >
      or =40 years old.

PMID- 10360924
TI  - Relevance of zinc in human sperm flagella and its relation to motility.
AB  - OBJECTIVE: To measure the zinc content of human sperm flagella and to analyze its
      relation to sperm motility. DESIGN: Prospective study. SETTING: Center of
      Dermatology and Andrology. PATIENT(S): Semen samples collected from 90 andrology
      patients and healthy donors after 3-5 days of sexual abstinence. INTERVENTION(S):
      None. MAIN OUTCOME MEASURE(S): Sperm morphology after Shorr staining, sperm
      motility, and patient age were recorded. In addition, zinc concentrations in the
      seminal plasma, sperm heads, and flagella were determined with the use of atomic
      absorption spectrometry. RESULT(S): The mean zinc concentration was 144.3 mg/L in
      the seminal plasma and 146.9 mg/L in the whole ejaculate and was significantly
      correlated with parameters of motility. The sperm heads contained only 6.7% of
      the zinc that was present in the whole spermatozoon. The zinc concentration in
      the flagella was negatively correlated with sperm motility and velocity. In
      addition, it was positively correlated with the percentage of abnormally blue
      stained flagella and the age of the patients. CONCLUSION(S): Our results clearly
      demonstrate the importance of zinc elimination during epididymal sperm maturation
      for functional competence of the outer dense fibers and, therefore, generation of
      motility.

PMID- 10360926
TI  - Aspiration of a single dominant follicle leads to improved cohort development and
      pregnancy in a patient with poor response to in vitro fertilization treatment.
AB  - OBJECTIVE: To report improved follicular cohort development and a healthy ongoing
      pregnancy after midcycle aspiration of a single dominant ovarian follicle in a
      patient with poor response to IVF treatment. DESIGN: Case report. SETTING:
      University-based infertility center. PATIENT(S): A 39-year-old woman (gravida 1,
      para 0) with a borderline FSH level and four previous unsuccessful IVF attempts.
      INTERVENTION(S): A single 27-mm follicular cyst was aspirated after 13 days of
      treatment, while controlled ovarian hyperstimulation was continued. MAIN OUTCOME
      MEASURE(S): Number of follicles developed, number of oocytes retrieved,
      development of a clinical pregnancy. RESULT(S): In previous attempts, the patient
      had no more than two dominant follicles and a maximum of three oocytes retrieved.
      After midcycle aspiration of the single lead follicle, a new cohort of seven
      follicles developed and seven oocytes were recovered. Six embryos were replaced
      by tubal ET and an ongoing singleton gestation resulted. CONCLUSION(S): Midcycle
      aspiration of a single lead follicle in a patient with poor response to IVF
      treatment allowed the development of a larger secondary cohort of follicles
      during the same cycle and ultimately led to a viable pregnancy. This intervention
      may have future implications for the treatment of poor responders.

PMID- 10360928
TI  - In vitro maturation of baboon oocytes retrieved at the time of cesarean section.
AB  - OBJECTIVE: To investigate the feasibility of oocyte retrieval at the time of
      cesarean delivery and the potential of such oocytes to undergo nuclear maturation
      in vitro using a baboon model and an established culture system. DESIGN:
      Randomized, controlled animal study. SETTING: Research foundation and university
      research laboratory. ANIMAL(S): Mature pregnant baboons. INTERVENTION(S): In
      vitro culture of aspirated oocytes with or without epidermal growth factor (EGF).
      MAIN OUTCOME MEASURE(S): Oocyte yield, germinal vesicle breakdown, polar body
      extrusion. RESULT(S): A total of 246 oocytes were retrieved (mean, 35; range, 14
      67). Eighty-seven oocytes (35%) underwent germinal vesicle breakdown and 72
      oocytes (29%) extruded a polar body. A chi2 analysis revealed no significant
      effect of EGF on outcome parameters. No effect of gestational age or maternal age
      on oocyte yield or development was observed. CONCLUSION(S): A sizeable proportion
      of oocytes obtained from puerperal primates exhibited the capacity to undergo
      nuclear maturation in vitro.

PMID- 10360927
TI  - Birth of twin males with normal karyotype after intracytoplasmic sperm injection
      with use of testicular spermatozoa from a nonmosaic patient with Klinefelter's
      syndrome.
AB  - OBJECTIVE: To report the birth of healthy twin males after the use of testicular
      spermatozoa from a nonmosaic patient with Klinefelter's syndrome. DESIGN: Case
      report. SETTING: Private reproduction center with university affiliation.
      PATIENT(S): A couple undergoing intracytoplasmic sperm injection (ICSI) combined
      with testicular sperm extraction because of the husband's secretory azoospermia
      and a nonmosaic 47,XXY peripheral blood karyotype. The wife, a healthy female,
      presented with a history of oligomenorrhea. INTERVENTION(S): ICSI was performed
      using testicular spermatozoa; 3 mM pentoxifylline solution was used to induce
      sperm motility because the spermatozoa recovered were all immotile. MAIN OUTCOME
      MEASURE(S): Normal fertilization, embryo cleavage, pregnancy outcome, and
      peripheral blood karyotype of the newborns. RESULT(S): Thirteen metaphase II
      oocytes were injected. Seven of them fertilized normally and six did not
      fertilize. Three good-quality embryos (4-cell stage class II) were transferred,
      and four were cryopreserved at the two-cell and four-cell stages using a slow
      freezing protocol. Twelve days after ET, a beta-hCG determination was positive.
      Ultrasonographic examination revealed three intrauterine fetal sacs, but one of
      them showed a fetal pole without cardiac activity and vanished in subsequent
      ultrasonographic examinations. The patient delivered twins with normal male
      peripheral blood karyotypes. CONCLUSION(S): Normal outcome after the use of
      testicular sperm extraction and ICSI in a nonmosaic patient with Klinefelter's
      syndrome reaffirms the notion of low transmission risk of this gonosomal
      aneuploidy.

PMID- 10360929
TI  - Diagnostic accuracy of transvaginal hydrolaparoscopy in infertility.
AB  - OBJECTIVE: To determine whether the accuracy of transvaginal hydrolaparoscopy is
      comparable to that of standard laparoscopy for the diagnosis of infertility.
      DESIGN: Prospective, comparative study. SETTING: General hospital in Belgium.
      PATIENT(S): Ten infertile patients without obvious pelvic pathology.
      INTERVENTION(S): Two gynecologists independently performed transvaginal
      hydrolaparoscopy and standard laparoscopy and reported the observations in a
      confidential manner to a third person. MAIN OUTCOME MEASURE(S): Endometriosis,
      adhesions, and other pelvic pathology related to infertility. RESULT(S): Minimal
      or mild endometriosis was diagnosed in seven patients and sequelae of pelvic
      inflammatory disease in one patient at both procedures. The interobserver
      agreement for tuboovarian adhesions was 95% at transvaginal hydrolaparoscopy and
      74% at standard laparoscopy. Ovarian adhesions were detected in 63% at
      transvaginal hydrolaparoscopy and in 37% at standard laparoscopy. CONCLUSION(S):
      Transvaginal hydrolaparoscopy is comparable in accuracy to standard laparoscopy
      for the diagnosis of adhesions and endometriosis in infertile patients without
      obvious pathology.

PMID- 10360930
TI  - Diagnosing amnionicity at 6 weeks of pregnancy with transvaginal three
      dimensional ultrasonography: case report.
AB  - OBJECTIVE: To report a case of monochorionic, diamniotic twin pregnancy diagnosed
      at 6 weeks of pregnancy with three-dimensional (3D) transvaginal sonography and
      to discuss the use of this diagnostic method in the evaluation of multifetal
      pregnancy in the first trimester. DESIGN: Case report. SETTING: University-based
      IVF program. PATIENT(S): A 30-year-old ovum recipient underwent ultrasonographic
      evaluation of a first-trimester twin pregnancy. INTERVENTION(S): Two-dimensional
      (2D) and 3D transvaginal sonography. MAIN OUTCOME MEASURE(S): Accurate diagnosis
      of chorionicity and amnionicity. RESULT(S): Monoamniotic pregnancy and conjoined
      twinning could not be ruled out by using 2D transvaginal sonography at 6 weeks,
      because only one yolk sac (YS) and no membranes could be visualized, and the two
      embryos were closely positioned within one gestational sac. Applying 3D
      technique, two YSs and two separate embryos could clearly be observed,
      establishing the correct diagnosis of a monochorionic, diamniotic pregnancy.
      CONCLUSION(S): The 3D transvaginal ultrasonography provides a quick and accurate
      diagnostic modality for the evaluation of a first-trimester multiple gestation.

PMID- 10360931
TI  - ICSI technique--impact on fertilization rate.

PMID- 10360932
TI  - Management of ovarian endometriomas and pregnancy?

PMID- 10360933
TI  - The search for gonadotropin-resistant ovary--a lost planet or a dinosaur?

PMID- 10360934
TI  - The search for the gonadotropin-resistant ovary -- a lost planet or a dinosaur?

PMID- 10360935
TI  - Factoring in complexity and oocyte memory--can transformations and cyperpathology
      distort reality?

PMID- 10360936
TI  - Factoring in complexity and oocyte memory -- can transformations and
      cyperpathology distort reality?

PMID- 10360937
TI  - Proximity between Glu126 and Arg144 in the lactose permease of Escherichia coli.
AB  - Evidence has been presented [Venkatesan, P., and Kaback, H. R. (1998) Proc. Natl.
      Acad. Sci. U.S.A. 95, 9802-9807] that Glu126 (helix IV) and Arg144 (helix V)
      which are critical for substrate binding in the lactose permease of Escherichia
      coli are charge paired and therefore in close proximity. To test this conclusion
      more directly, three different site-directed spectroscopic techniques were
      applied to permease mutants in which Glu126 and/or Arg144 were replaced with
      either His or Cys residues. (1) Glu126-->His/Arg144-->His permease containing a
      biotin acceptor domain was purified by monomeric avidin affinity chromatography,
      and Mn(II) binding was assessed by electron paramagnetic resonance spectroscopy.
      The mutant protein binds Mn(II) with a KD of about 40 microM at pH 7.5, while no
      binding is observed at pH 5.5. In addition, no binding is detected with Glu126-
      >His or Arg144-->His permease. (2) Permease with Glu126-->Cys/Arg144-->Cys and a
      biotin acceptor domain was purified, labeled with a thiol-specific nitroxide spin
      label, and shown to exhibit spin-spin interactions in the frozen state after
      reconstitution into proteoliposomes. (3) Glu126-->Cys/Arg144-->Cys permease with
      a biotin acceptor domain was purified and labeled with a thiol-specific pyrene
      derivative, and fluorescence spectra were obtained after reconstitution into
      lipid bilayers. An excimer band is observed with the reconstituted E126C/R144C
      mutant, but not with either single-Cys mutant or when the single-Cys mutants are
      mixed prior to reconstitution. The results provide strong support for the
      conclusion that Glu126 (helix IV) and Arg144 (helix V) are in close physical
      proximity.

PMID- 10360938
TI  - Escherichia coli primase zinc is sensitive to substrate and cofactor binding.
AB  - The ligation state of the single zinc site in primase from Escherichia coli
      changes when various substrates and cofactors are added alone or in combination
      as determined by X-ray absorption spectroscopy. X-ray absorption spectroscopy
      (XAS) provides information about the local structure (approximately 5 A) of atoms
      surrounding the metal and has been widely used to characterize metalloproteins.
      The zinc site in native primase and in primase bound to low (30 mM) magnesium
      acetate was found to be tetrahedrally ligated by three sulfurs at an average
      distance of 2.36 +/- 0.02 A and one histidine nitrogen located at a distance of
      2.15 +/- 0.03 A. When ATP, ATP and (dT)17, or ATP, low magnesium acetate and
      (dT)17 was added to primase, one (or two) additional nitrogen/oxygen ligands were
      coordinated to the zinc together with the histidine nitrogen at an average
      distance of 2.15 +/- 0.03 A. These additional ligands are likely from adjacent
      phosphates from ATP. Another structure was observed for the primase-(dT)17
      complex in which an additional nitrogen/oxygen ligand likely from the phosphate
      backbone together with the histidine nitrogen was located at a significantly
      shorter average distance of 2.05 +/- 0.03 A. High magnesium acetate (300 mM)
      completely inactivates primase in a reversible manner such that the region near
      the zinc ligands becomes accessible to proteolytic digestion [Urlacher, T. M.,
      and Griep, M. A. (1995) Biochemistry 34, 16708-16714]. In this inactive complex,
      additional oxygen/nitrogen ligands from acetate as well as the histidine nitrogen
      are located at a distance of 2.20 +/- 0.03 A from the zinc site. To test whether
      the catalytic magnesium was binding within approximately 5 A of the zinc, we
      incubated primase with high (300 mM) manganese acetate. The functional properties
      of magnesium and manganese are similar, but the larger atomic number of manganese
      enhances the X-ray backscattering, making it possible to identify. Since no
      significant difference was observed from the manganese-incubated sample, the
      catalytic metal-binding site is likely located >5 A from the zinc. These studies
      clearly show that primase zinc ligation changes upon binding substrates.

PMID- 10360939
TI  - Evidence for the proenkephalin processing enzyme prohormone thiol protease (PTP)
      as a multicatalytic cysteine protease complex: activation by glutathione
      localized to secretory vesicles.
AB  - The cysteine protease known as "prohormone thiol protease" (PTP) has been
      identified as a major proenkephalin processing enzyme in secretory vesicles of
      adrenal medulla (known as chromaffin granules). This study provides the first
      demonstration that PTP exists as a multicatalytic cysteine protease complex that
      can be activated by endogenous glutathione present in chromaffin granules. The
      high molecular mass nature of PTP, of approximately 185 kDa, was demonstrated by
      elution of a single peak of 35S-enkephalin precursor cleaving activity by
      Sephacryl S200 gel filtration chromatography and by a single band of 35S
      enkephalin precursor cleaving activity detected on radiozymogram gels under
      native buffer conditions. Importantly, when 0.1% SDS was included in
      radiozymogram gels, PTP activity was resolved into three bands of proteolytic
      activity with apparent molecular masses of 88, 81, and 61 kDa. These activities
      were all cysteine proteases, since they were inhibited by the cysteine protease
      inhibitor E-64c but not by pepstatin A or EDTA that inhibit aspartyl protease and
      metalloprotease, respectively. Purification of native PTP by preparative gel
      electrophoresis indicated that PTP was composed of four polypeptides of 66, 60,
      33, and 29 kDa detected on SDS-PAGE gels. These four protein subunits accounted
      for the three catalytic activities of PTP, as demonstrated on 35S-enkephalin
      precursor radiozymogram gels. Results also indicated that the electrophoretic
      mobilities of the four subunits differed under reducing compared to nonreducing
      conditions. The multicatalytic activities of the PTP complex all require reducing
      conditions for activity, which can be provided by endogenous reduced glutathione
      in chromaffin granules. These novel findings provide the first evidence for a
      role of a multicatalytic cysteine protease complex, PTP, in chromaffin granules
      that may be involved in the proteolytic processing of proenkephalin and perhaps
      other precursors into active neuropeptides.

PMID- 10360940
TI  - Design and synthesis of a globin fold.
AB  - We propose a simple method to find an amino acid sequence that is foldable into a
      globular protein with a desired structure based on a knowledge-based 3D-1D
      compatibility function. An asymmetric alpha-helical single-domain structure of
      sperm whale myoglobin consisting of 153 amino acid residues was chosen for the
      design target. The optimal sequence to fit the main-chain framework has been
      searched by recursive generation of the protein 3D profile. The heme-binding site
      was designed by fixing His64 and His93 at the distal and proximal positions,
      respectively, and by penalizing residues that protrude into the space with a
      repulsive function. The apparent bumps among side chains in the computer model of
      the converged, self-consistent sequence were removed by replacing some of the
      bumping residues with smaller ones according to the final 3D profile. The finally
      obtained sequence shares 26% of sequence with the natural myoglobin. The designed
      globin-1 (DG1) with the artificial sequence was obtained by expression of the
      synthetic gene in Escherichia coli. Analyses using size-exclusion chromatography,
      circular dichroism spectroscopy, and solution X-ray scattering showed that DG1
      folds into a monomeric, compact, highly helical, and globular form with an
      overall molecular shape similar to the target structure in an aqueous solution.
      Furthermore, it binds a single heme per protein molecule, which exhibited well
      defined spectroscopic properties. The radius of gyration of DG1 was determined to
      be 20.6 A, slightly larger than that of natural apoMb, and decreased to 19.5 A
      upon heme binding based on X-ray scattering analysis. However, the heme-bound DG1
      did not stably bind molecular oxygen as natural globins do, possibly due to high
      conformational diversity of side-chain structures observed in the NMR and
      denaturation experiments. These results give insight into the relationship
      between the sequence selection and the structural uniqueness of natural proteins
      to achieve biological functions.

PMID- 10360941
TI  - Crystal structure of macrophage migration inhibitory factor complexed with (E)-2
      fluoro-p-hydroxycinnamate at 1.8 A resolution: implications for enzymatic
      catalysis and inhibition.
AB  - Macrophage migration inhibitory factor (MIF) exhibits dual activities. It acts as
      an immunoregulatory protein as well as a phenylpyruvate tautomerase. To
      understand better the relationship between these two activities and to elucidate
      the structural basis for the enzymatic activity, a crystal structure of a complex
      between murine MIF and (E)-2-fluoro-p-hydroxycinnamate, a competitive inhibitor
      of the tautomerase activity, has been determined to 1.8 A resolution. The
      structure is nearly superimposable on that of the free protein indicating that
      the presence of the inhibitor does not result in any major structural changes.
      The inhibitor also confirms the location of the active site in a hydrophobic
      cavity containing the amino-terminal proline. Within this cavity, the inhibitor
      interacts with residues from adjacent subunits. At the back of the cavity, the
      side-chain carbonyl oxygen of Asn-97' interacts with the phenolic hydroxyl group
      of the inhibitor while at the mouth of the cavity the ammonium group of Lys-32
      interacts with a carboxylate oxygen. The other carboxylate oxygen of the
      inhibitor interacts with Pro-1. The hydroxyl group of Tyr-95' interacts weakly
      with the fluoro group on the inhibitor. The hydrophobic side chains of five
      active-site residues (Met-2, Ile-64, Met-101, Val-106, and Phe-113) and the
      phenyl moiety of Tyr-95' are responsible for the binding of the phenyl group.
      Further insight into the enzymatic activity of MIF was obtained by carrying out
      kinetic studies using the enol isomers of phenylpyruvate and (p
      hydroxyphenyl)pyruvate. The results demonstrate that MIF processes the enol
      isomers more efficiently than the keto isomers primarily because of a decrease in
      Km. On the basis of these results, a mechanism is proposed for the MIF-catalyzed
      tautomerization reaction.

PMID- 10360942
TI  - Cystic fibrosis transmembrane conductance regulator: solution structures of
      peptides based on the Phe508 region, the most common site of disease-causing
      DeltaF508 mutation.
AB  - Most cases of cystic fibrosis (CF), a common inherited disease of epithelial cell
      origin, are caused by the deletion of Phe508 located in the first nucleotide
      binding domain (NBF1) of the protein called CFTR (cystic fibrosis transmembrane
      conductance regulator). To gain greater insight into the structure within the
      Phe508 region of the wild-type protein and the change in structure that occurs
      when this residue is deleted, we conducted nuclear magnetic resonance (NMR)
      studies on representative synthetic 26 and 25 amino acid peptide segments. 2D 1H
      NMR studies at 600 MHz of the 26-residue peptide consisting of Met498 to Ala523
      in 10% DMSO, pH 4.0, at 25 degrees C show a continuous but labile helix from
      Gly500 to Lys522, based on both NH-NH(i,i+1) and alphaH-NH(i,i+1) NOEs. Phe508
      within this helix shows only short-range (i, </=i + 2) NOEs. The corresponding 25
      residue peptide lacking Phe508 also forms a labile helix from Gly500 to Lys522.
      However, the relative intensities of the NH-NH(i, i+1)/alphaH-NH(i,i+1) NOEs,
      fewer intermediate-range NOEs, and downfield alphaH and NH chemical shifts
      indicate a lower helical propensity of the 25-mer between residues 505 and 517,
      surrounding the missing residue, Phe508. 2D 1H NMR studies of both peptides in
      saturating (43%) TFE reveal stable alpha-helices from Gly500 to Lys522, based on
      NH-NH(i,i+1,2,3), alphaH-NH(i,i+2,3,4), alphaH-betaH(i,i+3), and weak alphaH
      NH(i,i+1) NOEs. However, downfield shifts of the alphaH resonances from residues
      Gly500 to Ile507 and fewer intermediate-range NOEs suggest a less stable alpha
      helix in the 25-mer even in saturating TFE. These findings show that the Phe508
      containing region of CFTR has a propensity to form an alpha-helix, which is
      destabilized by the DeltaF508 mutation found in most patients with CF. These
      studies have direct relevance to better understanding the CFTR misfolding problem
      associated with CF and to identifying chemical agents, which correct this
      problem.

PMID- 10360944
TI  - Effects of pressure on the kinetics of capture by yeast alcohol dehydrogenase.
AB  - High pressure causes biphasic effects on the oxidation of benzyl alcohol by yeast
      alcohol dehydrogenase as expressed in the kinetic parameter V/K which measures
      substrate capture. Moderate pressure increases the rate of capture of benzyl
      alcohol by activating the hydride transfer step. This means that the transition
      state for hydride transfer has a smaller volume than the free alcohol plus the
      capturing form of enzyme, with a DeltaV of -39 +/- 1 mL/mol, a value that is
      relatively large. This is the first physical property of an enzymatic transition
      state thus characterized, and it offers new possibilities for structure-activity
      analyses. Pressures of >1.5 kbar decrease the rate of capture of benzyl alcohol
      by favoring a conformation of the enzyme which binds nicotinamide adenine
      dinucleotide (NAD+) less tightly. This means that the ground state for tight
      binding, E-NAD+, has a larger volume than the collision complex, E-NAD+, with a
      DeltaV of 73 +/- 2 mL/mol. The equilibrium constant of the conformational change
      Keq is 75 +/- 13 at 1 atm. The effects of pressure on the capture of NAD+ have no
      activation phase because the conformational change is now being expressed
      kinetically instead of thermodynamically, together with but in opposition to
      hydride transfer, causing the effects to cancel. For yeast alcohol dehydrogenase,
      this conformational change had not been detected previously, but similar
      conformational changes have been found by spectroscopic means in other
      dehydrogenases, and some of them are also sensitive to pressure. The opposite
      signs for the volume change of tighter binding and hydride transfer run contrary
      to Pauling's hypothesis that substrates are bound more tightly in the transition
      state than in the Michaelian reactant state.

PMID- 10360943
TI  - Elucidation of a monovalent cation dependence and characterization of the
      divalent cation binding site of the fosfomycin resistance protein (FosA).
AB  - The fosfomycin resistance protein FosA is a member of a distinct superfamily of
      metalloenzymes containing glyoxalase I, extradiol dioxygenases, and methylmalonyl
      CoA epimerase. The dimeric enzyme, with the aid of a single mononuclear Mn2+ site
      in each subunit, catalyzes the addition of glutathione (GSH) to the oxirane ring
      of the antibiotic, rendering it inactive. Sequence alignments suggest that the
      metal binding site of FosA is composed of three residues: H7, H67, and E113. The
      single mutants H7A, H67A, and E113A as well as the more conservative mutants H7Q,
      H67Q, and E113Q exhibit marked decreases in the ability to bind Mn2+ and, in most
      instances, decreases in catalytic efficiency and the ability to confer resistance
      to the antibiotic. The enzyme also requires the monovalent cation K+ for optimal
      activity. The K+ ion activates the enzyme 100-fold with an activation constant of
      6 mM, well below the physiologic concentration of K+ in E. coli. K+ can be
      replaced by other monovalent cations of similar ionic radii. Several lines of
      evidence suggest that the K+ ion interacts directly with the active site.
      Interaction of the enzyme with K+ is found to be dependent on the presence of the
      substrate fosfomycin. Moreover, the E113Q mutant exhibits a kcat which is 40%
      that of wild-type in the absence of K+. This mutant is not activated by
      monovalent cations. The behavior of the E113Q mutant is consistent with the
      proposition that the K+ ion helps balance the charge at the metal center, further
      lowering the activation barrier for addition of the anionic nucleophile. The
      fully activated, native enzyme provides a rate acceleration of >10(15) with
      respect to the spontaneous addition of GSH to the oxirane.

PMID- 10360945
TI  - Nicotinic acetylcholine receptor probed with a photoactivatable agonist: improved
      labeling specificity by addition of CeIV/glutathione. Extension to laser flash
      photolabeling.
AB  - The molecular structure of Torpedo marmorata acetylcholine binding sites has been
      investigated previously by photoaffinity labeling. However, besides the nicotine
      molecule [Middleton et al. (1991) Biochemistry 30, 6987-6997], all other
      photosensitive probes used for this purpose interacted only with closed receptor
      states. In the perspective of mapping the functional activated state, we
      synthesized and developed a new photoactivatable agonist of nAChR capable of
      alkylation of the acetylcholine (ACh) binding sites, as reported previously
      [Kotzyba-Hibert et al. (1997) Bioconjugate Chem. 8, 472-480]. Here, we describe
      the setup of experimental conditions that were made in order to optimize the
      photolabeling reaction and in particular its specificity. We found that
      subsequent addition of the oxidant ceric ion (CeIV) and reduced glutathione
      before the photolabeling step lowered considerably nonspecific labeling (over 90%
      protection with d-tubocurarine) without affecting the binding properties of the
      ACh binding sites. As a consequence, irradiation at 360 nm for 20 min in these
      new conditions gave satisfactory coupling yields (7.5%). A general mechanism was
      proposed to explain the successive reactions occurring and their drastic effect
      on the specificity of the labeling reaction. Last, these incubation conditions
      can be extended to nanosecond pulsed laser photolysis leading to the same
      specific photoincorporation as for usual irradiations (8.5% coupling yield of ACh
      binding sites, 77% protection with carbamylcholine). Laser flash photocoupling of
      a diazocyclohexadienoyl probe on nAChR was achieved for the first time. Taken
      together, these data indicate that future investigation of the molecular dynamics
      of allosteric transitions occurring at the activated ACh binding sites should be
      possible.

PMID- 10360946
TI  - Preparation of Na+,K+-ATPase with near maximal specific activity and
      phosphorylation capacity: evidence that the reaction mechanism involves all of
      the sites.
AB  - The phosphorylation capacity of Na+,K+-ATPase preparations in common use is much
      less than expected on the basis of the molecular weight of the enzyme deduced
      from cDNA sequences. This has led to the popularity of half-of-the-sites or flip
      flop models for the enzyme reaction mechanism. We have prepared Na+,K+-ATPase
      from nasal salt glands of salt-adapted ducks which has a phosphorylation capacity
      and specific activity near the theoretical maxima. Preparations with specific
      activities of >60 micromol (mg of protein)-1 min-1 at 37 degrees C had
      phosphorylation capacities of >60 nmol/mg of protein, and the rate of turnover of
      the enzyme was 9690 min-1, within the range reported for the enzyme from other
      sources. The fraction of the maximal specific activity of the enzyme compared
      well with the fraction of the protein on SDS-PAGE which was alpha and beta
      chains, especially at the highest specific activity which indicates that all of
      the alphabeta protomers are active. The gels of the most reactive preparations
      contained only alpha and beta chains, but less active preparations contained a
      number of extraneous proteins. The major contaminant was actin. The preparation
      did not contain any protein which migrated in the molecular weight range of the
      gamma subunit. The subunit composition of the enzyme was alpha1 and beta1 only.
      This is the first report of a pure, homogeneous, fully active preparation of the
      protein. Reaction models which incorporate a half-of-the-sites or flip-flop
      mechanism do not apply to this enzyme.

PMID- 10360947
TI  - Apoptosis-linked gene product ALG-2 is a new member of the calpain small subunit
      subfamily of Ca2+-binding proteins.
AB  - ALG-2 is a newly discovered Ca2+-binding protein which has been demonstrated to
      be directly linked to apoptosis. Structurally, ALG-2 is expressed as a single
      polypeptide chain corresponding to a 22 kDa protein containing five putative EF
      hand Ca2+-binding sites. In this work, we have developed an efficient expression
      and purification scheme for recombinant ALG-2. Utilizing this protocol, we can
      routinely obtain purified recombinant protein with a yield of approximately 100
      mg per liter of bacterial cell cultures. Gel filtration and chemical cross
      linking experiments have shown that Ca2+-free ALG-2 forms a weak homodimer in
      solution. Biochemical and spectroscopic studies of truncated and point mutants of
      ALG-2 demonstrated that the fifth EF-hand Ca2+-binding motif is likely to
      participate in the formation of the dimer complex. Experimentally, both the amino
      and carboxyl-terminal truncated mutants of ALG-2 have shown their ability to
      retain the structural, as well as, Ca2+-binding integrity when individually
      expressed in bacteria. In this respect, the N-terminal domain encompasses the
      first two EF-hands, and the C-terminal domain contains the remaining three EF
      hands. Combining mutagenesis and spectroscopic studies, we showed that ALG-2
      possesses two strong Ca2+-binding sites. Employing fluorescence spectroscopy and
      circular dichroism, we showed that the binding of Ca2+ to ALG-2 induced
      significant conformational changes in both the N-terminal and C-terminal domains
      of the protein. Furthermore, our studies demonstrated that Ca2+ binding to both
      strong Ca2+-binding sites of ALG-2 is required for ion-induced aggregation of the
      protein. We also report here the expression, purification, and partial
      characterization of a Ca2+-binding-deficient ALG-2 mutant (Glu47Ala/Glu114Ala).
      In light of its much decreased affinity for Ca2+, this mutant could prove to be
      instrumental in elucidating the Ca2+-mediated function of ALG-2 within the
      context of its cellular environment.

PMID- 10360948
TI  - Orientation of LamB signal peptides in bilayers: influence of lipid probes on
      peptide binding and interpretation of fluorescence quenching data.
AB  - The orientation in lipid bilayers of the signal sequence of the bacterial protein
      LamB was studied using binding, circular dichroism, and fluorescence quenching
      experiments. Measurements were made of binding modifications caused by the
      incorporation of lipid probes (brominated or nitroxide-labeled phospholipids)
      used in the parallax fluorescence quenching method of determining peptide
      penetration depth [Abrams, F. S., and London, E. (1992) Biochemistry 31, 5312
      5322]. The signal peptide bound to a similar extent to neutral bilayers composed
      of either egg phosphatidylcholine (EPC) or phosphatidylcholines brominated at
      various positions on their acyl chains. The fluorescence of a tryptophan in
      either the 18 or 24 position of the peptide was quenched more by bromines in the
      6 and 7 than in the 9 and 10 positions on the lipid hydrocarbon chain. Parallax
      calculations showed that tryptophan-18 was located only 4 A from the hydrocarbon
      water interface, consistent with the peptide adopting a "hammock" configuration
      in the bilayer, with both termini exposed to the aqueous phase and the central
      alpha-helix located near the hydrocarbon-water interface. In contrast, the
      incorporation of 10% nitroxide-labeled lipids into EPC bilayers modified peptide
      binding in a manner dependent on the position of the nitroxide on the hydrocarbon
      chain; 7-Doxyl PC reduced the percent peptide bound by about one-half, whereas 12
      Doxyl PC had little effect on binding. These binding differences modified
      tryptophan quenching by these probes, making parallax analysis problematical. In
      the presence of the positively charged LamB peptide, the incorporation of
      negatively charged phospholipids into EPC bilayers increased the level of peptide
      binding and modified tryptophan quenching by nitroxide probes. These results
      suggest that the nitroxide probe could be partially excluded from negatively
      charged lipid domains where the peptide preferentially bound. Quite different
      binding and quenching results were obtained with a negatively charged peptide
      analogue, showing that the charge on both the peptide and bilayer affects peptide
      nitroxide probe interactions.

PMID- 10360949
TI  - Differential signaling of insulin and IGF-1 receptors to glycogen synthesis in
      murine hepatocytes.
AB  - We have used SV40-transformed hepatocytes from insulin receptor-deficient mice (
      /-) and normal mice (WT) to investigate the different abilities of insulin and
      IGF-1 receptors to stimulate glycogen synthesis. We report that insulin receptors
      are more potent than IGF-1 receptors in stimulating glycogen synthesis. Both
      receptors stimulate glycogen synthesis in a PI 3-kinase-dependent manner, but
      only the effect of insulin receptors is partially rapamycin-dependent. Insulin
      and IGF-1 receptors activate Akt to a similar extent, whereas GSK-3 inactivation
      in response to IGF-1 is considerably lower in both -/- and WT cells, compared to
      the effect of insulin in WT cells. The findings indicate that (i) the potency of
      insulin and IGF-1 receptors in stimulating glycogen synthesis correlates with
      their ability to inactivate GSK-3, (ii) the extent of GSK-3 inactivation does not
      correlate with the extent of Akt activation mediated by insulin or IGF-1
      receptors, indicating that the effect of insulin on GSK-3 requires additional
      kinases, and (iii) the pathways required for insulin stimulation of glycogen
      synthesis in mouse hepatocytes are PI 3-kinase-dependent and rapamycin-sensitive.

PMID- 10360951
TI  - Adenovirus-mediated overexpression of microsomal triglyceride transfer protein
      (MTP): mechanistic studies on the role of MTP in apolipoprotein B-100 biogenesis.
AB  - The intracellular concentration of the microsomal triglyceride transfer protein
      large subunit (lMTP), the abetalipoproteinemia gene product, is tightly
      controlled. To date, attempts at overexpressinglMTP in vivo or in vitro have been
      unsuccessful. We successfully overexpressed lMTP in HepG2 cells using an
      adenoviral vector containing an lMTP cDNA, AdMTP. AdMTP-transduced HepG2 cells
      overexpressed MTP activity. They secreted increased amounts of apoB-100
      lipoproteins with LDL and HDL density into the medium. lMTP overexpression alone
      minimally changed the density profile of apoB-containing lipoproteins, but
      addition of oleic acid shifted the profile toward lower densities. Oleic acid had
      a greater stimulatory effect on apoB-100 secretion in control HepG2 cells than in
      AdMTP-transduced cells, because (i) adenoviral transduction per se suppressed
      protein synthesis, affecting apoB-100 and albumin equally, and (ii) adenoviral
      transduction partially attenuated the increase in triglyceride synthesis in
      response to oleic acid supplementation. AdMTP treatment greatly diminished the
      intracellular degradation of apoB-100, but in comparison with recombinant virus
      containing luciferase cDNA (AdLuc), it caused no change in its biosynthetic rate.
      It greatly reduced, but did not eliminate, its proteasomal degradation. Our study
      constitutes the initial demonstration that adenovirus-mediated transfer of lMTP
      markedly stimulates MTP expression which in turn stimulates apoB-100 production.
      The mechanism involves a downregulation of ubiquitin-proteasome-mediated
      degradation without any change in synthetic rate.

PMID- 10360950
TI  - Acidic residues involved in cation and substrate interactions in the
      Na+/dicarboxylate cotransporter, NaDC-1.
AB  - The role of acidic amino acid residues in cation recognition and selectivity by
      the Na+/dicarboxylate cotransporter, NaDC-1, was investigated by site-directed
      mutagenesis and expression in Xenopus oocytes. Four of the residues tested, Asp
      52, Glu-74, Glu-101, and Glu-332, were found to be unimportant for transport
      activity. However, substitutions of Asp-373 and Glu-475, conserved residues found
      in transmembrane domains M8 and M9, respectively, altered transport kinetics.
      Replacements of Asp-373 with Ala, Glu, Asn, and Gln resulted in changes in sodium
      affinity and cation selectivity in NaDC-1, indicating that the carbonyl oxygen at
      this position may play a role in the topological organization of the cation
      binding site. In contrast, substitutions of Glu-475 led to dramatic reductions in
      transport activity and changes in transport kinetics. Substitution with Gln led
      to a transporter with increased substrate and sodium affinity, while the E475D
      mutant was inactive. The E475A mutant appeared to have poor sodium binding.
      Substrate-induced currents in the E475A mutant exhibited a strong voltage
      dependence, and a reversal of the current was seen at -30 mV. The results suggest
      that Glu-475 may play a role in cation binding and possibly also in mediating
      anion channel activity. Remarkably, mutations of both Asp-373 and Glu-475
      affected the Km for succinate in NaDC-1, suggesting dual roles for these residues
      in determining the affinity for substrate and cations. We propose that at least
      one of the cation-binding sites and the substrate-binding site are close together
      in the carboxy-terminal portion of NaDC-1, and thus transmembrane domains M8 and
      M9 are candidate structures for the formation of the translocation pathway.

PMID- 10360952
TI  - Primary charge separation routes in the BChl:BPhe heterodimer reaction centers of
      Rhodobacter sphaeroides.
AB  - Energy transfer and the primary charge separation process are studied as a
      function of excitation wavelength in membrane-bound reaction centers of
      Rhodobacter sphaeroides in which the excitonically coupled bacteriochlorophyll
      homodimer is converted to a bacteriochlorophyll-bacteriopheophytin heterodimer,
      denoted D [Bylina, E. J., and Youvan, D. C. (1988) Proc. Natl. Acad. Sci. U.S. A.
      85, 7226]. In the HM202L heterodimer reaction center, excitation of D using 880
      nm excitation light results in a 43 ps decay of the excited heterodimer, D. The
      decay of D results for about 30% in the formation of the charge separated state
      D+QA- and for about 70% in a decay directly to the ground state. Upon excitation
      of the monomeric bacteriochlorophylls using 798 nm excitation light,
      approximately 60% of the excitation energy is transferred downhill to D, forming
      D. Clear evidence is obtained that the other 40% of the excitations results in
      the formation of D+QA- via the pathway BA --> BA+HA- --> D+HA- --> D+QA-. In the
      membrane-bound "reversed" heterodimer reaction center HL173L, the simplest
      interpretation of the transient absorption spectra following B excitation is that
      charge separation occurs solely via the slow D-driven route. However, since a
      bleach at 812 nm is associated with the spectrum of D in the HL173L reaction
      center, it cannot be excluded that a state including BB is involved in the charge
      separation process in this complex.

PMID- 10360953
TI  - Internal electron transfer and structural dynamics of cd1 nitrite reductase
      revealed by laser CO photodissociation.
AB  - Laser photolysis techniques have been employed to investigate the internal
      electron transfer (eT) reaction within Pseudomonas aeruginosa nitrite reductase
      (Pa-NiR). We have measured the (d1--> c) internal eT rate for the wild-type
      protein and a site-directed mutant (Pa-NiR H327A) which has a substitution in the
      d1-heme binding pocket; we found the rate of eT to be fast, keT = 2.5 x 10(4) and
      3.5 x 10(4) s-1 for the wild-type and mutant Pa-NiR, respectively. We also
      investigated the photodissociation of CO from the fully reduced proteins and
      observed microsecond first-order relaxations; these imply that upon breakage of
      the Fe2+-CO bond, both Pa-NiR and Pa-NiR H327A populate a nonequilibrium state
      which decays to the ground state with a complex time course that may be described
      by two exponential processes (k1 = 3 x 10(4) s-1 and k2 = 0.25 x 10(4) s-1).
      These relaxations do not have a kinetic difference spectrum characteristic of CO
      recombination, and therefore we conclude that Pa-NiR undergoes structural
      rearrangements upon dissociation of CO. The bimolecular rate of CO rebinding is 5
      times faster in Pa-NiR H327A than in the wild-type enzyme (1.1 x 10(5) M-1 s-1
      compared to 2 x 10(4) M-1 s-1), indicating that this mutation in the active site
      alters the CO diffusion properties of the protein, probably reducing steric
      hindrance. CO rebinding to the wild-type mixed valence enzyme (c3+d12+) which is
      very slow (k = 0.25 s-1) is proposed to be rate-limited by the c --> d1 internal
      eT event, involving the oxidized d1-heme which has a structure characteristic of
      the fully oxidized and partially oxidized Pa-NiR.

PMID- 10360954
TI  - Time-resolved FT-IR studies on the CO adduct of Paracoccus denitrificans
      cytochrome c oxidase: comparison of the fully reduced and the mixed valence form.
AB  - The rebinding of CO to cytochrome c oxidase from Paracoccus denitrificans in the
      fully reduced and in the half-reduced (mixed valence) form as a function of
      temperature was investigated using time-resolved rapid-scan FT-IR spectroscopy in
      the mid-IR (1200-2100 cm-1). For the fully reduced enzyme, rebinding was complete
      in approximately 2 s at 268 K and showed a biphasic reaction. At 84 K,
      nonreversible transfer of CO from heme a3 to CuB was observed. Both photolysis at
      84 K and photolysis at 268 K result in FT-IR difference spectra which show
      similarities in the amide I, amide II, and heme modes. Both processes, however,
      differ in spectral features characteristic for amino acid side chain modes and
      may thus be indicative for the motional constraint of CO at low temperature.
      Rebinding of photodissociated CO for the mixed-valence enzyme at 268 K is also
      biphasic, but much slower as compared to the fully reduced enzyme. FT-IR
      difference spectra show band features similar to those for the fully reduced
      enzyme. Additional strong bands in the amide I and amide II range indicate local
      conformational changes induced by electron and coupled proton transfer. These
      signals disappear when the temperature is lowered to 84 K. At 268 K, a difference
      signal at 1746 cm-1 is observed which is shifted by 6 cm-1 to 1740 cm-1 in 2H2O.
      The absence of this signal for the mutant Glu 278 Gln allows assignment to the
      COOH stretching mode of Glu 278, and indicates changes of the conformation,
      proton position, or protonation of this residue upon electron transfer.

PMID- 10360955
TI  - Probing the conformational heterogeneity of the acetylaminofluorene-modified 2'
      deoxyguanosine and DNA by 19F NMR spectroscopy.
AB  - 19F NMR spectroscopy was used to probe the conformation of a DNA adduct derived
      from the carcinogen 7-fluoro-N-acetyl-2-aminofluorene (FAAF) in three structural
      contexts: as a monomer and incorporated into single- and double-stranded DNA. The
      19F NMR spectrum of dG-C8-FAAF [N-(deoxyguanosin-8-yl)-N-acetyl-7-fluoro-2
      aminofluorene] in methanol at -30 degrees C exhibited four interconvertible
      signals in a 11:52:26:11 ratio. Dynamic NMR analysis indicated that the four
      torsional isomers arise from restricted rotation about the amide (gamma) (14.4
      kcal/mol) and the guanyl-nitrogen (alpha) bonds. The conformational heterogeneity
      persisted in a single strand FAAF-12-mer, d(CTTCTTG[FAAF]ACCTC), whose 19F NMR
      spectrum at 22 degrees C and pH 7.0 gave only two signals in a 40:60 ratio,
      instead of four. The two 19F signals followed a two-site exchange with the
      rotation barrier of 14.7 kcal/mol about the amide (gamma') bond. A similar
      conformational theme was observed in the FAAF-12-mer duplex,
      d(CTTCTTG[FAAF]ACCTC).d(GAGGTCAAGAAG), which revealed two 19F resonances in a
      41:59 ratio at 22 degrees C and pH 7.0. According to solvent-induced isotope and
      magnetic anisotropy effects, the two duplex conformers adopt exclusively a base
      displacement structure, being different only in their relative acetyl group
      orientations, cis (gamma' approximately 180 degrees) or trans (gamma'
      approximately 0 degrees ). Dynamic NMR data indicated that the two conformers do
      not exchange over a wide range of temperatures. This contrasts with the
      nonacetylated counterpart, which exhibits an equilibrium between the "B-type" and
      "stacked" conformers [Zhou, L., et al. (1997) J. Am. Chem. Soc. 119, 5384-5389].
      The exclusive stacked nature of the AAF adducts may provide insight into why AAF
      adducts are more mutagenic and prone to repair than the nonacetylated AF adducts.

PMID- 10360956
TI  - Rhodocetin, a novel platelet aggregation inhibitor from the venom of Calloselasma
      rhodostoma (Malayan pit viper): synergistic and noncovalent interaction between
      its subunits.
AB  - A novel platelet aggregation inhibitor, rhodocetin, was purified from the crude
      venom of Calloselasma rhodostoma. It inhibited collagen-induced platelet
      aggregation in a dose-dependent manner, with an IC50 of 41 nM. Rhodocetin has a
      heterodimeric structure with alpha and beta subunits, which could be separated on
      a nonreducing denaturing gel or reverse-phase HPLC column. Individually neither
      subunit inhibited platelet aggregation even at 2.0 microM concentration.
      Titration and reconstitution experiments showed that, when these subunits are
      mixed to give a 1:1 complex, most of its biological activity was recovered. The
      reconstituted complex inhibited platelet aggregation with an IC50 of 112 nM,
      about 3-fold less effective than the native molecule. Circular dichroism analysis
      revealed that the reconstituted complex had a spectrum similar to that of the
      native protein. By using surface plasmon resonance studies, we established that
      the stoichiometry of binding between the two subunits is 1:1 and the subunits
      interact with a Kd of 0.14 +/- 0.04 microM. The complete amino acid sequences of
      the alpha (15956.16 Da, 133 residues) and beta (15185.10 Da, 129 residues)
      subunits show a high degree of homology with each other (49%) and with the Ca2+
      dependent lectin-related proteins (CLPs) (typically 29-48%) isolated from other
      snake venoms. Unlike the other members of the family in which the subunits are
      held together by an interchain disulfide bond, rhodocetin subunits are held
      together only through noncovalent interactions. The cysteinyl residues forming
      the intersubunit disulfide bridge in all other known CLPs are replaced by Ser-79
      and Arg-75 in the alpha and beta subunits of rhodocetin, respectively. These
      studies support the noncovalent and synergistic interactions between the two
      subunits of rhodocetin. This is the first reported CLP dimer with such a novel
      heterodimeric structure.

PMID- 10360957
TI  - Lipoxin A4: a new class of ligand for the Ah receptor.
AB  - The Ah receptor is a ligand-activated transcription factor that mediates many of
      the biological actions of a large class of environmental compounds. Support for a
      role of the Ah receptor in normal physiology also has been reported, but an
      endogenous regulating ligand has not been identified. We have examined candidate
      endogenous lipophilic substances and report here the ability of the arachidonic
      acid metabolite, lipoxin A4, to bind to and activate the Ah receptor in Hepa-1
      cells. Lipoxin A4 produced a concentration-dependent response in a DRE-driven CAT
      reporter construct, with a greater than 10-fold increase in CAT activity at 0. 3
      microM. Lipoxin A4 transformed the Ah receptor to an active DRE-binding form in a
      concentration-dependent manner as indicated by gel mobility shift analysis.
      Results of Ah receptor competitive binding experiments indicated that at a
      concentration of 100 nM, lipoxin A4 produced a half-maximum displacement (EC50)
      of [3H]TCDD binding. Results of Northern blot analyses indicated a transient
      increase in mRNA levels of the Ah receptor-responsive gene CYP1A1, which peaked
      at 4 h, consistent with the kinetics observed for lipoxin A4-induced CYP1A1
      enzyme activity. Further, lipoxin A4 was found to be a competitive inhibitor for
      the CYP1A1 enzyme, with a calculated Ki = 1.1 microM. These results establish
      lipoxin A4 as a new class of Ah receptor ligand, one that differs dramatically
      from classical Ah receptor ligands.

PMID- 10360958
TI  - Assignment of the heme axial ligand(s) for the ferric myoglobin (H93G) and heme
      oxygenase (H25A) cavity mutants as oxygen donors using magnetic circular
      dichroism.
AB  - UV-visible absorption and magnetic circular dichroism (MCD) data are reported for
      the cavity mutants of sperm whale H93G myoglobin and human H25A heme oxygenase in
      their ferric states at 4 degreesC. Detailed spectral analyses of H93G myoglobin
      reveal that its heme coordination structure has a single water ligand at pH 5.0,
      a single hydroxide ligand at pH 10.0, and a mixture of species at pH 7.0
      including five-coordinate hydroxide-bound, and six-coordinate structures. The
      five-coordinate aquo structure at pH 5 is supported by spectral similarity to
      acidic horseradish peroxidase (pH 3.1), whose MCD data are reported herein for
      the first time, and acidic myoglobin (pH 3.4), whose structures have been
      previously assigned by resonance Raman spectroscopy. The five-coordinate
      hydroxide structure at pH 10.0 is supported by MCD and resonance Raman data
      obtained here and by comparison with those of other known five-coordinate oxygen
      donor complexes. In particular, the MCD spectrum of alkaline ferric H93G
      myoglobin is strikingly similar to that of ferric tyrosinate-ligated human H93Y
      myoglobin, whose MCD data are reported herein for the first time, and that of the
      methoxide adduct of ferric protoporphyrin IX dimethyl ester (FeIIIPPIXDME).
      Analysis of the spectral data for ferric H25A heme oxygenase at neutral pH in the
      context of the spectra of other five-coordinate ferric heme complexes with
      proximal oxygen donor ligands, in particular the p-nitrophenolate and acetate
      adducts of FeIIIPPIXDME, is most consistent with ligation by a carboxylate group
      of a nearby glutamyl (or aspartic) acid residue.

PMID- 10360959
TI  - Away with words: commentary on the Atlan-Cohen essay 'Immune information, self
      organization and meaning'.
AB  - Drawing on metaphors from linguistics and information theory, Atlan and Cohen
      challenge us to take a very different view of the immune system, one that engages
      in constant chatter among the constituents and allows the immune system to arrive
      at a decision about what to, and not to, destroy. Our commentary responds to this
      challenge and points out many logical biological flaws in their view. We seem to
      agree that specificity is important, and that there is some kind of somatic
      selection process at work to distinguish self from non-self. Our analysis of
      models depends on the basis of how self and non-self are separated. There are
      only two possibilities, time or space; and space-based models are all but ruled
      out. There are two major kinds of time-based model, one based on the time taken
      for an organism to develop from embryo to adult, the other based on the time
      taken for a cell to differentiate from one state to another. With so many
      ambiguities in the metaphors and so little attention to mechanism, the Atlan and
      Cohen challenge is, we suspect, based on time measured in cell differentiation
      units. They also make the common mistake of assuming repertoires that are
      transcendental in size (>10(10)), making it impossible to have a functional
      immune system in animals smaller than a rabbit--a feature that does not instill
      confidence in the biological relevance of such models.

PMID- 10360960
TI  - CpG oligodeoxynucleotides rescue BKS-2 immature B cell lymphoma from anti-IgM
      mediated growth inhibition by up-regulation of egr-1.
AB  - Cross-linking of the IgM antigen receptor on an immature B cell lymphoma (BKS-2)
      induces growth arrest and apoptosis. This is accompanied by down-regulation of
      the immediate early genes, egr-1 and c-myc, and a reduction in NF-kappaB
      activity. Anti-IgM-induced growth arrest and apoptosis of this murine B cell
      lymphoma were prevented by oligodeoxynucleotides (ODN) containing the CpG motif,
      which are also known to be stimulatory for mature and immature B cells. The CpG
      but not non-CpG ODN rescued BKS-2 cells from anti-IgM-mediated growth inhibition
      by up-regulation of egr-1 and c-myc expression as well as by restoring NF-kappaB
      activity. Interestingly, changes in egr-1 expression occurred more rapidly than
      in c-myc expression. Also the c-myc levels remained high up to 6 h after addition
      of the anti-IgM, which was also the time until which the addition of CpG could be
      delayed without affecting its ability to provide complete protection. This CpG
      induced rescue of B lymphoma cells was blocked by antisense egr-1 ODN, suggesting
      that the expression of egr-1 is important for the effects of CpG ODN on the
      growth and survival of BKS-2 cells.

PMID- 10360961
TI  - A novel recognition motif of human NKT antigen receptor for a glycolipid ligand.
AB  - Murine NKT cells can recognize alpha-galactosylceramide (alpha-GalCer) in the
      context of a class Ib CD1d molecule. Here we show that alpha-GalCer can
      selectively activate freshly isolated human Valpha24(+)Vbeta11(+) cells,
      functionally defining the human NKT cells. The naive human NKT cell repertoire
      consisted of cells expressing an invariant Valpha24JalphaQ chain and a diverse
      array of beta chains derived from a single Vbeta11 gene segment. Stimulation with
      alpha-GalCer expanded a polyclonal subset of the human NKT cell repertoire
      carrying a novel complementarity-determining region (CDR) 3beta consensus motif
      that may directly interact with the sugar moiety of alpha-GalCer. Our data
      suggest that certain redundancy is allowed for CDR3beta of NKT antigen receptor
      to interact with the ligand and provide a first clue to understand the novel
      protein-carbohydrate interaction mechanisms.

PMID- 10360962
TI  - HLA-G in the human thymus: a subpopulation of medullary epithelial but not
      CD83(+) dendritic cells expresses HLA-G as a membrane-bound and soluble protein.
AB  - The human MHC class Ib gene HLA-G is transcribed and translated in different
      placental cell subpopulations during pregnancy. In addition to this restricted
      tissue distribution, HLA-G proteins were also recently detected in the thymus of
      HLA-G transgenic mice, as well as in some human thymic epithelial cells (TEC).
      There was a need to further define the phenotype of the HLA-G-expressing cells in
      the human thymus as well as the type of translated forms that they produce. Using
      several HLA-G-specific mAb and immunohistochemistry performed on cryosections of
      human thymi at different ages, we found that the HLA-G-expressing cells are
      present on medullary cells exhibiting the epithelial morphological type 6. Co
      localization experiments performed by double or triple immunofluorescence
      staining demonstrate that these HLA-G-expressing cells express various
      cytokeratins, epithelial cell markers but not the CD83 dendritic cell marker. We
      further show by ELISA measurements that a subset of primary cultured human TEC
      also expresses soluble HLA-G. Therefore, HLA-G protein tissue distribution is not
      restricted solely to placental cells. A subpopulation of medullary TEC also
      expresses HLA-G both at their cell surface and in secreted form, raising the
      question of the functional significance of such MHC class Ib molecules. Whether
      thymic soluble and/or membrane-bound HLA-G contribute to inhibit NK cells or to a
      negative selection of autoreactive T cells which could be harmful in case of
      pregnancy and/or to a positive selection of viral peptides/HLA-G-restricted
      CD8(+) T cells remains to be demonstrated.

PMID- 10360963
TI  - Expansion of neonatal tolerance to self in adult life: I. The role of a bacterial
      adjuvant in tolerance spread.
AB  - T cell neonatal tolerance to self evolves perturbation of the Th1/Th2 balance
      towards Th2-type self-specific T cells. In the current study we have demonstrated
      that a tolerant state could be extended to another encephalitogenic determinant
      only if the neonatally tolerizing determinant was co-administered in adult life
      with an emulsion of Mycobacterium tuberculosis (i.e. complete Freund's adjuvant).
      The mechanisms underlying tolerance elicitation and expansion were then explored
      by an in vitro system in which indirect suppression could be measured. Addition
      of a tolerizing epitope to splenic T cells from neonatally tolerized animals
      induced a marked suppression of the anti-MT response. This response could be
      restored by neutralizing antibodies to IL-4. In contrast, the neutralizing
      antibodies to IL-4 had no affect on the response of these cells to the tolerizing
      determinant. These findings are highly significant not only because they explore
      the important role of microbial antigens in neonatal tolerance, but also because
      they distinguish, for the first time, between tolerizing and tolerized T cells.

PMID- 10360964
TI  - Expansion of neonatal tolerance to self in adult life: II. Tolerance
      preferentially spreads in an intramolecular manner.
AB  - Newborn rats exposed to a myelin basic protein determinant acquired long-lasting
      resistance to experimental autoimmune encephalomyelitis induced by another
      determinant only if both determinants are co-administered in adult life. We
      demonstrate here that during the course of disease both the anti-self response
      and the tolerant state spread in an intramolecular and not an intermolecular
      manner. Mechanisms involved in tolerance elicitation and expansion are then
      explored using an in vitro system in which indirect suppression could be
      measured.

PMID- 10360965
TI  - IgG1 production by sIgD+ splenic B cells and peritoneal B-1 cells in response to
      IL-5 and CD38 ligation.
AB  - CD38 ligation on mouse B cells by CS/2, an anti-mouse CD38 mAb, induces
      proliferation, IL-5 receptor alpha chain expression and tyrosine phosphorylation
      of Bruton's tyrosine kinase. Furthermore, stimulation of splenic B cells with IL
      5 together with CS/2 induces Blimp-1 expression and differentiation into Ig
      producing cells. Here we examined the role of IL-5 in IgG1 and IgA production by
      B cells isolated from the spleen and peritoneal cavity. CD38 recognized by CS/2
      was expressed in the follicular mantle B cells surrounding the germinal center,
      sIgD+ splenic B cells and peritoneal B cells. IL-5 induced IgG1 production in
      splenic sIgD+ B cells stimulated with CS/2, while it was ineffective to induce
      IgA production. Among the various cytokines tested, only IL-5 had a synergistic
      effect on IgG1 production with CS/2. IL-5 could induce the generation of S micro
      Sgamma1 reciprocal recombination DNA products in CS/2-stimulated B cells. IL-4
      was ineffective to induce either micro-gamma1 switch recombination or IgG1
      secretion with CS/2, demonstrating that IL-5 promotes both micro-gamma1 switch
      recombination and IgG1 secretion in an IL-4-independent manner. The peritoneal B
      2 cells exhibited both IgG1 and IgA production in response to IL-5 plus CS/2,
      while B-1 cells produced IgG1. These results imply that the pattern of
      differentiation to Ig-producing cells seen with peritoneal B cells is not
      identical to the pattern seen with splenic B cells and that peritoneal B-2 cells
      contain precursors of IgA-producing cells responding to IL-5 plus CS/2.

PMID- 10360966
TI  - Therapeutic effect of an anti-Fas ligand mAb on lethal graft-versus-host disease.
AB  - Several anti-Fas ligand (FasL) inhibitory mAb (FLIM) were raised and
      characterized in this study. One, FLIM58, showed more potent neutralizing
      activity than Fas-Fc, the previously established artificial neutralizing agent
      for FasL. Several murine models of acute graft-versus-host disease (GVHD) after
      allogeneic bone marrow transplantation have been used to show that both FasL and
      perforin, the major effector molecules of cytotoxic T lymphocytes, are involved
      in this disease. In our GVHD model, FasL rather than perforin was associated with
      lethality. Administration of FLIM58 or Fas-Fc reduced the weight loss and
      mortality caused by GVHD, although other signs of GVHD, such as skin lesions,
      lymphoid hypoplasia and mononuclear cell infiltration in the liver, did not
      improve significantly. FLIM58 was more effective than Fas-Fc in reducing
      mortality. Our results demonstrated that neutralizing agents for FasL are
      therapeutic for lethal GVHD.

PMID- 10360967
TI  - Death signals from the B cell antigen receptor target mitochondria, activating
      necrotic and apoptotic death cascades in a murine B cell line, WEHI-231.
AB  - B cell antigen receptor (BCR)-mediated cell death has been proposed as a
      mechanism for purging the immune repertoire of anti-self specificities during B
      cell differentiation in bone marrow. Mitochondrial alterations and activation of
      caspases are required for certain aspects of apoptotic cell death, but how the
      mitochondria and caspases contribute to BCR-mediated cell death is not well
      understood. In the present study, we used the mouse WEHI-231 B cell line to
      demonstrate that mitochondrial alterations and activation of caspases are indeed
      participants in BCR-mediated cell death. The peptide inhibitor of caspases, N
      benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), blocked cleavage of
      poly(ADP-ribose) polymerase and various manifestation of nuclear apoptosis such
      as nuclear fragmentation, hypodiploidy and DNA fragmentation, indicating that
      signals from the BCR induced the activation of caspases. In addition, z-VAD-fmk
      delayed apoptosis-associated changes in cellular reduction-oxidation potentials
      as determined by hypergeneration of superoxide anion, as well as exposure of
      phosphatidylserine residues in the outer plasma membrane. By contrast, although z
      VAD-fmk retarded cytolysis, it was incapable of preventing disruption of the
      plasma membrane even under the same condition in which it completely blocked
      nuclear apoptosis. Mitochondrial membrane potential loss was also not blocked by
      z-VAD-fmk. Bongkrekic acid, a specific inhibitor of mitochondrial permeability
      transition pores, suppressed not only the mitochondrial membrane potential but
      also the change of plasma membrane permeability. Overexpression of Bcl-xL
      prevented mitochondrial dysfunction, nuclear apoptosis and membrane permeability
      cell death triggered by BCR signal transduction. These observations indicate that
      death signals from BCR may first cause mitochondrial alterations followed by
      activation of both necrotic and apoptotic cascades.

PMID- 10360968
TI  - Functional analysis of LAT in TCR-mediated signaling pathways using a LAT
      deficient Jurkat cell line.
AB  - The adaptor molecule LAT (linker for activation of T cells) is a palmitoylated
      integral membrane protein that localizes to the glycolipid-enriched microdomains
      in the plasma membrane. Upon TCR engagement, LAT becomes phosphorylated on
      multiple tyrosine residues and then binds several critical signaling molecules.
      Here, we describe the generation and characterization of a LAT-deficient cell
      line. Using this cell line, we demonstrate that LAT is required for TCR-mediated
      Ca2+ mobilization and optimal tyrosine phosphorylation of phospholipase C-gamma1,
      Vav and SLP-76. LAT is also required for Erk activation, CD69 up-regulation, and
      AP- and NFAT-mediated gene transcription. We also demonstrate, by reconstituting
      this cell line with LAT mutants, that the LAT transmembrane domain and
      palmitoylation at Cys26, but not Cys29, are required for LAT function and TCR
      signaling. These studies provide further evidence for the crucial role of the LAT
      molecule, and demonstrate the use of a LAT-deficient cell line for the analysis
      of LAT structure and function.

PMID- 10360969
TI  - A shared TCR CDR3 sequence in NOD mouse autoimmune diabetes.
AB  - T cells involved in autoimmune diseases have been characterized by the genetic
      elements used to construct their autoimmune TCR. In the present study, we
      sequenced the alpha and beta chains of the TCR expressed by a CD4(+) T cell
      clone, C9, functional in NOD mouse diabetes. Clone C9 can adoptively transfer
      diabetes or, when attenuated, C9 can be used to vaccinate NOD mice against
      diabetes. Clone C9 recognizes a peptide epitope (p277) of the 60 kDa heat shock
      protein (hsp60) molecule. We now report that the C9 TCR beta chain features a
      CDR3 peptide sequence that is prevalent among NOD mice. This CDR3 element is
      detectable by 2 weeks of age in the thymus, and later in the spleen and in the
      autoimmune insulitis. Thus, a TCR CDR3beta sequence appears to be a common
      idiotope associated with mouse diabetes.

PMID- 10360970
TI  - Regulation of NOD mouse autoimmune diabetes by T cells that recognize a TCR CDR3
      peptide.
AB  - NOD mice spontaneously develop type I diabetes resulting from autoimmune
      destruction of their insulin-producing beta cells. Among the self-antigens
      targeted by NOD autoimmune T cells is a peptide, p277, from the sequence of the
      60 kDa heat shock protein (hsp60). Common to the anti-p277 T cell populations of
      NOD mice is an idiotope, C9, that spans the CDR3 region of the C9 TCR. We now
      report: (i) that the C9 idiotope peptide can be presented directly to anti-C9
      anti-idiotypic T cells by C9 T cells, (ii) that spontaneous anti-C9 anti
      idiotypic T cell activity falls as disease progresses, but immunization can
      activate the anti-idiotypic T cells to regulate the autoimmune process, (iii)
      that the anti-idiotypic T cells secrete IFN-gamma, but appear to control the
      disease by down-regulating the IFN-gamma produced by the pathogenic population of
      anti-p277 T cells, (iv) that intrathymic administration of the C9 idiotope
      peptide at 1 week of age can accelerate the disease, and (v) that administering
      the p277 target peptide can up-regulate the anti-idiotypic T cells and arrest the
      disease process. Thus, the development of NOD diabetes can be regulated by a
      balance between anti-idiotypic and anti-target peptide autoimmunity, and anti
      idiotypic regulation can lead to changes in the cytokine secretion of the
      autoimmune T cells involved in the disease process.

PMID- 10360971
TI  - Characterization of the interaction of a TCR alpha chain variable domain with MHC
      II I-A molecules.
AB  - The alphabeta TCR recognizes peptides bound to MHC molecules. In the present
      study, we analyzed the interaction of a soluble TCR alpha chain variable domain
      (Valpha4.2-Jalpha40; abbreviated to Valpha4.2) with the MHC class II molecule I
      Au. Valpha4.2 bound specifically to I-Au expressed on the surface of a
      transfected thymoma cell line. Modifications in the amino acid residues located
      within the three complementarity-determining regions (CDRs) of the Valpha domain
      did not markedly affect this interaction. However, mutation of glutamic acid to
      alanine at position 69 of the fourth hypervariable region (HV4alpha)
      significantly increased the binding. Antibody inhibition studies suggested that
      the binding site was partly contributed by a region of the beta chain of I-Au.
      Furthermore, the binding of Valpha4.2 to the MHC molecule was dependent on the
      nature of the peptide bound in the groove. Soluble Valpha4.2 specifically
      inhibited the activation of TCR transfectants by I-Au-expressing cells pulsed
      with an N-terminal peptide of myelin basic protein. Valpha4.2 also bound to MHC
      class II-expressing spleen cell populations from mice of the H-2(u) and H-2(d)
      haplotypes. The binding of Valpha4.2 to I-A molecules might explain the
      immunoregulatory effects reported previously for TCR alpha chains. This Valpha4.2
      interaction may also be relevant to models of antigen presentation involving the
      binding of intact proteins to MHC class II molecules followed by their processing
      to generate epitopes suitable for T cell recognition.

PMID- 10360973
TI  - Establishment of antigen-specific IgE transgenic mice to study pathological and
      immunobiological roles of IgE in vivo.
AB  - We have established transgenic mice that carry the genes coding for heavy and
      light chains of TNP-specific IgE. They produced high titers of TNP-specific IgE
      (20-40 microg/ml in serum) and their mast cells were heavily loaded with IgE. The
      level of FcepsilonRI expression on their mast cells was 6-8 times higher than
      that in non-transgenic littermates. The expression of low-affinity IgE receptor
      FcepsilonRII (CD23) on splenic B cells was also 6-8 times higher in the
      transgenic mice. Consistent with this, substantial amounts of IgE were detected
      on B cells in the transgenic mice. When challenged with i.v. administration of
      the corresponding antigen, the transgenic mice exhibited systemic anaphylactic
      symptoms such as a drastic drop of body temperature and extravasation of
      administered dye. Biphasic (immediate and delayed) ear swelling response was also
      elicited in a TNP-specific manner by epicutaneous antigen challenge without any
      prior sensitization. Thus, IgE produced in the transgenic mice was found to be
      biologically active to induce both local and systemic allergic reactions in vivo
      upon the challenge of the corresponding antigen. Taken together, the antigen
      specific IgE transgenic mice established for the first time in this study appear
      to provide an attractive model system to study the pathological roles of IgE in
      acute and chronic phases of allergic inflammation as well as their
      immunobiological roles in vivo. They may also be useful to develop novel
      therapeutic strategies for atopic disorders.

PMID- 10360972
TI  - Upon dendritic cell (DC) activation chemokines and chemokine receptor expression
      are rapidly regulated for recruitment and maintenance of DC at the inflammatory
      site.
AB  - Dendritic cells (DC) are highly motile antigen-presenting cells that are
      recruited to sites of infection and inflammation to antigen uptake and
      processing. Then, to initiate T cell-dependent immune responses, they migrate
      from non-lymphoid organs to lymph nodes and the spleen. Since chemokines have
      been involved in human DC recruitment, we investigated the role of chemokines on
      mouse DC migration using the mouse growth factor-dependent immature DC line (D1).
      In this study, we characterized receptor expression, responsiveness to
      chemoattractants and chemokine expression of D1 cells during the maturation
      process induced by lipopolysaccharide (LPS). MIP-1alpha and MIP-5 were found to
      be the most effective chemoattractants, CCR1 was the main receptor expressed and
      modulated during LPS treatment, and MIP-2, RANTES, IP-10 and MCP-1 were the
      chemokines modulated during DC maturation. Thus, murine DC respond to a unique
      set of CC and CXC chemokines, and the maturational stage determines the program
      of chemokine receptors and chemokines that are expressed. Since CCR1 is modulated
      during the early phases of DC maturation, our results indicate that the CCR1
      receptor may participate in the recruitment and maintenance of DC at the
      inflammatory site.

PMID- 10360974
TI  - Requirement of IL-5 for induction of autoimmune hemolytic anemia in anti-red
      blood cell autoantibody transgenic mice.
AB  - IL-5, IL-10 and lipopolysaccharide (LPS) are known to activate B-1 cells in vivo
      in normal mice and anti-red blood cell autoantibody transgenic mice (HL mice). To
      assess the exact role of IL-5 in proliferation and activation of peritoneal B-1
      cells, we analyzed IL-5 receptor alpha chain-deficient HL (IL-5Ralpha-/- x HL)
      mice generated by the cross between IL-5Ralpha-/- and HL mice. In IL-5Ralpha-/- x
      HL mice, Ig-producing B-1 cells in the peritoneal cavity were negligible,
      although the total number of B-1 cells in the peritoneal cavity were as many as
      30% of that in HL mice. Moreover, LPS- or IL-10-induced differentiation of B-1
      cells into antibody-producing cells was severely impaired in IL-5Ralpha-/- x HL
      mice. We also used in vivo 5-bromo-2'-deoxyuridine labeling to estimate the
      proliferation of B-1 cells in IL-5Ralpha-/- mice. The absence of IL-5Ralpha did
      not affect spontaneous proliferation of peritoneal B-1 cells. However, induced
      proliferation of peritoreal B-1 cells by oral administration of LPS was markedly
      impaired in IL-5Ralpha-/- mice. These results suggest that IL-5 is required for
      activation-associated proliferation of B-1 cells but not for their spontaneous
      proliferation and support the idea that IL-5 plays an important role on the
      induction of autoantibody production from B-1 cells.

PMID- 10360975
TI  - Th1-derived cytokine IFN-gamma is a potent inhibitor of eotaxin synthesis in
      vitro.
AB  - Eotaxin potentially plays an integral role in tissue eosinophilia. Inasmuch as
      Th2-derived cytokine IL-4 has been shown to stimulate eotaxin generation, we
      investigated here the effect of Th1-derived cytokine IFN-gamma on human eotaxin
      production. IFN-gamma but not -alpha or -beta potently inhibited tumor necrosis
      factor (TNF)-alpha-induced eotaxin generation by dermal fibroblasts. The
      inhibitory effect was unique to eotaxin, because production of IL-8 or monocyte
      chemoattractant protein (MCP)-1 protein was not affected by the treatment with
      IFN-gamma. Furthermore, the suppressive effect of IFN-gamma was not cell-type or
      stimulus specific. The level of eotaxin mRNA increased within 2 h after
      activation with TNF-alpha and continued to increase up to 72 h. IFN-gamma did not
      inhibit, but rather augmented the TNF-alpha-induced accumulation of mRNA in the
      early phase ( approximately 6 h). However, in the later phase, IFN-gamma
      completely prevented the subsequent elevation of eotaxin mRNA and sustained it at
      low levels. Although the protective effect of IFN-gamma against allergic
      inflammation has been assumed to result from its sole regulation of the
      proliferation of Th2-type T lymphocytes, these results imply that IFN-gamma can
      also directly act on stromal cells to inhibit eotaxin production and consequently
      intervene in eosinophil recruitment.

PMID- 10360976
TI  - Proteolytic cleavage of gram-positive beta recombinase is required for
      crystallization.
AB  - Beta recombinase, a DNA resolvase-invertase, catalyzes in the presence of a
      chromatin-associated protein such as Hbsu, DNA resolution or DNA inversion on
      supercoiled substrates containing two directly or inversely oriented target (six)
      sites. Single crystals of the beta recombinase from plasmid pSM19035 were
      obtained using the vapor diffusion technique with ammonium phosphate as the
      precipitating agent. The crystals diffracted X-rays to a maximum resolution of
      2.5A. Due to proteolytic degradation during the crystallization experiment, the
      crystals contain only the N-terminal catalytic domain of beta recombinase
      corresponding to about 60% of the molecular mass of the initially assayed native
      protein. The proteolytic removal of the C-terminal DNA-binding domain
      demonstrated that protein modification can be essential to provide material
      suitable for X-ray analysis.

PMID- 10360977
TI  - DOMPLOT: a program to generate schematic diagrams of the structural domain
      organization within proteins, annotated by ligand contacts.
AB  - A program is described for automatically generating schematic linear
      representations of protein chains in terms of their structural domains. The
      program requires the co-ordinates of the chain, the domain assignment, PROSITE
      information and a file listing all intermolecular interactions in the protein
      structure. The output is a PostScript file in which each protein is represented
      by a set of linked boxes, each box corresponding to all or part of a structural
      domain. PROSITE motifs and residues involved in ligand interactions are
      highlighted. The diagrams allow immediate visualization of the domain arrangement
      within a protein chain, and by providing information on sequence motifs, and
      metal ion, ligand and DNA binding at the domain level, the program facilitates
      detection of remote evolutionary relationships between proteins.

PMID- 10360978
TI  - A novel method for predicting transmembrane segments in proteins based on a
      statistical analysis of the SwissProt database: the PRED-TMR algorithm.
AB  - We present a novel method that predicts transmembrane domains in proteins using
      solely information contained in the sequence itself. The PRED-TMR algorithm
      described, refines a standard hydrophobicity analysis with a detection of
      potential termini ('edges', starts and ends) of transmembrane regions. This
      allows one both to discard highly hydrophobic regions not delimited by clear
      start and end configurations and to confirm putative transmembrane segments not
      distinguishable by their hydrophobic composition. The accuracy obtained on a test
      set of 101 non-homologous transmembrane proteins with reliable topologies
      compares well with that of other popular existing methods. Only a slight decrease
      in prediction accuracy was observed when the algorithm was applied to all
      transmembrane proteins of the SwissProt database (release 35). A WWW server
      running the PRED-TMR algorithm is available at http://o2.db.uoa. gr/PRED-TMR/

PMID- 10360979
TI  - PSIC: profile extraction from sequence alignments with position-specific counts
      of independent observations.
AB  - Sequence weighting techniques are aimed at balancing redundant observed
      information from subsets of similar sequences in multiple alignments. Traditional
      approaches apply the same weight to all positions of a given sequence, hence
      equal efficiency of phylogenetic changes is assumed along the whole sequence.
      This restrictive assumption is not required for the new method PSIC (position
      specific independent counts) described in this paper. The number of independent
      observations (counts) of an amino acid type at a given alignment position is
      calculated from the overall similarity of the sequences that share the amino acid
      type at this position with the help of statistical concepts. This approach allows
      the fast computation of position-specific sequence weights even for alignments
      containing hundreds of sequences. The PSIC approach has been applied to profile
      extraction and to the fold family assignment of protein sequences with known
      structures. Our method was shown to be very productive in finding distantly
      related sequences and more powerful than Hidden Markov Models or the profile
      methods in WiseTools and PSI-BLAST in many cases. The profile extraction routine
      is available on the WWW (http://www.bork.embl-heidelberg. de/PSIC or
      http://www.imb.ac.ru/PSIC).

PMID- 10360980
TI  - Molecular modeling of single polypeptide chain of calcium-binding protein p26olf
      from dimeric S100B(betabeta).
AB  - P26olf from olfactory tissue of frog, which may be involved in olfactory
      transduction or adaptation, is a Ca2+-binding protein with 217 amino acids. The
      p26olf molecule contains two homologous parts consisting of the N-terminal half
      with amino acids 1-109 and the C-terminal half with amino acids 110-217. Each
      half resembles S100 protein with about 100 amino acids and contains two helix
      loop-helix Ca2+-binding structural motifs known as EF-hands: a normal EF-hand at
      the C-terminus and a pseudo EF-hand at the N-terminus. Multiple alignment of the
      two S100-like domains of p26olf with 18 S100 proteins indicated that the C
      terminal putative EF-hand of each domain contains a four-residue insertion when
      compared with the typical EF-hand motifs in the S100 protein, while the N
      terminal EF-hand is homologous to its pseudo EF-hand. We constructed a three
      dimensional model of the p26olf molecule based on results of the multiple
      alignment and NMR structures of dimeric S100B(betabeta) in the Ca2+-free state.
      The predicted structure of the p26olf single polypeptide chain satisfactorily
      adopts a folding pattern remarkably similar to dimeric S100B(betabeta). Each
      domain of p26olf consists of a unicornate-type four-helix bundle and they
      interact with each other in an antiparallel manner forming an X-type four-helix
      bundle between the two domains. The two S100-like domains of p26olf are linked by
      a loop with no steric hindrance, suggesting that this loop might play an
      important role in the function of p26olf. The circular dichroism spectral data
      support the predicted structure of p26olf and indicate that Ca2+-dependent
      conformational changes occur. Since the C-terminal putative EF-hand of each
      domain fully keeps the helix-loop-helix motif having a longer Ca2+-binding loop,
      regardless of the four-residue insertion, we propose that it is a new, novel EF
      hand, although it is unclear whether this EF-hand binds Ca2+. P26olf is a new
      member of the S100 protein family.

PMID- 10360981
TI  - Changes in the specificity of antibodies by site-specific mutagenesis followed by
      random mutagenesis.
AB  - The specificity for 11-deoxycortisol (11-DOC) of a monoclonal antibody (mAb),
      designated SCET, was changed to specificity for cortisol (CS) by site-specific
      mutagenesis followed by random mutagenesis. The Fab form of SCET was expressed on
      the surface of a phage. During the first step, mutations were introduced at 14
      amino acid positions in three complementarity-determining regions (CDRs) of the
      VH domain that seemed likely to form the steroid-binding pocket. A clone, DcC16,
      was isolated from the resultant library with multiple mutations and this clone
      was shown to have CS-binding activity but also to retain high 11-DOC-binding
      activity. During the second step, mutations were introduced randomly into the
      entire VH-coding region of the DcC16 clone by an error-prone polymerase chain
      reaction, and CS-specific mutant antibodies were selected in the presence of 11
      DOC as a competitor. Three representative clones were analyzed with the BIAcore
      instrument, and each revealed a large increase in the binding constant for CS and
      a decrease in that for 11-DOC. Structural models, constructed by computer
      simulation, indicated the probable molecular basis for these changes in
      specificity.

PMID- 10360982
TI  - Light-chain framework region residue Tyr71 of chimeric B72.3 antibody plays an
      important role in influencing the TAG72 antigen binding.
AB  - The crystallographic study of chimeric B72.3 antibody illustrated that there are
      three FR side-chain interactions with either CDR residue's side chain or main
      chain. For example, hydrogen bonds are formed between the hydroxyl group of
      threonine at L5 in FR1 and the guanidinal nitrogen group of arginine at L24 in
      CDR1, between the hydroxyl group of tyrosine at L36 in FR2 and the amide nitrogen
      group of glutamine at L89 in CDR3 and between the hydroxyl group of tyrosine at
      L71 in FR3 and the carbonyl group of isoleucine at L29 as well as the amide
      nitrogen group of serine at L31 in CDR1. Elimination of these hydrogen bonds at
      these FR positions may affect CDR loop conformations. To confirm these
      assumptions, we altered these FR residues by site-directed mutagenesis and
      determined binding affinities of these mutant chimeric antibodies for the TAG72
      antigen. We found that the substitution of tyrosine by phenylalanine at L71,
      altering main-chain hydrogen bonds, significantly reduced the binding affinity
      for the TAG72 antigen by 23-fold, whereas the substitution of threonine and
      tyrosine by alanine and phenylalanine at L5 and L36, eliminating hydrogen bonds
      to side-chain atoms, did not affect the binding affinity for the TAG72 antigen.
      Our results indicate that the light-chain FR residue tyrosine at L71 of chimeric
      B72.3 antibody plays an important role in influencing the TAG72 antigen binding.
      Our results will thus be of importance when the humanized B72.3 antibody is
      constructed, since this important mouse FR residue tyrosine at L71 must be
      maintained.

PMID- 10360984
TI  - Expression of a synthetic gene encoding canine milk lysozyme in Escherichia coli
      and characterization of the expressed protein.
AB  - A high-expression plasmid of the canine milk lysozyme, which belongs to the
      family of calcium-binding lysozymes, was constructed in order to study its
      physico-chemical properties. Because the cDNA sequence of the protein has not yet
      been determined, a 400 base-pair gene encoding canine milk lysozyme was first
      designed on the basis of the known amino acid sequence. The gene was constructed
      by an enzymatic assembly of 21 chemically synthesized oligonucleotides and
      inserted into an Escherichia coli expression vector by stepwise ligation. The
      expression plasmid thus constructed was transformed into BL21(DE3)/pLysS cells.
      The gene product accumulated as inclusion bodies in an insoluble fraction.
      Recombinant canine milk lysozyme was obtained by purification and refolding of
      the product and showed the same characteristics in terms of bacteriolytic
      activity and far- and near-UV circular dichroism spectra as the authentic
      protein. The NMR spectra of refolded lysozyme were also characteristic of a
      native globular protein. It was concluded that recombinant canine milk lysozyme
      was folded into the correct native structure. Moreover, the thermal unfolding
      profiles of the refolded recombinant lysozyme showed a stable equilibrium
      intermediate, indicating that the molten globule state of this protein was
      extraordinarily stable. This expression system of canine milk lysozyme will
      enable biophysical and structural studies of this protein to be extended.

PMID- 10360983
TI  - Construction, expression, purification and functional analysis of recombinant
      NFkappaB p50/p65 heterodimer.
AB  - NFkappaB plays an important role in mediating the gene expression of numerous
      cellular processes such as growth, development, the inflammatory response and
      virus proliferation. The p50/p65 heterodimer is the most abundant form of the
      NFkappaB dimers and plays a more elaborate role in gene regulation. Biochemical
      research on p50/p65 NFkappaB has not benefited however from the availability of
      easily purified recombinant protein. We report two methods for the large scale
      expression and purification of recombinant NFkappaB p50/p65 heterodimer. The
      first utilizes a bacterial double expression vector which contains two ribosomal
      binding sites to facilitate the coexpression of the polypeptides in the p50/p65
      NFkappaB heterodimer. The second method uses a mixed protein refolding strategy.
      Both methods yield crystallizable protein. Electrophoretic mobility shift assays
      confirm that the DNA binding affinity is independent of the method used to purify
      the protein. These methods will facilitate the numerous studies on various
      NFkappaB/Rel family members.

PMID- 10360985
TI  - 1999 visiting research professorship and young investigator award.

PMID- 10360986
TI  - Clostridium difficile diarrhea.

PMID- 10360987
TI  - Irritable bowel syndrome.

PMID- 10360988
TI  - Treatment of Helicobacter pylori in patients with upper abdominal pain syndromes.

PMID- 10360989
TI  - Are you as wealthy as you should be?

PMID- 10360990
TI  - Role of endoscopy in the investigation of upper gastrointestinal symptoms in HIV
      infected patients.
AB  - Endoscopy plays a pivotal role in the management of patients with the acquired
      immunodeficiency syndrome (AIDS), because tissue documentation of opportunistic
      processes is often necessary to establish a definitive diagnosis. With
      progression of immunodeficiency, endoscopy becomes more important because the
      predisposition to opportunistic disorders of the gastrointestinal tract is
      greatly increased. The yield of upper endoscopy in human immunodeficiency virus
      (HIV)-infected patients is dependent upon the indication for the procedure,
      including the clinical presentation and the stage of immunodeficiency.
      Indications for which endoscopy has a high yield include AIDS with esophageal
      symptoms refractory to empirical antifungal therapy, small bowel biopsy for
      chronic severe diarrhea and upper gastrointestinal bleeding. Although processes
      can be identified, a diagnosis is less likely in patients who present with nausea
      and vomiting or nonspecific abdominal pain. By tailoring the use of endoscopy to
      the presenting symptoms and CD4 lymphocyte count, the diagnostic benefit can be
      increased.

PMID- 10360991
TI  - Xenotransplantation: A potential solution to the critical organ donor shortage.
AB  - The success of allotransplantation as a treatment for end-stage organ failure has
      resulted in the need for an increasing number of organ donors. Attempts to meet
      this need include the use of organs from living related and unrelated donors,
      financial or other incentives for the donor family, and even the reuse of
      transplanted organs. Despite these initiatives, the supply of organs for
      transplantation still falls far short of the demand, as evidenced by longer
      waiting times for transplantation and decreasing transplantation rates. Even if
      Canada were able to increase its organ donor rate to that of Spain (40 to
      50/million), where organ donation is governed by 'presumed consent' legislation,
      this would not alleviate the problem of donor shortage. Interest in
      xenotransplantation stems from the need to overcome this increasingly severe
      shortage of human organs. Indeed, some argue that xenotransplantation is the only
      potential way of addressing this shortage. As immunological barriers to
      xenotransplantation are better understood, those hurdles are being addressed
      through genetic engineering of donor animals and the development of new drug
      therapies. However, before xenotransplantation can be fully implemented, both the
      scientific/medical communities and the general public must seriously consider and
      attempt to resolve the many complex ethical, social and economic issues that it
      presents.

PMID- 10360992
TI  - Undernournishment and Yersinia enterocolitica enterocolitis alter intestinal
      contractility in the rabbit: role of smooth muscle contractile protein content.
AB  - Previous studies have demonstrated that the longitudinal smooth muscle of rabbits
      infected with Yersinia enterocolitica and undernourished because of reduced food
      intake exhibit a significantly reduced ability to develop tension in response to
      carbachol compared with pair-fed animals, which are uninfected but equivalently
      undernourished. To determine whether the alteration in smooth muscle
      contractility results from changes in cell number (hypo- or hyperplasia), or in
      contractile protein content or isoform distribution, New Zealand White rabbits
      (600 to 1000 g) were randomly assigned to one of three treatment groups:
      infected, pair-fed or control. Tissue contractility was measured, morphometric
      studies were performed and immunoassays were developed for the measurement of
      total actin, gamma-enteric and alpha-vascular isoactins, and myosin heavy chain.
      Consistent with what was found in previous reports, the contractility of
      longitudinal smooth muscle in response to carbachol was found to increase in pair
      fed animals and to decrease in Y enterocolitica-infected animals. There was no
      significant change in the proportional thickness of the ileal longitudinal smooth
      muscle coat, and the number of cross-sectioned longitudinal smooth muscle
      cells/mm2 was not significantly different in infected, pair-fed or control
      tissues. Immunoassay indicated that the proportion of each specific contractile
      protein, relative to total protein content in the muscularis propria, was
      unaffected by Y enterocolitica infection or by pair-feeding. Thus, the
      alterations in intestinal longitudinal smooth muscle function observed after Y
      enterocolitica infection were concluded not to be associated with tissue hypo- or
      hyperplasia, or changes in the total content or isoform distribution of
      contractile proteins in the muscularis propria.

PMID- 10360994
TI  - The DINs and don'ts of herbal/natural preparations.

PMID- 10360993
TI  - Complementary and alternative medicine use by patients with inflammatory bowel
      disease: An Internet survey.
AB  - OBJECTIVES: To determine the degree and determinants of the use of complementary
      and alternative medicine (CAM) by patients with inflammatory bowel disease (IBD)
      with the use of the Internet and to compare the results with those found by using
      a similar survey in patients attending gastroenterology clinics in Calgary,
      Alberta. SUBJECTS AND METHODS: A cross-sectional survey of 263 patients with IBD
      with the use of a World Wide Web-based, structured questionnaire was conducted.
      RESULTS: Complementary therapies had been used by 46% of patients in the previous
      two years. Current use was reported by 34%. Vitamins, herbal products and natural
      health practices were the most commonly reported therapies. Side effects and lack
      of effectiveness of standard therapies were the most commonly cited reasons for
      seeking complementary medicine. However, despite this, respondents who had
      previously received surgery, or intravenous or oral steroids were less likely to
      be current CAM users. Important differences between the determinants of and
      reasons for CAM use in the present study and those of a similar study of IBD
      patients in a local tertiary care setting were noted. CONCLUSIONS: Complementary
      medicine use is common in patients with IBD. Differences in the determinants of
      and reasons for CAM use noted between the present Internet sample and a
      gastroenterology clinic sample suggest that conclusions from the present study
      and from previous studies based only on clinic samples provide a limited view of
      CAM use by people with IBD. More comprehensive assessments are needed.

PMID- 10360995
TI  - The clinician investigator: An endangered species.

PMID- 10360996
TI  - Gastrointestinal endoscopy: Do we perform too many or not enough procedures?

PMID- 10360997
TI  - Hyposplenism, antiendomysial antibodies and lymphocytic colitis in collagenous
      sprue.
AB  - A 66-year-old woman was seen repeatedly over a decade to remove recurrent colonic
      adenomas and investigate episodes of watery diarrhea. Although the diarrhea was
      believed to be due to lymphocytic colitis, she developed weight loss,
      hypoproteinemia and hyposplenism that resulted in further studies, specifically
      to exclude celiac disease. Small intestinal biopsies, however, showed severely
      'flattened' villous architecture with trichrome-positive subepithelial
      collagenous deposits, characteristic of collagenous sprue. Antiendomysial
      antibodies, known serological markers of celiac disease, were also detected.
      While collagenous sprue has been considered a distinct small intestinal disorder,
      the constellation of clinical and pathological findings in this patient suggests
      a close link with adult celiac disease.

PMID- 10360998
TI  - Voltammetric response and determination of DNA with a silver electrode.
AB  - A current from DNA was obtained using a silver electrode with low overpotentials
      for the first time. Experimental results revealed that the voltammetric response
      of DNA was attributed to the redox reactions of purine bases. It was also shown
      that such a method provided a convenient and practical way to determine DNA. A
      linear dependence of the peak currents on ssDNA concentrations was observed in
      the range 0.5-2.5 microg/mL. The relative standard deviation was 3.5% for six
      successive determinations at 0.5 microg/mL. The detection limit was 50 ng/mL.
      Influence of the structure and the length of the nucleic acids on their
      electrochemical behavior was discussed. In view of the merits of the silver
      electrode, this technique might provide new possibilities for further
      electrochemical research and determination of nucleic acids.

PMID- 10360999
TI  - Determination of amino acid isotope enrichment using liquid chromatography-mass
      spectrometry.
AB  - The change in amino acid enrichment, an indicator of a change in protein
      synthesis and/or degradation, is usually measured using gas chromatography-mass
      spectrometry and/or (GC-combustion) isotope ratio mass spectrometry.
      Unfortunately, often a complex and sensitive derivatization procedure and/or a
      large amount of sample is required. Also, these techniques are less suited to
      study intermediary metabolism, in which the simultaneous application (and thus
      measurement) of multiple amino acid tracers is preferred. Alternatively, in this
      study the possibilities of the coupling of liquid chromatography and mass
      spectrometry were explored, resulting in the measurement of both the
      concentration and isotope enrichment of o-phthaldialdehyde (OPA)-derivatizated
      plasma amino acids in one run. This was achieved by the injection of OPA
      derivatizated amino acids into an automated HPLC system. After the elution of
      buffer salts and reagent excess to drain using column switching, the column
      effluent was directed via a fluorescence detector into a Thermoquest Model LCQ
      benchtop LC-MS. Mass spectrometric measurements were performed in "zoom-scan"
      mode, employing multiple scan events if the target components were not baseline
      separated. Best signal-to-noise ratio's were obtained using the LCQ's
      electrospray probe in the negative mode. Still, when working under standard
      conditions the total ion current of OPA-amino acid derivatives eluting at the
      beginning of the chromatogram (e.g., citrulline, arginine and glycine) was by a
      factor of 5 lower, compared to components eluting in the last part of the
      chromatogram (leucine, valine, and ornithine). These differences could be
      minimized by increasing the temperature of the heated capillary to 260 degrees C
      and by applying 5% collision energy (between the skimmer and the first octapole)
      to the first eluting components. A further improvement could not be obtained by
      the addition of makeup liquids like ammonia, acetic acid, methanol, or
      acetonitrile (up to 25% of column effluent flow). Considering these results and
      the fact that the first eluting amino acid derivatives are the most polar ones,
      we hypothesized that hydration of these components interferes with the ionization
      process. A linear calibration curve was obtained for both fluorescent response
      and total ion current (TIC) for all amino acids in the range from 5 to 1000 pmol
      per injection. The coefficient of variation of the fluorescent response was
      typically on the order of 1-4%, for the TIC this was between 4 and 9%. However,
      measurement of isotope ratios requires not only the determination of the area of
      the base peak, but also of the area of the (enriched) isotopomeric peak(s),
      having a much lower abundance. Therefore, isotope ratio measurements require the
      injection of at least 25 pmol of the amino acid derivative of interest (except
      for ARG 50 pmol) to obtain true ratio's. The accuracy of the isotope enrichment
      measurement was determined by the injection of a standard containing all major
      physiological amino acids (400 pmol each) and a standard at physiological
      concentrations (ranging from 50 pmol (CIT) to 350 pmol (VAL). Standard deviation
      of the isotopic ratios ranged from 0.1 to 0. 5% for the high (400 pmol) standards
      and from 0.2 to 0.8% for the low (physiological) standard, which is comparable
      with GC-MS. A plot of the results against the theoretical values gave a linear
      curve for all isotopes studied (R2 ranged from 0.9984 to 0.9997). However, the [1
      13C]-enriched amino acids measured (LEU, GLY, and VAL) gave a closer agreement to
      the expected values as was found for [ureido-13C-5,5-2H2]-enriched citrulline and
      [guanidino-15N2]-enriched arginine. We could not determine whether this was due
      to the measurement procedure itself or resulting from an instability of the
      tracers in solution. Nevertheless, the results were reproducible and the
      theoretical value could be calculated using the tangent of the enrichment curves.
      (ABSTRACT TRUNCATED)

PMID- 10361000
TI  - Intracellular measurement of prostaglandin E2: effect of anti-inflammatory drugs
      on cyclooxygenase activity and prostanoid expression.
AB  - Cyclooxygenase (COX) converts arachidonic acid to prostaglandin (PG) H2, which is
      further metabolized to various prostaglandins, prostacyclin and thromboxane A2.
      COX exists in at least two different isoforms. COX-1 is constitutively expressed,
      whereas COX-2 is induced by proinflammatory stimuli. Prostaglandin E2 is a major
      metabolite of COX activation. In order to compare the activity of target ligands
      and COX inhibitors on PGE2 synthesis and release, the responsiveness of several
      cell lines to the calcium ionophore A23187, bacterial lipopolysaccharide (LPS),
      nonsteroidal anti-inflammatory drugs (NSAIDs), and the glucocorticoid,
      dexamethasone, were investigated. For intracellular measurements, the culture
      supernatant was aspirated, and the cells were thoroughly washed and lysed with
      dodecyltrimethylammonium bromide. Intracellular and secreted PGE2 were measured
      with an enzyme immunoassay. A23187 and LPS increased intracellular PGE2 in a dose
      dependent manner. Kinetic experiments with A23187-stimulated mouse 3T3 fibroblast
      cells revealed a distinct biphasic response in COX activity. In the presence of
      NSAIDs or dexamethasone, there was a dose-dependent inhibition in intracellular
      PGE2 with A23187-stimulated 3T3 cells. Inhibitory studies demonstrated an
      apparent increased sensitivity of COX activity to the action of inhibitors when
      measuring intracellular PGE2 compared with using cell culture supernatants.
      Indeed, intracellular PGE2 levels were comprehensively reduced in the presence of
      low concentrations of inhibitor. The utilization of cell culture lysates and, in
      particular, measurement of intracellular PGE2 should prove useful for identifying
      new COX inhibitors.

PMID- 10361001
TI  - A robotics-based automated assay for inorganic and organic phosphates.
AB  - Phosphate analyses are fundamental to a broad range of biochemical applications
      involving inorganic phosphate and organic phosphoesters such as phospholipids,
      phosphorylated proteins, and nucleic acids. A practical automated method
      utilizing robotics is described in this report. Five colorimetric methods of
      phosphate analyses based on formation of a phosphomolybdate complex and
      compatible with the automated assay were tested, and the fundamental chemistry is
      discussed. The relative sensitivities are malachite green > crystal violet >
      quinaldine red > ascorbate reduction > antimony-modified ascorbate reduction,
      although only a fourfold improvement was observed in going from the modified
      ascorbate procedure to malachite green. Malachite green was selected to optimize
      the assay because this dye provided the highest sensitivity. However, where color
      stability and low blanks are more important than sensitivity, the ascorbate
      reduction and quinaldine red methods were found to be better choices than
      malachite green. Automation using a robotic liquid-handling system substantially
      reduces the labor required to process large arrays of samples. The result is a
      sensitive, nonradioactive assay of inorganic phosphate with high throughput. A
      digestion step in an acid-resistant 96-well plate was developed to extend the
      assay to phosphate esters. The robotic-based assay was demonstrated with
      inorganic phosphate and a common phospholipid, phosphatidylcholine.

PMID- 10361002
TI  - Determination of beta1,4-galactosyltransferase enzymatic activity by capillary
      electrophoresis and laser-induced fluorescence detection.
AB  - We have developed a nonradioactive method to assay UDP-Gal:beta-d-GlcNAcbeta1,4
      galactosyltransferase (beta4GalT-I) enzymatic activity. Capillary electrophoresis
      combined with laser-induced fluorescence detection (CE-LIF) was employed to
      provide a baseline separation of FITC-conjugated O-GlcNAc-containing substrate
      peptides and galactose-capped product peptides, while at the same time allowing a
      level of detection in the low attomole range (10(-18)). The addition of 2 mM
      hexamethylene diamine to the borate-based capillary electrophoretic buffer
      modulated the electroosmotic flow, resulting in optimum separation of the
      glycopeptide product from reactant. beta4GalT-I activity was dependent upon the
      addition of both manganese and UDP-galactose. Using this assay, we show that two
      beta4GalT-I constructs, predicted to localize to different intracellular
      compartments, are enzymatically active when expressed in vitro using a rabbit
      reticulocyte transcription-translation system. The high sensitivity of product
      detection by CE-LIF in combination with in vitro transcription-translation is
      applicable to the facile determination of the enzymatic activity of other newly
      cloned glycosyltransferases.

PMID- 10361003
TI  - Optimized analysis of intracellular adenosine and guanosine phosphates in
      Escherichia coli.
AB  - To investigate the intracellular concentrations of adenosine phosphates in
      Escherichia coli, especially during bioreactor cultivations, a method that
      enables reproducible determination of adenosine phosphates in culture solutions
      containing at least 0.25 g dry cell weight/L has been developed. The detection
      limits of AMP, ADP, and ATP were found to be as low as 1 pmol. The method
      involves fast sampling, instantaneous inactivation of cell metabolism, extraction
      of nucleotides, and quantitative analysis by ion-pair reversed-phase HPLC.

PMID- 10361004
TI  - Analysis of reactive oxygen species generated by neutrophils using a
      chemiluminescence probe L-012.
AB  - Reactive oxygen species (ROS) play important roles in the defense mechanism
      against infection and in the pathogenesis of various diseases. Although chemical
      properties of ROS generated by leukocytes have been studied extensively, methods
      available for their analysis are not sufficiently sensitive. We found that 8
      amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione (L-012) reacted
      with various types of ROS generated by activated neutrophils in human blood and
      oral cavity, and from peritoneal cavity of the rat, and developed strong
      chemiluminescence (CHL). Under physiological conditions, opsonized zymosan
      dependent CHL intensity of L-012 in human blood and rat peritoneal neutrophils
      was about 100 and 10 times higher than that of luminol and luciferin analog MCLA,
      respectively. Phorbol ester-activated CHL of oral neutrophils was also higher
      with L-012 than that with luminol and MCLA. The presence of either superoxide
      dismutase, catalase, uric acid, deferoxamine, or azide decreased CHL intensity of
      L-012 by 52, 57, 57, 63, and 91%, respectively. Kinetic analysis revealed that L
      012 developed CHL predominantly by reacting with hydroxyl radical and
      hypochlorite. Thus, highly sensitive L-012 permits studies on ROS generation by
      complex biological systems, such as leukocytes, and on the role of ROS in the
      pathogenesis of various diseases.

PMID- 10361005
TI  - Optimization of the cost and sensitivity of receptor- and enzyme-based assays.
AB  - In detecting receptor antagonists or enzyme inhibitors, there are three
      parameters that often affect the outcome in a predictable quantitative manner:
      concentrations of the receptors (enzyme), labeled ligand (substrate), and
      antagonist (inhibitor). The usual goal of assay optimization is to maximize the
      ability of the assay to detect low concentrations of the analyte. Another
      question of practical importance, especially in screening of large numbers of
      samples, would be minimization of the reagent cost. Although the mathematical
      theory of optimization of the receptor binding assay was developed a long time
      ago, the resulting formulas (in the general case of unequal affinities of ligand
      and competitor) were not well suited for practical use. The current availability
      of computational programs, such as Mathematica, makes possible an efficient
      solution, both for receptor- and enzyme-based assays. We use a graphical approach
      to assay optimization and apply it to the following problems: (1) optimization of
      assay sensitivity, (2) optimization of the reagent cost, and (3) analysis of the
      entire range of the parameter values since the mathematically optimal values may
      sometimes be impractical. The computation is extremely simple and the problem can
      sometimes be solved in several minutes.

PMID- 10361006
TI  - The choice of reference cell in the analysis of kinetic data using BIAcore.
AB  - An important step in the analysis of sensorgram data for BIAcore experiments is
      the subtraction of reference cell data to remove the effects of the bulk shift on
      the sensorgram of interest. It is shown that this step can introduce errors in
      the measured kinetic constants. This phenomenon is investigated both
      theoretically and with experimental data.

PMID- 10361007
TI  - Real-time detection and quantification of adenosine triphosphate sulfurylase
      activity by a bioluminometric approach.
AB  - A real-time, sensitive, and simple assay for detection and quantification of
      adenosine triphosphate sulfurylase (ATP:sulfate adenylytransferase, EC 2.7.7.4)
      activity has been developed. The method is based on detection of ATP generated in
      the ATP sulfurylase reaction between APS and PPi by the firefly luciferase
      system. For the Saccharomyces cerevisiae ATP sulfurylase, the concentrations of
      APS and PPi at the half-maximal rate were found to be about 0.5 and 7 microM,
      respectively. The assay is sensitive and yields linear response between 0.1
      microU and 50 mU. The method can be used for monitoring and quantification of
      recombinant ATP sulfurylase activity in Escherichia coli lysate, as well as for
      detection of the activity during different purification procedures.

PMID- 10361008
TI  - An exact solution of abortive initiation rate equation.

PMID- 10361009
TI  - Direct lysis method for the rapid preparation of plasmid DNA.

PMID- 10361010
TI  - Dichromatic staining of electrophoretically separated extracellular matrix
      macromolecules.

PMID- 10361011
TI  - Quantification of endothelin ETA and ETB receptor mRNA by competitive reverse
      transcription-polymerase chain reaction: development of a multispecies assay.

PMID- 10361012
TI  - Microtiter well assays for protein tyrosine phosphatase activities directed
      against phosphorylated insulin receptor or insulin receptor substrate-1.

PMID- 10361013
TI  - Measurement of soluble tryptophan and total indole-3-acetic acid in Arabidopsis
      by capillary electrophoresis.

PMID- 10361014
TI  - Microaffinity columns for analysis of protein-protein interactions.

PMID- 10361015
TI  - A method for the measurement of plasma hydroxyeicosatetraenoic acid levels.

PMID- 10361016
TI  - Determination of transfection efficiency by direct polymerase chain reaction.

PMID- 10361017
TI  - Estimation of gene expression within the intestinal mucosa using semiquantitative
      reverse transcriptase-polymerase chain reaction.

PMID- 10361018
TI  - A rapid, sensitive, and nonradioactive method for assay of FHIT Ap3A hydrolase
      activity by fluorescence thin-layer chromatographic image analysis.

PMID- 10361019
TI  - Bisulfite sequencing protocol displays both 5-methylcytosine and N4
      methylcytosine.

PMID- 10361020
TI  - Refractive index of proteins in organic solvents.

PMID- 10361021
TI  - Poisson regression in mapping cancer mortality.
AB  - The aim of this study was to map standardized mortality ratios (SMRs) of specific
      cancers in Argentina and to examine some ecological relationships using Poisson
      regression, Poisson regression with frailties, and empirical Bayes estimates.
      Mortality data for lung cancer, nonmelanoma skin cancer, melanoma, and stomach
      cancer were obtained from national registers for the period 1989-1993.
      Overcrowding and unsatisfied basic needs (UBN) were used as indicators of
      socioeconomic status and people working permanently on farms as an indicator of
      rural activity. Empirical Bayes estimates provided a good solution for mapping
      rare causes of cancer when random fluctuations of observed deaths are important,
      as in the case of nonmelanoma skin cancer (NMSC) and melanoma. In the case of
      lung and stomach cancers the main improvement was the attenuation of confidence
      intervals. Lung cancer rates (males and females) were higher in jurisdictions
      with better socioeconomic status. When the variable UBN was categorized in
      tertiles (<20, 20-27, and 28% and higher) the rate ratios of lung cancer in men
      fell to 0.82 IC 95% (0. 78-0.85) in those with UNB index among 20-27% with
      respect to the reference level and to 0.56 IC 95% (0.54-0.59) in those with more
      than 28%. In contrast, stomach cancer rates were associated with worse economic
      conditions. NMSC and melanoma showed different patterns. The former was
      associated with working on farms, while the latter was not. Neither NMSC nor
      melanoma was increased in areas affected by Antarctica's ozone hole. Research
      appears to be warranted to further investigate associations of lung cancer with
      smoking and behavior in women living in southern Argentinean provinces. Public
      education must continue to promote personal responsibility in the intervention
      process to reduce the morbidity and mortality associated with cancers, such as
      lung and skin cancer, which are partially avoidable through behavioral changes.

PMID- 10361022
TI  - Identification of carcinogens in cooking oil fumes.
AB  - According to earlier studies, fumes from cooking oils were found to be genotoxic
      in several short-term tests such as the Ames test, sister chromatid exchange, and
      SOS chromotest. Fume samples from six different commercial cooking oils
      (safflower, olive, coconut, mustard, vegetable, and corn) frequently used in
      Taiwan were collected. Polycyclic aromatic hydrocarbons (PAHs) were extracted
      from the air samples and identified by high-performance liquid chromatography and
      confirmed by gas chromatography/mass spectrometry. Extracts of fumes from
      safflower oil, vegetable oil, and corn oil contained benzo[a]pyrene (BaP),
      dibenz[a,h]anthracene (DBahA), benzo[b]fluoranthene (BbFA), and
      benzo[a]anthracene (BaA). Concentrations of BaP, DbahA, BbFA, and BaA were 2.1,
      2.8, 1.8, and 2.5 microg/m3 in fumes from safflower oil; 2.7, 3.2, 2.6, and 2.1
      microg/m3 in vegetable oil; and 2.6, 2.4, 2.0, and 1.9 microg/m3 in corn oil,
      respectively. The authors constructed models to study the efficacy of table-edged
      fume extractors used commonly by Taiwanese restaurants. Concentrations of BaP
      were significantly decreased when the fume extractor was working (P<0.05) and the
      average reduction in percentage was 75%. The other identified PAHs were
      undetected. These results indicated that exposure to cooking oil fumes could
      possibly increase exposure to PAHs, which may be linked to an increased risk of
      lung cancer. The potential carcinogenic exposure could be reduced by placing
      table-edged fume extractors near cooking pots.

PMID- 10361023
TI  - Assessment of benzene and toluene emissions from automobile exhaust in Bangkok.
AB  - The use of unleaded gasoline, together with an increase in the number of vehicles
      in Bangkok, has significantly influenced benzene and toluene concentrations in
      vehicular emissions and contributes to the air pollution problem. As a matter of
      practical necessity, a quick test program is done for the measurement of emission
      concentrations/rates for vehicles driven on the road. Exhaust emission
      measurement at idle mode was conducted in a fleet of 12 vehicles of different
      model years and manufacturers. The study revealed that the benzene and toluene
      concentrations in the exhaust effluent averaged 4.4-22.02 and 12.24-44.75 mg/m3,
      respectively for 1990-1992 cars and decreased to 0.76-4.14 and 0.89-6.26 mg/m3,
      respectively for 1994-1995 cars. In another study, exhaust emission measurement
      on a chassis dynamometer was carried out in a fleet of nine selected, in-use
      cars. It was observed that benzene and toluene emission rates were considerably
      higher-in the range of 70.84-85.82 and 354.15- 429.00 mg/km, respectively, for
      1990-1991 model year cars. Lower benzene and toluene emission rates of 0.43-95.07
      and 2. 15-475.35 mg/km, respectively, were represented by newer cars with model
      years 1994-1995. These results indicated that there was a significant increase in
      benzene and toluene emission concentrations and rates with increasing car mileage
      and model year. The finding also revealed that only 28% of the tested vehicles
      complied to the approved emission standard.

PMID- 10361024
TI  - Factors affecting lead, cadmium, and arsenic levels in house dust in a smelter
      town in eastern Germany.
AB  - Hettstedt, a city in eastern Germany with a long history of mining and smelting
      of nonferrous ores, has several industrial sources of heavy metals. The indoor
      exposure to metals of children (5 to 14 years old) in the Hettstedt area was
      assessed by measuring the levels of lead, cadmium, and arsenic contamination in
      sedimented house dust. Factors which influence the dust loading rate and the
      surface loading rates of these contaminants in house dust were investigated. The
      geometric mean of the dust loading rate was 8.9 mg/m2 day. The geometric means of
      surface loading rates were 1.14, 0. 024, and 0.023 microg/m2 day for lead,
      cadmium, and arsenic, respectively. Factors that were significantly associated
      with surface loading rates included the city area of residence, automobile
      traffic near home, parent with occupational exposure to heavy metals, type of
      heating, housing characteristics, whether child's home is damp, number of persons
      living in the child's home, and parents' education. The most significant of these
      factors was the city area of residence, which reflects the distance from the
      metal sources; this factor accounted for about half of the variances explained by
      the regression models.

PMID- 10361025
TI  - Uranium and thorium in urine of United States residents: reference range
      concentrations.
AB  - We measured uranium and thorium in urine of 500 U. S. residents to establish
      reference range concentrations using a magnetic-sector inductively coupled argon
      plasma mass spectrometer (ICP-MS). We found uranium at detectable concentrations
      in 96.6% of the urine specimens and thorium in 39.6% of the specimens. The 95th
      percentile concenetration for uranium was 34.5 ng/L (parts per trillion);
      concentrations ranged up to 4080 ng/L. Thorium had a 95th percentile
      concentration of 3.09 ng/L; concentrations ranged up to 7.7 ng/L.

PMID- 10361026
TI  - A multivariate linear regression model for predicting children's blood lead
      levels based on soil lead levels: A study at four superfund sites.
AB  - For the purpose of examining the association between blood lead levels and
      household-specific soil lead levels, we used a multivariate linear regression
      model to find a slope factor relating soil lead levels to blood lead levels. We
      used previously collected data from the Agency for Toxic Substances and Disease
      Registry's (ATSDR's) multisite lead and cadmium study. The data included the
      blood lead measurements (0.5 to 40.2 microg/dL) of 1015 children aged 6-71
      months, and corresponding household-specific environmental samples. The
      environmental samples included lead in soil (18.1-9980 mg/kg), house dust (5.2
      71,000 mg/kg), interior paint (0-16.5 mg/cm2), and tap water (0.3-103 microg/L).
      After adjusting for income, education of the parents, presence of a smoker in the
      household, sex, and dust lead, and using a double log transformation, we found a
      slope factor of 0.1388 with a 95% confidence interval of 0.09-0.19 for the dose
      response relationship between the natural log of the soil lead level and the
      natural log of the blood lead level. The predicted blood lead level corresponding
      to a soil lead level of 500 mg/kg was 5.99 microg/kg with a 95% prediction
      interval of 2. 08-17.29. Predicted values and their corresponding prediction
      intervals varied by covariate level. The model shows that increased soil lead
      level is associated with elevated blood leads in children, but that predictions
      based on this regression model are subject to high levels of uncertainty and
      variability.

PMID- 10361027
TI  - Formation of N-(2-hydroxyethyl)valine due to exposure to ethylene oxide via
      tobacco smoke: A risk factor for onset of cancer.
AB  - Human exposure to ethylene oxide (EtO) occurs mainly through inhalation of
      occupational polluted air and tobacco smoke. EtO is able to react with DNA and
      proteins producing some molecular adducts. One of these, resulting from reaction
      between EtO and valine in hemoglobin, is N-(2-hydroxyethyl) valine (HOEtVal).
      This adduct represents a biological effective dose marker, the level of which
      correlates linearly with the alkylating activity occurring in DNA. The aim of the
      present study was to measure HOEtVal in 146 urbanized adult and healthy subjects,
      nonoccupationally exposed to EtO, and to correlate it with smoke habits. HOEtVal
      showed a direct positive relationship to tobacco smoke exposure quantified by
      questionnaire, urinary cotinine (r=0.64509), and the number of cigarettes (r=0.
      6308) actively or passively smoked. Results relative to HOEtVal and urinary
      cotinine in adults distinguish well between active and passive smokers but do not
      allow distinguishment between passive smokers and nonsmokers. Nevertheless,
      several authors demonstrated a very good capacity of cotinine to discriminate
      inside groups of adolescents passive smokers. Therefore, the future objective of
      the present study is a closer inspection of the two biomarkers with respect to
      passive exposure to tobacco smoke considering a large group of adolescents.
      Finally, the correlation between urinary cotinine and HOEtVal increases knowledge
      about early steps of the carcinogenic process due to active exposure to tobacco
      smoke.

PMID- 10361028
TI  - DNA strand breaks caused by exposure to ozone and nitrogen dioxide.
AB  - The present study demonstrates that exposure to ozone (O3) and nitrogen dioxide
      (NO2) can cause DNA single-strand breaks in alveolar macrophages. Three-month-old
      male Sprague-Dawley rats, specific pathogen free, were exposed to either 1.2 ppm
      NO2 or 0.3 ppm O3 alone or a combination of these two oxidants continuously for 3
      days. The control group was exposed to filtered room air. The oxidant effects
      were substantiated by determining total and differential cell counts, lactate
      dehydrogenase activity, and total soluble protein in bronchoalveolar lavage. DNA
      damage was measured as single-strand breaks by alkaline elution assay. The
      results showed that, relative to control, NO2 exposure did not cause any
      significant change in the parameters studied. Exposure to O3 and combined
      exposure to NO2 and O3 caused significant changes in all parameters studied
      except cell viability. The rates of elution (Kc) of single-strand DNA from
      polycarbonate filter for O3 exposure and combined exposure were 73 and 79% faster
      than that of the control, respectively. The amounts of DNA single-strand breaks
      caused by O3 and combined exposure were significantly greater than the amounts
      detected for the NO2-exposed and control groups.

PMID- 10361029
TI  - Embryotoxicity of zinc pyrithione, an antidandruff chemical, in fish.
AB  - Early-life-stage toxicity tests of zinc pyrithione (Zpt) and commercial shampoos
      containing or not containing Zpt were performed on zebra fish and Japanese
      Medaka. The results showed that Zpt induced significant teratogenic effects on
      larvae of both species of fish. The two antidandruff shampoos containing Zpt
      induced the same teratogenic effects as Zpt. The calculated EC50 concentrations
      of Zpt for each of the shampoos were consistent with the EC50 for Zpt
      concentrate. Furthermore, 23 other shampoos not containing Zpt showed no
      teratogenic effects. These results strongly suggest that Zpt is the main factor
      in the antidandruff shampoos.

PMID- 10361030
TI  - Antimicrobial phytoprotectants and fungal pathogens: a commentary.
AB  - Many plants produce antifungal secondary metabolites. These may be preformed
      compounds which are found in healthy plants and which may represent in-built
      chemical barriers to infection by potential pathogens (preformed antimicrobial
      compounds or phytoanticipins). Alternatively they may be synthesized in response
      to pathogen attack as part of the plant defence response (phytoalexins). If these
      molecules do play a role in protecting plants against pathogen attack, then
      successful pathogens are presumably able to circumvent or tolerate these
      defences. Strategies may include avoidance, enzymatic degradation, and/or
      nondegradative mechanisms. This review outlines the different ways in which
      fungal pathogens may counter the antifungal compounds produced by their host
      plants and summarizes the evidence for and against these compounds as
      antimicrobial phytoprotectants.

PMID- 10361031
TI  - Visualization of a conditionally dispensable chromosome in the filamentous
      ascomycete Nectria haematococca by fluorescence in situ hybridization.
AB  - Supernumerary chromosomes, termed "conditionally dispensable" (CD) chromosomes,
      are known in Nectria haematococca. Because these CD chromosomes had been revealed
      solely by pulsed-field gel electrophoresis, their morphological properties were
      unknown. In this study, we visualized a 1.6-Mb CD chromosome of this fungus by
      three different types of fluorescence in situ hybridization. The CD chromosome at
      mitotic metaphase was similar in its appearance to the other chromosomes in the
      genome. Heterochromatic condensation was not distinct in the CD chromosome,
      suggesting that it is primarily euchromatic. It was also evident that the CD
      chromosome is unique and not a duplicate of other chromosomes in the genome. At
      interphase and prophase, the CD chromosome was not dispersed throughout the
      nucleus, but occupied a limited domain. Occasionally, occurrence of two distinct
      unattached copies of the CD chromosome were observed during interphase and
      metaphase.

PMID- 10361032
TI  - Analysis of the heat-shock response displayed by two Chaetomium species
      originating from different thermal environments.
AB  - Three features of the heat shock response, reorganization of protein expression,
      intracellular accumulation of trehalose, and alteration in unsaturation degree of
      fatty acids were investigated in the thermophilic fungus Chaetomium thermophile
      and compared to the response displayed by a closely related mesophilic species,
      C. brasiliense. Thermophilic heat shock response paralleled the mesophilic
      response in many respects like (i) the temperature difference observed between
      normothermia and the upper limit of translational activity, (ii) the transient
      nature of the heat shock response at the level of protein expression including
      both the induction of heat shock proteins (HSPs) as well as the repression of
      housekeeping proteins, (iii) the presence of representatives of high-molecular
      weight HSPs families, (iv) intracellular accumulation of trehalose, and finally
      (v) modifications in fatty acid composition. On the other hand, a great
      variability between the two organisms was observed for the proteins expressed
      during stress, in particular a protein of the HSP60 family that was only observed
      in C. thermophile. This peptide was also present constitutively at normal
      temperature and may thus fulfil thermophilic functions. It is shown that
      accumulation of trehalose does not play a part in thermophily but is only a
      stress response. C. thermophile contains less polyunsaturated fatty acids at
      normal temperature than C. brasiliense, a fact that can be directly related to
      thermophily. When subjected to heat stress, both organisms tended to accumulate
      shorter and less unsaturated fatty acids.

PMID- 10361033
TI  - Ligand recognition in multiallelic pheromone receptors from the basidiomycete
      Schizophyllum commune studied in yeast.
AB  - The homobasidiomycete Schizophyllum commune encodes a multiallelic pheromone
      receptor system that distinguishes more than 20 nonself from at least 2 self
      pheromones. The well-investigated pheromone response system of the yeast
      Saccharomyces cerevisiae was used to link the FUS1::lacZ reporter system to the
      heterologous pheromone receptors from S. commune. To investigate yeast G-protein
      binding, the unchanged heterologous receptor was compared to constructs carrying
      an exchange of the 3rd cytoplasmatic loop for the Ste2 sequence. A better
      coupling could be achieved with the altered constructs. In order to examine
      activation by single pheromones, an artificial peptide based on the sequence of a
      new putative pheromone gene, bap2(1), in the Balpha2 mating-type locus encoding
      the shortest pheromone found so far in fungal mating types was used. Thus, we
      have reassembled the pheromone recognition of the basidiomycete S. commune and
      constructed a system ideal for specificity analysis in the yeast S. cerevisiae.

PMID- 10361034
TI  - The detection of nonhybrid, trisomic, and triploid offspring in sexual progeny of
      a mating of Phytophthora infestans.
AB  - Eighty single-oospore offspring of Phytophthora infestans from a mating of
      isolates, which had previously been analyzed for segregation of
      avirulence/virulence, were assessed for the inheritance of 20 RFLP markers. Three
      offspring were triploid; they inherited three alleles at all loci where this
      could be detected and when heterozygous, showed unequal intensities of
      hybridization with most probes. Twenty-four offspring were trisomic, as each had
      three doses of one or a few markers, evident from their inheritance of three
      alleles or from unequal hybridization to one probe. Coinheritance of the extra
      allele(s) and mitochondrial haplotype in the majority of trisomic offspring
      suggested that meiosis in oogonia was more aberrant than in antheridia. Linkage
      analysis was performed on 50 offspring, which were assumed to be euploid; six
      small linkage groups were detected and several avirulence loci were found to be
      linked. The origins of aberrant offspring are discussed.

PMID- 10361035
TI  - Ketosynthase domain probes identify two subclasses of fungal polyketide synthase
      genes.
AB  - Analysis of fungal polyketide synthase gene sequences suggested that these might
      be divided into two subclasses, designated WA-type and MSAS-type. Two pairs of
      degenerate PCR primers (LC1 and LC2c, LC3 and LC5c) were designed for the
      amplification of ketosynthase domain fragments from fungal PKS genes in each of
      these subclasses. Both primer pairs were shown to amplify one or more PCR
      products from the genomes of a range of ascomycetous Deuteromycetes and Southern
      blot analysis confirmed that the products obtained with each pair of primers
      emanated from distinct genomic loci. PCR products obtained from Penicillium
      patulum and Aspergillus parasiticus with the LC1/2c primer pair and from Phoma
      sp. C2932 with both primer pairs were cloned and sequenced; the deduced protein
      sequences were highly homologous to the ketosynthase domains of other fungal PKS
      genes. Genes from which LC1/2c fragments were amplified (WA-type) were shown by a
      phylogenetic analysis to be closely related to fungal PKS genes involved in
      pigment and aflatoxin biosynthetic pathways, whereas the gene from which the
      LC3/5c fragment was amplified (MSAS-type) was shown to be closely related to
      genes encoding 6-methylsalicylic acid synthase (MSAS). The phylogenetic tree
      strongly supported the division of fungal PKS genes into two subclasses. The LC
      series primers may be useful molecular tools to facilitate the cloning of novel
      fungal polyketide synthase genes.

PMID- 10361036
TI  - Characterization of a transcriptional activator controlling trichothecene toxin
      biosynthesis.
AB  - Trichothecene biosynthetic pathway genes are localized within a gene cluster in
      Fusarium sporotrichioides and require the zinc-finger containing protein, TRI6,
      for expression. We show here that TRI6 is able to bind within the promoter
      regions of nine different pathway genes and that TRI6 binding is involved in
      pathway gene activation. TRI6 binding occurs at three distinct sites in the TRI5
      promoter, all of which contain the sequence TNAGGCCT. DNA fragments from the
      promoter regions of six other pathway genes containing this sequence are also
      substrates for TRI6 binding. Specific nucleotide changes in the TNAGGCCT sequence
      dramatically reduced TRI6 binding. Analysis of TRI6 binding within the TRI3 and
      TRI11 promoters and the TRI4-TRI6 intergenic region which do not contain the
      TNAGGCCT motif suggests that the minimum sequence required for TRI6 binding is
      YNAGGCC. Two potential TRI6 binding sites, T4A and T4B, were identified within
      the intergenic region for the divergently transcribed TRI4 and TRI6 genes.
      Alteration or deletion of the T4A site resulted in the loss of nearly all in
      vitro TRI6 binding and was correlated with the loss of promoter activity in vivo
      as measured by the expression of mutant TRI4(p)/GUS fusions. This establishes a
      physiological role for TRI6 binding and demonstrates that TRI6 is directly
      involved in the regulation of pathway gene expression. To determine if a
      predicted Cys2His2 zinc-finger motif at the C-terminus of TRI6 is involved in DNA
      binding, a C187A mutant was constructed in TRI6 using site-directed mutagenesis.
      The C187A mutant did not bind promoter DNA fragments, supporting the role of C187
      in DNA binding. In addition, a TRI6 homologue in the distantly related
      macrocyclic trichothecene pathway of Myrothecium roridum (MRTRI6) was also shown
      to bind to the same TRI5 and TRI4 promoter fragments bound by TRI6. Together,
      these data confirm our previous proposal that TRI6 is an activator of
      trichothecene pathway gene expression and that DNA binding employs the C-terminal
      region of TRI6 containing three predicted Cys2His2 zinc fingers.

PMID- 10361037
TI  - sodVIC is an alpha-COP-related gene which is essential for establishing and
      maintaining polarized growth in Aspergillus nidulans.
AB  - Strains of Aspergillus nidulans carrying the conditional-lethal mutation sodVIC1
      (stabilization of disomy) are defective in nuclear division and hyphal extension.
      The mutation affects both the establishment and maintenance of polar growth,
      since mutant spores do not germinate at restrictive temperature and preexisting
      hyphae stop growing upon upshift. The defect is reversible within the first 3-4 h
      at restrictive temperature but longer periods of incubation are lethal due to
      cell lysis and morphological abnormalities. There is no evidence for a specific
      cell cycle lesion, suggesting the existence of a feedback mechanism whereby
      hyphal extension is coordinated with nuclear partitioning. The sodVIC gene has
      been cloned from a chromosome VI-specific cosmid library and its product exhibits
      strong homology to the alpha-COP subunit of the coatomer complex involved in the
      secretory pathway in yeast and higher organisms. Molecular disruption of the gene
      is lethal, indicating that SodVIC is essential for growth in A. nidulans.

PMID- 10361038
TI  - Carbon regulation of ribosomal genes in Neurospora crassa occurs by a mechanism
      which does not require Cre-1, the homologue of the Aspergillus carbon catabolite
      repressor, CreA.
AB  - Transcription of the ribosomal protein and 40S rRNA genes is coordinately
      regulated during steady state growth and carbon shifts in Neurospora crassa.
      Recognition sequences for the Aspergillus nidulans carbon catabolite repressor,
      CreA, overlap transcriptional elements of a 40S rRNA gene and the crp-2 ribosomal
      protein gene. They also occur in similar locations in the promoters of several
      other ribosomal protein genes. Substitutions encompassing the -74 and -167 CreA
      consensus sequences in the crp-2 promoter result in a decrease in transcription.
      A cDNA encoding the N. crassa homologue of CreA was cloned and designated Cre-1.
      The Cre-1 protein is 45% identical to CreA from A. nidulans. Cre-1 protein
      produced in Escherichia coli binds to the CreA sites in the promoters of the 40S
      rRNA and crp-2 genes. An amino acid change from histidine (92) to threonine
      changed the Cre-1 binding specificity from (5'G/CC/TGGG/AG3') to
      (5'G/CC/TGGCG3'). Base substitutions in the Cre-1 binding sites of the crp-2
      promoter disrupted binding of wildtype Cre-1 in vitro but had no effect on
      transcription during steady state growth or carbon shifts, indicating that
      regulation of ribosomal genes by carbon source is not mediated by Cre-1, but via
      different proteins binding the Cre-1 sites and the Dde boxes.

PMID- 10361039
TI  - Anorectic therapy and valvular heart disease: a reappraisal.

PMID- 10361040
TI  - Severe morbidity after coronary artery surgery.

PMID- 10361041
TI  - Assessment of risk of thromboembolism in atrial fibrillation: which patient
      should we anticoagulate?

PMID- 10361042
TI  - Can negative results for protein markers of myocardial damage justify discharge
      of acute chest pain patients after a few hours in hospital?

PMID- 10361043
TI  - Can calcium antagonists reverse atherosclerosis?

PMID- 10361044
TI  - Controversies in determining cardiovascular therapy.

PMID- 10361045
TI  - Cardiac and peripheral responses to exercise in patients with chronic heart
      failure.

PMID- 10361046
TI  - Aetiology and pathophysiological implications of oscillatory ventilation at rest
      and during exercise in chronic heart failure. Do Cheyne and Stokes have an
      important message for modern-day patients with heart failure?

PMID- 10361047
TI  - Risk factors for coronary heart disease and acute-phase proteins. A population
      based study.
AB  - AIMS: Circulating levels of C-reactive protein and serum amyloid A protein
      increase markedly, and albumin levels fall, during the acute-phase response to
      tissue injury, infection and inflammation. Some acute-phase proteins have been
      associated with increased risks of coronary heart disease in long-term
      prospective studies. The aim of the present study was to determine whether
      circulating concentrations of C-reactive protein, albumin and serum amyloid A
      protein are correlated with one another, standard vascular risk factors, markers
      of persistent infection, or indicators of socio-economic status. METHODS AND
      RESULTS: We report a cross-sectional study of 704 individuals without a history
      of coronary heart disease from five general practices in Bedfordshire, U.K.
      Plasma levels of C-reactive protein and serum amyloid A protein were strongly
      associated with each other (2 P<0.00001) and inversely related to levels of serum
      albumin (2 P<0.00001). There were highly significant associations of plasma C
      reactive protein concentrations with cigarette smoking and obesity (2 P<0.00001
      for each). Serum albumin levels were strongly associated with blood pressure (2
      P<0.0001) and plasma lipids (2 P<0.001), and concentrations of serum amyloid A
      protein were strongly correlated with obesity (2 P<0.0001). CONCLUSION:
      Previously reported long-term prospective studies have found an increased risk of
      coronary heart disease of about 50% in people with raised baseline levels of
      plasma C-reactive protein or low albumin. The strong cross-sectional associations
      we have found between levels of these proteins with each other and with
      concentrations of serum amyloid A protein suggest that some underlying process
      related to inflammation is likely to be of relevance to the causation of disease.
      Further studies are needed to determine if the strong associations of plasma
      levels of C-reactive protein with cigarette smoking and obesity indicate that
      this particular protein can mediate some of the effects of those risk factors on
      coronary heart disease.

PMID- 10361048
TI  - Severe morbidity after coronary artery surgery: development and validation of a
      simple predictive clinical score.
AB  - AIMS: To develop a predictive clinical risk score of post-operative morbidity
      after coronary artery bypass grafting. METHODS AND RESULTS: Data were collected
      retrospectively from 679 patients undergoing emergency or planned bypass surgery
      between 1 January and 31 December 1996. The incidence of morbidity was 23%.
      Multivariate stepwise logistic regression analysis on two-thirds of the patients
      identified eight independent risk factors for severe morbidity. Six of these were
      pre-operative: symptomatic right heart failure, previous ventricular arrhythmias,
      previous coronary bypass surgery, chronic pulmonary disease, ST changes on pre
      operative electrocardiogram, body mass index <24 kg. m-2, and two were intra
      operative factors: the surgeon who operated, and the cardiopulmonary bypass time.
      A predictive clinical risk score was developed with the six pre-operative risk
      factors. The negative predictive value of the model is 87% and the area under the
      receiver operating characteristic curve is 0.77. When tested on the remaining
      patients not used for developing the model, the area under the curve is 0.65.
      CONCLUSION: This pre-operative risk score provides a simple method of risk
      stratification for patients undergoing coronary artery surgery. However, as for
      all predictive models, the performance of the score decreases when applied to a
      population other than that used to develop it.

PMID- 10361049
TI  - Ruling out acute myocardial infarction early with two serial creatine kinase
      MBmass determinations.
AB  - AIMS: We studied the diagnostic value for acute myocardial infarction of serial
      creatine kinase-MBmass measurements on admission and at 7 h after the onset of
      symptoms. METHODS AND RESULTS: Patients presenting to our chest pain unit with
      symptoms of <5-h duration were eligible. Patients were kept under observation at
      least until 12 h after onset of symptoms. Blood samples were drawn on admission
      and 7 and 10 h after onset of symptoms. Creatine kinase-MBmass>7.0 microg x 1(-1)
      (upper reference limit for acute myocardial infarction), or an increase >2.0
      microg x 1(-1) (reference change value) between admission and at 7 h was
      considered abnormal. Of a total of 470 patients, 248 patients had acute
      myocardial infarction: 100 out of the 248 patients had a single creatine kinase
      MBmass>7.0 microg x 1(-1) on admission (sensitivity 40%, 95% CI:34-46%), 234/248
      patients at 7 h (sensitivity 94%, 95% CI:91-97%), and 240/248 at 10 h
      (sensitivity 97%, 95% CI:94-99%). At 7 h, 246/248 patients had either a single
      creatine kinase-MB >7.0 microg x 1(-1) or a significant increase between
      admission and 7 h (sensitivity 99%, 95% CI:98-100%). Of 222 patients without
      acute myocardial infarction, 214 had a normal serial creatine kinase-MBmass
      (specificity 96%, 95% CI:93-98%). CONCLUSION: In patients with symptoms of <5-h
      duration, acute myocardial infarction can be ruled out using serial creatine
      kinase-MBmass taken on admission and at 7 h.

PMID- 10361050
TI  - Accelerating impact of diabetes mellitus on mortality in the years following an
      acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation.
AB  - AIMS: The development of risk associated with diabetes mellitus during long-term
      follow-up after a myocardial infarction has not been studied in detail. We have
      studied time-related changes of risk of death during 10 years of follow-up in a
      cohort of patients not treated with thrombolytic therapy (the Glostrup cohort)
      and during 6 years in a cohort receiving such treatment in 40% of cases (the
      TRACE cohort). METHODS: A subgroup analysis of two cohorts: the Glostrup cohort,
      which consisted of consecutive cases of acute myocardial infarction who were
      admitted to one hospital between 1979 and 1983; the TRACE cohort which was
      comprised of patients with an acute myocardial infarction screened for entry into
      the Trandolapril Cardiac Evaluation study between May 1990 and June 1992. The
      Glostrup cohort consisted of 1954 patients and follow-up was for 10 years, The
      TRACE cohort consisted of 6676 patients and follow-up was for 6 years. Outcome
      measure was total death. RESULTS: A diagnosis of diabetes mellitus was present in
      12% of the two study populations. In multivariate analysis, diabetes mellitus had
      an independent adverse effect on mortality which increased with time. In the
      Glostrup cohort risk ratio between day 0 and day 30 was 1.17 and increased to
      2.51 (P=0.0002) 7-9 years after discharge from hospital. A similar increase in
      the risk ratio of diabetes mellitus on mortality was observed in the TRACE cohort
      (risk ratio for days 0-30 was 1.03, and for years 4-6 was 1.74 (P=0.0001).
      CONCLUSION: Diabetes mellitus has no independent influence on mortality
      immediately following an acute myocardial infarction, but has an important
      influence on long-term mortality which increases with time. The implication is
      that the effect of intervention against diabetes in patients with acute
      myocardial infarction and diabetes mellitus must be evaluated over a long course
      of time.

PMID- 10361052
TI  - Gerhard Herzberg (1904-1999).

PMID- 10361051
TI  - Importance of left atrial appendage flow as a predictor of thromboembolic events
      in patients with atrial fibrillation.
AB  - AIM: The purpose of this study was to investigate the role of transoesophageal
      echocardiography in predicting subsequent thromboembolic events in patients with
      atrial fibrillation. METHODS AND PATIENTS: Transoesophageal echocardiography was
      performed in 88 patients with documented paroxysmal (n=53) or chronic atrial
      fibrillation (n=35) to assess morphological and functional predictors of
      thromboembolic events. Prospective selection was from patients with non-valvular
      atrial fibrillation who had undergone transoesophageal echocardiography because
      of previous thromboembolism (n=30); prior to electrical cardioversion (n=31); or
      for other reasons (n=27). All patients were followed up for 1 year. RESULTS:
      During the period of follow-up new thromboembolic events occurred in 18 of 88
      patients (20%/year); 16 of these patients had a stroke and two a peripheral
      embolism. Univariate analysis revealed that previous thromboembolism (P<0.005;
      odds ratio 5.3 [CI 1.9, 12. 1]), history of hypertension (P<0.01; odds ratio 4.0
      [CI 1.4, 10.4), presence of left atrial spontaneous echo contrast (P<0.025; odds
      ratio 3.5 [CI 1.2, 10.0]), and presence of left atrial appendage peak velocity
      </=0.20 m. s-1(P<0.01; odds ratio 4.1 [CI 1.4, 11.6]) were significantly related
      to subsequent thromboembolic events. Stepwise logistic regression showed that
      independent predictors of thromboembolic events were: history of thromboembolism
      (P<0.005), history of hypertension (P<0.05) and low left atrial appendage peak
      velocity </=0.20 m. s-1(P<0.01). CONCLUSIONS: In patients with atrial
      fibrillation, the presence of spontaneous echo contrast in the left atrium, and
      in particular a low left atrial appendage peak flow velocity, can be used to
      identify a subgroup of atrial fibrillation patients at either increased or
      decreased risk of subsequent thromboembolism, which might have important
      implications for anticoagulation therapy.

PMID- 10361053
TI  - Far-Infrared Rotational and Fine-Structure Transition Frequencies and Molecular
      Constants of 14NO and 15NO in the X2Pi (v = 0) State.
AB  - We have made highly accurate measurements of the absorption spectrum of the 14NO
      and 15NO isotopomers of nitric oxide in the far-infrared. Pure rotational
      transitions up to J" = 3712 within the 2Pi1/2 and 2Pi3/2 spin components and
      several 2Pi3/2 <-- 2Pi1/2 fine-structure transitions were recorded within the
      ground vibrational state. A least-squares fit to these data combined with some
      lambda-doubling and rotational transitions measured by previous workers has
      resulted in accurate values for the rotational, fine, and hyperfine parameters of
      these two isotopomers. Most of the far-infrared transitions reported here have an
      experimental uncertainty of about 20 kHz and will be useful for astronomers and
      atmospheric scientists studying this important molecule. The more accurate
      calculated frequencies will also be useful as spectroscopic calibration
      standards. Copyright 1999 Academic Press.

PMID- 10361054
TI  - The C-C-H Bending Vibration Mode (nu4) in the Electronic A2Pi and &Xtilde;2Sigma+
      States of the CaCCH Radical.
AB  - The first excited C-C-H bending vibration levels in the CaCCH A2Pi and
      &Xtilde;2Sigma+ states have been rotationally analyzed through cw dye laser
      excitation spectroscopy of the band. The upper state is subject to Renner-Teller
      and spin-orbit splittings. Strong K-type resonance interactions were observed
      between the nearby 2Delta and 2Sigma vibronic components. A total of 667
      rotational lines were recorded with high precision and fitted to a model
      involving a full matrix treatment of the interactions. The Renner-Teller
      parameter has been determined as epsilon4omega4 = 1.85(4) cm-1. Copyright 1999
      Academic Press.

PMID- 10361055
TI  - The High-Lying Vibrational Levels and Dissociation Energy of the a3Sigma+u State
      of 7Li2.
AB  - Perturbation-facilitated optical-optical double resonance (PFOODR) has been used
      to access the 2(3)Pig state of 7Li2 via the excitation scheme using two single
      mode tunable lasers. The selected () mixed level provides a gateway through which
      the triplet manifold can be accessed. Fluorescence from single rovibrational
      levels of 2(3)Pig to the state was detected at high resolution using a Fourier
      transform spectrometer. Transitions to v = 0-9 in the state were observed,
      covering the potential well almost to the dissociation limit. The data were
      analyzed using a near dissociation expansion (NDE) technique and the resulting
      vibrational and rotational parameters were used to calculate a new RKR potential
      curve which reproduced the observed energy levels to within a rms error of 0.02
      cm-1. The following parameters were obtained for the state: D0 = 301.829 +/-
      0.015 cm-1, De = 333.69 +/- 0.10 cm-1, Te = 8183.12 +/- 0.12 cm-1. Copyright 1999
      Academic Press.

PMID- 10361056
TI  - The BaI X2Sigma+ and B2Sigma+ Electronic States Through B2Sigma+-X2Sigma+ and
      C2Pi-X2Sigma+ Band Systems Analysis.
AB  - The near-infrared spectrum of the B2Sigma+-X2Sigma+ band system of the BaI
      molecule, obtained from the chemiluminescent reaction Ba + I2 and also by laser
      induced fluorescence (LIF), was recorded by using Fourier transform spectroscopy
      (FTS). The LIF spectra were obtained by using a Ti:sapphire single-mode laser
      excitation. Resolved rotational data, originating from 32 vibrational levels (0
      </= v </= 31) in the X2Sigma+ state and from 24 vibrational levels (0 </= v </=
      19, and v = 21, 22, 23, 26) in the B2Sigma+ state, were used in the final
      analysis. Previously recorded data for the C2Pi-X2Sigma+ band system (with Deltav
      = 0), taken from C. A. Leach, A. A. Tsekouras, and R. N. Zare, J. Mol. Spectrosc.
      153, 59-72 (1992), were added to the present work data field. Accurate and
      improved molecular constants for the X2Sigma+, B2Sigma+, and C2Pi states were
      derived from a simultaneous treatment of the whole data set. Copyright 1999
      Academic Press.

PMID- 10361057
TI  - Electronic Spectra of YOH and YOD in the Visible Region: Strong Vibronic Coupling
      between the &Btilde;1Pi and &Ctilde;1Sigma+ States.
AB  - Laser excitation spectra of yttrium monohydroxide, YOH, have been recorded in the
      500-625 nm wavelength region. Rotational analysis of bands of YOH and YOD has
      shown that the ground state is &Xtilde;1Sigma+, with the structure r0(Y-O) =
      1.9486 A, r0(O-H) = 0.9206 A; the bending frequency (nu2, pi) is 313.73 cm-1
      (237.43 cm-1 in YOD) and the Y-O stretching frequency (nu3, varsigma+) is 673.83
      cm-1 (655.34 cm-1). Two excited electronic states have been identified; they are
      assigned as &Btilde;1Pi (16 449 cm-1) and &Ctilde;1Sigma+ (18 509 cm-1).
      Unusually strong vibronic coupling through the bending vibration occurs between
      these two states, which causes their vibrational structures to be highly
      irregular; assignments have only been possible following extensive wavelength
      resolved fluorescence experiments. The vibronic coupling raises the bending
      frequency of the &Ctilde;1Sigma+ state to 457 cm-1 and reduces that of the lower
      Born-Oppenheimer component of the &Btilde;1Pi state (which has A' symmetry in the
      Cs point group) to the extent that the molecule becomes nonlinear, with a
      potential barrier at the linear configuration of about 120 cm-1. The presence of
      the potential barrier is clearly demonstrated by the level structure of YOD,
      where the Sigma+ vibronic component of the 010 vibrational level (linear molecule
      notation) lies 1.4 cm-1 below the 000 level. The upper Born-Oppenheimer
      component, which has A" symmetry, is unaffected; its bending frequency is similar
      to that of the ground state. Perturbations occur in both the &Btilde;1Pi and
      &Ctilde;1Sigma+ states; some of these represent local interactions between the
      two of them, but others are caused by higher vibrational levels of lower-lying
      "dark" electronic states. Over 40 ground state vibrational levels have been
      identified for both YOH and YOD from the wavelength-resolved fluorescence
      spectra. Copyright 1999 Academic Press.

PMID- 10361058
TI  - Diode-Laser Measurements of He-, Ar-, and N2-Broadened HF Lineshapes in the First
      Overtone Band.
AB  - High-resolution lineshapes of the HF P(3) and P(6) transitions (2-0 band) have
      been recorded in a 14.9-cm long absorption cell (T = 296 K) using a pair of
      (InGaAsP)-distributed feedback diode lasers operating near 1.31 and 1.34 um,
      respectively. The absorption lineshapes were least-squares fit to Voigt, Rautian,
      and Galatry profiles to determine the collision widths and velocity-changing
      collision frequencies for the perturbers He, Ar, and N2. Motional narrowing was
      observed for the He-broadened lineshapes over a range of total pressures from 50
      to 646 Torr. The Ar- and N2-broadened spectra showed a strong narrowing effect
      for pressures less than 400 Torr. At higher pressures, narrowing parameters could
      not be reliably determined due to the relatively large Ar- and N2-pressure
      broadening. The collision widths inferred from Voigt-profile fits were
      systematically less than those determined from Rautian and Galatry fits (up to
      25% for the He-broadened P(6) transition). The measured pressure-induced
      broadening and shift coefficients were compared with other experimental data and
      full-quantal close-coupling (CC) scattering cross-section calculations. The
      measured Ar-broadening half-widths were in excellent agreement with calculated
      values, while the measured shifts were 10 and 20% less than calculated values for
      the P(3) and P(6) transitions, respectively. The measured N2-broadening and shift
      coefficients agree reasonably well with values determined from previous
      experiments. Copyright 1999 Academic Press.

PMID- 10361059
TI  - Ro-vibrational Raman Cross Sections of Water Vapor in the OH Stretching Region.
AB  - The Raman spectrum of H2O, in the gas phase at 26 mbar and 295 K, has been
      recorded from 3400 to 4130 cm-1 using an improved spectrometer of very high
      sensitivity. This spectrum is analyzed in terms of the wavefunctions and energy
      levels of Flaud and Camy-Peyret [J. Mol. Spectrosc. 51, 142 (1974)], and of the
      polarizability derivatives with respect to the dimensionless normal coordinates
      q1 and q3. It is shown that the anharmonic coupling between the vibrational
      states nu1 and nu3 has to be considered for a correct simulation of the observed
      spectrum. Tables with scattering strengths and energies of ro-vibrational
      transitions are provided in order to simulate the Raman spectrum of water vapor
      over a broad range of temperatures, from few Kelvin, under supersonic expansions,
      to high temperature, in combustion processes. Copyright 1999 Academic Press.

PMID- 10361060
TI  - New Analysis of 2nu1 + nu2, nu1 + nu2 + nu3, and nu2 + 2nu3 Bands of Ozone in the
      2600-2900 cm-1 Region.
AB  - The 2600-2900 cm-1 spectral range is revisited for an accurate determination of
      line intensities of the 2nu1 + nu2, nu1 + nu2 + nu3, and nu2 + 2nu3 bands of
      ozone. The fit on 1702 energy levels of (012), (111), and (210) states determined
      from observed transitions with Jmax </= 61 and Ka max </= 17 gives a rms = 5.6 x
      10(-4) cm-1 and provides a satisfactory agreement between calculated and observed
      line positions. Line intensities have been measured and fitted, leading to the
      determination of transition moment parameters for the three bands. Using these
      parameters, we have obtained the following estimations for the integrated band
      intensities S(nu1 + nu2 + nu3) = 2.509 x 10(-20), S(nu2 + 2nu3) = 0.330 x 10(
      20), and S(2nu1 + nu2) = 0.0802 x 10(-20) cm-1/mol cm-2 at 296 K, with a cutoff
      of 10(-26) cm-1/mol cm-2. The value of the u(210)-(000)1 parameter associated
      with the &phi;x operator for 2nu1 + nu2 band obtained in our analysis appears to
      be eight times smaller than the previously determined value of this parameter [M.
      A. H. Smith, C. P. Rinsland, J. M. Flaud, C. Camy-Peyret, and A. Barbe, J. Mol.
      Spectrosc. 139, 171-181 (1990)]. The general line listing of the 2nu1 + nu2, nu1
      + nu2 + nu3, and nu2 + 2nu3 bands (up to Jmax = 70 and Ka max = 23) has been
      generated with an intensity cutoff 10(-26) cm-1/mol cm-2. The perturbations of
      (111) and (012) states by the (040) state are discussed. Copyright 1999 Academic
      Press.

PMID- 10361061
TI  - Least-Squares Mass-Dependence Molecular Structures.
AB  - The major part of the difference between the zero-point and equilibrium moment of
      inertia of a molecule is a homogeneous function of degree 12 in the atomic
      masses. The use of explicit mathematical models of is studied here as a means of
      determining near-equilibrium molecular structures from the zero-point moments of
      inertia of a range of isotopomers. It is found that models with more than two
      parameters per axis generally give strongly correlated fits for the number of
      isotopomers typically available. The two-parameter model, where N is the number
      of atoms, mi are the atomic masses, and M is the molecular mass, usually gives
      well-conditioned fits with standard deviations in the parts-per-million range,
      and structures called that are often close to equilibrium structures. Laurie-type
      corrections for hydrogen atoms and parameters to describe isotopic rotations of
      the epsilon tensor can also be included. Copyright 1999 Academic Press.

PMID- 10361062
TI  - Infrared Spectroscopy of H3O+: The nu1 Fundamental Band.
AB  - The infrared spectrum of H3O+ in positive column discharges of H2/O2 gas mixtures
      has been studied by a difference frequency laser spectrometer. The nu1
      fundamental band of H3O+ was identified in the region of the strong. Molecular
      constants were obtained by the least-squares fitting of the observed frequencies,
      and band origins of the and subbands were determined to be 3389.656(2) and
      3491.170(2) cm-1, respectively. During this study, assignment of the nu3
      fundamental band was extended to higher J, K transitions, which do not fit to the
      calculated pattern well, but have definitely been assigned by using the ground
      state combination differences and relative intensities. Vibration-rotation
      interactions between the nu1 and nu3 states have been considered, which explained
      some large discrepancies between observed and calculated frequencies and led to
      the identification of forbidden transitions. Energy differences in the ground
      state between the DeltaK = 3 rotational levels were obtained from the combination
      differences of the forbidden and allowed transitions, which led to an accurate
      determination of C and DK. Equilibrium structure of H3O+ has been derived to be
      re = 0.974(1) A and alphae = 113.6(1) degrees. Copyright 1999 Academic Press.

PMID- 10361063
TI  - Terahertz Measurements of Rotational Transitions in Vibrationally Excited States
      of N2O.
AB  - We have measured and analyzed rotational transitions of N2O in the following
      vibrational states, 01(1e,f)0, 02(0,2e,f)0, 03(1,3e,f)0, 00(0)1, 01(1e,f)1, and
      10(0)0. The NAIR terahertz spectrometer was used to measure the frequencies of
      transitions in the range J = 25 <-- 24 to J = 31 <-- 30 with accuracies of +/
      0.020 MHz in most cases. These measurements were fit, along with other microwave
      and infrared measurements involving the same states, to obtain improved
      rovibrational term values for those vibrational states. It is shown that the
      measurements can be fit with fewer constants if both l-type resonance and the
      Fermi resonance among the levels 00(0)1 and 02(0,2)0 or 01(1)1 and 03(1,3)0 are
      included in the least-squares fit. These measurements also contribute to
      improving the N2O wavenumber calibration standards for the infrared region.
      Copyright 1999 Academic Press.

PMID- 10361065
TI  - Do Cooperative Effects Influence the Bending HOH Vibrational Spectra of Small
      (H2O)n Clusters (n = 2-4)?

PMID- 10361064
TI  - Submillimeter Detection of the van der Waals Stretching Vibration of the Ar-CO
      Complex.
AB  - With the Cologne submillimeter-wave supersonic jet spectrometer, we extended
      molecular jet spectroscopy with backward wave oscillators up to frequencies of
      about 600 GHz. For the first time, the van der Waals stretching vibration of the
      Ar-CO molecular complex was detected in direct absorption. We measured 13 ro
      vibrational transitions (Kvstretch = 1 <-- 0, Ka = 0 <-- 0) in the frequency
      range from 528 to 600 GHz and additionally the two R(3) K doublet (Ka = 4 <-- 3)
      pure rotational transitions at 447 GHz with an accuracy of about 200 kHz. The ro
      vibrational transitions were assigned and fitted within experimental accuracy to
      a simple Hamiltonian taking into account the Coriolis interaction between the
      stretching and bending states, i.e., between vstretch = 1, Ka = 0, and vbend = 1,
      Ka = 1. The intensity of the transitions in the van der Waals stretching mode was
      estimated to be a factor of 5-10 less than that in the bending mode of Ar-CO.
      Copyright 1999 Academic Press.

PMID- 10361066
TI  - The Molecular Structure of CO2-N2O.

PMID- 10361067
TI  - Biopolymers in wastewater treatment 
AB  - Studies investigating the formation and manipulation of biopolymers produced by
      the heterogeneous microbial cultures found in wastewater treatment are not
      advancing at a fast rate, reflecting the inherent complexity of the systems
      involved. Adjustment of the nutrients present within the treatment process
      currently appears to offer more potential than bioaugmentation with genetically
      modified organisms for improving certain aspects, such as sludge settling
      properties and chlorinated organic pollutant removal. An area likely to be of
      increasing importance in the future is the role of the microbial biopolymer in
      retaining water within the sludge matrix. Modification of the biopolymer to aid
      the removal of water from waste sludges could have immense implications for the
      treatment and minimization of the waste sludge produced.

PMID- 10361068
TI  - Developments in terrestrial bacterial remediation of metals.
AB  - Recent advances in understanding the role and application of bacteria to the
      remediation of toxic metal and radionuclide contaminated terrestrial environments
      have come from several avenues. Novel species capable of mobilization and
      immobilization of metal ions have been discovered. Remediation of toxicity has
      been accelerated by nutrient amendment, the use of chelating agents and novel
      methods for phosphate amendment. Major advances in the use of natural and
      genetically engineered species for bioprotection and remediation of organic co
      contaminants have been reported. Construction of wetland function continues to be
      developed for containment and decontamination of wastewaters.

PMID- 10361069
TI  - Molecular approaches to the study of aquatic microbial communities 
AB  - Molecular methods for studying microbial communities are still under development.
      Enormous sequence catalogues can be collected; they must now be related to
      microbial activities. Messenger RNA detection, fluorescent in situ hybridization,
      cell sorting, and oligonucleotide array technology are currently being explored.
      Biases are associated with all these methods, but combined approaches offer
      checks and balances.

PMID- 10361070
TI  - Fungi in lignocellulose breakdown and biopulping 
AB  - Biological pulping has the potential to improve the quality of pulp, properties
      of paper and to reduce energy costs and environmental impact relative to
      traditional pulping operations. It has been suggested that energy savings alone
      could make the process economically viable. Other benefits include improved burst
      strength and tear indices of the product and reduced pitch deposition during the
      production process. The technology has focused on the white rot fungi, which have
      complex extracellular ligninolytic enzyme systems that can selectively remove or
      alter lignin and allow cellulose fibers to be obtained. Although still far from
      completely understood, these enzyme systems are being characterized
      mechanistically and on a molecular level with primary emphasis on the enzymes
      lignin peroxidase, manganese peroxidase and laccase. Scale-up to industrial
      process requirements presents challenges that are difficult to simulate in
      laboratory or pilot-scale tests. Inoculation, aeration and heat dissipation are
      key parameters for maintaining fungal activity. It may be possible to monitor and
      maintain consistent treatments through a program of active wood chip pile
      management. Overcoming these challenges will determine, in large part, if
      biopulping becomes a reality.

PMID- 10361071
TI  - New perspectives towards analysing fungal communities in terrestrial environments
AB  - Fungi play key roles in numerous ecosystem functions, and recent advances in the
      study of fungal diversity and ecology have led to a greater appreciation of this
      group of microeukaryotes. The application of a variety of nucleic acid techniques
      to fungal classification and phylogeny has led to a number of evolutionary
      insights, and has also begun to provide the necessary information for
      identification of unknown isolates and DNA sequences. These data, together with
      direct molecular characterisation of fungi in the field, provide new
      possibilities to describe fungal diversity and distribution. Such advances will
      no doubt also provide the means for a more detailed interpretation of ecological
      experiments.

PMID- 10361072
TI  - Developments with antarctic microorganisms: culture collections, bioactivity
      screening, taxonomy, PUFA production and cold-adapted enzymes 
AB  - There have been recent research developments with Antarctic prokaryotes in the
      areas of isolations of novel bacterial, culture collections, bioactivity
      screening, taxonomy, production of polyunsaturated fatty acids (PUFAs), cold
      adapted enzymes and bioremediation. Research to date confirms the novelty of
      bacteria isolated from this extreme environment. Opportunities now exist to
      exploit these and other findings to develop possible new biotechnological
      products from Antarctic microorganisms.

PMID- 10361073
TI  - Bioremediation of petroleum hydrocarbon contaminants in marine habitats.
AB  - Bioremediation is being increasingly seen as an effective, environmentally benign
      treatment for shorelines contaminated as a result of marine oil spills. Despite a
      relatively long history of research on oil-spill bioremediation, it remains an
      essentially empirical technology and many of the factors that control
      bioremediation have yet to be adequately understood. Nutrient amendment is a
      widely accepted practice in oil-spill bioremediation but there is scant
      understanding of the systematic effects of nutrient amendment on biodegradative
      microbial populations or the progress of bioremediation. Recent laboratory and
      field research suggests that resource-ratio theory may provide a theoretical
      framework that explains the effects of nutrient amendment on indigenous microbial
      populations. In particular, the theory has been invoked to explain recent
      observations that nutrient levels, and their relative concentration, influence
      the composition of hydrocarbon-degrading microbial populations. This in turn
      influences the biodegradation rate of aliphatic and aromatic hydrocarbons. If
      such results are confirmed in the field, then it may be possible to use this
      theoretical framework to select bioremediation treatments that specifically
      encourage the rapid destruction of the most toxic components of complex pollutant
      mixtures.

PMID- 10361074
TI  - 16S rDNA methods in soil microbiology 
AB  - With the introduction of molecular methods, the past decade has seen renewed
      interest in soil microbiology. New and exciting molecular technologies and the
      promise of finally opening the microbial black box in soil drive much of this
      interest. Although these pioneering studies have added much to our knowledge of
      microbial diversity in soils, it is debatable whether they have as yet advanced
      our understanding of the relationship between this diversity and soil processes.
      Hopefully, over the next few years, the knowledge gained from molecular studies
      will provide a better understanding of microbial communities in soils and lead
      ultimately to improvements in land management and to the exploitation of the
      genetic resources of soil.

PMID- 10361075
TI  - Novel detection techniques for human pathogens that contaminate poultry.
AB  - Poultry products are presumed to be a major contributor to human foodborne
      illness due to their high frequency of contamination with pathogens Salmonella
      spp. and Campylobacter spp. This has stimulated the development of more sensitive
      and rapid methods for identifying pathogens present in poultry. These new methods
      include immunomagnetic separation of pathogen, PCR amplification of pathogen
      specific sequences, pathogen-specific DNA and RNA probes, and identification of
      pathogen-specific ions by mass spectrometry.

PMID- 10361076
TI  - Understanding microbially influenced corrosion as biofilm-mediated changes in
      surface chemistry 
AB  - Over the past year, the trend in understanding microbially influenced corrosion
      processes in terms of microbially mediated localized changes in the surface
      chemistry has continued. Also, the shift from studying carbon steel to studying
      other more resistant alloys has continued.

PMID- 10361077
TI  - Pharmaceutical provisions of the FDA Modernization Act of 1997: one year and
      counting.
AB  - The FDA Modernization Act of 1997 represents a notable public policy achievement
      that was conceived not out of crisis, but rather out of a shared commitment that
      the FDA can both protect patient health (by assuring drugs are safe and
      effective) and promote public health (by being given additional resources and new
      procedural efficiencies to accelerate the review of applications for new
      medicines). The FDA is conscientiously implementing this important new law, but
      there are areas where more work is required. On balance, the prospects are that
      this law will help usher in a much improved era for patients.

PMID- 10361078
TI  - Modern microscopy in biofilm research: confocal microscopy and other approaches.
AB  - Microscopy is the only technique whereby bacterial biofilms can be studied at the
      single-cell level in situ. Our understanding of biofilm structure, physiology and
      control hinges on the application of confocal scanning laser microscopy and other
      advanced microscopic techniques. Gene expression in four dimensions (x,y,z,t),
      interspecies interactions, and the role of exopolymer are being defined.

PMID- 10361079
TI  - Perspectives of medium chain length poly(hydroxyalkanoates), a versatile set of
      bacterial bioplastics 
AB  - Medium chain length (mcl) poly(hydroxyalkanoic acids) (PHAs) are polyesters
      accumulated by fluorescent Pseudomonads and other bacteria. Work on the genetics
      of mcl-PHA formation has led to polymer synthesis in recombinant bacteria and
      plants. Several high and medium cost applications are now emerging. With
      optimized bacterial mcl-PHA synthesis on inexpensive agro-substrates and the
      development of plant-based mcl-PHAs in the next decade, the production economics
      of these bioplastics will ultimately permit their sustainable production for bulk
      applications.

PMID- 10361080
TI  - Compliance with Good Manufacturing Practices for facilities engaged in vector
      production, cell isolation, and genetic manipulations.

PMID- 10361081
TI  - Laboratory identification of hereditary risk of breast and ovarian cancer.

PMID- 10361082
TI  - New drug approval process in Japan.

PMID- 10361083
TI  - Regulation of foods derived from genetically engineered crops.

PMID- 10361084
TI  - Structure, folding and catalysis of the small nucleolytic ribozymes.
AB  - The small nucleolytic ribozymes are largely (but not exclusively) found in the
      RNA of plant pathogens and are involved in the self-catalysed processing of the
      concatameric RNA resulting from rolling circle replication. They catalyse a site
      specific transesterification reaction in which their 2' hydroxyl attacks the 3'
      phosphate, with the exclusion of the 5' oxyanion. This requires an in-line
      geometry, which is not present in normal RNA structure. A significant part of the
      activation is probably provided by a distortion of the local conformation in
      order to facilitate the trajectory into the transition state and, thus, RNA
      folding and catalysis are intimately connected. A second element of the catalysis
      is provided by bound metal ions; however, a number of recent experiments cast
      doubt on the direct role of metal ions in the catalytic chemistry.

PMID- 10361086
TI  - Topological characteristics of helical repeat proteins.
AB  - The recent elucidation of protein structures based upon repeating amino acid
      motifs, including the armadillo motif, the HEAT motif and tetratricopeptide
      repeats, reveals that they belong to the class of helical repeat proteins. These
      proteins share the common property of being assembled from tandem repeats of an
      alpha-helical structural unit, creating extended superhelical structures that are
      ideally suited to create a protein recognition interface.

PMID- 10361087
TI  - A chemogenetic approach to RNA function/structure analysis.
AB  - Almost two dozen nucleotide analogs have been synthesized with alpha
      phosphorothioate-tagged triphosphates and utilized in an interference
      modification approach termed Nucleotide Analog Interference Mapping. This method
      has made it possible to determine the chemical basis of RNA function and
      structure, including the identification of new rules for RNA helix packing, the
      functional analysis of a binding site for monovalent metal ions within RNA and
      the characterization of the catalytic mechanism of RNA enzymes.

PMID- 10361088
TI  - Oligonucleotide aptamers that recognize small molecules.
AB  - Nucleic acid receptors ('aptamers'), which recognize a large variety of organic
      molecules of low molecular weight, have been isolated from combinatorial nucleic
      acid libraries by in vitro selection methods. Structural studies of nucleic acid
      small molecule complexes provide insight into both the principles of molecular
      recognition by this class of biopolymers and the architecture of tertiary motifs
      in nucleic acid folding. Aptamers that recognize small molecules are increasingly
      applied as tools in molecular biology, from the detection of oxidative damage in
      DNA to conditional gene expression and from their use as modules for the
      engineering of allosteric ribozymes to biosensors.

PMID- 10361089
TI  - DNA structure: cations in charge?
AB  - Recent X-ray diffraction, NMR spectroscopy and molecular mechanics results
      suggest that monovalent cations selectively partition into the minor groove of AT
      tracts in DNA. These observations are consistent with DNA deformation by
      electrostatic collapse around areas of uneven cation density. This model predicts
      the occurrence of known DNA deformations, such as AT-tract bending and changes in
      the minor-groove width.

PMID- 10361090
TI  - Exposing the kinetic traps in RNA folding.
AB  - Large ribozymes fold on a 'glacial' timescale compared to the folding of their
      protein counterparts. The sluggish folding exhibited by large RNAs results from
      the formation of kinetically trapped, misfolded intermediates, which are
      nonessential features of the folding mechanism. Newly developed mutant ribozymes
      that avoid kinetic traps should facilitate the study of the RNA folding problem.

PMID- 10361091
TI  - Peptide nucleic acids as therapeutic agents.
AB  - Peptide nucleic acids (PNAs) have been around for more than seven years and it
      was hoped, at their introduction, that they would quickly enter the fields of
      antisense and antigene technology and drug development. Despite their extremely
      favorable hybridization and stability properties, as well as the encouraging
      antisense and antigene activity of PNA in cell-free systems, progress has been
      slow and experiments on cells in culture and in animals have been lacking.
      Judging from the very promising results published within the past year, however,
      there is every reason to believe that both PNA antisense and, possibly, PNA
      antigene research will strongly pick up momentum again. Specifically, it has been
      demonstrated that certain peptide-PNA conjugates are taken up very efficiently
      by, at least some, eukaryotic cells and that antisense down regulation of target
      genes in nerve cells in culture is attainable using such PNA conjugates. Perhaps
      even more exciting is that antisense-compatible effects have been reported using
      PNAs injected into the brain of rats. Finally, it has been shown that the
      bacterium Escherichia coli is susceptible to antisense gene regulation using PNA.

PMID- 10361092
TI  - Multistranded DNA structures.
AB  - DNA oligonucleotides can form multistranded helices through either the folding of
      a single strand or the association of two, three or four strands of DNA.
      Structures of several new DNA triplexes, G-quartet DNA quadruplexes and I-motif
      DNA quadruplexes have been reported recently. These structures provide new
      insights into helix stability and folding, loop conformations and cation
      interactions.

PMID- 10361093
TI  - Regulatory elements and expression profiles.
AB  - There has been steady progress in the computational analysis of transcription
      control regions, but current methods of predicting the gene regulatory features
      of noncoding sequences are still not accurate enough to be useful in automatic
      genome annotation. Therefore, detailed information on the expression patterns of
      newly sequenced genes is more likely to come from microarray-based high
      throughput mRNA quantitation technologies, which have made revolutionary progress
      over the past few years and are now ready for genome-wide application. Future
      solutions to the regulatory element prediction problem may be found by the
      combined analysis of genome sequence and expression data.

PMID- 10361094
TI  - From protein structure to function.
AB  - Several databases of protein structural families now exist-organised according to
      both evolutionary relationships and common folding arrangements. Although these
      lag behind sequence databases in size, the prospect of structural genomics
      initiatives means that they may soon include representatives of many of the
      sequence families. To some extent, functional information can be derived from
      structural similarity. For some structural families, their function is highly
      conserved, whereas, for others, it can only be inherited or derived on the basis
      of additional information (e.g. sequence patterns, common residue clusters and
      characteristic surface properties).

PMID- 10361095
TI  - Deoxyribozymes: new players in the ancient game of biocatalysis.
AB  - The repetitive and extraordinarily stable polynucleotide chains of DNA serve as
      an ideal storage system for genetic information. Although it is best known for
      its helical structure and relatively inert character, in vitro selection can be
      used to compel DNA to perform a surprising variety of chemical reactions. These
      artificial DNA enzymes or 'deoxyribozymes' generate large chemical rate
      enhancements and demonstrate precise substrate recognition, much like their
      protein and RNA counterparts. Recent studies with these prototypic deoxyribozymes
      indicate that DNA has a substantial untapped potential for intricate structure
      formation that could be exploited in novel chemical and biological catalysis.

PMID- 10361096
TI  - Progress in protein structure prediction: assessment of CASP3.
AB  - The third comparative assessment of techniques of protein structure prediction
      (CASP3) was held during 1998. This is a blind trial in which structures are
      predicted prior to having knowledge of the coordinates, which are then revealed
      to enable the assessment. Three sections at the meeting evaluated different
      methodologies - comparative modelling, fold recognition and ab initio methods.
      For some, but not all of the target coordinates, high quality models were
      submitted in each of these sections. There have been improvements in prediction
      techniques since CASP2 in 1996, most notably for ab initio methods.

PMID- 10361097
TI  - Advances in structural genomics.
AB  - New computational techniques have allowed protein folds to be assigned to all or
      parts of between a quarter (Caenorhabditis elegans) and a half (Mycoplasma
      genitalium) of the individual protein sequences in different genomes. These
      assignments give a new perspective on domain structures, gene duplications,
      protein families and protein folds in genome sequences.

PMID- 10361098
TI  - Protein families in multicellular organisms.
AB  - The complete sequence of the nematode worm Caenorhabditis elegans contains the
      genetic machinery that is required to undertake the core biological processes of
      single cells. However, the genome also encodes proteins that are associated with
      multicellularity, as well as others that are lineage-specific expansions of
      phylogenetically widespread families and yet more that are absent in non
      nematodes. Ongoing analysis is beginning to illuminate the similarities and
      differences among human proteins and proteins that are encoded by the genomes of
      the multicellular worm and the unicellular yeast, and will be essential in
      determining the reliability of transferring experimental data among
      phylogenetically distant species.

PMID- 10361099
TI  - Inflammatory reactivation and angiogenicity of Kaposi's sarcoma-associated
      herpesvirus/HHV8: a missing link in the pathogenesis of acquired immunodeficiency
      syndrome-associated Kaposi's sarcoma.

PMID- 10361100
TI  - Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus
      encoded interleukin-6.
AB  - Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8
      [HHV-8]) is a herpesvirus linked to the development of Kaposi's sarcoma (KS),
      primary effusion lymphoma, and a proportion of Castleman's disease. KSHV encodes
      viral interleukin-6 (vIL-6), which is structurally homologous to human and murine
      IL-6. The biological activities of vIL-6 are largely unknown. To gain insight
      into the biology of vIL-6, we expressed vIL-6 in murine fibroblasts NIH3T3 cells
      and inoculated stable vIL-6-producing clones into athymic mice. vIL-6 was
      detected selectively in the blood of mice injected with vIL-6-expressing clones.
      Compared with controls, vIL-6-positive mice displayed increased hematopoiesis in
      the myeloid, erythroid, and megakaryocytic lineages; plasmacytosis in spleen and
      lymph nodes; hepatosplenomegaly; and polyclonal hypergammaglobulinemia. vIL-6
      expressing NIH3T3 cells gave rise to tumors more rapidly than did control cells,
      and vIL-6-positive tumors were more vascularized than controls. Vascular
      endothelial growth factor (VEGF) was detected at higher levels in the culture
      supernatant of vIL-6-expressing cells compared with controls, and
      immunohistochemical staining detected VEGF in spleen, lymph nodes, and tumor
      tissues from mice bearing vIL-6-producing tumors but not control tumors. Thus,
      vIL-6 is a multifunctional cytokine that promotes hematopoiesis, plasmacytosis,
      and angiogenesis. Through these functions, vIL-6 may play an important role in
      the pathogenesis of certain KSHV-associated disorders.

PMID- 10361101
TI  - Reactivation and persistence of human herpesvirus-8 infection in B cells and
      monocytes by Th-1 cytokines increased in Kaposi's sarcoma.
AB  - Patients with Kaposi's sarcoma (KS) have a human herpesvirus-8 (HHV-8) load
      higher than patients without KS and present a CD8(+) T-cell activation with
      production of Th1-type cytokines both in tissues and peripheral blood mononuclear
      cells (PBMC). Because in tissues of KS patients detection of inflammatory
      cytokines (IC) can precede detection of HHV-8 DNA and because signs of
      immunoactivation and/or dysregulation can precede KS development, we investigated
      the effect of IC on HHV-8 infection. To achieve this goal, PBMC and purified cell
      populations from 45 patients with KS and 45 patients at risk of KS were analyzed
      for HHV-8 DNA and/or gene expression and for cell survival, growth, and phenotype
      before or after culture with or without the IC increased in KS. The results
      indicate that PBMC that are polymerase chain reaction (PCR)-positive at day 0
      generally loose the virus upon culture. However, the presence of IC maintains HHV
      8 DNA load in cultured cells. In addition, IC increase viral load to detectable
      levels in PBMC from serologically positive patients that were PCR-negative before
      culture. gamma Interferon is sufficient for these effects, whereas tumor necrosis
      factor and interleukin-6 have little or no activity. The increase of HHV-8 DNA by
      IC is observed after short-term (7 days) or long-term (28 days) culture of the
      cells and occurs in one or both of the two circulating cell types that are
      infected in vivo: B cells and monocytes. In both cases it is associated with
      lytic gene expression, suggesting that virus reactivation is one of the most
      likely mechanisms for the effect of IC on virus load. However, IC have also
      effects on the cells target of HHV-8 infection, because they increase B-cell
      survival and induce the growth and differentiation of monocytes into KS-like
      spindle cells with markers of endothelial macrophages. Because cells with markers
      of endothelial macrophages are present in blood and lesions from KS patients and
      are infected by HHV-8, these data may explain the high HHV-8 load associated with
      KS development and suggest that infected monocytes may carry the virus to
      tissues, transmit the infection, or differentiate in loco in spindle cells with
      endothelial macrophage markers.

PMID- 10361102
TI  - DNA methylation.

PMID- 10361104
TI  - Ig heavy chain gene rearrangements in T-cell acute lymphoblastic leukemia exhibit
      predominant DH6-19 and DH7-27 gene usage, can result in complete V-D-J
      rearrangements, and are rare in T-cell receptor alpha beta lineage.
AB  - Rearranged IGH genes were detected by Southern blotting in 22% of 118 cases of T
      cell acute lymphoblastic leukemia (ALL) and involved monoallelic and biallelic
      rearrangements in 69% (18/26) and 31% (8/26) of these cases, respectively. IGH
      gene rearrangements were found in 19% (13/69) of CD3(-) T-ALL and in 50% of
      TCRgammadelta+ T-ALL (12/24), whereas only a single TCRalpha beta+ T-ALL (1/25)
      displayed a monoallelic IGH gene rearrangement. The association with the T-cell
      receptor (TCR) phenotype was further supported by the striking relationship
      between IGH and TCR delta (TCRD) gene rearrangements, ie, 32% of T-ALL (23/72)
      with monoallelic or biallelic TCRD gene rearrangements had IGH gene
      rearrangements, whereas only 1 of 26 T-ALL with biallelic TCRD gene deletions
      contained a monoallelic IGH gene rearrangement. Heteroduplex polymerase chain
      reaction (PCR) analysis with VH and DH family-specific primers in combination
      with a JH consensus primer showed a total of 39 clonal products, representing 7
      (18%) VH-(DH-)JH joinings and 32 (82%) DH-JH rearrangements. Whereas the usage of
      VH gene segments was seemingly random, preferential usage of DH6-19 (45%) and DH7
      27 (21%) gene segments was observed. Although the JH4 and JH6 gene segments were
      used most frequently (33% and 21%, respectively), a significant proportion of
      joinings (28%) used the most upstream JH1 and JH2 gene segments, which are rarely
      used in precursor-B-ALL and normal B cells (1% to 4%). In conclusion, the high
      frequency of incomplete DH-JH rearrangements, the frequent usage of the more
      downstream DH6-19 and DH7-27 gene segments, and the most upstream JH1 and JH2
      gene segments suggests a predominance of immature IGH rearrangements in immature
      (non-TCRalpha beta+) T-ALL as a result of continuing V(D)J recombinase activity.
      More mature alpha beta-lineage T-ALL with biallelic TCRD gene deletions
      apparently have switched off their recombination machinery and are less prone to
      cross-lineage IGH gene rearrangements. The combined results indicate that IGH
      gene rearrangements in T-ALL are postoncogenic processes, which are absent in T
      ALL with deleted TCRD genes and completed TCR alpha (TCRA) gene rearrangements.

PMID- 10361103
TI  - Granulocyte colony-stimulating factor-mobilized allogeneic stem cell
      transplantation maintains graft-versus-leukemia effects through a perforin
      dependent pathway while preventing graft-versus-host disease.
AB  - Minimization of graft-versus-host disease (GVHD) with preservation of the graft
      versus-leukemia (GVL) effect is a crucial step to improve the overall survival of
      allogeneic bone marrow transplantation (BMT) for patients with hematological
      malignancies. We and other investigators have shown that granulocyte colony
      stimulating factor (G-CSF)-mobilized allogeneic peripheral stem cell
      transplantation (PBSCT) reduces the severity of acute GVHD in murine models. In
      this study, we investigated whether G-CSF-mobilized PBSC maintain their GVL
      effect in a murine allogeneic transplant model (B6 --> B6D2F1). B6 mice (H-2(b))
      were injected subcutaneously with human G-CSF (100 micrograms/kg/d) for 6 days
      and their splenocytes were harvested on day 7 as a source of PBSC. G-CSF
      mobilization dramatically improved transplant survival compared with nonmobilized
      controls (95% v 0%, P <.001). Systemic levels of lipopolysaccharide and tumor
      necrosis factor-alpha were markedly reduced in recipients of allogeneic G-CSF
      mobilized donors, but cytolytic T lymphocyte (CTL) activity against host tumor
      target cells p815 was retained in those recipients. When leukemia was induced in
      recipients by coinjection of p815 tumor cells (H-2(d)) at the time of
      transplantation, all surviving recipients of G-CSF-mobilized B6 donors were
      leukemia-free at day 70 after transplant, whereas all mice who received T-cell
      depleted (TCD) splenocytes from G-CSF-mobilized B6 donors died of leukemia. When
      splenocytes from G-CSF-mobilized perforin-deficient (pfp-/-) mice were used for
      transplantation, 90% of recipients died of leukemia, demonstrating that perforin
      is a crucial pathway mediating GVL effects after G-CSF-mobilized PBSCT. These
      data illustrate that G-CSF-mobilized allogeneic PBSCT separate GVL from GVHD by
      preserving perforin-dependent donor CTL activity while reducing systemic
      inflammation.

PMID- 10361105
TI  - Altered multidrug resistance phenotype caused by anthracycline analogues and
      cytosine arabinoside in myeloid leukemia.
AB  - The expression of P-glycoprotein (Pgp) is often increased in acute myeloid
      leukemia (AML). However, little is known of the regulation of Pgp expression by
      cytotoxics in AML. We examined whether Pgp expression and function in leukemic
      blasts was altered after a short exposure to cytotoxics. Blasts were isolated
      from 19 patients with AML (15 patients) or chronic myeloid leukemia in blastic
      transformation (BT-CML, 4 patients). Pgp expression and function were analyzed by
      flow cytometric analysis of MRK 16 binding and Rhodamine 123 retention,
      respectively. At equitoxic concentrations, ex vivo exposure for 16 hours to the
      anthracyclines epirubicin (EPI), daunomycin (DAU), idarubicin (IDA), or MX2 or
      the nucleoside analogue cytosine arabinoside (AraC) differentially upregulated
      MDR1/Pgp expression in Pgp-negative and Pgp-positive blast cells. In Pgp-negative
      blasts, all four anthracyclines and AraC significantly increased Pgp expression
      (P =.01) and Pgp function (P =.03). In contrast, MX2, DAU, and AraC were the most
      potent in inducing Pgp expression and function in Pgp positive blasts (P <.05). A
      good correlation between increased Pgp expression and function was observed in
      Pgp-negative (r =.90, P =.0001) and Pgp-positive blasts (r =.77, P =.0002). This
      increase in Pgp expression and function was inhibited by the addition of 1
      micromol/L PSC 833 to blast cells at the time of their exposure to these
      cytotoxics. In 1 patient with AML, an increase in Pgp levels was observed in vivo
      at 4 and 16 hours after the administration of standard chemotherapy with
      DAU/AraC. Upregulation of Pgp expression was also demonstrated ex vivo in blasts
      harvested from this patient before the commencement of treatment. In 3 other
      cases (1 patient with AML and 2 with BT-CML) in which blasts were Pgp negative at
      the time of initial clinical presentation, serial samples at 1 to 5 months after
      chemotherapy showed the presence of Pgp-positive blasts. All 3 patients had
      refractory disease. Interestingly, in all 3 cases, upregulation of Pgp by
      cytotoxics was demonstrated ex vivo in blasts harvested at the time of
      presentation. These data suggest that upregulation of the MDR1 gene may represent
      a normal response of leukemic cells to cytotoxic stress and may contribute to
      clinical drug resistance.

PMID- 10361106
TI  - Purified photoproducts of merocyanine 540 trigger cytochrome C release and
      caspase 8-dependent apoptosis in human leukemia and melanoma cells.
AB  - If the interplay between caspase proteases and mitochondria decide the fate of
      the cell during apoptosis, they may constitute useful molecular targets for novel
      drug design. We have shown that photoactivated merocyanine 540 (pMC540) triggers
      caspase-mediated apoptosis in HL60 leukemia and M14 melanoma cells. Because
      pMC540 is a mixture of photoproducts, we set out to purify the biologically
      active component(s) from this mixture and to investigate their ability to
      directly activate intracellular caspases and/or trigger mitochondrial events
      associated with apoptosis. Two photoproducts, namely C1 and C2, purified and
      characterized by mass spectroscopy and nuclear magnetic resonance (NMR) analysis,
      effectively induced apoptosis in HL60 and M14 cells. Interestingly, both C1 and
      C2 induced non-receptor-dependent activation of caspase 8, which was responsible
      for the downstream activation of caspase 3 and cell death. Both compounds induced
      the release of cytochrome C from mitochondria of tumor cells and from purified
      rat liver mitochondria; however, different mechanisms were operative in
      cytochrome C translocation in response to C1 or C2. C1-induced cytochrome C
      release was mediated by the mitochondrial permeability transition (MPT) pore and
      accompanied by a decrease in mitochondrial transmembrane potential (triangle
      uppsim), whereas cytochrome C release in response to C2 was independent of MPT
      pore opening. These findings do not exclude the possibility that changes in
      mitochondrial triangle uppsim are critical for apoptosis in some instances, but
      support the notion that this may not be a universal step in the apoptotic
      process. Thus, identification of two novel anticancer agents that directly
      activate effector components of the apoptotic pathway could have potential
      implications for the development of newer chemotherapeutic drugs.

PMID- 10361107
TI  - Final height of patients who underwent bone marrow transplantation for
      hematological disorders during childhood: a study by the Working Party for Late
      Effects-EBMT.
AB  - Few data are available on the long-term effect of bone marrow transplantation
      (BMT) on growth. This study examines those factors that play a role in the final
      height outcome of patients who underwent BMT during childhood. Data on 181 of 230
      patients with aplastic anemia, leukemias, and lymphomas who had BMT before
      puberty (mean age, 9.8 +/- 2.6 years) and who had reached their final height were
      analyzed. An overall decrease in final height standard deviation score (SDS)
      value was found compared with the height at BMT (P < 10(7)) and with the genetic
      height (P < 10(7)). Girls did better than boys, and the younger in age the person
      was at time of BMT, the greater the loss in height. Previous cranial irradiation
      + single-dose total body irradiation (TBI) caused the greatest negative effect on
      final height achievement (P < 10(4)). Fractionation of TBI reduces this effect
      significantly and conditioning with busulfan and cyclophosphamide seems to
      eliminate it. The type of transplantation, graft-versus-host disease, growth
      hormone, or steroid treatment did not influence final height. Irradiation, male
      gender and young age at BMT were found to be major factors for long-term height
      loss. Nevertheless, the majority of patients (140/181) have reached adult height
      within the normal range of the general population.

PMID- 10361108
TI  - Double induction strategy for acute myeloid leukemia: the effect of high-dose
      cytarabine with mitoxantrone instead of standard-dose cytarabine with
      daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative
      Group.
AB  - Early intensification of chemotherapy with high-dose cytarabine either in the
      postremission or remission induction phase has recently been shown to improve
      long-term relapse-free survival (RFS) in patients with acute myeloid leukemia
      (AML). Comparable results have been produced with the double induction strategy.
      The present trial evaluated the contribution of high-dose versus standard-dose
      cytarabine to this strategy. Between March 1985 and November 1992, 725 eligible
      patients 16 to 60 years of age with newly diagnosed primary AML entered the
      trial. Before treatment started, patients were randomized between two versions of
      double induction: 2 courses of standard-dose cytarabine (ara-C) with daunorubicin
      and 6-thioguanine (TAD) were compared with 1 course of TAD followed by high-dose
      cytarabine (3 g/m2 every 12 hours for 6 times) with mitoxantrone (HAM). Second
      courses started on day 21 before remission criteria were reached, regardless of
      the presence or absence of blast cells in the bone marrow. Patients in remission
      received consolidation by TAD and monthly maintenance with reduced TAD courses
      for 3 years. The complete remission (CR) rate in the TAD-TAD compared with the
      TAD-HAM arm was 65% versus 71% (not significant [NS]), and the early and
      hypoplastic death rate was 18% versus 14% (NS). The corresponding RFS after 5
      years was 29% versus 35% (NS). An explorative analysis identified a subgroup of
      286 patients with a poor prognosis representing 39% of the entire population;
      they included patients with more than 40% residual blasts in the day-16 bone
      marrow, patients with unfavorable karyotype, and those with high levels of serum
      lactate dehydrogenase. Their CR rate was 65% versus 49% (p =.004) in favor of TAD
      HAM and was associated with a superior event-free survival (median, 7 v 3 months;
      5 years, 17% v 12%; P =.012) and overall survival (median, 13 v 8 months; 5
      years, 24% v 18%; P =.009). This suggests that the incorporation of high-dose
      cytarabine with mitoxantrone may contribute a specific benefit to poor-risk
      patients that, however, requires further substantiation. Double induction,
      followed by consolidation and maintenance, proved a safe and effective strategy
      and a new way of delivering early intensification treatment for AML.

PMID- 10361109
TI  - Cladribine activity in adult langerhans-cell histiocytosis.
AB  - Langerhans-cell histiocytosis (LCH) results from the accumulation of tissue
      histiocytes derived from the same progenitor cells as monocytes. Because
      cladribine is potently toxic to monocytes, we conducted a phase II trial of
      cladribine. Cladribine was administered to 13 LCH patients at 0.14 mg/kg per day
      by 2-hour intravenous infusion for 5 consecutive days, every 4 weeks for a
      maximum of six courses. Median age was 42 years (range, 19 to 72) and median
      pretreatment disease duration was 99 months (range, 6 to 252). One patient was
      untreated, one had received prior prednisone only, one prior radiation only, six
      prior radiation and chemotherapy, and four prior surgery, radiation, and
      chemotherapy. Seven patients had cutaneous involvement, six multifocal osseous,
      six pulmonary, two each with soft tissue and nodal involvement, and four had
      diabetes insipidus. Of 13 patients, 12 were evaluable for response and all for
      toxicity. After a median of three courses (range, 1 to 6), seven (58%) patients
      achieved complete responses (two pathologic and five clinical) and two (17%)
      patients achieved partial responses; overall response rate, 75%. Median response
      follow-up duration was 33 months (range, 1 to 65). Seven patients experienced
      grade 3 to 4 neutropenia. Only one patient had a documented infection, dermatomal
      herpes zoster. At a median follow-up of 42 months (range, 5 to 76), 12 patients
      remain alive and one patient has died. Thus, cladribine has major activity in
      adult LCH and warrants further investigation in both pediatric and adult LCH as a
      single agent and in combination with other drugs.

PMID- 10361110
TI  - Presenting white blood cell count and kinetics of molecular remission predict
      prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid:
      result of the Randomized MRC Trial.
AB  - All-trans retinoic acid (ATRA) is an essential component of the treatment of
      acute promyelocytic leukemia (APL), but the optimal timing and duration remain to
      be determined. Molecular characterization of this disease can refine the
      diagnosis and could be potentially useful in monitoring response to treatment.
      Patients defined morphologically to have APL were randomized to receive a 5-day
      course of ATRA before commencing chemotherapy or to receive daily ATRA commencing
      with chemotherapy and continuing until complete remission (CR). The chemotherapy
      was that used in current MRC Leukaemia Trials. Outcome comparisons were by
      intention to treat with additional analysis for relevant risk factors. Patients
      were characterized by molecular techniques for the fusion products of the
      t(15;17) and monitored by reverse transcriptase-polymerase chain reaction (RT
      PCR) during and after treatment. Two hundred thirty-nine patients were
      randomized. Treatment with extended ATRA resulted in a superior remission rate
      (87% v 70%, P <.001), due to fewer early and induction deaths (12% v 23%, P
      =.02), and less resistant disease (2% v 7%, P =.03), which was associated with a
      significantly more rapid recovery of neutrophils and platelets. Extended ATRA
      reduced relapse risk (20% v 36% at 4 years, P =.04) and resulted in superior
      survival (71% v 52% at 4 years, P =.005). Presenting white blood cell count (WBC)
      was a key determinant of outcome. The 70% of patients who presented with a WBC
      less than 10 x 10(9)/L had a better CR (85% v 62%, P =.0001) and reduced relapse
      risk (22% v 42%, P =.002) and superior survival (69% v 43%, P <. 0001). Within
      the low count group, extended ATRA resulted in a better CR (94% v 76%, P =.001),
      reduced relapse risk (13% v 35%, P =. 04), and improved survival (80% v 57%, P
      =.0009). There was no evidence of benefit in patients presenting with a higher
      WBC (>10 x 10(9)/L). Molecular monitoring after the third chemotherapy course had
      a correlation with risk of relapse. The relapse risk was 57% if the RT-PCR was
      positive versus 27% if the RT-PCR was negative (P =. 006). APL patients who
      present with a low WBC derive substantial benefit from combining ATRA with
      induction chemotherapy until remission is achieved, whereas patients with a
      higher WBC did not benefit. Molecular characterization of disease can improve
      diagnostic precision and a positive RT-PCR after consolidation identifies
      patients at a higher risk of relapse.

PMID- 10361111
TI  - Serum hyaluronan in patients with multiple myeloma: correlation with survival and
      Ig concentration.
AB  - Serum from 386 myeloma patients were analyzed for serum hyaluronan (HYA) at
      diagnosis. Median age was 68 years (range, 32 to 87 years). The distribution of
      Ig classes was typical (58% IgG, 21% IgA, 1% IgD, and 20% light chain disease).
      The patients comprised 58% in stage III, 33% in stage II, and 9% in stage I. The
      majority (82%) had HYA values within an intermediate range (10 to 120
      micrograms/L), 13% had high values (>120 micrograms/L), and 5% had abnormally low
      values (0 to 9 micrograms/L). For the first time, a patient group with abnormally
      low HYA serum values is reported. An inverse correlation between survival and HYA
      serum level was found (P =.015). When tested separately, patients with abnormally
      low or high HYA values had significantly shorter median survival (21.1 and 19.7
      months, respectively) than those with an intermediate HYA concentration (32. 6
      months; P =.005). Patients with abnormally low or high HYA levels had more
      advanced disease as judged by staging and biochemical markers. Interestingly,
      there was an inverse correlation between the HYA value and the M-component
      concentration in serum. Fifty percent of patients with abnormally low HYA values
      had IgA myelomas. In conclusion, the serum concentration of HYA may be of
      prognostic value in selected cases of multiple myeloma. Further studies will be
      performed to elucidate possible explanations for our findings, especially those
      related to the HYA cell surface binding proteins.

PMID- 10361112
TI  - Sequential homoharringtonine and interferon-alpha in the treatment of early
      chronic phase chronic myelogenous leukemia.
AB  - Homoharringtonine (HHT) is a novel plant alkaloid that produced a complete
      hematologic remission (CHR) in 72% of patients with late chronic phase chronic
      myelogenous leukemia (CML). Cytogenetic (CG) remissions were noted in 31%. In
      this study, six courses of HHT were administered to 90 patients with early
      chronic phase CML (< 1 year from diagnosis). Patients then received interferon
      alpha (IFN-alpha) with a target dose of 5 MU/m2 daily. Results were compared with
      those in a prior group of patients treated with IFN-alpha-based therapy between
      1982 and 1990. Ninety-two percent of patients achieved CHR with HHT; CG responses
      were observed in 60% and were major in 27%. Both CHR and CG response rates were
      significantly higher than those seen in historical control patients after 6
      months of IFN-alpha therapy. After receiving HHT, patients required lower doses
      of IFN-alpha to maintain a CHR. The median dose delivered was 2.4 MU/m2. This
      reduction in IFN-alpha dose was associated with a lower incidence of myalgia and
      gastrointestinal (GI) disturbances than that seen in patients treated at the 5
      MU/m2 dose. Overall, CG responses were seen in 66% of the patients who received
      HHT and IFN-alpha compared with 61% of the historical control patients. HHT is a
      very effective treatment of early chronic phase CML, and ongoing trials are
      investigating the simultaneous administration of HHT and IFN-alpha, as well as
      that of HHT and low-dose cytosine arabinoside in patients failing IFN-alpha
      therapy.

PMID- 10361114
TI  - Expression of p21(Cip1/Waf1/Sdi1) and p27(Kip1) cyclin-dependent kinase
      inhibitors during human hematopoiesis.
AB  - Expression of p21 and p27 cyclin-dependent kinase inhibitors is associated with
      induced differentiation and cell-cycle arrest in some hematopoietic cell lines.
      However, it is not clear how these inhibitors are expressed during normal
      hematopoiesis. We examined various human hematopoietic colonies derived from cord
      blood CD34(+) cells, bone marrow, and peripheral blood cells using a quantitative
      reverse transcription-polymerase chain reaction assay, immunochemistry, and/or
      Western blot analysis. p21 mRNA was expressed increasingly over time in all of
      the colonies examined (granulocytes, macrophages, megakaryocytes, and
      erythroblasts), whereas p27 mRNA levels remained low, except for erythroid
      bursts. Erythroid bursts expressed both p21 and p27 mRNAs with differentiation
      but expressed neither protein, whereas both proteins were expressed in
      megakaryocytes and peripheral blood monocytes. In bone marrow, p21 was
      immunostained almost exclusively in a subset of megakaryocytes and p27 protein
      was present in megakaryocytes, plasma cells, and endothelial cells. In
      megakaryocytes, reciprocal expression of p27 to Ki-67 was evident and an inverse
      relationship between p21 and Ki-67 positivities was also present, albeit less
      obvious. These observations suggest that a complex lineage-specific regulation is
      involved in p21 and p27 expression and that these inhibitors are involved in cell
      cycle exit in megakaryocytes.

PMID- 10361113
TI  - Dominant negative mutants implicate STAT5 in myeloid cell proliferation and
      neutrophil differentiation.
AB  - STAT5 is a member of the signal transducers and activation of transcription
      (STAT) family of latent transcription factors activated in a variety of cytokine
      signaling pathways. We introduced alanine substitution mutations in highly
      conserved regions of murine STAT5A and studied the mutants for dimerization, DNA
      binding, transactivation, and dominant negative effects on erythropoietin-induced
      STAT5-dependent transcriptional activation. The mutations included two near the
      amino-terminus (W255KR-->AAA and R290QQ-->AAA), two in the DNA-binding domain
      (E437E-->AA and V466VV-->AAA), and a carboxy-terminal truncation of STAT5A
      (STAT5A/triangle up53C) analogous to a naturally occurring isoform of rat STAT5B.
      All of the STAT mutant proteins were tyrosine phosphorylated by JAK2 and
      heterodimerized with STAT5B except for the WKR mutant, suggesting an important
      role for this region in STAT5 for stabilizing dimerization. The WKR, EE, and VVV
      mutants had no detectable DNA-binding activity, and the WKR and VVV mutants, but
      not EE, were defective in transcriptional induction. The VVV mutant had a
      moderate dominant negative effect on erythropoietin-induced STAT5 transcriptional
      activation, which was likely due to the formation of heterodimers that are
      defective in DNA binding. Interestingly, the WKR mutant had a potent dominant
      negative effect, comparable to the transactivation domain deletion mutant,
      triangle up53C. Stable expression of either the WKR or triangle up53C STAT5
      mutants in the murine myeloid cytokine-dependent cell line 32D inhibited both
      interleukin-3-dependent proliferation and granulocyte colony-stimulating factor
      (G-CSF)-dependent differentiation, without induction of apoptosis. Expression of
      these mutants in primary murine bone marrow inhibited G-CSF-dependent granulocyte
      colony formation in vitro. These results demonstrate that mutations in distinct
      regions of STAT5 exert dominant negative effects on cytokine signaling, likely
      through different mechanisms, and suggest a role for STAT5 in proliferation and
      differentiation of myeloid cells.

PMID- 10361115
TI  - Different effect of various mutant MITF encoded by mi, Mior, or Miwh allele on
      phenotype of murine mast cells.
AB  - The mi locus encodes a member of the basic-helix-loop-helix-leucine zipper
      protein family of transcription factors (hereafter called MITF). Mutant alleles
      of mi, Mior, and Miwh are deletion or point mutation of the basic domain by which
      MITF binds DNA. The basic domain also has nuclear localization potential. In the
      present study, we compared the mast cell abnormalities of Mior/Mior and Miwh/Miwh
      mice with those of mi/mi mice, of which many have been described by us. The
      number of mast cells in the skin of Mior/Mior suckling mice was remarkably
      decreased from that observed in mi/mi suckling mice, but the number was normal in
      the skin of Miwh/Miwh suckling mice. The decrease in skin mast cells was more
      severe in the mi/mi embryos than in mi/mi suckling mice, but the magnitude of the
      decrease was comparable between Mior/Mior embryos and Mior/Mior suckling mice.
      The poor mRNA expression of granzyme B and tryptophan hydroxylase genes was
      observed in all cultured mast cells (CMCs) derived from the spleens of Miwh/Miwh,
      Mior/Mior, and mi/mi mice. However, the poor expression of mouse mast cell
      protease-4 (MMCP-4), MMCP-5, and MMCP-6 was observed only in Mior/Mior and mi/mi
      CMCs. MITF encoded by Miwh mutant allele (Miwh-MITF) showed deficient but
      demonstratable DNA binding, but mi-MITF and Mior-MITF did not show any DNA
      binding ability. Although Miwh-MITF and Mior-MITF showed normal nuclear
      localization potential, the potential was significantly impaired in mi-MITF. The
      rank order of mast cell abnormality (mi/mi > Mior/Mior > Miwh/Miwh) appears to be
      related to the functional abnormality of MITF encoded by each mutant gene.

PMID- 10361116
TI  - Differentiation in culture of murine primitive lymphohematopoietic progenitors
      toward T-cell lineage.
AB  - Earlier, we described a stromal cell-free two-step clonal culture system in which
      murine primitive lymphohematopoietic progenitors produce myeloid and B-lymphoid
      lineage cells. In the same culture T-cell potential of the progenitors was
      maintained. We now report that, in addition to myeloid and B-lymphoid cells,
      putative T-cell progenitors are also produced in culture. Lineage-negative (Lin-)
      Ly-6A/E+ c-kit+ bone marrow cells from 5-fluorouracil-treated mice were cultured
      in methylcellulose in the presence of SF (Steel factor), interleukin (IL)-11, and
      IL-7, and the resulting primary colonies were picked and pooled. When injected
      into severe combined immune deficiency (scid) mice, the pooled cells
      reconstituted the T-cell compartment of the scid mice earlier than freshly
      prepared primitive marrow cells. This reconstitution activity of the pooled
      primary colony cells was enriched in the Ly-6A/E+ and FcgammaRII/III-/low cell
      fractions. Reverse transcriptase-polymerase chain reaction (RT-PCR) and DNA-PCR
      analyses showed that some of the primary colony cells are differentiated
      sufficiently to express messenger RNA (mRNA) of T-cell receptor (TCR) beta-chain
      and pre-TCR alpha (pTalpha) and, although not frequently, to perform Dbeta-Jbeta
      rearrangement of the TCR gene. Micromanipulation studies confirmed the clonal
      origin of myeloid lineage cells and the cells positive for the T-cell-specific
      transcripts and D-J rearrangement of TCR beta-chain. These results suggested
      that, in the presence of SF, IL-11, and IL-7, primitive lymphohematopoietic
      progenitors differentiate toward T-cell lineage in addition to myeloid and B-cell
      lineages.

PMID- 10361117
TI  - The mouse GATA-2 gene is expressed in the para-aortic splanchnopleura and aorta
      gonads and mesonephros region.
AB  - We previously reported that the mouse GATA-2 gene is regulated by two alternative
      promoters (Minegishi et al, J Biol Chem, 273:3625, 1998). Although the more
      proximal IG (general) promoter is active in almost all GATA-2-expressing cells,
      the distal IS (specific) promoter activity was selectively detected in
      hematopoietic tissues but not in other mesodermal tissues. We report here in vivo
      analysis of the GATA-2 locus and its regulatory characteristics in hematopoietic
      tissues of transgenic mice. Transgenes containing 6 or 7 kbp of sequence flanking
      the 5' end of the IS first exon direct expression of beta-galactosidase or green
      fluorescent protein (GFP) reporter genes specifically to the para-aortic
      splanchnopleura, aorta-gonads, and mesonephros (AGM) region, and in the neural
      tissues. In situ hybridization analysis showed that reporter gene expression
      specifically recapitulates the endogenous expression profile of GATA-2 in these
      tissues. The flk-1, CD34, c-kit, and CD45 antigens were identified in the GFP
      positive cells from the AGM region and fetal liver, indicating that GATA-2 is
      expressed in immature hematopoietic cells. Deletion of 3.5 kbp from the 5' end of
      the 6.0 kbp IS promoter construct, including one of the DNase I hypersensitive
      sites, completely abolished hematopoietic expression. These experiments describe
      an early developmental GATA-2 hematopoietic enhancer located between 6.0 and 2.5
      kbp 5' to the IS exon.

PMID- 10361118
TI  - Mpl ligand enhances the transcription of the cyclin D3 gene: a potential role for
      Sp1 transcription factor.
AB  - Cyclin D3 plays a major role in the development of polyploidy in megakaryocytes.
      The expression of cyclin D3 gene and the level of cyclin D3 protein are increased
      by the Mpl ligand in the Y10/L8057 megakaryocytic cell line, as indicated by
      Northern and Western blot analyses, and by nuclear run-on assays and transfection
      experiments with cyclin D3 promoter constructs. DNase I footprinting of the
      promoter region showed protected segments, at -75 to -60 bp and at -134 to -92
      bp, which display binding sites for the Sp family of transcription factors. Gel
      mobility shift assay and supershifts with specific antibodies indicate that Sp1
      binds to these regions in the cyclin D3 promoter and that Sp1 binding activity is
      significantly increased by Mpl ligand. Mutation of either Sp1 site both decreases
      the basal promoter activity and eliminates the induction by Mpl ligand. We find
      that the nonphosphorylated form of SP1 has greater affinity for the cyclin D3
      promoter and that the majority of Sp1 in the cells is nonphosphorylated. Mpl
      ligand treatment results in increased levels of Sp1 protein, which also appears
      as nonphosphorylated. Okadaic acid, which inhibits protein phosphatase 1 (PP1)
      and shifts Sp1 to a phosphorylated form, decreases cyclin D3 gene expression and
      suppresses Mpl ligand induction. Our data point to the potential of Mpl ligand to
      activate at once several Sp1-dependent genes during megakaryopoiesis.

PMID- 10361119
TI  - Role of caspase in a subset of human platelet activation responses.
AB  - Platelets function to protect the integrity of the vascular wall. A subset of
      platelet activation responses that are especially important for thrombus
      formation include exposure of phosphatidylserine and release of microparticles,
      which generate procoagulant surfaces. The resemblance of these platelet
      activation processes to events occurring in nucleated cells undergoing apoptosis
      suggests a possible role for caspases, which are major effector enzymes of
      nucleated cell apoptosis. We demonstrate here the presence of caspase-3 in human
      platelets and its activation by physiological platelet agonists. Using cell
      permeable specific inhibitors, we demonstrate a role for a caspase-3-like
      protease in the agonist-induced (collagen plus thrombin or Ca2+ ionophore)
      platelet activation events of phosphatidylserine exposure, microparticle release,
      and cleavage of moesin, a cytoskeletal-membrane linker protein. The role of
      caspase-3 in platelet activation is restricted rather than global, because other
      activation responses, alpha granule secretion, shape change, and aggregation were
      unaffected by caspase-3 inhibitors. Experiments with two classes of protease
      inhibitors show that caspase-3 function is distinct from that of calpain, which
      is also involved in late platelet activation events. These findings show novel
      functions of caspase and provide new insights for understanding of platelet
      activation.

PMID- 10361121
TI  - Familial overexpression of beta antithrombin caused by an Asn135Thr substitution.
AB  - We have investigated the basis of antithrombin deficiency in an asymptomatic
      individual (and family) with borderline levels (approximately 70% antigen and
      activity) of antithrombin. Direct sequencing of amplified DNA showed a mutation
      in codon 135, AAC to ACC, predicting a heterozygous Asn135Thr substitution. This
      substitution alters the predicted consensus sequence for glycosylation, Asn-X
      Ser, adjacent to the heparin interaction site of antithrombin. The antithrombin
      isolated from plasma of the proband by heparin-Sepharose chromatography contained
      amounts of beta antithrombin (the very high affinity fraction) greatly increased
      (approximately 20% to 30% of total) above the trace levels found in normals.
      Expression of the residue 135 variant in both a cell-free system and COS-7 cells
      confirmed altered glycosylation arising as a consequence of the mutation. Wild
      type and variant protein were translated and exported from COS-7 cells with
      apparently equal efficiency, in contrast to the reduced level of variant observed
      in plasma of the affected individual. This case represents a novel cause of
      antithrombin deficiency, removal of glycosylation concensus sequence, and
      highlights the potentially important role of beta antithrombin in regulating
      coagulation.

PMID- 10361120
TI  - Infection with human immunodeficiency virus-1 increases expression of vascular
      endothelial cell growth factor in T cells: implications for acquired
      immunodeficiency syndrome-associated vasculopathy.
AB  - Alterations in the vascular system and the onset of angioproliferative lesions
      such as Kaposi's sarcoma (KS) are common traits of human immunodeficiency virus-1
      (HIV-1)-infected patients. To investigate possible factors involved in acquired
      immunodeficiency syndrome (AIDS)-associated vasculopathy and vascular
      malfunction, expression of vascular endothelial cell growth factor-A (VEGF-A) was
      analyzed in HUT 78 T lymphocytes upon infection with HIV-1. VEGF-A was found to
      be increased in supernatants from infected cells as compared with uninfected
      cells. In addition, VEGF-A mRNA expression and protein secretion were
      significantly increased in HUT 78 cells incubated with conditioned medium (CM)
      derived from HIV-1 chronically infected HUT 78 cells (HIV-TCM) as compared with
      CM from uninfected cells (TCM). Increase of VEGF-A production in T cells was
      promoted by inflammatory cytokines (IC) present in HIV-TCM, including tumor
      necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), interleukin-1beta
      (IL-1beta), and IL-6. These IC that have been shown to be increased in sera of
      HIV-1-infected patients and to be increased by HIV-1 infection or cell activation
      in these individuals as well as HIV-TCM also increased VEGF-A expression in
      primary T lymphocytes. Consistent with this, VEGF-A concentrations were found to
      be higher in sera of HIV-1-infected patients with (mean, 357.1 +/- 197.9 pg/mL)
      and without KS (mean, 256.7 +/- 137.5 pg/mL) as compared with uninfected
      individuals (mean, 188.6 +/- 91.7 pg/mL). These data suggest that increased
      secretion of VEGF-A by T lymphocytes of HIV-1-infected individuals may induce
      vascular leakage and stimulate proliferation of vascular endothelial cells, which
      are hallmarks of AIDS-associated vasculopathy and especially of KS development.

PMID- 10361122
TI  - Some anticardiolipin antibodies recognize a combination of phospholipids with
      thrombin-modified antithrombin, complement C4b-binding protein, and
      lipopolysaccharide binding protein.
AB  - The standard enzyme-linked immunosorbent assay (ELISA) for anticardiolipin
      antibodies (ACA) detects a heterogenous group of antibodies against cardiolipin
      on its own, beta2-glycoprotein I (beta2GPI), and, potentially, other phospholipid
      binding plasma proteins from bovine or human origin. In an attempt to identify
      new proteic targets of ACA, we selected 6 patients who possessed cofactor
      dependent ACA but no antibody to human or bovine beta2GPI detectable in the
      beta2GPI-ELISA. Three of these samples proved to recognize beta2GPI in
      combination with cardiolipin, but not beta2GPI directly immobilized on gamma
      irradiated polystyrene or agarose beads. In the other cases, the component
      required for ACA binding was purified from adult bovine serum or plasma by means
      of ammonium sulfate precipitation and chromatography on Phenyl-Sepharose, diethyl
      aminoethyl (DEAE)-cellulose, heparin-Ultrogel, and Sephacryl S-300 columns.
      Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis
      coupled to N-terminal amino acid microsequencing identified the cofactors of
      patients no. 4, 5, and 6 ACA as lipopolysaccharide binding protein (LBP),
      complement C4b-binding protein (C4BP), and the thrombin-antithrombin (AT)
      complex, respectively. Adsorption of each of these cofactor preparations with
      cardiolipin liposomes led to suppression of ACA reactivity, concomitant with the
      loss of bands from SDS gels corresponding to sequenced material. Bacterial
      lipopolysaccharide (which forms high-affinity complexes with LBP) specifically
      neutralized the cofactor activity of the LBP preparation in a concentration
      dependent manner. Bovine serum and plasma, as well as the C4BP preparation,
      optimally supported the binding of a rabbit anti-C4BP antiserum to immobilized
      cardiolipin. The binding of a rabbit anti-AT antiserum to solid-phase cardiolipin
      was sustained by the thrombin-AT preparation and bovine serum, but neither by
      bovine plasma nor by native AT, thus reproducing the behavior of patient no. 6
      ACA. Taking advantage of the restricted recognition by the latter ACA of a
      cofactor from bovine origin appearing upon clotting, we studied the generation of
      such activity in human plasma supplemented with bovine AT or bovine prothrombin
      before clotting. In these conditions, patient no. 6 antibody binding to
      cardiolipin required the addition of bovine AT, whereas addition of bovine
      prothrombin alone was ineffective. We therefore concluded that those ACA targeted
      bovine AT once it has been modified/cleaved by thrombin. These findings underline
      the wide heterogeneity of ACA and the links that may exist between various
      coagulation pathways, inflammation and the complement system.

PMID- 10361123
TI  - The glycoprotein Ib/IX complex regulates cell proliferation.
AB  - The glycoprotein (Gp) Ib/IX complex contains three transmembranous leucine-rich
      repeat polypeptides (GpIbalpha, GpIbbeta, and GpIX) that form the platelet von
      Willebrand factor (vWF) receptor. GpIb/IX functions to effect platelet adhesion,
      activation, and aggregation under conditions of high shear stress. GpIb/IX is
      expressed late in the ontogeny of megakaryocytes, the precursor cell that
      releases platelets when it reaches its terminal stage of differentiation. Because
      signal pathways can be reused at different stages of development by integration
      with different effector pathways and because cellular adhesion through other
      receptor families often modulates cell growth, the hypothesis that GpIb/IX
      regulates cell growth was investigated. The surface expression of recombinant
      GpIbalpha decreases the proliferation of transduced CHO cells. GpIbalpha causes
      growth arrest in the G1 phase of the cell cycle associated with the induction of
      the cyclin-dependent kinase inhibitor p21. G1 arrest induced by recombinant
      GpIbalpha in heterologous cells requires signaling through the 14-3-3zeta binding
      domain of GpIbalpha and is partially dependent on its engagement by the
      extracellular ligand vWF. Growth arrest induced by the expression of recombinant
      GpIb/IX is followed by apoptosis of the transduced cells. The endogenous
      expression of GpIbalpha in human hematopoietic cells is associated with decreased
      proliferation. These results suggest that the expression of the GpIb/IX complex
      regulates megakaryocyte growth.

PMID- 10361125
TI  - Variation at the von Willebrand factor (vWF) gene locus is associated with plasma
      vWF:Ag levels: identification of three novel single nucleotide polymorphisms in
      the vWF gene promoter.
AB  - Both genetic and environmental factors contribute to the normal population
      variability of plasma von Willebrand Factor (vWF) levels, however, regulatory
      mechanisms at the vWF gene locus itself have not yet been identified. We have
      investigated the association between polymorphic variation in the 5'-regulatory
      region of the vWF gene and levels of plasma vWF:Ag in a study of 261 group O
      blood donors. Three novel single nucleotide polymorphisms (SNPs) were identified
      in the vWF promoter: C/T at -1234, A/G at -1185, and G/A at -1051. These SNPs had
      identical allele frequencies of 0.36 for the -1234C, -1185A, and -1051G alleles
      and 0.64 for the -1234T, -1185G, and -1051A alleles and were in strong linkage
      disequilibrium. In fact, these polymorphisms segregated as two distinct
      haplotypes: -1234C/-1185A/-1051G (haplotype 1) and -1234T/-1185G/-1051A
      (haplotype 2) with 12.6% of subjects homozygous for haplotype 1, 40. 6%
      homozygous for haplotype 2, and 42.5% of subjects heterozygous for both
      haplotypes. Only 4.3% of individuals had other genotypes. A significant
      association between promoter genotype and level of plasma vWF:Ag was established
      (analysis of covariance [ANCOVA], P =. 008; Kruskal-Wallis test, P =.006);
      individuals with the CC/AA/GG genotype had the highest mean vWF:Ag levels (0.962
      U/mL), intermediate values of vWF:Ag (0.867 U/mL) were observed for heterozygotes
      (CT/AG/GA), and those with the TT/GG/AA genotype had the lowest mean plasma
      vWF:Ag levels (0.776 U/mL). Interestingly, when the sample was subgrouped
      according to age, the significant association between promoter genotype and
      plasma vWF:Ag level was accentuated in subjects > 40 years of age (analysis of
      variance [ANOVA], P =.003; Kruskal-Wallis test, P =.001), but was not maintained
      for subjects </= 40 years of age (ANOVA, P >.4; Kruskal-Wallis test, P >.4). In
      the former subgroup, mean levels of plasma vWF:Ag for subjects with the CC/AA/GG,
      CT/AG/GA, and TT/GG/AA genotypes were 1.075, 0.954, and 0.794 U/mL, respectively.
      By searching a transcription factor binding site profile database, these
      polymorphic sequences were predicted to interact with several transcription
      factors expressed in endothelial cells, including Sp1, GATA-2, c-Ets, and
      NFkappaB. Furthermore, the binding sites at the -1234 and -1051 SNPs appeared to
      indicate allelic preferences for some of these proteins. Electrophoretic mobility
      shift assays (EMSAs) performed with recombinant human NFkappaB p50 showed
      preferential binding of the -1234T allele (confirmed by supershift EMSAs), and
      EMSAs using bovine aortic endothelial cell (BAEC) nuclear extracts produced
      specific binding of a nuclear protein to the -1051A allele, but not the -1051G
      allele. These findings suggest that circulating levels of vWF:Ag may be
      determined, at least in part, by polymorphic variation in the promoter region of
      the vWF gene, and that this association may be mediated by differential binding
      of nuclear proteins involved in the regulation of vWF gene expression.

PMID- 10361124
TI  - Physical interaction between retinoic acid receptor and Sp1: mechanism for
      induction of urokinase by retinoic acid.
AB  - Induction of urokinase plasminogen activator (uPA) by retinoic acid (RA) is the
      initial event preceding certain subsequent biological changes in vascular
      endothelial cells. We investigated the molecular mechanism by which RA stimulates
      the expression of uPA, which lacks a canonical RA receptor (RAR)-responsive
      element, in bovine and human aortic endothelial cells. Upon stimulation with RA,
      mRNA levels of RARalpha and beta transiently increased in parallel with the
      induction of uPA, and this increase was inhibited by cycloheximide. Results of
      transient transfection of RAR/RXR cDNAs and experiments using specific agonists
      and antagonists suggested that uPA induction is dependent upon RAR (initially,
      RARalpha) with the help of RXRalpha. Deletion analysis of the uPA promoter
      suggested that RAR/RXR acts on GC box region within the uPA promoter. This was
      further supported by inhibition of Sp1 binding to this region.
      Coimmunoprecipitation studies, glutathione S-transferase pull-down experiment,
      and mammalian two-hybrid assays suggested a physical interaction between RAR/RXR
      and Sp1. Furthermore, gel shift studies showed that the binding of Sp1 to the uPA
      GC box is significantly potentiated in the presence of RARs/RXRs. Finally, Sp1
      and RAR/RXR synergistically enhanced the transactivation activity of the uPA
      promoter. These results suggest that (1) RA induces RARs mainly via RARalpha and
      that (2) RAR/RXR physically and functionally interact with Sp1, resulting in a
      potentiation of uPA transcription.

PMID- 10361126
TI  - Identification of vascular endothelial growth factor (VEGF) receptor-2 (Flk-1)
      promoter/enhancer sequences sufficient for angioblast and endothelial cell
      specific transcription in transgenic mice.
AB  - The vascular endothelial growth factor (VEGF) receptor-2 (Flk-1) is the first
      endothelial receptor tyrosine kinase to be expressed in angioblast precursors,
      and its function is essential for the differentiation of endothelial cells and
      hematopoietic precursors. We have identified cis-acting regulatory elements of
      the murine Flk-1 gene that mediate endothelium-specific expression of a LacZ
      reporter gene in transgenic mice. Sequences within the 5'-flanking region of the
      Flk-1 gene, in combination with sequences located in the first intron,
      specifically targeted transgene expression to angioblasts and endothelial cells
      of transgenic mice. The intronic regulatory sequences functioned as an autonomous
      endothelium-specific enhancer. Sequences of the 5'-flanking region contributed to
      a strong, uniform, and reproducible transgene expression and were stimulated by
      the transcription factor HIF-2alpha. The Flk-1 gene regulatory elements described
      in this study should allow the elucidation of the molecular mechanisms involved
      in endothelial cell differentiation and angiogenesis.

PMID- 10361127
TI  - Induction and suppression of endothelial cell apoptosis by sphingolipids: a
      possible in vitro model for cell-cell interactions between platelets and
      endothelial cells.
AB  - Because sphingosine (Sph) is actively incorporated into platelets and rapidly
      converted to sphingosine 1-phosphate (Sph-1-P), which is then released
      extracellularly, it is important to study the effects of Sph and Sph-1-P on
      endothelial cells from the viewpoint of platelet-endothelial cell interaction. In
      this study, we found that Sph, as well as ceramide, induces apoptosis in human
      umbilical vein endothelial cells (HUVECs). In contrast, Sph-1-P acts as a HUVEC
      survival factor; this bioactive lipid was shown to protect HUVECs from apoptosis
      induced by the withdrawal of growth factors and to stimulate HUVEC DNA synthesis.
      In metabolic studies, [3H]Sph, incorporated into HUVECs, was converted to [3H]Cer
      and further to [3H]sphingomyelin in a time-dependent manner, whereas [3H]Sph-1-P
      formation from [3H]Sph was weak and transient. These findings in HUVECs are very
      different from those of platelets, which possess a highly active Sph kinase but
      lack Sph-1-P lyase. As a result, platelets abundantly store Sph-1-P, whereas
      HUVECs contain much less Sph-1-P. Finally, HUVECs, in contrast to platelets,
      failed to release Sph-1-P extracellularly, indicating that HUVECs themselves are
      not able to supply the survival factor Sph-1-P, but receive it from activated
      platelets. Our results suggest that platelets may maintain the integrity of
      endothelial cells by incorporating Sph and releasing Sph-1-P.

PMID- 10361128
TI  - Factor XII Tenri, a novel cross-reacting material negative factor XII deficiency,
      occurs through a proteasome-mediated degradation.
AB  - A homozygous cross-reacting material negative factor XII-deficient patient with
      3% antigen and activity levels of factor XII was screened for the identification
      of a mutation at the genomic level. Low-ionic strength single-stranded
      conformation polymorphism (SSCP) analysis and sequence analysis showed that the
      proband's gene for factor XII had an A-->G substitution at nucleotide position
      7832 in exon 3, resulting in a Tyr34 to Cys substitution in the NH2-terminal type
      II domain of factor XII. We designated this mutation as factor XII Tenri.
      Mutagenic polymerase chain reaction (PCR), followed by KpnI digestion, showed a
      homozygous mutation in the proband's gene and heterozygous mutations in his
      parents and sister. Immunoprecipitation and Western blot analyses of plasma
      samples from the factor XII Tenri family indicated that the proband had a trace
      amount of variant factor XII with an apparent molecular mass of 115 kD, which was
      converted to the normal 80-kD form after reduction, suggesting that factor XII
      Tenri was secreted as a disulfide-linked heterodimer with a approximately 35-kD
      protein, which we identified as alpha1-microglobulin by immunoblotting. Pulse
      chase experiments using baby hamster kidney (BHK) cells showed that Tenri-type
      factor XII was extensively degraded intracellularly, but the addition of cystine
      resulted in increased secretion of the mutant. Using membrane-permeable
      inhibitors, we observed that the degradation occurred in the pre-Golgi,
      nonlysosomal compartment and a proteasome appeared to play a major role in this
      process. On the basis of these in vitro results, we speculate that the majority
      of the factor XII Tenri is degraded intracellularly through a quality control
      mechanism in the endoplasmic reticulum (ER), and a small amount of factor XII
      Tenri that formed a disulfide-linked heterodimer with alpha1-microglobulin is
      secreted into the blood stream.

PMID- 10361129
TI  - Identification of HLA-A2-restricted T-cell epitopes derived from the MUC1 tumor
      antigen for broadly applicable vaccine therapies.
AB  - The tumor-associated antigen MUC1 is overexpressed on various hematological and
      epithelial malignancies and is therefore a suitable candidate for broadly
      applicable vaccine therapies. It was demonstrated that major histocompatibility
      complex (MHC)-unrestricted cytotoxic T cells can recognize epitopes of the MUC1
      protein core localized in the tandem repeat domain. There is increasing evidence
      now that MHC-restricted T cells can also be induced after immunization with the
      MUC1 protein or segments of the core tandem repeat. Using a computer analysis of
      the MUC1 amino acid sequence, we identified two novel peptides with a high
      binding probability to the HLA-A2 molecule. One of the peptides is derived from
      the tandem repeat region and the other is derived from the leader sequence of the
      MUC1 protein, suggesting that, in contrast to previous reports, the MUC1-directed
      immune responses are not limited to the extracellular tandem repeat domain.
      Cytotoxic T cells (CTL) were generated from several healthy donors by primary in
      vitro immunization using peptide-pulsed dendritic cells. The addition of a Pan
      HLA-DR binding peptide PADRE as a T-helper epitope during the in vitro priming
      resulted in an increased cytotoxic activity of the MUC1-specific CTL and a higher
      production of cytokines such as interleukin-12 and interferon-gamma in the cell
      cultures, demonstrating the importance of CD4 cells for an efficient CTL priming.
      The peptide induced CTL lysed tumors endogenously expressing MUC1 in an antigen
      specific and HLA-A2-restricted fashion, including breast and pancreatic tumor
      cells as well as renal cell carcinoma cells, showing that these peptides are
      shared among many tumors. The use of MUC1-derived peptides could provide a
      broadly applicable approach for the development of dendritic cell-based
      vaccination therapies.

PMID- 10361130
TI  - Interleukin-9 regulates NF-kappaB activity through BCL3 gene induction.
AB  - BCL3 encodes a protein with close homology to IkappaB proteins and interacts with
      p50 NF-kappaB homodimers. However, the regulation and transcriptional activity of
      BCL3 remain ill-defined. We observed here that interleukin-9 (IL-9) and IL-4, but
      not IL-2 or IL-3, transcriptionally upregulated BCL3 expression in T cells and
      mast cells. BCL3 induction by IL-9 was detected as soon as 4 hours after
      stimulation and appeared to be dependent on the Jak/STAT pathway. IL-9
      stimulation was associated with an increase in p50 homodimers DNA binding
      activity, which was mimicked by stable BCL3 expression. This contrasts with tumor
      necrosis factor (TNF)-dependent NF-kappaB activation, which occurs earlier,
      involves p65/p50 dimers, and is dependent on IkappaB degradation. Moreover, IL-9
      stimulation or BCL3 transient transfection similarly inhibited NF-kappaB-mediated
      transcription in response to TNF. Taken together, our observations show a new
      regulatory pathway for the NF-kappaB transcription factors through STAT-dependent
      upregulation of BCL3 gene expression.

PMID- 10361131
TI  - Activated dendritic cells from bone marrow cells of mice receiving cytokine
      expressing tumor cells are associated with the enhanced survival of mice bearing
      syngeneic tumors.
AB  - Dendritic cells (DCs), which phagocytose antigens and subsequently proliferate
      and migrate, may be the most powerful antigen-presenting cells that activate
      naive T cells. To determine their role in the immune response to tumors, we used
      WEHI-3B murine leukemia cells transduced with adenovirus vectors expressing
      cytokines. We found that mixtures of irradiated cells expressing granulocyte
      macrophage colony-stimulating factor (GM-CSF) plus those expressing interleukin-4
      (IL-4) or tumor necrosis factor alpha (TNFalpha) protected mice against WEHI-3B
      induced leukemias. When bone marrow mononuclear cells (BMMNCs) obtained from mice
      that had been injected with irradiated, cytokine-expressing tumor cells were
      injected into tumor-bearing mice, the survival of the latter was significantly
      prolonged; the longest survival was observed in mice receiving BMMNCs containing
      an increased number of DCs from animals injected with a mixture of tumor cells
      expressing GM-CSF with those expressing IL-4. Assay for antileukemic effects in
      spleen of the latter animals showed specific antitumor cytotoxicity against WEHI
      3B, suggesting that DCs from donor mice activate specific T cells in the tumor
      bearing recipients. These results suggest that the infusion of syngeneic BMMNCs
      stimulated with cytokine-expressing tumor cells may be effective in treating
      certain types of tumors.

PMID- 10361132
TI  - The human (PsiL+mu-) proB complex: cell surface expression and biochemical
      structure of a putative transducing receptor.
AB  - The surrogate light chain (PsiL) associates with mu and Igalpha-Igbeta chains to
      form the preB-cell receptor that plays a critical role in early B-cell
      differentiation. Discrepancies exist in human concerning the existence of PsiL+mu
      proB cells and the biochemical structure of such a proB-cell complex remains
      elusive. Among new antihuman VpreB monoclonal antibodies (MoAbs), 5 of the gamma
      kappa isotype bound to recombinant and native VpreB protein with high affinity.
      They recognized 4 discrete epitopes, upon which 2 were in the extra-loop
      fragment. Such MoAbs detected the PsiL at the cell surface of either preB or on
      both proB and preB cells. The previously reported SLC1/SLC2 MoAbs recognize a
      conformational epitope specific for the mu/PsiL association in accordance with
      their preB-cell reactivity. Using the proB/preB 4G7 MoAb, PsiL cell surface
      expression was detected on normal bone marrow, not only on CD34(-)CD19(+) preB
      but also on CD34(+)CD19(+) proB cells. Futhermore, this MoAb identified PsiL+mu-
      fresh proB leukemic cells of the TEL/AML1 type. Biochemical studies showed that,
      at the proB stage, the PsiL is associated noncovalently with two proteins of 105
      and 130 kD. Triggering of this complex induces intracellular Ca2+ flux,
      suggesting that the PsiL may be involved in a new receptor at this early step of
      the B-cell differentiation.

PMID- 10361133
TI  - Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell
      malignancies.
AB  - Death-associated protein kinase (DAP-Kinase) is a novel serine/threonine kinase
      whose expression is required for gamma interferon-induced apoptosis. A previous
      study suggested that DAP-Kinase expression may be lost epigenetically in cancer
      cell lines, because treatment of several nonexpressing cell lines with 5-aza-2'
      deoxycytidine resulted in the expression of DAP-Kinase. Using methylation
      specific polymerase chain reaction (MSP), we examined the DAP-Kinase CpG island
      for hypermethylation in cancer. Normal lymphocytes and lymphoblastoid cell lines
      are unmethylated in the 5' CpG island of DAP-Kinase. However, in primary tumor
      samples, all Burkitt's lymphomas and 84% of the B-cell non-Hodgkin's lymphomas
      were hypermethylated in the DAP-Kinase CpG island. In contrast, none of the T
      cell non-Hodgkin's lymphoma samples and 15% or less of leukemia samples examined
      had hypermethylated DAP-Kinase alleles. U937, an unmethylated, DAP-Kinase
      expressing leukemia cell line, was treated with gamma interferon and underwent
      apoptosis; however, Raji, a fully methylated, DAP-Kinase nonexpressing Burkitt's
      lymphoma cell line, only did so when treated with 5-aza-2'-deoxycytidine followed
      by gamma interferon. Our findings in cell lines and primary tumors suggest that
      hypermethylation of the DAP-Kinase gene and loss of gamma interferon-mediated
      apoptosis may be important in the development of B-cell malignancies and may
      provide a promising biomarker for B-cell-lineage lymphomas.

PMID- 10361134
TI  - Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak
      Stat signaling.
AB  - To study constitutive Janus kinase signaling, chimeric proteins were generated
      between the pointed domain of the ets transcription factor TEL and the cytosolic
      tyrosine kinase Jak2. The effects of these proteins on interleukin-3 (IL-3)
      dependent proliferation of the hematopoietic cell line, Ba/F3, were studied.
      Fusion of TEL to the functional kinase (JH1) domain of Jak2 resulted in
      conversion of Ba/F3 cells to factor-independence. Importantly, fusion of TEL to
      the Jak2 pseudokinase (JH2) domain or a kinase-inactive Jak2 JH1 domain had no
      effect on IL-3-dependent proliferation of Ba/F3 cells. Active TEL-Jak2 constructs
      (consisting of either Jak2 JH1 or Jak2 JH2+JH1 domain fusions) were
      constitutively tyrosine-phosphorylated but did not affect phosphorylation of
      endogeneous Jak1, Jak2, or Jak3. TEL-Jak2 activation resulted in the constitutive
      tyrosine phosphorylation of Stat1, Stat3, and Stat5 as determined by detection of
      phosphorylation using activation-specific antibodies and by binding of each
      protein to a preferential GAS sequence in electrophoretic mobility shift assays.
      Elucidation of signaling events downstream of TEL-Jak2 activation may provide
      insight into the mechanism of leukemogenesis mediated by this oncogenic fusion
      protein.

PMID- 10361135
TI  - Increased number of chromosomal imbalances and high-level DNA amplifications in
      mantle cell lymphoma are associated with blastoid variants.
AB  - Mantle cell lymphomas (MCLs) are characterized by 11q13 chromosomal
      translocations and cyclin D1 overexpression. The secondary genetic and molecular
      events involved in the progression of these tumors are not well known. In this
      study, we have analyzed 45 MCLs (32 typical and 13 blastoid variants) by
      comparative genomic hybridization (CGH). To identify the possible genes included
      in the abnormal chromosome regions, selected cases were analyzed for P53,
      P16(INK4a), RB, C-MYC, N-MYC, BCL2, BCL6, CDK4, and BMI-1 gene alterations. The
      most frequent imbalances detected by CGH were gains of chromosomes 3q (49%), 7p
      (27%), 8q (22%), 12q (20%), 18q (18%), and 9q34 (16%) and losses of chromosomes
      13 (44%), 6q (27%), 1p (24%), 11q14-q23 (22%), 10p14-p15 (18%), 17p (16%), and 9p
      (16%). High-level DNA amplifications were identified in 11 different regions of
      the genome, predominantly in 3q27-q29 (13%), 18q23 (9%), and Xq28 (7%). The CGH
      analysis allowed the identification of regional consensus areas in most of the
      frequently involved chromosomes. Chromosome gains (P =. 02) and losses (P =.01)
      and DNA amplifications (P =.015) were significantly higher in blastoid variants.
      The significant differences between blastoid and typical tumors were gains of 3q,
      7p, and 12q, and losses of 17p. CGH losses of 17p correlated with P53 gene
      deletions and mutations. Similarly, gains of 12q and high-level DNA
      amplifications of 10p12-p13 were associated with CDK4 and BMI-1 gene
      amplifications, respectively. One of 2 cases with 8q24 amplification showed C-MYC
      amplification by Southern blot. Alterations in 2p, 3q, 13, and 18q were not
      associated with N-MYC, BCL6, RB, or BCL2 alterations, respectively, suggesting
      that other genes may be the targets of these genetic abnormalities in MCLs.
      Increased number of gains (0 v 1-4 v >4 gains per case) (P =.002), gains of 3q (P
      =.02), gains of 12q (P =.03), and losses of 9p (P =. 003) were significantly
      associated with a shorter survival of the patients. These results indicate that
      an increased number of chromosome imbalances are associated with blastoid
      variants of MCLs and may have prognostic significance.

PMID- 10361136
TI  - Sialoadhesin-positive host macrophages play an essential role in graft-versus
      leukemia reactivity in mice.
AB  - We recently established an effective immune T-cell-mediated graft-versus-leukemia
      (GVL) murine model system in which complete tumor remissions were achievable even
      in advanced metastasized cancer. We now describe that this T-cell-mediated
      therapy is dependent on host macrophages expressing the lymphocyte adhesion
      molecule sialoadhesin (Sn). Depletion of Kupffer cells in tumor-bearing mice
      during adoptive immunotherapy (ADI) or the treatment of these animals with anti
      Sn monoclonal antibodies led to complete or partial inhibition of the immune T
      cell-mediated therapeutic effect. Furthermore, Sn+ host macrophages in livers
      formed clusters during ADI with donor CD8 T cells. To test for a possible antigen
      presentation function of these macrophages, we used as an in vitro model the
      antigen beta-galactosidase for which a dominant major histocompatibility complex
      (MHC) class I Ld-restricted peptide epitope is known to be recognized by specific
      CD8 cytotoxic T lymphocytes (CTL). We demonstrate that purified Sn+ macrophages
      can process exogenous beta-galactosidase and stimulate MHC class I peptide
      restricted CTL responses. Thus, Sn+ macrophages, which are significantly
      increased in the liver after ADI, may process tumor-derived proteins via the MHC
      class I pathway as well as via the MHC class II pathway, as shown previously, and
      present respective peptide epitopes to CD8 as well as to CD4 immune T cells,
      respectively. The synergistic interactions observed before between immune CD4 and
      CD8 T cells during ADI could thus occur in the observed clusters with Sn+ host
      macrophages.

PMID- 10361137
TI  - Human immunoglobulin A receptor (FcalphaRI, CD89) function in transgenic mice
      requires both FcR gamma chain and CR3 (CD11b/CD18).
AB  - Even though more immunoglobulin A (IgA) is produced in humans than all other
      isotypes combined, relatively little is known about receptors that bind the Fc
      part of IgA. The myeloid IgA receptor, FcalphaRI (CD89), triggers various
      effector functions in vitro, but its in vivo role remains unclear. Here, a
      transgenic mouse model is described in which FcalphaRI is expressed under its own
      regulatory sequences. Receptor expression and regulation by cytokines was
      comparable to the human situation and hFcalphaRI can trigger phagocytosis and
      lysis of tumor cells. To analyze the contribution of the FcR gamma chain or the
      beta2 integrin CR3 (CD11b/CD18) in FcalphaRI biological function, FcalphaRI
      transgenic mice were crossed with either FcR gamma chain -/- or CR3 -/- mice. In
      contrast to in vitro data, FcR gamma chain was essential for surface expression
      of hFcalphaRI in vivo. Functional studies in hFcalphaRI/ gamma-/-mice were,
      therefore, limited. In vitro studies showed FcR gamma chain to be necessary for
      phagocytosis. Neither hFcalphaRI expression nor phagocytosis, triggered via
      hFcalphaRI, were influenced by CR3. Remarkably, the capacity to lyse tumor
      targets was ablated in hFcalphaRI transgenic/ CR3-/- mice, although binding of
      neutrophils to tumor cells was intact. This shows a previously unrecognized
      importance of CR3 for hFcalphaRI-mediated antibody-dependent cellular
      cytotoxicity (ADCC).

PMID- 10361138
TI  - Lineage-specific modulation of calcium pump expression during myeloid
      differentiation.
AB  - Calcium is accumulated from the cytosol into the endoplasmic reticulum by sarco
      endoplasmic reticulum calcium transport ATPase (SERCA) enzymes. Because calcium
      stored in the endoplasmic reticulum is essential for cell growth,
      differentiation, calcium signaling, and apoptosis and because different SERCA
      enzymes possess distinct functional characteristics, in the present report we
      explored SERCA expression during in vitro differentiation of the human
      myeloid/promyelocytic cell lines HL-60 and NB4 and of freshly isolated acute
      promyelocytic leukemia cells. Two SERCA species have been found to be coexpressed
      in these cells: SERCA 2b and another isoform, SERCAPLIM, which is recognized by
      the PLIM430 monoclonal antibody. Induction of differentiation along the
      neutrophil granulocytic lineage by all-trans retinoic acid or cyclic AMP analogs
      led to an increased expression of SERCAPLIM, whereas the expression of the SERCA
      2b isoform was decreased. The modulation of SERCA expression was manifest also on
      the mRNA level. Experiments with retinoic acid receptor isoform-specific
      retinoids indicated that SERCA expression is modulated by retinoic acid receptor
      alpha-dependent signaling. SERCA expression of retinoic acid-resistant cell
      variants was refractory to treatment. Differentiation along the
      monocyte/macrophage lineage by phorbol ester resulted in an increased expression
      of both SERCA isoforms. In addition, when cells were treated by phorbol ester in
      the presence of the glucocorticoid dexamethasone, a known inhibitor of monocyte
      differentiation, a selective blockage of the induction of SERCAPLIM was observed.
      Altered SERCA expression modified the functional characteristics of calcium
      transport into the endoplasmic reticulum. These observations show for the first
      time that the modulation of calcium pump expression is an integral component of
      the differentiation program of myeloid precursors and indicate that a lineage
      specific remodelling of the endoplasmic reticulum occurs during cell maturation.
      In addition, these data show that SERCA isoforms may serve as useful markers for
      the study of myeloid differentiation.

PMID- 10361140
TI  - Normal human serum contains natural antibodies reactive with autologous ABO blood
      group antigens.
AB  - It is widely accepted that the serum of healthy individuals contains natural
      antibodies only against those blood group A or B antigens that are not expressed
      on the individual's red blood cells. The mechanisms involved in tolerance to
      autologous blood group antigens remain unclear. In the present study, we show
      that IgM and IgG antibodies reactive with autologous blood group antigens are
      present in the immunoglobulin fraction of normal human serum. Natural IgG anti-A
      antibodies purified by affinity chromatography from IgG of individuals of blood
      group A exhibited an affinity for A trisaccharide antigen in the micromolar range
      and agglutinated A red cells at sixfold higher concentrations than those required
      for agglutination with affinity-purified anti-A IgG of individuals of blood group
      B. Whereas autoantibodies reactive with self A and B antigens are readily
      detected in purified IgG and IgM fractions, their expression is restricted in
      whole serum as a result of complementary interactions between variable regions of
      antibodies. These observations suggest that tolerance to autologous ABO blood
      group antigens is dependent on peripheral control of antibody autoreactivity.

PMID- 10361139
TI  - Cellular and subcellular localization of the Nramp2 iron transporter in the
      intestinal brush border and regulation by dietary iron.
AB  - Genetic studies in animal models of microcytic anemia and biochemical studies of
      transport have implicated the Nramp2 gene in iron transport. Nramp2 generates two
      alternatively spliced mRNAs that differ at their 3' untranslated region by the
      presence or absence of an iron-response element (IRE) and that encode two
      proteins with distinct carboxy termini. Antisera raised against Nramp2 fusion
      proteins containing either the carboxy or amino termini of Nramp2 and that can
      help distinguish between the two Nramp2 protein isoforms (IRE: isoform I; non
      IRE: isoform II) were generated. These antibodies were used to identify the
      cellular and subcellular localization of Nramp2 in normal tissues and to study
      possible regulation by dietary iron deprivation. Immunoblotting experiments with
      membrane fractions from intact organs show that Nramp2 is expressed at low levels
      throughout the small intestine and to a higher extent in kidney. Dietary iron
      starvation results in a dramatic upregulation of the Nramp2 isoform I in the
      proximal portion of the duodenum only, whereas expression in the rest of the
      small intestine and in kidney remains largely unchanged in response to the lack
      of dietary iron. In proximal duodenum, immunostaining studies of tissue sections
      show that Nramp2 protein expression is abundant under iron deplete condition and
      limited to the villi and is absent in the crypts. In the villi, staining is
      limited to the columnar absorptive epithelium of the mucosa (enterocytes), with
      no expression in mucus-secreting goblet cells or in the lamina propria. Nramp2
      expression is strongest in the apical two thirds of the villi and is very intense
      at the brush border of the apical pole of the enterocytes, whereas the
      basolateral membrane of these cells is negative for Nramp2. These results
      strongly suggest that Nramp2 is indeed responsible for transferrin-independent
      iron uptake in the duodenum. These findings are discussed in the context of
      overall mechanisms of iron acquisition by the body.

PMID- 10361141
TI  - The expression of human blood group antigens during erythropoiesis in a cell
      culture system.
AB  - Phenotypic analysis of hematopoietic stem and progenitor cells has been an
      invaluable tool in defining the biology of stem cell populations. We use here
      flow cytometry to examine the expression of human erythroid-specific surface
      markers during the maturation of early committed erythroid cells derived from
      cord blood in vitro. The temporal order of the expression of erythroid specific
      markers was as follows: Kell glycoprotein (gp), Rh gp, Landsteiner Wiener (LW)
      gp, glycophorin A (GPA), Band 3, Lutheran (Lu) gp, and Duffy (Fy) gp. The time at
      which some of these markers appeared suggests possible roles for some of these
      erythroid-specific polypeptides during the differentiation of these committed
      progenitors. The early appearance of Kell gp raises the possibility that it may
      have an important role in the early stages of hematopoiesis or cell lineage
      determination. Kell gp may also be a useful marker for the diagnosis of
      erythroleukemia. The late expression of Lu gp suggests it may be involved in the
      migration of erythroid precursors from the marrow. Fy gp is also expressed late
      consistent with a role as a scavenger receptor for cytokines in the bone marrow
      and circulation. Rh c antigen appeared before Rh D antigen, and it is suggested
      that this may reflect a reorganization of the developing erythroid cell membrane
      involving the Rh polypeptides and other components, including GPA and Band 3.

PMID- 10361142
TI  - The impact of obesity and disease on busulfan oral clearance in adults.
AB  - The apparent oral clearance (CL/F, mL/min) of busulfan was measured in 279
      adolescent and adult patients. Significant (P <.05) determinants of CL/F by
      linear regression were: actual body weight (BW; r2 = 0.300), body surface area
      (BSA; r2 = 0.277), adjusted ideal body weight (AIBW; r2 = 0.265), and ideal body
      weight (IBW; r2 = 0.173); whereas body mass index (BMI), height, age, gender, and
      disease were less important predictors. CL/F (mL/min) for normal weight patients
      (BMI, 18 to 27 kg/m2) was 16.2% lower (P <.001) than for obese patients (BMI, 27
      to 35 kg/m2). Thus, expressing CL/F relative to BW did not eliminate
      statistically significant differences between normal and obese patients. However,
      busulfan CL/F expressed relative to BSA (110 +/- 24 v 110 +/- 24 mL/min/m2, P =
      1.0) or AIBW (3.04 +/- 0.65 v 3.19 +/- 0.67 mL/min/kg, P =.597) were similar in
      normal and obese patients. Non-Hodgkin's lymphoma patients (n = 10) had
      approximately 32% lower mean busulfan CL/F expressed relative to BW, BSA, or AIBW
      compared with patients with chronic myelogenous leukemia (n = 73). Routine dosing
      on the basis of BSA or AIBW in adults and adolescents does not require a specific
      accommodation for the obese. However, dosing based on BSA may be improved by
      considering CL/F differences in certain diseases. Adjusting dose for body size or
      disease does not diminish interpatient variability sufficiently to obviate plasma
      level monitoring in many indications.

PMID- 10361143
TI  - Nanospheres of cyclosporin A: poor oral absorption in dogs.
AB  - The cyclic undecapeptide cyclosporin A (CYA) used as first-line therapy in the
      prevention of xenograft rejection following organ transplantation, is extremely
      hydrophobic. Marketed formulations employ solubilising agents to facilitate
      absorption in the gastrointestinal tract. In this study, cyclosporin A
      nanospheres were prepared by precipitation in an aqueous surfactant solution. The
      particle matrix consists of the drug itself. Drug was dissolved in acetone and
      mixed rapidly with an aqueous solution of polysorbate 80 and sodium dodecyl
      sulphate (SDS). The acetone was evaporated to give a colloidal precipitate of
      spherical particles. Particle size could be controlled by varying the quantity of
      starting materials to give nanospheres of Z-average diameters in the range 250
      900 nm with low polydispersity. The oral absorption of CYA from these nanospheres
      was compared to absorption from a microemulsion formulation in the dog. The
      relative bioavailability of cyclosporin A from nanospheres was only 3%, based on
      comparison of the area under the blood concentration-time curve (AUC) values for
      the two formulations.

PMID- 10361144
TI  - Studies on the uptake of tomato lectin nanoparticles in everted gut sacs.
AB  - Tomato lectin (TL) is a bioadhesive glycoprotein that has been shown to bind
      selectively to the small intestine epithelium. When bound to polystyrene
      microspheres, intestinal uptake occurs not only through the gut associated
      lymphoid tissue (GALT) but also through normal enterocytes. In this study, the
      everted gut sac model was used to compare the rates and quantities of intestinal
      uptake of tomato lectin and that of TL coupled to microspheres. Using bovine
      serum albumin (BSA) and BSA coupled to microspheres as comparators. Uptake is
      time and concentration dependent. Transfer of TL from the lumen to the serosa was
      3.9 ng/mg per h whereas that of BSA was 0.5 ng/mg per h. Hence uptake of tomato
      lectin was 7-fold higher than BSA. The rate of uptake of TL coupled microspheres
      was 41.5 ng/mg per h, which was 4-fold higher than microspheres coupled to BSA
      (11.8 ng/mg per h). The uptake of TL conjugated microspheres was shown to be
      inhibited by N-acetyl-d-glucosamine tetramer [GlcNac]4.

PMID- 10361145
TI  - Influence of lipopolymer concentration on liposome degradation and blood
      clearance.
AB  - It is well known, that a prolonged liposome circulation time can be achieved by
      incorporation of lipopolymers into the lipid membrane thereby reducing
      interactions with destabilizing factors in the blood stream, e.g. phagocytic
      cells and lipoproteins. However, very little is known about the enzymatic
      degradation of steric hindered liposomes introduced into body fluids. In this
      study, the blood clearance and the PLA2 catalyzed degradation of unilamellar
      dipalmitoylphosphatidylcholine (DPPC) liposomes incorporated with increasing
      amounts of dipalmitoylphosphatidylethanolamine-polyethyleneglycol (DPPE-PEG), was
      investigated. The results demonstrated an increase in PLA2 activity for
      increasing amounts of lipopolymer in the lipid membrane, while the liposome blood
      clearance was prolonged by incorporation of DPPE-PEG into the liposomes. Hence,
      these results suggest that it may be possible for long circulating liposomes to
      obtain a site specific liposome degradation and release of drug substance in
      tissue with high levels of PLA2.

PMID- 10361146
TI  - The effect of controlled osmotic stress on release and swelling properties of a
      water-in-oil emulsion.
AB  - The purpose of this study was to investigate the effect of osmotic gradients in a
      water-in-oil (w/o) emulsion on release properties in order to control the release
      of hydrophilic drugs. The magnitude and direction of the osmotic gradient was
      shown to have a pronounced effect on the apparent permeability of the hydrophilic
      marker, [3H]glucose. The apparent permeability coefficient of glucose could be
      varied between 1.0x10(-5) and 5.0x10(-8) cm s-1 using osmotic gradients. The
      release rate of glucose was related to the swelling properties. The larger the
      degree of swelling, the lower the release rate. Furthermore the present w/o
      emulsion has a low viscosity and a long-term physical stability. This makes the
      emulsion a promising parenteral drug delivery system in which the release of
      hydrophilic drugs such as peptides, can be controlled.